PMID- 9389971
TI - Origins of ... tinctorial methods in histology.
PMID- 9389972
TI - ACP Broad Sheet no 151: September 1997. Investigation of dyslipidaemias.
PMID- 9389973
TI - Hepatic histology of patients with HIV infection and chronic hepatitis C treated
with interferon.
AB - AIMS: To evaluate the histological changes seen in liver biopsies after
interferon (IFN) treatment in patients with chronic hepatitis C and human
immunodeficiency virus (HIV) infection. METHODS: Twenty four intravenous drug
users with chronic hepatitis C were investigated histologically before beginning
a 12 month course of IFN treatment and 18 months later. Twelve were HIV positive,
without opportunistic or other viral infections (group A), and 12 were HIV
negative (group B). RESULTS: According to alanine amino-transferase
concentrations, four sustained responders and eight non-responders were found in
group A; six sustained responders, five relapsers, and one non-responder were
found in group B. HCV RNA became negative in one sustained responder of group A
and in the six sustained responders of group B. When histological findings of
biopsies performed before therapy and 18 months later were compared, no
significant changes in the mean value of Knodell's index and subindices were
found in group A, whereas in group B Knodell's index, piecemeal necrosis, and
focal hepatocellular necrosis decreased significantly. CONCLUSIONS: In chronic
hepatitis C, coinfection with HIV showed a tendency towards a lower response to
IFN, although this did not reach statistical significance; however, none of the
HIV positive patients developed cirrhosis during the follow up and this should be
considered in clinical management of such patients.
PMID- 9389974
TI - Gastric mucous neck cell and intestinal goblet cell phenotypes in gastric
adenocarcinoma.
AB - AIM: To investigate the phenotype of cells comprising diffuse and intestinal-type
gastric cancers using monoclonal antibodies to two antigens. One antigen
(designated D10) is characteristic of gastric mucous neck cells, cardiac glands,
pyloric glands, and Brunner's glands. The second antigen (designated 17NM) is
specific to the mucous vacuole of intestinal goblet cells. METHODS: Thirty two
gastrectomy specimens with adenocarcinoma were studied. Serial paraffin sections
were stained immunohistochemically for D10 and 17NM and histochemically for acid
and neutral mucins. The cancers were classified histologically as of either
diffuse or intestinal type according to Lauren. RESULTS: Of 15 diffuse-type
gastric carcinomas, 11 showed the majority of cancer cells staining for D10 while
four were typical signet ring cell cancers staining predominantly for 17NM; five
tumours displayed both phenotypes with the two phenotypes segregated in different
areas of the tumours. In contrast, of 16 intestinal-type cancers, six expressed
17NM, three D10, five neither antigen, and two expressed both antigens. One
indeterminate-type cancer expressed both antigens. The staining of individual
cells for D10 and 17NM was mutually exclusive in both diffuse and intestinal
types. In contrast to the diffuse cancers, intestinal-type cancers typically
expressed either antigen only in occasional small groups of cells and individual
cells. CONCLUSIONS: In disease, the gastric stem cell can assume the capacity of
the duodenal stem cell for divergent differentiation into either intestinal
goblet cells (for example, as in intestinal metaplasia) or Brunner's gland cells
(for example, as in pyloric gland/Brunner's gland metaplasia). With neoplastic
transformation, this potential for divergent differentiation is maintained and
gives rise to diffuse-type cancers that display either the D10 phenotype, the
17NM phenotype, or the clonal expression of both phenotypes. In the more cell
cohesive (intestinal-type) tumours, differentiation for antigen expression is
poorly developed and more frequently directed towards the intestinal goblet cell
phenotype.
PMID- 9389975
TI - Detection of parvovirus B19 in macerated fetal tissue using in situ
hybridisation.
AB - AIMS: To compare the application of a non-radioactive in situ hybridisation (ISH)
technique with an immunocytochemical technique for the detection of human
parvovirus B19 in formalin fixed, paraffin wax embedded sections of macerated
fetal tissue. METHODS: Archived samples of liver, lung or kidney from 19 human
fetuses were investigated for parvovirus B19 using a full length digoxigenin
labelled DNA probe of 5.5 kb; bound probe was detected using an anti-digoxigenin
(alkaline phosphatase) conjugate and visualised using NBT/BCIP.
Immunocytochemical detection of parvovirus B19 was performed using a monoclonal
mouse antiparvovirus B19 antiserum, with a streptavidin-biotin complex (horse
radish peroxidase) method. Cases were selected to provide a range of diagnostic
certainty and a range of degrees of macerative degeneration. RESULTS: Parvovirus
B19 was found in 15 of 19 cases using the B19 ISH technique compared with 8 of 19
cases using the immunocytochemical technique. The four negative cases were all
controls known to be parvovirus B19 free. All ISH positive cases showed excellent
staining with low background regardless of extent of maceration and tissue type.
In comparison, sections stained by the immunocytochemical method showed
considerable non-specific immunoreactivity in many cases, particularly with
severe maceration. Kidney and lung tissues gave the cleanest results.
CONCLUSIONS: ISH is more effective than the immunocytochemical technique for the
detection of human parvovirus B19 in macerated fetal tissue. The lack of
detectable background staining with the ISH technique led to easier
interpretation suggesting that this technique should be the method of choice for
the investigation of parvovirus B19 in macerated postmortem tissues.
PMID- 9389976
TI - Effects of oestrogen on the extracellular matrix in the endometrium of
postmenopausal women.
AB - AIM: To obtain insight into the effects of oestrogen on extracellular matrix
(ECM) in the postmenopausal endometrium. METHODS: The distribution of the
components of the ECM, including collagen types I, III, IV, and VI, and laminin,
was investigated in the human postmenopausal endometrium by an indirect
immunofluorescence method with specific monoclonal antibodies and a polyclonal
antibody. Collagens were also extracted from the endometrial tissues of
postmenopausal women who had or had not been treated with oestrogen for three
weeks. RESULTS: Immunohistochemical studies demonstrated that type I collagen was
the predominant interstitial collagen, and that types III and VI collagens were
absent or very sparsely distributed in the stroma of the postmenopausal
endometrium. However, types I, III, and VI collagens were diffusely localised in
the stroma of the postmenopausal endometrium after administration of oestrogen.
Even though type IV collagen was not seen in the basement membrane of the
endometrial glands in the endometrium of postmenopausal women in the absence of
oestrogen treatment, both type IV collagen and laminin were localised exclusively
in the basement membrane of the endometrial glands in the postmenopausal
endometrium after three weeks of oestrogen treatment. The level of type III
collagen relative to that of type I collagen was significantly increased (p <
0.01) in the endometrium of oestrogen treated postmenopausal women compared with
non-treated postmenopausal women. CONCLUSIONS: Conjugated equine oestrogen might
induce changes in the distribution of components and in the composition of the
ECM in the endometrium of postmenopausal women.
PMID- 9389977
TI - Differential patterns of osteoblast dysfunction in trabecular bone in patients
with established osteoporosis.
AB - AIMS: To analyse osteoblast function in 153 cases of established osteoporosis as
previous work has indicated that osteoporosis is a heterogeneous condition
characterised by different patterns of osteoclast and osteoblast dysfunction.
METHODS: Histomorphometric data from 153 cases with established osteoporosis was
used to analyse osteoblast function, using the following parameters: osteoblast
number was assessed using the ratio of osteoblast surface to bone surface
(ObS:BS); the percentage of active osteoblasts was assessed by using mineralising
surface as a proportion of osteoid surface (sLS + dLS/OS); and the efficiency of
active osteoblasts was assessed using the ratio of double to total labelled
surface (dLS:tLS). The values of each parameter were standardised using age and
sex matched control data and a three dimensional matrix was used to identify
groups of patients with similar patterns of altered function. RESULTS: The
largest group (60 cases) showed a reduction in all three parameters, while a
small group (9 cases) had normal osteoblast function. However, one group showed
reduction in osteoblast number only (23 cases), while another group showed a
normal number of osteoblasts but both reduced percentage and efficiency of
activity (14 cases). The results also suggest that efficiency of activity falls
first and that this eventually leads to exit from the active pool. CONCLUSIONS:
These results demonstrate the presence of heterogeneity of osteoblast dysfunction
in osteoporosis, indicating that the disease is caused by interference at a
variety of target sites along the pathway of osteoblast proliferation,
differentiation, and activation. Greater understanding of this pathway and of the
variety of alterations in the pathway that can occur in osteoporosis may allow
more focused therapy for different patient groups identified on the basis of
histomorphometric analysis.
PMID- 9389978
TI - Haemophilus influenzae: an underrated cause of vulvovaginitis in young girls.
AB - AIMS: To establish the common pathogens associated with infective vulvovaginitis
in young girls in the local population and to determine current management of
this condition. METHODS: A prospective laboratory based survey was carried out
over 19 months. A questionnaire was then sent to local general practitioners and
hospital doctors. RESULTS: One hundred and six swabs were received during the
study period of which 43 (40.5%) yielded organisms recognised as causes of
vulvovaginitis. The most common pathogen was group A beta haemolytic
streptococcus (19), with Haemophilus influenzae the second most common (11).
Candida was isolated on nine occasions. The users' questionnaire had an overall
response rate of 52%. Forty one per cent of respondents nominated candida as the
most common cause of this condition. Forty six per cent were aware that beta
haemolytic streptococci caused juvenile vulvovaginitis, but only four (3.6%) knew
that H influenzae was a possible pathogen. The most popular agent for empirical
treatment of vulvovaginitis was topical clotrimazole cream, although 24
respondents (22%) prescribed antibiotics that are active against both group A
beta haemolytic streptococci and H influenzae. CONCLUSIONS: Although H influenzae
is the second most common infective cause of juvenile vulvovaginitis in the local
population, most doctors managing these patients were unaware of its importance
and may not be prescribing appropriate empirical treatment.
PMID- 9389979
TI - Helicobacter pylori does not release cysteamine into gastric juice.
AB - AIM: To determine whether Helicobacter pylori releases cysteamine into gastric
juice as cysteamine is known to be ulcerogenic. METHODS: Samples of fasting
gastric juice were collected from 22 individuals (four women); 10 subjects were H
pylori negative. The presence of infection was confirmed by examination and
culture of gastric biopsies. Cysteamine in gastric juice was measured by reversed
phase gradient high performance liquid chromatography with a detection limit of
10 mumol/l. RESULTS: Cysteamine was not detected in any of the gastric juice
samples or in extracts of cultured H pylori. CONCLUSIONS: If H pylori produces
cysteamine then the amounts produced are insignificant and are unlikely to
explain the association between H pylori infection and the development of
duodenal ulcer disease.
PMID- 9389980
TI - Juvenile polyposis of the stomach: clinicopathological features and its malignant
potential.
AB - AIMS: To clarify a clinical entity of juvenile polyposis of the stomach compared
with generalised juvenile gastrointestinal polyposis. METHODS: The
clinicopathological features of juvenile polyposis dominantly involving the
stomach at initial presentation were reviewed in 12 patients (three new patients
and nine from the literature). These were compared with 29 cases of generalised
juvenile gastrointestinal polyposis. RESULTS: There were three men and nine women
with juvenile polyposis of the stomach, aged 10-63 years. Hypoproteinaemia was
present in nine patients, anaemia in seven, and a family history of intestinal
polyposis in seven. No patient presented with a congenital abnormality. During
the observation period, two patients developed colonic juvenile polyps. Gastric
polyps invariably affected the antrum and extended to the fundus, eventually
becoming more numerous, larger, and more pedunculated. Ten patients required
gastrectomy for associated malignancy or uncontrolled protein losing gastropathy.
Histological examinations of the resected specimens demonstrated neoplastic
tissue arising from juvenile polyps in four of the 12 patients. Atypism in these
mixed polyps varied from adenoma to well or moderately differentiated
adenocarcinoma. CONCLUSIONS: Juvenile polyposis of the stomach has malignant
potential, and may be a separate entity from generalised juvenile
gastrointestinal polyposis.
PMID- 9389981
TI - Diagnostic distance of high grade prostatic intraepithelial neoplasia from normal
prostate and adenocarcinoma.
AB - OBJECTIVE: To develop a distance measure based methodology to support the
morphological evaluation of high grade prostatic intraepithelial neoplasia (PIN),
a direct precursor of prostate cancer. METHODS: Eight morphological and cellular
features were analysed in 20 cases of high grade PIN found in radical
prostatectomy specimens from patients with adenocarcinoma. The diagnostic
distance was evaluated to measure the extent to which the feature outcomes of the
individual high grade PIN cases differed from the expected outcome profile of
normal prostate, low and high grade PIN, and cribriform and large acinar
adenocarcinoma. The belief value for high grade PIN was evaluated with a Bayesian
belief network (BBN). RESULTS: Complete separation existed between the cumulative
absolute diagnostic distances of these 20 cases from the prototype feature
outcomes of high grade PIN and normal prostate the values for which were < or = 3
(range 0 to 3) and > or = 9 (range 9 to 15), respectively. The distances from low
grade PIN (range 3 to 9), cribriform adenocarcinoma (range 2 to 8), and large
acinar adenocarcinoma (range 5 to 10) were intermediate and showed overlap in
their distribution. When taking into consideration whether the severity of
feature changes was increasing or decreasing in comparison with the category
prototype outcomes, the cumulative directional diagnostic distances from high
grade PIN ranged from -3 to +3. Positive distance values were seen relative to
low grade PIN (range +3 to +9) and relative to normal prostate (range +9 to +15).
Negative values were found relative to cribriform adenocarcinoma (range -8 to
+2). The distance values from large acinar adenocarcinoma ranged from -2 to +4
and partly overlapped with those from the high grade PIN category. A bivariate
scattergram derived from both diagnostic distance measures showed excellent
separation between the groups' distances. BBN analysis confirmed the morphology
based diagnosis. The distance evaluation resulted in 18 cases whose belief value
for high grade PIN ranged from 0.60 to 0.87. In the remaining two cases the
results of the BBN analysis showed a belief value of 0.50 and 0.57 for low grade
PIN and of 0.49 and 0.38 for high grade PIN, respectively. CONCLUSIONS: Distance
measure based methodology represents a useful diagnostic decision support tool
for the accurate evaluation of high grade PIN.
PMID- 9389982
TI - Local INR correction: justification for a simplified approach.
AB - AIMS: Errors in reporting International Normalised Ratios (INR) may be corrected
by assignment of a System International Sensitivity Index (System ISI). This 57
centre study tests the validity of several procedures for INR correction.
METHODS: Prothrombin times of eight lyophilised coumarin calibrants, a
lyophilised normal pool calibrant, and eight frozen coumarin plasmas were
determined at each centre. The calibrants were calibrated using international
reference preparations. The eight frozen coumarin plasmas were calibrated in a
four centre international exercise. The relations tested were: (a) the logarithm
of local prothrombin time against the logarithm of reference prothrombin time;
(b) reference INR against local prothrombin time; and (c) logarithm of reference
INR against logarithm of local prothrombin time. These methods were analysed by
both linear and orthogonal regression. RESULTS: All system groups required
correction, the mean percentage deviation of the uncorrected data from the
calibrated values was 19.0%. There was also considerable variation in INR, with
the coefficient of variance (CV) ranging from 11.30 to 17.29%. Correction of INR
was possible with all methods (CV reduced to < 7%). However, only when a plot of
the logarithm of local prothrombin time against the logarithm of reference
prothrombin time was fitted by orthogonal regression, or a plot of logarithm of
reference INR against logarithm of local prothrombin time was fitted by either
type of regression analysis, did the best fit line through the calibrant plasmas
also pass close to the local mean normal prothrombin time. CONCLUSIONS: While INR
correction may be achieved by all the above methods, that relating log reference
INR to log local prothrombin time by linear regression analysis is the simplest
to perform.
PMID- 9389983
TI - Screening for bacterial vaginosis: a novel application of artificial nose
technology.
AB - The AromaScan system was used to analyse vaginal swabs from 68 women attending a
genitourinary clinic. Using clinical criteria, subjects were assessed for
bacterial vaginosis. After training the AromaScan system to recognise patterns
generated from four patients with and four patients without bacterial vaginosis,
16 of the 17 (94%) remaining subjects were correctly identified as having the
condition. The positive predictive value of the test was 61.5%. These results
indicate that the AromaScan technology may be of value as a screening test for
bacterial vaginosis.
PMID- 9389984
TI - Origin of hepatocellular carcinoma recurring after allotransplantation revealed
by microsatellite analysis.
AB - A hepatocellular carcinoma was resected from a liver allotransplant after the
patient's original organ had been removed because of a liver carcinoma. DNA
analysis was performed to explore the origin of the carcinoma cells. DNA
extracted from the carcinoma tissue, from the carcinoma free liver tissue, and
from other cells of the recipient underwent polymerase chain reaction
amplification for seven microsatellite systems and the X-Y amelogenin system. The
allelic pattern from the carcinoma tissue was identical with that from the
patient and differed from the DNA profile of the liver tissue. The result
confirmed the assumption that the carcinoma tissue had originated from the
patient and not from the donor.
PMID- 9389985
TI - Lymphoepithelial cyst of the pancreas.
AB - A rare case of lymphoepithelial cyst of the pancreas is reported. Microscopically
the cyst content consisted of keratinous material and the walls were lined by
mature squamous epithelium surrounded by dense lymphoid tissue.
Immunohistochemistry showed diffuse reactivity for CD20 and CD3 in the lymphoid
tissue and uniform positivity for cytokeratins in the squamous epithelium.
Although the histogenesis of lymphoepithelial cysts of the pancreas is not
understood, awareness of this lesion is helpful in differentiating it from other
pancreatic cystic lesions.
PMID- 9389986
TI - Fatal Yersinia enterocolitica transfusion reaction.
PMID- 9389988
TI - Oil immersion magnification without the oil.
PMID- 9389987
TI - Alcohol estimation at necroscopy: epidemiology, economics and the elderly.
PMID- 9389989
TI - Structure and function of somatostatin receptors in growth hormone control.
AB - This new generation of SRIF analogs offer exciting opportunities to improve
hormone hypersecretion in patients with GH- and TSH-secreting pituitary adenomas
and possibly even in patients harboring prolactinomas and non-functioning tumors.
Future development of novel analogs with improved affinity for both SSTR2 and
SSTR5 may have even greater potency to suppress pituitary hormone hypersecretion
and block adenoma growth.
PMID- 9389990
TI - Acromegaly: the significance of serum total and free IGF-I and IGF-binding
protein-3 in diagnosis.
AB - We have studied the physiological and clinical relevance of measurements of serum
total and free IGF-I and IGF-binding protein-3 (IGFBP-3) in 57 previously
untreated patients with active acromegaly (32 males, 25 females; mean age 47
years) as compared with sex- and age-matched normal healthy controls. Serum total
and free IGF-I, but not IGFBP-3, are suitable biochemical parameters for
screening for acromegaly. In acromegalics, the mean 24 h serum GH, total IGF-I
and IGFBP-3 levels tend to decrease with age. However, in our series of patients,
mean 24 h serum GH levels, IGFBP-3, total and free IGF-I do not correlate with
disease activity in acromegaly.
PMID- 9389991
TI - Growth hormone, insulin-like growth factor-I and its binding proteins in the
follow-up of acromegaly.
AB - Elevated growth hormone is a cardinal feature of acromegaly from the biological
view point. Growth hormone stimulates IGF-I secretion and that of its major
binding protein IGFBP-3. In these circumstances, where hyperinsulinaemia is
present, IGFBP-1 levels, which are inversely related to insulin, are suppressed.
Failure of suppression of growth hormone after oral glucose (> 2 mU/l (1
microgram/l) is the cardinal biochemical feature of acromegaly. IGF-I values at
diagnosis are almost invariably raised. There is some overlap in the value of
basal IGFBP-3 between normal subjects and acromegalics. For monitoring purposes,
growth hormone values, either basal or during the day are useful. There is
overlap in the values of IGF-I and IGFBP-3 between normal subjects and patients
on treatment. Prognosis in acromegaly is determined by persistent elevation of
growth hormone levels above 5 mU/l (2.5 micrograms/ l). More data are required
for the prognostic use of IGF-I.
PMID- 9389992
TI - New developments in the management of acromegaly. Should we achieve absolute
biochemical cure?
PMID- 9389993
TI - Is growth hormone bad for your heart? Cardiovascular impact of GH deficiency and
of acromegaly.
AB - At present, there is growing evidence implicating GH and/or IGF-I in the
intricate cascade of events connected with the regulation of heart development
and hypertrophy. Moreover, GH excess and/or deficiency have been shown to include
in their advanced clinical manifestations almost always an impaired cardiac
function, which may reduce life expectancy. This finding is related both to a
primitive impairment of heart structure and function and to metabolic changes
such as hyperlipidemia, increase of body fat and premature atherosclerosis.
Patients with childhood or adulthood-onset GH deficiency have a reduced left
ventricular mass and ejection fraction and the indexes of left ventricular
systolic function remain markedly depressed during exercise. Conversely, in
acromegaly the cardiac enlargement, which is disproportionate to the increase in
size of other internal body organs, has been a rather uniform finding. The
severity of the acromegalic cardiomyopathy was reported to be correlated better
with the disease duration than with circulating GH and/or IGF-I levels.
Myocardial hypertrophy with interstitial fibrosis, lymphomononuclear infiltration
and areas of monocyte necrosis often results in concentric hypertrophy of both
ventricles. The treatment of GH deficiency and excess improved cardiac function.
Interestingly, based on the evidence that GH increases cardiac mass, recombinant
GH was administered to patients with idiopathic dilated cardiomyopathy. It
increased the myocardial mass and reduced the size of the left ventricular
chamber, resulting in improvement of hemodynamics, myocardial energy metabolism
and clinical status. These promising results open new perspectives for the use of
GH in heart failure.
PMID- 9389994
TI - Acromegalic arthropathy and sleep apnea.
PMID- 9389995
TI - Acromegaly and its treatment.
PMID- 9389996
TI - Evidence supporting surgery as treatment of choice for acromegaly.
AB - Within a period of fourteen years 531 operations for growth hormone (GH)
secreting adenomas were carried out. In this consecutive series 73% of the 396
patients who underwent primary transsphenoidal surgery achieved basal GH levels
below 5 micrograms/l, and 58% also had an adequate suppression following an oral
glucose tolerance test (OGTT). Slightly less favourable results were found in
patients requiring surgery following an initial therapy. However, 41% of 121 such
patients, who had either been operated upon previously or who had received
external or internal irradiation, nevertheless achieved basal GH levels below 5
micrograms/l after the surgical reintervention. Normal suppression of serum GH
during an OGTT was observed in 23% of these patients. The overall complication
rate was low and tumour recurrences were very rare. To facilitate easier tumour
removal, octreotide was preoperatively administered in 53 patients undergoing
primary surgery of large adenomas. Recurrences were documented in a few
exceptional cases. These data support our previous experience that once a normal
suppression of growth hormone has been documented following surgery of pituitary
adenomas, the long-term outcome is favourable.
PMID- 9389997
TI - Evidence for the effectiveness of radiotherapy in the treatment of acromegaly.
PMID- 9389998
TI - Evidence for dopamine agonists in the treatment of acromegaly.
PMID- 9389999
TI - Evidence for octreotide subcutaneously in the treatment of acromegaly.
PMID- 9390000
TI - Gametic imprinting in development and disease.
PMID- 9390001
TI - Extracellular calmodulin-binding proteins in body fluids of animals.
AB - The extracellular calmodulin-binding proteins (CaMBPs) were investigated in body
fluids of animals by using the biotinylated calmodulin gel overlay method. Four
major CaMBPs with molecular masses of 24, 31.5, 44/45 and 94 kDa were detected in
serum, two of 24 and 63 kDa in bovine milk and three of 14, 24 and 52 kDa in
human saliva. It suggested that extracellular CaMBPs exist commonly in body
fluids of animals, and this result may provide a new clue for understanding the
role of extracellular calmodulin.
PMID- 9390002
TI - Effect of GH administration on GH and IGF-I receptors in porcine skeletal muscle
and liver in relation to plasma GH-binding protein.
AB - The present study was undertaken to determine the effect of GH administration on
GH and IGF-I receptors in skeletal muscle compared with liver in growing pigs.
Plasma IGF-I and GH-binding protein (GHBP) levels were also determined. Twelve
Large White pigs (castrated males) were treated daily with 100 micrograms
pituitary porcine GH (pGH) per kg body weight or vehicle for 41 days
intramuscularly. Relative to controls, pGH administration increased plasma IGF-I
concentrations by 3.3-fold. Administration of pGH had no effect on plasma GHBP
levels. In liver, 125I-labelled bovine GH (bGH)-specific binding (P < 0.05) and
GH receptor (GHR) mRNA levels (P < 0.05) were higher in pGH-treated than in
control pigs. In longissimus dorsi (LD), 125I-labelled bGH specific binding did
not differ significantly between the two groups while GHR mRNA levels (P < 0.05)
were lower in pGH-treated than in control pigs. Administration of pGH had no
effect on 125I-labelled bGH-specific binding and GHR mRNA levels in trapezius
(TR). 125I-Labelled IGF-I-specific binding in liver was unaffected by pGH
administration. Similarly, in liver, LD and TR, IGF-I receptor mRNA levels were
not different between pGH-treated and control animals. It can be concluded that
(1) GH binding and IGF-I receptor mRNA are not affected by GH in skeletal muscle,
(2) GH influences GHR in a tissue-specific manner and (3) hepatic GHR and GHBP
levels are not co-regulated.
PMID- 9390003
TI - Ontogeny of inhibin secretion in the rat testis: secretion of inhibin-related
proteins from fetal Leydig cells and of bioactive inhibin from Sertoli cells.
AB - The ontogeny of inhibin secretion in the testis of rats was investigated.
Testicular localization, content of immunoactive and bioactive inhibin and its
molecular size in fetal and neonatal rats (from 16 days of gestation to 5 days of
age) were determined. Strong immunostaining with an antiserum against a
polypeptide of porcine inhibin alpha-subunit was noted in testicular interstitial
cells from 16 days of gestation. Co-localization of inhibin alpha-subunit and 3
beta-hydroxysteroid dehydrogenase (3 beta HSD) was observed in the interstitial
cells until 2 days of age. Immunoreactive inhibin alpha-subunit in the
interstitial tissue had disappeared by 5 days of age, although 3 beta HSD
positive cells were still detected. Weak immunostaining for the inhibin alpha
subunit was detected in the seminiferous tubules, probably in the cytoplasm of
Sertoli cells, from 20 days of gestation onward. No inhibin alpha-subunit
immunostaining was observed in germ cells throughout the experimental period.
Testicular inhibin was detected at 16 days of gestation (49.5 +/- 6.7 pg per
testis) by RIA. Testicular immunoreactive inhibin showed a tendency to increase
during fetal life and levels were maintained at a similar value after birth
(697.0 +/- 46.9 pg per testis at 5 days of age). Inhibin bioactivity and its
molecular size in testicular homogenate was examined at 17 days of gestation and
0 and 5 days of age. Although no bioactivity was detected at 17 days of
gestation, bioactivity was noted at 0 and 5 days of age (177.7 and 1303.9 pg per
testis respectively). Immunoblot analysis with antiserum against inhibin alpha
subunit revealed only approximately 40 kDa molecular masses in the testis at 17
days of gestation, probably inhibin-related proteins, but not inhibin. At 0 and 5
days of age, a protein of 30 kDa molecular mass, possibly inhibin, was detected
as well as material of approximately 40 kDa molecular mass. FSH in the plasma was
first detected at 19 days of gestation (1197.0 ng/l), increased towards birth,
and thereafter decreased (4588.5 +/- 572.3 ng/l at 21 days of gestation and
2400.0 +/- 179.6 ng/l at 5 days of age). These results indicate that Leydig cells
in fetal and neonatal rats produce inhibin-related substances with no inhibin
bioactivity, whereas Sertoli cells begin to produce inhibin during the perinatal
period as a possible regulator of FSH secretion.
PMID- 9390004
TI - Regulation of the mouse cellular retinoic acid-binding protein-I gene by thyroid
hormone and retinoids in transgenic mouse embryos and P19 cells.
AB - The regulation of mouse cellular retinoic acid-binding protein-I (CRABP-I) gene
expression by the retinoids and thyroid hormones was examined, by using a beta
galactosidase (lacZ) reporter gene and a CRABP-I specific antibody, in transgenic
mouse embryos and a mouse embryonal carcinoma cell line P19. The CRABP-lacZ
reporter gene expression recapitulated the expression pattern of endogenous CRABP
I in the developing central nervous system. In mid-gestation mouse embryos the
expression of both the transgene and the endogenous protein was elevated under
the condition of hypovitaminosis A, suggesting that depletion of retinoic acid
(RA) induced CRABP-I expression in embryos. Consistently, this reporter was
suppressed by RA in P19 cells. In co-transfection experiments it was demonstrated
that the expression of RAR beta, RAR gamma or RXR alpha suppressed this reporter
expression. In experiments designed to alter the thyroid hormone status in
animals it was demonstrated that both the reporter gene and the endogenous CRABP
I expression were reduced by triiodothyronine injection and were elevated in a
hypothyroidic condition induced by feeding with iodine-deficient diet
supplemented with 6-propyl-2-thiouracil. In co-transfection experiments it was
also demonstrated that the expression of T3R beta suppressed the reporter
expression in P19 cells. It was concluded that RA had a suppressive effect on
CRABP-I gene expression in embryos and P19 cells and the effect could be mediated
through RAR beta, RAR gamma or RXR alpha. A role of thyroid hormones in CRABP-I
gene expression and vitamin A metabolism in animals is discussed.
PMID- 9390005
TI - Ontogenic and nutritional changes in circulating insulin-like growth factor (IGF)
I, IGF-II and IGF-binding proteins in growing ewe and ram lambs.
AB - The ontogeny of the IGF endocrine system was investigated in 15 young lambs
before and after weaning at 62 days of age. Before weaning, plasma IGF-I
concentrations were higher in rams than ewes, and plasma concentrations of IGF-II
and IGF-binding protein-3 (IGFBP-3) also tended to be higher in rams than in
ewes. Feed intake of ewes and rams was restricted after weaning to remove sex
differences in feed intake. Plasma concentrations of IGF-I and IGFBP-3 did not
differ between rams and ewes at 100 days of age, but plasma IGF-II was higher in
rams than in ewes at this time. Since circulating concentrations of GH were
higher in rams than in ewes at 100 days of age, this implies that the restricted
feed intake blocked the IGF-I and IGFBP-3 responses to GH. We conclude that sex
differences in circulating IGF-I and IGFBP-3 concentrations in the growing lamb
alter with age, and are not present when nutrition is restricted.
PMID- 9390006
TI - Improvement of glucose homeostasis and hepatic insulin resistance in ob/ob mice
given oral molybdate.
AB - Molybdate (Mo) exerts insulinomimetic effects in vitro. In this study, we
evaluated whether Mo can improve glucose homeostasis in genetically obese,
insulin-resistant ob/ob mice. Oral administration of Mo (174 mg/kg molybdenum
element) for 7 weeks did not affect body weight, but decreased the hyperglycaemia
(approximately 20 mM) of obese mice to the levels of lean (L) (+/+) mice, and
reduced the hyperinsulinaemia to one-sixth of pretreatment levels. Tolerance to
oral glucose was improved: total glucose area was 30% lower in Mo-treated mice
than in untreated ob/ob mice (O), while the total insulin area was halved.
Hepatic glucokinase (GK) mRNA level and activity were unchanged in O mice
compared with L mice, but the mRNA level and activity of L-type pyruvate kinase
(L-PK) were increased in O mice by 3.5- and 1.7-fold respectively. Mo treatment
increased GK mRNA levels and activity (by approximately 2.2-fold and 61% compared
with O values), and had no, or only a mild, effect on the already increased L-PK
variables. mRNA levels and activity of the gluconeogenic enzyme,
phosphoenolpyruvate carboxykinase (PEPCK) were augmented in O liver (sixfold and
by 57% respectively), and these were reduced by Mo treatment. Insulin binding to
partially purified receptors from liver was reduced in O mice and restored by Mo
treatment. Despite this correction, overall receptor tyrosine kinase activity was
not improved in Mo mice. Moreover, the overexpression (by two- to fourfold) of
the cytokine tumour necrosis factor alpha (TNF alpha) in white adipose tissue,
which may have a determinant role in the insulin resistance of the O mice, was
unaffected by Mo. Likewise, overexpression of the ob gene in white adipose tissue
was unchanged by Mo. In conclusion, Mo markedly improved glucose homeostasis in
the ob/ob mice by an insulin-like action which appeared to be exerted distal to
the insulin receptor tyrosine kinase step. The blood glucose-lowering effect of
Mo was unrelated to over-expression of the TNF alpha and ob genes in O mice, but
resulted at least in part from attenuation of liver insulin resistance by the
reversal of pre-translational regulatory defects in these mice.
PMID- 9390007
TI - Inhibin, activin and follistatin bind preferentially to the transformed species
of alpha 2-macroglobulin.
AB - alpha 2-Macroglobulin (alpha 2-M), a major serum glycoprotein, has been
implicated as a low-affinity binding protein for inhibin and activin. In serum,
alpha 2-M exists as two major species, a native form that is abundant and stable,
and a transformed ('fast') species that is rapidly cleared from the circulation
via alpha 2-M receptors. In this study inhibin, activin and their major binding
protein follistatin were investigated for their ability to bind to the native or
transformed species of purified human alpha 2-M. Using native PAGE and size
exclusion chromatography, radiolabelled inhibin, activin and follistatin bound to
the transformed alpha 2-M. Inhibin and follistatin did not bind significantly to
native alpha 2-M, whereas activin was able to bind to the native species but with
a lower capacity compared with that to transformed alpha 2-M. Under reducing
conditions, binding of these hormones to alpha 2-M was abolished. These findings
implicate alpha 2-M as a mechanism whereby inhibin, activin and follistatin may
be removed from the circulation through alpha 2-M receptors, but also whereby
activin can be maintained in the circulation through its ability to bind to
native alpha 2-M.
PMID- 9390008
TI - The melanocortin 1, 3, 4 or 5 receptors do not have a binding epitope for ACTH
beyond the sequence of alpha-MSH.
AB - ACTH(1-39), and several shorter N- and/or C-terminally truncated fragments of
ACTH, with and without N-terminal acetylation and/or C-terminal amidation, were
tested for binding on a single eukaryotic cell line transiently and independently
expressing the melanocortin MC1, MC3, MC4 and MC5 receptors. The results show
that none of these MC receptors has specific binding epitopes for the ACTH
peptides beyond the amino acid sequence of alpha-MSH, when tested for their
ability to compete with 125I-labelled [Nle4,D-Phe7]alpha-MSH and ACTH. The MC3
receptor favours the natural desacetylated N-terminal end of the ACTH peptides,
and it has generally more than 10-fold higher affinity for the ACTH peptides than
the MC4 receptor. Considering earlier anatomical localisation data, together with
the present data, we suggest that the MC3 receptor is the most likely candidate
of the MC receptors to mediate the short-loop negative feedback release of
corticotrophin-releasing factor (CRF) caused by ACTH/MSH peptides.
PMID- 9390009
TI - Treatment effects of intranasal growth hormone releasing peptide-2 in children
with short stature.
AB - Growth hormone-releasing peptide (GHRP)-2 is a synthetic six amino acid peptide
that is a potent GH secretagogue. Although it shares no structural homology with
GH-releasing hormone, in clinical studies its actions on the pituitary release of
GH are similar. It is effective when administered orally and intranasally. For
children with GH deficiency, such noninvasive treatments are most desirable and
in need of development. Fifteen children with short stature participated in this
study. All of the children had a height < 2 S.D. below mean for age, poor height
velocity, delayed bone age, and low serum concentrations of IGF-1. These children
had been tested with standard GH secretagogues, e.g. arginine, insulin, and L
dopa. Fifty percent of the children were GH deficient, the remainder had
idiopathic short stature. The children received testing with GHRH and GHRP-2 as
an acute i.v. bolus of 1 microgram/kg; all children in this study demonstrated a
GH response > 20 micrograms/l. Each child in this study also demonstrated a GH
response > 10 micrograms/l in response to intranasal GHRP-2, in the dose range of
5-20 micrograms/kg. The children were administered intranasal GHRP-2, 5-15
micrograms/kg, twice a day for 3 months, then three times a day. Fifteen children
participated in the study for 6 months; six of the children have participated for
18-24 months. Height velocity, serum IGF-1, IGF-binding protein 3 (IGFBP-3) and
GH-binding protein (GHBP) concentrations, and GH responses to GHRP-2 by i.v.
bolus and intranasal spray were examined during treatment. Height velocity
increased from 3.7 +/- 0.2 cm/year to 6.1 +/- 0.3 cm/year at 6 months, 6.0 +/-
0.4 cm/year at 18-24 months. There were no significant changes in IGF-1 or IGF
PB3 concentrations, or in acute GH responses to i.v. or intranasal GHRP-2. GHBP
concentrations rose significantly, from 439 +/- 63 pmol/l to 688 +/- 48 pmol/l.
In this study, intranasal GHRP-2 administration was well tolerated, and produced
a modest but significant increase in growth velocity.
PMID- 9390010
TI - Effects of clodronate-containing liposomes on testicular macrophages and Leydig
cells in vitro.
AB - We undertook the present studies to determine if clodronate-containing liposomes
have direct effects on Leydig cells. Macrophages and Leydig cells were isolated
and maintained separately in culture. Following treatment with clodronate
containing liposomes, macrophages were killed in a dose-response fashion over a
range of 5-200 microliters liposomes. By comparison, a 500 microliters dose was
required to kill Leydig cells, but this was not dependent upon clodronate since
liposomes containing buffer elicited an identical response. The concentration of
testosterone in medium from Leydig cells treated with clodronate-containing
liposomes was significantly reduced compared with untreated cells. However, we
subsequently found that liposomes can adsorb testosterone. Therefore,
testosterone production was determined at various times following removal of
liposomes from Leydig cells, thereby circumventing this complication. It was
found that testosterone production was not altered by liposomes under these
conditions. Finally, free clodronate had no effect on testosterone production,
even at doses representing the amount present within the 500 microliters dose of
liposomes. In summary, clodronate-containing liposomes killed testicular
macrophages at a far smaller dose than required to kill Leydig cells. Most
importantly, neither liposomes no free clodronate had a direct effect on
testosterone production. Thus, clodronate-containing liposomes represent a
valuable tool to study Leydig cell-macrophage interactions.
PMID- 9390011
TI - Insulin-like growth factor-I, actin, and myosin heavy chain messenger RNAs in
skeletal muscle after an injection of growth hormone in subjects over 60 years
old.
AB - Growth hormone (GH) increases the amount of insulin-like growth factor-I (IGF-I)
mRNA in rat skeletal muscle, but this effect has not been demonstrated in human
muscle. An autocrine effect of IGF-I produced in muscle may be an important
determinant of the increased muscle mass associated with GH therapy. Thus, we
examined IGF-I mRNA abundance in skeletal muscle biopsy samples taken 10 h after
a subcutaneous injection of GH (0.03 mg/kg, n = 6) or placebo (normal saline, n =
5) in men and women over 60 years of age. Relative tissue concentrations of IGF-I
mRNA were evaluated with a competitive reverse transcriptase-polymerase chain
reaction assay. Mean plasma IGF-I concentrations rose steadily after the GH
injection, and were 74% higher in the GH group than in the control group at the
time of the muscle biopsies. There was no consistent difference between the GH
and control groups in muscle IGF-I mRNA abundance when expressed in relation to
total RNA or polyadenylated RNA. However, one GH-treated subject had three times
more IGF-I mRNA, relative to polyadenylated RNA, than the average control
subject. There was no effect of GH on levels of mRNAs encoding the most abundant
myofibrillar proteins, actin and myosin heavy chain. These data do not support
the hypothesis that increased IGF-I mRNA abundance in skeletal muscle is required
for the anabolic effect of GH in people over 60 years of age.
PMID- 9390012
TI - Opioidergic regulation of prolactin secretion during pregnancy: role of ovarian
hormones.
AB - We have recently demonstrated the existence of a neuromodulatory regulation of
prolactin secretion by the opioid system showing a paradoxical opioid-induced
prolactin suppression at the end of pregnancy. The aim of this study was to
determine a possible interaction between the opioid system and ovarian hormones
on the release of prolactin during pregnancy. Serum prolactin levels measured at
1800 h were significantly higher on days 3 and 6 of pregnancy when compared with
the other days of gestation. These increases in serum prolactin were reduced
significantly by naloxone (2 mg/kg) administered at 1730 h and by RU-486 (10
mg/kg) administered at 0800 h. The response induced by RU-486 was potentiated by
naloxone only on day 3. On days 7, 13 and 16, prolactin secretion was not
modified by RU-486 and/or naloxone treatment. In RU-486 pretreated rats, naloxone
administration increased serum prolactin levels only on day 16 of pregnancy.
Interestingly, progesterone treatment (0.5 mg/rat) on days 13, 14 and 15 of
pregnancy prevented the high increase in serum prolactin induced by RU-486 and
naloxone on day 16 of pregnancy. The progressive increase and decrease of serum
progesterone concentration during pregnancy was not modified by naloxone
treatment. The participation of oestrogen in the regulation of prolactin
secretion by the opioid system on days 3, 16 and 19 was examined by treating
these groups of rats with oestradiol benzoate or tamoxifen citrate. Oestradiol (2
micrograms/rat) significantly increased serum prolactin levels on day 3 and
naloxone administration did not modify this increase. No effect was observed
after oestradiol (5 micrograms/rat) and naloxone treatment on days 16 and 19 of
pregnancy. Oral administration of tamoxifen (500 micrograms/kg) the previous day
did not modify the serum prolactin concentration measured at 1800 h in oil
treated rats on days 3, 16 and 19 of pregnancy. The antioestrogen completely
abolished the naloxone-induced prolactin secretion on day 16 in rats pretreated
with RU-486 but no effect was observed on day 19. When tamoxifen was administered
on days 14 and 15 of pregnancy, the high serum prolactin levels on day 19 induced
by treatment with RU-486 and naloxone were significantly reduced. In conclusion,
these results provide an important new insight into the existence of a dual
neuromodulatory regulation of prolactin secretion by the opioid system during
pregnancy. After a stimulatory action during the first days, there is a change to
an inhibitory control at the end of pregnancy, starting around day 16. Moreover,
the activation of the inhibitory modulation of the opioid system on prolactin
secretion on days 16 and 19 of pregnancy seems to be mediated by changes in the
oestrogen and progesterone action.
PMID- 9390013
TI - The neuroendocrine control of clock-timed gonadotropin release in the female
Syrian hamster: role of serotonin.
AB - We hypothesized that rhythms in hypothalamic serotonergic activity were
permissive to daily and estrous cycle-related rhythms of LH, FSH and prolactin
(PRL). In the Syrian hamster, proestrus (PRO) is characterized by a surge of LH,
FSH and PRL; diestrus (DIE) by low LH and FSH and a small surge of PRL, while in
photoperiod-induced anestrous (PIA) animals there is a surge of LH and FSH and
low PRL. Turnover rates of serotonin (5HT) in four brain areas were determined
for the three reproductive states at 2-h intervals. Turnover in the preoptic area
and arcuate nuclei did not change, indicating that 5HT projections to these
regions probably do not control LH, FSH or PRL release. Serotonin turnover in the
median eminence (ME) was elevated at 0600 h in PIA females, at 0600 h, 0800 h,
and 1400 h on DIE and at 0600 h and 2200 h on PRO. Since the pattern of 5HT
turnover in the ME is different during each of the three reproductive states, 5HT
in this area is likely not crucial to the control of LH, FSH and PRL. Turnover of
5HT also did not change in the suprachiasmatic nuclei (SCN) of PRO or PIA
animals. However, 5HT turnover rates in the SCN were elevated at 1200 h, 2000 h,
and 2400 h on DIE. The correlation of high 5HT turnover in the SCN of DIE but not
PRO and PIA animals suggested that elevated serotonergic activity in the SCN is
part of the mechanism by which the gonadotropin surge is prevented on DIE. To
test this, PRO and DIE hamsters were injected with 5HT receptor ligands.
Administration of a 5HT agonist attenuated the PRO surge of LH and blocked the
surge of PRL. In contrast, administration of two 5HT antagonists failed to elicit
a surge of LH in DIE and phenobarbital-blocked PRO females, an indication that
other mechanisms also contribute to inhibition of gonadotropin and PRL surges.
PMID- 9390014
TI - Evidence that gonadotropin-releasing hormone (GnRH) functions as a prolactin
releasing factor in a teleost fish (Oreochromis mossambicus) and primary
structures for three native GnRH molecules.
AB - Three forms of gonadotropin-releasing hormone (GnRH) are isolated and identified
here by chemical sequence analysis for one species of tilapia, Oreochromis
niloticus, and by HPLC elution position for a second species of tilapia, O.
mossambicus. Of the three GnRH forms in O. mossambicus, chicken GnRH-II (cGnRH
II) and sea bream GnRH (sbGnRH) are present in greater abundance in the brain and
pituitary than salmon GnRH (sGnRH). These three native forms of GnRH are shown to
stimulate the release of prolactin (PRL) from the rostral pars distalis (RPD) of
the pituitary of O. mossambicus in vitro with the following order of potency:
cGnRH-II > sGnRH > sbGnRH. In addition, a mammalian GnRH analog stimulated the
release of PRL from the pituitary RPD incubated in either iso-osmotic (320
mosmol/l) or hyperosmotic (355 mosmol/l) medium, the latter normally inhibiting
PRL release. The response of the pituitary RPD to GnRH was augmented by co
incubation with testosterone or 17 beta-estradiol. The effects of GnRH on PRL
release appear to be direct effects on PRL cells because the RPD of tilapia
contains a nearly homogeneous mass of PRL cells without intermixing of
gonadotrophs. Our data suggest that GnRH plays a broad role in fish, depending on
the species, by affecting not only gonadotropins and growth hormone, but also
PRL.
PMID- 9390015
TI - Adaptation of parathyroid function to intravenous 1,25-dihydroxyvitamin D3 or
partial parathyroidectomy in normal dogs.
AB - Parathyroid function was studied in 14 normal dogs 1 month before and after daily
i.v. administration of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) (eight dogs), or
about 50% parathyroidectomy (six dogs), to test the hypothesis that degradation
of newly synthesized intact parathyroid hormone (I-PTH) is involved in
parathyroid gland adjustment to a modified demand for I-PTH. Parathyroid function
was studied through i.v. infusions of Na2EDTA and CaCl2 and measurement of
ionized calcium (Ca2+), I-PTH and carboxyl-terminal PTH (C-PTH) at various time
points. The C-PTH/I-PTH ratio was used as an index for change in the relative
proportion of circulating C-PTH vs I-PTH, 1 month prior to and following each
intervention. This ratio was further validated by looking at the HPLC profile of
I- and C-PTH in hypo- and hypercalcemia under experimental conditions. Basal Ca2+
was unaltered 1 month after surgery, and was maintained constant in the 1,25
(OH)2D3-treated group by gradually decreasing 1,25-(OH)2D3 doses over time from
0.25 to 0.13 microgram twice daily during the last week of the experimental
protocol. In this same group, basal 1,25-(OH)2D3 was increased by 65% (P <
0.0001) and basal I-PTH was decreased by 40% (P < 0.05), while basal C-PTH and
the C-PTH/I-PTH ratio remained unchanged. Stimulated and non-suppressible I- and
C-PTH followed the same pattern with, this time, an increase of stimulated and
non-suppressible C-PTH/I-PTH ratio of 60% (P < 0.05) and 85% (P < 0.05)
respectively. There was no change in basal I-PTH, C-PTH, or C-PTH/I-PTH ratio
after surgery. However, stimulated I- and C-PTH were decreased by 45% (P < 0.005)
and 65% (P < 0.005) respectively, with a 30% (P < 0.005) decrease of stimulated C
PTH/I-PTH ratio. There was no change in non-suppressible I-PTH, while non
suppressible C-PTH decreased by 55% (P < 0.005), with a 55% (P < 0.05) decrease
in non-suppressible C-PTH/I-PTH ratio. The HPLC profiles of I- and C-PTH obtained
in hypo- and hypercalcemia disclosed a similar distribution of the immuno
reactivity into peaks before and after i.v. administration of 1,25-(OH)2D3 as
well as partial parathyroidectomy. This indicated that C-PTH/I-PTH ratio changes
were related to different circulating levels of I- and C-PTH rather than to a
different composition of I- and C-PTH. These data indicate a shift in the
circulating PTH profile toward more PTH carboxyl-terminal fragments after 1 month
of i.v. 1,25-(OH)2D3, but toward more intact PTH 1 month after about 50%
parathyroidectomy, possibly reflecting adjustments in PTH degradation induced by
a modified demand for I-PTH. Although these changes are most likely modulated at
the parathyroid gland level, we cannot formally eliminate participation of the
hormone's peripheral metabolism.
PMID- 9390016
TI - Developmental regulation of preproenkephalin (PENK) gene expression in the
adrenal gland of the ovine fetus and newborn lamb: effects of hypoxemia and
exogenous cortisol infusion.
AB - Development of the fetal adrenal gland is crucial not only for maturation of
several fetal organ systems and the initiation of parturition, but also for the
development of the fetal response to stress. The enkephalin-related peptides are
present in the chromaffin cells of the fetal adrenal medulla and are secreted in
response to stress and with sympathetic stimulation. However, changes in
expression of preproenkephalin (PENK) with gestation and in response to stress
have not been studied in detail. Therefore we examined the developmental pattern
of PENK gene expression in the adrenal gland of fetal and newborn lambs, and of
adult sheep. We also determined whether levels of PENK mRNA in the fetal adrenal
gland changed in response to exogenous glucocorticoids in late gestation, or in
response to hypoxemia. Adrenal glands were removed from fetal sheep, lambs and
adult sheep at different stages of development for measurement of PENK mRNA.
Cortisol was infused (5 micrograms/min) for 12, 24 or 96 h beginning on day 124
129 of gestation. Moderate hypoxemia was induced for 48 h beginning on day 126
130, or at day 134-136 of gestation, by lowering the maternal fractional inspired
oxygen. At the end of the treatment periods, the ewes and fetuses were
euthanized. Adrenal PENK mRNA were measured by Northern blot analysis. PENK mRNA
levels in fetal adrenals were significantly higher (P < 0.05) on days 140-141 of
gestation than earlier in pregnancy, and then decreased significantly with the
onset of parturition (days 142-146). After cortisol infusion to the fetus for 96
h there was a significant reduction in adrenal PENK mRNA levels. Hypoxemia
resulted in a significant increase in PENK mRNA levels in fetuses at day 126-130
of gestation, but not at the later time in pregnancy when endogenous plasma
cortisol concentrations were higher. We conclude that there is a decrease in
levels of PENK mRNA in the fetal adrenal gland before parturition at the time of
the endogenous prepartum rise in plasma cortisol. Hypoxemia led to an elevation
of PENK mRNA levels in fetuses at less than 130 days, but after that time, when
the basal and stimulated cortisol responses had risen, there was no significant
effect of hypoxemia on PENK mRNA. Cortisol infusion to the fetus at this stage of
pregnancy resulted in a decrease in adrenal PENK mRNA levels. We suggest that
cortisol may play an important role in the regulation of fetal adrenal PENK mRNA
levels and enkephalin synthesis by the adrenal gland of the fetal sheep.
PMID- 9390017
TI - Effect of thyroid state on lipid peroxidation, antioxidant defences, and
susceptibility to oxidative stress in rat tissues.
AB - The effects of altered thyroid states on lipid peroxidation, antioxidant
capacity, and susceptibility to oxidative stress of rat tissues were examined.
Hypothyroidism was induced by administering methimazole in drinking water for 15
days. Hyperthyroidism was elicited by a 10-day treatment of hypothyroid rats with
tri-iodothyronine (10 micrograms/100 g body weight). In tissues of hypothyroid
rats the lipid peroxidation was not modified, whereas in hyperthyroid rats lipid
peroxidation increased in liver and heart but not in skeletal muscle. The
glutathione peroxidase activity increased significantly in heart and muscle of
hypothyroid rats and in muscle of hyperthyroid rats. The glutathione reductase
activity was not modified in tissues of hypothyroid and hyperthyroid rats. In
both rat groups the whole antioxidant capacity of tissues decreased, but
significantly only in liver and heart. The results obtained studying the response
to oxidative stress in vitro indicated that the susceptibility to oxidative
challenge was increased in all tissues of hyperthyroid rats and in heart and
muscle of hypothyroid animals. These results are explainable in terms of tissue
variations in haemoprotein content and/or of antioxidant capacity. Since it has
been reported that hypothyroidism offers in vivo protection against free radical
damage, we suggest that such an effect could be due to greater effectiveness of
cellular defence systems different from antioxidant ones.
PMID- 9390018
TI - Estrogen enhances growth hormone receptor expression and growth hormone action in
rat osteosarcoma cells and human osteoblast-like cells.
AB - Postmenopausal bone loss is primarily due to estrogen deficiency. Recent clinical
observation demonstrate that GH increases bone mass in GH deficient patients. The
present study investigates whether estrogen regulates GH action and GH receptor
expression in osteoblasts. 17 beta-estradiol or GH added to the culture medium as
single substances did not influence rat osteosarcoma cell proliferation nor human
osteoblast-like (hOB) cell proliferation. However, together they synergistically
induced osteoblast proliferation (rat osteosarcoma cells 160.1 +/- 15.5% of
control cells; human osteoblast-like cells 159.6 +/- 5.1% of control cells). 17
beta-estradiol stimulated 125I-GH binding and GH receptor (GHR) mRNA levels in
rat osteosarcoma cells. The stimulatory effect of estradiol was time dependent,
reaching a peak after 8 h of incubation with 17 beta-estradiol (binding 216.9 +/-
27.8% and mRNA 374.6 +/- 30.8% of control). The finding that estradiol stimulated
125I-GH binding was confirmed in human osteoblast-like cells. In these cells, 17
beta-estradiol (10(-12) M) increased 125I-GH binding to 203.8 +/- 3.6% of control
levels. We conclude that estrogen stimulates GH activity as well as GH binding
and GHR mRNA levels in osteoblasts. These findings indicate that estrogen
potentiates the effect of GH at the receptor level.
PMID- 9390019
TI - T and B cell development in pituitary deficient insulin-like growth factor-II
transgenic dwarf mice.
AB - Treatment of mice with IGF-I stimulates T and B cell development. We showed that
overexpression of IGF-II in transgenic FVB/N mice only stimulated T cell
development. In the present study, we further addressed the in vivo effects of
IGF-II in the absence of IGF-I to get more insight into the potential abilities
of IGF-II to influence T and B cell development. To this end, we studied
lymphocyte development in IGF-II transgenic Snell dwarf mice that are prolactin,
GH and thyroid-stimulating hormone deficient and as a consequence show low serum
IGF-I levels. We showed that T cell development was stimulated to the same extent
as in IGF-II transgenic FVB/N mice. Furthermore, IGF-II increased the number of
nucleated bone marrow cells and the number of immature B cells without having an
effect on the number of mature B cells in spleen and bone marrow. Our data show
that IGF-II has preferential effects on T cell development compared with B
development, and that these preferential effects also occur in the absence of
measurable IGF-I levels.
PMID- 9390021
TI - Who wants book reviews?
PMID- 9390020
TI - Inhibition of 11 beta-hydroxysteroid dehydrogenase activity enhances the
antiproliferative effect of glucocorticosteroids on MCF-7 and ZR-75-1 breast
cancer cells.
AB - This in vitro study on MCF-7 and ZR-75-1 breast cancer cells showed that the
antiproliferative action of glucocorticosteroids (GCS) on breast cancer cells is
weakened by a high oxidative activity of 11 beta-hydroxysteroid dehydrogenase (11
beta-HSD; EC 1.1.1.146): both endogenic as well as synthetic GCS (dexamethasone,
prednisolone) were metabolised to hormonally inactive 11-dehydro metabolites.
This enzymatic shield protected the breast cancer cells from the
antiproliferative action of GCS. Continuous exposure of breast cancer cells to
GCS resulted in enhanced 11 beta-HSD activity. The intracellular GCS
concentration was further reduced by this feedback and thus the antiproliferative
effect was additionally weakened. These mechanisms of GCS deactivation could be
influenced by inhibiting 11 beta-HSD with the liquorice compound glycyrrhetinic
acid (GLY). In MCF-7 and ZR-75-1 cultures the antiproliferative effect of GCS was
significantly increased by GLY.
PMID- 9390022
TI - Quantitative microscopy in studies of intrauterine growth retardation.
AB - In the past, the detection of fetal damage has tended to be restricted to the
naked eye identification of major malformations, with the period of organ
maturation being relatively neglected. Increasingly, however, unbiased design
based stereology is being used in developmental toxicological studies. In the
field of intrauterine growth retardation, such methods are capable of providing
new insights into fetal vulnerability during critical periods in organogenesis,
with consequences for both post-natal and adult disease.
PMID- 9390023
TI - The Heidelberg classification of renal cell tumours.
AB - This paper presents the conclusions of a workshop entitled 'Impact of Molecular
Genetics on the Classification of Renal Cell Tumours', which was held in
Heidelberg in October 1996. The focus on 'renal cell tumours' excludes any
discussion of Wilms' tumour and its variants, or of tumours metastatic to the
kidneys. The proposed classification subdivides renal cell tumours into benign
and malignant parenchymal neoplasms and, where possible, limits each subcategory
to the most commonly documented genetic abnormalities. Benign tumours are
subclassified into metanephric adenoma and adenofibroma, papillary renal cell
adenoma, and renal oncocytoma. Malignant tumours are subclassified into common or
conventional renal cell carcinoma; papillary renal cell carcinoma; chromophobe
renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the
kidney; and renal cell carcinoma, unclassified. This classification is based on
current genetic knowledge, correlates with recognizable histological findings,
and is applicable to routine diagnostic practice.
PMID- 9390024
TI - Multiple pathways control cell growth and transformation: overlapping and
independent activities of p53 and p21Cip1/WAF1/Sdi1.
AB - Many tumour therapies act by inducing a cellular damage response pathway mediated
by the tumour suppressor protein p53. Alternative outcomes of p53 induction
include apoptosis or transient cell-cycle arrest, both thought to require the
transcriptional activity of wild-type p53. Current research highlights the action
of a p53-activated gene, p21Cip1/WAF1/Sdi1, which encodes a cyclin-kinase
inhibitor important in mediating p53-dependent cell-cycle arrest, while
programmed cell death in response to DNA damage requires transcriptionally active
p53 but not activation of p21Cip1/WAF1/Sdi1. This review examines the roles of
p53 and p21Cip1/WAF1/Sdi1 in controlling cell proliferation, in the light of a
new study on expression of p53 and p21Cip1/WAF1/Sdi1 in squamous cell carcinoma
of the larynx.
PMID- 9390025
TI - Classification strategies for the grading of renal cell carcinomas, based on
nuclear morphometry and densitometry.
AB - The various grading systems proposed for renal cell carcinomas all suffer from
problems related to inter-observer variability. Some of these grading systems are
based, either partially or wholly, on morphonuclear criteria, such as nuclear
size and shape, anisonucleosis, and chromatin pattern. These criteria can be
quantitatively (and thus objectively) evaluated by means of the computer-assisted
microscopic analysis of Feulgen-stained nuclei. In the present work, 39
quantitative variables, including two morphometric, 28 chromatin pattern-related,
and nine DNA ploidy level-related, were computed for 65 renal cell carcinomas.
The actual diagnostic information contributed by each variable was determined by
means of multifactorial statistical analysis (discriminant analysis) and two
artificial intelligence-related methods of data classification (the decision tree
and production rule methods). The results show that quantitative information, as
provided by the computer-assisted microscopy of Feulgen-stained nuclei and
analysed by means of artificial intelligence-related methods of data
classification, contributes significant diagnostic information for the grading of
renal cell carcinoma, thus reducing the problem of inter-observer
reproducibility.
PMID- 9390026
TI - Loss of heterozygosity at chromosomes 8p, 9p, and 14q is associated with stage
and grade of non-papillary renal cell carcinomas.
AB - In this study, 105 non-papillary renal cell carcinomas (RCCs) have been examined
for allelic loss at the chromosome 8p12-21.1, 9p21, and 14q24.2-qter regions,
each by two highly polymorphic microsatellites. Loss of heterozygosity (LOH) was
detected at both chromosome 8p and 9p in 33 per cent of the cases and at
chromosome 14q in 45 per cent of the tumours. A correlation of variables such as
size, grade, and stage of tumours with these specific genetic alterations showed
that loss of chromosomes 8p and 9p, and especially loss of chromosome 14q
regions, is significantly associated with a higher grade of tumour and the
combined LOH at these chromosomal sites with advanced tumour stage. These genetic
alterations did not show any correlation with the size of non-papillary RCCs.
This study suggests that genetic markers at the above-mentioned chromosomal sites
can predict the clinical outcome of non-papillary RCCs.
PMID- 9390027
TI - p21WAF1/Cip1 expression is associated with cell differentiation but not with p53
mutations in squamous cell carcinomas of the larynx.
AB - p21WAF1/Cip1 is a recently identified gene involved in cell cycle regulation
through cyclin-CDK-complex inhibition. The expression of this gene in several
cell lines seems to be induced by wild-type, but not mutant, p53. p21WAF1/Cip1
expression has been studied at both mRNA and protein levels in a series of 49
normal mucosae and squamous cell carcinomas of the larynx. A significant
association was found between mRNA and protein expression in tumours (P <
0.0001). p21WAF1/Cip1 expression was strongly associated with squamous cell
differentiation of carcinomas, because six of seven (86 per cent)
undifferentiated carcinomas (grade 4) showed very low levels of p21WAF1/Cip1
expression, whereas 41 out of 42 (98 per cent) carcinomas with squamous cell
differentiation (grades 1-3) had normal or high levels of p21WAF1/Cip1 expression
(P < 0.0001). In addition, p21WAF1/Cip1 expression was topologically related to
the squamous differentiation of tumour cells with a distribution similar to that
seen in normal squamous epithelium. No correlation was found between p21WAF1/Cip1
expression and the global S-phase of the carcinomas. p53 mutations (exons 5-9)
were found in ten carcinomas with p21WAF1/Cip1 expression, but no p53 mutations
were detected in three p21WAF1/Cip1-negative tumours. In conclusion, p21WAF1/Cip1
expression is frequently upregulated in squamous cell carcinomas of the larynx
and is associated with tumour cell differentiation. p21WAF1/Cip1 expression in
these tumours is independent of p53 gene mutations.
PMID- 9390028
TI - The association of squamous cell carcinomas of the nasopharynx with Epstein-Barr
virus shows geographical variation reminiscent of Burkitt's lymphoma.
AB - Nasopharyngeal carcinoma (NPC) is rare in most parts of the world but occurs with
high incidence in certain regions, such as South-East Asia. Two major
histological types of NPC are recognized, non-keratinizing carcinoma and squamous
cell carcinoma. Non-keratinizing NPCs, which include undifferentiated NPC, are
invariably associated with Epstein-Barr virus (EBV) infection, regardless of the
geographical or ethnic origin of the patients. By contrast, conflicting results
have been published concerning a possible association of squamous cell NPC with
the virus. To address this question, squamous cell NPCs have been collated from
an area where NPC is endemic, Hong Kong, and from two regions where NPC occurs
with a lower incidence, Chengdu, PR China, and Birmingham, United Kingdom. In
situ hybridization for the detection of the small EBV-encoded nuclear RNAs
(EBERs) demonstrated that all 22 cases from Hong Kong were EBV-positive. By
contrast, EBV was detectable in 7 of 19 cases from central China, and in 3 of 7
cases from the U.K. Expression of the virus-encoded latent membrane protein 1
(LMP1) was detected in 3 of 32 EBV-positive squamous cell NPCs. These results
indicate that the association of squamous cell NPCs with EBV shows geographical
variability in a manner which is reminiscent of the situation encountered in
Burkitt's lymphoma. This suggests that squamous cell NPCs are a pathogenetically
heterogeneous group of tumours distinct from non-keratinizing NPCs.
PMID- 9390029
TI - Human ageing impairs injury-induced in vivo expression of tissue inhibitor of
matrix metalloproteinases (TIMP)-1 and -2 proteins and mRNA.
AB - Proteolysis is an essential component of wound healing but, if uncontrolled, it
may lead to degradation of the neo-matrix and a delay in wound repair. Despite
numerous reports of impaired wound healing associated with increasing age, the
control of proteolysis is completely unknown. Tissue inhibitor of matrix
metalloproteinases (TIMP)-1 and -2 inhibit the activity of matrix
metalloproteinases and the pattern of regulation of these molecules determines in
part the spatial and temporal regulation of proteolytic activity. This study
reports on TIMP-1 and -2 protein localization using immunocytochemistry in
healing wounds of healthy subjects of different ages from day 1 to 6 months post
wounding, and has quantified the mRNA levels for both inhibitors using reverse
transcriptase-polymerase chain reaction (RT-PCR). TIMP-1 and TIMP-2 proteins are
up-regulated from 24 h post-wounding, with a decrease in staining intensity by
day 7 for TIMP-2 and by day 14 for TIMP-1. Steady-state mRNA levels for both
TIMPs were significantly greater in normal young skin than in aged skin. In the
young, there was a significant increase in mRNA expression for TIMP-1 and -2 by
day 3 post-wounding, which decreased by day 14 and had returned to basal levels
at day 21. In the wounds of the aged subjects, basal levels were observed for
TIMP-1 and -2 at all time-points. These results suggest that intrinsic cutaneous
ageing is associated with reduced levels of TIMP mRNA both in normal skin and
during acute wound repair. These levels may be instrumental in dermal tissue
breakdown in normal skin, retarded wound healing, and the predisposition of the
elderly to chronic wound healing states.
PMID- 9390030
TI - UV but not gamma-irradiation induces specific transcriptional activity of p53 in
primary hepatocytes.
AB - The mechanisms are poorly understood by which p53 can stimulate different
downstream events, including growth arrest, DNA repair, and apoptosis, after DNA
damage. Changes in protein levels do not predict a particular p53 response, but
it is possible that differences in functional activities such as transactivation
are important. The present report describes the successful use of a specific p53
reporter plasmid transfected into primary murine hepatocytes to evaluate p53
transactivation activity over time after two different genotoxic injuries (gamma
irradiation, 15 Gy and UV-c irradiation, 10 J/m2) known to produce p53-dependent
growth arrest in this cell type. The results show that UV injury to hepatocytes
was followed by a transient increase in transcriptional activation of the
reporter plasmid by p53 and that this response preceded changes in p53 protein
levels, as assessed by immunocytochemistry. By contrast, gamma-irradiation injury
failed to induce detectable changes in either transactivation activity or
hepatocyte p53 protein levels. The data show that p53 responses to DNA damage are
dependent on both cell and injury type and suggest that in hepatocytes they can
be independent of protein concentration and specific transcriptional activity.
The results have implications for how particular dysfunctional p53 mutations in
carcinogenesis could alter hepatocyte responses to different DNA injuries.
PMID- 9390031
TI - In vivo expression of the CTLA4 inhibitory receptor in malignant and reactive
cells from human lymphomas.
AB - The CTLA4 receptor is a CD28 homologue which induces inhibitory effect on
activated T-cells. Peripheral T-cells proliferate spontaneously in CTLA4
deficient mice. These results led to an analysis of CTLA4 expression in human
lymphomas (n = 82) including Hodgkin's disease (HD) and non-Hodgkin's lymphomas
(NHLs), using immunohistochemistry. CTLA4 was present in neoplastic cells from
most (10/11) T-cell malignancies, except for anaplastic and lymphoblastic
subtypes (0/4). Malignant B-cells from rare (3/55) B-NHLs (all of follicular
subtype) were also CTLA4-positive. Other B-NHLs (52/55) were negative in
malignant B-cells and occasionally positive in T-cells. Reactive small
lymphocytes, but not Reed-Sternberg cells, from all (12/12) HD cases were
strongly CTLA4-positive. The CTLA4 ligands CD80 and CD86 were simultaneously
expressed in most CTLA4-negative lymphoma cases. CTLA4 is thus expressed either
in the reactive or in the malignant cell populations, depending on the lymphoma
subtype. These results provide new insights leading towards therapeutic
strategies based either on enhancement of anti-tumour immunity by CTLA4 blockade
in reactive lymphocytes or on triggering of a CTLA4-mediated inhibitory pathway
in lymphoma cells.
PMID- 9390032
TI - 'Revertant' DCIS in human axillary breast carcinoma metastases.
AB - Recent experimental evidence obtained in Scid mice has suggested that the
metastatic process is in large part epigenetically regulated and undergoes
partial reversion once the metastatic process is completed: the metastatic
colonies become more engaged in the process of growing in situ than actively
metastasizing. Based on this experimental evidence, examples were sought of
metastatic human cancers where similar reversion to an in situ growth state was
occurring. Review of 200 cases of metastatic human breast cancer revealed a 21
per cent incidence of reversion to a ductal carcinoma in situ (DCIS) growth
pattern within axillary nodal metastases. The revertant DCIS areas were
characterized by an intact and circumferential basement membrane, as demonstrated
by extracellular laminin and type IV collagen immunoreactivity. These revertant
DCIS areas could be distinguished from primary DCIS, however, by the absence of
surrounding myoepithelial cells in the former, identified in the latter by their
positive maspin, S-100, and smooth muscle actin immunoreactivity. The pattern of
revertant DCIS, poorly differentiated (comedo) (13 per cent), intermediate (non
comedo) (6 per cent), or well-differentiated (non-comedo) (2%), exhibited
complete 100 per cent concordance with the primary DCIS pattern. The concordance
of histological patterns held true for even the subtypes of DCIS determined by
architectural pattern, such as the micropapillary or cribriform subtypes. Nuclear
size by digital image analysis and Her-2/neu, p53, and Ki-67 status in the
revertant DCIS also exhibited complete concordance with the primary DCIS
counterparts. Cases exhibiting a revertant DCIS pattern tended to be ER
negative/EGFR-positive and exhibited significant nodal involvement (mean number,
9; mean area, 90 per cent) compared with cases lacking a revertant pattern (mean
number, 4; mean area, 15 per cent) (P < 0.01) These findings suggest that
reversion of the metastatic phenotype may also be occurring within autochthonous
human metastasis.
PMID- 9390033
TI - Grb2 overexpression in nuclei and cytoplasm of human breast cells: a
histochemical and biochemical study of normal and neoplastic mammary tissue
specimens.
AB - In 20-30 per cent of human breast cancers, the receptor tyrosine kinases
epidermal growth factor receptor (EGFR) and c-erbB2 are overexpressed. This
overexpression leads to increased mitogenic signalling and is correlated with
poor prognosis. Overexpression of associated adaptor proteins, like Grb2, can
also induce upregulation of signalling pathways. In this study, the expression of
the Grb2 adaptor protein was determined in both normal human breast tissue and
mammary cancers, using immunoblotting experiments and immunostaining on paraffin
embedded tissue sections. Both biochemical and immunohistochemical techniques
revealed overexpression of Grb2 in all breast cancer specimens. In addition,
although Grb2 protein is described as localized in the cytoplasm, it can also be
detected in the nucleus, both in normal and in tumour breast tissue. In tumour
breast tissue, 58 per cent of Grb2 protein is found in the nucleus, while 37 per
cent is detected in the cytoplasm. In normal breast tissue, 22 per cent of Grb2
is found in the nucleus and 70 per cent in the cytoplasm. These findings indicate
that in human breast cancer, Grb2 is overexpressed and appears to be
predominantly localized in the nucleus.
PMID- 9390034
TI - Variation of bcl-2 expression in breast ducts and lobules in relation to plasma
progesterone levels: overexpression and absence of variation in fibroadenomas.
AB - Some women with benign breast disease eventually develop breast cancer. The
mammary gland undergoes tissue remodelling according to hormonal influences,
involving a balance between quiescence, proliferation, and mechanisms of cell
death. Proliferation and/or apoptotic events could therefore be investigated to
help understand the mechanisms of benign lesion formation and identify
mastopathies with a poor prognosis. bcl-2 expression was analysed by
immunohistochemistry in 75 benign mastopathies. Protein levels were quantitated
with an image analyser in various epithelial structures on frozen sections,
including adenoses, fibroadenomas, ductal epithelial hyperplasias, cysts, and
apparently normal surrounding lobules and ducts. bcl-2 levels were equivalent in
apparently normal lobules and ducts, as well as in cysts and ductal hyperplasias.
bcl-2 staining was significantly higher in fibroadenomas, known to be of lobular
origin [mean = 10.1, quantitative immunochemistry score (QIC) arbitrary units
(AU), n = 19], than in normal lobules (mean = 5.1 AU, n = 43, P = 7 x 10(-5). bcl
2 levels in normal lobules and ducts varied according to the menstrual cycle,
being higher during the follicular than the luteal phase (P = 1.8 x 10(-2) and P
= 1.7 x 10(-2), respectively). This was further supported by a statistical link
(P = 5 x 10(-3) between high levels of circulating progesterone and weak bcl-2
staining in lobules and ducts. This progesterone-dependent variation was absent
in fibroadenomas. No statistical correlation was found between bcl-2 expression
and circulating levels of oestradiol, and follicle-stimulating or luteotrophic
hormones. Although these are only preliminary results, they suggest an influence
of progesterone on bcl-2 expression which might be lost in fibroadenomas. A
hypothesis is proposed concerning the potential involvement of altered regulation
of the apoptotic process in the formation of such benign lesions.
PMID- 9390035
TI - Expression of the receptor for parathyroid hormone-related protein in normal and
malignant breast tissue.
AB - Parathyroid hormone-related protein (PTHrP) is the cause of humoral
hypercalcaemia of malignancy and interacts with parathyroid hormone (PTH)
receptors. Breast cancer cells produce PTHrP in vitro and in vivo. The breast
cancer cell line MCF-7, which products PTHrP and expresses PTHrP receptors,
proliferates in response to PTHrP. The aim of these studies was to determine the
tissue location of PTHrP/PTH receptors (PTHrPR) in primary breast carcinomas and
to establish whether they had the potential to respond to PTHrP. The cellular
location of mRNA for the PTHrP/PTH receptor was identified using in situ
hybridization in primary breast carcinomas and normal breast tissue.
Immunohistochemistry for PTHrP was carried out on the same specimens. Tumours
were assessed and scored by two observers using the product of intensity of
signal and number of positive tumour cells (possible range 0-9). Tumours were
also assessed for Ki-67 expression by counting positive nuclei. Non-malignant
ductular epithelium expressed mRNA for the PTHrP receptor (mean score 2.6, range
1-4). Breast carcinomas (mean score 4.4, range 0-9) showed variable expression of
PTHrP receptor mRNA: eight tumours were negative, 50 had scores similar to normal
breast tissue, and 49 had higher scores for the receptor. Levels of expression of
the receptor within the primary breast carcinomas were unrelated to
immunohistochemical detection of PTHrP or to any standard prognostic factor.
There was a significant (P = 0.05) relationship between Ki-67 and PTHrPR
expression in individual tumours. The presence of PTHrP and its receptor in
normal breast epithelium and breast carcinomas demonstrates that most breast
tumours are able to respond to PTHrP. The Ki-67 data suggest that PTHrP is a
potential autocrine growth factor in primary breast carcinoma.
PMID- 9390036
TI - Expression of apoptosis-suppressing gene bcl-2 in human carotid body tumours.
AB - That carotid body tumours have a genetic aetiology is suggested by the familial
occurrence of the neoplasm. Environmental influences are also implied by the fact
that the tumour is more common in those living at high altitudes. However, the
mechanism of development of sporadic tumours occurring at sea level, which
account for the majority of cases, remains unknown. It has become increasingly
clear that the deregulation of programmed cell death is a critical component in
multistep tumourigenesis. Previous studies have demonstrated a high frequency of
bcl-2 expression in the tumours arising from cells derived from the neural crest
and tumour cell lines of neural origin. This investigation was undertaken to
determine whether similar molecular events occur in human carotid body tumours.
Western and Northern analysis revealed that the tumours expressed the 26 kD
protein and bcl-2 transcripts. Immunoperoxidase staining, using a monoclonal anti
bcl-2 antibody, revealed that 11 out of 13 specimens stained positively for bcl
2. These results suggest that the deregulation of programmed cell death may be a
critical component in the multistep tumourigenesis of carotid body tumours and
that the expression of oncoprotein bcl-2 may contribute to the generation of such
tumours.
PMID- 9390037
TI - Expression and prognostic value of the CD44 splicing variants v5 and v6 in
gastric cancer.
AB - In the present study, the expression and prognostic role of the CD44 splicing
variants v5 and v6 were immunohistochemically investigated in 418 curatively
resected gastric carcinomas. CD44v5 was expressed in 65.3 per cent (n = 273) and
CD44v6 in 77.0 per cent (n = 322) of the tumours. Whereas the expression of
CD44v5 was correlated with advanced pT categories, with lymph node involvement,
and with the presence of blood and lymphatic vessel invasion, such a correlation
could not be found for the variant v6. As shown by univariate analysis, patients
with CD44v5-positive tumours had a significantly shorter overall survival than
patients with CD44v5-negative tumours (P = 0.049). In contrast, expression of
CD44v6 had no impact on prognosis (P = 0.574). In a multivariate analysis
including the prognostic parameters pT category and pN category, as well as blood
and lymphatic vessel invasion, the prognostic impact of CD44v5 expression could
not, however, be maintained. Although in the present study the expression of
CD44v5 was correlated with a more aggressive tumour type, these data suggest that
neither CD44v5 nor CD44v6 can predict survival in patients with gastric cancer,
nor is their expression a suitable tool for identifying subgroups of patients who
may be at higher risk.
PMID- 9390038
TI - New monoclonal antibodies to oestrogen and progesterone receptors effective for
paraffin section immunohistochemistry.
AB - Assessment of oestrogen and progesterone receptors (ER and PgR) in breast cancer
is widely used for the prediction of response to endocrine therapy and as a
prognostic marker. Cytosolic assays have been replaced in many centres by
immunochemical techniques, which have many advantages including applicability to
small samples, simplicity, and cost-effectiveness. This study describes the
generation and characterisation of two novel murine monoclonal antibodies
recognizing ER and PgR, designated NCL-ER-6F11 and NCL-PGR respectively, which
are effective in heat-treated formalin-fixed, paraffin-embedded tissue. The
antibodies have been characterized by Western blotting and by
immunohistochemistry on normal and pathological breast and other tissues. NCL-ER
6F11 has been shown to compare favourably with a currently available ER antibody.
These antibodies may prove of value in the assessment of hormone receptor status
in human breast cancer.
PMID- 9390039
TI - Full thickness eosinophilia in oesophageal leiomyomatosis and idiopathic
eosinophilic oesophagitis. A common allergic inflammatory profile?
AB - Oesophageal leiomyomatosis and idiopathic eosinophilic oesophagitis are both
extremely rare. The former is a diffuse proliferation of smooth muscle in the
muscularis propria, whilst the latter is an idiopathic inflammatory condition,
thought to be associated with background atopy and characterized by an infiltrate
of eosinophils throughout the full thickness of the oesophagus. However, two
recent cases of oesophageal leiomyomatosis showed similar full thickness
infiltration of the oesophageal wall by eosinophils and this inflammatory cell
infiltrate was investigated in conjunction with one case of idiopathic
eosinophilic oesophagitis. All three had a similar allergic profile characterized
by CD45RO-positive primed T-lymphocytes, EG2-positive (i.e., activated)
eosinophils, and tryptasepositive mast cells, together with gene expression for
interleukin 4. Previous descriptions of leiomyomatosis describe an association
with systemic mastocytosis and urticaria and the possibility that there is a
common underlying allergic component to both disorders is raised.
PMID- 9390040
TI - A highly sensitive detection method for immunohistochemistry using biotinylated
tyramine.
AB - A highly sensitive method for light microscopic immunohistochemistry is
described. The increased sensitivity compared with current methodologies is based
on the horseradish peroxidase-catalysed deposition of biotinylated tyramine at
the sites of immunoreactivity, followed by the detection of the biotin with
streptavidin biotin horseradish peroxidase complex. This method is of general
applicability in immunohistochemistry and has several important advantages over
currently used immunohistochemical detection procedures. The most significant
advantage is that several antibodies which to data have been non-reactive, even
in antigen-retrieval formalin-fixed, was-embedded sections, now show strong and
reproducible immunoreactivity using biotinylated tyramine amplification. In
addition, many other antibodies can be used at significantly higher dilutions.
PMID- 9390041
TI - Intracytoplasmic sperm injection: offering hope for a term pregnancy and a
healthy child?
PMID- 9390042
TI - When lifesaving treatment in children is not the answer.
PMID- 9390043
TI - The future of preschool vision screening services in Britain.
PMID- 9390044
TI - Too soon to market.
PMID- 9390045
TI - Opiate detoxification under anaesthesia.
PMID- 9390046
TI - UK exempts motor racing from advertising ban.
PMID- 9390047
TI - UK bans powerful laser pointers.
PMID- 9390048
TI - Oregon reaffirms assisted suicide.
PMID- 9390049
TI - Methadone treatment increases in EU.
PMID- 9390050
TI - Milk intake and bone mineral acquisition in adolescent girls: randomised,
controlled intervention trial.
AB - OBJECTIVES: To investigate the effect of milk supplementation on total body bone
mineral acquisition in adolescent girls. DESIGN: 18 month, open randomised
intervention trial. SUBJECTS: 82 white girls aged 12.2 (SD 0.3) years, recruited
from four secondary schools in Sheffield. INTERVENTION: 568 ml (one pint) of
whole or reduced fat milk per day for 18 months. MAIN OUTCOME MEASURES: Total
body bone mineral content and bone mineral density measured by dual energy x ray
absorptiometry. Outcome measures to evaluate mechanism included biochemical
markers of bone turnover (osteocalcin, bone alkaline phosphatase,
deoxypyridinoline, N-telopeptide of type I collagen), and hormones important to
skeletal growth (parathyroid hormone, oestradiol, insulin-like growth factor I).
RESULTS: 80 subjects completed the trial. Daily milk intake at baseline averaged
150 ml in both groups. The intervention group consumed, on average, an additional
300 ml a day throughout the trial. Compared with the control group, the
intervention group had greater increases of bone mineral density (9.6% v 8.5%, P
= 0.017; repeated measures analysis of variance) and bone mineral content (27.0%
v 24.1%, P = 0.009). No significant differences in increments in height, weight,
lean body mass, and fat mass were observed between the groups. Bone turnover was
not affected by milk supplementation. Serum concentrations of insulin-like growth
factor I increased in the milk group compared with the control group (35% v 25%,
P = 0.02). CONCLUSION: Increased milk consumption significantly enhances bone
mineral acquisition in adolescent girls and could favourably modify attainment of
peak bone mass.
PMID- 9390051
TI - Birth defects in infants conceived by intracytoplasmic sperm injection: an
alternative interpretation.
AB - OBJECTIVE: To test the hypothesis that liveborn infants conceived by
intracytoplasmic sperm injection are at an increased risk of having a major birth
defect. DESIGN: Reclassification of the birth defects reported in infants born
after intracytoplasmic sperm injection in Belgium and comparison with prevalence
estimated in Western Australian population by means of same classification
system. SETTING AND SUBJECTS: 420 liveborn infants who were conceived after
intracytoplasmic sperm injection in Belgium and 100,454 liveborn infants in
Western Australia delivered during the same period. MAIN OUTCOME MEASURES:
Estimates of birth prevalence of birth defects and comparisons of odds ratios
between cohort conceived after intracytoplasmic sperm injection and Western
Australian infants. RESULTS: Infants born after intracytoplasmic sperm injection
were twice as likely as Western Australian infants to have a major birth defect
(odds ratio 2.03 (95% confidence interval 1.40 to 2.93); P = 0.0002) and nearly
50% more likely to have a minor defect (1.49 (0.48 to 4.66); P = 0.49). Secondary
data-led analyses, to be interpreted with caution, found an excess of major
cardiovascular defects (odds ratio 3.99), genitourinary defects (1.33), and
gastrointestinal defects (1.84), in particular cleft palate (5.11) and
diaphragmatic hernia (7.73). CONCLUSIONS: These results do not confirm the
apparently reassuring results published by the Belgian researchers of
intracytoplasmic sperm injection. Further research is clearly required.
Meanwhile, doctors practising intracytoplasmic sperm injection should bear this
alternative interpretation in mind when they counsel couples and obtain informed
consent for the procedure.
PMID- 9390053
TI - Variation in management of small invasive breast cancers detected on screening in
the former south east Thames region: observational study.
AB - OBJECTIVE: To examine the variation in surgical and adjuvant treatment of breast
cancer of known histology and detected on screening in a large cohort of patients
treated by the surgeons of a health region. DESIGN: Part prospective, part
retrospective observational study using the databases of a region's breast
screening programme and of the cancer registry. SETTING: The former South East
Thames region. SUBJECTS: 600 women aged 49-79 who presented during 1991-2 with
invasive breast cancer up to 20 mm in diameter that had been detected on
screening. These patients were treated by 35 surgeons. MAIN OUTCOME MEASURES:
Mastectomy rate by surgeon and the use of adjuvant treatment (radiotherapy,
tamoxifen, and chemotherapy) were compared with risk factors, tumour grade,
resection margins, and axillary node status. RESULTS: The mastectomy rate varied
between nil and 80%, although the numbers at these extremes were small (0/13 v
8/10). Surgeons operating on more than 20 such cases had a lower mastectomy rate
(15%) than surgeons treating fewer cases (23%), but this difference was
confounded by variation in casemix. There were also wide variations in mastectomy
rates and in axillary sampling rates that were independent of casemix or
caseload. There was broad agreement on the use of adjuvant tamoxifen (94%), but
few patients received chemotherapy (2.5%). 78 patients (19%) did not receive
radiotherapy, including 51 out of 317 patients with unfavourable tumours, and 26
patients did not receive tamoxifen. Whether the patient received adjuvant
treatment was more dependent on referral by the surgeon than the risk factors for
local recurrence and was independent of caseload. CONCLUSION: Mastectomy rates
for similar tumours vary widely by surgeon independently of casemix or caseload,
but surgeons with a higher caseload tend to have a lower mastectomy rate.
Omission of postoperative radiotherapy or tamoxifen after conservative treatment
is not related to risk factors for local recurrence or caseload. Confidential
feedback of treatment profiles to individual surgeons has been used, but when
benefit has been established treatment should be guided by evidence based
protocol.
PMID- 9390054
TI - Is the SF-36 a valid measure of change in population health? Results from the
Whitehall II Study.
AB - OBJECTIVE: To measure within-person change in scores on the short form general
health survey (SF-36) by age, sex, employment grade, and disease status. DESIGN:
Longitudinal study with a mean of 36 months (range 23-59 months) follow up, with
screening examination and questionnaire to detect physical and psychiatric
morbidity. SETTING: 20 civil service departments originally located in London.
PARTICIPANTS: 5070 male and 2197 female office based civil servants aged 39-63
years. MAIN OUTCOME MEASURES: Change in the eight scales of the SF-36 (adjusted
for baseline score and length of follow up) and effect sizes (adjusted change
standard deviation of differences). RESULTS: Within-person declines (worsening
health) with age were greater than estimated by cross sectional data alone.
General mental health showed greater declines among younger participants (P for
linear trend < 0.001). Employment grade was inversely related to change; lower
grades had greater deteriorations than higher grades (P < 0.001 for each scale in
men; P < 0.05 for each scale in women except general health perceptions and role
limitations due to physical problems). The greatest declines were seen among
participants with disease at baseline, with the effects of physical and
psychiatric morbidity being additive. Effect sizes ranged from 0.20 to 0.65 in
participants with both physical and psychiatric morbidity. CONCLUSIONS: Health
functioning, as measured by the SF-36, changed in hypothesised directions with
age, employment grade, and disease status. These changes occurred within a short
follow up period, in an occupational, high functioning cohort which has not been
the subject of intervention, suggesting that the SF-36 is sensitive to changes in
health in general populations.
PMID- 9390055
TI - Deficient colour vision and interpretation of histopathology slides: cross
sectional study.
AB - OBJECTIVE: To determine whether histopathologists with deficient colour vision
make more errors in slide interpretation than those with normal colour vision.
DESIGN: Examination of projected transparencies of histopathological slides under
standardised conditions by subjects whose colour discriminating ability was
accurately assessed. SETTING: Departments of histopathology in 45 hospitals in
the United Kingdom. SUBJECTS: 270 male histopathologists and medical laboratory
scientific officers. MAIN OUTCOME MEASURES: Number of slides correctly identified
by subjects whose colour vision was measured on the Ishihara, City University,
and Farnsworth-Munsell 100 hue tests. RESULTS: Mean (SD) scores (out of 10) for
doctors with colour deficient vision were 9.4 (0.7) v 9.9 (0.4) for controls (P <
0.01) and 7.5 (1.6) v 9.4 (0.7) for scientific officers (P < 0.001). When
subjects with colour deficient vision were categorised into severe, moderate, or
mild, there was a significant trend towards those with severe deficiency making
more mistakes (P < 0.001). CONCLUSIONS: Histopathologists and medical laboratory
scientific officers should have their colour vision tested; if they are found to
have a severe protan or deutan deficiency, they should be advised to adopt a safe
system of working.
PMID- 9390056
TI - Prevalence of HIV-1 infection among heterosexual men and women attending
genitourinary clinics in Scotland: unlinked anonymous testing.
PMID- 9390057
TI - Omeprazole, H2 blockers, and polyarthralgia: case-control study.
PMID- 9390058
TI - Challenges in managing dyspepsia in general practice.
PMID- 9390059
TI - Science, medicine, and the future. Gene therapy.
PMID- 9390060
TI - ABC of palliative care. Constipation and diarrhoea.
PMID- 9390061
TI - Why are doctors ambivalent about patients who misuse alcohol?
PMID- 9390063
TI - More widespread public debate on rationing is essential.
PMID- 9390062
TI - Women's health. The childbearing years and after.
AB - Health and development planners have tended to see women primarily in context of
their reproductive role. As a result, solutions to women's health needs have been
restricted to expanding and improving maternal and child health systems. There
has recently been a major shift in direction, largely because of the influence of
the world conference on population and development held in Cairo in 1994. Dr
Guiseppe Benagiano, director of the special programme of research, development
and research training in human reproduction based at the WHO, says, "We need to
remind ourselves constantly that reproductive health is not simply a biomedical
issue but one with serious implications for our general health and by extension,
for all our efforts in human social and economic development." The 1993 world
development report on health identified the lack of a clear strategy for engaging
women in health care and suggested that child health services, prenatal care,
treatment of sexually transmitted diseases, and family planning services should
be provided jointly at convenient times. In an example of this, the Chilean
Institute of Reproductive Medicine now offers integrated family planning services
at the same time as child health services, and Thailand is experimenting with
mobile health clinics to reach women in their homes. As the proportion of elderly
women increases, old age is increasingly being seen as a female issue. With the
impact of urbanisation and industrialisation, more of these women are living
isolated lives, often suffering from chronic debilitating diseases. In his
opening statement to the global commission on women's health in April 1995 which
focused on health conditions of women in old age, Dr Hiroshi Nakajima, the WHO's
director general, said: "Our goal should not be solely to extend lives in the
physical sense, but to ensure that the added years are worth living."
PMID- 9390064
TI - Patient's assessments of disability in multiple sclerosis. Most patients have
difficulty in rating themselves on visual analogue scales.
PMID- 9390065
TI - Screening people with a family history of cancer. Benefit of screening for
ovarian cancer is unproved.
PMID- 9390066
TI - Screening people with a family history of cancer. Taking a family history in
primary care is important.
PMID- 9390067
TI - Unsupervised surgical training. Logbooks are essential for assessing progress.
PMID- 9390068
TI - Unsupervised surgical training. Surgical training teaches surgical method,
surgical anatomy, and operative skills.
PMID- 9390069
TI - Unsupervised surgical training. Other specialties can learn from level of
supervision of surgical training.
PMID- 9390070
TI - Discontinuation of cervical spine immobilisation. Immobilisation should not be
discontinued in unconscious patients.
PMID- 9390071
TI - Discontinuation of cervical spine immobilisation. In children, cord injury may be
present despite normal radiographic appearances.
PMID- 9390072
TI - Resuscitation. New advisory statements on life support have been published.
PMID- 9390073
TI - Resuscitation. Resuscitation Council (UK) wants everyone who uses new recovery
position to report experiences.
PMID- 9390074
TI - Study to predict which elderly patients will fall shows difficulties in deriving
and validating a model.
PMID- 9390075
TI - Determining precise role of ethnicity in disease will be difficult.
PMID- 9390077
TI - New connections between medical knowledge and patient care. Intervention of
health professionals acts as an inductance, not as a resistor.
PMID- 9390076
TI - New connections between medical knowledge and patient care. Human condition is
full of decisions that aren't simple yes/no decisions.
PMID- 9390078
TI - New connections between medical knowledge and patient care. Patients in most need
of medical attention are least able to operate computers.
PMID- 9390079
TI - New connections between medical knowledge and patient care. Information
technology has much to offer certain aspects of health care.
PMID- 9390080
TI - General practitioners want to know whether a treatment works and is safe in
practice.
PMID- 9390081
TI - Pigeon fancier's lung. Current methodology is not sensitive enough to monitor
effectiveness of avoidance measures.
PMID- 9390082
TI - Pigeon fancier's lung. Pigeon racers will not want to reduce time spent in lofts.
PMID- 9390083
TI - Changing face of ectopic pregnancy. Medical treatment of ectopic pregnancy
preserves reproductive potential.
PMID- 9390084
TI - Changing face of ectopic pregnancy. Each centre should validate diagnostic
algorithms for its own patients.
PMID- 9390085
TI - Anaesthetists in Poland are on hunger strike.
PMID- 9390086
TI - If a wound is "neatly incised" it is not a laceration.
PMID- 9390087
TI - Multidrug resistant tuberculosis and HIV: a personal experience.
PMID- 9390088
TI - Understanding deaf and hard-of-hearing patients.
PMID- 9390089
TI - Different viewpoints on medical abortion.
PMID- 9390090
TI - Different viewpoints on medical abortion.
PMID- 9390091
TI - Different viewpoints on medical abortion.
PMID- 9390092
TI - Different viewpoints on medical abortion.
PMID- 9390093
TI - Venlafaxine.
PMID- 9390094
TI - Practical guidelines for antepartum fetal surveillance.
AB - Antepartum fetal assessment is used in pregnancies at high risk for perinatal
morbidity and mortality. Current testing options include the fetal movement
count, the nonstress test, the contraction stress test and the biophysical
profile. Vibroacoustic stimulation is a useful adjunctive procedure. All of these
modalities have limitations. A strict protocol for antepartum fetal surveillance
that is applicable to all patients is not possible. However, a testing approach
based on general principles and guidelines can be followed.
PMID- 9390095
TI - Common cardiovascular problems in the young: Part II. Hypertension,
hypercholesterolemia and preparticipation screening of athletes.
AB - Blood pressure should be measured during health maintenance visits in all
children three years of age and older. Cholesterol levels should be obtained in
children with a family history of hypercholesterolemia or premature coronary
artery disease and in children with other risk factors, such as hypertension,
smoking or obesity. Preparticipation screening for sports participation should
include a detailed questionnaire regarding the athlete's personal or family
history of syncope, sudden death or arrhythmia, as well as measurement of blood
pressure, auscultation of the heart and evaluation of upper and lower extremity
pulses.
PMID- 9390096
TI - Behavioral and pharmacologic treatment of delirium.
AB - Delirium is an acute confusional state with a fluctuating course. Since the
syndrome of delirium is associated with derangements of cognition, attention and
level of consciousness, it can cause behaviors that are difficult to manage.
Hallucinations, agitation, insomnia and anxiety are common in the delirious
patient. Behavioral and pharmacologic interventions can be used while the
underlying etiology of delirium is sought. Nonpharmacologic measures include
frequent reassurance, environmental cues to reorient the patient and the
judicious use of physical restraints. Haloperidol, which has negligible
anticholinergic effects, is the drug most often used to treat the symptoms of
delirium. Short-acting benzodiazepines may be useful in patients with delirium
caused by alcohol withdrawal, but these agents may cause increased agitation in
elderly patients and patients with hepatic dysfunction.
PMID- 9390097
TI - Guidelines on the care of diabetic nephropathy, retinopathy and foot disease.
AB - Diabetes mellitus is a common disease frequently managed by family physicians.
Because of its high prevalence and associated comorbidity, diabetes mellitus has
received a great deal of attention from several specialty organizations. The
American Diabetes Association, the American Board of Family Practice and the
Centers for Disease Control and Prevention have published specific practice
guidelines and recommendations for the care of diabetic patients. These
recommendations include annual comprehensive foot examinations, yearly
ophthalmologic screening for retinopathy, and urinalysis for microalbuminuria.
The use of angiotensin converting enzyme inhibitors is advocated for the majority
of diabetic patients with proteinuria or hypertension. Based on recent evidence,
improved glycemic control is also increasingly advocated. Compliance with
practice guidelines by primary care physicians has historically been poor.
Mechanisms such as the use of patient problem lists and diabetic flow sheets can
serve as reminders to physicians and can facilitate closer adherence to practice
guidelines.
PMID- 9390098
TI - Drug treatment of migraine: Part I. Acute therapy and drug-rebound headache.
AB - Most migraine patients need only abortive treatment for their headaches. By the
time they present to a physician, they have already tried many over-the-counter
medications for headache relief. Prioritizing treatment according to headache
severity and associated symptoms will help the physician determine the most
appropriate medications to use. Narcotics should be reserved for use only in
patients unresponsive to adequate trials of non-narcotic agents. In some
patients, the recurrent nausea and vomiting can be as disabling as the pain;
antiemetic agents are an important adjunct to analgesic therapy in these
patients. Sumatriptan and dihydroergotamine are more expensive than other
migraine agents but have distinct therapeutic advantages in patients with
moderate to severe headaches. Some patients experience rebound headache from
overuse of analgesics and other headache medications. Educating patients about
self-help measures and avoidance of triggers is an important element in the
effective management of migraine headaches.
PMID- 9390099
TI - Issues to consider in deaf and hard-of-hearing patients. The Committee on
Disabilities of the Group for the Advancement of Psychiatry.
AB - Successful interaction with patients who are deaf or hard of hearing requires an
understanding of background issues, including the significance of the age of
onset of deafness, the patient's choice of language, the patient's cultural
identification and educational history, and the type of hearing loss. All of
these factors should influence the physician's interview techniques and use of
resources.
PMID- 9390100
TI - Effect of maternal HIV-1 disease on infant outcome.
PMID- 9390101
TI - ADA recommends a lower fasting glucose value in the diagnosis of diabetes
mellitus.
PMID- 9390102
TI - UCSF creates Web site for information on HIV/AIDS.
PMID- 9390103
TI - Computational results may depend on personal computer processor.
PMID- 9390104
TI - Apparent decrease in population clearance of theophylline: implications for
dosage.
AB - BACKGROUND: Having observed in recent years that the theophylline dose
requirements needed to attain peak serum concentrations of 10 to 20 micrograms/ml
infrequently reached previously described mean values, we hypothesized that a
downward shift in the range of dose requirements had occurred among patients with
asthma. STUDY DESIGN: We examined dosage requirements needed to attain peak serum
concentrations of 10 to 20 micrograms/ml in all patients with chronic asthma
treated with theophylline by the Pediatric Allergy and Pulmonary Clinic at the
University of Iowa from 1990 to 1994 (n = 300) and at the Pediatric Pulmonary
Clinic at the University of Florida from 1992 to 1995 (n = 93). We then compared
these doses to previous dose requirements from 1978 to 1983 determined in the
same manner. RESULTS: Despite similar mean peak serum concentrations during both
time periods (14 micrograms/ml), mean theophylline dosage requirements during the
period of this study were approximately 25% lower among all age groups than those
previously observed (p < 0.001). There were no significant differences in mean
dosage requirements between the Iowa and Florida patients in any age group
examined. CONCLUSIONS: Theophylline dose requirements needed to attain serum
concentrations of 10 to 20 micrograms/ml have decreased significantly from those
on which current dosing recommendations are based. This suggests a decrease in
mean clearance of the population.
PMID- 9390105
TI - Influence of stiripentol on cytochrome P450-mediated metabolic pathways in
humans: in vitro and in vivo comparison and calculation of in vivo inhibition
constants.
AB - OBJECTIVE: The spectrum of cytochrome P450 inhibition of stiripentol, a new
anticonvulsant, was characterized in vitro and in vivo. METHODS: Stiripentol was
incubated in vitro with (R)-warfarin, coumarin, (S)-warfarin, (S)-mephenytoin,
bufuralol, p-nitrophenol, and carbamazepine as probes for CYPs 1A2, 2A6, 2C9,
2C19, 2D6, 2E1, and 3A4, respectively. Caffeine demethylation and the 6 beta
hydroxycortisol/cortisol ratio were monitored in vivo before and after 14 days of
treatment with stiripentol as measures of CYP1A2 and CYP3A4 activity, and
dextromethorphan O- and N-demethylation were used to measure CYP2D6 and CYP3A4
activity, respectively. In vivo inhibition constants for CYP3A4 were calculated
with use of data that previously documented the interaction between stripentol
and carbamazepine. RESULTS: In vitro, stiripentol inhibited CYPs 1A2, 2C9, 2C19,
2D6, and 3A4, with inhibition constant values at or slightly higher than
therapeutic (total) concentrations of stiripentol, but it did not inhibit CYPs
2A6 and 2E1 even at tenfold therapeutic concentrations. In vivo inhibition of
caffeine demethylation and dextromethorphan N-demethylation were consistent with
inhibition of CYP1A2 and CYP3A4, respectively. The 6 beta
hydroxycortisol/cortisol ratio did not provide a reliable index of CYP3A4
inhibition. Inhibition of CYP2D6-mediated O-demethylation was not observed in
vivo. With use of carbamazepine, in vivo inhibition constants for CYP3A4 ranged
between 12 and 35 mumol/L, whereas the corresponding in vitro value was 80
mumol/L. CONCLUSIONS: Stiripentol appears to inhibit several CYP450 enzymes in
vitro and in vivo. In vivo inhibition constants show that stiripentol inhibition
of CYP3A4 is linearly related to plasma concentration in patients with epilepsy.
PMID- 9390106
TI - Impact of long-term ethanol consumption on CYP1A2 activity.
AB - Ethanol is a well-known inducer of CYP2E1; whether or not it is an inducer of
other cytochromes has not been investigated systematically. The aim of our study
was to evaluate the impact of ethanol consumption on the activity of CYP1A2,
which has been shown to be influenced by drugs (inhibited or induced). We
evaluated CYP1A2 activity by the ratio of the molar urinary concentrations of the
three end products of paraxanthine demethylation of caffeine to the molar
concentration of a paraxanthine 8-hydroxylation product. This urinary metabolite
ratio has previously been shown to correlate with caffeine clearance. The
caffeine metabolites were measured in urine collected during the 3 hours after
oral administration of 200 mg caffeine. The caffeine test was performed in 12
smokers (> 25 cigarettes/day) and 12 nonsmokers, all of whom were alcoholic
inpatients (daily intake > 100 mg absolute ethanol), within the first 3 days of
their hospital stay and after 14 days of abstinence from ethanol. In alcoholic
patients who were smokers the molar urinary concentration ratio was 3.14 +/- 0.97
before withdrawal and 4.01 +/- 0.92 after 14 days of abstinence from ethanol. In
contrast, in alcoholic patients who were nonsmokers it was 2.62 +/- 0.95 and 2.18
+/- 0.96 before and after withdrawal, respectively. In volunteers who were
smokers the molar urinary concentration ratio was 5.02 +/- 1.51, whereas in
volunteers who were nonsmokers it was 3.22 +/- 1.46. Our results confirm the well
known induction of CYP1A2 activity by tobacco smoking and show that this
induction is masked by long-term ethanol consumption.
PMID- 9390107
TI - Itraconazole increases plasma concentrations of quinidine.
AB - BACKGROUND: Quinidine is eliminated mainly by CYP3A4-mediated metabolism.
Itraconazole interacts with some but not all of the substrates of CYP3A4; it is
therefore important to study the possible interaction of itraconazole with
quinidine. METHODS: A double-blind, randomized, two-phase crossover study design
was used with nine healthy volunteers. Itraconazole (200 mg) or placebo was
ingested once a day for 4 days. A single 100 mg oral dose of quinidine sulfate
was ingested on day 4. Plasma concentrations of quinidine, itraconazole, and
hydroxyitraconazole, as well as cumulative excretion of quinidine into urine,
were determined up to 24 hours. The ECG, heart rate, and blood pressure were also
recorded up to 24 hours. RESULTS: On average the peak plasma concentration of
quinidine increased to 1.6-fold (p < 0.05), and the area under the concentration
time curve of quinidine increased to 2.4-fold (p < 0.01) by itraconazole. The
elimination half-life of quinidine was prolonged 1.6-fold (p < 0.001), and the
area under the 3-hydroxyquinidine/quinidine ratio-time curve decreased to one
fifth (p < 0.001) by itraconazole. The renal clearance of quinidine decreased 50%
(p < 0.001) by itraconazole, whereas the creatinine clearance was unaffected. The
QTc interval correlated with the concentrations of quinidine during both
itraconazole and placebo phases (r2 = 0.71 and r2 = 0.79, respectively; p <
0.01), although only minor changes between the phases were observed in other
pharmacodynamic variables. CONCLUSIONS: Itraconazole increases plasma
concentrations of oral quinidine, probably by inhibiting the CYP3A4 isozyme
during the first-pass and elimination phases of quinidine. The decreased renal
clearance of quinidine might be the result of the inhibition of P-glycoprotein
mediated tubular secretion of quinidine by itraconazole. The concentrations of
quinidine should be closely monitored if itraconazole or some other potent CYP3A
inhibitors are used with quinidine.
PMID- 9390108
TI - Population pharmacokinetics of riluzole in patients with amyotrophic lateral
sclerosis.
AB - OBJECTIVES: To characterize the population pharmacokinetic of riluzole in
patients with amyotrophic lateral sclerosis (ALS). METHODS: One hundred patients
with ALS who were participating in a multicenter phase III dose-ranging trial of
riluzole were sampled on 179 visits. The sampling strategy (two samples per
visit) was varied across patients to define the population kinetic profile (full
screen). Riluzole plasma levels were determined by HPLC, and the data were
analyzed by nonlinear mixed-effect modeling (NONMEM program) with use of a one
compartment structural model. The model incorporated interoccasion (visit-to
visit) variability. RESULTS: In the basic one-compartment pharmacokinetic model,
interindividual variability in plasma clearance (51.4%) was higher than
intraindividual (visit-to-visit) variability (28.0%), indicating uniform
pharmacokinetic behavior during long-term therapy. Riluzole clearance was
independent of dosage (25 to 100 mg twice daily), treatment duration (up to 10
months), age, and renal function; gender and smoking were the most important
patient covariates, with hepatic function having lesser influence. Typical value
of clearance was 51.4 L/hr for a nonsmoking male patient. It was 32% lower in
women than in men and 36% lower in nonsmokers than in smokers. Gender- and
smoking-related variations in riluzole exposure at the recommended dosage (50 mg
twice daily) were within the range of exposures achieved (with no untoward
effect) in this dose-ranging study. CONCLUSION: The pharmacokinetics of riluzole
has been characterized in patients during long-term therapy. Riluzole clearance
is independent of dose and treatment duration. Within-patient variability is low.
Gender and smoking status are the main covariates to explain interpatient
variability.
PMID- 9390109
TI - Mephenytoin disposition and serum bile acids as indices of hepatic function in
chronic viral hepatitis.
AB - BACKGROUND AND OBJECTIVES: The effect of chronic viral hepatitis on liver
function may vary from none to hepatic failure. Changes in function are usually
the result of impaired hepatocyte function or altered vascular flow and
architecture. Conventional liver function tests usually cannot distinguish
contributions from these mechanisms or indicate degree of hepatic metabolic
dysfunction. An alternative approach is to measure the hepatic metabolism of a
highly extracted compound whose oral clearance and systemic bioavailability are
dependent on both hepatocyte function and degree of portosystemic shunt. METHODS:
The stereoselective metabolism of racemic mephenytoin (100 mg oral dose) was
investigated in 35 patients with chronic viral hepatitis and compared with 153
healthy subjects. The mephenytoin R/S enantiomeric ratio and cumulative excretion
of the 4'-hydroxymephenytoin metabolite in a 0- to 8-hour urine sample were used
in addition to serum bile acid levels and pathologic examination of biopsy
specimens to assess the severity of hepatic dysfunction and portosystemic
shunting. RESULTS: The patients as a group excreted less 4'-hydroxymephenytoin
and had a smaller R/S enantiomeric ratio of mephenytoin. The two measures were
discriminatory between the patient groups classified by either serum
cholylglycine level or pathologic examination of biopsy specimens. Combination of
the two measures of mephenytoin metabolism allowed the patients to be classified
into three groups: normal hepatocyte function without portosystemic shunt, normal
hepatocyte function with portosystemic shunt, and low hepatocyte function with or
without portosystemic shunt. CONCLUSION: This study has shown the potential
usefulness of mephenytoin metabolism as a sensitive indicator of hepatic
pathologic condition with an ability to discriminate between contributory
alternative mechanisms.
PMID- 9390110
TI - Lack of cross-tolerance to short-term linsidomine in forearm resistance vessels
and dorsal hand veins in subjects with nitroglycerin tolerance.
AB - BACKGROUND: Therapy with nitroglycerin is widely used in the treatment of angina
pectoris, but development of tolerance is a major problem. Nitrovasodilators
other than nitroglycerin may be less prone to induce vascular tolerance. This
investigation was designed to test whether the alternative nitric oxide donor
linsidomine maintains its vasodilator effects in the presence of nitroglycerin
tolerance. METHODS: We tested the vascular effects of nitroglycerin and
linsidomine (SIN-1) in forearm resistance arteries (venous occlusion
plethysmography) and hand veins (venous compliance technique) using a randomized,
double-blind placebo-controlled regimen in 33 healthy subjects (age range, 22 to
38 years; mean age, 26 years) before and after 7 days of assignment to either 1
week of nitroglycerin administration (0.83 mg/hr) for induction of tolerance or
placebo administration. RESULTS: Vascular responses of both vascular beds to
nitroglycerin (in veins: mean difference, 42.3%; confidence interval [CI], 3% to
81.7%; p < 0.05; in arteries: mean difference, 65.0%; CI, 38.9% to 91.1%; p <
0.01) but not to linsidomine (in veins: mean difference, -13.8%; CI, -53.5 to
25.8%; not significant; in arteries: -19.7%; CI, -33.7% to -5.6%; not
significant) were attenuated in the nitroglycerin patch group, whereas the
placebo group showed no differences to either nitroglycerin (in arteries: mean
difference, -7.5%; CI, -44.6% to 29.6%; in veins: -10.6%; CI, -58.2% to 36.9%) or
linsidomine (in arteries: 4.5%; CI, -12.8% to 21.7%; in veins: -13.1%; CI, -4.5%
to 29.8%). CONCLUSION: These results suggest that short-term administration of
sydnonimines can overcome the loss of vascular relaxation associated with long
term nitroglycerin therapy.
PMID- 9390111
TI - Clinical pharmacodynamics of SDZ HTF 919, a new 5-HT4 receptor agonist, in a
model of slow colonic transit.
AB - OBJECTIVES: To explore the pharmacodynamic effects of the new promotile agent SDZ
HTF 919, a selective partial 5-HT4 receptor agonist, in healthy subjects.
METHODS: A pharmacodynamic model was applied to prolong colonic transit by
dietary means. Subsequently, the effects of twice-daily multiple doses of SDZ HTF
919 (1, 5, 25, and 100 mg) were investigated in a randomized, double-blind,
placebo-controlled parallel-group study with 12 subjects per dose level. The
sequential design with three study periods of 7 days each included intake of a
self-selected diet, a liquid formula diet with soluble fiber supplementation, and
a fiber-supplemented diet together with either SDZ HTF 919 or placebo
administration. Stool characteristics (frequency and consistency) and total
colonic transit times (with use of radiopaque markers) were recorded in each
study period. RESULTS: SDZ HTF 919 was well tolerated at all dose levels. The
frequency of loose stool and headache increased with higher doses. After a fiber
supplemented diet intake, the median stool frequency decreased from 8 1/2-9 to 5
7 defecations per study period. SDZ HTF 919 in doses of 25 and 100 mg twice a day
increased the stool frequency (p < 0.05). Stool consistency was softened by all
but the lowest SDZ HTF 919 dose. A fiber-supplemented diet prolonged total
colonic transit time in all groups by 45 hours on average. Twice-a-day
administration of SDZ HTF 919 for 6 days in addition to a fiber-supplemented diet
significantly shortened the total colonic transit time only at the 5 mg dose. The
lack of effect at lower and higher SDZ HTF 919 doses suggests a biphasic dose
response relationship for total colonic transit time. CONCLUSIONS: The
suitability of total colonic transit time measurements in healthy subjects as a
surrogate marker should be confirmed by patient studies.
PMID- 9390112
TI - Dose-related protection of exercise bronchoconstriction by montelukast, a
cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing
interval.
AB - The dose-related protective effects of montelukast, a potent and selective
cysteinyl leukotriene-receptor antagonist, against exercise-induced
bronchoconstriction were investigated in a five-period, randomized, incomplete
block, crossover study with montelukast (0.4, 2, 10, 50 mg) and placebo. The
study subjects were 27 nonsmoking, healthy stable patients with asthma (mean
forced expiratory volume in 1 second [FEV1], 82.0% predicted) who demonstrated a
> or = 20% decrease in FEV1 while beta-agonist was withheld for 6 hours before
treadmill exercise. The standard exercise challenge was performed 20 to 24 hours,
and again 32 to 36 hours, after the second of two once-daily doses. The effect of
oral montelukast on exercise was measured by the area above the postexercise
percentage decrease in FEV1 versus time curve from 0 to 60 minutes [AUC(0-60)],
the maximal percentage decrease in FEV1 after exercise, and time after maximal
decrease to recovery of FEV1 to within 5% of the preexercise baseline. Twenty to
24 hours after administration, montelukast caused dose-related protection, while
providing similar protection against exercise-induced bronchoconstriction at the
two highest doses. The AUC(0-60) values (mean +/- SD) were 637 +/- 898, 715 +/-
870, 988 +/- 1147, and 927 +/- 968 min. % for 50, 10, 2, and 0.4 mg montelukast,
respectively, and 1193 +/- 1097 min. % for placebo (p = 0.003). No important
clinical effect was present 36 hours after dosing. Montelukast was generally well
tolerated at all dose levels. In conclusion, montelukast caused dose-related
protection against exercise-induced bronchoconstriction at the end of a once
daily dosing interval. Protection against exercise-induced bronchoconstriction
can be used to determine appropriate dose selection.
PMID- 9390113
TI - Dexamethasone down-regulates the expression of L-selectin on the surface of
neutrophils and lymphocytes in humans.
AB - OBJECTIVE: On the basis of previous animal studies, we hypothesized that
dexamethasone may reduce the expression of L-selectin on neutrophils and
lymphocytes in healthy men. METHODS: A double-blind, randomized, placebo
controlled, and three-way crossover trial was conducted in nine healthy men.
Every subject received four identical infusions of saline solution, 0.04 mg/kg
dexamethasone, or 1.0 mg/kg dexamethasone during three observation periods of 48
hours each. RESULTS: Dexamethasone time and dose dependently decreased the L
selectin expression on neutrophils and lymphocytes as measured by flowcytometry.
This effect occurred with a time lag of 8 hours after start of treatment: the L
selectin binding index of neutrophils decreased by a maximum of -50% (confidence
interval [CI], -37% to -63%) and that of lymphocytes by -26% (CI, -8% to -45%) at
32 hours after the start of treatment with high-dose dexamethasone (p < 0.016).
Low-dose dexamethasone had only a transient effect on L-selectin expression of
lymphocytes and a less pronounced effect on L-selectin expression of neutrophils.
CONCLUSION: Dexamethasone time and dose dependently decreases L-selectin
expression on neutrophils and lymphocytes in health men, an effect that is less
pronounced than that previously reported for animals.
PMID- 9390114
TI - Buprenorphine withdrawal syndrome in a newborn.
AB - A pregnant woman who was addicted to heroin rapidly withdrew from illicit drugs
after the onset of a 4 mg/day buprenorphine treatment. In the newborn's blood,
urine, and meconium 20 hours after birth, high concentrations of buprenorphine
and its metabolite norbuprenorphine were detected, with a higher
buprenorphine/norbuprenorphine ratio than in adults, possibly as a consequence of
immature hepatic function; no illicit drugs were found. The child had a weak
withdrawal syndrome on the second day of life and recovered rapidly. The measured
buprenorphine daily dose ingested by the newborn through mother's milk was very
low (3.28 micrograms) and probably had little pharmacologic effect because no
withdrawal signs could be noted when maternal feeding was later abruptly
interrupted. Further investigations are required to determine whether
buprenorphine can be considered to be a good alternative to methadone in the
treatment of pregnant heroin addicts to prevent marked withdrawal syndromes in
newborns.
PMID- 9390115
TI - Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of
CYP2C19.
AB - A patient who had taken a stable dose of phenytoin for 2 years had a coronary
stent placed for unstable angina and ticlopidine was added to his therapeutic
regimen. Twenty-five days later, he was hospitalized with acute symptomatic
phenytoin toxicity and a serum concentration of 46.5 micrograms/ml. Determination
of metabolic genotype revealed that the patient had a wild-type genotype for
CYP2C9, CYP2C19, and CYP2D6. Using human liver microsomes, we showed that
ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated
inhibition constant (Ki) of 3.7 +/- 0.2 mumol/L. The influence of ticlopidine on
CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is
relatively weak, with a calculated Ki of 38.8 +/- 27 mumol/L. These data suggest
that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by
ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism
of phenytoin.
PMID- 9390116
TI - Informing the public.
PMID- 9390117
TI - Toxicity of lidocaine desethyl metabolites.
PMID- 9390118
TI - Endoscopic ultrasound-guided fine needle aspiration.
PMID- 9390119
TI - Clinical utility of endoscopic ultrasound-guided fine needle aspiration.
AB - OBJECTIVE: To assess our institution's initial experience with the clinical
utility of endoscopic ultrasound (EUS)-guided fine needle aspiration. STUDY
DESIGN: Prospective analysis of the clinical utility of EUS-guided FNA. RESULTS:
Fifty-three patients underwent EUS-guided FNA of 64 sites, 28 for pancreatic
masses, 15 for lymph nodes, 10 for solid lesions, 7 for cystic masses, 2 for
submucosal masses and 2 for perigastrointestinal fluid. A cytopathologist was
present during all procedures. An average of four passes (range, one to nine) was
required to make a diagnosis in the 22 patients with pancreatic malignancies.
There was one possible complication among the 53 patients. In 36 of the 53
patients, the combination of diagnostic EUS findings and cytologic diagnosis made
a major change in the patient's management. CONCLUSION: Because of its ability to
affect patient management, EUS-guided FNA will become a more commonly used
procedure, especially at oncologic centers. Since the number of fine needle
passes needed for diagnosis is quite variable, it is important to have a
cytopathologist participate in these procedures.
PMID- 9390120
TI - Ultrasound-guided fine needle aspiration cytology of malignant gallbladder
masses.
AB - OBJECTIVE: To determine the accuracy and reliability of ultrasound (US)-guided
fine needle aspiration cytology (FNAC) over blind aspiration in gallbladder
masses. STUDY DESIGN: We performed FNAC in 107 cases of carcinoma of the
gallbladder; blind aspiration was done in 71 patients (66.36%) and US-guided
aspiration in 36 (33.64%). In cases where FNAC after the first aspiration showed
the aspirate to be inflammatory, acellular (inconclusive) or suspicious for
malignancy, FNAC was repeated under US guidance. Diagnosis was later confirmed by
histopathology in all cases. RESULTS: After the first aspiration, gallbladder
malignancy was confirmed in 77 (71.96%) cases. Of these 77 cases, 34 underwent US
guided aspiration, and the remaining 43 underwent blind aspiration. Cases with
inflammatory or acellular (inconclusive) aspirates or that were suspicious for
malignancy after the first aspiration underwent a second aspiration under
ultrasonic guidance. On the second aspiration of 30 cases, 16 (53.33%) proved to
be of adenocarcinoma, 7 (23.33%) were suspicious for malignancy, 5 (16.66%) were
inflammatory, and 2 (6.66%) were acellular. Diagnosis was later confirmed by
histopathology in all cases. US-guided FNAC had diagnostic accuracy of 95% as
compared to 60% on blind aspiration. There was no major complication or needle
tract recurrence of the disease. CONCLUSION: US-guided FNAC is safe, rapid,
reliable, cost-effective and accurate in diagnosing gallbladder carcinoma.
PMID- 9390121
TI - Identifying cytologic characteristics and grading endocervical columnar cell
abnormalities. A study aided by high-definition television.
AB - OBJECTIVE: To test the ability of cytotechnologists to recognize and accurately
interpret selected architectural, cellular and nuclear features presented on a
high-definition television (HDTV) and to make a reliable diagnosis with HDTV.
STUDY DESIGN: A total of 1,122 features considered diagnostic of different
endocervical columnar cell abnormalities were selected from 50 smears from 48
women with the help of a motor-driven-stage microscope by five observers who had
knowledge of the final diagnosis. The selected and stored features were presented
on an HDTV and evaluated in five successive sessions without knowledge of the
final diagnosis. RESULTS: Specific types of features were correctly identified in
a high number of cases. Considerable interobserver variability was demonstrated
in the scoring of grades of expression of features. Overrated and under-rated
monitor diagnoses were related to overvalued and undervalued features. From a
group of 437 images that were correctly diagnosed by four or five observers, five
features proved to be highly related to the correct diagnosis. CONCLUSION:
Observers were capable of making a reliable diagnosis on features, selected by
other observers, when presented on an HDTV. An overall correct diagnosis was made
in 93% of cases.
PMID- 9390122
TI - Atypical squamous cells of undetermined significance. A cytohistologic study of
52 cases.
AB - OBJECTIVE: To evaluate the significance of atypical squamous cells of
undetermined significance (ASCUS) by correlating the histologic findings
following a diagnosis of ASCUS on a cervical cytologic smear. STUDY DESIGN:
Eighty-four smears that had been called ASCUS over a five-month period and that
had corresponding histologic material were reviewed independently. Only 52 of the
84 cases on which a consensus was reached were retained for the current study.
RESULTS: The breakdown of the follow-up histologic diagnoses was as follows: 28
cases (54%) were negative (without squamous intraepithelial lesions [SIL]); 22
cases (42%) showed SILs, of which 14 (27%) were low grade, 5 (10%) were high
grade and 3 (5%) had SILs that could not be further classified because of
fragmentation of the endocervical curettings. Finally, two cases (4%) proved to
be invasive cervical carcinoma on histology despite smears that were satisfactory
and not limited by the quantity or quality of material; in these the discrepancy
was attributed to sampling error. CONCLUSION: Patients whose cervical cytologic
smears fall into the category of ASCUS may, on follow-up, exhibit a wide spectrum
of findings, ranging from no pathologic abnormality to frequent SIL and even to
invasive carcinoma in rare instances. A diagnosis of ASCUS on smears warrants
careful follow-up and investigation.
PMID- 9390123
TI - Cervical smear histories of 585 women with biopsy-proven carcinoma in situ.
AB - OBJECTIVE: To analyze the cervical cytologic smear history of women with
carcinoma in situ (CIS). STUDY DESIGN: We examined cytologic smears obtained
within the three-year period prior to a histologic diagnosis of CIS in 585 women
for whom at least one prebiopsy smear was available. RESULTS: Among 454 patients
with only one smear available for review, 9 (2%) had a negative cytologic
diagnosis, 58 (13%) had low grade squamous intraepithelial lesion (LSIL), and 387
(85%) had high grade squamous intraepithelial lesion (HSIL). One hundred thirty
one women had two to five smears taken within the previous three years available
for review. All the smears taken prior to biopsy showed HSIL. The original
diagnosis on the other smears was negative for 78 women (60%), HSIL for 46 (35%)
and LSIL for 7 (5%). ALl 132 smears originally classified as negative from 87 of
585 (14.8%) women were reviewed. Twenty-seven (20%) were then classified as
showing HSIL, 10 as LSIL, 10 as atypical squamous cells of undetermined
significance, 7 as unsatisfactory and 78 (59%) as remaining negative. CONCLUSION:
Of smears classified as negative and taken in the three years before biopsy
proven CIS, 41% were reclassified, with half reclassified as showing HSIL.
PMID- 9390124
TI - Wisconsin Cytology Proficiency Testing Program. Results of voluntary testing in
1994.
AB - OBJECTIVE: The Wisconsin Cytology Proficiency Testing Program (WCPTP) was
developed cooperatively by the Wisconsin State Laboratory of Hygiene, the
Wisconsin Society of Pathologists and the Wisconsin Society of Cytology to enable
pathologists and cytotechnologists in Wisconsin to meet Clinical Laboratory
Improvement Act of 1988 (CLIA '88) requirements for proficiency testing (PT).
STUDY DESIGN: A joint steering committee designed the WCPTP to comply with all
CLIA '88 regulations. The WCPTP application to the Health Care Financing
Administration received tentative approval in May 1994. In 1994, mock PT was
conducted at meetings of both state societies, and voluntary, on-site PT was
conducted at 19 laboratories. RESULTS: Each of the 119 participants (49
pathologists, 70 cytotechnologists) was tested with sets of 10 glass slides, each
representing one of four specified categories: A, unsatisfactory; B,
normal/benign; C, low grade squamous intraepithelial lesion; and D, high grade
squamous intraepithelial lesion and cancer. The failure rate for pathologists was
22.5% (11/49) and for cytotechnologists, 1.4% (1/70). The CLIA '88 scoring system
for pathologists is more stringent. If cytotechnologists were scored as
pathologists, 10% (7/70) would have failed. Using the cytotechnologist grid,
14.5% (7/49) of the pathologists would have failed. CONCLUSION: This voluntary
program provided some preliminary insights into the issues related to PT
evaluation of personnel competence and diagnostic criteria.
PMID- 9390125
TI - Cervical cytologic smear false negative fraction. Reduction in a small community
hospital.
AB - OBJECTIVE: To determine the false negative fraction (FNF) at a small community
hospital and its relation to the discovery of a significant error. STUDY DESIGN:
All cervical cytologic smears (6,889) initially interpreted over a one-year
period (1992) as "normal" or "near normal" were retrospectively rescreened and
interpreted by outside institutions, without knowledge of the initial
interpretation, to calculate yearly and quarterly FNFs. RESULTS: The overall FNF
for 1992 was 12.3% and was 19.1%, 22.2%, 3.8% and 6.1% per successive quarters in
1992. A significant error was discovered at the start of the third quarter that
subsequently received both local and national media attention. CONCLUSION: This
study gives further proof that the FNF can be reduced to < 5% by motivated
cytotechnologist/ pathologist teams, although it may not be possible to maintain
this low an FNF.
PMID- 9390126
TI - False positive cervicovaginal cytology. A follow-up study.
AB - OBJECTIVE: To determine what percentage of cervical cytologic diagnoses initially
classified as false positives (based on a negative cervical biopsy within three
months of the cervical cytologic smear) are recategorized as histologic false
negatives when subsequent studies reveal abnormalities. STUDY DESIGN: A three
year review of 1,242 cervicovaginal biopsies with corresponding cytology in the
preceding three months revealed 68 cases (5.5%) where the cytology was positive
for a squamous intraepithelial lesion but the biopsy was within normal limits or
showed benign cellular changes. Follow-up cytologic and/or histologic diagnoses
were obtained for 53 of the 68 cases from the patients' hospital and physician
office records. RESULTS: Of the 53 cases with follow-up, 24 (45%) were found to
have a subsequent squamous intraepithelial lesion (indicating a sampling error at
the time of the initial biopsy), and 9 showed atypical squamous cells of
undetermined significance. In addition, 9 of the 20 patients (45%) who had
negative follow-up studies had benign abnormalities on the initial,
noncorrelating biopsy that may have contributed to the discrepancy. CONCLUSION:
This study emphasized the importance of diligent follow-up of patients with
noncorrelating studies since they represent a population at high risk for the
subsequent detection of premalignant conditions.
PMID- 9390127
TI - Glandular cells in vaginal smears from posthysterectomy patients.
AB - OBJECTIVE: To assess the significance of nonatypical glandular cells in vaginal
smears from patients who had undergone total hysterectomy. STUDY DESIGN: Vaginal
smears with nonatypical glandular epithelium obtained from post-total
hysterectomy patients were identified in our files over a 4.5-year period. The
cytologic findings were correlated with the clinical data. RESULTS: Smears with
nonatypical glandular epithelium from 15 post-total hysterectomy patients were
identified, making this the largest series in the literature. The patients' mean
age was 59 years. Most patients (73%) had a history of gynecologic malignancy,
and 60% had received radiotherapy. All patients had a normal gynecologic
examination when the vaginal smear was obtained. None of the patients developed
recurrent or de novo vaginal adenocarcinoma. CONCLUSION: The presence of
nonatypical glandular epithelial cells in smears from total hysterectomy patients
is not indicative of adenocarcinoma.
PMID- 9390128
TI - Diagnostic role of testicular fine needle aspiration biopsy in male infertility.
AB - OBJECTIVE: To study the diagnostic role of fine needle aspiration biopsy (FNAB)
of the testis in male infertility. STUDY DESIGN: A retrospective study of 586
cases of infertile males with oligospermia and azoospermia. The material obtained
was stained with Diff-Quik. The proportion of Sertoli cells versus spermatogenic
cells was studied. RESULTS: Cytologic examination revealed normal spermatogenesis
in 10.2%, hypospermatogenesis in 31.4%, Sertoli cells only in 30.2% and an
atrophic pattern in 28.6%. CONCLUSION: The patterns recognized by FNAB were
comparable to those obtained by open biopsy. However, FNAB is less invasive, with
very few complications. The procedure was well tolerated by all patients. There
were very few complications. The findings of this study support the contention
that FNAB of the testis is a reliable, relatively noninvasive procedure that has
an important role in male infertility.
PMID- 9390129
TI - Cytomorphology of tyrosine-rich crystalloids in fine needle aspirates of salivary
gland adenomas.
AB - OBJECTIVE: To evaluate the presence of tyrosine-rich crystalloids (TRC) in fine
needle aspiration (FNA) specimens of pleomorphic adenomas of salivary gland.
STUDY DESIGN: FNA specimens from 12 patients were reviewed, and the percentage of
cases showing TRC was established. The staining properties of the TRC were
evaluated as well as spontaneous fluorescence under ultraviolet (UV) light.
RESULTS: Of the 12 pleomorphic adenomas, 4 showed TRC (30%) in the smears. Among
the eight cytologically negative cases there were two that showed a few TRCs on
histology. All positive cases were from African American patients. TRC stained
weakly with Papanicolaou stain. TRC were deep blue with Diff-Quik. They
fluoresced under UV light. CONCLUSION: TRC could be detected in FNA specimens.
They were best seen under UV light. The Papanicolaou technique stained TRC very
pale, making them difficult to see. Diff-Quik stained TRC dark blue, mimicking
deposits of dye. The amount of TRC in histology paralleled the detection rate in
cytology.
PMID- 9390130
TI - P53 protein expression and DNA ploidy in common epithelial tumors of the ovary.
AB - OBJECTIVE: To investigate p53 protein expression and DNA content in imprints from
surgical biopsies of common epithelial tumors of the ovary. STUDY DESIGN: The
study was based on 60 cases of epithelial tumors of the ovary (15 benign, 3
border-line and 42 malignant). For the demonstration of p53 protein,
immunocytochemical staining with the avidin-extravidin technique was performed
using monoclonal antibody p53 DO-7. DNA content was measured by image cytometry
after Feulgen staining. RESULTS: There was a strong correlation between p53
expression and aneuploidy, with the difference between diploid and aneuploid
tumors statistically significant (P < .001). A correlation was found between DNA
ploidy, histologic grade and clinical stage (P < .001 and P < .05), respectively.
There was no correlation between DNA ploidy and histologic type (P = .89). No
correlation was observed between p53 protein expression and grade or clinical
stage of the tumors. Nevertheless, a correlation of p53 expression between early
(I, II) and advanced stages (III, IV) (P < .05) was observed. All benign and
borderline tumors were diploid and did not express p53 protein. CONCLUSION: The
results of the present study and the data in the literature stress the value of
p53 expression and DNA ploidy in assessing the malignant potential of common
epithelial ovarian cancers. However, the clinical application of these data
requires further study.
PMID- 9390131
TI - Diagnostic value of p53 protein and flow cytometric DNA analysis in the study of
serous effusions.
AB - OBJECTIVE: To investigate the diagnostic value of p53 protein and DNA analysis in
the study of serous effusions. STUDY DESIGN: A total of 76 samples of serous
effusions were studied by immunohistochemistry for p53 protein and flow
cytometric (FCM) DNA analysis. The results were correlated with final cytologic
diagnoses, which were confirmed by immunohistochemistry using antibodies against
cytokeratin, carcinoembryonic antigen, epithelial membrane antigen and
fibronectin. RESULTS: Final cytologic diagnoses included 28 malignant effusions
and 48 benign effusions. No expression of p53 protein was seen in benign
effusions. In contrast, p53 protein expression was seen in 19/28 (sensitivity
68%) malignant effusions. FCM detected aneuploid cells in 12/28 (43% sensitivity)
of malignant and 0/46 of benign effusions. Immunohistochemical determination of
p53 protein combined with FCM DNA analysis increased sensitivity to 79%.
CONCLUSION: Immunohistochemical determination of p53 protein and FCM DNA analysis
can aid in making an accurate and specific diagnosis of serous effusions, but the
principal limitation of these tests is their relatively low sensitivity.
PMID- 9390132
TI - Nuclear grooves in ependymoma. Cytologic study of 21 cases.
AB - OBJECTIVE: To study the efficacy of crush preparation smears in the diagnosis of
ependymomas. STUDY DESIGN: The study group consisted of 21 patients aged 7-61
years. All were admitted to Shiraz University hospitals (Nemazi and Beheshti)
with intramedullary tumors. Fourteen were ventricular (fourth ventricle), 1 was
in the parietal lobe, 5 were in the lumbosacral region and 1 was in the cauda
equina. Intraoperative crush preparation smears were obtained from tissue, which
was sent for frozen section and diagnosed cytologically. The control group
consisted of 123 intracranial tumors (meningiomas, schwannomas, astrocytomas,
oligodendrogliomas, medulloblastomas, pituitary adenomas, choroid plexus
papilloma, craniopharyngioma and metastatic tumors). RESULTS: The smears in 11
cases revealed perivascular pseudorosettes, and the smears in 21 cases revealed
ependymal rosettes. Papillary clusters, calcification and intranuclear inclusions
were seen in two cases. Acinar structures were seen in seven cases. Myxomatous
material was seen in one case. Nuclear grooves were seen in 15 cases. All cases
were diagnosed as ependymomas. Biopsy specimens confirmed the cytologic
diagnosis. The tumors in the control group showed no evidence of nuclear grooves.
CONCLUSION: Fifteen cases of ependymoma showed a substantial number of nuclear
grooves. Intraoperative crush preparation smears were very useful in the
diagnosis of ependymomas and helped with the rapid interpretation of frozen
sections.
PMID- 9390133
TI - Urine cytology and the diagnosis of renal allograft rejection. I. Studies using
conventional staining.
AB - OBJECTIVE: To determine the reproducibility and validity of urine cytology for
the diagnosis of acute renal allograft rejection (AR). STUDY DESIGN: We conducted
a blind, prospective study of 10 renal allograft recipients. Freshly voided
aliquots of urine were obtained on each hospital day and at each outpatient visit
for a mean of 52.8 +/- 26.2 (SD) days following transplantation. The samples were
prepared by cytocentrifugation and then stained by a modified Papanicolaou
method. To determine interobserver reproducibility, the differential cell counts
of two blinded cytopathologists were compared. A cytodiagnosis of AR was made
when the urine sample contained < 55% neutrophils and > 20% lymphocytes. To
determine the validity of the cytology, the result was compared to the histologic
and clinical diagnoses. Biopsies were obtained one hour following vascular
anastomosis and at the time of graft dysfunction and were scored by two blinded
pathologists according to the Banff classification. The clinical diagnosis was
determined by a retrospective review conducted by four blinded clinicians.
RESULTS: The interoperator reading of urine cytology was more reproducible than
histology, with kappa values of 0.40 +/- 0.15 (SE) and 0.21 +/- 0.10 (SE),
respectively. Urine cytology was accurate for the diagnosis of AR, with a
sensitivity of 80% and a specificity of 96% as compared to the clinical and
histologic findings. CONCLUSION: Our observations support the claim that urine
cytology is useful for diagnosing AR.
PMID- 9390134
TI - Urine cytology and the diagnosis of renal allograft rejection. II. Studies using
immunostaining.
AB - BACKGROUND: Urine immunocytology may provide a noninvasive method of
investigating the antigens expressed by renal tubular cells. In previous
investigations of patients with acute renal allograft rejection (AR), we showed
that the adhesion molecule ICAM-1 is expressed by voided tubular cells. The up
regulation of ICAM-1, in turn, may be due to high circulating levels of
interferon-gamma and/or TNF-alpha. We investigated the regulation of receptors
for these cytokines and found a correlation between their expression and clinical
events. STUDY DESIGN: For 10 patients who received transplants consecutively,
freshly voided aliquots of urine were obtained on each hospital day and on each
outpatient visit for a mean of 52.8 +/- 26.2 (SD) days. After cytocentrifugation,
the samples were prepared by the avidin-biotin-immunoperoxidase technique in
order to detect the presence or absence of ICAM-1, interferon-gamma receptor and
TNF-alpha receptor (p 80) on the tubular cells. RESULTS: In nonrejecting
patients, the tubular cells expressed the interferon-gamma receptor but not ICAM
1 or the TNF-alpha receptor. In patients with AR, the pattern was different. The
tubular cells expressed ICAM-1 and the TNF-alpha receptor but not the interferon
gamma receptor. CONCLUSION: Urine immunocytochemistry may be useful to
demonstrate the expression of cytokine receptors by renal epithelia.
PMID- 9390135
TI - Stromal fragments in invasive carcinoma. Source of diagnostic difficulty in
aspiration cytology.
AB - OBJECTIVE: To analyze three cases of stromal fragments in invasive carcinoma that
created diagnostic difficulty in aspiration cytology. STUDY DESIGN: A
retrospective review of fine needle aspiration cytology (FNAC) smears of a breast
tumor, scalp tumor and neck mass. Cytomorphologic features of all the smears were
reviewed after histology became available. RESULTS: FNAC smears revealed a
biphasic pattern: a carcinomatous component and a stromal component that was
either discrete or in close apposition to the carcinoma. The cytopathologist had
suggested the diagnosis of a biphasic tumor in each case--phyllodes, malignant
skin adnexal and salivary gland tumor. Histopathology revealed an invasive
carcinoma with altered stroma in the first two cases and metastatic lymph node
with perinodal soft tissue extension in the third case. CONCLUSION: Stromal
changes in response to infiltrating carcinoma are well documented in surgical
pathology. However, these may also be encountered in FNAC smears. The above cases
stress the importance of recognizing stromal fragments in aspiration cytology in
order to avoid diagnostic errors.
PMID- 9390136
TI - Diagnosis of occult thyroid carcinoma by thyroid ultrasonography with fine needle
aspiration cytology.
AB - OBJECTIVE: To assess the role of ultrasonography and fine needle aspiration
cytology (FNAC) in preoperative diagnosis of patients with occult thyroid
carcinoma (OTC). STUDY DESIGN: Data on 768 thyroid carcinoma patients receiving
primary treatment at Chang Gung Medical Center were retrospectively reviewed. Of
these patients, 97 had OTC. To detect small thyroid nodules early and define the
characteristics of clinically palpable nodules, thyroid ultrasonography with FNAC
were performed on 67 histopathologically proven OTC patients. Analysis for
diagnostic value was done for ultrasonography and FNAC. RESULTS: In the 67
patients receiving ultrasonography with FNAC, 23 were preoperatively diagnosed as
having papillary thyroid carcinoma and 1 as having follicular carcinoma. The
tumor size of these 24 preoperative FNAC-proven OTC was 0.81 +/- 0.23 cm (mean +/
SD). In the remaining patients, 10 presented pictures suspicious for malignancy,
with a mean tumor size 0.63 +/- 0.24 cm, and 33 (49.3%) were diagnosed as having
benign thyroid lesions in preoperative FNAC. The tumor size in these 33 lesions
was 0.58 +/- 0.24 cm. Fifty-seven of the 67 OTC patients received frozen
sections. Thirty-eight papillary thyroid carcinomas and four follicular
carcinomas were correctly diagnosed on frozen sections. CONCLUSION: Although the
rate is not high, high-resolution ultrasonography and FNAC is the best approach
to preoperative diagnosis for OTC patients today.
PMID- 9390137
TI - Calretinin. A selective marker of normal and neoplastic mesothelial cells in
serous effusions.
AB - OBJECTIVE: To document that a polyclonal antiserum to calretinin, a 29-kd calcium
binding protein, consistently decorates normal and tumor mesothelial cells in
cytologic preparations. STUDY DESIGN: Thirty-three archival cytologic specimens
from eight patients with histologically confirmed malignant mesothelioma and 13
from patients with metastatic serous effusions were destained and then
immunostained with anticalretinin antiserum. For investigation of cell
suspensions, four pleural fluids were incubated with anticalretinin antiserum.
After cytocentrifugation the specimens were stained in accordance with the
alkaline phosphatase anti-alkaline phosphatase (APAAP) method. For electron
microscopic examination the cell suspensions were then incubated with gold
labeled antirabbit antibody. RESULTS: The diagnostic sensitivity of this new
immunocytochemical approach reached 100% for the eight malignant mesotheliomas
investigated. Only 3 of the 13 adenocarcinomas metastatic to the serous membranes
included in this study were weakly reactive, accounting for 81% specificity.
Binding of anticalretinin antiserum to living mesothelial cells was consistently
documented in all four cases investigated. CONCLUSION: Calretinin is a very
useful marker for positive identification of normal and tumor mesothelial cells
in serous effusions.
PMID- 9390138
TI - Correlation of the ratio of CD4+/CD8+ cells in lymph node fine needle aspiration
biopsies with HIV clinical status. A preliminary study.
AB - OBJECTIVE: To test the hypothesis that lymph node (LN) fine needle aspiration
biopsy (FNAB) may provide reliable measures of human immunodeficiency virus (HIV)
disease status. STUDY DESIGN: HIV+ participants in this study had persistent
generalized lymphadenopathy without clinical evidence of lymphoma or nodal
infections due to organisms other than HIV. Seven males and five females ranging
in age from 23 to 55 and at HIV Centers for Disease Control (CDC) stages A2-C3
were enrolled in this study. From each participant, LN and blood samples were
submitted for cytologic examination and flow cytometric analysis of lymphocyte
subsets. Flow cytometry measures included T, B, CD4+, CD8+ and natural killer
(NK) cells. The percentages of T, B and NK cells in LN and blood samples were
different and reflected the expected distribution of these cell types in the
respective tissues. RESULTS: The percentages of CD4+ and CD8+ cells in blood and
LN were different, but this variation was not statistically significant. In
contrast, the ratio of CD4+/CD8+ cells in LN and blood was different and
statistically significant (P < .001) for patients in CDC categories A2-B2 but not
different for categories B3-C3. More important, there was a significant (r = .76)
correlation between the ratio of CD4+/CD8+ cells in LN with CDC stage.
CONCLUSION: FNAB, in combination with flow cytometry, may prove to be an
important tool in HIV clinical staging. However, further assessment, including
clinical follow-up and participation of additional patients, is necessary and
currently under way.
PMID- 9390139
TI - Concurrent fluorescence in situ hybridization and immunocytochemistry for the
detection of chromosome aberrations in exfoliated bronchial epithelial cells.
AB - OBJECTIVE: A procedure was developed to allow concurrent detection of chromosome
aberrations and identification of bronchial epithelial cells. STUDY DESIGN:
Fluorescence in situ hybridization for chromosome 7 and immunocytochemistry for
cytokeratin were performed on exfoliated bronchial epithelial cells in a sputum
sample from a cancer patient. RESULTS: The Spectrum Orange-labeled alpha
satellite probe for chromosome 7 produced red fluorescence, nuclei were
counterstained with 4,6-diamidino-2-phenylindole (blue), and cytokeratin was
visualized using a fluorescein isothiocyanate (FITC)-conjugated secondary
antibody (green). CONCLUSION: This procedure allowed the rapid identification of
airway epithelial cells with numerical chromosome aberrations in this sample.
Ultimately, this procedure could increase the sensitivity and specificity of
sputum cytology as a laboratory diagnostic tool for the early detection of lung
cancer.
PMID- 9390140
TI - Saccomanno smear slides and Megafunnel slides for sputum specimens. A comparison.
AB - OBJECTIVE: To compare Megafunnel slides to standard Saccomanno smear slides of
sputum specimens and evaluate the use of Megafunnel slides for retrospective
studies. STUDY DESIGN: Papanicolaou-stained Saccomanno smear and Megafunnel
slides (Shandon Lipshaw, Inc., Shandon Inc., Pittsburgh, Pennsylvania, U.S.A.) of
65 clinical sputum specimens from 51 patients were compared for cellular
morphology, staining, background and cytologic diagnosis. Recovery of diagnostic
cells was quantitated using 10 of these specimens. Megafunnel slides prepared
from the clinical sputum samples were immunocytochemically stained. Diagnostic
cells were quantitated both before removal from 64 archived Saccomanno smear
slides and after placement of these cells onto 238 Megafunnel slides. RESULTS:
Saccomanno smear slides and Megafunnel slides of clinical specimens were similar
in morphology, background, staining, diagnosis and cell recovery. Megafunnel
slides were superior for multiple immunocytochemical stains. The production of
multiple Megafunnel slides from archival smear slides provided a method of
performing numerous retrospective studies. CONCLUSION: Megafunnel slides compared
favorably to Saccomanno smear slides in the quality of specimens but are more
expensive and labor intensive to prepare. However, the reduction in screening
time by cytotechnologists may be advantageous. Additionally, their potential use
for immunocytochemistry, fluorescence in situ hybridization, or other special
clinical and research analyses is very promising.
PMID- 9390141
TI - Taking a satisfactory cervical cytologic smear. Is it really an easy procedure?
AB - OBJECTIVE: To evaluate the correlation between the experience of the cervical
cytologic smear provider and the quality of the smears in terms of the
percentages of satisfactory smears and contribution of the various factors
affecting the smear's adequacy. STUDY DESIGN: A newly available quality control
system was used to evaluate the adequacy of 4,000 smears. RESULTS: Of 4,000
smears, 660 (16.5%) were classified as "satisfactory but limited" or
"unsatisfactory." Technical factors contributed 1.0%, while 15.5% were due to
sampling factors, considered human errors. Thus, human error accounted for 90% of
the total number of unsatisfactory smears. CONCLUSION: Greater experience with
smear sampling is associated with fewer unsatisfactory smears. The results
correlate directly with the total number of smears taken annually. Sampling skill
improves in steps, with improvement limited beyond a certain point.
PMID- 9390142
TI - Application of the CytoRich monolayer preparation system for cervical cytology. A
prelude to automated primary screening.
AB - OBJECTIVE: To compare AutoCyte's CytoRich monolayer preparation method with the
conventional cervical cytology smear method as a reliable alternative for
cervical cytology screening. STUDY DESIGN: After conventional smears were
prepared, sample collection devices were placed in vials containing CytoRich cell
preservative fluid. The residual sample material was rinsed into the vials and
prepared on glass slides by the CytoRich system. CytoRich monolayer preparations
were then compared microscopically with matched conventional smears in a blind
assessment in order to confirm whether diagnostic cells were present on the glass
slides when the CytoRich method was used. RESULTS: A total of 2,000 samples,
including cases with low grade squamous intraepithelial lesion (SIL), high grade
SIL and cancer were studied. Of 58 cases diagnosed as SIL from either the
conventional or CytoRich preparation, 46 cases were in agreement. The overall
agreement, including negatives and abnormal cases greater than low grade SIL, was
98.8%. CONCLUSION: Dysplastic and cancer cells were detected satisfactorily on
the 13-mm-diameter CytoRich monolayers. These preparations are not only
satisfactory for rapid manual microscopic examination but also are applicable for
evaluation using automated screening systems.
PMID- 9390143
TI - Primary malignant melanoma of the conjunctiva of the upper eyelid. A case report.
AB - BACKGROUND: Malignant melanoma of the conjunctiva is rare. The nomenclature and
clinical and pathologic features of cutaneous and conjunctival melanomas are
different. CASE: A 62-year-old male presented with a history of slight bleeding
of the upper conjunctiva for the previous six months. On clinical examination the
ophthalmologist observed a smooth, partly nodular, pigmented lesion on the
conjunctiva under the left eyelid, 1.5 cm in diameter. Fine needle aspiration
(FNA) biopsy of the mass showed tumor cells dispersed as single cells with
eccentric, round nuclei; coarsely granular chromatin; prominent nucleoli; and
dense cytoplasm with occasional brownish pigmentation as well as small aggregates
of spindle-shaped neoplastic cells with hyperchromatic nuclei and no cytoplasmic
pigment. CONCLUSION: FNA cytology is a simple and efficient method of making the
diagnosis of malignant melanoma in conjunctival masses. Careful correlation with
the clinical history and histologic findings is often necessary for confirmation
of the diagnosis.
PMID- 9390144
TI - Fine needle aspiration cytology of Langerhans cell histiocytosis confined to
lymph nodes. A case report.
AB - BACKGROUND: Lymph node involvement in Langerhans cell (LC) histiocytosis (LCH)
can be seen as a component of the systemic form, or it may be the initial and
sometimes exclusive manifestation of the disease. Descriptions of patients with
LCH whose disease is confined to lymph nodes are rare. CASE: We present a case of
LCH confined to lymph nodes initially diagnosed by fine needle aspiration (FNA)
cytology in a 43-year-old male. The cytologic findings in LCH included high
cellularity, isolated LCs with prominent nuclear indentations and grooves,
multinucleate giant cells, eosinophils and lymphocytes. Confirmation of LCH was
obtained by positive S-100 protein immunohistochemical staining and the
demonstration of Birbeck granules on electron microscopy. CONCLUSION: The
presence of LCs with prominent nuclear indentations and grooves is characteristic
of LCH confined to lymph nodes and serves as a key point in suggesting the
diagnosis of LCH.
PMID- 9390145
TI - Mucor pyelonephritis. Report of a case diagnosed by urine cytology, with
diagnostic considerations in the workup of funguria.
AB - BACKGROUND: Isolated renal mucormycosis is an uncommon kidney infection affecting
patients with underlying systemic diseases and intravenous (IV) drug abuse. We
report a unique case in the cytologic literature in which urine cytology provided
insight into the diagnosis, renal mucormycosis. CASE: The patient, a diabetic and
IV drug abuser, presented with complaints of left flank pain, fever and dysuria.
All urine cultures were negative. A computed tomography (CT) scan showed changes
consistent with left acute pyelonephritis, and the patient was treated for a
presumed diagnosis of bacterial pyelonephritis. Late in the hospital stay, the
cytology laboratory diagnosed Mucor in a single urine specimen, but the patient
had already been discharged. The patient was never treated for funguria, only to
present again with left flank pain 13 months later. An abdominopelvic CT scan
showed progression to left chronic pyelonephritis. The patient, however, left the
hospital against medical advice before any further workup could be completed.
CONCLUSION: Renal mucormycosis should be considered part of the differential
diagnosis in patients with underlying diseases or IV drug abuse who present with
symptoms of acute pyelonephritis. The differential diagnosis of Mucor funguria
should also include fungal ball in the renal pelvis or urinary bladder and fungal
cystitis.
PMID- 9390146
TI - Fine needle aspiration cytology of gastric epithelioid leiomyosarcoma
metastasized to the liver. A case report.
AB - BACKGROUND: There have been only a few reports on fine needle aspiration (FNA)
cytology of epithelioid leiomyosarcoma, especially of the stomach, and a summary
of the cytologic findings in this tumor is needed. CASE: A case of epithelioid
leiomyosarcoma of the stomach metastasized to the liver and was composed
cytologically of peculiar binucleated cells. CONCLUSION: Similar findings in most
cases are that the cells are round or polygonal, with eccentrically located
nuclei. The most variable findings relate to the texture of the cytoplasm, which
varies from granular to dense to vacuolar. FNA cytology of epithelioid
leiomyosarcoma can show cells that are mononuclear, binucleated or
multinucleated, with eccentric nuclei and dense to vacuolar cytoplasm, with the
variations probably depending on fixation status.
PMID- 9390147
TI - Granular cell tumor of the breast in a male. A case report.
AB - BACKGROUND: Granular cell tumor (GCT) is a rare tumor of the soft tissues; the
most common site of occurrence is the tongue. The diagnosis of GCT is fairly
straightforward on both fine needle aspiration cytology and histopathology.
Occasionally the tumor's presence in an unusual site may create confusion with
carcinoma, especially when it occurs in the breast, where carcinoma is more
common. CASE: A case of GCT occurred in the breast of a male with simultaneous
detection of the same type of tumor in the soft tissues of the upper arm and
back. The diagnosis was made on a fine needle aspirate of the breast mass, which
demonstrated characteristic diastase-resistant, periodic acid-Schiff-positive
intracytoplasmic granules. CONCLUSION: The breast, especially in males, is an
unusual location for GCT. Clinicians and pathologists must be alert, therefore,
to its existence and its inclusion in the differential diagnosis of tumors of the
breast.
PMID- 9390148
TI - Pigmented villonodular synovitis. Report of a case with diagnostic synovial fluid
cytologic features.
AB - BACKGROUND: The identification of neoplastic cells in synovial fluid is an
uncommon occurrence and most often is related to extension of extraarticular
tumor into the joint space than to primary neoplasm arising in the joint. CASE:
In this report the cytologic features of synovial fluid obtained from the right
knee of an 18-year-old male with biopsy-proven pigmented villonodular synovitis
are described and compared with the features of the concurrent surgical specimen.
CONCLUSION: The cytologic features of pigmented villonodular synovitis in
synovial fluid include abundant mononuclear histiocytic cells occurring singly
and in papillary clusters, hemosiderin within histiocytes and few multinucleated
giant cells.
PMID- 9390149
TI - Fine needle aspiration biopsy of progressive multifocal leukoencephalopathy in a
patient with AIDS. A case report.
AB - BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is one of the most
common opportunistic infections, with a range of 4-7% in acquired
immunodeficiency syndrome (AIDS) patients. Clinical diagnosis is often difficult,
and the specific pathologic agent requires cytologic and pathologic confirmation.
CASE: A 38-year-old, Haitian male was admitted with a new-onset seizure disorder.
On computed tomography (CT), there were right frontoparietal cortex, right
external capsule and right basal ganglia lucencies. Fine needle aspiration biopsy
(FNAB) of the radiolucent area revealed foci of white matter demyelination and a
few eosinophilic inclusions in oligodendrocytes plus abnormal giant astrocytes.
Ultrastructurally, JC virions were observed in the nuclei and cytoplasm of the
oligodendrocytes. CONCLUSION: Diagnostic cranial CT-guided FNAB, with cytologic
and histologic studies, is extremely valuable in evaluating the nature of central
nervous system demyelinated and space-occupying lesions in AIDS.
PMID- 9390150
TI - Subareolar abscess of the breast in a male. A report of two cases with fine
needle aspiration cytology diagnosis.
AB - BACKGROUND: Fine needle aspiration (FNA) is a well-established method for the
diagnosis of breast diseases in males, but very little attention has been focused
on inflammatory lesions. Previous reports do not mention subareolar abscess (SA),
which is a distinct entity in breasts of females. CASES: Two adult males
presented for FNA of recurrent breast masses located near the nipple. Smears from
both patients showed the typical cytologic features of SA. CONCLUSION:
Recognition of this troublesome and rare condition on FNA cytology from the
breasts in males will prevent recurrences since SA is not cured by excisional
biopsy.
PMID- 9390151
TI - Solid and papillary epithelial neoplasm of the pancreas. Report of a case with
diagnosis by fine needle aspiration cytology.
AB - BACKGROUND: Solid and papillary epithelial neoplasm of the pancreas is a distinct
clinicopathologic entity. It has a benign clinical course, and surgical resection
can be curative. CASE: A 17-year-old female presented with a mass measuring about
12 cm in the epigastrium and left hypochondrium. Fine needle aspiration cytology
(FNAC) showed papillae with a central fibrovascular core and lined with many
layers of bland-appearing cells exhibiting nuclear grooving. These features,
along with ultrasound and computed tomographic findings, led to an accurate
preoperative diagnosis. CONCLUSION: In the setting of typical clinical and
radiologic findings, it is possible to make a correct preoperative diagnosis by
FNAC. Doing so has important implications for management.
PMID- 9390152
TI - Aspiration cytology of signet-ring cell lymphoma. A case report.
AB - BACKGROUND: Signet-ring cell lymphoma is a rare subtype of non-Hodgkin's
lymphoma, composed of vacuolated cells with a signet-ring cell appearance. We
found only two cases that had been reported as diagnosed by fine needle
aspiration biopsy. CASE: A 61-year-old female had signet-ring cell lymphoma
diagnosed by computed tomography-guided aspiration biopsy. Smears of aspirates
from her retroperitoneal mass contained a population of small to medium-sized,
angular lymphoid cells; lymphoglandular bodies; and an abundance of signet-ring
cells. The signet-ring cells were negative for cytokeratin and positive for
leukocyte common antigen and CD20, a B-cell marker. Monoclonality for lambda
light chain determinant was noted, and a diagnosis of signet-ring cell lymphoma
of the B-cell type was made. A core biopsy specimen confirmed the diagnosis.
CONCLUSION: Signet-ring cell lymphoma should always be considered in the
differential diagnosis of tumors composed of signet-ring cells.
PMID- 9390153
TI - Pulmonary malakoplakia diagnosed by fine needle aspiration. A case report.
AB - BACKGROUND: Pulmonary malakoplakia is an uncommon disorder, with 24 previously
reported cases, only 4 of which were diagnosed by bronchial washings, bronchial
brushings or aspiration cytology. We report a case that was diagnosed initially
by computed tomography (CT)-guided fine needle aspiration (FNA) cytology. CASE: A
56-year-old male with follicular small cleaved cell lymphoma had a 10-cm left
lower lobe mass compressing the main bronchus to that lobe. A transthoracic, CT
guided FNA specimen consisted predominantly of foamy macrophages, many of which
contained typical Michaelis-Gutmann bodies. Microbiologic cultures identified
Rhodococcus equi. A subsequent transbronchial biopsy and left pneumonectomy
specimen confirmed the cytologic diagnosis. CONCLUSION: Pulmonary malakoplakia
associated with R equi pneumonia is a rare lesion that is essentially limited to
immunocompromised hosts. Awareness of the FNA cytomorphology of this lesion
permits resolution of the typical clinical differential diagnosis of pulmonary
masses in the immunocompromised host and can facilitate treatment.
PMID- 9390154
TI - Thymic carcinoid. Report of a case with diagnosis by fine needle aspiration
biopsy.
AB - BACKGROUND: Fine needle aspiration biopsy (FNAB) affords a less expensive, less
morbid approach to masses within the complex anatomy of the mediastinum as
opposed to surgical biopsy. Given the current state of computed tomography
guidance and the available cell block preparations and ancillary studies,
definitive diagnosis of mediastinal tumors is possible. CASE: A 19-year-old male
presented with weight loss and muscle weakness. Computed tomography revealed an
anterior superior mediastinal mass with attachment to the posterior sternum and
anterior aorta. FNAB yielded hyperchromatic cells with densely clumped chromatin
and prominent nucleoli. These were present as single cells and clusters. Cell
block preparations were studied with immunoperoxidase methods and were strongly
positive for chromogranin and glucagon, supporting the diagnosis of carcinoid
tumor. Surgical excision yielded a 7-cm, unencapsulated, red-brown tumor with
medium-sized cells with oval to round nuclei, scant and granular cytoplasm and
coarse "salt and pepper" chromatin with prominent nucleoli. The cells were
arranged in islands and bands and were associated with prominent capillaries and
dense, collagenous septae. Immunoperoxidase and electron microscopy demonstrated
numerous intracytoplasmic, nonspecific neurosecretory granules and positivity for
somatostatin, synaptophysin, cytokeratin and chromogranin. CONCLUSION: FNAB
affords an accurate and timely diagnosis of an anterior mediastinal tumor without
the necessity for open biopsy and also offers accurate surgical planning and
decreased morbidity.
PMID- 9390155
TI - Fine needle aspiration diagnosis of a subcutaneous abscess from Enterobius
vermicularis infestation. A case report.
AB - BACKGROUND: Extraintestinal infestation by Enterobius vermicularis is uncommon.
It has been reported to occur in the peritoneal cavity, ovary, fallopian tube,
endometrium, lung, liver and urinary tract. CASE REPORT: Fine needle aspiration
diagnosis was made in a case of enterobiasis presenting with a subcutaneous
abscess in the natal cleft. Eggs, as well as fragments of cuticle of the adult
worm, were found; the morphology of both was best visualized in Papanicolaou
stained smears. Polarizing microscopy highlighted the equally spaced parallel
grooves of the cuticle. CONCLUSION: Fine needle aspiration cytology of
subcutaneous abscesses due to enterobiasis can be diagnostic when eggs, or eggs
with cuticle, are identified in a suppurative or granulomatous inflammation.
PMID- 9390156
TI - Detecting false negative smears.
PMID- 9390157
TI - Fine needle aspiration cytology of injection-site pseudotumors.
PMID- 9390158
TI - Myoepithelioma of the soft palate.
PMID- 9390159
TI - Cytologic diagnosis of hepatoblastoma by fine needle aspiration biopsy cytology.
PMID- 9390160
TI - Recognition of rectal glandular cells in vaginal smears.
PMID- 9390161
TI - Use of water-soluble gel in obtaining the cervical cytologic smear.
PMID- 9390162
TI - Cytologic diagnosis of Bancroft's filariasis presenting as generalized
lymphadenopathy.
PMID- 9390163
TI - ASCUS: a misnomer.
PMID- 9390164
TI - Postmastectomy angiosarcoma (Stewart-Treves syndrome)
PMID- 9390165
TI - Human papillomavirus detection in archival Papanicolaou-stained cervical smears
by in situ polymerase chain reaction.
PMID- 9390166
TI - Reactive lymphoid hyperplasia presenting as a palpable nodule in the breast.
PMID- 9390167
TI - Trichosporon detected on bile cytology.
PMID- 9390168
TI - Isolation of carboxylester lipase (CEL) isoenzymes from Candida rugosa and
identification of the corresponding genes.
AB - The yeast Candida rugosa produces extracellular lipases which are widely used for
industrial purposes. A commercial lipase preparation from this yeast can be
separated into several isoenzymes which differ in carbohydrate content,
isolelectric point, substrate specificity, and primary sequence. We have here
purified and characterized three lipases, which also hydrolyze p-nitrophenyl
esters, from a commercial preparation of this yeast. These three carboxylester
lipases (CELs) elute differently on hydrophobic interaction chromatography, and
have different carbohydrate contents and substrate specificities. Sequence
analysis of their amino termini and peptides generated by LysC treatment showed
that CEL-1 and CEL-3 probably have identical primary structure while CEL-2 was
proven to be a different enzyme. Sequence comparison showed that both CEL-1 and
CEL-3 are products of the LIP1 gene and that CEL-2 is the gene product of LIP2,
cloned by Longhi et al. (Biochim. Biophys. Acta 1131, 227-232, 1992).
PMID- 9390169
TI - Mechanisms for metabolism of ethanol to 1-hydroxyethyl radicals in rat liver
microsomes.
AB - Experiments have been designed to reevaluate mechanisms for metabolism of ethanol
to 1-hydroxyethyl radicals (HER) in rat liver microsomes. The variables tested
include addition of azide, catalase, superoxide dismutase, and deferoxamine, or
use of phosphate or Tris buffers. The results indicate that several mechanisms of
HER formation are possible, depending on the experimental conditions used to
study this process. In the presence of phosphate buffer, which has been used
extensively in spite of its ability to chelate iron, HER formation is quite
sensitive to changes in hydrogen peroxide availability. These results suggest
that Fenton-type reactions produced the oxidizing intermediate responsible for
conversion of ethanol to a free radical in phosphate buffer. However, in Tris
buffer, HER formation was inhibited markedly by addition of superoxide dismutase,
whereas catalase or azide had little effect. These data indicate that the
apparent mechanism of radical formation may be influenced by the choice of buffer
used. HER formation was almost abolished by the combination of superoxide
dismutase and deferoxamine in both buffers, suggesting little enzymatic HER
formation by the cytochrome P450 enzymes. When changes in HER formation were
compared with rates of ethanol oxidation, it was inferred that 25 to 50% of the
acetaldehyde formed during microsomal ethanol oxidation under different
experimental conditions could arise via the HER intermediate.
PMID- 9390170
TI - Purification and characterization of a rat liver bile acid coenzyme A ligase from
rat liver microsomes.
AB - In the present study, using the C24 bile acid chenodeoxycholic acid as substrate,
rat liver bile acid CoA ligase activity (rBAL) was purified 200-fold from
detergent-solubilized microsomes using a combination of Q-Sepharose anion
exchange, hydroxyapatite, and CM-Sepharose chromatography. Purified rBAL had a
molecular weight of 65 kDa by SDS-PAGE analysis. Gel filtration of purified rBAL
indicated that rBAL activity forms a complex with other proteins with an apparent
aggregate molecular weight of 243 kDa. A monoclonal antibody raised against the
65-kDa protein and covalently coupled to 6B-Sepharose completely absorbed rBAL
activity from a semipurified preparation of rat liver microsomes. Western blot
analysis confirmed the elution of the 65-kDa protein from the affinity phase at
low pH. Optimum rBAL activity was found at pH 8.5, and activity was dependent on
the divalent cation Mg2+. In the presence of 50 microM CoA and 2.5 mM MgCl2,
kinetic analysis revealed that the apparent K(m)s of ATP and chenodeoxycholic
acid of the purified enzyme were 548 +/- 247 and 18.0 +/- 6.2 microM,
respectively, and the apparent Vmax was 9.53 +/- 2.0 nmol min-1 mg protein-1. The
formation of chenodeoxycholyl-CoA by rBAL was strongly inhibited by hydrophobic
bile acids (the C24 monohydroxy bile acid lithocholic acid and 3 alpha,7 alpha,12
alpha-trihydroxy-5 beta-cholestanoic acid, the C27 homolog of cholic acid), but
only weakly by cholic acid. Chenodeoxycholyl-CoA and 3 alpha,7 alpha,12 alpha
trihydroxy-5 beta-cholestan-27-oyl-CoA were confirmed as reaction products of
purified rBAL by HPLC-electrospray ionization mass spectrometry.
PMID- 9390171
TI - Cancer-preventive selenocompounds induce a specific redox modification of
cysteine-rich regions in Ca(2+)-dependent isoenzymes of protein kinase C.
AB - Since protein kinase C (PKC) serves as a receptor for phorbol ester type tumor
promoters and oxidants and has unique redox-active cysteine-rich regions, we have
determined whether various chemopreventive selenocompounds could affect this
enzyme. At lower concentrations, selenite decreased the kinase activity (IC50 =
0.5 microM), while at higher concentrations it decreased phorbol ester binding.
However, when the catalytic and regulatory domains of PKC were separated by
proteolysis, the catalytic domain retained its sensitivity to selenite, while the
regulatory domain lost its sensitivity. Cysteine residues were quantitated in PKC
modified with selenite by using 5,5'-dithiobis(2-nitrobenzoic acid) and also by
using 2-nitro-5-thiosulfobenzoic acid after sulfitolysis. At lower
concentrations, selenite induced a modification of four cysteine residues
resulting in the formation of two disulfides, while at higher concentrations it
induced a modification of seven to eight cysteine residues resulting in the
formation of three to four disulfides. Contrary to selenite, selenocystine and
selenodiglutathione (GSSeSG) readily inactivated the kinase activity, but not the
phorbol ester binding. These two agents induced a two-stage modification of PKC;
a limited modification at low concentrations leads to a loss of affinity for ATP,
while an excessive modification at high concentrations leads to a loss of Vmax.
Selenocystine and GSSeSG were 100,000-fold more potent than GSSG in inactivating
PKC. The isoenzymes alpha, beta, and gamma exhibited an identical susceptibility
to these selenocompounds. These results suggested that the cysteine residues
present within the catalytic domain of these isoenzymes, although apart in the
sequence, may be clustered in the tertiary structure to react with selenite, as
well as may be in close proximity to some of the cysteines in the regulatory
domain. Selenite did not affect protein kinase A, whereas GSSeSG and
selenocystine inactivated the catalytic subunit after dissociation from the
regulatory subunit at concentrations 100- and 800-fold, respectively, higher than
that required for PKC inactivation. All three selenocompounds did not affect the
activities of phosphorylase kinase and protein phosphatase 2A. Taken together,
these results suggest that the accessible redox-active cysteine residues present
in the PKC catalytic domain can react with certain specificity with redox-active
selenocompounds such as selenite, selenocystine, and GSSeSG relative to other
protein kinases tested.
PMID- 9390172
TI - Selenocompounds induce a redox modulation of protein kinase C in the cell,
compartmentally independent from cytosolic glutathione: its role in inhibition of
tumor promotion.
AB - Since selenite and other redox-active selenocompounds can modify protein kinase C
(PKC) in the test tube, we have determined whether or not this redox regulation
occurs inside the cell despite having high concentrations of GSH and the role of
this regulation in the inhibition of tumor promotion. By using phorbol ester
promoted JB6 epidermal cell transformation assay, the concentrations of selenite,
selenocystine, and selenodiglutathione which are optimal for chemopreventive
activity were determined. At such concentrations (0.5 to 2 microM) in the cells
treated with these agents, only a slight but transient decrease in PKC activity
was observed when measured with a low (5 microM), but not with a high (100
microM) concentration of ATP. However, when the cells were serum starved or
pretreated with 2-deoxyglucose, there was a pronounced but transient inactivation
of PKC when assayed with both low and high concentrations of ATP. The
inactivation was reversed in the cell by an endogenous mechanism or by treatment
with thiol agents in the test tube. In spite of a substantial (90%) depletion of
GSH in the cells by pretreatment with buthionine sulfoximine, there was no
further increase in the redox modification of PKC by selenite as well as no
change in the inhibitory effect of selenite on the phorbol ester-stimulated
induction of ornithine decarboxylase, which is an intermediate marker related to
cell transformation. While GSH is known to influence certain actions of selenium,
it may not be required to mediate the effects of selenite tested in this study.
The water-soluble cytosolic GSH did not interfere with the redox modification of
PKC probably due to the shielding of the cysteine-rich region of the enzyme by a
weak hydrophobic association with the membrane. Due to the presence of cofactors
in the crude cell extracts, PKC was more sensitive to selenite than in the
purified form and was inactivated by low concentrations of selenite (IC50 = 0.05
microM). This modification was reversed by thiol agents as well as by NADPH. A
protein disulfide reductase, which can regenerate PKC, was present in the
homogenate. Conceivably, selenite and other selenocompounds induce a redox
modification of cellular PKC, compartmentally independent from the cytosolic GSH,
but intimately connected to a NADPH-dependent reductase system, to mediate, at
least in part, some of the cancer-preventive actions.
PMID- 9390173
TI - Dependence of salt concentration on glycosaminoglycan-lysozyme interactions in
cartilage.
AB - The cationic protein, lysozyme, has an extracellular distribution in cartilage
but its precise role in this tissue has not yet been established. This study
describes the dependence of salt concentration on the binding properties of
lysozyme isoforms of different cationic charges, isolated from bovine cartilage,
to the two major and structurally similar glycosaminoglycans of cartilage, i.e.,
chondroitin sulfate and hyaluronan. The binding of most cartilage lysozyme
isoforms and hen egg-white lysozyme (control) to chondroitin sulfate and
hyaluronan linked to agarose supports displayed optimal levels at approximately
20 and 5-10 mM salt, respectively, but decreased at both lower and higher salt
concentrations indicating the electrostatic nature of the interactions. However,
optimal binding of the most cationic lysozyme isoform to chondroitin sulfate
occurred at 60 mM salt, with significant binding remaining at 150 mM. This
isoform also showed binding to hyaluronan up to 60 mM salt, while for the other
isoforms binding was observed only up to 150 and 40 mM salt for chondroitin
sulfate and hyaluronan, respectively. The low salt concentrations at which these
interactions occur are likely to exist in cartilage as shown from equilibrium
dialysis studies performed using solutions of chondroitin sulfate (up to 10%, a
concentration likely to occur in cartilage). From Scatchard analysis, the
affinity of binding of all lysozymes to chondroitin sulfate was similar (Kd = 10(
6) M) and slightly lower than their binding to hyaluronan (Kd = 10(-7) M) of
similar molecular mass.
PMID- 9390174
TI - Microsomal alcohol oxygenase: purification and characterization of a cytochrome
P450 responsible for oxidation of 7-hydroxy-delta 8-tetrahydrocannabinol to 7-oxo
delta 8-tetrahydrocannabinol in guinea pig liver.
AB - Guinea pig hepatic enzyme, microsomal alcohol oxygenase, was able to oxidize both
7 alpha- and 7 beta-hydroxy-delta 8-tetrahydrocannabinol (7 alpha- and 7 beta
hydroxy-delta 8-THC) to 7-oxo-delta 8-THC. A cytochrome P450, named P450GPF-B,
which mediates this oxidative metabolism was purified from hepatic microsomes of
untreated female guinea pigs. The purified enzyme showed a single protein band of
molecular mass 50,000 on sodium dodecyl sulfate-polyacrylamide gel
electrophoresis. The NH2-terminal amino acid sequence of P450GPF-B is highly
homologous with those of several cytochrome P450s belonging to the CYP3A
subfamily. 18O derived from atmospheric oxygen was incorporated into 31 and 6%,
respectively, of 7-oxo-delta 8-THC formed from 7 alpha- and 7 beta-hydroxy-delta
8-THC when the substrates were incubated with P450GPF-B under 18O2. The antibody
against P450GPF-B significantly suppressed the oxidative activities of 7 alpha-
and 7 beta-hydroxy-delta 8-THC to 7-oxo-delta 8-THC in hepatic microsomes of
guinea pig. These results indicate that P450GPF-B is a major enzyme responsible
for the hepatic microsomal alcohol oxygenase activities in the guinea pig.
PMID- 9390175
TI - Biochemical and molecular characterization of fumarase from plants: purification
and characterization of the enzyme--cloning, sequencing, and expression of the
gene.
AB - A cDNA EST clone encoding the C-terminal portion of Arabidopsis thaliana fumarase
was identified by homology analysis. A fragment of cDNA encoding the N-terminal
region of fumarase was amplified from a cDNA library using PCR and cloned.
Genomic DNA corresponding to the coding region of fumarase was amplified and
cloned. Arabidopsis fumarase was expressed as a chimeric fusion protein and
polyclonal antibodies were generated. Fumarase was purified to near-homogeneity
(over 600-fold) from etiolated Pisum sativum mitochondria. The identification of
fumarase was confirmed by a combination of immunoblot and N-terminal amino acid
sequencing. Kinetic analysis of highly purified fumarase yielded a KM(malate) of
0.45 mM and a Vmax(malate) of 650 mumol of fumarate/min/ mg. The pea fumarase was
inhibited by the alpha-keto acids pyruvate and alpha-ketoglutarate at low
millimolar concentrations. Adenylates were highly inhibitory; the degree of this
inhibition was reduced in the presence of Mg2+, suggesting that uncomplexed
adenylates are the inhibitory species.
PMID- 9390176
TI - Regulatory role of fructose-2,6-bisP on glucose metabolism in frog oocytes: in
vivo inhibition of glycogen synthesis.
AB - Glycogen synthesis following glucose microinjection in frog oocytes proceeds
preferentially by an indirect pathway involving gluconeogenesis from triose
compounds. Because of the known regulatory role of fructose-2,6-bisP on glucose
utilization in most vertebrate tissues we coinjected [U-14C]glucose and fructose
2,6-bisP into oocytes and observed a marked inhibition of label incorporation
into glycogen, with an I50 value of 2 microM, which is similar to the value
measured for the in vitro inhibition of oocyte fructose-1,6-bisphosphatase. Other
hexoses-bisP were tested: 2,5-anhydromannitol-1,6-bisP was as effective as
inhibitor as fructose-2,6-bisP; glucose-1,6-bisP showed some effect although 50%
inhibition was obtained at a concentration 10 times higher than with fructose-2,6
bisP; fructose-1,6-bisP had no effect at all. The inhibition pattern for the in
vivo glycogen synthesis by these analogs closely matched the one obtained with
partially purified oocyte fructose-1,6-bisphosphatase. The intracellular
concentration of fructose-2,6-bisP in unperturbed oocytes was found to be between
0.1 and 0.2 microM. Fructose-6-phosphate,2-kinase levels measured in oocyte
homogenates were between 0.02 and 0.06 mU per gram of ovary. After 60 min
incubation, fructose-2,6-bisP microinjected into the oocytes was almost
completely degraded, suggesting that fructose-2,6-bisphosphatase is active in
vivo. The results presented in this paper indicate that fructose-2,6-bisP plays
an important role in the in vivo regulation of glucose utilization in frog-grown
oocytes.
PMID- 9390177
TI - Facilitated reduction of beta-amyloid peptide precursor by synthetic
oligonucleotides in COS-7 cells expressing a hammerhead ribozyme.
AB - Synthetic deoxyoligonucleotides and phosphorothioate-capped oligonucleotides
targeted to bases 112-128 of beta-amyloid peptide precursor (beta APP) mRNA were
analyzed for their ability to reduce steady-state beta APP in COS-7 cells and in
pMEP4-Rz1 cells that express a hammerhead ribozyme targeted to bases beta APP
mRNA 133-148. Cells, incubated in the presence of 10 or 25 microM
oligonucleotide, remained viable and morphologically identical to untreated
control cells for up to 5 days. Antisense deoxyoligonucleotides beta 112C, beta
114C, and beta 116C specifically lowered beta APP in pMEP4-Rz1 cells compared to
noncognate and scrambled oligonucleotide controls. The extent of the beta APP
reduction did not depend on oligonucleotide length, although it did depend on the
presence and proximity of the ribozyme to the oligonucleotides. beta 117N, a
phosphorothioate-capped antisense oligonucleotide, also reduced beta APP levels
in pMEP4-Rz1 cells; however, in this case the sense control, beta 117S, affected
beta APP similarly, indicating that the observed reduction may be nonspecific.
These data imply that deoxyoligonucleotides targeted immediately upstream of a
ribozyme binding site can work cooperatively in vivo. Localizing the
oligonucleotides and ribozyme and substrate targets to the same cellular pools
further confirmed this possibility.
PMID- 9390178
TI - Identification of the subdomain in the nuclear receptor for the hormonal form of
vitamin D3, 1 alpha,25-dihydroxyvitamin D3, vitamin D receptor, that is
covalently modified by an affinity labeling reagent.
AB - Multiple physiological actions of the hormonal form of vitamin D3, 1 alpha,25
dihydroxyvitamin D3 (1,25(OH)2D3), are mediated by a genomic pathway which is
initiated by the highly specific recognition and binding by its cognate receptor
(vitamin D receptor, VDR) in the target cells. Thus, knowledge of the three
dimensional geometries of the ligand, i.e., 1,25(OH)2D3, and the 1,25(OH)2D3
binding domain of VDR is crucial for a better understanding of diverse
physiological roles of this hormone. Recently our laboratory has developed 1
alpha,25-dihydroxyvitamin D3-3 beta-bromoacetate (1,25(OH)2 D3-3-BE) as an
affinity labeling reagent for covalently modifying the hormone binding domain of
native VDRs from calf thymus and rat osteosarcoma cells and baculovirus-expressed
recombinant human VDR (hVDR). In the present report, we report affinity labeling
of the hormone binding domain of hVDR, expressed in Escherichia coli as a
glutathione S-transferase fusion partner, site-specific cleavage of the affinity
labeled VDR with 3-bromo-3-methyl-2-(2-nitrophenylmercapto)- 3H-indole, and
identification of the C-terminal subdomain of human VDR containing the putative
hormone binding site.
PMID- 9390179
TI - Chemosignal transduction in the vomeronasal organ of garter snakes: Ca(2+)
dependent regulation of adenylate cyclase.
AB - Earthworm shock secretion contains a 20-kDa vomeronasally mediated
chemoattractive protein for garter snakes. Both the ligand-receptor binding and
the chemoattractivity of ES20 are Ca(2+)-dependent. When ES20 binds to its G
protein-coupled receptors in the vomeronasal epithelium, the inositol 1,4,5
trisphosphate (IP3) level is increased, but the level of cAMP is reduced.
Furthermore, forskolin-stimulated levels of cAMP are completely blocked by ES20
receptor binding or by Ca2+ alone and the effect of calcium ions can be nullified
by EGTA. Previously, we hypothesized that the decrease in cAMP was due to
activation of a Ca(2+)-dependent phosphodiesterase. In the present study, we
provide evidence that the decrease in cAMP is due mainly to the regulation of
adenylate cyclase (AC) activity by Ca2+ or is indirectly mediated by ES20.
Results obtained with intact vomeronasal sensory epithelium suggest that the
binding of ES20 to its receptors facilitates generation of IP3 which mobilizes
intracellularly sequestered Ca2+, resulting in an increase of cystosolic Ca2+. A
further increase in cytosolic Ca2+ occurs through Ca2+ influx from extracellular
sources. Garter snake vomeronasal AC does not require calmodulin for its activity
and shows a biphasic response to increasing concentrations of Ca2+; its activity
is modulated both positively and negatively by this bivalent cation.
PMID- 9390180
TI - Reconstitution premixes for assays using purified recombinant human cytochrome
P450, NADPH-cytochrome P450 reductase, and cytochrome b5.
AB - The development of enzyme and buffer premixes for in vitro biotransformation
assays is described. The protein premixes contain a mixture of three recombinant
human proteins, cytochrome P450 (P450) 3A4, NADPH-P450 reductase, cytochrome b5,
and liposomes. The buffer premix contains reagents which, when diluted, provide
for optimal metabolic activity with selected P450 3A4 substrates. P450 3A4
premixes were competent in the oxidation of known substrates including
testosterone, midazolam, nifedipine, erythromycin, benzphetamine, and
amitriptyline. Premixes stored at -80 degrees C for 2 months and those that
underwent an additional five freeze/thaw cycles were able to hydroxylate
testosterone at turnover rates similar to freshly prepared reconstitution mixes.
In addition, premixes stored unfrozen at 4 degrees C for 2 weeks showed no
significant loss in the rate of testosterone 6 beta-hydroxylation by P450 3A4.
Premixes prepared with and without reduced glutathione, a component which had
previously been found to be important for P450 3A4 reactions, were equally
efficient at carrying out testosterone hydroxylation under these conditions.
Kinetic parameters determined for the metabolism of testosterone, amitriptyline,
nifedipine, and benzphetamine using P450 3A4 premixes were compared with human
pooled microsomes and insect microsomes prepared from cells infected with a
baculovirus containing two cDNA inserts coding for P450 3A4 and NADPH-P450
reductase. Each format gave different Vmax and K(m) values indicating different
catalytic efficiencies. Analysis of P450 1A2 premixes which contained different
lipid concentrations indicated that Vmax and K(m) could be altered. The
availability of human P450 recombinant enzymes and the development of the P450
premixes that remain active after being stored frozen should allow for rapid
identification of novel P450 substrates and inhibitors and the development of
large-scale screening assays.
PMID- 9390181
TI - Apparent equilibrium constants and standard transformed Gibbs energies of
biochemical reactions involving carbon dioxide.
AB - When carbon dioxide is produced in a biochemical reaction, the expression for the
apparent equilibrium constant K' can be written in terms of the partial pressure
of carbon dioxide in the gas phase or the total concentration of species
containing CO2 in the aqueous phase, referred to here as [TotCO2]. The values of
these two apparent equilibrium constants are different because they correspond to
different ways of writing the biochemical equations. Their dependencies on pH and
ionic strength are also different. The ratio of these two apparent equilibrium
constants is equal to the apparent Henry's law constant K'H. This article
provides derivations of equations for the calculation of the standard transformed
Gibbs energies of formation of TotCO2 and values of the apparent Henry's law
constant at various pH levels and ionic strengths. These equations involve the
four equilibrium constants interconnecting the five species [CO2(g), CO2(aq),
H2CO3, HCO3-, and CO3(2-)] of carbon dioxide. In the literature there are many
errors in the treatment of equilibrium data on biochemical reactions involving
carbon dioxide, and so several examples are discussed here, including calculation
of standard transformed Gibbs energies of formation of reactants. This approach
also applies to net reactions, and the net reaction for the oxidation of glucose
to carbon dioxide and water is discussed.
PMID- 9390182
TI - A model for the explanation of the thermally induced increase of the overall
fluorescence in tryptophan-X peptides.
AB - In the range of temperature 10-35 degrees C, Trp-X dipeptides show an unusual
increase of fluorescence intensity in solution at pH 7. This effect has been
recently studied by means of steady-state fluorescence. Although a model
involving the deprotonation at the ground state of the zwitterion was proposed,
the activation energy for that process could not rule out the involvement of
excited state. In order to understand the mechanism of the thermal-induced
increase of fluorescence, we present here time-resolved fluorescence experiments
on Trp-X and X-Trp dipeptides at different pH and excitation wave-length. The
fluorescence lifetimes (tau i) decrease in accord to thermal quenching, with
activation energies (Ei) ranging from 4.0 to 6.4 kcal/mol. Under those
circumstances where the anomaly was detected the preexponential factors of the
longer-lived component increased as well as their fractional fluorescence. This
component can be assigned to the anion species. Because of its larger (three- to
fourfold) fluorescence quantum yield, compared to that of the corresponding
zwitterion, the large increase of the concentration of the anion leads to an
increase of the overall emission despite the thermal quenching. Also the decay
associated spectra well account for the red shift of the emission fluorescence
spectrum, which accompanies the anomaly. Our model well fits the experimental
data using a simple equation which combines Van't Hoff and Arrhenius equations;
it also explains the presence of the anomalous thermal quenching exclusively in
Trp-X dipeptides excited above 290 nm and at pH around neutrality.
PMID- 9390183
TI - Molecular cloning and biochemical characterization of bovine spleen myristoyl
CoA:protein N-myristoyltransferase.
AB - Myristoyl-CoA:protein N-myristoyltransferase (NMT) is an essential eukaryotic
enzyme that catalyzes the cotranslational transfer of myristate to the NH2
terminal glycine residue of a number of important proteins of diverse function.
We have isolated full-length cDNA encoding bovine spleen NMT (sNMT). The single
long open reading frame of 1248 bp of sNMT specifies a protein of 416 amino acids
with a predicted mass of 46,686 Da. The protein coding sequence was expressed in
Escherichia coli resulting in the production of functionally active 50-kDa NMT.
Deletion mutagenesis showed that the C-terminus is essential for activity whereas
up to 52 amino acids can be deleted from the N-terminus without affecting the
function. One of the N-terminal deletions resulted in threefold higher NMT
activity. Genomic Southern analysis indicated the presence of two strong
hybridizing bands with three different restriction enzyme digests suggesting the
possibility of two copies of the NMT gene in the bovine genome. RNA blot
hybridization analysis of total cellular RNA prepared from bovine brain, heart,
spleen, lung, liver, kidney, and skeletal muscle probed with bovine sNMT cDNA
revealed a single 1.7-kb mRNA. Western blot analysis of various bovine tissues
with human NMT peptide antibody indicated a common prominent immunoreactive band
with an apparent molecular mass of 48.5-50 kDa in all tissues. Additional
immunoreactive bands were observed in brain (84 and 50 kDa), lung (58 kDa), and
skeletal muscle (58 kDa). Activity measurements demonstrated that brain contained
the highest NMT activity followed by spleen, lung, kidney, heart, skeletal
muscle, pancreas, and liver. It appears therefore that mRNA and protein
expression do not correlate with NMT activity, suggesting the presence of
regulators of the enzyme activity.
PMID- 9390184
TI - Partial purification and characterization of a Ca(2+)-dependent proteinase from
Arabidopsis roots.
AB - Ca2+, an important intracellular messenger in plants, is implicated in
controlling diverse cellular functions by regulating the activity of several
enzymes. Here we report the presence of a Ca(2+)-dependent proteinase (CDP)
activity in roots of Arabidopsis using in-gel assays (zymograms). The CDP
activity showed absolute Ca2+ requirement for its activation; other divalent ions
such as Mg2+, Sr2+, and Zn2+ did not substitute for Ca2+ in stimulating protease
activity. The CDP activity was inhibited by the proteinase inhibitors leupeptin,
E-64, and N-ethylmaleimide, whereas pepstatin A and phenylmethylsulfonyl fluoride
were without effect. These data indicate that the enzyme is likely to be a
cysteine proteinase. The CDP activity was partially purified from root cultures
using ammonium sulfate precipitation, DE-52, Mono-Q, and Superdex 200 column
chromatography. This purification scheme resulted in about 40-fold purification
of the CDP activity. Based on the elution of Arabidopsis CDP (ACDP) activity on
gel filtration column the molecular mass of CDP was estimated to be about 75 kDa.
Isoelectric focusing showed that the enzyme had a pI between 5.2 and 5.4. SDS
polyacrylamide gel analysis showed that activity was associated with a 45-kDa
polypeptide, suggesting that the native ACDP is a homodimer. Five different
antibodies raised to animal CDPs did not cross-react with the partially purified
protein. These data suggest that the plant CDP differs from the known CDPs
characterized from animals and is likely to be a new CDP that is unique to
plants.
PMID- 9390185
TI - Structural changes of the sarcoplasmic reticulum Ca(II)-ATPase nucleotide binding
domain by pH and La(III).
AB - The Ca(2+)-ATPase from sarcoplasmic reticulum couples the hydrolysis of one
molecule of ATP to the transport of two Ca2+ ions in skeletal muscle fibers.
Here, we study the accessibility of the fluorescein covalently attached to the
Lys515 at the nucleotide binding domain of the ATPase to the small collisional
quencher iodide at pH 6 and 8, as well as the effect of ligand binding (La3+,
La(3+)-nucleotide, and Ca2+). Our results indicate that bound fluorescein is
significantly more accessible at pH 6 than at pH 8, suggesting that pH modulates
the structure of the nucleotide binding domain of the ATPase. This notion was
further substantiated by the finding that La(3+)-nucleotide only interacted with
the catalytic center at acidic pH. Notably, the differential accessibility of the
nucleotide binding domain at acidic and basic pH cannot be rationalized in terms
of the ATPase E1/E2 conformational equilibrium since a shift of the ATPase toward
the E1 (plus Ca2+) or E2 (plus EGTA) did not affect the accessibility of
fluorescein-labeled ATPase to the quencher. Taken together, these findings show
the presence of structural flexibility in the FITC binding site and suggest a
structural modulation of the Ca(2+)-ATPase nucleotide binding domain by pH and
La3+ binding through long-range link-age mechanisms.
PMID- 9390186
TI - The role of cysteinyl residues in the activity of bacterial elongation factor Ts,
a guanosine nucleotide dissociation protein.
AB - The modification of E.coli elongation factor Ts (EF-Ts) by NEM and other
sulfhydryl reagents inactivates the protein's ability to bind EF-Tu.GDP and to
catalyze GDP exchange. The reactive residue was found to be Cys-22. Replacement
of Cys-22 by Ser or Gly only partially impairs the binding or catalytic
properties of EF-Ts while it completely protects EF-Ts from the inactivation by
NEM. Cys-22 of EF-Ts is not located at the EF-Ts.EF-Tu interface, yet it can be
modified only when EF-Ts is not bound to EF-Tu. These results support the
proposal that the conformation change around Cys-22 in the amino terminus of EF
Ts rather than Cys-22 itself is essential for binding EF-Tu. Apparently,
modification of Cys-22 by NEM disrupts the conformation change and inactivates EF
Ts. The return of EF-Ts to its native conformation may provide the driving force
for the rate-determining step in the catalytic cycle, the dissociation of EF-Ts
from EF-Tu.GNP.
PMID- 9390187
TI - Hypoxia regulates xanthine dehydrogenase activity at pre- and posttranslational
levels.
AB - Hypoxia increases the activity of xanthine oxidase (XO) and its precursor,
xanthine dehydrogenase (XDH), but the mechanism of regulation is unclear. In
hypoxic Swiss 3T3 cells, an early (0-24 h) cycloheximide-insensitive increase in
XO-XDH activity, coupled with a lack of increase in de novo XO-XDH synthesis
(immunoprecipitation) or mRNA levels (quantitative RT-PCR), demonstrated a
posttranslational effect of hypoxia. Similarly, hyperoxia decreased XO-XDH
activity faster than could be accounted for by cessation of XO-XDH protein
synthesis. In further support of a posttranslational effect, cells transfected
with a constitutively driven XDH construct displayed an exaggerated increase in
activity in hypoxia but no increase in activity in hyperoxia. However, more
prolonged exposure to hypoxia (24-48 h) induced an increase in XO-XDH mRNA levels
and de novo XO-XDH protein synthesis, suggesting an additional pretranslational
effect. Finally, hypoxic induction of XO-XDH activity was found to be cell-type
restricted. We conclude that control of XO-XDH levels by oxygen tension is a
complex process which involves several points of regulation.
PMID- 9390188
TI - Regulation of glucuronidation by glutathione redox state through the alteration
of UDP-glucose supply originating from glycogen metabolism.
AB - The effect of altered redox state of glutathione was investigated on p
nitrophenol glucuronidation in isolated mouse hepatocytes. Decrease of GSH/GSSG
ratio provoked by various agents caused increased glucuronidation which was
accompanied by stimulated glycogenolysis and elevated UDP-glucose content. The
stimulation of glycogenolysis and glucuronidation by glutathione consumption
could be prevented by the reduction of oxidized glutathione with dithiothreitol
and by the glycogenolysis inhibitor fructose. In permeabilized hepatocytes
glycogen metabolism, bypassed by the addition of UDP-glucose, stimulated
glucuronidation which was insensitive to glutathione depletion. In liver
microsomes either UDP-glucuronosyltransferase activity or UDP-glucuronic acid
transport was not influenced by GSH/GSSG ratio. These results suggest that
alteration of the GSH/GSSG ratio regulates glucuronidation by affecting enzymes
of the glycogen metabolism via the modification of UDP-glucuronate supply.
PMID- 9390189
TI - Studies on the relationship between estrogen receptor content, glutathione S
transferase pi expression, and induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin
and drug resistance in human breast cancer cells.
AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces both phase I and phase II drug
metabolizing enzymes in rodent liver and hepatoma cell lines and this induction
is mediated by the aryl hydrocarbon (Ah) receptor. Induction of CYP1A1 by TCDD in
human breast cancer cells has been reported and results of several studies
suggest that the estrogen receptor (ER) may be required for Ah responsiveness.
This study investigates the induction of GST pi by TCDD in human breast cancer
cells and the role of the ER in mediating this response. TCDD did not induce
chloramphenicol acetyl transferase (CAT) activity in ER positive (ER+) MCF-7 and
ER- MDA-MB-468 and MDA-MB-231 human breast cancer cell lines transiently
transfected with GST pi (human) or GSTP (rat) promoter-reporter constructs
containing the -291/+36 and -2.9/+59 region, respectively, of the GST pi and GSTP
gene promoters. Furthermore, TCDD did not induce GST pi or GSTP in MDA-MB-468 and
MDA-MB-231 human breast cancer cells stably transfected with the ER. RT-PCR
confirmed that GST pi mRNA levels were low in ER+ MCF-7 cells and high in ER- MDA
MB-468 and MDA-MB-231 cells; however, in MDA-MB-468 and MDA-MB-231 cells stably
transfected with the ER GST pi mRNA levels remained elevated and were not
inducible. MDA-MB-468 and MDA-MB-231 cells stably transfected with the ER
exhibited increased GST activity and decreased GSH content compared to wild-type
cells; however, in MDA-MB-468 cells stably transfected with ER, the
susceptibility to doxorubicin, ellipticine, chlorambucil, malphalan, or cisplatin
was similar to that observed in wild-type cells. Adriamycin accumulation was
similar in wild-type and ER stably transfected cells and verapamil did not affect
this response, suggesting that ER expression did not influence p-glycoprotein
activity. Taken together these data suggest that not all GST isoforms are
responsive to TCDD and stable transfection of ER- cells with ER is not sufficient
to restore the ER+ phenotype in some breast cancer cell lines.
PMID- 9390190
TI - Subunit interactions of Escherichia coli F1-ATPase: mutants of the gamma subunits
defective in interaction with the epsilon subunit isolated by the yeast two
hybrid system.
AB - Previously, we established a method to detect subunit interactions of F1-ATPase
by the yeast two-hybrid system (Moritani, C., et al. Biochim. Biophys. Acta 1274,
67-72, 1996). Here, we isolated mutants of the gamma subunits defective in
interaction with the epsilon subunit by this new procedure to study the molecular
basis of coupling mechanisms of the F1F0-ATPase. Based on the intensities of the
reporter gene expression in this system, five mutants of the gamma subunit with
different levels of gamma-epsilon interactions were isolated and their single
base substitutions were determined. Mutants with a substitution of Pro-55 for
Leu, Thr-102 for Met, Val-141 for Asp, or Gln-235 for Leu exhibited decreased
reporter gene expression, suggesting decreased levels of interaction, while Asp
85 for Gly mutation caused a higher level of expression, suggesting increased
interaction. Among these point mutations, G85D, M102T, or D141V mutations were
introduced into the gamma subunit gene in the plasmid carrying whole unc operon.
Transformants carrying a deletion mutant of the whole unc operon with these
expression plasmids were analyzed. Mutations M102T and D141V with decreased gamma
epsilon interaction caused increases of membrane-bound F1-ATPase activity and
proton pumping activity, while G85D with increased gamma-epsilon interaction
exhibited lower levels of F1-ATPase activity in the membranes. Molecular assembly
of the F1 subunits on the mutant membranes detected by Western blotting exhibited
no defect for all three mutants. These results suggested that the correlation
between the ATPase activity and gamma-epsilon interaction is reciprocal and this
interaction may regulate the ATPase activity. The topological and functional
importance of Gly-85, Met-102, and Asp-141 together with Leu-55 and Leu-235 in
gamma-epsilon interaction is discussed.
PMID- 9390191
TI - The Ah receptor is a sensitive target of geldanamycin-induced protein turnover.
AB - Geldanamycin (GA) binds directly to hsp90 and apparently disrupts certain hsp90
heterocomplexes. We have investigated the GA-hsp90 interaction and its effect on
other associated proteins. Incubation of 2-[125I]-iodo-3-azido-7,8-dibromo-p
dioxin-labeled Hepa 1c1c7 cytosol with GA-coupled beads revealed a stable
association of Ah receptor (AhR)/hsp90 complex with GA. In addition, sucrose
gradient sedimentation analysis demonstrated that GA does not disrupt the 9S Ah
receptor complex in vitro. HeLa and Hepa 1c1c7 cells were subjected to a dose
response and time-course treatment with GA and the level of the AhR was
determined. A 75% depletion in AhR levels was observed within an hour of exposure
to 100 nM GA. The relative stability of other proteins that associate with hsp90
was determined with the following rank order of sensitivity to GA exposure: AhR
>> c-Raf-1 > glucocorticoid receptor > CDK4 >> p50. A series of hsp90 deletion
mutants were used to map the domain that interacts with GA. Deletion of the first
221 amino acids in NH2-terminal domain resulted in loss of binding to solid-phase
GA. Epitopes of monoclonal antibodies specific for hsp90 were also determined by
direct immunoprecipitation with hsp90 mutants. Results indicated that monoclonal
antibodies 8D3 and 3G3 interact with hsp90 via the first 221 amino acids in NH2
terminal region, whereas AC88 requires a COOH-terminal region between amino acids
661-677.
PMID- 9390192
TI - Maintenance of transfection rates and physical characterization of lipid/DNA
complexes after freeze-drying and rehydration.
AB - It is well established that cationic liposomes form complexes with DNA and
effectively transfect cells in vivo and ex vivo. Lipid/DNA complexes have proven
safe and nonimmunogenic in clinical trials; however, they are known to aggregate
readily in liquid formulations. This physical instability requires clinicians to
prepare lipid/DNA complexes immediately prior to injection. In order to eliminate
problems associated with this temporal requirement, we investigated the
feasibility of preserving complexes as a dried preparation that could be tested,
stored, and rehydrated as needed. To this end, our study evaluated the ability of
different stabilizers to preserve transfection rates of complexes during acute
freeze-drying stress. Our data show that complexes lyophilized in 0.5 M sucrose
or trehalose possessed transfection rates similar to those of fresh preparations.
In addition, dried complexes that exhibited full transfection activity upon
rehydration had sizes comparable to nonlyophilized controls. Our work
demonstrates that lipid/DNA complexes can be stabilized as dried powders that
offer significant advantages over current liquid formulations. Furthermore, the
correlation of transfection rates with maintenance of complex diameter suggests
that size plays a critical role in lipid-based DNA delivery.
PMID- 9390193
TI - Identification of the subunits and target peptides of pig heart NAD-specific
isocitrate dehydrogenase modified by the affinity label 8-(4-bromo-2,3
dioxobutylthio)NAD.
AB - Pig heart NAD-dependent isocitrate dehydrogenase reacts with 8-(4-bromo-2,3
dioxobutylthio)-NAD (8-BDB-TNAD) with incorporation of 1.21 mol of reagent/mol of
average subunit when the enzyme reaches the limit of 25% residual activity
(Kumar, A., and Colman, R. F., Arch. Biochem. Biophys. 308, 357-366, 1994).
Inclusion of NADPH decreases both the extent of inactivation and the reagent
incorporation to 0.55 mol/mol of average subunit. We have now isolated the
peptides labeled by radioactive 8-(4-bromo-2,3-dioxobutylthio)-[2-3H]NAD and have
located them within the sequence of pig heart NAD-dependent isocitrate
dehydrogenase. The enzyme is composed of three types of subunits, present as
alpha 2 beta gamma. We have separated the subunits from unmodified and 8-BDBT[2
3H]NAD-modified enzymes by HPLC on a C4 reverse-phase column, after pretreatment
of the enzymes with sodium dodecyl sulfate or urea, and compared the subunit
sequences of the porcine enzyme with those of the corresponding subunits from
other mammalian NAD-dependent isocitrate dehydrogenases. The predominant
radioactivity of 8-BDBT[2-3H]NAD is observed in the alpha and gamma peaks, and
the NADPH-protected enzyme exhibits marked reduction in incorporation into these
peaks. However, evidence based on recombination of subunits from modified and
unmodified enzymes indicates that only labeling of the alpha-subunit is
responsible for inactivation by 8-BDB-TNAD. Cyanogen bromide was used to cleave
the modified enzyme, and we purified one labeled peptide from the alpha-subunit
(amino acids 84-177) as well as one from the gamma-subunit (amino acids 67-186).
In the alpha-subunit, decreased modification by [7-14C]-phenylglyoxal of Arg88
and Arg98 after prior labeling of the enzyme by 8-BDB-TNAD indicates that these
residues are the critical target sites of the reactive nucleotide analogue. We
conclude that alpha subunit's Arg88 and Arg98 are both at or near the allosteric
NADPH sites of the pig heart isocitrate dehydrogenase.
PMID- 9390194
TI - Substrate specificity and characterization of partially purified rat liver 13
hydroxyoctadecadienoic acid (13-HODE) dehydrogenase.
AB - Oxidation products of linoleic acid, such as 13-hydroxyoctadecadienoic acid (13
HODE), exhibit biological activity in a number of systems. One major metabolic
fate of 13-HODE is oxidation to the 2,4-dienone, 13-oxooctadecadienoic acid by an
NAD(+)-dependent dehydrogenase (13-HODE dehydrogenase). The present work
describes the partial purification and characterization of 13-HODE dehydrogenase
from rat liver cytosol. The enzyme was purified using a combination of ammonium
sulfate precipitation, as well as hydroxylapatite, gel permeation, and
hydrophobic interaction chromatography. Analysis of the most purified preparation
by SDS-polyacrylamide gel electrophoresis indicates two subunits of approximately
55 kDa, suggesting the possibility of a heterodimeric enzyme. However, due to
aggregation in the purified preparation, an accurate molecular mass for the
native enzyme has not yet been obtained. Using 13-HODE as a substrate, the
purified enzyme has a Km of 6.3 microM and a Vmax of 5.7 nmol/min/mg. More
importantly, the enzyme has a narrow substrate specificity with 13-HODE being the
preferred substrate. From a series of 17 potential substrates, only 9-HODE (53%
the activity of 13-HODE) and 15-hydroxyeicosatetraenoic acid (64% the activity of
13-HODE) showed significant activity as substrates. A number of other unsaturated
hydroxy fatty acids, including several eicosanoids, are not substrates. The
narrow substrate specificity displayed by the enzyme suggests that it could play
a key role in modulating the effects of oxidized derivatives of linoleic acid.
PMID- 9390195
TI - The homeodomain protein Pbx1 is involved in cAMP-dependent transcription of human
CYP17.
AB - Pbx1 is a homeodomain transcription factor involved in cAMP-dependent
transcriptional regulation of the bovine CYP17 gene. In this study, we have
investigated the involvement of Pbx1 in the transcriptional regulation of the
human CYP17 gene. Although a sequence identical to previously determined Pbx
binding sites is not present in the promoter region of the human CYP17 gene,
three putative Pbx-binding sites are identified by sequence similarity analysis.
Coexpression of Pbx1 and a catalytic subunit of protein kinase A (PKA) greatly
enhances reporter gene transcription via the 5'-flanking region of the human
CYP17 gene. Upon gel shift analysis utilizing nuclear extracts from human adrenal
H295R cells, one of the three putative Pbx1-binding sites, -250/-241 bp, shows
the typical intense doublet observed with other Pbx-binding sites. 5'-Deletion
analyses of the reporter construct containing this Pbx-binding site showed
approximately sixfold induction by coexpression of Pbx1 and PKA compared to the
basal transcription, suggesting that Pbx1 binds the -250/-241 bp sequence and
participates in cAMP-dependent regulation of the human CYP17 gene.
PMID- 9390196
TI - The tumor-bearing state induces augmented responses of organ-associated
lymphocytes to high-dose interleukin-2 therapy in mice.
AB - A high-dose bolus regimen for interleukin(IL)-2 administration to cancer patients
frequently causes serious side-effects in which various organs are involved. In
order to reveal the mechanism of toxicities associated with this regimen, we
compared the augmenting effect of high-dose IL-2 on murine organ-associated
lymphocytes between neoplastic and non-neoplastic states. Intraperitoneal
administration of IL-2 at a dose of 10(5) JRU (Japanese Reference Units) twice
daily for 3 days led to the death of all the syngeneic MH134-hepatoma- or X5563
myeloma-bearing mice, whereas it had no lethal effect on non-tumor-bearing mice.
Histological and morphometric analyses demonstrated that tumor-bearing mice
displayed more extensive infiltration of large granular lymphocytes and agranular
lymphocytes in the liver and lungs than did the non-tumor-bearing mice. Large
granular lymphocytes had the ultrastructural characteristics of lymphokine
activated killer cells. Lymphocytes often underwent extravasation into the
interstitial space and exhibited local proliferation without causing any direct
injury to apposed parenchymal cells. Flow-cytometric analysis of hepatic
mononuclear cells demonstrated that IL-2-receptor-beta (IL-2R beta)-bearing
lymphocytes, i.e., natural killer cells and intermediate CD3 cells, were
increased in number in the neoplastic state before the IL-2 injection. The
present study indicates that the tumor-bearing state increases the number of
organ-associated IL-2R beta + lymphocytes, which are then greatly amplified by
the challenge of high-dose IL-2, leading to the functional disturbance of organs.
We have further demonstrated here that an intermittent low-dose IL-2 regimen has
a potential therapeutic effect on tumor regression without causing lethal side
effects.
PMID- 9390197
TI - Restoration of macrophage tumoricidal activity by bleomycin correlates with the
decreased production of transforming growth factor beta in rats bearing KDH-8
hepatoma cells.
AB - To explore the mechanisms of immuno-modulatory activities of bleomycin, we
investigated interferon gamma (IFN gamma) mRNA expression, tumor necrosis factor
alpha (TNF alpha) production, nitric oxide (NO) production and macrophage
tumoricidal activities in rats bearing KDH-8 hepatoma cells, which secreted a
large amount of transforming growth factor beta (TGF beta), and these processes
in KDH-8 tumor-bearing rats treated with bleomycin. We found that IFN gamma mRNA
expression, TNF alpha production, NO production and macrophage cytotoxic
activities were lower in the KDH-8-bearing rats than in normal rats. On the other
hand, low-dose bleomycin restored the macrophage cytotoxic activities, NO
production, IFN gamma mRNA expression and TNF alpha production in the KDH-8
bearing rats. In vitro experiments showed that KDH-8-derived TGF beta decreased
the IFN gamma mRNA expression and TNF alpha production in splenocytes, and NO
production in peritoneal macrophages. These results suggest that low-dose
bleomycin restored the cytokine production and macrophage tumoricidal activities
in the KDH-8-bearing rats by decreasing KDH-8-derived TGF beta.
PMID- 9390198
TI - Treatment of recurrent glioma with intracavitary alloreactive cytotoxic T
lymphocytes and interleukin-2.
AB - For a single-dose toxicity assessment, five patients with recurrent malignant
glioma (ages 29-46 years) were treated with intracavitary alloreactive cytotoxic
T lymphocytes (CTL) and interleukin-2 (IL-2). The trial tested the hypothesis
that alloreactive CTL, sensitized to the major histocompatibility complex (MHC)
proteins of the patient, offer selective, targeted killing of glioma cells that
express MHC. Patient lymphocytes, which also express MHC, were irradiated and
placed into CellMax artificial capillary systems with lymphocytes from MHC
disparate donors and CTL developed over a 2- to 3-week period with a low
concentration of IL-2. The CTL largely expressed CD3 and CD11a/CD8 markers and
lysed targets displaying patient MHC. CTL were implanted into the tumor bed at
surgery and a catheter was used for subsequent infusions. Patients received one
to five treatment cycles every other month; one cycle generally consisted of two
or three CTL infusates administered within a 1- to 2-week period. Different
unrelated donors were used for each cycle. Treatment was well tolerated;
transient toxicity at grades 1-3 was recorded by NCI Common Toxicity Scale
criteria. Two glioblastoma patients have died; one from tumor recurrence locally
and the other from recurrence at a site distant from the treatment. Two of the
five patients completed five cycles; one anaplastic oligodendroglioma patient
shows no evidence of tumor 30 months from the start of immune therapy and an
anaplastic astrocytoma patient shows stable disease 28 months after initiation of
therapy. One anaplastic oligodendroglioma patient, who dropped the protocol
during her second treatment cycle, has no evidence of tumor 28 months after
recurrence.
PMID- 9390199
TI - Sequence variation in the monoclonal-antibody-U36-defined CD44v6 epitope.
AB - Monoclonal antibody (mAb) U36 was developed for the treatment of minimal residual
disease of head and neck squamous cell carcinoma (HNSCC). The mAb-U36-defined
antigen was characterized by cDNA cloning, and was shown to be identical to the
keratinocyte-specific CD44 splice variant epican. The epitope recognized by mAb
U36 was shown to be located in the v6 domain. Two amino acids within the epitope
appeared to differ from the sequences that have been described in literature. The
sequence of the epitope appeared to contain glutamic acid at position 367 and
lysine at position 374, while valine and arginine respectively have been
described before. Interestingly, another anti-CD44v6 antibody with possible
clinical application, VFF18, recognizes an epitope in the same area. With respect
to the applicability of these antibodies for tumor targeting, this variation
might have an influence on antibody-antigen interaction and mAb accumulation in
the tumor. Furthermore, this observation raised the question whether the
different epitopes are related to the malignant behavior of tumor cells. In this
paper we determine the relative affinity of mAb U36 for the variant epitope
sequences by tumor cell binding assays using synthetic peptides for competition.
The presence of glutamic acid instead of valine at position 367 caused strong
competition. Further evaluation showed that the published valine variant does not
exist in vivo, and is the result of a sequencing artefact. The effect of
substitution of lysine for arginine at position 374 had no effect on the binding
of mAb U36 to the cells. This amino acid variation was shown to be due to allelic
polymorphism. There was no trend towards allelic imbalance in tumor cells as
compared to normal cells.
PMID- 9390200
TI - Intrapleural instillation of interferon gamma in patients with malignant pleurisy
due to lung cancer.
AB - The effect of intrapleural instillation of recombinant human interferon gamma
(IFN gamma) at increasing doses of (1-12) x 10(6) U was examined in six patients
with cytologically positive pleural effusion due to lung cancer. Intrapleural
instillation was repeated up to three times. Clinically, no reaccumulation of
pleural effusion was observed in one patient and disappearance of lung cancer
cells from the pleural effusion was seen in two other patients. No severe side
effects were observed. Considerable levels of IFN gamma remained in the pleural
effusion as well as in patients' serum up to 7 days after instillation of 2 x
10(6) U and higher doses. The total cell number showed a transient decrease on
day 1 of therapy. Levels of pro-inflammatory cytokines, such as tumor necrosis
factor alpha, interleukin(IL)-1 beta and IL-6, in the pleural effusion remained
almost stable after IFN gamma instillation. On the other hand, intrapleural IL-1
receptor antagonist levels were remarkably elevated by the instillation of IFN
gamma. IL-2- and IL-12-inducible killer activity of pleural mononuclear cells
tended to increase slightly. Despite the inability of IFN gamma to control
pleural effusion in this treatment schedule, IFN gamma instilled by an
intrapleural route had a potential local antitumor activity. Moreover, since IFN
gamma persists in pleural effusions for a long time after a single instillation,
such a therapy in combination with other fibrogenic biological response modifiers
can be promising.
PMID- 9390201
TI - Antitumor effects of the combination immunotherapy with interleukin-12 and tumor
necrosis factor alpha in mice.
AB - There is strong evidence that antitumor activity of interleukin-12 (IL-12) in
vivo is mediated, in part, through interferon (IFN gamma) produced by IL-12
stimulated natural killer and T cells. Since IFN gamma and tumor necrosis factor
alpha (TNF alpha) have been reported to synergize in antitumor effects in a
number of models, we decided to examine whether the combined treatment with
recombinant mouse IL-12 and recombinant human TNF alpha would produce similar
effects. The efficacy of the combined IL-12/TNF alpha immunotherapy was evaluated
in three tumor models in mice: B16F10 melanoma, Lewis lung (LL/2) carcinoma and
L1 sarcoma. Intratumoral daily injections of 1 microgram IL-12 in combination
with 5 micrograms TNF alpha into B16F10-melanoma-bearing mice resulted in a
significant retardation of the tumor growth as compared with that in controls and
in mice treated with either cytokine alone. Similar effects were obtained using
0.1 microgram IL-12 and 5 micrograms TNF alpha in LL/2 carcinoma and L1 sarcoma
models. Antitumor activity against L1 sarcoma was still preserved when TNF alpha
at a low dose (1 microgram) was combined with 0.1 microgram IL-12 and applied for
a prolonged time. Potentiation of antitumor effects, which was observed in IL
12/TNF alpha-based immunotherapy, could result from at least three different
mechanisms, partly related to stimulation of IFN gamma and TNF alpha production
in treated mice: (a) direct cytostatic/cytotoxic effects on tumor cells, (b)
induction of antitumor activity of macrophages, and (c) inhibition of blood
vessel formation in the tumor. Our studies demonstrate that combination tumor
immunotherapy with IL-12 and TNF alpha may be more effective than single-cytokine
treatment, and suggest possible mechanisms by which IL-12 and TNF alpha may exert
potentiated therapeutic effects against locally growing tumors.
PMID- 9390202
TI - Active and indolent chronic lymphocytic leukaemia--immune and hormonal
peculiarities.
AB - A group of 138 B cell chronic lymphocytic leukaemia (B-CLL) patients, 83 with
active disease and 53 having the indolent form of the disease, were evaluated.
The aim of the study was to clarify whether indolent and active B-CLL differ in
their immune and hormonal characteristics. Peripheral blood lymphocyte
proliferation in response to phytohaemagglutinin, concanavalin A, recombinant
interleukin-2, dextran sulphate, Pisum sativatum agglutinin and wheat germ
agglutinin was investigated. Serum immunoglobulin and beta 2 microglobulin levels
were determined. Adrenocorticotropic hormone (ACTH), cortisol, follicle
stimulating hormone luteinizing hormone, 17 beta-oestradiol, testosterone,
triiodothyronine, thyroxine, thyroglobulin and thyrotropic hormone levels were
determined by radioimmunoassay. Active and indolent CLL presented differences in
immunological characteristics, as demonstrated by the more severe suppression of
T lymphocyte function, reduced IgA level and considerably higher serum beta 2
microglobulin values in active disease. Immune disturbances were accompanied by
hormonal imbalance, depending on disease status: lower ACTH, cortisol and
triiodothyronine levels were established to occur in active CLL compared to
indolent disease. Male patients demonstrated striking changes in sex hormones,
which were more evident in active disease. The findings point to the complexity
of immuno-hormonal disturbances in CLL with differences in the active and
indolent state of the disease.
PMID- 9390203
TI - The antitumor effects of levamisole in mice are mediated by NC-1.1+ cells.
AB - Murine natural cytotoxicity, which is a major component of the innate immune
response in cancer, is mediated by leukocytes that express the NC-1.1 receptor.
Mice depleted of natural cytotoxicity by treatment with an anti-NC-1.1 mAb show
enhanced growth of certain transplantable tumors, so agents that enhance natural
cytotoxicity by NC-1.1+ cells have the potential to be effective anticancer
therapeutic agents. We have examined the immunomodulatory effect of levamisole on
natural cytotoxicity mediated by NC-1.1+ cells against the BALB/c WEHI-164 murine
fibrosarcoma. Administration of levamisole to BALB/c mice significantly enhanced
in vitro splenic natural cytotoxicity against 51Cr-labeled WEHI-164 tumor cells.
The effect was most marked 48 h after levamisole treatment, at a dose of 10 mg/kg
body weight. This enhancement of natural cytotoxicity by levamisole could be
completely abrogated by pretreatment of mice with an anti-NC-1.1 mAb. Treatment
of BALB/c mice with 10 mg/kg levamisole significantly reduced the growth of WEHI
164 and this effect was abrogated by pretreatment of mice with anti-NC-1.1,
indicating that the antitumor effect of levamisole was mediated, at least in
part, via NC-1.1+ cells.
PMID- 9390204
TI - Utility of hyaluronic acid in pleural fluid for differential diagnosis of pleural
effusions: likelihood ratios for malignant mesothelioma.
AB - The level of hyaluronic acid (HA) was determined in the pleural fluid of 99
patients, including 19 with malignant mesothelioma, 27 with lung cancer, 1 with
breast cancer, 1 with mediastinal tumor and 51 with non-malignant diseases. With
a cut-off level at 100 micrograms/ml, the pleural fluid concentration of HA was
high in 36.8% of patients (7 of 19) with malignant mesothelioma and 1.3% of
patients (1 of 80) with lung cancer and other malignant and non-malignant
diseases. The mean concentration of pleural fluid HA was significantly higher in
patients with mesothelioma than in those with lung cancer and other malignant and
non-malignant diseases. The pre-test probability of MM was 5.9% in this series.
The LRs for > or = 100, 50-99 and < or = 49 micrograms/ml are 28.3, 3.3 and 0.5,
respectively; these put the post-test probabilities at 64, 17 and 3%,
respectively. Indeed, in cases of uncommon disease such as MM, the post-test
probability is low even if the cut-off level of HA is > or = 100 micrograms/ml.
The discrimination between malignant mesothelioma and lung cancer needs special
attention. In these two diseases, the LRs of MM for pleural fluid CEA > 30, 10-30
and < 10 ng/ml were 0.2, 1.9 and 2.4, respectively. The pre-test probability of
MM for HA > or = or 100 micrograms/ml is 64%. Furthermore, because the LR for CEA
is < 10 ng/ml, the post-test probability is 81%. When the combination of two
markers is considered, the high level of HA and the low level of CEA may be
useful for the differential diagnosis of MM from pleuritis carcinomatosa.
PMID- 9390205
TI - Prognostic significance of argyrophilic nucleolar organizer region (AgNOR) in
resected non-small cell lung cancer (NSCLC).
AB - The expression of the nucleolar organizer regions (NORs) was quantified in
paraffin sections of tumors and lymph node metastasis, by means of digital image
analysis, in 75 patients with resected non-small cell lung cancer (NSCLC).
Patients were divided in two groups: early stage (stages I and II) and advanced
stage (stages IIIa, IIIb and IV). The prognostic significance of AgNOR expression
was tested by Cox regression analysis in models controlled for age, sex, vital
status, stage and histological type. Tumors at early stages had a lower
expression of AgNOR than those at more advanced diseases. The mean values
obtained for NORs in advanced disease were almost the same as those in the
primary tumors when compared with the corresponding lymph node metastasis (r =
0.90; p < 0.01; linear regression). The prognostic role of AgNOR was significant
only for tumors at stages I and II and not for advanced neoplasms (stages IIIa,
IIIb and IV). These results encourage the inclusion of AgNOR quantitation in
routine material, especially in early lung cancer.
PMID- 9390206
TI - Revisit of primary malignant neoplasms of the trachea: clinical characteristics
and survival analysis.
AB - A clinical review with an analysis of prognostic factors, including clinical
characteristics, histological classifications, presenting symptoms/signs and
treatment modalities, was conducted in 67 patients with primary malignant
neoplasms of the trachea who were seen at the Veterans General Hospital-Taipei
between 1979 and 1994. The incidence of tracheal cancer was 140 times less than
lung cancer during this period. Delayed diagnosis of more than 6 months after
onset of symptoms occurred in one-third of the patients owing to lack of specific
symptoms/signs indicative of tracheal disease. Epidermoid carcinoma was the most
frequent histological type encountered and accounted for half of the cases.
Surgical resection was the first choice of treatment for all patients if the
disease was locally confined, except for small cell carcinoma and lymphoma.
Radiotherapy was given if the patient was not suitable for surgery. Single and
multivariate analyses showed that clinical symptoms and signs were not related to
prognosis, except for general malaise and acute respiratory failure. Patients
suffering from adenoid cystic carcinoma and mucoepidermoid carcinoma had a better
prognosis than other histological diagnoses. Whether the patient received
radiotherapy or not proved to be a significant prognostic factor in the patients.
Patients with tracheal cancers had a poorer prognosis than those with lung
cancer.
PMID- 9390207
TI - Feasibility of adjuvant chemotherapy for breast cancer patients.
AB - To evaluate the feasibility of adjuvant chemotherapy, we analyzed the toxicities
of chemotherapy for primary breast cancer in Japanese women. Since the opening of
the National Cancer Center Hospital East, 180 female breast cancer patients have
received adjuvant chemotherapy or chemo-hormonal therapy following surgical
treatment between June 1992 and December 1995. On the basis of informed consent
about prognosis and adjuvant therapy, most patients decided to choose the type of
cytotoxic chemotherapy themselves. Adjuvant chemotherapy consisted of oral
fluoropyrimidine compounds (OFP), cyclophosphamide + adriamycin +/- 5
fluorouracil [CA(F)] or cyclophosphamide + methotrexate + 5-fluorouracil (CMF).
Toxicity was determined using the Toxicity Grading Criteria of the Japan Clinical
Oncology Group (JCOG). Sixty-six patients received OFP, 59 CA(F) and the rest 55
CMF. The toxicity grading of leukocytes and neutrophils was significantly higher
in patients treated with CA(F) or CMF than in those treated with OFP. Similar
results were also seen relating to the toxicity of nausea/vomiting and alopecia.
There was no statistical difference in the toxicity grading of hemoglobin,
glutamic oxaloacetic transaminase/glutamic pyruvic transaminase (GOT/GPT) and
stomatitis/ gastritis between the three groups of patients. Interestingly, the
number of patients that were forced to discontinue chemotherapy was higher in
those receiving OFP than in those receiving CA(F) or CMF. Cytotoxic chemotherapy
of CA(F) or CMF results in greater toxicity than OFP, but is tolerated and
feasible in the adjuvant setting used in Japanese breast cancer patients from the
viewpoint of toxicities by anticancer chemotherapy.
PMID- 9390208
TI - Treatment of previously treated metastatic breast cancer by mitoxantrone and 48
hour continuous infusion of high-dose 5-FU and leucovorin (MFL): low palliative
benefit and high treatment-related toxicity.
AB - For previously treated advanced breast cancer, there is no standard second-line
therapy. Combination chemotherapy with mitoxantrone, high-dose 5-fluorouracil (5
FU) and leucovorin (MFL regimen) had been reported as an effective and well
tolerated regimen. From October 1993 to November 1995, we treated 13 patients
with previously chemotherapy-treated metastatic breast cancer by mitoxantrone, 12
mg/m2, on day 1 and continuous infusion of 5-FU, 3000 mg/m2, together with
leucovorin, 300 mg/m2, for 48 h from day 1 to 2. Each course of chemotherapy was
given every 4 weeks. Most of these patients had more than two metastatic sites,
with lung metastasis predominant. Seven patients had been treated with
anthracycline. Seven patients had previously received radiotherapy and seven had
received hormone therapy. Median number of courses of MFL regimen given was six
and the median cumulative dose of mitoxantrone was 68.35 mg/m2. One patient had
complete response, seven had stable disease, none had partial response and five
had progressive disease. The overall objective response rate was 7.6%. The median
follow-up period was 14 months. Median survival was 16 months. Median progression
free survival was 5 months. A complete responder had relapse-free survival up to
17 months. Major toxicities were cardiotoxicity and leukopenia. Eight patients
were dead in the last follow-up; two of them died of treatment-related toxicity.
The MFL regimen achieves little palliative benefit and induces severe toxicity at
a fairly high rate. Administration of this regimen to breast cancer patients who
have been treated by chemotherapy and those with impaired heart function requires
careful attention.
PMID- 9390209
TI - Predictive factors for tumor response to systemic chemotherapy in patients with
hepatocellular carcinoma.
AB - Chemotherapy is of limited value in the treatment of hepatocellular carcinoma
(HCC), since there are no established chemotherapeutic regimens proven to be
effective. The aim of the present study was to determine predictive factors for
tumor response to systemic chemotherapy in HCC patients. The relationship between
patients' characteristics and tumor response was examined in 147 previously
untreated HCC patients receiving systemic chemotherapy. Ten patients showed
partial response (PR) and none showed complete response (CR). The response rate
for all single anticancer agents was less than 10% and the overall response rate
was 6.8%. The response rate in patients with unilateral HCC was significantly
higher than in those with bilateral HCC. However, there were no responders among
patients with a performance status of 2-3, ascites, a tumor occupying more than
50% of the entire liver, tumor thrombus in the main portal trunk or a serum
bilirubin level of more than 2.0 mg/dl. There was a close relationship between
patients' characteristics and tumor response. It is concluded that patients with
fairly advanced HCC and/or poor hepatic reserve should not be given systemic
chemotherapy.
PMID- 9390210
TI - A phase II study of high-dose epirubicin (EPI) plus cyclophosphamide (CPA) with G
CSF for breast cancer patients with visceral metastases or hormone-independent
tumors: a trial of the Japan Clinical Oncology Group.
AB - To evaluate the efficacy and toxicity of high-dose epirubicin (EPI) plus
cyclophosphamide (CPA) therapy, a phase II study of EPI, 130 mg/m2, plus CPA,
1000 mg/m2, with G-CSF every 3 weeks was carried out for 51 advanced or recurrent
breast cancer patients by the Japan Clinical Oncology Group (JCOG). Fifty out of
the 51 patients who were eligible for our criteria were treated with this regimen
as first-line chemotherapy for visceral metastases or hormone-independent tumors.
In this trial, 203 cycles were administered with an average of four cycles per
patients. In 50 patients who were evaluable for response, there were 7 complete
(CR) and 25 partial responses (PR) with an overall response rate of 64% (95%
confidence interval, 50.1-75.9%). Symptomatic and hematological acute toxicity
more than grade 3 occurred frequently; however, no treatment-related death
occurred. The incidence of toxicities (> or = grade 3) was as follows: leukopenia
98%, thrombocytopenia 42%, nausea/vomiting 56% and hair loss 12%. In each cycle,
daily administration of 2 micrograms/kg G-CSF (granulocyte-colony stimulating
factor) was given on days 2-15 subcutaneously. The incidence of cardiotoxicity
was low. Arrhythmia (< or = grade 2) was observed in 8% and a slight decrease of
ejection fraction index (< or = grade 2) was observed in 2% in this trial. The
median follow-up period for patients was 37.2 (24.6-51.5) months and the median
survival period was 17.4 months. These data indicate that high-dose EPI + CPA
combination chemotherapy was effective and well tolerated for breast cancer
patients with visceral metastases or hormone-independent tumors. A randomized
trial of high-dose EPI vs conventional chemotherapy is required to ascertain the
usefulness of this regimen.
PMID- 9390211
TI - A pilot study of multimodality therapy for initially unresectable liver
metastases from colorectal carcinoma: hepatic resection after hepatic arterial
infusion chemotherapy and portal embolization.
AB - The prognosis of patients with unresectable liver metastases is poor, even if
hepatic arterial infusion chemotherapy (HAI) or systemic chemotherapy is
administered. A pilot study was performed to evaluate the feasibility and
efficacy of multimodality therapy with hepatectomy after HAI and portal
embolization for such patients. Eight patients with colorectal carcinoma and
synchronous unresectable liver metastases underwent resection of the primary
tumor and placement of a pump, followed by HAI with 5-fluorouracil and mitomycin
C. Owing to shrinkage of the liver metastases, two patients could undergo
extended right hepatic lobectomy after portal embolization, which was deemed to
be essential to prevent post-operative hepatic failure. The median survival time
of the eight patients was 30 months, with a response rate of 75%. Complications
including sclerosing cholangitis and duodenal ulcer were observed in five
patients (63%). Additional hepatectomy could be performed successfully after
portal embolization without morbidity in two patients. These two patients are
still alive more than 6 years after initiation of HAI and have been free of
disease for more than 5 years after hepatectomy. Hepatectomy after HAI and portal
embolization is feasible and may be an option to cure selected patients with
initially unresectable liver metastases.
PMID- 9390212
TI - Prolonged survival in a nasopharyngeal carcinoma patient with multiple
metastases: a case report and review of the literature.
AB - Nasopharyngeal carcinoma is a common cancer in South East Asia. In the early
stages, radiotherapy alone may achieve sustained control, but once metastasis
occurs, it becomes an incurable disease with limited survival time. We report a
case of nasopharyngeal carcinoma, initial stage T4N0M0, diagnosed in 1985 in a
patient aged 36 years who received 70 Gy radiotherapy to the head and neck
region. In 1988, relapse occurred with multiple lung metastases. The patient
received many chemotherapy regimens with a very good response, including near
complete remission with the first treatment regimen of cisplatin, 5-fluorouracil
and leucovorin for lung metastases, and with the fifth chemotherapy regimen of
ifosfamide as a single agent. After ifosfamide treatment, there was residual
fibrotic change in the lung and complete disappearance, lasting for almost a
year, of the liver and bone lesions. The patient eventually died in July 1995 due
to progressive disease. Prolonged survival after mainly thoracic metastasis is
possible in patients with nasopharyngeal carcinoma, especially if the tumor is
chemo-responsive.
PMID- 9390213
TI - Thyroglossal duct carcinoma: a case report.
AB - We describe a 47-year-old woman with a 13-year history of asymptomatic midline
submental swelling. Cytologic examination of a fine-needle aspiration specimen
from the solid mass revealed adenocarcinoma. The preoperative diagnosis was
thyroglossal duct carcinoma. A Sistrunk procedure was performed and microscopic
examination revealed papillary adenocarcinoma. The postoperative course was
uneventful and there were no signs of local recurrence or metastasis at one year
after surgery.
PMID- 9390214
TI - Hepatocellular carcinoma with gastrointestinal hemorrhage caused by direct tumor
invasion to the duodenum.
AB - Gastrointestinal hemorrhage from hepatocellular carcinoma invading the duodenum
is very rare. A 60-year-old man with multiple hepatocellular carcinoma was
admitted to our hospital because of massive melena and hematemesis. We succeeded
in hemostasis of an esophageal variceal rupture by endoscopic varicial ligation.
The duodenum could not be observed endoscopically due to extramural compression
to the stomach from the liver tumor. Massive gastrointestinal hemorrhage occurred
again and the patient died of hepatic failure. The postmortem examination
revealed that the liver tumor had invaded the second portion of the duodenum and
perforated into the lumen.
PMID- 9390215
TI - Pheochromocytoma growing exophytically from the right adrenal gland and
invaginating into the liver.
AB - A 5-cm pheochromocytoma located in segment 7 of the liver was found incidentally
in a 45-year-old man with mild diabetes mellitus and hypertension, and resected.
The tumor was demonstrated by computed tomography and magnetic resonance imaging
to have completely invaginated itself into the liver and to be receiving blood
from a dilated right hepatic artery alone. Surgery revealed the hepatic mass to
be tightly adherent to the right adrenal gland. The histopathologic diagnosis was
pheochromocytoma growing exophytically from the right adrenal gland. There was no
association with multiple endocrine neoplasia type 1 and type 2. A postoperative
131I metaiodobenzylguanidine scan revealed no accumulation, and the patient is
currently doing well without recurrence or hypertension one year after the
operation. A pheochromocytoma deeply invaginating into the liver should be
considered in the differential diagnosis of primary hypervascular hepatic tumors.
PMID- 9390216
TI - Adenomyomatous polyp of the uterus in a patient receiving tamoxifen.
AB - We report a case of adenomyomatous polyp that developed during treatment with
tamoxifen for breast cancer. A 63-year-old Japanese woman was admitted
complaining of atypical genital bleeding. Nine months earlier, she had undergone
a modified radical mastectomy for cancer of her right breast, estrogen receptor
positive stage I (T1N0M0). The administration of tamoxifen, 20 mg/day, was
started immediately postoperatively. Pelvic examination after tamoxifen
administration for 9 months revealed that the uterus was enlarged to the size of
a fist. Transvaginal ultrasonography and magnetic resonance imaging revealed a
large solid mass with multiple cystic areas in the uterine cavity. The
pathological diagnosis of the tumor after total hysterectomy was typical
adenomyomatous polyp. It was believed to have developed during tamoxifen
administration.
PMID- 9390217
TI - Coxalgia as the initial symptom in Hodgkin's disease: a case report.
AB - Primary Hodgkin's disease in the bone is extremely rare. We report the case of a
41-year-old woman with Hodgkin's disease, who had complained of left coxalgia 17
months prior to nodal involvement becoming evident clinically. She received
combination chemotherapy with doxorubicin, bleomycin, vincristine and dacarbazine
as well as radiotherapy to the pelvic lesion. Although the lymphadenopathy
responded well to this treatment, the bone lesion was never in remission. The
large mass of the bone lesion and its pelvic origin may explain the poor response
to the cytotoxic therapies this patient received. The 22 cases reviewed showed
that: 1, bony pain was the most frequent initial symptom; 2, nodal disease
appeared in their clinical course in most cases; 3, the bones most commonly
involved were pelvis, femur or tibia, and spine.
PMID- 9390218
TI - Localized muscular mucormycosis in a child with acute leukemia.
AB - Mucormycosis is a rare fungal infection of childhood, occurring mainly in
patients with chronic illnesses such as diabetes and malignancies. The fungus
seldom grows in culture and confirmation of the diagnosis depends on histologic
examination of infected tissues. To date, the reported natural history of the
disease has been rapid progression and a fatal outcome. Therefore, the importance
of early diagnosis by tissue biopsy and early treatment with surgical debridement
and systemic antifungal therapy cannot be overemphasized. The pulmonary system is
the most common site for mucormycosis in patients with leukemia. We report what
we believe to be the first successfully treated case of isolated muscular
mucormycosis occurring in a child with biphenotypic acute leukemia. The diagnosis
was made promptly by tissue examination at the time of surgical debridement. The
patient was also given systemic amphotericin-B therapy.
PMID- 9390219
TI - Report of the Tenth International Symposium of the Foundation for Promotion of
Cancer Research: Basic and Clinical Research in Head and Neck cancer.
PMID- 9390220
TI - Japanese challenge to gastric cancer surgeons: add 'meticulous accuracy' to
Halsted's 'gentleness, haemostasis and minimal trauma'.
PMID- 9390221
TI - Protein structure comparison using representation by line segment sequences.
AB - This paper proposes a new comparison method of tertiary protein structures. The
method consists of two parts. First, a sequence of line segments which
approximates each tertiary protein structure is computed. Then, an alignment of
the sequences of line segments corresponding to input structures is computed. The
proposed method is considered as an intermediate one between two comparison
methods: a method based on topology diagram and a method based on structure
alignment. Moreover it takes less CPU time than structure alignment methods
because most structures are represented by means of sequences of at most 100 line
segments. The effectiveness of the method is confirmed through a comparison with
a previous method and an application to database searching for similar
structures.
PMID- 9390222
TI - Quaternion contact ribbons: a new tool for visualizing intra- and intermolecular
interactions in proteins.
AB - Protein side chain interactions between residues separated by at least one loop
or turn or break in the amino acid sequence are called 'nonlocal contacts' in
this manuscript, and contiguous sets of such interactions located between
segments of secondary structure are called 'contact zones.' A new interactive
program, the quaternion contact ribbon tool, has been developed to help protein
chemists identify, straighten if twisted, and display contact zones between two
neighboring segments of helix.
PMID- 9390223
TI - Fast protein fold recognition via sequence to structure alignment and contact
capacity potentials.
AB - We propose new empirical scoring potentials and associated alignment procedures
for optimally aligning protein sequences to protein structures. The method has
two main applications: first, the recognition of a plausible fold for a protein
sequence of unknown structure out of a database of representative protein
structures and, second, the improvement of sequence alignments by using
structural information in order to find a better starting point for homology
based modelling. The empirical scoring function is derived from an analysis of a
nonredundant database of known structures by converting relative frequencies into
pseudoenergies using a normalization according to the inverse Bolzmann law. These
so called contact capacity-potentials turn out to be discriminative enough to
detect structural folds in the absence of significant sequence similarity and at
the same time simple enough to allow for a very fast optimization in an alignment
procedure.
PMID- 9390224
TI - A programming course in bioinformatics for computer and information science
students.
AB - We have created a course entitled "Representations and Algorithms for
Computational Molecular Biology" with three specific goals in mind. First, we
want to provide a technical introduction for computer science and medical
information science students to the challenges of computing with molecular
biology data, particularly the advantages of having easy access to real-world
data sets. Second, we want to equip the students with the skills required of
productive research assistants in molecular biology computing research projects.
Finally, we want to provide a showcase for local investigators to describe their
work in the context of a course that provide adequate background information. In
order to achieve these goals, we have created a programming course, in which
three major projects and six smaller assignments are assigned during the quarter.
We stress fundamental representations and algorithms during the first part of the
course in lectures given by the core faculty, and then have more focused lectures
in which faculty research interests are highlighted. The course stressed issues
of structural molecular biology, in order to better motivate the critical issues
in sequence analysis. The culmination of the course was a challenge to the
students to use a version of protein threading to predict which members of a set
of unknown sequences were globins. The course was well received, and has been
made a core requirement in the Medical Information Sciences program.
PMID- 9390225
TI - Massively parallel algorithms for chromosome reconstruction.
AB - Ordering clones from a genomic library into physical maps of whole chromosomes
presents a central computational problem in genetics. Chromosome reconstruction
via clone ordering is shown to be isomorphic to the NP-complete Optimal Linear
Ordering problem. Massively parallel algorithms for simulated annealing based on
Markov chain distribution are proposed and applied to this problem. Perturbation
methods and problem-specific annealing heuristics are proposed and described.
Experimental results on a 2048 processor MasPar MP-2 system are presented.
Convergence, speedup and scalability characteristics of the various algorithms
are analyzed and discussed.
PMID- 9390226
TI - Structure formation of biopolymers is complex, their evolution may be simple.
AB - Evolutionary strategies depend on the ability of evolving entities to conserve
acquired features and to quickly adapt to new requirements as well. We use
computer simulations of simplified exact biopolymers models to investigate the
influence of mutations on structure formation. Our computations on large
ensembles of random RNA secondary structures show that the sequence to structure
mapping is ideally suited for evolutionary optimisation under point mutations:
from any random structure it is not far to any target and yet most mutations will
preserve the structure. The aim of this paper is to discuss the analogies as well
as some recently developed methods to apply our approach to proteins: there we
use Dill's HP - model of lattice proteins and apply a novel fast and efficient
folding rule. There are remarkable similarities as both landscapes are rugged and
structure formation largely depends on local interactions such that it is
possible to accomplish a characterisation of the mapping similar to the RNA case.
PMID- 9390227
TI - RNA pseudoknot modeling using intersections of stochastic context free grammars
with applications to database search.
AB - A model based on intersections of stochastic context free grammars is presented
to allow for the modeling of RNA pseudoknot structures. The model runs relatively
fast, having the same order running time as stochastic context free grammar
parsers. The model is shown to be able to perform database searches and find RNA
sequences which resemble RNA pseudoknots which bind biotin. The problem domain of
RNA biotin binders has significance in the support of the RNA world model of
early life on earth.
PMID- 9390228
TI - How similar must a template protein be for homology modeling by side-chain
packing methods?
AB - Given the correct backbone coordinates of a globular protein, side-chain packing
methods can be generally expected to predict the side-chain coordinates of the
buried core residues accurately. In the context of a study in modeling a family
of bacteriophage DNA-binding proteins, we observed that when the coordinates of
the actual perfect backbone are not available, the side-chain packing methods are
still of predictive value using homologous but imperfect backbones. This is the
situation in practical homology modeling where a target protein sequence is
modeled from template structures of known protein homologs. In order to assess
the quality and degree of accuracy of such predictions and their dependence on
the extent of homology, we have now extended these studies to a well
characterized family of globin structures that span a much wider range of
sequence-structure similarity. The collective results show a clear relationship
that is independent of protein family between side-chain prediction accuracy and
the level of similarity between the template and target proteins. We judge this
similarity in terms of sequence identity and the backbone r.m.s. deviation of the
template structure used for modeling and the actual target structure in cases
where the target structures are available. In summary, as sequence identity drops
from 100% to about 50%, or when the backbone r.m.s. deviation between template
and target structures increases from 0 A to about 1 A, the overall average r.m.s.
error for the buried-core residues rises from 1.2 A to 1.5 A while the chi 1
prediction accuracy drops from 85% to 70-75% and the chi 2 prediction accuracy
drops from 80% to 60-65%. When the sequence identity drops below 50% or the
backbone r.m.s. deviation rises above 1 A, all 3 measures of prediction accuracy
decrease rapidly. When the sequence identity edges to the so-called twilight zone
of sequence similarity at around 22%, or when the backbone r.m.s. deviation
exceeds 2 A, the prediction accuracy approaches the values to be expected for
random predictions, namely, 3.1 A for average r.m.s. error, 22% and 29% for
accuracy of chi 1 and chi 2 prediction. These observations provide a practical
evaluation of the side-chain packing methods and are of value to the homology
modeler. The extent and degree to which the backbone topology of a protein fold
can constrain internal side-chain orientation gives insight into the plasticity
of the sequence-structure relationship found in the architecture of proteins.
PMID- 9390229
TI - Mixed direct-iterative methods for boundary integral formulations of dielectric
solvation models.
AB - This paper describes a mixed direct-iterative method for boundary integral
formulations of dielectric solvation models. We give an example for which a
direct solution at thermal accuracy is nontrivial and for which Gauss-Seidel
iteration diverges in rare but reproducible cases. This difficulty is analyzed by
obtaining the eigenvalues and the spectral radius of the iteration matrix. This
establishes that the nonconvergence is due to inaccuracies of the asymptotic
approximations for the matrix elements for accidentally close boundary element
pairs on different spheres. This difficulty is cured by checking for boundary
element pairs closer than the typical spatial extent of the boundary elements and
for those pairs performing an 'in-line' Monte Carlo integration to evaluate the
required matrix elements. This difficulty are not expected and have not been
observed when only a direct solution is sought. Finally, we give an example
application of these methods to deprotonation of monosilicic acid in water.
PMID- 9390230
TI - (Probably) all possible protein folds at low resolution.
AB - For decades, a large number of investigators have been sifting the database of
experimentally determined three-dimensional protein structures to discover
recurring patterns of all types. Now that there are over a thousand such
structures available, the natural question is whether we have seen all
substantially different protein folds, and if not, how many have yet to be
discovered? Answering the question can be broken down into three steps: (1)
choose the range and domain for a similarity function, then (2) choose a
particular similarity function, and (3) construct a corresponding protein model
space that can be searched for dissimilar structures. In our analysis of the
problem, we first chose to examine different conformations of the same protein,
taking into account only C alpha atomic coordinates. In particular, we do not
compare proteins of different chain lengths on the basis of some kind of gapped
alignment. Secondly, we use a measure of conformational similarity based on rigid
body superposition that emphasizes overall geometric resemblance, rather than
agreement in secondary structure, for example. Third, we employed the discrete
cosine transform to construct exhaustive sets of globular self-avoiding C alpha
traces that were all different from each other by a given level. These sets of
artificial structures were not too large to explicitly enumerate as long as the
level of dissimilarity was high, and the chain flexibility was low. For chains
flexible enough to match all experimental structures of 170 residue or less that
are not beta-barrels, we find 128 artificial structures, of which 28 resemble
nothing in the Protein Data Bank.
PMID- 9390231
TI - DNA computing based on splicing: universality results.
AB - The paper extends some of the most recently obtained results on the computational
universality of specific variants of H systems (e.g. with regular sets of rules)
and proves that we can construct universal computers based on various types of H
systems with a finite set of splicing rules as well as a finite set of axioms,
i.e. we show the theoretical possibility to design programmable universal DNA
computers based on the splicing operation. For H systems working in the multiset
style (where the numbers of copies of all available strings are counted) we
elaborate how a Turing machine computing a partial recursive function can be
simulated by an equivalent H system computing the same function; in that way,
from a universal Turning machine we obtain a universal H system. Considering H
systems as language generating devices we have to add various simple control
mechanisms (checking the presence/absence of certain symbols in the spliced
strings) to systems with a finite set of splicing rules as well as with a finite
set of axioms in order to obtain the full computational power, i.e. to get a
characterization of the family of recursively enumerable languages. We also
introduce test tube systems, where several H systems work in parallel in their
tubes and from time to time the contents of each tube are redistributed to all
tubes according to certain separation conditions. By the construction of
universal test tube systems we show that also such systems could serve as the
theoretical basis for the development of biological (DNA) computers.
PMID- 9390232
TI - Parallel discrete event simulation of Lyme disease.
AB - Our research concerns the dynamic processes underlying the rapid increase in the
geographic distribution of Lyme disease, currently the most frequently reported
vector-borne disease of humans in the United States [10, 1]. More specifically,
we ask how spatially localized ecological interactions drive the Lyme disease
epidemic at extended spatial and temporal scales. We have developed a parallel
discrete event simulation system in C++ for the IBM SP2. The simulation model
discussed here models the mouse-tick interaction, an essential element of the
epidemic's ecology. The main entities of the simulation are ticks in various
stages of development (larval, nymphal, and adult) and mice. We track the
behavior of mice and the spread of disease over the course of 180 days (late
spring, summer, and early fall). Our goal is to understand patterns in the Lyme
disease epidemic at the regional scale through studying the spread of the
pathogen across a single white-footed mouse deme.
PMID- 9390233
TI - Distance education through the Internet: the GNA-VSNS biocomputing course.
AB - A prototype course on biocomputing was delivered via international computer
networks in early summer 1995. The course lasted 11 weeks, and was offered free
of charge. It was organized by the BioComputing Division of the Virtual School of
Natural Sciences, which is a member school of the Globewide Network Academy. It
brought together 34 students and 7 instructors from all over the world, and
covered the basics of sequence analysis. Five authors from Germany and USA
prepared a hypertext book which was discussed in weekly study sessions that took
place in a virtual classroom at the BioMOO electronic conferencing system. The
course aimed at students with backgrounds in molecular biology, biomedicine or
computer science, complementing and extending their skills with an
interdisciplinary curriculum. Special emphasis was placed on the use of Internet
resources, and the development of new teaching tools. The hypertext book includes
direct links to sequence analysis and databank search services on the Internet. A
tool for the interactive visualization of unit-cost pairwise sequence alignment
was developed for the course. All course material will stay accessible at the
World Wide Web address (Uniform Resource Locator) http://+www.techfak.uni
bielefeld.de/bcd/welcome .html. This paper describes the aims and organization of
the course, and gives a preliminary account of this novel experience in distance
education.
PMID- 9390234
TI - Multifractals, encoded walks and the ergodicity of protein sequences.
AB - A variety of statistical methods have been developed to explore correlations in
protein and nucleic acid sequences. Such correlations have important implications
for the evolution and stability of these macromolecules. Recently, a number of
fractal analyses of sequence data have been developed. These analyses have
considerable appeal as they are extremely sensitive to long range correlations
and to hierarchical structures. One such analysis decodes sequence information
into a random walk and the statistics of the resulting random walk is
investigated. Anomalous scaling of such walks has been interpreted as indicative
of a fractal structure. Alternatively, a generalized box counting analysis of
decoded sequences can be used to establish multifractal properties. In this work,
the connection between these two seemingly disparate approaches is established.
This connection is exploited to investigate correlations in protein sequences. An
ensemble consisting of a comprehensive data set of representative protein
sequences is analyzed to establish the ergodicity of protein sequences. The
implications of this ergodicity for information theoretical approaches to protein
structure prediction is explored.
PMID- 9390235
TI - List update processing (LUP)--solving the sequence database update problem.
AB - Sequence databases of today require frequent updating. Mirror procedures to copy
incrementally updated databases as cumulative sets are the preferred method and
can be implemented by straightforward scripting. However, limited bandwidth of
networks and the increase of data require more powerful paradigms to reduce the
workload reliably. We suggest the List Update Processing (LUP) principle. The
system has been implemented on an experimental basis to update the Swiss EMBnet
Node (BioComputing Basel, CH) with data from the European Bioinformatics
Institute (EMBL Outstation, Hinxton Hall, UK). The results obtained from the
prototype suggest to expand the system to several sites.
PMID- 9390236
TI - Circular clustering of protein dihedral angles by Minimum Message Length.
AB - Early work on proteins identified the existence of helices and extended sheets in
protein secondary structures, a high-level classification which remains popular
today. Using the Snob program for information-theoretic Minimum Message Length
(MML) classification, we are able to take the protein dihedral angles as
determined by X-ray crystallography, and cluster sets of dihedral angles into
groups. Previous work by Hunter and States has applied a similar Bayesian
classification method, AutoClass, to protein data with site position represented
by 3 Cartesian co-ordinates for each of the alpha-Carbon, beta-Carbon and
Nitrogen, totalling 9 co-ordinates. By using the von Mises circular distribution
in the Snob program, we are instead able to represent local site properties by
the two dihedral angles, phi and psi. Since each site can be modelled as having 2
degrees of freedom, this orientation-invariant dihedral angle representation of
the data is more compact than that of nine highly-correlated Cartesian co
ordinates. Using the information-theoretic message length concepts discussed in
the paper, such a more concise model is more likely to represent the underlying
generating process from which the data came. We report on the results of our
classification, plotting the classes in (phi, psi) space; and introducing a
symmetric information-theoretic distance measure to build a minimum spanning tree
between the classes. We also give a transition matrix between the classes and
note the existence of three classes in the region phi approximately -1.09 rad and
psi approximately -0.75 rad which are close on the spanning tree and have high
inter-transition probabilities. This gives rise to a tight, abundant and self
perpetuating structure.
PMID- 9390237
TI - An object-oriented data-driven migration model.
AB - This research uses object-oriented simulation to derive the migratory patterns of
animal populations. These patterns are then compared with the trajectories of
aquatic pollutant releases to yield quantitative biological impact assessments.
These estimates are more realistic than those based on assumptions of uniform or
random distributions of animals in a region--a common approach to this problem.
The general migration model (MIGMOD) employs stochastic movement routines driven
by biological field data to derive heterogenous migration patterns similar to
those observed in nature. This data-driven approach circumvents many of the
difficulties involved in migratory modelling from first principles. However, we
also discuss the importance of selected causal mechanisms in these models.
PMID- 9390238
TI - On the definition and the construction of pockets in macromolecules.
AB - The shape of a protein is important for its functions. This includes the location
and size of identifiable regions in its complement space. We formally define
pockets as regions in the complement with limited accessibility from the outside.
Pockets can be efficiently constructed by an algorithm based on alpha complexes.
The algorithm is implemented and applied to proteins with known three-dimensional
conformations.
PMID- 9390239
TI - DNA splicing systems and post systems.
AB - This paper concerns the formal study on the generative powers of extended
splicing (H) systems. First, using a classical result by Post which characterizes
the recursively enumerable languages in terms of his Post Normal systems, we
establish several new characterizations of extended H systems which not only
allow us to have very simple alternative proof methods for the previous results
mentioned above, but also give a new insight into the relationships between
families of extended H systems. We show a kind of normal form for extended H
systems exactly characterizing the class of regular languages. We also show a new
representation result for the family of context-free languages in terms of
extended H systems.
PMID- 9390240
TI - Assessing the performance of fold recognition methods by means of a comprehensive
benchmark.
AB - Recently there has been an explosion of methods for fold recognition. These
methods seek to align a protein sequence to a three-dimensional structure and
measure the compatibility of the sequence to the structure. In this work, we
present a benchmark to assess the performance of such methods. The benchmark
consists of a set of protein sequences matched by superposition to known
structures. This set covers a wide range of protein families, and includes
matching proteins with insignificant sequence similarity. To demonstrate the
usefulness of this benchmark, we apply it here to compare different fold
recognition methods developed through the years in our group as well as several
sequence-sequence substitution matrices. The results show that "global-local"
alignments are superior to either local or global alignments. The most effective
sequence-sequence matching matrix is the Gonnet table. The best performance
overall is obtained by a method which combines the 3D-1D profiles of Bowie et al.
with a substitution matrix and takes into account residue pairwise interactions.
PMID- 9390241
TI - Biocomputing education by the Australian National Genomic Information Service.
PMID- 9390242
TI - Puzzle pieces defined: locating common packing units in tertiary protein
contacts.
AB - Puzzle pieces are defined as small packing units which make up the unique
tertiary interactions in proteins. Anti-parallel and perpendicular helix-helix
contacts were broken down into basic puzzle-piece pairs in order to study the
traits of such contacts: their limited geometry, preferred residue involvement,
residue conformation and other common constraints. These traits can then be used
for continued comparison of other protein structures, improving models of and
designing proteins de novo and, in time, predicting 3D structure from primary
sequence. Results from a small (100 proteins) database of anti-parallel helix
helix contacts and from preliminary work on a large database (600 proteins) of
perpendicular helix-helix contacts are presented.
PMID- 9390243
TI - Using multiple alignments and phylogenetic trees to detect RNA secondary
structure.
AB - We describe a statistical method to determine if a pair of columns in a multiple
alignment of a homologous family of RNA sequences shows evidence of being base
paired. The method makes explicit use of a given phylogenetic tree for the
sequences in the alignment. It is tested on a multiple alignment of 16S rRNA
sequences with good results.
PMID- 9390244
TI - A branch and bound algorithm for local multiple alignment.
AB - A Branch and Bound Algorithm has been developed to find a set of window positions
in a compilation of sequences with globally maximal information content. We have
also developed an algorithm for brute force evaluation of solutions which is
faster by a factor of the length of the windows than the naive brute force
algorithm. The combination of these two algorithms allows us to solve problems to
optimality that were previously amenable only to heuristic algorithms.
PMID- 9390245
TI - Beyond the hyperactive molecule: search, salvage and visualization of chemical
information from the Internet.
AB - The established exchange mechanisms for chemical information are under attack
from new information distribution channels on the Internet. Increasingly chemical
information is distributed by means of WWW pages and similar media. However, most
of this information is still primarily intended for human browsing. The search
for chemical information and the reuse of encoded structures and their attached
data is complicated and often impossible because of the unorganized structure of
the information and the lack of tools for search, display and salvage of chemical
information to help with the extraction of reusable information from Webspace.
The situation is complicated by the lack of standards and formats powerful enough
to encode in computer-readable form sophisticated chemical information and
informational relationships. The rapid evolution of information exchange
mechanisms on the Internet is another problem. The unsettled situation demands a
new generation of intelligent chemistry-aware tools for information retrieval
from the Net. These tools must be capable of adapting to new trends and
information models as well as new information types without constant redesign and
should be themselves extendable and updatable by components distributed via the
same network connections as the chemical data they are supposed to deal with. We
introduce a set of tools which encapsulate the established Internet (especially
WWW) information transfer and visualization methods and extend them to a new
level of chemical information handling.
PMID- 9390246
TI - An introductory course in computation molecular biology: rationale, history,
observations, and course description.
AB - A course called "Molecular Biology Computer Techniques" was implemented in 1987
and has been evolving ever since. Currently the semester-long three credit course
consists of thirty hours of lecture (three hours/week for the first ten weeks of
the semester) and a minimum of 45 hours of laboratory instruction (three
hours/week). The lectures survey both bioinformatics and structure based methods.
The laboratory has two tracks, one that can be described loosely as "sequence
analysis" and the other as "molecular modelling." Most students choose one of the
two laboratory tracks, although a small number have done both, either
simultaneously or in successive years. For each student, the goal of the course
is the completion of a student-initiated research project. The culmination of the
course is the presentation of the completed projects at a "Poster Session Final."
During this final, which is conducted like a poster session at a typical
biological science meeting, students are examined, not only by the instructors in
the course, but also by a diverse cross-section of the university community at
large, including non-scientists (who are specially invited to attend).
Questioning by non-scientists provides opportunity for the students to improve
their communication skills with the lay public. In this manuscript we discuss our
views regarding the rationale for the development of formal courses in
computational molecular biology, relate our experiences in the development of our
course, and describe the course as it stood the last time it was taught, which
was in the Fall of 1994.
PMID- 9390247
TI - Visualisation in the SPROUT molecular design program.
AB - SPROUT is an interactive computer system for structure based molecular design.
The system consists of several modules that address the different subproblems of
structure based drug design. This paper describes the visualisation techniques
applied in the program: the display of the novel (geometric region)
representation of the interaction sites and the molecular surface display based
on a 3D grid representation of the cavity. The hydrogen bonding regions are
represented by set operations (subtraction and intersection) of simple spherical
and conical 3D objects (with given radii and opening angle) Some complex hydrogen
bonding regions are represented by intersections of six or more basic objects. A
method for calculating a triangular mesh representation (with normal vectors) of
the analytical surfaces of the objects, that have sharp edges and corners because
of the intersections, is presented in the paper. The geometric parameters of the
interaction regions can be changed interactively in which case the surface
display is updated real-time. The volume of space that is available for ligand
generation (the cavity of the receptor site) is represented on a 3D grid within
SPROUT. The surface of the available space is visualised using an algorithm
presented in the paper, that generates a polygonial mesh of the grid points. The
grid is also used to cut out stericaly forbidden parts of the interaction site
regions. The surface of the reduced object is also visualised using further
sphere subtractions. The presented algorithms are fast, aplicable in interactive
visualisation programs. Result images of the rendering of the surfaces,
calculated by the algorithms, are demonstrated on examples taken from
applications of SPROUT to practical ligand design problems.
PMID- 9390248
TI - Computational evolution of a model polymer that folds to a specified target
conformation.
AB - A method is described for folding polymers to specific target conformations. The
approach uses a fast but approximate dynamics algorithm, coupled with a genetic
algorithm that is used to evolve the large number of free parameters needed. The
dynamics algorithm uses a state transition matrix approach. At each time step,
the distances between pairs of atoms are adjusted by shifting them from Dij to
Dij + Sij where Sij is an element of the state transition matrix S. Atom pairs
that are attractive have Sij < 0 and pairs that are repulsive have S ij > 0. The
atomic movement is carried out by gradient minimizing the molecular mechanics
energy of the molecule subject to harmonic distance constraints. The method is
applied to a simple test case, a 19 atom 2-D polymer. The paper also show that
the S matrices can correctly fold a limited variety of initial conformations that
differ from the one used during the evolution phase.
PMID- 9390249
TI - A protocol for maintaining multidatabase referential integrity.
AB - The bioinformatics community is becoming increasingly reliant on the creation of
links among biological databases (DBs) as a foundation for DB interoperability.
For example, a link might be created from a protein in one DB (such as PIR), to a
gene in another DB (such as GDB), by storing the unique identifier (id) of the
gene object within an attribute of the protein object. User interfaces can then
support navigation from the protein to the gene, and multiDB queries can join the
protein with the gene. The unique id of the gene is serving as a foreign key.
However, a variety of factors, such as changes in the underlying biology, can
cause object ids to become invalid, thus producing invalid links among DBs.
Invalid links are a violation of multidatabase referential integrity. We propose
a network protocol whereby a database administrator can provide information about
changes to the identifiers of objects in their database via Internet, to allow
other databases to maintain referential integrity. We request comments from the
bioinformatics community for the purpose of building a consensus on the proposed
protocol.
PMID- 9390250
TI - An algorithm for prediction of structural elements in small proteins.
AB - A method for predicting the location of surface loops/turns and assigning the
intervening secondary structure of the transglobular linkers in small, single
domain globular proteins has been developed. Application to a set of 10 proteins
of known structure indicates a high level of accuracy. The secondary structure
assignment in the center of transglobular connections is correct in more than 85%
of the cases. A similar error rate is found for loops. Since more global
information about the fold is provided, it is complementary to standard secondary
structure prediction approaches. Consequently, it may be useful in early stages
of tertiary structure prediction when establishment of the structural class and
possible folding topologies is of interest.
PMID- 9390251
TI - Sequence sizes of eukaryotic enzymes.
AB - We have shown in earlier studies that an appreciable fraction of proteins display
sequence size periodicity with periods of approximately 123 aa and approximately
152 aa for eukaryotes and prokaryotes, respectively. For any firm conclusions to
be made, the issue of possible bias due to an overabundance of some protein
families should be addressed in more than one way. Here we present the size
distributions for various sequence ensembles of eukaryotic enzymes that differ by
level of data bank cleaning. The sequences were purged by applying several
successive thresholds of relatedness irrespective of the sequence lengths. The
previously observed preference to typical sizes is confirmed. Possible reasons
for the observed excess of the typical size sequences are discussed.
PMID- 9390252
TI - A high performance system for molecular dynamics simulation of biomolecules using
a special-purpose computer.
AB - GRAPE (GRavity PipE) processors are special purpose computers for simulation of
classical particles. The performance of MD-GRAPE, one of the GRAPEs developed for
molecular dynamics, was investigated. The effective speed of MD-GRAPE was
equivalent to approximately 6 Gflops. The precision of MD-GRAPE was good judging
from the acceptable fluctuation of the total energy. Then a software named PEACH
(Program for Energetic Analysis of bioCHemical molecules) was developed for
molecular dynamics of biomolecules in combination with MD-GRAPE. Molecular
dynamics simulation was performed for several protein-solvent systems with
different sizes. Simulation of the largest system investigated (27,000 atoms)
took only 5 sec/step. Thus, the PEACH-GRAPE system is expected to be useful in
accurate and reliable simulation of large biomolecules.
PMID- 9390253
TI - Correlating structure-dependent mutation matrices with physical-chemical
properties.
AB - We have investigated how structure-dependent mutation matrices derived in
previous work correlate with various physical-chemical properties of the 20
naturally occurring amino acids. Among the properties we investigated were delta
G of transfer from water to octanol and cyclohexane, alpha helical and beta sheet
propensity, size, and charge. We found that the delta G of transfer to octanol
had a high correlation with matrices for all categories of residues, especially
the matrices for buried and exposed positions. This result suggests that octanol
is a good model for understanding both the changes in stability resulting from
substitutions of buried residues and changes in foldability resulting from
varying exposed residues. We also found the correlations of the matrices with
size and charge varied with the local environment, and that neither alpha helical
nor beta sheet propensity had high correlations with most matrices. Thus,
conservation of size and charge appear to be important in specific environments,
and conservation of alpha helix and beta sheet propensity do not seem to be key
factors.
PMID- 9390254
TI - A case study where biology inspired a solution to a computer science problem.
AB - This paper describes how the biological theory of gene duplication described in
Susumu Ohno's provocative book, Evolution by Means of Gene Duplication, was
brought to bear on a vexatious problem from the domain of automated machine
learning, namely the problem of architecture discovery. Six new architecture
altering operations for genetic programming were motivated by the way that new
biological structures, functions, and behaviors arise in nature using gene
duplication. Genetic programming with the new architecture-altering operations
was then applied to the transmembrane protein segment identification problem. The
out-of-sample error rate for the best genetically-evolved program achieved was
slightly better than that of previously-reported human-written algorithms for
this problem.
PMID- 9390255
TI - Protein phylogenetic inference using maximum likelihood with a genetic algorithm.
AB - This paper presents a method to construct phylogenetic trees from amino acid
sequences. Our method uses a maximum likelihood approach which gives a confidence
score for each possible alternative tree. Based on this approach, we developed a
genetic algorithm for exploring the best score tree: randomly generated
alternative trees are rearranged so that their scores are improved by utilizing
crossover and mutation operators. In a test of our algorithm on a data set of EF
1 alpha sequences, we found that the performance of our algorithm is comparable
to that of other tree-construction methods.
PMID- 9390256
TI - Ab initio calculations of free energy barriers for chemical reactions in
solution: proton transfer in [FHF]-.
AB - This paper describes a hybrid ab initio quantum mechanical/molecular mechanics
(QM/MM) method for calculating activation free energies of chemical reactions in
solution, using molecular mechanics force fields for the solvent and an ab initio
technique that incorporates the potential from the solvent in its Hamiltonian for
the solute. The empirical valence bond (EVB) method is used as a reference
potential for the ab initio free energy calculation, and drives the reaction
along the proper coordinate, thus overcoming problems encountered by direct
attempts to use molecular orbital methods in calculations of activation free
energies. The utility of our method is illustrated by calculating the activation
free energy for proton transfer between fluoride ions in the [FHF]-system, in
both polar and nonpolar solution.
PMID- 9390257
TI - Mixed quantum mechanical/molecular mechanical simulations of chemical reactions
in solution and in enzymes by the classical trajectory mapping approach.
AB - We present a practical hybrid quantum mechanical/molecular mechanical approach to
study chemical reactions in solution and in enzymes. In this method, referred to
as the "Classical Trajectory Mapping" method, trajectories are calculated on the
classical potential surfaces and, by using the classical surfaces as a reference
state for the actual quantum mechanical ground state potential, the free energy
profile of the chemical reaction is obtained by the free energy perturbation
technique. This method was applied to proton-transfer reactions both in aqueous
solution and in papain. The encouraging results indicate the applicability of our
method to chemical reactions in the condensed phase and the biological systems.
PMID- 9390258
TI - Molecular modeling of protocellular functions.
AB - The mechanisms of three protocellular functions have been studied using molecular
modeling techniques. These functions are (1) the transport of ions across
membranes, (2) the formation of photoactivated proton gradient that could drive
chemical synthesis in the protocell, and (3) the organization of small peptides
necessary for catalytic activity. In all these processes, membranes play an
essential role. The transfer of ions across the barrier formed by protocellular
walls is facilitated by the formation of deep, thinning defects in the membrane.
Membranes also form a barrier to charged species that allows for retaining proton
gradients. These gradients can be generated by a simple transmembrane proton pump
consisting of a proton source and two acceptors. The directionality of the pump
is ensured by a "gate-keeping" mechanism involving a water molecule,
conformational change of the primary acceptor or tautomerization of a histidine.
The pump can be formed by two transmembrane helices but not one helix. They
provide surfaces at which organic molecules concentrate and small peptides can
organize into ordered, amphiphilic structures. In general, valuable information
about the origins and evolution of protocells can be obtained from the knowledge
of physical and chemical principles that govern functioning of contemporary
cells.
PMID- 9390259
TI - Analysis, clustering and prediction of the conformation of short and medium size
loops connecting regular secondary structures.
AB - Loops are regions of non-repetitive conformation connecting regular secondary
structures. They are both the most difficult and error prone regions of a protein
to solve by X-ray crystallography and the hardest regions to model using
knowledge-based procedures. While the core of a protein can be straight forwardly
modelled from the structurally conserved regions of homologues of known
structure, loops must be modelled from a selected homologue or from a loop chosen
from outside the family. Here we present a loop prediction procedure that
attempts to identify the conformational class of the loop rather than to select a
specific loop from a database of fragments. The structures of some 2083 loops of
one to eight residues in length were extracted from a database of 225 protein and
protein domain structures. For each loop, the relative disposition of its
bounding secondary structures is described by the separation between the tips of
their axes, the angle and dihedral angle between their axes. From the clustering
of the loops according to the root mean square deviation of their spatial fit, a
total of 162 loop conformational classes, including 79% of loops, were
identified. One-hundred and eight of these, involving 66% of the loops, were
populated by at least four non-homologous loops or four loops sharing a low
sequence identity. Another 54 classes, including 13% of the loops, were populated
by at least three loops of low sequence similarity from three or fewer non
homologous groups. Most of the previously described loop conformations were found
among the populated classes. For each class a template was constructed containing
both sequence preferences and the relative disposition of bounding secondary
structures among member loops. During comparative modelling, the conformation of
a loop can be predicted by identifying a loop class with which its sequence and
disposition of bounding secondary structures are compatible.
PMID- 9390260
TI - Computational biology instruction at the University of Washington Center for
Bioengineering.
AB - Computational tools are rapidly becoming an essential component of molecular
biology research. However, there is as yet relatively little attention paid to
computational biology in the standard curricula of most biology programs. We
describe here some of the graduate computational biology courses we have
developed in the Center for Bioengineering at the University of Washington, with
special emphasis on instructional methods and approaches that appear to work
well.
PMID- 9390261
TI - A greedy strategy for finding motifs from yes-no examples.
AB - We define a motif as an expression Z1.Z2...Zn with sets Z1, Z2,..., Zn of strings
in a specified family omega called the type. This notion can capture the most of
the motifs in PROSITE as well as regular pattern languages. A greedy strategy is
developed for finding such motifs with ambiguity just from positive and negative
examples by exploiting the probabilistic argument. This paper concentrates on
describing the idea of the greedy algorithm with its underlying theory. Its
experimental results on splicing sites and E. coli promoters are also presented.
PMID- 9390262
TI - Statistical geometry analysis of proteins: implications for inverted structure
prediction.
AB - The topology of folded proteins from the representative dataset of well-defined
three-dimensional protein structures is studied using a statistical geometry
approach. Amino acid residues in protein chains are represented by C alpha atoms,
thus reducing the protein three-dimensional structure to a set of points in three
dimensional space. The Delaunay tessellation of a protein structure generates an
aggregate of space-filling irregular tetrahedra, or Delaunay simplices. Each
simplex objectively defines four nearest neighbor C alpha atoms, i.e. four
nearest neighbor residues. The statistical analysis of residue composition of
Delaunay simplices reveals nonrandom preferences for certain quadruplets of amino
acids. These nonrandom preferences are used to develop a fitness function that
evaluates sequence-structure compatibility. Using this fitness function, several
tested native proteins score the highest among 100,000 random sequences with
average protein amino acid composition. The statistical geometry approach, based
solely on first principles, provides a unique means for protein structure
analysis and has direct implications for inverted protein structure prediction.
PMID- 9390263
TI - Determination of proton transfer rate constants using Ab initio, molecular
dynamics and density matrix evolution calculations.
AB - In this work we give an overview of the methodologies required to compute the
rate of proton transfer in hydrogen bonded systems in solution. Using ab initio
or density functional methods we determine proton potentials of a truncated
system as a function of proton-donor proton-acceptor distance as well as
nonbonding parameters. By classical molecular dynamics we evaluate a swarm of
proton potentials with the proton fixed in the reactant well. The rate of proton
transfer is calculated perturbatively using the Density Matrix Evolution (DME)
method, going beyond the Born Oppenheimer approximation. The method is
illustrated by two examples: hydrogen malonate and the active center of HIV-1
protease.
PMID- 9390264
TI - Empirical free energy calculations of human immunodeficiency virus type 1
protease crystallographic complexes. II. Knowledge-based ligand-protein
interaction potentials applied to thermodynamic analysis of hydrophobic
mutations.
AB - Empirical free energy calculations of HIV-1 protease crystallographic complexes
based on the developed knowledge-based ligand-protein interaction potentials have
enabled a detailed thermodynamic analysis. Binding free energies are estimated
within an empirical model that postulates that hydrophobic effect, mean field
ligand-protein interaction potentials and conformational entropy changes are the
dominant forces that determine complex formation. To provide a quantitative
framework of the binding thermodynamics contributions the derived knowledge-based
potentials have been linked with the hydrophobicity and conformational entropy
scales originally developed to explain protein stability. The comparative
analysis of studied inhibitors provides reasonable estimates of distinctions in
their binding affinity with HIV-1 protease and gives insight into the nature of
the binding determinants. The binding free energy changes upon a simple
hydrophobic mutation Ile -> Val in the JG-365, MVT-101 and U75875 inhibitors of
HIV-1 protease have been evaluated within a model that includes the effects of
solvation, cavity formation, conformational entropy and mean field ligand-protein
interactions. In general, free energy changes associated with a particular
perturbation of a system can not be rigorously decomposed into separate terms
from first principles. We explored the relationships between the changes in
hydrophobic contributions and mean field ligand-protein interaction energies in
the context of a totally buried and dense area of the binding site. We assume,
therefore, that these simple hydrophobic deletions would not induce noticeable
conformational changes in the enzyme and can be interpreted with some confidence
in the framework of the model. The analysis has revealed the decisive effect of
the energetics of ligand-protein interactions on the estimated free energy
changes.
PMID- 9390265
TI - Prediction of the quaternary structure of coiled coils: GCN4 leucine zipper and
its mutants.
AB - A methodology for predicting coiled coil quaternary structure and for the
dissection of the interactions responsible for the global fold is described.
Application is made to the equilibrium between different oligomeric species of
the wild type GCN4 leucine zipper and seven of its mutants that were studied by
Harbury et al. Over the entire experimental concentration range, agreement with
experiment is found in five cases, while in two other cases, agreement is found
over a portion of the concentration range. These simulations suggest that the
degree of chain association is determined by the balance between specific side
chain packing preferences and the entropy reduction associated with side chain
burial in higher order multimers.
PMID- 9390266
TI - 3D molecular graphics on the World Wide Web.
AB - The Virtual Reality Modeling Language (VRML) is a new tool for the information
transfer on the World Wide Web (WWW). We present a short description and some
applications in the field of molecular graphics of this new, object oriented
language. It is shown that the usage of VRML is a very efficient and powerful
method for the transport of molecular models over the net.
PMID- 9390267
TI - Motif identification neural design for rapid and sensitive protein family search.
AB - The accelerated growth of the molecular sequencing data has generated a pressing
need for advanced sequence annotation tools. This paper reports a new method,
termed MOTIFIND (Motif Identification Neural Design), for rapid and sensitive
protein family identification. The method is extended from our previous gene
classification artificial neural system and employs two new designs to enhance
the detection of distant relationships. These include an n-gram term weighting
algorithm for extracting local motif patterns, and integrated neural networks for
combining global and local sequence information. The system has been tested with
three protein families of electron transferases, namely cytochrome c, cytochrome
b and flavodoxin, with a 100% sensitivity and more than 99.6% specificity. The
accuracy of MOTIFIND is comparable to the BLAST database search method, but its
speed is more than 20 times faster. The system is much more robust than the
PROSITE search which is based on simple signature patterns. MOTIFIND also
compares favorably with the BLIMPS search of BLOCKS in detecting fragmentary
sequences lacking complete motif regions. The method has the potential to become
a full-scale database search and sequence analysis tool.
PMID- 9390268
TI - Extraction of hidden Markov model representations of signal patterns in DNA
sequences.
AB - We have developed a method to extract the signal patterns in DNA sequences. In
this method, the Genetic Algorithm (GA) and Baum-Welch algorithm are used to
obtain the best Hidden Markov Model (HMM) representations of the signal patterns
in DNA sequences. The GA is used to search the best network shapes and the
initial parameters of the HMMs. Baum-Welch algorithm is used to optimize the HMM
parameters for the given network shapes. Akaike Information Criterion (AIC),
which gives a criterion for the balance of adaptation and complexity of a model,
is applied in the HMM evaluation. We have applied the method to the extraction of
the signal patterns in human promoters and 5' ends of yeast introns. As a result,
we obtained HMM representations of characteristic features in these sequences. To
validate the efficiency of the method, we have performed promoter recognition
using obtained HMMs. Two entries including nine promoters are selected from
GenBank 76.0, and it is observed that the HMM can predicts eight promoters
correctly. These results imply that the method is efficient to design preferable
HMM networks, and provides reliable models for the recognition of the signal
patterns.
PMID- 9390269
TI - [Extending the capabilities of human chromosome analysis: from high-resolution
banding to chromatin fiber-FISH].
AB - The rapid development in human chromosome studies during the past 2 decades has
opened up a variety of new avenues in both basic and clinical human genetics.
This has been due to the extended resolution of chromosome analysis especially by
the introduction of high-resolution banding and fluorescence in situ
hybridization (FISH) techniques. High-resolution banding methods using elongated
chromosomes from cells at early mitotic stage can be divided into two main
categories: one involves S-phase synchronization using methotrexate or thymidine
with subsequent release from the block, and the other involves the application of
DNA-binding agents, such as ethidium bromide, which inhibit mitotic chromosome
condensation. High-resolution band analysis facilitates refined determination of
the breakpoints on rearranged chromosomes, and thus minute deletions, small
translocations and other subtle chromosome mutations can readily be detected and
identified. It has also proved to be valuable for accurate gene mapping and
comparative cytogenetics. Each of the high-resolution bands consists of DNA
molecules as long as approximately 3Mb on the average, and this resolution
limitation has been overcome by the introduction of the FISH method, which
enables chromosome and genomic analyses to be carried out at the DNA molecule
level. For FISH analysis, appropriate DNA probes of various insert sizes can be
chosen for different purposes, and FISH with specific probes permits high
resolution analysis of chromosome DNA constitution at particular loci. For
instance, it is possible to detect and map unique sequences more than 1 kb in
size on mitotic chromosomes, and to identify cryptic chromosome rearrangements
not recognizable even by high-resolution band analysis. Better resolution of
breakpoint determination can also be expected by FISH using an adequate series of
DNA clones arrayed on the physical map within the relevant chromosome region. An
even better genomic resolution by FISH can be obtained by utilizing free
chromatin DNA fibers released from interphase nuclei as a hybrization target. The
FISH signals on the chromatin fiber preparations are shown to be "linear", unlike
the standard FISH signals that have a "dot" appearance, and the resolution
attainable should be comparable to analysis of a straight DNA double helix
itself. The degree of resolution in the so-called fiber-FISH method ranges from a
few to 300 kb, and thus the method can readily be applied to the high-resolution
assessment of ordering and overlapping of isolated DNA clones from a specific
chromosome region, as well as sizing of gaps between the clones. Fiber-FISH may
prove most valuable for the precise determination of breakpoints at the kilobase
level, and also for identifying minute deletions and duplications. By presenting
some examples of our own recent works, this review attempts to summarize the
current contribution of the above strategies in mediating the two separate ranges
of resolution achieved by the classical chromosome and molecular DNA analyses.
PMID- 9390270
TI - Costimulation of human natural killer cell proliferation: role of accessory
cytokines and cell contact-dependent signals.
AB - Despite the importance of natural killer (NK) cells in the immune response, the
regulation of human NK cell growth has not been well characterized. We have
hypothesized that, similar to the proliferation of T and B lymphocytes, optimal
proliferation of NK cells requires costimulatory signals as well as a primary
mitogenic stimulus. Evidence for costimulation by both soluble cytokines and cell
contact-dependent factors is presented. Soluble IL-1 and TNF were found to
augment NK cell proliferation in response to primary mitogenic cytokines,
including IL-2, IL-4, IL-7, and IL-12. The costimulatory effect of IL-1 and TNF
is strongly enhanced by the calcium ionophore ionomycin. Coculture of NK cells
with irradiated K562 cells can largely substitute for the costimulatory signal
provided by ionomycin. Costimulation by K562 requires intimate cell contact and
is not reconstituted by cell-free supernatants. Activated T lymphocytes can also
mediate contact-dependent costimulation of NK cells; resting PBMC, several NK
sensitive cell lines, and all NK-resistant cell lines tested were not found to be
costimulatory. Engagement of CD16 did not augment NK cell proliferation. Thus,
triggering of natural killing or antibody-dependent cell-mediated cytotoxicity
(ADCC) does not consistently provide a costimulatory signal for NK cell
proliferation. Cell contact-dependent costimulation of NK cells does not appear
to involve known receptors that can costimulate T cells, including CD2, CD27,
CD28, CD29, or LFA-1. The molecular nature of the putative NK cell costimulatory
receptor remains to be elucidated. Nevertheless, human NK cells could be expanded
in vitro using leukocyte-conditioned medium (LCM) as a source of IL-2 and
accessory cytokines and ionomycin to bypass the putative receptor for cell
contact-dependent costimulation. NK cells expanded in LCM and ionomycin express
typical NK cell antigens and mediate natural killing and ADCC. Further
characterization of the costimulatory signals for NK cell proliferation may
elucidate the physiologic regulation of NK cell growth and may ultimately allow
more effective manipulation of these lymphocytes in the immunotherapy of human
diseases.
PMID- 9390271
TI - Positive selection of CD56+ lymphocytes by magnetic cell sorting.
AB - A new method for the isolation of CD56+ lymphocytes from peripheral mononuclear
blood cells is described. Magnetic microbeads conjugated to goat antimouse
antiserum in combination with a murine monoclonal anti-CD56 antibody were coated
to the CD56+ target cells. CD56+ cells were then isolated with the use of a
magnetic cell sorter. The purity of the CD56+ cells was 98.4 +/- 1% (n = 12) with
a recovery of the CD56+ lymphocytes of 57.2 +/- 9% (range 48-77%). The natural
killer, activity of the CD56+ lymphocytes as well as the interleukin-2-induced
proliferative response were not affected by the isolation procedure or the
presence of the magnetic microbeads on the CD56+ cells. The described method
might be a useful tool for the further characterization of CD56+ cells and their
subsets and can easily be upgraded for clinical use in adoptive immunotherapy
with CD56+ lymphocytes.
PMID- 9390272
TI - Mannan-binding protein in human umbilical cord blood.
AB - Mannan binding protein (MBP) may be important for host defence particularly in
infancy. MBP concentration was measured in 237 umbilical cord blood samples from
singleton pregnancies and compared to those of 352 blood donors. Both data sets
yielded a bimodal frequency distribution, consisting of a log-normal peak and a
long tail of lower values. The range (0-23 U/ml) and median (7.2 U/ml) of cord
blood values were significantly lower than those of blood donors (range 0-43
U/ml; median 8.3 U/ml). MBP was also measured in the cord blood samples of 8
pairs of twin siblings. Discordant values in two pairs of twins suggest that cord
blood MBP is derived from the fetoplacental unit and not from the maternal
circulation by transplacental passage.
PMID- 9390273
TI - Natural resistance to Mycoplasma pulmonis infection in mice: host resistance
gene(s) map to chromosome 4.
AB - Strains of mice differ greatly in resistance to infection in their lungs with
virulent Mycoplasma pulmonis (MP) organisms even during the first 5 days, prior
to detection of humoral or T cell mediated acquired immune responses. C57BL/6
mice are resistant, and BALB/c and C3H mice are susceptible, and one major gene,
MP, not linked to the H2 major histocompatibility complex, regulates resistance.
C57BL/6 x C3H (B x H) and BALB/c x C57BL/6 (C x B) recombinant inbred strain mice
were infected intratracheally with the T2 strain of MP. Five days later, the
recovery of organisms from tracheolung lavages and lung tissue was determined.
The strain distribution pattern of resistance indicated that the MP gene maps to
chromosome 4. B6.C-H18 (B6 mice congenic for the BALB/c H18 gene of chromosome 4)
were much more susceptible than B6 mice, but were less susceptible than BALB/c
mice, supporting the data obtained with the recombinant inbred strain mice, but
suggesting that other genes may also influence resistance to infection with MP.
PMID- 9390274
TI - Exacerbation of toxoplasmosis in neutrophil-depleted mice.
AB - Studies were performed to determine whether resistance to Toxoplasma gondii
infection in mice depends on a mechanism involving neutrophils. Immunocompetent
C57BL/6 and C.B-17 mice infected with T. gondii by gavage had an increased
percentage of neutrophils in their peripheral blood. C57BL/6 mice selectively
depleted of neutrophils by injections of RB6-8C5 monoclonal antibody died during
the acute phase of the disease. Depletion of neutrophils had no effect on
interferon gamma production, but had a profound effect on the total numbers of
peripheral blood CD4+ and CD8+ T cells. Neutrophil-depleted C.B-17 mice survived
longer than neutrophil-depleted C57BL/6 mice when infected with T. gondii,
however they became much sicker, and were less able to survive long-term than
infected, control mAb-treated mice as indicated by severe sustained weight loss.
This study shows that neutrophils play an important role in resistance to acute
primary T. gondii infection and that depletion of neutrophils reduces the numbers
of CD4+ and CD8+ lymphocytes recoverable from peripheral blood of infected but
not uninfected mice. This effect on lymphocytes may contribute to the reduced
long-term survival of neutrophil-depleted mice.
PMID- 9390276
TI - New challenges in computational biochemistry.
PMID- 9390275
TI - NKR-P1dim/TCR alpha beta + T cells and natural killer cells share expression of
NKR-P1A and NKR-P1D.
AB - Natural killer (NK) cells and a T cell subset express NKR-P1s; however, it is not
known if NKR-P1s on these cells are homologous. By molecular and biochemical
means, we determined that NKR-P1s on NK cells and T cells were similar. Also,
sequencing of polymerase chain reaction products derived from these populations
indicated expression of a novel form, termed NKR-P1D, with approximately 60%
nucleotide homology to NKR-P1A. NKR-P1D shares approximately 50% amino acid
homology, overall and in the carbohydrate recognition domain, with rat NKR-P1A
and mouse NKR-P1A -B, and -C. Transcripts for NKR-P1A (1.1 kb) and NKR-P1D (2.0
kb) were produced by NK cells and NKR-P1dim/TCR alpha beta + T cells. Some NK
cell clones coexpressed NKR-P1A and NKR-P1D. However, other clones lacking NKR
P1A produced message for NKR-P1D.
PMID- 9390277
TI - Computer simulations of prebiotic evolution.
AB - This paper is a review of our previous work on the field of possible ways of
prebiotic evolution. We propose an algorithm providing sequences of model
proteins with rapid folding into a given native conformation. Thermodynamical
analysis shows that the increase in speed is matched by an increase in stability:
the evolved sequences are much more stable in their native conformation than the
initial random sequence. We discuss a possible origin of the first biopolymers,
having stable unique structure. We suggest that at the prebiotic stage of
evolution, long organic polymers had to be compact in order to avoid hydrolysis
and had to be soluble and thus must not be exceedingly hydrophobic. We present an
algorithm that generates such sequences of model proteins. The evolved sequences
turn out to have a stable unique structure, into which they quickly fold. This
result illustrates the idea that the unique three-dimensional native structure of
first biopolymers could have evolved as a side effect of a nonspecific physico
chemical factors acting at the prebiotic stage of evolution.
PMID- 9390278
TI - Ubiquitous distributed objects with CORBA.
AB - Database interoperation is becoming a bottleneck for the research community in
biology. In this paper, we first discuss the question of interoperability and
give a brief overview of CORBA. Then, an example is explained in some detail: a
simple but realistic data bank of STSs is implemented. The Object Request Broker
is the media for communication between an object server (the data bank) and a
client (possibly a genome center). Since CORBA enables easy development of
networked applications, we meant this paper to provide an incentive for the
bioinformatics community to develop distributed objects.
PMID- 9390279
TI - Towards a density functional treatment of chemical reactions in complex media.
AB - We discuss two techniques involving density functional theory (i.e., ab initio
molecular dynamics simulations and frozen density functional theory) which show
promise for applications directed towards understanding reactions in complex
media. Preliminary results for the simulation of the conformational dynamics of
an isolated analogue of alanine dipeptide and for the interaction between F- and
H2O are included. These results represent the first steps towards a combined
theoretical approach of reactions in complex media.
PMID- 9390280
TI - Combinatorial tools for the analysis of transcriptional regulation.
AB - In this paper, we discuss virtual experiments for the study of major regulatory
processes such as translation, signalization or transcription pathways. An
essential part of these processes is the formation of protein clusters held
together by a small number of binding domains that can be shared by many
different proteins. Analysis of these clusters is complicated by the vast number
of different arrangements of proteins that can trigger a specific reaction. We
propose combinatorial tools that can help predict the effects on the rate of
transcription of either changes in transcriptional factors concentration, or due
to the introduction of chimeras combining domains not usually present on a
protein.
PMID- 9390281
TI - The generalization method of relationships among nucleotide sequences reveals an
order in assimilation of amino acid codons during the isoacceptor tRNAs
evolution.
AB - A new method, generalization of relationships among the nucleotide sequences has
been used to analyze divergency both within and across the families of
isoaccepting tRNAs. Dendrogram, dipicting relations between tRNA sets with
different amino acid specificities, presents the results of analysis. The method
allowed to interpret dendrogram, as a reflection of final stage of the evolution
of ambiguous molecules-adaptors to highly specific tRNAs. We have proposed a
model of amino acid codons assimilation at this stage. According to the model,
the final formation of specific adaptors was followed by assimilation of codon
clusters (four codons, differing in the third position), the first dinucleotides
of which were connected by transitions. Alternate steps along double-stranded
coding DNA accompanied the establishment of tRNA sets with strict specificities.
Complementary codons, to which specific adaptors were assigned at step the last,
were involved into the process afterwards.
PMID- 9390282
TI - Using Tcl for molecular visualization and analysis.
AB - Reading and manipulating molecular structure data is a standard task in every
molecular visualization and analysis program, but is rarely available in a form
readily accessible to the user. Instead, the development of new methods for
analysis, display, and interaction is often achieved by writing a new program,
rather than building on pre-existing software. We present the Tcl-based script
language used in our molecular modeling program, VMD, and show how it can access
information about the molecular structure, perform analysis, and graphically
display and animate the results. The commands are available to the user and make
VMD a useful environment for studying biomolecules.
PMID- 9390283
TI - On some operations suggested by genome evolution.
AB - Three operations involved in the genome evolution namely, inversion,
transposition and duplication, are considered as operations on strings and
languages. We show that, for any pair of these operations, there is a language
family which is closed under one of the operations and not closed under the
second one, however, under some mild conditions the closure of a language family
under one of the operations implies that it also closed with respect to another
one.
PMID- 9390284
TI - The inverse protein folding problem: self consistent mean field optimisation of a
structure specific mutation matrix.
AB - The goal of the inverse folding problem is to supply a list of sequences
compatible with a known protein structure. If two-body interactions are taken
into account in energy calculations, an exhaustive exploration of the energy
landscape in sequence space cannot be achieved because of the huge number of
possible combinations. To circumvent this problem, we propose a method in which
multiple copies corresponding to every possible side-chain type are attached to
each C alpha position in the protein. The weights of each copy (stored in the
sequence matrix SM) are refined using mean field theory: each side-chain copy
interacts with the mean field generated by all possible side-chain copies at
neighbouring positions, weighted by their respective probabilities. The potential
energy is simply taken to be amino acid pair potentials of mean force. The method
converges in a few cycles to a self-consistent solution. The refined matrix does
not depend on the starting point; therefore the method succeeds in removing
memory effects. Starting solely from the backbone of the known structure, and
without information from the initial sequence, the final sequence matrix SM is
shown to be able to retrieve significant sequence information, as observed
through a series of structure-recognizes-sequence(s) computer experiments. The
issue of specificity is discussed in detail.
PMID- 9390285
TI - Theoretical and algorithmical optimization of the dead-end elimination theorem.
AB - The dead-end elimination theorem has proved to be a powerful method to reduce the
theoretically accessible conformational space when modeling protein side chains
by using a rotameric representation of possible conformations. In this work,
theoretical details about variants to the original criterion are discussed. We
also provide information on how the equations can be algorithmically implemented
in such a way that both computational performance and structural accuracy are
optimized. In addition, we discuss the theoretical and practical aspects of three
new methods called the "bottom line theorem", dead-end elimination assisted by
local modeling and a combinatorial search combined with conventional dead-end
elimination. It is shown that the algorithm in its current from enables the
determination of the global minimum energy side chain conformation of large
proteins on a time scale of hours while for small proteins of up to 30 residues
the calculations are done on a time scale of seconds. The latter opens a way to
combine a main chain sampling algorithm with the dead-end elimination method to
locally model entire fragments of a protein chain.
PMID- 9390286
TI - Using views for retrieving data from extremely heterogeneous databanks.
AB - Information in molecular biology or biology in general is contained in a
multitude of different databanks each specializing in a certain area. This
specialization is useful since it improves the maintainability of the data and
the flexibility of the overall structure which until now manages to exist without
almost any standards. However, information gathering from these extremely
heterogeneous sources is difficult since the desired data may be scattered over
many databanks. This paper presents the concept of views implemented in the
retrieval system SRS that uses links between databanks and a sophisticated
parsing engine for information extraction to provide a flexible way of searching
and obtaining data across databank boundaries. The implementation provides
homogeneous access to all databanks using two types of views: the list-view which
displays selected data-fields in their original format and the table-view
available for HTML and plain ASCII text which tries to represent the data in a
format independent from that of the source databank.
PMID- 9390287
TI - Length scales of lipid dynamics and molecular dynamics.
AB - Following a brief overview of length scales and system size in computer
simulation, it is demonstrated that a simulation sized lipid bilayer (typically a
50 x 50 A2 patch) is in the regime where stretching dominates undulation, while
the reverse holds for a flaccid macroscopic membrane. Then it is estimated that
current system sizes of membrane simulations must be increased by at least a
factor of 10 before thermodynamic limits are approached for quantities such as
surface tension.
PMID- 9390288
TI - Specific modelling of regulatory units in DNA sequences.
AB - Transcriptional control regions are usually composed of a complex arrangement of
individual transcriptional elements like protein binding sites. This modular
structure allows generation of enormous functional diversity of regulatory
regions with a limited set of individual elements. We implemented simple formal
representations of these general features of regulatory regions into an algorithm
capable of developing complex models reflecting both the element composition and
the functional organization of individual elements. Our method (ModelGenerator)
requires a training set of at least 10 sequences containing the regulatory
regions to be modelled and a very simple initial model which may consist of just
two characteristic transcription factor binding sites. We show the capability of
our algorithm to expand the initial model solely by comparative sequence analysis
leading to complex, biologically meaningful models. A second program
(ModelInspector) is capable to scan new sequence data for matches to models
defined by ModelGenerator. We show two models for retroviral transcriptional
control regions to be highly specific. A search against GenBank using one of the
models is shown to be free of false negatives and to produce less than 2 false
positives/million nucleotides. Thus, our algorithms appear to be useful tools for
the analysis of extremely long genomic sequences which are now becoming available
as results of various genome sequencing projects.
PMID- 9390289
TI - Test tube systems with cutting/recombination operations.
AB - We introduce test tube systems based on operations that are closely related to
the splicing operation, i.e. we consider the operations of cutting a string at a
specific site into two pieces with marking them at the cut ends and of
recombining two strings with specifically marked endings. Whereas in the splicing
of two strings these strings are cut at specific sites and the cut pieces are
recombined immediately in a crosswise way, in CR(cutting/recombination)-schemes
cutting can happen independently from recombining the cut pieces. Test tube
systems based on these operations of cutting and recombination turn out to have
maximal generative power even if only very restricted types of input filters for
the test tubes are used for the redistribution of the contents of the test tubes
after a period of cuttings and recombinations in the test tubes.
PMID- 9390290
TI - Organizing and computing metabolic pathway data in terms of binary relations.
AB - A new database system named KEGG is being organised to computerize functional
aspects of genes and genomes in terms of the binary relations of interacting
molecules or genes. We are currently working on the metabolic pathway database
that is composed of three interconnected sections: genes, molecules, and
pathways, which are also linked to a number of existing databases through our
DBGET retrieval system. Here we present the basic concept of binary relations and
hierarchical classifications to represent the metabolic pathway data. The
database operations are then defined as an extension of the relational
operations, and the path computation problem is considered as a deduction from
binary relations. An example of using KEGG for the functional prediction of
genomic sequences is presented.
PMID- 9390291
TI - Development of a cell signaling networks database.
AB - In multicellular organisms cell signaling networks play important roles in wide
range of biological phenomena, such as development, differentiation,
reproduction, morphogenesis, carcinogenesis, apoptosis, and even learning. In
order to explain biological phenomena based on cell signaling models, we have
developed a database for cell signaling networks. The system contains mechanisms
of signal transduction and structure and functional data and references of
extracellular chemicals and biomolecules. CSNDB is constructed using ACEDB
system, and includes various graphical representations such as pathway diagrams,
map diagrams, 3-D images, pictures, and VRML environment. The system will be
useful for modeling cells and their information processing, and to explain
important biological phenomena based on these models.
PMID- 9390292
TI - The native sequence determines sidechain packing in a protein, but does optimal
sidechain packing determine the native sequence?
AB - Globular proteins have highly compact structures and the corresponding packing
interactions are widely considered as the principal determinant of the native
structure. It is therefore important that theoretical approaches to protein
design explicitly take in account packing, which requires that a full atomic
representation of the designed protein is maintained. As a first step towards
this goal, we have developed in this report an inverse folding algorithm with the
aim of specifically designing amino acid sequences which optimise sidechain
packing for a given protein fold. The design is performed by a global Monte Carlo
optimisation in sequence space, with constant amino acid composition and a full
atom representation of the various protein models. Packing is defined by a
Lennard-Jones potential. The program was tested by designing stable sequence
variants for the chymotrypsin inhibitor fold. The final protein models showed an
increase in intramolecular atomic contacts and a decrease in the overall volume
compared to the native structure. Starting from the backbone only of the target
structure, the algorithm did gradually retrieve reliable though limited sequence
information. Higher compatibility might be achieved by improving the potential,
however our results suggest that packing interactions are an essential element of
a yet-to-be-defined successful energy function for protein design.
PMID- 9390293
TI - Design of hydrophobic core of E. coli malate dehydrogenase based on the side
chain packing.
AB - We have developed computational programs for the de novo design of hydrophobic
cores of proteins. The first program optimizes side-chain conformations using an
updated rotamer library for potential hydrophobic residues, based on the backbone
structure of the protein of interest. The second program selects candidates to be
engineered among the sequences by estimating changes in Gibbs free energy between
the folded and unfolded structure of the proteins with new sequence. Using these
programs, we constructed several variants of E. coli malate dehydrogenase (eMDH)
which could have increased stability at 25 degrees C, compared to the wild type
enzyme. To quantitate stability change between variants and the wild type,
circular dichroism spectra were measured as a function of guanidine hydrochloride
concentration at 25 degrees C, pH 7.0. This analysis showed that three variants
constructed in this study were stabilized more than or equal to the wild type.
This demonstrated that our programs may be powerful tools to design new proteins
with high stability.
PMID- 9390294
TI - Latent periodicity of DNA sequences of many genes.
AB - A method of latent periodicity search being developed. Mutual information is used
to reveal of DNA or mRNA sequence latent periodicity. The latent periodicity of
DNA sequence is a periodicity with low level of homology between any two periods
inside DNA sequence. The mutual information between artificial numerical sequence
and DNA sequence is calculated. The length of the artificial sequence period is
varied from 2 to 150. The high level of the mutual information between artificial
and DNA sequences allows to find any type of latent periodicity of DNA sequence.
The latent periodicity of many DNA coding regions has been found. Potential
significance of latent periodicity is discussed.
PMID- 9390295
TI - Integrating database homology in a probabilistic gene structure model.
AB - We present an improved stochastic model of genes in DNA, and describe a method
for integrating database homology into the probabilistic framework. A generalized
hidden Markov model (GHMM) describes the grammar of a legal parse of a DNA
sequence. Probabilities are estimated for gene features by using dynamic
programming to combine information from multiple sensors. We show how matches to
homologous sequences from a database can be integrated into the probability
estimation by interpreting the likelihood of a sequence in terms of the bit-cost
to encode a sequence given a homology match. We also demonstrate how homology
matches in protein databases can be exploited to help identify splice sites. Our
experiments show significant improvements in the sensitivity and specificity of
gene structure identification when these new features are added to our gene
finding system, Genie. Experimental results in tests using a standard set of
annotated genes showed that Genie identified 95% of coding nucleotides correctly
with a specificity of 91%, and 77% of exons were identified exactly.
PMID- 9390296
TI - Packing as a structural basis of protein stability: understanding mutant
properties from wildtype structure.
AB - Modeling of protein core mutations using sidechain packing can forecast their
effects on stability. We have assessed the structural basis of this approach, by
evaluating the accuracy of our 1991 model of a three-site mutant of lambda
repressor (V36L/M40L/V47I), against the recently reported crystal structure. The
three mutated residues matched the crystal structure to within 0.89A (1.11A for
sidechain atoms), giving fairly accurate sidechain placement and packing (81-99th
percentile rank in coordinate accuracy). However, the model used different
sidechain torsional angles than seen in the crystal structure at residues 36 and
40, apparently to compensate for the backbone shifts present in the actual mutant
structure, but not accounted for in our modeling method. To understand the
structural basis of stability across a set of lambda repressor core mutants, we
have analyzed the mutant models, revealing several simple packing effects: V36I,
predicted to be stabilized by filling a hydrophobic cavity; M40V, destabilized by
a steric clash with the unusual structural demands of a helix-turn transition.
These effects illustrate how mutant stability can often be understood directly
from scrutiny of wildtype structure. Simply adding the calculated energies of
neighboring point mutations predicts the stability effect of the combined mutant
relatively well, with little apparent cooperativity, yielding simple rules for
each site's amino acid preferences. Our treatment of core packing indicates that
it can permit a large fraction of sequences to fit the native fold, as observed
experimentally, far more than indicated by rotamer hard-sphere models.
PMID- 9390297
TI - Facilities for exploring molecular biology databases on the Web: a comparative
study.
AB - We discuss criteria for evaluating and comparing the main facilities provided by
molecular biology databases (MBDs) for exploring (that is, retrieving and
interpreting data) on the Web. We use these criteria for examining the facilities
supported by typical MBDs such as Genbank, AtDB, GSDB, GDB, and MGD (as of
September 5, 1996).
PMID- 9390298
TI - Towards a bacteriorhodopsin-silicon neuromorphic photosensor.
AB - We describe our efforts towards constructing a hybrid protein-silicon
neuromorphic photosensor based on the photo-active protein bacteriohodopsin. This
protein displays an differential photosensitivity similar to the response of the
receptive field of an X-type retinal ganglion cell. Similar bacteriohodopsin
photoelectrode arrays display inherent edge detection and motion enhancement. We
discuss challenges associated with constructing and understanding the protein
silicon interface and possible chemical solutions for our experimental device.
PMID- 9390299
TI - An approach to detection of protein structural motifs using an encoding scheme of
backbone conformations.
AB - This paper presents an approach to detection of protein structural motifs. In our
approach, first all protein backbone conformations are converted into character
strings using an encoding scheme. Then we use the Smith-Waterman local alignment
algorithm to detect common structural motifs. By comparing results with the
PROSITE regular expression patterns, our method can detect several motifs which
the PROSITE patterns fail to detect.
PMID- 9390300
TI - An algorithm to assemble pathways from processes.
AB - To understand or to modify a biological pathway, the first step is to determine
the patterns of coupling among its processes that are compatible with its input
output relation. Algorithms for this purpose have been devised for metabolic
pathways, in which the reactions typically leave the enzymes unmodified. As shown
here, one of these algorithms can also assemble molecular networks in which
reactions modify proteins, if the proteins are included among the inputs to the
reactions. Thus one procedure suffices to assemble pathways for metabolism,
cytoplasmic signal transduction, and gene regulation.
PMID- 9390301
TI - Toward a virtual-labo-system for metabolic engineering: development of
biochemical engineering system analyzing tool-kit (BEST-KIT).
AB - BEST-KIT is an efficient and user-friendly "biochemical engineering system
analyzing tool-kit" integrated the following key modules: 1) mathematical
modeling and editing of reaction-scheme, 2) automatic derivation of differential
equations, 3) numerical calculation, 4) nonlinear optimization, 5) visualization,
6) retrieve the information on reaction mechanism and kinetic parameters from
data-base of metabolic pathways. The users of this simulator are assumed to be
unfamiliar with computer technology and with computer programming. The integrated
interface (UNIX version) is based on Xlib, XToolkit and OSF/Motif Widget.
PMID- 9390302
TI - Method for low resolution prediction of small protein tertiary structure.
AB - A new method for the de novo prediction of protein structures at low resolution
has been developed. Starting from a multiple sequence alignment, protein
secondary structure is predicted, and only those topological elements with high
reliability are selected. Then, the multiple sequence alignment and the secondary
structure prediction are combined to predict side chain contacts. Such contact
map prediction is carried out in two stages. First, an analysis of correlated
mutations is carried out to identify pairs of topological elements of secondary
structure which are in contact. Then, inverse folding is used to select
compatible fragments in contact, thereby enriching the number and identity of
predicted side chain contacts. The final outcome of the procedure is a set of
noisy secondary and tertiary restraints. These are used as a restrained potential
in a Monte Carlo simulation of simplified protein models driven by statistical
potentials. Low energy structures are then searched for by using simulated
annealing techniques. Implementation of the restraints is carried out so as to
take into account of their low resolution. Using this procedure, it has been
possible to predict de novo the structure of three very different protein
topologies: an alpha/beta protein, the bovine pancreatic trypsin inhibitor
(6pti), an alpha-helical protein, calbindin (3icb), and an all beta- protein, the
SH3 domain of spectrin (1shg). In all cases, low resolution folds have been
obtained with a root mean square deviation (RMSD) of 4.5-5.5 A with respect to
the native structure. Some misfolded topologies appear in the simulations, but it
is possible to select the native one on energetic grounds. Thus, it is
demonstrated that the methodology is general for all protein motifs. Work is in
progress in order to test the methodology on a larger set of protein structures.
PMID- 9390303
TI - Multiple model approach--dealing with alignment ambiguities in protein modeling.
AB - Sequence alignments for distantly homologous proteins are often ambiguous, which
creates a weak link in structure prediction by homology. We address this problem
by using several plausible alignments in a modeling procedure, obtaining many
models of the target. All are subsequently evaluated by a threading algorithm. It
is shown that this approach can identify best alignments and produce reasonable
models, whose quality is now limited only by the extent of the structural
similarity between the known and predicted protein. Using a similar approach
structure prediction for the oxidized dimer of S100A1 protein, for which the
structure is not known, is presented.
PMID- 9390304
TI - Search for DNA conformational features for functional sites. Investigation of the
TATA box.
AB - A method for search of DNA conformational features significant for functional
sites is developed. The method uses helical angles averaged for known X-ray
structures. Nucleotide sequences are assigned mean angles in a given region.
Choice of the significant angles is based on their capabilities to discriminate
functional sites from random sequences. The yeast, invertebrate and vertebrate
TATA boxes are analyzed using this method. Regions neighboring the TATA boxes are
found to have smaller helical twist and roll angles. The results agree with the
experimental data on Dickerson-Drew dodecamers. There is a significant decrease
in the length of a small roll angle region with increasing complexity of taxon
organization.
PMID- 9390306
TI - Exploring the fitness landscapes of lattice proteins.
AB - We present methods to investigate the sequence to structure relation for
proteins. We use random structures of HP-type lattice models as a coarse grained
model to study generic properties of biopolymers. To circumvent the computational
limitations imposed by most lattice protein folding algorithms we apply a simple
and fast deterministic approximation algorithm with a tunable accuracy. We
investigate ensemble properties such as the conditional probability to find
structures with a certain similarity at a given distance of the underlying
sequence for various alphabets. Our results suggest that the structure landscapes
for lattice proteins are generally very rugged, while larger alphabets fine tune
the folding process and smoothen the map. This implies a simplification for
evolutionary strategies. The applied methods appear to be helpful in the study of
the complex interplay between folding strategies, energy functions and alphabets.
Possible implications to the investigation of evolutionary strategies or the
optimization of biopolymers are discussed.
PMID- 9390305
TI - Algorithmic complexity of growth hormone release in humans.
AB - Most hormones are secreted in an pulsatile rather than in a constant manner. This
temporal pattern of pulsatile hormone release plays an important role in the
regulation of cellular function and structure. In healthy humans growth hormone
(GH) secretion is characterized by distinct pulses whereas patients bearing a GH
producing tumor accompanied with excessive secretion (acromegaly) exhibit a
highly irregular pattern of GH release. It has been hypothesized that this highly
disorderly pattern of GH release in acromegaly arises from random events in the
GH-producing tumor under decreased normal control of GH secretion. Using a
context-free grammar complexity measure (algorithmic complexity) in conjunction
with random surrogate data sets we demonstrate that the temporal pattern of GH
release in acromegaly is not significantly different from a variety of stochastic
processes. In contrast, normal subjects clearly exhibit deterministic structure
in their temporal patterns of GH secretion. Our results support the hypothesis
that GH release in acromegaly is due to random events in the GH-producing
tumorous cells which might become independent from hypothalamic regulation.
PMID- 9390307
TI - Accurate mean-force pairwise-residue potentials for discrimination of protein
folds.
AB - We present two new sets of energy functions for protein structure recognition.
The first set of potentials is based on the positions of alpha- and the second on
positions of beta-carbon atoms of amino acid residues. The potentials are derived
using a theory of Boltzmann-like statistics of protein structure by Finkelstein
et al. The energy terms incorporate both long-range interactions between residues
remote along a chain and short-range interactions between near neighbors.
Distance-dependence is approximated by a piecewise constant function defined on
intervals of equal size. The size of this interval is optimized. A database of
222 non-homologous proteins was used both for the derivation of the potentials,
and for the "threading" test originally suggested by Hendlich et al. For
threading, we used 102 non-homologous protein chains of 60 to 200 residues. The
energy of each of the native structures was compared with the energy of 45 to 20
thousand alternative structures generated by threading. Of these 102 native
structures 94 have the lowest energy with alpha-carbon-based potentials, and even
more, 100 of these 102 structures, have the lowest energy with the beta-carbon
based potentials.
PMID- 9390308
TI - Real time surface reconstruction for moving molecular fragments.
AB - Recently we introduced the Reduced Surface as an efficient tool to built
molecular surfaces. We describe here how this geometric construct can be used to
efficiently reconstruct the solvent excluded surface of a protein for which the
coordinates of a subset of atoms are changing. We show that, the complexity of
that operation is not dependent upon the size of the molecule and is in
O[tlog(t)] where t is the maximum of the number of probes and atoms involved in
the reconstruction of the surface. The algorithms described here have been
implemented and tested on several proteins. The triangulation of the solvent
excluded surface of proteins in which a side chain was changing conformation
could be updated at rates ranging from 7 to 22 frames per second. We also applied
this method to compute the surface area fluctuation of the FIV protease
undergoing a constrained molecular dynamics simulation (16 mobile residues). Rate
of 6 frames per second were obtained in this case.
PMID- 9390309
TI - Finding association rules on heterogeneous genome data.
AB - A novel approach for discovery of knowledge from genome data, which has been
recently watched with interest in the research area of database, is applied to
finding unified rules spreading over sequence, structure, and function of
protein. As the result of experiments using data extracted from PDB, SWISS-PROT,
and PROSITE, some association rules stating sequential/structural/functional
aspects of two kinds of endopeptidases were found.
PMID- 9390310
TI - Enumerating suboptimal alignments of multiple biological sequences efficiently.
AB - The multiple sequence alignment problem is very applicable and important in
various fields in molecular biology. Because the optimal alignment that maximizes
the score is not always biologically most significant, providing many suboptimal
alignments as alternatives for the optimal one is very useful. As for the
alignment of two sequences, this suboptimal problem is well-studied, but for the
alignment of multiple sequences, it has been considered impossible to investigate
such suboptimal alignments because of the enormous size of the problem. The
optimal multiple alignment can be obtained with A* algorithm, and an efficient
algorithm for the k shortest paths problem on general graphs is discovered
recently. We extend these algorithms for computation of set of all aligned groups
of residues in optimal and suboptimal alignments, and for enumeration of
suboptimal alignments. The suboptimal alignments are numerous. Thus we discuss
what kind of suboptimal alignment is unnecessary to enumerate, and propose an
efficient technique to enumerate only necessary alignments. The practicality of
these algorithms are demonstrated through experiments. Moreover, the property of
suboptimal alignments of multiple sequences are also examined through
experiments.
PMID- 9390311
TI - Redox properties of cytochrome c: novel linear response and hybrid continuum
microscopic methodologies.
AB - Redox properties of yeast cytochrome c are estimated using molecular dynamics
combined with a simple linear response approximation, as well as a hybrid
continuum-molecular dynamics (COMD) approach. In both approaches, the free energy
associated with an electrostatic perturbation (a redox electron) is separated
into its relaxation and static (non-relaxation) components. The static component
is calculated from the molecular dynamics simulation. The relaxation component is
then calculated with a linear response approximation, either from the molecular
dynamics, or from a separate continuum calculation. This latter hybrid approach
exploits the relative robustness of continuum models for dealing with large
perturbations, while avoiding some of their limitations. It is quite general, and
could be applied for example to pKa calculations.
PMID- 9390312
TI - Protein superfamily members as targets for computer modeling: the carbohydrate
recognition domain of a macrophage lectin.
AB - Members of protein superfamilies display similar folds, but share only limited
sequence identity, often 25% or less. Thus, it is not straightforward to apply
standard homology modeling methods to construct reliable three-dimensional models
of such proteins. A three-dimensional model of the carbohydrate recognition
domain of the rat macrophage lectin, a member of the calcium-dependent (C-type)
lectin superfamily, has been generated to illustrate how information provided by
comparison of X-ray structures and sequence-structure alignments can aid in
comparative modeling when primary sequence similarities are low.
PMID- 9390313
TI - Definite-clause grammars for the analysis of cis-regulatory regions in E. coli.
AB - Based on an extensive collection of sigma 70 associated regulatory mechanisms, a
grammatical model has been constructed that define the functional positions and
combinations of sites within DNA regulatory regions. The syntactic rules and the
dictionary implemented in a Prolog program were coupled to consensus matrices
used as "sensors" to integrate a syntactic recognizer. A systematic comparison
between the syntactic recognizer and the standard weight matrix methodology is
presented using 12 regulatory proteins and the whole collection of about 130
sigma 70 DNA regulatory regions. On the average an increased sensitivity of 5 to
10 fold is obtained with this novel approach.
PMID- 9390314
TI - Enumeration of flux routes through complex biochemical reactions.
AB - In the present work, a general algorithm for enumeration of the flux routes via
which a chemical species "flows" through a complex biochemical reaction is
outlined and presented by way of a biological example, a kinetic model for
potassium ion permeation through a voltage-gated ion channel. The algorithm is
readily amenable to computer based implementation and when used in conjunction
with an existing algorithm provides a convenient means for simulation of the
equilibrium and steady-state isotope exchange kinetics of complex biochemical
reactions.
PMID- 9390315
TI - Using the radial distributions of physical features to compare amino acid
environments and align amino acid sequences.
AB - We have performed a comprehensive analysis of the microenvironments surrounding
the twenty amino acids. Our analysis includes comparison of amino acid
environments with random control environments as well as with each of the other
amino acid environments. We describe the amino acid environments with a set of 21
features summarizing atomic, chemical group, residue, and secondary structural
features. The environments are divided into radial shells of 1 A thickness to
represent the distance of the features from the amino acid C beta atoms. We make
the results of our analysis available graphically over the world wide web. To
illustrate the validity and utility of our analysis, we used the amino acid
comparative profiles to construct a substitution matrix, the WAC matrix, based on
a simple summary of the computed environmental differences. We compared our
matrix to BLOSUM62 and PAM250 in BLAST searches with query sequences selected
from 39 protein families found in the PROSITE database. Although BLOSUM62 was the
most sensitive matrix overall, our matrix was more sensitive for some families,
and exhibited overall performance similar to PAM250. Our results suggest that the
radial distribution of biochemical and biophysical features is useful for
comparing amino acid environments, and that similarity matrices based on the
geometric distribution of features around amino acids may produce improved search
sensitivity.
PMID- 9390316
TI - TRANSFAC database as a bridge between sequence data libraries and biological
function.
AB - The TRANSFAC database contains information about regulatory DNA sequences and the
proteins (transcription factors) binding to and acting through them. It may thus
serve as a dictionary for the biological meaning of these sequence elements.
Moreover, the TRANSFAC data can be used to describe these elements, to define
consensi and matrices for elements of certain function, and thus to provide means
of identifying regulatory signals in newly unravelled genomic sequences.
PMID- 9390317
TI - A new approach to protein fold recognition based on Delaunay tessellation of
protein structure.
AB - We propose new algorithms for sequence-structure compatibility (fold recognition)
searches in multi-dimensional sequence-structure space. Individual amino acid
residues in protein structures are represented by their C alpha atoms; thus each
protein is described as a collection of points in three-dimensional space.
Delaunay tessellation of a protein generates an aggregate of space-filling,
irregular tetrahedra, or Delaunay simplices. Statistical analysis of quadruplet
residue compositions of all Delaunay simplices in a representative dataset of
protein structures leads to a novel four body contact residue potential expressed
as log likelihood factor q. The q factors are calculated for native 20 letter
amino acid alphabet and several reduced alphabets. Two sequence-structure
compatibility functions are computed as (i) the sum of q factors for all Delaunay
simplices in a given protein, or (ii) 3D-1D Delaunay tessellation profiles where
the individual residue profile value is calculated as the sum of q factors for
all simplices that share this vertex residue. Both threading functions have been
implemented in structure-recognizes-sequence and sequence-recognizes-structure
protocols for protein fold recognition. We find that both profile and total score
based threading functions can distinguish both the native fold from incorrect
folds for a sequence, and the native sequence from non-native sequences for a
fold.
PMID- 9390318
TI - Dental care associated with an outbreak of HIV infection among dialysis patients.
AB - An outbreak of 14 cases of human immunodeficiency virus (HIV) infection was
discovered by chance in May 1993 among hemodialysis patients at a university
hospital in Bucaramanga, Colombia. The outbreak occurred in 1992. Stored sera
were used to establish the probable period of infection (PPI) for 10 of the 14
cases. A nested case-control study was carried out to evaluate possible
transmission mechanisms. The health care experience of each HIV-positive patient
during that patient's PPI was compared to the experience of time-matched
controls. Only invasive dental procedures were significantly associated with the
risk of infection. Patients upon whom invasive dental procedures were performed
during their PPIs had an average risk of HIV infection 8.15 times greater than
comparable controls (P = 0.006), and seven out of nine cases of HIV infection
with known PPIs in 1992 had an invasive dental procedure performed one to six
months before seroconversion. None of the dental care personnel were found to be
infected. Based on the available evidence, it seems most likely that the
infection was transmitted from patient to patient by contaminated dental
instruments.
PMID- 9390319
TI - Virtual elimination of iodine deficiency disorders in Bolivia.
PMID- 9390320
TI - [Nefazodon (Nefadar)--a new dual serotoninergic antidepressant. Introductory
press conference: "Nefazodone--new perspectives in antidepressive therapy." 25-26
April 1997].
PMID- 9390321
TI - The inherited palmoplantar keratodermas.
AB - The inherited palmoplantar keratodermas (PPK) constitute a complex heterogeneous
group of genodermatoses, which are difficult to classify clinically. The
application of modern molecular biology techniques are leading to an increased
understanding of the genetic bases of these disorders and are paving the way
towards a classification based upon molecular pathology. We review the recent
research advances in this field and the implications for development of novel
approaches to disease management.
PMID- 9390322
TI - Topical FK506: a potent immunotherapy for alopecia areata? Studies using the
Dundee experimental bald rat model.
AB - We elected to examine the efficacy of the topically applied immunosuppressive
agent FK506 (Prograf) in the treatment of alopecia areata (AA) using the Dundee
experimental bald rat (DEBR) model. Thirty lesional DEBR rats were allocated to
five groups of six. Group 1 rats received 0.1 mL of a 0.25% solution of FK506
within a 2 x 2 cm marked area on one bald flank twice a week (125 micrograms
FK506/cm2 per week) for 8 weeks, while the contralateral flank was left
untreated. In group II, 0.05 mL of a 0.1% solution of FK 506 was applied 5 days
per week on one flank (62.5 micrograms FK506/ cm2 per week) and control vehicle
to the opposite flank for 8 weeks. Group III rats were treated as in group II
except that drug and vehicle were applied twice a week (25 micrograms FK506/cm2
per week) for 4 weeks. A positive control group received orally administered
cyclosporin A (CsA) (10 mg/kg daily) for 8 weeks and a further group was left
untreated. Rats were regularly examined and photographed with skin biopsies taken
from groups II and III. All FK 506-treated rats regrew hair at the site of drug
application within 14-21 days. Growth continued for 3 weeks beyond termination of
treatment after which gradual hair loss was observed. No hair growth was seen as
a result of vehicle application and hair loss continued on untreated areas and in
the untreated control group. Immunohistology revealed a drastic reduction in the
follicular inflammatory infiltrate at the site of the FK506 application. The oral
CsA group responded by simultaneous regrowth of hair over the whole body. Our
findings suggest that FK506 may have considerable potential as a topical
treatment for AA.
PMID- 9390323
TI - Serum-free culture of wool follicles: effects of nutrients, growth factors and
hormones.
AB - A serum-free culture system allowed the continued growth of fibre from follicles
for 8-10 days. Fibre growth was responsive to changes in the level of calcium,
glucose and amino acids in the culture medium, and was stimulated by the
inclusion of insulin (10 micrograms/mL) in the medium. Culture of follicles in
the presence of conditioned media from dermal papilla cells or of mitomycin
treated dermal papilla cells had no effect on fibre growth. Neither thyroid
hormones nor hydrocortisone altered fibre growth. The progressive decline in
fibre growth during follicle culture was accompanied by morphological changes in
the follicle bulb. Oxidative damage did not appear to be the cause of these
changes as there was no increase in fibre growth rate or longevity when
antioxidants were used. This model provides a useful system to study the direct
effects of various hormonal, nutritional and growth factors of fibre growth and
follicle metabolism.
PMID- 9390324
TI - Postsurgical wound progression monitored by temporal changes in the expression of
matrix metalloproteinase-9.
AB - It is important to monitor the early stages of postoperative wound repair in
order to identify those problems associated with impaired healing. Many of the
crucial cellular responses of early wound healing, such as inflammatory
infiltration, angiogenesis and re-epithelialization, are made possible through
the action of matrix metalloproteinases (MMPs). Expression of MMP-2 and MMP-9 is
elevated in acute wounds, and still greater levels are found in chronic wounds,
indicating that uncontrolled proteolysis is a characteristic of retarded healing.
Therefore, comparative measurements of MMPs may be used to monitor the
progression of early wound healing. To investigate this, wound fluids and sera
were collected from mastectomy and colectomy patients throughout early stages of
repair, and the temporal expression profile established. Wounds which were
healing were expressed maximal levels of MMP-9 at 24 h, followed by a significant
decline by 48 h. Persistent elevation of MMP-9 expression was associated with
infected and chronic wounds, and was identified in postoperative wounds by the
absence of the significant decline between 24 and 48 h. Measurement of MMP-9 in
postoperative wound fluids, therefore, provides an early indicator of impaired
healing, which may be evaluated non-invasively within 48 h of closure.
PMID- 9390325
TI - Increased expression of gelatinases A and B by skin explants from patients with
anetoderma.
AB - The extent of alterations to the elastic fibre network in lesional skin areas of
three patients with anetoderma was assessed by quantitative image analysis of
tissue sections and compared with morphometric parameters from unaffected sites
of the same individuals. In the anetodermic skins pre-elastic fibres were
undetectable or extremely rare: the volume fraction (Vv%) occupied by these pre
elastic fibres was 0-0.3%, while in unaffected skins the Vv% occupied by pre
elastic fibres was 0.5-0.8%. A nearly complete absence of dermal elastic fibres
in lesional skins from the three patients was evidenced (Vv% = 0.2-0.3%). Organ
cultures were performed using explants from skin with or without anetodermic
lesions to quantify the expressions of elastase-type proteinases. All tissues
from anetodermic lesions expressed proforms of gelatinases A and B and the
activated form of gelatinase A; their levels increased with the culture time. In
comparison, enzymatic activities on oligopeptide substrates specific for
leucocyte elastase and fibroblast plasma membrane-associated metalloelastase were
not detected in the conditioned media of any explants at any time of culture from
1 to 5 days. Increased production of progelatinases A and B and activation of
progelatinase A could be mainly responsible for the degradation of skin elastic
fibres demonstrated in anetodermic skins.
PMID- 9390326
TI - Linear IgA disease: a report of two dermal binding sera which recognize a pepsin
sensitive epitope (?NC-1 domain) of collagen type VII.
AB - Linear IgA disease is a subepidermal blistering disease characterized by IgA
autoantibody deposition at the basement membrane zone of skin and mucosa. The
antigens targeted in linear IgA disease have been defined by their molecular
weight and localization. It has been proposed that a minority of linear IgA
disease sera that bind to the dermal aspect of salt-split skin target collagen
type VII. We have identified two patients with linear IgA disease using dermal
binding IgA autoantibodies on salt-split skin which recognize collagen type VII
by immunoblot analysis. The reactive epitope was destroyed by the proteolytic
enzymes pepsin, which destroys the NC-1 domain of collagen type VII, and protease
type VIII. Localization studies compared the IgA autoantibodies from these
patients with the monoclonal antibody LH7.2 to the NC-1 domain of collagen type
VII and showed colocalization on a dermal cylindroma tumour tissue, and a similar
distribution with immunogold electron microscopy, using purified blister fluid
from one patient. We propose from these results that the IgA autoantibodies from
these two patients recognize the NC-1 domain of collagen type VII, the classical
immunodominant epitope for epidermolysis bullosa acquisita.
PMID- 9390327
TI - One single erythemagenic UV irradiation is more effective in increasing the
proliferative activity of melanocytes in melanocytic naevi compared with
fractionally applied high doses.
AB - The effect of a single irradiation with UV light on the expression of Ki67
antigen, topoisomerase II alpha, proliferating cell nuclear antigen (PCNA), the
melanocyte activation marker HMB-45 and protein p53 in melanocytic naevi was
investigated 1 week after application of a single erythemagenic UV dose and after
daily exposures with suberythemagenic doses over 4-6 weeks. To assess the effect
of UV irradiation, one half of each naevus was shielded with black tape during
the UV exposure, and the irradiated part and the non-irradiated parts were
evaluated separately. Except for HMB-45, a double staining procedure was
performed to distinguish between labelled melanocytes and keratinocytes. After
semiquantitative assessment of the staining signal the irradiated part was
compared with the non-irradiated part of the same naevus. Morphological changes
and an enhanced proliferative/ reparative activity in melanocytes were much more
frequent in the naevi irradiated with a single erythemagenic UV dose than in
those given repeated suberythemagenic doses. In addition, the keratinocytes
showed an increased labelling for PCNA and p53 after the single irradiation.
These data may support the importance of intermittent UV exposure and sunburns in
the development of both benign and malignant melanocytic lesions.
PMID- 9390328
TI - Contact allergens and sodium lauryl sulphate upregulate vascular endothelial
growth factor in normal keratinocytes.
AB - In allergic and irritant contact dermatitis, keratinocytes are major target cells
that can be activated to take part in local reactions by secreting soluble
mediators. Among the growth factors produced by keratinocytes, vascular
endothelial growth factor (VEGF) is a powerful inducer of permeability of
endothelial cells, and is involved in inflammation. We determined whether
different contact allergens, dinitrosulphobenzene (DNSB), para-phenylenediamine
(pPD) and the metals nickel and chromium, as distinct from cobalt, which has been
shown to mimic the effects of hypoxia, can modify the basal level of VEGF in
normal human keratinocytes when tested at various, non-toxic concentrations. The
effects of an irritant, sodium lauryl sulphate (SLS), and of hydrocortisone were
also tested. Our results showed an intense dose-dependent upregulation of VEGF
release by keratinocytes after treatments by metals, pPD and SLS. DNSB induced
only a moderate increase of VEGF. Hydrocortisone reduced the basal level as well
as the nickel-induced upregulation of VEGF. These findings suggest that contact
allergens and irritants probably upregulate VEGF in keratinocytes by different
mechanisms and may contribute directly to the microvascular hyperpermeability
which characterizes both contact and irritant dermatitis.
PMID- 9390329
TI - Lack of effect of growth hormone therapy on the count and density of melanocytic
naevi in children.
AB - An observation of accelerated growth of acquired melanocytic naevi (AMN) during
treatment with human growth hormone (GH) raised concerns about the potential risk
of melanoma in treated patients. An increased number of AMN, rather than growth
rate, is associated with a higher risk for melanoma. It is unknown whether
treatment with GH causes an increase in numbers of AMN. We evaluated the effect
of GH treatment on the number of AMN in a cross-sectional study of 90 children
with GH deficiency. AMN counts and densities in these children were compared with
those found in a control group of 100 children. Factors potentially related to
increased numbers of AMN, such as age, sex, skin colour, number of episodes of
sunburn and duration of GH therapy were determined. Among the various factors,
only the age and colour of unexposed skin area were predictive for the total
number and density of AMN. No correlation was found between the AMN counts or
density and the duration of GH therapy. There was no difference in AMN counts or
density between the GH-deficient patient group and the control groups. We
conclude that GH therapy in children is not associated with increased AMN count
and density and is unlikely to potentiate the risk for melanoma in these
children.
PMID- 9390330
TI - Extracorporeal photochemotherapy induces apoptosis of infiltrating lymphoid cells
in patients with mycosis fungoides in early stages. A quantitative histological
study.
AB - Extracorporeal photochemotherapy (ExP) is a well-tolerated new form of
chemoimmunotherapy, which is considered to be effective for cutaneous T-cell
lymphoma (CTCL) and the treatment of choice for Sezary syndrome. Improvements
have also been seen in patients with non-erythrodermic mycosis fungoides (MF) in
the early stages, even when tumour cells are not detectable in the peripheral
blood. In this study, we used ExP as a monotherapy in seven patients who had
early stage (Ib) MF, and who were no longer responsive to or had
contraindications for other therapies. We observed a clinical improvement in the
disease after 12 months of treatment: one patient showed a complete response,
five a partial response, and one remained stable. In each patient we compared
skin biopsies of large plaque lesions before and after the treatment. We
undertook a histological evaluation of the infiltrate. The lymphoid cell
proliferation and death rates were quantified using the following parameters;
lymphoid cell density (LCD), Ki67 + lymphoid cell nuclei percentage (Ki67 + Lcn
percentage), and apoptotic index (AI). Significant decreases in the lymphoid cell
infiltrate and in cell proliferation, and a significant increase in AI were
observed after therapy. The mean LCD decreased from 187 +/- 33 to 34 +/- 17.7,
Ki67 + Lcn mean percentage decreased from 16.9 +/- 3.9 to 4.9 +/- 2.4, and the AI
mean value increased from 0.05 +/- 0.03 to 2.41 +/- 1.54. Our results suggest a
role for apoptosis in the improvement of the skin lesions and are in line with
some reports on the mode of action of ExP. Although the way in which ExP works
needs to be clarified further, it does seem to stimulate a CD8+ cell-mediated
anticlonotypic activity against circulating pathogenic clones. Furthermore, a
release of tumour necrosis factor alpha (TNF-alpha) by circulating monocytes has
been demonstrated after ExP. Both are known to induce cell death by apoptosis.
PMID- 9390331
TI - Experiences with the severity scoring of atopic dermatitis in a population of
German pre-school children.
AB - Severity scoring of atopic dermatitis (SCORAD) was introduced as a standard tool
but has not been used in a population-based epidemiological study; the objective
of the present study was to determine the practicability of this instrument in
this setting. We assessed the distribution of the severity of atopic eczema in
the community and investigated differences between east and west Germany. A
factor analysis was then carried out to characterize the variables of this
scoring system and to analyse possible relationships within them. A multicentre
cross-sectional study was carried out in five east German and two west German
locations in 1994; pre-school children (5-6 years old) were investigated and
cases of atopic eczema identified by a dermatological examination. The SCORAD was
used to determine the severity of atopic eczema and the results assessed using
analysis of variance and principal component analysis (varimax rotation). In all,
1511 (76.2%) of the children originally contacted participated and 11.3% were
diagnosed with atopic eczema at the time of examination. The median severity
scores was 21.4 (interquartile range 13.5) and there was a tendency to higher
scores in west Germany for the mean overall score, the intensity score and the
extent. 'Erythema' (1.30 vs. 1.06; P = 0.006) and 'excoriation' (0.77 vs. 0.36; P
= 0.002) were significantly more prominent in children with eczema from west
Germany (adjusted for observer). Interobserver variabilities of the SCORAD
parameters were calculated, adjusted for location and were in accordance with
earlier findings. Principal component analysis identified three independent
factors accounting for 54.1% of the total variance. A severity factor,
characterized by 'extent', 'lichenification', 'excoriation' and 'pruritus', was
separated from a factor with an acute eczema-type profile ('erythema', 'oedema',
'oozing') and a factor whose major characteristics were 'extent', 'dryness', and
'sleep loss'. We conclude that atopic eczema is frequent in pre-school children.
The SCORAD proved to be readily applicable and useful in epidemiological studies,
but further validation is needed.
PMID- 9390332
TI - The effectiveness of acne treatment: an assessment by patients of the outcome of
therapy.
AB - The impact of acne on quality of life can be profound. Although treatment
improves the clinical features of acne, there is little information on its
benefit from the patients' point of view. In this study, patients with acne
referred to a dermatology clinic were sent questionnaires before being seen, and
4 and 12 months afterwards. Clinical severity was assessed by a dermatologist at
baseline and at 4 months. Quality of life was assessed by patients using the
Short Form 36 instrument (SF-36), the Dermatology Life Quality Index (DLQI),
Rosenberg's measure of self-esteem and the General Health Questionnaire (GHQ-28).
Of 90 available patients, 79 (89%) returned at least one follow-up questionnaire.
The clinical acne grade improved substantially with treatment. There were also
significant improvements either at 4 or 12 months in the DLQI, self-esteem. GHQ
28 and all five dimensions of the SF-36 that were impaired at baseline. Quality
of life continued to improve between the 4- and 12-month follow-up
questionnaires. Clinical and patient-assessed outcomes were significantly better
in patients treated with isotretinoin. The study showed that disability caused by
acne can be largely reversed by effective treatment. It also showed that patient
assessed measures of outcome can respond to changes over time and discriminate
between treatments differing in effectiveness.
PMID- 9390333
TI - A novel anti-inflammatory drug, SDZ ASM 981, for the topical and oral treatment
of skin diseases: in vivo pharmacology.
AB - There is a need for safe and effective therapies for inflammatory skin diseases.
Current topical and systemic treatment of psoriasis is effective but suffers from
side-effects or is inconvenient. The therapeutic armamentarium for atopic
dermatitis is very limited and far from satisfactory. In vivo preclinical data
are presented for SDZ ASM 981, a novel ascomycin macrolactam derivative with high
anti-inflammatory activity. Anti-inflammatory activity was observed in mouse, rat
and pig models of allergic contact dermatitis. In the pig model, topical SDZ ASM
981 was as effective as the ultrapotent corticosteroid clobetasol-17-propionate,
and when compared with a series of commercial topical corticosteroid
preparations, 0.1% SDZ ASM 981 had equivalent efficacy to clobetasol-17
propionate (0.05%), the most potent product on the market. Unlike the
corticosteroid, however, SDZ ASM 981 did not cause skin atrophy in pigs. SDZ ASM
981 potently inhibited allergic contact dermatitis in mice and rats when given
systemically, and oral treatment was more effective than cyclosporin A in rats.
Furthermore, SDZ ASM 981 has a low potential for affecting systemic immune
responses, as demonstrated in rat models of localized graft vs. host reaction and
allogeneic kidney transplantation. Preclinical results suggest that SDZ ASM 981
has the potential to be a well-tolerated and effective drug for topical as well
as oral treatment of inflammatory skin diseases.
PMID- 9390334
TI - Toenail onychomycosis in patients with acquired immune deficiency syndrome:
treatment with terbinafine.
AB - Skin infections caused by dermatophytes are one of the most frequent
dermatological complications in patients with acquired immunodeficiency syndrome
(AIDS) resulting from infection with human immunodeficiency virus (HIV). Tinea
unguium associated with AIDS is characterized by being clinically more aggressive
and therapeutically more difficult to treat than in the general population.
Terbinafine is considered to be a first-choice option for the treatment of
dermatophyte onychomycosis in immunocompetent individuals. This drug has been
used in a series of 21 HIV-positive patients diagnosed with tinea unguium for 1
year in the University Hospital La Paz, Madrid. All patients underwent a
subsequent clinical follow-up for 6 months. The results showed a high percentage
of clinical and mycological cures, as well as maintenance of the response after
follow-up; no drug interactions or significant adverse effects related to the
drug under study were recorded.
PMID- 9390335
TI - Once daily treatment of psoriasis with tacalcitol compared with twice daily
treatment with calcipotriol. A double-blind trial.
AB - Once daily topical treatment of psoriasis with tacalcitol ointment (4
micrograms/g) was compared with twice daily treatment with calcipotriol ointment
(50 micrograms/g) in a double-blind, randomized study over a treatment period of
8 weeks. The severity of pruritus, erythema, infiltration and scaling was scored
on a scale from 0 to 4. These features were scored at the initiation of
treatment, after 2, 4, 6 and 8 weeks of treatment, and at 4 weeks after
discontinuation of treatment. The sum score was the total score for erythema,
infiltration and scaling. Serum levels of calcium, phosphate, ionized calcium and
intact parathyroid hormone were used as safety parameters. Two hundred and eighty
seven adults with stable plaque psoriasis participated and were treated at least
once. Both tacalcitol and calcipotriol ointments effectively reduced the severity
of psoriasis. The mean reduction in the sum score in the intention-to-treat
population of 287 patients was 4.03 in the group treated with tacalcitol compared
with 5.05 in the group treated with calcipotriol. The mean baseline sum scores
were 7.64 and 7.15, respectively. The acceptability of both ointments was
excellent, and none of the patients had adverse effects in terms of increased
serum calcium or other alterations in calcium metabolism. Although less effective
than calcipotriol ointment used twice daily, tacalcitol ointment is an effective
and useful once daily treatment of chronic plaque psoriasis.
PMID- 9390336
TI - The combination of oral acitretin and bath PUVA for the treatment of severe
psoriasis.
AB - We report four patients with severe erythrodermic, pustular psoriasis, or plaque
type psoriasis, who were treated with a combination of acitretin and bath PUVA.
After 4 weeks out-patient treatment, the psoriasis in all patients had improved
by > or = 90%. No patient had relapsed when reviewed at 3 months. No significant
side-effects were seen with the combined retinoid/bath PUVA treatment. Acitretin
and bath PUVA may be safely combined for the treatment of severe psoriasis.
PMID- 9390337
TI - CO2 laser debridement of sulphur mustard (bis-2-chloroethyl sulphide) induced
cutaneous lesions accelerates production of a normal epidermis with elimination
of cytological atypia.
AB - Sulphur mustard (bis-2-chloroethyl sulphide; HD) exposure acutely produces
lesions that vary from mild erythema, to blister formation, to necrosis. When
blisters occur, with or without necrosis, healing of the lesions is delayed.
Weanling pigs exposed to a mild erythema-producing dose of HD and to a moderate
erythema-producing dose that consistently gave microblister formation were
treated with CO2 laser (Tru-Pulse) debridement at 6, 24 or 48 h after exposure.
The histopathological features observed at 14 days after exposure in control skin
and skin exposed to both HD doses were compared with the features observed in CO2
laser-debrided skin in non-exposed and HD-exposed skin sites. The overlying
epidermis in the non-laser treated lesions was thin, with cytological atypia and
squamoid changes within the basal cell layer, as well as scattered
apoptotic/necrotic keratinocytes. An increased inflammatory infiltrate and
necrobiotic changes in the dermis were seen at the higher HD dose. All laser
treated lesions appeared identical, with a thick, differentiated epidermis and a
well-formed basal cell layer. There was minimal inflammatory infiltrate. In the
papillary dermis there were increased stromal cells. Laser debridement of mild
clinical lesions induced by HD produced a more functional epidermis by 14 days as
well as clearing the epidermis of damaged keratinocytes.
PMID- 9390338
TI - The prevalence of skin disease in HIV infection and its relationship to the
degree of immunosuppression.
AB - A cross-sectional study of human immunodeficiency virus (HIV) positive patients
who attended the HIV clinic in Brighton over a 4-month period was carried out to
describe the prevalence and severity of skin manifestations in HIV-positive
patients and to elucidate their association with the peripheral CD4 cell count
and with the HIV disease stage. The subjects were consecutively examined by an
experienced dermatologist. Skin manifestations were classified into infections,
dermatoses, pruritus and neoplasm. A severity index was derived by scoring each
condition as either absent, mild, moderate or severe. One hundred and fifty-one
patients were enrolled with a mean age of 38.3 years. One hundred and thirty-nine
were homo/bisexual men; 58 were asymptomatic and 35 had acquired immune
deficiency syndrome (AIDS); 37 had CD4 counts below 200. Skin conditions were
present in 138 of the 151 subjects (91.4%). The total number of events was 331.
The most frequent problem was infection followed by dermatoses, pruritus and
malignancy. The most frequent condition was seborrhoeic eczema followed by tinea
and xerosis. We have demonstrated a statistically significant association between
CD4 count, disease stage and skin manifestations in HIV-positive individuals.
PMID- 9390339
TI - A subepidermal blistering disease with histopathological features of dermatitis
herpetiformis and immunofluorescence characteristics of bullous pemphigoid: a
novel subepidermal blistering disease or a variant of bullous pemphigoid?
AB - A 64-year-old man presented with a bullous eruption which clinically and
histopathologically resembled dermatitis herpetiformis. However, direct
immunofluorescence analysis showed IgG deposits at the basement membrane zone,
indicating a relationship with bullous pemphigoid or epidermolysis bullosa
acquisita. Indirect immunofluorescence studies on salt-split skin showed binding
of IgG mainly on the dermal side of the blister. Immunoblot analysis revealed a
novel 200 kDa dermal antigen that could be associated with a major pathogen in
this blistering disease. The histopathological similarity to dermatitis
herpetiformis and the immunofluorescence findings indicating bullous pemphigoid
or epidermolysis bullosa acquisita seem typical of a distinct subepidermal
blistering disease characterized by this 200 kDa antigen. However, the
pathogenetic role of autoantibodies against this antigen should be further
elucidated before confirming whether this case represents a novel subepidermal
blistering disease or a special variant of bullous pemphigoid.
PMID- 9390340
TI - Human herpesvirus 6 infection associated with anticonvulsant hypersensitivity
syndrome and reactive haemophagocytic syndrome.
AB - Viral infections are thought to play a part in some cutaneous drug reactions.
Human herpesvirus 6 (HHV6), which is the agent of exanthema subitum (sixth
disease), has never been implicated in a drug reaction. We report a patient with
severe phenobarbital-induced anticonvulsant hypersensitivity syndrome in whom a
fulminant haemophagocytic syndrome was associated with HHV6 infection. We discuss
the possible role of HHV6 in this reactive condition.
PMID- 9390341
TI - Sweet's syndrome and malignancy in the U.K.
AB - Acute febrile neutrophilic dermatosis (Sweet's syndrome) is reported to be a
marker for underlying malignancy. Much of the evidence for this is based on case
reports, small series of cases and reviews of the literature. In order to clarify
the association with malignancy and determine the common clinical features of
Sweet's syndrome, we reviewed the case notes of patients presenting to six
dermatology units in the U.K. Eighty-seven cases of histologically proven Sweet's
syndrome were reviewed. Fourteen patients (16%) developed associated malignancy,
predominantly haematological, two patients (2%) had a history of previous
malignancy and four patients (5%) had premalignant conditions (monoclonal
gammopathy, two: myelodysplasia, two). Malignancy developed up to a year after
presentation with Sweet's syndrome. Patients with associated malignancy were more
likely to be anaemic (P < 0.01) at presentation, had a lower mean platelet count
(207 x 10(9)/L vs. 332 x 10(9)/L; P < 0.003) and were, on average, older (59
years vs. 49 years; P = 0.002). Contrary to previous reports, a greater
percentage of females developed malignancy than males.
PMID- 9390342
TI - Lupus miliaris disseminatus faciei--the DNA of Mycobacterium tuberculosis is not
detectable in active lesions by polymerase chain reaction.
AB - There has been a controversy as to the origin of lupus miliaris disseminatus
faciei (LMDF). It was originally thought to be associated with tuberculosis, due
to its histopathological similarity. Recently, this association has been doubted,
although there remain reported cases of LMDF associated with Mycobacterium
tuberculosis. Three patients with the clinical and histopathological features of
LMDF are described. Skin from these patients was analysed by polymerase chain
reaction (PCR) using two different oligoprimers for the detection of 123 bp and
165 bp DNA fragments specific for M. tuberculosis complex. With these two PCR
systems, no M. tuberculosis DNA was detected in any of the LMDF patients. It was
present in all positive controls and absent in all negative controls. In this
study we could not demonstrate an association between LMDF and tuberculosis.
PMID- 9390343
TI - Aquagenic urticaria and human immunodeficiency virus infection: treatment with
stanozolol.
AB - We report the first case of aquagenic urticaria in a patient with human
immunodeficiency virus (HIV) infection. This is a rare physical urticaria not
previously described in this context. The disorder proved unamenable to
conventional treatment with antihistamines, but did respond dramatically to
stanozolol, suggesting a novel indication for this anabolic steroid.
PMID- 9390344
TI - Cutaneous manifestation of Chagas' disease after heart transplantation:
successful treatment with allopurinol.
AB - We describe two patients who underwent cardiac transplantation for chronic
cardiomyopathy of Chagas' disease, and in whom the disease was reactivated with
the development of cutaneous lesions. In both cases, the skin lesions regressed
completely after 2 months of therapy with allopurinol.
PMID- 9390345
TI - Increased plasma interleukin-6 in cutaneous plasmacytoma: the effect of
intralesional steroid therapy.
AB - Cutaneous plasmacytosis is a rare disorder without systemic plasma cell
proliferation in organs other than the skin, with a possible malignant
transformation. However, there are few effective therapies available. It has been
reported that interleukin-6 (IL-6), which is a cytokine inducing B-cell
differentiation to immunoglobulin-producing cells, plays a part in systemic
plasmacytosis. In this study, we performed intralesional steroid therapy in the
lesions of cutaneous plasmacytosis in three patients, which resulted in
sufficient clinical effects. We demonstrated that before treatment, plasma IL-6
levels were significantly elevated in all the patients, and that levels were
reduced in parallel with the clinical improvement after therapy.
Immunohistochemistry revealed IL-6 protein expression on tumour cells in the
lesional skin. Reverse transcription-polymerase chain reaction (RT-PCR) detected
IL-6 mRNA in the lesional skin in all cases, levels of which were decreased after
the effective intralesional steroid therapy, but which were unchanged after
ineffective topical photochemotherapy (PUVA). Peripheral blood mononuclear cells
from the patients produced significantly large quantities of IL-6 which were
reduced by addition of steroid in vitro. These results suggest that the
generation of IL-6 plays the key role in cutaneous plasmacytosis and that
intralesional steroid therapy is effective in reducing the production of IL-6 in
this disorder.
PMID- 9390346
TI - Merkel cell carcinoma arising after therapeutic immunosuppression.
AB - Azathioprine and cyclosporin have been used as immunosuppressants for many years,
but long-term use has also been associated with neoplasia. We report three cases
of rapidly fatal Merkel cell carcinoma in patients who had been treated with
azathioprine for many years either for rheumatoid arthritis or following organ
transplantation. Two of these patients had also received cyclosporin. We suggest
that Merkel cell carcinoma may be seen more commonly in immunosuppressed patients
than in the normal population and that the oncogenic potential of azathioprine
and cyclosporin should be borne in mind when prescribing these drugs.
PMID- 9390347
TI - Multiple apocrine hidrocystomas of the eyelids.
AB - We report a patient with multiple apocrine hidrocystoma (cystadenoma) which was
characterized by bilateral distribution of the lesions on the eyelids. The
disease is benign, but it may be a marker of two rare inherited disorders, the
Schopf-Schulz-Passarge syndrome and a peculiar form of focal dermal hypoplasia.
PMID- 9390348
TI - Protease inhibitors protect growth factor activity in chronic wounds.
PMID- 9390349
TI - Thermal injury induces both necrosis and apoptosis in rat skin.
PMID- 9390351
TI - Subacute cutaneous lupus erythematosus induced by radiation therapy.
PMID- 9390352
TI - Milia en plaque arising in discoid lupus erythematosus.
PMID- 9390353
TI - Lupus erythematosus profundus with partial C4 deficiency.
PMID- 9390354
TI - Erythema elevatum diutinum associated with pulmonary infiltrates.
PMID- 9390355
TI - Ehlers-Danlos type IV: non-invasive techniques as diagnostic support.
PMID- 9390356
TI - Majocchi's disease in a newborn baby: a familial case.
PMID- 9390357
TI - Human orf complicated by bullous pemphigoid.
PMID- 9390358
TI - The dapsone hypersensitivity syndrome occurring in a patient with dermatitis
herpetiformis.
PMID- 9390359
TI - Median canaliform dystrophy following isotretinoin therapy.
PMID- 9390360
TI - Weathering nodules of the ear in a young woman.
PMID- 9390361
TI - Bowen's disease developing within a Becker's melanosis (Becker's naevus)
PMID- 9390362
TI - Tropaeolum majus and contact dermatitis.
PMID- 9390363
TI - The Psoriasis Area and Severity Index and alternative approaches for the
assessment of severity: persisting areas of confusion.
PMID- 9390364
TI - Vision and driving--a literature review and commentary.
AB - The visual requirements that currently have to be met those applying for and
holding current UK driving licenses for private motor vehicles are discussed,
together with the incidence of road accidents and the general scientific and
social problems of setting visual standards for driving. Literature relating to
the effectiveness of various visual tests in predicting the accident-proneness of
individual drivers is reviewed. A striking feature of the data on the age
dependence of accidents and visual performance is that although visual
performance by most tests steadily declines after early middle age, older drivers
have less accidents than their younger counter-parts, whose visual performance is
superior. It is concluded that, although correlations between poor vision as
assessed by some tests and accident rates can be shown in large samples of
drivers, as yet, no single test or combination of tests has been shown to be able
to effectively screen out those at risk of accidents without also leading to the
disqualification of a substantial number of potentially safe drivers. Thus no
change in the present visual requirements is recommended at the present time.
PMID- 9390365
TI - Eye movements and reading with simulated visual impairment.
AB - The purpose of this study was to investigate the effects of simulated visual
impairment on the reading speed and reading eye movements of young, normally
sighted observers. Afocal diffusing filters (Ryser occlusion foils) were used to
create three levels of impairment and eye movements were recorded using a
spectacle-mounted, infra-red limbal reflection system. Reading speed decreased
significantly (P < 0.01) as the level of impairment increased. Eye movement
analysis revealed the main contributory factors to be increased fixation
durations, shorter saccades (resulting in increased numbers of forward saccades
per line) and, to a lesser extent, increased time required for page navigation.
The results suggest that in order to achieve optimal reading speeds, print size
should be at least four times the acuity threshold and that print contrast should
be at least twenty times contrast threshold.
PMID- 9390366
TI - Efficiency of the Ishihara test for identifying red-green colour deficiency.
AB - The Ishihara test is the most widely used screening test for red-green colour
deficiency. Results obtained by 401 people with red-green colour deficiency show
that the combined sensitivity of the Transformation and Vanishing plates of the
38 plate Edition of the Ishihara plates is 95.5% on eight errors, 97.5% on six
errors and 99.0% on three errors. The Hidden digit designs only identified
approximately 50% of colour-deficient subjects. The protan/deutan classification
plates were found to be more effective for deutans than for protans. No
classification was obtained for 18% of protanopes and 3% of deuteranopes who saw
neither figure on classification plates; 40% of protanomalous trichromats and
37.5% of deuteranomalous trichromats saw both classification figures and were
classified on the relative luminance (clarity) of these figures. The specificity
of the Ishihara test was determined in a previous study (Birch and McKeever,
1993) and the results combined with the present data to obtain the overall
efficiency of the Ishihara plates for a representative cross section of colour
deficient subjects.
PMID- 9390367
TI - Comparison of a videokeratoscope and an autokeratometer as predictors of the
optimum back surface curves of rigid corneal contact lenses.
AB - PURPOSE: To determine the differences in the corneal topography derived using a
16 mire videokerascope and a 2 mire autokeratometer and to examine whether the
differences are clinically significant in the contact lens fitting context.
METHODS: The right corneas of 20 subjects were measured by an Eyesys
videokeratoscope (windows workstation: version 2000 W) and a Topcon
Autokeratometer (KR 3500). The corneal vertex radius and p-value were deduced and
used to calculate the back surface specifications of a rigid corneal tricurve
contact lens design required for an optimal fit on the corneal model. The study
was aimed to evaluate the differences in contact lens specifications related to
the current British Standards on contact lens tolerances. RESULTS: In general
there was good agreement in the lens specification derived from the two
instruments. The differences that were present were small and, with the exception
of the second back peripheral radius, were within tolerance limits. CONCLUSIONS:
The corneal topography was adequately described by the two mire keratometer for
the purpose of fitting this particular lens design on the corneas of the 20
subjects examined.
PMID- 9390368
TI - The effect of an artificially-elevated intraocular pressure on corneal thickness
in Chinese eye.
AB - We measured the central corneal thickness and the applanation intraocular
pressure (IOP) on 45 Hong Kong Chinese. There was no obvious relationship between
these two parameters, as different from other literatures. It could be due to
either a limited number of subjects with a high IOP level (only six subjects with
IOP > or = 22 mmHg), or Chinese has a thicker central cornea in general. The mean
central cornea of our subjects was thicker (566 +/- 36 microns) than some
previous findings. Thirty subjects had their intraocular pressure further
increased by adopting a 40 degrees head-down posture. Their IOP and topographic
corneal thickness were measured again. There was no significant change in the
central corneal thickness even though the IOP was elevated by 11.7 mmHg. However
the nasal cornea demonstrated a thinning effect (by some 18 microns) during the
IOP elevation but it returned to the pre-inverted level after returning to a
sitting posture for 5 min. Further investigation with more corneal regions being
measured would be valuable to evaluate the in vivo effect of IOP elevation from
glaucoma attack on corneal thickness.
PMID- 9390369
TI - Some methodological issues in the assessment of the spontaneous eyeblink
frequency in man.
AB - Previous assessments of spontaneous eyeblink frequency (SEBF) or interblink
intervals (IBI) have been made over period of 0.5 to 15 min and average values
calculated; the reliability of the methods has not been validated. Video
recordings were made of 14 healthy volunteers, aged 20 to 38 years, while
silently fixating on a 2 m distant, 35 mm high target under 350 lux illumination
and the traces assessed with an event marker. Significant fluctuations in SEBF or
IBI were generally observed, but which did not conform to a minute-by-minute
periodicity. Time-dependent trends were uncommon, although uncritical pooling or
averaging of data can effectively conceal such fluctuations or trends.
Correlation's between SEBF and IBI indicate that eyeblink monitoring over at
least 3 min is required. Simple averaging calculations are not appropriate
because of a high chance of non-Gaussian distribution of data. Modal IBI values
correlated well with an adjusted modal calculated SEBF which is thus recommended
for further use.
PMID- 9390370
TI - Improved computing scheme for measuring eye alignment with Purkinje images I and
IV.
AB - This study introduces an improved computing scheme for determining eye rotation
from Purkinje images I and IV. The original computing scheme systematically
underestimated eye rotation. Paraxial raytracing calculations revealed that this
error resulted from failure to account for the fact that Purkinje images I and IV
fall at different distances behind the cornea. The error could be overcome with a
correction factor derived from paraxial raytracing calculations. A series of
experiments were carried out to test the validity of this correlation factor,
involving exact raytracing calculations as well as measurements on physical model
eyes and human eyes. The influence on the correction factor of ocular surface
asphericity, accommodation, age and ocular component variations were examined.
The new method was also compared to Hirschberg's technique, which makes use of
Purkinje image I alone, as a means of screening for strabismus.
PMID- 9390371
TI - Graphical representation of visual acuity data.
AB - Accurate graphical depiction of data requires that distances between points map
precisely to the quantitative differences they represent. In the case of Snellen
visual acuity, consecutive line sizes do not generally correspond to equal
increments in visual angle, hence scores plotted against axes marked off in equal
intervals provide a false representation of the relation between plotted values.
A worked example illustrates the nature of this problem and its solution.
PMID- 9390372
TI - Active emmetropization--evidence for its existence and ramifications for clinical
practice.
AB - There is increasing evidence from animal studies in support of the concept of an
active emmetropization mechanism which has potentially important clinical
ramifications for the management of refractive errors. Recent research into
refractive development and emmetropization is reviewed, with emphasis given to
work involving the chick, tree shrew and monkey, which represent the three most
widely used animal models in this field. The findings of this research are
reviewed in a clinical context. Compensatory eye growth responses to focusing
errors imposed by lenses represent the most compelling evidence for active
emmetropization. These observations are complemented by other evidence showing
recovery from induced refractive errors such as form-deprivation myopia. Of the
animals listed above, chicks show the most impressive emmetropization, being able
to compensate fully (using choroidal and scleral mechanisms) to lens powers
ranging from +15 D to -10 D. The range of lens powers eliciting appropriate
compensatory responses is narrower in the tree shrew and monkey, and the response
patterns generally are also more complex to interpret. These data relate to young
animals and together indicate refractive plasticity during development.
Extrapolation of these findings to humans predicts that natural emmetropization
will be inhibited in neonates by early intervention with prescription lenses, and
that refractive correction of myopia will lead to accelerated progression. This
convincing evidence for active emmetropization warrants due consideration in
developing clinical management strategies for refractive errors.
PMID- 9390373
TI - Accommodation and acuity under night-driving illumination levels.
AB - Laboratory experiments are described in which the monocular changes in the
refractive error and acuity of six young, normal, adult subjects were measured as
the field luminance was reduced from approximately 100 to 10(-3) cd/m2. It was
found that, at luminance levels equal to those recommended for road lighting
(about 1 cd/m2), acuity fell from its photopic value of > or = 6/6 to about 6/9,
with little change in the measured refraction. Marked changes in refraction, i.e.
night myopia, only started to become manifest when the luminance was further
reduced to below about 0.03 cd/m2, much less than that applying under normal
night-driving conditions. Direct experiments under street-lighting conditions
confirmed the absence of any significant night myopia. It is concluded,
therefore, that neural changes, rather than night myopia, normally are
responsible for the acuity loss suffered by drivers at night.
PMID- 9390374
TI - Patterns of cataract referral in the West Midlands.
AB - Optometrists are required to refer patients with any abnormality of the eye,
excluding normal changes due to age, to a General Practitioner. It can be
difficult to decide when a cataract ceases to be a normal age-related change and
becomes an ocular abnormality. This questionnaire-based study examines the
criteria adopted by Optometrists and GPs for referring patients with cataract and
compares this to the referral criteria suggested by Ophthalmologists. For all
professions, the main factors influencing referral are visual acuity, subjective
visual impairment and the need to drive. Optometrists and GPs generally refer
patients with cataract at a VA level of 6/18-6/24, whilst most Ophthalmologists
would be willing to see patients with cataract at a VA of 6/9-6/12. However,
Ophthalmologists report that sometimes patients are referred too soon, regardless
of their acuity level, because the patient is not yet impaired by their level of
vision or does not want surgery. Suggestions for improvements in the referral of
cataract are discussed. It is important for Optometrists to make clear whether a
letter to a GP is for information only or for referral. If referral is warranted,
information in addition to acuity will assist an Ophthalmologist in prioritizing
appointments, including age, occupation, brief description of disability and the
need to drive without contravening any laws.
PMID- 9390375
TI - The AC/A ratio, age and presbyopia.
AB - Previous reports concerning the effect of age on the AC/A ratio have been
equivocal. Therefore, the present study investigated both the stimulus (AC/As)
and response (AC/Ar) ratios using a subjective haploscope-optometer in a
relatively large sample of subjects (n = 42) over a wide range of ages (22-65
years). The AC/As showed a small but significant decrease with age (approximately
0.04 delta/D/year). When the older subjects (> 45 years of age) were excluded,
however, there was no systematic age effect. The AC/Ar exhibited a small but
significant increase with age (approximately 0.08 delta/D/year) for subjects
under 45 years of age. However, when the older pre-presbyopes and younger
presbyopes (35-44 years of age) were excluded, there was no systematic age
effect. In subjects 45 years of age and older, the AC/Ar could not be reliably
assessed. This was attributed to physiological and instrumentation noise as a
result of the minimal change in accommodative response. In the mid-aged subjects
(35-44 years of age), the apparent increase in AC/Ar with age was speculated to
be due to neural adaptation of the crosslink gain from the accommodative to the
vergence system and/or slight intrusion into the upper non-linear response region
of accommodation with the measurements. The finding of AC/Ar constancy with age
when mid-aged pre-presbyopes and early presbyopes were excluded supports the non
linearity hypothesis, and thus there appears to be no real change in AC/Ar with
increased age. The results support the Hess-Gullstrand theory of presbyopia.
PMID- 9390376
TI - Pupil size, mean accommodation response and the fluctuations of accommodation.
AB - We wished to determine how pupil size and mean accommodation response level
interact to influence the fluctuations of accommodation. A dynamic infra-red
optometer was used to record accommodation responses while subjects viewed a
steady target at two stimulus levels (1.5 and 3 D) through four pupils (1, 2, 4
and 6 mm). It was found for most subjects that the fluctuations of accommodation
increase at higher mean accommodation response levels, and small pupils lead to
an increase in the low frequency (but not the high frequency) fluctuations of
accommodation. The effects of mean accommodation response are independent of
pupil size, and the effects of pupil size are independent of mean response level.
PMID- 9390377
TI - Fixation disparity and accommodation as a function of viewing distance and prism
load.
AB - Fixation disparity was measured with dichoptically presented nonius lines at
viewing distances of 20, 30, 40, 60, and 100 cm, so that both vergence and
accommodation were stimulated adequately as in normal vision. As the viewing
distance was shortened, mean fixation disparity changed monotonically from 1 min
arc eso (i.e., the eyes converged in front of the target) to 3 min arc exo. The
average standard deviation of the psychometric function of fixation disparity,
which is a measure of the temporal variability of vergence, was smallest at 100
cm (when fixation disparity was eso) and increased as viewing distance decreased.
Fixation disparity itself and the change of fixation disparity with distance
differed reliably among subjects with normal binocular vision, but neither was
related to the momentary degree of accommodation. Fixation disparity was also
measured at a constant distance of 40 cm, but with prisms in front of the eyes
that induced the same vergence angles as viewing distances between 20 and 100 cm.
The slope of these conventional fixation disparity curves as a function of prism
load was generally larger than the slope of fixation disparity as a function of
viewing distance (which can be explained by accommodative vergence), but the
slopes of the two types of curves were correlated (r = 0.39, P = 0.02, n = 25).
PMID- 9390378
TI - Partition of perceived space within the fusional area on the basis of apparent
fronto-parallel plane criterion.
AB - The relationship between visual space and physical space was investigated by
means of the apparent fronto-parallel plane percept. A set of curves in physical
space, corresponding to fronto-parallel planes perceived in front or behind a
given fixation point, was determined. The curvature at the apex of these curves
follows a hyperbolic law that depends on the distance between the perceived plane
and the fixation point. Our results are interpreted by distinguishing absolute
disparity, which sets the position of the perceived plane, from relative
disparity measured by adjusting in this plane eccentric vertical lines. We show
that Foley's model, which interprets the shape of the apparent fronto-parallel
planes on the mis-evaluation of egocentric distance, works for absolute disparity
judgements, but seems to be inadequate for relative disparity judgements in our
experimental conditions.
PMID- 9390379
TI - Measurement of posterior corneal asphericity on Hong Kong Chinese: a pilot study.
AB - The posterior corneal p-value and apical radius of 60 Hong Kong Chinese were
assessed. The values were derived based on the information of the anterior
corneal topography and the corneal thickness in different regions. The mean
posterior corneal apical radius along the horizontal meridian was 6.51 mm (SD +/-
0.40 mm) and the p-value was 0.34 (SD +/- 0.38). The apical radius is greater
while the p-value is smaller than a previous study using a similar principle.
This may indicate a flatter posterior cornea and greater peripheral flattening in
Hong Kong Chinese. No significant difference between the nasal and temporal
corneal thickness, nasal and temporal posterior p-value and apical radius was
demonstrated. The right and left eyes were also similar in different ocular
parameters apart from a smaller anterior corneal p-value on the right eye (R eye:
0.70 +/- 0.13; L eye: 0.67 +/- 0.12), but the difference may not be significant
clinically. The method used here is simple and the generation of posterior
corneal topography is informative.
PMID- 9390380
TI - Double-pass measurements of retinal image quality in monofocal contact lens
wearers.
AB - The double-pass method is applied to determine the optical image quality in
monofocal contact lens (CL) wearers. This is an objective non-invasive technique
that permits in vivo testing of the optical performance of CL wearers' eyes.
Retinal image quality was measured for three subjects wearing two types of
monofocal CLs: a rigid gas permeable (RGP) CL and a soft contact lens (SL), for
pupil diameters of 3 mm and 5 mm. Results show the importance of ocular
astigmatism regarding retinal image quality. In eyes presenting corneal
astigmatism, the best results are obtained when wearing RGP CLs, because the lens
compensates the corneal astigmatism. The modulation transfer function (MTF) is
considerably smaller when no lens or soft lenses are worn, even for small amounts
of astigmatism (0.5 D). When the astigmatism is corrected, the retinal image
quality obtained with both types of CLs and with no lens is similar.
PMID- 9390381
TI - Proteins of morula-like cells in hemolymph of the giant clam, Tridacna derasa.
AB - The morula-like cell, a hemocyte packed with many large (about 3 microns in
diameter) electron-dense granules, is found only in the hemolymph of giant clams
belonging to the Tridacnidae. To clarify the function of the morula-like cell, we
investigated its proteins, especially those found in the large granules. Proteins
with molecular weights of 64 kDa, 17 kDa and 7.4 kDa were found to be specific to
this type of hemocyte. N-terminal amino acid sequence analysis revealed that the
17-kDa and 7.4-kDa proteins were novel proteins rich in aromatic amino acids.
Rabbit polyclonal antibody against a synthetic peptide of the 7.4-kDa protein
reacted not only with that protein but also with a larger molecular weight (about
16-kDa) protein in the morula-like cell. Examination of the N-terminal amino acid
sequences showed that the 16-kDa protein is distinct from the 17-kDa protein, and
Western blot analysis suggested that it is a precursor of the 7.4-kDa protein.
The zooxanthellate portion of clam mantle and kidney contained proteins
immunoreactive to the antibody, but the azooxanthellate portion of the mantle did
not contain any immunoreactive protein. These results suggest that the morula
like cells interact with the zooxanthellae.
PMID- 9390382
TI - DNA-dependent protein phosphorylation activity in Xenopus is coupled to a Ku-like
protein.
AB - DNA-dependent protein kinase (DNA-PK) is a nuclear enzyme and functions as a
serine/threonine kinase that has been well characterized in both the human and
the mouse. The regulatory subunit of DNA-PK is the Ku autoantigen. To demonstrate
that a Ku-like protein is present in Xenopus oocytes, we used immunoprecipitation
analysis with a monoclonal antibody raised against human Ku antigen and
autoimmune serum containing anti-Ku antibodies. Metabolic labeling studies
indicate that the Ku-like protein is synthesized mainly in late vitellogenic
oocytes. By using a specific peptide substrate for DNA-PK, we demonstrate the
activity of a DNA-dependent protein kinase in oocyte extracts. The kinase
activity requires the Ku-like protein, since extracts depleted of Ku protein by
immunoadsorption with human anti-Ku antibodies fail to demonstrate the DNA
dependent phosphorylation activity. The increased enzyme activity in vitellogenic
oocytes may be correlated to the increased levels of Ku protein observed in these
oocytes compared to the pre- and early vitellogenic oocytes.
PMID- 9390384
TI - Circadian rhythms in the lateral eye of the Japanese horseshoe crab.
PMID- 9390385
TI - Prediction of maximum allowable retinal slip speed in the fiddler crab, Uca
pugilator.
PMID- 9390386
TI - Histamine: putative transmitter for lateral inhibition in Limulus eye.
PMID- 9390387
TI - Visual performance of horseshoe crabs: role of underwater lighting.
PMID- 9390388
TI - UV cutting of MAPs-bound microtubules.
PMID- 9390389
TI - Actin bundles in neuronal growth cone observed with the Pol-Scope.
PMID- 9390390
TI - Characterization of antibodies to the head and tail domains of squid brain myosin
V.
PMID- 9390391
TI - Dynamics of GFP-coronin and eupodia in live Dictyostelium observed with real-time
confocal optics.
PMID- 9390392
TI - Effect of gossypol on Spisula sperm observed with real-time confocal microscopy,
polarized light microscopy, and video microscopy.
PMID- 9390393
TI - Effect of in vitro culture of mammalian embryos on the architecture of the zona
pellucida.
PMID- 9390394
TI - Phylogenetic analysis of the 5-aminolevulinate synthase gene.
PMID- 9390395
TI - Phylogenetic analysis of olfactory receptor genes from mudpuppy (Necturus
maculosus).
PMID- 9390396
TI - Genes coding for reverse transcriptase, DNA-directed RNA polymerase, and chitin
synthase from the microsporidian Spraguea lophii.
PMID- 9390397
TI - Apparatus for measuring steady-state ATP utilization rates of single muscle
fibers.
PMID- 9390398
TI - Do alpha-crystallins protect catalase against UV damage?
PMID- 9390400
TI - Fast voltage-sensitive dye recording of membrane potential changes at multiple
sites on an individual nerve cell in the rat cortical slice.
PMID- 9390401
TI - Protein solution structure calculations in solution: solvated molecular dynamics
refinement of calbindin D9k.
AB - The three-dimensional solution structures of proteins determined with NMR-derived
constraints are almost always calculated in vacuo. The solution structure of
(Ca2+)2-calbindin D9k has been redetermined by new restrained molecular dynamics
(MD) calculations that include Ca2+ ions and explicit solvent molecules. Four
parallel sets of MD refinements were run to provide accurate comparisons of
structures produced in vacuo, in vacuo with Ca2+ ions, and with two different
protocols in a solvent bath with Ca2+ ions. The structural ensembles were
analyzed in terms of structural definition, molecular energies, packing density,
solvent-accessible surface, hydrogen bonds, and the coordination of calcium ions
in the two binding loops. Refinement including Ca2+ ions and explicit solvent
results in significant improvements in the precision and accuracy of the
structure, particularly in the binding loops. These results are consistent with
results previously obtained in free MD simulations of proteins in solution and
show that the rMD refined NMR-derived solution structures of proteins, especially
metalloproteins, can be significantly improved by these strategies.
PMID- 9390402
TI - Efficient enzymatic synthesis of 13C,15N-labeled DNA for NMR studies.
AB - The power of heteronuclear NMR spectroscopy to study macromolecules and their
complexes has been amply demonstrated over the last decade. The obstacle to
routinely applying these techniques to the study of DNA has been the synthesis of
13C,15N-labeled DNA. Here we present a simple and efficient method to generate
isotope-labeled DNA for NMR studies that is as easy as that for isotope labeling
of RNA. The method was used to synthesize a uniformly 13C,15N-labeled 32
nucleotide DNA that binds to human basic fibroblast growth factor with high
affinity and specificity. Isotope-edited experiments were applied to the 13C,15N
labeled DNA bound to unlabeled protein, and the 13C,15N-labeled DNA was also
examined in complex with 15N-labeled protein. The NMR experiments show that the
DNA adopts a well-defined stable structure when bound to the protein, and
illustrate the potential of 13C,15N-labeled DNA for structural studies of DNA
protein complexes.
PMID- 9390403
TI - Measurement of diffusion constants for nucleic acids by NMR.
AB - Pulsed field-gradient NMR experiments can be used to measure the diffusion
constants of nucleic acids. The diffusion constants measured in this way for
double-helical DNAs of defined length agree well both with theory and with
measurements done using other techniques. When applied to RNAs, this experiment
easily distinguishes duplex RNAs from RNA hairpins and thus it can solve one of
the perennial problems faced by RNA spectroscopists, i.e. assessing whether their
samples are monomeric or not.
PMID- 9390404
TI - Three-dimensional structure of the Hck SH2 domain in solution.
AB - The hematopoietic cellular kinase (Hck) is a member of the Src family of non
receptor protein-tyrosine kinases that is expressed predominantly in
granulocytes, monocytes and macrophages. Recent observations suggest that Hck may
be activated in HIV-infected macrophages and in chronic myelogenous leukemia
cells that express Bcr-Abl. In order to increase our understanding of the
structural basis for regulation of Hck activity under normal and pathological
conditions, we have solved the solution structure of the uncomplexed Hck SH2
domain using NMR spectroscopy. A novel procedure that uses intraresidue HN-H
alpha distances as references for converting NOE intensities into distance
restraints has been described. A total of 1757 significant experimental
restraints were derived from NMR spectroscopic data including 238 medium-range
and 487 long-range distance restraints and 177 torsion angle restraints. These
restraints were used in a simulated annealing procedure to generate 20 structures
with the program DYANA. Superimposition of residues 5-104 upon the mean
coordinate set yielded an average atomic rmsd values of 0.42 +/- 0.08 A for the
N,C alpha,C' atoms and 0.81 +/- 0.08 A for all heavy atoms. Rmsd values for those
residues in the regions of ordered secondary structure were 0.27 +/- 0.04 A for
the N,C alpha,C' atoms and 0.73 +/- 0.06 A for all heavy atoms.
PMID- 9390406
TI - The button test: a small scale method using microdialysis cells for assessing
protein solubility at concentrations suitable for NMR.
AB - A simple method has been developed for screening solution conditions to determine
conditions under which a protein is soluble at the high concentrations typically
used for NMR spectroscopy. The method employs microdialysis cells or 'buttons'.
The low sample volume (5 microliters) required for each microdialysis button
permits testing of a wide range of solution conditions and temperatures with high
protein concentrations, using a small amount of protein. Following precipitation
of several NMR samples of the C-terminal core domain of human TFIIB, the
microdialysis button screen facilitated identification of conditions in which
precipitation of the TFIIB core domain was eliminated. The microdialysis button
method for screening solution conditions is generally applicable and has been
used to permit rapid identification of suitable NMR sample solution conditions
for proteins involved in transcription and cell adhesion.
PMID- 9390405
TI - Conformation of an Shc-derived phosphotyrosine-containing peptide complexed with
the Grb2 SH2 domain.
AB - We have determined the structure of an Shc-derived phosphotyrosine-containing
peptide complexed with Grb2 SH2 based on intra- and intermolecular NOE
correlations observed by a series of isotope-filtered NMR experiments using a PFG
z-filter. In contrast to an extended conformation of phosphotyrosine-containing
peptides bound to Src, Syp and PLC gamma SH2s, the Shc-derived peptide formed a
turn at the +1 and +2 positions next to the phosphotyrosine residue. Trp121,
located at the EF1 site of Grb2 SH2, blocked the peptide binding in an extended
conformation. The present study confirms that each phosphotyrosine-containing
peptide binds to the cognate SH2 with a specific conformation, which gives the
structural basis for the binding specificity between SH2s and target proteins.
PMID- 9390407
TI - High-resolution heteronuclear NMR of human ubiquitin in an aqueous liquid
crystalline medium.
AB - A mixture of dihexanoyl phosphatidylcholine and dimyristoyl phosphatidylcholine
in water forms disc-shaped particles, often referred to as bicelles [Sanders and
Schwonek (1992) Biochemistry, 31, 8898-8905]. These adopt an ordered, liquid
crystalline phase, which can be maintained at very low concentrations of the
bicelles (down to 3% w/v). At this concentration the spacing between individual
bicelles, on average, exceeds 300 A. The bicelles are shown to have a negligible
effect on the rotational diffusion of ubiquitin as judged by the 15N T1p values
of the backbone amides relative to those in isotropic aqueous solution. The
protein exhibits a residual degree of alignment which is proportional to the
bicelle concentration, and approximately collinear with ubiquitin's rotational
diffusion tensor. The degree of alignment obtained offers unique opportunities
for studying the protein's structure and dynamics.
PMID- 9390409
TI - Assignment of the 1H, 15N and 13C resonances of the calcium-free and calcium
bound forms of the first C2-domain of synaptotagmin I.
PMID- 9390408
TI - Tritium NMR studies of the human carbonic anhydrase I-benzenesulfonamide complex.
AB - Tritium NMR spectroscopy has been used to examine the complex formed by [4
3H]benzenesulfon-amide and human carbonic anhydrase I. The results show that in
solution the inhibitor forms a 1:1 complex with the enzyme. A 100-spin
computational model of the system, constructed with reference to crystallographic
results, was used to interpret tritium relaxation behavior and 3H{1H} NOEs. The
analysis shows that the rate of dissociation of the enzyme-sulfonamide complex is
0.35 s-1 and that the aromatic ring of the inhibitor undergoes rapid rotation
while complexed.
PMID- 9390410
TI - Backbone assignment of double labelled 23.7 kDa phosphoglycerate mutase from
Schizosaccharomyces pombe.
PMID- 9390411
TI - Sequence-specific assignments of the inner lipoyl domain of human pyruvate
dehydrogenase.
PMID- 9390412
TI - Human nucleotide excision repair protein XPA: expression and NMR backbone
assignments of the 14.7 kDa minimal damaged DNA binding domain (Met98-Phe219).
PMID- 9390413
TI - The effects of self-esteem and source credibility on self-denying prophecies.
AB - Self-fulfilling prophecies are a well-studied phenomenon. The study of self
denying prophecies, however, is rare. Self-denying prophecies shift people's
behavior in the direction opposite to the prophecy. The existence of self-denying
prophecies was investigated in 222 students. The effects of self-esteem and the
source of the prophecy were also investigated. The results suggest that self
denying prophecies exist and that self-esteem is an important moderator of self
denying prophecies. If managers and industrial/organizational psychologists had
an understanding of self-denying prophecies, they might be better able to
structure negative performance reviews in a way that could lead to improved
employee performance.
PMID- 9390414
TI - Psychosocial adjustment in male-to-female transsexuals: an overview of the
research evidence.
AB - Transsexualism has been defined as an extreme gender dysphoria; it refers to
unhappiness with one's biological sex and the desire to have the body of the
opposite sex and to be regarded by others as a member of that other sex.
Transsexualism is not a common condition, but its prevalence is not yet known. A
large number of transsexuals receive hormonal treatment and sex reassignment
surgery (SRS). In spite of years of poor quality research, due in part to
methodological problems, recent research on surgical outcomes has provided
important information. However, psychological research into transsexualism has
ignored the cognitive style and psychological functioning of transsexuals, and
very little effort has been made to incorporate research findings into the
development of psychological treatments to improve the quality of life for
transsexuals.
PMID- 9390415
TI - Psychophysiological aspects of Tourette's syndrome.
AB - Tourette's syndrome (TS), once considered a rare disorder, has been investigated
extensively in the last two decades. It is inherited, usually beginning in
childhood, and waxes and wanes, usually decreasing in frequency and severity in
adolescence and early adulthood. Pharmacotherapy is the usual treatment approach,
reducing frequency and severity of symptoms, but it is not a cure and often has
side effects. Psychological help for people with TS and their families may be
needed for this complex disorder.
PMID- 9390416
TI - Assessing the learning processes of black South African students.
AB - Data based on responses of 126 male and 201 female 14- and 15-year-old Black
South African secondary school students showed the Learning Process Questionnaire
(LPQ; Biggs, 1987) to be fairly reliable and factorially valid. Comparison with
the LPQ means for like-aged students from Australia and Hong Kong called into
question the common assertion that Black South African students are more prone to
use superficial learning processes than are Western students. In particular, the
South African responses to the LPQ indicated that they were less shallow and more
oriented toward achievement in their approach to learning than the Australian
students were.
PMID- 9390417
TI - Children's perceptions of purposes for studying different subjects in school.
AB - Examiners explored 4th and 6th graders' perceptions of studying 6 subjects in
school: language, math, science, social studies, music, and visual arts.
Participants were asked to indicate whether they agreed or disagreed with each of
12 reasons for studying each of the 6 subjects. Five of the reasons included
general educational goals that were applicable to all subjects (cross-curricular
goals), 5 included objectives established for a particular subject (subject
specific objectives), and 2 represented goals irrelevant to the subject. Both 4th
and 6th graders selected mainly subject-specific objectives (e.g., "learn about
different rhythms") as reasons for studying music and visual arts. Many children
used some of the general cross-curricular goals (e.g., "do well in school in the
future"), in addition to the subject-specific goals, to describe why they were
studying core subjects: language, math, social studies, and science.
PMID- 9390418
TI - Examining the generalizability of the orality-depression link.
PMID- 9390419
TI - Cloning and characterization of a cDNA encoding an elicitor of Phytophthora
parasitica var. nicotianae that shows cellulose-binding and lectin-like
activities.
AB - Phytophthora parasitica var. nicotianae produces a 34-kDa glycoprotein elicitor
(CBEL) that is localized in the cell wall. A cDNA encoding the protein moiety of
this elicitor was cloned and characterized. The deduced amino acid sequence
consisted of two direct repeats of a cysteine-rich domain, joined by a Thr/Pro
rich region. Although having no general homology with published sequences, the
positions of the cysteine residues in the two repeats show a conserved pattern,
similar to that of the cellulose-binding domain of fungal glycanases. CBEL did
not possess hydrolytic activity on a variety of glycans, but bound to fibrous
cellulose and plant cell walls. In addition, it exerted a lectin-like
hemagglutinating activity. Infiltration of tobacco leaves (cultivar 46-8) with
this molecule elicited necrosis and defense gene expression at 150 nM. Elicitor
pretreatment of this tobacco cultivar resulted in protection against subsequent
inoculation with an otherwise virulent race of P. parasitica var. nicotianae. All
these biological activities were exerted within a low concentration range. This
is the first report that a fungal elicitor exhibits cellulose-binding and lectin
like activities. The possible implications of such a multifunctional elicitor in
plant-microbe interactions are discussed.
PMID- 9390420
TI - A regulatory locus, pehSR, controls polygalacturonase production and other
virulence functions in Ralstonia solanacearum.
AB - We previously identified a locus that regulates production of polygalacturonase
(PG), an extracellular plant cell wall-degrading enzyme important in bacterial
wilt of plants caused by Ralstonia (Pseudomonas) solanacearum. The DNA sequence
of this locus, called pehSR, was determined and two consecutive open reading
frames (ORFs) of 1,905 and 1,680 bp were identified. The amino acid sequences
predicted to be encoded by these ORFs are similar to those of regulators of pilin
synthesis in Pseudomonas aeruginosa and Myxococcus xanthus and to a regulator of
flagellin synthesis and adhesion in P. aeruginosa, as well as to other two
component regulators of the NtrB/C subfamily. pehSR mutants produced negligible
levels of endo-PG activity, while exo-PG activity was reduced by 50%. Northern
(RNA) blot analysis showed that PehSR regulates endo-PG expression at the
transcriptional level. pehSR mutants grew normally in culture and in planta but
were dramatically reduced in virulence; this loss of virulence was substantially
greater than that observed for endo-PG structural gene mutants, suggesting that
pehSR regulates additional factors important in virulence. Although pehSR mutants
were essentially nonmotile, like the wild-type strain, multiple copies of pehSR
conferred motility on the bacterium. Reporter gene studies indicated that pehSR
expression increased when bacteria grew in plant tissue, and that the pehSR locus
was itself negatively regulated by the global virulence gene regulator PhcA.
PMID- 9390421
TI - Phenotypic variation in transgenic tobacco expressing mutated geminivirus
movement/pathogenicity (BC1) proteins.
AB - Tobacco plants were transformed with the movement protein (pathogenicity) gene
(BC1) from tomato mottle geminivirus (TMoV), using Agrobacterium-mediated
transformation. Different transgenic tobacco lines that expressed high levels of
the BC1 protein had phenotypes ranging from plants with severe stunting and leaf
mottling (resembling geminivirus symptoms) to plants with no visible symptoms.
The sequence data for the BC1 transgene from the transgenic plants with the
different phenotypes indicated an association of spontaneously mutated forms of
the BC1 gene in the transformed tobacco with phenotype variations. One mutated
transgene associated with an asymptomatic phenotype had a major deletion at the C
terminus of 119 amino acid residues with a recombination resulting in the
addition of 26 amino acid residues of unidentified origin. This asymptomatic,
mutated BC1 attenuated the phenotypic expression of the symptomatic BC1 in a
tobacco line containing both copies of the BC1 gene. Another mutated form of the
BC1 gene amplified from an asymptomatic, multicopy transgenic tobacco plant did
not induce symptoms when transiently expressed in tobacco via a virus vector. The
symptom attenuation in the transgenic tobacco by the asymptomatic BC1 may involve
trans-dominant negative interference.
PMID- 9390422
TI - G protein alpha subunit genes control growth, development, and pathogenicity of
Magnaporthe grisea.
AB - Three G protein alpha subunit genes have been cloned and characterized from
Magnaporthe grisea: magA is very similar to CPG-2 of Cryphonectria parasitica;
magB is virtually identical to CPG-1 of Cryphonectria parasitica, to gna1 of
Neurospora crassa, and to fadA of Emericella nidulans; and magC is most similar
to gna2 of Neurospora crassa. Homologous recombination resulting in targeted
deletion of magA had no effect on vegetative growth, conidiation, or appressorium
formation. Deletion of magC reduced conidiation, but did not affect vegetative
growth or appressorium formation. However, disruption of magB significantly
reduced vegetative growth, conidiation, and appressorium formation. magB-
transformants, unlike magA- and magC- transformants, exhibited a reduced ability
to infect and colonize susceptible rice leaves. G protein alpha subunit genes are
required for M. grisea mating. magB- transformants failed to form perithecia,
whereas magA- and magC- transformants did not produce mature asci. These results
suggest that G protein alpha subunit genes are involved in signal transduction
pathways in M. grisea that control vegetative growth, conidiation, conidium
attachment, appressorium formation, mating, and pathogenicity.
PMID- 9390423
TI - Iron-dependent transcription of the regulatory gene ros of Agrobacterium
radiobacter.
AB - Transcription of the regulatory gene ros of Agrobacterium radiobacter requires
growth in the presence of Fe although this regulation was not mediated by ros
itself. The ros gene repressed its own transcription, independently of the Fe
status of the growth media. It was shown that the two cysteine residues in the
Ros protein were essential for the complementation of the exopolysaccharide
synthesis defect of ros mutant strains. It was found that the mutation in one exo
mutant strain that was complemented both by ros and by the "structural" exoY gene
was not, in fact, in ros but is in some other, unknown gene. The two cysteines
were also essential for the correction of this mutant. This mutant affected the
expression of exoY but not of ros.
PMID- 9390424
TI - Transgenic Arabidopsis lines expressing gene VI from cauliflower mosaic virus
variants exhibit a range of symptom-like phenotypes and accumulate inclusion
bodies.
AB - Gene VI of cauliflower mosaic virus (CaMV) is an important determinant of symptom
expression during infection. We have constructed a series of transgenic
Arabidopsis lines that express gene VI protein (P6) from two CaMV isolates (Bari
1 and Cabb B-JI) that cause mild and severe symptoms, respectively, in
Arabidopsis, and from a recombinant virus (Baji-31) with a hybrid gene VI that
causes very severe symptoms. From 41 transgenic lines analyzed, 17 showed symptom
like phenotypes that ranged from mild vein chlorosis to severe chlorosis and
stunting. P6 levels in transgenic lines varied from undetectable in the lowest
expressors to levels greater than those in CaMV-infected plants. There was a
strong correlation between phenotype severity and the level of P6, and with the
gene VI origin in the order, Baji-31 > B-JI > Bari-1. This was similar to symptom
severity in Arabidopsis infected with the respective CaMV variant. We also found
that transgenic P6 accumulated in inclusion bodies that were similar to those
found in infected plants but lacking virions. We conclude that expression of P6,
in the absence of virus replication, elicits a subset of the host symptom
responses normally observed during infection and that the level, sequence, and
possibly the form of P6 are important in potentiating the process.
PMID- 9390425
TI - Starvation-induced genes of the tomato pathogen Cladosporium fulvum are also
induced during growth in planta.
AB - The pathogenicity of fungal pathogens is presumably dependent on genes that are
expressed during infection. In order to isolate such genes from the tomato
pathogen Cladosporium fulvum, and to test the hypothesis that starvation-induced
genes are also plant induced, a cDNA library was prepared from mycelia grown in a
defined medium and then transferred to a starvation medium. The library was then
screened with cDNA prepared from starved and replete fungal mycelium. Five
unique, differentially expressed cDNAs were isolated from 1,000 clones screened.
Northern (RNA) hybridization confirmed that all five were starvation induced.
Interestingly, all five were also found to be plant induced. The identity of two
of the clones was indicated by partial DNA sequencing as alcohol and aldehyde
dehydrogenase. The observed correlation between starvation induction and plant
induction in discussed.
PMID- 9390426
TI - Diverse amino acid residues function within the type 1 peroxisomal targeting
signal. Implications for the role of accessory residues upstream of the type 1
peroxisomal targeting signal.
AB - The purpose of this study was to determine whether the plant type 1 peroxisomal
targeting signal (PTS1) utilizes amino acid residues that do not strictly adhere
to the serine-lysine-leucine (SKL) motif (small-basic-hydrophobic residues).
Selected residues were appended to the C terminus of chloramphenicol
acetyltransferase (CAT) and were tested for their ability to target CAT fusion
proteins to glyoxysomes in tobacco (Nicotiana tabacum L.) cv Bright Yellow 2
suspension-cultured cells. CAT was redirected from the cytosol into glyoxysomes
by a wide range of residues, i.e. A/C/G/S/T-H/K/ L/N/R-I/L/M/Y. Although L and N
at the -2 position (-SLL, -ANL) do not conform to the SKL motif, both functioned,
but in a temporally less-efficient manner. Other SKL divergent residues, however,
did not target CAT to glyoxysomes, i.e. F or P at the -3 position (-FKL, -PKL), S
or T at the -2 position (-SSI, STL), or D at the -1 position (-SKD). The
targeting inefficiency of CAT-ANL could be ameliorated when K was included at the
-4 position (-KANL). In summary, the plant PTS1 mostly conforms to the SKL motif.
For those PTS1s that possess nonconforming residue(s), other residues upstream of
the PTS1 appear to function as accessory sequences that enhance the temporal
efficiency of peroxisomal targeting.
PMID- 9390427
TI - bor1-1, an Arabidopsis thaliana mutant that requires a high level of boron.
AB - bor1-1 (high boron requiring), an Arabidopsis thaliana mutant that requires a
high level of B, was isolated. When the B concentration in the medium was reduced
to 3 microM, the expansion of rosette leaves was severely affected in bor1-1 but
not in wild-type plants. In a medium containing 30 microM B the mutant grew
normally but showed female sterility, whereas the wild type was able to set
seeds. These defects of the bor1-1 mutant were not detected with supplementation
of 100 microM B. In vivo concentrations of B in bor1-1 mutants were lower than
those of the wild type, especially in the inflorescence stems. Tracer experiments
using 10B suggested that the mutant has defects in uptake and/or translocation of
B. The mutation was mapped on the lower arm of chromosome 2.
PMID- 9390428
TI - Gene fusions of signal sequences with a modified beta-glucuronidase gene results
in retention of the beta-glucuronidase protein in the secretory pathway/plasma
membrane.
AB - Signal sequences and endoplasmic reticulum (ER) retention signals are known to
play central roles in targeting and translocation in the secretory pathway, but
molecular aspects about their involvement are poorly understood. We tested the
effectiveness of deduced signal sequences from various genes (hydroxyproline-rich
glycoprotein [HRGP] from Phaseolus vulgaris; Serpin from Manduca sexta) to direct
a modified beta-glucuronidase (GUS) protein into the secretory pathway in
transgenic tobacco (Nicotiana tabacum L.). The reporter protein was not secreted
to the cell wall/extracellular space as monitored using extracellular fluid
analysis (low- or high-ionic-strength conditions) but occurred in membranes with
a density of 1.16 to 1.20 g/mL. Membrane-bound GUS equilibrated with the plasma
membrane (PM) and the ER on linear sucrose gradients with or without
ethylenediaminetetraacetic acid, suggesting that GUS associates with the ER and
the PM. Confocal microscopy of fixed cultured cells prepared from GUS control and
HRGP signal peptide (SP)-GUS-expressing plants suggested only cytosolic
localization in GUS-expressing plants but substantial peripheral localization in
HRGP SP-GUS plants, which is consistent with GUS being associated with the PM.
Aqueous two-phase partitioning of microsomal membranes from HRGP SP-GUS and
Serpin SP-GUS transgenic leaves also indicated that GUS activity was enriched in
the ER and the PM. These observations, together with hydrophobic moment plot
analysis, suggest that properties of the SP-GUS protein result in its retention
in the secretory pathway and PM.
PMID- 9390429
TI - Developmental and hormonal regulation of the arabidopsis CER2 gene that codes for
a nuclear-localized protein required for the normal accumulation of cuticular
waxes.
AB - The previously cloned CER2 gene is required for the normal accumulation of
cuticular waxes and encodes a novel protein. Earlier reports suggested that the
CER2 protein is either a membrane-bound component of the fatty acid elongase
complex or a regulatory protein. Cell fractionation and immunoblot analyses using
polyclonal antibodies raised against a chemically synthesized peptide with a
sequence based on the predicted CER2 protein sequence have demonstrated that the
47-kD CER2 protein is soluble and nuclear localized. These results are consistent
with CER2 being a regulatory protein. Detailed studies of plants harboring a CER2
promoter/GUS transgene (CER2-GUS), in combination with immunoblot analyses,
revealed that CER2 is expressed and the CER2 protein accumulates in a variety of
organs and cell types. Expression is highest early in the development of these
organs and is epidermis specific in most tissues. In agreement with the activity
of the CER2 promoter in hypocotyls, cuticular wax accumulates on this organ in a
CER2-dependent fashion. In leaves CER2 expression is confined to the guard cells,
trichomes, and petioles. However, application of the cytokinin 6
benzylaminopurine induces ectopic expression of CER2-GUS in all cell types of
leaves that emerge following treatment.
PMID- 9390430
TI - Heat treatment results in a loss of transgene-encoded activities in several
tobacco lines.
AB - Heat treatment (37 degrees C) of transgenic tobacco (Nicotiana tabacum) plants
led to a reversible reduction or complete loss of transgene-encoded activities in
about 40% of 10 independent transformants carrying the luciferase-coding region
fused to the 355 cauliflower mosaic virus or the soybean small subunit promoter
and the nopaline synthase promoter driving the neomycin phosphotransferase gene,
whereas the other lines had temperature-tolerant activities. Temperature
sensitivity or tolerance of transgene-encoded activities was heritable. In some
of the lines, temperature sensitivity of the transgene-encoded activities
depended on the stage of development, occurring in either seedlings (40%
luciferase and 50% neomycin phosphotransferase) or adult plants (both 40%). The
phenomenon did not correlate with copy numbers or the homo- or hemizygous state
of the transgenes. In lines harboring a temperature-sensitive luciferase
activity, reduction of bioluminescence was observed after 2 to 3 h at 37 degrees
C. Activity was regained after 2 h of subsequent cultivation at 25 degrees C.
Irrespective of the reaction to the heat treatment, the level of luciferase RNA
was slightly increased at 37 degrees C. Only in lines showing temperature
sensitivity of transgene-encoded activities was the amount of luciferase and
neomycin phosphotransferase strongly reduced. In sterile culture, heat treatment
for 15 d did not cause visible damage or changes in plant morphology. In all
plants tested a slight induction of the heat-shock response was observed at 37
degrees C.
PMID- 9390431
TI - Starches from A to C. Chlamydomonas reinhardtii as a model microbial system to
investigate the biosynthesis of the plant amylopectin crystal.
AB - Wide-angle powder x-ray diffraction analysis was carried out on starch extracted
from wild-type and mutant Chlamydomonas reinhardtii cells. Strains containing no
defective starch synthases as well as mutants carrying a disrupted granule-bound
starch synthase structural gene displayed the A type of diffraction pattern with
a high degree of crystallinity. Mutants carrying a defect for the major soluble
starch synthase (SSS), SSS II, were characterized by a switch to the B type of
diffraction pattern with very low crystallinity. Mutant strains carrying SSS I as
the only glucan elongation enzyme regained some of their crystallinity but
switched to the C type of diffraction pattern. Differential scanning calorimetry
analysis correlated tightly with the x-ray diffraction results. Together with the
electron microscopy analyses, these results establish C. reinhardtii as a
microbial model system displaying all aspects of cereal starch synthesis and
structure. We further show that SSS II is the major enzyme involved in the
synthesis of crystalline structures in starch and demonstrate that SSS I alone
builds a new type of amylopectin structure.
PMID- 9390432
TI - Differential patterns of expression of the Arabidopsis PHYB, PHYD, and PHYE
phytochrome genes.
AB - The Arabidopsis thaliana phyB, phyD, and phyE phytochrome apoproteins show higher
amino acid sequence similarity to each other than to phyA or phyC, they are the
most recently evolved members of this photoreceptor family, and they may interact
in regulating photomorphogenesis. The expression patterns of translational
fusions of the 5' upstream regions of the PHYB, PHYD, and PHYE genes to the beta
glucuronidase (GUS) coding sequence were compared. PD-GUS and PE-GUS fusions were
5- to 10-fold less active than a PB-GUS fusion, but all three promoter regions
drove expression of the reporter gene in all stages of the plant's life cycle.
Over the first 10 d of seedling growth, the PHYB and PHYD promoters were more
active in the dark than in the light, whereas the opposite was true of the PHYE
promoter. Unlike the PB-GUS construct, which was expressed in most parts of
seedlings and mature plants, the PD-GUS and PE-GUS transgenes showed differential
expression, notably in leaves, flower organs, and root tips. Tissue sections
showed that the three promoters are coexpressed in at least some leaf cells.
Hence, the PHYB, PHYD, and PHYE genes differ in expression pattern but these
patterns overlap and interaction of these receptor forms within individual cells
is possible.
PMID- 9390433
TI - The COW1 locus of arabidopsis acts after RHD2, and in parallel with RHD3 and
TIP1, to determine the shape, rate of elongation, and number of root hairs
produced from each site of hair formation.
AB - Two recessive mutant alleles at CAN OF WORMS1 (COW1), a new locus involved in
root hair morphogenesis, have been identified in Arabidopsis thaliana L. Heynh.
Root hairs on Cow1- mutants are short and wide and occasionally formed as pairs
at a single site of hair formation. The COW1 locus maps to chromosome 4. Root
hairs on Cow1- plants form in the usual positions, suggesting that the phenotype
is not the result of abnormal positional signals. Root hairs on Cow1- roots begin
hair formation normally, forming a small bulge, or root hair initiation site, of
normal size and shape and in the usual position on the hair-forming cell.
However, when Cow1- root hairs start to elongate by tip growth, abnormalities in
the shape and elongation rate of the hairs become apparent. Genetic evidence from
double-mutant analysis of cow1-1 and other loci involved in root hair development
supports our conclusion that COW1 is required during root hair elongation.
PMID- 9390434
TI - The characterization of plasma membrane-bound tubulin of cauliflower using Triton
X-114 fractionation.
AB - The cortical microtubules determine how cellulose microfibrils are deposited in
the plant cell wall and are thus important for the control of cell expansion. To
understand how microtubules can control microfibril deposition, the components
that link the microtubules to the plasma membrane (PM) of plant cells must be
isolated. To obtain information on the properties of the tubulin-membrane
associations, cauliflower (Brassica oleracea) PM was subjected to Triton X-114
fractionation, and the distribution of alpha- and beta-tubulin was analyzed using
immunoblotting. Approximately one-half of the PM-associated tubulin was
solubilized by Triton X-114 and 10 to 15% of both alpha- and beta-tubulin was
recovered in the detergent phase (indicative of hydrophobic properties) and 30 to
40% was recovered in the aqueous phase. The hydrophobic tubulin could be released
from the membrane by high pH extraction with preserved hydrophobicity. A large
part of the PM-associated tubulin was found in the Triton-insoluble fraction.
When this insoluble material was extracted a second time, a substantial amount of
hydrophobic tubulin was released if the salt concentration was increased,
suggesting that the hydrophobic tubulin was linked to a high-salt-sensitive
protein aggregate that probably includes other components of the cytoskeleton.
The hydrophobicity of a fraction of PM-associated tubulin could reflect a direct
or indirect interaction of this tubulin with the lipid bilayer or with an
integral membrane protein and may represent the anchoring of the cortical
microtubules to the PM, a key element in the regulation of cell expansion.
PMID- 9390435
TI - Characterization of new gibberellin-responsive semidwarf mutants of arabidopsis.
AB - Chemical mutagenesis of Arabidopsis thaliana (L.) Heynh. yielded four semidwarf
mutants, all of which appeared to be gibberellin (GA)-biosynthesis mutants. All
four had atypical response profiles to C20-GAs, suggesting that each had impaired
20-oxidation. One mutant, 11.2, was shown to be allelic to ga5 and has been named
ga5-2. It had altered metabolism of [14C]GA15 relative to that in wild-type
plants and undetectable levels of C19-GAs in young stems, consistent with the
known function of GA5 as a stem-expressed GA 20-oxidase. Two mutants (2.1 and
10.3), which had very short inflorescences and siliques, were allelic to each
other but not to the known GA-responding mutants, ga1 to ga5. The locus defined
by these two mutations is provisionally named GA6 and is purported to encode an
inflorescence- and silique-expressed GA 20-oxidase. A double mutant, ga5-2 ga6-2,
had an extreme dwarf phenotype with very short siliques. The fourth mutation,
1.1, gave a phenotype like ga5, but was not allelic to any of the known ga
mutations. It has not yet been given a gene symbol pending further studies.
PMID- 9390436
TI - Differential expression of chitinases in Vitis vinifera L. responding to systemic
acquired resistance activators or fungal challenge.
AB - The concept of systemic acquired resistance (SAR) enables a novel approach to
crop protection, and particular pathogenesis-related proteins, i.e. an acidic
chitinase, have been classified as markers of the SAR response. Basic class I
(VCHIT1b) and a class III (VCH3) chitinase cDNAs were cloned from cultured Vitis
vinifera L. cv Pinot Noir cells and used to probe the induction response of
grapevine cells to salicylic acid or yeast elicitor. Furthermore, the cells were
treated with the commercial SAR activators 2,6-dichloroiso-nicotinic acid or
benzo(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester. Elicitor or salicylic
acid induced both VCHIT1b and VCH3 transcript abundances, whereas 2,6-dichloroiso
nicotinic acid or benzo(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester
enhanced exclusively the expression of VCH3. To assess the systemic sensation of
chitinase expression, single leaves of Vitis vinifera L. cv Pinot Noir or Vitis
rupestris plants were inoculated with Plasmopara viticola spore suspensions, and
the VCH3 and VCHIT1b mRNA amounts in the infected versus the adjacent, healthy
leaf were monitored. Two VCH3 mRNA maxima were observed 2 and 6 d postinoculation
in the infected, susceptible V. vinifera tissue, whereas in the healthy leaf the
transcript increased from low levels d 2 postinoculation to prominent levels d 6
to 8 postinoculation. The level of VCH3 mRNA increased also over 4 d in the
inoculated, resistant V. rupestris tissue. However, necrotic spots rapidly
limited the infection, and the VCH3 transcript was undetectable in the upper
stage, healthy leaf. The expression of VCHIT1b remained negligible under either
experimental condition. Overall, the results suggest that the selective
expression of VCH3 might be a reliable indicator of the SAR response in V.
vinifera L.
PMID- 9390437
TI - Characterization and expression of caffeoyl-coenzyme A 3-O-methyltransferase
proposed for the induced resistance response of Vitis vinifera L.
AB - Cell-suspension cultures of Vitis vinifera L. cv Pinot Noir accumulated
resveratrol upon fungal elicitation, and the activity of S-adenosyl-L
methionine:trans-caffeoyl-coenzyme A 3-O-methyl-transferase (CCoAOMT), yielding
feruloyl-CoA, increased to a transient maximum at 12 to 15 h. CCoAOMT cDNA was
cloned from the elicited cells and was shown to encode a polypeptide highly
homologous to CCoAOMTs from cells of Petroselinum species or Zinnia species. The
expression of the cDNA in Escherichia coli revealed that grapevine CCoAOMT
methylates both caffeoyl- and 5-hydroxyferuloyl-coenzyme A and is probably
involved in phenolic esterification and lignification. Commercial plant
activators induce the disease-resistance response of test plants and are
considered to mimic the action of salicylic acid. Among these chemicals, 2,6
dichloroisonicotinic acid and benzo(1,2,3)-thiadiazole-7-carbothioic acid S
methyl ester provoke systemic acquired resistance (SAR) and were also shown to
induce the expression of class III chitinase in grapevine. The SAR response is
classified by an unchanged phenotype of tissues, but the mechanistic basis is
unknown. Treatment of the cultured V. vinifera cells with either fungal elicitor
or low concentrations of salicylic acid and 2,6-dichloroisonicotinic acid,
respectively, raised the CCoAOMT or stilbene synthase transcript abundance,
suggesting that grapevine is capable of the SAR response, whereas benzo(1,2,3)
thiadiazole-7-carbothioic acid S-methyl ester was ineffective. The data imply for
the first time (to our knowledge) that the expression of phenyl-propanoid genes
in grapevine is induced by SAR activators without phenotypic consequences and
suggest a role for CCoAOMT and stilbene synthase in the disease-resistance
response leading beyond the level of pathogenesis-related proteins as markers of
the SAR.
PMID- 9390438
TI - Induction of 12-oxo-phytodienoic acid in wounded plants and elicited plant cell
cultures.
AB - Jasmonic acid (JA) is rapidly biosynthesized from alpha-linolenic acid in plants
upon contact with pathogens or wounding, and triggers gene activation, leading to
the synthesis of defensive secondary metabolites and proteins. Despite the recent
finding that its precursor, 12-oxo-phytodienoic acid (PDA), is a more powerful
inducer of gene activation, interest has focused so far almost exclusively on JA.
A validated negative chemical ionization-gas chromatography-mass spectrometry
method has been developed that allows the simultaneous quantification of
endogenous 12-oxo-PDA and JA in plant tissues. In six out of eight plant species
tested maximal levels of 12-oxo-PDA exceeded peak levels of JA by approximately 3
to 5-fold after elicitation with a yeast cell wall preparation or when plants
were wounded. These experiments support the hypothesis that 12-oxo-PDA acts as
the predominant jasmonate signal in most plants, whereas JA remains an active
metabolite of its precursor. Furthermore, JA but not 12-oxo-PDA was shown to be
secreted into the medium from cultured plant cells, suggesting that JA may also
act as an intercellular signal.
PMID- 9390439
TI - Expression of a vacuolar protein (VP24) in anthocyanin-producing cells of sweet
potato in suspension culture.
AB - VP24, an abundant protein of 24 kD, was found to accumulate in the anthocyanin
containing vacuoles of cells of sweet potato (Ipomoea batatas) in suspension
culture. Light-induced expression of VP24 was analyzed by immunoblotting in three
different cell lines that produced anthocyanins at different rates. The
expression of VP24 was closely correlated with the accumulation of anthocyanin in
these cell lines. Immunocytochemical detection of VP24 with specific antibodies
on thin sections showed that VP24 was localized in the intravacuolar pigmented
globules (cyanoplasts) in the anthocyanin-containing vacuoles and not in the
tonoplast. No VP24 immunogold labeling was detected in the vacuoles of the cell
line that does not produce anthocyanin. We suggest that VP24 may be involved in
the formation of the cyanoplast via an interaction with anthocyanin, and that it
may play an important role in the trapping in vacuoles of large amounts of
anthocyanins that have been transported into these vacuoles.
PMID- 9390440
TI - Characterization of maize elongation factor 1A and its relationship to protein
quality in the endosperm.
AB - The protein synthesis elongation factor 1A (eEF1A) is a multifunctional protein
in eukaryotic cells. In maize (Zea mays L.) endosperm eEF1A co-localizes with
actin around protein bodies, and its accumulation is highly correlated with the
protein-bound lysine (Lys) content. We purified eEF1A from maize kernels by
ammonium sulfate precipitation, ion-exchange, and chromatofocusing. The identify
of the purified protein was confirmed by microsequencing of an endoproteinase
glutamic acid-C fragment and by its ability to bundle actin. Using purified eEF1A
as a standard, we found that this protein contributes 0.4% of the total protein
in W64A+ endosperm and approximately 1% of the protein in W64Ao2. Because eEF1A
contains 10% Lys, it accounts for 2.2% of the total Lys in W64A+ and 2.3% of the
Lys in W64Ao2. However, its concentration predicts 90% of the Lys found in
endosperm proteins of both genotypes, indicating that eEF1A is a key component of
the group of proteins that determines the nutritional quality of the grain. This
notion is further supported by the fact that in floury2, another high-Lys mutant,
the content of eEF1A increases with the dosage of the floury2 gene. These data
provide the biochemical basis for further investigation of the relationship
between eEF1A content and the nutritional quality of cereals.
PMID- 9390441
TI - LHT1, a lysine- and histidine-specific amino acid transporter in arabidopsis.
AB - We have identified a new amino acid transporter from the Arabidopsis thaliana
expressed sequence tag cDNA collection by functional complementation of a yeast
amino acid transport mutant. Transport analysis of the expressed protein in yeast
shows that it is a high-affinity transporter for both lysine (Lys) and histidine
with Michaelis constant values of 175 and 400 microM, respectively. This
transporter (LHT1, lysine histidine transporter) has little affinity for arginine
when measured directly in uptake experiments or indirectly with substrate
competition. The cDNA is 1.7 kb with an open reading frame that codes for a
protein with 446 amino acids and a calculated molecular mass of 50.5 kD.
Hydropathy analysis shows that LHT1 is an integral membrane protein with 9 to 10
putative membrane-spanning domains. Southern-blot analysis suggests that LHT1 is
a single-copy gene in the Arabidopsis genome. RNA gel-blot analysis shows that
this transporter is present in all tissues, with the strongest expression in
young leaves, flowers, and siliques. Wholemount, in situ hybridization revealed
that expression is further localized on the surface of roots in young seedlings
and in pollen. Overall, LHT1 belongs to a new class of amino acid transporter
that is specific for Lys and histidine, and, given its substrate specificity, it
has significant promise as a tool for improving the Lys content of Lys-deficient
grains.
PMID- 9390442
TI - Analysis of wild-type and mutant plant nitrate reductase expressed in the
methylotrophic yeast Pichia pastoris.
AB - Recombinant Arabidopsis thaliana NADH:nitrate reductase (NR; EC 1.6.6.1) was
produced in the methylotrophic yeast Pichia pastoris and purified to near
electrophoretic homogeneity. Purified enzyme had the spectral and kinetic
properties typical of highly purified NR from natural plant sources. Site
directed mutagenesis altering several key residues and regions was carried out,
and the mutant enzyme forms were expressed in P. pastoris. When the invariant
cysteine residue, cysteine-191, in the molybdo-pterin region of the A. thaliana
NIA2 protein was replaced with serine or alanine, the NR protein was still
produced but was inactive, showing that this residue is essential for enzyme
activity. Deletions or substitutions of the conserved N terminus of NR retained
activity and the ability to be inactivated in vitro when incubated with ATP.
Enzyme with a histidine sequence appended to the N terminus was still active and
was easily purified using metal-chelate affinity chromatography. These results
demonstrate that P. pastoris is a useful and reliable system for producing
recombinant holo-NR from plants.
PMID- 9390443
TI - Changes in the composition of the photosynthetic apparatus in the galactolipid
deficient dgd1 mutant of Arabidopsis thaliana.
AB - The glycerolipid digalactosyl diacylglycerol (DGDG) is exclusively associated
with photosynthetic membranes and thus may play a role in the proper assembly and
maintenance of the photosynthetic apparatus. Here we employ a genetic approach
based on the dgd1 mutant of Arabidopsis thaliana to investigate the function of
DGDG in thylakoid membranes. The primary defect in the genetically well
characterized dgd1 mutant resulted in a 90% reduction of the DGDG content. The
mutant showed a decreased photosystem II (PSII) to photosystem I ratio. In vivo
room- and low-temperature (77 K) chlorophyll fluorescence measurements with
thylakoid preparations are in agreement with a drastically altered excitation
energy allocation to the reaction centers. Quantification of pigment-binding
apoproteins and pigments supports an altered stoichiometry of individual pigment
protein complexes in the mutant. Most strikingly, an increase in the amount of
peripheral light-harvesting complexes of PSII relative to the inner antenna
complexes and the PSII reaction center/core complexes was observed. Regardless of
the severe alterations in thylakoid organization, photosynthetic oxygen evolution
was virtually not compromised in dgd1 mutant leaves.
PMID- 9390444
TI - A ubiquitous plant housekeeping gene, PAP, encodes a major protein component of
bell pepper chromoplasts.
AB - We have isolated a cDNA (PAP) corresponding to a single nuclear gene that encodes
an approximately 30-kD major protein of bell pepper (Capsicum annuum L.) fruit
chromoplasts. RNA and protein analyses revealed that, although at a low level,
this gene is also expressed in every organ of the plant, the amount of the
corresponding transcript and protein dramatically increasing in the latter stages
of fruit development. Western-blot and immunocytochemical analyses of purified
chloroplasts from leaves and fruits and of chromoplasts from red fruits showed
that the encoded protein is the major component of plastoglobules and fibrils and
is localized on the outer surface of these lipid structures. Analyses of PAP in
plants belonging to different taxa revealed that it is expressed and highly
conserved in both monocotyledonous and dicotyledonous plants. The presence of the
protein in plastids not differentiating into chromoplasts indicates that PAP is
expressed irrespective of the ontogeny of various plastid lines. In light of our
results and since the encoded protein, identical to that previously named ChrB or
fibrillin, is present in plastoglobules from several species and accumulates in
the fibrils of bell pepper chromoplast, we propose to designate it as a plastid
lipid-associated protein.
PMID- 9390445
TI - Expression and characterization of pea chloroplastic glyceraldehyde-3-phosphate
dehydrogenase composed of only the B-subunit.
AB - A cDNA fragment coding for the pea (Pisum sativum L.) chloroplastic
glyceraldehyde-3-P dehydrogenase (EC 1.2.1.13) B-subunit and a truncated form
corresponding in length to the A-subunit have been cloned into an expression
vector, expressed in the absence of the A-subunit in a gap- Escherichia coli
strain, purified, and studied. Like the isolated enzyme from higher plant
chloroplasts, the recombinant enzymes have dual specificity for NADPH and NADH.
The recombinant glyceraldehyde-3-P dehydrogenases have the same optimal pH as the
enzyme isolated from pea chloroplasts. Like the native chloroplast enzyme, the
recombinant B-subunit has a marked tendency to form large aggregates, whereas the
truncated B-subunit exists as the tetramer. The recombinant B-subunit
glyceraldehyde 3-P dehydrogenase is more sensitive to dithiothreitol than its
truncated form. It seems likely that a different pair of cysteines is responsible
for the redox sensitivity of the activity of the enzyme composed of B-subunits
than the cysteine residues implicated in the modulation of the activity of the
enzyme composed of A-subunits by previous work in this laboratory.
PMID- 9390447
TI - Rice hemoglobins. Gene cloning, analysis, and O2-binding kinetics of a
recombinant protein synthesized in Escherichia coli.
AB - Although nonsymbiotic hemoglobins (Hbs) are found in different tissues of dicots
and monocots, very little is known about hb genes in monocots and the function of
Hbs in nonsymbiotic tissues. We report the cloning and analysis of two rice
(Oryza sativa L.) hb genes, hb1 and hb2, that code for plant Hbs. Rice hb1 and
hb2 genes contain four exons and three introns, as with all of the known plant hb
genes. At least three copies of the hb gene were detected in rice DNA, and
analysis of gene expression shows that hb1 and hb2 are expressed in leaves but
only hb1 is expressed in roots. A cDNA for rice Hb1 was expressed in Escherichia
coli, and the recombinant Hb (rHb1) shows an unusually high affinity for O2
because of a very low dissociation constant. The absorbance spectra of the ferric
and deoxyferrous rHb1 indicate that, in contrast to symbiotic Hbs, a distal
ligand is coordinated to the ligand-binding site. Mutation of the distal His
demonstrates that this residue coordinates the heme Fe of ferric and deoxyferrous
rHb1 and stabilizes O2 in oxy-rHb1. The biochemical properties of rice rHb1
suggest that this protein probably does not function to facilitate the diffusion
of O2.
PMID- 9390449
TI - The electronic Plant Gene Register.
PMID- 9390448
TI - L-ascorbic acid metabolism in the ascorbate-deficient arabidopsis mutant vtc1.
AB - The biosynthesis of L-ascorbic acid (vitamin C) is not well understood in plants.
The ozone-sensitive Arabidopsis thaliana mutant vitamin c-1 (vtc1; formerly known
as soz1) is deficient in ascorbic acid, accumulating approximately 30% of wild
type levels. This deficiency could result from elevated catabolism or decreased
biosynthesis. No differences that could account for the deficiency were found in
the activities of enzymes that catalyze the oxidation or reduction of ascorbic
acid. The absolute rate of ascorbic acid turnover is actually less in vtc1 than
in wild type; however, the turnover rate relative to the pool of ascorbic acid is
not significantly different. The results from [U-14C]Glc labeling experiments
suggest that the deficiency is the result of a biosynthetic defect: less L
[14C]ascorbic acid as a percentage of total soluble 14C accumulates in vtc1 than
in wild type. The feeding of two putative biosynthetic intermediates, D-glucosone
and L-sorbosone, had no positive effect on ascorbic acid levels in either
genotype. The vtc1 defect does not appear to be the result of a deficiency in L
galactono-1,4-lactone dehydrogenase, an enzyme able to convert L-galactono-1,4
lactone to ascorbic acid.
PMID- 9390450
TI - Potato pulp: microbiological characterization, physical modification, and
application of this agricultural waste product.
AB - Potato pulp, one of the agricultural waste products obtained in high quantities
during starch production, contains starch, cellulose, hemicelluloses, pectin,
proteins, free amino acids and salts. It exhibits physical and physicochemical
properties of a typical colloid. It is mainly used, in a dried and pelleted form,
as cattle feed. Its autochthonic microbial flora (bacteria, fungi) was identified
and studied with a view towards the degradative potential of the microorganisms
and ways of conserving the pulp for subsequent technical applications; 33
isolates (28 bacteria, 4 fungi, 1 yeast), belonging to 15 genera were
characterized. Biological conservation was possible at very low oxygen pressure,
brought about by the autochthonic anaerobic microorganisms causing acidification.
Chemical conservation was achieved with sorbic acid. By treatment with hot water
vapour under pressure (autoclaving), followed by a pressure release procedure,
intact cells in the pulp (both potato cells and microorganisms, not spores) were
destroyed, and their contents and wall fragments were set free. This process
resulted in low drying costs and was a prerequisite for the production of a
powder that can be used as glue or as animal feed.
PMID- 9390451
TI - Biodegradation of the pesticide 4,6-dinitro-ortho-cresol by microorganisms in
batch cultures and in fixed-bed column reactors.
AB - A mixed culture of microorganisms able to utilize 4,6-dinitro-ortho-cresol (DNOC)
as the sole source of carbon, nitrogen and energy was isolated from soil
contaminated with pesticides and from activated sludge. DNOC was decomposed
aerobically in batch cultures as well as in fixed-bed column reactors. Between
65% and 84% of the substrate nitrogen was released as nitrate into the medium,
and 61% of the carbon from uniformly 14C-labelled DNOC was recovered as 14CO2.
The mixed microbial culture also decomposed 4-nitrophenol and 2,4-dinitrophenol
but not 2,3-dinitrophenol, 2,6-dinitrophenol, 2,4-dinitrotoluene, 2,4
dinitrobenzoic acid or 2-sec-butyl-4,6-dinitrophenol (Dinoseb). Maximal
degradation rates for DNOC by the bacterial biofilm immobilized on glass beads in
fixed-bed column reactors were 30 mmol day-1 (1 reactor volume)-1, leaving an
effluent concentration of less than 5 micrograms l-1 DNOC in the outflowing
medium. The apparent Ks value of the immobilized mixed culture for DNOC was 17
microM. Degradation was inhibited at DNOC concentrations above 30 microM and it
ceased at 340 microM, possibly because of the uncoupling action of the
nitroaromatic compound on the cellular energy-transducing mechanism.
PMID- 9390452
TI - The effect of nisin concentration and nutrient depletion on nisin production of
Lactococcus lactis.
AB - The kinetics of nisin production was studied in batch cultures using a construct
of Lactococcus lactis subsp. lactis C2SmPrt-, containing a transposon (TnNip)
that encodes nisin production. The introduction of TnNip into C2SmPrt-
significantly lowered the specific growth rate and the maximum A620 reached was
reduced from 15.2 to 11.0. The effect of nisin concentration and nutrient
depletion on nisin production of the construct, C2SmPrt-(TnNip), was examined.
Nisin production was found to be inhibited by high concentrations of nisin, when
grown in excess nutrient, even though growth of the culture continued because
nutrient limitation was not operating. However, in low nutrient concentrations
nisin production was limited by nutrient depletion. The specific growth rate of
C2SmPrt-(TnNip) was altered, by using different nutrient concentrations and
different sugars, in order to examine the relationship between nisin production
and growth. Nisin production was shown to be growth-associated for most of
growth, but near the end of growth, when the specific growth rate was 0.05 h-1 or
less, the production ceased.
PMID- 9390453
TI - Cytochrome c peroxidase from a methylotrophic yeast: physiological role and
isolation.
AB - Mutant strains of the methylotrophic yeast Hansenula polymorpha defective in
catalase (cat) and in glucose repression of alcohol oxidase synthesis (gcr1) have
been isolated following multiple UV mutagenesis steps. One representative gcr1
cat mutant C-105 grows during batch cultivation in a glucose/methanol medium.
However, growth is preceded by a prolonged lag period. C-105 and other gcr1 cat
mutants do not grow on methanol medium without an alternative carbon source. A
large collection of second-site suppressor catalase-defective (scd) revertants
were isolated with restored ability for methylotrophic growth (Mth+) in the
absence of catalase activity. These Mth+ gcr1 cat scd strains utilize methanol as
a sole source of carbon and energy, although biomass yields are reduced relative
to the wild-type strain. In contrast to the parental C-105 strain, H2O2 does not
accumulate in the methanol medium of the revertants. We show that restoration of
methylotrophic growth in the suppressor strains is strongly correlated with
increased levels of the alternative H2O2-destroying enzyme, cytochrome c
peroxidase. Cytochrome c peroxidase from cell-free extracts of one of the scd
revertants has been purified to homogeneity and crystallized.
PMID- 9390454
TI - Characterization of Leuconostoc mesenteroides NRRL B-512F dextransucrase (DSRS)
and identification of amino-acid residues playing a key role in enzyme activity.
AB - Dextransucrase (DSRS) from Leuconostoc mesenteroides NRRL B-512F is a
glucosyltransferase that catalyzes the synthesis of soluble dextran from sucrose
or oligosaccharides when acceptor molecules, like maltose, are present. The L.
mesenteroides NRRL B-512F dextransucrase-encoding gene (dsrS) was amplified by
the polymerase chain reaction and cloned in an overexpression plasmid. The
characteristics of DSRS were found to be similar to the characteristics of the
extracellular dextransucrase produced by L. mesenteroides NRRL B-512F. The enzyme
also exhibited a high homology with other glucosyltransferases. In order to
identify critical amino acid residues, the DSRS sequence was aligned with
glucosyltransferase sequences and four amino acid residues were selected for site
directed mutagenesis experiments: aspartic acid 511, aspartic acid 513, aspartic
acid 551 and histidine 661. Asp-511, Asp-513 and Asp-551 were independently
replaced with asparagine and His-661 with arginine. Mutation at Asp-511 and Asp
551 completely suppressed dextran and oligosaccharide synthesis activities,
showing that at least two carboxyl groups (Asp-511 and Asp-551) are essential for
the catalysis process. However, glucan-binding properties were retained, showing
that DSRS has a two-domain structure like other glucosyltransferases. Mutations
at Asp-513 and His-661 resulted in greatly reduced dextransucrase activity.
According to amino acid sequence alignments of glucosyltransferases, alpha
amylases or cyclodextrin glucanotransferases, His-661 may have a hydrogen-bonding
function.
PMID- 9390455
TI - Possible roles for a non-modular, thermostable and proteinase-resistant cellulase
from the mesophilic aerobic soil bacterium Cellvibrio mixtus.
AB - The widespread presence of cellulose-binding domains in cellulases from aerobic
bacteria and fungi suggests the existence of a strong selective pressure for the
retention of these non-catalytic modules. The complete nucleotide sequence of the
cellulase gene, celA, from the aerobic soil bacterium Cellvibrio mixtus, was
determined. It revealed an open reading frame of 1089 bp that encoded a
polypeptide, defined as cellulase A (CelA), of M(r) 41,548. CelA displayed
features characteristic of an endo-beta-1,4-glucanase, rapidly decreasing the
viscosity of the substrate while releasing only moderate amounts of reducing
sugar. Deletion studies in celA revealed that removal of 78 nucleotides from the
5' end or 75 from the 3' end of the gene led to the complete loss of cellulase
activity of the encoded polypeptides. The deduced primary structure of CelA
revealed an N-terminal signal peptide followed by a region that exhibited
significant identity with the catalytic domains of cellulases belonging to
glycosyl hydrolase family 5. These data suggest that CelA is a single-domain
endoglucanase with no distinct non-catalytic cellulose-binding domain. Analysis
of the biochemical properties of CelA revealed that the enzyme hydrolyses a range
of soluble cellulosic substrates, but was inactive against Avicel, xylan or any
other hemicellulose. CelA was resistant to proteolytic inactivation by pancreatic
proteinases and surprisingly, in view of its mesophylic origin, was shown to be
thermostable. The significance of these findings in relation to the role of
single-domain cellulases in plant cell wall hydrolysis by aerobic microorganisms
is discussed.
PMID- 9390456
TI - Biosynthetic production of type II fish antifreeze protein: fermentation by
Pichia pastoris.
AB - Sea raven type II antifreeze protein (SRAFP) is one of three different fish
antifreeze proteins isolated to date. These proteins are known to bind to the
surface of ice and inhibit its growth. To solve the three-dimensional structure
of SRAFP, study its ice-binding mechanism, and as a basis for engineering these
molecules, an efficient system for its biosynthetic production was developed.
Several different expression systems have been tested including baculovirus,
Escherichia coli and yeast. The latter, using the methylotrophic organism Pichia
pastoris as the host, was the most productive. In shake-flask cultures the levels
of SRAFP secreted from Pichia were up to 5 mg/l. The recombinant protein has an
identical activity to SRAFP from sea raven serum. In order to increase yields
further, four different strategies were tested in 10-l fermentation vessels,
including: (1) optimization of pH and dissolved oxygen, (2) mixed feeding of
methanol and glycerol with Mut(s) clones, (3) supplementation of amino acid
building blocks, and (4) methanol feeding with Mut+ clones. The mixed
feeding/Mut(s) strategy proved to be the most efficient with SRAFP yields
reaching 30 mg/l.
PMID- 9390457
TI - Efficient production of a functional mouse/human chimeric Fab' against human
urokinase-type plasminogen activator by Bacillus brevis.
AB - Expression/secretion vectors for the production of Fab' and single-chain (sc)
Fab' by Bacillus brevis have been constructed. For the production of Fab', the
cDNAs encoding the L chain and Fd' fragment (Fd with the hinge region) of a mouse
human chimeric Fab' against human urokinase-type plasminogen activator were fused
directly with the translation-start and signal-peptide-encoding regions of the
mwp gene, the gene for one of the major cell-wall proteins of Bacillus brevis.
The two fused genes were placed tandemly downstream from the promoter of the cell
wall protein gene operon (cwp) of B. brevis. For the production of scFab', the
two cDNAs were linked with a synthetic oligonucleotide encoding a flexible
peptide linker of 17 or 24 amino acids, and fused with the translation start and
signal-peptide-encoding regions of the mwp gene. Fab' was efficiently produced by
B. brevis, being accumulated at a level of 100 mg/l in the culture medium in a
simple shake-flask culture, which is the highest level obtained so far for a gram
positive bacterium. On the other hand, the scFab' remained at a level of a few
milligrams per liter in the culture medium. The Fab' produced by B. brevis showed
comparable antigen-binding activity to that of the parental antibody. The L chain
and Fd' fragment, constituting the Fab', had the correct N-terminal amino acid
sequences. These results indicate that B. brevis is a very promising host for the
production of native Ig fragments.
PMID- 9390458
TI - Competition of plasmid-bearing Pseudomonas putida strains catabolizing
naphthalene via various pathways in chemostat culture.
AB - Plasmid-carrying Pseudomonas putida strains degrade naphthalene through different
biochemical pathways. The influence of various combinations of host bacteria and
plasmids on growth characteristics and competitiveness of P. putida strains was
studied in chemostat culture at a low dilution rate (D = 0.05 h-1) with
naphthalene as the sole source of carbon and energy. Under naphthalene
limitation, the plasmid-bearing strains degrading naphthalene that use catechol
1,2-dioxygenase for catechol oxidation (ortho pathway), were the most
competitive. The strains bearing plasmids that control naphthalene catabolism via
catechol 2,3-dioxygenase (meta pathway), were less competitive. Under these
conditions the strain carrying plasmid pBS4, which encodes for naphthalene
catabolism via gentisic acid, was the least competitive.
PMID- 9390459
TI - Genetic immobilization of cellulase on the cell surface of Saccharomyces
cerevisiae.
AB - We tried genetically to immobilize cellulase protein on the cell surface of the
yeast Saccharomyces cerevisiae in its active form. A cDNA encoding FI
carboxymethylcellulase (CMCase) of the fungus Aspergillus aculeatus, with its
secretion signal peptide, was fused with the gene encoding the C-terminal half
(320 amino acid residues from the C terminus) of yeast alpha-agglutinin a protein
involved in mating and covalently anchored to the cell wall. The plasmid
constructed containing this fusion gene was introduced into S. cerevisiae and
expressed under the control of the glyceraldehyde-3-phosphate dehydrogenase
promoter from S. cerevisiae. The CMCase activity was detected in the cell pellet
fraction. The CMCase protein was solubilized from the cell wall fraction by
glucanase treatment but not by sodium dodecyl sulphate treatment, indicating the
covalent binding of the fusion protein to the cell wall. The appearance of the
fused protein on the cell surface was further confirmed by immunofluorescence
microscopy and immunoelectron microscopy. These results proved that the CMCase
was anchored on the cell wall in its active form.
PMID- 9390460
TI - Effect of growth rate on alpha-amylase production by Streptomyces sp. IMD 2679.
AB - The alpha-amylase of Streptomyces sp. IMD 2679 was subject to catabolite
repression. Four different growth rates were achieved when the organism was grown
at 40 degrees C and 55 degrees C in the presence and absence of cobalt, with an
inverse relationship between alpha-amylase production and growth rate. Highest
alpha-amylase yields (520 units/ml) were obtained at the lowest growth rate
(0.062 h-1), at 40 degrees C in the absence of cobalt, while at the highest
growth rate (0.35 h-1), at 55 degrees C in the presence of cobalt, alpha-amylase
production was decreased to 150 units/ml. As growth rate increased, the rate of
specific utilisation of the carbon source maltose also increased, from 46 to 123
micrograms maltose (mg biomass)-1 h-1. The pattern and levels of alpha
glucosidase (the enzyme degrading maltose) detected intracellularly in each case,
indicate that growth rate effectively controls the rate of feeding of glucose to
the cell, and thus catabolite repression.
PMID- 9390461
TI - Influence of phosphate on rhamnose-containing exopolysaccharide rheology and
production by Klebsiella I-714.
AB - Physiological conditions enhancing rhamnose-containing polysaccharide synthesis
by Klebsiella I-714 were studied in batch culture (0.3-l and 2-l bioreactors).
The four carbon sources tested, sucrose, sorbitol, Neosorb and Cerelose, allowed
exopolysaccharide production. Larger amounts of polymer were produced when high
carbon/nitrogen ratios and complex nitrogen sources were used. Exopolysaccharide
synthesis was greatest at 30 degrees C, which was a suboptimal growth
temperature. A reduction in the phosphate content of the medium enhanced rhamnose
containing polysaccharide production. When the initial carbon source
concentration was augmented, byproducts other than exopolysaccharide were formed.
Rhamnose-containing polysaccharide rheology can be modulated by changing the
phosphate content of the medium.
PMID- 9390462
TI - Relationship between cadmium sensitivity and degree of plasma membrane fatty acid
unsaturation in Saccharomyces cerevisiae.
AB - The sensitivity of Saccharomyces cerevisiae to the redox-active metal copper has
recently been found to be influenced by cellular fatty acid composition. This
study sought to investigate whether fatty acid composition affected plasma
membrane permeabilisation and whole-cell toxicity induced by the redox-inactive
metal cadmium. S. cerevisiae NCYC 1383 was enriched with the polyunsaturated
fatty acids linoleate (18:2) and linolenate (18:3) by growth in 18:2- or 18:3
supplemented medium. Incorporation of the exogenous fatty acids resulted in them
comprising more than 65% of the total fatty acids in plasma membrane lipids.
Inhibition of cell division in the presence of Cd(NO3)2 was accentuated by growth
in the presence of a polyunsaturated fatty acid. Furthermore, susceptibility to
Cd(2+)-induced plasma membrane permeabilisation increased with the degree of
fatty acid unsaturation. Thus, during exposure to Cd2+, K+ efflux from 18:2- and
18:3-enriched cells was up to 2.5-fold or 3-fold greater, respectively than that
from unsupplemented cells. In addition, reductions in cell viability during
exposure to Cd2+ were most marked in polyunsaturated-fatty-acid-supplemented
cells. At certain times, unsupplemented Cd(2+)-exposed cells displayed up to 7
fold greater viability than supplemented Cd(2+)-exposed cells. The study
demonstrates that the toxicity of the redox-inactive metal Cd2+ towards S.
cerevisiae becomes markedly amplified with increased cellular and plasma membrane
fatty acid unsaturation.
PMID- 9390463
TI - The ability of soil-borne fungi to degrade organophosphonate carbon-to-phosphorus
bonds.
AB - The ability of a wide variety of soil-borne fungal strains to degrade four
structurally different compounds containing P-C bonds, namely the naturally
occurring amino acid ciliatine, the popular herbicide glyphosate, phosphonoacetic
acid and 2-amino-3-phosphonopropionic acid, was studied in order to show that
soil fungi may play an important role in the biodegradation of
organophosphonates. Most of the strains appeared to utilize ciliatine as the sole
source of phosphorus for growth. Only a limited number of strains were able to
grow on the other phosphonates used in this work. The strains of Trichoderma
harzianum, Scopulariopsis sp. and Aspergillus niger chosen for more detailed
study show the ability to degrade ciliatine, glyphosate and also amino(3
methoxyphenyl)methylphosphonic acid effectively.
PMID- 9390464
TI - [The 33rd autumn meeting of the Japan Radiological Society. Nara City, Japan.
October 7-9, 1997. Abstracts].
PMID- 9390465
TI - [The 98th Congress of the Japanese Society of Otolaryngology. Ohsaka, Japan. May
22-24, 1997. Abstracts].
PMID- 9390466
TI - The Institute of Medical Illustrators and Glasgow Caledonian University BSc
degree in Medical Illustration.
AB - This paper relates the history leading to the validation of the Institute of
Medical Illustrators (IMI) Diploma as a part-time, work-based, Bachelor of
Science Degree by Glasgow Caledonian University (GCU) on the 11th June 1996. It
also outlines a description of the structure and content of this degree
programme. The BSc is a joint venture between GCU, who are the awarding academic
institution, and the IMI, who are the professional examining body. The Institute
hopes that it will become a standard qualification for the profession.
PMID- 9390467
TI - The Institute of Medical Illustrators and Glasgow Caledonian University BSc in
Medical Illustration assessment system.
AB - As a part-time work-based degree with students registered from all parts of the
United Kingdom, and potentially from abroad, the Bachelor of Science (BSc) in
Medical illustration does not have assessment in the conventional form as used by
full-time courses undertaken in a university. It incorporates the expertise of
medical illustrators actually working in the profession. The unique nature of the
Institute of Medical Illustrators (IMI) and Glasgow Caledonian University (GCU)
BSc has required the development of an assessment system that satisfies the
quality assurance demands of both the awarding and professional body. This paper
details the system devised to meet the needs of the provision and to ensure
consistent assessment.
PMID- 9390468
TI - 'Conversion course' to allow holders of the IMI Diploma in Medical Illustration
to gain a BSc in Medical Illustration from Glasgow Caledonian University.
AB - The 'conversion course' described in this paper has been set up following
discussions between the Institute of Medical Illustrators (IMI) and Glasgow
Caledonian University (GCU). The 'conversion course' will take the form of a
degree triple module with a credit rating of 60 Scottish Credit and Accumulation
Transfer (SCOTCAT) credits at Scottish Degree (SD) level 3. This module will
require the student to undertake an extended theoretical based investigative
project. The project will permit the student to study in-depth an aspect of
his/her specialist interest that has a particular professional relevance. The
topic of the project will be negotiated between the student and a scrutiny panel
under the aegis of the department of Biological Sciences at Glasgow Caledonian
University. The project will be written up in the style of an academic paper for
the Institute's journal. Successful students will be awarded the BSc in Medical
Illustration.
PMID- 9390469
TI - Using accreditation of prior learning and accreditation of prior experiential
learning for entry on to the BSc in Medical Illustration.
AB - The Accreditation of Prior Learning (APL) and Accreditation of Prior Experiential
Learning (APEL) scheme described in this paper has been prepared following
discussions between the Institute of Medical Illustrators (IMI) and Glasgow
Caledonian University (GCU), departments of Learning and Educational Development
and Biological Sciences. The scheme gives specific academic credit under the
Scottish Credit Accumulation and Transfer (SCOTCAT) scheme for learning gained
from experience, allowing access onto the Bachelor of Science Degree (BSc) in
Medical Illustration to potential students who do not have the required Higher
National Diploma (HND) or equivalent entry qualification. The need, rationale and
structure of the scheme are described.
PMID- 9390470
TI - Research for medical illustrators. Part 2: Trial design, protocols, results and
reporting.
AB - Medical illustrators have long been involved in the research projects of other
workers, by providing photographic and other visual records. These illustrations
may be used for measurement purposes, in which case it is important that medical
illustrators understand the requirements for using tested protocols, which ensure
that all variables of the recording medium are controlled. Now that there are
degree courses in medical illustration an increasing number of medical
illustrators in the UK are instigating their own research projects, making it all
the more important that they understand the research process. In this second of a
two-part article, consideration is given to: the design of experiments and
research trials; the production of research protocols; data analysis and
interpretation; the writing of the research report or dissertation; and the role
of the supervisor or mentor.
PMID- 9390471
TI - Thomas Albert Longmore, Hon FSR, FRPS (1905-1957).
PMID- 9390472
TI - From chromatograph to cuspid: dental clinical research and the future of
technology transfer.
PMID- 9390473
TI - Melvin L. Moss and the functional matrix.
PMID- 9390474
TI - Structural and functional association between substance P- and calcitonin gene
related peptide-immunoreactive nerves and accessory cells in the rat dental pulp.
AB - Defense mechanisms of the dentin/pulp complex involve a variety of biological
systems in which immunocompetent cells, the nervous system, and the vascular
supply play important roles. In the present study, pulpal accessory cells were
examined regarding (i) their structural relationship to nerves and (ii) how the
functional capacities of these cells were affected by neuropeptides. Micro
anatomic association was investigated in the normal rat molar pulp with the use
of double-immunofluorescence staining and dual-channel confocal laser scanning
microscopy. Examinations of confocal laser scanning microscopic images from
single focal planes revealed the presence of apparent contacts between thin,
varicose nerve fibers and immunocompetent cells, indicating proximity between
these two structures. The close associations were most frequently observed in the
para-odontoblastic region of the coronal pulp, where more than 70% of class II
antigen-expressing (OX6+) cells showed proximity to nerve fibers immunoreactive
to calcitonin gene-related peptide. The corresponding figure for substance P was
about 50%. ED2+ macrophages closely associated with nerves were less frequently
observed. Functional studies conducted in vitro demonstrated that 10(-9) to 10(
7) mol/L of substance P significantly increased (p < 0.05), while 10(-7) to 10(
6) mol/L of calcitonin gene-related peptide suppressed (p < 0.01) proliferation
of purified T-lymphocytes stimulated with sub-optimal concentrations of
concanavalin A in the presence of rat incisor pulpal cells as accessory cells.
These data suggest that pulpal sensory nerve fibers and their products may have
an influence upon the immune defense of the dental pulp.
PMID- 9390475
TI - HLA-D types and serum IgG responses to Capnocytophaga in diabetes and
periodontitis.
AB - Serum IgG responses to the cell envelope proteins (CEPs) from Capnocytophaga
sputigena, Capnocytophaga ochracea, and Capnocytophaga gingivalis were examined
in periodontally healthy and periodontitis subjects, both with and without type 1
diabetes (n = 60). Serum IgG responses to CEPs were determined by immunoblotting
with biotin-goat anti-human IgG and an alkaline phosphatase-streptavidin system.
Reactivity was analyzed by transmission densitometry, digitization, and computer
manipulation. The patients with diabetes showed significantly (p < 0.01) fewer
responses to 14 CEPs (from 81 to 10 kDa) from C. sputigena, 5 CEPs (from 90 to 17
kDa) from C. gingivalis, and the 27-kDa CEP from C. ochracea than in the non
diabetic group. The periodontitis patients showed significantly (p < 0.01) fewer
responses to the 25- and 11-kDa CEPs from C. sputigena, the 125- and 17-kDa CEPs
from C. gingivalis, and the 42-kDa CEP from C. ochracea than in the periodontally
healthy group. HLA-DR4, HLA-DR53, and HLA-DQw3 were associated with
periodontitis, while only HLA-DR4 was associated with diabetes (p < 0.02).
Significant (p < 0.01) correlations were found between HLA-DR2 and IgG reactivity
patterns associated with non-diabetics, and between HLA-DR4 and IgG reactivity
patterns associated with diabetic and periodontitis subjects. These results
indicate that both type 1 diabetics and periodontitis subjects have a depressed
IgG antibody profile to Capnocytophaga, which may account for an increased
susceptibility to periodontitis infection. Periodontitis in type 1 diabetes may
be related more to the HLA-D type and altered immune function than to the
diabetes itself.
PMID- 9390476
TI - Profile of cytokine mRNA expression in chronic adult periodontitis.
AB - Chronic inflammation induced by bacteria often leads to host-mediated destruction
of tissues adjacent to the sites of microbial insult. The chronic inflammatory
process of adult periodontitis results in the destruction of supporting osseous
and connective tissues of the teeth. We hypothesized that virulence factors of
periodontal pathogens such as lipopolysaccharide stimulate inflammatory cytokine
expression by mononuclear cells of the host which contribute to disease
development. In this study, to elucidate the role of these cytokines in chronic
adult periodontitis, we tested whether the prevalence of mRNA for inflammatory
cytokines generally associated with mononuclear phagocytes was higher in diseased
than in healthy gingival tissue. Gingival mononuclear cells or whole gingival
biopsies from 32 adult periodontitis patients and five healthy individuals used
as controls were evaluated for inflammatory cytokine mRNA expression by reverse
transcription polymerase chain-reaction (RT-PCR) procedures. The cytokines
assessed included IL-1 alpha, IL-1 beta, IL-1ra, IL-6, IL-8, IL-12, IL-13, TNF
alpha, TGF-beta, and IFN-gamma. The monocyte/macrophage lipopolysaccharide (LPS)
receptor CD14 was also assessed. Results showed that TNF-alpha mRNA was present
significantly more frequently in diseased than in healthy biopsies, whereas IL-1
alpha, IL-1 beta, and IL-1ra mRNA were found in most (from 80 to 100%) healthy
tissues. Message for CD14 was present in both healthy and diseased tissue samples
(100%). This study provides evidence for a major role of TNF-alpha in chronic
adult periodontitis. Moreover, our results suggest that the mononuclear cells
derived from periodontal tissues have the capacity to respond to components of
periodontal pathogens and express both pro- and anti-inflammatory cytokines in
these tissues.
PMID- 9390477
TI - Prevalence and distribution of six capsular serotypes of Porphyromonas gingivalis
in periodontitis patients.
AB - Previous reports have described six serotypes based on K antigens in
Porphyromonas gingivalis strains. The purpose of the present study was to
investigate the prevalence and distribution of these serotypes in 185 patients
with P. gingivalis-associated periodontitis. Polyclonal rabbit antisera, raised
against each of the different type strains, were used in double-immunodiffusion
and immunoelectrophoresis assays. In addition, a subset of 76 strains was
investigated for the presence of capsular structures by means of the India ink
and Bruce White staining techniques. These strains were also tested for auto
aggregation in phosphate-buffered saline (PBS). All six K serotypes were present
in the study sample. In total, 84 (45.4%) patients were colonized with a K
typeable P. gingivalis strain with a predominance of types K5 (12%) and K6
(23.2%). A correlation was found between arbitrary age categories and the
prevalence of currently known K serotypes, which were found in 60% of patients
aged 12 to 30 years, in 49% of patients aged 31 to 50, and in 25% of patients
aged 51 to 70 years. In the subset of 76 P. gingivalis strains, 32 (42.1%) were K
typeable. Fifty-three strains (69.7%) showed microscopic evidence of
encapsulation, suggesting the existence of K serotypes other than K1 to K6.
Twenty-one strains (27.6%) auto-aggregated in PBS and were not K-typeable, nor
did they show any evidence of encapsulation. It was concluded that the majority
of clinical P. gingivalis isolates is encapsulated and that encapsulation is
associated with the presence of a K antigen. Auto-aggregation seems to be
associated with the absence of a capsular structure and, consequently, the
absence of a K antigen.
PMID- 9390478
TI - Arrest of root surface caries in situ.
AB - This study tests the hypothesis that daily oral hygiene combined with topical
fluoride arrests active root-surface caries lesions without changing the mineral
content of the lesions. Therefore, changes in mineral content and distribution
were studied in root surfaces during caries lesion development and subsequent
arrest of lesion progression in situ. In 18 subjects, lesions were developed
during 3 months in sound root-surface specimens inserted into lower partial
dentures. After 3 months, ground sections were prepared from each lesion prior to
re-insertion of the specimens into the dentures. In addition, one sound root
specimen was added per subject. During the following 3 months, half of the
subjects cleaned both sound and carious specimens once a day with an 1100-ppm
fluoride toothpaste, and the specimens were treated twice with 2% NaF for 2 min
in situ. The other half of the subjects continued the experiment without
cleaning. During the initial three-month period, all specimens developed
subsurface lesions extending 187 to 583 microm into the dentin. Lesion depth
increased somewhat in both experimental groups during the following 3 months (P >
or = 0.1). There was a non-significant increase in mineral loss in the plaque
covered specimens (P = 0.08). However, the total mineral content of specimens
subjected to plaque removal and topical fluoride did not change. This treatment
resulted in an increased mineral content in the surface layer (P < 0.01) and
formation of a zone of higher mineral content within the body of the lesion. The
sound root surfaces which had been cleaned for a three-month period showed
mineral uptake in the surface layer, occasionally associated with subsurface
demineralization extending 20 to 70 microm into the tissue. The mineral loss of
these specimens was significantly smaller than that of plaque-covered surfaces (P
< 0.001). It is concluded that daily plaque removal and topical fluoride use
influence the distribution of mineral in sound and carious root surfaces and may
arrest lesion progression without affecting the total mineral content.
PMID- 9390479
TI - Prevalence and depth of artificial caries-like lesions adjacent to cavities
prepared in roots and restored with a glass ionomer or a dentin-bonded composite
material.
AB - One potential advantage of glass-ionomer materials for the treatment of root
caries is their ability to release fluoride and so resist cariogenic attack. A
commercially available composite material has also been reported to release
fluoride which reduced caries lesions in the tooth tissue adjacent to it. The aim
of this study was to assess the effectiveness of a conventional glass-ionomer
restoration compared with a dentin-bonded, fluoride-releasing, composite
restoration when exposed to a microbial artificial caries system. Artificial
caries-like lesions produced in relation to the restorations were examined and
classified either as outer (surface) lesions or as wall lesions. A split-unit
experimental design allowed for within-tooth comparisons of the 2 experimental
restorations at different sites on the root surface. These were either totally
within the root surface or positioned at the amelo-cemental junction. Outer
lesion depths were significantly (p < 0.001) shallower at all sites adjacent to
the glass ionomer when compared with the composite restorations. Wall lesions
were significantly (p < 0.01) more prevalent adjacent to the composite material.
In addition, the cavity margin position significantly (p < 0.05) affected the
incidence of wall lesions, particularly in the composite group. In conclusion,
glass ionomer was successful in reducing the caries-like lesion production in the
adjacent root surface. This resulted from improved marginal integrity and
fluoride release from this material when compared with the composite bonding
system used.
PMID- 9390480
TI - The relationship between clinical tooth status and receipt of sealants among
child Medicaid recipients.
AB - This study investigated the association between caries status and sealant need at
a prior survey and subsequent sealant use in a Medicaid program. Clinical data
from a 1986-87 statewide epidemiological survey (N = 8026) representative of
North Carolina (NC) schoolchildren (grades K-12) were linked with all NC Medicaid
dental claims submitted during 1987-92, yielding 570 children in the survey who
had at least one dental visit during 1987-1992. From the 570, 390 children were
included: 71 who received sealants (S) and 319 who received non-sealant care
(NS). Children were excluded based on age, having preexisting sealants, or having
no sealant-eligible molars or premolars. S and NS were compared on baseline dfs,
DMFS, and sealant need, controlling for the patient's age, number of visits, and
the provider's propensity to seal. At all ages, NS was twice as likely to have
had prior dfs or DMFS (OR = 2.04, 95% CI = 1.15, 3.70). The association between
sealant receipt and prior sealant need varied by age. At 6 to 11 years, S and NS
had equal likelihood of sealant need (OR = 1.41, 95% CI = 0.62, 3.18). At 12 to
15 years, NS had a greater likelihood of sealant need (OR = 6.82, 95% CI = 1.60,
29.08). Caries-free status was associated with subsequent sealant receipt. Prior
sealant need caused variability in dentists' decisions, depending on the child's
age and past caries experience. Sealants were used infrequently by most providers
and for a minority of patients. These findings are important for the Medicaid
program and for future non-randomized studies of sealant effectiveness.
PMID- 9390481
TI - Connections between polarization curves and log(a[i]/a[ref])-pe diagram.
AB - When reading papers concerning studies of corrosion of dental amalgam and its
phases by means of polarization curves, one often finds it difficult to
understand the reasons for the chemical reactions proposed from the form of the
polarization curve. Thermodynamic data represented in the form of
log(a[i]/a[ref])-pe diagrams, i.e., the logarithm of the activity of a metal or
an alloy with reference to the activity of the corresponding metal ion, as a
function of pe (a recalculated form of the potential), make it possible for one
to determine which chemical reactions can occur on the specimen surface or in the
solution within the potential difference used in the polarization experiment and
to decide which of these reactions is the most probable. The hypothesis examined
in this study is that a log(a[i]/a[ref])-pe diagram can be used in the
interpretation of polarization curves. Potentiodynamic polarization curves and
log(a[i]/a[ref])-pe diagrams were compared for the corrosion of Ag, Hg, and gamma
1 with and without Sn. It was found that there was a connection between the
polarization curves and the log(a[i]/a[ref])-pe diagrams. From the composition of
the specimens and the solution and by means of thermodynamic data, pe values for
solid corrosion products and relative concentrations of soluble complexes at
these pe values were obtained independently of the polarization curves. A much
more reliable value for the nobility of metals and alloys was attained by use of
the log(a[i]/a[ref])-pe diagrams than by use of the potential of the starting
point of the polarization curves. It was found that pe corresponding to the
potential of the starting point of the polarization curves in de-aerated
synthetic saliva was obtained about two pe units before pe of the most insoluble
solid compound formed on the specimen surface or in the solution.
PMID- 9390482
TI - Paint the ceiling: reflections on illness.
PMID- 9390483
TI - Multicenter, randomized, prospective trial of early tracheostomy.
AB - OBJECTIVES: Determine the effect of early (days 3-5) or late (days 10-14)
tracheostomy on intensive care unit length of stay (ICU LOS), frequency of
pneumonia, and mortality, and evidence of short-term or long-term pharyngeal,
laryngeal, or tracheal injury in head trauma, non-head trauma, and critically ill
nontrauma patients. STUDY DESIGN: Randomized, prospective. SETTING: Five Level I
trauma centers. METHODS: Data were obtained prospectively and included Acute
Physiology and Chronic Health Evaluation III score (AIII), Glasgow Coma Scale
score, Emergency Room Trauma Score, Injury Severity Score, Acute Injury Score,
type of endotracheal tube or tracheostomy, level of positive end-expiratory
pressure, and peak inspiratory pressure. Patients were to undergo laryngoscopy
for detection of injury according to the Lindholm criteria at the time of
endotracheal tube or tracheostomy removal and be reevaluated at 3 to 5 months
after discharge. RESULTS: One hundred fifty-seven patients were entered, 127 to
early randomization (3-5 days) and 28 to late randomization (10-14 days);
however, only 112 patients with early and 14 with late randomization had
completed data forms for the primary study goals. An additional 22 patients from
the early entry groups were rerandomized late. Early randomization data: the AIII
score was higher (p < 0.05) in the head trauma tracheostomy (65 +/- 4) than in
the nontracheostomy group (51 +/- 4) and in the nontrauma tracheostomy (92 +/- 6)
than in the nontracheostomy group (68 +/- 7), but was equivalent in the non-head
trauma group. Glasgow Coma Scale score, Emergency Room Trauma Score, Injury
Severity Score, Acute Injury Score, positive end-expiratory pressure, and peak
inspiratory pressure were not significantly different in any of the groups. There
were no significant differences in ICU LOS, frequency of pneumonia, or death in
any of the groups after either early or late tracheostomy compared with continued
endotracheal intubation. Only 83 patients underwent postextubation laryngoscopy.
There were no significant differences between the groups; however, there were
trends to more vocal cord ulceration and subglottic inflammation in the continued
intubation group. No patient was seen in this study with late vocal cord or
laryngeal stenosis; there were no tracheal-innominate artery fistulae. Seven of
the patients with abnormal findings at extubation had normal 3- to 5-month
postextubation laryngoscopy. CONCLUSION: Physician bias limited patient entry
into the study. Although there were higher AIII scores in the head trauma early
tracheostomy patients, there were no differences in the primary end points of ICU
LOS, pneumonia, or death in any of the groups studied. Long-term endoscopic
follow-up was poor, but no known late tracheal stenosis was seen.
PMID- 9390484
TI - Nonoperative management of splenic injury: are follow-up computed tomographic
scans of any value?
AB - OBJECTIVE: To determine the value of follow-up abdominal computed tomography in
patients with splenic trauma managed nonoperatively. DESIGN: Retrospective chart
review. MATERIALS AND METHODS: A total of 108 consecutive patients with splenic
injuries treated at a single institution from 1990 to 1996 were studied. All
admission and follow-up computed tomographic (CT) scans were reviewed by the
authors. RESULTS: Initial management was surgical in 35 patients (32%) and
intentionally nonoperative in 73 patients (68%). Nonoperative management was
successful in 45 of 49 adults (92%) and 21 of 24 children(88%). Sixty-two follow
up abdominal CT scans were obtained in 49 patients. Information that affected
management was evident on only one follow-up CT scan performed in the absence of
clinical indications. Potential savings in hospital and physician charges for
routine follow-up CT scans in this study were $54,302.00. CONCLUSIONS: Follow-up
abdominal CT scans are not routinely necessary in patients with splenic injuries
managed nonoperatively.
PMID- 9390485
TI - Cost-effective method for bedside insertion of vena caval filters in trauma
patients.
AB - BACKGROUND: The need for patient transport for inferior vena cava (IVC) filter
placement impacts patient safety, comfort, charges, and nursing care. Bedside,
ultrasound-guided IVC filter placement may offer an acceptable, cost-effective
alternative. METHODS: Prospective cohort study of 55 consecutive trauma patients
requiring IVC filter placement. During a 13-month period (August of 1995
September of 1996), patients meeting criteria for IVC filter were evaluated.
Complications were recorded, and the potential financial savings were determined.
RESULTS: Of 3,172 trauma admissions, 55 patients met IVC filter criteria and 49
patients had IVC filters placed under ultrasound guidance. In six patients
(10.9%), ultrasound guided filter placement failed. There were four complications
in four patients (8.2%). Over 13 months, charges were reduced by $69,800 when
compared with radiology suite placement and $118,300 when compared with operative
placement. CONCLUSIONS: Ultrasound guided, bedside placement of IVC filters is a
safe, cost-effective method of pulmonary embolism prophylaxis in select trauma
patients.
PMID- 9390486
TI - Secretory immunoglobulin A blocks hypoxia-augmented bacterial passage across
Madin-Darby canine kidney cell monolayers.
AB - OBJECTIVE: To study the relative impact of previous hypoxic exposure and the
addition of secretory immunoglobulin A (IgA) on bacterial translocation. DESIGN:
In vitro randomized experimental study. MATERIALS AND METHODS: Transfected Madin
Darby canine kidney epithelial cells were grown as monolayers in a two-chamber
tissue culture system. Stationary growth phase Escherichia coli M14 were
inoculated in the apical chamber with medium or medium containing polymeric
secretory IgA. Tissue culture dishes were then placed in a 21 or 5% O2 incubator
environment for 90 minutes followed by a 21% O2 environment. Medium from the
basal compartment was then obtained at timed intervals for bacterial culture.
MEASUREMENT AND MAIN RESULTS: Bacterial translocation increased with time in co
culture. Previous hypoxic exposure augmented translocation across the monolayers.
The addition of IgA blocked translocation under both normoxic and hypoxic
conditions. CONCLUSION: Secretory IgA is important in mucosal defense under both
normal and shock conditions.
PMID- 9390487
TI - Posttraumatic empyema thoracis: a 24-year experience at a major trauma center.
AB - The purpose of this paper is to review the outcome of patients with posttraumatic
empyema thoracis. Between April 1972 and March 1996, the Division of
Cardiothoracic Surgery at the King-Drew Medical Center managed or was consulted
on 5,474 trauma patients (4,584 patients with penetrating injuries and 890 with
blunt injuries) who were admitted emergently for thoracic and thoracoabdominal
injuries and who underwent tube thoracostomy. Patients were not given routine
prophylactic antibiotics merely because they had a chest tube placed. Based on
our previous reports on thoracic trauma, our criteria for empiric antibiotic
administration included (1) emergent or urgent thoracotomy, (2) soft-tissue
destruction of the chest wall by shotgun injuries, (3) lung contusion with
hemoptysis, (4) associated abdominal trauma requiring exploratory laparotomy, or
(5) associated open long-bone fractures. Eighty-seven of these 5,474 patients
developed posttraumatic empyema thoracis, for an incidence of 1.6%. These 87
patients were treated with tube thoracostomy, image-guided catheter drainage, or
open thoracotomy with decortication. Seventy-nine of 87 patients (91%) were cured
without conversion to open thoracostomy. Four patients required conversion to
open thoracostomy, and there were three deaths. Even though a majority of our
patients required decortication, successful management of posttraumatic empyema
thoracis also was achieved with closed-tube thoracostomy or image-guided catheter
drainage based on clinical and radiographic findings with appropriate patient
selection. When thoracic empyema did occur in our group, Staphylococcus aureus
was the most common microbe isolated, followed by anaerobic bacteria. In
correlating microbiologic data with outcomes, S. aureus, especially methicillin
resistant S. aureus, was the most frequent cause of antibiotic failure. Because
of the low incidence of posttraumatic empyema thoracis, we do not recommend
routine antibiotic prophylaxis for all trauma patients who undergo closed-tube
thoracostomy. A review of the role of tube thoracostomy, intrapleural
fibrinolytic therapy, image-guided catheter drainage, video-assisted
thoracoscopy, and open thoracotomy for the management of thoracic empyema is
provided.
PMID- 9390488
TI - The importance of the command-physician in trauma resuscitation.
AB - OBJECTIVE: Definitive trauma team leadership, although difficult to measure, has
been shown to improve trauma resuscitation performance. The purpose of this study
was to evaluate the effect of an identified command-physician on resuscitation
performance. In addition, the leadership capability of four physician
combinations functioning as command-physician was studied. DESIGN: Retrospective
review. METHODS: Videotapes of trauma resuscitations performed at a Level I
trauma center over a 25-month period were reviewed. The presence of an identified
command-physician was determined by multidisciplinary consensus. Resuscitation
performance was measured by compliance with three objective criteria: primary
survey, secondary survey, and definitive plan; and two subjective criteria:
orderliness, and adherence to Advanced Trauma Life Support protocol. Performance
was then analyzed (1) as a function of the presence or absence of a command
physician, and (2) between four identified physician combinations: AF (attending
surgeon + trauma fellow); F (trauma fellow); ASR (attending surgeon + senior
surgical resident); SR (senior surgical resident). Chi square and the Mann
Whitney U tests were applied. RESULTS: A total of 425 trauma resuscitations were
reviewed. A command-physician was identified (CP[Pos]) in 365 resuscitations
(85.7%); no command-physician was identified (CP[NEG]) in 60 (14.3%). Compliance
with completion of secondary survey (81.4%) and formulation of a definitive plan
(89.6%) was significantly higher in the CP(POS) group. Subjective scores for
orderliness and adherence to Advanced Trauma Life Support protocol were
significantly higher in the CP(POS) group. In the CP(POS) resuscitations,
formulation of a definitive plan was lower in SR when compared with the other
three physician combinations. CONCLUSIONS: An identified command-physician
enhances trauma resuscitation performance. Completion of the primary and
secondary survey is not affected by the physician combination. Prompt formulation
of a definitive plan is facilitated by the active involvement of an attending
traumatologist or a properly mentored trauma fellow.
PMID- 9390489
TI - Complications of plate fixation in fresh displaced midclavicular fractures.
AB - BACKGROUND: The role of plate fixation in the management of fresh displaced
midclavicular fractures is unsettled. The objective of this study was to evaluate
the drawbacks and pitfalls of this treatment method. METHODS: We analyzed the
complications encountered in 103 consecutive adult patients with severely
displaced fresh fractures of the middle third of the clavicle who were treated by
open reduction and internal fixation using AO/ASIF plates. These 103 patients
accounted for 9.5% of the 1,081 patients with fresh midclavicular fractures seen
between 1989 and 1995. The mean age of the 103 patients was 33.4 years (range, 19
62 years). RESULTS: Seventy-nine patients had an uneventful recovery, whereas 24
(23%) suffered one or several complications. The major complications included
deep infection, plate breakage, nonunion, and refracture after plate removal. The
most common of the minor complications was plate loosening resulting in malunion.
The infection rate was 7.8%. A total of 14 reoperations were performed because of
the complications. Permanent nonunion ensued in two patients. A severely
comminuted fracture (relative risk of failure, 5.15) as well as a state of
alcohol intoxication on admission (relative risk of failure, 3.12) were
identified as markers of increased complication risk. CONCLUSIONS: Patient
noncompliance with the postoperative regimen could be suspected to have been a
major cause of the failures. The high complication rate supports a reserved
attitude toward plate fixation of fresh midclavicular fractures. The method
should be reserved for patients who have trustworthy personal motives for quick
pain relief and functional recovery.
PMID- 9390490
TI - Free fibula osteoseptocutaneous graft for reconstruction of segmental femoral
shaft defects.
AB - Seventeen major reconstructions of the femoral shaft using vascularized fibula
osteoseptocutaneous grafts were performed from August 1984 to September 1993.
Patients were 14 males and 3 females, with an average age of 34 years. All
patients had sustained high-energy trauma in motor vehicle crashes and had bone
defects averaging 10 cm. The skeletal defect was primary attributable to bone
loss at the time of injury (2 cases) or secondary after infection and
sequestrectomy (15 cases). Vascularized fibular transfer was performed at an
average of 6 months after trauma. The fibular graft was inserted as a single
strut in 10 cases and as a double-barrel composite in 7 cases. Patients were
evaluated at an average of 43 months after surgery. All grafts eventually united,
and no patient showed evidence of recurrent or persistent infection. The average
time to radiologic union was 8 months, and the average time to full weight
bearing was 14 months. Secondary bone grafting and internal fixation were
required in five cases because of delayed union, stress fracture, or screw
loosening. All cases of delayed union and stress fracture were in those
reconstructed by single-strut fibular graft. Four cases (24%) required quadriceps
plasty and arthrolysis. The final average arc of active knee motion was from 0 to
80 degrees. Limb length discrepancy ranged from 0 to 7 cm (average, 3 cm). Five
cases (29%) had varus deformity averaging 30 degrees. The fibular graft
hypertrophied to 100% of the femoral circumference in cases followed for 3 years.
Donor site morbidity was negligible. At the time of final follow-up, 13 patients
had returned to their original jobs, two were permanently disabled because of
below-knee amputation, and two were retired. The study suggests that vascularized
fibula osteoseptocutaneous transfer is a valuable procedure for reconstruction of
large, previously infected femoral shaft defects.
PMID- 9390491
TI - Staged management of infected humeral nonunion.
AB - Fourteen patients with infected humeral nonunion complicated by sinus discharge
were treated with a staged protocol consisting of (1) radical debridement with
local antibiotic beads implantation, and (2) external skeletal fixation with
autologous bone grafting. In the first stage, a thorough debridement and
sequestrectomy were done. Antibiotic beads were used to obliterate the bone
defect, and the wound was then directly closed. In the second stage, the bead
chains were replaced with autogenous cancellous bone graft. Unilateral Hoffman
external skeletal fixators were applied simultaneously. The mean follow-up period
was 73.6 months (range, 29 months to 9 years). The length of time to achieve bony
union ranged from 3.5 to 8 months (average, 4.3 months). Hoffman pin complication
was found in two cases, which were then shifted to plate internal fixation. All
the infections were eradicated, and the wounds healed without further skin graft
or flap coverage. All the fractures achieved bony union except for one in a
patient who died. Most patients acquired satisfactory function of elbow motion
after removal of external fixation and physical therapy. The method of two-stage
management was effective for infected humeral nonunion. Not only was the
infection eradicated and osseous union achieved, but also the limb function and
joint motion were preserved.
PMID- 9390492
TI - Effect of heating on extracellular bioactive substances in stored human blood: in
vitro study.
AB - BACKGROUND: We have previously shown extracellular accumulation of various
leukocyte and platelet-derived bioactive substances in human blood during
storage. Release of bioactive substances may be temperature-dependent, and we
studied the effect of heating during in vitro transfusion on bioactive substance
accumulation in stored human blood. METHODS: Eight units of whole blood and eight
units of prestorage leukofiltered whole blood were stored at 4 degrees C for 7
days. Subsequently, the blood from all 16 units was transfused via a blood
heating device, which increased the blood temperature to 37 degrees C at outlet.
Samples for enzyme-linked immunosorbent assay or radioimmunoassay analyses of
histamine, myeloperoxidase (MPO), eosinophil cationic protein (ECP), and
plasminogen activator inhibitor-1 (PAI-1) were drawn from the units at donation,
after 7 days of storage just before transfusion, and during the in vitro
transfusion. RESULTS: Extracellular concentrations of histamine, MPO, ECP, and
PAI-1 were significantly (p < 0.05) increased in nonfiltered whole blood stored
for 7 days compared with concentrations in fresh donated blood and in prestorage
leukofiltered whole blood stored for 7 days. Heating reduced histamine, MPO, and
ECP concentrations significantly (p < 0.05) in nonfiltered whole blood, whereas
PAI-1 concentrations increased significantly (p < 0.05). Finally, there was no
difference in concentrations of histamine, MPO, ECP, and PAI-1 in samples
collected before and after heating of leukofiltered whole blood. CONCLUSIONS:
Heating reduces accumulation of extracellular leukocyte-derived bioactive
substances in whole blood, whereas it increases platelet-derived substances.
Prestorage leukofiltration, however, reduces the obligatory extracellular
accumulation of leukocyte and platelet-derived bioactive substances, which in
addition is unchanged by heating.
PMID- 9390493
TI - Optimized mesh expansion of composite skin grafts in rats treated with direct
current.
AB - BACKGROUND: The purpose of this study was to determine the optimum autoepidermal
and allodermal expansion ratio of each component of a meshed composite skin graft
(MCSG) that would lead to successful healing. METHODS: Male Sprague-Dawley rats
were used as hosts of the MCSG and donors of autologous tissue. Male ACI rats
were used as donors of allodermis. MCSGs with open meshed area
(autoepidermal/allodermal) of 9:1/1.5:1, 9:1/3:1, 9:1/6:1, or 6:1/6:1 were
applied to full-thickness skin defects and treated with a silver nylon dressing
(SN) or SN with direct current (DC). Wound size, hair regrowth, and thickness of
dermal layer were evaluated at 3 months. RESULTS: MCSGs of 9:1/1.5:1, 9:1/3:1,
and 6:1/6:1 mesh ratios healed completely within 3 months with no difference in
wound size between SN dressing groups or DC-treated groups. Application of DC
reduced MCSG contraction and stimulated regrowth of hair. CONCLUSION: Fresh
autoepidermis can be expanded 6:1 on a 6:1 allodermis or 9:1 on a 3:1 allodermis
and achieve successful wound healing.
PMID- 9390494
TI - Biodistribution of indocyanine green in a porcine burn model: light and
fluorescence microscopy.
AB - BACKGROUND: Infrared-excited fluorescence of intravenously administered
indocyanine green (ICG) is being used as a method of early determination of burn
depth. METHODS: Fluorescence microscopy and tissue fluorescence were recorded in
a porcine burn model and correlated to burn severity and age. RESULTS: Recently
placed superficial burns show significant fluorescence compared with adjacent
normal tissue as a result of a strong inflammatory reaction in the superficial
dermis with minimal vascular occlusion. The magnitude of the inflammatory
reaction decreases with time. For deeper burns, vascular occlusion prevents
transport of ICG into the burn and the intensity of ICG fluorescence in burn
eschar is negligible. CONCLUSION: The intensity of ICG fluorescence measured at
the surface of the wound for burns of similar age was shown to decrease
exponentially with the depth of the burn. The enhanced fluorescence of partial
thickness burns is attributable to increased permeability, and the decreased
signal associated with deeper injuries is attributable to vascular occlusion.
These results suggest that it is possible to differentiate burns that will heal
spontaneously with minimal granulation from those that will not by measuring the
intensity of ICG fluorescence.
PMID- 9390495
TI - Practice patterns of pediatric surgeons caring for stable patients with traumatic
solid organ injury.
AB - BACKGROUND: Managed care financing has resulted in pressure to decrease hospital
days and lower per diem costs. This influence may ultimately affect nonoperative
management of blunt solid organ injuries in children (spleen, liver, kidneys).
METHODS: Pediatric surgeons caring for trauma patients were surveyed regarding
current practice patterns. One survey was sent to a representative staff
pediatric surgeon at each major children's hospital or children's unit involved
in the care of the injured child in the United States. RESULTS: There were 87
responses to 117 surveys (75%). Relatively few children fail nonoperative
management. For major management decisions, including radiographic study of
choice; when to transfuse; and when to allow out of bed, home, and back to
school, there was often a clear majority opinion of appropriate care. However,
there was a wide variance in response for some questions. CONCLUSIONS: Surgical
judgment must be individualized, but a low number of failures of nonoperative
management is helpful in delineating safe practice guidelines. Surgeons using
fewer resources than the norm may help delineate management schemes that are
equally effective to more expensive care. Based on these responses a management
protocol is recommended.
PMID- 9390496
TI - Geographic variation in serious nonfatal firearm injuries in Pennsylvania.
AB - OBJECTIVE: The purpose of this study was to characterize the geographic
epidemiology of serious nonfatal firearm injuries (NFFI) within Pennsylvania
during a 6-year period. METHODS: A historical review of data from the
Pennsylvania Trauma System Foundation trauma registry was completed using county
level data. Based on a format adapted from the United States Department of
Agriculture, NFFI in Pennsylvania were classified by their county of occurrence:
central city counties, metropolitan counties, nonmetropolitan counties, or rural
counties. Population-based rates of NFFI were then calculated, as were NFFI as a
proportion of the number of injuries within each region. These rates were
stratified by intent of injury, scene of injury, and type of firearm. RESULTS: A
total of 100,703 trauma cases were reported to the Pennsylvania Trauma System
Foundation from 1988 through 1993, of which 5,847 were serious NFFI. Nonfatal
firearm assaults increased from rural counties to central city counties, whereas
unintentional NFFI decreased (p < 0.05). A 225% increase in the number of NFFI,
from 445 cases in 1988 to 1,004 cases in 1993, was noted in the central city
counties. Comparatively, the increase in the noncity regions was 145%, from 182
cases in 1988 to 263 in 1993. Nonfatal firearm injuries occurred most often at
home in noncity counties (rural, nonmetropolitan, and metropolitan counties)
(47.9%). This is in contrast to central city counties, where NFFI occurred
significantly more often in the street (53.5%) (p < 0.05). Handgun NFFI
increased, whereas rifle NFFI decreased, from rural counties to central city
counties (p < 0.05). Relative to population size, the risk of shotgun injuries
was greatest in central city counties and lowest in rural counties. Shotgun
injuries also accounted for a significantly longer hospital stay (15.06 days)
compared with handgun injuries (10.38 days) and rifle injuries (11.81 days) (p <
0.05). CONCLUSION: Significant variation in NFFI was observed across population
based regions in Pennsylvania. Rural areas demonstrated relatively high risks of
NFFI committed unintentionally, in the home, and with rifles. As regional
populations increase, relatively high risks of NFFI, committed as assaults, in
the street, and by handguns, are highlighted. Although handguns were the most
prominent firearm associated with NFFI, nonfatal shotgun injuries produced
substantially longer hospital stays and may be an underappreciated cause of
nonfatal firearm assaults in the urban setting.
PMID- 9390497
TI - Reproducibility of preventable death judgments and problem identification in 60
consecutive road trauma fatalities in Victoria, Australia. Consultative Committee
on Road Traffic Fatalities in Victoria.
AB - BACKGROUND: Since 1992, the Consultative Committee on Road Traffic Fatalities in
Victoria has identified problems in the management of traffic fatalities. Its two
evaluative committees have additionally assessed the potential preventability of
death. Previous studies have shown only poor to fair reproducibility of death
judgments. METHODS: Problems in the management of 60 consecutive road traffic
fatalities and the potential preventability of death were independently evaluated
by the two committees. Inter-rater and inter-committee concordance were analyzed
using the kappa statistic. RESULTS: Reproducibility was high. Inter-committee
agreement on nonpreventable, potentially preventable, and preventable death
judgments was high (kappa = 0.73, 95% confidence interval = 0.57-0.89). Agreement
within the two evaluative committees was also high (average weighted kappa = 0.73
and 0.74). There was good agreement between committees on problems identified,
including those contributing to death. CONCLUSION: The high kappa concordance on
preventable death judgments and the agreement on problem identification supports
the reproducibility of the methodology used.
PMID- 9390498
TI - Bilateral craniotomies for blunt head trauma.
AB - Development of delayed or recurrent intracranial hematomas requiring
reexploration or a secondary craniotomy is well known. Patients with bilateral
pathology requiring bilateral craniotomies as the initial emergency operative
intervention, however, are uncommon. The lack of available literature and the
large volume of head trauma seen at our institution prompted us to analyze the
retrospective data on blunt head injury requiring bilateral craniotomies. Twenty
patients underwent bilateral craniotomies at the University of Miami/Jackson
Memorial Medical Center between January 1986 and June 1994. Ages ranged from 18
to 85 years. Mechanism of injury included motor vehicle crash (n = 4), pedestrian
hit by automobile (n = 4), assault (n = 8), fall from height (n = 3), and unknown
(n = 1). Epidural hematomas, acute subdural hematomas, contusions, and
intracerebral hematomas were seen in varying combinations. The preoperative
Glasgow Coma Scale (GCS) score ranged from 4 to 14, with a mean of 8.8 (+/-0.82
SE). Sixteen of the 20 patients survived and were discharged from the hospital.
The survivors' Rancho Los Amigos Scale score on discharge ranged from 2 to 8,
with a mean of 6.1 (+/-0.45 SE). A Fisher's exact test was performed to compare
the outcome between the patients with mild (GCS score 13-15) to moderate (GCS
score 9-12) head injury and those with severe (GCS score 4-8) head injury. It
showed a statistically higher frequency of death in the severe category (p <
0.05). In conclusion, the outcome of patients with bilateral pathology requiring
emergency bilateral craniotomy at initial treatment correlated well with their
GCS scores at initial presentation.
PMID- 9390499
TI - Outcome of blunt thoracic aortic injury in a level I trauma center: an 8-year
review.
AB - BACKGROUND: The purpose of this study was to evaluate our experience with blunt
thoracic aortic injury and identify factors predictive of outcome. METHODS:
Hospital charts, trauma registry data, and autopsies of 64 patients with blunt
thoracic aortic injury from 1988 to 1995 were reviewed. RESULTS: Patients were
identified and segregated based on admission physiology. Group 1 patients (n =
19) arrived in arrest. Group 2 patients (n = 10) arrived in shock with systolic
BP 90. Group 3 patients (n = 35) arrived with systolic BP>90. All patients in
groups 1 and 2 expired. Injury Severity Scores for nonsurvivors in group 3 (n =
12) were significantly higher than survivors. There were no significant
differences when comparing time of injury to repair or arrival between groups, or
in mortality or paralysis comparing repair techniques or clamp/bypass times.
Double lumen endotracheal tubes caused significant operative delays compared to
single lumen tubes. CONCLUSIONS: Predictors of survivability were hemodynamic
stability on arrival and lower Injury Severity Scores. In thoracic aortic injury
patients arriving hemodynamically stable, Injury Severity Score correlated with
mortality but not paralysis.
PMID- 9390500
TI - Splanchnic ischemia and bacterial translocation in the abdominal compartment
syndrome.
AB - BACKGROUND AND METHODS: Major trauma or abdominal injury may lead to the
development of increased intra-abdominal pressure (IAP) and the onset of the
abdominal compartment syndrome. Although the effect of raised IAP on systemic and
splanchnic hemodynamics have been described, the consequences of the resultant
gut hypoperfusion in this setting are unknown. Bacterial translocation (BT)
occurs after a period of splanchnic ischemia and may contribute to later organ
failure. A rodent model was used to examine the effect of raised IAP on ileal
mucosal blood flow (MBF) and BT. IAP was increased to 25 mm Hg for 60 minutes and
mean arterial blood pressure was maintained with fluid. Animals were killed 24
hours later and examined for BT. RESULTS: Increased IAP resulted in a decrease of
MBF to 63% of baseline despite maintaining normal mean arterial blood pressure.
BT occurred principally to the mesenteric lymph nodes after 60 minutes of IAP at
25 mm Hg. CONCLUSIONS: Increased IAP leads to decreased MBF and to BT, which may
contribute to later septic complications and organ failure.
PMID- 9390501
TI - A case of deep laceration of the lung treated with video-assisted thoracic
surgical lobectomy: case report.
PMID- 9390502
TI - Three-year follow-up of a posttraumatic right coronary aneurysm.
AB - Posttraumatic saccular aneurysm of the right coronary artery is a rare
complication of nonpenetrating chest trauma. We observed a posttraumatic coronary
aneurysm for 3 years and noted that the aneurysm has changed in shape, with
partial obliteration of the aneurysm sac, and that its clinical course was
uneventful with conservative treatment. Surgical removal of aneurysms has been
advocated in the literature; however, conservative medical treatment and a wait
and-see policy can be considered as a treatment modality for posttraumatic
coronary aneurysm.
PMID- 9390503
TI - Aortoiliac dissection after blunt abdominal trauma: case report.
AB - The distal abdominal aorta is rarely injured after blunt trauma but a direct blow
to the abdomen from a seatbelt or handlebars may cause intimal dissection or
rupture. We present the diagnosis and surgical management of aortoiliac
dissection in a 16-year-old boy injured in a motorcycle accident. The technical
aspects of vascular repair are emphasized.
PMID- 9390504
TI - Intrathoracic migration of a Kirschner wire: case report.
PMID- 9390505
TI - Pelvic injuries in equestrians on buck-jumping horses.
PMID- 9390506
TI - Laterally based skin flap for below-knee amputation: case report.
PMID- 9390507
TI - How hearing happens.
PMID- 9390508
TI - Fish n' chicks: model recipes for hair-cell regeneration?
PMID- 9390509
TI - Myosin and adaptation by hair cells.
PMID- 9390510
TI - Encoding of timing in the brain stem auditory nuclei of vertebrates.
PMID- 9390511
TI - Distributed time-domain representations in the birdsong system.
PMID- 9390512
TI - A turning point in schizophrenia genetics.
PMID- 9390513
TI - Xath5 participates in a network of bHLH genes in the developing Xenopus retina.
AB - We examined the function of basic-helix-loop-helix (bHLH) transcription factors
during retinal neurogenesis. We identified Xath5, a Xenopus bHLH gene related to
Drosophila atonal, which is expressed in the developing Xenopus retina. Targeted
expression of Xath5 in retinal progenitor cells biased the differentiation of
these cells toward a ganglion cell fate, suggesting that Xath5 can regulate the
differentiation of retinal neurons. We examined the relationship between the
three bHLH genes Xash3, NeuroD, and Xath5 during retinal neurogenesis and found
that Xash3 is expressed in early retinoblasts, followed by coexpression of Xath5
and NeuroD in differentiating cells. We provide evidence that the expression of
Xash3, NeuroD, and Xath5 is coupled and propose that these bHLH genes regulate
successive stages of neuronal differentiation in the developing retina.
PMID- 9390514
TI - Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role
in peripheral nerve projection in mice.
AB - Neuropilin is a neuronal cell surface protein and has been shown to function as a
receptor for a secreted protein, semaphorin III/D, that can induce neuronal
growth cone collapse and repulsion of neurites in vitro. The roles of neuropilin
in vivo, however, are unknown. Here, we report that neuropilin-deficient mutant
mice produced by targeted disruption of the neuropilin gene show severe
abnormalities in the trajectory of efferent fibers of the PNS. We also describe
that neuropilin-deprived dorsal root ganglion neurons are perfectly protected
from growth cone collapse elicited by semaphorin III/D. Our results indicate that
neuropilin-semaphorin III/D-mediated chemorepulsive signals play a major role in
guidance of PNS efferents.
PMID- 9390515
TI - Synaptic clustering of Fascilin II and Shaker: essential targeting sequences and
role of Dlg.
AB - Previous studies have shown that both the Fasciclin II (Fas II) cell adhesion
molecule and the Shaker potassium channel are localized at the Drosophila
neuromuscular junction, where they function in the growth and plasticity of the
synapse. Here, we use the GAL4-UAS system to drive expression of the chimeric
proteins CD8-Fas II and CD8-Shaker and show that the C-terminal sequences of both
Fas II and Shaker are necessary and sufficient to drive the synaptic localization
of a heterologous protein. Moreover, we show that the PDZ-containing protein
Discs-Large (Dlg) controls the localization of these proteins, most likely
through a direct interaction with their C-terminal amino acids. Finally,
transient expression studies show that the pathway these proteins take to the
synapse involves either an active clustering or a selective stabilization in the
synaptic membrane.
PMID- 9390516
TI - Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates
photoreceptor cell-specific genes.
AB - The otd/Otx gene family encodes paired-like homeodomain proteins that are
involved in the regulation of anterior head structure and sensory organ
development. Using the yeast one-hybrid screen with a bait containing the Ret 4
site from the bovine rhodopsin promoter, we have cloned a new member of the
family, Crx (Cone rod homeobox). Crx encodes a 299 amino acid residue protein
with a paired-like homeodomain near its N terminus. In the adult, it is expressed
predominantly in photoreceptors and pinealocytes. In the developing mouse retina,
it is expressed by embryonic day 12.5 (E12.5). Recombinant Crx binds in vitro not
only to the Ret 4 site but also to the Ret 1 and BAT-1 sites. In transient
transfection studies, Crx transactivates rhodopsin promoter-reporter constructs.
Its activity is synergistic with that of Nrl. Crx also binds to and
transactivates the genes for several other photoreceptor cell-specific proteins
(interphotoreceptor retinoid-binding protein, beta-phosphodiesterase, and
arrestin). Human Crx maps to chromosome 19q13.3, the site of a cone rod dystrophy
(CORDII). These studies implicate Crx as a potentially important regulator of
photoreceptor cell development and gene expression and also identify it as a
candidate gene for CORDII and other retinal diseases.
PMID- 9390517
TI - CREB: a major mediator of neuronal neurotrophin responses.
AB - Neurotrophins regulate neuronal survival, differentiation, and synaptic function.
To understand how neurotrophins elicit such diverse responses, we elucidated
signaling pathways by which brain-derived neurotrophic factor (BDNF) activates
gene expression in cultured neurons and hippocampal slices. We found,
unexpectedly, that the transcription factor cyclic AMP response element-binding
protein (CREB) is an important regulator of BDNF-induced gene expression.
Exposure of neurons to BDNF stimulates CREB phosphorylation and activation via at
least two signaling pathways: by a calcium/calmodulin-dependent kinase IV
(CaMKIV)-regulated pathway that is activated by the release of intracellular
calcium and by a Ras-dependent pathway. These findings reveal a previously
unrecognized, CaMK-dependent mechanism by which neurotrophins activate CREB and
suggest that CREB plays a central role in mediating neurotrophin responses in
neurons.
PMID- 9390518
TI - Localized changes in immediate-early gene regulation during sensory and motor
learning in zebra finches.
AB - A complex neural system controls birdsong learning, but its organization is not
understood, nor is it known why learning only occurs during a critical period in
adolescence. Here, we analyzed developmental regulation in zebra finches of zenk,
an immediate-early gene (IEG) implicated in memory consolidation. Basal
expression was elevated within auditory telencephalon (specifically, within the
caudomedial neostriatum [NCM]) during song acquisition. Expression could be
further induced by song playbacks 30 days after hatching but not at 20 days nor
in juveniles reared in severe isolation. Singing itself induced zenk in song
production nuclei, including Area X, even in adults. Within a compartment of the
robust nucleus of the archistriatum (RA), however, this response dwindled as
singing matured. These results suggest that the onset of sensory memory storage
may be regulated in part at NCM, and motor plasticity may be regulated at RA.
PMID- 9390519
TI - Distribution of Ca2+-activated K+ channel isoforms along the tonotopic gradient
of the chicken's cochlea.
AB - In some cochleae, the number and kinetic properties of Ca2+-activated K+ (KCa)
channels partly determine the characteristic frequency of each hair cell and thus
help establish a tonotopic map. In the chicken's basilar papilla, we found
numerous isoforms of KCa channels generated by alternative mRNA splicing at seven
sites in a single gene, cSlo. In situ polymerase chain reactions demonstrated
cSlo expression in hair cells and revealed differential distributions of KCa
channel isoforms along the basilar papilla. Analysis of single hair cells by the
reverse transcription polymerase chain reaction confirmed the differential
expression of channel variants. Heterologously expressed cSlo variants differed
in their sensitivities to Ca2+ and voltage, suggesting that the distinct spatial
distributions of cSlo variants help determine the tonotopic map.
PMID- 9390520
TI - Differential distribution of Ca2+-activated K+ channel splice variants among hair
cells along the tonotopic axis of the chick cochlea.
AB - We have cloned from the receptor epithelium of the chick cochlea a family of
alternatively spliced cDNAs derived from cslo, which encodes a Ca2+-activated K+
channel like those shown to help determine the resonant frequency of electrically
tuned hair cells. Our results from PCRs using template RNAs from both
tonotopically subdivided receptor epithelia and single hair cells demonstrate
differential exon usage along the frequency axis of the epithelium at multiple
splice sites in cslo. We also show that single hair cells express more than one
splice variant at a given splice site. Since channel isoforms encoded by
differentially spliced slo transcripts in other species are functionally
heterogeneous, these data suggest that differential processing of slo transcripts
may account, at least in part, for the systematic variation in hair-cell membrane
properties along the frequency axis of electrically tuned auditory receptor
epithelia.
PMID- 9390521
TI - Structural organization of the synaptic exocytosis core complex.
AB - Syntaxin, vesicle-associated membrane protein (VAMP), and synaptosome-associated
protein of 25 kDa (SNAP-25) form a ternary "core complex" central to the process
of synaptic vesicle docking and fusion. Several lines of evidence support the
hypothesis that the proteins assemble in a coiled-coil structure, but the
alignment of alpha helices in this coil and the overall conformation of the coil
are unknown. We employ the technique of fluorescence resonance energy transfer
(FRET) to investigate the alignment between syntaxin and VAMP. With the acceptor
probe coupled to the amino-terminal end of the VAMP coiled-coil domain, the donor
probe fluorescence is quenched to a greater extent when it is on the amino
terminal end of the syntaxin H3 domain than when it is on the carboxy-terminal
end. The data indicate that syntaxin and VAMP bind primarily in a parallel
arrangement and suggest a coiled-coil structure that is bent rather than fully
extended. We propose a model in which binding of SNAP receptor (SNARE) protein
coiled-coil domains helps drive vesicle fusion.
PMID- 9390522
TI - Neuronal peptide release is limited by secretory granule mobility.
AB - Neuropeptides are slowly released from a limited pool of secretory granules. To
visualize this process, GFP-tagged preproatrial natriuretic factor (ANF) was
expressed in nerve growth factor-treated PC12 cells. Biochemical and
microfluorimetric experiments demonstrate that proANF-EGFP is packaged in
granules that accumulate at neurite endings and is released in a Ca2+-dependent
manner by secretagogs. Confocal microscopy shows that secretion is associated
with depletion of granules distributed throughout the terminal. Fluorescence
recovery after photobleaching and time-lapse particle tracking reveal that only a
subpopulation of cytoplasmic secretory granules, similar in size to the
releasable pool, can move quickly enough (D = 6 x 10(-11) cm2/s) to support
release. Therefore, sustained secretory responses are limited by the number of
mobile granules and their slow rate of diffusion.
PMID- 9390523
TI - Plasticity in fast synaptic inhibition of adult oxytocin neurons caused by switch
in GABA(A) receptor subunit expression.
AB - We found that magnocellular oxytocin neurons in adult female rats exhibit an
endogenous GABA(A) receptor subunit switch around parturition: a decrease in
alpha1:alpha2 subunit mRNA ratio correlated with a decrease in allopregnanolone
potentiation and increase in decay time constant of the GABA(A) receptor-mediated
IPSCs in these cells. The causal relationship between changes in alpha1:alpha2
mRNA ratio and the ion channel kinetics was confirmed using in vitro antisense
deletion. Further, GABA(A) receptors exhibited a tonic inhibitory influence upon
oxytocin release in vivo, and allopregnanolone helped to restrain oxytocin neuron
in vitro firing only before parturition, when the alpha1:alpha2 subunit mRNA
ratio was still high. Such observations provide evidence for the physiological
significance of GABA(A) receptor subunit heterogeneity and plasticity in the
adult brain.
PMID- 9390524
TI - D5 dopamine receptors enhance Zn2+-sensitive GABA(A) currents in striatal
cholinergic interneurons through a PKA/PP1 cascade.
AB - Cholinergic interneurons have been implicated in striatally mediated associative
learning. In classical conditioning paradigms, conditioned stimuli trigger a
transient suppression of neuronal activity that is dependent upon an intact
dopaminergic innervation. Our hypothesis was that this suppression reflected
dopaminergic enhancement of sensory-linked GABAergic input. As a test, the impact
of dopamine on interneuronal GABA(A) receptor function was studied by combined
patch-clamp recording and single-cell reverse transcription PCR. Activation of D5
dopamine receptors reversibly enhanced a Zn2+-sensitive component of GABA(A)
currents. Although dependent upon protein kinase A (PKA) activation, the
modulation was blocked by protein phosphatase 1 (PP1) inhibition, suggesting it
was dependent upon dephosphorylation. These results establish a novel mechanism
by which intrastriatally released dopamine mediates changes in GABAergic
signaling that could underlie the initial stages of associative learning.
PMID- 9390525
TI - Characterizing voltage-dependent conformational changes in the Shaker K+ channel
with fluorescence.
AB - We examined voltage-dependent conformational changes in three specific regions of
the Shaker potassium channel with site-directed fluorescent labeling: the fourth
transmembrane segment (S4), the second transmembrane segment (S2), and the
putative pore region. The fluorescence changes displayed distinctive properties
that correlate with gating, activation, and slow inactivation of the channel. The
fluorescence signals measured near the S2 and S4 segments suggest that the S2
segment may undergo voltage-sensitive conformational changes that precede those
in the S4 segment. In contrast, fluorescence changes in the pore correlated with
the voltage dependence and time course of ionic activation and slow inactivation.
Spectroscopy indicated that the mechanism of fluorescence change involves voltage
dependent quenching of the probe in an aqueous environment by other parts of the
protein.
PMID- 9390526
TI - Rat GluR7 and a carboxy-terminal splice variant, GluR7b, are functional kainate
receptor subunits with a low sensitivity to glutamate.
AB - Glutamate receptors of the kainate-preferring subtype have recently been shown to
mediate synaptic transmission in the hippocampus. The low-affinity kainate
receptor subunit GluR7 was found to be nonfunctional in previous studies. We
report here that the GluR7 subunit and a novel carboxy-terminal splice variant,
GluR7b, are functional glutamate receptors with unique pharmacological
properties. In particular, glutamate exhibits a 10-fold lower potency for (non
desensitized) GluR7-mediated currents as compared to other non-NMDA receptor
channels. These data will facilitate understanding of the distinct role played by
GluR7 receptors in synaptic transmission.
PMID- 9390528
TI - Heterogeneity of health maintenance organizations and quality of care.
PMID- 9390527
TI - Adjuvant therapy for early breast cancer: a time to refine.
PMID- 9390529
TI - Association of oral cancers with alcohol consumption: exploring mechanisms.
PMID- 9390530
TI - Angiogenesis: the unifying concept in cancer?
PMID- 9390531
TI - Apoptosis research is yielding many potential drug targets.
PMID- 9390532
TI - CNS consortia reshaping brain tumor research.
PMID- 9390533
TI - Exposing the defenses of gliomas.
PMID- 9390534
TI - HPV vaccines for cervical cancer move toward clinic, encounter social issues.
PMID- 9390535
TI - Meeting report: genetic environmental interactions in cancer susceptibility in
animal models.
PMID- 9390536
TI - Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive
breast cancer.
AB - BACKGROUND: The B-20 study of the National Surgical Adjuvant Breast and Bowel
Project (NSABP) was conducted to determine whether chemotherapy plus tamoxifen
would be of greater benefit than tamoxifen alone in the treatment of patients
with axillary lymph node-negative, estrogen receptor-positive breast cancer.
METHODS: Eligible patients (n = 2306) were randomly assigned to one of three
treatment groups following surgery. A total of 771 patients with follow-up data
received tamoxifen alone; 767 received methotrexate, fluorouracil, and tamoxifen
(MFT); and 768 received cyclophosphamide, methotrexate, fluorouracil, and
tamoxifen (CMFT). The Kaplan-Meier method was used to estimate disease-free
survival, distant disease-free survival, and survival. Reported P values are two
sided. RESULTS: Through 5 years of follow-up, chemotherapy plus tamoxifen
resulted in significantly better disease-free survival than tamoxifen alone (90%
for MFT versus 85% for tamoxifen [P = .01]; 89% for CMFT versus 85% for tamoxifen
[P = .001]). A similar benefit was observed in both distant disease-free survival
(92% for MFT versus 87% for tamoxifen [P = .008]; 91% for CMFT versus 87% for
tamoxifen [P = .006]) and survival (97% for MFT versus 94% for tamoxifen [P =
.05]; 96% for CMFT versus 94% for tamoxifen [P = .03]). Compared with tamoxifen
alone, MFT and CMFT reduced the risk of ipsilateral breast tumor recurrence after
lumpectomy and the risk of recurrence at other local, regional, and distant
sites. Risk of treatment failure was reduced after both types of chemotherapy,
regardless of tumor size, tumor estrogen or progesterone receptor level, or
patient age; however, the reduction was greatest in patients aged 49 years or
less. No subgroup of patients evaluated in this study failed to benefit from
chemotherapy. CONCLUSIONS: Findings from this and other NSABP studies indicate
that patients with breast cancer who meet NSABP protocol criteria, regardless of
age, lymph node status, tumor size, or estrogen receptor status, are candidates
for chemotherapy.
PMID- 9390537
TI - Breast cancer survival and treatment in health maintenance organization and fee
for-service settings.
AB - BACKGROUND: Enrollment in health maintenance organizations (HMOs) has increased
rapidly during the past 10 years, reflecting a growing emphasis on health care
cost containment. To determine whether there is a difference in the treatment and
outcome for female patients with breast cancer enrolled in HMOs versus a fee-for
service setting, we compared the 10-year survival and initial treatment of
patients with breast cancer enrolled in both types of plans. METHODS: With the
use of tumor registries covering the greater San Francisco-Oakland and Seattle
Puget Sound areas, respectively, we obtained information on the treatment and
outcome for 13,358 female patients with breast cancer, aged 65 years and older,
diagnosed between 1985 and 1992. We linked registry information with Medicare
data and data from the two large HMOs included in the study. We compared the
survival and treatment differences between HMO and fee-for-service care after
adjusting for tumor stage, comorbidity, and sociodemographic characteristics.
RESULTS: In San Francisco-Oakland, the 10-year adjusted risk ratio for breast
cancer deaths among HMO patients compared with fee-for-service patients was 0.71
(95% confidence interval [CI] = 0.59-0.87) and was comparable for all deaths. In
Seattle-Puget Sound, the risk ratio for breast cancer deaths was 1.01 (95% CI =
0.77-1.33) but somewhat lower for all deaths. Women enrolled in HMOs were more
likely to receive breast-conserving surgery than women in fee-for-service (odds
ratio = 1.55 in San Francisco-Oakland; 3.39 in Seattle). HMO enrollees undergoing
breast-conserving surgery were also more likely to receive adjuvant radiotherapy
(San Francisco-Oakland odds ratio = 2.49; Seattle odds ratio = 4.62).
CONCLUSIONS: Long-term survival outcomes in the two prepaid group practice HMOs
in this study were at least equal to, and possibly better than, outcomes in the
fee-for-service system. In addition, the use of recommended therapy for early
stage breast cancer was more frequent in the two HMOs.
PMID- 9390538
TI - Effects of acetaldehyde on cell regeneration and differentiation of the upper
gastrointestinal tract mucosa.
AB - BACKGROUND: The tumor-promoting effect of ethanol on cancer of the upper
respiratory-digestive tract is not well understood. Although ethanol itself is
not carcinogenic, the first product of ethanol metabolism-acetaldehyde is.
Acetaldehyde can be produced from ethanol by oral bacteria, and high
concentrations have been observed in human saliva after ethanol consumption. The
purpose of this study was to investigate whether acetaldehyde administered orally
to rats induces altered differentiation and proliferation in the animals' upper
gastrointestinal tracts. METHODS: Twenty Wistar rats were given either water
containing acetaldehyde at a concentration of 120 mM or tap water to drink for 8
months. Tissue specimens were then taken from the tongue, epiglottis, and
forestomach of each animal and immunohistochemically stained for markers of
cellular proliferation (Ki67 nuclear antigen) or differentiation (cytokeratins 1,
4, 10, 11, 14, and 19). The mean epithelial thickness of each sample was measured
via light microscopy, using an eyepiece containing grid lines. Differences
between the control and acetaldehyde-treated groups were analyzed by use of the
unpaired Student's t test. All reported P values are two-sided. RESULTS: Although
no tumors were observed, staining for cytokeratins 4 and 14 revealed an enlarged
basal layer of squamous epithelia in the rats receiving acetaldehyde. In these
animals, cell proliferation was significantly greater than that observed in the
control animals for samples from the tongue (P<.0001), epiglottis (P<.001), and
forestomach (P<.0001). In addition, the epithelia from acetaldehyde-treated rats
were significantly thicker than in epithelia from control animals (P<.05 for all
three sites). CONCLUSIONS: Acetaldehyde, administered orally to rats, can cause
hyperplastic and hyperproliferative changes in epithelia of the upper
gastrointestinal tract. This finding suggests that microbially produced
acetaldehyde in saliva may explain the tumor-promoting effect of ethanol on these
epithelia.
PMID- 9390540
TI - P-glycoprotein expression: critical determinant in the response to osteosarcoma
chemotherapy.
AB - BACKGROUND: Fewer than 20% of patients with bone cancer who are treated with
surgery alone are cured. Even with the best current treatment, surgery combined
with chemotherapy, only 60%-80% of patients with nonmetastatic bone cancer and
10% of patients with metastatic bone cancer are cured. Thus far, the reason for
treatment failure in the nonresponding subset has not been identified. It has
been hypothesized that P-glycoprotein, which confers multidrug resistance, might
be the cause. We sought to determine whether the expression of P-glycoprotein is
associated with poor treatment outcome in osteosarcoma. METHODS: In a
retrospective study, we correlated P-glycoprotein expression with the outcome of
conventional chemotherapy in 62 consecutive, clinically staged patients diagnosed
as having osteosarcoma between 1980 and 1989. RESULTS: P-glycoprotein was
overexpressed in 27 patients but not in another 34 patients, and expression was
ambiguous in the sample from one patient. At a median follow-up of 8.9 years, the
34 patients whose tumors did not express P-glycoprotein had significantly better
relapse-free rates than the 27 subjects whose tumors expressed the protein (87%
versus 0%; P<.00001) and had improved survival rates (94% versus 35%; P<.00001).
Among the 46 patients who received chemotherapy before surgery, the 23 whose
tumors were negative for P-glycoprotein showed significantly better long-term
outcomes (P<.00002), although differences in tumor necrosis in response to
therapy were only of borderline significance (P = .057). CONCLUSIONS: P
glycoprotein expression does correlate with treatment failure in patients with
osteosarcoma. This correlation raises the possibility that inhibiting the action
of P-glycoprotein as part of therapy for this disease would improve outcome.
PMID- 9390539
TI - Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers.
AB - BACKGROUND: The consumption of alcoholic beverages is a strong risk factor for
cancers of the oral cavity and pharynx (oral cancers). Alcohol dehydrogenase type
3 (ADH3) metabolizes ethanol to acetaldehyde, a carcinogen. We evaluated whether
individuals homozygous for the fast-metabolizing ADH3(1) allele (ADH3[1-1]) have
a greater risk of developing oral cancer in the presence of alcoholic beverage
consumption than those with the slow-metabolizing ADH3(2) allele (ADH3[1-2] and
ADH3[2-2]). METHODS: As part of a population-based study of oral cancer conducted
in Puerto Rico, the ADH3 genotypes of 137 patients with histologically confirmed
oral cancer and of 146 control subjects (i.e., individuals with no history of
oral cancer) were determined by molecular genetic analysis of oral epithelial
cell samples. Risks were estimated by use of multiple logistic regression
analyses. RESULTS: Compared with nondrinkers with the ADH3(1-1) genotype,
consumers of at least 57 alcoholic drinks per week with the ADH3(1-1), ADH3(1-2),
and ADH3(2-2) genotypes had 40.1-fold (95% confidence interval [CI] = 5.4-296.0),
7.0-fold (95% CI = 1.4-35.0), and 4.4-fold (95% CI = 0.6-33.0) increased risks of
oral cancer, respectively; the risk associated with the ADH3(1-1) genotype,
compared with the ADH3(1-2) and ADH3(2-2) genotypes combined, was 5.3 (95% CI =
1.0-28.8) among such drinkers. Considering all levels of alcohol consumption, the
risk of oral cancer per additional alcoholic drink per week increased 3.6% (95%
CI = 1.9%-5.4%) for subjects with the ADH3(1-1) genotype and 2.0% (95% CI = 0.9%
3.0%) for subjects with the ADH3(1-2) or ADH3(2-2) genotype (two-sided P = .04).
CONCLUSIONS: The ADH3(1-1) genotype appears to substantially increase the risk of
ethanol-related oral cancer, thus providing further evidence for the
carcinogenicity of acetaldehyde.
PMID- 9390542
TI - Breast density and cancer.
PMID- 9390541
TI - Serum levels of prostate-specific antigen among Japanese-American and native
Japanese men.
AB - BACKGROUND: Fourfold to sixfold higher prostate cancer rates in Japanese-American
men in the United States compared with Japanese men in Japan have been cited to
support a role for environmental risk factors in the etiology of the disease. To
examine the hypothesis that part or all of the elevated prostate cancer rates in
Japanese-American men may reflect more intensive prostate cancer screening in the
United States than in Japan, we compared prostate-specific antigen (PSA) levels
in community-based samples of serum from men without prostate cancer. METHODS:
Japanese-American men aged 40-85 years and native Japanese men aged 40-89 years
with no history of prostate cancer provided sera, respectively, in the United
States from March 1990 through March 1992 (n = 237) or in Japan from January 1992
through December 1993 (n = 3522). Age-specific PSA levels were used to estimate
the prevalences of undetected prostate cancer in the two populations. RESULTS:
Age-specific mean PSA levels were significantly lower in Japanese-Americans than
in native Japanese (two-sided P<.001). The prevalence of an elevated PSA level
increased with age in both populations and exceeded 5% among men aged 60 years or
more. Combined with data on prevalence of detected prostate cancer in the two
populations, our data suggest that some 10.0% of Japanese-Americans aged 75 years
have prostate cancer, with 31% of that fraction remaining undiagnosed. The
corresponding estimates in Japan are a total cancer prevalence of 5.4%, of which
81% has not been detected clinically. CONCLUSIONS: The total cancer prevalence
ratio 10.0/5.4 = 1.9 (95% confidence interval = 1.5-2.3) in Japanese-American men
compared with Japanese men in Japan suggests an increased risk for Japanese
American men, but of less magnitude than the fourfold to sixfold increase
indicated by the incidence data.
PMID- 9390543
TI - Re: Risk factors for lung cancer and for intervention effects in CARET, the Beta
Carotene and Retinol Efficacy Trial.
PMID- 9390544
TI - Re: saturated fat intake and lung cancer risk among nonsmoking women in Missouri.
PMID- 9390545
TI - Re: Correlating nutrition to recent cancer mortality statistics.
PMID- 9390546
TI - Re: Relationship between lifetime ovulatory cycles and overexpression of mutant
p53 in epithelial ovarian cancer.
PMID- 9390547
TI - Re: Carcinogenicity of the drinking water mutagen 3-chloro-4-(dichloromethyl)-5
hydroxy-2(5H)-furanone in the rat.
PMID- 9390548
TI - Re: Benzene and the dose-related incidence of hematologic neoplasms in China.
PMID- 9390549
TI - Viral proteases: evolution of diverse structural motifs to optimize function.
PMID- 9390550
TI - Protein translocation channels in the proteasome and other proteases.
PMID- 9390551
TI - Regulatory subunits of energy-dependent proteases.
PMID- 9390552
TI - ECM and cell surface proteolysis: regulating cellular ecology.
PMID- 9390553
TI - Caspases: intracellular signaling by proteolysis.
PMID- 9390554
TI - The structure of ClpP at 2.3 A resolution suggests a model for ATP-dependent
proteolysis.
AB - We have determined the crystal structure of the proteolytic component of the
caseinolytic Clp protease (ClpP) from E. coli at 2.3 A resolution using an ab
initio phasing procedure that exploits the internal 14-fold symmetry of the
oligomer. The structure of a ClpP monomer has a distinct fold that defines a
fifth structural family of serine proteases but a conserved catalytic apparatus.
The active protease resembles a hollow, solid-walled cylinder composed of two 7
fold symmetric rings stacked back-to-back. Its 14 proteolytic active sites are
located within a central, roughly spherical chamber approximately 51 A in
diameter. Access to the proteolytic chamber is controlled by two axial pores,
each having a minimum diameter of approximately 10 A. From the structural
features of ClpP, we suggest a model for its action in degrading proteins.
PMID- 9390555
TI - The exosome: a conserved eukaryotic RNA processing complex containing multiple 3'
->5' exoribonucleases.
AB - We identified a complex in S. cerevisiae, the "exosome," consisting of the five
essential proteins Rrp4p, Rrp41p, Rrp42p, Rrp43p, and Rrp44p (Dis3p). Remarkably,
four of these proteins are homologous to characterized bacterial 3'-->5'
exoribonucleases; Rrp44p is homologous to RNase II, while Rrp41p, Rrp42p, and
Rrp43p are related to RNase PH. Recombinant Rrp4p, Rrp44p, and Rrp41p are 3'-->5'
exoribonucleases in vitro that have distributive, processive, and phosphorolytic
activities, respectively. All components of the exosome are required for 3'
processing of the 5.8S rRNA. Human Rrp4p is found in a comparably sized complex,
and expression of the hRRP4 gene in yeast complements the rrp4-1 mutation. We
conclude that the exosome constitutes a highly conserved eukaryotic RNA
processing complex.
PMID- 9390556
TI - Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.
AB - Mice carrying a null mutation in the mismatch repair gene Msh6 were generated by
gene targeting. Cells that were homozygous for the mutation did not produce any
detectable MSH6 protein, and extracts prepared from these cells were defective
for repair of single nucleotide mismatches. Repair of 1, 2, and 4 nucleotide
insertion/deletion mismatches was unaffected. Mice that were homozygous for the
mutation had a reduced life span. The mice developed a spectrum of tumors, the
most predominant of which were gastrointestinal tumors and B- as well as T-cell
lymphomas. The tumors did not show any microsatellite instability. We conclude
that MSH6 mutations, like those in some other members of the family of mismatch
repair genes, lead to cancer susceptibility, and germline mutations in this gene
may be associated with a cancer predisposition syndrome that does not show
microsatellite instability.
PMID- 9390557
TI - Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates
an apoptotic protease cascade.
AB - We report here the purification of the third protein factor, Apaf-3, that
participates in caspase-3 activation in vitro. Apaf-3 was identified as a member
of the caspase family, caspase-9. Caspase-9 and Apaf-1 bind to each other via
their respective NH2-terminal CED-3 homologous domains in the presence of
cytochrome c and dATP, an event that leads to caspase-9 activation. Activated
caspase-9 in turn cleaves and activates caspase-3. Depletion of caspase-9 from S
100 extracts diminished caspase-3 activation. Mutation of the active site of
caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response
in vivo, indicating that caspase-9 is the most upstream member of the apoptotic
protease cascade that is triggered by cytochrome c and dATP.
PMID- 9390558
TI - Regulating the yeast kinetochore by ubiquitin-dependent degradation and Skp1p
mediated phosphorylation.
AB - In S. cerevisiae, the four-protein Cbf3 complex binds to the essential CDEIII
region of centromeric DNA to initiate kinetochore assembly. We report the
reconstitution of Cbf3p from recombinant proteins and an analysis of its p58Ctf13
and p23Skp1 subunits. p23Skp1 has both G1- and G2-specific functions in yeast and
binds to p58Ctf13 and to the essential Cdc4p component of the ubiquitin
conjugating complex Scul(Cdc4). We show that the function of p23Skp1 in Cbf3p is
to activate p58Ctf13 by phosphorylation. p58Ctf13 is an unstable protein that is
targeted to the proteosome, probably by Scul(Cdc4)-mediated ubiquitination. Thus,
p58 appears to be activated by phosphorylation in a p23Skp1-dependent step and
degraded by the proteosome in a ubiquitin-dependent step. We propose that coupled
activation and destruction link the assembly of Cbf3p to the duplication of
centromeres in S phase.
PMID- 9390559
TI - Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and
its transposition in human cells.
AB - Members of the Tc1/mariner superfamily of transposons isolated from fish appear
to be transpositionally inactive due to the accumulation of mutations. Molecular
phylogenetic data were used to construct a synthetic transposon, Sleeping Beauty,
which could be identical or equivalent to an ancient element that dispersed in
fish genomes in part by horizontal transmission between species. A consensus
sequence of a transposase gene of the salmonid subfamily of elements was
engineered by eliminating the inactivating mutations. Sleeping Beauty transposase
binds to the inverted repeats of salmonid transposons in a substrate-specific
manner, and it mediates precise cut-and-paste transposition in fish as well as in
mouse and human cells. Sleeping Beauty is an active DNA-transposon system from
vertebrates for genetic transformation and insertional mutagenesis.
PMID- 9390560
TI - Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence
into mammalian cells.
AB - Enteropathogenic E. coli (EPEC) belongs to a group of bacterial pathogens that
induce epithelial cell actin rearrangements resulting in pedestal formation
beneath adherent bacteria. This requires the secretion of specific virulence
proteins needed for signal transduction and intimate adherence. EPEC interaction
induces tyrosine phosphorylation of a protein in the host membrane, Hp90, which
is the receptor for the EPEC outer membrane protein, intimin. Hp90-intimin
interaction is essential for intimate attachment and pedestal formation. Here, we
demonstrate that Hp90 is actually a bacterial protein (Tir). Thus, this bacterial
pathogen inserts its own receptor into mammalian cell surfaces, to which it then
adheres to trigger additional host signaling events and actin nucleation. It is
also tyrosine-phosphorylated upon transfer into the host cell.
PMID- 9390561
TI - Identification and molecular characterization of fractalkine receptor CX3CR1,
which mediates both leukocyte migration and adhesion.
AB - Leukocyte trafficking at the endothelium requires both cellular adhesion
molecules and chemotactic factors. Fractalkine, a novel transmembrane molecule
with a CX3C-motif chemokine domain atop a mucin stalk, induces both adhesion and
migration of leukocytes. Here we identify a seven-transmembrane high-affinity
receptor for fractalkine and show that it mediates both the adhesive and
migratory functions of fractalkine. The receptor, now termed CX3CR1, requires
pertussis toxin-sensitive G protein signaling to induce migration but not to
support adhesion, which also occurs without other adhesion molecules but requires
the architecture of a chemokine domain atop the mucin stalk. Natural killer cells
predominantly express CX3CR1 and respond to fractalkine in both migration and
adhesion. Thus, fractalkine and CX3CR1 represent new types of leukocyte
trafficking regulators, performing both adhesive and chemotactic functions.
PMID- 9390562
TI - Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and
regulates photoreceptor differentiation.
AB - We have isolated a novel otx-like homeobox gene, Crx, from the mouse retina. Crx
expression is restricted to developing and mature photoreceptor cells. CRX bound
and transactivated the sequence TAATCC/A, which is found upstream of several
photoreceptor-specific genes, including the opsin genes from many species.
Overexpression of Crx using a retroviral vector increased the frequency of clones
containing exclusively rod photoreceptors and reduced the frequency of clones
containing amacrine interneurons and Muller glial cells. In addition, presumptive
photoreceptor cells expressing a dominant-negative form of CRX failed to form
proper photoreceptor outer segments and terminals. Crx is a novel photoreceptor
specific transcription factor and plays a crucial role in the differentiation of
photoreceptor cells.
PMID- 9390564
TI - Enhancement of natural killer and antibody-dependent cytolytic activities of the
peripheral blood mononuclear cells of HIV-infected patients by recombinant IL-15.
AB - Natural killer (NK) cells are an important subset of lymphocytes capable of
killing virus-infected target cells without prior sensitization. HIV-infected
individuals show impairment of their NK cell activity. Although the mechanism
responsible for this defect remains unclear, NK cytotoxicity of lymphocytes from
these individuals can be partially restored by interleukin (IL)-2. IL-15 is a
recently discovered cytokine that shares many biologic activities with IL-2--for
example, enhancement of NK activity. In this study, we investigated the effect of
recombinant IL-15 (rIL-15) on the NK and antibody-dependent cellular cytotoxicity
(ADCC) effector activities of peripheral blood mononuclear cells (PBMCs) from HIV
infected individuals using K562 cell line and HIV gp120-expressing cells. The
effect of anti-IL-15 antibodies on NK activity was also examined using PBMCs of
HIV-seronegative individuals. Our results show that NK and ADCC activities of
PBMCs in HIV-seropositive patients were significantly lower than those of
seronegative donors (p < or = 0.05). However, these two activities were
significantly enhanced when rIL-15 was added to the assay wells (p < or = 0.05).
Moreover, addition of saturating concentrations of neutralizing monoclonal
antibodies (mAb) specific for IL-2, IL-12, or interferon (IFN)-gamma in the
assays failed to inhibit IL-15-mediated enhancement of NK cell functions. Only
the antibody against IL-15 abrogated the upregulation of NK and ADCC activities
mediated by IL-15, suggesting that this cytokine enhances NK cell functions
through a mechanism that is independent of the induction of other cytokines. IL
15 did not exert any modulatory effect on the expression of CD16 or CD56
molecules. Our results show that IL-15 can increase the NK and ADCC activities of
the PBMCs of HIV-infected individuals in vitro. In view of its higher therapeutic
index as determined using murine models, IL-15 may represent a better
immunotherapeutic agent than IL-2 to restore these functions in HIV-seropositive
patients.
PMID- 9390563
TI - Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox
gene (CRX) essential for maintenance of the photoreceptor.
AB - Genes associated with inherited retinal degeneration have been found to encode
proteins required for phototransduction, metabolism, or structural support of
photoreceptors. Here we show that mutations in a novel photoreceptor-specific
homeodomain transcription factor gene (CRX) cause an autosomal dominant form of
cone-rod dystrophy (adCRD) at the CORD2 locus on chromosome 19q13. In affected
members of a CORD2-linked family, the highly conserved glutamic acid at the first
position of the recognition helix is replaced by alanine (E80A). In another CRD
family, a 1 bp deletion (E168 [delta1 bp]) within a novel sequence, the WSP
motif, predicts truncation of the C-terminal 132 residues of CRX. Mutations in
the CRX gene cause adCRD either by haploinsufficiency or by a dominant negative
effect and demonstrate that CRX is essential for the maintenance of mammalian
photoreceptors.
PMID- 9390565
TI - HIV-1 proviral DNA load across neuroanatomic regions of individuals with evidence
for HIV-1-associated dementia.
AB - A definitive relation between HIV-1 load and the clinical diagnosis of HIV-1
associated dementia (HAD) has not yet been established. Knowledge of the
neuroanatomic distribution of HIV-1 load in the brain of individuals with HAD and
HIV-1 encephalitis may facilitate elucidation of this relation. Nine individuals
with AIDS were analyzed postmortem by three independent methods with each
assessment performed blinded to the others: 1) a neuropsychiatric review of
clinical records for evidence of possible HAD, 2) HIV-1 DNA load determination by
quantitative polymerase chain reaction (PCR) across several neuroanatomic
regions, and 3) a pathologic examination for diagnosis of HIV-1 encephalitis by
immunohistochemical techniques. Of eight AIDS cases with clinical records
sufficient for neuropsychiatric review, seven were shown to have evidence for
HAD. HIV-1 DNA was detected and quantified in specimens from all of the medial
temporal lobe regions analyzed but was not detectable in the frontal lobe at the
same level of sensitivity in two of these cases (<1 per 1000 cellular genomes).
HIV-1 DNA load in the medial temporal lobe region was significantly larger than
that in the frontal lobe. Only four of seven cases with evidence for HAD were
also diagnosed with HIV-1 encephalitis.
PMID- 9390566
TI - Regional differences in use of antiretroviral agents and primary prophylaxis in
3122 European HIV-infected patients. EuroSIDA Study Group.
AB - Little is known about how widely HIV-related drugs are used outside controlled
clinical trials. We therefore assessed factors associated with use of
antiretroviral (ARV) therapy and primary prophylactic regimens to prevent HIV
associated opportunistic infections. Baseline data from a prospective study from
May to August 1994, on 3122 consecutive HIV infected patients with a CD4 count
<500 cells/microl, followed in 37 centers from 16 European countries, were
analyzed. Two thousand and twenty patients (65%) were receiving at least 1 ARV
drug at the time of the study. ARV therapy was more frequently used among
patients from southern and central Europe as compared with patients from northern
Europe, especially among patients with CD4 counts >200 cells/microl (73%, 57%,
and 42%, respectively, p < 0.0001). Of patients on ARV therapy, 34% received open
label combination therapy. This proportion was higher in central Europe compared
with other regions (27%, 50%, and 31% for southern, central, and northern Europe,
respectively, p < 0.0001). Primary prophylaxis against Pneumocystis carinii
pneumonia (PCP) was used by 85% of patients with a CD4 count <200 cells/microl,
without marked regional differences. In patients without esophageal candidiasis
or other invasive fungal infections, antifungal drugs were far less frequently
used in patients from southern and central Europe compared with patients from
northern Europe (10%, 10%, and 25%, respectively, p < 0.0001). Only 5% of
patients with a CD4 count <100 cells/microl received rifabutine as primary
prophylaxis against nontuberculous mycobacterioses. ARV and antifungal therapies
are used differently in different parts of Europe, whereas primary PCP
prophylaxis is uniformly administered to most at-risk patients. U.S.
recommendations on the use of antimycobacterial prophylaxis have not been
implemented in Europe.
PMID- 9390567
TI - Evaluation of immunologic markers in cervicovaginal fluid of HIV-infected and
uninfected women: implications for the immunologic response to HIV in the female
genital tract.
AB - We analyzed 21 cervicovaginal lavage (CVL) specimens from 19 women participating
in the Women's Interagency HIV Study to characterize levels of antibody,
cytokine, and complement and to determine associations between these levels and
stage of the menstrual cycle, HIV status, and the presence of concurrent genital
infection and genital dysplasia. Sixteen samples were collected from HIV-infected
women and five from high-risk HIV-seronegative women. CVL fluid was assayed for
levels of IgG, secretory IgA (s-IgA), interleukin 2 (IL-2), IL-10, IL-6, tumor
necrosis factor alpha (TNF-alpha), IL-1beta, interferon gamma (IFN-gamma), C3,
C1q, and C4. Women with HIV were more likely to have cervicovaginal dysplasia
(9/16 vs. 0/5; p = 0.027) but were not more likely to have concurrent vaginal
infection (10/16 vs. 2/5; p = 0.38). Antibody, cytokine, and complement were
detectable in all samples, although not all samples had measurable IL-10, C3, or
C4. HIV-infected women demonstrated a trend toward higher levels of IFN-gamma
than did uninfected women (p = 0.098); no differences were noted in other
parameters. HIV-infected women with vaginal infections had significantly higher
CVL levels of IgG (p = 0.023) and IFN-gamma (p = 0.02) than did HIV-infected
women without genital infections. HIV-infected women with cervicovaginal
dysplasia were found to have higher levels of IL-1beta (p = 0.045) and IFN-gamma
(p = 0.039) than those without. Analysis of the HIV-infected cohort by CD4 cell
count revealed higher levels of IgG and IFN-gamma in CVL from women with lower
CD4 cell counts, although these differences were not statistically significant.
Higher levels of proinflammatory cytokines in CVL fluid of women with genital
infection or cervicovaginal dysplasia may affect local HIV replication and may
influence the risk of acquisition or transmission of HIV for women with these
underlying conditions.
PMID- 9390568
TI - Are HTLV-II-seropositive injection drug users at increased risk of bacterial
pneumonia, abscess, and lymphadenopathy?
AB - Disease associations of HTLV-II are poorly defined, despite a high seroprevalence
among injection drug users (IDU). One hundred twenty-four HTLV-II-seropositive
emergency room and clinic patients were matched by age, sex, and clinic to 120
HTLV-I/II-seronegative patients. Medical records were reviewed blinded to HTLV-II
status, and International Classification of Disease 9th Clinical Modification
(ICD-9CM)-coded diagnoses were compared between seropositive patients and
controls. After adjustment for relevant confounding variables such as human
immunodeficiency virus infection, HTLV-II-seropositive IDU had an increased risk
of bacterial pneumonia (odds ratio [OR], 3.45; 95% confidence interval [CI],
1.58, 7.56), abscess (OR, 8.30; 95% CI, 4.02, 17.11), and lymphadenopathy (OR,
3.91; 95% CI, 1.24, 12.32) compared with HTLV-II-negative non-IDU patients. In
contrast, HTLV-II-negative IDU were at only marginally increased risk of the same
conditions, with OR of 1.76 (95% CI, 0.42, 7.40), 3.00 (95% CI, 0.94, 9.59), and
1.31 (95% CI, 0.15, 11.66), respectively. These results indicate that HTLV-II
seropositivity may define a subgroup of IDU who are at particularly high risk of
bacterial pneumonia, skin and soft tissue abscess, and lymphadenopathy. Whether
HTLV-II has an etiologic role in predisposing IDU to bacterial infections and
lymphadenopathy will require further investigation.
PMID- 9390569
TI - Clostridium difficile-associated diarrhea in HIV-infected patients: epidemiology
and risk factors.
AB - A retrospective analysis of all the cases of Clostridium difficile-associated
diarrhea (CDAD) in hospitalized patients infected with HIV was performed over a
52-month period to assess the incidence, epidemiology, and risk factors of CDAD.
A case of CDAD was defined as a patient with diarrhea and a positive stool
cytotoxin B assay. Sixty-seven cases of CDAD were recorded in HIV-infected
patients between January 1991 and April 1995. The annual incidence of CDAD ranged
from 1.7 to 6.4 per 100 HIV-infected patients discharged from hospital. The 67
CDAD cases included 48 (72%) first episodes and 19 (28%) relapses. Serogroup C
accounted for 69% of strains from initial episodes of CDAD. To identify risk
factors for CDAD, 34 HIV-infected patients with a first episode were compared
with 66 HIV-infected controls matched for the length of hospital stay. Three
independent factors remained significantly associated with CDAD among HIV
infected patients: CD4+ cell counts <50/mm3 (OR = 5.2; 95% CI = 1.4-19.3; p =
0.01), clindamycin use (OR = 5.0; 95% CI = 1.3-18.3; p = 0.02) and penicillin use
(OR = 4.6; 95% CI = 1.1-18.8; p = 0.03). C. difficile is a common enteric
pathogen responsible for nosocomial diarrhea in HIV-infected patients. Clinicians
should keep this pathogen in mind when searching for the cause of diarrhea in
these patients, especially those who are severely immunocompromised or have
received clindamycin or penicillin.
PMID- 9390570
TI - Projected incidence of AIDS in San Francisco: the peak and decline of the
epidemic.
AB - To predict the incidence of AIDS from 1978 through 1998 in San Francisco, we
developed a model that combined annual HIV seroconversion rates for homosexual
and bisexual men and for heterosexual injecting drug users with estimates of the
incubation period distribution between HIV seroconversion and AIDS diagnosis and
with estimates of the size of the at-risk populations. Our model assumed the
availability of antiretroviral therapy at the efficacy level of zidovudine
monotherapy. The annual number of new AIDS cases is estimated to have peaked at
3332 in 1992, and is projected to decline to 1196 annually by 1998. Although the
projected number of cases decreased steadily during this period for homosexual
and bisexual men, the projected number of cases for injection drug users, women,
and persons with other risks increased between 1993 and 1998. The decline in the
incidence of AIDS in San Francisco reflects the dramatic reductions in new HIV
infections that occurred a decade previously and that were achieved as a result
of significant changes in high-risk behaviors, primarily among homosexual and
bisexual men. Changes in HIV seroincidence must be factored in before attributing
the decrease in AIDS incidence to more effective combination antiretroviral
treatment.
PMID- 9390571
TI - A population-based study determining the incidence of tuberculosis attributable
to HIV infection.
AB - Although the tuberculosis (TB) epidemic has been attributed in part to the AIDS
epidemic, few studies in the United States have measured the risk attributable to
HIV infection. We linked the TB registry of Alameda County, California, 1985 to
1994, with the AIDS registry, 1982 to 1994. We defined a person with TB and HIV
infection as a patient in the TB registry with the same name, race/ethnicity,
gender, and date of birth as a patient in the AIDS registry. We used population
and HIV seroprevalence estimates to determine the HIV-seropositive and
seronegative population at risk of TB in 1994. Of 1990 TB cases reported by
Alameda County from 1985 to 1994, 116 (5.8%) had an AIDS diagnosis. Among 25- to
44-year-old TB patients, 25.2% of U.S.-born men and 8.4% of U.S.-born women had
an AIDS diagnosis. In 1994, the estimated TB incidence rate in persons with HIV
infection was 198.1 per 100,000 versus a rate of 13.9 of 100,000 among persons
without HIV infection (rate ratio, 13.8; 95% confidence interval, 8.0, 23.8). In
1994, 93% of TB cases among HIV seropositive persons, 6.4% of all TB cases, and
16.7% of TB cases aged 25 to 44 years were attributable to HIV infection. The
high attributable risk underscores the impact of HIV on the TB epidemic. All
persons with HIV infection should be screened for TB, and persons with TB
infection should be screened for HIV infection. TB/HIV coinfected patients should
be provided with TB preventive therapy.
PMID- 9390572
TI - Intermediate-size trials for the evaluation of HIV vaccine candidates: a workshop
summary.
AB - There has been considerable debate over what evidence from preclinical and
clinical studies is required to advance an HIV vaccine candidate to phase III
efficacy testing. Given this situation, conduct of intermediate-size trials is
proposed as a method for assessing the plausibility that a vaccine candidate
would prevent chronic HIV infection. Designed to observe 45 incident infections
in the control group, these preliminary efficacy trials could rule out candidates
with low or no efficacy while advancing those candidates with some evidence of
protection to definitive trials. In addition, these trials could provide clues
about correlates of immunity. A threefold or greater difference in the
postvaccination geometric mean titer of neutralizing antibody can be readily
detected between infected and uninfected vaccinees. Differences in CD8+ cytotoxic
T lymphocytes, however, are more difficult to detect. Intermediate-size trials
could also discern a 0.5 log10 or greater difference in plasma HIV-1 RNA levels
between infected vaccinees and infected controls. Such differences in viral load
might suggest disease amelioration or reduction in infectiousness. Given the
large variability in CD4 count and its relatively modest average decline in the
year after infection, a slower decline in CD4 count among infected vaccinees
would not be detectable. With limited resources, intermediate-size trials could
contribute significantly to HIV vaccine development.
PMID- 9390573
TI - Seroprevalence of HIV-1, HIV-2, and HIV-1 group O in Nigeria: evidence for a
growing increase of HIV infection.
AB - To determine current data on HIV infection and to further confirm the presence of
HIV-1 group O infection in Nigeria, 2300 samples from five states were tested for
the presence of HIV antibody. A convenience sampling was obtained from pregnant
women, tuberculosis (TB) patients, commercial sex workers (CSWs), blood donors,
patients with sexually transmitted diseases (STDs), patients with skin diseases,
male clients of CSWs, outpatients suspected to have AIDS, truck drivers, and
community dwellers. With the exception of pregnant women, the HIV prevalences in
all these groups were high: 60.6% in CSWs, 16.2% in TB patients, 7.7% in blood
donors in some states, and 16% in the rural area of Kano State. Male clients of
CSWs, truck drivers, and STD patients had prevalences of 7.8%, 8.6%, and 21.2%,
respectively. Regional differences in relation to HIV prevalences were observed;
HIV-2 and most of the HIV-1/2 infections were found in the southern states of
Nigeria. Higher HIV prevalences were observed in the north-northeast in pregnant
women, TB patients, and CSWs, but for blood donors, higher rates were seen in the
southeast-southwest. One asymptomatic 50-year-old woman, a community dweller in
Kano, was identified to be HIV-1 group O-positive. Compared with data from
national surveillance studies in 1991/1992 and 1993/1994, a substantial increase
in HIV infection was observed. Our results show a growing incidence of HIV
infection in Nigeria and suggest the presence of a rural HIV epidemic. The
identification of HIV-1 group O in Kano shows that this virus strain is
geographically widespread in Nigeria.
PMID- 9390574
TI - HIV risk profile of drug-using women who have sex with women in 19 United States
cities.
AB - The objective of this study was to analyze HIV-related risks of women injection
drug users (IDU) and crack cocaine users (CCU) who have sex with women (WSW). IDU
and CCU women (N = 3856) were recruited from street settings in 19 U.S. cities
between 1992 and 1994. For this study, we analyze data on 231 women who reported
female sex partners in the 30 days before interview. In the 30 days before
interview, 53% of IDUs had shared syringes, and 66% had shared injection
supplies. Only 11 women (6%) always used barrier protection while giving oral sex
to women and 5 (3%) while receiving oral sex from women in the 30 days before
interview. Fifty percent had sex with men as well as women in the previous 30
days. Thirty percent of women who reported sex with men had used condoms for
penile-vaginal sex, and 26% for penile-anal sex. In logistic regression analysis
modeling sex with men in the previous 30 days, sex work was predictive, "lesbian"
self-identification was protective, and the interaction between these two terms
was predictive, while controlling for race and age. Differences in risk
perception were significant between women who reported varying sexual risks, but
not significant between women who reported varying injection-related risks. There
is a high prevalence of risky sex and drug behaviors among drug-using WSWs. There
is a need for epidemiological studies specifically geared toward studying risk
behaviors among WSWs. Risk reduction activities need to focus on injection
related risks, as well as sex-related risks, among WSWs.
PMID- 9390575
TI - Subtyping HIV-1 by improved resolution of heteroduplexes on agarose gels.
PMID- 9390576
TI - Successful use of boric acid to control azole-refractory Candida vaginitis in a
woman with AIDS.
PMID- 9390577
TI - Subspecialty training in pediatric anesthesiology: what does it mean?
PMID- 9390578
TI - Multi-institutional survey of graduates of pediatric anesthesia fellowship:
assessment of training and current professional activities.
AB - We surveyed all the graduates of four fellowship programs in pediatric anesthesia
between 1985 and 1993 to assess their current professional activities, their
evaluation of fellowship training, and their opinions on future directions of
such training. One-hundred ninety-one (62%) of the graduates responded. Nearly
all of the respondents had sought fellowship training for pediatric anesthesia
and thought that the training was worthwhile. At the time of the survey, 40%
worked in a children's hospital, 72% had university or affiliate positions, and
54% had a practice that was > 50% pediatric. Those with > or = 12 mo fellowship
and/or board certification in pediatrics were the most likely to have a pediatric
dedicated practice. Seventy percent of the respondents thought that fellowship
training should be for 12 mo, and the proportion of respondents who recommended
inclusion of training in pain management and clinical research was greater than
the number who had actually received such training. Fifty-eight percent of
respondents supported restriction of fellowship positions in the future, but 83%
did not support a mandatory 2-yr fellowship with research training. We conclude
that fellowships in pediatric anesthesia seem to be successful in providing
training that is not only satisfying to the trainees, but that is also followed
by active involvement in the care of children and in the training of residents
and fellows in anesthesia. Additional information should be gathered to assess
the impact of this training on pediatric care, to formulate a standardized
curriculum, and to justify support for such training in the future. IMPLICATIONS:
We surveyed graduates of four fellowship programs in pediatric anesthesia (1985
1993) to assess current professional activities, fellowship training, and future
directions of such training. Fellowships in pediatric anesthesia seem to provide
training that is satisfying to trainees and that is followed by active
involvement in the care of children.
PMID- 9390579
TI - Predicting and treating coagulopathies after cardiopulmonary bypass in children.
AB - Coagulopathies in children after cardiopulmonary bypass (CPB) are complex. There
are very limited data correlating coagulation tests with postoperative bleeding.
We evaluated coagulation changes after CPB and after the administration of
coagulation products to 75 children. Baseline coagulation tests were obtained and
repeated after protamine administration, after transfusion of individual
coagulation products, and on arrival in the intensive care unit (ICU). Regression
analysis demonstrated no baseline coagulation test to predict postoperative chest
tube drainage. Weight and duration of CPB were determined to be the only
predictors of bleeding. Further analyses demonstrated that children <8 kg had
more bleeding and required more coagulation products than children >8 kg.
Postprotamine platelet count and fibrinogen level correlated independently with
24-h chest tube drainage in children <8 kg, whereas postprotamine platelet count
and thrombelastographic values did so in patients weighing >8 kg. Platelet
administration alone was found to restore effective hemostasis in many patients.
With ongoing bleeding, cryoprecipitate improved coagulation parameters and
limited blood loss. Fresh-frozen plasma administration after platelets worsened
coagulation parameters and was associated with greater chest tube drainage and
more coagulation product transfusions in the ICU. Objective data to guide post
CPB component therapy transfusion in children are suggested. IMPLICATIONS:
Children <8 kg can be expected to have more severe coagulopathies, require more
coagulation product transfusions, and bleed more after cardiopulmonary bypass.
Correlations between coagulation tests and postoperative chest tube drainage are
defined. Platelets and, if necessary, cryoprecipitate optimally restore
hemostasis. Fresh-frozen plasma offers no benefits in correcting
postcardiopulmonary bypass coagulopathies in children.
PMID- 9390580
TI - Sevoflurane or halothane anesthesia: can we tell the difference?
AB - This study was performed to evaluate the ability of anesthesiologists to
differentiate between sevoflurane, a newer, more expensive anesthetic, and
halothane. A total of 113 assessments were made by 36 anesthesiologists on 58
children, aged 6 mo to 6 yr, scheduled for bilateral myringotomy and tube
placement. All patients received midazolam (0.5 mg/kg per os) approximately 30
min before the induction of anesthesia. Sevoflurane or halothane was randomly
selected for anesthetic induction and maintenance. The anesthesiologists, who
were unaware of the anesthetic being used, were asked to identify the anesthetic
based on clinical signs and to assess the quality of induction, speed of
induction, and speed of emergence using a visual analog scale (VAS; minimum score
= 0, maximum score = 100). The anesthesiologists correctly identified the
anesthetic only 56.6% of the time. This was not significantly different from the
50% that would result from random guessing (P = 0.08). Further, there were no
significant differences in VAS scores between the two groups. This study suggests
that in premedicated pediatric patients undergoing brief surgical procedures,
anesthesiologists cannot correctly differentiate between sevoflurane and
halothane. The lack of significant differences in VAS scores suggests that the
speed of induction, the speed of emergence, and the quality of induction are
similar under these clinical conditions. Any purported benefits of sevoflurane
seem to be of minor consequence under the circumstances studied. IMPLICATIONS:
When the anesthetic halothane or sevoflurane is administered in a blind,
randomized fashion, anesthesiologists could not reliably identify which drug was
being used to anesthetize children for a brief surgical procedure. These results
suggest that the differences between the two drugs in clinical practice are small
and may not justify the additional cost of sevoflurane.
PMID- 9390581
TI - Adverse events and risk factors associated with the sedation of children by
nonanesthesiologists.
AB - After implementation of hospital-wide monitoring standards, a quality assurance
(QA) tool was prospectively completed for 1140 children (aged 2.96 +/- 3.7 yr)
sedated for procedures by nonanesthesiologists. The tool captured data regarding
demographics, medications used, adequacy of sedation, monitoring, adverse events,
and requirement for escalated care. The medical records of children who
experienced adverse events were reviewed. Most (99%) children were monitored with
pulse oximetry. Chloral hydrate was the most frequently used sedative (74.9% of
cases). Of the children, 239 (20.1%) experienced adverse events related to
sedation, including inadequate sedation in 150 (13.2%) and decrease in oxygen
saturation in 63 (5.5%). Five of these children experienced airway obstruction
and two became apneic. No adverse event resulted in long-term sequelae. Of the
854 children who received chloral hydrate, 46 (5.4%) experienced decreased oxygen
saturation (> or = 90% of baseline). Children experienced desaturation after the
use of chloral hydrate had received the recommended doses of chloral hydrate (38
83 mg/kg). ASA physical status III or IV and age < 1 yr were predictors of
increased risk of sedation-related adverse events. These data underscore the
importance of appropriate monitoring that includes pulse oximetry to permit early
detection of adverse events. IMPLICATIONS: This quality assurance study
highlights the risks associated with the sedation of children and emphasizes the
importance of appropriate monitoring by trained personnel. Children with
underlying medical conditions and those who are very young are at increased risk
of adverse events, which indicates that a greater degree of vigilance may be
required in these patients.
PMID- 9390582
TI - Sinus venosus atrial septal defect?
PMID- 9390583
TI - Successful treatment of uncontrollable posttraumatic intracranial hypertension
with dihydroergotamin in a child.
PMID- 9390584
TI - The effects of epsilon-aminocaproic acid on fibrinolysis and thrombin generation
during cardiac surgery.
AB - Despite the efficacy of antifibrinolytic drugs in reducing bleeding after cardiac
surgery, concerns remain regarding their potential to promote thrombosis. We
examined the effect of the antifibrinolytic drug, epsilon-aminocaproic acid
(EACA) on fibrinolysis and thrombin generation during cardiac surgery. Forty-one
adults undergoing primary coronary artery bypass graft surgery requiring
cardiopulmonary bypass (CPB) were prospectively randomized in a double-blind
trial to receive either saline or EACA. A loading dose of 150 mg/kg EACA was
given before anesthetic induction, followed by a 15 mg x kg(-1) x h(-1) infusion,
which continued until 3 h after CPB. Plasma samples for the measurement of D
dimer, thrombin-antithrombin III, and soluble fibrin were obtained before
surgery, 1 h on CPB, and 3 and 20 h after CPB. In the EACA group, fibrinolytic
activity, as measured by D-dimer, was significantly decreased 3 h after CPB,
(0.51 +/- 0.15 mg/L vs 1.13 +/- 0.14 mg/L, P < 0.005). Decreased fibrinolytic
activity was accompanied by decreased bleeding in the EACA group (660 +/- 127 mL
vs 931 +/- 113 mL, P < 0.05). No differences in the generation of thrombin or
soluble fibrin were apparent between the two groups. Suppression of fibrinolytic
activity in the absence of concomitant reductions in thrombin generation suggests
that EACA could potentiate a hypercoagulable prethrombotic state in the
perioperative setting. IMPLICATIONS: In a randomized, prospective trial of
primary cardiac surgery, we demonstrated that the synthetic antifibrinolytic drug
epsilon-aminocaproic acid suppresses fibrinolysis with no effects on thrombin
generation. These results suggest the potential for synthetic antifibrinolytic
drugs to induce a hypercoagulable prethrombotic state in the perioperative
setting.
PMID- 9390585
TI - Risk factors for acute postoperative renal failure in thoracic or
thoracoabdominal aortic surgery: a prospective study.
AB - Acute postoperative renal failure is a common complication of thoracic aorta,
thoracoabdominal aorta, or aortic arch surgery. To identify variables associated
with acute postoperative renal failure, we prospectively studied 475 consecutive
patients undergoing thoracoabdominal aortic surgery over a 12-yr period,
including those requiring emergent surgery. One hundred twenty-one (25%) patients
developed acute postoperative renal failure, and 39 (8%) required hemodialysis.
Using multivariate analysis, acute postoperative renal failure was significantly
associated with the following variables: age >50 yr (odds ratio [OR] 2.90 [95%
confidence interval 1.52-5.53]), preoperative serum creatinine >120 micromol/L
(OR 2.76 [1.70-4.48]), duration of left kidney ischemia >30 min (OR 2.01 [1.27
3.17]), packed red cells administration >5 units (OR 2.04 [1.24-3.37]), and Cell
Saver administration >5 units (OR 2.31 [1.34-1.96]). Reimplantation of visceral,
renal arteries and the Adamkievicz artery; duration of visceral, spinal, and
right kidney ischemia; requirement for fresh frozen plasma; administration of
aprotinin; extracorporeal circulation; and procedures with circulatory arrest and
profound hypothermia were not predictive of postoperative renal failure. In
addition, age >50 yr (OR 5.59 [1.31-23.91]), requirement for packed red blood
cells >5 unit (OR 3.91 [1.58-9.67]), and preoperative serum creatinine
concentration >120 micromol/L (OR 2.26 [1.13-4.53]) were independent factors for
acute renal failure requiring hemodialysis. In conclusion, acute renal failure is
often observed after thoracic aortic surgery. Numerous predictive factors must be
considered when evaluating the etiology of this complication. IMPLICATIONS: Acute
postoperative renal insufficiency is a common complication of thoracic aortic
surgery. This study found that age >50 yr, preoperative renal dysfunction,
duration of renal ischemia, and amount of blood transfusion are significant
predictors of this complication.
PMID- 9390586
TI - Epidural analgesia and intravenous patient-controlled analgesia result in similar
rates of postoperative myocardial ischemia after aortic surgery.
AB - To assess the role of postoperative analgesia on myocardial ischemia after aortic
surgery, we compared intravenous patient-controlled analgesia (PCA) with thoracic
epidural analgesia (TEA). One hundred twenty-four patients were prospectively
randomized to the PCA or TEA group. In the TEA group, a T6-7 or T7-8 epidural
catheter was inserted before the induction of general anesthesia. Within 1 h of
the end of surgery, analgesia and 24-h two-channel Holter monitoring were begun.
Myocardial ischemia was defined as ST segment depression > or = 1 mm, 0.06 s
after the J point, and lasting for more than 1 min. In the PCA group, a bolus of
morphine, 0.05 mg/kg, was given, followed by 0.02 mg/kg of morphine on demand
every 10 min. Bupivacaine 0.125% and fentanyl 10 microg/mL was used in the TEA
group. Analgesics were titrated to maintain a visual analog scale score < or = 3.
The overall incidence of myocardial ischemia was 18.4%-18.2% for TEA and 18.6%
for PCA (P = not significant). There were no differences between the groups in
the total duration of ischemia per patient (22.2 +/- 119.8 min for TEA and 20.5
+/- 99 min for PCA) and the number of episodes per patient (0.69 +/- 2.1 for TEA
and 1.2 +/- 4.9 for PCA). Twenty-three patients had an adverse cardiac outcome,
although there were no differences between the groups. The postoperative pain
control was superior with TEA. In these patients undergoing elective aortic
surgery, the use of postoperative TEA did not result in a lower incidence of
early myocardial ischemia compared with intravenous PCA with morphine, despite
better analgesia with TEA. IMPLICATIONS: Postoperative myocardial ischemia is
associated with adverse cardiac outcome. Using Holter monitoring after aortic
surgery, this study shows that the use of thoracic epidural analgesia with
bupivacaine and fentanyl did not result in a lower incidence of myocardial
ischemia compared with intravenous patient-controlled analgesia with morphine.
PMID- 9390587
TI - Cytokine and lipid mediator blood concentrations after coronary artery surgery.
AB - This study investigates whether increased levels of cytokines and lipid mediators
may be associated with complications after coronary artery bypass grafting (CABG)
with extracorporeal circulation (ECC). Hemodynamic measurements and blood samples
were obtained in 32 patients before and after the end of ECC and at the 6th and
the 24th postoperative hours. Coagulation and pulmonary and cardiovascular
functions were specifically assessed postoperatively at the same time. Patients
with cardiovascular dysfunction had higher interleukin 8 (IL-8) levels. Higher
platelet-activating factor (PAF) and decreased PAF acetylhydrolase activity (AHA,
the enzyme that inactivates PAF) levels were found in patients with moderate
cardiovascular dysfunction. Interleukin 6 (IL-6), IL-8, and AHA levels correlated
with most hemodynamic parameters and creatine phosphokinase myocardial band
levels obtained after surgery. Patients with severe lung injury had lower PAF, 6
keto prostaglandin (Pg)F1alpha, and PgE2 levels and higher thromboxane (Tx) B2
concentrations compared with patients without lung injury. Increased IL6 levels
were only associated with moderate lung injury. Impaired hemostasis was
associated with higher IL6 levels. AHA, IL-6, and IL-8 seem to be associated with
cardiovascular dysfunction. The IL-6 blood levels and the ratio of TxB2/6 keto
PgF1alpha blood levels are increased during post-CABG lung injury. These results
identify an association between specific post-CABG complications and the systemic
inflammatory response. The clinical significance of this association remains to
be evaluated. IMPLICATIONS: Patients with pulmonary, cardiovascular, or
hemostasis dysfunction after cardiopulmonary bypass demonstrate aberrancies in a
variety of cytokines and lipid mediators in arterial blood or plasma. The
relationship between these findings and inflammatory response-induced
complications remains to be determined.
PMID- 9390588
TI - Optimal dose of nicardipine for maintenance of hemodynamic stability after
tracheal intubation and skin incision.
AB - To determine the optimal dose of nicardipine (N) for maintenance of hemodynamic
stability during the postinduction period, we designed a randomized, double
blind, placebo-controlled, dose-ranging study using four different doses of N
administered after a standardized anesthetic induction sequence. A total of 106
patients were assigned to one of the following treatment groups: saline
(control), N 0.5 mg (N0.5), N 1 mg (N1), N 2 mg (N2), and N 4 mg (N4). The study
medication was administered intravenously (I.V.) in 2.5 mL of saline over 30 s 2
min before laryngoscopy. Mean arterial pressure (MAP) and heart rate (HR) were
recorded at 1-min intervals for 15 min after tracheal intubation and for 5 min
after skin incision. After intubation, the peak MAP values differed from the
preinduction baseline MAP values by 21% +/- 20%, 9% +/- 12%, 1% +/- 13%, -10% +/-
12%, and -15% +/- 13% (mean +/- SD) in the control, N0.5, N1, N2, and N4 groups,
respectively. However, the percent change in the pre- to postintubation MAP
values (37% to 47%) was similar in all five groups. The highest postintubation HR
values were recorded in the N4 group (P < 0.05 versus the other groups). However,
the increases in MAP values after skin incision were the least in the N4 group.
In conclusion, N1 I.V., administered 2 min before laryngoscopy provides optimal
control of arterial blood pressure during the postinduction period. IMPLICATIONS:
Acute increases in blood pressure during anesthesia are undesirable in patients
with preexisting cardiovascular diseases. This double-blind study found that the
calcium-channel blocker, nicardipine, 1 mg intravenously 2 min before tracheal
intubation maintained hemodynamic stability during the intraoperative period.
PMID- 9390589
TI - Acute hypovolemia may cause segmental wall motion abnormalities in the absence of
myocardial ischemia.
AB - New segmental wall motion abnormalities (SWMA) detected by echocardiography are
considered sensitive and specific markers of myocardial ischemia. However, we
have observed new SWMA during pacing-induced reductions in left ventricular
filling, which resolved immediately with cessation of the atrial pacing and
simultaneous restoration of filling. Therefore, we designed this study to
determine whether acute reduction in filling can induce new SWMA in the absence
of ischemia. Institution of cardiopulmonary bypass was used as a clinical model
of acute reduction in filling, and a beat-by-beat analysis of left ventricular
contraction, filling, blood pressures, and electrocardiogram was performed when
the drainage of blood to the cardiopulmonary bypass machine rapidly emptied the
heart. Acute reduction in filling induced new SWMA in 4 of 38 study patients. All
4 patients had preexisting abnormalities of left ventricular contraction, but
translocation of these preexisting SWMA did not explain the new SWMA, nor did
myocardial ischemia. We conclude that acute reduction in left ventricular filling
can cause new SWMA in the absence of ischemia. This finding limits the usefulness
of new SWMA as a marker of ischemia in the presence of acute reduction in
filling, such as that secondary to severe hypovolemia. IMPLICATIONS: This study
documented that acute reduction in cardiac filling can be associated with new
systolic wall motion abnormalities detected by transesophageal echocardiography
in the absence of documented myocardial ischemia. These findings indicate that
segmental wall motion may not be a valid marker for ischemia in the setting of
acute hypovolemia.
PMID- 9390590
TI - Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses
using perioperative blood transfusion as the outcome. The International Study of
Peri-operative Transfusion (ISPOT) Investigators.
AB - Concern about the side effects of allogeneic red blood cell transfusion has
increased interest in methods of minimizing perioperative transfusion. We
performed meta-analyses of randomized trials evaluating the efficacy and safety
of aprotinin, desmopressin, tranexamic acid, and epsilon-aminocaproic acid in
cardiac surgery. All identified randomized trials in cardiac surgery were
included in the meta-analyses. The primary outcome was the proportion of patients
who received at least one perioperative allogeneic red cell transfusion. Sixty
studies were included in the meta-analyses. The largest number of patients (5808)
was available for the meta-analysis of aprotinin, which significantly decreased
exposure to allogeneic blood (odds ratio [OR] 0.31, 95% confidence interval [CI]
0.25-0.39; P < 0.0001). The efficacy of aprotinin was not significantly different
regardless of the type of surgery (primary or reoperation), aspirin use, or
reported transfusion threshold. The use of aprotinin was associated with a
significant decrease in the need for reoperation because of bleeding (OR 0.44,
95% CI 0.27-0.73; P = 0.001). Desmopressin was not effective, with an OR of 0.98
(95% CI 0.64-1.50; P = 0.92). Tranexamic acid significantly decreased the
proportion of patients transfused (OR 0.50, 95% CI 0.34-0.76; P = 0.0009).
Epsilon-aminocaproic acid did not have a statistically significant effect on the
proportion of patients transfused (OR 0.20, 95% CI 0.04-1.12; P = 0.07). There
were not enough patients to exclude a small but clinically important increase in
myocardial infarction or other side effects for any of the medications. We
conclude that aprotinin and tranexamic acid, but not desmopressin, decrease the
number of patients exposed to perioperative allogeneic transfusions in
association with cardiac surgery. IMPLICATIONS: Aprotinin, desmopressin,
tranexamic acid, and epsilon-aminocaproic acid are used in cardiac surgery in an
attempt to decrease the proportion of patients requiring blood transfusion. This
meta-analysis of all published randomized trials provides a good estimate of the
efficacy of these medications and is useful in guiding clinical practice. We
conclude that aprotinin and tranexamic acid, but not desmopressin, decrease the
exposure of patients to allogeneic blood transfusion perioperatively in
relationship to cardiac surgery.
PMID- 9390591
TI - Right heart failure in the setting of hemorrhagic shock after pneumonectomy:
successful treatment with percutaneous cardiopulmonary bypass.
PMID- 9390592
TI - Phlegmasia cerulea dolens, cerebral venous thrombosis, and fatal pulmonary
embolism due to heparin-induced thrombocytopenic thrombosis syndrome.
PMID- 9390593
TI - Postoperative ulnar neuropathy associated with prolonged ischemia in the upper
extremity during coronary artery bypass surgery.
PMID- 9390594
TI - The clinical neuromuscular pharmacology of cisatracurium versus vecuronium during
outpatient anesthesia.
AB - Neither comparisons of the clinical neuromuscular effects of cisatracurium and
vecuronium nor comparative studies of their antagonism by neostigmine have been
reported. In addition, the efficacy of administering cisatracurium in divided
doses has not been investigated. Accordingly, we applied supramaximal electrical
stimuli to the ulnar nerve of 165 ASA physical status I and II patients receiving
nitrous oxide/alfentanil/propofol anesthesia. Forty-five patients received
cisatracurium 5, 10, or 15 microg/kg, and the evoked response at the adductor
pollicis was recorded for 15 min. One hundred-twenty patients received
cisatracurium 5, 10, or 15 microg/kg or normal saline placebo followed 5 min
later by either cisatracurium 100 microg/kg or vecuronium 100 microg/kg (always
after placebo). Time to clinical onset (maximal ablation of single twitch
response) was measured. When the evoked response spontaneously recovered to 10%
of control height, neostigmine 5, 10, 30, or 50 microg/kg or placebo was
administered, and recovery of neuromuscular function was recorded for the next 15
min. The clinical onset of vecuronium without priming (2.8 +/- 0.8 min) (mean +/-
SD) was significantly (P < 0.05) faster than the onset of cisatracurium without
priming (4.6 +/- 1.4 min). Cisatracurium 5, 10, or 15 microg/kg administered
before cisatracurium 100 microg/kg significantly (P < 0.05) accelerated the time
to complete ablation of the evoked response (3.9 +/- 0.9, 2.9 +/- 0.8, or 3.0 +/-
0.9 min, respectively) compared with cisatracurium 100 microg/kg without priming.
The dose of neostigmine required to achieve 50% assisted recovery of the train-of
four ratio at 5 min was significantly (P < 0.05) smaller in patients who received
vecuronium (29.1 [17.9-55.3] microg/kg) (mean [95% confidence interval]) compared
with those who received cisatracurium (53.7 [31.6-131.5] microg/kg). Given its
faster clinical onset and greater sensitivity to antagonism by neostigmine, we
conclude that vecuronium may be more suitable than cisatracurium for use in
outpatient anesthesia. IMPLICATIONS: We investigated the onset of muscle
relaxation using intravenous vecuronium and cisatracurium and assessed the
ability of neostigmine to antagonize (reverse) this effect. Our results suggest
that vecuronium works faster than cisatracurium and is more sensitive to
neostigmine. Vecuronium therefore may be more useful than cisatracurium in
outpatient anesthesia.
PMID- 9390595
TI - The effects of sevoflurane on cerebral hemodynamics during propofol anesthesia.
AB - We investigated the cerebral hemodynamic effects of 0.5 and 1.5 minimum alveolar
anesthetic concentration (MAC) sevoflurane during propofol anesthesia in 10
patients undergoing supratentorial tumor resection. All patients received a
standardized anesthetic, and their lungs were ventilated with a mixture of air
and oxygen to produce mild hypocapnia. Anesthesia was then maintained with a
propofol infusion. Muscle relaxation was obtained by infusion of atracurium. A
transcranial Doppler probe was used to measure red cell flow velocity in the
right middle cerebral artery (Vmca). A right-sided jugular bulb catheter was
inserted for sampling of jugular bulb blood. After a 30-min period of
stabilization and before the start of surgery, baseline arterial and jugular bulb
blood samples were drawn to define the arterial-venous oxygen content difference
(AVDO2). Mean arterial pressure and Vmca were recorded. Sevoflurane (0.5 and 1.5
MAC) in oxygen/air was then administered, and all measurements were repeated.
Administration of sevoflurane at 0.5 MAC did not change Vmca or AVDO2.
Sevoflurane (1.5 MAC) did not change Vmca. There was an approximately 25%
reduction in AVDO2 (P < 0.05). This suggests that during propofol anesthesia,
although 1.5 MAC sevoflurane does not increase red blood cell velocity, there is
a relative increase in flow with respect to metabolism. Administration of large
dose sevoflurane may be associated with a degree of luxury perfusion.
IMPLICATIONS: We investigated the cerebral hemodynamic effects of sevoflurane in
patients undergoing neurosurgery. Small-dose sevoflurane (1%) did not change
brain blood flow or oxygen consumption. Large-dose sevoflurane (3%) did not
change flow velocity but reduced brain oxygen consumption by 25%. Sevoflurane may
provide a degree of luxury perfusion.
PMID- 9390596
TI - Intrathecal sufentanil, fentanyl, or placebo added to bupivacaine for cesarean
section.
AB - We compared the effects of intrathecal sufentanil 2.5 and 5 microg, fentanyl 10
microg, and placebo when administered together with hyperbaric bupivacaine 0.5%
12.5 mg for cesarean section. The study was performed in a randomized, double
blind fashion in 80 (20 per group) healthy, full-term parturients presenting for
elective cesarean section. Postoperative pain was assessed using the visual
analog scale (VAS). Duration of complete analgesia was defined as the time from
the intrathecal injection to VAS score > 0. Duration of effective analgesia was
defined as the time to VAS score > or = 4. No patient experienced intraoperative
pain. Complete analgesia was prolonged in all groups receiving opioids. Effective
analgesia was prolonged and the 0- to 6-h intravenous opioid requirements were
lower in the groups receiving sufentanil compared with those receiving fentanyl
and placebo. The need for intraoperative antiemetic medication was greater in the
placebo group. Pruritus was a frequent and dose-related side effect in the groups
receiving sufentanil. There were no differences in umbilical cord blood gases or
neonatal Apgar scores and neurological and adaptive capacity scores among the
groups. In conclusion, the addition of sufentanil or fentanyl improved the
quality of subarachnoid block compared with placebo. The duration of action was
longer for sufentanil than fentanyl. IMPLICATIONS: Small doses of fentanyl or
sufentanil (synthetic opioids) added to bupivacaine (local anesthetic) for spinal
anesthesia for cesarean section reduce the need for intraoperative antiemetic
medication and increase the duration of analgesia in the early postoperative
period compared with placebo.
PMID- 9390597
TI - Postoperative analgesic requirement after cesarean section: a comparison of
anesthetic induction with ketamine or thiopental.
AB - In a randomized, double-blind study, we compared postoperative pain and analgesic
requirement in patients who underwent elective cesarean section under general
anesthesia induced with thiopental 4 mg/kg (n = 20) or ketamine 1 mg/kg (n = 20).
Anesthesia was maintained with nitrous oxide and isoflurane. Postoperative
analgesia was provided by patient-controlled analgesia (PCA) using morphine.
Median (range) time to first PCA demand was greater in the ketamine group (28 [3
134] min) compared with the thiopental group (20.5 [3-60] min; P = 0.04). Median
(range) morphine consumption over 24 h was less in the ketamine group (24.3 [3
41] mg) compared with the thiopental group (35 [4-67] mg; P = 0.017). Visual
analog scale pain scores were similar between groups. No patients had recall of
intraoperative events or unpleasant dreams. Two patients in the thiopental group
and one patient in the ketamine group had pleasant intraoperative dreams. Apgar
scores were similar between groups. Median umbilical venous pH was higher (7.33
vs 7.31; P = 0.04) and attributable to lower median umbilical venous Pco2 (5.72
vs 6.14 kPa; P = 0.02) in the ketamine group compared with the thiopental group.
Induction of anesthesia for cesarean section using ketamine is associated with a
lower postoperative analgesic requirement compared with thiopental. IMPLICATIONS:
Patients who had anesthesia for cesarean section induced with ketamine required
less analgesic drugs in the first 24 h compared with patients who received
thiopental. Ketamine, unlike thiopental, has analgesic properties that may reduce
sensitization of pain pathways and extend into the postoperative period.
PMID- 9390599
TI - Use of outpatient preoperative evaluation to decrease length of stay for vascular
surgery.
AB - Interventions that decrease perioperative length of stay can result in
considerable cost-savings. This study assesses the impact of same-day admission
using outpatient preoperative evaluation on the lengths of stay and hospital
costs for patients who underwent carotid end-arterectomy (CEA) or lower extremity
revascularization (LER). Patient characteristics and length of stay were compared
for two 1-yr periods before and after outpatient preoperative evaluation had been
implemented. There were no significant differences before and after the
initiation of outpatient preoperative evaluation in the CEA and LER groups in
mean age and ASA physical status distributions. The average preoperative length
of stay decreased significantly from 7.0 to 1.9 days in the CEA group and from
9.0 to 2.8 days in the LER group. This reduction in the length of stay was
associated with a cost-savings of $900 per patient and did not have an adverse
effect on patient outcome. We conclude that outpatient preoperative evaluation
clinics reduce the cost and length of stay in vascular surgery patients.
IMPLICATIONS: We found that outpatient preoperative evaluation and same-day
admission were associated with a decrease of 4.5 days in the preoperative length
of stay for carotid endarterectomy and lower-extremity revascularization. This
was not accompanied by increased mortality and led to hospital cost-savings of
approximately $900 per patient.
PMID- 9390598
TI - The effects of bupivacaine, L-nitro-L-arginine-methyl ester, and phenylephrine on
cardiovascular adaptations to asphyxia in the preterm fetal lamb.
AB - The preterm fetal lamb that is exposed to clinically relevant plasma
concentrations of lidocaine loses its cardiovascular adaptations to asphyxia, and
its condition deteriorates further. Nitric oxide (NO) is an important regulator
of vascular tone, and local anesthetics are known to inhibit endothelium
dependent vasodilation. The purpose of the present study was to determine whether
the adverse effects of lidocaine noted in the preterm fetal lamb also occur with
bupivacaine and whether the inhibition of NO results in effects similar to those
of bupivacaine. Thirty-two chronically prepared pregnant sheep were studied at
117-119 days' gestation. Maternal and fetal blood pressure, heart rate, and acid
base state were evaluated. Fetal organ blood flows were determined using 15
microM diameter dye-labeled microspheres. After a control period, mild to
moderate asphyxia (fetal PaO2 15 mm Hg) was induced by partial umbilical cord
occlusion and maintained throughout the experiment. Ewes in Group I (n = 13) were
given a two-step intravenous infusion of bupivacaine for 180 min. Fetuses in
Group II (n = 12) received an intravenous injection of L-nitro-L-arginine-methyl
ester (L-NAME) (25 mg/kg), and measurements were taken 10 and 30 min after the
injection. A third group (Group III) of fetuses (n = 7) were given an intravenous
infusion of phenylephrine to mimic the blood pressure increases noted in L-NAME
treated fetuses. At 90 min of stable asphyxia, there was a significant decrease
in fetal PaO2 and pHa and an increase in PaCO2 and mean arterial blood pressure.
There was also an increase in blood flow to the adrenals, myocardium, and
cerebral cortex, whereas blood flow to the placenta decreased. Administration of
bupivacaine during asphyxia did not affect the changes in mean arterial blood
pressure and acid-base state but did abolish the increases in blood flows to the
myocardium and cerebral cortex. Injection of L-NAME to the asphyxiated fetus
resulted in an increase in mean arterial blood pressure above the level noted at
90 min of cord occlusion, and an increase in fetal PaO2 toward control levels.
This was accompanied by a reduction in organ blood flows to preasphyxia levels.
In asphyxiated Group III fetuses, titration of the phenylephrine infusion to
achieve blood pressure increases similar to those noted with L-NAME were also
associated with an increase in fetal PaO2. These data indicate that bupivacaine
abolishes some of the circulatory adaptations to mild to moderate asphyxia
induced by partial cord occlusion in the preterm fetal lamb. It is not clear
whether these effects of bupivacaine are due to inhibition of NO. IMPLICATIONS:
In the preterm fetal lamb, clinically relevant plasma concentrations of
bupivacaine achieved by intravenous infusion to the pregnant ewe (80% gestation)
abolished some of the fetal cardiovascular adaptations to asphyxia induced by
partial umbilical cord occlusion.
PMID- 9390600
TI - Transdiscal lumbar sympathetic block: a new technique for a chemical
sympathectomy.
AB - Genitofemoral neuritis, which occurs when the neurolytic solution spreads into
the psoas muscle, is the most common complication after neurolytic lumbar
sympathetic block. We developed a transdiscal approach for neurolytic lumbar
sympathetic block to reduce the danger of genitofemoral neuritis by making a
sympathectomy without penetration of the psoas muscle, through which the
genitofemoral nerve passes. We attempted transdiscal lumbar sympathetic block in
14 patients for whom the last previous lumbar sympathetic block performed by
using the conventional paravertebral method was unsuccessful. Under fluoroscopic
guidance, the needle was inserted transdiscally at L2-3 and/or L3-4 and was
advanced until its tip pierced the anterior longitudinal ligament. Radiography
and computed tomography revealed that the injected contrast media spread along
the anterolateral surface of the vertebral column without any flow into the psoas
muscle. Alcohol was injected successfully in all patients. During the 1-mo follow
up period, no patients had any symptom of genitofemoral neuritis. Thirteen
patients who had been suffering from lower extremity pain achieved partial or
complete pain relief. One patient with plantar hyperhidrosis achieved persistent
anhidrosis. These results suggest that the transdiscal approach can be a
technical option for neurolytic lumbar sympathetic block. IMPLICATIONS:
Neurolytic lumbar sympathetic block was performed with the needle advanced
through the intervertebral disc. With this technique, the risk of genitofemoral
neuritis, the most common complication after neurolytic lumbar sympathetic block,
was reduced because the needle does not penetrate the psoas muscle, through which
the genitofemoral nerve passes.
PMID- 9390601
TI - Late-onset preemptive analgesia associated with preincisional large-dose
alfentanil.
AB - Few studies using systemic opioids have been adequately designed to demonstrate a
preemptive effect. We investigated the preemptive effect of intraoperative large
dose intravenous (I.V.) opioids over a 72-h period after lower abdominal surgery.
Thirty-eight ASA physical status I or II patients undergoing abdominal
hysterectomy were studied in a prospective, randomized, double-blind design.
Group PRE received alfentanil 70 microg/kg over 10 min before surgical incision;
Group POST received alfentanil 70 microg/kg over 10 min after incision. Patients
received no other intraoperative opioid. Pain was treated in the recovery room
with 2-mg I.V. boluses of morphine and was subsequently managed via patient
controlled analgesia (PCA) using morphine sulfate. Visual analog scale pain
scores at rest (VAS-R) and on movement (VAS-M) and PCA morphine consumption were
recorded for 72 hours. VAS-M and VAS-R scores did not differ at any point, and
morphine consumption was similar in both groups over the initial 48 h. Group PRE
used significantly less morphine from 48 to 72 h postoperatively (P < 0.02). We
conclude that presurgical incisional (i.e., compared with postincisional) large
dose opioid exposure results in a modest, late decrease in postoperative morphine
consumption, with no clinical impact on early postoperative pain. Timing of the
observed reduction coincides with maximal output of substances implicated in
experimental hyperalgesia. IMPLICATIONS: When given before surgical incision,
alfentanil, a short-acting narcotic, was associated with a reduction in morphine
requirements 48-72 h after surgery. Brief interventions may have a delayed and
sustained impact on pain perception, possibly by reducing mechanisms of
sensitization.
PMID- 9390602
TI - Pharmacokinetics and efficacy of long-term epidural ropivacaine infusion for
postoperative analgesia.
AB - The aim of this study was to evaluate the pharmacokinetics and efficacy of the
new local anesthetic ropivacaine when used for epidural infusion for up to 72 h
after major orthopedic surgery. Immediately after surgery, an epidural infusion
of ropivacaine 2 mg/mL was begun at a rate of 6 mL/h in 11 patients. The infusion
rate was then adjusted according to patient analgesic needs or side effects.
Blood samples were taken during and after the infusion to determine total and
unbound ropivacaine and alpha1-acid glycoprotein (AAG) concentrations. Patients
were assessed regularly for sensory and motor block and pain using a visual
analog scale (VAS) score (0-100 mm). Ten patients received 63-72 h of infusion.
Total plasma concentrations of ropivacaine and binding protein (AAG) increased
during the infusion such that free concentrations plateaued or began to fall over
time. VAS values during mobilization were less than 40 mm in 93% of patients. The
majority of patients had no measurable motor block once the surgical block had
regressed. When epidural ropivacaine was titrated to achieve a stable sensory
block, there was a low incidence of motor block, and free plasma ropivacaine
levels were well below the toxic range. IMPLICATIONS: The pharmacokinetics of
continuous epidural infusions of ropivacaine are described in patients for up to
72 h postoperatively. Clinical efficacy and side effects are also reported. An
understanding of the plasma concentrations obtained and modes of elimination
during prolonged epidural infusion is important for safe, routine clinical use in
postoperative analgesia.
PMID- 9390603
TI - Neurotoxicological assessment after intracisternal injection of liposomal
bupivacaine in rabbits.
AB - Experiments were performed on rabbits randomly assigned to intracisternally
receive 0.3 mL of plain bupivacaine 5 mg/mL, liposomal bupivacaine 5 mg/mL,
bupivacaine-free liposomes, or isotonic phosphate-buffered saline. Mechanical
ventilation was initiated or intravenous dopamine was infused when respiratory
depression or hypotension occurred. Seven days after the injection, the whole
spinal cord was removed and histopathologic characteristics were studied on
transverse sections. All preparations were devoid of phosphatidylcholine
hydrolysis or oxidation compounds. Solutions without bupivacaine produced
transient irritative signs that required sedation in most rabbits. Despite the
similar duration of respiratory depression in groups receiving liposomal or plain
bupivacaine, liposomes produced significantly prolonged motor blockade (126 vs 70
min). Correction of hypotension after plain bupivacaine required a longer
dopamine infusion and larger doses than after liposomal bupivacaine (28 vs 18 min
and 74 vs 47 mg). Necrosis was observed in the cervical area of two rabbits (one
in the liposomal bupivacaine group and another in the phosphate buffer group). No
demyelinated areas were noted in spinal cord examinations. We conclude that
liposomal bupivacaine leads to a less severe sympathetic block and to a prolonged
motor block, whereas histologic changes are not significantly different among
groups. IMPLICATIONS: Multilamellar liposomes containing bupivacaine administered
intracisternally to rabbits produce spinal cord histopathologic changes not
significantly different from those observed with plain bupivacaine. Sustained
release of bupivacaine from liposomes is suggested by the prolonged motor
blockade and the reduced severity of arterial hypotension. Use of these liposomes
could prolong the local anesthetic effects of bupivacaine.
PMID- 9390604
TI - Modulation of synaptosomal plasma membrane-bound enzyme activity through the
perturbation of plasma membrane lipid structure by bupivacaine.
AB - We investigated modulations of lipid dynamics and lipid-protein interactions of
rat brain synaptosomal plasma membrane (SPM) as one of the possible mechanisms by
which the local anesthetic bupivacaine (BPV) has an adverse effect on nerve cell
function, with SPM-bound enzyme activity used as a functional probe. The kinetics
of BPV impact on the activity of the endoenzymes Ca2+/Mg2+-stimulated ATPase and
Na+/K+-stimulated ATPase and the active concentrations of the drug were relevant
to those that produce biphasic systemic toxicity. Arrhenius plots of these
enzymes showed a transition temperature of 26.6 +/- 1.8 degrees C and 24.5 +/-
1.2 degrees C (mean +/- SD), respectively, in control SPM, which shifted to 17.1
+/- 0.95 degrees C (P < 0.01) and 18.2 +/- 0.85 degrees C (P < 0.05) in SPM
treated with 10(-5) M BPV. The Hill coefficients for the allosteric inhibition of
Ca2+/Mg2+-stimulated ATPase by Na+ and Na+/K+-stimulated ATPase by fluoride
decreased from 1.73 +/- 0.20 and 1.95 +/- 0.25, respectively, in controls to 0.92
+/- 0.09 (P < 0.001) and 1.09 +/- 0.11 (P < 0.001) in the presence of 10(-5) M
BPV. The fluidity perturbation in the microenvironment of the ectoenzyme
acetylcholinesterase was observed only at 5 x 10(-3) M BPV, as confirmed by the
disparity in transition temperature between the controls (22.3 +/- 1.2 degrees C)
and the BPV-treated SPM (17.5 +/- 0.8 degrees C, P < 0.01) and that in the Hill
coefficient in the two groups: 2.15 +/- 0.24 and 0.97 +/- 0.12 (P < 0.001),
respectively. IMPLICATIONS: We propose that under physiological conditions, the
neutral and protonated forms of local anesthetics can affect nerve cell function
through the asymmetric perturbation of the membrane lipid structure, accompanied
by synaptosomal plasma membrane-bound enzyme dysfunction.
PMID- 9390605
TI - An osteoid osteoma as an undiagnosed cause of three years of severe pain.
PMID- 9390606
TI - Safety steps for epidural injection of local anesthetics: review of the
literature and recommendations.
PMID- 9390607
TI - Spinal anesthesia, hypothermia, and sedation: a case of resedation with forced
air warming.
PMID- 9390608
TI - Reversal of neuromuscular blockade with neostigmine has no effect on the
incidence or severity of postoperative nausea and vomiting.
AB - We performed this randomized, double-blind, placebo-controlled study to determine
whether reversal of neuromuscular block with neostigmine increases the incidence
and severity of postoperative nausea and vomiting (PONV). We studied 162 women
undergoing abdominal hysterectomy and randomly allocated them into two groups. In
Group A, neuromuscular block produced with mivacurium was antagonized with
neostigmine 2.0 mg and glycopyrrolate 0.4 mg intravenously, whereas Group B
received no drugs to facilitate antagonism of blockade. The incidence and
severity of PONV was assessed up to 27 h after the operation. There was no
difference in PONV between the groups (in Group A 35% had nausea and 33% vomited;
in Group B 28% nauseated and 40% vomited) or in the amount of antiemetics given.
We had a 75% chance to find a 30% difference in PONV. We conclude that the
administration of neostigmine and glycopyrrolate at the end of anesthesia to
reverse neuromuscular block does not increase the incidence or severity of PONV.
IMPLICATIONS: Neostigmine may increase postoperative nausea and vomiting. In this
study, omission of reversal of neuromuscular block with neostigmine failed to
decrease the incidence or severity of postoperative nausea and vomiting.
PMID- 9390609
TI - Time-dependent changes in heart rate and pupil size during desflurane or
sevoflurane anesthesia.
AB - To better characterize alterations in autonomic function associated with
prolonged anesthesia, we tested the hypothesis that the time-dependent effects of
sevoflurane and desflurane differ. We studied seven male volunteers, each
anesthetized for 8 h with 1.25 minimum alveolar anesthetic concentration
desflurane on one study day and with 8 h sevoflurane on another. These volunteers
did not undergo surgery and were minimally stimulated during the study.
Measurements included blood pressure, heart rate, pupillary size and light
reactivity, concentrations of serum catecholamines, and carbon dioxide
production. Over time, heart rate and pupil size increased significantly. During
6 of the 14 anesthetics (45%), heart rate at some point exceeded 95 bpm;
similarly, pupil size at some time exceeded 5 mm during 8 anesthetics (57%). In
contrast, plasma catecholamine concentrations and carbon dioxide production
remained unchanged, and blood pressure remained nearly constant. There are thus
substantial time-dependent changes in autonomic functions during prolonged
anesthesia, even in unstimulated, nonsurgical volunteers, but we could not detect
a difference in these changes during desflurane compared with sevoflurane
anesthesia. IMPLICATIONS: Pupil size and heart rate changes are used to guide the
delivery of anesthesia. In volunteers, pupil size and heart rate increased with
increasing duration of constant desflurane or sevoflurane anesthesia. Thus,
anesthetic duration alters heart rate and pupil size independent of surgery and
changes in anesthetic delivery.
PMID- 9390610
TI - Argon pneumoperitoneum is more dangerous than CO2 pneumoperitoneum during venous
gas embolism.
AB - We investigated the possibility of using argon, an inert gas, as a replacement
for carbon dioxide (CO2). The tolerance of argon pneumoperitoneum was compared
with that of CO2 pneumoperitoneum. Twenty pigs were anesthetized with enflurane
1.5%. Argon (n = 11) or CO2 (n = 9) pneumoperitoneum was created at 15 mm Hg over
20 min, and serial intravenous injections of each gas (ranging from 0.1 to 20
mL/kg) were made. Cardiorespiratory variables were measured. Transesophageal
Doppler and capnographic monitoring were assessed in the detection of embolism.
During argon pneumoperitoneum, there was no significant change from baseline in
arterial pressure and pulmonary excretion of CO2, mean systemic arterial pressure
(MAP), mean pulmonary artery pressure (PAP), or systemic and pulmonary vascular
resistances, whereas CO2 pneumoperitoneum significantly increased these values (P
< 0.05). During the embolic trial and from gas volumes of 2 and 0.2 mL/kg, the
decrease in MAP and the increase in PAP were significantly higher with argon than
with CO2 (P < 0.05). In contrast to CO2, argon pneumoperitoneum was not
associated with significant changes in cardiorespiratory functions. However,
argon embolism seems to be more deleterious than CO2 embolism. The possibility of
using argon pneumoperitoneum during laparoscopy remains uncertain. IMPLICATIONS:
Laparoscopic surgery requires insufflation of gas into the peritoneal cavity. We
compared the hemodynamic effects of argon, an inert gas, and carbon dioxide in a
pig model of laparoscopic surgery. We conclude that argon carries a high risk
factor in the case of an accidental gas embolism.
PMID- 9390611
TI - Carbon dioxide spirogram (but not capnogram) detects leaking inspiratory valve in
a circle circuit.
AB - Expiratory valve incompetence in the circle circuit is diagnosed by using
capnography (PCO2 versus time) when significant CO2 is present throughout
inspiration. However, inspiratory valve incompetence will allow CO2-containing
expirate to reverse flow into the inspiratory limb. CO2 rebreathing occurs early
during the next inspiration, generating a short extension of the alveolar plateau
and decreased inspiratory downslope of the capnogram, which may be
indistinguishable from normal. We hypothesized that CO2 spirography (PCO2 versus
volume) would correctly measure inspired CO2 volume (VCO2) during inspiratory
valve leak. Accordingly, a metabolic chamber (alcohol combustion) was connected
to a lung simulator, which was mechanically ventilated through a standard
anesthesia circle circuit. By multiplying and integrating airway flow and PCO2,
overall, expired, and inspired VCO2 (VCO2,br = VCO2,E - VCO2,I) were measured.
When the inspiratory valve was compromised (by placing a wire between the valve
seat and diaphragm), VCO2,I increased from 2.7 +/- 1.7 to 5.7 +/- 0.2 mL (P <
0.05), as measured by using CO2 spirography. In contrast, the capnogram
demonstrated only an imperceptible lengthening of the alveolar plateau and did
not measure VCO2,I. To maintain effective alveolar ventilation and CO2
elimination, increased VCO2,I requires a larger tidal volume, which could result
in pulmonary barotrauma, decreased cardiac output, and increased intracranial
pressure. IMPLICATIONS: Circle circuit inspiratory valve leak will allow CO2
containing expirate to reverse flow into the inspiratory limb, with subsequent
rebreathing during the next inspiration. This CO2 rebreathing causes
imperceptible lengthening of the alveolar plateau of the capnogram and is
detected only by using the CO2 spirogram (PCO2 versus volume).
PMID- 9390612
TI - The UpsherScope in routine and difficult airway management: a randomized,
controlled clinical trial.
AB - The UpsherScope, a rigid fiberoptic laryngoscope, may facilitate tracheal
intubation. We performed a randomized, controlled trial of tracheal intubation
using the UpsherScope and compared the success rate with that of direct
laryngoscopy. Three hundred patients were randomly assigned to either fiberoptic
oral intubation using the UpsherScope (Group US, n = 148) or to direct
laryngoscopy (Group DL, n = 152). No significant differences in airway variables
were observed between the groups. US intubation was successful in 129 of 148
patients (87%). A second or third attempt was required in 15% and 3%,
respectively, of the patients successfully intubated with US. The remaining
patients were intubated using DL (n = 17) or the flexible fiberoptic bronchoscope
(n = 2). The success rate of DL was significantly higher (97%; P < 0.05), with a
second or third attempt required in only seven patients. Time needed to perform
successful intubation was 50 +/- 41 s for the US group compared with 23 +/- 13 s
for the DL group (P < 0.05). We found no advantage of the UpsherScope over direct
laryngoscopy during routine and difficult airway management. Time needed, number
of attempts required to perform intubation, and incidence of failure were
significantly longer and higher in group US. IMPLICATIONS: We studied tracheal
intubation using the fiberoptic UpsherScope and compared the success rate with
that of a control group of patients intubated using conventional laryngoscopy. No
advantages of the new device were found. On the contrary, time needed, number of
attempts required, and incidence of failure were even longer and higher.
PMID- 9390613
TI - Dehydration of Baralyme increases compound A resulting from sevoflurane
degradation in a standard anesthetic circuit used to anesthetize swine.
AB - In a model anesthetic circuit, dehydration of Baralyme brand carbon dioxide
absorbent increases degradation of sevoflurane to CF2=C(CF3)OCH2F, a nephrotoxic
vinyl ether called Compound A. In the present study, we quantified this increase
using "conditioned" Baralyme in a circle absorbent system to deliver sevoflurane
anesthesia to swine. Mimicking continuing oxygen delivery for 2 days after
completion of an anesthetic, we directed a conditioning fresh gas flow of 5 L/min
retrograde through fresh absorbent in situ in a standard absorbent system for 40
h. The conditioned absorbent was subsequently used (without mixing of the
granules) in a standard anesthetic circuit to deliver sevoflurane to swine
weighing 78 +/- 2 kg. The initial inflow rate of fresh gas flow was set at 10
L/min with the vaporizer at 8% to achieve the target end-tidal concentration of
3.0%-3.2% sevoflurane in approximately 20 min. The flow was later decreased to 2
L/min, and the vaporizer concentration was decreased to sustain the 3.0%-3.2%
value for a total of 2 h (three pigs) or 4 h (eight pigs). Inspired Compound A
increased over the first 30 +/- 60 min to a peak concentration of 357 +/- 49 ppm
(mean +/- SD), slowly decreasing thereafter to 74 +/- 6 ppm at 4 h. The average
concentration over 2 h was 208 +/- 25 ppm, and the average concentration over 4 h
was 153 +/- 19 ppm. Pigs were killed 1 or 4 days after anesthesia. The kidneys
from pigs anesthetized for both 2 h and 4 h showed mild inflammation but little
or no tubular necrosis. These results suggest that dehydration of Baralyme may
produce concentrations of Compound A that would have nephrotoxic effects in
humans in a shorter time than would be the case with normally hydrated Baralyme.
IMPLICATIONS: The vapor known as Compound A can injure the kidney. Dehydration of
Baralyme, a standard absorbent of carbon dioxide in inhaled anesthetic delivery
systems, can cause a 5- to 10-fold increase in Compound A concentrations produced
from the inhaled anesthetic, sevoflurane, given at anesthetizing concentrations
in a conventional anesthetic system.
PMID- 9390614
TI - Contribution of the spinal cord to arousal from inhaled anesthesia: comparison of
epidural and intravenous fentanyl on awakening concentration of isoflurane.
AB - To investigate the contribution of modulation of afferent nociceptive inputs by
an opioid in the spinal cord to arousal from inhaled anesthesia, we determined
the awakening concentration of isoflurane in 50 unpremedicated patients scheduled
for abdominal hysterectomy. Patients were assigned randomly to three groups.
Group I received bolus injections of both epidural and intravenous (I.V.) saline,
followed by both epidural and I.V. infusions at the rate of 0.2 mL x kg(-1) h(
1). Group II received an I.V. injection of fentanyl 2 microg/kg, followed by an
infusion at the rate of 25 ng x kg(-1) x min(-1), and Group III received an
epidural injection and infusion in the same administration regimen as Group II.
Anesthesia was induced with and maintained by isoflurane in an air/oxygen mixture
(fraction of inspired oxygen = 0.5) with no adjuvant drugs. The study drug was
administered at the start of retroperitoneal suturing. The awakening
concentrations of isoflurane in Groups I, II, and III (mean +/- SD) were 0.32% +/
0.07%, 0.31% +/- 0.06%, and 0.24% +/- 0.06%, respectively. At that time, plasma
fentanyl concentrations in Groups II and III were 1.12 +/- 0.09 ng/mL and 0.65 +/
0.04 ng/mL, respectively. Epidural fentanyl infusion reduced the awakening
concentration of isoflurane more (P < 0.01) than I.V. fentanyl infusion, despite
the lower plasma concentration (P < 0.01) in the epidural group. These findings
suggest that epidural fentanyl delays arousal from inhaled anesthesia by
modulating the afferent nociceptive inputs in the spinal cord. The spinal cord
may contribute to arousal from inhaled anesthesia through the regulation of
afferent inputs by opioids along with the supraspinal region of the central
nervous system (CNS), even if the effects of subarachnoid fentanyl on the higher
CNS via the cephalad migration is taken into consideration. IMPLICATIONS: The
present study revealed that the spinal cord, the lower level of central nervous
system, contributed to arousal from general anesthesia, along with the higher
central nervous system, by comparing the concentrations of an inhaled anesthetic,
isoflurane, in the expiration of patients receiving systemic or regional
administration of an opioid, fentanyl.
PMID- 9390615
TI - The choice of anesthetic maintenance technique influences the antiinflammatory
cytokine response to abdominal surgery.
AB - Outcome in some diseases is determined by the relationship between pro- and
antiinflammatory cytokines. Surgery may also provoke a cytokine response, which
has both pro- and antiinflammatory components. The aim of this study was to
ascertain whether anesthetic technique can modify the balance of cytokines
associated with abdominal surgery. Twenty patients scheduled to undergo elective
abdominal hysterectomy were randomly allocated to receive maintenance of
anesthesia with isoflurane (IH group) or propofol (IV group). Venous blood
samples for measurement of tumor necrosis factor alpha (TNF-alpha), interleukin-6
(IL-6), interleukin-10 (IL-10), and interleukin-1 receptor antagonist (IL-1ra)
were taken before the induction of anesthesia and at set intervals until 24 h
postoperatively. TNF-alpha levels remained low throughout the study; however, all
patients showed a significant postoperative increase in IL-6, IL-10, and IL-1ra
(P < 0.05). Levels of the proinflammatory cytokine IL-6 were similar in both
groups, whereas the antiinflammatory cytokine IL-10 was higher in the IV group at
4 h postoperatively (P < 0.02). The difference between groups in terms of IL-1ra
production just failed to reach significance (P < 0.06). We conclude that the
cytokine response to abdominal surgery has both pro- and antiinflammatory
components and that the choice of anesthetic may modify the balance of these
cytokines. IMPLICATIONS: This study demonstrates that in addition to the widely
reported proinflammatory cytokine response, elective abdominal surgery provokes
an antiinflammatory response, which may be enhanced by total intravenous
anesthesia. The ability of anesthetics to modify the cytokine response to surgery
may have therapeutic potential.
PMID- 9390616
TI - Pharmacokinetics and pharmacodynamics of propofol in a new solvent.
AB - Pain on injection is the most commonly reported adverse event after propofol
injection. In a randomized, cross-over study in two groups of 12 healthy male
volunteers (24-42 yr), we compared the pharmacokinetics and pharmacodynamics of
two new propofol formulations (1% and 2% concentrations) in a fat emulsion
consisting of medium- and long-chain triglycerides with the standard propofol
formulation. After a single intravenous bolus injection of 2 mg/kg, propofol
blood levels were measured for 24 h and evaluated according to an open three
compartment model. The derived pharmacokinetic variables were not different among
formulations. Additionally, electroencephalographic recordings of the onset and
duration of hypnotic action were comparable with all formulations. After propofol
1% in the new formulation, fewer volunteers reported severe or moderate pain on
injection (9%) than after the standard formulation (59%) (P < 0.05). We attribute
this result to a lower concentration of free propofol in the aqueous phase of the
new formulation. IMPLICATIONS: Changing the composition of the carrier fat
emulsion for propofol does not have an impact on the pharmacokinetics and
efficacy of propofol, but it promises to provide better patient acceptance by
lowering the incidence of moderate and severe pain on injection.
PMID- 9390617
TI - Anesthetic considerations in patients presenting with mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.
PMID- 9390618
TI - A case of nonoliguric renal failure after general anesthesia with sevoflurane and
desflurane.
PMID- 9390619
TI - Cremasteric reflex for identification of successful spinal anesthesia.
PMID- 9390620
TI - Use of gabapentin in a case of facial neuritis.
PMID- 9390621
TI - Detection of intraoperative segmental wall motion abnormalities by
transesophageal echocardiography.
PMID- 9390622
TI - Adequate humidification?
PMID- 9390623
TI - Preoperative acute normovolemic hemodilution is an alternative to hypervolemic
hemodilution--in case of proper use.
PMID- 9390624
TI - Device designed to facilitate endotracheal intubation in the absence of a trained
assistant (the anesthesiologist's third hand)
PMID- 9390625
TI - Pulse oximeter probe sheath for buccal use.
PMID- 9390626
TI - Activation of apnea alarm by a surgical theater light during ophthalmological
surgery.
PMID- 9390627
TI - Light-guided tracheal intubation through the laryngeal mask airway.
PMID- 9390628
TI - Resolution of primary vaginismus and introital hyperesthesia by topical
anesthesia.
PMID- 9390629
TI - Pneumothorax and "mini" thoracotomy.
PMID- 9390630
TI - Respiratory depression with addition of fentanyl to spinal anesthesia.
PMID- 9390631
TI - Transforming growth factor-beta, other growth factors, and the extracellular
matrix.
PMID- 9390632
TI - Renal cell proliferation and the two faces of cyclic adenosine monophosphate.
PMID- 9390633
TI - Genetic and antigenic variation in Pneumocystis carinii organisms: tools for
examining the epidemiology and pathogenesis of infection.
PMID- 9390634
TI - Regulation of the human immune response during tuberculosis.
AB - Pulmonary tuberculosis is characterized by depression of purified protein
derivative-stimulated (PPD-stimulated) blastogenesis in peripheral blood
mononuclear cells (PBMCs) as well as decreased production of interleukin-2 (IL-2)
and interferon-gamma (IFN-gamma). Circulating T cells and monocytes (MNs) are
nonspecifically activated in situ. PPD directly stimulates the primed MNs from
patients with tuberculosis (TB) to overproduce a panoply of cytokines including
transforming growth factor-beta (TGF-beta) and IL-10, which serve to depress PPD
stimulated blastogenesis and cytokine expression. Cross-modulation by these
immunosuppressive MN products is superimposed on a primary T cell abnormality
that persists for at least 12 months after the diagnosis of TB and involves
apoptotic mechanisms.
PMID- 9390635
TI - Modulation of collagen gene expression by cytokines: stimulatory effect of
transforming growth factor-beta1, with divergent effects of epidermal growth
factor and tumor necrosis factor-alpha on collagen type I and collagen type IV.
AB - Transforming growth factor-beta1 (TGF-beta1) is well recognized as a potent
mediator of both fibrillar (collagen type I) and basement membrane (collagen type
IV) production. However, tissue injury is characterized by the concomitant
expression of many cytokines and/or growth factors in addition to TGF-beta1, and
the ultimate extent of extracellular-matrix (ECM) deposition may reflect the
interacting effects of TGF-beta1 and these other cytokines and/or growth factors.
We, therefore, sought to determine whether other cytokines and/or growth factors,
known to be produced after tissue injury, are capable either alone or in
combination with TGF-beta1 of modulating collagen gene expression. Collagen type
I and collagen type IV gene expression was assessed in NIH-3T3 cells, a murine
fibroblast-like cell line that responds to TGF-beta1, with increases in both
collagen type I and collagen type IV production. TGF-beta1 coordinately induced
production of collagen type IV messenger ribonucleic acid (mRNA) to a level 3.8
fold above its baseline value (p < 0.001) and collagen type I mRNA to a level 2.6
fold above its baseline value (p < 0.001). Of the other cytokines and/or growth
factors tested, only epidermal growth factor (EGF) had significant effects on
collagen mRNA expression. We report the novel observation that EGF significantly
induced collagen type IV mRNA (3.0-fold; p < 0.001) but did not alter collagen
type I mRNA expression. Platelet-derived growth factor (PDGF), basic fibroblast
growth factor (bFGF), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL
1), and insulin-like growth factor-1 (IGF-1) did not alter the expression of mRNA
for collagen type IV or collagen type I. Addition of TGF-beta1 to cytokine-
and/or growth factor-treated cells increased both collagen type IV and collagen
type I mRNA levels. However, collagen type IV mRNA levels were similar in
cultures given TGF-beta1 alone and cultures given TGF-beta1 with other cytokines
and/or growth factors; there were no additive, synergistic, or antagonistic
effects after coadministration of TGF-beta1 and other cytokines and/or growth
factors. With regard to collagen type I mRNA expression, all cytokines and/or
growth factors tested, with the exception of TNF-alpha, had no effect on collagen
type I mRNA levels in TGF-beta1-treated cultures. Importantly, TNF-alpha
antagonized the stimulatory effect of TGF-beta1 on collagen type I mRNA levels.
These observations support a dominant role for TGF-beta1 in stimulating
coordinate expression of collagen type I and collagen type IV mRNAs by NIH-3T3
cells; EGF and TNF-alpha are capable of inducing divergent expression of the
genes for these two types of collagen.
PMID- 9390637
TI - Aspirin treatment of the low-dose-endotoxin-treated pregnant rat:
pathophysiologic and immunohistologic aspects.
AB - In the present study, we evaluated the effect of low-dose aspirin
(acetylsalicylic acid (ASA); 1.0 mg/kg daily) on blood pressure, albumin
excretion, glomerular fibrinogen deposits, and glomerular (basement) membrane
bound adenosine diphosphatase (ecto-ADPase) activity, as well as on glomerular
inflammation in pregnant rats infused with low-dose endotoxin (1.0 mg/kg). Rats
(day 14 of pregnancy) were infused with endotoxin (ET rats) or saline (control
rats) and received ASA in their drinking water. These rats were compared with non
ASA-treated rats. Blood pressure and albumin excretion were measured from day 15
to day 21, and glomerular fibrinogen and ecto-ADPase activity were measured at
day 21. Glomerular inflammation was evaluated at various times after the start of
the infusion. The results show that treatment with ASA had a significant
beneficial effect on hypertension and inflammation induced by endotoxin in
pregnant rats, whereas it reduced albumin excretion and glomerular fibrinogen
deposits in some of the rats.
PMID- 9390636
TI - Inhibitors of cyclic nucleotide phosphodiesterase isozymes block renal tubular
cell proliferation induced by folic acid.
AB - In previous studies we observed that inhibition of cyclic 3',5'-nucleotide
phosphodiesterase (PDE) isozymes, namely isozyme PDE3, suppresses proliferation
of rat renal glomerular mesangial cells in vitro and in vivo. To determine
whether activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A
(PKA) signaling pathway coupled to specific PDE isozymes modulates accelerated
proliferation of renal epithelial cells, we investigated the effect of selective
PDE isozyme inhibition on renal epithelial cell proliferation induced in rats by
injection of folic acid (FA). In extracts from suspensions of renal cortical
tubules, cAMP was metabolized predominantly by isozyme PDE4; activity of PDE3 was
about three times lower. The increase in proliferative activity of renal cortical
tissue from FA-injected rats, evaluated by immunostaining with Mib-1 antibody,
was limited to tubular epithelial cells. Administration of the PDE3 inhibitors
cilostazol or cilostamide together with the PDE4 inhibitor rolipram blocked
mitogenic synthesis of DNA, as determined by (3H)-thymidine incorporation into
renal cortical DNA, in FA-treated rats. FA injection caused an increase of more
than 10-fold in proliferating cell nuclear antigen (PCNA) in renal cortical
tissue; administration of the potent PDE3 inhibitor lixazinone or, to a lesser
degree, cilostazol suppressed these high PCNA levels, whereas rolipram alone had
no effect. The results indicate that FA-stimulated in vivo proliferation of renal
tubular epithelial cells is down-regulated by activation of a cAMP-PKA signaling
pathway linked to PDE3 isozymes. These observations are consistent with the
notion that negative crosstalk between cAMP signaling and mitogen-stimulated
signaling pathways regulates mitogenesis of renal cells of different terminal
differentiation, including tubular epithelial cells.
PMID- 9390638
TI - Evaluation of the hepatic iron index as a diagnostic criterion for genetic
hemochromatosis.
AB - The hepatic iron index was originally described as a useful test to discriminate
genetic hemochromatosis from alcoholic siderosis. To evaluate the hepatic iron
index as a diagnostic criterion, it is essential to evaluate a cohort of
hemochromatosis patients in whom the diagnosis has been established with great
certainty. The presence of a sibling with identical human leukocyte antigen (HLA)
and with iron overload was considered to be the gold standard for the diagnosis.
Hepatic iron index was reviewed retrospectively in 55 homozygotes and in 189
patients who did not have hemochromatosis and were referred for hepatic iron
analysis. Four of 55 homozygotes (7%) had a hepatic iron index of < or = 1.9.
Hepatic iron concentration was increased in all 4 patients, ranging from 36 to
100 micromol/gm dry weight, (normal value <35.5 micromol/gm). Twelve of 189 (6%)
patients without hemochromatosis had hepatic iron indexes > 1.9. The positive
likelihood ratio for a hepatic iron index of 1.9 was 12.4. Area under the
receiver operating characteristic curve was 0.94 (0.9 to 0.99, 95% confidence
interval). The hepatic iron index remains a useful tool in the diagnosis of
genetic hemochromatosis. However, it should not be an absolute criterion for the
diagnosis and should be interpreted in combination with clinical assessment and
genetic studies.
PMID- 9390639
TI - Viridans streptococcal isolates from patients with septic shock induce tumor
necrosis factor-alpha production by murine macrophages.
AB - Viridans streptococci are an important cause of bacteremia and septic shock in
neutropenic patients, especially patients receiving chemotherapeutic agents that
induce severe mucositis. The mechanisms by which viridans streptococci cause
septic shock are unclear. We hypothesized that septic shock due to viridans
streptococci is attributable to host cytokine production. Three clinical isolates
of viridans streptococci were evaluated for their ability to induce production of
tumor necrosis factor-alpha (TNF-alpha) by RAW 264.7 murine macrophages. These
three strains of viridans streptococci induced TNF-alpha in a dose-dependent
fashion, and the kinetics of TNF-alpha induction were similar to those observed
with a clinical isolate of Escherichia coli.
PMID- 9390640
TI - Energy-dependent expression of platelet-von Willebrand factor on the surface of
unstimulated and stimulated platelets.
AB - We have studied the energy requirements (adenosine triphosphate) for the
expression of platelet-von Willbrand factor on platelets under conditions in
which glycolysis and/or oxidative phosphorylation were inhibited. We found that
platelet-vWf expression on the surfaces of both unstimulated and stimulated
platelets required energy and was maximally decreased when metabolic ATP was
maximally depleted. Platelet-vWf expression correlated directly with estimates of
adenylate energy charge in both unstimulated and stimulated platelets. In
addition, platelet shape change and agonist-induced intracellular Ca2+ flux were
maintained at lower AECs than were either platelet aggregation or alpha-granule
secretion. Our results indicate that the surface expression of platelet-vWf on
unstimulated platelets is a dynamic process, and that energy is required to
maintain basal amounts of platelet-vWf on the platelet surface. Our data also
suggest that the metabolic ATP required to effect changes in platelet shape is
less than that necessary to maintain basal platelet-vWf surface expression or to
produce full alpha-granule secretion. We show that platelet-shape change in the
absence of alpha-granule secretion can result in an increase in platelet-vWf
surface expression.
PMID- 9390641
TI - Inhibition of proliferation and induction of apoptosis by doxycycline in cultured
human osteosarcoma cells.
AB - Matrix metalloproteinases (MMPs) play a major role in the phenomena of growth,
invasion, and metastasis of malignant disease. We studied the effects of
doxycycline, a synthetic tetracycline that has been shown to suppress MMP
activity in other solid tumors, on osteosarcoma (OSA) cell proliferation and MMP
activity in vitro. OSA cells from 6 patients and from one established human tumor
cell line (U2OS) (American Type Culture Collection) were cultured in the presence
or absence of doxycycline. Doxycycline (10 microg/ml) suppressed OSA cell
proliferation threefold to sevenfold in all cultures. MMP activity was assessed
by gelatin zymography and was diminished by approximately 50% in all cultures. We
examined the hypothesis that induction of apoptosis is one of the mechanisms by
which doxycycline inhibits OSA cell proliferation. Ethidium bromide-stained gels
of DNA from cells grown in the presence of 5 microg/ml and 10 microg/ml of
doxycycline revealed laddering consistent with apoptosis after 24 hours in
culture. The demonstration that doxycycline suppresses cell proliferation and MMP
activity and induces apoptosis in human OSA cells in vitro suggests that this
well-tolerated oral agent may be effective in the in vivo treatment of OSA.
PMID- 9390642
TI - Proinflammatory cytokines: indicators of infection in high-risk patients.
AB - Proinflammatory cytokines play an eminent role in pathophysiology of infection
and inflammation. Their actual clinical importance is, however, uncertain. In
this study, we tested the hypothesis that inflammatory cytokines could be useful
in detection of infections in high-risk patients. We prospectively studied the
diagnostic value of determination of concentrations of interleukin-6 (IL-6),
tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and the 55
and 75-kd soluble TNF receptors (sTNFR-p55 and sTNFR-p75) in detection of
nosocomial infections in 52 patients with acute ischemic stroke, as an exemplary
high-risk group, and compared these findings to those of conventional
inflammatory indicators of inflammation (C-reactive protein and leukocyte count).
After 1 week of hospitalization, 27% of the patients had minor or moderately
severe nosocomial infections. This subpopulation exhibited significantly
increased concentrations of IL-6 and sTNFR-p55 but not of IL-1beta, TNF-alpha, or
sTNFR-p75. As expected, levels of C-reactive protein and leukocytes were
increased in infected patients. The sensitivity and specificity for detection of
nosocomial infections at day 7 of hospitalization was highest for IL-6, followed
by C-reactive protein and the leukocyte count. The data suggest that the
proinflammatory cytokine IL-6, in addition to its considerable pathophysiologic
importance in systemic inflammation, may be valuable in detection of infections
in high-risk patients.
PMID- 9390643
TI - Heterozygosity for the Leiden mutation of the factor V gene, a common
pathoetiology for osteonecrosis of the jaw, with thrombophilia augmented by
exogenous estrogens.
AB - We assessed whether heterozygosity for the thrombophilic Leiden mutation of the
factor V gene (MFV) was pathogenetic for alveolar osteonecrosis of the jaw and
chronic facial pain (neuralgia-inducing cavitational osteonecrosis (NICO)) in 89
patients with NICO. A second specific aim was to assess for thrombophilic
synergism between exogenous estrogens and MFV for development of osteonecrosis of
the jaw. MFV was found in 24% of the patients, 16 (21%) of 76 women and 5 (39%)
of 13 men. The mutation was much less common in healthy normal controls: 3 (3%)
of 101 women (chi2 = 14.8, p = 0.001) and 4 (3.7%) of 108 men (chi2 = 20.4, p =
0.001). Patients with and without MFV did not differ in tissue plasminogen
activator activity, plasminogen activator inhibitor activity, proteins C and S,
lipoprotein (a), or anticardiolipin antibodies (p > 0.05). Use of standard-dose
oral contraceptives and/or postmenopausal estrogens before the development of
NICO was more common in female patients with MFV (13 (81%) of 16) than in those
without it (23 (38%) of 60; chi2 = 9.33, p = 0.002). When the thrombophilic
effects of such exogenous estrogens were superimposed on the familial resistance
to activated protein C associated with MFV, thrombophilia was augmented and the
risk of osteonecrosis was increased. Since heterozygosity for this mutation
occurs in at least 3% of unselected, healthy women, measurement of resistance to
activated protein C and MFV would identify women at high risk for venous
thrombosis and osteonecrosis, in whom use of oral contraceptives or
postmenopausal estrogens might be contraindicated, while identifying a much
larger group of women (approximately 97%) without the mutation whose risk from
exogenous estrogens would be low.
PMID- 9390644
TI - Neuroprotective effects of inhibiting poly(ADP-ribose) synthetase on focal
cerebral ischemia in rats.
AB - Poly(adenosine 5'-diphosphoribose) synthetase (PARS) has been described as an
important candidate for mediation of neurotoxicity by nitric oxide. In the
current study, we demonstrate for the first time that in vivo administration of a
potent PARS inhibitor, 3,4-dihydro 5-[4-1(1-piperidinyl) butoxy]-1(2H)
isoquinolinone, leads to a significant reduction of infarct volume in a focal
cerebral ischemia model in the rat. Focal cerebral ischemia was produced by
cauterization of the right distal middle cerebral artery (MCA) with bilateral
temporary common carotid artery occlusion for 90 minutes. 3,4-Dihydro 5[4-(1
piperidinyl) butoxy]-1(2H)-isoquinolinone was dissolved in dimethyl sulfoxide and
injected intraperitoneally. Animals were treated 2 hours before MCA occlusion
(control, n = 14; 5 mg/kg, n = 7; 10 mg/kg, n = 7; 20 mg/kg, n = 7; 40 mg/kg, n =
7), and 2 hours after MCA occlusion (same doses as before treatment). Twenty-four
hours after MCA occlusion, the total infarct volume was measured using 2,3,5
triphenyltetrazolium chloride. Inhibition of PARS leads to a significant decrease
in the damaged volume in the 5 mg/kg-treated group (106.7 +/- 23.2 mm3; mean +/-
SD, P < 0.002), the 10 mg/kg-treated group (76.4 +/- 16.8 mm3, P < 0.001), and
the 20 mg/kg-treated group (110.2 +/- 42.0 mm3, P < 0.02) compared with the
control group (165.2 +/- 34.0 mm3). The substantial reduction in infarct volume
indicates that the activation of PARS may play an important role in the
pathogenesis of brain damage in cerebral ischemia through intracellular energy
depletion.
PMID- 9390645
TI - Ischemic brain injury is mediated by the activation of poly(ADP
ribose)polymerase.
AB - Poly(ADP-ribose)polymerase (PARP, EC 2.4.2.30), an abundant nuclear protein
activated by DNA nicks, mediates cell death in vitro by nicotinamide adenine
dinucleotide (NAD) depletion after exposure to nitric oxide. The authors examined
whether genetic deletion of PARP (PARP null mice) or its pharmacologic inhibition
by 3-aminobenzamide (3-AB) attenuates tissue injury after transient cerebral
ischemia. Twenty-two hours after reperfusion following 2 hours of filamentous
middle cerebral artery occlusion, ischemic injury was decreased in PARP-/- and
PARP+/- mice compared with PARP+/+ litter mates, and also was attenuated in
129/SV wild-type mice after 3-AB treatment compared with controls. Infarct
sparing was accompanied by functional recovery in PARP-/- and 3-AB-treated mice.
Increased poly(ADP-ribose) immunostaining observed in ischemic cell nuclei 5
minutes after reperfusion was reduced by 3-AB treatment. Levels of NAD--the
substrate of PARP--were reduced 2 hours after reperfusion and were 35% of
contralateral levels at 24 hours. The decreases were attenuated in PARP-/- mice
and in 3-AB-treated animals. Poly(ADP-ribose)polymerase cleavage by caspase-3
(CPP-32) has been proposed as an important step in apoptotic cell death. Markers
of apoptosis, such as oligonucleosomal DNA damage, total DNA fragmentation, and
the density of terminal deoxynucleotidyl transferase dUTP nick-end-labelled
(TUNEL +) cells, however, did not differ in ischemic brain tissue of PARP-/- mice
or in 3-AB-treated animals versus controls, although there were differences in
the number of TUNEL-stained cells reflecting the decrease in infarct size. Thus,
ischemic brain injury activates PARP and contributes to cell death most likely by
NAD depletion and energy failure, although the authors have not excluded a role
for PARP in apoptotic cell death at earlier or later stages in ischemic cell
death. Inhibitors of PARP activation could provide a potential therapy in acute
stroke.
PMID- 9390646
TI - Calcium-activated K+ channels in cerebral arterioles in piglets are resistant to
ischemia.
AB - Our previous studies indicate that function of ATP-dependent K+ channels (K(ATP))
in cerebral arterioles is suppressed after ischemia. In the current study, we
examined pial arteriolar responses to forskolin, dibutyryl-cAMP, NS-1619, and
methionine (met)-enkephalin, activators of calcium-dependent K+ channels (K(Ca))
before and 1 hour after 10 minutes of total, global ischemia in anesthetized
piglets. Arteriolar diameters were measured using a closed cranial window and
intravital microscopy. All pharmacologic agents were given topically. Baseline
diameters were approximately 100 microm, and diameters had returned to normal by
1 hour after ischemia. Forskolin dilated arterioles by 9 +/- 3%, 18 +/- 4%, and
31 +/- 12% at 5 x 10(-8), 5 x 10(-7), and 10(-6) mol/L, respectively (P < 0.05, n
= 10). In addition, dibutyryl-cAMP dilated arterioles by 8 +/- 2% at 10(-4) mol/L
and 14 +/- 2% at 3 x 10(-4) mol/L (P < 0.05, n = 6). Also, NS-1619 increased
diameter of arterioles by 9 +/- 2% at 10(-7) mol/L and 17 +/- 9% at 10(-5) mol/L
(P < 0.05, n = 5). Finally, met-enkephalin dilated arterioles by 9 +/- 2% at 10(
8) mol/L and 16 +/- 3% at 10(-6) mol/L (P < 0.05, n = 5). At 1 hour after
ischemia, arteriolar dilator effects to forskolin, dibutyryl-cAMP and NS-1619,
and met-enkephalin were intact. Thus, in contrast to K(ATP), K(Ca) in cerebral
arterioles are resistant to ischemic stress.
PMID- 9390647
TI - Endothelin-B receptors in cerebral resistance arterioles and their functional
significance after focal cerebral ischemia in cats.
AB - In the cerebral circulation, endothelin-A receptor activation mediates marked
prolonged vasoconstriction whereas endothelin-B (ETB) receptor activation effects
dilation. In contrast to some peripheral vascular beds, ET(B) receptor-induced
vasoconstriction has not yet been demonstrated in brain vessels. In this study in
chloralose-anesthetized cats, with perivascular microapplications of ET(B)
selective agonist (BQ-3020) and antagonist (BQ-788), we investigated whether
ET(B) receptor-mediated constriction could be uncovered in cortical arterioles in
vivo. In addition, we examined whether normal dilator response to ET(B) receptor
activation is preserved in postischemic cerebral arterioles. The first
microapplication of the selective ET(B) receptor agonist BQ-3020 (1 micromol/L)
onto a pial cortical arteriole elicited marked dilation (caliber increased by
26.3 +/- 15.1% from preinjection baseline). A second application of BQ-3020 (10
minute interval) onto the same vessel failed to evoke any significant vasomotor
response. Subsequent (third and fourth) adventitial microapplication of the ET(B)
receptor agonist on the same arteriolar site effected a significant constriction
of cerebral arterioles (-15.3 +/- 12.7% and -9.7 +/- 6.3% from preinjection
baseline, respectively, at 20 and 30 minutes after the first application). The
pial arterioles did not display tachyphylaxis to repeated applications of
potassium (10 mmol/L). The perivascular application of the ET(B) receptor
antagonist BQ-788 (0.001 to 1 micromol/L) had no effect on arteriolar caliber per
se but blocked both BQ-3020-induced dilation (inhibitory concentration
approximately 5 nmol/L) and vasoconstriction elicited by repeated activation of
ET(B) receptors. After middle cerebral artery occlusion, most of the arterioles
examined displayed a sustained dilation. The microapplication of BQ-3020 into the
perivascular space surrounding postischemic dilated arterioles elicited a
constriction of a similar magnitude to that induced by application of CSF (-17 +/
7% and -17 +/- 7% from preinjection baseline, respectively). The adventitial
microapplication of the ET(B) receptor antagonist (BQ-788, 0.1 micromol/L) on
postocclusion dilated pial arterioles effected no change in the arteriolar
caliber when compared with preinjection baseline. This BQ-788-induced response
was significantly different from that induced by perivascular microinjection of
CSF (P < 0.001, analysis of variance). These investigations indicate that (1)
repeated activation of ET(B) receptors displays tachyphylaxis of the vasodilator
response but also uncovers significant constriction of cerebral arterioles in
vivo; (2) the ability of BQ-3020 to elicit dilation is lost within 30 minutes of
induced focal ischemia; and (3) ET(B)-mediated contractile tone contributes in a
small but significant manner in limiting postischemia dilation of cortical pial
arterioles.
PMID- 9390648
TI - Activity of mitochondrial respiratory chain enzymes after transient focal
ischemia in the rat.
AB - Previous results demonstrated that after 2-hour middle cerebral artery occlusion
(MCAO) in the rat, 1- to 2-hour recirculation temporarily restored the
bioenergetic state and mitochondrial function, but secondary deterioration took
place after 4 hours. The authors measured the activity of mitochondrial
respiratory chain complexes, citrate synthase, and glutamate dehydrogenase as
possible targets of secondary damage. Focal and penumbral tissues were sampled in
the control condition, after 2 hours of MCAO, and after 1, 2, or 4 hours of
postischemic recirculation; two groups were treated with alpha-phenyl-N-tert
butyl-nitrone (PBN). Complex IV activity transiently decreased after MCAO, but
after recirculation all measured activities returned to control values.
PMID- 9390649
TI - Profiles of cortical tissue depolarization in cat focal cerebral ischemia in
relation to calcium ion homeostasis and nitric oxide production.
AB - Cortical depolarization was investigated in a topographic gradient of ischemic
density after 1-hour transient middle cerebral artery occlusion in halothane
anesthetized cats. A laser Doppler flow probe, an ion-selective microelectrode,
and a nitric oxide (NO) electrode measured regional CBF (rCBF), direct current
(DC) potential, extracellular Ca2+ concentration ([Ca2+]o), and NO concentration
in ectosylvian and suprasylvian gyri of nine animals. Recordings revealed 12 of
18 sites with persistent negative shifts of the DC potential, severe rCBF
reduction, and a drop of [Ca2+]o characteristic for core regions of focal
ischemia. Among these sites, two types were distinguished by further analysis. In
Type 1 (n = 5), rapid, negative DC shifts resembled anoxic depolarization as
described for complete global ischemia. In this type, ischemia was most severe
(8.9 +/- 2.5% of control rCBF), [Ca2+]o dropped fast and deepest (0.48 +/- 0.20
mmol/L), and NO concentration increased transiently (36.1 +/- 24.0 nmol/L at 2.5
minutes), and decreased thereafter. In Type 2 (n = 7), the DC potential fell
gradually over the first half of the ischemic episode, rCBF and [Ca2+]o
reductions were smaller than in Type 1 (16.2 +/- 8.2%; 0.77 +/- 0.41 mmol/L), and
NO increased continuously during ischemia (53.1 +/- 60.4 nmol/L at 60 minutes)
suggesting that in this type NO most likely exerts its diverse actions on
ischemia-threatened tissue. In the remaining six recording sites, a third type
(Type 3) attributable to the ischemic periphery was characterized by minimal DC
shifts, mild ischemia (37.2 +/- 13.3%), nonsignificant alterations of [Ca2+]o,
but decreased NO concentrations during middle cerebral artery occlusion.
Reperfusion returned the various parameters to baseline levels within 1 hour, the
recovery of [Ca2+]o and NO concentration being delayed in Type 1. An NO synthase
inhibitor (N(G)-nitro-L-arginine, 50 mg/kg intravenously; four animals) abolished
NO elevation during ischemia. In conclusion, even in the core of focal cerebral
ischemia and reperfusion, different ischemic densities produce different types of
cortical tissue manifesting distinctive chronological profiles of depolarization,
Ca2+ influx, and NO synthesis.
PMID- 9390650
TI - The effect of nitric oxide synthase inhibition on acute platelet accumulation and
hemodynamic depression in a rat model of thromboembolic stroke.
AB - The relative importance of hemodynamic factors in the pathogenesis of thrombotic
or embolic stroke is unclear. Of particular therapeutic interest are those
substances that facilitate vasodilation and the clearance of platelet aggregates
in the compromised microvasculature. A likely contributor to these functions is
nitric oxide because it is known to inhibit platelet aggregability and promote
vascular relaxation. To investigate the involvement of nitric oxide in the
hemodynamic changes after experimental ischemia, photochemically induced
nonocclusive common carotid artery thrombosis (CCAT) was studied. CCAT is a rat
model of unilateral carotid artery stenosis and platelet embolization to the
brain. This study characterized the acute hemodynamic consequences of CCAT and
the resultant pattern of platelet deposits with and without nitric oxide synthase
inhibition by nitro-L-arginine methyl ester (L-NAME). In addition, the subacute
local cerebral blood flow changes were studied at 24 hours. Right CCAT was
produced in 30 male Wistar rats injected with (111)In-labeled platelets. Between
5 and 15 minutes after thrombosis, rats were treated with either 15 mg/kg of L
NAME (intravenously) or saline vehicle. Hemodynamic changes were studied 30 to 45
minutes after thrombosis using [14C]iodoantipyrine autoradiography. Eight coronal
levels were analyzed, and cortical and subcortical regions of interest were
defined. Significant increases were observed in total platelets in the
ipsilateral hemisphere after L-NAME treatment, and in the distribution of
platelets in the anterior frontal and occipital cortices with nitric oxide
synthase inhibition, encompassing the anterior and posterior border zone areas of
the ipsilateral cortex. Otherwise, foci of labeled platelets were detected
throughout the ipsilateral and contralateral hemispheres. Mean local cerebral
blood flow images (n = 5) revealed a moderate bilateral global reduction in flow
acutely, which normalized in the untreated thrombosed group by 24 hours. In
contrast, the L-NAME-treated groups (sham and experimental) had lasting,
widespread reductions in flow of approximately 25%. Pairwise comparisons between
groups showed that CCAT/L-NAME was significantly different from shams in the
corpus callosum and different from L-NAME shams in the internal capsule (P <
0.05) These hemodynamic and platelet accumulation changes may partially account
for the aggravation of cognitive and sensorimotor deficits previously reported in
this model of thromboembolic stroke.
PMID- 9390651
TI - Local uncoupling of the cerebrovascular and metabolic responses to somatosensory
stimulation after neuronal nitric oxide synthase inhibition.
AB - It has recently been shown, using either genetically engineered mutant mice
(nitric oxide synthase [NOS] knockout) or specific pharmacological tools, that
type I NOS (neuronal isoform of NOS, [nNOS]) participates in coupling cerebral
blood flow to functional activation. However, it has not been clearly established
whether the associated metabolic response was preserved under nNOS inhibition and
whether this action was exerted homogeneously within the brain. To address these
issues, we analyzed the combined circulatory and metabolic consequences of
inhibiting the nNOS both at rest and during functional activation in the rat
anesthetized with alpha-chloralose. Cerebral blood flow and cerebral glucose use
(CGU) were measured autoradiographically using [14C]iodoantipyrine and [14C]2
deoxyglucose during trigeminal activation induced by unilateral whiskers
stimulation in vehicle- and 7-nitroindazole-treated rats. Our data show that
inhibition of nNOS globally decreased CBF without altering CGU, indicating that
NO-releasing neurons play a significant role in maintaining a resting
cerebrovascular tone in the whole brain. During whisker stimulation, nNOS
inhibition totally abolished the cerebrovascular response only in the second
order relay stations (thalamus and somatosensory cortex) of the trigeminal relay
without altering the metabolic response. These findings provide evidence that the
involvement of neurally-derived NO in coupling flow to somatosensory activation
is region-dependent, and that under nNOS inhibition, CBF and CGU may vary
independently during neuronal activation.
PMID- 9390652
TI - Functional activation of cerebral blood flow after cardiac arrest in rat.
AB - After a period of global cerebral ischemia, CO2 reactivity and the hemodynamic
metabolic activation to functional stimulation are transiently suppressed. This
raises the question of whether the impaired functional coupling reflects
disturbances of functional integrity of the brain or an impaired cerebrovascular
reactivity. We, therefore, compared the recovery of CO2 reactivity with that of
somatosensory evoked potentials, functional flow activation and neurologic
deficits in a rodent model of cardiac arrest-induced cerebral ischemia, followed
by up to 7 days of reperfusion. Cardiac arrest of 10 minutes' duration was
produced in 24 animals by electrical fibrillation of the heart. Five animals were
sham-operated controls. Resuscitation was performed by external cardiac massage,
using standard resuscitation procedures. Functional activation was carried out
under chloralose anesthesia by electrical stimulation of forepaws. CO2 reactivity
was tested by ventilation of animals with 6% CO2. During functional and
hypercapnic stimulation CBF was measured in the somatosensory cortex using laser
Doppler flowmetry, and at the end of the experiment by 14C-iodoantipyrine
autoradiography. Neurologic deficits were scored by evaluating consciousness and
various sensory and motor functions. In control animals 6% CO2 increased CBF
measured by laser-Doppler flowmetry by 28.8% +/- 8.7%. Forepaw stimulation
generated somatosensory evoked potentials with an amplitude of 750 +/- 217 microV
and increased CBF measured by laser-Doppler flowmetry by 86.0% +/- 18.1%. After
return of spontaneous circulation, CO2 reactivity was transiently reduced to
about 30% of control at 1 hour of reperfusion (P < 0.05) but returned to near
control at 5 hours. Somatosensory evoked potential amplitudes were reduced to 15%
of control at 45 minutes of reperfusion and returned to only 50% to 60% at 3 and
7 days after return of spontaneous circulation (P < 0.05). Functional activation
of blood flow was completely suppressed during the first hour after return of
spontaneous circulation but also recovered to 50% to 60% of control at 3 days
after return of spontaneous circulation (P < 0.05). Linear regression analysis
revealed a significant correlation between recovery of functional activation of
blood flow and both recovery of the amplitude of somatosensory evoked potentials
(P = 0.03) and the neurologic deficit score (P = 0.02), but not between
neurologic deficit score and recovery of CO2 reactivity or somatosensory evoked
potential amplitudes. These data demonstrate that the suppression of functional
activation of blood flow after 10 minutes cardiac arrest is not related to
impairment of coupling mechanisms but reflects ongoing disturbances of the
functional integrity of the brain. Assessment of functional flow coupling is a
reliable way to study postischemic recovery of the brain.
PMID- 9390653
TI - Early white blood cell dynamics after traumatic brain injury: effects on the
cerebral microcirculation.
AB - Increasing clinical and experimental evidence suggests that traumatic brain
injury (TBI) elicits an acute inflammatory response. In the present study we
investigated whether white blood cells (WBC) are activated in the cerebral
microcirculation early after TBI and whether WBC accumulation affects the
posttraumatic cerebrovascular response. Twenty-four anesthetized rabbits had
chronic cranial windows implanted 3 weeks before experimentation. Animals were
divided into four experimental groups and were studied for 7 hours (groups I,
IIa, and III) or 2 hours (group IIb). Intravital fluorescence videomicroscopy was
used to visualize WBC (rhodamine 6G, intravenously), pial vessel diameters, and
blood-brain barrier (BBB) integrity (Na+-fluorescein) at 6 hours (groups I, IIa,
and III) or 1 hour (group IIb) after TBI. Group I (n = 5) consisted of sham
operated animals. Groups IIa (n = 7) and IIb (n = 5) received fluid-percussion
injury at 1 hour. Group III (n = 7) received fluid-percussion injury and 1 mg/kg
anti-adhesion monoclonal antibody (MoAb) "IB4" 5 minutes before injury. Venular
WBC sticking, intracranial pressure (ICP), and arterial vessel diameters
increased significantly for 6 hours after trauma. IB4 reduced WBC margination and
prevented vasodilation. Intracranial pressure was not reduced by treatment with
IB4. Blood-brain barrier damage occurred at 1 hour but not at 6 hours after TBI
and was independent of WBC activation. This first report using intravital
videomicroscopy to study the inflammatory response after TBI reveals upregulated
interaction between WBC and cerebral endothelium that can be manipulated
pharmacologically. White blood cell activation is associated with pial arteriolar
vasodilation. White blood cells do not induce BBB breakdown less than 6 hours
after TBI and do not contribute to posttraumatic ICP elevation. The role of WBC
more than 6 hours after TBI should be investigated further.
PMID- 9390654
TI - Heparin inhibits leukocyte rolling in pial vessels and attenuates inflammatory
changes in a rat model of experimental bacterial meningitis.
AB - Heparin is a natural proteoglycan that was first described in 1916. In addition
to its well characterized effect on blood coagulation, it is becoming clear that
heparin also modulates inflammatory processes on several levels, including the
interference with leukocyte-endothelium interaction. Anecdotal observations
suggest a better clinical outcome of heparin-treated patients with bacterial
meningitis. The authors demonstrate that heparin, a glycosaminoglycan, inhibits
significantly in the early phase of experimental pneumococcal meningitis the
increase of 1) regional cerebral blood flow (125 +/- 18 versus 247 +/- 42%), 2)
intracranial pressure (4.5 +/- 2.0 versus 12.1 +/- 2.2 mm Hg), 3) brain edema
(brain water content: 78.23 +/- 0.33 versus 79.49 +/- 0.46%), and 4) influx of
leukocytes (571 +/- 397 versus 2400 +/- 875 cells/microL) to the cerebrospinal
fluid compared with untreated rats. To elucidate the possible mechanism of this
observation, the authors investigated for the first time leukocyte rolling in an
inflammatory model in brain venules by confocal laser scanning microscopy in
vivo. Heparin significantly attenuates leukocyte rolling at 2, 3, and 4 hours
(2.8 +/- 1.3 versus 7.9 +/- 3.2/100 microm/min), as well as leukocyte sticking at
4 hours (2.1 +/- 0.4 versus 3.5 +/- 1.0/100 microm/min) after meningitis
induction compared with untreated animals. The authors conclude that heparin can
modulate acute central nervous system inflammation and, in particular, leukocyte
endothelium interaction, a key process in the cascade of injury in bacterial
meningitis. They propose to evaluate further the potential of heparin in central
nervous system inflammation in basic and clinical studies.
PMID- 9390655
TI - Trafficking of amino acids between neurons and glia in vivo. Effects of
inhibition of glial metabolism by fluoroacetate.
AB - Glial-neuronal interchange of amino acids was studied by 13C nuclear magnetic
resonance spectroscopy of brain extracts from fluoroacetate-treated mice that
received [1,2-(13)C]acetate and [1-(13)C]glucose simultaneously. [13C]Acetate was
found to be a specific marker for glial metabolism even with the large doses
necessary for nuclear magnetic resonance spectroscopy. Fluoroacetate, 100 mg/kg,
blocked the glial, but not the neuronal tricarboxylic acid cycles as seen from
the 13C labeling of glutamine, glutamate, and gamma-aminobutyric acid. Glutamine,
but not citrate, was the only glial metabolite that could account for the
transfer of 13C from glia to neurons. Massive glial uptake of transmitter
glutamate was indicated by the labeling of glutamine from [1-(13)C]glucose in
fluoroacetate-treated mice. The C-3/C-4 enrichment ratio, which indicates the
degree of cycling of label, was higher in glutamine than in glutamate in the
presence of fluoroacetate, suggesting that transmitter glutamate (which was
converted to glutamine after release) is associated with a tricarboxylic acid
cycle that turns more rapidly than the overall cerebral tricarboxylic acid cycle.
PMID- 9390656
TI - Imaging experimental brain tumors with 1-aminocyclopentane carboxylic acid and
alpha-aminoisobutyric acid: comparison to fluorodeoxyglucose and
diethylenetriaminepentaacetic acid in morphologically defined tumor regions.
AB - The goal of this study was to evaluate the differences and define the advantages
of imaging experimental brain tumors in rats with two nonmetabolized amino acids,
1-aminocyclopentane carboxylic (ACPC) acid and alpha-aminoisobutyric (AIB) acid
compared with imaging with fluorodeoxyglucose (FDG) or the gallium
diethylenetriaminepentaacetic acid chelate (Ga-DTPA). 1-aminocyclopentane
carboxylic acid, AIB, and FDG autoradiograms were obtained 60 minutes after
intravenous injection to simulate positron emission tomography (PET) imaging,
whereas the Ga-DTPA autoradiograms were obtained 5 or 10 minutes after injection
to simulate gadolinium (Gd)-DTPA-enhanced magnetic resonance (MR) images. Three
experimental tumors were studied (C6, RG2, and Walker 256) to provide a range of
tumor types. Triple-label quantitative autoradiography was performed, and
parametric images of the apparent distribution volume (Va, mL/g) for ACPC or AIB,
relative glucose metabolism (R, micromol/100 g/min), vascular permeability to Ga
DTPA (K1, microL/min/g), and histology were obtained from the same tissue
section. The four images were registered in an image array processor, and regions
of interest in tumor and contralateral brain were defined on morphologic criteria
(histology) and were transferred to the autoradiographic images. A comparative
analysis of all measured values was performed. The location and morphologic
characteristics of the tumor had an effect on the images and measurements of Va,
R, and K1. Meningeal extensions of all three tumors consistently had the highest
amino acid uptake (Va) and vascular permeability (K1) values, and subcortical
portions of the tumors usually had the lowest values. Va and R (FDG) values
generally were higher in tumor regions with high-cell density and lower in
regions with low-cell density. Tumor areas identified as "impending" necrosis on
morphologic criteria consistently had high R values, but little or no change in
Va or K1. Tumor necrosis was seen consistently only in the larger Walker 256
tumors; low values of R and Va for AIB (less for ACPC) were measured in the
necrotic-appearing regions, whereas K1 was not different from the mean tumor
value. The highest correlations were observed between vascular permeability (K1
for Ga-DTPA) and Va for AIB in all three tumors; little or no correlation between
vascular permeability and R was observed. The advantages of ACPC and AIB imaging
were most convincingly demonstrated in C6 gliomas and in Walker 256 tumors. 1
aminocyclopentane was substantially better than FDG or Ga-DTPA for identifying
tumor infiltration of adjacent brain tissue beyond the macroscopic border of the
tumor; ACPC also may be useful for identifying low-grade tumors with an intact
blood-brain barrier. Contrast-enhancing regions of the tumors were visualized
more clearly with AIB than with FDG or Ga-DTPA; viable and necrotic-appearing
tumor regions could be distinguished more readily with AIB than with FDG. [11C]
labeled ACPC and AIB are likely to have similar advantages for imaging human
brain tumors with PET.
PMID- 9390657
TI - In vivo regulation of DOPA decarboxylase by dopamine receptors in rat brain.
AB - To test the hypothesis that dopamine (DA) receptors influence cerebral DOPA
decarboxylase (DDC) activity in vivo, we used HPLC to measure the kinetics of the
cerebral uptake and metabolism of [3H]DOPA in carbidopa-treated rats, and in rats
also treated acutely with a DA receptor antagonist (flupenthixol, 2 mg/kg,
intraperitoneally) or a DA receptor agonist (apomorphine, 200 microg/g,
subcutaneously). The unidirectional blood-brain clearance of [3H]DOPA (K1DOPA,
0.030 mL g(-1) min(-1)) increased by 50% after flupenthixol. The magnitudes of
the relative DDC activity (k3DOPA) in striatum (0.20 min(-1)), olfactory tubercle
(0.11 min(-1)), and hypothalamus (0.15 min(-1)) of carbidopa-treated rats were
doubled with flupenthixol, but cortical DDC activity was unaffected (0.02 min(
1)). Apomorphine reduced the magnitude of k3DOPA in striatum by 20%. The rate
constant for catabolism of [3H]DA formed in brain (k7', monoamine oxidase [MAO]
activity), which ranged from 0.025 min(-1) in striatum to 0.08 min(-1) in
hypothalamus of carbidopa-treated rats, globally increased 2- to 4-fold after
flupenthixol, and decreased to 0.003 min(-1) in striatum after apomorphine. These
in vivo results confirm the claim that acute blockade of DA receptors with
flupenthixol stimulates the synthesis of [3H]DA from [3H]DOPA, and that this
[3H]DA is subject to accelerated catabolism. Conversely, activation of the DA
receptors with apomorphine inhibits DDC activity and DA catabolism.
PMID- 9390658
TI - Effects of extracranial radioactivity on measurement of cerebral glucose
metabolism by rat-PET with [18F]-2-fluoro-2-deoxy-D-glucose.
PMID- 9390659
TI - AAEM minimonograph #26: the electrodiagnosis of carpal tunnel syndrome. American
Association of Electrodiagnostic Medicine.
AB - The electrodiagnosis of carpal tunnel syndrome (CTS) is reviewed, including
discussions of old and new techniques of motor and sensory nerve conduction,
anomalous innervation, and needle electrode examination. A variety of sensitive
nerve conduction studies (NCSs) are available for the evaluation of a patient
with suspected CTS. For any particular patient, the NCS method chosen by the
clinical neurophysiologist may vary for a number of reasons, including the
severity of the deficit and the presence of superimposed conditions.
PMID- 9390660
TI - Interaction of thyroid state and denervation on skeletal myosin heavy chain
expression.
AB - The goal of this study was to examine the effects of altered thyroid state and
denervation (Den) on skeletal myosin heavy chain (MHC) expression in the
plantaris and soleus muscles. Rats were subjected to unilateral denervation (Den)
and randomly assigned to one of three groups: (1) euthyroid; (2) hyperthyroid;
(3) and hypothyroid. Denervation caused severe muscle atrophy and muscle-type
specific MHC transformation. Denervation transformed the soleus to a faster
muscle, and its effects required the presence of circulating thyroid hormone. In
contrast, denervation transformed the plantaris to a slower muscle independently
of thyroid state. Furthermore, thyroid hormone effects did not depend upon
innervation status in the soleus, while they required the presence of the nerve
in the plantaris. Collectively, these findings suggest that both thyroid hormone
and intact nerve (a) differentially affect MHC transformations in fast and slow
muscle; and (b) are important factors in regulating the optimal expression of
both type I and IIB MHC genes. This research suggests that for patients with
nerve damage and/or paralysis, both muscle mass and biochemical properties can
also be affected by the thyroid state.
PMID- 9390661
TI - Smooth muscle electromyography from rat urethra.
AB - Electrical signals recorded from the penis have been suggested as reflecting
electromyographic activity in the underlying smooth muscles. In order to verify
this assertion, we manipulated the signal recorded from rat urethra surface.
Stimulation of the pelvic nerve brought about a reduction of activity (965 +/-
826 to 166 +/- 143 microV, root mean square of the power at range 0.005-1 Hz, P =
0.008), with a significant frequency-response relationship (P = 0.0002). This
effect was not altered by temporary closure of the aorta (P = 0.89), thus ruling
out hemodynamic artifact as a possible cause of signal change during stimulation.
Our findings support the assertion that the signal indeed reflects activity in
smooth muscle.
PMID- 9390662
TI - A randomized, controlled trial of creatine monohydrate in patients with
mitochondrial cytopathies.
AB - Fatigue in patients with mitochondrial cytopathies is associated with decreased
basal and postactivity muscle phosphocreatine (PCr). Creatine monohydrate
supplementation has been shown to increase muscle PCr and high-intensity power
output in healthy subjects. We studied the effects of creatine monohydrate
administration (5 g PO b.i.d. x 14 days --> 2 g PO b.i.d. x 7 days) in 7
mitochondrial cytopathy patients using a randomized, crossover design.
Measurements included: activities of daily living (visual analog scale); ischemic
isometric handgrip strength (1 min); basal and postischemic exercise lactate;
evoked and voluntary contraction strength of the dorsiflexors; nonischemic,
isometric, dorsiflexion torque (NIDFT, 2 min); and aerobic cycle ergometry with
pre- and post-lactate measurements. Creatine treatment resulted in significantly
(P < 0.05) increased handgrip strength, NIDFT, and postexercise lactate, with no
changes in the other measured variables. We concluded that creatine monohydrate
increased the strength of high-intensity anaerobic and aerobic type activities in
patients with mitochondrial cytopathies but had no apparent effects upon lower
intensity aerobic activities.
PMID- 9390663
TI - Computing normative ranges without recruiting normal subjects.
AB - Computing normative data by recruiting normal subjects is extremely difficult.
However, many who are examined in a typical clinical neurophysiology lab are
normal. In this study we show how to use this abundance of referred subjects to
compute normative distal latency statistics from the values themselves. If all
latencies are displayed on a frequency distribution, the very left side, the
shorter latencies, belong to the left side of the Gaussian "bell" of normal
subjects. By curve-fitting that side one can compute the coefficients of the
latter. We started with an initial range of 2.0-3.6 ms and then recursively added
data points until a "goodness-of-fit" criterion maximized. We computed these
coefficients from 982 median motor distal latencies, showing highly significant
fit (P < 0.00001): mean at 3.76 ms and SD of 0.45 ms. The data analyzed in this
study are only an example of the technique. The results are unique in that they
were derived mathematically, without using normal subjects.
PMID- 9390664
TI - Abscence of laminin alpha1 chain in the skeletal muscle of dystrophic dy/dy mice.
AB - In Duchenne muscular dystrophy (DMD) and laminin alpha2 defective congenital
muscular dystrophies (CMD) there are reports of an induction of laminin alpha1
chain in regenerating muscle fibers. These studies are based on
immunohistochemistry data with one monoclonal antibody alone. Based on these data
we sought to establish if the laminin alpha1 chain is induced in the muscle of
dy/dy mice. We found no evidence of induction of laminin alpha1 chain protein or
mRNA in dystrophic dy/dy skeletal muscle fibers as determined by
immunohistochemistry, Western blotting, Northern blotting, or PCR analysis. Our
data point to the need for additional immunological reagents specific for human
laminin-alpha1 to resolve whether the conflicting data on laminin-alpha1
distribution in human and mouse tissues is due to species differences or,
alternatively, due to differences in reagent specificity. Our data might be
important when designing therapy strategies for CMD.
PMID- 9390665
TI - Concentric and single fiber electrode spatial recording characteristics.
AB - A better appreciation of the specific spatial recording characteristics of the
single fiber and concentric needle electrode can result in more accurate
physiologic and theoretical interpretations of single fiber and quantitative
motor unit action potential analysis. We demonstrate by physical modeling that
the 90% and 99% amplitude sensitivity envelopes are not simple hemispherical
shapes. The 90% sensitivity concentric electrode volume does not extend beyond
the insulated portion of the 15 degree beveled surface between the core and
cannula and extends only 280 microm perpendicularly from the center of the core's
surface. The 99% envelope extends approximately 830 microm perpendicularly from
the core's center. This is a much smaller volume of sensitivity than exists for a
similarly modeled monopolar electrode. The 90% and 99% envelopes extend to 110
and 320 microm perpendicularly from the exposed single fiber core. Both the
single fiber and concentric needle volumes of sensitivity have specific
asymmetries described.
PMID- 9390666
TI - Human leukocyte antigen class I in polymyositis: leukocyte infiltrates,
regeneration, and impulse block.
AB - In polymyositis (PM), T-cell mediated myocytotoxicity is directed against
strongly human leukocyte antigen class I positive (HLA-I+) muscle fibers. Fiber
regeneration probably is partly responsible for this HLA-I up-regulation. We have
evaluated regeneration, denervation/impulse blockade, and focal leukocyte
infiltrates as possible HLA-I inducing factors in PM. Distinctive patterns of HLA
I, nerve cell adhesion molecule (NCAM), and vimentin expression accompany
denervation and regeneration. Regenerating fibers also have centralized nuclei.
Using semiquantitative methods, we examined strongly HLA-I+ fibers in PM muscle
biopsies for these markers. Sarcoplasmic HLA-I levels were related to the
presence of leukocyte infiltrates and invasion of fibers. Strongly HLA-I+ fibers
were frequently invaded, and regeneration-associated changes were usually
observed at sites of fiber damage. Sarcoplasmic HLA-I levels were stable along
intact fibers, also adjacent to leukocyte infiltrates. A majority of the strongly
HLA-I+ fibers were nonregenerating (NCAM+ only). Though other mechanisms cannot
be excluded, this suggests that impulse blockade or denervation may contribute to
extra HLA-I up-regulation in these fibers.
PMID- 9390667
TI - Acetazolamide reduces peripheral afferent transmission in humans.
AB - Carbonic anhydrase has been localized in skeletal muscle and nerve, thus,
inhibition with acetazolamide (ACZ) may alter nerve and/or muscle function in
healthy humans. ACZ (3 oral doses 14, 8, and 2 h prior to testing) reduced
isometric force (37%) and peak to peak electromyographic (EMG) amplitude (1.38 mV
to 0.83 mV), while increasing EMG latency associated with a unilateral Achilles
tendon-tap. Reflex recovery profiles, following a contralateral conditioning tap,
were similar in both placebo and ACZ experiments. ACZ led to significant changes
in Hmax/Mmax ratio (52.19/14.42 to 45.73/15.65) and H-reflex latency (34.18 +/-
2.54 ms to 35.24 +/- 2.74 ms). Motor nerve conduction velocity and maximal
voluntary isometric torque (knee extensors) were unaltered by ACZ. These data
suggest that inhibition of the tendon-tap reflex and associated isometric force,
following ACZ, is related to impairment of synaptic integrity between la fibers
of the muscle spindle and the alpha motor neuron and not impairment of the muscle
spindle or force-generating capacity.
PMID- 9390668
TI - Afferent-inherent regulation of myosin heavy chain isoforms in rat muscle
spindles.
AB - Whether afferents exert their morphogenetic influence on spindles through release
of trophic factors at intrafusal fiber junctions or via participation in
proprioceptive pathways which modulate the motor activity to muscles was
investigated by comparing myosin heavy chain (MHC) expression in intrafusal
fibers after ablation of afferents (deafferentation, or DA) to the extensor
digitorum longus (EDL) of adult rats or after ablation of the corresponding
central processes of afferents to the spinal cord (central-process ablation, or
CPA). DA and CPA elicited an exaggerated pedal plantarflexion, and hypertrophy of
the EDL concomitant with atrophy of the soleus in the affected hindlimb.
Frequencies and patterns of expression of seven MHCs expressed by intrafusal
fibers in CPA muscles were indistinguishable from normal rats. However,
frequencies and patterns of expression of several MHCs were abnormal following
DA. Thus factors transported anterogradely from afferents to intrafusal fibers
may regulate MHC expression in intrafusal fibers.
PMID- 9390669
TI - Effect of age and gender on sudomotor and cardiovagal function and blood pressure
response to tilt in normal subjects.
AB - Normative data are limited on autonomic function tests, especially beyond age 60
years. We therefore evaluated these tests in a total of 557 normal subjects
evenly distributed by age and gender from 10 to 83 years. Heart rate (HR)
response to deep breathing fell with increasing age. Valsalva ratio varied with
both age and gender. QSART (quantitative sudomotor axon-reflex test) volume was
consistently greater in men (approximately double) and progressively declined
with age for all three lower extremity sites but not the forearm site.
Orthostatic blood pressure reduction was greater with increasing age. HR at rest
was significantly higher in women, and the increment with head-up tilt fell with
increasing age. For no tests did we find a regression to zero, and some tests
seem to level off with increasing age, indicating that diagnosis of autonomic
failure was possible to over 80 years of age.
PMID- 9390670
TI - Chronic inflammatory demyelinating polyradiculoneuropathy in children: II. Long
term follow-up, with comparison to adults.
AB - We previously reviewed the presentation, initial clinical course, and
electrodiagnostic features of children with chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP). We now report the long-term follow-up of 12
children with idiopathic CIDP, and compare these to 62 adults with idiopathic
CIDP. Children often had more rapidly fluctuating courses than adults. A
relapsing course was significantly more common in children than in adults. The
recovery of children from each episode of deterioration was usually excellent,
and better, on average, than in adults. Ventilatory support was never required
for children with slowly evolving illness; only 2 children with a precipitous
onset clinically resembling Guillain-Barre syndrome required ventilatory support.
Prednisone, plasma exchange, and intravenous immunoglobulin (IVIg) usually were
effective in children. Multiple courses of IVIg could be given with continued
efficacy. Treatment often could be discontinued in children with relapsing
courses. The prognosis for children was excellent. Adults demonstrated a good,
but more variable, outcome.
PMID- 9390671
TI - Anti-Hu-associated paraneoplastic sensory neuropathy responding to early
aggressive immunotherapy: report of two cases and review of literature.
AB - Anti-Hu-associated paraneoplastic sensory neuropathy (PSN) has been reported to
be nonresponsive to immunotherapy or cancer therapy. We report 2 patients with
anti-Hu-associated PSN who achieved sustained clinical improvement with early and
aggressive immunotherapy 10-15 months before the diagnosis of small-cell lung
carcinoma. Both had chronic "sensory neuronopathy plus"; in addition to sensory
neuronopathy, case 1 had a motor-autonomic dysfunction with encephalopathy, and
case 2 had a motor-autonomic dysfunction with swallowing difficulty. These two
cases were unusual in that sustained clinical improvement was achieved with early
aggressive immunotherapy before the detection of cancer and without any
concomitant anticancer therapy or lowering of anti-Hu antibody titer. We believe
that early and aggressive immunotherapy should be tried in any patient with anti
Hu-associated PSN, as it may induce sustained clinical improvement.
PMID- 9390672
TI - Remission of myasthenia gravis caused by proteinuria in nephrotic syndrome.
AB - Myasthenia gravis is caused by antibodies against acetylcholine receptors and is
treated with inhibition or elimination of antibody production. We report a 43
year-old myasthenic female who was symptomatic until she developed proteinuria
from nephrotic syndrome, which caused a marked drop in acetylcholine receptor
antibody titer with remission of myasthenia. Treatment of the nephrotic syndrome
produced exacerbation of her myasthenia and a rise in antibody level. This
patient's improvement is the result of antibody elimination during proteinuria in
nephrotic syndrome.
PMID- 9390673
TI - Reversible paralysis with status asthmaticus, steroids, and pancuronium: clinical
electrophysiological correlates.
AB - Prolonged neuromuscular weakness has been identified after neuromuscular blockade
in intensive care unit patients on mechanical ventilation. Previously reported
electromyographic studies in these patients documented both neurogenic features
and features consistent with a myopathy. We recorded sequential
electrophysiological parameters during recovery from neuromuscular blockade in 5
patients with clinical weakness. An evolving pattern was identified. The early
features were in keeping with previous reports of neurogenic changes, and this
evolved into features consistent with a primary myopathy. Several potential
underlying mechanisms are discussed.
PMID- 9390674
TI - Anterior interosseous nerve syndrome presenting with pronator teres weakness: a
case report.
AB - Anterior interosseous nerve syndrome (AINS) has been well described. A key muscle
to examine clinically and on electromyography is the pronator teres, as this can
differentiate between forearm and more proximal entrapment sites. We present a
case of AINS with marked weakness and denervation of pronator teres. At operation
the anterior interosseous nerve gave rise to the nerve to pronator teres and was
entrapped by a fibrous band from the deep head of pronator teres.
PMID- 9390675
TI - Fulminant demyelinating neuropathy mimicking cerebral death.
AB - Guillain-Barre syndrome can very rarely present with acute quadripares and
cranial nerve involvement resembling a locked-in state. We describe a very
unusual case of fulminant neuropathy in a child who was previously exposed to
vincristine. The clinical picture resembled brain death; however,
electrodiagnostic studies led to the diagnosis of a peripheral neuropathy. Serial
electrodiagnostic studies and pathologic findings confirmed demyelination.
PMID- 9390676
TI - Focal myopathy associated with chronic intramuscular injection of piritramide.
AB - We report a patient in whom chronic intramuscular piritramide led to a focal
fibrotic myopathy. Since piritramide myotoxicity has never been reported, we have
studied its effect on rat skeletal muscle. Chronic intramuscular piritramide led
to fibrous connective tissue replacement of rat skeletal muscle, similar to that
found in the patient's muscle. Although the pathogenetic mechanism of piritramide
myopathy is unclear, we caution against prolonged intramuscular use of
piritramide to prevent this potentially debilitating adverse effect.
PMID- 9390677
TI - Acoustic myography.
PMID- 9390679
TI - Numb chin syndrome heralding myeloma relapse.
PMID- 9390678
TI - Peripheral myoclonus due to spinal root lesion.
PMID- 9390680
TI - Selective inhibition of ipsilateral and contralateral R3 of the blink reflex by
capsaicin.
PMID- 9390681
TI - Variation of calculated ulnar motor conduction velocity across the elbow with
body mass index.
PMID- 9390682
TI - T cell turnover in HIV-1 disease.
PMID- 9390683
TI - Exit of the pre-TCR from the ER/cis-Golgi is necessary for signaling
differentiation, proliferation, and allelic exclusion in immature thymocytes.
AB - A major issue is whether surface expression of the pre-TCR is necessary for
signaling the development of immature thymocytes. To address this question, we
generated transgenic mice expressing a TCRbeta chain that had a strong
endoplasmic reticulum (ER) retrieval signal (TCRbetaER) and that was expressed
intracellularly but failed to reach the cell surface. In TCRbetaER transgenic
mice, there was a failure of allelic exclusion. Also, the transgene failed to
rescue the developmental defects observed in TCRbeta-null mice. In contrast,
TCRbeta transgenes with a mutant ER retrieval sequence or lacking this sequence
signaled efficient allelic exclusion and suppressed the TCRbeta-/- defect. These
data show that exit of the pre-TCR from the ER/cis-Golgi is required for
progression through the double-negative thymocyte checkpoint.
PMID- 9390684
TI - Essential role of the pre-T cell receptor in allelic exclusion of the T cell
receptor beta locus.
AB - Following the recent realization that TCR beta transgenes can severely inhibit
the rearrangement of endogenous Vbeta gene segments in the absence of pre-TCR
alpha (pT alpha) chains, we tested whether the pre-TCR has an essential role in
TCR beta allelic exclusion under more physiological conditions by analyzing TCR
rearrangement in immature thymocytes by single-cell PCR. Our results in pT alpha+
mice are consistent with an ordered model of TCR beta rearrangement beginning on
one allele and continuing on the other only when the first attempt is
unsuccessful. By contrast, a higher proportion of thymocytes from pT alpha-/-
mice exhibited two productive TCR beta alleles. Thus, the pre-TCR-independent
suppression of rearrangement by TCR beta transgenes represents a transgene
artifact, whereas under physiological conditions the pre-TCR is essential for
allelic exclusion.
PMID- 9390686
TI - Activation of the Lck tyrosine kinase targets cell surface T cell antigen
receptors for lysosomal degradation.
AB - The mechanism by which TCR expression is regulated was explored by expressing a
constitutively active form of the tyrosine kinase Lck (Lck505F) in T cells.
Expression of Lck505F down-regulated TCR levels, an effect that was even more
pronounced in CD45- T cells, in which the activity of this tyrosine kinase is
further enhanced. Cells expressing Lck505F synthesized all TCR subunits, but
lysosomal degradation of assembled receptors was enhanced. TCRs were rapidly
internalized and degraded after removal of a tyrosine kinase inhibitor that had
permitted cell surface expression. Finally, TCR levels on thymocytes were
increased by an Lck inhibitor, and activation- but not phorbol ester-induced
internalization of TCRs on Jurkat cells was prevented by inhibition or loss of
Lck. These studies identify a regulated nonreceptor tyrosine kinase-mediated
pathway for targeting cell surface receptors for lysosomal degradation.
PMID- 9390685
TI - The influence of the MAPK pathway on T cell lineage commitment.
AB - During development, progenitor thymocytes differentiate into either CD4 or CD8 T
cells, and this fate decision depends on the specificity of the T cell antigen
receptor (TCR) for MHC class II or class I molecules. Based on the mechanisms of
fate specification known for simple metazoan organisms, we sought to determine
whether the extracellular signal-related kinases (ERKs) play a role in T cell
differentiation and lineage commitment. Using a dominant gain-of-function mutant
of the erk2 gene, we show that differentiation into the CD4 lineage is favored.
We also show that, conversely, the addition of a pharmacological inhibitor of the
ERK pathway favors differentiation into the CD8 lineage. We present a
quantitative selection model that incorporates these results as well as those of
recent reports on the role of Notch in T cell lineage specification.
PMID- 9390687
TI - A novel Bcl-x isoform connected to the T cell receptor regulates apoptosis in T
cells.
AB - We define a novel Bcl-x isoform, Bcl-x gamma, that is generated by alternative
splicing and characterized by a unique 47 amino acid C-terminus. Bcl-x gamma is
expressed primarily in thymocytes, where it may depend on an interaction between
the TCR and host MHC products, and in mature T cells, where its expression is
associated with ligation of the T cell receptor. Overexpression of Bcl-x gamma in
T cells inhibits activation-induced apoptosis; inhibition of Bcl-x gamma, after
stable expression of Bcl-x gamma antisense cDNA, enhances activation-induced
apoptosis. In contrast to other Bcl-x isoforms, cells that fail to express Bcl-x
gamma after CD3 ligation undergo programmed cell death, while activated T cells
that express Bcl-x gamma are spared. Identification of Bcl-x gamma helps provide
a molecular explanation of T cell activation and death after antigen engagement.
PMID- 9390688
TI - A new MHC locus that influences class I peptide presentation.
AB - We have investigated the HLA-B27-restricted CTL response to HY minor
histocompatibility antigens in rats and mice transgenic for HLA-B27 and human
beta2-microglobulin. A polymorphism was found at a locus within the H2 complex,
producing two distinct but overlapping sets of B27-presented HY peptides. The
locus, named Cim2, mapped between the K and Pb loci, and its product is therefore
distinct from TAP, LMP, and tapasin. Identical findings in rats and mice,
including identical HY peptide sequences and the failure of a rat Tap2A transgene
to alter CTL recognition, suggest that a homologous locus with similar
polymorphism exists in the rat. Cim2, or a closely linked locus, was found to
exert a broad effect on peptide loading of both HLA-B27 and mouse class I
alleles. The data thus establish a strong, previously unrecognized MHC-encoded
influence on the class I antigen pathway.
PMID- 9390689
TI - Growth retardation and leaky SCID phenotype of Ku70-deficient mice.
AB - Ku70, Ku80, and DNA-PKcs are subunits of the DNA-dependent protein kinase (DNA
PK), an enzyme implicated in DNA double-stranded break repair and V(D)J
recombination. Our Ku70-deficient mice were about 50% the size of control
littermates, and their fibroblasts were ionizing radiation sensitive and
displayed premature senescence associated with the accumulation of nondividing
cells. Ku70-deficient mice lacked mature B cells or serum immunoglobulin but,
unexpectedly, reproducibly developed small populations of thymic and peripheral
alpha/beta T lineage cells and had a significant incidence of thymic lymphomas.
In association with B and T cell developmental defects, Ku70-deficient cells were
severely impaired for joining of V(D)J coding and recombination signal sequences.
These unanticipated features of the Ku70-deficient phenotype with respect to
lymphocyte development and V(D)J recombination may reflect differential functions
of the three DNA-PK components.
PMID- 9390690
TI - Reversal of EBV immortalization precedes apoptosis in IL-6-induced human B cell
terminal differentiation.
AB - Cell death in B cell terminal differentiation rapidly follows cell cycle arrest
in IL-6 differentiation of EBV-immortalized, IgG-bearing human lymphoblastoid
cells in vitro. G1 arrest is now found to coincide with repression of EBNA2 and
LMP1, two EBV genes essential for B cell transformation, without activation of
the viral lytic cycle. IL-6-differentiated B cells die by apoptosis, as evidenced
by increases in Annexin V binding activity, PARP cleavage, and chromatin
disorganization. Expression of Mcl-1, a Bcl-2 family member, was specifically
induced during IL-6 differentiation and down-regulated during apoptosis. Thus, IL
6 reverses EBV immortalization and activates the terminal differentiation program
in IgG-bearing human B lymphoblastoid cells, including regulation of an anti
apoptotic gene to coordinate differentiation, cell cycle arrest, and cell death.
PMID- 9390691
TI - Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell
cycle regulator E2F.
AB - Cell cycle progression initiated by interleukin-2 (IL-2) in T cells is critical
for lymphoproliferation and an immune response. Phosphatidyl inositol 3-kinase
(PI3K) is activated by IL-2. However, nuclear targets for PI3K are not known.
Here we identify the cell cycle regulator E2F as an IL-2 target in T lymphocytes
and PI3K as the critical signaling pathway. We eliminate both Stat5 and Raf/MEK
pathways from E2F regulation. Protein kinase B (PKB) is activated by IL-2 via
PI3K. The expression of an active PKB is sufficient to induce E2F activity.
Inhibition of PI3K inhibits phosphorylation of Rb, induction of cyclin D3, and
degradation of p27kip1. These results establish a crucial PI3K/PKB-mediated link
between the IL-2 teceptor and the cell cycle machinery.
PMID- 9390692
TI - An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for
Stat5a in IL-2-mediated IL-2 receptor alpha chain induction.
AB - Stat5a was identified as a prolactin-induced transcription factor but also is
activated by other cytokines, including interleukin-2 (IL-2) and IL-7. We have
now analyzed the immune system of Stat5a-deficient mice. Stat5a-/- splenocytes
exhibited defective IL-2-induced expression of the IL-2 receptor alpha chain (IL
2R alpha), a protein that together with IL-2R beta and the common cytokine
receptor gamma chain (gamma(c)) mediates high-affinity IL-2 binding.
Correspondingly, Stat5a-/- splenocytes exhibited markedly decreased proliferation
to IL-2, although maximal proliferation was still achieved at IL-2 concentrations
high enough to titrate intermediate-affinity IL-2R beta/gamma(c) receptors. Thus,
defective Stat5a expression results in diminished proliferation by an indirect
mechanism, resulting from defective receptor expression. Correspondingly, we show
that Stat5a is essential for maximal responsiveness to antigenic stimuli in vivo,
underscoring the physiological importance of IL-2-induced IL-2R alpha expression.
PMID- 9390693
TI - TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte
proliferation and survival.
AB - TRAF2 is believed to mediate the activation of NF-kappaB and JNK induced by the
tumor necrosis factor receptor (TNFR) superfamily, which elicits pleiotropic
responses in lymphocytes. We have investigated the physiological roles of TRAF2
in these processes by expressing a lymphocyte-specific dominant negative form of
TRAF2, thereby blocking this protein's effector function. We find that the TNFR
superfamily signals require TRAF2 for activation of JNK but not NF-kappaB. In
addition, we show that TRAF2 induces NF-kappaB-independent antiapoptotic pathways
during TNF-induced apoptosis. Inhibition of TRAF2 leads to splenomegaly,
lymphadenopathy, and an increased number of B cells. These findings indicate that
TRAF2 is involved in the regulation of lymphocyte function and growth in vivo.
PMID- 9390694
TI - Early lethality, functional NF-kappaB activation, and increased sensitivity to
TNF-induced cell death in TRAF2-deficient mice.
AB - TRAF2 is an intracellular signal-transducing protein recruited to the TNFR1 and
TNFR2 receptors following TNF stimulation. To investigate the physiological role
of TRAF2, we generated TRAF2-deficient mice. traf2-/- mice appeared normal at
birth but became progressively runted and died prematurely. Atrophy of the thymus
and spleen and depletion of B cell precursors also were observed. Thymocytes and
other hematopoietic progenitors were highly sensitive to TNF-induced cell death
and serum TNF levels were elevated in these TRAF2-deficient animals. Examination
of traf2-/- cells revealed a severe reduction in TNF-mediated JNK/SAPK activation
but a mild effect on NF-kappaB activation. These results suggest that TRAF2
independent pathways of NF-kappaB activation exist and that TRAF2 is required for
an NF-kappaB-independent signal that protects against TNF-induced apoptosis.
PMID- 9390695
TI - Lennox-Gastaut syndrome.
AB - Lennox-Gastaut syndrome (LGS) is one of the intractable epilepsies of childhood
that is associated with an epileptic encephalopathy. Although LGS has been
accepted as a distinct epilepsy syndrome for the last 30 years, understanding of
its pathogenesis is still incomplete. Because this heterogenous entity has many
diverse etiologies, some with specific therapy, a complete evaluation is
necessary. The natural history is well defined; most children with LGS will
ultimately be mentally retarded, will continue to have seizures, and as adults
will be dependent for their daily care. Therefore, their only hope is new
therapies and advances in our understanding of the pathogenesis of LGS. Several
new treatment options have emerged. For the first time in the last 20 years, we
have several medications with documented efficacy. In addition, there are
effective nonpharmacologic treatments. These treatments offer the potential for
improved seizure control, which we hope will have impact and lessen the
subsequent epileptic encephalopathy. Children with LGS require multidisciplinary
assessment and treatment along with vigorous intervention aimed at minimizing
their seizures to maximize their potential. Pediatric neurologists should be
familiar with the treatments with proven efficacy, including new antiepileptic
drugs, and should develop a rational plan of treatment for each child with LGS.
PMID- 9390696
TI - Intraventricular urokinase for the treatment of posthemorrhagic hydrocephalus.
AB - This case series pilot study assessed the safety of intraventricular urokinase
administration, alternating with cerebrospinal fluid (CSF) drainage. A secondary
objective was to comment on whether this therapy achieves fibrinolysis, and
whether this fibrinolysis is sufficient to prevent progression of hydrocephalus
to requirement for ventriculoperitoneal shunt. Six preterm infants with
progressive posthemorrhagic hydrocephalus requiring treatment with a ventricular
drain received an infusion of intraventricular urokinase alternating with CSF
drainage for 3 days. Of the 6 treated patients, the median gestation at birth was
26.5 weeks and the median age at treatment was 30 days. One patient had an
elevation in CSF erythrocyte count most likely due to successful clot lysis. One
patient had an elevated CSF leukocyte count consistent with transient meningeal
irritation. No other side effects were noted. Fibrinolysis was achieved in the
CSF, as documented by markedly elevated D-dimer levels. Clot size diminished
ultrasonographically. However, all 6 patients eventually required a
ventriculoperitoneal shunt. We conclude that intermittent infusion of
intraventricular urokinase alternating with periods of CSF drainage is probably a
safe way to achieve a fibrinolytic state. However, when administered at the
relatively late point in the neonatal course when a ventricular drain is
required, this fibrinolytic state is not sufficient to decrease the requirement
for ventriculoperitoneal shunt.
PMID- 9390697
TI - Regional differences in spectral EEG measures between healthy term and preterm
infants.
AB - State-specific spectral electroencephalographic (EEG) values were compared among
14 bipolar channel derivations between two healthy neonatal cohorts. Fifty-five
healthy preterm neonates of < or = 32 weeks gestational age at birth were studied
with 24-channel recordings over 3 hours at term conceptional age. These were
compared with studies of 45 healthy term neonates. Five spectral measures for
each channel (i.e., total spectral EEG, delta, theta, alpha, and beta frequency
ranges) were calculated for each minute, which was identified as active or quiet
sleep, based on visual analysis. Using multivariate analysis of variance,
differences at each channel were assessed between neonatal cohorts for both
states and cohorts; higher total EEG spectral values were noted during active
sleep; whereas higher delta and theta spectral values were noted during quiet
sleep. The term cohort had higher values for spectral theta, alpha, and beta
power spectra in multiple channels, most significantly in the left central (i.e.,
C3O1) and sagittal regions (FzCz, CzPz) during both states (P < .0001, adj r2 >
or = .2). Both interhemispheric and intrahemispheric differences in spectral
values were present. For a healthy preterm cohort, lower spectral energies are
expressed during sleep in specific head regions. Physiologic asymmetries exist in
the newborn brain which are unique for the preterm infant, emphasizing functional
alterations in brain development. How these asymmetries are altered by prenatal
or postnatal stress or disease states needs to be explored.
PMID- 9390698
TI - West syndrome: cerebrospinal fluid nerve growth factor and effect of ACTH.
AB - West syndrome is a strictly age-limited encephalopathy of early infancy with
unknown pathogenesis. It is often progressive, leading to mental retardation.
Neurotrophic factors are important for the regulation of neuronal survival and
differentiation, and their expression is influenced by hormones. Levels of beta
nerve growth factor in the cerebrospinal fluid were examined by two-site enzyme
linked immunosorbent assay method. Human antigen was used as a standard. We
present data on largely normal levels of nerve growth factor in the cerebrospinal
fluid of infants with cryptogenic etiology, but low or negligible levels in
infants with symptomatic etiology, and very high levels in infants with
symptomatic postinfectious etiology. Treatment with ACTH led to a greater
increase in patients with a good response than in those with a poor response. Low
nerve growth factor in patients with symptomatic infantile spasms possibly
reflects massive neuronal death. The regression seen in these infants and their
poor response to ACTH therapy may be due in part to lack of growth factors
supporting neuron survival. This study, previously only demonstrated in animal
models, is the first to depict nerve growth factor gene activity in humans as
modulated by steroids.
PMID- 9390699
TI - Chronic oral VP-16 for recurrent medulloblastoma.
AB - Chronic oral VP-16 (Etoposide) is a chemotherapy regimen with wide application in
oncology and documented efficacy against germ cell tumors, lymphomas, Kaposi
sarcoma, and glial brain tumors. Eight patients ranging in age from 4 to 36 years
(median 7.5 years) with locally recurrent medulloblastoma were treated with VP
16. No patient displayed evidence of cerebrospinal fluid dissemination, distant
brain or spine parenchymal metastases, or extraneural metastatic disease. All
patients had previously been treated with surgery (gross total resection, 5;
subtotal resection, 3), craniospinal radiotherapy, and platinum-based
chemotherapy (adjuvant, 3; salvage, 8). Each cycle of therapy consisted of 21
days of VP-16 (50 mg/m2/day) followed by a 7 to 14 day rest followed by an
additional 21 days of VP-16 (50 mg/m2/day). Complete blood counts were obtained
weekly. Neurologic examination and brain magnetic resonance imaging scan with
contrast were performed prior to each cycle of therapy. Treatment-related
complications included: partial alopecia (5 patients); diarrhea (4); weight loss
(3); anemia (2); neutropenia (4); and thrombocytopenia (4). Two patients required
transfusion and 1 patient received antibiotics for neutropenic fever. All
patients were evaluable for response: 3 demonstrated progressive disease after
the first cycle of VP-16, 3 had stable disease (range 4 to 6 months) and 2 had
partial neuroradiographic responses (8 and 10 months). Median duration of
response and stable disease was 6 months (range: 4 to 10 months) in 5 of 8
(62.5%) patients. Chronic oral VP-16 is a well-tolerated and relatively non-toxic
chemotherapeutic agent with demonstrated activity in locally recurrent
medulloblastoma.
PMID- 9390700
TI - Early expression of proteolipid protein in human fetal and infantile cerebri.
AB - Proteolipid protein (PLP) is the major myelin protein of the central nervous
system and is widely believed to play an important structural role in maintaining
the myelin compaction. We have studied the early developmental changes of PLP
with immunohistochemical methods. Our data demonstrate for the first time a
comparable scheme for the development of PLP during myelination in human fetal
and infant cerebrum. Expression of PLP was first detected in the pallidothalamic
fibers and globus pallidus at 20 weeks; it then extended to the striatum at 28
weeks, pericentral gyri and optic radiation at 35 weeks, and acoustic radiation
at 40 weeks. Compared to the expression of myelin basic protein (MBP), another
major myelin protein in the central nervous system, the developmental changes of
PLP is in the same order as MBP, but the PLP immunoreactivity revealed greater
and earlier appearance in the cerebrum than that of MBP in the fetal period.
These results imply that PLP is a sensitive and useful marker for early
myelination and its disorders.
PMID- 9390701
TI - Neurodevelopmental outcome in very low birth weight infants at 24 months and 5 to
7 years of age: changing diagnosis.
AB - We describe the long-term development of 53 very low birth weight premature
infants. The children were divided into 2 groups on the basis of ultrasound scan,
and classified as: group I, patients with normal ultrasound scan or with
uncomplicated hemorrhage; and group II, patients with complicated hemorrhage or
only parenchymal lesions. Minor and major sequelae detected at 2 years of age
were compared with those observed at 5 to 7 years. Our study confirms that most
severely handicapped children are identified by age 2 years. Minor sequelae are
more evident at 5 to 7 years and subjects with good outcome, as expressed by a
McCarthy General Cognitive Index score > 80, present a discordant cognitive
profile with verbal scores higher than performance scores. Therefore, we
emphasize the importance of follow-up of very low birth weight premature infants
until school age and stress that neonatal ultrasound scan diagnosis of
parenchymal damage represents an important diagnostic tool in terms of both short
and long-term neurodevelopmental outcome.
PMID- 9390702
TI - Ragged-red fibers and complex I deficiency in a neonate with arthrogryposis
congenita.
AB - We describe a neonate with hypotonia, weakness, early death owing to respiratory
failure, and a severe form of arthrogryposis multiplex congenita. Postmortem
studies revealed numerous ragged-red fibers and central nervous system
abnormalities consistent with a mitochondrial disease. No NADH:ubiquinone-1
oxidoreductase (complex I) activity could be detected in skeletal muscle. These
findings suggest that mitochondrial cytopathies can be associated with
arthrogryposis multiplex congenita and should therefore be sought in neonates
presenting with severe arthrogryposis.
PMID- 9390703
TI - Regional cortical dysplasia associated with suspected hypomelanosis of Ito.
AB - A 15-year-old girl with epilepsy, whose skin lesions were reminiscent of
hypomelanosis of Ito, is reported. She manifested hypopigmented linear streaks on
her upper and lower limbs. Brain magnetic resonance imaging examinations
demonstrated poor differentiation of cerebral gray and white matter of her left
occipital lobe, with accompanying gliosis. This region also revealed narrowing of
sulci, considered to be mass effect. In this region, almost continuous spike
discharges were evident on electroencephalograms, and low-perfusion status was
observed on single photon emission computed tomography at rest. She also
manifested right lower homonymous quadrant anopsia, which may have its origin in
the lesion detected, which appeared to be a migration disorder of neuroblasts in
our patient, suggesting that the spectrum of hypomelanosis of Ito might be
involved.
PMID- 9390704
TI - Early neuroradiologic evidence of degeneration in Menkes' disease.
AB - We report the case of an infant with Menkes' disease who presented with
moderately abnormal neurologic findings at birth and with extraaxial bleeding in
the posterior fossa. Early cerebellar atrophy and hypomyelination were evident on
magnetic resonance imaging at 5 weeks of age. We suggest that neurodegeneration
occurs earlier than has been previously reported and may be identifiable even in
neonates.
PMID- 9390705
TI - Echocardiographic sign for cerebral ischemia.
AB - We describe a newborn who underwent balloon dilatation of critical aortic
stenosis and surgical correction of coarctation of the aorta. Postoperative
Doppler echocardiogram revealed diastolic retrograde flow in the distal aortic
arch and increased systolic flow as well as diastolic forward flow in the left
common carotid artery. Cranial computed tomography suggested increased left
middle cerebral artery flow and a subacute infarction with luxury perfusion and
damage to the blood brain barrier. Therefore, in the absence of another reason
for diastolic "run-off" in the distal aortic arch, this flow pattern may
represent the echocardiographic sign for cerebral hyperemia associated with
subacute ischemia.
PMID- 9390706
TI - Enhanced magnetic resonance imaging of leptomeningeal angiomatosis.
AB - We present two patients with unilateral occipital gyriform calcification and
seizures. Gyriform or serpentine calcification as revealed by computed tomography
(CT) scan is rare and is a characteristic finding of Sturge-Weber syndrome (SWS)
and celiac disease (CD). These patients had neither the facial nevus flammeus or
neurological deficits characteristic of SWS, nor the gastrointestinal symptoms
characteristic of CD. CD is often accompanied by cerebral occipital calcification
indistinguishable from that of SWS. We demonstrate the presence of cerebral
leptomeningeal angiomatosis (LA) by Gadolinium-DTPA-enhanced magnetic resonance
imaging (MRI) but could not detect LA by either CT scanning or angiography. It
has been reported that contrast-enhanced MRI is useful to detect LA in SWS.
However, we found no reports of enhanced MRI in patients with SWS without facial
angioma. If future studies can demonstrate the absence of cortical enhancement by
contrast-enhanced MRI in CD with cerebral calcifications, enhanced MRI would
become an important tool for differentiating CD from SWS.
PMID- 9390707
TI - A case of Noonan syndrome with cortical dysplasia.
AB - We report the case of a 20-year-old woman with Noonan syndrome. She had severe
mental retardation and intractable epilepsy. Magnetic resonance imaging revealed
dilated perivascular spaces and a dysplastic lesion in the left temporal lobe,
which is thought to have caused her neurologic symptoms. These findings suggest
that neuronal in addition to somatic migration can be impaired in Noonan
syndrome.
PMID- 9390708
TI - Acute hydrocephalus following carbon monoxide poisoning.
AB - Carbon monoxide remains a significant cause of poisoning in children. Cerebral
edema is often the cause of significant morbidity and mortality in exposed
children. While lesions of the basal ganglia have been well documented, the
advent of neuroimaging has allowed antemortem demonstration of infarctions of the
globus pallidus and putamen with carbon monoxide intoxication. Acute
hydrocephalus following carbon monoxide poisoning has been a rare occurrence. We
report a 2 year 6 month-old boy who, to our knowledge, represents the first
reported case in which repeat computed tomography documented the evolution of
hydrocephalus due to carbon monoxide exposure in a child.
PMID- 9390709
TI - Purification and gas chromatographic-mass spectrometric characterization of non
methylene interrupted fatty acid incorporated in rat liver.
AB - A C20 non-methylene interrupted trienoic acid detected in the liver of rat fed
with a pine (Pinus koraiensis) seed oil diet was purified by two-step argentation
thin-layer chromatography (AgTLC) and characterized by gas chromatography-mass
spectrometry (GC-MS). First, a C20 methyl trienoate fraction was obtained from
fatty acid methyl esters prepared from rat liver by 5% AgTLC developed with
petroleum ether-diethyl ether-acetic acid (70:20:2, v/v) as a solvent system. The
fraction was then subjected to AgTLC developed with benzene-acetone-diethyl ether
acetic acid (65:15:15:5, v/v) which could separate non-methylene interrupted
fatty acids (NMIFA) from usual MIFAs. The purified C20 NMIFA was partially
hydrogenated, and the resulting three kinds of the C20 monoenoate were analyzed
by GC-MS after conversion to their dimethyl disulfide (DMDS) adducts. The results
revealed that the original C20 non-methylene interrupted trienoic acid detected
in the liver of rats fed with a pine seed oil diet was delta-5,11,14/20:3, a
minor component of pine seed oil.
PMID- 9390710
TI - Quantitative analysis of exogenous peptides in plasma using immobilized enzyme
cleavage and gas chromatography-mass spectrometry with negative ion chemical
ionization.
AB - A method is presented for the analysis of peptides in plasma at picomole to
femtomole levels. Peptides are isolated from plasma by solid-phase extraction,
the peptide of interest is purified by reversed-phase high-performance liquid
chromatography (HPLC) and selectively digested using immobilized trypsin or
chymotrypsin to yield specific di- or tripeptides. These di- and tripeptides are
esterified using heptafluorobutyric anhydride, alkylated with pentafluorobenzyl
bromide, then quantified by gas chromatography-mass spectrometry with negative
ion chemical ionization. This method has been evaluated for a model synthetic
heptapeptide, using a deuterium labeled analog as an internal standard. The half
life of the heptapeptide in human plasma was found to be 2 min. Extraction
efficiencies of a tritiated peptide of similar size to the heptapeptide,
[3H]DSLET, from plasma using either C18 or strong cation-exchange columns were
85+/-3 and 70+/-2%, respectively. Quantitation of fragments from the heptapeptide
indicated that the analysis was linear from 1-50 ng of the heptapeptide per ml of
plasma. This method was subsequently employed for pharmacokinetic studies of the
biologically active peptide Met-enkephalin-Arg-Gly-Leu, where linearity was
obtained from 50 to 1000 ng/ml in rat plasma. This method demonstrated negligible
side reaction by-products due to autolysis, and has potential for extensive use
given the wide availability of gas chromatography-mass spectrometry.
PMID- 9390711
TI - Simultaneous determination of polyamines, N-acetylated polyamines and the
polyamine analogues BE-3-3-3 and BE-4-4-4-4 by capillary gas chromatography with
nitrogen-phosphorus detection.
AB - We describe a method for the profiling of polyamines, N-acetylated polyamines and
the polyamine analogues N1,N11-bis(ethyl)norspermine (BE-3-3-3) and 1,19
bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) in L1210 murine leukaemia
cells by capillary gas chromatography with nitrogen-phosphorus detection. The
method makes use of four intemal standards. Prepurification comprises
deproteinization, isolation with Sep-Pak silica at pH 9.0, conversion to
heptafluorobutyryl derivatives and postderivatization organic fluid extraction.
Within- and between-series precisions (given as CV.s) for analysis of 1-2x10(6)
cells were: putrescine 5.5 and 29.4%; spermidine 1.6 and 7.1%; and spermine 3.2
and 7.6%, respectively. Recoveries relative to the respective internal standards,
were in the 70.6-104.7% range. Accuracy and precision of measurements of BE-4-4-4
4 can probably be improved by the introduction of a separate pentamine internal
standard. We conclude that the method can be used for studying the effect of BE-3
3-3 and BE-4-4-4-4, and possibly their metabolites, on polyamine homeostasis
(biosynthesis, retroconversion, transport, terminal catabolism) and polyamine
function.
PMID- 9390712
TI - Determination of endogenous levels of 13-cis-retinoic acid (isotretinoin), all
trans-retinoic acid (tretinoin) and their 4-oxo metabolites in human and animal
plasma by high-performance liquid chromatography with automated column switching
and ultraviolet detection.
AB - A highly sensitive HPLC method with automated column switching was developed for
the simultaneous determination of endogenous levels of 13-cis-retinoic acid
(isotretinoin), all-trans-retinoic acid (tretinoin) and their 4-oxo metabolites
in plasma samples from man, Cynomolgus monkey, rabbit, rat and mouse. Plasma (0.4
ml) was deproteinated by adding ethanol (1.5 ml) containing the internal standard
acitretin. After centrifugation, 1.4 ml of the supernatant were directly injected
onto the precolumn packed with LiChrospher 100 RP-18 (5 microm). 1.25% ammonium
acetate and acetic acid-ethanol (8:2, v/v) was used as mobile phase during
injection and 1% ammonium acetate and 2% acetic acid-ethanol (102:4, v/v) was
added, on-line, to decrease the elution strength of the injection solution. After
backflush purging of the precolumn, the retained components were transferred to
the analytical column in the backflush mode, separated by gradient elution and
detected at 360 nm. Two coupled Superspher 100 RP-18 endcapped columns (both
250x4 mm) were used for the separation, together with a mobile phase consisting
of acetonitrile-water-10% ammonium acetate-acetic acid: (A) 600:300:60:10
(v/v/v/v), (B) 950:20:5:20 (v/v/v/v), and (C) 990:5:0:5 (v/v/v/v). The method was
linear in the range 0.3-100 ng/ml, at least, with a quantification limit of 0.3
ng/ml. The mean recoveries from human plasma were 93.2%-94.4% and the mean inter
assay precision was 2.8%-3.2% (range 0.3-100 ng/ml). Similar results were
obtained for animal plasma. The analytes were found to be stable in the plasma of
all investigated species stored at -20 degrees C for 4.3 months and at -80
degrees C for 9 months, at least. At this temperature, human plasma samples were
even stable for 2 years. The method was successfully applied to more than 6000
human and 1000 animal plasma samples from clinical and toxicokinetic studies.
Endogenous levels determined in control patients and pregnant women were similar
to published data from volunteers.
PMID- 9390713
TI - Combination of high-performance liquid chromatography and thin-layer
chromatography separation of five adducted nucleotides isolated from liver
resulting from intraperitoneal administration with 7H-dibenzo[c,g]carbazole to
mice.
AB - 7H-Dibenzo[c,g]carbazole, DBC, is a potent environmental liver carcinogen. Liver
DNA from mice treated with DBC exhibited seven distinct DBC-DNA adducts as
detected by 32P-postlabeling using multidimensional TLC. To improve quantitation
and chemically characterize the adducts, DNA samples were hydrolyzed, 32P
postlabeled and the adducts were separated from the unadducted normal nucleotides
on TLC using a D1 solvent, 0.65 M sodium phosphate (pH 6.8). Adducts were eluted
from the TLC plates with 4.0 M pyridinium formate, concentrated, resuspended in
50% aqueous methanol and injected onto the HPLC; five individual adduct peaks
were resolved and collected by this method. This approach will prove useful to
decrease analysis time and improve chemical characterization of tightly clustered
DNA adducts generated in vivo.
PMID- 9390714
TI - Bile acid kinetics in man studied by radio thin-layer chromatography and
densitometry coupling.
AB - A method based on coupling of the techniques of radioscanning a TLC plate and
densitometry has been developed for the determination of pool sizes and
fractional turnover rate of bile acids in man after intraduodenal administration
of 14C-labelled acid. The validity of the method has been checked by comparison
of the results obtained with those of an enzymatic spectrophotometric analysis,
and a measurement of the radioactivity by liquid scintillation counting, after
elution of the separated bile acid from a TLC plate. Advantages of the proposed
method over the previous one include a reduced number of manipulations, the
possibility of automation, a better reproducibility, and the possibility of
elaborating the radiometric data obtained for the primary bile acid for better
characterising its metabolism inside the enterohepatic circulation.
PMID- 9390715
TI - Capillary electrophoresis of glutamate and aspartate in rat brain dialysate.
Improvements in detection and analysis time using cyclodextrins.
AB - Addition of cyclodextrins (CDs) to the electrolyte buffer in the capillary zone
electrophoresis (CZE) separation of derivatized amino acids was evaluated in
terms of fluorescence signal enhancement, resolution, and migration time effects.
Maximum fluorescence signal enhancement was observed with separation buffers
containing 4 mM beta-cyclodextrin or 10 mM hydroxypropyl beta-cyclodextrin.
Resolution values decreased as the CD concentrations increased. Migration times
were dependent on CD concentration. Inclusion complex formation constants
calculated using changes in migration time showed slight agreement with those
calculated by the steady-state fluorescence enhancement technique. Analysis of 20
microl of rat brain microdialysate by CZE using 4 mM beta-cyclodextrin in borate
buffer resulted in baseline resolution of glutamate and aspartate in 3.6 min. The
results of this work indicate that, when used as separation buffer additives,
cyclodextrins are capable of increasing the fluorescence signal and decreasing
the migration times of NDA-derivatized acidic amino acids.
PMID- 9390716
TI - Simultaneous determination of amphetamine and its analogs in human whole blood by
gas chromatography-mass spectrometry.
AB - A sensitive and specific gas chromatography-mass spectrometry (GC-MS) method for
the determination of amphetamine (AM), methamphetamine (MA),
methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA) and
methylenedioxyethylamphetamine (MDEA) in whole blood was designed, using the
respective pentadeuterated analogs of the analytes as internal standards (I.S.).
After alkalinisation of blood samples, the amphetamines were extracted using
diethyl ether, derivatized with heptafluorobutyric anhydride, then purified by
successive washings with deionized water and 4% NH4OH. Extraction recoveries were
85.2% for AM, 90.9% for MA, 76.5% for MDA, 84.1% for MDMA and 63.6% for MDEA.
Chromatographic separation was performed on a non-polar 30 m x 0.32 mm HP 5 MS
capillary column using a temperature program. Detection was carried out in the
electron-impact, selected ion-monitoring mode, using three mass-to-charge ratios
for each analyte and one for each I.S. Limits of detection ranged from 0.5 to 8
ng/ml and limits of quantification were 10 ng/ml for AM, MDMA and MDEA; 20 ng/ml
for MA; and 50 ng/ml for MDA. The method was linear from this limit up to 1000
ng/ml for all analytes, with good intra-assay precision and good intermediate
precision and accuracy over these ranges. There was no interferences from other
sympathomimetic drugs such as ephedrine, norephedrine or methoxyphenamine. This
method is thus suitable for clinical and forensic toxicology, as well as for
doping control.
PMID- 9390717
TI - Hair analysis for drugs of abuse. XIX. Determination of ephedrine and its
homologs in rat hair and human hair.
AB - A sensitive GC-MS method was developed for the quantitative analysis of ephedrine
(EP), phenylpropanolamine (PPA) and methylephedrine (ME) in animal and human
hair. After washing with 0.1% sodium dodecyl sulfate, hair samples (10 mg) were
added with deuterated internal standards, extracted by 1-h sonication and over
night soaking in 2 ml of 5 M HCl-methanol (1:20) at room temperature. Following
evaporation of the liquid phase, the residue was dissolved in phosphate buffer
solution (pH 6.0) and purified using a solid-phase extraction procedure with Bond
Elut Certify columns. Two types of derivatization were compared - using
trifluoroacetic anhydride (TFAA) and pentafluoropropionic anhydride (PFPA) - for
discrimination of EP and methamphetamine (MA). Derivatized extracts were analyzed
by GC-MS in the EI mode using a capillary column (OV-1 equivalent). From the
results comparing three GC-MS conditions, PFP-derivatives separated with a
temperature gradient of 20 degrees C/min from 60 degrees C to 280 degrees C gave
the best resolution between EP and MA. ME was analyzed as a trimethylsilyl
derivative using N,O-bis-trimethylsilyl acetamide at the above GC condition. The
assay was linear from 0.5 to 50 ng/mg (r=0.998) and capable of detecting less
than 50 pg of derivatized EP, PPA and ME on-column. Intra-assay precision was
characterized by C.V. values from 5 to 16% in the concentration range of 1-10
ng/mg hair. The method was used for the quantitative determination of EP, PPA and
ME in the hair obtained from three rats with dark brown hair after ten
intraperitoneal injections (5 mg/kg/day) of the three drugs and from three male
and one female volunteers with black hair after an oral dose of 50 mg/day of EP
HCl for three days. Hair samples were collected by shaving from the back of rats
and cutting from the scalp of humans 28 days after the first dose. The
incorporation rates of EP, PPA and ME into hair (the ratios of [hair
concentration] to [AUC]) obtained from the animal experiment were 0.10, 0.07 and
0.03, respectively, which are a little lower than those (0.14, 0.10 and 0.04) of
their desoxy-compounds, MA, amphetamine and dimethylamphetamine. EP was detected
at an average of 2.25 ng/mg (n=4) in human scalp hair and at a range of 1-29
ng/mg (n=3) in human beard hair until day 14, but its metabolite (PPA) was at a
trace level in the hair of the four subjects. The method was successfully used
for detection of ME and EP in the hair of a neonate and its mother who was
abusing Bron syrup containing ME during the pregnancy.
PMID- 9390718
TI - Determination of low levels of poly(ethylene glycol) 400 in plasma and urine by
capillary gas chromatography-selected ion-monitoring mass spectrometry after
solid-phase extraction.
AB - A convenient and sensitive method for the quantitative determination of
poly(ethylene glycol) 400 in plasma and urine with capillary gas chromatography
mass spectrometry has been developed. The sample preparation involves solid-phase
extraction with subsequent derivatization with heptafluorobutyric anhydride,
which proved to give the most stable derivative. The derivatization procedure was
optimized using experimental design, and different solid-phase extraction columns
were evaluated. The limit of quantitation was 1 micromol/l (0.4 microg/ml) for
both plasma and urine.
PMID- 9390719
TI - High-performance liquid chromatography of unmodified rosin and its applications
in contact dermatology.
AB - Rosin is a well recognised skin sensitiser and is also amongst the most common
causes of occupational asthma. Due to its complex chemical composition, it is
difficult to isolate its many components and this has hindered progress in the
identification of the specific respiratory and contact allergens it contains.
This paper reports the application of high-performance liquid chromatography and
other analytical techniques to the isolation and identification of contact
allergens in complex mixtures such as rosin. HPLC methods were developed in order
to isolate as many rosin components as possible and these were then patch tested
on rosin sensitive individuals. The structure of the most dermatologically active
component was then determined using mass spectrometry, nuclear magnetic resonance
and infrared techniques. An HPLC method has also been developed which will enable
the identification of rosin in commercial products, providing a valuable tool for
determining the cause of rosin contact allergy. Furthermore, mass spectral data
for the common abieitic-type resin acids are compiled which were used to confirm
the identification of the HPLC resin acid peaks and have not been reported
previously.
PMID- 9390720
TI - Analysis of a novel antiinflammatory agent, 1-(7-tert.-butyl-2,3-dihydro-3,3
dimethylbenzo[b]furan-5-yl)-4- cyclopylbutan-1-one (PGV-20229), in plasma
matrices by stable-isotope-dilution gas chromatography-mass spectrometry.
AB - A sensitive and selective GC-MS method was developed for the determination of low
levels of a novel antiinflammatory agent, 1-(7-tert.-butyl-2,3-dihydro-3,3
dimethylbenzo[b]furan-5-yl)-4- cyclopropylbutan-1-one (I), in small volumes of
animal plasma. The method involved the addition of 13C6-labeled-I to plasma
samples, followed by a simple liquid-liquid extraction with hexane to isolate the
analytes from matrix components. The levels of I in the sample extracts were
determined by isotope-dilution GC-MS analysis using selected-ion monitoring. The
method was linear over three orders of magnitude, with a limit of quantitation of
1.8 ng/ml I, using plasma sample volumes of 0.1 ml. The method was utilized to
determine the pharmacokinetic parameters of I in rats and dogs, following
intravenous administration.
PMID- 9390721
TI - Screening for forensically relevant benzodiazepines in human hair by gas
chromatography-negative ion chemical ionization-mass spectrometry.
AB - A procedure is presented for the detection in human hair of forensically relevant
benzodiazepines, i.e. nordiazepam, oxazepam, bromazepam, diazepam, lorazepam,
flunitrazepam, alprazolam and triazolam. The method involves decontamination of
hair with methylene chloride, pulverization in a ball mill, incubation of 50 mg
powdered hair in Soerensen buffer (pH 7.6) in the presence of prazepam-d5 used as
internal standard, liquid-liquid extraction with diethyl ether-chloroform (80:20,
v/v) and gas chromatography-mass spectrometry using negative chemical ionization
after derivatization with N,O-bis(trimethylsilyl)trifluoroacetamide plus 1%
trimethylchlorosilane. The limits of detection for all benzodiazepines ranged
from 1 to 20 pg/mg using a 50-mg hair sample. Coefficients of variation and
extraction recoveries, ranging from 7.4 to 25.4% and 47.6 to 90%, respectively,
were found suitable for a screening procedure. One hundred and fifteen samples
were submitted to this screening procedure, and specimens tested positive for
nordiazepam (0.20-18.87 ng/mg, n=42) and its major metabolite oxazepam (0.10-0.50
ng/mg, n=14), flunitrazepam (19-148 pg/mg, n=31), lorazepam (31-49 pg/mg, n=4)
and alprazolam (0.3-1.24 ng/mg, n=2). Bromazepam, diazepam and triazolam were not
detected.
PMID- 9390722
TI - Validated assay for the quantification of anastrozole in human plasma by
capillary gas chromatography-63Ni electron capture detection.
AB - An assay was developed for the quantification of anastrozole [2,2'-[5-(1H-1,2,4
triazol-1-ymethyl)-1,3-phenylene]bis(2-++ +methylpropiononitrile)] in human
plasma using liquid-liquid extraction. Anastrozole and an internal standard were
chromatographed and detected by gas chromatography with electron capture
detection, using a combination temperature-pressure program. The range of the
assay is 3 to 100 ng/ml. Anastrozole was quantified by comparing its peak area to
that of an internal standard. A cross-validation of this assay was also
successfully performed between several laboratories.
PMID- 9390723
TI - Determination of the substance P receptor antagonist CP-122,721 in plasma by
narrow-bore high-performance liquid chromatography-ionspray tandem mass
spectrometry.
AB - A simple, highly sensitive and specific LC-MS-MS assay was developed for the
determination of CP-122,721 (I) in rat and human plasma. I and a structural
analog, CP-129,943 (II, internal standard), were extracted from plasma with
methyl tert.-butyl ether (MTBE). The dried MTBE extracts were reconstituted and
analyzed using a narrow-bore (2.1 mm I.D.) YMC basic HPLC column and a mobile
phase of acetonitrile-20 mM ammonium acetate, pH 5 (50:50, v/v). Column effluents
were monitored by ionspray tandem mass spectrometry. Multiple reaction monitoring
(MRM) using the parent to product ion combinations of m/z 381-->205 and 395-->219
was used to quantitate I and II, respectively. The assay exhibited a linear
dynamic range of 0.2-100 ng/ml. Absolute recoveries from plasma were above 80%
for both I and II. The precision and accuracy values for the method were within
+/-3 and +/-9%, respectively. Sample analysis times were less than 5 min from one
injection to the next. The assay has proved to be applicable to the
pharmacokinetic study of I in rats.
PMID- 9390724
TI - Simultaneous quantification of cefotaxime, desacetylcefotaxime, ofloxacine and
ciprofloxacine in ocular aqueous humor and in plasma by high-performance liquid
chromatography.
AB - Cefotaxime, given intravenously, is currently used as a broad-spectrum antibiotic
for prophylaxis of intra- and postoperative infections in ocular lens surgery. A
proposed therapeutic and economic alternative is the use of orally active
fluoroquinolone ofloxacine as prophylactic agent. A HPLC method was developed for
determination of both antibiotics in ocular aqueous humor and plasma in order to
optimize dosage for safe surpassing minimal inhibitory concentration in the humor
compartment. For plasma determinations a solid-phase extraction procedure was
used with ciprofloxacine as internal standard. Detection limits for direct HPLC
analysis of ocular aqueous humor was 0.08 microg/ml for all compounds, whereas in
plasma 0.31 microg/ml could be determined after solid-phase extraction.
PMID- 9390725
TI - Enantioselective high-performance liquid chromatography determination of
methadone enantiomers and its major metabolite in human biological fluids using a
new derivatized cyclodextrin-bonded phase.
AB - The simultaneous determination of methadone (Mtd) enantiomers and its major
metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in human
urine and serum by enantioselective HPLC using a new Cyclobond 1-2000 RSP column
is described. After alkaline extraction from urine or serum with estazolam as an
internal standard, Mtd enantiomers and its metabolite (EDDP) are separated on the
previous column with reversed-mobile phase and detected at 210 nm. Peak
resolutions are about 2.0 for Mtd enantiomers. The relative standard deviations
(R.S.D.) of Mtd and EDDP standards are between 0.5 and 4.5%. Most drugs of abuse
are shown not to interfere with this technique. The method has been applied to
study the levels of each Mtd enantiomer and of its racemic metabolite in urine
and serum of patients under maintenance treatment for opiate dependence. In
urine, R-(-)-Mtd levels are always higher (about 2+/-0.5-fold) than those of S
(+)-Mtd and in most cases, metabolite concentrations are greater than those of
global Mtd enantiomers. However, the R-(-) enantiomer levels of residual drug in
serum of some patients were lower than those of its antipode. This method is
suitable for pharmacokinetic and toxicological studies of Mtd enantiomers and its
major metabolite in biological fluids.
PMID- 9390726
TI - Stereoselective determination of R-(+)- and S-(-)-remoxipride, a dopamine D2
receptor antagonist, in human plasma by chiral high-performance liquid
chromatography.
AB - A stereoselective high-performance liquid chromatographic (HPLC) method is
described for the selective and sensitive quantitation in human plasma of R-(+)-
and S-(-)-enantiomers of remoxipride. Remoxipride was extracted from basified
plasma into hexane-methyl-tert.-butyl ether (20:80, v/v), washed with sodium
hydroxide (1.0 M), then back-extracted into phosphoric acid (0.1 M). A structural
analog of remoxipride was used as an internal standard. The sample extracts were
chromatographed using a silica-based derivatized cellulose chiral column,
Chiralcel OD-R, and a reversed-phase eluent containing 30-32% acetonitrile in 0.1
M potassium hexafluorophosphate. Ultraviolet (UV) absorbance detection was
performed at 214 nm. Using 0.5-ml plasma aliquots, the method was validated in
the concentration range 0.02-2.0 microg/ml and was applied in the investigation
of systemic inversion of remoxipride enantiomers in man.
PMID- 9390727
TI - Quantitation of trimipramine enantiomers in human serum by enantioselective high
performance liquid chromatography and mixed-mode disc solid-phase extraction.
AB - A sensitive and stereospecific method for the quantitation of trimipramine
enantiomers in human serum was developed. The assay involves the use of a novel
mixed-mode disc solid-phase extraction for serum sample clean-up prior to HPLC
analysis and is also free of interference from the enantiomers of
desmethyltrimipramine, 2-hydroxytrimipramine, and 2-hydroxydesmethyltrimipramine,
the three major metabolites of trimipramine. Chromatographic resolution of
trimipramine enantiomers was performed on a reversed-phase cellulose-based chiral
column (Chiralcel OD-R) under isocratic conditions using a mobile phase
consisting of 0.3 M aqueous sodium perchlorate-acetonitrile (58:42, v/v) at a
flow-rate of 0.5 ml/min. Recoveries for R- and S-trimipramine enantiomers were in
the range of 93-96% at 25-185 ng/ml levels. Intra-day and inter-day precisions
calculated as R.S.D. were in the ranges of 0.30-8.00% and 1.60-10.20% for both
enantiomers, respectively. Intra-day and inter-day accuracies calculated as
percent error were in the 0.01-2.10% and 1.00-3.00% ranges for both enantiomers,
respectively. Linear calibration curves were in the concentration range 15-250
ng/ml for each enantiomer in serum. The limit of quantification of each
enantiomer was 15 ng/ml. The detection limit for each enantiomer in serum using a
UV detector set at 210 nm was 10 ng/ml (S/N=2). In addition, separation of the
enantiomers of desmethyltrimipramine, 2-hydroxytrimipramine, and 2
hydroxydesmethyltrimipramine were investigated. The desmethyltrimipramine
enantiomers could be resolved on the Chiralcel OD-R column under the same
chromatographic conditions as the trimipramine enantiomers, but the other two
metabolite enantiomers required different mobile phases on the Chiralcel OD-R
column to achieve satisfactory resolution with Rs values of 1.00.
PMID- 9390728
TI - Sensitive and rapid method for the simultaneous quantification of five
antidepressants with their respective metabolites in plasma using high
performance liquid chromatography with diode-array detection.
AB - A high-performance liquid chromatographic method with diode array detection (HPLC
DAD) has been developed for the simultaneous separation and quantification of
imipramine, amitriptyline, maprotiline, fluoxetine, clomipramine and their
respective metabolites using a 500-microl plasma sample and clovoxamine as the
internal standard. The substances were eluted on a Symmetry C18 5-microm column
(250x4.6 mm, I.D.). Full UV spectra from 200 to 450 nm were recorded on-line
during the entire analysis and were automatically compared to spectra stored in a
library. The quantification was performed at 226, 254, and 400 nm. Peak height
ratios were linear over a concentration range of 10-3000 ng/ml: the correlation
coefficient (r) was better than 0.998 for all substances at each wavelength.
Acceptable coefficients of variation are demonstrated for both within-run and day
to-day assays. The method is simple, highly specific and currently being used for
drug monitoring and toxicological studies in children and adult patients.
PMID- 9390729
TI - Determination of SDZ ICM 567 in blood and muscle microdialysis samples by
microbore liquid chromatography with ultraviolet and fluorescence detection.
AB - Fast, simple and accurate methods for the determination of SDZ ICM 567, the 7
methoxy derivative of tropisetron, in microdialysates have been developed.
Sampling by microdialysis from freely moving rats in the portal and jugular vein
offers a new technology for pharmacokinetic studies by direct and continuous
measurement of unbound drug concentrations with time. SDZ ICM 567 can be
identified in small sample volumes of dialysates on a microbore high-performance
liquid chromatography column-switching system with ultraviolet detection. In
addition, determination of SDZ ICM 567 by fluorimetric detection has been
developed for muscle microdialysates from rats. [14C]SDZ ICM 567 was used as
reference substance for the estimation of the amount of substance transferred
through the dialysis membrane. The radioactive measurement (RA) gave the recovery
information, whereas the liquid chromatographic method detected the sum of
[14C]SDZ ICM 567 and dialyzed SDZ ICM 567.
PMID- 9390730
TI - Determination of propiomazine in rat plasma by direct injection on coupled liquid
chromatography columns with electrochemical detection.
AB - This method describes the determination of propiomazine by direct injection of
rat plasma into a chromatography system based on coupled reversed-phase columns.
An extraction column, packed with porous silica particles with covalent-bound
alpha1-acid glycoprotein (AGP), was used to separate the plasma proteins from the
analyte. After isolation the analyte was transferred to the analytical column for
separation and detection. Propiomazine was detected by an electrochemical
detector and the limit of quantification was 2.0 ng/ml (100 pg injected). The
absolute recovery was 80.9+/-2.4% at 9.0 ng/ml level. The inter-day and intra-day
precision was 10.9% (5.6 ng/ml) and 2.8% (9.0 ng/ml), respectively.
PMID- 9390731
TI - Determination of 6,4'-bis-(2-imidazolinylhydrazone)-2-phenylimidazo[1,2-a]py
ridine in plasma and whole blood by high-performance liquid chromatography.
AB - A selective and sensitive HPLC assay for the quantitative determination of a new
antifilarial drug, 6,4'-bis-(2-imidazolinylhydrazone)-2-phenylimidazo[1,2-a]pyr
idine (CDR 101) is described. After extraction from plasma and blood, CDR 101 was
analysed using a C18 Nucleosil ODS column (250x4.6 mm, 5 microm particle size)
and mobile phase of acetonitrile-0.05 M ammonium acetate adjusted to pH 3.0, with
UV detection at 318 nm. The mean recoveries of CDR 101 in plasma and blood over a
concentration range of 25-500 ng/ml were 95.5+/-2.01% and 83.3+/-1.87%,
respectively. The within-day and day-to-day coefficient of variations for plasma
were 3.23-6.21% and 2.59-9.90%, respectively, those for blood were 2.59-5.92% and
2.89-6.82%, respectively. The minimum detectable concentration for CDR 101 was 1
ng/ml in plasma and 2.5 ng/ml in whole blood. This method was found to be
suitable for clinical pharmacokinetic studies.
PMID- 9390732
TI - Stereospecific determination of mefloquine in biological fluids by high
performance liquid chromatography.
AB - A sensitive stereoselective HPLC method was developed for determination of
mefloquine (MFQ) enantiomers in plasma, urine and whole blood. The assay involved
liquid-liquid extraction of MFQ from biological fluids with a mixture of hexane
and isopropanol in the presence of sodium hydroxide and derivatization of the
residue by (+)-(S)-naphthylethylisocyanate (NEIC) as chiral derivatizing reagent.
Separation of the resulting diastereomers was performed on a silica normal-phase
column using chloroform-hexane-methanol (25:74:1) as the mobile phase with a flow
rate of 1 ml/min. Using 200 microl of plasma or whole blood, the limit of
determination was 0.2 microg/ml with UV detection for both enantiomers. The limit
of determination in 500 microl of urine was 0.08 microg/ml with UV detection.
PMID- 9390733
TI - Confirmation of malachite green, gentian violet and their leuco analogs in
catfish and trout tissue by high-performance liquid chromatography utilizing
electrochemistry with ultraviolet-visible diode array detection and fluorescence
detection.
AB - A sensitive analytical procedure for the confirmation of residues of malachite
green (MG), gentian violet (GV) and their leuco analogs (LMG and LGV) in catfish
and trout tissue at 10 ng/g is described. Frozen (-20 degrees C) fish fillets
were cut into small pieces and homogenized in Waring blendors. The compounds of
interest were extracted from 20-g amounts of homogenized fish tissue with
acetonitrile-buffer, partitioned against methylene chloride, and isolated with
tandem neutral alumina and propylsulfonic acid cation-exchange solid-phase
extraction cartridges. Samples of 100 microl (0.8 g equiv.) were chromatographed
isocratically in 10 min using an acetonitrile-buffer mobile phase on a short
chain deactivated (SCD) reversed-phase column (150x4.6 mm I.D.) in-line with a
post-column oxidation coulometric electrochemical cell (EC), a UV-Vis diode array
detector and a fluorescence detector.
PMID- 9390734
TI - Quantitative comparison on the refinement of horse antivenom by salt
fractionation and ion-exchange chromatography.
AB - A quantitative comparison was made on the fractionation of pepsin-digested horse
antivenoms by ammonium sulfate (AS) fractional precipitation and ion-exchange
chromatography on Q-Sepharose. In the precipitation process, pepsin digested
horse anti-Naja kaouthia serum was precipitated by 30% saturated AS followed by
50% saturated AS. The recovery of antibody activity [as measured by an enzyme
linked immunosorbent assay (ELISA) against the cobra postsynaptic neurotoxin 3]
from the 30-50% saturated AS precipitate was 53% with a 1.93-fold purification.
For the chromatographic process, the behavior of the horse antitoxin antibody and
its F(ab')2 fragments was first studied. The pepsin digested horse serum was then
desalted on a Bio-gel P-2 column followed by chromatography on Q-Sepharose using
a linear gradient (20 mM Tris-HCl, pH 8.0 containing 0.0 to 0.5 M NaCl) A peak
containing primarily the F(ab')2 antibody could be obtained. This peak
constituted 73% of the total antivenom activity with 2.08-fold purification. The
total recovery of antibody activity by the chromatographic process was 90%. The
yield of antibody activity was about 2-fold higher than that reported previously
with other fractionation procedures. The implications of these results for the
refining of horse therapeutic antivenoms are discussed.
PMID- 9390736
TI - Analysis of the antidiabetic drug acarbose by capillary electrophoresis.
AB - This study describes the derivatization of the pseudooligosaccharide acarbose and
its main metabolite, component 2, with 7-aminonaphthalene-1,3-disulfonic acid
(ANDS) in human urine. Their efficient separation was possible by means of
capillary zone electrophoresis, using a capillary tube of fused-silica containing
100 mM triethylammonium phosphate buffer, pH 1.5. On column laser-induced
fluorescence allowed the detection of the pseudooligosaccharides in human urine
in the nanomolar range. With this method, acarbose and component 2 were
quantified in human urine after application of 300 mg of acarbose.
PMID- 9390735
TI - Characterisation of a chromatographically produced anti-D immunoglobulin product.
AB - A chromatographic fractionation method has been developed for the production of a
liquid-stable anti-D immunoglobulin product for intravenous and intramuscular
use. An immunoglobulin fraction, highly enriched with anti-D immunoglobulins, was
isolated by cation-exchange column chromatography and further polished, first by
anion-exchange chromatography, followed by an aluminium hydroxide gel treatment.
The process includes two specific steps for virus inactivation and removal,
namely S/D treatment and nanofiltration. The overall anti-D process yield is
about 56%. The final product is stabilised with human albumin and glycine and
placed in ready-to-use syringes. The anti-D product was shown to be stable in
liquid state for at least 30 months at 4 degrees C.
PMID- 9390737
TI - Detection of microbial-derived fatty acids in carious dentin by gas
chromatography and gas chromatography-mass spectrometry.
AB - The aim of the present study was to analyze the fatty acid content of carious and
sound human dentin. Gas chromatography and gas chromatography-mass spectrometry
revealed the presence of fatty acids of C10-C18 size in the carious dentin,
whereas fatty acids of C16 size were present in minute amounts in three samples
of the corresponding sound dentine controls. No fatty acids were detected in the
other sound dentin control samples. The source of fatty acids was considered to
be microorganisms invading the dentin during the progression of the caries
lesion. The presence of bacterial fatty acids in carious dentin may serve as a
marker for the pathological process and thus contribute to the understanding of
the mechanisms involved.
PMID- 9390738
TI - Measurement of oxalate in human plasma ultrafiltrate by ion chromatography.
AB - An improved ion chromatographic method for the measurement of oxalate in human
plasma ultrafiltrate is described. Ultrafiltration was carried out using an
appropriate device and procedure. Centrifugation of 0.5 ml heparin plasma at 4
degrees C for 50 min yielded water-clear ultrafiltrate in amounts allowing
replicate measurements of oxalate. The specificity of the method was confirmed.
The recovery of oxalate added to plasma was approximately 80%, whereas dilution
of plasma, and of an oxalate-containing salt solution, resulted in falsely high
values; the mechanism(s) underlying this phenomenon are insufficiently understood
at present. The intra-assay precision of the method was assessed and from ten
replicates of a pool plasma, the inter-assay precision from ten measurements of
the same plasma on different days; the observed ranges of oxalate were 1.32-1.56
(mean 1.42) and 1.42-1.64 (mean 1.53) micromol/l, respectively. In plasma
ultrafiltrate of a limited number of healthy volunteers the range of oxalate was
1.18-2.50 micromol/l, thus permitting renal oxalate handling to be studied.
PMID- 9390739
TI - Microchromatographic quantitation of hemoglobin A levels in phenotypes of sickle
cell-beta(+) thalassemia.
AB - The inheritance of the sickle cell gene in combination with a gene for beta(+)
thalassemia results in a spectrum of sickle cell-beta(+) thalassemia syndromes
with varying levels of hemoglobin A (HbA). Some severe sickle cell-beta(+)
thalassemia syndromes have small amounts of HbA, which may be difficult to
quantitate in the presence of fetal hemoglobin. A microcolumn chromatographic
method, using 0.5 M Tris-acetic acid developers with varying pH values from 9.0
to 6.0, appears to adequately quantitate small amounts of HbA. This method is
relatively simple and cheaper than high-performance liquid chromatography, a
major consideration in developing countries.
PMID- 9390740
TI - Thiopurine methyltransferase activity: new high-performance liquid
chromatographic assay conditions.
AB - This paper reports changes to our previously published high-performance liquid
chromatographic method for the measurement of 6-methylmercaptopurine (6-MMP) in
red blood cell lysates. The extraction procedure and chromatographic conditions
have been improved and the range of the calibration curves has been modified. The
recoveries of 10 and 100 ng ml(-1) 6-MMP were 99.0+/-6.0% and 96.3+/-4.0%
respectively and the limit of quantification was lowered to 5 ng ml(-1). This
method, which does not require radioactive S-adenosyl-L-methionine, is more
sensitive, specific and reproducible and may prove useful for routine
determination of thiopurine methyltransferase activity in red blood cells.
PMID- 9390741
TI - Simultaneous determination of L-dopa and 3-O-methyldopa in human platelets and
plasma using high-performance liquid chromatography with electrochemical
detection.
AB - Various high-performance liquid chromatographic (HPLC) methods for the
determination of plasma levels of L-dopa and of its metabolite, 3-O-methyldopa (3
OMD), have been previously described. In this study, we report a modification of
these methods, that enables the assay of these two compounds in platelets and
plasma obtained from the same sample of whole blood. Reversed-phase (RP) HPLC
with electrochemical (coulometric) detection was used. The within-run and between
run coefficients of variations, for the two compounds, were less than 10%, in
both platelets and plasma; the detection limits for platelet levels of L-dopa and
3-OMD were 2 and 6 ng/10(9) platelets, respectively. In plasma, the detection
limits for L-dopa and 3-OMD were 1 and 3 ng/ml, respectively. The method is rapid
and simple. When applied to a population of patients with Parkinson's disease
under treatment with L-dopa, this method revealed detectable levels of L-dopa and
3-OMD in the platelets of all patients. The application of this technique may
provide new insights into the pharmacokinetics of L-dopa in patients with
Parkinson's disease.
PMID- 9390742
TI - High-performance thin-layer chromatographic determination of 5-methoxypsoralen in
serum from patients.
AB - A simple and rapid high-performance thin-layer chromatographic (HPTLC)
determination of 5-methoxypsoralen in serum is necessary for the therapeutic
survey of patients treated with Puvatherapy (psoralen+UVA). The assay for this
biological fluid involves an extraction with heptane-dichloromethane (4:1, v/v).
The analytical method is linear from 50 to 250 ng/ml. This assay range is
adequate for analysing human serum, as it corresponds to psoralen concentrations
measured in serum from patients treated with psoralen and UVA against psoriasis
and vitiligo. The limit of detection is 15 ng/ml. The coefficient of variation
was less than 7%.
PMID- 9390743
TI - Dynamics of syncytium-inducing and non-syncytium-inducing type 1 human
immunodeficiency viruses during primary infection.
AB - Syncytium-inducing (SI) type 1 human immunodeficiency viruses (HIV-1) replicate
faster in vitro and are generally more cytopathic to T cells than non-syncytium
inducing (NSI) HIV-1. Early in infection, the virus population typically consists
of NSI viruses, with SI viruses appearing later. This is true even when both SI
and NSI viruses are transmitted, and when SI viruses dominate the virus
population peak seen during primary infection. Here, Phillips's model of HIV
dynamics during primary infection (Science 271:497-499) is modified to map the
growth trajectories of SI and NSI subpopulations. The model predicts that with
certain rate constants, SI viruses may show a more precipitous decline in their
numbers during primary infection than NSI viruses, and this may account for the
observed dominance of NSI viruses early in infection.
PMID- 9390744
TI - Thy/Liv-SCID-Hu mice implanted with human intestine: an in vivo model for
investigation of mucosal transmission of HIV.
AB - Mucosal transmission is a major route by which individuals become infected with
HIV. Investigation into the mechanism by which mucosal transmission of HIV occurs
would be greatly facilitated by the development of a small animal model
infectible with HIV by the mucosal route. We have previously described a SCID-hu
mouse model, in which human thymic and liver tissues are implanted under both
kidney capsules (thy/liv-SCID-hu mice), which are populated in the periphery with
high numbers of human T cells and that develop disseminated HIV-1 infection after
intraperitoneal injection. To expand further the usefulness of the thy/liv-SCID
hu mouse as a model for studying mucosal transmission of HIV, thy/liv-SCID-hu
mice were subcutaneously implanted with human intestinal tissue in a manner that
maintained the lumen. Four months later, the histological appearance of the
implanted intestine resembled that of normal human bowel tissue and the lamina
propria was populated with human T cells. Six weeks after introduction of HIV
into the lumen of the intestinal implant, the mice developed disseminated HIV
infection. Scattered HIV-infected cells were detected in the lamina propria of
the implant, indicating that HIV infection in these mice was mediated by
transmission of the virus across the mucosa of the human intestinal implant.
Thus, our modified thy/liv-SCID-hu mice transplanted with human bowel tissue
should provide a novel model for investigating mucosal transmission of HIV.
PMID- 9390745
TI - Human immunodeficiency virus type 1 glycoprotein 120-specific T lymphocytes
provide intermolecular help for anti-CD4 autoantibody production in exposed
uninfected subjects.
AB - Anti-CD4 antibodies have been documented in about 10-20% of HIV-infected
patients. This autoimmune response could be triggered by increased CD4 processing
and unveiling of hidden (cryptic) epitopes. Multiple markers of exposure to HIV
have been described in exposed uninfected individuals. Here, we investigated the
mechanisms underlying the generation of anti-CD4 antibodies in a cohort of 54
seronegative exposed uninfected individuals. We identified anti-CD4 antibodies
above normal levels in 16 of 47 (34%) exposed uninfected subjects. The fine
specificity of these antibodies was different in this cohort when compared with
those found in HIV+ patients. This suggested the possibility of different
mechanisms underlying the generation of anti-CD4 antibodies in these two groups.
Indeed, in exposed uninfected subjects, we found circulating CD4 T cells specific
for gp120, but not for CD4. In contrast, HIV-1-seropositive patients had
peripheral blood T cells specific for both molecules. Noncovalent binding of
gp120 to soluble CD4 enhanced activation of gp120-specific T lymphocytes in
exposed uninfected subjects, but not in HIV+ subjects. Moreover, gp120-specific T
cells isolated from exposed uninfected, but not from HIV+, subjects provided help
for anti-CD4 antibody production by B cells pulsed with CD4-gp120 complex. We
conclude that gp120-specific T cells are present in exposed uninfected
individuals, and can provide intermolecular help for anti-CD4 antibody
production. This mechanism is distinct from that found in HIV-1-seropositive
patients and may play a protective role against HIV-1 infection in vivo.
PMID- 9390746
TI - Restricted specificity of anti-V3 antibodies induced in humans by HIV candidate
vaccines.
AB - We analyzed the fine specificity of anti-V3 antibodies elicited in three
different species (human, guinea pig, and macaque) by various HIV candidate
vaccines. Following immunization with recombinant canarypox virus expressing
gp160MN or with recombinant gp160MN/LAI, this antibody response was shown to be
directed against the NH2-terminal region of the V3 loop. Although this response
was increased by a prime-boost regimen using immunization with canarypox
expressing gp160 followed by an rgp160 boost, its specificity remained restricted
mainly to the recognition of this region of the V3 loop. Pepscan analysis of sera
confirmed the results obtained by ELISA and allowed the definition of an
immunodominant common binding site for these sera located within the sequence
NKRKRIHIGPGR. In contrast to these results, a boost with the V3 peptide was shown
to broaden the antibody response and pepscan analysis showed that sera from
individuals boosted with the V3 synthetic peptide recognize determinants all
along the V3 loop. Similar fine specificity of anti-V3 antibodies was obtained in
human, guinea pig, and macaque following immunization by a prime-boost regimen
using canarypox recombinants expressing gp160 or gp120 and purified rgp160. In
contrast, a V3 synthetic peptide boost stimulated the production of antibodies
that recognize multiple epitopes within the V3 loop. Because the induction of
antibodies that recognize multiple sites in the V3 loop could be of major
importance to neutralize different HIV isolates, these results may have
implications for the design and selection of HIV candidate vaccines.
PMID- 9390747
TI - Outcome of immunization of cynomolgus monkeys with recombinant Semliki Forest
virus encoding human immunodeficiency virus type 1 envelope protein and challenge
with a high dose of SHIV-4 virus.
AB - Infection of macaques with chimeric simian-human immunodeficiency viruses (SHIVs)
allows evaluation of HIV-1 envelope vaccines. SHIV-4 is based on SIVmac239 but
carries the env, tat, and rev genes of HIV-1IIIB. In this study we used Semliki
Forest virus (SFV) RNA vectors to express the envelope protein gp160 of HIV-1IIIB
in cynomolgus macaques. Monkeys were immunized four times with recombinant
suicide SFV. Whereas two of four monkeys showed T cell-proliferative responses,
only one monkey had demonstrable levels of antibodies to HIV-1 gp41 and gp120 as
shown by enzyme-linked immunosorbent assay (ELISA) and Western blot. The
vaccinated monkeys and four control animals were challenged with 10,000 MID100
(100% minimum infectious doses) of cell-free monkey cell-grown SHIV-4 virus. As
demonstrated by virus isolation, all macaques became infected after challenge.
All vaccinated monkeys showed an HIV-1-specific anamnestic T cell-proliferative
response. Three of four vaccines had developed HIV-1-Env-specific antibodies 2
weeks after challenge whereas none of the four controls showed any detectable
immune response at this time point. Furthermore, three of four vaccinated monkeys
had no demonstrable viral antigenemia and low viral load as opposed to one of the
four naive control animals.
PMID- 9390748
TI - Immunogenicity of recombinant vaccinia viruses that display the HIV type 1
envelope glycoprotein on the surface of infectious virions.
AB - A chimeric protein, consisting of the extracellular domain of the human
immunodeficiency virus type 1 (HIV-1) envelope glycoprotein attached to the
transmembrane and cytoplasmic domains of the vaccinia virus B5R glycoprotein, is
displayed on the surface of extracellular recombinant vaccinia virus particles,
whereas the unmodified full-length HIV-1 glycoprotein is not (Katz E, et al., J
Virol 1997;71:3178-3187). Here, we report that rabbits and mice inoculated with
recombinant vaccinia viruses that express the chimeric protein developed higher
HIV-specific antibody responses than animals inoculated with vaccinia virus that
expressed the unmodified HIV glycoprotein. These data suggest that the
immunogenicity of recombinant proteins may be enhanced by their presentation on
the surface of vaccinia virus particles.
PMID- 9390749
TI - Study of spontaneous apoptosis in HIV+ patients: correlation with clinical
progression and T cell loss.
AB - In vitro spontaneous apoptosis (SA) of lymphocytes was studied in HIV infection
to evaluate possible clinical and prognostic correlations, in a transsectional
study of 101 individuals in different clinical categories and in a prospective
longitudinal study of 18 asymptomatic individuals (mean follow-up, 17.2 months).
The rate of SA was higher in HIV+ patients than in healthy controls (p < 0.001)
and was higher in patients with AIDS than in the other HIV+ individuals (p <
0.001). It was inversely correlated with the peripheral blood CD4+ (R -0.61; p <
0.001) and CD8+ (R -0.46; p < 0.001) cell numbers. In a group of long-term
survivors (LTS), it was significantly lower than in a control group of
asymptomatic HIV+ patients with a similar number of circulating CD4+ lymphocytes
but a shorter follow-up (p < 0.02). In the five asymptomatic HIV-infected
individuals who showed a clinical progression, peaks of SA rates above the normal
range before the clinical event were much more frequent than in those who
remained asymptomatic (p < 0.0001), even though they were fairly homogeneous as
far as CD4+ cell count and viral load were concerned. The median levels of SA
rates were moreover correlated with the rate of total T cell loss (R -0.46; p
0.053). This study suggests that evaluation of the SA levels may provide a
predictive factor for clinical and immunological progression of HIV-related
immunodeficiencies and strengthen the hypothesis for the role of this phenomenon
in the pathogenesis of this progression.
PMID- 9390750
TI - Downregulation of HLA class I antigen expression in CD4+ T lymphocytes from HIV
type 1-infected individuals.
AB - The expression of HLA class I antigens is downregulated in CD4+ T cells following
in vitro HIV-1 infection. We determined whether the expression of HLA class I
antigens is downmodulated in peripheral blood lymphocytes (PBLs) of HIV-1
positive subjects and whether this defect correlates with disease progression. A
cohort of 62 HIV-1-seropositive individuals in different stages of disease was
studied. Among these, four subjects were evaluated at yearly intervals for 6
years. The expression of HLA class I, HLA class II, and CD38 antigens was
analyzed in PBLs and in CD4+ and CD8+ T lymphocyte subpopulations. The percentage
of HLA class I-positive cells and the membrane density of HLA class I antigens
were significantly lower in PBLs from HIV-1-positive individuals than in PBLs
from HIV-negative controls, proportionally decreased with disease progression,
and significantly correlated with the decrease in CD4+ T lymphocytes.
Furthermore, the percentage of HLA class I-positive cells and the membrane
density of HLA class I antigens were significantly lower in CD4+ T lymphocytes
from AIDS patients with respect to CD4+ T lymphocytes from HIV-negative controls
and to CD8+ T lymphocytes from HIV-negative controls and AIDS patients. By
contrast, the expression of HLA class II and CD38 antigens was upregulated in
CD4+ and CD8+ T lymphocytes from HIV-1-positive subjects. The defective
expression of HLA class I antigens could impair the lysis of HIV-infected CD4+
cells by virus-specific HLA class I-restricted cytotoxic T lymphocytes and
contribute to the progression of disease.
PMID- 9390751
TI - Inhibition of plating of human T cell leukemia virus type I and syncytium
inducing types of human immunodeficiency virus type 1 by polycations.
AB - We examined the effects of polycations, namely, diethylaminoethyl-dextran (DEAE
dextran) and hexadimethrine bromide (Polybrene), on infection with the
retroviruses human T cell leukemia virus types I and II (HTLV-I and HTLV-II) and
human immunodeficiency virus type 1 (HIV-1). The plating of vesicular stomatitis
virus (VSV) pseudotype bearing envelope antigens of HTLV-I [VSV(HTLV-I)] was
inhibited about 2- and 10-fold by treatment with DEAE-dextran and Polybrene,
respectively. The formation of HTLV-I viral DNA detected 1 day after infection
was also inhibited by these polycations. In contrast, polycations enhanced the
plating of the VSV (HTLV-II) pseudotype two- to threefold. The polycations did
not affect the plating efficiency of HTLV-I or HTLV-II when added after virus
adsorption. Infection of human T cell lines, peripheral blood lymphocytes (PBLs),
or brain-derived cells with syncytium-inducing (SI) types of HIV-1 strains (GUN1
and IIIB) was inhibited 3- to 20-fold by polycations. However, infection of PBLs
or monocyte-derived macrophages with the macrophage-tropic Ba-L or SF162 strain
was enhanced 1.5- to twofold by polycations. On the other hand, syncytium
formation in coculture induced by HTLV-I, HTLV-II, or HIV-1 was enhanced two- to
threefold unanimously by DEAE-dextran or Polybrene. Although polycations have
been used to potentiate human retrovirus adsorption, they inhibited infection of
cell-free HTLV-I or SI-type HIV-1 strains.
PMID- 9390752
TI - A synthetic peptide corresponding to the carboxy terminus of human
immunodeficiency virus type 1 transmembrane glycoprotein induces alterations in
the ionic permeability of Xenopus laevis oocytes.
AB - The carboxy-terminal 29 amino acids of the human immunodeficiency virus type 1
transmembrane glycoprotein (HIV-1 TM) are referred to as lentivirus lytic peptide
1 (LLP-1). Synthetic peptides corresponding to LLP-1 have been shown to induce
cytolysis and to alter the permeability of cultured cells to various small
molecules. To address the mechanisms by which LLP-1 induces cytolysis and
membrane permeability changes, various concentrations of LLP-1 were incubated
with Xenopus laevis oocytes, and two-electrode, voltage-clamp recording
measurements were performed. LLP-1 at concentrations of 75 nM and above induced
dramatic alterations in the resting membrane potential and ionic permeability of
Xenopus oocytes. These concentrations of LLP-1 appeared to induce a major
disruption of plasma membrane electrophysiological integrity. In contrast,
concentrations of LLP-1 of 20-50 nM induced changes in membrane ionic
permeability that mimic changes induced by compounds, such as the bee venom
peptide melittin, that are known to form channel-like structures in biological
membranes at sublytic concentrations. An analog of LLP-1 with greatly reduced
cytolytic activity failed to alter the electrophysiological properties of Xenopus
oocytes. Thus, by altering plasma membrane ionic permeability, the carboxy
terminus of TM may contribute to cytolysis of HIV-1-infected CD4+ cells.
PMID- 9390753
TI - Effects of tapering doses of oral prednisone on viral load among HIV-infected
patients with unexplained weight loss.
AB - In an exploratory study of virologic and immunomodulatory effects of
corticosteroid therapy for wasting syndrome, four HIV-infected adults with recent
unexplained weight loss were given tapering doses of prednisone over a 2-month
period. Serum neopterin and TNF receptor II levels decreased from baseline after
7 days. An antiretroviral effect was observed initially, peaking on days 14-21
(mean change in HIV-1 branched chain DNA assay on day 21 of -0.52 log10; mean
change, from baseline to nadir for each individual, of -0.63 log10); subsequent
bDNA levels returned toward baseline as prednisone was tapered. No patient lost
weight and there was a mean weight gain of 3.5 kg. Anecdotal reports of
corticosteroid benefits in the wasting syndrome may result in part from decreased
T cell activation leading to decreased HIV replication, an effect that may be
self-limited or that may occur only at higher prednisone doses. Studies involving
more targeted immunomodulatory agents for wasting syndrome are warranted.
PMID- 9390754
TI - Diversity and distribution of gag and env subtypes among 146 HIV type 1 isolates
in Taiwan.
PMID- 9390755
TI - Phylogenetic analysis of a simian T lymphotropic virus type I from a hamadryas
baboon.
PMID- 9390756
TI - Regional and cellular distribution of serotonin 5-hydroxytryptamine2a receptor
mRNA in the nucleus accumbens, olfactory tubercle, and caudate putamen of the
rat.
AB - This paper describes the regional and cellular distribution of serotonin 5
hydroxytryptamine2a (5-HT2a) receptor mRNA in (sub)regions of the rat striatum by
using in situ hybridization. Our results indicate that 5-HT2a mRNA is distributed
heterogeneously in this brain region. Regional densitometry of autoradiograms
from striatal sections hybridized with isotope-labeled cRNA probes showed that
mRNA levels were highest in the olfactory tubercle, lower in the nucleus
accumbens, and lowest in the caudate-putamen. In the nucleus accumbens, the
average mRNA levels in the shell were higher than those in the core. These data
suggest a particular relevance for the 5-HT2a receptor for olfactory tubercle-
and shell-related functions. Therefore, in the nucleus accumbens and the
olfactory tubercle, the cellular localization of 5-HT2a mRNA was investigated by
determining the colocalization of 5-HT2a mRNA with enkephalin mRNA or dynorphin
mRNA. 5-HT2a mRNA was found in enkephalinergic as well as dynorphinergic neurons.
Thus, there does not seem to be a differential distribution of this receptor in
the output routes of the ventral striatum. In all of the subregions investigated
(core, medial shell, and lateral shell of the nucleus accumbens and the olfactory
tubercle), only subpopulations of the total enkephalinergic and dynorphinergic
populations were found to contain 5-HT2a mRNA. For enkephalin, the percentage
colocalization was higher in the lateral shell (61%) compared with the other
subregions (38-45%). For dynorphin, the percentage colocalization was higher in
the olfactory tubercle (68%) than in the other subregions (34-43%). The
differences in (sub)regional mRNA levels and in colocalization with opioids
suggest a considerable regional differentiation in the effects of 5-HT2a-mediated
neurotransmission in the striatum.
PMID- 9390757
TI - Ultrastructural observations of synaptic connections of vibrissa afferent
terminals in cat principal sensory nucleus and morphometry of related synaptic
elements.
AB - Previous work suggests that slowly adapting (SA) periodontal afferents have
different synaptic arrangements in the principal (Vp) and oral trigeminal nuclei
and that the synaptic structure associated with transmitter release may be
related directly to bouton size. The present study examined the ultrastructures
of SA and fast adapting (FA) vibrissa afferents and their associated unlabeled
axonal endings in the cat Vp by using intra-axonal labeling with horseradish
peroxidase and a morphometric analysis. All SA and FA afferent boutons contained
clear, round, synaptic vesicles. All the FA and most SA boutons were presynaptic
to dendrites, but a few SA boutons were axosomatic. Both types of bouton were
frequently postsynaptic to unlabeled axonal ending(s) containing pleomorphic,
synaptic vesicles (P-ending). The size of labeled boutons was larger in FA than
SA afferents, but the size of dendrites postsynaptic to labeled boutons was
larger for SA than FA afferents. Large-sized FA and SA boutons made synaptic
contacts with small-diameter dendrites. The size of FA and SA boutons was larger
than that of their associated P-endings. A morphometric analysis made on the
pooled data of SA and FA boutons indicated that apposed surface area, active zone
number, total active zone area, vesicle number, and mitochondrial volume were
highly correlated in a positive linear manner with labeled bouton volume. These
relationships were also applicable to unlabeled P-endings, but the range of each
parameter was smaller than that of the labeled boutons. These observations
provide evidence that the two functionally distinct types of vibrissa afferent
manifest unique differences but share certain structural features in the synaptic
organization and that the ultrastructural "size principle" proposed by Pierce and
Mendell ([1993] J. Neurosci. 13:4748-4763) for Ia-motoneuron synapses is
applicable to the somatosensory system.
PMID- 9390758
TI - Reevaluation of ipsilateral corticocortical inputs to the orofacial region of the
primary motor cortex in the macaque monkey.
AB - An anatomical approach to possible areas in the cerebral cortex involved in
somatic motor behavior is to analyze the cortical areas containing neurons that
connect directly to the primary motor cortex (MI). To define the cortical areas
related to orofacial movements, we examined the distribution of cortical neurons
that send their axons to the orofacial region of the MI in the macaque monkey.
Injections of retrograde tracers into the electrophysiologically identified
orofacial region of the MI revealed that labeled neurons were distributed in the
following cortical areas: the orbital cortex (area 12), insular cortex,
frontoparietal operculum (including the deep part of the cortical masticatory
area and the secondary somatosensory cortex), ventral division of the premotor
cortex (especially in its lateral part), orofacial region of the supplementary
motor area, rostral division of the cingulate motor area (CMA), and CMA on the
ventral bank. A number of labeled neurons were also seen in the MI around the
injection sites and in the parietal cortex (including the primary somatosensory
cortex and area 7b). No labeled neurons were found in the dorsal division of the
premotor cortex. Fluorescent retrograde double labeling further revealed
virtually no overlap of distribution between cortical neurons projecting to the
orofacial and forelimb regions of the MI. Based on the present results, we
discuss the functional diversity of the cortical areas related to orofacial motor
behavior and the somatotopical organization in the premotor areas of the frontal
cortex.
PMID- 9390759
TI - Connections of the basal forebrain of the weakly electric fish, Eigenmannia
virescens.
AB - The organization of the ventral nucleus of the ventral telencephalon (Vv) was
examined in the weakly electric fish, Eigenmannia virescens. This nucleus, which
is considered the teleost homologue to the basal forebrain nuclei of other
vertebrates, was subdivided into dorsal and ventral subdivisions, based upon
cytoarchitectonic, immunohistochemical, and connectional criteria. Afferent
projections were observed from the medial olfactory bulb as well as the terminal
nerve ganglion. Telencephalic afferents to the Vv were very restricted,
consisting of the supracommissural and the dorsal intermediate nuclei of the
ventral telencephalon, the nucleus taenia, and the medial region of the posterior
nucleus of the dorsal telencephalon. However, the major afferents to the Vv were
diencephalic, particularly those originating from the rostral preoptic area and
other hypothalamic nuclei. Additional afferents included the posterior tubercular
nucleus, the locus coeruleus, the medial perilemniscal nucleus, and the
periventricular nucleus of the posterior tuberculum. Relatively weak projections
were observed from the ventral thalamus and the dorsal posterior thalamic
nucleus. As described previously, the diencephalic complex of the central
posterior thalamic nucleus/prepacemaker nucleus (CP/PPn), which also has cells
that innervate the pacemaker circuitry controlling the production of an electric
organ discharge, projects to the Vv. Terminal fields of the Vv were observed to
be coextensive with afferent cell groups in the preoptic area, lateral and caudal
hypothalamic nuclei, and thalamus. An additional efferent target of the Vv was
the pretectal nucleus electrosensorius. That many cell groups that are connected
with the Vv are also connected with the CP/PPn, particularly the preoptic and
hypothalamic nuclei, suggests that the electrocommunicatory system is intimately
linked with basal forebrain limbic pathways.
PMID- 9390760
TI - N-methyl-D-aspartate receptor 1 mRNA distribution in the central nervous system
of the weakly electric fish Apteronotus leptorhynchus.
AB - We have isolated a partial cDNA for the N-methyl-D-aspartate (NMDA) receptor 1
(NMDAR1) subunit from an Apteronotus leptorhynchus brain cDNA library. The A.
leptorhynchus cDNA fragment, which corresponds to nucleotides 135-903 within the
5' region of the rat NR1 mRNA, encodes 252 amino acids that are >80% identical to
the homologous segments of the rat, human, and duck NR1 proteins. RNAse
protection assays revealed that the A. leptorhynchus NR1 mRNA was highly enriched
in the forebrain and hypothalamus, with lesser amounts in the brainstem, and very
low levels in the cerebellum. In situ hybridization also demonstrated that
neurons in the pallial forebrain were highly enriched in NR1 transcripts. High
levels of NR1 mRNA were found in pyramidal cells within the optic tectum and
octavolateral regions. Pyramidal cells of the electrosensory lateral line lobe
had the highest levels of expression, and the NR1 mRNA was found to be
selectively enriched in their apical dendrites.
PMID- 9390761
TI - Postnatal development and sex difference in neurons containing estrogen receptor
alpha immunoreactivity in the preoptic brain, the diencephalon, and the amygdala
in the rat.
AB - Estrogen has been considered as a key substance that induces sexual
differentiation of the brain during fetal and neonatal life in the rat. Thus, to
define the brain regions involved in the brain sexual differentiation, we
examined the regions where the estrogen receptor (ER) is located in the
developing rat brain. We examined immunohistochemical distribution of the cells
containing estrogen receptor-alpha (ER-alpha) in the preoptic region, the
diencephalon, and the amygdala in male and female rats on postnatal days 1-35
(PD1-PD35). The antibody used recognizes ER-alpha equally well for both occupied
and unoccupied forms. ER-alpha immunostaining was restricted to the cell nuclei
of specific cell groups. In PD1 rats, ER-alpha-immunoreactive (ER-IR) signals
were detected in the lateral septum, the organum vasculosum lamina terminalis,
the medial preoptic nucleus (MPN), the median preoptic nucleus, the bed nucleus
of the stria terminalis, the hypothalamic periventricular nucleus, the lateral
habenula, the posterodorsal part of the medial amygdala nucleus, the posterior
part of the cortical amygdala nucleus, the hypothalamic ventromedial nucleus
(VMH), the hypothalamic arcuate nucleus, and the posterior hypothalamic
periventricular nucleus. The distribution pattern of ER-IR cells in the newborn
rat was much the same as that in the adult in the preoptic-hypothalamic and
amygdala regions. Moreover, the signals in the MPN and the VMH were stronger in
the female than in the male, perhaps reflecting the ability ofestrogen generated
by aromatization of testosterone in the male to down-regulate the ER signal.
Thus, the brain regions showing sex differences may be sites of sexual
differentiation of the brain by aromatizable androgen during the neonatal period.
PMID- 9390762
TI - Distribution of N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate
receptor subunits on respiratory motor and premotor neurons in the rat.
AB - Glutamate is required for the transmission of inspiratory drive in respiratory
premotor and motor neurons. The glutamate receptors (GluRs) responsible for this
essential function have yet to be anatomically characterized. We mapped the GluR
subtypes expressed by respiratory premotor and motor neurons by using combined
immunohistochemistry and retrograde labeling in adult rats. Phrenic motoneurons
and bulbospinal ventral respiratory group (VRG) neurons were retrogradely labeled
and immunolabeled with subunit-specific antibodies against the N-methyl-D
aspartate (NMDA) receptor subtype (NMDAR1) and the non-NMDA receptor subtypes,
alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA; GluR1, GluR2/3,
GluR4) and kainate (GluR5-7). Phrenic motoneurons and bulbospinal VRG neurons
showed positive immunolabeling for all five GluR subunits. These results support
the hypothesis that NMDA and non-NMDA receptor subtypes underlie the excitation
of bulbospinal VRG neurons and phrenic motoneurons. Furthermore, immunolabeling
for each receptor subtype demonstrated a unique distribution along the neuronal
membrane. Immunoreactivity for AMPA receptor subunits was distributed throughout
somata and proximal dendrites, NMDAR1 subunit immunolabeling was localized to
somata, and GluR5-7 subunit immunolabeling was confined largely to dendrites. The
differential distribution of AMPA, kainate, and NMDA receptors on the somal and
dendritic surface of respiratory neurons suggests that the location of
glutamatergic synapses along the neuronal surface is an important determinant of
glutamate-mediated postsynaptic currents. Consequently, different patterns of
glutamatergic excitation of respiratory neurons could be achieved by selective
activation of different profiles of GluR subtypes on different portions of the
neuronal membrane.
PMID- 9390763
TI - Immunocytochemical localization of gamma-aminobutyric acid plasma membrane
transporters in the tiger salamander retina.
AB - Gamma-aminobutyric acid (GABA) plasma membrane transporters (GATs) play an
important role in regulating GABA neurotransmission in the nervous system. The
distribution of two GATs, GAT 1 and GAT 3, in salamander retina was investigated
by using affinity-purified polyclonal antisera directed to the predicted C
terminals of rat GAT 1 and rat GAT 3. GAT 1-immunoreactivity (-IR) was found in
type IB and IIB orthotopic bipolar cells (BCs) located in the distal and middle
of the inner nuclear layer (INL), respectively; in type IIA and IA amacrine cells
(ACs) located in the middle and proximal INL, respectively; and in interplexiform
cells and cells in the ganglion cell layer (GCL). No detectable staining was
found in horizontal cells (HCs) or in structures resembling Muller cells. GAT 1
immunoreactive fibers were present in the outer plexiform layer (OPL) and inner
plexiform layer (IPL) in three bands corresponding to the three bands previously
reported to be GABA-IR. GAT 3 antibodies labeled fewer cells and cell types than
GAT 1 antibodies. GAT 3-IR was localized to type IIA and IA ACs and cells in the
GCL, but not to BCs, HCs, or Muller cell-like structures. There was weak labeling
of the OPL and stronger labeling of the IPL, with three distinct bands at the
same depth as observed with GAT 1-IR. Double-labeling showed that the majority of
GAT 1-IR BCs (88%), ACs (88%), and cells in the GCL (78%) colocalized with GABA
IR. The present study provides the first direct evidence of the expression of two
GAT subtypes in neurons of nonmammalian retinas. These transporters could
regulate GABA neurotransmission by reuptake and termination of GABA's action and,
perhaps, by GABA release mechanisms. The presence of GAT 1-IR/GABA-IR bipolar
cells further supports our earlier observations that a subgroup of orthotopic
bipolar cells are likely to be GABAergic.
PMID- 9390764
TI - Identification of gamma-aminobutyric acid-immunoreactive axon endings associated
with mesencephalic periodontal afferent terminals and morphometry of the two
types of terminals in the cat supratrigeminal nucleus.
AB - A previous study has shown that mesencephalic periodontal afferent terminals
receive contacts more frequently from axonal endings containing pleomorphic,
synaptic vesicles (P-endings) in the supratrigeminal nucleus (Vsup) than in the
trigeminal motor nucleus, suggesting that interneurons in Vsup play an important
role in modulating the jaw-closing reflex. The present study was attempted to
identify neurotransmitters in P-endings associated with mesencephalic periodontal
afferents in cat Vsup through the use of intracellular staining of horseradish
peroxidase combined with the postembedding immunogold methods. A morphometric
analysis was carried out to compare the ultrastructural features of these two
types of terminals. Serial sections of 31 labeled boutons and of their associated
38 P-endings were examined. They were processed for postembedding immunogold
labeling with antibodies to the neurotransmitter gamma-aminobutyric acid (GABA).
The 38 P-endings presynaptic to periodontal afferents showed GABA-like
immunoreactivity, but the afferent terminals were free from the labeling. The
morphometric analysis indicated that bouton volume, apposed surface area, total
active zone size, and mitochondrial volume were smaller in GABA-immunoreactive P
endings than in periodontal afferents, but the pooled data of the two types of
terminals showed that each synaptic parameter was highly correlated in a
positive, linear manner with bouton volume. These observations provide evidence
that P-endings presynaptic to mesencephalic periodontal afferents contain the
neurotransmitter GABA and that their axoaxonic synapses are organized in
accordance with the ultrastructural "size principle" proposed by Pierce and
Mendell (Pierce and Mendell [1993] J. Neurosci. 13:4748-4763) on Ia-motoneuron
synapses.
PMID- 9390765
TI - Distribution of GABAergic premotor nonspiking local interneurones in the terminal
abdominal ganglion of the crayfish.
AB - The inhibitory neurotransmitter of premotor nonspiking local interneurones in the
crayfish terminal abdominal ganglion was investigated physiologically and
immunocytochemically. Depolarization of a nonspiking interneurone evoked a
hyperpolarization in a uropod motor neurone. The amplitude of hyperpolarization
in the motor neurone was gradually decreased under low-calcium/high-magnesium
saline. Local pressure injection of gamma-aminobutyric acid (GABA) into the
neuropil caused a similar hyperpolarization of the motor neurone. These
physiological studies suggested a GABAergic inhibitory interaction between
nonspiking interneurones and the motor neurones. Premotor nonspiking
interneurones are classified into two subgroups ofposterolateral (PL) and
anterolateral (AL) interneurones, and AL interneurones are further divided into
three subtypes. A combination of intracellular staining from nonspiking local
interneurones with Lucifer yellow and immunocytochemical staining with an
antiserum directed against GABA revealed that all the PL interneurones sampled in
this study showed GABA-like immunoreactivity. A population of cell bodies (n = 6
11) with a small diameter (15-30 microm) packed together forming a cluster showed
GABA-like immunoreactivity, and the cell bodies of most PL interneurones were
found in this cluster. To compare the number and the pattern of main branches of
PL interneurones, cells were classified into three identifiable sets of
interneurones, called PL-1, PL-2, and PL-3. By contrast, about one-half of AL
interneurones, especially the third subtype of AL interneurones, which have cell
bodies located ventrolaterally in the ganglion, did not show GABA-like
immunoreactivity. Furthermore, the position of cell bodies of GABA-immunoreactive
AL interneurones was scattered compared to that of PL interneurones.
PMID- 9390766
TI - Direct projections from the lumbosacral spinal cord to Barrington's nucleus in
the rat: a special reference to micturition reflex.
AB - In the present study, direct projections from the lumbosacral cord to
Barrington's nucleus in the rat were investigated by using retrograde and
anterograde tracing techniques. After injection of cholera toxin B subunit (CTb)
into Barrington's nucleus, a number of moderately CTb-labeled neurons were
observed in the lumbosacral cord, with a slight ipsilateral dominance; most were
located in the spinal parasympathetic and dorsal commissural nuclei of the
lumbosacral cord. In addition, some retrogradely labeled neurons were found in
the periaqueductal gray (PAG). These findings were confirmed by an anterograde
labeling experiment. After biotinylated dextran amine (BDA) was injected into the
lumbosacral cord, dense BDA-labeled axon terminals were found in Barrington's
nucleus as well as in the PAG. Injection of BDA into the PAG resulted in many BDA
labeled terminals in Barrington's nucleus. The present results provided clear
evidence for a direct projection from the spinal parasympathetic and dorsal
commissural nuclei to Barrington's nucleus that could subserve conveying bladder
filling information from the lumbosacral cord to Barrington's nucleus in the
micturition reflex of the rat.
PMID- 9390767
TI - Starburst cholinergic amacrine cells in the tree shrew retina.
AB - In all mammalian retinae studied to date, starburst cholinergic amacrine cells
are a consistently occurring cell type. Here, we show that the cone-dominated
retina of the tree shrew also has starburst cells with the characteristic
radially symmetric branching pattern known from other species. Dendritic field
sizes increase from 150 microm in the central retina to 300 microm in the retinal
periphery. The characteristic morphology is established early during postnatal
development. Labelling the starburst cholinergic cells with an antibody against
choline acetyltransferase (ChAT) reveals two dendritic strata in the inner
plexiform layer and two corresponding soma populations in the inner nuclear layer
(orthotopic) and ganglion cell layer (displaced). These features are present in
the adult and in early postnatal stages. In the adult, the density of the
orthotopic population as well as the displaced population peaks in the central
retina at about 2,200 cells/mm2 and has a peripheral minimum of 400 cells/mm2.
These properties are qualitatively similar to those of starburst cells in rod
dominated retinae. In contrast to findings in other mammals, we did not see gamma
aminobutyric acid (GABA) or glutamic acid decarboxylase 65 kDa (GAD65)
immunoreactivity in tree shrew starburst cells. These cells also appear to lack
synaptophysin, a ubiquitous synaptic vesicle protein detected in the starburst
cells of some other mammals. However, synaptoporin, a homologous synaptic vesicle
protein, appears to be present in tree shrew starburst cells.
PMID- 9390768
TI - Scanning and transmission electron microscopy of Ruffini endings in the
periodontal ligament of rat incisors.
AB - The Ruffini organ is an arborized axon ending categorized as a low-threshold
stretch receptor. We have previously shown that the lingual periodontal ligament
of rat incisors is densely innervated with Ruffini endings. In the present study,
fine structures in the surface of the periodontal Ruffini endings and their
topographical relationship with the surrounding collagen fibers were observed by
a combination of scanning and transmission electron microscopy to analyze the
mechanism of the stretch reception. The entire length of the branches of the
Ruffini endings, excepting their terminal portions, corresponded well with those
depicted by previous investigators in the following points: (1) their cylindrical
appearance covered by Schwann cell processes; (2) the presence of numerous axon
fingers protruding through gaps in the Schwann sheath and; (3) their isolation
from collagen fibers by multilayered basal lamina. On the other hand, tips of the
axon branches-together with their Schwann sheaths-became attenuated and projected
into tight bundles of collagen, indicating their susceptibility to mechanical
deformations of the surrounding tissue. Margins of the axon terminals were
conspicuously ruffled with long tongue-like projections of Schwann cells. The
Schwann cell tongues twined around collagen bundles in their distal portions, and
associated closely with fine axon projections in their proximal portions,
suggesting their involvement in the mechanical transmission of stimuli to axon
terminals.
PMID- 9390769
TI - Sensitive period for lesion-induced reorganization of intracortical projections
within the vibrissae representation of rat's primary somatosensory cortex.
AB - Previous experiments from this laboratory demonstrated that intracortical
connections in lamina IV of the rat primary somatosensory cortex (SI) are most
dense outside the patches of cytochrome oxidase (CO) staining that correspond to
the mystacial vibrissae. This pattern of intracortical connections becomes
apparent on postnatal day 4 (P-4), at least 2 days after the appearance of the
vibrissae-related pattern of thalamocortical afferents. Transection of the
infraorbital nerve (ION) on the day of birth (P-0) disrupts both the CO and
intracortical projection patterns. This series of experiments was undertaken to
determine whether the patterning of either thalamocortical afferents or
intracortical projections defines the end of the period over which peripheral
damage can alter intracortical projections in lamina IV of SI. The infraorbital
nerve (ION) was transected in different cohorts of rats on P-1 through P-5, and
animals were allowed to survive > or =45 days, at which time biotinylated dextran
amine (BDA) injections were made into the SI. After 7 days, animals were killed,
and alternate cortical sections were processed for the demonstration of BDA or
CO. Transection of the ION on P-1 or P-2 altered the patterning of both CO and
intracortical connections in the SI. In contrast, cutting the ION on P-3 left the
pattern of CO densities in the SI intact, but significantly altered the
patterning of intracortical connections. Transection of the nerve on P-5 resulted
in qualitatively and quantitatively normal patterns of both CO densities and BDA
labelled intracortical projections. These results indicate that the establishment
of a stable barrel pattern in layer IV of the SI is not sufficient for normal
adult patterning of intracortical projections in this lamina. However, once the
mature pattern of intracortical projections in layer IV is established, ION
lesions can no longer alter it.
PMID- 9390770
TI - Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease.
AB - 4-Hydroxynonenal (4-HNE), an aldehyde by-product of the peroxidation of fatty
acids, has been shown to have toxic properties for neurons in culture. In light
of increasing evidence that oxidative stress contributes to the neurodegenerative
process in Alzheimer's disease (AD), we quantified levels of free and protein
bound 4-HNE in the ventricular fluid from 19 AD subjects and 13 control subjects
by high-pressure liquid chromatography and dot-blot immunoassay. Free 4-HNE
levels were found to be significantly elevated in the ventricular fluid of AD
subjects compared with control subjects (p = 0.0096). These results demonstrate
increased lipid peroxidation in AD brain and suggest a role for 4-HNE in the
neurodegenerative process.
PMID- 9390771
TI - Alzheimer's disease: in vivo detection of differential vulnerability of brain
regions.
AB - The severe cognitive impairment during the later stages of Alzheimer's disease is
usually preceded by a selective disturbance in the ability to remember new
experiences. With quantitative, high-resolution magnetic resonance imaging
techniques, it is now possible to determine, in vivo, differences in the pattern
of anatomical changes that might reflect behavioral symptomatology during
different stages of the disease. In the present investigation, magnetic resonance
imaging examinations were carried out in aged controls and in clinically
diagnosed Alzheimer's disease patients who were divided into three groups based
upon dementia severity. Atrophy of the hippocampal formation, a region important
for memory function, was observed even in Alzheimer's disease patients with the
mildest dementia. With more prominent dementia, atrophy extended to the
parahippocampal gyrus and the temporal neocortex.
PMID- 9390772
TI - GLUT-1 expression in the cerebra of patients with Alzheimer's disease.
AB - To investigate the molecular basis of reduced GLUT-1 concentration of the blood
brain barrier in patients with Alzheimer's disease (AD), the GLUT-1 mass, mRNA
content, and structure were studied in eight patients with AD and seven age
matched controls. The results indicate that the 55-kDa GLUT-1 is significantly
reduced in AD without a significant change in GLUT-1 mRNA concentrations. Because
in some animal models changes in GLUT-1 expression is associated with changes in
GLUT-1 mRNA structure, the length of the poly(A) tail of the GLUT-1 mRNA was
estimated with a reverse transcription-polymerase chain reaction technique. The
length of poly(A) tail of GLUT-1 mRNA in AD subjects was not significantly
different from the controls. It is concluded that the AD-related change in GLUT-1
expression is not the result of altered poly(A) length of GLUT-1 mRNA.
PMID- 9390773
TI - Low initial tau phosphorylation in human brain biopsy samples.
AB - A rapid reversible tau phosphorylation at Ser 396/404 was observed in adult human
cortical biopsy tissue and rat primary cortical cell cultures. Tau
phosphorylation increased usually during the first 20-30 min in phosphate
buffered saline, followed by a decrease. The time course of tau phosphorylation
and dephosphorylation in biopsy tissue could be lengthened by culturing in
defined, oxygenated medium, instead of in phosphate-buffered saline.
Phosphorylation of total protein in biopsy tissue occurred in two phases, with
peaks at 30 and 90 min. The first peak of total protein phosphorylation coincided
with the peak of tau phosphorylation, although both the first and second peaks of
total protein phosphorylation coincided with the first and second peaks of
neurofilament-H phosphorylation.
PMID- 9390774
TI - Age diminishes performance on an antisaccade eye movement task.
AB - Tthe antisaccade eye movement task, which has been linked to frontal lobe
function, presents a target in one visual field and asks subjects to move their
eyes to the same location in the opposite field. The task requires inhibition of
the reflexive prosaccade to the cue, initiation of the antisaccade to the
opposite field, and visuo-spatial memory of the cue location. Forty-two subjects
from 19-79 years of age performed this task and a control task, visually guided
saccades to the cue itself, to determine which functions are affected by aging.
The time to initiate antisaccades increased linearly with age at a rate greater
than the time to initiate visually guided saccades. This difference suggests that
the processing time to inhibit the incorrect movement to the cue is selectively
increased with age. Older subjects also made more incorrect prosaccadic movements
to the cue, a finding consistent with the loss of inhibitory processing capacity.
The accuracy of movements did not change, which suggests that visuo-spatial
memory is unaffected by aging.
PMID- 9390775
TI - Reduced efficacy of growth hormone-releasing hormone in modulating sleep
endocrine activity in the elderly.
AB - In aging, a decline in sleep continuity, a decreased slow wave sleep, an earlier
nocturnal cortisol rise, and a blunted growth hormone (GH) secretion occur.
Pulsatile administration of GH-releasing hormone (GHRH) in young controls
enhanced slow wave sleep and suppressed cortisol release. We administered GHRH 4
x 50 microg or placebo i.v. to 13 healthy seniors (5 women, 8 men, mean age 69.3
y +/- 8.3 SD). We observed significantly reduced nocturnal awakenings and an
increased first non-rapid-eye-movement sleep period. In a subgroup (n = 9), we
found a significant activation of GH secretion but unchanged cortisol secretion.
Our data underscore that GHRH is capable of promoting sleep in the elderly, but
much less than in young subjects. Contrasting to young subjects, the hypothalamic
pituitary-adrenocortical system remains unaffected by GHRH in the elderly. These
results provide further evidence that a decrease in the efficacy of GHRH is
involved in the biological mechanisms underlying aging.
PMID- 9390776
TI - Biphasic and region-specific MAO-B response to aging in normal human brain.
AB - Variations of monoamine oxidases (MAO) A and B were studied during aging in 27
human subjects (age range 17-93 years) in 18 brain structures of temporal cortex,
frontal gyrus, hippocampal formation, striatum, cerebellum, and brainstem.
[3H]Ro41-1049 and [3H]lazabemide were used as selective radioligands to image and
quantify MAO-A and MAO-B respectively by enzyme autoradiography. Postmortem delay
or time of tissue storage did not affect MAO-A or MAO-B levels. There was,
moreover, no evidence of sexual dimorphism. A marked age-related increase in MAO
B was observed in most structures. This increase started at the age of 50-60
years. Before this age, MAO-B levels were constant in all structures studied. MAO
B-rich senile plaques were observed in some cortical areas but they did not
significantly influence the age-related MAO-B increase. Surprisingly, no age
related MAO-B changes were observed in the substantia nigra. In contrast to MAO
B, no clear age-related changes in MAO-A were observed, indicating an independent
regulation of the two isoenzymes, also suggested by the cross-correlation
analysis of these data.
PMID- 9390777
TI - Aging, dominance history, and social behavior in Java-monkeys (Macaca
fascicularis).
AB - The aim of this study was to investigate the influence of the dominance history
of socially housed Java-monkeys on the aging process. In monkeys, social
subordinance is generally associated with elevated levels of cortisol, which, in
turn, have been suggested to influence cognitive decline. As cognitive skills are
necessary for successful social life, we investigated the effect of old age in
relation to the dominance history of the animals on their social behavior by
comparing old females with their younger daughters. Old age, especially in
combination with a history of low rank, led to a withdrawal from social
interactions with unfamiliar animals and to a decrease in amounts of aggression
received. Still, however, old animals showed an increase in behaviors associated
with arousal. A reduced ability to deal with complex social interactions, caused
by a decline in information processing abilities, is suggested as an explanation
for these results.
PMID- 9390778
TI - T2-weighted MRI studies of mouse lemurs: a primate model of brain aging.
AB - Previous histological and behavioral studies of aging mouse lemurs have
demonstrated changes similar to those observed in elderly humans and in patients
with Alzheimer's disease. We explored 18 animals of ages 6 months to 9 years.
Axial T2-weighted images of the brain were performed on a 4.7 Tesla Bruker
Biospec 47/30 system. We estimated cerebral atrophy by adding measures of high
signal areas characteristic of cerebrospinal fluid (interlobular and sylvian
fissures, lateral and third ventricles) of four contiguous cortical slices. We
observed a significant increase of cerebral atrophy with aging and one case of an
apathetic 8-year-old animal presenting a considerably higher cerebral atrophy. We
also observed high correlations between decreased signal intensities and age for
the pallidum, the substantia nigra, and the putamen. These results suggest that
aging mouse lemurs present similar magnetic resonance images of cerebral
alterations to those encountered in aging humans and that high-field T2-weighted
magnetic resonance images can help in the early detection, in vivo, of animals
suspected of pathological aging.
PMID- 9390779
TI - Life-long dietary restriction attenuates age-related increases in hippocampal
glial fibrillary acidic protein mRNA.
AB - The expression of astrocyte-specific glial fibrillary acidic protein increases
after experimental lesions and is elevated throughout the brain in aged rodents
and primates. Clusterin (ApoJ) expression increases in astrocytes and microglia
after lesions, but changes during aging have not been reported. Dietary
restriction (DR) delays the onset and progression of many age-related
physiological deficits in rodents. This study showed that the age-related
increase in glial fibrillary acidic protein mRNA in the hippocampus was
attenuated in 24-month-old male Fischer 344 rats subjected to a 50% DR beginning
at 6 weeks of age. ApoJ mRNA expression in astrocytes was unchanged by DR. These
results demonstrate that DR can delay neurodegeneration in aged rats as assessed
by a marker of reactive astrogliosis.
PMID- 9390780
TI - Antidepressants restore hypothalamic-pituitary-adrenal feedback function in aged,
cognitively-impaired rats.
AB - Aged, cognitively-impaired rats (and humans) show hypothalamic-pituitary-adrenal
(HPA) hyperactivity that correlates with hippocampal damage. The resultant
increase in plasma glucocorticoid exposure is thought to contribute to impaired
hippocampal function and to potentiate hippocampal neuron death. In young, adult
rats antidepressant drugs increase corticosteroid receptor expression in brain
regions known to regulate the HPA axis, leading to increased negative-feedback
control and decreased HPA activity. In the present study we examined basal levels
of plasma adrenocorticotropin hormone (ACTH) and corticosterone in aged,
cognitively-impaired (AI), aged, cognitively-unimpaired (AU) and young, adult
(Yg) rats. Plasma ACTH and corticosterone levels were significantly elevated in
the AI rats, but only in samples obtained during the diurnal peak. Five weeks of
treatment with desipramine (15 mg/kg) significantly reduced evening levels of
both ACTH and corticosterone in all groups, and eliminated the group differences.
We then examined delayed, glucocorticoid negative feedback in these animals.
Among vehicle-treated animals, a bolus injection of corticosterone (10 mg/kg),
administered 3 hours prior to testing, completely inhibited the plasma ACTH
response to restraint in AU and Yg, but not AI animals. In contrast, plasma ACTH
responses to restraint were completely inhibited in AI rats following chronic
treatment with desipramine. These findings indicate that the antidepressant,
desipramine, decreases HPA activity and increases glucocorticoid negative
feedback sensitivity in AI rats, suggesting that antidepressant drugs may form a
useful therapeutic approach to HPA dysfunction in elderly human populations.
PMID- 9390782
TI - Titers of murine leukemia virus are higher in brains of SAMP8 than SAMR1 mice.
AB - To elucidate possible causes of premature aging seen in a strain of senescence
accelerated prone (SAMP8) mice, levels of murine leukemia virus (MuLV) were
quantitated in various tissues of SAMP8 by an SC-1/UV plaque assay. MuLV levels
in SAMP8 tissues were compared to those seen in the closely related SAMR1 strain,
which is resistant to premature aging. MuLV titers were found to be higher in
blood and spleen and much higher in brain of SAMP8 than in the same tissues of
SAMR1. MuLV levels were seen to increase in SAMP8 brain with increasing age.
Virus typing experiments indicated that the MuLV from SAMP8 brain is N-tropic, as
is the MuLV seen in the AKR strain, one of the SAM progenitor strains. MuLV from
SAMP8 brain was able to grow well in SAMR1 mouse embryo cells, indicating that it
may be possible to infect SAMR1 mice with the SAMP8 MuLV to determine the effects
of the virus on aging of SAMR1 mice.
PMID- 9390781
TI - NMDA receptor activation in the aged rat: electrophysiological investigations in
the CA1 area of the hippocampal slice ex vivo.
AB - The effects of aging on activation of N-methyl-D-aspartate (NMDA) receptors were
studied in the CA1 field of hippocampal slices from young (2-4 months old) and
aged (25-32 months old) Sprague-Dawley rats with the use of ex vivo extra- and
intracellular electrophysiological recording techniques. No significant age
related changes of the unitary NMDA-receptor mediated excitatory postsynaptic
potentials (EPSPs), recorded from the pyramidal cells after stimulation of the
stratum radiatum in a magnesium-free medium and isolated in the presence of the
non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, were found.
Simultaneously, the magnitude of synaptic plasticity which involved NMDA receptor
activation was not altered. No significant age-related modifications in the
mechanisms controlling glutamate release and of postsynaptic NMDA receptor
responsiveness were revealed. Considering the 30-40% decrease in NMDA binding
sites in the aged hippocampus, our results suggest the occurrence of compensatory
mechanisms which are discussed.
PMID- 9390783
TI - Preserved number of entorhinal cortex layer II neurons in aged macaque monkeys.
AB - The perforant path, which consists of the projection from the layer II neurons of
the entorhinal cortex to the outer molecular layer of the dentate gyrus, is a
critical circuit involved in learning and memory formation. Accordingly,
disturbances in this circuit may contribute to age-related cognitive deficits. In
a previous study, we demonstrated a decrease in N-methyl-D-aspartate receptor
subunit 1 immunofluorescence intensity in the outer molecular layer of aged
macaque monkeys. In this study, we used the optical fractionator, a stereological
method, to determine if a loss of layer II neurons occurred in the same animals
in which the N-methyl-D-aspartate receptor subunit 1 alteration was observed. Our
results revealed no significant differences in the number of layer II neurons
between juvenile, young adult, and aged macaque monkeys. These results suggest
that the circuit-specific decrease in N-methyl-D-aspartate receptor subunit 1
reported previously occurs in the absence of structural compromise of the
perforant path, and thus may be linked to an age-related change in the
physiological properties of this circuit.
PMID- 9390784
TI - Cerebrospinal fluid C3a increases with age, but does not increase further in
Alzheimer's disease.
AB - Complement activation is present in the brain in Alzheimer's disease (AD), and
C1q concentrations are decreased in AD cerebrospinal fluid (CSF). To determine
whether concentrations of other complement proteins are also altered in AD CSF,
we measured concentrations of C3a and SC5b-9 in CSF from patients with probable
AD (n = 19), normal aged controls (n = 11), and normal younger controls (n = 15).
C3a concentrations were similar between AD and aged controls, but threefold
higher than in younger controls (p < 0.05 vs. both groups). A similar pattern was
found with SC5b-9, though the increase was only twofold and statistically
significant only for AD vs. younger controls. These results suggest that an
increased generation of complement proteins in localized areas of the AD brain
does not result in elevated concentrations of these proteins in CSF, compared
with age-matched controls. Increased C3a (and, to a lesser extent, SC5b-9) in
aged controls may be due to increased complement activation, increased central
nervous system production, and/or blood-brain barrier leakage of these proteins.
PMID- 9390786
TI - Nonlinearity of mechanoelectrical transduction of outer hair cells as the source
of nonlinear basilar-membrane motion and loudness recruitment.
AB - The sound-induced travelling wave in the mammalian cochlea is believed to be
enhanced and sharpened by a positive-feedback mechanism, causing the passive,
linear growth function of the basilar membrane (BM) to become nonlinear. Based on
direct measurements of the receptor potential of isolated outer hair cells, it is
shown here how nonlinear BM motion might be due predominantly to the nonlinear
growth function of the receptor potential. Since intensity coding in the inner
ear is supposed to depend on an interaction of nonlinear BM motion with afferent
fibres of different synaptic thresholds, intensity coding is expected to be
directly dependent on the mechanoelectrical transduction of outer hair cells
(OHC). According to the present experimental data and the feedback concept of
outer hair cell action, disruption of the mechanoelectrical transduction of OHC
leads to both a reduction of gain and linearizing of the response; that is, to
both hearing loss and loudness recruitment.
PMID- 9390785
TI - Intracellular inositol (1,4,5)-trisphosphate receptor levels are preserved in
Alzheimer's disease platelets.
AB - An increasing number of signal transduction disturbances have been reported in
Alzheimer's disease. These changes are not restricted to histopathologically
changed brain areas but are seen also in peripheral tissues. One of the most
severe disturbances is a loss of calcium-mobilizing intracellular inositol(1,4,5)
trisphosphate receptors in Alzheimer cerebellar and cortical tissues. In the
present study, the binding of [3H]inositol(1,4,5)trisphosphate ([3H]Ins(1,4,5)P3)
to the calcium-mobilizing inositol(1,4,5)trisphosphate receptors in platelet
membranes from eight Alzheimer's disease patients and eight control subjects were
investigated to determine its possible role as a biological marker in Alzheimer's
disease. It was found that there were no significant difference in
[3H]Ins(1,4,5)P3 binding with respect to the number of sites measured at
different protein concentrations or to the sensitivity of the binding to
inhibition by nonradioactive Ins(1,4,5)P3 between Alzheimer disease platelets and
controls. It is concluded that inositol(1,4,5)trisphosphate receptor levels are
preserved in platelets from patients with Alzheimer's disease.
PMID- 9390787
TI - The temporal window of two-tone facilitation in onset units of the ventral
cochlear nucleus.
AB - Effects of a tone, not at the best frequency (BF), on the responses of onset
units to BF tones were recorded in the ventral cochlear nucleus of the guinea
pig. The off-BF tone was at a fixed non-excitatory sound level. When the two
tones were gated simultaneously, a marked threshold facilitation was observed;
however, no facilitation was observed if the off-BF tone burst was delayed by 5
10 ms. Facilitation in some units declined and was either absent or only just
detectable, when the start of the off-BF tone preceded that of the BF by more
than 10 ms. However, the responses of the majority of onset units were
facilitated when the off-BF tone preceded the BF tone by as much as 20 ms.
Similar results were obtained when the roles of the BF and off-BF tones were
reversed. These data suggest that depolarization due to BF inputs is of shorter
duration than that due to off-BF inputs.
PMID- 9390788
TI - Immunologically defined component of the circumferential ring around the
cuticular plate in mammalian hair cells.
AB - A monoclonal antibody (CAR) was raised by in vitro immunisation to a component of
the circumferential actin ring that is associated with the apical junctions
encircling the cuticular plates of mammalian hair cells. On western blots it
bound a protein band at about 42 kD, equivalent to the normal location of actin,
but it did not label the paracrystalline bundle of actin filaments in the
stereocilia, the complex actin filament gel that forms the cuticular plate or the
filamentous actin in the cell cortex. When applied to whole mounts of the
auditory sensory epithelium in the guinea pig it provided a clear, unambiguous
map of the distribution of inner and outer hair cells. In this respect, it can
provide an accurate guide to patterns of hair cell differentiation and repair.
CAR cross-reacted with the membrane-associated cytoskeleton in selected cells
from a wide range of other tissues.
PMID- 9390789
TI - Localization of the hair-cell-specific protein fimbrin during regeneration in the
chicken cochlea.
AB - Fimbrin is an actin-binding protein that organizes actin filaments into parallel
bundles. We have used fluorescence immunocytochemistry and confocal laser
scanning microscopy to demonstrate that the detection of fimbrin in the chicken
basilar papilla (BP) by this method was limited to the hair cells. These
experiments indicate that it was concentrated in the bundles of stereocilia. In
addition, there was no evidence for the presence of fimbrin in the supporting
cells, border cells, or hyaline cells. During recovery of the BP following
acoustic trauma, the appearance of fimbrin in regenerating hair cells was first
seen approximately 96 h after the onset of the sound exposure. This was the time
at which new hair cells first appear in the BP. Reverse transcriptase polymerase
chain reaction (RT-PCR) was used to detect transcription of the fimbrin gene in
both control and sound-damaged BP. Semiquantitative RT-PCR indicated no
detectable changes in fimbrin transcription levels 2 or 5 days after the onset of
pure-tone exposure. These data indicate that fimbrin can be used
immunocytochemically as a hair-cell-specific marker during regeneration in the
chicken cochlea.
PMID- 9390790
TI - Localization of dopamine-beta-hydroxylase-like immunoreactivity in the superior
olivary complex of the rat.
AB - The noradrenergic (NA) innervation of the superior olivary complex (SOC) was
investigated using a monoclonal antibody against dopamine-beta-hydroxylase (D
beta H), the synthesizing enzyme for noradrenaline. In addition, positive
labelling of D beta H in the inferior colliculus, the lateral lemniscus (LL) and
the cochlear nucleus were documented. The antibody was detected using the highly
specific and sensitive ABC immunocytochemical method. The specific aim of the
study was to show the distribution of putative NA cells and fibres in the SOC in
greater detail than had been previously reported. All investigated auditory
regions contained D beta H-positive fibres in varying densities. All superior
olivary and periolivary nuclei showed NA innervation by mainly fine, weakly
staining fibres. Both nuclei of the LL were also found to contain D beta H
positive fibres. D beta H-positive cell bodies were found in the region of the
ventral lateral lemniscus and immediately lateral and dorsal to the lateral
superior olivary nucleus. Thus the NA innervation of the superior olivary complex
could originate from these regions and/or the locus coeruleus.
PMID- 9390791
TI - Tectorial membrane repair in the quail following multiple exposures to intense
sound.
AB - Adult quail were exposed one, two or three times to an intense octave band noise.
Birds were sacrificed 0 or 14 days after the last exposure and their ears
processed for scanning electron microscopy (SEM). SEM observations demonstrated a
patch lesion in every ear at 0 and 14 days after exposure. In the single-exposed
ear immediately after noise, the lesion lacked any tectorial membrane (TM). At 14
days of recovery, the site of injury was covered by a partially regenerated TM
(referred to as the honeycomb). However, the patterns of TM damage and repair
varied among the twice- and thrice-exposed papillae. At 0 days after exposure,
the multiple-exposed ear displayed a lesion with two segments. In one portion the
TM was missing, and in the other portion the TM was present as one or two
honeycomb layers. Fourteen days later, a new honeycomb was observed underneath
the remaining honeycomb. These results suggest that the quail is able to
repeatedly repair its TM following multiple noise exposures.
PMID- 9390792
TI - Activation of aminoglycoside antibiotics to cytotoxins.
AB - We have previously postulated an enzymatic transformation of gentamicin (to a
metabolite or an 'activated' molecule) as part of its ototoxic action. Here we
test with eight aminoglycosides whether the proposed mechanism applies to these
antibiotics as a group. Drugs were activated by incubation with a subcellular
fraction from liver, and cytotoxicity was tested in a bioassay using isolated
outer hair cells from guinea pig. None of the aminoglycosides compromised the
viability of the cells when assayed directly, i.e. without a preceding
activation. In contrast, all clinically ototoxic aminoglycosides tested were
significantly cytotoxic following the incubation. Neamine, considered to be non
ototoxic, did not yield a cytotoxin. A subcellular fraction from cochlear lateral
wall tissues also converted gentamicin to a cytotoxin. The results support the
hypothesis that activation of aminoglycosides precedes their toxic actions and
demonstrate that the capability for activation is not confined to liver.
PMID- 9390793
TI - Incomplete recovery of chicken distortion product otoacoustic emissions following
acoustic overstimulation.
AB - Distortion product otoacoustic emissions (DPOAEs) were measured in chickens
before and after exposure to a 525-Hz pure tone (120 dB SPL, 48 h). The exposure
caused extensive hair cell loss and destroyed the tectorial membrane along the
abneural edge of the basilar papilla in the low-to-mid-frequency region of the
cochlea. Although the lesion was restricted, DPOAEs were greatly depressed at all
frequencies immediately after the exposure. The high-frequency DPOAEs gradually
recovered to preexposure values after the exposure; however, there was little or
no improvement in DPOAEs at test frequencies equal to or slightly above the
exposure frequency even after 16 weeks of recovery. By 28 days of recovery, the
previously damaged region of the basilar papilla had been repopulated by hair
cells and the lower honeycomb layer of the tectorial membrane had regenerated,
but not the upper fibrous layer. The upper fibrous layer of the tectorial
membrane was still missing after 16 weeks of recovery and the region of damage
corresponded closely to the frequency regions where the DPOAEs were depressed.
PMID- 9390794
TI - Binaural unmasking returns to normal in teenagers who had otitis media in
infancy.
AB - Several studies have shown that the binaural masking level difference (MLD) is
reduced in children who have a history of recurrent otitis media (OM) in infancy.
In this prospective study we have retested the MLD in two groups of teenagers who
were originally tested 6 years ago. Members of one of these groups (OM group; n =
26) had at least 5 recorded episodes of OM before the age of 5 years. The other
group (controls; n = 17) had no known history of OM. The mean MLD (500-Hz tone in
a narrow band noise masker) of the OM group was, at 6-12 years of age,
significantly lower than that of the controls. In this study (at ages 12-18
years), we found no difference between the mean MLDs of the OM and control
groups. These results show that the reduced MLD that occurs following OM in
infancy can recover in later childhood.
PMID- 9390795
TI - On the clinical relevance of mismatch negativity: results from subjects with
normal hearing and cochlear implant users.
AB - Mismatch negativity (MMN) provides an objective measure for evaluating subjects
with problems related to speech processing. For a valid neurophysiological
profile of speech-processing mechanisms, an efficient procedure to elicit MMNs is
needed. In Experiment 1 of this study, MMN recordings were conducted in adults
with normal hearing on the effects of decreasing the duration of the
interstimulus interval (ISI). Shortening ISI duration does not seem to have a
high impact on the individual MMN quality, whereas it does influence group MMN
quality. In Experiment 2, MMNs were elicited in a group of cochlear implant users
by using a speech sound contrast/ba/-/da/. A group of good performers produced a
significant MMN, whereas a group of moderate performers did not. There seems to
be a relation between speech perception ability and MMN quality. To fundamentally
understand the effects of electrical stimulation of the inner ear and to
clinically adjust rehabilitation, diverse data are needed on different aspects of
auditory processing. Optimizing the procedure to elicit and MMN is therefore of
great clinical value.
PMID- 9390796
TI - Diagnosis of endolymphatic hydrops by low-frequency masking.
AB - Low-frequency masking is a new method for the diagnosis of endolymphatic hydrops.
A short acoustic stimulus and a low-frequency masker tone are applied to the same
ear in an adjustable phase relationship. We recorded phase-dependent masked
thresholds from normal-hearing subjects, and patients with Meniere's disease and
sensory hearing loss without vertigo. In normal hearing, there is a mean maximal
difference in masking (modulation depth) of 28 dB between the phase delays of 0
degree and 270 degrees. In patients with sensory hearing loss without vertigo,
modulation depth is reduced due to recruitment. In Meniere cases, the phase
dependence may be totally absent and varies as the disease progresses. Therefore,
repeated measurements of masking are required: patients and subjects with normal
hearing were tested for a period of 1 year. Also, modulation depth is
significantly reduced in the contralateral nonsymptomatic ears of Meniere
patients. The results indicate that low-frequency masking is a quick, noninvasive
and relevant method for the diagnosis of endolymphatic hydrops.
PMID- 9390797
TI - The importance of thyroid hormone for auditory development in the fetus and
neonate.
AB - It seems that many auditory maturational events are regulated by thyroid hormone
since elevation in thyroid hormone level always precedes the onset of hearing in
the fetus-neonate; low thyroid activity in the developing human fetus or rat
neonate leads to hearing loss; earlier, elevated thyroid levels in rat neonate
lead to earlier onset of hearing. The hormone, bound to its receptors in the
nucleus, acts as a transcription factor activating genes which lead to the
synthesis of several proteins and enzymes involved in the structural and
functional development of many tissues (e.g. brain, heart, kidney, skeletal
muscle) including the ear. Several types of congenital hearing loss of
unexplained etiology may be due to abnormalities in one or more stages of this
gene cascade since several types of congenital hearing loss have been shown to
involve defects in genes related to these events.
PMID- 9390798
TI - Noise-induced cochlear hypoxia is intensity dependent, correlates with hearing
loss and precedes reduction of cochlear blood flow.
AB - Anesthetized and artificially ventilated guinea pigs were exposed to broad-band
noise of 95, 101, 106 or 115 dB SPL for 30 min and studied for 180 min after
cessation of noise. The partial pressure of oxygen (pO2) in the perilymph, the
cochlear blood flow (CoBF) and auditory-evoked potentials were continuously
recorded. Arterial blood pressure, electrocardiogram, inspiratory and expiratory
gas levels, arterial blood gas levels and acid-base status were kept stable to
exclude influences of these parameters on cochlear parameters. Exposure to 95 dB
SPL did not affect perilymphatic pO2 or CoBF. Cochlear microphonics (CMs) were
reduced, but compound action potentials of the auditory nerve (CAPs) and auditory
brainstem potentials (ABRs) increased after exposure to this low-level noise.
Perilymphatic pO2 decreased during exposure to 101 dB SPL and then further
decreased during the subsequent 60 min after cessation of the noise. CoBF did not
change significantly during and 30 min after noise but then paralleled the
decline of perilymphatic pO2. However, both parameters showed a clear indication
of recovery in the second and third hours after noise. At 101 dB SPL, CMs were
again reduced immediately, CAPs were unaltered and ABRs again increased. Exposure
to 106 and to 115 dB SPL resulted in a decrease in both perilymphatic pO2 and
CoBF; this decrease began during the exposure but became progressively worse
after the noise. Hearing loss was observed immediately with exposure and showed
no signs of further deterioration after cessation. The observed time courses of
changes are important. They reveal that hearing loss and cochlear hypoxia precede
reduction in CoBF due to noise exposure. The potential mechanisms underlying
these effects are discussed.
PMID- 9390799
TI - Neurophysiological correlate of the auditory after-image ('Zwicker tone').
AB - The 'Zwicker tone' (ZT) is an auditory after-image that can be evoked most
effectively when a band-suppressed noise (relative width of gap 1/3 octave)
presented for a certain period of time has been switched off. The sensation of
this purely monaural phenomenon is that of a pure tone with a frequency
corresponding to the center frequency of the gap and an equivalent level of 10-15
dB above auditory threshold. The sensation decays gradually; it may last as long
as 10 s depending on how long the evoking noise was presented. The search for a
physiological correlate has been futile so far, probably because the search was
confined to more peripheral levels of the auditory system (inferior colliculus).
A neuromagnetic study was performed in normal-hearing subjects in order to look
for a neurophysiological correlate of the ZT in the auditory cortex. With a
stimulation paradigm especially designed for this study, we have been able to
isolate poststimulus activity which appears to be related to the ZT and which
originates in the supratemporal auditory cortex. It is a sustained neuromagnetic
activity that shows a clear-cut dipolar field distribution, and it appears that
this activity has certain similarities with the tone-evoked auditory sustained
response. The hypothesis is put forward that during the sensation of the ZT a
process takes place in the auditory cortex which is similar to that underlying
the sustained response, and which gives rise to the sensation of the ZT. In
contrast to the sustained response, however, which is due to neural activity
evoked by an external acoustic stimulus, the sustained activity associated with
the ZT is due to a temporary absolute or relative reduction of neural activity
originating from those regions in which the ZT exciting stimulus caused an
adaptation. These differences in neural activity cannot be distinguished by the
auditory system from a corresponding external acoustic signal. Preliminary
studies in patients suffering from tonal tinnitus yielded results which exhibit a
certain similarity with those obtained in the ZT experiment.
PMID- 9390800
TI - Measures of binaural hearing in children with a history of asymmetric otitis
media with effusion.
AB - This study addresses the effect of early asymmetric hearing loss in children,
owing to otitis media with effusion (OME), on binaural hearing. Five children who
had suffered from predominantly unilateral OME between the ages of 2 and 4 years
and who were not treated for OME at any time participated in this study when they
were about 12 years of age. All children had normal hearing at the time of
testing. Data were compared to normative values obtained previously from normal
hearing adults. We measured the auditory brainstem response (ABR), the binaural
interaction component (BIC) in the ABR, the masking level difference (MLD) and
the suppression of transient evoked otoacoustic emissions (OAEs) with
contralateral noise stimulation. The results indicated that the children's ABRs
and BICs were comparable to normative data, that there was evident suppression of
transient evoked OAEs in 4 of the 5 children and that the children's MLD values
were within the normal (adult) range. The present results therefore do not
support the presence of long-term auditory processing deficits induced by early
asymmetric OME in man.
PMID- 9390801
TI - Cervical vertigo--reality or fiction?
AB - Neck afferents not only assist the coordination of eye, head, and body, but they
also affect spatial orientation and control of posture. This implies that
stimulation of, or lesions in, these structures can produce cervical vertigo. In
fact, unilateral local anesthesia of the upper dorsal cervical roots induces
ataxia and nystagmus in animals, and ataxia without nystagmus in humans. If
cervical vertigo exists outside these experimental conditions, it is obviously
characterized by ataxia and unsteadiness of gait, and not by a clear rotational
or linear vertigo. Neurological, vestibular, and psychosomatic disorders must
first be excluded before the dizziness and unsteadiness in cervical pain
syndromes can be attributed to a cervical origin. To date, however, the syndrome
remains only a theoretical possibility awaiting a reliable clinical test to
demonstrate its independent existence.
PMID- 9390802
TI - 2f1-f2 distortion product otoacoustic emissions in White Leghorn chickens (Gallus
domesticus): effects of frequency ratio and relative level.
AB - The effects of primary tone frequency ratio (f2/f1 ratio) and relative level
(L2/L1) on the amplitude of the cubic difference tone (CDT: 2f1-f2) distortion
product otoacoustic emissions (DPOAEs) were investigated in adult White Leghorn
chickens (Gallus domesticus). In experiment 1, 9 f2/f1 ratios ranging from 1.05
to 1.8 were investigated. Measurements were obtained from both ears of 4 chickens
at 7 f1 frequencies ranging from 0.8 to 4.0 kHz. The primary tones were equal in
level, and varied from 20 to 80 dB SPL. The mean CDT amplitude increased with
increasing primary tone level once the measurement noise floor was exceeded. The
input/ output functions assumed one of two shapes: one in which there was a
systematic increase in DPOAE amplitude with increasing primary tone level, and
the other in which there was a plateau in the input/output function near 65-70 dB
SPL. At the highest primary tone level (80 dB SPL), there was a decrease in the
CDT amplitude with increasing f2/f1 ratio. At high primary tone levels, the f2/f1
ratio which produced the largest CDT was 1.05 or 1.1, while at lower primary tone
levels the largest CDT occurred at f2/f1 ratios of 1.2-1.3. In experiment 2, L2
was held constant at 70 dB SPL, and L1 varied from 50 to 80 dB SPL. For f1
frequencies of 0.8 and 3.2 kHz, there was an increase in the CDT amplitude with
increasing L1, followed by an asymptote at higher levels. In contrast, for 1.6
and 2.0 kHz f1 frequencies, the amplitude increased, plateaued and then increased
again at higher levels. Informal measurements suggest that spontaneous
otoacoustic emissions (SOAEs) are rarely seen in chickens. However, a reliable
SOAE was observed in 1 chicken, which could be suppressed by external sounds and
anoxia.
PMID- 9390803
TI - A method for determining interaural attenuation in animal models of asymmetric
hearing loss.
AB - Asymmetric or unilateral sensorineural hearing loss is an important hall-mark of
various forms of sensorineural hearing loss. Animal research regarding the
etiology and mechanism of these disorders often requires hearing estimates in
each ear of experimental animals. Monaural auditory testing of animals with
experimentally induced unilateral hearing loss therefore requires prior knowledge
of interaural attenuation (IAA) to facilitate contralateral masking. The purpose
of this study is to describe a method of determining frequency-specific IAA data
and to present relevant information obtained in the rats--a frequently used
animal in studies of acquired sensorineural hearing loss. A custom-made sound
source was designed to accomplish threshold determination at important
frequencies in the dynamic range of rats. Six male Long-Evans rats were
surgically monauralized by ablation/obliteration of the cochlea. Auditory
brainstem response (ABR) thresholds were determined for ipsilateral and
contralateral presentations of 2-kHz, 10-kHz, and 40-kHz toneburst. IAA was
calculated by subtracting the frequency-specific ABR threshold obtained from the
normal ear from that obtained following tone presentation to the 'dead' ear, and
was found to average 65.0 +/- 10.5 dB at 2 kHz, 45.0 +/- 8.4 dB at 10 kHz, and 47
+/- 15.1 dB at 40 kHz (+/- standard deviation). Using data obtained from the
animal demonstrating the smallest IAA, masking is not needed until a threshold
asymmetry of 50 dB at 2 kHz and 30 dB at 10 and 40 kHz is observed. In order to
obtain bilateral auditory threshold information in any animal model of asymmetric
hearing loss, data regarding IAA are needed in order to know when to apply
contralateral masking and therefore avoid crossover stimulation of the non-test
ear. The protocol presented herein provides guidelines for use in any animal
model of sensorineural hearing loss which may demonstrate unilateral or
asymmetric deficits.
PMID- 9390804
TI - Effect of trial-by-trial variation in center frequency on detection of interaural
temporal and intensitive differences in bands of noise.
AB - Sensitivity to interaural temporal disparities (ITDs) and interaural intensitive
disparities (IIDs) was measured as a function of duration in conditions where the
center frequency (CF) of the stimuli was constant and, separately, in conditions
where the CF of the stimuli was varied on a trial-by-trial basis. Stimuli were
bands of noise centered at either 300, 1200, 2400, or 4800 Hz with the bandwidth
of the noise being 40% of their CF. The largest effects of shortening duration
and varying center CF of the stimuli were degradations of sensitivity to ITDs for
stimuli centered at 2400 or 4800 Hz. Overall, the data confirm and extend
previous findings which indicate that ITDs and IIDs are processed separately
within the central nervous system.
PMID- 9390805
TI - A new method of measurement of most comfortable loudness.
AB - A new computer-assisted method for the measurement of most comfortable loudness
(MCL) is presented, where not only MCL but also its reliability can be
graphically displayed and measured. Two unique features concerning the
reliability of MCL measurement are obtained in this method: sharpness and
stability. Sharpness is defined by the rate of repeat selection of the same level
as MCL, and stability is used to express the consistency of a subject's response
during the experiment. A method of analyzing sharpness and stability was
explained by showing two contrasting cases. Based on the graph configurations,
the subjects were divided into two major categories, type A and type B, defined
by sharpness of judgment. Type A subjects' judgments are sharper than those of
type B. Decreasing the frequency increased the occurrence of type A subjects.
Retest results revealed that this method has a high degree of reproducibility of
MCL judgment, which supports the reliability of this method.
PMID- 9390806
TI - Cerebrospinal fluid loss and threshold changes. 1. Hearing loss in the
contralateral ear after operation for acoustic neuroma: an analysis of the
incidence, time course, frequency range, size and pathophysiological
considerations.
AB - In a prospective study, 60 patients who underwent surgery for unilateral acoustic
neuromas had the hearing on the contralateral ear tested before and several times
after surgery. In 40 patients, a threshold increase was found during the
following 9 days. The changes were greatest in the low frequencies immediately
after surgery, but after 1 week the treble also became involved. After 3 months,
the hearing was normalized. The elder patients more than 50 years of age were
more often affected, whereas sex, tumor size, surgical approach or duration of
surgery had no influence. The pathophysiological mechanisms are discussed and an
intracochlear fluid dysfunction caused by the loss of cerebrospinal fluid is
suggested.
PMID- 9390807
TI - Cerebrospinal fluid loss and threshold changes. 2. Electrocochleographic changes
of the compound action potential after CSF aspiration: an experimental study.
AB - Hearing loss has been reported following leakage of cerebrospinal fluid (CSF).
The etiology has been attributed to an induced imbalance in the intracochlear
hydrodynamics. The present study reports a guinea pig model with surgically
induced loss of CSF. In 18 anesthetized animals, CSF was drained by a
suboccipital incision in the dura: Eighteen animals were used as controls. The
compound action potentials were recorded by an ear canal silver electrode. The
animals with CSF loss showed a small increase in threshold and latency, while the
control group was unchanged. The concept of an induced inner ear fluid
dysfunction after CSF leak is supported by these findings.
PMID- 9390808
TI - Cochlear implant place psychophysics 1. Pitch estimation with deeply inserted
electrodes.
AB - Numerical estimation of pitch was performed by 8 adult subjects implanted with
cochlear prostheses manufactured by Cochlear Limited. The electrode arrays had
been inserted into the scale tympani to between one and one and a half turns of
the cochlea. Using bipolar stimulation, the pitch estimates for each subjects
showed an overall reduction with insertion depth of the stimulated electrode.
However, for several subjects, after decreasing regularly for the more basal
electrodes, pitch estimates showed an abrupt decrease, followed in some cases by
a region of low pitch. Two of the subjects, implanted with a modified electrode
array, the '20 + 2' which allowed monopolar in addition to bipolar stimulation,
exhibited an abrupt decrease in pitch estimate with bipolar but not with
monopolar stimulation. In these two subjects, for stimulating electrodes inserted
more deeply than about three quarters of a turn, bipolar stimuli produced lower
pitch sensations, and presumably more apical neural excitation patterns, than
monopolar stimuli.
PMID- 9390809
TI - Cochlear implant place psychophysics. 2. Comparison of forward masking and pitch
estimation data.
AB - Results for forward masking and numerical estimation of pitch were compared in a
group of 6 adult subjects implanted with cochlear prostheses manufactured by
Cochlear Limited. Data were collected for bipolar + 1 stimulation in all
subjects, and for stimulation in one other mode, either common ground or
monopolar, for all subjects but one. The pitch data show various irregularities
and in each case can be seen to be broadly consistent with the corresponding
forward masking data. It is shown that a 'centre of gravity' of the forward
masking distribution varies with masker electrode in a manner that is
qualitatively very similar to the variation of pitch estimate. It is suggested
that, while pitch estimation results are consistent with those from forward
masking, the latter contain more detailed information that may be useful in
understanding intersubject variations in speech comprehension.
PMID- 9390810
TI - Factors affecting auditory performance of postlinguistically deaf adults using
cochlear implants.
AB - A model of auditory performance and a model of ganglion cell survival in
postlinguistically deafened adult cochlear implant users are suggested to
describe the effects of aetiology, duration of deafness, age at implantation, age
at onset of deafness, and duration of implant use. The models were compared with
published data and a composite data set including 808 implant users. Qualitative
agreement with the model of auditory performance was found. Duration of deafness
had a strong negative effect on performance. Age at implantation had a slight
negative effect on performance, increasing after age 60 years. Age at onset of
deafness had little effect on performance up to age 60. Duration of implant use
had a positive effect on performance. Aetiology had a relatively weak effect on
performance.
PMID- 9390811
TI - Outer hair cell activity is not required for the generation of the forward
masking curve.
AB - Forward masking of the auditory brainstem response (ABR) was achieved by
increasing the time interval from 0 to 12 ms between the masker offset and the
probe onset. The forward masking response demonstrated a near linear function
with an approximate 3.0-dB increase in masking threshold for every millisecond
interval increase in the control guinea pig. The slope of the masking curve at
selected frequencies together with the quantification of hair cell loss through
the analysis of cochlear surface morphology was studied before and after chemical
insult. The intracochlear infusion of sodium salicylate caused an approximately
45-dB threshold shift of the ABR whereas the slope of the forward masking curve
was not significantly different from the control values at the tested frequencies
(1, 4, and 8 kHz). Systemic kanamycin administration (400 mg/kg body weight for 9
consecutive days) caused a permanent ABR threshold shift of 43-63 dB at 1, 4, and
8 kHz. The slope of the forward masking curve was not significantly different at
1 kHz despite significant outer hair cell loss. The slope of the forward masking
curve at 4 and 8 kHz showed significant reductions at the time intervals between
0 and 4 ms. Analysis of the kanamycin-treated cochleae revealed not only
significant outer hair cell loss throughout the cochlea but significant inner
hair cell and inner pillar cell loss in the basal end of the cochlea. The results
suggest that the outer hair cells are not needed for maintaining a normal forward
masking curve, whereas the slope of the forward masking curve is sensitive to
alterations induced to either the inner hair cells or the inner pillar cells.
PMID- 9390813
TI - Differences in forward masking after a temporary and a permanent noise-induced
hearing loss.
AB - The forward masking curve of the auditory brainstem response (ABR) at selected
frequencies together with the quantification of hair cell loss through the
analysis of cochlear surface morphology was studied in guinea pigs before and
after acoustic trauma resulting in either a temporary or a permanent threshold
shift. In the presence of a noise-induced temporary threshold shift, the slope of
the forward masking curve was not significantly different from the pre-exposure
curve. In contrast, during the acute phase of the permanent threshold shift, the
slope of the forward masking curve was significantly reduced compared to the pre
exposure value. After a recovery period of 2 weeks, the slope of the forward
masking curve from the permanently damaged group returned to nearly normal values
despite a persisting ABR threshold shift and significant loss of outer hair
cells. The potential for analyzing the slope of the forward masking curve in
order to distinguish between the acute phase of a permanent threshold shift and a
temporary threshold shift is discussed.
PMID- 9390812
TI - Forward masking is dependent on inner hair cell activity.
AB - The goal of this study was to test the hypothesis that the inner hair cell
complex (inner hair cell and dendritic contacts) is solely responsible for
generating the slope of the forward masking curve. To test this hypothesis two
experiments were performed. The first was to measure forward masking from the
Bronx waltzing mouse, a mutant possessing an inner hair cell defect. The Bronx
waltzing mouse demonstrated an approximately 60-dB auditory brainstem response
(ABR) threshold shift compared to CBA/CBA mice at 8 and 12 kHz. The slope of the
forward masking curve was significantly reduced compared to the control group,
particularly at the early delay times between 0 and 4 ms. The second model
employed kainic acid to affect the dendrites beneath the inner hair cell. After
the intracochlear infusion of kainic acid, there was an approximately 47-dB ABR
threshold shift at 4 and 8 kHz compared to pre-infusion thresholds. The slope of
the forward masking curve from the kainic-acid group was significantly reduced
compared to the artificial-perilymph group. Primarily the early delay times were
affected by kainic acid (0-4 ms). Morphological analysis showed that there was
extensive swelling of the afferent nerve radial dendrites under the inner hair
cells. The results from the present study, as well as the preceding article,
suggest that the analysis of the slope of the forward masking curve may be used
for the detection of inner hair cell or radial dendrite damage, independent of
outer hair cell damage. The present finding could provide a useful means of
employing a clinical test for determining the function of the inner hair cell
complex using a non-invasive measure of auditory function.
PMID- 9390814
TI - Stability of efferent-mediated protection against acoustic overexposure with long
maintenance under barbiturate anaesthesia.
AB - When anaesthetized animals are maintained over a long period, crossed-cochlear
suppressive and enhancement-in-noise effects mediated by the olivocochlear bundle
(OCB), as well as some OCB neuronal responses, show time-dependent variations.
The present study determined if there were any such changes in OCB-mediated
crossed-cochlear protection against compound action potential (CAP) threshold
losses caused by a standard loud sound exposure at 11 kHz, presented under
conditions either not evoking OCB-mediated protection (i.e. monaural exposure) or
evoking protection (binaural exposure). Maintaining animals for periods up to
approximately 30 h from initial anaesthetization resulted in non-significant
changes in pre-exposure CAP thresholds. There were also only small changes over
select frequency ranges in threshold losses caused by the monaural or binaural
loud sound, after a single exposure as well as when the testing of OCB function
was extended to examine effects after dual successive exposures, the latter
result being determined by application of a previously described additivity
model. The features of OCB-mediated protection also showed good stability over
the long maintenance. These results are discussed as providing further
circumstantial evidence that protection is mediated by a different OCB
subcomponent to that/those responsible for other OCB-mediated crossed-cochlear
effects. In general, the results show that the barbiturate anaesthetic used here
does not significantly modulate the crossed-cochlear OCB effect of protection,
even though it has been shown elsewhere to significantly depress other crossed
cochlear OCB effects.
PMID- 9390816
TI - Research in otology.
PMID- 9390815
TI - Detection of the acoustic reflex below 80 dB HL.
AB - A new method for detecting the acoustic reflex that utilizes standard otoacoustic
emissions recording techniques is introduced and discussed. Two successive
identical tone bursts of 100 ms duration and 10 ms interstimulus interval are
presented in the occluded ear canal at a repetition rate of one per second. If
the acoustic reflex is elicited, the contraction of the stapedius muscle is
delayed with respect to the onset of the first stimulus. Hence, the acoustic
compliance in the ear canal decreases primarily during the second stimulus. The
difference of the microphone signals produced by the two stimuli is computed and
averaged across a certain number of repetitions of the sequence. The presentation
level is increased until this difference is larger than -40 dB (with respect to
the stimulus level) and if its signal-to-noise ratio exceeds 20 dB. For normal
hearing subjects, the acoustic reflex threshold measured with this method is on
average 8 dB lower than in a standard clinical setup. In 5 out of the 10 tested
hearing-impaired subjects, the new method could detect an acoustic reflex at one
or more frequencies where no reflex was detected in the clinical setup.
PMID- 9390818
TI - In vivo gene transfer into the embryonic inner ear using retroviral vectors.
AB - Retrovirus-mediated gene transfer holds great promise for elucidating key genes
in the development and function of the inner ear. Retroviral vectors offer a
number of advantages over other gene transfer methods including stable and
efficient integration into the host genome, high levels of transcription and
restriction of expression to a target area. Because of the wide variety of
recombinant retroviral vectors currently available, this review outlines which
vectors are appropriate for particular applications. Successful strategies for
infecting the ear are reviewed and current drawbacks and future directions are
discussed.
PMID- 9390817
TI - Paradigms and paradoxes: mouse (and human) models of genetic deafness.
AB - Mouse models have proved valuable tools in the analysis of human genetic
disorders. The identification of the genes mutated in classical mouse mutants and
the analysis of the phenotype of mutants following targeted gene disruption have
provided some clarification of the development and functioning of the inner ear.
A number of these genes also play a role in human deafness. Analysis of mutations
in both human and mouse deafness genes has identified a number of distinct
phenomena that contribute to the observed phenotype.
PMID- 9390819
TI - Production of conditionally immortalised cell lines from a transgenic mouse.
AB - This review describes the H2kbtsA58 transgenic mouse (Immortomouse) and its
application to the production of conditionally immortalised cell lines from
sensory epithelia within the mammalian inner ear. Established cell lines should
overcome many of the technical difficulties associated with experimental
procedures in auditory and vestibular research. These include the limited amount
of tissue available and the relatively complex and laborious dissection.
Conditional immortalisation should also allow essential studies on the molecular
and cellular mechanisms that govern both the differentiation of sensory cells and
the development of sensory epithelia.
PMID- 9390820
TI - Transcription factors in the ear: molecular switches for development and
differentiation.
AB - In order to understand the molecular events underlying differentiation and
development in the inner ear, we need to identify and characterize the molecular
'switches' involved in the regulation of gene expression in the system. The most
important molecular regulators are represented by a family of proteins
generically called transcription factors. This article reviews our current
knowledge of the expression of several transcription factors in the ear and their
implications for both development and homeostasis in the auditory organs.
PMID- 9390821
TI - Cellular commitment and differentiation in the cochlea: potential advances using
gene transfer.
AB - The development of individual cells as hair cells and supporting cells is a key
step during the embryonic formation of the auditory system. However, at present
the factors that play a role in the commitment and differentiation of cells as
hair cells and supporting cells have not been identified. Recent advances in
molecular biological techniques have led to the identification of candidate genes
that may be involved in hair cell and supporting cell development, however it has
been difficult to determine the specific effects of these genes. The development
of new methods for gene transfer into post-mitotic cells should provide powerful
new techniques for examining the specific effects of candidate genes. Virally
mediated vectors, such as adenovirus and herpes simplex virus, and non-virally
mediated vectors, such as lipofectins and biolistics, have been shown to
efficiently transfer candidate genes into many different cell types, including
hair cells, supporting cells, and spiral ganglion neurons. In addition, studies
in other developing systems have demonstrated that these techniques can be used
to determine the effects of expression of candidate genes during the
specification of individual cell phenotypes. These results suggest that these
vectors can be used effectively to study the role of specific genes during the
development of the auditory system.
PMID- 9390822
TI - The molecular biology of hair cell regeneration in the avian cochlea.
AB - The sensory cells of the ear, the hair cells, are damaged by loud noise or
certain types of drugs. In the bird cochlea, new hair cells are produced to
replace those that are lost. Regeneration also occurs in the vestibular epithelia
of birds, fish, and mammals but does not occur in the mammalian cochlea. In order
to further our understanding of the regeneration process in the bird cochlea, we
have begun to identify the genes that are involved. However, the small size of
this organ has made it difficult to use traditional molecular biology methods to
address these problems. Recently, many molecular techniques have been adapted for
use with small amounts of tissue. Northern blot analysis, the ribonuclease
protection assay, semiquantitative PCR and differential display of mRNA are all
techniques that are being used to greatly improve our understanding of hair cell
regeneration and may eventually provide the information necessary to induce
regeneration in hearing-impaired humans.
PMID- 9390823
TI - Analysis of gene expression in the organ of Corti revealed by single-cell RT-PCR.
AB - Many genes encoding proteins which are expressed in the auditory periphery have
been identified in the last years. With single-cell reverse transcription
polymerase chain reaction (RT-PCR), the molecular analysis of gene expression can
be done on the single-cell level. Furthermore a single-cell RT-PCR experiment can
be combined with the electrophysiological characterization of an individual cell.
The combination of these two methods will lead to a better understanding of how
functional properties of neurons are controlled by the expression of complex
proteins.
PMID- 9390824
TI - Molecular analysis of excitatory amino acid receptor expression in the cochlea.
AB - Our present understanding of excitatory neurotransmission has expanded enormously
in the last decade through the use of molecular biology. In the mammalian
cochlea, the analysis of excitatory amino acid receptor expression by the reverse
transcription-polymease chain reaction (RT-PCR), in situ hybridization and
immunochemistry has provided considerable evidence for glutamate as the afferent
neurotransmitter. Using these molecular techniques, the ionotropic alpha-amino-3
hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, N-methyl-D-aspartic acid
(NMDA) and delta receptor subunits and the metabotropic glutamate receptors have
all been detected in the cochlea, in either the spiral ganglion neurons, the hair
cells or both. Due to the utility of the techniques and the diversity of
expressed neurotransmitter receptors, molecular biology will continue to provide
important information for researchers of the auditory periphery.
PMID- 9390826
TI - Age-dependent effects of the onset of a conductive hearing loss on the volume of
the cochlear nucleus subdivisions and the expression of c-fos in the mongolian
gerbil (Meriones unguiculatus).
AB - A monaural conductive hearing loss was induced by interrupting the chain of the
middle ear ossicles on the right side in gerbils of four different age groups
(P12-14, P20-21, P42 and P84). The volumes of the cochlear nucleus subdivisions
and the number of cells that expressed immunoreactivity for c-fos after noise
stimulation were determined on the left and right side in the deprived animals,
and in undeprived control animals when they reached the age of 6 months. The
anteroventral cochlear nucleus on the deprived side was reduced in volume when
the deprivation started before the age of 3 months. The other cochlear nucleus
subdivisions showed no systematic age-dependent reductions. The expression of c
fos in the dorsal cochlear nucleus appeared more resistant to a hearing loss,
with deprivation being more effective in younger animals. c-fos expression was
also dramatically reduced in the ventral cochlear nucleus, regardless of age at
the onset of hearing loss.
PMID- 9390825
TI - Cholinergic and purinergic neurohumoral signalling in the inner ear: a molecular
physiological analysis.
AB - The ability to identify the expression of the protein subunits which assemble to
form ionotropic receptors for acetylcholine and extracellular adenosine 5'
triphosphate (ATP) in individual cells of the inner ear provides examples of the
high resolution and exquisite sensitivity which molecular biology brings to the
study of hearing and balance. The data from these studies provide both fine
detail with respect to the classification of the elements involved and an
overview of the sites of potential interaction of both extracellular and
intracellular signalling pathways. The high sensitivity necessitates a molecular
physiological approach when using these techniques so that these data on the site
and extent of expression can be balanced against functional significance. With
the demonstration of expression of the alpha 9 subunit of the nicotinic
acetylcholine receptor in cochlear outer hair cells, molecular biology has
provided an explanation for the unusual cholinergic receptor pharmacology of the
olivocochlear efferent innervation which has confounded investigators for
decades. In addition, a role for extracellular ATP as a signalling molecule
regulating electrochemical gradients and neurotransmission within the inner ear
is supported by the extent of P2 receptor expression in this tissue, data which
beg for intense functional study.
PMID- 9390827
TI - Remote masking in normal-hearing and noise-exposed chinchillas.
AB - Remote masking (RM), the phenomenon whereby an intense high-frequency masking
noise elevates thresholds for low-frequency signals, has been shown to be
sensitive to various types of hearing loss in humans. We performed two
experiments to evaluate the chinchilla as a model of RM and to examine changes in
RM associated with temporary threshold shifts (TTSs) induced by low-frequency
noise exposure. Thresholds for 0.5-, 1- and 2-kHz tones were measured in quiet,
then in the presence of a narrow-band (300-Hz-wide) masking noise centered at 3
kHz. In Experiment I, effective masking was measured as a function of masker
level, from 48 to 98 dB sound pressure level (SPL; referenced to 20 microPa), to
determine threshold and rate of growth of RM in the chinchilla. In Experiment II,
RM was measured before, during and after exposure to a low-frequency noise known
to produce TTSs in chinchillas (i.e., a 0.5-kHz octave band noise at 90 dB SPL
for 6 h/day for 10 days). The results show that normal-hearing chinchillas have
the same pattern of RM as humans, and that a noise exposure that produces TTSs
also produces rapid and significant changes in RM.
PMID- 9390828
TI - A five-generation family with late-onset progressive hereditary hearing
impairment due to cochleosaccular degeneration.
AB - Cochleosaccular dysplasia or degeneration (Scheibe degeneration) is considered
the most common cause of profound congenital hearing impairment, and accounts for
approximately 70% of cases 2 with hereditary deafness. A five-generation family
with hereditary hearing impairment associated with cochleosaccular degeneration
has recently been identified. The diagnosis of classical Scheibe degeneration was
based on histopathological findings in the temporal bones of the proband, a 61
year-old profoundly deaf male. Auditory structures in the brainstem of the
proband were also studied. Twenty-two members of the family were contacted for
surveys and blood samples. Of these, 6 males and 2 females have hearing
impairment. Complete audiological evaluation was done on 12 family members, and
prior audiologic records of the proband and affected family members were
available for study. Affected family members suffer a mild bilateral high
frequency hearing loss during childhood and adolescence, and progress to moderate
to-profound deafness in the second and third decades of life. The family is
suitable for linkage analysis and does not map to previously reported loci
harboring autosomal dominant, nonsyndromic hereditary hearing impairment genes.
The genetic study of this family will be helpful in identifying the genes which,
when mutated, result in Scheibe degeneration.
PMID- 9390830
TI - Harold Frederick Schuknecht. 1917-1996.
PMID- 9390829
TI - Early damage in the chinchilla vestibular sensory epithelium from carboplatin.
AB - Carboplatin, a second-generation platinum drug used in the treatment of cancer,
can damage the hair cells in the vestibular system; however, little is known
about the time course of its vestibulotoxic effects. The present study examined
the acute vestibulotoxic effects of carboplatin (50 mg/kg) in the chinchilla. The
duration of the nystagmus response evoked by cold caloric stimulation was
significantly reduced 6 h following carboplatin treatment and showed a maximum,
permanent reduction of approximately 50% by 24 h after injection. Light
microscopic observations at 6 h subsequent to injection revealed swollen afferent
dendrites beneath type-I hair cells and the appearance of small vacuoles within
the type-I hair cells; these changes were most pronounced in the crista
ampullaris of the semicircular canals compared to the maculae of the utricle and
saccule. Many mitochondria were swollen and partially depleted of their
membranous infoldings. The mitochondrial abnormalities tended to be somewhat more
severe in the hair cells than in their afferent terminals. The structural
abnormalities in the mitochondria were more severe at 24 h following injection
resulting in the appearance of larger and more numerous vacuoles in the hair
cells. By 3 days after injection, many type-I hair cells were filled with large
vacuoles which often caused severe distortion of the nucleus and disruption of
the plasma membrane. Small vacuoles were occasionally observed in type-II hair
cells, mainly in the crista ampullaris. These results indicate that the
vestibulotoxic effects of carboplatin occur quite rapidly and cause significant
disruption of the mitochondria in hair cells and their afferent terminals.
PMID- 9390831
TI - Progression of cochlear and retinal degeneration in the tubby (rd5) mouse.
AB - Mice homozygous for a defect of the tub (rd5) gene exhibit cochlear and retinal
degeneration combined with obesity, and resemble certain human autosomal
recessive sensory deficit syndromes. To establish the progressive nature of
sensory cell loss associated with the tub gene, and to differentiate tub-related
losses from those associated with the C57 background on which tub arose, we
evaluated cochleas and retinas from tub/tub, tub/+, and +/+ mice, aged 2 weeks to
1 year by light and electron microscopy. Cochleas from mice of all three
genotypes show progressive inner (IHC) and outer hair cell (OHC) loss. Relative
to tub/+ and +/+ animals, however, tub homozygotes show accelerated OHC loss,
affecting the extreme cochlear base (hook region) by 1 month, and the apex by 6
months. IHC loss in tub/tub animals is accelerated in the basal half of the
cochlea, affecting the hook region by 6 months. Spiral ganglion cell losses were
observed only in tub/tub mice, and only in the cochlear base. Retinas of tub/tub
mice are abnormal at maturity, exhibiting shortened photoreceptor outer segments
by 2 weeks, and progressive photoreceptor loss thereafter. Because the tub
mutation causes degeneration of sensory cells in the ear and eye but has no other
neurological effects, tubby mice hold unique promise for the study of human
syndromic sensory loss.
PMID- 9390832
TI - Thresholds of intracranially recorded auditory field potentials in the pigeon
compared with compound action potential thresholds.
AB - The compound action potential (CAP) thresholds provide a reliable indicator for
cochlear functional integrity during experimentation in birds as well as in
mammals. However, if experimental manipulations are necessary in the middle
ear/inner ear spaces, the round window electrodes are often inconvenient. In
search for an alternative for CAP recordings, intracranial recordings of
acoustically evoked field potentials from the nucleus angularis/magnocellularis
were made in pigeons using stereotactically placed electrodes. The responses were
compared with those recorded from intracranial surface electrodes placed on the
dura mater and compared with CAP responses recorded from the round window. The
field potentials recorded from the nucleus angularis/magnocellularis contain a
significant contribution from the auditory nerve, as large in amplitude as the
CAP recorded at the round window. The recordings from the intracranial surface
electrodes were noisier and the contribution from the auditory nerve was too
small to be used as a fast monitor of the condition of the inner ear. Threshold
curves as a function of frequency could be determined with an automated method
from the nucleus angularis/magnocellularis with the same sensitivity and accuracy
as from the round window CAP within a few minutes. These results demonstrate that
stereotactic recordings of field potentials from the nucleus
magnocellularis/angularis region are a suitable alternative to reliably monitor
the condition of the inner ear when round window electrodes cannot be used.
PMID- 9390833
TI - Attenuation of salicylate-induced tinnitus by Ginkgo biloba extract in rats.
AB - The effects of an extract from Ginkgo biloba, EGb 761, on tinnitus were tested
using an animal model of tinnitus. Daily oral administration of EGb 761 in doses
from 10 to 100 mg/ kg/day began 2 weeks before behavioral procedures and
continued until the end of the experiment. Tinnitus was induced by daily
administration of 321 mg/kg sodium salicylate s.c. (corresponding to 275
mg/kg/day of salicylate acid) in fourteen groups of pigmented rats, 6
animals/group. The results from salicylate- and EGb-761-treated animals were
compared to control groups receiving either salicylate, saline, or EGb 761 only
in doses of 100 mg/kg. Administration of EGb 761 resulted in a statistically
significant decrease of the behavioral manifestation of tinnitus for doses of 25,
50 and 100 mg/kg/ day.
PMID- 9390834
TI - Arrangement of vestibular nerve fibers in the semicircular canal crista of the
chinchilla.
AB - The topographic arrangement of vestibular nerve fibers innervating semicircular
canal cristae of the chinchilla was studied using computer-aided video-microscopy
and three-dimensional reconstruction. At the level 20 microns proximal to the
base of the crista, bundles consisting of 30-50 nerve fibers each were
identified. Nerve fibers in bundles were classified into seven categories
depending on the diameter. We confirmed that large nerve fibers were more
frequently found in the central bundles and small nerve fibers were more
frequently found in the peripheral bundles. The central bundle might function as
a physiological unit coding various types of head movements, whereas the
peripheral bundle might contribute more to the detection of slow and long-lasting
movements giving rise to tonus and posture changes. The canalicular nerve may
code rotational acceleration of the head via function- and locus-specific nerve
fiber bundles.
PMID- 9390835
TI - Cochlear potentials in clinical audiology.
AB - The recording of cochlear and auditory nerve potentials in humans via
Electrocochleography (ECochG) has emerged as a valuable tool for a variety of
clinical applications. This review consolidates current research on the use of
cochlear potentials and ECochG in the clinical setting and identifies several
areas in need of additional study. Methodological topics discussed include a
review of ECochG recording approaches (i.e. transtympanic versus extratympanic)
and issues related to choice of stimuli (clicks versus tonebursts). The review of
current applications for cochlear potentials focuses primarily on the use of
ECochG in the identification and treatment of Meniere's disease/endolymphatic
hydrops (MD/ELH). Other uses for ECochG also are presented (e.g. intraoperative
monitoring, enhancement of ABR wave I, estimation of hearing sensitivity).
Several suggestions are offered to maximize the predictive value of ECochG in the
diagnosis of MD/ELH.
PMID- 9390836
TI - Estimation of the pure-tone audiogram by the auditory brainstem response: a
review.
AB - This review paper briefly considers how stimulus, noise masking and recording
parameters affect the frequency and place specificity of auditory brainstem
responses (ABRs) to air- and bone-conducted stimuli. Issues concerning the use of
clicks for ABR threshold estimates will first be presented, followed by results
for tone-evoked ABR thresholds and how well they predict the pure-tone behavioral
audiogram. Noise-masking options (e.g. high-pass noise, notched noise and white
noise) to improve the frequency specificity of tone-evoked ABRs, which are now
available on clinical ABR units, will also be discussed. The goal of this article
is to demonstrate that ABRs to tonal stimuli can be successfully recorded in most
clinical environments and can provide reasonably accurate estimates of 500- to
4000-Hz pure-tone behavioral thresholds in infants, children and adults. Specific
parameters and protocols for obtaining frequency-specific ABR threshold responses
are provided.
PMID- 9390837
TI - The N1 response and its applications.
AB - Some properties and applications of the N1-P2 complex (100-200 ms latency) are
reviewed. N1-P2 is currently the auditory-evoked potential (AEP) of choice for
estimating the pure-tone audiogram in certain subjects for whom a frequency
specific, non-behavioural measure is required. It is accurate in passively
cooperative and alert older children and adults. Although generally
underutilized, it is an excellent tool for assessment of functional hearing loss,
and in medicolegal and industrial injury compensation claimants. Successful use
of N1-P2 requires substantial tester training and skill, as well as carefully
designed and efficient measurement protocols. N1-P2 reflects conscious detection
of any discrete change in any subjective dimension of the auditory environment.
In principle, it could be used to measure almost any threshold of discriminable
change, such as in pitch, loudness, quality and source location. It is
established as a physiologic correlate of phenomena such as the masking level
difference. Thus, N1-P2 may have many applications as an 'objective' proxy for
psychoacoustic measures that may be impractical in clinical subjects. Advances in
dipole source localization and in auditory-evoked magnetic fields (AEMFs) have
clarified the multiple, cortical origins of N1 and P2. These potentials are
promising tools for the neurophysiologic characterization of many disorders of
central auditory processing and of speech and language development. They also may
be useful in direct 'functional imaging' of specific brain regions. A wide
variety of potential research and clinical applications of N1 and P2, and
considerable value as part of an integrated, goal-directed AEP/AEMF measurement
scheme, have yet to be fully realized.
PMID- 9390838
TI - Auditory event-related potentials in the study of developmental language-related
disorders.
AB - This article reviews recent auditory event-related potential (ERP) studies of
developmental language disorder (DLD) and dyslexia/reading disorder (RD). The
possibility of using ERPs in searching for precursors of these disorders in the
early development of infants at risk is also discussed. Differences in
exogenous/sensory ERPs at the latency range of P1 and N1-P2 components have been
reported between groups with DLD and RD and control groups. Latency differences
between the groups may be related to a common timing deficit suggested by some
researchers to be one of the possible underlying factors both in DLD and
dyslexia. N1 amplitude group differences may be partly related to
arousal/attentional factors and partly to the 'tuning' of the auditory sensory
system. Mismatch negativity deviations in DLD children seem to indicate
differences in sensory memory functions. Differences between the reviewed
clinical groups and controls exist also in the endogenous P3 component, though
less consistently in DLD children. In both clinical groups the P3 amplitudes are,
in general, lower and the latencies longer compared to those in controls. These
findings are discussed in terms of possible differences in higher cognitive
functions that are not specific to modality. Altered hemispheric asymmetries in
DLD and RD children, as compared to controls, are commonly found in many of the
reviewed ERP components. Differences in ERPs of DLD and dyslexic children in
comparison to controls may not reflect only maturational lag but also more
fundamental processing deficiencies.
PMID- 9390839
TI - Mismatch negativity--the measure for central sound representation accuracy.
AB - The mismatch negativity (MMN), elicited by any discriminable change in a
repetitive sound even when this sound is not attended to, provides a pre
perceptual physiological measure of the accuracy of the central sound
representation in the human brain. This accuracy, which can be measured
separately for the different features of the sound, determines the individual's
sound discrimination accuracy in normal and various pathological conditions.
PMID- 9390840
TI - Towards the possible clinical application of the mismatch negativity component of
event-related potentials.
AB - The mismatch negativity (MMN) is an event-related potential component that
signifies neurophysiological processing of fine acoustic differences. The MMN
indicates attention-independent change detection, reflects auditory sensory
memory and provides a physiological measure of difference sensitivity. This paper
will provide an overview of current research where results gained by MMN testing
in different patient groups were central to the interpretation of an assumed
abnormality of processing or storing acoustic features.
PMID- 9390841
TI - Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo).
AB - Episodic ataxia (EA) is a rare, disabling condition of autosomal dominant
inheritance, but it is not a distinct clinical entity. Synonyms are familial
periodic ataxia or hereditary paroxysmal cerebellar ataxia. Family members have a
similar clinical syndrome; however, the syndrome varies considerably from family
to family. At least two groups of disorders have been separated clinically: (1)
episodic ataxia type 1 (EA-1), which manifests without vertigo and is associated
with 'interictal' myokymia, and (2) episodic ataxia type 2 (EA-2), which often
manifests with vertigo and is associated with 'interictal' nystagmus. EA-1 and EA
2 have been identified as channelopathies. EA-1 is due to different heterozygous
missense point mutations in a voltage-gated (delayed rectifier) potassium channel
gene (KCNA1/Kv1.1) on chromosome 12p13, whereas EA-2 is caused by mutations of
the cerebral P/Q-type calcium channel alpha 1 subunit gene CACNL1A4 localized on
chromosome 19p, which is highly expressed in the cerebellum. The diagnosis of EA
1 and EA-2 is important, since they can be easily treated and are often
mislabeled. As effective as acetazolamide is in preventing attacks, prospective
studies still have to prove whether it can prevent progressive ataxia in EA-2 or
even improve chronic cerebellar deficits.
PMID- 9390842
TI - Limits of normal for pressure sensitivity in the fistula test.
AB - In patients with perilymphatic fistula (PLF), nystagmus may sometimes be elicited
by application of pressure to the external ear canal. The extent to which the
normal population also exhibits such 'pressure sensitivity' is presently unknown.
Our goal was to determine the limits of normal pressure sensitivity and to
quantify the performance of the fistula test. Our subjects consisted of 13 normal
controls and 7 patients with a history of pressure sensitivity who later
underwent exploratory tympanotomy. We measured nystagmus prior to and following
pressurization of the external ear canal. Pressure was applied manually over 60 s
with a pneumatic otoscope bulb. In normal subjects, change in nystagmus between
prepressure and postpressure tests ranged from -1.3 to 0.9%s. In patients, change
in nystagmus greater than the 95th percentile limits of normal was not a reliable
indication of PLF.
PMID- 9390843
TI - Transtympanic electrocochleography in the assessment of perilymphatic fistulas.
AB - An objective method for the pre-operative diagnosis and the post-operative
assessment of a presumed perilymphatic fistula (PLF) using transtympanic
electrocochleography is presented. Three cases are reported in which the history
of the disease and the symptoms strongly suggested the presence of a PLF. Pre
operative transtympanic electrocochleography (TT ECoG) recordings at rest showed
changes similar to those of endolymphatic hydrops and signs of instability of the
inner ear hydrodynamic system during raised intrathoracic pressure. Surgery
revealed a visible leak in two of the three cases. Both windows were repaired in
all the patients. All patients were relieved from their vestibular symptoms at
the time when the post-operative TT ECoG was conducted 3-6 months later. The post
operative recordings were stable during raised intrathoracic pressure and the
previously elevated summating potentials decreased which was interpreted as an
objective indication of the recovery of the hydrodynamic system. However, later
one of the patients again developed recurrent vertigo. Twenty patients with well
documented Meniere's disease were used as a control group. TT ECoG was conducted
during raised intrathoracic pressure. The Meniere patients showed stable
recordings. It is suggested that among patients with suspected PLF and signs of
hydrops in TT ECoG, a dependence on the intrathoracic pressure reflected in the
recordings may indicate a possible fistula.
PMID- 9390844
TI - Tinnitus and translabyrinthine acoustic neuroma surgery.
AB - The purpose of this investigation was to study the effects of translabyrinthine
acoustic neuroma surgery on tinnitus in a consecutive sample of patients operated
on between 1988 and 1994 in Uppsala (Sweden). A postal questionnaire was returned
by 141 patients, yielding a 90% response rate without reminder. The results
showed that tinnitus was experienced by 70% of the patients before surgery and
60% after surgery. In general, low degrees of tinnitus distress were found, which
was confirmed by the questionnaire results. Ratings of tinnitus distress after
surgery, using the Klockhoff and Lindblom grading system, showed that 48% had
tinnitus of grade I, 46% of grade II, and 6% of grade III. Pre- and postsurgery
grading of distress did not change significantly. There was a 35% risk for
developing tinnitus when no preoperative tinnitus was present and a 15% chance
that tinnitus disappears when present preoperatively.
PMID- 9390845
TI - Surgical strategy of cochlear implantation in patients with chronic middle ear
disease.
AB - We report 10 postlingually deafened adults in whom the electrophysical criteria
for cochlear implant were fulfilled, except that they showed the following
unfavorable middle ear lesions: otitis media with effusion, chronic perforative
otitis media, cholesteatoma and previous radical ear operation. Staged operations
for cochlear implant were performed in 8 cases, and 2 patients who had undergone
radical ear operation had a single-stage operation. As a first step, one of the
following was performed in each patient as surgically indicated: myringoplasty
with or without mastoidectomy, mastoidectomy with reconstruction of the posterior
wall of the external canal, mastoidectomy with the insertion of a ventilation
tube, radical mastoidectomy or surgical cleansing of the radical cavity. From 6
months to 2.5 years after the first operation, the actual cochlear implant was
performed in the second or third stage. There was no major complication as a
result of electrode insertion into the cochlea and the results of speech
perception in these cases were not different from those in patients with normal
middle ears. In our experience, it was considered that the staged operations
would enable successful cochlear implants in selected patients with pathological
middle ear lesions even if they had previously been diagnosed as contraindicated
for this procedure. In a case with radical ear cavity a single-stage operation
could be performed when there was no cavity problem.
PMID- 9390846
TI - The history of pH and blood gas analysis.
AB - It is difficult for today's clinician to appreciate the rapid evolution of
technology relevant to pH and blood gas measurements. Discovery of the scientific
foundations took three centuries, whereas development of practical methods for
clinical application took only three decades from the realization of their
potential clinical importance. All indications are that advancement will continue
at the same pace for the next several decades.
PMID- 9390847
TI - Acid-base balance.
AB - This article emphasizes the interactions between the respiratory and metabolic
sources of acid and their clearance. It includes the chemistry of acid-based
balance as expressed by the Henderson-Hasselbach equation, the principles and
importance of biologic buffering systems, and a brief review of renal regulation
of acid-based balance. Finally, the reader is given a set of guidelines for a
systematic approach to the analysis of acid-base data.
PMID- 9390848
TI - Oxygen transport.
AB - The most important factor in the development of complex life forms is the ability
to deliver oxygen to cells within complex tissues and organs. Hemoglobin plays a
significant role in this scheme. Oxygen transport is a complex phenomenon that
encompasses the oxygen content, oxygen delivery mechanisms, and oxygen use. All
three components must operate appropriately if the organism is to function and
survive.
PMID- 9390849
TI - Blood gas analyzers.
AB - Laboratory-based blood gas analyzers have reliably produced pH, PCO2, and PO2
analyses for several decades. Over this time, their design changes reduced
maintenance procedures, microprocessor-controlled functions simplified operation,
and regulations governing their use have expanded. This article presents the
electrochemical principles of the pH and blood gas electrodes and the operational
procedures necessary to satisfy regulatory standards.
PMID- 9390850
TI - Co-oximetry.
AB - The adequacy of tissue oxygenation depends on the interaction of many factors.
Assuming the presence of sufficient tissue perfusion, oxygenation failure must be
caused by depressed respiratory efficiency (shunt or other ventilation/perfusion
mismatch), inadequate FIO2/PaO2 relationships (alveolar-capillary diffusion
deficits, for example), or oxygen transport difficulties (hemoglobin
loading/unloading dysfunction). When presented with patients whose respiratory
distress is not alleviated by application of increasing levels of FIO2 and
seemingly adequate SaO2 values, one must look toward less obvious reasons for the
disparity between subjective and objective findings. Early response by clinicians
to situations such as those just mentioned should include a survey and analysis
of hemoglobin status. It is important to note that meaningful co-oximetry results
depend on the quality of the patient history and other laboratory tests to rule
out factors that might affect the co-oximetry results. Good preparation of the
sample is essential to ensure that adequate hemolysis has occurred and that the
sample was not contaminated prior to analysis. A well designed and executed
program of preventive maintenance and QA is important. It should include
preparation and sampling as well as technique and instrument integrity. All of
these are essential for safe, effective, and accurate determination and
dissemination of this important clinical information.
PMID- 9390851
TI - Temperature correction of blood gas values.
AB - The popularity of routine temperature correcting of pH, PCO2 and PO2 values is
based on the observation that large differences in the blood gas values are
present when the patient's temperature is profoundly hypo- or hyperthermic. This
observation leads some clinicians to the unsubstantiated conclusion that
uncorrected 37 degrees C values are "wrong." The danger in this superficial
thought process is that one might reach the unfounded conclusion that temperature
corrected values are "right." The simple truth is: With significant changes in
patient temperature, we do not fully understand the complexity of the effects on
metabolism, vascular function, and respiration. Both corrected and uncorrected
blood gas values, therefore, are of uncertain usefulness in patients with
significant deviations in body temperature. There is no logical or scientific
basis for the assumption that temperature-corrected values are better than the
values obtained at 37 degrees C. In fact, the available technical and biological
data lead to the conclusion that, in almost all circumstances, there is no
clinical advantage to using values other than those at 37 degrees C. In addition,
the routine process of temperature correction of blood gases involves several
practical disadvantages. First, interpretation of the corrected values demands
deviation from the familiar and well-documented guidelines for interpreting 37
degrees C values. Second, temperature correction assumes the laboratory has
received the patient's true temperature at the time of sampling. My experience is
that the patient's true temperature often is not reported or is reported
erroneously. Third, temperature-corrected values can be confused with uncorrected
values and vice versa. Available data support the practice that only uncorrected
(37 degrees C) blood gas values should be used and reported routinely.
Temperature-corrected values should be calculated only when specifically
requested and the onus for clinical use of temperature-corrected values lies with
the clinician who requests them.
PMID- 9390852
TI - Pulse oximetry.
AB - Pulse oximetry is a reliable, noninvasive, easy to use means of continuously
determining arterial oxygen saturation in virtually any setting. This article
details the historical and technical development of this monitor; reviews the
literature on application, accuracy, and response; and presents an overview of
future advances.
PMID- 9390853
TI - Capnography.
AB - Capnography measures exhaled carbon dioxide and is most useful when applied
directly to patient care. This is in circumstances of detecting misplacement of
the tracheal tube, dysfunction of respiratory apparatuses, detection of abnormal
lung function, successful cardiopulmonary resuscitation, and trending of
deadspace changes. The least reliable application is to reflect alveolar
ventilation (PaCO2). This application is most common during general anesthesia
and weaning from mechanical ventilation. Provided the patient has a stable
cardiac status, stable body temperature, absence of lung disease, and normal
capnogram, PETCO2 monitoring may assist in estimating PaCO2. The use of
capnography in patients with severe respiratory failure should be applied with
careful reflection. The increased V/Q mismatch that is consistent with a widened
P(a-ET) gradient, as well as worsening hypercapnea with increased peripheral
carbon dioxide production, can lead to erroneous PETCO2 values. Capnography may
be least useful in the sickest patients.
PMID- 9390854
TI - Transcutaneous measurement of partial pressure of oxygen and carbon dioxide.
AB - Transcutaneous monitoring is noninvasive and relatively simple to use. In
neonates and small infants, this monitoring technique may provide very useful
clinical information. Transcutaneous gas monitoring, using conventional
electrochemical techniques, provides a means of trending the values of PaO2 and
PaCO2 in most patients with relatively normal cardiovascular function. In
patients with compromised cardiopulmonary function and in many adults, because of
different skin structure, transcutaneous gas monitoring will not accurately
reflect arterial blood gas tensions. Because transcutaneous gases depend on skin
perfusion, however, it may be useful in monitoring tissue perfusion, especially
in patients with peripheral vascular disease and tissue flaps. The heating of the
monitoring probe necessitates frequent site changes to avoid thermal injury,
which make it more labor intensive than other noninvasive monitoring methods.
PMID- 9390855
TI - Point-of-care testing.
AB - Point-of-care testing refers to testing outside of the central laboratory at or
near the patient's bedside. The practice greatly decreases turnaround time for
testing and has improved outcome and decreased length of stay in some patient
groups. Advances in technology have made analyzers increasingly portable with
expanded testing capacities while maintaining standards for accuracy required by
regulatory agencies. It is possible for clinicians to perform testing that
historically was performed only in the central laboratory by trained laboratory
technicians. Determination of all appropriate bedside testing for different
clinical areas and patient groups will require further investigation and debate.
PMID- 9390856
TI - Blood gas monitors.
AB - In vitro blood gas analysis requires limitation of the frequency of serial blood
gas measurements for two major reasons--blood loss and cost. In vivo or ex vivo
blood gas monitors eliminate these factors because the measurements are available
continuously, or as frequently as deemed desirable, without permanently removing
blood or imparting additional cost. For patients with arterial catheters in
place, the propriety of blood gas monitors is obvious as long as there is no
requirement to alter the size, location, or placement of the arterial catheter
and the routine use of the arterial catheter system is unaffected. Further,
personnel exposure to the patient's blood, and the risk of nosocomial infection
from contaminated arterial catheters, should be reduced because the integrity of
the arterial catheter and tubing system is not interrupted to obtain blood gas
values. Blood gas monitors and point-of-care analyzers should significantly
reduce therapeutic decision time (the interval from ordering the test to
initiating a therapeutic action based on the test results), thereby enabling
rapid titration of common therapeutic modalities such as oxygen administration,
positive pressure ventilation, positive end-expiratory pressure, and manipulation
of acid-base balance. The transfer of blood gas measurements from laboratory
analyzers to the combination of blood gas monitors and point-of-care analyzers
should have as profound an impact on acute care medicine as did the introduction
of laboratory-based blood gas analysis over 30 years ago. In the current medico
economic environment, however, we must be certain that these devices are
reliable, consistent, and cost beneficial in order to avoid widespread
application of yet another technology that provides more data, greater costs, and
only questionable patient benefits.
PMID- 9390857
TI - The rising tide of asthma. Trends in the epidemiology of morbidity and mortality
from asthma.
AB - The increase in the asthma mortality rate seen in the past decade has stimulated
much discussion, research, and controversy. The epidemiology of asthma morbidity
is reviewed, with special attention to the roles of demographics, socioeconomic
status, and iatrogenesis in the rising tide of asthma mortality.
PMID- 9390858
TI - Pathophysiology and management of life-threatening asthma.
AB - With sound medical management and good patient education, only a small minority
of patients with asthma ever experience a life-threatening episode. The
pathophysiology, clinical presentation, and management of life-threatening asthma
are reviewed. Special emphasis is placed on identification of the fatality-prone
asthmatic patient and on avoidance of complications of treatment that
significantly add to morbidity and mortality rates.
PMID- 9390859
TI - Ambulatory care of the adult asthma patient.
AB - Asthma is a chronic airway disorder that is a serious public health problem in
many countries. Asthma affects people of all ages. It ranges from mild to severe
and sometimes is fatal. Over 100 million people worldwide have asthma and the
prevalence is increasing, especially in the cohort aged 1 to 14 years. Risk
factors that lead to the development of asthma appear to be largely environmental
and therefore potentially preventable. Lifestyle changes and exposure to
allergens may be responsible for the increase in prevalence.
PMID- 9390860
TI - The role of allergy in asthma.
AB - Allergic triggers remain vitally important for a large proportion of asthmatics.
Increasing evidence indicates that allergic sensitivity may not only cause
ongoing asthmatic symptoms with bronchial hyperreactivity and airway inflammation
but may also serve as an inducer of the asthmatic condition. Patients with a
history and clinical setting suggestive of allergic sensitivity should be
evaluated carefully. Whenever possible, allergen avoidance should be encouraged
strongly in allergen-sensitive patients with a strong emphasis on patient
education. In those patients who continue to be symptomatic with good avoidance
measures and appropriate pharmacotherapy, allergy immunotherapy should be
considered as an additional treatment measure.
PMID- 9390861
TI - Aerosol therapy.
AB - Aerosols are commonly used in the treatment of patients with pulmonary disease.
The clinician must choose the appropriate aerosol delivery device. For both
spontaneously breathing and mechanically ventilated patients, the first choice of
device is usually the metered-dose inhaler. There are important differences among
devices in the dosage delivered to the lungs. For the typical prescription,
nebulizers deliver more drug to the lungs than metered-dose inhalers, which may
be particularly important for acutely ill patients.
PMID- 9390862
TI - Bronchial challenge testing.
AB - Airways hyperresponsiveness can occur as solitary evidence of airways
dysfunction. Because hyperresponsiveness is associated with the presence and
severity of disease, it is important to measure and quantitate airways
responsiveness. The most useful challenge procedure appears to be the
methacholine challenge, not so much because it offers the best specificity of the
challenge procedures but because it has been characterized well. Although the
procedures are simple, interpretation of the results is problematic. It is
important to remember that the key features of asthma are the periodicity and
lability of signs and symptoms. Assessment of airways responsiveness is a
significant addition to the armamentarium of the modern diagnosis and treatment
of asthma.
PMID- 9390863
TI - Management of the difficult asthmatic. Gastroesophageal reflux, sinusitis, and
pregnancy.
AB - The frustration of treating the difficult asthmatic can be minimized by
recognizing that interactions of disease processes can complicate therapy. At the
same time, therapy of asthma can be simplified by the awareness that control of
allied conditions can improve the response to treatment directed at the airways.
The future likely will bring more challenges as our ability to cope with
complicated asthma patients improves.
PMID- 9390864
TI - Diagnosis and management of acute asthma.
AB - Deaths from asthma are relatively uncommon but have continued to rise worldwide
in the past few decades, despite a better understanding of the disease and an
increased number of patient medications. This often is attributed to inadequate
assessment and treatment of the disease. This article focuses on defining several
items that pertain to acute severe asthma. In addition, the pathophysiology and
clinical manifestation of acute asthma, as well as current investigational tools,
are reviewed. Traditional and nontraditional therapies of acute asthma are
discussed. Finally, complications of severe asthma and the long-term outcome are
discussed, with appropriate preventive measures stressed strongly.
PMID- 9390865
TI - Mechanical ventilation in asthma.
AB - The goal of respiratory support in asthma is similar to the goals in other forms
of respiratory failure: to support gas exchange while avoiding complications. The
specific respiratory support goals for asthmatics are discussed in this article,
as well as recommended ventilator adjustments to meet these goals.
PMID- 9390866
TI - Asthma rehabilitation program.
AB - Comprehensive management of asthma includes proper use of medication adjustments
in patient lifestyle, exercise conditioning, and patient education to maximize
self-management capabilities. Pulmonary rehabilitation programs have used these
strategies successfully to improve the functional status and reduce the health
care costs of patients with chronic obstructive pulmonary disease. Adapting these
programs to the asthmatic population is an important and cost-effective goal.
PMID- 9390867
TI - The rationale for therapist-driven protocols.
AB - Misallocation of respiratory care, defined as ordering therapy unlikely to
provide benefit (overordering) and failing to provide beneficial therapy
(underordering), is common and provides the rationale for implementing therapist
driven protocols. This article reviews the frequency of misallocation of
respiratory care and explores possible reasons for misallocation. Therapist
driven protocols represent a new model for delivering respiratory care that is
designed to minimize misallocation.
PMID- 9390868
TI - A short history of therapist-driven respiratory care protocols.
AB - The literature of the TDP movement continues to grow, but a legitimate concern
regarding mindless acceptance of the new paradigm is now being voiced. As this
issue goes to press, it appears clear to this writer that the orderly growth of
the TDP paradigm has led to its widespread acceptance. The future will determine
whether our early predictions of its success are well founded.
PMID- 9390869
TI - Constructing a therapist-driven protocol. Spectrum of types and quality control.
AB - Therapist-driven protocols for the implementation and delivery of respiratory
care must be tailored to fit the needs of the individual institution. The method
that is chosen for constructing a therapist-driven protocol depends on the type
of protocol desired (disease-, symptom-, or treatment-based) and on whether a
narrative or flow-diagram format is preferred. Because the goal of therapist
driven protocols is to provide a systematic method for determining appropriate
respiratory care, quality control measures are necessary to ensure that desired
outcomes are achieved. Quality control monitoring can be performed through the
use of case-study exercises, verbal shift reports, and care-plan audits. Results
of quality control monitoring techniques can be used to guide modification of
protocols.
PMID- 9390870
TI - Implementing therapist-driven protocols.
AB - In January of 1993, as part of a hospital-wide cost-reduction strategy, the
University of California San Diego (UCSD) Medical Center Respiratory Care
Department implemented a patient-driven protocol program designed to utilize the
assessment skills and judgments of respiratory care staff, within physician
approved guidelines. This program produced a 60% reduction in the use of hand
held nebulizer therapy and chest physical therapy in the institution, with a
substantial decrease in operational expenses. This article describes key elements
of the implementation of protocol-driven programs, provides examples from the
UCSD experience, and offers insights gained from others who have been successful
agents of change. It describes patient-driven protocols, how they can be
implemented, the barriers to and promoters of such protocols, and what the
results can be for a respiratory care department.
PMID- 9390871
TI - Assessment instruments in respiratory care.
AB - The basis for using therapist-driven protocols effectively is an accurate
assessment of the patient's respiratory status. Patients must be assessed to
initiate indicated therapy and reassessed so that therapy can be modified or
discontinued if no longer needed. This article addresses the role of respiratory
therapists in patient assessment for the selection of appropriate and effective
protocols. It also describes the use of a systematic and consistent process for
patient assessment.
PMID- 9390872
TI - Therapist-driven protocols for adult non-intensive care unit patients.
Availability and efficacy.
AB - As the growth of TDPs increases throughout the country, the need to evaluate the
efficacy of TDPs becomes paramount. For TDPs to become a standard of practice
they must respond adequately to their intended purpose. TDPs must reduce the
amount of misallocation of respiratory services without compromising quality
care. As the reduction of misallocation occurs, the results should show a
reduction in department and patient costs. Protocols are not new to the medical
community, but their need and use for respiratory care has increased. Preliminary
studies thus far suggest that the use of TDPs can lessen misallocation of care
without adverse events, and with the use of TDPs the number of respiratory
modalities and the cost associated with these therapies have decreased. Further
examinations of the efficacy of TDPs must be ongoing, however, in order to ensure
that these preliminary studies truly reflect the outcomes of the use of TDPs.
PMID- 9390873
TI - Therapist-driven protocols in adult intensive care unit patients.
AB - TDPs occasionally are used to standardize or control respiratory management of
the critically ill. Weaning protocols are most common. Little objective
evaluation of the effects of TDPs in the critically ill has been published. Most
protocols have been developed to improve efficiency of respiratory care staff and
reduce unnecessary treatments in non-ICU patients. The most important reason for
using TDPs in the ICU is to improve consistency of care. Reduction of variation
between individual therapist style improves physicians' trust in the respiratory
care department. Improved consistency may allow novel ICU therapies to be
evaluated objectively. In general, TDPs are not directly transportable from one
area or institution to another. TDPs require local development, and all
interested parties must be part of the development process for success. The
process of creating TDPs provides a forum for physicians, nurses, and therapists
to establish mutual respect and understanding. The analytic approach needed to
create useful TDPs provides a critical evaluation of unit procedures and promotes
changes in care delivery extending outside the TDP. The complexity of disease
process and patient care in the ICU makes comprehensive TDPs difficult to
establish; however, use of computers for decision support can overcome the
limitations of paper flow charts. Even without comprehensive TDPs, the
development process is important to improving and understanding care of the
critically ill. The effects of TDPs on ICU patient outcome are unknown currently.
Benefits are possible and improved collaboration, better respiratory care staff
morale, consistency of approach to care, and critical approach to clinical
decision making can be gained by attempting to develop TDPs for respiratory care
delivery in the ICU.
PMID- 9390874
TI - Therapist-driven protocols for pediatric patients.
AB - Most therapist-driven respiratory care protocols deal with adult care. The
greatest difficulty we have encountered when implementing pediatric protocols
involves patient assessment. We have found that with any protocol the key factor
is to monitor closely the result of the treatment and to analyze that outcome and
compare it with the purpose of the therapy. When careful clinical assessments are
accomplished, pediatric protocols can be established.
PMID- 9390875
TI - Legal aspects of therapist-driven protocols. Do therapist-driven protocols place
therapists in a legally compromising position?
AB - The recent introduction of therapist-driven protocols has given the appearance of
restricting the professional judgment of respiratory therapists with decision
tree robotics while contemporaneously catapulting them into the practice of
medicine. This is happening in the midst of a spiraling litigation climate. This
article examines the legal aspects--from malpractice to licensure--of this
exciting new practice known as therapist-driven respiratory protocols.
PMID- 9390876
TI - Therapist-driven protocols and newer models for patient care delivery.
AB - There continues to be increased scrutiny regarding the quality and cost
effectiveness of health care delivery in this country. As stated previously, new
models of patient care delivery are designed to streamline and simplify hospital
procedures in order to enhance this quality and cost efficiency. There is
evidence that many of the elements of patient-focused care are adding value to
the quality and efficiency of care. Evidence also indicates that therapist-driven
protocols offer a promising solution to the misallocation of respiratory care,
which is now widespread. The greatest cost savings to hospitals, it has been
shown, comes from the elimination of unnecessary care, which therapist-driven
protocols are designed to reduce. In the bigger picture of patient care delivery,
however, more extensive and critical evaluation is needed before hospitals commit
large sums of money to redesign their infrastructures. In other words, it is not
yet proved conclusively that new models of patient care delivery are enhancing
quality while cutting costs. To date, there is little documentation by hospitals
of improved service or financial outcomes associated with new models of patient
care delivery. It is likely that decentralizing ancillary services, streamlining
procedures, and cross-training employees can help hospitals improve patient
satisfaction and staff efficiency. In fact, there is evidence that the cost
savings potential for hospitals that implement employee redeployment and cross
training can be significant. Although patient-focused care is worthwhile
primarily as an effort to simplify care delivery, the biggest cost savings comes
from eliminating unnecessary care entirely. Although the evidence does not yet
support hospitals' taking a major plunge into patient-focused care, it has been
shown that many elements of patient-focused care are worth implementing and can
be done inexpensively. Inexpensive activities that are likely to produce
meaningful cost and quality gains include cross-training employees in bedside
ancillaries, redeploying medical records, redeploying admitting, redeploying
support services, and adding automated drug and supply dispensing to nursing
units. Hospitals can minimize their financial risks and still achieve many of the
benefits of patient-focused care by taking a middle-of-the-road approach to
restructuring and redesign.
PMID- 9390877
TI - A historical perspective on the use of noninvasive ventilatory support
alternatives.
AB - This article traces the development of mechanical ventilatory support methods
from the use of body ventilators to tracheal cannulation to the use of
noninvasive ventilatory support and airway secretion management alternatives.
Although it has been known that tracheostomy tubes could be used for ventilatory
support and airway secretion management since 1869, body ventilators continued to
be the main methods of long-term ventilatory support in the United States, with
tracheostomy performed only for patients with severe bulbar muscle dysfunction,
until the late 1950s. Recent technological developments, however, have created
renewed interest in noninvasive alternatives.
PMID- 9390878
TI - Noninvasive positive pressure ventilation. Equipment and techniques.
AB - Successful application of noninvasive positive pressure ventilation is largely
dependent on available equipment and the approaches used to apply it. Third
generation intensive care unit ventilators and portable volume and pressure
ventilators may be used for noninvasive positive pressure ventilation. A variety
of facial interfaces currently are manufactured, and all should be available. A
well-trained therapist with available time is the final ingredient for successful
use of noninvasive positive pressure ventilation.
PMID- 9390879
TI - Body ventilators. Equipment and techniques.
AB - Body ventilators have been used since the late 1800s and are still used today.
This article reviews all of the body ventilators available today including tanks,
cuirasses, wraps, rocking beds, and intermittent abdominal pressure ventilators.
Diaphragm pacers and glossopharyngeal breathing also are reviewed. Clinical
application of the ventilators, initiation, patient monitoring, and follow-up are
reviewed.
PMID- 9390880
TI - The use of noninvasive respiratory muscle aids in the management of patients with
progressive neuromuscular diseases.
AB - Most patients with primarily ventilation impairment can use noninvasive
alternatives to tracheostomy for long-term ventilatory support and airway
secretion management. The most important and versatile method of noninvasive
ventilatory support is mouthpiece intermittent positive pressure ventilation.
Mouthpiece intermittent positive pressure ventilation also can be used via a
Lipseal for nocturnal support. The intermittent abdominal pressure ventilator is
an option for daytime aid, and nasal intermittent positive pressure ventilation
is usually preferred for nocturnal support. Manually assisted coughing and
mechanical insufflation-exsufflation can be critical for airway secretion
elimination.
PMID- 9390881
TI - Long-term noninvasive ventilation for patients with thoracic cage abnormalities.
AB - Long-term noninvasive ventilation offers the patient with thoracovertebral
deformities, including deformities that result from the severe skeletal and chest
wall sequelae of tuberculosis, what long-term oxygen therapy has offered patients
with chronic obstructive pulmonary disease: improved survival and prevention or
alleviation of cor pulmonale. Long-term noninvasive intermittent positive
pressure ventilation, particularly nocturnal use, has little inconvenience,
because ventilation during the night often suffices. Major advantages include
correction of hypoventilation during autonomous breathing time that is usually
sufficient to permit patients to resume their activities of daily living without
need for ventilatory assistance during the day and efficacy comparable to that of
intermittent positive pressure ventilation via an indwelling tracheostomy tube,
without the inconveniences (tracheostomy is always available if necessary).
PMID- 9390882
TI - Chronic noninvasive ventilation in obstructive airways disease.
AB - Early experience with noninvasive ventilation in patients with chronic
obstructive pulmonary disease was largely unsuccessful, with no benefit over long
term oxygen therapy. Nasal positive pressure ventilation, however, produces
improvements in arterial blood gases, nocturnal-hypoventilation, and quality of
life. Experience with nasal ventilation in other obstructive airways diseases,
such as bronchiectasis and cystic fibrosis, is limited and less favorable.
PMID- 9390883
TI - Noninvasive ventilation in acute respiratory failure.
AB - Noninvasive PPV has been employed for decades in patients with chronic
respiratory failure. Increasing use in patients with acute respiratory failure is
a more recent phenomenon, mainly because of advances in noninvasive interfaces
and ventilator modes. Noninvasive PPV delivered by nasal or oronasal mask has
been demonstrated to reduce the need for endotracheal intubation, decrease
lengths of stay in the ICU and hospital, and possibly reduce mortality. In the
acute care setting, evidence now demonstrates the efficacy of noninvasive PPV for
acute exacerbations of COPD, pulmonary edema, pulmonary contusions, and acute
respiratory failure in patients who decline or who are not believed to be
candidates for intubation. No firm conclusions can yet be made regarding patients
with respiratory failure due to other causes, but studies suggest that
noninvasive PPV may also be of benefit in patients with postoperative respiratory
insufficiency, chest wall disease, and cystic fibrosis. Several factors are vital
to the success of this therapy, including careful patient selection, properly
timed intervention, a comfortable, well-fitting interface, patient coaching and
encouragement, and careful monitoring. Noninvasive ventilation should be used as
a way to avoid endotracheal intubation rather than as an alternative.
Accordingly, a trial of noninvasive ventilation should be instituted in the
course of acute respiratory failure before respiratory arrest is imminent, to
provide ventilatory assistance while the factors responsible for the respiratory
failure are aggressively treated. Moreover, the authors favor conservative
management with expeditious intubation in patients who have other conditions that
place them at risk during use of noninvasive ventilation or in patients failing
to respond to noninvasive PPV. Noninvasive PPV clearly represents an important
addition to the techniques available to manage patients with acute respiratory
failure; however, because most studies have been retrospective and uncontrolled,
many issues remain unresolved. Further controlled studies are needed to confirm
the safety and efficacy of noninvasive PPV, evaluate the most appropriate
selection of patients and timing of intervention, define the best type of
interface, and assess the costs of noninvasive PPV in comparison with
conventional therapy.
PMID- 9390884
TI - Noninvasive ventilation for postoperative support and facilitation of weaning.
AB - Noninvasive ventilation includes continuous positive airway pressure with mask,
positive pressure ventilation with mask, and negative pressure body ventilation.
Noninvasive ventilation is a ventilatory support mode intermediate in both
effectiveness and potential complications between oxygen administration and
intubation with mechanical ventilation. The advantages, disadvantages, and
experimental results of the use of noninvasive ventilation in patients who have
been extubated following recovery from surgery and subsequently experience
respiratory difficulties are discussed. In general, noninvasive ventilation seems
to provide useful ventilatory support in about three of four patients in whom it
is tried. In addition, the use of noninvasive ventilation as an aid to weaning of
patients from mechanical ventilation is discussed. This use of noninvasive
ventilation has not yet been extensively reported, although it appears to be
potentially useful.
PMID- 9390885
TI - Respiratory management, survival, and quality of life for high-level traumatic
tetraplegics.
AB - Although spinal cord injury is devastating and can compromise the respiratory
system, particularly when the cervical cord is injured, aggressive use of
noninvasive respiratory muscle aids can reduce the otherwise commonly seen
complications of pneumonia, bronchial mucous plugging, atelectasis, and
respiratory failure. Accessory muscle function can also usually be improved and
the muscles then recruited to help maintain adequate alveolar ventilation during
the acute spinal cord injury recovery period. Noninvasive assisted ventilation
can be successful for patients with compromised lung function during the acute
rehabilitation period as well as on a long-term basis. Removal of an indwelling
tracheostomy tube results in improved quality of life from many points of view, a
decreased number of local tracheostomy complications, a decreased number of
serious respiratory infections, an improved ability to communicate, and an
increased ability to use the mouth for functions such as operating computers and
wheelchairs.
PMID- 9390886
TI - Noninvasive clearance of airway secretions.
AB - Airway clearance techniques are indicated for specific diseases that have known
clearance abnormalities (Table 2). Murray and others have commented that such
techniques are required only for patients with a daily sputum production of
greater than 30 mL. The authors have observed that patients with diseases known
to cause clearance abnormalities can have sputum clearance with some techniques,
such as positive expiratory pressure, autogenic drainage, and active cycle of
breathing techniques, when PDPV has not been effective. Hasani et al has shown
that use of the forced exhalatory technique in patients with nonproductive cough
still resulted in movement of secretions proximally from all regions of the lung
in patients with airway obstruction. It is therefore reasonable to consider
airway clearance techniques for any patient who has a disease known to alter
mucous clearance, including CF, dyskinetic cilia syndromes, and bronchiectasis
from any cause. Patients with atelectasis from mucous plugs and hypersecretory
states, such as asthma and chronic bronchitis, patients with pain secondary to
surgical procedures, and patients with neuromuscular disease, weak cough, and
abnormal patency of the airway may also benefit from the application of airway
clearance techniques. Infants and children up to 3 years of age with airway
clearance problems need to be treated with PDPV. Manual percussion with hands
alone or a flexible face mask or cup and small mechanical vibrator/percussors,
such as the ultrasonic devices, can be used. The intrapulmonary percussive
ventilator shows growing promise in this area. The high-frequency oscillator is
not supplied with vests of appropriate sizes for tiny babies and has not been
studied in this group. Young patients with neuromuscular disease may require
assisted ventilation and airway oscillations can be applied. CPAP alone has been
shown to improve achievable flow rates that will increase air-liquid interactions
for patients with these diseases or airway malacia. Use of positive pressure to
maintain airway patency in these children allows cephalad clearance of
secretions. Patients with segmental atelectasis, particularly related to asthma,
may benefit from intrapulmonary percussive ventilator, positive expiratory
pressure, or PDPV. Prevention of postoperative atelectasis is particularly well
suited to positive expiratory pressure, which is not as painful as techniques
using oscillations. Neurologically abnormal patients who are unable to cooperate
with any active method are also treated using intrapulmonary percussive
ventilator, PDPV, and suctioning, if necessary. Musculoskeletal abnormalities,
muscular dystrophies, myasthenia gravis, poliomyelitis, or other similar diseases
require stabilization of bellows function. Optimizing ventilation in patients
with such abnormalities may require positive pressure ventilation either during
sleep or continuously. Externally applied pressure, such as with the In
Exsufflator or the cyclically inflated pneumatic belt, can augment the patient's
own efforts and is sometimes helpful. Normalizing the vital capacity and
functional residual capacity typically helps to improve the ability to cough and
clear secretions. Assisted cough devices or maneuvers are described in other
papers by Bach and Hill. Not all patients who have weak muscles require nocturnal
or continuous support, and may benefit from positive expiratory pressure mask
treatments. Further studies are sorely needed for this population. Long-term
controlled trials are urgently needed to help establish the best types of
treatment for patients with CF and bronchiectasis. Such studies will become more
complicated by the introduction of new treatments, such as DNase and other
therapies that alter secretions, and may begin to change mucociliary or cough
clearance. The selection of appropriate outcome measures is central to studying
these questions, and it is unclear which are the most important. (ABSTRACT
TRUNCATED)
PMID- 9390887
TI - Ventilatory support in the field.
AB - Ventilatory support during cardiopulmonary resuscitation can be accomplished with
an array of methods and devices. These run the gamut from expired air
resuscitation, including mouth-to-mouth and mouth-to-mask, to the use of
ventilators including ventilator-to-mask and ventilator-to-artificial airway
techniques. Appropriate application of these techniques depends on the clinical
situation, rescuer training, and availability of equipment. This article
discusses the proposed standards of emergency ventilatory support, the advantages
and disadvantages of the techniques and devices used, and current controversies
surrounding this topic.
PMID- 9390888
TI - Respiratory issues in aeromedical patient transport.
AB - Respiratory considerations in aeromedically evacuated patients are the
cornerstone of safe, successful transport. Maintenance of the ABCs and ongoing
resuscitation including pulmonary/ventilator stabilization and management en
route are paramount. All of these goals are predicated on a well-developed
understanding of hypobaric pulmonary physiology and hypobaric effects on medical
devices, a solid grasp of the inherent limits of an aeromedical environment, and
the resolute accomplishment of both initial and follow-up team member training.
PMID- 9390889
TI - Pulmonary consequences of severe chest trauma.
AB - Combined flail chest and pulmonary contusion is a frequent problem in patients
with blunt multisystem trauma admitted to the intensive care unit. These patients
are at high risk for pneumonia and adult respiratory distress syndrome, which
adds substantially to their morbidity and mortality rates. This article discusses
the epidemiology and pathophysiology of this condition and the role of the
respiratory care practitioner in the optimal management of these critically
injured patients.
PMID- 9390890
TI - Ventilatory support of the trauma patient with pulmonary contusion.
AB - Pulmonary contusion is a common clinical condition seen in patients with thoracic
trauma. The mortality rate from isolated pulmonary contusion is low, but when
combined with other severe injuries patients with pulmonary contusion can have
mortality rates as high as 10% to 57%. Early aggressive mechanical ventilatory
support can prevent progressive atelectasis and worsening of arterial
oxygenation. Careful titration of ventilatory support to physiologic end points
is a reasonable approach. Unfortunately, data comparing the means of achieving
the end points are lacking and no published prospective, randomized trials
demonstrate superiority of any particular mode of support. Careful attention to
detail and physiologic management of the patient in a goal-directed fashion using
a multidisciplinary team approach involving the respiratory care practitioner,
nurse, and physician is the current state of the art in the management of
patients with pulmonary contusion.
PMID- 9390891
TI - Management of blunt chest injury.
AB - The development of regional techniques of analgesia has revolutionized the
management of blunt thoracic trauma. The standard of care has evolved from
intubation and mechanical ventilation for all patients to optimization of pain
control combined with chest physiotherapy. Although many methods have been used,
it appears that in appropriately selected patients, epidural analgesia is the
preferred technique for pain control in severe thoracic trauma. Epidural
catheters for continuous narcotic or local anesthetic administration are both the
most reliable and the most effective, and once in place they can be managed by
nursing outside of the intensive care setting. It still remains for improvement
in outcome to be demonstrated when epidural analgesia is used, but it is clear
that subjective patient comfort is increased and that pulmonary parameters can be
improved. In appropriately selected patients, those without head injury or who
have been adequately evaluated for intra-abdominal injury, epidural analgesia is
currently the preferred method for pain control following severe thoracic trauma.
PMID- 9390892
TI - Outcomes of pediatric mechanical ventilation.
AB - Mechanical ventilation is one of the most commonly used life-support technologies
in the PICU, is an absolute indicator of the need for PICU care, and adds
considerably to the cost of intensive care. Patients with chronic disease account
for a large proportion of admissions to the PICU and of patients undergoing
cardiovascular surgery and neurosurgery. Although the average length of use of
mechanical ventilation in the PICU is about 5 days, there is tremendous
variability in the length of ventilation (SD approximately 9 days). Survival
among ventilated patients varies greatly and depends mostly on the nature and
severity of the underlying disease.
PMID- 9390893
TI - Pediatric mechanical ventilation technology.
AB - An in-depth examination of ventilators currently marketed for the pediatric
population and the technology associated with each is provided with this article.
Also included is a discussion of an "ideal pediatric ventilator" and its
application to the pediatric intensive care patient. Triggering, cycling, and
limiting variability, costs, and special features currently available are
detailed.
PMID- 9390895
TI - High-frequency oscillatory ventilation in pediatric patients.
AB - High-frequency oscillatory ventilation (HFOV) offers the potential to maintain
adequate gas exchange without imposing the large pressure swings and tidal
volumes associated with ventilatory-induced lung injury. This article reviews the
studies evaluating the use of HFOV to treat pediatric respiratory failure,
discusses the complications associated with HFOV, and details an approach to the
practical application of HFOV in the non-neonatal pediatric population.
PMID- 9390894
TI - Sedation, analgesia, and neuromuscular blockade during pediatric mechanical
ventilation.
AB - The mechanically ventilated PICU patient is subjected to multiple noxious stimuli
ranging from a bright, noisy, and intimidating environment to painful but
necessary procedures. His or her primary disease process or processes obviously
constitutes another potential source of noxious stimuli as well. As a result,
these patients almost certainly need some combination of medications to allay
anxiety, treat discomfort, and perhaps otherwise optimize medical management.
Intensivists now have at hand an impressive array of medications that can be used
to blunt the stresses imposed by these stimuli. Sedatives to induce anxiolysis
and calmness, analgesics to alleviate pain, and occasionally neuromuscular
blocking agents to inhibit movement may be used. Use of these medications can be
tailored to meet the varied requirements of the diverse PICU population. The
consequences of incorrect use can be sobering. Familiarity with the pharmacology,
indications, and side effects of the individual medications is a necessity for
all ICU care providers to prevent misuse. Although the frequent need for
analgesics, sedatives, and NMBDs in the PICU is undisputed, the development of
reliable methods for accurately assessing the degree of patient sedation or
analgesia will greatly facilitate efforts to improve patient care Appropriate use
of sedatives, analgesics, and NMBDs provides an invaluable service. It is
important to remember, however, that even in the high-technology PICU environment
verbal and physical reassurance remains a powerful tool for providing comfort and
anxiolysis to critically ill children. There is no pharmacologic equivalent of
human compassion.
PMID- 9390896
TI - High-frequency jet ventilation in the pediatric intensive care unit.
AB - Scientific data and anecdote on the utility of HFJV in children remain divergent.
There seems to be some evidence that ventilation and oxygenation in critically
ill patients can sometimes be achieved at lower peak airway pressures and tidal
volumes. There is also growing consensus that HFJV may be a superior ventilatory
technique for patients with air leak syndrome. However, conclusive evidence of
the effect of this technology on overall survival, length of ventilation, or even
resource consumption remains illusive. Until such time, a general recommendation
for the use of HFJV in pediatric patients is not possible.
PMID- 9390897
TI - Metabolic measurements during mechanical ventilation in the pediatric intensive
care unit.
AB - The metabolism of critically ill infants and children is significantly influenced
by their underlying diseases, and standard predictive equations result in
inappropriate nutritional support in most of these patients. Furthermore,
significant day-to-day variability in energy expenditure may be present in
individual patients. Inadequate or excessive energy supply can adversely affect
the clinical course of many critically ill patients. For these reasons, serial
measurements of energy expenditure should be considered whenever accurate
determination of energy needs is deemed necessary. With the wide availability of
proprietary metabolic carts suitable for use in mechanically ventilated pediatric
patients, serial metabolic measurements via indirect calorimetry are feasible in
most critically ill infants and children. The use of indirect calorimetry should
also be considered in this population to assess changes in oxygen consumption and
the relationship of oxygen consumption to oxygen delivery in response to changes
in therapy, such as manipulation of cardiac output using vasoactive medications,
or during weaning of mechanical ventilation.
PMID- 9390898
TI - Nitric oxide administration during pediatric mechanical ventilation.
AB - The administration of inhaled NO in the management of pulmonary hypertension and
respiratory failure is an important development in pediatric critical care. The
long-term effects of this therapy are yet to be understood. An appreciation for
the potential hazards and the development of accurate and safe delivery systems
are paramount to the successful application of this new therapy.
PMID- 9390899
TI - Volume and pressure modes of mechanical ventilation in pediatric patients.
AB - There are few controlled pediatric studies comparing the various modes of
ventilation in terms of patient outcomes. Thus at this time the choice of
ventilator mode depends largely on the apparatus available, the patient's disease
state, and personal preference based on one's experience. The next generation of
ventilators may well allow the use of the best of both modes, setting both
pressure and volume minimums and maximums, safely meeting ventilation targets.
Today's challenges are to become familiar with the various modes of ventilators
available, understand the developing physiology of the lung and lung disease
pathophysiology, and incorporate all this into proper ventilator strategies to
prevent ventilator-induced lung injury.
PMID- 9390900
TI - Early versus late tracheostomy in the trauma patient.
AB - The use of early tracheostomy in the multiply injured trauma patient has many
advantages both in terms of patient management and reduction of morbidity
associated with prolonged translaryngeal intubation. Tracheostomy (percutaneous
or open technique) has been associated with very low risk of mortality and
comparable morbidity to prolonged endotracheal intubation. There exist improved
clinical criteria for predicting which patients will require prolonged mechanical
ventilation in the trauma and critical care setting. A delay in converting
translaryngeal intubation to tracheostomy had been associated with longer ICU
stays; conversely, early tracheostomy has been associated with a reduction in ICU
stays, incidence of hospital-acquired pneumonias, mechanically ventilated days,
and length of hospital stay. Thus, the benefits of early tracheostomy are
improved care for patients in the trauma or critical care setting and reduced
hospital and patient costs.
PMID- 9390901
TI - Ventilatory support following burns and smoke-inhalation injury.
AB - The first major improvement in the treatment of burn injury came with the
recognition of the importance of fluid resuscitation to prevent shock and renal
failure. Subsequently, the use of topical antibiotics to control burn-wound
infection and prevent invasive burn-wound sepsis led to the next significant
reduction in morbidity and mortality of burn patients. Although progress has been
made in the treatment of inhalation injury, the pathophysiology of the injury is
still incompletely defined. A better understanding of pathogenic mechanisms will
lead to the development of therapeutic agents and treatment regimens that will
modulate the cascades of humoral mediators of organ dysfunction and reduce the
morbidity and mortality associated with inhalation injury. The recognition of
ventilator-induced lung injury has led to adoption of alternative ventilatory
techniques such as high-frequency percussive ventilation, which has been shown to
substantially reduce the morbidity associated with inhalation injury.
PMID- 9390902
TI - Respiratory support of the head-injured patient.
AB - Approximately 500,000 patients present with a CHI annually in the United States
alone. Up to 20% of these injuries are classified as severe. Appropriate and
aggressive intensive care of CHI patients will certainly reduce both the
morbidity and mortality rates. Early therapy includes provision of adequate
ventilation and oxygenation and definitive care based on clinical assessment.
Once the acute phase of the injury has passed, supportive therapy should be
maintained as long as secondary injury or complications are avoided. Respiratory
care of CHI patients is important though different in each phase of the disease.
Proper placement of and maintenance of airways, efficient use of and withdrawal
from the mechanical ventilator, and providing adequate pulmonary toilet in order
to treat or avoid pneumonia are but a few of the very important respiratory care
practices necessary to provide optimal outcomes in patients with CHI.
PMID- 9390903
TI - Nutritional support of the mechanically ventilated patient.
AB - As with all critically ill patients, those requiring mechanical ventilation are
susceptible to the wasting of illness and cannot survive without prompt
nutritional support. It may be fair to say that the proper provision of
nutrients, and in particular the avoidance of overfeeding, are even more crucial
for this subset of critically ill patients. To maximize the overall benefits of
feeding, it is crucial to provide the nutritional support early and enterally
whenever possible. Therefore, the best strategy for early removal of the
mechanical ventilatory support must include the timely and careful administration
of nutrients, micronutrients, minerals, vitamins, and fluid, in conjunction with
standard intensive care therapeutics and the appropriate respiratory muscle
strengthening program.
PMID- 9390904
TI - Paralyzation and sedation of the ventilated patient.
AB - The selection of pharmacologic agents for the sedation and paralysis of
critically ill patients should be based on clinical and pharmacoeconomic trials
in this patient population. There is a need for the design and evaluation of cost
effective regimens, especially with the continued development and release of
newer agents. Additionally, clinicians must continue to be sensitive to the
monitoring techniques of sedation and paralysis to ensure maximal clinical
benefit while minimizing the adverse effect profile of pharmacologic agents.
PMID- 9390905
TI - To everything turn, turn, turn.... An overview of continuous lateral rotational
therapy.
AB - Continuous lateral rotational therapy can be a significant adjunct in the care of
the critically ill patient. CLRT has a great impact on both patient outcomes as
well as cost containment in the care of the critically ill. These systems should
be used with clear guidelines to determine when CLRT is indicated, its
therapeutic benefit, and when to discontinue the therapy. Much research is needed
to validate efficacy of particular systems, cost-effectiveness, and necessary
frequency and degree of rotation to attain optimal clinical benefits.
PMID- 9390906
TI - Integrating education with diagnostics. Patient and technologist.
AB - Crape states that in relation to the results of spirometry in the Lung Health
Study that perhaps the most important message is that pulmonary function
technologists need continuous monitoring and feedback to maintain optimum
performance. Technologist education is an essential component of producing valid
test results.
PMID- 9390907
TI - Spirometry.
AB - Spirometry is the most widely used pulmonary function test. It is used for
diagnosis and monitoring in a wide variety of obstructive and restrictive disease
patterns. Spirometry is the primary measure in determining disability due to
pulmonary disease, and is widely applied in the evaluation of bronchodilator
response and airway hyperreactivity. A wide variety of spirometry equipment is
currently available, from small portable units to large laboratory systems
capable of multiple functions. Most spirometers rely heavily on computerization,
which makes them easy to use, but require training and experience on the part of
the user. Valid spirometry demands equipment that conforms to recommended
standards, and performance of the tests to meet criteria for acceptability and
reproducibility. Interpretation of spirometry requires attention to these
standards and to careful selection of reference values.
PMID- 9390908
TI - Derivation, application, and utility of static lung volume measurements.
AB - Measurement of static lung volumes remains an important tool to verify and
quantify the existence of pulmonary dysfunction. The utility of these
measurements, however, is dependent on the knowledge and skills of the
technologist, who must ensure that the equipment is operating in an acceptable
fashion as well as ensuring that the subject is performing the tests as directed.
The technologist as well as the physician interpreting the final results must be
cognizant of the limitations associated with each procedure employed in the
testing process and be able to verify if the derived data are compatible with the
patient's clinical presentation. Laboratories are encouraged to develop their own
quality-control programs and monitors to ensure testing is in accordance with
published recommendations. By standardizing the testing process, variability is
reduced. Ultimately, test quality and patient management will improve.
PMID- 9390909
TI - Diffusing capacity of the lung for carbon monoxide.
AB - The measurement of co uptake (VCO and DLCO) from alveolar gas is a unique way to
noninvasively assess pulmonary vascular function, specifically the functional
volume of the pulmonary capillary bed. Proper interpretation of results, however,
needs to account for inherent assumptions regarding co distribution and timing
procedures. Moreover, reasonable airway mechanics, lung volumes, and patient
cooperation are required for accurate measurements. Potential clinical utility
may be increased if measurements are made in different positions or under
exercise conditions.
PMID- 9390910
TI - Airway resistance measurements.
AB - Resistance measurements are the most useful parameters for assessing acute
changes in airway caliber associated with bronchodilation or bronchial
provocation. Used in addition to spirometry, Raw can provide a better
differentiation of the causes of airflow impairment as well as the presence of
concurrent processes. A simple, noninvasive Raw measurement can provide
definitive answers in the absence of other changes. Finally, the addition of
practical, nonplethysmographic measurements opens a new application for bedside,
office, and home monitoring.
PMID- 9390911
TI - Exercise testing.
PMID- 9390912
TI - Quality assurance.
AB - Every pulmonary function laboratory should develop and implement a quality
assurance program to minimize various technical sources of variation. This
article has discussed six major components. First, the education and training of
the technologists in the pulmonary function laboratory is probably the most
important factor in obtaining accurate and reproducible results. A college-level
education with an emphasis on math and science is recommended. After an
appropriate training program, continued evaluation and feedback are important.
Second, instrument maintenance should be performed on a scheduled basis to reduce
or prevent instrument malfunctions. Corrective maintenance, which is usually
unscheduled, should be performed by knowledgeable individuals and any repairs
should be documented. Third, a procedure manual is very important to any
successful quality assurance program. It should contain a broad range of
information including administrative issues, quality-control procedures, stepwise
instructions on test performance, and infection-control policies and procedures.
Fourth, the procedures should be performed using published guidelines to help
minimize the effects of the many variables. Fifth, a method to quality control
each test procedure should be developed. The specific method(s) will vary
according to the type of instrumentation and the manufacturer. Finally, the well
run quality assurance program must properly analyze and store the data collected.
Sound statistical methods should be applied and various logs and lists should be
developed.
PMID- 9390913
TI - Indirect calorimetry.
AB - Indirect calorimetry can be a useful tool to define nutritional status, determine
nutritional requirements, and assess response to nutritional interventions.
Measurements of oxygen consumption and carbon dioxide production may be used to
determine cardiac output and work of breathing, and estimate the components of
minute ventilation. An understanding of the potential technical and physiological
pitfalls is necessary to obtain meaningful and useful information.
PMID- 9390914
TI - Pulmonary function in the mechanically ventilated patient.
AB - Implementing the knowledge and skills obtained from the pulmonary function
laboratory is useful in the assessment of pulmonary function in the ventilated
patient. In the critically ill patient, special constraints and problems (such as
safety and ability to cooperate) are important considerations for the therapist
performing the testing. Basic measurements such as MIP, VC, VT, MVV, VE, and
respiratory rate are commonly made to assess weanability. For the difficult-to
wean patient, WOB, PTP, P0.1 and O2COB may be of potential value in selected
patients. Evidence of their value in routine weaning assessment, however, is
lacking. Monitoring has evolved with increased understanding of pulmonary
mechanics of the mechanically ventilated patient. Measurements of compliance,
resistance, MAP, and autoPEEP provide useful diagnostic and therapeutic
information, and guide in the selection of appropriate machine settings to
provide effective and safe ventilatory support. Although currently confined to
the research setting, P-V curves have contributed to our understanding of the
pathophysiology of ALI, and may prove useful in defining an optimal ventilatory
strategy in patients with ALI. Finally, waveform monitoring can reveal,
graphically and in real time, patient-ventilator interactions such as autoPEEP,
lung overdistension, patient effort, or the presence of secretions. Waveform
monitoring can bring important issues to the close attention of the practitioners
involved in management of the ventilated patient.
PMID- 9390915
TI - Neonatal pulmonary function testing.
AB - Recent advances in technology have made it possible for use to measure neonatal
pulmonary function, even in very small infants. Applying PM measurement as a tool
for ventilator-patient management improves outcome in the NICU. With PFT in the
laboratory, we can diagnose and determine severity of pulmonary illness and
evaluate therapies through infancy and childhood. Although the task of safely
measuring pulmonary function in infants can be daunting, there is no reason why
more PFT labs should not offer services to these patients.
PMID- 9390916
TI - The biologic basis for inhaled nitric oxide.
AB - Nitric oxide is produced by nitric oxide synthase enzymes, which cleave the amino
acid L-arginine to form nitric oxide and the amino acid L-citrulline. Many of the
biologic actions of nitric oxide occur because nitric oxide activates guanylate
cyclase, which in turn synthesizes a second-messenger molecule, cyclic guanosine
3',5'-monophosphate (cGMP). The increased concentration of cGMP activates cGMP
dependent protein kinase, reducing intracellular concentrations of calcium and
relaxing smooth muscle. Nitric oxide also has many important effects that may not
be mediated through increases of pulmonary cGMP activity. These include the
ability to scavenge oxygen free radicals, reduce oxygen toxicity, and inhibit
platelet and leukocyte aggregation. Nitric oxide is metabolized and excreted via
a number of diverse pathways that may modify the toxicity of the molecule.
PMID- 9390917
TI - Delivery systems for inhaled nitric oxide.
AB - From a practical standpoint, technical issues related to NO delivery are as
important as therapeutic issues. The benefits can be appreciated only if a
reliable delivery system is used. Further, hazards and toxicity may be more
problematic with an unreliable delivery system. It is incumbent on clinicians
using inhaled NO to ensure that the delivery system is safe and reliable.
PMID- 9390918
TI - Manufacture and measurement of nitrogen oxides.
AB - A decade of research has identified nitric oxide as a unique endogenous biologic
mediator with functions as diverse as vasodilation, macrophage cytotoxicity,
platelet adhesion, and memory formation. Measurement devices, previously used in
research on atmospheric nitrogen oxides, are being adapted for and applied to
clinical situations without approval, regulation, or rigorous testing, and with
little understanding of how the devices work or their limitations. This article
discusses the chemistry, manufacture, and measurement of nitrogen oxides.
PMID- 9390919
TI - Use of inhaled nitric oxide for ARDS.
AB - Inhalation of low inspired concentration of nitric oxide reduces pulmonary
hypertension and increases arterial oxygen tension in patients with acute
respiratory distress syndrome (ARDS), and appears to be safe. Research on the
physiologic mechanisms regulating the action of inhaled nitric oxide may provide
clinicians with ways to further potentiate and prolong its beneficial effects.
PMID- 9390920
TI - Inhaled nitric oxide in the management of cardiopulmonary disorders in infants
and children.
AB - The administration of NO has become an important and effective therapy in the
clinical management of pulmonary hypertension associated with cardiopulmonary
disorders in infants and children. It is likely to become a routine therapy in
the treatment of PPHN, although dosing and timing strategies, early indicators of
treatment failure, and long-term outcomes are not completely understood. The use
of NO has also been beneficial in the evaluation and management of pulmonary
hypertension associated with congenital heart disease. The role of NO in the
management of pediatric ARDS holds promise, although further clinical trials are
needed. Additional research should also be directed toward the use of NO in
preterm infants and those born with CDH. Future endeavors may also include the
use of NO in the evaluation and management of asthma.
PMID- 9390921
TI - A symposium on controversies in the pathology of transitional cell carcinomas of
the urinary bladder. Part I.
PMID- 9390922
TI - Flow cytometry phenotyping and molecular techniques in nongynecologic cytology.
PMID- 9390923
TI - Mammary lymphoid tissue: a unique component of the mucosal immune system.
PMID- 9390924
TI - Temporal artery biopsy diagnosis of giant cell arteritis: lessons from 1109
biopsies.
PMID- 9390925
TI - Large needle biopsy of the thyroid gland.
PMID- 9390926
TI - Cervical squamous cell carcinoma and its precursor lesions: cytodiagnostic
criteria and pitfalls.
PMID- 9390927
TI - "God's first cancer and man's first cure": milestones in gestational
trophoblastic disease.
PMID- 9390928
TI - Transitional cell carcinoma and other transitional cell tumors of the ovary.
PMID- 9390929
TI - An epidemiologic study of differences between mammary ductal and lobular
carcinoma in situ: analysis of 11,436 cases from the California Cancer Registry.
PMID- 9390930
TI - Multiple papillomas of the breast: morphologic findings and clinical evolution.
PMID- 9390931
TI - Latitudinal variation in the abundance and oxidative capacities of muscle
mitochondria in perciform fishes
AB - The abundance, distribution and oxidative capacities of mitochondria have been
investigated in the red pectoral fin adductor muscles of fish (Order Perciformes)
that use a predominantly labriform style of swimming. Mediterranean Sea species
from the families Labridae, Serranidae, Sparidae and Antarctic Nototheniidae and
non-Antarctic Nototheniidae and Channichthyidae were studied. Sub-Antarctic
species from the Beagle Channel, Tierra del Fuego, included the pelagic
haemoglobin-less icefish (Champsocephalus esox) and the robalo (Eleginops
maclovinus), which occurs as far north as 35 degrees S. In Champsocephalus esox,
the mitochondrial volume density of red muscle was 0.51 and mitochondrial cristae
surface density (43. 9 microm2 microm-3) was higher than reported for Antarctic
icefishes. In the red-blooded, active pelagic or semi-pelagic species,
mitochondrial volume density was within the range 0.27-0.33 regardless of habitat
temperature. Amongst less active demersal species, mitochondrial volume density
ranged from 0.29-0.33 in polar species to 0.08-0.13 in Mediterranean species. In
Antarctic species and Champsocephalus esox, myofibrils occurred in ribbons or
clusters one fibril thick entirely surrounded by mitochondria. The volume density
of intracellular lipid droplets was not correlated with activity patterns or
habitat temperature. In a comparison of Eleginops maclovinus caught in summer
(approximately 10 degrees C) and winter (approximately 4 degrees C),
mitochondrial volume density did not differ, whereas the surface density of
mitochondrial clusters was higher in summer fish. The temperature-dependence of
the state 3 respiration rate of isolated mitochondria with pyruvate as substrate
was described by a single quadratic relationship for all species, indicating no
significant up-regulation of the maximum rate of oxygen uptake per milligram
mitochondrial protein in Antarctic species. Our results support the conclusion
that increasing the volume and surface density of mitochondrial clusters is the
primary mechanism for enhancing the aerobic capacity of muscle in cold-water
fish.
PMID- 9390932
TI - Membrane potential responses of paramecium caudatum to bitter substances:
existence of multiple pathways for bitter responses
AB - The membrane potential responses of Paramecium caudatum to the external
application of bitter substances were examined by employing conventional
electrophysiological techniques. Mutant cells defective in voltage-gated Ca2+
channels were used to record the potential responses in the absence of
contamination by Ca2+ action potentials. The cells produced a transient
depolarization followed by a transient hyperpolarization in response to a rapid
whole-cell application of chloroquine, strychnine nitrate or brucine. Of these
chemicals, chloroquine was the most potent. Cells produced a simple
depolarization in response to a localized application of test chemicals to the
anterior region, whereas they produced a transient hyperpolarization in response
to an application to the posterior region. Membrane potential responses to an
application of chloroquine declined with repeated application. The presence of
chloroquine in the external bathing solution strongly inhibited the membrane
potential responses to an application of brucine or strychnine. However, the
presence of chloroquine did not affect the membrane potential responses to an
application of quinine. It is suggested that chloroquine, strychnine and brucine
share a common component of their transduction pathways, but that the
transduction pathway for quinine is different.
PMID- 9390933
TI - Alterations of ionic membrane permeabilities in multidrug-resistant neuroblastoma
x glioma hybrid cells.
AB - A population of NG108-15 neuroblastoma cells resistant to doxorubicin (NG/DOXR)
was established. The cells exhibited a multidrug resistance phenotype with cross
resistance to vinblastin and colchicine, overexpression of a 170 kDa membrane
protein identified as P-glycoprotein and reversal of resistance by verapamil and
quinine. Compared with NG108-15 cells, NG/DOXR cells showed an increase in Na+
current density and a decrease in cyclic-AMP-activated Cl- current density with
no change in K+- and volume-sensitive Cl- current densities. As previously
observed in NG108-15 cells, the vacuolar-type H+-ATPase inhibitors bafilomycin A1
and nitrate induced membrane depolarizations in NG/DOXR cells. The resting
potentials of sensitive and resistant cells were not significantly different, but
the depolarizations evoked by these agents were significantly larger in NG/DOXR
than in NG108-15 cells. The resting membrane potential of NG/DOXR cells, but not
that of NG108-15 cells, was depolarized by verapamil, and this effect was
abolished by bafilomycin. The volume-sensitive Cl- currents of drug-sensitive and
drug-resistant cells were inhibited by a decrease in intracellular pH from 7.3 to
6.8. Whereas bafilomycin prevents activation of Cl- currents in both drug
sensitive and drug-resistant cells, verapamil inhibited the Cl- current only in
NG/DOXR cells. The results are discussed in terms of the roles of cytoplasmic pH
and membrane potential in multidrug resistance.
PMID- 9390935
TI - Acid-base regulation, metabolism and energetics in sipunculus nudus as a function
of ambient carbon dioxide level
AB - Changes in the rates of oxygen consumption and ammonium excretion, in intra- and
extracellular acid-base status and in the rate of H+-equivalent ion transfer
between animals and ambient water were measured during environmental hypercapnia
in the peanut worm Sipunculus nudus. During exposure to 1 % CO2 in air,
intracellular and coelomic plasma PCO2 values rose to levels above those expected
from the increase in ambient CO2 tension. Simultaneously, coelomic plasma PO2 was
reduced below control values. The rise in PCO2 also induced a fall in intra- and
extracellular pH, but intracellular pH was rapidly and completely restored. This
was achieved during the early period of hypercapnia at the expense of a non
respiratory increase in the extracellular acidosis. The pH of the extracellular
space was only partially compensated (by 37 %) during long-term hypercapnia. The
net release of basic equivalents under control conditions turned to a net release
of protons to the ambient water before a net, albeit reduced, rate of base
release was re-established after a new steady state had been achieved with
respect to acid-base parameters. Hypercapnia also affected the mode and rate of
metabolism. It caused the rate of oxygen consumption to fall, whereas the rate of
ammonium excretion remained constant or even increased, reflecting a reduction of
the O/N ratio in both cases. The transient intracellular acidosis preceded a
depletion of the phosphagen phospho-l-arginine, an accumulation of free ADP and a
decrease in the level of Gibbs free energy change of ATP hydrolysis, before
replenishment of phosphagen and restoration of pHi and energy status occurred in
parallel. In conclusion, long-term hypercapnia in vivo causes metabolic
depression, a parallel shift in acid-base status and increased gas partial
pressure gradients, which are related to a reduction in ventilatory activity. The
steady-state rise in H+-equivalent ion transfer to the environment reflects an
increased rate of production of protons by metabolism. This observation and the
reduction of the O/N ratio suggest that a shift to protein/amino acid catabolism
has taken place. Metabolic depression prevails, with completely compensated
intracellular acidosis during long-term hypercapnia eliminating intracellular pH
as a significant factor in the regulation of metabolic rate in vivo. Fluctuating
levels of the phosphagen, of free ADP and in the ATP free energy change values
independent of pH are interpreted as being correlated with oscillating ATP
turnover rates during early hypercapnia and as reflecting a tight coupling of ATP
turnover and energy status via the level of free ADP.
PMID- 9390934
TI - Intergeneric distribution and immunolocalization of a putative odorant-binding
protein in true bugs (Hemiptera, Heteroptera).
AB - Lygus antennal protein (LAP) is an olfactory-related protein of the tarnished
plant bug Lygus lineolaris (Hemiptera, Heteroptera: Miridae), a hemimetabolous
insect. In previous work, a polyclonal antiserum was generated against the N
terminal sequence of LAP; LAP immunoreactivity was strongest in antennae of adult
males, but was also present in antennae of adult females and of nymphs. In the
current study, LAP immunoreactivity was examined to determine the species
specificity and the tissue and cellular localization of LAP expression. Western
blot analysis indicated that LAP immunoreactivity was present in the antennae of
the male congeners L. lineolaris and L. hesperous, but was not detectable in male
antennae of the more distant relatives Podisus maculiventris or Nezara viridula
(Hemiptera, Heteroptera: Pentatomidae). Western blot analysis further confirmed
that LAP expression was restricted to antennal tissue. Histological analyses
showed that LAP expression within the antennae was specifically associated with
chemosensory sensilla on the antenna. Within the sensilla, LAP immunoreactivity
was distributed throughout the extracellular lumen and was concentrated in dense
granules within the cytoplasm of sensillar support cells. LAP immunoreactivity
was restricted to a subset of antennal chemosensory sensilla, specifically the
multiporous olfactory sensilla. These findings suggest that LAP has an important
olfactory function in Lygus sp., possibly related to that of odorant-binding
proteins (OBP) found in other insect orders. If so, LAP would be the first OBP
like protein characterized outside the Endopterygota.
PMID- 9390936
TI - BCECF in single cultured cells: inhomogeneous distribution but homogeneous
response.
AB - Using confocal laser scanning microscopy with a dual-wavelength laser system, the
behaviour of BCECF [(2',7'-bis-2-carboxyethyl)-5-(and-6)carboxyfluorescein] was
investigated in a variety of cell lines. Selection of a small area for monitoring
allowed discrimination between various intracellular organelles, whose identity
was established by vital staining. It was found that, after loading the cells
with BCECF, both the nucleus and the mitochondria showed a higher level of
fluorescence than the cytoplasm. Calibration of the pH-sensitivity of these
fluorescence signals using the nigericin method yielded identical curves, as did
exposure of the cells to NH4Cl. These studies suggest that BCECF, despite its
inhomogeneous intracellular distribution, reports the pH of only one cellular
compartment, the cytosol.
PMID- 9390937
TI - Stresses in human leg muscles in running and jumping determined by force plate
analysis and from published magnetic resonance images.
AB - Calculation of the stresses exerted by human muscles requires knowledge of their
physiological cross-sectional area (PCSA). Magnetic resonance imaging (MRI) has
made it possible to measure PCSAs of leg muscles of healthy human subjects, which
are much larger than the PCSAs of cadaveric leg muscles that have been used in
previous studies. We have used published MRI data, together with our own force
plate records and films of running and jumping humans, to calculate stresses in
the major groups of leg muscles. Peak stresses in the triceps surae ranged from
100 kN m-2 during take off for standing high jumps to 150 kN m-2 during running
at 4 m s-1. In the quadriceps, peak stresses ranged from 190 kN m-2 during
standing long jumps to 280 kN m-2 during standing high jumps. Similar stresses
were calculated from published measurements of joint moments. These stresses are
lower than those previously calculated from cadaveric data, but are in the range
expected from physiological experiments on isolated muscles.
PMID- 9390938
TI - Effects of temperature on cuticular lipids and water balance in a desert
Drosophila: is thermal acclimation beneficial?
AB - The desert fruit fly Drosophila mojavensis experiences environmental conditions
of high temperature and low humidity. To understand the physiological mechanisms
allowing these small insects to survive in such stressful conditions, we studied
the effects of thermal acclimation on cuticular lipids and rates of water loss of
adult D. mojavensis. Mean hydrocarbon chain length increased at higher
temperatures, but cuticular lipid melting temperature (Tm) did not. Lipid
quantity doubled in the first 14 days of adult life, but was unaffected by
acclimation temperature. Despite these changes in cuticular properties,
organismal rates of water loss were unaffected by either acclimation temperature
or age. Owing to the smaller body size of warm-acclimated flies, D. mojavensis
reared for 14 days at 33 degrees C lost water more rapidly on a mass-specific
basis than flies acclimated to 25 degrees C or 17 degrees C. Thus, apparently
adaptive changes in cuticular lipids do not necessarily result in reduced rates
of water loss. Avoidance of high temperatures and desiccating conditions is more
likely to contribute to survival in nature than changes in water balance mediated
by surface lipids.
PMID- 9390940
TI - Peripheral encoding of moving sources by the lateral line system of a sit-and
wait predator
AB - Video-tape recordings of prey-capture behaviour were made to demonstrate that
stargazers can detect and capture prey in the dark and to determine the range of
prey movement velocities that resulted in prey capture. Electrophysiological
recording techniques were then used to determine how an artificial source (a
sphere), moving at speeds within the range of recorded prey movement velocities,
was encoded by anterior lateral line nerve fibres innervating the preopercular
mandibular canals on the head. A vibrating sphere was also used to measure
frequency-response characteristics to determine the bandwidth of response and
fibre origin (type of neuromast and location). In order to measure the relevant
stimulus parameters likely to govern neural responses, the pressure-gradient
pattern produced by the moving sphere was characterised with a pair of miniature
hydrophones separated by approximately the same distance as head lateral line
canal pores on stargazers. At least four different features of neural response
patterns, including direction-dependent changes in the overall envelope of the
firing rate pattern, could be predicted on the basis of measured pressure
gradient patterns. The dominant features of both the pressure-gradient and neural
response patterns were produced by the wake behind the moving sphere, but
behavioural observations indicated that stargazers were responding to the bow of
an approaching prey, rather than its wake. Although the form of the wake behind
the moving sphere is unlikely to be a good match for the stimulus mediating prey
detection, these results clearly establish that pressure-gradient patterns are
good predictors of neural response patterns. Thus, similar measurements of
pressure-gradient patterns produced by more biologically relevant sources can be
used to predict peripheral lateral line responses and stimulus features likely to
be of key importance.
PMID- 9390939
TI - Fatty acids from the cyanobacterium Microcystis aeruginosa with potent inhibitory
effects on fish gill Na+/K+-ATPase activity.
AB - Fatty acids from two strains of the cyanobacterium Microcystis aeruginosa, PCC
7820 (a strain that produces the hepatotoxin microcystin-LR, MC-LR) and CYA 43 (a
strain that produces only small quantities of MC-LR), were extracted, partially
characterised and tested for their inhibitory effect on the K+-dependent p
nitrophenol phosphatase (pNPPase) activity of tilapia (Oreochromis mossambicus)
gill basolateral membrane. Thin-layer chromatography of the lipids from
dichloromethane:methanol extracts of M. aeruginosa PCC 7820 and CYA 43, using
diethylether:isopropanol:formic acid (100:4.5:2.5) as solvent, yielded five
inhibitory products from M. aeruginosa 7820 and six from M. aeruginosa CYA 43.
None of these products could be related to MC-LR. The inhibitory behaviour of the
products mimics that of a slow, tight-binding inhibitor. The inhibitory activity
is removed by incubation of extracts with fatty-acid-free bovine serum albumin
(FAF-BSA). However, FAF-BSA only partially reversed the inhibition of K+
dependent pNPPase on fish gills pre-exposed to the extracted products. We
conclude that M. aeruginosa strains PCC 7820 and CYA 43 produce fatty acids with
potent inhibitory effects on K+-dependent pNPPase. The release of these products
following lysis of cyanobacterial blooms may help to explain fish kills through a
disturbance of gill functioning.
PMID- 9390941
TI - Predictions of the time course of force and power output by dogfish white muscle
fibres during brief tetani.
AB - The aim of this study was to identify the principal factors that determine the
time course of force and power output by muscle during patterns of stimulation
and movement similar to those during fish swimming. Fully activated, white muscle
fibres isolated from dogfish Scyliorhinus canicula were used to characterize the
force-velocity relationship of the contractile component (CC) and the stress
strain relationship of the passive, elastic component (SEC) in series with the
CC. A simple model of the time course of crossbridge activation during brief
contractions was devised. Using the mechanical properties of the CC and SEC and
the activation time course, force and power were predicted for brief contractions
with constant-velocity movement and also for brief contractions starting at
various times during sinusoidal movement. The predicted force and power were
compared with observations for these patterns of stimulation and movement. The
predictions matched the observations well for the period during stimulation.
Matching of force was much less good for some specific conditions during
relaxation, the period during which force persists after the end of stimulation.
If either the slow rise of activation or the SEC was omitted from the
calculation, the predictions were poor, even during stimulation. Additional
factors which may influence force are discussed. These include the after-effects
of shortening and stretch, the variation of force during constant-velocity
stretch and non-uniform behaviour within the muscle.
PMID- 9390943
TI - Faecal firing in a skipper caterpillar is pressure-driven
AB - Many leaf-rolling caterpillars have a rigid anal comb attached to the lower
surface of the anal plate (or shield) situated above the anus. This comb is
widely assumed to be a lever used to 'flick' away frass pellets. An alternative
mechanism to explain pellet discharge is proposed on the basis of observations on
the caterpillar of the skipper Calpodes ethlius. The model proposes that the
underside of the anal plate serves as a blood-pressure-driven surface for the
ejection of faecal pellets. Rather than acting as a lever, the anal comb serves
as a latch to prevent the premature distortion of the lower wall of the anal
plate until the anal haemocoel compartment is fully pressurized. The anal comb is
swung into position during pellet extrusion by retractor muscles attached at its
base and held in place by a catch formed by a blood-swollen torus of everted
rectal wall. As the caterpillar raises the blood pressure in its anal compartment
by contracting its anal prolegs, the comb eventually slips over the toral catch.
This causes the underside of the anal plate to move rapidly backwards as the
blood pressure is released, projecting the pellet resting against it through the
air. Simulation suggests that a local blood pressure of at least 10 kPa (75 mmHg)
would be required to accelerate the lower surface of the anal plate outwards at a
rate fast enough to discharge a 10 mg pellet at an observed mean velocity of 1.3
m s-1.
PMID- 9390942
TI - Metal ions suppress the abnormal taste behavior of the Drosophila mutant
malvolio.
AB - A mutation in the malvolio (mvl) gene affects taste behavior in Drosophila
melanogaster. The malvolio gene encodes a protein (MVL) that exhibits homology to
the mammalian natural resistance-associated macrophage proteins. It is also
homologous to the Smf1 protein from Saccharomyces cerevisiae, which we have
recently demonstrated to function as a Mn2+/Zn2+ transporter. We proposed that
the Drosophila and mammalian proteins, like the yeast SMF1 gene product, are
metal-ion transporters. To test this hypothesis, malvolio mutant flies were
allowed to develop, from egg to adulthood, on a medium containing elevated
concentrations of metal ions. Mutant flies that were reared in the presence of 10
mmol l-1 MnCl2 or FeCl2 developed into adults with recovered taste behavior.
CaCl2 or MgCl2 had no effect on the mutant's taste perception. ZnCl2 inhibited
the effect of MnCl2 when both ions were supplied together. Similar suppression of
the abnormal taste behavior was observed when mvl mutants were fed MnCl2 or FeCl2
only at the adult stage. Furthermore, exposure of adult mutant flies to these
ions in the testing plate for only 2 h was sufficient to restore normal taste
behavior. The suppression of the defective taste behavior suggests that MVL
functions as a Mn2+/Fe2+ transporter and that Mn2+ and/or Fe2+ are involved in
the signal transduction of taste perception in Drosophila adults.
PMID- 9390944
TI - Collagen orientation and molecular spacing during creep and stress-relaxation in
soft connective tissues.
AB - Collagen fibres form cross-helical, cross-ply or quasi-random feltworks in
extensible connective tissues; strain-induced reorientation of these networks
gives rise to the non-linear mechanical properties of connective tissue at finite
strains. Such tissues are also generally viscoelastic (i.e. display time
dependent properties). The hypothesis that time-dependent reorientation of
collagen fibres is responsible for the viscoelasticity of such tissues is
examined here using time-resolved X-ray diffraction measurements during stress
relaxation and creep transients applied to rat skin and bovine intramuscular
connective tissue. Differences in the intensity and angular orientation of the
third and fifth orders of the 67 nm meridional D-spacing of collagen molecules
were shown before and after the application of loads or displacements. However,
no changes in the D-spacing or angular orientation of collagen occurred during
the time course of either stress-relaxation or creep in both tissues. This
indicates that collagen fibre reorientation is not a primary source of their
viscoelastic properties. The non-linear (strain-dependent) nature of the stress
relaxation response in these tissues suggests that relaxation processes within
the collagen fibres or at the fibre-matrix interface may be responsible for their
viscoelastic nature.
PMID- 9390945
TI - Hearing and hunting in red bats (Lasiurus borealis, Vespertilionidae): audiogram
and ear properties.
AB - We examined aspects of hearing in the red bat (Lasiurus borealis) related to its
use of biosonar. Evoked potential audiograms, obtained from volume-conducted
auditory brainstem responses, were obtained in two bats, and the sound pressure
transformation of the pinna was measured in three specimens. Field-recorded
echolocation signals were analysed for comparison. The fundamental sonar search
calls sweep from 45 to 30 kHz (peak energy at 35 kHz), approach-phase calls sweep
from 65 to 35 kHz (peak 40 kHz) and terminal calls sweep from 70 to 30 kHz (peak
45 kHz). The most sensitive region of the audiogram extended from 10 kHz to 45-55
kHz, with maximum sensitivity as low as 20 dB SPL occurring between 25 and 30
kHz. A relative threshold minimum occurred between 40 and 50 kHz. With increasing
frequency, the acoustic axis of the pinna moves upwards and medially. The sound
pressure transformation was noteworthy near 40-45 kHz; the acoustic axis was
closest to the midline, the -3 dB acceptance angles showed local minima, and the
pinna gain and interaural intensity difference were maximal. These results are
related to the known echolocation and foraging behavior of this species and match
the spectral components of approach- and final-phase calls. We conclude that co
evolution with hearing prey has put a higher selective pressure on optimizing
localization and tracking of prey than on improving detection performance.
PMID- 9390946
TI - Representation of behaviorally relevant sound frequencies by auditory receptors
in the cricket teleogryllus oceanicus
AB - Teleogryllus oceanicus is particularly sensitive to two ranges of sound
frequency, one corresponding to intraspecific acoustical signals (4-5 kHz) and
the other to the echolocation cries of bats (25-50 kHz). We recorded summed
responses of the auditory nerve to stimuli in these two ranges. Nerve responses
consist of trains of compound action potentials (CAPs), each produced by the
summed activity of a number of receptor neurons. The amplitude of the CAP is up
to four times larger for stimuli at 4.5 kHz than for stimuli at 30 kHz,
suggesting either that the extracellular spikes produced by receptors that
respond to 4.5 kHz are larger than those that respond to 30 kHz, or that
receptors fire more synchronously in response to stimulation at 4.5 kHz, or that
more receptors respond to stimulation at 4.5 kHz. Neither unit spike amplitude
nor conduction velocity (which is expected to vary with spike amplitude) differs
for the two frequencies, and the responses to 4.5 kHz are not produced by more
tightly synchronized receptor populations, as judged by CAP breadth. We conclude
that more receptors respond to 4. 5 kHz than to 30 kHz.
PMID- 9390947
TI - Nitric oxide and vasodilation in human limbs.
AB - Both the skeletal muscle and skin of humans possess remarkable abilities to
vasodilate. Marked vasodilation can be seen in these vascular beds in response to
a variety of common physiological stimuli. These stimuli include reactive
hyperemia (skin and muscle), exercise hyperemia (muscle), mental stress (muscle),
and whole body heating (skin). The physiological mechanisms that cause
vasodilation in response to these stimuli are poorly understood, and the
substance(s) responsible for it remain unclear. In this context, recent attention
has been focused on the possible contribution of nitric oxide (NO) to the
regulation of hyperemic responses in human skin and skeletal muscle. The emerging
picture is that NO is not an essential component of the dilator response seen
during reactive hyperemia. However, it does appear that NO may play a modest role
in exercise hyperemia. NO appears to play a major role in the skeletal muscle
vasodilation seen in response to mental stress in humans. Preliminary evidence
also indicates that NO is not essential for the normal dilator responses observed
in the cutaneous circulation during body heating in humans, but this issue needs
further study. There are a number of possible mechanisms that might mediate NO
release in humans, and the role of these mechanisms in the various hyperemic
responses is also poorly understood. The role of altered NO-mediated vasodilation
in some disease states is also discussed. Whereas NO is a potent vasodilating
substance, the actions of NO alone do not explain a variety of poorly understood
vasodilator mechanisms in conscious humans. Much work remains for those
interested in the role of NO in the regulation of blood flow to the skin and
skeletal muscle of humans.
PMID- 9390948
TI - Invited editorial on "Coupled vs. uncoupled pericardial constraint: effects on
cardiac chamber interactions".
PMID- 9390949
TI - Coupled vs. uncoupled pericardial constraint: effects on cardiac chamber
interactions.
AB - The effects of pericardial constraint on cardiac chamber interactions were
evaluated by mathematical model analyses based on a novel concept of coupled vs.
uncoupled pericardial constraint. We hypothesized that the nature of pericardial
constraint can be classified as a "coupled" constraint exerted by uniform liquid
pressure or an "uncoupled" constraint exerted by regional surface pressure. The
numerical solution of the model of atrioventricular interaction produced the
characteristic waveforms in venous flows and right atrial/ventricular pressures
in classical pericardial diseases. Coupled constraint accounted for the patterns
in cardiac tamponade; uncoupled constraint accounted for those in constrictive
pericarditis. Analytic solution of the model of ventricular interdependence
demonstrated that coupled constraint (tamponade) produced greater gains in
ventricular interdependence, increasing the occurrence of pulsus paradoxus,
whereas uncoupled constraint (constriction) produced a greater effective right
ventricular elastance, increasing the likelihood of Kussmaul's sign. Thus the
concept of coupled vs. uncoupled constraint may offer a coherent framework to
understand the characteristic steady-state and respiratory-induced hemodynamic
events in multiple forms of pericardial diseases.
PMID- 9390950
TI - On the mechanism of mucosal folding in normal and asthmatic airways.
AB - Previous studies have demonstrated that the airway wall in asthma and chronic
obstructive pulmonary disease is markedly thickened. It has also been observed
that when the smooth muscle constricts the mucosa buckles, forming folds that
penetrate into the airway lumen. This folding pattern may influence the amount of
luminal obstruction associated with smooth muscle activation. A finite-element
analysis of a two-layer composite model for an airway is used to investigate the
factors that determine the mucosal folding pattern and how it is altered as a
result of changes in the thickness or stiffness of the different layers that
comprise the airway wall. Results demonstrate that the most critical physical
characteristic is the thickness of the thin inner layer of the model. Thickening
of this inner layer likely is represented by the enhanced subepithelial collagen
deposition seen in asthma. Other findings show a high shear stress at or near the
epithelial layer, which may explain the pronounced epithelial sloughing that
occurs in asthma, and steep gradients in pressure that could cause significant
shifts of liquid between wall compartments or between the wall and luminal or
vascular spaces.
PMID- 9390951
TI - Hormonal and metabolic responses to exercise across time of day and menstrual
cycle phase.
AB - Two studies, each utilizing short-term treadmill exercise of a different
intensity, assessed the metabolic and hormonal responses of women to exercise in
the morning (AM) and late afternoon (PM). In study 1, plasma concentrations of
growth hormone, arginine vasopressin, catecholamines, adrenocorticotropic
hormone, cortisol, lactate, and glucose were measured before, during, and after
high-intensity exercise (90% maximal O2 uptake) in the AM and PM. In study 2,
plasma concentrations of adrenocorticotropic hormone, cortisol, lactate, and
glucose were measured before, during, and after moderate-intensity exercise (70%
maximal O2 uptake) in the AM and PM in the follicular (days 3-9), midcycle (days
10-16), and luteal (days 18-26) phases of the menstrual cycle. The results of
studies 1 and 2 revealed no significant diurnal differences in the magnitude of
responses for any measured variable. In addition, study 2 revealed a significant
time-by-phase interaction for glucose (P = 0. 014). However, net integrated
responses were similar across cycle phases. These data suggest that metabolic and
hormonal responses to short-term, high-intensity exercise can be assessed with
equal reliability in the AM and PM and that there are subtle differences in blood
glucose responses to moderate-intensity exercise across menstrual cycle phase.
PMID- 9390952
TI - Myocardial blood flow heterogeneity in shock and small-volume resuscitation in
pigs with coronary stenosis.
AB - Myocardial blood flow heterogeneity in shock and small-volume resuscitation in
pigs with coronary stenosis. J. Appl. Physiol. 83(6): 1832-1841, 1997.-We
analyzed the effects of shock and small-volume resuscitation in the presence of
coronary stenosis on fractal dimension (D) and spatial correlation (SC) of
regional myocardial perfusion. Hemorrhagic shock was induced and maintained for 1
h. Pigs were resuscitated with hypertonic saline-dextran 60 [HSDex, 10% of shed
blood volume (SBV)] or normal saline (NS; 80% of SBV). Therapy was continued
after 30 min with dextran (10% SBV). At baseline, D was 1.39 +/- 0.06 (mean +/-
SE; HSDex group) and 1.34 +/- 0.04 (NS group). SC was 0.26 +/- 0.07 (HSDex) and
0.26 +/- 0.04 (NS). Left anterior descending coronary artery stenosis changed
neither D nor SC. Shock significantly reduced D (i.e., homogenized perfusion):
1.26 +/- 0.06 (HSDex) and 1.23 +/- 0.05 (NS). SC was increased: 0.41 +/- 0.1
(HSDex) and 0.48 +/- 0.07 (NS). Fluid therapy with HSDex further decreased D to
1.22 +/- 0.05, whereas NS did not change D. SC was increased by both HSDex (0.56
+/- 0.1) and NS (0.53 +/- 0.06). At 1 h after resuscitation, SC was constant in
both groups, and D was reduced only in the NS group (1.18 +/- 0.02). We conclude
that hemorrhagic shock homogenized regional myocardial perfusion in coronary
stenosis and that fluid therapy failed to restore this.
PMID- 9390953
TI - Redox behavior of cytochrome oxidase in the rat brain measured by near-infrared
spectroscopy.
AB - Using near-infrared spectroscopy, we developed a new approach for measuring the
redox state of cytochrome oxidase in the brain under normal blood-circulation
conditions. Our algorithm does not require the absorption coefficient of
cytochrome oxidase, which differs from study to study. We employed this method
for evaluation of effects of changes in oxygen delivery on cerebral oxygenation
in rats. When fractional inspired oxygen was decreased in a stepwise manner from
100 to <10%, at which point the concentration of oxygenated hemoglobin ([HbO2])
decreased by approximately 60%, cytochrome oxidase started to be reduced.
Increases in arterial PO2 under hyperoxic conditions caused an increase in
[HbO2], whereas further oxidation of cytochrome oxidase was not observed. The
dissociation of the responses of hemogloblin and cytochrome oxidase was also
clearly observed after the injection of epinephrine under severely hypoxic
conditions; that is, cytochrome oxidase was reoxidized with increasing blood
pressure, whereas hemoglobin oxygenation was not changed. These data indicated
that oxygen-dependent redox changes in cytochrome oxidase occur only when oxygen
delivery is extremely impaired. This is consistent with the in vitro data of our
previous study.
PMID- 9390954
TI - Effects of surfactant proteins SP-B and SP-C on dynamic and static mechanics of
immature lungs.
AB - To investigate the effects of surfactant proteins B (SP-B) and C (SP-C) on lung
mechanics, we compared tidal and static lung volumes of immature rabbits
anesthetized with pentobarbital sodium and given reconstituted test surfactants
(RTS). With a series of RTS having various SP-B concentrations (0-0.7%) but a
fixed SP-C concentration (1.4%), both the tidal volume with 25-cmH2O insufflation
pressure and the static volume deflated to 5-cmH2O airway pressure increased,
significantly correlating with the SP-B concentration: the former increased from
6.5 to 26.0 ml/kg (mean), and the latter increased from 6.4 to 31.8 ml/kg. With
another series of RTS having a fixed SP-B concentration (0.7%) but various SP-C
concentrations (0-1.4%), the tidal volume increased from 5.1 to 24.8 ml/kg,
significantly correlating with the SP-C concentration, whereas the static volume
increased from 3.4 to 32.0 ml/kg, the ceiling value, in the presence of a minimal
concentration of SP-C (0. 18%). In conclusion, certain doses of SP-B and SP-C
were indispensable for optimizing dynamic lung mechanics; the static mechanics,
however, required significantly less SP-C.
PMID- 9390955
TI - Growth hormone/IGF-I and/or resistive exercise maintains myonuclear number in
hindlimb unweighted muscles.
AB - In the present study of rats, we examined the role, during 2 wk of hindlimb
suspension, of growth hormone/insulin-like growth factor I (GH/IGF-I)
administration and/or brief bouts of resistance exercise in ameliorating the loss
of myonuclei in fibers of the soleus muscle that express type I myosin heavy
chain. Hindlimb suspension resulted in a significant decrease in mean soleus wet
weight that was attenuated either by exercise alone or by exercise plus GH/IGF-I
treatment but was not attenuated by hormonal treatment alone. Both mean
myonuclear number and mean fiber cross-sectional area (CSA) of fibers expressing
type I myosin heavy chain decreased after 2 wk of suspension compared with
control (134 vs. 162 myonuclei/mm and 917 vs. 2,076 micron2, respectively).
Neither GH/IGF-I treatment nor exercise alone affected myonuclear number or fiber
CSA, but the combination of exercise and growth-factor treatment attenuated the
decrease in both variables. A significant correlation was found between mean
myonuclear number and mean CSA across all groups. Thus GH/IGF-I administration
and brief bouts of muscle loading had an interactive effect in attenuating the
loss of myonuclei induced by chronic unloading.
PMID- 9390956
TI - Atrial distension in humans during microgravity induced by parabolic flights.
AB - The hypothesis was tested that human cardiac filling pressures increase and the
left atrium is distended during 20-s periods of microgravity (microG) created by
parabolic flights, compared with values of the 1-G supine position. Left atrial
diameter (n = 8, echocardiography) increased significantly during microG from
26.8 +/- 1.2 to 30.4 +/- 0.7 mm (P < 0.05). Simultaneously, central venous
pressure (CVP; n = 6, transducer-tipped catheter) decreased from 5.8 +/- 1.5 to
4.5 +/- 1.1 mmHg (P < 0.05), and esophageal pressure (EP; n = 6) decreased from
1.5 +/- 1.6 to -4.1 +/- 1.7 mmHg (P < 0.05). Thus transmural CVP (TCVP = CVP -
EP; n = 4) increased during microG from 6.1 +/- 3. 2 to 10.4 +/- 2.7 mmHg (P <
0.05). It is concluded that short periods of microG during parabolic flights
induce an increase in TCVP and left atrial diameter in humans, compared with the
results obtained in the 1-G horizontal supine position, despite a decrease in
CVP.
PMID- 9390957
TI - Regional intramuscular pressure development and fatigue in the canine
gastrocnemius muscle in situ.
AB - Intramuscular pressure (PIM) was measured simultaneously in zones of the medial
head of the gastrocnemius-plantaris muscle group (zone I, popliteal origin; zone
II, central; zone III, near calcaneus tendon) to determine regional muscle
mechanics during isometric tetanic contractions. Peak PIM averages were 586,
1,676, and 993 mmHg deep in zones I, II, and III and 170, 371, and 351 mmHg
superficially in zones I, II, and III, respectively. During fatigue, loss of PIM
across zones was greatest in zone III (-81%) and least in zone I (-60%) when
whole muscle tension loss was -49%. Recovery of PIM was greatest in zone III and
least in zone II, achieving 86% and 67% of initial PIM, respectively, when
tension recovered to 89%. These data demonstrate that 1) regional mechanical
performance can be measured as PIM within a whole muscle, 2) PIM is nonuniform
within the canine gastrocnemius-plantaris muscle, being greatest in the deep
central zone, and 3) fatigue and recovery of PIM are dissimilar across regions.
These differences suggest distinct local effects that integrate to determine
whole muscle mechanical capacity during and after intense exercise.
PMID- 9390958
TI - Postexercise protein-carbohydrate and carbohydrate supplements increase muscle
glycogen in men and women.
AB - We have previously demonstrated that women did not increase intramuscular
glycogen in response to an increased percent of dietary carbohydrate (CHO) (from
60 to 75% of energy intake) (M. A. Tarnopolsky, S. A. Atkinson, S. M. Phillips,
and J. D. MacDougall. J. Appl. Physiol. 78: 1360-1368, 1995). CHO and CHO-protein
(Pro) supplementation postexercise can potentiate glycogen resynthesis compared
with placebo (K. M. Zawadzki, B. B. Yaspelkis, and J. L. Ivy. J. Appl. Physiol.
72: 1854-1859, 1992). We studied the effect of isoenergetic CHO and CHO-Pro-Fat
supplements on muscle glycogen resynthesis in the first 4 h after endurance
exercise (90 min at 65% peak O2 consumption) in trained endurance athletes (men,
n = 8; women, tested in midfollicular phase, n = 8). Each subject completed three
sequential trials separated by 3 wk; a supplement was provided immediately and 1
h postexercise: 1) CHO (0.75 g/kg) + Pro (0.1 g/kg) + Fat (0.02 g/kg), 2) CHO (1
g/kg), and 3) placebo (Pl; artificial sweetener). Subjects were given
prepackaged, isoenergetic, isonitrogenous diets, individualized to their habitual
diet, for the day before and during the exercise trial. During exercise, women
oxidized more lipid than did men (P < 0.05). Both of the supplement trials
resulted in greater postexercise glucose and insulin compared with Pl (P < 0.01),
with no gender differences. Similarly, both of these trials resulted in increased
glycogen resynthesis (37.2 vs. 24. 6 mmol . kg dry muscle-1 . h-1, CHO vs. CHO
Pro-Fat, respectively) compared with Pl (7.5 mmol . kg dry muscle-1 . h-1; P <
0.001) with no gender differences. We conclude that postexercise CHO and CHO-Pro
Fat nutritional supplements can increase glycogen resynthesis to a greater extent
than Pl for both men and women.
PMID- 9390959
TI - Hyperventilation-induced airway injury and vascular leakage in dogs: effects of
alpha1-adrenergic agonists.
AB - alpha1-Adrenergic agonists inhibit hyperventilation-induced bronchoconstriction
(HIB) in dogs. We tested the hypothesis that alpha-agonists inhibit HIB by
reducing bronchovascular leakage and edema that theoretically could cause airway
obstruction. Peripheral airways were isolated by using a bronchoscope; pretreated
with either methoxamine (Mx), norepinephrine (NE), or saline aerosol; and then
exposed to a 2,000 ml/min dry-air challenge (DAC) for 2 min. Colloidal carbon was
injected before DAC and used to quantify bronchovascular permeability. Mx-, NE-,
and vehicle-treated airways were prepared for morphometric analysis within 1 h
after DAC. Light microscopy revealed that the 2-min DAC produced minimal
bronchovascular leakage and little epithelial damage. However, pretreatment with
either Mx or NE significantly enhanced dry air-induced bronchovascular
hyperpermeability and mucosal injury. The increased damage associated with these
alpha1-agonists implicates a protective role for the bronchial circulation. The
fact that alpha1-agonists inhibit HIB suggests that neither dry air-induced
leakage nor injury directly contributes to the development of airway obstruction.
In addition, our data suggest that alpha-agonists attenuate HIB in part by
augmenting hyperventilation-induced bronchovascular leakage and by replacing
airway water lost during a DAC.
PMID- 9390960
TI - Intensity and frequency dependence of laryngeal afferent inputs to respiratory
hypoglossal motoneurons.
AB - Inspiratory hypoglossal motoneurons (IHMs) mediate contraction of the
genioglossus muscle and contribute to the regulation of upper airway patency.
Intracellular recordings were obtained from antidromically identified IHMs in
anesthetized, vagotomized cats, and IHM responses to electrical activation of
superior laryngeal nerve (SLN) afferent fibers at various frequencies and
intensities were examined. SLN stimulus frequencies <2 Hz evoked an excitatory
inhibitory postsynaptic potential (EPSP-IPSP) sequence or only an IPSP in most
IHMs that did not change in amplitude as the stimulus was maintained. During
sustained stimulus frequencies of 5-10 Hz, there was a reduction in the amplitude
of SLN-evoked IPSPs with time with variable changes in the EPSP. At stimulus
frequencies >25 Hz, the amplitude of EPSPs and IPSPs was reduced over time. At a
given stimulus frequency, increasing stimulus intensity enhanced the decay of the
SLN-evoked postsynaptic potentials (PSPs). Frequency-dependent attenuation of SLN
inputs to IHMs also occurred in newborn kittens. These results suggest that
activation of SLN afferents evokes different PSP responses in IHMs depending on
the stimulus frequency. At intermediate frequencies, inhibitory inputs are
selectively filtered so that excitatory inputs predominate. At higher frequencies
there was no discernible SLN-evoked PSP temporally locked to the SLN stimuli.
Alterations in SLN-evoked PSPs could play a role in the coordination of
genioglossal contraction during respiration, swallowing, and other complex motor
acts where laryngeal afferents are activated.
PMID- 9390961
TI - Cardiovascular adaptations to 10 days of cycle exercise.
AB - We hypothesized that 10 days of training would enhance cardiac output (CO) and
stroke volume (SV) during peak exercise and increase the inotropic response to
beta-adrenergic stimulation. Ten subjects [age 26 +/- 2 (SE) yr] trained on a
cycle ergometer for 10 days. At peak exercise, training increased O2 uptake, CO,
and SV (P < 0.001). Left ventricular (LV) size and function at rest were assessed
with two-dimensional echocardiography before (baseline) and after atropine
injection (1.0 mg) and during four graded doses of dobutamine. LV end-diastolic
diameter increased with training (P < 0.02), whereas LV wall thickness was
unchanged. LV contractile performance was assessed by relating fractional
shortening (FS) to the estimated end-systolic wall stress (sigmaES). Training
increased the slope of the FS-sigmaES relationship (P < 0.05), indicating
enhanced systolic function. The increase in slope correlated with increases in CO
(r = -0.71, P < 0.05) and SV (r = -0.70, P < 0.05). The increase in blood volume
also correlated with increases in CO (r = 0.80, P < 0.01) and SV (r = 0.85, P <
0.004). These data show that 10 days of training enhance the inotropic response
to beta-adrenergic stimulation, associated with increases in CO and SV during
peak exercise.
PMID- 9390962
TI - Ventilation distribution during histamine provocation.
AB - We investigated ventilation inhomogeneity during provocation with inhaled
histamine in 20 asymptomatic nonsmoking subjects. We used N2 multiple-breath
washout (MBW) to derive parameters Scond and Sacin as a measurement of
ventilation inhomogeneity in conductive and acinar zones of the lungs,
respectively. A 20% decrease of forced expiratory volume in 1 s (FEV1) was used
to distinguish responders from nonresponders. In the responder group, average
FEV1 decreased by 26%, whereas Scond increased by 390% with no significant change
in Sacin. In the nonresponder group, FEV1 decreased by 11%, whereas Scond
increased by 198% with no significant Sacin change. Despite the absence of change
in Sacin during provocation, baseline Sacin was significantly larger in the
responder vs. the nonresponder group. The main findings of our study are that
during provocation large ventilation inhomogeneities occur, that the small
airways affected by the provocation process are situated proximal to the acinar
zone where the diffusion front stands, and that, in addition to overall decrease
in airway caliber, there is inhomogeneous narrowing of parallel airways.
PMID- 9390963
TI - Endurance training attenuates the decrease in skeletal muscle malonyl-CoA with
exercise.
AB - Muscle malonyl-CoA has been postulated to regulate fatty acid metabolism by
inhibiting carnitine palmitoyltransferase 1. In nontrained rats, malonyl-CoA
decreases in working muscle during exercise. Endurance training is known to
increase a muscle's reliance on fatty acids as a substrate. This study was
designed to investigate whether the decline in malonyl-CoA with exercise would be
greater in trained than in nontrained muscle, thereby allowing increased fatty
acid oxidation. After 6-10 wk of endurance training (2 h/day) or treadmill
habituation (5-10 min/day), rats were killed at rest or after running up a 15%
grade at 21 m/min for 5, 20, or 60 min. Training attenuated the exercise-induced
drop in malonyl-CoA and prevented the exercise-induced increase in the constant
for citrate activation of acetyl-CoA carboxylase in the red quadriceps muscle of
rats run for 20 and 60 min. Hence, contrary to expectations, the decrease in
malonyl-CoA was less in trained than in nontrained muscle during a single bout of
prolonged submaximal exercise.
PMID- 9390964
TI - Neural-mechanical coupling of breathing in REM sleep.
AB - During rapid-eye-movement (REM) sleep the ventilatory response to airway
occlusion is reduced. Possible mechanisms are reduced chemosensitivity,
mechanical impairment of the chest wall secondary to the atonia of REM sleep, or
phasic REM events that interrupt or fractionate ongoing diaphragm electromyogram
(EMG) activity. To differentiate between these possibilities, we studied three
chronically instrumented dogs before, during, and after 15-20 s of airway
occlusion during non-REM (NREM) and phasic REM sleep. We found that 1) for a
given inspiratory time the integrated diaphragm EMG (Di) was similar or reduced
in REM sleep relative to NREM sleep; 2) for a given Di in response to airway
occlusion and the hyperpnea following occlusion, the mechanical output (flow or
pressure) was similar or reduced during REM sleep relative to NREM sleep; 3) for
comparable durations of airway occlusion the Di and integrated inspiratory
tracheal pressure tended to be smaller and more variable in REM than in NREM
sleep, and 4) significant fractionations (caused visible changes in tracheal
pressure) of the diaphragm EMG during airway occlusion in REM sleep occurred in
approximately 40% of breathing efforts. Thus reduced and/or erratic mechanical
output during and after airway occlusion in REM sleep in terms of flow rate,
tidal volume, and/or pressure generation is attributable largely to reduced
neural activity of the diaphragm, which in turn is likely attributable to REM
effects, causing reduced chemosensitivity at the level of the peripheral
chemoreceptors or, more likely, at the central integrator. Chest wall distortion
secondary to the atonia of REM sleep may contribute to the reduced mechanical
output following airway occlusion when ventilatory drive is highest.
PMID- 9390965
TI - Prostaglandin production contributes to exercise-induced vasodilation in heart
failure.
AB - Endothelial release of prostaglandins may contribute to exercise-induced skeletal
muscle arteriolar vasodilation in patients with heart failure. To test this
hypothesis, we examined the effect of indomethacin on leg circulation and
metabolism in eight chronic heart failure patients, aged 55 +/- 4 yr. Central
hemodynamics and leg blood flow, determined by thermodilution, and leg metabolic
parameters were measured during maximum treadmill exercise before and 2 h after
oral administration of indomethacin (75 mg). Leg release of 6-ketoprostaglandin
F1alpha was also measured. During control exercise, leg blood flow increased from
0.34 +/- 0.03 to 1. 99 +/- 0.19 l/min (P < 0.001), leg O2 consumption from 13.6
+/- 1.8 to 164.5 +/- 16.2 ml/min (P < 0.001), and leg prostanoid release from
54.1 +/- 8.5 to 267.4 +/- 35.8 pg/min (P < 0.001). Indomethacin suppressed
release of prostaglandin F1alpha (P < 0.001) throughout exercise and decreased
leg blood flow during exercise (P < 0.05). This was associated with a
corresponding decrease in leg O2 consumption (P < 0.05) and a higher level of
femoral venous lactate at peak exercise (P < 0.01). These data suggest that
release of vasodilatory prostaglandins contributes to skeletal muscle arteriolar
vasodilation in patients with heart failure.
PMID- 9390966
TI - Nitric oxide and endothelial permeability.
AB - Nitric oxide synthase inhibition reverses systemic vasodilation during sepsis but
may increase endothelial permeability. To assess adverse effects on the pulmonary
vasculature, 12 sheep were chronically instrumented with lung lymph fistulas and
hydraulic pulmonary venous occluders. Escherichia coli endotoxin
(lipopolysaccharide; 10 ng . kg-1 . min-1) was continuously infused for 32 h.
After 24 h, six animals received 25 mg/kg of Nomega-nitro-L-arginine methyl ester
(L-NAME), and six received saline. All sheep developed a hyperdynamic circulatory
response and elevated lymph flows by 24 h of lipopolysaccharide infusion. L-NAME
reversed systemic vasodilation, increased pre- and postcapillary pulmonary
vascular resistance index, pulmonary arterial pressure, and, transiently,
effective pulmonary capillary pressure. Lung lymph flows were not different
between groups at 24 h or thereafter. Calculated as changes from baseline,
however, lung lymph flow was higher in the L-NAME group than in the control
animals, with a trend toward lower lymph-to-plasma protein concentration ratio at
25 h. Permeability analysis at 32 h by the venous occlusion technique showed
normal reflection coefficients and elevated filtration coefficients without
differences between groups. Reversal by L-NAME of the systemic vasodilation
during endotoxemia was associated with high pulmonary vascular resistance without
evidence of impaired pulmonary endothelial barrier function.
PMID- 9390967
TI - Greater rate of decline in maximal aerobic capacity with age in physically active
vs. sedentary healthy women.
AB - Using a meta-analytic approach, we recently reported that the rate of decline in
maximal oxygen uptake (VO2 max) with age in healthy women is greatest in the most
physically active and smallest in the least active when expressed in milliliters
per kilogram per minute per decade. We tested this hypothesis prospectively under
well-controlled laboratory conditions by studying 156 healthy, nonobese women
(age 20-75 yr): 84 endurance-trained runners (ET) and 72 sedentary subjects (S).
ET were matched across the age range for age-adjusted 10-km running performance.
Body mass was positively related with age in S but not in ET. Fat-free mass was
not different with age in ET or S. Maximal respiratory exchange ratio and rating
of perceived exertion were similar across age in ET and S, suggesting equivalent
voluntary maximal efforts. There was a significant but modest decline in running
mileage, frequency, and speed with advancing age in ET. VO2 max (ml . kg-1 . min
1) was inversely related to age (P < 0.001) in ET (r = -0.82) and S (r = -0.71)
and was higher at any age in ET. Consistent with our meta-analysic findings, the
absolute rate of decline in VO2 max was greater in ET (-5.7 ml . kg-1 . min-1 .
decade-1) compared with S (-3.2 ml . kg-1 . min-1 . decade-1; P < 0. 01), but the
relative (%) rate of decline was similar (-9.7 vs -9. 1%/decade; not
significant). The greater absolute rate of decline in VO2 max in ET compared with
S was not associated with a greater rate of decline in maximal heart rate (-5.6
vs. -6.2 beats . min-1 . decade-1), nor was it related to training factors. The
present cross-sectional findings provide additional evidence that the absolute,
but not the relative, rate of decline in maximal aerobic capacity with age may be
greater in highly physically active women compared with their sedentary healthy
peers. This difference does not appear to be related to age-associated changes in
maximal heart rate, body composition, or training factors.
PMID- 9390968
TI - Cardiopulmonary control in sleeping Sprague-Dawley rats treated with hydralazine.
AB - To test the hypothesis that hydralazine can suppress spontaneous sleep-related
central apnea, respiratory pattern, blood pressure, and heart period were
monitored in Sprague-Dawley rats. In random order and on separate days, rats were
recorded after intraperitoneal injection of 1) saline or 2) 2 mg/kg hydralazine.
Normalized minute ventilation (NVI) declined significantly with transitions from
wake to non-rapid-eye-movement (NREM) sleep (-5.1%; P = 0.01) and rapid-eye
movement (REM) sleep (-4.2%; P = 0.022). Hydralazine stimulated respiration (NVI
increased by 21%; P < 0.03) and eliminated the effect of state on NVI. Blood
pressure decreased by 17% after hydralazine, and the correlation between
fluctuations in mean blood pressure and NVI changed from strongly positive during
control recordings to weakly negative after hydralazine (P < 0.0001 for each).
Postsigh and spontaneous apneas were reduced during NREM and REM sleep after
hydralazine (P < 0.05 for each). This suppression was strongly correlated with
the reduction in blood pressure and with the degree of respiratory stimulation.
We conclude that mild hydralazine-induced hypotension leads to respiratory
stimulation and apnea suppression.
PMID- 9390969
TI - Isoproterenol attenuates high vascular pressure-induced permeability increases in
isolated rat lungs.
AB - To separate the contributions of cellular and basement membrane components of the
alveolar capillary barrier to the increased microvascular permeability induced by
high pulmonary venous pressures (Ppv), we subjected isolated rat lungs to
increases in Ppv, which increased capillary filtration coefficient (Kfc) without
significant hemorrhage (31 cmH2O) and with obvious extravasation of red blood
cells (43 cmH2O). Isoproterenol (20 microM) was infused in one group (Iso) to
identify a reversible cellular component of injury, and residual blood volumes
were measured to assess extravasation of red blood cells through ruptured
basement membranes. In untreated lungs (High Ppv group), Kfc increased 6.2 +/-
1.3 and 38.3 +/- 15.2 times baseline during the 31 and 43 cmH2O Ppv states. In
Iso lungs, Kfc was 36.2% (P < 0.05) and 64.3% of that in the High Ppv group at
these Ppv states. Residual blood volumes calculated from tissue hemoglobin
contents were significantly increased by 53-66% in the high Ppv groups, compared
with low vascular pressure controls, but there was no significant difference
between High Ppv and Iso groups. Thus isoproterenol significantly attenuated
vascular pressure-induced Kfc increases at moderate Ppv, possibly because of an
endothelial effect, but it did not affect red cell extravasation at higher
vascular pressures.
PMID- 9390970
TI - Intratracheal instillation of a novel NO/nucleophile adduct selectively reduces
pulmonary hypertension.
AB - We examined the pulmonary and systemic hemodynamic effects of administering
soluble nitric oxide (NO) donor compounds (NO/nucleophile adducts, i.e.,
NONOates) directly into the trachea of animals with experimentally induced
pulmonary hypertension. Steady-state pulmonary hypertension was created by using
the thromboxane agonist U-46619. Yorkshire pigs were randomly assigned to one of
four groups: group 1, intratracheal saline (control; n = 8); group 2,
intratracheal sodium nitroprusside (n = 6); group 3, intratracheal
ethylputreanine NONOate (n = 6); and group 4, intratracheal 2-(dimethylamino)
ethylputreanine NONOate (DMAEP/NO; n = 6). Pulmonary and systemic hemodynamics
were monitored after drug instillation. Group 4 had significant reductions in
pulmonary vascular resistance index (PVRI) at all time points compared with
steady state and compared with group 1 (P < 0.05), whereas systemic vascular
resistance index did not change. The mean change in mean pulmonary arterial
pressure in group 4 was -33.1 +/- 1.2% compared with +6.4 +/- 1.3% in group 1 (P
< 0.001), and the mean change in mean arterial pressure was -9.3 +/- 0.7%
compared with a control value of -0.9 +/- 0.5% (P < 0.05). Groups 2 and 3 had
significant decreases in both PVRI and systemic vascular resistance index
compared with steady state and with group 1. In conclusion, intratracheal
instillation of a polar-charged tertiary amine NONOate DMAEP/NO results in the
selective reduction of PVRI. Intermittent intratracheal instillation of selective
NONOates may be an alternative to continuously inhaled NO in the treatment of
pulmonary hypertension.
PMID- 9390971
TI - Optical measurement of isolated canine lung filtration coefficients at normal
hematocrits.
AB - In this study, lung filtration coefficient (Kfc) values were measured in eight
isolated canine lung preparations at normal hematocrit values using three
methods: gravimetric, blood-corrected gravimetric, and optical. The lungs were
kept in zone 3 conditions and subjected to an average venous pressure increase of
10.24 +/- 0.27 (SE) cmH2O. The resulting Kfc (ml . min-1 . cmH2O-1 . 100 g dry
lung wt-1) measured with the gravimetric technique was 0.420 +/- 0.017, which was
statistically different from the Kfc measured by the blood-corrected gravimetric
method (0.273 +/- 0.018) or the product of the reflection coefficient (sigmaf)
and Kfc measured optically (0. 272 +/- 0.018). The optical method involved the
use of a Cellco filter cartridge to separate red blood cells from plasma, which
allowed measurement of the concentration of the tracer in plasma at normal
hematocrits (34 +/- 1.5). The permeability-surface area product was measured
using radioactive multiple indicator-dilution methods before, during, and after
venous pressure elevations. Results showed that the surface area of the lung did
not change significantly during the measurement of Kfc. These studies suggest
that sigmafKfc can be measured optically at normal hematocrits, that this
measurement is not influenced by blood volume changes that occur during the
measurement, and that the optical sigmafKfc agrees with the Kfc obtained via the
blood-corrected gravimetric method.
PMID- 9390972
TI - Gender differences in airway resistance during sleep.
AB - At the onset of non-rapid-eye-movement (NREM) sleep there is a fall in
ventilation and an increase in upper airway resistance (UAR). In healthy men
there is a progressive increase in UAR as NREM sleep deepens. This study compared
the pattern of change in UAR and ventilation in 14 men and 14 women (aged 18-25
yr) both during sleep onset and over the NREM phase of a sleep cycle (from
wakefulness to slow-wave sleep). During sleep onset, fluctuations between
electroencephalographic alpha and theta activity were associated with mean
alterations in inspiratory minute ventilation and UAR of between 1 and 4.5 l/min
and between 0.70 and 5.0 cmH2O . l-1 . s, respectively, with no significant
effect of gender on either change (P > 0.05). During NREM sleep, however, the
increment in UAR was larger in men than in women (P < 0.01), such that the mean
levels of UAR at peak flow reached during slow-wave sleep were approximately 25
and 10 cmH2O . l-1 . s in men and women, respectively. We speculate that the
greater increase in UAR in healthy young men may represent a gender-related
susceptibility to sleep-disordered breathing that, in conjunction with other
predisposing factors, may contribute to the development of obstructive sleep
apnea.
PMID- 9390973
TI - Strength, skeletal muscle composition, and enzyme activity in multiple sclerosis.
AB - This study examined functional, biochemical, and morphological characteristics of
skeletal muscle in nine multiple sclerosis (MS) patients and eight healthy
controls in an effort to ascertain whether intramuscular adaptations could
account for excessive fatigue in this disease. Analyses of biopsies of the
tibialis anterior muscle showed that there were fewer type I fibers (66 +/- 6 vs.
76 +/- 6%), and that fibers of all types were smaller (average downward arrow26%)
and had lower succinic dehydrogenase (SDH; average downward arrow40%) and
SDH/alpha-glycerol-phosphate dehydrogenase (GPDH) but not GPDH activities in MS
vs. control subjects, suggesting that muscle in this disease is smaller and
relies more on anaerobic than aerobic-oxidative energy supply than does muscle of
healthy individuals. Maximal voluntary isometric force for dorsiflexion was
associated with both average fiber cross-sectional area (r = 0.71, P = 0.005) and
muscle fat-free cross-sectional area by magnetic resonance imaging (r = 0.80, P <
0. 001). Physical activity, assessed by accelerometer, was associated with
average fiber SDH/GPDH (r = 0.78, P = 0.008). There was a tendency for
symptomatic fatigue to be inversely associated with average fiber SDH activity (r
= -0.57, P = 0.068). The results of this study suggest that the inherent
characteristics of skeletal muscle fibers per se and of skeletal muscle as a
whole are altered in the direction of disuse in MS. They also suggest that
changes in skeletal muscle in MS may significantly affect function.
PMID- 9390974
TI - Correlation between ventilation and EEG-defined arousal during sleep onset in
young subjects.
AB - In studies of elderly individuals, ventilation and EEG-defined arousal have been
shown to vary periodically and synchronously. Such results have been interpreted
as indicating the primacy of sleep/wake state in causing ventilatory instability
during sleep onset. However, because the elderly individuals studied were
periodic breathers, the results do not unequivocally support this conclusion. In
this study the relationship between ventilation and EEG-defined arousal was
assessed in a group of 21 young, healthy men in whom ventilatory instability
during sleep onset was not periodic. Ventilation and EEG (O1-A2) recordings were
collected, and the longest uncontaminated periods from early and late in sleep
onset were selected for subsequent analysis. The 84 time series (21 subjects, 2
variables, and 2 occasions in sleep onset) were subjected to spectral analysis to
identify periodicity, and the relationship between the two variables was
determined by cross-correlational methods. The results indicated that the time
series were nonperiodic, yet significant correlations were observed between the
two variables. The data support the view that during sleep onset ventilatory
instability is driven primarily by variations in sleep/wake arousal level.
PMID- 9390975
TI - Modification of active cutaneous vasodilation by oral contraceptive hormones.
AB - It is not clear whether the altered thermoregulatory reflex control of the
cutaneous circulation seen among phases of the menstrual cycle also occurs with
the synthetic estrogen and progesterone in oral contraceptive pills and whether
any such modifications include altered control of the cutaneous active
vasodilator system. To address these questions, we conducted controlled whole
body heating experiments in seven women at the end of the third week of hormone
pills (HH) and at the end of the week of placebo/no pills (LH). A water-perfused
suit was used to control body temperature. Laser Doppler flowmetry was used to
monitor cutaneous blood flow at a control site and at a site at which
noradrenergic vasoconstrictor control had been eliminated by iontophoresis of
bretylium (BT), isolating the active cutaneous vasodilator system. The oral
temperature (Tor) thresholds for cutaneous vasodilation were higher in HH at both
control [37.09 +/- 0.12 vs. 36.83 +/- 0.07 degrees C (LH), P < 0.01] and BT
treated [37. 19 +/- 0.05 vs. 36.88 +/- 0.12 degrees C (LH), P < 0.01] sites. The
Tor threshold for sweating was similarly shifted (HH: 37.15 +/- 0.11 degrees C
vs. LH: 36.94 +/- 0.11 degrees C, P < 0.01). A rightward shift in the
relationship of heart rate to Tor was seen in HH. The sensitivities (slopes of
the responses vs. Tor) did not differ statistically between phases. The similar
threshold shifts at control and BT-treated sites suggest that the hormones shift
the function of the active vasodilator system to higher internal temperatures.
The similarity of the shifts among thermoregulatory effectors suggests a
centrally mediated action of these hormones.
PMID- 9390976
TI - Effects of training and a single session of exercise on lipids and
apolipoproteins in hypercholesterolemic men.
AB - To differentiate between transient (acute) and training (chronic) effects of
exercise at two different intensities on blood lipids and apolipoproteins (apo),
26 hypercholesterolemic men (cholesterol = 258 mg/dl, age = 47 yr, weight = 81.9
kg) trained three times per week for 24 wk, 350 kcal/session at high (80% maximal
O2 uptake, n = 12) or moderate (50% maximal O2 uptake, n = 14) intensity. Serum
lipid and apolipoprotein (apo) concentrations (plasma volume adjusted) were
measured before and immediately, 24, and 48 h after exercise on four different
occasions corresponding to 0, 8, 16, and 24 wk of training. Data were analyzed
using three-way repeated-measures multivariate analysis of variance followed by
analysis of variance and Duncan's procedures (alpha = 0.05). A transient 6% rise
in low-density-lipoprotein cholesterol measured before training at the 24-h time
point was no longer evident after training. Triglycerides fell and total
cholesterol, high-density-lipoprotein cholesterol (HDL-C), HDL3-C, apo A-I, and
apo B rose 24-48 h after exercise regardless of training or intensity. Total
cholesterol, HDL3-C, apo A-I, and apo B were lower and HDL2-C was higher after
training than before training. Thus exercise training and a single session of
exercise exert distinct and interactive effects on lipids and apolipoproteins.
These results support the practice of training at least every other day to obtain
optimal exercise benefits.
PMID- 9390977
TI - Effect of microgravity and hypergravity on deposition of 0.5- to 3-micron
diameter aerosol in the human lung.
AB - We measured intrapulmonary deposition of 0. 5-, 1-, 2-, and 3-micron-diameter
particles in four subjects on the ground (1 G) and during parabolic flights both
in microgravity (microG) and at approximately 1.6 G. Subjects breathed aerosols
at a constant flow rate (0.4 l/s) and tidal volume (0.75 liter). At 1 G and
approximately 1.6 G, deposition increased with increasing particle size. In
microG, differences in deposition as a function of particle size were almost
abolished. Deposition was a nearly linear function of the G level for 2- and 3
micron-diameter particles, whereas for 0.5- and 1.0-micron-diameter particles,
deposition increased less between microG and 1 G than between 1 G and
approximately 1.6 G. Comparison with numerical predictions showed good agreement
for 1-, 2-, and 3-micron-diameter particles at 1 and approximately 1.6 G, whereas
the model consistently underestimated deposition in microG. The higher deposition
observed in microG compared with model predictions might be explained by a larger
deposition by diffusion because of a higher alveolar concentration of aerosol in
microG and to the nonreversibility of the flow, causing additional mixing of the
aerosols.
PMID- 9390978
TI - Autonomic control of skeletal muscle vasodilation during exercise.
AB - Despite extensive investigation, the control of blood flow during dynamic
exercise is not fully understood. The purpose of this study was to determine
whether beta-adrenergic or muscarinic receptors are involved in the vasodilation
in exercising skeletal muscle. Six mongrel dogs were instrumented with ultrasonic
flow probes on both external iliac arteries and with a catheter in a branch of
one femoral artery. The dogs exercised on a treadmill at 6 miles/h while drugs
were injected intra-arterially into one hindlimb. Isoproterenol (0.2 microg) or
acetylcholine (1 microg) elicited increases in iliac blood flow of 89.8 +/- 14.4
and 95.6 +/- 17.4%, respectively, without affecting systemic blood pressure or
blood flow in the contralateral iliac artery. Intra-arterial propranolol (1 mg)
or atropine (500 microg) had no effect on iliac blood flow, although they
abolished the isoproterenol and acetylcholine-induced increases in iliac blood
flow. These data indicate that exogenous activation of beta-adrenergic or
muscarinic receptors in the hindlimb vasculature increases blood flow to
dynamically exercising muscle. More importantly, because neither propranolol nor
atropine affected iliac blood flow, we conclude that beta-adrenergic and
muscarinic receptors are not involved in the control of blood flow to skeletal
muscle during moderate steady-state dynamic exercise in dogs.
PMID- 9390979
TI - Changes in insulin-stimulated glucose transport and GLUT-4 protein in rat
skeletal muscle after training.
AB - After running training, which increased GLUT-4 protein content in rat skeletal
muscle by <40% compared with control rats, the training effect on insulin
stimulated maximal glucose transport (insulin responsiveness) in skeletal muscle
was short lived (24 h). A recent study reported that GLUT-4 protein content in
rat epitrochlearis muscle increased dramatically ( approximately 2-fold) after
swimming training (J.-M. Ren, C. F. Semenkovich, E. A. Gulve, J. Gao, and J. O.
Holloszy. J. Biol. Chem. 269, 14396-14401, 1994). Because GLUT-4 protein content
is known to be closely related to skeletal muscle insulin responsiveness, we
thought it possible that the training effect on insulin responsiveness may remain
for >24 h after swimming training if GLUT-4 protein content decreases gradually
from the relatively high level and still remains higher than control level for
>24 h after swimming training. Therefore, we examined this possibility. Male
Sprague-Dawley rats swam 2 h a day for 5 days with a weight equal to 2% of body
mass. Approximately 18, 42, and 90 h after cessation of training, GLUT-4 protein
concentration and 2-[1,2-3H]deoxy-D-glucose transport in the presence of a
maximally stimulating concentration of insulin (2 mU/ml) were examined by using
incubated epitrochlearis muscle preparation. Swimming training increased GLUT-4
protein concentration and insulin responsiveness by 87 and 85%, respectively,
relative to age-matched controls when examined 18 h after training. Forty-two
hours after training, GLUT-4 protein concentration and insulin responsiveness
were still higher by 52 and 51%, respectively, in muscle from trained rats
compared with control. GLUT-4 protein concentration and insulin responsiveness in
trained muscle returned to sedentary control level within 90 h after training. We
conclude that 1) the change in insulin responsiveness during detraining is
directly related to muscle GLUT-4 protein content, and 2) consequently, the
greater the increase in GLUT-4 protein content that is induced by training, the
longer an effect on insulin responsiveness persists after the training.
PMID- 9390980
TI - Neural mechanism of the pressor response to obstructive and nonobstructive apnea.
AB - Obstructive and nonobstructive apneas elicit substantial increases in muscle
sympathetic nerve activity and arterial pressure. The time course of change in
these variables suggests a causal relationship; however, mechanical influences,
such as release of negative intrathoracic pressure and reinflation of the lungs,
are potential contributors to the arterial pressure rise. To test the hypothesis
that apnea-induced pressor responses are neurally mediated, we measured arterial
pressure (photoelectric plethysmography), muscle sympathetic nerve activity
(peroneal microneurography), arterial O2 saturation (pulse oximeter), and end
tidal CO2 tension (gas analyzer) during sustained Mueller maneuvers, intermittent
Mueller maneuvers, and simple breath holds in six healthy humans before, during,
and after ganglionic blockade with trimethaphan (3-4 mg/min, titrated to produce
complete disappearance of sympathetic bursts from the neurogram). Ganglionic
blockade abolished the pressor responses to sustained and intermittent Mueller
maneuvers (-4 +/- 1 vs. +15 +/- 3 and 0 +/- 2 vs. +15 +/- 5 mmHg) and breath
holds (0 +/- 3 vs. +11 +/- 3, all P < 0.05). We conclude that the acute pressor
response to obstructive and nonobstructive voluntary apnea is sympathetically
mediated.
PMID- 9390981
TI - Long-term creatine intake is beneficial to muscle performance during resistance
training.
AB - The effects of oral creatine supplementation on muscle phosphocreatine (PCr)
concentration, muscle strength, and body composition were investigated in young
female volunteers (n = 19) during 10 wk of resistance training (3 h/wk). Compared
with placebo, 4 days of high-dose creatine intake (20 g/day) increased (P < 0.05)
muscle PCr concentration by 6%. Thereafter, this increase was maintained during
10 wk of training associated with low-dose creatine intake (5 g/day). Compared
with placebo, maximal strength of the muscle groups trained, maximal intermittent
exercise capacity of the arm flexors, and fat-free mass were increased 20-25, 10
25, and 60% more (P < 0. 05), respectively, during creatine supplementation.
Muscle PCr and strength, intermittent exercise capacity, and fat-free mass
subsequently remained at a higher level in the creatine group than in the placebo
group during 10 wk of detraining while low-dose creatine was continued. Finally,
on cessation of creatine intake, muscle PCr in the creatine group returned to
normal within 4 wk. It is concluded that long-term creatine supplementation
enhances the progress of muscle strength during resistance training in sedentary
females.
PMID- 9390982
TI - A dual-respiration chamber system with automated calibration.
AB - This study characterizes respiration chambers with fully automated calibration.
The system consists of two 14-m3 pull-type chambers. Care was taken to provide a
friendly environment for the subjects, with the possibility of social contact
during the experiment. Gas analysis was automated to correct for analyzer drift
and barometric pressure variations and to provide ease of use. Methods used for
checking the system's performance are described. The gas-analysis repeatability
was within 0.002%. Results of alcohol combustion (50-350 ml/min CO2) show an
accuracy of 0.5 +/- 2.0 (SD) % for O2 consumption and -0.3 +/- 1.6% for CO2
production for 2- to 24-h experiments. It is concluded that response time is not
the main factor with respect to the smallest practical measurement interval
(duration); volume, mixing, gas-analysis accuracy, and levels of O2 consumption
and CO2 production are at least equally important. The smallest practical
interval was 15-25 min, as also found with most chamber systems described in the
literature. We chose to standardize 0.5 h as the minimum measurement interval.
PMID- 9390983
TI - Lower extremity muscle activation during horizontal and uphill running.
AB - To provide more comprehensive information on the extent and pattern of muscle
activation during running, we determined lower extremity muscle activation by
using exercise-induced contrast shifts in magnetic resonance (MR) images during
horizontal and uphill high-intensity (115% of peak oxygen uptake) running to
exhaustion (2.0-3.9 min) in 12 young women. The mean percentage of muscle volume
activated in the right lower extremity was significantly (P <0.05) greater during
uphill (73 +/- 7%) than during horizontal (67 +/- 8%) running. The percentage of
13 individual muscles or groups activated varied from 41 to 90% during horizontal
running and from 44 to 83% during uphill running. During horizontal running, the
muscles or groups most activated were the adductors (90 +/- 5%), semitendinosus
(86 +/- 13%), gracilis (76 +/- 20%), biceps femoris (76 +/- 12%), and
semimembranosus (75 +/- 12%). During uphill running, the muscles most activated
were the adductors (83 +/- 8%), biceps femoris (79 +/- 7%), gluteal group (79 +/-
11%), gastrocnemius (76 +/- 15%), and vastus group (75 +/- 13%). Compared with
horizontal running, uphill running required considerably greater activation of
the vastus group (23%) and soleus (14%) and less activation of the rectus femoris
(29%), gracilis (18%), and semitendinosus (17%). We conclude that during high
intensity horizontal and uphill running to exhaustion, lasting 2-3 min, muscles
of the lower extremity are not maximally activated, suggesting there is a limit
to the extent to which additional muscle mass recruitment can be utilized to meet
the demand for force and energy. Greater total muscle activation during
exhaustive uphill than during horizontal running is achieved through an altered
pattern of muscle activation that involves increased use of some muscles and less
use of others.
PMID- 9390984
TI - Effects of chronic exercise and deconditioning on platelet function in women.
AB - To investigate the effects of chronic exercise and deconditioning on platelet
function in women, 16 healthy sedentary women were divided into control and
exercise groups. The exercise group cycled on an ergometer at 50% maximal oxygen
consumption for 30 min/day, 5 days/wk, for two consecutive menstrual cycles and
then were deconditioned for three menstrual cycles. During this period, platelet
adhesiveness on a fibrinogen-coated surface, ADP-induced platelet aggregation and
intracellular calcium concentration elevation, guanosine 3',5'-cyclic
monophosphate (cGMP) content in platelets, and plasma nitric oxide metabolite
levels were measured before and immediately after a progressive exercise test in
the midfollicular phase. Our results indicated that, after exercise training, 1)
resting heart rates and blood pressures were reduced, and exercise performance
was improved; 2) resting platelet function was decreased, whereas plasma nitrite
and nitrate levels and platelet cGMP contents were enhanced; and 3) the
potentiation of platelet function by acute strenuous exercise was decreased,
whereas the increases in plasma nitrite and nitrate levels and platelet cGMP
contents were enhanced by acute exercise. Furthermore, deconditioning reversed
these training effects. This implies that training-induced platelet functional
changes in women in the midfollicular phase may be mediated by nitric oxide.
PMID- 9390985
TI - Bed rest suppresses bioassayable growth hormone release in response to muscle
activity.
AB - Hormonal responses to muscle activity were studied in eight men before (-13 or
12 and -8 or -7 days), during (2 or 3, 8 or 9, and 13 or 14 days) and after (+2
or +3 and +10 or +11 days) 17 days of bed rest. Muscle activity consisted of a
series of unilateral isometric plantar flexions, including 4 maximal voluntary
contractions (MVCs), 48 contractions at 30% MVC, and 12 contractions at 80% MVC,
all performed at a 4:1-s work-to-rest ratio. Blood was collected before and
immediately after muscle activity to measure plasma growth hormone by
radioimmunoassay (IGH) and by bioassay (BGH) of tibia epiphyseal cartilage growth
in hypophysectomized rats. Plasma IGH was unchanged by muscle activity before,
during, or after bed rest. Before bed rest, muscle activity increased (P < 0.05)
BGH by 66% at -13 or -12 days (2,146 +/- 192 to 3,565 +/- 197 microg/l) and by
92% at -8 or -7 days (2,162 +/- 159 to 4,161 +/- 204 microg/l). After 2 or 3 days
of bed rest, there was no response of BGH to the muscle activity, a pattern that
persisted through 8 or 9 days of bed rest. However, after 13 or 14 days of bed
rest, plasma concentration of BGH was significantly lower after than before
muscle activity (2,594 +/- 211 to 2,085 +/- 109 microg/l). After completion of
bed rest, muscle activity increased BGH by 31% at 2 or 3 days (1,807 +/- 117 to
2,379 +/- 473 microg/l; P < 0.05), and by 10 or 11 days the BGH response was
similar to that before bed rest (1,881 +/- 75 to 4,160 +/- 315 microg/l; P <
0.05). These data demonstrate that the ambulatory state of an individual can have
a major impact on the release of BGH, but not IGH, in response to a single bout
of muscle activity.
PMID- 9390986
TI - Arterial baroreflex modulation of heat-induced vasodilation in the rabbit ear.
AB - The purpose of this study was to determine whether nonthermal baroreflexes
arising from cardiopulmonary and/or arterial baroreceptors modulate rabbit ear
blood flow (EBF) during hyperthermia. Intact and sinoaortic-denervated (SAD)
rabbits were chronically instrumented with a Doppler ultrasonic flow probe for
measurement of EBF velocity (kHz). During whole body heating in conscious
rabbits, EBF and ear vascular conductance (EVC) increased as core temperature
increased until maximal plateau levels of EBF and EVC were reached. The maximal
plateau level of EVC attained during heat stress was lower in SAD than in intact
rabbits. Subsequent intrapericardial administration of procaine at maximal EBF
blocked cardiac afferents but did not alter EVC in either animal group. In a
second experiment, ramp decreases in mean arterial pressure were produced by vena
caval occlusion at maximal EBF. In intact rabbits, EBF and EVC decreased linearly
as mean arterial pressure fell, but EBF and EVC did not decrease during vena
caval occlusion in SAD rabbits. Thus neither pharmacological nor mechanical
unloading of cardiac baroreceptors results in reflex vasoconstriction in the heat
stressed rabbit ear. However, baroreflexes arising from arterial baroreceptors
may modulate EBF in heat-stressed rabbits.
PMID- 9390987
TI - Ventilation and hypoxic ventilatory responsiveness in Chinese-Tibetan residents
at 3,658 m.
AB - When breathing ambient air at rest at 3,658 m altitude, Tibetan lifelong
residents of 3,658 m ventilate as much as newcomers acclimatized to high
altitude; they also ventilate more and have greater hypoxic ventilatory responses
(HVRs) than do Han ("Chinese") long-term residents at 3,658 m. This suggests that
Tibetan ancestry is advantageous in protecting resting ventilation levels during
years of hypoxic exposure and is of interest in light of the permissive role of
hypoventilation in the development of chronic mountain sickness, which is nearly
absent among Tibetans. The existence of individuals with mixed Tibetan-Chinese
ancestry (Han-Tibetans) residing at 3,658 m affords an opportunity to test this
hypothesis. Eighteen men born in Lhasa, Tibet, China (3,658 m) to Tibetan mothers
and Han fathers were compared with 27 Tibetan men and 30 Han men residing at
3,658 m who were previously studied. We used the same study procedures (minute
ventilation was measured with a dry-gas flowmeter during room air breathing and
hyperoxia and with a 13-liter spirometer-rebreathing system during the hypoxic
and hypercapnic tests). During room air breathing at 3,658 m (inspired O2
pressure = 93 Torr), Han-Tibetans resembled Tibetans in ventilation (12.1 +/- 0.6
vs. 11.5+/- 0.5 l/min BTPS, respectively) but had HVR that were blunted (63 +/-
16 vs. 121 +/- 13, respectively, for HVR shape parameter A) and declined with
increasing duration of high-altitude residence. During administered hyperoxia
(inspired O2 pressure = 310 Torr) at 3,658 m, the paradoxical hyperventilation
previously seen in Tibetan but not Han residents at 3,658 m (11.8 +/- 0.5 vs.
10.1 +/- 0.5 l/min BTPS) was absent in these Han-Tibetans (9.8 +/- 0.6 l/min
BTPS). Thus, although longer duration of high-altitude residence appears to
progressively blunt HVR among Han-Tibetans born and residing at 3, 658 m, their
Tibetan ancestry appears protective in their maintenance of high resting
ventilation levels despite diminished chemosensitivity.
PMID- 9390988
TI - Resistance training and human cervical muscle recruitment plasticity.
AB - This study examined cervical neuromuscular adaptations to resistance training.
The ResX group performed conventional resistance training plus head-extension
exercise. Another group performed only conventional resistance training, and the
control group performed no resistance exercise. Muscle use during head extension
was determined by quantifying shifts in T2 in serial-transaxial magnetic
resonance images of the neck. ResX was the only group that showed a training
effect. Training decreased (P < 0.05) the cross-sectional area (CSA) of cervical
muscle used to perform submaximal head extension by 31%. This reflected a
decrease (P < 0.05) in relative use of the splenius capitis, semispinalis
capitis, and semispinalis cervicis and multifidus muscles by about one-third;
their percentage of CSA showing contrast shift was reduced from 60 to 40% on
average. This same exercise evoked no contrast shift in the levator scapulae,
longissimus capitis and cervicis, and scalenus medius and anterior muscles
posttraining, yet 20% or more of their CSA was engaged pretraining. The relative
CSA of cervical musculature that was used to perform maximal head extension was
increased (P < 0.05) 16% by training. The findings suggest functional redundancy
of neck musculature that can be modified by training; submaximal tasks can be
performed despite cessation of recruitment of individual muscles, yet recruitment
can be increased for maximal efforts. These results also suggest that
neuromuscular adaptations to training require a specific cervical exercise.
PMID- 9390989
TI - Improving energy expenditure estimation by using a triaxial accelerometer.
AB - In our study of 125 subjects (53 men and 72 women) for two 24-h periods, we
validated energy expenditure (EE), estimated by a triaxial accelerometer (Tritrac
R3D), by using a whole-room indirect calorimeter under close-to-normal living
conditions. The estimated EE was correlated with the measured total EE for the 2
days (r = 0. 925 and r = 0.855; P < 0.001) and in minute-by-minute EE (P < 0.01).
Resting EE formulated by the Tritrac was found to be similar to the measured
values [standard errors of estimation (SEE) = 0.112 W/kg; P = 0.822]. The Tritrac
significantly underestimated total EE, EE for physical activities, EE of
sedentary and light-intensity activities, and EE for exercise such as stepping
(all P < 0.001). We developed a linear and a nonlinear model to predict EE by
using the acceleration components from the Tritrac. Predicted EE was
significantly improved with both models in estimating total EE, total EE for
physical activities, EE in low-intensity activities, minute-by-minute averaged
relative difference, and minute-by-minute SEE (all P < 0. 05). Furthermore, with
our generalized models and by using subjects' physical characteristics and body
acceleration, EE can be estimated with higher accuracy (averaged SEE = 0.418
W/kg) than with the Tritrac model.
PMID- 9390990
TI - Modulation of pulmonary arterial input impedance during transition from
inspiration to expiration.
AB - We investigated whether respiration influences pulmonary arterial input impedance
during transition from inspiration to expiration in five anesthetized,
spontaneously breathing dogs. Impedance (Z) was separately assessed for heart
beats occurring in inspiration, in expiration, and during the transition from
inspiration to expiration (transitional beat). Transitional beats were scored by
the ratio between the fraction of beat falling in expiration and the total beat
duration [expiratory fraction (Efr)] to quantify their position within the
transition. In transitional beats, input resistance linearly increased with Efr;
Z modulus at the heart-rate frequency (fHR) decreased up to -50% for Efr = 50%. Z
phase at fHR was greater than in inspiration for Efr <40% and lower for Efr >50%.
Unlike blood flow velocity, mean value and first harmonic of pulmonary arterial
pressure were correlated to Efr and paralleled the changes of input resistance
and Z at fHR. This indicates that respiration influences Z through modifications
in arterial pressure. The evidence of important respiratory influences on Z
function may help the pathophysiological interpretation of dysfunctions of the
right heart pumping action, such as the so-called cor pulmonale.
PMID- 9390991
TI - Posttetanic potentiation of human dorsiflexors.
AB - Twitch contractions of the ankle dorsiflexors were evoked before and after
applied 7-s tetanic stimulation at 100 Hz in 20 young adults. Torque decreased
15% during the tetanus. At 5 s after tetanus, twitch peak torque had potentiated
45%. Potentiation declined to 28% after 1 min, rose slightly to 33% at 2 min, and
declined slowly with potentiation still 25% after 5 min. There was large
intersubject variation in the amount of potentiation (5-140%) and its persistence
(5 to >/=20 min). The muscle compound action potential (M wave) did not change
significantly (from pretetanic value) at 5 s after tetanus but increased sharply
(26%) at 2 min and then subsided. Twitch half relaxation time (23%) decreased
significantly more than twitch rise time (13%) 5 s after tetanus and recovered
more slowly. Twitch rates of torque development (75%) and relaxation (71%)
increased similarly 5 s after tetanus and were still elevated (approximately 25%)
at 5 min. The extent of twitch torque potentiation was significantly inversely
correlated with pretetanic twitch rise time (r = -0.69), half relaxation time (r
= -0.61), and twitch-to-tetanus ratio (r = -0.66). The data indicate that
posttetanic potentiation has a greater effect on twitch half relaxation time than
on time to peak torque and is more prominent in muscles with a short twitch time
course and small twitch-to-tetanus ratio.
PMID- 9390992
TI - Effects of head-down-tilt bed rest on cerebral hemodynamics during orthostatic
stress.
AB - Our aim was to determine whether the adaptation to simulated microgravity
(microG) impairs regulation of cerebral blood flow (CBF) during orthostatic
stress and contributes to orthostatic intolerance. Twelve healthy subjects (aged
24 +/- 5 yr) underwent 2 wk of -6 degrees head-down-tilt (HDT) bed rest to
simulate hemodynamic changes that occur when humans are exposed to microG. CBF
velocity in the middle cerebral artery (transcranial Doppler), blood pressure,
cardiac output (acetylene rebreathing), and forearm blood flow were measured at
each level of a ramped protocol of lower body negative pressure (LBNP; -15, -30,
and -40 mmHg x 5 min, -50 mmHg x 3 min, then -10 mmHg every 3 min to presyncope)
before and after bed rest. Orthostatic tolerance was assessed by using the
cumulative stress index (CSI; mmHg x minutes) for the LBNP protocol. After bed
rest, each individual's orthostatic tolerance was reduced, with the group CSI
decreased by 24% associated with greater decreases in cardiac output and greater
increases in systemic vascular resistance at each level of LBNP. Before bed rest,
mean CBF velocity decreased by 14, 10, and 45% at -40 mmHg, -50 mmHg, and maximal
LBNP, respectively. After bed rest, mean velocity decreased by 16% at -30 mmHg
and by 21, 35, and 39% at -40 mmHg, -50 mmHg, and maximal LBNP, respectively.
Compared with pre-bed rest, post-bed-rest mean velocity was less by 11, 10, and
21% at -30, -40, and -50 mmHg, respectively. However, there was no significant
difference at maximal LBNP. We conclude that cerebral autoregulation during
orthostatic stress is impaired by adaptation to simulated microG as evidenced by
an earlier and greater fall in CBF velocity during LBNP. We speculate that
impairment of cerebral autoregulation may contribute to the reduced orthostatic
tolerance after bed rest.
PMID- 9390993
TI - An improved statistical methodology to estimate and analyze impedances and
transfer functions.
AB - Estimating the mathematical relationship between pulsatile time series (e.g.,
pressure and flow) is an effective technique for studying dynamic systems. The
frequency-domain relationship between time series, often calculated as an
impedance (pressure/flow), is known more generally as a frequency-response or
transfer function (output/input). Current statistical methods for transfer
function analysis 1) assume erroneously that repeated observations on a subject
are independent, 2) have limited statistical value and power, or 3) are
restricted to use in single subjects rather than in an entire sample. This paper
develops a regression model for transfer function analysis that corrects each of
these deficiencies. Spectral densities of the input and output time series and
the cross-spectral density between them are first estimated from discrete Fourier
transforms and then used to obtain regression estimates of the transfer function.
Statistical comparisons of the transfer function estimates use a test statistic
that is distributed as chi2. Confidence intervals for amplitude and phase can
also be calculated. By correctly modeling repeated observations on each subject,
this improved statistical approach to transfer function estimation and analysis
permits the simultaneous analysis of data from all subjects in a sample, improves
the power of the transfer function model, and has broad relevance to the study of
dynamic physiological systems.
PMID- 9390994
TI - Allometric modeling does not determine a dimensionless power function ratio for
maximal muscular function.
AB - In the exercise sciences, simple allometry (y = axb) is rapidly becoming the
method of choice for scaling physiological and human performance data for
differences in body size. The purpose of this study is to detail the specific
regression diagnostics required to validate such models. The sum (T, in kg) of
the "snatch" and "clean-and-jerk" lifts of the medalists from the 1995 Men's and
Women's World Weightlifting Championships was modeled as a function of body mass
(M, in kg). A log-linearized allometric model (ln T = ln a + b ln M) yielded a
common mass exponent (b) of 0. 47 (95% confidence interval = 0.43-0.51, P <
0.01). However, size-related patterned deviations in the residuals were evident,
indicating that the allometric model was poorly specified and that the mass
exponent was not size independent. Model respecification revealed that second
order polynomials provided the best fit, supporting previous modeling of
weightlifting data (R. G. Sinclair. Can. J. Appl. Sport Sci. 10: 94-98, 1985).
The model parameters (means +/- SE) were T = (21.48 +/- 16.55) + (6.119 +/-
0.359)M - (0. 022 +/- 0.002)M2 (R2 = 0.97) for men and T = (-20.73 +/- 24.14) +
(5. 662 +/- 0.722)M - (0.031 +/- 0.005)M2 (R2 = 0.92) for women. We conclude that
allometric scaling should be applied only when all underlying model assumptions
have been rigorously evaluated.
PMID- 9390995
TI - Differential dependence on GluR2 expression of three characteristic features of
AMPA receptors.
AB - The GluR2 subunit controls three key features of ion flux through the AMPA
subtype of glutamate receptors-calcium permeability, inward rectification, and
channel block by external polyamines, but whether each of these features is
equally sensitive to GluR2 abundance is unknown. The relations among these
properties were compared in native AMPA receptors expressed by acutely isolated
hippocampal interneurons and in recombinant receptors expressed by Xenopus
oocytes. The shape of current-voltage (I-V) relations between -100 and +50 mV for
either recombinant or native AMPA receptors was well described by a Woodhull
block model in which the affinity for internal polyamine varied over a 1000-fold
range in different cells. In oocytes injected with mixtures of GluR2:non-GluR2
mRNA, the relative abundance of GluR2 required to reduce the log of internal
blocker affinity by 50% was two- to fourfold higher than that needed to half
maximally reduce divalent permeability or channel block by external polyamines.
Likewise, in interneurons the affinity of externally applied argiotoxin for its
blocking site was a steep function of internal blocker affinity. These results
indicate that the number of GluR2 subunits in AMPA receptors is variable in both
oocytes and interneurons. More GluR2 subunits in an AMPA receptor are required to
maximally reduce internal blocker affinity than to abolish calcium permeability
or external polyamine channel block. Accordingly, single-cell RT-PCR showed that
approximately one-half of the physiologically characterized interneurons
exhibiting inwardly rectifying AMPA receptors expressed detectable levels of
edited GluR2. The physiological effects of a moderate change in GluR2 relative
abundance, such as occurs after ischemia or seizures or after chronic exposure to
morphine, thus will be dependent on the ambient GluR2 level in a cell-specific
manner.
PMID- 9390996
TI - The beta-amyloid precursor protein of Alzheimer's disease enhances neuron
viability and modulates neuronal polarity.
AB - beta-Amyloid precursor protein (betaPP) can reside at neuron and glial cell
surfaces or undergo proteolytic processing into secreted fragments. Although
betaPP has been studied extensively, its precise physiological role is unknown. A
line of transgenic knock-out mice selectively deficient in betaPP survive and
breed but exhibit motor dysfunction and brain gliosis, consistent with a
physiological role for betaPP in neuron development. To elucidate these
functions, we cultured hippocampal neurons from wild-type and betaPP-deficient
mice and compared their ability to attach, survive, and develop neurites. We
found that hippocampal neurons from betaPP-deficient mice had diminished
viability and retarded neurite development. We also compared the effects of
betaPP secretory products, released from wild-type astrocytes, on process
outgrowth from wild-type and betaPP-deficient hippocampal neurons. Outgrowth was
enhanced at 1 d in the presence of wild-type astrocytes, as compared with betaPP
deficient astrocytes. However, by 3 d, neurons had shorter axons but more minor
processes with more branching when cocultured with wild-type astrocytes, as
compared with betaPP-deficient astrocytes. Our data demonstrate that cell
associated neuronal betaPP contributes to neuron viability, axonogenesis, and
arborization and that betaPP secretory products modulate axon growth, dendrite
branching, and dendrite numbers.
PMID- 9390997
TI - Regulation of amyloid precursor protein catabolism involves the mitogen-activated
protein kinase signal transduction pathway.
AB - Catabolic processing of the amyloid precursor protein (APP) is subject to
regulatory control by protein kinases. We hypothesized that this regulation
involves sequential activation of the enzymes mitogen-activated protein kinase
kinase (MEK) and extracellular signal-regulated protein kinase (ERK). In the
present investigation, we provide evidence that MEK is critically involved in
regulating APP processing by both nerve growth factor and phorbol esters. Western
blot analysis of the soluble N-terminal APP derivative APPs demonstrated that the
synthetic MEK inhibitor PD 98059 antagonized nerve growth factor stimulation of
both APPs production and ERK activation in PC12 cells. Moreover, PD 98059
inhibited phorbol ester stimulation of APPs production and activation of ERK in
both human embryonic kidney cells and cortical neurons. Furthermore,
overexpression of a kinase-inactive MEK mutant inhibited phorbol ester
stimulation of APP secretion and activation of ERK in human embryonic kidney cell
lines. Most important, PD 98059 antagonized phorbol ester-mediated inhibition of
Abeta secretion from cells overexpressing human APP695 carrying the "Swedish
mutation." Taken together, these data indicate that MEK and ERK may be critically
involved in protein kinase C and nerve growth factor regulation of APP
processing. The mitogen-activated protein kinase cascade may provide a novel
target for altering catabolic processing of APP.
PMID- 9390998
TI - Identification of two nervous system-specific members of the erg potassium
channel gene family.
AB - Two new potassium channel genes, erg2 and erg3, that are expressed in the nervous
system of the rat were identified. These two genes form a small gene family with
the previously described erg1 (HERG) gene. The erg2 and erg3 genes are expressed
exclusively in the nervous system, in marked contrast to erg1, which is expressed
in both neural and non-neural tissues. All three genes are expressed in
peripheral sympathetic ganglia. The erg3 channel produces a current that has a
large transient component at positive potentials, whereas the other two channels
are slowly activating delayed rectifiers. Expression of the erg1 gene in the
sympathetic nervous system has potential implications for the etiology of the
LQT2 form of the human genetic disease long QT syndrome.
PMID- 9390999
TI - Crossed rhythmic synaptic input to motoneurons during selective activation of the
contralateral spinal locomotor network.
AB - To investigate the cellular mechanisms underlying locomotor-related left-right
coordination, we monitored the crossed synaptic input to lumbar motoneurons
during contralateral ventral root rhythmicity in the neonatal rat spinal cord in
vitro. Using a longitudinal split-bath setup, one hemicord was kept in normal
solution, whereas the contralateral hemicord was exposed to 5-HT and NMDA. With
this approach, rhythmic bursting could be induced in the ventral roots on the
agonist-exposed side, whereas the ventral roots on the agonist-free side remained
silent. Intracellular recordings were made from L1-L3 motoneurons on the silent
agonist-free side during rhythmic activity in the contralateral ventral roots. At
the resting membrane potential, the typical crossed synaptic input was a rhythmic
barrage of depolarizing IPSPs. This input modulated the frequency of spikes
induced with depolarizing direct current by inhibiting firing in phase with the
contralateral bursts. Intracellular chloride loading increased the amplitude of
the IPSPs, suggesting that they were chloride-dependent. Strychnine but not
bicuculline generally blocked the rhythmic inhibitory input when added to the
agonist-free side during contralateral rhythmicity. APV and CNQX on the agonist
free side abolished the rhythmic inhibitory input in most motoneurons but not in
all. We suggest that rat spinal motoneurons receive a mainly glycinergic rhythmic
inhibition from the contralateral half of the locomotor network. Unlike in
simpler vertebrates, the crossed inhibition often appears to be at least
disynaptic, involving inhibitory premotor neurons located on the same side as the
receiving motoneurons. These premotor neurons are rhythmically excited via a
crossed pathway that depends on glutamatergic transmission.
PMID- 9391000
TI - Endogenous monocarboxylates sustain hippocampal synaptic function and
morphological integrity during energy deprivation.
AB - The ability to fuel neurons via glycogenolysis is believed to be an important
function of glia. Indeed, the slow, rather than immediate, depression of synaptic
transmission in hippocampal slices during exogenous glucose deprivation suggests
that intrinsic energy reservoirs help to sustain neurotransmission. It is
believed that glia fuel neighboring neurons via diffusible monocarboxylates such
as pyruvate and lactate, although a role for glucose has been proposed also.
Using alpha-cyano-4-hydroxycinnamate (4-CIN) to inhibit monocarboxylate transport
and cytochalasin B (CCB) to inhibit glucose transport, we examined the role of
glucose and monocarboxylates in supporting the functional and morphological
integrity of hippocampal neurons during glucose deprivation. Although 200 microM
4-CIN failed to depress EPSPs supported by 10 mM glucose, pretreatment with 4-CIN
accelerated the depression of EPSPs during glucose deprivation. 4-CIN also
accelerated the decline in glucose-supported EPSPs after administration of 50
microM CCB, whereas CCB failed to alter the slow decay of pyruvate-supported
EPSPs during pyruvate deprivation. 4-CIN did not alter the morphology of
pyramidal neurons in the presence of 10 mM glucose but produced significant
damage during glucose deprivation or CCB administration. These results suggest
that endogenous monocarboxylates rather than glucose maintain neuronal integrity
during energy deprivation. Furthermore, EPSPs supported by 2-3.3 mM glucose were
sensitive to 4-CIN, suggesting that endogenous monocarboxylates are involved in
maintaining neuronal function even under conditions of mild glucose deprivation.
PMID- 9391001
TI - Importance of polysynaptic inputs and horizontal connectivity in the generation
of tetanus-induced long-term potentiation in the rat auditory cortex.
AB - Supragranular pyramidal neurons in the adult rat auditory cortex (AC) show marked
long-term potentiation (LTP) of population spikes after tetanic white matter
stimulation (TS). For determination of whether this marked LTP is specific to AC,
LTP in rat AC slices was compared with LTP in slices of the visual cortex (VC).
The amplitude of TS-induced LTP in AC was twice that in VC. LTP of EPSPs was also
studied with perforated patch or whole-cell recording. Although the amplitude of
TS-induced LTP of EPSPs in AC was larger that in VC, no cortical difference was
found in LTP elicited by low-frequency stimulation paired with current injection.
Neocortical LTP is dependent on the activation of NMDA receptors, and induction
of LTP requires postsynaptic depolarization for removal of Mg2+ blockade of NMDA
receptors. The postsynaptic depolarization elicited by TS in supragranular
pyramidal neurons in AC was significantly larger than that in VC. Cutting of
supragranular horizontal connections resulted in a decrease in the depolarization
amplitude in AC but an increase in the depolarization amplitude in VC. The
cortical difference in TS-induced LTP was diminished in the slices in which
horizontal connections in supragranular layers were cut. The estimated density of
horizontal axon collaterals of supragranular pyramidal neurons in AC was
approximately twice that in VC. These results strongly suggest that the marked
polysynaptic and postsynaptic depolarization during TS and the resulting marked
LTP in AC are attributed to well developed horizontal axon collaterals of
supragranular pyramidal neurons in AC.
PMID- 9391002
TI - Study of proline-directed protein kinases involved in phosphorylation of the
heavy neurofilament subunit.
AB - The high-molecular-mass neurofilament subunit (NFH) is normally
hypophosphorylated in the neuronal perikaryon and undergoes extensive
phosphorylation after entering the initial axon segment. Aberrant
hyperphosphorylation of perikaryal NFH is a common feature of many neurological
diseases. In a previous study (), we demonstrated a correlation between
phosphorylation of perikaryal NFH and induction of stress-activated protein
kinase (SAPK)-gamma. In this report, we present direct evidence showing that the
in vivo activation of SAPKs by an upstream activator (MEKK-1) caused extensive
NFH phosphorylation. We also show that stress-activated p38 kinases were not
involved in the phosphorylation of perikaryal NFH in cultured dorsal root
ganglion neurons and that this process was reversible. SAPKgamma was shown to be
located in both the cell body and the neurites of the cultured neurons,
suggesting that it is likely to be involved in the phosphorylation of cytoplasmic
substrates. These could include neuritic NFH, which is highly phosphorylated
despite the demonstrated lack of cyclin-dependent kinase-5 activity in these
neurons. Neuritic NFH was also highly phosphorylated in neuronal cultures devoid
of Schwann cells, indicating that this form of post-translational modification
does not require cues stemming from Schwann cell-axon contacts. Collectively,
these findings provide significant new insights into mechanisms involved in NFH
phosphorylation in normal neurons and in disease states characterized by aberrant
phosphorylation of neurofilaments.
PMID- 9391003
TI - Modulation of hypothalamic-pituitary-adrenal function by transgenic expression of
interleukin-6 in the CNS of mice.
AB - Interleukin-6 (IL-6) and IL-6 receptor mRNA and protein have been reported in
different brain regions under normal and pathophysiological conditions. Although
much is known about the hypothalamic-pituitary-adrenal (HPA) axis stimulation
after acute administration, less is known about the chronic effects of IL-6 on
the function of the HPA axis. In the present study, we examined the function of
the HPA axis in transgenic mice in which constitutive expression of IL-6 under
the control of the glial fibrillary acidic protein (GFAP) promoter was targeted
to astrocytes in the CNS. GFAP-IL6 mice heterozygous or homozygous for the IL-6
transgene had normal basal plasma corticosterone levels but, after restraint
stress, showed abnormally increased levels in a gene dose-dependent manner. The
increased plasma corticosterone levels in the IL-6 transgenic mice were
associated with increased adrenal corticosterone content and hyperplasia of both
adrenal cortex and medulla. Notably, plasma adrenocorticotrophic hormone (ACTH)
levels and pituitary ACTH content were either not changed or decreased in these
mice, whereas plasma arginine vasopressin (AVP) was increased, supporting a role
for AVP in response to acute immobilization stress. The reduced ACTH response
together with the adrenal hyperplasia in the IL-6 transgenic mice suggests direct
activation at the level of the adrenal gland that may be directly activated by
AVP or sensitized to ACTH. A similar mechanism may play a role in the blunted
ACTH response and elevated corticosterone levels under pathophysiological
conditions observed in humans with high brain levels of IL-6.
PMID- 9391004
TI - Luteinizing hormone-releasing hormone (LHRH) neurons maintained in hypothalamic
slice explant cultures exhibit a rapid LHRH mRNA turnover rate.
AB - Evidence indicates that neuropeptide gene expression is tightly coupled to
biosynthesis and secretion. Moreover, rhythmic gene expression often accompanies
rhythmic secretion. Luteinizing hormone-releasing hormone (LHRH) neurosecretion,
which regulates gonadal function, is pulsatile, with interpulse intervals of
approximately 1 hr and pulse decays of <30 min in rats. As a basis for a rapid
fall in peptide secretion, we hypothesize that LHRH mRNA levels rapidly decay. To
address this hypothesis, we examined LHRH mRNA turnover in primary postnatal LHRH
neurons maintained in long-term hypothalamic/preoptic area slice explant
cultures, using in situ hybridization histochemistry (ISHH). Relative LHRH mRNA
content per cell was quantitated by single-cell analysis after transcription
inhibition with 5, 6-dichloro-1-D-ribofuranosyl-benzimidazole (DRB) or
actinomycin D. Cultures were maintained in serum-free medium with tetrodotoxin to
suppress spontaneous electrical activity and hence assess only intrinsic cellular
activity. A plot of LHRH mRNA level per cell versus DRB treatment time showed a
rapid initial decay of LHRH mRNA (t1/2, 5-13 min), followed by a slower decay
rate (t1/2, 329-344 hr). LHRH cell number after drug treatment as determined by
immunocytochemistry did not change. Comparison of mammalian LHRH mRNA 3'
untranslated regions showed two conserved regions. These data indicate that, in
primary LHRH neurons, LHRH mRNA has an intrinsically high rate of turnover and a
mRNA stabilization component. Foremost, decay of LHRH mRNA, the fastest reported
for a neuropeptide to date, corresponds to the decay of LHRH peptide pulses.
PMID- 9391006
TI - Myosin VIIA is required for aminoglycoside accumulation in cochlear hair cells.
AB - Myosin VIIA is expressed by sensory hair cells and has a primary structure
predicting a role in membrane trafficking and turnover, processes that may
underlie the susceptibility of hair cells to aminoglycoside antibiotics.
[3H]Gentamicin accumulation and the effects of aminoglycosides were therefore
examined in cochlear cultures of mice with different missense mutations in the
myosin VIIA gene, Myo7a, to see whether myosin VIIA plays a role in
aminoglycoside ototoxicity. Hair cells from homozygous mutant Myo7ash1 mice, with
a mutation in a nonconserved region of the myosin VIIA head, respond rapidly to
aminoglycoside treatment and accumulate high levels of gentamicin. Hair cells
from homozygous mutant Myo7a6J mice, with a mutation at a highly conserved
residue close to the ATP binding site of the myosin VIIA head, do not accumulate
[3H]gentamicin and are protected from aminoglycoside ototoxicity. Hair cells from
heterozygotes of both alleles accumulate [3H]gentamicin and respond to
aminoglycosides. Although aminoglycoside uptake is thought to be via apical
surface-associated endocytosis, coated pit numbers on the apical membrane of
heterozygous and homozygous Myo7a6J hair cells are similar. Pulse-chase
experiments with cationic ferritin confirm that the apical endocytotic pathway is
functional in homozygous Myo7a6J hair cells. Transduction currents can be
recorded from both heterozygous and homozygous Myo7a6J hair cells, suggesting it
is unlikely that the drug enters via diffusion through the mechanotransducer
channel. The results show that myosin VIIA is required for aminoglycoside
accumulation in hair cells. Myosin VIIA may transport a putative aminoglycoside
receptor to the hair cell surface, indirectly translocate it to sites of membrane
retrieval, or retain it in the endocytotic pathway.
PMID- 9391005
TI - Activity-dependent dendritic targeting of BDNF and TrkB mRNAs in hippocampal
neurons.
AB - The mechanisms underlying the subcellular localization of neurotrophins and their
receptors are poorly understood. We show that in cultured hippocampal neurons,
the mRNAs for BDNF and TrkB have a somatodendritic localization, and we quantify
the extent of their dendritic mRNA localization. In the dendrites the labeling
covers on average the proximal 30% of the total dendritic length. On high
potassium depolarization, the labeling of BDNF and TrkB mRNA extends on average
to 68% of the dendritic length. This increase does not depend on new RNA
synthesis, is inhibited by the Na+ channel blocker tetrodotoxin, and involves the
activation of glutamate receptors. Extracellular Ca2+, partly flowing through L
type Ca2+ channels, is absolutely required for this process to occur. At the
protein level, a brief stimulation of hippocampal neurons with 10 mM KCl leads to
a marked increase of BDNF and TrkB immunofluorescence density in the distal
portion of dendrites, which also occurs, even if at lower levels, when transport
is inhibited by nocodazole. The protein synthesis inhibitor cycloheximide
abolishes this increase. The activity-dependent modulation of mRNA targeting and
protein accumulation in the dendrites may provide a mechanism for achieving a
selective local regulation of the activity of neurotrophins and their receptors,
close to their sites of action.
PMID- 9391007
TI - Identification of caveolin and caveolin-related proteins in the brain.
AB - Caveolae are 50-100 nm, nonclathrin-coated, flask-shaped plasma membrane
microdomains that have been identified in most mammalian cell types, except
lymphocytes and neurons. To date, multiple functions have been ascribed to
caveolae, including the compartmentalization of lipid and protein components that
function in transmembrane signaling events, biosynthetic transport functions,
endocytosis, potocytosis, and transcytosis. Caveolin, a 21-24 kDa integral
membrane protein, is the principal structural component of caveolae. We have
initiated studies to examine the relationship of detergent-insoluble complexes
identified in astrocytes to the caveolin-caveolae compartment detected in cells
of peripheral tissues. Immunolocalization studies performed in astrocytes reveal
caveolin immunoreactivity in regions that correlate well to the distribution of
caveolae and caveolin determined in other cell types, and electron microscopic
studies reveal multiple clusters of flask-shaped invaginations aligned along the
plasma membrane. Immunoblot analyses demonstrate that detergent-insoluble
complexes isolated from astrocytes are composed of caveolin-1alpha, an
identification verified by Northern blot analyses and by the cloning of a cDNA
using reverse transcriptase-PCR amplification from total astrocyte RNA. Using a
full-length caveolin-1 probe, Northern blot analyses suggest that the expression
of caveolin-1 may be regulated during brain development. Immunoblot analyses of
detergent-insoluble complexes isolated from cerebral cortex and cerebellum
identify two immunoreactive polypeptides with apparent molecular weight and
isoelectric points appropriate for caveolin. The identification of caveolae
microdomains and caveolin-1 in astrocytes and brain, as well as the apparent
regulation of caveolin-1 expression during brain development, identifies a cell
compartment not detected previously in brain.
PMID- 9391008
TI - Sublethal oxygen-glucose deprivation alters hippocampal neuronal AMPA receptor
expression and vulnerability to kainate-induced death.
AB - Recent studies have suggested that rats subjected to transient global brain
ischemia develop depressed expression of GluR-B in CA1 hippocampal neurons. The
present study was performed to determine whether a similar change in AMPA
receptor expression could be triggered in vitro by sublethal oxygen-glucose
deprivation in rat hippocampal neuronal cultures. mRNA was extracted from
individual hippocampal neurons via patch electrodes and amplified by RT-PCR 24-48
hr after sublethal oxygen-glucose deprivation. Compared with controls, insulted
neurons expressed increased levels of GluR-D flop. As an indication that this
change in receptor expression was functionally significant, insulted cultures
exhibited increased AMPA- or kainate-induced 45Ca2+ accumulation sensitive to
Joro spider toxin and increased vulnerability to kainate-induced death. These
data support the hypothesis that exposure to ischemia may enhance subsequent
hippocampal neuronal vulnerability to AMPA receptor-mediated excitotoxicity by
modifying the relative expression of AMPA receptor subunits in a manner that
promotes Ca2+ permeability.
PMID- 9391009
TI - Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor
activation.
AB - We have investigated the control of calcitonin gene-related peptide (CGRP)
expression by a serotonergic agonist that is related pharmacologically to
currently used antimigraine drugs. During migraines, CGRP levels are elevated but
then returned to normal by a 5-HT1 receptor agonist, sumatriptan. However,
neither the molecular nor cellular targets of this drug are known. Trigeminal
neurons are the major source of cerebrovascular CGRP, and thus we have used
trigeminal primary cultures and the neuronal-like CA77 thyroid C-cell line as a
model. We first demonstrate that sumatriptan and another 5-HT1 agonist, CGS
12066A (CGS), cause a robust and prolonged increase with oscillations in
intracellular calcium in CA77 cells. CGS caused a similar increase in trigeminal
cultures. We then show that CGS treatment leads to a decrease in CGRP mRNA levels
in the CA77 cells. This decrease is attributable to the repression of promoter
activity through two discrete elements: (1) the cAMP-responsive region, via a
cAMP-independent mechanism; and (2) the cell-specific enhancer, which binds the
upstream stimulatory factor helix-loop-helix protein and a cell-specific
activator. These results demonstrate that activation of the endogenous 5-HT1
receptor is coupled to calcium signaling pathways and leads to inhibition of CGRP
gene transcription.
PMID- 9391010
TI - Measurement of intracellular free zinc in living cortical neurons: routes of
entry.
AB - We used the ratioable fluorescent dye mag-fura-5 to measure intracellular free
Zn2+ ([Zn2+]i) in cultured neocortical neurons exposed to neurotoxic
concentrations of Zn2+ in concert with depolarization or glutamate receptor
activation and identified four routes of Zn2+ entry. Neurons exposed to
extracellular Zn2+ plus high K+ responded with a peak cell body signal
corresponding to a [Zn2+]i of 35-45 nM. This increase in [Zn2+]i was attenuated
by concurrent addition of Gd3+, verapamil, omega-conotoxin GVIA, or nimodipine,
consistent with Zn2+ entry through voltage-gated Ca2+channels. Furthermore, under
conditions favoring reverse operation of the Na+-Ca2+ exchanger, Zn2+ application
induced a slow increase in [Zn2+]i and outward whole-cell current sensitive to
benzamil-amiloride. Thus, a second route of Zn2+ entry into neurons may be via
transporter-mediated exchange with intracellular Na+. Both NMDA and kainate also
induced rapid increases in neuronal [Zn2+]i. The NMDA-induced increase was only
partly sensitive to Gd3+ or to removal of extracellular Na+, consistent with a
third route of entry directly through NMDA receptor-gated channels. The kainate
induced increase was highly sensitive to Gd3+ or Na+ removal in most neurons but
insensitive in a minority subpopulation ("cobalt-positive cells"), suggesting
that a fourth route of neuronal Zn2+ entry is through the Ca2+-permeable channels
gated by certain subtypes of AMPA or kainate receptors.
PMID- 9391011
TI - Isoform specificity in the relationship of actin to dendritic spines.
AB - Dendritic spines contain high concentrations of actin, but neither the isoforms
involved nor the mechanism of accumulation is known. In situ hybridization with
specific probes established that beta- and gamma-cytoplasmic actins are
selectively expressed at high levels by spine-bearing neurons. Transfecting
cultured hippocampal neurons with epitope-tagged actin isoforms showed that
cytoplasmic beta- and gamma-cytoplasmic actins are correctly targeted to spines,
whereas alpha-cardiac muscle actin, which is normally absent from neurons, formed
aggregates in dendrites. The transfected actin cDNAs contained only coding
domains, suggesting that spine targeting involves amino acid sequences in the
proteins, an interpretation supported by experiments with chimeric cDNAs in which
C-terminal actin sequences were found to be determinative in spine targeting. By
contrast to actin, microtubule components, including tubulin and MAP2, were
restricted to the dendritic shaft domain. The close association of cytoplasmic
actins with spines together with their general involvement in cell surface
motility further supports the idea that actin motility-based changes in spine
shape may contribute to synaptic plasticity.
PMID- 9391012
TI - Nerve growth factor modulates synaptic transmission between sympathetic neurons
and cardiac myocytes.
AB - Regulation of heart rate by the sympathetic nervous system involves the release
of norepinephrine (NE) from nerve terminals onto heart tissue, resulting in an
elevation in beat rate. Nerve growth factor (NGF) is a neurotrophin produced by
the heart that supports the survival and differentiation of sympathetic neurons.
Here we report that NGF also functions as a modulator of sympathetic synaptic
transmission. We determined the effect of NGF on the strength of synaptic
transmission in co-cultures of neonatal rat cardiac myocytes and sympathetic
neurons from the superior cervical ganglion (SCG). Synaptic transmission was
assayed functionally, as an increase in the beat rate of a cardiac myocyte during
stimulation of a connected neuron. Application of NGF produced a pronounced,
reversible enhancement of synaptic strength. We found that TrkA, the receptor
tyrosine kinase that mediates many NGF responses, is expressed primarily by
neurons in these cultures, suggesting a presynaptic mechanism for the effects of
NGF. A presynaptic model is further supported by the finding that NGF did not
alter the response of myocytes to application of NE. In addition to the acute
modulatory effects of NGF, we found that the concentration of NGF in the growth
medium affects the level of synaptic transmission in cultures of sympathetic
neurons and cardiac myocytes. These results indicate that in addition to its role
as a survival factor, NGF plays both acute and long-term roles in the regulation
of developing sympathetic synapses in the cardiac system.
PMID- 9391014
TI - Experience-dependent modifications in MAP2 phosphorylation in rat olfactory bulb.
AB - Microtubule-associated protein 2 (MAP2) is a neuron-specific cytoskeletal
protein, enriched in dendrites and cell bodies, that helps determine dendritic
shape. MAP2 regulates microtubule stability in a phosphorylation-dependent
manner. The present study used immunocytochemistry with phosphoepitope-specific
and phosphorylation state-independent antibodies to examine experience-dependent
changes in MAP2 expression during postnatal development of the olfactory bulb.
Our results demonstrate that immunoreactivity reflecting total MAP2 expression
reaches a maximal level by postnatal day 20 (P20). The degree of staining for
phosphoindependent forms of MAP2 is relatively unaffected by blocking odorant
passage to one half the nasal epithelium via unilateral naris closure, a
manipulation that attenuates physiological activity in the bulb. However,
olfactory restriction from P1 dramatically reduces immunoreactivity for antibody
AP18, which recognizes MAP2 only when phosphorylated on Ser136. Quantification of
staining in the granule cell layer indicates that the greatest difference (64%)
between control and experimental bulbs occurs after occlusion from P1 to P30
compared with animals deprived from P1 to P10 or P1 to P20. The shift in MAP2
phosphorylation occurs even when deprivation is delayed until P30, after the
sensitive period for experience-dependent changes in bulb volume. Thus, the
degree of the phosphorylation shift depends on the duration but not the time of
onset of naris closure. Because staining for phosphorylation-independent forms of
MAP2 is unchanged by naris closure, the total amount of the protein per unit area
is probably not significantly altered. However, the large reductions of AP18
immunoreactivity in the bulb after olfactory restriction suggest that there is an
activity-dependent stimulation of MAP2 phosphorylation.
PMID- 9391013
TI - BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical
axotomy, stimulate GAP-43 and Talpha1-tubulin mRNA expression, and promote axonal
regeneration.
AB - Rubrospinal neurons (RSNs) undergo a marked atrophy in the second week after
cervical axotomy. This delayed atrophy is accompanied by a decline in the
expression of regeneration-associated genes such as GAP-43 and Talpha1-tubulin,
which are initially elevated after injury. These responses may reflect a
deficiency in the trophic support of axotomized RSNs. To test this hypothesis, we
first analyzed the expression of mRNAs encoding the trk family of neurotrophin
receptors. In situ hybridization revealed expression of full-length trkB
receptors in virtually all RSNs, which declined 7 d after axotomy. Full-length
trkC mRNA was expressed at low levels. Using RT-PCR, we found that mRNAs encoding
trkC isoforms with kinase domain inserts were present at levels comparable to
that for the unmodified receptor. TrkA mRNA expression was not detected in RSNs,
and the expression of p75 was restricted to a small subpopulation of axotomized
cells. In agreement with the pattern of trk receptor expression, infusion of
recombinant human BDNF or NT-4/5 into the vicinity of the axotomized RSNs,
between days 7 and 14 after axotomy, fully prevented their atrophy. This effect
was still evident 2 weeks after the termination of BDNF treatment. Moreover, BDNF
or NT-4/5 treatment stimulated the expression of GAP-43 and Talpha1-tubulin mRNA
and maintained the level of trkB expression. Vehicle, NGF, or NT-3 treatment had
no significant effect on cell size or GAP-43 and Talpha1-tubulin expression. In a
separate experiment, infusion of BDNF also was found to increase the number of
axotomized RSNs that regenerated into a peripheral nerve graft. Thus, in BDNF
treated animals, the prevention of neuronal atrophy and the stimulation GAP-43
and Talpha1-tubulin expression is correlated with an increased regenerative
capacity of axotomized RSNs.
PMID- 9391015
TI - Sexual dimorphism in the spinal cord is absent in mice lacking the ciliary
neurotrophic factor receptor.
AB - Ciliary neurotrophic factor (CNTF) has potent survival-promoting effects on
motoneurons in vitro and in vivo. We examined knockout mice with null mutations
of the gene for either CNTF itself or the alpha-subunit of the CNTF receptor
(CNTFRalpha) to assess whether CNTF and/or its receptors are involved in the
development of a sexually dimorphic neuromuscular system. Male rodents have many
more motoneurons in the spinal nucleus of the bulbocavernosus (SNB) than do
females. This sex difference is caused by hormone-regulated death of SNB
motoneurons and their target muscles. Sexual dimorphism of SNB motoneuron number
developed completely normally in CNTF knockout (CNTF -/-) mice. In contrast, a
sex difference in the SNB was absent in CNTFRalpha -/- animals: male mice lacking
a functional CNTF alpha-receptor had fewer than half as many SNB motoneurons than
did wild-type males and no more than did their female counterparts. Size of the
bulbocavernosus and levator ani muscles, the main targets of SNB motoneurons, was
not affected in either CNTF or CNTFRalpha knockout males. These observations
suggest that signaling through the CNTF receptor is involved in sexually
dimorphic development of SNB motoneuron number and that target muscle survival
per se is not sufficient to ensure motoneuron survival in this system. In
addition, our observations are consistent with the suggestion that CNTF itself is
not the only endogenous ligand for the CNTF receptor. A second, as yet unknown,
ligand may be important for neural development, including sexually dimorphic
motoneuron development.
PMID- 9391016
TI - Impaired parallel fiber-->Purkinje cell synapse stabilization during cerebellar
development of mutant mice lacking the glutamate receptor delta2 subunit.
AB - The glutamate receptor delta2 subunit (GluRdelta2) is specifically expressed in
cerebellar Purkinje cells (PCs) from early developmental stages and is
selectively localized at dendritic spines forming synapses with parallel fibers
(PFs). Targeted disruption of the GluRdelta2 gene leads to a significant
reduction of PF-->PC synapses. To address its role in the synaptogenesis, the
morphology and electrophysiology of PF-->PC synapses were comparatively examined
in developing GluRdelta2 mutant and wild-type cerebella. PCs in GluRdelta2 mutant
mice were normally produced, migrated, and formed spines, as did those in wild
type mice. At the end of the first postnatal week, 74-78% of PC spines in both
mice formed immature synapses, which were characterized by small synaptic
contact, few synaptic vesicles, and incomplete surrounding by astroglial
processes, eliciting little electrophysiological response. During the second and
third postnatal weeks when spines and terminals are actively generated, the
percentage of PC spines forming synapses attained 98-99% in wild type but
remained as low as 55-60% in mutants, and the rest were unattached to any nerve
terminals. As a result, the number of PF synapses per single-mutant PCs was
reduced to nearly a half-level of wild-type PCs. Parallelly, PF stimulation less
effectively elicited EPSCs in mutant PCs than in wild-type PCs during and after
the second postnatal week. These results suggest that the GluRdelta2 is involved
in the stabilization and strengthening of synaptic connectivity between PFs and
PCs, leading to the association of all PC spines with PF terminals to form
functionally mature synapses.
PMID- 9391017
TI - Macrophage/Microglia regulation of astrocytic tenascin: synergistic action of
transforming growth factor-beta and basic fibroblast growth factor.
AB - After injury to the CNS, extracellular matrix molecules such as tenascin are
upregulated around the injury site and may be involved in inhibition of axon
growth. In the present study, astrocytes were investigated to determine which
cell types, growth factors, or cytokines are responsible for the injury-induced
regulation of tenascin. The addition of activated macrophage- or microglial
conditioned medium increased astrocytic expression of tenascin 2.5-fold, as
determined by Northern and Western blot analysis and ELISA. Of the cytokines and
growth factors examined, only transforming growth factor-beta1 (TGF-beta1) and
basic fibroblast growth factor (bFGF) significantly induced an increase in the
production of astrocytic tenascin. Examination of macrophage and microglial
supernatants showed the presence of TGF-beta1 but not bFGF; however, the TGF
beta1 concentration in supernatants was lower than that expected to induce an
increase in astrocytic tenascin similar to that seen with recombinant TGF-beta1.
Western blot analysis of astrocytes showed only the presence of bFGF. Compared
with the responses of the individual growth factors, tenascin production by
astrocytes was dramatically potentiated when grown in the presence of a
combination of both TGF-beta1 and bFGF. A similar synergistic effect was observed
after the addition of either TGF-beta1 or bFGF to macrophage-conditioned medium.
Northern analysis also showed concomitant increases in TGF-beta1, bFGF, and
tenascin after CNS injury to animals 14 d of age or older. These results show
that the regulation of astrocytic tenascin is mediated by the synergistic action
of TGF-beta1 and bFGF in vitro and after injury in vivo.
PMID- 9391018
TI - Development of membrane properties in taste cells of fungiform papillae:
functional evidence for early presence of amiloride-sensitive sodium channels.
AB - Behavioral and physiological studies have demonstrated a reduced sensitivity to
several taste stimuli early in development. It has been suggested that this
reduced sensitivity results from a late maturation of underlying transduction
mechanisms. Little is known, however, about maturation of membrane properties of
taste cells early in development. We have obtained whole-cell recordings from
single fungiform taste cells of rat pups to examine the development of the NaCl
transduction system. Although taste buds undergo a considerable increase in size
during development, membrane capacitance measurements revealed no change in
membrane surface area of individual taste cells, suggesting that the increase in
size results from an increase in the total number of cells per bud. Whole-cell
recordings showed that taste cells from very young pups [postnatal day 2 (PND2)]
already possessed voltage-activated Na+ and K+ currents with no apparent
differences in size or kinetics compared with adults. Surprisingly, amiloride
sensitive Na+ responses, important for Na+ transduction, were found as early as
PND2. The magnitude of responses to amiloride and the percentage of amiloride
sensitive cells remained the same throughout all age groups. Furthermore, the
similarity of amiloride inhibition constants suggested that the channel in
neonates is the same channel that is expressed in adult taste buds. Our results
indicate that taste cells at PND2 already have acquired the transduction elements
necessary for signaling NaCl responses to the afferent nerve. We hypothesize that
complete functionality of the salt taste transduction system, however, may not be
reached until amiloride-sensitive Na+ channels become selectively localized at
the apical membrane. This would explain previous studies indicating that
amiloride sensitivity cannot be detected before PND12 in the intact tongue.
Apical clustering of channels along with the opening of the taste pore and an
increase in the total number of taste cells per bud likely constitute additional
important steps toward a fully functional sensory system.
PMID- 9391019
TI - The origin, location, and projections of the embryonic abdominal motorneurons of
Drosophila.
AB - We have used a retrograde labeling technique to identify motorneurons for each of
the 30 body wall muscles of an abdominal hemisegment in the late stage 16
Drosophila embryo. Each motorneuron has a characteristic cell body position,
dendritic arborization, and axonal projection. In addition, we have determined
the neuroblasts of origin for most of the motorneurons we describe. Some
organizational principles for the neuromuscular system have become apparent: (1)
There is no obvious topographic relationship between the cell body positions of
motorneurons and the position or orientation of the muscles they innervate; (2)
motorneurons that innervate muscles of similar position and orientation are often
clustered and have overlapping dendritic trees; (3) morphologically similar
motorneurons are generally derived from a common neuroblast and innervate
operationally related muscles; and (4) neuroblasts can give rise to more than one
morphological type of motorneuron.
PMID- 9391020
TI - Analysis of the mechanism of loss of trophic factor dependence associated with
neuronal maturation: a phenotype indistinguishable from Bax deletion.
AB - During development, sympathetic neurons are critically dependent on nerve growth
factor (NGF) for survival. Neurons isolated from the superior cervical ganglia
(SCG) of embryonic rodents and maintained for 1 week in vitro undergo programmed
cell death in response to NGF deprivation. As the cells mature in vitro and in
vivo, however, these neurons develop a resistance to NGF deprivation and become
much less acutely dependent on NGF for survival. Using an in vitro model of
neuronal maturation, we confirmed that SCG neurons maintained in culture for 3-4
weeks did not experience a dramatic loss in viability after NGF removal, yet they
did undergo the initial biochemical and genetic changes elicited by NGF
deprivation of young neurons. NGF deprivation of mature neurons produced rapid
decreases in glucose uptake and protein and RNA synthesis rates, increased
phosphorylation of c-Jun, and an increase in c-jun mRNA. Mature neurons, however,
experienced a block in the cell death program before the final stages of the
pathway activated in young neurons, which includes the induction of c-fos mRNA
and characteristic apoptotic nuclear changes. This maturation-induced block was
indistinguishable by these criteria from the block produced by Bax deficiency.
Expression of Bax in mature neurons restored the apoptotic pathway, such that
after NGF removal, Bax-overexpressing mature neurons resumed the apoptotic
program, including the induction of c-Fos and passage through a caspase
checkpoint. Thus, a block in the apoptotic program at or near the BAX checkpoint
accounts for the decreased dependence of mature neurons on neurotrophic factor to
maintain survival.
PMID- 9391021
TI - Role of the supplementary motor area and the right premotor cortex in the
coordination of bimanual finger movements.
AB - To obtain a better understanding of the cortical representation of bimanual
coordination, we measured regional cerebral blood flow (rCBF) with 15O-labeled
water and positron emission tomography (PET). To detect areas with changes of
rCBF during bimanual finger movements of different characteristics, we studied 12
right-handed normal volunteers. A complete session consisted of three rest scans
and six scans with acoustically paced (1 Hz) bimanual, mirror, or parallel
sequential finger movements. Activation of the right dorsal premotor area (PMd)
extending to the posterior supplementary motor area (SMA) was significantly
stronger during the parallel movements than during the mirror sequential
movements (p < 0.05, at cluster level with correction for multiple comparisons).
To determine whether these cortical areas truly represented bimanual
coordination, a different group of nine normal volunteers was studied with a
different task. Subjects performed acoustically paced (2 Hz) abduction-adduction
movements of the index finger, making right only, left only, and bimanual mirror
and parallel movements. Activation of the posterior SMA and right PMd was
significantly greater during the parallel movements than during the bimanual
mirror movements or the unimanual movements of either hand (p < 0.01, with
anatomical constraint). Thus, the posterior SMA and right PMd appear to be
related to the bimanual coordination of finger movements.
PMID- 9391022
TI - Lobular patterns of cerebellar activation in verbal working-memory and finger
tapping tasks as revealed by functional MRI.
AB - The lobular distributions of functional activation of the cerebellum during
verbal working-memory and finger movement tasks were investigated using
functional magnetic resonance imaging (fMRI). Relative to a rest control, finger
tapping of the right hand produced ipsilateral-increased activation in HIV/HV
[Roman numeral designations based on Larsell's () nomenclature] and HVI and
weaker activation in HVIII that was stronger on the ipsilateral side. For a
working-memory task, subjects were asked to remember six (high load) or one (low
load) visually presented letters across a brief delay. To assess the motoric
aspects of rehearsal in the absence of working memory, we asked the subjects to
repeatedly read subvocally six or one letters at a rate that approximated the
internally generated rehearsal of working memory (motoric rehearsal task). For
both tasks, bilateral regions of the superior cerebellar hemispheres (left
superior HVIIA and right HVI) and portions of posterior vermis (VI and superior
VIIA) exhibited increased activation during high relative to low load conditions.
In contrast, the right inferior cerebellar hemisphere (HVIIB) exhibited this load
effect only during the working-memory task. We hypothesize that HVI and superior
HVIIA activation represents input from the articulatory control system of working
memory from the frontal lobes and that HVIIB activation is derived from the
phonological store in temporal and parietal regions. From these inputs, the
cerebellum could compute the discrepancy between actual and intended phonological
rehearsal and use this information to update a feedforward command to the frontal
lobes, thereby facilitating the phonological loop.
PMID- 9391023
TI - Insular cortical projections to functional regions of the striatum correlate with
cortical cytoarchitectonic organization in the primate.
AB - We examined the striatal projections from different cytoarchitectonic regions of
the insular cortex using anterograde and retrograde techniques. The shell and
medial ventral striatum receive inputs primarily from the agranular and ventral
dysgranular insula. The central ventral striatum receives inputs primarily from
the dorsal agranular and dysgranular insula. Projections to the central ventral
striatum originate from more posterior and dorsal insular regions than
projections to the medial ventral striatum. The dorsolateral striatum receives
projections primarily from the dorsal dysgranular and granular insula. These
results show that cytoarchitectonically less differentiated (agranular) insular
regions project to the ventromedial "limbic" part of the ventral striatum,
whereas more differentiated (granular) insular regions project to the
dorsolateral "sensorimotor" part of the striatum. The finding that the ventral
"limbic" striatum receives inputs from less differentiated regions of the insula
is consistent with the general principle that less differentiated cortical
regions project primarily to the "limbic" striatum. Functionally, the ventral
striatum receives insular projections primarily related to integrating feeding
behavior with rewards and memory, whereas the dorsolateral striatum receives
insular inputs related to the somatosensation. Information regarding food
acquisition in the insula may be sent to the intermediate area of the striatum.
PMID- 9391024
TI - A neural model of multimodal adaptive saccadic eye movement control by superior
colliculus.
AB - How does the saccadic movement system select a target when visual, auditory, and
planned movement commands differ? How do retinal, head-centered, and motor error
coordinates interact during the selection process? Recent data on superior
colliculus (SC) reveal a spreading wave of activation across buildup cells the
peak activity of which covaries with the current gaze error. In contrast, the
locus of peak activity remains constant at burst cells, whereas their activity
level decays with residual gaze error. A neural model answers these questions and
simulates burst and buildup responses in visual, overlap, memory, and gap tasks.
The model also simulates data on multimodal enhancement and suppression of
activity in the deeper SC layers and suggests a functional role for NMDA
receptors in this region. In particular, the model suggests how auditory and
planned saccadic target positions become aligned and compete with visually
reactive target positions to select a movement command. For this to occur, a
transformation between auditory and planned head-centered representations and a
retinotopic target representation is learned. Burst cells in the model generate
teaching signals to the spreading wave layer. Spreading waves are produced by
corollary discharges that render planned and visually reactive targets
dimensionally consistent and enable them to compete for attention to generate a
movement command in motor error coordinates. The attentional selection process
also helps to stabilize the map-learning process. The model functionally
interprets cells in the superior colliculus, frontal eye field, parietal cortex,
mesencephalic reticular formation, paramedian pontine reticular formation, and
substantia nigra pars reticulata.
PMID- 9391025
TI - The circumventricular organs form a potential neural pathway for lactate
sensitivity: implications for panic disorder.
AB - Patients with panic disorder experience panic attacks after intravenous sodium
lactate infusions by an as yet unexplained mechanism. Lactate elicits a panic
like response in rats with chronic dysfunction of GABA neurotransmission in the
dorsomedial hypothalamus (DMH). The circumventricular organs, organum vasculosum
lamina terminalis (OVLT) and subfornical organ (SFO), are potential sites that
could detect increases in plasma lactate levels and activate the DMH. To test
this, we obtained baseline heart rate (HR) and blood pressure (BP) responses to
lactate infusions in rats fit with femoral arterial and venous catheters. Next,
unilateral chronic injection cannulae connected to an Alzet infusion pump filled
with the GABA synthesis inhibitor L-allylglycine (L-AG) were implanted into the
DMH. Another chronic injection cannula was implanted into the region of the OVLT,
SFO, or an adjacent control site, the median preoptic area (MePOA). These rats
were tested once again with lactate infusions after injection of either
artificial cerebrospinal fluid (ACSF) or tetrodotoxin (TTX) into the CVO sites.
Injecting TTX into the OVLT completely blocked the lactate-induced response,
whereas TTX injections into the SFO or MePOA did not. Also, direct injections of
lactate (100 or 500 nl) into the OVLT elicited robust anxiety-like responses in
these rats. These results suggest that the OVLT may be the primary site that
detects lactate infusions, activating an anxiety-like response in a compromised
DMH, and provide the first neuroanatomical basis for lactate response in panic
disorder.
PMID- 9391026
TI - The cerebellum and red nucleus are not required for In vitro classical
conditioning of the turtle abducens nerve response.
AB - The role of the cerebellum during motor learning is a controversial issue. Many
authors have suggested that the cerebellum and its connections with the red
nucleus are essential for the acquisition of the conditioned eye blink reflex.
Although there is little argument that the cerebellum is an important component
to the generation of the conditioned response (CR), a number of studies have
suggested that the cerebellum is not essential for conditioning. Using an in
vitro model of the classically conditioned turtle abducens nerve response, we
investigated the effect of cerebellar and red nucleus lesions on the acquisition,
extinction, and reacquisition of CRs. Neural discharge was recorded from the
abducens nerve after a single shock unconditioned stimulus (US) was applied to
the ipsilateral trigeminal nerve. When the US was paired with a conditioned
stimulus (CS) applied to the posterior eighth, or auditory, nerve, a positive
slope of CR acquisition was recorded in the abducens nerve. After extinction
stimuli in which the CS and US were alternated, the number of CRs decreased to
near zero. When the CS and US were once again paired, reacquisition at a faster
rate was recorded. The CRs showed unusual timing features compared with
preparations in which the cerebellum was intact; they had significantly shorter
latencies and showed burst-like responses. These data demonstrate that it is
possible to classically condition this in vitro preparation in the absence of the
cerebellum and red nucleus. However, the latencies of CRs were found to be
dramatically altered in the cerebellar-lesioned preparations, suggesting that the
cerebellum does play a role in the timing of the CR.
PMID- 9391027
TI - Effects of sleep on wake-induced c-fos expression.
AB - We investigated the effects of sleep on wake-induced c-fos expression in the
cerebral cortex of rats and c-fos-lacZ transgenic mice. In the cortex of rats,
the levels of c-Fos, detected both by immunocytochemistry and Western blot,
remained high during 6 or 12 hr of enforced wakefulness but declined rapidly
(within 1 hr) with increasing time of recovery sleep. Similarly, in the
transgenic mice in which lacZ expression is driven from the c-fos promoter, beta
galactosidase activity was high after enforced wakefulness and declined with
increasing amounts of sleep. These results suggest that the decrease in c-Fos
protein in cortical neurons during sleep may be attributable to cessation of c
fos expression, activation of a process that degrades the wake-induced c-Fos, or
both.
PMID- 9391029
TI - On the utility of nitrogen in leaves.
PMID- 9391028
TI - A hypothesis about the endogenous analogue of general anesthesia.
PMID- 9391030
TI - Weaving cartilage at zero g: the reality of tissue engineering in space.
PMID- 9391031
TI - Ways and means for left shifts in the MaxiK channel.
PMID- 9391032
TI - Metal ions and synaptic transmission: think zinc.
PMID- 9391034
TI - Electric field-induced reorganization of two-component supported bilayer
membranes.
AB - Application of electric fields tangent to the plane of a confined patch of fluid
bilayer membrane can create lateral concentration gradients of the lipids. A
thermodynamic model of this steady-state behavior is developed for binary systems
and tested with experiments in supported lipid bilayers. The model uses Flory's
approximation for the entropy of mixing and allows for effects arising when the
components have different molecular areas. In the special case of equal area
molecules the concentration gradient reduces to a Fermi-Dirac distribution. The
theory is extended to include effects from charged molecules in the membrane.
Calculations show that surface charge on the supporting substrate substantially
screens electrostatic interactions within the membrane. It also is shown that
concentration profiles can be affected by other intermolecular interactions such
as clustering. Qualitative agreement with this prediction is provided by
comparing phosphatidylserine- and cardiolipin-containing membranes.
PMID- 9391033
TI - Transcriptional activation: is it rocket science?
PMID- 9391035
TI - A yeast genetic system for selecting small molecule inhibitors of protein-protein
interactions in nanodroplets.
AB - Cellular processes are mediated by complex networks of molecular interactions.
Dissection of their role most commonly is achieved by using genetic mutations
that alter, for example, protein-protein interactions. Small molecules that
accomplish the same result would provide a powerful complement to the genetic
approach, but it generally is believed that such molecules are rare. There are
several natural products, however, that illustrate the feasibility of this
approach. Split-pool synthesis now provides a simple mechanical means to prepare
vast numbers of complex, even natural product-like, molecules individually
attached to cell-sized polymer beads. Here, we describe a genetic system
compatible with split-pool synthesis that allows the detection of cell-permeable,
small molecule inhibitors of protein-protein interactions in 100- to 200-nl cell
culture droplets, prepared by a recently described technique that arrays large
numbers of such droplets. These "nanodroplets" contain defined media, cells, and
one or more beads containing approximately 100 pmol of a photoreleasable small
molecule and a controlled number of cells. The engineered Saccharomyces
cerevisiae cells used in this study express two interacting proteins after
induction with galactose whose interaction results in cell death in the presence
of 5-fluoroorotic acid (inducible reverse two-hybrid assay). Disruption of the
interaction by a small molecule allows growth, and the small molecule can be
introduced into the system hours before induction of the toxic interaction. We
demonstrate that the interaction between the activin receptor R1 and the
immunophilin protein FKBP12 can be disrupted by the small molecule FK506 at
nanomolar concentrations in nanodroplets. This system should provide a general
method for selecting cell-permeable ligands that can be used to study the
relevance of protein-protein interactions in living cells or organisms.
PMID- 9391037
TI - Isotropic isotopy and symplectic null sets.
AB - Capacity is an important numerical invariant of symplectic manifolds. This paper
studies when a subset of a symplectic manifold is null, i.e., can be removed
without affecting the ambient capacity. After examples of open null sets and
codimension-2 non-null sets, geometric techniques are developed to perturb any
isotopy of a loop to a hamiltonian flow; it follows that sets of dimension 0 and
1 are null. For isotropic sets of higher dimensions, obstructions to the
perturbation are found in homotopy groups of the orthogonal groups.
PMID- 9391036
TI - A nonnatural transcriptional coactivator.
AB - In eukaryotes, sequence-specific DNA-binding proteins activate gene expression by
recruiting the transcriptional apparatus and chromatin remodeling proteins to the
promoter through protein-protein contacts. In many instances, the connection
between DNA-binding proteins and the transcriptional apparatus is established
through the intermediacy of adapter proteins known as coactivators. Here we
describe synthetic molecules with low molecular weight that act as
transcriptional coactivators. We demonstrate that a completely nonnatural
activation domain in one such molecule is capable of stimulating transcription in
vitro and in vivo. The present strategy provides a means of gaining external
control over gene activation through intervention using small molecules.
PMID- 9391038
TI - Characterization of residual structure in the thermally denatured state of
barnase by simulation and experiment: description of the folding pathway.
AB - Residual structure in the denatured state of a protein may contain clues about
the early events in folding. We have simulated by molecular dynamics the
denatured state of barnase, which has been studied by NMR spectroscopy. An
ensemble of 10(4) structures was generated after 2 ns of unfolding and following
for a further 2 ns. The ensemble was heterogeneous, but there was nonrandom,
residual structure with persistent interactions. Helical structure in the C
terminal portion of helix alpha1 (residues 13-17) and in helix alpha2 as well as
a turn and nonnative hydrophobic clustering between beta3 and beta4 were
observed, consistent with NMR data. In addition, there were tertiary contacts
between residues in alpha1 and the C-terminal portion of the beta-sheet. The
simulated structures allow the rudimentary NMR data to be fleshed out. The
consistency between simulation and experiment inspires confidence in the methods.
A description of the folding pathway of barnase from the denatured to the native
state can be constructed by combining the simulation with experimental data from
phi value analysis and NMR.
PMID- 9391039
TI - Catalytic mechanism of the adenylyl and guanylyl cyclases: modeling and
mutational analysis.
AB - The adenylyl and guanylyl cyclases catalyze the formation of 3', 5'-cyclic
adenosine or guanosine monophosphate from the corresponding nucleoside 5'
triphosphate. The guanylyl cyclases, the mammalian adenylyl cyclases, and their
microbial homologues function as pairs of homologous catalytic domains. The
crystal structure of the rat type II adenylyl cyclase C2 catalytic domain was
used to model by homology a mammalian adenylyl cyclase C1-C2 domain pair, a
homodimeric adenylyl cyclase of Dictyostelium discoideum, a heterodimeric soluble
guanylyl cyclase, and a homodimeric membrane guanylyl cyclase. Mg2+ATP or Mg2+GTP
were docked into the active sites based on known stereochemical constraints on
their conformation. The models are consistent with the activities of seven active
site mutants. Asp-310 and Glu-432 of type I adenylyl cyclase coordinate a Mg2+
ion. The D310S and D310A mutants have 10-fold reduced Vmax and altered [Mg2+]
dependence. The NTP purine moieties bind in mostly hydrophobic pockets.
Specificity is conferred by a Lys and an Asp in adenylyl cyclase, and a Glu, an
Arg, and a Cys in guanylyl cyclase. The models predict that an Asp from one
domain is a general base in the reaction, and that the transition state is
stabilized by a conserved Asn-Arg pair on the other domain.
PMID- 9391040
TI - Identification of a second aryl phosphate-binding site in protein-tyrosine
phosphatase 1B: a paradigm for inhibitor design.
AB - The structure of the catalytically inactive mutant (C215S) of the human protein
tyrosine phosphatase 1B (PTP1B) has been solved to high resolution in two
complexes. In the first, crystals were grown in the presence of bis-(para
phosphophenyl) methane (BPPM), a synthetic high-affinity low-molecular weight
nonpeptidic substrate (Km = 16 microM), and the structure was refined to an R
factor of 18. 2% at 1.9 A resolution. In the second, crystals were grown in a
saturating concentration of phosphotyrosine (pTyr), and the structure was refined
to an R-factor of 18.1% at 1.85 A. Difference Fourier maps showed that BPPM binds
PTP1B in two mutually exclusive modes, one in which it occupies the canonical
pTyr-binding site (the active site), and another in which a phosphophenyl moiety
interacts with a set of residues not previously observed to bind aryl phosphates.
The identification of a second pTyr molecule at the same site in the PTP1B/C215S
pTyr complex confirms that these residues constitute a low-affinity noncatalytic
aryl phosphate-binding site. Identification of a second aryl phosphate binding
site adjacent to the active site provides a paradigm for the design of tight
binding, highly specific PTP1B inhibitors that can span both the active site and
the adjacent noncatalytic site. This design can be achieved by tethering together
two small ligands that are individually targeted to the active site and the
proximal noncatalytic site.
PMID- 9391041
TI - Inhibition of HIV type 1 infectivity by constrained alpha-helical peptides:
implications for the viral fusion mechanism.
AB - Linear peptides derived from the membrane proximal region of the gp41 ectodomain
are effective inhibitors of HIV type 1 (HIV-1)-mediated fusion events. These
inhibitory peptides lack structure in solution, rendering mechanistic
interpretation of their activity difficult. Using structurally constrained
analogs of these molecules, we demonstrate that the peptides inhibit infectivity
by adopting a helical conformation. Moreover, we show that a specific face of the
helix must be exposed to block viral infectivity. Recent crystal structures show
that the region of gp41 corresponding to the inhibitory peptides is helical and
uses the analogous face to pack against a groove formed by an N-terminal coiled
coil trimer. Our results provide a direct link between the inhibition of HIV-1
infectivity by these peptides and the x-ray structures, and suggest that the
conformation of gp41 observed by crystallography represents the fusogenic state.
Other agents that block HIV-1 infectivity by binding to this groove may hold
promise for the treatment of AIDS.
PMID- 9391042
TI - Overexpression of a glutamate receptor (GluR2) ligand binding domain in
Escherichia coli: application of a novel protein folding screen.
AB - Expression of the S1S2 ligand binding domain [Kuusinen, A., Arvola, M. &
Keinanen, K. (1995) EMBO J. 14, 6327-6332] of the rat alpha-amino-3-hydroxy-5
methylisoxazole-4-propionic acid-selective glutamate receptor GluR2 in
Escherichia coli under control of a T7 promoter leads to production of >100
mg/liter of histidine-tagged S1S2 protein (HS1S2) in the form of inclusion
bodies. Using a novel fractional factorial folding screen and a rational, step-by
step approach, multiple conditions were determined for the folding of the HS1S2
alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding domain.
Characterization of the HS1S2 ligand binding domain showed that it is water
soluble, monomeric, has significant secondary structure, and is sensitive to
trypsinolysis at sites close to the beginning of the putative transmembrane
regions. Application of a fractional factorial folding screen to other proteins
may provide a useful means to evaluate E. coli as an economical and convenient
expression host.
PMID- 9391043
TI - Regulation of ribonuclease III processing by double-helical sequence
antideterminants.
AB - The double helix is a ubiquitous feature of RNA molecules and provides a target
for nucleases involved in RNA maturation and decay. Escherichia coli ribonuclease
III participates in maturation and decay pathways by site-specifically cleaving
double-helical structures in cellular and viral RNAs. The site of cleavage can
determine RNA functional activity and half-life and is specified in part by local
tertiary structure elements such as internal loops. The involvement of base pair
sequence in determining cleavage sites is unclear, because RNase III can
efficiently degrade polymeric double-stranded RNAs of low sequence complexity. An
alignment of RNase III substrates revealed an exclusion of specific Watson-Crick
bp sequences at defined positions relative to the cleavage site. Inclusion of
these "disfavored" sequences in a model substrate strongly inhibited cleavage in
vitro by interfering with RNase III binding. Substrate cleavage also was
inhibited by a 3-bp sequence from the selenocysteine-accepting tRNASec, which
acts as an antideterminant of EF-Tu binding to tRNASec. The inhibitory bp
sequences, together with local tertiary structure, can confer site specificity to
cleavage of cellular and viral substrates without constraining the degradative
action of RNase III on polymeric double-stranded RNA. Base pair antideterminants
also may protect double-helical elements in other RNA molecules with essential
functions.
PMID- 9391044
TI - The C9 methyl group of retinal interacts with glycine-121 in rhodopsin.
AB - The visual pigment rhodopsin is a prototypical G protein-coupled receptor. These
receptors have seven transmembrane helices and are activated by specific receptor
ligand interactions. Rhodopsin is unusual in that its retinal prosthetic group
serves as an antagonist in the dark in the 11-cis conformation but is rapidly
converted to an agonist on photochemical cis to trans isomerization. Receptor
ligand interactions in rhodopsin were studied in the light and dark by
regenerating site-directed opsin mutants with synthetic retinal analogues. A
progressive decrease in light-dependent transducin activity was observed when a
mutant opsin with a replacement of Gly121 was regenerated with 11-cis-retinal
analogues bearing progressively larger R groups (methyl, ethyl, propyl) at the C9
position of the polyene chain. A progressive decrease in light activity was also
observed as a function of increasing size of the residue at position 121 for both
the 11-cis-9-ethyl- and the 11-cis-9-propylretinal pigments. In contrast, a
striking increase of receptor activity in the dark-i.e., without chromophore
isomerization-was observed when the molecular volume at either position 121 of
opsin or C9 of retinal was increased. The ability of bulky replacements at either
position to hinder ligand incorporation and to activate rhodopsin in the dark
suggests a direct interaction between these two sites. A molecular model of the
retinal-binding site of rhodopsin is proposed that illustrates the specific
interaction between Gly121 and the C9 methyl group of 11-cis-retinal. Steric
interactions in this region of rhodopsin are consistent with the proposal that
movement of transmembrane helices 3 and 6 is concomitant with receptor
activation.
PMID- 9391045
TI - The major chromatin protein histone H1 binds preferentially to cis-platinum
damaged DNA.
AB - Both cis-diamminedichloroplatinum(II) (cisplatin or cis-DDP) and trans
diamminedichloroplatinum(II) form covalent adducts with DNA. However, only the
cis isomer is a potent anticancer agent. It has been postulated that the
selective action of cis-DDP occurs through specific binding of nuclear proteins
to cis-DDP-damaged DNA sites and that binding blocks DNA repair. We find that a
very abundant nuclear protein, the linker histone H1, binds much more strongly to
cis-platinated DNA than to trans-platinated or unmodified DNA. In competition
experiments, H1 is shown to bind much more strongly than HMG1, which had been
previously considered a major candidate for such binding in vivo.
PMID- 9391046
TI - Structure of the recombinant full-length hamster prion protein PrP(29-231): the N
terminus is highly flexible.
AB - The prion diseases seem to be caused by a conformational change of the prion
protein (PrP) from the benign cellular form PrPC to the infectious scrapie form
PrPSc; thus, detailed information about PrP structure may provide essential
insights into the mechanism by which these diseases develop. In this study, the
secondary structure of the recombinant Syrian hamster PrP of residues 29-231
[PrP(29-231)] is investigated by multidimensional heteronuclear NMR. Chemical
shift index analysis and nuclear Overhauser effect data show that PrP(29-231)
contains three helices and possibly one short beta-strand. Most striking is the
random-coil nature of chemical shifts for residues 30-124 in the full-length PrP.
Although the secondary structure elements are similar to those found in mouse PrP
fragment PrP(121-231), the secondary structure boundaries of PrP(29-231) are
different from those in mouse PrP(121-231) but similar to those found in the
structure of Syrian hamster PrP(90-231). Comparison of resonance assignments of
PrP(29-231) and PrP(90-231) indicates that there may be transient interactions
between the additional residues and the structured core. Backbone dynamics
studies done by using the heteronuclear [1H]-15N nuclear Overhauser effect
indicate that almost half of PrP(29-231), residues 29-124, is highly flexible.
This plastic region could feature in the conversion of PrPC to PrPSc by template
assisted formation of beta-structure.
PMID- 9391047
TI - Histones H3 and H4 are components of upstream activation factor required for the
high-level transcription of yeast rDNA by RNA polymerase I.
AB - RNA polymerase I (Pol I) transcription in the yeast Saccharomyces cerevisiae is
greatly stimulated in vivo and in vitro by the multiprotein complex, upstream
activation factor (UAF). UAF binds tightly to the upstream element of the rDNA
promoter, such that once bound (in vitro), UAF does not readily exchange onto a
competing template. Of the polypeptides previously identified in purified UAF,
three are encoded by genes required for Pol I transcription in vivo: RRN5, RRN9,
and RRN10. Two others, p30 and p18, have remained uncharacterized. We report here
that the N-terminal amino acid sequence, its mobility in gel electrophoresis, and
the immunoreactivity of p18 shows that it is histone H3. In addition, histone H4
was found in UAF, and myc-tagged histone H4 could be used to affinity-purify UAF.
Histones H2A and H2B were not detectable in UAF. These results suggest that
histones H3 and H4 probably account for the strong binding of UAF to DNA and may
offer a means by which general nuclear regulatory signals could be transmitted to
Pol I.
PMID- 9391048
TI - Metabolism of an insect diuretic hormone by Malpighian tubules studied by liquid
chromatography coupled with electrospray ionization mass spectrometry.
AB - The larger of two diuretic hormones of the tobacco hornworm, Manduca sexta, (Mas
DH) is a peptide of 41 residues. It is one of a family of seven currently known
insect diuretic hormones that are similar to the corticotropin-releasing factor
urotensin-sauvagine family of peptides. We investigated the possible inactivation
of Mas-DH by incubating it in vitro with larval Malpighian tubules (Mt), the
target organ of the hormone. The medium was analyzed, and degradation products
were identified, using on-line microbore reversed-phase liquid chromatography
coupled to electrospray ionization mass spectrometry (RPLC-ESI-MS). This
sensitive technique allows identification of metabolites of Mas-DH (present at an
initial level of approximately 1 microM). An accurate Mr value for a metabolite
is usually sufficient for unambiguous identification. Mas-DH is cleaved by Mt
proteases initially at L29-R30 and R30-A31 under our assay conditions; some Mas
DH is also oxidized, apparently at M2 and M11. The proteolysis can be inhibited
by 5 mM EDTA, suggesting that divalent metals are needed for peptide cleavage.
The oxidation of the hormone can be inhibited by catalase or 1 mM methionine,
indicating that H2O2 or related reactive oxygen species are responsible for the
oxidative degradation observed. RPLC-ESI-MS is shown here to be an elegant and
efficient method for studying peptide hormone metabolism resulting from unknown
proteases and pathways.
PMID- 9391049
TI - Studies on the enzymatic and transcriptional activity of the dimerization
cofactor for hepatocyte nuclear factor 1.
AB - The relationship between the enzymatic and the transcriptional activity of the
bifunctional protein pterin-4a-carbinolamine dehydratase/dimerization cofactor
for hepatocyte nuclear factor 1 (DCoH) has been elucidated by site-directed
mutagenesis. DCoH dimers harbor a binding site for hepatocyte nuclear factor 1
(HNF1), two active centers that bind pterins, and a saddle-shaped surface that
resembles nucleic acid binding domains. Two domains of the protein have been
selectively targeted to determine if a change in one activity affects the other.
No strong correlation has been found, supporting the idea that carbinolamine
dehydratase activity is not required for HNF1 binding in vitro or transcriptional
coactivation in vivo. Double mutations in the active center, however, influence
the in vivo transcriptional activity but not HNF1 binding. This finding suggests
that some active center residues also are used during transcription, possibly for
binding of another (macro)molecule. Several mutations in the saddle led to a
surprising increase in transcription, therefore linking this domain to
transcriptional regulation as well. The transcriptional function of DCoH
therefore is composed of two parts, HNF1 binding and another contributing effect
that involves the active site and, indirectly, the saddle.
PMID- 9391051
TI - A mutant RNA polymerase that forms unusual open promoter complexes.
AB - We describe a mutant Escherichia coli RNA polymerase (RNAP) that forms stable
open promoter complexes even at -20 degrees C but with a shortened melted region
that extends downstream to only position -7. In the presence of initiating
transcription substrates, the mutant RNAP undergoes a temperature-dependent
isomerization, resulting in a promoter complex that is indistinguishable from the
wild-type RNAP-promoter complex, with the melted region extended downstream to
position +4. We propose that the open complex formed by the mutant RNAP
represents an intermediate on the normal promoter-opening pathway and that our
results support earlier findings that initial promoter opening occurs in the
upstream region of the -10 promoter consensus element and subsequently extends
downstream to encompass the transcription start site.
PMID- 9391050
TI - Bidirectional binding of the TATA box binding protein to the TATA box.
AB - By selective attachment of a DNA cleavage agent to specific residues in the yeast
TATA box binding protein (yTBP), we demonstrate that, in solution, yTBP binds to
the TATA boxes of both the adenovirus major late promoter and the yeast CYC1
promoter with only a modest preference in orientation and binds well to several
overlapping binding sites. The general factors TFIIA and TFIIB each increase the
rotational and translational selectivity of yTBP but are not sufficient, at least
individually, to confer a unique polarity to the preinitiation complex. We
conclude that TBP alone cannot define the productive orientation of general
factor assembly on a promoter.
PMID- 9391052
TI - B12-dependent ribonucleotide reductases from deeply rooted eubacteria are
structurally related to the aerobic enzyme from Escherichia coli.
AB - The ribonucleotide reductases from three ancient eubacteria, the
hyperthermophilic Thermotoga maritima (TM), the radioresistant Deinococcus
radiodurans (DR), and the thermophilic photosynthetic Chloroflexus aurantiacus,
were found to be coenzyme-B12 (class II) enzymes, similar to the earlier
described reductases from the archaebacteria Thermoplasma acidophila and
Pyrococcus furiosus. Reduction of CDP by the purified TM and DR enzymes requires
adenosylcobalamin and DTT. dATP is a positive allosteric effector, but
stimulation of the TM enzyme only occurs close to the temperature optimum of 80
90 degrees C. The TM and DR genes were cloned by PCR from peptide sequence
information. The TM gene was sequenced completely and expressed in Escherichia
coli. The deduced amino acid sequences of the two eubacterial enzymes are
homologous to those of the archaebacteria. They can also be aligned to the
sequence of the large protein of the aerobic E. coli ribonucleotide reductase
that belongs to a different class (class I), which is not dependent on B12.
Structure determinations of the E. coli reductase complexed with substrate and
allosteric effectors earlier demonstrated a 10-stranded beta/alpha-barrel in the
active site. From the conservation of substrate- and effector-binding residues we
propose that the B12-dependent class II enzymes contain a similar barrel.
PMID- 9391053
TI - Computer-based analysis of the binding steps in protein complex formation.
AB - Computer models were used to examine whether and under what conditions the
multimeric protein complex is inhibited by high concentrations of one of its
components-an effect analogous to the prozone phenomenon in precipitin tests. A
series of idealized simple "ball-and-stick" structures representing small
oligomeric complexes of protein molecules formed by reversible binding reactions
were analyzed to determine the binding steps leading to each structure. The
equilibrium state of each system was then determined over a range of starting
concentrations and Kds and the steady-state concentration of structurally
complete oligomer calculated for each situation. A strong inhibitory effect at
high concentrations was shown by any protein molecule forming a bridge between
two or more separable parts of the complex. By contrast, proteins linked to the
outside of the complex by a single bond showed no inhibition whatsoever at any
concentration. Nonbridging, multivalent proteins in the body of the complex could
show an inhibitory effect or not depending on the structure of the complex and
the strength of its bonds. On the basis of this study, we suggest that the
prozone phenomenon will occur widely in living cells and that it could be a
crucial factor in the regulation of protein complex formation.
PMID- 9391054
TI - Ultraspiracle: an invertebrate nuclear receptor for juvenile hormones.
AB - Juvenile hormones (JH), a sesquiterpenoid group of ligands that regulate
developmental transitions in insects, bind to the nuclear receptor ultraspiracle
(USP). In fluorescence-based binding assays, USP protein binds JH III and JH III
acid with specificity, adopting for each ligand a different final conformational
state. JH III treatment of Saccharomyces cerevisiae expressing a LexA-USP fusion
protein stabilizes an oligomeric association containing this protein, as detected
by formation of a protein-DNA complex, and induces USP-dependent transcription in
a reporter assay. We propose that regulation of morphogenetic transitions in
invertebrates involves binding of JH or JH-like structures to USP.
PMID- 9391056
TI - Coagulation initiated on herpesviruses.
AB - Herpesviruses have been previously correlated to vascular disease and shown to
cause thrombogenic and atherogenic changes to host cells. Herein we show that
even in the absence of cells, purified cytomegalovirus (CMV) and herpes simplex
virus type 1 (HSV-1) and type 2 (HSV-2) can initiate thrombin production.
Functional assays demonstrated that purified HSV-1 and HSV-2 provide the
necessary phospholipid (proPL) for assembling the coagulation factors Xa and Va
into prothrombinase, which is responsible for generating thrombin. These
observations are consistent with our earlier studies involving CMV. The presence
of proPL on all three herpesviruses was confirmed directly by flow cytometry and
electron microscopy by using annexin V and factor Va, respectively, as proPL
specific probes. Of equal importance, we found that CMV, HSV-1, and HSV-2 were
also able to facilitate factor Xa generation from the inactive precursor factor
X, but only when factor VII/VIIa and Ca2+ were present. Monoclonal antibodies
specific for tissue factor (TF), the coagulation initiator, inhibited this factor
X activation and, furthermore, enabled identification of TF antigen on each virus
type by flow cytometry and electron microscopy. Collectively, these data show
that CMV, HSV-1, and HSV-2 can initiate the generation of thrombin by having
essential proPL and TF activities on their surface. Unlike the normal cellular
source, the viral activity is constitutive and, therefore, not restricted to
sites of vascular injury. Thus cell-independent thrombin production may be the
earliest event in vascular pathology mediated by herpesviruses.
PMID- 9391055
TI - Glucocorticoid-mediated repression of nuclear factor-kappaB-dependent
transcription involves direct interference with transactivation.
AB - Glucocorticoids exert multiple anti-inflammatory activities, one of which is the
inhibition of transcription dependent on the nuclear factor (NF)-kappaB. It has
been suggested that the effect of dexamethasone (DEX), a glucocorticoid analog,
is attributed to an increased production of the inhibitory IkappaB molecule,
which in turn would bind and remove activated, DNA-bound NF-kappaB complexes in
the cell nucleus. Upon investigating DEX-mediated repression of interleukin-6
expression induced by tumor necrosis factor, DEX treatment was found to act
directly on NF-kappaB-dependent transcription, without changing the expression
level of IkappaB. Neither the mRNA of IkappaB nor the protein was significantly
elevated by a combined treatment with tumor necrosis factor and DEX of murine
endothelial or fibroblast cells. The DNA-binding activity of induced NF-kappaB
also remained unchanged after stimulation of cells with DEX. Evidence for a
direct nuclear mechanism of action was obtained by analysis of cell lines stably
expressing a fusion protein between the DNA-binding domain of the yeast Gal4
protein and the transactivating p65 subunit of NF-kappaB. Expression of a Gal4
dependent luciferase reporter gene activated by this nuclear fusion protein was
also strongly repressed after addition of DEX. Because the DNA-binding activity
of the Gal4 fusion protein was not affected by DEX, it can be concluded that the
reduction of gene activation was caused by interference of the activated
glucocorticoid receptor with the transactivation potential of the NF-kappaB p65
subunit.
PMID- 9391057
TI - Topology of allosteric regulation of lactose permease.
AB - Sugar transport by some permeases in Escherichia coli is allosterically regulated
by the phosphorylation state of the intracellular regulatory protein, enzyme
IIAglc of the phosphoenolpyruvate:sugar phosphotransferase system. A sensitive
radiochemical assay for the interaction of enzyme IIAglc with membrane-associated
lactose permease was used to characterize the binding reaction. The binding is
stimulated by transportable substrates such as lactose, melibiose, and raffinose,
but not by sugars that are not transported (maltose and sucrose). Treatment of
lactose permease with N-ethylmaleimide, which blocks ligand binding and transport
by alkylating Cys-148, also blocks enzyme IIAglc binding. Preincubation with the
substrate analog beta-D-galactopyranosyl 1-thio-beta-D-galactopyranoside protects
both lactose transport and enzyme IIAglc binding against inhibition by N
ethylmaleimide. A collection of lactose permease replacement mutants at Cys-148
showed, with the exception of C148V, a good correlation of relative transport
activity and enzyme IIAglc binding. The nature of the interaction of enzyme
IIAglc with the cytoplasmic face of lactose permease was explored. The N- and C
termini, as well as five hydrophilic loops in the permease, are exposed on the
cytoplasmic surface of the membrane and it has been proposed that the central
cytoplasmic loop of lactose permease is the major determinant for interaction
with enzyme IIAglc. Lactose permease mutants with polyhistidine insertions in
cytoplasmic loops IV/V and VI/VII and periplasmic loop VII/VIII retain transport
activity and therefore substrate binding, but do not bind enzyme IIAglc,
indicating that these regions of lactose permease may be involved in recognition
of enzyme IIAglc. Taken together, these results suggest that interaction of
lactose permease with substrate promotes a conformational change that brings
several cytoplasmic loops into an arrangement optimal for interaction with the
regulatory protein, enzyme IIAglc. A topological map of the proposed interaction
is presented.
PMID- 9391058
TI - Correct protein folding in glycerol.
AB - Water is the natural medium for protein folding, which is also used in all in
vitro studies. In the present work, we posed, and answered affirmatively, a
question of whether it is possible to fold correctly a typical protein in a
nonaqueous solvent. To this end, unfolded and reduced hen egg-white lysozyme was
refolded and reoxidized in glycerol containing varying amounts of water. The
unfolded/reduced enzyme was found to regain spontaneously substantial catalytic
activity even in the nearly anhydrous solvent; for example, the refolding yield
in 99% glycerol was still some one-third of that in pure water, and one-half of
that was regained even in 99.8% glycerol. The less than full recovery of the
enzymatic activity in glycerol is, as in water, because of competing protein
aggregation during the refolding. Lysozyme reoxidation in glycerol was
successfully mediated by two dissimilar oxidizing systems, and the refolding
yield was markedly affected by the pH of the last aqueous solution before the
transfer into glycerol. No recovery of the lysozyme activity was observed when
the refolding/reoxidation reaction was carried out in the denaturing solvent
dimethyl sulfoxide. This study paves the way for a systematic investigation of
the solvent effect on protein folding and demonstrates that water is not a unique
milieu for this process.
PMID- 9391059
TI - Suppressor mutations in Escherichia coli methionyl-tRNA formyltransferase: role
of a 16-amino acid insertion module in initiator tRNA recognition.
AB - The specific formylation of initiator methionyl-tRNA by methionyl-tRNA
formyltransferase (MTF; EC 2.1.2.9) is important for the initiation of protein
synthesis in eubacteria and in eukaryotic organelles. The determinants for
formylation in the tRNA are clustered mostly in the acceptor stem. As part of
studies on the molecular mechanism of recognition of the initiator tRNA by MTF,
we report here on the isolation and characterization of suppressor mutations in
Escherichia coli MTF, which compensate for the formylation defect of a mutant
initiator tRNA, lacking a critical determinant in the acceptor stem. We show that
the suppressor mutant in MTF has a glycine-41 to arginine change within a 16
amino acid insertion found in MTF from many sources. A mutant with glycine-41
changed to lysine also acts as a suppressor, whereas mutants with changes to
aspartic acid, glutamine, and leucine do not. The kinetic parameters of the
purified wild-type and mutant Arg-41 and Lys-41 enzymes, determined by using the
wild-type and mutant tRNAs as substrates, show that the Arg-41 and Lys-41 mutant
enzymes compensate specifically for the strong negative effect of the acceptor
stem mutation on formylation. These and other considerations suggest that the 16
amino acid insertion in MTF plays an important role in the specific recognition
of the determinants for formylation in the acceptor stem of the initiator tRNA.
PMID- 9391060
TI - The nucleocapsid protein specifically anneals tRNALys-3 onto a noncomplementary
primer binding site within the HIV-1 RNA genome in vitro.
AB - HIV type 1 (HIV-1) specifically uses host cell tRNALys-3 as a primer for reverse
transcription. The 3' 18 nucleotides of this tRNA are complementary to a region
on the HIV RNA genome known as the primer binding site (PBS). HIV-1 has a strong
preference for maintaining a lysine-specific PBS in vivo, and viral genomes with
mutated PBS sequences quickly revert to be complementary to tRNALys-3. To
investigate the mechanism for the observed PBS reversion events in vitro, we
examined the capability of the nucleocapsid protein (NC) to anneal various tRNA
primer sequences onto either complementary or noncomplementary PBSs. We show that
NC can anneal different full-length tRNAs onto viral RNA transcripts derived from
the HIV-1 MAL or HXB2 isolates, provided that the PBS is complementary to the
tRNA used. In contrast, NC promotes specific annealing of only tRNALys-3 onto an
RNA template (HXB2) whose PBS sequence has been mutated to be complementary to
the 3' 18 nt of human tRNAPro. Moreover, HIV-1 reverse transcriptase extends this
binary complex from the proline-specific PBS. The formation of the
noncomplementary binary complex does not occur when a chimeric tRNALys/Pro
containing proline-specific D and anticodon domains is used as the primer. Thus,
elements outside the acceptor-TPsiC domains of tRNALys-3 play an important role
in preferential primer use in vitro. Our results support the hypothesis that
mutant PBS reversion is a result of tRNALys-3 annealing onto and extension from a
PBS that specifies an alternate host cell tRNA.
PMID- 9391061
TI - Functional separation of pre-rRNA processing steps revealed by truncation of the
U3 small nucleolar ribonucleoprotein component, Mpp10.
AB - The U3 small nucleolar ribonucleoprotein (snoRNP) is required for three cleavage
events that generate the mature 18S rRNA from the pre-rRNA. In Saccharomyces
cerevisiae, depletion of Mpp10, a U3 snoRNP-specific protein, halts 18S rRNA
production and impairs cleavage at the three U3 snoRNP-dependent sites: A0, A1,
and A2. We have identified truncation mutations of Mpp10 that affect 18S rRNA
synthesis and confer cold-sensitivity and slow growth. However, distinct from
yeast cells depleted of Mpp10, the mutants carrying these truncated Mpp10
proteins accumulate a novel precursor, resulting from cleavage at only A0. The
Mpp10 truncations do not alter association of Mpp10 with the U3 snoRNA, nor do
they affect snoRNA or protein stability. Thus, the role in processing of the U3
snoRNP can be separated into cleavage at the A0 site, which occurs in the
presence of truncated Mpp10, and cleavage at the A1/A2 sites, which occurs only
with intact Mpp10. These results strongly argue for a role for Mpp10 in
processing at the A1/A2 sites.
PMID- 9391062
TI - Formation of stable adducts and absence of depurinating DNA adducts in cells and
DNA treated with the potent carcinogen dibenzo[a,l]pyrene or its diol epoxides.
AB - Polycyclic aromatic hydrocarbons (PAH) are widespread environmental contaminants,
and some are potent carcinogens in rodents. Carcinogenic PAH are activated in
cells to metabolites that react with DNA to form stable covalent DNA adducts. It
has been proposed [Cavalieri, E. L. & Roger, E. G. (1995) Xenobiotica 25, 677
688] that unstable DNA adducts are also formed and that apurinic sites in the DNA
resulting from unstable PAH adducts play a key role in the initiation of cancer.
The potent carcinogen dibenzo[a,l]pyrene (DB[a, l]P) is activated in cells to (+)
syn- and (-)-anti-DB[a,l]P-11, 12-diol-13,14-epoxide (DB[a,l]PDE), which have
been shown to form stable adducts with DNA. To evaluate the importance of
unstable PAH adducts, we compared stable adduct formation to apurinic site
formation. Stable DB[a,l]PDE adducts were determined by 33P-postlabeling and
HPLC. To measure apurinic sites they were converted to strand breaks, and these
were monitored by examining the integrity of a particular restriction fragment of
the dihydrofolate reductase gene. The method easily detected apurinic sites
resulting from methylation by treatment of cells or DNA with dimethyl sulfate or
from reaction of DNA with DB[a,l]P in the presence of horseradish peroxidase. We
estimate the method could detect 0.1 apurinic site in the 14-kb fragment
examined. However, apurinic sites were below our limit of detection in DNA
treated directly with (+)-syn- or (-)-anti-DB[a,l]PDE or in DNA from Chinese
hamster ovary B11 cells so treated, although in these samples the frequency of
stable adducts ranged from 3 to 10 per 14 kb. We also treated the human mammary
carcinoma cell line MCF-7 with DB[a,l]P and again could not detect significant
amounts of unstable adducts. These results indicate that the proportion of stable
adducts formed by DB[a,l]P activated in cells and its diol epoxides is greater
than 99% and suggest a predominant role for stable DNA adducts in the
carcinogenic activity of DB[a,l]P.
PMID- 9391063
TI - Escherichia coli RNA polymerase terminates transcription efficiently at rho
independent terminators on single-stranded DNA templates.
AB - Several models have been proposed for the mechanism of transcript termination by
Escherichia coli RNA polymerase at rho-independent terminators. Yager and von
Hippel (Yager, T. D. & von Hippel, P. H. (1991) Biochemistry 30, 1097-118)
postulated that the transcription complex is stabilized by enzyme-nucleic acid
interactions and the favorable free energy of a 12-bp RNA-DNA hybrid but is
destabilized by the free energy required to maintain an extended transcription
bubble. Termination, by their model, is viewed simply as displacement of the RNA
transcript from the hybrid helix by reformation of the DNA helix. We have
proposed an alternative model where the RNA transcript is stably bound to RNA
polymerase primarily through interactions with two single-strand specific RNA
binding sites; termination is triggered by formation of an RNA hairpin that
reduces binding of the RNA to one RNA-binding site and, ultimately, leads to its
ejection from the complex. To distinguish between these models, we have tested
whether E. coli RNA polymerase can terminate transcription at rho-independent
terminators on single-stranded DNA. RNA polymerase cannot form a transcription
bubble on these templates; thus, the Yager-von Hippel model predicts that
intrinsic termination will not occur. We find that transcript elongation on
single-stranded DNA templates is hindered somewhat by DNA secondary structure.
However, E. coli RNA polymerase efficiently terminates and releases transcripts
at several rho-independent terminators on such templates at the same positions as
termination occurs on duplex DNAs. Therefore, neither the nontranscribed DNA
strand nor the transcription bubble is essential for rho-independent termination
by E. coli RNA polymerase.
PMID- 9391064
TI - A direct electrode-driven P450 cycle for biocatalysis.
AB - The large potential of redox enzymes to carry out formation of high value organic
compounds motivates the search for innovative strategies to regenerate the
cofactors needed by their biocatalytic cycles. Here, we describe a bioreactor
where the reducing power to the cycle is supplied directly to purified cytochrome
CYP101 (P450cam; EC 1.14.15.1) through its natural redox partner (putidaredoxin)
using an antimony-doped tin oxide working electrode. Required oxygen was produced
at a Pt counter electrode by water electrolysis. A continuous catalytic cycle was
sustained for more than 5 h and 2,600 enzyme turnovers. The maximum product
formation rate was 36 nmol of 5-exo-hydroxycamphor/nmol of CYP101 per min.
PMID- 9391065
TI - Synthesis and characterization of a novel retinylamine analog inhibitor of
constitutively active rhodopsin mutants found in patients with autosomal dominant
retinitis pigmentosa.
AB - Two different mutations of the active-site Lys-296 in rhodopsin, K296E and K296M,
have been found to cause autosomal dominant retinitis pigmentosa (ADRP). In vitro
studies have shown that both mutations result in constitutive activation of the
protein, suggesting that the activated state of the receptor may be responsible
for retinal degeneration in patients with these mutations. Previous work has
highlighted the potential of retinylamine analogs as active-site directed
inactivators of constitutively active mutants of rhodopsin with the idea that
these or related compounds might be used therapeutically for cases of ADRP
involving mutations of the active-site Lys. Unfortunately, however, amine
derivatives of 11-cis-retinal, although highly effective against a K296G mutant
of rhodopsin, were without affect on the two naturally occurring ADRP mutants,
presumably because of the greater steric bulk of Glu and Met side chains in
comparison to Gly. For this reason we synthesized a retinylamine analog one
carbon shorter than the parent 11-cis-retinal and show that this compound is
indeed an effective inhibitor of both the K296E and K296M mutants. The 11-cis C19
retinylamine analog 1 inhibits constitutive activation of transducin by these
mutants and their constitutive phosphorylation by rhodopsin kinase, and it does
so in the presence of continuous illumination from room lights.
PMID- 9391066
TI - A terbenzimidazole that preferentially binds and conformationally alters
structurally distinct DNA duplex domains: a potential mechanism for topoisomerase
I poisoning.
AB - The terbenzimidazoles are a class of synthetic ligands that poison the human
topoisomerase I (TOP1) enzyme and promote cancer cell death. It has been proposed
that drugs of this class act as TOP1 poisons by binding to the minor groove of
the DNA substrate of TOP1 and altering its structure in a manner that results in
enzyme-mediated DNA cleavage. To test this hypothesis, we characterize and
compare the binding properties of a 5-phenylterbenzimidazole derivative (5PTB) to
the d(GA4T4C)2 and d(GT4A4C)2 duplexes. The d(GA4T4C)2 duplex contains an
uninterrupted 8-bp A.T domain, which, on the basis of x-ray crystallographic
data, should induce a highly hydrated "A-tract" conformation. This duplex also
exhibits anomalously slow migration in a polyacrylamide gel, a feature
characteristic of a noncanonical global conformational state frequently described
as "bent." By contrast, the d(GT4A4C)2 duplex contains two 4-bp A.T tracts
separated by a TpA dinucleotide step, which should induce a less hydrated "B
like" conformation. This duplex also migrates normally in a polyacrylamide gel, a
feature further characteristic of a global, canonical B-form duplex. Our data
reveal that, at 20 degrees C, 5PTB exhibits an approximately 2. 3 kcal/mol
greater affinity for the d(GA4T4C)2 duplex than for the d(GT4A4C)2 duplex.
Significantly, we find this sequence/conformational binding specificity of 5PTB
to be entropic in origin, an observation consistent with a greater degree of drug
binding-induced dehydration of the more solvated d(GA4T4C)2 duplex. By contrast
with the differential duplex affinity exhibited by 5PTB, netropsin and 4',6
diamidino-2-phenylindole (DAPI), two AT-specific minor groove binding ligands
that are inactive as human TOP1 poisons, bind to both duplexes with similar
affinities. The electrophoretic behaviors of the ligand-free and ligand-bound
duplexes are consistent with 5PTB-induced bending and/or unwinding of both
duplexes, which, for the d(GA4T4C)2 duplex, is synergistic with the endogenous
sequence-directed electrophoretic properties of the ligand-free duplex state. By
contrast, the binding to either duplex of netropsin or DAPI induces little or no
change in the electrophoretic mobilities of the duplexes. Our results demonstrate
that the TOP1 poison 5PTB binds differentially to and alters the structures of
the two duplexes, in contrast to netropsin and DAPI, which bind with similar
affinities to the two duplexes and do not significantly alter their structures.
These results are consistent with a mechanism for TOP1 poisoning in which drugs
such as 5PTB differentially target conformationally distinct DNA sites and induce
structural changes that promote enzyme-mediated DNA cleavage.
PMID- 9391067
TI - Repression of transcription mediated by dual elements in the CCAAT/enhancer
binding protein alpha gene.
AB - During adipocyte differentiation, the expression of C/EBPalpha is activated,
which in turn serves to transcriptionally activate numerous adipocyte genes. A
previous search for cis elements that regulate transcription of the C/EBPalpha
gene led to the identification of a potential repressive element within the
proximal 5' flanking region of the gene. Nuclear extracts from 3T3-L1
preadipocytes, but not adipocytes, were found to contain a factor, CUP
(C/EBPalpha undifferentiated protein), that binds to this site (the CUP-1 site).
In the present investigation, we show that C/EBPalpha promoter-luciferase
constructs containing both the proximal 5' flanking and the entire 5'
untranslated regions of the gene exhibit an expression pattern during adipocyte
differentiation comparable to that of the endogenous C/EBPalpha gene. Mutation of
the CUP-1 site in these constructs had little effect on reporter gene expression;
however, when this mutation was combined with deletion of the 5' untranslated
region, reporter gene expression by preadipocytes was dramatically up-regulated.
Consistent with this finding, a second CUP binding site (the CUP-2 site) was
identified in the 5' untranslated region. Although mutation of either CUP element
in constructs containing both the 5' flanking and 5' untranslated region had
little effect on reporter gene transcription, mutation of both CUP elements
markedly activated transcription. Thus, it appears that dual CUP regulatory
elements repress transcription of the C/EBPalpha gene prior to induction of the
adipocyte differentiation program.
PMID- 9391068
TI - Mode matches and their locations in the hydrophobic free energy sequences of
peptide ligands and their receptor eigenfunctions.
AB - Patterns in sequences of amino acid hydrophobic free energies predict secondary
structures in proteins. In protein folding, matches in hydrophobic free energy
statistical wavelengths appear to contribute to selective aggregation of
secondary structures in "hydrophobic zippers." In a similar setting, the use of
Fourier analysis to characterize the dominant statistical wavelengths of peptide
ligands' and receptor proteins' hydrophobic modes to predict such matches has
been limited by the aliasing and end effects of short peptide lengths, as well as
the broad-band, mode multiplicity of many of their frequency (power) spectra. In
addition, the sequence locations of the matching modes are lost in this
transformation. We make new use of three techniques to address these
difficulties: (i) eigenfunction construction from the linear decomposition of the
lagged covariance matrices of the ligands and receptors as hydrophobic free
energy sequences; (ii) maximum entropy, complex poles power spectra, which select
the dominant modes of the hydrophobic free energy sequences or their
eigenfunctions; and (iii) discrete, best bases, trigonometric wavelet
transformations, which confirm the dominant spectral frequencies of the
eigenfunctions and locate them as (absolute valued) moduli in the peptide or
receptor sequence. The leading eigenfunction of the covariance matrix of a
transmembrane receptor sequence locates the same transmembrane segments seen in n
block-averaged hydropathy plots while leaving the remaining hydrophobic modes
unsmoothed and available for further analyses as secondary eigenfunctions. In
these receptor eigenfunctions, we find a set of statistical wavelength matches
between peptide ligands and their G-protein and tyrosine kinase coupled
receptors, ranging across examples from 13.10 amino acids in acid fibroblast
growth factor to 2.18 residues in corticotropin releasing factor. We find that
the wavelet-located receptor modes in the extracellular loops are compatible with
studies of receptor chimeric exchanges and point mutations. A nonbinding
corticotropin-releasing factor receptor mutant is shown to have lost the
signatory mode common to the normal receptor and its ligand. Hydrophobic free
energy eigenfunctions and their transformations offer new quantitative physical
homologies in database searches for peptide-receptor matches.
PMID- 9391069
TI - Relationship between the oxidation potential and electron spin density of the
primary electron donor in reaction centers from Rhodobacter sphaeroides.
AB - The primary electron donor in bacterial reaction centers is a dimer of
bacteriochlorophyll a molecules, labeled L or M based on their proximity to the
symmetry-related protein subunits. The electronic structure of the
bacteriochlorophyll dimer was probed by introducing small systematic variations
in the bacteriochlorophyll-protein interactions by a series of site-directed
mutations that replaced residue Leu M160 with histidine, tyrosine, glutamic acid,
glutamine, aspartic acid, asparagine, lysine, and serine. The midpoint potentials
for oxidation of the dimer in the mutants showed an almost continuous increase up
to approximately 60 mV compared with wild type. The spin density distribution of
the unpaired electron in the cation radical state of the dimer was determined by
electron-nuclear-nuclear triple resonance spectroscopy in solution. The ratio of
the spin density on the L side of the dimer to the M side varied from
approximately 2:1 to approximately 5:1 in the mutants compared with approximately
2:1 for wild type. The correlation between the midpoint potential and spin
density distribution was described using a simple molecular orbital model, in
which the major effect of the mutations is assumed to be a change in the energy
of the M half of the dimer, providing estimates for the coupling and energy
levels of the orbitals in the dimer. These results demonstrate that the midpoint
potential can be fine-tuned by electrostatic interactions with amino acids near
the dimer and show that the properties of the electronic structure of a donor or
acceptor in a protein complex can be directly related to functional properties
such as the oxidation-reduction midpoint potential.
PMID- 9391070
TI - Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects
of ionizing radiation on growth, survival, and development.
AB - We recently have shown that mice deficient for the 86-kDa component (Ku80) of the
DNA-dependent protein kinase exhibit growth retardation and a profound deficiency
in V(D)J (variable, diversity, and joining) recombination. These defects may be
related to abnormalities in DNA metabolism that arise from the inability of Ku80
mutant cells to process DNA double-strand breaks. To further characterize the
role of Ku80 in DNA double-strand break repair, we have generated embryonic stem
cells and pre-B cells and examined their response to ionizing radiation. Ku80(-/
) embryonic stem cells are more sensitive than controls to gamma-irradiation, and
pre-B cells derived from Ku80 mutant mice display enhanced spontaneous and gamma
ray-induced apoptosis. We then determined the effects of ionizing radiation on
the survival, growth, and lymphocyte development in Ku80-deficient mice. Ku80(-/
) mice display a hypersensitivity to gamma-irradiation, characterized by loss of
hair pigmentation, severe injury to the gastrointestinal tract, and enhanced
mortality. Exposure of newborn Ku80(-/-) mice to sublethal doses of ionizing
radiation enhances their growth retardation and results in the induction of T
cell-specific differentiation. However, unlike severe combined immunodeficient
mice, radiation-induced T cell development in Ku80(-/-) mice is not accompanied
by extensive thymocyte proliferation. The response of Ku80-deficient cell lines
and mice to DNA-damaging agents provides important insights into the role of Ku80
in growth regulation, lymphocyte development, and DNA repair.
PMID- 9391071
TI - Aldehyde dehydrogenase class 3 expression: identification of a cornea-preferred
gene promoter in transgenic mice.
AB - Aldehyde dehydrogenase class 3 (ALDH3) constitutes 20-40% of the total water
soluble proteins in the mammalian cornea. Here, we show by Northern blot analysis
that ALDH3 expression in the mouse is at least 500-fold higher in the cornea than
in any other tissue examined, with very low levels of expression detected in the
stomach, urinary bladder, ocular lens, and lung. Histochemical localization
reveals that this exceptional level of expression in the mouse cornea occurs in
the anterior epithelial cells and that little ALDH3 is present in the keratocytes
or corneal endothelial cells. A 13-kbp mouse ALDH3 promoter fragment containing
>12 kbp of the 5' flanking sequence, the 40-bp untranslated first exon, and 29 bp
of intron 1 directed cat reporter gene expression to tissues that express the
endogenous ALDH3 gene, except that transgene promoter activity was higher in the
stomach and bladder than in the cornea. By contrast, when driven by a 4.4-kbp
mouse ALDH3 promoter fragment [1,050-bp 5' flanking region, exon 1, intron 1 (3.4
kbp), and 7 bp of exon 2] expression of the cat reporter gene was confined to the
corneal epithelial cells, except for very low levels in the liver, effectively
reproducing the corneal expression pattern of the endogenous ALDH3 gene. These
results indicate that tissue-specific expression of ALDH3 is determined by
positive and negative elements in the 5' flanking region of the gene and suggests
putative silencers located in intron 1. We demonstrate regulatory sequences
capable of directing cornea-specific gene expression, affording the opportunity
for genetic engineering in this transparent tissue.
PMID- 9391072
TI - Scavenger receptor class B, type I (SR-BI) is the major route for the delivery of
high density lipoprotein cholesterol to the steroidogenic pathway in cultured
mouse adrenocortical cells.
AB - The class B, type I scavenger receptor, SR-BI, binds high density lipoprotein
(HDL) and mediates the selective uptake of HDL cholesteryl ester (CE) by cultured
transfected cells. The high levels of SR-BI expression in steroidogenic cells in
vivo and its regulation by tropic hormones provides support for the hypothesis
that SR-BI is a physiologically relevant HDL receptor that supplies substrate
cholesterol for steroid hormone synthesis. This hypothesis was tested by
determining the ability of antibody directed against murine (m) SR-BI to inhibit
the selective uptake of HDL CE in Y1-BS1 adrenocortical cells. Anti-mSR-BI IgG
inhibited HDL CE-selective uptake by 70% and cell association of HDL particles by
50% in a dose-dependent manner. The secretion of [3H]steroids derived from HDL
containing [3H]CE was inhibited by 78% by anti-mSR-BI IgG. These results
establish mSR-BI as the major route for the selective uptake of HDL CE and the
delivery of HDL cholesterol to the steroidogenic pathway in cultured mouse
adrenal cells.
PMID- 9391073
TI - Baculovirus inhibitors of apoptosis (IAPs) block activation of Sf-caspase-1.
AB - We have investigated the ability of Sf-caspase-1 and two mammalian caspases,
caspase-1 and caspase-3, to induce apoptosis in Spodoptera frugiperda Sf-21
insect cells. While the transient expression of the pro-Sf-caspase-1 did not
induce apoptosis, expression of the pro-domain deleted form, p31, or coexpression
of the two subunits of mature Sf-caspase-1, p19 and p12, induced apoptosis in Sf
21 cells. The behavior of Sf-caspase-1 resembled that of the closely related
mammalian caspase, caspase-3, and contrasted with that of the mammalian caspase
1, the pro-form of which was active in inducing apoptosis in Sf-21 cells. The
baculovirus caspase inhibitor P35 blocked apoptosis induced by active forms of
all three caspases. In contrast, members of the baculovirus inhibitor of
apoptosis (IAP) family failed to block active caspase-induced apoptosis. However,
during viral infection, expression of OpIAP or CpIAP blocked the activation of
pro-Sf-caspase-1 and the associated induction of apoptosis. Thus, the mechanism
by which baculovirus IAPs inhibit apoptosis is distinct from the mechanism by
which P35 blocks apoptosis and involves inhibition of the activation of pro
caspases like Sf-caspase-1.
PMID- 9391074
TI - Angiogenesis promoted by vascular endothelial growth factor: regulation through
alpha1beta1 and alpha2beta1 integrins.
AB - Vascular endothelial growth factor (VEGF), also known as vascular permeability
factor, is a cytokine of central importance for the angiogenesis associated with
cancers and other pathologies. Because angiogenesis often involves endothelial
cell (EC) migration and proliferation within a collagen-rich extracellular
matrix, we investigated the possibility that VEGF promotes neovascularization
through regulation of collagen receptor expression. VEGF induced a 5- to 7-fold
increase in dermal microvascular EC surface protein expression of two collagen
receptors-the alpha1beta1 and alpha2beta1 integrins-through induction of mRNAs
encoding the alpha1 and alpha2 subunits. In contrast, VEGF did not induce
increased expression of the alpha3beta1 integrin, which also has been implicated
in collagen binding. Integrin alpha1-blocking and alpha2-blocking antibodies (Ab)
each partially inhibited attachment of microvascular EC to collagen I, and alpha1
blocking Ab also inhibited attachment to collagen IV and laminin-1. Induction of
alpha1beta1 and alpha2beta1 expression by VEGF promoted cell spreading on
collagen I gels which was abolished by a combination of alpha1-blocking and
alpha2-blocking Abs. In vivo, a combination of alpha1-blocking and alpha2
blocking Abs markedly inhibited VEGF-driven angiogenesis; average cross-sectional
area of individual new blood vessels was reduced 90% and average total new
vascular area was reduced 82% without detectable effects on the pre-existing
vasculature. These data indicate that induction of alpha1beta1 and alpha2beta1
expression by EC is an important mechanism by which VEGF promotes angiogenesis
and that alpha1beta1 and alpha2beta1 antagonists may prove effective in
inhibiting VEGF-driven angiogenesis in cancers and other important pathologies.
PMID- 9391075
TI - Characterization and cell cycle regulation of the related human telomeric
proteins Pin2 and TRF1 suggest a role in mitosis.
AB - Telomeres are essential for preserving chromosome integrity during the cell cycle
and have been specifically implicated in mitotic progression, but little is known
about the signaling molecule(s) involved. The human telomeric repeat binding
factor protein (TRF1) is shown to be important in regulating telomere length.
However, nothing is known about its function and regulation during the cell
cycle. The sequence of PIN2, one of three human genes (PIN1-3) we previously
cloned whose products interact with the Aspergillus NIMA cell cycle regulatory
protein kinase, reveals that it encodes a protein that is identical in sequence
to TRF1 apart from an internal deletion of 20 amino acids; Pin2 and TRF1 may be
derived from the same gene, PIN2/TRF1. However, in the cell Pin2 was found to be
the major expressed product and to form homo- and heterodimers with TRF1; both
dimers were localized at telomeres. Pin2 directly bound the human telomeric
repeat DNA in vitro, and was localized to all telomeres uniformly in telomerase
positive cells. In contrast, in several cell lines that contain barely detectable
telomerase activity, Pin2 was highly concentrated at only a few telomeres.
Interestingly, the protein level of Pin2 was highly regulated during the cell
cycle, being strikingly increased in G2+M and decreased in G1 cells. Moreover,
overexpression of Pin2 resulted in an accumulation of HeLa cells in G2+M. These
results indicate that Pin2 is the major human telomeric protein and is highly
regulated during the cell cycle, with a possible role in mitosis. The results
also suggest that Pin2/TRF1 may connect mitotic control to the telomere
regulatory machinery whose deregulation has been implicated in cancer and aging.
PMID- 9391076
TI - The glyoxysomal and plastid molecular chaperones (70-kDa heat shock protein) of
watermelon cotyledons are encoded by a single gene.
AB - The monoclonal a-70-kDa heat shock protein (hsp70) antibody recognizes in crude
extracts from watermelon (Citrullus vulgaris) cotyledons two hsps with molecular
masses of 70 and 72 kDa. Immunocytochemistry on watermelon cotyledon tissue and
on isolated glyoxysomes identified hsp70s in the matrix of glyoxysomes and
plastids. Affinity purification and partial amino acid determination revealed the
70-kDa protein to share high sequence identity with cytosolic hsp70s from a
number of plant species, while the 72 kDa protein was very similar to plastid
hsp70s from pea and cucumber. A full-length cDNA clone encoding the 72-kDa hsp70
was isolated and identified two start methionines in frame within the N-terminal
presequence leading either to an N-terminal extension of 67 amino acids or to a
shorter one of 47 amino acids. The longer presequence was necessary and
sufficient to target a reporter protein into watermelon proplastids in vitro. The
shorter extension starting from the second methionine within the long version
harbored a consensus peroxisomal targeting signal (RT-X5-KL) that directed in
vivo a reporter protein into peroxisomes of the yeast Hansenula polymorpha.
Peroxisomal targeting was however prevented, when the 67-residue presequence was
fused to the reporter protein, indicating that the peroxisomal targeting signal 2
information is hidden in this context. We propose that the 72-kDa hsp70 is
encoded by a single gene, but targeted alternatively into two organelles by the
modulated use of its presequence.
PMID- 9391077
TI - Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related
protein in vascular smooth muscle cells: a critical role for nuclear targeting.
AB - Parathyroid hormone-related protein (PTHrP) is a prohormone that is
posttranslationally processed to a family of mature secretory forms, each of
which has its own cognate receptor(s) on the cell surface that mediate the
actions of PTHrP. In addition to being secreted via the classical secretory
pathway and interacting with cell surface receptors in a paracrine/autocrine
fashion, PTHrP appears to be able to enter the nucleus directly following
translation and influence cellular events in an "intracrine" fashion. In this
report, we demonstrate that PTHrP can be targeted to the nucleus in vascular
smooth muscle cells, that this nuclear targeting is associated with a striking
increase in mitogenesis, that this nuclear effect on proliferation is the
diametric opposite of the effects of PTHrP resulting from interaction with cell
surface receptors on vascular smooth muscle cells, and that the regions of the
PTHrP sequence responsible for this nuclear targeting represent a classical
bipartite nuclear localization signal. This report describes the activation of
the cell cycle in association with nuclear localization of PTHrP in any cell
type. These findings have important implications for the normal physiology of
PTHrP in the many tissues which produce it, and suggest that gene delivery of
PTHrP or modified variants may be useful in the management of atherosclerotic
vascular disease.
PMID- 9391078
TI - SARPs: a family of secreted apoptosis-related proteins.
AB - Quiescent mouse embryonic C3H/10T1/2 cells are more resistant to different
proapoptotic stimuli than are these cells in the exponential phase of growth.
However, the exponentially growing 10T1/2 cells are resistant to inhibitors of
RNA or protein synthesis, whereas quiescent cells die upon these treatments.
Conditioned medium from quiescent 10T1/2 cells possesses anti-apoptotic activity,
suggesting the presence of protein(s) that function as an inhibitor of the
apoptotic program. Using differential display technique, we identified and cloned
a cDNA designated sarp1 (secreted apoptosis-related protein) that is expressed in
quiescent but not in exponentially growing 10T1/2 cells. Hybridization studies
with sarp1 revealed two additional family members. Cloning and sequencing of
sarp2 and sarp3 revealed 38% and 40% sequence identity to sarp1, respectively.
Human breast adenocarcinoma MCF7 cells stably transfected with sarp1 or infected
with SARP1-expressing adenovirus became more resistant, whereas cells transfected
with sarp2 displayed increased sensitivity to different proapoptotic stimuli.
Expression of sarp family members is tissue specific. sarp mRNAs encode secreted
proteins that possess a cysteine-rich domain (CRD) homologous to the CRD of
frizzled proteins but lack putative membrane-spanning segments. Expression of
SARPs modifies the intracellular levels of beta-catenin, suggesting that SARPs
interfere with the Wnt-frizzled proteins signaling pathway.
PMID- 9391079
TI - Activation of hPAK65 by caspase cleavage induces some of the morphological and
biochemical changes of apoptosis.
AB - Apoptosis is a highly regulated form of cell death, characterized by distinctive
features such as cellular shrinkage and nuclear condensation. We demonstrate here
that proteolytic activation of hPAK65, a p21-activated kinase, induces
morphological changes and elicits apoptosis. hPAK65 is cleaved both in vitro and
in vivo by caspases at a single site between the N-terminal regulatory p21
binding domain and the C-terminal kinase domain. The C-terminal cleavage product
becomes activated, with a kinetic profile that parallels caspase activation
during apoptosis. This C-terminal hPAK65 fragment also activates the c-Jun N
terminal kinase pathway in vivo. Microinjection or transfection of this truncated
hPAK65 causes striking alterations in cellular and nuclear morphology, which
subsequently promotes apoptosis in both CHO and Hela cells. Conversely, apoptosis
is delayed in cells expressing a dominant-negative form of hPAK65. These findings
provide a direct evidence that the activated form of hPAK65 generated by caspase
cleavage is a proapoptotic effector that mediates morphological and biochemical
changes seen in apoptosis.
PMID- 9391080
TI - Expansion in vitro of adult murine hematopoietic stem cells with transplantable
lympho-myeloid reconstituting ability.
AB - Elucidation of mechanisms that regulate hematopoietic stem cell self-renewal and
differentiation would be facilitated by the identification of defined culture
conditions that allow these cells to be amplified. We now demonstrate a
significant net increase (3-fold, P < 0.001) in vitro of cells that are
individually able to permanently and competitively reconstitute the lymphoid and
myeloid systems of syngeneic recipient mice when Sca-1(+)lin- adult marrow cells
are incubated for 10 days in serum-free medium with interleukin 11, flt3-ligand,
and Steel factor. Moreover, the culture-derived repopulating cells continued to
expand their numbers in the primary hosts at the same rate seen in recipients of
noncultured stem cells. In the expansion cultures, long-term culture-initiating
cells increased 7- +/- 2-fold, myeloid colony-forming cells increased 140- +/- 36
fold, and total nucleated cells increased 230- +/- 62-fold. Twenty-seven of 100
cultures initiated with 15 Sca-1(+)lin- marrow cells were found to contain
transplantable stem cells 10 days later. This frequency of positive cultures is
the same as the frequency of transplantable stem cells in the original input
suspension, suggesting that most had undergone at least one self-renewal division
in vitro. No expansion of stem cells was seen when Sca-1+TER119- CD34+ day 14.5
fetal liver cells were cultured under the same conditions. These findings set the
stage for further investigations of the mechanisms by which cytokine stimulation
may elicit different outcomes in mitotically activated hematopoietic stem cells
during ontogeny and in the adult.
PMID- 9391081
TI - Structural features of the kringle domain determine the intracellular degradation
of under-gamma-carboxylated prothrombin: studies of chimeric rat/human
prothrombin.
AB - Vitamin K antagonists such as warfarin inhibit the vitamin K-dependent gamma
glutamyl carboxylation during protein processing and block the secretion of under
gamma-carboxylated prothrombin (FII) in the rat but not in the human or bovine.
Under-gamma-carboxylated prothrombin is also secreted from warfarin-treated human
(HepG2) cell cultures but is degraded in the endoplasmic reticulum in warfarin
treated rat (H-35) cell cultures. This differential response to warfarin has been
shown to be determined by the structural difference in the proteins rather than
by the origin of the cell line. When recombinant rat prothrombin (rFII) and human
prothrombin (hFII) were expressed in a transformed human kidney cell line
(HEK293), secretion of rFII but not hFII was drastically decreased in response to
warfarin. To determine the structural signal required for this differential
response, chimeric cDNAs with the propeptide/Gla domains, kringle domain, and
serine protease domain exchanged between rFII and hFII were generated (FIIRHH and
FIIHRR, FIIRRH and FIIHHR, FIIRHR and FIIHRH) and expressed in both warfarin
treated HEK293 cells and HepG2 cells. The presence of the hFII kringle domain
changed the stability of rFII to that of hFII, and the rFII kringle domain
changed the stability of hFII to that of rFII. The kringle domain therefore is
critical in determining the metabolic fate of under-gamma-carboxylated
prothrombin precursors during processing. Prothrombin contains two kringle
structures, and expression of additional rFII/hFII chimeras (FIIHrhH and FIIHhrH,
FIIRrhR, and FIIRhrR) was used to determine that the first of the two kringles
plays a more important role in the recognition process.
PMID- 9391082
TI - Cell locomotion and focal adhesions are regulated by substrate flexibility.
AB - Responses of cells to mechanical properties of the adhesion substrate were
examined by culturing normal rat kidney epithelial and 3T3 fibroblastic cells on
a collagen-coated polyacrylamide substrate that allows the flexibility to be
varied while maintaining a constant chemical environment. Compared with cells on
rigid substrates, those on flexible substrates showed reduced spreading and
increased rates of motility or lamellipodial activity. Microinjection of
fluorescent vinculin indicated that focal adhesions on flexible substrates were
irregularly shaped and highly dynamic whereas those on firm substrates had a
normal morphology and were much more stable. Cells on flexible substrates also
contained a reduced amount of phosphotyrosine at adhesion sites. Treatment of
these cells with phenylarsine oxide, a tyrosine phosphatase inhibitor, induced
the formation of normal, stable focal adhesions similar to those on firm
substrates. Conversely, treatment of cells on firm substrates with myosin
inhibitors 2,3-butanedione monoxime or KT5926 caused the reduction of both
vinculin and phosphotyrosine at adhesion sites. These results demonstrate the
ability of cells to survey the mechanical properties of their surrounding
environment and suggest the possible involvement of both protein tyrosine
phosphorylation and myosin-generated cortical forces in this process. Such
response to physical parameters likely represents an important mechanism of
cellular interaction with the surrounding environment within a complex organism.
PMID- 9391083
TI - Platelet-derived growth factor activates mitogen-activated protein kinase in
isolated caveolae.
AB - The ability of a peptide hormone to affect many different intracellular targets
is thought to be possible because of the modular organization of signal
transducing molecules in the cell. Evidence for the presence of signaling modules
in metazoan cells, however, is incomplete. Herein we show, with morphology and
cell fractionation, that all the components of a mitogen-activated protein kinase
pathway are concentrated in caveolae of unstimulated human fibroblasts. Addition
of platelet-derived growth factor to either the intact cell or caveolae isolated
from these cells stimulates tyrosine phosphorylation and activates mitogen
activated protein kinases in caveolae. The molecular machinery for kinase
activation, therefore, is preorganized at the cell surface of quiescent cells.
PMID- 9391085
TI - Telomerase activity: a biomarker of cell proliferation, not malignant
transformation.
AB - Telomerase activity is readily detected in most cancer biopsies, but not in
premalignant lesions or in normal tissue samples with a few exceptions that
include germ cells and hemopoietic stem cells. Telomerase activity may,
therefore, be a useful biomarker for diagnosis of malignancies and a target for
inactivation in chemotherapy or gene therapy. These observations have led to the
hypothesis that activation of telomerase may be an important step in
tumorigenesis. To test this hypothesis, we studied telomerase activity in
isogeneic samples of uncultured and cultured specimens of normal human
uroepithelial cells (HUCs) and in uncultured and cultured biopsies of superficial
and myoinvasive transitional cell carcinoma (TCC) of the bladder. Our results
demonstrated that four of four TCC biopsies, representing both superficial and
myoinvasive TCCs, were positive for telomerase activity, but all samples of
uncultured HUC were telomerase negative. However, when the same normal HUC
samples were established as proliferating cultures in vitro, telomerase activity
was readily detected but usually at lower levels than in TCCs. Consistent with
the above observation of the telomerase activity in HUCs, telomeres did not
shorten during the HUC in vitro lifespan. Demonstration of telomerase in
proliferating human epithelial cells in vitro was not restricted to HUCs, because
it was also present in prostate and mammary cell cultures. Notably, telomerase
activity was relatively low or undetectable in nonproliferating HUC cultures.
These data do not support a model in which telomerase is inactive in normal cells
and activated during tumorigenic transformation. Rather, these data support a
model in which the detection of telomerase in TCC biopsies, but not uncultured
HUC samples, reflects differences in proliferation between tumor and normal cells
in vivo.
PMID- 9391084
TI - Mannose-6-phosphate/insulin-like growth factor-II receptor is a receptor for
retinoic acid.
AB - Retinoic acid (RA) exerts diverse biological effects in the control of cell
growth in embryogenesis and oncogenesis. These effects of RA are thought to be
mediated by the nuclear retinoid receptors. Mannose-6-phosphate (M6P)/insulin
like growth factor-II (IGF-II) receptor is a multifunctional membrane
glycoprotein that is known to bind both M6P and IGF-II and function primarily in
the binding and trafficking of lysosomal enzymes, the activation of transforming
growth factor-beta, and the degradation of IGF-II. M6P/IGF-II receptor has
recently been implicated in fetal development and carcinogenesis. Despite the
functional similarities between RA and the M6P/IGF-II receptor, no direct
biochemical link has been established. Here, we show that the M6P/IGF-II receptor
also binds RA with high affinity at a site that is distinct from those for M6P
and IGF-II, as identified by a photoaffinity labeling technique. We also show
that the binding of RA to the M6P/IGF-II receptor enhances the primary functions
of this receptor. The biological consequence of the interaction appears to be the
suppression of cell proliferation and/or induction of apoptosis. These findings
suggest that the M6P/IGF-II receptor mediates a RA response pathway that is
important in cell growth regulation. This discovery of the interaction of RA with
the M6P/IGF-II receptor may have important implications for our understanding of
the roles of RA and the M6P/IGF-II receptor in development, carcinogenesis, and
lysosomal enzyme-related diseases.
PMID- 9391086
TI - Syntenin, a PDZ protein that binds syndecan cytoplasmic domains.
AB - The syndecans are transmembrane proteoglycans that place structurally
heterogeneous heparan sulfate chains at the cell surface and a highly conserved
polypeptide in the cytoplasm. Their versatile heparan sulfate moieties support
various processes of molecular recognition, signaling, and trafficking. Here we
report the identification of a protein that binds to the cytoplasmic domains of
the syndecans in yeast two-hybrid screens, surface plasmon resonance experiments,
and ligand-overlay assays. This protein, syntenin, contains a tandem repeat of
PDZ domains that reacts with the FYA C-terminal amino acid sequence of the
syndecans. Recombinant enhanced green fluorescent protein (eGFP)-syntenin fusion
proteins decorate the plasmamembrane and intracellular vesicles, where they
colocalize and cosegregate with syndecans. Cells that overexpress eGFP-syntenin
show numerous cell surface extensions, suggesting effects of syntenin on
cytoskeleton-membrane organization. We propose that syntenin may function as an
adaptor that couples syndecans to cytoskeletal proteins or cytosolic downstream
signal-effectors.
PMID- 9391087
TI - Targeted expression of constitutively active receptors for parathyroid hormone
and parathyroid hormone-related peptide delays endochondral bone formation and
rescues mice that lack parathyroid hormone-related peptide.
AB - Mice in which the genes encoding the parathyroid hormone (PTH)-related peptide
(PTHrP) or the PTH/PTHrP receptor have been ablated by homologous recombination
show skeletal dysplasia due to accelerated endochondral bone formation, and die
at birth or in utero, respectively. Skeletal abnormalities due to decelerated
chondrocyte maturation are observed in transgenic mice where PTHrP expression is
targeted to the growth plate, and in patients with Jansen metaphyseal
chondrodysplasia, a rare genetic disorder caused by constitutively active
PTH/PTHrP receptors. These and other findings thus indicate that PTHrP and its
receptor are essential for chondrocyte differentiation. To further explore the
role of the PTH/PTHrP receptor in this process, we generated transgenic mice in
which expression of a constitutively active receptor, HKrk-H223R, was targeted to
the growth plate by the rat alpha1 (II) collagen promoter. Two major goals were
pursued: (i) to investigate how constitutively active PTH/PTHrP receptors affect
the program of chondrocyte maturation; and (ii) to determine whether expression
of the mutant receptor would correct the severe growth plate abnormalities of
PTHrP-ablated mice (PTHrP-/-). The targeted expression of constitutively active
PTH/PTHrP receptors led to delayed mineralization, decelerated conversion of
proliferative chondrocytes into hypertrophic cells in skeletal segments that are
formed by the endochondral process, and prolonged presence of hypertrophic
chondrocytes with delay of vascular invasion. Furthermore, it corrected at birth
the growth plate abnormalities of PTHrP-/- mice and allowed their prolonged
survival. "Rescued" animals lacked tooth eruption and showed premature epiphyseal
closure, indicating that both processes involve PTHrP. These findings suggest
that rescued PTHrP-/- mice may gain considerable importance for studying the
diverse, possibly tissue-specific role(s) of PTHrP in postnatal development.
PMID- 9391088
TI - Regulation of number and size of digits by posterior Hox genes: a dose-dependent
mechanism with potential evolutionary implications.
AB - The proper development of digits, in tetrapods, requires the activity of several
genes of the HoxA and HoxD homeobox gene complexes. By using a variety of loss-of
function alleles involving the five Hox genes that have been described to affect
digit patterning, we report here that the group 11, 12, and 13 genes control both
the size and number of murine digits in a dose-dependent fashion, rather than
through a Hox code involving differential qualitative functions. A similar dose
response is observed in the morphogenesis of the penian bone, the baculum, which
further suggests that digits and external genitalia share this genetic control
mechanism. A progressive reduction in the dose of Hox gene products led first to
ectrodactyly, then to olygodactyly and adactyly. Interestingly, this transition
between the pentadactyl to the adactyl formula went through a step of
polydactyly. We propose that in the distal appendage of polydactylous short
digited ancestral tetrapods, such as Acanthostega, the HoxA complex was
predominantly active. Subsequent recruitment of the HoxD complex contributed to
both reductions in digit number and increase in digit length. Thus, transition
through a polydactylous limb before reaching and stabilizing the pentadactyl
pattern may have relied, at least in part, on asynchronous and independent
changes in the regulation of HoxA and HoxD gene complexes.
PMID- 9391089
TI - Conservation of fibroblast growth factor function in lens regeneration.
AB - In urodele amphibians, lens induction during development and regeneration occurs
through different pathways. During development, the lens is induced from the
mutual interaction of the ectoderm and the optic vesicle, whereas after
lentectomy the lens is regenerated through the transdifferentiation of the iris
pigmented epithelial cells. Given the known role of fibroblast growth factors
(FGFs) during lens development, we examined whether or not the expression and the
effects of exogenous FGF during urodele lens regeneration were conserved. In this
paper, we describe expression of FGF-1 and its receptors, FGFR-2 (KGFR and bek
variants) and FGFR-3, in newts during lens regeneration. Expression of these
genes was readily observed in the dedifferentiating pigmented epithelial cells,
and the levels of expression were high in the lens epithelium and the
differentiating fibers and lower in the retina. These patterns of expression
implied involvement of FGFs in lens regeneration. To further elucidate this
function, we examined the effects of exogenous FGF-1 and FGF-4 during lens
regeneration. FGF-1 or FGF-4 treatment in lentectomized eyes resulted in the
induction of abnormalities reminiscent to the ones induced during lens
development in transgenic mice. Effects included transformation of epithelial
cells to fiber cells, double lens regeneration, and lenses with abnormal
polarity. These results establish that FGF molecules are key factors in fiber
differentiation, polarity, and morphogenesis of the lens during regeneration even
though the regenerating lens is induced by a different mechanism than in lens
development. In this sense, FGF function in lens regeneration and development
should be regarded as conserved. Such conservation should help elucidate the
mechanisms of lens regeneration in urodeles and its absence in higher
vertebrates.
PMID- 9391090
TI - The LIM-domain binding protein Ldb1 and its partner LMO2 act as negative
regulators of erythroid differentiation.
AB - The nuclear LIM domain protein LMO2, a T cell oncoprotein, is essential for
embryonic erythropoiesis. LIM-only proteins are presumed to act primarily through
protein-protein interactions. We, and others, have identified a widely expressed
protein, Ldb1, whose C-terminal 76-residues are sufficient to mediate interaction
with LMO2. In murine erythroleukemia cells, the endogenous Lbd1 and LMO2 proteins
exist in a stable complex, whose binding affinity appears greater than that
between LMO2 and the bHLH transcription factor SCL. However, Ldb1, LMO2, and
SCL/E12 can assemble as a multiprotein complex on a consensus SCL binding site.
Like LMO2, the Ldb1 gene is expressed in fetal liver and erythroid cell lines.
Forced expression of Ldb1 in G1ER proerythroblast cells inhibited cellular
maturation, a finding compatible with the decrease in Ldb1 gene expression that
normally occurs during erythroid differentiation. Overexpression of the LMO2 gene
also inhibited erythroid differentiation. Our studies demonstrate a function for
Ldb1 in hemopoietic cells and suggest that one role of the Ldb1/LMO2 complex is
to maintain erythroid precursors in an immature state.
PMID- 9391092
TI - Selection for spiral waves in the social amoebae Dictyostelium.
AB - Starving Dictyostelium amoebae emit pulses of the chemoattractant cAMP that are
relayed from cell to cell as circular and spiral waves. We have recently modeled
spiral wave formation in Dictyostelium. Our model suggests that a secreted
protein inhibitor of an extracellular cAMP phosphodiesterase selects for spirals.
Herein we test the essential features of this prediction by comparing wave
propagation in wild type and inhibitor mutants. We find that mutants rarely form
spirals. The territory size of mutant strains is approximately 50 times smaller
than wild type, and the mature fruiting bodies are smaller but otherwise normal.
These results identify a mechanism for selecting one wave symmetry over another
in an excitable system and suggest that the phosphodiesterase inhibitor may be
under selection because it helps regulate territory size.
PMID- 9391091
TI - Regulation of dorsal fate in the neuraxis by Wnt-1 and Wnt-3a.
AB - Members of the Wnt family of signaling molecules are expressed differentially
along the dorsal-ventral axis of the developing neural tube. Thus we asked
whether Wnt factors are involved in patterning of the nervous system along this
axis. We show that Wnt-1 and Wnt-3a, both of which are expressed in the dorsal
portion of the neural tube, could synergize with the neural inducers noggin and
chordin in Xenopus animal explants to generate the most dorsal neural structure,
the neural crest, as determined by the expression of Krox-20, AP-2, and slug.
Overexpression of Wnt-1 or Wnt-3a in the neuroectoderm of whole embryos led to a
dramatic increase of slug and Krox-20-expressing cells, but the hindbrain
expression of Krox-20 remained unaffected. Enlargement in the neural crest
population could occur even when cell proliferation was inhibited. Wnt-5A and Wnt
8, neither of which is expressed in the dorsal neuroectoderm, failed to induce
neural crest markers. Overexpression of glycogen synthase kinase 3, known to
antagonize Wnt signaling, blocked the neural-crest-inducing activity of Wnt-3a in
animal explants and inhibited neural crest formation in whole embryos. We suggest
that Wnt-1 and Wnt-3a have a role in patterning the neural tube along its
dorsoventral axis and function in the differentiation of the neural crest.
PMID- 9391094
TI - From tropics to tundra: global convergence in plant functioning.
AB - Despite striking differences in climate, soils, and evolutionary history among
diverse biomes ranging from tropical and temperate forests to alpine tundra and
desert, we found similar interspecific relationships among leaf structure and
function and plant growth in all biomes. Our results thus demonstrate convergent
evolution and global generality in plant functioning, despite the enormous
diversity of plant species and biomes. For 280 plant species from two global data
sets, we found that potential carbon gain (photosynthesis) and carbon loss
(respiration) increase in similar proportion with decreasing leaf life-span,
increasing leaf nitrogen concentration, and increasing leaf surface area-to-mass
ratio. Productivity of individual plants and of leaves in vegetation canopies
also changes in constant proportion to leaf life-span and surface area-to-mass
ratio. These global plant functional relationships have significant implications
for global scale modeling of vegetation-atmosphere CO2 exchange.
PMID- 9391093
TI - Methylation of the minimal promoter of an embryonic globin gene silences
transcription in primary erythroid cells.
AB - Methylation of cytosines in the dinucleotide CpG has been shown to suppress
transcription of a number of tissue-specific genes, yet the precise mechanism is
not fully understood. The vertebrate globin genes were among the first examples
in which an inverse correlation was shown between CpG methylation and
transcription. We studied the methylation pattern of the 235-bp rho-globin gene
promoter in genomic DNA from primary chicken erythroid cells using the sodium
bisulfite conversion technique and found all CpGs in the promoter to be
methylated in erythroid cells from adult chickens in which the rho-globin gene is
silent but unmethylated in 5-day (primitive) embryonic red cells in which the
gene is transcribed. To elucidate further the mechanism of methylation-induced
silencing, an expression construct consisting of 235 bp of 5' promoter sequence
of the rho-globin gene along with a strong 5' erythroid enhancer driving a
chloramphenicol acetyltransferase reporter gene, rho-CAT, was transfected into
primary avian erythroid cells derived from 5-day embryos. Methylation of just the
235-bp rho-globin gene promoter fragment at every CpG resulted in a 20- to 30
fold inhibition of transcription, and this effect was not overridden by the
presence of potent erythroid-specific enhancers. The ability of the 235-bp rho
globin gene promoter to bind to a DNA Methyl Cytosine binding Protein Complex
(MeCPC) was tested in electrophoretic mobility shift assays utilizing primary
avian erythroid cell nuclear extract. The results were that fully methylated but
not unmethylated 235-bp rho-globin gene promoter fragment could compete
efficiently for MeCPC binding. These results are a direct demonstration that site
specific methylation of a globin gene promoter at the exact CpGs that are
methylated in vivo can silence transcription in homologous primary erythroid
cells. Further, these data implicate binding of MeCPC to the promoter in the
mechanism of silencing.
PMID- 9391095
TI - Ambient UV-B radiation causes deformities in amphibian embryos.
AB - There has been a great deal of recent attention on the suspected increase in
amphibian deformities. However, most reports of amphibian deformities have been
anecdotal, and no experiments in the field under natural conditions have been
performed to investigate this phenomenon. Under laboratory conditions, a variety
of agents can induce deformities in amphibians. We investigated one of these
agents, UV-B radiation, in field experiments, as a cause for amphibian
deformities. We monitored hatching success and development in long-toed
salamanders under UV-B shields and in regimes that allowed UV-B radiation.
Embryos under UV-B shields had a significantly higher hatching rate and fewer
deformities, and developed more quickly than those exposed to UV-B. Deformities
may contribute directly to embryo mortality, and they may affect an individual's
subsequent survival after hatching.
PMID- 9391096
TI - Evolutionary specialization of the nuclear targeting apparatus.
AB - The alpha- and beta-karyopherins (Kaps), also called importins, mediate the
nuclear transport of proteins. All alpha-Kaps contain a central domain composed
of eight approximately 40 amino acid, tandemly arranged, armadillo-like (Arm)
repeats. The number and order of these repeats have not changed since the common
origin of fungi, plants, and mammals. Phylogenetic analysis suggests that the
various alpha-Kaps fall into two groups, alpha1 and alpha2. Whereas animals
encode both types, the yeast genome encodes only an alpha1-Kap. The beta-Kaps are
characterized by 14-15 tandemly arranged HEAT motifs. We show that the Arm
repeats of alpha-Kaps and the HEAT motifs of beta-Kaps are similar, suggesting
that the alpha-Kaps and beta-Kaps (and for that matter, all Arm and HEAT repeat
containing proteins) are members of the same protein superfamily. Phylogenetic
analysis indicates that there are at least three major groups of beta-Kaps,
consistent with their proposed cargo specificities. We present a model in which
an alpha-independent beta-Kap progenitor gave rise to the alpha-dependent beta
Kaps and the alpha-Kaps.
PMID- 9391098
TI - Did homeodomain proteins duplicate before the origin of angiosperms, fungi, and
metazoa?
AB - Homeodomain proteins are transcription factors that play a critical role in early
development in eukaryotes. These proteins previously have been classified into
numerous subgroups whose phylogenetic relationships are unclear. Our phylogenetic
analysis of representative eukaryotic sequences suggests that there are two major
groups of homeodomain proteins, each containing sequences from angiosperms,
metazoa, and fungi. This result, based on parsimony and neighbor-joining analyses
of primary amino acid sequences, was supported by two additional features of the
proteins. The two protein groups are distinguished by an insertion/deletion in
the homeodomain, between helices I and II. In addition, an amphipathic alpha
helical secondary structure in the region N terminal of the homeodomain is shared
by angiosperm and metazoan sequences in one group. These results support the
hypothesis that there was at least one duplication of homeobox genes before the
origin of angiosperms, fungi, and metazoa. This duplication, in turn, suggests
that these proteins had diverse functions early in the evolution of eukaryotes.
The shared secondary structure in angiosperm and metazoan sequences points to an
ancient conserved functional domain.
PMID- 9391097
TI - Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1
and AHR2) and the PAS family.
AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor
through which halogenated aromatic hydrocarbons such as 2,3,7,8
tetrachlorodibenzo-p-dioxin (TCDD) cause altered gene expression and toxicity.
The AHR belongs to the basic helix-loop-helix/Per-ARNT-Sim (bHLH-PAS) family of
transcriptional regulatory proteins, whose members play key roles in development,
circadian rhythmicity, and environmental homeostasis; however, the normal
cellular function of the AHR is not yet known. As part of a phylogenetic approach
to understanding the function and evolutionary origin of the AHR, we sequenced
the PAS homology domain of AHRs from several species of early vertebrates and
performed phylogenetic analyses of these AHR amino acid sequences in relation to
mammalian AHRs and 24 other members of the PAS family. AHR sequences were
identified in a teleost (the killifish Fundulus heteroclitus), two elasmobranch
species (the skate Raja erinacea and the dogfish Mustelus canis), and a jawless
fish (the lamprey Petromyzon marinus). Two putative AHR genes, designated AHR1
and AHR2, were found both in Fundulus and Mustelus. Phylogenetic analyses
indicate that the AHR2 genes in these two species are orthologous, suggesting
that an AHR gene duplication occurred early in vertebrate evolution and that
multiple AHR genes may be present in other vertebrates. Database searches and
phylogenetic analyses identified four putative PAS proteins in the nematode
Caenorhabditis elegans, including possible AHR and ARNT homologs. Phylogenetic
analysis of the PAS gene family reveals distinct clades containing both
invertebrate and vertebrate PAS family members; the latter include paralogous
sequences that we propose have arisen by gene duplication early in vertebrate
evolution. Overall, our analyses indicate that the AHR is a phylogenetically
ancient protein present in all living vertebrate groups (with a possible
invertebrate homolog), thus providing an evolutionary perspective to the study of
dioxin toxicity and AHR function.
PMID- 9391099
TI - The interphotoreceptor retinoid binding protein gene in therian mammals:
implications for higher level relationships and evidence for loss of function in
the marsupial mole.
AB - The subclass Theria of Mammalia includes marsupials (infraclass Metatheria) and
placentals (infraclass Eutheria). Within each group, interordinal relationships
remain unclear. One limitation of many studies is incomplete ordinal
representation. Here, we analyze DNA sequences for part of exon 1 of the
interphotoreceptor retinoid binding protein gene, including 10 that are newly
reported, for representatives of all therian orders. Among placentals, the most
robust clades are Cetartiodactyla, Paenungulata, and an expanded African clade
that includes paenungulates, tubulidentates, and macroscelideans. Anagalida,
Archonta, Altungulata, Hyracoidea + Perissodactyla, Ungulata, and the "flying
primate" hypothesis are rejected by statistical tests. Among marsupials, the most
robust clade includes all orders except Didelphimorphia. The phylogenetic
placement of the monito del monte and the marsupial mole remains unclear.
However, the marsupial mole sequence contains three frameshift indels and
numerous stop codons in all three reading frames. Given that the
interphotoreceptor retinoid binding protein gene is a single-copy gene that
functions in the visual cycle and that the marsupial mole is blind with
degenerate eyes, this finding suggests that phenotypic degeneration of the eyes
is accompanied by parallel changes at the molecular level as a result of relaxed
selective constraints.
PMID- 9391100
TI - Dentition of Proteopithecus sylviae, an archaic anthropoid from the Fayum, Egypt.
AB - Proteopithecus sylviae is an archaic anthropoid from the late Eocene quarry L-41,
Fayum Province, Egypt. The dentition of Proteopithecus is very primitive and does
not closely resemble that of other, better known, primates from the Fayum (e.g.,
parapithecids and propliopithecids). The dental morphology, much of which is
described herein, shows a platyrrhine-like level of organization, suggesting that
P. sylviae may occupy a position near the base of the modern anthropoid
radiation.
PMID- 9391101
TI - Transcription factor Mts1/Mts2 (Atf1/Pcr1, Gad7/Pcr1) activates the M26 meiotic
recombination hotspot in Schizosaccharomyces pombe.
AB - Homologous recombination hotspots increase the frequency of recombination in
nearby DNA. The M26 hotspot in the ade6 gene of Schizosaccharomyces pombe is a
meiotic hotspot with a discrete, cis-acting nucleotide sequence (5'-ATGACGT-3')
defined by extensive mutagenesis. A heterodimeric M26 DNA binding protein,
composed of subunits Mts1 and Mts2, has been identified and purified 40,000-fold.
Cloning, disruption, and genetic analyses of the mts genes demonstrate that the
Mts1/Mts2 heterodimer is essential for hotspot activity. This provides direct
evidence that a specific trans-acting factor, binding to a cis-acting site with a
unique nucleotide sequence, is required to activate this meiotic hotspot.
Intriguingly, the Mts1/Mts2 protein subunits are identical to the recently
described transcription factors Atf1 (Gad7) and Pcr1, which are required for a
variety of stress responses. However, we report differential dependence on the
Mts proteins for hotspot activation and stress response, suggesting that these
proteins are multifunctional and have distinct activities. Furthermore, ade6 mRNA
levels are equivalent in hotspot and nonhotspot meioses and do not change in mts
mutants, indicating that hotspot activation is not a consequence of elevated
transcription levels. These findings suggest an intimate but separable link
between the regulation of transcription and meiotic recombination. Other studies
have recently shown that the Mts1/Mts2 protein and M26 sites are involved in
meiotic recombination elsewhere in the S. pombe genome, suggesting that these
factors help regulate the timing and distribution of homologous recombination.
PMID- 9391102
TI - Replacement of Fhit in cancer cells suppresses tumorigenicity.
AB - The candidate tumor suppressor gene, FHIT, encompasses the common human
chromosomal fragile site at 3p14.2, the hereditary renal cancer translocation
breakpoint, and cancer cell homozygous deletions. Fhit hydrolyzes dinucleotide
5',5"'-P1,P3-triphosphate in vitro and mutation of a central histidine abolishes
hydrolase activity. To study Fhit function, wild-type and mutant FHIT genes were
transfected into cancer cell lines that lacked endogenous Fhit. No consistent
effect of exogenous Fhit on growth in culture was observed, but Fhit and
hydrolase "dead" Fhit mutant proteins suppressed tumorigenicity in nude mice,
indicating that 5',5"'-P1, P3-triphosphate hydrolysis is not required for tumor
suppression.
PMID- 9391103
TI - A ribozyme-mediated, gene "knockdown" strategy for the identification of gene
function in zebrafish.
AB - The zebrafish system offers many unique opportunities for the study of molecular
biology. To date, only random mutagenesis, and not directed gene knockouts, have
been demonstrated in this system. To more fully develop the potential of the
zebrafish system, an approach to effectively inhibit the expression of any
targeted gene in the developing zebrafish embryo has been developed. This
approach uses a transient, cytoplasmic, T7 expression system, injected into the
fertilized zebrafish egg to rapidly produce high levels of a ribozyme directed
against the mRNA encoded by the targeted gene to inhibit its expression. In a
demonstration of this strategy, expression of the recessive dominant zebrafish no
tail gene was effectively inhibited by using this strategy to yield a phenotype
identical to that resulting from a known defective mutation in this same gene.
This, ribozyme-mediated, message deletion strategy may have use in determining
the function of genetic coding sequences of unknown function.
PMID- 9391104
TI - In vivo telomere dynamics of human hematopoietic stem cells.
AB - Aging in vivo and cell division in vitro are associated with telomere shortening.
Several lines of evidence suggest that telomere length may be a good predictor of
the long term replicative capacity of cells. To investigate the natural fate of
chromosome telomeres of hematopoietic stem cells in vivo, we measured the
telomere length of peripheral blood granulocytes from 11 fully engrafted bone
marrow transplant recipients and from their respective donors. In 10 of 11 donor
recipient pairs, the telomere length was significantly reduced in the recipient
and the extent of reduction correlated inversely with the number of nucleated
cells infused. These data provide internally controlled in vivo evidence that,
concomitantly with their proliferation, hematopoietic stem cells lose telomere
length; it is possible that, as a result, their proliferative potential is
reduced. These findings must be taken into account when developing new protocols
in which few stem cells are used for bone marrow transplantation or for gene
therapy.
PMID- 9391105
TI - Genetic recombination of poliovirus in a cell-free system.
AB - Genetic recombination of plus-strand RNA viruses is an important process for
promoting genetic variation. By using genetically marked poliovirus RNAs, we have
demonstrated that genetic recombination can occur in a cell-free system that
generates infective virus from added poliovirus RNA. Recombinant polioviruses
were isolated, and the region of crossing over was roughly mapped. Recombinants
could be isolated even under conditions where the yield of viruses from one of
the parental RNAs was depressed to levels comparable to or less than the yield of
recombinant viruses, an observation suggesting that only one of the recombining
RNAs needs to be replication-competent. The generation of poliovirus recombinants
in a cell-free system offers new possibilities for studying recombination and
evolution of RNA viruses.
PMID- 9391106
TI - Multiple pathways for SOS-induced mutagenesis in Escherichia coli: an
overexpression of dinB/dinP results in strongly enhancing mutagenesis in the
absence of any exogenous treatment to damage DNA.
AB - dinP is an Escherichia coli gene recently identified at 5.5 min of the genetic
map, whose product shows a similarity in amino acid sequence to the E. coli UmuC
protein involved in DNA damage-induced mutagenesis. In this paper we show that
the gene is identical to dinB, an SOS gene previously localized near the lac
locus at 8 min, the function of which was shown to be required for mutagenesis of
nonirradiated lambda phage infecting UV-preirradiated bacterial cells (termed
lambdaUTM for lambda untargeted mutagenesis). A newly constructed dinP null
mutant exhibited the same defect for lambdaUTM as observed previously with a
dinB::Mu mutant, and the defect was complemented by plasmids carrying dinP as the
only intact bacterial gene. Furthermore, merely increasing the dinP gene
expression, without UV irradiation or any other DNA-damaging treatment, resulted
in a strong enhancement of mutagenesis in F'lac plasmids; at most, 800-fold
increase in the G6-to-G5 change. The enhanced mutagenesis did not depend on recA,
uvrA, or umuDC. Thus, our results establish that E. coli has at least two
distinct pathways for SOS-induced mutagenesis: one dependent on umuDC and the
other on dinB/P.
PMID- 9391107
TI - Mitochondrial mutational spectra in human cells and tissues.
AB - We have found that human organs such as colon, lung, and muscle, as well as their
derived tumors, share nearly all mitochondrial hotspot point mutations. Seventeen
hotspots, primarily G --> A and A --> G transitions, have been identified in the
mitochondrial sequence of base pairs 10,030-10,130. Mutant fractions increase
with the number of cell generations in a human B cell line, TK6, indicating that
they are heritable changes. The mitochondrial point mutation rate appears to be
more than two orders of magnitude higher than the nuclear point mutation rate in
TK6 cells and in human tissues. The similarity of the hotspot sets in vivo and in
vitro leads us to conclude that human mitochondrial point mutations in the
sequence studied are primarily spontaneous in origin and arise either from DNA
replication error or reactions of DNA with endogenous metabolites. The
predominance of transition mutations and the high number of hotspots in this
short sequence resembles spectra produced by DNA polymerases in vitro.
PMID- 9391109
TI - Yeast mutations in multiple complementation groups inhibit brome mosaic virus RNA
replication and transcription and perturb regulated expression of the viral
polymerase-like gene.
AB - Brome mosaic virus (BMV), a member of the alphavirus-like superfamily of positive
strand RNA viruses, encodes two proteins, 1a and 2a, that interact with each
other, with unidentified host proteins, and with host membranes to form the viral
RNA replication complex. Yeast expressing 1a and 2a support replication and
subgenomic mRNA synthesis by BMV RNA3 derivatives. Using a multistep selection
and screening process, we have isolated yeast mutants in multiple complementation
groups that inhibit BMV-directed gene expression. Three complementation groups,
represented by mutants mab1-1, mab2-1, and mab3-1 (for maintenance of BMV
functions), were selected for initial study. Each of these mutants has a single,
recessive, chromosomal mutation that inhibits accumulation of positive- and
negative-strand RNA3 and subgenomic mRNA. BMV-directed gene expression was
inhibited when the RNA replication template was introduced by in vivo
transcription from DNA or by transfection of yeast with in vitro transcripts,
confirming that cytoplasmic RNA replication steps were defective. mab1-1, mab2-1,
and mab3-1 slowed yeast growth to varying degrees and were temperature-sensitive,
showing that the affected genes contribute to normal cell growth. In wild-type
yeast, expression of the helicase-like 1a protein increased the accumulation of
2a mRNA and the polymerase-like 2a protein, revealing a new level of viral
regulation. In association with their other effects, mab1-1 and mab2-1 blocked
the ability of 1a to stimulate 2a mRNA and protein accumulation, whereas mab3-1
had elevated 2a protein accumulation. Together, these results show that BMV RNA
replication in yeast depends on multiple host genes, some of which directly or
indirectly affect the regulated expression and accumulation of 2a.
PMID- 9391108
TI - A family of genes required for maintenance of cell wall integrity and for the
stress response in Saccharomyces cerevisiae.
AB - The PKC1-MPK1 pathway in yeast functions in the maintenance of cell wall
integrity and in the stress response. We have identified a family of genes that
are putative regulators of this pathway. WSC1, WSC2, and WSC3 encode predicted
integral membrane proteins with a conserved cysteine motif and a WSC1-green
fluorescence protein fusion protein localizes to the plasma membrane. Deletion of
WSC results in phenotypes similar to mutants in the PKC1-MPK1 pathway and an
increase in the activity of MPK1 upon a mild heat treatment is impaired in a
wscDelta mutant. Genetic analysis places the function of WSC upstream of PKC1,
suggesting that they play a role in its activation. We also find a genetic
interaction between WSC and the RAS-cAMP pathway. The RAS-cAMP pathway is
required for cell cycle progression and for the heat shock response.
Overexpression of WSC suppresses the heat shock sensitivity of a strain in which
RAS is hyperactivated and the heat shock sensitivity of a wscDelta strain is
rescued by deletion of RAS2. The functional characteristics and cellular
localization of WSC suggest that they may mediate intracellular responses to
environmental stress in yeast.
PMID- 9391110
TI - Ascorbate recycling in human neutrophils: induction by bacteria.
AB - Ascorbate (vitamin C) recycling occurs when extracellular ascorbate is oxidized,
transported as dehydroascorbic acid, and reduced intracellularly to ascorbate. We
investigated microorganism induction of ascorbate recycling in human neutrophils
and in microorganisms themselves. Ascorbate recycling was determined by measuring
intracellular ascorbate accumulation. Ascorbate recycling in neutrophils was
induced by both Gram-positive and Gram-negative pathogenic bacteria, and the
fungal pathogen Candida albicans. Induction of recycling resulted in as high as a
30-fold increase in intracellular ascorbate compared with neutrophils not exposed
to microorganisms. Recycling occurred at physiologic concentrations of
extracellular ascorbate within 20 min, occurred over a 100-fold range of
effector/target ratios, and depended on oxidation of extracellular ascorbate to
dehydroascorbic acid. Ascorbate recycling did not occur in bacteria nor in C.
albicans. Ascorbate did not enter microorganisms, and dehydroascorbic acid entry
was less than could be accounted for by diffusion. Because microorganism lysates
reduced dehydroascorbic acid to ascorbate, ascorbate recycling was absent because
of negligible entry of the substrate dehydroascorbic acid. Because ascorbate
recycling occurs in human neutrophils but not in microorganisms, it may represent
a eukaryotic defense mechanism against oxidants with possible clinical
implications.
PMID- 9391111
TI - Phosphatidylinositol 3-kinase-gamma activates Bruton's tyrosine kinase in concert
with Src family kinases.
AB - Bruton's tyrosine kinase (Btk) is essential for normal B lymphocyte development
and function. The activity of Btk is partially regulated by transphosphorylation
within its kinase domain by Src family kinases at residue Tyr-551 and subsequent
autophosphorylation at Tyr-223. Activation correlates with Btk association with
cellular membranes. Based on specific loss of function mutations, the Btk
pleckstrin homology (PH) domain plays an essential role in this activation
process. The Btk PH domain can bind in vitro to several lipid end products of the
phosphatidylinositol 3-kinase (PI 3-kinase) family including phosphatidylinositol
3,4,5-trisphosphate. Activation of Btk as monitored by elevation of
phosphotyrosine content and a cellular transformation response was dramatically
enhanced by coexpressing a weakly activated allele of Src (E378G) and the two
subunits of PI 3-kinase-gamma. This activation correlates with new sites of
phosphorylation on Btk identified by two-dimensional phosphopeptide mapping.
Activation of Btk was dependent on the catalytic activity of all three enzymes
and an intact Btk PH domain and Src transphosphorylation site. These combined
data define Btk as a downstream target of PI 3-kinase-gamma and Src family
kinases.
PMID- 9391112
TI - An in vitro study of the dynamic features of the major histocompatibility complex
class I complex relevant to its role as a versatile peptide-receptive molecule.
AB - The major histocompatibility complex class I complex consists of a heavy chain
and a light chain (beta2-microglobulin, beta2m), which assemble with a short
endogenously derived peptide in the endoplasmic reticulum. The class I peptide
can be directly exchanged, either at the cell surface or, as recently described,
in vesicles of the endocytic compartments, thus allowing exogenous peptides to
enter the class I presentation pathway. To probe the interactions between the
components of the class I molecule, we analyzed the exchange of peptide and
beta2m by using purified, recombinant H2-Kb/peptide complexes in a cell-free in
vitro system. The exchange of competitor peptide was primarily dependent on the
off-rate of the original peptide in the class I binding groove. Peptide exchange
was not enhanced by the presence of exogenous beta2m, as exchange occurred to the
same extent in its absence. Thus, the exchange of peptide and beta2m are
independent events. The exchange rate of beta2m also was not affected by the
dissociation rates of the original peptides. Furthermore, peptides could
substantially exchange into class I molecules over a pH range of 5.5 to 7.5,
conditions prevalent in certain endocytic compartments. We conclude that the
dynamic properties of the components of class I molecules explain its function as
a highly peptide-receptive molecule. The major histocompatibility complex class I
can readily receive peptides independent of the presence of exogenous beta2m,
even at a low pH. Such properties are relevant to class I peptide acquisition,
which can occur at the cell surface, as well as in specialized endosomes.
PMID- 9391113
TI - Decreased ability of HIV-1 tat protein-treated accessory cells to organize
cellular clusters is associated with partial activation of T cells.
AB - It has been shown in several animal models that HIV infection of accessory cells
(ACs) plays an important role in development of AIDS. Here, we report that ACs
treated with HIV-1 Tat protein (Tat-ACs) have a decreased ability to organize
cellular aggregates as compared with untreated ACs, resulting in incomplete
activation of T cells in responses to anti-CD3 mAb or staphylococcal enterotoxin
B stimulation. The T cells failed to up-regulate adhesion molecules CD11a and CD2
on the cell surface and had reduced proliferative responses, as determined by
[3H]thymidine incorporation, but they obtained lymphoblast-like morphology and
expressed early activation antigens on the cell surface such as Fas and CD69 and
interleukin 2 receptor, at comparable levels as those T cells undergoing a
maximal proliferation. These results suggest that the Tat-AC-induced defect
occurs in the late, but not in the early, phases of T cell activation. Normal
expression of cell surface Fas antigen accompanied by defects in late activation
thus may result in the susceptibility of these T cells to apoptosis. Our studies
suggest that dysfunction, hyperactivation, and susceptibility to apoptosis, as
observed with T cells isolated from HIV-infected individuals, may be, at least in
part, a consequence of abnormal functions of ACs.
PMID- 9391114
TI - Alphabeta T cell receptor interactions with syngeneic and allogeneic ligands:
affinity measurements and crystallization.
AB - Cellular immunity is mediated by the interaction of an alphabeta T cell receptor
(TCR) with a peptide presented within the context of a major histocompatibility
complex (MHC) molecule. Alloreactive T cells have alphabeta TCRs that can
recognize both self- and foreign peptide-MHC (pMHC) complexes, implying that the
TCR has significant complementarity with different pMHC. To characterize the
molecular basis for alloreactive TCR recognition of pMHC, we have produced a
soluble, recombinant form of an alloreactive alphabeta T cell receptor in
Drosophila melanogaster cells. This recombinant TCR, 2C, is expressed as a
correctly paired alphabeta heterodimer, with the chains covalently connected via
a disulfide bond in the C-terminal region. The native conformation of the 2C TCR
was probed by surface plasmon resonance (SPR) analysis by using conformation
specific monoclonal antibodies, as well as syngeneic and allogeneic pMHC ligands.
The 2C interaction with H-2Kb-dEV8, H-2Kbm3-dEV8, H-2Kb-SIYR, and H-2Ld-p2Ca
spans a range of affinities from Kd = 10(-4) to 10(-6)M for the syngeneic (H-2Kb)
and allogeneic (H-2Kbm3, H-2Ld) ligands. In general, the syngeneic ligands bind
with weaker affinities than the allogeneic ligands, consistent with current
threshold models of thymic selection and T cell activation. Crystallization of
the 2C TCR required proteolytic trimming of the C-terminal residues of the alpha
and beta chains. X-ray quality crystals of complexes of 2C with H-2Kb-dEV8, H
2Kbm3-dEV8 and H-2Kb-SIYR have been grown.
PMID- 9391115
TI - Interferon-gamma impacts at multiple points during the progression of autoimmune
diabetes.
AB - The role of interferon-gamma in autoimmune diabetes was assessed by breeding a
null mutation of the interferon-gamma receptor alpha chain into the nonobese
diabetic mouse strain, as well as into a simplified T cell receptor transgenic
model of diabetes. In contrast to a previous report on abrogation of the
interferon-gamma gene, mutation of the gene encoding its receptor led to drastic
effects on disease in both mouse lines. Nonobese diabetic mice showed a marked
inhibition of insulitis-both the kinetics and penetrance-and no signs of
diabetes; the transgenic model exhibited near-normal insulitis, but this never
evolved into diabetes, either spontaneously or after experimental provocation.
This failure could not be explained by perturbations in the ratio of T helper
cell phenotypes; rather, it reflected a defect in antigen-presenting cells or in
the islet beta cell targets.
PMID- 9391116
TI - Distinct tyrosine phosphorylation sites in JAK3 kinase domain positively and
negatively regulate its enzymatic activity.
AB - Cytokines are critically important for the growth and development of a variety of
cells. Janus kinases (JAKs) associate with cytokine receptors and are essential
for transmitting downstream cytokine signals. However, the regulation of the
enzymatic activity of the JAKs is not well understood. Here, we investigated the
role of tyrosine phosphorylation of JAK3 in regulating its kinase activity by
analyzing mutations of tyrosine residues within the putative activation loop of
the kinase domain. Specifically, tyrosine residues 980 and 981 of JAK3 were
mutated to phenylalanine individually or doubly. We found that JAK3 is
autophosphorylated on multiple sites including Y980 and Y981. Compared with the
activity of wild-type (WT) JAK3, mutant Y980F demonstrated markedly decreased
kinase activity, and optimal phosphorylation of JAK3 on other sites was dependent
on Y980 phosphorylation. The mutant Y980F also exhibited reduced phosphorylation
of its substrates, gammac and STAT5A. In contrast, mutant Y981F had greatly
increased kinase activity, whereas the double mutant, YY980/981FF, had
intermediate activity. These results indicate that Y980 positively regulates JAK3
kinase activity whereas Y981 negatively regulates JAK3 kinase activity. These
observations in JAK3 are similar to the findings in the kinase that is closely
related to the JAK family, ZAP-70; mutations of tyrosine residues within the
putative activation loop of ZAP-70 also have opposing actions. Thus, it will be
important to determine whether this feature of regulation is unique to JAK3 or if
it is also a feature of other JAKs. Given the importance of JAKs and particularly
JAK3, it will be critical to fully dissect the positive and negative regulatory
function of these and other tyrosine residues in the control of kinase activity
and hence cytokine signaling.
PMID- 9391117
TI - Production, specificity, and functionality of monoclonal antibodies to specific
peptide-major histocompatibility complex class II complexes formed by processing
of exogenous protein.
AB - Several unanswered questions in T cell immunobiology relating to intracellular
processing or in vivo antigen presentation could be approached if convenient,
specific, and sensitive reagents were available for detecting the peptide-major
histocompatibility complex (MHC) class I or class II ligands recognized by
alphabeta T cell receptors. For this reason, we have developed a method using
homogeneously loaded peptide-MHC class II complexes to generate and select
specific mAb reactive with these structures using hen egg lysozyme (HEL) and I-Ak
as a model system. mAbs specific for either HEL-(46-61)-Ak or HEL-(116-129)-Ak
have been isolated. They cross-react with a small subset of I-Ak molecules loaded
with self peptides but can nonetheless be used for flow cytometry,
immunoprecipitation, Western blotting, and intracellular immunofluorescence to
detect specific HEL peptide-MHC class II complexes formed by either peptide
exposure or natural processing of native HEL. An example of the utility of these
reagents is provided herein by using one of the anti-HEL-(46-61)-Ak specific mAbs
to visualize intracellular compartments where I-Ak is loaded with HEL-derived
peptides early after antigen administration. Other uses, especially for in vivo
tracking of specific ligand-bearing antigen-presenting cells, are discussed.
PMID- 9391118
TI - Gene transfer of Fas ligand induces tumor regression in vivo.
AB - The Fas-Fas ligand (FasL) system plays an important role in the induction of
lymphoid apoptosis and has been implicated in the suppression of immune
responses. Herein, we report that gene transfer of FasL inhibits tumor cell
growth in vivo. Although such inhibition is expected in Fas+ tumor cell lines,
marked regression was unexpectedly observed after FasL gene transfer into the
CT26 colon carcinoma that does not express Fas. Infection by an adenoviral vector
encoding FasL rapidly eliminated tumor masses in the Fas+ Renca tumor by inducing
cell death, whereas the elimination of Fas- CT26 cells was mediated by
inflammatory cells. Analysis of human malignancies revealed Fas, but not FasL,
expression in a majority of tumors and susceptibility to FasL in most Fas+ cell
lines. These findings suggest that gene transfer of FasL generates apoptotic
responses and induces potent inflammatory reactions that can be used to induce
the regression of malignancies.
PMID- 9391119
TI - A point mutation in the MET oncogene abrogates metastasis without affecting
transformation.
AB - The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth
factor/scatter factor (HGF), known to stimulate invasive growth of epithelial
cells. MET is overexpressed in a significant percentage of human cancers and is
amplified during the transition between primary tumors and metastasis. To
investigate whether this oncogene is directly responsible for the acquisition of
the metastatic phenotype, we exploited a single-hit oncogenic version of MET,
able to transform and to confer invasive and metastatic properties to
nontumorigenic cells, both in vitro and in nude mice. We mutagenized the signal
transducer docking site of Met (Y1349VHVX3Y1356VNV), which has the uncommon
property of binding and activating multiple src homology region 2 (SH2)
containing intracellular effectors. Notably, a point mutation (H1351 --> N)
increased the transforming ability of the oncogene but abolished its metastatic
potential. This mutation duplicates the Grb2 binding site, super-activating the
Ras pathway and preventing the binding of the other intracellular transducers.
Complementation in trans with another nonmetastatic mutant (N1358 --> H),
recruiting all the transducers downstream to Met except Grb2, rescued the
invasive-metastatic phenotype. It is concluded that the metastatic potential of
the MET oncogene relies on the properties of its multifunctional docking site,
and that a single point mutation affecting signal transduction can dissociate
neoplastic transformation from metastasis.
PMID- 9391120
TI - Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same
gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin
associated glycoprotein complex.
AB - Cardiomyopathy (CM) is a primary degenerative disease of myocardium and is
traditionally categorized into hypertrophic and dilated CMs (HCM and DCM)
according to its gross appearance. Cardiomyopathic hamster (CM hamster), a
representative model of human hereditary CM, has HCM and DCM inbred sublines,
both of which descend from the same ancestor. Herein we show that both HCM and
DCM hamsters share a common defect in a gene for delta-sarcoglycan (delta-SG),
the functional role of which is yet to be characterized. A breakpoint causing
genomic deletion was found to be located at 6.1 kb 5' upstream of the second exon
of delta-SG gene, and its 5' upstream region of more than 27.4 kb, including the
authentic first exon of delta-SG gene, was deleted. This deletion included the
major transcription initiation site, resulting in a deficiency of delta-SG
transcripts with the consequent loss of delta-SG protein in all the CM hamsters,
despite the fact that the protein coding region of delta-SG starting from the
second exon was conserved in all the CM hamsters. We elucidated the molecular
interaction of dystrophin-associated glycoproteins including delta-SG, by using
an in vitro pull-down study and ligand overlay assay, which indicates the
functional role of delta-SG in stabilizing sarcolemma. The present study not only
identifies CM hamster as a valuable animal model for studying the function of
delta-SG in vivo but also provides a genetic target for diagnosis and treatment
of human CM.
PMID- 9391121
TI - Identification, isolation, and characterization of daintain (allograft
inflammatory factor 1), a macrophage polypeptide with effects on insulin
secretion and abundantly present in the pancreas of prediabetic BB rats.
AB - A bioactive macrophage factor, the polypeptide daintain/allograft inflammatory
factor 1 (AIF1), has been isolated from porcine intestine. It was discovered when
searching for intestinal peptides with effects on insulin release, and its
purification was monitored by the influence of the peptide fractions on
pancreatic glucose-induced insulin secretion. Daintain/AIF1 is a 146-aa residue
polypeptide with a mass of 16,603 Da and an acetylated N terminus. An internal 44
residue segment with the sequence pattern -KR-KK-GKR- has a motif typical of
peptide hormone precursors, i.e., dibasic sites for potential activation
cleavages and at the sequentially last such site, the structure GKR. The latter
is a signal for C-terminal amide formation in the processing of peptide hormones.
Daintain/AIF1 is immunohistochemically localized to microglial cells in the
central nervous system and to dendritic cells and macrophages in several organs.
A particularly dense accumulation of daintain/AIF1-immunoreactive macrophages was
observed in the insulitis affecting the pancreatic islets of prediabetic BB rats.
When injected intravenously in mice, daintain/AIF1 at 75 pmol/kg inhibited
glucose (1 g/kg)-stimulated insulin secretion, with a concomitant impairment of
the glucose elimination, whereas at higher doses (7.5 and 75 nmol/kg),
daintain/AIF1 potentiated glucose-stimulated insulin secretion and enhanced the
glucose elimination. Its dual influence on insulin secretion in vivo at different
peptide concentrations, and the abundance of macrophages expressing daintain/AIF1
in the pancreatic islets of prediabetic rats, suggest that daintain/AIF1 may have
a role in connection with the pathogenesis of insulin-dependent diabetes
mellitus.
PMID- 9391122
TI - Tissue engineering of cartilage in space.
AB - Tissue engineering of cartilage, i.e., the in vitro cultivation of cartilage
cells on synthetic polymer scaffolds, was studied on the Mir Space Station and on
Earth. Specifically, three-dimensional cell-polymer constructs consisting of
bovine articular chondrocytes and polyglycolic acid scaffolds were grown in
rotating bioreactors, first for 3 months on Earth and then for an additional 4
months on either Mir (10(-4)-10(-6) g) or Earth (1 g). This mission provided a
unique opportunity to study the feasibility of long-term cell culture flight
experiments and to assess the effects of spaceflight on the growth and function
of a model musculoskeletal tissue. Both environments yielded cartilaginous
constructs, each weighing between 0.3 and 0.4 g and consisting of viable,
differentiated cells that synthesized proteoglycan and type II collagen. Compared
with the Earth group, Mir-grown constructs were more spherical, smaller, and
mechanically inferior. The same bioreactor system can be used for a variety of
controlled microgravity studies of cartilage and other tissues. These results may
have implications for human spaceflight, e.g., a Mars mission, and clinical
medicine, e.g., improved understanding of the effects of pseudo-weightlessness in
prolonged immobilization, hydrotherapy, and intrauterine development.
PMID- 9391123
TI - Tissue-specific expression of herpes simplex virus thymidine kinase gene
delivered by adeno-associated virus inhibits the growth of human hepatocellular
carcinoma in athymic mice.
AB - About 70% of hepatocellular carcinomas are known to express alpha-fetoprotein,
which is normally expressed in fetal but not in adult livers. To induce herpes
simplex virus-thymidine kinase expression in these cancer cells, we constructed
an adeno-associated viral vector containing the HSV-TK gene under the control of
the alpha-fetoprotein enhancer and albumin promoter. We previously demonstrated
in vitro that although this vector can transduce a variety of human cells, only
transduced AFP and albumin-expressing hepatocellular carcinoma cell lines were
sensitive to killing by ganciclovir (GCV). In the present study, we explored the
effect of this vector on hepatocellular carcinoma cells in vivo. Subcutaneous
tumors generated in nude mice by implanting hepatocellular carcinoma cells
previously transduced with this vector shrank dramatically after treatment with
GCV. Bystander effect was also observed on the tumors generated by mixing
transduced and untransduced cells. To test whether the tumor cells can be
transduced by the virus in vivo, we injected the recombinant adeno-associated
virus into tumors generated by untransduced hepatocarcinoma cell line. Tumor
growth were retarded after treatment with GCV. These experiments demonstrate the
feasibility of in vivo transduction of tumor cell with rAAV.
PMID- 9391124
TI - Proliferation of adult T cell leukemia/lymphoma cells is associated with the
constitutive activation of JAK/STAT proteins.
AB - Human T cell leukemia/lymphotropic virus type I (HTLV-I) induces adult T cell
leukemia/lymphoma (ATLL). The mechanism of HTLV-I oncogenesis in T cells remains
partly elusive. In vitro, HTLV-I induces ligand-independent transformation of
human CD4+ T cells, an event that correlates with acquisition of constitutive
phosphorylation of Janus kinases (JAK) and signal transducers and activators of
transcription (STAT) proteins. However, it is unclear whether the in vitro model
of HTLV-I transformation has relevance to viral leukemogenesis in vivo. Here we
tested the status of JAK/STAT phosphorylation and DNA-binding activity of STAT
proteins in cell extracts of uncultured leukemic cells from 12 patients with ATLL
by either DNA-binding assays, using DNA oligonucleotides specific for STAT-1 and
STAT-3, STAT-5 and STAT-6 or, more directly, by immunoprecipitation and
immunoblotting with anti-phosphotyrosine antibody for JAK and STAT proteins.
Leukemic cells from 8 of 12 patients studied displayed constitutive DNA-binding
activity of one or more STAT proteins, and the constitutive activation of the
JAK/STAT pathway was found to persist over time in the 2 patients followed
longitudinally. Furthermore, an association between JAK3 and STAT-1, STAT-3, and
STAT-5 activation and cell-cycle progression was demonstrated by both propidium
iodide staining and bromodeoxyuridine incorporation in cells of four patients
tested. These results imply that JAK/STAT activation is associated with
replication of leukemic cells and that therapeutic approaches aimed at JAK/STAT
inhibition may be considered to halt neoplastic growth.
PMID- 9391125
TI - Inflammatory mediators are perpetuated in macrophages resistant to apoptosis
induced by hypoxia.
AB - A hypoxic/anoxic microenvironment has been proposed to exist within a vascular
lesion due to intimal or medial cell proliferation in vascular diseases. Here, we
examined whether hypoxia alters macrophage function by exposing murine macrophage
like RAW 264.7 (RAW) cells to hypoxia (2% O2). When cells were exposed to
hypoxia, a significant number of RAW cells underwent apoptosis. Additionally,
small subpopulations of RAW cells were resistant to hypoxia-induced apoptosis.
Through repeated cycles of hypoxia exposure, hypoxia-induced apoptosis-resistant
macrophages (HARMs) were selected; HARM cells demonstrate >70% resistance to
hypoxia-induced apoptosis, as compared with the parental RAW cells. When heat
shock protein (HSP) expression was examined after hypoxia, we observed a
significant decrease in constitutive heat shock protein 70 (HSC 70) in RAW cells,
but not in HARMs, as compared with the control normoxic condition (21% O2). In
contrast, the expression level of glucose-regulated protein 78 (GRP 78) in RAW
and HARM cells after hypoxia treatment was not altered, suggesting that HSC 70
and not GRP 78 may play a role in protection against hypoxia-induced apoptosis.
When tumor necrosis factor alpha (TNF-alpha) production was examined after
hypoxic treatment, a significant increase in TNF-alpha production in HARM but
decrease in RAW was observed, as compared with cells cultured in normoxic
conditions. HARM cells also exhibit a much lower level of modified-LDL uptake
than do RAW cells, suggesting that HARMs may not transform into foam cells. These
results suggest that a selective population of macrophages may adapt to
potentially pathological hypoxic conditions by overcoming the apoptotic signal.
PMID- 9391126
TI - How Escherichia coli can bias the results of molecular cloning: preferential
selection of defective genomes of hepatitis C virus during the cloning procedure.
AB - Cloned PCR products containing hepatitis C virus (HCV) genomic fragments have
been used for analyses of HCV genomic heterogeneity and protein expression. These
studies assume that the clones derived are representative of the entire virus
population and that subsets are not inadvertently selected. The aim of the
present study was to express HCV structural proteins. However, we found that
there was a strong cloning selection for defective genomes and that most clones
generated initially were incapable of expressing the HCV proteins. The HCV
structural region (C-E1-E2-p7) was directly amplified by long reverse
transcription-PCR from the plasma of an HCV-infected patient or from a control
plasmid containing a viable full-length cDNA of HCV derived from the same patient
but cloned in a different vector. The PCR products were cloned into a mammalian
expression vector, amplified in Escherichia coli, and tested for their ability to
produce HCV structural proteins. Twenty randomly picked clones derived from the
HCV-infected patient all contained nucleotide mutations leading to absence or
truncation of the expected HCV products. Of 25 clones derived from the control
plasmid, only 8% were fully functional for polyprotein synthesis. The insertion
of extra nucleotides in the region just upstream of the start codon of the HCV
insert led to a statistically significant increase in the number of fully
functional clones derived from the patient (42%) and from the control plasmid (72
92%). Nonrandom selection of clones during the cloning procedure has enormous
implications for the study of viral heterogeneity, because it can produce a false
spectrum of genomic diversity. It can also be an impediment to the construction
of infectious viral clones.
PMID- 9391127
TI - Tobacco smoke is a source of toxic reactive glycation products.
AB - Smokers have a significantly higher risk for developing coronary and
cerebrovascular disease than nonsmokers. Advanced glycation end products (AGEs)
are reactive, cross-linking moieties that form from the reaction of reducing
sugars and the amino groups of proteins, lipids, and nucleic acids. AGEs
circulate in high concentrations in the plasma of patients with diabetes or renal
insufficiency and have been linked to the accelerated vasculopathy seen in
patients with these diseases. Because the curing of tobacco takes place under
conditions that could lead to the formation of glycation products, we examined
whether tobacco and tobacco smoke could generate these reactive species that
would increase AGE formation in vivo. Our findings show that reactive glycation
products are present in aqueous extracts of tobacco and in tobacco smoke in a
form that can rapidly react with proteins to form AGEs. This reaction can be
inhibited by aminoguanidine, a known inhibitor of AGE formation. We have named
these glycation products "glycotoxins." Like other known reducing sugars and
reactive glycation products, glycotoxins form smoke, react with protein, exhibit
a specific fluorescence when cross-linked to proteins, and are mutagenic.
Glycotoxins are transferred to the serum proteins of human smokers. AGE
apolipoprotein B and serum AGE levels in cigarette smokers were significantly
higher than those in nonsmokers. These results suggest that increased glycotoxin
exposure may contribute to the increased incidence of atherosclerosis and high
prevalence of cancer in smokers.
PMID- 9391128
TI - Long-term correction of obesity and diabetes in genetically obese mice by a
single intramuscular injection of recombinant adeno-associated virus encoding
mouse leptin.
AB - The ob/ob mouse is genetically deficient in leptin and exhibits a phenotype that
includes obesity and non-insulin-dependent diabetes mellitus. This phenotype
closely resembles the morbid obesity seen in humans. In this study, we
demonstrate that a single intramuscular injection of a recombinant adeno
associated virus (AAV) vector encoding mouse leptin (rAAV-leptin) in ob/ob mice
leads to prevention of obesity and diabetes. The treated animals show
normalization of metabolic abnormalities including hyperglycemia, insulin
resistance, impaired glucose tolerance, and lethargy. The effects of a single
injection have lasted through the 6-month course of the study. At all time points
measured the circulating levels of leptin in the serum were similar to age
matched control C57 mice. These results demonstrate that maintenance of normal
levels of leptin (2-5 ng/ml) in the circulation can prevent both the onset of
obesity and associated non-insulin-dependent diabetes. Thus a single injection of
a rAAV vector expressing a therapeutic gene can lead to complete and long-term
correction of a genetic disorder. Our study demonstrates the long-term correction
of a disease caused by a genetic defect and proves the feasibility of using rAAV
based vectors for the treatment of chronic disorders like obesity.
PMID- 9391129
TI - Polyclonal structure of intestinal adenomas in ApcMin/+ mice with concomitant
loss of Apc+ from all tumor lineages.
AB - When tumors form in intestinal epithelia, it is important to know whether they
involve single initiated somatic clones. Advanced carcinomas in humans and mice
are known to be monoclonal. However, earlier stages of tumorigenesis may instead
involve an interaction between cells that belong to separate somatic clones
within the epithelium. The clonality of early tumors has been investigated in
mice with an inherited predisposition to intestinal tumors. Analysis of Min
(multiple intestinal neoplasia) mice chimeric for a ubiquitously expressed cell
lineage marker revealed that normal intestinal crypts are monoclonal, but
intestinal adenomas frequently have a polyclonal structure, presenting even when
very small as single, focal adenomas composed of at least two somatic lineages.
Furthermore, within these polyclonal adenomas, all tumor lineages frequently lose
the wild-type Apc allele. These observations can be interpreted by several models
for clonal interaction within the epithelium, ranging from passive fusion within
regions of high neoplastic potential to a requirement for active clonal
cooperation.
PMID- 9391130
TI - Interactions of the chaperone Hsp104 with yeast Sup35 and mammalian PrP.
AB - [PSI+] is a genetic element in yeast for which a heritable change in phenotype
appears to be caused by a heritable change in the conformational state of the
Sup35 protein. The inheritance of [PSI+] and the physical state of Sup35 in vivo
depend on the protein chaperone Hsp104 (heat shock protein 104). Although these
observations provide a strong genetic argument in support of the "protein-only"
or "prion" hypothesis for [PSI+], there is, as yet, no direct evidence of an
interaction between the two proteins. We report that when purified Sup35 and
Hsp104 are mixed, the circular dichroism (CD) spectrum differs from that
predicted by the addition of the proteins' individual spectra, and the ATPase
activity of Hsp104 is inhibited. Similar results are obtained with two other
amyloidogenic substrates, mammalian PrP and beta-amyloid 1-42 peptide, but not
with several control proteins. With a group of peptides that span the PrP protein
sequence, those that produced the largest changes in CD spectra also caused the
strongest inhibition of ATPase activity in Hsp104. Our observations suggest that
(i) previously described genetic interactions between Hsp104 and [PSI+] are
caused by direct interaction between Hsp104 and Sup35; (ii) Sup35 and PrP, the
determinants of the yeast and mammalian prions, respectively, share structural
features that lead to a specific interaction with Hsp104; and (iii) these
interactions couple a change in structure to the ATPase activity of Hsp104.
PMID- 9391131
TI - Chaperone-supervised conversion of prion protein to its protease-resistant form.
AB - Transmissible spongiform encephalopathies (TSEs) are lethal, infectious disorders
of the mammalian nervous system. A TSE hallmark is the conversion of the cellular
protein PrPC to disease-associated PrPSc (named for scrapie, the first known
TSE). PrPC is protease-sensitive, monomeric, detergent soluble, and primarily
alpha-helical; PrPSc is protease-resistant, polymerized, detergent insoluble, and
rich in beta-sheet. The "protein-only" hypothesis posits that PrPSc is the
infectious TSE agent that directly converts host-encoded PrPC to fresh PrPSc,
harming neurons and creating new agents of infection. To gain insight on the
conformational transitions of PrP, we tested the ability of several protein
chaperones, which supervise the conformational transitions of proteins in diverse
ways, to affect conversion of PrPC to its protease-resistant state. None affected
conversion in the absence of pre-existing PrPSc. In its presence, only two, GroEL
and Hsp104 (heat shock protein 104), significantly affected conversion. Both
promoted it, but the reaction characteristics of conversions with the two
chaperones were distinct. In contrast, chemical chaperones inhibited conversion.
Our findings provide new mechanistic insights into nature of PrP conversions, and
provide a new set of tools for studying the process underlying TSE pathogenesis.
PMID- 9391132
TI - Mutations in dihydropteroate synthase are responsible for sulfone and sulfonamide
resistance in Plasmodium falciparum.
AB - Plasmodium falciparum causes the most severe form of malaria in humans. An
important class of drugs in malaria treatment is the sulfone/sulfonamide group,
of which sulfadoxine is the most commonly used. The target of sulfadoxine is the
enzyme dihydropteroate synthase (DHPS), and sequencing of the DHPS gene has
identified amino acid differences that may be involved in the mechanism of
resistance to this drug. In this study we have sequenced the DHPS gene in 10
isolates from Thailand and identified a new allele of DHPS that has a previously
unidentified amino acid difference. We have expressed eight alleles of P.
falciparum PPPK-DHPS in Escherichia coli and purified the functional enzymes to
homogeneity. Strikingly, the Ki for sulfadoxine varies by almost three orders of
magnitude from 0.14 microM for the DHPS allele from sensitive isolates to 112
microM for an enzyme expressed in a highly resistant isolate. Comparison of the
Ki of different sulfonamides and the sulfone dapsone has suggested that the amino
acid differences in DHPS would confer cross-resistance to these compounds. These
results show that the amino acid differences in the DHPS enzyme of sulfadoxine
resistant isolates of P. falciparum are central to the mechanism of resistance to
sulfones and sulfonamides.
PMID- 9391133
TI - Backtracking leukemia to birth: identification of clonotypic gene fusion
sequences in neonatal blood spots.
AB - Epidemiological evidence has suggested that some pediatric leukemias may be
initiated in utero and, for some pairs of identical twins with concordant
leukemia, this possibility has been strongly endorsed by molecular studies of
clonality. Direct evidence for a prenatal origin can only be derived by
prospective or retrospective detection of leukemia-specific molecular
abnormalities in fetal or newborn samples. We report a PCR-based method that has
been developed to scrutinize neonatal blood spots (Guthrie cards) for the
presence of numerically infrequent leukemic cells at birth in individuals who
subsequently developed leukemia. We demonstrate that unique or clonotypic MLL-AF4
genomic fusion sequences are present and detectable in neonatal blood spots from
individuals who were diagnosed with acute lymphoblastic leukemia at ages 5 months
to 2 years and, therefore, have arisen during fetal hematopoiesis in utero. This
result provides unequivocal evidence for a prenatal initiation of acute leukemia
in young patients. The method should be applicable to other fusion genes in
children with common subtypes of leukemia and will be of value in attempts to
unravel the natural history and etiology of this major subtype of pediatric
cancer.
PMID- 9391134
TI - A dichotomous role for nitric oxide during acute Toxoplasma gondii infection in
mice.
AB - Production of nitric oxide by macrophages is believed to be an important
microbicidal mechanism for a variety of intracellular pathogens, including
Toxoplasma gondii. Mice with a targeted disruption of the inducible nitric oxide
synthase gene (iNOS) were infected orally with T. gondii tissue cysts. Time to
death was prolonged compared with parental controls. Histologic analysis of
tissue from infected mice showed scattered small foci of inflammation with
parasites in various tissues of iNOS-/- mice, whereas tissue from the parental
C57BL/6 mice had more extensive tissue inflammation with few visible parasites.
In particular, extensive ulceration and necrosis of distal small intestine and
fatty degeneration of the liver was seen in the parental mice at day 7
postinfection, as compared with the iNOS-/- mice where these tissues appeared
normal. Serum interferon gamma and tumor necrosis factor alpha levels
postinfection were equally elevated in both mouse strains. Treatment of the
parental mice with a NO synthase inhibitor, aminoguanidine, prevented early death
in these mice as well as the hepatic degeneration and small bowel necrosis seen
in acutely infected control parentals. These findings indicate that NO production
during acute infection with T. gondii can kill intracellular parasites but can be
detrimental, even lethal, to the host.
PMID- 9391135
TI - Respiratory syncytial virus (RSV) SH and G proteins are not essential for viral
replication in vitro: clinical evaluation and molecular characterization of a
cold-passaged, attenuated RSV subgroup B mutant.
AB - A live, cold-passaged (cp) candidate vaccine virus, designated respiratory
syncytial virus (RSV) B1 cp-52/2B5 (cp-52), replicated efficiently in Vero cells,
but was found to be overattenuated for RSV-seronegative infants and children.
Sequence analysis of reverse-transcription-PCR-amplified fragments of this mutant
revealed a large deletion spanning most of the coding sequences for the small
hydrophobic (SH) and attachment (G) proteins. Northern blot analysis of cp-52
detected multiple unique read-through mRNAs containing SH and G sequences,
consistent with a deletion mutation spanning the SH:G gene junction.
Immunological studies confirmed that an intact G glycoprotein was not produced by
the cp-52 virus. Nonetheless, cp-52 was infectious and replicated to high titer
in tissue culture despite the absence of the viral surface SH and G
glycoproteins. Thus, our characterization of this negative-strand RNA virus
identified a novel replication-competent deletion mutant lacking two of its three
surface glycoproteins. The requirement of SH and G for efficient replication in
vivo suggests that selective deletion of one or both of these RSV genes may
provide an alternative or additive strategy for developing an optimally
attenuated vaccine candidate.
PMID- 9391136
TI - Two forms of replication initiator protein: positive and negative controls.
AB - The pir gene of plasmid R6K encodes the protein, pi, a replication and
transcription factor. Two translational options for the pir gene give rise to two
forms of pi protein: a 35.0-kDa form (pi35.0) and a shortened 30.5-kDa form
(pi30.5). Although both proteins bind to a series of 22-bp direct repeats
essential for plasmid R6K replication, only pi35.0 can bind to a site in the
(A.T)-rich segment of its gamma ori and activate the gamma ori in vivo and in
vitro. However, unlike pi35.0, pi30.5can inhibit in vivo and in vitro replication
(activated by pi35.0). We propose that the two forms of pi might have distinct
functions in replication. We show that although both forms of pi produce dimers,
the nature of these dimers is not identical. The N-terminal 37 amino acid
residues appear to control the formation of the more stable pi35.0 dimers,
whereas another, apparently weaker interface holds together dimers of pi30.5. We
speculate that the leucine zipper-like motif, absent in pi30.5, controls very
specific functions of pi protein.
PMID- 9391137
TI - Us9, a stable lysine-less herpes simplex virus 1 protein, is ubiquitinated before
packaging into virions and associates with proteasomes.
AB - The US9 gene of herpes simplex virus 1 encodes a virion tegument protein with a
predicted Mr of 10,000. Earlier studies have shown that the gene is not essential
for viral replication in cells in culture. We report that (i) US9 forms in
denaturing polyacrylamide gels multiple overlapping bands ranging in Mr from
12,000 to 25,000; (ii) the protein recovered from infected cells or purified
virions reacts with anti-ubiquitin antibodies; (iii) autoradiographic images of
US9 protein immunoprecipitated from cells infected with [35S]methionine-labeled
virus indicate that the protein is stable for at least 4 h after entry into cells
(the protein was also stable for at least 4 h after a 1-h labeling interval 12 h
after infection); (iv) antibody to subunit 12 of proteasomes pulls down US9
protein from herpes simplex virus-infected cell lysates; and (v) the US9 gene is
highly conserved among the members of the alpha subfamily of herpes viruses, and
the US9 gene product lacks lysines. We conclude that US9 is a lysine-less,
ubiquitinated protein that interacts with the ubiquitin-dependent pathway for
degradation of proteins and that this function may be initiated at the time of
entry of the virus into the cell.
PMID- 9391138
TI - Loss of HMW1 and HMW3 in noncytadhering mutants of Mycoplasma pneumoniae occurs
post-translationally.
AB - The genomic sequence of Mycoplasma pneumoniae establish this cell-wall-less
prokaryote as among the smallest known microorganisms capable of self
replication. However, this genomic simplicity and corresponding biosynthetic
austerity are sharply contrasted by the complex terminal structure found in this
species. This tip structure (attachment organelle) directs colonization of the
human respiratory mucosa, leading to bronchitis and atypical pneumonia.
Furthermore, formation of a second tip structure appears to precede cell
division, implying temporal regulation. However, the organization, regulation,
and assembly of the attachment organelle in M. pneumoniae are poorly understood,
and no counterparts have been identified among the walled bacteria. M. pneumoniae
possesses a cytoskeleton-like structure required to localize adhesin proteins to
the attachment organelle. The cytadherence-associated proteins HMW1, HMW2, and
HMW3 are components of the mycoplasma cytoskeleton, with HMW1 localizing strictly
along the filamentous extensions from the cell body and HMW3 being a key
structural element of the terminal organelle. Disruptions in hmw2 result in the
loss of HMW1 and HMW3. However, the hmw1 and hmw3 genes were transcribed and
translated at wild-type levels in hmw2 mutants. HMW1 and HMW3 were relatively
stable in the wild-type background over 8 h but disappeared in the mutants over
this time period. Evaluation of recombinant HMW1 levels in mycoplasma mutants
suggested a requirement for the C-terminal domain of HMW1 for turnover. Finally,
an apparent defect in the processing of the precursor for the adhesin protein P1
was noted in the HMW- mutants.
PMID- 9391139
TI - Use of differential display analysis to assess the effect of human
cytomegalovirus infection on the accumulation of cellular RNAs: induction of
interferon-responsive RNAs.
AB - We used differential display analysis to identify mRNAs that accumulate to
enhanced levels in human cytomegalovirus-infected cells as compared with mock
infected cells. RNAs were compared at 8 hr after infection of primary human
fibroblasts. Fifty-seven partial cDNA clones were isolated, representing about 26
differentially expressed mRNAs. Eleven of the mRNAs were virus-coded, and 15 were
of cellular origin. Six of the partial cDNA sequences have not been reported
previously. All of the cellular mRNAs identified in the screen are induced by
interferon alpha. The induction in virus-infected cells, however, does not
involve the action of interferon or other small signaling molecules. Neutralizing
antibodies that block virus infection also block the induction. These RNAs
accumulate after infection with virus that has been inactivated by treatment with
UV light, indicating that the inducer is present in virions. We conclude that
human cytomegalovirus induces interferon-responsive mRNAs.
PMID- 9391140
TI - DNA topoisomerase targets of the fluoroquinolones: a strategy for avoiding
bacterial resistance.
AB - Fluoroquinolones are antibacterial agents that attack DNA gyrase and
topoisomerase IV on chromosomal DNA. The existence of two fluoroquinolone targets
and stepwise accumulation of resistance suggested that new quinolones could be
found that would require cells to obtain two topoisomerase mutations to display
resistance. For wild-type cells to become resistant, the two mutations must be
acquired concomitantly. That is expected to occur infrequently. To identify such
compounds, fluoroquinolones were tested for the ability to kill a moderately
resistant gyrase mutant. Compounds containing a C8-methoxyl group were
particularly lethal, and incubation of wild-type cultures on agar containing C8
methoxyl fluoroquinolones produced no resistant mutant, whereas thousands arose
during comparable treatment with control compounds lacking the C8 substituent.
When the test strain contained a preexisting topoisomerase IV mutation, which by
itself conferred no resistance, equally high numbers of resistant mutants were
obtained for C8-methoxyl and control compounds. Thus C8-methoxyl fluoroquinolones
required two mutations for expression of resistance. Although highly lethal, C8
methoxyl fluoroquinolones were not more effective than C8-H controls at blocking
bacterial growth. Consequently, quinolone action involves two events, which we
envision as formation of drug-enzyme-DNA complexes followed by release of lethal
double-strand DNA breaks. Release of DNA breaks, which must occur less frequently
than complex formation, is probably the process stimulated by the C8-methoxyl
group. Understanding this stimulation should provide insight into intracellular
quinolone action and contribute to development of fluoroquinolones that prevent
selection of resistant bacteria.
PMID- 9391141
TI - Periplasmic superoxide dismutase protects Salmonella from products of phagocyte
NADPH-oxidase and nitric oxide synthase.
AB - Superoxide dismutase (SOD) catalyzes the conversion of superoxide radical to
hydrogen peroxide. Periplasmic localization of bacterial Cu,Zn-SOD has suggested
a role of this enzyme in defense against extracellular phagocyte-derived reactive
oxygen species. Sequence analysis of regions flanking the Salmonella typhimurium
sodC gene encoding Cu,Zn-SOD demonstrates significant homology to lambda phage
proteins, reflecting possible bacteriophage-mediated horizontal gene transfer of
this determinant among pathogenic bacteria. Salmonella deficient in Cu,Zn-SOD has
reduced survival in macrophages and attenuated virulence in mice, which can be
restored by abrogation of either the phagocyte respiratory burst or inducible
nitric oxide synthase. Moreover, a sodC mutant is extremely susceptible to the
combination of superoxide and nitric oxide. These observations suggest that SOD
protects periplasmic or inner membrane targets by diverting superoxide and
limiting peroxynitrite formation, and they demonstrate the ability of the
respiratory burst and nitric oxide synthase to synergistically kill microbial
pathogens in vivo.
PMID- 9391142
TI - Chronic stress alters synaptic terminal structure in hippocampus.
AB - Repeated psychosocial or restraint stress causes atrophy of apical dendrites in
CA3 pyramidal neurons of the hippocampus, accompanied by specific cognitive
deficits in spatial learning and memory. Excitatory amino acids mediate this
atrophy together with adrenal steroids and the neurotransmitter serotonin.
Because the mossy fibers from dentate granule neurons provide a major excitatory
input to the CA3 proximal apical dendrites, we measured ultrastructural
parameters associated with the mossy fiber-CA3 synapses in control and 21-day
restraint-stressed rats in an effort to find additional morphological
consequences of stress that could help elucidate the underlying anatomical as
well as cellular and molecular mechanisms. Although mossy fiber terminals of
control rats were packed with small, clear synaptic vesicles, terminals from
stressed animals showed a marked rearrangement of vesicles, with more densely
packed clusters localized in the vicinity of active zones. Moreover, compared
with controls, restraint stress increased the area of the mossy fiber terminal
occupied by mitochondrial profiles and consequently, a larger, localized energy
generating capacity. A single stress session did not produce these changes either
immediately after or the next day following the restraint session. These findings
provide a morphological marker of the effects of chronic stress on the
hippocampus that points to possible underlying neuroanatomical as well as
cellular and molecular mechanisms for the ability of repeated stress to cause
structural changes within the hippocampus.
PMID- 9391143
TI - Induction of long-term depression and rebound potentiation by inositol
trisphosphate in cerebellar Purkinje neurons.
AB - Cerebellar Purkinje neurons receive two major excitatory inputs, the climbing
fibers (CFs) and parallel fibers (PFs). Simultaneous, repeated activation of CFs
and PFs results in the long-term depression (LTD) of the amplitude of PF-evoked
synaptic currents. To induce LTD, activation of CFs may be substituted with
depolarization of the Purkinje neuron to turn on voltage-activated calcium
channels and increase the intracellular calcium concentration. The role of PFs in
the induction of LTD, however, is less clear. PFs activate glutamate metabotropic
receptors that increase phosphoinositide turnover and elevate cytosolic inositol
1,4,5-trisphosphate (InsP3). It has been proposed that calcium release from
intracellular stores via InsP3 receptors may be important in the induction of
LTD. We studied the role of InsP3 in the induction of LTD by photolytic release
of InsP3 from its biologically inactive "caged" precursor in voltage-clamped
Purkinje neurons in acutely prepared cerebellar slices. We find that InsP3-evoked
calcium release is as effective in LTD induction as activation of PFs. InsP3
induced LTD was prevented by calcium chelator 1,2-bis(2-amino phenoxy)ethane
N,N,N', N'-tetraacetic acid. LTD produced either by repeated activation of PFs
combined with depolarization (PF+DeltaV), or by InsP3 combined with
depolarization (InsP3+DeltaV) saturated at approximately 50%. Maximal LTD induced
by PF+DeltaV could not be further increased by InsP3+DeltaV and vice versa, which
suggests that both protocols for induction of LTD share a common path. In
addition to inducing LTD, photo-release of InsP3+DeltaV resulted in the rebound
potentiation of inhibitory synaptic currents. In the presence of heparin, an
InsP3 receptor antagonist, repeated activation of PF+DeltaV failed to induce LTD,
suggesting that InsP3 receptors play an important role in LTD induction under
physiological conditions.
PMID- 9391144
TI - Functional activation in motor cortex reflects the direction and the degree of
handedness.
AB - Handedness is the clearest example of behavioral lateralization in humans. It is
not known whether the obvious asymmetry manifested by hand preference is
associated with similar asymmetry in brain activation during movement. We
examined the functional activation in cortical motor areas during movement of the
dominant and nondominant hand in groups of right-handed and left-handed subjects
and found that use of the dominant hand was associated with a greater volume of
activation in the contralateral motor cortex. Furthermore, there was a separate
relation between the degree of handedness and the extent of functional
lateralization in the motor cortex. The patterns of functional activation
associated with the direction and degree of handedness suggest that these aspects
are independent and are coded separately in the brain.
PMID- 9391145
TI - Syntax processing by auditory cortical neurons in the FM-FM area of the mustached
bat Pteronotus parnellii.
AB - Syntax denotes a rule system that allows one to predict the sequencing of
communication signals. Despite its significance for both human speech processing
and animal acoustic communication, the representation of syntactic structure in
the mammalian brain has not been studied electrophysiologically at the single
unit level. In the search for a neuronal correlate for syntax, we used playback
of natural and temporally destructured complex species-specific communication
calls-so-called composites-while recording extracellularly from neurons in a
physiologically well defined area (the FM-FM area) of the mustached bat's
auditory cortex. Even though this area is known to be involved in the processing
of target distance information for echolocation, we found that units in the FM-FM
area were highly responsive to composites. The finding that neuronal responses
were strongly affected by manipulation in the time domain of the natural
composite structure lends support to the hypothesis that syntax processing in
mammals occurs at least at the level of the nonprimary auditory cortex.
PMID- 9391146
TI - The seven-transmembrane spanning topography of the Alzheimer disease-related
presenilin proteins in the plasma membranes of cultured cells.
AB - To ascertain the membrane topography of the multi-transmembrane spanning
presenilin proteins PS-1 and PS-2, anti-peptide antibodies were raised to several
specific amino acid sequences in the two proteins, and, after their specificity
was ascertained, the anti-peptide antibodies were used in immunofluorescent
labeling of live PS-transfected, cultured DAMI cells, which are impermeable to
the antibodies, as well as of their fixed and permeabilized counterparts. In such
experiments, antibodies that specifically stain the intact live cells must label
epitopes of the PS proteins that are on the exterior face of the plasma membrane
whereas those antibodies that do not stain the live cells but do stain the fixed
and permeabilized cells must label epitopes that face the cytoplasmic side of the
membrane. The results obtained were entirely in accord with the predictions of
the seven-transmembrane spanning topography (like that of rhodopsin and the beta
adrenergic receptor) and were totally inconsistent with the expectations for
either the six- or eight-transmembrane topographies that have been proposed.
PMID- 9391147
TI - On the spurious endoproteolytic processing of the presenilin proteins in cultured
cells and tissues.
AB - It has been widely reported that the presenilin proteins PS-1 and PS-2 in
extracts derived from a variety of cultured cells and from tissues are fragmented
extensively by endoproteolytic processing events. It generally has been presumed
that this endoproteolysis is a physiologically normal intracellular event
following presenilin expression, which might play an important role in the still
unknown functions of these molecules in connection with Alzheimer disease. We
demonstrate herein, however, that, if a variety of cultured cells and several
mouse tissues are examined under conditions minimizing cell trauma, the
presenilin molecules in the extracts are found to be intact but that, if the
cells and tissues are prepared under somewhat more stressful conditions, the
endoproteolytic fragments are then observed. We conclude that these particular
endoproteolytic events are not the result of physiologically normal processing of
the presenilins but are rather artifacts occurring during the common procedures
of specimen preparation.
PMID- 9391148
TI - Widespread expression and estrogen regulation of PPEIA-3' nuclear RNA in the rat
brain.
AB - We previously identified a novel nuclear RNA species derived from the
preproenkephalin (PPE) gene. This transcript, which we have named PPEIA-3' RNA,
hybridizes with probes directed at a region of PPE intron A downstream of an
alternative germ-cell transcription start site, but does not contain PPE protein
coding sequences. We now report that estrogen treatment of ovariectomized rats
increases the expression of conventional PPE heteronuclear RNA, and also induces
the expression of PPEIA-3' RNA, apparently in separate cell populations within
the ventromedial nucleus of the hypothalamus. Further, we show that cells
expressing PPEIA-3' are found in several neuronal groups in the rat forebrain and
brainstem, with a distinct topographical distribution. High densities of PPEIA-3'
containing cells are found in the reticular thalamic nucleus, the basal
forebrain, the vestibular complex, the deep cerebellar nuclei, and the trapezoid
body, a pattern that parallels the distribution of atypical nuclear RNAs
described by other groups. These results suggest that this diverse neuronal
population shares a common set of nuclear factors responsible for the expression
and retention of this atypical RNA transcript. The implication of these results
for cell-specific gene transcription and regulation in the brain and the possible
relationship of PPEIA-3' RNA and other atypical nuclear RNAs is discussed.
PMID- 9391149
TI - beta subunits influence the biophysical and pharmacological differences between P
and Q-type calcium currents expressed in a mammalian cell line.
AB - Human epithelial kidney cells (HEK) were prepared to coexpress alpha1A,
alpha2delta with different beta calcium channel subunits and green fluorescence
protein. To compare the calcium currents observed in these cells with the native
neuronal currents, electrophysiological and pharmacological tools were used
conjointly. Whole-cell current recordings of human epithelial kidney alpha1A
transfected cells showed small inactivating currents in 80 mM Ba2+ that were
relatively insensitive to calcium blockers. Coexpression of alpha1A, betaIb, and
alpha2delta produced a robust inactivating current detected in 10 mM Ba2+,
reversibly blockable with low concentration of omega-agatoxin IVA (omega-Aga IVA)
or synthetic funnel-web spider toxin (sFTX). Barium currents were also supported
by alpha1A, beta2a, alpha2delta subunits, which demonstrated the slowest
inactivation and were relatively insensitive to omega-Aga IVA and sFTX.
Coexpression of beta3 with the same combination as above produced inactivating
currents also insensitive to low concentration of omega-Aga IVA and sFTX. These
data indicate that the combination alpha1A, betaIb, alpha2delta best resembles P
type channels given the rate of inactivation and the high sensitivity to omega
Aga IVA and sFTX. More importantly, the specificity of the channel blocker is
highly influenced by the beta subunit associated with the alpha1A subunit.
PMID- 9391150
TI - Glucocorticoid enhancement of memory storage involves noradrenergic activation in
the basolateral amygdala.
AB - Evidence indicates that the modulatory effects of the adrenergic stress hormone
epinephrine as well as several other neuromodulatory systems on memory storage
are mediated by activation of beta-adrenergic mechanisms in the amygdala. In view
of our recent findings indicating that the amygdala is involved in mediating the
effects of glucocorticoids on memory storage, the present study examined whether
the glucocorticoid-induced effects on memory storage depend on beta-adrenergic
activation within the amygdala. Microinfusions (0.5 microg in 0.2 microl) of
either propranolol (a nonspecific beta-adrenergic antagonist), atenolol (a beta1
adrenergic antagonist), or zinterol (a beta2-adrenergic antagonist) administered
bilaterally into the basolateral nucleus of the amygdala (BLA) of male Sprague
Dawley rats 10 min before training blocked the enhancing effect of posttraining
systemic injections of dexamethasone (0.3 mg/kg) on 48-h memory for inhibitory
avoidance training. Infusions of these beta-adrenergic antagonists into the
central nucleus of the amygdala did not block the dexamethasone-induced memory
enhancement. Furthermore, atenolol (0.5 microg) blocked the memory-enhancing
effects of the specific glucocorticoid receptor (GR or type II) agonist RU 28362
infused concurrently into the BLA immediately posttraining. These results
strongly suggest that beta-adrenergic activation is an essential step in
mediating glucocorticoid effects on memory storage and that the BLA is a locus of
interaction for these two systems.
PMID- 9391151
TI - Insulin-like growth factors-I and -II differentially regulate endogenous
acetylcholine release from the rat hippocampal formation.
AB - Insulin-like growth factors-I and -II (IGF-I and -II) are structurally related
mitogenic polypeptides with potent growth promoting effects. These peptides and
their corresponding IGF-I and -II receptors are selectively localized in the
brain. To date, most of the effects of IGFs are believed to be mediated by IGF-I
receptors whereas the significance of IGF-II receptor in mediating biological
responses remains unclear. In the present study, we characterized the
distribution of IGF-I and IGF-II receptor sites and investigated the effects of
both factors on endogenous acetylcholine (ACh) release in adult rat hippocampus.
[125I]IGF-I receptor binding sites are recognized by IGF-I> IGF-II> insulin,
whereas [125I]IGF-II binding was competed potently by IGF-II> IGF-I but not by
insulin. At the cellular level, IGF-I receptor sites were primarily noted in the
molecular layer of the dentate gyrus and the CA2-CA3 subfields of the Ammon's
horn whereas IGF-II sites were localized predominantly in the pyramidal cell
layer of the CA1-CA3 subfields and in the granular cell layer of the dentate
gyrus. IGF-I (10(-14)-10(-8) M) and des(1-3) IGF-I (10(-10)-10(-8) M) were found
to inhibit whereas IGF-II (10(-14)-10(-8) M) potentiated K+-evoked ACh release
from hippocampal slices. Tetrodotoxin altered the effects of IGF-I but not those
of IGF-II suggesting that IGF-I acts indirectly via the release of other
modulators whereas IGF-II acts directly on or in close proximity to the
cholinergic terminals. The inhibitory effects of IGF-I were also observed in the
frontal cortex but not in the striatum. In contrast, the stimulatory effects of
IGF-II were evident both in the frontal cortex and striatum. Taken together,
these results reveal the differential localization of IGF-I and IGF-II receptor
sites in the hippocampal formation and the opposite role for these growth factors
in the acute regulation of ACh release likely via two distinct mechanisms.
Additionally, these data provide the first evidence for a direct role for IGF-II
and its receptors in the regulation of transmitter release in the central nervous
system.
PMID- 9391152
TI - Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase.
AB - gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the
mammalian brain, is synthesized by two glutamate decarboxylase isoforms, GAD65
and GAD67. The separate role of the two isoforms is unknown, but differences in
saturation with cofactor and subcellular localization suggest that GAD65 may
provide reserve pools of GABA for regulation of inhibitory neurotransmission. We
have disrupted the gene encoding GAD65 and backcrossed the mutation into the
C57BL/6 strain of mice. In contrast to GAD67-/- animals, which are born with
developmental abnormalities and die shortly after birth, GAD65-/- mice appear
normal at birth. Basal GABA levels and holo-GAD activity are normal, but the
pyridoxal 5' phosphate-inducible apo-enzyme reservoir is significantly decreased.
GAD65-/- mice develop spontaneous seizures that result in increased mortality.
Seizures can be precipitated by fear or mild stress. Seizure susceptibility is
dramatically increased in GAD65-/- mice backcrossed into a second genetic
background, the nonobese diabetic (NOD/LtJ) strain of mice enabling
electroencephalogram analysis of the seizures. The generally higher basal brain
GABA levels in this backcross are significantly decreased by the GAD65-/-
mutation, suggesting that the relative contribution of GABA synthesized by GAD65
to total brain GABA levels is genetically determined. Seizure-associated c-fos
like immunoreactivity reveals the involvement of limbic regions of the brain.
These data suggest that GABA synthesized by GAD65 is important in the dynamic
regulation of neural network excitability, implicate at least one modifier locus
in the NOD/LtJ strain, and present GAD65-/- animals as a model of epilepsy
involving GABA-ergic pathways.
PMID- 9391153
TI - Large conductance voltage- and calcium-dependent K+ channel, a distinct member of
voltage-dependent ion channels with seven N-terminal transmembrane segments (S0
S6), an extracellular N terminus, and an intracellular (S9-S10) C terminus.
AB - Large conductance voltage- and Ca2+-dependent K+ (MaxiK) channels show sequence
similarities to voltage-gated ion channels. They have a homologous S1-S6 region,
but are unique at the N and C termini. At the C terminus, MaxiK channels have
four additional hydrophobic regions (S7-S10) of unknown topology. At the N
terminus, we have recently proposed a new model where MaxiK channels have an
additional transmembrane region (S0) that confers beta subunit regulation. Using
transient expression of epitope tagged MaxiK channels, in vitro translation,
functional, and "in vivo" reconstitution assays, we now show that MaxiK channels
have seven transmembrane segments (S0-S6) at the N terminus and a S1-S6 region
that folds in a similar way as in voltage-gated ion channels. Further, our
results indicate that hydrophobic segments S9-S10 in the C terminus are
cytoplasmic and unequivocally demonstrate that S0 forms an additional
transmembrane segment leading to an exoplasmic N terminus.
PMID- 9391154
TI - Altered gene expression in the host brain caused by a trematode parasite:
neuropeptide genes are preferentially affected during parasitosis.
AB - Schistosome parasites adjust the physiology and behavior of their intermediate
molluscan hosts to their own benefit. Previous studies demonstrated effects of
the avian-schistosome Trichobilharzia ocellata on peptidergic centers in the
brain of the intermediate snail host Lymnaea stagnalis. In particular,
electrophysiological properties and peptide release of growth- and reproduction
controlling neuroendocrine neurons were affected. We now have examined the
possibility that the expression of genes that control physiology and behavior of
the host might be altered during parasitosis. A cDNA library of the brain of
parasitized Lymnaea was constructed and differentially screened by using mRNA
from the brain of both parasitized and nonparasitized snails. This screening
yielded a number of clones, including previously identified cDNAs as well as
novel neuronal transcripts, which appear to be differentially regulated. The
majority of these transcripts encode neuropeptides. Reverse Northern blot
analysis confirmed that neuropeptide gene expression is indeed affected in
parasitized animals. Moreover, the expression profiles of 10 transcripts tested
showed a differential, parasitic stage-specific regulation. Changes in expression
could in many cases already be observed between 1.5 and 5 hr postinfection,
suggesting that changes in gene expression are a direct effect of parasitosis. We
suggest that direct regulation of neuropeptide gene expression is a strategy of
parasites to induce physiological and behavioral changes in the host.
PMID- 9391155
TI - Estrogen receptor-dependent sexual differentiation of dopaminergic neurons in the
preoptic region of the mouse.
AB - Although it has been known for some time that estrogen exerts a profound
influence on brain development a definitive demonstration of the role of the
classical estrogen receptor (ERalpha) in sexual differentiation has remained
elusive. In the present study we used a sexually dimorphic population of
dopaminergic neurons in the anteroventral periventricular nucleus of the
hypothalamus (AVPV) to test the dependence of sexual differentiation on a
functional ERalpha by comparing the number of tyrosine hydroxylase (TH)
immunoreactive neurons in the AVPV of wild-type (WT) mice with that of mice in
which the ERalpha had been disrupted by homologous recombination (ERKOalpha).
Only a few ERalpha-immunoreactive neurons were detected in the AVPV of ERKOalpha
mice, and the number of TH-immunoreactive neurons was three times that of WT
mice, suggesting that disruption of the ERalpha gene feminized the number of TH
immunoreactive neurons. In contrast, the AVPV contains the same number of TH
immunoreactive neurons in testicular feminized male mice as in WT males,
indicating that sexual differentiation of this population of neurons is not
dependent on an intact androgen receptor. The number of TH-immunoreactive neurons
in the AVPV of female ERKOalpha mice remained higher than that of WT males, but
TH staining appeared to be lower than that of WT females. Thus, the sexual
differentiation of dopamine neurons in the AVPV appears to be receptor specific
and dependent on the perinatal steroid environment.
PMID- 9391156
TI - Midbrain injection of recombinant adeno-associated virus encoding rat glial cell
line-derived neurotrophic factor protects nigral neurons in a progressive 6
hydroxydopamine-induced degeneration model of Parkinson's disease in rats.
AB - A recombinant adeno-associated virus (rAAV) vector capable of infecting cells and
expressing rat glial cell line-derived neurotrophic factor (rGDNF), a putative
central nervous system dopaminergic survival factor, under the control of a
potent cytomegalovirus (CMV) immediate/early promoter (AAV-MD-rGDNF) was
constructed. Two experiments were performed to evaluate the time course of
expression of rAAV-mediated GDNF protein expression and to test the vector in an
animal model of Parkinson's disease. To evaluate the ability of rAAV-rGDNF to
protect nigral dopaminergic neurons in the progressive Sauer and Oertel 6
hydroxydopamine (6-OHDA) lesion model, rats received perinigral injections of
either rAAV-rGDNF virus or rAAV-lacZ control virus 3 weeks prior to a striatal 6
OHDA lesion and were sacrificed 4 weeks after 6-OHDA. Cell counts of back-labeled
fluorogold-positive neurons in the substantia nigra revealed that rAAV-MD-rGDNF
protected a significant number of cells when compared with cell counts of rAAV
CMV-lacZ-injected rats (94% vs. 51%, respectively). In close agreement, 85% of
tyrosine hydroxylase-positive cells remained in the nigral rAAV-MD-rGDNF group
vs. only 49% in the lacZ group. A separate group of rats were given identical
perinigral virus injections and were sacrificed at 3 and 10 weeks after surgery.
Nigral GDNF protein expression remained relatively stable over the 10 weeks
investigated. These data indicate that the use of rAAV, a noncytopathic viral
vector, can promote delivery of functional levels of GDNF in a degenerative model
of Parkinson's disease.
PMID- 9391157
TI - Impaired motor coordination and persistent multiple climbing fiber innervation of
cerebellar Purkinje cells in mice lacking Galphaq.
AB - Mice lacking the alpha-subunit of the heterotrimeric guanine nucleotide binding
protein Gq (Galphaq) are viable but suffer from ataxia with typical signs of
motor discoordination. The anatomy of the cerebellum is not overtly disturbed,
and excitatory synaptic transmission from parallel fibers to cerebellar Purkinje
cells (PCs) and from climbing fibers (CFs) to PCs is functional. However, about
40% of adult Galphaq mutant PCs remain multiply innervated by CFs because of a
defect in regression of supernumerary CFs in the third postnatal week. Evidence
is provided suggesting that Galphaq is part of a signaling pathway that is
involved in the elimination of multiple CF innervation during this period.
PMID- 9391158
TI - Ca2+/calmodulin-binding peptides block phototransduction in Limulus ventral
photoreceptors: evidence for direct inhibition of phospholipase C.
AB - Phototransduction in Limulus photoreceptors involves a G protein-mediated
activation of phospholipase C (PLC) and subsequent steps involving InsP3-mediated
release of intracellular Ca2+. While exploring the role of calmodulin in this
cascade, we found that intracellular injection of Ca2+/calmodulin-binding
peptides (CCBPs) strongly inhibited the light response. By chemically exciting
the cascade at various stages, we found the primary target of this effect was not
in late stages of the cascade but rather at the level of G protein and PLC. That
PLCdelta1 contains a calmodulin-like structure raised the possibility that PLC
might be directly affected by CCBPs. To test this possibility, in vitro
experiments were conducted on purified PLC. The activity of this enzyme was
strongly inhibited by CCBPs and also inhibited by calmodulin itself. Our results
suggest that the calmodulin-like region of PLC has an important role in
regulating this enzyme.
PMID- 9391159
TI - Adenylyl cyclase 6 is selectively regulated by protein kinase A phosphorylation
in a region involved in Galphas stimulation.
AB - Receptors activate adenylyl cyclases through the Galphas subunit. Previous
studies from our laboratory have shown in certain cell types that express
adenylyl cyclase 6 (AC6), heterologous desensitization included reduction of the
capability of adenylyl cyclases to be stimulated by Galphas. Here we further
analyze protein kinase A (PKA) effects on adenylyl cyclases. PKA treatment of
recombinant AC6 in insect cell membranes results in a selective loss of
stimulation by high (>10 nM) concentrations of Galphas. Similar treatment of AC1
or AC2 did not affect Galphas stimulation. Conversion of Ser-674 in AC6 to an Ala
blocks PKA phosphorylation and PKA-mediated loss of Galphas stimulation. A
peptide encoding the region 660-682 of AC6 blocks stimulation of AC6 and AC2 by
high concentrations of Galphas. Substitution of Ser-674 to Asp in the peptide
renders the peptide ineffective, indicating that the region 660-682 of AC6 is
involved in regulation of signal transfer from Galphas. This region contains a
conserved motif present in most adenylyl cyclases; however, the PKA
phosphorylation site is unique to members of the AC6 family. These observations
suggest a mechanism of how isoform selective regulatory diversity can be obtained
within conserved regions involved in signal communication.
PMID- 9391160
TI - Molecular determinants of tissue selectivity in estrogen receptor modulators.
AB - Interaction of the estrogen receptor/ligand complex with a DNA estrogen response
element is known to regulate gene transcription. In turn, specific conformations
of the receptor-ligand complex have been postulated to influence unique subsets
of estrogen-responsive genes resulting in differential modulation and,
ultimately, tissue-selective outcomes. The estrogen receptor ligands raloxifene
and tamoxifen have demonstrated such tissue-specific estrogen agonist/antagonist
effects. Both agents antagonize the effects of estrogen on mammary tissue while
mimicking the actions of estrogen on bone. However, tamoxifen induces significant
stimulation of uterine tissue whereas raloxifene does not. We postulate that
structural differences between raloxifene and tamoxifen may influence the
conformations of their respective receptor/ligand complexes, thereby affecting
which estrogen-responsive genes are modulated in various tissues. These
structural differences are 4-fold: (A) the presence of phenolic hydroxyls, (B)
different substituents on the basic amine, (C) incorporation of the stilbene
moiety into a cyclic benzothiophene framework, and (D) the imposition of a
carbonyl "hinge" between the basic amine-containing side chain and the olefin. A
series of raloxifene analogs that separately exemplify each of these differences
have been prepared and evaluated in a series of in vitro and in vivo assays. This
strategy has resulted in the development of a pharmacophore model that attributes
the differences in effects on the uterus between raloxifene and tamoxifen to a
low-energy conformational preference imparting an orthogonal orientation of the
basic side chain with respect to the stilbene plane. This three-dimensional array
is dictated by a single carbon atom in the hinge region of raloxifene. These data
indicate that differences in tissue selective actions among benzothiophene and
triarylethylene estrogen receptor modulators can be ascribed to discrete ligand
conformations.
PMID- 9391161
TI - Pharmacological and immunohistochemical evidence for a functional nitric oxide
synthase system in rat peritoneal eosinophils.
AB - Eosinophil migration in vivo is markedly attenuated in rats treated chronically
with the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L
NAME). In this study, we investigated the existence of a NOS system in
eosinophils. Our results demonstrated that rat peritoneal eosinophils strongly
express both type II (30.2 +/- 11.6% of counted cells) and type III (24.7 +/-
7.4% of counted cells) NOS, as detected by immunohistochemistry using affinity
purified mouse mAbs. Eosinophil migration in vitro was evaluated by using 48-well
microchemotaxis chambers and the chemotactic agents used were N-formyl-methionyl
leucyl-phenylalanine (fMLP, 5 x 10(-8) M) and leukotriene B4 (LTB4, 10(-8) M). L
NAME (but not D-NAME) significantly inhibited the eosinophil migration induced by
both fMLP (54% reduction for 1.0 mM; P < 0.05) and LTB4 (61% reduction for 1.0
mM; P < 0.05). In addition, the type II NOS inhibitor 2-amino-5,6-dihydro-6
methyl-4H-1,3-thiazine and the type I/II NOS inhibitor 1-(2
trifluoromethylphenyl) imidazole also markedly (P < 0. 05) attenuated fMLP- (52%
and 38% reduction for 1.0 mM, respectively) and LTB4- (52% and 51% reduction for
1.0 mM, respectively) induced migration. The inhibition of eosinophil migration
by L-NAME was mimicked by the soluble guanylate cyclase inhibitor 1H-[1,2,4]
oxadiazolo [4,3,-a] quinoxalin-1-one (0.01 and 0.1 mM) and reversed by either
sodium nitroprusside (0.1 mM) or dibutyryl cyclic GMP (1 mM). We conclude that
eosinophils do express NO synthase(s) and that nitric oxide plays an essential
role in eosinophil locomotion by acting through a cyclic GMP transduction
mechanism.
PMID- 9391162
TI - Unique allosteric regulation of 5-hydroxytryptamine receptor-mediated signal
transduction by oleamide.
AB - The effects of oleamide, an amidated lipid isolated from the cerebrospinal fluid
of sleep-deprived cats, on serotonin receptor-mediated responses were
investigated in cultured mammalian cells. In rat P11 cells, which endogenously
express the 5-hydroxytryptamine2A (5HT2A) receptor, oleamide significantly
potentiated 5HT-induced phosphoinositide hydrolysis. In HeLa cells expressing the
5HT7 receptor subtype, oleamide caused a concentration-dependent increase in cAMP
accumulation but with lower efficacy than that observed by 5HT. This effect was
not observed in untransfected HeLa cells. Clozapine did not prevent the increase
in cAMP elicited by oleamide, and ketanserin caused an approximately 65%
decrease. In the presence of 5HT, oleamide had the opposite effect on cAMP,
causing insurmountable antagonism of the concentration-effect curve to 5HT, but
had no effect on cAMP levels elicited by isoproterenol or forskolin. These
results indicate that oleamide can modulate 5HT-mediated signal transduction at
different subtypes of mammalian 5HT receptors. Additionally, our data indicate
that oleamide acts at an apparent allosteric site on the 5HT7 receptor and
elicits functional responses via activation of this site. This represents a
unique mechanism of activation for 5HT G protein-coupled receptors and suggests
that G protein-coupled neurotransmitter receptors may act like their iontropic
counterparts (i.e., gamma-aminobutyric acid type A receptors) in that there may
be several binding sites on the receptor that regulate functional activity with
varying efficacies.
PMID- 9391163
TI - Selection of peptides that functionally replace a zinc finger in the Sp1
transcription factor by using a yeast combinatorial library.
AB - We have developed a strategy for the identification of peptides able to
functionally replace a zinc finger domain in a transcription factor. This
strategy could have important ramifications for basic research on gene regulation
and for the development of therapeutic agents. In this study in yeast, we
expressed chimeric proteins that included a random peptide combinatorial library
in association with two zinc finger domains and a transactivating domain. The
library was screened for chimeric proteins capable of activating transcription
from a target sequence in the upstream regulatory regions of selectable or
reporter genes. In a screen of approximately 1.5 x 10(7) transformants we
identified 30 chimeric proteins that exhibited transcriptional activation, some
of which were able to discriminate between wild-type and mutant DNA targets.
Chimeric library proteins expressed as glutathione S-transferase fusions bound to
double-stranded oligonucleotides containing the target sequence, suggesting that
the chimeras bind directly to DNA. Surprisingly, none of the peptides identified
resembled a zinc finger or other well-known transcription factor DNA binding
domain.
PMID- 9391164
TI - Sodium channel selectivity filter regulates antiarrhythmic drug binding.
AB - Local anesthetic antiarrhythmic drugs block Na+ channels and have important
clinical uses. However, the molecular mechanism by which these drugs block the
channel has not been established. The family of drugs is characterized by having
an ionizable amino group and a hydrophobic tail. We hypothesized that the charged
amino group of the drug may interact with charged residues in the channel's
selectivity filter. Mutation of the putative domain III selectivity filter
residue of the adult rat skeletal muscle Na+ channel (micro1) K1237E increased
resting lidocaine block, but no change was observed in block by neutral analogs
of lidocaine. An intermediate effect on the lidocaine block resulted from K1237S
and there was no effect from K1237R, implying an electrostatic effect of Lys.
Mutation of the other selectivity residues, D400A (domain I), E755A (domain II),
and A1529D (domain IV) allowed block by externally applied quaternary membrane
impermeant derivatives of lidocaine (QX314 and QX222) and accelerated recovery
from block by internal QX314. Neo-saxitoxin and tetrodotoxin, which occlude the
channel pore, reduced the amount of QX314 bound in D400A and A1529D,
respectively. Block by outside QX314 in E755A was inhibited by mutation of
residues in transmembrane segment S6 of domain IV that are thought to be part of
an internal binding site. The results demonstrate that the Na+ channel
selectivity filter is involved in interactions with the hydrophilic part of the
drugs, and it normally limits extracellular access to and escape from their
binding site just within the selectivity filter. Participation of the selectivity
ring in antiarrhythmic drug binding and access locates this structure adjacent to
the S6 segment.
PMID- 9391165
TI - Multi-responsiveness of single anterior pituitary cells to hypothalamic-releasing
hormones: a cellular basis for paradoxical secretion.
AB - The classic view for hypothalamic regulation of anterior pituitary (AP) hormone
secretion holds that release of each AP hormone is controlled specifically by a
corresponding hypothalamic-releasing hormone (HRH). In this scenario, binding of
a given HRH (thyrotropin-, growth hormone-, corticotropin-, and luteinizing
hormone-releasing hormones) to specific receptors in its target cell increases
the concentration of cytosolic Ca2+ ([Ca2+]i), thereby selectively stimulating
the release of the appropriate hormone. However, "paradoxical" responses of AP
cells to the four well-established HRHs have been observed repeatedly with both
in vivo and in vitro systems, raising the possibility of functional overlap
between the different AP cell types. To explore this possibility, we evaluated
the effects of HRHs on [Ca2+]i in single AP cells identified immunocytochemically
by the hormone they stored. We found that each of the five major AP cell types
contained discrete subpopulations that were able to respond to several HRHs. The
relative abundance of these multi-responsive cells was 59% for lactotropes, 33%
for thyrotropes, and in the range of 47-55% for gonadotropes, corticotropes, and
somatotropes. Analysis of prolactin release from single living cells revealed
that each of the four HRHs tested were able to induce hormone release from a
discrete lactotrope subpopulation, the size of which corresponded closely to that
in which [Ca2+]i changes were induced by the same secretagogues. When viewed as a
whole, our diverse functional measurements of multi-responsiveness suggest that
hypothalamic control of pituitary function is more complicated than previously
envisioned. Moreover, they provide a cellular basis for the so-called
"paradoxical" behavior of pituitary cells to hypothalamic hypophysiotropic
agents.
PMID- 9391166
TI - Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for
the estrogen receptor.
AB - The phytochemical resveratrol, which is found in grapes and wine, has been
reported to have a variety of anti-inflammatory, anti-platelet, and anti
carcinogenic effects. Based on its structural similarity to diethylstilbestrol, a
synthetic estrogen, we examined whether resveratrol might be a phytoestrogen. At
concentrations (approximately 3-10 microM) comparable to those required for its
other biological effects, resveratrol inhibited the binding of labeled estradiol
to the estrogen receptor and it activated transcription of estrogen-responsive
reporter genes transfected into human breast cancer cells. This transcriptional
activation was estrogen receptor-dependent, required an estrogen response element
in the reporter gene, and was inhibited by specific estrogen antagonists. In some
cell types (e.g., MCF-7 cells), resveratrol functioned as a superagonist (i.e.,
produced a greater maximal transcriptional response than estradiol) whereas in
others it produced activation equal to or less than that of estradiol.
Resveratrol also increased the expression of native estrogen-regulated genes, and
it stimulated the proliferation of estrogen-dependent T47D breast cancer cells.
We conclude that resveratrol is a phytoestrogen and that it exhibits variable
degrees of estrogen receptor agonism in different test systems. The estrogenic
actions of resveratrol broaden the spectrum of its biological actions and may be
relevant to the reported cardiovascular benefits of drinking wine.
PMID- 9391168
TI - Phloem sap proteins from Cucurbita maxima and Ricinus communis have the capacity
to traffic cell to cell through plasmodesmata.
AB - In angiosperms, the functional enucleate sieve tube system of the phloem appears
to be maintained by the surrounding companion cells. In this study, we tested the
hypothesis that polypeptides present within the phloem sap traffic cell to cell
from the companion cells, where they are synthesized, into the sieve tube via
plasmodesmata. Coinjection of fluorescently labeled dextrans along with size
fractionated Cucurbita maxima phloem proteins, ranging in size from 10 to 200
kDa, as well as injection of individual fluorescently labeled phloem proteins,
provided unambiguous evidence that these proteins have the capacity to interact
with mesophyll plasmodesmata in cucurbit cotyledons to induce an increase in size
exclusion limit and traffic cell to cell. Plasmodesmal size exclusion limit
increased to greater than 20 kDa, but less than 40 kDa, irrespective of the size
of the injected protein, indicating that partial protein unfolding may be a
requirement for transport. A threshold concentration in the 20-100 nM range was
required for cell-to-cell transport indicating that phloem proteins have a high
affinity for the mesophyll plasmodesmal binding site(s). Parallel experiments
with glutaredoxin and cystatin, phloem sap proteins from Ricinus communis,
established that these proteins can also traffic through cucurbit mesophyll
plasmodesmata. These results are discussed in terms of the requirements for
regulated protein trafficking between companion cells and the sieve tube system.
As the threshold value for plasmodesmal transport of phloem sap proteins falls
within the same range as many plant hormones, the possibility is discussed that
some of these proteins may act as long-distance signaling molecules.
PMID- 9391167
TI - Structural activity of a cloned potassium channel (ROMK1) monitored with the
atomic force microscope: the "molecular-sandwich" technique.
AB - The atomic force microscope (AFM) was used to continuously follow height changes
of individual protein molecules exposed to physiological stimuli. A AFM tip was
coated with ROMK1 (a cloned renal epithelial potassium channel known to be highly
pH sensitive) and lowered onto atomically flat mica surface until the protein was
sandwiched between AFM tip and mica. Because the AFM tip was an integral part of
a highly flexible cantilever, any structural alterations of the sandwiched
molecule were transmitted to the cantilever. This resulted in a distortion of the
cantilever that was monitored by means of a laser beam. With this system it was
possible to resolve vertical height changes in the ROMK1 protein of >/=0.2 nm
(approximately 5% of the molecule's height) with a time resolution of >/=1 msec.
When bathed in electrolyte solution that contained the catalytic subunit of
protein kinase A and 0.1 mM ATP (conditions that activate the native ion
channel), we found stochastically occurring height fluctuations in the ROMK1
molecule. These changes in height were pH-dependent, being greatest at pH 7.6,
and lowering the pH (either by titration or by the application of CO2) reduced
their magnitude. The data show that overall changes in shape of proteins occur
stochastically and increase in size and frequency when the proteins are active.
This AFM "molecular-sandwich" technique, called MOST, measures structural
activity of proteins in real time and could prove useful for studies on the
relationship between structure and function of proteins at the molecular level.
PMID- 9391169
TI - Evidence for the existence of a sulfonylurea-receptor-like protein in plants:
modulation of stomatal movements and guard cell potassium channels by
sulfonylureas and potassium channel openers.
AB - Limitation of water loss and control of gas exchange is accomplished in plant
leaves via stomatal guard cells. Stomata open in response to light when an
increase in guard cell turgor is triggered by ions and water influx across the
plasma membrane. Recent evidence demonstrating the existence of ATP-binding
cassette proteins in plants led us to analyze the effect of compounds known for
their ability to modulate ATP-sensitive potassium channels (K-ATP) in animal
cells. By using epidermal strip bioassays and whole-cell patch-clamp experiments
with Vicia faba guard cell protoplasts, we describe a pharmacological profile
that is specific for the outward K+ channel and very similar to the one described
for ATP-sensitive potassium channels in mammalian cells. Tolbutamide and
glibenclamide induced stomatal opening in bioassays and in patch-clamp
experiments, a specific inhibition of the outward K+ channel by these compounds
was observed. Conversely, application of potassium channel openers such as
cromakalim or RP49356 triggered stomatal closure. An apparent competition between
sulfonylureas and potassium channel openers occurred in bioassays, and outward
potassium currents, previously inhibited by glibenclamide, were partially
recovered after application of cromakalim. By using an expressed sequence tag
clone from an Arabidopsis thaliana homologue of the sulfonylurea receptor, a 7-kb
transcript was detected by Northern blot analysis in guard cells and other
tissues. Beside the molecular evidence recently obtained for the expression of
ATP-binding cassette protein transcripts in plants, these results give
pharmacological support to the presence of a sulfonylurea-receptor-like protein
in the guard-cell plasma membrane tightly involved in the outward potassium
channel regulation during stomatal movements.
PMID- 9391170
TI - The roles of specific xanthophylls in photoprotection.
AB - Xanthophyll pigments have critical structural and functional roles in the
photosynthetic light-harvesting complexes of algae and vascular plants. Genetic
dissection of xanthophyll metabolism in the green alga Chlamydomonas reinhardtii
revealed functions for specific xanthophylls in the nonradiative dissipation of
excess absorbed light energy, measured as nonphotochemical quenching of
chlorophyll fluorescence. Mutants with a defect in either the alpha- or beta
branch of carotenoid biosynthesis exhibited less nonphotochemical quenching but
were still able to tolerate high light. In contrast, a double mutant that was
defective in the synthesis of lutein, loroxanthin (alpha-carotene branch),
zeaxanthin, and antheraxanthin (beta-carotene branch) had almost no
nonphotochemical quenching and was extremely sensitive to high light. These
results strongly suggest that in addition to the xanthophyll cycle pigments
(zeaxanthin and antheraxanthin), alpha-carotene-derived xanthophylls such as
lutein, which are structural components of the subunits of the light-harvesting
complexes, contribute to the dissipation of excess absorbed light energy and the
protection of plants from photo-oxidative damage.
PMID- 9391171
TI - Chlorophyll precursors are signals of chloroplast origin involved in light
induction of nuclear heat-shock genes.
AB - Coordination between the activities of organelles and the nucleus requires the
exchange of signals. Using Chlamydomonas, we provide evidence that plastid
derived chlorophyll precursors may replace light in the induction of two nuclear
heat-shock genes (HSP70A and HSP70B) and thus qualify as plastidic signal.
Mutants defective in the synthesis of Mg-protoporphyrin IX were no longer
inducible by light. Feeding of Mg-protoporphyrin IX or its dimethyl ester to wild
type or mutant cells in the dark resulted in induction. The analysis of HSP70A
promoter mutants that do or do not respond to light revealed that these
chlorophyll precursors specifically activate the light signaling pathway.
Activation of gene expression was not observed when protoporphyrin IX,
protochlorophyllide, or chlorophyllide were added. A specific interaction of
defined chlorophyll precursors with factor(s) that regulate nuclear gene
expression is suggested.
PMID- 9391172
TI - Structural model of cytochrome b559 in photosystem II based on a mutant with
genetically fused subunits.
AB - Photosystem II is a reaction center protein complex located in photosynthetic
membranes of plants, algae, and cyanobacteria. Using light energy, photosystem II
catalyzes the oxidation of water and the reduction of plastoquinone, resulting in
the release of molecular oxygen. A key component of photosystem II is cytochrome
b559, a membrane-embedded heme protein with an unknown function. The cytochrome
is unusual in that a heme links two separate polypeptide subunits, alpha and
beta, either as a heterodimer (alphabeta) or as two homodimers (alpha2 and
beta2). To determine the structural organization of cytochrome b559 in the
membrane, we used site-directed mutagenesis to fuse the coding regions of the two
respective genes in the cyanobacterium Synechocystis sp. PCC 6803. In this
construction, the C terminus of the alpha subunit (9 kDa) is attached to the N
terminus of the beta subunit (5 kDa) to form a 14-kDa alphabeta fusion protein
that is predicted to have two membrane-spanning alpha-helices with antiparallel
orientations. Cells containing the alphabeta fusion protein grow
photoautotrophically and assemble functional photosystem II complexes. Optical
spectroscopy shows that the alphabeta fusion protein binds heme and is
incorporated into photosystem II. These data support a structural model of
cytochrome b559 in which one heme is coordinated to an alpha2 homodimer and a
second heme is coordinated to a beta2 homodimer. In this model, each photosystem
II complex contains two cytochrome b559 hemes, with the alpha2 heme located near
the stromal side of the membrane and the beta2 heme located near the lumenal
side.
PMID- 9391174
TI - Adaptive evolution via a major gene effect: paedomorphosis in the Mexican
axolotl.
AB - Although adaptive evolution is thought to depend primarily on mutations of small
effect, major gene effects may underlie many of the important differences
observed among species in nature. The Mexican axolotl (Ambystoma mexicanum) has a
derived mode of development that is characterized by metamorphic failure
(paedomorphosis), an adaptation for an entirely aquatic life cycle. By using an
interspecific crossing design and genetic linkage analysis, a major quantitative
trait locus for expression of metamorphosis was identified in a local map of
amplified fragment length polymorphisms. These data are consistent with a major
gene hypothesis for the evolution of paedomorphosis in A. mexicanum.
PMID- 9391173
TI - Plastid-localized acetyl-CoA carboxylase of bread wheat is encoded by a single
gene on each of the three ancestral chromosome sets.
AB - 5'-End fragments of two genes encoding plastid-localized acetyl-CoA carboxylase
(ACCase; EC 6.4.1.2) of wheat (Triticum aestivum) were cloned and sequenced. The
sequences of the two genes, Acc-1,1 and Acc-1,2, are 89% identical. Their exon
sequences are 98% identical. The amino acid sequence of the biotin carboxylase
domain encoded by Acc-1,1 and Acc-1,2 is 93% identical with the maize plastid
ACCase but only 80-84% identical with the cytosolic ACCases from other plants and
from wheat. Four overlapping fragments of cDNA covering the entire coding region
were cloned by PCR and sequenced. The wheat plastid ACCase ORF contains 2,311
amino acids with a predicted molecular mass of 255 kDa. A putative transit
peptide is present at the N terminus. Comparison of the genomic and cDNA
sequences revealed introns at conserved sites found in the genes of other plant
multifunctional ACCases, including two introns absent from the wheat cytosolic
ACCase genes. Transcription start sites of the plastid ACCase genes were
estimated from the longest cDNA clones obtained by 5'-RACE (rapid amplification
of cDNA ends). The untranslated leader sequence encoded by the Acc-1 genes is at
least 130-170 nucleotides long and is interrupted by an intron. Southern analysis
indicates the presence of only one copy of the gene in each ancestral chromosome
set. The gene maps near the telomere on the short arm of chromosomes 2A, 2B, and
2D. Identification of three different cDNAs, two corresponding to genes Acc-1,1
and Acc-1,2, indicates that all three genes are transcriptionally active.
PMID- 9391175
TI - Is blindsight like normal, near-threshold vision?
AB - Blindsight is the rare and paradoxical ability of some human subjects with
occipital lobe brain damage to discriminate unseen stimuli in their clinically
blind field defects when forced-choice procedures are used, implying that lesions
of striate cortex produce a sharp dissociation between visual performance and
visual awareness. Skeptics have argued that this is no different from the
behavior of normal subjects at the lower limits of conscious vision, at which
such dissociations could arise trivially by using different response criteria
during clinical and forced-choice tests. We tested this claim explicitly by
measuring the sensitivity of a hemianopic patient independently of his response
criterion in yes-no and forced-choice detection tasks with the same stimulus and
found that, unlike normal controls, his sensitivity was significantly higher
during the forced-choice task. Thus, the dissociation by which blindsight is
defined is not simply due to a difference in the patients' response bias between
the two paradigms. This result implies that blindsight is unlike normal, near
threshold vision and that information about the stimulus is processed in
blindsighted patients in an unusual way.
PMID- 9391176
TI - Spatial memory is related to hippocampal subcellular concentrations of calcium
dependent protein kinase C isoforms in young and aged rats.
AB - Relationships were examined between spatial learning and hippocampal
concentrations of the alpha, beta2, and gamma isoforms of protein kinase C (PKC),
an enzyme implicated in neuronal plasticity and memory formation. Concentrations
of PKC were determined for individual 6-month-old (n = 13) and 24-month-old (n =
27) male Long-Evans rats trained in the water maze on a standard place-learning
task and a transfer task designed for rapid acquisition. The results showed
significant relationships between spatial learning and the amount of PKC among
individual subjects, and those relationships differed according to age, isoform,
and subcellular fraction. Among 6-month-old rats, those with the best spatial
memory were those with the highest concentrations of PKCgamma in the particulate
fraction and of PKCbeta2 in the soluble fraction. Aged rats had increased
hippocampal PKCgamma concentrations in both subcellular fractions in comparison
with young rats, and memory impairment was correlated with higher PKCgamma
concentrations in the soluble fraction. No age difference or correlations with
behavior were found for concentrations of PKCgamma in a comparison structure, the
neostriatum, or for PKCalpha in the hippocampus. Relationships between spatial
learning and hippocampal concentrations of calcium-dependent PKC are isoform
specific. Moreover, age-related spatial memory impairment is associated with
altered subcellular concentrations of PKCgamma and may be indicative of deficient
signal transduction and neuronal plasticity in the hippocampal formation.
PMID- 9391177
TI - A model of long-term memory storage in the cerebellar cortex: a possible role for
plasticity at parallel fiber synapses onto stellate/basket interneurons.
AB - By evoking changes in climbing fiber activity, movement errors are thought to
modify synapses from parallel fibers onto Purkinje cells (pf*Pkj) so as to
improve subsequent motor performance. Theoretical arguments suggest there is an
intrinsic tradeoff, however, between motor adaptation and long-term storage.
Assuming a baseline rate of motor errors is always present, then repeated
performance of any learned movement will generate a series of climbing fiber
mediated corrections. By reshuffling the synaptic weights responsible for any
given movement, such corrections will degrade the memories for other learned
movements stored in overlapping sets of synapses. The present paper shows that
long-term storage can be accomplished by a second site of plasticity at synapses
from parallel fibers onto stellate/basket interneurons (pf*St/Bk). Plasticity at
pf*St/Bk synapses can be insulated from ongoing fluctuations in climbing fiber
activity by assuming that changes in pf*St/Bk synapses occur only after changes
in pf*Pkj synapses have built up to a threshold level. Although climbing fiber
dependent plasticity at pf*Pkj synapses allows for the exploration of novel motor
strategies in response to changing environmental conditions, plasticity at
pf*St/Bk synapses transfers successful strategies to stable long-term storage. To
quantify this hypothesis, both sites of plasticity are incorporated into a
dynamical model of the cerebellar cortex and its interactions with the inferior
olive. When used to simulate idealized motor conditioning trials, the model
predicts that plasticity develops first at pf*Pkj synapses, but with additional
training is transferred to pf*St/Bk synapses for long-term storage.
PMID- 9391179
TI - Radionuclide therapy dose calculations: what accuracy can be achieved?
PMID- 9391178
TI - Recovery of hearing and vocal behavior after hair-cell regeneration.
AB - Postmitotic hair-cell regeneration in the inner ear of birds provides an
opportunity to study the effect of renewed auditory input on auditory perception,
vocal production, and vocal learning in a vertebrate. We used behavioral
conditioning to test both perception and vocal production in a small Australian
parrot, the budgerigar. Results show that both auditory perception and vocal
production are disrupted when hair cells are damaged or lost but that these
behaviors return to near normal over time. Precision in vocal production
completely recovers well before recovery of full auditory function. These results
may have particular relevance for understanding the relation between hearing loss
and human speech production especially where there is consideration of an
auditory prosthetic device. The present results show, at least for a bird, that
even limited recovery of auditory input soon after deafening can support full
recovery of vocal precision.
PMID- 9391180
TI - Outpatient management of patients with large multinodular goitres treated with
fractionated radioiodine.
AB - The efficacy of fractionated out-patient radioiodine therapy in 38 patients with
compressive symptoms due to long-standing large multinodular goitres was
assessed. The diagnosis was established by clinical assessment in addition to
technetium-99m pertechnetate thyroid scan or computed tomography scan of the
thyroid and mediastinum. Oral iodine-131 therapy was administered as a 2.22 GBq
(60 mCi) cumulative dose over 4 months (555 MBq per month). All patients were
monitored with serum thyroid-stimulating hormone and free thyroxine (+/- free tri
iodothyronine) assays before the treatment and after each dose fraction. Clinical
and biochemical follow-up was performed on all patients and ranged from 6 to 45
months after therapy. The patients consisted of 35 female and three male patients
with a median age of 59 years (range 37-87 years). Prior to treatment 20 patients
were biochemically hyperthyroid and 18 were euthyroid. Overall, 71% of patients
reported a subjective improvement in compressive symptoms and 29% reported no
change. Clinically assessed reduction in goitre size occurred in 92% of patients
while there was no change in 8%. At 3 months of follow-up, 31% of patients had
become hypothyroid and at 18 months 66% were hypothyroid. Seven hyperthyroid
patients (35%) became euthyroid and 13 hyperthyroid patients (65%) became
hypothyroid. Three patients who became hypothyroid experienced neck soreness
(transient in one patient, persistent in two patients). There were no differences
in outcome between patients who were hyperthyroid and those who were euthyroid
prior to treatment. Fractionated out-patient radioiodine therapy showed excellent
short- and medium-term safety, was very well tolerated and offered a satisfactory
alternative treatment to surgery.
PMID- 9391181
TI - Thyroid volume measurement in thyrotoxic patients: comparison between
ultrasonography and iodine-124 positron emission tomography.
AB - The aim of this paper was to compare ultrasound (US) assessment of thyroid volume
with that obtained by positron emission tomography (PET), in patients scheduled
for adaptive radioiodine therapy, in which 50 Gy was prescribed to the functional
PET volume. Firstly a pilot study was performed to ascertain the optimum method
for US assessment of thyroid volume. Then 17 comparative measurements of thyroid
volume by US and PET were made on 15 patients (two male and thirteen female, ages
28-73 years) with suspected Graves' disease. This comparison showed that in
normal sized and enlarged thyroid glands (n=13), the ratio of functional PET to
anatomical US volume was approximately 2:3. However, using the same ellipsoid
model, PET and US assessment of anatomical volume agreed within the measurement
errors. Owing to the presence of nodules and non-uniform distribution of
radioiodine, the functional PET volume and anatomical US volume are often not
equivalent. If high-resolution emission tomography (e.g. PET) is unavailable, the
comparative data presented in this paper could be used to derive the functional
volume from the US volume for calculating functional thyroid dose in hyperthyroid
patients undergoing radioiodine therapy.
PMID- 9391182
TI - Extraction and retention of technetium-99m Q12, technetium-99m sestamibi, and
thallium-201 in isolated rat heart during coronary acidemia.
AB - Technetium-99m Q12 and 99mTc-sestamibi are cationic lipophilic myocardial
perfusion imaging tracers. Because myocardium in areas of ischemia becomes
acidotic, experiments were designed to differentiate the effects of myocardial
perfusate pH on radiotracer extraction and retention independent of substrate
availability. We hypothesized that 99mTc-Q12 and 99mTc-sestamibi single-pass
uptake and retention would be unaffected by a modest reduction in coronary
perfusate pH. Isolated rat hearts were perfused at constant flow with Krebs
Henseleit buffer enriched with bovine red blood cells (20%). The indicator
dilution method was used to measure the maximum extraction (Emax) and net
extraction (Enet) of thallium-201 and 99mTc-Q12 (n = 8) or 201Tl and 99mTc
sestamibi (n = 7) during baseline perfusion (pH = 7.4), during acidemic (pH =
6.7) perfusion, and during a restitution period with normal perfusate (pH = 7.4).
201Tl Emax (0.71+/-0.03) was greater than either 99mTc-Q12 or 99mTc-sestamibi
Emax (0.27+/-0.02 and 0.26+/-0.01 respectively, P<0.0001). Acidemia significantly
reduced 201Tl Emax (0.65+/-0.03, P<0.02) but not 99mTc-Q12 or 99mTc-sestamibi
Emax (0.25+/-0.02 and 0.24+/-0.02 respectively). During control perfusion Enet of
201Tl was greater than that of 99mTc-Q12 at 3 and 5 min and greater than that of
99mTc-sestamibi at 3 min. 99mTc-Q12 Enet was less than 99mTc-sestamibi Enet at 3,
5, and 10 min. Acidemia decreased 201Tl and 99mTc-sestamibi Enet at 3, 5, and 10
min but had no effect on 99mTc-Q12 Enet. It is concluded that Emax of 99mTc-Q12
is less than that of 201Tl but is not different from that of 99mTc-sestamibi.
Enet of 99mTc-Q12 is less than that of 99mTc-sestamibi.
PMID- 9391183
TI - Comparison of flow capacities of arterial and venous grafts for coronary artery
bypass grafting: evaluation with exercise thallium-201 single-photon emission
tomography.
AB - Stress thallium-201 tomography was performed to compare the flow capacities of
arterial and saphenous vein grafts in patients with coronary artery bypass
grafting (CABG). One hundred and seven consecutive patients (95 male and 12
female; mean age 58+/-9.1 years) underwent exercise-redistribution 201Tl
myocardial single-photon emission tomography 4-5 weeks after CABG. When a
reversible perfusion defect was present in the area covered by a patent bypass
graft, the flow capacity of the graft was defined as insufficient. Of all 285
grafts, 211 were considered as complete bypass. Reversible perfusion defects were
present in 29 (27%) of 108 myocardial areas supplied by patent arterial grafts
but in only 5 (5%) of 103 myocardial areas supplied by patent saphenous vein
grafts (P<0.0001). In the LAD area reversible defects were observed in 22 of 82
areas covered by arterial grafts, in contrast to only 1 of 29 areas covered by
venous grafts (P<0.01); in the RCA area reversible defects were observed in 7 of
17 and 4 of 41 areas respectively (P<0.01). There was no difference between the
native coronary artery stenosis bypassed by patent arterial and venous grafts
(88%+/-12% vs 86%+/-14% respectively, P=0.27). In conclusion, flow capacities
during peak myocardial demand were more frequently insufficient in arterial
bypass grafts than in saphenous vein grafts.
PMID- 9391184
TI - Preoperative parathyroid gland localization with technetium-99m sestamibi in
secondary hyperparathyroidism.
AB - Technetium-99m sestamibi scintigraphy has become a valuable tool in locating
parathyroid glands in patients with primary hyperparathyroidism. The aim of this
study was to evaluate its usefulness in secondary hyperparathyroidism. Twenty
patients were injected intravenously with 740 MBq of 99mTc-sestamibi and images
were obtained at 15 min and 2 h post injection. All patients underwent
parathyroid ultrasonography (US) as well as bilateral surgical neck exploration
and 64 parathyroid glands were removed. US revealed at least one enlarged gland
in 15/20 patients (75%), while 99mTc-sestamibi scintigraphy showed focal areas of
increased uptake in at least one gland in 17/20 patients (85%). When imaging
results for all glands were evaluated according to surgical results, sensitivity
was 54% for parathyroid scintigraphy and 41% for US, and specificity was 89% for
both imaging techniques. There was a discrepancy between the two imaging
modalities in 28 glands (35%). The mean surgical weight of US-positive glands
(1492+/-1436 mg) was significantly higher than that of US-negative glands (775+/
703 mg) (P<0.05). However, there were no significant differences in weight
between sestamibi-positive and sestamibi-negative glands. When only sestamibi
positive glands were considered, a positive correlation between uptake and weight
was found (r=0.4, P<0.05). In conclusion, parathyroid US and 99mTc-sestamibi
scintigraphy are complementary imaging techniques in the preoperative
localization of abnormal parathyroid glands in patients with secondary
hyperparathyroidism. The limited sensitivity of the techniques means that
patients will still require bilateral neck exploration; therefore routine
preoperative parathyroid scanning in renal patients is not justified.
PMID- 9391185
TI - Revisiting the prognostic role of gallium scintigraphy in low-grade non-Hodgkin's
lymphoma.
AB - The purpose of this study was threefold: to evaluate the role of gallium-67
scintigraphy in the staging of low-grade non-Hodgkin's lymphomas (LGNHL), to
assess the relationship between the expression of CD71 on the surface of the
neoplastic cells and the 67Ga uptake by the tumour, and to establish the
contribution of 67Ga scan in defining the prognosis of LGNHL. Forty-eight
patients with untreated LGNHL diagnosed in a single institution over a decade
were reviewed. The end point of the study was survival of the patients according
to the scintigraphic 67Ga score at diagnosis. In addition to 67Ga scan, other
prognostic variables were studied, relating to the neoplastic burden, the biology
of the tumour and the host. Univariate and multivariate analyses were used. 67Ga
scan identified only 116/286 (41%) nodes involved by lymphoma that were detected
by clinical examination or computed tomography scan. A scintigraphic scoring
system with an arbitrary cut-off value of 3 (high scan score) was able to predict
patients with a dismal prognosis: with a mean follow-up of 47 months (range: 1
146 months) the median survival time was 28 months in patients with a high scan
score and 74 months in patients with a low scan score (P=0.002). CD71 values were
27. 4%+/-14.9% (mean +/-SD) in the former and 8.9%+/-7.2% in the latter
(P=0.0001). Only performance status and extranodal sites were significant
variables for prognosis in multivariate analysis. It is concluded that 67Ga scan
is inaccurate in staging but might be very important in defining the prognosis in
LGNHL, in association with other prognostic variables.
PMID- 9391186
TI - Semi-quantitative assessment of cerebral blood flow with 99mTc-HMPAO SPET in type
I diabetic patients with no clinical history of cerebrovascular disease.
AB - In 65 type I diabetic patients we prospectively evaluated brain perfusion by
means of single-photon emission tomography after the injection of 740- 1110 MBq
of technetium-99m hexamethylpropylene amine oxime. Thirty-five of the patients
presented complications secondary to their diabetes. None showed CNS symptoms. A
semiquantitative analysis was performed drawing 50 symmetrical regions of
interest (ROIs) per patient. The relative contribution of each ROI to the total
blood flow in each slice was compared with the relative contribution of the same
ROI in a control group of ten healthy volunteers. Relative values of any ROI in
the study group higher or lower than the mean +/-2 SD in respect of the same ROI
in the control group were considered abnormal. The results revealed hypoperfusion
in 207 ROIs in the 65 patients with diabetes mellitus: of these ROIs, 113 were
frontal, 10 frontotemporal, 20 temporal, 18 parietal, 11 occipital and 35
cerebellar. A total of 137 ROIs showed hyperperfusion: 17 frontal, 3
frontotemporal, 19 temporal, 18 parietal, 19 parieto-occipital, 29 occipital and
32 cerebellar. Out of 65 type I diabetic patients, 61 showed at least one
hypoperfused ROI (P = 0.0064 vs. controls) and 25 showed more than three
hypoperfused ROIs. None of the control subjects showed more than three
hypoperfused regions (P<0.001). The results obtained demonstrate the existence of
subclinical abnormalities of brain blood perfusion in patients with type I
diabetes mellitus and no history of cerebrovascular disease, thereby allowing the
initiation of intensive preventive measures.
PMID- 9391187
TI - Calculation of residence times and radiation doses using the standard PC software
Excel.
AB - We developed a program which aims to facilitate the calculation of radiation
doses to single organs and the whole body. IMEDOSE uses Excel to include
calculations, graphical displays, and interactions with the user in a single
general-purpose PC software tool. To start the procedure the input data are
copied into a spreadsheet. They must represent percentage uptake values of
several organs derived from measurements in animals or humans. To extrapolate
these data up to seven half-lives of the radionuclide, fitting to one or two
exponentional functions is included and can be checked by the user. By means of
the approximate time-activity information the cumulated activity or residence
times are calculated. Finally these data are combined with the absorbed fraction
doses (S-values) given by MIRD pamphlet No. 11 to yield radiation doses, the
effective dose equivalent and the effective dose. These results are presented in
a final table. Interactions are realized with push-buttons and drop-down menus.
Calculations use the Visual Basic tool of Excel. In order to test our program,
biodistribution data of fluorine-18 fluorodeoxyglucose were taken from the
literature (Meija et al., J Nucl Med 1991; 32:699-706). For a 70-kg adult the
resulting radiation doses of all target organs listed in MIRD 11 were different
from the ICRP 53 values by 1%+/-18% on the average. When the residence times were
introduced into MIRDOSE3 (Stabin, J Nucl Med 1996; 37:538-546) the mean
difference between our results and those of MIRDOSE3 was -3%+/-6%. Both outcomes
indicate the validity of the present approach.
PMID- 9391188
TI - The role of technetium-99m sestamibi single photon emission tomography in the
follow-up of malignant melanoma and the detection of lymph node metastases.
AB - In the follow-up of patients with malignant melanoma treated by surgical
resection of the cutaneous tumour, it is important to achieve early detection of
possible lymph node metastasis. In many cases, clinical examination alone will
not be sufficient. In our study, single-photon emission tomography (SPET) with
technetium-99m sestamibi (MIBI) was used in the assessment of 30 patients with
previously resected malignant melanoma when the clinical examination raised the
suspicion of lymph node metastasis. Using MIBI, 16 out of 17 lymph node
metastases were detected and confirmed by histology. No false-positive results
were obtained during this prospective study. It is concluded that MIBI
scintigraphy may be useful in the early detection of lymph node metastases of
malignant melanomas. If our preliminary results are confirmed, early detection of
lymph node metastasis of previously resected malignant melanoma by 99mTc-MIBI
scintigraphy may have a significant impact on the management of these patients.
PMID- 9391189
TI - Highlights of the annual meeting of the European Association of Nuclear Medicine:
Glasgow 1997. The flowering of science and art of nuclear medicine in Europe.
PMID- 9391190
TI - Radiation dose rates from patients receiving iodine-131 therapy for carcinoma of
the thyroid
PMID- 9391191
TI - Rare infections in pediatric surgery
PMID- 9391193
TI - Pyogenic liver abscess complicating a ventriculoperitoneal shunt.
AB - Pyogenic liver abscess is a rare complication of ventriculoperitoneal (VP)
shunting. We report a 4-month-old female with this complication who was
successfully treat ed by computed tomography-guided percutaneous transhepatic
catheter drainage, shunt externalization, and parenteral antibiotics. Liver
abscess is a possible intra-abdominal complication of VP shunting, and imaging
studies are good adjuncts in making the clinical diagnosis.
PMID- 9391192
TI - Surgical aspects of an outbreak of Yersinia enterocolitis.
AB - Eleven patients with Yersinia enterocolitica infections were identified in the
Upper Valley of New Hampshire and Vermont during October and November of 1995.
Three children presented with an appendicitis-like picture. Two underwent
appendectomy, one of whom was the outbreak's index case. Both appendectomy
patients presented with lower abdominal pain, fever, vomiting, and a right lower
quadrant mass associated with leukocytosis. Both had terminal ileitis, and in
both, cultures of peritoneal fluid and a mesenteric lymph node grew Y.
enterocolitica. Even during an outbreak there is no consistently reliable
nonoperative way to separate a sporadic case of appendicitis from one whose
appendicitis-like symptoms are due to Yersinia. In addition, a small percentage
of Yersinia patients will present with true appendicitis as a complication of
their disease.
PMID- 9391194
TI - Hepatic duct stone associated with chlamydia sepsis: a rare condition in
childhood.
AB - Stone formation in the biliary system is a rare condition in infants. A few cases
of bile stones in the biliary tree have been reported with underlying
predisposing factors, such as sepsis and antibiotic usage. This article describes
a surgically treated 16-week-old infant with recurrent cholangitis who had a bile
stone in the hepatic duct after chlamydia sepsis.
PMID- 9391195
TI - Lung resection in pediatric patients.
AB - An evaluation of all pediatric patients with primary or secondary pulmonary
disease operated upon from January 1993 to July 1996 by the same senior surgeon
was carried out. The inclusion criterion was a lung resection in patients aged
less than 14 years. Children were divided into two categories according to the
neoplastic or non-neoplastic nature of their disease. In the first group a
lobectomy was performed for primary lesions and wedge resection for secondary
ones. In the second group lobar emphysema and cystic dysplasia were the major
indications for lobectomy, while diagnostic wedge resections were performed for
interstitial/infiltrative lesions. Several groups of techniques were identified
according to the type of approach and the suture method. Video-assisted
thoracoscopic surgery and a muscle-sparing approach were compared to classic
posterolateral thoracotomy. The mechanical stapler-suturing method was compared
to the manual suturing. Our results demonstrate the importance of mechanical
suturing, particularly in decreasing anesthesia time and reducing the risk of
dehiscence. The minimally invasive approach associated with mini-thoracotomy was
particularly useful for patients with reduced oxygen saturation due to
ventilatory and gas-exchange problems. The roles of staplers in lung parenchymal
resection and minimally invasive procedures for improving the postoperative
thoracic compliance of pediatric patients are stressed.
PMID- 9391196
TI - The significance of biliary sludge in children with sickle cell disease.
AB - The prevalence of cholelithiasis was studied prospectively by abdominal
ultrasound (US) examination in 305 children with sickle cell disease aged 1-18
years (mean 10.45). Gallstones were present in 60 children (19.7%); an additional
50 had biliary sludge only (16.4%). On follow-up of 35 of the 50 children with
sludge, 23 (65.7%) had developed gallstones and 5 had already had a
cholecystectomy. Five continued to have sludge on follow-up while 7 were reported
to have no sludge. Children with US evidence of sludge should be followed up
regularly by US, and those who develop gallstones should undergo elective
cholecystectomy. For those with biliary sludge only, we recommend elective
cholecystectomy if there are hepatobiliary symptoms.
PMID- 9391197
TI - Is a normally functioning gastrointestinal tract necessary for normal growth in
late gestation?
AB - It is known that neonates with congenital abnormalities of the intestine tend to
be growth-retarded. We wished to explore the hypothesis that normal fetal gut
function is needed for normal growth in late gestation. If this is true, then
different populations of babies with different congenital gut abnormalities would
be expected to have similar impairments of growth and be small at birth. This
growth retardation would be more marked in term than in preterm babies and would
be independent of other congenital anomalies. To test these hypotheses, we
examined 43 babies born with gastroschisis (GS) in Auckland, New Zealand; 69
babies born with GS in Birmingham, England; and 60 babies born with intestinal
atresia (IA) in Auckland. For Auckland babies with GS, the mean weight standard
deviation score (WSDS) (i.e., birth weight relative to the mean birth weight for
gestation) for term babies was lower than that for preterm babies (-0.932+/-0.180
vs -0.064+/-0.237, P=0.014). This was also true for Birmingham babies with GS (
0.991+/-0.193 vs -0.36 +/-0.153, P=0.028). For babies with IA, the mean WSDS for
term babies was lower than that for preterm babies (-0.627+/-0.266 vs 0. 057+/
0.211, P=0.034). There was no significant difference between the mean WSDS of
babies with and without major congenital abnormalities (-0.402+/-0.201 vs -0.271,
P=0.70). Our results demonstrate that term babies born with GS are significantly
growth-retarded compared with premature babies born with GS. Term babies born
with a proximal IA are also growth-retarded. This strongly suggests that in late
gestation, the normal growth is dependent on a normally functioning
gastrointestinal tract that allows exposure of the proximal intestinal mucosa to
ingested amniotic fluid.
PMID- 9391198
TI - Laparoscopic versus conventional appendectomy in children.
AB - Over a period of 6 months, 48 children who underwent conventional appendectomy
(CA) were compared to 34 children who had laparoscopic appendectomy (LA) for
acute and recurrent subacute appendicitis. Their ages ranged from 4 to 12 years
(mean 8). LA took significantly longer, 76 min, versus 50 min for CA. Less than 2
days' hospitalization was required in 95% of LA cases and 45% of CA cases. Time
to return to normal activity averaged 7 days for LA and 12 days for CA (P <
0.001). Wound complications were fewer and the cosmetic appearance was most
satisfactory in LA patients. LA is a safe operation that has the advantage of
being exploratory, with shorter hospitalization time, early ambulation, and
superior cosmetic results.
PMID- 9391199
TI - Long-term functional, manometric, and endosonographic evaluation of patients
operated upon with the Duhamel technique.
AB - Long-term functional results, anal endosonography (AES), and anal canal manometry
were recorded in 48 patients aged 10 to 24 years (median 18) operated upon with
the Duhamel technique for Hirschsprung's disease; 60.4% had perfect fecal
control, 31.3% occasional staining and/or gas incontinence, and 8.3% constant
fecal soiling, and 10.4% complained of constipation. Compared to normals, the
patients had significantly reduced anal canal resting and squeeze pressures. AES
visualized scar tissue in both the internal and external anal sphincter.
PMID- 9391200
TI - Temporal stability of acetylcholinesterase staining in colonic and rectal neural
tissue.
AB - Confirmation of the clinical diagnosis of Hirschsprung's disease on standard
rectal suction biopsy requires demonstration of aganglionosis in 60 adequate
serial sections of submucosa. Positive staining for acetylcholinesterase (AChE),
demonstrating an increase in nerve fibres within the lamina propria, muscularis
mucosae, and subjacent submucosa, is a useful adjunctive test. In this study,
sections of distal colonic muscularis propria and rectal mucosa were stained for
AChE over a period of days following storage at 4 degrees C and at room
temperature (15-20 degrees C). Positive staining of neural tissue was
demonstrated in specimens stored at 4 degrees C for up to 14 days, at which time
the experiment was discontinued due to tissue autolysis. Positive staining of the
myenteric plexus in colonic specimens stored at room temperature also continued
until tissue dissolution became marked at 5 days. This study has demonstrated
stability of AChE staining of intestinal neural tissue in specimens stored at 4
degrees C for 14 days, which suggests that reliable staining for AChE should
still be achievable if rectal biopsies are taken in clinics/hospitals without
access to staining facilities, provided that tissues are transferred (fresh and
moist, at 4 degrees C) to a reference laboratory for staining within several days
of the biopsy procedure.
PMID- 9391201
TI - Treatment of vesicoureteric reflux in a sheep model using subureteric injection
of cultured fetal-bladder tissue.
AB - To investigate the role of injecting cultured fetal-bladder tissue into the
region of the vesicoureteric orifice (VUO) to correct surgically produced
vesicoureteric reflux (VUR), 12 Coopworth ewe lambs were studied. Four weeks
after incising the intravesical segment of ureter, VUR was demonstrated by
micturating cystourethrography. Bladder tissue was obtained from a fetal
Coopworth lamb at 10 weeks' gestation, cultured in RPMI 1640, and injected into
the region of the VUO of 1 ureter of each lamb using an open surgical approach.
The lambs were killed between 1 and 6 months after the injection. Smooth-muscle
cells from the cultured fetal bladder tissue were identified by the monoclonal
antibodies HHF-35 for muscle alpha-actin and D33 for muscle desmin, and by
electron microscopy. One lamb died of a gastrointestinal infection at 8 weeks of
age. Of the remaining 11 animals, the injection of fetal-bladder tissue corrected
the reflux in 7, while it was reduced in degree in 3 and persisted unchanged in
1. The reflux on the contralateral control side was also corrected in 6 ureters
and improved in 2. Using histochemical techniques, grafted fetal-bladder tissue
could not be differentiated from host tissue in the region of the VUO.
Histopathological studies failed to show any injected tissue in distant organs.
This study has shown that surgically-induced VUR in lambs was corrected or
improved by the injection of cultured fetal-bladder tissue into the submucosa
adjacent to the VUO.
PMID- 9391202
TI - Undescended testes: incidence in 1,002 consecutive male infants and outcome at 1
year of age.
AB - In a study of 1,002 consecutive Malaysian male newborns, 48 (4.8%) were found to
have undescended testes (UDT). The rate and laterality of the UDT were associated
with lower birth weight (P < 0.001) and prematurity (P < 0.001). Boys with UDT
were also more likely to have other congenital abnormalities of the external
genitalia, the commonest being hydrocele. No correlation between UDT and maternal
age, birth order, social class, or mode of delivery was demonstrated in this
study. Although 26/34 (76.5%) of UDT achieved full spontaneous descent by 1 year
of age, 1.1% of all infants whose testes remained undescended required regular
long-term follow-up with surgical referral and correction at an appropriate time.
A premature infant with UDT is more likely to achieve full testicular descent at
1 year of age than a term infant.
PMID- 9391203
TI - Results of Wilms' tumour management in two tertiary-care hospitals in Asia.
AB - In the period 1985-1995, 87 children underwent surgery for Wilms' tumour; 16 were
lost to follow-up. Of the remaining children, 27 presented with stage I disease,
11 with stage II, 12 with stage III, 14 with stage IV, and 6 with stage V. One
child was not staged. The histology was favourable Wilms' tumour in 44,
anaplastic in 12, unclassified in 8, clear-cell sarcoma in 4, and rhabdoid tumour
in 3. Although a total nephrectomy was generally performed, partial renal surgery
was performed for 6 bilateral and 4 unilateral tumours, the latter including 2
fused kidneys. Preoperative chemotherapy was employed with benefit in massive
tumours, tumour in fused kidneys, bilateral tumours, and preoperatively diagnosed
inferior vena caval tumour thrombi. Postoperative chemotherapy, employed in all
cases, consisted of actinomycin D and vincristine with the addition of adriamycin
in anaplastic and advanced-stage tumours. Ten children underwent second-line
chemotherapy for disease unresponsive to the above management, but only 1 of
these is currently free of disease. Postoperative tumour-bed radiotherapy, used
in selected cases, prevented local recurrence in stage I and II disease. However,
20% of stage I and II patients not receiving radiotherapy developed tumour-bed
recurrence. Twenty-three children have died and 5 with advanced disease and
incomplete follow-up are presumed to be dead. Nine children are currently on
treatment; 34 have successfully completed treatment, the disease-free survival in
stages I-V being 81%, 75%, 42%, 14%, and 50%, respectively. Overall disease-free
survival was 69% for Wilms' tumour of favourable histology and 50% for anaplastic
tumours. The 3 patients with rhabdoid tumours and 3 of 4 with clear-cell sarcomas
have died. Wilms' tumour management in the developing world is compromised by
cases lost to follow-up and late presentation with massive tumours and advanced
stage. Preoperative chemotherapy is advantageous in a number of cases, and
postoperative radiotherapy should be deployed more frequently.
PMID- 9391204
TI - Leiomyoma of the esophagus and bronchus in a child.
AB - Leiomyomas of the esophagus and/or the bronchus have rarely been reported in
children. To our knowledge, the simultaneous presence of this tumor in both the
esophagus and a bronchus in a child has not been previously reported. A 7-year
old boy presented with respiratory and esophageal symptoms and was found to have
a leiomyoma of the esophagus and right main bronchus. The esophageal leiomyoma
was treated with limited myotomy, but bronchoscopic resection was possible for
the bronchial lesion. The postoperative result was excellent, with normal
swallowing and no residual respiratory problems at 1-year follow-up.
PMID- 9391205
TI - Abdominal wall plasty for a premature infant with congenital diaphragmatic
hernia.
AB - This paper reports a premature infant with a congenital diaphragmatic hernia
(CDH) who underwent an abdominal wall plasty to enlarge the abdominal cavity, one
of twin infants born at 32 weeks weighing 1,255 g. After stabilization, the
herniated viscera were reduced from the pleural cavity and the abdominal wall
muscle and skin layers were replaced by a Gore-tex patch without closure of the
diaphragmatic defect. Respiratory and circulatory conditions were stable during
the perioperative period. Postoperatively, a roentogenogram showed expansion of
the lung. However, his condition deteriorated 24 h after surgery, triggered by
intratracheal suction, and he died on the 4th day of life despite the use of high
frequency oscillation, catecholamines, and vasodilators. Postmortem examination
showed severely hypoplastic lungs. Abdominal wall plasty may be a less invasive
initial procedure, however, further studies, such as comparison with the standard
method or conservative management, are needed using a large clinical group or
animal models to justify the usefulness of this procedure.
PMID- 9391206
TI - Pancreatic inflammatory pseudotumour: an uncommon childhood lesion mimicking a
malignant tumour.
AB - We describe a rare case of pancreatic inflammatory pseudotumour that clinically
presented as a malignant tumour in an 11-year-old boy. We also review all six
previously described cases, including three that occurred in children. Complete
surgical removal is regarded as the best choice of therapy, and follow-up in our
case showed no evidence of disease after 3 years. It is important to be aware of
this lesion, since it can be confused with a malignant tumour both radiologically
and clinically.
PMID- 9391207
TI - A stercoraceous ulcer of the colon in neglected Hirschsprung's disease.
AB - A large, nonspecific, chronic ulcer was found in the sigmoid colon of a 13-year
old child with neglected, undiagnosed Hirschsprung's disease (HD). There is no
known association between HD and colonic ulcers, suggesting that the ulcer was a
true stercoraceous ulcer of the colon and not an intrinsic defect of the
aganglionotic bowel.
PMID- 9391208
TI - Two unusual cases of megacolons.
AB - A 13-year-old boy with features of intestinal obstruction was found at laparotomy
to have a sigmoid volvulus. A 7-year-old girl with a similar presentation had a
tight stricture at the rectosigmoid junction causing obstruction. In both cases
the proximal colon was grossly loaded with faeces. In the first child, a
colostomy after resecting the sigmoid colon was considered the safer option,
whereas in the second, an innovative method to decompress the proximal loaded
colon using a sterilised colostomy bag was employed, enabling a primary
anastomosis to be performed.
PMID- 9391209
TI - Surgical management of complete ureteric duplication abnormalities.
AB - In 2 decades (1974-1993), the senior author (S.A.) managed 148 patients with
various abnormalities associated with complete ureteric duplication. Included
were 72 patients with primary vesicoureteric reflux, 50 with ureteroceles, and 26
with upper-pole ectopic ureters. The majority of the patients were female, and
the common clinical presentations included urinary tract infection (UTI), UTI
with septicemia, and urinary incontinence. Ten cases were diagnosed after
recognition of a renal abnormality on prenatal ultrasonography, an avenue that
has provided new challenges, new opportunities, and new dilemmas. This review
article is based on the authors' experience together with an analysis of current
emphasis on early diagnosis, minimal surgery, and maximum preservation of renal
function.
PMID- 9391210
TI - Polyorchidism.
AB - Polyorchidism is defined as the presence of more than two testes. We report the
case of a 3-year-old boy and review the embryology and surgical management of the
condition.
PMID- 9391211
TI - Supernumerary ovary associated with Wilms' tumor.
AB - Supernumerary ovaries are gynecological rarities. To the best of our knowledge,
only 18 histologically confirmed cases have been documented so far, all reported
in adult women. We present the first such case in a 5-year-old child, who also
had a Wilms' tumor of the left kidney.
PMID- 9391212
TI - Bilateral testicular tumors in an infant.
AB - A 7-month-old infant showed bilateral enlarged, nontender scrotal masses. The
level of alpha-fetoprotein was greater than 10,000 ng/ml preoperatively; a high
left inguinal orchiectomy was performed for a suspected yolk-sac tumor. The right
testis was diagnosed as a mature teratoma because it was not possible to
establish a line of cleavage between the tumor and the normal tissue, and a high
right inguinal orchiectomy was performed. Only one case of bilateral testicular
teratomas has been reported in the literature to date. We report a rare second
case of bilateral testicular tumors, one a yolk-sac tumor and the other a
teratoma.
PMID- 9391213
TI - Presacral teratoma presenting with congenital urinary ascites.
AB - Congenital teratomas occur most frequently in the sacrococcygeal region. Most
grown into a large perineo-sacral swelling that is conspicuous externally.
Infrequently, the neoplasm is contained almost entirely within the pelvis in the
presacral space. Congenital urinary ascites is observed in patients with
obstructive uropathy; posterior urethral valves in a newborn is one of the most
prominent causes of urinary ascites. We report a case of presacral teratoma
leading to rupture of the urinary bladder due to outflow obstruction and causing
urinary ascites. The ascites was drained, the bladder was repaired, and the
teratoma was successfully excised. A review of the literature did not reveal any
similar case.
PMID- 9391214
TI - Telomere length, chromatin structure and chromosome fusigenic potential.
AB - Telomeres are specialized structures at chromosome ends that are thought to
function as buffers against chromosome fusion. Several studies suggest that
telomere shortening may render chromosomes fusigenic. We used a novel
quantitative fluorescence in situ hybridization procedure to estimate telomere
length in individual mammalian chromosomes, and G-banding and chromosome painting
techniques to determine chromosome fusigenic potential. All analysed Chinese
hamster and mouse cell lines exhibited shorter telomeres at short chromosome arms
than at long chromosome arms. However, no clear link between short telomeres and
chromosome fusigenic potential was observed, i.e. frequencies of telomeric
associations were higher in cell lines exhibiting longer telomeres. We speculate
that chromosome fusigenic potential in mammalian cell lines may be determined not
only by telomere length but also by the status of telomere chromatin structure.
This is supported by the observed presence of chromatin filaments linking
telomeres in Chinese hamster chromosomes and of multibranched chromosomes
oriented end-to-end in the murine severe combined immunodeficient (SCID) cell
line. Multibranched chromosomes are the hallmark of the human ICF (Immune
deficiency, Centromeric instability, Facial abnormalities) syndrome,
characterized by alterations in heterochromatin structure.
PMID- 9391215
TI - The role of sister chromatid cohesiveness and structure in meiotic behaviour.
AB - Sister chromatid cores, kinetochores and the connecting strand between sister
kinetochores were differentially silver stained to analyse the behaviour of these
structures during meiosis in normal and two spontaneous desynaptic individuals of
Chorthippus jucundus (Orthoptera). In these desynaptic individuals most of the
chromosomes appear as univalents and orient equationally in the first meiotic
division. Despite this abnormal segregation pattern, the changes in chromosome
structure follow the same timing as in normal individuals and seem to be strictly
phase dependent. Chromosomes in the first prometaphase have associated sister
kinetochores and sister chromatid cores that lie in the chromosome midline; we
propose that this promotes the initial monopolar orientation of chromosomes.
However, the requirements of tension for stable attachment to the spindle force
the autosomal univalents to acquire amphitelic orientation. Sister kinetochores
behave in a chromosome orientation-dependent manner and, in the first metaphase,
they appear to be interconnected by a strand that can be detected by silver
impregnation, as seen in the second metaphase of wild-type individuals. The
disappearance of the sister kinetochore-connecting strand, needed for equational
chromatid segregation, however, can only take place in the second meiotic
division. This connecting strand is ultimately responsible for the inability of
chromosomes to segregate sister chromatids in the first anaphase.
PMID- 9391216
TI - Immunocytochemical visualization of the centromeres during male and female
meiosis in Lilium longiflorum.
AB - Immunofluorescence staining with an antiserum raised against a presumptive
meiotic histone, which has been shown to appear prior to male meiosis in
liliaceous plants, preferentially stained the centromere (kinetochore) region of
meiotic chromosomes in microsporocytes and megasporocytes. Using this antiserum,
we were able clearly to visualize the centromeres at all important meiotic stages
in microsporocytes, namely, the association and fusion of centromeres of
homologous chromosomes at zygotene-pachytene in prophase I, the disjunction of
the homologous centromeres at diplotene, the doubling of each centromere at
metaphase I and nonseparation of the sister centromeres at anaphase I, by
confocal laser scanning microscopy. Thus, this report provides a complete picture
of the behavior of centromeres during meiosis in a eukaryote for the first time.
This antiserum also decorated centromeres during female meiosis in cryo-sectioned
megasporocytes, but did not stain the centromeres of mitotic chromosomes in root
tip meristem. From these observations, it is suggested that a meiosis-specific
centromere protein is required for the meiosis-specific behavior of the
centromere.
PMID- 9391217
TI - Localization of CENP-E in the fibrous corona and outer plate of mammalian
kinetochores from prometaphase through anaphase.
AB - We have conducted a detailed ultrastructural analysis of the distribution of the
kinesin-related centromere protein CENP-E during mitosis in cultured human, rat
kangaroo and Indian muntjac cells. Using an affinity-purified polyclonal antibody
and detection by 0.8 nm colloidal gold particles, CENP-E was localized primarily
to the fibrous corona of the kinetochore in prometaphase and metaphase cells.
Some labeling of the kinetochore outer plate was also observed. The distribution
of fibrous corona-associated CENP-E did not change dramatically following the
attachment of microtubules to the kinetochore. Thus, the normal disappearance of
this kinetochore substructure in conventional electron micrographs of mitotic
chromosomes with attached kinetochores is not due to the corona becoming
stretched along the spindle microtubules as has been suggested. Examination of
cells undergoing anaphase chromatid movement revealed the presence of CENP-E
still associated with the outer surface of the kinetochore plate. At the same
time, the majority of detectable CENP-E in these cells was associated with the
bundles of antiparallel microtubules in the central spindle. CENP-E in this
region of the cell is apparently associated with the stem body matrix material.
The simultaneous localization of CENP-E on centromeres and the central spindle
during anaphase was confirmed by both wide-field microscopy of human cells and
conventional fluorescence microscopy of rat kangaroo cells. Together, the
observations reported here are consistent with models in which CENP-E has a role
in promoting the poleward migration of sister chromatids during anaphase A.
PMID- 9391218
TI - Antibodies against the D-domain of a Chironomus ecdysone receptor protein react
with DNA puff sites in Trichosia pubescens.
AB - An antiserum (called AScE/D) against the semiconserved D-domain of a Chironomus
tentans ecdysone receptor protein (cEcR) gave indirect immunofluorescence signals
at DNA puff sites in Trichosia pubescens. The signals varied in maximum intensity
at different DNA puff sites. Control experiments using the secondary rhodamine
labeled anti-rabbit IgG alone, preimmune serum, affinity purified AScE/D (called
pABcE/D) and AScE/D preabsorbed with expressing bacterial extract or highly
purified bacterially expressed cEcR indicated that the signals obtained at these
chromosomal sites were likely to be due to specific interaction between an
endogenous sciarid EcR and antibodies against cEcR. This conclusion was supported
by observation of signals at certain Ec-inducible primary RNA puff sites. AScE/D
signals began to appear at DNA puff sites during L3, the stage when amplification
initiates, but at most sites their mean intensity was low and not statistically
significant. Sites with AScE/D signals of significant mean intensity at this
stage already showed evidence of transcription. The number and strength of
transcription signals increased during L4. Comparison of the developmental course
of signals for AScE/D, DNA synthesis, RNA presence/synthesis, and puff size for
several DNA puffs during late larval- prepupal development showed a closer
relationship of AScE/D signals with the initiation of RNA synthesis than with the
initiation of DNA synthesis. Therefore, although we cannot absolutely eliminate a
direct involvement of EcR in the amplification process at some sites, this
investigation gives stronger support for its direct involvement in transcription.
Since AScE/D signals are observed at DNA puff sites from the time the latter
begin amplification/transcription through their regression, it appears that Ec
and EcR are necessary as a sustained stimulus at these regions.
PMID- 9391219
TI - Biogeographic analysis of the Uhu and LOA elements in the Hawaiian Drosophila.
AB - Two transposable elements have been isolated from the Hawaiian Drosophila, the
Uhu and LOA elements. The Uhu element has been shown to be present in a group of
closely related species, the planitibia subgroup of the picture-winged
Drosophila. This study examines the distribution of the Uhu element in several
other subgroups of the picture-winged Drosophila, as well as the modified
mouthparts and antopocerus groups of the Hawaiian Drosophila. The LOA element has
a much more limited distribution, having only been found in representatives of
the planitibia and grimshawi subgroups of the picture-winged Drosophila. For both
the Uhu and LOA elements there is an inverse correlation between the copy number
of the element and the age of the island on which the species is endemic, i.e.,
species endemic to the Island of Hawaii, the youngest island, have the highest
copy number, while species endemic to Kauai, the oldest island, have the lowest
copy number of the element. The correlation suggests there is a relationship
between speciation and the activity of transposable elements.
PMID- 9391220
TI - Comparing treatment intensities of tactile-thermal application.
AB - The purpose of this study was to investigate the relationships of four
intensities of tactile-thermal application (TTA) to changes in duration of stage
transition (DST) and performance on a newly designed scale of penetration and
aspiration by groups of patients made dysphagic by stroke. Patients were randomly
assigned to receive 150, 300, 450, or 600 trials of TTA during each of 2 weeks.
Data on the time required to provide such treatment, the actual number of trials
clinicians were able to provide, and on the influence of the four intensities are
provided. No single intensity emerged as the most therapeutic. It is suggested
that subsequent studies with larger groups include intensities between 300 and
550.
PMID- 9391221
TI - The need for clinical trials in dysphagia.
PMID- 9391222
TI - Pharmacological treatment of dysphagia in stroke.
AB - The pharynx is important for a normal swallow and it has been suggested that
pharmacological agents may play a role in the management of pharyngeal dysphagia,
but none have been formally evaluated. A pilot double-blind, placebo-controlled
study was undertaken in 17 hospitalized patients with persistent dysphagia 2
weeks after stroke. Patients were randomized to treatment with slow-release
nifedipine 30 mg orally (n = 8) or placebo (n = 9) following specialist
swallowing assessment and videofluoroscopy to exclude severe dysphagia.
Videofluoroscopy was repeated after 4 weeks of treatment. Fourteen patients
(active 6, placebo 8) completed the study. Two patients died (active 1, placebo
1) and 1 patient in the active group had to be withdrawn because of progressive
heart failure. Initial assessment showed impairment in the pharyngeal phase with
delayed triggering of swallow, poor laryngeal elevation, and prolonged pharyngeal
transit times in all patients. Silent aspiration was seen in 4 patients (active
2, placebo 2). Improvement in swallowing was seen in 8 patients (active 5,
placebo 3) at the end of 4 weeks. There were significant changes in the
pharyngeal transit time (mean -1.34 second; 95% C.I. -2.56, -0.11) and swallow
delay (mean -1.91 seconds; 95% C.I. -3.58, -0.24) in the active group suggesting
improvement in the initiation of pharyngeal contractions and reduction in the
time taken for the bolus to transverse the pharynx. A similar change was not seen
in the placebo group. It is suggested that pharmacological agents such as
nifedipine may have a role in the management of stroke-related dysphagia and
merit further investigation.
PMID- 9391223
TI - Deglutitive pharmacotherapy--a new angle?
PMID- 9391224
TI - Fiberoptic endoscopic evaluation of dysphagia to identify silent aspiration.
AB - The traditional bedside dysphagia evaluation has not been able to identify silent
aspiration because the pharyngeal phase of swallowing could not be objectively
assessed. To date, only videofluoroscopy has been used to detect silent
aspiration. This investigation assessed the aspiration status of 400 consecutive,
at risk subjects by fiberoptic endoscopic evaluation of swallowing (FEES). Our
study demonstrated that 175 of 400 (44%) subjects were without aspiration, 115 of
400 (29%) exhibited aspiration with a cough reflex, and 110 of 400 (28%)
aspirated silently. No significant differences were observed for age or gender
and aspiration status. The FEES, done at bedside, avoids irradiation exposure, is
repeatable as often as necessary, uses regular food, can be videotaped for
review, and is a patient-friendly method of identifying silent aspiration.
PMID- 9391225
TI - Fiberoptic endoscopic evaluation of dysphagia and videofluoroscopy.
PMID- 9391226
TI - Do psychogenic dysphagia patients have an eating disorder?
AB - Patients who report dysphagia, but have no detectable physical defect, have often
been diagnosed as having an eating disorder. This diagnosis was evaluated by
administering the Eating Disorders Inventory-2 (EDI-2) and a measure of distress,
the Symptom Checklist-90 (SCL-90R), to a sample of 21 adult psychogenic dysphagia
patients (PDPs). Their EDI-2 responses were then compared with samples of
anorexics, college men, and college women, and their SCL-90R responses were
compared with published data of patients with dysphagia due to a motility
disorder, an obstruction, or neither. Relative to the anorexics, the PDPs scored
significantly lower on all EDI-2 dimensions except maturity fears. For the SCL
90R, PDPs scored significantly higher on the interpersonal sensitivity,
depression, anxiety, and general severity index than did the dysphagia comparison
groups. Moreover, PDP scores on the anxiety and interpersonal sensitivity
dimensions were indicative of clinically significant distress. These findings
suggest that PDPs do not appear to have an eating disorder, but that they report
clinically significant levels of psychological distress, particularly anxiety.
PMID- 9391227
TI - Esophageal manometric abnormalities in Parkinson's disease.
AB - The gastrointestinal tract, and especially the esophagus, is frequently involved
in neurological diseases; however, objective studies of gut motor function are
few. We carried out an esophageal manometric study in 18 patients with various
stages of Parkinson's disease (4 stage I, 4 stage II, 7 stage III, and 3 stage
IV) to evaluate the function of the viscus in this disease. Clinical assessment
showed that 61% complained of esophageal symptoms such as dysphagia, acid
regurgitation, pyrosis, and noncardiac chest pain. Manometric abnormalities were
documented also in 61% patients, and were represented by repetitive contractions,
simultaneous contractions, reduced LES pressure, and high-amplitude contractions.
However, only 33.3% of patients had both symptoms and manometric abnormalities.
We conclude that esophageal motor abnormalities are frequent in Parkinson's
disease, and may appear at an early stage of the disease.
PMID- 9391228
TI - Dysphagia in stroke: a prospective study of quantitative aspects of swallowing in
dysphagic patients.
AB - This is a prospective study of 100 consecutive stroke patients. Within 24 h after
stroke onset they were asked specifically about swallowing complaints and
subjected to a clinical examination including neurologic examination, Mini-Mental
test, and Barthel score. Dysphagic patients were examined with the repetitive
oral suction swallow test (the ROSS test) for quantitative evaluation of oral and
pharyngeal function at 24 h, after 1 week, and after 1 month. At 6 months, the
patients were interviewed about persistent dysphagia. Seventy-two patients could
respond reliably at 24 h after the stroke onset and 14 of these complained of
dysphagia. Non-evaluable patients were either unconscious, aphasic, or demented.
The presence of dysphagia was not influenced by age or other risk factors for
stroke. Facial paresis, but no other clinical findings, were associated with
dysphagia. Dysphagia 24 h after stroke increased the risk of pneumonia but did
not influence the length of hospital stay, the manner of discharge from hospital,
or the mortality. The initial ROSS test, during which the seated patient ingests
water through a straw, was abnormal in all dysphagic stroke patients. One-third
of the patients were unable to perform the test completely. Above all,
dysfunction was disclosed during forced, repetitive swallow. All phases of the
ingestion cycle were prolonged whereas the suction pressures, bolus volumes, and
swallowing capacities were low. Abnormalities of quantitative swallowing
variables decreased with time whereas the prevalences of swallowing
incoordination and abnormal feeding-respiratory pattern became more frequent.
After 6 months, 7 patients had persistent dysphagia. Five of these were initially
non-evaluable because of unconsciousness, aphasia, or dementia.
PMID- 9391229
TI - The physiologic cause of swallowing sounds: answers from heart sounds and vocal
tract acoustics.
AB - A hypothetical discussion of the cause of swallowing sounds is presented. It is
suggested that the pharynx contains a number of valves and pumps that produce
reverberations within the pharynx to generate swallowing sounds. As heart sounds
are propagated via vibration of muscles and valves, it is further suggested that
an analogy exists between the generation of heart sounds and swallowing sounds.
This new theory is known as the cardiac analogy hypothesis. The inability of the
current literature to explain the cause of swallowing sounds is seen to limit the
diagnostic potential of cervical auscultation for dysphagia assessment. Future
investigators are encouraged to prove or disprove the cardiac analogy hypothesis.
PMID- 9391230
TI - Dysphagia in patients with Chagas' disease.
AB - Some patients with Chagas' disease and apparent normal esophageal function
complain of dysphagia. With the objective of investigating the esophageal
motility of these patients we studied the esophageal contraction amplitude,
duration, velocity, and lower esophageal sphincter (LES) pressure of 34 patients
with a positive serologic test for Chagas' disease, normal radiologic esophageal
examination, peristaltic contractions in the esophageal body, and complete LES
relaxation. Fourteen patients complained of dysphagia and 20 had no symptoms. The
results were compared with those of 22 healthy controls. We used the manometric
method with continuous perfusion. In patients without dysphagia, the LES pressure
(17.8 +/- 1.2 mmHg, mean +/- SEM) and distal esophageal amplitude (71.8 +/- 7.9
mmHg) were lower than those of control subjects (24.3 +/- 1.8 mmHg and 100. 4 +/-
10.6 mmHg, respectively). The velocity of peristaltic contractions was higher in
patients than in controls, but there was no difference between patients with or
without dysphagia. The duration of contraction in the distal esophagus was longer
in patients with dysphagia (3.9 +/- 0.2 sec) than in patients without dysphagia
(3.1 +/- 0.2 sec) and controls (3.2 +/- 0.2 sec). We conclude that dysphagia in
patients with Chagas' disease and a nondilated esophagus with peristaltic
contractions and complete LES relaxation is related to a longer duration of
contractions in the middle and distal esophageal body.
PMID- 9391231
TI - Cervical osteophytic dysphagia: single and combined mechanisms.
AB - Cervical osteophytes are common in the aging population. Dysphagia induced by
cervical osteophytes, although uncommon, is an important and treatable cause of
dysphagia that must be identified during the modified barium swallow. Previous
authors have described osteophyte impingement as a cause for dysphagia. This
report describes a case of this classic obstructive osteophytic dysphagia and one
of combined osteophytic and neurogenic dysphagia. This is the first time that a
combined mechanism is described in the literature.
PMID- 9391232
TI - Comments on selected recent dysphagia literature
PMID- 9391233
TI - Aging and the alimentary tract.
PMID- 9391234
TI - The aging oesophagus.
PMID- 9391235
TI - The aging stomach: implications for NSAID gastropathy.
PMID- 9391236
TI - Gastrointestinal surgery in old age: issues of equality and quality.
PMID- 9391237
TI - Parenchymal liver disease in the elderly.
PMID- 9391238
TI - Biliary tract diseases in the elderly: management and outcomes.
AB - Elderly people commonly present with biliary tract disease. Gallstone disease is
an important cause of recurrent abdominal symptoms, and we advocate an aggressive
approach in stable patients not at risk to improve the quality of their lives.
Choledocholithiasis is optimally treated by ERCP (98% success) even in patients
who are at great risk. Endoscopic intervention often obviates the need for
emergency biliary tract surgery in the elderly, is better tolerated, and is
associated with significantly less risk and a lower mortality. In contrast,
emergency surgery in the elderly is poorly tolerated. Even cholecystitis and
biliary pancreatitis (not discussed here) are amenable to endoscopic treatment.
Malignant biliary obstruction should not and cannot be treated as aggressively as
benign disorders affecting the biliary tree as the long term outlook is poor.
Endoscopic palliation usually suffices in maximising treatment and improving the
patient's quality of life with few associated complications or postprocedural
machinations (drainage bags or tubes). The afflicted population in general and
the elderly in particular benefit from minimally invasive endoscopic
decompression techniques.
PMID- 9391239
TI - Hirschsprung's disease: genetic mutations in mice and men.
AB - Hirschsprung's disease is a neuronal dysplasia of the hindgut, characterised by a
loss of neurones, which affects about 1 in 5000 live births. Genetic factors have
been implicated in the aetiology of this disease in about 20% of cases and a
dominant pattern of inheritance has been revealed in several families. The
pathogenesis of the aganglionosis is often attributed to a failure of migration
of neural crest cells, although this has not been proven. Recently, mutations in
a developmentally regulated receptor tyrosine kinase gene, ret, and mutations in
the endothelin receptor-B gene (ENDR-B) have both been linked to familial
Hirschsprung's disease in humans. Moreover, certain mutant mouse strains--namely
piebald lethal and lethal spotted--exhibit striking similarities to the human
condition. The mutation which gives rise to piebald lethal has now been found to
be in the ENDR-B gene, and the mutation associated with lethal spotted occurs in
the gene for endothelin-3 (ET-3), a ligand for ENDR-B. Two transgenic mouse lines
have been developed which also reflect the human disease: ret-k-, which has a
loss of function mutation of the ret gene, and ENDR-B null. In addition, the
introduction of a Lac-Z reporter gene into neural crest cells of aganglionic mice
has made it possible to study directly the fate of enteric neuroblasts which are
affected by "Hirschsprung's-like" mutations. Here, we review the possible roles
of RET and endothelin in the normal development of the enteric nervous system,
and the significance of their mutated forms in the pathogenesis of familial
aganglionosis. This review focuses on recent advances in our understanding of the
genetic basis of the lesions which have been implicated in congenital forms of
Hirschsprung's disease. Disruption of these genes in the mouse, either by
transgenic "knockout" approaches or in mutant mouse lines, offers the prospect of
greater understanding of both the cellular and developmental bases of the human
disease.
PMID- 9391240
TI - Induction of various cytokines and development of severe mucosal inflammation by
cagA gene positive Helicobacter pylori strains.
AB - BACKGROUND: Helicobacter pylori strains possessing the cagA gene are thought to
induce interleukin 8 (IL-8) in gastric mucosa. However, it is still unclear
whether a relation exists between the cagA gene and the expression patterns of
cytokines other than IL-8. AIMS: To investigate the relation between the cagA
gene and the production of various cytokine proteins using an enzyme linked
immunosorbent assay (ELISA). PATIENTS AND METHODS: In 184 patients, the cagA gene
was detected by polymerase chain reaction (PCR), and levels of production of IL-1
beta, IL-6, IL-7, IL-8, IL-10, and tumour necrosis factor alpha (TNF-alpha) in
antral biopsy specimens were measured by ELISA. RESULTS: Mucosal levels of IL-1
beta, IL-6, IL-8, and TNF-alpha were significantly higher in H pylori positive
than in H pylori negative patients. Furthermore, the mucosal levels of IL-1 beta
and IL-8 were significantly higher in specimens infected with cagA positive
strains than in those infected with cagA negative strains. In H pylori positive
patients, the mucosal level of IL-8 was closely correlated with that of IL-1 beta
(p < 0.0001), and the mucosal level of IL-6 was closely correlated with that of
TNF-alpha (p < 0.0001). CONCLUSION: These findings suggest that the ability to
induce cytokines differs among the strains; cagA+ strains induce various kinds of
cytokines and may cause severe inflammation, whereas cagA- strains induce IL-8
and IL-1 beta only weakly and may cause only mild inflammation. However, as most
patients infected with the cagA+ strains have gastritis, these strains may not be
equivalent to ulcerogenic strains.
PMID- 9391242
TI - Peptic ulcer bleeding in the elderly: relative roles of Helicobacter pylori and
non-steroidal anti-inflammatory drugs.
AB - BACKGROUND: Most ulcers are caused, one can deduce, by Helicobacter pylori or by
use of non-steroidal anti-inflammatory drugs (NSAIDs). Whether both together are
worse than one alone is something that is quite unknown. AIM: To study both
factors in order to see wither they interact together positively. METHOD: A case
control study of ulcer bleeding in elderly patients chosen without weeding.
RESULTS: NSAID usage increased risk substantially. So did H pylori infection (but
relative risk less than three). Neither seemed to interact. Their actions were
discretely intact. CONCLUSION: H pylori effects ulcer bleeding in an adverse
manner but does not make the risk of NSAIDs worse.
PMID- 9391241
TI - Helicobacter pylori independent chronological change in gastric acid secretion in
the Japanese.
AB - BACKGROUND: Gastric acid secretion in Japanese subjects decreases with aging. One
of the possible causative mechanisms of this attenuated acid secretion is
speculated to be a Helicobacter pylori induced chronic gastritis. The infection
rate of this microorganism has decreased recently in Japan. AIMS: To investigate
whether gastric acid secretion has altered over the past 20 years, and if so,
what the influence of H pylori infection might be in the Japanese population.
SUBJECTS AND METHODS: Gastric acid secretion, serum gastrin and pepsinogen I and
II concentrations, and H pylori infection were determined in 110 Japanese
subjects in both the 1970s and 1990s. RESULTS: Basal acid output as well as
maximal acid output have greatly increased over the past 20 years, not only in
individuals with H pylori infection but also in those without infection.
Furthermore, subjects with H pylori infection tended to show decreased gastric
acid secretion in comparison with those without infection, particularly in
geriatric subjects. There was a positive correlation between gastric acid
secretion and serum pepsinogen I concentrations. CONCLUSIONS: In Japan, both
basal and stimulated gastric acid secretion have increased over the past 20
years; some unknown factors other than the decrease in H pylori infection may
play an important role in this phenomenon.
PMID- 9391244
TI - Association between genetic polymorphism of the pepsinogen C gene and gastric
body ulcer: the genetic predisposition is not associated with Helicobacter pylori
infection.
AB - BACKGROUND AND AIMS: The genetic trait plays a part in the pathogenesis of peptic
ulcer disease. To identify a DNA marker for peptic ulcer disease, the association
between the restriction fragment length polymorphism (RFLP) of the pepsinogen C
(PGC) gene and peptic ulcer disease was investigated. PATIENTS AND METHODS: One
hundred and seventy seven unrelated controls, 75 patients with gastric ulcer, and
70 with duodenal ulcer were studied. PGC-RFLP was analysed by polymerase chain
reaction (PCR), and the association between PGC-RFLP and peptic ulcer disease was
examined. The relation between the genetic association of PGC polymorphism with
peptic ulcer and Helicobacter pylori infection was also examined. RESULTS: Four
alleles, 480 (allele 1), 450 (allele 2), 400 (allele 3), and 310 bp (allele 4),
were detected by PCR. The frequency of allele 4 was significantly higher in
patients with gastric body ulcer than in controls (chi (2) = 9.92, p < 0.005).
Genotypes containing allele 4 were significantly more frequent in patients with
gastric body ulcer than in controls and patients with gastric angular or antral
ulcer. The relative risk of gastric body ulcer associated with the presence of
allele 4, compared with its absence, was 4.63 and was statistically significant
(chi (2) = 14.84, p < 0.005). There were no significant differences in the
allelic frequencies between H pylori positive and H pylori negative groups in
controls, patients with gastric body ulcer, or patients with gastric angular or
antral ulcer. Both in H pylori negative and H pylori positive cases, there was an
increased frequency of allele 4 in patients with gastric body ulcer compared with
controls. CONCLUSIONS: These results suggest that there is a significant
association between this genetic polymorphism at the PGC gene locus and gastric
body ulcer. There are differences in the genetic aetiology between gastric body
ulcer and gastric angular or antral ulcer. PGC-RFLP may be used as a genetic
marker for a genetic predisposition to gastric body ulcer; this genetic
predisposition is not associated with H pylori infection.
PMID- 9391243
TI - High prevalence of cytotoxin positive Helicobacter pylori in patients unrelated
to the presence of peptic ulcers in Japan.
AB - BACKGROUND: It has been reported that infection with vacuolating cytotoxin
positive Helicobacter pylori strains is associated with gastroduodenal disease in
Western countries. AIMS: To evaluate the prevalence of cytotoxin producing
strains among patients with H pylori infection in relation to gastrointestinal
diseases in Japan. PATIENTS: Ninety seven patients undergoing endoscopy. METHODS:
A Western blot assay was conducted to detect serum antibodies against the
cytotoxin using recombinant cytotoxin (VacA protein) as an antigen. To obtain a
purified recombinant cytotoxin, the vacA gene (2233 nucleotides) was cloned into
an expression vector to produce the protein (744 amino acids), which was
expressed in Escherichia coli. RESULTS: Serum IgG antibodies to the cytotoxin
were present in 85%, 95%, 95%, and 100% of infected patients with gastric ulcer
(n = 26), duodenal ulcer (n = 21), chronic gastritis (n = 19), and endoscopically
normal mucosa (n = 14), respectively. CONCLUSION: The western blot method using
recombinant VacA protein is simple and useful for detecting antibody to
vacuolating cytotoxin. This method showed antibodies against cytotoxin were
highly prevalent, even in subjects with endoscopically normal mucosa in Japan,
indicating that the cytotoxin may not be an independent cause of gastrointestinal
diseases induced by H pylori infection.
PMID- 9391245
TI - Prospective evaluation of protein bound vitamin B12 (cobalamin) malabsorption in
the elderly using trout flesh labelled in vivo with 57Co-cobalamin.
AB - BACKGROUND: The frequency of dietary protein bound vitamin B12 malabsorption in
elderly patients remains controversial. AIMS: To evaluate this malabsorption in
elderly hospitalised patients using a modified Schilling test. PATIENTS: Fourteen
elderly patients with low B12 blood levels were prospectively selected from 394
hospitalised patients. METHODS: The modified Schilling test was performed with
trout labelled in vivo. RESULTS: The test was normal in five healthy elderly
subjects, in 7/8 patients with pancreatic insufficiency, and in nine non-elderly
patients with antral gastritis. The low decision limit was established at 3.3%
(median 4.8%). From the 14 elderly patients with low B12 prospectively selected
from 394 hospitalised patients, seven had a real deficiency with anaemia and an
increased homocysteine and/or methylmalonate serum level. The modified Schilling
test showed malabsorption in five of these patients, including two in which the
standard Schilling test was normal, and three in which the standard Schilling
test was partially corrected by an intrinsic factor. CONCLUSIONS: Protein bound
vitamin B12 malabsorption was detected in at least 0.5% of elderly hospitalised
patients, using the labelled trout flesh absorption test.
PMID- 9391246
TI - Incidence of Crohn's disease in Stockholm County 1955-1989.
AB - AIM: To evaluate the incidence of Crohn's disease in Stockholm County between
1955 and 1989. METHODS: A cohort of 1936 patients with Crohn's disease was
retrospectively assembled. Incidence rates and changes in disease distribution
were assessed. RESULTS: The mean increase in incidence was 15% (95% confidence
intervals 12% to 18%) per five year period with a mean annual incidence rate at
4.6/10(5) during the last two decades. The mean incidence for the entire study
period was similar for men and women. The mean age at diagnosis increased from 25
years in 1960-64 to 32 years in 1985-89, partly because of an increasing
proportion of patients aged at least 60 years at diagnosis. The proportion of
patients with colonic Crohn's disease at the time of diagnosis increased from 15%
to 32% (17% difference; 95% confidence intervals 12% to 23%) whereas the
proportion of patients with ileocaecal disease decreased from 58% to 41% (17%
difference; 95% confidence intervals 10% to 24%) during the study period. Elderly
patients had a higher proportion of small bowel disease and a lower proportion of
ileocolonic disease compared with the younger patients. CONCLUSION: The incidence
rate of Crohn's disease in Stockholm has stabilised at 4.6/10(5) and the
proportion of elderly patients has increased during a 35 year period. Colonic
Crohn's disease has increased in frequency with a reciprocal decrease in
ileocaecal disease.
PMID- 9391247
TI - Prophylactic effect of dietary glutamine supplementation on interleukin 8 and
tumour necrosis factor alpha production in trinitrobenzene sulphonic acid induced
colitis.
AB - BACKGROUND: It is well established that glutamine supplemented elemental diets
result in less severe intestinal damage in experimental colitis. However, few
studies have examined the mode of action of glutamine in reducing intestinal
damage. AIMS: To examine the effects of glutamine supplemented elemental diets on
the potent inflammatory cytokines interleukin 8 (IL-8) and tumour necrosis factor
alpha (TNF-alpha) in trinitrobenzene sulphonic acid (TNBS) induced colitis which
presents with both acute and chronic features of ulcerative colitis. METHODS:
Sprague-Dawley rats were randomised into three dietary groups and fed 20% casein
(controls), or 20% casein supplemented with either 2% glutamine (2% Gln) or 4%
glutamine (4% Gln). After two weeks they received intracolonic TNBS to induce
colitis. RESULTS: Both Gln groups of rats gained more weight than the control
group (p < 0.05) which had progressive weight loss. Colon weight, macroscopic,
and microscopic damage scores for the Gln groups were lower than in the control
group (p < 0.05). IL-8 and TNF-alpha concentrations in inflamed colonic tissues
were lower in the Gln groups than in the control group (p < 0.05), and correlated
well with disease severity. Bacterial translocation was lower both in incidence
(p < 0.05) and in the number of colony forming units (p < 0.05) for the Gln
groups, than in the control group. With respect to all indices studied, the 4%
Gln group performed better than did the 2% Gln group. CONCLUSION: Prophylactic
glutamine supplementation modulates the inflammatory activities of IL-8 and TNF
alpha in TNBS induced colitis.
PMID- 9391248
TI - Acute hyperglycaemia affects anorectal motor and sensory function in normal
subjects.
AB - BACKGROUND: The pathogenesis of anorectal dysfunction, which occurs frequently in
patients with diabetes mellitus, is poorly defined. Recent studies indicate that
changes in the blood glucose concentration have a major reversible effect on
gastrointestinal motor function. AIMS: To determine the effects of physiological
changes in blood glucose and hyperglycaemia on anorectal motor and sensory
function in normal subjects. SUBJECTS: In eight normal subjects measurements of
anorectal motility and sensation were performed on separate days while blood
glucose concentrations were stabilised at 4, 8, and 12 mmol/l. METHODS: Anorectal
motor and sensory function was measured using a sleeve/sidehole catheter
incorporating a balloon, and electromyography. RESULTS: The number of spontaneous
anal relaxations was greater at 12 mmol/l than at 8 and 4 mmol/l glucose (p <
0.05 for both). Anal squeeze pressures were less at a blood glucose of 12 mmol/l
when compared with 8 and 4 mmol/l (p < 0.05 for both). During rectal distension,
residual anal pressures were not significantly different between the three blood
glucose concentrations. Rectal compliance was greater (p < 0.05) at a blood
glucose of 12 mmol/l when compared with 4 mmol/l. The threshold volume for
initial perception of rectal distension was less at 12 mmol/l when compared with
4 mmol/l (40 (20-100) ml versus 10 (10-150) ml, p < 0.05). CONCLUSIONS: An acute
elevation of blood glucose to 12 mmol/l inhibits internal and external anal
sphincter function and increases rectal sensitivity in normal subjects. In
contrast, physiological changes in blood glucose do not have a significant effect
on anorectal motor and sensory function.
PMID- 9391250
TI - Evidence for two distinct perceptual alterations in irritable bowel syndrome.
AB - BACKGROUND: Visceral hyperalgesia has been implicated as a factor contributing to
symptom generation in irritable bowel syndrome (IBS). However, previous studies
using intestinal balloon distension have used psychophysical procedures which do
not provide adequate and unbiased measures of visceral sensitivity. METHODS:
Three psychophysical tasks were examined in 45 patients with IBS (positive Rome
criteria) and 14 controls using rectal balloon distension with a computerised
distension device. Discomfort threshold and tolerance were assessed during an
ascending series of phasic pressure stimuli and during an interactive threshold
tracking procedure. In addition, stimulus response functions were generated from
intensity and unpleasantness ratings of the rectal distensions. RESULTS:
Discomfort threshold and tolerance for the ascending stimuli were significantly
lower for the patients with IBS compared with the controls. In contrast,
discomfort thresholds during the tracking procedure and stimulus response curves
for the ascending series were not different between the groups. A factor analysis
of the psychophysical data was consistent with the presence of two distinct and
unrelated perceptual alterations related to rectal distension: hypervigilance for
visceral stimuli, manifested as lowered response criteria for using the
descriptor "discomfort"; and rectal hypersensitivity, manifested as a lower
discomfort threshold and left shift of the stimulus response curves. CONCLUSIONS:
Patients with IBS as a group have a greater propensity to label visceral
sensations negatively and show a lower tolerance for rectal balloon distension. A
subgroup of patients also have baseline rectal hypersensitivity, assessed by
unbiased measures of discomfort threshold and stimulus intensity judgements.
PMID- 9391249
TI - Role of cholecystokinin in the regulation of liquid gastric emptying and gastric
motility in humans: studies with the CCK antagonist loxiglumide.
AB - BACKGROUND: Exogenous cholecystokinin (CCK) inhibits antral motility and slows
gastric emptying (GE) but the effect of endogenous CCK on the gastric motor
mechanisms responsible for GE remains unclear. METHODS: The effect of the CCK-A
antagonist loxiglumide (LOX) on GE and motility was studied using magnetic
resonance imaging in six healthy volunteers after ingestion of 500 ml Intralipid
10% (550 kcal). Subjects were studied in the supine position on two occasions
during intravenous infusion of LOX (66 mumol/kg/h for 10 min followed by 22
mumol/kg/h) or placebo. GE was determined every 15 minutes using transaxial
abdominal scans and motility was studied by means of 120 coronal scans, 1.2
seconds apart. For each coronal image the proximal and distal (antral) diameters
were measured at a fixed point in the stomach to determine contraction frequency
(ACF) and amplitude (AMP). RESULTS: GE was faster during LOX infusion than
placebo (t1/2 31 (22) versus 115 (67) minutes, p < 0.03). There was little
variation in the diameter of the proximal stomach with either LOX or placebo. In
the distal stomach marked contractile activity was observed during LOX (ACF 2.9
(0.2) versus 1.5 (2.9) during placebo, p < 0.01). AMP also increased during LOX
compared with placebo (56 (22)% versus 27 (16)%, p < 0.001). CONCLUSION: The
increases in antral motility are likely to contribute to the acceleration of GE
and suggest that CCK may regulate GE by acting on the distal stomach although an
effect on the proximal stomach cannot be excluded.
PMID- 9391251
TI - Gastric cancer below the age of 55: implications for screening patients with
uncomplicated dyspepsia.
AB - AIMS: To test the hypothesis that gastric cancer presenting with uncomplicated
dyspepsia is rare below the age of 55. PATIENTS AND METHODS: The area studied was
the postcode defined catchment area of a district general hospital
(Gloucestershire Royal) serving a population of 280,500. An open access endoscopy
service has been available in this district for more than 17 years. All cases of
gastric cancer during a seven year period (1986-92) were drawn from the local
pathology database. The database of the neighbouring hospital and the South West
Cancer Registry were searched for missed cases from the postcoded area. Hospital
and general practitioner records were retrospectively reviewed with respect to
duration of symptoms, and previous consultation and investigation for dyspepsia;
and alarming symptoms and signs suggestive of underlying malignancy (unexplained
recent weight loss, dysphagia, haematemesis or melaena, anaemia, previous gastric
surgery, palpable mass, and perforation). RESULTS: Twenty five of 319 cases of
gastric cancer detected during the seven year period were aged less than 55.
Twenty four of these 25 patients presented with one or more suspicious symptoms
or signs. Only one patient (4%) aged less than 55 presented with uncomplicated
dyspepsia. In two patients there was a delay in diagnosis of more than six months
after first presenting to the general practitioner. Both these patients had
significant symptoms at presentation. CONCLUSION: Gastric cancer is rare below
the of 55 (7.8% of all cases) and, even in the presence of established open
access endoscopy, presents with suspicious symptoms or signs in 96% of cases. The
age limit for screening uncomplicated dyspepsia can be raised safely to 55.
PMID- 9391252
TI - Severe upper gastrointestinal polyposis associated with sparse colonic polyposis
in a familial adenomatous polyposis family with an APC mutation at codon 1520.
AB - BACKGROUND: Familial adenomatous polyposis usually results in colonic polyposis
with hundreds to thousands of polyps, congenital hypertrophy of the retinal
pigment epithelium (CHRPE), and variable extracolonic features. Recent reports
indicate that patients with distal mutations between codons 1445 and 1578 do not
express CHRPE and have a high incidence of desmoid tumours. PATIENTS: The family
studied has an unusual phenotype of sparse colonic polyposis but profuse upper
gastrointestinal polyposis. Affected subjects do not have CHRPE. METHODS: The
protein truncation test followed by sequencing identified a 2 base pair deletion
at codon 1520 in the APC gene. This results in a frameshift creating a stop codon
13 codons downstream. RESULTS: This family demonstrates that sparse colonic
polyposis but severe upper tract polyposis may be associated with mutations
between codons 1445 and 1578. CONCLUSIONS: Study of duodenal and colonic polyps
in further cases with mutations in this region is warranted. Such mutations may
preferentially cause duodenal adenomas and desmoid tumours as somatic mutations
in these tumours also occur in this region, unlike colorectal tumours where
somatic mutations occur more proximally. This study emphasises the importance of
screening the upper gastrointestinal tract even when the colonic disease is mild.
PMID- 9391253
TI - Is there an excess risk for colorectal cancer in patients with ulcerative colitis
and concomitant primary sclerosing cholangitis? A population based study.
AB - BACKGROUND: Patients with ulcerative colitis have an increased risk of colorectal
cancer. Duration, age, and extent of the disease at diagnosis are the only
established risk factors. Patients with ulcerative colitis and concomitant
primary sclerosing cholangitis (PSC) have been reported to have a higher
frequency of colonic DNA aneuploidy and/or dysplasia than expected, findings
indicating an increased risk of colorectal cancer compared with other patients
with ulcerative colitis. METHODS: A population based cohort consisting of 125
patients with a verified diagnosis of PSC was followed up by linkage to the
Swedish Cancer Registry for the occurrence of colorectal cancer. RESULTS: There
were 12 colorectal cancers. Six cancers were diagnosed prior to the diagnosis of
PSC. Among the 104 patients with an intact colon at the time of the diagnosis of
PSC there was a cumulative risk for colorectal cancer of 16% after 10 years.
Among the 58 patients with a diagnosis of ulcerative colitis and colorectal
cancer prior to the diagnosis of PSC, there were five colorectal cancers
corresponding to a cumulative risk of 25% after 10 years. CONCLUSIONS: Patients
with ulcerative colitis and concomitant PSC seem to constitute a subgroup with a
high risk for colorectal cancer.
PMID- 9391254
TI - A multicentre randomised trial comparing octreotide and injection sclerotherapy
in the management and outcome of acute variceal haemorrhage.
AB - BACKGROUND: Few studies have compared vasoactive drugs with endoscopic
sclerotherapy in the control of acute variceal haemorrhage. Octreotide is widely
used for this purpose, but its value remains undetermined. AIMS: To compare
octreotide with endoscopic sclerotherapy for acute variceal haemorrhage.
PATIENTS: Consecutive patients with acute variceal haemorrhage. METHODS: Patients
were randomised at endoscopy to receive either a 48 hour intravenous infusion of
50 pg/h octreotide (n = 73), or emergency sclerotherapy (n = 77). RESULTS:
Overall control of bleeding and mortality was not significantly different between
octreotide (85%, 62 patients) and sclerotherapy (82%, 63 patients) over the 48
hour trial period (relative risk of rebleeding 0.83; 95% confidence interval (CI)
0.38 to 1.82), irrespective of Child's grading or active bleeding at endoscopy.
One major complication was observed in the sclerotherapy group (aspiration) and
two in the octreotide group (pulmonary oedema, severe paralytic ileus). During 60
days of follow up there was an overall trend towards an increased mortality in
the octreotide group which was not statistically significant (relative risk of
dying at 60 days 1.91, 95% CI 0.97 to 3.78, p = 0.06). CONCLUSIONS: The results
of this study indicate that intravenous octreotide is as effective as injection
sclerotherapy in the control of acute variceal bleeding, but further controlled
trials are necessary to evaluate the safety of this treatment.
PMID- 9391255
TI - Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug
induced liver injury.
AB - BACKGROUND: Diagnosis of drug induced liver injury is usually based on a temporal
relation between drug intake and clinical picture as well as on the exclusion of
alternative causes. More precise diagnosis has been attempted by using in vitro
specific T cell reactivity to drugs but the test has never reached general
acceptability because of frequent negative results which could be explained, in
part, by prostaglandin producing suppressor cells (PPSC). AIM: To analyse the
diagnostic value of a modified test where lymphocyte responses to drugs are
detected in the presence of a prostaglandin inhibitor. PATIENTS: Ninety five
patients with a clinical diagnosis of drug induced liver injury, 106 healthy
controls, 35 individuals with recent exposure to the same drugs without adverse
effects, and 15 patients with liver disease unrelated to drugs. METHODS:
Peripheral blood mononuclear cells (PBMC) were cultured in the presence of drugs
alone and in the presence of drugs and a prostaglandin inhibitor. Responses were
assessed by 3H-thymidine incorporation in lymphocytes. Results were expressed as
counts per minute and as stimulation indexes (SI). RESULTS: When PBMC were
stimulated with drugs alone, lymphocyte sensitisation to drugs (SI > 2) was
detected in 26% of the cases. This was noticeably increased (56%) when a
prostaglandin inhibitor was added to the cultures. No reactivity was found in
controls. In patients with possible sensitivity to several drugs, lymphocyte
reactivity was detected to only one drug. The severity of the lesions, as
assessed by aminotransferase concentrations and disease duration, was lower in
patients with evidence of PPSC. CONCLUSIONS: This new approach is useful for the
diagnosis of drug induced liver injury, particularly in patients exposed to more
than one drug; furthermore, the presence of putative PPSC is associated with less
severe forms of drug induced hepatitis.
PMID- 9391256
TI - Endoscopic papillary balloon dilatation may preserve sphincter of Oddi function
after common bile duct stone management: evaluation from the viewpoint of
endoscopic manometry.
AB - BACKGROUND: Endoscopic papillary balloon dilatation (EPBD) has been reported as a
safe and effective alternative to endoscopic sphincterotomy in the management of
common bile duct (CBD) stones; its effect on papillary function has yet to be
elucidated. AIM: To investigate sphincter of Oddi (SO) motility before and after
EPBD to determine its effect on SO function. PATIENTS AND METHODS: The papillary
function of 10 patients with CBD stones was studied using endoscopic manometry
before and one week after EPBD. The manometric studies were repeated one month
after EPBD in seven patients. RESULTS: One week after EPBD, CBD pressure, SO peak
pressure, SO basal pressure, and SO frequency decreased significantly. One month
after EPBD, however, all parameters increased although the increases in SO basal
pressure and CBD pressure were not significant. There was no significant
difference in values of any parameter before and one month after EPBD. No serious
complications occurred. CONCLUSION: These data suggest at least partial recovery
of papillary function one month after the procedure. EPBD seems to preserve
papillary function in treatment of CBD stones; a longer term follow up study with
SO manometry should be performed to clarify the effect of EPBD on SO function.
PMID- 9391257
TI - Are complications of endoscopic sphincterotomy age related?
AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography sphincterotomy is
increasingly performed in younger patients undergoing laparoscopic
cholecystectomy. However, the safety of endoscopic sphincterotomy in this age
group, relative to that in older patients, is unknown. AIM: To determine whether
the development of short term complications following endoscopic sphincterotomy
is age related. PATIENTS AND METHODS: A prospective multicentre audit of 958
patients (mean age 73, range 14-97, years) undergoing a total of 1000 endoscopic
sphincterotomies. RESULTS: Two deaths occurred, both from postsphincterotomy
acute pancreatitis. Postprocedural complications developed in 24 patients:
pancreatitis in 10, ascending cholangitis in seven, bleeding in four, and
retroperitoneal perforation in three. There were six complications (five cases of
pancreatitis and one bleed; 2.2%) and no deaths in the 281 (29.3%) patients aged
under 65 years. In comparison, 18 (2.6%) of the 677 patients aged over 65 years
developed a complication (cholangitis in seven, pancreatitis in five, bleeding in
three, and perforation in three). Patients under 35, 45, 55, and 65 years were
not at significantly increased risk of complication than those over these ages
(relative risk for those under compared with those over 65 years 0.83, 95%
confidence intervals 0.41-1.67, p = 0.74). CONCLUSION: Short term complications
following endoscopic sphincterotomy are not related to age. Younger patients
undergoing laparoscopic cholecystectomy need not be denied endoscopic
sphincterotomy for fear that the risks are greater than if they undergo surgical
exploration of the common bile duct.
PMID- 9391259
TI - Monozygotic twins with Crohn's disease and ulcerative colitis: a unique case
report.
AB - BACKGROUND: A large number of monozygotic and dizygotic twin pairs with
inflammatory bowel disease have been reported. To date no twin pair has developed
phenotypically discordant inflammatory bowel disease. This case report is the
first documented occurrence of discordant inflammatory bowel disease occurring in
monozygotic twins. CASE REPORT: Twenty two year old identical male twins
presented within three months of each other with inflammatory bowel disease that
proved to be discordant in overall disease type, disease distribution, clinical
course, and histopathological findings. Twin 1 developed a severe pancolitis
necessitating total colectomy while twin 2 developed a predominantly distal
patchy colitis with frequent granulomas, controlled by aminosalicylates. Twin 1
was antineutrophil cytoplasmic antibody (ANCA) negative at the time of testing
while twin 2 (Crohn's disease) was ANCA positive. Significantly, the twins
possessed the HLA type DR3-DR52-DQ2 previously associated with extensive colitis.
CONCLUSION: This case report confirms the important role played by genetic
factors in the development of inflammatory bowel disease. It also highlights the
crucial role of undetermined environmental agents in dictating disease expression
and phenotype.
PMID- 9391258
TI - Liposome mediated gene transfer into the rat oesophagus.
AB - BACKGROUND: Cancer of the oesophagus has so far eluded every attempt at
pharmacological treatment. The recent advent of somatic gene therapy offers a new
therapeutic approach to malignant tumours. AIM: To investigate whether and how
gene transfer into the oesophagus can be achieved. METHODS: A LacZ reporter gene
was used as marker and transferred into the oesophagus of rats using cationic
liposomes. Gene transfer was achieved by either luminal instillation into a
closed segment using a double balloon catheter, or by intramural injection
through a needle. Expression of beta-galactosidase was monitored in the
oesophagus and various control tissues by histochemistry, polymerase chain
reaction (PCR), reverse transcriptase PCR, and Southern blotting. RESULTS: Up to
100 days after in vivo gene transfer beta-galactosidase activity could be
demonstrated in the oesophagus. Following luminal application, the transgene was
expressed in epithelial cells whereas intramural injection induced preferential
expression in fibroblasts. CONCLUSION: In vivo gene transfer into the esophagus
is feasible and safe, and the route of administration largely determines cell
type specificity. This novel approach will enable in vivo studies of growth,
differentiation, and malignant transformation in the oesophagus, and may open new
avenues to the confinement of oesophageal malignancies.
PMID- 9391260
TI - Primary ileal villous atrophy is often associated with microscopic colitis.
AB - Three cases of apparent primary villous atrophy of the terminal ileum in women
with chronic diarrhoea are reported. Eight cases have previously been reported in
the literature. Clinical characteristics are the presence of severe chronic
secretory diarrhoea with episodes of hypokalaemia combined with signs of ileal
malabsorption and/or efficacy of cholestyramine. Diagnosis is based on ileoscopy
and histology. An association with microscopic colitis was present in the three
patients and in four cases in the literature. The pathogenesis of primary ileal
villous atrophy remains unknown and may involve dysimmunity. Its association with
microscopic colitis may indicate a common pathogenesis or support the hypothesis
that the faecal stream or bile salts play a role in the pathogenesis of
microscopic colitis.
PMID- 9391261
TI - Tissue transglutaminase as the autoantigen of coeliac disease.
AB - Dieterich et al show that immunoprecipitation of human fibrosarcoma cell lysates
(cell line HT1080) using the IgA fraction from serum samples of patients with
coeliac disease results in a single protein band with a molecular weight of 85
kDa. Immunoprecipitation occurred exclusively with 25 coeliac disease serum
samples, but with none of the 25 control samples. The 85 kDa antigen was cleaved
with endoproteinase Asp-N, and after amino-terminal sequence analysis, the three
cleavage products tested all yielded sequences that could be assigned to tissue
transglutaminase (EC 2.3.2.13; tTG). In order to prove that tTG obtained from the
fibrosarcoma cells binds to the endomysial antibody fraction of coeliac serum
IgA, the authors performed indirect immunofluorescence with high titre coeliac
disease serum samples on monkey oesophagus with or without prior incubation of
those samples with a commercially available tTG extract (Sigma, Deisenhofer,
Germany). Pretreatment with tTG almost completely abolished endomysial antibody
labelling. Also, when the Sigma tTG was used as antigen in an enzyme linked
immunosorbent assay (ELISA), 12 coeliac disease patient samples but none of the
seven control serum samples displayed increased IgA immunoreactivity. Dieterich
et al conclude they have identified tTG as the unknown endomysial autoantigen.
PMID- 9391262
TI - Opening the doors of perception in the irritable bowel syndrome.
PMID- 9391263
TI - "Deja vu all over again".
PMID- 9391264
TI - Ulcerative colitis: sclerosing cholangitis today, cancer tomorrow?
PMID- 9391265
TI - Sense and sensitisation: in vitro testing for hepatotoxic drug hypersensitivity.
PMID- 9391266
TI - The aging stomach or the stomachs of the ages.
PMID- 9391267
TI - Endoscopic findings and clinical patterns are not useful for distinguishing low
from high grade gastric MALT lymphoma.
PMID- 9391268
TI - Natural history of polypoid lesions of the gall bladder.
PMID- 9391269
TI - Polypoid lesions of the gall bladder.
PMID- 9391270
TI - Bone mineral density in Crohn's disease.
PMID- 9391271
TI - Incidence of persistent symptoms after laparoscopic cholecystectomy.
PMID- 9391272
TI - An exceptional high concentration of serum CA 19.9 in a patient with alcoholic
liver disease.
PMID- 9391273
TI - Imaging the thoracic aorta in the injured patient.
PMID- 9391274
TI - Should clinical cardiologists incorporate the proximal isovelocity surface area
(PISA) method into their ever enlarging armamentarium?
PMID- 9391275
TI - Echocardiographic assessment of long axis function: a simple solution to a
complex problem?
PMID- 9391276
TI - Harvey Williams Cushing (1869-1939).
PMID- 9391277
TI - Aortic stenosis and angina with normal coronary arteries: the role of coronary
flow abnormalities.
PMID- 9391278
TI - Management of asymptomatic aortic stenosis: masterly inactivity but cat-like
observation.
PMID- 9391279
TI - Pacemaker mode selection and survival: a plea to apply the principles of evidence
based medicine to cardiac pacing practice.
PMID- 9391280
TI - The United Kingdom pacing and cardiovascular events (UKPACE) trial. United
Kingdom Pacing and Cardiovascular Events.
PMID- 9391281
TI - Systematic trial of pacing to prevent atrial fibrillation (STOP-AF).
PMID- 9391282
TI - Non-penetrating cardiac and aortic trauma.
PMID- 9391283
TI - Left ventricular atrioventricular plane displacement: an echocardiographic
technique for rapid assessment of prognosis in heart failure.
AB - OBJECTIVE: To assess the prognostic value of atrioventricular plane displacement
in heart failure patients. DESIGN: Patients were followed prospectively for one
year after atrioventricular plane displacement determination. SETTING: Malmo
University Hospital, with a primary catchment area of 250,000 inhabitants.
PATIENTS: 181 patients with a clinical diagnosis of heart failure; age 75.7 (SD
5.2) years, duration of heart failure 2.7 (5.7) years; 100 men, 81 women. MAIN
OUTCOME MEASURES: Mortality in relation to atrioventricular plane displacement.
RESULTS: Total mortality was 22.7% (41/181), and was highly significantly (P =
0.001) related to atrioventricular plane displacement. Mortality within
prospectively defined categories of displacement was: > or = 10.0 mm, 0% (0/19);
8.2 to 9.9 mm, 10.3% (3/29); 6.4 to 8.1 mm, 19.4% (12/62); and < 6.4 mm, 36.6%
(26/71). The groups were similar in age, sex, angiotensin converting enzyme
inhibitor and beta blocker treatment, and cause and duration of heart failure.
CONCLUSIONS: Mortality in heart failure is strongly related to atrioventricular
plane displacement.
PMID- 9391284
TI - Prognostic implications of qualitative assessment of left ventricular function
compared to simple routine quantitative echocardiography.
AB - OBJECTIVE: To compare the prognostic value of qualitative estimates of left
ventricular function with that of routine simple quantitative indices used in
echocardiography. DESIGN: Retrospective follow up study. SETTING: University
hospital. PATIENTS: The records of 2,964 patients who had undergone
echocardiography and who could be traced on the family health services register
were examined; 919 cases were included in the study, and a further 458 were used
to validate the statistical models for prognostic assessment. There were 928
exclusions on the basis of referral for or diagnosis of alternative conditions,
and 659 because of incomplete collection of the qualitative and quantitative data
used in the study. MAIN OUTCOME MEASURE: Survival over the study period. RESULTS:
A qualitative "eyeball" estimate of left ventricular function was of prognostic
significance (relative risk of poor v good, 2.248; P << 0.001; 95% confidence
interval 1.620 to 3.119). None of the quantitative echocardiographic indices was
of independent prognostic significance when all variables were tested
simultaneously in the regression model. CONCLUSIONS: A qualitative
echocardiographic estimate of left ventricular dysfunction is of prognostic
value, supporting the view of many cardiologists who use their overall impression
of left ventricular function at echocardiography as the basis for treatment
decisions.
PMID- 9391285
TI - Long-term follow up of patients with implantable cardioverter-defibrillators and
mild, moderate, or severe impairment of left ventricular function.
AB - OBJECTIVE: To determine whether patients with life threatening ventricular
tachyarrhythmias, impaired left ventricular function, and severe heart failure
will benefit from implantable cardioverter-defibrillator (ICD) treatment. DESIGN:
410 patients were followed up after ICD implant. Left ventricular function was
assessed by the New York Heart Association (NYHA) functional class of heart
failure: 50 patients (12%) were in NYHA I-II, 151 (37%) in NYHA II, 117 (29%) in
NYHA II-III, and 92 (22%) in NYHA III. Epicardial ICD implantation was performed
in 209 patients (51%) and 201 patients (49%) received non-thoracotomy ICDs.
RESULTS: Perioperatively, 12 patients (3%) died, more often after epicardial ICD
implant (11/209 patients, 5%) than after transvenous implant (1/201 patients, <
1%) (P < 0.05). During a mean (SD) follow up of 28 (24) months (range < 1 to 114
months), 90 patients (23%) died: nine (2%) died from sudden arrhythmia; five (1%)
also died suddenly but probably not from arrhythmic causes; 55 (14%) died from
cardiac causes (congestive heart failure, myocardial reinfarction); 21 (5%) died
from non-cardiac causes. The three year, five year, and seven year survival was
92-96% for arrhythmic mortality in NYHA class I, II and III, compared to a three
year survival of 94% and a five year and seven year survival of 84% for patients
in NYHA class II-III. 338 patients (82%) received ICD shocks (21 (SD 43) shocks
per patient); patients in NYHA class II (83%), class II-III (84%), and class III
(90%) received ICD discharges more often than those in class I-II (64%) (P <
0.05). The mean (SD) time interval between ICD implant and the first ICD shock
was shorter in NYHA class II (16 (17) months), class II-III (19 (27) months), and
class III (16 (19) months) than in class 0-I (22 (24) months) (P < 0.05).
CONCLUSIONS: Patients with mild, moderate, and severe left ventricular
dysfunction benefit from ICD treatment and these patients survive for a
considerable time after the first shock. Survival is influenced by the degree of
left ventricular dysfunction; aggressive treatment of heart failure is necessary
as well as ICD therapy.
PMID- 9391286
TI - Left atrial appendage function in patients with atrial flutter.
AB - OBJECTIVE: To determine whether echocardiographic markers thromboembolic risk
differ between patients with pure atrial flutter and patients with atrial flutter
and intermittent atrial fibrillation. DESIGN: Patients with atrial flutter were
followed up prospectively for 12 months to identify intermittent atrial
fibrillation. After the follow up period, transthoracic and multiplane
transoesophageal echocardiography were performed to assess left atrial chamber
and appendage size, peak emptying velocities, and emptying fraction of the left
atrial appendage. The presence of spontaneous echo contrast was also determined.
SETTING: Tertiary cardiac care centre. PATIENTS: 20 consecutive patients with
atrial flutter; 11 healthy subjects in sinus rhythm served as controls. RESULTS:
Intermittent atrial fibrillation was documented in 11 patients by Holter
monitoring or surface ECG; atrial fibrillation was not found in the other nine
patients. Compared with the patients with pure atrial flutter, patients with
atrial flutter and intermittent atrial fibrillation had larger left atrial
chamber (mean (SD) 4.5 (0.6) v 3.8 (0.5) cm; 95% confidence interval 0.2 to 1.2;
P = 0.01) and appendage areas (6.7 (2.2) v 4.8 (4.9) cm; 95% CI 0.4 to 3.5; P =
0.02), lower left atrial appendage emptying fractions (33 (11)% v 52 (11)%; 95%
CI 8 to 29; P = 0.008), and also lower left atrial appendage emptying velocities
(0.44 (0.21) v 0.79 (0.27) m/s; 95% CI 0.13 to 0.56; P = 0.005). In addition, a
higher incidence of spontaneous echo contrast (11% v 36%) was observed in
patients with atrial flutter and intermittent atrial fibrillation. CONCLUSIONS:
Left atrial appendage function is depressed and spontaneous echo contrast more
frequent in patients with atrial flutter and intermittent atrial fibrillation, as
opposed to patients with pure atrial flutter. These data support the concept that
patients with atrial flutter and intermittent atrial fibrillation have an
increased risk of thromboembolic events and should therefore receive adequate
anticoagulant treatment.
PMID- 9391287
TI - Radiofrequency catheter ablation for idiopathic right ventricular tachycardia
with special reference to morphological variation and long-term outcome.
AB - OBJECTIVE: To assess the long term outcome of radiofrequency (RF) catheter
ablation for idiopathic ventricular tachycardia (VT) originating from the outflow
tract of the right ventricle, with special reference to the morphological
variation in the VT-QRS complexes. PATIENTS: 13 patients whose ventricular
tachycardia was treated with RF ablation were followed up more than 18 months
after RF ablation. RESULTS: Endocardial mapping revealed the various extensions
of ventricular tachycardia origin (from 0.5 x 0.5 cm to 2.0 x 2.0 cm) in which
the earliest local electrogram was recorded during ventricular tachycardia. In
all five tachycardias from a relatively wider origin (more than 0.5 x 0.5 cm) and
in four of eight from a narrow origin (< 0.5 x 0.5 cm), subtle morphological
variation in the VT-QRS complexes was observed. In tachycardias with
morphological variation, the local electrogram at the tachycardia origin also
showed concomitant variation in morphology and activation sequence. Ventricular
tachycardia from a narrow site was eliminated by RF ablation to the confined
site, but a larger number of RF applications was required in tachycardias from a
wider origin. All 13 tachycardias were successfully ablated by RF current, and
during the follow up period of 28.2 (SD 7.2) months, recurrence was observed in
only one patient who had a wider origin. CONCLUSIONS: Long term efficacy of RF
ablation was excellent in idiopathic ventricular tachycardia originating from the
outflow tract of the right ventricle. Subtle morphological variations were
frequently observed in this type of ventricular tachycardia, and about half of
them represented a relatively wider arrhythmogenic area.
PMID- 9391288
TI - Left atrial spontaneous echo contrast in patients with permanent pacemakers.
AB - OBJECTIVE: To determine the relations between left atrial appendage function,
spontaneous echo contrast, and thromboembolism in patients with different modes
of permanent pacemakers. PATIENTS AND METHODS: 88 patients with pacemaker
implantation and 25 healthy controls in sinus rhythm had transoesophageal
echocardiographic examination of the left atrial appendage. Left atrial size,
appendage area, peak filling and emptying velocities of the atrial appendage, and
the presence or absence of spontaneous echo contrast and thromboembolism were
determined. The results in 63 patients with ventricular pacing (group 1,
subdivided into subgroup 1A: 42 patients with sinus rhythm, and subgroup 1B: 21
patients with atrial fibrillation) were compared with those in 25 patients with
synchronous pacing (group 2), and 25 normal control subjects (group 3). RESULTS:
Patients with ventricular pacing had two distinct appendage flow patterns: well
defined biphasic filling and emptying waves in subgroup 1A, and irregular very
low filling and emptying waves in subgroup 1B. The ejection fraction of the left
atrial appendage in subgroup 1A was significantly better than that in subgroup 1B
(mean (SD) 40.6 (12.0)% v 7.6 (5.0)%, P < 0.0001). The spontaneous echo contrast
was observed in 90% of subgroup 1B patients but in only 19% in subgroup 1A (P <
0.05) and was not found in groups 2 and 3 (P < 0.0001). There was a trend for
increased prevalence of spontaneous echo contrast in subgroup 1A v group 2 (P =
0.053). Thrombi were detected in two cases, and cardiogenic embolism occurred in
one case in subgroup 1B. All patients with spontaneous echo contrast had
ventricular pacing. Multivariate analysis showed that atrial fibrillation was
associated with occurrence of spontaneous echo contrast in patients with
ventricular pacing (P = 0.005). CONCLUSIONS: The left atrial appendage ejection
fraction was lower with ventricular pacing than with synchronous pacing. With
ventricular pacing there was a trend towards increased prevalence of left atrial
spontaneous echo contrast in patients in sinus rhythm, and a significantly
increased prevalence in patients with atrial fibrillation.
PMID- 9391289
TI - QT dispersion as a risk factor for sudden cardiac death and fatal myocardial
infarction in a coronary risk population.
AB - OBJECTIVE: To test in a prospective study the hypothesis that increased QT
dispersion in resting 12-lead ECG is a predictor of sudden cardiac death. DESIGN:
A nested case-control study during a mean (SD) follow up time of 6.5 (2.8) years.
SETTING: A prospective, placebo controlled, coronary prevention trial with
gemfibrozil among dyslipidaemic middle aged men in primary (occupational) health
care units: the Helsinki heart study. PATIENTS: 24 victims of fatal myocardial
infarction, 48 victims of sudden cardiac death without acute myocardial
infarction, and their matched controls. MAIN OUTCOME MEASURES: QT dispersion in
baseline and pre-event electrocardiograms. RESULTS: At study baseline, QT
dispersion was similar in all victims and controls. When estimated from the pre
event ECG on average 14 months before death, the risk of sudden cardiac death in
the highest QTPEAK (up to the peak of the T wave) dispersion tertile (> or = 50
ms) was 6.2-fold (95% confidence interval 1.7 to 23.5) compared with the risk in
the lowest tertile (< or = 30 ms), and 4.9-fold (1.2 to 19.5) after adjustment
for the presence of left ventricular hypertrophy, while QTPEAK dispersion could
not predict fatal myocardial infarction. QTEND dispersion (up to the end of the T
wave) in pre-event ECGs could not discriminate victims of either sudden cardiac
death or fatal myocardial infarction from their matched controls. CONCLUSIONS: In
middle aged men with a normal conventional QT interval in 12-lead resting ECG,
increased QTPEAK dispersion is an independent risk factor for sudden cardiac
death, but not for fatal myocardial infarction.
PMID- 9391290
TI - Relation of serum cytokine concentrations to cardiovascular risk factors and
coronary heart disease.
AB - OBJECTIVE: To determine whether serum concentrations of the cytokines tumour
necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6), which regulate C
reactive protein, are associated with cardiovascular risk factors and prevalent
coronary heart disease. DESIGN: A population based cross sectional study.
SUBJECTS AND METHODS: 198 men aged 50 to 69 years were part of a random
population sample drawn from south London. Serum cytokine and C reactive protein
concentrations were determined by enzyme linked immunosorbent assay. The presence
of coronary heart disease was determined by Rose angina questionnaire and
Minnesota coded electrocardiogram. RESULTS: Serum TNF alpha concentrations were
positively related to body mass index and Helicobacter pylori infection, but
inversely related to alcohol consumption. IL-6 concentrations were positively
associated with smoking, symptoms of chronic bronchitis, age, and father having a
manual occupation. TNF alpha was associated with increased IL-6 and
triglycerides, and reduced high density lipoprotein cholesterol. IL-6 was
associated with raised fibrinogen, sialic acid, and triglycerides. ECG
abnormalities were independently associated with increases in IL-6 and TNF alpha,
each by approximately 50% (P < 0.05 for TNF alpha, P < 0.1 for IL-6). The
corresponding increases in men with an abnormal ECG or symptomatic coronary heart
disease were 28% for TNF alpha and 36% for IL-6 (P = 0.14 for TNF alpha and P <
0.05 for IL-6). CONCLUSIONS: This study confirms that many of the phenomena with
which C reactive protein is associated, are also associated with serum levels of
cytokine, which may be the mechanism.
PMID- 9391292
TI - Comparison of captopril and ibopamine in mild to moderate heart failure.
AB - OBJECTIVE: To determine the effects of ibopamine 100 mg three times daily
compared with captopril 25 mg three times daily on exercise capacity in patients
with chronic heart failure. DESIGN: A randomised, double blind, parallel group
comparison of the addition of ibopamine versus captopril during a period of 24
weeks. SETTING: 26 outpatient cardiology clinics in seven European countries.
PATIENTS: 266 patients, with mild to moderate chronic heart failure (New York
Heart Association (NYHA) functional class II, 81% and III, 19%) and evidence of
an enlarged left ventricle. Patients received concomitant treatment with
diuretics and/or digitalis. MAIN OUTCOME MEASURE: Exercise duration after 24
weeks of treatment, compared with baseline. RESULTS: Mean (SD) ejection fraction
was 29 (8)% and the baseline exercise duration in the captopril and ibopamine
groups 665 (160) and 675 (174) seconds, respectively. At the end of the study,
exercise duration had improved in both groups, by 29 seconds in the ibopamine
group (P < 0.01), and by 24 seconds in the captopril group (P < 0.05). There was
no difference between groups (P = 0.69, 95% confidence interval -22 to 33). NYHA
class, signs and symptoms score, and dyspnoea and fatigue index improved equally
in both groups. The total number of adverse events was the same in both treatment
groups, but gastrointestinal complaints occurred more often in the ibopamine
group. The number of patients with premature withdrawals was no different.
CONCLUSIONS: No difference was detected between the effect of captopril and
ibopamine on exercise time in patients with mild to moderate heart failure during
a treatment period of 24 weeks.
PMID- 9391291
TI - Time dependent alterations of serum matrix metalloproteinase-1 and
metalloproteinase-1 tissue inhibitor after successful reperfusion of acute
myocardial infarction.
AB - OBJECTIVE: To test the hypothesis that changes in serum matrix metalloproteinase
1 (MMP-1) and tissue inhibitors of metalloproteinase-1 (TIMP-1) after acute
myocardial infarction reflect extracellular matrix remodelling and the infarct
healing process. PATIENTS: 13 consecutive patients with their first acute
myocardial infarction who underwent successful reperfusion. METHODS: Blood was
sampled on the day of admission, and on days 2, 3, 4, 5, 7, 14, and 28. Serum MMP
1 and TIMP-1 were measured by one step sandwich enzyme immunoassay. Left
ventricular volume indices were determined by left ventriculography performed
four weeks after the infarct. RESULTS: Serum concentrations of both MMP-1 and
TIMP-1 changed over time. The average serum MMP-1 was more than 1 SD below the
mean control values during the initial four days, increased thereafter, reaching
a peak concentration around day 14, and then returned to the middle control
range. Negative correlations with left ventricular end systolic volume index and
positive correlations with left ventricular ejection fraction were obtained for
serum MMP-1 on day 5, when it began to rise, and for the magnitude of rise in MMP
1 on day 5 compared to admission. Serum TIMP-1 at admission was more than 1 SD
below the mean control value, and increased gradually thereafter, reaching a peak
on around day 14. Negative correlations with left ventricular end systolic volume
index and positive correlations with left ventricular ejection fraction were
obtained for serum TIMP-1 on days 5 and 7, and for the magnitude of rise in TIMP
1 on days 5 and 7 compared to admission. CONCLUSIONS: Both MMP-1 and TIMP-1
showed significant time dependent alteration after acute myocardial infarction.
Thus MMP-1 and TIMP-1 may provide useful information in evaluating the healing
process as it affects left ventricular remodelling after acute myocardial
infarction.
PMID- 9391293
TI - Early changes in left ventricular anterior wall dynamics and coordination after
coronary artery surgery.
AB - OBJECTIVE: To study how asynchronous left ventricular wall motion changes early
after uncomplicated coronary artery surgery. DESIGN: A prospective study done
before, and at 0.5, 1, and 3 hours after coronary artery grafting, with
intraoperative transoesophageal cross sectional guided M mode echocardiograms,
high fidelity left ventricular pressure, and thermodilution cardiac output
measurements. The extent and velocity of left ventricular anterior wall
thickening were measured, along with regional work and power production. Abnormal
thickness changes during the isovolumic periods were detected, and their effect
on energy transfer quantified as cycle efficiency. SETTING: Tertiary referral
cardiac centre. PATIENTS: 25 patients with a history of chronic stable angina,
mean (SD) age 60 (9) years with three vessel coronary artery disease, undergoing
uncomplicated coronary artery bypass grafting. RESULTS: 4 patients had primary
incoordination, as shown by wall thinning during isovolumic contraction and
delayed onset of thickening (group A), and nine had premature thickening due to
incoordination elsewhere (group B). The extent (thickening fraction 43 (12)% v 73
(19)%) and velocity (1.7 (0.4) v 2.5 (0.6) cm/s) of thickening were reduced in
group A v group B (P < 0.001), as were regional stroke work (2.2 (0.8) v 3.3
(0.4) mJ/cm2) and peak power production (19 (5) v 32 (7) mW/cm2), P < 0.05. In
group A, these values all increased significantly within 30 minutes of operation.
In group B, the extent of wall thickening and peak power production were
unaffected by surgery, though cycle efficiency and regional stroke work both
improved by 30 minutes v before operation (73 (9)% v 61 (8)%, 4.5 (0.9) v 3.3
(0.4) mJ/cm2, P < 0.01). Surgery had no consistent effect on left ventricular
cavity size, shortening fraction, or cardiac output in either group. CONCLUSIONS:
Even in the absence of evidence of overt ischaemia, major disturbances of
ventricular synchrony--both regional and generalised--are present in patients
with a history of chronic stable angina requiring coronary artery bypass
grafting. They regress within 30 minutes of revascularisation, suggesting that
they are the direct result of coronary stenosis.
PMID- 9391294
TI - Anatomical criteria for the diagnosis of sinus venosus defects.
AB - BACKGROUND: The diagnosis of sinus venosus defects remains a matter of debate. It
is crucial to provide solid anatomical criteria, by identifying the very nature
of the atrial septum relative to sinus venosus defects, to diagnose and
differentiate them from other interatrial communications. OBJECTIVE: This study
was designed to reestablish the anatomical criteria for the diagnosis of sinus
venosus defects. METHODS: Five specimens with sinus venosus defects from the
cardiopathological museum were examined. Study of the abnormal hearts was
supplemented by examining the extent and structure of the atrial septum in 10
normal hearts. The echocardiograms and surgical notes were reviewed from 18
patients seen between July 1991 and August 1996 at the Royal Brompton Hospital in
London diagnosed preoperatively to have a sinus venosus defect. RESULTS: The
nature of the oval fossa and its muscular borders were identified in the normal
hearts. In all three autopsied specimens of the superior variety of sinus venosus
defect, the mouth of the superior caval vein was overriding the intact muscular
anterosuperior border of the oval fossa. Two specimens thought initially to have
the inferior variety of sinus venosus defect were re-classified as having defects
within the oval fossa as it was the deficient oval fossa itself, rather than its
intact muscular border, that was overridden by the mouth of the inferior caval
vein. Sixteen patients had been diagnosed echocardiographically as exhibiting the
superior variant of the defect. Retrospective review showed overriding of the
superior caval vein across the upper rim of the oval fossa in 12 patients. These
findings were confirmed by surgery in 11 patients with the 12th awaiting
operation. Overriding of the fossa by the caval vein was not found in the other
four patients. Surgery in all of these showed the defect to be within the oval
fossa. In two patients diagnosed echocardiographically as having inferior
defects, the surgical findings confirmed a biatrial connection of the inferior
caval vein in one patient, the findings in the second were equivocal.
CONCLUSIONS: The key anatomical criterion for the diagnosis of sinus venosus
defects is overriding of the mouth of the superior or inferior caval vein across
the intact muscular border of the oval fossa. The interatrial communication is
then formed within the mouth of the overriding vein, and is outside the confines
of the oval fossa.
PMID- 9391295
TI - Quantitative, non-invasive assessment of ventricular septal defect shunt flow by
measuring proximal isovelocity surface area on colour Doppler mapping.
AB - OBJECTIVE: To determine whether the proximal isovelocity surface area (PISA)
method could be applied to estimate the magnitude of ventricular septal defect
(VSD) shunt flow. DESIGN: Prospective analysis of clinical, echocardiographic,
and angiographic data. SETTING: University hospital. PATIENTS: 14 children with
VSD. METHODS: Colour Doppler images of VSD shunt flow were obtained in
parasternal long axis view, four chamber view or both, adjusted to provide the
best imaging of flow. The VSD shunt flow rate and shunt volume were calculated as
follows: shunt flow rate (SFR) = 2 pi r2 V/BSA in ml/s/m2; shunt volume = SFR x
shunt duration time. The shunt volume, shunt fraction, and pulmonary to systemic
flow ratio (Qp:Qs) were confirmed by cardiac catheterisation. RESULTS: There was
a correlation between shunt variables determined by PISA and those by
catheterisation, including shunt volume (r = 0.78, P = 0.001) and shunt fraction
(r = 0.74, P = 0.003). Qp:Qs was also significantly correlated with SFR (r =
0.79, P = 0.0007). The SFR was significantly different between the four patients
with Qp:Qs < 2.0 (mean (SD) 54 (33) ml/s/m2) and the 10 patients with Qp:Qs > 2.0
(186 (69) ml/s/m2) (P = 0.004). CONCLUSIONS: These data suggest that the PISA
method is a reliable non-invasive investigation for the quantitative assessment
of VSD shunt flow and provides important information for decisions regarding
surgical repair.
PMID- 9391296
TI - Two teenagers, traumatic aortic disruption, and transoesophageal
echocardiography.
AB - A report of two teenagers is presented who were passengers of the same vehicle
when it was involved in a serious road traffic accident. Their vehicle was hit on
the side at high speed by a second vehicle. Both teenagers sustained multiple
injuries. On arrival at a district general hospital they required resuscitation,
exploratory laparotomies, and postoperative intensive care. Neither had
radiographic evidence to suggest any mediastinal injury, but transoesophageal
echocardiography demonstrated aortic disruption in both patients. They were
transferred to a regional cardiothoracic centre where their lesions were
successfully repaired and both have made a full recovery.
PMID- 9391297
TI - Concrete induced cardiac contusion.
AB - A previously fit 22 year old man was struck in the chest by a concrete block
dropped through the windscreen of his car while he was driving on the motorway.
He suffered extensive chest wall trauma and lung contusion, which subsequently
precipitated acute respiratory distress. On admission ECG showed right bundle
branch block and left axis deviation. Three days later QRS duration was normal
but there was anterior ST segment elevation and subsequent T wave change. There
was a large rise in creatine kinase, and echocardiography revealed septal and
apical hyokinesis as well as a mobile mass attached to the left side of the
interventricular septum, which had the echogenic texture of myocardium. The
patient had fixed perfusion defects in the areas of hypokinesis on thallium
scanning but the coronary arteries were unobstructed at angiography. He was
treated with warfarin in the short term and an angiotensin converting enzyme
inhibitor in the longer term and has made an asymptomatic recovery. Outpatient
echocardiography two months after the injury demonstrated some recovery in
overall left ventricular systolic function and no evidence of the intracardiac
mass. This case illustrates some of the typical features of non-fatal cardiac
contusion associated with non-penetrating cardiac trauma, and was complicated by
partial thickness avulsion of a strip of the myocardium in the interventricular
septum.
PMID- 9391298
TI - Traumatic ventricular septal defect.
AB - A 26 year old man was admitted to hospital following a traffic accident. He had
been sitting in the back of a car without wearing a seat belt. He suffered crush
injuries on the anterior chest wall, trunk, and legs. On admission he was awake
and cooperative, but restless, and obviously in severe pain. Radiography of the
skull, facial bones, chest, spine, pelvis, and legs revealed a shaft fracture of
the left femur and tibia and fracture of the 7th and 8th right ribs. The patient
was transferred to the University Hospital of Zurich for further assessment and
surgical repair of the lower limb fractures three days later. Because of
worsening clinical condition with onset of partial respiratory insufficiency and
new loud systolic murmur at the left sternal edge, a transthoracic
echocardiography was performed, which showed an apical ventricular septal defect.
Surgery was performed immediately. The ventricular septal defect was successfully
repaired using a Teflon felt patch and interrupted sutures with pledgets, and
sealed with glue. At six months' follow up the patient was doing well.
Ventricular septal defects after blunt chest trauma occur either because of heart
compression between sternum and the spine or because of myocardial infarction. In
the present case the ventricular septal defect appeared three days after the
accident, probably secondary to a post-traumatic myocardial infarction. Patients
with blunt chest trauma and suspicion of cardiac contusion should be monitored
carefully.
PMID- 9391300
TI - Flecainide levels--a cautionary note.
PMID- 9391299
TI - Iatrogenic atrioventricular bypass tract following a Fontan operation for
tricuspid atresia.
PMID- 9391301
TI - Prognostic significance of ST-T segment alterations in patients with non-Q wave
myocardial infarction.
PMID- 9391302
TI - Stent placement in the outlet of the right ventricle.
PMID- 9391303
TI - Raised plasma BNP in a patient with acute pulmonary thromboembolism.
PMID- 9391304
TI - Assessment of endothelial function using plasma markers.
PMID- 9391305
TI - [Newer approach of screening test for antinuclear antibodies: an enzyme-linked
immunosorbent assay detecting antinuclear antibodies characteristic of connective
tissue diseases].
AB - An enzyme-linked immunosorbent assay (ELISA) has been developed for the detection
of antinuclear antibodies (ANAs) previously established as diagnostic and/or
prognostic marker ANAs for various connective tissue diseases. The antigen used
in ELISA is a mixture of purified recombinant or natural antigens including
single-and double-stranded DNA, RNP, Sm, SS-A/Ro, SS-B/La, centromere,
topoisomerase I and Jo-1 antigens. Thirty hundred and fifty nine patients sera
from a variety of connective tissue diseases and 113 normal human sera (NHS) were
examined. ELISA ANAs were positive in 3.5% of NHS and 80.2% of patients sera at
cut off index 11.5, whereas indirect immunofluorescent antinuclear antibodies
(FANAs) using HEp-2 cells were positive in 9.7% of NHS and 92.5% of patients sera
at 1:160 serum dilution. More than 80% of sera from systemic lupus erythematosus,
mixed connective tissue disease and primary Sjogrens disease were ELISA ANAs
positive. Mean value of ELISA ANAs was highest in sera of patients with MCTD.
ELISA ANAs were positive in 92.5% of sera with marker ANAs for connective tissue
diseases. Mean value of ELISA ANAs was higher in sera with more than two marker
ANAs than in sera with a single ANA or in sera without marker ANAs. In contrast
incidence and mean value of ELISA ANAs were low in sera positive for anti
topoisomerase I antibody or anti Jo-1 antibody. Sensitivity, specificity and
agreement (accuracy) for connective tissue diseases with marker ANAs were as
follows: ELISA ANAs (at index 11.5): 92.5%, 88.3% and 90.9%: FANAs (at 1:160
serum dilution): 99.0%, 70.4% and 88.1%, respectively. ELISA ANAs, thus, are
specific for connective tissue diseases when compared to FANAs and previous ELISA
for the detection of total ANAs. Moreover, ELISA ANAs are able to measure precise
ANAs titers and are much less labor intensive when screening a large number of
clinical specimens.
PMID- 9391306
TI - [2-5 AS activity in serum and peripheral blood mononuclear cells for chronic
active hepatitis C and the relationship to clinical outcome of interferon
therapy].
AB - Of 49 patients with chronic hepatitis C treated by interferon (IFN), we measured
2'-5'-oligoadenylate synthetase (2-5 AS) activity in peripheral blood mononuclear
cells (PBMC) and serum before and after the IFN therapy and studied the
correlation with the clinical outcome. Before IFN therapy, the levels of 2-5 AS
in PBMC and serum were significantly higher in patients with chronic hepatitis C
than in healthy controls, though there was no correlation between the 2-5 AS
activity and the clinical outcome. When PBMC were stimulated with IFN in vitro,
the induced 2-5 AS activities in patients with chronic hepatitis C were almost
same as those in healthy controls. Among patients infected with hepatitis C virus
(HCV) genotype II which was considered relatively resistant to IFN, patients
whose HCV was disappeared from serum by IFN therapy showed good induction of 2-5
AS activity by IFN in vitro, whereas patients in which serum HCV remained
positive after the therapy showed poor response to IFN in vitro. The levels of 2
5 AS in PBMC 2 months after IFN therapy were still higher in patients whose HCV
was continuously disappeared from serum by the therapy (complete remission) than
in healthy controls. The in vitro induction of 2-5 AS in patients whose HCV in
serum remained positive after the therapy was significantly lower than in
patients with complete remission. The induction of 2-5 AS activity in patients to
whom IFN therapy was ineffective, significantly decreased after the IFN therapy
as compared with the activity measured before the therapy. These findings suggest
that measurement of 2-5 AS activity in PBMC in vitro through IFN therapy might be
useful for predicting in vivo responsibility to IFN and also knowing the change
of the responsibility.
PMID- 9391307
TI - [A case of congenital complete heart block in a mother with anti-52 kD SS-A/Ro
antibodies].
AB - We report a case of congenital complete heart block (CCHB). A 38-year-old woman
was admitted our hospital because of fetal bradycardia at 21 weeks 3 days of
gestational age. She had no symptom of collagen disease. On admission, laboratory
data showed positive anti-nuclear antibodies, anti-SS-A/Ro antibodies and anti-52
kD SS-A/Ro antibodies. But anti-60 kD SS-A/Ro and anti-SS-B/La antibodies were
negative. Consequently anti-52 kD SS-A/Ro antibodies positive woman had an infant
with CCHB. The baby was equipped with pacemaker at the age of 2 months. This
report suggests that anti-52 kD SS-A/Ro antibodies may play an important role in
the development of CCHB.
PMID- 9391308
TI - [Pernicious anemia associated with chronic thyroiditis and suspected latent
adrenal insufficiency].
AB - A 64-year-old female referred to our hospital because of severe anemia.
Peripheral blood examination showed macrocytic anemia; red blood cell count was
1.49 x 10(6)/microliters, hemoglobin concentration was 5.6 g/dl, hematocrit was
16.1% and MCV was 108 fl. Serum VB 12 level was significantly low as 58 pg/ml.
Upper gastrointestinal examination disclosed chronic atrophic gastritis. Anti
intrinsic factor and anti-parietal cell antibodies were detected in the serum and
Schilling's test was positive. Thus a diagnosis of pernicious anemia was made.
Though the serum free T 3 and free T 4 levels were in normal ranges, the elevated
serum TSH and positive tests for anti-microsome and anti-thyroglobulin antibodies
indicated that the patient had chronic thyroiditis. Then other endocrinological
examinations were performed. Low level of urinary 17-OHCS and a hypo-reactive
pattern of rapid ACTH test led to a diagnosis of latent adrenal insufficiency.
This case could be categorized into polyglandular autoimmune syndrome.
PMID- 9391309
TI - [A case of hemophagocytic syndrome with severe liver injury manifestating adult
Still's disease].
AB - In April 1988, a 23 year-old woman developed high fever, arthralgia, eruptions
and splenomegaly. She was treated with non Steroid anti-inflammatory drugs, and
the symptoms disappeared. In June 1991, she was diagnosed as adult Still's
disease and treated with prednisolone. In July 1994, she was treated with pulse
therapy methylprednisolone due to high fever, eruptions, arthralgia and the high
levels of ferritin. However, due to the marked increase of serum transaminase and
bilirubin levels, she was referred to University hospital. She developed hepatic
failure after admission Bone-marrow puncture revealed hemophagocytosis. She died
ten days after admission. She was diagnosed as hemophagocytic syndrome combined
with acute hepatic failure.
PMID- 9391310
TI - [A case of reactive arthritis fallen after shigellosis infection].
AB - A 25-year-old woman was admitted for general arthralgia in July, 1989. Reactive
arthritis with arthralgia after Shigellosis was diagnosed by sex, localization of
arthralgia and positive for HLA-B 27. Within 3 weeks after starting diclifenac
sodium 75 mg/day, the arthralgia remitted. It has been reported that patients who
are positive for HLA-B 27 have a more severe acute or chronic sacroiliitis, and
our case may support this report.
PMID- 9391311
TI - [A case of Wegener's granulomatosis associated with refractory bowel
granulomatous ulcers].
AB - We describe a 58-year-old woman who developed Wegener's granulomatosis (WG)
complicated by a perforation of the transverse colon caused by necrotizing
granulomatous vasculitis. In addition, her colon lesion continued in spite of
high dose corticosteroid and cyclophosphamide therapy. She was admitted to our
hospital because of her severe tonsillitis in Dec., 1994. She was diagnosed as
having WG because she had oral ulcer, antibiotics-resistant lung infiltration,
renal dysfunction and positive C-ANCA. Just after we started high dose steroid
therapy, the transverse colon was perforated because of vasculitis, and she
underwent emergency operation. Many vasculitic lesions were found in the small
intestine, colon, and mesenterium. The disease was improved by corticosteroid and
cyclophosphamide therapy except for a sustained ulcer with necrotizing vasculitis
in the sigmoid colon region even 1 year after the operation. Although WG rarely
complicates digestive tract lesions as initial manifestations, they reach 12% of
the causes of death of WG in Japan. Therefore, we should take care of digestive
tract lesions when we follow-up patients with WG.
PMID- 9391312
TI - [Survival of Vibrio cholerae non-O1 in freshwater river].
AB - The survival of Vibrio cholerae non-O1 was investigated in sterile and untreated
river water. The essential nutrients for growth of the organism were also
investigated using a compound medium. V. cholerae non-O1 was shown to increase in
autoclaved sterile river water, but did not increase in filtrated river water,
and starting with an initial number of 10(6) CFU/ml organism, the organism could
not be isolated from untreated river water after day 10. The growth or survival
of the organism was also studied with filtrated river water to which all
essential nutrients except one was added. In this water, V. cholerae non-O1 did
not increase when either phosphate or a carbon source was not present. These
results indicate that V. cholerae non-O1 can survive in river water by taking
nutrients for growth from solutes and particle matter in the river water.
PMID- 9391313
TI - [A survey of cognitive probability structure of risk of death by cause].
AB - A person is believed to choose a health related behavioral alternative based on
his/her perception of the health risk. This survey tried to clarify the structure
of perceptions relating to risk of death, which seems to be the most fundamental
among various health risks. A survey was performed in 1995 on 350 employees of
two major companies. Subjects were shown two paired causes of death and asked
which diseases caused deaths more frequently in the Japanese. Diseases included
cancer, cerebral apoplexy, heart disease, traffic accident, tuberculosis, and
lung cancer. The results obtained were as follows: 1. Generally, the order of
perceived risk for each cause of death was similar to the real death numbers. 2.
While traffic accidents tended to be overestimated for its risk, the risk
perception for heart disease and cancer tended to be underestimated. 3. Young
people tended to overestimate the risk of traffic accidents more than older
people. Based on these results, it is suggested that people tend to overestimate
current risks, and to underestimate future risks. This may contribute to the
improvement of risk communication between health care providers and
residents/patients.
PMID- 9391314
TI - [Association of participation in health checkups with medical service utilization
in a rural town].
AB - Association of participation in health checkups in 1983-94 with medical service
utilization in 1989-94 was studied. The study subjects consisted of 1,198 males
and 1,247 females aged 30 years or over, who were members of the National Health
Insurance in a rural town in Kyoto prefecture. One hundred and four males and 95
females died during 1989-94. Cumulative death rates were higher among both males
and females with less participation in checkups than among those with higher
participation, however, there was no difference seen for medical service
utilization. Regarding subjects alive in 1994, both males and females who
participated frequently in checking in 1983-88 also visited medical facilities
more frequently and had higher medical costs in 1989-94 than those with less
frequent participation. Similar analysis for checkups in 1989-94, showed that
only females had that tendency. Among participants in checkups in 1989-94, there
were smaller numbers of hypertensives, current smokers, and current drinkers than
among non-participants, therefore, the participants are thought to have decreased
their risk for chronic diseases. In conclusion, frequent participation in health
checkups are thought to increase medical utilization even with a lower prevalence
or risk of chronic diseases.
PMID- 9391315
TI - [Health conditions and life styles of residential elderly. Part 1.
Characteristics and factors related to being healthy elderly persons from a
survey of health life style].
AB - A survey was conducted in a highland community of Gifu prefecture on 815
residential elderly persons, over 65 years old, utilizing self-administered
questionnaires to study the degree of association between life style factors and
health conditions. A total of 718 valid participants (90.6% of the total) were
analyzed and cross-examined by applying Breslow's seven health factors, daily
behavior factors, physical health consciousness, social mobility factors (13
behavior factors which were determined by the Institute of the Elderly) to
determine associations with respondents health conditions. Of the participants,
310 were male and 408 were female with mean ages of 73.8 +/- 6.9 years old and
74.0 +/- 6.9 respectively. The survey results indicated that there were no
prominent gender differences over the mobility rate and physical health
consciousness among participants. However, it was also found that in the male
participants the per person prevalence of past history of illness was higher than
in females. In the daily activity analysis, female participants indicated a
higher prevalence of difficulty in walking and balance maintenance while
ascending and descending stairs. In the general daily activity analysis, male
participants had a higher requirement for an aide. In social mobility, male
participants recorded a high degree of self-reliance by being physically,
socially, and intellectually active and the female participants by fulfilling
their social responsibilities. Breslow's seven health indicators were applied and
their evaluation points were calculated as 3.9 +/- 1.7 for male participants and
3.5 +/- 1.8 for female participants which showed a significantly higher score for
the male participants. The survey also indicated that factors which increase the
Breslow score for males, were having a spouse, hobbies, a satisfactory life, a
habit of exercising, and non-smoking which in females an appropriate sleeping
habit (not less than 7 hours), and working, were the positively related factors.
PMID- 9391316
TI - [Support plan for children with chronic intractable diseases and their family-
results of inquiries about patients and their family].
PMID- 9391317
TI - [Analysis of Vi antigen genes of Salmonella typhi and study of its regulation].
PMID- 9391318
TI - [Studies on the regulation of toxin production in Clostridium perfringens].
PMID- 9391319
TI - [Environmental regulation of the fimbriae and toxin expression in Actinobacillus
actinomycetemcomitans].
PMID- 9391320
TI - [Current topics of pathogenicity in Salmonella].
PMID- 9391321
TI - [Staphylococcal leukocidin and gamma-hemolysin].
PMID- 9391322
TI - [Characteristics of the cellulolytic ruminal bacterium Fibrobacter succinogenes
and its attachment to cellulose].
PMID- 9391323
TI - [The GTP-binding proteins as targets for bacterial toxins].
PMID- 9391325
TI - [Clinical study of the application of the concepts of systemic inflammatory
response syndrome (SIRS) in liver cirrhosis with or without hepatocellular
carcinoma with upper gastrointestinal hemorrhage--a retrospective study].
AB - The retrospective study was aimed at assessing the usefulness of the application
of the criteria of SIRS for identifying a subset of patients with higher
mortality in 22 cases (21 patients) of liver cirrhosis with upper
gastrointestinal hemorrhage (GIH) and 16 cases (14 patients) of liver cirrhosis
with hepatocellular carcinoma with upper GIH. The following results were
obtained; (1) The incidence of SIRS on upper GIH was 66%. (2) The mortality rate
in patients with SIRS on GIH was significantly higher than in patients with non
SIRS on GIH in 60 days after GIH was significantly higher than in patients with
non-SIRS on GIH in 60 days after GIH (50% vs. 8%; p < 0.01). (3) The rate of
patients who met four criteria of SIRS on GIH or during admission and of patients
whose durations of SIRS was over 5 days was significantly higher in the died
patients with SIRS on GIH than in the survived patients with SIRS on GIH (67% vs.
0%; p < 0.01, 67% vs. 0%; p < 0.01, respectively). These results suggested that
the application of the criteria of SIRS was useful for identifying a subset of
patients with higher mortality in chronic liver disease with GIH.
PMID- 9391324
TI - [Studies on bacillary dysentery cases of overseas travellers--during 1979 to
1995].
AB - A total of 36,780,440 overseas travellers during 1979-1995 (17 years) were
quarantined at Osaka and Kansai Airport Quarantine Station, 84,777 travellers
reported themselves suffer from diarrhoea. Stools from 29,587 persons were
bacteriologically examined. Various enteropathogenic bacteria were isolated from
9,766 (33.0%) patients of the stools examined. Isolated species were as follows:
Plesiomonas shigelloides (3,234 cases); Salmonella spp. (2,236 cases);
enterotoxgenic Escherichia coli (1,621 cases); Vibrio parahaemolyticus (1,959
cases); and Shigella spp. (1,242 cases). 1,278 different Shigella strains were
isolated from 1,242 cases who were thus diagnosed as bacillary dysentery
patients. The suspected regions or countries for infection of these cases were
analysed. The serovars and antibiotic-sensitivities of the isolated strains were
examined. Colicine typing of S. sonnei strains were also done. The results can be
summarized as follows. 1) The most cases (53.4%) were infected in India. 2) The
percentage distribution of sub-species of the strains was as follows; S. sonnei
(57.8%), S flexneri (29.8%), S. boydii (8.4%), and S. dysenteriae (4.0%),
respectively. 3) The major colicine type of S. sonnei strains were type 6 and 0.
4) The percentage of Antibiotic-resistant strains of each sub-species was S.
dysenteriae (92.2%), S. sonnei (89.4%), S. flexneri (87.1%), and S. boydii
(84.9%), respectively. The percentage of Antibiotic-resistant strains of S.
flexneri were increased annually.
PMID- 9391326
TI - [Pathological and immunohistochemical analysis of giant cells of pancreas].
AB - Multinucleated giant cells in the pancreas (five giant cell carcinomas, a
mucinous cystadenocarcinoma attended with many osteoclast-like giant cells, 42
invasive ductal carcinomas and 29 chronic pancreatitises) were examined. Three
types of multinucleated giant cell were identified: epithelial type, coexpressive
type, mesenchymal type. Epithelial type expressed epithelial markers, such as
keratin and EMA in 23 ductal carcinomas. Coexpressive type expressed both
epithelial markers and mesenchymal marker vimentin was in four ductal carcinomas.
Mesenchymal type expressed mesenchymal markers, vimentin and CD68 in four
osteoclastoid type giant cell carcinomas, the mucinous cystadenocarcinoma, six
ductal carcinomas and ten chronic pancreatitises. Epithelial and coexpressive
type were considered to be epithelial neoplastic origin, those had bizarre
appearance and transitional area from definite adenocarcinoma area. Vimentin
expression is associated with sarcomatous proliferation. Mesenchymal type was
considered to be nonneoplastic and a certain type of macrophage polykaryons.
PMID- 9391327
TI - [A case of solitary gastric varices treated with B-RTO method followed by MR
angiography].
PMID- 9391328
TI - [A case of colitic cancer arising from villous type of dysplasia].
PMID- 9391329
TI - [Sigmo-sigmoid fistula formation in a case of ulcerative colitis].
PMID- 9391330
TI - [A case of metastatic carcinoma of the duodenum from bladder].
PMID- 9391331
TI - [A case of drug-induced liver injury caused by Saiko-Keishi-Kankyoto with
thrombocytopenia].
PMID- 9391332
TI - [An autopsied case of adult onset Still's disease accompanied by fatal liver
failure, and simultaneously complicating adenocarcinomatous peritonitis from
unidentified primary site].
PMID- 9391333
TI - [A case of autoimmune hepatitis associated with anti-phospholipid antibody
syndrome].
PMID- 9391334
TI - [A case of double cholecysto-duodenal fistula associated with gallstone ileus].
PMID- 9391335
TI - [A case of anaplastic carcinoma of the pancreas, disclosed a hemosuccus
pancreaticus].
PMID- 9391336
TI - [Successful treatment of pancreatic pseudocyst with octreotide; a case report].
PMID- 9391337
TI - [Evaluation of modified rapid urease test (MR urea S) in diagnosis of
Helicobacter pylori (HP)].
PMID- 9391338
TI - [The discovery and molecular mechanism of protein splicing].
PMID- 9391339
TI - [Natural killer T cells: their origin and functions].
PMID- 9391340
TI - [Human NK inhibitory and activating receptors that bind to human leukocyte
antigens (HLA) regulate NK cells and T cells].
PMID- 9391341
TI - [Development of animal cloning by nuclear transfer].
PMID- 9391342
TI - [Organic solvent tolerance in Escherichia coli].
PMID- 9391343
TI - [Calorimetry of proteins (II)].
PMID- 9391345
TI - 'The evidence suggests that ...'.
PMID- 9391346
TI - Paving the way: stepping stones to evidence-based nursing.
AB - Evidence-based practice is an emerging paradigm in health care. This paper
outlines the main features of this paradigm and its potential value to nursing.
Evidence-based practice is based on a conceptual framework that examines the
extent of evidence available in support of particular clinical practices. The
Quality of Evidence Ratings adapted by the National Health and Medical Research
Council (NHMRC) from the United States Preventive Services Task Force are
discussed, and the strengths and weaknesses of different categories of evidence
are highlighted. Potential barriers to implementation of research into practice
are identified. The authors suggest that legal, ethical, economic and humane
imperatives oblige nursing to develop evidence-based practice as one of several
viable contributions to nursing knowledge. Suggestions for analysing current
research and for the planning of the direction of future nursing research are
made.
PMID- 9391347
TI - The acceptance of a philosophically based research culture?
AB - This paper addresses a trend that emerged at a nursing research conference held
in New South Wales during 1996. The trend was a downplaying of the relevance of
philosophical and theoretical bases for research in nursing. Such a trend would
not be of concern if all research aimed to merely generate local, non
generalizable conclusions and recommendations. However, research that aims to
develop knowledge that can provide relevant knowledge on a broader, or universal
scale, needs to be based on coherent and relevant philosophical and/or
theoretical foundations. To adequately critique such research it should ideally
be linked to a philosophy or theory that situates it in both historical and
intellectual loci and consequently, the raison d'etre for the research should
arise. This paper begins with an exploration of Immanuel Kant's philosophy and
proceeds to a discussion on the philosophical underpinnings of Dorothea Orem. It
is intended that such discussion will assist the clinician to see the relevance
that philosophy has to clinically based research in nursing and, importantly, the
critique of such research. In conclusion, two possible reasons are suggested as
to why philosophy and theory in nursing research may appear to be increasingly
frowned upon. It is hoped that a greater understanding of the power of
philosophically based research will contribute to an increased enthusiasm and
uptake of philosophically based research projects by nurses.
PMID- 9391348
TI - Nursing, a bridge to peace in our region: opinions on mutual co-operation between
Israeli and Palestinian professional nurses and nurse educators.
AB - The purpose of this study was to assess the activities and future direction of
mutual co-operation of professional nurses from Israel and Judea and Samaria.
Questionnaires were distributed to the participants, nurse educators and
professional nurses from Judea and Samaria who were attending a workshop in
clinical instruction at the Assaf HaRofeh School of Nursing, in Israel. Most of
the nurses polled were interested in continued educational dialogue and expanded
educational programmes in various nursing specialties both in education and
service. The areas that received priority included: intensive care, operating
room and emergency room nursing. Areas that received lower priorities included;
midwifery, geriatrics and nephrology nursing. The participants expressed positive
reactions to continued joint educational activities such as full length courses,
workshops, day seminars and joint educational projects. The results showed an
overwhelming interest for continued professional ties. Areas in the fields of
clinical expertise and nursing education reflected the needs of their respective
communities.
PMID- 9391349
TI - The elderly adult in the emergency department.
AB - Over 65-year olds were nominated by emergency staff at a Melbourne regional
hospital as a patient group of particular concern. With nurse academics from
Monash University, a collaborative study was undertaken of elderly patients and
the circumstances of their attendance. The focus of the study was on those
elderly patients who were triaged as non-acute and who may have been
disadvantaged by the priority given to acute cases. The triage records obtained
over a 5 month period were analyzed, and a survey administered to selected
patients. Over 65-year olds were found to constitute 19% of incoming patients.
They figured more prominently in urgent triage categories than those under 65
years of age, were more likely to be referred by a health professional, and more
likely to be admitted or transferred. There was no evidence to suggest slower
progress through the emergency department for the non-acute elderly than for
their counterparts under 65 years of age.
PMID- 9391350
TI - Breaking a social silence: registered nurses share their stories about tertiary
nursing education.
AB - This research presents some of the qualitative findings from a mixed methods
study exploring the personal and professional effects of tertiary education for
post registration women nurses. The researcher combined both qualitative and
quantitative approaches. The specific methods employed were survey questionnaire,
'journalling' and interviews. The results demonstrated that the participants were
able to identify and verbalise personal and professional experiences associated
with tertiary study, through multiple voices. A distinctive theme of empowerment
emerged in their stories. However, by sharing their stories, it was evident that
encounters in their lives were enmeshed with dialectical relationships. In
conclusion, the associated tension that characterized their personal and
professional relationships, indicated that these women could not control their
social worlds and that their experiences were integrally linked to their
engendered nature.
PMID- 9391351
TI - Role identity and job satisfaction of community health nurses.
AB - Although many efforts have been made to articulate the nature of community health
nursing practice, there continues to be a great deal of confusion about the roles
and functions of community health nurses. This article reports a descriptive
research study of the role identity and job satisfaction of 43 staff community
health nurses practicing in home health care, generalized public health nursing,
combined public health/home health care (PH/HHC), and specialized programmes.
Although differences were found, the home health, generalized public health, and
PH/HHC nurses shared a similar core identity. The major differences were seen for
the nurses working in specialized programmes. No significant differences were
found in job satisfaction among the four groups.
PMID- 9391352
TI - The specialist learning disability nurse in Wales.
AB - This paper reflects on the development of services for people with learning
disabilities within the United Kingdom and focuses on the role of the specialist
nurse. The nurse's contribution to the care of this client group has been the
subject of debate and controversy for a number of years. Developments within the
learning disability filed in Wales in particular are explored, with the All Wales
Strategy for People with Learning Disabilities providing the background and
context for these developments. An example of how specialist nurses from around
Wales came together in order to share good and best practice is discussed. The
conclusion is that the specialist learning disability nurse has a great deal to
offer, but must be prepared to work together with other professionals as well as
service users and their families.
PMID- 9391353
TI - A therapeutic programme for people with dementia.
AB - A programme involving Tai Chi and structured reminiscence was trialed with nine
people suffering from moderately advanced dementia. The analysis reported here
aimed to examine stories the people told with a view to understanding the purpose
of story telling in their lives. Themes derived from the narrative data had a
strong evaluative quality, ranging from simple evocative expressions to more
cognitive complex insights or treasures. The study indicated a major aim in story
telling as being able to generate life values, both for the enrichment of
identification of self, and to pass on or leave for today's youth. Findings here
further substantiate Luke and Freiden's view that old age has its own cognitive
and spiritual goals to achieve. There is strong evidence that people with
moderate dementia still aim to participate in that endeavour.
PMID- 9391354
TI - Where does rehabilitation fit in the picture of care for the trauma patient?
PMID- 9391355
TI - The history of the Glasgow Coma Scale: an interview with professor Bryan Jennett.
Interview by Carole Rush.
AB - An interview with one of the founders of the Glasgow Coma Scale provides a
partial history of the development and dissemination of this assessment tool.
Professor Bryan Jennett credits nurses with the rapid spread and universal
acceptance of the scale.
PMID- 9391356
TI - Attitudes and beliefs of Afro-Americans related to organ and tissue donation.
AB - A descriptive study was conducted to identify problems associated with the
attitudes, beliefs, and lack of participation of a small Afro-American population
concerning organ donation. I. King's theory of goal attainment was used to
compare stated beliefs with reported behaviors that would indicate a willingness
to participate in organ donation.
PMID- 9391358
TI - Termination of resuscitation for traumatic cardiac arrest.
PMID- 9391359
TI - Easing pain in children.
AB - The assessment and management of pain in children has been essentially ignored
until recently. Thankfully, these "dark ages of pain" are ending. The trauma
nurse is an integral part of the pain management team and can have a positive
impact on outcome by using a combination of relatively simple strategies. These
include using multiple types of assessment to measure the severity of pain;
providing adequate pain relief with a combination of pharmacologic and
nonpharmacologic interventions; and carefully monitoring and documenting the
efficacy of all pain management approaches.
PMID- 9391360
TI - Helpful Websites.
PMID- 9391361
TI - Babygard infant transport.
PMID- 9391362
TI - Relationship of breastfeeding and formula-feeding practices with infant health
outcomes in an urban poor population.
AB - The article reports a study examining symptoms of infection and use of
medications and the health care system by breastfeeding or formula-feeding urban
poor mothers. A prospective, self-report design was used. Mothers completed a
demographic and anthropometric questionnaire, an infection checklist, and a
medication and health care system survey. Results showed that more of the
breastfeeders were white, older, and economically better off than formula
feeders. Scores on the infection checklist were higher for those feeding their
infants by bottle. Colds, rashes, episodes of vomiting, ear infections, colic,
and health care utilization were less frequent for breastfed infants. This small
study suggests that there is a protective effect of breastfeeding in this
population and provides a basis for larger epidemiologic and cross-sectional
studies.
PMID- 9391363
TI - Breastfeeding education for early discharge: a three-tiered approach.
AB - Discharge teaching has presented many challenges since 48-hour stays have become
routine for uncomplicated obstetric patients and their term infants. Sleepy
infants, lack of maternal psychologic readiness, and lack of a full milk supply
may frustrate efforts to teach breastfeeding during this limited time frame. The
key is to develop a three-tiered teaching approach that includes affective,
psychomotor, and cognitive learning during the antepartum, immediate postpartum,
and long-term postpartum course. This approach focuses on: (1) the mother's
critical concerns and the infant's critical biologic needs during breastfeeding
initiation and (2) a collaborative approach that enhances the overall success of
breastfeeding continuation.
PMID- 9391364
TI - Combining breastfeeding and employment: increasing success.
AB - As more families recognize the tremendous advantages of breastfeeding, more
mothers are choosing to continue breastfeeding when they return to an employment
setting. Using a chronological format, this section describes strategies health
care providers can use to assist employed mothers to prepare for continued
breastfeeding, develop skills needed to continue breastfeeding, overcome
challenges, and successfully meet their breastfeeding goals. Numerous
charts/tables that can be shared with mothers are included.
PMID- 9391365
TI - Comparison of confidence between mothers who breastfed and formula fed their
preterm infants.
AB - Mothers develop confidence to care for their preterm infants in challenging
situations. To date no studies have explored the effects of choice of feeding
method on the development of maternal confidence in the preterm population. A
descriptive, longitudinal design was used to explore the demographic
characteristics of a convenience sample of 173 maternal-preterm infant dyads to
examine whether confidence increased over time and to compare levels of
confidence between mothers who formula fed and mothers who breastfed their
preterm infants. There were no significant differences between feeding groups in
maternal confidence; however, maternal confidence within each group increased
significantly over time.
PMID- 9391366
TI - Cup feeding the newborn: what you should know.
AB - Cup feeding is gaining increased recognition as an alternative method of feeding
infants breast milk. For the term infant, cup feeding is suggested when the
mother is unavailable to put the infant to breast. In the preterm population, cup
feeding may be initiated before the preterm infant is ready to be put to the
breast. Although further research is needed to substantiate the proposed benefits
of cup feeding, the article provides information about selecting the appropriate
candidates for cup feeding and offers step-by-step instructions to ensure that
cup feeding is done safely.
PMID- 9391367
TI - Maternal feelings after cessation of breastfeeding: influence of factors related
to employment and duration.
AB - The purpose of this study was to measure feelings following weaning in women
planning employment within 1 year postpartum and to examine the effects of
factors related to duration and employment on these feelings. No significant
differences in feelings of sadness, anger, guilt, and relief were reported by
women who weaned due to mother-led reasons or baby-led reasons or in women who
did or did not meet their breastfeeding goal. Women who did not feed their babies
as planned when employed, however, felt significantly more sadness/depression and
guilt compared to women who achieved their planned method of feeding.
PMID- 9391368
TI - Minimizing infant exposure to and risks from medications while breastfeeding.
AB - The advantages of breastfeeding to the mother and newborn are many. Lactating
mothers frequently ask about the safety of taking medications and the risk to
their newborn. It is well established that all drugs are excreted into breast
milk. However, most medications appear in only small amounts within the breast
milk. With the availability of numerous resources on drug use while
breastfeeding, a medication can be identified as contraindicated or compatible
with breastfeeding. By understanding the anatomy of the breast, principles of
lactation, and drug passage into breast milk, an approach to minimize the
transfer of the medications in the breast milk to the newborn can be developed.
The plan should usually support and encourage the mother to continue to
breastfeed her infant.
PMID- 9391369
TI - Nurse practitioner descriptions for primary care centers: opportunities for
ownership.
AB - The drastic shift in health care delivery and the accompanying emphasis on health
care outcomes has contributed to a rapid proliferation of nurse practitioner
services. Prepared as advanced practice nurses with specific assessment skills,
primary care nurse practitioners have the opportunity to be participant players
rather than observers in business negotiations. To gain a market share of the
expanding field, these nurses must assert their position on establishing primary
care centers. This qualitative study focused on nurse practitioner descriptions
of their needs in a university primary care group practice. Four major response
patterns, Vision, Structure, Incentives, and Significance, were clarified by
multiple themes defined by explanatory elements for a research-based topology to
guide nurse practitioners and schools into positions of ownership of primary care
centers in interdisciplinary partnerships.
PMID- 9391370
TI - Put prevention into practice. Alcohol and other drug abuse.
PMID- 9391371
TI - A comparison of conventional percussion and auscultation percussion in the
detection of pleural effusions of hospitalized patients.
PMID- 9391372
TI - Dermatology on the Internet.
PMID- 9391373
TI - Clinical health problem: failure to thrive.
AB - Families in which NOFTT is present need interventions that target behaviors and
identify stressors that contribute to decreased caloric intake. A holistic
approach to the situation is required, to deal with considering the problem which
may stem from multiple sources. Maternal perceptions of health and diet can be
influenced by the practitioner in a sensitive manner, encouraging balance. Infant
feeding difficulties can be identified by the practitioner and appropriate
referrals can be made to FTT clinics that are experienced in working with these
infants and their caregivers. Public health nurses can be utilized to further
assess families, follow up on health teaching, and provide referrals to community
resources to alleviate stressors. Management of NOFTT by a practitioner in the
primary care setting is feasible and cost-effective.
PMID- 9391374
TI - After four years, it's back to being 'just' a member. Interview by Tina Steger
Gratz.
PMID- 9391375
TI - AIM--helping Michigan children get their immunizations.
PMID- 9391376
TI - Legislative liaison: is it for me?
PMID- 9391377
TI - Survey results offer insight.
PMID- 9391378
TI - Direct Medicare reimbursement for NPs, CNSs takes effect Jan. 1.
PMID- 9391380
TI - Nursing reaches out to the media.
PMID- 9391381
TI - Cost or quality?
PMID- 9391379
TI - ANA quality indicators: meaningful measurement.
PMID- 9391382
TI - For health-care reform, call a nurse.
PMID- 9391383
TI - Trends affecting nursing and patient care in hospitals.
PMID- 9391384
TI - Acute care surgical nurses during downsizing: stress, self-esteem, and social
intimacy.
PMID- 9391385
TI - ASTP addresses transplant issues for decade ahead with position paper .
PMID- 9391386
TI - Chloramines in municipal water: considerations for dialysis facilities.
PMID- 9391387
TI - Getting it right: how to design your water treatment system from the ground up.
PMID- 9391388
TI - Drug resistant organisms and their implications for the outpatient dialysis
setting.
AB - Ever since antibiotics have been used to combat infection, resistance to them has
also developed. The elderly and immunosuppressed populations found in today's
dialysis facility comprise a group at risk for acquiring infection caused by drug
resistant organisms. By utilizing antibiotics prudently and developing infection
control strategies based on the disease/organism epidemiology, mode of
transmission and individualized needs of the patient as well as the care setting,
the proliferation of drug resistant organisms may be curtailed.
PMID- 9391389
TI - Study points to latex glove permeability.
PMID- 9391390
TI - Anemia guidelines suggest iron as missing link in managing hematocrits .
PMID- 9391391
TI - National program hopes to improve outcomes for ESRD patients with indicator tool.
PMID- 9391392
TI - Hiring renal RNs: start with love, compassion.
PMID- 9391393
TI - Local networks essential for success in implementing global capitation.
PMID- 9391394
TI - Looking to the future for renal care. Randolph highlights plans for one-year term
as NRAA president.
PMID- 9391395
TI - Rehabilitation on the other side of the world. Hong Kong encourages ESRD patients
to stay healthy with exercise.
PMID- 9391396
TI - Fitness training: an ongoing effort.
PMID- 9391397
TI - Telemedicine project looks to improve ESRD care, lower costs. TRC/Georgetown
University Medical Center begin two-year experiment.
PMID- 9391399
TI - ASN at 30.
PMID- 9391398
TI - Focus on pre-dialysis logical, but how will nephrologists define it?
PMID- 9391400
TI - Council of American Kidney Societies predicts "critical shortage" of
nephrologists by 2010.
PMID- 9391401
TI - Why choose nephrology?
PMID- 9391402
TI - Is there a nephrologist in the house?
PMID- 9391403
TI - How will we manage ESRD patients in the future?
PMID- 9391404
TI - Rekindling the flame.
PMID- 9391405
TI - Control of drug resistant organisms in the outpatient dialysis unit.
PMID- 9391406
TI - Reshuffling the ESRD food chain.
PMID- 9391407
TI - Bureaucracy a major discouragement in getting ESRD patients back to work.
PMID- 9391408
TI - IDPN: is there a future?
PMID- 9391409
TI - What are the options beyond IDPN?
PMID- 9391410
TI - Latest look at Canadian register data shows lower mortality among PD patients.
PMID- 9391412
TI - Dearing. So what?
PMID- 9391413
TI - Lesson-planning.
PMID- 9391411
TI - Canadian Association to launch on-line dialysis course in January '98.
PMID- 9391414
TI - Marshalling the arguments for community practice teachers.
PMID- 9391415
TI - Choosing your first post.
PMID- 9391416
TI - Health promotion in professional practice.
PMID- 9391417
TI - Recording what you learn from reading.
PMID- 9391418
TI - What's the point of ... systematic reviews?
PMID- 9391419
TI - Gems of thought from Florence Nightingale.
PMID- 9391420
TI - Gelastic epilepsy. A case study of neurological disorder.
PMID- 9391421
TI - Discipline and interpersonal relations in operation theatre.
PMID- 9391422
TI - SCNA peer assistance program in nursing.
PMID- 9391423
TI - Promoting ethics in the acute care setting.
PMID- 9391424
TI - Trust, too valuable to lose.
PMID- 9391425
TI - Tips on getting a good start in a new job.
PMID- 9391426
TI - Enhancing student learning and employee health through university-community
partnerships.
PMID- 9391428
TI - Spiritual care: a challenge for the occupational health nurse.
PMID- 9391427
TI - Ambulatory care: changing roles for school nurse.
PMID- 9391429
TI - Depositions: what you need to know.
PMID- 9391430
TI - Writing for publication: a primer.
PMID- 9391431
TI - Medicare reimbursement for NPs and CNSs to be a reality, January 1, 1998.
PMID- 9391432
TI - Nursing ethics at the juncture of two kinds of care.
PMID- 9391433
TI - Theories of justice and care: a paradigm for nursing ethics.
PMID- 9391434
TI - New frontiers in health care decision-making: information, decision-making, and
divided loyalties.
PMID- 9391435
TI - Failure of the cure model in intensive care.
PMID- 9391436
TI - Calling all schools of nursing: we want to know about death.
PMID- 9391437
TI - Legal nurse consulting in South Carolina--emergence of a nursing specialty and an
innovative educational program.
PMID- 9391438
TI - Making the decision to change careers.
PMID- 9391440
TI - Patient advocates speak out about unsafe care and whistle-blowing retribution.
PMID- 9391439
TI - The return of health care inflation meets preventive care.
PMID- 9391441
TI - The Wellness celebration: a community-wide approach to health promotion.
PMID- 9391442
TI - Greenwood nurses support a partnership of caring people.
PMID- 9391443
TI - Don't become extinct, wear a helmet!
PMID- 9391444
TI - Caring for the Korean-American community.
PMID- 9391445
TI - Parish nursing: caring for the community.
PMID- 9391446
TI - SCNA papin column: hope for addicted nurses.
PMID- 9391447
TI - The seduction of Ethel.
PMID- 9391448
TI - Not for profit or for profit health care does it really matter?
PMID- 9391449
TI - Human relations weakness--a leading cause of unsuccessful job campaigns.
PMID- 9391450
TI - Survey results SCNA Ethics Committee.
PMID- 9391451
TI - Nurses express views on health care reform.
PMID- 9391453
TI - SCNA CEAC Column: selling nursing.
PMID- 9391452
TI - Transfusion of red blood cells/platelets. The State Board of Nursing for South
Carolina.
PMID- 9391454
TI - PAPIN column--program for impaired nurses.
PMID- 9391455
TI - The Cowboy Model of reform.
PMID- 9391456
TI - Janice Weinberg's Career Clinic: mail vs. telephone--how should you initiate
contact with your targeted employers?
PMID- 9391457
TI - The impact of managed care on a state agency.
PMID- 9391458
TI - The times they are a changin'.
PMID- 9391459
TI - The role of the clinical nurse specialist in a managed care environment.
PMID- 9391460
TI - Patient Safety Act.
PMID- 9391461
TI - The times they are a'changing.
PMID- 9391462
TI - The chemically dependent nurse and intervention.
PMID- 9391463
TI - Managed care or terrorism? You be the judge.
PMID- 9391464
TI - Are you committing strategic resume errors that can sabotage your job-search
campaign?
PMID- 9391465
TI - Advanced practice nursing.
PMID- 9391466
TI - Work force diversity: nursing perspectives.
AB - All too frequently, diversity is viewed negatively or, at best, neutrally. The
challenge of diversity is one of embracing it. The extent to which we are
successful in meeting this challenge will determine South Carolina's and
America's competitiveness and effectiveness in health care and in the global
marketplace. Although much of the focus of this article has been work force
diversity within nursing, attention to diversity is applicable within all health
services markets, where human resources is the primary conduit for progress.
Therefore, elements of this report can be generalized to all health care
providers, where racial under-representation, in comparison to the populations
served, is present.
PMID- 9391468
TI - Nursing education in transition.
PMID- 9391467
TI - "Promoting cultural competence in the baccalaureate nursing student".
PMID- 9391469
TI - Nursing workforce planning: the RWJF Colleagues in Caring Project.
PMID- 9391470
TI - RNs voice critical concerns about patient care.
PMID- 9391471
TI - What is N-STAT?
PMID- 9391473
TI - How to get elected to a state position voted on by the entire SC General
Assembly.
PMID- 9391472
TI - The Patient Safety Act of 1996 (H.R. 3355).
PMID- 9391474
TI - Office of public health nursing--SC DHEC.
PMID- 9391475
TI - Clinical ethics and the South Carolina nurse.
PMID- 9391477
TI - Emerging infectious diseases: a challenge to nurses.
PMID- 9391476
TI - Medical reform: the long and short of it.
PMID- 9391478
TI - Disease reporting: the first step in surveillance.
PMID- 9391479
TI - HIV/AIDS in aging: concerns and challenges.
PMID- 9391480
TI - Scientific and cultural exchange trip to China.
PMID- 9391481
TI - Who's taking care of mama?
PMID- 9391482
TI - Delegation: concepts and decision-making process.
PMID- 9391483
TI - American Nurses Association position statement on home care for mother, infant
and family following birth.
PMID- 9391484
TI - HIV, hepatitis--B, hepatitis--C, blood-borne diseases nurses' risks, rights, and
responsibilities.
PMID- 9391485
TI - Clinical ethics and the South Carolina nurse.
PMID- 9391486
TI - Re-engineering--threat of opportunity?
PMID- 9391487
TI - Educational technologies in the information age.
PMID- 9391488
TI - Nursing informatics--application to clinical practice.
PMID- 9391489
TI - Information management in nursing.
AB - The information technology environment is here to stay. Computers are the devices
being used to manage the extension of care out of hospitals and into the
community. Nurses are the focal point of clinical documentation because they
access patient data most often. Nurses know what information is needed and seek
ways to collect that information. Nurses can dictate the type of data collected
and how that data is presented to allow the most appropriate, well-informed
decisions possible. Nurses have the knowledge to make decisions, and with
information management skills, we will have the means to communicate that
knowledge to others.
PMID- 9391490
TI - A practice model for nursing in developmental disabilities.
PMID- 9391491
TI - Applications for ultrasonography in the emergency department.
AB - The primary emergency applications of diagnostic ultrasonography are now
reasonably well defined. Basic characteristics of the emergency department
examination, including its rapid and highly focused nature, determine both the
limitations and advantages of this technique. As greater experience and more
advanced technologies develop in the emergency department setting, the role of
ultrasonography will likely expand into areas that are not generally practiced
today. Doppler technology, especially, promises to provide the emergency
department physician of the future an even more powerful tool for the rapid
diagnosis of a variety of common and critical conditions.
PMID- 9391492
TI - Cardiac ultrasonography.
AB - The use of cardiac ultrasonography in the emergency department currently has two
primary indications: determining the presence of cardiac tamponade and
determining cardiac activity in patients with apparent pulselessness. Physicians
are able to recognize both conditions after appropriate, but not overextensive,
training sessions. The evaluation of penetrating trauma, acute myocardial
infarction, and severe shock of uncertain origin require a higher degree of
training and experience. All of these conditions are discussed in this article.
PMID- 9391493
TI - Ultrasonography in blunt abdominal trauma.
AB - This article discusses studies of the use of ultrasound in patients with blunt
abdominal trauma, both in initial assessment and ongoing evaluation. Reviews of
studies of children and adults to detect the presence and extent of
hemoperitoneum and organ injuries are presented. Ultrasound results are compared
with diagnostic peritoneal lavage, computed tomography, clinical course, and
autopsy results. The central question addressed is to what extent can
ultrasonography replace or supplement other techniques, particularly diagnostic
peritoneal lavage, in the assessment of patients with blunt abdominal trauma.
Ultrasound equipment, technique, scoring scales, limitations, and training issues
are also addressed.
PMID- 9391494
TI - Pelvic ultrasonography.
AB - Pelvic ultrasonography is a valuable tool for the emergency physician in the
evaluation of the wide spectrum of pelvic complaints presenting to the emergency
department. The goal of this article is to outline pelvic problems that can be
readily identified by the emergency physician using pelvic sonography early in
the patient's evaluation. A special emphasis is placed on the sonographic
diagnosis of ectopic pregnancy.
PMID- 9391495
TI - Abdominal ultrasonography.
AB - This article focuses on ultrasonographic examinations of the abdomen and
important intra-abdominal pathology. The liver and biliary tree are discussed
first, followed by the use of ultrasonography in diagnosing appendicitis,
ascites, and bowel obstruction. Pyloric stenosis and intussusception, important
pediatric intra-abdominal problems, are also discussed.
PMID- 9391496
TI - Vascular ultrasonography.
AB - Although vascular ultrasonography has been established as an essential diagnostic
tool in many clinical settings, its role in the emergency department patient
population is uncertain. Preliminary reports of emergency physician--directed
ultrasonography are promising. Further studies are needed to establish its
reliability and suitability in the emergency department setting.
PMID- 9391497
TI - Renal ultrasonography.
AB - Renal US is one of several imaging modalities available to the emergency
physician in the evaluation of patients with acute urologic disorders. It offers
excellent anatomic detail without exposure to radiation or contrast agents but
does not assess renal function. It is particularly useful in the evaluation of
renal colic, although its role here may decrease with increasing availability of
helical CT. It also has an important role in excluding bilateral renal
obstruction as the cause of acute renal failure. Doppler renal US is likely to
take on a more prominent role in the evaluation of renal trauma and is the
diagnostic study of choice to rule out renal vein thrombosis. Bedside emergency
renal US performed and interpreted by emergency physicians with limited training
and experience is gaining in use and acceptance. Its role at present is primarily
to identify unilateral hydronephrosis in patients with suspected renal colic.
This role is likely to expand in the future as emergency US use grows and
technology advances. Bedside emergency renal US may eventually be used in the
evaluation of patients with acute renal failure, suspected renal vein thrombosis,
and renal trauma.
PMID- 9391498
TI - Ultrasound detection of foreign bodies and procedure guidance.
AB - As emergency physicians become familiar with the use of ultrasonography, this
safe procedure will likely become a standard technique having multiple uses in
the emergency department. Ultrasonography assists in foreign body localization
and retrieval and is potentially important in applications, such as reliable
endotracheal tube placement, visualization of ingested medication, vascular
access, and drainage of collected fluids.
PMID- 9391499
TI - Credentialing issues in emergency ultrasonography.
AB - The use of ultrasonography, traditionally performed by radiologists, is becoming
increasingly widespread in emergency medicine. Consequently, much debate has
evolved over whether emergency medicine physicians are qualified to provide this
service, and the criteria by which training and credentialing can be achieved.
This article discusses training and credentialing guidelines, paths to becoming
credentialed in emergency sonography, and quality assurance issues. Also,
strategies are proposed for emergency departments seeking to perform emergency
sonography.
PMID- 9391500
TI - Mibefradil--a new calcium-channel blocker.
PMID- 9391501
TI - Two new retinoids for psoriasis.
PMID- 9391502
TI - Emerging and resurgent infections.
PMID- 9391503
TI - Measuring hygiene practices: a comparison of questionnaires with direct
observations in rural Zaire.
AB - To date questionnaire surveys have been the most commonly used instruments to
measure hygiene behaviours related to water and sanitation. More recently, a
number of studies have used structured observations to study practices related to
diarrhoea. During a trial of a hygiene education intervention to reduce diarrhoea
among young children in Bandundu, Zaire, both instruments were used to measure
the disposal of child faeces and various hand-washing practices. Three hundred
families were observed and follow-up interviews performed with 274 (91%) mothers.
At the individual level, agreement between observed and reported behaviour was
little better than might be expected by chance. There was evidence of over
reporting of hand-washing before food preparation (44% vs 33%; P = 0.03), hand
washing before eating (76% vs 60%; P < 0.001) and disposal of the child's faeces
in a latrine (75% vs 40%; P < 0.001). On the other hand, hand-washing before
feeding the child was reported less often than it was observed (7% vs 64%; P <
0.001). Our data are consistent with the hypothesis that, in general, mothers
over-report 'desirable' behaviours. At the same time, our data indicate that open
questions may lead to under-reporting of certain behaviours. The repeatability of
observations at both the individual and population levels remains to be
established.
PMID- 9391504
TI - Issues in the design and interpretation of studies to evaluate the impact of
community-based interventions.
AB - Increasingly, epidemiologists are faced with the need to evaluate the impact of
an intervention that is delivered at the level of a community or cluster of
individuals, rather than at the individual level. This has profound implications
for the design and interpretation of a study to evaluate its impact. We start by
discussing the issues arising in the extension of the randomized double-blind
controlled trial methodology to the evaluation of interventions delivered to
clusters of individuals, or to whole communities, where the unit of randomization
is a cluster of individuals rather than an individual. We then consider
alternative approaches to design, discuss their relative strengths and weaknesses
and present a framework of design options. Finally we propose a pragmatic
approach to evaluation design in this setting. We believe that the answer lies in
the judicious selection of different design elements, combined in such a way that
when the evidence from each is presented together, a clear picture of the impact
of the intervention emerges. We illustrate this using an example from the recent
literature.
PMID- 9391505
TI - Incidence estimates of late stages of trachoma among women in a hyperendemic area
of central Tanzania.
AB - The purpose of this study is to estimate 5-year incidences of conjunctival
scarring and trichiasis, and 10-year incidence of corneal opacities due to
trachoma, using prevalence data from a population sample of 6038 women living in
a trachoma-hyperendemic area of central Tanzania. Previous surveys have
documented the age-specific prevalence of scarring, trichiasis, and corneal
opacities in women in hyperendemic areas. Using the age-stratified prevalences of
these different clinical signs, corresponding incidence rates were estimated.
Transition rates from one sign to the next were also obtained by restricting the
risk group to only women with a specific trachoma sign. Thus, the 5-year
incidence of trichiasis among women with conjunctival scarring, and the 10-year
incidence of corneal opacities among women with trichiasis were estimated.
Incidences of all the signs markedly increased with age. For scarring, 5-year
incidence rates increased from 3.1% in the 15-19 age category to 14.3% for women
between 55 and 59 years. The 5-year incidence of trichiasis ranged from 0.3% in
the 15-19 age category to 7.5% in the age group 55-59. Corneal opacities due to
trachoma were highest in the age group 45-54; the 10-year incidence increased to
2.8%. The 5-year incidence of trichiasis among only women with scars increased
from 3.2% in the 15-19 age group to 15.1% in women in the 55-59 age group. Once
trichiasis is present, almost one-third of the women below 35 and more than 40%
of the women older than 45 will develop corneal opacities in a 10-year interval.
These estimates are important in understanding the dynamics of progression of
trachoma from conjunctival scarring to the potentially blinding signs of
trichiasis and corneal opacities. They provide important information for planning
adequate services in areas where trachoma is endemic and surgery for trichiasis
is a key factor to avoid blindness from trachoma. They also provide clues to the
pathogenesis that may be useful in the development of new methods of control.
PMID- 9391506
TI - Nationwide prevalence study of hypertension and related non-communicable diseases
in The Gambia.
AB - The prevalence of hypertension, diabetes and obesity in The Gambia was assessed
in a 1% population sample of 6048 adults over 15 years of age, 572 (9.5%)
subjects were hypertensive according to WHO criteria (a diastolic blood pressure
(DBP) of 95 mmHg or above and/or a systolic blood pressure (SBP) of 160 mmHg or
above); 325 (5.4%) had a DBP of 95 mmHg or above, and 39 (2.3%) a DBP of 105 mmHg
or above; 428 (7.1%) had a SBP of 160 mmHg or above. By less conservative
criteria (a DBP of 90 mmHg or above and/or SBP of 140 mmHg or above), 24.2% of
subjects were hypertensive. The prevalence of hypertension was similar in the
major ethnic groups and in urban and rural communities. Age and obesity were risk
factors for hypertension; female sex was an additional risk factor for diastolic
hypertension. Several communities had a prevalence of diastolic hypertension
double the national rate, and significant community clustering of diastolic
hypertension (P < 0.01) was confirmed by Monte Carlo methods. Genetic and/or
localized environmental factors (such as diet or Schistosoma haematobium
infection), may be involved 140 (2.3%) subjects were obese. Obesity was
associated with female sex, increasing age, urban environment, non-manual work
and diastolic hypertension. Only 14 (0.3%) subjects were found to be diabetic.
Hypertension appears to be very prevalent in The Gambia, with a substantial
population at risk of developing target organ damage. Further studies to
delineate this risk and appropriate interventions to reduce it are needed.
PMID- 9391507
TI - Resistance of falciparum malaria to chloroquine and sulfadoxine-pyrimethamine in
Afghan refugee settlements in western Pakistan: surveys by the general health
services using a simplified in vivo test.
AB - Surveys of drug resistant falciparum malaria were conducted in several Afghan
refugee settlements, distributed over a 700 km range in western Pakistan, during
the transmission seasons of 1994 and 1995. Symptomatic malaria patients were
recruited by a process of passive case detection at the refugees' basic health
units. To facilitate follow-up by local health workers, a modified version of the
WHO extended in vivo test was adopted in which blood smears were taken from each
subject, and clinical symptoms recorded, at weekly intervals. Resistance to
chloroquine and sulfadoxine-pyrimethamine was identified in every settlement. The
frequency of chloroquine resistance ranged from 18% to 62%. Resistance occurred
mostly as RI, with RII resistance never exceeding 11%. Resistance to sulfadoxine
pyrimethamine occurred at much lower frequencies, ranging from 4% to 25%. There
was a resumption of clinical symptoms at the onset of parasite recrudescence in
over 90% of cases. The policy of using chloroquine as first-line treatment might
be changed in favour of sulfadoxine-pyrimethamine in most camps and areas of
western Pakistan. The modified in vivo test was almost as accurate as the normal
WHO in vivo test in identifying the grade of resistance, and should prove a
useful tool for the monitoring of resistance to common antimalarials by district
health services.
PMID- 9391508
TI - Optimizing the malaria data recording system through a study of case detection
and treatment in Sri Lanka.
AB - The potential of using malaria incidence data routinely collected from endemic
regions for disease control and research has increased with the availability of
advanced computer-based technologies, but will depend on the quality of the data
itself. We report here an investigation into the relevance of malaria statistics
provided by the routine data collection system in Moneragala, a rural malaria
endemic region in Sri Lanka. All patients (n = 321) treated for malaria in 2
clusters of health care centres (HCCs) of both the private and the public sector
in the administrative regions of Moneragala and Buttala Divisional Secretariat
(D.S.). Divisions were studied in December 1995/ January 1996. The catchment area
of these HCCs included a population resident in 53 Grama Niladhari (GN) areas,
the smallest administrative units of the country. Almost equal numbers of malaria
patients were detected and treated at Government and private health care
institutions, and in 70% of them treatment was based on a diagnosis confirmed by
microscopy. The routine data recording system, however, included only statistics
from the Government sector, and only of patients whose diagnosis was
microscopically confirmed. In compiling data, the origin of a case of malaria is
attributed to the D.S. Division in which the institution (at which the patient
was treated) was located, rather than the area in which the patient was resident,
which was inaccurate because 90% of malaria patients sought health care at
institutions located closest to their residence, thus crossing administrative
boundaries. It also led to a loss of resolution of spatial data because patients'
addresses recorded at the Government HCCs to the village-level are replaced in
the statistics by the D.S. Division, which is a coarse spatial unit.
Modifications to the system for malaria case recording needed to correct these
anomalies are defined here. If implemented, these could result in major
improvements to the quality of data, a valuable resource for the future of
malaria control. The paper reiterates the call for the use of a standard spatial
unit within a country to facilitate exchange of data among health and other
sectors for the control of tropical diseases.
PMID- 9391509
TI - Konzo associated with war in Mozambique.
AB - We report an epidemic of konzo, symmetric spastic paraparesis associated with
cassava consumption and cyanide exposure: 384 patients were treated in
rehabilitation centres; the prevalence rate in a badly affected area was 30/1000.
Most patients were children over 3 and women. Owing to war, communities turned to
bitter cassava as their staple and took shortcuts in its processing. When the war
ended, they continued to depend on inadequately processed bitter cassava. The
epidemic lasted 2 years (the last year of war and the first of peace) with peaks
each year during the cassava harvest. Although most cases were reported from
rural inland areas, patients also came from small towns and the coast. School
children had raised urinary thiocyanate and linamarin and low inorganic sulphate
concentrations. Urinary thiocyanate values were lower than those previously
reported in konzo epidemics, probably because we collected specimens before the
cassava harvest and epidemic peak. The necessary conditions for konzo were
present: intensive cultivation of bitter casava, insufficient processing, a
probable high cyanide intake, and a low intake of protein-rich foods.
PMID- 9391510
TI - High prevalence of mutations in the dihydrofolate reductase gene of Plasmodium
falciparum in isolates from Tanzania without evidence of an association to
clinical sulfadoxine/pyrimethamine resistance.
AB - Recently the efficacy of sulfadoxine/pyrimethamine (S/P) in treatment of
uncomplicated falciparum malaria in Tanzania has been seriously compromised by
the development of resistance. The occurrence of active site mutations in the
Plasmodium falciparum gene sequence coding for dihydrofolate reductase (DHFR) is
known to confer resistance to pyrimethamine. This study investigates the
occurrence of these mutations in infected blood samples taken from Tanzanian
children before treatment with S/P and their relationship to parasite
breakthrough by day 7. The results confirm the occurrence of one or more DHFR
mutations in all the samples, but no relationship was found with the presence of
parasites in the blood at day 7. The results suggest that alterations in the
coding region for dihydropteroate synthetase (DHPS), the enzyme target for
sulfadoxine, should be studied in order to predict resistance to the S/P
combination. It has been proposed earlier that sulfadoxine could itself act on
DHFR, because of a false dihydrofolate produced by drug metabolism through DHPS
and dihydrofolate synthase. The results of this treatment study suggest that such
a possibility is unlikely.
PMID- 9391511
TI - Maternal nutrition and socio-economic status as determinants of birthweight in
chronically malnourished African women.
AB - The birthweight is the most important determinant of mortality and morbidity in
the neonatal period and may have an influence on health in adult life. The high
rate of low birthweight in developing countries is therefore a major health
problem. Maternal malnutrition is usually assumed to be a causal factor but other
environmental factors are also involved. In this study we analysed maternal
nutritional and socio-economic factors as determinants of birthweight in term
infants from a rural African society characterised by a high rate of chronic
malnutrition. Relations of maternal weight, gestational weight gain, parity,
socio-economic status and infant sex with birthweight were analysed in 1,477
women and child pairs. The selected women were followed from early pregnancy and
had an uncomplicated delivery at term of a living singleton child. The
gestational weight gain was 5.6 (SD 6.0) kg and the mean birthweight 2.933 kg (SD
408). Maternal weight, representing the maternal long-term nutritional situation,
was the most important independent determinant of birthweight, accounting for
13.0% of the variance in birthweight. The weight gain, representing the short
term nutritional situation, explained only 5.6% of the variance. Birthweight
increased by 20 g (CI 18-23) for each kg maternal weight and by 15 g (CI 12-18)
for each kg gestational weight gained. The socio-economic difference in birth
weight was 153 g (CI 109-196) 88 of which (CI 48-128) remained unexplained after
adjustment for differences in maternal weight, parity and gender. Improved long
term nutritional situation and living conditions seems to be the most important
prerequisites to counteract low birthweight in developing countries.
PMID- 9391512
TI - Typhoid fever in Ujung Pandang, Indonesia--high-risk groups and high-risk
behaviours.
AB - We performed a hospital-based case-control study to identify high risk groups and
routes of transmission of typhoid fever in the city of Ujung Pandang on the
island of Sulawesi, Indonesia. The annual incidence of this disease in southern
Sulawesi is estimated at 3.1/1000 and the case fatality at 5.1% Cases were 50
patients over 13 years of age admitted to Stella Maris Hospital with a diagnosis
of typhoid fever between June and September 1991. Diagnosis was made on clinical
grounds and in 90% of cases confirmed by a Widal test. Controls were 42 patients
admitted for non-infectious disorders during the same period and individually
matched by age and sex. Controls did not have a history of typhoid fever.
Interviews took place in hospital. Analysis was by unconditional logistic
regression. High-risk groups consisted of those who were single, unemployed and
those who had a university education. Median age of cases was 22 years.
Consumption of food from warungs (food stalls in the street) was strongly
associated with risk (OR = 45). Both cases and controls washed hands after use of
the toilet and before meals, but cases used soap significantly less often (OR =
30). The results of this study can be used to take preventive measures against
this severe disease of educated and single young adults by targetting them for
IEC-activities emphasizing the importance of thorough hand-washing and the need
to take care in the selection of street-foods.
PMID- 9391513
TI - Evaluation of Amplicor- and IS6110-PCR for direct detection of Mycobacterium
tuberculosis complex in Singapore.
AB - One hundred and seventy-eight samples from 168 individuals were tested for
Mycobacterum tuberculosis complex (Mtc) using Amplicor PCR, IS6110-PCR (in
house), acid fast (AF)-staining and culture. Thirty-one samples were positive by
culture, but 37 samples were later resolved to be truly positive for Mtc. Of
these, Amplicor detected 32 (86.5%), IS6110-PCR detected 31 (83.6%), and AF
staining 21 (56.8%). None of the 141 Mtc-negative samples was positive by these
tests, thus giving 100% specificity. Although the IS6110-PCR was more sensitive
than Amplicor in detecting spiked Mtc DNA, it was not more sensitive than the
latter in detecting Mtc in clinical samples. Reasons likely to account for the
PCR false negativity were (i) sample inoculum size, (ii) nonuniform samples due
to clumping effect of Mtc and (iii) the absence of target gene sequences for
IS6110-PCR. Culture negativity, on the other hand, was likely to be associated
with nonviable Mtc. Amplicor PCR is promising for direct detection of Mtc. The
IS6110-PCR, however, may not be as suitable because of possible existence of
IS6110-deleted Mtc strain in Singapore.
PMID- 9391514
TI - Conference report: international conference on HIV and iron, Brugge 1997.
PMID- 9391515
TI - A time to eradicate and a time to control.
PMID- 9391516
TI - Human behaviour and cultural context in disease control.
PMID- 9391517
TI - Human behaviour and cultural context in disease control.
PMID- 9391518
TI - The relevance of anthropology for tropical public health: a historical
perspective.
AB - Despite the fact that tropical diseases have long been linked to human behaviour
and local cultures, the written record of anthropologists involved in the study
of tropical disease is relatively recent. In this article, the authors review how
anthropologists have shifted their focus from the ecological modeling of disease
transmission to the more recent cultural-epidemiological and historical
approaches. The list of authors reviewed does not pretend to be exhaustive but
rather is intended to reveal the co-existence of multiple paradigms in explaining
the emergence of tropical disease within cultures.
PMID- 9391519
TI - What anthropology can contribute to tropical medicine: overview of methods for
control programmes.
AB - In the last two decades anthropologists have begun to carry out studies in
tropical medicine and health scientists have followed with the use of qualitative
methods and techniques that represent a more person-centered view of planning
control programmes. This paper is an overview of selected works by
anthropologists and others that suggest the effectiveness of anthropological
methodology.
PMID- 9391520
TI - Anthropological contributions to a community-based schistosomiasis control
project in northern Cameroun.
AB - This paper describes how anthropological contributions and extensive cooperation
between tropical medicine and medical anthropology researchers contributed to a
successful community-based cost recovery schistosomiasis control project in
northern Cameroun. The project led to increased knowledge about urinary
schistosomiasis by local people, significant decreases in prevalence and
intensity of the disease, and increased utilization of primary health care
centers.
PMID- 9391521
TI - Factors affecting knowledge of the symptoms of schistosomiasis in two rural areas
near Ismailia, Egypt.
AB - The primary method of control of schistosomiasis in Egypt is through passive
chemotherapy, in which people who suspect they have the disease are encouraged to
go to their local health unit to be tested and treated. If people are unable to
recognize the symptoms of schistosomiasis, this strategy may fail. This paper
presents data on local knowledge of the symptoms of schistosomiasis from two
areas recently reclaimed from the desert near Ismailia. Using data from free
listing and triadic comparisons, it is shown that schistosomiasis is primarily
seen as a urinary disease. Factor analysis performed on a series of 12 questions
on the symptoms of schistosomiasis included in a survey demonstrated that
responses group into three patterns, the first stressing constitutional symptoms
such as weakness, the second stressing abdominal symptoms and the third blood in
the urine, burning on urination and blood in the stool. The paper discusses the
implications of these findings for efforts to promote regular treatment with
praziquantel of people living in or near the Nile Delta who are at risk for
intestinal schistosomiasis.
PMID- 9391522
TI - Human behaviour, cost-effectiveness analysis and research and development
priorities: the case of a schistosomiasis vaccine.
AB - Cost-effectiveness analysis has been widely used in the health sector to guide
decisions about where scarce resources aimed at disease prevention or control
should be invested. It has rarely been used to guide decisions about what type of
health research should be funded. In addition, the validity of the behavioural
assumptions underlying the economic analysis is rarely considered explicitly.
This paper explores the use of cost-effectiveness analysis to set priorities for
research using the development of a schistosomiasis vaccine as an example. It
then explicitly considers behavioural factors which might affect the accuracy of
the calculations. A 'product profile' for the new technology is derived which can
be used by developers as a target to aim at. To ensure that the vaccine would be
more cost-effective than the currently preferred option for the control of
schistosomiasis, chemotherapy based on praziquantel, researchers need a vaccine
which has sufficient duration of protection to be delivered as part of the
regular childhood immunization programme me. The cost of adding it to existing
vaccination schedules should not be more than US$4.30 per child in excess of the
cost of one round of chemotherapy. It should, ideally, have an efficacy over 80%.
These results, however, depend on a number of cultural and behavioural factors
which are often ignored in cost-effectiveness studies. For example, low rates of
school attendance would increase the cost of contacting children for a
chemotherapy programme and increase the relative attractiveness of a vaccine. For
chemotherapy to be effective, children also need to comply each year for a number
of years. Falling rates of compliance over time would reduce the effectiveness of
chemotherapy and increase the attractiveness of a vaccine. But on the other hand,
even though a vaccine may still be more cost-effective than chemotherapy at
relatively low levels of vaccine efficacy, if mothers perceived the vaccine to be
ineffective and refused to bring their children for vaccination, the success of
the entire childhood immunization programme could be threatened.
PMID- 9391523
TI - Historical perspective of the use of bowel in urology.
AB - The use of bowel has been used in urinary tract reconstruction for more than a
century. In the past 20 years, however, indications and methods for bowel
utilization have multiplied enormously. This article outlines some of these
exciting developments.
PMID- 9391524
TI - The use of in bowel urology. Metabolic and nutritional complications.
AB - Metabolic and nutritional complications of urinary diversion through bowel or
stomach segments are common, but fortunately, not often severe. When metabolic
abnormalities are problematic, deterioration or baseline insufficiency in renal
function is the most likely cause. Deterioration is most commonly associated with
obstruction or infection. The urologist should be acutely aware of the potential
for metabolic derangements when the prediversion creatinine is greater than 2.0
mg/dL. In this situation, the urologist should employ the basic principles in
this article when planning the procedure in order to minimize metabolic
complications and morbidities. In the setting of significant renal insufficiency,
a short colon or ileal conduit would likely be superior to an ileal or colonic
neobladder, or a diversion, incorporating a large gastric segment. Furthermore,
in the absence of symptomatic metabolic abnormalities, we advocate treatment of
minor laboratory abnormalities, particularly acidosis, to reduce the incidence of
metabolic bone disease. Nutritional and gastrointestinal complications are
treated on an "as needed" basis, with the exception of metabolic bone disease,
which we would hope to prevent with alkalinization and Vitamin C supplementation.
Some of the nutritional and gastrointestinal complications are best avoided by
leaving the ileocecal valve intact, or by minimizing the use of certain segments.
Some evidence exists that over time, histologic changes in the epithelium of
diversion segments may impair absorption and contribute to greater resistance
against metabolic derangements. Whether the changes truly reduce the incidence of
metabolic abnormalities remains to be studied. The ideal, complication-free,
diversion with universal application does not exist; however, the urologist must
strive to select an option that will provide a functional result for the patient
with minimal associated morbidity.
PMID- 9391525
TI - Carcinogenesis. The fate of intestinal segments used in urinary reconstruction.
AB - The actual mechanism for risk of developing cancer in intestinal segments used
for urinary diversion remains uncertain. The clinical and laboratory experiences
are reviewed in this article. The pathogenesis is multifaceted, involving
initiators and promoters of carcinogenesis. Molecular genetic technology may
provide the key to decoding the mechanisms involved.
PMID- 9391526
TI - Stomal construction, complications, and reconstruction.
AB - This article reviews stomal complications and their management. To accomplish
this goal, the authors review techniques used for planning and creating the
stomas for both continent reservoirs and incontinent conduits.
PMID- 9391527
TI - Noncontinent urinary diversion.
AB - When the need for urinary diversion arises, whether from carcinoma of the urinary
tract, malfunction, or malformation, a decision must be made about the type of
diversion to be performed. Currently, the patient and surgeon must decide on
continent versus noncontinent versus neobladder, and on the type of intestinal
segment to be used.
PMID- 9391528
TI - Augmentation cystoplasty.
AB - The past 15 years have been witness to an explosion in the number of
reconstructive procedures using bowel in the urinary tract. As with many concepts
in medicine, one must rely on clinical experience while laboratory models and
other advancements develop. This article attempts to address bladder
reconstruction by enterocystoplasty, as well as the indications for augmentation,
types of procedures available, and the early and late complications.
PMID- 9391529
TI - The Kock pouch urinary reservoir.
AB - The use of detubularized ileum for the Kock pouch produced a low pressure, high
capacity system superior to large bowel segments that provided excellent
continence and protection of the upper urinary tracts. The early enthusiasm was
tempered, however, by the technically demanding aspects of the construction of
the nipple valves, the early and late complications, and occasional
catheterization problems. With simple modifications in the fixation of the
intussuscepted nipples, limiting use of staples and mesh collars, and tapering of
the stoma, much of those problems have been resolved. The nipple valve is
reliable and superior to the tunneled implant for the dilated ureter. With more
widespread indications for continent neobladders, the hemi-Kock reservoir remains
one of the most dependable and stable neobladders.
PMID- 9391530
TI - The Indiana pouch continent urinary reservoir.
AB - The right colon reservoir using a stapled plicated ileal efferent limb (Indiana
continent urinary reservoir) has been demonstrated to be a reproducible durable
form of continent diversion. The overall day and nocturnal continence rate of 94%
compares favorably with all other forms of continent cutaneous diversion.
Carefully following the technique of stapling and plicating the ileal efferent
limb and ileocecal valve as described in this article nearly ensures adequate
competence of the outlet valve. In the rare case in which incontinence occurs, it
is almost always on the basis of high-pressure unit contractions of the
reservoir. On occasion, patients who develop incontinence are observed to have
high pressures within the reservoir despite complete detubularization of the
right colon segment. When this problem is encountered it can be corrected
successfully by adding an ileal patch augmentation to the previously
detubularized reservoir. The issue of ureteral implantation in continent urinary
diversions is as yet unsettled. Many authors have not used ureteral tenial
tunnels and have reported a reflux rate of < 13%. Furthermore, these patients
have not developed any long-term sequelae of their reflux. Although favorable
results have been obtained without creating tunneled tenial reimplantation, we
believe that continent cutaneous reservoirs are almost always colonized with
bacteria, and an antireflux mechanism may offer protection against subsequent
pyelonephritis. Closure of the reservoir traditionally has been conducted by hand
at our institution; however, the development of smaller absorbable
gastrointestinal anastomosis stapling devices offers the theoretic advantage of
shortening the operative time. We anxiously await follow-up, including larger
patient numbers and longer term follow-up of the absorbable staple technique. The
use of continent cutaneous urinary diversion clearly has decreased as bladder
replacement has become a more viable procedure over the past decade. Despite
this, the urologic reconstructive surgeon must maintain the ability to perform
continent cutaneous diversion in patients who are unwilling to accept the
potential for nocturnal incontinence observed in all forms of bladder replacement
as well as the patients who have ineffective sphincter mechanism or who need a
urethrectomy due to their primary disease.
PMID- 9391531
TI - Ileal orthotopic bladder substitutes. What we have learned from 12 years'
experience with 200 patients.
AB - The perfect bladder substitute has not been devised yet. The ileal orthotopic
bladder substitute, however, provides adequate capacity, convenient voiding
patterns, optimal continence rate, preservation of renal function, acid-base
balance, and calcium metabolism. The authors describe important surgical details
based on experience with more than 200 patients. To achieve a good functional
result, patient selection, postoperative voiding reeducation, and meticulous
follow-up are important.
PMID- 9391532
TI - The Mitrofanoff principle in continent urinary reconstruction.
AB - Continent urinary diversion has increasingly become important for treating
children and adults with urinary tract pathology that cannot be managed by direct
reconstructive techniques. The Mitrofanoff principle, a term that has become
synonymous with the flap valve mechanism for promoting the unidirectorial flow of
a fluid medium, is a recapitulation of nature's design for the competent
ureterovesical junction. Construction of a catheterizable channel using this
principle can be performed with a variety of tissues and serves well as a
continence mechanism for either the native bladder or intestinal reservoirs. In
addition to its utility in managing urinary incontinence, implantation of a
catheterizable channel into the cecum can be used to manage fecal incontinence in
patients with neurogenic bowel dysfunction.
PMID- 9391533
TI - Ileal ureter.
AB - Ureteral replacement with ileal bowel segments has become common in the
armamentarium of the reconstructive urologist. The use of ileal bowel
substitution, whether total or segmental, has provided yet another surgical
alternative for renal preservation. The indications, surgical technique, and
results with the ileal ureter are reviewed.
PMID- 9391534
TI - The ileal neobladder to the female urethra.
AB - In the author's opinion, in the properly selected woman undergoing radical
cystectomy for transitional cell carcinoma of the bladder, the ileal neobladder
to the female urethra is a viable option. Ten years of experience with 23
patients have led to a nerve and urethral support cystectomy technique with the
ileal neobladder anastomosed to the proximal urethra. Even then, however,
retention in 20% of patients rather than the expected incontinence is the
critical issue. Incontinence has never been a problem. The advent of orthotopic
lower urinary reconstruction in women is a major achievement in the evolution of
urinary diversion. With our increasing understanding of the continence mechanism
in women and with increasing evidence that the female urethra can be safely
preserved after cystectomy, orthotopic lower urinary tract reconstruction by the
ileal neobladder can now be offered safely not only to men but also to women
undergoing cystectomy with superb functional results.
PMID- 9391535
TI - Use of small and large bowel in renal transplantation.
AB - The continued success of renal transplantation has provided a higher quality of
life for properly selected patients with ESRD. It is also a much more cost
effective and efficient treatment of ESRD compared with chronic dialysis.
Innovative urologic reconstructive surgery using enteric segments for both
continent and incontinent urinary diversions has permitted this therapeutic
modality to be offered to the recipient with lower urinary tract disease not
previously amenable to renal transplantation. These same reconstructive
techniques using ileal segments have also permitted preservation of renal
allografts with previously nonreconstructable renal pelvic or ureteral disease.
PMID- 9391536
TI - Bilateral breast carcinoma versus unilateral disease. Review of 498 patients.
AB - In literature data, an uncertainty exists whether occurrence of bilateral breast
cancer decreases the survival probability of affected patients. Therefore, we
analyzed the medical records of 498 postoperatively irradiated (1977-1982) female
breast cancer patients (T1-4,N0-3,M0). In the follow-up time, in 36 patients a
bilateral breast carcinoma treated by surgery with or without radiotherapy was
found. The 10-year overall survival rates were 54% in patients who had unilateral
disease, compared with 56% in bilateral carcinoma patients, respectively. The
incidence of metastasis did not differ between both groups: 24.2% versus 38.8%.
Eleven percent of unilateral cancers recurred; in the other group, local failure
of the first and second tumor was observed in 19.4% and 11.1%, respectively. We
conclude that the occurrence of bilateral breast cancer has no significant impact
on survival, although the development of local failures and metastases seems to
be more frequent. The therapeutic strategy in bilateral carcinoma should resemble
the treatment procedure in unilaterally affected patients.
PMID- 9391537
TI - The prognostic significance of steroid receptor activity in tumor tissues of
patients with primary breast cancer.
AB - The prognostic significance of steroid-receptor activity is still debatable.
Discrepancies in results are probably attributable to few patients, heterogeneous
patient populations, and short follow-up. We investigated the prognostic
significance of estrogen- and progesterone-receptor (ER and PgR, respectively)
activity as a continuous variable in a homogeneous patient population. The
prognostic significance of steroid-receptor activity was examined in 329 node
negative and 320 node-positive unselected breast cancer patients. In node
negative patients, ER values of primary tumors between 100 and 400 fmol/mg
protein appeared to be a significant predictor for low risk of recurrence,
whereas high ER (> 400) revealed an unfavorable prognosis. The classic cutoff
level of ER (< 10 fmol/mg proteins) had no prognostic significance, however. In
patients receiving adjuvant chemotherapy--the node-positive breast cancer
patients--the classic cutoff value of ER (10 fmol/mg protein) predicts
significantly distant metastases-free survival and overall survival only in the
first 4 years of follow-up after diagnosis. Progesterone receptor is a time
dependent prognosticator in node-negative breast cancer patients (cutoff point
for PgR, 80 fmol/mg). In node-positive breast cancer patients treated with
chemotherapy or a combination of chemo- and hormonal therapy, PgR values lower
than 60 fmol/mg had a worse prognosis. The results show the poor performance of
standard cutoff points for ER and PgR positivity in predicting prognosis. Better
prognosis is related to higher receptor levels but this relation is predominantly
time-dependent. Moreover, patients who have high ER levels have a prognosis that
is worse when compared with intermediate ER levels. Standard cutoff points for
steroid receptors should not be used to select patients for prognosis.
PMID- 9391538
TI - Malignant eccrine spiradenoma. Case report and review of the literature.
AB - Malignant eccrine spiradenoma is an exceedingly rare tumor. A case of a 72-year
old women with this highly aggressive malignancy arising from a long-standing
lower leg lesion is reported. Management during the course of disease included
surgery, radiation therapy (RT), hyperthermic limb perfusion chemotherapy, and
chemotherapy. The patient died of her disease, with widespread metastatic disease
20 months after the diagnosis. A review of the literature is presented, and
treatment considerations are summarized.
PMID- 9391539
TI - Use of the somatostatin analogue octreotide acetate in the treatment of
encephalopathy associated with carcinoid tumor. Case report.
AB - Carcinoid tumors may present in a variety of ways dependent on sites of disease
and ectopic hormone secretion. This case report describes a patient having
metastatic carcinoid tumor who developed encephalopathy of uncertain etiology.
Treatment with the somatostatin analogue octreotide acetate resulted in dramatic
improvement in his mental status. Several plausible mechanisms are discussed.
PMID- 9391540
TI - Hypofractionated radiotherapy with 5-fluorouracil radiosensitization for locally
"far advanced" breast cancer.
AB - Seventeen patients who had locally far-advanced breast cancer were treated with
hypofractionated radiotherapy (4-5 Gy/fraction, twice a week) and concomitant 5
fluorouracil (5-FU 300 mg/m2 intravenously, 1 hour before every radiotherapy
fraction). Fourteen of the seventeen patients had disease that was not responding
to chemotherapy. Early toxicity was low and none developed grade III/IV toxicity.
Two of the seventeen patients showed moist skin desquamation and four of
seventeen had grade II anemia. Of eight patients who survived longer than 12
months, symptomatic breast fibrosis was observed in one (12%), asymptomatic
pericarditis in one (12%) and symptomatic radiation pneumonitis in one (12%).
Plexopathy and arm edema grade II were observed in one patient and two patients,
respectively. Quality of life substantially improved. Complete response was
documented in five of the seventeen patients (29%), with pathologic confirmation
in three. Seven of the seventeen (41%) patients were considered to be partial
responders, four (23%) had a minimal response, and one (6%) progressed during
treatment. Local progression-free survival (1-24 months) was achieved in 12 of 17
patients. Four of the seventeen (23%) patients are alive, with no evidence of
disease (local or distant) 8 to 24 months after radiotherapy. Hypofractionated
chemoradiotherapy with 5-FU is an effective, convenient, and well-tolerated
regimen for far-advanced breast tumors.
PMID- 9391541
TI - Herpetic geometric glossitis in a pediatric patient with acute myelogenous
leukemia.
AB - Herpetic geometric glossitis, a recently described form of lingual herpes simplex
virus type 1 (HSV-1) infection, has been reported in 6 human immunodeficiency
virus (HIV) patients and 1 cardiac transplant patient who was receiving
immunosuppressant therapy. An HIV-seronegative immunocompromised pediatric
patient with acute myelogenous leukemia who developed herpetic geometric
glossitis is described. Herpetic geometric glossitis can present in both adult
and pediatric immunocompromised patients. The symptoms, morphology, laboratory
findings and treatment of this infection are summarized. The possible
consequences of untreated herpetic glossitis include superinfection and
undernourishment. Although previously described patients responded to 1000 mg per
day (divided in 5 doses) or oral acyclovir, with complete resolution of fissures,
this patient developed herpetic geometric glossitis while receiving acyclovir and
required higher doses of oral antiviral therapy (acyclovir, 3000 mg/day divided
in 5 doses) to treat his HSV-1 lingual infection. Empiric treatment of an
immunocompromised patient who has newly acquired painful tongue fissures or
furrows with systemic acyclovir should be considered.
PMID- 9391542
TI - A comparative study of intravenous granisetron versus intravenous and oral
ondansetron in the prevention of nausea and vomiting associated with moderately
emetogenic chemotherapy.
AB - We conducted a prospective, randomized, open, single-center, parallel group study
comparing the anti-emetic efficacy and toxicity of granisetron with that of
ondansetron in patients receiving moderately emetogenic chemotherapy. From
December 1994 to May 1995, patients who were to receive moderately emetogenic
chemotherapy for the first time or who had not received chemotherapy (80 to 100
mg/m2 of cisplatin or 40 mg/m2 of doxorubicin) within 4 weeks previously were
enrolled in this study. The following anti-emetic regimens were used: 3 mg of
granisetron were given intravenously before chemotherapy for a single dose; 8 mg
of ondansetron were given intravenously before chemotherapy and then every 8
hours for a total of 3 doses, plus 8 mg of an oral maintenance dose every 12
hours for 5 consecutive days. We evaluated 97 patients (48 received granisetron
and 49 received ondansetron). In the first 24 hours after chemotherapy, complete
and major responses were achieved in 76.6% of the patients receiving granisetron
and in 72.9% of patients receiving ondansetron (p = 0.9033). Additionally, there
was no difference in the control of delayed nausea and vomiting between the two
groups (51.1% versus 54.2%, p = 0.9200), and there were no significant adverse
effects or toxicities. We have concluded that a single dose of granisetron is as
effective in prophylaxis of emesis induced by moderately emetogenic chemotherapy
as a triple dose of ondansetron plus oral maintenance.
PMID- 9391543
TI - Phase II trial of intravenous CI-980 (NSC 370147) in patients with metastatic
colorectal carcinoma. Model for prospective evaluation of neurotoxicity.
AB - CI-980 (NSC 370147)--a synthetic mitotic inhibitor that binds to tubulin at the
colchicine binding site--has significant activity against a broad spectrum of
tumor models and greater in vitro cytotoxicity when given over > 24 hours than 4
hours or less. Phase I studies demonstrated central nervous system (CNS) toxicity
to be dose-limiting when CI-980 was administered as a 24-hour infusion. When a 72
hour infusion was given, CNS toxicity was reduced and granulocytopenia became the
dose-limiting toxicity. In this phase II study, CI-980, 4.5 mg/m2, was
administered as a 24-hour continuous intravenous infusion for 3 consecutive days
and repeated every 21 days. Fourteen patients who had measurable metastatic
colorectal cancer were entered in the trial. Eight patients had received one
prior chemotherapy regimen for metastatic disease. Patients were prospectively
monitored by neurologic examinations and neuropsychologic assessment of cognitive
functioning. No complete or partial responses were observed. Grade 4
granulocytopenia was the dose-limiting toxicity. Reversible declines in recent
memory function were noted in all patients. After each course of CI-980, there
were also transient non-significant declines in motor coordination, compared with
the preinfusion assessment. At the stated dose and schedule, CI-980 lacks
activity in metastatic colorectal carcinoma. The agent's toxicity profile
(granulocytopenia and CNS effects) was comparable with previously described
effects of this agent.
PMID- 9391544
TI - Secondary syringomyelia due to intramedullary spinal cord metastasis. Case report
and review of literature.
AB - Intramedullary spinal cord metastasis is relatively rare. We describe a patient
having intramedullary spinal cord metastasis associated with syringomyelia,
confirmed by magnetic resonance imaging, in a patient who had poorly
differentiated carcinoma of the lung. The patient responded to treatment with
steroids and radiotherapy, with complete resolution of neurologic symptoms and
syringomyelia.
PMID- 9391545
TI - Neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy for
locally advanced esophageal carcinoma with bulky upper abdominal lymphadenopathy.
Case report.
AB - A 60-year old male patient who had locally advanced esophageal carcinoma with
bulky upper abdominal lymphadenopathy underwent neoadjuvant chemotherapy
consisting of 5-fluorouracil (5-FU) and cisplatin (CDDP), followed by concurrent
radiotherapy and chemotherapy using protracted low-dose continuous infusion of 5
FU and CDDP. The treatment brought about complete remission in the primary lesion
and good partial remission in the upper abdominal lymphadenopathy. He
subsequently underwent trans-hiatal esophagectomy after one cycle of adjuvant
chemotherapy because local recurrence was suspected. Histopathologic study of the
resected specimen demonstrated no malignant tissue in the primary lesion and the
lymph nodes. The patient is still alive and disease-free at 26+ months. This
result suggests that neoadjuvant chemotherapy followed by concomitant
chemotherapy and radiotherapy for patients who have locally advanced squamous
cell carcinoma of the esophagus with intensive abdominal lymphadenopathy may
offer some chance for sterilization of local and regional metastases and longer
survival.
PMID- 9391546
TI - The heterogeneity of leukemia occurring after treatment for sarcoma.
AB - The successful treatment of sarcomas with intensive regimens combining high-dose
chemotherapy and irradiation has led to not only improved survival but also to an
increased incidence of therapy-related acute non-lymphocytic leukemia (t-ANLL)
and myelodysplastic syndrome (MDS). We report 4 patients having sarcoma treated
with chemotherapy or chemoradiotherapy who subsequently developed MDS or t-ANLL.
PMID- 9391547
TI - Contamination of the pleural surfaces in childhood sarcoma. Use of colloidal P-32
to reduce radiation dose to the whole lung.
AB - Children with pulmonary sarcomas who have diffuse contamination of the pleural
cavity present a difficult management problem for the radiation oncologist. Doses
required to control even microscopic disease exceed lung tolerance. We report on
the use of intracavity colloid P-32 in an attempt to treat the pleural surface
and spare normal lung parenchyma and tissues of the chest wall. Three children-
18 months, 12 years, and 3 years of age--had spillage of pulmonary sarcomas into
the chest cavity. All children were treated with systemic chemotherapy.
Initially, 0.5 mCi of technetium sulfur colloid (99mTc-sulfur colloid) was
instilled into the pleural space to ascertain even distribution of isotope. This
was then followed by installation of 5.0 mCi of colloidal P-32. Uniform
distribution was then confirmed by bremsstrahlung scanning. All three patients
are in complete remission 3.5 years, 3 years, and 1 year after treatment,
respectively. The major toxicity was asymptomatic pleural thickening, which could
be confused with disease. This was confirmed histologically to be fibrous in the
first patient. The process diminished or stabilized with time in all 3 patients
over the period of observation. In this small series, intrapleural colloidal P-32
appeared to be safe and well tolerated and would be expected to be less toxic
than wide-field external beam in the treatment of spilled pulmonary sarcomas.
PMID- 9391548
TI - Predicting drug interactions in vivo from experiments in vitro. Human studies
with paclitaxel and ketoconazole.
AB - This study was performed to evaluate whether concomitant treatment with
ketoconazole could reduce the clearance of paclitaxel given to ovarian cancer
patients. Paclitaxel, 175 mg/m2, was given as a 3-hour continuous intravenous
infusion and repeated every 21 days. Initially, ketoconazole, 100 to 1600 mg, was
given as a single oral dose 3 hours after paclitaxel. Later, ketoconazole, 200
mg, was given perorally 3 hours before paclitaxel. Plasma drug concentrations
were measured by high-pressure liquid chromatography (HPLC), and cytochrome P450
3A (CYP3A) activity was measured with the erythromycin breath test (ERMBT).
Ketoconazole did not alter plasma concentrations of paclitaxel or its principal
metabolite, 6 alpha-hydroxypaclitaxel. Although there was marked inter- and
intrapatient variability in ketoconazole pharmacokinetics, peak plasma
concentrations in all but one course were below the 50% inhibitory concentration
(IC50) point determined for inhibition of paclitaxel metabolism in vitro.
Therefore, paclitaxel and ketoconazole can be coadministered safely without dose
adjustments. There was no correlation between ERMBT measurements and serial
plasma concentrations of paclitaxel. The erythromycin breath-test measurements
did correlate with the corresponding ketoconazole plasma concentrations. The
erythromycin breath test is a valuable tool for measuring instantaneous CYP3A
activity in vivo. This clinical study confirms the results of prior studies with
human-derived materials in vitro, reinforcing the notion that such studies are
useful predictors of drug pharmacokinetics and interactions in vivo.
PMID- 9391549
TI - Comparison of patient characteristics and outcome between a single-institution
phase II trial and a cooperative-group phase II trial with identical eligibility
in metastatic melanoma.
AB - Differences in overall survival and response rates are often noted when promising
single-institution phase II treatment regimens are evaluated in a cooperative
group setting. One reason for this discrepancy may be the differences in patient
characteristics at the time of registration. In the metastatic melanoma
literature, the prognostic factors for survival that are most frequently
identified are the number of metastatic sites, visceral involvement, performance
status, liver involvement, and possibly the disease-free interval and gender. A
prognostic factor for response appears to be sites of involvement. A comparison
of patient characteristics and outcome was conducted for patients entered in
similar phase II melanoma trials at a single institution versus those in a
cooperative group. Sixty-four patients at Wayne State University (WSU) were
compared with 96 patients who had nearly identical eligibility criteria and were
registered in the Southwest Oncology Group (SWOG). All patients were receiving
comparable phase II treatments for metastatic melanoma. Southwest Oncology Group
patients were significantly older (p < 0.001), had worse performance status (p =
0.03), had more visceral involvement (p = 0.001), and were more likely to have
two or more metastatic sites (p = 0.02). No significant differences in gender (p
= 0.55), absence or presence of liver involvement (p = 0.12), or disease-free
interval were noted. These disparities, despite similar eligibility, may partly
explain the observed differences in survival (WSU median = 10 months, SWOG median
= 7 months; p = 0.13) and response rates (WSU = 31%, SWOG = 15%; p = 0.02)
between the two groups of patients. Investigators should report these important
patient characteristics in treatment reports. These differences highlight the
difficulty in comparing single-institution and cooperative-group phase II trials,
even with comparable patient eligibility. This serves to emphasize the need for
well-designed phase III trials when comparing treatment approaches and
stratification for the prognostic factors identified.
PMID- 9391550
TI - Low serum testosterone and a younger age predict for a poor outcome in metastatic
prostate cancer.
AB - Carcinoma of the prostate gland is one of the most common malignancies in males.
This study was undertaken to determine which factors predict the course and
outcome of patients treated with first line hormonal manipulation. A total of 144
patients with Stage D2 prostate cancer who received androgen deprivation therapy
were studied. Pretreatment parameters analyzed were age, performance status,
analgesia usage, concurrent disease, histologic differentiation, hemoglobin,
leukocyte and platelet count, serum creatinine, alkaline phosphatase, lactate
dehydrogenase, prostate specific antigen, total and prostatic acid phosphatase,
serum testosterone, follicle stimulating and luteinizing hormone levels, number
of metastatic sites and bone scan grade. Only initial serum testosterone (> 10
nmol/l) had a positive impact on response (p = 0.0304), whereas age older than 60
years had a positive impact on time to progression (16 vs. 11 months, p =
0.0414). Both serum testosterone (26 vs. 20 months, p = 0.003), and age (28 vs.
17 months, p = 0.036) had a significant influence on overall survival. Low
testosterone, indicating androgen independence, and a younger age, seem to result
in a more aggressive disease and a poorer prognosis in advanced prostate cancer.
PMID- 9391551
TI - Safety of radiating jejunal interposition grafts in head and neck cancer.
AB - The safety of high-dose postoperative radiation therapy to a jejunal graft has
not been established in the literature. The purpose of the present study is to
review the effect of postoperative radiation on swallow function in patients who
have received a jejunal interposition graft as part of their reconstruction after
cancer resection. Charts of patients undergoing hypopharyngeal resections for
cancers with placement of jejunal interposition grafts who received postoperative
radiation therapy were reviewed. Swallow function was determined from records of
patients' subjective characterization of their swallow function, records of
weights at each visit, use of gastrostomy tube, need for jejunal dilatation and
review of barium swallows. Seventeen patients were identified who had undergone
resection of cancers with jejunal interpositions and postoperative radiation
therapy. Four patients never regained adequate swallow function postoperatively
to allow G-tube removal. The remaining thirteen patients had their G-tubes
removed, generally several months after resection, and were able to obtain
adequate nutrition orally to maintain or increase their weights. The present
series suggests that a segment of jejunum transferred into the neck after
laryngopharyngoesophagectomy can be irradiated to high dose with generally
acceptable morbidity.
PMID- 9391552
TI - Continuous infusion of carboplatin during conventional radiotherapy treatment in
advanced squamous carcinoma of the cervix uteri IIB-IIIB (UICC). A phase I/II and
pharmacokinetic study.
AB - OBJECTIVE: A prospective, single-arm phase-I/II trial performed to assess the
efficacy and toxicity of the concomitant use continuous infusion of low-dose
carboplatin and pelvic conventional radiotherapy in patients with locally
advanced squamous cell carcinoma of the cervix. MATERIALS AND METHODS: Between
January and July 1994, a total of 12 patients consecutively diagnosed to have
squamous cell carcinoma of the cervix uteri stages IIB-IIIB UICC-TNM (five
patients, IIB; and seven patients, IIIB) entered the study. All patients were
evaluated by a gynecologist and a radiation oncologist and were submitted to
standard pretreatment staging procedures. Radiation was delivered with 10-MeV
photon beams with the shrinking-field technique. The patients received 2 Gy
radiotherapy daily, 5 fractions per week, up to a planned total of 60 Gy in 6
weeks to the primary tumor and 46 Gy in 4 weeks to the whole pelvis. Irradiation
was performed using four fixed orthogonal fields. One intracavitary insertion, 8
Gy to point A (dose rate, 1.1 Gy/h), was performed immediately after external
pelvic irradiation. Carboplatin (12 mg/m2/day) was also administered in a
continuous infusion, starting 1 day before the first fraction of radiotherapy.
The platinum in plasma and urine, as well as the platinum concentration in the
cytosols of lymphocytes and tumor, was measured weekly. RESULTS: A complete
response was seen in nine (75%) of the 12 patients. Of the nine patients who
achieved a complete remission, only one had subsequent failure in the pelvis. The
total pelvic failure rate was 33.3% (four of 12 patients). With a median follow
up time of 20 months, the actuarial survival rate at 24 months was 64.8%. All
patients completed the treatment without major protocol violations. Grade-2
leukopenia (in nine patients) and grade-1 nausea and vomiting (in five) were the
most common acute toxicities. There was one grade-3 hematologic toxicity. Grade-3
late complications were observed in 16.6% of cases (two of 12 patients). On days
28 and 42 of the treatment, the mean total platinum plasma concentrations were
491 micrograms/L (SD = 129) and 672 micrograms/L (SD = 160), and the
ultrafilterable fraction was 8-10%. At the same time points, the concentration in
lymphocytes was constant at 21 picograms (pg) platinum/lymphocyte. The levels of
platinum concentration measured on days 14 and 28 in the cytosols of tumor cells
were 0.3 microgram/g (SD = 0.1) and 0.93 microgram/g (SD = 0.2). CONCLUSION: The
combination of continuous infusion of carboplatin and radiotherapy at the
aforementioned doses in patients with locally advanced cervical carcinoma
resulted in a relatively low frequency of significant acute and late
complications. Platinum in normal tissue (picograms per lymphocyte) was stable
from week 1 of treatment, whereas the platinum steady state in plasma and in
tumor cells was not reached in 6 weeks and was below that required in vitro to
produce radiopotentiation. Further studies to determine the optimal dose of
carboplatin and irradiation are needed prior to the initiation of phase-III
studies.
PMID- 9391553
TI - A phase II study of topotecan administered five times daily in patients with
advanced gastric cancer.
AB - OBJECTIVE: Topotecan (Tpt), a semisynthetic analogue of camptothecin (Cpt), has
shown excellent preclinical activity in a number of solid tumors. Cpt, the parent
compound, has preclinical activity against several gastrointestinal tumors,
including a gastric adenocarcinoma xenograft. A phase-II clinical trial was
conducted to assess the activity to Tpt in patients with advanced gastric cancer.
MATERIALS AND METHODS: 15 patients with advanced, incurable gastric
adenocarcinomas were treated. Tpt 1.5 (mg/m2/day) was administered intravenously
as a 30-min infusion daily for 5 consecutive days. Treatments were repeated on a
21-days cycle. RESULTS: No major objective responses were observed in 13
evaluable patients (response rate = 0%; 95% confidence interval = 0-22%). The
major dose-limiting toxicity in this trial was myelosuppression, which was severe
in this patient population. CONCLUSIONS: Tpt at the dose and schedule studies
does not possess substantial antitumor activity in patient with gastric cancer,
and the toxicities were formidable. We do not advocate further development of
this drug in the treatment of gastric cancer. Tpt has shown more promising
activity and tolerability in other patient populations, and these areas deserve
further exploration.
PMID- 9391555
TI - A rare event of megestrol acetate (Megace)-induced adrenal suppression in a
breast cancer patient.
PMID- 9391554
TI - A phase II trial of amonafide in patients with nonsquamous cell carcinoma of the
cervix. A Gynecologic Oncology Group study.
AB - Twenty-seven patients with nonsquamous cell carcinoma of the cervix were entered
into a Phase II study of amonatide; 24 patients were evaluable for toxicity,
while 23 were evaluable for response. Patients received amonafide, 300 mg/m2,
intravenously for 5 consecutive days every 3 weeks. The median age of patients
was 45 years. All but two patients were completely ambulatory. Twelve patients
had received prior chemotherapy, while 22 had been treated with radiation
therapy. One of 27 (4.3%) patients had a partial response (PR) to this regimen
and 13 (56.5%) had stable disease. Sixteen patients experienced a median white
blood cell (WBC) nadir of 350/mm3, seven developed life-threatening
thrombocytopenia, and one had severe anemia requiring transfusion. Nonhematologic
toxicity was mild. Amonafide had insignificant activity in these patients with
nonsquamous cell carcinoma of the cervix.
PMID- 9391556
TI - Advances in skin cancer. A tribute to Professor Frederick Helm on the occasion of
his 70th birthday.
PMID- 9391557
TI - The actinic keratosis. A perspective and update.
AB - BACKGROUND: Actinic keratosis (AK) is a common sun-induced precancerous neoplasm
confined to the epidermis. It is the initial manifestation of a continuum of
clinical and histologic abnormalities that progresses to invasive squamous cell
carcinoma (SCC), a disorder that accounts for thousands of preventable deaths in
America each year. OBJECTIVE: The purpose of this work is to describe the actinic
keratosis. METHODS: This effort was performed by a literature review and
analysis. RESULTS: Like SCCs, the vast majority of AKs are asymptomatic. Although
some actinic keratoses may become clinically inapparent, possibly either due to
immune rejection or simply having their external surface unknowingly scraped off,
an untreated AK represents a potentially curable fatal cancer. CONCLUSIONS: Each
AK should be treated before it progresses to invasive squamous cell carcinoma.
Destructive modalities such as cryosurgery using liquid nitrogen and
electrodesiccation and curettage are the mainstays of therapy. Each case must be
individualized. LEARNING OBJECTIVES: After studying this article, participant
should be able to: 1. Understand the concept of an actinic keratosis. 2. Learn
how to recognize its clinical manifestations. 3. Be aware of the danger it poses
as an easily curable papulonodule that may become a fatal cancer.
PMID- 9391558
TI - Presence of human papillomavirus DNA and expression of L-fucose moiety in some
vulvar intraepithelial lesions and vulvar squamous cell carcinoma.
AB - BACKGROUND: Human papillomavirus could reside and play an etiological role in
some vulvar epithelial lesions. Human papillomavirus-infected keratinocytes might
have certain biochemical changes that could be of significance in helping
clinical diagnosis or elucidating the pathogenesis of some vulvar epithelial
diseases. OBJECTIVE: To detect the presence of human papillomavirus DNA and
observe the expression pattern of L-fucose moiety in some vulvar intraepithelial
lesions and vulvar squamous cell carcinoma. METHODS: Nineteen cases of vulvar
intraepithelial lesions and 13 cases of vulvar squamous cell carcinoma from the
inner aspect of labia majora or the outer aspect of labia minora were selected.
Polymerase chain reaction was employed to detect the presence of human
papillomavirus DNA in lesional skin. Ulex europeaus agglutinin-1 histochemistry
was used to observe the L-fucose expression pattern. RESULTS: A large proportion
of vulvar intraepithelial lesions had the presence of human papillomavirus DNA,
but the positive rate was low in vulvar squamous cell carcinoma and squamous cell
hyperplasia. L-Fucose expression was much more pronounced in human papillomavirus
DNA-positive lesions than those negative ones. CONCLUSIONS: Human papillomavirus
had an important impact on some vulvar intraepithelial lesions in this Oriental
population. The expression pattern of L-fucose may be used as an indicator for
vulvar keratinocyte transformation by human papillomavirus.
PMID- 9391559
TI - Perianal Paget's disease years after rectal adenocarcinoma removal.
AB - BACKGROUND: Perianal Paget's disease often coincides with anorectal carcinoma,
which extends into the epidermis from a contiguous organ. OBJECTIVE: Our purpose
was to present a patient with perianal Paget's disease who had a rectal
adenocarcinoma excised 14 years previously in another hospital and to determine
whether there is a relationship between the perianal Paget's disease and the
rectal adenocarcinoma. METHODS: We examined the resected specimens of the rectal
adenocarcinoma and the perianal Paget's disease histologically. RESULTS: In the
resected specimen of the rectal adenocarcinoma, Paget cells were present within
the anal epidermis adjacent to the rectal adenocarcinoma. The Paget cells showed
the same histochemical and immunohistological findings as the adenocarcinoma
cells. CONCLUSION: There was a close relationship between the perianal Paget's
disease and the rectal adenocarcinoma. It is probable that the Paget cells were
derived from direct spread from the rectal adenocarcinoma.
PMID- 9391560
TI - Triple extramammary Paget's disease.
AB - BACKGROUND: Triple extramammary Paget's disease (TEPD) has been considered to be
rare in the English literature, and its incidence and characteristics are
unclear. There are many therapeutic options for treating extramammary Paget's
disease (EPD). OBJECTIVE: Our purpose was to investigate how many TEPD cases have
been reported previously and to describe their characteristics. We also describe
the effectiveness of radiotherapy for them. METHODS: We report two TEPD cases,
and summarize previously reported TEPD cases together with our cases. RESULTS:
Twenty-three TEPD cases have been reported previously. Of these, 19 cases have
been in Japan. All but one patient with TEPD were male. Their axillary lesions
often showed no eruptions or very slight erythema. Radiotherapy for our cases was
effective although the effectiveness of radiotherapy is controversial.
CONCLUSION: In genital Paget's disease bilateral axillae should be examined
histologically, even if they show no or slight eruptions. Radiotherapy may be
useful for EPD, particularly axillary Paget's disease.
PMID- 9391561
TI - Identification of melanoma risk factors in the Polish population.
AB - BACKGROUND: There is a great deal of literature regarding malignant melanoma risk
factors all over the world. However, such data concerning the Polish population
has not been published as of yet. OBJECTIVE: To identify the importance of
melanoma risk factors including number and distribution of common and atypical
nevi of the patients, phenotypic features, and environmental conditions. METHODS:
This is a case-control study of 74 melanoma patients and 300 controls. We used
histopathological examination to confirm diagnosis of melanoma. Epiluminescence
microscopy was introduced for differential diagnosis of all pigmented lesions.
RESULTS: The mean number of common nevi in melanoma patients was significantly
higher compared with the control group (22.1 vs 15.2; P < 0.05). Atypical nevi in
the melanoma patients group and in the control group were encountered in 16.2%
and 6.6%, respectively (P < 0.05). In the melanoma group more patients with fair
complexion, intense sun exposure, and sunburn were identified compared with the
control group. CONCLUSION: It was stated that an increased number of nevi
(especially atypical ones), fair skin, and blue/green eyes, as well as intense UV
exposure and sunburns, are important risk factors for melanoma development.
PMID- 9391562
TI - Does surgical removal of primary melanoma trigger growth of occult metastases? An
analytical epidemiological approach.
AB - BACKGROUND: In several human tumor systems a potential role of surgical removal
of the primary tumor upon metastatic tumor growth has been evaluated, as it has
been in experimental models. The present study addresses the question of whether
the removal of primary melanomas disinhibits growth of metastatic disease and
results in more rapid progression. METHODS: In a data set of 1224 primary
cutaneous melanomas the risk of "thin" melanomas to develop metastases within 1
year was compared with the risk of matched pairs of "thick" melanomas to present
metastases at the time of diagnosis. For this purpose, a pairwise matching
procedure based on certain assumptions as to tumor volume and tumor doubling time
has been applied. RESULTS: When a long tumor doubling time is assumed (200, 400,
or 800 days), the tumors removed seem to have a significantly higher risk of
metastases to become clinically apparent within 1 year than the matched pairs of
tumors to present metastatic disease at the time of diagnosis (chi-square <
0.01). When short tumor doubling time is assumed (50 or 100 days), the difference
is not significant, but there also seems to be no benefit for the operated
patients. CONCLUSION: In the present data set there is evidence that surgery of
primary melanoma may enhance tumor growth at metastatic sites.
PMID- 9391563
TI - Malignant melanomas simulating various types of soft tissue tumors.
AB - BACKGROUND: Primary malignant melanomas, recurrences, and metastases thereof can
present with a wide variety of clinicopathologic aspects. OBJECTIVE: The present
series describes eight primary malignant melanomas and/or 10 local
recurrences/metastases (from eight patients) misdiagnosed as various types of
soft tissue tumors: two dermatofibrosarcoma protuberans, two atypical
fibroxanthomas, two storiform-pleomorphic malignant fibrous histiocytomas, one
myxofibrosarcoma ("myxoid malignant fibrous histiocytoma"), two malignant
hemangiopericytomas, and nine malignant schwannomas. METHODS: In three cases
correct diagnosis was established by clinicopathologic correlation during follow
up; all the others were only discovered during a retrospective work-up of all
soft tissue tumors diagnosed at the Dermatohistopathological Laboratory of the
Department of Dermatology, University of Innsbruck. RESULTS: Helpful clues
derived from subtle intraepidermal, irregular spread of melanocytes, focal nested
arrangement of tumor cells, sparse melanin deposition, neurotropism, and
prominent peripheral lymphohistiocytic response, partially forming lymph
follicles. Besides clinicopathologic correlation, histology of serial sections as
well as immunohistochemistry (S100 protein more important than NK1/C3; HMB45
without benefit) and electron microscopy (melanosomes) proved helpful for
definitive diagnosis. In contrast to the general assumption that spindle
cell/desmoplastic malignant melanomas have an unequivocal bad prognosis, our
series, as well as evidence from the literature, document a better prognosis than
that of other types with comparable tumor thickness (70% vs 50% 5-year survival).
Moreover, labeling with E9, an antimetallothionein marker, confirmed its
usefulness for prognosis being strongly positive in primary lesions followed by
rapid progression, but mostly negative in those without. CONCLUSION: These cases
document that malignant melanoma may mimic various types of soft tissue tumors;
correct interpretation is important as prognosis and therapeutic management
differ considerably between these entities.
PMID- 9391564
TI - Cutaneous malignant melanoma treated by Mohs surgery. Review of the treatment
results of 179 cases from the Mohs Melanoma Registry.
AB - BACKGROUND: There has been much debate regarding the efficacy of the Mohs
chemosurgery fixed-tissue technique vs the fresh-tissue technique in the
treatment of cutaneous melanoma. OBJECTIVE: To review the treatment results of
the 179 cases of melanoma registered with the Mohs melanoma tumor registry from
1981 to 1991, accumulated from nine referring Mohs surgeons. METHODS: Review of
the two treatment techniques using a case presentation format. There were 113
cases treated by the hybrid fixed-tissue technique and 61 cases treated by the
fresh-tissue technique. The data compared technique of treatment vs degree of
invasion by both Clark level and Breslow thickness determinations. Analysis of
the data using Kaplan-Meier graph. RESULTS: Five-year survival data for melanomas
treated by either the fresh-tissue or fixed-tissue method appear concordant.
CONCLUSION: For thin and intermediate melanoma thicknesses treatment by either
method appears to be equally efficacious. For deep melanomas, the number of cases
were insufficient to evaluate. Further study of this high-risk category is
warranted.
PMID- 9391565
TI - Tissue repair after Mohs surgery. A plastic surgeon's view.
AB - BACKGROUND: Goals of the treatment for skin cancer include completeness of
removal of the lesion, minimal functional disability, and a good aesthetic
result. With increasing standards for the quality assurance and the demand for
cost-effectiveness, assessment of resource-consuming treatment modalities,
especially those involving multidisciplinary approaches, seems appropriate.
OBJECTIVE: The purpose of this study was to review the strategy of management and
the approaches to tissue repair following cutaneous micrographic surgery from the
plastic surgeon's point of view. METHOD: Retrospective review of personal
experience based on approximately 800 patients treated between 1989 and 1996 and
current plastic surgery literature. RESULTS AND CONCLUSIONS: Teamwork with the
Mohs surgeon, recognition of the post-Mohs' procedure wound components, and
familiarity with reconstructive techniques are essential for the
multidisciplinary practice success. The pitfalls of the reconstructive approaches
are discussed.
PMID- 9391566
TI - Anti-human epithelial antigen (Ber-EP4) helps define basal cell carcinoma masked
by inflammation.
AB - BACKGROUND: Anti-human epithelial antigen (Dako-Ber-EP4) is an antibody raised in
mice that reacts with two glycoproteins of 34 and 49 kD. These glycoproteins are
present on the cell surface and in the cytoplasm of basal cell carcinoma (BCC)
cells, sweat glands, and some hair follicles in the skin. METHODS: We selected 27
BCCs (15 nodular, 11 morpheic/infiltrative, and one adenoid) and one
trichoblastoma and performed rapid immunohistochemical studies with Ber-EP4 and a
labeled streptavidin biotin alkaline phosphatase system. RESULTS: Twenty-seven of
27 BCCs and one of one trichoblastoma were positive for Ber-EP4. Thirteen of 27
BCCs stained with Ber-EP4 showed areas of BCC in dense inflammation that were
better defined by the Ber-EP4 immunostain than by the H&E stain. In two cases
persistent infiltrative BCC was found in the final Mohs margins while appearing
negative with routine H&E. Several instances occurred where negative Ber-EP4 in
inflammatory fields resulted in tissue sparing with the avoidance of a further
Mohs (insurance) layer. CONCLUSION: In conclusion, we found mouse anti-human Ber
EP4 a useful and reliable marker for BCC. This antibody helps to locate latent
BCC tumor in inflammatory Mohs margins.
PMID- 9391567
TI - Combination of an island advancement flap and a composite graft for
reconstruction of the nasolabial defect.
AB - BACKGROUND: The alar region is one of the most difficult areas of the face to
reconstruct. Up until now, various methods have been demonstrated for achieving
the best possible results in terms of cosmetic appearance and function. This
report deals with a combination of a random pattern flap and a free composite
graft, carried out in two stages. OBJECTIVE: In order to reconstruct the alar
region, an island advancement flap as well as a composite graft from the
contralateral ear were used. METHODS: The defect in the cheek-upper lip region
was closed using an island advancement flap. In a second operation 2 weeks later,
the reconstruction of the alar region was attempted using a composite graft from
the right ear. RESULTS: The reconstruction of the contour of the wing of the nose
succeeded in a satisfactory manner. There are no functional restrictions on nose
breathing. CONCLUSIONS: The combination of an island advancement flap with a
composite graft from the ear for the reconstruction of the alar region is
essentially a less invasive operation that can be carried out under local
anaesthesia and that represents an addition to the previously stated methods.
PMID- 9391568
TI - Upper lip reconstruction with local island flap after neoplasm excision.
AB - BACKGROUND: The upper lip is an important esthetic unit of the face and its
reconstruction is a big challenge to the dermatosurgeon. OBJECTIVE: The aim of
the paper is to present results of upper lip reconstruction for moderately sized
defects with single island subcutaneously pedicled flaps, or in combination with
additional local flaps. METHODS: Thirteen patients were operated upon mostly for
malignant skin neoplasms. Defects of skin only were covered with island flaps
planned individually to fit esthetic units of the face. Defects in skin and
vermillion were covered with island flaps, and additionally and independently
with flaps that reconstructed the vermilion. RESULTS: The healing process was in
all the cases but one (partial flap necrosis) free of complications. Follow-up
results were also very good functionally and esthetically.
PMID- 9391569
TI - Cryosurgery for cutaneous malignancy. An update.
AB - BACKGROUND: Cryosurgery is a successful modality for destruction of basal and
squamous cell carcinomas. There is a trend toward more aggressive freezing of
lesions and treatment of selected difficult tumors. OBJECTIVE: The indications
and advantages for cryosurgery, recent treatment techniques, tissue response,
complications, and results merit description. METHOD: The standard method of
treatment is used with aggressive freezing of the lesion, including a greater
lateral spread of freeze and attainment of lower tissue temperatures. RESULTS:
The cure rate of cryosurgery is high and the cosmetic results are good to
excellent. CONCLUSION: The results of cryosurgery are comparable with other
modalities. It may be preferable or advantageous for some patients because of the
quickness and safety of the procedure and its low cost. With changes in health
care spending due to law or regulation, and within the environment of a managed
care system, dermatologists may choose cryosurgery on the basis of outcome and
cost.
PMID- 9391570
TI - Radiation therapy in skin cancer. A historical perspective and current
applications.
AB - BACKGROUND: Radiation therapy has been used for skin cancer for nearly a century.
During this protracted period, techniques of administering superficial
irradiation have developed continuously. More recently, the availability of
electron beams for treatment of skin cancer has improved further our ability to
treat skin cancer more efficiently and with less toxicity. These include primary
skin cancers as well as any metastatic skin lesion. OBJECTIVE: Indications and
advantages of modern radiation therapy in skin cancer are confusing at times. In
this review, an attempt was made to clarify the role of this discipline in
dermatologic use. METHODS: Old literature has been reviewed in order to give an
appropriate historical perspective of treatment of skin with irradiation.
Literature has also been selected for updating information on current indications
and practice of radiation therapy for skin lesions. RESULTS: Radiation therapy is
very effective in many situations where other modalities are contraindicated or
functionally or cosmetically impairing. With the most efficient methods of
fractionation and administration, the control rate of most skin cancers with
radiation is as high as 90% or more. CONCLUSION: Modern day radiation therapy is
very effective in treatment of skin cancers. Not only the control rate is as good
as any other modality, but, with irradiation, cosmetic appearance and function
are better preserved under most circumstances.
PMID- 9391571
TI - Physician-patient confidentiality. Legal and ethical implications in the setting
of basal cell nevus syndrome.
AB - Physician-patient confidentiality represents one of the core aspects of any
medical practice. Dermatologic surgeons need no advice regarding the privacy of a
patient's records. However, occasionally, the boundaries of this confidentiality
become obscure. This paper, describing a potential real case scenario, looks at
the legal and ethical issues surrounding physician-patient confidentiality.
PMID- 9391572
TI - Mohs surgery for nonagenarians.
PMID- 9391573
TI - Tattoo formation from suture or from cosmetics?
PMID- 9391574
TI - Cochlear implants: what can be achieved?
AB - Cochlear implants in children are effective in terms of speech perception and
production. Onset of deafness, date of implantation, and duration of deafness are
important prognostic factors for long-term results. Sophisticated intraoperative
and postoperative device control measurements enable detection of partial or
total device failure and calculation of the reliability of the implant. However,
the present technological status is far from an optimal device. Future
developments will include improvements of both electrode design and speech
processing. The number and separation of channels will be increased, and the
pattern of stimulation will approach the natural excitation pattern of the
auditory nerve. Behind-the-ear implants or totally implantable devices will
further increase the acceptance and reliability of this technology. The implant
systems will become more versatile and adaptable to the physiological conditions
of the individual patient. Apart from these technological improvements,
rehabilitation and proper selection of patients will still play a major role in
successful implantation in children. Outcome studies are necessary to calculate
the cost-benefit ratio and justify a further extension of implantation. We are
still on the way toward the artificial ear.
PMID- 9391575
TI - The Children Cochlear Implantation Project in Hannover.
PMID- 9391576
TI - Basic neurophysiology of cochlear-implants.
AB - Cochlear implants work because the fibers of the auditory nerve can be stimulated
electrically. Currently used multi-channel electrodes distribute the stimuli to
different cochlear places (place principle) and provide information on the fine
time structure of the acoustic stimulus thus allowing periodicity analysis by the
central nervous system. The paper treats the limitations of current cochlear
implant technologies and discusses conceivable improvements.
PMID- 9391577
TI - Are spiral ganglion cell numbers important for speech perception with a cochlear
implant?
AB - OBJECTIVE: Studies of factors affecting the survival of ganglion cells in adults
with profound hearing loss and speech perception in cochlear implant users are
reviewed in order to assess the hypothesis that ganglion cell numbers have a
strong influence on the level of speech perception achieved by adult implant
users. DATA SOURCES: All histopathologic data have been published as tables or
figures in refereed papers. Speech perception data were collected from published
papers and directly from clinics and from Cochlear Corporation's database. STUDY
SELECTION: Histopathologic studies with reasonably large groups of patients were
selected. The speech perception data were from the largest study available. DATA
EXTRACTION: All data used have been published in refereed journals of high
repute. No other assessment of quality or validity was available to the author.
DATA SYNTHESIS: Trends in the speech perception data were compared qualitatively
and quantitatively with trends in the histopathologic ganglion cell data.
CONCLUSIONS: The analysis found no strong evidence that spiral ganglion cell
numbers have a strong influence on the level of speech perception achieved with a
cochlear implant. A possible explanation for this surprising result may be that
the minimum number of cells required for good speech perception is quite low, and
the majority of implant users exceed this minimum requirement.
PMID- 9391578
TI - Intracochlear, electrical, multichannel stimulation effects on the development of
auditory system in neonatally deafened kittens.
AB - OBJECTIVE: To investigate the effect of chronic electrical stimulation in
acoustically deprivated animals during maturation. MATERIALS AND METHODS:
Latencies of EABR measurements from acoustically deprivated and acoustically
deprivated, but electrically stimulated animals were compared with ABR from
normal hearing cats. In addition, morphological analyses of the cochlear nuclei
and the auditory cortex and their subdivisions were done. RESULTS AND DISCUSSION:
EABR latencies demonstrated that the most peripheral auditory pathway is more
independent from the normal auditory or external electrical stimulation than the
more central regions. Morphological analysis also demonstrated the reverse of the
acoustically deprivation effect during maturation in the auditory cortex via
intracochlear electrical stimulation.
PMID- 9391579
TI - Ontogeny of electrically evoked brain stem potentials in neonatally deafened
gerbils (Meriones unguiculatus) after cochlear implantation.
AB - To investigate the ontogeny of the electrically evoked auditory brainstem
response (E-ABR) we used an animal model of neonatally deafened gerbils with an
intracochlear implanted electrode. The E-ABR were recorded in three groups:
normal hearing animals (NORM) and binaural deafened without chronical
electrostimulation (BD) in comparison to binaural deafened animals with chronical
stimulation (BDS). In group BD the deafening lead to inter-peak-latency II-V
increase and histological degeneration in the Cochlear Nucleus. In chronical
stimulated animals (BDS) we could not observe significant differences compared to
unstimulated gerbils until the day after birth. In further studies longer
stimulation periods, recordings of electrically evoked middle latency response as
well as histological examinations of more central parts of the auditory pathway
will be included.
PMID- 9391580
TI - Optical imaging of cat auditory cortical organization after electrical
stimulation of a multichannel cochlear implant: differential effects of acute and
chronic stimulation.
AB - OBJECTIVE: To study the effects of electrical stimulation on cortical activation
patterns. MATERIALS AND METHODS: Optical imaging of auditory cortex in cats that
are acutely and chronically electrically stimulated with cochlear implants.
RESULTS: Chronic electrical stimulation results in expansion of cortical
territory and overlap. CONCLUSION: Effects of chronic electrical stimulation are
comparable to use-dependent cortical plastic reorganization.
PMID- 9391581
TI - Acute effects of electrical intracochlear multichannel high-rate stimulation of
the auditory nerve of cats.
AB - OBJECTIVE: To investigate the short-term effects of electrical stimulation of the
cochlea in cats. MATERIALS AND METHODS: Deafened cats were implanted with human
cochlear electrodes, electrical stimulation at clinical levels was given, and
evoked auditory brain stem responses (EABR) were recorded. RESULTS AND
DISCUSSION: No long-term reduction in the excitability of the auditory nerve or
in brain stem responses was seen.
PMID- 9391582
TI - Meriones unguiculatus (Gerbil) as an animal model for the ontogenetic cochlear
implant research.
AB - The rehabilitation of prelingually deafened children using cochlear implants
still raises several basic problems, e.g. growth of the skull and maturation of
the auditory system. Systematic research in these problems requires a reliable
animal model. The gerbil (Meriones unguiculatus) was investigated in respect of
its suitability as an animal model for ontogenetic cochlear implant research.
Gerbil pups were deafened by a single intracochlear application of neomycine on
their 14th day after birth before the onset of natural hearing and implanted with
an animal specific cochlea implant at day 30 after birth. To maintain the
biological relevance the social sounds of gerbils were frequency transformed and
used in daily electrostimulation until the 90th day after birth. As well
established animal in hearing research the gerbil appears to be an appropriate
animal model for ontogenetic cochlear implant research.
PMID- 9391583
TI - Development of the evoked auditory brain stem response amplitude peak IV during
chronic electrical, intracochlear, multichannel high-rate stimulation.
AB - OBJECTIVE: To investigate the effect of high stimulation rates on the developing
auditory system. MATERIALS AND METHODS: Neonatally deafened kittens with human
intracochlear electrode implants received sustained electric stimulation. RESULTS
AND DISCUSSION: No loss of brain stem responses was observed.
PMID- 9391584
TI - Histologic and immunohistochemical investigations on the development of the
auditory brain stem modified by auditory deprivation.
PMID- 9391585
TI - Measurements of threshold shifts observed when using normal and preformed
electrodes.
AB - OBJECTIVE: To investigate the efficacy of short-term electrical stimulation with
different human electrodes using high stimulation rates and different electrode
designs. MATERIALS AND METHODS: Human electrodes of two different designs were
implanted in cats, and electrically evoked auditory brain stem responses (EABR)
were recorded. RESULTS AND DISCUSSION: Thresholds from the EABR recordings at the
apical end of the electrode array were comparable in both types of implants.
There were significantly higher thresholds at the basal end than at the apical
end of the electrodes in both types of electrodes.
PMID- 9391586
TI - Effect of high-frequency electrical stimulation of the auditory nerve in an
animal model of cochlear implants.
AB - HYPOTHESIS: Electrical stimulation of the cochlea at high rates induces
significant adaptation of the auditory nerve. BACKGROUND: A new development of
cochlear implants is the use of speech processors delivering electrical pulses on
the implanted electrodes at high rates, such as 1,000 pulses per second (pps) and
above. Such a stimulation mode allows subjects with cochlear implants to reach
excellent understanding of speech. METHODS: Long Evans-rats received implantation
of stimulating electrodes in the left cochlea. Two hundred-millisecond trains of
short (20 microns) monophasic pulses were delivered in 50% duty cycle at 500
microA above threshold. The pulse rate in the train was increased from 100 pps to
1,500 pps. Electrically evoked auditory brainstem responses (EABR) were recorded.
The amplitude of the compound action potential of the auditory nerve to each
single pulse in the train was measured as the first vertex positive wave (WAVE I)
of the EABR. RESULTS: At 100 and 200 pps, WAVE I amplitudes to each pulse were
large and remained stable throughout the pulse train. For increasing pulse rates,
WAVE I amplitudes progressively decreased during the first 40 to 50 ms of the
train and reached 80% at 300 pps to 15% at 1,500 pps of the maximal amplitude
observed for the first pulse in the train. CONCLUSIONS: The decrease of the WAVE
I amplitude in response to high-rate pulsatile stimulation reflects an adaptation
of the auditory nerve due, at least in part, to the refractory period of auditory
nerve fibers.
PMID- 9391587
TI - Temporal representations with cochlear implants.
AB - OBJECTIVE: To record and characterize intracochlear evoked potentials (EPs) for a
variety of electrical stimuli in studies with cochlear implant patients. METHODS:
Recordings were made with patients having direct percutaneous access to their
implanted electrodes. Intracochlear voltages were recorded via unstimulated
electrodes. The stimuli included trains of identical pulses, with pulse rates
ranging from 100 to 4065/s, and a modulated pulse train produced by a single
channel speech processor, with the pulse rate of 824/s. RESULTS: Magnitudes of
EPs for each pulse in trains of identical pulses were uniform for pulse rates
below about 200/s. For rates between about 400 and 1000/s, an alternating pattern
of EP magnitudes was observed, with relatively large EPs following the odd
numbered pulses. For rates between about 1000 and 3000/s, more complex patterns
were observed. After the first millisecond of each train at even higher rates,
uniform EPs again were observed across pulses, although the absolute magnitude of
the EPs was much lower than that observed for low rates of stimulation. The
approximate rates corresponding to boundaries between these different regions
varied among subjects and among electrodes within subjects. EP magnitudes for the
modulated pulse train reflected the gross periodicity of the modulation waveform
but did not reflect temporal details within the periods. CONCLUSIONS: Population
responses of the human auditory nerve, as indicated by EP magnitudes, reflect the
amplitudes of electrical pulses for pulse rates below about 200/s and above about
3000/s. Use of intermediate rates may introduce distortions in the transmission
of stimulus information with cochlear implants.
PMID- 9391588
TI - Results from a pilot study using the nucleus CI24M/SP5 cochlear implant system.
AB - OBJECTIVE: To conduct a pilot study in adults with the Nucleus CI24M/SP5 cochlear
implant system. PATIENTS AND METHODS: Eight postlingually deafened adults who had
received little or no benefit from conventional hearing aids, equipped with the
Nucleus CI24M/SP5 cochlear implant system. RESULTS AND CONCLUSIONS: The results
indicate that most of the subjects were able to perform well in speech
recognition tests. The test performances appeared to be strongly affected by the
duration of deafness. The speech processor's four user-selectable program
memories have been extremely useful for the subjects to evaluate variations to
the speech coding strategies in ordinary surroundings outside of the laboratory.
The telemetry functions of the new implant provide a set of useful clinical and
research tools for gathering greater insights into the in-situ operation of the
implant.
PMID- 9391589
TI - The advanced Combi 40+ cochlear implant.
AB - A 12-channel cochlear implant (CI) for high-rate pulsatile stimulation strategies
is presented. Symmetric biphasic current pulses can be generated up to a maximum
pulse repetition rate of 18.18 kpulses/second. The stimulation pulse amplitude
can be selected within 1.5 microA-1.5 mA. Data and power are transcutaneously
transferred using a single radiofrequency (RF) channel. A fully digital data
transfer format is employed at an overall data rate of 600 kBit/second. The
implant contains a single mixed analog/digital CMOS-ASIC (Application Specific
Integrated Description) for data synchronization and stimulus generation.
Stimulation signals are applied via a monopolar intracochlear multichannel
electrode. Output capacitors for each channel are employed for safety reasons. A
self-calibrating back telemetry system is included for estimating the channel
impedances and field distribution along the electrode array. Dimensions of the
ceramic package of the implant are only 33.50 x 23.40 x 3.95 mm3.
PMID- 9391591
TI - Electrodes for ossified cochleas.
PMID- 9391590
TI - Nucleus double electrode array: a new approach for ossified cochleae.
AB - INTRODUCTION: The ossified cochlea is still a special surgical issue that
requires a special surgical procedure. The current cochlear implants only have
one electrode lead, which can be placed only partially in the drilled out basal
turn. The small number of used active electrodes leads to worse performance as
compared with patients with full insertion. METHODS: To overcome this limitation,
a special electrode was developed consisting of two arrays. One array with 11
active electrode rings is placed in the drilled out basal turn, the second array
with 10 active electrodes in the opened second turn. The number of inserted
electrodes can be significantly increased. The surgery is similar to that in
nonossified cochleae. After the posterior tympanotomy, the bridge is removed and
the incus is located. A cochleostomy is performed at the basal turn and the new
built tissue removed. A second cochleostomy is placed below the cochleariform
process. In most cases, the second turn is not obliterated and the second
electrode array can be fully inserted. RESULTS: The surgical procedure was in all
nine cases uneventful. Intraoperative stapedius reflex could be recorded with
elevated thresholds. The wide variety of stimulation modes and sites allows an
individual fitting to maximize the performance. All patients show a gap in the
pitch scale between the apical and the basal array. The pitch variation is much
smaller in the apical array. All patients have some benefit from the additional
apical array and an improved performance. CONCLUSION: The nucleus double
electrode array is an advanced treatment option for patients with ossified
cochleae. The receiver/stimulator is a regular nucleus cochlear implant.
PMID- 9391592
TI - Pediatric experience of the reliability of the nucleus mini 22-channel cochlear
implant.
PMID- 9391593
TI - Evaluation of noise reduction systems for cochlear implant users in different
acoustic environment.
AB - Evaluation of two different noise reduction algorithms for speech intelligibility
enhancement in cochlear implant (CI) users is described in this report. The
algorithms accomplish sophisticated interchannel processing of the noisy speech
signals, picked up with two microphones, to form an improved monaural output
signal, which is directly fed into the auxiliary input of the CI speech
processor. Speech intelligibility tests were carried out in different realistic
everyday life listening conditions to provide general and expressive performance
assessment. Extensive tests in four CI users showed considerable speech
intelligibility improvement using these noise reduction systems in adverse
everyday life listening conditions.
PMID- 9391594
TI - Magnetless cochlear implant: relevance of adult experience for children.
AB - A method of implanting magnetless cochlear implants without alignment problems is
outlined and the first adult experience is presented. Some special considerations
relevant for implanting such an implant in children are discussed.
PMID- 9391595
TI - Evaluating the plasticity potential of the auditory brain stem nucleus in the
rat.
AB - OBJECTIVE: To study the adaptation of the auditory brainstem to auditory loss.
STUDY DESIGN: Growth-associated protein 43 (GAP-43) immunoreactivity was studied
in in rats whose cochleas had been removed. RESULTS AND DISCUSSION: Neurons in
the lateral superior olive were found to synthesize GAP-43 in a pattern that
paralleled the changes in GAP-43 immunoreactivity in the cochlear nucleus after
cochlear ablation. These findings suggest that new patterns of synaptic
communication can be established after damage to the cochlea.
PMID- 9391596
TI - Submillimeter imaging and reconstruction of the inner ear.
AB - OBJECTIVE: To present new radiological developments using high-resolution
magnetic resonance imaging (MRI). MATERIALS AND METHODS: Using heavily T2
weighted sequences at a 1.5 Tesla scanner, maximum-intensity projections (MIP) of
the inner ear were generated. The imaging time was less than 20 minutes, and
imaging could be performed with adults and children of all age groups alike. This
method enables us to visualize and identify the different neural structures of
the internal auditory canal. Aplasia or schwannoma of a single or a variation of
nerves could be clearly demonstrated. RESULTS: Three-dimensional reconstruction
enabled unprecedented clear and precise presentation of the fluid content of the
inner ear. The size and shape of 2 to 2 1/2 turns of the cochlea could be
routinely demonstrated and analyzed in 45 subjects. Eight patients subsequently
received an intracochlear implant electrode, and the intraoperative findings
correlated with the imaging. CONCLUSION: The most recent high-resolution MRI
techniques provide reliable visualization of submillimeter anatomical structures
of the inner ear and auditory nerve.
PMID- 9391597
TI - Large vestibular aqueduct syndrome and its implication for cochlear implant
surgery.
AB - The large vestibular aqueduct syndrome (LVAS) is commonly found when presurgical
computed tomography is performed in advance of cochlear implantation. We present
data on two patients with LVAS, in whom computed tomography (CT) and magnetic
resonance imaging (MRI) was performed. Cochlear implantation when these
malformations are present may be complicated by an intraoperative gusher, but it
appears to be safe and produces a favorable outcome.
PMID- 9391598
TI - Intact canal wall drill-out procedure for implantation of the totally ossified
cochlea.
AB - OBJECTIVE: To describe a simplified drill-out technique for insertion of a
multichannel electrode in the completely ossified cochlea without radical
mastoidectomy and obliteration. STUDY DESIGN: Description of a new surgical
technique and case report. SETTING: Temporal bone dissection laboratory and
tertiary referral center. PATIENTS: Adult and pediatric cochlear implant (CI)
recipients. MAIN OUTCOME MEASURES: Access for circum-modular drill-out and
electrode insertion without radical mastoidectomy and adequate function of
multichannel CI. RESULTS: Dissection of 10 cadaver temporal bones demonstrated
feasibility of this technique. Highlights include facial recess cochleostomy and
8 mm tunnel; elevation of superiorly based tympanomeatal flap; removal of incus,
cochleariform process, and tensor tympani; and identification of carotid canal
and use of facial nerve monitor. A case report of an 11-year-year old child with
total cochlear ossification and previous failure of a short (8 electrode) CI
electrode insertion is presented. Complete insertion of a 22-channel electrode
was successful and open-set word recognition is commencing. CONCLUSIONS: The
canal wall-up drill-out procedure allows complete electrode insertion without
mastoid obliteration in patients with obliterated cochleas. Appropriate attention
to the carotid artery and facial nerve is essential.
PMID- 9391599
TI - Cochlear implant reimplantation.
AB - The objective of this study was to determine whether insertion length and number
of active channels remained the same after reimplantation of a cochlear implant.
A retrospective case review of 170 consecutively implanted multichannedl cochlear
implants was conducted. Seventeen of these devices had to be replaced. Data were
analyzed for the Nucleus cochlear implant users who were reimplanted in the same
ear. For most subjects, insertion length and number of channels remained
unchanged, but a few subjects experienced substantial decreases. When the whole
group was considered, a small but statistically significant drop was noted for
both parameters. In conclusion, although reimplantation is technically possible,
the first procedure provides the optimal surgical environment.
PMID- 9391600
TI - Complications of cochlear implant surgery in children.
AB - OBJECTIVE: To evaluate the intraoperative problems and postoperative
complications in children receiving cochlear implants. STUDY DESIGN: A
retrospective analysis of the clinical records of 366 children, aged 1 to 14
years, who had received cochlear implants. RESULTS: Intraoperatively,
obliteration of the cochlea occurred in 66 patients, cochlear dysplasia in 8, and
CSF leakage in 7, and nearly 5% of patients had signs of infection in the mucosa
of the middle ear. Postoperatively, early complications occurred in 1% to 2.5% of
patients: flap complications, electrode dislocation, facial nerve problems, and
incorrect insertion of the electrode. Delayed complications included otitis media
and stimulation of the facial nerve. CONCLUSION: Proper preparation of the
implantation site, experienced and well-trained surgeons, and awareness of the
operative and postoperative risks are necessary.
PMID- 9391601
TI - Malformations in cochlear implant patients.
AB - OBJECTIVE: To report on cochlear implantation in children with bony inner ear
malformations. PATIENTS: 30 children with bony inner ear malformations who have
received cochlear implants. INTERVENTIONS: High-resolution spiral computed
tomography is used to identify malformations. Magnetic resonance imaging is used
to detect the presence of an acoustic nerve and determine the integrity of the
auditory pathway and central nervous system structures. Both imaging techniques
may be used intraoperatively, as well as facial nerve monitoring and electrical
auditory brainstem response monitoring. Three-dimensional reconstructions are
helpful in preoperative planning. Large vestibular aqueducts and vestibular
malformations can be successfully managed. RESULTS: Postoperative results have
been encouraging, although children with malformations tend to occupy the lower
third of rehabilitation results of all children with implants.
PMID- 9391602
TI - Surgical techniques for cochlear implantation of the malformed inner ear.
AB - OBJECTIVE: The objective was to describe surgical techniques helpful in
implanting children with inner ear malformations. STUDY DESIGN: This was a
retrospective chart review and description of surgical techniques in the setting
of a tertiary referral center. PATIENTS: The study population was composed of 10
children with inner ear deformities who received 22-channel implants. RESULTS:
The primary surgical challenges encountered in these procedures include complete
electrode insertion, cerebrospinal fluid gusher, identification of cochleostomy
site in the absence of the round window and aberrant facial nerve, and fixation
and stabilization of the electrode. CONCLUSIONS: The techniques described allow
safe and effective insertion of multichannel electrodes in patients with inner
ear malformations.
PMID- 9391603
TI - Medical, surgical, and technical complications with the COMBI-40.
AB - We present the first report on complications of cochlear implantation with the
COMBI-40 (Med-el, Innsbruck, Austria). Between January 1995 and May 1996 325
devices had been implanted by 58 different surgeons. Complications were reported
with the help of standardized complication report form. The overall rate of
complications was 4.6%. Most common problems were flap necrosis and incorrect
positioning of the electrode. No technical failures occurred. The incidence of
complications was lower than those reported by other authors.
PMID- 9391604
TI - Surgical aspects of cochlear implantation in young children: a review of 115
cases.
AB - A review of the surgical complications of the first 115 patients who received a
cochlear implant in this program demonstrate a negligible complication rate in
the perioperative period and a low complication rate in the long term. The
surgical technique is described in detail and the reasons for this low
complication rate are analysed.
PMID- 9391605
TI - Selection criteria for cochlear implants in children.
AB - OBJECTIVE: To determine the selection criteria for cochlear implantation in
children. SETTING: Hospital pediatric implant center. PATIENTS AND INTERVENTIONS:
Selection of patients depends on medical evaluation, audiometric data, speech
discrimination, communication skills, cognitive skills, and psychosocial factors.
Patient selection is based on tonal audiometry, computed tomography, magnetic
resonance imaging, and electrophysiologic tests. Side of implantation is chosen
according to cochlear structure, duration of deafness, and dominant handedness.
RESULTS: Ninety-eight cochlear implantations with the Nucleus multichannel
implant have been performed at this center since 1990. CONCLUSION: The selection
of children for cochlear implantation require close collaboration between the
pediatric surgical team, the educational team, and the family.
PMID- 9391606
TI - Preoperative radiologic evaluation in cochlear implantation.
AB - AIM OF STUDY: Assess the value of computed tomography (CT) in the evaluation of
abnormalities in the cochlea and auditory pathways. MATERIAL AND METHODS: We used
CT to evaluate 108 children before cochlear implantation surgery. Children's ages
at implantation ranged from 21 months to 16 years (mean age, 5.4 years). The
etiology of deafness was meningitis in 44 children (40.8%), congenital in 51
(47.2%), and other in 13 children (12%). RESULTS: Eighteen of the 108 (16.6%)
children and 34% of the postmeningitic children were found to have at least
partial obliteration of the cochlea. Two (2%) children had congenital
malformations of the cochlea and 12 children (11.1%) had abnormalities in the
brain CT-scan. CT diagnostic values in postmeningitic children regarding cochlear
obliteration were accuracy, 75%; sensitivity, 62%; specificity, 82%; positive
predictive value, 66.6%; and negative predictive value, 79.3%. In six (20.6%) of
postmeningitic children with normal CT-scans, some scala tympani drillout was
required. CONCLUSION: CT-scan is capable neither of predicting with certainty the
presence of minor degrees of cochlear obliteration nor of specifically imaging
either the auditory nerve or its central connections.
PMID- 9391607
TI - A European perspective on pediatric cochlear implantation, rehabilitation
services, and their educational implications.
AB - OBJECTIVE: To assess the educational implications of pediatric cochlear
implantation from the perspective of the implant team. METHODS: Coordinators of
pediatric cochlear implant teams throughout Europe took part in a survey using
forced-choice questions. Fifty-four centers were originally sent the
questionnaire; 41 centers replied. RESULTS: Of 504 children planned to receive
cochlear implants in Europe during 1996, 54% (273/504) were aged 2-5 years and
12% (60/504) aged 0-2 years, indicating a trend toward pediatric implantation in
younger children. There is a strong commitment to rehabilitation in the teams;
66% (27/41) employ a teacher of the deaf, the ratio of medical/audiological to
rehabilitation personnel is 1:2, and 76% (31/41) of the implant teams visit local
educators. Of all the children receiving implants to the date of this report, 23%
were considered to be in unfavorable educational environments; these were
environments where children were taught with an emphasis on sign language and
little expectation from audition, and mainstream provision without support from
experienced teachers of the deaf. CONCLUSION: There is a high staff input to
children with cochlear implants from implant rehabilitation personnel over and
above the input received in the educational environment. Hence, it is important
for the school and the implant team to mutually agree on their shared
responsibilities. Moreover, as the provision of service is variable and
inconsistent, the development of guidelines for practice in each country should
ensure consistency of rehabilitative and educational support to children with
cochlear implants.
PMID- 9391608
TI - Use of a parent-report scale to assess benefit in children given the Clarion
cochlear implant.
AB - OBJECTIVE: To assess the auditory skills in everyday situations of prelingually
deafened children with Clarion cochlear implants compared with hearing aids used
preoperatively. STUDY DESIGN: The Meaningful Auditory Integration Scale (MAIS)
was used to determine the preoperative and postoperative auditory skills of the
children. RESULTS AND DISCUSSION: After implantation, the children showed
improvement in three skill areas: bonding to the device, spontaneous alerting to
sound in everyday situations, and ability to derive meaning from sound in the
environment.
PMID- 9391609
TI - Assessment of auditory skills in hearing-impaired children: theoretical
foundations and a practical approach.
AB - A proposal of a performance profile for the assessment of auditory skills of
hearing-impaired children with cochlear implants or hearing-aids is described
here. The associated tests have been realized either with conventional material
or on the Auditory Visual Test and Therapy System developed by the Aachen
research group. Acoustic stimuli and answering tasks have been chosen according
to the special needs of hearing-impaired children in the age range of 3-6 years
of developmental age. Two tests will be described exemplary.
PMID- 9391611
TI - Keynote lecture: objective measures.
AB - The number of young children receiving cochlear implants for management of
profound hearing loss is increasing world-wide. In these children, objective
measures play a vital role both before and after implantation. They have the
capability to assess the degree of hearing loss, guide the selection of the ear
and patient for implantation, and provide valuable assistance with the tuning of
the device in the difficult-to-test and very young children. There is
considerable opportunity for further development of these techniques in the
future and, in particular, for accessing central perception and cognition.
PMID- 9391610
TI - The HSM sentence test as a tool for evaluating the speech understanding in noise
of cochlear implant users.
AB - The German HSM Sentence Test, available on compact disc (CD), consists of 30
lists of 20 everyday sentences. It was developed in the desire to have a
sufficient number of test sentences for the repeated evaluation of speech
understanding of CI users. A noise with speech-shaped spectrum on the CD allows
the evaluation of speech understanding in noise. With the HSM Sentence Test we
evaluated the speech understanding of participants of the Combi-40 European
Multicentric Study. Results are shown for sentences presented without noise and
with signal-to-noise ratios of 15, 10, 5 and 0 dB.
PMID- 9391612
TI - Comparison of preoperative electrostimulation data using an ear-canal electrode
and a promontory needle electrode.
AB - OBJECTIVE: To compare the electrical stimulation results of the ear-canal
electrode with those of a promontory needle. PATIENTS AND METHODS: In thirty
three adult patients, the ear-canal electrode test was compared with the needle
electrode promontory test with respect to sound perception, rhythm detection,
frequency, and disturbing side effects. RESULTS: The ear-canal electrode test, in
comparison with the needle electrode promontory test, resulted in vibrotactile
sensation in addition to auditory sensation in some patients, less auditory
fatigue, higher threshold levels, and lower discomfort levels. CONCLUSION:
Reliable assessment of deafness in children requires, in addition to electrical
stimulation, determination of the electrical evoked auditory brainstem response
with the patient under anesthesia.
PMID- 9391613
TI - Electrically evoked auditory potentials: current clinical applications in
children with cochlear implants.
AB - OBJECTIVE: To summarize the current applications of auditory evoked potential in
children with cochlear implants and candidates for implantation. PATIENTS AND
METHODS: Perioperative transtympanic EABR is used routinely for ear selection and
to establish the electrical stimulability of the ear intended to be implanted.
The perioperative transtympanic EABR is supplemented with EABR obtained
immediately following the insertion of the electrode array and the seating of the
implant's receiver. Postoperatively, EABR and averaged electrode voltages are
used effectively to properly adjust the implant stimulus parameters and to
determine whether the implant is functioning adequately. Postoperatively,
cognitive evoked potentials to speech and tonal stimuli may also be obtained.
RESULTS: EABR results have contributed to effective implant placement and
function. There were several significant correlations between speech recognition
and cognitive evoked potential. CONCLUSION: These measures help assure proper
implant function and effective stimulus delivery.
PMID- 9391614
TI - Intraoperative test of auditory nerve function.
AB - OBJECTIVE: To develop a preoperative objective test of auditory nerve function
for the assessment of cochlear implant candidacy, especially in children.
PATIENTS AND METHODS: We stimulated electrically with a ball electrode before
insertion of the implant. First the stimulus was applied bipolar between the
promontory and the round window. To record auditory brain stem responses (EABRs)
very high stimulus intensities were needed, which was not possible in all
patients. RESULTS: By stimulation in the basal turn of the cochlea, evoked
potentials could be derived. Although in some patients the facial nerve was
stimulated as a side effect, auditory evoked potentials could be recorded. A
facial muscle artifact can be differentiated from the EABRs by latency and the
slope of the input-output function. CONCLUSION: For the present, the only
reliable test seems to be the EABR recording stimulated within the cochlea.
PMID- 9391615
TI - Monitoring the electrode position during acoustic neuroma surgery.
AB - OBJECTIVE: To obtain information about the auditory brain stem responses during
auditory brain stem implantation. SETTING: Operating room during acoustic neuroma
surgery. METHODS: Electrical stimulation of the auditory system during acoustic
neuroma surgery, by placement of a monopolar or bipolar electrode on the nerve or
nerve entry zone of the brain stem, and monitoring of the evoked auditory brain
stem responses (EABR) recorded from the scalp. In some patients, a multichannel
silicon electrode array was placed at the foramen of Luschka. Biphasic
rectangular current pulses were applied, and EABRs were recorded. RESULTS:
Usually the derived potentials consisted of three peaks with a latency below 4
ms. Sometimes we got a complex of two or more peaks. The interpeak interval
between the first and second peak was about 0.7 to 1.0 ms, independently of the
stimulating electrode position, but the absolute latency of the first peak
increased from a minimum of 0.7 ms stimulated at the foramen of Luschka to a
maximum of 1.3 ms stimulated at the nerve.
PMID- 9391616
TI - Assessment of electrostimulation in children supplied with cochlear implants.
AB - OBJECTIVE: In children supplied with cochlear implants (CIs), there is an urgent
need for objective tests for the assessment of electrostimulation. SETTING: An
optimized procedure for intraoperative and post-operative applications with short
duration test time, based on the measurement of the electrical farfield picked up
from surface electrodes on the scalp, is presented; therefore, assessment of
stimulation is independent of the stimulating electronic circuitry. OUTCOME: The
setup was designed for the COMBI40 multichannel CI using a synchronized sampling
technique of the amplified signals. The evaluation procedure includes examination
of the time course of the signal and calculation of the input output function.
With these options, a straightforward judgment of the electrical performance of
the implant in situ, reflecting the input to the auditory nerve, is provided.
PMID- 9391617
TI - Electrode and device problems: manifestation and management.
AB - A total of 119 children were implanted with the Nucleus 22 implant on the
Nottingham program by March 1996. Twenty-five (i.e. 21%) of these had an
electrophysiologically confirmed fault on at least 1 channel and 6 (i.e. 5%) had
experienced total device failure. How these problems were first manifested and
what the subsequent effects were on the child and family were determined by means
of questionnaires and detailed examination of clinical notes. Our findings
indicated that 76% of all internal device faults were initially detected in
tuning or electrophysiological measurement. All parents expressed deep anxiety
about the threat of device failure; cases of total failure occurring over a long
period of time resulted in the greatest distress and effect on the family.
Recommendations are made for companies to assist clinics in minimizing such
effects.
PMID- 9391618
TI - Which sensitivity setting should a child use?
AB - The influence of the sensitivity setting of the cochlear implant speech processor
on speech recognition is investigated with 15 experienced postlinguistically
deafened adult cochlear implant users. We describe the use of loudness scaling in
the course of speech processor fine tuning and checkup of the speech processor
map to demonstrate how their speech processors are programmed. The Freiburg
monosyllabic word test, a standardized German open set speech intelligibility
test, is used in silence and the very difficult Gottingen sentence test is used
in silence and noise to measure speech recognition scores as a function of
sensitivity setting. The median of the optimal sensitivity setting was four steps
higher than the value recommended by the manufacturer. In noisy everyday hearing
situations patients generally use a sensitivity setting one step lower than the
one we found to be optimal for openset word understanding under test room
conditions. With children who cannot select optimal speech processor settings by
themselves, we do not recommend the use of noise reduction and set the
sensitivity three steps higher than the one recommended by the manufacturer.
PMID- 9391619
TI - Optimization of channel number and stimulation rate for the fast continuous
interleaved sampling strategy in the COMBI 40+.
AB - OBJECTIVE: To investigate the interrelation between number of channels and
stimulation rate in the continuous interleaved sampling strategy (CIS). SUBJECTS
AND METHODS: Three of the first recipients of the new COMBI 40+ cochlear implant
participated in consonant, vowel, number, and sentence tests. Speech
understanding was evaluated for different combinations of number of active
channels from two to twelve and stimulation rate per channel between 1,515 and
9,090 pulses per second. RESULTS: The results indicate that the optimum number of
active channels is not necessarily the maximum number of usable channels.
PMID- 9391620
TI - Evaluation of electrically elicited stapedius reflex threshold measured through
three different cochlear implant systems.
AB - OBJECTIVE: To evaluate intraoperative electrically elicited stapedius reflex
thresholds (ESRTs) measured through three different cochlear implant systems: the
Nucleus Mini 22, the Clarion Enhanced Bipolar, and the Med-El Combi-40. SUBJECTS
AND METHODS: Relations between intraoperative ESRT and postoperative maximum
comfort level (MCL) were examined in seven children (4 Nucleus, 2 Clarion, and 1
Med-El) and one adult (Clarion). RESULTS: Preliminary results indicated most
ESRTs were either higher or both higher and lower (across the electrode array
within a subject) than MCLs. All systems provided satisfactory means for
measuring ERSTs. CONCLUSION: It is recommended that hand-held systems have a
direct readout to the programming station and that audio and visual feedback be
improved for all units.
PMID- 9391621
TI - Long-term stability of fitting parameters with the COMBI 40.
AB - Having experience with the COMBI 40 for over two years, it is now possible to
look at the development of patient fittings over a longer period of time. In this
study we look at patient fitting data (thresholds, dynamic ranges, etc.) at two
days, one month, three months, six months and twelve months post first fitting.
Subjects are CI-users participating in the COMBI 40 European Multicentric Study.
Long-term fitting parameters show a favourable development. Stable fitting
parameters and the safety features implemented in the COMBI 40 serve as a basis
for a reliable long-term speech understanding.
PMID- 9391622
TI - Amplitude modulation following response in children as a clinical audiometric
tool.
AB - The current study was designed to investigate the clinical application of
amplitude modulation following response (AMFR) in cochlear implant candidates. A
new digital signal processor (DSP)-assisted PC-based hardware and software was
developed to perform both simultaneous generation of amplitude-modulated stimuli
and the recording, and synchronized signal processing of the electrode signals.
Our first results show that AMFR can be recorded in adults as well as in children
without any contamination by response-like stimulus artifacts. Very high sound
pressure levels can be applied, allowing frequency-specific assessment of
residual hearing. Response threshold detection, using spectral analysis, proved
to be superior compared to visual evaluation of average time waveforms.
PMID- 9391624
TI - Single electrode maps in device troubleshooting.
AB - This article presents case studies in which single-channel mapping was used with
patients who were experiencing discomfort while using their cochlear implant
devices. Repeated psychophysical testing together with integrity testing had
failed to locate the source of the problem in each of the described cases. Single
channel mapping was then used as another means of device troubleshooting. Single
channel maps were created for each electrode across the array. In each case, the
patient was able to identify the offending electrode(s) during the presentation
of speech stimuli, whereas the problem had not been evident during psychophysical
testing with pulse stimuli. Eliminating these electrodes from the map alleviated
the problems experienced by these implant users in each case.
PMID- 9391623
TI - Speech intelligibility as a function of the number of channels of stimulation for
normal-hearing listeners and patients with cochlear implants.
AB - OBJECTIVE: One goal was to determine for normal-hearing listeners the number of
channels of stimulation necessary to achieve a high level of speech
understanding. The second goal was to determine whether patients with a six
channel cochlear implant could achieve the same level of speech understanding as
normal-hearing subjects listening to speech processed through six channels.
METHODS: Speech signals were processed, for normal-hearing listeners, either in
the manner of cochlear-implant processors with 2-9 fixed channels, or in the
manner of a processor which picked, on each update cycle, 6 of 16 channels.
RESULTS: For the most difficult test material eight fixed channels were necessary
to achieve the level of performance achieved with the "n of m" processor. Some
cochlear implant patients with a six-channel continuous interleaved sampling
processor achieved the same level of performance as normal-hearing subjects
listening to speech via six channels. CONCLUSIONS: A signal processor for
cochlear implants with eight channels should produce the same level of
intelligibility as a processor with many more channels. Processors using
continuous interleaved sampling technology can provide a signal which results in
the same level of speech understanding as normal, acoustic stimulation.
PMID- 9391625
TI - Auditory event-related potentials in post- and prelingually deaf cochlear implant
recipients.
AB - The development of central auditory functions in cochlear implant (CI) patients
was studied over six months of rehabilitation. Examinations were performed
beginning with the first week after processor calibration, and in monthly follow
up sessions thereafter. The subjects were given a simple auditory perception task
(detection of a 400 Hz and a 1450 Hz tone), as well as an oddball-paradigm
(detection of one of the tones as a rare deviant). Auditory evoked potentials,
reaction time and errors were recorded. Results from five patients, two
postlingually deaf and three prelingually deaf CI recipients are shown.
Generally, in the auditory evoked potentials of patients a shortening of N100
latency towards those of subjects with normal hearing was seen from month to
month. However, in the prelingually deaf patients this effect was weaker and more
variable over time. Three CI recipients showed a P300 component in the oddball
paradigm in correlation with their performance. Two prelingually deaf patients
failed to show a P300 in the oddball-paradigm. For both components, the N100 and
the P300 we found a larger spreading over the skull in the patients compared to a
normal hearing person. The results show that from the very first days after
initial processor fitting prelingually and postlingually deaf CI recipients may
show cortical correlates of stimulus processing and discrimination. For some
components of the auditory evoked potentials an initial temporal change but a
maintained larger spreading over the skull was seen.
PMID- 9391626
TI - Intraoperative electrical stimulation of the stapedius reflex in children.
AB - OBJECTIVE: To describe the use of intraoperative electrical stimulation on the
stapedius reflex in children. SETTING: Hospital cochlear implantation center.
PATIENTS AND METHODS: Eighteen children under the age of 10 years, who have
undergone cochlear implantation, have been examined during surgery with the
electrically elicited stapedius reflex in the monopolar stimulation mode.
RESULTS: A stapedius reflex could visually be detected for all subjects.
CONCLUSION: The responses serve to test the implant, provide guidance in avoiding
overstimulation of the child when the device is switched on, and estimate the
optimal C-levels.
PMID- 9391627
TI - Electric auditory brain stem response in pediatric patients with cochlear
implants.
AB - OBJECTIVE: To introduce four comprehensive electrical auditory brain stem
response (EABR) parameters that objectively measure the input-output function and
may be the base of comparison in related studies. MATERIALS AND METHODS: In 53
children (106 ears), recordings of the EABR evoked by electrical stimulation at
the promontory were made at the time of surgery after the child was anesthetized
and before cochlear implantation. RESULTS: Of the 106 ears studied, 81 (76.4%)
produced clearly defined responses. These responses were used to develop a
package of four comprehensive EABR parameters (slope, maximal slope, relative
growth rate, and maximal relative growth rate) that measure objectively the input
output function. The methods of calculation are described in detail. CONCLUSION:
These parameters may help us to refine and make more consistent the subjective
EABR evaluation. They will also enable a comparison of the results from different
cochlear implant centers and promote the progress of related research.
PMID- 9391628
TI - Phoneme acquisition in the first 4 years of implant use.
AB - OBJECTIVE: To investigate the phonetic inventory development in a group of
profoundly hearing impaired children fitted with the 22-electrode cochlear
implant (Cochlear Ltd, NSW, Australia) at < or = 5 years of age. BACKGROUND: The
cochlear implant provided access to auditory perceptual information that was not
previously available. Investigation into the speech production skills of these
children postimplant is of interest because the speech of these young profoundly
hearing-impaired children is in a constant state of development. METHOD: Phonetic
inventories of nine children were monitored at preimplant and over the first 4
years of implant use using spontaneous speech samples collected at regular
intervals for each child. Progress of phoneme acquisition was measured using two
different criteria: targetless and target production. RESULTS: At 4 years
postimplant, 87% of all phonemes had been acquired as targetless productions and
62% of all phonemes had been acquired as target productions. All monophthongs
were acquired as target phonemes, but only 38% of the diphthongs and 54% of all
consonants were acquired as targets over the time of the study. The average time
taken for a phoneme to progress from targetless acquisition to target acquisition
was 21.6 months, although variation among phonemes was evident. CONCLUSIONS:
Overall, the data suggest similar trends in the order of phoneme acquisition when
compared to normally-hearing children, although it would appear that the process
of acquisition in children with cochlear implants occurs at a slower rate.
PMID- 9391629
TI - Speech perception results for children with implants with different levels of
preoperative residual hearing.
AB - OBJECTIVE: Many reports have established that hearing-impaired children using the
Nucleus 22-channel cochlear implant may show both significant benefits to
lipreading and significant scores on open-set words and sentences using
electrical stimulation only. These findings have raised questions about whether
severely or severely-to-profoundly deaf children should be candidates for
cochlear implants. To study this question, postoperative results for implanted
children with different levels of preoperative residual hearing were evaluated in
terms of speech perception benefits. STUDY DESIGN/SETTING: A retrospective study
of the first 117 children, sequentially, to undergo implantation in the Melbourne
and Sydney Cochlear Implant Clinics was undertaken. All children had been
assessed by and received their implants in a tertiary referral centre. MAIN
OUTCOME MEASURES: To assess aided residual hearing, the children were grouped
into four categories of hearing on the basis of their aided residual hearing
thresholds measured preoperatively. To assess benefits, the scores of children on
standard speech perception tests were reviewed. As different tests were used for
children with different ages and language skills, children were grouped into
categories according to the level of postoperative speech perception benefit.
RESULTS: The results showed that children in the higher categories of aided
preoperative residual hearing showed significant scores on open-set word and
sentence perception tests using the implant alone. For children in lower
categories of aided residual hearing, results were variable within the groups.
More than 90% of children with implants with aided residual hearing thresholds in
the speech range above 1 kHz achieved open-set understanding of words and
sentences. CONCLUSION: While the results of this preliminary study confirm
previous findings of differential outcomes for children with different levels of
preoperative residual hearing, they suggest that children with severe to profound
hearing impairments should be considered for cochlear implantation.
PMID- 9391630
TI - Profiling linguistic outcomes in young children after cochlear implantation.
AB - OBJECTIVE: To summarize the results of cost-utility analyses of pediatric
cochlear implantation (PCI) in the United Kingdom. METHOD: Analyses were based on
measured costs of health care and measured educational placements, but on
estimates of the gain utility which results from PCI and estimates of the costs
of educational placements. RESULTS: The cost-utility ratio calculated from the
costs of health care falls on the margin of the range considered acceptable
within the British health-care system. If estimates of cost-savings associated
with educational placements are also considered, the resulting ratio is similar
to that of other therapies provided within the British health-care system.
CONCLUSION: The analysis is highly sensitive to assumptions about future costs
and benefits. There is a need to reduce the number of assumptions by measuring
those values which are currently estimated: in particular, the gain in utility
associated with PCI and the costs of different educational placements.
PMID- 9391631
TI - Long-term speech perception in children with cochlear implants compared with
children with conventional hearing aids.
AB - OBJECTIVE: To determine the speech perception of children with cochlear implants.
SUBJECTS AND METHODS: Speech perception results of seven children with cochlear
implants (excellent performers), who showed stable speech recognition scores in
the long term, were compared with those of severely hearing-impaired children
with conventional hearing aids (reference group). The groups of children were
matched according to their mean free-field aided thresholds. RESULTS: The results
of the open-set word recognition test were comparable in the two groups.
CONCLUSION: If we consider the results of the hearing aid users as the gold
standard, the results suggest that speech recognition in selected children with a
cochlear implant is close to optimal.
PMID- 9391632
TI - Some aspects of language development in normal-hearing children and children with
cochlear implants.
AB - OBJECTIVE: This article presents some important processes of normal child
language acquisition and applies them to language acquisition data of children
with cochlear implants. DATA SOURCES: Modern studies of language acquisition,
covering various languages, have demonstrated a close link between linguistic and
cognitive development. Sensorimotor intelligence provides a construction of
reality on which the first grammatical structures are built, encoding a number of
relations which hold between objects, persons, events, and localizations. When
acquiring the more complex morphological and syntactic aspects of their mother
tongue, children use a number of characteristic information processing strategies
which make some formal markings easier to learn than others. There is
considerable variability across children with respect to rate of acquisition, the
use of imitation, and analytic versus holistic processing strategies. Caregivers'
language input can facilitate language acquisition, notably the use of expansions
and reformulations, and a generally accepting style. EMPIRICAL STUDY OF CHILDREN
WITH COCHLEAR IMPLANTS: Language acquisition data from two children with cochlear
implants show great differences with respect to rate of acquisition, construction
of the German case system, and syntax. Whereas one child discovers the
regularities of the case inflectional system quickly, the other child appears to
prefer holistic and rote learning processes and uses a sequential strategy for
combining words. It is suggested that variability between children with cochlear
implants may be due to different frequencies of actually processed linguistic
items. CONCLUSIONS: Future research should compare language development in
children with cochlear implants and those with normal hearing making use of
psycholinguistic methods of research design and analysis.
PMID- 9391634
TI - Speech perception performance of congenitally deaf patients with a cochlear
implant: the effect of age at implantation.
AB - The relation between age at cochlear implantation and long-term open-set speech
recognition was studied in a group of nine congenitally deaf children. The age at
cochlear implant surgery ranged from 4 to 13 years. The results showed that there
was a tendency toward poorer results in the children implanted at a relatively
older age. However, the results also indicated that an upper limit for age at
implantation cannot yet be defined in these children.
PMID- 9391633
TI - The effect of language knowledge on speech perception: what are we really
assessing?
AB - OBJECTIVE: The authors examined whether open-set speech perception scores are
limited by knowledge of vocabulary and syntax and further considered whether
remediation of vocabulary and syntax will increase open-set speech perception
scores. STUDY DESIGN: This was a repeated-measures study design in the setting of
a primary (elementary) school for the hearing-impaired. PATIENTS: The study
population was composed of three hearing-impaired children using Nucleus 22
channel cochlear implant. INTERVENTION: Intervention used was language
remediation sessions. MAIN OUTCOME MEASURES: The main outcome measures were
assessment of auditory-alone speech perception benefit using open-set words and
sentences and assessment of syntactic knowledge using the Test of Syntactic
Ability. Outcome measures were applied before and after remediation. RESULTS:
Child 1 and child 2 showed a significant postremediation improvement in their
overall scores on the Test of Syntactic Ability and in their ability to perceive
words learned during remediation. Child 1 and child 2 also showed a significant
improvement in their scores on a modified Bamford-Kowal-Bench open-set sentence
test, which specifically targeted grammatical constructs trained in remediation
sessions. CONCLUSIONS: Remediation of language knowledge deficits significantly
improved open-set speech perception for two children, suggesting a need to
include language remediation in cochlear implant habilitation programs.
PMID- 9391635
TI - Speech perception in noise with implant and hearing aid.
AB - OBJECTIVE: To compare the perception of speech in quiet and in noise by adults
using a cochlear implant on its own or a cochlear implant and hearing aid
together. STUDY DESIGN: Repeated measures. SETTING: Laboratory study using
subjects' own speech processors. PATIENTS: Two groups of cochlear implant users
(Australian and American) with some residual hearing in the non-implanted ear
(pure tone average thresholds at 500 Hz, 1 kHz, and 2 kHz of 75-112 dB HL).
INTERVENTION(S): Conventional hearing aid and cochlear implant in opposite ears.
MAIN OUTCOME MEASURES: Speech perception was evaluated using recorded lists of
CUNY sentences and lists of CNC words in quiet and in background noise. RESULTS:
Speech scores were significantly higher with implant and hearing aid together
compared to implant alone. The binaural advantage was greater in background noise
than it was in quiet for CUNY sentences in the American listeners. CONCLUSION:
Severely-to-profoundly hearing impaired adults may benefit from combined fitting
of implants and conventional hearing aids in opposite ears.
PMID- 9391636
TI - Auditory perceptual abilities in a child with a nucleus and a Clarion cochlear
implant.
AB - This case study will review the performance of a 7-year-old female who was
implanted at the age of 3 years 9 months with a Nucleus 22 channel device. This
child was deafened from pneumococcal meningis at the age of 8 months and was
placed in an early intervention program which uses simultaneous communication
(i.e. speech with sign language). The teaching staff of this particular
educational setting has collaborated closely with the Cochlear Implant Center at
Manhattan Eye, Ear and Throat Hospital and the team's teacher of the deaf. The
child utilized the implant on a daily basis for a period of 2 years 10 months.
Performance on a variety of auditory perceptual tests were obtained at 1 year and
two year intervals. After almost 3 years of implant use, the child suffered an
internal receiver failure. The Nucleus device was explanted and the child was
implanted with a Clarion Cochlear Implant System. Performance on a similar set of
auditory perceptual tests obtained after 3 and 6 months use indicated better
performance with the Clarion device. In addition to the scores on the individual
tests, a comparison questionnaire was used to obtain impressions from the parents
and the school personnel. Results should be reviewed with caution since this
study investigates the responses of a single child who uses each of these two
different implants and cannot be generalized.
PMID- 9391637
TI - Performance of the new Clarion speech processor 1.2 in quiet and in noise.
AB - OBJECTIVE: To evaluate the benefit of the new Clarion speech processor 1.2. STUDY
DESIGN: Fifty-two subjects who received a Clarion cochlear implant during 1993
and 1995 were upgraded with the new Clarion speech processor 1.2. All subjects
were tested with a speech test battery in quiet and in noise, first with the 1.0
processor and 1 month later with the new 1.2 processor. To avoid ceiling or floor
effects, the subjects were divided into three groups according to their test
results with the Freiburger Monosyllabic Word Test (group A < 10%, group B 10
50%, and group C > 50%). RESULTS: The results indicated that all subjects had an
improvement with the new speech processor. This improvement was statistically
significant (p < 0.05) for group C in all conditions, and for group B in the
tests with noise. CONCLUSION: While the better and good performers improved their
test scores significantly, low performers seemed to derive little benefit from
the technical improvements of the same speech processing strategy. Perhaps this
group might gain more from a different processing scheme.
PMID- 9391638
TI - Multichannel cochlear implantation in postmeningitic and congenitally deaf
children.
AB - OBJECTIVE: To test the view that prelinguistic postmeningitic deaf (PMD) children
outperform congenitally deaf children (CD) in the first year following cochlear
implantation. STUDY DESIGN AND PATIENTS: We evaluated 85 children with ages (at
implantation) ranging from 1.9 years to 13.5 years (mean age 5.4 years). The
Listening Progress scale was used to assess the developing use of audition 3, 6,
and 12 months after implantation. RESULTS: In contrast to previous reports, the
PMD children achieved statistically significantly lower scores than CD children.
PMID- 9391639
TI - Some experiences with the nucleus 20 + 2 cochlear implant in adults and children.
AB - OBJECTIVE: To evaluate the effectiveness of the Nucleus 20 + 2 implant in a group
of patients. PATIENTS: Fifteen children and 11 adults who have received the
Nucleus 20 + 2 implant since late 1993. RESULTS: The outcome in most patients has
been favorable.
PMID- 9391640
TI - Telephone speech comprehension in children with multichannel cochlear implants.
AB - Telephone speech comprehension is being evaluated in six prelingually deaf
children implanted with the Nucleus 22 prosthesis fitted with the Speak strategy.
All of them have had at least 1.5 years of experience with their implant. When
the tests began, they had already had at least 2 months' experience with the same
map in their speech processor. The children were trained in the use of the
telephone as part of the rehabilitation program. None of them used it regularly
but as a game that they found very entertaining. A special battery, the Bate-fon
(bateria para telefono = telephone battery), was designed for training and
evaluation purposes. It includes the five Spanish vowels in isolation,
diphthongs, onomatopoetic animal voices, two-syllable, and three-syllable words.
The tests were administered 1.5-2 years after the switch-on of their speech
processor. Standard acoustic telephone coupling was used. The speech material was
presented to the child on colored cards. Stimuli were presented twice. Children
were informed when the response was incorrect. Averaged results indicated that
the percentages of correct responses for all the speech material increase in the
second presentation. All children have shown some degree of telephone
communication abilities. As a result of the training, some of the children are
using the telephone to communicate with their families.
PMID- 9391641
TI - Speech recognition performance of pediatric Clarion patients.
AB - OBJECTIVE: To evaluate the speech performance of children with the Clarion Multi
Strategy Cochlear Implant. PATIENTS: Prelingually deafened children who had
received the Clarion implant. METHODS: The Spondee and Monosyllable Word
Identification subtest of the Early Speech Perception test, the Glendonald
Auditory Screening Procedure (GASP), and the Phonetically Balanced Kindergarten
test (PB-K) were administered to subjects 3 and 6 months after implantation.
RESULTS: At 3 months, subjects' performance was higher than preoperatively with
hearing aids. At 6 months, performance improved further. Scores were higher on
the ESP and GASP than on the PB-K. The scores indicate better levels of speech
recognition than were obtained with older implant processing strategies. Subjects
varied considerably in their performance. The results are preliminary because of
the small sample.
PMID- 9391642
TI - Speech recognition in children with hearing aids versus results in children with
implants.
PMID- 9391643
TI - Performance of 2- and 3-year-old children and prediction of 4-year from 1-year
performance.
AB - OBJECTIVE: To examine whether children perform better when they receive cochlear
implants when they are 2 to 4 years of age than when they are older, and to
determine whether 4-year performance can be predicted from 1-year results.
METHOD: Children in two age groups (2 to 4, 4 to 9 years) were tested for
performance, and the age groups were compared. Children were also tested 1 and 4
years after implantation. RESULTS: The results suggest that the "implanted young"
group scored higher than the "implanted old" group after 36 months, and that 1
year performance is helpful in predicting 4-year performance. CONCLUSION: It may
be desirable for children to undergo implantation when they are under 2 years of
age, provided that appropriate selection criteria can be determined.
PMID- 9391644
TI - Initial results from the clinical trial of the nucleus 21-channel auditory brain
stem implant.
PMID- 9391645
TI - Stress experienced by parents of children with cochlear implants compared with
parents of deaf children and hearing children.
AB - OBJECTIVE: To compare the stress experienced by parents of children with cochlear
implants with that experienced by parents of deaf children and hearing children.
STUDY DESIGN: The Parenting Stress Index and problem-oriented interviews were
used with the parents of these three groups of children. RESULTS: Parents of deaf
children were found to experience greater levels of stress than parents in the
other two groups. CONCLUSION: Parents of children with cochlear implants
experience about the same level of stress as parents of hearing children.
PMID- 9391646
TI - Comparative study of English- and German-speaking children with the Clarion
cochlear implant.
AB - OBJECTIVE: To compare the performance of English-speaking and German-speaking
children with Clarion cochlear implants on the Meaningful Auditory Integration
Scale (MAIS). SUBJECTS AND METHODS: Prelingually deafened German-speaking
children and English-speaking children with Clarion cochlear implants were
assessed on the MAIS pre- and postoperatively. Data were analyzed in terms of the
absolute score, preoperatively and at two postoperative intervals, and the
improvement score. RESULTS AND DISCUSSION: Preoperatively, the MAIS scores of
German-speaking children were slightly lower than those of English-speaking
children. Postoperatively, this difference became more pronounced. Substantial
deviation within each group of subjects was suggested by the size of the standard
deviations.
PMID- 9391647
TI - Cost-effectiveness considerations in pediatric cochlear implantation.
AB - OBJECTIVE: To summarizes the results of cost-utility analyses of pediatric
cochlear implantation (CI) in the United Kingdom. METHOD: Analysis is based on
the direct costs of medical and rehabilitative management and also on emerging
evidence that implantation leads to a shift in educational placements in favor of
mainstreaming with support. RESULT: The resulting cost-utility ratio falls on the
margin of the range considered acceptable within the British health-care system.
The analysis also suggests that pediatric CI could be acceptably cost-effective.
CONCLUSION: The next step should be to measure the costs of alternative
educational settings directly.
PMID- 9391648
TI - Preliminary conversation with the parents before cochlear implantation.
AB - OBJECTIVE: To provide parents of hearing-impaired children about to undergo
cochlear implantation with an opportunity to discuss their expectations and the
pedagogical implications of surgery. SETTING: Parents and children participate in
discussions at the medical center where the cochlear implantation will take
place. PATIENTS: More than 700 children and their parents have participated.
OUTCOMES: Parents of congenitally deaf children differ somewhat in their
expectations and behavior from the parents of postlingually deafened children.
PMID- 9391649
TI - Nucleoprotein complexes harboring an extrachromosomal DNA closely related to 7 S
DNA of avian myeloblastosis virus: physico-chemical properties and representation
of nucleic acids.
AB - The source of avian myeloblastosis virus (AMV) DNA, an extrachromosomal small
polydisperse DNA, present in the material forming the postmicrosomal sediment
(POMS) of lysed chicken leukemic myeloblasts (CHLMs) is organized into
nucleoprotein (NP) complexes containing always RNA. This material, radioactively
double-labelled for DNA and RNA, separated in isopycnic sucrose gradients into
three POMS components (A,B,C) differing from one another in properties of
labelling for DNA and RNA, sucrose densities (1.21, 1.18 and 1.08 g/cm3 for
components A, B and C, respectively) and sedimentation properties of NP complexes
which constituted the individual POMS components. The NP complexes present in
representative fractions of POMS components A, B and C sedimented at 37.3 and
27.3, at 15.3 and 7.4, and at 11.3 and 5.5, respectively. They differed also in
the length of DNAs they were harboring. Radioactively double-labelled nucleic
acids (NAs) of POMS components A, B and C sedimented at 9, 7 and 3.5 S,
respectively, and the sedimentation characteristics of both labels corresponded
with those significant for replication intermediates. Electrophoretic
characteristics of these NAs indicated that we dealt with DNA and RNA products of
a lagging DNA strand synthesis (LSS) taking place, evidently, on pieces of the
lagging sites of replicating DNA strands that were cut out at predicted sites by
nucleases. As regards the origin of AMV DNA, we show that the major and minor
portions of this DNA might be descending from NAs harbored in NP complexes of
POMS components B and C, respectively, pointing out selectivity of segregation of
this DNA from the cell into AMV core.
PMID- 9391650
TI - Activities of a lagging DNA strand synthesis of nucleoprotein complexes harboring
an extrachromosomal DNA closely related to avian myeloblastosis virus core-bound
DNA.
AB - Nucleoprotein (NP) complexes constituting the material of the postmicrosomal
sediment (POMS) and its three basic components (A, B, C) (Riman and Sulova,
1997a), harboring an extrachromosomal DNA closely related to AMV DNA were found
to possess DNA- and RNA-synthesizing activities (SAs) reflecting the ability of
this material to be intensely labelled for DNA and RNA, respectively. The types
of these NA-SAs were compatible with those significant for a lagging DNA strand
synthesis (LSS). The use of selective inhibitors and of the proliferating cell
nuclear antigen (PCNA) disclosed a successive involvement of alpha DNA polymerase
(pol) and PCNA-insensitive delta DNA pol in LSS. In this respect, we show gradual
changes in the representation of activities (As) of both mentioned DNA pols in
the NP complexes of the individual POMS components. Those of POMS component C
contained alpha DNA pol As only, while a distinct portion of DNA SAs of POMS
component B was represented on expense of alpha DNA pol As by PCNA-insensitive
delta DNA pol (epsilon DNA pol), As which represented practically all the DNA SAs
of POMS component A. The type of RNA SAs of this material represented mostly by
primase (Pr) As corresponded well with the nature of LSS. An exception was
represented by a minor portion of RNA-SAs of POMS component A which was alpha
amanitin-sensitive like RNA pol II. Moreover, analyzing this natural model
replication system, we found that the carbonyldiphosphonate (COMDP), a selective
inhibitor of the PCNA-insensitive delta DNA pol, was a strong activator of Pr-As
and/or Pr-alpha DNA pol As of NP complexes of POMS component C.
PMID- 9391651
TI - Products of a lagging DNA strand synthesis of nucleoprotein complexes harboring
an extrachromosomal DNA closely related to avian myeloblastosis virus core-bound
DNA.
AB - Nucleoprotein (NP) complexes present in selected fractions of the separated three
basic components A, B, C of the postmicrosomal sediment (POMS) (Riman and Sulova,
1997a) were used as a source of nucleic acid synthesizing activities (NA-SAs)
expressed in reactions in vitro. These were performed in the absence and presence
of N2-(p-butylphenyl) deoxyguanosine 5'-triphosphate (BuPdGTP), aphidicolin (Aph)
and carbonyldiphosphonate (COMDP), inhibitors allowing differentiation between
two DNA polymerases (pols) involved in a lagging DNA strand synthesis (LSS).
Reaction products were isolated and analyzed by polyacrylamide gel
electrophoresis (PAGE) in denaturing conditions. Products labelled with [alpha
32P]dAMP or [alpha-32P]AMP were represented by intermediates significant for LSS.
Okazaki fragment precursors, whose synthesis was inhibited by BuPdGTP and
resistant to Aph, and whose radioactive RNA label was DNase I-sensitive,
represented products formed in vitro by NP complexes of POMS component C. Okazaki
fragments 127 b in length, whose synthesis was insensitive to BuPdGTP but
inhibited by Aph and COMDP, were characteristic of the reactions accomplished by
NP complexes of POMS component B while products of NA-SAs of NP complexes of POMS
component A were represented by Okazaki fragments up to 280 b in length, whose
synthesis was most sensitive to Aph. In accord with previous data (Riman and
Sulova, 1997b), COMDP strongly stimulated production of RNAs corresponding in
length with initiator RNAs (iRNAs). However, in dependence on reaction conditions
also ribodeoxyribonucleotide primers can be produced by NP complexes of POMS
component C, suggesting the occurrence of two primase (Pr) catalytic modes
influenced by dNTP/rNTP relation and thus, by COMDP, a strong competitor for
dNTPs. These results represent the first direct evidence that an extrachromosomal
DNA organized into special NP complexes can be replicated extrachromosomally by a
mechanism of LSS.
PMID- 9391652
TI - Augmentation of natural killer cell activity induced by cytomegalovirus infection
in mice treated with FK506.
AB - Comparable rates of patient and graft survival after FK506 and cyclosporine
treatments have been reported in the prevention of liver allograft rejection. On
this basis, we examined the effect of FK506 on pathogenesis of cytomegalovirus
(CMV) infection in mice. FK506 induced apparent immunosuppression in mice which
could be monitored by the level of antibody production. The effective dose of
trinitrophenyl-keyhole limpet hemocyanin (TNP-KLH) for 50% reduction in antibody
production was 0.9 mg/kg. Even in such an immunosuppressed status at this or
higher dose of FK506, CMV infection was relatively alleviated, which was observed
by the frequency of virus isolation and the mean virus titer of the lungs of mice
treated with 0.1-1 mg/kg FK506 in comparison to untreated mice. The dose of FK506
attaining 50% frequency of lung infection was 1.5 mg/kg. The activity of natural
killer (NK) cells was enhanced in infected mice. This enhancement was stronger in
infected mice treated with FK506 at 0.32 mg/kg and 10 mg/kg than in untreated
infected mice on day 3 post infection (p.i.). Thus, an immunosuppressant FK506
augmented inducible NK cell activity and alleviated MCMV infection even under
immunosuppression.
PMID- 9391653
TI - Electronmicroscopic study of human herpesvirus 6-infected human T cell lines
superinfected with human immunodeficiency virus type 1.
AB - Human herpesvirus 6 (HHV-6) has been proposed as one of the co-factors
responsible for the development of acquired immunodeficiency syndrome (AIDS) in
human immunodeficiency virus (HIV) carriers. We analyzed the interaction between
HHV-6 and HIV-1 in superinfected cells. Cell-free HIV-1 could superinfect human T
cell lines, MT-4 and Molt-4, which had been previously infected with HHV-6. Both
HHV-1 and HHV-6 replicated in the same cells. We observed two types of
morphologically distinguished cells as early as 4 days after superinfection. One
type (D) was degenerate cells with intracellular and extracellular HHV-6 and with
less HIV-1 virions. The other type (I) was relatively intact cells with both HIV
1 and HHV-6 virions. Replication of HIV-1 was more active in the type I as
compared with type D cells. The level of HIV-1 reverse transcriptase (RT)
activity in the culture supernatants of cells superinfected on day 0 declined
after day 7, while that in the supernatants of cell cultures infected with HIV-1
alone remained high between days 12 and 40. These results suggest that the
superinfection of the HHV-6-infected cells with HIV-1 may induce a degenerative
process in these cells.
PMID- 9391654
TI - Evolutionary stasis of M1 gene of human influenza A viruses and the possibility
of their subtyping by restriction analysis of M1 gene polymerase chain reaction
product.
AB - Nucleotide (nt) and amino acid (aa) sequences of the M1 protein in 36 human
influenza A viruses were analyzed. The neighbor joining tree of the nt sequences
revealed several lineages associated with past epidemics of human influenza.
However, the tree of aa sequences revealed only few specific lineages. This
discrepancy in phylogeny between nt and aa sequences indicates that the M1
protein of human influenza A virus nearly reached an evolutionary stasis. A
simple subtyping method of human influenza A viruses by restriction fragment
length polymorphism (RFLP) analysis of M1 gene polymerase chain reaction (PCR)
products is discussed.
PMID- 9391655
TI - Detection of strawberry vein banding virus by polymerase chain reaction and dot
blot hybridization.
AB - Strawberry vein banding virus (SVBV) is one of seventeen members of the family
Caulimoviridae. Natural infection with the virus is known in Fragaria species
only. Infections caused by SVBV are often symptomless (1), but their significance
increases in mixed infections with strawberry crinkle or strawberry latent C
viruses (2,3). This virus has been originally found on strawberries in USA and
firstly described by Frazier (4), but it is probably world-wide distributed by
planting or breeding materials. SVBV has been observed on cultivated strawberries
in North America, Australia, Brazil, Japan (5) and recently in Europe (6,7). The
concentration of SVBV in infected plants is usually very low. Its detection by
ELISA is impossible because of lack of specific antibodies. Evidence of the
caulimovirus nature of SVBV has been confirmed by its circular dsDNA genome,
shape and size of viral particles (8), presence of cytoplasmic inclusion bodies
typical for caulimoviruses, and distant serological relationship with cauliflower
mosaic virus (CaMV, 9). In this paper we present detection of SVBV by combination
of two detection methods--polymerase chain reaction (PCR) and dot blot
hybridization with a non-radioactive probe.
PMID- 9391656
TI - Gay youth and their precautionary sexual behaviors: the Sydney men and sexual
health study.
AB - Many commentators have positioned Western gay youth as a high-risk group for HIV
infection and obscured important cultural, social, and contextual differences
between populations. This study compares risk of HIV transmission factors among
216 young (under 25 years) and 822 older (25 years or over) homosexually active
men, recruited through Sydney gay community and other sources. Bivariate and
multivariate analyses of survey data that were collected by personal interviews
consistently supported our hypothesis of no difference in HIV-related risk
factors between young and older men. Although young men in this cohort were more
likely to be of unknown serostatus, they were at least as knowledgeable, as
attached to gay community, and as precautionary in their sexual behaviors with
regular and casual male partners as their older counterparts. Safety campaigns
targeting these young gay men should focus, for example, on their lower rates of
HIV antibody testing and not be based on a false premise of hedonistic,
uninformed, and disenfranchised youth.
PMID- 9391657
TI - Condom use by Dutch men with commercial heterosexual contacts: determinants and
considerations.
AB - We report responses from 559 clients of female prostitutes, with a view to
determining to what extent previously identified factors play a part in condom
use. To increase the response rate to advertisements in daily and weekly
newspapers, interviews were held by phone. This procedure had the advantage of
ensuring the anonymity many clients demanded. Of those clients having vaginal or
anal contact (91%), 14% had not always used condoms in the previous year.
Compared with consistent condom users, these men were less highly educated, had
twice as many commercial contacts, and had more contacts with "steady"
prostitutes. They were either more emotionally motivated to visit prostitutes
than were consistent condom users or exhibited a stronger need for sexual
variation. They showed a more compulsive attitude toward visiting prostitutes,
had a more negative attitude toward prostitution in general, evaluated condoms
more negatively, had a higher personal efficacy to achieve unsafe contacts, and
had a higher general risk assessment, commensurate with their behavior. Men with
only safe contacts had either an intrinsic or an extrinsic motivation for condom
use. Among extrinsically motivated men, their behavior change was more recent and
had not yet taken root: They still envisioned unsafe commercial sex to be
possible in the future. Education aimed at the small group of men practicing
unsafe contacts will not easily and directly lead to behavior change. But these
educational activities may support prostitutes to persist in (consistent) condom
use, regardless of clients' pressure to do otherwise.
PMID- 9391658
TI - Attitudes, norms, self-efficacy, and stage of change among out-of-treatment
female crack cocaine users: a pilot study.
AB - The level of sexual risk among crack cocaine uses had remained high, regardless
of their level of AIDS knowledge. Consequently, researchers have advocated the
use of rigorous behavioral theory in aiding epidemiological research and
intervention. To test whether stage of change for "insisting that men (besides
your main partner) use condoms every time you have sex with them" was associated
with behavioral attitudes, subjective norms, and self-efficacy among female crack
cocaine users, a behavioral context questionnaire was administered to 61 female
crack cocaine users who were recruited in the field and interviewed in an urban
HIV testing center. Results indicated that all three were associated with stage
of change and that self-efficacy was the variable most strongly related to stage
of change.
PMID- 9391659
TI - Psychosocial antecedents of needle/syringe disinfection by drug users: a theory
based prospective analysis.
AB - Working from the AIDS risk reduction model and other theories of behavior change,
we tested psychosocial antecedents of needle/syringe disinfection by 136
injection drug users. High perceived self-efficacy for risk reduction exerted a
positive effect on needles/syringe disinfection attempts 1 year later. Self
efficacy was, in turn, related to lower perceived infection risk, peer norms more
favorable to risk reduction, and greater knowledge of AIDS. Behavioral intention
had no significant effect on subsequent disinfection attempts. These results
suggest that disinfecting needles/syringes is partly non-volitional; that high
perceived infection risk may be counterproductive to injection risk reduction;
and that perceive self-efficacy, but not intention to change behavior, may be a
useful leverage point for AIDS preventive intervention.
PMID- 9391660
TI - AIDS knowledge and risk perception of cocaine and crack users in a national
household survey.
AB - Awareness of AIDS among cocaine and crack users has never been studied using
national data representative of the U.S. household population. Data from the 1991
National Health Interview Survey were analyzed. Respondents who reported cocaine
(n = 448) or crack use (n = 100) in the past year were compared with those who
reported never using any form of cocaine (n = 17,259). AIDS knowledge, HIV
testing, risk behavior, and perceived risk for HIV were outcomes studied. Over
96% of the drug users know the term HIV compared with 89% of the nonusers. A
higher proportion of cocaine users reorganized the effectiveness of condoms
compared with nonusers (93% vs. 84%). Over 96% of all groups knew the risk of
sharing needles. Cocaine and crack users were more likely to have been tested for
HIV (27% and 28%) compared with nonusers (19%), yet less than one third of those
tested actually received HIV counseling. High-risk behavior was acknowledged by
22% of cocaine users and 33% of crack users. However, only 10% and 14%
respectively considered themselves to be at increased risk for having or getting
HIV. These data suggest that cocaine and crack users are knowledgeable regarding
HIV/AIDS, however they are underestimating their real risk of infection with HIV.
PMID- 9391661
TI - AIDS and condoms in Brasilia: a telephone survey.
AB - A telephone survey was conducted to measure AIDS knowledge, media usage and
condom attitudes and behaviors among 500 adults aged 18 to 49 in Brasilia, as
well as to evaluate the feasibility of the telephone survey method in a
developing country. The response rate was 91.6%. Respondents had good knowledge
about correct modes of HIV transmission and prevention but also believed HIV was
transmitted through blood donation, public toilets, swimming pools, and mosquito
bites. TV and newspapers were the most important sources of information on health
matters and AIDS, though health workers were considered the most credible sources
of such information. Only 19% of sexual encounters in the 4 weeks prior to the
survey included condoms. Single and younger respondents and those with more
positive attitudes used condoms more frequently. More work is needed to identify
appropriate messages to motivate people to use condoms. Telephone surveys
regarding AIDS and sexual attitudes and behaviors are feasible in Brasilia, a
planned community with universal telephone coverage.
PMID- 9391662
TI - Perspectives on the future of temporal bone research.
PMID- 9391663
TI - Labyrinthine fistula as a complication of cholesteatoma.
AB - HYPOTHESIS: The objective of this study was to present the authors' experience in
the management of labyrinthine fistula caused by cholesteatoma. METHODS: The
clinical charts of 92 patients who underwent surgical procedures for
cholesteatoma complicated by labyrinthine fistula between 1979 and 1975 were
reviewed retrospectively. In this period, 1,205 patients were operated on for
cholesteatoma. In each patient, the site and size of the fistula were evaluated
during surgery and the hearing thresholds were compared before and after surgery.
RESULTS: The fistula involved the lateral semicircular canal in 71 patients.
Multiple fistulas were observed in nine patients. Postoperative hearing levels
were unchanged or improved in 83.7% of patients. Comparison between hearing
outcomes and size of the fistula showed better findings when smaller size
fistulas were found. No significant differences between open and closed
techniques were detected. Favorable outcomes were obtained in patients treated
with surgical obliteration of the interrupted labyrinth. CONCLUSIONS: The current
study confirmed that careful manipulation of the labyrinthine fistula is
mandatory to preserve hearing functions for these patients. According to the
authors' experience, the future trend for fistula treatment could be directed
toward less conservative techniques compared with the previous indications
favoring methods of interruption and subsequent obliteration of the semicircular
canals.
PMID- 9391664
TI - Stimulation of epithelial healing in chronic postoperative otorrhea using
lyophilized cultured keratinocyte lysates.
AB - OBJECTIVE: After tympanoplasty, despite a closed tympanic graft, some patients
continue to have persistent otorrhea due to insufficient epithelial healing and
granulation tissue formation in the depths of the outer ear canal. When all
medical therapies fail, many otologists undertake revision surgery, usually with
free skin grafting. To avoid surgery, the authors sought to improve this
condition with a lysate of lyophilized cultured allogeneic keratinocytes. STUDY
DESIGN AND PATIENTS: In this prospective pilot study, lyophilized cultured
allogeneic keratinocyte lysates have been administered in 27 patients. These
patients had uncontrollable otorrhea that resisted medical (topical) therapy for
at least 6 months. MAIN OUTCOME MEASURE: The criterion of success was a complete
epithelialization and cessation of otorrhea. RESULTS: After an average of 2
applications, cessation of otorrhea was achieved in 20 cases (74%). Three
patients (11%) relapsed after 3 months. The other ears (63%) still were dry at
the 1-year final evaluation. CONCLUSIONS: These results are similar to those
obtained after application of sheets of viable cultured keratinocytes of
autologous as well as of allogeneic origin. Because the soluble lysate can be
incorporated into ototopical drops, the lysate technique is more "user-friendly"
and can be applicable in any outpatient clinic. Because keratinocytes contain
many growth factors (e.g., epidermal growth factor, basic fibroblast growth
factor, platelet-derived growth factor, transforming growth factor), the authors
speculate that the release of those intracellular growth factors is responsible
for the observed therapeutic effect. This form of therapy by its combination of
several growth factors might be considered a more physiologic method than the,
also still experimental, growth factor therapy in which high doses of only single
growth factor are used.
PMID- 9391665
TI - Intra-operative electrocochleography in stapedectomy and ossicular
reconstruction.
AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of
intraoperative electrocochleography (ECOG) in predicating the postoperative
hearing improvement in surgery for conductive hearing loss. STUDY DESIGN: This
study was a prospective study of 22 patients undergoing intraoperative
electrocochleography during a stapedectomy. SETTING: The study was performed in a
tertiary referral center. PATIENTS: Intraoperative electrocochleography was
performed in 22 patients 27-73 years of age undergoing a stapedectomy for
otosclerosis under general anesthesia. INTERVENTION: For each patient, the N1
threshold to click stimulation was measured intraoperatively, before and after
the reconstruction. MAIN OUTCOME MEASURES: The intraoperative ECOG thresholds
were compared with the pre and postoperative audiograms. RESULTS:
Postreconstruction ECOG's demonstrated improvements in the N1 threshold in 19
cases, and were unchanged in 1 case. In each of these cases, improvement in the
intraoperative N1 threshold corresponded with improvement in the postoperative
audiogram compared with the preoperative studies. In two other cases the
postreconstruction ECOG was nearly unobtainable, despite improved hearing
postoperatively. CONCLUSION: Intraoperative ECOG appears to be an effective tool
for verifying the functional integrity of ossicular reconstructions as in
stapedectomies. We speculate that intraoperative ECOG may allow the surgeon to
"fine tune" the reconstruction to optimize the hearing results.
PMID- 9391666
TI - Cost analysis of cochlear implants in deaf children in The Netherlands.
AB - OBJECTIVE: The purpose of the study was to determine the costs of cochlear
implants in children regarding the phases of selection, implantation,
rehabilitation, and aftercare. STUDY DESIGN: This study was a prospective cost
analysis paralleling a noncomparative observational study. SETTING: This study
was conducted at a university hospital to evaluate cost data on selection and
implantation and at an institute for the deaf to evaluate cost data on
rehabilitation and aftercare. PATIENTS: The study group consisted of prelingual
deaf children (mean age, 7 years; range, 4-11 years). INTERVENTION: A total of
106 deaf children were screened, of whom 20 received a cochlear implant. MAIN
OUTCOME MEASURES: This study concentrated on the cost of cochlear implants.
Volumes of utilization of human resources and materials were registered during
the 1-year follow-up. For the subsequent period, volumes were modeled on planned
aftercare activities. RESULTS: Real total medical costs per implanted child were
$63,922; selection phase, $7,747; implantation phase, $30,442; rehabilitation
phase, $13,428; and aftercare, $12,305. Nonmedical costs were $1,839.
Calculations were based on 1994 prices, and a time horizon of 5 years was used.
The economic consequences of cochlear implants on educational needs were not
taken into account because of the limited follow-up period. A sensitivity
analysis of the rate of implanted children as part of the number of screened
children showed a moderate impact on the total cost. CONCLUSIONS: Compared to the
results of cost analysis in other countries, the costs of the pediatric cochlear
implants program in The Netherlands are relatively high. Most discrepancies can
be explained by methodologic differences in the cost analyses.
PMID- 9391667
TI - Clarion cochlear implant: short-term effects on voice parameters.
AB - OBJECTIVE: This study aimed to evaluate the moment-to-moment auditory control of
voice at an early stage after implantation with Clarion cochlear implants. STUDY
DESIGN: A perceptive and electroacoustic evaluation of the voice was carried out
through a digital analysis immediately after the activation of the implant,
before the fitting procedure has begun. SETTING: The study was performed at the
Department of Otolaryngology, University "La Sapienza" of Rome. PATIENTS: Nine
profoundly deaf subjects (five post-linguistic deaf adults, two pre-linguistic
deaf children and two peri-linguistic deaf subjects, one adult and one child).
INTERVENTION: Surgical insertion of a Clarion cochlear device. MAIN OUTCOME
MEASURES: Qualitative (short-term pitch and energy perturbation, intonation,
vocal attack, quality, and intensity) and quantitative (F0, F1, F2 and F3
frequency values), under non activated (NAI) and activated (AI) condition, have
been obtained. RESULTS: In the majority of patients, the perceptive evaluation
under AI showed a lowering of voice intonation, a better control of voice
intensity, and a reduction of nasal quality. These findings were confirmed by a
significant lowering of F0 (Wicoxon non parametric test) in all cases and
lowering of F1 and F2 in five cases. Additionally, a better definition of all
formats in the majority of cases as well as by a parallelism of pitch and energy
profile was observed. CONCLUSIONS: The Clarion cochlear implant device provided a
recognizable moment-to-moment auditory control on voice and articulatory
patterns. By monitoring the articulated voice during adjustment of the electrical
stimulation at the first fitting session, one may be able to include these data
and assist in the selection of the best rehabilitative strategy.
PMID- 9391668
TI - Immediate effects of middle ear pressure changes on the electrocochleographic
recordings in patients with Meniere's disease: a clinical placebo-controlled
study.
AB - OBJECTIVE: The aim of the study was to evaluate effects of middle ear pressure
changes on the electrocochleographic responses in patients with well-defined
Meniere's disease. STUDY DESIGN AND INTERVENTIONS: The investigation was
conducted as a placebo-controlled, randomized clinical study.
Electrocochleographic measurements were performed before and after the insertion
of a transtympanic ventilation tube and immediately after the exposure to active
or placebo treatment. SETTING: The study was carried out in one secondary
referral center and one tertiary referral center on an ambulatory basis.
PATIENTS: Thirty-nine patients with well-defined Meniere's disease were included
in the study. MAIN OUTCOME MEASURES: The summating potential/action potential
ratio of the electrocochleographic response complex was chosen as the main
variable for statistical evaluation of results. Other parameters of the
recordings such as responses to low-frequency burst stimulation also were
evaluated. Subjective symptoms (e.g., vertigo, tinnitus, and aural pressure) were
assessed before and after insertion of the ventilation tube and before and after
exposure to treatment. RESULTS: A statistical difference was shown in the
electrocochleographic response in the active group before and after exposure to
middle ear pressure changes. In the placebo group, no change was found. Changes
in electrocochleographic parameters in the active group indicated an improvement
in inner ear electrophysiology. No significant changes were found in subjective
symptoms in the active or the placebo group. Evaluation before and after
insertion of the ventilation tube showed no significant improvement in any
variable. CONCLUSIONS: This is the first study in which electrophysiologic
parameters were evaluated in a placebo-controlled clinical trial of overpressure
treatment in Meniere's disease. The results show that electrophysiologic
parameters can be improved by the application of positive pressure pulses of low
amplitude in the middle ear.
PMID- 9391669
TI - Detection of viral DNA in vestibular ganglia tissue from patients with Meniere's
disease.
AB - OBJECTIVE: The main goal of this study was to examine the vestibular ganglia from
11 patients with intractable classic Meniere's disease (MD) for the presence or
absence of DNA from three neurotropic viruses (herpes simplex virus,
cytomegalovirus, and varicella zoster virus) using exquisitely sensitive
molecular biologic techniques. STUDY DESIGN: This was a prospective controlled
study with vestibular ganglia from patients with MD and from patients with small
vestibular schwannomas undergoing resection. Polymerase chain reaction was used
for viral DNA detection from the ganglia along with known positive and negative
polymerase chain reaction control subjects. SETTING: The study was performed in
an academic tertiary referral center. PATIENTS: Patients for inclusion had
medically uncontrolled MD, including documented fluctuating sensorineural hearing
loss, episodic vertigo, and tinnitus who elected to undergo vestibular nerve
section. Control patients were undergoing vestibular schwannoma removal.
INTERVENTIONS: The intervention was vestibular nerve section with removal of
vestibular ganglion. MAIN OUTCOME MEASURES: The presence or absence of viral DNA
(herpes simplex virus, cytomegalovirus, and varicella zoster virus) in vestibular
ganglion tissues detected by polymerase chain reaction. RESULTS: No viral DNA was
detected in the vestibular ganglia of patients with MD (p = 0.028) nor in the
control group. The likelihood of a type II or beta type error was < 10%.
CONCLUSIONS: In patients with MD requiring surgical intervention, infection with
herpes simplex virus, cytomegalovirus, or varicella zoster virus of the
vestibular ganglia does not appear to play a major role in the pathoetiology of
the disease.
PMID- 9391671
TI - Role of transient-evoked otoacoustic emissions for hearing preservation in
acoustic neuroma surgery.
AB - OBJECTIVE: This study aimed to assess whether transient-evoked otoacoustic
emissions (TEOAEs), which are known to be expressions of an intact cochlear
function, could be useful for the rationale of hearing preservation in acoustic
neuroma (AN) surgery. STUDY DESIGN: The TEOAEs were measured before, during, and
after surgery in a consecutive series of patients affected by cerebellopontine
angle tumors. SETTING: The study was performed at the Department of
Otolaryngology, University "La Sapienza" of Rome. PATIENTS: Five patients with AN
and one with a meningioma totally involving the Cochlear (VIII) nerve.
INTERVENTION: Retrosigmoid approach on the ground of the limited AN size (within
20 mm) and the 30/70 rule, as proposed by the American Academy of Otolaryngology
Head and Neck Surgery nomogram. Two patients also were selected despite a poor
hearing level and the absence of TEOAEs. MAIN OUTCOME MEASURES: Preoperative and
postoperative pure tone audiometry compared with TEOAEs. Intraoperative TEOAEs
were compared with electrocochleographic findings. RESULTS: The TEOAEs were found
to be present also in patients with AN with poor pure-tone average (PTA)
threshold (i.e., > 75 dB). Intraoperatively, TEOAEs recording showed to be
markedly affected by the environmental noise as well as by specific
intraoperative maneuvers, such as drilling of the internal auditory canal or
tumor removal or both. In the three patients in whom hearing successfully was
preserved. TEOAEs were present in the first postoperative days, despite a
temporary deterioration of the PTA threshold. CONCLUSIONS: The intraoperative use
of TEOAEs showed to be scarcely reliable, whereas their presence in the
preoperative assessment of patients with AN could lead to an extended number of
patients to be selected for hearing-preservation surgery. Finally, an early
postoperative identification of TEOAEs may be considered a favorable prognostic
sign for foreseeing a delayed pure-tone hearing threshold recovery.
PMID- 9391670
TI - Nonsurgical factors predictive of postoperative hearing for patients with
vestibular schwannoma.
AB - OBJECTIVE: The purposes of the study were to determine whether preoperative
cochlear reserve as measured by evoked otoacoustic emissions (EOAE) as well as
other hearing variables often associated with hearing preservation are correlated
with hearing preservation after tumor removal and to determine whether any
hearing variables are independent of tumor size as a predictor of hearing
preservation. STUDY DESIGN: Preoperative audiologic data for 104 patients having
vestibular nerve schwannomas removed via a retrosigmoid surgical approach were
reviewed and subjected to factor analysis. SETTING: All patients were seen at the
Mayo Clinic, Rochester, Minnesota. PATIENTS: The patient sample was divided into
two groups based on hearing thresholds after surgery. Group I consisted of 73
ears without hearing preservation. The remaining 31 ears, group II, had preserved
hearing (defined as average postoperative pure-tone thresholds < or = 85-dB HL
for 0.5, 1, 2, and 3 kHz). MAIN OUTCOME MEASURES: Variables not predictive of
hearing preservation were age, gender, tumor laterality, and cochlear reserve
(EOAE). Variables predictive of hearing preservation were small tumor size, pure
tone hearing sensitivity, speech reception thresholds, word recognition scores,
integrity of cochlear nerve (acoustic reflex thresholds, and auditory brain stem
response [ABR] waveforms). RESULTS: A multivariate logistic regression analysis
showed that only word recognition scores at 40-dB sensation level were
independent of tumor size as a predictor of hearing preservation.
PMID- 9391672
TI - Radioimmunoimaging of glomus tympanicum tumors by In-111 labeled monoclonal
antibody using single photon emission computed tomography.
AB - OBJECTIVE: This study aimed to evaluate the diagnostic value of
radioimmunoimaging by radionuclide-labeled monoclonal antibody F023C5 (MAb),
raised originally against carcinoembryonic antigen (CEA), in patients with glomus
tympanicum tumors. STUDY DESIGN: Prospective. SETTING: Preoperative imaging
versus radioactivity of removed tumor. PATIENTS: Two patients with paraganglioma
(glomus tympanicum). INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE: Radiolabeled
MAb accumulates in paraganglioma tissue. Single photon emission computed
tomography (SPECT) provides improved detection of lesions. RESULTS: SPECT using
F023C5 MAb detected the abnormal accumulation of radioactivity in the middle ear
region. This method detected paraganglioma less than 1 cm in diameter.
CONCLUSIONS: Successful detection of glomus tympanicum in two patients using In
111-labeled F023C5 MAb is reported. The result suggests the radioimmunoimaging
using this antibody is useful for the detection of not only primary glomus
tumors, but also of local recurrence and unsuspected lesion in patients with
paragangliomas.
PMID- 9391673
TI - Somatic neurofibromatosis type 2 gene mutations and growth characteristics in
vestibular schwannoma.
AB - BACKGROUND: The growth of hereditary and sporadic vestibular schwannomas shows
wide variation, but what determines this is poorly understood. HYPOTHESIS: In
neurofibromatosis type 2 (NF2), there is some correlation between the nature of
the germline NF2 gene mutation and phenotype. Somatic mutations in the NF2 gene
occur in sporadic tumors, but their relation to tumor behavior is unknown.
METHODS: This study has investigated the molecular pathogenesis of vestibular
schwannoma by looking for NF2 gene mutations. The authors have screened 17 exons
of the NF2 gene in 91 sporadic vestibular schwannomas, 2 NF2, and 1 vagal
schwannoma. These data have been correlated with a clinical growth index and a
tumor cell proliferation index, determined using a monoclonal antibody to the
proliferating cell nuclear antigen. RESULTS: Of the 94 tumors studied, 40 somatic
gene mutations (38%) have been sequenced in 36 tumors. The mutations included 36
protein truncating mutations, 1 in-frame deletion, 2 splice site mutations, and 1
missense mutation. Regression analysis showed no correlation between the nature
of the NF2 gene mutation and either the clinical (R2 = 0.006) or the
proliferative index (R2 = 4 x 10(-8). CONCLUSION: The results of this study show
no association between the nature of the intragenic NF2 gene mutation and tumor
behavior. It is likely therefore that NF2 gene inactivation is not the only
determinant of tumor behavior in vestibular schwannoma.
PMID- 9391674
TI - Does the stapes reflex remain the same after Bell's palsy?
AB - OBJECTIVE: The authors investigated the integrity and function of nervus
stapedius 1 year after facial paralysis. STUDY DESIGN: Patients with Bell's palsy
were observed prospectively for 1 year and compared with healthy patients.
SETTING: The follow-up of patients was done in the outpatient clinic and tests
were applied in the audiology unit. PATIENTS: The mean age of 32 patients was
41.03 years. Eight of 32 patients were grade II (25%), 11 were grade III (35%),
and 13 were grade IV (40%) according to House-Brackman grading system. The mean
age of the control group (10 persons) was 36.5 years. INTERVENTION: Contralateral
stimulus was used in acoustic reflex test at 500 and 1,000 Hz with 80-, 90-, 100
, and 110-dB stimulus intensity. Tests were applied in three ways: normal
position, eye-closed position, and grin position. Tests were done in the first 15
days of facial paralysis and repeated at least 1 year thereafter. The millimeter
difference in amplitude of impedance recording of middle ear between the normal
ear and paralyzed ear was accepted as criterion. MAIN OUTCOME MEASURES: There
were 6- to 9-mm amplitude differences between normal side and healed side of
grade IV patients with 100- and 110-dB stimuli. RESULTS: In the second test
(after 1 year), statistically significant differences were present between
control group and grade IV patients on 1,000 and 500 Hz frequencies with 100- and
110-dB stimulus intensity (p < 0.05). There were no significant differences
between grade II and control group and between grade III and control group.
CONCLUSIONS: A permanent partial denervation is present on the stapedial nerve,
especially after grade IV paralysis, and it affects the function of stapes muscle
in high decibel sounds. But it does not affect the stapes reflex threshold. No
synkinetic innervation was found in the authors' patient group with their test
method.
PMID- 9391675
TI - Surface temperature distributions in carbon dioxide, argon, and KTP (Nd:YAG)
laser ablated otic capsule and calvarial bone.
AB - HYPOTHESIS: The spatial and temporal surface temperature distribution was
measured after laser irradiation in fresh porcine otic capsule and calvarial bone
tissue using an HgCdTe (mercury-cadmium-tellurium) infrared camera. BACKGROUND:
Carbon dioxide (CO2) (lambda = 10.6 mm), argon (lambda = 514 nm), and Potassium
Titanyl-Phosphate Neodynium: Yttrium-Aluminum-Garnet (KTP[Nd:YAG]) (lambda = 532
nm) lasers are used for stapes surgery and in the treatment of chronic ear
disease. Despite extensive clinical use, little is known about the thermal
perturbations in otic capsule calcified tissues and what are safe energy
parameters for laser use. METHODS: A microspot manipulator, lens, and microfiber
were used for continuous wave (CW) and super-pulse (SP) CO2, argon, and
KTP(Nd:YAG) lasers, respectively. Peak temperatures after ablation were measured
simultaneously along with the full-width--half-maximum of the thermal disturbance
and fitted to a Gaussian distribution. The cooling time for the hot spot to
return to ambient temperature also was recorded. RESULTS: Temperature changes
with CW CO2 irradiation were markedly elevated relative to SP mode and also
required longer to cool. The KTP and argon-treated bone were irradiated in the
presence and absence of an initiator (black ink): minimal surface temperature
elevation was recorded in the absence of an initiator. Further, no surface
modification was observed. In contrast, the addition of an initiator resulted in
marked temperature elevations and significant surface carbonization with these
two visible wavelength lasers. Cooling times varied from 10-40 seconds. No
consistent relation to the measured thermal values and tissue microarchitecture
was observed. CONCLUSIONS: The measured cooling times and Gaussian distribution
of surface temperatures serve as empiric guidelines for minimizing thermal injury
to critical structures during laser surgery in the middle ear.
PMID- 9391676
TI - Juvenile keratin inoculation induces chronic ear pathology.
AB - OBJECTIVE: Human neonatal temporal bones frequently show the formation of
granulation tissue provoked by amniotic fluid keratin contents, desquamated
keratinized epithelial cells and lanugo hair. Similar histopathologic findings
have been produced previously in a short-term animal model. To test the
hypothesis that those short-term pathologic observations could have theoretical
relevance for ear disease in older patients, a longer term animal model study was
necessary. METHODS: Into the right bulla of 10 chinchilla pups was placed an
aliquot of autogenous, nonviable epidermal scrapings and hair. Into the left
bulla was placed 1 mm2 viable autogenous epidermal tissue. Animals were killed at
intervals up to 11 months and then studied by light microscopy. RESULTS: Chronic
ear histopathologic changes such as granulation tissue, osteoneogenesis,
adhesions, and cholesteatoma were present. Over time, these secondary pathologic
changes became more obvious than the initial keratin implant. CONCLUSIONS: The
authors conclude that chronic pathologic changes resembling human ear disorders
persist and that this model further extends the hypothesis that prenatally
acquired keratin eventually could account for some cases of human ear disease.
PMID- 9391677
TI - Imaging case of the month: the narrow internal auditory canal.
PMID- 9391678
TI - Ear drop ototoxicity: reality or myth?
PMID- 9391679
TI - Mechanism of anaphylactoid reactions: improper preparation of high-dose
intravenous cyclosporine leads to bolus infusion of Cremophor EL and
cyclosporine.
AB - BACKGROUND: During a Phase I/II trial of high-dose intravenous cyclosporine, a
high incidence of anaphylactoid reactions was observed. Epidemiologic
investigations revealed that the occurrence of anaphylactoid reactions was
significantly associated with improper mixing during preparation of the
infusions. It was hypothesized that improper mixing during the preparation of the
infusion may have caused initial bolus infusions of the vehicle, Cremophor EL.
These inadvertent bolus infusions may have caused the anaphylactoid reactions.
OBJECTIVE: To investigate the effect of different mixing techniques on the
distribution of the components of cyclosporine concentrate for infusion:
cyclosporine, Cremophor EL, and ethanol in the infusions administered to the
patients. METHODS: Infusions were prepared in a similar fashion as those
administered to study patients enrolled in a high-dose cyclosporine therapy
protocol. Samples were collected at defined time points of the infusions.
Concentrations of cyclosporine and Cremophor EL were spectrophotometrically
determined; ethanol concentrations were measured enzymatically. RESULTS:
Cyclosporine and Cremophor EL concentrations were up to ninefold higher than
intended during the first 10 minutes of the infusions that were not appropriately
mixed. In contrast, the concentrations of cyclosporine and Cremophor EL were
similar to the intended concentrations in all of the well-mixed infusions.
CONCLUSIONS: Inappropriate mixing of high-dose cyclosporine infusions can lead to
initial bolus infusion of cyclosporine and Cremophor EL. Bolus infusions of
Cremophor EL have been associated with anaphylactoid reactions. Thus, through
mixing of high-dose cyclosporine infusions may be important to reduce the
possibility of life-threatening anaphylactoid reactions.
PMID- 9391680
TI - Formulation and stability of naltrexone oral liquid for rapid withdrawal from
methadone.
AB - OBJECTIVE: To assess the stability of naltrexone oral liquid prepared from
tablets and powder, and to evaluate its use in precipitating rapid withdrawal
from methadone. DESIGN: Naltrexone 1 mg/mL oral liquids were prepared from
tablets and powder and stored in the dark at 4, 25, and 70 degrees C. Similar
formulations containing 5 mg/mL were stored at 70 degrees C. The 1-mg/mL
formulation prepared from tablets was clinically evaluated in inducing rapid
withdrawal in two drug-dependent individuals receiving methadone maintenance
treatment using a naltrexone dose titration protocol. SETTING: A university
pharmacy school and affiliated urban teaching hospital. MAIN OUTCOME MEASURES:
Samples removed at six time points were analyzed for naltrexone concentration to
assess decomposition over 90 days. An opioid withdrawal symptom checklist was
used to assess the severity of the withdrawal symptoms prior to, and 30 minutes
after, each dose of naltrexone. RESULTS: Decomposition of naltrexone in all
formulations stored at 4 and 25 degrees C was not significant over 90 days. Both
patients tolerated naltrexone 1 mg/mL oral liquid, but found it bitter and
gritty. Withdrawal symptoms were experienced immediately after the first dose,
but were resolving by the end of day 3 of naltrexone treatment, at which stage
both patients were able to tolerate a 50-mg tablet of naltrexone as maintenance.
CONCLUSIONS: Naltrexone 1 mg/mL oral liquids prepared from tablets or powder are
stable when stored in the dark for 60 days at 4 degrees C and for 30 days at 25
degrees C. The formulation prepared from tablets provides flexible dosing in
patients undergoing rapid withdrawal from methadone.
PMID- 9391681
TI - Drug samples and family practice residents.
AB - OBJECTIVE: To describe residents' knowledge, attitudes, and behaviors regarding
sample medications and to determine the education provided in residency training
regarding sample use. METHODS: A 6-item survey was sent to directors of US family
practice residency programs. Residents of a sample of these programs were sent an
anonymous, self-administered, 21-item questionnaire assessing knowledge,
attitudes, and practices relating to sample use. Both surveys consisted of
initial and follow-up mailings. RESULTS: The residency directors' survey was
returned by 232 of the 436 residency directors (53%). Although 66% of the
programs had a policy regarding samples, only 15% of the policies completely
incorporated recommendations of the Society of Teachers of Family Medicine. After
two mailings, 248 resident responses were received from 43 of 47 residencies
(92%). Only 21% of respondents thought that they received adequate training about
sample use in medical school; this number increased to 49% for residency
training. Agreement with the adequate training statement was highest among
respondents from residencies that had both a sample distribution policy and a
pharmacist (p = 0.044). Fifty-five percent thought that samples influenced their
prescribing and 70% thought that samples helped them to learn more about the
sampled medication. CONCLUSIONS: Family practice residents value and use samples,
although they are often unaware of the rules governing the labeling of samples.
While reported distribution of samples by residents often is appropriate,
education about effective sample use could be improved. Drug samples play a
significant role in residency training.
PMID- 9391682
TI - Consumer requests for information regarding psychotropic drugs: experience from a
national medicines phone-in.
AB - OBJECTIVE: To undertake a qualitative analysis of calls regarding psychotropic
drugs that were received during a national medicines phone-in day. BACKGROUND: In
July 1996, The Society of Hospital Pharmacists of Australia coordinated a
national medications phone-in day, allowing consumers to seek information about
medications from pharmacists and physicians using a toll-free telephone number.
METHODS: Data collection forms were used to record the details of all calls
answered during the phone-in day. Demographic data collected included the
estimated age and gender of the caller. Other data collected included the drugs
that were the subject of the inquiry and the category of questions. RESULTS:
There were 42,096 attempted connections to the service, but because of limited
telecommunications capacity, only 2245 callers were successfully connected.
Psychotropic drugs were the primary subject of 367 calls, representing 16.4% of
all inquiries for which data collection forms were completed. Antidepressants
(56.1%) and benzodiazepines (24.8%) were the two most commonly encountered
classes of psychotropic drugs. The greatest proportion of calls (57.2%) was
related to adverse effects of medications. The nature of the inquiries regarding
adverse drug effects was generally consistent with the adverse effects detailed
in the scientific literature. CONCLUSIONS: The results of this 1-day, consumer
oriented drug information project suggest that there is a substantial need for
this type of service. Patients treated with psychotropic medications should have
access to unbiased, high-quality information about drug therapy.
PMID- 9391683
TI - Continuous intrathecal meperidine via an implantable infusion pump for chronic,
nonmalignant pain.
AB - OBJECTIVE: To report a continuous infusion of intrathecal meperidine via an
implanted infusion pump for nonmalignant, chronic pain. CASE SUMMARY: A 69-year
old white woman had chronic, nonmalignant low-back pain and bilateral leg pain.
Multiple drug therapies and other interventional techniques had failed. The
patient achieved significant pain relief by a continuous infusion of intrathecal
meperidine via an implanted infusion pump. DISCUSSION: To our knowledge, this is
the first report of meperidine administered intrathecally by continuous infusion.
Continuous infusion of intrathecal and epidural opiates by implanted infusion
pumps is becoming more widely recognized as an alternative treatment for patients
with chronic, benign pain. Epidural and intrathecal meperidine is an effective
analgesic for short-term surgical procedures. Data reporting effective relief and
safety with continuous intrathecal meperidine remain limited. CONCLUSIONS:
Continuous intrathecal meperidine via an implantable infusion pump may be an
effective alternative in the treatment of chronic pain.
PMID- 9391684
TI - Symptomatic syndrome of inappropriate antidiuretic hormone secretion associated
with azithromycin.
AB - OBJECTIVE: To report a case of symptomatic syndrome of inappropriate antidiuretic
hormone (SIADH) secretion associated with azithromycin and review the literature
related to this adverse drug reaction. DATA SOURCES: Review articles identified
by a computerized (MEDLINE) (1966-April 1996) and manual (Index Medicus) search.
DATA SYNTHESIS: Azithromycin is a well-tolerated broad-spectrum macrolide
antibiotic. We report a symptomatic case of SIADH secretion associated with
azithromycin. The patient received two doses of azithromycin before the
development of sudden mental status changes associated with severe hyponatremia.
All other potential causes were ruled out. No previous reports exist in the
literature. CONCLUSIONS: Azithromycin may be associated with symptomatic SIADH
secretion. Awareness and attention are required if patients develop mental status
changes or hyponatremia while receiving azithromycin so that appropriate
diagnostic and therapeutic actions can be implemented.
PMID- 9391685
TI - Use of estrogen therapy in a patient with gastrointestinal bleeding secondary to
arteriovenous malformations.
AB - OBJECTIVE: To describe a patient with gastrointestinal (GI) bleeding caused by
arteriovenous malformations (AVMs) that was treated with estrogen therapy. CASE
SUMMARY: A 70-year-old white man was diagnosed with multiple AVMs in the cecum,
duodenum, and stomach. Pharmacologic management included the use of ferrous
sulfate; however, the patient continued to have recurrent bleeding that required
multiple transfusions and endoscopic cauterization. Therapy was initiated with
ethinyl estradiol 0.05 mg po qd; no further transfusions have been required for
10 months. DISCUSSION: It is estimated that AVMs of the GI tract account for 1-8%
of upper GI bleeding episodes and up to 6% of lower GI bleeding episodes.
Hormonal agents have been reported to decrease bleeding in patients with both
hereditary and acquired AVMs. CONCLUSIONS: The role of estrogen therapy in
treating AVMs of the GI tract is unclear and supported by only one clinical
study.
PMID- 9391686
TI - Baclofen toxicity in patients with severely impaired renal function.
AB - OBJECTIVE: To report the toxic effects of baclofen in patients with severely
impaired renal function. DATA SOURCES: From 1991 to 1995, nine patients with
severely impaired renal function (2 not receiving dialysis, 1 undergoing
continuous ambulatory peritoneal dialysis [CAPD], and 6 receiving maintenance
hemodialysis), who exhibited clinical toxicity after baclofen therapy at our
hospital were included for analysis. Another seven cases from the literature
obtained by computerized (MEDLINE) and manual (Index Medicus) search methods
published between 1980 and 1995 were also reviewed. INTERVENTION: Among our nine
patients, the six undergoing chronic hemodialysis and one not undergoing dialysis
received early (< 48 h) hemodialysis after toxic symptoms developed. The patient
undergoing CAPD received late hemodialysis (> 72 h), and the other patient who
had not undergone dialysis received only supportive care. RESULTS: A review of
these 16 cases revealed that most patients received only small doses and very
short-term baclofen therapy. Altered consciousness was the major presenting
feature. Severe acute complications, such as seizures and respiratory depression,
were relatively uncommon among patients with severely impaired renal function.
However, abdominal pain, which has previously rarely been reported, was noted in
five of our nine patients. Most patients showed clinical improvement after
hemodialysis. An analysis of these nine patients revealed that those who received
early hemodialysis had a shorter recovery time than the patient who received only
supportive care (2.71 +/- 0.42, respectively, vs. 9 d; p < 0.01). A lag of
several hours between the end of the hemodialysis session and an improvement in
the level of consciousness was noted. DISCUSSION: As most patients with severely
impaired renal function developed toxic symptoms soon after initiating a low-dose
baclofen regimen, the accumulated dosage was small and severe complications were
less common. Abdominal pain may have occurred as a result of the gamma
aminobutyric acid-mediated cholinergic effect exerted by baclofen. The delay in
conscious recovery after hemodialysis may be due to a delay in the clearance of
baclofen from the central nervous system. CONCLUSIONS: Patients with severely
impaired renal function generally develop baclofen intoxication soon after the
initiation of low-dose therapy. Thus, the administration of baclofen, regardless
of the dosage, in these patients is not appropriate. Abdominal pain, in addition
to altered consciousness, is a common presenting feature in patients with renal
failure who have baclofen intoxication. Hemodialysis is effective in alleviating
the clinical symptoms and shortening the recovery time for such patients.
PMID- 9391687
TI - Agranulocytosis induced by vancomycin or ticarcillin/clavulanate.
AB - OBJECTIVE: To reacquaint clinicians with a reportedly rare adverse event of
agranulocytosis occurring after long-term administration of vancomycin and
ticarcillin/clavulanate, with a subsequent review of other reported cases in the
literature. CASE SUMMARY: A 45-year-old white woman with spina bifida developed
agranulocytosis (2.7 x 10(3)/mm3 white blood cells with only 3% polymorphonuclear
leukocytes and no reported eosinophils or basophils) after long-term
administration of vancomycin and ticarcillin/clavulanate for decubitus ulcers and
chronic osteomyelitis. Consequently, the cell counts rebounded rapidly on
discontinuation of both medications and returned to normal within 1 week.
DISCUSSION: The incidence of vancomycin-associated neutropenia is presumably
rare, but the increased use of vancomycin may disclose a more frequent
occurrence. It is suggested that the mechanism for the reaction is
immunologically mediated, yet this remains unclear. Although it is difficult to
determine the causative agent in this case, vancomycin was most suspect
clinically. Ticarcillin/clavulanate is less likely because our patient has since
been readmitted and treated with oxacillin, imipenem/cilastatin, and
amoxicillin/clavulanate without affecting the white blood cell count. In that
regard, it could be reasoned that an immunologic reaction to ticarcillin would
have resulted in a similar outcome with other penicillins. CONCLUSIONS: This case
serves as a reminder to clinicians that patients receiving long-term treatment
with vancomycin should have their white blood cell count monitored at least
weekly.
PMID- 9391688
TI - Olanzapine: a new antipsychotic agent with efficacy in the management of
schizophrenia.
AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy data, and
adverse effects of olanzapine as a treatment for schizophrenia and to determine
the advantages and disadvantages of this atypical antipsychotic agent compared
with currently marketed agents. DATA SOURCES: A MEDLINE computer literature
search was conducted to retrieve all English-language studies and review articles
involving olanzapine published as of October 1, 1996. The manufacturer of the
drug, Eli Lilly and Company, provided the clinical investigator's brochure and
abstracts of unpublished Phase III clinical trials. STUDY SELECTION: Animal
studies evaluating the pharmacology of olanzapine were evaluated, as were all
open-label and double-blind studies involving the evaluation of olanzapine for
the treatment of patients with schizophrenia. DATA EXTRACTION: All available
clinical studies were reviewed and the interpretation of data for each study was
influenced by the size of the study sample, the nature of the inclusion and
exclusion criteria, and the data analysis techniques used. DATA SYNTHESIS:
Olanzapine is a thienobenzodiazepine analog with an in vitro receptor affinity
profile similar to that of clozapine. Olanzapine exhibits linear kinetics over
the dosage range studied and is extensively metabolized in humans. Clinical
evaluations to date have shown olanzapine to be at least as efficacious as
typical antipsychotic agents in the treatment of the acute phase of
schizophrenia. The drug was well tolerated, with significantly fewer
extrapyramidal adverse effects than haloperidol. Current data suggest that
olanzapine may be more effective than haloperidol for the treatment of negative
symptoms; moreover, preliminary data suggest that fewer relapses occur over the
course of treatment in patients treated with olanzapine compared with those
taking haloperidol. CONCLUSIONS: The exact place of olanzapine in the therapy of
psychotic patients remains unclear, as more data are needed to evaluate the long
term efficacy of this agent, its impact on negative symptoms, and its potential
use in patients resistant to the standard agents. Despite limitations in the
current database, olanzapine is a promising treatment option for patients with
schizophrenia.
PMID- 9391689
TI - Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein
(TNFR:Fc) in rheumatoid arthritis.
AB - BACKGROUND: Tumor necrosis factor (TNF) is the dominant mediator of the cytokine
cascade that causes inflammation and joint destruction in rheumatoid arthritis. A
new class of agents under investigation, the biologic TNF inhibitors, inhibits
the activity of TNF. Recombinant human TNF receptor p75 Fc fusion protein
(TNFR:Fc; Enbrel) blocks the activity of the cytokine TNF. The preclinical, Phase
I, and Phase II data of TNFR:Fc in rheumatoid arthritis are reviewed in this
article. METHODS: All available data on TNFR:Fc in rheumatoid arthritis were
reviewed. These data included published literature and data on file at the
manufacturer. RESULTS: TNFR:Fc has been effective in many models of inflammation,
including animal models of rheumatoid arthritis and in clinical rheumatoid
arthritis trials. Conclusions from a study with TNFR "knockout" mice (genetically
altered mice incapable of producing TNFR proteins) demonstrated that p75 TNFR is
a natural antagonist of TNF-mediated inflammation. A placebo-controlled, dose
escalation, Phase I trial evaluated the safety and efficacy of TNFR:Fc in
patients with rheumatoid arthritis. There were no serious adverse effects
reported. A Phase II, randomized, double-blind, placebo-controlled trial
evaluated 180 patients with active rheumatoid arthritis whose previous therapy
had failed. A dose-response relationship was observed in the number of tender and
swollen joints; patients who received the highest dose (16 mg/m2) of TNFR:Fc had
the greatest improvement. Treatment was generally well tolerated. TNFR:Fc is
nonimmunogenic; no antibodies to TNFR:Fc have been detected thus far in human
studies. CONCLUSIONS: Preliminary data indicate that TNFR:Fc is an excellent
candidate for future long-term studies in the treatment of rheumatoid arthritis.
PMID- 9391690
TI - Prehospital-initiated thrombolysis.
AB - OBJECTIVE: To evaluate the feasibility, safety, and efficacy of prehospital
initiated thrombolysis in decreasing the mortality rate due to acute myocardial
infarction. DATA SOURCES: English-language clinical studies, abstracts, and
review articles identified from MEDLINE searches and bibliographies of identified
articles. Epidemiologic data were extracted from the Internet. STUDY SELECTION:
Eight randomized clinical trials and two meta-analyses that compared prehospital
initiated thrombolysis with in-hospital-initiated thrombolysis. DATA EXTRACTION:
Pertinent studies were selected and the data were synthesized into a review
format. DATA SYNTHESIS: Early reperfusion of an infarct-related coronary artery
is associated with lower mortality rates. Most of the delay in initiating
treatment is caused by patient delay rather than transport delay or hospital
delay. In addition, more than 30% of eligible patients do not receive
thrombolytic therapy. Prehospital initiation of thrombolysis has been evaluated
as a means of decreasing hospital delay and increasing the number of eligible
patients receiving thrombolysis. Clinical trials document that prehospital
initiated thrombolysis is feasible and safe, and saves time. Of the eight
randomized trials, three demonstrated a decrease in either cardiac or total
mortality with prehospital thrombolysis. All studies were limited by relatively
small sample sizes. Two published meta-analyses suggest a 16-17% reduction in
mortality with prehospital thrombolysis. In the US, prehospital thrombolysis is
not routinely recommended due to medical issues related to diagnostic accuracy
and monitoring, legal concerns, and economic implications. Additional strategies,
such as community-wide education and prehospital diagnostic electrocardiograms
(ECGs), are being studied. CONCLUSIONS: In clinical trials, prehospital-initiated
thrombolytic therapy was shown to be safe and probably more effective than in
hospital administration of thrombolytic therapy, but this has not proven feasible
in the US at this time. Despite time-savings by decreasing treatment delay with
prehospital-initiated thrombolysis, patient delay still persists and accounts for
the majority of delay. Future investigations will center on increasing the number
of patients treated with thrombolytic agents through patient education, in
patient and out-patient programs that rapidly identify eligible patients, as well
as prehospital diagnostic ECGs.
PMID- 9391691
TI - Pharmacologic management of supraventricular tachycardias in children. Part 2:
Atrial flutter, atrial fibrillation, and junctional and atrial ectopic
tachycardia.
AB - OBJECTIVE: To review the literature regarding the use of antiarrhythmic agents in
the management of atrial flutter (AF), atrial fibrillation (Afib), junctional
ectopic tachycardia (JET), and atrial ectopic tachycardia (AET) in infants and
children. To discuss the advantages and disadvantages of specific agents in each
type of arrhythmia in an effort to develop treatment guidelines. DATA SOURCE: A
MEDLINE search encompassing the years 1966-1996 was used to identify pertinent
literature for discussion. Additional references were found in the articles,
which were retrieved via MEDLINE. STUDY SELECTION: Clinical trials that address
the use of antiarrhythmic agents for the treatment of supraventricular
tachycardia, AF, Afib, JET, and AET in children were selected. Literature
pertaining to dosage, pharmacokinetics, efficacy, and toxicity of antiarrhythmic
agents in children were considered for possible inclusion in the review;
information judged to be pertinent by the authors was included in the discussion.
DATA EXTRACTION: Although there are numerous reports of antiarrhythmic use in
children, there are very few large studies designed that evaluate the use of
specific antiarrhythmic agents in the treatment of AF, Afib, JET, or AET.
Ideally, controlled clinical trials are used to develop clinical guidelines;
however, in this situation, most data and information must be obtained from case
series of children treated. Although the results from these types of studies may
be useful in developing guidelines for the optimal use of these agents for the
treatment of AF, Afib, JET, and AET, controlled trials are required for
establishing standard treatment guidelines for all patients. DATA SYNTHESIS:
Despite limited scientific evaluation of conventional agents in the treatment of
AF, Afib, JET, or AET in children, they continue to be the standards of care.
Most information regarding the use of conventional agents in children has been
extrapolated from the adult literature. Little justification for the use of the
agents or dosing in children is available. Controlled trials regarding the use of
newer antiarrhythmic agents (propafenone, amiodarone, flecainide) are available;
however, the variance in dosing schemes, presence of structural heart disease,
and patient age may confound the results. CONCLUSIONS: Because of greater
clinical experience, conventional antiarrhythmic agents generally remain as first
line therapy in the management of most supraventricular tachycardias in children.
Atrial pacing or cardioversion to reestablish sinus rhythm is indicated for
initial episodes of AF in infants, followed by chronic prophylactic therapy in
those with significant structural heart disease or in infants in whom AF recurs.
Attempts to eliminate AF in children outside the neonatal or infancy period
should begin with trials of traditional agents such as digoxin or procainamide,
and if unsuccessful, subsequent trials of amiodarone. Digoxin and beta-blockers
remain the mainstay of therapy for children with Afib, followed by procainamide
for treatment failures. Intravenous amiodarone, the newest addition to our
antiarrhythmic armamentarium, is the most promising agent in the treatment of
postoperative JET. This arrhythmia has been traditionally managed with corporal
cooling and/or digoxin therapy; however, intravenous amiodarone may now be a
valuable option. Although relatively unsuccessful in the management of congenital
JET and AET, conventional agents are typically used prior to the initiation of
long-term therapy with potentially more toxic agents such as amiodarone or
propafenone. Additional well-designed, controlled trials are needed to further
evaluate the comparative efficacy of agents such as flecainide, sotalol,
moricizine, propafenone, and amiodarone in the management of AF, Afib, JET, and
AET in children, as well as to evaluate the dosing and toxicity in various age
groups.
PMID- 9391692
TI - Ethnicity and antipsychotic response.
AB - OBJECTIVE: To review the data generated by studies examining interethnic/racial
differences in response to antipsychotics. DATA SOURCES: A MEDLINE search (1966
1996) identified all articles examining differences in antipsychotic response
among Caucasians, Asians, Hispanics, and African-Americans, as well as articles
evaluating postulated mechanisms for these differences. STUDY SELECTION: All
abstracts, studies, and review articles were evaluated. DATA SYNTHESIS:
Ethnic/racial differences in response to antipsychotic medications have been
reported and may be due to genetics, kinetic variations, dietary or environmental
factors, or variations in the prescribing practices of clinicians. Studies
suggest that Asians may respond to lower doses of antipsychotics due to
pharmacokinetic and pharmacodynamic differences. Research relevant to African
Americans is limited, but some studies suggest that differences in this group may
be due to clinician biases and prescribing practices, rather than to
pharmacokinetic or pharmacodynamic variability. CONCLUSIONS: Future research
directed at validating the hypotheses that different ethnic/racial groups show
variations in response to antipsychotics should focus on homogeneous ethnic
groups, use recent advances in pharmacogenetic testing, and control for such
variables as observer bias, gender, disease chronicity, dietary and environmental
factors, and exposure to enzyme-inducing and -inhibiting agents. Clinicians
should be aware that potential interethnic/racial differences in pharmacodynamics
and pharmacokinetics may exist that can alter response to antipsychotics.
PMID- 9391693
TI - Muromonab-CD3 and antithymocyte globulin in renal transplantation.
AB - OBJECTIVE: To review the recently published medical literature for the practical
and efficient use of muromonab-CD3 (OKT-3) and antithymocyte globulin (ATG) in
renal transplantation. DATA SOURCES: MEDLINE and EMBASE were searched (1985
February 1996). Key words used were antithymocyte globulin (ATG, Atgam),
muromonab-CD3 (OKT-3, Orthoclone), and kidney transplantation. Thereafter, the
search was restricted to English-language articles, clinical trials, and human
studies. STUDY SELECTION AND DATA EXTRACTION: The search was reviewed for
articles of interest, and pertinent references from these articles were further
reviewed to supplement the initial search. The review focused on antibody therapy
as induction and/or rejection therapy in renal transplantation. DATA SYNTHESIS:
Although ATG and OKT-3 are effective in delaying and reducing the occurrence of
acute rejection, their impact on long-term graft survival has not been
established. Improved graft survival has, however, been demonstrated in patients
at high risk for rejection. These risks are described in the review. As first
line or steroid-resistant rejection therapy, ATG and OKT-3 have proven
efficacious. Some studies have shown improved graft survival with OKT-3. Although
serious infections may occur, OKT-3 has been shown to be effective in reversing
rejections resistant to both steroids and ATG. Therefore, reserving OKT-3 for
steroid- or ATG-resistant rejections may be preferred over the first-line use of
OKT-3, which is limited by the development of antimurine antibodies with
subsequent uses. However, the benefits of first-line antibody therapy may
outweigh the risks of developing these antibodies in patients for whom high-dose
steroids may not be the most appropriate treatment. Other factors that need to be
considered are adverse effects, which appear to be lower with ATG, cost, and
total hospital charges. The accuracy of treatment outcomes analysis among these
studies is limited by variations in the immunosuppressive regimens of the study
centers, doses of concomitant therapies, use of prophylactic antibiotics, and
time to follow-up. CONCLUSIONS: While important benefits are realized from using
antibody therapies in renal transplantation, their use is often associated with
excess immunosuppression and increased treatment costs. Despite encouraging
results from published trials, questions regarding the extent of their
prophylactic use and impact on long-term outcomes need to be answered. The
current literature contains no prospective, controlled, randomized comparisons of
OKT-3 and ATG with standardized regimens of conventional immunosuppressive agents
and antirejection protocols. The majority of studies use OKT-3 as part of the
treatment protocol. Well-designed studies using ATG are lacking. Further research
is needed to refine treatment protocols for ATG and OKT-3 to determine the
optimal timing and dosing for these agents.
PMID- 9391694
TI - The role of reactive drug metabolites in immune-mediated adverse drug reactions.
AB - OBJECTIVE: To highlight recent advances in the understanding of adverse drug
reactions (ADRs), with a focus on models outlining interactions between drug
metabolism, disease processes, and immunity. Specific mechanisms that identify
the metabolic pathways responsible for drug bioactivation to reactive drug
metabolites (RDMs) involved in the initiation and propagation of specific immune
mediated hypersensitivity reactions are discussed. Drug classes well known to be
associated with immune-mediated ADRs are reviewed and the clinical implications
of current research are discussed. DATA SOURCES: Original experimental research
and immunologic review articles relevant to ADR diagnosis and etiology. DATA
EXTRACTION: Results of relevant in vitro experiments and clinical reactions to
drug therapy were compiled and reviewed. Critical discoveries concerning the
identification of RDMs involved in ADRs were highlighted, with respect to RDM
involvement in the production of an immune response to drug haptens. DATA
SYNTHESIS: Drug adverse effects are classified according to clinical
characteristics, immune interactions, and mechanistic similarities. Cytochrome
P450 bioactivation of drug molecules to RDMs is a prerequisite to many ADRs. An
electrophilic metabolite may react with cellular macromolecules (i.e., lipids,
proteins, nucleic acids), resulting in direct cellular damage and organ toxicity.
Covalent binding of an RDM to cellular macromolecules may also result in the
formation of a hapten that is capable of eliciting a cellular or humoral immune
response against drug or protein epitopes, culminating in the characteristic
symptoms of hypersensitivity reactions. Mechanistic details concerning the
identification of stable protein-metabolite conjugates and their interaction with
the immune system remain unclear. Genetic imbalance between bioactivation and
detoxification pathways, as well as reduced cellular defense against RDMs due to
disease or concomitant drug therapy, act as risk factors to the onset and
severity of ADRs. CONCLUSIONS: Adverse reactions to drug therapy cause
significant morbidity and mortality. Identification of the pathways involved in
drug bioactivation and detoxification may elucidate the potential of chemical
agents to induce immune-mediated ADRs. Understanding the mechanisms of ADRs to
current xenobiotics is helpful in the prevention and management of ADRs, and may
prove useful in the design of novel therapeutic agents with reduced incidence of
severe adverse events.
PMID- 9391695
TI - Losartan versus ACE inhibitors in the treatment of hypertension.
PMID- 9391696
TI - Vaginal misoprostol for term labor induction.
AB - Misoprostol is an effective agent for cervical ripening and induction of labor.
The use of oxytocin was significantly decreased in patients treated with
misoprostol versus dinoprostone. It has been used to induce over 1000 women in
reported studies and has demonstrated a safety profile comparable with that of
endocervical and vaginal dinoprostone. Uterine hyperstimulation was a concern in
earlier trials, but at a reduced dose of 25 micrograms, the incidence has
decreased to a level that is comparable with the values reported for
dinoprostone. Misoprostol tablets are stable at room temperature and are
considerably less expensive than the dinoprostone alternatives. Two additional
factors pertaining to misoprostol administration must be taken into account
before the drug is selected for vaginal use. First, Cytotec tablets are currently
available in two strengths, 100 and 200 micrograms. This can lead to confusion or
error if the clinician orders a quarter or half tablet. The order should always
identify the strength in micrograms (25 or 50 micrograms). Second, the 100
microgram tablet is not scored; therefore, the proper dose should be carefully
prepared by a pharmacist using a pill cutter. Key members of the hospital staff
must be trained about the proper use of misoprostol for labor induction before
initiating therapy. One alternative to directly inserting the tablet is to
pulverize it and mix with a gel such as hydroxyethylcellulose gel. However, such
compounding introduces the same problems with stability and uniformity of dose as
experienced with dinoprostone gels. Despite the success of misoprostol in
clinical trials, it is not approved for this indication, and the manufacturer of
Cytotec does not plan to pursue approval. Therefore, independent, large-scale
studies are warranted to more accurately assess the efficacy and overall safety
of using intravaginal alprostadil for cervical ripening and labor induction.
Additional clinical experience should also help to determine the best regimen and
method of administration. From the data currently available, it appears that
either a 25- or 50-microgram dose (one-fourth or one-half of a 100-microgram
tablet) inserted into the posterior vaginal fornix and repeated at 4-5-hour
intervals if needed, is a clinically effective regimen, and is associated with
the least amount of adverse effects and complications. As with all labor
inductions, uterine contractions and fetal heart rate should be monitored
carefully throughout the procedure.
PMID- 9391697
TI - Hydroxyurea in the treatment of sickle-cell anemia.
AB - Sickle-cell anemia is a congenital hemolytic anemia characterized by sickle
shaped RBCs. The deformed RBCs become distorted and rigid and may occlude small
arterioles and capillaries leading to tissue ischemia and infarction. Sickled
RBCs are too fragile to withstand the trauma of circulation, and hemolysis occurs
after they enter the circulation. RBCs with a high level of Hb F are resistant to
sickling. Hydroxyurea has been shown to stimulate Hb F synthesis, leading to a
reduction in the incidence of hemolytic and vaso-occlusive manifestations;
however, hydroxyurea has no role in the treatment of crises already in progress.
The National Heart, Lung, and Blood Institute announced in January 1995 that
treatment with hydroxyurea leads to an increase in Hb F production within RBCs
and a reduction in the frequency of painful crises in patients with sickle-cell
anemia. Although the mechanism by which hydroxyurea increases Hb F is not known,
one possible explanation is that hydroxyurea is cytotoxic to the more rapidly
dividing late erythroid precursors, leading to the recruitment of early erythroid
precursors that have demonstrated increased capacities to produce Hb F. Clinical
trials have demonstrated that hydroxyurea results in an increase in Hb F
concentrations; however, this increase may not dramatically affect the
progressive vascular changes associated with sickle-cell anemia; thus, patients
may still experience complications related to sickle-cell anemia. At North
Carolina Baptist Hospital in Winston-Salem, NC, compliant patients with sickle
cell anemia are started on hydroxyurea. There are no specific criteria for
patient selection or monitoring. The dosage is started at 10-15 mg/kg/d. Platelet
count, complete blood count, and Hb F are monitored and hydroxyurea dosages are
adjusted accordingly. Although hydroxyurea has been effective in the treatment of
sickle-cell anemia, large double-blind, placebo-controlled clinical trials are
needed to determine whether the risks of long-term administration outweight the
risk of vaso-occlusive disease in untreated patients.
PMID- 9391698
TI - Perspectives on alternative medicine.
PMID- 9391699
TI - Induction of labor: a clinician's viewpoint.
PMID- 9391700
TI - Methods for preventing reactions secondary to Cremophor EL.
PMID- 9391701
TI - Rifabutin-associated uveitis.
PMID- 9391702
TI - Absence of cross-reaction between lisinopril and enalapril in drug-induced lupus.
PMID- 9391703
TI - Hypertension exacerbated by amphotericin B administration.
PMID- 9391704
TI - Psychotic episode after melatonin.
PMID- 9391705
TI - Comment: zolpidem: distinct from triazolam?
PMID- 9391706
TI - Correction and comment: possible toxicity from propylene glycol in injectable
drug preparations.
PMID- 9391707
TI - Prenatal fluoride for growth and development: Part X.
AB - Examinations of prenatal fluoride supplemented (PNF) teeth in an animal model and
in a five-month human fetus find these teeth to be more developed than the non
supplemented controls. The fact that PNF allows teeth to develop to their full
potential suggests that PNF could be an essential nutrient for the entire human
and this could be demonstrated most easily during rapid fetal growth. A review of
the recent literature, including trials by NIH and The World Health Organization,
provide evidence that fluoride (F) does allow the fetus to grow and develop to
its full potential. The authors conclude that PNF must be supplied in at least a
2 mg/day pulse dose, and then F must be given from shortly after birth in a daily
amount appropriate for the weight of the child with some consideration for the
amount of F water utilized.
PMID- 9391708
TI - Linguistic maturity as a determinant of child patient behavior in the dental
office.
AB - Progressively during the 20th century dentistry for children has become more
efficient, less painful, and more prevention oriented. In the last quarter of the
20th century there was a dramatic decrease in dental decay for many American
children. These two facts paired with the fact that stories about dentistry being
painful are gone in many American communities and have been replaced with stories
about how pleasant the dental appointment can be would seem to predict that child
patient management and the interception of inappropriate behavior would not be a
critical skill for the dental clinician that treats children today. This finding
however is not the case. It is submitted that misbehavior now stems from the fact
that today's parents are not encouraged to raise their children as urgently as in
the earlier part of the century. It is offered that the child's incompetence in
working with other people in the constituent speech acts of requests and promises
causes the child confusion, frustration, and perhaps anxiety. The child's dental
experience is a complex conversation between the dentists as requester and the
child patient as the promisor of effective actions to the dentists' reasonable
requests.
PMID- 9391709
TI - The pulp capping procedure in primary teeth "revisited".
AB - The purpose of this review is to "revisit" an earlier paper (1992) on the subject
of direct pulp capping in primary teeth and bring some new considerations for the
procedure by the use of dentin bonding adhesives. It has come to be recognized
that the customary employment of calcium hydroxide for this therapy has some
shortcomings that reduce the prognosis for a favorable outcome. For at least a
decade, many investigations have found that postoperative sensitivity, thermal
stimuli, pulp inflammation and pathosis can be attributed not to the composition
of various dental materials and their insertion techniques, but to microleakage
with subsequent bacterial invasion at the enamel/restoration and the dentin/pulp
interfaces. It is imperative, as pointed out, that there be an impervious
resinous bond between the dentin and the dentinopulpal complex which can be
achieved by the use of dentinal adhesive agents to eliminate microleakage outward
movement of pulpal fluids. Various steps in the bonding technique for the
treatment of deep dentin caries and/or a pulp exposure has raised some concerns
for their effect on the pulp. This review discusses these concerns, which can
lead to the conclusion that the use of dentinal bonding adhesives is a safe and
biologically feasible procedure, whether it be in permanent or primary teeth.
PMID- 9391710
TI - Comparison of two tooth-saving preparation techniques in a treatment approach of
one-surface cavities: design of a study.
PMID- 9391711
TI - Uprighting the mandibular molars stimulates mandibular growth during treatment of
class II malocclusion.
AB - We hypothesized that uprighting of the mandibular molars creates a counter
clockwise rotation of the mandible and stimulates mandibular forward growth
during the treatment of a Class II malocclusion. This investigation used 33
longitudinal lateral cephalometric radiographs of Class II, Division 1 female
patients. All cases were treated with non-extraction. Treatment was started in
early adolescence with .018 slot edgewise Alexander appliances. High-pull head
gear and Class II elastics were used. Seventeen cases that showed more than 5
degrees of uprighting of the mandibular first molars were selected as the
uprighted group. Cases that showed less than 5 degrees of uprighting of the
mandibular first molars were selected as the non-uprighted group. There was a
significant correlation coefficient between the uprighted degree of the
mandibular first molars and the degree of clockwise rotation of the mandibular
plane to FH.
PMID- 9391712
TI - Effect of acid-etching on fluoride-treated caries-like lesions of enamel: a SEM
study.
AB - Etching patterns by 20 percent phosphoric acid on caries-like lesions of enamel
(white spot) untreated and treated with 0.4 APF were studied at 30, 60, 120
seconds of etch-times using the Scanning Electron Microscope (SEM). The surface
topography of acid-etched teeth varied according to the etch time. Acid etching
of caries-like lesions treated with fluoride showed etching patterns similar to
sound enamel. Based on Silverstone's classification, thirty seconds etch-time
produced type III pattern of surface morphology, while type I and type II were
observed with 60 and 120 seconds of etch time. Fluoride treated lesions showed
increased porosity and in addition to a surface coating of numerous small
globules of calcium fluoride. Low level of topical fluoride before sealant
application should be beneficial, since this allows a more rapid rate and
increased degree of remineralization and possible arrest in the progress of
caries lesions.
PMID- 9391713
TI - Children of divorce.
AB - Limited attention has been directed in the dental literature to the emotional,
economic and associated consequences of divorces on children. A general
introduction is provided on 1) the numbers of children involved in divorces in
different single-parent population groups, with 2) emphasis on the emotional
impact of divorce on children and 3) the potential significance for pediatric
dental practices.
PMID- 9391714
TI - Minority children in single-parent families.
AB - Information is now available from the Bureau of the Census with details about the
increasing number of single-parent families. A summary review is provided with
particular emphasis on minority families.
PMID- 9391715
TI - Caries prevalence in Ashkelon children in 1994.
AB - In the five-year-old group, 182 children were examined, ninety males and ninety
two females. Forty-three percent of the children were found to be caries-free
with a dmf(t) of 2.08 + 2.64 (mean +/- S.D.). More boys than girls were caries
free (46 percent vs 41 percent). In general, caries prevalence is lower and
dental health is better in boys than girls. The f(t) component is 0. Children at
this age are not treated. In the twelve-year-olds group, 129 boys and 132 girls
(total of 261) were examined. Forty-one percent of the children were found to be
caries-free with a DMF(T) of 1.43 + 1.70. In this group more girls than boys were
caries-free (43 percent vs 39 percent). In general caries prevalence is higher,
treatment levels are lower in boys than in girls in this age-group. The results
show that dental health is better in Ashkelon children than in other partly
fluoridated areas in Israel. Dental treatment levels are higher and caries
prevalence is lower in Ashkelon than in comparable places in the country. The WHO
goals for 2000 were achieved in Ashkelon by 1994.
PMID- 9391716
TI - Ectodermal dysplasia with associated double tooth.
AB - The case describes a double molar tooth in a seven-year-old girl who has
ectodermal dysplasia. The most characteristic dental findings in ectodermal
dysplasia are hypodontia and conically shaped crowns. In our case a double tooth
was also present in the primary molar region, in addition to these characteristic
findings.
PMID- 9391717
TI - Veno-occlusive disease of the liver after bone marrow transplantation: is
hypercoagulability really part of the problem?
AB - Patients undergoing bone marrow transplantation (BMT) experience changes in
various proteins with important functions in the coagulation and fibrinolysis
system. Veno-occlusive disease (VOD) of the liver is a leading cause of non
relapse mortality after BMT. Because of the concurrent occurrence of changes in
the coagulation and fibrinolysis system and development of VOD, most authors
assume a causative relationship between these two observations, but the results
leading to this conclusion are not unequivocal. Data currently available do not
allow the conclusion that coagulation activation and local excess fibrin
generation are key factors in the pathogenesis of VOD. One approach to deciding
whether there is, in fact, excessive local fibrin generation during the
development of VOD might be the monitoring of high risk patients with tools that
enable differentiation of local and systemic hypercoagulability (e.g. anti-D
dimer immunoscintigraphy). Screening of patients at risk for VOD with special
coagulation parameters pretransplant does not seem appropriate at present.
However, markedly increased plasminogen activator inhibitor-1 levels (from
baseline) seem to be appropriate tool to confirm the diagnosis of VOD when
clinical suspicion exists. More research is needed in order to advance our
understanding of the disease and to improve outcomes in both the prophylaxis and
treatment of VOD.
PMID- 9391718
TI - Increased soluble P-selectin following myocardial infarction: a new marker for
the progression of atherosclerosis.
AB - Increased soluble P-selectin has been described in atherosclerosis, but the
mechanisms for this and its clinical significance are unknown. In an attempt to
clarify these points we measured soluble P-selectin and von Willebrand factor, an
endothelial cell marker, by ELISA in 116 patients who had survived a myocardial
infarction and in 116 matched controls. Raised levels of both soluble P-selectin
(median 272 ng/ml, range 55-850 ng/ml vs 190 ng/ml, range 40-395 ng/ml) and von
Willebrand factor (mean +/- SD 128 +/- 37 IU/dl vs 100 +/- 33 IU/dl; both P <
0.001) failed to correlate (r = 0.12), and soluble P-selectin failed to correlate
with any of the major risk factors for atherosclerosis. A four-year follow-up of
68 of these patients revealed that soluble P-selectin was higher in the 33 (48%)
who had suffered an additional cardiovascular event (e.g. subsequent myocardial
infarction, arterial surgery; median 350 ng/ml, range 275-460 ng/ml) compared
with those free of an end-point (270 ng/ml, range 140-400 ng/ml, P = 0.0012). We
conclude that increased soluble P-selectin is unrelated to the risk factors for
atherosclerosis but is a new marker of disease progression in patients who have
survived a myocardial infarction.
PMID- 9391719
TI - Plasma levels of thrombomodulin and lipoprotein (a) in patients with cerebral
thrombosis.
AB - To evaluate the clinical implications of soluble thrombomodulin and lipoprotein
(a) [Lp(a)] in patients with cerebral thrombosis, these parameters were measured
in the plasma of 28 patients with cerebral thrombosis within 3 days of onset, 36
with cerebral thrombosis more than 1 month after onset, six with cerebral
hemorrhage more than 3 months after onset and 37 healthy volunteers. In the
patients with chronic-phase cerebral thrombosis, the thrombomodulin and Lp(a)
levels were significantly higher and the total cholesterol level was
significantly lower than in the normal group, while the patients with acute-phase
cerebral thrombosis had significantly lower total cholesterol levels. The plasma
level of Lp(a) in acute-phase cerebral thrombosis, but not that of
thrombomodulin, was significantly higher in thromboses located in the cortex area
and in patients with recurrent attacks than in the normal controls. There were no
significant differences in thrombomodulin, Lp(a) or total cholesterol levels
between the chronic-phase cerebral hemorrhage and normal groups. These findings
support the hypothesis that Lp(a) plays a part as a risk factor in cerebral
thrombosis, especially in patients with a cortex area thrombosis and in patients
with a recurrent attack. The high levels of thrombomodulin in the chronic-phase
cerebral thrombosis group suggests the presence of continuous endothelial cell
damage.
PMID- 9391720
TI - Inherited abnormalities of blood coagulation in juvenile stroke. A case-control
study.
AB - The nature of the relationship between inherited abnormalities of the clotting
system and the occurrence of cerebrovascular accidents in young subjects is
controversial. To evaluate the risk of cerebrovascular disease associated with
such abnormalities, we analyzed a series of 23 consecutive patients in a case
control study with ischemic stroke proven by computerised tomography and aged
below 45 years at admission, and a control group of 115 age- and sex-matched
controls from the general population. No differences in antithrombin, protein C,
protein S, heparin cofactor II, plasminogen or response to activated protein C
were observed between cases and controls. None of the patients had a history of
personal or familial thrombosis, and none had a reduction in the considered
clotting factor below the reference range. We conclude that abnormalities of the
clotting system are not associated with the occurrence of cerebrovascular
abnormalities in the young and that routine screening for inherited thrombophilia
is not appropriate in young patients with cerebrovascular disease.
PMID- 9391721
TI - Insight into the profibrinolytic activity of heparin: effects on the activation
of plasminogen mediated by urokinase.
AB - The aim of this work was to clarify the role of urokinase-type plasminogen
activator (uPA) on the profibrinolytic activity of heparin, chemically modified
heparins [partially: N-desulfated (N-des), N-desulfated N-acetylated (N-des N
ac), O-desulfated (O-des), O/N-desulfated N-acetylated (O/N-des N-ac)] and
heparan sulfate. Binding competition assays of plasminogen and uPA to heparin
sepharose demonstrated that heparin bound to both enzymes. Moreover, in the
presence of increasing amounts of heparin, plasminogen activation mediated by uPA
occurred as a bell-shaped curve, suggesting the formation of a ternary complex.
In contrast, all chemically-modified heparins lacked this cofactor activity,
although N-des and heparan sulfate partially retained the uPA binding capacity,
and O-des partially bound to both plasminogen and uPA. Plasmatic euglobulins from
mice treated with heparin, as well as with modified heparins with uPA binding
capacity, presented a 2-fold enhancement of 47 kDa lytic band, as assessed by
zymographic analysis. Western blotting analysis anti-uPA (47 kDa) showed that the
enhanced uPA activity correlated with a true increase in uPA protein levels.
These results suggest that the profibrinolytic activity of heparin mediated by
uPA could be caused by an increase in uPA protein levels rather than by a
cofactor activity mediated by a formation of ternary complexes.
PMID- 9391722
TI - Assessment of mental ability in elderly anticoagulated patients: its reduction is
associated with a less satisfactory quality of treatment.
AB - Mental capacity was assessed in 311 apparently self-sufficient patients (> or =
60 years of age, 170 men) under stabilised oral anticoagulant treatment (OAT) by
administering the Hodkinson's Abbreviated Mental Test (AMT). The international
normalized ratios (INR) recorded during the 3 months before and the 3 after the
data of test administration were examined by the INR-Day software program. The
percentage of time spent within, below or above the intended therapeutic range
was calculated in patients who scored abnormally at AMT, and compared with
matched controls with normal AMT results. Forty patients [12.9%; 28 women (19.8%)
and 12 men (7.1%), P < 0.0011] had abnormal AMT results; the rate seemed to
increase with age. Most of these patients (35, 75%) had only elementary
education. Patients with abnormal AMT results spent more time outside the
intended therapeutic ranges than 40 matched controls (20.9% of the observed time
vs 13.7%, P < 0.0001; odds ratio 1.68, CI 1.53-1.84). Unsuspected reduction of
mental ability or attention levels was found in a number of elderly patients
receiving OAT; these patients presented longer periods of either under- or over
anticoagulation and were, therefore, exposed to a higher risk of thrombotic or
bleeding complications. Anticoagulation clinics would be advised to assess mental
abilities in elderly patients before starting OAT.
PMID- 9391723
TI - A comparison between continuous infusion versus standard bolus administration of
heparin based on monitoring in cardiac surgery.
AB - This study was designed to determine prospectively if stable heparin
concentrations can be maintained during extracorporeal circulation by using a
continuous infusion technique, compared with a bolus regimen based on whole blood
heparin concentration monitoring. Forty patients were assigned randomly to either
an infusion or a monitoring group. The reference heparin concentration was
defined as the whole blood heparin concentration associated with a kaolin
activated clotting time (ACT) of approximately 480 s prior to institution of
cardiopulmonary bypass (CPB) for both cohorts. For infusion patients, doses of
heparin were administered using a continuous infusion based on the initial
patient-specific heparin dose per unit weight; heparin was also added to
solutions administered after the initiation of CPB based on the reference heparin
concentration. For monitoring patients, the dose of heparin administered during
CPB was calculated by the Hepcon instrument. Blood specimens collected prior to
and during the CPB period were used to measure anti-Xa plasma heparin
concentration and complete blood counts, kaolin ACT and whole blood heparin
concentration. Doses of heparin and protamine administered and transfusion
requirements were similar in patient cohorts. The apparent rate of clearance of
heparin from plasma was variable among patients in the monitoring group prior to
CPB. Stable heparin concentrations were maintained using whole blood heparin
measurements, whereas mean heparin concentrations were slightly lower using the
continuous infusion technique. Therefore, an optimal approach might involve the
combined use of these regimens.
PMID- 9391724
TI - Influence of plasma volumetric errors on the prothrombin time ratio and
International Sensitivity Index.
AB - The International Sensitivity Index (ISI) for prothrombin time systems depends on
the thromboplastin manufacturer's recommended method for use. The purpose of the
present study was to investigate the influence of small deviations from the
recommended sample volume on the prothrombin time ratio and ISI. Four commercial
reagents were studied; three with low ISI and one with high ISI. The effects of
volumetric errors on the ISI were used to assess the associated effects on the
International Normalized Ratio (INR). The effect of 10% volume error on the INR
was not greater than 5%. The effects with the three low-ISI reagents were
slightly greater than those with the high-ISI reagent. It is recommended that
each laboratory should check the volumes of sample and reagent used for the
prothrombin time test.
PMID- 9391725
TI - Recurrent venous thromboembolic disease and factor XI concentrate in a patient
with severe factor XI deficiency, chronic myelomonocytic leukaemia, factor V
Leiden and heterozygous plasminogen deficiency.
AB - There are increasing concerns about the potential thrombogenic risks associated
with the use of factor XI concentrates. We describe the case of a 49 year-old man
with chronic myelomonocytic leukaemia and severe factor XI deficiency (< 1 u/dl),
in whom the use of factor XI concentrate appeared to be associated with the
development of venous thromboembolic disease. Subsequent investigations revealed
the presence of both the factor V Leiden abnormality and heterozygous plasminogen
deficiency. This case highlights the risks associated with the use of factor XI
concentrates and suggests that these risks may be further increased in patients
with an inherited or acquired prothrombotic abnormality or an underlying
malignancy. Prothrombotic screening of patients with severe factor XI deficiency
may be indicated particularly in younger patients in whom treatment with factor
XI concentrates is a possibility.
PMID- 9391726
TI - Fibrinogen Poissy I: a new case of the A alpha Arg 16His fibrinogen variant.
AB - A fibrinogen variant was identified in a patient with disseminated intravascular
coagulation and in one member of her family. Coagulation studies showed marked
prolongation of both the thrombin and reptilase times and discrepancy was noted
between the levels of plasma fibrinogen, determined by a kinetic vs immunological
determination or light scattering assay. Studies on purified fibrinogen revealed
an impaired release of fibrinopeptides by thrombin. DNA sequencing revealed a
heterozygous A to G point mutation in exon 2 of the A alpha chain, which
substituted Arg for His at position 16. This mutation creates a Nla III cleavage
site which was used to confirm the mutation.
PMID- 9391727
TI - Variant of intron 22 inversions in the factor VIII gene in severe hemophilia A.
AB - Recurrent DNA inversions, which disrupt the factor VIII (FVIII) gene, generally
occur between a region of intron 22 (int22h) and one of two homologous copies of
this region, located 300 to 400 kb telomeric to the FVIII gene. This report
describes a patient with severe hemophilia A and a high level inhibitor with
atypical hybridization patterns. A Bcl I Southern blot assay was altered to 17.5,
16, and 14 kb. His mother and two out of four aunts tested had normal and
abnormal restriction patterns which led to a total of five different fragments,
suggesting that they were carriers. The Xba I plus Kpn I restriction fragment
length polymorphism in intron 22 by Southern blotting using the same probe (probe
a) yielded the 6.2 kb polymorphic band, with a clearly separated 6.6 kb band from
the non-factor VIII region; an alternative int22h hybridization probe (probe x)
detected no additional fragment. These results suggest that probe a as well as
probe x could recognize an intron-22-sized fragment. This report shows a
variation in the number of int22h copies although we could not find the inversion
junction.
PMID- 9391728
TI - Natural anticoagulation with thrombocytopenia may spare the thromboembolic
complications in severe cyanotic congenital heart disease.
PMID- 9391729
TI - Neural networks for the analysis of small pulmonary nodules.
AB - PURPOSE: Small pulmonary nodules can be readily detected by computed tomography
(CT). The goal of this detection is to diagnose early lung cancer as the five
year survival at this early stage is over 70% in contradistinction to the overall
5-year survival of around 10%. Critical to the efficacy of CT for early lung
cancer detection is the ability to distinguish between benign and malignant
nodules. We explored the usefulness of neural networks (NNs) to help in this
differentiation. METHODS: CT images of 28 pulmonary nodules, 14 benign and 14
malignant, each having a diameter less than 3 cm were selected. All were
sufficiently malignant in appearance to require needle biopsy and surgery. The
statistical-multiple object detection and location system (S-MODALS) NN technique
developed for automatic target recognition (ATR) was used to differentiate
between these benign and malignant nodules. RESULTS: S-MODALS was able to
correctly identify all but three benign nodules. S-MODALS classified a nodule as
malignant because it looked similar to other malignant nodules. It identified the
most similar nodules to display them to the radiologist. The specific features of
the nodule that determined its classification were also shown, so that S-MODALS
is not simply a "black box" technique but gives insight into the NN diagnostics.
CONCLUSION: This initial evaluation of S-MODALS NNs using pulmonary nodules whose
CT features were very suspicious for lung cancer demonstrated the potential to
reduce the number of biopsies without missing malignant nodules. S-MODALS
performed well, but additional optimization of the techniques specifically for CT
images would further enhance its performance.
PMID- 9391730
TI - Giant bronchogenic cyst masquerading as tension pneumothorax. Radiographic and CT
findings.
AB - Pulmonary bronchogenic cysts with tracheobronchial communication may occasionally
mimic tension pneumothorax leading to unnecessary thoracostomy. We describe such
a case to emphasize that cautious identification of the direction of displacement
of the collapsed lung tissue on chest radiograph or computed tomography (CT) may
help in differentiating these two diseases. Tension pneumothorax should lead to
centripetal compression of the ipsilateral lung toward the hilum while giant
bronchogenic cysts result in centrifugal displacement of the adjacent lung away
from the hilum.
PMID- 9391731
TI - Gadolinium utilization in the MR evaluation of cardiac paraganglioma.
PMID- 9391732
TI - Accuracy of CT in estimating extent of pancreatic necrosis.
AB - The objective of this study was to determine whether nonenhancing pancreatic
lesions are accurate in estimating pancreatic necrosis. Twenty-six consecutive
abdominal computed tomography (CT) examinations performed over a 3-year period
that met the CT criteria for pancreatic necrosis were reviewed. Follow-up CTs in
three of 26 patients demonstrated pancreatic enhancement, indicating viable
parenchyma, within the previously nonenhancing regions. All three patients had
undergone surgical debridement in that area. Twenty-three cases demonstrated
either no change or enlargement of the nonenhancing pancreatic lesions. Follow-up
ranged from 1 week to 26 months. While CT is accurate in diagnosing pancreatic
necrosis, lack of enhancement in CT may occasionally overestimate the extent of
necrosis. Nonenhancing, viable but at-risk tissue may be present adjacent to
frankly necrotic tissue. Surgical debridement may facilitate recovery of this
viable tissue, which may enhance normally on follow-up CT.
PMID- 9391733
TI - MRI findings in headbangers.
AB - Magnetic resonance imaging (MRI) findings in a mentally retarded adult female who
exhibits headbanging behavior are presented. Radiographic changes include
enlargement of the diploic space in the parietal and occipital bones, and gray
matter loss adjacent to the bony changes. This pattern of injury is compared with
skull changes previously reported in headbangers, and neuronal injury seen in
boxers (dementia pugilistica) and Minimata disease.
PMID- 9391734
TI - CT and US of the pancreas.
AB - The diagnostic capabilities of pancreatic imaging continue to improve with
technological advancements in computed tomography (CT), ultrasound (US), and
magnetic resonance imaging (MRI). To update the practicing radiologist, this
article summarizes the current literature on pancreatic imaging, with particular
emphasis on CT and US. Pertinent clinical considerations of the disease entities
are included, along with illustrative material from the authors' experience.
PMID- 9391735
TI - Management of asymptomatic term neonates whose mothers received intrapartum
antibiotics--Part 2: Diagnostic tests and management strategies. Center of
Disease Control and Prevention.
AB - The evaluation of the potentially septic newborn is often a source of frustration
for practitioners. In the past, it has often been standard practice to evaluate
and treat empirically all neonates whose mothers received antibiotics during
labor, regardless of whether the infant had any signs or symptoms suggestive of
infection. With the advent of recommendations for intrapartum antibiotic therapy
to prevent early-onset neonatal group B streptococcal infections, this strategy
is no longer practicable because too many infants would thus be evaluated and
treated needlessly. This two-part review addresses the issues involved in
managing asymptomatic newborns whose mothers received intrapartum antibiotics.
Part I, published separately, reviewed the rationale behind strategies for
preventing intrapartum transmission of bacterial infection. This final part
addresses the evaluation and management of the newborn. A number of diagnostic
tests are often used in looking for bacterial infections in the neonate.
Unfortunately, none of these is both rapid and reliable. A clinical pathway
provided here can serve as a useful guide for the clinician, but uncertainty will
always remain. Ultimately, each practitioner must determine the degree of risk or
uncertainty that he or she can accept on the basis of clinical experience.
PMID- 9391736
TI - The moral challenge of children at risk: protective policies and pediatrics. A
report of the Children's Services, Inc. Task Force of Greater Cleveland.
AB - Social workers and pediatricians are among the professionals who share a society
wide concern with current public policies regarding the placement of children at
extreme risk. A healthcare professional may successfully treat a child, only to
learn later that this same child was the victim of a tragic incident of domestic
violence after returning home. Such events are not uncommon, create considerable
frustration for pediatricians, and demand an integrated interprofessional and
interdisciplinary response. This report emerged from 6 months of task force
dialogue with leaders of children's services programs, healthcare professionals,
clergy, ethicists, and other community leaders in one major urban environment. It
indicates innovative directions in children's protective services with regard to
family preservation, foster care, residential care, and adoption. The latter two
options could be used much more creatively than is the case currently. The report
also asserts that far too few resources are being directed to this problem area.
PMID- 9391737
TI - Using the clinical linguistic and auditory milestone scale for developmental
screening in high-risk preterm infants.
AB - Eighty-one preterm infants (mean gestational age 29 weeks, range 24-36 weeks)
discharged from The Johns Hopkins Hospital Neonatal Intensive Care Unit were
followed up sequentially from birth to 2 years of age by use of the Clinical
Linguistic and Auditory Milestone Scale (CLAMS) to evaluate language development.
Children were studied during three time intervals: Interval 1: 3-5 months
chronologic age (CA); Interval 2: 9-14 months (CA); and Interval 3: 18-24 months
(CA). Psychometric test scores were compared with CLAMS Language Quotients (LQ)
by use of full, partial (75%, 50%, 25%), and no "correction" for weeks of
prematurity to determine whether "correcting" for prematurity would yield a more
accurate estimate of eventual cognitive outcome. CLAMS LQ at Interval 1 was
highly correlated with CLAMS LQ at Interval 2 and CLAMS LQ at Interval 2
correlated well with CLAMS LQ at Interval 3 (r = 0.57 and 0.64, respectively, P =
0.0001). Correlations indicated that there was an orderly, sequential development
of language in the preterm infant. CLAMS evaluations correlated significantly
with psychometric test results during Interval 2 and Interval 3 (r = 0.34, P <
0.02 and r = 0.75, P = 0.0001, respectively). The CLAMS proved to be a useful
instrument for monitoring preterm language development in the primary pediatric
care setting.
PMID- 9391738
TI - The incidence of acute and remote seizures in children with intraventricular
hemorrhage.
AB - Seizures are a well-known complication of intraventricular hemorrhage (IVH) in
premature infants; however, the rate at which they occur is not known. The
authors decided, therefore, to investigate both the incidence of acute and remote
seizures in infants with IVH and the association with the grade of hemorrhage.
One hundred and three infants with IVH were identified and their records were
reviewed for acute seizures, remote seizures, and associated morbidity and
mortality. The average gestational age of these infants was 29 weeks (range, 23
40 weeks). Of the 103 infants, 32 (31%) developed grade 4 IVH; 19 (18%), grade 3
IVH; and 52 (50%), grades 1 and 2 IVH. Seventeen (17%) patients had acute
seizures during their first month of life. Six of the 61 patients (10%) who
survived the neonatal period and for whom follow-up data were available had
remote seizures. Infants with grade 4 IVH had significantly more acute seizures
than infants with grades 1 and 2. In this cohort, only infants with grades 3 and
4 IVH developed remote seizures. Furthermore, among infants with grade 4 IVH
acute seizures were a significant risk factor for development of remote seizures.
The use of long-term antiepileptic drug therapy in neonates with a history of
acute seizures is not established. These results suggest that antiepileptic drug
therapy beyond the neonatal period should be reserved for infants with grade 4
IVH with history of acute seizures.
PMID- 9391739
TI - The plantar response in normal newborn infants.
AB - The neonatal plantar response has been reported as extensor in 90% of newborns
and flexor in 93% of newborns, leading to uncertainty about its reliability and
significance. To determine the normal neonatal plantar response we examined 349
healthy newborn infants, > 32 weeks gestation within 24 hours of birth. A
supramaximal noxious stimulus was applied in a standardized manner to the lateral
plantar surface of each foot. The plantar response was extensor in 90%, equivocal
in 7%, and flexor in 3%. With proper physiologic technique, the normal neonatal
plantar response is extensor.
PMID- 9391740
TI - Bilateral neonatal testicular torsion.
PMID- 9391741
TI - Comments on bilateral neonatal testicular torsion.
PMID- 9391742
TI - Successful treatment of steroid-resistant chorea associated with lupus by use of
valproic acid and clonidine-HCL patch.
PMID- 9391743
TI - Endovascular management of vein of Galen aneurysms in neonates: two case reports
and a review of the literature.
PMID- 9391744
TI - An unusual presentation of a hemangioma in an adolescent female.
PMID- 9391745
TI - Size, myths and the clinical pharmacokinetics of analgesia in paediatric
patients.
AB - In the paediatric population, developmental changes can be predicted by age and
are independent of size, which is predicted by bodyweight. Size is commonly
standardised using either the per kilogram or the body surface area models. A
great many physiological-, structural- and time-related variables scale
predictably within and between species with weight exponents of 0.75, 1 and 0.25,
respectively. Use of the per kilogram size model has led to the misconception
that children have an enhanced capacity to metabolise drugs because of their
relatively large liver size or increased hepatic blood flow. This is not
necessarily the case. For example, the clearance of opioids often approaches
adult rates within the first few months of life when an allometric 3/4 power
model is used to scale for size. Age-related changes in physiological processes,
such as respiration and cardiac output, disappear with appropriate size models.
Size is an important, but little recognised, component in the speed of onset of
drugs effects and uptake of inhalational anaesthetic agents. Size models cannot
be reliably used to predict dose regimens for children from schedules established
for adult patients. Dosage regimens are dependent on clearance and volume of
distribution as well as pharmacodynamic factors, which change with age. The age
dependent pharmacodynamic changes described for some opioids in the very young
have not yet been completely disentangled from age-related pharmacokinetic
changes. When bodyweight is standardised and disentangled from age, developmental
changes can be understood more clearly. The future investigation of drugs used in
paediatric practice must also include an appropriate size model in order to
differentiate age-related factors from size-related factors.
PMID- 9391746
TI - Pharmacokinetic changes during pregnancy and their clinical relevance.
AB - The dynamic physiological changes that occur in the maternal-placental-fetal unit
during pregnancy influence the pharmacokinetic processes of drug absorption,
distribution and elimination. Pregnancy-induced maternal physiological changes
may affect gastrointestinal function and hence drug absorption rates. Ventilatory
changes may influence the pulmonary absorption of inhaled drugs. As the
glomerular filtration rate usually increases during pregnancy, renal drug
elimination is generally enhanced, whereas hepatic drug metabolism may increase,
decrease or remain unchanged. A mean increase of 8 L in total body water alters
drug distribution and results in decreased peak serum concentrations of many
drugs. Decreased steady-state concentrations have been documented for many agents
as a result of their increased clearance. Pregnancy-related hypoalbuminaemia,
leading to decreased protein binding, results in increased free drug fraction.
However, as more free drug is available for either hepatic biotransformation or
renal excretion, the overall effect is an unaltered free drug concentration.
Since the free drug concentration is responsible for drug effects, the above
mentioned changes are probably of no clinical relevance. The placental and fetal
capacity to metabolise drugs together with physiological factors, such as
differences acid-base equilibrium of the mother versus the fetus, determine the
fetal exposure to the drugs taken by the mother. As most drugs are excreted into
the milk by passive diffusion, the drug concentration in milk is directly
proportional to the corresponding concentration in maternal plasma. The milk to
plasma (M:P) ratio, which compares milk with maternal plasma drug concentrations,
serves as an index of the extent of drug excretion in the milk. For most drugs
the amount ingested by the infant rarely attains therapeutic levels.
PMID- 9391748
TI - Renal inflammatory disease: the current role of CT.
AB - Computed tomography (CT) plays a significant role in establishing the diagnosis
in clinically equivocal cases of renal infection, determining the extent of the
disease process, and assessing its complications. Gas, calculi, renal parenchymal
calcifications, hemorrhage, and masses can be revealed with unenhanced CT. A
subsequent study with contrast enhancement is crucial for the complete evaluation
of patients with renal infection in order to demonstrate the areas of altered
nephrogram that occur as a result of the inflammatory process and to identify
complications. In this article we review a spectrum of renal inflammatory
disease, with illustrations of the CT findings in representative cases. We also
review the role and potential pitfalls of fast scanning techniques that can image
a particular phase of the nephrogram in a renal infection. In acute
pyelonephritis, enhanced CT scans obtained during the cortical nephrographic
phase typically demonstrate solitary or multifocal hypodense areas with
obliteration of the corticomedullary differentiation. Delayed images obtained
during the excretory phase are frequently more helpful in defining the extent of
the disease process, identifying the complications such as renal abscess, and
confirming the presence of urinary obstruction than are early images.
PMID- 9391749
TI - MR imaging of the female pelvis: current perspectives and review of genital tract
congenital anomalies, and benign and malignant diseases.
AB - MR imaging continues to be an integral problem-solving modality in the evaluation
of congenital anomalies and acquired diseases of the female genital tract organs
and provides effective clinical information to the practicing gynecologist in
those patients in whom sonography is technically suboptimal or the results are
equivocal. This article describes the state-of-the art MR imaging of the female
pelvis and addresses its current perspectives in the following sections: (1)
technical aspects of MR in imaging the female pelvis, (2) normal pelvic anatomy
and variations that are seen on MRI, (3) role of MRI in the diagnosis of
congenital uterine and vaginal anomalies, (4) MR imaging approach to diagnose
congenital uterine and vaginal anomalies, (5) advantages and limitations of MR in
the evaluation of various benign diseases and malignant neoplasms of the female
genital tract, (6) a MR staging system and criteria for each gynecologic
malignancy, (7) fundamental MR criteria to differentiate benign from malignant
tumors and recurrent tumors from fibrosis, and (8) the present cost-effective
value of MR in pregnancy and obstetrics. Magnetic resonance (MR) technology
continues to be an important problem-solving modality in the evaluation of
benign, malignant, and recurrent diseases of the female pelvic organs with the
development of new software and improved hardware over the last few years. The
main issues addressed in this article are (1) to review the basic and expanded
applications of the current state-of-the art MR imaging in the diagnosis and
management of various congenital and acquired disorders of the female pelvic
organs, (2) to illustrate a simplified clinico-radiologic (MRI) approach to the
diagnosis of congenital and acquired pathologies of the pelvic organs, (3) to
provide relevant information to the clinicians to make rational choices among the
competing imaging modalities, and (4) to outline the future potential of this
modality in the pelvis.
PMID- 9391750
TI - Phosphorylation of the proteins of the extracellular matrix of mineralized
tissues by casein kinase-like activity.
AB - The extracellular matrix of the connective tissue contains non-collagenous
proteins (NCP) which are acidic in character. The NCP of mineralizing systems
(bone, dentin) differ from those of the non-mineralizing systems (skin, tendon)
in that the mineralized tissue NCP are frequently phosphorylated. The
phosphorylated proteins have been implicated in various aspects of the
mineralization process. Thus, it is of interest to consider the mechanism and
regulation of phosphorylation of the major matrix NCP. The majority of the
phosphorylation takes place at Ser or Thr residues embedded within acidic
sequences, and therefore are targets for casein kinase I (CK1) or casein kinase
II (CK2)-like kinases. CK1 and CK2 are distantly related members of the protein
kinase family. They are ubiquitous, constitutively active, second-messenger
independent kinases. CK1 is found in a variety of isoforms, all homologous to the
alpha-subunit of the protein kinase family. It acts as a monomer. The active form
of CK2 is a tetrameric holoenzyme, with 2 alpha catalytic subunits and 2 beta
regulatory subunits. The CK2 alpha has activity alone, but the holoenzyme is four
to five-fold that activity. CK2 can use either ATP or GTP as the phosphate
donor, but CK1 can use only ATP. The CK2 activity which phosphorylates the
mineralized tissue NCP appears to be localized to membrane-associated cell
fractions, and is present in the endoplasmic reticulum and Golgi compartments in
osteoblasts, where phosphorylation of the secreted proteins appears to take place
as co- and post-translational processes. Data indicate that both alpha and beta
subunits of the membrane-associated CK2 are isoforms of the cytosolic CK2 in the
same cells. The CK1 has not been specifically localized. Studies of
dephosphorylated NCP such as phosphophoryn (PP) have shown that CK1 will not
phosphorylate dephosphorylated dPP unless prior phosphorylation with CK2 has been
carried out. In turn, CK2 activity may be initiated only after an initial
phosphorylation of one of the messenger-dependent kinases. Thus, the
phosphorylation reactions in mineralized tissues may be a tightly regulated
hierarchical or sequential cascade of intracellular phosphorylation events.
PMID- 9391751
TI - Leukocyte adhesion molecules.
AB - Recruitment of leukocytes is critical to many of the processes studied in oral
biology. With the development of new tools such as monoclonal antibody production
and transgenic mice, the specific adhesion molecules thought to be important in
leukocyte recruitment have been identified and their function examined. These
molecules can be divided into three major classes: selectins, members of the
immunoglobulin superfamily, and integrins. They mediate interactions between
leukocytes and endothelial cells, facilitating the initial process of leukocyte
rolling, firm attachment to endothelium, transendothelial migration, diapedesis,
and migration along connective tissue. The goal of this paper is to provide an
understanding of which molecules are involved in the above processes by
discussing their cellular distribution, counter-receptors, and physiologic
function.
PMID- 9391752
TI - Models of invasion of enteric and periodontal pathogens into epithelial cells: a
comparative analysis.
AB - Bacterial invasion of epithelial cells is associated with the initiation of
infection by many bacteria. To carry out this action, bacteria have developed
remarkable processes and mechanisms that co-opt host cell function and stimulate
their own uptake and adaptation to the environment of the host cell. Two general
types of invasion processes have been observed. In one type, the pathogens (e.g.,
Salmonella and Yersinia spp.) remain in the vacuole in which they are
internalized and replicate within the vacuole. In the other type, the organism
(e.g., Actinobacillus actinomycetemcomitans, Shigella flexneri, and Listeria
monocytogenes) is able to escape from the vacuole, replicate in the host cell
cytoplasm, and spread to adjacent host cells. The much-studied enteropathogenic
bacteria usurp primarily host cell microfilaments for entry. Those organisms
which can escape from the vacuole do so by means of hemolytic factors and C type
phospholipases. The cell-to-cell spread of these organisms is mediated by
microfilaments. The investigation of invasion by periodontopathogens is in its
infancy in comparison with that of the enteric pathogens. However, studies to
date on two invasive periodontopathogens. A actinomycetemcomitans and
Porphyromonas (Bacteroides) gingivalis, reveal that these bacteria have developed
invasion strategies and mechanisms similar to those of the enteropathogens. Entry
of A. actinomycetemcomitans is mediated by microfilaments, whereas entry of P.
gingivalis is mediated by both microfilaments and microtubules. A.
actinomycetemcomitans, like Shigella and Listeria, can escape from the vacuole
and spread to adjacent cells. However, the spread of A. actinomycetemcomitans is
linked to host cell microtubules, not microfilaments. The paradigms presented
establish that bacteria which cause chronic infections, such as periodontitis,
and bacteria which cause acute diseases, such as dysentery, have developed
similar invasion strategies.
PMID- 9391753
TI - Mercury exposure from dental amalgam fillings: absorbed dose and the potential
for adverse health effects.
AB - This review examines the question of whether adverse health effects are
attributable to amalgam-derived mercury. The issue of absorbed dose of mercury
from amalgam is addressed first. The use of intra-oral Hg vapor measurements to
estimate daily uptake must take into account the differences between the
collection volume and flow rate of the measuring instrument and the inspiratory
volume and flow rate of air through the mouth during inhalation of a single
breath. Failure to account for these differences will result in substantial
overestimation of the absorbed dose. Other factors that must be considered when
making estimates of Hg uptake from amalgam include the accurate measurement of
baseline (unstimulated) mercury release rates and the greater stimulation of Hg
release afforded by chewing gum relative to ordinary food. The measured levels of
amalgam-derived mercury in brain, blood, and urine are shown to be consistent
with low absorbed doses (1-3 micrograms/day). Published relationships between the
number of amalgam surfaces and urine levels are used to estimate the number of
amalgam surfaces that would be required to produce the 30 micrograms/g creatinine
urine mercury level stated by WHO to be associated with the most subtle, pre
clinical effects in the most sensitive individuals. From 450 to 530 amalgam
surfaces would be required to produce the 30 micrograms/g creatinine urine
mercury level for people without any excessive gum-chewing habits. The potential
for adverse health effects and for improvement in health following amalgam
removal is also addressed. Finally, the issue of whether any material can ever be
completely exonerated of claims of producing adverse health effects is
considered.
PMID- 9391754
TI - Tobacco and smoking: environmental factors that modify the host response (immune
system) and have an impact on periodontal health.
AB - This review summarizes the current data on the effects of smoking and tobacco on
the immune system and its potential impact on periodontal health. Smokers are 2.5
6 times more likely to develop periodontal disease than non-smokers, and there is
evidence for a direct correlation between the number of cigarettes smoked and the
risk of developing disease. Tobacco users also tend to exhibit increased severity
of periodontal disease. Direct correlations between tobacco use and increased
attachment loss and pocket depth and reduced bone crest height have been
reported. Although the correlation between tobacco use and periodontal disease is
quite strong, the role of tobacco in the pathogenesis of periodontal disease is
uncertain. Recent studies indicate that one potential mechanism is that tobacco
use exacerbates periodontal disease because it alters the immune response to
periodontal pathogens. Indeed, smokers exhibit increased numbers of peripheral
blood mononuclear phagocytes which appear to be functionally compromised.
Inadequate phagocyte activity could reduce the clearance of pathogens from the
oral cavity and thereby facilitate the development of periodontal disease.
Tobacco-exposed B- and T-lymphocytes exhibit reduced proliferative capacities
which could limit the production of protective immunoglobulins against oral
pathogens. The risk factors for periodontal disease can be broadly classified as
genetic, environmental, host-response factors, and host-related factors such as
age. Tobacco, an environmental factor, undermines the host response and may
facilitate the development and progression of periodontal disease. This review
highlights the inter-relatedness of two of the risk factors associated with
periodontal disease.
PMID- 9391755
TI - Psychosocial factors and secretory immunoglobulin A.
AB - This review focuses on studies that have examined the relation between
psychosocial factors and secretory immunoglobulin A (s-IgA). Several studies have
examined the relation between s-IgA and stressful circumstances ranging from
major life events to minor daily events. The findings from these studies were
often contradictory, since different experimenters reported different stress
related changes in s-IgA. The effects of stress reduction interventions, such as
relaxation and imagery, on s-IgA levels have also been examined. Although these
studies indicate that various interventions are associated with increases in s
IgA levels, methodological refinements are needed before more definitive
conclusions can be made. The possibility that the relation between stress and s
IgA may be moderated by personality characteristics or mediated by psychological
distress was supported in some studies. The review concludes with suggestions for
future research.
PMID- 9391756
TI - Cystic fibrosis.
PMID- 9391757
TI - Early pulmonary disease in cystic fibrosis.
AB - In cystic fibrosis, airway infection and inflammation lead to chronic progressive
lung disease. The pathogenesis of cystic fibrosis is still not completely
understood, but increasing evidence indicates that the disease process occurs in
young patients. Treatment of respiratory symptoms in young patients, although not
well studied, is commonly accepted and includes the full range of treatments used
in older patients-secretion clearance techniques, bronchodilators, anti
inflammatory agents, and antibiotics by oral, inhaled, and systemic routes. It is
not clear, however, whether early treatment can delay or prevent progressive lung
disease in these patients. Outcome measures, including determination of infant
lung function, imaging techniques, and direct lower airway sampling through
bronchoalveolar lavage are under development and will allow large, multicenter
interventional trials in young children. These studies will be aimed at delaying
the initiation of lung disease and slowing disease progression.
PMID- 9391758
TI - Update on clinical trials of cystic fibrosis.
AB - This review attempts to summarize the important areas of cystic fibrosis (CF)
clinical research. Some of the trials outlined are incomplete or the data are not
yet published. Focus is given to gene therapy and to studies that probe our
understanding of CF cellular biology by attempting to correct or bypass abnormal
cystic fibrosis transmembrane regulator. Trials of more immediate clinical value
include improvement of mucociliary transport and inhaled tobramycin. Finally,
mention is made of the significant nonpulmonary treatments for CF including
ursodeoxycholic acid for CF liver disease and intracytoplasmic sperm injection
for male infertility.
PMID- 9391759
TI - The overuse or underuse of dornase alfa.
AB - The poor clearance of airway secretions in patients with cystic fibrosis
perpetuates the chronic bronchopulmonary sepsis that is predominant. In recent
years, novel drugs have been developed to alter the rheologic properties of the
secretions in an attempt to improve airway clearance. Dornase alfa reduces the
viscoelasticity of sputum from patients with cystic fibrosis and may enhance the
clearance of secretions. Current clinical knowledge suggests that it is a safe
treatment that improves pulmonary function and reduces respiratory exacerbations.
The response, however, is heterogeneous and unpredictable. Scientific studies
support the therapeutic rationale for the use of dornase alfa in that treatment
reduces the viscoelasticity of airway secretions. Its effect on bacterial
persistence and airway inflammation, however, is marginal. The key piece of
information that would influence the long-term use of dornase alfa is how it
affects disease progression, and at present this is unknown.
PMID- 9391761
TI - Ethical considerations in the treatment of cystic fibrosis.
AB - Over the last several decades, rapid medical advancement in the treatment of
persons with cystic fibrosis (CF) has brought with it a number of ethical
concerns. The increasing life expectancy of persons with CF has made transitions
in care increasingly common. This change in life expectancy along with advances
in assisted reproductive technologies has focused attention on reproductive
decision making in CF. Living lobar lung transplantation, although technically
developed, remains ethically problematic. The understanding of ethical issues
arising in the treatment of CF is crucial to providing optimal care.
PMID- 9391760
TI - Choosing a nebulizer for cystic fibrosis applications.
AB - As the number of inhaled drugs available for cystic fibrosis grows, there is
increasing awareness of delivery device issues. Current jet and ultrasonic
nebulizers are inefficient at delivering drugs to the lower respiratory tract.
There are large differences in output characteristics between nebulizers and high
intersubject variability in lung deposition. The clinical effects of inhaled
drugs depend on adequate dosing to the lower airway, so we must choose a
nebulizer and patient characteristics that will affect lung deposition
positively. Aerosols with particle sizes at the smaller end of the respirable
range (2 to 3 microns) may enhance the clinical benefit of some drugs, regardless
of patient age or disease severity. Breath-enhanced (Venturi) jet nebulizers are
less wasteful than constant-output nebulizers and perform better than
conventional nebulizers with many drugs. Patient breathing patterns and degree of
airway obstruction are important in determining the site of airway deposition.
With increased attention to aerosol delivery issues by clinicians, industry, and
regulatory agencies, improved technologies will evolve to target therapies to the
lung.
PMID- 9391762
TI - Managed care and the cystic fibrosis patient.
AB - Since the first published report of mortality in cystic fibrosis in 1969, the
median survival among cystic fibrosis patients has risen from 14 to 31 years. The
reasons for this improved survival are complex and include earlier diagnosis;
improved control of pulmonary infection; aggressive nutritional intervention; and
enhanced monitoring of patients in peer-reviewed, accredited centers for cystic
fibrosis care, teaching, and research. Emphasis on the importance of research on
changing and improved treatment has been effectively communicated to patients and
families. As a result, a group of highly educated medical consumers has been
created. During the last decade, another focus of rapid change has appeared, that
of cost containment in the medical profession, creating the field of managed
care. Practicing medical professionals perceive the need for reduction in
excessive spending in medicine and have taken a variety of approaches to balance
better the value and cost of medical care while maintaining superb quality.
Physicians and consumers continue to have concerns about the potential negative
impact of managed care on a relatively rare, specialized, and chronic illness
such as cystic fibrosis if managed care concepts are applied without proper
understanding of the disease. A great concern is that managed care in cystic
fibrosis may cause reversal of trends in improved quality and length of survival.
The increased length of survival places an increasing demand on the already
stressed system of health care financing. Understanding the changing area of
managed care is therefore of paramount importance to clinicians involved in
cystic fibrosis care. The Cystic Fibrosis Foundation has presented symposia on
managed care at each of the last three annual meetings, including the North
American Cystic Fibrosis Meeting, October 1996. The following issues were
addressed by speakers and panel discussants, with portions excerpted for this
review: trends in managed care, measures and guidelines useful in managed care,
Medicaid managed care and cystic fibrosis, and practical aspects of using
pathways in caring for patients with cystic fibrosis.
PMID- 9391763
TI - Early life and the pathophysiology of breathing.
PMID- 9391764
TI - New insights into the ontogeny of breathing from genetically engineered mice.
AB - Development of breathing behavior depends on the coordinated maturation of
central and peripheral neural pathways, respiratory muscles, airways, and lung
tissues. Each of these components contains cellular elements in which
derangements of gene expression may perturb development of normal respiratory
function. Application in recent years of genetic engineering techniques has led
to detailed analyses of gene structure and function. In particular, targeted gene
deletions provide the opportunity to relate gene function to physiologic
mechanisms in intact animals. This review summarizes recent studies in mice
designed to alter, by targeted disruption of specific genes, development of
individual components of the respiratory control system. We also discuss an
example of the human therapeutic potential of transgenic methods.
PMID- 9391747
TI - Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment
of illicit drug users.
AB - Many clinicians are confronted by the use of illicit drugs on a daily basis. The
unsanctioned use of opioids, psychostimulants, benzodiazepines, alcohol and
nicotine is a major cause of morbidity and mortality. Multiple factors have
inhibited the scientific study of these agents including prohibition, public
denial and lack of commercial interests. In dealing with problems related to
these drugs, clinicians need a scientific understanding of their pharmacology,
quantifiable effects and potential adverse effects. Illicit drug users select
drugs with particular pharmacokinetic parameters and pharmacodynamic properties.
Generally, rapid absorption, rapid entry into the central nervous system, high
bioavailability, short half-life, small volume of distribution and high free drug
clearance are pharmacokinetic characteristics which predict a high potential for
harmful use because these factors increase positive reinforcement. Drug users
adapt the method and route of drug administration to optimise the delivery of the
drug to the brain while attempting to maximise the bioavailability of the drug.
Inhalation and smoking are the routes of administration which allow the most
rapid delivery of drug to the brain, while intravenous injection maximises the
bioavailability of an administered drug. Each route of administration results in
attendant complications related to mucosal damage, carcinogenesis and risk of
infection. Negative reinforcement or withdrawal is a major drive to recurrent
use. Many illicit drugs have pharmacological features that promote dependence,
including long half-life, low free drug clearance and sufficient drug exposure to
allow development of tolerance. The preventive or reductive pharmacotherapeutics
of illicit drug use makes use of several subsets of agents: those which act on
the same receptor or system as the illicit drug (such as methadone), those which
produce an adverse reaction on consumption of the illicit drug (such as
disulfiram) and those which symptomatically attenuate illicit drug withdrawal
symptoms (such as clonidine). Many new agents are being trialled as potential
preventive or reductive agents. It is important to consider pharmacotherapy as
only one potential part of the treatment of illicit drug users. The complications
of illicit drug use present many therapeutic challenges. As with all patients
consuming multiple drugs, illicit drug users are prone to developing drug
interactions. The most common interactions seen in practice are pharmacodynamic
in nature, most often due to the additive effects of different drugs on the
central nervous system. However, alcohol, cocaine, disulfiram, methadone and
tricyclic antidepressants may be involved in important pharmacokinetic
interactions. Of these the effect of long term alcohol consumption in increasing
the hepatotoxicity of paracetamol and of cytochrome P450 3A microsomal enzyme
stimulating drugs in diminishing the efficacy of methadone are the most commonly
encountered.
PMID- 9391765
TI - Development of cardiopulmonary integration and the role of arousability from
sleep.
AB - The recent literature on cardiopulmonary integration in infants is surveyed here,
focusing on arousals from sleep. Recent studies reported that the ontogenicity of
cardiopulmonary integration cannot be evaluated independently from that of sleep
wake cycles. The issue is of importance for researchers and clinicians evaluating
cardiorespiratory characteristics in infants. It also has significant
implications in the understanding of clinical conditions, such as parasomnias,
obstructive sleep apneas, or some cases of sudden infant death syndrome. The
propensity to arouse can be evaluated by exposing the sleeper to awakening
challenges. Arousal thresholds are determined by measuring the intensity of the
stimulus needed to induce arousals. However, these studies are complicated by
factors such as the scoring of the arousal responses. Another difficulty lies in
the choice and modality of the arousal stimulus. Noise, gases, light, and
nociceptive, mechanical, chemical, or temperature stimuli have all been used to
induce arousals. Confounding factors modify the sleeper's responses to a given
stimulus. Prenatal drug, alcohol, or cigarette use and the infant's age or,
previous sleep deprivation also modify thresholds. Other confounding factors
include time of the night, sleep stages, the sleeper's body position, and
sleeping conditions. Arousal can also occur spontaneously because of endogenous
stimuli. The literature surveyed here also covers such unresolved issues as the
clinical significance of aborted arousals, or the mechanisms responsible for the
arousal reactions.
PMID- 9391766
TI - Pediatric hypoventilation syndromes.
AB - Hypoventilation syndromes are an uncommon but important group of respiratory
control disorders in infants and children. Congenital central hypoventilation
syndrome (CCHS) is the principal and most important example. No specific
anatomical or biochemical mechanism has yet been identified. This article
summarizes current knowledge regarding CCHS in infants and children, and
emphasizes the most recent and most important publications. The most recent
advances in CCHS pertain to its genetics, pathophysiology, diagnosis, and
treatment and provide state-of-the-art information regarding advances in
diaphragm pacing, responses to exercise, and long-term outcome. CCHS is now being
recognized more frequently, treatment is more successful, and long-term outcomes
are encouraging with timely diagnosis, state-of-the-art treatment, and
comprehensive follow-up at an experienced pediatric referral center.
PMID- 9391767
TI - Sleep disorders in infancy, childhood, and adolescence.
AB - Sleep disorders cause substantial problems during infancy, toddlerhood, preschool
ages, school ages, and adolescence. They represent the most common behavioral
problems facing most parents, as well as some of the most unusual and fascinating
disorders known to medicine. Sleep disorders can result from pulmonary problems,
neurologic problems, family problems, or psychologic or psychiatric problems. The
majority of these disorders can be diagnosed by a comprehensive sleep and medical
assessment, but special studies such as polysomnography, multiple sleep latency
testing, or video electroencephalographic monitoring are necessary for certain
diagnoses. Pediatric sleep disorders represent a true interdisciplinary and
developmental field, richly connected with many aspects of health care and
medical science. Physicians and other pediatric care providers must become
increasingly knowledgeable about sleep disorders to offer the best care to their
patients.
PMID- 9391768
TI - Consequences of sleep-disordered breathing in childhood.
AB - Obstructive sleep-disordered breathing (SDB) is a common problem in children that
may lead to growth failure, neurocognitive and behavioral abnormalities, cor
pulmonale, and death. Primary snoring, upper airway resistance syndrome, and
obstructive sleep apnea syndrome represent a spectrum of clinical manifestations
accompanying increasing degrees of upper airway obstruction. Clearly, children
with severe SDB need to be identified and treated promptly. Appropriate
management strategies for milder forms of SDB are less clear. Some snoring
children, for example, may have an increased frequency of obstructive apnea
during sleep, with or without mild hypoxemia, but have essentially no daytime
symptoms or apparent clinical consequences. Should these children be treated? If
untreated, will these children eventually develop more severe obstructive SDB?
Development of management strategies is hampered by the lack of data on the
natural history of childhood SDB and on the correlation of specific
polysomnographic abnormalities to symptoms and complications. In this review, we
highlight recent information about the consequences of obstructive SDB in
children, with particular emphasis on areas in which more data are needed.
PMID- 9391769
TI - Management of obstructive sleep apnea in childhood.
AB - The childhood obstructive sleep apnea syndrome is a common and serious problem.
Adenotonsillectomy remains the mainstay of treatment. Nasal continuous positive
airway pressure is effective and well tolerated in those who do not respond to
adenotonsillectomy. In selected cases, additional surgery or supplemental oxygen
(with careful monitoring) may play a role. New guidelines for pediatric
polysomnography should help standardize methods, thus enabling a better
comparison of outcomes. More research in this area is sorely needed.
PMID- 9391770
TI - Cystic fibrosis.
PMID- 9391771
TI - Sleep and respiratory neurobiology.
PMID- 9391772
TI - NSAIDs and increased blood pressure. What is the clinical significance?
AB - Several randomised studies have demonstrated that various nonsteroidal anti
inflammatory drugs (NSAIDs) elevate blood pressure in normotensive and
hypertensive individuals; however, these data have been contradicted by numerous
negative studies. Two meta-analyses have demonstrated that, after pooling data
drawn from published reports of randomised trials of younger adults, NSAID use
produces a clinically significant increment in mean blood pressure of 5 mm Hg,
most marked in patients with controlled hypertension. Stratification by NSAID
type revealed that piroxicam, naproxen and indomethacin had the greatest, and
sulindac the smallest, pressor effect. These data were supported by 2 large
community studies involving elderly patients. Recent NSAID users had a 1.7-fold
higher risk of requiring the initiation of antihypertensive therapy compared with
nonusers; NSAID users also had a 40% increased risk of receiving a diagnosis of
hypertension compared with nonusers. It is vital to determine the nature of the
association in the elderly, 12 to 15% of whom are concurrently receiving an NSAID
and an antihypertensive agent. Importantly, a 5 to 6 mm Hg increase in diastolic
blood pressure maintained over a few years may be associated with a 67% increase
in total stroke risk and a 15% increase in coronary heart disease events. While
the mechanism(s) remain speculative, salt and water retention through several
factors operating in parallel, coupled with increased total peripheral vascular
resistance, via increased renal endothelin-1 synthesis, are potentially
important. Clinicians should strive to avoid excessive use of NSAID treatment and
consider well-tolerated therapeutic alternatives, including simple analgesics and
physical therapy. For patients who require concomitant NSAID and antihypertensive
treatment, physicians should be aware that indomethacin, naproxen and piroxicam
may be associated with a greater pressor effect than many other NSAIDs, and that
antagonism of beta-blockers may be greater than that of vasodilators (including
ACE inhibitors and calcium antagonists) and diuretics. Finally, the progress of
each patient should be monitored by careful blood pressure measurement,
particularly during the period of initiation of NSAID therapy.
PMID- 9391773
TI - Therapeutic options for HIV-associated bodyweight loss. A risk-benefit analysis.
AB - Involuntary bodyweight loss, a common complication of infection with HIV, is an
indicator of poor prognosis and decreased survival. Because of the multifactorial
pathogenesis of HIV-related wasting, emerging therapies are directed at the
multiple proposed mechanisms of involuntary bodyweight loss. The initial
evaluation and treatment of HIV-related bodyweight loss is focused on the
identification and treatment of reversible causes of bodyweight loss, such as
secondary opportunistic infections or endocrine dysfunction. Nutritional
intervention should begin in the early stages of HIV infection and continue
throughout the life of the patient. Of the appetite stimulants, megestrol most
consistently promotes bodyweight gain, but with a predominance of fat, not lean,
body mass. Anabolic therapies such as testosterone derivatives and recombinant
human growth hormone (somatropin) stimulate the addition of lean body mass and
are begin actively researched for the treatment of HIV-associated wasting.
Finally, thalidomide, a potent inhibitor of tumour necrosis factor-alpha, is a
potentially useful therapy that is still under investigation. New research into
the treatment of HIV-related bodyweight loss is focusing on combination
therapies.
PMID- 9391774
TI - A risk-benefit assessment of growth hormone use in children.
AB - Growth hormone prepared by recombinant DNA technology (somatropin) has been
commercially available for over 11 years. More than 38,000 children have been
treated with different growth hormone products. While the best response to
treatment occurs in children with severe growth hormone deficiency, therapy with
growth hormone will increase the rate of statural growth in children with short
stature of many different aetiologies. There are few studies of the effect of
growth hormone treatment of final adult height, and the magnitude of this effect
is harder to gauge, particularly in children with idiopathic short stature. Other
benefits of growth hormone treatment in children include improvement in
psychosocial functioning and physiological parameters, such as bone mineral
density. Adverse effects associated with growth hormone treatment have been
relatively uncommon. Most of the safety data on growth hormone have come from
large postmarketing databases maintained by 2 pharmaceutical companies. The
adverse event profile reported in children treated with growth hormone is
different from that found in adults. Peripheral oedema and carpal tunnel
syndrome, which are common in adults treated with growth hormone and frequently
result in treatment discontinuation, are rare in children. Intracranial
hypertension is rare, but can occur in children with growth hormone deficiency,
Ullrich-Turner syndrome or renal insufficiency during the first 8 to 12 weeks
after the start of growth hormone treatment; it has seldom been reported in
adults with growth hormone deficiency. Children with growth hormone deficiency,
Ullrich-Turner syndrome or renal insufficiency are prone to develop slipped
capital femoral epiphyses both before and during growth hormone treatment.
Therefore, limping and complaints of hip or knee pain should be carefully
investigated.
PMID- 9391775
TI - A risk-benefit assessment of octreotide in the treatment of acromegaly.
AB - Acromegaly was the first pituitary disease to be recognised as a clinical entity,
although initially it was not clear whether the eosinophilic adenomas causing
pituitary enlargement were causative or just a manifestation of the syndrome
itself. Following the documented clinical improvement of patients with acromegaly
after partial hypophysectomy, it was proven that the pituitary adenomas were
aetiological. The treatment of acromegaly has changed during the last decades;
the introduction of the somatostatin (SMS) analogue octreotide has had major
implications. Octreotide was the first SMS analogue to become available for
clinical use. It is generally well tolerated, but is associated with the
development of gallstones in 15 to 20% of patients. Other adverse effects include
transient injection-site pain, abdominal, diarrhoea, gastritis (long term
therapy) and loss of scalp hair. No long haematological or biochemical adverse
effects have been reported. Desensitisation to the beneficial effects of
octreotide therapy is highly unusual. A long-acting formulation of octreotide is
being studied, and should be available by the end of 1997.
PMID- 9391778
TI - Assessing disease activity in Crohn's disease--are we there yet?
AB - Many attempts have been made over recent years to assess accurately disease
activity in Crohn's disease. We review some of these attempts, giving particular
emphasis to the combination of serum levels of proinflammatory cytokines
(interleukin-6, tumour necrosis factor alpha, recombinant interleukin-2 and acid
alpha-1-glycoprotein).
PMID- 9391776
TI - Heparin-induced thrombocytopenia. Pathogenesis, frequency, avoidance and
management.
AB - Heparin-induced thrombocytopenia (HIT) is an immunoglobulin-mediated adverse drug
reaction associated with a high risk of thrombotic complications. The pathogenic
antibody, usually immunoglobulin (Ig) G (HIT-IgG), recognises a multimolecular
complex of heparin and platelet factor 4, resulting in platelet activation via
platelet Fc receptors. In addition to in vivo platelet activation, it is now
recognised that there is a concomitant activation of coagulation, as shown by
marked elevations in thrombin-antithrombin complex levels. It is possible that
this increased thrombin generation predisposes HIT patients to a newly recognised
complication: warfarin-induced venous limb gangrene. This syndrome is
characterised clinically by necrosis complicating deep venous thrombosis in the
absence of large-vessel arterial occlusion, and appears to result from acquired
protein C deficiency during warfarin therapy for deep vein thrombosis and HIT.
The recommended treatment for HIT is an agent that reduces thrombin generation,
either indirectly via factor Xa inhibition [e.g. danaparoid sodium (a mixture of
anticoagulant glycosaminoglycans)] or directly using a specific thrombin
inhibitor (e.g. recombinant hirudin; argatroban). HIT is potentially preventable:
there is a lower frequency of HIT, associated thrombosis and HIT-IgG
seroconversion in patients treated with low-molecular-weight heparins, compared
with unfractionated heparin.
PMID- 9391777
TI - Traditional remedies and food supplements. A 5-year toxicological study (1991
1995).
AB - Since 1991, the Medical Toxicology Unit (MTU) at Guys' Hospital, London, has been
assessing the toxicological problems associated with the use of traditional and
herbal remedies and dietary supplements. This assessment was carried out by
evaluating reports to the National Poisons Information Service (London) [NPIS(L)]
which provides emergency information to medical professionals. Relevant telephone
enquiries to NPIS(L) were identified. Further case details were obtained by
follow-up questionnaire, clinical consultation, toxicological analysis of samples
from patients and/or products and botanical identification of plant material. Of
1297 symptomatic enquiries evaluated there was a possible/confirmed association
in 785 cases. Case series have been identified which substantiate previous
reports, including liver problems following the use of Chinese herbal medicine
for skin disorders, allergic reactions to royal jelly and propolis and heavy
metal poisoning caused by remedies from the Indian subcontinent. Although the
overall risk to public health appears to be low, certain groups of traditional
remedies have been associated with a number of potentially serious adverse
effects. Considering the extent of use of herbal remedies and food supplements a
comprehensive surveillance system for monitoring the adverse health effects of
these products is essential. Surveillance of a large population is needed for the
complex task of identifying the uncommon and unpredictable adverse effects which
are potentially serious. In the UK, the Medicines Control Agency responded to the
MTU report by recognising the need for vigilance and by incorporating adverse
reactions reporting on unlicensed herbal remedies into their drug reaction
monitoring function. As a further step to safeguard the patients/consumers an
effective single regulatory system is required which would ensure the safety and
quality of all herbal remedies and food supplements available in the UK.
PMID- 9391779
TI - Detection of osteoporosis in patients with inflammatory bowel disease.
AB - The risk of osteoporosis is increased in patients with inflammatory bowel
disease: particularly in those with additional strong risk factors such as
glucocorticoid therapy, hypogonadism, past history of fragility fracture or
malnutrition. Where possible, bone densitometry should be performed to identify
those in need of treatment, to avoid unnecessary treatment if bone density is
normal and to monitor the effects of treatment designed to prevent bone loss. If
bone densitometry is not available, treatment should be advised on the basis of
strong risk factors. Hormone replacement therapy should be given to patients with
hypogonadism and bisphosphonate therapy to those receiving long-term
glucocorticoid treatment. The dose of glucocorticoids should be kept to a minimum
and, where present, vitamin D deficiency should be corrected.
PMID- 9391780
TI - Helicobacter pylori and non-steroidal anti-inflammatory drugs: lone agents or
partners in crime?
AB - A variety of mechanisms are responsible for the gastric and duodenal mucosal
injury known to result from the consumption of non-steroidal anti-inflammatory
drugs (NSAIDs). Many of these mechanisms may be influenced by coexistent
infection with Helicobacter pylori. However, evidence of increased risk from
NSAIDs in patients with this bacterium is contradictory. While some authors have
reported that symptoms, severity and prevalence of mucosal damage are higher in
H. pylori-positive individuals taking NSAIDs than in those who are H. pylori
negative, others have noted no significant difference. Reasons for this conflict
may include the age of the subjects studied, duration of treatment, toxicity of
the NSAID employed and pathogenicity factors related to different strains of H.
pylori.
PMID- 9391781
TI - A high serum concentration of interleukin-6 is predictive of relapse in quiescent
Crohn's disease.
AB - BACKGROUND/AIMS: Relapses of Crohn's disease are difficult to predict. We
assessed the value of serum level of interleukin-6, tumour necrosis factor alpha
(TNF-alpha) and soluble TNF receptors as predictors of relapse in quiescent
Crohn's disease. PATIENTS/METHODS: Thirty-six patients with inactive Crohn's
disease, treated or not, were included. Various clinical and biological
parameters, including interleukin-6, TNF-alpha and soluble TNF receptors serum
levels were measured at inclusion in the study and the patients were followed
clinically for 1 year. The relapse was defined as a Crohn's Disease Activity
Index (CDAI) greater than 150 with an increase greater than 100 compared to the
inclusion value. We analysed the ability of these parameters to predict relapse
in parallel to clinical characteristics and other laboratory parameters. RESULTS:
Among the 32 variables tested, interleukin-6 serum level had the greatest ability
to predict the time-to-relapse, with 17-fold chance of relapse over a 1-year
period for patients with an interleukin-6 serum level greater than 20 pg/ml than
for patients with a lower level (P < 0.001). A high serum level of the soluble
TNF receptors p55 and p75 also had significant predictive value, in contrast to
TNF-alpha serum levels. An interleukin-6 serum level greater than 20 pg/ml and
either an acid alpha-1-glycoprotein level greater than 1.1 g/l or a soluble
interleukin-2 receptor serum level greater than 95 pM/l were risk factors
selected by a stepwise multivariate analysis. In both models a good prognosis
group was defined by the absence of the two risk factors, a bad prognostic group
by the presence of the two risk factors and an intermediate in between. With both
models, the good prognosis group included 17 patients who experienced no relapse
over the 1-year follow-up, whereas all patients (seven with the first model and
six with the second) in the bad prognosis group had a relapse during the follow
up. Looking specifically at two homogeneous subgroups including either
naturally/5-aminosalicylic acid (5-ASA) quiescent or corticoid quiescent
patients, a very good predictive value for interleukin-6 serum concentration was
also found. CONCLUSION: Interleukin-6 serum level alone or in association with
other biological parameters such as acid alpha-1-glycoprotein or the soluble
interleukin-2 receptor serum level may be useful for predicting the course of the
disease in patients with quiescent Crohn's disease.
PMID- 9391782
TI - The relation of hand skin-fold thickness to bone mineral density in patients with
Crohn's disease.
AB - OBJECTIVES: In healthy postmenopausal women, the association of skin-fold
thickness (SFT) with bone mineral density (BMD) is well described, and a low SFT
is a useful predictor of osteoporosis. In this study the association between hand
SFT and BMD in patients with Crohn's disease was assessed; and the potential for
hand SFT as a screening test for osteoporosis evaluated. DESIGN/METHODS: In a
cross-sectional study, BMD was measured at the hip and lumbar spine by dual
energy x-ray absorptiometry (DEXA). SFT was measured on the dorsum of the right
hand using Holtain Tanner Whitehouse calipers. One hundred and seventeen patients
(48 male) with Crohn's disease and 50 (25 male) controls were studied. RESULTS:
There was a significant correlation between hand SFT and BMD (expressed as t
scores) at all four measured sites (lumbar spine r = 0.41, P < 0.0001, 95% CI
0.25-0.55, Ward's triangle r = 0.38, P < 0.0001, 95% CI 0.21-0.53, trochanter r =
0.33, P < 0.0001, 95% CI 0.16-0.48, femoral neck r = 0.38, P < 0.0001, 95% CI
0.21-0.53). On stepwise regression analysis, the association remained significant
after correcting for age, weight, menstrual status and current steroid use (P <
0.05). Hand SFT was significantly lower in patients with Crohn's disease than
controls (difference in means 0.51 mm, 95% CI 0.3-0.72, P < 0.0001). Mean hand
SFT was significantly lower in patients with osteoporosis compared to patients
with normal BMD (difference in means 0.74 mm, 95% CI 0.33-1.15, P < 0.001), as
was that of osteopenic patients compared to patients with normal BMD (difference
in means 0.28 mm, 95% CI 0.01-0.55, P < 0.05). In the diagnosis of osteoporosis,
the sensitivity of hand SFT ranged from 29% to 93%, with specificities of 54% to
95%. CONCLUSIONS: Hand SFT is independently associated with BMD in Crohn's
disease and is lower than in age-matched healthy subjects. Hand SFT in
combination with other easily measurable confounding variables might be useful in
screening for osteoporosis in patients with Crohn's disease.
PMID- 9391783
TI - The effect of Helicobacter pylori infection on NSAID-related gastroduodenal
damage in the elderly.
AB - OBJECTIVE: To evaluate the effect of Helicobacter pylori infection on the
prevalence and severity of non-steroidal anti-inflammatory drug (NSAID)-related
upper gastrointestinal lesions in the elderly. PATIENTS AND METHODS: One hundred
and twenty-eight symptomatic NSAID users (47 males, 81 females; mean age 79.5
years, range 67-95 years) were evaluated by endoscopy. NSAID use was evaluated at
the time of endoscopy by interview and general practitioners' clinical records.
Patients were separated by the following use patterns: (1) Occasional Users:
patients who had taken NSAIDs sporadically, on an as-needed basis in the 7-day
period before endoscopy; (2) Acute Users: patients who had taken NSAIDs regularly
during the last month; and (3) Chronic Users: patients who had taken NSAIDs
regularly for more than 1 month. H. pylori infection was diagnosed by gastric
histology (modified Giemsa stain) and the rapid urease test. Statistical analysis
was performed by means of the chi 2 test with standardized deviates. RESULTS: Of
the 128 subjects, 107 (83.6%) presented with gastroduodenal damage: 3 patients
(2.3%) had erosive oesophagitis; 38 patients (29.7%) had gastric ulcer (GU); 43
patients (33.6%) had duodenal ulcer (DU); 3 patients (2.3%) had both GU and DU
and 20 patients (15.6%) had erosive gastritis. Seventy-four of the 128 patients
(57.8%) were found to be H. pylori positive. In comparison to H. pylori-negative
subjects, those who were H. pylori-positive had a significantly higher percentage
of GU and DU (74.3% vs. 53.7%, P = 0.02) and a lower percentage of non
gastroduodenal lesions (10.8% vs. 24.0%, P = 0.05). No significant trend in H.
pylori positivity was found in the 50/128 (39.06%) patients who presented with
bleeding lesions (H. pylori positive 36.5%, H. pylori negative 42.6%, not
significant). At endoscopy 78% of occasional NSAID users, 93.8% of acute users
and 88.7% of chronic users presented with upper gastrointestinal lesions (not
significant). No significant differences in NSAID use patterns were observed
between H. pylori-positive and H. pylori-negative subjects. CONCLUSION: H. pylori
infection in the elderly is associated with an increase in the NSAID-related GU
and DU, but not with a higher prevalence of upper gastrointestinal bleeding.
PMID- 9391784
TI - Erosive duodenitis: prevalence of Helicobacter pylori infection and response to
eradication therapy with omeprazole plus two antibiotics.
AB - OBJECTIVES: To study the prevalence of Helicobacter pylori infection in patients
with erosive duodenitis (ED), the associated gastric histological lesions and
their response to eradication therapy with omeprazole plus two antibiotics.
METHODS: A prospective study was made of 57 patients with ED (mean age 46 +/- 16
years, 72% males). At endoscopy, biopsies from gastric antrum and body were
obtained for histological study (haematoxylin and eosin). A 13C-urea breath test
was also performed. Omeprazole 20 mg twice daily plus two antibiotics
(amoxycillin 1 g twice daily, clarithromycin 500 mg twice daily, metronidazole
500 mg twice daily) were administered for 1 week. Endoscopy and breath test were
repeated 1 month after completing therapy, and the breath test was performed
again at 6 months. RESULTS: All patients were H. pylori positive. Overall
eradication was achieved in 86% (95% CI 75-93%). Duodenal erosion healing was
obtained in 45 patients (79%). Healing was achieved in 86% (CI 73-93%) of cases
with successful eradication therapy, but only in 3/8 (37%; CI 8.5-75%) patients
with therapy failure (P < 0.01). In the multivariate analysis, H. pylori
eradication was the only variable which correlated with erosion healing (odds
ratio 10; CI 2-51; P < 0.01). Histological improvement, in both the gastric
antrum and body, was demonstrated when eradication was achieved (P < 0.001). Six
months after diagnosis H. pylori absence was confirmed in all patients with
initial therapy success (all of them asymptomatic), and infection was confirmed
in the eight patients who were H. pylori positive after therapy (six of them
symptomatic). At 6-month follow-up, endoscopy was normal in 6/7 H. pylori
negative patients with previously persistent ED, while erosions were still
present in 4/5 H. pylori-positive patients with previously persistent ED.
CONCLUSION: A high prevalence (100%) of H. pylori infection in patients with ED
was observed. A 1-week twice daily therapy with omeprazole plus two antibiotics
(clarithromycin plus amoxycillin or metronidazole) was very effective in H.
pylori eradication, duodenal erosion healing, symptomatic improvement, and in
disappearance of associated histological gastritis. These observations suggest
that ED should be considered a variant form of duodenal ulcer disease and treated
accordingly; that is, with H. pylori eradication therapy.
PMID- 9391785
TI - No evidence of activated blood coagulation in Crohn's disease.
AB - BACKGROUND: Thromboembolism seems to be a significant and serious complication in
Crohn's disease (CD), and multifocal microvascular infarction of the intestinal
mucosa may be an important effector mechanism in the pathogenesis of CD.
Therefore, it has been hypothesized that an increased activation of the blood
coagulation system may favour thromboembolic complications. OBJECTIVES: To assess
the activity of blood coagulation as a potential index of thromboembolic risk in
CD using thrombin-antithrombin III complex (TAT). DESIGN: Prospective evaluation
of TAT. SETTING: Out-patients at the gastroenterological department of a
university hospital. PATIENTS: Eighty patients with CD, 47 with inactive (Crohn's
disease activity index (CDAI) < 150) and 33 with active disease, and 80 healthy
controls were investigated in this study. METHODS: TAT and fibrinogen were used
as parameters of blood coagulation. C-reactive protein and orosomucoid were used
as serum inflammatory parameters. RESULTS: Fibrinogen was significantly higher in
patients with active CD (median 535 mg/dl; interquartile range 402-620 mg/dl)
than in patients with inactive CD (357 mg/dl; 300-467 mg/dl) or controls (268
mg/dl; 231-299 mg/dl). Fibrinogen correlated with CDAI, C-reactive protein and
orosomucoid. TAT did not show any difference between patients with active CD (3.2
ng/ml; 2.5-4.6 ng/ml), inactive CD (3.0 ng/ml; 2.4-3.9 ng/ml) and controls (3.1
ng/ml; 2.3-3.6 ng/ml). Correspondingly, TAT correlated neither with serum
inflammatory parameters and CDAI nor with fibrinogen. CONCLUSION: We could not
find evidence of activation of the blood coagulation system as determined by TAT
plasma levels in CD, not even in patients with active disease. TAT is not,
therefore, a potential index of thromboembolic risk in CD and of microvascular
infarction as an effector mechanism in the pathogenesis of CD.
PMID- 9391786
TI - Transjugular intrahepatic portosystemic shunt: a limited role in refractory
ascites.
AB - OBJECTIVE: To evaluate the role of the transjugular intrahepatic portosystemic
shunt (TIPS) in the management of patients with refractory ascites. DESIGN: A
retrospective study of 25 consecutive patients for whom refractory ascites was
the primary indication for TIPS insertion. SETTING: Regional liver unit at
Freeman Hospital, Newcastle upon Tyne, UK. PARTICIPANTS AND INTERVENTIONS: Twelve
male and 13 female patients with a mean age of 58 years and mean Child-Pugh score
of 10, treated with TIPS for refractory ascites between July 1992 and September
1995. MAIN OUTCOME MEASURES: Effect of TIPS on mortality, ascites and hospital
admission rate. RESULTS: TIPS was successfully placed in all patients with a 59%
mean reduction in portosystemic pressure gradient. Response rate was 68%, 48% and
33% at 1, 3 and 12 months, respectively. Mortality was 48% at 3 months and 67% at
12 months, being higher in those patients older than 60, those with renal
impairment and those with higher Child-Pugh score. Amongst nine patients
surviving long term (> 12 months) the mean time spent in hospital in the 3 months
before TIPS was 35 days and in the year following TIPS 30 days. Patients who died
(16 in total) spent a mean of 19 days in hospital before TIPS, 10 never leaving
hospital, and 6 who were discharged spent a mean of 19 days post procedure in
hospital (mean survival 84 days). CONCLUSION: TIPS has a limited role in the
management of patients with refractory ascites. It is not an appropriate
treatment where patients are older than 60, have renal impairment (creatinine >
200 mumol/l) or have a Child-Pugh score greater than 10.
PMID- 9391787
TI - Relationship between cytochrome P-450 induction by rifampicin, hepatic volume and
portal blood flow in man.
AB - OBJECTIVE: Induction of hepatic cytochrome P-450-dependent oxidative metabolism
is related to an almost identical increase (30%) in both the liver weight and
portal blood flow in animals. In humans by contrast, an increased liver blood
flow (44%) but no significant increase in liver volume has been reported. DESIGN:
Therefore, we studied prospectively the relationship between P-450 induction by
rifampicin, hepatic volume and portal blood flow in 10 healthy volunteers.
METHODS: After a pre-treatment phase (day 1 to 7) the 10 volunteers received 600
mg/day of rifampicin from day 7 to 12. The urinary 6-beta-hydroxycortisol output
as a measure of oxidative metabolism (CYP3A4) and portal blood flow (pulsed
Doppler ultrasound) were determined on days 1, 7, 11 and 13. Hepatic magnetic
resonance volumetry was performed on days 1 and 13. RESULTS: Urinary 6-beta
hydroxycortisol output increased in all volunteers (P = 0.0051) from a median of
2.15 micrograms/day/kg (1.8-3.3 micrograms/day/kg) on day 1 to 9.9
micrograms/day/kg (5.7-14 micrograms/day/kg) on day 13. In 9 of 10 volunteers
induction by rifampicin was related to an increase (P = 0.0218) in liver volume
from a median of 1570 cm3 (1390-1830 cm3) to a median of 1690 cm3 (1420-1860
cm3). The portal flow as assessed by colour Doppler ultrasound did not change
significantly between day 1 (median 22 cm/s (15-35 cm/s)) and day 13 (median 19
cm/s (16-39 cm/s)). CONCLUSION: A fourfold increase of urinary 6-beta
hydroxycortisol output after induction of cytochrome P-450 by rifampicin is
associated with a significant but less than 10% increase in human liver volume.
No increase of portal perfusion as assessed by Doppler ultrasound could be
detected in this study.
PMID- 9391788
TI - Natural history of advanced hepatocellular carcinoma in Crete. Association with
hepatitis C virus.
AB - OBJECTIVE: To investigate the clinical characteristics of advanced hepatocellular
carcinoma (HCC) in Crete and to analyse the natural course of the untreated
disease. PARTICIPANTS: Seventy-three patients (62 men) were enrolled in a
prospective 4-year study. Clinical and virological parameters were recorded.
Diagnosis was based on either ultrasound guided liver biopsy or a pathognomonic
increase in alpha-fetoprotein plus compatible imaging. METHODS: Statistical
analysis was performed using histograms, contingency tables and one-way analyses
of variance to analyse the characteristics of the disease. For survival analysis
Kaplan-Meier survival curves and Cox's proportional hazards models were
constructed. RESULTS: HCC in Crete is a mostly male disease (7:1 male:female
ratio) and unlike in mainland Greece, it is mostly a hepatitis C virus (HCV)
related disease (54% HCV positive as opposed to only 13% in mainland Greece).
Prognosis was associated with Okuda classification (Okuda stage III patients have
a relative risk of dying that is seven to nine times higher than for Okuda stage
I), the presence or absence of hepatitis Be antigen (HBeAg) and antibody to
hepatitis B core antigen (anti-HBc). By contrast the presence of anti-HCV was not
associated with a worse prognosis. A unit increase of albumin concentration was
associated with an 11% decrease in the hazard rate. CONCLUSION: In general,
Crete, despite the extremely similar population to the rest of Greece, resembles
more closely the situation in Spain or Italy rather than mainland Greece.
PMID- 9391789
TI - Platelet function in cirrhosis and the role of humoral factors.
AB - BACKGROUND: Haemorrhagic complications are common in patients with cirrhosis of
the liver and contribute to the morbidity and mortality seen in this condition.
Several pathological processes are involved in these complications, including a
delay and overall reduction in platelet aggregation. OBJECTIVE: To determine
whether impaired aggregation in cirrhosis is the result of an intrinsic
abnormality in platelet function or is induced by a factor present in the blood
of cirrhotic patients. SETTING: Liver unit patients in a teaching hospital.
DESIGN: Blood was taken from 11 patients with cirrhosis (Child's B or C) and 11
healthy controls. Crossover experiments were carried out, suspending platelet
pellets from patients in platelet-poor plasma from controls, and vice versa.
Aggregation of both samples and also of platelet-rich plasma from patients and
controls was measured. RESULTS: Aggregation after 1 min was impaired
significantly in patient, compared with control, platelets following incubation
in either patient (P = 0.0012), or control (P = 0.0242), plasma. Correspondingly,
maximum aggregation of patient platelets was also reduced significantly (P =
0.0036) after incubation in patient plasma. Aggregation after 1 min, and maximum
aggregation, of control platelets was increased significantly (P = 0.034 and
0.013, respectively) following incubation in patient plasma. Furthermore, there
was a trend (non-significant) towards reduced aggregation of patient platelets
incubated in control plasma. CONCLUSION: These results confirm both an intrinsic
platelet defect causing impaired aggregation and a circulating factor in the
plasma of patients with cirrhosis which may compensate for this functional
defect.
PMID- 9391790
TI - Cancer of the pancreas: from concordant classification to standardized treatment.
International Symposium at Kloster Irsee, Germany, 2-5 October 1996.
AB - There has been a slow but steady improvement in the results of treatment for
exocrine pancreatic cancer in the last decade. One obstacle to further
improvement has been lack of standardization for reporting of results, from
classification to surgery and follow-up. This four-day symposium was organized in
order to bridge the clinical praxis of curatively intended radical pancreatic
surgery to scientific evaluation of its results. The meeting comprised four
workshops, three special lectures, and seven plenary sessions.
PMID- 9391791
TI - Hyperkalaemia and diarrhoea in a patient with surreptitious ingestion of
potassium sparing diuretics.
AB - We report a patient who presented with the unusual combination of chronic
diarrhoea and hyperkalaemia. The patient was admitted to our hospital after
repeated negative evaluations elsewhere including exploratory laparotomy. The
patient had a long history of diarrhoea with hypokalaemia which was documented on
several occasions in the past. Several months before admission to our hospital
for evaluation of diarrhoea the patient developed hyperkalaemia. Her daily stool
output reached 1200 g and her serum potassium was as high as 6.0 mmol/l.
Extensive evaluation revealed surreptitious ingestion of the diuretics
triamterene, hydrochlorothiazide and spironolactone as the cause of hyperkalaemia
and diarrhoea. In addition, she had melanosis coli which was interpreted to be
the consequence of surreptitious ingestion of anthraquinone-containing laxatives
in the past although no current laxative intake could be proven. We postulate
that diarrhoea in our patient was mainly due to the decreased sodium absorption
in the small intestine and colon caused by diuretics. Serum aldosterone levels
were more than eight times the upper limit of normal. Increased aldosterone
levels presumably arose secondary to volume contraction and sodium chloride
depletion, but presumably were not able to affect renal and colonic electrolyte
transport because of blockage of mineralocorticoid receptors by spironolactone.
Thus, the unusual combination of diarrhoea and hyperkalaemia resulted.
PMID- 9391792
TI - Diffuse abdominal pain, nausea and vomiting due to retroperitoneal fibrosis: a
rare but often missed diagnosis.
AB - Retroperitoneal fibrosis is a rare chronic inflammatory disease usually involving
the ureters, retroperitoneal vessels and nerves; however, any intestinal organ
may also be involved. In recent years, a few successful immunosuppressive
treatments of this disease have been described and surgery can, therefore,
probably be avoided in most cases. We report here on a case of secondary
retroperitoneal fibrosis with compression and midline deviation of the ureters
and impaired renal function which was probably caused by ergotamine abuse because
of migraine. The patient complained of diffuse abdominal pain, nausea and
vomiting. After immunosuppressive treatment with azathioprine and prednisone for
a year, we observed a complete resolution of the retroperitoneal mass on computed
tomography, although renal function remained impaired. Eleven months after the
cessation of treatment, the patient had not relapsed.
PMID- 9391793
TI - Palliation of a malignant gastrocolic fistula by endoscopic human fibrin sealant
injection.
AB - We report the case of a female patient with Hodgkin's disease resistant to
therapy who developed a gastrocolic fistula as a consequence of her disease,
leading to distressing faeculent vomiting. This was not considered to be amenable
to surgical resection and her symptoms were successfully palliated endoscopically
using injection of human fibrin sealant into the gastric and colonic aspect of
the fistula tract. Both mechanical sealing and promotion of healing by human
fibrin sealant are likely to be responsible for its efficacy.
PMID- 9391794
TI - Post-cholecystectomy transient hundred-fold increase in CA 19-9.
PMID- 9391795
TI - Helicobacter pylori infection and acid secretion.
PMID- 9391796
TI - Slide presentations: think about colour blindness.
PMID- 9391797
TI - Survey of spinal therapeutic procedures in the United Kingdom.
AB - The type and frequency of spinal therapeutic work being undertaken in the United
Kingdom (UK) by clinicians with an interest in the surgical treatment of
disorders of the spine (primary and secondary subspecialty interest) were
evaluated by means of a postal questionnaire. The willingness of respondents to
take part in postgraduate spinal training was determined along with issues
regarding accessibility of spinal services to non-specialist physicians in the
health service in the UK. The results of 450 respondents provided insight into
the types of procedures taking place, for example: primary spinal decompression
was regularly carried out by 76% of surgeons, while at least 20% of respondents
regularly carried out 66% of the procedures surveyed. We found that 10% of
surgeons indicated that they were prepared to participate actively in
postgraduate spinal surgical training.
PMID- 9391798
TI - Cavernous angiomas of the spinal district: surgical treatment of 11 patients.
AB - Cavernous angiomas, also called cavernous malformations or cavernomas, are
vascular hamartomas accounting for 3-16% of all angiomatous lesions of the spinal
district. Although histologically identical, these vascular anomalies may exhibit
different clinical behavior and radiological features, depending on their
location, hinting at different managements and therapeutic approaches. The
authors report 11 cases of symptomatic spinal cavernous angiomas diagnosed and
surgically treated over the past 18 years. Age of patients ranged from 15-75
years; males outnumbered females. Three patients had vertebral cavernous
malformations, secondarily invading the epidural space; two had pure epidural
lesions; two patients had intradural extramedullary lesions, and four
intramedullary lesions. Surgical removal was completely achieved in four patients
with intramedullary lesions, in two with subdural extramedullary lesions, and in
one with a pure epidural lesion. Subtotal excision of another one epidural and
three vertebral cavernous angiomas was followed by radiotherapy. There was no
morbidity related to surgery; the mean follow-up was 2 years. The outcome was
excellent in two cases, good in six, and unchanged in the other three. The
authors discuss the different modalities of treatment of these vascular lesions
variously placed along the spine.
PMID- 9391799
TI - Pregnancy and delivery in patients operated by the Harrington method for
idiopathic scoliosis.
AB - The course and outcome of 142 pregnancies in 146 patients operated between 1970
and 1975 by the Harrington method for idiopathic scoliosis were studied to
determine the effects of scoliosis on pregnancy and childbirth and the effects of
pregnancy on the remaining fused and unfused scoliotic curvatures. Occurrence of
and sick leave due to low back pain during pregnancy was determined. The
patients, all originally treated at the Orthopaedic Hospital of the Invalid
Foundation (Orton) in Helsinki, Finland, were invited to a clinical and
radiological re-examination on average 19 years following surgery. The results
show that pregnancy does not significantly increase fused scoliotic curvatures
nor the remaining unfused curvatures. A somewhat higher proportion of children
(23%) were delivered by cesarean section than in the general population (15%; P <
0.01), but this result should only be taken as suggestive. Rates of complications
of pregnancy and in labor did not differ from those in the background population.
The offspring were healthy. Low back pain during pregnancy occurred in about 40%
of our patients, but was severe enough to cause sick leave only in 11% of the
pregnancies.
PMID- 9391800
TI - Quantitative assessment of the motion of the lumbar spine in the low back pain
population and the effect of different spinal pathologies of this motion.
AB - There are few objective means by which disability caused by low back pain (LBP)
can be quantified. The purpose of this study was to investigate the usefulness of
motion measurements in the assessment of LBP. The motion characteristics of 138
LBP subjects were investigated, and the data compared with a previously published
database of normal subjects. Values of range of motion and angular velocity were
obtained for all subjects in each plane of motion. Analysis of these motion
characteristics demonstrated significant differences (P < 0.0001) between the two
populations; however both populations demonstrated considerable intersubject
variation. Multiple regression analysis revealed that some of the variance in the
LBP population was attributable to the underlying diagnosis. Patients with a
spondylolisthesis tended to be hypermobile whilst those with spinal stenosis,
disc prolapse or degenerative disc disease tended to be hypomobile. All
diagnostic groups showed impairments in their velocity characteristics.
PMID- 9391801
TI - Intraoperative control by somatosensory evoked potentials in the treatment of
cervical myeloradiculopathy. Results in 210 cases.
AB - Somatosensory evoked potentials (SEPs) were used for continuous monitoring of 210
patients during anterior surgery for cervical myeloradiculopathy, to test how
effectively they help avoid irreversible neurological damage during surgery. The
pathologies differed in severity and were treated by diskectomy or by extended
corporectomy using the Senegas technique. Intraoperative SEP changes were
recorded in 84 patients (40%); in 13 (6.2%) of these, changes in SEP amplitude
and latency were caused by mechanical stress. SEPs revealed transient episodes of
regional ischaemia or neurophysiological anomalies during anaesthesia (mainly
hypotension) in 27 patients (12.8%). The traces detected incipient and
potentially dangerous mechanical pressure on, or metabolic anomalies of, the
spinal cord during manipulation and placement procedures of spinal fixation
devices. They were particularly sensitive indicators of ischaemia; one of the
most common causes of irreversible injury. The traces of 44 patients (21.0%)
improved markedly during surgery. There were no false-negatives in this series
and, thanks to the fact that SEPs gave immediate warnings of incipient ischaemia
to the surgical team, we had no case of irreversible medullary or nerve-root
deficit.
PMID- 9391802
TI - Early complications of spinal pedicle screw.
AB - The complications of 648 consecutively inserted Universal AO pedicle screws (140
in the thoracic spine and 508 in the lumbar spine) performed by one surgical team
to treat 91 patients with spinal problems, were reviewed. The spinal pathology
consisted of: scoliosis (34 patients), degenerative lower lumbar spinal disease
(25 patients), neoplastic spinal disease (11 patients), thoracic kyphosis (8
patients), spinal fractures (7 patients), lumbo-sacral spondylolisthesis (3
patients), and osteomyelitis (3 patients). Intraoperative complications were:
screw misplacement (n = 3), nerve root impingement (n = 1), cerebrospinal fluid
leak (n = 2) and pedicle fracture (n = 2). Postoperative complications were; deep
wound infection (n = 4), screw loosening (n = 2) and rod-screw disconnection (n =
1). The conclusion was that pedicle screw fixation has an acceptable complication
rate and neurological injury during this procedure is unlikely.
PMID- 9391803
TI - Aseptic spondylitis as the initial manifestation of the SAPHO syndrome.
AB - We describe the case of a 61-year-old female patient who presented with
spondylitis of the lumbar spine. Although the microbiological cultures of the
bone biopsy specimens obtained during laminotomy remained negative, the patient
was treated with broad-spectrum antimicrobials for 2 months. Eight months later
she started to suffer from pain and tenderness in her sternum and the medial
portion of her left clavicle. The findings of computed tomography and gallium
labelled isotope scan were indicative of sternoclavicular arthritis. Again, all
surgically obtained biopsy specimens yielded negative results in microbiological
studies. The diagnosis of the SAPHO (synovitis, acne, pustulosis, hyperostosis,
and osteomyelitis) syndrome was then made based on the clinical presentation with
recurrent sterile osteitis in two characteristic locations, and the patient was
started on immunosuppressive therapy. This case is a reminder that SAPHO may
sometimes occur without any skin manifestations. Since this type of patient may
be admitted to an orthopedic ward, it is important that orthopedic surgeons are
familiar with the syndrome.
PMID- 9391804
TI - Tuberculosis of the sacroiliac joint.
AB - A 23-year-old woman presented with low back pain of several months' duration. A
tuberculous infection of the left sacroiliac joint was diagnosed by closed-needle
biopsy. The clinical presentation, radiological features and outcome of this
patient are discussed.
PMID- 9391805
TI - Surgical decompression: a life-saving procedure for an extensive spinal epidural
abscess.
AB - Extensive spinal epidural abscesses (SEAs) carry a high mortality rate.
Traditionally they are treated non-operatively with long-term antibiotics and/or
surgical decompression, but there is a continuing debate as to whether they
should be managed by emergency surgical decompression. However, such decisions
are made in the light of the clinical setting. We report the successful
management of a female patient who presented with features of upper cervical cord
compression and later developed septic shock and multisystem failure. Surgical
decompression of the cervical spine and irrigation of the epidural space with a
paediatric catheter was performed followed by tricortical strut grafting and
plating. At review, 36 weeks after surgery, the patient remained asymptomatic,
having made full neurological recovery. The purpose of this report is to
highlight the importance of emergency surgical intervention for extensive SEA in
the presence of progressive neurological loss associated with multisystem
failure.
PMID- 9391807
TI - Anteriorly displaced transverse fractures of the sacrum in adolescents: report of
two cases.
AB - A fracture of the sacrum at the level of the first and second segments, with
forward displacement of the first segment, is a very rare injury in adolescents.
The cases of two patients, who both suffered a displaced transverse fracture of
the sacrum with resulting neural disturbance, are reported here. We consider that
these unstable fractures may be treated surgically, by extensive laminectomies of
the lumbosacral area and posterolateral fusion. Stabilization of the displaced
fracture is possibly preferable, because it provides the prerequisites for early
mobilization and reduces pain.
PMID- 9391808
TI - Fracture of the vertebral limbus.
AB - An 18-year-old young man suffering from fracture of the limbus of L4 was admitted
to the emergency ward after a car collision. Radiological evidence of the lesion
was visible on plain film radiographs and CT scans. On surgery the posterior
column was found to be intact. Treatment included a wide laminectomy, excision of
the fragment, and osteosynthesis with Cotrel-Dubous-set instrumentation. The
characteristics of these lesions are reviewed on the basis of the latest reports.
The possibility of misreading these fractures is emphasized, especially in
traumatic adult spine surgery.
PMID- 9391806
TI - Iliopsoas bursitis and pseudogout of the knee mimicking L2-L3 radiculopathy: case
report and review of the literature.
AB - We report the case of a 74-year-old woman who presented with acute-onset right
groin pain irradiating to the thigh anteriorly after having suffered for a few
weeks from slight knee pain. As a CT scan showed multiple herniated
intervertebral discs and spinal stenosis at the L3-L4 level, she was referred to
a neurosurgical unit with the tentative diagnosis of L2-L3 radicular pain.
Investigations (MR, myelography with CT scan) showed severe acquired lumbar canal
stenosis. Decompression surgery was finally postponed because of the patient's
serious cardiac medical history and she was referred to us for conservative
treatment. She was found to have iliopsoas bursitis with chondrocalcinosis of the
knee. Local steroid injections of the two sites abolished her symptoms. We draw
attention to the possible pitfalls that the radiographic appearance and one of
the multiple clinical presentations of this unrare pathology may represent.
Whenever a patient comes walking with crutches, avoids putting weight on his or
her leg, and radicular pain is suspected, we advise consideration of other extra
spinal causes for the pain.
PMID- 9391809
TI - Chondromyxoid fibroma of the ala of the sacrum presenting as a cause of lumbar
pain in an adolescent.
AB - We report a case of chondromyxoid fibroma of the ala of the sacrum: its
presentation, diagnosis, treatment, and resolution. Although this tumor is
admittedly rare, our case demonstrates the need for careful evaluation of pack
pain in an adolescent.
PMID- 9391810
TI - Congenital absence of the pedicles and the neural arch of L2.
AB - Congenital pedicle abnormalities are rare. Unilateral aplastic and hypoplastic
lumbar pedicles have been reported, but these were usually discovered
incidentally and did not need surgical treatment. We present a case of absence of
both pedicles and the neural arch of L2, with associated kyphoscoliosis with
neurological involvement, that needed a two-stage corrective surgery. An L1-L4
fusion was achieved with relief of the symptoms.
PMID- 9391812
TI - Fractures of the calcaneus: open reduction and internal fixation from the medial
side a 21-year prospective study.
AB - Since 1974, 61 displaced fractures of the calcaneus have been treated by open
reduction and internal fixation by a modified medial approach technique. Surgery
was performed through a 5-cm incision posterior to the neurovascular bundle. A
single threaded pin was passed longitudinally through the tuberosity and into the
sustentacular fragment, giving stable fixation. Reduction of the depressed
posterior facet fragments was accomplished from the medial side in 77% of cases,
occasionally assisted by fluoroscopy. Postoperatively all fractures were
immobilized in a cast for 4 weeks. At the end of 4 weeks the pin was removed, and
full weight bearing in a walking cast was started and continued for 4 weeks. At 8
weeks after surgery, the walking cast was removed, and the patient began walking
in a shoe. These cases were evaluated at a mean follow-up of 4.4 years. There
were 49 successful cases (80.3%) and 12 unsuccessful cases (19.7%). A high number
of superior results was found in the successful group as shown by the mean score
of 94.7 (American Orthopaedic Foot & Ankle Society Scoring System). Time to
return to work was a mean of 4.9 months.
PMID- 9391813
TI - Radiographic and CT evaluation of tibiofibular syndesmotic diastasis: a cadaver
study.
AB - Twelve cadaver lower limbs were used for radiographic and CT assessment of the
tibiofibular syndesmosis. Plastic spacers were placed in the distal tibiofibular
intervals of each specimen in successive 1-mm increments until diastasis could be
appreciated on the plain radiographs. All 2- and 3-mm diastases could be noted
and clearly identified on CT scans, while the 1-, 2-mm, and half of the 3-mm
syndesmotic diastases could not be appreciated with routine radiographs. CT
scanning is more sensitive than radiography for detecting the minor degrees of
syndesmotic injuries. Therefore, a CT scan can be performed in cases of
syndesmotic instability after ankle injuries and for preoperative or
postoperative evaluation of the integrity of the distal tibiofibular syndesmosis
in cases of doubtful condition of the syndesmosis.
PMID- 9391814
TI - Charcot ankle fusion with a retrograde locked intramedullary nail.
AB - Twenty patients with severe neuropathic (Charcot) ankle deformities underwent 21
attempted ankle fusions with a retrograde locked intramedullary nail as an
alternative to amputation. All had insensate heel pads and had failed at
nonoperative methods of accommodative ambulatory bracing. In 11, the talus was
either absent, or the deformity was of sufficient magnitude to require talectomy
to align the calcaneus under the tibia for plantigrade weightbearing. Ages ranged
from 28 to -68 (average 56.3) years. Nineteen were diabetic, 12 being insulin
dependent. Their average body weight was 102 kg, with 11 greater than 90 kg at
the time of surgery. Eight had chronic large full thickness ulcers overlying, but
not involving bone of the medial malleolus, medial midfoot, or proximal fifth
metatarsal, at the time of surgery. At a follow-up of 12 to 31 months, 19
achieved bony fusion. In the 10 patients where talectomy was not required, fusion
was achieved at an average of 5.3 months without complications. In the patients
who required talectomy, six of the patients required eight additional operations
to achieve fusion. Three achieved fusion following removal of the nail and
prolonged bracing. One opted for ankle disarticulation for chronic persistent
infection, rather than attempt reoperation. One died of unrelated causes during
the early postoperative period. Retrograde locked intramedullary ankle fusion is
a reasonable alternative to amputation in the neuropathic (Charcot) ankle that
cannot be controlled with standard bracing techniques. The potential for
morbidity requiring reoperation is greatly increased when the deformity is of
sufficient magnitude to require talectomy to achieve alignment of the calcaneus
in a plantigrade weight-bearing position under the tibia or when there are large
open ulcers.
PMID- 9391811
TI - Lumbar epidural perineural injection: a new technique.
AB - Two controlled studies for a new epidural, perineural, single-shot, selective
nerve root injection with a double-needle approach to the anterior epidural space
of the lumbar spinal canal are presented. The results were analysed to determine
the effectiveness of the new epidural perineural injection technique. The trial
comprised two controlled studies on 182 patients. One study compared
prospectively randomized results of patients with lumbar radicular syndromes who
received epidural perineural injections (n = 47), conventional posterior epidural
injections (n = 40) and, as a control group, paravertebral local anaesthetic (n =
46). A second, prospective, double-blind study compared the effect of epidural
perineural injections with triamcinolone (n = 24) and pure saline (n = 25).
Epidural perineural injections were more effective than conventional posterior
epidural injections. Both epidural groups had better results than the
paravertebral local injection group. Epidural perineural injections with steroids
(10 mg triamcinolone) were more effective than saline alone. A systemic steroid
effect was excluded by additional intramuscular steroid injections in the saline
group. There were no severe complications or side effects in any of the three
groups. The studies concluded that single-shot epidural perineural injection is
effective in the treatment of lumbar radicular pain. It is a "one drop only"
therapy to the source of pain.
PMID- 9391815
TI - Alterations in talar morphology associated with adult flatfoot.
AB - To gain a better understanding on the anatomy of the factors contributing to
symptomatic flatfoot, we compared the shape of the talus in feet that were flat
to that in control tali from feet with a normal arch. Computed tomographic (CT)
scans were performed on 9 adult patients with 10 symptomatic flatfoot
deformities. CT scans of 10 feet being evaluated for acute trauma not involving
the talus were randomly selected as controls. Flatfoot tali tended to be of
greater overall length than the control tali, and this difference was not
statistically significant. Statistically significant differences were found when
comparing ratios of talar length with talar width (P = 0.011), talar length with
talar height (P = 0.001) (they were long relative to their height and width), and
head length with head width (P = 0.001) for individual tali from the two groups.
The tali from the flatfoot group were narrower in width and shorter in height
when compared with overall length and had heads that were more elongated in the
transverse plane than tali in feet with a normal appearance. CLINICAL
CORRELATION: When performing surgical correction of a flatfoot in an adult,
appearance of the foot rather than standard radiographic parameters should be
used to judge the reduction. The altered shape of the bone may alter the standard
radiographic parameters.
PMID- 9391816
TI - Subtalar arthrodesis versus flexor digitorum longus tendon transfer for severe
flatfoot deformity: an in vitro biomechanical analysis.
AB - We defined the mechanical behavior of the foot after an operation for treatment
of the flatfoot deformity, subtalar arthrodesis, and compared results with those
from flexor digitorum longus tendon transfer. Twelve fresh-frozen human foot
specimens were used. Supporting elements were sectioned to create a flatfoot
deformity. To simulate midstance phase of gait, loads were applied axially to the
plantar foot and to five tendons. Reduction of deformity in metatarsal-talar,
calcaneal-talar, and talar-tibial positions was achieved and was significantly
greater after subtalar arthrodesis operation than after flexor digitorum longus
transfer.
PMID- 9391817
TI - Clinical characteristics and outcome in 223 diabetic patients with deep foot
infections.
AB - Clinical characteristics and outcome in 223 consecutive diabetic patients with
deep foot infections are reported. Patients were treated by a multidisciplinary
diabetic foot-care team at the University Hospital, Lund, Sweden, and were
prospectively followed until healing or death. About 50% of patients lacked
clinical signs of infection, such as a body temperature > 37.8 degrees C, a
sedimentation rate > 70 mm/hour, and white blood cell count (WBC) > 10 x
10(9)/liter. Eighty-six percent had surgery before healing or death. Thirty-nine
percent healed without amputation; 34% healed after a minor and 8% after a major
amputation. Sixteen percent were unhealed at death, and 3% were unhealed at the
end of the observation period. Of those unhealed at death or follow-up, 4
patients had had a major and 11 a minor amputation. After correction for age and
sex, duration of diabetes < 14 years, palpable popliteal pulse, a toe pressure >
45 mmHg, and an ankle pressure > 80 mm Hg, absence of exposed bone and a white
blood cell count < 12 x 10(9)/liter were all related to healing without
amputation in a logistic regression analysis. We conclude that although only 1 in
10 had a major amputation, nearly all diabetic patients with a deep foot
infection needed surgery and more than one third had a minor amputation before
healing or death in spite of a well-functioning diabetic foot-care team
responsible for all included patients.
PMID- 9391818
TI - Reconstruction of the lateral ankle ligaments using an inferior extensor
retinaculum flap.
AB - The aim of this study was to assess the results of 32 cases of chronic ankle
instability. These were treated by ligament shortening and reinforced with an
inferior extensor retinaculum flap. All patients complained of persistent
functional instability unrelieved with proprioceptive exercises. Results were
assessed clinically (pain, instability, recovery of sports activity, mobility)
and radiologically (correction of laxity on stress x-rays). This enabled us to
draw up a revision score on a scale of 100 points. We obtained a mean score of
86.7 points (45-100 points), and subjective results showed that 88% of the
patients were satisfied with the surgery.
PMID- 9391819
TI - A kinematic study of ankle joint instability due to rupture of the lateral
ligaments.
AB - Kinematic analysis of patients who have ruptured the ligaments of the ankle joint
was performed to evaluate the function of those ligaments. Ten patients with
ruptured lateral collateral ligaments and 10 normal volunteers were examined.
Patients' ages ranged from 17 to 29, averaging 20.9 years old. We performed
kinematic evaluation by a three-dimensional optical analytic technique using
surface markers. According to our results, the ankles with lateral ligament
injury abnormally pronated and rotated externally at the time of heel strike and
abnormally supinated and rotated internally during the acceleration phase.
PMID- 9391820
TI - Isolated dislocation of the middle cuneiform in a farmer: a case report and
review of the literature.
AB - Isolated dislocations of the middle cuneiform are uncommon. There have been four
reported previously. Significant force is required to produce these injuries, and
they can have serious neurovascular consequences. In this case report and review
of the literature, we present an isolated middle cuneiform dislocation in a 69
year-old farmer with impending skin and soft tissue loss over the dislocated
bone.
PMID- 9391821
TI - Metatarsal lengthening: case report and review of literature.
AB - Shortening of one or more metatarsals may be a cause of metatarsalgia and painful
toe deformity. Usually, symptoms are limited and may be successfully addressed
with nonoperative treatment. Rarely, operation indicated. This report reviews the
surgical techniques, results, and complications. These operations include
osteotomy and one-stage distraction with bone grafting, osteotomy and one-stage
distraction without bone grafting, osteotomy with gradual distraction and bone
grafting, and osteotomy with gradual distraction without bone grafting.
PMID- 9391822
TI - Adamantinoma arising in the distal fibula treated with distal fibulectomy: a case
report and review of the literature.
AB - Adamantinoma is a rare primary bone tumor occurring in the mandible and the long
tubular bones. The diaphysis of the tibia is the most common site of extragnathic
presentation. Fibular involvement is rare and usually has coexisting tibial
involvement. Adamantinoma arising in the distal fibular metaphysis has not been
previously reported. This is a case of a teenage boy presenting with a cystic
lesion of the distal fibula, initially diagnosed and treated as a unicameral bone
cyst. Aggressive behavior ultimately led to a diagnosis of adamantinoma. He was
treated with distal fibulectomy without surgical reconstruction with good
functional outcome.
PMID- 9391823
TI - Linkage disequilibrium measures for fine-scale mapping: a comparison.
AB - We investigate properties of simple linkage disequilibrium mapping for five
measures in the presence of mutation at the marker and/or the disease locus and
of initial incomplete linkage disequilibrium. In contrast to the stimulation
approach that Devlin and Risch used, we calculate the expected values of various
linkage disequilibrium measures under different assumptions based on a framework
for linkage disequilibrium mapping. These expected values clearly demonstrate the
expected performance of these measures. We find that the impact of marker
mutation on their performance depends on the magnitude of the mutation relative
to the proximity of the marker (i.e. recombination fraction between the marker
and the disease locus). In the presence of recurrent mutation at the marker
and/or disease locus, the performance of all measures, including the robust one,
depends on the marker allele frequency. The initial incomplete linkage
disequilibrium could render all measures useless. These expected values also show
clearly why in Devlin and Risch's simulation some measures performed very badly
under certain circumstances.
PMID- 9391824
TI - Estimating the age of mutant disease alleles based on linkage disequilibrium.
AB - With more and more disease genes being mapped and/or cloned, there is a growing
interest in dating the age of underlying mutations. The knowledge of the age of
mutation is important to finely map disease genes by linkage disequilibrium
mapping. It would also help us understand the origin, evolution, and dispersion
of the mutant disease genes. Despite increasing interests in dating disease
mutations, the development of appropriate statistical methods is largely
fragmentary, and there is a lack of systematic treatment of the topic. We propose
two classes of methods for estimating the age of mutant allele at the disease
locus based on linked marker data. Our methods can not handle only single-locus
marker data, but also multi-locus marker data as well. Moreover, our methods can
be used even when the location of the disease locus is unknown, and/or when there
are mutations at the marker or disease locus. We show that some previous results
are special cases of our methods. We also derive a recursive equation previously
obtained by Serre et al. [Hum Genet 1990;84:449-454] and provide an explicit
solution to the equation. To illustrate our methods, we applied them to two
groups of data sets, one is cystic fibrosis data collected from several European
populations, and the other is data on several genetic diseases (diastrophic
dysplasia, progressive myoclonus epilepsy, congenital chloride diarrhea, and
Batten disease) all collected from the Finnish population. The former data set
allows us to trace the origin and dispersion of the most common mutation for
cystic fibrosis. The latter provides an opportunity to examine whether all
mutations for these diseases have the same age.
PMID- 9391825
TI - AvaI polymorphism in the human transferrin gene.
AB - A guanine-adenine substitution was observed in exon 5 of the human transferrin
(TF) gene. The nucleotide change led to an AvaI digestion site. Analysis of the
segregation of the AvaI polymorphism and serum TF phenotypes indicated that an
intragenic recombination occurred between the AvaI polymorphic site and the
mutation site in the TF gene which determines the two common TF alleles, TF*C1
and TF*C2.
PMID- 9391826
TI - A transmission disequilibrium test for quantitative trait loci.
AB - The transmission disequilibrium test uses association between marker alleles and
dichotomous traits for precise genetic mapping while avoiding confounding due to
population admixture. Here, the methodology is generalized from dichotomous
traits to quantitative traits. The generalization is computationally
straightforward and may be used with multiple alleles and with siblings.
Parametric assumptions on the distribution of the quantitative traits are not
needed. Environmental and demographic covariates may be incorporated into the
analysis. The results of simulation studies that provide information about the
power of the approach are reported.
PMID- 9391827
TI - Feasibility of collecting disease reports from relatives for genetic
epidemiologic investigations.
AB - Self-reports of disease from relatives are generally believed to be more detailed
than those received from a family informant, although differential participation
may exist among the relatives who provide information. To investigate the
potential for differential participation, we requested permission to contact
relatives of mothers (informants) who had provided family history information for
a population-based case-control study of orofacial clefts. Birth defect and
cancer self-reports were received from 345 (65.6%) case and 380 (68.8%) control
relatives. Participants and nonparticipants differed little by type (maternal or
paternal) or degree of relationship. Informants, however, were more likely to
permit contact with relatives who were maternal, first-degree and female.
Relatives appeared willing to provide self-reports, although the potential for
differential selection introduced by informants should be considered.
PMID- 9391828
TI - Structural and functional adaptations of skeletal muscle to weightlessness.
AB - This brief review examines the effects of weightlessness on the structure and
function of human and rat skeletal muscle. Data collected from spaceflights or
Earth-based models suggest that a rapid atrophy (5-8 days) occurs in lower limb
muscles associated with impairments in muscle strength, physical work capacity
and locomotor coordination. The reduction in muscle cross-sectional area cannot
entirely explain the loss of strength in postural muscles suggesting a reduced
neural drive. Muscle atrophy is accompanied by a general shift in the contractile
and enzymatic profiles of a slow-twitch oxidative muscle toward that of a fast
twitch glycolytic muscle. In humans, limited structural and functional data
collected in astronauts after short periods of microgravity are qualitatively
similar to those observed in rats after real or simulated microgravity suggesting
that animal models are relevant to muscle research in space. A preventive
prescription i.e. exercise or pharmacological treatment, cannot be proposed until
future research has better defined the basic mechanisms of muscle plasticity
during long duration spaceflights.
PMID- 9391829
TI - Molecular events underlying skeletal muscle atrophy and the development of
effective countermeasures.
AB - Skeletal muscle adapts to loading; atrophying when exposed to unloading on Earth
or in spaceflight. Significant atrophy (decreases in muscle fiber cross-section
of 11-24%) in humans has been noted after only 5 days in space. Since muscle
strength is determined both by muscle cross-section and synchronization of motor
unit recruitment, a loss in muscle size weakens astronauts, which would increase
risks to their safety if an emergency required maximal muscle force. Numerous
countermeasures have been tested to prevent atrophy. Resistant exercise together
with growth hormone and IGF-I are effective countermeasures to unloading as most
atrophy is prevented in animal models. The loss of muscle protein is due to an
early decrease in protein synthesis rate and a later increase in protein
degradation. The initial decrease in protein synthesis is a result of decreased
protein translation, caused by a prolongation in the elongation rate. A decrease
in HSP70 by a sight increase in ATP may be the factors prolonging elongation
rate. Increases in the activities of proteolytic enzymes and in ubiquitin
contribute to the increased protein degradation rate in unloaded muscle. Numerous
mRNA concentrations have been shown to be altered in unloaded muscles. Decreases
in mRNAs for contractile proteins usually occur after the initial fall in protein
synthesis rates. Much additional research is needed to determine the mechanism by
which muscle senses the absence of gravity with an adaptive atrophy. The
development of effective countermeasures to unloading atrophy will require more
research.
PMID- 9391830
TI - The contribution of NMR, NIRS and their combination to the functional assessment
of human muscle.
AB - In the last decade the study of the human muscle mechanics and energetics in
physiology and pathology underwent a radical change. Indeed, the use of biopsy is
being progressively accompanied by non-invasive techniques which allow a more
integrative assessment of muscle function in vivo. Magnetic resonance imaging
(MRI) provides a better insight into muscle structure down to the fascicular
level, proving to be an essential source of information, particularly for the
study of biomechanics. Magnetic resonance spectroscopy (MRS), besides the study
of muscle anaerobic (high energy phosphate compounds by 31P and 1H) and aerobic
metabolism as well as of metabolic control, makes it possible to follow the time
course of glycogen concentration (13C) as a function of exercise intensity and
duration and of its recovery both in healthy trained and untrained subjects and
in diabetic patients. Near-infrared spectroscopy (NIRS) allows to assess muscle
oxidative metabolism, providing changes of total, deoxy- and oxy-hemoglobin in
the resting and contracting muscle. The concomitant use of the above techniques
is expected to provide a synergic functional picture of the human muscle that is
complementary to the structural and ultrastructural microscopic approach.
PMID- 9391831
TI - Recommendations for muscle research in space.
PMID- 9391832
TI - Muscle atrophy during long duration bed rest.
PMID- 9391833
TI - Changes in mechanical properties of human muscle as a result of spaceflight.
PMID- 9391834
TI - The effect of prolonged bed rest on maximal instantaneous muscle power and its
determinants.
PMID- 9391835
TI - Changes in electrically evoked skeletal muscle contractions during 17-day
spaceflight and bed rest.
PMID- 9391836
TI - Muscle fiber atrophy and degeneration induced by experimental immobility and
hindlimb suspension.
PMID- 9391837
TI - Role of gravitational loading on the development of soleus muscle in rats.
PMID- 9391838
TI - Interactive effects of loading and thyroid states on skeletal isomyosins.
PMID- 9391839
TI - Postnatal muscle development in unloading conditions.
PMID- 9391840
TI - Molecular biology of human muscle adaptation.
PMID- 9391841
TI - Functional and biochemical adaptations to low-frequency stimulation: possible
applications to microgravity.
PMID- 9391842
TI - Integrated human muscle bioenergetic studies by magnetic resonance methods.
PMID- 9391843
TI - Muscle energetics by 31P-NMRS: recent developments and possible applications in
space research.
PMID- 9391844
TI - Changes in calf muscle performance, energy metabolism, and muscle volume caused
by long-term stay on space station MIR.
PMID- 9391845
TI - MR-spectroscopy (MRS) of different nuclei applied to human muscle: additional
information obtained by 1H-MRS.
PMID- 9391846
TI - Metabolic studies of human skeletal muscle by near infrared spectroscopy:
possible applications in space research.
PMID- 9391847
TI - Eccentric exercise and muscle damage.
PMID- 9391848
TI - Muscle research in space--increased muscle susceptibility to exercise-induced
damage after a prolonged bedrest.
PMID- 9391849
TI - Mechanism of fatigue in small muscle groups.
PMID- 9391850
TI - Resistance training in space.
PMID- 9391851
TI - Cycling in space to simulate gravity.
PMID- 9391852
TI - Stretch-shortening-cycle in microgravity, spinal proprioceptive and tendomuscular
elastic energy release.
PMID- 9391853
TI - Activation of muscles and microgravity.
PMID- 9391854
TI - Continuous monitoring of spine geometry: a new approach to study back pain in
space.
PMID- 9391855
TI - Treatment of endstage heart disease with mechanical circulatory assistance.
AB - A great number of patients suffer and die from the sequelae of acute and chronic
heart failure each year. Although advances in medical and surgical therapy have
benefited many of these patients, the majority suffer from disease refractory to
any definitive therapy. For these patients, cardiac transplantation is the only
remaining hope. Unfortunately, because of the increasing demand for donor organs
in the face of a fixed and limited supply, this option is only available to a
small percentage of these patients. Even in patients accepted for
transplantation, a significant waiting list mortality has been observed. A
variety of ventricular assist devices (VAD) have been developed since the first
successful case of mechanical cardiac assistance over 30 years ago. These devices
differ in basic mechanical function, method of insertion, and degree of
implantability, and thus have different indications and potential applications.
While the intra-aortic balloon pump and centrifugal pumps are effective short
term support modalities, extracorporeal and implantable pulsatile devices have
been used successfully for long-term support of patients with reversible and non
reversible cardiac failure. These pumps have most commonly been utilized as
bridges to transplantation, but increasing clinical experience has supported the
notion of long-term mechanical assistance as a definitive therapy for endstage
heart disease. While complications, particularly infection and thromboembolism,
pose significant challenges and long-term device reliability remains to be fully
determined, available implantable devices seem capable of providing effective
long-term support. As data is obtained from currently ongoing trials comparing
VAD support to medical therapy for endstage heart failure, ethical and economic
issues will assume increasing importance.
PMID- 9391856
TI - Arterial wall neovascularization--potential role in atherosclerosis and
restenosis.
AB - Neointimal formation and arterial wall remodeling are pivotal causes of luminal
narrowing in atherogenesis and restenosis. Arterial remodeling refers to a series
of dynamic structural changes that arteries may undergo in response to various
stimuli, including changes in blood flow and pressure, and acute injury. The
biological mechanisms involved in arterial remodeling are poorly understood and
are currently a main target for research. We have recently focused on the role of
the arterial wall microcirculation (ie, vasa vasorum) in arterial remodeling
after injury. In the past, a correlation between arterial wall neovascularization
and the accumulation of arterial plaque has been documented; however, the dynamic
role of these microvessels in arterial repair and luminal narrowing has not been
examined. The type of arterial injury, the nature of the lesion that develops,
and the arterial compartment in which angiogenesis occurs may determine the role
of the vasa vasorum in arterial narrowing. In this review, we highlight the data
that link arterial wall neovascularization with lesion formation and the process
of arterial remodeling.
PMID- 9391857
TI - An enhanced method for measuring cardiac output using Doppler color flow
echocardiography.
AB - An enhanced method for determining cardiac output using Doppler color flow
imaging techniques to measure mitral orifice diameter was developed and validated
in an experimental model and in clinical patients. In an in vitro circuit model,
color jet width correlated well with actual orifice dimension from 12 to 24 mm (r
= 0.99). In the clinical application, mitral valve area was calculated as a X b X
pi/4 where a and b represent the width of the color flow stream in the mitral
orifice just distal to the annulus in apical long-axis (short-diameter) and 4
chamber (90 degrees rotated, long-diameter) views, respectively. Cardiac output
was then computed as the product of mitral valve area and time-velocity integral
of transmitral flow from the same site. Cardiac output was also measured by
thermodilution and conventional echocardiographic methods using diameters and
time-velocity integrals from the left ventricular outflow tract. In 30 patients
with nonvalvular heart disease, cardiac output measured by thermodilution ranged
from 3.40 to 8.40 L/min. Cardiac output was determined in 28 of 30 patients (93%)
by the Doppler color flow imaging technique; it ranged from 3.00 to 8.36 L/min
and correlated well with thermodilution: y = 0.90x + 0.63, r = 0.91. Cardiac
output was determined in 24 of 30 patients by the conventional left ventricular
outflow method (80%). The cardiac output measured by the conventional method
correlated less closely with thermodilution (r = 0.84), although there was no
statistical difference in correlation coefficiencies between the 2 methods. These
results indicate that the Doppler color flow imaging technique can be used to
enhance the determination of cardiac output by echocardiography, particularly
when the conventional method has resulted in technically inadequate recordings.
PMID- 9391858
TI - Mitral insufficiency as a complication of acute myocardial infarction and left
ventricular remodeling.
AB - The presence of mitral insufficiency after acute myocardial infarction (AMI)
often leads to hemodynamic impairment and heart failure. This study was designed
to examine the relationship between mitral regurgitation (MR), an indicator of
mitral insufficiency, and the course of recovery from AMI. We evaluated the
course of MR after AMI in 223 patients by color Doppler echocardiography. MR was
detected in 21% (47/223) of patients at the onset of AMI, and developed in 18%
(40/223) of patients during follow-up. Patients were grouped according to the
course of MR as well as the success of acute recanalization therapy. No
correlation was observed between the presence or course of MR and the site of
infarction. The incidence of successful recanalization was higher in patients
with MR that improved during follow-up than in patients with MR that was
unchanged or that worsened during follow-up. Although no significant differences
in hemodynamic variables were noted among the groups at admission, the group with
unsuccessful recanalization and unimproved MR (BS-) showed a significantly
greater left ventricular end-diastolic diameter (LVDd), left ventricular end
systolic diameter, and left ventricular end-diastolic volume (LVEDV) as well as a
lower left ventricular ejection fraction than patients with successful
recanalization and no MR (CS+) during the convalescent period. The extent of
change in LVDd and LVEDV between admission and convalescence was significantly
greater in the BS(-) group than in the CS(+) group. The results suggest that
successful recanalization after AMI reduces the incidence of MR. Acute
recanalization therapy after AMI may prevent left ventricular remodeling,
resulting in a secondary improvement of MR.
PMID- 9391859
TI - Induction of ST-segment elevation by regional myocardial stretch in normal canine
hearts in vivo.
AB - The purpose of this study was to evaluate ST-segment elevation induced by
regional myocardial stretch without myocardial ischemia in canine hearts. A
strain gauge arch (TH-601T) was sutured to the left ventricular epicardium,
parallel to the short axis, to shorten the end-diastolic length of the myocardium
beneath the arch (stretch zone; SZ) and to produce regional myocardial stretch in
each of 6 dogs. An increase in preload caused by altering the height of a saline
filled reservoir affected prolongation or shortening of the myocardium both in
the SZ and outside the arch (normal zone; NZ) to increase myocardial stretch. An
epicardial electrocardiogram was recorded in both the SZ and the NZ. After suture
of the strain gauge arch, the ST segment was elevated in the SZ. An increase in
preload augmented stretch during systole in the SZ, resulting in additional ST
segment elevation. These results suggest that regional myocardial stretch itself
plays an important role in ST-segment elevation.
PMID- 9391860
TI - Effects of alpha 1-adrenoreceptor subtype blockade on ischemia-reperfusion
injury.
AB - To clarify the roles of subclasses of alpha 1-adrenoreceptors in ischemic
reperfused myocardium, we compared the effect of the nonselective alpha 1-blocker
bunazosin with that of the alpha 1A-blocker WB4101 and the alpha 1B-blocker
chlorethylclonidine (CEC) in isolated rat hearts. After 30 min of preperfusion,
Langendorff-perfused hearts were subjected to 25 min of global ischemia followed
by 30 min of reperfusion. Hearts were randomly divided into 4 groups, with one of
the following substances being added to the perfusate: buffer alone (control),
10(-6) mol/L bunazosin, 10(-7) mol/L WB4101, or 10(-7) mol/L CEC. Bunazosin had a
negative inotropic effect and preserved the postischemic ATP content, reduced the
postischemic increase in intracellular Na+ content and then enhanced
postreperfusion recovery of creatine phosphate. Bunazosin also reduced myocardial
45Ca2+ uptake during reperfusion (control 5.2 vs bunazosin 2.5 mumol/g dry weight
of tissue (dwt), p < 0.01). However, the recovery of left ventricular developed
pressure (DP) was not improved when bunazosin was added to the perfusate during
reperfusion. WB4101 had neither a negative inotropic nor an energy-sparing
effect, but it improved the recovery of DP (control 43% vs WB4101 56% of
preischemic value, p < 0.05) with no reduction in myocardial 45Ca2+ uptake. CEC
had a negative inotropic and energy-sparing effect and then reduced myocardial
45Ca2+ uptake (CEC 3.1 mumol/g dwt, p < 0.05), but it did not improve the
recovery of DP. These results suggest that the preischemic administration of an
alpha 1B-adrenoreceptor subtype blocker protected ischemic-reperfused myocardium
via reduction of Ca2+ overload, whereas the selective blockade of the alpha 1A
adrenoreceptor subtype reduced myocardial damage via mechanism(s) other than Ca2+
metabolism.
PMID- 9391861
TI - The delayed recovery of impaired endothelium-dependent vasodilatory response
after hemodynamic improvement in dogs with congestive heart failure.
AB - We investigated whether impaired endothelium-dependent vasodilatory response
recovers as heart failure improves. The femoral blood flow responses to intra
arterial administration of nitroglycerin (NTG) and acetylcholine (ACh) were
examined in dogs with 2-week pacing-induced chronic congestive heart failure
(congestive heart failure group; CHF, n = 12). Thereafter, pacing was stopped and
hemodynamic changes and femoral blood flow responses were re-examined either 1
week (recover 1 week group; Re 1W, n = 6) or 4 weeks (recover 4 weeks group; Re
4W, n = 6) after the cessation of pacing. Another group in which a pacemaker was
implanted without pacing served as the control group (n = 8). In CHF, heart rate
and pulmonary artery pressure increased, and echocardiography revealed increased
left ventricular diastolic dimension and reduced percent fractional shortening
compared with those in the control group. In Re 1W, all hemodynamic parameters
returned to the basal levels and did not differ from those in the control group.
Although there was no significant difference in the blood flow responses to NTG
among the 4 groups, the responses to ACh in CHF were significantly reduced
compared with those in the control group. Despite the recovered hemodynamics,
femoral blood flow responses to ACh were still reduced in Re 1W, but they
returned to the levels of the control group in Re 4W. Thus, vascular endothelial
dysfunction recovers along with improvement in CHF, however, the recovery of
endothelial function is delayed in comparison with improvement in cardiac
function.
PMID- 9391862
TI - A case of primary malignant fibrous histiocytoma of the heart with a left-to
right atrial shunt.
AB - A previously healthy 64-year-old woman attended our hospital with chest pain,
facial edema, and general fatigue. A chest radiograph revealed cardiomegaly,
small bilateral pleural effusions, and hilar congestion--findings that improved
after early therapy with furosemide and methyldigoxin. A chest radiograph
recorded 7 years earlier had revealed no dilation of cardiac shadow. There were
no findings suggesting atrial septal defect (ASD) or valvular heart disease.
Echocardiography revealed a tumor-like mass adhering to the posterior wall of the
left atrium. Color-flow Doppler echocardiography revealed a left-to-right shunt
at the atrial level. The Qp/Qs ratio as measured by cardiac catheterization was
2.0. Coronary angiography revealed abnormal dilated arteries from the
atrioventricular nodal branch and several feeding arteries from the left
circumflex branch. We hypothesized that the left-to-right shunt could be due to
the tumor, which extended to the rim of the patent foramen ovale, or to the very
small, previously unrecognized, ASD. This patient died 6 months after her first
admission and an autopsy was performed. Light microscopic examination of the
tumor revealed spindle-shaped fibroblast-like cells arranged in a storiform or
fascicular pattern. The immunohistochemical findings were consistent with
malignant fibrous histiocytoma (MFH). In the literature, left-to-right shunt at
the atrial level has not been reported in patients with cardiac MFH.
PMID- 9391863
TI - The coexistence of abdominal aortic aneurysm and advanced gastric cancer
associated with recurrent angina after coronary artery bypass grafting.
AB - A 76-year-old man with abdominal aortic aneurysm (AAA) and concomitant gastric
cancer, who had undergone coronary artery bypass grafting (CABG), presented with
recurrent exertional angina. Both lesions, the AAA and advanced gastric cancer,
exhibited an absolute indication for urgent surgery. Coronary revascularization
with percutaneous transluminal coronary angioplasty (PTCA) was carried out
successfully before abdominal surgery. A one-stage abdominal operation was
performed safely. The need for coronary revascularization complicates the
treatment strategy for these patients with associated coronary artery disease.
PTCA is the best option, especially if the patient presents with recurrent angina
after prior CABG.
PMID- 9391864
TI - Ventricular septal defect secondary to non-penetrating chest trauma.
AB - A 52-year-old man acquired a ventricular septal defect following non-penetrating
chest trauma. Four days after the traumatic accident, he showed signs of
congestive heart failure. Imaging techniques using echocardiography and left
ventriculography were helpful in diagnosing the condition. Surgical repair by
patch closure of the ventricular septal defect was accomplished 7 days after the
traumatic accident.
PMID- 9391865
TI - A case of acute myocardial infarction due to primary coronary dissection.
AB - A case of acute myocardial infarction associated with primary coronary dissection
was followed up angiographically. A 46-year-old woman complained of chest
oppression. Electrocardiogram on admission showed ST-segment elevation in V1-5.
Urgent coronary angiography was performed under a diagnosis of acute anterior
myocardial infarction, and showed a significant stenosis with multiple filling
defects in segments 7-8 (99% with severe delay) in the left anterior descending
artery. There was no organic lesion in the right coronary artery. Intracoronary
thrombolytic therapy was unsuccessful, and thereafter she was treated with
aspirin, warfarin and isosorbide dinitrate. Coronary angiography performed 1
month later revealed a long dissection with double lumens in segments 7-8. The
septal branches emerged from the smaller lumen. Two months later, the 2 lumens
were almost equal in size. These findings indicated that coronary dissection
produced a false lumen with an entry in segment 7 and a reentry in segment 8, and
that the false lumen was responsible for the greater flow. Four months later, the
flow in the true lumen had improved remarkably while that in the false lumen had
almost disappeared. She remained in stable condition during the follow-up period
of 4 months.
PMID- 9391866
TI - Successful thromboendarterectomy for chronic pulmonary embolism in a patient with
systemic lupus erythematosus and antiphospholipid syndrome.
AB - Chronic pulmonary thromboembolism is known to be associated with poor prognosis
with conservative medical treatment. Pulmonary thromboendarterectomy for chronic
pulmonary thromboembolic disease is a potentially lifesaving procedure that
prevents right-sided cardiac failure as a result of secondary pulmonary
hypertension caused by pulmonary thromboembolism. We report a rare case of
systemic lupus erythematosus with antiphospholipid syndrome in a patient who
presented with pulmonary hypertension secondary to chronic proximal multiple
pulmonary thromboembolism. To our knowledge, this is the first case report of
chronic pulmonary thromboembolism complicated by systemic lupus erythematosus
with antiphospholipid syndrome. Thromboendarterectomy was performed with
satisfactory results.
PMID- 9391867
TI - The viscoelastic behavior of the non-degenerate human lumbar nucleus pulposus in
shear.
AB - The viscoelastic behavior of the nucleus pulposus was determined in shear under
transient and dynamic conditions and was modeled using a linear viscoelastic
model with a variable amplitude relaxation spectrum. During stress-relaxation
tests, the shear stress of the nucleus pulposus relaxed nearly to zero indicative
of the fluid nature of the tissue. Under dynamic conditions, however, the nucleus
pulposus exhibited predominantly 'solid-like' behavior with values for dynamic
modulus (magnitude of G*) ranging from 7 to 20 kPa and loss angle (delta) ranging
from 23 to 30 degrees over the range of angular frequencies tested (1-100 rad s
1). This frequency-sensitive viscoelastic behavior is likely to be related to the
highly polydisperse populations of nucleus pulposus molecular constituents. The
stress-relaxation behavior, which was not linear on a semi-log plot (in the range
t1 << t << t2), required a variable amplitude relaxation spectrum capable of
describing this frequency sensitive behavior. The stress-relaxation behavior was
well described by this linear viscoelastic model with variable amplitude
relaxation spectrum; however, the dynamic moduli were underpredicted by the model
which may be related to non-linearities in the material behavior.
PMID- 9391868
TI - Dependence of cruciate-ligament loading on muscle forces and external load.
AB - A sagittal-plane model of the knee is used to predict and explain the
relationships between the forces developed by the muscles, the external loads
applied to the leg, and the forces induced in the cruciate ligaments during
isometric exercises. The geometry of the model bones is adapted from cadaver
data. Eleven elastic elements describe the geometric and mechanical properties of
the cruciate ligaments, the collateral ligaments, and the posterior capsule. The
model is actuated by 11 musculotendinous units, each unit represented as a three
element muscle in series with tendon. For isolated contractions of the
quadriceps, ACL force increases as quadriceps force increases for all flexion
angles between 0 and 80 degrees; the ACL is unloaded at flexion angles greater
than 80 degrees. When quadriceps force is held constant, ACL force decreases
monotonically as knee-flexion angle increases. The relationship between ACL
force, quadriceps force, and knee-flexion angle is explained by the geometry of
the knee-extensor mechanism and by the changing orientation of the ACL in the
sagittal plane. For isolated contractions of the hamstrings, PCL force increases
as hamstrings force increases for all flexion angles greater than 10 degrees; the
PCL is unloaded at flexion angles less than 10 degrees. When hamstrings force is
held constant, PCL force increases monotonically with increasing knee flexion.
The relationship between PCL force, hamstrings force, and knee-flexion angle is
explained by the geometry of the hamstrings and by the changing orientation of
the PCL in the sagittal plane. At nearly all knee-flexion angles, hamstrings co
contraction is an effective means of reducing ACL force. Hamstrings co
contraction cannot protect the ACL near full extension of the knee because these
muscles meet the tibia at small angles near full extension, and so cannot apply a
sufficiently large posterior shear force to the leg. Moving the restraining force
closer to the knee-flexion axis decreases ACL force; varying the orientation of
the restraining force has only a small effect on cruciate-ligament loading.
PMID- 9391869
TI - Forces of individual cat ankle extensor muscles during locomotion predicted using
static optimization.
AB - In order to test the principles of the control of synergistic muscles that were
proposed in the literature, forces of cat soleus (SO), gastrocnemius (GA), and
plantaris (PL) measured during locomotion were compared with the corresponding
forces predicted using different optimization criteria. Forces of cat SO, GA, and
PL, and the corresponding cat kinematics were recorded simultaneously using E
shaped force transducers and high-speed video, respectively. Measurements were
obtained from three cats walking and trotting on a treadmill at five nominal
speeds ranging from 0.4 to 1.8 m s-1. Muscle forces were predicted using static
optimization and a musculoskeletal model of the cat hindlimb consisting of three
segments (foot, shank, and thigh) and three muscles (SO, GA, and PL). Six
optimization criteria which had been proposed in the literature were tested.
Linear criteria based on the principles of minimum muscle force and stress
predicted forces during the stance phase with an average normalized error of 59
322%. Three other criteria--minimization of the sum of the relative muscle forces
squared, minimization of the sum of the muscle stresses cubed, and minimization
of the upper bound for all of the muscle stresses-showed a better performance:
(i) the average error was 43-119% and (ii) the correlation coefficient calculated
between the predicted and actual forces exceeded 0.9 for all three muscles. A
criterion that was based on the principle of minimum fatigue and accounted for
the percentage of slow-twitch fibers in the muscles, had the lowest average error
(26-52%). The high correlation (0.97-0.99) between the measured forces and forces
predicted by using the minimum fatigue criterion suggested that force sharing
among SO, GA, and PL during cat locomotion may be the same for a given set of
joint moments and muscle moment arms. It was concluded that static optimization
with the appropriate criterion can predict muscle forces adequately for specific
movement conditions.
PMID- 9391870
TI - Force response of the fingertip pulp to repeated compression--effects of loading
rate, loading angle and anthropometry.
AB - Repeated loading of the fingertips has been postulated to contribute to tendon
and nerve disorders at the wrist during activities associated with prolonged
fingertip loading such as typing. To fully understand the pathomechanics of these
soft tissue disorders, the role of the fingertip pulp in attenuating the applied
dynamic forces must be known. An experiment was conducted to characterize the
response of the in vivo fingertip pulp under repeated, dynamic, compressive
loadings, to identify factors that influence pulp dynamics, and to better
understand the force modulation by the pulp. Twenty subjects tapped repeatedly on
a flat plate with their left index finger, while the contact force and pulp
displacement were measured simultaneously. Tapping trials were conducted at three
fingertip contact angles from the horizontal plane (0 degree, 45 degrees, and 90
degrees) and five tapping rates (0.25, 0.5, 1, 2, and 3 Hz). The fingertip pulp
responds as a viscoelastic material, exhibiting rate-dependence, hysteresis, and
a nonlinear force-displacement relationship. The pulp was relatively compliant at
forces less than 1 N, but stiffened rapidly with displacement at higher forces
for all loading conditions. This suggests that high-frequency forces of a small
magnitude (< 1 N) are attenuated by the nonlinearly stiffening pulp while these
forces of larger magnitude are transmitted to the bone. Pulp response was
significantly influenced by the angle of loading. Fingertip dimensions, gender,
and subject age had little to no influence on pulp parameters.
PMID- 9391871
TI - Optimization of cardiac fiber orientation for homogeneous fiber strain at
beginning of ejection.
AB - Mathematical models of left ventricular (LV) wall mechanics show that fiber
stress depends heavily on the choice of muscle fiber orientation in the wall.
This finding brought us to the hypothesis that fiber orientation may be such that
mechanical load in the wall is homogeneous. Aim of this study was to use the
hypothesis to compute a distribution of fiber orientation within the wall. In a
finite element model of LV wall mechanics, fiber stresses and strains were
calculated at beginning of ejection (BE). Local fiber orientation was quantified
by helix (HA) and transverse (TA) fiber angles using a coordinate system with
local r-, c-, and l-directions perpendicular to the wall, along the circumference
and along the meridian, respectively. The angle between the c-direction and the
projection of the fiber direction on the cl-plane (HA) varied linearly with
transmural position in the wall. The angle between the c-direction and the
projection of the fiber direction on the cr-plane (TA) was zero at the epicardial
and endocardial surfaces. Midwall TA increased with distance from the equator.
Fiber orientation was optimized so that fiber strains at BE were as homogeneous
as possible. By optimization with TA = 0 degree, HA was found to vary from 81.0
degrees at the endocardium to -35.8 degrees at the epicardium. Inclusion of TA in
the optimization changed these angles to respectively 90.1 degrees and -48.2
degrees while maximum TA was 15.3 degrees. Then the standard deviation of fiber
strain (epsilon f) at BE decreased from +/- 12.5% of mean epsilon f to +/- 9.5%.
The root mean square (RMS) difference between computed HA and experimental data
reported in literature was 15.0 degrees compared to an RMS difference of 11.6
degrees for a linear regression line through the latter data.
PMID- 9391872
TI - The effect of pedaling rate on coordination in cycling.
AB - To further understand lower extremity neuromuscular coordination in cycling, the
objectives of this study were to examine the effect of pedaling rate on
coordination strategies and interpret any apparent changes. These objectives were
achieved by collecting electromyography (EMG) data of eight lower extremity
muscles and crank angle data from ten subjects at 250 W across pedaling rates
ranging from 45 to 120 RPM. To examine the effect of pedaling rate on
coordination, EMG burst onset and offset and integrated EMG (iEMG) were computed.
In addition, a phase-controlled functional group (PCFG) analysis was performed to
interpret observed changes in the EMG patterns in the context of muscle function.
Results showed that the EMG onset and offset systematically advanced as pedaling
rate increased except for the soleus which shifted later in the crank cycle. The
iEMG results revealed that muscles responded differently to increased pedaling
rate. The gastrocnemius, hamstring muscles and vastus medialis systematically
increased muscle activity as pedaling rate increased. The gluteus maximus and
soleus had significant quadratic trends with minimum values at 90 RPM, while the
tibialis anterior and rectus femoris showed no significant association with
pedaling rate. The PCFG analysis showed that the primary function of each lower
extremity muscle remained the same at all pedaling rates. The PCFG analysis,
which accounts for muscle activation dynamics, revealed that the earlier onset of
muscle excitation produced muscle activity in the same region of the crank cycle.
Also, while most of the muscles were excited for a single functional phase, the
soleus and rectus femoris were excited during two functional phases. The soleus
was classified as an extensor-bottom transition muscle, while the rectus femoris
was classified as a top transition-extensor muscle. Further, the relative
emphasis of each function appeared to shift as pedaling rate was increased,
although each muscle remained bifunctional.
PMID- 9391873
TI - Microhardness anisotropy of lamellar bone.
AB - The Knoop microhardness test has been utilised to observe in-plane microhardness
anisotropy of rat tibiae. The elongated rhombohedral geometry of the Knoop
indenter enables the Knoop microhardness (HK) to be calculated for a given
indenter orientation. Two indenter orientations were used: the major axis of the
indenter was aligned along the length of, and across the mid-sagittal section.
The statistical analysis demonstrated that the variation in HK was primarily due
to the orientation of the Knoop indenter (p < 0.001). HK was consistently greater
when the indenter was aligned with the major diagonal radial on the mid-sagittal
section.
PMID- 9391874
TI - A three-dimensional finite analysis of adaptive remodelling in the proximal
femur.
AB - A finite element analysis of adaptive bone remodelling in the proximal femur is
presented. The use of a three-dimensional model permits a realistic
representation of femur geometry, and also allows the possibility of examining
the effects of fully three-dimensional loading situations. The long-term pattern
of remodelling shows a realistic evolution of density distribution, with a
tendency towards a steady state, though the simplified load cases used to model
gait are not sufficient to predict the formation of the cortical shell.
PMID- 9391875
TI - An improved method for finite element mesh generation of geometrically complex
structures with application to the skullbase.
AB - An automated method has been developed to generate finite element meshes of
geometrically complex structures from CT images using solely hexahedral elements.
This technique improves upon previous voxel-based mesh reconstruction approaches
by smoothing the irregular boundaries at model surfaces and material interfaces.
Over a range of mesh densities, RMS error in surface Von Mises stress was higher
in the unsmoothed circular ring models (0.11-0.24 MPa) than in the smoothed
models (0.080-0.15 MPa) at each mesh density. The element-to-element oscillation
in surface element stress, as measured by the average second spatial derivative
of Von Mises stress along the outer surface of the ring, was higher in the
unsmoothed models (11.5-15.0 kPa mm-2) than in the smoothed models (4.0-6.8 kPa
mm-2). Similarly, in a human skullbase model, the element-to-element oscillation
in surface Von Mises stress was higher in the unsmoothed model (5.52 kPa mm-2)
than in the smoothed model (1.83 kPa mm-2). Using this technique, finite element
models of complex geometries can be rapidly reconstructed which produce less
error at the surface than voxel-based models with discontinuous surfaces.
PMID- 9391876
TI - A three-component force vector cell for in vitro quantification of the force
exerted by the papillary muscle on the left ventricular wall.
AB - Recent clinical studies indicate that functional mitral regurgitation, which is a
common complication in patients who suffer from ischemic heart disease, is
related to an increase in the tethering forces acting on the mitral valve
leaflets. Alterations in the valvular assembly, displacement of the papillary
muscles or dilatation of the mitral valve annulus can disrupt the normal force
balance on the mitral leaflets and result in an abnormal coaptation geometry with
incomplete mitral leaflet closure. The force balance imposed on the mitral
leaflets is created by the coapting forces generated by the transmitral pressure
difference and the tethering forces at the leaflet attachments. A unique force
vector cell capable of accurately measuring the three-component force vector
applied by the papillary muscle on the left-ventricular wall was designed and
manufactured to permit quantification of the alteration in the force balance
acting on the mitral leaflets, and to allow for the study of the influence of
papillary muscle displacement on mitral regurgitation.
PMID- 9391877
TI - A mechanical device for studying mechanical properties of human muscles in vivo.
AB - A mechanical device, primarily devoted to biomechanical studies of human calf
muscles during microgravity experiments is presented. It allows investigation of
both contractile and visco-elastic properties of musculo-articular systems using,
respectively, isokinetic movements, quick-release tests and sinusoidal
perturbations. This device is a specifically designed ergometer associated to an
experimental protocol designed for pre- and post-flight tests. The protocol was
evaluated on 22 healthy subjects and typical results are briefly presented.
Preliminary results are discussed in terms of agreement with currently available
data and a detailed evaluation of test-retest measurements is provided for quick
release experiments. Complementary investigations are suggested and potential
fields of research are indicated.
PMID- 9391878
TI - Clustering of Y chromosome deletions in subinterval E of interval 6 supports the
existence of an oligozoospermia critical region outside the DAZ gene.
AB - Y chromosome molecular analysis was performed using the STS-PCR technique in 50
patients with oligozoospermia. Microdeletions of interval 6 of the Y chromosome
were detected in seven patients, in six of whom subinterval E was affected. All
patients retained the RBM1 and DAZ genes, while in one deletion involved the SPGY
gene. The size of the deletion was not apparently related to the severity of the
disease. These results suggest the presence of an oligozoospermia critical region
on the Y chromosome within subinterval E of interval 6.
PMID- 9391879
TI - Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer
families.
AB - In this study we investigated 45 German breast/ovarian cancer families for
germline mutations in the BRCA1 gene. We identified four germline mutations in
three breast cancer families and in one breast-ovarian cancer family. among these
were one frameshift mutation, one nonsense mutation, one novel splice site
mutation, and one missense mutation. The missense mutation was also found in 2.8%
of the general population, suggesting that it is not disease associated. The
average age of disease onset in those families harbouring causative mutations was
between 32.3 and 37.4 years, whereas the family harbouring the missense mutation
had an average age of onset of 51.2 years. These findings show that BRCA1 is
implicated in a small fraction of breast/ovarian cancer families suggesting the
involvement of another susceptibility gene(s).
PMID- 9391880
TI - Atypical hereditary neuropathy with liability to pressure palsies (HNPP): the
value of direct DNA diagnosis.
AB - We report two patients with suspected hereditary liability to pressure palsies.
Neurophysiological studies showed a mixed axonal-demyelinating sensory-motor
polyneuropathy with focal slowing of conduction velocities at the common sites of
entrapment. Morphological studies on sural nerve biopsy from the proband showed
active axonal regeneration without typical tomacula. Molecular analysis confirmed
the presence of a deletion of chromosome 17p11.2 in both patients. Our
observation confirms the heterogeneity of hereditary liability to pressure
palsies and the relevance of DNA testing for the diagnosis of this hereditary
neuropathy.
PMID- 9391881
TI - Mutation and haplotype analysis of phenylalanine hydroxylase alleles in classical
PKU patients from the Czech Republic: identification of four novel mutations.
AB - Mutations, haplotypes, and other polymorphic markers in the phenylalanine
hydroxylase (PAH) gene were analysed in 133 unrelated Czech families with
classical phenylketonuria (PKU). Almost 95% of all mutant alleles were
identified, using a combination of PCR and restriction analysis, denaturing
gradient gel electrophoresis (DGGE), and sequencing. A total of 30 different
mutations, 16 various RFLP/VNTR haplotypes, and four polymorphisms were detected
on 266 independent mutant chromosomes. The most common molecular defect observed
in the Czech population was R408W (54.9%). Each of the other 29 mutations was
present in no more than 5% of alleles and 13 mutations were found in only one PKU
allele each (0.4%). Four novel mutations G239A, R270fsdel5bp, A342P, and IVS11nt
8g-->a were identified. In 14 (5.1%) alleles, linked to four different RFLP/VNTR
haplotypes, the sequence alterations still remain unknown. Our results confirm
that PKU is a heterogeneous disorder at the molecular level. Since there is
evidence for the gene flow coming from northern, western, and southern parts of
Europe into our Slavic population, it is clear that human migration has been the
most important factor in the spread of PKU alleles in Europe.
PMID- 9391882
TI - Different proximal and distal rearrangements of chromosome 7q associated with
holoprosencephaly.
AB - Four new cases of holoprosencephaly are described in fetuses exhibiting abnormal
karyotypes with different distal and proximal rearrangements of the long arm of
chromosome 7. Three of them showed terminal deletions of chromosome 7q,
confirming the importance of the 7q36 region in holoprosencephaly. The karyotype
of the fourth fetus showed an apparently balanced de novo translocation, t(7;13)
(q21.2;q33), without any visible loss of the distal part of chromosome 7q. The
involvement of new genes, different from the human Sonic Hedgehog gene (hShh)
responsible for holoprosencephaly, or a positional effect are discussed.
PMID- 9391883
TI - Familial streptomycin ototoxicity in a South African family: a mitochondrial
disorder.
AB - The vestibular and ototoxic effects of the aminoglycoside antibiotics
(streptomycin, gentamycin, kanamycin, tobramycin, neomycin) are well known;
streptomycin, in particular, has been found to cause irreversible, profound, high
frequency sensorineural deafness in hypersensitive persons. Aminoglycoside
ototoxicity occurs both sporadically and within families and has been associated
with a mitochondrial DNA (mtDNA) 1555A to G point mutation in the 12S ribosomal
RNA gene. We report on the molecular analysis of a South African family with
streptomycin induced sensorineural deafness in which we have found transmission
of this same predisposing mutation. It is now possible to identify people who are
at risk of hearing loss if treated with aminoglycosides in the future and to
counsel them accordingly. In view of the fact that aminoglycoside antibiotics
remain in widespread use for the treatment of infections, in particular for
tuberculosis, which is currently of epidemic proportions in South Africa, this
finding has important implications for the family concerned. In addition, other
South African families may potentially be at risk if they carry the same
mutation.
PMID- 9391884
TI - DNA testing for fragile X syndrome: implications for parents and family.
AB - The fragile X syndrome is an X linked, semidominant mental retardation disorder
caused by the amplification of a CGG repeat in the 5' UTR of the FMR1 gene.
Nineteen fragile X families in which the mutated FMR1 gene segregated were
evaluated. The implications of the diagnosis for the parents and family were
studied through pedigree information, interviews, and questionnaires. Information
about the heredity of fragile X syndrome was only disseminated by family members
to a third (124/366) of the relatives with an a priori risk of being a carrier of
the fragile X syndrome. Twenty-six percent (94/366) of the relatives were tested.
Transmission of information among first degree relatives seemed satisfactory but
dropped off sharply with increasing distance of the genetic relationship, leaving
66% uninformed. This is particularly disadvantageous in an X linked disease. Of
those subjects tested, 42% (39/94) had a premutation and 18% (17/94) had a full
mutation. On average, in each family one new fragile X patient and two new
carriers were found. When people have the task of transmitting genetic
information to their relatives, they usually feel responsible and capable;
however, reduced acquaintance and contact with more distant relative severely
reduces the effectiveness of such transfer of information in fragile X families.
PMID- 9391885
TI - Rapid identification of multiple supernumerary ring chromosomes with a new FISH
technique.
AB - Multiple supernumerary ring chromosomes are a rare cytogenetic finding which is
poorly understood. With the introduction of FISH techniques, their chromosomal
origin can now be defined clearly. The techniques described previously are
complicated and time consuming. We report a new rapid technique which has been
used to investigate two new cases. Multiple probes were hybridised to a single
slide by means of marking the underside with a diamond pen to form a grid of
squares, pipetting fixed cell suspension into the centre of each square, forming
a rubber solution grid on the denatured, dehydrated slide following the lines on
the underside, adding a mixture of probes into each square, and sealing the slide
with a silicone rubber rim and a covering slide. The type of probe and the size,
dimensions, and number of squares in the grid can be tailored to individual
cases. The two new cases examined here are mosaic for three (case 1) and four
(case 2) supernumerary ring chromosomes derived from different chromosomes.
Normal cell lines were also present. The karyotypes were established as
47,XY,+r(4)/47,XY,+r(17)/.../48,XY,+r(17),+r(20)/ 49,XY,+r(4),+r(17),+r(20)/46,XY
for case 1 and 47,XX,+r(4)/47,XX,+r(8)/47,XX,+r (10)/48,XX,+r(X),+r(4)/...
/49,XX,+r(X),+r (8),+r(10)/46,XX for case 2. Our findings suggest that the ring
chromosomes were formed during meiosis, perhaps involving complex rearrangements,
resulting in a germ cell containing all markers, with subsequent loss of markers
during cell division. Our second case also shows that the outcome is not
invariably mental or physical handicap.
PMID- 9391887
TI - Prenatal diagnosis of the fragile X syndrome: loss of mutation owing to a double
recombinant or gene conversion event at the FMR1 locus.
AB - The fragile X syndrome, an X linked mental retardation syndrome, is caused by an
expanded CGG repeat in the first exon of the FMR1 gene. In patients with an
expanded repeat the FMR1 promoter is methylated and, consequently, the gene is
silenced and no FMR1 protein (FMRP) is produced, thus leading to the clinical
phenotype. Here we describe a prenatal diagnosis performed in a female from a
fragile X family carrying a large premutation. In chorionic villus DNA of the
male fetus the normal maternal CGG allele and a normal pattern on Southern blot
analysis were found in combination with the FRAXAC2 and DXS297 allele of the
maternal at risk haplotype. A second chorionic villus sampling was performed
giving identical results on DNA analysis and, in addition, expression of FMRP was
shown by immunohistochemistry. We concluded that the male fetus was not affected
with the fragile X syndrome. Subsequent detailed haplotype analysis showed a
complex recombination pattern resembling either gene conversion or a double
crossover within a 20 kb genomic region.
PMID- 9391886
TI - Prader-Willi syndrome.
AB - Prader-Willi syndrome is a complex disorder affecting multiple systems with many
manifestations relating to hypothalamic insufficiency. Major findings include
infantile hypotonia, developmental delay and mental retardation, behaviour
disorder, characteristic facial appearance, obesity, hypogonadism, and short
stature. Obesity and the behavioural problems are the major causes of morbidity
and mortality. Prader-Willi syndrome is caused by abnormalities of the imprinted
region of proximal 15q and results from absence of the normally active paternal
genes in this region. Such absence results from paternal interstitial deletion,
maternal uniparental disomy, or a mutation or other abnormality in the imprinting
process. Diagnostic identification of all causes has become available in recent
years, permitting early detection and institution of appropriate management. This
testing has permitted recent identification of some phenotypic differences among
affected subjects of different race and between those with deletions and
uniparental disomy as a cause.
PMID- 9391888
TI - Conotruncal heart defect/microphthalmia syndrome: delineation of an autosomal
recessive syndrome.
AB - We report on three sibs born to healthy parents, one livebirth and two terminated
pregnancies, presenting with a malformation complex characterised by conotruncal
heart defect (CTHD), microphthalmia, genital anomalies, and facial dysmorphism.
The recurrence of the association of CTHD, particularly truncus arteriosus, and
microphthalmia in sibs has previously been reported in rare instances, but a
correlation between the single descriptions has never been noted. CTHDs are
included among the cardiac malformations characteristically associated with the
group of syndromes caused by the microdeletion of chromosome 22q11, but no
detectable hemizygosity has been found in our family. An autosomal recessive gene
seems to be involved in syndromic patients with the combination of CTHD and
microphthalmia. The map location of this gene is at present unknown, but
autosomal recessive inheritance must be considered in genetic counselling of
families with children presenting with this malformation complex.
PMID- 9391889
TI - Paternal transmission of congenital myotonic dystrophy.
AB - We report a rare case of paternally transmitted congenital myotonic dystrophy
(DM). The proband is a 23 year old, mentally retarded male who suffers severe
muscular weakness. He presented with respiratory and feeding difficulties at
birth. His two sibs suffer from childhood onset DM. Their late father had the
adult type of DM, with onset around 30 years. Only six other cases of paternal
transmission of congenital DM have been reported recently. We review the sex
related effects on transmission of congenital DM. Decreased fertility of males
with adult onset DM and contraction of the repeat upon male transmission
contribute to the almost absent occurrence of paternal transmission of congenital
DM. Also the fathers of the reported congenitally affected children showed, on
average, shorter CTG repeat lengths and hence less severe clinical symptoms than
the mothers of children with congenital DM. We conclude that paternal
transmission of congenital DM is rare and preferentially occurs with onset of DM
past 30 years in the father.
PMID- 9391890
TI - Misleading linkage results in an NF2 presymptomatic test owing to mosaicism.
AB - A two generation family with neurofibromatosis type 2 (NF2) is presented in which
a family member requested presymptomatic molecular diagnosis. Since the
consultand's mother had clinically well defined NF2, he was quoted to be at 50%
risk of carrying an NF2 mutation. Mutation screening in the mother did not show
the causative mutation and, consequently, presymptomatic testing was based on
linkage analysis. This showed that the consultand carried the high risk
chromosome 22. Subsequent mutation screening of his clinically affected sister
showed a nonsense mutation, R262X in exon 8 of the NF2 gene. The mother turned
out to be a mosaic for R262X; the son had not inherited the mutation. Mosaicism
may be a common mechanism in NF2 and other autosomal dominant diseases with a
high new mutation rate. This may be one explanation for a difference in
expression in generations. Caution has to be exercised when giving results based
on linkage tests which imply a very high risk to people in the second generation.
PMID- 9391891
TI - Associated malformations in the family of a patient with Meckel syndrome:
heterozygous expression?
AB - Meckel syndrome is an inherited autosomal recessive disease. A family is
described in which four persons had minor malformations related to the syndrome,
suggesting the possibility of manifesting heterozygotes. It is uncertain whether
these malformations represent partial expression of the disease or are
coincidental. However, partial expression has been described in heterozygotes for
other autosomal recessive diseases. Until the gene responsible for this lethal
syndrome is cloned and sequenced, such relatives of the proband may be offered
genetic counselling and prenatal diagnosis.
PMID- 9391892
TI - Mucopolysaccharidosis type I: identification of novel mutations that cause
Hurler/Scheie syndrome in Chinese families.
AB - The complementary and genomic DNA segments of the alpha-L-iduronidase gene from
two Chinese mucopolysaccharidosis type I Hurler/Scheie (MPS IH/S) patients were
amplified by polymerase chain reaction (PCR) and DNA sequencing was done to study
their molecular lesions. Patient W3 has heterozygous mutations; the maternal
allele has M1I (G to A transition in the initiation codon ATG) and the paternal
allele has Y343X (C to G transversion in exon 8 leading to in frame deletion of
codons 325-343 from the mRNA owing to false splicing). Patient W2 is homozygous
for mutation T364M (C to T transition in codon 364). The mutation was paternally
inherited. A de novo deletion or gene conversion event may have resulted in
apparent homozygosity for T364M. Expression of Y343X and T364M showed trace
amounts of alpha-L-iduronidase activity compared to that of normal cDNA upon
transfection into COS-7 cells.
PMID- 9391893
TI - Radial aplasia and chromosome 22q11 deletion.
AB - We report on a neonate with deletion 22q11 (del22q11) presenting with facial
dysmorphism, ocular coloboma, congenital heart defect, urogenital malformations,
and unilateral radial aplasia. This malformation complex includes features
frequently occurring in velocardiofacial syndrome as well as findings described
in the CHARGE and VACTERL associations. To our knowledge, the present case is the
first report of radial aplasia in del22q11. This observation further supports and
extends the clinical variability of del22q11.
PMID- 9391894
TI - Double partial trisomy 9q34.1-->qter and 21pter-->q22.11: FISH and clinical
findings.
AB - We describe a patient with double trisomy 9q34.1-->qter and 21pter-->q22.1
resulting from 3:1 segregation of a maternal balanced translocation. The patient
shows a clinical syndrome similar to that observed in patients with duplication
of the chromosome 9q distal region, while no signs of trisomy 21 were observed.
The use of high resolution banding and FISH were of fundamental importance for
the cytogenetic diagnosis and for definition of the breakpoints on both
chromosomes 9 and 21.
PMID- 9391895
TI - Germline duplication of chromosome 2p and neuroblastoma.
AB - A child with a germline duplication of chromosome 2p,
46,XY,der(13)t(2;13)(p23;q34), who developed a fatal neuroblastoma confirmed at
necropsy is reported. Fluorescent in situ hybridisation studies showed chromosome
2p (p23-pter) duplicated on chromosome 13 (q34). The clinical features of the
present case shared many similarities to previous reports of trisomy 2p and there
have been two cases described with neuroblastoma. Germline duplication of
chromosome 2p including the N-myc proto-oncogene may have pre-disposed to the
development of neuroblastoma in this case.
PMID- 9391896
TI - Median cleft of upper lip and pedunculated skin masses associated with de novo
reciprocal translocation 46,X,t(X;16)(q28;q11.2).
AB - We describe a de novo apparently balanced reciprocal translocation,
46,X,t(X;16)(q28;q11.2), in a 13 year old girl with median cleft of the upper
lip, pedunculated skin masses on the nasal septum, short stature, and mental
retardation. Pai syndrome is characterised by median cleft of the upper lip,
pedunculated skin mass(es) on the face, and midline lipoma(s) of the central
nervous system. The cause of this syndrome is unknown, although autosomal
dominant inheritance has been proposed. The translocation breakpoints in the
present patient may be candidate regions for a gene responsible for median cleft
of the upper lip and pedunculated skin mass(es) on the face, including Pai
syndrome.
PMID- 9391897
TI - Rapid detection of the major deletion in the Batten disease gene CLN3 by allele
specific PCR.
AB - The recent isolation of the CLN3 gene involved in Batten disease (juvenile
neuronal ceroid lipofuscinosis) creates possibilities for direct detection of
mutations which can confirm or indicate the clinical diagnosis of Batten disease.
We have designed a rapid and reliable allele specific PCR test for the detection
of the major deletion, which can be used in carrier diagnosis, presymptomatic
diagnosis, and prenatal diagnosis.
PMID- 9391898
TI - Methionine synthase and neural tube defects.
PMID- 9391899
TI - Limb-girdle muscular dystrophy or spinal muscular atrophy: a source of diagnostic
confusion?
PMID- 9391900
TI - The early historical roots of pediatric and adolescent gynecology.
AB - BACKGROUND: The science of medicine is a constantly evolving process that builds
on the experiences and observations of the past. We hypothesized that the issues
of pediatric and adolescent gynecology were also of concern to physicians
practicing in the 19th century. We sought to determine the extent to which our
forebears of over 100 years ago considered, diagnosed, and treated these
problems. METHODS: We conducted an exhaustive search through two English-language
medical journals, The Obstetrical Journal of Great Britain and Ireland (vol. 1-7,
1873-1880) and The American Journal of Obstetrics (vol. 1-32, 1869-1895), for
articles relating to pediatric and adolescent gynecology. RESULTS: The most
frequently encountered subject was the surgical management of congenital absence
or atresia of the vagina and associated anomalies of adjacent organs. By 1881,
the opinion expressed by many investigators was that the method used by Thomas
Addis Emmet to create an artificial vagina between the bladder and the rectum by
a single-stage procedure of blunt dissection and the immediate placement of a
glass vaginal dilator gave the best chance of a favorable outcome. The practice
of making an artificial opening through the rectum was abandoned. In 1882, a
review of published reports noted 43% postoperative mortality in children treated
for benign and malignant ovarian tumors. A review article in 1891 reported a 10%
mortality rate associated with treatment of the imperforate hymen. A research
article in 1870 noted the mean age at menarche in England to be 14.96 years.
Additional subjects in the literature included: "Acquired Venereal Disease in
Children" warning of the need for "rigid ... scrutiny of the attendants and
playmates of children" (1893), the enigmatic occurrence of "Vaginal Hemorrhage in
an Infant Five-Days-Old" (1874), the brutal atrocities perpetrated against "The
Child Wives of India" (1895), "Early Pregnancy" reviewing childbirth by young
adolescents (1874), "Hermaphrodism" (1886), "The ... Hymen and Its Remains ..."
(1871), a "Case of Fatal Hemorrhage from the Genital Organs" in which a 17-year
old exsanguinated from a vaginal laceration (1879), and "Primary Sarcoma of the
Vagina ... in a Child Three-Years-Old" (1881). CONCLUSION: Modern pediatric and
adolescent gynecology can trace its roots to well over a century ago.
PMID- 9391901
TI - Use of hormonal methods of birth control among sexually active adolescent girls.
AB - OBJECTIVE: To identify factors associated with the use of various birth control
methods among sexually active adolescent girls. DESIGN: A survey distributed as
part of a larger study measuring compliance with hepatitis B vaccination.
SETTING: A hospital-based and a school-based clinic. MEASURES: Demographic and
health behavior data including sexual activity, contraceptive method, substance
use, condom use, and history of sexually transmitted diseases (STDs) were
collected. Birth control method was confirmed by medical record review.
Associations with the outcome variable of birth control method were analyzed
using chi square, Kruskal-Wallis analyses of variance, and t-tests, followed by
logistic regression analysis. RESULTS: Among sexually experienced girls, 39% (n =
123) reported using oral contraceptive pills (OCPs), 5.4% (n = 17) used Depo
Provera (medroxyprogesterone acetate) or Norplant (levonorgestrel), and 55.6% (n
= 175) used no hormonal method. Logistic regression analysis revealed that the
factors most significantly associated with the use of hormonal methods were older
age (odds ratio [OR] = 1.19; 95% confidence interval [CI], 1.07-1.33), not using
a condom at last intercourse (OR = 0.55; CI, 0.34-0.90), and having had a well
visit within 1 year (OR = 2.11; CI, 1.12-3.70). OCP users were less likely than
Depo-Provera or Norplant users to have used alcohol (p = 0.041), cigarettes (p =
0.002), or marijuana (p = 0.018) in the past 30 days. OCP users were less likely
than nonusers of hormonal methods to have smoked cigarettes (p = 0.034) or
marijuana (p = 0.052). The school-based clinic had a greater proportion of
subjects using long-acting progestins (p < 0.001). CONCLUSIONS: The decreased
rate of condom use among those who used hormonal birth control methods and the
different rates of health risk behaviors among users of various methods require
targeted counseling efforts to decrease pregnancy and STD rates among young
women.
PMID- 9391902
TI - Prevalence of endometriosis in adolescent girls with chronic pelvic pain not
responding to conventional therapy.
AB - STUDY OBJECTIVE: To evaluate adolescent girls with chronic pelvic pain not
responding to conventional medical therapy, using advances in operative
laparoscopy to determine endometriosis prevalence, clinical stage, and type of
lesion. DESIGN: A descriptive retrospective study of subjects who (1) were
referred for the evaluation of chronic pelvic pain, (2) did not respond to a
nonsteroidal anti-inflammatory drug and an oral contraceptive pill, and (3)
underwent a laparoscopy to determine the etiology of the pelvic pain. SETTING:
Patients referred to a surgical gynecologist in a pediatric/adolescent gynecology
and reproductive endocrine academic practice. PARTICIPANTS: All patients younger
than 22 years of age with chronic pelvic pain. INTERVENTION: Operative
laparoscopy to determine the etiology of the chronic pelvic pain. MAIN OUTCOME
MEASURES: Operative laparoscopy results including stage and description of
endometriosis. RESULTS: More than two thirds of the study population (69.6%) was
found to have endometriosis. All subjects had either stage I or II as determined
by the American Fertility Society's classification system. The nature of the pain
in the 32 subjects with endometriosis was both acyclic and cyclic in 20 (62.5%),
acyclic only in 9 (28.1%), and cyclic only in 3 (9.4%). Other presenting symptoms
included gastrointestinal in 11 (34.3%), urinary in 4 (12.5%), and irregular
menses in 3 (9.4%). CONCLUSIONS: Adolescents with chronic pelvic pain not
responding to medical therapy have a high rate of endometriosis and should be
referred to a gynecologist who is experienced with the subtle laparoscopic
findings of atypical endometriosis to diagnose the etiology of the pelvic pain
and initiate appropriate therapy.
PMID- 9391903
TI - Attitudes of female college students toward over-the-counter availability of oral
contraceptives.
AB - STUDY OBJECTIVE: To determine female college students' beliefs about oral
contraceptive pill (OCP) availability and use, and to examine significant factors
associated with these beliefs. DESIGN: Cross-sectional survey. SETTING: Urban
women's liberal arts college. PARTICIPANTS: Two hundred ninety female
undergraduates who completed surveys. INTERVENTION: An anonymous survey was
placed in all undergraduate mailboxes. Surveys were returned to a locked
collection box in the mailroom. Within 4 weeks after distribution. 290 surveys
were completed. MAIN OUTCOME MEASURES: Sexual and contraceptive practices and
students' beliefs regarding whether OCPs should be made available without
prescription. RESULTS: The respondents' average age was 20.9 +/- 3.3 years; 84%
reported previous sexual intercourse with the mean age of first intercourse at
16.6 +/- 2.2 years. Seventy-five percent of the sexually active women reported
use of OCPs and 52% had used OCPs at their last intercourse. Sixty-five percent
of all respondents felt OCPs should not be available without prescription. The
two most commonly cited reasons for not wanting OCPs to be available over the
counter (OTC) were that (1) side effects might occur that a health care provider
could have prevented (59%), and (2) people would not go to their providers for
regular check ups (56%). The most commonly cited reason for believing that OCPs
should be available OTC was that there would be fewer unwanted pregnancies (74%).
Race, previous OCP use, previous sexual activity, and perceived risk of pregnancy
were not significant predictors of believing OCPs should be available OTC. Having
had a previous pregnancy was a significant predictor of believing OCPs should be
available OTC (p = 0.047). Those who believed OCPs should be available only with
a prescription were willing to pay more for OCPs (p = 0.033). Logistic regression
controlling for race revealed that both younger age (p = 0.03) and previous
pregnancy (p = 0.002) were independent predictors of believing OCPs should be
available OTC. CONCLUSIONS: The majority of our sample believe that OCPs should
remain as a prescription medication. Previous pregnancy and younger age are
important factors in determining beliefs regarding OCP availability. Further
studies in a more diverse population are needed to explore the relationship
between age, previous pregnancy, and desire for contraceptive availability
without prescription.
PMID- 9391904
TI - Adolescent girls' understanding of Papanicolaou smear results.
AB - STUDY OBJECTIVE: Human papillomavirus (HPV) urogenital infections are common in
sexually active adolescents. Previous research has indicated that adolescent
girls do not reliably report histories of HPV infection. This study examined
whether asking an adolescent girl if she had ever had an abnormal Papanicolaou
(PAP) smear was a good screening question for evidence of HPV urogenital
infection. DESIGN: The responses to the question about abnormal PAP smears, were
compared with their charts for documented abnormal PAP smear, HPV infection, and
sexually transmitted infection. SETTING: An urban, hospital-based adolescent
clinic. PARTICIPANTS: Fifty adolescent girls (mean age, 14.8 years). MAIN OUTCOME
MEASURES: Degree of agreement (kappa statistic). RESULTS: Using a kappa
statistic, reported history of an abnormal PAP smear had "fair" agreement with
documented dysplasia on PAP smear and "moderate" agreement with documented HPV
infection (i.e., either condyloma on PAP smear or genital warts noted on
examination). This reported history of an abnormal PAP smear agreed better with
documented HPV infection than with documented dysplasia on PAP smear.
CONCLUSIONS: There appears to be considerable confusion among adolescent girls
regarding their PAP smear results. Care providers need to be sensitive to this
when they are collecting historical information and when they are diagnosing HPV
infection or an abnormal PAP smear.
PMID- 9391905
TI - Congenital cervicovaginal aplasia with septate uterus and functioning
endometrium.
AB - A 14-year-old adolescent girl presented with primary amenorrhea and uncontrolled
pelvic pain. Evaluation using pelvic sonogram, magnetic resonance imaging, and
laparoscopy confirmed the diagnosis of cervicovaginal aplasia with functioning
endometrium and a vaginal fistulous tract. At age 19 years, hysterectomy and
vaginoplasty allowed the patient to be free of pain and to have normal sexual
function.
PMID- 9391906
TI - Non-Hodgkin's ovarian lymphoma during adolescence: report of two cases.
AB - STUDY OBJECTIVE: To present two cases of non-Hodgkin's ovarian lymphoma during
adolescence. DESIGN: Follow up of the patients. Report of diagnostic and
therapeutic approaches. SETTING: Division of Pediatric and Adolescent Gynecology
and Corrective Gynecological Surgery, University of Athens (Athens, Greece).
INTERVENTIONS: Laparotomy and chemotherapy. RESULTS AND MAIN OUTCOME: Three- and
five-year survival rates. CONCLUSIONS: Ovarian lymphoma constitutes a rare entity
with guarded prognosis. Selective surgery and chemotherapy constitute the
treatment of choice.
PMID- 9391907
TI - Design, synthesis and conformational analysis of hGM-CSF(13-31)-Gly-Pro-Gly-(103
116).
AB - On the basis of the X-ray structure and results from structure-activity
relationship studies, the following GM-CSF analogue was designed and synthesized
by solid-phase methodology: hGM-CSF[13-31]-Gly-Pro-Gly-[103-116]-NH2. This
analogue was constructed to comprise helices A and D of the native hGM-CSF,
covalently linked in an antiparallel orientation by the tripeptide spacer Gly-Pro
Gly, which is known as a turn-inducing sequence. The conformational analysis of
the analogue by CD spectroscopy revealed an essentially random structure in
water, while alpha-helix formation was observed upon addition of TFE. In 40% TFE
the helix content was approximately 45%. By two-dimensional NMR experiments in
1:1 water/trifluoroethanol mixture two helical sequences were identified
comprising the segments corresponding to helix A and helix D. In addition to
medium-range NOESY connectivities, a long-range cross-peak was found involving
the leucine residues at positions 13 and 35. Based on the experimentally derived
data (54 NOEs), the structure was refined by restrained molecular dynamics
simulations over 120 ps at various temperatures. A representative conformation
derived from the computer simulation is mainly characterized by two helical
segments connected by a loop region. The overall three-dimensional structure of
the analogue is comparable to the X-ray structure of hGM-CSF in that helices A
and D are oriented in an antiparallel fashion, forming a two alpha-helix bundle.
Nevertheless, there are small differences in the topology of the helices between
the solution structure of the designed analogue and the X-ray structure of hGM
CSF. The possible implications of these conformational features at the effects of
biological activity are discussed.
PMID- 9391908
TI - Conformation of four peptides corresponding to the alpha-helical segments of
human GM-CSF.
AB - The conformation of segments corresponding to the four alpha-helical stretches
found in human granulocyte-macrophage colony-stimulating factor was studied in
water solution in the presence of different amounts of 2,2,2-trifluoroethanol
(TFE). The CD spectra reveal the onset of secondary structure upon addition of
TFE. The final amount of helical conformation varies among the four peptides. In
all cases, the conformational transition is complete before 50% TFE (v/v). 1H-NMR
studies were conducted at this solvent composition, leading to the assignment of
all the resonances and to the definition of the secondary structure for all four
fragments.
PMID- 9391910
TI - Optically active aromatic amino acids. Part V: Some N-t-butyloxycarbonyl-O-methyl
L-tyrosine analogues with ring substitution at position 3.
PMID- 9391909
TI - Synthesis and CD studies of an 88-residue peptide containing the main receptor
binding site of HTLV-I SU-glycoprotein.
AB - Essential HTLV-1 biological functions, like host-cell receptor recognition,
depend on the structural motives on the surface glycoprotein gp46. We defined a
peptide of 88 amino acids [Arg147-Leu234] corresponding to the central part of
the protein sequence, where major neutralizing epitopes are localized. After
evaluating the feasibility of its chemical synthesis, the chosen sequence was
realized using the stepwise solid-phase methodology. Multiple chromatographic
purification steps were required to obtain a sample suitable for structural
analysis. Correct folding was supported by strong binding of monooclonal
antibodies, recognizing known exposed immunodominant regions. Circular dichroism
studies confirmed a non-random conformation of at least 70-80% of the synthetic
peptide. Investigation of the 3D-structure of the synthetic peptide will provide
useful information for future vaccine and drug-design strategies.
PMID- 9391911
TI - Enzymatic synthesis of isotopically labelled serine and tryptophan for
application in peptide synthesis.
AB - L-[1.2-13C2, 15N]Serine was prepared from [1,2-13C2, 15N]glycine on a gram scale
by the use of the enzyme serine hydroxymethyltransferase. The reaction was
monitored by 13C-NMR spectroscopy. This is the first simultaneously 13C- and 15N
labelled serine isotopomer so far reported. Part of the product was directly
converted by tryptophan synthase to L-[1,2-13C2, 15N]tryptophan which could
conveniently be purified and isolated as Boc-derivative in a yield of 71%. Most
of the serine was isolated similarly but to remove remaining starting material in
this case purification by column chromatography was required.
PMID- 9391912
TI - Conformational characterization of peptides rich in the cycloaliphatic C
alpha,alpha-disubstituted glycine 1-aminocyclononane-1-carboxylic acid.
AB - A series of N- and C-protected, monodispersed homo-oligopeptides (to the pentamer
level) from the cycloaliphatic C alpha,alpha-dialkylated glycine 1
aminocyclononane-1-carboxylic acid (Ac9c) and two Ala/Ac9c tripeptides have been
synthesized by solution methods and fully characterized. The conformational
preferences of all the model peptides were determined in deuterochloroform
solution by FT-IR absorption and 1H-NMR. The molecular structures of the amino
acid derivatives mCIAc-Ac9c-OH and Z-Ac9c-OtBu, the dipeptide pBrBz-(Ac9c)2-OtBu,
the tetrapeptide Z-(Ac9c)4-OtBu, and the pentapeptide Z-(Ac9c)5-OtBu were
determined in the crystal state by X-ray diffraction. Based on this information,
the average geometry and the preferred conformation for the cyclononyl moiety of
the Ac9c residue have been assessed. The backbone conformational data are
strongly in favour of the conclusion that the Ac9c residue is a strong beta-turn
and helix former. A comparison with the structural propensity of alpha
aminoisobutyric acid, the prototype of C alpha,alpha-dialkylated glycines, and
the other extensively investigated members of the family of 1-aminocycloalkane-1
carboxylic acids (Acnc, with n = 3-8) is made and the implications for the use of
the Ac9c residue in conformationally constrained analogues of bioactive peptides
are briefly examined.
PMID- 9391914
TI - The regiospecific N-derivatization of histidine side chains: reinvestigation of a
supposed N tau to N pi migration.
AB - A report claiming that AcHisOMe reacts regiospecifically with 4
fluoronitrobenzene to give AcHis[tau Ph(NO2)]OMe, which on treatment with
H2/Pd(C) undergoes a partial tau-pi shift to give some AcHis[pi Ph(NH2)]OMe,
cannot be substantiated. 4(5)-Methylimidazole, a model for AcHisOMe, gives on
reaction with 4-fluoronitrobenzene a 4:1 mixture of the regioisomers 1-(4
nitrophenyl),4-methylimidazole, corresponding to tau-substitution, and 1-(4
nitrophenyl),5-methylimidazole, corresponding to pi-substitution, each of which
has been isolated and fully characterized, including proof of orientation. In
both cases, treatment with H2/Pd(C) gives a single product, without any change of
orientation in either case.
PMID- 9391913
TI - The design of a specific ligand of HIV gp120.
AB - The crystal structure of CD4 suggested that the C/G38 and C/L44 replacements with
the consequent cystine bridge formation are compatible with the native structure
of that molecular moiety. As the NQGSF sequence, corresponding to the 39-43
fragment of human CD4 protein, was found to be involved in the HIV gp120
interaction, it has been synthesized in a cyclic form by adding two cysteine
residues at the amino and carboxy termini. 1H-NMR studies show that the
predominant solution conformation of cyclo-[CNQGSFC] is a type II beta-turn
centred on the NQGS segment. Structural and dynamic properties of the peptide are
also analysed in relation to the in vitro activity.
PMID- 9391915
TI - Prevalence, incidence and stability of drinking problems among whites, blacks and
Hispanics: 1984-1992.
AB - OBJECTIVE: This article reports on the prevalence, incidence and stability of
dependence-related problems and social consequences from drinking among whites,
blacks and Hispanics between 1984 and 1992. METHOD: A probability sample of 1,777
whites, 1,947 blacks and 1,453 Hispanics from the U.S. adult household population
was interviewed in 1984. In 1992 a subsample consisting of 788 whites, 723 blacks
and 703 Hispanics was reinterviewed. Interviews averaging 1 hour in length were
conducted in respondents' homes by trained interviewers. RESULTS: The prevalence
of a number of alcohol-related problems, the stability and incidence of
dependence-related problems and the incidence of social consequences from
drinking are higher among Hispanic than among white men. Dependence-related
problems are more stable among black than among white men. Among women, the
incidence of dependence-related problems and social consequences from drinking is
higher among blacks than whites. Hispanic women have a higher incidence of social
consequences from drinking than white women. Having a problem at Time 1
correlates only moderately with having a problem at Time 2, independent of
ethnicity. CONCLUSIONS: In general, Hispanics and blacks continue to be more at
risk than whites for developing a number of alcohol-related problems. These two
ethnic groups should be the focus of renewed efforts to address alcohol problems
and inequalities in income distribution, employment, education and lack of access
to adequate health care.
PMID- 9391916
TI - Mate similarity, heavy substance use and family history of problem drinking among
young adult women.
AB - OBJECTIVE: This study used data from a national sample of young adult women to
evaluate issues about spousal similarity for problem drinking. Paternal and
maternal problem drinking were also evaluated in regard to daughters' marriage to
a problem drinking spouse, and daughters' problem drinking and substance use.
METHOD: Data from over 5,000 young adult women (ages 23-30 yrs) from the National
Longitudinal Survey of Youth (NLSY) archive were used to evaluate associations
between marrying a problem-drinking spouse, family history of problem drinking,
and women's problem drinking and lifetime marijuana and cocaine use. RESULTS:
Findings indicated that black women were less likely to marry a problem-drinking
spouse than were Hispanic, Native American or white women. Problem-drinking women
were twice as likely to have married a problem-drinking spouse than were non
drinking women, and heavier lifetime marijuana or cocaine use by women was also
associated with an almost twofold increase in marrying a problem-drinking spouse.
Random effects ordinal probit regression models indicated that, while controlling
for major sociodemographic variables (e.g., race, poverty status), maternal,
paternal and spousal problem drinking all significantly predicted problem
drinking and heavier levels of substance use among the women. CONCLUSIONS:
Nonrandom matching of problem drinking among marital partners was indicated in
this study and women's problem drinking and substance use practices were
predicted by paternal, maternal and spousal problem drinking. The similarity of
problem-drinking spouses was not constant across racial/ethnic groups, as black
women were less likely to marry a problem-drinking spouse, though racial
differences in the age of onset of heavier drinking may have influenced this
finding.
PMID- 9391917
TI - Periods of abstinence following the onset of alcohol dependence in 1,853 men and
women.
AB - OBJECTIVE: Data from both laboratory experiments and retrospective histories of
alcoholics indicate that alternations between periods of abstinence and heavy
drinking are common in the course of alcoholism. This article examines the
prevalence, chronological characteristics and clinical features associated with
periods of abstinence in a large sample of alcohol dependent men and women.
METHOD: As part of the Collaborative Study on the Genetics of Alcoholism (COGA),
semistructured personal interviews were used to gather data on the course of
alcoholism in 1,853 alcohol dependent men and women. Data were evaluated
regarding the characteristics of alcoholics with and without periods of
abstinence lasting 3 or more months, and the course of these periods over time
were evaluated separately for subjects with one, two, three or four episodes of
abstention. RESULTS: Despite a relatively high threshold of 3 months for defining
an abstinence period, 62.3% of the subjects had at least one such episode,
including 55.6% of the 1,853 alcoholics for whom complete data were available.
Those alcohol dependent subjects with periods of abstention had an average (+/-
SD) of 1.7 +/- 0.99 such periods, and 43% of abstainers had two or more. Logistic
regression analyses revealed that the predictors of history of abstention were
female gender (odds ratio [OR] = 1.78), older age at interview (OR = 1.04 per
year), younger age of onset of alcoholism (OR 0.93 per year), ever having been
married (OR = 1.45), the number of DSM-III-R dependence items endorsed (OR = 1.03
per item) and attendance in AA (OR = 2.82). Among abstainers, a period lasting 5
or more years was predicted by older age (OR = 1.03 per year) and AA
participation (OR = 3.23), but also by more years of alcoholism (OR = 1.06 per
year), white racial background (OR = 1.79) and the absence of history of having
been a proband (OR = 3.39). CONCLUSIONS: Periods of abstinence of 3 or more
months were commonly observed in the course of alcohol dependence. This
information is important for clinicians who need to avoid inappropriate
stereotypes of alcoholism and who wish to educate their alcohol dependent
patients about the course of this disorder.
PMID- 9391918
TI - Sex and strain influence the effect of ethanol on central monoamines.
AB - OBJECTIVE: We recently investigated the effects of EtOH on the mesolimbic
dopamine and serotonin systems in male and female C57BL/6 (B6) and DBA/2J (D2)
mice. METHOD: Male and female rodents from the B6 and D2 mouse strains (n = 11
per strain, sex and dose) were used in this study. Doses of EtOH (vs saline)
administered were 1.0, 2.0 or 3.0 g/kg. RESULTS: Treatment with saline or EtOH
produced both strain- and sex-dependent differences in patterns of monoamine
response. For example, D2s exhibited significantly higher overall dopamine (DA)
levels than did B6s in the frontal cortex (FC), nucleus accumbens (NA) and
caudate-putamen (CP). In the FC, female D2 evinced elevated 5HIAA at 1.0 g/kg. In
the NA, D2 females showed dose related increases in levels of DA up to 3.0 g/kg,
whereas in the D2 males and in B6 males and females we observed no response. Also
in the NA, B6 males showed increases in dihydroxyphenyacetic acid (DOPAC) at 1.0
and 3.0 g/kg. In the CP, B6 males showed higher DA levels than B6 females at the
saline, and all EtOH doses. For serotoninergic activity in the CP as well as the
NA, EtOH produced a distinctive triphasic response, with the 1.0 and 3.0 g/kg
doses of EtOH producing higher levels than saline and 2.0 g/kg of 5HIAA in B6
males than in B6 females. CONCLUSIONS: Our findings indicate strain and sex
differences in monoamine response to acute doses of ethanol, and further
implicate (via changes in DOPAC) presynaptic mechanisms in the effects of ethanol
on dopamine.
PMID- 9391919
TI - Alcohol and the ability to inhibit behavior in men and women.
AB - OBJECTIVE: This experiment tested the impairing effect of alcohol on cognitive
inhibitory control of behavior in the absence of any motivational consequences
for exhibiting or inhibiting a response. METHOD: Men (n = 24) and women (n = 24)
were trained on a computerized "go-stop" task that measured response reaction
time (RT) to a go signal and inhibitory control by the number of inhibitions to a
randomly occurring stop signal. Equal numbers of men (n = 8) and women (n = 8)
were assigned to one of three groups (n = 16), and they performed the task alone
in a room under either alcohol (A), placebo (P) or no-treatment control (C)
conditions. Blood alcohol concentrations of men and women were matched in Group A
by administering 0.62 and 0.54 g/kg of alcohol, respectively. RESULTS: Alcohol
impaired inhibitory control and had no significant effect on response RT. Under P
and C conditions, no changes in inhibitions or response RT were observed. In
addition, no significant gender effects were found. CONCLUSIONS: The results
showed that inhibitory control of behavior was impaired by a moderate dose of
alcohol that did not affect response RT.
PMID- 9391920
TI - P300 from men with a family history of alcoholism under different incentive
conditions.
AB - OBJECTIVE: Males with a family history of alcoholism (Family History Positive
[FHP]) have frequently been reported to show an attenuated amplitude of the P300
component of the EEG event-related potential (ERP). The purpose of the present
study was to explore the influence of incentives on the amplitude of the P300 to
Target stimuli in FHP and FHN (Family History Negative) men. METHOD: The ERPs of
20 FHP and 20 FHN men were recorded in a visual discrimination task under two
conditions: a no incentive (Neutral) and a reward/loss of reward (Incentive)
conditions. ERPs following Target, Non-Target and Novel stimuli were examined.
RESULTS: The FHP subjects displayed the expected attenuation of P300 amplitude,
regardless of the stimulus type (Target, Non-Target or Novel), compared to the
FHN subjects. The FHN subjects showed the predicted effect of a significantly
increased P300 amplitude following Target stimuli in the Incentive condition
whereas the FHP subjects did not display significantly greater P300 amplitudes in
response to the incentive. CONCLUSIONS: These results may reflect a deficit in
the motivational-cognitive system of FHP subjects. Analyses suggest that changes
in P300 amplitude in response to the incentive can be predicted by subjects'
scores on self-report measures of sensation seeking and behavioral undercontrol.
However, such measures could not explain subjects' absolute P300 amplitude to
Target stimuli.
PMID- 9391921
TI - Stability of neuropsychological assessments early in alcoholism treatment.
AB - OBJECTIVE: Current trends in managed mental health care have telescoped the
assessment and treatment of individuals diagnosed with an alcohol or other drug
use disorder. Yet, there is limited empirical information about the short-term
stability of neuropsychological status and other person characteristics that are
useful to assess early in treatment. This study examined the stability of
neuropsychological test scores within the first 3 weeks following diagnosis of an
alcohol use disorder. METHOD: An eclectic neuropsychological battery made up of
commonly used, sensitive tests of abstraction, executive functions, memory,
visuospatial abilities and verbal ability was administered to female and male
alcohol use disordered individuals within 3 days of treatment entry (or following
detoxification), 3-5 days later and 21 days later. The three test administrations
were completed by 35, 32 and 24 subjects, respectively. RESULTS: Across tests,
the average stability coefficient (Pearson correlation) was .82 between Days 3
and 5, .86 between Days 5 and 21, and .79 between Days 3 and 21. Intraclass
correlations ranged from .79 to .98 across tests (mean = .92). Clinical
stability, defined as the likelihood that a test score fell consistently above or
below a standardized impairement cutoff score, was also good. Across tests,
percent agreement in impairment diagnoses for the same three time intervals
averaged 84%, 92% and 87%, respectively. The chance-corrected kappa (Kappa)
coefficients of diagnostic agreement were generally moderate to substantial from
Day 3 to Days 5 or 21, and mostly substantial from Day 5 to 21. CONCLUSIONS:
Early assessments of neuropsychological status were psychometrically stable, and
also provided reasonably stable indicants of clinically significant impairment.
It was likely that the data provided lower bound estimates of the stability of
impairment classifications due to the repeated measures design and power
limitations.
PMID- 9391922
TI - The effect of question structure on self-reports of heavy drinking: closed-ended
versus open-ended questions.
AB - OBJECTIVE: We compared open-ended versus closed-ended questions on the frequency
of consuming five or more drinks in a single sitting. METHOD: From a general
population survey of Ontario adults (N = 2,022, 62% male), we analyzed a
subsample of 649 respondents who reported drinking five or more drinks in a
single sitting at least once in the past year. Differences in agreement between
the two questions and rates of missing data were evaluated. RESULTS: For the most
part, the two measures were not consistent, with the closed-ended question
eliciting higher rates of heavier drinking. Rates of missing data were also
higher for the open-ended question. CONCLUSIONS: Open-ended question may not
necessarily be more suitable than closed-ended questions for estimating the
frequency of heavy alcohol use.
PMID- 9391923
TI - Relationship between inpatient alcoholism treatment and longitudinal changes in
health care utilization.
AB - OBJECTIVE: The purpose of the study was to evaluate changes in health care
utilization associated with inpatient alcoholism treatment in alcoholics of low
socioeconomic status with different histories of treatment relapse. METHOD: The
sample consisted of more than 85,000 male alcoholics using inpatient care in
Department of Veterans Affairs medical centers in fiscal year 1987. Five
treatment groups were identified to represent a continuum of length and intensity
of alcoholism treatment, including formal inpatient alcoholism treatment, short
detoxification and hospitalizations for primary diagnoses other than alcoholism.
All inpatient and outpatient health services for 3 years before and 3 years after
the index hospitalization were examined for differential changes in utilization
associated with the five treatment groups after controlling for patient
predisposing, enabling and need characteristics. RESULTS: Both total inpatient
days and outpatient visits increased significantly for all treatment groups, with
the greatest increases occurring in the group completing inpatient alcoholism
treatment (both p < .0001). However, use of inpatient medical care decreased and
substance abuse inpatient care increased significantly for most groups, with the
largest increases in substance abuse care found for the completed treatment
group. CONCLUSIONS: In a hospital system that does not deny care on the basis of
ability to pay, certain groups of chronic alcoholics who cannot sustain prolonged
remission will continue to be heavy utilizers of services. Alcoholism treatment
may be associated with higher short-term costs but it remains to be seen whether
provision of more focused treatment services is able to achieve longer term
better outcomes and, ultimately, lower costs.
PMID- 9391924
TI - Age of first use: its reliability and predictive utility.
AB - OBJECTIVE: The purpose of this study was: (1) to assess the utility of age of
first licit use and age of first illicit use as predictors of alcohol and drug
use at ages 20 and 30; and (2) to examine the reliability of retrospectively
recalled ages of onset of use. METHOD: Subjects (N = 839) from the Rutgers Health
and Human Development Project provided four waves of longitudinal data spanning
the age range from 15 to 31. RESULTS: Retrospective recall of age of onset
revealed a fair degree of relative agreement but a lack of absolute agreement
because of an upward shift in recalled ages as individuals became older. Repeated
measures ANOVAS revealed normative declines in alcohol and drug use from 20 to 30
even though individual differences in use remained quite stable across time.
Regression analyses indicated that: (1) age of first licit use as recalled at age
18 did not predict alcohol or drug use at age 20; (2) age of first illicit use
was a weak predictor of alcohol use at 20 but a fairly strong predictor of drug
use at 20; and (3) neither age predicted use or use consequences at age 30.
CONCLUSIONS: In the general population, illicit drug use and heavier alcohol use
are, regardless of age of onset, adolescence-limited phenomena for most
individuals. Findings suggest that intervention efforts need to be aimed
simultaneously at delaying the onset of illicit use and reducing use levels among
young adult users.
PMID- 9391925
TI - Stress, alcohol-related expectancies and coping preferences: a replication with
adolescents of the Cooper et al. (1992) model.
AB - OBJECTIVE: The present study attempted to replicate with adolescents the stressor
vulnerability model of adult drinking proposed by Cooper et al. (J. Abnorm.
Psychol. 101: 139-152, 1992). The Cooper et al. model simultaneously assesses the
stress-moderating effects of gender, expectancies and coping on alcohol use and
abuse. METHOD: Adolescents in Grades 7-12 (N = 184, 59% female) completed the
Alcohol Expectancy Questionnaire-Adolescent form, the COPE, the Adolescent
Perceived Events Scale and the Drinking to Cope scale. RESULTS: The pattern of
results was very similar to those of earlier studies using adults or
undergraduates. Generally, positive expectancies for alcohol, an avoidant coping
preference and stress were predictive of drinking to cope, alcohol use and
alcohol-related problems. A number of two-way interactions were also reported.
Although gender did not play a prominent role in prediction, as it typically does
with adults, grade was a significant predictor; older students reported more
alcohol use and alcohol-related problems than younger students. CONCLUSIONS:
Results were similar to those reported by Cooper et al. with adults and Evans and
Dunn (J. Stud. Alcohol 56: 186-193, 1995) with undergraduates, and support the
utility of the stressor vulnerability model for understanding alcohol use among
adolescents.
PMID- 9391927
TI - Blood alcohol concentration and driver record factors.
PMID- 9391926
TI - Risk and protective factors as predictors of adolescent alcohol involvement and
transitions in alcohol use: a prospective analysis.
AB - OBJECTIVE: Determinants of initial alcohol use may differ from predictors of
accelerated or problematic consumption. Social influences may be strong
predictors of initial drinking; however, later stages of problem drinking may be
linked developmentally to intrapersonal deficits. This study prospectively
examined the influence of chronic and changing risk and protective status in
predicting adolescent alcohol involvement and transitions in alcohol use. METHOD:
Data were obtained from a three-wave cohort (N = 823) of 8th-10th grade
nonintervention students participating in a school-based drug abuse prevention
trial. Cognitive, attitudinal and social influence measures were dichotomized
using empirical cut-offs to designate risk or protective status. Using a
conceptually based assignment scheme, additive risk indices were created
assessing chronic (averaging across time) and changing features of competence,
psychological and interpersonal functioning, cognitive-affective and social
influences. Three chronic and change protective indices were created tapping
competence, psychological, and interpersonal functioning. RESULTS: Controlling
for initial drinking and gender, chronic risk for social influence and
psychological functioning and increased risk for social influences and competency
predicted subsequent drinking behavior. Chronic psychological protection
attenuated subsequent drinking. Using categorical measures of drinking behavior
to designate nonuse, experimental or moderate-heavy use, chronic social influence
and competency risk were associated with an increased likelihood of accelerated
drinking, whereas improved psychological functioning diminished the likelihood of
increased drinking behavior. CONCLUSIONS: Findings underscore the need for
implementing prevention strategies that reinforce developmentally appropriate
skills and enhance personal competence and psychological functioning as effective
barriers against initial and more problematic alcohol use. The unique
contribution of protective forces also underscores that risk reduction and
protection enhancement are complementary processes and are both required to
offset social influences for alcohol consumption.
PMID- 9391928
TI - Telemedicine and the national information infrastructure: are the realities of
health care being ignored?
AB - Health care is shifting from a focus on hospital-based acute care toward
prevention, promotion of wellness, and maintenance of function in community and
home-based facilities. Telemedicine can facilitate this shifted focus, but the
bulk of the current projects emphasize academic medical center consultations to
rural hospitals. Home-based projects encounter barriers of cost and inadequate
infrastructure. The 1996 Telecommunications Act as implemented by the Federal
Communications commission holds out significant promise to overcome these
barriers, although it has serious limitations in its application to health care
providers. Health care advocates must work actively on the federal, state, and
local public and private sector levels to address these shortcomings and develop
cost effective partnerships with other community-based organizations to build
network links to facilitate telemedicine-generated services to the home, where
the majority of health care decisions are made.
PMID- 9391929
TI - The virtual visit: using telecommunications technology to take care of patients.
AB - Telephone-Linked Care (TLC) technology has been developed and applied as an
alternative to and a supplement for office visits as a means to deliver
ambulatory care. TLC is used to monitor patients with chronic diseases, counsel
patients on important health behaviors, and provide information and support to
home caregivers of patients with disabling conditions. TLC speaks to patients
over the telephone in their homes using computer-controlled digitized human
speech. Patients use their telephone keypad to communicate. TLC conversations
last 2-15 minutes per call and take place weekly for periods of at least 3
months. The conversations consist of a salutation, password verification, the
core clinical part, and a closing. The structure of the clinical part is similar
for each of the application groups: chronic disease, health behavior, and
caregiver support. The system architecture consists of linked voice and database
components and their subcomponents. Preliminary evaluation indicates that TLC is
well accepted by patients and their providers and can improve clinical outcomes.
PMID- 9391930
TI - Quality-of-life research on the Internet: feasibility and potential biases in
patients with ulcerative colitis.
AB - OBJECTIVE: The World Wide Web (WWW) is a new communications medium that permits
investigators to contact patients in nonmedical settings and study the effects of
disease on quality of life through self-administered questionnaires. However,
little is known about the feasibility and, what is more important, the validity
of this approach. An on-line survey for patients with ulcerative colitis (UC) and
patients whose UC had been treated with surgical procedures was developed. To
understand how patients on the WWW might differ from those in practice and the
potential biases in conducting epidemiological research in volunteers recruited
on the Internet, post-surgery patients who responded to the WWW survey were
compared with those in a surgical practice. SETTING: The Internet and private
practice surgical clinic. MAIN OUTCOMES: Scores from the Short form 36 (SF-36)
Health Assessment Questionnaire and the Self-Administered Inflammatory Bowel
Disease Questionnaire (IBDQ). RESULTS: Over a 5-month period, 53 post-surgery
patients enrolled in the Internet study; 47 patients from a surgical clinic
completed the same computer-based questionnaire. Surgically treated patients on
the WWW were younger than their clinic counterparts (median age category 35-44
years vs. 45-54 years, p = 0.01) but more ill with a lower summary IBDQ score
(168 vs. 186, p = 0.019) and lower health status across almost all dimensions of
the SF-36 (p = 0.016). CONCLUSIONS: It is feasible to conduct epidemiological
research on the effects of UC on quality of life on the Web; however, systematic
differences in disease activity between volunteer patients on the WWW and "in the
clinic" may limit the applicability of results.
PMID- 9391931
TI - A voice-enabled, structured medical reporting system.
AB - Kurzweil Applied Intelligence received a research grant from the National
Institute of Standards and Technology (NIST) Advanced Technology Program to
develop a prototype voice-enabled, structured medical reporting system. In
typical usage, the physician dictates to the system, which then uses automatic
speech recognition and medical knowledge bases to produce a structured report.
This report can then be formatted and viewed on a computer screen, stored in
databases of patient information, transmitted to other systems, used to support
outcome studies, or viewed on a Web browser. The output reports are structured
according to two standard, platform-independent formats: SGML and CORBA. These
formats represent the data in a way that can be read by both computers and
humans, and efficiently communicated to a wide range of databases and
communications protocols.
PMID- 9391933
TI - A WWW implementation of national recommendations for protecting electronic health
information.
AB - In March of 1997, the National Research Council (NRC) of the National Academy of
Sciences issued the report, "For the Record: Protecting Electronic Health
Information." Concluding that the current practices at the majority of health
care facilities in the United States are insufficient, the Council delineated
both technical and organizational approaches to protecting electronic health
information. The Beth Israel Deaconess Medical Center recently implemented a
proof-of-concept, Web-based, cross-institutional medical record, CareWeb, which
incorporates the NRC security and confidentiality recommendations. We report on
our WWW implementation of the NRC recommendations and an initial evaluation of
the balance between ease of use and confidentiality.
PMID- 9391932
TI - Recommendations for responsible monitoring and regulation of clinical software
systems. American Medical Informatics Association, Computer-based Patient Record
Institute, Medical Library Association, Association of Academic Health Science
Libraries, American Health Information Management Association, American Nurses
Association.
AB - In mid-1996, the FDA called for discussions on regulation of clinical software
programs as medical devices. In response, a consortium of organizations dedicated
to improving health care through information technology has developed
recommendations for the responsible regulation and monitoring of clinical
software systems by users, vendors, and regulatory agencies. Organizations
assisting in development of recommendations, or endorsing the consortium position
include the American Medical Informatics Association, the Computer-based Patient
Record Institute, the Medical Library Association, the Association of Academic
Health Sciences Libraries, the American Health Information Management
Association, the American Nurses Association, the Center for Healthcare
Information Management, and the American College of Physicians. The consortium
proposes four categories of clinical system risks and four classes of measured
monitoring and regulatory actions that can be applied strategically based on the
level of risk in a given setting. The consortium recommends local oversight of
clinical software systems, and adoption by healthcare information system
developers of a code of good business practices. Budgetary and other constraints
limit the type and number of systems that the FDA can regulate effectively. FDA
regulation should exempt most clinical software systems and focus on those
systems posing highest clinical risk, with limited opportunities for competent
human intervention.
PMID- 9391934
TI - Updating the Read Codes: user-interactive maintenance of a dynamic clinical
vocabulary.
AB - The Read Codes are a hierarchically-arranged controlled clinical vocabulary
introduced in the early 1980s and now consisting of three maintained versions of
differing complexity. The code sets are dynamic, and are updated quarterly in
response to requests from users including clinicians in both primary and
secondary care, software suppliers, and advice from a network of specialist
healthcare professionals. The codes' continual evolution of content, both across
and within versions, highlights tensions between different users and uses of
coded clinical data. Internal processes, external interactions and new structural
features implemented by the NHS Centre for Coding and Classification (NHSCCC) for
user interactive maintenance of the Read Codes are described, and over 2000 items
of user feedback episodes received over a 15-month period are analysed.
PMID- 9391935
TI - Natural language generation in health care.
AB - Good communication is vital in health care, both among health care professionals,
and between health care professionals and their patients. And well-written
documents, describing and/or explaining the information in structured databases
may be easier to comprehend, more edifying, and even more convincing than the
structured data, even when presented in tabular or graphic form. Documents may be
automatically generated from structured data, using techniques from the field of
natural language generation. These techniques are concerned with how the content,
organization and language used in a document can be dynamically selected,
depending on the audience and context. They have been used to generate health
education materials, explanations and critiques in decision support systems, and
medical reports and progress notes.
PMID- 9391936
TI - Evaluating the coverage of controlled health data terminologies: report on the
results of the NLM/AHCPR large scale vocabulary test.
AB - OBJECTIVE: To determine the extent to which a combination of existing machine
readable health terminologies cover the concepts and terms needed for a
comprehensive controlled vocabulary for health information systems by carrying
out a distributed national experiment using the Internet and the UMLS Knowledge
Sources, lexical programs, and server. METHODS: Using a specially designed Web
based interface to the UMLS Knowledge Source Server, participants searched the
more than 30 vocabularies in the 1996 UMLS Metathesaurus and three planned
additions to determine if concepts for which they desired controlled terminology
were present or absent. For each term submitted, the interface presented a
candidate exact match or a set of potential approximate matches from which the
participant selected the most closely related concept. The interface captured a
profile of the terms submitted by the participant and for each term searched,
information about the concept (if any) selected by the participant. The term
information was loaded into a database at NLM for review and analysis and was
also available to be downloaded by the participant. A team of subject experts
reviewed records to identify matches missed by participants and to correct any
obvious errors in relationships. The editors of SNOMED International and the Read
Codes were given a random sample of reviewed terms for which exact meaning
matches were not found to identify exact matches that were missed or any valid
combinations of concepts that were synonymous to input terms. The 1997 UMLS
Metathesaurus was used in the semantic type and vocabulary source analysis
because it included most of the three planned additions. RESULTS: Sixty-three
participants submitted a total of 41,127 terms, which represented 32,679
normalized strings. More than 80% of the terms submitted were wanted for parts of
the patient record related to the patient's condition. Following review, 58% of
all submitted terms had exact meaning matches in the controlled vocabularies in
the test, 41% had related concepts, and 1% were not found. Of the 28% of the
terms which were narrower in meaning than a concept in the controlled
vocabularies, 86% shared lexical items with the broader concept, but had
additional modification. The percentage of exact meanings matches varied by
specialty from 45% to 71%. Twenty-nine different vocabularies contained meanings
for some of the 23,837 terms (a maximum of 12,707 discrete concepts) with exact
meaning matches. Based on preliminary data and analysis, individual vocabularies
contained < 1% to 63% of the terms and < 1% to 54% of the concepts. Only SNOMED
International and the Read Codes had more than 60% of the terms and more than 50%
of the concepts. CONCLUSIONS: The combination of existing controlled vocabularies
included in the test represents the meanings of the majority of the terminology
needed to record patient conditions, providing substantially more exact matches
than any individual vocabulary in the set. From a technical and organizational
perspective, the test was successful and should serve as a useful model, both for
distributed input to the enhancement of controlled vocabularies and for other
kinds of collaborative informatics research.
PMID- 9391937
TI - Q-methodology: definition and application in health care informatics.
AB - OBJECTIVE: To introduce the Q-methodology research technique to the field of
health informatics. Q-methodology--the systematic study of subjectivity--was used
to identify and categorize the opinions of primary care physicians and medical
students that contributed to our understanding of their reasons for acceptance of
and/or resistance to adapting information technologies in the health care
workplace. DESIGN: Thirty-four physicians and 25 medical students from the
Chicago area were surveyed and asked to rank-order 30 opinion statements about
information technologies within the health care workplace. The Q-methodology
research technique was employed to structure an opinion typology from their rank
ordered statements. (The rank-ordered sorts were subjected to correlation and by
person factor analysis to obtain groupings of participants who sorted the opinion
statements into similar arrangements.) RESULTS: The typology for this study
revealed groupings of similar opinion-types associated with the likelihood of
physicians and medical students to adapt information technology into their health
care workplace. A typology of six opinions was identified in the following
groups: (1) Full-Range Adopters; (2) Skills-Concerned Adopters; (3) Technology
Critical Adopters; (4) Independently-Minded and Concerned; (5) Inexperienced and
Worried; and (6) Business-Minded and Adaptive. It is imperative to understand
that in the application of Q-methodology, the domain is subjectivity and research
is performed on small samples. The methodology is a combination of qualitative
and quantitative research techniques that reveals dimensions of subjective
phenomena from a perspective intrinsic to the individual to determine what is
statistically different about the dimensions and to identify characteristics of
individuals who share common viewpoints. Low response rates do not bias Q
methodology because the primary purpose is to identify a typology, not to test
the typology's proportional distribution within the larger population.
CONCLUSION: Q-methodology can allow for the simultaneous study of objective and
subjective issues to determine an individual's opinion and forecast their
likeliness to adapt information technologies in the health care workplace. This
study suggests that an organization's system implementers could employ Q
methodology to individualize and customize their approach to understanding the
personality complexities of physicians in their organization and their
willingness to adapt and utilize information technologies within the workplace.
PMID- 9391938
TI - Automated evidence-based critiquing of orders for abdominal radiographs: impact
on utilization and appropriateness.
AB - OBJECTIVE: Inappropriate utilization of diagnostic testing has been well
documented. The purpose of this study was to measure the impact of presenting
real time, evidence-based critiques about the appropriateness of abdominal
radiograph (KUB) orders on physician decision making. DESIGN: Prospective trial
where evidence-based critiques were presented to ordering clinicians in two kinds
of situations: (1) a KUB was likely to have a low probability of providing useful
information, or (2) an alternative view(s) was more appropriate given the
clinical circumstance. There were two phases of the trial: Phase 1 was a 9-week
period where evidence-based critiques were presented at the time of ordering a
KUB, followed by Phase 2, a 19-week period in which orderers were randomized to
receive critiques either amended to include both institutional data regarding the
utility of the critiques and stronger messages about the lack of utility of the
study, or the same critiques as presented in Phase 1, depending upon indication.
Based upon the radiologist's report of their interpretation of the exams, the
results of the examinations were scored as positive, equivocal, or negative using
structured criteria. RESULTS: 299 KUBs in Phase 1 and 385 KUBs in Phase 2
received at least one critique. Cancellation rates of low yield films were low,
and were similar in Phase 1 and 2, 8/258 (3%) vs. 10/283 (4%). Compliance with
the recommendation for alternative view(s) was higher: 19/104 (38%) in Phase 1
vs. 96/176 (55%) in Phase 2 (p = 0.006). The results differentiated low-yield
from non-low-yield films: 5% of low-yield films vs. 20% of non-low-yield films
were positive in Phase 2 (p < 0.0001). Surgical physicians were less likely to
cancel (p = 0.07) or to change to the suggested view(s) (p < 0.0001) than medical
physicians or nurses. CONCLUSIONS: The intervention identified clinical
situations in which KUBs appeared to have a low clinical yield. In response to
evidence-based critiques, providers were reluctant to cancel their order, but
were more willing to change to different views. To reduce the number of
inappropriate radiographic films, stronger incentives or interventions may be
required.
PMID- 9391939
TI - Information technology in the community: the right tools for the job.
PMID- 9391940
TI - Complex PTSD in victims exposed to sexual and physical abuse: results from the
DSM-IV Field Trial for Posttraumatic Stress Disorder.
AB - Two hundred thirty four participants in the DSM-IV Posttraumatic Stress Disorder
(PTSD) Field Trial who reported sexual and/or physical abuse were evaluated.
Participants were categorized according to type of abuse (physical, sexual,
both), duration of abuse (acute versus chronic), and onset of abuse (early versus
late). Separate logistic regression analyses examined the relationship between
age of onset, duration, abuse type, and the complex PTSD (CP) lifetime diagnosis
for women and men. Sexually abused women, especially those who also experienced
physical abuse, had a higher risk of developing CP, although CP symptoms occurred
at a high base rate among physically abused women. The theoretical implications
and incremental clinical usefulness of targeting CP symptoms with abused
populations are discussed.
PMID- 9391941
TI - Adult memories of childhood trauma: a naturalistic clinical study.
AB - The clinical evaluations of 77 adult psychiatric outpatients reporting memories
of childhood trauma were reviewed. A majority of patients reported some degree of
continuous recall. Roughly half (53%) said they had never forgotten the traumatic
events. Two smaller groups described a mixture of continuous and delayed recall
(17%) or a period of complete amnesia followed by delayed recall (16%). Patients
with and without delayed recall did not differ significantly in the proportions
reporting corroboration of their memories from other sources. Idiosyncratic,
trauma-specific reminders and recent life crises were most commonly cited as
precipitants to delayed recall. A previous psychotherapy was cited as a factor in
a minority (28%) of cases. By contrast, intrusion of new memories after a period
of amnesia was frequently cited as a factor leading to the decision to seek
psychotherapy. The implications of these findings are discussed with respect to
the role of psychotherapy in the process of recovering traumatic memories.
PMID- 9391942
TI - Predicting PTSD in women with a history of childhood rape.
AB - The impact of factors that predispose childhood rape victims to develop
posttraumatic stress disorder (PTSD) is important in understanding both the
impact of childhood rape and the development of PTSD as a psychological disorder.
The present study attempted to determine which crime, perpetrator, victim, and
aftermath characteristics are related to PTSD status. A national representative
sample of women (N = 3,220) were interviewed about their history of rape, trauma
related variables, and PTSD status. Consistent with research on crime victims,
life threat and physical injury discriminated PTSD status in a sample of
childhood rape victims. In addition, two other domains were related to PTSD
development: (1) testification about rape and (2) rape types. The present
findings are discussed in relation to previous research.
PMID- 9391943
TI - The process in psychological debriefings.
AB - Critical Incident Stress Debriefings have become an intervention method used in
various cultures, countries and groups following critical incidents. Although the
structure of such meetings has been adequately described, utilization of the
group processes involved has received less attention. A model, process debriefing
(PD), based on experiences from Europe, is presented. Some differences between
the current CISD process in the United States and the Europe based model are
outlined. Various factors that impact the process of debriefings are discussed
with a special emphasis on leadership, and implications of these group process
variables for psychological debriefing are presented. It is emphasized that the
continued exploration and discussion of process issues is critical to advance the
understanding of the critical elements of debriefing.
PMID- 9391944
TI - Predictors of emotional numbing in posttraumatic stress disorder.
AB - Little is known about the mechanisms underlying emotional numbing (EN). The
functional relationship between other classes of posttraumatic stress disorder
(PTSD) symptoms and EN is also not well understood. In the present study, we
examined the statistical predictors of EN. We hypothesized that the severity of
EN would be most strongly associated with the hyperarousal symptoms rather than
the avoidance symptoms of PTSD, or comorbid depression or substance abuse. This
prediction was derived from psychological and biological models that posit EN to
be a product of the depletion of emotional resources subsequent to chronic
hyperarousal. Using hierarchical multiple regression in two separate samples of
Vietnam combat veterans, we found hyperarousal symptoms to be the most robust
predictor of EN. These data suggest that there is a substantive relationship
between hyperarousal symptoms and EN in PTSD.
PMID- 9391946
TI - Attentional bias in posttraumatic stress disorder.
AB - This study investigated preferential encoding of threat material in subjects with
posttraumatic stress disorder (PTSD) with a modified dot-probe paradigm. This
paradigm indexes attentional bias by measuring response latency to name neutral
target words that are presented adjacent to or distant from threat words. Motor
vehicle accident survivors with PTSD (n = 15), subclinical PTSD (n = 15), and low
anxiety (n = 15) were required to name target words that were presented either
adjacent to or distant from strong threat, mild threat, positive, and neutral
words. PTSD subjects named targets faster when they were in close proximity to
mild threat words. Results suggested that PTSD subjects' attention was drawn to
the mild threat stimuli and are discussed in the context of network models of
PTSD.
PMID- 9391945
TI - Prolonged trauma and subsequent suicidal behavior: child abuse and combat trauma
reviewed.
AB - Stressful events have long been acknowledged as important risk factors for
suicidal behavior. Although suicide research has generally focused on less severe
stressful events, a long-standing vulnerability for suicidal behavior may be a
sequela of prolonged traumatic stressors. The present paper discusses the
relationship between prolonged traumatic stress and subsequent suicidality by
reviewing studies that have examined suicidal behavior in relationship to child
abuse and combat trauma. Traumatic stress is conceptualized according to a person
environment interactional paradigm, and this paradigm is used to discuss the
characteristics of traumatic events, recovery environments, and individuals that
may contribute to subsequent suicidality.
PMID- 9391947
TI - Replication and extension of a risk profile for Amerasian youth.
AB - The relationship between number of risk factors and symptoms of anxiety and
depression was examined in a cohort of Vietnamese Amerasians, replicating a study
done with a previous cohort. One hundred forty seven subjects awaiting U.S.
placement completed the Hopkins Symptom Checklist, the Vietnamese Depression
Scale, and a questionnaire which included items found to be risk factors for
psychological distress among Amerasians. Number of risk factors was linearly
related to symptoms of both depression and anxiety. Results are consistent with
previous findings of the relationship between risk factors and symptoms of
psychological distress. The profile may be helpful in anticipating which refugees
may be at risk for future psychological distress, and thus be useful in
preventively allocating scarce treatment resources.
PMID- 9391948
TI - Time-limited psychotherapy with Operation Desert Storm veterans.
AB - Time-limited psychotherapy conducted 2 to 9 months after demobilization was
evaluated with Persian Gulf Theater veterans of Operation Desert Storm (ODS).
Thirty five treatment-seeking veterans were contrasted with 20 non-treatment
seeking ODS Persian Gulf veterans in a repeated measures design at pretest,
posttest, and 6-week followup assessments. In addition, psychotherapy
participants at followup were contrasted with 80 non-treatment-seeking ODS
Persian Gulf veterans from the same military units who were assessed one time at
a comparable time point. Time-limited psychotherapy was associated with sustained
improved psychosocial functioning and reduced levels of psychiatric and stress
related symptomatology.
PMID- 9391949
TI - An empirical evaluation of eye movement desensitization and reprocessing (EMDR)
with survivors of a natural disaster.
AB - Controlled studies of treatments effective with victims of natural disasters are
almost nonexistent. This is a small study conducted under difficult conditions to
test the effectiveness of Eye Movement Desensitization and Reprocessing (EMDR) in
treating trauma related reactions following Hurricane Andrew. The results were
positive in that EMDR produced significant improvement over wait list controls in
perceived posttraumatic avoidance behaviors and thoughts as measured by changes
in the Impact of Event Scale and significant improvement in subjective aversive
reactions to representative experiences of the hurricane. These results suggest
and support other studies that EMDR can be an effective therapeutic intervention
for trauma reactions.
PMID- 9391950
TI - Measurement of perceived disruption during rebuilding following Hurricane Andrew.
AB - The purpose of this study was to develop and evaluate a measure of perceived
disruption during rebuilding following a disaster. Two eight-item scales, which
measured intensity of disruption during the entire repair phase (Intensity-RP)
and intensity of disruption during the past month (Intensity-PM) were developed
and administered to 135 survivors of Hurricane Andrew. At 9 to 12 months
postdisaster, Intensity-RP and Intensity-PM were both significantly associated
with scores on the Global Severity Index of the SCL-90-R, and with scores on the
Impact of Event-Intrusion Scale; Intensity-PM alone was significantly associated
with PTSD scores. Regression analyses indicated that each scale contributed
significant unique variance in predicting mental health symptoms, even after
controlling for relevant demographic and initial disaster exposure variables.
PMID- 9391951
TI - Frequency and severity of panic attack symptoms in a treatment seeking sample of
trauma victims.
AB - This study assessed the frequency and severity of panic attack symptoms and panic
attacks that develop in relation to the experience of traumatic events in 62
subjects seeking treatment for trauma-related symptomatology. Results indicated a
high incidence of panic attacks (69%). Many individuals also thought they were
going crazy or losing control (72%) or having a heart attack (38%) within the 2
weeks prior to assessment. These findings indicate that similar to panic
disordered patients, many trauma victims with posttraumatic stress disorder
(PTSD) not only experience physiological symptoms of panic, but are also fearful
of these symptoms.
PMID- 9391952
TI - Antidepressant treatment, posttraumatic stress disorder, survivor guilt, and
spiritual awakening.
AB - A patient with posttraumatic stress disorder (PTSD) had a major depressive
episode that was responsive to treatment with the antidepressant fluoxetine. In
contrast to the remission of other symptoms of depression, the associated feature
of survivor guilt became more dramatically obvious. Individualized treatment of
survivor guilt may be needed for patients with PTSD and major depression.
PMID- 9391953
TI - Perspectives on the diagnosis, epizootiology, and control of the 1973 duck plague
epizootic in wild waterfowl at Lake Andes, South Dakota.
AB - An epizootic of duck plague occurred in early 1973 in a population of 163,500
wild waterfowl, primarily mallards (Anas platyrhynchos), wintering on Lake Andes
and the nearby Missouri River in southeastern South Dakota (USA). The diagnosis
was based on pathologic lesions and confirmed by virus isolation. Control
measures included quarantine, attempts to reduce virus contamination of the area,
dispersal of waterfowl, and monitoring of wild waterfowl populations for
mortality. The epizootic resulted in documented mortality of 18% and estimated
mortality of 26% of the waterfowl at risk. Prompt implementation of control
measures might have limited mortality to approximately 8%. Losses during the
epizootic were equivalent to 0.12% of the annual mortality in the North American
1996 fall population of 80,000,000 wild ducks. The most likely sources of the
infection were free-flying wild mallard or American black duck (Anas rubripes)
carriers from the upper midwestern or northeastern United States. Duck plague
serum neutralization antibodies were demonstrated in 31% of 395 apparently
healthy mallards sampled prior to dispersal of the flock at Lake Andes,
suggesting that tens of thousands of potential duck plague carriers entered the
wild waterfowl populations of all four major flyways. Consequently, the absence
of major epizootics of duck plague in wild waterfowl in the subsequent two
decades is evidence that substantial numbers of duck plague carriers can occur in
wild waterfowl populations without resulting in epizootic mortalities. The
failure to isolate duck plague virus from apparently healthy mallards sampled
during the epizootic raises questions concerning the validity of conclusions
regarding the status of duck plague in wild waterfowl based upon negative results
of random surveys conducted in the absence of epizootics.
PMID- 9391954
TI - Dynamics of plague in a Gunnison's prairie dog colony complex from New Mexico.
AB - A plague (Yersinia pestis) epizootic spread through Gunnison's prairie dogs
(Cynomys gunnisoni), and possibly other rodent species, in the Moreno Valley in
north-central New Mexico between winter 1984-1985 and autumn 1987. We observed
the progress of the epizootic and subsequent population recovery at four prairie
dog towns within the valley during this period. At two towns (Midlake and Val
Verde) the prairie dogs were marked prior to the epizootic. At two additional
towns (Vega and South Entrance) prairie dogs were marked following the epizootic.
In 1988, a second epizootic occurred at Vega. One hundred thirty-nine serum
samples were collected from prairie dogs and other rodents and 1,750 fleas were
collected from animals and burrows. Fleas infected with Y. pestis were collected
from prairie dogs, deer mice (Peromyscus maniculatus), and thirteen-lined ground
squirrels (Spermophilus tridecemlineatus). Prairie dog fleas included Oropsylla
hirsuta, O. labis and O. tuberculata, deermouse associated fleas were Aetheca
wagneri and Rhadinopsylla sectilis, and Oropsylla bacchi was associated with
thirteen-lined ground squirrels. All of the above flea species were collected
from prairie dog burrows. All rodent species shared some flea species. Thirteen
lined ground squirrels disappeared shortly before plague was identified in
prairie dogs at Midlake. Meadow voles were rare following the epizootic at Vega
in 1986, became abundant in 1987, and disappeared at the time of the second
prairie dog epizootic in summer 1988. Although we collected serum from Gunnison's
prairie dogs, thirteen-lined ground squirrels, deer mice, and meadow voles
(Microtus pennsylvanicus), we identified elevated serum titers against Y. pestis
only in Gunnison's prairie dogs. Prairie dog mortality at all towns affected by
plague was in excess of 99%. Serum antibody titers indicate that more than 40% of
the few prairie dogs left to establish colonies following epizootics survived
plague infection.
PMID- 9391955
TI - Plague in a complex of white-tailed prairie dogs and associated small mammals in
Wyoming.
AB - Fleas were collected from white-tailed prairie dogs (Cynomys leucurus) and other
small mammals trapped on six grids during a field study near Meeteetse (Wyoming,
USA) in 1989 and 1990 to investigate the dynamics of plague in this rodent
population. Fleas were identified and tested for Yersinia pestis by mouse
inoculation. Yersinia pestis-positive fleas were found on prairie dogs and in
their burrows. Flea species on prairie dogs changed from spring to late summer.
White-tailed prairie dog numbers were significantly lower in the presence of Y.
pestis-positive fleas; however, affected populations generally recovered 1 to 2
yr following absence of detectable plague. Grids where recovery occurred had a
high proportion of juvenile male prairie dogs. Eighteen flea species were
identified on small mammals, six of which were infected with Y. pestis. Some flea
species were associated with a particular small mammal species, while others were
found on a broad range of host species. Flea species most important in the
potential interchange of Y. pestis between associated small mammals and white
tailed prairie dogs were Oropsylla tuberculata cynomuris, Oropsylla idahoensis,
and Oropsylla labis. Plague cycled through the white-tailed prairie dog complex
in an unpredictable manner. Each summer the complex was a mixture of colonies
variously impacted by plague: some were declining, some were unaffected by
plague, and others were recovering from plague population declines. These data
provide insight into the dynamics of plague in white-tailed prairie dog
complexes, but predicting movement of plague is not yet possible and the role of
associated mammals in maintenance of plague is not understood.
PMID- 9391956
TI - Humoral immune response of cottontail rabbits naturally infected with Francisella
tularensis in southern Illinois.
AB - Cottontail rabbits (Sylvilagus floridanus) usually are thought to succumb to
infection with Francisella tularensis. Reports of a rabbit population from
southern Illinois (USA) with a high prevalence of F. tularensis antibodies
suggested that some cottontails survived infection with this typically fatal
bacterium. Our goal was to examine the humoral response of cottontails from a
study area in southern Illinois for which multiple serum samples existed.
Multiple sera were collected from 79 cottontails from 1986 to 1990 and 63%
gained, lost, or maintained ELISA titers of IgM and IgG isotype antibodies. The
typical pattern of antibody response appeared to be IgM isotype antibodies first,
followed by IgG isotype antibodies, with both generally increasing to high
titers. Negative culture attempts of liver tissue from 51 cottontails with
varying antibody responses suggested that chronic infection did not occur in
rabbits that developed antibody. The significance of the cottontail antibody
response in resolution or prevention of tularemia infection remains unclear.
PMID- 9391957
TI - Evaluation of a multivalent Pasteurella haemolytica vaccine in bighorn sheep:
safety and serologic responses.
AB - We examined effects of a multivalent Pasteurella haemolytica vaccine (serotypes
A1, A2, T10) on humoral immune responses and P. haemolytica isolation rates in
bighorn sheep (Ovis canadensis). Thirty captive bighorns, divided into groups of
three on the basis of age, sex, and previous history of pneumonic pasteurellosis,
received 0, 1, or 2 vaccine doses. Mild, transient lameness in most bighorns 1
day after initial vaccination was the only adverse effect observed. Oropharyngeal
(> or = 75%) and nasal (< or = 50%) isolation rates for P. haemolytica did not
differ among treatment groups. Ten of 36 distinguishable biogroup variants
accounted for about 87% of the 464 P. haemolytica isolates from bighorns, but
prevalences of specific biogroups were not affected by vaccination. Bighorns
receiving 1 or 2 vaccine doses showed marked elevations in leukotoxin
neutralizing antibody titers beginning 1 wk after vaccination. Agglutinating
antibody titers to serotype A1 and A2 surface antigens were also elevated in
vaccinated bighorns within 2 wk after vaccination; agglutinating antibody titers
to serotype T10 surface antigens were relatively high in all three groups but
appeared unaffected by vaccination. Vaccination 7 to 14 wk prior to parturition
elevated leukotoxin neutralizing antibody titers in colostrum, but neither
leukotoxin neutralizing nor serotype A1 surface antigen agglutinating antibody
titers differed through 16 wk of age among lambs born to dams from different
vaccine dose groups. Our data demonstrate that this multivalent P. haemolytica
vaccine is safe and stimulates marked antibody responses in bighorn sheep.
Further evaluation of this vaccine as a tool in preventing and managing
pasteurellosis in bighorn sheep appears warranted.
PMID- 9391958
TI - Bovine tuberculosis in free-ranging white-tailed deer from Michigan.
AB - A 4.5 yr-old male white-tailed deer (Odocoileus virginianus) killed by a hunter
during the 1994 firearm hunting season in northeastern Michigan (USA) had lesions
suggestive of tuberculosis and was positive on culture for Mycobacterium bovis
the causative agent for bovine tuberculosis. Subsequently, a survey of 354 hunter
harvested white-tailed deer for tuberculosis was conducted in this area from 15
November 1995 through 5 January 1996. Heads and/or lungs from deer were examined
grossly and microscopically for lesions suggestive of bovine tuberculosis. Gross
lesions suggestive of tuberculosis were seen in 15 deer. Tissues from 16 deer had
acid-fast bacilli on histological examination and in 12 cases mycobacterial
isolates from lymph nodes and/or lungs were identified as M. bovis. In addition,
lymph nodes from 12 deer (11 females and 1 male) without gross or microscopic
lesions were pooled into 1 sample from which M. bovis was cultured. Although more
male (9) than female (3) deer had bovine tuberculosis infections, this difference
was not statistically significant. Mycobacterium bovis culture positive deer
ranged in age from 1.5 to 5.5 yr with a mean of 2.7 yr (median 2.5 yr) for males
and 3.2 yr (median 3.5 yr) for females. This appears to be the first epidemic
occurrence of M. bovis in free-ranging cervids in North America. A combination of
environmental (high deer density and poor quality habit) and management-related
factors (extensive supplemental feeding) may be responsible for this epizootic.
PMID- 9391959
TI - Upper respiratory tract disease and mycoplasmosis in desert tortoises from
Nevada.
AB - A population of desert tortoises (Gopherus agassizii) at Yucca Mountain (Nevada,
USA) was monitored during four sampling periods using enzyme-linked immunosorbent
assays (ELISA) to determine the percentage of individuals that had been exposed
to Mycoplasma agassizii, a causative agent of upper respiratory tract disease.
Respiratory tract disease has been considered a significant factor in the decline
of desert tortoise populations in the Mojave Desert (USA). Few differences
between sexes in ELISA values or percentages testing positive were noted. From 15
to 23% of samples per period tested positive for exposure to the mycoplasma.
However, we noted few clinical signs of upper respiratory tract disease. This is
in contrast to an earlier study which reported a similar proportion of
seropositive tortoises as well as a high percentage of tortoises with clinical
signs. However, our results are consistent with that study's conclusion that
seropositivity for M. agassizii was a poor predictor of the likelihood to exhibit
clinical signs of upper respiratory tract disease. Earlier reported epizootics of
mycoplasma-associated respiratory disease occurred mainly during times of
drought. Our samples were collected during a period of average to above-average
rainfall, suggesting that manifestation of clinical signs of the disease may
depend upon the physiological condition of tortoises which, in turn, is related
to environmental conditions.
PMID- 9391960
TI - Duration of Borrelia burgdorferi infectivity in white-footed mice for the tick
vector Ixodes scapularis under laboratory and field conditions in Ontario.
AB - The duration of Borrelia burgdorferi infectivity in white-footed mice (Peromyscus
leucopus) experimentally inoculated or infested with infected Ixodes scapularis
nymphs was evaluated. Infectivity was assessed by infesting these mice with unfed
I. scapularis larvae at 7, 21, 35 and 49 days post-inoculation (DPI) or post
infestation (PI). At 7 DPI, B. burgdorferi was transmitted from 18 of 24 syringe
inoculated mice and all three tick-infected mice to I. scapularis larvae which
fed upon them. However, at 21, 35 and 49 DPI, significantly fewer mice were
infective. Borrelia burgdorferi was isolated from tissues of 14 of 22 syringe
inoculated mice about 56 DPI, and from all three tick-infected mice. However, the
level of agreement between xenodiagnosis and bacterial culture was no greater
than would be expected by chance alone. We also determined if B. burgdorferi
infectivity of mice varied in relation to periods of tick feeding in the field.
White-footed mice were trapped during April, July and August 1993 from two
habitats on Long Point peninsula (Ontario, Canada), where B. burgdorferi is
endemic. Mice from each habitat were infested with laboratory-reared I.
scapularis larvae. Ticks from each mouse were subsequently examined by
immunofluorescent assay for B. burgdorferi infection and mice were cultured for
B. burgdorferi. None of 3577 I. scapularis larvae fed on 62 mice captured within
the cottonwood dune habitat were infected with B. burgdorferi, although it was
isolated from six of these mice. Within the maple forest habitat, 0/24, 8/21
(38%) and 1/21 (5%) mice transmitted B. burgdorferi to I. scapularis larvae
during April, July and August, respectively. Most mice from the maple forest with
B. burgdorferi-positive tissues (14/21) were collected during July, although the
level of agreement between xenodiagnosis and tissue culture was poor. Because B.
burgdorferi infectivity in mice appears to be of short duration, overwintered I.
scapularis larvae and nymphs may have to feed upon infected hosts at the same
time of year in order for a cycle of B. burgdorferi infection to be maintained on
Long Point. Infected I. scapularis nymphs, rather than persistently infected
vertebrate hosts, likely serve as the overwintering "reservoir" for B.
burgdorferi on Long Point.
PMID- 9391961
TI - Vitreous humor analysis for selected biochemical parameters from cervids in
Idaho.
AB - Vitreous humor and liver samples were collected from hunter-harvested elk (Cervus
elaphus) and mule deer (Odocoileus hemionus) in Idaho (USA). Concentrations of
calcium, chloride, potassium, sodium, urea nitrogen and selenium were determined
and evaluated according to species, age, gender, geographic location, and time
elapsed following death. Vitreous humor analysis yielded reliable biochemical
information for < or = 96 hr subsequent to the death of the animal. Vitreous
potassium concentration changes over time could be used to estimate the time that
elapsed following death.
PMID- 9391963
TI - Effects of sex, age, capturing method, and season on serum chemistry values of
brown bears in Croatia.
AB - Sixty seven serum samples collected from 43 European brown bears (Ursus arctos)
from Croatia were tested for < or = 31 serum chemistry parameters. Results were
grouped and compared by bears origin (method of capture), sex, age, mass, and
season sampled. Greatest differences were found between captive and free-living
bears, and minor differences were found when sex, age, mass, or season of
sampling were compared. Creatine kinase was significantly different among three
categories of bears with the highest mean value of 924 IU/l in snare captured
free-living bears compared to 67.8 IU/l in captive ones. Results of these tests
provide reference values for European brown bears.
PMID- 9391962
TI - Hematologic and serum biochemical reference intervals for Florida panthers.
AB - Ninety-four blood samples were collected from 48 (29 males and 19 females) free
ranging Florida panthers (Felis concolor coryi) captured in southern Florida
(USA) from 1983 to 1994 for routine hematological and serum biochemical analysis.
Florida panthers in the northern portion of their range had significantly higher
red blood cell (mean +/- SD = 7.923 x 10(6) +/- 0.854 x 10(6)/microliter),
hemoglobin (12.53 +/- 1.66 g/dl), and packed cell volume (36.97 +/- 4.27%) values
compared to those of panthers localized in more southern parts of Florida (7.148
x 10(6) +/- 1.045 x 10(6)/microliter, 11.60 +/- 1.62 g/dl, and 34.82 +/- 5.99%,
respectively). Adults had significantly higher mean serum total protein (7.50 +/-
0.59 g/dl) and packed cell volume (36.90 +/- 4.97%) values than juveniles (6.88
+/- 0.49 g/dl and 34.54 +/- 5.30%). However, mean serum albumin concentrations
were significantly higher in juveniles (3.80 +/- 0.26 g/dl) when compared to
adult values (3.58 +/- 0.26 g/dl). Mean serum calcium concentrations were
significantly higher in juveniles (10.33 +/- 0.39 mg/dl) than in adults (9.66 +/-
0.45 mg/dl). Additionally, mean serum iron concentrations were significantly
higher in those panthers of intergrade genetic stock compared to values in those
of authentic genetic stock (105.6 +/- 72.1 micrograms/dl versus 59.3 +/- 19.7
micrograms/dl, respectively).
PMID- 9391964
TI - Immobilization of wild collared anteaters with ketamine- and xylazine
hydrochloride.
AB - Collared anteaters (Tamandua tetradactyla) were immobilized for clinical
procedures as part of a wildlife rescue during the filling of a hydroelectric dam
(Petit Saut, French Guiana) from March 1994 to March 1995. Two doses of ketamine
hydrochloride (KH) (group I mean +/- SD = 11.2 +/- 1.4 mg/kg, group II = 19.7 +/-
1.3 mg/kg) in combination with xylazine hydrochloride (XH) (1.0 +/- 0.1 mg/kg)
were evaluated in seven and 10 collared anteaters, respectively. Induction time
did not differ between the two groups. Immobilization time was significantly
longer in group II than in group I (48.3 +/- 15.8 min and 35.0 +/- 9.5 min,
respectively), without lengthening the recovery process. Adverse effects were not
observed. The degree of anesthesia and the muscle relaxation were better in group
II than in group I. Rectal temperature decreased in both groups and was
significantly higher in group II than in group I. Heart rate was significantly
higher in group II than in group I at 5 min post-injection and decreased in group
II. No effects on respiratory rate were observed. We recommend the 20 mg/kg KH -1
mg/kg XH combination, especially for manipulations longer than 30 to 40 min and
for minor surgery procedures.
PMID- 9391965
TI - Experimental adenovirus hemorrhagic disease in yearling black-tailed deer.
AB - An apparently novel adenovirus was associated with an epizootic of hemorrhagic
disease that is believed to have killed thousands of mule deer (Odocoileus
hemionus) in California (USA) during 1993-1994. A systemic vasculitis with
pulmonary edema and hemorrhagic enteropathy or a localized vasculitis associated
with necrotizing stomatitis/pharyngitis/glossitis or osteomyelitis of the jaw
were common necropsy findings in animals that died during this epizootic. Six
black-tailed yearling deer (O. hemionus columbianus) were inoculated with
purified adenovirus isolated from a black-tailed fawn that died of acute
adenovirus hemorrhagic disease during the epizootic. Three of six inoculated deer
also received intramuscular injections of dexamethasone sodium phosphate every 3
days during the study. Eight days post-inoculation, one deer (without
dexamethasone) developed bloody diarrhea and died. Necropsy and histopathologic
findings were identical to lesions in free-ranging animals that died of the
natural disease. Hemorrhagic enteropathy and pulmonary edema were the significant
necropsy findings and there was microscopic vascular damage and endothelial
intranuclear inclusion bodies in the vessels of the intestines and lungs.
Adenovirus was identified in necrotic endothelial cells in the lungs by
fluorescent antibody staining, immunohistochemistry and by transmission electron
microscopy. Adenovirus was reisolated from tissues of the animal that died of
experimental adenovirus hemorrhagic disease. Similar gross and microscopic
lesions were absent in four of six adenovirus-inoculated deer and in the negative
control animal which were necropsied at variable intervals during the 14 wk
study. One deer was inoculated with purified adenovirus a second time, 12 wk
after the first inoculation. Fifteen days after the second inoculation, this deer
developed severe ulceration of the tongue, pharynx and rumen and necrotizing
osteomyelitis of the mandible which was associated with vasculitis and thrombosis
of adjacent large vessels and endothelial intranuclear inclusions. Transmission
electron microscopy demonstrated adenovirus within the nuclei of vascular cells
and immunohistochemistry demonstrated adenovirus antigen within tonsilar
epithelium and in rare vessels.
PMID- 9391966
TI - Antibodies against equine herpesviruses in free-ranging mountain zebras from
Namibia.
AB - Twenty-one blood samples of free-ranging mountain zebras (Equus zebra) from
Namibia were tested for equine herpesvirus (EHV-1, -2, -3, -4) specific
antibodies by immunofluorescence assay (IFA) and neutralization test (NT).
Additionally, type-specific nested polymerase chain reactions (nested PCR) were
employed for detection of EHV-1, -2 and -4 DNA. Equine herpesvirus-1 antibodies
were detected by IFA in all zebras, while only seven serum samples contained EHV
4 IFA antibodies. Sera with high IFA antibodies also were found to neutralize EHV
1 and -4. Furthermore, 20 zebras were EHV-2 seropositive by IFA, and one zebra
had EHV-2 neutralizing antibodies. Equine herpesvirus-3 specific antibodies were
not detected. We did not amplify EHV-1, -2 or -4 specific DNA sequences in
peripheral blood leukocytes of the same zebras using type-specific nested PCR.
EHV infections appear to be widespread in free-ranging zebras, as they are in
domestic horses.
PMID- 9391967
TI - A small-scale survey of hantavirus in mammals from Indiana.
AB - In order to determine if hantaviruses were present in mice and other small
mammals in Indiana (USA), small mammals were trapped in Brown, LaPorte,
Tippecanoe and Whitley counties. Sixty-seven small mammals were trapped during
August and September 1994. Sixty-three Peromyscus leucopus, one Microtus
pennsylvanicus, one Zapus hudsonius and two Blarina brevicauda were captured and
tested for hantaviruses. Six P. leucopus were found to have antibody to Sin
Nombre virus (SN) by IgG ELISA, and a 139 bp fragment of SN-like hantavirus was
amplified from five of them. All six of the positive P. leucopus were from
LaPorte County. No other small mammals had evidence of infection with SN virus.
This study presents the first report of Sin Nombre-like hantavirus in P. leucopus
from Indiana.
PMID- 9391968
TI - Serosurvey for selected viral diseases and demography of African wild dogs in
Tanzania.
AB - African wild dogs (Lycaon pictus) are endangered, with only 3,000-5,000 remaining
in the wild. It is believed that wild dogs are unusually vulnerable to viral
diseases, particularly rabies and canine distemper (CDV). However, canine
distemper has been confirmed by laboratory diagnosis in only one free-living wild
dog. The 43,000 km2 Selous Game Reserve (SGR; Tanzania) holds approximately 900
adult wild dogs. In a study area of 2,600 km2, the population maintained high
density (> or = 1 dog/20.5 km2) from 1991 to 1996. The population was stable,
varying 18% below and 9% above the mean density over the 6-yr period. Serum
samples (n = 22) collected over 3 yr showed that most individuals were exposed to
CDV (59%:95% confidence interval = 43-76% seropositive) and canine parvovirus
(68%:95% CI = 54-81% seropositive), although none were seropositive for rabies
(0%:95% CI = 0-17%). CDV titers were positively related to age, with no
seropositive dogs younger than 1.9 yr. At least five of 13 dogs positive for CDV
seroconverted during the study. Dogs with high CDV titers did not survive better
in the years after sampling (mean survival +/- SE for those that died = 638 +/-
92 days,). Variation in mean litter size was inversely related to CPV exposure in
the SGR and elsewhere. Annual mortality rates were low in comparison to other
populations for all age classes (pups: 31 +/- 8%, n = 127, yearlings: 22 +/- 10%,
n = 93, adults: 20 +/- 6%, n = 235). Annual mortality rates fluctuated little
between 1992 and 1996. These data show that wild dog populations, like those of
other canids, can remain stable and demographically healthy despite exposure to
CDV and CPV.
PMID- 9391969
TI - Winter mortality of common loons in Florida coastal waters.
AB - Diagnostic findings are presented for 434 common loons (Gavia immer) found sick
or dead on Florida beaches from 1970 through 1994, primarily during the months of
December to April. The most commonly recognized problem was an emaciation
syndrome (66%), followed by oiling (18%), aspergillosis (7%), trauma (5%) and
miscellaneous disease entities (1%). The cause-of-death for 3% of the birds was
not determined. Many of the carcasses examined (n = 173) were obtained during an
epizootic which occurred from January to March of 1983 in which more than 13,000
loons were estimated to have died. An emaciation syndrome, characterized by
severe atrophy of pectoral muscles, loss of body fat and hemorrhagic enteritis,
was the primary finding in this epizootic. It was postulated to have a complex
etiologic basis involving synergistic effects and energy costs of migration,
molting and replacement of flight feathers, food resource changes, salt-loading,
intestinal parasitism, environmental contaminants, and inclement weather.
PMID- 9391970
TI - Uncinariasis in northern fur seal and California sea lion pups from California.
AB - Northern fur seal (Callorhinus ursinus) (n = 25) and California sea lion
(Zalophus californianus) (n = 53) pups, found dead on rookeries on San Miguel
Island (California, USA), were examined for adult Uncinaria spp. Prevalence of
these nematodes was 96% in fur seal pups and 100% in sea lion pups. Mean
intensity of Uncinaria spp. per infected pup was 643 in fur seals and 1,284 in
sea lions. Eggs of Uncinaria spp. from dead sea lion pups underwent embryonation
in an incubator; development to the free-living third stage larva occurred within
the egg. This study provided some specific information on hookworm infections in
northern fur seal and California sea lion pups on San Miguel Island. High
prevalence rate of Uncinaria spp. in both species of pinnipeds was documented and
much higher numbers (2X) of hookworms were present in sea lion than fur seal
pups.
PMID- 9391971
TI - Ultrastructure of the cyst wall of Sarcocystis sp. in roe deer.
AB - Samples of heart, tongue, oesophagus and diaphragm muscle from twenty-two
naturally infected roe deer (Capreolus capreolus) harvested in central Italy were
examined for sarcosporidiasis. The structure of Sarcocystis spp. muscle cysts was
examined by light and electron microscopy. Only one type of thin-walled cyst was
distinguished by light microscopy. Electron microscopy showed cysts having a thin
highly folded primary cyst wall, without fibrillar material, that formed thin
hair-like protrusions often having a T-form, especially close to host cell
mithocondria. The cysts appeared to belong to a single Sarcocystis sp. so that
all the animals had monospecific infections. This cyst was compared with cysts
described in other cervid in an attempt to determine if single or multiple
species of the genus Sarcocystis occur in the Cervidae. Apparently, a single
Sarcocystis sp. with a low specificity for the intermediate host can infect the
Cervidae.
PMID- 9391972
TI - Sarcosporidiasis in rodents from Thailand.
AB - One to six Sarcocystis spp. were identified in the skeletal muscles of 41 (33%)
of 124 wild rodents (Rattus spp. and Bandicota indica) mainly captured in the
central plains of Thailand throughout the year in 1995. Included were S.
singaporensis, S. villivillosi, and S. murinotechis-like cysts all of which
showed a striated cyst wall at the light microscopical level, and Sarcocystis
cymruensis, S. sulawesiensis, and S. zamani which possessed smooth cyst walls.
The ultrastructure of the cyst wall and other morphological characteristics used
to distinguish species are described. By inoculation of muscle cysts from wild
caught rodents into coccidia-free pythons (Python reticulatus, P. molurus
bivittatus), we confirmed that P. reticulatus is a suitable definitive host for
S. singaporensis and S. zamani in Thailand. Furthermore, we showed by fecal
examination of reticulated pythons collected in the wild and subsequent
experimental infection of laboratory rats that these hosts also are naturally
infected with both species. Sarcocystis cymruensis is reported for the first time
from Southeast Asia. This parasite was prevalent in brown rats (Rattus
norvegicus) and bandicoot rats (B. indica) which were captured near human
habitations; it is likely to be transmitted to rats via cats. The definitive
hosts of S. sulawesiensis and S. murinotechis are unknown. Hence, at least three
Sarcocystis spp. (S. singaporensis, S. zamani, S. villivillosi) are likely to
cycle between snakes and rodents in agricultural areas in Thailand. Among these,
S. singaporensis appears to be the most prevalent species.
PMID- 9391973
TI - Extracting Protostrongylus spp. larvae from bighorn sheep feces.
AB - First-stage larvae of Protostrongylus spp. were more numerous in the core of
bighorn sheep (Ovis canadiensis canadiensis) pellets than near the surface. As a
result, only 22% could be extracted from whole pellets and the numbers collected
did not reflect the total number of larvae present in samples. Crushing semi
dried pellets yielded seven times as many larvae and numbers collected were
correlated with totals present. The use of tissue, in addition to a screen filter
in a beaker extraction method, produced a cleaner sample and did not affect
larval collection or the correlation. By comparison, most first-stage larvae of
Parelaphostrongylus tenuis from white-tailed deer (Odocoileus virginianus) were
near the surface of fecal pellets where they may be removed readily by water.
PMID- 9391974
TI - Filarial dermatitis in a striped skunk.
AB - A striped skunk (Mephitis mephitis) from Kansas (USA) with severe diffuse
dermatitis characterized by extensive alopecic areas, thickened skin, and
multiple, scattered cutaneous abscesses on the dorsal aspect of the head, neck,
and trunk was submitted for diagnostic evaluation. More than 50 nematodes
identified as Filaria taxideae were found in the dorsal subcutaneous tissue.
Histologic examination of the skin revealed multifocal pyogranulomatous
inflammation with intralesional larvated nematode eggs, moderate orthokeratotic
hyperkeratosis, and mild acanthosis. The lesions resemble those reported from
badgers (Taxidea taxus) and a lesser panda (Ailurus fulgens) with dermatitis
caused by Filaria taxideae. Although F. taxideae has been previously collected
from skunks, this is the first report of filarid dermatitis caused by this
nematode in a striped skunk.
PMID- 9391975
TI - Gnathostomiasis in frog-eating snakes from Japan.
AB - Gnathostoma doloresi parasitizes the gastric wall of wild (boars) and domestic
(pigs) swine (Sus scrofa). Its larvae cause cutaneous larva migrans in humans.
Amphibians, reptiles and a freshwater fish are infected with the advanced 3rd
stage larvae. Prevalence of G. doloresi larvae were surveyed in several snakes,
especially in a common frog-eating snake (Rhabdophis tigrinus). All species of
snakes examined were infected with G. doloresi larvae suggesting that snakes are
important reservoir hosts. Prevalence of G. doloresi larvae in frog-eating snakes
was lower than that found in mammal-eating snakes. Thus, as a source of infection
to snakes, small mammals may be more important than frogs in the natural life
cycle of G. doloresi in Japan.
PMID- 9391976
TI - Capillariasis in the trachea of a raccoon.
AB - Cross-sections of nematodes were seen in histologic sections of trachea from a
raccoon (Procyon lotor) collected in Virginia (USA); they occupied epithelium and
contained unembryonated, bioperculated eggs characteristic of the genus
Capillaria (= Eucoleus). A mild inflammatory cell infiltrate in the lamina
propria subjacent to the nematode was the only apparent host response. This is
the first report of capillariasis in the trachea of raccoons.
PMID- 9391977
TI - Fascioloidiasis in game-ranched elk from Montana.
AB - The distribution of Fascioloides magna in game-ranched elk and the potential for
spread of the parasite through movement of infected animals was examined in
Montana (USA). Fecal samples (n = 448) collected from captive elk on 29 game
ranches were examined for eggs of F. magna by fecal sedimentation. Eggs were
detected in elk on 5 ranches. This suggests that F. magna has been translocated
by infected game-ranched elk. The wide distribution of snail intermediate hosts
for F. magna in Montana indicates a potential to spread the parasite to other
captive cervids domestic livestock or free-ranging wildlife.
PMID- 9391978
TI - A trematode metacercaria causing gill cartilage proliferation in steelhead trout
from Oregon.
AB - Gills of steelhead trout (Oncorhynchus mykiss) held in liveboxes to detect the
presence of pathogens in the Willamette River (Oregon, USA) became heavily
infected with trematode metacercariae. The metacercariae encysted adjacent to the
cartilaginous rods of gill filaments and elicited a host response of cartilage
proliferation from the perichondrium. Although some hyperplasia of gill
epithelium and fusion of lamellae was apparent, the extent of damage to the
respiratory surface was apparently insufficient to cause trout mortality.
Morphological characteristics of the metacercariae did not allow precise
identification, but they suggested affinities to either the Heterophyidae or
Cryptogonimidae. Some heterophyids are known to cause proliferation of cartilage
in fish gills, while cryptogonimids are not. This is the first report of
trematode induced gill cartilage proliferation in steelhead trout.
PMID- 9391979
TI - Tetraphyllidean cysticerci in the peritoneal cavity of the common dolphin.
AB - Cysticerci of the cestodes Monorygma grimaldii and Phyllobothrium delphini were
encountered during necropsy of an adult common dolphin (Delphinus delphis) found
dead on the southeastern coast of Australia. Monorygma grimaldii cysticerci were
found within highly organized retroperitoneal cysts, whereas P. delphini
cysticerci in the subcutaneous blubber did not occupy specialized structures.
There was a localized lymphoplasmacytic host response to the presence of
cysticerci of both species, but M. grimaldii provoked a more severe suppurative
response than P. delphini. The systematics and life history of both parasites are
incompletely known, but sharks postulated as the potential definitive hosts are
found in the region. A unique cysticercus of M. grimaldii was found lying free in
the peritoneal cavity of this dolphin. Two rare records of M. grimaldii
cysticerci in pinnipeds from the literature include one case of aberrant
migration to the testis.
PMID- 9391980
TI - Toxoplasmosis in naturally infected deer from Brazil.
AB - Serum samples from 107 cervids were examined for Toxoplasma gondii antibodies
using indirect hemagglutination (IHA), indirect immunofluorescence (IFA), enzyme
linked immunosorbent assay (ELISA) and Dot-ELISA. Samples were obtained from 66
marsh deer (Blastocerus dichotomus) in the State of Sao Paulo (Brazil) and from
41 pampas deer (Ozotocerus bezoarticus) in the State of Goias (Brazil).
Antibodies to T. gondii were found in 23 (22%) of the deer, with 18 and 5
positive samples, respectively, for B. dichotomus and O. bezoarticus. The highest
prevalence of T. gondii antibodies were young adults (32%), following by adults
(27%) and fawns (13%). Only one serum sample (8%) from a newborn fawn was
positive in the serological tests. The convenience of the Dot-ELISA test is
obvious when compared with other serological tests for both laboratory or field
surveys, mainly due to its features of practicability and reagent stability.
PMID- 9391981
TI - Tick paralysis in a red wolf.
AB - A free-ranging male red wolf (Canis rufus) in North Carolina (USA), exhibiting
paresis, anorexia and heavy tick infection was diagnosed with tick paralysis. The
wolf recovered completely following the removal of all ticks. This is the first
record of tick paralysis in the red wolf.
PMID- 9391982
TI - Mucormycosis in a free-ranging green tree frog from Australia.
AB - Mucor amphibiorum is reported for the first time from a free-ranging native
amphibian, a green tree frog (Litoria caerulea) from Queensland, Australia. The
nasal cavity was largely replaced by granulomatous inflammatory tissue, and most
internal organs had nodular granulomas. Typical mother and daughter sphaerules of
M. amphibiorum occurred in these nodules which were due to granulomatous
inflammation as well as areas of more active mixed inflammation with necrosis.
Tissue homogenate from the spleen was inoculated into two cane toads (Bufo
marinus), and one toad became infected with M. amphibiorum.
PMID- 9391983
TI - Salmonella arizonae sepsis in a lynx.
AB - A 4.5-wk-old lynx (Felis lynx) was presented for necropsy with a history of poor
growth, mild diarrhea, anemia, and lethargy. The liver was enlarged and had a 7
mm long fracture that resulted in severe intraabdominal hemorrhage and death.
Microscopic lesions were indicative of severe ulcerative cystitis and septicemia.
Pure cultures of Salmonella arizonae were isolated from the liver, kidney, and
spleen. Based on differences in the chronicity of inflammation in the urinary
bladder versus other organs, we speculate that chronic cystitis caused by S
arizonae lead to septicemic infection.
PMID- 9391984
TI - Rabies virus in the decomposed brain of an Ethiopian wolf detected by nested
reverse transcription-polymerase chain reaction.
AB - Approximately 75 individuals from a population of 111 Ethiopian wolves (Canis
simensis) died or disappeared from the Bale Mountains National Park (Ethiopia)
between 1988 and 1992 during two significant population declines. Confirmation of
rabies virus in two carcasses was based on the fluorescent antibody test (FAT)
and the mouse inoculation test (MIT). In an Ethiopian wolf brain previously
designated rabies negative by both FAT and MIT, rabies virus was identified by
nested reverse transcription-polymerase chain reaction (RT-PCR) and confirmed by
Southern blot hybridization. These methods were successfully used on a highly
decomposed brain sample which had been stored in 20% dimethyl sulfoxide. This
test system allows early and sensitive detection to be undertaken to more
effectively prevent spread of disease and thus protect surviving animals.
PMID- 9391985
TI - Pseudorabies in captive coyotes.
AB - Pseudorabies (Aujeszky's disease) was diagnosed in three adult captive coyotes
(Canis latrans) from southern Indiana (USA). The coyotes died in their outdoor
enclosure within a 48 hr period. Histopathology revealed multifocal,
nonsuppurative meningioencephalitis and eosinophilic intranuclear inclusion
bodies within neurons. Samples of brain were positive for pseudorabies virus by
fluorescent antibody testing and virus isolation. Source of infection was the
probable consumption of pseudorabies virus-infected pig carcasses.
PMID- 9391986
TI - Serological evidence of bovine herpesviruses 1 and 2 in Asian elephants.
AB - Antibodies were detected against bovine herpesviruses 1 (BHV 1) and 2 (BHV 2) in
Asian elephants (Elephas maximus) using the passive hemagglutination (PHA) test.
The study was conducted during May to December 1994 using sera collected from
zoological gardens and national parks in India. Four (4%) of 109 elephant sera
had PHA titers ranging from 1:8 to 1:32 against BHV 1. Twenty-five (23%) of the
109 elephant sera had PHA titers ranging from 1:8 to 1:64 against BHV 2. Asian
elephants appear to be better reservoirs for herpesviruses which are
serologically related to BHV 2.
PMID- 9391987
TI - A stingray spine in the scapula of a bottlenose dolphin.
AB - A stingray spine was found lodged in the scapula of a deceased 272 cm, male
bottlenose dolphin (Tursiops truncatus) from South Carolina (USA) following
skeletal preparation, nearly 6 mo after necropsy. No external puncture wound,
internal bruising, or laceration of muscle tissue surrounding the scapula was
evident during necropsy of the animal. Implantation of the spine did not appear
to be related to the death of the dolphin, but probably occurred at an early age.
Abnormal development of bone surrounding the spine resulted in the formation of a
cavity at the wound site. Two mechanisms were considered as contributors for the
cavity formation. These were the mechanical action of the spine stimulating the
body's defense system for managing foreign objects, and the release of potent
toxins from the spine sheath.
PMID- 9391988
TI - Epidermal tumors of rainbow smelt with associated virus.
AB - Epithelial tumors of the skin occurred in landlocked populations of rainbow smelt
(Osmerus mordax) in several lakes in New Hampshire (USA) during the spawning
runs. Histologically, these were noninvasive epithelial cell lesions. Herpesvirus
like particles could be seen in the nucleus and cytoplasm. The lesions occurred
in both males and females. Prevalence which varied annually, was as high as 30%.
PMID- 9391989
TI - Psychosocial factors associated with the use of hormonal replacement therapy in a
longitudinal follow-up of Swedish women.
AB - OBJECTIVES: To follow up a cohort of 1400 women aged 52 years who had replied to
a health questionnaire 4 years previously. The follow-up covered general and
gynecological health, experience of symptoms, the use of hormone replacement, the
reasons for starting HRT and effectiveness of treatment as well as comparison of
users and nonusers concerning psychosocial factors and life style. METHODS: A
questionnaire together with a letter was mailed to the women who had responded
previously. The questionnaire covered four different areas: sociodemographic
background, general and gynecological health, a 20-item symptom rating scale, and
questions concerning work role. RESULTS: A total of 1194 women (85%) responded to
the questionnaire; 40% of the women were currently using hormone replacement. The
reasons for starting treatment were: relief of somatic (55%) and psychological
symptoms (20%), increased wellbeing (5%), to prevent disease (5%) and other
reasons, such as keeping young (15%). Positive effects were experienced by 86%
and negative effects by 26%. Women using HRT had less frequent vasomotor
symptoms, sleep problems and vaginal dryness and were more harmonious than
nonusers. There were no differences between HRT users and nonusers regarding
negative mood and sexual desire. Women with psychologically demanding and
stressful jobs requiring concentration were more likely to use hormone
replacement. CONCLUSIONS: Swedish women are increasingly willing to start hormone
replacement, particularly those who suffer from vasomotor symptoms and who have
stressful and psychologically demanding occupations. The majority of these
experience relief of symptoms. A certain proportion will suffer from side effects
and are likely to discontinue treatment.
PMID- 9391991
TI - Menorrhagia--a search for epidemiological risk markers.
AB - OBJECTIVE: To isolate epidemiological risk factors for menorrhagia. METHODS:
Menstrual blood loss (MBL) of one bleeding episode of 182 healthy women was
measured with the alkaline hematin method and the results were related to age,
parity, body mass index and smoking habits. Multiple and logistic regression
analysis was performed to isolate the variables that most influence MBL. Two
consecutive menstrual episodes were measured in 117 women, to determine
individual constancy. RESULTS: MBL increased significantly with age (Kruskal
Wallis, P < 0.03) and the percentage of women with menorrhagia was significantly
higher above 40 years of age (Mann-Whitney's ranks sum test, P < 0.05). The odds
ratio of parous:nulliparous women for menorrhagia was 2.27:1, but after
adjustment for age this influence disappeared. Body mass index and smoking habits
were not significantly related to menorrhagia. The mean difference between the
MBL of two consecutive menstruations is 2.1 ml (S.E.: 1.7, 95% CI: -1.3 to 5.5
ml). CONCLUSIONS: Only age could be indicated as a risk marker for menorrhagia.
Parity, body mass index and smoking habits appear to have no significant effect
on MBL, when adjusted for age. The individual constancy in MBL between two
consecutive cycles is very high and therefore one single measurement suffices in
studies of MBL.
PMID- 9391990
TI - Comparison of the long-term effects of oral estriol with the effects of
conjugated estrogen, 1-alpha-hydroxyvitamin D3 and calcium lactate on vertebral
bone loss in early menopausal women.
AB - We investigated the long-term effects of oral estriol (E3) on bone mineral
density (BMD) at the lumbar spine and biochemical indices of bone turnover in
early menopausal women. We studied 64 healthy early menopausal women who were
treated for 24 months with 2.0 mg E3 plus 2.5 mg medroxyprogesterone acetate
daily (E3 group, n = 15), 0.625 mg of conjugated estrogen plus 2.5 mg
medroxyprogesterone acetate daily (CE group, n = 19), 1.0 microgram 1-alpha
hydroxyvitamin D3 daily (D3 group, n = 13), or 1.8 g calcium lactate containing
250 mg of elemental calcium daily (Ca group, n = 17). The BMD at the third lumbar
vertebra was determined by quantitative computed tomography, and serum levels of
osteocalcin (OC) and total alkaline phosphatase (Alp), as well as urinary ratios
of calcium-to-creatinine (Ca/Cr) and hydroxyproline-to-creatine (Hyp/Cr), were
evaluated at baseline and every 6 months. After 24 months of treatment, the BMD
decreased significantly by 12 +/- 4.5% (mean +/- S.E.) in the D3 group and 14 +/-
2.5% in the Ca group, but not in the E3 group (-4.1 +/- 4.8% from baseline) and
in the CE group (-0.9 +/- 3.2% from baseline). The serum levels of Alp and OC
decreased or remained unchanged in the E3 and CE groups, but increased in the D3
and Ca groups. The urinary Ca/Cr was decreased in the E3 and CE groups, but not
in the D3 and Ca groups. The urinary Hyp/Cr decreased in the CE group, was
unchanged in the E3 and D3 groups, and increased in the Ca group. Uterine
bleeding occurred less frequently in the E3 than in the CE group (2.4 +/- 4.2
versus 13.1 +/- 14.8 days/person per year, P < 0.001). The bone-preserving effect
of 2.0 mg of oral E3 was comparable to that of 0.625 mg of conjugated estrogen
and was superior to that of 1.0 microgram 1-alpha-hydroxyvitamin D3 and 1.8 g Ca.
Our findings suggest that a reduction in bone turnover in the E3 group may have
contributed to the preservation of bone.
PMID- 9391993
TI - Menopause in normal and uncomplicated NIDDM women: physical and emotional
symptoms and hormone profile.
AB - OBJECTIVE: To compare the physical characteristics, emotional symptoms and
metabolic conditions of menopausal women with and without non insulin dependent
diabetes mellitus (NIDDM). METHODS: We studied 100 menopausal women 45-72 years
of age, 51 with and 49 without NIDDM, in a cross-sectional design. Biological
characteristics were collected and emotional symptoms were assessed with a
modified Hamilton and Bech-Rafaelsen scale, scoring depression, anxiety, non
specific symptoms of depression (NSSD) and the empty nest syndrome (ENS). Weight,
body mass index (BMI), waist/hip and abdomen/hip ratios and percent of body fat
were registered. The sulfoconjugated form of the dehydroepiandrosterone (DHEAS),
follicle stimulating hormone (FSH), cortisol and fasting, as well as postprandial
insulin/glucose ratios, were measured in blood. RESULTS: Women with NIDDM had
earlier mean age for menopause, more central obesity and less peripheral fat;
they had also more prevalent emotional symptoms than non diabetic menopausal
women. In women with NIDDM, symptoms were associated with years since diagnosis
and with BMI. In non diabetic menopausal women schooling and attitudes to
sexuality were associated with symptoms. FSH was inversely associated with BMI in
both diabetic and non diabetic women; postprandial insulin/glucose ratio was
correlated with central obesity in the group without NIDDM and cortisol with
sitting systolic blood pressure (SBP) in the group with NIDDM. CONCLUSION: The
diagnosis of NIDDM and its metabolic conditions were associated with an increased
frequency of some symptoms in menopausal women.
PMID- 9391992
TI - Modulatory effects of a synthetic steroid (tibolone) and estradiol on spontaneous
and GH-RH-induced GH secretion in postmenopausal women.
AB - OBJECTIVE: Since hormonal replacement therapy (HRT) affects plasma GH levels, the
present study aimed to verify the effect of tibolone, a synthetic steroid, on
modulating spontaneous and growth hormone releasing hormone (GH-RH) induced GH
secretion. METHODS: Postmenopausal women (n = 30) were enrolled and randomly
subdivided in three groups (n = 10 each group): (1) treated with transdermal
estradiol (50 micrograms) (Dermestrill, Rottapharm, Monza, Italy) biweekly; (2)
treated with transdermal estradiol (100 micrograms) (Dermestrill, Rottapharm,
Monza, Italy) biweekly; (3) treated with tibolone 2.5 mg/day (Livial, Organon
Italia, Rome, Italy). Patients underwent a GH-RH test (1 microgram/kg) and 15 of
them underwent to a pulsatility study before and 5 weeks after treatment.
RESULTS: Mean (+ S.E.M.) GH plasma levels increased in all patients after any
type of HRT. GH response to GH-RH stimulation (expressed as maximal response to
GH-RH or as delta value) was similar in the three groups while significant
changes occurred in spontaneous pulsatile GH release. Tibolone and both dosages
of transdermal estradiol significantly reduced GH pulse frequency and increased
pulse amplitude. CONCLUSIONS: The reduced plasma GH levels observed during
postmenopause are probably related to a reduced endogenous GH-RH and not to a
reduced pituitary ability to respond to GH-RH. In addition tibolone, as well as
transdermal estradiol, are effective in restoring the spontaneous GH episodic
release.
PMID- 9391994
TI - The effect of postmenopause and postmenopausal HRT on measured voice values and
vocal symptoms.
AB - OBJECTIVES: To study the effect of postmenopause and postmenopausal hormone
replacement therapy (HRT) on the measured fundamental frequency (F0) and sound
pressure level (SPL) of sustained phonation and speaking voice samples and on
subjective vocal/laryngeal symptoms. METHODS: Forty-three postmenopausal women
(mean age 51.6) were divided into three groups: a group with no HRT, an estrogen
group (daily oral dose of 2 mg of estradiol valerate), and an estrogen-progestin
group (daily oral dose of 2 mg of 17-B-estradiol and 1 mg of northisterone
acetate). Voice measurements were made before and after 1 year of treatment.
Subjective symptoms were registered using a questionnaire. RESULTS: The mean F0
and SPL decreased significantly in the group with no HRT in spontaneous speech
and reading samples as did SPL in the normal phonation sample. In both groups
with HRT, the mean F0 decreased significantly only in the spontaneous speech
sample and the decrease was smaller than in the group with no HRT. The mean SPL
decrease in the estrogen group was significant in the normal phonation sample
while in the estrogen-progestin group it was significant in both the normal
phonation and the reading sample. The number of subjective symptoms was smallest
in the estrogen group. CONCLUSIONS: The changes in the measured voice values and
the subjective symptoms experienced suggest that at least the early
postmenopausal years are associated with vocal changes and that HRT counteracts
this phenomenon. This seems to be more pronounced with estrogen than with a
combination of estrogen and progestin.
PMID- 9391995
TI - Hormone replacement therapy and intraocular pressure.
AB - OBJECTIVES: To evaluate the effect of hormone replacement therapy (HRT) on
intraocular pressure (IOP) in menopausal women. METHODS: The IOP of 25 white
menopausal women without an abnormal ophthalmologic history was measured before
and during HRT regimen. IOP fluctations were recorded before and 1, 4, and 12
weeks after the beginning of HRT. These measurements were obtained according to a
standardized time schedule (08:00, 12:00, 16:00, and 19:00 h). RESULTS: The mean
IOP in the left eye decreased from 16.2 +/- 2.4 mmHg before therapy to 14.0 +/-
2.1 mmHg after 12 weeks of therapy (P < 0.001). In the right eye, whose IOP was
at 15.3 +/- 2.3 mmHg before therapy there was a decrease to 14.0 +/- 1.9 mmHg
after 12 weeks of therapy (P < 0.001). CONCLUSION: Hormone replacement therapy
has a positive effect on IOP in menopausal women.
PMID- 9391996
TI - Decrease of bone formation in adult women with fragility fractures.
AB - OBJECTIVES: To compare bone mineral density (BMD) and some markers of bone
metabolism in women with fragility fractures and in normal age-matched subjects.
METHODS: A 100 women with at least one vertebral deformity > 25%, and 219 age-,
BMI- and parity-matched healthy women, were recruited for the study. In all the
patients fractures were symptomatic and occurred at least 1 year before
densitometric measurement. Forearm bone mineral density (BMD) as well as
biochemical assessment of some markers of bone turnover were measured in all the
subjects. RESULTS: BMD was significantly lower in the fracture than in the
control group (0.326 +/- 0.073 vs. 0.379 +/- 0.079; P < 0.001). Fractured women
showed alkaline phosphatase (ALP) and osteocalcin (OC) serum levels significantly
lower than controls, while no differences were found in fasting urinary calcium
and hydroxyproline excretion. Women without fractures showed a significant
correlation between ALP and both age and years since menopause (YSM). Such a
correlation is lacking in the fracture group. CONCLUSIONS: Women with vertebral
deformities likely due to a fracture had a forearm BMD and markers of bone
formation lower than normal. Whether low bone density is due to a low peak of
bone mass or to an increased postmenopausal bone loss sustained by an uncoupling
between the two bone remodelling processes is still unclear.
PMID- 9391997
TI - Influence of weight and gonadal status on total and regional bone mineral content
and on weight-bearing and non-weight-bearing bones, measured by dual-energy X-ray
absosorptiometry.
AB - OBJECTIVE: To evaluate the influence of weight on total body bone mineral content
(BMCTB) and regional body bone mineral content (head, arms, trunk and legs). This
was studied in accordance with gonadal status and the weight-bearing or non
weight-bearing status of each region. METHODS: The study included 94
postmenopausal women (mean age 60.6 +/- 10.5 years), 36 perimenopausal women
(mean age 49.0 +/- 2.3 years) and 60 premenopausal women (mean age 36.1 +/- 6.9
years). Full-body bone densitometry (DXA), for measuring total body bone and
regional bone mineral content, was carried out in all the women. RESULTS: Among
these groups, the influence of 1 kg of body weight on total and regional bone
mineral content (percent) did not differ (paired test P ns). In the overall group
of women, paired comparison showed differences between the head and other zones
measured (P = 0.036-0.004). In the overall group of women, no differences were
found in the percent influence of 1 kg body weight on bone mineral content in any
study zone (by ANOVA, Fisher's PLSD post hoc test and the Kruskal-Wallis test).
In the overall group of women, Fisher's r to z test revealed a non-significant
relationship between weight and the bone mineral content of the head (r = 0.49, P
ns) but in every other region the relationship between weight and bone mineral
content was significant (r = 0.36-0.54, P < 0.0001 in all). CONCLUSIONS: The
effect of body weight on BMCTB and regional did not differ significantly with
either gonadal status or weight-bearing (legs) and non-weight-bearing bones
(arms).
PMID- 9391998
TI - Effects of combined low dose of the isoflavone derivative ipriflavone and
estrogen replacement on bone mineral density and metabolism in postmenopausal
women.
AB - OBJECTIVES: To assess the pattern of biochemical markers of bone metabolism and
vertebral bone mineral density in early postmenopausal women treated with
combined ipriflavone and low dose conjugated estrogens. METHODS: Bone biochemical
markers and vertebral bone density were evaluated in a longitudinal, comparative,
2 year study conducted in postmenopausal women treated with sole calcium
supplementation (500 mg/day), or with either ipriflavone (IP) at the standard
dose (600 mg/day) plus the same calcium dose, low dose conjugated estrogens (CE)
(0.3 mg/day) plus calcium, or low dose IP (400 mg/day) plus low dose CE (0.3
mg/day) plus calcium. The results were analyzed by repeated measures analysis of
variance, as appropriate. RESULTS: No modifications of both urinary excretion of
hydroxyproline and plasma osteocalcin levels were observed in calcium and in CE
treated women, while vertebral bone density significantly decreased (P < 0.0001)
in both groups. In IP or IP + CE-treated women, plasma osteocalcin did not show
any modification, while urinary hydroxyproline showed a significant (P < 0.05)
decrease, that paralleled a significant (P < 0.05) increase in vertebral bone
density. CONCLUSION: Postmenopausal IP administration, at the standard dose of
600 mg/day, can prevent the increase in bone turnover and the decrease in bone
density that follow ovarian failure. The same effect can be obtained with the
combined administration of low dose (400 mg/day) IP with low dose (0.3 mg/day)
CE.
PMID- 9391999
TI - Endometrial effects of three doses of trimegestone, a new orally active
progestogen, on the postmenopausal endometrium.
AB - OBJECTIVE: To study the effects of oral trimegestone on endometrial histology and
vaginal bleeding when given in combination with oral 17-beta-oestradiol. METHODS:
This was a prospective, randomised, double-blind, parallel groups, pilot
comparative study. Thirty-eight healthy postmenopausal women with normal
endometrial histology were given oral 17-beta-oestradiol, 2 mg/day for three
continuous cycles of 28 days, plus oral trimegestone, 0.10, 0.25 or 0.50 mg/day
from day 15 to day 28 of each cycle. A Vabra biopsy was performed late in the
oestradiol/trimegestone phase of cycle 3 and examined for histological evidence
of secretory transformation of the endometrium. Characteristics of vaginal
bleeding were recorded on a daily basis. RESULTS: Thirty-seven women completed
the study, of whom 31 yielded adequate tissue for histological assessment. All
showed secretory transformation of the endometrium. Bleeding was of earlier onset
and longer duration with the lowest dose of trimegestone. CONCLUSIONS:
Trimegestone is a highly effective oral progestogen for endometrial protection,
all doses inducing secretory endometrial transformation. Although bleeding
patterns suggest a weaker effect of the lowest dose used, the minimum effective
dose for endometrial protection has still to be determined and may be lower than
those used in this study.
PMID- 9392000
TI - Palo Alto Medical Foundation, Research Institute.
PMID- 9392001
TI - Recent advances in the treatment of malignant melanoma with gene therapy.
PMID- 9392002
TI - Altered procollagen mRNA expression during the progression of avian scleroderma.
AB - BACKGROUND: Spontaneous animal models of human autoimmune diseases provide the
means to study the very first pathogenetic events, which is not possible in their
human counterparts. This is particularly true for connective tissue diseases in
which clinical symptoms become manifest only after a long and still obscure
course of immunologic, inflammatory, and fibrotic processes. University of
California at Davis line 200 chickens (UCD-200) develop a hereditary scleroderma
like disease resembling the entire spectrum of human systemic sclerosis, such as
early endothelial cell damage, severe lymphocytic infiltration, and accumulation
of collagen in skin and internal organs. MATERIALS AND METHODS: In the present
study, we investigated mRNA levels of alpha 1(I), alpha 2(I), alpha 1(II), alpha
1(III), alpha 1(VI), alpha 2(VI), and alpha 3(VI) procollagen and GAPDH using
digoxigenin-labeled antisense probes in a nonradioactive ribonuclease protection
assay (RPA). We analyzed tissue samples from comb, esophagus, heart, lung, and
liver of UCD-200 chickens at different stages of the disease, and healthy UCD-058
chickens. RESULTS: During the early inflammatory stage of the disease, the ratios
of procollagen types VI/I and types VI/III increased 7-fold in comb tissue,
followed by a 3-fold elevation in type I procollagen transcripts in the late
acute stage. In the chronic stage, alpha 1(III) procollagen message was increased
2-fold. Additionally, hybridization with the 180 bp alpha 2(I) antisense probe
resulted in two bands of 180 bp and 115 bp, respectively, in the RPA. The ratio
of these two previously undescribed bands changes in the early stage of the
disease both in comb and esophagus. CONCLUSIONS: In an animal model with a
spontaneous scleroderma-like disease we found a characteristic, sequential
increase in type VI, type I, and type III procollagen transcripts, and we found
evidence for the presence and altered ratio of two mRNA variants of alpha 2(I)
procollagen, possibly caused by alternative splicing. Comparative analysis of
alpha 2(I) procollagen variants in early stages of avian scleroderma and human
SSc might provide answers to unresolved questions concerning the molecular basis
for generalized fibrosis in scleroderma.
PMID- 9392003
TI - Linkage and association studies between the melanocortin receptors 4 and 5 genes
and obesity-related phenotypes in the Quebec Family Study.
AB - BACKGROUND: The agouti yellow mouse shows adult onset of moderate obesity and
diabetes. A depressed basal lipolytic rate in adipocytes or a decreased
adrenergic tone arising from antagonizing alpha-melanocyte-stimulating hormone
(MSH) activation of melanocortin receptors (MCR) could be at the origin of the
obesity phenotype. MATERIAL AND METHODS: MCR 4 and 5 (MC4R, MC5R) genes were
studied in the Quebec Family Study. Sequence variations were detected by Southern
blot probing of restricted genomic DNA, and mRNA tissue expression was detected
by RT-PCR. Subjects with a wide range of weight were used for single-point sib
pair linkage studies (maximum of 289 sibships from 124 nuclear families).
Analysis of variance across genotypes in unrelated males (n = 143) and females (n
= 156) was also undertaken. Body mass index (BMI), sum of six skin-folds (SF6),
fat mass (FM), percent body fat (%FAT), respiratory quotient (RQ), resting
metabolic rate (RMR), fasting glucose and insulin, and glucose and insulin area
during an oral glucose tolerance test were analyzed. RESULTS: MC4R showed
polymorphism with NcoI, and MC5R, with PstI and PvuII, with a heterozygosity of
0.38, 0.10, and 0.20, respectively. Linkages were observed between MC5R and BMI
(p = 0.001), SF6 (p = 0.005), FM (p = 0.001), and RMR (p = 0.002), whereas
associations were observed in females between MC5R and BMI (p = 0.003), and
between MC4R and FM (p = 0.002) and %FAT (p = 0.004). After correction for
multiple tests, these p values are lowered by one tenth. MC4R and MC5R mRNAs have
been detected in brain, adipose tissue, and skeletal muscle. CONCLUSIONS: MC4R
and MC5R exhibit evidence of linkage or association with obesity phenotypes, but
this evidence is strongest for MC5R.
PMID- 9392005
TI - Inducible nitric oxide synthase and proinflammatory cytokine expression by human
keratinocytes during acute urticaria.
AB - BACKGROUND: IgE/allergen-dependent activation of skin mast cells is involved in
acute urticaria and leads to their IL-4 release. Previously we have demonstrated
in vitro the induction of the low-affinity receptor for IgE (CD23/Fc epsilon RII)
in human keratinocytes (HK) upon stimulation with IL-4. In addition, we have
observed that ligation of CD23 on keratinocytes induced type II nitric oxide
synthase (iNOS), leading to the release of nitric oxide (NO) and proinflammatory
cytokines (TNF-alpha, IL-6). According to these in vitro data, we explored
whether keratinocytes could also express iNOS, TNF-alpha, IL-6, and CD23 in acute
urticaria, an in vivo model in which activation of mast cells by IgE/allergen
immune complexes is involved. MATERIALS AND METHODS: INOS, TNF-alpha, IL-6, and
CD23 expression by keratinocytes was studied in acute urticaria (n = 11) in
biopsies from lesional and autologous normal skin by immunohistochemistry, in
situ hybridization, or RT-PCR. Nitrites and TNF-alpha synthesis were assayed in
supernatants of cultured lesional keratinocytes. RESULTS: INOS mRNA expression
was demonstrated with RT-PCR in 10 biopsies out of 11 sections of acute urticaria
lesional skin. Immunohistochemistry showed that this iNOS positivity originated
from keratinocytes located close to the dermoepidermal junction; TNF-alpha and IL
6 mRNA transcription was observed in all but one iNOS+ biopsy. Immunostaining and
in situ hybridization with CD23-specific probes were strong in all but one iNOS+
skin biopsy. Noninflamed autologous skin was negative for iNOS (except for a weak
positivity in one case), cytokines, and CD23. CONCLUSION: The colocalization of
iNOS, proinflammatory cytokines, and CD23 within keratinocytes in acute urticaria
demonstrates that these cells play an important role in the initiation and
maintenance of the inflammatory reaction during this disease in humans through
activation of the iNOS pathway by CD23 ligation with IgE/allergen immune
complexes.
PMID- 9392004
TI - Constitutive modulation of Raf-1 protein kinase is associated with differential
gene expression of several known and unknown genes.
AB - BACKGROUND: Raf-1, a cytoplasmic serine/threonine protein kinase, plays an
important role in mitogen- and damage-responsive cellular signal transduction
pathways. Consistent with this notion is the fact that constitutive modulation of
expression and/or activity of Raf-1 protein kinase modifies cell growth,
proliferation, and cell survival. Although these effects are controlled at least
in part by transcriptional mechanisms, the role of Raf-1 in the regulation of
specific gene expression is unclear. MATERIALS AND METHODS: Differential display
of mRNA was used to identify the genes differentially expressed in human head and
neck squamous carcinoma cells (PCI-06A) transfected with either the antisense c
raf-1 cDNA (PCI-06A-Raf(AS)), or a portion of cDNA coding for the kinase domain
of Raf-1 (PCI-06A-Raf(K)). The differentially expressed fragments were cloned and
sequenced, and they were used as probes to compare the expression patterns in
parent transfectants by Northern blot analysis. In addition, expression patterns
of the novel genes were examined in normal tissues and cancer cell lines.
RESULTS: Six differentially expressed cDNA fragments were identified and
sequenced. Northern blot analysis revealed that four of these fragments
representing human alpha 1-antichymotrypsin (alpha 1-ACT), mitochondrial
cytochrome c oxidase subunit II (COX-II), and two as-yet unidentified cDNAs (KAS
110 and KAS-111) were relatively overexpressed in PCI-06A-Raf(AS) transfectants
compared with PCI-06A-Raf(K) transfectants. The other two cDNA fragments
representing human elongation factor-1 alpha (HEF-1 alpha) and ornithine
decarboxylase antizyme (OAz) were overexpressed in PCI-06A-Raf(K) transfectants
compared with PCI-06A-Raf(AS) transfectants. The KAS-110 (114 bp) and KAS-111
(202 bp) cDNAs did not show significant matches with sequences in the GenEMBL,
TIGR, and HGS DNA databases, and these may represent novel genes. The KAS-110 and
KAS-111 transcripts, approximately 0.9 kb and approximately 0.5 kb, were observed
in most normal tissues and several cancer cell types, indicating their
housekeeping function. CONCLUSIONS: This study reports novel components of the
Raf-1 signaling pathway. alpha 1-ACT, HEF-1 alpha, COX-II, and OAz have been
previously implicated in diverse cellular responses including transformation,
energy metabolism, and cell survival. Our data suggest that expression of these
genes may play a role in the Raf-1-mediated biological activity of PCI-06A cells.
The KAS-110 and KAS-111 cDNAs represent unknown genes, and further investigations
are necessary to determine their role in the cellular response. Identification of
specific targets may provide useful markers for prognosis and therapy selection
in squamous cell carcinoma.
PMID- 9392007
TI - Report on the first international symposium on oculopharyngeal muscular
dystrophy.
PMID- 9392009
TI - Hereditary ptosis of late onset: early observations on oculopharyngeal muscular
dystrophy in Quebec by Roma Amyot.
AB - In 1948, Roma Amyot, a well-known French-Canadian neurologist, observed in ten
families a late onset syndrome consisting of hereditary ptosis which was
sometimes associated with dysphagia but rarely with limb weakness. At that time,
Taylor's original work dating back to 1915 was still unknown to him. Nonetheless,
these reports constitute the two earliest publications about this syndrome
prevalent in the French-Canadian population. Amyot recognized the myopathic
nature of this disease which was later called oculopharyngeal muscular dystrophy
(OPMD) by Victor et al.
PMID- 9392008
TI - Andre Barbeau and the oculopharyngeal muscular dystrophy in French Canada and
North America.
AB - Andre Barbeau (1931-1986) is best known world-wide in the neurologic community
for his contributions to the study of Parkinson's disease, Huntington's chorea
and Friedreich's ataxia. But in Quebec, Canada, his name is associated with
oculopharyngeal muscular dystrophy (OPMD), often called here 'maladie de
Barbeau', on which he conducted a series of genealogic, genetic and clinical
studies early in his career, most intensively from 1964 to 1966. He then
demonstrated that most of the reported cases in North America could be traced
back to French-Canadian ancestors. Furthermore, he identified this ancestor
couple and linked them with a probable case in Niort, in France. Because he was
the first to see over a hundred patients, his clinical studies were definitive.
He did little work on OPMD after 1967 when he rushed back to the study of L-DOPA
in the treatment of Parkinson's disease, a work that he had previously so
brilliantly pioneered.
PMID- 9392006
TI - Characterization of new polyclonal antibodies specific for 40 and 42 amino acid
long amyloid beta peptides: their use to examine the cell biology of presenilins
and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid
angiopathy cases.
AB - BACKGROUND: In Alzheimer's disease (AD), the main histological lesion is a
proteinaceous deposit, the senile plaque, which is mainly composed of a peptide
called A beta. The aggregation process is thought to occur through enhanced
concentration of A beta 40 or increased production of the more readily
aggregating 42 amino acid-long A beta 42 species. MATERIALS AND METHODS:
Specificity of the antibodies was assessed by dot blot, Western blot, ELISA, and
immunoprecipitation procedures on synthetic and endogenous A beta produced by
secreted HK293 cells. A beta and p3 production by wild-type and mutated
presenilin 1-expressing cells transiently transfected with beta APP751 was
monitored after metabolic labeling and immunoprecipitation procedures.
Immunohistochemical analysis was performed on brains of sporadic and typical
cerebrovascular amyloid angiopathy (CAA) cases. RESULTS: Dot and Western blot
analyses indicate that IgG-purified fractions of antisera recognize native and
denaturated A beta s. FCA3340 and FCA 3542 display full specificity for A beta 40
and A beta 42, respectively. Antibodies immunoprecipitate their respective
synthetic A beta species but also A beta s and their related p3 counterparts
endogenously secreted by transfected human kidney 293 cells. This allowed us to
show that mutations on presenilin 1 triggered similar increased ratios of A beta
42 and its p 342 counterpart over total A beta and p3. ELISA assays allow
detection of about 25-50 pg/ml of A beta s and remain linear up to 750 to 1500
pg/ml without any cross-reactivity. FCA18 and FCA3542 label diffuse and mature
plaques of a sporadic AD case whereas FCA3340 only reveals the mature lesions and
particularly labels their central dense core. In a CAA case, FCA18 and FCA3340
reveal leptomeningeal and cortical arterioles whereas FCA3542 only faintly labels
such structures. CONCLUSIONS: Polyclonal antibodies exclusively recognizing A
beta 40 (FCA 3340) or A beta 42 (FCA3542) were obtained. These demonstrated that
FAD-linked presenilins similarly affect both p342 and A beta 42, suggesting that
these mutations misroute the beta APP to a compartment where gamma-secretase, but
not alpha-secretase, cleavages are modified. Overall, these antibodies should
prove useful for fundamental and diagnostic approaches, as suggested by their
usefulness for biochemical, cell biological, and immunohistochemical techniques.
PMID- 9392010
TI - Oculopharyngeal muscular dystrophy, other ocular myopathies, and progressive
external ophthalmoplegia.
AB - Progressive external ophthalmoplegia comprises many different disorders. Those of
childhood onset can be separated from juvenile or adult onset. Among those of
later onset the most common causes are oculopharyngeal muscular dystrophy,
oculopharyngodistal muscular dystrophy and the several mitochondrial disorders,
especially those with large deletions of mitochondrial DNA (mtDNA) (sporadic),
those with maternal inheritance (point mutations), or the autosomal dominant
forms with multiple deletions of mtDNA. Ophthalmoplegia of presumably neurogenic
origin is seen in some of the familial spinocerebellar ataxias. Advances in
molecular genetics should provide information about affected gene products and,
therefore, pathogenesis.
PMID- 9392012
TI - Oculopharyngeal muscular dystrophy in France.
AB - The clinical, histopathological, ultrastructural and geographical data on 29
cases of oculopharyngeal muscular dystrophy (OPMD) identified by the authors in
France is briefly presented. The mean age of the patients was 53.8 +/- 8.1 years.
Onset symptoms were ptosis (14/29), dysphagia (12/29) and limb girdle weakness
(3/29). The evolution of the disease was always progressive and followed
different clinical patterns. The main histological changes in muscle biopsies
were atrophic angulated fibers (29/29) and rimmed vacuoles (25/29); muscle fiber
necrosis was very rare (1/29). The characteristic nuclear inclusions made of 8.5
nm filaments were observed in all cases, and found in 2-5% of the nuclei in a
given ultrathin section. They are the morphological marker of the disease.
PMID- 9392011
TI - Recent studies on oculopharyngeal muscular dystrophy in Quebec.
AB - In 1990, we launched a major study to ascertain the clinical picture of OPMD in
Quebec and to identify large families for linkage analysis. In 14 patients, the
chromosomes were karyotyped to eliminate any deletion or translocation. Relevant
family information and clinical data were computerized and correlations were
sought for the age of onset, the identification of the first symptom and the
distribution of weakness. A simple test to detect dysphagia was validated. Twenty
one families have taken part in the study, which led to our localization of the
gene in 1995 [Brais B, Xie Y-G, Sanson M, et al. Hum Mol Genet 1995; 4:429-434].
At least one case in each family underwent muscle biopsy to confirm the presence
of the typical nuclear filaments found in OPMD. Electrodiagnostic and pathologic
studies were also conducted to better understand the disease process. An
illustrative case is presented.
PMID- 9392013
TI - Genealogical study of oculopharyngeal muscular dystrophy in France.
AB - This work is based on 54 probands affected by oculopharyngeal muscular dystrophy
(OPMD). The muscle biopsy of all these patients showed the presence of the
intranuclear inclusions, specific of this disease. The residence of the probands
is concentrated in three clusters: the Paris, Marseilles and Bordeaux regions.
The genealogical study was carried out on 43 probands, 10 of which did not have
any ascendance in France for more than two generations. The geographic origin of
the 33 patients of French descent was distributed over numerous regions, not
including the Paris and Marseilles regions where many patients lived. This
geographic dispersion and the rarity of common genealogies of the probands, did
not suggest the existence of a recent founder effect, in contrast to what is
observed in the French-Canadian community. The existence of a link between French
and French-Canadian families is currently being investigated.
PMID- 9392014
TI - Epidemiology and inheritance of oculopharyngeal muscular dystrophy in Israel.
AB - Oculopharyngeal muscular dystrophy (OPMD) is considered frequent among French
Canadians. Our previous observations suggested it is common also among the Jews
originating from Bukhara in Uzbekistan, many of whom are now living in Israel.
One hundred and seventeen OPMD patients were identified in a population of 70,000
people of Bukharian descent, resulting in a calculated minimal prevalence of
1:600. In all but three families age dependent autosomal dominant inheritance was
documented. There is some evidence for genetic anticipation. Three young,
severely ill, patients from two different families may be homozygotes, their
parents being both affected. Bukhara Jews present the second largest known
cluster and the prevalence is the highest in the world. The existence of very
large families, intermarriage among carriers and probably homozygote offspring
may be useful for genetic studies. A 'founder effect' may explain the high
prevalence of OPMD in this population.
PMID- 9392015
TI - Oculopharyngeal muscular dystrophy in Japan.
AB - Oculopharyngeal muscular dystrophy (OPMD) in the European population has been
frequently diagnosed, but except for one black family, the occurrence in other
ethnic groups is uncertain. We identified two unrelated OPMD Japanese families,
including 34 affected individuals. Major clinical manifestations were bilateral
ptosis and dysphagia starting after age 40. Histologic studies of limb muscles
revealed mild myogenic changes, occasional rimmed vacuoles, and small angulated
fibers. By contrast, cricopharyngeal muscle showed a marked loss of fibers and
massive proliferation of connective tissue. Intranuclear tubulofilamentous
inclusions (ITFI) of 8.5 nm outer diameter were observed in 2-5% of the nuclei in
four different biopsied muscles. One patient with recurrent aspirations underwent
successful cricopharyngeal myotomy. Aerodynamic examination was useful to
evaluate velopharyngeal closure function. Our investigations revealed that OPMD
is a geographically widespread disorder, and ITFI may be the specific morphologic
hallmark.
PMID- 9392016
TI - Oculopharyngeal muscular dystrophy in Uruguay.
AB - Within the last 30 years, sixty-five patients exhibiting the clinical symptoms of
oculopharyngeal muscular dystrophy (OPMD) were studied at the Neuromuscular
Diseases Unit of the Neurological Institute of Montevideo. They are members of
five unrelated families which came from the Canary Islands to Uruguay between
1850 and 1900. In the three families examined, the typical inclusions
characteristic of OPMD were found in the nuclei of muscle fibers. Treatment for
ptosis and dysphagia was discussed. The particular migratory pattern of this
group of patients could be of considerable interest in the study of molecular
genetics.
PMID- 9392017
TI - Oculopharyngeal muscular dystrophy in Italy.
AB - Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant myopathy
particularly frequent in Quebec. The few Italian cases thus far described with
bilateral ptosis, dysphagia and variable muscle weakness, show non-specific
dystrophic findings on muscle biopsies by light microscopy. We describe a 70-year
old Italian woman with an adult-onset ptosis, mild dysphagia and proximal muscle
weakness belonging to a family segregating OPMD according to an autosomal
dominant mode of inheritance. Clinical features of four of her relatives are
reviewed. Muscle biopsy studied by electron microscopy showed the typical 8.5 nm
in diameter intranuclear filamentous inclusions (INI). To our knowledge, this is
the first Italian report of OPMD with INI. The identification of nuclear
inclusions is mandatory in order to confirm the diagnosis prior to linkage
analysis.
PMID- 9392018
TI - Oculopharyngeal muscular dystrophy in a northern German family linked to
chromosome 14q, and presenting carnitine deficiency.
AB - We report the evaluation of oculopharyngeal muscular dystrophy (OPMD) in a large
northern German family, which can be traced back six generations and is unrelated
to French-Canadian families. The symptoms in this family start at about 50 years
of age and include dysphagia, bilateral ptosis, and in some cases a slowly
progressive atrophy and weakness of other extraocular, facial or limb girdle
muscles. The muscle biopsies showed the pathognomonic ultrastructural finding of
characteristic intranuclear filaments. Linkage analysis confirmed that this
family is also linked to chromosome 14q markers. Haplotype analysis revealed that
a unique haplotype segregates with the disease which is different from the one
found in French-Canadian OPMD. Although approximately half of the probands with
OPMD showed mild clinical and neurophysiological signs of a distal symmetrical
neuropathy, the association between the neurogenic lesions and OPMD is still
unclear. Some family members with or without OPMD complained of exercise related
muscle pain, and a lipid storage myopathy with low muscular carnitine
concentrations was found, while the carnitine contents in blood and urine samples
as well as the activity of the carnitine-palmitoyl-transferase were normal,
fitting the pattern of a primary muscular carnitine deficiency, independent of
OPMD.
PMID- 9392019
TI - Morphological changes in muscle fibers in oculopharyngeal muscular dystrophy.
AB - The study of muscle biopsies of 29 cases of oculopharyngeal muscular dystrophy
(OPMD) showed the two main morphological features of this disease: rimmed
vacuoles (in 26 cases) and intranuclear inclusions (in all cases). These
inclusions are made of 8.5 nm tubular filaments and the areas occupied by them
are lighter than the surrounded nucleoplasm. This can be seen by light
microscopy, facilitating the detection of the tubulo-filamentous inclusions which
can only be identified with certitude by electron microscopy. In a given
ultrathin section the area occupied by these inclusions varied from 2% to 5% of
the nuclei. The intranuclear inclusions are the morphological marker of OPMD and
their finding in a muscle biopsy allows the exact diagnosis of this disease. The
origin and biochemical nature of the intranuclear inclusions is unknown.
PMID- 9392020
TI - Using the full power of linkage analysis in 11 French Canadian families to fine
map the oculopharyngeal muscular dystrophy gene.
AB - Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant
muscular dystrophy with a high prevalence in the French Canadian population. We
report linkage analysis with 7 chromosome 14q polymorphic markers in 11 large
French Canadian families. An observed recombination in one family establishes
D14S283 as the new centromeric flanking marker, therefore reducing the previously
reported candidate interval from 5cM to 2cM. The highest two-point LOD score was
26.05 at theta = 0.01 for MYH7.1. Multipoint analysis suggested that the OPMD
genes lies within a 1.5cM region around D14S990. This study of large French
Canadian families underlines the great power of this population to fine map
disease genes.
PMID- 9392021
TI - Confirmation of linkage of oculopharyngeal muscular dystrophy to chromosome
14q11.2-q13 in American families suggests the existence of a second causal
mutation.
AB - Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, autosomal dominant
disorder characterized by progressive ptosis, dysphagia, and extremity weakness.
Linkage of OPMD to 14q11.2-q13 has been reported in a series of French-Canadian
families. Tightly linked markers have been defined and haplotype analysis in
these data show a single segregating disease chromosome throughout the OPMD
French-Canadian families. We have ascertained and sampled five multigenerational
outbred American OPMD families. Four of the five families have known French
Canadian ancestry while the fifth is of English/Scottish origin. Linkage analysis
was performed using standard likelihood methods. A peak multipoint lod score of
6.30 was obtained for the marker MYH7.1 in the OPMD families. The English/
Scottish family exhibited a different chromosomal haplotype for the OPMD alleles
than the families of French-Canadian origin. These data suggest this family may
represent a second, possibly independent mutation in this disorder. Linkage was
confirmed to chromosome 14q11.2-q13 with no evidence of genetic heterogeneity.
PMID- 9392022
TI - Surgical correction of blepharoptosis in oculopharyngeal muscular dystrophy.
AB - Progressive, usually symmetric blepharoptosis with or without dysphagia appears
in most instances in the fifth decade in oculopharyngeal muscular dystrophy
(OPMD). We review our experience over 20 years of applying Beard's surgical
guidelines for correction of ptosis to OPMD patients with satisfactory results.
As the disease continues to progress, the rate of recurrence of ptosis among
follow-up patients of a 9-year minimum period was 13%.
PMID- 9392023
TI - Cricopharyngeal myotomy in the management of neurogenic and muscular dysphagia.
AB - Oropharyngeal dysphagia results from disruption of the integrated mechanism of
swallowing. Neurogenic dysphagia is caused by central nervous system disorders or
by cranial nerve involvement and it may be distinguished from muscular dysphagia
such as that seen mostly in oculopharyngeal muscular dystrophy (OPMD). Based on
our 20-year experience in a university hospital thoracic surgery service, we
describe the results of the clinical evaluation, the laboratory testing and the
surgical management of a recent subgroup of patients experiencing dysphagia from
neurogenic and muscular disorders.
PMID- 9392024
TI - Upper esophageal sphincter myotomy in oculopharyngeal muscular dystrophy: long
term clinical results.
AB - From 1980 to 1995, 53 patients with oculopharyngeal muscular dystrophy (OPMD)
underwent an upper esophageal sphincter (UES) myotomy for the control of marked
dysphagia. From this number, a group of 21 patients had been evaluated for
preoperative and postoperative symptoms in 1987. The same clinical assessment was
performed in 1995 by an independent evaluator for a total of 37 patients
including 12 patients from the first group. As a whole, after a mean follow-up of
6.2 years, surgery succeeded in 18 patients (49%), gave a partial improvement in
12 (32%) and failed in seven (19%). The 12 patients evaluated twice (in 1987 and
1995) have had very good early results, 8-69 months after UES myotomy: dysphagia
was totally relieved in eight patients, occurred rarely in three and was moderate
in one. Nevertheless, the very long-term follow-up (8 years later) has shown a
recurrence of the swallowing and tracheobronchial symptoms in many cases.
PMID- 9392025
TI - Dysphagia in oculopharyngeal muscular dystrophy: a series of 22 French cases.
AB - Twenty-two patients (mean age = 67.9 years) with oculopharyngeal muscular
dystrophy (OPMD) were referred for dysphagia from 1987 to January 1995. Six
patients had suffered aspiration pneumonia, and three had significantly lost
weight, while 19 complained of discomfort during swallowing but without weight
loss. Swallowing was assessed by fiberscopy during swallowing (last eight
patients), videofluoroscopy (12 cases) and manometry (19 cases). Twelve patients
underwent a cricopharyngeal (CP) myotomy: 10 showed improvement, one had a
partial improvement, and the procedure failed in one (mean follow-up = 29.6
months). In the other cases, CP myotomy was postponed, refused or
contraindicated. Of the 22 patients, three died from OPMD consequences. Factors
associated with favorable outcome were adequate residual pharyngeal propulsion
and no weight loss. In a majority of cases, CP myotomy constitutes an effective
treatment of dysphagia with adequate residual propulsion but does not modify the
final prognosis and is contraindicated in cases with pharyngeal aperistalsis.
PMID- 9392027
TI - Attempting to fathom the unfathomable: descriptive views of spirituality.
AB - OBJECTIVES: To examine the various views of "spirituality and its uses in the
disciplines of philosophy, theology, psychology, and nursing. DATA SOURCES:
Definitions and descriptions of spirituality and related terms from the
disciplines of philosophy, theology, psychology, and nursing. CONCLUSION:
Although it is widely accepted that holistic nursing care incorporates care of
the spirit, nursing's view of spirituality is influenced by varying paradigms.
Nursing researchers are exploring spirituality. Spiritual care that is ethical
and sensitive is an invaluable part of total patient care. IMPLICATIONS FOR
NURSING PRACTICE: Appreciating various views of spirituality and recognizing the
possible discrepancy between a nurse's and a patient's view of spirituality
allows the reader to use such terms carefully and appropriately in providing
sensitive patient care.
PMID- 9392026
TI - A pilot study on upper esophageal sphincter dilatation for the treatment of
dysphagia in patients with oculopharyngeal muscular dystrophy.
AB - Upper esophageal sphincter (UES) dilatation was done for the treatment of
moderate to severe dysphagia with a Maloney bougie in 14 patients with
oculopharyngeal muscular dystrophy (OPMD) or with an achalasia dilator in three
patients. The severity of dysphagia prior to UES dilatation was evaluated by a 15
point dysphagia score, a pharyngeal and esophageal manometry and a radionuclide
pharyngoesophageal transit study. Using actuarial life table, the improvement
rate after dilatation with Maloney bougie was 64.3% (95% CI 39.2-89.4) at 3- and
6-month follow-ups, and was 55.7% (95% CI 28.9-82.5) at 12- and 18-month follow
ups. At 3-month post-dilatation, we observed a significant reduction of the mean
dysphagia score from 9.6 to 7.2 (P = 0.05). No significant manometric or
radionuclide factors were found to predict effective dilatation. The results of
this pilot study showed that UES dilatation with Maloney bougie or achalasia
dilator may be an effective treatment of moderate dysphagia in patients with
OPMD. However, further studies with larger sample sizes are needed to corroborate
these results and to assess long-term outcome.
PMID- 9392028
TI - Cultural aspects of spirituality in cancer care.
AB - OBJECTIVES: To recognize the significant relationship between culture and
spirituality; to offer techniques for assessing the influence of culture on
spirituality. DATA SOURCES: Books and journal articles from nursing and
anthropology. CONCLUSION: Patients' spirituality may be determined entirely by
cultural norms, in opposition to cultural norms, or by both these norms and
individual life experiences. A thorough assessment of a patient's spirituality
with careful attention to the degree to which that spirituality is affected by
the patient's cultural background is essential. IMPLICATIONS FOR NURSING
PRACTICE: Nurses who care for persons with cancer need to undertake a process of
self-assessment of their spirituality before providing spiritual care for
patients. Such an assessment helps to prevent cultural imposition.
PMID- 9392030
TI - The arts in spiritual care.
AB - OBJECTIVES: To explore the role of the arts in spirituality and spiritual care
and the importance of the arts and creativity in health care settings,
particularly where individuals are confronting life-threatening illnesses. DATA
SOURCES: Professional and lay journals/magazines, and personal experience with
oncology and hospice patients. CONCLUSION: The arts are now viewed as an integral
component of holistic care for patients and families. By offering opportunities
to engage in the arts and creative expression, persons with cancer can be enabled
to mourn, grieve, celebrate life, be empowered to endure their situation, and
find healing and meaning. IMPLICATIONS FOR NURSING PRACTICE: Comprehensive
supportive care for cancer patients requires the efforts of an interdisciplinary
team. Artists can play a role as a part of this team. Oncology nurses must be
knowledgeable of the role of the arts and creative expression in the provision of
care to patients with cancer and how to incorporate the arts into the cancer care
setting.
PMID- 9392029
TI - Spiritual assessment across the cancer trajectory: methods and reflections.
AB - OBJECTIVES: To provide information about spiritual assessment strategies and the
spiritual stages through which persons with cancer pass. DATA SOURCES: Books and
articles (including research reports) from various disciplines including nursing,
medicine, theology, and other health care professions: personal narratives and
reflections of individuals with cancer. CONCLUSION: Sound spiritual assessment is
prerequisite for sound spiritual intervention. Nurses must find the time, means,
and knowledge to incorporate spiritual assessment into nursing care. Patients
agree. IMPLICATIONS FOR NURSING PRACTICE: Nurses can improve spiritual assessment
by eliciting patient accounts of the evolving spiritual journey and prayers that
parallel changes in health status.
PMID- 9392031
TI - Constructing meaning from the experience of cancer.
AB - OBJECTIVES: To describe how people with cancer create new sources of meaning at
significant times in the illness trajectory. DATA SOURCES: Nursing research,
including that of the author; documented observations and theories of
psychiatrists and psychologists. CONCLUSION: There are turning points within the
cancer trajectory when choices made by persons with cancer and their families may
have far reaching consequences in terms of new goals to pursue and new sources of
meaning to create. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can assist
by carefully listening to what is important to patients, assisting to clarify
values when necessary, and encouraging patients to seek connections with similar
others that facilitate finding meaning and healing.
PMID- 9392032
TI - The story behind the story: the use of storytelling in spiritual caregiving.
AB - OBJECTIVES: To briefly discuss the nature and function of stories that patients
tell, and offer practical tips on how to listen and make sense of these stories.
DATA SOURCES: Books and articles from disciplines in the humanities and health
care professions. CONCLUSION: Stories are a medium for assessment and
intervention in areas that essentially reflect an individual's spirituality.
IMPLICATIONS FOR NURSING PRACTICE: Encouraging storytelling is an intervention
nurses can use to promote spiritual health. Suggestions for eliciting and
analyzing stories are offered.
PMID- 9392033
TI - Replenishing the spirit by meditative prayer and guided imagery.
AB - OBJECTIVES: To review relevant literature describing prayer and guided imagery,
and to demonstrate via the use of a vignette, the use of both prayer and guided
imagery as one approach to offer spiritual care to oncology patients. DATA
SOURCES: Review and research articles from multiple disciplines, and personal
clinical experience. CONCLUSION: Meditative prayer and guided imagery are two
approaches that can be used to provide spiritual care to cancer patients and
families. While research has focused on elements of spirituality, research
related to clinical interventions is limited. IMPLICATIONS FOR NURSING PRACTICE:
Guided imagery, metaphors, meditative prayer, and prayers of silence are
effective approaches the nurse can implement when caring for the patient with
cancer.
PMID- 9392034
TI - The practice of presencing.
AB - OBJECTIVES: To understand philosophical foundations for this fundamental nursing
intervention, and to review literature and expert nurses' experiences to describe
how to be present to persons with cancer. DATA SOURCES: Author's qualitative
research of nurses' experiences of presencing; theoretical and clinical nursing
perspectives; books by theologian Martin Buber. CONCLUSION: Presencing requires
deliberate focused attention, receptivity to the other person, and persistent
awareness of the other's shared humanity. "Being there" provides comfort for both
patient and nurse. IMPLICATIONS FOR NURSING PRACTICE: Literature reviewed offer
the elements of presenting (eg, providing affirmation, communication of empathy,
being without words). Identification of such elements can assist the reader to
implement this intervention.
PMID- 9392035
TI - Spiritual care for children with cancer.
AB - OBJECTIVES: To review literature pertinent to spirituality of children with
cancer and to identify practical strategies for providing care for this dimension
in children. DATA SOURCES: Nursing research and literature about pediatric
nursing care and spirituality; theoretical formulations of Piaget, Fowler, and
Erikson. CONCLUSION: Children diagnosed with cancer have unique spiritual needs
that place them at risk for developing spiritual distress. With the diagnosis may
come experiences of loss of normalcy, physical stamina, relationships, body
image, and future goals. Spiritual care includes interventions that assist
children to find meaning and purpose in life, to continue relationships, and to
transcend beyond the self. IMPLICATIONS FOR NURSING PRACTICE: Spiritual care
includes caregiver and child assessment and interventions appropriate to the
developmental stages of infancy through adolescents. Tables outlining how this
can be done by oncology nurses are included.
PMID- 9392036
TI - Spiritual care: the needs of the caregiver.
AB - OBJECTIVES: To explore the spiritual needs of the family caregiver and to provide
suggestions for giving spiritual care to this caregiver. DATA SOURCES: A
caregiver's personal experience and nursing texts. CONCLUSION: Providing care for
a loved one with cancer can be stressful for the family caregiver; yet, it can
also produce spiritual growth. By providing care for the caregiver, the oncology
nurse is equipping this caregiver to address the spiritual needs of the patient.
IMPLICATIONS FOR NURSING PRACTICE: Nurses can assist caregivers by offering
actions that communicate love, support, acceptance, and faithfulness. Such
measures can ease the pain and encourage spiritual wellness.
PMID- 9392037
TI - Healing partners: the oncology nurse and the parish nurse.
AB - OBJECTIVES: To explore the role of the parish nurse and to examine elements of a
parish nurse program and standards of care. DATA SOURCES: Journal articles, book
chapters, and personal experience related to parish nursing. CONCLUSION: Parish
nursing is a fairly new specialized area of nursing with standards of care and
professional performance. The parish nurse concept has gained acceptance across
the country and the number of parish nurse programs are increasing. IMPLICATIONS
FOR NURSING PRACTICE: The parish nurse focuses on health promotion within the
context of the beliefs, values, and practices of a faith community. The role of
the parish nurse centers on providing education and support to members of a
congregation. Oncology nurses and parish nurses can work together as partners in
providing care to patients with cancer and their families.
PMID- 9392038
TI - Collaboration between nurses and chaplains for spiritual caregiving.
AB - OBJECTIVES: To discuss three ambiguities that may accompany nurse-chaplain
collaboration in providing spiritual care: confusion about the meaning of
"spiritual" and related terms, spiritual assessment and the referral process, and
the role of clergy. DATA SOURCES: Review and research articles related to nursing
and pastoral care, and documented standards. CONCLUSION: Effective nurse-chaplain
collaboration is necessary (especially considering current health care system
changes) to provide adequate spiritual care. Additionally, the increased
involvement of both nurses and chaplains in ethical issues is likely to make
nurse-chaplain collaboration increasingly important. IMPLICATIONS FOR NURSING
PRACTICE: Nurses must collaborate with chaplains and relate to clergy to provide
spiritual care for cancer patients and families. Knowledge of assessment
differences between nurses and chaplains, terminology, and role of clergy will
enhance this collaboration.
PMID- 9392039
TI - A report on the development and work of the Labor Welfare Corporation Spinal
Injuries Center in Japan.
PMID- 9392040
TI - Rehabilitation of spinal cord injury in the national rehabilitation center for
the disabled of Japan: profile of a spinal service.
AB - The National Rehabilitation Center for the Disabled (hereunder abbreviated NRC)
in Japan was established in 1979. It consists of four divisions: the hospital,
the rehabilitation training center, the research institute, and the information
service section. The spinal unit has been functioning and cooperating
corelatively with all of these divisions. There were 1047 patients with a spinal
cord injury treated in the 15 years from September, 1980 to August, 1994;
consisting of 924 males (88.3%), and 123 females (11.7%). The breakdown of causes
of injury were traffic accidents 44.9%, having a fall 14.7%, sports accidents
6.7%, and other causes of spinal paralysis 10.5%. The sites of the spinal cord
lesions were cervical 372 (35.5%), thoracic 547 (52.5%), and lumbar spinal cord
128 patients (12.3%). The incidence of complete paralysis in those with a
cervical spinal cord injury (SCI) was 68.8%, and for thoracic and lumbar SCI 79%
each. The time for completion of activities of daily living (ADL) was 12.0 +/-
1.54 months in those with tetraplegia, and 5.6 +/- 1.71 months for those with
paraplegia. The rate of employment for reentry into society was 59% in those with
a cervical spinal cord injury, and 74% each in those with a thoracic or lumbar
spinal cord injury.
PMID- 9392041
TI - Extraforaminal lumbar disc herniation at two contiguous intervertebral levels.
AB - We describe two unusual surgical cases who presented with extraforaminal lumbar
disc herniation that occurred at two adjacent vertebral levels simultaneously and
unilaterally. Magnetic resonance imaging and selective nerve root infiltration
followed by radiculography helped to outline the herniated disc material. Lateral
fenestration and microsurgical foraminal widening of the affected vertebral
levels allowed a complete and safe relief of the compressed nerves.
PMID- 9392042
TI - Decreased choline acetyltransferase activity in the murine spinal cord
motoneurons under chronic mechanical compression.
AB - The tiptoe-walking Yoshimura (twy) mouse is a model of chronic spinal cord
compression caused by ossification of intraspinal ligaments. Choline
acetyltransferase (CAT), which is known to be a specific marker of cholinergic
neurons, best reflects spinal motoneuron function. Changes in CAT
immunoreactivity following chronic spinal cord compression in twy mice were
investigated quantitatively in order to elucidate spinal motoneuron functional
changes according to the degree and direction of compression. Thirty 24-week-old
twy mice were used in this study. They were divided into three groups according
to the direction of spinal cord compression (anterior, posterior, and lateral)
and the CAT immunoreactivities in whole sections of their upper cervical spinal
cords were investigated quantitatively using a fluorescence microphotometry
system. The lateral compression group showed histological spinal motoneuron
atrophy and loss on the compressed, but not the non-compressed, side. Spinal
motoneuron atrophy and loss were observed when the severity of spinal canal
stenosis due to the ossified lesion, expressed as the occupation rate, was 30% or
more, but the spinal motoneurons appeared normal when it was below 30%. The CAT
immunofluorescence intensity of the anterior horn showed a linear negative
correlation with the degree of canal stenosis. When the occupation rate was below
20%, the CAT immunofluorescence intensities in the anterior horns of the
compression and control groups did not differ significantly. The CAT
immunofluorescence intensity of twy mice with occupation rates of 20% or more
were significantly lower than that of those with occupation rates below 20%.
Furthermore, the CAT immunofluorescence intensity was significantly lower on the
compressed than the non-compressed side of the lateral compression group. Thus,
our findings indicate that an occupation rate of about 20% may be the critical
level for functional changes in the spinal motoneurons.
PMID- 9392043
TI - Lumbar cerebrospinal fluid pulse wave rising from pulsations of both the spinal
cord and the brain in humans.
AB - There are two theories regarding the origin of the lumbar cerebrospinal fluid
pulse wave (L-CSFPW): that it arises from the arteries supplying the spinal cord,
and that it is due to the pulsations of the brain transmitted through the
subarachnoid space of the spine. We investigated L-CSFPW of 11 myelopathic
patients with a complete (five patients, CB-group) or an incomplete spinal block
(six, ICB-group) on myelography to determine the origin of L-CSFPW. Since
arterial pressure amplitude (APA), the energy source of L-CSFPW, is not the same
between individuals or between before and after operation, not only L-CSFPW
itself but also the transfer function between the arterial pressure wave and the
L-CSFPW calculated by the system analysis method was analyzed to eliminate the
influence of hemodynamic fluctuations. In the system analysis, the arterial
pressure wave, L-CSFPW and transfer function were decomposed into five harmonic
waves (HW). In the CB group, L-CSFPW was observed to be 0.72 mmHg on average
(range, 0.25-1.00) in spite of blocking pulsations of the brain, showing that
there was a contribution to L-CSFPW unrelated to the brain, that is, the spinal
cord. In the CB group, however, the preoperative transfer function value of HW1
(mean, 0.056; range, 0.012-0.170) was lower than that in the ICB group (mean,
0.137; range, 0.061-0.236) (P < 0.05), indicating that the brain pulsation also
contributed to L-CSFPW. In the ICB group, there was significant reduction of HW1
(P < 0.01) and HW2 (P < 0.05) transfer function after posterior decompression
surgery in spite of improvement in the subarachnoid space narrowing: preoperative
HW1, mean, 0.137, range, 0.061-0.236; postoperative HW1, mean, 0.065, range,
0.021-0.153; preoperative HW2, mean, 0.092, range, 0.011-0.148; postoperative
HW2, mean, 0.044, range, 0.030-0.066. It has been reported that the spinal cord
blood flow is decreased 20% or more by laminectomy, therefore, L-CSFPW
measurement may be sensitive enough to detect a 20% or higher decrease in this
flow. This suggests that L-CSFPW could possibly be used clinically as a non
invasive method of monitoring the spinal cord blood flow. For broad clinical
application of CSFPW, however, further studies are needed, especially on the
direct relationship between CSFPW and spinal cord blood flow itself.
PMID- 9392044
TI - Experimental chronic compression on the spinal cord of the rabbit by ectopic bone
formation in the ligamentum flavum with bone morphogenetic protein.
AB - This study was conducted to induce chronic spinal cord compression myelopathy in
rabbits. The L5 lumbar lamina was cut partially in 70 rabbits, and bone
morphogenetic protein (BMP) was implanted on the ligamentum flavum in 35 of them.
In the BMP group, new bone formed on the dorsal side of the spinal canal and
flattened the spinal cord in an anteroposterior direction. No pathological
changes were detected in the intramedullary tissues by light microscopic
examination. In rabbits it is possible to induce compression of the cord by using
BMP, although sufficient cord compression to induce myelopathy was not achieved.
PMID- 9392045
TI - Later health-related quality of life in adults who have sustained spinal cord
injury in childhood.
AB - The outcome in terms of health-related quality of life (HRQL) in pediatric spinal
cord injury (SCI) was studied in 36 adults who had sustained an SCI in childhood.
The patients were interviewed and clinically examined. HRQL was assessed with the
15D, a generic fifteen-dimensional self-administered HRQL instrument. The 15
multiple-level dimensions are moving, seeing, hearing, breathing, sleeping,
eating, communicating, urinary continence, working, social participation, mental
functioning, pain, depression, distress and perceived health. The respondents
choose, for each dimension, the level that best describe their health status. In
the 15D valuation system the respondents first assign a relative importance
weight to each dimension and then a relative value to the levels on each
dimension. To derive the 15D HRQL score on a 0-1 scale the level values and
importance weights are multiplied and combined with the levels chosen. The
average HRQL score of this SCI group was significantly lower than that measured
in the population sample. The average importance weights assigned by the SCI
group differed significantly (P < 0.05) from those assigned by the general
population on several dimensions. The weights assigned by the SCI group were
higher for the dimensions of mental functioning, communicating, social
participation and seeing and lower for moving, working, sleeping and eating.
These differences in valuing the dimensions of HRQL can influence behaviour and
should therefore be taken into consideration in rehabilitation.
PMID- 9392046
TI - Muscle reorganization following incomplete cervical spinal cord injury in rats.
AB - This study on rats was designed to evaluate the change of biceps muscle fibers by
enzyme histochemical examination and the change of distribution of motoneurons
innervating biceps muscle fibers by retrograde tracer examination after
incomplete spinal cord injury. Incomplete spinal cord injury was produced by
placing a 20 g weight on exposed dura at the C6 level. The number of the labeled
motoneurons of C6 segment significantly decreased compared with that in the
control, but there were no significant changes in the other segments at 4 weeks
after the injury. Moreover, there was type grouping of biceps muscle fibers at 4
weeks after the injury. These findings indicated that the incomplete cervical
spinal cord injury at C6 level in rats caused the partial denervation and then
reinnervation of biceps muscle fibers by the collateral sprouting of the
remaining motoneurons which belonged to the same motoneuron pool of the injured
motoneurons.
PMID- 9392047
TI - Objective evaluation of pain in various spinal diseases: neuropeptide
immunoreactivity in the cerebrospinal fluid.
AB - A quantitative analysis was performed of substance P-like immunoreactivity (SPLI)
and of beta-endorphin-like immunoreactivity (beta-ENDLI), in the cerebrospinal
fluid (CSF) in various diseases. The results reported to date have not been
consistent. The purpose of this study was to investigate whether or not the
concentration of SPLI or that of beta-ENDLI in CSF demonstrated any potential for
assessing the degree of subjective pain in various spinal diseases. SPLI in CSF
was measured by radioimmunoassay in 158 patients with a spinal disease; involving
57 patients with a lumbar disc herniation (LDH), 38 with lumbar canal stenosis
(LCS), 46 with cervical myelopathy (CM) and 17 with cervical radiculopathy (CR),
and also in 20 healthy controls. beta-ENDLI in CSF was measured in 25 of these
same patients; involving 12 with LDH, seven with LCS and six with CM, and also
five of the same controls. The concentration of serum SPLI was also measured in
50 of these 158. The severity of pain was self-evaluated by each patient using a
linear visual analogue scale (VAS). Their Japanese Orthopaedic Association (JOA)
score was also calculated objectively using the clinical findings. Correlations
were investigated among the concentrations of SPLI and beta-ENDLI in the CSF and
the VAS and JOA clinical assessments of these patients. The concentration of SPLI
in CSF was significantly higher in various spinal diseases than in control (P <
0.05), and was correlated with the severity on the VAS and with the JOA score.
However, beta-ENDLI was not correlated with either the VAS or the JOA score. We
conclude that the measurement of the SPLI concentration in CSF has the potential
for assessing objectively the severity of pain associated with various spinal
diseases.
PMID- 9392048
TI - Prediction of the surgical outcome for the treatment of cervical myelopathy by
using hyperbaric oxygen therapy.
AB - The effectiveness of hyperbaric oxygen therapy (HBO) in predicting the recovery
after surgery in patients with cervical compression myelopathy was evaluated. HBO
has been used to treat brain and spinal cord diseases, but the effect is
generally temporary. This is the first paper to utilize HBO as a diagnostic tool
to evaluate the functional integrity of the spinal cord. The study group
consisted of 41 cervical myelopathy patients aged 32-78 years. Before surgery,
the effect of HBO was evaluated and was categorized as four grades. The severity
of the myelopathy and the recovery after surgery were evaluated by the score
proposed by the Japanese Orthopaedic Association (JOA score). The correlation
between many clinical parameters including the HBO effect and the recovery rate
of JOA score was evaluated. The recovery rate of JOA score was found to be 75.2
+/- 20.8% in the excellent group, 78.1 +/- 17.0% in the good group, 66.7 +/-
21.9% in the fair group and 31.7 +/- 16.4% in the poor group. There was a
statistically significant correlation between the HBO effect and the recovery
rate of the JOA score after surgery (r = 0.641, P < 0.0001). The effect of HBO
showed a high correlation with the recovery rate after surgery as compared to the
other investigated parameters. HBO can be employed to assess the chance of
recovery of spinal cord function after surgical decompression.
PMID- 9392049
TI - Cervical spondylosis in paraplegic patients and analysis of the wheelchair
driving action: a preliminary communication.
AB - We investigated cervical spondylotic changes in paraplegic patients by examining
the radiographs of their cervical spine. The incidence of cervical spondylosis in
these patients was significantly higher than was found in normal control subjects
of a matching age. We attributed this finding to the mechanical stress on the
cervical spine during wheelchair driving. We then performed a biomechanical
analysis using electromyography and goniometer. Paraplegic patients frequently
flexed and extended their cervical spine shown by the goniometer, whilst the
normal control subjects walked almost without moving their cervical spine.
However, the integrated electron myography (IEMG) of the paraplegic patients was
not synchronously increased with the integration of goniometer (IGOM) and the
IEMG of the normal controls was significantly larger than that found in
paraplegic patients on increasing their speed. This was thought to be necessary
for steadying the head whilst walking or running.
PMID- 9392050
TI - Huge solitary osteochondroma at T11 level causing myelopathy: case report.
AB - A solitary osteochondroma of the vertebral column is rare, and also it will
rarely cause neurological deficits. Myelopathy from a tumour usually presents
insidiously with neurological deficits. We report a case of a huge solitary
osteochondroma at T11 level with an acute onset of myelopathy induced by a minor
trauma. MRI findings of a spinal osteochondroma has rarely been described. In our
patient, the MRI demonstrated an outer osteochondral layer and an ossified centre
of the mass. A literature review has also been undertaken.
PMID- 9392051
TI - Myelopathy secondary to ossification of the posterior longitudinal ligament of
the thoracic spine treated by anterior decompression and bony fusion.
AB - We examined the utility of anterior decompression and bony fusion via the
extrapleural approach in the treatment of thoracic myelopathy secondary to
ossification of the posterior longitudinal ligament (OPLL). Patient outcome and
complications were analyzed in 48 patients treated with this procedure, with a
follow-up of at least 2 years. The Japanese Orthopaedic Association score was
used to evaluate the severity of the thoracic myelopathy, and the recovery rate
was used to evaluate the surgical outcome. The outcome, postoperative
complications, radiographic evaluations of bony union, and progression of OPLL
within the area of anterior decompression were examined. The T3 vertebral body
was the highest level to which anterior decompression was applied. The average
follow-up period was 57 months with a recovery rate of 56.7% which stabilized 1
year after operation. However, the surgical outcome was less favorable in
patients with long-standing myelopathy, extensive OPLL, or thoracic OPLL with
coexisting intraspinal ligament ossification. Four patients experienced
deterioration of their myelopathy, and seven patients had the postoperative
complication of extraspinal leakage of cerebrospinal fluid. The myelopathy was
transient in all but one patient. Radiographic studies showed that bony union was
achieved and restenosis of the spinal canal due to progression of OPLL within the
area of decompression did not occur. We conclude that anterior decompression and
bony fusion using the extrapleural approach provides a good outcome and is useful
in treating mid- and lower thoracic OPLL when performed carefully at an early
stage of disease.
PMID- 9392052
TI - Interactions between stone-forming calcific crystals and macromolecules.
PMID- 9392053
TI - Induction of ICAM-1, HLA-DR molecules by IFN-gamma and oncogene expression in
human bladder cancer cell lines.
AB - It is well known that the expression level of the ICAM-1 and MHC is frequently
altered in accordance with tumor progression, and the expression of oncogenes is
significantly related to tumorigenesis, tumor progression, and/or metastatic
potential. In this study, to investigate the relationship between the alteration
in ICAM-1 and MHC expression with the tumor grade and/or cell differentiation, we
examined the expression of ICAM-1 and HLA-DR before and after treatment with IFN
gamma in 4 human bladder cancer cell lines. We also analyzed the expression of c
Ha-ras and c-myc. Using flow cytometry, highly constitutive expression of ICAM-1
was detected in all cell lines tested except RT4 (grade I, well-differentiated,
superficial). IFN-gamma was found to somewhat induce the expression of ICAM-1 in
all cell lines except RT4. The constitutive expression of HLA-DR was not detected
in any of the cell lines tested by flow cytometry and Northern blot. HLA-DR
expression was induced by IFN-gamma in RT4 and J82 (grade III, anaplastic,
invasive). Codon 12 point mutation of c-Ha-ras (GGC-->GTC; Gly-->Val) was
detected in T24 (grade III, epidermoid, superficial) through single-strand
conformation polymorphism, and sequencing analysis. Another point mutation at
codon 27 was detected in TCCSUP (grade IV, distant metastatic), but this mutation
was found to be silent (CAT-->CAC; His). Expression of c-myc was detected in J82
and TCCSUP by Northern blot. These findings, along with the clinical and
pathological characteristics of the patients from whom the cell lines were
established, might suggest that the expression of ICAM-1 seems to be associated
with cell differentiation, and the inducibility of HLA-DR by IFN-gamma seems to
be associated with the degree of malignancy. Expression of c-myc seems to be
associated with invasiveness. However, a significant correlation between c-Ha-ras
activation and tumor grade could not be observed.
PMID- 9392054
TI - Immunohistochemical studies of proliferating cell nuclear antigen and cathepsin D
in transitional cell carcinoma of the urinary bladder.
AB - Immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and
cathepsin D was performed on 60 transitional cell carcinoma (TCC) specimens from
60 patients with bladder cancer. The percentage of PCNA-positive cells (PCNA
labelling index) was determined by counting 500 or 1,000 cells, and cathepsin D
expression was graded according to the extent of immunoreactivity to anti
cathepsin D antibody. The PCNA-labelling index was significantly higher in high
grade and high-stage tumors compared to that in low-grade and low-stage tumors.
Cathepsin D was highly positive in grade-1 tumors. In contrast, 82% of grade-3
tumors and 76% of advanced tumors showed negative or low reactivity to anti
cathepsin D. Groups of high PCNA-labelling index and negative cathepsin D had
significantly poorer prognoses compared to those of the low PCNA group and
cathepsin D highly positive group, respectively, in univariate analyses. However,
neither of these two factors were independent prognostic factors in multivariate
analyses. These results suggest that the PCNA-labelling index and cathepsin D
expression may indicate the malignant potential of TCC and may be able to provide
additional information for predicting survival when stratifying for grade of
bladder cancer.
PMID- 9392055
TI - Expression of immunohistochemical markers (PCNA, Ki-67, 486p and p53) on paraffin
sections and their relation to the recurrence rate of superficial bladder tumors.
AB - We present a retrospective study using four different immunohistochemical markers
(PCNA, Ki-67, 486p and p53) on paraffin sections from 104 selected cases with
primary superficial transitional cell carcinomas of the bladder (59 cases pTa, 45
cases pT1, 40 cases G1, 64 cases G2). 53 of the 104 patients experienced
recurrence of their bladder lesion, while 51 remained free of tumor. The
distribution of staging, grading and multifocality was comparable in both groups
of patients. Overall, the tumors that recurred had a significantly higher
proportion of labeled cells for PCNA (p < or = 0.0001), Ki-67 (p < or = 0.006)
and 486p (p < or = 0.0001). The latter antigen proved to be the most reliable
marker. A less significant difference in staining pattern was found for p53 (p <
or = 0.01). Evaluating the predictive value of the various antibodies separately
for the groups with G1 vs. G2 carcinomas and pTa vs. pT1 tumors revealed a lower
significance for all antibodies. The technique of immunostaining on paraffin
sections facilitates further retrospective studies on archival material. These
markers may provide additional information about the probability of recurrence of
superficial bladder tumors. But at the moment they should only be utilized in
selected cases.
PMID- 9392056
TI - Inhibitory effect of capsaicin on detrusor contractility: further study in the
presence of ganglionic blocker and neurokinin receptor antagonist in the rat
urinary bladder.
AB - In order to understand the mechanisms by which capsaicin at high concentrations
affects the micturition reflex and detrusor contractility, in vivo and in vitro
whole bladder studies were conducted using ganglionic blockers and a neurokinin
receptor antagonist. Thirty-eight adult rats were divided into control (normal
saline cystometry) and experimental (1,000 microM capsaicin cystometry) groups.
Both groups were subdivided to receive pretreatment with intravesical
hexamethonium, perivesical hexamethonium, or intravesical spantide ([D-Arg1, D
Trp7,9, Leu11]-substance P). After in vivo cystometry, the bladders were removed
and in vitro whole bladder contractility studies using electrical field
stimulation as well as bethanechol and KCl stimulations were performed. In the
bladders pretreated with perivesical hexamethonium, the amplitudes of
contractions and in vitro detrusor contractility under electrical stimulation
were decreased. Other bladder preparations showed no significant differences from
the controls. However, when 1,000 microM capsaicin was infused into the bladders,
both control and experimental bladders showed an initial excitation and a final
inhibition with an elevated basal intravesical pressure and retention. Capsaicin
at 100 microM did not have this effect. The results of this study conclude that
blockage of perivesical ganglia or neurokinin receptors in the submucosa did not
influence the depressant effects of 1,000 microM capsaicin on the micturition
reflex and detrusor contractility in rats. Nonspecific toxic effects on detrusor
muscle or nerves is likely when intravesical high-concentration capsaicin is
administered.
PMID- 9392057
TI - Indications for open stone removal of urinary calculi.
AB - In a retrospective study we analyzed patients undergoing open stone removal in
the Department of Urology of the University of Tubingen. In 2.7% of all urinary
calculi, open stone surgery was necessary. Open operation was performed on all
patients with complete staghorn calculi as well as on patients with renal pelvic
stones and simultaneous morphological obstruction. Partial staghorn calculi were
operated on only after endoscopic treatment had failed. Small renal pelvic stones
and ureteral stones were surgically removed only after extracorporeal shock wave
lithotripsy (ESWL) and endoscopic surgery had been unsuccessful. The treatment of
choice for ureteral calculi is ESWL. If ESWL is impossible, an endoscopic
approach is advisable. Open operations of ureteral calculi only have to be
performed if endoscopic therapy has failed or if there is a simultaneous
morphological obstruction. Meta-analysis of publications from 1981 to 1995
confirmed our approach regarding indications for open stone removal. Comparison
of the results reported in the literature is very difficult because of the
missing, but generally accepted definition of stone free. In addition different
examination techniques to determine the status 'stone free' make it difficult to
compare the various studies.
PMID- 9392058
TI - Is deep dorsal vein arterialization an alternative surgical approach to treat
venogenic impotence?
AB - OBJECTIVE: Several surgical techniques have been applied for the treatment of
cavernosal venous leakage, sufficient enough to create erectile dysfunction. In
light of the variable success rates, we report our experience with deep dorsal
penile vein arterialization for the management of severe cavernosal venous
leakage. PATIENTS AND METHODS: Twenty-four impotent patients with venous leakage
were treated by the Virag-II type of end-to-end anastomosis of the inferior
epigastric artery to the deep dorsal penile vein and ligation of the vein
proximally. Diagnostic evaluation included color flow Doppler sonography before
and after intracavernous 60 mg papaverine injection and dynamic cavernosometry/
cavernosography, which indicated veno-occlusive dysfunction in 28 patients.
Revascularization was technically possible in 24 of the patients, although in 4
anastomosis could not be achieved due to the poor quality of the inferior
epigastric artery. RESULTS: Five patients had early occlusion in the immediate
postoperative period and 4 had late occlusion within 8 months. Potency was
improved initially in 9 (38%) of the 24 patients in whom successful anastomosis
had been achieved, with longer term improvement in 6 (25%) of 24 who realized
restoration of erectile potency as defined by clinical investigations. The mean
follow-up was 24 months (range 3-36 months). CONCLUSION: We believe that
anastomosis of the inferior epigastric artery to the deep dorsal penile vein and
ligation of the vein proximally in cases of venous leakage results in a low
success rate due probably to a pancavernosal alteration in corporal tissue
compliance.
PMID- 9392060
TI - Symptomatic adrenal myelolipoma. Clinicopathological analysis of 7 cases and
brief review of the literature.
AB - Seven cases of adrenal myelolipoma comprising 5.8% of total adrenal tumors are
described with a male-to-female ratio of 1.3:1. Five were symptomatic, of which 4
had a palpable abdominal mass, 2 cases detected incidentally were associated with
carcinoma of the uterine cervix and renal cell carcinoma, respectively. The
average age and duration of symptoms at presentation were 56 years (range 38-70
years) and 3.16 months (range 1-9 months). A CT scan was done in all cases, of
which 5 showed a nonenhancing mass lesion with fat density diagnosed as adrenal
myelolipoma. However, in 1 case radiological diagnosis of liposarcoma was
maintained because of the huge size of the lesion whereas in another case the
lesion was missed because of associated renal cell carcinoma. Interestingly the
right adrenal was involved in all cases and the weight varied from 7 to 2,000 g.
No recurrence was noted in the follow-up period (ranging from 3 months to 10
years).
PMID- 9392059
TI - Right colonic reservoir with submucosally embedded tapered ileum--'Tiflis pouch'.
AB - Seventeen patients with invasive bladder cancer aged between 44 and 67 years
underwent radical cystectomy and construction of the continent urinary reservoir
from 20 to 25 cm cecoascendum reconfigurated a.m. Heineke-Mikulicz. and
submucosally embedded tapered ileum as a continence mechanism--'Tiflis pouch'.
There were no perioperative mortalities and only minor complication but abdominal
wound dehiscence occurred with a subsequent hernia in 1 obese patient. One
patient died of urethral recurrence and malignancy progression 14 months after
surgery. During the follow-up period of 9-37 months, all renal units remained
unobstructed. Eleven of 15 preoperatively dilated units improved. No case of
pouch stone formation, stomal stenosis or difficulties with catheterization was
observed. All patients are continent but 4 need catheterization at 3-hour
intervals. The functional capacity is in the range of 310-560 ml. The Tiflis
pouch is a capacious reservoir in which the continence state is satisfactory,
perioperative complication rate is low and quality of life is high.
PMID- 9392061
TI - Hemangioma of the bladder with extravesical extension.
AB - Bladder hemangioma is a rare benign tumor occurring in any age group. We report
the case of a 76-year-old woman having a bladder hemangioma. On cystoscopic
examination no typical features of the bladder hemangioma were found. Biopsy of
the lesion revealed a cavernous hemangioma. A partial cystectomy was performed
for the control of macroscopic hematuria.
PMID- 9392062
TI - An unusual complication following uroflowmetry: water intoxication resulting in
hyponatremia and seizure.
AB - Uroflowmetry is considered a simple and noninvasive test in the evaluation of
urinary symptoms. It requires patients to consume fluid orally for a full bladder
prior to undertaking the test. Guidelines regarding the amount and rate of oral
fluid intake have not been accurately defined. We report on a patient who
suffered a serious complication of water intoxication with hyponatremia and
seizure due to excessive water consumption and absorption during uroflowmetry. We
discuss the underlying factors concerning this complication and recommend a more
conservative approach to attain a full bladder in a certain subgroup of patients
at risk of developing such a complication.
PMID- 9392063
TI - Influence of the force applied and its period of application on the outcome of
the flexion test of the distal forelimb of the horse.
AB - The influence of the force applied and its period of application on the outcome
of the flexion test of the distal forelimb was investigated in a group of eight
sound horses. The degree of lameness after the flexion test was scored by a
standard clinical classification, and by measuring the angle of maximum fetlock
extension by means of the infrared light-based MacReflex gait analysis system.
There was a good correlation between the clinical score and this electronically
recorded kinematic parameter (r = 0.96). Both the force applied and the period of
application affected the outcome of the test. Increasing the force applied by 25
per cent led to three horses being judged positive, instead of two when the
normal force was applied. Doubling the time to 120 seconds resulted in four
horses rather than two being classified as lame after the test. Reducing the
force to 75 per cent or the time to 30 seconds resulted in all the horses being
classified as sound. A flexion test lasting five minutes, either at 100 per cent
force or at 75 per cent, classified six of the eight horses as lame. It is
concluded that the flexion test should be defined more precisely in terms of
these two factors in order to make its results more consistent and hence more
useful.
PMID- 9392064
TI - Omasal and abomasal impaction in beef suckler cows.
AB - A group of late gestation suckler cows were housed in straw yards and had been
fed solely on pea haulm for the previous three weeks. Four cows became ill, with
a variety of clinical signs, two died, one was euthanased and one recovered
spontaneously. Postmortem examination revealed severe omasal and abomasal
impaction. No further cases occurred after changes were made to the diet of the
cows.
PMID- 9392065
TI - Immunotoxicological effects on piglets of feeding sows diets containing
aflatoxins.
AB - Three groups of four Large White sows were fed diets containing either 800 ppb
purified aflatoxin B1 (group 1), 800 ppb purified aflatoxin G1 (group 2) or 400
ppb B1 and 400 ppb G1 (group 3) throughout gestation and lactation. A control
group of four sows was fed a diet free of aflatoxins. Aflatoxins B1 and M1 were
found in milk samples taken five and 25 days after parturition from the sows of
group 1, aflatoxin G1 was present in the milk of the sows of group 2 and all
three aflatoxins were present in samples from the sows of group 3. The
concentration of aflatoxin in the milk was about 1000-fold lower than that in the
feed, but increased over the 25 days after parturition. The piglet suckling on a
central teat was selected from each sow, given sow milk until the fourth day of
age, and was then free to eat prepared feed while suckling. At the 25th day of
age the selected piglets were removed from the sow and sacrificed. Blood samples
were collected from each piglet and cellular populations were separated for
immunological measurements: an in vitro lymphocyte proliferation test, and tests
to derive the phagocytic activity, phagocytic index and superoxide anion
production of monocyte-derived macrophages were carried out along with studies on
the motility, differential chemotaxis and chemotactic index of circulating
granulocytes. The lymphoproliferative response to mitogens was reduced and
monocyte-derived macrophages failed to efficiently produce superoxide anions
after oxidative burst stimulation in vitro, while their ability to phagocytose
red blood cells was not compromised. Granulocytic cells showed a reduction of
chemotactic response in vitro to chemoattractant bacteria factor and casein.
PMID- 9392066
TI - Use of arithmetic and geometric means in the calculation of anthelmintic
efficacy.
PMID- 9392067
TI - Cutaneous lymphoma in a Scottish blackface ram.
PMID- 9392068
TI - Endogenous lipid pneumonia (alveolar histiocytosis) and hydrocephalus in an adult
llama (Llama glama).
PMID- 9392069
TI - Vaccination of farmed crocodiles (Crocodylus niloticus) against Mycoplasma
crocodyli infection.
PMID- 9392070
TI - Generalised caseous lymphadenitis.
PMID- 9392071
TI - Porcine dermatitis and nephropathy syndrome in the USA.
PMID- 9392072
TI - Therapeutic claims for unlicensed products.
PMID- 9392073
TI - Ragwort poisoning in a pedigree cow.
PMID- 9392074
TI - The homeodomain protein Pho2p binds at an A/T-rich segment flanking the binding
site of the basic-helix-loop-helix protein Pho4p in the yeast PHO promoters.
AB - Transcription of the genomic PHO5, PHO81 and PHO84 genes of the PHO regulon
requires Pho4p and Pho2p activity, whereas transcription of PHO8 is directed by
Pho4p alone. Pho4p binds to two 9-bp motifs, 5'-GCACGTGGG-3' (type 1. e.g. UASp2
of PHO5 and site D of PHO84) and 5'-GCACGTTTT-3' (type 2, e.g. UASp1 of PHO5 and
site E of PHO84) in the PHO promoter. Experiments were performed to evaluate the
ability of these 9-bp motifs to function as upstream activation sites (UASs) by
insertion of various 36-bp fragments bearing the 9-bp motif in a CYC1-lacZ fusion
gene. No expression of the lacZ gene was detected with the 36-bp fragment bearing
UASp2 of PHO5, whereas similar 36-bp fragments bearing UASp1 of PHO5 and sites D
and E of PHO84 showed UAS activity in response to Pi concentration in the medium
and to the pho2 mutation. The Pho2p-responsive UASs are flanked by one or two
copies of an A/T-rich segment, whereas UASp2 is not. Gel retardation and
competition experiments performed using a T7-Pho2p-His chimeric protein showed
that Pho2p binds to the 36-bp fragments bearing A/T-rich segment(s) but not
appreciably to the 36-bp fragments not bearing such segment(s). Thus, the A/T
segments flanking the PHO UASs are Pho2p binding sites and play an important role
in PHO regulation.
PMID- 9392075
TI - Purification and characterization of phosphofructokinase from the yeast
Kluyveromyces lactis.
AB - Phosphofructokinase from Kluyveromyces lactis was purified by 180-fold
enrichment, elaborating the following steps: cell disruption, polyethylene glycol
precipitation, affinity chromatography, size exclusion chromatography on
Sepharose 6B and on Bio-Sil SEC 400 and ion exchange chromatography. The
homogeneous enzyme exhibits a molecular mass of 845 +/- 20 kDa as determined by
sedimentation equilibrium measurements and a specific activity of 100 units/mg
protein. The apparent sedimentation coefficient was found to be s20,c = 20.7 +/-
0.6 S and no significant dependence on the protein concentration was observed in
a range from 0.2 to 8 mg protein/ml. Sodium dodecyl sulfate-polyacrylamide gel
electrophoresis revealed two bands corresponding to molecular masses of 119 +/- 5
kDa and 102 +/- 5 kDa, respectively. Thus, the enzyme assembles as octamer
composed of two types of subunits. From Western blot analysis applying subunit
specific monoclonal antibodies raised against Saccharomyces cerevisiae
phosphofructokinase and from the determination of the N-terminal amino acid
sequence, the conclusion was drawn that the 102 kDa-subunit corresponds to the
beta-subunit of the S. cerevisiae enzyme. In contrast to bakers' yeast
phosphofructokinase, the K. lactis enzyme exhibits no cooperativity with respect
to the substrate fructose 6-phosphate. Both activators AMP and fructose 2,6
bisphosphate decrease the Michaelis constant with respect to this substrate. The
enzyme from K. lactis is also inhibited by ATP. Fructose 2,6-bisphosphate or AMP
diminish the ATP-inhibition. In contrast to the phosphofructokinase from S.
cerevisiae, where fructose 2,6-bisphosphate turned out to be more efficient than
AMP, both activators exert similar effects on the K. lactis enzyme.
PMID- 9392076
TI - The ALD6 gene of Saccharomyces cerevisiae encodes a cytosolic, Mg(2+)-activated
acetaldehyde dehydrogenase.
AB - The deduced translation product of an open reading frame on the left arm of
chromosome XVI of Saccharomyces cerevisiae, with the systematic name of YPL061w,
is 500 amino acids in length and shares significant homology with aldehyde
dehydrogenases. Amino acids 2 to 16 of the protein encoded by YPL061w were found
to be identical to the N-terminal 15 amino acids of the purified cytosolic,
Mg(2+)-activated acetaldehyde dehydrogenase (ACDH) of S. cerevisiae. This enzyme
is thought to be involved in the production of acetate from which cytosolic
acetyl-CoA is then synthesized. Deletion of YPL061w was detrimental to the growth
of haploid strains of yeast; an analysis of one deletion mutant revealed a
maximum specific growth rate (in complex medium containing glucose) of one-third
of that displayed by the wild-type strain. Mutants deleted in YPL061w were also
unable to use ethanol as a carbon source. As expected, the cytosolic, Mg(2+)
activated ACDH activity had been lost from the mutants, although the
mitochondrial, K(+)-activated ACDH was readily detected.
PMID- 9392077
TI - Measurement of nuclear DNA content in fission yeast by flow cytometry.
AB - Cell division cycle (cdc) mutants of Schizosaccharomyces pombe are arrested at
specific points in the cell cycle when grown at restrictive temperature. Flow
cytometry of such cells reveals an anomalous increase in the DNA fluorescence
signal, which represents a problem in experiments designed to determine the cell
cycle arrest point. The increased fluorescence signal is due to cytoplasmic
constituents and has been attributed to mitochondrial DNA synthesis (S. Sazer and
S. W. Sherwood, J. Cell Sci. 97: 509-516, 1990). Here we have studied the cdc10
mutant by flow cytometry using different DNA-binding fluorochromes and found no
evidence that the increased fluorescence signal was caused by mitochondrial DNA
synthesis. To determine more accurately the nuclear DNA content we have developed
a novel method to remove most of the cytoplasmic material by exposing the cells
to Triton X-100 and hypotonic conditions after cell wall digestion. The DNA
fluorescence from cells treated in this way was more constant with time of
incubation at restrictive temperature in spite of a considerable increase in cell
size. With this method we could determine that the recently isolated temperature
sensitive orp1 mutant is arrested with a 1C DNA content. Premature and abnormal
mitosis ('cut') could be observed for the orp1 mutant after only 4 h at
restrictive temperature.
PMID- 9392078
TI - Lys80p of Saccharomyces cerevisiae, previously proposed as a specific repressor
of LYS genes, is a pleiotropic regulatory factor identical to Mks1p.
AB - In Saccharomyces cerevisiae, an intermediate of the lysine pathway, alpha
aminoadipate semialdehyde (alpha AASA), acts as a coinducer for the
transcriptional activation of LYS genes by Lys14p. The limitation of the
production of this intermediate through feedback inhibition of the first step of
the pathway results in apparent repression by lysine. Previously, the lys80
mutations, reducing the lysine repression and increasing the production of
lysine, were interpreted as impairing a repressor of LYS genes expression. In
order to understand the role of Lys80p in the control of the lysine pathway, we
have analysed the effects of mutations epistatic to lys80 mutations. The effects
of lys80 mutations on LYS genes expression were dependent on the integrity of the
activation system (Lys14p and alpha AASA). The increased production of lysine in
lys80 mutants appeared to result from an improvement of the metabolic flux
through the pathway and was correlated to an increase of the alpha-ketoglutarate
pool and of the level of several enzymes of the tricarboxylic acid cycle. The
LYS80 genes has been cloned and sequenced; it turned out to be identical to gene
MKS1 cloned as a gene encoding a negative regulator of the RAS-cAMP pathway. We
conclude that Lys80p is a pleiotropic regulatory factor rather than a specific
repressor of LYS genes.
PMID- 9392079
TI - A rapid and reliable method for metabolite extraction in yeast using boiling
buffered ethanol.
AB - A simple and reliable method for the efficient inactivation of metabolism and for
quantitative metabolite extraction from yeast cells is presented. It is based on
the use of a boiling solution made of 75% ethanol (volume/final volume) buffered
with 70 mM-Hepes (final concentration), pH 7.5, to guarantee the stability
throughout the whole procedure of a large variety of metabolites, including all
glycolytic intermediates, nucleotides, pyridine nucleotides and organic acids
compounds. The extraction is fast, requiring only 3 min incubation of yeast cells
in the ethanol-buffered mixture maintained at 80 degrees C. It can be carried out
either directly by spraying the cells into the boiling mixture, or after
quenching the whole culture in 60% methanol kept at -40 degrees C. Extracts are
subsequently concentrated by evaporation under partial vacuum and the residue is
resuspended in a small volume of water. This concentration step and the use of a
highly sensitive analytical method allow us to quantify metabolites in less than
10 mg dry weight cells. This method, which can be applied to other fungi, could
be very helpful for the determination of true metabolites in mutants generated
through the EUROFAN programme and for metabolic flux analysis.
PMID- 9392080
TI - Functional differences among the six Saccharomyces cerevisiae tRNATrp genes.
AB - The Saccharomyces cerevisiae haploid genome includes six copies of the gene
encoding tRNATrp which are scattered on five chromosomes. Other, non-functional
tDNATrp fragments also occur in the genome. The segments of all six genes which
encode the 72-nucleotide mature tRNATrp, as well as a 34-nucleotide intervening
sequence, are identical. However, the 5' and 3' flanking sequences diverge
virtually at the boundaries of the coding region. We have used an assay based on
suppression of UGA mutations by multi-copy clones of tDNATrp to search for
functional differences among these genes. Previous studies with one tDNATrp had
demonstrated that moderate suppression of a UGA mutation, leu2-2, resulted from
introduction of a multi-copy clone of the gene. Attempts to use this assay to
select tDNATrp clones from a yeast genomic library yielded only four of the six
different clones. The other two genes were amplified by PCR and cloned in pRS202,
a 2 mu vector also used for the genomic library. Plasmids bearing the six tRNA
genes were transformed into S. cerevisiae strain JG369.3B and scored for their
ability to suppress the leu2-2 mutation as well as his4-260, another UGA marker.
Two of the six tRNATrp clones were unable to suppress either marker, two
evidenced weak suppression of the Leu auxotrophy, and two were able to suppress
both markers. Growth rates in liquid media requiring suppression were measured
for cell lines carrying each of the clones. Differences greater than 50-fold were
observed in media lacking histidine. An evolutionary tree based on 5'-flanking
sequence corresponds reasonably well with suppressor activity, while a similar
analysis of 3'-flanking sequence does not. This suggests that the functional
differences are based on divergence in the 5'-flanking sequences of the tRNATrp
genes.
PMID- 9392081
TI - Characterization of new proteins found by analysis of short open reading frames
from the full yeast genome.
AB - We have analysed short open reading frames (between 150 and 300 base pairs long)
of the yeast genome (Saccharomyces cerevisiae) with a two-step strategy. The
first step selects a candidate set of open reading frames from the DNA sequence
based on statistical evaluation of DNA and protein sequence properties. The
second step filters the candidate set by selecting open reading frames with high
similarity to other known sequences (from any organism). As a result, we report
ten new predicted proteins not present in the current sequence databases. These
include a new alcohol dehydrogenase, a protein probably related to the cell
cycle, as well as a homolog of the prokaryotic ribosomal protein L36 likely to be
a mitochondrial ribosomal protein coded in the nuclear genome. We conclude that
the analysis of short open reading frames leads to biologically interesting
discoveries, even though the quantitative yield of new proteins is relatively
low.
PMID- 9392082
TI - Isolation of a putative prolyl-tRNA synthetase (CaPRS) gene from Candida
albicans.
AB - We have isolated a 4.0-kb fragment from a genomic library of Candida albicans
which contained two open reading frames (ORFs). One of them is homologous to a
prolyl-tRNA synthetase that catalyses the charging of a specific tRNA by proline
(CaPRS). A deduced sequence of 575 amino acids representing a polypeptide of 66.2
kDa was determined. A FASTA search indicated that the CaPRSp had an overall
similarity of 54.4% with the product of a Saccharomyces cerevisiae ORF (YER087)
and 43.8% with the prolyl-tRNA synthetase of Escherichia coli (COLIPRO).
Consensus Class II aminoacyl-tRNA synthetase sequences were identified by the
PROSITE program. CaPRS was localized to chromosome R of the C. albicans genome
and CaPRS DNA hybridized to a major RNA transcript of 1.7 kb under all conditions
tested.
PMID- 9392083
TI - Isolation and sequence of the gene encoding ornithine decarboxylase, SPE1, from
Candida albicans by complementation of a spe1 delta strain of Saccharomyces
cerevisiae.
AB - The gene encoding ornithine decarboxylase, SPE1, from the pathogenic yeast
Candida albicans has been isolated by complementation of an ornithine
decarboxylase-negative (spe1 delta) strain of Saccharomyces cerevisiae. Four
transformants, three of which contain plasmids with the SPE1 gene, were isolated
by selection on polyamine-free medium. The C. albicans ornithine decarboxylase
(ODC) showed high homology with other eukaryotic ODCs at both the amino acid and
nucleic acid levels.
PMID- 9392084
TI - Current awareness on yeast.
PMID- 9392086
TI - [Carbohydrates and the human being].
PMID- 9392087
TI - [Glycogen synthesis and glycogenolysis].
PMID- 9392085
TI - [Several problems in the clinical aspects of diabetes mellitus].
PMID- 9392088
TI - [Gluconeogenesis and glycolysis].
PMID- 9392089
TI - [TCA cycle and electron transport system].
PMID- 9392090
TI - [Glucose transporter].
PMID- 9392092
TI - [Glucose transport in the kidney].
PMID- 9392091
TI - [Mechanisms of carbohydrate digestion and absorption in the intestinal tract].
PMID- 9392093
TI - [Review: regulatory factors of glucose metabolism].
PMID- 9392094
TI - [Insulin gene: gene organization and its regulatory mechanism of transcription].
PMID- 9392095
TI - [Insulin biosynthesis and its chemical structure].
PMID- 9392096
TI - [Molecular mechanism of insulin secretion].
PMID- 9392097
TI - [Biphasic insulin secretion and glucose metabolism].
PMID- 9392098
TI - [The structure and the regulation of the gene expression of human insulin
receptor gene].
PMID- 9392099
TI - [Structure and biosynthesis of human insulin receptor].
PMID- 9392100
TI - [Mechanism of insulin actions].
PMID- 9392101
TI - [Insulin, its kinetics and metabolism].
PMID- 9392102
TI - [Glucagon, GLP].
PMID- 9392103
TI - [Somatostatin].
PMID- 9392104
TI - [Gastrointestinal hormones in diabetes mellitus].
PMID- 9392105
TI - [Anterior pituitary hormones--mainly about growth hormone].
PMID- 9392106
TI - [Biogenic amines].
PMID- 9392107
TI - [Glucocorticoid].
PMID- 9392108
TI - [Regulation of glucose metabolism by thyroid hormones].
PMID- 9392110
TI - [Glucose, protein, and lipid metabolism and their regulation system in
adipocyte].
PMID- 9392109
TI - [Hepatocyte].
PMID- 9392111
TI - [Specific glucose metabolism in muscle].
PMID- 9392112
TI - [Brain energy metabolism].
PMID- 9392113
TI - [Vascular endothelial cells].
PMID- 9392114
TI - [Intestinal epithelial cells].
PMID- 9392115
TI - [Renal tubular cells].
PMID- 9392116
TI - [Definition and classification of diabetes mellitus].
PMID- 9392117
TI - [Problems on the diagnostic criteria for diabetes mellitus].
PMID- 9392118
TI - [Early diagnosis of NIDDM--theory and direction].
PMID- 9392119
TI - [Natural history of diabetes mellitus].
PMID- 9392120
TI - [IDDM--overview].
PMID- 9392121
TI - [Susceptibility genes for IDDM].
PMID- 9392122
TI - [Molecular mechanisms of pancreatic beta-cell destruction in IDDM].
PMID- 9392123
TI - [Destruction and regeneration of pancreatic beta cells].
PMID- 9392124
TI - [Adhesion molecules and diabetes mellitus].
PMID- 9392125
TI - [General aspects of etiology and pathogenesis of NIDDM].
PMID- 9392126
TI - [Molecular genetics of NIDDM].
PMID- 9392127
TI - [Molecular mechanisms for impaired insulin secretion in NIDDM].
PMID- 9392128
TI - [Defects in insulin's signalling process and diabetes mellitus].
PMID- 9392129
TI - [Primary, secondary, tertiary prevention of diabetes mellitus].
PMID- 9392130
TI - [Lifestyle interventions for preventing non insulin-dependent diabetes mellitus].
PMID- 9392131
TI - [Possible primary prevention of NIDDM (type 2 diabetes) by pharmacological
interventions].
PMID- 9392133
TI - [Association of HLA genes with IDDM: a review].
PMID- 9392132
TI - [Gene mutations in diabetes mellitus].
PMID- 9392134
TI - [IDDM and variable number of tandem repeats (VNTR) in the 5'region of the insulin
gene: a review].
PMID- 9392135
TI - [TNF gene polymorphism and IDDM].
PMID- 9392136
TI - [Glutamic acid decarboxylase gene].
PMID- 9392137
TI - [Type 1 diabetes susceptibility genes on human chromosome 2q].
PMID- 9392138
TI - [Insulin gene].
PMID- 9392139
TI - [Insulin receptor gene].
PMID- 9392140
TI - [Insulin promoter factor-1].
PMID- 9392141
TI - [Glucokinase gene and its dual promoter regions].
PMID- 9392142
TI - [Insulin receptor substrate-1 (IRS-1) gene].
PMID- 9392143
TI - [Glucagon receptor gene].
PMID- 9392144
TI - [Glucagon-like peptide-1 (GLP-1) receptor gene].
PMID- 9392145
TI - [Fatty acid binding protein-2(FABP-2) gene].
PMID- 9392146
TI - [Glycogen synthase gene].
PMID- 9392147
TI - [Amylin (IAPP) gene].
PMID- 9392148
TI - [ATP sensitive potassium channels--Kir6.2 gene].
PMID- 9392149
TI - [ATP-sensitive potassium channel--sulfonylurea receptor].
PMID- 9392150
TI - [Proinsulin converting enzyme (PC2, PC3) gene].
PMID- 9392151
TI - [Beta 3-adrenergic receptors].
PMID- 9392152
TI - [Glucose transporter gene].
PMID- 9392153
TI - [Hexokinase gene].
PMID- 9392155
TI - [Apolipoprotein genes].
PMID- 9392154
TI - [ob gene (leptin gene)].
PMID- 9392156
TI - [Mitochondria glycerol-3-phosphate dehydrogenase gene].
PMID- 9392157
TI - [Mutation/polymorphism of phosphofructokinase (PFK) genes in diabetes mellitus].
PMID- 9392158
TI - [Islet 1 gene].
PMID- 9392159
TI - [Gastric inhibitory polypeptide (GIP) receptor].
PMID- 9392160
TI - [Secondary forms of diabetes].
PMID- 9392161
TI - [Pathology of diabetes mellitus].
PMID- 9392162
TI - [Epidemiology of diabetes mellitus in Japan].
PMID- 9392163
TI - [Prognosis and causes of death in patients with non-insulin-dependent diabetes
mellitus (NIDDM)].
PMID- 9392164
TI - [Epidemiology of diabetes mellitus in the elderly].
PMID- 9392165
TI - [Epidemiology of diabetes mellitus in the world except Japan].
PMID- 9392166
TI - [Family history of diabetes].
PMID- 9392167
TI - [Symptomatology of diabetes mellitus].
PMID- 9392168
TI - [Abnormal carbohydrate metabolism in diabetes mellitus].
PMID- 9392169
TI - [Abnormalities in lipid metabolism associated with diabetes mellitus].
PMID- 9392170
TI - [Lipoprotein abnormalities in normolipidemic diabetics].
PMID- 9392171
TI - [Diabetes-induced abnormality in protein metabolism].
PMID- 9392172
TI - [Abnormalities of amino acid metabolism in diabetes mellitus].
PMID- 9392173
TI - [Metabolic disorders of organic acids in diabetes].
PMID- 9392174
TI - [Altered uric acid metabolism in diabetes mellitus].
PMID- 9392175
TI - [Diabetes and vitamin deficiency].
PMID- 9392176
TI - [Water and electrolyte disorders and acid-base imbalance in diabetic patients].
PMID- 9392177
TI - [Disturbance of mineral metabolism].
PMID- 9392178
TI - [Trace elements in diabetes mellitus].
PMID- 9392179
TI - [Endocrine disorders in diabetes mellitus].
PMID- 9392180
TI - [Platelet dysfunction].
PMID- 9392181
TI - [Abnormality of clotting and fibrinolysis in diabetes mellitus].
PMID- 9392182
TI - [Hemorheological abnormality in diabetes mellitus].
PMID- 9392183
TI - [Diabetes mellitus and associated hypertension].
PMID- 9392184
TI - [Immunological disorder in diabetes mellitus].
PMID- 9392185
TI - [Abnormal arachidonate metabolites in diabetes mellitus].
PMID- 9392186
TI - [Abnormalities in inositol phospholipid metabolism].
PMID- 9392187
TI - [Diabetic complications--definition, classification, epidemiology].
PMID- 9392188
TI - [Risk factors for the development of diabetic complications].
PMID- 9392189
TI - [Molecular biology of atherosclerosis].
PMID- 9392190
TI - [Vascular endothelial cell injury in diabetes mellitus].
PMID- 9392191
TI - [Metabolic disorder of polyol pathway].
PMID- 9392192
TI - [Oxidative stress and atherosclerosis].
PMID- 9392193
TI - [Diabetes mellitus and cerebrovascular disorders].
PMID- 9392194
TI - [Coronary artery disease, heart failure and cardiomyopathy in diabetic patients].
PMID- 9392195
TI - [Arteriosclerosis obliterans in diabetes mellitus].
PMID- 9392196
TI - [Diabetic nephropathy--definition, stages, measurement of albuminuria, and
therapy].
PMID- 9392197
TI - [Pathology of diabetic nephropathy].
PMID- 9392198
TI - [Diabetic nephropathy--risk factors and incidences].
PMID- 9392199
TI - [Familial clustering and genetics of diabetic nephropathy].
PMID- 9392200
TI - [Diabetic nephropathy--predictive methods].
PMID- 9392201
TI - [The effect of nutritional arrangement and glycemic control on the progression of
chronic renal failure in diabetic patients].
PMID- 9392202
TI - [Renal replacement therapy for diabetic nephropathy].
PMID- 9392203
TI - [Survival of patients with diabetic nephropathy on hemodialysis or CAPD].
PMID- 9392204
TI - [Diabetic neuropathy--concept, classification, diagnosis, treatment].
PMID- 9392205
TI - [Diabetic neuropathy--its pathology].
PMID- 9392206
TI - [Diabetic neuropathy--risk factors and pathogenesis].
PMID- 9392207
TI - [Early detection for diabetic neuropathy].
PMID- 9392208
TI - [Electrophysiology in diabetic neurological complications].
PMID- 9392209
TI - [Sensory disorders and pain treatment in diabetic neuropathy].
PMID- 9392210
TI - [Diabetic autonomic neuropathy].
PMID- 9392211
TI - [Diabetic urinary bladder and urethral dysfunction].
PMID- 9392212
TI - [Diabetic neurogenic arthropathy (Charcot's joint)].
PMID- 9392213
TI - [Infectious complications of diabetes mellitus].
PMID- 9392214
TI - [Liver, biliary, and pancreas disease in diabetes mellitus].
PMID- 9392215
TI - [Gastrointestinal complications of diabetes mellitus].
PMID- 9392216
TI - [Diabetic gastropathy].
PMID- 9392217
TI - [Diabetic foot].
PMID- 9392218
TI - [Autoimmune disease in patients with diabetes mellitus].
PMID- 9392219
TI - [Endocrinopathy associated with diabetes mellitus].
PMID- 9392220
TI - [Diabetic sexual impotence].
PMID- 9392221
TI - [Diabetic osteopenia].
PMID- 9392222
TI - [Diabetic retinopathy--classification, diagnosis, treatment].
PMID- 9392223
TI - [Diabetic retinopathy--pathology].
PMID- 9392224
TI - [Risk factors for diabetic retinopathy].
PMID- 9392225
TI - [Molecular pathogenesis of diabetic retinopathy].
PMID- 9392226
TI - [Method of early detection at every stage of diabetic retinopathy].
PMID- 9392227
TI - [Conservative therapy of diabetic retinopathy].
PMID- 9392228
TI - [Treatment for diabetic retinopathy using photocoagulation and vitrectomy].
PMID- 9392229
TI - [The cutaneous manifestations of diabetes mellitus].
PMID- 9392230
TI - [Diabetic orthostatic hypotension].
PMID- 9392231
TI - [Primary glomerulonephritis complicating diabetes mellitus].
PMID- 9392232
TI - [Diabetes mellitus and periodontal disease].
PMID- 9392233
TI - [Diabetes mellitus and sleep apnea syndrome].
PMID- 9392234
TI - [Diabetic amyotrophy].
PMID- 9392235
TI - [Rhabdomyolysis in the diabetic state].
PMID- 9392237
TI - [Hyperosmolar nonketotic coma].
PMID- 9392236
TI - [Diabetic ketoacidotic coma].
PMID- 9392238
TI - [Lactic acidosis].
PMID- 9392239
TI - Healthcare assistants: the substitute nurse.
PMID- 9392240
TI - New deal for people with learning difficulties.
PMID- 9392241
TI - I.v. therapy: selection, use and management of infusion pumps.
AB - A locally agreed, coordinated policy is essential for the selection and purchase
of infusion pumps, and should form part of overall policy for medical device
management. When developing a purchasing policy the core needs of all relevant
professional groups should be addressed, to ensure that an informed, integrated
strategy evolves. This will enhance the wider responsibilities associated with,
for example, device training and education, and medical device maintenance, as
well as the basic clinical requirements of the infusion pump. The Medical Devices
Agency provides guidance on the selection and purchasing of infusion pumps
through its medical device evaluation programme, which uses evidence-based
systems that categorize devices by clinical infusion risk.
PMID- 9392242
TI - Why should acute trusts be interested in cardiac rehabilitation?
AB - This questionnaire survey of 100 ex-coronary care unit (CCU) patients in the
Royal Devon and Exeter Hospital NHS Trust sought to determine patients' views
(i.e. consumers' rather than professionals' views) regarding their perceived need
for individual of group support following myocardial infarction, and whether the
information received in hospital was adequate for their needs. A literature
review of the evidence suggesting that cardiac rehabilitation is effective is
included. Responses indicated that 42 of the 62 patients who responded (67.7%)
felt that they would have benefited from a relaxation and/or support group, with
40 (69%) stating that they would have attended such a facility after discharge.
The nature of the information offered by nursing staff while patients were in
hospital was clearly that which was 'convenient' and 'unthreatening' for nurses
to deliver. Only 35 respondents (56.4%) agreed that this information was adequate
for their needs. These results indicate the preferences of our local consumers,
whose views should be paramount in the contemporary NHS. There is a significant
unmet demand for such services, which acute sector staff have the expertise to
meet.
PMID- 9392243
TI - Participatory research methods: people with learning difficulties.
AB - The use of participatory research methods as a means of empowering disadvantaged
and oppressed groups or individuals has attracted increasing interest in recent
years. This article critically examines the use of such methods to empower people
with learning difficulties as co-researchers. Emancipatory research would, by
definition, be led and processed by people with learning difficulties. For the
time being, however, the possibility of engaging people with learning
difficulties in truly emancipatory nursing research is regarded as highly
problematic, since it assumes empowerment as a precondition. As a step towards
emancipatory research, participatory research represents a radical shift in the
research process. It may potentially strengthen the voice of people with learning
difficulties and enable them to express their views on nursing. The author
proposes a methodology which addresses a number of critical issues facing the
nurse researcher. It is a step towards developing more liberating and
emancipatory methodologies.
PMID- 9392244
TI - Future directions for learning disability nursing.
AB - Over the past decade learning disability nurses have had to make many changes in
the way they practice. Changes in attitude towards the way in which people with
learning disabilities are cared for has meant that nurses have had to adjust
their practice to address different expectations in the way these services are
delivered. Nursing now provides opportunities for people with learning
disabilities to express themselves and become involved in decision-making that
affects their lives. For nurses this is a totally new way of working with this
client group. Learning disability nurses have risen to the challenge that has
resulted from moving into community care and forming links with primary
healthcare teams.
PMID- 9392245
TI - Malnutrition in hospital: detection and consequences.
AB - Malnutrition in hospital is not a new concept. Studies carried out over 20 years
ago identified that 50% of surgical patients (Hill et al, 1977) and 44% of
medical patients (Bistrian et al, 1976) showed evidence of malnutrition. A more
recent study demonstrated that the problem still exists (McWhirter and
Pennington, 1994). This research showed that 40% of patients were undernourished
on admission to hospital and 78% of these suffered further deterioration in their
nutritional status during their hospital stay. This article, the first in the
series, aims to identify patient groups which are likely to become malnourished
during hospitalization and outlines how nurses and doctors can detect
malnutrition and/or potential malnutrition in patients. The consequences of
malnutrition and the current issues surrounding the reported problems of patients
who do not receive enough food and drink while in hospital (Association of
Community Health Councils, 1997) are discussed. The article also explores what
measures can be taken to improve patients nutritional intake while in hospital.
It describes the way forward in terms of clinical practice, current projects and
the information and training available to nurses and other members of the
multidisciplinary team. The author's overall aim is to improve healthcare
professionals' knowledge within this field and to raise the profile of
nutritional care.
PMID- 9392246
TI - The abuse of specialist nursing titles must stop.
PMID- 9392247
TI - Caring in the nineties.
PMID- 9392248
TI - A Christian perspective of caring.
PMID- 9392249
TI - Making a difference: competent to care.
PMID- 9392250
TI - History in nursing.
PMID- 9392251
TI - [Cesarean section].
PMID- 9392252
TI - [Approval of course].
PMID- 9392253
TI - [Women should be able to choose cesarean section themselves. Interview by Bjorg
Engdahl].
PMID- 9392254
TI - [Cesarean section for the 3rd time. Interview by Bjorg Engdahl].
PMID- 9392255
TI - [Disagreement among obstetricians: one cannot squander cesarean sections.
Interview by Bjorg Engdahl].
PMID- 9392256
TI - [Committed midwife becomes clinical specialist. Interview by Ingrid M Hoie].
PMID- 9392257
TI - [Many rare diagnoses collected in Sunaas. Interview by Per Flakstad].
PMID- 9392258
TI - [Health care failure--midwife's responsibility?].
PMID- 9392259
TI - Performance improvement, accreditation, and case management: defining the link.
PMID- 9392260
TI - Complementary nursing--an acute care case management model. Part I--development
and implementation.
AB - Complementary nursing was developed in response to the need for maintaining high
quality care while controlling health care costs. The complementary nurse
provides comprehensive management of complex patients through an entire episode
of an acute illness, to transition them back to a prehospital state through
interdisciplinary discharge planning. In this article, the authors describe the
process used in developing and implementing this new integrated role of acute
care case management. The article contains role responsibilities, communication
tools, and lessons learned from experience.
PMID- 9392261
TI - The need for information-based practice in case management.
AB - For case management, information-based practice is not only important but
mandatory in the current competitive healthcare settings that require "cutting
edge" knowledge of clinical research, business administration, managed care
principles, and quality and cost-effective standards of practice. Obtaining case
management-related electronic information through the Internet and CD-ROM
computer databases can provide critical tools to obtain this knowledge quickly
and promote higher quality practice of case management.
PMID- 9392262
TI - Ethical decisions with limited resources. How is that possible?
AB - Ethical decision making is a process case managers can use to help negotiate
through complicated situations. In our complex health care delivery systems, case
managers often have competing benefits and burdens to balance. In this article,
the author presents an ethical decision making model that can assist in the
process of decision making. The obligations of case managers to patients remain
constant-attempting to be of benefit, but as the trajectory of care changes from
acute to chronic to dying, the understanding of benefit will change. Caring for
patients and their families within a managed care environment entails always
keeping the benefit of the self, patient, family, employers, and society all in
balance.
PMID- 9392263
TI - Consistency in prevention and treatment of pressure ulcers through a wound care
team.
PMID- 9392264
TI - Case management for the self-insured hospital.
AB - It is rare for employers who self insure to have on-site case management.
Generally, self-insured employers rely on the third-party-plan administrators to
control health care costs, provide enrollees with health care benefit management
services, and maintain customer satisfaction. In this article, the author
discusses the internal workings of an employee case management program
implemented in a self-insured hospital in Northwest Indiana. Information is
presented on the goals and role of the case manager, scope of practice, barriers
to the program, and resources involved to deliver health care services to its
enrollees. Also presented is pertinent information to track and trend data for
administrative reports. In addition, customer satisfaction and the value of an on
site case manager for self-insured organizations will be addressed. The results
demonstrate a reduction in the volume of inpatient admissions, length of stay,
and, therefore, an improved use of the health plan.
PMID- 9392265
TI - Building stress resilience for nurse case managers.
PMID- 9392266
TI - A case map reduces time to administration of thrombolytic therapy in patients
experiencing an acute myocardial infarction.
AB - As one of the first hospitals in northwest Arkansas to begin administering
thrombolytic therapy to patients with heart attack, or acute myocardial
infarction (AMI), Crawford Memorial Hospital (CMH) first administered
streptokinase to a patient experiencing an AMI on April 26, 1984. A national
standard in lytic therapy was set in 1992 by the National Heart Attack Alert
Program Coordinating Committee. The committee set a benchmark of having every
appropriate AMI patient receive thrombolytic therapy within 30 minutes of
hospital arrival. To monitor quality in lytic therapy administration, CMH began
to participate in the National Registry for Myocardial Infarction (NRMI), in
January 1995. The first quarter of data revealed a median door-to-drug time (time
from arrival at hospital to administration of drug) of 67 minutes. As a quality
improvement project, a research experiment was conducted to assess the effect of
a case map, also referred to as a clinical pathway, on time to administration of
thrombolytic therapy. A case map is a written management plan that provides the
ideal sequence and timing of health care staff actions to achieve optimal patient
outcomes with minimal variation in care. The researcher developed a case map
designed to increase efficiency in delivery of thrombolytic agents. The research
was conducted throughout an 18-month period from July 1995 until December 1996.
Median time to administration of thrombolytic therapy was reduced from 64 minutes
to 25 minutes as a result of case map use (p = 0.028). In this article, research
findings are presented regarding the use of case maps in thrombolytic therapy, as
well as implications for practice.
PMID- 9392267
TI - The RCN unveils the results of its ward leadership project.
PMID- 9392268
TI - Lights, camera ... action?
PMID- 9392269
TI - Day of reckoning.
PMID- 9392270
TI - Digging for labour.
PMID- 9392271
TI - My sham trial.
PMID- 9392272
TI - Human rights?
PMID- 9392273
TI - Free for all.
PMID- 9392274
TI - Ward leadership.
PMID- 9392275
TI - It's good to talk. Interview by Kate Williams.
PMID- 9392276
TI - Clean hands.
PMID- 9392277
TI - Standards of nursing care 1987-1997.
PMID- 9392279
TI - Trust-wide core care plans.
AB - This article discusses the concept and implication of core care plans. The
authors also assess the effect of the introduction of core care plans
introduction within the Scarborough and North East Yorkshire Healthcare NHS
Trust.
PMID- 9392278
TI - Evaluation of a nurse-led minor injuries unit.
AB - This article, the first of two, reports the evaluation of a minor injuries
clinic. The authors describe the background to the service and the methodology
and results of the study. Some 20,000 patients attended the clinic during its
first two years, at an average cost of 33 pounds per patient. Waiting times were
low and 67 per cent of patients were discharged. Independent clinical audit rated
98 per cent of cases as satisfactorily treated. The clinic has generally been
accepted by the local medical community and was funded permanently in late 1996.
PMID- 9392280
TI - Surviving cancer: a review of the impact and consequences.
AB - In this critical review of the literature, the author examines articles assessing
the effects on patients of cancer survival. Implications for nursing practice,
education and research are also discussed.
PMID- 9392281
TI - Comparing asthma and chronic obstructive pulmonary disease (COPD).
PMID- 9392282
TI - Plans for a nurse recruitment campaign.
PMID- 9392283
TI - Funding shift needs a lesson in clarity.
PMID- 9392284
TI - Capital crisis.
PMID- 9392285
TI - Don't shoot the tsar.
PMID- 9392286
TI - Security guard.
PMID- 9392287
TI - People's contract.
PMID- 9392288
TI - Bad science.
PMID- 9392289
TI - Violence at work.
PMID- 9392290
TI - Peaceful means.
PMID- 9392292
TI - Learn to surf.
PMID- 9392291
TI - Family support. Interview by Dina Leifer.
PMID- 9392293
TI - Mental health network: a research programme.
AB - This report is based on information supplied by the Network for Psychiatric
Nursing Research in Oxford. Each month, we highlight work being carried out in
key areas of interest to mental health nurses. This week, we concentrate on a
selection of research and views about how psychiatric nurses manage risk.
PMID- 9392294
TI - Intravenous sedation for short procedures and investigations.
PMID- 9392295
TI - Reducing the risk of complications in i.v. therapy.
PMID- 9392296
TI - Minor injuries units: evaluating patients' perceptions.
AB - In the second of two articles, the authors report on an evaluation of a minor
injuries clinic run by nurse practitioners. The first article was published last
week.
PMID- 9392297
TI - Violence to nurses: prevalence and risk factors.
AB - This article provides a review of current knowledge on the problem of violence to
nurses by patients and relatives. In particular, the article discusses the extent
of such violence in nursing generally and across different specialties.
PMID- 9392298
TI - High-dose/activation-associated tolerance: a mechanism for allograft tolerance.
PMID- 9392299
TI - Characterization of pigs transgenic for human decay-accelerating factor.
AB - BACKGROUND: To prevent the central role played by complement activation in the
hyperacute rejection of pig organs transplanted into primates, pigs transgenic
for human decay-accelerating factor (HDAF) have recently been produced. The data
presented here extend previous immunohistochemical findings by documenting the
immunological characterization and the levels of expression of HDAF in these
transgenic pigs. METHODS: Animals from 30 independently derived lines were
included in this study. HDAF expression was characterized by immunoprecipitation
and epitope mapping. Quantitative analysis was performed by radiometric assays
followed by Scatchard analysis and by double-determinant radioimmunoassay.
Deposition of iC3b on porcine aortic endothelial cells was determined by
radioimmunoassay. DNA slot-blot analysis and densitometric scanning were used to
evaluate HDAF transgene copy number. RESULTS: The integrity of HDAF expressed by
these transgenic pigs could be demonstrated. HDAF was present in 72% of the
organs analyzed, although considerable variation in expression occurred, both
between animals and within the same pig. High levels of HDAF on porcine aortic
endothelial cells resulted in iC3b deposition at levels as low as that detected
on human endothelial cells. Twenty-six organs expressed levels of HDAF greater
than those observed in the equivalent human tissue. HDAF expression did not
correlate with the number of copies of the transgene incorporated into the
porcine genome. CONCLUSIONS: Transgenic pigs, which express levels of functional
HDAF even greater than those observed in humans, have successfully been produced.
Pigs transgenic for human complement inhibiting molecules could represent a
source of organs for future clinical xenotransplantation.
PMID- 9392300
TI - Apoptosis after intestinal ischemia-reperfusion injury: a morphological study.
AB - BACKGROUND: Apoptosis has been identified after ischemia-reperfusion (IR) injury
to the brain, heart, kidney, retina, and the adrenals. Intestinal IR injury
causes villous and crypt damage, which has so far been attributed to cellular
necrosis. This study was undertaken to investigate the possible role of apoptosis
after reperfusion of cold-stored small bowel grafts in syngeneic rats. METHODS:
Small intestinal grafts were stored at 4 degrees C for 24 hr in saline (n=6) or
in modified University of Wisconsin solution (n=6), followed by reperfusion for 1
hr in syngeneic Lewis rats. Small bowel samples were obtained before storage,
after preservation and after 1 hr of reperfusion. They were processed for light
and electron microscopy and analyzed for cell death, with particular emphasis on
apoptosis. RESULTS: Less than one apoptotic event was seen per 10 crypts in
normal and stored bowels. An occasional normal and some denuded villous
epithelial cells of stored bowels exhibited apoptosis. After isotransplantation
and 1 hr of reperfusion, marked increase in apoptosis was seen in the crypts and
denuded villous epithelial cells of both saline- and modified University of
Wisconsin-stored bowels. Secondary necrosis was seen in apoptotic cells, as were
dark cells. Only a few cells showed signs of primary ischemic necrosis.
CONCLUSIONS: Apoptosis occurs after intestinal IR injury. Modulation of its
genetic regulatory and biochemical effector machinery might alleviate or even
prevent IR injury in small bowel transplanted after similar periods of storage.
PMID- 9392301
TI - Up-regulation of oxygen-derived free radicals by interleukin-1 in hepatic
ischemia/reperfusion injury.
AB - BACKGROUND: Oxygen-derived free radicals (FRs) are critical mediators of
ischemia/reperfusion injury. Inflammatory cytokines have been shown to play
important roles in tissue injury. To examine the relationship between FRs and
interleukin-1 (IL-1) in hepatic ischemia/reperfusion injury, we used interleukin
1 receptor antagonist (IL-1ra) to block endogenous IL-1 production in a rat model
of hepatic ischemia/reperfusion. METHODS: Female SD rats were subjected to 30 min
of hepatic ischemia followed by reperfusion. The animals were divided into two
groups, control group and IL-1ra-treated group, according to the rinse solution.
In both groups, FR production, histological changes, and interactions between
leukocytes and endothelial cells were analyzed in the course of reperfusion.
RESULTS: In the control group, production of FRs increased significantly after 60
min of reperfusion. After 60 and 180 min of reperfusion, histological examination
showed atrophy and degeneration of hepatocytes. Hepatic microcirculation
demonstrated a marked increase in the number of leukocytes adherent to
endothelial cells and of injured cells after reperfusion. In the IL-1ra-treated
group, IL-1ra pretreatment markedly reduced FR production after 60 min of
reperfusion, the number of leukocytes adherent to endothelial cells, and tissue
injury. CONCLUSION: These data clearly show an important role for IL-1 in the
induction of FR production, leukocyte adhesion, and tissue injury after hepatic
ischemia/reperfusion injury.
PMID- 9392302
TI - Pentoxifylline reduces nephrotoxicity associated with cyclosporine in the rat by
its rheological properties.
AB - BACKGROUND: The goals of this study were to evaluate whether administration of
pentoxifylline (POF) reduces the nephrotoxicity associated with cyclosporine
(CsA) in the rat, and whether the effect of POF is related to its rheological
properties. METHODS: Mean arterial pressure was measured by an intraarterial
catheter. Glomerular filtration rate and renal plasma flow were determined by
measuring inulin and para-aminohippurate clearances, after double-blind
coadministration for 10 days of CsA (25 mg/kg/day) with either vehicle or POF (45
mg/kg every 12 hr). These results were compared with those obtained in control
rats. Blood viscosity and erythrocyte deformability were also evaluated after
treatment using a cone plate viscometer and a filtration method, respectively.
RESULTS: No changes were observed in mean arterial pressure in both groups
compared with controls. Glomerular filtration rate was significantly lower in CsA
treated rats (0.3+/-0.1 ml/min/100 g) than in control animals (0.6+/-0.1
ml/min/100 g, P<0.02). The coadministration of CsA with POF normalized the
glomerular filtration rate (0.6+/-0.1 ml/min/100 g). A parallel decrease in renal
plasma flow was observed in CsA-treated rats compared with controls (CsA+vehicle:
1.5+/-0.2 vs. control: 2.2+/-0.1 ml/min/100 g, P<0.02), this effect completely
reversed by cotreatment with POF (3.1+/-0.2 ml/min/100 g). Blood viscosity was
significantly higher in CsA-treated rats than in the control group (CsA+vehicle:
5.6+/-0.7 vs. control: 5.0+/-0.4 m x Pa x s, P<0.05). This effect was associated
with a lower erythrocyte deformability (CsA+vehicle: 1.2+/-0.2 vs. control: 1.5+/
0.3 ml/min, P<0.05). These rheological abnormalities were normalized by
coadministration with POF (blood viscosity: 4.9+/-0.7 m x Pa x s and erythrocyte
deformability: 1.9+/-0.4 ml/min, P<0.05). CONCLUSIONS: Our results show that
administration of POF prevents the nephrotoxicity associated with CsA. This
beneficial effect could be related to its rheological properties.
PMID- 9392303
TI - Induction of tolerance toward rat cardiac allografts by treatment with
allochimeric class I MHC antigen and FTY720.
AB - BACKGROUND: The combination of FTY 720, a novel immunosuppressant, and
allochimeric class I MHC proteins bearing donor-type amino acid (aa) epitope
substitutions for host-type sequences induces tolerance of Wistar Furth (WF;
RT1.Au) heart allografts in ACI (RT1.Aa) recipients. METHODS: Allochimeric
alpha(1h)l58-80-RT1.Aa proteins were produced by substituting the allogeneic
nucleotide sequence encoding 10 aa residues unique to the alpha1 helical
(alpha1h) region of RT1.Al Lewis (Asp58, Arg62, Glu63, Gln65, Lys66, Gly69,
Asn70, Asn73, Ser77, and Asn80) for native RT1.Aa residues. The RT1.Au and the
RT1.Al haplotypes share four of these aa (Arg62, Glu63, Gln65, and Gly69). A
baculovirus/Spodoptera frugiperda insect cell system was used to express the
alpha(1h)l58-80-RT1.Aa proteins. RESULTS: The addition of a 3-day oral gavage of
0.05 mg/kg/day FTY720 to a single portal vein injection of 10 microg alpha(1h)l58
80-RT1.Aa protein induced permanent acceptance of WF heart allografts in 16 of 26
ACI recipients (>100 days); the alpha(1h)l58-80-RT1.Aa protein alone only
modestly prolonged WF heart survival (13.8+/-0.8 days). The same tolerogenic
protocol did not prolong the survival of third-party Brown Norway (RT1.An) heart
allografts (14.3+/-2.5 days) compared with FTY720 alone (14.0+/-2.3 days; NS).
Tolerant ACI recipients bearing primary WF heart allografts for more than 100
days accepted second WF hearts, but promptly rejected third-party Brown Norway
heart grafts (9.3+/-1.5 days). The tolerant state was transferred to irradiated
ACI rats (400 rad) with either purified T cells (4-10 x 10[7]) or serum (1-2 ml)
from tolerant hosts, and was not broken by daily intraperitoneal injections of
interleukin-2 (1000 U/day; 7 days). CONCLUSIONS: The combination of allochimeric
protein with FTY720 induces transplantation tolerance, a state that may be
associated with the appearance of donor-specific regulatory factors.
PMID- 9392304
TI - Expression of an allogeneic MHC DRB transgene, through retroviral transduction of
bone marrow, induces specific reduction of alloreactivity.
AB - BACKGROUND: Transfer of MHC class II genes, through allogeneic bone marrow (BM)
transplantation, induced long-lasting acceptance of renal allografts in miniature
swine. To adapt this approach to the clinic, we have now examined whether somatic
transfer of allogeneic class II DR genes, into otherwise autologous bone marrow
cells (BMC), can provide the matching required for inducing immune tolerance.
METHODS: Autologous BMC were transduced ex vivo with recombinant retroviruses for
allogeneic DRB followed by BM transplantation. The recipients were then
challenged with kidney allografts solely matched to the DRB transgene. RESULTS:
Five miniature swine received autologous BMC conditioned with growth factors and
transduced with recombinant retrovirus vectors containing allogeneic (n=4) or
syngeneic (n=1) class II DRB genes and a drug-resistance marker. Expression of
retrovirus-derived products in BM-derived cells was demonstrated by the detection
of drug-resistant colony-forming progenitors and the presence of DRB retrovirus
transcripts in peripheral cells. Analysis of selective mixed lymphocyte reaction
responses to DR or DQ antigens indicated decreased reactivity toward the
transduced DR gene product. Among all of the animals receiving fully mismatched
kidney allografts, but with DRB matched to the transduced DRB, the one with the
highest gene transduction rate showed stable allograft function and essentially
normal renal histology for 2.5 years. A control animal, which received a
syngeneic DRB gene, rejected its kidney allograft in 120 days after an earlier
rejection crisis. CONCLUSIONS: These studies demonstrate that allogeneic MHC gene
transfer into BM provides a new strategy for inducing tolerance across MHC
barriers.
PMID- 9392305
TI - Influence of donor and recipient ages and sex on graft function after pediatric
renal transplantation.
AB - BACKGROUND: Adult donor grafts adapt to the smaller size of the child recipient
by reducing their absolute glomerular filtration rate (GFR) (ml/min). The
question arises whether these grafts can increase the absolute GFR when the child
recipient grows or whether a child donor graft can better increase its function.
The aim of this study was to evaluate the influence of donor and recipient ages
and sex on renal function. METHODS: Eighty-five children and adolescents, aged
0.4-20.5 years at transplantation, were monitored annually, by GFR and effective
renal plasma flow (ERPF), determined by clearances of inulin and para
aminohippuric acid. The patients received 90 grafts from donors aged 3-67 years.
Follow-up time was around 5 years. RESULTS: Absolute GFR and ERPF (ml/min) of
grafts from donors <20 years of age (all cadaveric donor grafts) increased during
follow-up, resulting in a constant relative GFR and ERPF (ml/min/1.73 m2),
whereas absolute GFR and ERPF of grafts from donors >20 years of age remained
constant during follow-up, resulting in a significant decrease in relative
values. Relative GFR and ERPF fell during follow-up in young recipients (<12
years of age), but remained constant in older recipients (>12 years). Donor and
recipient sex did not influence renal function. CONCLUSIONS: Child donor grafts
seem better able to increase their function with the growth of the child
recipient than adult grafts. However, the limited access to pediatric grafts and
the fact that pediatric cadaveric grafts might involve technical problems in
connection with grafting restrict their use.
PMID- 9392306
TI - Efficacy of OKT3 as primary therapy for histologically confirmed acute renal
allograft rejection.
AB - BACKGROUND: OKT3 is often used as primary treatment for acute renal allograft
rejection. In a retrospective study, we sought to determine the efficacy of OKT3
as a first-line agent in reversing histologically confirmed acute renal allograft
rejection. METHODS: Patients with mild to moderate, moderate, or severe acute
cellular and acute vascular rejection who had not received any other anti
rejection treatment were included in this analysis. A total of 88 patients, who
received OKT3 between 1987 and 1995, fulfilled these criteria. RESULT: Seventy of
these patients were renal transplant recipients, and 18 were combined kidney and
pancreas transplant recipients. The median time to the diagnosis of rejection
from transplantation was 32 days (range, 6 days to 13 years). On histology, 6
were graded as mild to moderate, 36 as moderate, 29 as moderate to severe, and 17
as severe rejection. The mean baseline serum creatinine was 1.62 mg/dl (range,
0.7-10.1 mg/dl), and the mean serum creatinine at the time of diagnosis of
rejection was 2.60 mg/dl (range, 1.4-12.7 mg/dl) (P=<0.0001). The mean duration
of OKT3 treatment was 11.2 days (range, 8-18 days). The mean serum creatinine at
the end of OKT3 treatment was 1.73 mg/dl (range, 0.6-5.0 mg/dl; P=0.24 compared
with baseline serum creatinine). Rejection was reversed in 86 (98%) patients.
Graft survival at 1 year after OKT3 therapy was 87.5% (77 of 88). At a mean
follow-up of 38 months, 8 patients had died and 26 grafts were lost. The mean
serum creatinine level in the 64 patients with a functioning graft was 1.76 mg/dl
(range, 0.8-4.0 mg/dl) at the last follow-up. CONCLUSION: OKT3 when utilized as
first-line therapy reversed 98% of the acute rejection episodes, with a 1-year
post-OKT3 graft survival of 87.5%.
PMID- 9392307
TI - Persistent long-term changes in lymphocyte subsets induced by polyclonal
antibodies.
AB - BACKGROUND: Clinicians are well aware of the short-term effects of
immunosuppression by mono- or polyclonal antibodies. Little is known about long
term changes induced by these therapies. METHODS: Forty-three renal allograft
recipients were selected according to their initial postoperative
immunosuppression: (1) BI group=basic immunosuppression with steroids and
cyclosporine, n=16; (2) ATG group=basic immunosuppression plus polyclonal
antibody antithymocyte globulin (ATG), n=11; and (3) OKT3 group=basic
immunosuppression plus monoclonal antibody OKT3, n=16 patients. At intervals of 6
months, the following parameters were measured prospectively: lymphocyte surface
antigens (HLA-DR, CD3, CD4, CD8, CD16, CD19, CD56, and CD57); serum and urine
neopterin; serum amyloid A; and indirect and direct tests for herpes viruses.
RESULTS: The mean period of observation was 58.4 months. The most significant
differences between the groups occurred for CD4+ and CD8+ T cells. The ratios of
CD4+ to CD8+ cells (n=278 measurements) were significantly and persistently lower
in the ATG group (P<0.001, Brown-Mood test). Five years after transplantation,
the ATG group had a CD4+ to CD8+ cell ratio of x=0.6 versus x=1.7 in the OKT3
group and x=2.0 in the BI group. This inversion was due to a persistent depletion
of the CD4+ cells and an increased regeneration of the CD8+ cells, in particular
of the CD8+brightCD57+ subpopulation. Extent and duration of CD4+ depletion
correlated with the cumulative ATG dose (r=0.7, P<0.05, Spearman rank correlation
test). CONCLUSION: Therapy with polyclonal antibody ATG induces dose-dependent
long-term changes in T-cell lymphocyte subsets, which persist over a period of
years.
PMID- 9392308
TI - Early signs and risk factors for the increased incidence of Epstein-Barr virus
related posttransplant lymphoproliferative diseases in pediatric liver transplant
recipients treated with tacrolimus.
AB - BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a life
threatening condition the incidence of which in pediatric solid organ
transplantation may be related to the immunosuppressive load. It has been
suggested that tacrolimus, a new and potent immunosuppressor, causes an increased
incidence of this syndrome. METHODS: The incidence, early signs, and risk factors
for lymphoproliferative disease were reviewed in a cohort of 89 pediatric liver
transplant recipients treated with tacrolimus. RESULTS: Eighteen patients (20%)
developed a PTLD-16 concomitant to a primary Epstein-Barr virus (EBV) infection
and 2 with previous immunity against EBV. Three additional patients had
preliminary signs of PTLD concomitant to primary EBV infection, but did not
develop individualized lymphoid masses. Six patients died (6.7% of all tacrolimus
treated patients). Mean tacrolimus blood level during the 3 months preceding EBV
infection reached 11.8+/-1.8 ng/ml in PTLD patients versus 9.4+/-3.4 ng/ml in non
PTLD patients (0.05
50% above the upper limit of the reference range at a
median of 1 day before the equivalent change in alanine transaminase in
association with allograft rejection in the combined groups (95% confidence
interval=1 to 2 days) but was lower on the day of diagnosis of rejection in the
reporting group (P=0.02). This is compatible with the earlier diagnosis of
rejection in the reporting group. CONCLUSIONS: We conclude that the monitoring of
GST may improve patient care, reducing both mortality and morbidity.
PMID- 9392311
TI - Expansion of CD4+CD7- T cells, a memory subset with preferential interleukin-4
production, after bone marrow transplantation.
AB - BACKGROUND: Inadequate reconstitution of CD4+ lymphocyte and interleukin (IL)-2
production defect are observed after bone marrow or peripheral blood stem cell
transplantation (SCT). METHODS: We studied immune reconstitution after SCT in 33
consecutive patients who received allogeneic SCT (17 patients) or autologous SCT
(16 patients). The aims were to assess the regeneration of the CD4+ T-cell subset
with regard to helper cell differentiation. CD4+ T-cell subset regeneration and
expansion of the CD4+CD7- subset were studied by immunofluorescence analysis.
CD4+CD7- cell cytokine secretion was analyzed after cell sorting and
costimulation of the CD3 and CD28 pathways, in enzyme-linked immunosorbent assay
and reverse transcription-polymerase chain reaction assays. RESULTS: We report a
relative expansion of the CD4+CD7- subset within CD4+ T cells, detected as early
as 1 month after bone marrow transplantation and decreasing after day 60. CD4+CD7
T cells preferentially expressed CD45RO and activation markers such as CD57,
CD25, and HLA-DR. No relationship was observed between the CD4+CD7- expansion and
transplant-related complications. We observed no significant IL-2 production in
supernatants from sorted CD4+CD7- T cells, whereas IL-4 levels were comparable to
those produced by cells from normal individuals. Autologous CD4+CD7+ cells showed
little, if any, IL-4 production, and IL-2 production was lower than that by
normal CD4+CD7+ T cells. Reverse transcription-polymerase chain reaction assays
showed similar amounts of interferon-gamma transcripts in the two subsets; tumor
necrosis factor-alpha, IL-4, and IL-10 transcripts were detected in CD4+CD7- T
cells but not in their CD4+CD7+ counterparts. CONCLUSIONS: These data confirm the
IL-2 production defect after bone marrow transplantation and suggest that the
CD4+CD7- T-cell subset might be preferentially involved in the enhanced
production of IL-4 and low production of IL-2. These data show that the early
immune reconstitution in CD4+ T cells after SCT preferentially involves memory T
cells with a Th0/Th2 differentiation that might participate in the T-helper cell
defect.
PMID- 9392312
TI - Immunosuppression by D-isomers of HLA class I heavy chain (amino acid 75 to 84)
derived peptides is independent of binding to HSC70.
AB - BACKGROUND: Peptides derived from the class I heavy chain were shown to modulate
immune responses in vitro and in vivo. A peptide derived from HLA-B2702 (2702.75
84) inhibited differentiation of cytotoxic T cells as well as T cell and natural
killer cell-mediated cytotoxicity in vitro. Peptide-mediated immunomodulation
seemed to be independent of the MHC proteins expressed by responder and
stimulator cells. In vivo studies in rodents demonstrated prolongation of heart
and skin allograft survival after peptide therapy. Here, the correlation between
the peptide's biological activity and its amino acid sequence was analyzed using
peptides derived from amino acid 75-84 of several mouse, rat, and human MHC class
I proteins as well as peptides with single amino acid substitutions in the
2702.75-84 sequence. METHODS: Peptides consisting of both L- and D-amino acids
were tested for inhibition of murine and human T cell-mediated and lymphokine
activated killer cell-mediated cytotoxicity, binding to hsc70, and prolongation
of heart allograft survival in vivo. RESULTS: Replacement of glutamic acid
residue (E) at position 75 with valine (V) resulted in a peptide [2702.75
84(E>V)] with increased in vitro and in vivo activity but unchanged affinity for
hsc70. Surprisingly, both L- and D-isomers of 2702.75-84 and 2702.75-84(E>V)
inhibited cytotoxic cells in vitro and prolonged heart allograft survival in
vivo. However, as expected, the peptides consisting of D-amino acids did not bind
to hsc70. CONCLUSION: Assuming that both D- and L-isomers modulate immune
responses by similar mechanisms, these results suggest that the peptides' effect
is independent of binding to hsc70.
PMID- 9392313
TI - An increase in peripheral blood progenitor cells in primates by coadministration
of recombinant human interleukin 6 and recombinant human granulocyte colony
stimulating factor.
AB - BACKGROUND: We recently demonstrated that coadministration of recombinant human
interleukin 6 (rhIL-6) and recombinant human granulocyte colony-stimulating
factor (rhG-CSF) in mice synergistically increases peripheral blood stem cells
(PBSC), which can rescue lethally irradiated recipient mice. However, there is
little information about the effect of coadministration of rhIL-6 and rhG-CSF on
PBSC in a primate system. METHODS: In cynomolgus monkeys, rhG-CSF (5 microg/kg
day) alone was administered for 5 days (first cycle). After the wash-out period,
rhIL-6 (0, 10, or 20 microg/kg/day) and rhG-CSF were coadministered for 5 days
(second cycle). RESULTS: Total peripheral colony-forming cells levels were
increased earlier by coadministration of rhIL-6 and rhG-CSF than by the
administration of rhG-CSF alone. The maximum level in the coadministration cycle
was obtained on day 5, and a high level was obtained for a further 3 days after
cessation. The maximum number of peripheral total colony-forming cells in the
coadministration cycle was a mean of 2.12-fold (range 1.38 to 3.35) higher than
that in the rhG-CSF alone cycle. Coadministration also increased the peripheral
mixed colony-forming units by a mean of 3.62-fold (range 1.02 to 5.52).
Interestingly, monkeys that showed a low response to the administration of rhG
CSF alone also had a higher response to the coadministration. No significant
difference was observed between the two cycles of administration of rhG-CSF
alone. CONCLUSIONS: These findings suggest that coadministration of rhIL-6 and
rhG-CSF may be useful for clinical PBSC collection.
PMID- 9392314
TI - Impact of HLA compatibility on survival of kidney transplants from unrelated live
donors.
AB - BACKGROUND: Kidney transplants from unrelated live donors have been reported to
perform exceedingly well despite poor HLA compatibility. These results were
extrapolated to indicate that HLA matching in cadaver kidney transplantation is
superfluous provided the ischemic preservation time is kept very short. METHODS:
The influence of HLA matching on the outcome of 2281 transplants from unrelated
live donors from 1986 to 1995 was analyzed at 198 transplant centers. RESULTS:
The 5-year transplant success rate was significantly associated with the number
of HLA-A, -B, and -DR mismatches (P<0.0001). There was a significant impact on
graft survival of mismatches at the class I HLA-A, and -B loci (P=0.001) as well
as at the class II HLA-DR locus (P=0.005). In transplants from both spouses and
nonspouses, cases with no HLA-DR mismatch were found more often than would be
expected if transplant donors were selected by chance, which indicates that
efforts of prospective HLA matching had been made. CONCLUSIONS: The outcome of
kidney transplants from unrelated live donors is strongly influenced by HLA
compatibility. Short exposure of donor kidneys to ischemia does not eliminate the
influence of HLA matching on graft survival.
PMID- 9392315
TI - Effect of troglitazone on blood insulin levels after pancreas transplantation
with systemic venous drainage in rats.
AB - BACKGROUND: Troglitazone is a new oral antidiabetic agent and has been reported
to reduce insulin resistance and improve peripheral hyperinsulinemia in patients
with noninsulin-dependent diabetes mellitus. To examine the effect of
troglitazone on insulin regulation after pancreas transplantation with systemic
venous drainage, we measured peripheral glucose and insulin levels and performed
an intravenous glucose tolerance test. METHODS: We divided the rats into four
groups: diabetic rats with a pancreas graft and administration of troglitazone at
40 mg/day orally (group P+T, n=4), rats with a pancreas graft only (group P,
n=4), age-matched normal rats (group N, n=5), and diabetic rats (group DM, n=4).
RESULTS: Fasting insulin levels in group P were relatively higher than those in
group N, whereas the values in group P+T were normalized. In the intravenous
glucose tolerance test, troglitazone clearly regulates sigma immunoreactive
insulin levels of pancreas transplanted rats (P vs. P+T: 244+/-23 vs. 145+/-14
microU/ml, P<0.05). CONCLUSION: Hyperinsulinemia induced by systemic venous
drainage, which may progress atherosclerosis, can be controlled with troglitazone
treatment.
PMID- 9392316
TI - Common bile duct stenosis caused by chronic pancreatitis after liver
transplantation for alcoholic cirrhosis.
AB - BACKGROUND: The prevalence of chronic pancreatitis in patients with alcoholic
cirrhosis ranges from 7% to 11% and is not considered a contraindication for
liver transplantation. METHODS: Among 59 liver transplant recipients grafted for
alcoholic cirrhosis, we report two observations of common bile duct stenosis due
to chronic pancreatitis. RESULTS: In both cases, pretransplant work-up disclosed
no clinical or radiological evidence of chronic pancreatitis. The diagnosis of
common bile duct stricture was made 6 and 60 months after liver transplantation.
One patient was reoperated upon, and his choledochocholedochostomy was converted
into a Rouxen-Y choledochojejunostomy. The second patient experienced metastatic
laryngeal carcinoma and died before reoperation. CONCLUSIONS: These observations
suggest that common bile duct stricture caused by chronic pancreatitis may occur
after liver transplantation for alcoholic cirrhosis, even after a long-standing
history of abstinence.
PMID- 9392317
TI - Persistent hypersplenism early after liver transplant: the role of splenectomy.
AB - BACKGROUND: Transient thrombocytopenia is common after liver transplantation, but
persisting thrombocytopenia worsens the prognosis after transplant. METHODS: Two
patients underwent splenectomy for persistent thrombocytopenia early after liver
transplantation. The first patient had a platelet count of 17,000/mm3 on
postoperative day (POD) 6; her hemoglobin and white blood cell counts were
normal. Work-ups including bone marrow aspiration, Coombs test, and antiplatelet
antibody test were negative. On POD 9, she had abdominal bleeding with a platelet
count of 17,000/mm3 despite repeated platelet transfusions, and splenectomy was
done. The second patient had a platelet count of 3000/mm3 on POD 14, white blood
cell was 1600/mm3, and hemoglobin was 7.7 g/dl. Bone marrow biopsy revealed
hypercellular marrow. Because his platelet count remained at 2000/mm3 despite
empiric treatment with intravenous immune globulin and methylprednisolone,
splenectomy was performed. RESULTS: The first patient's platelet count rose to
155,000/mm3 by POD 8. The second patient's platelet count reached 210,000/mm3 on
POD 5. Neither patient has had an episode of thrombocytopenia at 36 and 32 months
after splenectomy. CONCLUSIONS: Splenectomy can be used after liver
transplantation for severe, persistent thrombocytopenic states that cannot be
attributed to sepsis, intravascular coagulation, immunological causes, or drug
effects.
PMID- 9392318
TI - Adenovirus hepatitis in the adult allograft liver.
AB - BACKGROUND: Adenovirus hepatitis in the allograft liver is an uncommon condition
hitherto recognized only in pediatric patients. We describe two adult cases.
METHODS: Clinical information was obtained by reviewing the medical records. The
diagnosis of adenoviral infection was made by immunohistochemistry or culture.
RESULTS: Both patients had received recent antirejection treatment and presented
with fever, hepatic dysfunction, and progressive leukopenia. One patient had some
viral inclusions resembling those described in herpes simplex infections.
Adenovirus was cultured from the liver in both cases and from the lung in one
case. Both patients were treated by decreasing the immunosuppression and
intravenous acyclovir, but died. CONCLUSIONS: Adenovirus infection should be
considered when evaluating adult liver transplant patients with necrotizing
lesions or microabscess formation at allograft biopsy. A review of the literature
shows that most previously reported infections have led to graft loss or death,
but occasional remissions of disease are also on record.
PMID- 9392319
TI - Calcineurin activity in children with renal transplants receiving cyclosporine.
AB - BACKGROUND: The major immunosuppressive effect of cyclosporine is through the
inhibition of calcineurin, an enzyme important in the activation of T
lymphocytes. In children, neither calcineurin activity nor its inhibition by
cyclosporine (CsA) has been investigated. METHODS: Calcineurin activity, was
measured in stable pediatric renal transplant patients, with healthy children
used as controls. Whole blood CsA concentrations were measured by monoclonal
radioimmunoassay. Simultaneous calcineurin and CsA levels were measured before
and 1, 2, 3.5, 5, and 12 hr after their routine morning CsA dose. RESULTS:
Calcineurin activity was approximately 50% inhibited at trough blood
concentrations (148 microg/L); moreover, inhibition increased as CsA
concentrations rose and declined as concentrations fell. Maximum calcineurin
inhibition was about 70% at concentrations of about 431 microg/L. Linear
regression analysis revealed a significant correlation between mean CsA blood
concentration and the mean degree of inhibition of calcineurin activity (P=0.005,
one-tailed). CONCLUSION: We conclude that inhibition of calcineurin activity by
CsA in pediatric renal transplant recipients correlates with CsA blood
concentrations.
PMID- 9392320
TI - Focal acute tubular necrosis in a renal allograft.
AB - Nuclear imaging is used to evaluate renal allografts demonstrating delayed
function after transplantation. Interpretation of the nuclear scan in the context
of clinical data, provides helpful information in the management of the
transplant recipient. The better quality of images obtained with technetium-99m
mercaptoacetyltriglycine (Tc-99m MAG3) has made it the radiotracer of choice
compared to technetium-99m diethylenetriamine pentaacetic acid (Tc-99m DTPA) for
imaging of the renal allograft. Tc-99m MAG3 is cleared from the kidney by tubular
secretion, whereas Tc-99m DTPA is cleared by glomerular filtration. In this
report, we discuss a unique abnormality found on nuclear imaging of a renal
allograft. Utilizing our understanding of the characteristic handling of various
radiotracers by the kidney, we were able to demonstrate that the renal scan was
consistent with an area of focal acute tubular necrosis in the newly transplanted
kidney.
PMID- 9392321
TI - Recurrent immunoglobulin A nephropathy after renal transplantation: a significant
contributor to graft loss.
AB - BACKGROUND: Although most transplanted patients with underlying IgA nephropathy
(IgAN) develop histological recurrence, its clinical relevance is considered low.
METHODS: We performed a single-center analysis of 61 renal transplant patients
with IgAN. RESULTS: Forty-four percent of the patients showed a stable graft
function. Progressive graft dysfunction apparently due to recurrent IgAN occurred
in 23% of the patients (16% required dialysis). Five patients were
retransplanted, and three again developed dialysis-dependent renal failure
apparently due to recurrent IgAN. In 20% of the patients, chronic transplant
dysfunction was due to other reasons, whereas no reason was identified in 13% of
the patients. Neither findings before transplantation, the ACE genotype, the type
of immunosuppression, nor the course after transplantation predicted transplant
dysfunction due to recurrent IgAN. Follow-up after transplantation was longer in
the group with dysfunction due to recurrent disease than in the group with
dysfunction due to chronic rejection or in the stable group. CONCLUSION:
Recurrent IgAN is a clinically relevant problem in renal transplant patients. Its
importance may have been underestimated in the past due to inadequate lengths of
follow-up.
PMID- 9392322
TI - Differential down-regulation of CD28 by B7-1 and B7-2 engagement.
AB - Physiologically relevant full activation of T cells requires signal transduction
through the T cell receptor and additional costimulatory cell surface molecules.
Best understood of these costimulatory interactions are those between CD28 and
its ligands B7-1 (CD80) and B7-2 (CD86). While B7-1 and B7-2 bind the same
receptors (CD28 and CTLA-4), they share only 25% sequence homology, are expressed
at different times during immune responses, and in some systems have been shown
to differentially affect T cell cytokine expression. Although CD28 is an
activation antigen, its expression is down-regulated after engagement by B7-1.
Here we show that B7-2 engagement is considerably less effective at down
regulating CD28, which indicates a differential effect of these two CD28 ligands
on activated T cells.
PMID- 9392323
TI - Comment on "Delayed correction of portal hypertension after portal vein conduit
arterialization in liver transplantation" by Neelamekam et al.
PMID- 9392324
TI - Increased benefit from shorter screening mammography intervals for women ages 40
49 years.
PMID- 9392325
TI - An interdisciplinary approach to avoid the overtreatment of patients with central
nervous system lesions.
PMID- 9392326
TI - Cytologic detection of esophageal squamous cell carcinoma and precursor lesions
using balloon and sponge samplers in asymptomatic adults in Linxian, China.
AB - BACKGROUND: The principal reason for the poor prognosis of esophageal carcinoma
is that most tumors are asymptomatic and go undetected until they are
unresectable. Previous studies have shown that cytologic screening of
asymptomatic high risk individuals can detect curable esophageal carcinomas and
precursor lesions, but the sensitivity of such screening is not well documented.
The current study evaluated the sensitivity and specificity of currently
available balloon and sponge cytologic samplers for detecting biopsy-proven
squamous dysplasia and carcinoma in asymptomatic individuals from a high risk
population in Linxian, China. METHODS: Asymptomatic adults were examined with
both balloon and sponge samplers, in random order, followed by endoscopy with
mucosal iodine staining and biopsy of all unstained lesions. The cytology slides
were interpreted using the criteria of the Bethesda System. The balloon and
sponge cytologic diagnoses (test) were compared with the biopsy diagnosis (truth)
in each patient to estimate the sensitivity and specificity of each sampler.
RESULTS: Of the 439 patients with adequate biopsies, 123 (28%) had histologic
squamous dysplasia and 16 (4%) had an invasive squamous carcinoma. The
sensitivities/specificities of the balloon and sponge were 44%/99% and 18%/100%,
respectively, for detecting biopsy-proven squamous cell carcinoma, and 47%/81%
and 24%/92%, respectively, for identifying squamous dysplasia or carcinoma.
CONCLUSIONS: In this study, the balloon sampler was more sensitive than the
sponge sampler for detecting esophageal squamous disease, but both techniques
were less than optimal. Improved samplers and/or cytologic criteria should
increase the sensitivities observed in this baseline study.
PMID- 9392327
TI - Does dual infection by hepatitis B and C viruses play an important role in the
pathogenesis of hepatocellular carcinoma in Japan?
AB - BACKGROUND: There are contradictory data concerning the synergistic effect of
hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on the progression
from chronic hepatitis to hepatocellular carcinoma (HCC). METHODS: To clarify the
role of coinfection with HBV and HCV in the progression and pathogenesis of HCC,
viral and clinicopathologic features were studied in 368 consecutive HCC patients
at the University of Tokyo from 1991-1995. RESULTS: Approximately 83% of patients
(305 patients) were seropositive for the HCV antibody ("C-viral") and
approximately 10% (37 patients) were positive for the hepatitis B surface antigen
("B-viral"). Positivity for both (dual infection) was found in only 2% of
patients, and negativity for both in 5%. The incidence of dual infection in HCC
patients was Similar to that in 549 patients with chronic hepatitis (1%) and 119
patients with cirrhosis (1%). Of the six HCC patients with dual infection, five
patients were positive for the HBV early antigen and HBV DNA was less than
measurable, whereas HCV RNA was detected and ranged from 10(3)-10(6) copies/50
microL of serum by competitive reverse transcriptase-polymerase chain reaction,
and the clinical features resembled those of "C-viral" HCC. The remaining patient
was early antigen positive and had HBV DNA by slot blot analysis, but the serum
HCV RNA level was less than measurable. These data indicate that mutually
exclusive viral replication occurred in patients with persistent coinfection. To
further clarify further the possible involvement of HBV infection in "C-viral"
HCC, HBV core antibody (HBcAb) was tested in 192 patients and was found to be
positive in 111 and negative in 81. The serum HCV RNA level and clinicopathologic
features (such as age and the severity of liver disease) were similar among the
"C-viral" HCC patients irrespective of the presence or absence of HBcAb.
CONCLUSIONS: Based on these results, coinfection was found to be much less
prevalent than generally is claimed, and even in a few HCC patients with the
coinfection the mutually exclusive viral replication was noted, suggesting that
coinfection plays little if any role in the development of HCC.
PMID- 9392328
TI - Thrombin receptor activation results in calcium signaling and protein kinase C
dependent stimulation of DNA synthesis in HEp-2g laryngeal carcinoma cells.
AB - BACKGROUND: Recently, the expression of the "tethered ligand" thrombin receptor
in carcinosarcoma and melanoma cells has been shown. However, the role of the
thrombin receptor in tumor cell metabolism still is undefined. METHODS: In this
article, the "tethered ligand" thrombin receptor was identified on human
epidermoid carcinoma cells (HEp-2g cell line) by using immunofluorescence studies
with a monoclonal antithrombin receptor antibody and radioligand binding.
Furthermore, the effects of alpha-thrombin and thrombin receptor activating
peptides (TRAP)-6 on calcium mobilization, protein kinase C (PKC) translocation,
and DNA synthesis were estimated. RESULTS: Pharmacologic characterization using
[3H]TRAP-6 as a radioligand demonstrated a single class of high affinity binding
sites (dissociation constant [KD] = 7.2 +/- 2.2 x 10(-7) M) and a binding
capacity of 27 +/- 3.4 fmol/mg protein. The function of these binding sites was
demonstrated by alpha-thrombin- and TRAP-6-induced mobilization of free
intracellular calcium, and translocation of PKC from cytosol to cell membrane.
Moreover, alpha-thrombin and TRAP-6 induced an increase in [3H]thymidine
incorporation in HEp-2g cells that could be blocked by the PKC inhibitor
bisindolylmaleimide. CONCLUSIONS: To the authors' knowledge, the results of this
study demonstrate for the first time functional thrombin receptors in epidermoid
carcinoma cells. The thrombin receptor appears to be involved in growth
regulation in HEp-2g cells by a PKC-dependent mechanism.
PMID- 9392329
TI - Stereotactic radiosurgery for patients with nonsmall cell lung carcinoma
metastatic to the brain.
AB - BACKGROUND: A retrospective study of patients undergoing stereotactic
radiosurgery for one to four brain metastases from nonsmall lung cell carcinoma
(NSCLC) was performed to document outcomes and risks. METHODS: Seventy-seven
patients underwent radiosurgery during a 7-year interval; 71 also underwent whole
brain radiation therapy. Univariate and multivariate analyses were used to
determine significant prognostic factors affecting survival. RESULTS: The overall
median survival was 10 months after radiosurgery, and 15 months from the
diagnosis of brain metastases. Five factors significantly affected survival:
extent of systemic disease, presence of a neurologic deficit, size of the
intracranial tumor, initial imaging appearance of intratumoral necrosis, and
initial resection of the primary tumor of the chest. Median survival time was 26
months in a subgroup of patients with no extracranial metastases, no neurologic
deficits, and a small tumor without necrosis. The authors evaluated 91 tumors
with imaging. Local tumor control was achieved in 77 lesions (85%) and tumoral
radiation necrosis developed in 4 lesions (4.4%). Nineteen new metastatic tumors
developed during the observation interval. CONCLUSIONS: Stereotactic radiosurgery
for NSCLC brain metastases is effective and is associated with few complications.
The early detection of brain metastases and treatment with radiosurgery combined
with radiation therapy provide the opportunity for extended high quality
survival.
PMID- 9392330
TI - Isolated limb reperfusion with tumor necrosis factor and melphalan in patients
with extremity melanoma after failure of isolated limb perfusion with
chemotherapeutics.
AB - BACKGROUND: This retrospective study evaluated the benefit of using tumor
necrosis factor (TNF) and melphalan administered via an isolated limb perfusion
(ILP) in a series of patients with metastatic melanoma who failed initial ILP
with chemotherapeutics. METHODS: Seventeen patients with extremity melanoma who
underwent prior ILP with conventional chemotherapeutics (10 with melphalan; 4
with platinum; 2 with platinum, dacarbazine, thiotepa, actinomycin D, and
nitrogen mustard; and 1 with thiotepa, actinomycin D, and nitrogen mustard) and
had local recurrences were treated with a 90-minute isolated hyperthermic limb
reperfusion with melphalan (10 mg/L limb volume) plus TNF (2-6 mg). Five prior
ILPs were adjuvant and 12 were therapeutic. RESULTS: Reperfusion was associated
with an overall 94% response rate and a 65% complete response (CR) rate. Of the
patients who failed an initial ILP with melphalan alone the overall response rate
was 90% after the reperfusion with TNF and melphalan. In patients who failed an
initial ILP with agents other than melphalan the CR rate was 100% after ILP with
TNF and melphalan. TNF/melphalan isolated limb reperfusion was found to be more
effective in terms of CR after initial ILP regimens that did not utilize
melphalan (100% CR after nonmelphalan ILP vs. 50% CR after melphalan ILP [P =
0.04]). Regional toxicity was comprised of mild skin blistering and peeling in
47% of patients. One patient developed Grade 3 (based on National Cancer
Institute Common Toxicity Criteria) skin necrosis, and one developed Grade 5
muscle and nerve toxicity, requiring an amputation. CONCLUSIONS: Isolated limb
reperfusion with TNF and melphalan can be performed safely with response rates
similar to those of other trials of single perfusions. Repeat ILP using TNF and
melphalan in patients with melanoma who have failed prior ILP with
chemotherapeutics is justified. The utility of TNF (vs. melphalan alone) will be
defined in ongoing Phase III trials.
PMID- 9392331
TI - The Gothenburg breast screening trial: first results on mortality, incidence, and
mode of detection for women ages 39-49 years at randomization.
AB - BACKGROUND: The effect of mammography screening on breast carcinoma mortality in
women ages < 50 years remains unclear. METHODS: A randomized trial of invitation
to breast carcinoma screening with mammography was performed in the city of
Gothenburg, Sweden. The purpose was to estimate the effect of mammographic
screening on breast carcinoma mortality in women ages < 50 years. Randomization
was initially by day-of-birth cluster (18% of subjects), and subsequently by
individual (82% of subjects). Between September 1983 and April 1984, 11,724 women
ages 39-49 years were randomized to the study group. This group was invited to
mammographic screening every 18 months. Two-view mammography was used at each
screen unless the density of the breast at the previous screen indicated that
single view was adequate. Fourteen thousand two hundred and seventeen women in
the same age range were randomized to a control group that was not invited to
undergo screening until the fifth screen of the study group (between 6 and 7
years after randomization). Women with breast carcinoma diagnosed up to the time
immediately after the first screen of the control group were followed for death
from breast carcinoma until the end of December 1994. RESULTS: A 45% reduction in
mortality from breast carcinoma was observed in the study group compared with the
control group (relative risk [RR] = 0.55, P = 0.035, 95% confidence interval
[CI], 0.31-0.96). A conservative estimate based on removal of the tumors detected
at the first screen of the control group gave a mortality reduction of 44% (RR =
0.56, P = 0.046, 95% CI, 0.31-0.99). In both cases, the effect was statistically
significant. CONCLUSIONS: Mammographic screening can reduce mortality from breast
carcinoma in women ages < 50 years. The mortality reduction can be substantial if
high quality mammography is used and an 18-month interscreening interval is
strictly adhered to.
PMID- 9392332
TI - Analysis of bcl-2 in sporadic breast carcinoma.
AB - BACKGROUND: The bcl-2 gene encodes a protein that blocks apoptosis and might help
to promote tumor development. It is expressed in a high percentage of breast
tumors and is associated with good prognostic features. However, the mechanisms
that regulate bcl-2 expression in breast carcinoma are unknown. Moreover,
immunohistochemical detection of bcl-2 is related inversely to p53 expression.
This notwithstanding, the immunohistochemical detection of p53 does not always
correlate with the detection of p53 gene mutations. The authors studied the
molecular organization of bcl-2 as well as the methylation status of its CpG
island and analyzed the correlation between bcl-2 expression and p53 gene
mutations. METHODS: The molecular organization of the bcl-2 gene and the
methylation pattern of its CpG island were analyzed by Southern blot analysis. In
addition, immunohistochemical analysis of bcl-2 and p53 protein expression was
performed. Finally, the presence of mutations at exons 5-9 of the p53 gene were
analyzed by polymerase chain reaction and single-strand conformation
polymorphism. RESULTS: No molecular abnormality was found at the bcl-2 locus in
cases of sporadic breast carcinoma. Moreover, loss of heterozygosity analysis
failed to detect any allelic loss in the study cases. It also was found that the
bcl-2 CpG island was demethylated in all cases. These results point to a lack of
correlation between bcl-2 protein expression and the presence of p53 gene
mutations. CONCLUSIONS: The level of bcl-2 expression in breast carcinoma is not
associated with any somatic abnormality or epigenetic change at the bcl-2 locus.
Conversely, although bcl-2 expression is related inversely to p53 protein
expression, the analysis of p53 mutations (limited to exons 5-9) failed to
demonstrate any relationship between p53 mutations and bcl-2 protein expression.
PMID- 9392333
TI - Cathepsin D and chromogranin A as predictors of long term disease specific
survival after radical prostatectomy for localized carcinoma of the prostate.
AB - BACKGROUND: The accumulation of chromogranin A (Chr A) and cathepsin D (Cath D)
gene products may be important in prostate carcinoma progression. This study
assessed whether the levels of immunoreactivity for Chr A and Cath D are better
predictors of disease specific survival than conventional pathologic parameters
of the primary tumor such as Gleason score, capsular penetration, seminal vesicle
invasion, and percent tumor in the specimen for patients with clinically
localized prostate carcinoma managed by radical prostatectomy. METHODS: Seventy
one patients with modified Jewett clinical stages A1 to B2 adenocarcinoma of the
prostate underwent a radical prostatectomy after a negative metastatic workup. No
neoadjuvant or adjuvant treatments were given and all disease recurrences and
causes of death were recorded. Analysis of prostatectomy specimens was undertaken
to determine the conventional pathologic parameters of the primary tumor and Chr
A and Cath D immunohistochemical staining. Univariate and multivariate analyses
were performed to determine the independent contributions of Chr A and Cath D in
predicting survival. RESULTS: On univariate analysis Chr A was the only variable
that reached statistical significance for disease specific survival (P = 0.035).
Cath D nearly reached significance with a P value of 0.079 for disease specific
survival. On multivariate analysis, the only independent factor predicting
disease specific survival was the Chr A staining score (P < 0.05). In patients
with unequivocal foci of Chr A immunoreactivity, the 14-year disease specific
survival was 50% compared with 68% for patients lacking such foci. CONCLUSIONS:
The level of Chr A immunohistochemical staining is a strong predictor of disease
specific survival and is superior to standard pathologic prognostic factors. Such
findings lay the groundwork for future prospective study of the utility of such
markers on biopsy specimens to predict patient outcome.
PMID- 9392334
TI - Testicular "tumor" of the adrenogenital syndrome: a case report of an unusual
association with myelolipoma and seminoma in cryptorchidism.
AB - BACKGROUND: Males with congenital adrenal hyperplasia may develop bilateral
testicular masses in early adult life. These are not malignant and generally
regress with corticosteroid therapy. The authors report a case occurring in a 44
year-old man with associated seminoma and myelolipoma in an undescended testis.
METHODS: The testicular tumors were analyzed by histologic, flow cytometric, and
ultrastructural techniques. RESULTS: The tumors in both testes were comprised of
polygonal cells with abundant granular eosinophilic cytoplasm, occasionally with
brown (lipochrome) pigment and round nuclei of various sizes with prominent
nucleoli. These cells were grouped into nodules by dense and sometimes thick
fibrous trabeculae in the right testis. The areas corresponding to the fibrous
trabeculae in the left (intraabdominal) testis were replaced by mixture of
hematopoietic (myeloid) and fatty tissue in various proportions characteristic of
myelolipoma. The left testis also had a well demarcated tumor that was diagnostic
of seminoma. Electron microscopy demonstrated abundant smooth endoplasmic
reticulum, a moderate number of mitochondria with tubulovesicular cristae, lipid
droplets, and lipofuscin granules in the polygonal cells. No Reinke's crystals
were observed. The patient received corticosteroids for his adrenocorticoid
deficiency and also underwent external beam irradiation to the retroperitoneum
for seminoma. CONCLUSIONS: This case illustrates an unusual presentation of a
testicular tumor in a patient with the adrenogenital syndrome as well as with
myelolipoma and seminoma in a cryptorchid testis. The possibility of an
associated neoplasm that could be potentially fatal should be considered whenever
a testicular tumor of the adrenogenital syndrome continues to grow despite
adequate hormonal treatment.
PMID- 9392336
TI - Immunohistochemical analysis of progesterone receptor and Ki-67 labeling index in
astrocytic tumors.
AB - BACKGROUND: Intracranial tumors such as meningiomas express steroid hormone
receptors but little is known regarding progesterone receptor (PR) in astrocytic
tumors. The authors evaluated expression of PR in 86 astrocytic tumors in
relation to tumor proliferative potential. METHODS: Paraffin embedded tumor
sections were stained with polyclonal antiprogesterone antibody by the peroxidase
antiperoxidase method and with monoclonal MIB-1-Ki-67 antibody by avidin-biotin
complex immunohistochemistry. RESULTS: Sixty-three of the 86 astrocytic tumors
(73%) showed positive PR immunoreactivity. PR expression was observed in 4 of 9
pilocytic astrocytomas, 13 of 24 Grade 2 astrocytomas, 15 of 20 anaplastic
astrocytomas, and 31 of 33 glioblastomas. In addition to the tumor cells, cells
of microvascular endothelial proliferation and the smooth muscle of tumor vessel
walls were frequently PR positive. Glioblastomas had a significantly higher
percentage of PR positive cells compared with anaplastic (P < 0.0008) and low
grade (P < 0.0001) astrocytomas. Patients with PR positive astrocytomas were of
an older age than patients with PR negative astrocytomas (48.71 +/- 21.95 years
vs. 37.09 +/- 24.69 years; P < 0.04). The mean Ki-67 labeling index (LI) was
significantly higher in the high grade (3-4) astrocytomas compared with low grade
(1-2) astrocytomas (P < 0.0001). PR positive astrocytic tumors had higher Ki-67
LI than PR negative tumors. PR expression was not correlated with tumor
recurrence and patient survival. CONCLUSIONS: The current study suggests that PR
in the astrocytic tumors correlates with histologic grade and PR may participate
in the growth of these tumors and tumor angiogenesis. The measurement of PR in
these tumors may indirectly represent tumor growth potential.
PMID- 9392335
TI - Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion
interleukin-2 for patients with metastatic renal cell carcinoma.
AB - BACKGROUND: This study was designed to evaluate the efficacy and toxicity of the
combination of 5-fluorouracil, interferon-alpha, and interleukin-2 for patients
with metastatic renal cell carcinoma. METHODS: Previously untreated patients with
a Zubrod performance status of < or =2; adequate cardiac, pulmonary, and renal
function; and absence of brain metastases were eligible. One course of therapy
was 28 days. 5-fluorouracil was administered at a dose of 600 mg/m2/day as a
continuous infusions on Days 1-5. Interleukin-2 also was administered as a
continuous infusion on Days 1-5 at a dose of 2 million Roche U/m2/day. Interferon
alpha was given as a daily subcutaneous injection of 4 million U/m2/day. RESULTS:
Fifty-five patients were enrolled in the trial and 52 were evaluable for
response. All patients experienced fever and flu-like symptoms. Grade 3 or 4
nonhematologic toxic effects included hypertension (48%), dermatitis (12%),
stomatitis (11%), and altered mental status (9%). There was one toxic death. Four
complete responses and 12 partial responses were observed for a total response
rate of 31% (95% confidence interval, 18-46%). The survival of responding
patients was significantly better than that of nonresponding patients. The
improvement in survival was even more significant when comparing patients with at
least stable disease with those who progressed through treatment. CONCLUSIONS:
The three-drug combination described in this study demonstrates activity.
However, it appears to be more toxic than other regimens with similar response
rates and cannot be recommended for standard practice. Changing the interleukin-2
route to subcutaneous administration may permit more continuous administration
with less toxic effects.
PMID- 9392337
TI - Pleomorphic xanthoastrocytoma: DNA flow cytometry and outcome analysis of 12
patients.
AB - BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is an astrocytic tumor occurring
primarily in childhood and adolescence with some malignant histologic features
but a relatively slow clinical course. However, some tumors progress more rapidly
and can undergo malignant degeneration. The authors attempted to determine
whether various histologic features or tumor cell proliferative indices might
help identify lesions at risk for early progression and distinguish PXAs from
malignant gliomas. METHODS: In a retrospective study of 12 patients with PXA, the
tumor's histologic features and DNA flow cytometric parameters were compared with
their clinical course. DNA flow cytometry values for the S- and G2-phase of the
PXAs also were compared with control group samples of malignant and low grade
astrocytomas. RESULTS: Of the 12 tumors at initial diagnosis, 5 were considered
typical PXAs whereas 7 had some atypical features (4 with paucity of reticulin
fibers, 1 with focal necrosis, and 2 with both atypical reticulin and focal
necrosis). During the follow-up period (range, 3.75-11 years; mean, 6.8 years), 2
patients had recurrences; 1 atypical reticulin PXA progressed to glioblastoma
after 6.5 years and the 1 tumor with focal necrosis recurred at 6 months and
again at 2 years with typical histologic features. DNA flow cytometry parameters
of the typical PXA group were similar to values for malignant astrocytoma and
significantly higher than values for control specimens of low grade astrocytomas.
There were no distinctive DNA flow cytometric features that could distinguish
this last tumor from others with a more benign clinical course. CONCLUSIONS:
Measurements of the S-phase and G2-phase obtained from DNA flow cytometry and
atypical histologic features cannot reliably identify PXA patients at risk for
early progression and overall are significantly higher than values obtained for
low grade gliomas. Therefore, frequent (i.e., two to three times per year)
postoperative clinical and radiologic examinations are necessary to judge the
appropriateness of adjuvant therapy in patients with PXA. The paradox of slow
growth but DNA flow cytometry consistent with aggressive malignant lesions may
represent a cell-cycle arrest mechanism in these lesions that could be verified
in subsequent studies.
PMID- 9392338
TI - Primary non-Hodgkin's lymphoma of the lacrimal sac: a case report and a review of
the literature.
AB - BACKGROUND: Primary non-Hodgkin's lymphoma of the lacrimal sac is extremely rare,
with most reported cases representing secondary involvement of a systemic
malignancy. METHODS: The clinical record of a 70-year-old female who presented
with epiphora and swelling of the lacrimal sac area is described. A review of the
literature of patients with primary lacrimal sac lymphoma also is presented.
RESULTS: Computed tomography demonstrated a lacrimal sac mass involving the
nasolacrimal canal. Histopathologic examination of a biopsy specimen revealed a
diffuse large cell lymphoma. Using immunohistologic staining, the tumor was a B
cell type, similar to those described in the literature. The patient was treated
with 50 gray of irradiation and chemotherapy with cyclophosphamide, doxorubicin,
vincristine, and prednisone. The patient remained free of lymphoma 26 months
after initial treatment. An ocular examination was unremarkable except for
epiphora. CONCLUSIONS: Radiotherapy and/or chemotherapy can treat localized
lymphoma of the lacrimal sac successfully.
PMID- 9392339
TI - Characteristics of differentiated thyroid carcinoma in children and adolescents
with respect to age, gender, and histology.
AB - BACKGROUND: Because of its rarity there have been only a few detailed studies on
differentiated thyroid carcinoma (DTC) in children. The current investigation was
undertaken to assess the characteristics of DTC with respect to age, gender, and
histology in children and adolescents. METHODS: In a questionnaire-based survey,
data from 114 children and adolescents with DTC (age range, 3-18 years) was
collected from 65 clinical institutions in Germany. Characteristics of 80 females
and 34 males were evaluated and the influence of age, gender, histology,
multicentric growth, tumor stage, and lymph node involvement on distant
metastases was tested using multivariate discriminant analysis. Comparison
between groups was performed using the Student's t test and chi-square test.
Correlation between incidence and age was assessed by linear regression analysis.
RESULTS: The overall incidence of thyroid carcinoma in females was higher than in
males, with a peak of female/male ratio occurring at puberty. The incidence of
DTC correlated with age in females < 16 years (correlation coefficient [r] =
0.84; P = 0.0006), which was more pronounced in children with papillary thyroid
carcinoma (PTC) (r = 0.83; P = 0.006) but not in those with follicular thyroid
carcinoma (FTC) (r = 0.20; P = 0.16). FTC was associated with less advanced
disease (P = 0.009), fewer lymph nodes involved (P = 0.007), and fewer metastases
(P = 0.02) compared with PTC. Males tended to have a higher risk for distant
metastases. However, statistical analysis failed to reach a level of significance
(P = 0.08). Multivariate analysis revealed tumor stage as the only powerful
factor (P = 0.02) correlated with distant metastasis. CONCLUSIONS: The incidence
of PTC shows a marked increase in females with the highest female/male ratio
occurring at puberty. Childhood thyroid carcinoma frequently is associated with
lymph node involvement, distant metastases, and extrathyroidal tumor
infiltration. In children FTC appears to be less aggressive than PTC. Advanced
local-regional extension stage appears to be the most powerful factor influencing
the risk for distant metastases in children.
PMID- 9392341
TI - The National Cancer Data Base: report on kidney cancers. The American College of
Surgeons Commission on Cancer and the American Cancer Society.
AB - BACKGROUND: The National Cancer Data Base (NCDB) examining current time trends
(1993) in stage of disease, treatment patterns, and survival of patients with
kidney cancer are reported. METHODS: Five calls for data have yielded a total of
3,700,000 cancer cases for the years 1985 through 1993, including 8140 kidney
cancer cases in 1988 and 10,617 in 1993 from hospital cancer registries across
the U.S. These data represent 36% and 39% of all cases of kidney cancers
diagnosed in the U.S. in 1988 and 1993, respectively. RESULTS: Three trends were
observed. 1) Stage II disease is being diagnosed with increasing frequency. 2)
There has been an overall increase in the frequency with which surgery alone is
utilized as the primary treatment for patients with Stage I, II, and III disease;
however, surgical treatment of patients with Stage IV kidney cancer has declined.
3) Partial nephrectomy rather than total nephrectomy is performed with increasing
frequency as surgical treatment of patients with Stage I renal carcinoma.
CONCLUSIONS: The NCDB data have important implications for analyzing cancer
treatments and outcomes in the U.S. These data suggest that kidney cancers are
being diagnosed at an earlier stage and with greater precision. As a result,
changes in surgical practice are apparent in the treatment of patients with lower
stage disease (Stage I and II). Stage for stage, surgery remains the most
effective form of treatment for patients with kidney cancer.
PMID- 9392342
TI - Infective endocarditis.
PMID- 9392343
TI - Novel feature of infection in diabetic compromized hosts.
PMID- 9392344
TI - Idiopathic CD4+ T-lymphocytopenia.
PMID- 9392345
TI - Coronary spasm: clinical features and pathogenesis.
AB - Coronary artery spasm (coronary spasm) is an abnormal contraction of an
epicardial coronary artery resulting in myocardial ischemia and its incidence is
relatively high in Japanese as compared with Caucasians. Coronary spasm occurs
most often from midnight to early morning when the patient is at rest and it is
usually not induced by exercise in the daytime. Coronary spasm can be induced by
acetylcholine, an endothelium-dependent vasodilator which causes vasodilatation
in the normal coronary artery. Spasm artery is hyperresponsive to the vasodilator
effect of nitroglycerin, an nitric oxide (NO) donor and is deficient in NO
activity. The major risk factor for coronary spasm is cigarette smoking. Coronary
spasm can be a cause of not only variant angina but also ischemic heart disease
in general, including unstable angina, acute myocardial infarction and sudden
ischemic death.
PMID- 9392346
TI - Involvement of peribiliary glands in primary sclerosing cholangitis: a
histopathologic study.
AB - We examined the histological changes of the peribiliary glands (PBGs), a hitherto
pooly recognized anatomical element around the biliary tree, in 7 cases of
primary sclerosing cholangitis (PSC). These glands showed proliferation, and
nonspecific inflammation with lymphoplasmacytic infiltration, fibrosis, and
destruction. In addition, there were cystic lesions around the bile ducts, and
they were considered to reflect dilatation of the PBGs. These changes were found
around the intrahepatic and extrahepatic bile ducts in the cases examined. It is
of interest that changes in the PBGs tended to correlate with the inflammatory
changes of the bile duct wall itself, though 2 cases showed changes in the duct
walls and PBGs unrelated to their distribution along the biliary tree. These
findings suggest that the PBGs are also a target structure in addition to the
bile ducts themselves in PSC.
PMID- 9392347
TI - Effect of respiratory rate on respiratory patterns in patients with chronic
obstructive pulmonary disease.
AB - We enrolled 22 patients with chronic obstructive pulmonary disease (COPD) and 20
normal subjects as controls. Using a hot-wire flow meter, we obtained tidal
volume (VT), duty ratio (Ti/Ttot), and mean inspiratory flow (VT/Ti) as measures
of respiratory pattern at two different respiratory rates; 0.5 Hz and 1.5 Hz. At
0.5 Hz, there were significant differences in Ti/Ttot and VT/Ti. At 1.5 Hz,
patients with COPD had significantly lower values of VT and VT/Ti. Furthermore,
we calculated the change ratios from 0.5 Hz to 1.5 Hz in these parameters as new
parameters of respiratory pattern change by respiratory rate. VT0.5/1.5 and
VT/Ti0.5/1.5 significantly correlated with FEV1.0/FVC. The findings suggest that
the parameters of the respiratory pattern may change depending on respiratory
rates, and that the ratios of those parameters obtained at two different rates
could be helpful in diagnosing airflow obstruction.
PMID- 9392348
TI - Ventilatory responses and subjective sensations during arm exercise and
hypercapnia in patients with lower-cervical and upper-thoracic spinal cord
injuries.
AB - We measured the ventilatory responses and subjective sensations during arm
exercise in patients with lower cervical and upper thoracic spinal cord injuries
in order to evaluate the effects of chest wall deafferentation on these
responses. Visual analog scales with verbal descriptors were used to quantify
respiratory sensations of different affectional qualities. Patients as well as
normal subjects reported stronger respiratory sensations upon CO2 rebreathing as
compared to during arm exercise with an equivalent minute ventilation (p<0.05).
There were no qualitative nor quantitative differences in the respiratory
sensations during CO2 rebreathing between the patients and normal subjects.
However, patients with spinal cord injuries showed a higher minute ventilation
and a lower end-tidal PCO2 during incremental arm exercises (p<0.01), and thus
tended to hyperventilate. We conclude that chest wall afferent denervation does
not contribute significantly to the perception of breathlessness in patients with
spinal cord injuries.
PMID- 9392350
TI - Multiple gastric carcinoids and pituitary adenoma in type A gastritis.
AB - A 48-year-old male with type A atrophic gastritis developed multiple gastric
carcinoids and a pituitary adenoma. Laboratory tests revealed high levels of
serum gastrin and growth hormone (GH). He underwent subtotal gastrectomy,
resulting in a return of the previously elevated gastrin level to normal. Serum
GH concentration remained high. Three months after the surgery, the pituitary
tumor, composed greatly of GH-immunoreactive cells, was partially removed. Since
hypergastrinemia plays a pivotal role in gastric carcinoid formation and induces
GH-releasing factor (GHRH) release resulting in GH-producing pituitary tumor
formation, GH-producing pituitary adenoma might be a clinical manifestation in
type A gastritis.
PMID- 9392349
TI - Detection of polyanion-restricted anti-histone antibodies in patients with
systemic lupus erythematosus.
AB - The nature of the antibodies responsible for lupus erythematosus (LE) cells in
systemic lupus erythematosus (SLE) remains obscure. We examined whether polyanion
restricted anti-histone antibodies were present in serum of patients with SLE
using Western blotting analysis. Dextran sulfate or alginate was used as a
polyanion compound in place of DNA. Antibodies which recognized dextran sulfate
histone complexes were present in serum of patients with SLE (17/34, 50%). These
antibodies were detected in most SLE patients positive for LE cells (17/18, 94%)
but not in those negative for LE cells or in patients with other collagen
diseases. Similar results were obtained using alginate-histone complexes as
antigens for Western blotting analysis. The antibodies to dextran sulfate-histone
or alginate-histone complexes in serum of SLE patients were completely absorbed
by treatment of serum with DNA-histone complexes, while they were unaffected by
treatment with DNA only. The presence of antibodies to free histones and dextran
sulfate-histone complexes did not seem to be related to the titer of anti-single
stranded DNA antibody and anti-double stranded DNA antibody. We demonstrated the
presence of polyanion-restricted antibodies in SLE, which may be responsible for
the LE factor.
PMID- 9392351
TI - Portal-hepatic venous shunt through a portal aneurysm complicated by hepatic
encephalopathy and pulmonary hypertension.
AB - We report a rare case of portal-hepatic venous shunt through an enormous portal
aneurysm complicated by pulmonary hypertension. A 66-year-old woman was admitted
to our hospital for hepatic encephalopathy. Chest roentgenography revealed
pulmonary hypertension. Computed tomography and ultrasound examination
demonstrated a shunt between the portal and hepatic veins through an enormous
portal aneurysm. The diagnoses of portal-hepatic venous shunt and pulmonary
hypertension were confirmed by hepatic venous catheterization and cardiac
catheterization. Pulmonary hypertension might result from the effects of
vasoconstrictive agents, which should be metabolized by the liver in normal
subjects, passing through the intrahepatic shunt into the lung.
PMID- 9392352
TI - Long-term continuous intravenous infusion of prostacyclin for severe primary
pulmonary hypertension.
AB - A patient suffering from severe symptomatic primary pulmonary hypertension (PPH)
underwent long-term intravenous prostacyclin therapy; the first time for such
treatment in Japan. A 26-year-old male had experienced gradually progressive
dyspnea for about one year. Despite conventional therapy he suffered repeated
syncopal attacks. However, after receiving a permanent central venous access
device and a portable infusion pump, he recovered fully and was discharged. This
remedy seems to be promising for PPH as has already been proven in Europe and
North Americas, although in Japan it is not as yet commercially available and
some problems still need to be resolved.
PMID- 9392353
TI - Tricuspid valve endocarditis in a non-drug addict associated with peliosis
hepatis.
AB - A 31-year-old woman was admitted because of persistent remittent fever. Tricuspid
valve endocarditis due to Staphylococcus aureus was identified as the cause of
fever. The patient had no history of intravenous drug abuse, oral contraceptives
or predisposing cardiac disease. Huge hepatomegaly was found without any signs of
congestive heart failure. Liver enzyme abnormalities were not detected throughout
the entire course of therapy. The liver biopsy specimen revealed peliosis
hepatis. Treatment with panipenem/betamipron was successful, although recurrent
septic pulmonary embolism occurred. The cause of the huge hepatomegaly
encountered in the present case may be attributable to peliosis due to severe
infection.
PMID- 9392354
TI - Cushing's syndrome due to bilateral adrenocortical adenomas with different
pathological features.
AB - A 48-year-old woman with Cushing's syndrome due to bilateral adrenocortical
adenomas is reported. The patient presented with a typical Cushingoid appearance.
The serum cortisol level was elevated with loss of the diurnal rhythm and the
plasma adrenocorticotropic hormone (ACTH) level was undetectable. Dynamic testing
showed no suppression of urinary 17-OHCS by high-dose dexamethasone and no
stimulation by metyrapone. An abdominal computed tomography (CT) scan showed
bilateral adrenal tumors. Bilateral adrenalectomy was performed. The right
adrenal gland contained a tumor that was encapsulated and consisted mainly of
compact cells. The surrounding cortex was atrophic. The left adrenal gland
contained an encapsulated tumor composed predominantly of clear cells. There were
numerous small adrenocortical nodules in the surrounding cortex.
Immunohistochemical analysis of steroidogenic enzymes (P450scc, 3beta-HSD,
P450c21, P450c17 and P450c11) was performed. Immunoreactivity of all the enzymes
was intense in the compact cells of the right adrenocortical adenoma, while the
adjacent non-neoplastic cortex was negative for the enzymes. In the left adrenal
tumor, the immunoreactivity of 3beta-HSD was intense, while that of P450c17 was
weak. In the adrenocortical nodules, 3beta-HSD activity was sporadically
observed. G protein genes encoding Gs alpha and Gi2 were examined for activating
mutations at codons 201 and 227 (Gs alpha) and codons 179 and 205 (Gi2 alpha) in
the bilateral adrenal tumors, but no mutations were found. The bilateral adenomas
of this patient showed marked differences in microscopic and immunohistochemical
studies, suggesting that the capacity of steroidogenesis differs between the
right and left tumors.
PMID- 9392355
TI - Pyogenic clavicular osteomyelitis associated with disseminated intravascular
coagulation and acute renal failure in a patient with non-insulin-dependent
diabetes mellitus.
AB - Pyogenic osteomyelitis is often accompanied by diabetes, but the disease in the
clavicula has rarely been reported. We describe an unusual case of a 53-year-old
man with poorly controlled non-insulin-dependent diabetes mellitus who presented
with pyogenic clavicular osteomyelitis and developed DIC and acute renal failure.
A 67Ga scintigram revealed an abnormal accumulation of the isotope in the right
clavicula, where magnetic resonance imaging (MRI) showed inflammatory changes.
This suggests that a 67Ga scintigram and MRI are of clinical value for the early
diagnosis of the disease. Antibiotic chemotherapy with gamma-globulin and
gebexate mesilate, and hemodialysis almost cured his serious condition.
PMID- 9392356
TI - Massive adrenal hemorrhage secondary to metastasis of lung cancer.
AB - Hemorrhagic adrenal metastasis from lung cancer is extremely rare, although
adrenal involvement is common in widely disseminated cancer. We report a case of
massive adrenal hemorrhage secondary to metastasis of lung cancer. A 47-year-old
female was treated by left upper lobectomy and mediastinal lymph node resection
for an adenocarcinoma with intrapulmonary metastasis in the left upper lobe.
Eight months later, she presented with right flank and back pain, and abdominal
ultrasonography and computed tomography showed a right solitary adrenal tumor
with massive hemorrhage. The tumor was not resectable and partially responded to
chemotherapy. A massive adrenal hemorrhage, secondary to metastasis of lung
cancer, presents with nonspecific clinical signs and symptoms. In lung cancer
patients with an acute flank or back pain, hemorrhagic adrenal metastasis should
be considered in the differential diagnosis.
PMID- 9392357
TI - Acute lymphoblastic leukemia with isolated adrenocorticotropic hormone
deficiency.
AB - A 57-year-old female was admitted to our hospital because of Philadelphia
chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). On admission,
disturbance of consciousness and hyponatremia were recognized. The patient's
endocrinological data showed low levels of adrenocorticotropic hormone (ACTH)
(less than 5 pg/ml) and cortisol (5.9 microg/dl). Other anterior pituitary
hormones were normal. Plasma ACTH and cortisol did not respond to the
corticotropin releasing factor (CRF) test. A diagnosis of isolated ACTH
deficiency was made. This is a rare case of isolated ACTH deficiency complicated
with hematological malignancies.
PMID- 9392359
TI - Facial nerve enhancement on gadolinium-DTPA in a case with neurosarcoidosis.
AB - In a case of neurosarcoidosis with bilateral facial nerve palsy and
hydrocephalus, contrast-enhanced magnetic resonance imaging (MRI) study and
angiotensin converting enzyme (ACE) activities in cerebrospinal fluid (CSF) were
valuable for the diagnosis and the follow up. Facial nerve lesions were
demonstrated on gadolinium-DTPA enhanced MRI. The disappearance of enhancement
was concomitant with the amelioration of facial nerve palsy after corticosteroid
therapy.
PMID- 9392358
TI - Idiopathic CD4+ T-lymphocytopenia with Bowen's disease.
AB - A 39-year-old man with Bowen's disease was troubled with multiple molluscum
contagiosum over the trunk and lower extremities. Subsequently oral candidiasis
was complicated. Laboratory examination revealed lymphocytopenia and a decrease
in the CD4/CD8 ratio. His CD4+ T-lymphocyte count was only 187 cells/microl one
time and 222 cells/microl another time. No evidence for human immunodeficiency
virus (HIV) infection was found. He had no family history of immunodeficiencies.
PMID- 9392361
TI - Spontaneous dissection associated with proximal vertebral artery anomaly.
AB - A 47-year-old man was admitted because of acute lateral medullary syndrome with
severe posterior cervical pain. Cerebral angiography was performed three hours
after the onset, which demonstrated that two arteries branched separately from
the right subclavian artery, ran upward and formed a single right vertebral
artery (VA). One of the two arteries showed both stenosis and luminal dilatation.
We thought the structure of these arteries was proximal vertebral artery anomaly
and diagnosed him as having dissection of the vertebral artery. We consider that
the proximal vertebral anomaly may be a risk for spontaneous VA dissection.
PMID- 9392360
TI - Sensory conduction study of cisplatin neuropathy: preservation of small
myelinated fibers.
AB - We report a patient with peripheral neuropathy caused by cisplatin for the
treatment of testicular tumor. Routine studies of nerve conduction and
somatosensory evoked potentials demonstrated large myelinated fiber neuropathy
suggesting ganglioneuronopathy. We also performed a CO2 laser evoked potential
study, and found that small myelinated fibers, which are related to pain
sensation, were well preserved in this patient.
PMID- 9392362
TI - Pulmonary fibrosis associated with polymyalgia rheumatica.
AB - Polymyalgia rheumatica (PMR) and exacerbated pulmonary fibrosis presented
concurrently in a 69-year-old woman with a 5-year history of idiopathic
interstitial pneumonia. The radiographic and histological examinations suggested
usual interstitial pneumonia (UIP) as a more likely diagnosis. Corticosteroid
therapy resulted in relief of the patient's muscle symptoms and improvement in
the functional and radiographical signs of the pulmonary fibrosis. The final
diagnosis was pulmonary fibrosis associated with PMR, because PMR is believed to
be one of the causes contributing to interstitial lung diseases.
PMID- 9392363
TI - Myeloperoxidase-antineutrophil cytoplasmic antibody-associated glomerulonephritis
with membranous nephropathy in remission.
AB - A 47-year-old woman developed pulmonary hemorrhage and an increase in proteinuria
during remission of membranous nephropathy. Renal biopsy revealed crescentic
glomerulonephritis. She also had a high perinuclear antineutrophil cytoplasmic
antibody level, so a diagnosis of myeloperoxidase-antineutrophil cytoplasmic
antibody-associated glomerulonephritis was made. After immunosuppressive therapy
was started, the pulmonary hemorrhage resolved and her proteinuria decreased.
Renal biopsy was repeated after treatment and showed histological improvement.
This case suggests that there may be a relationship between membranous
nephropathy and myeloperoxidase-antineutrophil cytoplasmic antibody-associated
glomerulonephritis.
PMID- 9392364
TI - Reuse of a Japanese familial amyloidotic polyneuropathy patient's liver for a
cancer patient: the domino liver transplantation procedure.
PMID- 9392365
TI - New packing materials for protein chromatography.
AB - This review describes new packing materials designed for protein chromatography,
covering advances in base supports and stationary phases. Base supports are
classified according to their chemical composition. Since most separation media
are bead shaped, typical procedures used for their preparation are also
presented. In order to provide matrices combining improved chemical stability and
chromatographic performances, composite materials continue to be developed,
including bonded stationary phases, pore composites and mixed carriers. The
different approaches to their preparation are described and characteristics that
play a major role in the chromatographic process are discussed. Recently
introduced materials and some of their applications under non-denaturing
conditions in the different chromatographic modes are also presented.
PMID- 9392366
TI - Protein separation using non-porous sorbents.
AB - This article overviews the development of non-porous sorbents having small
particle diameters which have proven effective for rapid analysis and
micropreparative separation of proteins by liquid chromatography. Much attention
is given to the preparation and application of silica- and polystyrene-based non
porous packings for various chromatographic modes, especially affinity
chromatography. Modeling works on the prediction and parameter estimation for the
dynamics of protein adsorption using non-porous sorbents are reviewed and briefly
described. To conclude this review, future prospects of the application of non
porous sorbents are also presented.
PMID- 9392367
TI - Permeable packings and perfusion chromatography in protein separation.
AB - The use of permeable packings in perfusion chromatography for protein separation
is reviewed. Mass transport mechanisms in large-pore materials include forced
convection in addition to diffusive transport. The key concept in perfusion
chromatography is the "augmented" diffusivity by convection which explains the
improved efficiency of perfusive packings compared with conventional supports. An
extended Van Deemter equation has to be applied when calculating the height
equivalent to a theoretical plate (HETP) of chromatographic columns with flow
through particles. It is shown that the effect of forced convective flow in pores
is to drive the separation performance between diffusion-controlled and
equilibrium limits. A methodology to understand mass transfer mechanisms in
permeable packings is proposed. Experimental results for protein separation by
high-performance liquid chromatography in new packing media are discussed.
Simulated moving bed technology is addressed.
PMID- 9392368
TI - Electrophoresis gel media: the state of the art.
AB - Some unique events have occurred in the last few years which might revolutionize
the field of polyacrylamide gel electrophoresis. While it was widely recognized
that such matrices could normally be cast with a small pore size distribution,
typically of the order of a few nanometers diameter (for protein sieving), recent
developments suggest that "macroporous" gels could also be produced in the domain
of polyacrylamides. If constraints to chain motion are imposed during gel
polymerization, large-pore structures can be grown. Such constraints can
originate either from low temperatures or from the presence of preformed polymers
in the gelling solution; in both cases, the growing chains are forced to
"laterally aggregate" via inter-chain hydrogen bond formation. Upon consumption
of pendant double bonds, such bundles are frozen in the three-dimensional space
by permanent cross-links. As an additional development, a novel
photopolymerization system is described, comprising a cationic dye (methylene
blue) and a redox couple (sodium toluene sulfinate, a reducer, and
diphenyliodonium chloride, a mild oxidizer). Methylene blue catalysis is
characterized by a unique efficiency, ensuring >96% conversion of monomers, even
in hydro-organic solvents and in the presence of surfactants, which normally
quench or completely inhibit the persulphate-driven reaction. In addition,
methylene blue-sustained photopolymerization can be operated in the entire pH 3
10 interval, where most other systems fail. Perhaps the most striking novelty in
the field is the appearance of a novel monomer (N-acryloylaminopropanol, AAP)
coupling a high hydrophilicity with a unique resistance to alkaline hydrolysis.
Given the fact that a poly(AAP) matrix is 500 times more stable than a
poly(acrylamide) gel, while being twice as hydrophilic, it is anticipated that
this novel chemistry will have no difficulties in replacing the old
electrophoretic anticonvective media. The review ends with a glimpse at novel
sieving media in capillary zone electrophoresis: polymer networks. Such media, by
providing an almost infinite range of pore sizes, due to the absence of a rigid
support, allow sieving mechanisms to be operative over a wide interval of
particle sizes, even up to genomic DNA. Viscous solutions of polymer networks,
made with the novel poly(AAP) chemistry, allow repeated use of the same
separation column, well above 50 injections. Silica-bound poly(AAP) chains
provide effective quenching of electroosmosis and >200 analyses by isoelectric
focusing.
PMID- 9392369
TI - Isoelectric focusing in immobilized pH gradients: an update.
AB - The latest trends on isoelectric focusing (IEF) in immobilized pH gradients (IPG)
are here reviewed. The major advances on IPG technologies have been made when
interfacing this technique with sodium dodecyl sulfate-polyacrylamide gel
electrophoresis to produce two-dimensional (2-D) maps. Previous 2-D maps were
routinely performed using conventional IEF as a first dimension, which typically
resulted in poor reproducibility of spot position. With IPGs, correlation between
experimental and calculated protein pI values is as good as +0.01 to 0.02 pH
units. A new software has also been released, permitting easy calculation and
optimization of linear, concave and convex exponential gradients, even in very
complex recipes utilizing all ten Immobiline chemicals. It has also been proven
that IPGs can be interfaced with mass spectrometry, thus obtaining a novel 2-D
map with the best of pI measurements in the first dimension coupled with the best
of mass determination in the second dimension. Recently, it has been shown that
IPGs can be exploited to charter forbidden grounds, with the creation of non
linear pH gradients covering the extreme alkaline pH 10-12 gradient. In such
basic regions, excellent steady-state patterns of histones and subtilisin mutants
have been reported. Different families of histones could be mapped not only in
this pH 10-12 interval, but also in 2-D maps exploiting this very alkaline
gradient in the first dimension. Although the IPG technique is now a trouble
free, user-friendly technique, some annoying artefacts, producing severe protein
smears and precipitation, were very recently reported, but found to be linked to
some commercial Immobiline preparations containing up to 5% oligomers. Better
quality control on the part of the company producing such chemicals should
eliminate even this last source of troubles.
PMID- 9392370
TI - Current trends in capillary isoelectric focusing of proteins.
AB - Isoelectric focusing (IEF) in thin capillaries is reviewed here. After an
introduction on the genesis and chemistry of the carrier ampholyte buffers,
different approaches to IEF are discussed and evaluated. The classical approach
consists on IEF under conditions of suppressed electroosmotic (EOF) flow, usually
obtained by covalently bonding hydrophilic polymers to the inner capillary wall.
The other approach consists of IEF in dynamically (and partially) coated
capillaries, so as to allow a reduced EOF flow to coexist with the IEF process,
so that focusing and transport of the train of stacked bands occurs
simultaneously. The various experimental parameters: focusing, elution and
detection steps, pI measurements, as well as typical drawbacks, such as
isoelectric precipitation are evaluated. The review ends with some examples of
analytical separations, at the moment mostly limited to focusing of native
hemoglobins (normal and point mutants). These separations are compared with those
obtained by slab-gel IEF and in immobilized pH gradients.
PMID- 9392371
TI - Protein purification in multicompartment electrolyzers with isoelectric
membranes.
AB - Preparative purification of proteins under isoelectric conditions is reviewed,
with particular regard to novel equipment, a multicompartment electrolyzer with
isoelectric membranes, which can capture any desired protein into an isoelectric
trap as the sole, ultra-pure component. This novel machine is based on the
Immobiline chemistry, i.e. the novel generation of non-amphoteric buffers, based
on the chemistry of acrylamides, which can be insolubilized onto polyacrylamide
supports. After a description of the instrument and of its performance, a number
of protein purification protocols are described, leading to truly homogeneous (by
the most stringent criterion of surface charge) protein fractions. Such a high
charge purity has been found to be often a fundamental prerequisite for the
growth of protein crystals. Interfacing the electrolyzer with mass spectrometry
has permitted the decoding of the structure of minor components generated from a
parental molecule, especially ones having a higher pI. It was found that these
species were often generated either by proteolytic cleavage or by the formation
of a trisulphide bridge between two Cys residues. A unique application of the
electrolyzer is finally described: its use as an immobilized enzyme reactor under
an electric field. The performance of this reaction is outstanding, in that the
kinetic parameters of the immobilized enzyme are identical to those of a free
enzyme form.
PMID- 9392372
TI - Factors affecting protein interaction at sorbent interfaces.
AB - Interactions between surfaces and macromolecules are the fundamentals in
separation and detection of diverse solutes. In this very brief review the
central aspects of protein-surface interactions are discussed with the intention
of identifying the important factors influencing such processes and placing them
in relation to the established knowledge in this field. Some perspectives of new
techniques related to scanning probe microscopy for studying interactions at the
nanometer level are also discussed.
PMID- 9392373
TI - Rules relating electrophoretic mobility, charge and molecular size of peptides
and proteins.
AB - The absence of supporting media in free solution high-performance capillary
electrophoresis (HPCE) makes it an ideal system for the study of the relationship
between electrophoretic mobility (mu(em)) and the molecular size and charge of
proteins and peptides. In this review, the theory of electrophoresis, developed
for rigid, insulating, spherical particles, is modified to develop models for the
electrophoretic behaviour of proteins and peptides. For a given set of
experimental conditions, mu(em) of a protein/peptide is proportional to its
charge (q) and is inversely proportional to its Stoke's radius (r). Furthermore,
mu(em) is most sensitive to changes in q and, as a consequence, the reliability
of equations relating mu(em) to protein/peptide q and r is dependent upon the
accurate calculation or determination of q. For convenience, q and r of proteins
and peptides are generally expressed in terms of calculated valence (Zc) and
molecular mass (M), respectively, both of which can be determined from the amino
acid sequence of the protein/peptide. However, the calculation of q using Zc is
made more complex by the effects of electrostatic charge suppression, such that
Zc is an overestimation of actual charge. Charge suppression becomes increasingly
significant as the protein/peptide charge increases, such that, for peptides, the
relationship between q and Zc can be approximated by a logarithmic function. The
mu(em) for peptides, therefore, can be approximated by the equation: mu(em) =
ln(Zc + 1)/K Ms where s varies between 1/3 and 2/3, and K is a constant that is
valid for a particular set of experimental conditions. The rather simplistic
compensation for charge suppression in this equation is inadequate for proteins
where the magnitude of charge suppression is greater and the mechanisms are more
complex. For proteins, the relationship suggested for the prediction of mu(em)
from Zc and M is: mu(em) = Zc/KFzMs where s again varies between 1/3 and 2/3 and
Fz is a pH-independent proportionality factor defined as the quotient, Zc/Za,
with Za being actual protein valence. The factor Fz can be determined
empirically, however, it is valid only for the particular set of experimental
conditions under which it is determined. For peptides, the mass exponent, s,
approaches 1/3 when the peptides have high charge densities and open structures.
However, s approaches 1/2 for peptides with lower charge densities that are
capable of more randomized motion during electrophoresis. Finally, s approaches
2/3 for proteins, suggesting that the frictional forces acting on a protein
undergoing electrophoretic motion are proportional to the surface area of these
larger, more rigid, structures. In conclusion, the development of relationships
between mu(em), M and Zc for peptides and proteins offers a powerful tool, not
only for predicting electrophoretic mobility, but also for optimising HPCE
separations, studying structural modifications (e.g. phosphorylation,
glycosylation, deamidation, etc.), and for the investigation of surface charge
characteristics and conformation.
PMID- 9392374
TI - Peptide analysis by capillary (zone) electrophoresis.
AB - In this review various aspects concerning the application of capillary (zone)
electrophoresis for peptide analysis will be critically examined. First, the
basic instrumental requirements of CE apparatus and the strategies employed to
enhance sensitivity in the analysis of underivatized sample are described.
Multidimensional separative techniques of complex peptide mixtures that use CE as
final step and the coupling of CE with mass spectrometry are subsequently
discussed. A theoretical section describes the relationships existing between
peptide mobility and the pH of the separation buffer. These relationships
evidence that proton dissociation constants and Stokes radius at different
protonation stages can be calculated by measuring the electrophoretic mobility at
different pH values. Investigation of peptide mobility dependence on pH allows us
to establish the optimum conditions, in terms of resolution, for peptide
separation. Subsequently, a critical discussion about semiempirical models
predicting peptide mobility as a function of chemico-physical peptide properties
is presented. A section is devoted to the description of principles of peptide
affinity capillary electrophoresis, underlining the similarity with peptide
proton interaction. CE separations performed in aquo-organic solvents are also
critically discussed, showing the good performance obtained by using water-2,2,2
trifluoroethanol solutions. Finally, selected CE applications for the
determination of peptide chemico-physical properties and conventional analysis,
like peptide mapping, are reported.
PMID- 9392375
TI - Labeling reactions applicable to chromatography and electrophoresis of minute
amounts of proteins.
AB - Chromatography and electrophoresis have become extremely valuable and important
methods for the separation, purification, detection and analysis of biopolymers
and HPLC/HPCE may become the premier, preferable approaches for both qualitative
and quantitative analyses of most proteins, especially from recombinant
materials. This includes smaller peptides, polypeptides, proteins, antibodies and
all types of protein or antibody-conjugates (antibody-enzyme, protein-fluorescent
probe, antibody-drug and so forth). This entire Topical Issue of Journal of
Chromatography emphasizes the application of chromatography and electrophoresis
to protein analysis. This particular review deals with approaches to the
selective tagging or labeling of proteins at trace (minute) levels, again using
either chromatography or electrophoresis, with the emphasis on modern HPLC/HPCE
methods and approaches. We discuss here both pre- and post-column labeling
methods and reagents, techniques for realizing selective labeling of proteins or
antibodies, applicable approaches to protein preconcentration in both HPLC and
HPCE areas and in general, methods for improving (lowering) detection limits for
proteins utilizing chemical or physical derivatization and/or preconcentration
techniques. There are really two major goals or emphases in that which follows:
(1) methods for selective labeling of proteins prior to or after HPLC/HPCE and
(2) labeling of proteins at trace levels for improved separation-detection and
lowered detection limits. We discuss here a large number of specific references
related to both pre- and post-column/capillary derivatizations for proteins, as
well as methods for improved detectability in both HPLC and HPCE by, for example,
analyte preconcentration on a solid-phase extractor or membrane support,
capillary isotachophoresis and other methods. Selective reactions or
derivatizations on proteins refers to the ability to tag the protein at specific
(e.g. reactive amino sites) in a controlled manner, with the products having the
same number of tags all at the very same site or sites. The products are all the
same species, having the same number of tags at the same locations on the
protein. Selective reactions can also refer to the idea of tagging all of the
protein sample at only a single, same site or at all available sites,
homogeneously.
PMID- 9392376
TI - Chromatography on cells and biomolecular assemblies.
AB - Red cells, biomembrane vesicles, proteoliposomes and liposomes non-covalently
immobilized in gel particles or beads have been used as stationary phases for
biomembrane affinity analyses and ion-exchange chromatographic separation. Lipid
monolayers coupled to silica beads have been utilized for membrane protein
purification in detergent solution and plant cell walls for group separation of
macromolecules according to size and charge. Further methodological studies are
essential to implement general practical application.
PMID- 9392377
TI - Buffer additives other than the surfactant sodium dodecyl sulfate for protein
separations by capillary electrophoresis.
AB - The different compounds utilized as additives to the electrolyte solutions
employed in protein capillary zone electrophoresis (CZE) for minimizing protein
capillary wall interactions, for improving selectivity and resolution and for
controlling the electroosmotic flow are reviewed. The dependence of the
electroosmotic flow on the different variables that can be affected by the
incorporation of an additive into the electrolytic solution is discussed. A list
of the most effective additives employed for protein separations by CZE is
reported in Appendix A.
PMID- 9392378
TI - Capillary electrophoresis procedures for serum protein analysis: comparison with
established techniques.
AB - Methods using automated capillary electrophoresis (CE) instrumentation are
available for serum protein electrophoresis with monoclonal band quantitation,
isoelectric focusing and sodium dodecyl sulphate-polyacrylamide gel
electrophoresis separations. The advantages of CE over previous gel methods
relate to the time and labour saved by the automated instrumentation. High pI
monoclonal bands and cryoglobulin specimens can be successfully analysed by CE.
However, if the CE application uses a standard company supplied kit, then the
cost savings are often negated by the high cost of the kit. Improvements such as
the inclusion of both a UV-Vis as well as a fluorescence detector as standard
within the one commercial instrument, the production of coated IEF capillaries
with a useful life of at least 100 samples, and the introduction of a capillary
array into all commercial instrumentation would ensure greater use of CE within
both the clinical and other protein laboratories.
PMID- 9392379
TI - Chromatographic and electrophoretic methods for modified hemoglobins.
AB - The discovery of the clinically important glycohemoglobin adducts and their
relation to diabetes mellitus have greatly stimulated the study of other minor
post-translational modifications of hemoglobin. Chromatographic and
electrophoretic procedures have played an important role in these studies. Today
several hemoglobin adducts are known and the formation of adducts with glucose,
phosphorylated carbohydrates, urea/cyanate, aspirin, vitamins, acetaldehyde,
penicillin and acetyl CoA have been described. Furthermore, new adducts, such as
those observed using hemoglobin as a biochemical marker monitoring environmental,
occupational and lifestyle exposures to reactive toxic chemicals are constantly
being reported. This review deals with chromatographic and electrophoretic
separation methods available for the study of non-enzymatic post-translational
modifications of hemoglobin. Suitability, perspectives and biomedical
applications are discussed.
PMID- 9392381
TI - Post-translational non-enzymatic modification of proteins. II. Separation of
selected protein species after glycation and other carbonyl-mediated
modifications.
AB - There are two strategies applicable to revealing non-enzymatic post-translational
modifications of proteins; while assaying of the hydrolytically stable adducts
was the subject of our previous communication [1], here we attempted to review
separation technologies for the unfragmented modified proteins. There are a few
standard procedures used for this purpose, namely Laemmli gel electrophoresis,
different modes of gel permeation chromatography and boronate affinity
chromatography. The latter approach makes use of the vicinal hydroxy groups
present in glycated proteins. Some (but not all) arising adducts exhibit typical
fluorescence which can be exploited for detection. In most cases fluorescence is
measured at 370/440 nm for the so-called advanced glycation products or at
335/385 nm for the only so far well characterized glycation marker (pentosidine).
Some indication exists that, e.g., synchronous fluorescence detection will
probably in the future add to the selectivity and allow the distinction of the
different adducts arising during non-enzymatic post-translational modifications
(glycation). The proteins reviewed are serum albumin, collagen and lens proteins
while glycation of hemoglobin is the subject of another review within the present
volume.
PMID- 9392380
TI - Post-translational non-enzymatic modification of proteins. I. Chromatography of
marker adducts with special emphasis to glycation reactions.
AB - Analytical methods for marker compounds formed during post-translational
modifications of proteins are reviewed. Only adducts arising either in vivo or
under in vitro conditions simulating the in vivo situations are discussed. All of
these compounds stem from either the reaction of free amino groups (i.e., lysine,
arginine or N-terminal amino acid). In most cases the reactive counterpart is an
aldehydic moiety containing endogenous compound; however, other functional groups
containing metabolites are considered as well. The main demand put upon such
marker compounds is that they are stable in acid or enzymatic hydrolysis or,
alternatively, can be stabilized by simple sample pretreatment (e.g., by
reduction). Practically all categories of separation procedures can be applied
provided that the chemical characteristics of a particular marker are adequately
respected; frequently combination of two different separation procedures based on
different principles must be used. Because of the low level of such marker
compounds under in vivo conditions, an appropriate sample enrichment step must be
involved. Emphasis is put upon the analysis of Amadori products, pentosidine (and
pentosidine related compounds), pyrraline, furosine, N-carboxymethylamino acids,
amino acid hydantoins and stabilized dicarbonyl intermediates.
PMID- 9392382
TI - Unstable proteins: how to subject them to chromatographic separations for
purification procedures.
AB - The chromatographic separation of an unstable protein is often a challenge to the
scientist working in the field of life sciences. Especially for the purification
of sensitive enzymes, making use of conventional chromatographic techniques is
difficult and frequently results in a complete loss of biological activity of the
target protein. This report summarizes some general strategies that may help to
keep unstable proteins in their native conformation during the rather harsh
conditions of a purification procedure. In this context, a recently developed
hollow fiber membrane module, suitable for performing on-line dialysis, is
introduced and examples of its application to liquid column chromatography are
given. Many innovative separation techniques, characterized by dramatic
improvements in both performance and separation time, have recently been
developed. Since the chromatographic separation of unstable proteins requires the
use of modern state-of-the-art equipment and technology, emphasis is given to
newly developed separation techniques such as expanded bed adsorption, perfusion
chromatography, protein free flow electrophoresis and the use of tentacle gels.
In addition, examples of recently published purifications of unstable proteins
are discussed with respect to strategies ensuring the preservation of the native
protein structure during chromatographic separation.
PMID- 9392383
TI - Separation methods for glycoprotein analysis and preparation.
AB - Several chromatographic methods have been developed for the isolation and
characterization of glycoproteins. In these methods, affinity chromatography, a
single-step method, or combined use with general chromatographic methods have now
become essential for the purification of many biologically important
glycoproteins, including alpha1-acid glycoprotein, immunoglobulins, ceruloplasmin
and erythropoietin. On the other hand, almost all glycoproteins exhibit
polymorphism associated with their glycan moieties. This feature is wide-spread
and has been observed in natural as well as in recombinant DNA glycoproteins.
Recently, several sophisticated techniques--such as electromigration method (high
performance capillary electrophoresis) and chromatographic methods (two
dimensional polyacrylamide gel electrophoresis, high-pH anion-exchange
chromatography with pulsed-amperometric detection)--have been introduced for
qualitative or quantitative estimation of the microheterogeneity of
glycoproteins. For gaining further insight into the structure-function relations
for microheterogeneity, preparative chromatographic techniques that can yield
sufficient quantities of glycoprotein variants must be developed.
PMID- 9392385
TI - High-performance separations in isolation and characterization of allergens.
AB - The present state of the use of separation techniques in the identification and
characterization of allergens and in the monitoring of the quality of allergenic
preparations is critically surveyed. After a brief summary of the range of
problems encountered in obtaining and in the application of allergenic
preparations and of the principal physico-chemical properties of allergens,
chromatographic and electromigration methods of separation of components of these
systems and their combinations with immunochemical procedures are discussed, with
selected examples of application to real materials. Emphasis is placed on
evaluation of the most important analytical parameters, such as reliability of
the results, separation efficiency and resolution, and on the most recent results
in the field.
PMID- 9392384
TI - Separation used for purification of recombinant proteins.
AB - The purification of molecules from recombinant cells may be strongly influenced
by the molecular biology of gene isolation and expression. At the beginning of
the process there may be a demand for information on the minute amounts of
proteins and thus for ever increasingly sensitive techniques. Purification of
recombinant proteins can differ from conventional purifications in several ways,
depending on the solubility of the protein, occurrence in inclusion bodies,
creation of fusion proteins with tags that enable simpler purification. Sometimes
a (re)naturation step is required to get a bioactive protein. On the other hand,
the techniques used in separation are essentially the same as for purification
from the natural source and environment.
PMID- 9392386
TI - Lipoproteins: comparison of different separation strategies.
AB - This review describes two chromatographic techniques for the separation of three
main classes of lipoproteins (HDLs, LDLs and VLDLs) from human serum:
hydroxyapatite chromatography and counter-current chromatography. The HDLs, LDLs
and VLDLs were purified by the combined use of the two chromatographic techniques
without prior ultracentrifugation.
PMID- 9392387
TI - Analysis of protein aggregates by combination of cross-linking reactions and
chromatographic separations.
AB - Chemical cross-linking provides a method that covalently bridges near-neighbour
associations within proteins and protein aggregates. Combined with
chromatographic separations and protein-chemical methods, it may be used to
localize and to investigate three-dimensional relations as present under natural
conditions. This paper reviews the chemistry and application of cross-linking
reagents and the development of combination experimental approaches in view of
chromatographic separations and cross-linking reactions. Investigations of
homooligomeric and heterooligomeric protein associations as well as
conformational analysis are presented.
PMID- 9392388
TI - Capillary electrophoretic immunoassays.
AB - Capillary electrophoretic immunoassay (CEIA) has recently emerged as a new
analytical technique. CEIA, when combined with sensitive detection methods such
as laser induced fluorescence (LIF), offers several advantages over conventional
immunoassays. CEIA can perform rapid separations with high mass sensitivity,
simultaneously determine multiple analytes and is compatible with automation. The
objective of this review is to describe the applications of CE in antibody
related studies, focussing especially on recent developments of CEIA technique.
The principles for competitive and non-competitive CEIA are described with
examples. Several detection methods and various applications are summarized and
future developments in CEIA are speculated. CEIA has many potential applications,
especially if the throughput is improved by using either multicapillary array or
microchips with multiple channels.
PMID- 9392389
TI - Determination of minute enzymatic activities by means of capillary
electrophoretic techniques.
AB - Capillary electrophoretic analysis of enzymes, co-enzymes, substrates and other
chemical species that can be linked to an enzymatic reaction is reviewed with 80
references. Both off-line and on-line assays of minute enzymatic activities are
discussed. In addition to heterogeneous on-line enzyme assays, a special emphasis
is given to a newly established on-line technique called electrophoretically
mediated microanalysis (EMMA). The basic principle, procedure, and various
detection modes of EMMA are discussed. The recent developments in on-line
determination of various enzyme substrates as well as on-line enzyme kinetic
studies are also summarized. Some potential future developments in the
determination of enzymatic activities by means of CE are also presented.
PMID- 9392390
TI - Recent advances in chromatographic and electrophoretic methods for the study of
drug-protein interactions.
AB - Drug-protein binding is an important process in determining the activity and fate
of a pharmaceutical agent once it has entered the body. This review examines
various chromatographic and electrophoretic methods that have been developed to
study such interactions. An overview of each technique is presented along with a
discussion of its strengths, weaknesses and potential applications. Formats that
are discussed include the use of both soluble and immobilized drugs or proteins,
and approaches based on zonal elution, frontal analysis or vacancy peak
measurements. Furthermore, examples are provided that illustrate the use of these
methods in determining the overall extent of drug-protein binding, in examining
the displacement of a drug by other agents and in measuring the equilibrium or
rate constants for drug-protein interactions. Examples are also given
demonstrating how the same methods, particularly when used in high-performance
liquid chromatography or capillary electrophoresis systems, can be employed as
rapid screening tools for investigating the binding of different forms of a
chiral drug to a protein or the binding of different proteins and peptides to a
given pharmaceutical agent.
PMID- 9392391
TI - Glutaric aciduria type 1 (glutaryl-CoA-dehydrogenase deficiency): advances and
unanswered questions. Report from an international meeting.
AB - Infants with macrocephaly, young children with acute disease resembling
encephalitis, and children with truncal hypotonia, ataxia, or dystonia may be
affected by glutaric aciduria type I (GA 1, glutaryl-CoA-dehydrogenase
deficiency), a not-so-rare autosomal recessive neurometabolic disease. Well-known
features of GA1 are fronto-temporal brain atrophy with macrocephaly and acute
encephalopathic episodes with striatal necrosis followed by dystonia, but some
patients develop motor disease without overt crises and other biochemically
affected individuals remain asymptomatic. Biochemical and molecular
characterization is available and allows post- and prenatal diagnosis. The
pathogenesis of fronto-temporal atrophy, macrocephaly, and basal ganglia necrosis
is still not understood, and there is no close correlation between biochemical
parameters and clinical outcome. There is, however, evidence suggesting that
carnitine supplementation and anticatabolic treatment of intercurrent illness may
arrest or prevent neurological deterioration, while the role of limitation of
dietary lysine and tryptophane is not yet clear. Although pathogenetic aspects
are poorly understood, the natural course of glutaric aciduria type 1 can be
changed by early diagnosis and treatment. Coordinated research is needed to
understand the pathogenesis of brain toxicity, to define the role of dietary
therapy, and to explore the possibility of neonatal screening.
PMID- 9392392
TI - Pituitary dwarfism in the R271W Pit-1 gene mutation.
AB - The Pit-1 gene encodes the POU-domain transcription factor Pit-1 which is
important for the differentiation of the anterior pituitary and regulation of the
PRL, GH and TSH genes. As a member of the POU domain transcription factors, Pit-1
contains a DNA-binding region, consisting of a POU-specific domain and a POU
homeodomain. Mutation of the Pit-1 gene causes hypoplasia of the pituitary gland
and deficiencies of GH, PRL and TSH. In a DNA sample from a 3-month-old girl with
severe growth deficiency from birth, single stranded conformational polymorphism
analysis of the Pit-1 gene identified a gel shift in exon 6. DNA-sequencing
disclosed a single base mutation in codon 271 (CGG to TGG) that changes arginine
to tryptophan (R271W) in the POU homeodomain. The patient presented distinct
facial features with prominent forehead, marked mid-facial hypoplasia with
depressed nasal bridge, deep-set eyes and a short nose with anteverted nostrils.
MRI examination showed a hypoplastic pituitary gland. Low serum GH did not
respond to insulin-arginine provocation or GHRH tests. PRL levels below the
detection limit did not increase in response to a TRH test. T4 and free T4 was
below detection limit (< 20 nmol/l and < 4 pmol/l). TSH was 2.0 mU/l and showed a
blunt response to 6.0 mU/l following TRH test. TBG was normal. In spite of
inappropriately low TSH and very low T4, T3 was in the low normal range (1.4-1.6
nmol/l) and she was clinically euthyroid. The thyroid function tests are
consistent with increased monodeiodination activity and increased conversion of
T4 to T3, possibly related to the Pit-1 gene mutation. GH and T4 treatment
resulted in catch-up growth continued during 5 years of therapy. CONCLUSION:
Reports of nine other cases of R271W mutations of different populations as well
as the present Norwegian patient suggest codon 271 of exon 6 to be a "hot spot"
for Pit-1 mutations. To enable rapid and simple detection of this type of de novo
mutation we have designed a specific amplification-created-restriction-site assay
to check for the R271W mutation in patients suspected to have this rare form of
genetic defect in growth hormone production.
PMID- 9392393
TI - Combined pituitary deficiencies of growth hormone, thyroid stimulating hormone
and prolactin due to Pit-1 gene mutation: a case report.
AB - A child exhibited postnatal obstipation and icterus together with severe growth
failure during the 1st year of life, a small facial skull and a prominent
forehead. Endocrine work-up established the diagnosis of combined pituitary
deficiencies of growth hormone, TSH and prolactin. Subsequently, the Pit-1 gene
was analysed in the patient and both parents. A single point mutation was
detected in exon 6 of the child: a C to G transversion on one allele, causing
arginine in position 271 to be substituted by tryptophan (R271 W). This position
is known as a "hot spot" for mutations. The inheritance is autosomal-dominant, as
the mutated gene product interferes with DNA-binding of the wild-type protein. In
contrast, other mutations in the PIT-1 gene are inherited in an autosomal
recessive mode. CONCLUSION: Diagnosing Pit-1 gene mutations as a rare cause of
combined pituitary deficiency is important both for genetic counselling as well
as for predicting the future course in the patient (spontaneous puberty, no
glucocorticoid substitution necessary during stress periods).
PMID- 9392394
TI - Postprandial glycaemia after regular and lispro insulin in children and
adolescents with diabetes.
AB - We compared the postprandial blood glucose (BG)-levels following preprandial
regular insulin or lispro insulin before and after eating in adolescents with
diabetes. Lispro is a rapidly absorbed insulin analogue. Lispro insulin injected
immediately before breakfast reduced the postprandial BG-rise significantly
compared to the 20 min preprandially administered regular insulin (P < 0.01).
Postprandial lispro injection resulted in similar BG values as the standard
treatment with regular insulin 20 min preprandially. CONCLUSION: Lispro insulin
injected immediately before the meal leads to lower postprandial BG levels and
seems to be an option for teenagers who use multiple preprandial insulin
injections. Postprandial lispro administration could be a benefit in certain
situations since it resulted in similar BG values to preprandial regular insulin.
PMID- 9392395
TI - Cure of infantile myofibromatosis with severe respiratory complications without
antitumour therapy.
AB - The prognosis of infantile myofibromatosis (IMF) depends on the organs involved:
the prognosis is very poor if vital viscera are affected, but excellent if there
is no visceral involvement. We report the case of a boy presenting with a
pathological fracture at the age of 6 weeks. Progressive osteolytic lesions in
the whole skeleton until the age of 8 months led to respiratory failure due to a
softened thoracic wall requiring mechanical ventilation for 11 months. No
pulmonary, laryngeal or other visceral involvement was found. In spite of the
rapidly progressing disease and serious complications only supportive therapy was
given. The lesions subsided gradually leaving slight deformities but normal
function. At the age of 3.5 years the boy has an excellent quality of life.
CONCLUSION: This case illustrates that even in progressing, complicated
multifocal infantile myofibromatosis (without visceral involvement) the lesions
can resolve without antitumour treatment if high quality intensive care is
supplemented.
PMID- 9392396
TI - Generalised bone disease with abundant periosteal reaction in megakaryocytic
leukaemia.
AB - We report an 18-month-old boy with trisomy 21 who presented with abundant,
symmetrical periosteal hyperostosis and generalised osteolytic bone disease.
Although adequate cytological and immunological studies have not been performed,
the clinical course, routine blood and marrow studies allowed us to recognise
megakaryoblastic leukaemia (ML) as the cause of these unique X-ray appearances.
CONCLUSION: We present a unique case of generalised bone disease in an infant
with trisomy 21. The appearances--clinical course and radiographic appearances-
are consistent with ML. Such severe bony changes have not yet been reported in
this association. This observation widens the spectrum of ML.
PMID- 9392397
TI - Changes in coagulation and fibrinolysis in childhood acute lymphoblastic
leukaemia re-induction therapy using three different asparaginase preparations.
AB - Recently we reported the influence of two different Escherichia coli asparaginase
(ASP) preparations on fibrinolytic proteins in childhood acute lymphoblastic
leukaemia (ALL) demonstrating a significant association between ASP activity and
haemostatic alterations. The present study was designed for prospective
evaluation of coagulation and fibrinolytic parameters in leukaemic children
receiving different ASP preparations during the course of re-induction. Forty
leukaemic children receiving ASP (Medac: n = 13; Bayer: n = 10; Erwinia: n = 17)
at 3-day intervals during re-induction were enrolled in this study. Blood samples
for coagulation studies were obtained before each ASP administration together
with serum samples for pharmacokinetic monitoring. Compared with Medac ASP 10,000
IU/m2, patients receiving Bayer ASP or Erwinia ASP showed significantly higher
fibrinogen values. Antithrombin and plasminogen showed normal values in children
after Erwinia ASP. Alpha2-antiplasmin and D-Dimer were no different in the groups
studied. Neither side-effects, nor sustained asparagine depletion was observed in
the majority of children treated with Erwinia ASP. CONCLUSION: Data of this study
show a down-regulation of coagulation proteins in children treated with Medac
ASP, less pronounced in patients after Bayer or Erwinia ASP. Since children
treated with Erwinia ASP showed no adequate asparagine depletion during the
course of ASP therapy, a dose adjustment should be discussed to guarantee
asparagine depletion, the specific metabolic therapy for ALL.
PMID- 9392398
TI - Conditions currently associated with erythema nodosum in Swiss children.
AB - A review was made of the 36 paediatric patients in whom the diagnosis of erythema
nodosum had been established between 1977 and 1996 at the Department of
Paediatrics, University of Bern, Switzerland. Infectious diseases were associated
with erythema nodosum in 20 (including 10 streptococcal infections) and non
infectious inflammatory diseases in 8 patients. None of the 36 patients had
tuberculosis or had been exposed to sulphonamides, phenytoin or hormonal
contraceptives. There were eight patients in whom either the associated disease
was not diagnosed, or there was no other disease. CONCLUSION: Most cases of
erythema nodosum are nowadays caused by non-mycobacterial infectious diseases or
by non-infectious inflammatory diseases.
PMID- 9392399
TI - Vertical transmission of cytomegalovirus, most probably by breast milk, to an
infant with Wiskott-Aldrich syndrome with fatal outcome.
AB - A 4-month-old boy with prenatally diagnosed Wiskott-Aldrich syndrome became ill
with a severe cytomegalovirus (CMV) infection, the outcome of which was fatal.
The parents had isolated the infant from other children and adhered to standards
of hygiene in order to avoid CMV infection because their first child had died of
Wiskott-Aldrich syndrome and CMV infection. The mother breast-fed her child
although she was CMV IgG positive. The source of infection was most probably
breast milk, which contained CMV at the time the infant developed the generalized
CMV infection. CONCLUSION: In infants with immunodeficiency syndromes, CMV
infection may have a fatal outcome. Since the virus can be transmitted by breast
milk, the advantages and disadvantages of breast-feeding should, therefore, be
weighed in newborn infants with an immunodeficiency syndrome whose mother is a
CMV carrier.
PMID- 9392400
TI - Septic arthritis of the hip by Fusobacterium necrophorum after tonsillectomy: a
form of Lemierre syndrome?
AB - Lemierre syndrome used to be a complication of severe oropharyngeal infection
with regional thrombophlebitis, septicaemia and septic metastatic infections
caused by Fusobacterium necrophorum in the pre-antibiotic era. A case of septic
arthritis of the hip caused by F. necrophorum as a complication of tonsillectomy
is reported in a 9-year-old boy. CONCLUSION: Lemierre syndrome, usually seen
after an oropharyngeal infection, can also complicate tonsillectomy.
PMID- 9392401
TI - Intramuscular ceftriaxone compared with oral amoxicillin-clavulanate for
treatment of acute otitis media in children.
AB - Two hundred and fifteen children aged 4 months 6 years with acute otitis media
(AOM) were randomized to be treated either by a single i.m. injection of
ceftriaxone, 50 mg/kg, with a second dose in the event of unsatisfactory response
after 48 h or a history of recurrent AOM (109 patients) or amoxicillin
clavulanate 12.5 mg tid (106 patients). The failure rate was similar in children
treated by ceftriaxone and amoxicillin clavulanate, 4.6% and 4.7%, respectively
(standard error for intergroup difference -2.87%, 95% confidence interval -5.62%
to 5.87%). No significant differences between the groups were found in the
dynamics of the resolution of the acute symptomatology, otoscopy findings,
relapse rate at 30 days or tympanographic evidence of middle ear effusion at the
scheduled visits on days 30, 60 and 90. Recurrence of AOM between days 31 and 90
was observed significantly in more children treated with amoxicillin clavulanate
than with ceftriaxone--25 out of 84 (29.4%) versus 11 out of 81 (13.6%) (P =
0.012). CONCLUSION: Ceftriaxone injection(s) is as efficient at least as 10-day
oral amoxicillin clavulanate for treatment of acute otitis media in children.
Although not recommended as routine, ceftriaxone can be considered in the
management of acute otitis media under special circumstances, particularly in
cases when the ability to tolerate or absorb oral drugs is compromised, in
children refusing or unable to take oral therapy or when the compliance is
questionable.
PMID- 9392402
TI - Acquired carnitine abnormalities in critically ill children.
AB - In order to characterize the role of carnitine during metabolic stress, we
prospectively determined carnitine profiles in plasma and urine on admission,
days 2, 5, 10 and 15, among 28 critically ill children free of any known
conditions associated with secondary carnitine deficiency. More than 25% of
plasma and 50% of urinary carnitine measurements were abnormal; 96% (27/28) of
patients displayed on at least one occasion an abnormal [< -2 SD or > +2 SD]
carnitine value in plasma. Three children had extremely low [< 10 micromol/l]
free carnitine (FC) levels in plasma. Plasma esterified and FC levels on
admission were not related to the risk of mortality [PRISM score], to muscle
lysis [CK values], and to the caloric intake. Levels of FC and esterified
carnitine in plasma were unrelated to those measured in urine. CONCLUSION:
Abnormal plasma and urine carnitine measurements are frequently found in
critically ill children; the biological significance of these perturbations
remains unclear. Caution must be exercised before concluding that an abnormal
carnitine value is indicative of an underlying hereditary metabolic disorder in
this population.
PMID- 9392403
TI - Succinyl-CoA:acetoacetate transferase deficiency: identification of a new patient
with a neonatal onset and review of the literature.
AB - We describe the clinical symptoms and biochemical findings of a patient with
succinyl-CoA:acetoacetate transferase deficiency who presented in the neonatal
period and review the current literature on this subject. Our patient was
initially suspected to have distal renal tubular acidosis, and subsequently, a
fasting test revealed severe metabolic ketoacidosis with normal blood glucose
after 13 h which suggest a defect in ketolysis. In his cultured skin fibroblasts
succinyl-CoA:acetoacetate transferase was deficient (residual activity 15%).
Treatment in the acute phase consisted of sodium bicarbonate. At the present age
of 9 years, psychomotor and physical development are within normal limits.
CONCLUSION: Defects of ketolysis probably are underdiagnosed disorders and should
be considered in infants and young children with persistent ketosis.
PMID- 9392404
TI - UNICEF/WHO baby-friendly hospital initiative: does the use of bottles and
pacifiers in the neonatal nursery prevent successful breastfeeding? Neonatal
Study Group.
AB - To promote breastfeeding, UNICEF/WHO have launched the "baby-friendly hospital
initiative" focusing on hospital care routines during delivery and the first days
of life. In industrialised countries, two aspects of the initiative have raised
controversy: how do restriction of supplemental feedings and ban of bottles and
pacifiers affect long-term breastfeeding performance? From ten centres 602
healthy newborns were randomly assigned either to a UNICEF group with restrictive
fluid supplements and avoidance of bottles and pacifiers during the first 5 days
of life, or to a standard group with conventional feeding practice. Breastfeeding
was encouraged in both groups. The main study endpoints were the prevalences of
breast-feeding on day 5, and after 2, 4 and 6 months. Of the newborns 46%
violated the UNICEF protocol, mostly because of maternal requests to give a
pacifier or supplements by bottle. In the standard group, the drop-out rate was
9.7%. No significant differences in breastfeeding frequency and duration could be
found: (UNICEF vs standard) day 5: 100% vs 99%; 2 months: 88% vs 88%; 4 months:
75% vs 71%; 6 months: 57% vs 55%. Inclusion of drop-outs due to pacifier use did
not alter the results. CONCLUSION: In our study population fluid supplements
offered by bottle with or without the use of pacifiers during the first 5 days of
life were not associated with a lower frequency or shorter duration of
breastfeeding during the first 6 months of life.
PMID- 9392405
TI - Home oxygen therapy in infants with bronchopulmonary dysplasia: a prospective
study.
AB - We followed the clinical course of 21 infants with bronchopulmonary dysplasia
enrolled in a prospective home O2 therapy programme during a 4-year-period. Mean
gestational age was 28.5 weeks (range, 25-36 weeks) and mean birth weight 1093 g
(range 630-2750 g). Infants were regularly monitored to maintain pulse oximeter
O2 saturation over 94%-95%. The source of O2 was liquid oxygen and was delivered
by nasal cannula. During the follow up oxygenation was assessed by SatO2
measurement, cardiac function by Doppler echocardiography and respiratory
function by the occlusion technique. All patients had an ophthalmological follow
up. The mean age of the infants at discharge was 3.7 months (range 1.7-8.6) and
mean weight 2830 g (range 2150-3780 g). At discharge 8 infants had right
ventricular hypertrophy (RVH) and four of them had pulmonary hypertension. Mean
duration of home O2 therapy was 97 days (range 15-320 days) and the mean age of
discontinuation of O2 was 6.9 months (range 3-14.7 months). The cardiological
follow up was benign: the ECG signs of RVH disappeared by 12 months of age in six
out of eight infants and the right ventricular pulmonary pressure, as measured by
the Doppler method, normalised in the four patients in whom it was detected. No
relationship was found between respiratory mechanics and the duration of O2
therapy. Weight gain was poor with mean growth at the 3rd percentile for females
and just below the 3rd percentile for males. Twelve of the 21 infants required 25
rehospitalizations. No one presented deterioration of retinopathy of prematurity
that was present in 16 infants at discharge; at 12 months retinopathy was
resolved in 14 infants. A total of 2025 hospital days were saved, representing a
significant financial saving. CONCLUSION: Home O2 therapy permits the safe early
discharge of O2-dependent BPD infants and it reduces significantly the length of
time spent in hospital which represents a considerable financial saving.
PMID- 9392407
TI - A girl with congenital adrenal hyperplasia and recurrent abdominal pain.
PMID- 9392406
TI - Altered cardiovascular autonomic regulation after 2-week inhaled salbutamol
treatment in asthmatic children.
AB - We studied the effects of therapeutic 2-week inhaled salbutamol treatment on the
cardiovascular and respiratory autonomic nervous regulation in eight children
with asthma. In this randomized, double-blind, placebo-controlled crossover study
our test subjects inhaled 200 microg salbutamol or placebo thrice daily for 14
days. After the 14-day treatment we continuously measured electrocardiogram,
finger systolic arterial pressure (SAP) and flow-volume spirometry at baseline
and the response to a single 600 microg salbutamol inhalation. The periodic
variability components of R-R intervals (the time between successive heart beats)
and SAP in relation to respiration were assessed using spectral analysis. Two
week salbutamol treatment increased baseline low frequency (LF) variability (P <
0.05) and low frequency/high frequency (LF/HF) variability ratio of R-R intervals
(P < 0.05) when compared to the placebo treatment. As a response to the single
salbutamol inhalation the increase in LF/HF ratio of R-R intervals was smaller
after the 2-week salbutamol treatment (P < 0.01). No significant differences were
found in the bronchodilatory response after the treatment period. CONCLUSION: Two
week salbutamol treatment shifts the cardiovascular autonomic regulation to a new
level characterized by greater sympathetic responsiveness and slight beta2
receptor tolerance. Because these effects were evident 18 h after cessation of
the therapy they are likely to reflect the adaptation of organ responses to
regular therapy or altered central autonomic regulation rather than direct drug
effect. A slight tolerance developed in the sympathovagal cardiac response but
not in the bronchodilatory response.
PMID- 9392408
TI - A neonate with respiratory distress after a traumatic delivery.
PMID- 9392409
TI - Visualization of injection depot after subcutaneous administration by syringe and
needle-free device (Medi-Jector): first results with magnetic resonance imaging.
PMID- 9392410
TI - Lack of insulin-like growth factor I for therapeutic research. European Society
for Paediatric Endocrinology.
PMID- 9392411
TI - Dangers of recreational helmet use in playgrounds.
PMID- 9392412
TI - Juvenile pityriasis rubra pilaris with isolated IgA deficiency.
PMID- 9392413
TI - Balanced translocation t(4q; 10q) in infantile spinal muscular atrophy.
PMID- 9392414
TI - Transumbilical venous access with small diameter silastic catheters in very low
birth weight infants.
PMID- 9392415
TI - Macroscopic haematuria following immunisation with tetanus toxoid and oral polio
vaccine.
PMID- 9392416
TI - Hepatic uptake of chylomicron remnants.
AB - Chylomicrons are formed in the intestine and transport dietary triglyceride to
peripheral tissues and cholesterol to the liver. The enzyme lipoprotein lipase,
with apolipoprotein (apo)C-II as a co-factor, hydrolyzes chylomicron triglyceride
allowing the delivery of free fatty acids to muscle and adipose tissue. As a
result, a new particle called a chylomicron remnant is formed. This particle is
enriched in cholesteryl ester and fat-soluble vitamins and contains apoB-48 and
apoE. It is rapidly removed from the circulation by the liver. ApoE is the moiety
required for rapid hepatic removal. Its activity is inhibited by C
apolipoproteins, especially apoC-I. Hepatic removal appears to be accomplished by
several overlapping mechanisms. The particle must first achieve a size that
allows it to be "sieved" through the endothelial fenestre allowing entrance into
the space of Disse. Here, it may 1) be removed directly by LDL receptors; 2)
acquire additional apoE that is secreted free into the space, and then be removed
directly by the LDL receptor-related protein (LRP); or 3) it may be sequestered
in the space. Sequestration occurs by binding of apoE to heparan sulfate
proteoglycans and/or binding of apoB to hepatic lipase. Sequestered particles may
be further metabolized allowing apoE, and lysophospholipid enrichment, followed
by transfer to one of the above receptors for hepatic uptake. The above
formulation is based upon animal studies. In humans, delayed removal of
chylomicron remnants has been documented in diabetes, renal failure, and familial
combined hyperlipemia and is the abnormality resulting in type III
hyperlipidemia. Case control studies have identified delayed remnant removal as
an independent risk factor for atherosclerotic cardiovascular disease. Thus,
understanding the further details of the processes, and how it can be regulated
in humans, is an important challenge for the future.
PMID- 9392417
TI - Learning about the structure and biology of human lipoprotein [a] through
dissection by enzymes of the elastase family: facts and speculations.
AB - Lipoprotein[a], Lp[a], represents a class of lipoprotein particles that have as a
protein moiety apoB-100 linked by a disulfide bridge to a multi-kringle
structure, apolipoprotein[a], or apo[a]. It is now possible to separate from
Lp[a] a free apo[a] able to reassociate with apoB-100-containing lipoproteins to
restore the parent lipoprotein complex. Apo[a], whether free or a constitutive
component of Lp[a], can be cleaved at interkringle sites by the action of enzymes
of the elastase family generating fragments that differ in structural,
functional, and metabolic properties. In the case of Lp[a], elastase digestion
generates a miniLp[a] particle, which contains the apo[a] COOH-terminal domain
able to bind to lysine, fibrinogen, fibronectin, and proteoglycans. This domain
may also be generated by elastase type enzymes secreted by activated macrophages
and smooth muscle cells in the arterial intima as a part of the chronic
inflammation that characterizes the atherosclerotic process. Thus, the apo[a]
immunoreactive material, which has been described in the atherosclerotic plaque,
may represent miniLp[a] and/or apo[a] fragments accumulating in the vessel wall
as a function of their relative affinity for the components of the extracellular
matrix and producing complexes with an atherothrombogenic potential. This
potential may depend on several factors: kringle folding and conformation,
susceptibility of the linkers to proteolytic cleavage, binding specificity of
given apo[a] fragments to the matrix components of the arterial intima, and the
overall inflammatory status of the arterial wall.
PMID- 9392418
TI - Fresh mouse peritoneal macrophages have low scavenger receptor activity.
AB - Peritoneal macrophages are easily isolated by lavage, suggesting that they are
either nonadherent or weakly adherent in situ. Cultured macrophages express class
A scavenger receptors (SCR), which mediate Ca2+-independent adhesion in vitro. We
examined fresh peritoneal macrophages from mice and from women with endometriosis
to determine whether the adherence of these cells was associated with increased
expression of class A SCR. Fresh human macrophages were not immunoreactive to SCR
antibodies; however, SCR immunoreactivity increased with time in culture. Fresh
mouse and human macrophages took up minimal amounts of 1,1'-dioctadecyl-3,3,3',3'
tetramethylindocarbocyanine (DiI)-acetyl-low density lipoproteins (Ac-LDL), a
class A SCR ligand. Murine macrophages in culture for 24-72 h internalized four
times more Ac-LDL than fresh cells. Cells cultured for 2 days incorporated 3.2
times more [14C] oleate than freshly isolated cells (55.7 +/- 7.9 versus 17.6 +/-
3.0 nmol/mg cell protein). In contrast to SCR activity, mouse macrophage SCR mRNA
expression was similar in freshly isolated macrophages and those cultured for 3
days. These results suggest that peritoneal macrophages express only low levels
of SCR activity in situ and that posttranscriptional regulation after isolation
leads to an increase in SCR activity that correlates with adherence of the
macrophages in vitro.
PMID- 9392419
TI - Post-translational regulation of mevalonate kinase by intermediates of the
cholesterol and nonsterol isoprene biosynthetic pathways.
AB - To assess the potential for feedback inhibition by isoprene intermediates in the
cholesterol and nonsterol isoprene biosynthetic pathway, we expressed human cDNAs
encoding mevalonate kinase (MKase), phosphomevalonate kinase (PMKase), and
mevalonate diphosphate decarboxylase (MDDase) as fusion proteins in Escherichia
coli DH5alpha, and purified these proteins by affinity chromatography. Several
phosphorylated and non-phosphorylated isoprenes were analyzed as inhibitors of
the enzymes using a standard spectrophotometric assay. Of the three proteins,
only MKase was inhibited through competitive interaction at the ATP-binding site.
The intermediates studied (and their relative inhibitory capacity) were:
geranylgeranyl-diphosphate (GGPP, C20) > farnesyl-diphosphate (FPP, C15) >
geranyl-diphosphate (GPP, C10) > isopentenyl-diphosphate (IPP, C5) > or = 3,3
dimethylallyl-diphosphate (DMAPP, C5) > farnesol (C15) > dolichol-phosphate (DP,
C(80-100)). Mevalonate-diphosphate, geraniol, and dolichol were not inhibitors.
Our data further define the spectrum of physiologic inhibitors of MKase, and
provide the first evidence for feedback inhibition of MKase by a nonsterol
isoprene produced by the branched pathway, dolichol-phosphate. These results
provide additional evidence that MKase may occupy a central regulatory role in
the control of cholesterol and nonsterol isoprene biosynthesis.
PMID- 9392420
TI - Diacylglycerol is the preferred substrate in high density lipoproteins for human
hepatic lipase.
AB - The hydrolysis of HDL phospholipids (PL) and glycerides by hepatic lipase (HL)
has been investigated in native and reconstituted HDL particles (Lp2A-I).
Fasting, normolipidemic HDL exhibit total lipid hydrolytic rates of between 10
and 36 nM FA/h per microM PL. Of the total fatty acids liberated with HDL3 only
1% are from triolein (TG), while 49% are from diolein (DG) and 50% are from PL. A
spherical reconstituted particle containing 2 molecules of apoA-I, 120 molecules
of PL, and 20 molecules of TG exhibits a total lipid hydrolytic rate of 18 nM
FA/h per microM PL and 93% of the fatty acids liberated are from PL. Inclusion of
40 molecules of TG into the Lp2A-I particle doubles the rate of fatty acid
hydrolysis by HL through a stimulation of TG hydrolysis. Further addition of 10
molecules of DG to the Lp2A-I complex has no effect on the overall rates of
hydrolysis, but changes the substrate specificity, wherein 61% of the fatty acids
are from DG and both TG and PL hydrolytic rates are significantly reduced.
Increasing the amount of DG in the Lp2A-I particle further stimulates total lipid
hydrolysis by raising DG hydrolytic rates at the expense of PL and TG hydrolysis.
A particle containing 10 molecules of TG and 40 molecules DG yields the fastest
lipid hydrolytic rate of 143 nM FA/h per microM PL, which constitutes 96% DG
hydrolysis, 3% TG hydrolysis, and 1% PC hydrolysis. These data indicate that
hepatic lipase acts primarily as a surface lipid lipase with HDL particles. DG is
the preferred substrate of HL in HDL and the HDL-DG content regulates the
hydrolysis of both PL and TG by HL.
PMID- 9392421
TI - Secretory non-pancreatic phospholipase A2: influence on lipoprotein metabolism.
AB - Lipoprotein metabolism is markedly altered during inflammation. The concentration
of human secretory phospholipase A2 (sPLA2) can increase hundreds of fold in
inflammatory fluids and in the circulation. It was detected in atherosclerotic
lesions where many inflammatory genes are induced. As sPLA2 has been reported to
act on lipoproteins as substrates, lipoprotein profiles in transgenic mice
expressing sPLA2 were studied. HDL levels were markedly decreased in transgenic
mice overexpressing sPLA2. HDL in the transgenics were smaller in size, with a
significant decrease (11%) in phospholipid content compared to nontransgenic
littermates. In sPLA2 transgenic mice and transgenic mice expressing both sPLA2
and human apolipoprotein B (apoB), the concentrations of apoB-containing
lipoproteins were not altered. We conclude that sPLA2 alters HDL metabolism and
could be responsible for the depressed levels of HDL that exist during chronic
inflammatory diseases.
PMID- 9392422
TI - Phorbol ester-induced low density lipoprotein receptor gene expression in HepG2
cells involves protein kinase C-mediated p42/44 MAP kinase activation.
AB - The signaling pathway involved in low density lipoprotein (LDL) receptor gene
expression induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate
(TPA) was investigated in the human hepatoma HepG2 cell line. Treatment of HepG2
cells with 100 nM TPA resulted in an approximately 20-fold increase in LDL
receptor mRNA level, as determined by RT-PCR, which peaked at 2-4 h of treatment
and subsequently declined. The protein kinase C (PKC) inhibitors calphostin C and
staurosporine prevented TPA-mediated LDL receptor mRNA induction. In contrast,
TPA did not affect squalene synthase mRNA expression. Immunoblotting of cell
extracts with isozyme-specific PKC antibodies revealed that HepG2 cells expressed
PKC alpha, which was mainly cytosolic, and PKC beta, PK epsilon, and PKC zeta,
all of which were present in both the cytosolic and particulate fractions.
Treatment of HepG2 cells with 100 nM TPA resulted in translocation of cytosolic
PKC alpha to the particulate fraction, with a maximum at 30 min-2 h of treatment,
but was without effect on the subcellular distribution of the other isozymes. TPA
treatment also led to activation of the mitogen-activated protein kinase (MAPK)
ERK cascade. The specific MAPK pathway inhibitor PD98059 blocked TPA-induced ERK
activation. Furthermore, pretreatment of cells with PD98059 inhibited TPA-induced
LDL receptor mRNA induction. Moreover, pretreatment of cells with calphostin C
inhibited TPA-mediated ERK activation and LDL receptor mRNA induction in a dose
dependent fashion. Based on a close kinetic correlation between PKC alpha
translocation and ERK activation, and the effects of specific inhibitors, these
findings suggest that translocation/activation of PKC alpha, and subsequent
activation of the Raf-1/MEK/ERK MAPK cascade, represent key events in the
transcriptional induction of LDL receptor gene by TPA in HepG2 cells.
PMID- 9392423
TI - Adipose differentiation-related protein is an ubiquitously expressed lipid
storage droplet-associated protein.
AB - The adipose differentiation-related protein (ADRP) was first characterized as a
mRNA induced early during adipocyte differentiation (Jiang, H. P., and G.
Serrero. 1992. Proc. Natl. Acad. Sci. USA. 89:7856-7860). The present study
demonstrates that ADRP mRNA is expressed in a variety of tissues and cultured
cell lines. Immunocytochemical examination revealed that ADRP localizes to
neutral lipid storage droplets in cultured murine 3T3-L1 adipocytes, murine MA-10
Leydig cells, Chinese hamster ovary (CHO) fibroblasts, and human HepG2 hepatoma
cells; the association of ADRP with lipid droplets was confirmed by subcellular
fractionation of MA-10 Leydig cells. In addition to ADRP, steroidogenic cells and
adipocytes express the perilipins, a family of lipid droplet-associated proteins
that share a highly related sequence domain with ADRP. ADRP and perilipins co
localize on lipid droplets in MA-10 Leydig cells. While ADRP was found on small
lipid droplets in 3T3-L1 preadipocytes and early differentiated adipocytes, it
was absent in maturing adipocytes. In contrast, perilipins were absent early
during differentiation, but were found on small and large lipid droplets at later
stages. The transition in surface protein composition of adipocyte lipid droplets
from ADRP to perilipins occurred 3 days after the initiation of differentiation
when cells displayed co-localizatioin of both proteins on the same lipid
droplets. The specific localization of adipose differentiation-related protein to
lipid droplets in a wide variety of cells suggests that ADRP plays a role in
management of neutral lipid stores.
PMID- 9392424
TI - Use of cyclodextrins for manipulating cellular cholesterol content.
AB - Previous studies from this laboratory have demonstrated that exposure of tissue
culture cells to cyclodextrins results in rapid cholesterol depletion. In the
present study, we have developed experimental systems for using solutions of
cyclodextrins, either 2-hydroxypropyl beta-cyclodextrin or methylated beta
cyclodextrin, complexed with varying amounts of free cholesterol to manipulate
cell cholesterol content. Cholesterol delivered via the cyclodextrin has been
found to be metabolically active, as measured by the acyl-coenzyme A:cholesterol
acyltransferase (ACAT)-mediated esterification of [3H]cholesterol in Fu5AH rat
hepatoma cells and Chinese hamster ovary cells. The methylated beta-cyclodextrin
was found to be a more efficient donor in all cell types studied, with an average
cholesterol uptake of at least 100 microg cholesterol/mg protein within 6 h. By
modifying the cyclodextrin:cholesterol molar ratio, it is possible to manipulate
the cellular cholesterol content of cells, producing conditions ranging from net
cholesterol enrichment to depletion. The use of cyclodextrins provides a
convenient, precise and reproducible method for modulating the cholesterol
content of tissue culture cells.
PMID- 9392425
TI - Mechanism of the slow induction of apolipoprotein A-I synthesis by retinoids in
cynomolgus hepatocytes: involvement of retinoic acid and retinoid X receptors.
AB - We showed previously that retinoids stimulate apolipoprotein A-I (apoA-I)
synthesis in cultured cynomolgus hepatocytes only after a 24-h lag phase. Here we
report on the biochemical background of the slow response, the requirement for
high retinoic acid concentrations, and the involvement of different retinoid
receptors. The time course of the effect of 10 microM all-trans retinoic acid (at
RA) on apoA-I mRNA levels and protein secretion were comparable, i.e., minor
increases were observed after a 24-h incubation and mRNA levels were increased
2.2- and 3.5-fold after 48 h and 72 h, respectively. In contrast, apoA-I gene
transcription was already increased (2.6-fold) after a 4-h incubation with 10
microM at-RA. At-RA disappeared rapidly from the cultures: after 2 h of
incubation 40% of the added amount was left and after 24 h only 2%. RAR beta mRNA
and gene expression were increased after incubation with 10 microM at-RA, whereas
RAR alpha and RXR alpha mRNA levels and expression remained unchanged. No
transcriptional activity and mRNA for other retinoid receptors were detectable.
Both RAR-selective (TTNPB) and RXR-selective (3-methyl-TTNEB) agonists induced
apoA-I synthesis at 1 and 10 microM. These results show that i) the slow increase
in apoA-I secretion is caused by a slow increase of its mRNA level; ii) the apoA
I gene transcription in cynomolgus hepatocytes is induced rapidly by retinoids;
iii) the added at-RA disappeared rapidly from the cultures, explaining the
necessity for high initial concentrations; iv) RLR alpha and/or RAR beta and RXR
alpha are involved in the activation of apoA-I expression by retinoids.
PMID- 9392426
TI - Determinants of plasma platelet-activating factor acetylhydrolase: heritability
and relationship to plasma lipoproteins.
AB - Plasma platelet-activating factor acetylhydrolase (PAF-AH) is the enzyme that
inactivates PAF (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine). We determined the
relative contributions of genetic and environmental factors to variation in
plasma PAF-AH activity in 240 individuals from 60 nuclear families. Regression of
mean-offspring PAF-AH activity on the mid-parent value indicated that 62% of the
variation in plasma PAF-AH activity was heritable. Spousal values were weakly
negatively correlated, indicating that familial aggregation of PAF-AH activity is
due to genetic rather than to environmental factors. Among normolipidemic
individuals, plasma PAF-AH activity was strongly correlated with the plasma
concentration of low density lipoprotein cholesterol (LDL-C), and treatment with
lovastatin resulted in proportional decreases in plasma PAF-AH activity and LDL-C
concentrations. To further elucidate the relationship between PAF-AH and plasma
concentrations of LDL, plasma PAF-AH activity was measured in families with well
defined, monogenic disorders of LDL metabolism. Plasma PAF-AH activity
cosegregated with plasma LDL-C concentrations in familial hypercholesterolemia,
but not in familial hypobetalipoproteinemia. We speculate that the rate of
removal of LDL from the circulation may determine the clearance rate of PAF-AH,
thereby modulating the activity of PAF-AH in blood.
PMID- 9392427
TI - Diet modification alters plasma HDL cholesterol concentrations but not the
transport of HDL cholesteryl esters to the liver in the hamster.
AB - These studies were undertaken to investigate the mechanism whereby diet
modification alters the plasma concentration of high density lipoprotein (HDL)
cholesteryl ester and apoA-I and to determine whether diet-induced alterations in
circulating HDL levels are associated with changes in the rate of reverse
cholesterol transport. Rates of HDL cholesteryl ester and apoA-I transport were
measured in hamsters fed a control low-cholesterol, low-fat diet or the same diet
supplemented with soluble fiber (psyllium) or with cholesterol and triglyceride
(Western-type diet). The Western-type diet increased the plasma concentration of
HDL cholesteryl ester by 46% compared to the control diet and by 86% compared to
the psyllium-supplemented diet; nevertheless, the absolute rates of HDL
cholesteryl ester transport to the liver were identical in the three groups. Diet
induced alterations in circulating HDL cholesteryl ester levels were due to
changes in the rate of HDL cholesteryl ester entry into HDL (whole body HDL
cholesteryl ester transport) and not to regulation of HDL cholesteryl ester
clearance mechanisms. The Western-type diet increased the plasma concentration of
HDL apoA-I by 25% compared to the control diet and by 45% relative to the
psyllium-supplemented diet. Diet-induced alterations in plasma HDL apoA-I
concentrations were also due entirely to changes in the rate of apoA-I entry into
HDL (whole body HDL apoA-I transport). These studies demonstrate that the
absolute flux of HDL cholesteryl ester to the liver, which reflects the rate of
reverse cholesterol transport, remains constant under conditions in which plasma
HDL cholesteryl ester concentrations are altered over a nearly 2-fold range by
diet modification.
PMID- 9392428
TI - A two-base deletion in exon 6 of the 3-hydroxy-3-methylglutaryl coenzyme A lyase
(HL) gene producing the skipping of exons 5 and 6 determines 3-hydroxy-3
methylglutaric aciduria.
AB - A novel two-base deletion in the 3-hydroxy-3-methylglutaryl coenzyme A lyase (HL)
gene was found in a Spanish patient with homozygous 3-hydroxy-3-methylglutaric
aciduria. Amplification by RT-PCR of the mRNAs showed that the gene was
transcribed into three different mRNAs. One showed the complete deletion of exons
5 and 6 located between nucleotides 348 and 561 of the HL cDNA. The second
transcript showed deletion of exon 6 only, and the third contained a two-base
deletion CT in exon 6, corresponding to nucleotides 504 and 505 of the HL cDNA.
These aberrant mRNAs are predicted to encode three abnormal HMG-CoA lyase
proteins; the first (from skipped exons 5 and 6) lacks 71 amino acids, which
represents 24% of the mature protein; the second, (from the skipping of exon 6,
producing a frameshift) contains only 192 amino acids, the last 26 of which are
missense amino acids preceding a stop codon; the third contains only 175 amino
acids, the last 7 of which are missense. Northern blot analysis showed that the
HL mRNA levels of the patient were 4% of the control. PCR quantitative analysis
indicated that the mRNA lacking exons 5 and 6 was the most abundant, representing
88% of the total. The other two mRNAs represented 8% and 4%, respectively. In the
genomic DNA only one CT deletion was found at positions +7 and +8 at beginning of
exon 6. No mutations were observed in the splice donor, splice acceptor, or
pyrimidine-rich sequences of the intronic regions flanking exons 5 and 6. All
three aberrant mRNAs resulted only from the deletion of nucleotides CT. We
suggest that this deletion may affect the interaction between the small nuclear
ribonucleoproteins (snRNPs) and exon 6, and that, as a result, the abnormal
splicing of the pre-mRNA produces two different aberrant transcripts.
PMID- 9392430
TI - Four novel mutations of sterol 27-hydroxylase gene in Italian patients with
cerebrotendinous xanthomatosis.
AB - We report the characterization of eight mutations of sterol 27-hydroxylase gene
(CYP27) in five Italian patients with cerebrotendinous xanthomatosis, who were
found to be compound heterozygotes. Four mutations (C --> T at nt 45 of exon 4,
G(+1) --> A in intron 6, G(+5) --> T in intron 7, and G(-1) --> A in intron 7)
are novel. The C --> T at nt 45 of exon 4 converts the arginine codon into a stop
codon thus generating a truncated protein of 198 amino acids. The three splice
site mutations reduced the content of CYP27 mRNA in skin fibroblasts to very low
or undetectable levels and generated minute amounts of abnormal mRNAs. The G(+1)
-> A transition in intron 6 produced three abnormal mRNAs. In the first, the 5'
half of exon 6 joins to exon 7, skipping 89 bp of exon 6, and in the second, exon
5 joins directly to exon 7. The predicted translation products of these mRNAs are
truncated proteins. In the third abnormal mRNA, exon 5 joins to exon 8 with an in
frame deletion of 246 bp. The G(+5) --> T transversion in intron 7 generates a
single abnormal mRNA in which exon 6 joins directly to exon 8, with a frameshift
and a premature stop codon. In the G(-1) --> A transition in intron 7, two mRNAs
are generated. In the first, the retention of the whole intron 7 causes a
frameshift and a premature stop codon; in the second, the joining of exon 7 to
exon 8 is associated with an in-frame deletion of the first 6 nucleotides. All
these novel mutations are predicted to produce structurally abnormal enzymatic
proteins with no measurable biological activity.
PMID- 9392429
TI - High density lipoprotein particle size restriction in apolipoprotein A-I(Milano)
transgenic mice.
AB - Human carriers of apolipoprotein A-I(Milano) (Arg173 --> Cys substitution in
apolipoprotein A-I) are characterized by an HDL deficiency in which small, dense
HDL accumulate in plasma. Because affected individuals are heterozygous for this
mutation, the full impact of apolipoprotein A-I(Milano) (apoA-I(Milano)) on HDL
cholesterol metabolism is unknown. In this study, apoA-I(Milano) transgenic mice
were used to evaluate the extent of apoA-I(Milano) dimerization and HDL particle
size restriction in the absence of wild-type apoA-I. Murine apoA-I knockout mice
were utilized to express apoA-I(Milano) and human apoA-II in the presence of wild
type, human apoA-I (apoA-IMilano/A-Iwt/A-II) and in its absence (apoA-IMilano/A
II). Plasma HDL-cholesterol concentrations were similar (30 mg/dl) in both lines
of apoA-I(Milano) transgenic mice. In the apoA-IMilano/A-Iwt/A-II phenotype, 14%
of the apoA-I(Milano) formed homodimers and 33% formed heterodimers with apoA-II.
ApoA-I(Milano) homodimers increased by 71% in the apoA-IMilano/A-II transgenics
and was associated with an abundance of small, 7.6-nm HDL3-sized particles
compared to the 9.5, 8.3, and 7.6-nm-sized particles in apoA-IMilano/A-Iwt/A-II
mice. The unesterified cholesterol/cholesteryl ester mole ratio of HDL was
elevated by 45% in apoA-IMilano/A-Iwt/A-II mice and by 90% in apoA-IMilano/A-II
transgenics compared to wild-type (human apoA-I/A-II). Both apoA-I(Milano)
transgenics possessed normal levels of plasma LCAT activity, but endogenous
cholesterol esterification rates were reduced by 50% compared to controls. Thus,
HDL particle size restriction was not the result of impaired LCAT activation;
rather, dimerization of apoA-I(Milano) limited the esterification of cholesterol
on endogenous HDL. In the absence of wild-type apoA-I, the more extensive
dimerization of apoA-I(Milano) severely limited cholesteryl ester accumulation on
plasma HDL accounting for the abundance of small, 7.6-nm HDL3 particles in apoA
IMilano/A-II mice.
PMID- 9392431
TI - Clearance of lipoprotein remnant particles in adipose tissue and muscle in
humans.
AB - A major proportion of triglycerides in plasma triglyceride-rich lipoproteins
(TRL) are removed in peripheral tissues by lipoprotein lipase, and hypothetically
a minor proportion can also be removed by whole-lipoprotein particle uptake. This
second removal pathway has not previously been directly demonstrated in humans.
Simultaneous blood samples were drawn from arterialized blood, a vein draining
the subcutaneous abdominal adipose tissue, and a deep antecubital vein of the
forearm to provide arterio-venous gradients from blood-draining adipose tissue
and muscle in seven male subjects. The men were given a fat-rich mixed meal
containing vitamin A and the triglyceride and retinyl palmitate (RP)
concentrations were quantified in the plasma. Density gradient
ultracentrifugation was used to isolate TRL fractions, in which triglycerides,
RP, apoB-48, and apoB-100 were quantified. There was clearance of triglycerides
in muscle and adipose tissue and, in addition, removal of RP. By analysis of the
TRL subfractions, the RP removal was likely to be confined to the largest
chylomicron remnant particles. For the Sf > 400 fraction, the area under curve
(AUC) relative to arterial for triglycerides were 79% (66-91%) and 81% (72-89%)
in adipose tissue and muscle venous outflow, respectively (each P < 0.02 versus
arterial). The corresponding values for RP were 87% (73-101%) and 85% (69-100%),
respectively, (each P < 0.05 versus arterial). In the Sf 60-400 fraction there
was further uptake of triglycerides, but not of RP. We hypothesize that the
periphery could be of importance for removal of the largest chylomicron remnants,
as their size might partially exclude them penetrating the fenestrated hepatic
sinusoidal endothelium to reach the hepatic chylomicron remnant receptors.
PMID- 9392432
TI - Transforming growth factor beta is sequestered into an inactive pool by
lipoproteins.
AB - Elevated plasma concentrations of low density lipoprotein (LDL) and very-low
density lipoprotein (VLDL) have been correlated with the development of
atherosclerosis. These lipoproteins may promote atherogenesis by direct
deposition of lipid in the vessel wall. In addition, previous data suggested that
there was an inverse correlation between serum LDL-cholesterol concentration and
the proportion of transforming growth factor beta (TGF-beta) in an active form
(Grainger et al. 1995. Nature Med. 1:74). Here we have investigated whether
lipoproteins can affect the activity of TGF-beta1 in plasma and show that TGF
beta can associate with the lipoprotein fraction. In the plasma of healthy males,
16 +/- 5% (mean +/- standard deviation; n = 57) of the total plasma TGF-beta1 was
associated with the lipoprotein fraction, with the major proportion (64 +/- 15%)
in the HDL-3 subfraction. However, in ten diabetic subjects with moderately poor
glucose control (Hb alc > 8.0), the proportion of total plasma TGF-beta in the
lipoprotein fraction was 68 +/- 21%. This large increase in TGF-beta1 associated
with the lipoprotein fraction was mainly due to association with VLDL,
chylomicrons, and LDL. The lipoprotein fraction inhibits TGF-beta1 binding to the
type II TGF-beta receptor extracellular domain in an ELISA and inhibits TGF-beta1
activity in the mink lung cell bioassay. We propose that sequestration of TGF
beta into lipoproteins represents a novel mechanism by which TGF-beta activity in
circulation may be regulated. Lipoprotein sequestration of TGF-beta may therefore
contribute to the severe depression of TGF-beta activity in advanced
atherosclerosis.
PMID- 9392433
TI - Quantification of HDL2 and HDL3 cholesterol by the Vertical Auto Profile-II (VAP
II) methodology.
AB - Of the several existing methods for quantification of major subspecies of high
density lipoprotein (HDL), HDL2 and HDL3, the methods based upon double
precipitation are particularly useful for large-scale studies or for routine
assay because of their high speed and low cost. The Vertical Auto Profile-II (VAP
II) method developed in our laboratory primarily for the direct single test
measurement of cholesterol (C) in all major lipoproteins, including Lp[a] and
IDL, is rapid, highly sensitive, and suitable for large-scale studies. Here we
describe the modification of this procedure so as to be able to quantify both
HDL2- and HDL3-C in addition to all major lipoproteins without any additional
assay steps, time, or cost. The VAP-II procedure was validated by comparison with
four other methods using plasma samples obtained from 35 healthy subjects: 1) HDL
VAP-II (a variation of the VAP-II procedure designed specifically to separate HDL
subspecies); 2) dextran sulfate (DS)/Mg2+ double precipitation method performed
at Northwest Lipid Research Laboratories (NWLRL), Seattle, WA; 3) 4-30%
polyacrylamide-agarose (4/30 PAA) nondenaturing gradient gel electrophoresis
(GGE); and 4) analytical ultracentrifugation (AUC), with both GGE and AUC
performed at the Donner Laboratory, University of California at Berkeley. Both
HDL2- and HDL3-C measurements by VAP-II correlated well with the measurements by
all comparison methods (r for HDL3-C: HDL-VAP-II, 0.948; NWLRL, 0.947; GGE,
0.861; and AUC, 0.706, and r for HDL2-C: HDL-VAP-II, 0.867; NWLRL, 0.854; GGE,
0.885; and AUC, 0.721). The measurements of HDL2- and HDL3-C by the VAP-II method
are reproducible, with the long-term between-rotor CV of 5.0% for HDL3-C and 9.0%
for HDL2-C.
PMID- 9392434
TI - A cDNA-dependent scintillation proximity assay for quantifying apolipoprotein A
I.
AB - We have developed a cDNA-dependent scintillation proximity assay (SPA) for rabbit
apolipoprotein A-I that follows a classic radioimmunoassay scheme, in that
antiserum and radiolabeled ligand are used in a process to quantify a source
containing unlabeled ligand. To synthesize radiolabeled ligand we isolated a full
length rabbit apolipoprotein A-I (apoA-I) cDNA, transcribed the corresponding RNA
in vitro, and synthesized radiolabeled apoA-I by including tritiated leucine in
an in vitro translation reaction. Assay conditions were established which allowed
quantification of unlabeled apoA-I over a range of 0.2 to 4 nanograms with intra-
and interassay coefficients of variation of 5% and 10%, respectively. Purified
rabbit apoA-I, apoA-I in rabbit liver parenchymal cell conditioned media, and
apoA-I contained in rabbit plasma all generated parallel titration curves.
Quantification of rabbit plasma apoA-I was not affected when sheep anti-rabbit
apoA-I serum was mixed with sheep anti-rabbit apoB or apoE serum; thus, the
antibody need not be specific to quantify the ligand of interest. To show utility
of the assay, apoA-I mass was quantified in in vitro and in vivo models
displaying altered apoA-I levels. In each model apoA-I values from the cDNA
dependent SPA and the established methodologies of Western blotting and
electroimmunodiffusion were highly correlated. The approach outlined in this
report should permit rapid development of scintillation proximity assays for
other proteins given the widespread availability of full-length cDNAs.
PMID- 9392435
TI - Quantitative determination of thiolipids in organic solution, in membranes, and
on HPTLC plates.
AB - In the presence of ortho-phthalaldehyde and glucosamine, thiolipids form
fluorescent isoindole derivatives. This reaction can be used to quantify single-
and double-chain mercaptans in membranes (liposomes) and micellar solutions. The
lower detection limit is 100 pmol. In addition, the assay allows the detection of
1.9 nmol thiolipids on HPTLC plates and the fluorescence signal is stable for
days. A minor modification of the commonly used DTNB (Ellman's) assay allows the
quantification of thiolipids in organic solutions at a concentration down to 3
nmol.
PMID- 9392436
TI - Mathematical theory of competitive binding assays: an exact and practical model.
AB - In the usual formulation of the equations for competitive binding assays, the
free concentrations of the various unlabeled ligands are approximated by the
known values of their total concentrations, since the free concentrations are not
easily determined. Although equations have been derived previously that give the
exact solution with the free concentrations of unlabeled ligands treated as
variables, these have not been useful in practice. We have devised a mathematical
model for the competitive binding that which is both exact and practical for the
general case of one labeled ligand, any number of unlabeled ligands, and any
number of classes of binding sites. In this model, the total concentrations of
unlabeled ligands are the explicit variables, instead of their free
concentrations. The free concentrations of unlabeled ligands can be estimated
from the model. The model is based on the law of mass action and the dilution
principle, as well as a new concept, called the equivalent competitive binding
principle.
PMID- 9392437
TI - The unliganded mineralocorticoid receptor is associated with heat shock proteins
70 and 90 and the immunophilin FKBP-52.
AB - The human mineralocorticoid receptor (MR) is a member of the steroid-thyroid
hormone receptor superfamily, which includes receptors for retinoic acid, vitamin
D, and other steroids, such as the glucocorticoids (which bind the glucocorticoid
receptor, GR). MR and GR, the corticosteroid receptors, share significant
homology and are activated by steroid binding, resulting in a conformational
change, nuclear translocation, and DNA binding. Despite these similarities with
GR, the MR remains less well characterized. However, protein components known to
be present in the unliganded GR are also likely to be components of the
heteromeric MR complex. In the current study, we investigated whether or not
hsp70, hsp90, and the immunophilin FKBP-52 are present in the nonsteroid-bound MR
complex, because these proteins are known to be present in the unliganded GR
complex. The unliganded MR complex was assembled in vitro using reticulocyte
lysate and in vivo using the baculovirus overexpression system and Spodoptera
frugiperda (Sf9) cells. Western blot analysis revealed the presence of hsp70,
hsp90, and FKBP-52 in the unliganded complexes, but hsp90 and FKBP-52 were not
detected following exposure to aldosterone. Electrophoretic mobility shift
analysis demonstrated that DNA binding of MR occurred only after treatment with
aldosterone. These studies indicate that proteins associated with the unliganded
GR are also present in the unliganded MR complex, and that hsp90 and FKBP-52
dissociate prior to DNA binding in a manner similar to that described for GR.
Finally, the stoichiometric analysis of the proteins present within the
heteromeric MR complex suggests a divergence between this receptor and the GR.
PMID- 9392438
TI - Myosin phosphorylation by human cdc42-dependent S6/H4 kinase/gammaPAK from
placenta and lymphoid cells.
AB - The p21-activated kinase (PAK) family includes protein phosphotransferases
regulated by the GTPases rho, rac, and cdc42. Sequence homology, activation
mechanism, and substrate specificity suggest that the well-characterized human
placenta S6/H4 kinase is a member of this family. In these studies, S6/H4 kinase
purified to homogeneity from human placenta was activated in vitro by cdc42-GTP,
or protease incubation and MgATP-dependent autophosphorylation. The cdc42
activated enzyme demonstrated an Mr 60,000, and shares sequence homology with the
gammaPAK family. Antipeptide antibodies against one of the autophosphorylation
site sequences recognized a single p60 protein in the purified placenta
preparation or Jurkat cell extracts. An autophosphorylated Mr 40,000 protein,
previously identified as the catalytic domain of the enzyme, was also detected by
the antibody after protease activation. Crude PAK60 obtained from Mono Q
chromatography of Jurkat cell extracts and purified placenta enzyme catalyzed
phosphorylation of histone H4 and myelin basic protein as well as a variety of
synthetic peptides previously identified as S6/H4 kinase substrates. In addition,
Jurkat myosin II and the regulatory myosin light chain were phosphorylated by the
Jurkat and placenta gammaPAK. Synthetic peptides were used to demonstrate that
the site of light chain phosphorylation occurs at the serine which results in
ATPase activation. The data suggest that human gammaPAK may regulate cell
motility by a GTP-dependent and calcium-independent mechanism.
PMID- 9392439
TI - Surfactant protein-A receptor-mediated inhibition of calcium signaling in
alveolar type II cells.
AB - Receptor-mediated inhibition of cellular activating signals is not well
understood. Type II alveolar cells secrete surfactant in response to such
secretagogs as terbutaline, calcium (Ca) ionophores (e.g., ionomycin [Io]), and
adenosine triphosphate (ATP). A cell membrane receptor for SP-A, one of the
surfactant proteins, regulates secretion by negative feedback. We used
quantitative fluorescence microscopy to study the effects of SP-A on alterations
in cytosolic Ca2+ ([Ca2+]i) elicited by surfactant secretagogs. Freshly isolated
type II cells were loaded with Fura-2, then treated with secretagog, in the
presence or absence of SP-A. Io and ATP produced biphasic increases in cytosol
[Ca2+]i, reflecting first Ca2+ release from intracellular stores, and then influx
through the cell membrane. Thapsigargin (TG) and Io directly initiate Ca2+
release; ATP elicits Ca2+ release via receptor-mediated mechanisms. Ca2+ release
causes cell membrane Ca channels to open by as yet poorly understood mechanisms.
Io itself acts as an additional Ca2+ channel. SP-A blocks much of the Ca2+
release and some of the Ca2+ influx elicited by these secretagogs. Antibody
against SP-A receptor restores secretagog-induced Ca2+ fluxes from inhibition by
SP-A, confirming that the inhibitory activity of SP-A is mediated through its
receptor. Type II cells incubated in Ca2+-free medium plus SP-A show diminished
Ca2+ release responses to TG or ATP, suggesting that the action of SP-A to
prevent secretagog initiated increases in [Ca2+]i may reflect its ability to
block Ca2+ release from cytoplasmic Ca stores. The feedback inhibition of
surfactant secretion by SP-A may, correspondingly, be a manifestation of this
effect. Because recent work suggests that TGF-beta also inhibits Ca2+ fluxes, SP
A and TGF-beta could be representative of a group of physiologic regulators that
act by modulating intracellular Ca signaling.
PMID- 9392440
TI - G-protein-coupled receptor agonists augment adenylyl cyclase activity induced by
forskolin in human corpus cavernosum smooth muscle cells.
AB - The goal of this study was to investigate the synergistic effects between G
protein-coupled receptor agonists and forskolin-induced activation of adenylyl
cyclases, in cultured human corpus cavernosum smooth-muscle cells. Treatment of
human corpus cavernosum smooth-muscle cells with forskolin (0.1-10 microM)
produced an increase in cAMP synthesis in a concentration-dependent manner.
Forskolin-induced adenylyl cyclase activity was markedly augmented by
prostaglandin E1 (PGE1) and its metabolite, PGE0, isoproterenol, carbachol, and
phenylephrine. Augmentation of forskolin-induced cAMP by PGE1, and PGE0 is
probably mediated by prostaglandin E receptors (EP). Enhancement of forskolin
induced cAMP synthesis by isoproterenol is mediated by beta-adrenergic receptors
(beta-AR), since this activity was inhibited by propranolol. Stimulation of
forskolin-induced cAMP synthesis by carbachol is attributed to activation of
muscarinic acetylcholine receptors (mAChR), as demonstrated by inhibition with
atropine. The augmentation of forskolin-induced cAMP synthesis by phenylephrine,
an alpha1-adrenergic receptor (AR) agonist, however, was unexpected and cannot be
attributed to increased intracellular Ca2+, since treatment of cells with either
the Ca2+ ionophore, A23187, or 80 mM KCl did not affect forskolin-induced cAMP
synthesis. Stimulation of forskolin-induced cAMP synthesis by phenylephrine is
explained by its binding to beta-AR and activation of Gs protein, since this
augmentation was inhibited by the beta-AR antagonist, propranolol. This
observation was further supported by physiological studies in organ bath
chambers, in which forskolin-induced relaxation of precontracted corpus
cavernosum strips was enhanced by phenylephrine. These studies suggest that
synergism between agonist-induced cAMP synthesis and forskolin is attributed to
increased conformational stabilization of activated adenylyl cyclase catalytic
domains by forskolin and the Gs(alpha)-subunit of activated Gs proteins.
PMID- 9392441
TI - Melatonin protects against gastric ischemia-reperfusion injury in rats.
AB - Lipid peroxidation and active oxygen metabolites have been suggested to play an
important role in the pathogenesis of acute gastric mucosal injury induced by
ischemia-reperfusion. The aim of this study was to examine the in vivo protective
effects of melatonin on ischemia-reperfusion induced gastric damage in rats. The
peroxidation of lipids and changes in the activities of related enzymes such as
glutathione peroxidase and myeloperoxidase, as a marker of neutrophil
infiltration, were also studied. Our results show that gastric injury was
significantly increased after 30 min ischemia induced by clamping the celiac
artery and 60 min reperfusion. Intraperitoneal administration of melatonin
prevented postischemic mucosal injury. The mean ulcer indices of rats treated
with 5, 10, and 20 mg kg(-1) were significantly lower (P<0.01, P<0.001) than that
of control rats. These protective effects were likely in part related to a
reduction of neutrophil infiltration (myeloperoxidase values). Lipid peroxidation
in the stomach was increased by ischemia-reperfusion injury and this increase was
inhibited by the administration of melatonin. In addition, treatment with
melatonin limited the decreased glutathione peroxidase activity. The results
suggest that melatonin confers a marked protection against ischemia-reperfusion
gastric injury which could be due to melatonin's free radical scavenging activity
and its ability to reduce neutrophil-induced toxicity.
PMID- 9392442
TI - Nocturnal urinary 6-sulphatoxymelatonin excretion is decreased in primary breast
cancer patients compared to age-matched controls and shows negative correlation
with tumor-size.
AB - In previous studies a tumor-size dependent decline of the circadian amplitude of
serum melatonin was found in primary unoperated breast cancer patients, which was
not due to changes of the hepatic metabolism of melatonin since its main
peripheral metabolite, 6-sulphatoxymelatonin (aMT6s), showed similar serum
levels. The aim of the current study was to verify these previous results by
measurements of the nocturnal excretion of aMT6s in urine. The determination of
aMT6s was carried out by radioimmunoassay. 17 primary unoperated breast cancer
(BC) patients and 34 age-matched control patients with different types of benign
gynecological diseases awaiting operation (breast diseases, n=13; ovarian
diseases, n=12; and uterine diseases, n=9) were analysed. The median nocturnal
urinary aMT6s excretion (22:00-6:00 hr) was significantly lower (-48%, P = 0.033)
in BC patients than in controls. Controls showed a significant negative linear
regression with age (r = -0.419, P = 0.014). According to multivariate linear
regression analysis, BC revealed no age-dependency but a significant negative
effect of increasing tumor-size on aMT6s-excretion (P = 0.036) was detected.
These results confirm previous findings of a decreased pineal melatonin secretion
in BC patients as well as an inverse relationship with tumor-size excluding a
possible distortion due to age. The mechanisms involved are unknown but indicate
that BC may lead to an impaired production of pineal melatonin. The clinical
relevance of these findings from therapeutic and diagnostic point of view is
discussed.
PMID- 9392443
TI - A note on the time dependence of pineal gland research publications.
AB - Counts of the number of publication titles containing the search truncation
"pinea*" were compiled via Current Contents over the time period 1978-1994. These
counts and their time dependence were examined for autocorrelations and frequency
spectral components. Such analyses were carried out irrespective of either
author, research laboratory, funding, or other factors. Interestingly, the
results show the research publication rate in pineal studies to be linked to
community history. In particular, the interactions affecting output among
community members operate on a few characteristic time scales ranging from one to
several years.
PMID- 9392444
TI - The role of the intracellular and extracellular serotonin in the regulation of
melatonin production in rat pinealocytes.
AB - This study investigated whether the activation of pinealocyte beta-adrenergic
receptors is involved in the regulation of serotonin (5-HT) synthesis and
release, as it is for melatonin production. In addition, the role of the intra-
and extra-cellular 5-HT in modulating the synthesis of melatonin induced by the
beta-adrenergic agonist isoproterenol (ISO) was also studied. The incubation of
dissociated pinealocytes with 0.1-10 microM ISO resulted in a concentration
dependent increase of melatonin synthesis. 5-HT release and intracellular 5-HT
content were increased by 0.1 and 1 microM ISO but they were reduced after ISO 10
microM. Moreover, when incubated with the tryptophan hydroxylase inhibitor p
chlorophenylalanine (PCPA), the secretion of 5-HT as well as the intracellular 5
HT levels were markedly reduced in both ISO-stimulated and unstimulated
conditions. Melatonin release was also inhibited by PCPA, although it responded
in the expected manner to increasing concentrations of ISO. These data indicate
that the release of 5-HT from pinealocytes depends on the availability of
cytoplasmic 5-HT, which in turn is highly dependent on the tryptophan hydroxylase
activity. In cells stimulated with moderate ISO concentrations, 5-HT release may
be an important regulatory process of pineal 5-HT. After a large stimulation of N
acetyltransferase (NAT) activity by ISO, the synthesis of melatonin prevails on 5
HT release, whose decrease is associated to a deficit of intracellular 5-HT. On
the other hand, the present study shows that the incubation of pineal cells with
high concentrations of 5-HT or with a selective 5-HT2 receptor agonist, alpha
methyl-5-hydroxytryptamine, reverses partially the inhibitory effect of PCPA on
the ISO-stimulated melatonin synthesis. In contrast the 5-HT2 antagonist,
ketanserin, results in an inhibiton of the release of melatonin following ISO
stimulation. These results suggest that released 5-HT may have a role in the full
expression of the beta-adrenergically induced NAT activity and, thus, may
contribute to the optimal melatonin synthesis at night.
PMID- 9392445
TI - Circadian rhythm in experimental granulomatous inflammation is modulated by
melatonin.
AB - Biological rhythms are detected in a variety of physiological and pathological
conditions in man and animals, such as rheumatoid arthritis and asthma. Here we
describe a circadian rhythm in experimental infectious and non-infectious
granuloma. After 30 days of BCG (Bacillus Calmette-Guerin) or nystatin
inoculation in the left hind foot of C57B1/6 mice, there is an oscillation with a
period of approximately 24 hr in the variation of paw thickness, indicating a
circadian rhythm. The acrophase occurred during the light phase, between 9:00 and
13:00 hr, while the nadir occurred in the dark phase, between 21:00 and 01:00 hr.
The vascular permeability around the granulomatous lesions was higher at 12:00 hr
than at 24:00 hr. This is in agreement with the observation that the thickness of
a paw with granulomatous lesion is larger during the light phase. This rhythmic
variation was eliminated by either pinealectomy or superior cervical
ganglionectomy, which greatly reduce melatonin levels in the blood. Nocturnal
replacement of melatonin in pinealectomized mice led to the re-establishment of
the circadian rhythm. Thus, the rhythm of the granulomatous lesion is due to the
rhythmic melatonin release by the pineal gland. This approach opens new questions
regarding the modulation of chronic inflammation in inflammatory diseases that
present rhythmic symptoms throughout the day.
PMID- 9392446
TI - The role of melatonin and L-tryptophan in prevention of acute gastric lesions
induced by stress, ethanol, ischemia, and aspirin.
AB - Melatonin, a pineal hormone, synthesized from L-tryptophan, is known to exist in
the gut and to scavenge oxygen free radicals but its role in gastroprotection
against acute lesions induced by various strong irritants has been little
studied. In this study, we determined the effects of melatonin and L-tryptophan
on gastric secretion and the formation of acute gastric lesions induced by
absolute ethanol, acidified aspirin (ASA), stress, and ischemia-reperfusion
(I/R). Area of gastric lesions was determined by planimetry, gastric blood flow
(GBF) was measured using a H2-gas clearance technique, and blood was withdrawn
for the measurement of free radicals, plasma gastrin, and melatonin concentration
by specific radioimmunoassay. Intragastric (i.g.) administration of melatonin
(2.5-10 mg/kg) or L-tryptophan (25-200 mg/kg) failed to affect gastric lesions by
ethanol and ASA but dose-dependently reduced the lesions provoked by stress and
I/R; this protective effect was accompanied by a significant rise in plasma
melatonin level, GBF, and DNA synthesis and by a marked fall in blood free
radicals. L-tryptophan, which significantly elevated the plasma melatonin by
about 3-5-fold, also reduced the stress and I/R-induced lesions and blood levels
of free radicals, while increasing the GBF, DNA synthesis, and plasma gastrin
levels. Inhibition of mucosal generation of PGE2 by indomethacin abolished the
protection and the rise of GBF afforded by melatonin and L-tryptophan, whereas
pretreatment with N(G)-nitro-L-arginine (L-NNA), to suppress nitric oxide (NO)
synthase, was without any effect. We conclude that melatonin applied exogenously
in pharmacological doses and that released by the administration of its
precursor, L-tryptophan, protect gastric mucosa from the damage induced by stress
and I/R possibly by a mechanism involving the scavenging of free radicals and
gastric hyperemia probably mediated by endogenous prostaglandin but not NO.
PMID- 9392447
TI - Nocturnal urinary 6-sulfatoxymelatonin and proliferating cell nuclear antigen
immunopositive tumor cells show strong positive correlations in patients with
gastrointestinal and lung cancer.
AB - The hormone melatonin plays a key role in coordinating neuroendocrine signals
involved in the control of biological rhythms and also appears to be involved in
the regulation of cellular proliferation. In this study on patients with
gastrointestinal and lung cancer the nocturnal urinary excretion of 6
sulfatoxymelatonin (aMT6s) reflecting pineal melatonin production as well as
immunohistochemically detectable proliferating cell nuclear antigen (PCNA) and
melatonin were measured in corresponding tumor specimens (6 colorectal, 8
stomach, and 12 lung cancers). Strong positive correlations were detected between
aMT6s and PCNA for the different types of tumors analysed (1 > or = Rs > or =
0.736, P < 0.01-0.0001). These findings provide support to the concept of an
involvement of the pineal gland in malignancy and suggest that aMT6s-measurements
may be considered as a non-invasive tool to estimate tumor cell proliferation.
Negative correlations found between urinary aMT6s and melatonin in tumor cells (
0.735 > or = Rs > or = -0.928, P < 0.01-0.0025) could be interpreted as an effort
of the pineal gland to secrete melatonin to compensate for the decrease in the
number of melatonin-immunopositive cells within tumor tissue where it may possess
important regulatory functions.
PMID- 9392448
TI - Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a
child with severe myoclonic epilepsy: two years' experience.
AB - Recent data indicate that melatonin inhibits brain glutamate receptors and nitric
oxide production, thus suggesting that it may exert a neuroprotective and
antiexcitotoxic effect. Melatonin has been seen to prevent seizures in several
animal models and to decrease epileptic manifestations in humans. The lack of
response to conventional anticonvulsants in an epileptic child led us to use
melatonin in this case. A female child who began to have convulsive seizures at
the age of 1.5 months and was diagnosed as having severe myoclonic epilepsy was
unsuccessfully treated with different combinations of anticonvulsants, including
valproic acid, phenobarbital, clonazepam, vigabatrin, lamotrigin, and clobazam.
Melatonin was thus added to the treatment. Imaging studies (CT, SPECT, and MNR),
EEG recordings, blood biochemical, and hematological analyses, including measures
of the circadian rhythm of melatonin, were made. The child was initially treated
with various anticonvulsants. Severe neurological and psychomotor deterioration
combined with increased seizure activity showed a lack of response to the
treatment. At the age of 29 mon the patient was in a pre-comatose stage at which
time melatonin was added to treatment. After 1 month of melatonin plus
phenobarbital therapy and for a year thereafter, the child's seizures were under
control. On reducing the melatonin dose after this time, however, seizures
resumed and the patient's condition was re-stabilized after restoring melatonin.
Prior to our attempts to reduce melatonin, all analyses, including EEG recordings
and SPECT, were normal. As far as the results of neurological examination are
concerned, only mild hypotony without focalization remained. Changes in the
therapeutic schedules during the second year of melatonin treatment, including
the withdrawal of phenobarbital, did not result in the same degree of seizure
control, although progressively the child became satisfactorily controlled. At
the present moment the child continues to have mild hypotony and shows attention
disorder and irritability. Melatonin has proven to be useful as adjunctive
therapy in the clinical control of this case of severe infantile myoclonic
epilepsy. The results suggest that melatonin may have a useful role in mechanisms
of neuroprotection and also indicate its use in other cases of untreatable
epilepsy. Further studies using more patients and placebo-treatment would be
beneficial in understanding the potential use of melatonin as a co-therapy in
some cases of seizures.
PMID- 9392449
TI - Protective effect of melatonin in carrageenan-induced models of local
inflammation: relationship to its inhibitory effect on nitric oxide production
and its peroxynitrite scavenging activity.
AB - In vitro studies have demonstrated that melatonin is a scavenger of oxyradicals
and peroxynitrite and an inhibitor of nitric oxide (NO) production. In the
present study, we evaluated the effect of melatonin treatment in two models of
acute inflammation (carrageenan-induced paw edema and pleurisy), where
oxyradicals, NO, and peroxynitrite play a crucial role in the inflammatory
process. Our data show that melatonin (given at 62.5 and 125 microg/paw in the
paw edema model or 25 and 50 mg/kg in the pleurisy model) inhibits the
inflammatory response (paw swelling, pleural exudate formation, mononuclear cell
infiltration, and histological injury) in dose-dependent manner in both models.
Furthermore, our data suggest that melatonin exerts an inhibitory effect on the
expression of the inducible isoform of NO synthase. Melatonin also prevented the
formation of nitrotyrosine, an indicator of peroxynitrite, in both models of
inflammation. Taken together, the present results demonstrate that melatonin
exerts potent antiinflammatory effects. Part of these antiinflammatory effects
may be related to an inhibition of the expression of the inducible NO synthase,
while another part may be related to oxyradical and peroxynitrite scavenging.
PMID- 9392450
TI - Regional brain distribution of metallothionein, zinc and copper in toxic milk
mutant and transgenic mice.
AB - The regional distribution of metallothionein (MT), zinc and copper was measured
in brains of transgenic MT-I overexpressor (MT-I*) mice, MT-I/MT-II gene knockout
(MT-I/MT-II null) mice, and in brains of control C57BL/6J mice with normal MT
expression. Toxic milk (tx) mutant mice with abnormally high MT and copper
accumulation were also assessed. Although there were significant differences in
MT levels (assessed by a cadmium-binding assay) in whole brain of MT-I/MT-II null
and control mice (16.5 +/- 2.9 microg/g vs 25.6 +/- 7.4 microg/g), different
regions of the brain (cerebral cortex, corpus striatum, hippocampus, thalamus
plus hypothalamus, cerebellum, and brain stem) contained similar amounts of MT.
Male MT-I* mice had significantly higher whole brain MT level than controls (35.5
+/- 8.1 microg/g vs 25.6 +/- 7.4 microg/g), and had a 2-fold higher MT level in
cerebellum, but not in other brain regions. Female MT-I* mice had significantly
increased MT levels in all brain regions, with the highest increase in cerebellum
(3.5-fold), and the lowest increase in cortex (2-fold). MT level in whole brain
of female MT-I* mice was also significantly higher than that of male MT-I* (75.2
+/- 8.0 microg/g vs 35.4 +/- 8.1 microg/g). Toxic milk mice had significantly
higher MT levels in all brain regions compared to age-matched controls (51.8 +/-
10.8 microg/g vs 30.3 +/- 5.8 microg/g), while no specific region of tx mouse
brain showed a preferential increase in MT. In MT-I* and MT-I/MT-II null mice,
altered MT levels did not always result in altered zinc and/or copper
concentrations. However, all mouse strains exhibited region-specific accumulation
of zinc, with the highest level in hippocampus. In control, MT-I/MT-II null, and
male MT-I* mice, the hippocampus accumulated the highest level of copper.
However, MT-I/MT-II null and both male and female MT-I* mice had similar levels
of copper, compared to control mice. Toxic milk mice, on the other hand, had
significantly higher copper levels in cerebral cortex, corpus striatum,
thalamus/hypothalamus, and brain stem, compared to control mice. Zinc levels in
corpus striatum, hippocampus, and cerebellum were also significantly increased.
These data indicate that, in normal control and MT-I/MT-II null mice, MT is
expressed uniformly in different regions of the brain. MT-I* mice, on the other
hand, exhibit regional and gender-associated change in brain MT, and tx mice have
markedly increased MT, copper, and zinc levels in most brain regions. These mouse
strains will be useful models in elucidating the role of MT in the pathological
effects of altered zinc and copper in brain.
PMID- 9392451
TI - Cosubstrates involved in the reduction of cytosolic glutathione disulfide in rat
heart.
AB - The functionality of glutathione (GSH), which is present in separate
mitochondrial and cytosolic pools, hinges on a steady supply of reducing
equivalents, provided by NADPH, to convert glutathione disulfide (GSSG) to GSH.
It is believed traditionally that glucose 6-phosphate (G6-P) via the pentose
phosphate pathway is the main cellular source of NADPH. The current study
examined the ability of NADH- and NADPH-linked cosubstrates to support cardiac
cytosolic GSSG reduction. Exogenous NADP+ was added to the incubation mixtures
because of the loss of this nucleotide during homogenization. Exogenous GSSG was
added to all samples to levels that were approximately 60% of total glutathione.
In both the 500 x g (with mitochondria) and 10,000 x g (without mitochondria) rat
heart supernatants, isocitrate supported reduction of approximately 90% of
available GSSG within 10 min. Malate, pyruvate and palmitoyl carnitine did not
support GSSG reduction in either supernatant. G6-P yielded GSH levels within 10
min equal to 77% of total glutathione in the 1,0000 x g supernatant and 47% in
the 500 x g supernatant. The current data indicate: (1) The pentose phosphate
pathway, alone, is less efficient than isocitrate at supplying reducing
equivalents for cytosolic GSSG reduction; and (2) some confounding factor(s)
occur in the 500 x g and reconstituted 500 x g supernatants whereby G6-P
supported GSSG reduction is attenuated.
PMID- 9392452
TI - The mechanisms of nickel uptake by rat primary hepatocyte cultures: role of
calcium channels.
AB - The present study was designed to clarify the mechanism of nickel (Ni) uptake in
primary cultures of rat hepatocytes. Exposure of the hepatocytes to Ni (2-50
microM; as NiCl2) for up to 6 h was not cytotoxic, as assessed by the tetrazolium
based dye (MTT) assay. Hepatocytes were treated with 10 microM NiCl2 in the
absence or presence of calcium (Ca) and magnesium (Mg) (1 mM). Ni uptake was
increased by 19% in medium lacking Mg or Ca and was increased by 37% in Ca- and
Mg-free medium. The role of Ca channels on Ni uptake by the hepatocytes was
investigated. Pretreatment with nicardipine or verapamil (200 microM), potent
inhibitors of Ca channels, decreased Ni uptake by 20%. This effect was only
observed when the cells were incubated in the absence of Ca. Pretreatment with
vasopressin (100 nM), a well-known Ca channel agonist, significantly increased Ni
uptake by the hepatocytes (24%). To determine the involvement of carrier-mediated
processes on Ni uptake, the effect of temperature was also investigated. At 4
degrees C the Ni uptake was decreased by 20% compared to uptake at 37 degrees C.
These results indicate that Ni uptake by the hepatocytes occurs, at least in
part, through the Ca channel transport processes. Further study will be required
to assess what other mechanisms are involved.
PMID- 9392453
TI - Modulation of TCDD-induced fetotoxicity and oxidative stress in embryonic and
placental tissues of C57BL/6J mice by vitamin E succinate and ellagic acid.
AB - The ability of vitamin E succinate and ellagic acid to modulate 2,3,7,8
tetrachlorodibenzo-p-dioxin (TCDD)-induced developmental toxicity and oxidative
damage in embryonic/fetal and placental tissues was studied in C57BL/6J mice.
Vitamin E succinate (100 mg/kg per day) and ellagic acid(6 mg/kg per day) were
administered by gavage to groups of pregnant mice on days 10, 11 and 12 of
gestation and 40 mg vitamin E succinate/kg or 3 mg ellagic acid/kg on day 13 of
gestation. A number of animals from the vitamin E succinate and ellagic acid
treated groups also received 30 microg TCDD/kg on day 12 of gestation, 2 h prior
to vitamin E succinate or ellagic acid treatment. Groups of treated animals were
terminated on day 14 of gestation, and the biomarkers of oxidative stress,
including superoxide anion production and the induction of lipid peroxidation and
DNA-single strand breaks (SSB), were determined in whole embryonic and placental
tissues homogenates. Groups of treated animals were also killed on day 18 of
gestation for investigation of the fetotoxic and teratogenic effects as well as
effects on the placentae. Vitamin E succinate and ellagic acid significantly
decreased TCDD-induced fetal growth retardation fetal death and placental weight
reduction, with no significant ameliorating effects on TCDD-induced malformations
including cleft palate and hydronephrosis. Vitamin E succinate treatment resulted
in decreases of 77-88%, 70-87%, and 21-47% in the production of superoxide anion,
lipid peroxidation and DNA-SSB, respectively, in embryonic and placental tissues,
while ellagic acid caused 47-98%, 79-93%, and 37-53% decreases, respectively, in
these parameters. These results indicate that TCDD-induced fetal death and fetal
and placental weight reductions in C57BL/6J mice may be due to oxidative damage
induced by TCDD, and ellagic acid and vitamin E succinate provide protection
against those effects. Ellagic acid provided better protection than vitamin E
succinate against TCDD-induced fetal growth retardation and increases in lipid
peroxidation in embryonic and placental tissues.
PMID- 9392454
TI - Cytochrome P450 1A1 induction in rat lymphoid tissues following in vivo and in
vitro exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin requires protein kinase C.
AB - The induction of cytochrome P450 1A1 (CYP1A1) is one of the most sensitive
responses associated with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
and related compounds. The mechanisms that underlie this response are not
completely understood, particularly in lymphoid tissues that may be used in
biomarker studies in humans. CYP1A1 mRNA expression and enzyme activity
(ethoxyresorufin-o-deethylase, EROD) were investigated in rat thymus and spleen
and isolated thymocytes and splenocytes in culture. Thymus- or spleen-derived
microsomes from rats treated in vivo with TCDD showed induced EROD activity after
as little as 12 h following a single exposure to TCDD (5 microg/kg body weight).
Resting rat thymocytes in culture had detectable levels of EROD activity and
CYP1A1 mRNA expression which increased following in vitro exposure to > or = 0.1
nM TCDD for 24 or 48 h. Interestingly, concomitant in vitro exposure of rat
thymocytes to TCDD and the mitogen concanavalin A (Con A) inhibited the induction
of EROD activity, which is in contrast to the response of cultured human
peripheral blood lymphocytes (Landi et al., 1994; Pharmacogenetics 4, 242 246).
Resting rat splenocytes in culture had no detectable EROD activity and CYP1A1
activity could not be induced by in vitro TCDD exposure, in the presence or
absence of Con A. These results suggest that the relative maturation state of the
cells is important in regulating the expression of CYP1A1, since splenocytes
represent a more mature population of B and T lymphocytes. TCDD-induced CYP1A1
expression in cultured rat thymocytes was inhibited by the addition of calphostin
C, a specific protein kinase C (PKC) inhibitor, suggesting a role for PKC as a
second messenger in the CYP1A1 induction pathway. In vivo co-exposure with
phorbol-myristate-acetate (PMA) and TCDD also inhibited CYP1A1 induction. Again,
suggesting a role for PKC in CYP1A1 induction. Together, these results indicate
that relative lymphocyte maturation state and the PKC pathway are important
factors in regulating the expression of CYP1A1.
PMID- 9392455
TI - Dichloroacetic acid pretreatment of male and female rats increases chloroform
metabolism in vitro.
AB - The role of metabolism in dichloroacetic acid (DCA) potentiation of CHCl3
hepatotoxicity was investigated. Male and female Sprague-Dawley rats were given
three doses (09:00, 16:00 and 09:00 the next morning) of DCA (each 2.45 mmol/kg)
by gavage. The rats were euthanized 3 h after the last dose, hepatic microsomes
were prepared and 14CHCl3 metabolism was measured in vitro. The binding of
14CHCl3-derivatives to microsomal proteins and lipids was increased 65 and 100%,
respectively, in DCA-treated rats compared to their respective NaCl-treated
controls. The formation of CO2 (nmol 14CO2/incubation) was significantly elevated
in DCA-treated rats compared to controls (10.4 vs 6.3 in males; 10.8 vs 6.1 in
females). DCA treatment decreased the apparent Michaelis constant (Km app) for
conversion of 14CHCl3 to 14CO2 in rats (0.665 vs 0.415 mM in males, P < 0.05;
0.161 vs 0.081 in females). 14CO2 production and 14C binding were observed under
N2 atmosphere, indicating that reactive metabolites of 14CHCl3 were formed by
oxidation as well as reduction. Male and female rats metabolized CHCl3
differently. The Km app for CO2 production was up to 5-fold higher in the males
than in the females, regardless of DCA treatment. Inhibition by SKF 525-A and
piperonyl butoxide was gender dependent in both control and DCA-treated groups.
The results showed, that increased bioactivation of CHCl3 by DCA treatment is one
element in the DCA-CHCl3 interaction.
PMID- 9392456
TI - Dichloroacetic acid pretreatment of male and female rats increases chloroform
induced hepatotoxicity.
AB - Dichloroacetic acid (DCA) and chloroform (CHCl3) are both major by-products of
drinking water chlorination and DCA increases the hepatotoxicity of CHCl3. In
this study, we further characterized this effect and investigated DCA-induced
alterations of CHCl3 disposition and metabolism as a possible mechanism for this
interaction. Both adult male and female Sprague-Dawley rats were gavaged with
three doses (09:00, 16:00 and 09:00 the next morning) of DCA (each 2.45 mmol/kg),
then challenged with an i.p. injection of CHCl3 (3.12 or 9.35 mmol/kg). Hepatic
damage was assessed 24 h after CHCl3 administration as increased alanine
aminotransferase (ALT), ornithine carbomyl transferase (OCT) and bilirubin in
plasma. In a separate experiment, rats were pretreated with DCA or were given
14CHCl3 at the same dosages. The disposition of 14C in various tissues and
covalent binding of 14CHCl3-derivatives to liver proteins and lipids were
determined 1 h later. CHCl3-induced hepatotoxicity was significantly more severe
in DCA-pretreated groups. ALT and OCT were more markedly elevated in DCA + CHCl3
(3.12 mmol/kg) groups than NaCl +CHCl3 animals. Plasma bilirubin content was
elevated only in DCA + CHCl3 groups and females were more susceptible to this
effect. The responses of rats to DCA treatment were somewhat gender-different.
DCA treatment increased total cytochrome P450 in females, but not in males.
Hepatic glutathione concentration was elevated in males after DCA treatment, but
not in females. In the present study we confirmed that DCA pretreatment
potentiates the CHCl3-hepatotoxicity of both male and female rats. However, there
was little evidence that DCA pretreatment significantly affected CHCl3
disposition or increased CHCl3 binding in vivo.
PMID- 9392457
TI - Dietary alpha-tocopherol supplementation on antioxidant defenses after in vivo
iron overload in rats.
AB - The effect of dietary alpha-tocopherol (alpha-T) supplementation on iron overload
dependent oxidative damage was studied. Male Wistar rats were fed diets
supplemented with 2.5% carbonyl iron and/or 200 mg/kg of alpha-tocopheryl acetate
for 6 weeks. Oxidation of lipids and proteins were increased by iron overload in
rat liver, and alpha-T dietary supplementation effectively prevented these
effects. Iron overload decreased both, catalase and Mn-superoxide dismutase
activities by 49 and 54%, respectively, with no effect on glutathione peroxidase
activity. Alpha-T supplementation did not prevent the inhibition measured in
catalase and Mn-superoxide dismutase activities. Iron dietary excess had no
effect on liver alpha-T and ubiquinol 9 (UQ9) content. Ubiquinol 10 (UQ10)
content after iron overload was decreased by 58 and 54% in whole liver and liver
mitochondria, respectively. Alpha-T supplementation led to significant increases
in alpha-T, UQ9 and UQ10 content in liver, as compared to control values, and
partially prevented the decrease in UQ10 content due to iron excess. The results
presented here indicate that initial stages of iron overload led to oxidative
damage in liver (evaluated in terms of lipid and protein oxidation) with a
decline in antioxidant defenses. alpha-T supplementation affected the liver
content of lipid soluble antioxidants, suggesting a concerted antioxidant
response at the cellular level to modulate the effect of excess iron
availability.
PMID- 9392458
TI - The current role of the barium examination of the small intestine.
PMID- 9392459
TI - The role of CT and MR in imaging the complications of sickle cell disease.
AB - Sickle cell disease is the most common inherited haemoglobinopathy described.
Complications of sickle cell disease (SCD) are due to chronic haemolysis of
fragile red cells or secondary to vascular occlusion by sickled red cells with
subsequent tissue infarction. Traditionally plain film radiography has been the
mainstay in the assessment of patients with SCD, but increasingly magnetic
resonance (MR) imaging and computed tomography (CT) are being used. In this
review the imaging features of a range of complications of SCD are demonstrated
with particular emphasis on CT and MR.
PMID- 9392460
TI - Three-dimensional computed tomography bronchoscopy using clinical datasets: a
comparison with fibreoptic bronchoscopy.
AB - OBJECTIVE: To assess three-dimensional computed tomography 'bronchoscopic' (3
DCTB) reconstruction of routine CT data as a non-invasive method of airway
visualization, and compare it with fibreoptic bronchoscopy (FOB). METHODS:
Fourteen datasets were acquired from 13 patients undergoing both FOB and CT
examination of the chest. Standard continuous volume CT using 6 mm collimation
and clinical FOB techniques were employed. Images were obtained from 3-DCTB
reconstructions by segmentation and surface recognition algorithms generating
surface rendered 'bronchoscopic views'. These were scored for technical quality
and anatomical detail. The most distal bronchi seen in left upper and right lower
lobes were recorded for FOB and 3-DCTB. RESULTS: On FOB, the subsegmental bronchi
were seen in right lower and in left upper lobe in 10/14 cases and 4/14 cases,
respectively. Visualization of the subsegmental airways was not achieved with 3
DCTB, as they could not be identified with confidence. 3-DCTB never achieved a
more distal view than obtained by FOB. Using 3-DCT, the right, lower lobe
segmental bronchi were seen in 10/14 cases, and lobar bronchus in 14/14 cases
(two occluded). In the left upper lobe, 3-DCT showed segmental bronchi in 6/14
cases, lobar bronchus in 11/14 cases (one occluded) and the left main bronchus
appeared occluded in 3/14 cases. Overall, technical quality and anatomical detail
scores of the carina and proximal bronchi ranked significantly higher than views
of segmental bronchi. CONCLUSIONS: 3-DCTB cannot routinely replace FOB for
inspection of major and segmental bronchi. Subsegmental bronchi cannot be
adequately demonstrated by 3-DCTB using 6 mm collimation datasets.
PMID- 9392462
TI - Prognostic indicators in acute pancreatitis: CT vs APACHE II.
AB - PURPOSE: To investigate the correlation between established contrast-enhanced
computed tomography (CECT) criteria of disease severity in acute pancreatitis and
the APACHE (Acute Physiology and Chronic Health Evaluation) II score and to
assess the utility of each as prognostic indicators in acute pancreatitis.
MATERIALS AND METHODS: Over a 1-year period, prospective, consensus
interpretation of the CECTs of 35 consecutive inpatients was performed with
determination of the CECT grade, degree of necrosis, and severity index. The
APACHE II score was calculated within 24 h of CECT. Multiple clinical endpoints
were recorded: local complications (pseudocyst, abscess, or acute fluid
collections requiring urgent surgical or radiological intervention), systemic
disease (intensive care unit admission), and duration of hospitalization.
Statistical analysis was performed to determine correlations. RESULTS: No
statistically significant correlation existed between the APACHE II score and
CECT grade, the degree of necrosis, or the CECT severity index. Only the CECT
grade and severity index correlated significantly with the occurrence of local
complications (P = 0.0035 and 0.0048, respectively). The APACHE II score was
superior to the CECT grade as a predictor of the need for ICU admission (P =
0.022 vs P = 0.035), and no other CECT criteria was a significant predictor of
ICU admission. CONCLUSION: The preferred clinical and imaging prognostic measures
in acute pancreatitis, the APACHE II score and CECT criteria, do not correlate
with one another in the commonly encountered, mixed primary and tertiary care
population. The mathematical integration of CECT criteria and the APACHE II score
fails to yield a predictor of outcome superior to the use of any one measure
alone. CECT criteria best define local anatomic abnormality, and are superior to
the APACHE II score as predictors of local complications. The APACHE II score is
superior to all CECT criteria as an indicator of systemic disease severity
(reflected in the need for ICU admission). The most effective initial triage
would be immediate APACHE II calculation. Further use of imaging vs clinical
assessment can then be individualized.
PMID- 9392461
TI - Radiological features of pulmonary tuberculosis in 963 HIV-infected adults at
three Central African Hospitals.
AB - Tuberculosis is one of the most important infectious complications in human
immunodeficiency virus (HIV)-infected individuals in sub-Saharan Africa. In this
radiological study, we detail the chest radiographic findings of Zairean and
Zambian adults with a diagnosis of AIDS and tuberculosis as seen at three Central
African Hospitals. Between 1992 and 1995, consecutive chest radiographs of 963
HIV-infected adults aged between 16 years and 56 years with microbiologically
confirmed tuberculosis (TB) were reviewed: (1) 362 adults from Sendwe General
Hospital, Lubumbashi, Zaire, (2) 175 from Mama Yemo Hospital, Kinshasa, Zaire,
and (3) 426 adults from The University Teaching Hospital (UTH), Lusaka, Zambia.
During the same period consecutive chest radiographs from 1000 age-matched HIV
negative adults with tuberculosis were collected for comparative purposes.
Comparison of the two groups showed that the HIV-infected group of patients with
tuberculosis had a significantly higher proportion of lymphadenopathy (26% vs
13%; P = 0.001), pleural effusions (16% vs 6.8%; P = 0.001), miliary shadowing
(9.8% vs 5%; P = 0.001), an interstitial pattern (12% vs 7%; P = 0.01) and
consolidation (10% vs 3%; P = 0.001). There was significantly less cavitation
(33% vs 78%; P = 0.001) and atelectasis (12% vs 24%; P = 0.001) seen in the HIV
positive group compared to the HIV-negative group of patients. These patterns of
radiographic changes were consistently seen across all three hospital sites. The
radiographic appearances in HIV-infected individuals with TB is discussed.
PMID- 9392463
TI - End stage renal transplant failure: allograft appearances on CT.
AB - INTRODUCTION: Failed renal allografts often are left in situ in patients who
revert to chronic dialysis therapy or who undergo retransplantation. These
patients may be investigated with computed tomography (CT) imaging for allograft
related or other abdominopelvic disease. This study describes the appearances of
failed renal transplants on CT. METHODS: A retrospective study was made of the
clinical records and CT findings on 25 studies in 14 patients, 5-156 months
(average, 44 months) following allograft failure. CT studies were reviewed for
allograft position, size, shape, attenuation value, calcification, cyst
formation, related abdominopelvic findings and the presence of other allografts.
Correlation was made with clinical findings in all patients and with pathological
findings in six. RESULTS: Global shrinkage was noted in eight failed allografts,
all of which were asymptomatic. Enlargement of two failed allografts was due to
symptomatic acute infarction of the allograft in one patient and subacute
haemorrhagic infarction simulating a tumour mass in another. CT attenuation
values in individual allografts varied markedly due to fatty replacement,
hydronephrosis, haemorrhage or dense calcification. Both a failed longstanding
and a functioning more recently placed renal allograft were present in seven
patients, four of whom had acute complications related to the more recently
transplanted kidney. Two of six calcified allografts were mistaken for opacified
bowel on CT. CONCLUSION: A wide spectrum in size, shape and attenuation values
may be detected in failed renal allografts by CT. These organs may be the site of
acute disease despite their lack of physiological function or may be
diagnostically confusing findings in patients with acute disease related to more
recently transplanted organs.
PMID- 9392464
TI - Breast MR and the appearance of the normal and abnormal nipple.
AB - AIM: To identify the magnetic resonance (MR) morphological and enhancement
characteristics of the normal and diseased nipple. MATERIALS AND METHODS: The MR
appearances of the nipple in 35 patients with known primary breast cancer who
went on to mastectomy was reviewed by two radiologists (blinded to the clinical,
mammographic and histopathological information) and correlated with histology.
The appearance of the contra-lateral nipple in 31 patients was reviewed and
compared with that of the affected side. MR was performed at 1.0T using a receive
only double breast coil in 33 patients and a single breast coil in two patients.
Three dimensional (3-D) T1-weighted gradient-echo images were made before and
immediately after a fast hand injection of gadolinium-DTPA (0.1 mmol/kg).
RESULTS: Twenty-six breasts had histopathologically normal nipples and
retroareolar tissue, four had evidence of tumour within the nipple and four had
retroareolar tumour but with nipple sparing. Fifteen normal nipples were everted
and 11 were inverted (flat). All showed superficial linear dermal enhancement
above a non-enhancing zone in the nipple areolar complex. Linear or patchy
enhancement deep to the non-enhancing zone was seen in four breasts and linear
enhancement through the non-enhancing zone was seen in two. The nipple in all
four breasts with tumour involvement showed increased thickening/bulkiness and
enhancement of the nipple-areolar complex and retroareolar tissue. The four
breasts with retroareolar tumour and nipple sparing showed increased thickening
and enhancement of the retroareolar tissue only. There was one false positive
result on breast MR for retroareolar tumour involvement. In this case the
abnormally enhancing retroareolar tissue adjacent to the focal mass was shown to
be an area of sclerosing adenosis on histology. The 31 contra-lateral nipples had
the characteristic 'normal' appearance and when compared with its normal
ipsilateral nipple showed marked symmetry. When compared with its abnormal
ipsilateral nipple showed marked asymmetry. CONCLUSION: MR of the breast can show
nipple involvement even when clinically unsuspected. This is important for
treatment planning of breast cancer, in particular nipple preserving surgery.
PMID- 9392465
TI - Reduction of adverse events in MRI of the breast by personal patient care.
AB - PURPOSE: To determine the difference in anxiety reactions in patients undergoing
standard (non-breast) magnetic resonance imaging (MRI) compared to breast
magnetic resonance imaging (MRM) and to evaluate the influence of patient
information before the breast imaging examination on the rate of premature
termination of the procedure. MATERIALS AND METHODS: Over 2 years, 5837 non
breast and 336 breast magnetic resonance examinations were performed at our
institution. One group of breast MRM patients (n = 144) received detailed
information and a second group (n = 189) received only routine information before
MRI. The rates of premature termination were recorded for all groups. RESULTS: In
0.5% (27/5837) of patients undergoing standard MRI examinations the study had to
be stopped prematurely. Of the breast MRM patients, those who had received only
routine information had a significantly higher rate of premature termination when
compared to the better-informed patients and those undergoing standard MRI (5.5%,
10/189, P= 0.01). A significantly lower rate of premature termination occurred in
the better-informed breast group (0%, 0/144). CONCLUSION: MRM is associated with
an increase in patient anxiety and higher rates of incomplete examination than
other MR procedures. We recommend careful patient preparation including detailed
verbal information before MRM and support during the procedure to obtain optimal
patient compliance.
PMID- 9392466
TI - Radiological features of papillary carcinoma of the breast.
AB - Seventeen patients with papillary carcinoma of the breast were analysed with
respect to the radiological findings by three experienced breast radiologists.
The most frequent mammographic appearance of papillary tumours was of an ill
defined (70%) and lobulated (60%) mass and at ultrasound as a well-defined (76%),
inhomogeneous (62%) and hypoechoic (92%) lesion. Histopathological subtypes of
encysted papillary carcinoma, encysted papillary carcinoma with an invasive focus
and invasive papillary carcinomas could not be predicted from the radiological
features, although invasive tumours tended to be larger at presentation than the
other subtypes.
PMID- 9392467
TI - Technical report: double-phase technetium-99m-sestamibi parathyroid imaging with
an in-field photopenic marker for better mapping.
AB - The author introduces a photopenic marker that was used to delineate better
anatomic mapping in a double-phase technetium-99m-sestamibi parathyroid imaging.
This home-marker was placed on a patient within the imaging field to increase
reproducibility of the images: early versus delayed images.
PMID- 9392469
TI - Case report: an unusual interval breast cancer masquerading as a simple cyst.
PMID- 9392468
TI - Case report: Sylvian fissure meningioma without dural attachment in a 4-year-old
child.
PMID- 9392470
TI - Case report: imaging features of pleural lymphoma complicating a long-standing
pyothorax.
PMID- 9392471
TI - Case report: portal hypertension causing massive enlargement of an accessory
spleen -- a rare cause of splenic pseudotumour.
PMID- 9392472
TI - Administration of intravascular contrast media to children: current practice in
the UK.
PMID- 9392473
TI - Fluoroscopically guided retrograde ureteric stent retrieval and replacement.
PMID- 9392474
TI - What is acceptable radiological performance?
PMID- 9392475
TI - Hypatia: change, limits, and interconnectedness.
PMID- 9392476
TI - Augmentation of insulin release by glucose in the absence of extracellular Ca2+:
new insights into stimulus-secretion coupling.
AB - Glucose stimulates insulin secretion in the pancreatic beta-cell by means of a
synergistic interaction between at least two signaling pathways. One, the K(ATP)
channel-dependent pathway, increases the entry of Ca2+ through voltage-gated
channels by closure of the K(ATP) channels and depolarization of the beta-cell
membrane. The resulting increase in [Ca2+]i stimulates insulin exocytosis. The
other, a K(ATP) channel-independent pathway, requires that [Ca2+]i be elevated
and augments the Ca2+-stimulated release. These mechanisms are in accord with the
belief that glucose-stimulated insulin secretion has an essential requirement for
extracellular Ca2+ and increased [Ca2+]i. However, when protein kinases A and C
are activated simultaneously, a large effect of glucose to augment insulin
release can be seen in the absence of extracellular Ca2+, under conditions in
which [Ca2+]i is not increased, and even when [Ca2+]i is decreased to low levels
by intracellular chelation with BAPTA. In the presence or absence of Ca2+, there
are similarities in the characteristics of augmentation of insulin release that
suggest that only one augmentation mechanism may be involved. These similarities
include time course, glucose dose-responses, augmentation by nutrients other than
glucose such as alpha-ketoisocaproate (alpha-KIC), and augmentation by the fatty
acids palmitate and myristate. However, augmentation in the presence and absence
of Ca2+ is distinctly different in GTP dependency. Therefore, exocytosis under
these two conditions appears to be triggered differently-one by Ca2+ and the
other by GTP or a GTP-dependent mechanism. The augmentation pathways are likely
responsible for time-dependent potentiation of secretion and for the second phase
of glucose-stimulated insulin release.
PMID- 9392477
TI - Tumor necrosis factor-alpha induces apoptosis of human adipose cells.
AB - Tumor necrosis factor-alpha (TNF-alpha) production by adipocytes is elevated in
obesity, as shown by increased adipose tissue TNF-alpha mRNA and protein levels
and by increased circulating concentrations of the cytokine. Furthermore, TNF
alpha has distinct effects on adipose tissue including induction of insulin
resistance, induction of leptin production, stimulation of lipolysis, suppression
of lipogenesis, induction of adipocyte dedifferentiation, and impairment of
preadipocyte differentiation in vitro. Taken together, these effects all tend to
decrease adipocyte volume and number and suggest a role for TNF-alpha in limiting
increase in fat mass. The aim of the present study was to determine if TNF-alpha
could induce apoptosis in human adipose cells, hence delineating another
mechanism by which the cytokine could act to limit the development of, or extent
of, obesity. Cultured human preadipocytes and mature adipocytes in explant
cultures were exposed in vitro to human TNF-alpha at varying concentrations for
up to 24 h. Apoptosis was assessed using morphological (histology, nuclear
morphology following acridine orange staining, electron microscopy) and
biochemical (demonstration of internucleosomal DNA cleavage by gel
electrophoresis and of annexin V staining using immunocytochemistry) criteria. In
control cultures, apoptotic indexes were between 0 and 2.3% in all experiments.
In the experimental systems, TNF-alpha induced apoptosis in both preadipocytes
and adipocytes, with indexes between 5 and 25%. Therefore, TNF-alpha induces
apoptosis of human preadipocytes and adipocytes in vitro. In view of the major
metabolic role of TNF-alpha in human adipose tissue, and the knowledge that
adipose tissue is dynamic (with cell acquisition via preadipocyte
replication/differentiation and cell loss via apoptosis), these findings describe
a further mechanism whereby adipose tissue mass may be modified by TNF-alpha.
PMID- 9392478
TI - Regulation of hepatic glutaminase in the streptozotocin-induced diabetic rat.
AB - The liver of diabetic animals removes increased quantities of glutamine. We
therefore examined factors that affect hepatic glutaminase activity in
hepatocytes and mitochondria. Glutamine use, through glutaminase, was measured in
isolated rat hepatocytes by monitoring the production of 14CO2 from [1
(14)C]glutamine. Hepatocytes from streptozotocin-induced diabetic rats use
glutamine more rapidly than do hepatocytes from normal or insulin-maintained
diabetic rats. Glutamine use in all of these hepatocytes was stimulated by
glucagon and epinephrine. Glutaminase activity, assayed in broken mitochondrial
membranes, was increased approximately 2.5-fold in diabetic rats. The sensitivity
of glutaminase, measured in intact liver mitochondria, to phosphate was markedly
left-shifted in mitochondria from diabetic rats compared with those from
controls. In fact, glutaminase was increased 10-fold at 2.5 mmol/l phosphate
compared with controls. This increased sensitivity of glutaminase to
physiological concentrations of phosphate is characteristic of its hormonal
activation. Therefore, activation of glutaminase plays a major role in diabetes
and is as important as increases in its total enzyme amount in determining the
increased glutamine uptake in diabetes.
PMID- 9392479
TI - Effect of captopril, losartan, and bradykinin on early steps of insulin action.
AB - Insulin initiates its metabolic and growth-promoting effects by binding to the
alpha subunit of its receptor, thereby activating the kinase in the beta subunit.
This event leads to tyrosyl phosphorylation of its cytosolic substrate, insulin
receptor substrate 1 (IRS-1), which in turn associates with and activates
phosphatidylinositol (PI) 3-kinase. The clinical use of ACE inhibitors has been
associated with increased insulin sensitivity. However, the exact molecular
mechanism is unknown. In the present study, we examined the phosphorylation
status of the insulin receptor and IRS-1, as well as the association between IRS
1 and PI 3-kinase in the liver and muscle of 20-month-old rats treated acutely
with captopril, using immunoprecipitation with antipeptide antibodies to the
insulin receptor and IRS-1, and immunoblotting with antiphosphotyrosine and anti
PI 3-kinase antibodies. Insulin stimulation increased receptor
autophosphorylation to 462 +/- 253% (P < 0.05) in the liver and 697 +/- 78% (P <
0.001) in the muscle of ACE inhibitor-treated rats. There were also increases to
250 +/- 17% (P < 0.001) and 280 +/- 50% (P < 0.05) in the insulin-stimulated IRS
1 phosphorylation levels in the liver and muscle, respectively, of animals
treated with captopril. The insulin-stimulated IRS-1 association with PI 3-kinase
rose to 305 +/- 20% (P < 0.001) in liver and 267 +/- 48% (P < 0.05) in muscle.
Losartan, an ANG receptor blocker, had no significant effect on insulin
stimulated IRS-1 phosphorylation in both tissues. The acute administration of
bradykinin increased insulin-stimulated tyrosine phosphorylation of the insulin
receptor and IRS-1 in the liver and muscle. These data demonstrate that ACE
inhibitors modulate the early steps of insulin signaling, and that this effect
may be simulated by the administration of bradykinin.
PMID- 9392480
TI - Sensitization to insulin induced by beta,beta'-methyl-substituted hexadecanedioic
acid (MEDICA 16) in obese Zucker rats in vivo.
AB - Beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) consists of a
nonmetabolizable long-chain fatty acid designed to probe the effect exerted by
fatty acids on insulin sensitivity. The effect of MEDICA 16 was evaluated in
insulin-resistant Zucker (fa/fa) rats in terms of liver, muscle, and adipose
tissue response to clamped euglycemic hyperinsulinemia in vivo. Nontreated Zucker
rats were insulin resistant, maintaining basal rates of total-body glucose
disposal, glucose production in liver, free fatty acid (FFA) flux into plasma,
and FFA reesterification in adipose tissue, irrespective of the insulin levels
induced. MEDICA 16 treatment resulted in an insulin-induced decrease in hepatic
glucose production, together with an insulin-induced increase in total-body
glucose disposal. Intracellular reesterification of lipolysed FFA in adipose
tissue was specifically activated by MEDICA 16, resulting in a pronounced
decrease in FFA release, with a concomitant decrease in plasma FFA. In
conclusion, MEDICA 16 treatment results in the sensitization of liver, muscle,
and adipose tissue to insulin in an animal model for obesity-induced insulin
resistance.
PMID- 9392481
TI - Effect of insulin on GLUT4 cell surface content and turnover rate in human
skeletal muscle as measured by the exofacial bis-mannose photolabeling technique.
AB - Insulin-stimulated glucose transport across the skeletal muscle cell membrane is
a major regulatory step in postprandial glucose disposal. To estimate the total
molar concentration of GLUT4 as well as the turnover rate of GLUT4 in human
vastus lateralis muscles at the cell surface in the basal state and after insulin
exposure, we have applied the sensitive exofacial bis-mannose photolabeling
technique on in vitro incubated human skeletal muscle strips from healthy
subjects. In addition, we have measured 3-O-methylglucose transport in other
muscle strips prepared from the same surgically removed human skeletal muscle
biopsies to compare glucose transport with cell surface level of GLUT4. Maximal
in vitro insulin stimulation (2,400 pmol/l) resulted in a twofold increase
compared with basal in both surface GLUT4 content (0.38 +/- 0.05 vs. 0.19 +/-
0.03 pmol/g wet muscle wt, P < 0.005) and 3-O-methylglucose transport (1.24 +/-
0.13 vs. 0.63 +/- 0.08 pmol x ml(-1) x h(-1), P < 0.005). The insulin-induced
increment in 3-O-methylglucose transport was strongly correlated with the insulin
induced increase in cell surface GLUT4 content (r2 = 0.91; P < 0.005). The
calculated turnover rate of human skeletal muscle GLUT4 amounted to approximately
8 x 10(4) min(-1) at 35 degrees C and was unaffected by insulin. In conclusion,
maximal in vitro insulin stimulation of vastus lateralis muscle strips from
healthy subjects resulted in a twofold rise in glucose transport as well as in
cell surface content, whereas the turnover rate of GLUT4 was unaffected by
insulin under the chosen experimental conditions.
PMID- 9392482
TI - Reduction in diabetes incidence in an I-Ag7 transgenic nonobese diabetic mouse
line.
AB - Susceptibility to IDDM is strongly associated with major histocompatibility
complex (MHC) class II genotypes. Nonobese diabetic (NOD) mice develop a similar
autoimmune diabetes and have a unique MHC class II I-A allele that is required
for the development of diabetes. A number of groups have shown that the
introduction of resistant MHC class II alleles as transgenes into the NOD mouse
protects from diabetes. We made control transgenic NOD mice, expressing their own
I-Abetag7 molecule as a transgene. One of two lines of these mice showed a
reduced incidence of diabetes, without any change in T-cell proliferative
response to a number of diabetes autoantigens or any change in insulitis
severity. This line developed a subtle decrease in the percentage of splenic B
cells that progressed with age. This defect was not associated with any other
phenotypic abnormalities. Our findings suggest that assessment of splenic B-cell
number is necessary in interpretation of the effects of MHC class II transgenes
on the development of diabetes in the NOD mouse.
PMID- 9392483
TI - Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic
administration of candidate beta-cell antigens.
AB - A single injection of syngeneic islet cells into the thymus of 4-week-old NOD/Lt
female mice strongly retards diabetogenesis. The present study used the
intrathymic route of antigen administration to compare the relative efficacy of
peptides/proteins derived from two major candidate pancreatic beta-cell
autoantigens, insulin and GAD65, to modulate diabetogenesis. Intrathymic
administration of insulin B chain or recombinant human GAD65 significantly
suppressed diabetogenesis during a 20-week follow-up period, whereas no
protection was mediated by either insulin A chain or a synthetic peptide (A2)
derived from it. Quite unexpectedly, two GAD65-derived peptides near the COOH
terminus (p34 and p35) accelerated diabetes onset. Semiquantitative reverse
transcription-polymerase chain reaction analysis was performed on cDNAs from
isolated islets or whole pancreases of NOD/Lt females 4 weeks after intrathymic
injections. Protection mediated by intrathymic administration with either intact
islet cells or GAD65 were correlated with an upregulation of mRNA for T-helper 2
(Th2)-associated cytokines (interleukin [IL]-4, IL-10), concomitant with
downregulation of Th1-associated interferon (IFN) transcripts (all normalized to
T-cell receptor Cbeta transcripts) in islet-infiltrating lymphocytes. Protection
mediated by the intrathymic administration of insulin B chain, however,
correlated only with a modest upregulation of IL-4 and IL-10 transcript levels,
and no diminution in IFN-gamma transcripts. In contrast, the diabetes
accelerating GAD65 p34 and p35 peptides were not associated with an immune
deviation, expressing levels of IFN-gamma characteristic of islet-infiltrating
lymphocytes in vehicle-injected NOD controls. Hence, Th1-to-Th2 immune deviation
provides only a partial explanation for peptide immunotherapy of diabetes in NOD
mice. The finding that certain peptides can accelerate rather than retard
diabetogenesis as a function of route and age of administration adds a cautionary
note to this type of therapy.
PMID- 9392484
TI - Long-term function (6 years) of islet allografts in type 1 diabetes.
AB - Eight type 1 diabetic patients, ages 29-41 years, with mean diabetes duration of
23 years (range 18-29 years) received islet transplants from 1 to 5 donors. Seven
patients had stable kidney allografts 1-11 years before the islet transplant, and
one patient had a simultaneous islet-kidney allograft. Patients' blood glucose
control was poor as reflected by the mean +/- SD HbA1c of 9.1 +/- 1.7% before
transplant. Of the first three patients, two (1 and 3) achieved insulin
independence for 36 and 38 days, respectively. Two recipients rejected their
islet grafts within 1 month (2 and 8) and therefore were excluded from analysis.
The HbA1c and insulin requirement of the six remaining patients who had
persistent islet function for more than 60 days was significantly reduced from
9.3 +/- 1.9 to 6.4 +/- 1.0% (P = 0.002) and from 0.75 +/- 0.15 to 0.35 +/- 0.12 U
x kg(-1) x day(-1) (P < 0.001), respectively. The two patients with the longest
graft survival (4 and 6) achieved a normalization or near-normalization of their
HbA1c levels during 6 years in the absence of severe episodes of hypoglycemia. As
demonstrated by a decline in C-peptide response during Sustacal challenge tests
over a 6-year period, there was a diminution of islet allograft function over
time, despite persistence of normal or near normal HbA1c. We concluded that
transplantation of allogeneic islets with an islet mass comparable with whole or
segmental pancreas transplants in type 1 diabetic patients can result in long
term islet allograft function; further, we concluded that, in conjunction with
small dosages of exogenous insulin, a functioning islet allograft can result in
near-normalization of blood glucose levels and significant improvement in HbA1c.
The occurrence of severe hypoglycemic episodes observed for patients in the
Diabetes Control and Complications Trial was not observed in recipients with
functioning islet transplants, despite the continuous need for exogenous insulin
therapy to sustain normal HbA1c over the 6-year follow-up. The significant
improvement in metabolic control observed for the patients described in this
study, and the potential to significantly decrease or halt the progression of
diabetic complications, support the continued application of islet
allotransplantation as a treatment modality for type 1 diabetic patients.
PMID- 9392485
TI - The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin
sensitivity and acute insulin response in normoglycemic subjects.
AB - Plasma levels of proinsulin and its conversion intermediates are elevated in
NIDDM patients. Recent studies have suggested that proinsulin levels are also
increased relative to insulin levels in subjects who subsequently develop NIDDM.
This may be due to insulin resistance or a defect in proinsulin processing or
insulin secretion. If insulin resistance is the trigger, the proinsulin-to
insulin ratio would be higher in insulin-resistant subjects than in insulin
sensitive subjects. We examined the association of fasting proinsulin, 32,33
split proinsulin, and the proinsulin-to-insulin ratio with insulin sensitivity
(SI), estimated by a frequently sampled intravenous glucose tolerance test and
the minimal model in 138 normoglycemic subjects ages 53-61 years. We also
investigated the relation of proinsulins and the proinsulin-to-insulin ratio to
acute insulin response (AIR). Fasting specific insulin (r = -0.64), intact
proinsulin (r = -0.43), and 32,33 split proinsulin (r = -0.54) concentrations
were inversely correlated and the proinsulin-to-insulin ratio positively (r =
0.31) correlated with SI (P < 0.001). Fasting specific insulin (r = 0.64), intact
proinsulin (r = 0.35), and 32,33 split proinsulin (r = 0.45) concentrations were
positively correlated and proinsulin-to-insulin ratio (r = -0.40) inversely
correlated with AIR (P < 0.001). The proinsulin-to-insulin ratio increased by
increasing levels of SI (quartiles of SI from low to high: 0.048, 0.078, 0.078,
0.068; P = 0.012) and decreased by increasing AIR (quartiles of AIR from low to
high: 0.088, 0.068, 0.058, 0.058; P = 0.005). These associations were independent
of age, sex, BMI, and waist-to-hip ratio. Furthermore, the relation between the
proinsulin-to-insulin ratio and AIR was independent of SI. In conclusion, in
normoglycemic subjects, insulin resistance (low SI) was associated with a low
rather than a high proinsulin-to-insulin ratio. Subjects who maintained
normoglycemia with a low AIR had an increased proinsulin-to-insulin ratio
compared with those who needed high AIR to maintain normoglycemia. These results
suggest that, in subjects with normal glucose tolerance, insulin resistance does
not induce increased proinsulin relative to insulin secretion, but rather is
associated with enhanced processing of proinsulin.
PMID- 9392486
TI - Oscillations in activities of enzymes in pancreatic islet subcellular fractions
induced by physiological concentrations of effectors.
AB - Glucose, the most potent insulin secretagogue, stimulates insulin secretion by
aerobic glycolysis, but other secretagogues stimulate insulin release exclusively
by mitochondrial metabolism. It is well known that in the intact pancreatic beta
cell, either kind of secretagogue can induce oscillations in metabolism (e.g.,
glycolysis, ATP/ADP, NAD(P)/NAD(P)H ratios) that occur with a periodicity similar
to oscillations in membrane electrical potential and insulin secretion. In this
study, pancreatic islet cytosol or mitochondrial fractions were incubated in the
presence of physiological concentrations of substrates. Repeated additions of
physiological effectors caused oscillations in the activities of the three
enzymes studied. Succinate dehydrogenase activity in islet mitochondrial extracts
was made to oscillate by adding oxaloacetate (5 micromol/l) to inhibit the
enzyme. The enzyme was reactivated by adding acetyl-CoA (3 micromol/l), which
combines with oxaloacetate in the citrate synthase reaction and lowers the
concentration of oxaloacetate, thus beginning another oscillation. Pyruvate
kinase activity was made to oscillate by adding fructose bisphosphate (10
micromol/l). Fructose bisphosphate was degraded to triose phosphates fairly
rapidly, and, as it was degraded, there was a parallel decrease in pyruvate
kinase activity. The enzyme was reactivated and made to oscillate with subsequent
additions of fructose bisphosphate. The mitochondrial glycerol phosphate
dehydrogenase was made to oscillate by adding EGTA to chelate calcium, which
activates the enzyme. When the concentration of free calcium was raised to >0.1
micromol/l by adding more calcium, the activity of the enzyme increased. Repeated
additions of chelator and calcium caused the enzyme activity to oscillate. The
results with these three enzymes and physiological concentrations of naturally
occurring effectors raise the possibility that the activities of not only these
enzymes but of numerous enzymes oscillate in vivo in response to levels of
allosteric effectors and substrates. If this is the case, pacemaker activity may
result from complex effects distributed across multiple regulatory sites in both
the cytosol and mitochondria, rather than from a single enzyme acting as a
primary pacemaker.
PMID- 9392487
TI - Localization and functional role of synaptotagmin III in insulin secretory
vesicles in pancreatic beta-cells.
AB - Pancreatic beta-cells secrete insulin by Ca2+-triggered exocytosis of insulin
containing large dense-core vesicles. Synaptotagmin is a Ca2+/phospholipid
binding protein and is a good candidate for the Ca2+ sensor for exocytosis of
synaptic vesicles in neurons. In the present study, we generated a polyclonal
antibody against synaptotagmin III, and found that synaptotagmin III
immunoreactivity was present at high levels in insulin-containing pancreatic
islet cells and insulin-secreting clonal MIN6 cells. In subcellular
fractionations of MIN6 cells, synaptotagmin III was recovered in the vesicular
fractions containing both insulin and vesicle-associated membrane protein-2 (VAMP
2), but not in synaptophysin-positive fractions. The secretory vesicles
immunoprecipitated by anti-VAMP-2 antibody contained synaptotagmin III and
insulin. In addition, treatment of streptolysin-O-permeabilized MIN6 cells with
anti-synaptotagmin III antibody significantly inhibited Ca2+-triggered insulin
secretion. These results indicate that synaptotagmin III is localized in insulin
containing dense-core vesicles in pancreatic beta-cells, and further strongly
suggest that synaptotagmin III is the Ca2+ sensor in the exocytosis of insulin
secretory vesicles.
PMID- 9392488
TI - Assessment of hepatic sensitivity to glucagon in NIDDM: use as a tool to estimate
the contribution of the indirect pathway to nocturnal glycogen synthesis.
AB - NIDDM is associated with excessive rates of endogenous glucose production in both
the postabsorptive and postprandial states. To determine whether this is due to
an intrinsic increase in hepatic sensitivity to glucagon, 9 NIDDM and 10
nondiabetic subjects were studied on three occasions. On each occasion, glycogen
was labeled the evening before the study with subjects ingesting meals containing
[6-3H]galactose. Beginning at 6:00 A.M. on the following morning, somatostatin
was infused to inhibit endogenous hormone secretion. Insulin concentrations were
maintained constant at basal levels (defined as that necessary to keep glucose at
approximately 5 mmol/l) in each individual. On one occasion, glucagon was infused
at a rate of 0.65 ng x kg(-1) x min(-1) throughout the experiment, resulting in
glucagon concentrations of approximately 130 pg/ml and a slow but comparable fall
in endogenous glucose production with time in both groups. On the other two
occasions, the glucagon infusion was increased at 10:00 A.M. to either 1.5 or 3.0
ng x kg(-1) x min(-1), resulting in an increase in glucagon concentrations to
approximately 180 and 310 pg/ml, respectively. The increment in endogenous
glucose production (i.e., area above basal) did not differ in diabetic and
nondiabetic subjects during either the 1.5 ng x kg(-1) x min(-1) (0.75 +/- 0.055
vs. 0.78 +/- 0.048 mmol/kg) or 3.0 ng x kg(-1) x min(-1) (1.06 +/- 0.066 vs. 1.10
+/- 0.073 mmol/kg) glucagon infusions. In contrast, the amount of [6-3H]glucose
released from glycogen was lower (P < 0.05) in the diabetic than nondiabetic
subjects during both glucagon infusions. The specific activity of glycogen,
calculated as the integrated release of [6-3H]glucose divided by the integrated
release of unlabeled glucose, was lower (P < 0.05) in diabetic subjects than in
nondiabetic subjects during both the 1.5 ng x kg(-1) x min(-1) (19.0 +/- 3.9 vs.
41.4 +/- 5.7 dpm/micromol) and 3.0 ng x kg(-1) x min(-1) (19.1 +/- 3.1 vs. 36.5
+/- 7.2 dpm/micromol) glucagon infusions, implying that a greater portion of the
glucose released from glycogen was derived from the indirect pathway. We
concluded that although NIDDM is not associated with an intrinsic alteration in
hepatic sensitivity to glucagon, it does alter the relative contributions of the
direct and indirect pathways to nocturnal glycogen synthesis.
PMID- 9392489
TI - Effects of insulin on blood flow and volume in skeletal muscle of patients with
IDDM: studies using [15O]H2O, [15O]CO, and positron emission tomography.
AB - Exaggerated vasoconstriction and blunted vasodilation of peripheral resistance
arteries to various vasoactive agents characterize patients with IDDM. We
characterized the hemodynamic effects of insulin in skeletal muscle in patients
with IDDM. Muscle blood flow and blood volume were measured basally and during a
high-dose insulin infusion (5 mU x kg(-1) x min[-1]) in seven normotensive
patients with IDDM (age, 30 +/- 6 years; BMI, 24.5 +/- 2.0 kg/m2; blood pressure,
124 +/- 12/78 +/- 11 mmHg) and nine matched normal subjects, using [15O]H2O,
[15O]CO, and positron emission tomography (PET). Whole-body insulin sensitivity
was determined using the euglycemic insulin clamp technique. Insulin-stimulated
whole-body glucose uptake was significantly lower in the patients with IDDM (45
+/- 15 micromol x kg(-1) x min[-1]) than in the normal subjects (62 +/- 14
micromol x kg(-1) x min[-1]) (P < 0.05). Insulin increased muscle blood flow by
111 +/- 69% above basal from 3.0 +/- 2.0 to 5.8 +/- 3.0 ml x 100 g(-1) muscle x
min(-1) (P < 0.005) in the normal subjects, but only by 42 +/- 30% from 2.0 +/-
0.9 to 2.9 +/- 1.4 ml x 100 g(-1) muscle x min(-1) (P < 0.005) in patients with
IDDM (P < 0.05 for change in flow in IDDM vs. normal subjects). The calculated
muscle vascular resistances were comparable basally, but higher during
hyperinsulinemia in the patients with IDDM (37 +/- 17 mmHg x 100 g x min x ml[
1]) than in the normal subjects (16 +/- 7 mmHg x 100 g x min x ml[-l]) (P <
0.05). Muscle blood volume increased significantly by insulin in both groups
without any difference between the groups. We conclude that the ability of
supraphysiological concentrations of insulin to stimulate muscle blood flow is
blunted in patients with IDDM, because of the inability of insulin to stimulate
linear flow velocity rather than blood volume in skeletal muscle. This defect
adds yet another defect to the list of abnormalities in vascular function in
IDDM, which might predispose these patients to develop hypertension.
PMID- 9392490
TI - Diet-induced muscle insulin resistance in rats is ameliorated by acute dietary
lipid withdrawal or a single bout of exercise: parallel relationship between
insulin stimulation of glucose uptake and suppression of long-chain fatty acyl
CoA.
AB - Chronic high-fat feeding in rats induces profound whole-body insulin resistance,
mainly due to effects in oxidative skeletal muscle. The mechanisms of this
reaction remain unclear, but local lipid availability has been implicated. The
aim of this study was to examine the influence of three short-term physiological
manipulations intended to lower muscle lipid availability on insulin sensitivity
in high-fat-fed rats. Adult male Wistar rats fed a high-fat diet for 3 weeks were
divided into four groups the day before the study: one group was fed the normal
daily high-fat meal (FM); another group was fed an isocaloric low-fat high
glucose meal (GM); a third group was fasted overnight (NM); and a fourth group
underwent a single bout of exercise (2-h swim), then were fed the normal high-fat
meal (EX). In vivo insulin action was assessed using the hyperinsulinemic glucose
clamp (plasma insulin 745 pmol/l, glucose 7.2 mmol/l). Prior exercise, a single
low-fat meal, or fasting all significantly increased insulin-stimulated glucose
utilization, estimated at either the whole-body level (P < 0.01 vs. FM) or in red
quadriceps muscle (EX 18.2, GM 28.1, and NM 19.3 vs. FM 12.6 +/- 1.1 micromol x
100 g(-1) x min(-1); P < 0.05), as well as increased insulin suppressibility of
muscle total long-chain fatty acyl-CoA (LC-CoA), the metabolically available form
of fatty acid (EX 24.0, GM 15.5, and NM 30.6 vs. FM 45.4 nmol/g; P < 0.05). There
was a strong inverse correlation between glucose uptake and LC-CoA in red
quadriceps during the clamp (r = -0.7, P = 0.001). Muscle triglyceride was
significantly reduced by short-term dietary lipid withdrawal (GM -22 and NM -24%
vs. FM; P < 0.01), but not prior exercise. We concluded that muscle insulin
resistance induced by high-fat feeding is readily ameliorated by three
independent, short-term physiological manipulations. The data suggest that
insulin resistance is an important factor in the elevated muscle lipid
availability induced by chronic high-fat feeding.
PMID- 9392491
TI - Leptin sensitivity in nonobese glucagon-like peptide I receptor -/- mice.
AB - Glucagon-like peptide I (GLP-I) stimulates glucose-dependent insulin secretion
and inhibits food intake in the central nervous system. Because leptin reduces
food intake but inhibits insulin secretion, we examined leptin action in mice
with a null mutation in the GLP-I receptor. Intracerebroventricular leptin
administration inhibited food intake in both wild-type and GLP-I receptor (GLP
IR) -/- mice, and daily intraperitoneal administration of leptin for 2 weeks
produced comparable reductions in food intake and body weight in control and GLP
IR -/- mice. Glucose tolerance was improved in both wild-type and GLP-IR -/-
mice, whether pair fed or leptin treated; however, blood sugars were
significantly lower in the leptin-treated GLP-IR -/- mice following oral glucose
challenge (P < 0.01). Glucose-stimulated insulin was reduced in both pair-fed and
leptin-treated mice (P < 0.01-0.001); however, insulin levels were significantly
lower in leptin-treated versus pair-fed GLP-IR -/- mice (P < 0.01). A single
leptin injection had no effect on glucose tolerance in GLP-IR -/- mice, but
decreased hepatic PEPCK mRNA in both wild-type and GLP-IR -/- mice. The
improvement in blood glucose excursion, despite lower levels of glucose
stimulated insulin in lean leptin-treated GLP-IR -/- mice, suggests that leptin
may have beneficial effects on control of blood glucose in the absence of
obesity. Furthermore, the greater effects of leptin on glucose and insulin in
leptin-treated versus pair-fed GLP-IR -/- mice raises the possibility that
disruption of GLP-I signaling modifies the sensitivity to leptin in vivo.
PMID- 9392492
TI - Leptin gene expression increases with age independent of increasing adiposity in
rats.
AB - Humans and rats tend to gain weight as they age. Leptin is one regulator of food
intake and energy expenditure. To determine if the increase in adiposity with age
is related to altered leptin gene expression, we assessed adiposity levels,
leptin mRNA levels in epididymal and inguinal white adipose tissue (EWAT and
IWAT), and uncoupling protein (UCP1) mRNA levels in interscapular brown adipose
tissue (IBAT) from F344 x BN rats ages 3, 12, 18, 24, and 30 months (n = 8/age).
Levels of adiposity determined by the adiposity index and the Lee index increased
between ages 3 and 24 months, with a decrease at age 30 months. There were
parallel increases with age in body weight, EWAT, and IWAT depot size up to age
24 months, followed by a nonsignificant decrease at age 30 months. Daily food
intake was unchanged with age. In EWAT, leptin mRNA per microgram of RNA was
unchanged with age, whereas in IWAT, it increased up to 24 months, then declined
at 30 months. Total leptin mRNA levels in both IWAT and EWAT depots increased
with age, peaking at age 24 months, and were correlated with adiposity. Serum
leptin levels increased with age, also peaking at age 24 months, and were
correlated with total leptin mRNA in WAT pads and adiposity. The rate of increase
in serum leptin was greater than the increase in adiposity with age, suggesting
contributions from both the increase in leptin expression per unit of WAT and the
increase in WAT depot size. In addition, UCP1 mRNA levels in IBAT did not change
with age. These data suggest that adiposity increases with age and cannot be
attributed to increased food intake, impaired leptin gene expression, or
decreased UCP1 mRNA level in IBAT. Furthermore, leptin gene expression in IWAT
increases with age independent of increasing adiposity.
PMID- 9392493
TI - Intracerebroventricular leptin increases lumbar and renal sympathetic nerve
activity and blood pressure in normal rats.
AB - Obesity and hyperinsulinism are known to be major stimuli of leptin production by
adipose tissue, leading to increased leptin levels in the circulation. It has
also been demonstrated that increased leptin production leads to satiety,
possibly by decreasing the levels of neuropeptide Y (NPY) in the central nervous
system (CNS). Because obesity and hyperinsulinism are also frequently associated
with hypertension, we studied the effect of the intracerebroventricular (ICV)
administration of leptin on mean arterial pressure (MAP), heart rate, vascular
flows, and lumbar and renal sympathetic nerve activity (SNA). Normal Wistar rats
were implanted with an ICV cannula and allowed to recover. On the day of the
study, the animals were fasted and anesthetized with chloralose/urethane.
Catheters were placed in a femoral artery and vein, and Doppler flow probes were
placed around the iliac, renal, and superior mesenteric arteries for measurement
of MAP, heart rate, and blood flows. In other experiments, lumbar SNA and renal
SNA were recorded. ICV leptin administration resulted in an MAP that was slowly
but progressively increasing. Blood flows decreased in the iliac and superior
mesenteric arteries, but not in the renal artery. Leptin injection increased the
lumbar SNA and renal SNA. The plasma glucose and insulin levels were not changed.
We concluded that ICV leptin increases MAP by decreasing arterial blood flow to
the skeletal muscle and the splanchnic vascular bed. This increased peripheral
resistance is the result of an increased activity of the sympathetic nerves. We
suggest that increased leptin may serve as a link in the triad of obesity and
hyperinsulinism and hypertension.
PMID- 9392494
TI - Method of insulin administration has no effect on insulin sensitivity estimates
from the insulin-modified minimal model protocol.
AB - The effect of the method of insulin administration on insulin sensitivity
estimates from the insulin modified minimal model (MINMOD) protocol was evaluated
using the tolbutamide-boosted protocol as a reference. The study included 21
nondiabetic men ages 40 +/- 2 years (mean +/- SE) with a BMI of 26.6 +/- 1.1
kg/m2. Each subject underwent four frequently sampled intravenous glucose
tolerance tests (FSIGTT), one with tolbutamide and three with the same insulin
dosage (0.03 U/kg) given as a bolus or infusion over 5 or 10 min. The insulin
sensitivity index (SI) of each subject was calculated from each FSIGTT with
MINMOD. Insulin sensitivity indexes from the four FSIGTTs were highly correlated
(r > 0.85, P < 0.001). SI(insulin) from the bolus and the 5- and 10-min infusion
protocols were similar, but were 21 +/- 5, 29 +/- 5, and 23 +/- 4% lower than
SI(tolbutamide), respectively. SG(tolbutamide) and SG(insulin) were not different
among the four protocols and were significantly correlated (r > 0.55, P < 0.01).
Thus the tolbutamide and insulin protocols must not be used interchangeably in
any single cross-sectional or longitudinal study. When the same insulin dosage is
used, the method of its administration has no bearing on insulin sensitivity
estimates from the insulin-modified FSIGTT. The same method of insulin
administration should be used, however, in any single study for purpose of
standardization.
PMID- 9392496
TI - Impaired molecular regenerative responses in sensory neurones of diabetic rats:
gene expression changes in dorsal root ganglia after sciatic nerve crush.
AB - This study investigated changes in gene expression in lumbar dorsal root ganglia
(DRG), contralateral and ipsilateral to a sciatic nerve crush in control and
streptozotocin (STZ)-induced diabetic rats. After 10 weeks of diabetes, the left
sciatic nerves of all rats were crushed at mid-thigh level, and the rats were
maintained for a further 2 weeks. Northern blots, with internal standards, were
made from L4 and L5 (pooled) DRG on each side to compare RNA hybrids from ganglia
attached to crushed nerves with those attached to intact nerves. The expression
of growth-associated proteins, GAP-43 and Talpha1 alpha-tubulin mRNA in DRG, was
stimulated (all P < 0.05) by crush injury in control and diabetic rats. Steady
state expression of transcripts for neurofilament (NF) proteins (NF-L, NF-H) and
the high-affinity NGF receptor, trkA was decreased by diabetes in the
contralateral ganglia to the crush (all P < 0.05). Crush injury further decreased
expression of these transcripts in both control and diabetic rats (all P < 0.05).
This reduced expression of mRNA coding for both growth-associated proteins, and
neurofilament proteins in ganglia of diabetic rats could participate in the
reduced competence of the regenerative response to nerve crush.
PMID- 9392495
TI - Induction of renal kallikrein and renin gene expression by insulin and IGF-I in
the diabetic rat.
AB - The renal kallikrein-kinin system and the renin-angiotensin system are implicated
in the pathogenesis of diabetic nephropathy. We have shown that renal kallikrein
and renin gene expression are altered by diabetes. To investigate the cellular
mechanisms responsible for these changes, we examined the effects of acute
insulin and insulin-like growth factor I (IGF-I) treatment on renal kallikrein
kinin and renin-angiotensin system components. Three weeks after induction of
diabetes, we measured renal kallikrein and renin mRNA levels, renal kallikrein
and renal renin activity, and plasma renin activity in control and diabetic rats
and diabetic rats treated with insulin or IGF-I for 2 or 5 h. In diabetic rats,
kallikrein and renin mRNA levels were reduced >50% compared with control rats.
Renal tissue kallikrein levels and plasma renin activity were decreased, whereas
renal renin content was unchanged. Insulin increased kallikrein and renin mRNA
levels after 2 h. IGF-I, at a dosage that stimulated kallikrein mRNA levels in
control rats, had no effect on renal kallikrein and renin content or mRNA levels
in diabetic rats. However, infusion of a fivefold higher IGF-I dosage resulted in
a two- to threefold increase in kallikrein and renin mRNA levels in 2 h. These
data suggest that 1) diabetes suppresses kallikrein and renin gene expression,
and these abnormalities are reversed by insulin or IGF-I; and 2) the diabetic
state produces resistance to IGF-I induction of kallikrein and renin gene
expression. These changes in regulated synthesis of kallikrein and renin in the
kidney may underlie renal vascular changes that develop in diabetes.
PMID- 9392497
TI - Hyperinsulinemia and abdominal obesity affect the expression of
hypertriglyceridemia in heterozygous familial lipoprotein lipase deficiency.
AB - We have reported three missense mutations (G188E, P207L, and D250N) in the
lipoprotein lipase (LPL) gene among French-Canadians, resulting in the absence of
measurable postheparin plasma LPL activity in homozygotes. Presence of
triglyceride- and cholesterol-rich VLDL, as well as cholesterol-poor HDL
particles, has been shown in heterozygotes affected by partial reduction in
postheparin LPL activity. However, significant heterogeneity in their plasma
triglyceride levels has been found, even among individuals carrying the same LPL
gene mutation, indicating that factors other than LPL deficiency could affect the
phenotypic expression of hypertriglyceridemia in the heterozygous state. The aim
of the present study was to examine the combined effects of abdominal fat
accumulation and hyperinsulinemia on plasma triglyceride levels among
heterozygous patients for familial LPL deficiency. Based on sex and BMI, 43
heterozygotes (25 women and 18 men) were matched with noncarrier control
subjects. Our data indicate that heterozygotes with higher abdominal fat
deposition, as defined as waist girth values above the 50th percentile, had
higher plasma triglyceride levels than nonobese heterozygotes. However, an
important proportion of male heterozygote subjects were hypertriglyceridemic,
even in absence of abdominal obesity, suggesting that another factor(s) was
involved in the modulation of hypertriglyceridemia in these subjects. Indeed,
multivariate analyses revealed that fasting hyperinsulinemia was a significant
correlate of hypertriglyceridemia among these heterozygotes. Results of the
present study indicate that abdominal obesity and hyperinsulinemia both have
deleterious effects on plasma triglyceride levels in familial LPL deficiency. It
is suggested that heterozygotes with moderate obesity and/or insulin resistance
may be at higher risk of coronary artery disease because of the expression of an
atherogenic lipoprotein phenotype among these patients.
PMID- 9392498
TI - Altered platelet membrane dynamic properties in type 1 diabetes.
AB - A modified platelet response to aggregating stimuli is supposed to play a role in
the pathogenesis of diabetic macroangiopathy. We studied the fluidity and
microheterogeneity of the external surface of the platelet membrane and the
activities of the plasma membrane Na+-K+-ATPase and Ca2+-ATPase in 21 men with
type 1 diabetes and in 20 control subjects before and after in vitro thrombin
addition. In the resting state, platelets from type 1 diabetic patients showed an
increased fluidity and microheterogeneity of the platelet membrane, a higher Ca2+
ATPase activity, and a reduced Na+-K+-ATPase activity in comparison with
platelets from healthy subjects. The fatty acid composition was also modified,
with increased C 16:1 and decreased C 18:0 content. Control cells incubated with
thrombin showed a modification of the membrane parameters opposite to the
response observed in type 1 cells after the stimulation. The incubation of
control platelets in the resting state with high concentrations of glucose
modified the fluidity of the plasma membrane Na+-K+-ATPase and Ca2+-ATPase
activities in an opposite way in comparison with the alterations observed in type
1 platelets. This study suggests that in type 1 diabetic patients, the platelet
membrane responds to activation with a molecular remodeling different from the
response of healthy subjects. The abnormal organization of the membrane might
contribute to the altered platelet functions in type 1 diabetic patients, but
acute exposure to high glucose levels does not seem able to modify the platelet
membrane in the way observed in type 1 diabetes.
PMID- 9392499
TI - Increased expression of intercellular adhesion molecule-1 (ICAM-1) in diabetic
rat glomeruli: glomerular hyperfiltration is a potential mechanism of ICAM-1
upregulation.
AB - Mononuclear cells, including monocytes/macrophages and T-cells, are considered to
be involved in the progression of diabetic nephropathy, although the mechanism of
their recruitment into diabetic glomeruli is unclear. The intercellular adhesion
molecule-1 (ICAM-1) promotes the infiltration of leukocytes into atherosclerotic
lesions as well as inflammatory tissues. In the present study, we investigated
the expression of ICAM-1 in the glomeruli of streptozotocin-induced diabetic
rats. The expression of ICAM-1 was increased significantly during the early stage
of diabetes. The number of mononuclear cells, primarily monocytes/macrophages and
lymphocytes, was significantly increased in diabetic glomeruli. Mononuclear cell
infiltration into diabetic glomeruli was prevented by anti-ICAM-1 monoclonal
antibody. Insulin treatment decreased ICAM-1 expression and mononuclear cell
infiltration. The ICAM-1 expression on cultured human umbilical vein endothelial
cells was not induced under high glucose culture conditions. Glomerular
hyperfiltration is a characteristic change in the early stage of diabetic
nephropathy. Treatment with aldose reductase inhibitor, which prevented
glomerular hyperfiltration without changes in blood glucose levels, decreased
ICAM-1 expression and mononuclear cell infiltration. Moreover, we examined the
ICAM-1 expression in the glomeruli of the 5/6 nephrectomized rat, which is a
model for glomerular hyperfiltration without hyperglycemia. The ICAM-1 expression
and infiltration of mononuclear cells was significantly increased in the
glomeruli of 5/6 nephrectomized rats. We conclude that ICAM-1 is upregulated and
promotes the recruitment of mononuclear cells in diabetic glomeruli. Moreover,
glomerular hyperfiltration that occurs in the early stage of diabetic glomeruli
may be one of the potential mechanisms of ICAM-1 upregulation in diabetic
nephropathy.
PMID- 9392500
TI - Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL
cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1
diabetes.
AB - The TaqIB cholesteryl ester transfer protein (CETP) gene polymorphism (B1B2) is a
determinant of HDL cholesterol in nondiabetic populations. Remarkably, this gene
effect appears to be modified by environmental factors. We evaluated the effect
of this polymorphism on HDL cholesterol levels and on the lipoprotein response to
a linoleic acid-enriched, low-cholesterol diet in patients with type 1 diabetes.
In 44 consecutive type 1 diabetic patients (35 men), CETP polymorphism,
apolipoprotein (apo) E genotype, serum lipoproteins, serum CETP activity
(measured with an exogenous substrate assay, n = 30), clinical variables, and a
diet history were documented. The 1-year response to diet was assessed in 14 type
1 diabetic patients, including 6 B1B1 and 6 B1B2 individuals. HDL cholesterol was
higher in 10 B2B2 than in 14 B1B1 homozygotes (1.63 +/- 0.38 vs. 1.24 +/- 0.23
mmol/l, P < 0.01). HDL cholesterol, adjusted for triglycerides and smoking, was
0.19 mmol/l higher for each B2 allele present. CETP activity levels were not
significantly different between CETP genotypes. Multiple regression analysis
showed that VLDL + LDL cholesterol was associated with dietary
polyunsaturated:saturated fatty acids ratio (P < 0.02) and total fat intake (P <
0.05) in the B1B1 homozygotes only and tended to be related to the presence of
the apo E4 allele (P < 0.10). In response to diet, VLDL + LDL cholesterol fell (P
< 0.05) and HDL cholesterol remained unchanged in 6 B1B1 homozygotes. In
contrast, VLDL + LDL cholesterol was unaltered and HDL cholesterol decreased (P <
0.05) in 6 B1B2 heterozygotes (P < 0.05 for difference in change in VLDL +
LDL/HDL cholesterol ratio). This difference in response was unrelated to the apo
E genotype. Thus, the TaqIB CETP gene polymorphism is a strong determinant of HDL
cholesterol in type 1 diabetes. This gene effect is unlikely to be explained by a
major influence on the serum level of CETP activity, as an indirect measure of
CETP mass. Our preliminary data suggest that this polymorphism may be a marker of
the lipoprotein response to dietary intervention.
PMID- 9392501
TI - Pyruvate improves deleterious effects of high glucose on activation of pentose
phosphate pathway and glutathione redox cycle in endothelial cells.
AB - In our previous study (Diabetes 44:520-526, 1995), endothelial cells cultured in
high glucose condition showed impairment of an oxidant-induced activation of the
pentose phosphate pathway (PPP) and a reduced supply of NADPH to the glutathione
redox cycle. To gain insight into the mechanisms of this impairment, the
protective effect of pyruvate was studied in human umbilical vein endothelial
cells cultured in either 5.5 mmol/l glucose (normal glucose [NG] condition) or 33
mmol/l glucose (high glucose [HG] condition). Through pretreatment of cells with
0.2 mmol/l pyruvate for 5-7 days in the HG condition, glucose oxidation through
the PPP and total cellular NADPH content in the presence of 0.2 mmol/l H2O2 were
increased by 54 (P < 0.05) and 34%, respectively, and glutathione-dependent
degradation of H2O2 in HG cells was enhanced by 41% (P < 0.01), when compared
with those cells to which pyruvate was not added. The addition of pyruvate
significantly reduced the fructose 1,6-bisphosphate (FDP) content and free
cytoplasmic NADH/NAD ratio, estimated by increased pyruvate/lactate ratio in NG
and HG cells exposed to H2O2. Furthermore, the addition of pyruvate also showed a
46% reduction (P < 0.01) of endothelial cell damage induced by H2O2 in HG cells.
These results indicate that abnormalities in PPP activation and glutathione redox
cycle activity induced by H2O2 in HG cells are compensated, and that the
accentuated reductive stress is improved by an addition of pyruvate. These
pyruvate effects are associated with protection against an oxidant-induced
endothelial cell injury in the high glucose condition.
PMID- 9392502
TI - Circulating vascular cell adhesion molecule-1 (VCAM-1) in atherosclerotic NIDDM
patients.
AB - Vascular cell adhesion molecule-1 (VCAM-1) has been shown to be highly expressed
in atherosclerotic lesions. Although the soluble form of VCAM-1 (sVCAM-1) is
detected in human sera, the relation between the degree of atherosclerosis and
serum sVCAM-1 level has not been defined. In the present study, sVCAM-1
concentrations were measured in sera from 101 Japanese NIDDM patients. The mean
+/- SD serum sVCAM-1 concentration in 26 patients with symptomatic
atherosclerotic vascular diseases (789 +/- 187 ng/ml) was higher than that in 75
patients without the disease (664 +/- 175 ng/ml). Among the 101 NIDDM patients,
56 had atherosclerotic change of the carotid arteries, based on the evaluation by
high-resolution B-mode ultrasonography. Their sVCAM-1 level was 759 +/- 201
ng/ml, higher than that in 45 patients without any detectable atherosclerosis of
the carotid arteries (619 +/- 130 ng/ml). In addition, there was a positive
correlation between sVCAM-1 concentration and thickness of the intimal plus
medial complex (IMT) of the carotid arteries in the NIDDM patients (r = 0.41, P <
0.0001). Multivariate regression analysis revealed significant predictors of mean
IMT value to be sVCAM-1 concentration (F = 62.88, P = 0.0001) and age (F = 9.59,
P = 0.0026). By contrast, sVCAM-1 concentration was not increased in nondiabetic
patients with atherosclerotic change of the carotid arteries (668 +/- 191 ng/ml;
n = 36) compared with those without the atherosclerotic change (632 +/- 177
ng/ml; n = 28), and there was no correlation between sVCAM-1 level and IMT of the
carotid arteries in the nondiabetic subjects. These results indicate that
circulating sVCAM-1 may be a marker of atherosclerotic lesions in NIDDM patients
with symptomatic and asymptomatic atherosclerosis.
PMID- 9392503
TI - Association of methylenetetrahydrofolate reductase gene polymorphism with carotid
arterial wall thickening and myocardial infarction risk in NIDDM.
PMID- 9392504
TI - Uncoupling protein 2 region on chromosome 11q13 is not linked to markers of
obesity in familial type 2 diabetes.
PMID- 9392505
TI - An automated fluorescent single-strand conformation polymorphism technique for
screening mutations in the hepatocyte nuclear factor-1alpha gene (maturity-onset
diabetes of the young).
PMID- 9392506
TI - Improved glucose tolerance restores insulin-stimulated Akt kinase activity and
glucose transport in skeletal muscle from diabetic Goto-Kakizaki rats.
AB - The serine/threonine kinase Akt (protein kinase B [PKB] or related to A and C
protein kinase [RAC]) has recently been implicated to play a role in the
signaling pathway to glucose transport. However, little is known concerning the
regulation of Akt activity in insulin-sensitive tissues such as skeletal muscle.
To explore the role of hyperglycemia on Akt kinase activity in skeletal muscle,
normal Wistar rats or Goto-Kakizaki (GK) diabetic rats were treated with
phlorizin. Phlorizin treatment normalized fasting blood glucose and significantly
improved glucose tolerance (P < 0.001) in GK rats, whereas in Wistar rats, the
compound had no effect on glucose homeostasis. In soleus muscle from GK rats,
maximal insulin-stimulated (120 nmol/l) Akt kinase activity was reduced by 68% (P
< 0.01) and glucose transport was decreased by 39% (P < 0.05), compared with
Wistar rats. Importantly, the defects at the level of Akt kinase and glucose
transport were completely restored by phlorizin treatment. There was no
significant difference in Akt kinase protein expression among the three groups.
At a submaximal insulin concentration (2.4 nmol/l), activity of Akt kinase and
glucose transport were unaltered. In conclusion, improved glucose tolerance in
diabetic GK rats by phlorizin treatment fully restored insulin-stimulated
activity of Akt kinase and glucose transport. Thus, hyperglycemia may directly
contribute to the development of muscle insulin resistance through alterations in
insulin action on Akt kinase and glucose transport.
PMID- 9392507
TI - Thiazolidinediones downregulate stearoyl-CoA desaturase 1 gene expression in 3T3
L1 adipocytes.
AB - Thiazolidinediones (TZDs) are known to have potent increases of insulin
sensitivity. Because peroxisome proliferator-activated receptor-gamma (PPAR
gamma), a receptor for TZDs, is mainly expressed in adipocytes, we tried to
search the TZD-targeted genes in mouse 3T3-L1 adipocytes. By the mRNA
differential display method, one band repressed by troglitazone was obtained,
which corresponded to the partial sequences of the stearoyl-CoA desaturase 1
(SCD1) gene. Troglitazone dramatically decreased SCD1 mRNA levels in 3T3-L1
adipocytes in a dose-dependent manner. Pioglitazone also repressed the SCD1 mRNA
expression, whereas WY-14,643 had no apparent effect. Both troglitazone and
pioglitazone raised the composition (weight percentage) of myristic acid (C14:0),
palmitic acid (C16:0), and stearic acid (C18:0), but lowered the composition of
the delta9-cis desaturated fatty acids such as myristoleic acid (C14:1, delta9),
palmitoleic acid (C16:1, delta9), oleic acid (C18:1, delta9), and linoleic acid
(C18:2, delta9,12). These results indicate that TZDs repress SCD1 activity in 3T3
L1 adipocytes via downregulating SCD1 enzyme gene expression.
PMID- 9392508
TI - Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral
arcuate nucleus.
AB - Melanocortins are peptides, cleaved from the pro-opiomelanocortin (POMC)
precursor, that act in the brain to reduce food intake and are potential
mediators of leptin action. In the forebrain, melanocortins are derived from POMC
containing neurons of the hypothalamic arcuate nucleus. To test the hypothesis
that these POMC neurons are regulated by leptin, we used in situ hybridization to
determine whether reduced leptin signaling (as occurs in fasting), genetic leptin
deficiency (in obese ob/ob mice), or genetic leptin resistance (in obese db/db
mice) lower expression of POMC mRNA. We further hypothesized that leptin
administration would raise hypothalamic POMC mRNA levels in leptin-deficient
animals, but not in mice with defective leptin receptors. In wild-type mice (n =
12), fasting for 48 h lowered POMC mRNA levels in the rostral arcuate nucleus by
53%, relative to values in fed controls (n = 8; P < 0.001). Similarly, arcuate
nucleus POMC mRNA levels were reduced by 46 and 70% in genetically obese ob/ob (n
= 6) and db/db mice (n = 6), respectively, as compared with wild-type mice (n =
5) (P < 0.01 for both comparisons). Five daily intraperitoneal injections of
recombinant murine leptin (150 microg) raised levels of POMC mRNA in the rostral
arcuate nucleus of ob/ob mice (n = 8) by 73% over saline-treated ob/ob control
values (n = 8; P < 0.01), but was without effect in db/db mice (n = 6). In normal
rats, two injections of a low dose of leptin (3.5 microg) into the third cerebral
ventricle (n = 15) during a 40-h period of fasting also increased POMC mRNA
levels in the rostral arcuate nucleus to values 39% greater than those in vehicle
treated controls (n = 14; P = 0.02). We conclude that reduced central nervous
system leptin signaling owing to fasting or to genetic defects in leptin or its
receptor lower POMC mRNA levels in the rostral arcuate nucleus. The finding that
leptin reverses this effect in ob/ob, but not db/db, mice suggests that leptin
stimulates arcuate nucleus POMC gene expression via a pathway involving leptin
receptors. These findings support the hypothesis that leptin signaling in the
brain involves activation of the hypothalamic melanocortin system.
PMID- 9392509
TI - Harold Rifkin, MD. 1916-1997.
PMID- 9392510
TI - Signalling networks regulating dental development.
AB - There has been rapid progress recently in the identification of signalling
pathways regulating tooth development. It has become apparent that signalling
networks involved in Drosophila development and development of mammalian organs
such as the limb are also used in tooth development. Teeth are epithelial
appendages formed in the oral region of vertebrates and their early developmental
anatomy resembles that of other appendages, such as hairs and glands. The neural
crest origin of tooth mesenchyme has been confirmed and recent evidence suggests
that specific combinations of homeobox genes expressed in the neural crest cells
may regulate the types of teeth and their patterning. Signalling molecules in the
Shh, FGF, BMP and Wnt families appear to regulate the early steps of tooth
morphogenesis and some transcription factors associated with these pathways have
been shown to be necessary for tooth development. Several of the conserved
signals are also transiently expressed in the enamel knots in the dental
epithelium. The enamel knots are associated with the characteristic epithelial
folding morphogenesis which is responsible for the development of tooth shape and
it is currently believed that the enamel knots function as signalling centres
regulating tooth shape development. The developing tooth has proven to be an
excellent model in studies of the molecular basis of patterning and morphogenesis
of organs and it can be expected that continuing studies will rapidly increase
the understanding of these mechanisms.
PMID- 9392511
TI - Nerve-induced disruption and reformation of beta1-integrin aggregates during
development of the neuromuscular junction.
AB - The earliest biochemical change detected during synaptogenesis is a local
elimination of muscle basal lamina proteins. To explore whether this provides
signal(s) that regulate postsynaptic differentiation, we examined the effects of
innervation on the distribution of beta1-integrins, which were initially present
in scattered aggregates complexed with basal lamina ligands. These beta1-integrin
aggregates disappear along paths of nerve contact as their basal lamina ligands
are eliminated. New accumulations of these proteins then form during assembly of
the postsynaptic apparatus. The new beta1-integrin aggregates at developing
synapses form partly via a redistribution of mobile molecules on muscle surface.
We thus consider whether (a) the removal of integrins' basal lamina ligands
alters their cytoplasmic ligand-interactions, causing the dissociation of
integrin clusters, and (b) this receptor modulation helps to transduce local
changes in pericellular protease activity into cytoplasmic signals that control
postsynaptic differentiation.
PMID- 9392512
TI - Cloning and characterization of cDNAs encoding the integrin alpha2 and alpha3
subunits from Xenopus laevis.
AB - Integrins containing the alpha2 and alpha3 subunits associate with the beta1
subunit to form distinct receptors with partially overlapping adhesive
specificities. We report the cloning and sequence of cDNAs that encode the
Xenopus orthologues of integrins alpha2 and alpha3 and the expression of these
subunits during embryogenesis. Integrin alpha2 and alpha3 mRNAs are first
expressed in the dorsal mesoderm and developing notochord at gastrulation. We
also show that alpha3 mRNAs are expressed in the entire marginal zone of
gastrulae dorsalized with LiCl but that this localization is lost in embryos
ventralized by ultraviolet light. Immunoblots reveal that the alpha3 protein is
expressed throughout early development, however, the alpha2 protein is not
detected until late tailbud stages. Injection of full-length alpha3 transcripts
into the animal poles of fertilized eggs results in embryonic defects in paraxial
mesoderm attributed to the failure of somites to form segments. Injection of the
alpha3 transcripts into the vegetal pole and overexpression of a 5'-truncated
alpha3 control construct have no apparent affect on development or somite
formation. These data suggest that normal position-specific expression of
integrins is important in maintaining the proper organization of tissues during
early amphibian morphogenesis.
PMID- 9392513
TI - Regulation of the CRABP-I gene during mouse embryogenesis.
AB - The cellular retinoic acid binding protein type I (CRABP-I) shows a highly
specific expression pattern during mouse embryonic development. The tissues that
express CRABP-I, i.e. the central nervous system (CNS), neural crest, branchial
arches, limb bud and frontonasal mass, coincide with those that are most
sensitive to unphysiological retinoic acid (RA) concentrations. We have
investigated the transcriptional elements that are responsible for the
spatiotemporal regulation of CRABP-I expression in the mouse embryo. We show here
that a 16 kb fragment harbours all the elements needed for the correct
spatiotemporal expression pattern. Upon further dissection of this fragment we
have found that expression in the CNS is driven by elements in the upstream
region of the gene, while expression in mesenchymal and neural crest tissue is
regulated via element(s) located downstream of exon II of the gene. Two distinct
fragments in the upstream region are required for expression in the CNS, as
neither of these fragments alone is able to drive correct expression of a
reporter gene in transgenic mice. DNAseI footprinting analysis of the two
upstream fragments revealed the presence of a number of protected elements. One
of these regulatory elements has the hallmarks of an RA response element,
suggesting that CRABP-I expression in neural tissue can be directly modulated by
RA via the RARs/RXRs.
PMID- 9392514
TI - The SpHE gene is downregulated in sea urchin late blastulae despite persistence
of multiple positive factors sufficient to activate its promoter.
AB - Previous studies of the regulatory region of the SpHE (hatching enzyme) gene of
the sea urchin Strongylocentrotus purpuratus (Wei, Z., Angerer, L.M., Gagnon,
M.L. and Angerer, R.C. (1995) Characterization of the SpHE promoter that are
spatially regulated along the animal-vegetal axis of the sea urchin embryo. Dev.
Biol. 171, 195-211) have shown that approximately 330 bp is necessary and
sufficient to promote high level expression in embryos of transgenes that
reproduce the spatially asymmetric pattern of endogenous gene activity along the
maternally determined animal-vegetal embryonic axis. Furthermore, SpHE regulatory
elements appear to be redundant since several different combinations are
sufficient to elicit strong promoter activity and many subsets function like the
endogenous gene only in non-vegetal cells of the blastula (Wei, Z., Angerer, L.M.
and Angerer, R.C. (1997) Multiple positive cis-elements regulate the asymmetric
expression of the SpHE gene along the sea urchin embryo animal-vegetal axis. Dev.
Biol., 187, 71-88). Here we demonstrate by in vivo footprinting that many cis
elements on the endogenous promoter are occupied when the gene is active in early
blastulae, but the binding of corresponding trans factors is significantly
reduced when the gene becomes inactive in late blastulae. In addition,
downregulation of the promoter is accompanied by a transition from a non
nucleosomal to a nucleosome-like chromatin structure. Surprisingly, in vitro
DNase I footprints of the 300 bp promoter using nuclear protein extracts from
early and late blastulae are not detectably different and neither this sequence,
nor a longer one extending to -1255, reproduces the loss of endogenous SpHE
transcriptional activity after very early blastula stage. These observations
imply that temporal repression of SpHE transcription involves a decrease in
accessibility of the promoter to activators that are nevertheless present in
nuclei and capable of activating transgene promoters. Temporal, but not spatial,
downregulation is therefore likely to be regulated by negative activities
functioning outside the -1255 promoter region which may serve as direct
repressors or mediate an inactive chromatin structure.
PMID- 9392515
TI - The characterization of novel Pax genes of the sea urchin and Drosophila reveal
an ancient evolutionary origin of the Pax2/5/8 subfamily.
AB - The developmental control genes of the Pax family can be grouped into different
subclasses according to structure and sequence homology. Here we describe the
isolation and characterization of three novel Pax genes of the sea urchin for
which no homologues are yet known in other animal phyla. One of these genes,
suPaxB, codes for the previously characterized transcription factor TSAP which is
involved in the developmental regulation of two pairs of late histone genes.
Furthermore, conserved members of the Pax2/5/8 subfamily, which have so far been
described only in vertebrates, were isolated not only from the sea urchin, but
also from Drosophila and C. elegans. Hence, the Pax2/5/8 transcription factors
constitute an ancient subfamily of highly conserved Pax proteins. During
Drosophila embryogenesis, the Pax258 gene is shown to be expressed in the
precursor cells of the external sensory organs, thus suggesting a role for Pax258
in the early development of the peripheral nervous system of insects.
PMID- 9392516
TI - Synergism between temporally distinct growth factors: bFGF, insulin and lens cell
differentiation.
AB - Fibroblast growth factors (FGFs) are the only known factors that can induce
differentiation of the mammalian lens epithelial cell, while insulin acts only as
a mitogen, not as a morphogen. We show here that insulin enhances expression of
the alphaA-crystallin gene in lens epithelial cells and induces the synthesis of
lens fibre cell specific betaB2- and gamma-crystallins in early differentiated
fibre cells. Different signal transduction pathways are required for bFGF or
insulin maintained fibre cell differentiation. A 15 min preincubation with bFGF
was sufficient for the lens epithelial cells to become competent to undergo
insulin maintained differentiation. The phorbol ester TPA could replace bFGF. The
bFGF instructed competence to differentiate decays with a half-life of about 30
h. Hence, bFGF and insulin can act in concert to produce a differentiated
phenotype even when they are not present simultaneously.
PMID- 9392517
TI - Wing surface interactions in venation patterning in Drosophila.
AB - The adult wing of Drosophila consists of two wing surfaces apposed by their basal
membranes which first came into contact following disc eversion at metamorphosis.
Veins appear in these surfaces in a dorsal-ventral symmetric pattern, but are
'corrugated' (vein cells are more compacted and more pigmented) in a dorsal
ventral asymmetric pattern. We prevented dorsal-ventral contact apposition during
wing imaginal disc morphogenesis by implanting fragments of discs into
metamorphosing hosts. In these implants, longitudinal veins differentiate but
with wider corrugation and in both surfaces. These results and those of genetic
mosaics of mutants removing veins or causing ectopic veins reveal mutual dorso
ventral induction/inhibition at work to modulate the final vein differentiation
pattern and corrugation.
PMID- 9392518
TI - Progesterone acts through protein kinase C to remodel the cytoplasm as the
amphibian oocyte becomes the fertilization-competent egg.
AB - The fertilization-competent Xenopus egg undergoes a contraction of its cortex
towards the apex of the pigmented animal hemisphere within 10 min of
fertilization. Evidence suggests that protein kinase C (PKC) is involved in the
assembly of this contractile network and we show that PKC is rapidly activated as
a result of exposure of oocytes to progesterone. Xenopus oocytes contain at least
five different isotypes of PKC. Three actin-binding proteins (i.e. vinculin,
talin and ankyrin) appear to play an early role in the assembly of the
contractile network and one of the proteins (vinculin) becomes phosphorylated
shortly after progesterone treatment as the contractile network is assembling.
Our results indicated that progesterone acts through a phospholipase to activate
PKC and that PKC participates in the remodeling of the cytoplasmic compartment as
the oocyte becomes the egg.
PMID- 9392519
TI - Analysis of a cDNA sequence encoding a novel member of the snake venom
metalloproteinase, disintegrin-like, cysteine-rich (MDC) protein family from
Agkistrodon contortrix laticinctus.
AB - In this paper, we present a cDNA sequence encoding a full-length precursor form
of a new member (ACLD) of the metalloproteinase-disintegrin-like protein family
from the venom glands of Agkistrodon contortrix laticinctus (broad-banded
copperhead) snake. Comparison of the deduced amino acid sequence of ACLD with
those of other members of the metalloproteinase-disintegrin protein family from
both mammalian and snake venom origin suggests that some conserved residues may
be involved in processing of the disintegrin domain.
PMID- 9392520
TI - Fungal riboflavin 5'-hydroxymethyl dehydrogenase catalyzes formation of both the
aldehyde (riboflavinal) and the acid (riboflavinoic acid).
AB - The purified enzyme from Schizophyllum commune that readily catalyzes the
oxidation of the 5'-hydroxymethyl function of riboflavin (vitamin B2) with a
redox dye and O2 to form the 5'-aldehyde can more slowly further oxidize the 5'
aldehyde to the 5'-acid. Hence, the formation of these so-called 'schizoflavins'
can be accounted for by the action of one enzyme.
PMID- 9392521
TI - Psychrophilic enzymes: a thermodynamic challenge.
AB - Psychrophilic microorganisms, hosts of permanently cold habitats, produce enzymes
which are adapted to work at low temperatures. When compared to their mesophilic
counterparts, these enzymes display a higher catalytic efficiency over a
temperature range of roughly 0-30 degrees C and a high thermosensitivity. The
molecular characteristics of cold enzymes originating from Antarctic bacteria
have been approached through protein modelling and X-ray crystallography. The
deduced three-dimensional structures of cold alpha-amylase, beta-lactamase,
lipase and subtilisin have been compared to their mesophilic homologs. It appears
that the molecular adaptation resides in a weakening of the intramolecular
interactions, and in some cases in an increase of the interaction with the
solvent, leading to more flexible molecular edifices capable of performing
catalysis at a lower energy cost.
PMID- 9392522
TI - Carboxyl terminal deletion analysis of tryptophan hydroxylase.
AB - Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step in the synthesis of
serotonin and participates (in a non-rate-limiting fashion) in melatonin
biosynthesis. In rabbit, TPH exists as a tetramer of four identical 51007 dalton
(444 amino acids) protein subunits. An intersubunit binding domain responsible
for tetramer formation of TPH was identified by assessing the role of a carboxyl
terminal leucine heptad and 4-3 hydrophobic repeat. These repeats are conserved
in all of the aromatic amino acid hydroxylases and have been shown to be required
for the assembly of tyrosine hydroxylase tetramers. Polymerase chain reaction was
utilized to create three TPH carboxyl terminal deletions (C delta8, C delta12 and
C delta17) that sequentially remove members of the leucine heptad and 4-3
hydrophobic repeat. Each deletion and full-length recombinant TPH was expressed
in bacteria to obtain soluble enzyme extracts for subsequent activity and
structural analysis. It was found that removal of 8, 12 or 17 amino acids from
the carboxyl terminus of TPH did not significantly alter enzymatic activity when
compared to full-length recombinant TPH. However, the macromolecular structure of
the deletions was dramatically affected as determined by dimeric and monomeric
profiles on size exclusion chromatography. It can be concluded that amino acids
428-444 (the C-terminal 17 amino acids) comprise an intersubunit binding domain
that is required for tetramer formation of TPH, but that tetramer assembly is not
essential for full enzymatic activity.
PMID- 9392523
TI - Adaptational changes in kinetic parameters of G6PDH but not of PGDH during
contamination-induced carcinogenesis in livers of North Sea flatfish.
AB - Kinetic parameters of glucose-6-phosphate dehydrogenase (G6PDH) and
phosphogluconate dehydrogenase (PGDH) were determined in situ in livers of marine
flatfish flounder that were caught in unpolluted areas in the open sea and in the
highly polluted river Elbe (Germany). Analysis was performed quantitatively in
liver sections using valid enzyme histochemical methods and image analysis. G6PDH
but not PGDH was strongly affected by contaminant exposure and subsequent
carcinogenesis. G6PDH showed a gradual decrease in Vmax and Km for glucose-6
phosphate in extralesional normal-looking liver tissue. Hepatocellular carcinomas
also showed a low Km, whereas the Vmax was upregulated. These findings are
interpreted as follows: prolonged challenges of the livers by pollutants inhibit
or inactivate G6PDH and this is compensated for by reduction in Km. In
carcinomas, G6PDH levels are upregulated but the low Km values are kept to
increase the NADPH production capacity required in cancer cells showing that
posttranslational regulation processes are important to control cellular
metabolism under various environmental conditions.
PMID- 9392524
TI - Further characterization of the two tetraheme cytochromes c3 from Desulfovibiro
africanus: nucleotide sequences, EPR spectroscopy and biological activity.
AB - The genes encoding the basic and acidic tetraheme cytochromes c3 from
Desulfovibrio africanus have been sequenced. The corresponding amino acid
sequences of the basic and acidic cytochromes c3 indicate that the mature
proteins consist of a single polypeptide chain of 117 and 103 residues,
respectively. Their molecular masses, 15102 and 13742 Da, respectively,
determined by mass spectrometry, are in perfect agreement with those calculated
from their amino acid sequences. Both D. africanus cytochromes c3 are synthesized
as precursor proteins with signal peptides of 23 and 24 residues for the basic
and acidic cytochromes, respectively. These cytochromes c3 exhibit the main
structural features of the cytochrome c3 family and contain the 16 strictly
conserved cysteine + histidine residues directly involved in the heme binding
sites. The D. africanus acidic cytochrome c3 differs from all the other
homologous cytochromes by its low content of basic residues and its distribution
of charged residues in the amino acid sequence. The presence of four hemes per
molecule was confirmed by EPR spectroscopy in both cytochromes c3. The g-value
analysis suggests that in both cytochromes, the angle between imidazole planes of
the axial histidine ligands is close to 90 degrees for one heme and much lower
for the three others. Moreover, an unusually high exchange interaction
(approximately 10[-2] cm[-1]) was evidenced between the highest potential heme (
90 mV) and one of the low potential hemes in the basic cytochrome c3. The
reactivity of D. africanus cytochromes c3 with heterologous [NiFe] and [Fe]
hydrogenases was investigated. Only the basic one interacts with the two types of
hydrogenase to achieve efficient electron transfer, whereas the acidic cytochrome
c3 exchanges electrons specifically with the basic cytochrome c3. The difference
in the specificity of the two D. africanus cytochromes c3 has been correlated
with their highly different content of basic and acidic residues.
PMID- 9392525
TI - Calcium binding to recoverin: implications for secondary structure and membrane
association.
AB - Recoverin is an EF-hand calcium-binding protein reportedly involved in the
transduction of light by vertebrate photoreceptor cells. It also is an
autoantigen in a cancer-associated degenerative disease of the retina.
Measurements by circular dichroism presented here demonstrate that the binding of
calcium to recoverin causes large structural changes. increasing the alpha
helical content of the protein and decreasing its beta-turn, beta-sheet and
'other' structures. The maximum helical content (67%) was observed at 100 microM
free calcium and, unlike calmodulin, decreased as the calcium concentration was
modulated in either direction from this value. Fluorescence measurements
indicated that recoverin may aggregate or undergo structural changes independent
of calcium binding as the calcium concentration is increased above 100 microM.
EGTA also appeared to affect the structure of recoverin independent of its
chelation of calcium. While calcium-induced conformational changes have been
proposed to alter the membrane binding of recoverin through association of its
myristoylated amino terminus, in the experiments presented here the partitioning
of recoverin between the cytoplasmic and membrane compartments of the rod
photoreceptor outer segment was unaffected by the concentration of calcium,
therefore it appears unlikely that a calcium-myristoyl switch acts alone to
anchor recoverin directly to the membrane. These experiments were conducted with
native recoverin which is heterogeneously acylated, but mass spectrometry
confirmed that simple chromatographic methods could be devised to isolate the
different forms of recoverin for further studies.
PMID- 9392526
TI - Enzymatic characteristics of retinal dehydrogenase type I expressed in
Escherichia coli.
AB - We expressed RalDH(I) in Escherichia coli and have shown that it functions in
vitro with the complex CRBP-retinal (cellular retinol-binding protein) as
substrate, either generated in situ from the complex CRBP-retinol and microsomal
retinol dehydrogenases or provided directly as CRBP-retinal. Recombinant RalDH(I)
had kinetic constants with CRBP-retinal of: Hill coefficient 1.8; K0.5 0.8
microM; and Vm 1.5 nmol/min/mg of protein at 25 degrees C. Apo-CRBP inhibited the
reaction with CRBP-retinal with an IC50 of 1.4 microM. Citral inhibited RalDH(I)
with an IC50 of approximately 1 microM compared to an IC50 of approximately 12
microM for RalDH(II), but did not serve as substrate for RalDH(I). RalDH(I) did
not catalyze efficiently the dehydrogenation of acetaldehyde, but showed higher
Vmax/Km values for hexanal, octanal, decanal and benzaldehyde than for either
propanal or retinal. These data extend the characterization of RalDH(I), show
that apo-CRBP competes with holo-CRBP as substrate for RalDH(I), and expand
insight into the pathways of retinoic acid biogenesis from the most abundant
substrates in vivo, retinoid-liganded CRBP.
PMID- 9392527
TI - New aspects on the kinetics of activation of ribosomal peptidyltransferase
catalyzed peptide bond formation by monovalent ions and spermine.
AB - The effect of NH4+ and K+ ions on the activity of ribosomal peptidyltransferase
was investigated in a model system derived from Escherichia coli, in which AcPhe
puromycin is produced by a pseudo-first-order reaction between the preformed
AcPhe-tRNA-poly(U)-ribosome complex (complex C) and excess puromycin. Detailed
kinetic analysis suggests that both NH4+ and K+ ions act as essential activators
of peptidyltransferase by filling randomly, but not cooperatively, multiple sites
on the ribosome. With respect to the NH4+ effect at 25 degrees C. the values of
the molecular interaction coefficient (n), the dissociation constant (KA), and
the apparent catalytic rate constant (kmax) of peptidyltransferase at saturating
levels of NH4+ and puromycin are 1.99, 268.7 mM and 24.8 min(-1), respectively.
The stimulation of peptidyltransferase by K+ ions at 25 degrees C (n = 4.38, KA =
95.5 mM, kmax = 9.6 min[-1]) is not as marked as that caused by NH4+ ions.
Furthermore, it is evident that NH4+ at high concentration (200 mM) is effective
in filling regulatory sites of complex C, which are responsible for the
modulatory effect of spermine. The combination of NH4+ ions (200 mM) with
spermine (300 microM) produces an additive increase in peptidyltransferase
activity. Taken together, these findings suggest the involvement of two related
pathways in the regulation of peptidyltransferase activity, one mediated by
specific monovalent cations and the other mediated by spermine.
PMID- 9392528
TI - Effect of genetic variation on the fatty acid-binding properties of human serum
albumin and proalbumin.
AB - In the circulation, non-esterified fatty acids are transported by albumin which
also facilitates their removal from donor cells and uptake into receptor cells.
We have studied whether genetic variations in the albumin molecule can affect its
in vivo fatty acid-binding properties. The fatty acids bound to 25 structurally
different variants and to their wildtype counterparts, isolated from heterozygous
carriers, were determined gas chromatographically. The variants were proalbumins,
albumins with single amino acid substitutions and glycosylated or truncated
albumins. In eight cases the total amount bound to the variants was diminished
(0.4-0.8-fold), and in seven cases the load was increased to 1.3 or more of
normal. Twenty-one fatty acids were quantitated, and for 19 alloalbumins
significant deviations from normal were found. Usually, changes in total and
individual fatty acid binding were of the same type, but several exceptions to
this rule was found. The glycosylated albumin Casebrook showed the largest
changes, the total load and the amount of bound palmitate was 8.6 and 14 times,
respectively, the normal. The most pronounced changes and the majority of cases
of increased binding were caused by molecular changes in domain III. Mutations in
domain I, II and the propeptide resulted in smaller effects, if any, and these
were often reductions in binding.
PMID- 9392529
TI - A new meiotic endonuclease from Coprinus meiocytes.
AB - Two different types of Coprinus meiotic nuclease have been previously reported by
the authors which are believed to be involved in meiotic chromosome recombination
[1,2]. A third meiotic endonuclease was purified from the cap tissues of the
basidiocarp of Coprinus cinereus. The enzyme is a 60 kDa molecule composed of a
monopolypeptide as revealed by SDS-PAGE and FPLC-Sephacryl S-300 gel filtration.
The enzyme belongs to a type of endonuclease which can preferentially digest
single-stranded DNA and requires divalent cations as a co-factor, most commonly
Mg2+ ions. In the presence of this co-factor, the enzyme converts the supercoiled
plasmid DNA (form I) to both the relaxed form (form II) and the linear form (form
III). Ca2+ ions can also function as a co-factor, though, in this case, not only
is form I plasmid converted to form II, but a few ladder bands between form I and
form II are also produced. The Ca2+ ion effect as a cofactor can be prevented
with ATP. Immunohistochemical observation shows that the enzyme is distributed in
the surface of the gills, which contain the meiotic tissues. These
characteristics clearly differ from those of the meiotic nucleases reported
previously.
PMID- 9392530
TI - Different pathways for radiation-induced apoptosis.
PMID- 9392531
TI - Long-term results of total lymphoid irradiation in the treatment of cardiac
allograft rejection.
AB - PURPOSE: To evaluate the short and long-term effects of total lymphoid
irradiation (TLI) in the treatment of cardiac transplant rejection. METHODS AND
MATERIALS: Between 1986 and 1995, 48 courses of TLI were delivered to 47 cardiac
transplant patients. In 37 patients, TLI was administered for intractable
allograft rejection despite conventional therapy while 10 patients received TLI
prophylactically. The prescribed radiation dose was 8 Gy in 0.8 Gy fractions
twice weekly to mantle and inverted-Y plus spleen fields. Postirradiation follow
up ranged from 6 months to 9.1 years, with a mean of 3.1 years. RESULTS: The
actual mean dose was 7.3 Gy delivered over a mean of 39 days. Fifty-six percent
of patients required treatment delay or abbreviation because of thrombocytopenia,
leukopenia, infection, or unrelated problems. In patients treated for intractable
rejection, rejection rates dropped from 0.46 to 0.14 and to 0.06
episodes/patient/month before, during, and after TLI (p < 0.0001). Rejection
rates continued to drop throughout follow-up. Prednisone requirements decreased
from 0.41 mg/kg before treatment to 0.21 mg/kg afterward (p < 0.0001). The ratio
of helper to cytotoxic-suppressor T-cells decreased during TLI from 1.33 to 0.89,
and remained low at 0.44, 2-4 months after treatment. Infection rates were not
increased and two patients developed malignancy. Rejection rates were high during
prophylactic treatment and this protocol was abandoned. Three-year actuarial
survival after irradiation was 60% for patients with intractable rejection and
70% for the prophylactic cohort. CONCLUSION: TLI is an effective treatment for
control of intractable cardiac rejection. Episodes of rejection and steroid
dosage requirements are decreased for up to 9.1 years. A possible mechanism of
action is long term alteration in T-lymphocyte subsets. Patients experience
transient bone marrow suppression but no increase in infection or bleeding. Long
term complications of TLI are not appreciably different than conventional
immunosuppression.
PMID- 9392532
TI - Randomized trial comparing early postoperative irradiation vs. the use of
nonsteroidal antiinflammatory drugs for prevention of heterotopic ossification
following prosthetic total hip replacement.
AB - PURPOSE: A randomized trial was undertaken to assess the comparative efficacy of
early postoperative irradiation with either 5 or 7 Gy vs. the use of nonsteroidal
antiinflammatory drug (NSAID) for prevention of heterotopic ossification (HO)
following prosthetic total hip replacement (THP). METHODS AND MATERIALS: Between
1993 and 1994, 301 patients were randomized to receive postoperative irradiation
(5 or 7 Gy) or NSAID. One hundred and thirteen patients were treated with NSAID
(indomethacin 2 x 50 mg/day for 1 week), 93 patients were irradiated with a
single 7 Gy fraction, 95 patients with a single 5 Gy fraction. The treatment
volume included the soft tissues between the periacetabular region of pelvis and
the intertrochanteric portion of the femur. X-rays of treated hips were obtained
immediately and 6 months after surgery. Heterotopic ossification was scored
according to the Brooker Grading system. One hundred patients receiving no
prophylactic therapy after total hip arthroplasty between 1988 and 1992, were
analyzed and defined as historical control group. RESULTS: Incidence of
heterotopic ossification was 16.0% in NSAID-group (Brooker Score I: 8.0%; II:
6.2%; III: 1.8%; IV: 0%), 30.1% in 5 Gy group (Brooker Score I: 24.7%; II: 4.3%;
III: 1.1%; IV: 0%), and 11.1% in 7 Gy group (Brooker Score I: 11.6%; II: 0%; III:
0%; IV: 0%). Regarding overall heterotopic ossification there was a significant
difference between the NSAID group and the 5 Gy group (p < .015), respectively,
between the 7 Gy group and the 5 Gy group (p < .0001). No significant difference
was noted in the influence of overall HO between the NSAID and the 7 Gy group (p
> 0.3). Analyzing the clinically significant HO (Brooker Score III and IV)
patients irradiated with 7 Gy developed less HO than those treated with NSAID (p
= 0.003). Incidence of HO was greater in the untreated historical control group
(Brooker Score I: 26%; II: 15%; III: 19%; IV: 5%) than in all three
prophylacticly treated groups. CONCLUSION: Prophylactic irradiation of the
operative site after hip replacement with single a 7 Gy fraction is the most
effective postoperative treatment schedule in prevention of clinically
significant heterotopic ossification. This therapy modality is more effective
than irradiation with a single 5 Gy fraction or use of NSAID.
PMID- 9392533
TI - Brainstem tolerance to conformal radiotherapy of skull base tumors.
AB - PURPOSE: The aim of this study was to analyze the long-term incidence of
brainstem toxicity in patients treated for skull base tumors with high dose
conformal radiotherapy. METHODS AND MATERIALS: Between 1974 and 1995, 367
patients with chordomas (n = 195) and chondrosarcomas (n = 172) of the base of
skull have been treated with combined megavoltage photon and 160 MeV proton
radiotherapy. Following 3D treatment planning with delineation of target volumes
and critical nontarget structures dose distributions and dose-volume histograms
were calculated. Radiotherapy was given an 1.8 Gy or CGE (=Cobalt Gray
Equivalent) dose per fraction, with prescribed target doses ranging from 63 CGE
to 79.2 CGE (mean = 67.8 CGE). Doses to the brainstem surface were limited to <
or = 64 CGE and to the brainstem center to < or = 53 CGE. RESULTS: Follow-up time
ranged from 6 months to 21.4 years (mean = 42.5 months). Brainstem toxicity was
observed in 17 of 367 patients attributable to treatment, resulting in death of
three patients. Actuarial rates of 5 and 10-year high-grade toxicity-free
survival were 94 and 88%, respectively. Increased risk of brainstem toxicity was
significantly associated with maximum dose to brainstem, volume of brainstem
receiving > or = 50 CGE, > or = 55 CGE, and > or = 60 CGE, number of surgical
procedures, and prevalence of diabetes or high blood pressure. Multivariate
analysis identified three independent factors as important prognosticators:
number of surgical procedures (p < 0.001), volume of the brainstem receiving 60
CGE (p < 0.001), and prevalence of diabetes (p < 0.01). CONCLUSIONS: Tolerance of
brainstem to fractionated radiotherapy appears to be a steep function of tissue
volume included in high dose regions rather than the maximum dose of brainstem
alone. In addition, presence of predisposing factors as well as extent of
surgical manipulation can significantly lower brainstem tolerance in the
individual patient.
PMID- 9392534
TI - The role of stereotactic radiosurgery in the treatment of malignant skull base
tumors.
AB - PURPOSE: To determine the efficacy and toxicity of stereotactic radiosurgery in
the treatment of malignant skull base tumors. METHODS AND MATERIALS: Thirty-two
patients with 35 newly diagnosed or recurrent malignant skull base tumors < or =
33.5 cm3 were treated using the Leksell Gamma unit. Tumor histologies included:
adenoid cystic carcinoma [12], basal cell carcinoma [1], chondrosarcoma [1],
chordoma [8], nasopharyngeal carcinoma [3], osteogenic sarcoma [2], and squamous
cell carcinoma [8]. RESULTS: After a median follow-up of 2.3 years, 83% +/- 15%
(+/-95% confidence interval) of patients experienced a symptomatic response to
treatment. Local control at the skull base was 95 +/- 9% at 2 years and 78 +/-
23% at 3 years. Local-regional control above the clavicles was 75 +/- 15% at 1
year and 51 +/- 20% at 2 years. Overall and cause specific survival were
identical, 82 +/- 13% at 1 year, 76 +/- 14% at 2 years, and 72 +/- 16% at 3
years. One patient developed a radiation-induced optic neuropathy 12 months after
radiosurgery. CONCLUSION: Stereotactic radiosurgery using the Leksell Gamma Unit
can provide durable tumor control and symptomatic relief with acceptable toxicity
in the majority of patients with malignant tumors 4 cm or less in size involving
the skull base. Further evaluation of more patients with longer follow-up is
warranted.
PMID- 9392535
TI - Analyses of neuro-otological complications after radiosurgery for acoustic
neurinomas.
AB - PURPOSE: To find out the optimum treatment parameters and the proper indications
for treatment of acoustic neurinomas, univariate and multivariate actuarial
analyses of neuro-otological complications after stereotactic radiosurgery for
acoustic neurinomas were performed. METHODS AND MATERIALS: The subjects were 46
patients with acoustic neurinomas who underwent unilateral radiosurgery between
June 1990 and June 1994 and were followed up at the University of Tokyo. Age
ranged from 13 to 77 years (median, 54 years). Tumor diameter ranged from 0 to 25
mm (mean, 12 mm) at the cerebellopontine angle and from 2 to 15 mm (mean, 8.3 mm)
in the internal auditory meatus. Maximum tumor doses ranged from 20 to 40 Gy
(mean, 31.4 Gy), and peripheral doses from 12 to 25 Gy (mean, 16.8 Gy). One to
eight isocenters were used (mean, 3.2). Median follow-up was 39 months. Eight
events concerning neuro-otological complications were chosen, and the potential
risk factors for them were analyzed by the actuarial analyses (univariate and
multivariate). The events examined include hearing loss, vestibular function
loss, facial palsy, and trigeminal nerve dysfunction. In order to point out
potential risk factors for neuro-otological complications, univariate analyses
were performed using both the Wilcoxon test and the log rank test, and
multivariate analyses were performed with the Cox proportional hazards model.
Variables nominated as potential risk factors were 1) demographic variables such
as patient age and sex, 2) tumor dimensions, 3) treatment variables such as tumor
doses and number of isocenters, and 4) pretreatment hearing levels. A variable
with significant p-values (p < 0.05) in two or more of the three actuarial
analyses (two univariate and one multivariate) was considered a possible risk
factor. RESULTS: The possible variables that increase the risk for each event
analyzed were: neurofibromatosis type II (NF2) and the number of isocenters for
total hearing loss; experience of prior operation, the tumor diameter in the
internal auditory meatus, and NF2 for hearing threshold elevation; peripheral
tumor dose for vestibular function loss; patient age or midporus transverse tumor
diameter (the two variables were correlated), and the number of isocenters for
facial palsy; and the number of isocenters for trigeminal neuropathy. CONCLUSION:
NF2 and the tumor diameter were the common risk factors for hearing loss in
previous studies and ours. For the 5th/7th nerve dysfunction, the tumor diameter
was the common risk factor. The risk of using more isocenters remains
controversial. The difference in risk factors for hearing impairment and
vestibular function loss suggests different mechanisms for the two. Further
studies with larger populations and longer follow-up periods are required in
order to draw conclusions on the risk factors in radiosurgery.
PMID- 9392536
TI - 15 years experience with helium ion radiotherapy for uveal melanoma.
AB - PURPOSE: To review the long-term experience of helium ion therapy as a
therapeutic alternative to enucleation for uveal melanoma, particularly with
respect to survival, local control, and morbidity. METHODS AND MATERIALS: 347
patients with uveal melanoma were treated with helium ion RT from 1978-1992. A
nonrandomized dose-searching study was undertaken, with doses progressively
reduced from 80 GyE in five fractions to 48 GyE in four fractions, given in 3-15
days, mean of 7 days. RESULTS: Local control was achieved in 96% of patients,
with no difference in the rate of local control being seen at 80, 70, 60, or 50
GyE in five fractions. At the lowest dose level of 48 GyE in four fractions, the
local control rate fell to 87%. Fifteen of 347 patients (4%) had local regrowth
in the eye requiring enucleation (12 patients), laser (1 patient) or
reirradiation (2 patients). The time of appearance of local regrowth ranged from
4 months to 5 years posttreatment, with 85% occurring within 3 years. Of the 347
patients, 208 are alive as of May 1, 1997. The median follow up of all patients
is 8.5 years, range 1-17 years. Kaplan-Maier (K-M) survival is 80% at 5 years,
76% at 10 years, and 72% at 15 years posttreatment. Patients with tumors not
involving the ciliary body have a 15-year K-M survival of 80%. The results for
patients whose tumors involved the ciliary body are poor, with a 15-year K-M
survival of 43%. Seventy-five percent of patients with tumors at least 3.0 mm
from the fovea and optic nerve, and initial ultrasound height less than 6.0 mm,
retained vision of 20/200 or better posttreatment. Patients with tumors larger
than 6 mm in thickness, or with tumors lying close to the optic nerve or fovea,
have a reduced chance of retaining useful vision. The enucleation rate is 19%, 3%
for local failure and 16% because of complications of the helium RT, particularly
neovascular glaucoma, which occurred in 35% of patients. CONCLUSIONS: Local
control and retention of the eye are excellent. Complications of therapy reduce
vision and eye preservation. Twenty-four percent of patients manifested distant
metastases 6 to 146 months posttreatment, mean of 43 months, median of 36 months.
Late-appearing distant metastases do not appear to be caused by persistent tumor
in the eye. The risk of metastases is high for patients with tumors greater than
7 mm in initial ultrasound height (37%), anterior tumors involving the ciliary
body (47%), and in those with local failure (53%). Patients with tumors not
involving the ciliary body and initial dimensions less than 10 mm had only an 8%
chance of death from melanoma. A search for effective adjuvant therapy is needed
for patients at high risk of metastases (large tumors, ciliary body involved,
local regrowth in eye).
PMID- 9392537
TI - Anterior segment sparing to reduce charged particle radiotherapy complications in
uveal melanoma.
AB - PURPOSE: The purpose of this investigation is to delineate the risk factors in
the development of neovascular glaucoma (NVG) after helium-ion irradiation of
uveal melanoma patients and to propose treatment technique that may reduce this
risk. METHODS AND MATERIALS: 347 uveal melanoma patients were treated with helium
ions using a single-port treatment technique. Using univariate and multivariate
statistics, the NVG complication rate was analyzed according to the percent of
anterior chamber in the radiation field, tumor size, tumor location, sex, age,
dose, and other risk factors. Several University of California San Francisco
Lawrence Berkeley National Laboratory (LBNL) patients in each size category
(medium, large, and extralarge) were retrospectively replanned using two ports
instead of a single port. By using appropriate polar and azimuthal gaze angles or
by treating patients with two ports, the maximum dose to the anterior segment of
the eye can often be reduced. Although a larger volume of anterior chamber may
receive a lower dose by using two ports than a single port treatment. We
hypothesize that this could reduce the level of complications that result from
the irradiation of the anterior chamber of the eye. Dose-volume histograms were
calculated for the lens, and compared for the single and two-port techniques.
RESULTS: NVG developed in 121 (35%) patients. The risk of NVG peaked between 1
and 2.5 years posttreatment. By univariate and multivariate analysis, the percent
of lens in the field was strongly correlated with the development of NVG. Other
contributing factors were tumor height, history of diabetes, and vitreous
hemorrhage. Dose-volume histogram analysis of single-port vs. two-port techniques
demonstrate that for some patients in the medium and large category tumor groups,
a significant decrease in dose to the structures in the anterior segment of the
eye could have been achieved with the use of two ports. CONCLUSION: The
development of NVG after helium-ion irradiation is correlated to the amount of
lens, anterior chamber in the treatment field, tumor height, proximity to the
fovea, history of diabetes, and the development of vitreous hemorrhage. Although
the influence of the higher LET deposition of helium-ions is unclear, this study
suggests that by reducing the dose to the anterior segment of the eye may reduce
the NVG complications. Based on this retrospective analysis of LBNL patients, we
have implemented techniques to reduce the amount of the anterior segment
receiving a high dose in our new series of patients treated with protons using
the cyclotron at the UC Davis Crocker Nuclear Laboratory (CNL).
PMID- 9392538
TI - External beam radiotherapy dose response of prostate cancer.
AB - PURPOSE: To determine the external beam radiotherapy dose response of palpable
Stage T1-T4, mostly Nx, patients with adenocarcinoma of the prostate. METHODS AND
MATERIALS: There were 938 men consecutively treated between 1987 and 1995 who had
pretreatment prostate specific antigen (PSA) levels. Posttreatment failure was
defined as disease recurrence and/or two elevations in PSA on consecutive follow
up visits. The radiotherapy technique consisted of a four-field box with a small
four-field reduction after 46 Gy in 844 patients (total dose of 60-70 Gy) or with
a six-field conformal boost after 46 Gy in 94 patients (total dose of 74-78 Gy).
Neoadjuvant or adjuvant androgen ablation was not used in any patient. Median
follow-up was 40 months. RESULTS: The mean and median radiotherapy doses for the
entire group were 67.8 +/- 13.3 Gy (+/-SEM) and 66 Gy. The mean radiotherapy dose
was higher in those who had Stage T3/T4 disease, Gleason scores of 8-10, or
pretreatment PSAs of > 4 ng/ml. In general, patients with more aggressive
pretreatment prognostic features were treated to higher doses; yet, those that
relapsed or had a rising PSA were treated to significantly lower doses. Actuarial
analyses were facilitated by dividing patients into three dose groups: < or = 67,
> 67-77, and > 77 Gy. The actuarial freedom from failure rates at 3 years were
61, 74, and 96% for the low, intermediate, and high dose groups. Stratification
of the patients by pretreatment PSA revealed that dose was a significant
correlate of freedom from relapse or a rising PSA for those with PSAs > 4-10, >
10-20, and > 20 ng/ml. The only patients in which an improvement in outcome was
not related to higher doses were those with a pretreatment PSA < or = 4 ng/ml.
Dose was significantly associated with freedom from failure for Stage T1/T2 and
Stage T3/T4 patients, as well as for those stratified by Gleason score.
Multivariate analysis using Cox proportional hazards models showed that dose was
an independent and highly significant predictor of relapse or a rising PSA.
CONCLUSION: This retrospective review strongly indicates that radiotherapy dose
to the prostate is critical to the cure of prostate cancer, even for favorable
patients with pretreatment PSAs of > 4-10 ng/ml, Stages T1/T2, or Gleason scores
of 2-6. Final confirmation awaits the results of our randomized trial.
PMID- 9392539
TI - If you 'watch and wait,' prostate cancer may progress dramatically.
AB - PURPOSE: Observation has been proposed as an option for localized prostate
cancer. However, most series reporting on 'watch and wait' include patients
treated by TUR or hormones that may affect results. We retrospectively reviewed
the natural history of truly untreated prostate cancer and report the outcome for
these patients. METHODS AND MATERIALS: From 1976 to 1992, 34 patients of median
age 70 years (range 56-88) with biopsy proven localized adenocarcinoma of the
prostate refused therapy. All had negative bone scan and none underwent TUR or
hormone treatment. No patient was lost to follow-up (median 76 months). Failure
patterns and survival were analyzed. RESULTS: At diagnosis 27 patients had
palpable nodules (T2), of which 13 were well differentiated and 14 moderately
differentiated. Seven had moderately differentiated T3 lesions. Mild prostatitis
including nocturia, hesistancy, and urgency were reported in 16 T2 and 6 T3
patients. Within 36 months, local progression requiring therapy occurred in all
T3, all T2 moderate and 5 of 13 T2 well-differentiated patients. Systemic
progression occurred in 6 of 7 T3, 9 of 14 T2 (mod), and 2 of 13 T2 (well)
patients. Overall 59% are alive, 26% succumbed to prostate carcinoma and 15% to
other causes. CONCLUSION: Observation results in a high rate of local progression
requiring intervention (77%) and excessive systemic disease development (50%) for
patients with clinically palpable disease. Perhaps this strategy is viable for
earlier stage lesions detected by PSA but it must be tested in a rigorous fashion
before accepted.
PMID- 9392540
TI - Prostate cancer patient subsets showing improved bNED control with adjuvant
androgen deprivation.
AB - PURPOSE: Cooperative groups have investigated the outcome of androgen deprivation
therapy combined with radiation therapy in prostate cancer patients with variable
pretreatment prognostic indicators. This report describes an objective means of
selecting patients for adjuvant hormonal therapy by a retrospective matched
case/control comparison of outcome between patients with specific pretreatment
characteristics who receive adjuvant hormones (RT+H) vs. patients with identical
pretreatment characteristics treated with radiation therapy alone (RT). In
addition, this report shows the 5-year bNED control for patients selected by this
method for RT+H vs. RT alone. METHODS AND MATERIALS: From 10/88 to 12/93, 517 T1
T3 NXM0 patients with known pretreatment PSA level were treated at Fox Chase
Cancer Center. Four hundred fifty-nine of those patients were treated with RT
alone while 58 were treated with RT+H. The patients were categorized according to
putative prognostic factors indicative of bNED control, which include the
palpation stage, Gleason score, and pretreatment PSA. We compared actuarial bNED
control rates according to treatment group within each of the prognostic groups.
In addition, we devised a retrospective matched case/control selection of RT
patients for comparison with the RT+H group. Five-year bNED control was compared
for the two treatment groups, excluding the best prognosis group, using 56 RT+H
patients and 56 matched (by stage, grade, and pretreatment PSA level) controls
randomly selected from the RT alone group. bNED control for the entire group of
517 patients was then analyzed multivariately using step-wise Cox regression to
determine independent predictors of outcome. Covariates considered for entry into
the model included stage (T1/T2AB vs. T2C/T3), grade (2-6 vs. 7-10), pretreatment
PSA (0-15 vs. > 15), treatment (RT vs. RT+H), and center of prostate dose. bNED
failure is defined as PSA > or = 1.5 ngm/ml and rising on two consecutive
determinations. The median follow-up for the 112 matched case/control patients
was 41 months. The median follow-up was 46 months for the RT (range 11-102
months) and 37 months for the RT+H group (range 6-82 months). RESULTS: Univariate
analysis according to treatment for the prognostic factors of palpation stage,
Gleason score, and pretreatment PSA demonstrates a significant improvement in 3
year bNED control with the addition of hormones for patients with T2C/T3, Gleason
score 7-10, or pretreatment PSA > 15 ngm/ml. A comparison of bNED control
according to treatment demonstrates improvement in 5-year bNED control of 55% for
patients treated with RT+H vs. 31% for those patients treated with RT alone (p =
0.0088), although there is not a survival advantage. Multivariate analysis
demonstrates that hormonal treatment is a highly significant independent
predictor of bNED control (p = 0.0006) along with pretreatment PSA (p = 0.0001),
palpation stage (p = 0.0001), grade (p = 0.0030), and dose (p = 0.0001).
CONCLUSIONS: (1) Patients with specific adverse pretreatment prognostic factors
(i.e., T2C/T3, Gleason score 7-10, pretreatment PSA > 15) benefit from adjuvant
hormonal therapy. (2) Upon multivariate analysis, hormonal therapy is determined
to be a highly significant predictor of bNED control, after adjusting for all
other covariates. (3) The 5-year bNED control rates of 55% for RT+H vs. 31% for
RT alone represents the magnitude of benefit from adjuvant hormone therapy. (4)
The bNED control curves are separated by about 20 months, representing a delay in
disease progression with adjuvant hormonal therapy, as there is no overall
survival difference.
PMID- 9392541
TI - Combined castration and fractionated radiotherapy in an experimental prostatic
adenocarcinoma.
AB - PURPOSE: The present study using the Dunning R3327-PAP rat prostatic
adenocarcinoma model was designed to study the effect on tumor growth of
castration prior to or after irradiation with 20-25 Gy as compared with either
irradiation or castration alone. METHODS AND MATERIALS: Rats were bilaterally
orchidectomized. During the irradiation procedure the nonanesthetized animals
were held in a metallic frame with a strong cotton net and they were observed by
means of a video camera. The suboptimal irradiation dose was given once daily
with a 4-MeV linear accelerator, 4-5 Gy/fraction, during 5 consecutive days.
Tumor volumes and rat weights were followed. At the end point of the study the
animals were sacrificed and the tumors were morphometrically analyzed. RESULTS:
The combination of irradiation and castration delayed tumor regrowth better than
irradiation alone with the same suboptimal dose. Castration before irradiation
delayed tumor regrowth more efficiently than castration after irradiation.
However, castration alone delayed tumor regrowth even more effectively than
suboptimal irradiation doses combined with castration. CONCLUSIONS: In
combination with suboptimal irradiation neoadjuvant androgen deprivation was more
inhibitory to rat prostatic adenocarcinoma regrowth than adjuvant androgen
deprivation. Irradiation with suboptimal doses combined with castration may cause
an earlier relapse to androgen-independent tumor growth than castration alone.
PMID- 9392542
TI - Source localization following permanent transperineal prostate interstitial
brachytherapy using magnetic resonance imaging.
AB - PURPOSE: Dosimetric evaluation of completed brachytherapy implant procedures is
crucial in developing proper technique and has prognostic implications. Accurate
definition of the prostate gland and localization of the implanted radioactive
sources are critical to attain meaningful dosimetric data. Methods using
radiographs and CT accurately localize sources, but poorly delineate the prostate
gland. MRI has been recognized as a superior imaging modality in delineating the
prostate gland, but poor in localizing sources due to lack of source visibility.
The purpose of this study was to optimize the visualization of sources using MRI
and compare to CT derived source localization. METHODS AND MATERIALS: Multiple
MRI scanning techniques were attempted until an acceptable sequence to visualize
both the prostate gland and the implanted sources was found. The exams were
performed using a pelvic coil only in approximately 15 min. The CT and MRI scans
of 20 consecutive patients who had received TRUS-guided permanent transperineal
interstitial prostate 125Iodine or 103Palladium brachytherapy were evaluated
using an in-house dosimetry system. To eliminate anatomical dependence, the MRI
derived DVHs for the entire calculation volume were then compared to those
derived from the CT scans. RESULTS: The differences in isodose volumes, of the
calculation volumes, for all implants at all dose levels were not statistically
significant at the 95% confidence level. Calculation volume isodose volumes
derived from MR images were statistically similar to those derived from CT images
at the prescription dose for both 125Iodine (p < 0.01) and 103Palladium (p <
0.026). CONCLUSION: This study presents the first evidence that MRI may be
reliably used to identify permanently implanted 125Iodine and 103Palladium
sources. Given the advantage of target definition characteristics of MRI,
substantially more accurate dosimetric analysis of prostate implants is now
possible. The cost of the optimized and abbreviated MR scanning sequence used in
this study is comparable to a pelvic CT scan. Postimplant MRI allows more
accurate volumetric and anatomically relevant evaluation of permanent prostate
implants, which may provide useful clinical correlation.
PMID- 9392543
TI - Muscle invasive bladder cancer treated by transurethral resection, followed by
external beam radiation and interstitial iridium-192.
AB - PURPOSE: To evaluate the results of transurethral resection (TUR), external beam
radiotherapy (EBRT), and interstitial radiation (IRT) with iridium-192, using the
afterloading technique in patients with muscle invasive bladder cancer. METHODS
AND MATERIALS: From May 1989 until September 1995, 66 patients with primary,
solitary muscle invasive bladder cancer were treated with TUR, EBRT, and IRT,
aiming at bladder preservation. According to the protocol, in three patients low
dose EBRT was applied, whereas 63 patients received high-dose EBRT. Immediately
prior to IRT, 42 patients underwent a lymphnode dissection, and in 16 cases a
partial cystectomy was performed. For IRT, two to five catheters were used and
IRT was started within 24 h after surgery. The majority of patients received 30
Gy of IRT, with a mean dose rate of .58 Gy/h. In three patients, additional EBRT
was applied following IRT. Follow-up consisted of regular cystoscopies, mostly
done during joint clinics of urologist and radiation oncologist, with urine
cytology routinely performed. The median follow-up period was 26 months. The
Kaplan-Meier method was used for the determination of survival rates. RESULTS: In
seven patients, a bladder relapse developed. The probability of remaining bladder
relapse free at 5 years was 88%. The bladder was preserved in 98% of the
surviving patients. Metastases developed in 16 patients, and the probability of
remaining metastasis free at 5 years was 66%. The cumulative 5-year overall and
bladder and distant relapse free survival were 48% and 69%, respectively. Acute
toxicity was not serious in the majority of cases; surgical correction of a
persisting vesicocutaneous fistula was necessary in two patients, whereas a wound
toilet had to be performed in another patient. Serious late toxicity (bladder,
RTOG Grade 3) was experienced by only one patient. CONCLUSIONS: Interstitial
radiation preceded by TUR and EBRT, in a selected group of patients with muscle
invasive bladder cancer, yields an excellent bladder tumor control rate with a
high probability of bladder preservation. Survival was mainly dependent on the
development of distant metastases. Serious acute and late toxicity was rare.
PMID- 9392544
TI - Radiosensitivity of Koch ileal reservoir.
AB - PURPOSE: To acquire preliminary information on the radiosensitivity of the Koch
ileal reservoir by reviewing acute and late toxicity incurred by nine patients
who received pelvic radiotherapy after cystoprostatectomy with lower urinary
reconstruction utilizing a Koch ileal reservoir with bilateral uretero-ileal
urethrostomy. METHODS AND MATERIALS: All patients were irradiated because of
synchronous locally advanced prostate cancer (pT3). A fourfield box technique at
100 cm source-axis-distance (SAD) with all fields treated every day at 1.8 Gy
daily fractions, to a total dose of 45-50.40 Gy was used. The average AP portal
dimension was 11 x 11 cm, and the average lateral was 7 x 8 cm. All portals were
shaped using custom shields to optimize protection of normal tissues not
suspected of tumor involvement (small bowel, posterior rectal wall). No attempt
was made to shield the Koch ileal reservoir. For each patient, comparison of the
treatment portals with the Kochgram radiography (gravity cystogram) confirmed the
inclusion of the majority of the Koch ileal reservoir within the radiation
fields. Acute and late morbidity was measured by RTOG toxicity criteria by
retrospectively reviewing the patients' records. RESULTS: Only mild acute
toxicity was reported by the patients: Six patients experienced grade 1 acute
urinary toxicity and one suffered Grade 2 acute urinary toxicity. In four
patients Grade 1 acute gastrointestinal toxicity occurred and in two patients
Grade 2 toxicity occurred. With a median follow-up of 50 months late toxicity
consisted mainly of microscopic hematuria in six patients and persistent
frequency in two patients (with spontaneous improvement respectively at 4 and 6
months after radiation). No patients experienced acute or late Grade 3 or 4
genitourinary or gastrointestinal toxicity. CONCLUSION: The use of moderate doses
of pelvic radiotherapy (45-50.40 Gy) at standard fractionation was well tolerated
among nine patients who received pelvic radiation for invasive prostate cancer
detected at the time of cystectomy and Koch ileal reservoir diversion. These
preliminary data support the evidence that patients with a Koch ileal reservoir
could safely undergo postoperative pelvic radiotherapy in these dose ranges and
fractionation.
PMID- 9392545
TI - Original p53 status predicts for pathological response in locally advanced breast
cancer patients treated preoperatively with continuous infusion 5-fluorouracil
and radiation therapy.
AB - PURPOSE/OBJECTIVE: 1) To test feasibility of preoperative continuous infusion
(c.i.) 5-Fluorouracil (5-FU) and radiation (RT) in locally advanced breast
cancer. 2) To study clinical and pathological response rates of 5-FU and
radiation. 3) To attempt preliminary correlations between biological probes and
pathological response. METHODS AND MATERIALS: Previously untreated, locally
advanced breast cancer patients were eligible: only patients who presented with
T3/T4 tumors that could not be resected with primary wound closure were eligible,
while inflammatory breast cancer patients were excluded. The protocol consisted
of preoperative c.i. infusion 5-FU, 200 mg/m2/day with radiotherapy, 50 Gy at 2
Gy fractions to the breast and regional nodes. At mastectomy, pathological
findings were classified based on persistence of invasive cancer: pathological
complete response (pCR) = no residual invasive cells in the breast and axillary
contents; pathological partial response (pPR) = presence of microscopic foci of
invasive cells in either the breast or nodal specimens; no pathological response
(pNR) = pathological persistence of tumor. For each patient pretreatment breast
cancer biopsies were analyzed by immunohistochemistry for nuclear grade, ER/PR
hormonal receptors, her2/neu and p53 overexpression. RESULTS: Thirty-five women
have completed the protocol and are available for analysis. 5-FU was interrupted
during radiation in 10 of 35 patients because of oral mucositis in 8 patients,
cellulitis in 1, and patient choice in another. Objective clinical response rate
before mastectomy was 71% (25 of 35 patients): 4 CR, 21 PR. However, in all 35
patients tumor response was sufficient to make them resectable with primary wound
closure. Accordingly, all patients underwent modified radical mastectomy: primary
wound closure was achieved in all patients. At mastectomy there were 7 pCR (20%),
5 pPR (14%) and the remaining 23 patients (66%) had pathological persistence of
cancer (pNR). Variables analyzed as potential predictors for pathological
response (pPR and pCR) were: initial TNM clinical stage, clinical response,
nuclear grade, hormonal receptor status, p53 overexpression, and Her2/neu
overexpression in the pretreatment tumor biopsy. Only initial p53 status (lack of
overexpression at immunohistochemistry) significantly correlated with achievement
of a pathological response to this regimen (p = 0.010). CONCLUSION: The
combination of c.i. 5-FU and radiation was well tolerated and generated objective
clinical responses in 71% of the patients. With the limitation of the small
sample size, the complete pathological response achieved (20%) compares favorably
with that reported in other series of neoadjuvant therapy for similar stage
breast cancer. These preliminary data suggest that initial p53 status predicts
for pathological response (pPR and pCR) to the combination of c.i. 5-FU and
radiotherapy in locally advanced breast cancer.
PMID- 9392546
TI - The role of regional nodal irradiation in the management of patients with early
stage breast cancer treated with breast-conserving therapy.
AB - PURPOSE: To determine the incidence of regional nodal failure (RNF) and
indications for regional nodal irradiation (RNI) in patients with Stage I and II
breast cancer treated with breast-conserving therapy (BCT). METHODS AND
MATERIALS: Four hundred fifty-six patients with Stage I/II breast cancer were
treated with BCT at William Beaumont Hospital. All patients underwent excisional
biopsy and 288 (63%) were reexcised. A Level I/II ipsilateral axillary lymph node
dissection was performed on 431 patients (95%). Pathologically involved nodes
were found in 106 (23%) cases (69 with one to three nodes and 37 with > or = four
nodes involved). All patients received whole breast irradiation (median dose 50
Gy) and 415 (91%) were boosted to the tumor bed (median total dose 60.4 Gy).
Three hundred and sixty (79%) patients received breast alone irradiation and 96
(21%) also received RNI. The median axilla/supraclavicular fossa dose was 50 Gy.
RESULTS: With a median follow-up of 83 months, 15 patients developed a RNF for a
5- and 8-year actuarial rate of 3 and 4%, respectively. The 5- and 8-year
actuarial rates of axillary failure (AF) were 0.7 and 1.0%, respectively. The
incidence of RNF or AF was not affected by the use of RNI in N0 or N1 patients
with one to three positive nodes. Only in patients with four or more positive
nodes was there a trend towards improved regional control with RNI (p = 0.09).
However, patient numbers were extremely small, and this improvement was limited
to a reduction in the rate of failure in the supraclavicular fossa (SCF) (20 vs.
0%, p = 0.04). Multiple clinical, pathologic, and treatment related factors were
analyzed for an association with AF. On univariate analysis, AF was associated
with the number of lymph nodes excised (p < 0.0001) estrogen receptor status (p =
0.0016), and pathologic node status (p = 0.0021). CONCLUSIONS: Regional nodal
failure as the first site of failure is uncommon in patients with early-stage
breast cancer treated with BCT with < or = three positive lymph nodes and appears
unaffected by RNI. For patients with four or more positive lymph nodes, a trend
towards improved RNF was noted with RNI, primarily in the SCF. However, patient
numbers were extremely small in all subsets analyzed. Additional studies are
needed to further define the need for RNI in these patients and help determine
other factors associated with RNF.
PMID- 9392547
TI - Influence of prognostic groupings and treatment results in the management of
unresectable hepatoma: experience with Cisplatinum-based chemoradiotherapy in 76
patients.
AB - PURPOSE: Internationally, hepatoma is a common cause of cancer death. Although
the only curative therapy is surgical, most tumors are unresectable and cause
death. The value of nonsurgical, antineoplastic therapy for such tumors is
controversial. This study was undertaken to extend and confirm promising, but
preliminary, treatment observations in the unresectable context. METHODS AND
MATERIALS: From 1988 to 1993, 76 patients with unresectable, biopsy proven,
hepatoma underwent uniform pretreatment assessment followed by induction therapy
with external beam radiotherapy (21 Gy/7 fractions/10 days) and intravenous
Cisplatinum, 50 mg/m2. One month later patients began monthly intrahepatic artery
Cisplatinum, 50 mg/m2. Clinical course and treatment outcomes were correlated
with previously published prognostic factors and groupings (Nomura et al., Okuda
et al., Stillwagon, et al.). RESULTS: The toxicity of this therapy was modest and
nonlimiting. Twenty-four patients (32%) progressed during induction and prior to
receiving two cycles of intrahepatic artery Cisplatinum without evidence of
benefit. Patients showing this early progression were more likely to be
Stillwagon unfavorable than favorable (p = 0.013), Okuda Stage II than Stage I (p
= 0.024), and slightly but not statistically more likely to be alpha-fetoprotein
positive than alpha-fetoprotein negative (p = 0.098). The overall objective
response rate was 43% (38% among AFP positive and 62% among AFP negative
patients) (p = 0.15). Although 21 patients had evidence of extra hepatic
metastases, survival for these patients did not differ from patients without
metastases (p = 0.09) and patients with extra hepatic metastases were just as
likely to show intrahepatic response (p = 0.84). CONCLUSION: The
chemoradiotherapy program utilized produced objective response and minimal
toxicity. One-third of patients progressed rapidly in spite of treatment. Among
the remaining patients, response occurred frequently. This treatment appears to
represent an important therapeutic option for many, but not all, patients with
unresectable hepatoma.
PMID- 9392548
TI - A phase I trial of hepatic arterial bromodeoxyuridine and conformal radiation
therapy for patients with primary hepatobiliary cancers or colorectal liver
metastases.
AB - PURPOSE: We have previously found that conformal radiation therapy (RT) and
hepatic arterial fluorodeoxyuridine was associated with durable responses and
long-term survival for patients treated for nondiffuse primary hepatobiliary
tumors and colorectal liver metastases. Further improvements in hepatic control
may result from the addition of selective radiosensitization using
bromodeoxyuridine (BrdU) infused through the hepatic artery (HA) concurrently
with RT. This is a Phase I study of escalating doses of HA BrdU combined with our
standard hepatic RT. METHODS AND MATERIALS: Patients with unresectable primary
hepatobiliary cancer or colorectal liver metastases were treated with concurrent
HA BrdU and conformal RT (1.5 Gy per fraction, twice a day). Three-dimensional
treatment planning was used to define both the target and normal liver volumes.
The total dose of RT (24, 48, or 66 Gy) was determined by the fractional volume
of normal liver excluded from the high dose volume. HA BrdU was escalated in
standard Phase I fashion with at least three patients receiving each combination
of RT dose and BrdU dose. The starting dose of HA BrdU was 10 mg/kg/day, with two
potential escalations to a maximum of 25 mg/kg/day (the maximum tolerable dose of
HA BrdU when given alone on this same schedule). Grade > or = 3 toxicity was
considered dose limiting. Patients receiving 24 Gy had one cycle of HA BrdU,
while those receiving either 48 or 66 Gy had two cycles. Patients were followed
for toxicity, complications, and response (when evaluable). RESULTS: A total of
41 patients (18 with colorectal liver metastases, 16 with cholangiocarcinoma and
7 with hepatoma) were treated. Five patients were removed from the protocol
(three had HA catheter complications, one developed atrial fibrillation, and one
was removed due to recurrent Grade 4 toxicity), although all five are included
for toxicity purposes. Dose-limiting toxicity was primarily thrombocytopenia and
there was no obvious relationship with the RT dose. Only 2 of 17 cycles given at
25 mg/kg/day had Grade > or = 3 toxicity. Complications developed in four
patients, including one patient with radiation-induced liver disease. Response
rates were not improved compared to our previous experience. CONCLUSIONS: The
appropriate dose of HA BrdU for Phase II evaluation is 25 mg/kg/day. Neither the
hepatic parenchyma nor the gastrointestinal mucosa appeared to be sensitized by
this method of BrdU administration. It is anticipated that these, or still newer
methods of therapy, can improve treatment results in the near future.
PMID- 9392549
TI - Intraoperative radiation therapy combined with limited lymph node resection in
gastric cancer: an alternative to extended dissection?
AB - PURPOSE: To describe the results of a series of 63 Western patients presenting
with gastric adenocarcinoma and treated with surgery and intraoperative radiation
therapy (IORT) over a 8-year period and to discuss the role of IORT when combined
with limited lymph node dissection. METHODS AND MATERIALS: From 1986 to 1993, 63
patients with gastric adenocarcinoma have been operated in the department of
radiation oncology of the Hospices Civils de Lyon. The stage was: I in 17, II in
11, IIIA in 9, IIIB in 20, and IV in 6. The lymph node dissection was considered
to be limited in 56 patients and extended in 7. The IORT dose ranged from 12 to
23 Gy (median: 15). Thirty patients also underwent a postoperative external beam
irradiation with a standard dose of 44-46 Gy. RESULTS: The postoperative
mortality rate was 4.8%. The 5-year overall survival in the entire series was 47%
and was 82, 55, 78, 20, and 0% in Stages I, II, IIIA, IIIB, and IV, respectively.
Loco-regional relapse occurred in 15 of 63 patients and metastases in 15 of 63.
CONCLUSION: In Western patients treated by gastrectomy for adenocarcinoma of the
stomach, IORT combined with limited lymph node dissection may provide overall
survival similar to that observed after gastrectomy with extended lymph node
dissection but with less postoperative mortality.
PMID- 9392550
TI - Impact of clinical and therapeutic factors on major late complications after
radiotherapy with or without concomitant chemotherapy for anal carcinoma.
AB - PURPOSE: To investigate factors potentially influencing major late morbidity
after sphincter-conserving treatment for anal carcinoma. METHODS AND MATERIALS:
Grade 3-4 complications were retrospectively analyzed in 144 evaluable patients
(pts), 55 pts after split-course radiotherapy (RT), and 89 after concomitant
chemo-RT. First sequence RT delivered a median dose of 39.6 Gy using megavoltage
photon beams. Boost treatment used either 192Ir implantation or external beam RT
(median dose 20 Gy). Chemotherapy started on day 1 and in 83% of pts consisted of
Mitomycin-C (10 mg/m2) and a 5-day infusion of 5-fluorourcil (600-800 mg/m2/day).
Uni- and multivariate analyses tested the association of following factors with
complication rate: age, gender, stage, anatomic tumor extent, type of biopsy,
external RT technique (dose, fraction size, field arrangement), boost type
(brachytherapy vs. external), brachytherapy dose and dose rate, overall treatment
time, and addition of chemotherapy. RESULTS: Five-year actuarial complication
rate was 16%. Two variables were significantly associated with complication rate:
anatomic tumor extent (canal or margin vs. both +/- rectum; 10 vs. 31%
complications, p = 0.0004) and first sequence prescribed dose (< 39.6 Gy vs. > or
= 39.6 Gy; 7 vs. 23% complications, p = 0.012), confirmed as independent factors
by Cox analysis. Grade 4 anal morbidity correlated significantly with prior local
excision. All six bone complications were observed in pts treated by chemo-RT
using large pelvic fields, five occurring in pts older than 66. CONCLUSION: Pts
with tumors involving more than one anatomic subsite or treated with the higher
first sequence RT dose are at greater risk of major complications. Prior tumor
excision and combined modality therapy in older pts appear to favor major anal
and bone complications, respectively.
PMID- 9392551
TI - A phase I/II study of paclitaxel (TAXOL) and concurrent radiotherapy in advanced
nonsmall cell lung cancer.
AB - PURPOSE: The addition of chemotherapy to radical radiotherapy (XRT) has been
shown to improve survival in locally advanced nonsmall cell lung cancer (9).
Consequently, different chemotherapeutic regimens in combination with XRT are
being evaluated in the treatment of this disease. Paclitaxel (TAXOL) may be a
valuable drug in this situation as, in addition to a demonstrated activity in
NSCLC, it has been shown to enhance the effect of radiation on cell lines in
vitro. METHODS AND MATERIALS: Seventeen patients were enrolled onto a Phase I/II
trial to determine the maximum tolerated dose of paclitaxel given by a 3-h
infusion every 2 weeks throughout a 6-week course of XRT, 60 Gy in 30 daily
fractions, in patients with Stage III NSCLC and then to describe the response
rate of this combination in an expanded cohort of patients treated at the
recommended phase II dose. Three patients were entered at each dose level (45,
90, 120, and 135 mg/m2), except for the 120 mg/m2 dose level, which was expanded
to nine patients. RESULTS: The dose limiting toxicity was neutropenia--two of
three patients treated at the 135 mg/m2 level experienced Grade 3 neutropenia on
day 15, which precluded administration of scheduled chemotherapy. Esophagitis was
mild to moderate, and although profound lymphopenia was observed at all dose
levels, there was no evidence of associated opportunistic infections. Of the nine
patients treated at the recommended Phase II dose of 120 mg/m2, there were one
complete and six partial responses (response rate 78%). CONCLUSION: The
combination of XRT, 60 Gy in 6 weeks and paclitaxel, 120 mg/m2 q 2 weeks, can be
safely given to patients with NSCLC, and although it demonstrates activity in
this situation, consideration should be given to the addition of other agents,
such as platinum compounds.
PMID- 9392552
TI - High dose rate brachytherapy for carcinoma of the oral tongue.
AB - PURPOSE: The purpose of this study is to assess the feasibility of treating early
staged tongue cancer with high dose rate (HDR) remote afterloading technique.
Furthermore, a new figure of merit, the Geometry Index (GI), is introduced to
quantify the quality of the implants. METHODS AND MATERIALS: Between 1994 and
1995, eight patients with carcinoma of the oral tongue were treated solely with
interstitial implant using the HDR remote afterloading technique. Five patients
had T1 N0 disease and the remaining three had T2 N0 disease. Elective neck
treatment was withheld. The male-to-female ratio was 1:1, and the mean age 60
years (range: 32-72 years). The median follow-up time was 26 months (range: 6-30
months). The afterloading catheters were positioned through the submandibular
approach with the assistance of templates. Six patients had single planar implant
and the remaining two had double planar implant. The median number of catheters
inserted was 5 (range: 4-9). The median dose given was 60 Gy in 10 fractions over
6 days. The interfraction interval was 7 h. Mandibular and maxillary shields were
inserted prior to treatment. Thomadsen et al. introduced the use of Implant
Quality Index (QI). We introduce a new parameter, GI, which is defined as ratio
of the QI of the nonoptimized executed implant to the corresponding QI value of
the nonoptimized idealized implant. RESULTS: The mucositis lasted for 6 to 20
weeks (median: 10 weeks). There was no local failure up to a median follow-up of
26 months. Two patients developed ipsilateral neck node metastases at 2 and 4
months following implant, respectively. One patient had involvement at level II
and the other failed at level I to III. Both patients were salvaged by neck node
dissection and regionally remained in control. One patient with multiple nodal
metastases and extracapsular spread developed biopsy-proven liver metastases and
succumbed 6 months following implant. One patient treated with double planar
implant developed Grade 3 necrosis of the soft tissue and bone. This complication
is largely preventable now, as we have acquired more technical expertise. The
mean GI values for the single and double planar implants were 0.88 (range: 0.84
0.91) and 0.8, respectively. This correlates with our practical experience that
it is more difficult to maintain a good geometry as double planar implant is
required. The GI gives a better view of the geometry of implant as it compares
the nonoptimized QI of the executed implant with its ideal counterpart. The
failure to achieve a high GI in double planar implants is presumed to relate to
technical difficulties rather than variation in individual performance.
CONCLUSION: Our preliminary experience in treating early-staged tongue cancer
with the HDR remote afterloading technique is inspiring, as it gives a local
control rate of 100% with acceptable morbidity. Further studies are eagerly
awaited to delineate the optimum schedule for this modality of treatment. It is
hoped that the GI values, which represents the skills of insertion, could be
routinely reported so that treatment results between different centers could be
compared in a more precise manner.
PMID- 9392553
TI - A technique for the use of afterloading 137Cs brachytherapy in renal-sparing
irradiation of bilateral Wilms tumor.
AB - PURPOSE: To describe a renal sparing brachytherapy technique for treating
patients with bilateral Wilms tumor who have limited residual tumor measuring 2
cm or less after initial chemotherapy. METHODS AND MATERIALS: A technique for
using brachytherapy in the radiotherapeutic management of bilateral Wilms tumor
is described. Three patients with bilateral Wilms tumor were treated at our
institutions. All three patients had initial nephrectomy of the contralateral
kidney followed by chemotherapy. Local excision of residual tumor in the
remaining kidney was done in all three cases. A 137Cs isotopic source was placed
in the tumor bed at the time of the second surgery using a simple afterloading
applicator. The techniques of applicator placement, localization, and
brachytherapy dosimetry are described. The minimum tumor dose varied from 16 to
25 Gy. RESULTS: All three patients are alive and well at 28, 48, and 66 months
after the procedure. There were no serious operative or postoperative sequelae.
CONCLUSIONS: This simple brachytherapy technique was effective in selected cases
of bilateral Wilms tumor where a renal-sparing radiotherapy approach was needed.
This technique is most applicable when there is residual intrarenal tumor after
partial nephrectomy, when the tumor is unifocal, and when the tumor bed is less
than 2 cm diameter.
PMID- 9392554
TI - Radiotherapy for cancer patients aged 80 and older: a study of effectiveness and
side effects.
AB - PURPOSE: To profile cancer patients aged 80 and older undergoing radiotherapy and
to study the tumor response and side effects of therapy. METHODS AND MATERIALS:
We retrospectively analyzed the records of patients aged 80 and older who
received radiation therapy at James A. Haley Veterans Hospital and H. Lee Moffitt
Cancer Center between 1988 and 1995. A total of 203 patients aged 80-94 received
radiotherapy during this period. Treatment sites included head and neck [50],
breast [16], chest [37], pelvis [53], and miscellaneous [39]. Age, treatment
site, field size, total dose, response to treatment, treatment interruptions,
incidence and severity of weight loss, myelosuppression, diarrhea, mucositis,
dermatitis, and follow-up status are assessed using our departmental records and
hospital tumor registry. RESULTS: Of 191 patients evaluated, 179 (94%) completed
the treatment without serious complications. A total of 195 sites were
irradiated. Twelve patients (6%) required interruption of the treatment.
Therapeutic responses were seen in 86 out of 112 patients (77%) treated with
curative intent (with 67% complete response) and in 67 out of 83 patients (81%)
treated with palliative intent. The causes of treatment interruptions included
weight loss from diarrhea, dysphagia, and progressive disease. Treatment
interruptions were more likely in patients treated with large treatment fields.
In patients treated for upper aero-digestive tract cancer, Grade 3 and 4
mucositis was noted in 20 and 2% of patients, respectively. Grade 1 and 2
enteritis was noted in 43% of patients treated for pelvic malignancies. Grade 3
dermatitis was noted only in 2% of patients. CONCLUSION: Radiotherapy is highly
effective and well tolerated by the oldest old. Age is not a contraindication to
aggressive radiotherapy.
PMID- 9392555
TI - A prospective, randomized study addressing the need for physical simulation
following virtual simulation.
AB - PURPOSE: To accurately implement a treatment plan obtained by virtual or CT
simulation, conventional or physical simulation is still widely used. To evaluate
the need for physical simulation, we prospectively randomized patients to undergo
physical simulation or no additional simulation after virtual simulation. METHODS
AND MATERIALS: From July 1995 to September 1996, 75 patients underwent conformal
four-field radiation therapy planning for prostate cancer with a commercial grade
CT simulator. The patients were randomized to undergo either port filming
immediately following physical simulation or port filming alone. The precision of
implementing the devised plan was evaluated by comparing simulator radiographs
and/or port films against the digitally reconstructed radiographs (DRRs) for x,
y, and z displacements of the isocenter. Changes in beam aperture were also
prospectively evaluated. RESULTS: Thirty-seven patients were randomized to
undergo physical simulation and first day port filming, and 38 had first day
treatment verification films only without a physical simulation. Seventy-eight
simulator radiographs and 195 first day treatment port films were reviewed. There
was no statistically significant reduction in treatment setup error (>5 mm) if
patients underwent physical simulation following virtual simulation. No patient
required a resimulation, and there was no significant difference in changes of
beam aperture. CONCLUSIONS: Following virtual simulation, physical simulation may
not be necessary to accurately implement the conformal four-field technique.
Because port filming appears to be sufficient to assure precise and reliable
execution of a devised treatment plan, physical simulation may be eliminated from
the process of CT based planning when virtual simulation is available.
PMID- 9392556
TI - A correlation between residual DNA double-strand breaks and clonogenic
measurements of radiosensitivity in fibroblasts from preradiotherapy cervix
cancer patients.
AB - PURPOSE: To study the relationship between residual DNA damage and clonogenic
measurements of radiosensitivity in fibroblasts from pretreatment cervix cancer
patients. METHODS AND MATERIALS: Early passage vaginal fibroblasts from nine
preradiotherapy cervix cancer patients and two radiosensitive skin fibroblast
cell strains were studied. Cell survival was measured by clonogenic assay
following both high and low dose rate irradiation. Residual DNA damage was
measured using pulsed-field gel electrophoresis (PFGE) after irradiating
radiolabeled, plateau-phase cells at 37 degrees C and allowing 24 h for repair.
DNA damage was expressed both in terms of the residual damage slope (fitted to
data from 60 to 150 Gy) and the fraction of activity released (FAR) following 150
Gy. RESULTS: The surviving fraction at 2 Gy (SF2) values after high dose rate
irradiation for the vaginal fibroblasts ranged from 0.15 to 0.32 (a 2.2-fold
difference). When the two radiosensitive cell strains were included, residual
damage, expressed as the residual damage slope, correlated with alpha (r = 0.82,
p = 0.002), D bar (r = -0.91, p < 0.001) and SF2 (p = -0.79, p = 0.004), and when
the vaginal fibroblasts alone were studied, the residual damage slope again
correlated with clonogenic survival, although less strongly [alpha (r = 0.66, p =
0.053), D bar (r = -0.83, p = 0.006), and SF2 (r = -0.63, p = 0.07)]. Within the
group of vaginal fibroblasts there was a 4.0-fold difference in residual DNA
damage slope. When residual damage was expressed as FAR at 150 Gy, then for all
cell strains the correlations were alpha: r = 0.78, p = 0.004, D bar: r = -0.86,
p = 0.001, and SF2: r = -0.78, p = 0.004, and for the vaginal fibroblast strains
alone the correlations were alpha: r = 0.60, p = 0.088, D bar: r = -0.75, p =
0.02, and SF2: r = 0.62, p = 0.077. CONCLUSION: This study confirms previous
findings that residual DNA damage correlates with clonogenic survival in
fibroblasts. In addition, it demonstrates a correlation for fibroblasts from
pretreatment cervix cancer patients demonstrating a relatively small range of SF2
values.
PMID- 9392557
TI - Radiation enhancement by biochemical modulation and 5-fluorouracil.
AB - PURPOSE: To evaluate the effects of biochemical modulation by N-(phosphonacetyl)
L-aspartate (PALA), 6-methylmercaptopurine riboside (MMPR), and 6
aminonicotinamide (6AN), (PALA + MMPR + 6AN is referred to as PMA) on tumor
radiosensitivity, and evaluate the efficacy of the addition of 5-FU to the PMA +
XRT regimen for enhancement of tumor response to radiation without exceeding
normal tissue tolerance. METHODS AND MATERIALS: A first generation transplant of
the CD8F1 spontaneous murine tumor was studied. 31P nuclear magnetic resonance
spectroscopy was used to determine the interval between chemotherapy and
radiation based on energy depletion. PMA was administered three times with
fractionated XRT (15 Gy x 3 = 45 Gy) on days 1, 10, or 11, and 21. The addition
of 5-fluorouracil (5-FU) at maximum tolerated doses was evaluated and intergroup
comparisons were made for tumor growth delay, local control, and disproportionate
normal tissue damage. RESULTS: The combination of 5-FU + XRT induced a tumor
doubling time of 75.4 days (67.4-84.4) (p < 0.0001 compared to XRT), validating
that in this tumor model, pretreatment with bolus i.p. 5-FU enhanced XRT. In
comparison, mice treated with PMA + XRT had a tumor doubling time (TDT) > 123.2
days (109.4-138.7), (p < 0.0001 compared to 5-FU + XRT). The addition of 5-FU to
PMA + XRT induced a doubling time of > 170.8 days (150.7-193.7) (p = 0.0002
compared to PMA + XRT). The doubling time for the PMA + XRT cohort and the PMA +
5-FU + XRT cohorts are underestimates since some of the tumor bearing mice
continue to have a complete regression (CR). The CR rate (measured on day 250)
for the PMA + 5-FU + XRT cohort was 31.7% compared to 0% for 5-FU + XRT and 10%
for PMA + XRT (p < 0.05). Mortality and local effects induced by radiation in the
PMA + XRT group were comparable to the toxicity for the PMA + 5-FU + XRT group
indicating that the addition of 5-FU at 75 mg/kg to PMA + XRT was tolerated and
induced both greater CR and tumor doubling times than XRT alone, 5-FU (150 mg/kg)
+ XRT, or PMA + XRT. CONCLUSIONS: PMA is superior to 5-FU as a radiosensitizer in
the schedule studied. The combination of PMA + 5-FU further enhanced XRT without
exceeding normal tissue tolerance.
PMID- 9392558
TI - The effect of UCN-01 (7-hydroxystaurosporine), a potent inhibitor of protein
kinase C, on fractionated radiotherapy or daily chemotherapy of a murine
fibrosarcoma.
AB - PURPOSE: To investigate the effect of UCN-01 (7-hydroxystaurosporine), a potent
and selective protein kinase C inhibitor, on fractionated irradiation or daily
chemotherapy; cis-diamminedichloroplatinum(II) (cis-DDP) or 5-fluorouracil (5-FU)
in vivo. Radiosensitivity and chemosensitivity given in combination with UCN-01
were further studied in vitro to analyze these in vivo results. METHODS AND
MATERIALS: For in vivo studies, single-cell suspension was prepared from fourth
generation FSa-II tumors and transplanted subcutaneously into the leg of 8-10
week-old C3Hf/Sed mice. Treatments were initiated when tumors reached an average
diameter of 4 mm. Tumor response was studied using tumor growth and growth delay
time assays. UCN-01 was given continuously for 7 days using Alzet osmotic pump
(4.0 microg/microl/h or approximately 3.2 mg/kg/day). A daily gamma-ray dose of
10 Gy each was given in air for 7 days. Cis-DDP (0.7 mg/kg/day) or 5-FU (20
mg/kg/day) was given by an i.p. injection for 7 days. For in vitro studies, an
established FSa-II cell line was used and cell survival was studied by colony
formation assay. RESULTS: UCN-01 acted synergistically with fractionated
irradiation, though it was slightly radioprotective in vitro and had no effect on
SLD repair. The surviving fraction of the FSa-II cells treated with both UCN-01
and cis-DDP in vitro was lower than the calculated additive effect; however, the
sensitizing effect of UCN-01 was not found when combined with either of the
chemotherapeutic agents in vivo. Possible causes of synergism of combined UCN-01
and fractionated radiation may be that a continuous UCN-01 treatment inhibited
clonogen repopulation during the course of fractionated irradiation and
accumulated cells in the G2-M phase where cells are most sensitive to
irradiation. CONCLUSION: UCN-01 is a promising agent that may indirectly interact
with fractionated irradiation in vivo but may not with chemotherapeutic agents.
PMID- 9392559
TI - Dose-response relationship for late functional changes in the rat brain after
radiosurgery evaluated by magnetic resonance imaging.
AB - PURPOSE: Only few quantitative data are available on late effects in the healthy
brain after radiosurgery. An animal model can contribute to systematically
investigate such late effects. Therefore, a model applying radiosurgery at the
rat brain was established. A long-term (19 months) follow up study with 66
animals after radiosurgery was carried out. METHODS AND MATERIALS: In 60 animals,
an area in the frontal lobe of the brain was irradiated stereotactically with a
15 MV linac. Different doses of 20, 30, 40, 50, and 100 Gy with two field sizes
(3.9 and 5.9 mm collimator) were selected, using the integrated logistic formula
with input parameters from human brain. The induced alteration of the blood-brain
barrier permeability was investigated by means of contrast enhanced magnetic
resonance imaging. RESULTS: A first intracranial signal enhancement was observed
in one animal 160 days after irradiation with 100 Gy. Beginning at 5 months all
animals in the two 100 Gy groups homogeneously showed contrast enhancement, but
none of the other groups. This remained until 13 months after irradiation. The
volume of contrast enhancement as well as the increase of signal intensity were
different between the two 100 Gy groups. After 19 months, the animals irradiated
with lower doses also showed contrast enhancements, although not uniformly
throughout one group. A maximum likelihood fit of the logistic formula P(D) =
1/[1 + (D50/D)k] to the incidence of late effects for the 5.9 mm collimator at 19
months after irradiation results in the parameters D50 = 37.4(-5.2,+6.1) Gy and k
= 4.7 +/- 2.4. CONCLUSIONS: An animal model was established to study late normal
brain tissue response. The observed late effects appeared very similar to the
estimation of the integrated logistic formula for human brain. Based on these
radiosurgery techniques, future experiments will focus on modifications in the
irradiation modalities, i.e., irregular volumes, radiation quality or
fractionation.
PMID- 9392560
TI - Modelling the optimal radiotherapy regime for the control of T2 laryngeal
carcinoma using parameters derived from several datasets.
AB - PURPOSE: A number of previous studies have used direct maximum-likelihood methods
to derive the values of radiobiological parameters of the linear-quadratic model
for head and neck tumors from large clinical datasets. Time factors for
accelerated repopulation were included, along with a lag period before the start
of this repopulation. This study was performed to attempt to utilise these
results from clinical datasets to compare treatment regimes in common clinical
use in the UK, along with other schedules used historically in a number of
clinical series in North America and elsewhere, and to determine if an optimal
treatment regime could be derived based on these clinical data. METHODS: The
biologically-based linear-quadratic model, applied to local tumor control and
late morbidity, has been used to derive theoretical optimum (maximising tumor
control whilst not exceeding tolerance for late reactions) radiotherapy schedules
based on daily fractions. The specific case of T2 laryngeal carcinoma was
considered as this is treated primarily by radiotherapy in many centers.
Parameter values for local control were taken from previous analyses of several
large single-center and national datasets. A time factor and a lag period were
included in the modelling. Values for the alpha/beta ratio for late morbidity
were used in the range 1-4 Gy, which is compatible with the limited range of
values reported in the literature for particular complications following
radiotherapy for head and neck cancer. Early reactions and their consequential
late morbidity were not modelled in this study, but assumed to be within
tolerance. RESULTS: For treatments using daily fractions there was a broad
optimum treatment time of between 3-6 weeks. The theoretical optimum depended to
some extent on the value of the alpha/beta ratio for late morbidity, but in many
cases was at or just beyond the end of the purported lag period of 3-4 weeks,
although small values of alpha/beta between 1-2 Gy favour longer treatment times.
Similar results were obtained using a range of parameter values derived from four
independent clinical datasets. CONCLUSION: The mathematical modelling of this
broad range of once-daily treatments for most of which differences in local
control and late morbidity are essentially undetectable (< 5%) has shown how this
clinically-recognised phenomenon is interpreted in terms of the combination of
dose-response slopes, fractionation sensitivities and time factors for both tumor
control and normal tissue morbidity. Although the conclusions are inevitably
tempered by a number of caveats concerning confounding factors in different
centers; for example, the use of different treatment volumes, the present
analysis provides a framework with which to explore the potential value of
modifications to conventional treatment schedules, such as the use of multiple
fractions per day.
PMID- 9392561
TI - Optimized beam planning for linear accelerator-based stereotactic radiosurgery.
AB - PURPOSE: Current treatment planning for linear accelerator-based stereotactic
radiosurgery and radiotherapy is a lengthy and iterative procedure. The planner
has to manually select the beam arcs and carefully consider many different
selections to ensure target volume coverage while sparing dose to critical
organs. In this article we report an optimization procedure that can
automatically select the beam arcs based on geometric and dosimetric analysis of
the treatment parameters. METHODS AND MATERIALS: The optimization problem is
introduced by using a Beam's Eye View (BEV) map where a pattern of lines
represents a beam arc combination for a treatment plan. The collection of all
possible treatment plans is described by using the concept of phase space where
each point corresponds to a particular configuration of the system under
consideration, and in this case, a particular beam arc combination. A geometric
reduction of the phase space is performed by excluding static beam ports that
irradiate too much critical organs and too little target volume. The phase space
is further reduced by excluding beam arc combinations that do not comply with
treatment convenience considerations and established planning experiences. These
reductions significantly reduces the number of beam arc combinations to be
considered and thus dramatically simplifies the computational complexity. The
method of simulated annealing is then used to the reduced phase space to select
the set of beam arcs that provides the best surface dose distribution for the
target volume. The optimization procedure is applied to a radiosurgery case to
compare the optimized beam arcs with the previously manually planned beam arcs.
The procedure is also applied to 10 randomly selected cases for a comparison in
terms of tissue-volume ratio calculations. RESULTS: The system is a highly
automated beam arc planning tool for stereotactic radiosurgery and stereotactic
radiotherapy. Its interactive nature allows the planner to rapidly consider many
treatment plans to search for the best option. For the case presented, it is
shown that the optimized beams substantially reduce the dose to the postrema. The
tissue-volume ratio calculations demonstrate that the optimization often produces
clinically superior treatment plans than the manual beam planning method.
CONCLUSIONS: Our method of phase space reduction proves to be very useful in
approaching the complex problem of treatment planning optimization. Not only does
it substantially reduce the number of beam arcs that need to be considered, but
it also simplifies the evaluation of the beam arc options. Both of these greatly
reduce the computational complexity of the optimization and make the procedure
fast and efficient. Moreover, the reduction of phase space adds another layer of
interaction between the user and the beam selection procedure, so that the
optimization process is well controlled and thus very effective.
PMID- 9392562
TI - Total body irradiation with an arc and a gravity-oriented compensator.
AB - PURPOSE: To deliver uniform dose distributions for total-body irradiation (TBI)
with an arc field and a gravity-oriented compensator. This technique allows the
patient to be treated lying on the floor in a small treatment room. METHODS AND
MATERIALS: Through the sweeping motion of the gantry, a continuous arc field can
deliver a large field to a patient lying on the floor. The dose profile, however,
would not be uniform if no compensator were used, due to the effects of inverse
square variation of beam intensity with distance as well as the slanted depth in
patient. To solve this problem, a gravity-oriented compensator made of cerrobend
alloy was designed. This compensator has a cross-section of an inverted isosceles
triangle, with the apex always pointing downward, due to gravity. By properly
selecting the thickness of the compensator, the width of the base, and the
distance between the pivots to the base, the difference in the path length
through the compensator can be made just right to compensate the effects of
inverse-square and slanted depth, thus producing a uniform dose profile. RESULTS:
Arc fields with a gravity-oriented compensator were used for 6, 10, 15, and 18 MV
photon beams. The arc field can cover a patient with a height up to 180 cm. The
field width was chosen from 32 to 40 cm at the machine isocenter. The optimal
thickness of the compensator was found to be 2.5 cm, and its base was 25 cm wide.
The distance from the pivot points to the flat surface of the compensator
proximal to the beam ranges from 13 to 14 cm for different beam energies. The
dose uniformity at a depth of 10 cm is within +/-5% for all beam energies used in
this study. CONCLUSIONS: Highly uniform dose profiles for TBI treatments can be
delivered with an arc and a gravity-oriented compensator. The proposed technique
is simple and versatile. A single compensator can be used for all energies,
because the amount of compensation can be adjusted by changing the distance to
the pivot and/or the field size.
PMID- 9392563
TI - Re: Clifford Chao et al., IJROBP 36(5):1039-1043; 1996.
PMID- 9392564
TI - Regarding Aref et al., IJROBP 37:269-273; 1997.
PMID- 9392565
TI - Measuring the "viral load" in cerebrospinal fluid in human immunodeficiency virus
infection: window into brain infection?
PMID- 9392566
TI - Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated
in neurocognitively impaired individuals with acquired immunodeficiency syndrome.
HIV Neurobehavioral Research Center Group.
AB - To determine whether cerebrospinal fluid (CSF) viral burden measurements can
assist in the evaluation of human immunodeficiency virus (HIV)-associated
neurocognitive disorders, we quantified HIV type 1 (HIV-1) RNA in CSF. Because
previous findings suggested that disease stage, lymphocytic pleocytosis, and HIV
1 RNA levels in plasma may influence CSF viral burden, these variables were
examined as potential modifying factors. HIV-1 RNA levels were quantified by
using a reverse transcriptase-polymerase chain reaction assay. Performance on a
comprehensive neuropsychological (NP) battery was noted in 97 prospectively
enrolled, HIV-infected subjects. Among subjects with acquired immunodeficiency
syndrome (AIDS) (<200 CD4+ lymphocytes), NP impairment was associated with
significantly higher CSF RNA levels (3.1 vs 1.8 log10 copies/ml; p = 0.02); most
impaired subjects met criteria for HIV-associated dementia or minor cognitive
motor disorder. In subjects without AIDS, CSF RNA and NP impairment were
unrelated. Before AIDS, CSF RNA was strongly correlated to plasma RNA and to
pleocytosis, but in AIDS, CSF and plasma RNA were independent. In conclusion, we
found elevated CSF HIV-1 RNA levels in NP impaired subjects with AIDS. Before
AIDS, systemic viral replication, possibly through CD4+ mononuclear cell
trafficking, may govern virus levels in CSF, whereas in AIDS, CD4 cell depletion
may unmask a correlation between increased productive central nervous system HIV
infection and clinical neurocognitive disorders.
PMID- 9392568
TI - Long-term stroke risk in children with sickle cell disease screened with
transcranial Doppler.
AB - Stroke is an important complication of sickle cell disease. Stroke prediction is
clinically important because it offers the possibility of primary prevention. In
1992, transcranial Doppler (TCD) evidence of elevated intracranial internal
carotid or middle cerebral artery velocity was demonstrated to be associated
strongly with an increased risk of ischemic stroke. This study extends the
original study and includes 125 more children, longer follow-up, and intracranial
hemorrhage in the stroke-risk model. Elevated time averaged mean maximum blood
flow velocity, especially when velocity is 200 cm/sec or greater by TCD, was
associated strongly with stroke risk. The cases not predicted by TCD point to the
need for more information on the optimal timing of TCD surveillance for stroke
risk.
PMID- 9392567
TI - Relationship between human immunodeficiency virus-associated dementia and viral
load in cerebrospinal fluid and brain.
AB - Cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA levels were
measured with the Nucleic Acid Sequence-Based Amplification (NASBA) assay to
determine the relationship with neurological status; 37 subjects with HIV
dementia (HIV-D) were compared with 77 with HIV with minor neurological signs
(HIV-MCMD) and 93 neurologically normal HIV-seropositive individuals (HIV-NML).
The NASBA assay had a lower limit of detection of 100 copies per milliliter. Mean
CSF log HIV RNA levels were significantly higher in those with dementia after
adjusting for CD4 count and were correlated with dementia severity. Plasma levels
did not distinguish comparably immunosuppressed subjects with or without
dementia. CSF and plasma RNA levels were significantly intercorrelated for
subjects with CD4 counts <200/mm3 and also correlated inversely with CSF beta2
microglobulin. CSF RNA levels were independent of CSF pleocytosis or
antiretroviral exposure. Brain RNA levels were consistently higher than CSF but
correlated with CSF values for dementia subjects. The NASBA assay can be used
reliably to determine HIV RNA levels in CSF, brain, and plasma samples. CSF HIV
RNA may be a surrogate marker for brain infection, based on the observed
correlation with brain levels. The association between plasma HIV RNA and CSF
levels of HIV and beta2-microglobulin suggests that both viral load and CNS
immune activation are important determinants of neurological disease.
PMID- 9392569
TI - Ontogeny of ipsilateral corticospinal projections: a developmental study with
transcranial magnetic stimulation.
AB - Transcranial magnetic stimulation (TMS) has been used to describe the maturation
of the corticospinal tract in children. Ipsilateral corticospinal connections
have been demonstrated with TMS in patients with congenital mirror movements, in
patients after hemispherectomy, and in children with hemiplegic cerebral palsy.
The goal of the study was to find out whether corticospinal ipsilateral
projections in children can be demonstrated during the first decade of life as
part of normal ontogeny. For this purpose, we examined 50 normal children (age
range, 3-11 years) with focal TMS over the left and right hemispheres to target
muscles in proximal and distal parts of the upper extremity (first dorsal
interosseus, biceps brachii, and brachioradialis). To lower the stimulation
threshold, we stimulated under voluntary preinnervation. In two-thirds of the
children we elicited ipsilateral motor evoked potentials (MEPs). This occurred
more often in proximal than in distal muscles. The latency of the ipsilateral
MEPs was about 12 to 14 msec longer than the usual contralateral response. From
the age of 10, and in adults, ipsilateral MEPs could not be detected. Also
considering lesion data from adult patients, the most likely explanation for the
disappearance of ipsilateral corticospinal connections after the age of 10 years
is an increasing transcallosal inhibitory influence during development. The
presence of ipsilateral corticospinal connections appears to be a normal state in
ontogeny.
PMID- 9392570
TI - Differential distribution of the normal and mutated forms of huntingtin in the
human brain.
AB - Huntington's disease is an inherited disorder caused by expansion of a CAG
trinucleotide repeat in the IT15 gene, which leads to expansion of a
polyglutamine tract within the protein called huntingtin. Despite the
characterization of the IT15 gene and the mutation involved in the disease, the
normal function of huntingtin and the effects of the mutation on its function and
on its neuronal location remain unknown. To study whether mutated huntingtin has
the same neuronal distribution and intracellular location as normal huntingtin,
we analyzed immunohistochemically both forms of this protein in the brain of 5
controls and 5 patients with Huntington's disease. We show that the distribution
of mutated huntingtin is, like that of the normal form, heterogeneous throughout
the brain, but is not limited to vulnerable neurons in Huntington's disease,
supporting the hypothesis that the presence of the mutated huntingtin in a neuron
is not in itself sufficient to lead to neuronal death. Moreover, whereas normal
huntingtin is detected in some neuronal perikarya, nerve fibers, and nerve
endings, the mutated form is observed in some neuronal perikarya and proximal
nerve processes but is not detectable in nerve endings. Our results suggest that
the expression or processing of the mutated huntingtin in perikarya and nerve
endings differs quantitatively or qualitatively from the expression of the normal
form in the same neuronal compartments.
PMID- 9392572
TI - Long-term effects of pancreatic transplantation on diabetic neuropathy.
AB - Restoration of a long-lasting euglycemic state by a functioning pancreatic
transplantation (PTx) is the most logical treatment for insulin-dependent
diabetes mellitus and for amelioration of secondary complications, including
neuropathy. We evaluated neurological function by clinical examination, nerve
conduction studies, and autonomic function tests in 115 patients with a
functioning PTx and in 92 control patients treated with insulin, at baseline and
1, 2, 3.5, 5, 7, and 10 years later. In control patients, neuropathy
progressively worsened during follow-up. The clinical examination score and
composite indices of abnormality of motor and sensory nerve conduction decreased
significantly at all intervals tested. Autonomic function indices also decreased,
but significantly only after 1 year. In patients who received a successful PTx
the neuropathy improved. The motor and sensory nerve conduction indices increased
significantly at all intervals after transplantation, whereas the clinical
examination and autonomic tests improved only slightly. Patients who received
either a PTx alone, a PTx after a kidney graft, or simultaneous pancreatic and
kidney transplantations improved similarly over the follow-up. These results
indicate that a functioning PTx halts the progression and improves the signs of
diabetic polyneuropathy by restoration of a normoglycemic state.
PMID- 9392571
TI - Alterations in opioid receptor binding in Parkinson's disease patients with
levodopa-induced dyskinesias.
AB - Levodopa-induced dyskinesias remain a major challenge in the therapeutic
management of Parkinson's disease (PD). Their etiology is unknown although
dysfunction of striatal opioid transmission has been implicated in experimental
models of PD. To determine whether the opioid system is involved in human
dyskinetic PD, we measured in vivo opioid receptor binding in PD patients with
and without levodopa-induced dyskinesias, using positron emission tomography
(PET) and the opioid receptor ligand [11C]diprenorphine. Striatal and
thalamic/occipital uptake ratios were calculated using a region of interest (ROI)
approach. In addition, we used statistical parametric mapping (SPM) and images
reflecting the volume of distribution of [11C]diprenorphine to assess changes in
cerebral receptor binding on a voxel-by-voxel basis. By using the ROI approach,
we found significantly reduced striatal and thalamic opioid binding in
dyskinetic, but not in nondyskinetic, PD patients. The SPM approach confirmed
reduced availability in these areas and, in addition, showed decreased cingulate
and increased prefrontal opioid receptor binding in the dyskinetic patients. Our
findings confirm that altered opioid transmission is part of the pathophysiology
of levodopa-induced dyskinesias in PD and support further investigation into the
role of opioid agents in the management of these involuntary movements.
PMID- 9392573
TI - Proton magnetic resonance spectroscopic imaging and magnetic resonance imaging
volumetry in the lateralization of temporal lobe epilepsy: a series of 100
patients.
AB - Surgery is a safe and effective treatment for drug-resistant temporal lobe
epilepsy (TLE). However, bilateral electroencephalographic (EEG) abnormalities
are frequently present, making presurgical lateralization difficult. New magnetic
resonance (MR) techniques can help; proton magnetic resonance spectroscopic
imaging (MRSI) can detect and quantify focal neuronal damage or dysfunction based
on reduced signals from the neuronal marker N-acetylaspartate, and magnetic
resonance imaging (MRI)-based measurements of amygdala-hippocampal volumes
(MRIVol) can improve the detection of atrophy of these structures. We performed
proton MRSI and MRIVol in 100 consecutive patients with medically intractable TLE
to determine how well these techniques agreed with the lateralization by
extensive EEG investigation. We found that the EEG, MRSI, and MRIVol findings
were highly concordant. The MRSI was abnormal in 99 of 100 patients (bilateral in
54%). The MRIVol was abnormal in 86 of 98 patients (bilateral in 28%). We
obtained lateralization in 83% of patients using MRIVol alone, in 86% using MRSI
alone, and in 90% by combining MRSI and MRIVol (vs 93% lateralization by EEG).
MRSI was abnormal in 12 patients with normal MRIVol. The combination of proton
MRSI and MRIVol can lateralize TLE accurately and noninvasively in the great
majority of patients. By reducing reliance on EEG, these imaging techniques could
reduce prolonged presurgical evaluation and make seizure surgery available to
more patients.
PMID- 9392574
TI - Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease
patients. Parkinson Study Group.
AB - Motor fluctuations associated with levodopa therapy are common problems
encountered in the long-term treatment of Parkinson's disease (PD). Entacapone, a
peripherally acting, reversible inhibitor of catechol-O-methyltransferase, slows
the elimination of levodopa in humans by reducing the formation of 3-O
methyldopa. We conducted a placebo-controlled, double-blind, parallel-group,
multicenter trial of entacapone in PD patients with motor fluctuations. Two
hundred five patients were randomized to receive either entacapone 200 mg or
matching placebo with each dose of levodopa and were followed for 24 weeks. The
primary measure of efficacy was the change in percentage of "on" time (relief of
parkinsonism) while awake, as recorded by subjects at home in diaries completed
at 30-minute intervals. At baseline, patients averaged approximately 10 hours of
"on" time per day while awake (60.5% "on" time), and entacapone treatment
increased the percent "on" time by 5.0 percentage points. The effect of
entacapone was more prominent in patients with a smaller percent "on" time (<55%)
at baseline, and increased as the day wore on. Entacapone is effective at
increasing the duration of response to levodopa and at relieving parkinsonism in
patients experiencing motor fluctuations and was well tolerated during the 24
weeks of treatment.
PMID- 9392575
TI - Quantitative neuropathology and quantitative magnetic resonance imaging of the
hippocampus in temporal lobe epilepsy.
AB - The aims of this study were to examine the relationships of hippocampal T2 (HCT2)
relaxation time and magnetic resonance (MR)-based hippocampal volume (HCV) to
neuronal (ND) and glial cell densities (GD) of hippocampal neuronal cell layers,
and to obtain a better clinicopathological definition of hippocampal sclerosis
(HS) and end folium sclerosis (EFS). Fifty-three hippocampi with HS, 6 with EFS,
and 6 control hippocampi were studied. Pathologically, the HS group had a
significantly higher logarithm (log) GD/ND than the controls in all hippocampal
subregions, and than the EFS group in all subregions except the granule cell
layer of the dentate gyrus (GCDG). The EFS group had a significantly higher log
GD/ND than the control group only in the GCDG. Clinical correlations suggested
that EFS may be the consequence of temporal lobe seizures and not an
epileptogenic entity. Hippocampal atrophy in HS was associated with neuronal cell
depletion and concomitant gliosis in the cornu Ammonis (CA) 1, CA2, CA3, and
hilus. An increased HCT2 was associated with damage in the CA1 and also the hilus
and has a different neuropathological basis than HCV loss. MR-based HCV
measurement and HCT2 mapping, therefore, give complementary information in the
presurgical evaluation of temporal lobe epilepsy and longitudinal studies.
PMID- 9392576
TI - Effects of apomorphine on globus pallidus neurons in parkinsonian patients.
AB - Current hypotheses of basal ganglia dysfunction in Parkinson's disease (PD)
propose that neuronal hypoactivity in the globus pallidus externus (GPe), and
hyperactivity in the output nuclei and the external and internal portions of the
globus pallidus internus (GPi,e and GPi,i, respectively), result in the cardinal
symptoms of PD. To test this theory, the nonselective D1- and D2-dopamine
receptor agonist apomorphine (30-100 microg/kg SC) was administered to 14
levodopa-responsive PD patients who were off medication ("off" state) while
recording neurons in GP. For 15 neurons that were continuously monitored,
apomorphine was found to increase the firing rate of 3 neurons in GPe, and
decrease the rate of 12 in GPi. The mean firing rates of many different neurons
were determined before (n = 285) and at various intervals after (n = 184) the
injection of the drug. The mean rates before apomorphine were as follows: GPe, 45
Hz (SD 15, n = 85); GPi,e, 67 Hz (SD 14, n = 125); and GPi,i, 85 Hz (SD 19, n =
75). At 25 to 35 minutes after APO, the rate of GPe neurons had increased to 72
Hz (SD 18, n = 7), the rate of GPi,e neurons had decreased to 39 Hz (SD 15, n =
15), and in GPi,i the rate decreased to 34 Hz (SD 22, n = 18). Eighty minutes
after apomorphine administration, the mean firing rates returned to
preadministration values. This study supports current models of basal ganglia
dysfunction in PD and suggests that the therapeutic effect of apomorphine results
from a normalization of the imbalance of neuronal activity in the direct and
indirect pathways.
PMID- 9392577
TI - Dietary fat intake and the risk of incident dementia in the Rotterdam Study.
AB - A high intake of saturated fat and cholesterol and a low intake of
polyunsaturated fatty acids have been related to an increased risk of
cardiovascular disease. Cardiovascular disease has been associated with dementia.
We investigated the association between fat intake and incident dementia among
participants, age 55 years or older, from the population-based prospective
Rotterdam Study. Food intake of 5,386 nondemented participants was assessed at
baseline with a semiquantitative food-frequency questionnaire. At baseline and
after an average of 2.1 years of follow-up, we screened for dementia with a three
step protocol that included a clinical examination. The risk of dementia at
follow-up (RR [95% CI]) was assessed with logistic regression. After adjustment
for age, sex, education, and energy intake, high intakes of the following
nutrients were associated with an increased risk of dementia: total fat (RR = 2.4
[1.1-5.2]), saturated fat (RR = 1.9 [0.9-4.0]), and cholesterol (RR = 1.7 [0.9
3.2]). Dementia with a vascular component was most strongly related to total fat
and saturated fat. Fish consumption, an important source of n-3 polyunsaturated
fatty acids, was inversely related to incident dementia (RR = 0.4 [0.2-0.91), and
in particular to Alzheimer's disease (RR = 0.3 [0.1-0.9]). This study suggests
that a high saturated fat and cholesterol intake increases the risk of dementia,
whereas fish consumption may decrease this risk.
PMID- 9392578
TI - Inflammatory central nervous system demyelination: correlation of magnetic
resonance imaging findings with lesion pathology.
AB - Magnetic resonance imaging (MRI) is widely used to evaluate and monitor disease
activity in inflammatory demyelinating central nervous system (CNS) diseases such
as multiple sclerosis. The present study aimed at correlating MRI findings with
histological parameters in 6 cases of biopsy-proven inflammatory demyelination of
the CNS. The earliest stages of demyelinating activity manifested as almost
isointense lesions with a massive gadolinium-DTPA (Gd-DTPA) enhancement in T1
weighted scans. In T2-weighted scans, early active lesions formed a border of
decreased intensity compared with the lesion center and the perifocal edema. The
morphological correlate of this pattern in our patients was activated macrophages
in the zone of myelin destruction at the plaque border. Late active lesions were
hypointense in T1 and hyperintense in T2 scans. Inactive demyelinated and
remyelinating lesions were hyperintense in T2 scans and enhanced inhomogenously
after Gd-DTPA application. T1 scans revealed major differences in the degree of
hypointensity that correlated with the extent of axonal damage, extracellular
edema, and the degree of demyelination or remyelination.
PMID- 9392580
TI - Clinical and magnetic resonance imaging findings in Batten disease: analysis of
the major mutation (1.02-kb deletion).
AB - A total of 36 patients with Batten disease (juvenile-onset neuronal ceroid
lipofuscinosis), homozygous or heterozygous for the major mutation, a 1.02-kb
deletion, in the CLN3 gene, were studied to relate their genotype to their
clinical phenotype. The onset of visual failure and epilepsy was highly
concordant in both groups. Great inter- and intrafamilial heterogeneity was
demonstrated in the development of mental and physical handicap and in magnetic
resonance imaging findings among both homozygous and heterozygous patients. The
1.02-kb deletion in homozygous form was always associated with mental and
physical handicap, whereas the heterozygous phenotype could be extremely benign
without affecting the intellectual level of the patient. Our data suggest that
genetic background, modifying genes, and environmental factors all influence the
final phenotype of Batten disease.
PMID- 9392579
TI - Localization of frontotemporal dementia with parkinsonism in an Australian
kindred to chromosome 17q21-22.
AB - An Australian family with autosomal dominant presenile nonspecific dementia was
recently described. The disease results in behavioral changes, usually
disinhibition, followed by the onset of dementia accompanied occasionally by
parkinsonism. Twenty-eight affected individuals were identified with an age of
onset of 39 to 66 years (mean, 53 +/- 8.9 years). We mapped the disease locus to
an approximately 26-cM region of chromosome 17q21-22 with a maximum two-point LOD
score of 2.87. Affected individuals share a common haplotype between markers
D17S783 and D17S808. This region of chromosome 17 contains the loci for several
neurodegenerative diseases that lack distinctive pathological features,
suggesting that these dementias, collectively referred to as frontotemporal
dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by
mutations in the same gene. The entire coding region of five genes, mapped to the
FTDP-17 candidate region, were also sequenced. This analysis included the
microtubule-associated protein tau that is the major component of the paired
helical filaments observed in Alzheimer's disease. No pathogenic mutations were
identified in either the tau gene or in any of the other genes analyzed.
PMID- 9392581
TI - Copper/zinc superoxide dismutase 1 and sporadic amyotrophic lateral sclerosis:
analysis of 155 cases and identification of a novel insertion mutation.
AB - Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting
from the degeneration of motor neurons in the brain and spinal cord and leading
to death within 5 years of symptom onset. The great majority of ALS cases are
sporadic, with the familial form (FALS) representing fewer than 10% of all cases.
Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) gene have previously
been identified as the underlying cause of approximately 20% of FALS cases. As
the familial and sporadic forms of the disease are clinically similar, we have
sought to determine whether such mutations in SOD-1 underlie any sporadic ALS
cases. We have screened 155 sporadic cases by single-strand conformation
polymorphism and have identified 4 sporadic cases that possess point mutations in
exon 4 of the SOD-1 gene. Two of these mutations are identical to those
previously reported in FALS cases. One mutation is novel, resulting in a
frameshift at Val118 due to the replacement of G (first base in the last codon of
exon 4) by AAAAC. This mutation results in a truncated SOD-1 protein due to the
introduction of a stop codon three residues into exon 5.
PMID- 9392583
TI - A novel muscle sodium channel mutation causes painful congenital myotonia.
AB - Mutations in the skeletal muscle voltage-gated sodium channel alpha-subunit gene
(SCN4A) have been associated with a spectrum of inherited nondystrophic myotonias
and periodic paralyses. Most disease-associated SCN4A alleles occur in portions
of the gene that encode the third and fourth repeat domains with the conspicuous
absence of mutations in domain 1. Here we describe a family segregating an
unusual autosomal dominant congenital myotonia associated with debilitating pain
especially severe in the intercostal muscles. A novel SCN4A mutation causing the
replacement of Val445 in the sixth transmembrane segment of domain 1 with
methionine was discovered in all affected individuals and is the likely genetic
basis for the syndrome. Myotonia was resistant to treatment; however, the most
severely affected family member responded dramatically to the sodium channel
blocking agent flecainide.
PMID- 9392582
TI - Pallidotomy for hemiballismus: efficacy and characteristics of neuronal activity.
AB - A patient with unremitting, medically intractable hemiballismus underwent a
pallidotomy that abolished his involuntary movements. Firing rates of cells in
the internal segment of the globus pallidus (GPi) recorded during this procedure
were significantly lower than those observed during pallidotomy for Parkinson's
disease, either "on" or "off" medication. Firing patterns in hemiballismus were
characterized by low-frequency modulation of the firing rate. These results are
consistent with the hyperkinetic model, which suggests that hemiballismus results
from decreased inhibition of the pallidal relay nucleus of the thalamus by the
GPi. The efficacy of surgery in the case of hemiballismus demonstrates that
pallidotomy can be an effective treatment for this condition and suggests that
patterned neuronal activity in the GPi is important in the mechanism of
hyperkinetic disorders.
PMID- 9392584
TI - SMI-31 immunoreactivity in inclusion body myositis.
PMID- 9392585
TI - Clinically definite multiple sclerosis following optic neuritis.
PMID- 9392586
TI - Involvement of cytokines in the histopathology of cerebral malaria.
AB - Histopathologic and immunohistologic studies were performed in two cases of fatal
cerebral malaria. On admission, both patients were in unarousable coma with
hyperparasitemia. Examination of the tissue sections from various organs showed
parasite sequestration in both cases with more extensive area of sequestration in
case 1 than in case 2. A panel of monoclonal antibodies against cytokines applied
to these tissues clearly detected tumor necrosis factor-alpha (TNF alpha),
interferon-gamma (IFN gamma), interleukin-1beta (IL-1beta), and IL-10 in the
tissues from brain and liver of case 1. A different cytokine profile, IL-4 and IL
10, was found in the brain tissues of case 2; no TNF alpha nor IFN gamma was
detected. There was no cytokine detected in the tissues of other organs in either
case. Results of the study suggest that histopathology in the brain of fatal
cerebral malaria may be associated with focal accumulation of cytokines.
Additionally, the type of cytokines produced locally in a particular tissue
during malaria infection may be regulated by the degree of regional parasite
sequestration.
PMID- 9392587
TI - Prognostic significance of reduced red blood cell deformability in severe
falciparum malaria.
AB - Severe falciparum malaria is associated with microvascular obstruction resulting
from sequestration of erythrocytes containing mature stages of the parasite.
Since reduced red blood cell deformability (RBC-D) can contribute to impaired
microcirculatory flow, RBC-D was measured in 23 patients with severe falciparum
malaria (seven of whom subsequently died), 30 patients with uncomplicated
malaria, and 17 healthy controls. The RBC-D, measured by ektacytometry, was
significantly reduced in severe malaria and was particularly low in all fatal
cases. At a low shear stress of 1.7 Pascal (Pa), a red blood cell elongation
index less than 0.21 on admission to the hospital predicted fatal outcome with a
sensitivity of 100% (confidence interval [CI] = 59-100%) and a specificity of 88%
(CI = 61-98%). The reduction in the RBC-D appeared to result mainly from changes
in unparasitized erythrocytes. Reduced deformability of unparasitized red blood
cells in severe malaria may contribute to impaired microcirculatory flow and a
fatal outcome in severe falciparum malaria.
PMID- 9392588
TI - Molecular investigation of a multisource outbreak of Crimean-Congo hemorrhagic
fever in the United Arab Emirates.
AB - During the investigation of an outbreak of Crimean-Congo hemorrhagic fever (CCHF)
in the United Arab Emirates (UAE) between 1994 and 1995, blood samples from
suspected CCHF cases and ticks collected from livestock were tested for CCHF
virus by antigen-capture ELISA and by a reverse transcription-polymerase chain
reaction. Phylogenetic analysis of partial small (S) segment nucleotide sequences
from four ticks and five human samples showed that with one exception, all the
human and tick viruses clustered along with samples from Pakistan and Madagascar
in one distinct lineage. Within this lineage, sequences from the UAE patients
were identical or closely related to those from three Hyalomma spp. ticks
obtained from livestock recently imported from Somalia. Another sequence from a
UAE patient was more closely related to a CCHF virus from Nigeria. These data
indicate that the 1994-1995 CCHF epidemic in the UAE was a multisource outbreak
possibly associated with importation of CCHF virus-infected livestock and ticks.
PMID- 9392589
TI - An outbreak of Crimean-Congo hemorrhagic fever in the United Arab Emirates, 1994
1995.
AB - A multi-faceted investigation was conducted in the United Arab Emirates to
characterize the epidemiologic and ecologic factors underlying an outbreak of
Crimean-Congo hemorrhagic fever (CCHF) noted in November 1994 among abattoir
workers. A chart review was conducted among hospitalized suspected cases of viral
hemorrhagic fever with onset between January 1994 and March 1995 coupled with
serologic testing of available specimens for the presence of virus antigen and
IgG and IgM antibodies by ELISA. Livestock handlers and animal skin processors
were interviewed and tested for the presence of IgG antibody. Sera from imported
and domestic ruminants were examined for antibody for CCHF virus, and ticks
collected from these animals were tested with an antigen-capture ELISA. Thirty
five suspected cases of CCHF were identified (case fatality = 62%). Livestock
market employees, abattoir workers, and animal skin processors accounted for 16
(57%) of 28 cases with known occupational status. Serologic evidence of past
asymptomatic infection was noted in 12 (4%) of 291 livestock and abattoir workers
but in none of the controls. Nineteen (7%) of 268 animals were positive for CCHF
virus antibodies by ELISA including 12 ruminants from Somalia and Iran and five
indigenous camels. One Hyalomma impeltatum and two H. excavatum from Somali
cattle and one H. anatolicum from a Somali goat were positive for CCHF virus
antigen.
PMID- 9392590
TI - Prevalence of antibodies to western equine encephalomyelitis and St. Louis
encephalitis viruses in residents of California exposed to sporadic and
consistent enzootic transmission.
AB - Sera from outpatients attending county health department clinics in areas of
California with consistent (Imperial Valley) and sporadic (Sacramento Valley)
enzootic transmission of western equine encephalomyelitis (WEE) and St. Louis
encephalitis (SLE) viruses exhibited neutralizing antibody prevalence rates of
1.3% (n = 690) and 0.5% (n = 1,066) for WEE and 11.0% and 0.8% for SLE,
respectively. Seroprevalence for SLE virus in Imperial County increased as a
function of both age and years of residence, indicating that this virus was
endemic with a low rate of annual infection. Of 26 sera that tested positive for
SLE virus antibody by an enzyme immunoassay, but were negative by plaque
reduction neutralization test, 14 (53%) had neutralizing antibody that reacted
with > or = one type of dengue (DEN) virus. The DEN virus infections presumably
were acquired elsewhere because neither the vectors nor DEN virus transmission
occurs in California. The low prevalence of neutralizing antibody for WEE and SLE
in the California human population indicated that despite recent increases in
enzootic transmission, contact between humans and infectious mosquitoes have
remained low.
PMID- 9392591
TI - Prospective study of Entamoeba dispar infection in a cohort of mothers and their
infants: relationship to serum antibody response.
AB - The sera of cohorts of newborn infants and their mothers, characterized as cyst
passers of Entamoeba with nonpathogenic zymodemes (E. dispar) and seropositive
for amoebic antigens, were analyzed. Both cohorts were followed for a period of
12 months by microscopic examination of feces and determination of serum anti
amoebic antibody titers using the indirect hemagglutination assay. Control groups
(noncyst passer mothers and their infants) were included and followed. To
characterize antigens involved in the induction of IgG and IgA antibody
responses, Western blots of serum from all participants were tested and
immunoplots of the frequency of antigenic recognition were constructed. Results
of clinical follow-up and microscopic examination of feces showed that during the
12-month period none of the cyst passer mothers had episodes of diarrhea
attributable to E. histolytica invasion; five of 21 children of cyst passer
mothers became infected during the study, five of five infected children
developed serum antiamebic antibodies (titers 1:64-1:128); none of the cohort of
children from cyst passer mothers had diarrhea due to E. histolytica. Western
blot analysis showed that there are antigenic fractions that induce serum
antibodies of the IgG and IgA classes against E. dispar very early in the host
parasite relationship. Our results suggest that mechanisms of antibody induction
different from intestinal invasion may be operating in amebic infection.
Intestinal absorption of antigen, systemic reflection of secretory antibody
response, and priming of newborns by maternal anti-idiotypic antibody transfer
are discussed.
PMID- 9392592
TI - Genetic epidemiology of seropositivity for Trypanosoma cruzi infection in rural
Goias, Brazil.
AB - Chagas' disease is a zoonotic disease found throughout Latin America. Despite
control programs in many of the affected countries, infection with Trypanosoma
cruzi continues to be a major public health concern. In Brazil alone,
approximately 53 million people live in endemic areas. Research with humans and
with animal models indicates that there is variation in susceptibility to
infection with T. cruzi. The reasons for this variation are not known although
several studies have implicated genetic factors. An indirect immunofluorescence
assay was used to assess seropositivity for T. cruzi infection in 716 adults from
the municipality of Posse, Goias, Brazil. Detailed genealogic information was
gathered at the time of sampling, which allowed assignment of 525 individuals to
146 pedigrees containing between two and 103 individuals; the remaining 191
unrelated individuals were retained as independents in the analysis. Using a
maximum likelihood variance decomposition approach, we performed quantitative
genetic analyses to determine if genetic factors could partially account for the
observed pattern of seropositivity. The maximum likelihood estimate of the
heritability of T. cruzi infection was 0.56 +/- 0.27 (mean +/- SE), indicating
that genetic factors account for more than half of the observed variation in
infection status. An additional 23% of the variation (c2 = 0.23 +/- 0.09) is
attributable to the effects of shared environment, as assessed by common
household. The results indicate that genetic factors play an important role in
determining epidemiologic patterns of T. cruzi infection. Further
characterization of these genetic factors may suggest new biologic areas to be
targeted by prevention and intervention programs.
PMID- 9392593
TI - Natural history of Giardia lamblia and Cryptosporidium infections in a cohort of
Israeli Bedouin infants: a study of a population in transition.
AB - The natural history of Giardia lamblia and Cryptosporidium infections were
determined in a cohort of 164 Bedouin children, from a population not previously
studied, which is in transition from nomadism to a settled life style. Stools
were sampled monthly from birth to two years of age and at all diarrhea episodes.
The risk of infection with G. lamblia and Cryptosporidium infection by age two
was 91.5% and 48.8%, respectively. Cryptosporidium prevalence was 3-4% at all
ages, whereas G. lamblia prevalence was > 30% after age one. Giardia lamblia and
Cryptosporidium asymptomatic detection rates were high, 28.5% and 1.6%,
respectively. Detection of G. lamblia was higher in diarrhea episode samples
obtained before six months of age, but after that age and overall, the detection
was lower than in nondiarrhea samples (odds ratio [OR] = 0.8, 95% confidence
interval [CI] = 0.7-0.9, P < 0.05). Detection rates of C. parvum were higher in
episode-related samples in all age groups (OR = 2.8, 95% CI = 1.9-4.2, P < 0.05)
and infections in boys were more frequently symptomatic than in girls. While G.
lamblia does not appear to be a consistent pathogen in this population where it
is hyperendemic, Cryptosporidium has been shown to be an important cause of
diarrhea in young children in the community.
PMID- 9392594
TI - The Matola malaria project: a temporal and spatial study of malaria transmission
and disease in a suburban area of Maputo, Mozambique.
AB - A temporal and spatial study of malaria transmission in a suburban area of
Maputo, Mozambique with a mean population density of 2,737/km2 was made from
December 1992 to June 1995. A steep but continuous gradient was observed in the
Plasmodium falciparum prevalence from 59.0% adjacent to the breeding sites to
5.4% only a few hundred meters distant. The entomologic inoculation rate ranged
from a number too low to be determined in some districts to 20 infectious bites
per person per year in the others. The risk of malaria was 6.2 times higher for
individuals living less than 200 meters from the breeding sites than for
individuals living 500 meters or more away from the breeding sites. In areas of
high human density, mosquito and parasite dispersion is very limited, and
therefore malaria control strategies could be more specifically targeted.
PMID- 9392595
TI - Pediatric malaria in Houston, Texas.
AB - We retrospectively reviewed the medical records of all infants and children (< 18
years of age) with the discharge diagnosis of malaria who were admitted to the
four major pediatric teaching hospitals in Houston, Texas from January 1988
through December 1993. Thirty-four cases of pediatric malaria were identified in
three newborns, 22 travelers, and nine recent immigrants. The travel destination
was West Africa in 68%, Central America in 14%, India in 14%, and unknown in 4%.
The location of the child's and parents' birthplace was available in 77% of the
travel-related cases and in all cases the destination of travel was the parents'
country of origin. The peak incident of the travel-related cases was late summer
and early January corresponding to return from summer or Christmas vacation.
Sixteen (75%) of the 22 travel-related cases had received either no prophylaxis
(12 of 22) or inadequate (4 of 22) chemoprophylaxis. Half of the patients who
were given appropriate chemoprophylaxis admitted to poor compliance. The clinical
presentation was usually nonspecific. Fever was the most common symptom (97%) and
was paroxysmal in one-third. Splenomegaly was the most common physical finding
(68%). The malaria species identified included Plasmodium falciparum (56%), P.
vivax (23%), P. malariae (3%), and unidentified (18%). Moderate anemia
(hemoglobin level = 7.0-10 g/dL) occurred in 38% and severe anemia (hemoglobin
level < 7.0 g/dL) in 29%. Three patients required transfusion. There were no end
organ complications. In summary, pediatric malaria in Houston was primarily seen
in immigrants or children of immigrants who returned to their native country.
Education and preventive strategies should target these families and should be
part of the routine well child care of these children.
PMID- 9392596
TI - Human schistosomiasis in Puerto Rico: reduced prevalence rate and absence of
Biomphalaria glabrata.
AB - A combined epidemiologic and malacologic survey of schistosomiasis in Puerto Rico
was carried out in areas where previous surveys had reported the prevalence of
the disease. This limited survey, with 495 persons examined, found a low
prevalence (0.6%) of Schistosoma mansoni infections. The infections were
restricted to three people more than 36 years of age. No infections were detected
in children 16 years of age or less, and this cohort comprised 57.8% of the study
group. Malacologic surveys of the four streams, 10 rivers, and eight lakes
throughout the island revealed the absence of intermediate host Biomphalaria
glabrata and the presence of Thiara granifera, a competitive species of B.
glabrata and the predatory snail Marisa cornuarietis. We believe that the absence
of B. glabrata is the primary reason for the sustained reduction in the
prevalence of schistosomiasis in Puerto Rico.
PMID- 9392597
TI - Short report: surveillance of rickettsial infections in Indonesian military
personnel during peace keeping operations in Cambodia.
AB - Indonesian peacekeepers in Cambodia provided a unique study population to
estimate the threat of rickettsial exposure to Rickettsia typhi (murine typhus),
Orientia tsutsugamushi, (scrub typhus), and R. conorii (spotted fever) for the
region. Prescreening prevalence measure showed a large proportion (36%) of
soldiers with antibodies to R. typhi. Predeployment prevalence for antibodies to
O. tsutsugamushi was 8%, with no evidence of background R. conorii infections.
Actual seroconversions of R. typhi (3) and O. tsutsugamushi (1), attributed to
exposure(s) in Cambodia, translated into annualized incidence rates of 24 and 8
per 1,000 per year, respectively. Surveillance of rickettsial infections and/or
disease is particularly warranted in Cambodia with recent recognition of drug
resistant scrub typhus in neighboring Thailand.
PMID- 9392598
TI - Intraspecimen fecal egg count variation in Schistosoma mansoni infection.
AB - To determine the degree of intraspecimen fecal egg count variation in Schistosoma
mansoni infection and its impact on commonly used parasitologic parameters
obtained by single egg counts, 10 25-mg Kato-Katz slides were prepared from each
of three stool specimens collected on different days in a study group of 20
infected people. Individual fecal egg counts in these series of examinations
varied considerably and this had profound consequences for the reliability of
both qualitative and quantitative diagnosis. In light infections, S. mansoni eggs
in stools appeared to be homogeneously mixed. However, this distribution became
heterogeneous as the intensity of infection increased, indicating clustering of
eggs in stool. The cumulative egg counts in the 10 slides of the same 20 people
examined in this study were compared with those in 14 slides prepared from seven
stool samples collected on different days. This revealed significantly different
mean egg counts for six people, even after such exhaustive series of
examinations. Intraspecimen variation also biased considerably some operational
parameters used to determine the infection status at the group level,
particularly when these were determined by the examination of single 25-mg
slides. The examination of duplicate or multiple slides improved the
intraspecimen estimates of these parameters but did not overcome day-to-day
variation. The examination of fewer samples taken on different days proved to be
more adequate than examining more slides from one stool specimen for the
determination of precise estimates of the real infection status.
PMID- 9392599
TI - Distribution, diversity, and host specificity of Bartonella in rodents from the
Southeastern United States.
AB - A number of Bartonella isolates were obtained from seven species of rodents
sampled from 12 geographic sites representing the major biotic communities of the
southeastern United States. Bartonella were isolated from the blood of 42.2% of
279 tested rodents. The highest prevalence of infection typically occurred among
the most commonly captured species in the rodent community. Four phylogenetic
groups, uniting 14 genotypic variants of Bartonella, were identified by sequence
analysis of the citrate synthase gene. The level of sequence homology between
genotypic groups varied from 88.8% to 96.4%, and the degree of homology among
variants within groups was > or = 97%. Cotton rats (Sigmodon hispidus) harbored
up to three phylogenetic groups of Bartonella at a single site, and Bartonella of
two phylogenetic groups were isolated from a single rodent. All the Bartonella
isolated from three species of Peromyscus clustered in a single distinct
phylogenetic group, suggesting some host specificity may occur. Mouse ascitic
fluids produced in BALB/c mice inoculated with Bartonella of three phylogenetic
groups demonstrated high indirect fluorescent antibody (IFA) titers to homologous
antigens. However, use of eight Bartonella antigens in an IFA test with sera from
394 wild-caught rodents resulted in either little or extremely low titers of
antibody.
PMID- 9392600
TI - Acquisition of Lyme disease spirochetes by cofeeding Ixodes scapularis ticks.
AB - Ixodes scapularis ticks acquired spirochetes while cofeeding with Borrelia
burgdorferi-infected nymphs (donors) on uninfected naive gerbils. Overall, 19%
(67 of 345) of the recipient nymphs randomly exposed to gerbils with donor nymphs
acquired spirochetes by fluorescent antibody (FA) tests, 18% (62 of 345) by the
polymerase chain reaction. In a second experiment, donor nymphs were placed on
the left ears, recipient nymphs were placed on the left and right ears, and
xenodiagnostic larvae were placed on the gerbils' backs. Only recipient nymphs
and larvae removed from the left ears were infected with B. burgdorferi.
Infection rates were 47% (9 of 19), 87% (13 of 15) and 88% (14 of 16) in
recipient nymphs placed on gerbils 0, 3, or 5 days after the donor nymphs,
respectively, and 48% (12 of 25) in the larvae by FA analysis. Spirochetes appear
to be acquired by cofeeding ticks from a localized infection near the feeding
site rather than from a disseminated infection in the skin or blood.
PMID- 9392601
TI - Differential effects of human serum and cells on the growth of Plasmodium
falciparum adapted to serum-free in vitro culture conditions.
AB - A single Plasmodium falciparum isolate was adapted for growth in serum-free
culture medium. The parasitemia increased from 0.5% to 20% on day 7 after
thawing. The asexual forms of the parasites appeared morphologically normal and
pigment formation was comparable with that seen under standard conditions with
serum present. Parasites were coincubated in 96-well plates with serum,
peripheral blood mononuclear cells (PBMC), and PBMC in the presence of autologous
serum from healthy non-immune individuals (n = 12), healthy semi-immune
individuals (n = 12), and malaria patients (n = 7). Growth was monitored for six
days. The concentration of interleukin-6 and interferon-gamma (IFN-gamma) in
supernatants from the continuous cultures were measured by a bioassay and an
enzyme-amplified sensitivity immunoassay. The results of this study showed that
parasites cultured in serum-free medium in the presence of PBMC develop more
rapidly, particularly with cells from malaria patients, compared with parasites
cultured alone. The growth of parasites was different if 10% autologous serum was
added to the culture. Parasite growth with sera from acutely infected individuals
was similar with that with sera from aparasitemic, nonimmune individuals, and
both supported significantly higher parasite growth over the six-day culture
period compared with sera from the uninfected semi-immune individuals. Production
of IFN-gamma by cells from nonimmune individuals and malaria patients was higher
when cultures did not contain autologous serum. Nonimmune donor cells produced
high amounts of IFN-gamma, but cells from the semi-immune donors produced little
of this cytokine. There was no marked inhibition of parasite growth with any
combination of serum and cells over six days of culture. A difference between the
groups was observed after two days of culture, when growth with cells and serum
from the uninfected, semi-immune group was significantly lower than that from the
nonimmune group, but this was not subsequently sustained. The results of the
study show that continuous cultivation of P. falciparum in serum-free medium
provides a novel in vitro model to study mechanisms of the interplay between
components of the human immune system and the malarial parasite, in which any
possible influence of human serum is removed.
PMID- 9392602
TI - Risk factors for cholera infection in the initial phase of an epidemic in Guinea
Bissau: protection by lime juice.
AB - Previous studies of cholera transmission have been conducted in the middle or at
the end of an epidemic. Since modes of transmission could be different in
different phases of an epidemic, we initiated a case-referent study immediately
after the first cases had been hospitalized in a recent cholera epidemic in
Guinea-Bissau in West Africa in October 1994. The cases investigated were
consecutive adult patients resident in the capital of Bissau who were admitted
the the National Hospital during the first two weeks of the epidemic. Referents
were matched for district, gender, and age. The study showed a protective effect
of using limes in the main meal (odds ratio [OR] = 0.2, 95% confidence interval
[CI] = 0.1-0.3) and having soap in the house (OR = 0.3, 95% CI = 0.1-0.8). Not
eating with the fingers and using water from a public standpipe were also
protective. No specific source or mode of transmission was identified. Thus,
cholera control programs in Africa may have to emphasize general hygienic
conditions and the use of acidifiers in food preparation.
PMID- 9392603
TI - Kinetic study of Russell's viper venom in envenomed patients.
AB - Serum levels of Russell's viper venom in 30 patients bitten by Russell's viper
were measured by an ELISA. In the initial serum samples, which were collected
immediately after admission to the hospital (0.5-19 hr after the bite), venom was
detected in 24 patients (80%), with levels ranging from 3 to 92 ng/ml. These
levels correlated well with the patient's clinical signs. At 6-12 hr after
antivenom therapy, the venom levels in most of the serum samples (21 of 24, 87%)
had decreased to undetectable levels. In the remaining patients, whose serum
venom levels could be detected 36-72 hr after therapy, the levels varied
according to the effect of the antivenom therapy and the release of venom from a
deposit at the bite site.
PMID- 9392604
TI - Prospective study of tetanus-induced acute renal dysfunction: role of adrenergic
overactivity.
AB - To assess the mechanisms related to tetanus-induced acute renal failure (ARF), 30
patients with tetanus had their renal function prospectively studied and factors
possibly related to renal changes were evaluated during four weeks of
hospitalization. Fifty percent of these patients had a glomerular filtration rate
(GFR) < or = 50 ml/min in the first or second week of hospitalization (Group I)
and 50% had a GFR > 50 ml/min throughout the entire hospitalization period (Group
II). Age, gender, tetanus incubation time and tetanus onset time, hospitalization
time, use of nephrotoxic drugs, need for mechanical ventilation with intermittent
positive pressure, and presence of systemic infection were similar in both
groups. None of the patients presented with oliguria. Autonomic nervous system
(ANS) overactivity, characterized by intense variations in systolic and diastolic
blood pressure, by increased heart rate and elevated urinary metanephrine
excretion, was higher in Group I compared with Group II. Plasma renin activity,
serum creatinephosphokinase levels, and myoglobinuria were not significantly
different between the two groups. These results strongly suggest that tetanus
induced ARF has a high prevalence, is characterized by early onset, and is
probably related to ANS overactivity.
PMID- 9392605
TI - Discovery of encysted Paragonimus westermani eggs in the omentum of an
asymptomatic elderly woman.
AB - We report a case of asymptomatic chronic infiltrate of the omentum by eggs of
Paragonimus westermani in an elderly woman who had immigrated to Taiwan from
mainland China 46 years ago. The patient had a habit of eating raw freshwater
crabs from the lakes of eastern China during her period of residence in that
country. She stopped eating raw crabs after coming to Taiwan 20 years ago. During
surgery for a peptic ulcer complicated by severe bleeding in 1995, her omentum
was found to contain many small nodules approximately 2 x 2 x 1.5 cm in size.
Biopsy of the nodules revealed eggs of P. westermani embedded in necrotic debris
surrounded by capsules. A sputum examination result was negative and a chest
radiograph was normal. The majority of the nodules in the omentum were removed
during the surgery and praziquantel was given. At the present time, the patient
remains asymptomatic.
PMID- 9392606
TI - Cellular and humoral immune responses of hydatidosis patients to Echinococcus
granulosus purified antigens.
AB - The cellular and humoral immune responses of 41 hydatidosis patients, 12 healthy
uninfected individuals, and seven patients with other parasitic diseases were
determined using serologic and lymphoproliferative assays (LPAs), respectively.
Echinococcal antigens were obtained by gel filtration of crude hydatid cyst fluid
(HCF) on a Sephadex G-200 column. The fractions contained either a mixture of
antigens A plus B or antigen B alone that was further enriched by boiling. All
the hydatidosis patients responded positively by LPA to either crude or purified
echinococcal antigens: 95% of them responded to either crude HCF, or a mixture of
antigens A plus B and 83% to antigen B alone. The degree of the response to crude
HCF (mean stimulation index [SI] = 75.3) was higher than that of purified
antigens (SI = 39.1 for a mixture of antigens A plus B and SI = 36.9 for antigen
B alone). No positive LPA response was obtained with the control groups.
Serologic examinations showed that 78% of cases were positive by immunoblot, 73%
by indirect hemagglutination, and 46% by immunoelectrophoresis. No correlation
between the degree of cellular and humoral responsiveness to both crude and
purified echinococcal antigens was observed. Nine of the 41 patients examined who
were serologically negative also developed a high lymphoproliferative (LP)
response to either crude or purified echinococcal antigens. The LP response
remained positive over a long period after successful treatment. No relationship
was observed between the results of treatment and the LP response. The present
study indicates that the LPA could be used as an additional tool for the
diagnosis of hydatid disease, particularly in seronegative cases, although it is
unsuitable for effective monitoring treatment/surgery.
PMID- 9392607
TI - Characterization of a recombinant Onchocerca volvulus antigen (Ov33) produced in
yeast.
AB - A yeast (Saccharomyces cerevisiae) expression system has been adapted to produce
reagent quantities of a major Onchocerca antigen, Ov33. Using a pool of
monoclonal antibodies produced against third-stage larvae, a cDNA library
constructed from adult O. volvulus worms was screened. Twenty-seven cDNAs were
isolated, two of which had sequence homology to Ov33, a putative aspartyl
protease inhibitor, which is the immunodominant antigen of O. volvulus. These
cDNAs were expressed at high levels intracellularly or through the secretory
pathway of S. cerevisiae. Localization studies using antisera produced against
purified recombinant protein demonstrated that Ov33 is a very abundant parasite
protein present in the hypodermis, muscle, and uterus of female worms, as well as
in embryonic microfilariae. The soluble recombinant protein secreted by yeast
(C71) demonstrated inhibitory activity against the aspartyl protease pepsin.
Antibodies to the recombinant protein-mediated leukocyte adherence to and killing
of skin microfilariae. The sensitivity of a diagnostic test using recombinant
Ov33 was evaluated using sera from 441 patients. The mean sensitivities for the
two recombinant constructs, C27 and C71, were 82.2% and 85.4%, respectively. The
combined sensitivity using both recombinant proteins was 94%.
PMID- 9392608
TI - Pesticides and breast cancer: fact or fad?
PMID- 9392609
TI - Survival after treatment of small-cell lung cancer: an endless uphill battle.
PMID- 9392610
TI - Genetic tests for many rare diseases headed for orphan status.
PMID- 9392611
TI - Chernobyl "liquidators" show increased risk of suicide, not cancer.
PMID- 9392612
TI - Panel makes point about acupuncture.
PMID- 9392614
TI - What causes thyroid cancer?
PMID- 9392613
TI - Treatments sought for intractable forms of thyroid cancer.
PMID- 9392615
TI - NCI selects first Director's Consumer Liaison Group.
PMID- 9392616
TI - A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer
Syndrome: meeting highlights and Bethesda guidelines.
PMID- 9392617
TI - Biology of cachexia.
AB - About half of all cancer patients show a syndrome of cachexia, characterized by
loss of adipose tissue and skeletal muscle mass. Such patients have a decreased
survival time, compared with the survival time among patients without weight
loss, and loss of total body protein leads to substantial impairment of
respiratory muscle function. These changes cannot be fully explained by the
accompanying anorexia, and nutritional supplementation alone is unable to reverse
the wasting process. Despite a falling caloric intake, patients with cachexia
frequently show an elevated resting energy expenditure as a result of increases
in Cori cycle (i.e., catalytic conversion of lactic acid to glucose) activity,
glucose and triglyceride-fatty acid cycling, and gluconeogenesis. A number of
cytokines, including tumor necrosis factor-apha, interleukins 1 and 6, interferon
gamma, and leukemia-inhibitory factor, have been proposed as mediators of the
cachectic process. However, the results of a number of clinical and laboratory
studies suggest that the action of the cytokines alone is unable to explain the
complex mechanism of wasting in cancer cachexia. In addition, cachexia has been
observed in some xenograft models even without a cytokine involvement, suggesting
that other factors may be involved. These probably include catabolic factors,
which act directly on skeletal muscle and adipose tissue and the presence of
which has been associated with the clinical development of cachexia. A
polyunsaturated fatty acid, eicosapentaenoic acid, attenuates the action of such
catabolic factors and has been shown to stabilize the process of wasting and
resting energy expenditure in patients with pancreatic cancer. Such a
pharmacologic approach may provide new insights into the treatment of cachexia.
PMID- 9392618
TI - Environmental estrogen stimulation of growth and estrogen receptor function in
preneoplastic and cancerous human breast cell lines.
AB - BACKGROUND: DDT and polychlorinated biphenyls (PCBs), which are widespread in the
ecosystem, can mimic estrogen-mediated cell activities. Thus, they can
potentially interfere with many physiologic processes. We compared the effects of
organochlorines belonging to the DDT and PCB families, alone and in combination,
for their ability to influence the estrogen receptor-mediated activities in
preneoplastic breast epithelial cells and breast cancer cells. METHODS: Multiple
assay systems requiring functional estrogen receptor were employed to test
estrogen-like activity of organochlorine ligands. Two-sided statistical tests
were used to compare the data. RESULTS: p,p'-DDT, the predominant form of DDT in
the environment, is a more potent estrogen than o,p'-DDT (P<.001), although it is
less effective than o,p'-DDT in inhibiting the binding of estradiol (natural
estrogen) to estrogen receptor. Among the PCBs, Heptachlor is estrogenic (in
transient reporter assays; P< or =.001), whereas Aroclor 1221 and Aroclor 1254,
both individually and in combination, are only weakly estrogenic. CONCLUSION:
p,p'-DDT is the most effective organochlorine in regulating estrogen receptor
mediated cellular responses. In estrogen receptor-positive breast cancer cells,
p,p'-DDT evokes responses by itself and enhances the responses in collaboration
with estradiol or o,p'-DDT.
PMID- 9392619
TI - Second primary cancers related to smoking and treatment of small-cell lung
cancer. Lung Cancer Working Cadre.
AB - BACKGROUND: An increased risk of second primary cancers has been reported in
patients who survive small-cell carcinoma of the lung. The treatment's
contribution to the development of second cancers is difficult to assess, in part
because the number of long-term survivors seen at any one institution is small.
We designed a multi-institution study to investigate the risk among survivors of
developing second primary cancers other than small-cell lung carcinoma. METHODS:
Demographic, smoking, and treatment information were obtained from the medical
records of 611 patients who had been cancer free for more than 2 years after
therapy for histologically proven small-cell lung cancer, and person-years of
follow-up were cumulated. Population-based rates of cancer incidence and
mortality were used to estimate the expected number of cancers or deaths. The
actuarial risk of second cancers was estimated by the Kaplan-Meier method.
RESULTS: Relative to the general population, the risk of all second cancers among
these patients (mostly non-small-cell cancers of the lung) was increased 3.5
fold. Second lung cancer risk was increased 13-fold among those who received
chest irradiation in comparison to a sevenfold increase among nonirradiated
patients. It was higher in those who continued smoking, with evidence of an
interaction between chest irradiation and continued smoking (relative risk = 21).
Patients treated with various forms of combination chemotherapy had comparable
increases in risk (9.4- to 13-fold, overall), except for a 19-fold risk increase
among those treated with alkylating agents who continued smoking. IMPLICATIONS:
Because of their substantially increased risk, survivors should stop smoking and
may consider entering trials of secondary chemoprevention.
PMID- 9392621
TI - Phase I study of human chorionic gonadotropin given subcutaneously to patients
with acquired immunodeficiency syndrome-related mucocutaneous Kaposi's sarcoma.
AB - BACKGROUND: In vitro and in vivo clinical studies have shown that certain
preparations of human chorionic gonadotropin have antitumor activity against
Kaposi's sarcoma, the most common tumor in patients infected with human
immunodeficiency virus type 1 (HIV-1). METHODS: A phase I trial was conducted in
18 male patients with acquired immunodeficiency syndrome-related Kaposi's
sarcoma. Successive cohorts of six patients each received human chorionic
gonadotropin (A.P.L.; Wyeth-Ayerst, Radnor, PA) subcutaneously at doses of 5000
IU daily (level I), 10,000 IU three times a week (level II), or 10,000 IU daily
(level III). Toxic effects, changes in reproductive hormone levels, HIV-1 RNA
plasma levels, and response to therapy were evaluated. RESULTS: A.P.L. treatment
was well tolerated at all dose levels, and no maximum-tolerated, dose-defined
toxic effects were observed at the highest dose tested. The most common side
effects were weight gain, increased libido, and increased energy. A persistent
increase in testosterone level and a persistent decline in luteinizing hormone
and follicle-stimulating hormone levels were seen over time. Major responses were
observed in six patients. Partial remissions (> or =50% decrease in lesion
numbers, volume, or surface area) were observed at dose level I and dose level II
(two patients each); biopsy-confirmed complete remissions (resolution of all
lesions) were observed at dose level III (two patients). All but one major
response have persisted from 207 to more than 515 days. Nine patients had stable
disease lasting 10 weeks or longer. CONCLUSIONS: A.P.L. given at daily doses
ranging from 5000 to 10,000 IU has antitumor activity in patients with acquired
immunodeficiency syndrome-related Kaposi's sarcoma. A.P.L. can be given for more
than 1 year with minimal side effects. Larger efficacy studies are warranted.
PMID- 9392620
TI - Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with
intravenous melphalan.
AB - BACKGROUND: Increased intracellular glutathione has long been associated with
tumor cell resistance to various cytotoxic agents. An inhibitor of glutathione
biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been shown to enhance the
cytotoxicity of chemotherapeutic agents in vitro and in vivo. We performed a
phase I study of BSO administered with the anticancer drug melphalan to determine
the combination's safety/tolerability and to determine clinically whether BSO
produced the desired biochemical end point of glutathione depletion (<10% of
pretreatment value). METHODS: Twenty-one patients with advanced cancers received
an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a
continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per
hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four
patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per
hour for 48 hours (three patients). During week 1, the patients received BSO
alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2);
thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione
concentrations in peripheral blood lymphocytes were determined for all patients;
in 10 patients on three of the administration schedules, these measurements were
made in multiple sections from tumor biopsy specimens taken before, during, and
after continuous-infusion BSO. RESULTS: Continuous-infusion BSO alone produced
minimal toxic effects, although BSO plus melphalan produced occasional severe
myelosuppression (grade 4) and frequent low-grade nausea/vomiting (grade 1-2).
This treatment also produced consistent, profound glutathione depletion (<10% of
pretreatment value). The degree of glutathione depletion in peripheral
lymphocytes was considerably less than that observed in tumor sections.
CONCLUSIONS: Continuous-infusion BSO is relatively nontoxic and results in
depletion of tumor glutathione.
PMID- 9392622
TI - Growth inhibition of human ovarian cancers by cytotoxic analogues of luteinizing
hormone-releasing hormone.
AB - BACKGROUND: Receptors for luteinizing hormone-releasing hormone (LH-RH) are found
in nearly 80% of human ovarian cancers. The chemotherapeutic agent doxorubicin
can be linked to [D-lysine6]LH-RH to form a cytotoxic analogue (AN-152) that may
have greater specificity for tumor cells. This study was conducted to investigate
the effects of AN-152 on the growth of LH-RH receptor-positive OV-1063 human
epithelial ovarian cancers. METHODS: Nude mice bearing human ovarian tumors, OV
1063 or UCI-107 (LH-RH receptor negative), were injected intraperitoneally with
saline (control) or with equimolar doses of AN-152 or doxorubicin; experiments
involving mice with OV-1063 tumors also included groups that were administered [D
lysine6]LH-RH either alone or in combination with doxorubicin. Tumor volume,
weight, doubling time, and burden (i.e., tumor weight/body weight) as well as
tumor apoptotic and mitotic indices were determined. The levels of receptors for
LH-RH and epidermal growth factor (EGF) and their messenger RNAs were measured by
use of radioreceptor and reverse transcription-polymerase chain reaction assays,
respectively. RESULTS: The growth of OV-1063 ovarian tumors in nude mice, as
based on reduction in tumor volume, was inhibited significantly (all P<.05, two
sided) 4 weeks after treatment with AN-152, even at the lowest dose tested (413
nmol/20 g weight); the toxic effects of an equivalent dose of doxorubicin caused
substantial mortality. High-affinity receptors for LH-RH and EGF were found on
cell membranes of OV-1063 cancers; however, after in vivo treatment with AN-152,
LH-RH receptor-binding sites were not detectable and EGF receptors were reduced
in number. The growth of UCI-107 ovarian cancers was not inhibited by AN-152.
CONCLUSIONS: In nude mice bearing LH-RH receptor positive OV-1063 epithelial
ovarian cancers, systemic administration of AN-152 is less toxic and inhibits
tumor growth better than equimolar doses of doxorubicin.
PMID- 9392623
TI - Re: Recent trends in U.S. breast cancer incidence, survival, and mortality rates.
PMID- 9392624
TI - Re: A science for the art of consensus.
PMID- 9392625
TI - Loss of imprinting of the IGF2 gene in a Wilms' tumor in an adult.
PMID- 9392626
TI - Shiga toxin mode of action in E. coli O157:H7 disease.
AB - Shiga toxins (Stx) are virulence factors produced by selected bacteria pathogenic
for humans. These multicomponent protein complexes are among the more potent
toxins known. As inhibitors of eukaryotic protein synthesis, these toxins
selectively inactivate ribosomes in an enzymatic manner. Specificity of cell
targeting is determined by the high-affinity binding of Stx to its receptor, a
glycosphingolipid (Gb3) located in the plasma membrane or some eukaryotic cells.
Elaborated by food-borne E. coli O157:H7 bacteria, isotypes of Stx (Stx1 & Stx2)
are required for the ensuing vascular changes in humans, including hemorrhagic
colitis and renal hemolytic uremic syndrome. Experimental therapeutic
intervention of Stx-associated disease includes the Stx receptor immobilized on
biologically inert particles designed for oral presentation.
PMID- 9392686
TI - Immunophenotyping of B lymphocytes by multiparametric flow cytometry in bone
marrow aspirates and peripheral blood of healthy adults.
AB - Establishing reference ranges by multiparametric immunophenotyping of mature B
cells in bone marrow and peripheral blood of healthy adults is of interest
because the detection of bone marrow infiltration, persistance of light chain
restriction as well as discrimination between reactice and malignant lymphocytes
are important applications of B-cell immunophenotyping. To determine the pattern
of antigens as expressed by malignant mature B lymphocytes, bone marrow aspirates
and peripheral blood of healthy adults in the present study were investigated for
the presence and percentage frequency of those antigens as defined for
immunophenotyping of B-cells by the REAL-Classification. For this purpose
analysis of CD19 positive B lymphocytes by Live Gate analysis was performed. The
established two-color as well as three-color stainings will serve as a basis for
future investigations designed to test multiparametric analysis of B lymphocytes
in bone marrow aspirates and peripheral blood. In conclusion, all investigated
antibodies stained in varying percentage frequency on B-cell subtypes and
statistical significant differences could be considered only for the CD19/CD10
staining in bone marrow aspirates. On the basis of this analysis, all the
reported lineage antigen combinations are present both in malignant B lymphocytes
as well as normal B cells in considerable percentage frequency. These findings
are of important interest for follow-up investigations of patients with non
Hodgkin s lymphomas by multiparametric immunophenotyping.
PMID- 9392687
TI - Decreased function of monocytes and granulocytes during HIV-1 infection
correlates with CD4 cell counts.
AB - Monocytes and neutrophils are involved in the primary immune response against
opportunistic infections that occur during the progression of human
immunodeficiency virus (HIV) infection towards development of acquired immune
deficiency syndrome (AIDS). Phagocytic cells operate through the generation of
reactive oxygen species which may be toxic for fungi, bacteria and viruses. In
the present study we evaluated the function of monocytes and granulocytes in
whole blood samples of 16 healthy controls, 12 HIV infected subjects who had not
undergone significant infections and of 17 individuals with AIDS. Using flow
cytometric methods we were able to determine phagocytosis and respiratory burst
under conditions that reflect the normal environment of these cells. Compared
with results in samples from controls, granulocytes and monocytes from
asymptomatic HIV infected patients exhibited a significantly increased capacity
to phagocytose bacteria. The production of reactive oxygen intermediates was in
the normal range. In comparison to asymptomatic HIV infected individuals,
patients with AIDS showed a significant reduction of phagocytosis and respiratory
burst which correlated with the number of CD4+ cells. In comparison to controls,
patients infected with HIV, whether they were symptomatic or not, revealed a
significantly diminished number of oxygen radical producing cells compared with
the number of phagocytic cells. These results indicate that monocytes and
granulocytes show reduced antimicrobial activity even in early stages of HIV
infection. This defect is only partly due to the HIV infection itself as
neutrophils are not target cells for HIV.
PMID- 9392688
TI - Biotransformation and uric acid lowering effect of benzbromarone in patients with
liver cirrhosis - evidence for active benzbromarone metabolites?
AB - The disposition of benzbromarone and its uric acid lowering effect were
investigated in 8 patients with compensated liver cirrhosis in order to obtain
evidence whether dose requirements differ from subjects with normal liver
function. Following a single oral dose of 100 mg benzbromarone, the plasma
concentrations of the parent drug and the two hydroxylated main metabolites M1
and M2 as well as uric acid were determined up to at least 72 h. All patients
were found to be rapid benzbromarone eliminators. In patients 2-8 the extent of
systemic availability of benzbromarone, as estimated by the average AUC(0
infinite), was similar to previous observations in healthy individuals, whereas
the values of both metabolites M1 and M2 tended to be lower in patients with
liver cirrhosis. Cmax of benzbromarone and M1 also were lower in patients, M2 was
equivalent to the data in subjects with normal liver function. tmax and the
plasma elimination half-life t(1/2) varied within the same range as previously
observed in healthy individuals. One patient exhibited much higher values in
AUC(0-infinite); and Cmax of benzbromarone and both metabolites, and in addition
of the elimination half-life of M1 and M2, whereas the plasma elimination of
benzbromarone itself was not delayed. An effect of altered liver function cannot
be excluded in this patient. Ten hours after benzbromarone administration the
mean plasma uric acid in patients 2-8 was reduced by 31.5% and in patient 1 by
44.2% as compared to pretreatment values. Baseline levels were not regained until
72 h. These data are compatible with a prolonged uric acid lowering effect of an
active benzbromarone metabolite. Altogether, the present observations do not
suggest dose adjustment to be necessary in patients with compensated liver
cirrhosis Child A and B.
PMID- 9392690
TI - The influence of electromagnetic fields on human brain activity.
AB - Possible effects of electromagnetic fields on human brain activity were studied.
In a single-blind, cross-over-designed and placebo-controlled study 36 volunteers
were exposed firstly to an electromagnetic field originating form a MediLine
"MEGA-WAVE 150/1" therapy instrument and secondly to a field originating from a
mobile, digital tetlephone as used for wireless telecommunication. All volunteers
also underwent a control experiment with no field exposure. Application of the
MEGA-WAVE instrument caused an increase in EEG power in the frequency bands
Alpha2, Beta1 and Beta2 during and after field exposure. Operation of the mobile
telephone caused an increase in the same frequency bands with a delay of
approximately 15 minutes after exposure.
PMID- 9392689
TI - High incidence of antibodies to 5-hydroxytryptamine, gangliosides and
phospholipids in patients with chronic fatigue and fibromyalgia syndrome and
their relatives: evidence for a clinical entity of both disorders.
AB - The fibromyalgia syndrome (FMS) is one of the most frequent rheumatic disorders
showing a wide spectrum of different symptoms. An association with the chronic
fatigue syndrome (CFS) has been discussed. Recently, a defined autoantibody
pattern consisting of antibodies to serotonin (5-hydroxytryptamine, 5-HT),
gangliosides and phospholipids was found in about 70% of the patients with FMS.
We were therefore interested in seeing whether patients with CFS express similar
humoral immunoreactivity. Sera from 42 CFS patients were analysed by ELISA for
these antibodies, and the results were compared with those previously observed in
100 FMS patients. 73% of the FMS and 62% of the CFS patients had antibodies to
serotonin, and 71% or 43% to gangliosides, respectively. Antibodies to
phospholipids could be detected in 54% of the FMS and 38% of the CFS patients.
49% of FMS and 17% of the CFS patients had all three antibodies in parallel, 70%
and 55%, respectively had at least two of these antibody types. 21% of FMS and
29% of CFS patients were completely negative for these antibodies. Antibodies to
5-HT were closely related with FMS/CFS while antibodies to gangliosides and
phospholipids could also be detected in other disorders. The observation that
family members of CFS and FMS patients also had these antibodies represents an
argument in favour of a genetic predisposition. These data support the concept
that FMS and CFS may belong to the same clinical entity and may manifest
themselves as 'psycho-neuro-endocrinological autoimmune diseases'.
PMID- 9392691
TI - Erythrocyte indices as screening tests for the differentiation of microcytic
anemias.
AB - Algorithms for the differential diagnosis of anemias are commonly based on
suspected incidences and simple laboratory parameters. Especially microcytic
anemias are diagnosed using algorithms created in Mediterranean or Northern
American regions. In a West German region we observe relatively high diagnostic
uncertainty regarding common forms of anemias. As a hypothesis, this may be a
result of inadequate algorithms not designed for regions with high incidences of
anemias of chronic disease and low incidences of thalassemias. To further
elucidate diagnostic problems we here report the frequencies of anemias in
university hospital outpatients. Based on these data, the diagnostic values of
different erythrocyte indices and of red cell distribution width in the
differential diagnosis of anemias were calculated. 4525 patient files were
reviewed retrospectively. 872 patients presented with anemia, 107 of which were
hereditary forms and 765 of other forms. In hereditary anemias the frequency of
thalassaemias (50 patients) and corpuscular hemolytic anemias (49 patients) was
the same. Nearly half of the other anemias were covered by anemias of chronic
disease and true iron deficiency anemias. Several indices intended to separate
thalassemias from other microcytic anemias were tested for relevance. Sensitivity
was between 0.75 and 0.85. Specificity was between 0.78 and 0.95. Red cell
distribution width was not significantly different between thalassemias and iron
deficiency. Only a red cell distribution width above 17.0 resulted in a
specificity for iron deficiency of 0.91. Red cell distribution width is
considered to be an unreliable screening test in a population with a low
incidence of thalassemias. The high incidence of anemias of chronic disease in
the region investigated should lead to more complex diagnostic procedures than
offered by blood count values alone.
PMID- 9392692
TI - Metabolism of apolipoprotein B in primary moderate hypercholesterolaemia: effects
of acipimox and cholestyramine therapy.
AB - The effects of combined therapy with acipimox (1250 mg/day) and cholestyramine
(20 g/day) were examined in a group of 7 subjects with primary moderate
hypercholesterolaemia (total cholesterol >=7 mmol/L). Radiolabeled VLDL
subfraction turnovers were performed at baseline, during acipimox therapy and
during combined therapy. Acipimox and combined therapies lowered plasma low
density lipoprotein (LDL)-cholesterol by 20% (P<0.001) and 27% (P<0.001)
respectively. The marked fall in LDL-cholesterol associated with acipimox
therapy, was due to a reduced production rate of LDL (apolipoprotein) apoB. This
is shown to be a result of reduced direct LDL apoB production, reduced IDL to LDL
transfer consistent with inhibition of hepatic triglyceride lipase, and with a
reduction in the overall throughput of VLDL1 apoB. With combined therapy both
reduced production and increased catabolism of apoB containing LDL precursors and
of LDL itself have to be invoked to explain the fall in plasma LDL-cholesterol.
PMID- 9392693
TI - Talc granuloma of the uterus.
AB - A 40-year-old woman presented with acute obstructive lung disease. She was
treated with steroids and achieved a good response. However, she had two previous
pelvic operations with histological findings of uterine serosal caseating
granulomas presenting in the latter operation. Antituberculosis (TB) prophylaxis
was suggested due to the suspicion of TB reactivation under steroid management.
Investigation for TB infection or exposure was negative while revision of the
histological slides disclosed talc granulomas. Although talc granuloma is
reported in starch powder gloves which should not contain talc, it is still very
uncommon.
PMID- 9392695
TI - Alcohol consumption and mortality among middle-aged and elderly U.S. adults.
AB - BACKGROUND: Alcohol consumption has both adverse and beneficial effects on
survival. We examined the balance of these in a large prospective study of
mortality among U.S. adults. METHODS: Of 490,000 men and women (mean age, 56
years; range, 30 to 104) who reported their alcohol and tobacco use in 1982,
46,000 died during nine years of follow-up. We compared cause-specific and rates
of death from all causes across categories of base-line alcohol consumption,
adjusting for other risk factors, and related drinking and smoking habits to the
cumulative probability of dying between the ages of 35 and 69 years. RESULTS:
Causes of death associated with drinking were cirrhosis and alcoholism; cancers
of the mouth, esophagus, pharynx, larynx, and liver combined; breast cancer in
women; and injuries and other external causes in men. The mortality from breast
cancer was 30 percent higher among women reporting at least one drink daily than
among nondrinkers (relative risk, 1.3; 95 percent confidence interval, 1.1 to
1.6). The rates of death from all cardiovascular diseases were 30 to 40 percent
lower among men (relative risk, 0.7; 95 percent confidence interval, 0.7 to 0.8)
and women (relative risk, 0.6; 95 percent confidence interval, 0.6 to 0.7)
reporting at least one drink daily than among nondrinkers, with little relation
to the level of consumption. The overall death rates were lowest among men and
women reporting about one drink daily. Mortality from all causes increased with
heavier drinking, particularly among adults under age 60 with lower risk of
cardiovascular disease. Alcohol consumption was associated with a small reduction
in the overall risk of death in middle age (ages 35 to 69), whereas smoking
approximately doubled this risk. CONCLUSIONS: In this middle-aged and elderly
population, moderate alcohol consumption slightly reduced overall mortality. The
benefit depended in part on age and background cardiovascular risk and was far
smaller than the large increase in risk produced by tobacco.
PMID- 9392696
TI - Epidural analgesia compared with combined spinal-epidural analgesia during labor
in nulliparous women.
AB - BACKGROUND: Among nulliparous women, there appears to be an association between
the use of epidural analgesia during labor and an increased risk of dystocia. We
tested the hypothesis that combined spinal-epidural analgesia, which permits
ambulation during labor, is associated with a lower incidence of dystocia than
continuous lumbar epidural analgesia. METHODS: Between July 1995 and September
1996, we randomly assigned 761 nulliparous women in spontaneous labor at term who
requested epidural analgesia to receive either continuous lumbar epidural
analgesia or a combination of spinal and epidural analgesia. Among the women who
received combined spinal-epidural analgesia, some were discouraged from walking
and others were encouraged to walk. Maternal and neonatal outcomes, the incidence
of dystocia necessitating cesarean section, and measures of patients'
satisfaction were compared in the two groups. RESULTS: There were no significant
differences in the overall rate of cesarean section, the incidence of dystocia,
the frequency of maternal or fetal complications, the patients' or nursing
staff's assessment of the adequacy of analgesia, or the degree of overall
satisfaction between the two groups. Significantly more women receiving combined
spinal-epidural analgesia had pruritus (P<0.001) and requested additional
epidural bolus doses of local anesthetic (P=0.01). For all the women, dystocia
necessitating cesarean section was significantly more likely when analgesia was
administered with the fetal vertex at a negative station (odds ratio, 2.5;
P<0.001) or at less than 4 cm of cervical dilatation (odds ratio, 2.2; P<0.001).
CONCLUSIONS: As compared with continuous lumbar epidural analgesia, the
combination of spinal and epidural analgesia is not associated with an overall
decrease in the incidence of cesarean delivery.
PMID- 9392697
TI - The association of atopy with a gain-of-function mutation in the alpha subunit of
the interleukin-4 receptor.
AB - BACKGROUND: Atopic diseases are very common, and atopy has a strong genetic
predisposition. METHODS: Using single-strand conformation polymorphism analysis
and DNA sequencing, we searched for mutations in the a subunit of the interleukin
4 receptor that would predispose persons to atopy. We examined the prevalence of
the alleles among patients with allergic inflammatory disorders and among 50
prospectively recruited adults. Subjects with atopy were identified on the basis
of an elevated serum IgE level (> or = 95 IU per milliliter) or a positive
radioimmunosorbent test in response to standard inhalant allergens. The signaling
function of mutant interleukin-4 receptor a was examined by flow cytometry,
binding assays, and immunoblotting. RESULTS: A novel interleukin-4 receptor alpha
allele was identified in which guanine was substituted for adenine at nucleotide
1902, causing a change from glutamine to arginine at position 576 (R576) in the
cytoplasmic domain of the interleukin-4 receptor alpha protein. The R576 allele
was common among patients with allergic inflammatory disorders (found in 3 of 3
patients with the hyper-IgE syndrome and 4 of 7 patients with severe atopic
dermatitis) and among the 50 prospectively recruited adults (found in 13 of 20
subjects with atopy and 5 of 30 without atopy; P=0.001; relative risk of atopy
among those with a mutant allele, 9.3). The R576 allele was associated with
higher levels of expression of CD23 by interleukin-4 than the wild-type allele.
This enhanced signaling was associated with a change in the binding specificity
of the adjacent tyrosine residue at position 575 to signal-transducing molecules.
CONCLUSIONS: The R576 allele of interleukin-4 receptor alpha is strongly
associated with atopy. This mutation may predispose persons to allergic diseases
by altering the signaling function of the receptor.
PMID- 9392698
TI - Effect of ticlopidine on the long-term patency of saphenous-vein bypass grafts in
the legs. Etude de la Ticlopidine apres Pontage Femoro-Poplite and the
Association Universitaire de Recherche en Chirurgie.
AB - BACKGROUND: Optimal therapy to prevent late occlusion of arterial bypass grafts
in the legs has not been determined. We assessed the effect of ticlopidine, an
inhibitor of platelet aggregation, on the long-term patency of saphenous-vein
bypass grafts for the treatment of peripheral vascular disease. METHODS: A total
of 243 patients with femoropopliteal or femorotibial saphenous-vein bypass grafts
were randomly assigned to receive either ticlopidine (250 mg twice a day) or
matching placebo for two years. The primary end point was graft patency at two
years, as assessed by physical examination, measurement of the ankle brachial
index, and duplex ultrasonography or arteriography. The incidence of death and
major ischemic events was also analyzed in the two groups. RESULTS: After two
years, 66.4 percent of the patients were alive with a patent graft in the
ticlopidine group, as compared with 51.2 percent in the placebo group (95 percent
confidence interval for the difference between the two groups, 2.9 to 27.4
percent; P=0.02). The two-year cumulative patency rate was 82 percent in the
ticlopidine group and 63 percent in the placebo group (P=0.002). There was no
significant difference between groups in overall mortality or major ischemic
events. CONCLUSIONS: Ticlopidine significantly improved the long-term patency of
saphenous-vein bypass grafts in the legs. Since the drug was well tolerated, its
use can be recommended after peripheral-vein bypass surgery.
PMID- 9392699
TI - Images in clinical medicine. Subdural hematoma.
PMID- 9392700
TI - Hepatitis B virus infection.
PMID- 9392701
TI - Noninvasive ventilation.
PMID- 9392703
TI - Prepublication release of Journal articles.
PMID- 9392704
TI - Hazards and benefits of alcohol.
PMID- 9392705
TI - Analgesia for labor.
PMID- 9392706
TI - Interleukin-4 and the genetics of atopy.
PMID- 9392707
TI - The rule of double effect--a critique of its role in end-of-life decision making.
PMID- 9392708
TI - Electronic fetal heart rate monitoring: a primer for the critical care nurse.
AB - Fetal assessment is an essential component of nursing care for a pregnant woman
who is critically ill. If the fetus has reached the gestational age for which
electronic fetal monitoring (EFM) is possible, intermittent or continuous fetal
assessment with EFM may be used. Most nurses who specialize in adult intensive
care nursing do not have the education or clinical experience to interpret EFM
data. Collaboration with perinatal care providers is necessary to insure that
fetal assessments are timely and accurate and that nursing interventions based on
the data are appropriate. When perinatal providers participate as members of the
team caring for critically ill pregnant women, terminology and physiologic
parameters may be used that are not standard or routinely used in the ICU
setting. The physiologic and hemodynamic changes that occur during pregnancy add
another dimension to the nursing care required. This article reviews common terms
used to describe fetal status and appropriate nursing interventions used in
caring for the critically ill pregnant woman.
PMID- 9392709
TI - Aggressive management of HELLP syndrome and eclampsia.
AB - The nursing care of women critically ill during pregnancy is an ever-changing
specialty that presents unique clinical problems and issues. The woman and the
fetus can be profoundly affected by the hypertensive disorders of pregnancy. The
underlying pathology must be identified in relation to its effects on the
pregnancy, the effects of the pregnancy on the disease, and the implications for
the woman and the fetus. Severe preeclampsia, the HELLP syndrome (hemolysis,
elevated liver enzymes, and low platelets), and eclampsia present such challenges
and management problems. This article discusses the pathophysiology and
management implications of severe preeclampsia, the HELLP syndrome, and
eclampsia.
PMID- 9392710
TI - Support of the breast-feeding mother in critical care.
AB - Physiologic stabilization and maintenance of life of a critically ill, newly
delivered woman is the immediate priority for the critical care team. Once
stabilized however, each mother must be evaluated for lactation status. For the
mother who has chosen to bottle-feed her infant, the nurse should initiate
nursing care measures to suppress lactation. With the mother who has chosen to
breast-feed her infant, the nurse has additional responsibility. Because actual
breast-feeding will most likely be suspended temporarily, the nursing staff
should be knowledgeable in breast care associated with establishing a milk
supply, expressing milk to prevent breast engorgement, and initiating actual
breast-feeding when the mother's condition permits. This article provides the
advanced practice nurse with information, skills, and resources necessary to
assess, initiate, and maintain breast-feeding, one of the most important
physiologic and psychologic needs of the mother-infant dyad.
PMID- 9392711
TI - Meeting the challenges of critical care obstetrics in today's health care system:
collaborative education and practice strategies.
AB - The transformation of health care in the United States necessitates developing
creative strategies to provide quality and cost-effective care for the critically
ill obstetric patient population. A discussion of the care of these patients is
presented in a multidisciplinary framework, using a case study to illustrate the
management process. The significance of contributions and collaboration of
advanced practice nurses in perinatology and critical care in the care management
of the critically ill obstetric patient is described. Such strategies as location
of the patient and educational preparation for nurses caring for these complex
patients are offered for consideration. Implications are described and
recommendations are made for administrative and clinical practice.
PMID- 9392712
TI - A collaborative approach to fetal assessment in the adult intensive care unit.
AB - When a pregnant woman is admitted to the adult intensive care unit (ICU),
responsibility for fetal assessment must be assumed by a nurse who is competent
in interpreting data obtained by auscultation of the fetal heart rate or by the
electronic fetal monitor. The fetus is a distinct patient requiring assessments,
interventions, and evaluation, including documentation of nursing care provided,
similar to any patient in the ICU setting. Most ICU nurses do not have adequate
knowledge and clinical experience to assume this responsibility. Therefore, in
institutions in which critically ill pregnant women are transferred to the adult
ICU, a formal plan should be in place that includes care provided by nurses who
are competent in fetal assessment. This article describes a collaborative
approach to ensure that fetal assessments are performed by nurses who have the
experience and education to do so and includes common terminology used to
describe fetal status so that ICU nurses are familiar with the language and
appropriate nursing intervention.
PMID- 9392713
TI - Maternal-fetal assessment of the critically ill parturient: decisions related to
delivery.
AB - Preparation for delivery of the critically ill pregnant women begins soon after
admission to the intensive care unit. Unless maternal or fetal condition
deteriorates, remaining in utero may be more beneficial to the premature fetus. A
decision regarding the timing of delivery is based on the impact on maternal and
fetal well-being of maintaining the fetus in utero. Maternal or fetal instability
may necessitate immediate delivery, and specialist from critical care,
obstetrics, neonatology, and anesthesiology should decide on the most appropriate
location for labor and delivery. Personnel from affected departments are alerted
as soon as possible to facilitate the gathering of necessary equipment and
supplies and the attendance of skilled professionals in intrapartum management
and neonatal resuscitation.
PMID- 9392714
TI - Cardiopulmonary resuscitation: pregnant women are different.
AB - Although cardiopulmonary arrest rarely occurs in the pregnant woman, it is
important that the health care team know the appropriate actions to take in such
an event, to promote positive outcomes for both mother and fetus. Specific
techniques, personnel, and equipment are required to manage this grave situation.
The principles of airway, breathing, and circulation are used as with any client
in cardiopulmonary arrest; however, modifications must made because of the
physiologic changes that normally occur during pregnancy. If the pregnant woman
does not respond to treatment, a cesarean delivery must be attempted within 5
minutes of the arrest if uterine size indicates gestational age of at least 20
weeks. This article describes the adaptations of traditional cardiopulmonary
arrest procedures required to treat the pregnant woman who sustains a
cardiopulmonary arrest, protocols for managing the communication of the emergency
code, emergency equipment that must be available, and the importance of teams in
managing mother and neonate.
PMID- 9392715
TI - Beneficence toward whom? Ethical decision-making in a maternal-fetal conflict.
AB - Ethical dilemmas and conflicts occur frequently in critical care units. When
these dilemmas involve a pregnant patient, the conflicts are further complicated,
because they also involve the interests of the fetus. Using an ethical decision
making process facilitates the analysis of ethical dilemmas and their
resolutions. This process is used to analyze the dilemma of selecting appropriate
treatment for a woman at 30 weeks' gestation, diagnosed with acute lymphocytic
leukemia. The case is examined from the perspective of the mother and the fetus,
using the decision-making process. The medical indications include the patient's
physical state, disease process, and treatment options. Patient preferences are
the ethical and legal center of the patient-physician, and patient-nurse
relationship. Contextual features include religious beliefs, cultural values,
family dynamics, and financial and legal aspects of the care options. Finally,
the ethical principles, relevant and in conflict, are assessed. Exploring these
areas clarifies the best treatment option in consideration of the issues and
facts of the case.
PMID- 9392716
TI - Neutralizing ageism in critical care via outcomes research.
AB - Ageism, as a mind-set, amplifies a belief that intensive care for the elderly is
ineffectual. However, there are little data to support the notion that advanced
chronological age alone predicts unfavorable outcomes in response to intensive
care. A lack of outcome data, combined with ageism, may place older patients at
risk for rationing of intensive care. Currently, neither public policy nor
cultural norms directly support a limitation in services to the elderly. However,
as pressure to reduce health care costs increases, critically ill elderly
patients may be targeted for rationing. In this context, outcomes research
involving elderly populations is crucial. The purpose of this report is to
explicate the risk of ageism in the delivery of intensive care and to describe
methods for implementing outcomes assessment for critically ill elderly patients
as an essential element in a continuum of care.
PMID- 9392717
TI - Impact of a gerontological nurse practitioner on the nursing home elderly in the
acute care setting.
AB - A retrospective analysis of the length of stay of nursing home elderly patients
admitted to the hospital demonstrates a significant decrease when patients are
comanaged by a nurse practitioner and attending physicians. A comparison of the
20 most heavily populated diagnostic groups between 1993 and 1994 reveals a
shorter average length of stay in 17 of the 20 diagnostic groups, and an overall
mean decrease of 2.78 days for all groups. This article discusses the impact of
the gerontological nurse practitioner on hospital length of stay of the nursing
home elderly with acute illness. Research is needed to document advanced
practices that decrease length of stay, as well as to control for extraneous
variables.
PMID- 9392718
TI - Current trends in the clinical management of an old enemy: congestive heart
failure in the elderly.
AB - Much has been learned in the past decade, through quality medical and nursing
research, regarding the pathophysiology and management of congestive heart
failure. Primary care practitioners are challenged to apply the latest data to
the clinical management of these patients when there is clear evidence of
improvement in the control of symptoms and quality of life. Because of the
complexities of the disease process, older adults with congestive heart failure
require a comprehensive approach that is particularly well suited to the
knowledge and skills of the advanced practice nurse.
PMID- 9392719
TI - Decreasing polypharmacy in clients most at risk.
AB - Approximately one third of all drugs prescribed in the United States are
considered unnecessary. Polypharmacy, the unnecessary, excessive use of
prescription and over-the-counter medications, increases clients' risk for
adverse drug reactions and drug-drug interactions. Reducing the incidence of
polypharmacy is a health protection goal of Healthy People 2000. Older clients,
particularly older women living independently in the community, are at highest
risk for polypharmacy caused by age-related changes in pharmacokinetics and
pharmacodynamics, the presence of comorbidities requiring pharmacologic
management, and high rates of unintentional noncompliance with their therapeutic
regimen. Health providers may contribute to polypharmacy directly by excessive or
inappropriate prescribing practices or indirectly through their inability to
resist client's demands for pharmacologic interventions. Strategies to prevent
and detect polypharmacy are suggested to reduce its incidence and the severity of
its consequences.
PMID- 9392720
TI - Case management of critically ill elders: a case study.
AB - As the number of elderly increase, new challenges for the management of their
health care arise. Elders who become critically ill are one of the most complex
subsets of this population. Their special needs, risk factors, and diminished
resources create a demand for comprehensive and creative approaches to care
management. The purpose of this article is to explore the needs of the critically
ill elderly and the role of nursing case management in meeting these needs. A
case study approach is used to illustrate typical needs, interventions, and
outcomes.
PMID- 9392721
TI - Hospice volunteers: a push back to the future.
PMID- 9392723
TI - Going one step further: skilled pain assessment and the art of adjuvant
analgesia.
AB - Evolving pain management practice has two phases: 1) the development of
confidence and competence in prescribing opioids at whatever dose is needed to
control pain; and, 2) advanced assessment skills and understanding when adjuvant
analgesics must be employed with or without opioids to manage certain types of
pain. A growing reliance on opioids alone is illustrated in case study by a nurse
pain consultant. Dramatic improvements occur in patient function and coping when
clinicians move beyond the sole utilization of opioids to understand the
importance of skillful assessment of the patient's experience and the artful use
of adjuvant medications.
PMID- 9392722
TI - Comfort care: a framework for hospice nursing.
AB - Provision of comfort is paramount to the practice of hospice nurses. However, the
approach to meeting needs holistically is often intuitive or based on
multidisciplinary rather than nursing models. A review of the nursing literature
identified only one article describing the application of a nursing framework to
hospice nursing practice. The purpose of this article is to describe a theory of
comfort care that offers definitions and a grid for the art of comfort care that
are relevant to hospice nursing practice. Using Kolcaba's framework of holistic
comfort, nurses can be comprehensive and consistent in assessing comfort and in
designing interventions to enhance the comfort of patients and families. The
content domain of holistic comfort is conceptualized as interrelated parts (types
and contexts) as they are experienced simultaneously. The framework of comfort
care, which includes, the content domain and the theory of comfort, is explained
and applied through the presentation of a hospice case study. Potential
application of the framework to hospice research is proposed.
PMID- 9392724
TI - Advanced media training for hospice CEOs and communication directors.
PMID- 9392725
TI - The family with AIDS: multiple challenges for caregivers.
AB - Acquired Immune Deficiency Syndrome (AIDS) continues to increase in the United
States, especially among minority groups. The disease is impacting not only
individuals, but entire families through multiple infections of family members.
This results in simultaneous illness and multiple loss within the family system.
Delivery and management of quality care for the family is often made difficult by
the lack of resources experienced by families with limited income and the
multiplicity of problems associated with poverty in the US. This presents
numerous challenges to health care providers. Utilizing a case study, this
article presents a model demonstrating the coordination of services among several
providers as a means of meeting a variety of family needs and providing quality,
cost-effective care.
PMID- 9392726
TI - Malignant pleural effusions: a brief synopsis.
PMID- 9392727
TI - Low-tech nursing guidelines for hospice patients with degenerative neurological
disease.
PMID- 9392728
TI - Resuscitating and transforming hospice volunteer services.
AB - This article is designed for hospice leaders and volunteers to explore creative
ways to deal with the stagnancy that can occur in volunteer programs. Specific
strategies, such as nurturing caregivers, transitioning into a gift-based
program, and integrating spirituality and creativity into volunteer efforts,
provide the focus of the article.
PMID- 9392729
TI - Gabapentin (Neurontin, Parke-Davis).
PMID- 9392730
TI - Hospice and/or palliative care?
PMID- 9392731
TI - Nurses do make a difference: but we need to document it!
PMID- 9392732
TI - The Pew Commission Report: nursing's challenge to address it.
AB - The Pew Health Professions Commission was established in the Spring of 1989 and
is administered by the University of California at San Francisco, Center for the
Health Professionals. The Commission is charged with assisting health
professionals, workforce policy makers, and educational institutions in
responding to the challenges of the changing health care system. The Commission's
work will identify and explore how regulations protect the public's health, and
will propose a new approach to health professionals' licensure, certification,
and regulations. In December 1995, the Commission released a full report,
Reforming Health Care Workforce Regulation: Policy Considerations for the 21st
Century, including 10 recommendations. These recommendations are found in Table
1. In her presentation made during ANNA's 28th National Symposium in Minneapolis
on April 28, 1997, Barbara Donaho--a Commissioner on the Pew Health Professions
Commission--challenged nephrology nurses to address issues brought up in the
Commission Report. The fundamental concepts in Ms. Donaho's keynote presentation
were: Articulate the issues that are critical to nurses' licensure as reform is
considered. Describe public and professional forces of change if licensure is
going to protect the public. Discuss the alternatives that may need to be
considered when reform is undertaken by the states to ensure that professionals
may practice nursing throughout the country without regulatory and licensing
barriers. In this article, based on her ANNA keynote presentation, Ms. Donaho
makes it clear that nursing's response to proposed health care reform must be
aggressive and swift.
PMID- 9392733
TI - ANNA's brief of the response to the report of the taskforce on health care
workforce regulation.
AB - In December 1995 the Pew Health Professions Commission, a program of the Pew
Charitable Trust, released its report titled "Reforming Health Care Workforce
Regulations: Policy Considerations for the 21st Century." One of ANNA's external
projects for the 1996-97 year was responding to the Commission's report. Western
Region Vice President Christine Mudge was selected to serve as project director.
In consultation with President Christy Price, she spearheaded ANNA's formal
response. Each of the 10 recommendations was assigned to six to eight ANNA
members, plus everyone was invited to comment on any portion of the report that
they chose. Letters of request for participation were mailed to 66 nephrology
nurses. The Board of Directors, committee chairpersons, past ANNA leaders, ANNA
consultants, and members at large were involved. The response rate was 59%, or 39
thoughtful critiques of the Commission's recommendations. As project director,
Christine Mudge analyzed all responses and formed a draft document. Every effort
was made to include all concerns and issues raised by the ANNA participants. The
draft document was reviewed at the November ANNA Board of Directors meeting and
accepted with some editorial changes. ANNA's response is a 35-page document.
Excerpts from ANNA's full response are included on the following two pages. Any
ANNA member who desires to receive a copy of ANNA's full response to the Pew
Health Professions Commission report may request a copy from the ANNA National
Office by calling (609) 256-2320. The Pew Commission is now in the process of
reviewing all responses and recommendations to its report. Stay informed by
following the ongoing story in the ANNA Update.
PMID- 9392734
TI - Evaluation of the pediatric renal transplant recipient.
AB - Renal transplantation is the preferred therapy for children with end stage renal
disease. A functioning renal allograft can dramatically improve a child's quality
of life. Advances in immunosuppressive therapy and clinical practice approaches
have significantly improved graft survival rates allowing children to attain near
normal growth and development. Accurate assessment and appropriate nursing care
enhances long-term survival of these young patients.
PMID- 9392735
TI - Subjective burden and quality of life in family caregivers of patients with end
stage renal disease.
AB - OBJECTIVE: The purpose of this study was to determine the quality of life (QoL)
and level of subjective burden reported by family caregivers of persons with ESRD
and to examine the relationship between these variables. The influence of patient
(gender), illness (dialysis and diabetes status), and caregiver (race, gender,
employment status, relationship to patient, and self-rated health) factors on
burden and QoL was also examined. DESIGN: An exploratory descriptive design was
used. SAMPLE: The convenience sample consisted of 96 caregivers of 96 transplant
candidates diagnosed with end-stage renal disease. Participants were recruited
from a University transplant service located in the Mid-South. METHODS:
Caregivers of patients attending pretransplant clinic evaluations were invited to
participate in the study. Caregivers completed a demographic data form, the
Caregiver Burden Interview, and General QoL measure. Patient demographic data and
dialysis and diabetes status were retrieved from the patient health history
database of an ongoing study conducted by our transplant research team. Data were
analyzed using descriptive statistics, Spearman's correlation analysis, and the
appropriate parametric and nonparametric tests of group differences. RESULTS:
Caregivers, most of whom were women, reported good QoL and little to no burden.
Caregiver QoL was significantly related to caregiver burden and caregiver self
rated health. Neither caregiver race, gender, relationship to the patient, nor
patient gender significantly contributed to caregiver burden or caregiver QoL.
Caregiver burden did not differ by dialysis type (CAPD, incenter hemodialysis,
etc.) or employment category (full-time, part-time, etc.), however QoL differed
by employment status. CONCLUSIONS: Findings document the linkages among burden,
QoL, and self-rated health as well as illness factors, such as diabetes status.
Knowledge about these relationships may facilitate the development of
interventions that enhance patient and family outcomes.
PMID- 9392737
TI - Vision screening in older adults on dialysis: do nephrology nurses have a role?
AB - Undetected vision loss commonly occurs in older adults adding undue stress to
those on dialysis. Poor vision is associated with increased risk of falls and
decreased quality of life. Common visual impairments--presbyopia, cataracts, age
related macular degeneration, glaucoma, and diabetic retinopathy--often are
detectable by visual acuity testing. Using various methods of visual acuity
testing, nephrology nurses can perform vision testing quickly and inexpensively.
Other nursing interventions also can improve eyesight.
PMID- 9392738
TI - Pulse dose oral calcitriol therapy for renal osteodystrophy: literature review
and practice recommendations.
AB - Oral pulse dosing of calcitriol has been proposed as an alternative to
intravenous administration in the treatment of renal osteodystrophy. A review of
the literature suggests it can provide a safe and effective method that is
especially convenient for peritoneal dialysis patients with mild to moderate bone
disease. However, its use should be accompanied by careful monitoring and control
of serum calcium, phosphorus, and parathyroid hormone levels. Some practical
suggestions are provided.
PMID- 9392739
TI - Flipping or rotating fistula needles: readers' responses.
PMID- 9392740
TI - Epoetin alfa: focus on maintaining a higher, stable, Hct. Case study of the
anemic patient.
AB - Clinical evidence indicates that maintaining a stable hematocrit (Hct) higher in
the target range of 30% to 36% can lead to improvement in overall patient
outcomes. On the basis of these data, a recent analysis by the Dialysis Outcomes
Quality Initiative Anemia Work Group has recommended a target Hct of 33% to 36%
(hemoglobin 11 g/dl to 12 g/dl). Maintaining a stable Hct higher in the target
range provides nurses and other dialysis clinicians with two benefits: improved
patient care and decreased time and costs for patient management. This article
focuses on the data supporting such a policy. Clinical practices from two
prominent dialysis centers are presented as models of good anemia management.
PMID- 9392741
TI - Authors' response: no increased risk for peritonitis by insulin injected into the
peritoneal dialysis solution bag through Coloplast.
PMID- 9392742
TI - Implementing innovation.
PMID- 9392743
TI - Protecting our youngest girls.
PMID- 9392744
TI - Are you diagnosing domestic violence?
PMID- 9392745
TI - Preventing osteoporosis.
PMID- 9392746
TI - Emergency contraception. The pill's little-known secret goes public.
PMID- 9392747
TI - On your markers. Research advances in breast cancer in women.
PMID- 9392748
TI - News from the front. This nurse soldier is waging war on breast cancer.
PMID- 9392749
TI - Fluid check. Making the case for intrapartum amnioinfusion.
PMID- 9392750
TI - Shark-proof your practice. How the law is every nurse's best ally.
PMID- 9392751
TI - Taking time to care. Making ways to help teen parents.
PMID- 9392752
TI - Recognizing and preventing antibiotic-associated complications in the critical
care setting.
AB - Antibiotics are commonly used, even overused, in the intensive care unit (ICU)
patient population. These agents, though useful and often lifesaving, are
associated with many toxicities. These include infusion-related problems,
allergic reactions, organ-system toxicities, drug accumulation in patients with
renal disease, drug interactions, antibiotic resistance, diarrhea, interference
with laboratory tests, and more. Informed vigilance by the ICU nurse can be
helpful in increasing the benefit/toxicity ratio associated with these agents.
PMID- 9392753
TI - Antifungals: use in high-risk patients.
AB - Advanced medical technology has resulted in a growing population of patients with
altered defense mechanisms against nosocomial infections. Fungal infections,
primarily Candida species, account for a significant proportion of hospital
acquired infections and are associated with increased morbidity and mortality.
This article discusses current issues and controversies related to nosocomial
fungal infections and summarizes optimal management strategies.
PMID- 9392754
TI - Antimicrobial resistance: implications for the clinician.
AB - Antimicrobial resistance has become an issue of global proportion, and this
dilemma has greatly affected the intensive care unit (ICU) setting. Increased
antimicrobial use and other selective pressures have created an environment in
the ICU that is a testing ground for survival of microorganisms. By various
mechanisms, gram-positive cocci and gram-negative bacilli are becoming more
resistant to our current armamentarium of antimicrobials. Strategies to improve
the current situation of reduced microbial susceptibility include the following:
continued and specific surveillance in ICUs, antimicrobial protocols, continued
isolation precautions and appropriate handwashing, increased education at all
levels, increased use of immunotherapies, better use of our current antimicrobial
agents, and increased research in finding new and innovative antimicrobial agents
while curtailing the marketing ploys that promote excessive and inappropriate use
of these valuable medications.
PMID- 9392755
TI - Hospital-acquired pneumonia and its management.
AB - Hospital-acquired pneumonia (HAP) is an important cause of morbidity and
mortality in the United States. Classifying the patient's pneumonia by the
presence or absence of risk factors helps determine what organisms need to be
considered as etiologic agents so that empiric antibiotic therapy can be
initiated while cultures are pending. Medical care personnel can also use
preventive strategies to help decrease the incidence of nosocomial pneumonia.
This article will discuss pathogenesis, diagnosis, management, and prevention of
HAP.
PMID- 9392756
TI - The microbiology laboratory's role in life-threatening infections.
AB - The microbiology laboratory's contribution to the care of patients who are
critically ill is explored. The economic and epidemiologic impact of broad
spectrum antibiotic use is discussed, along with methodology of antimicrobial
susceptibility testing and the potential value of an antibiogram. The clinical
benefits of blood, sputum, urine, spinal fluid, and wound cultures are discussed,
with an emphasis on interpretation of culture results. The significance of, and
procedures for, proper specimen collection are emphasized throughout the article,
and the ramifications of improper specimen collection are presented.
PMID- 9392757
TI - Antibiotics: why they fail in patients who are critically ill.
AB - Most of the failures of antimicrobial therapy can be related to advanced
infections in patients with serious comorbid processes or altered immunity.
However, some of the failures are related to the type of antimicrobial therapy
used, the length of therapy, the pharmacokinetic or pharmacodynamic properties of
the antimicrobial agent, the development of antimicrobial resistance, microbial
factors that influence antimicrobial efficacy, and the site and type of
infection. This report will review the common mechanisms by which antimicrobials
fail.
PMID- 9392759
TI - Prevention of infections related to central venous catheters.
AB - Infections related to central venous catheters (CVCs) increase hospital costs,
length of stay, and patient mortality. Review of the literature and research
pertaining to CVCs have provided some guidelines to reduce the risk of infections
related to CVCs. Recommended guidelines include use of sterile technique with
insertion, maintenance of site dressings, avoidance of routine changes of CVCs,
and reduction of hub manipulation. Critical care nurses have the primary
opportunity to improve patient outcomes by reducing CVC infections.
PMID- 9392758
TI - Management of wounds and wound infections in the intensive care unit.
AB - Many factors combine to make management of wounds and wound infections in
patients in intensive care units (ICUs) a complex task. An understanding of the
anatomy, pathophysiology, and bacteriology provides a framework to approach these
patients. The patient's underlying disease influences the care of the wound.
Wound factors such as necrotic tissue, bacterial load, or presence of fistulae or
a foreign body have important impact on the patient's care. With assessment and
knowledge of normal healing, timely intervention in the ICU can identify patients
whose wounds are not healing properly and allow for corrective interventions to
help the patient return to normal function.
PMID- 9392761
TI - New treatment options for psoriasis.
AB - Psoriasis is a chronic genetic disease characterized by hyperproliferation and
inflammation of the epidermis and dermis. Presently there is no cure for
psoriasis, only treatments to alleviate the symptoms. Tazarotene (Tazorac) is a
new vitamin A derivative and the first topical retinoid to demonstrate
therapeutic success in treating plaque-type psoriasis. This article will
introduce you and your patients to the safe and effective use of tazarotene.
PMID- 9392762
TI - UVB therapy: dermatology nursing considerations.
AB - Each patient responds uniquely to phototherapy treatment. Not every patient can
tolerate daily treatment. Different areas of the body require different amounts
of light in order to clear. Precise documentation of erythema is important for
both treatment and legal reasons. A negative response to UVB therapy can be from
either ineffective treatment or an adverse reaction to UVB.
PMID- 9392760
TI - Antibiotic classification: implications for drug selection.
AB - This article presents a useful antibiotic classification model for the busy
clinician who must select agents for patients in the critical care setting. The
model organizes antibiotics based on their mechanism of action, ie, cell-wall
inhibitors, nucleic acid inhibitors, and protein-synthesis inhibitors; clinicians
are encouraged to further segregate agents within the broader categories by
generation. An overview of the antimicrobial spectrum for each class is
presented, and important differences within individual classes are highlighted.
The most common indications for each antibiotic class are reviewed, and key
pharmacokinetic characteristics that help distinguish one drug from another are
outlined.
PMID- 9392763
TI - Facial rejuvenation with botulinum.
AB - Botulinum toxin type A (Botox) blocks the release of neurotransmitter
acetylcholine at the presynaptic neuromuscular junction leading to an
irreversible, but temporary muscular paralysis and weakness. This can produce a
significant improvement of wrinkling in the upper face caused by the actions of
the facial muscles. A prospective clinical study representing a 15-month
experience with this new technique is presented. Patient selection and
evaluation, classification of animation lines, techniques, results, and
complications are discussed.
PMID- 9392764
TI - What's your assessment? Tinea versicolor.
PMID- 9392765
TI - Azelaic acid 20% cream (AZELEX) and the medical management of acne vulgaris.
AB - Azelaic acid 20% cream (AZELEX) is a novel anti-acne agent with antimicrobial
activity and keratinization-normalizing properties. In acne it is broadly
comparable in efficacy to 0.05% tretinoin, 5% benzoyl peroxide, and 2%
erythromycin, but is less irritating than tretinoin and benzoyl peroxide.
PMID- 9392766
TI - Latex as a killer: one nurse's story.
PMID- 9392767
TI - "The future of ASORN and ophthalmic nursing: where are we going"?
PMID- 9392768
TI - The bigger the crisis, the bigger the opportunity!
AB - Every time I pick up the newspaper, a scientific or nursing journal, or more
recently, an issue of Time, I find data, complete with startling facts and
figures, that pierce my very soul, about the tragedies occurring in our nation's
hospitals caused by the restructuring movement attempting to make health care a
"bottom line" business. And I know all too well, as do most of you, how
undetermined and tentative we are about the future for nurses.
PMID- 9392769
TI - Coats' disease.
AB - A 3-year-old boy had leukocoria in his right eye that could have been confused
for retinoblastoma because leukocoria is the most common presenting sign of
retinoblastoma. Educating parents, nurse practitioners, pediatricians, and fellow
health care professionals about such presenting ocular signs will help expedite
ophthalmic examinations and accurate diagnosis for these children.
PMID- 9392770
TI - Ophthalmic side effects of hyperbaric oxygen therapy.
AB - Hyperbaric oxygen (HBO) treatments are documented to cause ocular side effects.
According to Palmquist et al., HBO therapy has been used for many years, yet
there are only a few reports of its effects on the eye. With current studies
reporting lens changes, as well as hyperopic and myopic fluctuations, the role of
the nurse in assessing and reporting vision changes needs to be defined and
clarified.
PMID- 9392771
TI - Choroidal osteoma: acoustic shadowing and reduplication echoes.
AB - A 27-year-old woman had a curious choroidal mass of 12 years duration in her
right eye. Interesting ultrasonic findings of a choroidal osteoma, including
acoustic shadowing and reduplication echoes on A-scan and B-scan are presented.
Ophthalmic nurses can assist in performing ophthalmic examinations and in
reinforcing regular follow-up examinations for these patients.
PMID- 9392772
TI - Genetic teaching for the retinoblastoma patient.
AB - Retinoblastoma is the most common primary intraocular tumor in children.
Retinoblastoma can be hereditary (familial) or nonhereditary (nonfamilial).
Nurses who have an understanding of the genetic patterns for retinoblastoma can
participate in the counseling of these patients. A chart is provided as a tool
for teaching patients about family patterns of retinoblastoma.
PMID- 9392773
TI - ASORN member Von Best Whitaker elected to American Academy of Nursing.
PMID- 9392774
TI - Career options: the increasing demand for courtroom nurses.
AB - Gail Hoffman and Lisa Michaels first met at the University of Miami School of
Nursing in the early seventies. Because of their mutual interest in pediatrics
and their desire to stay in South Florida, both expected that their paths would
cross again at some time during their nursing careers. But neither of them
expected that 20 years later the crossroads would be in a courtroom, both working
for a defense attorney on a medical malpractice case. Now, in Smith v Mizrahi,
Gail is a nurse paralegal assigned to the case through her employment at Green,
Williams, & Conrad, P.A., and Lisa was called to serve as an expert witness.
Although the coincidence of Gail and Lisa's reacquaintance is unique, their
career change stories are not.
PMID- 9392775
TI - RNdex Top 100, CD-ROM.
PMID- 9392776
TI - Penetrating ocular trauma and visual outcome.
PMID- 9392777
TI - Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury.
AB - A cohort of 1022 consecutive singleton births was generated during 1986-1987 in
the Faroe Islands. Increased methylmercury exposure from maternal consumption of
pilot whale meat was indicated by mercury concentrations in cord blood and
maternal hair. At approximately 7 years of age, 917 of the children underwent
detailed neurobehavioral examination. Neuropsychological tests included Finger
Tapping; Hand-Eye Coordination; reaction time on a Continuous Performance Test;
Wechsler Intelligence Scale for Children-Revised Digit Spans, Similarities, and
Block Designs; Bender Visual Motor Gestalt Test; Boston Naming Test; and
California Verbal Learning Test (Children). Clinical examination and
neurophysiological testing did not reveal any clear-cut mercury-related
abnormalities. However, mercury-related neuropsychological dysfunctions were most
pronounced in the domains of language, attention, and memory, and to a lesser
extent in visuospatial and motor functions. These associations remained after
adjustment for covariates and after exclusion of children with maternal hair
mercury concentrations above 10 microgram(s) (50 nmol/g). The effects on brain
function associated with prenatal methylmercury exposure therefore appear
widespread, and early dysfunction is detectable at exposure levels currently
considered safe.
PMID- 9392778
TI - Effect of postnatal exposure to a PCB mixture in monkeys on multiple fixed
interval-fixed ratio performance.
AB - Behavioral impairment as a consequence of PCB exposure beginning in utero has
been reported in both humans and animals. The present study assessed the
behavioral consequences of postnatal exposure to PCBs. Male monkeys (Macaca
fascicularis) were dosed from birth to 20 weeks of age with 7.5
microgram(s)/kg/day of a PCB mixture representative of the PCBs typically found
in human breast milk (eight monkeys) or vehicle (four monkeys). At 4 years of
age, performance under a multiple fixed interval (FI)-fixed ratio (FR) schedule
of reinforcement was assessed. The FI component was more sensitive to disruption
as a result of PCB exposure than was the FR component. PCB-exposed monkeys
displayed shorter mean interresponse times (IRTs) than controls, particularly
during the earlier sessions of the experiment. Similarly, the increase in pause
time characteristic of the acquisition of typical FI performance emerged more
slowly across sessions in the PCB-treated group. However, the number of short
IRTs (less than 5 s) remained greater in the treated group compared to controls
over the 48-session duration of the experiment. On the FR component, control
monkeys decreases the mean pause time across sessions whereas the PCB-treated
group did not; there were no differences between groups for absolute value of
average IRT or pause time. The results of this study extend previous research in
this cohort of monkeys, and provide further evidence that PCB exposure limited to
the early postnatal period and resulting in environmentally relevant body burdens
produces long-term behavioral effects.
PMID- 9392779
TI - Neonatal binge ethanol exposure using intubation: timing and dose effects on
place learning.
AB - Neonatal rats were given ethanol using an acute intubation procedure that
resulted in daily binge-like exposure with minimal effects on somatic growth.
Acquisition of place learning in the Morris water maze was evaluated on postnatal
days (PD) 26-31. In Experiment 1, a total of 5.25 g/kg/day of ethanol was
administered in two daily intubations on PD 4-6, PD 7-9, or PD 4-9, producing
mean peak BACs of 265 mg/dL. Place learning acquisition deficits in a 114-cm
diameter tank were found for the PD 4-9 and PD 7-9 groups, but not the PD 4-6
group. In Experiment 2, either 4.5 or 5.25 g/kg/day of ethanol was administered
on PD 7-9 and place learning was tested in a 171-cm-diameter tank. Significant
acquisition deficits resulted from the higher dose, and probe trial search
patterns for both ethanol groups were significantly less localized than controls.
In Experiment 3, no significant effects of either PD 7-9 dose were found on a
visible platform task. These findings reveal selective place learning deficits in
this intubation model of neonatal binge exposure, and confirm a temporal window
of vulnerability to spatial learning deficits during the second neonatal week.
PMID- 9392780
TI - Evaluation of tremor in aluminum production workers.
AB - A cross-sectional study of 63 current and former aluminum potroom workers and 37
comparison workers was conducted to evaluate for evidence of neurological
dysfunction, including tremor from long-term exposures to aluminum using
sensitive quantitative measures of arm/hand and leg tremor. Signs of upper
extremity tremor were also evaluated by neurological examination and compared
with the quantitative measures of arm/hand tremor. Both arm/hand and leg tremor
were measured using fatiguing test conditions, but no statistically significant
differences due to exposure to aluminum were present between the potroom workers
and the comparison workers. The neurological examination also showed no
statistically significant differences between the groups on the evaluation of
signs of tremor. These results do not support the findings of Best-Pettersen et
al., who reported evidence of increased tremor in aluminum workers using the
static steadiness test in the Halstead-Reitan battery. Differences between the
studies that may have contributed to the contrasting results are discussed. In
addition, techniques are presented for using microcomputer-controlled devices to
evaluate tremor in both the visible (1-6 Hz) and nonvisible (7-18 Hz) frequencies
of the tremor spectrum.
PMID- 9392781
TI - Critical issues in the use and analysis of the Lanthony Desaturate Color Vision
test.
AB - The Lanthony Desaturate Color Vision test (D-15d) has been used to demonstrate
the incidence of acquired color vision defects resulting from toxic exposure. The
D-15d is a sensitive test designed to grade color deficiencies, but results can
be difficult to interpret beyond the qualitative level, and the high incidence of
errors reported for controls in some toxicology studies raises questions about
how to effectively use this test. This article reviews standard administration of
the test, physical determinants of performance, classification of acquired color
vision defects, and methods of analysis that have been used to quantify results.
The basis for a new method of analysis is discussed, illustrating the source of
some characteristic errors, and recommendations are made for test protocols to
attempt to more closely identify the type of color vision loss with the goal of
identifying the site of toxicological insult.
PMID- 9392782
TI - Prenatal nicotine sex-dependently alters agonist-induced locomotion and
stereotypy.
AB - This study examined the effects of prenatal nicotine exposure (2 mg/kg/day) via
s.c. osmotic minipumps, gestational days 7-22, on nicotine- and lobeline-induced
locomotor activity and stereotypy in 14-day-old rat pups. Prenatal nicotine
exposure increased fetal mortality and produced decreases in weight gain apparent
after weaning, but did not affect acquisition of developmental milestones.
Compared to male pups prenatally exposed to saline, those prenatally exposed to
nicotine and challenged with nicotine (1 mg/kg, i.p.) exhibited significantly
greater locomotor activity, whereas a lobeline challenge (1 mg/kg, s.c.) produced
significantly greater stereotypy. No effects of prenatal exposure were observed
on locomotor activity or stereotypy in females. Results suggest that 1) central
control of motor function may be more vulnerable to prenatal nicotine in males,
and 2) nicotine and lobeline possess distinct pharmacological profiles.
PMID- 9392783
TI - Perinatal delta(9)-tetrahydrocannabinol exposure alters the responsiveness of
hypothalamic dopaminergic neurons to dopamine-acting drugs in adult rats.
AB - We have recently reported that perinatal cannabinoid exposure altered the normal
development of dopaminergic neurons in the medial basal hypothalamus at early
postnatal and peripubertal ages. Most of these effects tended to disappear in
adulthood, although we suspect the existence of a persistent, but possibly
silent, alteration in the adult activity of these neurons. To further explore
this possibility, we evaluated the responsiveness of these neurons to
pharmacological challenges with a variety of dopaminergic drugs administered to
adult male and female rats that had been exposed to delta(9)-tetrahydrocannabinol
(delta(9)-THC) or vehicle during the perinatal period. In the first experiment,
we evaluated the sensitivity of hypothalamic dopaminergic neurons to amphetamine
(AMPH), which causes enhancement of dopaminergic activity by a variety of
mechanisms. The most interesting observation was that both adult males and
females, when perinatally exposed to delta(9)-THC, showed a more marked AMPH
induced decrease in the production of L-3,4-dihydroxyphenylacetic acid (DOPAC),
the main intraneuronal metabolite of dopamine (DA), although this did not affect
the prolactin (PRL) release. In the second experiment, we evaluated the in vivo
synthesis of DA by analyzing the magnitude of L-3,4-dihydroxyphenylalanine (L
DOPA) accumulation caused by the blockade of L-DOPA decarboxylase with NSD 1015.
As expected, NSD 1015 increased L-DOPA accumulation and decreased DOPAC
production, with a parallel increase in PRL release, all of similar magnitude in
both delta(9)-THC- and oil-exposed adult animals. In the last experiment, we
tested the magnitude of the increase in PRL release produced by the
administration of either SKF 38393, a specific D1 agonist, or sulpiride, a
specific D2 antagonist. Both compounds increased plasma PRL levels in adult
animals of both sexes, the effects in females being significantly more marked.
The perinatal exposure to delta(9)-THC also modified the degree of increase in
plasma PRL levels induced by both compounds, with opposite responses as a
function of sex. Thus, delta(9)-THC-exposed females responded more intensely to
SKF 38393 and, particularly, to sulpiride than oil-exposed females, whereas
delta(9)-THC-exposed males responded to SKF 38393 lesser than oil-exposed males,
although both responded equally to sulpiride. In summary, our results are
consistent with the possible existence of subtle changes in the activity of
hypothalamic dopaminergic neurons in adulthood caused by the exposure to delta(9)
THC during perinatal development. These silent changes could be revealed after
the administration of drugs such as: (i) AMPH, whose effect producing a decreased
DOPAC accumulation was more marked in delta(9)-THC-exposed males and females; and
(ii) SKF 38393 and sulpiride, whose stimulatory effects on PRL secretion were of
different magnitude in delta(9)-THC-exposed animals, with an evident sexual
dimorphism in the response. The neurochemical basis for these differences remains
to be determined.
PMID- 9392785
TI - Effects of neonatal naltrexone on neurological and somatic development in rats of
both genders.
AB - The effects of a daily injection of the opioid antagonist naltrexone (NALTX, 1
mg/kg, s.c.) from birth to weaning on various parameters were investigated in
male and female rats during postnatal development until adulthood. NALTX
increased cerebellar DNA and protein content as well as cerebellar weight at 7
days. Eye opening was not affected by NALTX but it appeared advanced by 1 day in
all groups compared to other studies, possibly due to a handling effect caused by
the daily injection. Water and food consumption were augmented by NALTX during
days 23-32 and days 55-70. Treated preweaning animals showed lower body growth
rates than controls. However, NALTX caused a moderate increase in body weight
measured during postweaning until adulthood. The effects of NALTX on the
parameters evaluated (excepting the cerebellar measurements on day 7), although
clearly statistically significant, were small in absolute terms. The preweaning
opioid blockade caused by our NALTX treatment seems to affect more markedly the
neural and behavioural development than the somatic growth. This work also
provides potentially useful baseline data for the study of male and female rats
during postnatal development.
PMID- 9392784
TI - Effects of lead-arsenic combined exposure on central monoaminergic systems.
AB - Lead acetate (116 mg/kg/day), arsenic (11 or 13.8 mg/kg/day as sodium arsenite),
a lead-arsenic mixture or vehicle were administered to adult mice through gastric
intubation during 14 days. Then, the regional content of norepinephrine (NE),
dopamine (DA), serotonin (5-HT), 3,4 dihydroxyphenyl-acetic acid (DOPAC), 5
hydroxyindole-3-acetic acid (5-HIAA), arsenic, and lead were quantified. Compared
with the accumulation after single element exposures, the mixture elicited a
higher accumulation of lead and a lower arsenic accumulation in the brain.
Compared to controls, lead induced only an augmentation of DOPAC (200%) in the
hypothalamus. By contrast, the mixture provoked increases of DOPAC in the
hypothalamus (250%), DA and 5-HIAA in the striatum (67 and 187%, respectively)
and NE decreased in the hypothalamus (45%). Although these alterations were
similar to those produced by arsenic alone, the mixture provoked a 38% decrease
of NE in the hippocampus and increases of 5-HT in midbrain and frontal cortex
(100 and 90%, respectively) over control values, alterations that were not
elicited by either metal alone. These results demonstrate an interaction
arsenic/lead on the central monoaminergic systems of the adult mouse.
PMID- 9392786
TI - Prenatal exposure of rats to diphenhydramine: effects on physical development,
open field, and gonadal hormone levels in adults.
AB - Diphenhydramine (DPH), a classical H1 receptor antagonist, has been used in
pregnancy for the treatment of allergies, nausea, and vomiting. It has been
reported that 10-20% of pregnant women take antihistamine-containing preparations
at some point during pregnancy. The present study analyzed the influence of
prenatal exposure to DPH of rats on: 1) maternal behavior and milk production of
dams; 2) physical and reflexologic development of offspring; and 3) long-term
effects on open field behaviors and gonadal hormone levels in offspring. Female
pregnant rats were injected s.c., daily, with 20 mg/kg DPH or saline from
embryonic day (E) 0 to 21. After delivery, maternal behavior was assessed and
offspring physical and reflexologic development was examined. Open field activity
of male and female rats was measured at 21 and 75 days of age and plasma hormone
levels were evaluated in both sexes at 120 days of age. Neither maternal behavior
nor milk production was affected by DPH treatment. Treated offspring showed an
accelerated pinna unfolding, eye opening, and a delay of testes descent and
vaginal opening. Both righting reflex and negative geotaxis development were
accelerated, but prenatal exposure to DPH did not modify offspring locomotor
activity. When tested as adults, a lack of sexual dimorphism in the open field
activity of males and females was observed. No differences were observed between
gonadal hormone levels of control and experimental groups of either sex. The
findings suggest that prenatal DPH exposure influences physical and reflex
development of rat pups.
PMID- 9392787
TI - Susceptibility of adult rats to lead-induced changes in NMDA receptor complex
function.
AB - Because cognitive impairments can occur with occupational Pb exposures, changes
in NMDA receptor complex function might be expected to occur in adult rats
treated with Pb. Using drug discrimination procedures, MK-801 sensitivity was
determined in adult rats at three time points: after chronic exposure to 0, 50,
or 150 ppm Pb acetate; again after exposure levels were increased to 500 and 1000
ppm; and 6 months after termination of Pb exposure. Changes in blood (PbB) and
brain Pb levels, and in MK-801 and CGP-39653 binding, were examined in additional
groups of nonbehaviorally tested rats. Pb decreased MK-801 sensitivity after Pb
exposure levels were increased, but only at 500 ppm, indicating biphasic effects
and precluding any correspondence between behavioral changes and biomarkers of
exposure. Associated PbBs were higher, but brain Pbs similar to those associated
with MK-801 sensitivity changes following postnatal and postweaning exposures.
Neither MK-801 nor CGP-39653 binding was systematically affected by chronic Pb
exposure in adults. Although adult Pb exposures do produce changes in NMDA
function, at least as indicated by changes in MK-801 sensitivity, vulnerability
to such effects is clearly less pronounced than with exposures occurring earlier
in development.
PMID- 9392788
TI - Not all DMSA defects are scars.
PMID- 9392789
TI - Diagnostic usefulness of lung SPET in pulmonary thromboembolism: an outcome
study.
AB - The lung single photon emission tomographic (SPET) images of 985 consecutive
patients referred for suspected pulmonary embolism were correlated with clinical
outcome and angiography to evaluate the clinical usefulness of lung SPET compared
to conventional planar ventilation/perfusion lung imaging. SPET interpretations
followed the revised PIOPED criteria and clinical outcome was determined from
referring physicians, hospital records, direct patient contact and county hall
records. Patients were deemed to have had no clinically significant pulmonary
embolism at the time of the SPET examination if, within the following 3 months:
(1) the patient was alive and had no clinical evidence of pulmonary embolism or,
(2) if deceased, pulmonary embolism was unlikely to have been the cause of death.
Operating characteristics were based on the methods of Choi and of Simel. SPET
interpretation was categorized as follows: high probability, 143 (14%); low
probability, 840 (82%); intermediate, 41 (4%) (in contrast to PIOPED, with 39%
intermediate interpretations). Pulmonary angiography was performed in only 4% of
patients. Adequate follow-up data were available for 97% of patients. To
facilitate comparison with PIOPED, either a high-probability or an intermediate
probability or an intermediate-probability study was considered to be a positive
test, and either a low-probability or a normal study was considered to be a
negative test. The sensitivity was 83% (PIOPED 82%), specificity 92% (PIOPED
52%), positive predictive value 62% (PIOPED 47%) and negative predictive value
97% (PIOPED 85%). The positive and negative predictive values have not been
corrected for prevalence, which was approximately twice as high in the PIOPED
study. Lung SPET provided accurate diagnostic information in 96% of patients and
specificity was greatly improved compared to planar lung imaging reported in
PIOPED. The diminished need for angiography greatly reduced the cost of
evaluating patients suspected of having pulmonary embolism.
PMID- 9392790
TI - Pentavalent 99Tcm-DMSA imaging in patients with bone metastases.
AB - Pentavalent 99Tcm-dimercaptosuccinic acid (99Tcm-(V)DMSA) has an established role
in imaging medullary thyroid carcinoma. There have been case reports of uptake in
bone metastases. Our aims were to compare 99Tcm-(V)DMSA with 99Tcm
hydroxymethylene diphosphonate (99Tcm-HDP) in bone metastases, to assess its
value in imaging of bone metastases, and to assess the prospects of the beta
emitting analogues 186/188Re-(V)DMSA as palliative agents for painful bone
metastases. Ten patients confirmed by a 99Tcm-HDP bone scan to have bone
metastases secondary to carcinoma of the prostate, lung or breast were injected
with 99Tcm-(V)DMSA (600 MBq). Whole-body scans acquired at 3 and 24 h were
compared with the 99Tcm-HDP bone scans. 99Tcm-(V)DMSA showed high soft tissue
background, kidney retention and avid uptake in most bone metastases: 86% of bone
lesions identified on bone scans were detected with 99Tcm-(V)DMSA. The lesion-to
normal ratios were comparable to or lower than those for 99Tcm-HDP at 3 h, but
increased by 24 h. Instances of abnormal uptake in liver, primary lung tumour,
lymph nodes and pleural effusion were observed. We conclude that 99Tcm-(V)DMSA is
a tracer for bone metastases (with lower sensitivity than 99Tcm-HDP) and soft
tissue tumours. If 186/188Re-(V)DMSA behave similarly, they may find use in
therapy for soft tissue tumours and bony metastases.
PMID- 9392791
TI - How does gated SPET alter reporting of myocardial perfusion studies?
AB - Gated single photon emission tomography (SPET) during myocardial perfusion
scintigraphy has been proposed as a method for distinguishing artefact from
myocardial infarction and for assessing myocardial viability. This study
describes the alterations in the specialist report produced when gated SPET was
included in 50 consecutive myocardial perfusion studies. Diagnostic confidence
was scored following an initial assessment using non-gated images alone and then
re-scored after a review of the gated SPET data. The change in diagnostic
confidence and the presence of additional information about myocardial viability
were recorded. These were correlated with various clinical parameters, including
a subjective assessment of the likelihood of an attenuation artefact as
determined by clinical examination prior to imaging. Diagnostic confidence was
altered by identification of attenuation artefacts in 11 (22%) patients, moving
towards normality in all cases. In three of these (6%), the change was sufficient
to make coronary angiography potentially unnecessary. Attenuation artefacts were
equally common in men and women. Whereas breast attenuation artefacts could be
anticipated from clinical examination, this was not so far diaphragmatic
attenuation artefacts, which occurred most commonly in men under 55 years of age.
The gated study provided additional information about myocardial viability in 13
(26%) patients, most commonly those referred following myocardial infarction. In
view of the frequent alterations in the specialist's final report and the
difficulties in pre-selecting patients likely to benefit from the technique, the
use of gated SPET can be justified for all patients undergoing sestamibi
myocardial perfusion imaging.
PMID- 9392792
TI - The effect of training on the interpretation of 99Tcm-sestamibi myocardial
perfusion SPET in patients with suspected coronary artery disease.
AB - The aim of this study was to examine the effect of a period of concentrated
training in nuclear cardiology on the accuracy of reporting 99Tcm-sestamibi
(99Tcm-MIBI) single photon emission tomographic (SPET) images. Two visiting
cardiologists, with no previous experience in nuclear cardiology, were asked to
report blindly 60 99Tcm-MIBI SPET scans after 2 weeks of training in nuclear
cardiology. One (observer 2) reported the same scans blindly after 2 months of
further training. The results were compared with the assessment made by two
experienced nuclear cardiologists and by using kappa statistics. Kappa values for
the overall interpretation of the scan (normal or abnormal), segmental analysis
(normal, ischaemic, fixed or mixed) and the three arterial territories were 0.7,
0.58 and 0.67 respectively. Following 2 months of further intensive training of
observer 2, the kappa values were 0.857, 0.78 and 0.91 respectively. The
difference between the two readings of observer 2 was significantly different for
the segmental analysis (P < 0.001) and arterial territories (P = 0.006) but it
did not reach statistical significance for the overall interpretation (P = 0.7).
Thus, cardiologists without previous interpretation skills in nuclear cardiology
required about 2 months of intensive training to achieve good accuracy in the
interpretation of 99Tcm-MIBI SPET images. Accordingly, these techniques can be
established in centres other than tertiary sites.
PMID- 9392794
TI - Hydration does not influence the image quality in bone scintigraphy: an
investigation using 99Tcm-HDP.
AB - We investigated the possibility that the increased diuresis caused by hydration
leads to enhanced renal excretion of radiotracer and thereby increases the target
to-background activity ratio and improves the image quality in bone scintigraphy.
The study was carried out using paired comparisons in 10 healthy volunteers.
Whole-body antero-posterior and postero-anterior acquisitions were obtained for 4
h after the administration of 99Tcm-hydroxymethylene diphosphonate with and
without hydration. The bone-to-soft tissue activity ratio was semi-quantified by
comparing regions of interest acquired from geometrical means of the
acquisitions. Hydration was performed by slowly drinking 1.5 litres of water
after administration of the tracer. Hydration induced a slight enhancement of
excretion of the activity, but it had no effect on the bone-to-soft tissue
activity ratio, nor did it influence image quality. We conclude that hydration
could be avoided when it is cumbersome for the patient. However, as hydration
reduces the radiation dose to the urinary bladder wall, which is the critical
organ, hydration should be maintained in younger patients.
PMID- 9392793
TI - 99Tcm-MDP blood-pool phase in the assessment of repetitive strain injury.
AB - We reviewed three-phase bone scans of the limbs of 7 patients suffering from limb
pain suggestive of occupational repetitive strain injury (RSI) and compared them
with 13 patients with limb pain due to various aetiologies. Doppler ultrasound
measurement of blood flow had been performed in 13 of the 20 patients. The bone
scan results showed increased blood flow and pooling (second phase) in the
affected limbs of patients with RSI as compared to those with algodystrophy or
non-specific limb pain (sensitivity 86%, specificity 85%). Doppler ultrasound
also demonstrated increased blood flow to the affected limbs (sensitivity 83%)
but failed to differentiate between the different aetiologies of pain
(specificity 14%). We conclude that the blood-pool phase of three-phase bone
scans can play a potential role in screening RSI patients.
PMID- 9392795
TI - Functional evaluation of the remaining kidney in kidney donors by radionuclide
dynamic imaging using a graphic method with factor analysis.
AB - An uptake coefficient proportional to the glomerular filtration rate (GFR) can be
estimated from dynamic renal images with 99Tcm-DTPA using Rutland's graphic
method. We have developed a new method of extracting the input and retention
functions by applying factor analysis to the renal dynamic images obtained with
99Tcm-DTPA, which we have called the 'factor uptake coefficient' (Factor UC). In
the present study, we followed 13 living kidney donors (7 males, 6 females) by
measuring the Factor UC in each kidney before nephrectomy and in the remaining
kidney 3 weeks and 1 year after nephrectomy. The median Factor UC in the
remaining kidney increased from a pre-nephrectomy value of 0.31 to 0.52 three
weeks post-nephrectomy, which then remained unchanged for up to 1 year. These
results indicate that functional compensation occurs following unilateral
nephrectomy, and that this process is complete within 3 weeks after nephrectomy.
PMID- 9392796
TI - Visualization of frontal postural hypoperfusion in patients with Takayasu
arteritis with upright 99Tcm-HMPAO brain SPET.
AB - Takayasu arteritis is a chronic inflammatory angiopathy involving the cerebral
arteries. We performed upright and supine 99Tcm-HMPAO brain single photon
emission tomography (SPET) to investigate the cerebral perfusion pattern in eight
patients with Takayasu arteritis, and we compared the results with those acquired
using 123I-IMP and acetazolamide in six patients. SPET images were evaluated
visually and semi-quantitatively. Hypoperfusion was visually detected in all
eight patients during the provocative upright test with 99Tcm-HMPAO, and in three
of six tested using acetazolamide and 123I-IMP. Semiquantitative analysis
revealed that the mean cortical-to-cerebellar ratio in the upright position was
significantly changed compared to that in the supine position in the right
frontal area (from 0.86 +/- 0.07 to 0.91 +/- 0.09; P < 0.05). Change was also
seen in the left frontal area (from 0.85 +/- 0.08 to 0.91 +/- 0.08; P < 0.05). No
significant change was seen in other cortical areas with the upright test or in
any areas with the acetazolamide test. We postulate that reduced arterial
compliance may cause frontal postural hypoperfusion in patients with Takayasu
arteritis due to poor functioning of autoregulation and arterial stenosis or
occlusion. We conclude that the provocative upright test with 99Tcm-HMPAO brain
SPET can detect abnormal patterns of cerebral perfusion in patients with Takayasu
arteritis that might be missed by brain SPET using 123I-IMP and acetazolamide.
PMID- 9392797
TI - Scintigraphic varieties in Hashimoto's thyroiditis and comparison with
ultrasonography.
AB - The scintigraphic findings in Hashimoto's thyroiditis are highly variable and can
mimic any thyroid abnormality. In this study, we compared the scintigraphic
findings with ultrasonography in 48 patients with Hashimoto's thyroiditis.
Thyroid scintigrams revealed diffuse hyperplasia in 12 patients, multinodular
goiter in 20 patients and a solitary nodule in 16 patients (toxic adenoma, n = 1;
hypoactive nodule, n = 4; hyperactive nodule with no suppression, n = 3;
normoactive nodule, n = 8). Ultrasonography revealed diffuse hyperplasia in 19
patients, multinodular goiter in 20 patients and a solitary nodule in 9 patients.
The thyroid scan and ultrasonography revealed the same findings of diffuse
hyperplasia in 12 patients and multinodular goiter in 20 patients. Of the 16
patients with a solitary nodule on scintigraphy, only 9 showed the same finding
on ultrasonography, with the other 7 showing diffuse hyperplasia. The difference
in nodularity between thyroid scanning (74.9%) and sonography (60.4%) has been
attributed to pseudonodularity in Hashimoto's thyroiditis. In conclusion, our
results confirmed that Hashimoto's thyroiditis can mimic any thyroid abnormality,
including diffuse hyperplasia, nodular goiter and multinodular goiter on
scintigraphy. Therefore, scintigraphy, ultrasonography and serum thyroid hormone
estimation alone may not be helpful for the final diagnosis of Hashimoto's
disease. To eliminate unnecessary surgical intervention, all patients should be
evaluated by means of physical examination and thyroid autoantibodies, in
addition to a thyroid scan, ultrasonography, serum thyroid hormones and fine
needle aspiration biopsy when necessary.
PMID- 9392798
TI - An evaluation of FDG-PET in the detection and differentiation of thyroid tumours.
AB - We evaluated the usefulness of FDG-PET for the detection of thyroid tumours and
the differentiation between benign and malignant tumours. The subjects consisted
of 5 normal volunteers and 22 patients, including 3 with follicular adenoma, 16
with papillary carcinoma and 3 with follicular carcinoma. The results were then
evaluated both visually and semi-quantitatively using the standardized uptake
value (SUV). All 22 tumours were seen as areas of high FDG uptake. FDG uptake in
the normal thyroid gland, follicular adenoma, papillary carcinoma and follicular
carcinoma was 1.0 +/- 0.2, 2.1 +/- 0.4, 4.7 +/- 3.2 and 4.6 +/- 2.9,
respectively. Significant differences were observed between papillary carcinoma
and both follicular adenoma (P < 0.05) and the normal thyroid gland (P < 0.001),
and between follicular adenoma and the normal thyroid gland (P < 0.001). For the
diagnosis of carcinoma, 58% sensitivity, 100% specificity and 73% accuracy were
obtained when the highest FDG uptake value in adenoma was taken as the threshold.
Our results thus indicate that high FDG uptake in a thyroid tumour suggests
malignancy even though low levels of FDG uptake cannot completely rule out
malignancy.
PMID- 9392799
TI - Colonic transit time assessed by 67 Ga-citrate in a case-series of patients with
recto-sigmoid adenomas.
AB - One plausible mechanism by which dietary factors may influence colorectal
carcinogenesis is through their effect on intestinal transit time. This study
examined colonic transit by means of oral 67Ga-citrate in a case-series of
patients who had developed recto-sigmoid adenoma. Adenoma patients had a
significantly shorter transit time than constipated patients (P = 0.01) and our
results also suggest (but do not show conclusively) that colonic transit in
adenoma patients is similar to that of normal controls. Although these findings
require confirmation from a larger study, they raise the hypothesis that colonic
transit times are not delayed in patients who harbour recto-sigmoid adenomas.
PMID- 9392800
TI - Detection of metastatic bone lesions in patients with prostate carcinoma: 99Tcm
monoclonal antibody imaging.
AB - Bone scintigraphy has been shown to be sensitive in determining bone involvement
in patients with malignancy, but it does not allow the assessment of bone marrow
lesions in early disease. The aim of this study was to detect bone marrow
invasion using 99Tcm-labelled monoclonal antigranulocyte antibody (AgMoAb) in
patients with prostate carcinoma. We studied 56 patients whose mean (+/- S.D.)
age was 67 +/- 7 years. The mean prostate-specific antigen level was 6.1 ng ml-1
(normal range 0-5 ng ml-1). Twelve patients were in stage A, 16 in stage B, 17 in
stage C and 11 in stage D. Six patients had been receiving chemotherapy and four
patients radiotherapy before scanning. Bone scans were obtained 2 h after the
intravenous injection of 555 MBq 99Tcm-methylene diphosphonate (99Tcm-MDP).
Within a week, bone marrow imaging was performed 4 and 24 h after the injection
of 555 MBq 99Tcm-AgMoAb. Metastatic bone lesions were detected on the 99Tcm-MDP
scans of 14/56 (25%) patients, of whom one was in stage A, two in stage B, four
in stage C and seven in stage D. Hypoactive lesions in bone marrow were detected
in 25/56 (45%) patients, of whom two were in stage A, five in stage B, seven in
stage C and 11 in stage D. Bone marrow metastases were confirmed in six patients
by computed tomography (CT) and magnetic resonance imaging (MRI) and in two
patients by marrow aspiration biopsy. A false-positive immune scintigram was
found in three patients previously receiving radiotherapy or chemotherapy. We
suggest that 99Tcm-AgMoAb scintigraphy is a sensitive procedure for the detection
of bone marrow lesions. However, the reason for false-positive and false-negative
results should be considered and CT, MRI and marrow biopsy should be performed
when clinically necessary.
PMID- 9392801
TI - Validation of a technique for the preparation of individual patient doses of 14 C
urea.
PMID- 9392802
TI - Permanent multisite cardiac pacing.
PMID- 9392803
TI - Analysis of the intraventricular electrogram for differentiation of distinct
monomorphic ventricular arrhythmias.
AB - This study investigated the effectiveness of correlation waveform analysis for
identifying different ventricular electrogram morphologies of multiple VTs in the
same patient. Patients with implantable antitachycardia devices are commonly
subject to the occurrence of more than one distinct monomorphic VT. Each of these
VTs may have unique therapeutic alternatives for termination. VTs with identical
and different monomorphic configurations were recorded (1-500 Hz) using distal
bipolar (1 cm) and distal unipolar electrograms from the right ventricular apex.
Thirty-six distinct monomorphic VTs induced in 15 patients were analyzed. Nine
VTs with identical morphologies (12/12 surface ECGs) were induced twice and used
as a control. A template was created for each VT induced. Correlation waveform
analysis was used to compare each depolarization of all other VTs induced
subsequently in the same patient. The mean correlation coefficient (p mu) of
cycle-by-cycle analysis was used as a discriminant function: p mu > or = 0.95 was
considered matched; and p mu < 0.95 was considered distinct. From the control
population, VTs were successfully classified as identical in 9 of 9 cases (100%)
using both bipolar and unipolar electrograms. VTs with different monomorphic
configurations were successfully classified as being different in 31 of 33 cases
(94%) using bipolar electrogram analysis and in 29 of 33 cases (88%) using the
unipolar. Template matching is effective for detecting: (1) the recurrence of
VTs, which are identical; and (2) the occurrence of a VT with a different
configuration. This method appears effective using either unipolar or bipolar
intracardiac waveforms.
PMID- 9392804
TI - Atrial septal pacing: a method for pacing both atria simultaneously.
AB - By pacing both atria simultaneously, one could reliably predict and optimize left
sided AV timing without concern for IACT. With synchronous depolarization of the
atria, reentrant arrhythmias might be suppressed. We studied four male patients
(73 +/- 3 years) with paroxysmal atrial fibrillation and symptomatic
bradyarrhythmias using TEE and fluoroscopy as guides; a standard active fixation
screw-in lead (Medtronic model #4058) was attached to the interatrial septum and
a standard tined lead was placed in the ventricle. The generators were Medtronic
model 7960. The baseline ECG was compared to the paced ECG and the conduction
time were measured to the high right atrium, distal coronary sinus and atrial
septum in normal sinus rhythm, atrial septal pacing, and AAT pacing. On the
surface ECG, no acceleration or delay in AV conduction was noted during AAI
pacing from the interatrial septum as compared with normal sinus rhythm. The mean
interatrial conduction time for all 4 patients was 106 +/- 2 ms; the interatrial
conduction time measured during AAT pacing utilizing the atrial septal pacing
lead was 97 +/- 4 ms (P = NS). During atrial septal pacing, the mean conduction
time to the high right atrium was 53 +/- 2 ms. The mean conduction time to the
lateral left atrium during atrial septal pacing, was likewise 53 +/- 2 ms. We
conclude that it is possible to pace both atria simultaneously from a single site
using a standard active fixation lead guided by TEE and fluoroscopy. Such a
pacing system allows accurate timing of the left-sided AV delay.
PMID- 9392805
TI - Asystolic cardiac arrest during head-up tilt test: incidence and therapeutic
implications.
AB - Occasionally, the cardioinhibitory response may be profound during tilt induced
syncope. Whether this response is associated with more severe symptoms or
predicts a poor response to pharmacotherapy remains controversial. The aim of
this study was to characterize patients with vasovagally mediated asystole
occurring during head-up tilt test and to evaluate the respective interests of
sequential pacing and beta-blockers to treat them. We performed 60 degree tilt
testing in 179 consecutive patients with unexplained syncope (91 women and 88
men, age 36.6 +/- 20.1 years). Asystole was defined as a ventricular pause > 5
seconds. All patients with tilt induced asystole received therapy with either
beta-blockers or sequential pacing, the efficacy of which was evaluated with
serial tilt tests. Of 77 patients with positive tilt test, 10 developed syncope
related to asystole (mean duration 11.9 +/- 4.9 s), 2 with spontaneous recovery,
and 8 with seizures needing a brief cardiopulmonary resuscitation. When compared
with patients without asystole, asystolic patients had more severe symptoms
(seizures: 6/10 vs 9/67, P = 0.05, injury 9/10 vs 27/67, P = 0.0048). In the
first six patients in whom cardiac pacing was considered, syncope or presyncope
still occurred despite atrioventricular pacing at 45 beats/min. Five of these 6
patients, as well as the remaining 4 asystolic patients, were tilted with beta
blockers: 3 patients became tilt-negative; 3 were significantly improved; and 3
did not respond. During follow-up (mean 22.7 +/- 11.7 months) with every patient
taking beta-blockers and seven having a permanent pacemaker, no syncopal
recurrence was observed. Tilt-induced asystole that may require resuscitative
maneuvers occurs especially in patients with a history of seizures or injury.
Therapy with beta-blockers in often effective to prevent induction of syncope as
well as recurrences.
PMID- 9392806
TI - Permanent left atrial pacing with a specifically designed coronary sinus lead.
AB - This article reports the original use of a specifically designed coronary sinus
(CS) lead for permanent left atrial (LA) pacing. The device is characterized by
its distal end shape featuring a double 45 degree angulation, which ensures very
close contact with the CS upper wall. The device was successfully implanted in 39
out of 40 patients (97.5%). The tip electrode was eventually positioned in the
distal CS in 9 patients, in the middle CS in 21 patients, and close to the ostium
in the proximal CS in 9 patients. The mean acute pacing threshold voltage was 0.9
+/- 0.5 V with a mean impedance of 578 +/- 144 omega as measured in unipolar
distal configuration at 0.5 ms pulse width (PW). The mean A wave amplitude was
3.5 +/- 2.1 mV. Early lead dislodgment occurred only once (3%) when the tip
electrode was placed in the distal or middle CS, but more often (4/9 cases) when
it was placed in the proximal CS. After a mean follow-up duration of 14 +/- 8.5
months, 35 of the 39 successfully implanted leads (89.7%) were still functional
in terms of LA pacing and sensing. The mean chronic pacing threshold voltage was
1.5 +/- 0.8 V and the mean A wave amplitude was 2.7 +/- 1.6 mV. There were no
lead related complications. In conclusion, the device proved to be safe and
highly effective for permanent LA pacing, provided the distal tip could be
positioned in the distal or middle part of the CS.
PMID- 9392807
TI - Efficacy and safety of a new protocol for continuous infusion of midazolam and
fentanyl and its effects on patient distress during electrophysiological studies.
AB - Electrophysiological studies are often distressing for patients. We devised a
regime of continuous infusion of midazolam and fentanyl during
electrophysiological studies without the presence of a specialist anaesthetist.
The effects on key hemodynamic and respiratory variables and level of sedation
were evaluated in detail in the first 775 patients. The safety of this practice
was evaluated in 1,344 consecutive patients. Doses were calculated according to
patients' weight and age. A mean total dose of 26 mg of midazolam and 115 mcg of
fentanyl were infused. Satisfactory sedation was achieved in 97% of patients. The
mean duration of procedure was 188 +/- 90 minutes. Complete amnesia of the
procedure was obtained in 87% of patients. Sedation caused clinically
insignificant changes in respiratory rate, oxygen saturation, end-tidal CO2 and
blood pressure. There were no major complications related to sedation. Upper
airway obstruction, usually minor, occurred in 42% and some restlessness in 20%
of sedated patients. The assistance of a specialist anesthetist was required in
0.3% of sedated patients for management of restlessness, hypoventilation, or
obstructive sleep apnea. The amount of distress experienced by sedated patients
(n = 775) was significantly less compared to a previous series of nonsedated
patients (n = 775) undergoing electrophysiological studies (P < 0.001). The
degree of distress experienced by patients during electrophysiological studies
can be reduced significantly by sedation with intravenous midazolam and fentanyl.
Continuous infusion is an efficient, safe, and effective way of administering
midazolam and fentanyl.
PMID- 9392808
TI - The combined transvenous implantation of cardioverter defibrillators and
permanent pacemakers.
AB - We developed criteria for implantation and programming of permanent endocardial
pacemakers in patients with a nonthoracotomy ICD system. These criteria were
prospectively used in 10 patients who recieved an ICD prior to (n = 5) or
following (n = 5) implantation of a dual chamber (n = 6) or ventricular (n = 4)
pacemaker with a unipolar (n = 4) or bipolar (n = 6) lead configuration. All
patients were tested for interactions or malfunctions. Undersensing of
ventricular fibrillation by the atrial sense amplifier and inadequate atrial
pacing occurred in one patient with a unipolar dual chamber system programmed to
AAIR but didn't impair ICD sensing. Transient or permanent loss of capture or
sensing of the pacemaker was not observed after ICD shocks with the output
programmed to double pulse width and voltage of stimulation threshold and the
sensitivity to 50% of the detected R wave. One episode of transient reprogramming
occurred without clinical consequences. One unipolar ventricular pacemaker lead
had to be exchanged against a bipolar lead because of oversensing of the pacing
artifact by the ICD. There was no failure of an ICD to detect ventricular
arrhythmias due to inadequate pacemaker activity. During a follow-up period of 21
+/- 11 months, a total of 78 ventricular arrhythmias were effectively treated in
six patients. Thus, a combined use of transvenous ICD and pacemaker is possible
despite the close vicinity of pacing and defibrillations leads. Optimized
programming different to the common settings is required. As interactions
occurred only in unipolar pacemaker leads bipolar systems should be used in these
patients.
PMID- 9392809
TI - Neurohumoral and hemodynamic mechanisms of diuresis during atrioventricular nodal
reentrant tachycardia.
AB - Thirty-two consecutive patients with paroxysmal supraventricular tachycardias,
with previously defined mechanisms of the tachycardias, were interviewed by
noninvestigators about whether they experienced symptoms of diuresis during or at
the termination of the tachycardias, to test the hypothesis that patients with AV
nodal reentrant tachycardia would have a feeling of diuresis, polyuria, or both
during or at the termination of the tachycardia. Twelve of the 13 patients with
AV nodal reentrant tachycardia (92%), two of the 15 patients with AV reentrant
tachycardia (13%), and one of the 4 patients with atrial flutter associated with
2:1 AV conduction (25%) felt diuresis during or at the termination of the
tachycardias (AV nodal reentrant tachycardia vs other forms of tachycardia; P <
0.001). In 14 of the 32 patients, the right atrial pressure and plasma atrial
natriuretic peptide (ANP) concentration were measured during both the
tachycardias and sinus rhythm. The mean right atrial pressure during AV nodal
reentrant tachycardia was significantly elevated compared to that during other
forms of tachycardia (P < 0.01). The plasma ANP concentration during AV nodal
reentrant tachycardia was also elevated significantly compared to that during
other forms of tachycardias (P < 0.001). There were no significant differences in
the cycle lengths of the tachycardias, age, left atrial dimensions, or the left
ventricular ejection fraction between the AV nodal reentrant tachycardia and the
other forms of tachycardia. We concluded that the feeling of diuresis during or
at the termination of tachycardia was a more common symptom in patients with AV
nodal reentrant tachycardia. The higher secretion of plasma ANP from the right
atrium might be involved in the mechanism of this symptom.
PMID- 9392810
TI - Procainamide induced change of the width of the zone of entrainment and its
relation to the inducibility of reentrant ventricular tachycardia.
AB - Procainamide depresses conduction velocity and prolongs refractoriness in
myocardium responsible for reentrant VT, but the mechanism by which the induction
of VT is suppressed after procainamide administration remains to be determined.
In the present study, the relationship between electrophysiological parameters
and the noninducibility of VT was assessed during procainamide therapy with a
special reference to the change of an excitable gap. Clinically documented
monomorphic sustained VT was induced in 30 patients and, utilizing the phenomenon
of transient entrainment, the zone of entrainment was measured as the difference
between the cycle length of VT and the longest paced cycle length interrupting VT
(block cycle length) which was determined as the paced cycle length decreased in
steps of 10 ms, and used as an index of the excitable gap. The effective
refractory period was measured at the pacing site and the paced QRS duration was
used as an index of the global conduction time in the ventricle. The cycle length
of VT, the block cycle length, and the width of the zone of entrainment were
determined and compared between the responders and nonresponders. In 15 patients,
these parameters were determined at the intermediate dose and related to
subsequent noninducibility at the final dose. At the final doses of procainamide,
VT was suppressed in 8 (26.7%) of 30 patients. However, the cycle length of VT,
the block cycle length, and the width of the zone of entrainment were unable to
predict the drug efficacy, i.e., noninducibility. The change in the effective
refractory period at the pacing site or the width of the paced QRS duration was
not different between the responders and nonresponders. Among the variables, only
the width of the zone of entrainment showed a significant narrowing in the
responders at the intermediate dose of procainamide, and it was smaller than that
of the nonresponders. The significant narrowing of the width of the zone of
entrainment was associated with the subsequent noninducibility of VT at the final
dose. The present study showed that the baseline cycle length of VT, the block
cycle length, the drug induced change of the effective refractory period, or the
paced QRS duration was not a predictor of the noninducibility after procainamide
administration. However, a significant narrowing of the width of the zone of
entrainment at the intermediate dose was associated with the noninducibility of
VT at the final dose.
PMID- 9392811
TI - Clinical performance of steroid-eluting pacing leads with 1.2-mm2 electrodes.
AB - To raise pacing impedance and reduce battery current drain, new tined steroid
eluting leads were developed with 1.2-mm2 hemispherical electrodes, instead of
conventional 5-8 mm2. Twenty-two unipolar J-shaped atrial leads and 25 unipolar
ventricular leads (models 4533 and 4033, respectively) were implanted in 33
consecutive patients and followed for a mean of 25 months (range 18-29). Handling
characteristics of atrial leads were found favorable. The leads slipped easily
into the right atrial appendage and were easy to position. Handling
characteristics of ventricular leads were satisfying, but more efforts had to be
applied to cross the tricuspid valve. Special care was taken to avoid perforation
of the myocardium due to the small lead tip. Following implantation, four
ventricular and one atrial lead exhibited instability of pacing thresholds that
resolved spontaneously within 1-3 days of implantation. Except for this, no lead
malfunctioned. The reoperation rate was zero. The mean electrogram amplitudes of
15 mV (ventricle) and 4 mV (atrium), and the mean chronic pacing threshold of
0.085 ms at 1.6 V (app. 0.43 V at 0.5 ms) were comparable with the best values
seen in the literature on passive fixation leads. The rest of the
electrophysiological parameters were enhanced: mean pacing impedances were 984
omega (acute) and 900 Q (chronic), mean slew rates 3.26 V/s (ventricle) and 1.75
V/s (atrium), mean acute voltage threshold at 0.5 ms was 0.25 V, mean current and
energy thresholds calculated at 0.5 ms were 260 microA and 32 nJ (acute) and 478
microA and 103 nJ (chronic). The electrical characteristics of these leads
provide for increased pacemaker longevity in combination with substantial safety
margins for pacing and sensing.
PMID- 9392812
TI - Long QTc and torsades de pointes in human immunodeficiency virus disease.
AB - Three patients with human immunodeficiency virus (HIV) infection presented with
QT, prolongation (> 440 ms) and torsades de pointes. We sought to evaluate the
etiology of the long QT syndrome in these patients without previously identified
causes for QT, prolongation, and determine the prevalence among patients with HIV
infection. The three index patients underwent: (1) left stellate ganglion block;
(2) beta-blocker challenge; and (3) electrocardiographic stress testing. QTc
interval was measured before and after intervention. We undertook a retrospective
analysis of prevalence of QTC prolongation among all patients with computerized
ECGs over a 6-month period at one institution and compared it to the prevalence
in hospitalized patients with HIV disease. Thirty-four thousand one hundred
eighty-one patients with computerized ECGs were screened for QTc prolongation.
Forty-two hospitalized patients with HI disease had computerized ECG during the
same 6-month period. In the three index patients, the QTc failed to shorten with
left stellate ganglion blockade, beta-blocker challenge, or stress testing,
suggesting an acquired form of the long QT syndrome in these patients with HIV
disease. None had previously recognized acquired causes of QT, prolongation.
Mexiletine hydrochloride was useful in preventing recurrences of torsades de
pointes. We observed a 7.0% prevalence of QT, prolongation among all patients
screened. Hospitalized patients with HIV disease (n = 42) during this same
period, demonstrated an increased prevalence of QT, prolongation (28.6%, P =
0.002). Patients with HIV disease have a significantly higher prevalence of QTc
prolongation than a general hospital-based population, may have an unrecognized
acquired form of the long QT syndrome, and are at risk for torsades de pointes.
PMID- 9392813
TI - Retroconduction selective recognition in wide-dipole floating atrial sensing. The
Multicenter Study Group.
AB - Effective discrimination of retrogradely conducted P waves would allow
distinguishing sinus tachycardia from supraventricular tachycardias due to AV or
nodal reentry, and would prevent pacemaker-mediated tachycardia in AV sequential
pacing. This might be especially relevant in VDD implants, where retroconduction
could be induced by escape ventricular stimulation. In order to analyze the
respective waveform properties, anterograde and retrograde atrial signals were
recorded by a wide floating electrode dipole, on the implantation of a permanent
single-pass lead for VDD pacing. Generally, bipolar recording did not allow
reliable discrimination, while the signal nature could be readily diagnosed from
the main features of the unipolar atrial electrograms. The unipolar waveform
recorded under sinus rhythm in high right atrium, close to the superior vena cava
opening (proximal EGM), started with a negative deflection in 88% of the
patients. In 7% of the patients, the first deflection of the signal was positive
in some cardiac cycles only, and, on the average, the amplitude of the positive
phase was not higher than 5% of the signal peak-to-peak amplitude. Conversely,
under retroconduction, the starting deflection attained higher positive values in
98% of the patients, being stably over 15% of the peak-to-peak amplitude in 86%
of the Furthermore, in 69% of the cases, the lag time between the onset of the
negative deflection of proximal and distal (mid-low atrium) unipolar EGM changed
unambiguously when retroconduction occurred, exceeding the range of variation
observed in each patient during sinus activity. The combined evaluation of
unipolar EGM shape and lag time allowed specific retroconduction recognition in
95% of the patients. We suggest that this approach may yield useful information
for the discrimination of retrograde atrial signals, provided that the recording
dipole is sufficiently long and the proximal electrode is properly positioned in
the high right atrium.
PMID- 9392814
TI - The top ten fallacies of nonsustained ventricular tachycardia.
AB - Nonsustained ventricular tachycardia (NSVT) continues to remain a subject of
controversy. This is true despite a wealth of epidemiologic and basic/clinical
laboratory findings that have accumulated during the past 2 decades. However,
these data not only generate the impetus to conduct further research, but also
provide compelling arguments against continued adherence to time honored precepts
about NSVT that evolved since the inception of the "PVC Hypothesis," although
never substantiated by rigorous scientific inquiry. This paper discusses the "top
ten" fallacies of NSVT and details the data that support abandonment of them.
PMID- 9392815
TI - Graphical representation of complex data--diurnal patterns of initiations of
atrial fibrillation episodes.
AB - A construction of a purpose designed graphical display is demonstrated in a study
investigating the circadian distribution of patterns of RR interval sequences
preceding episodes of paroxysmal atrial fibrillation (PAF). Based on a comparison
with a (80%, 120%) range around the median of preceding 10 RR intervals, each RR
interval is classified as normal, short, or long. Classifications of RR intervals
in n-tuplets (n = 1, ...,5) preceding PAF episodes are used to compute
probabilities of individual types of sequences occurring within 4-hour periods of
the day (between 1 am, 5 am, 9 am, 1 pm, 5 pm, and 9 pm). Graphical
representation of the data is proposed using a hierarchy of bar graphs. The
graphical system has been filled with data of 327 atrial fibrillation episodes
recorded in 46 24-hour ECGs in PAF patients. The graphical analysis supports a
link between PAF initiation and cardiac autonomic status.
PMID- 9392816
TI - Practice expense: applying accounting principles in a specialty practice.
PMID- 9392817
TI - Idiopathic left ventricular tachycardia: what is the mechanism?
PMID- 9392818
TI - Interaction between electronic article surveillance systems and implantable
defibrillators: insights from a fourth generation ICD.
AB - We present a case report of an inappropriate discharge from a fourth generation
implantable cardioverter defibrillator (ICD) as a result of exposure to
electromagnetic interference. A 60-year-old man implanted with a Medtronic 7219D
defibrillator experienced shocks without preceding symptoms while walking through
an electronic surveillance system in a store. Though this has been reported, the
mechanism of the interaction remains unexplained. The electrogram storage
capabilities of this particular device enabled us to establish that this resulted
from inappropriate sensing of the electromagnetic interference.
PMID- 9392819
TI - Ventricular output failure in a DDD permanent pacemaker associated with increased
atrial output.
AB - Previous reports have described the occurrence of ventricular output failure in a
permanent DDD pacemaker system related to an increase in the atrial output in the
presence of low atrial lead impedance (Medtronic Synergyst/Synergyst II). This
phenomenon is seen exclusively following atrial paced events and may potentially
lead to significant bradyarrhythmia or ventricular asystole in a pacemaker
dependent patient. We describe the occurrence of analogous behavior in a
Medtronic Symbios 7006 generator.
PMID- 9392820
TI - A pitfall in using far-field bipolar electrograms in arrhythmia discrimination in
a patient with an implantable cardioverter defibrillator.
AB - Analysis of stored electrograms from bipolar far-field electrodes is considered
to be useful in differentiating supraventricular from ventricular arrhythmias. A
case of inappropriate ICD shocks for sinus tachycardia is presented whereby
successive shocks caused marked widening of the ventricular electrograms.
Analysis of these stored electrograms, recorded from far-field bipolar
electrodes, gave the false impression of ventricular tachycardia. The widening
was due to the current of injury effects, probably a consequence of the large
amount of intervening myocardium between the bipoles. While analyzing recordings
from far-field bipolar electrodes is generally useful, it is not always reliable,
for changes in electrogram morphology, relative to baseline rhythm, may result
from other factors like current of injury.
PMID- 9392821
TI - Near doubling of heart rate after intravenous verapamil for treatment of atrial
fibrillation without preexcitation.
AB - Initial treatment of atrial fibrillation often involves pharmacological therapy
to control ventricular response. While verapamil is usually safe and effective
when used for this purpose, we report a proarrhythmic response. In this report a
30-year-old female presented with palpitations associated with atrial
fibrillation and a ventricular response of 145 beats/min. Soon after she was
given 5 mg of intravenous verapamil her ECG documented a regular wide QRS
tachycardia at 290 beats/min. After 7 seconds the rhythm returned to an
irregularly irregular narrow QRS tachycardia at 125-150 beats/min. At a later
electrophysiology study there was neither evidence of preexcitation nor inducible
supraventricular or ventricular tachycardia. These data suggest that verapamil
may have been associated with acceleration of the heart rate. The mechanism of
proarrhythmia may be related to an alteration in the atrial rhythm from atrial
fibrillation to atrial flutter, with additional factors as well.
PMID- 9392822
TI - Runaway in a modern "soft top" pacemaker.
AB - Although runaway pacemaker was a relatively common occurrence, modern pacemaker
design has made it extremely rare. We report a case occurring with a modern "soft
top" pacemaker that resulted from a loss of hermeticity. Although the different
treatment options are discussed, the definitive maneuvre is explantation of the
faulty pacemakers
PMID- 9392824
TI - Classification of atrial fibrillation.
PMID- 9392823
TI - Pectoral muscle stimulation after falling off a ladder.
AB - A-pacemaker that had been implanted correctly was found at follow-up to have
"flipped over" as a result of a fall from a ladder. Symptomatic pectoral muscle
stimulation ceased immediately when the generator was manually flipped back into
the correct position.
PMID- 9392825
TI - STIMAREC report.
PMID- 9392826
TI - DIFIMAREC report.
PMID- 9392827
TI - Synthetic peptide from the V3 loop consensus motif with a potent anti-HIV
activity inhibits ristocetin-mediated vWF-GPIb interaction.
AB - The V3 loop consensus motif. Arg-Gly-Pro-Gly-Arg-Ala-Phe-Val-Thr-Ile (HIV-1
IIIB), inhibits an interaction of HIV with CD4-positive lymphocytes. Recently,
both proline-rich peptides and peptides containing proline-glycine loops (beta
turns) form a complex with ristocetin dimers. These peptides interact with
ristocetin-loaded platelet membrane glycoprotein (GP) Ib and act as inhibitors of
von Willebrand factor (vWF)-GPIb interaction by preventing the subsequent
formation of ristocetin dimer bridges. The Pro-Gly sequence is also present in
the V3 loop consensus motif, Arg-Gly-Pro-Gly-Arg-Ala-Phe-Val-Thr-Ile (HIV-1
IIIB). In this report, we have evaluated the effect of the HIV-1 IIIB peptide on
vWF binding to GPIb. This peptide only inhibited vWF binding to GPIb as well as
platelet aggregation in the presence of ristocetin while it had no effect on
botrocetin-mediated vWF interaction with platelets. The peptide inhibited a
binding of anti-vWF monoclonal antibody (RG-46) to immobilized vWF. Furthermore,
ristocetin inhibited the binding of HIV-1 IIIB peptide to immobilized CXC
chemokine receptor-4 (CXCR-4) peptide. These results indicate that ristocetin may
prevent HIV infection and would be useful a tool to understand the mechanism of
HIV tissue tropism and infection.
PMID- 9392828
TI - Expression of rat pro cholecystokinin (CCK) in bacteria and in insect cells
infected with recombinant baculovirus.
AB - Neuropeptide prohormones are generally not abundant in nature as they exits to be
processed and contain sites which could be cleaved by a number of cellular
proteases. In order to study the processing of prohormones in vitro it is
necessary to produce them in quantity. Finding an expression system which
produces intact prohormone has been a matter of trial and error. We report that
intact rat pro CCK was produced with an amino-terminal His-Tag in e. coli, and it
was secreted from sf9 and other insect cells infected with a recombinant
baculovirus vector. The bacteria contained about 0.1 micrograms pro CCK/ml of
cells. The High 5 insect cells produced 4.3 micrograms/ml medium (as determined
by RIA), 10 times as much as sf9 or sf21. Using a combination of ion exchange,
gel filtration and HPLC, the insect cell protein was purified about 150 fold with
a recovery of about 16%. The secreted insect cell pro CCK is tyrosine sulfated
like its mammalian equivalent. Using these expression systems it is possible to
produce significant (microgram to mg) quantities of pro CCK for immunologic,
enzymatic and structural studies.
PMID- 9392829
TI - Lepidopteran peptides of the allatostatin superfamily.
AB - Peptides of the allatostatin superfamily with the C-terminal amino acid sequence
YXFGL-NH2 have been isolated and identified from the lepidopterans, the codling
moth, Cydia pomonella (Tortricidae) and the bollworm, Helicoverpa armigera
(Noctuidae). The peptides, designated cydiastatins and helicostatins
respectively, were monitored during purification with radioimmunoassays based on
the callatostatins of the blowfly Calliphora vomitoria. The eight peptides from
each of the two species appear to form an homologous series with four identical
and three that differ by a single amino acid. This study demonstrates the
ubiquitous nature of this family of peptides in insects.
PMID- 9392830
TI - Protein phosphorylation in snail cardiocytes stimulated with molluscan peptide
SCPb.
AB - Dissociated muscle cells prepared from hearts of the pulmonate snail Helix
aspersa were used to study signal transduction induced by molluscan cardioactive
peptides. The effects of SCPb on the cAMP levels of whole hearts and the cell
preparation were compared. The cells responded to SCPb with a dose-dependent
increase in cAMP that had the same structure-activity relations as seen in the
intact tissue. SCPb increased the phosphorylation of a 53 kDa protein in a dose
dependent manner; threshold was 10(-9) M. The SCPb-induced phosphorylation was
mimicked by forskolin and 8-CPT-cAMP. FMRFamide stimulation had no effect on the
phosphorylation of this protein.
PMID- 9392831
TI - Thyrotropin-releasing activity of histone H2A, H2B and peptide MB35.
AB - Histones possess multiple hormone-like activities. We studied the specificity and
signal transduction pathways involved in the thyrotrophin (TSH)-releasing
activity of histones H2A, H2B and peptide MB35, a H2A fragment, using perifused
and incubated dispersed rat pituitary cells and measuring TSH release by a
specific R1A. Histones released TSH in a dose- and time-dependent fashion while
peptide MB35 behaved as a weaker secretagogue. Trifluoperazine and EGTA blocked
histone-stimulated TSH release while forskolin and other cAMP enhancers did not.
We conclude that the TSH-releasing activity of histones H2A and H2B is mediated
by calcium- and diacylglycerol-associated pathways.
PMID- 9392832
TI - Influence of [4Cl-D-Phe6,Leu17]VIP on VIP- and central TRH-induced gastric
hyperemia.
AB - The specific VIP receptor antagonist, [4Cl-D-Phe6,Leu17]VIP, infused i.v. blocked
close-intra-arterial infusion of VIP-induced increase in gastric mucosal blood
flow (GMBF, measured by the hydrogen gas clearance), and decrease in mean
arterial blood pressure while not influencing basal levels in urethane
anesthetized rats. The thyrotropin-releasing hormone (TRH) stable analog, RX
77368, injected intracisternally (IC, 30 ng) increased GMBF and blood pressure.
The VIP antagonist did not significantly reduce the GMBF response to IC RX 77368
while enhancing the rise in blood pressure. These findings indicate that [4Cl-D
Phe6,Leu17]VIP is an antagonist for exogenous VIP-induced gastric hyperemia and
hypotension and that VIP modulates the systemic blood pressure response to IC RX
77368 at 30 ng while not playing a primary role in the increase of GMBF.
PMID- 9392833
TI - Effects of non-glycated and glycated glucagon-like peptide-1(7-36) amide on
glucose metabolism in isolated mouse abdominal muscle.
AB - This study investigated the actions of non-glycated and glycated glucagon-like
peptide-1(7-36)amide (tGLP-1) on glucose uptake and metabolism in isolated mouse
abdominal muscle. Monoglycated tGLP-1 (Mr 3463.8) was prepared under
hyperglycemic reducing conditions and purified by HPLC. Non-glycated tGLP-1 (10(
10)-10(-8) mol/l) stimulated both 2-deoxy-D-[1-3H]glucose uptake (1.3-1.5 fold)
and 14C-glucose oxidation (1.4-1.7 fold) in muscle compared to controls without
tGLP-1. Glycation reduced these stimulatory effects by 27-33% and 25% (at 10(-9)
mol/l), respectively. tGLP-1 (10(-10)-10(-8) mol/l) promoted muscle glycogenesis
and lactate production, whereas glycated peptide was ineffective below 10(-9)
mol/l. This study demonstrates that tGLP-1 has potent glycogenic effects in mouse
abdominal muscle in vitro and that glycation impairs its action.
PMID- 9392834
TI - Elevated neuropeptide Y gene expression and release during hypoglycemic stress.
AB - Our previous studies show that neuropeptide Y (NPY) is involved in mediating
sympathetic nerve stimulation-induced vasoconstriction. Insulin hypoglycemia is
known to produce increased sympathetic output and elevated arterial pressure. The
present study examined the role of NPY in the hypertensive response to insulin by
examining the effects of insulin on NPY gene expression, tissue content and
release. Subcutaneous injection of insulin produced an immediate increase in
plasma NPY immunoreactivity (NPYir) and delayed increases in adrenal and neuronal
NPY mRNA and adrenal NPYir in rats. These results suggest that NPY may play a
role in insulin-induced hypertension.
PMID- 9392835
TI - Enterostatin actions in the amygdala and PVN to suppress feeding in the rat.
AB - The pentapeptide enterostatin (ENT) inhibits feeding after injection into the
cerebral ventricles. To localize the central sites of action of ENT, the peptide
(0.01 to 3.3 nM) was microinjected into several brain regions and the intake of a
high fat diet was measured. The results show that ENT injection in the
paraventricular nucleus (PVN) or the amygdala (AMYG) produced a bi-phasic dose
related feeding response, low doses of ENT inhibited feeding while higher dose
had no effect. The effective dose to inhibit feeding in the AMYG was 10 fold
lower than that in the PVN. No changes in food intake were observed after ENT
injection into the ventromedial hypothalamus and nucleus tractus solitarius. The
data provide further support that there are targets in the CNS for ENT and
suggest that central ENT function is site specific.
PMID- 9392836
TI - Stimulation of tachykinin NK-3 receptors in the nucleus basalis magnocellularis
reduces alcohol intake in rats.
AB - Injections in the nucleus basalis magnocellularis (NBM) of the tachykinin (TK) NK
3 receptor agonist [Asp5,6,MePhe8]substance P(5-11), also referred to as amino
senktide (NH2-SENK), markedly reduced alcohol intake in genetically selected
alcohol-preferring rats, offered 10% ethanol 2 h/day. The threshold dose in the
NBM was 0.5 ng/site, while neither 1 nor 10 ng/rat of NH2-SENK inhibited alcohol
intake following administration into the lateral ventricle. Injection of NH2
SENK, 25 ng/site, in the NBM did not modify water or food intake in water
deprived rats, providing evidence for the behavioral selectivity of the effect on
ethanol intake. The selective TK NK-3 receptor antagonist, R-820, injected in the
NBM at the dose of 1000 ng/site 5 min before NH2-SENK 5 ng/site, significantly
reduced the effect of NH2-SENK. The selective TK NK-1 receptor agonist
[Sar9,Met(O2)11]substance P inhibited alcohol intake following injection in the
NBM only at 25 ng/site; but the same dose induced marked grooming and inhibited
also water intake in water deprived rats. The present results confirm that TK NK
3, but not NK-1, receptor agonists selectively inhibit ethanol intake in alcohol
preferring rats and suggest that the NBM is a site of action for their effect.
PMID- 9392837
TI - Comparison of responses to T-kinin and bradykinin in the mesenteric vascular bed
of the cat.
AB - Responses to T-kinin and bradykinin were compared in the mesenteric vascular bed
of the cat. Under constant-flow conditions, injection of T-kinin and bradykinin
into the perfusion circuit induced similar dose-related decreases in perfusion
pressure. Responses to T-kinin and bradykinin were inhibited by the kinin B2
receptor antagonist Hoe-140, but were not altered by the B1 receptor antagonist
des-Arg9-[Leu8]-BK, the histamine H1 antagonist pyrilamine, the histamine H2
receptor antagonist cimetidine, or the H3 receptor antagonist thioperamide.
Vasodilator responses to T-kinin and bradykinin were attenuated by the nitric
oxide synthase inhibitor, N omega Nitro-L-arginine methyl ester (L-NAME), but
were not altered by the cyclooxygenase inhibitor, sodium meclofenamate, or the K+
ATP channel antagonist, U37883A. These data suggest that vasodilator responses to
T-kinin and bradykinin are mediated by kinin B2 receptor stimulated release of
nitric oxide from the endothelium, but that the activation of kinin B1 receptors,
the release of vasodilator prostaglandins, or the opening of K+ ATP channels are
not involved in the response to T-kinin in the mesenteric vascular bed of the
cat.
PMID- 9392838
TI - Differential regulation of angiotensinogen and natriuretic peptide mRNAs in rat
brain by osmotic stimulation: focus on anterior hypothalamus and supraoptic
nucleus.
AB - Central angiotensin II and natriuretic peptide systems have been shown to be
involved in the central regulation of blood fluid homeostasis with alterations in
central peptide and/or receptor levels observed following changes in osmotic
status. The present study investigated the effects of sodium loading on mRNA
encoding the angiotensin II precursor, angiotensinogen (AOGEN), and the
natriuretic peptides, atrial natriuretic peptide (ANP) and C-type natriuretic
peptide (CNP) in rat brain using quantitative in situ hybridization
histochemistry of [35S]- and [33P]-labeled oligonucleotide probes. Following 7
and 14 days of 2% sodium chloride in drinking water a significant increase was
detected in preproAOGEN (ppAOGEN) mRNA in presumed astrocytes in regions of the
anterior hypothalamus, including the periventricular nucleus, the medial preoptic
area and medial preoptic nucleus, while a decrease was observed in astrocytes in
the supraoptic nucleus. Other forebrain regions examined including the
subfornical organ, bed nucleus of the stria terminalis and the arcuate nucleus
showed no significant alteration in the level of ppAOGEN mRNA. Sodium loading did
not appreciably alter ppANP or ppCNP mRNA levels in neurons of the anteromedial
preoptic or arcuate nuclei or hippocampus at the times studied. PpANP mRNA levels
were also unaltered in Barrington's nucleus following sodium loading, while
preprocorticotropin-releasing hormone mRNA was significantly decreased. These
results indicate that AOGEN mRNA transcription/stability in vivo is modulated by
alterations in osmotic balance, consistent with previous reports of a central
role for AII in cardiovascular and body fluid homeostasis. In contrast, despite
reports of modulation of hypothalamic ANP-immunoreactivity following changes in
osmotic status, it would appear that osmotic stimulation over periods of 7-14
days does not markedly alter the transcription or stability of hypothalamic
natriuretic peptide mRNAs in vivo.
PMID- 9392840
TI - Arginine vasotocin gene expression in hypothalamic neurons is up-regulated in
chickens drinking hypertonic saline: an in situ hybridization study.
AB - Osmotic stress stimulates the release of the avian hypothalamic neuropeptide
arginine vasotocin (AVT) into the peripheral circulation. We conducted the
present study to investigate the effects of salt-loading on AVT secretion and AVT
gene expression in specific hypothalamic nuclei in chickens. White Leghorn
chickens were provided food ad lib and either water or 2% NaCl to drink. Both
plasma osmolality and plasma AVT levels were significantly increased in chickens
that drank 2% NaCl for either two or four days compared to that in chickens that
drank water. Results from in situ hybridization analysis demonstrated an increase
in the number of neurons expressing AVT mRNA in the supraoptic (SON) and
paraventricular nuclei (PVN) in chickens provided 2% NaCl to drink compared to
chickens that were provided water to drink. The number of grains per neuron
increased in the PVN, but not in the SON of osmotically stimulated birds. Thus,
increased osmolality resulting from ingestion of hypertonic saline is an
effective stimulus to increase hypothalamic AVT mRNA content in chickens.
PMID- 9392839
TI - Oxytocin releases atrial natriuretic peptide from rat atria in vitro that exerts
negative inotropic and chronotropic action.
AB - Our previous experiments suggested that natriuresis induced by blood volume
expansion, was brought about by oxytocin (OT)-stimulated atrial natriuretic
peptide (ANP) release from the right atrium. We hypothesized that the ANP
released might exert effects on the atrium itself and therefore carried out in
vitro experiments to test this hypothesis. Heart rate and isometric tension were
recorded from isolated rat atria mounted in an organ bath. Oxytocin exerted a
dose-related, negative chrono- and inotropic effect with a minimal effective
concentration (MEC) of 3 microM, 10-fold higher than required for ANP to exert
comparable effects. The effects of OT were not blocked by atropine suggesting
that they were not mediated via release of acetylcholine. Eight-bromoguanosine 3'
5'-cyclic monophosphate (cGMP) had similar effects to those of OT and ANP,
suggesting that the effects of ANP were mediated by cGMP. When isolated
ventricles, left or right atria, were incubated in vitro, OT had a dose-related
effect to stimulate the release of ANP into the medium only from right atria with
a MEC of 0.1 microM. A specific OT antagonist, F792 (1 microM), inhibited basal
release of ANP and blocked the stimulatory action of OT on ANP release. The
results support the hypothesis that OT, acting on its putative receptors in the
right atrium, stimulates the release of ANP which then exerts a negative chrono-
and inotropic effect via activation of guanylyl cyclase and release of cGMP. The
ability of the oxytocin antagonist to reduce basal release of ANP from atria
incubated in vitro supports the hypothesis that these effects could be
physiologically significant. We hypothesize that blood volume expansion via
baroreceptor input to the brain causes the release of OT which circulates to the
heart and stimulates the release of ANP from the right atrium. This ANP then has
a negative ino- and chronotropic effect in the atrium and possibly a negative
inotropic effect in the right ventricle, left atrium and left ventricle, to
produce an acute reduction in cardiac output that, coupled with its peripheral
vasodilating actions, causes a rapid reduction in effective circulating blood
volume. The ANP released would also act on the kidneys to cause natriuresis and
ANP acts within the brain to inhibit water and salt intake leading to a gradual
recovery of circulating blood volume to normal.
PMID- 9392841
TI - The block of central vasopressin V1 but not V2 receptors suppresses grooming
behavior and hypothermia induced by intracerebroventricular vasopressin in male
rats.
AB - The role of central vasopressin V1 receptors in grooming behavior induced by
vasopressin and oxytocin was studied in male rats of the Wistar strain. The
intracerebroventricular (ICV) injection of vasopressin (3 micrograms/5
microliters) induced hypothermia and enhanced novelty-induced grooming behavior.
Enhanced grooming but not hypothermia was also induced by ICV injection of
oxytocin (3 micrograms/5 microliters). The central administration of a selective
vasopressin V1 receptor antagonist prevented the stimulating action of
vasopressin on novelty-induced grooming and its hypothermic effect. The ICV
injection of a selective vasopressin V2 receptor antagonist failed to affect
vasopressin-induced grooming and hypothermic effect. An increase in core
temperature was observed in oxytocin-injected animals pretreated with the
vasopressin V1 receptor antagonist. Furthermore, pretreatment with the antagonist
did not affect grooming induced by oxytocin. These results suggest that
enhancement of grooming behavior and influence on thermoregulation are
differently regulated by central receptors for vasopressin and oxytocin.
PMID- 9392842
TI - Endomorphin 1 and 2, endogenous ligands for the mu-opioid receptor, decrease
cardiac output, and total peripheral resistance in the rat.
AB - Endomorphin 1 and 2 are recently discovered endogenous ligands for the mu-opioid
receptor. In the present study, responses to intravenous administration of
endomorphin 1 and 2 were investigated in the systemic vascular bed of the rat.
Endomorphin 1 and 2 induced dose-related decreases in systemic arterial pressure
when injected in doses of 10-100 nmol/kg i.v.. The decreases in systemic arterial
pressure in response to endomorphin 1 and 2 were associated with significant
decreases in heart rate, cardiac output, and total peripheral resistance. The
endogenous ligand for the ORL1 receptor, nociceptin/OFQ had similar effects on
systemic arterial pressure, heart rate, cardiac output, and total peripheral
resistance in the rat. Injections of isoproterenol (1 microgram/kg i.v.) and
calcitonin gene-related peptide (CGRP; 0.3 nmol/kg i.v.), decreased systemic
arterial pressure and total peripheral resistance. However these decreases in
arterial pressure were associated with increases in heart rate and cardiac
output. The results of the present study demonstrate that the endomorphin
peptides have significant vasodilator activity in the systemic vascular bed of
the rat and show that this response is associated with a decrease in heart rate
and cardiac output.
PMID- 9392843
TI - Beta-endorphin-containing proteins in the human pituitary.
AB - Two new proopiomelanocortin (POMC)-derived beta-endorphin (BE)-containing
proteins were detected in the human pituitary, using HPLC, trypsin digestion, and
a high sensitivity search with liquid secondary ion mass spectrometry (LSIMS) for
the protonated molecule ion, (M + H)+, of tryptic peptides that are unique to BE.
Proteins were extracted from pituitary tissues and were purified by solid phase
extraction (SPE) chromatography and RP-HPLC. Each HPLC fraction was treated with
trypsin, and each unseparated peptide mixture was analyzed by LSIMS to detect the
two selected marker peptides (BE 20-24 and BE 10-19) that have excellent LSIMS
desorption-ionization properties. The detection of both of those peptides
indicated the presence of BE-containing proteins in two HPLC fractions (number 47
and 51). Tandem MS determined the amino acid sequence of the marker peptide BE 20
24 (NAIIK), and those sequence data optimized the specificity of the method. The
two new BE-containing proteins derive from the C-terminal region of POMC, and
were minor components in the two HPLC fractions. The major component in fraction
51 derived from the vasopressin-neurophysin 2-copeptin precursor.
PMID- 9392844
TI - Pro-opiomelanocortin (POMC) expression and immunolocalization of POMC-related
peptides in the ovary of Protopterus annectens, an African lungfish.
AB - Antisera against adrenocorticotropic hormone (ACTH), alpha-melanocyte-stimulating
hormone (alpha MSH) and beta-endorphin were used to localize pro-opiomelanocortin
(POMC)-derived peptides in the ovary of the African lungfish Protopterus
annectens by immunohistochemistry. Immunoreactivity was observed in the granulosa
and the internal theca of the vitellogenic follicles. No immunoreactivity was
observed in immature follicles. Using human POMC cDNA as the hybridization probe
POMC-like mRNA was identified in situ in cells of the granulosa and internal
theca of the vitellogenic follicles. No labeling was observed in primordial
follicles. The demonstration in the same cells of POMC mRNA and POMC-related
peptides immunoreactivity indicates a local production of the opiate hormones.
PMID- 9392845
TI - Interactions of islet hormones with acetylcholine in the isolated rat pancreas.
AB - This study investigates the effects of the islet hormones, insulin (INS),
glucagon (GLU) and somatostatin (SOM) on acetylcholine (ACh)-evoked amylase
secretion and calcium (Ca2+) mobilization in the isolated rat pancreas.
Stimulation of pancreatic segments and acini with either INS, GLU or SOM resulted
in small increases of amylase output compared to much large increases in enzyme
output with ACh. Combinations of the peptide hormones with ACh resulted in
enhanced secretory responses compared to the effects obtained with either ACh or
each of the islet hormone alone. Genistein, the tyrosine kinase inhibitor, evoked
a decrease in amylase output from pancreatic segments. It had no effect on the
ACh evoke secretory response but it markedly inhibited the potentiation of the
islet hormones with ACh. In pancreatic acinar cells either INS, GLU or SOM
elicited moderate increases in amylase output compared to much larger responses
with ACh. Furthermore, the islet hormones failed to potentiate the secretory
effect of ACh in pancreatic acini. In fura-2 AM loaded acinar cells both INS and
GLU evoked small increases in intracellular free calcium concentration [Ca2+]i
compared to a much larger elevation with ACh. Both INS and GLU enhanced the ACh
evoked [Ca2+]i. Genistein elicited a decrease in [Ca2+]i both in the absence and
presence of both INS and GLU. It also decreased the rise in [Ca2+]i resulting
from the combined presence of ACh with both INS and GLU. SOM had no significant
effect on the ACh-induced [Ca2+]i. When genistein was combined with ACh and SOM
there was a decrease in [Ca2+]i compared to the response obtained with SOM and
ACh alone. The results indicate that both tyrosine kinase and cellular Ca2+ seem
to be the intracellular mediators associated with the enhanced secretory
responses obtained with a combination of the islet hormones with ACh. Finally,
our results using immunohistochemical techniques confirm the presence of INS-,
GLU- SOM- and ACh-immunoreactive cells in the endocrine and neural elements of
the rat pancreas.
PMID- 9392846
TI - Transport of insulin across the blood-brain barrier: saturability at euglycemic
doses of insulin.
AB - Blood-borne insulin is known to cross the blood-brain barrier (BBB) where it can
act as a satiety peptide. We examined in mice the pharmacokinetics and
characteristics of such passage by multiple-time regression analysis. The
unidirectional influx constant (Ki) of human insulin radioactively labeled with
iodine (I-Ins) ranged from 0.87 to 1.7 microliters/g-min. The transport of I-Ins
was inhibited almost 50% by 0.1 micrograms/mouse of unlabeled human insulin, a
dose that had no effect on serum glucose. Similar results were found with rat
insulin. The results with self-inhibition suggest that any hemoencephalic signal
transmitted by the blood to brain transport of insulin is independent of the
effects of insulin on glucose. The transport of I-Ins was altered by aluminum but
not by administration of tyrosine, verapamil, or leptin, indicating independence
from amino acid transport, the p-glycoprotein system, a slow calcium channel, or
leptin transport. By contrast with insulin, enzyme degradation limited the uptake
and accumulation by brain of intravenously injected, radioactively labeled
glucagon and glucagon-like peptide. In conclusion, these results are consistent
with the view that insulin can affect satiety and related behaviors independently
of its peripheral effects by crossing the BBB to act within the brain.
PMID- 9392847
TI - Bioavailability and transport of peptides and peptide drugs into the brain.
AB - Rational drug design and the targeting of specific organs has become a reality in
modern drug development, with the emergence of molecular biology and receptor
chemistry as powerful tools for the pharmacologist. A greater understanding of
peptide function as one of the major extracellular message systems has made
neuropeptides an important target in neuropharmaceutical drug design. The major
obstacle to targeting the brain with therapeutics is the presence of the blood
brain barrier (BBB), which controls the concentration and entry of solutes into
the central nervous system. Peptides are generally polar in nature, do not easily
cross the blood-brain barrier by diffusion, and except for a small number do not
have specific transport systems. Peptides can also undergo metabolic deactivation
by peptidases of the blood, brain and the endothelial cells that comprise the
BBB. In this review, we discuss a number of the recent strategies which have been
used to promote peptide stability and peptide entry into the brain. In addition,
we approach the subject of targeting specific transport systems that can be found
on the brain endothelial cells, and describe the limitations of the methodologies
that are currently used to study brain entry of neuropharmaceuticals.
PMID- 9392848
TI - Inhibition of bacterial growth by synthetic SP-B1-78 peptides.
AB - Residues 12-34 of mature human pulmonary surfactant protein B (SP-B1-78) are 68%
homologous to residues 48-72 of the frog peptide antibiotic dermaseptin b I. We
examined the effects of SP-B1-78 on the growth of Escherichia coli in order to
find whether full length SP-B1-78 might act as a peptide antibiotic. We found
that SP-B1-78 peptide inhibited growth of E. coli (MIC = 210 micrograms.ml-1),
but that the SP-B variant [R/K-->S]SP-B1-78 was less potent (MIC = 500
micrograms.ml-1).
PMID- 9392849
TI - Staurosporine-dependent activation of human endothelial cell monolayers for
neutrophil adherence by secretoneurin.
AB - Functions of secretoneurin include chemotaxis for monocytes and endothelial
cells, and inhibition of endothelial cell proliferation. Inhibition of monocyte
chemotaxis by staurosporine indicated involvement of specific signaling
mechanisms. We have tested effects of kinase inhibitors on activation of
endothelial cells for neutrophil adherence by secretoneurin. Pretreatment of
endothelial cells by secretoneurin induced in endothelium increased adhesiveness
to neutrophils. Addition of staurosporine, an inhibitor of protein kinase C,
completely abolished endothelial cell activation, whereas tyrphostin-23, a
tyrosin kinase inhibitor, had no effect. Results on activation of neutrophil
endothelial cell adherence by secretoneurin demonstrate that specific signaling
mechanisms are involved in endothelial cell activation.
PMID- 9392850
TI - Endothelin-1 induces bronchial myofibroblast differentiation.
AB - Endothelin-1 may contribute to bronchial smooth muscle constriction and airway
remodelling in asthma, where bronchial epithelial cells represent an important
source of this peptide. We report here that asthmatic bronchial epithelial cells
exposed to allergens in vitro induce the differentiation of airway fibroblasts
into myofibroblasts, and that they do so through a granulocyte/macrophage colony
stimulating factor-mediated upregulation of endothelin-1 production. By this
mechanism bronchial epithelial cells may participate in the genesis of bronchial
subepithelial fibrosis, a process which contributes to airway narrowing in
asthma.
PMID- 9392851
TI - Rat corpus luteum expresses both PACAP and PACAP type IA receptor mRNAs.
AB - Both pituitary adenylate cyclase-activating polypeptide (PACAP) and PACAP type I
receptor gene expressions were detected in the corpus luteum of pregnant mare's
serum gonadotropin (PMSG)-human chorionic gonadotropin (hCG)-treated immature
rats using reverse transcription-polymerase chain reaction (RT-PCR). RT-PCR
products of the poly(A)+ RNA extracted from rat corpora lutea yielded dominant
DNA bands that corresponded to segments of PACAP mRNA (453 bp) and PACAP type IA
receptor mRNA (290 bp) spanned by the PCR primers. The identities of the PACAP
cDNA and the PACAP receptor cDNA fragments were confirmed by Southern blot
hybridization analyses. Our results showed that PACAP mRNA and PACAP type IA
receptor mRNA are synthesized within luteinized cells of rat ovary, and suggest
that PACAP is closely linked to the reproductive process.
PMID- 9392852
TI - Pro-dopamine effects of neurotensin on sensorimotor gating deficits.
AB - Neurotensin is a neuropeptide which coexists with mesolimbic dopamine and has
exhibited neuroleptic-like activity in the nucleus accumbens. This study examined
the effects of neurotensin infused into the nucleus accumbens on prepulse
inhibition (PPI) of the rat's acoustic startle reflex, a measure which is
relevant to the sensorimotor gating deficits seen in schizophrenia. Neurotensin
(5 micrograms) had no effect on the amplitude of the acoustic startle reflex nor
on baseline PPI, but it potentiated the disruption of PPI produced by amphetamine
and apomorphine. This is the first report of a pro-dopamine action for intra
accumbens neurotensin, and suggests that a complex behavioral pharmacology is
associated with this neuropeptide.
PMID- 9392853
TI - CGRP-beta unlike CGRP-alpha has no osteogenic stimulatory effect in vitro.
AB - The purpose of this study is to test whether CGRP-beta has an osteogenic
stimulating effect, as does CGRP-alpha, on rat bone marrow cells in vitro. CGRP
beta in different doses was added daily to bone marrow white cells, which were
harvested from rats, then seeded onto a previously prepared layer of fibroblasts.
CGRP-alpha in different doses was used as a positive control. Fourteen days after
the start of the experiment, there was no statistical difference in the number of
bone colonies between the control and CGRP-beta dishes. The CGRP-alpha dishes
demonstrated an increase in the number of colonies with an increase of peptide
dose.
PMID- 9392854
TI - Gastrin-releasing peptide1-27, unlike bombesin, does not reduce sham feeding in
rats.
AB - We compared the potencies of systemic administration of bombesin (BN) and its
mammalian homologue gastrin-releasing peptide (GRP) to decrease sham feeding in
rats. Bombesin (at doses of 8, 16 and 32 micrograms/kg, intraperitoneally)
inhibited sham feeding by 37% (p < 0.001), 58% (p < 0.001) and 65% (p < 0.001),
respectively, confirming previous results. Gastrin-releasing peptide (16, 32, and
64 micrograms/kg) failed to affect sham feeding. Bombesin (16 micrograms/kg) and
gastrin-releasing peptide (32 micrograms/kg) inhibited real feeding by 64% (p <
0.001) and 44% (p < 0.004), respectively. Pregastric food stimulation is not
sufficient for the inhibitory action of GRP.
PMID- 9392855
TI - Homology modeling of glycosyl hydrolase family 18 enzymes and proteins.
AB - Using state-of-the-art homology modeling methods, three-dimensional coordinates
for three family 18 glycosyl hydrolases were determined. The structures for Gp39,
Brp39, and chitotriosidase were computer determined using the X-ray coordinates
from SmChiA. The results of the modeling efforts are assessed, and comparison of
the modeled structures to other known family 18 members is made.
PMID- 9392856
TI - Modeling studies of binding of sea raven type II antifreeze protein to ice.
AB - Certain plants, insects, and fish living in cold environments prevent tissue
damage due to freezing by producing antifreeze proteins or antifreeze
glycoproteins that inhibit ice growth below the normal equilibrium freezing point
of water in a noncolligative fashion. In polar fish these macromolecules, taking
into account their structural characteristics, are grouped into three broad
classes, namely Type I, Type II, and Type III. In this paper we report the
results of our studies on the stereospecific binding of sea raven, a Type II
antifreeze protein (AFP) to (111) hexagonal bipyramidal faces of ice. Earlier
studies of Type I and Type III AFPs have shown that stereospecific binding of
these proteins, recognizing specific planes of ice, is essential for their
noncolligative antifreeze point depression. Moreover, as it has been shown for
the AFT of Type I, this binding also occurs along specific vectors on these
planes and also is enantioselective, distinguishing between the mirror related
directions. In this study we will show, by using molecular modeling, that the
fold of Type II AFP could facilitate a stereospecific mode of interaction with
(111) planes of ice. Similar to Type I AFP, preferential directionality of
binding was also observed in the simulations.
PMID- 9392857
TI - Structural characterization of the molecular dimer of the peptide antibiotic
vancomycin by distance geometry in four spatial dimensions.
AB - The conformation of a dimer of the peptide antibiotic vancomycin is developed
from computer simulations based on experimental distance constraints derived from
high-resolution NMR measurements. The conformation and topological array of the
dimer are determined by a distance geometry based method using the molecules cast
into four spatial dimensions. This method was imperative for the refinement of
vancomycin given the entwining of the monomers (including hydrogen bonding and
interactions between the aromatic ring systems) within the dimer. The development
of the high-resolution structure of the monomer and then simple molecular
modeling to create the dimer which fulfills all of the experimental observations
was not possible. In contrast, the refinement protocol using the dimer cast into
four spatial dimensions was able to quickly locate conformations in which both
the intra- and intermolecular nuclear Overhauser effects were satisfied. These
structures, once converted back to three dimensions, were further refined using
standard molecular mechanics energy minimization. The structural characteristics
of the dimer with respect to binding to the cell-wall precursor are described.
PMID- 9392858
TI - Using neural network predicted secondary structure information in automatic
protein NMR assignment.
AB - In CAPRI, an automated NMR assignment software package that was developed in our
laboratory, both chemical shift values and coupling topologies of spin patterns
are used in a procedure for amino acids recognition. By using a knowledge base of
chemical shift distributions of the 20 amino acid types, fuzzy mathematics, and
pattern recognition theory, the spin coupling topological graphs are mapped onto
specific amino acid residues. In this work, we investigated the feasibility of
using secondary structure information of proteins as predicted by neural networks
in the automated NMR assignment. As the 1H and 13C chemical shifts of proteins
are known to correlate to their secondary structures, secondary structure
information is useful in improving the amino acid recognition. In this study, the
secondary structures of proteins predicted by the PHD protein server and our own
trained neural networks are used in the amino acid type recognition. The results
show that the predicted secondary structure information can help to improve the
accuracy of the amino acid recognition.
PMID- 9392859
TI - Using artificial neural networks to classify the activity of capsaicin and its
analogues.
AB - Back-propagation artificial neural networks (ANNs) were trained with parameters
derived from different molecular structure representation methods, including
topological indices, molecular connectivity, and novel physicochemical
descriptors to model the structure--activity relationship of a large series of
capsaicin analogues. The ANN QSAR model produced a high level of correlation
between the experimental and predicted data. After optimization, using cross
validation and selective pruning techniques, the ANNs predicted the EC50 values
of 101 capsaicin analogues, correctly classifying 34 of 41 inactive compounds and
58 of 60 active compounds. These results demonstrate the capability of ANNs for
predicting the biological activity of drugs, when trained on an optimal set of
input parameters derived from a combination of different molecular structure
representations.
PMID- 9392860
TI - Distribution analysis of the variation of B-factors of X-ray crystal structures;
temperature and structural variations in lysozyme.
AB - The B-factor (isotropic temperature factor) data for X-ray structures of hen egg
white lysozyme from the study of Young et al. (Young, Dewan, Nave, and Tilton J.
Appl. Cryst. 1993, 26, 309-319) potentially contain information about the
relative contributions of static and dynamic variation to these factors. The six
structures of the protein were obtained at two widely different temperatures (100
and 298 K), with two crystal forms (monoclinic and tetragonal) and other
experimental differences. In addition, the monoclinic lysozyme crystals with two
molecules per asymmetric unit allow direct examination of variation between
structures determined under identical conditions at both temperatures. The B
factors from these structures all have complex distribution functions as might be
expected considering all of the influences that these values must reflect. The
empirical cumulative distribution functions (eCDF's) of these data show that they
are representative of complex, multicomponent distributions. Distribution
analysis using the DANFIP procedure (Wampler, Anal. Biochemistry 1990, 186, 209
218) of the data sets reveals that they can be modeled as four to six Gaussian
subpopulations, that these subpopulations do not correlate with specific atom
types, specific amino acid residues or fixed locations in the structure. While
they do seem to correlate with localized groupings of atoms, these grouping vary
from structure to structure even within the same crystal under the same
conditions. Temperature seems to have a global effect in this case, but it is
clear that other factors including experimental error influence the distribution
of B-factors within a given structure. This analysis also helps explain the oft
observed lack of atomic level correlation between experimental B-factors and
calculated mean square displacements from molecular dynamics simulations.
PMID- 9392861
TI - Intracellular transmission in cell volume regulation in Ehrlich ascites tumor
cells.
PMID- 9392863
TI - Role of actin filament organization in cell volume and ion channel regulation.
AB - The actin cytoskeleton is an intracellular structure, which is involved in the
onset and control of cell shape and function. In order for this relevant network
to control its own and thus cell volume, specific interactions between the actin
cytoskeleton and ion channel regulation controlling intracellular salt and water
homeostasis may be invoked. The hypotonic shock-induced, cell volume regulatory
decrease (RVD) of most eukaryotic cells is a particularly useful example, as it
is initiated and regulated by concerted processes involving both adaptive changes
in actin filament organization and bulk fluid extrusion triggered by saline
movement and the consequent decrease in cell water. The onset of RVD is linked to
the selective activation of osmotically-sensitive ion channels and other relevant
ion transport mechanisms involved in the net ionic movement from the cytosol.
Such regulatory processes, entailing effector changes in actin filament
organization which target the plasma membrane, are largely unknown. In this
report, recent studies are summarized implicating dynamic changes in gel
properties of the actin cytoskeleton as the effector mechanism in the regulation
of ion channel activity, and thus cell volume, in human melanoma cells. Based on
the characterization of the hypotonic cell volume regulatory response of human
melanoma cells devoid of a functional actin-binding protein (ABP-280, a filamin
homolog) and their genetically rescued counterpart transfected with a functional
ABP, a hypothesis is raised which is consistent with a regulatory "sensory"
mechanism based on the ability of actin networks to respond to changes in the
intracellular water-salt homeostasis, which in turn effects signals controlling
membrane function, including ion channel activity.
PMID- 9392862
TI - Confocal microscopic observation of cytoskeletal reorganizations in cultured
shark rectal gland cells following treatment with hypotonic shock and high
external K+.
AB - The dogfish shark (Squalus acanthias) rectal gland (SRG) cell has served as a
model experimental system for investigating the relationship between the actin
cytoskeleton and cell volume regulation. Previous reports employing conventional
fluorescence microscopy of tissue slices have shown that cells exposed to high
external K+ and hypotonically-induced cell swelling displayed a fading of F-actin
staining intensity, particularly at the basolateral cell borders. However,
spectroscopic measurement of the F-actin present in similarly treated rectal
gland slices failed to demonstrate a net change in F-actin amount. In an effort
to resolve the structural reorganizations of F-actin which may be occurring
during high K+ and hypotonic shock treatments, we have used cultured SRG cells in
conjunction with confocal microscopic immunocytochemical localization techniques
to examine actin filament, microtubule, and cytokeratin filament dynamics under
these two experimental conditions. The results reveal that F-actin in control
cells exists in an array of parallel linear bundles (which do not appear to be
stress fiber-like given their lack of staining for myosin II or alpha-actinin)
that is reorganized to a punctate pattern in hypotonic shock and a dense meshwork
in high K+. The linear bundle pattern of F-actin returns in cells undergoing
regulatory volume decrease. Quantitative western blotting of F-actin in SRG cell
detergent extracted cytoskeletons indicates no significant difference in the
relative amounts of F-actin present in control, hypotonic shocked, or high K+
cells. Anti-tubulin and anti-cytokeratin labeling of the treated SRG cells
suggest that these other major cytoskeletal elements are not significantly
altered by the treatments. Taken together, our results reinforce the concept that
there is an association between the structural organization of the actin
cytoskeleton and cell volume regulation in the SRG epithelial cells.
PMID- 9392864
TI - Biochemistry and physiology of carbohydrates in the renal collecting duct.
AB - Using 13C-NMR analysis of cell extracts, enzymatic determination of metabolites
and cofactors as well as enzyme assays on cell homogenates aerobic and anaerobic
glycolysis, sorbitol formation by aldose reductase, the pentose phosphate shunt,
and gluconeogenesis could be identified as the major pathways of D-glucose
metabolism in renal inner medullary collecting ducts. In flux studies it was
shown that D-glucose enters the collecting duct cells via a sodium-independent,
cytochalasin- and phloretin-inhibitable transport system located at the basal
lateral cell side. At the same side sorbitol leaves the cells during regulatory
volume decrease in a calcium-calmodulin-dependent fashion. From cell isolation
studies it is proposed that sorbitol is taken up by adjacent (interstitial)
cells, converted into fructose and then recycled to the collecting duct cells.
This cycle might prevent carbohydrate wasting. Thus, IMCD cells exhibit unique
aspects of carbohydrate biochemistry and physiology which enable them to function
in a surrounding of low oxygen tension, low substrate supply, and extreme changes
in extracellular osmolality.
PMID- 9392865
TI - Characterization and regulation of H-K-ATPase in intercalated cells of rabbit
cortical collecting duct.
AB - K-dependent H+ extrusion was investigated using fluorescence techniques in rabbit
cortical collecting tubules (CCTs). Experiments were performed in split-open
tubules from normal animals exposed to the intracellular pH indicator 2',7'
bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). This preparation permitted the
study of individual intercalated cells (ICs). In the ICs, partial recovery of
pH(i) was observed in response to an acute acid load upon readdition of 5 mM K to
the superfusate. This recovery was SCH 28080-inhibitable (10(-5) M) and ouabain
insensitive suggesting the process is mediated by a gastric-type H-K ATPase. To
see if H-K ATPase plays a role in acid secretion its function was evaluated under
chronic metabolic acidosis (CMA) conditions. CMA was induced by replacing
drinking water with 75 mM NH4Cl in 5% sucrose for 10-14 days. The SCH 28080
inhibitable K-dependent pH(i) recovery rate was three-fold higher in CMA ICs
compared to controls. To determine the location of the H-K ATPase, CCTs were
microperfused and individual peanut lectin binding (PNA) ICs studied. K-dependent
pH(i) recovery was measured in response to an NH4Cl pulse. An apical SCH 28080
inhibited K-dependent pH(i) recovery process was observed in control and CMA ICs.
Taken together these data confirm the existence of a gastric-type H-K ATPase in
ICs of rabbit CCT. Based on our findings the H-K ATPase is found on the apical
side of the cell and is stimulated under conditions of CMA.
PMID- 9392866
TI - Volume-activated osmolyte channel in skate erythrocytes: inhibition by pyridoxal
derivatives.
AB - Volume expansion of erythrocytes of little skate, Raja erinacea, triggers the
opening of an osmolyte channel. We review this transport mechanism and further
investigate the channel's physicochemical nature by probing the channel with a
series of pyridoxine derivatives in skate RBC as well as in epithelial cells:
MDCK and C6 glioma cells and in skate hepatocytes. The identity of the transport
mechanism (band 3 vs. an anion channel) which mediates the swelling-activated
efflux of osmolytes in fish RBC is controversial. Therefore, we compared taurine
and Cl- effluxes in similar conditions. We found that there is significant Cl-
loss from volume-expanded skate RBC. However, there was no effect of either
hypotonicity or a number of taurine transport inhibitors on this loss. Utilizing
changes in intracellular pH as a means of indirectly measuring H+/Cl-
cotransport, we found that a rise in cell pH accompanied the loss of Cl-. This
suggests that Cl- efflux could occur via a H+/Cl- cotransporter. To probe and
compare the osmolyte channel (taurine efflux) of the skate RBC and three other
cell types we used a family of pyridoxine inhibitors. The inhibitory patterns for
the skate erythrocytes and hepatocytes differed from those for MDCK and C6 glioma
cells and the two former cell types differed from each other. Therefore, the
results show that the osmolyte channel in the skate differs from that in other
epithelial cells with regard to pyridoxine derivative binding properties.
PMID- 9392867
TI - Dual pathways for organic anion secretion in renal proximal tubule.
AB - Transport on the "classical" organic anion system in renal proximal tubule is
specific, active, Na-dependent, and ouabain sensitive. Here we review recent
studies using intact teleost proximal tubules and laser scanning confocal
microscopy which show that the secretion of large organic anions, such as,
fluorescein-methotrexate (FL-MTX, Mw 923 Da) is handled by a separate and
distinct organic anion transport system. In contrast to the classical system, FL
MTX uptake into cells and secretion into the tubular lumen was ouabain
insensitive and largely Na-independent. KCN did not affect cellular uptake but
abolished secretion into the lumen. PAH and probenecid, potent inhibitors of
transport on the classical system, were weak inhibitors of FL-MTX transport.
Uptake and secretion of FL-MTX were inhibited by micromolar concentrations of
other organic anions (MTX, folate, bromocresol green, bromosulfonphthalein). FL
MTX secretion into the lumen was inhibited by leukotriene C4 and cyclosporine A,
neither of which affected transport of the model substrate for the classical
system, fluorescein. Thus, FL-MTX secretion is specific, but largely Na
independent and ouabain-insensitive. Both the basolateral and luminal steps in FL
MTX transport differ from those associated with fluorescein and P-aminohippurate
secretion.
PMID- 9392868
TI - ATP regulation of a swelling-activated osmolyte channel in skate hepatocytes.
AB - Hypotonic swelling of isolated skate hepatocytes activates a regulatory volume
decrease (RVD) which is achieved in part by the release of taurine and other
intracellular organic osmolytes. Volume-activated taurine efflux appears to be
mediated by an anion channel that exhibits a taurine/chloride permeability ratio
of approximately 0.2. Of significance, this channel was shown to be regulated by
intracellular nucleotide. When intracellular ATP was decreased to about 50% of
control levels, channel opening was completely prevented. Many putative ion
channel blockers were found to inhibit the channel indirectly, by depleting
intracellular ATP, rather than by directly interacting with the channel.
Investigators using these channel blockers in whole cell preparations should be
aware of this alternative mechanism. Cell swelling-activated taurine efflux was
also inhibited by HgCl2, DIDS, and pyridoxal 5-phosphate, at concentrations of
these agents that had no effect on intracellular ATP levels, suggesting
additional mechanisms of inhibition and regulation of the volume-sensitive
osmolyte channels.
PMID- 9392869
TI - Pump-leak parallelism in sodium-absorbing epithelia: the role of ATP-regulated
potassium channels.
AB - In all Na(+)-absorbing and Cl(-)-secreting epithelia, an increase in the activity
of the Na+,K(+)-pump at the basolateral membrane is accompanied by an increase in
the K+ conductance of that barrier and vice versa. We have recently identified an
ATP-regulated K+ channel, K(ATP), in basolateral membrane vesicles isolated from
Necturus maculosa small intestinal epithelial cells that could be responsible for
this parallelism between pump activity and leak. Thus, an increase in pump
activity would result in a decrease in local ATP activity and an increase in
local ADP activity and, in turn, an increase in the open-probability of the
channel whereas a decrease in in pump activity would have the opposite effect.
Further, the likelihood that the number of pumps far exceeds the number of leaks
per unit area of membrane suggests that the ATP and ADP activities that influence
K(ATP) channel activity may differ markedly from the "bulk" cytoplasmic values.
PMID- 9392870
TI - Potential interplay between luminal growth factors and increased tight junction
permeability in epithelial carcinogenesis.
PMID- 9392871
TI - Sulfonamides and secretion of aqueous humor.
AB - The connection between carbonic anhydrase and the formation of aqueous humor
arose in the decade 1950-1960 when a number of experiments of differing types
showed that HCO3- ion catalytically formed in the ciliary process from CO2 was a
principal element in the production of the aqueous. It was soon shown that
inhibitors of the enzyme, given systemically, slowed HCO3- formation and sodium
and fluid transport and thereby lowered intraocular flow and pressure in normal
vertebrates and in patients with glaucoma. In the past 15 years successful
efforts have been made to produce sulfonamide inhibitors that reach the ciliary
process after local application to the cornea. The effects of locally acting
sulfonamides are largely due to their amphoteric properties. They are soluble in
both lipid and non-lipid media and penetrate cornea and sclera to reach ciliary
process. Potency against carbonic anhydrase II is of the order of K(I) = 10(-9)
M, so that topical application inhibits essentially all enzyme in the processes
and is an effective nontoxic treatment for glaucoma.
PMID- 9392873
TI - Transport mechanisms that mediate the secretion of chloride by the rectal gland
of Squalus acanthias.
AB - The rectal gland of Squalus acanthias secretes chloride by a mechanism that has
been termed "secondary active transport" because it depends on the activity of Na
K-ATPase. As currently described, chloride enters the cell across the basolateral
cell membrane via the 2 chloride: sodium: potassium cotransporter. The energy for
this electroneutral uphill movement of chloride and potassium is provided by the
gradient for sodium directed into the cell. Present in the basolateral cell
membrane is Na-K-ATPase that maintains the gradient for sodium. A potassium
conductance, present as well in the basolateral cell membrane, recirculates the
potassium. Chloride exits the cell across the luminal membrane via CFTR, the
chloride conductance. This mechanism is widely distributed throughout
vertebrates. This report reviews the experimental observations that led to the
current definition of the mechanism of chloride transport in the rectal gland.
PMID- 9392872
TI - Potential contribution of epithelial Na+ channel to net secretion of aqueous
humor.
AB - The aqueous humor of the eye is secreted by the bilayered ciliary epithelium,
consisting of the pigmented (PE) cell layer facing the stroma and the
nonpigmented (NPE) cell layer facing the aqueous humor. Cells within each layer
and between the two layers are linked by gap junctions, forming a ciliary
epithelial syncytium. Unidirectional secretion from the stroma to the aqueous
proceeds both through the cells (the transcellular pathway) and between the cells
(the paracellular pathway). Net formation of aqueous humor must, however, be the
algebraic sum of unidirectional secretion and unidirectional reabsorption from
the aqueous humor back into the stoma. The mechanisms potentially underlying
reabsorption of aqueous humor by the NPE cells have recently been addressed by
studying the regulatory response (RVI) of anisosmotically shrunken NPE cells. The
results indicated that epithelial Na+ channels with a high affinity to amiloride
likely contribute to reabsorption of solute from the aqueous humor. We have
substantiated this possibility by using Northern analysis to identify in human
ciliary body RNA a 3.7-kb transcript corresponding to the alpha-subunit of the
amiloride-sensitive, alpha beta gamma-ENaC epithelial sodium channel. We have
also found that the Na(+)-channel inhibitor benzamil inhibits the RVI without
affecting the cell volume of isotonic cell suspensions. This observation supports
the hypothesis that the low conductance, highly selective epithelial Na+ channel
is activated by shrinkage and contributes to unidirectional reabsorption as
aqueous humor. Examples are provided of how the integrative regulation of aqueous
humor formation can involve conjugate actions on both unidirectional secretion
and reabsorption.
PMID- 9392874
TI - Cadmium disrupts the signal transduction pathway of both inhibitory and
stimulatory receptors regulating chloride secretion in the shark rectal gland.
AB - The heavy metal cadmium causes nephrotoxicity and alters the transport function
of epithelial cells. In the shark rectal gland, chloride secretion is regulated
by secretagogues and inhibitors acting through receptors coupled to G proteins
and the cyclic AMP-protein kinase A pathway. We examined the effects of cadmium
on the response to the inhibitory peptide somatostatin (SRIF), and to the
stimulatory secretagogues forskolin and vasoactive intestinal peptide (VIP). In
control experiments, SRIF (100 nM) entirely inhibited the chloride secretory
response to 10 microM forskolin (maximum chloride secretion with forskolin 1984
+/- 176 microEq/h/g; with forskolin + SRIF 466 +/- 93 microEq/h/g, P < 0.001).
Cadmium (25 microM) entirely reversed the inhibitory response to SRIF (chloride
secretion 2143 +/- 222 microEq/h/g) and caused an overshoot (2917 +/- 293
microEq/h/g) that exceeded the response to forskolin (P < 0.01). Cadmium also
enhanced forskolin-stimulated chloride secretion (2628 +/- 418 vs. 1673 +/- 340
microEq/h/g, P < 0.02) and reversed the declining phase of the forskolin
response. Cadmium had a concentration-dependent, biphasic effect on the response
to VIP. Cd (10-100 microM) increased both chloride secretion and tissue cyclic
AMP content, whereas higher concentrations (1 mM) inhibited chloride secretion
and cyclic AMP accumulation. Our findings provide evidence that Cd disrupts the
signal transduction pathways of both inhibitory receptors and secretagogues
regulating cAMP mediated transport in an intact epithelia. The results are
consistent with direct effects of cadmium on adenylate cyclase and/or
phosphodiesterase activity in this marine epithelial model.
PMID- 9392875
TI - New protopine and benzyltetrahydroprotoberberine alkaloids from Aristolochia
constricta and their activity on isolated guinea-pig ileum.
AB - Five new protopine-type alkaloids, 3,5-di-O-methylconstrictosine (1), 5,6-dihydro
3,5-di-O-methylconstrictosine (2), 5,6-dihydroconstrictosine (3), constrictosine
(4), 3-O-methylconstrictosine (5), and a novel 8-benzylberberine-type alkaloid, (
)-8 beta-(4'-hydroxybenzyl)-2,3-dimethoxyberbin-10-ol (6) were isolated from the
aerial parts of Aristolochia constricta. Their structures were elucidated by
physical and spectroscopic data. The results of our pharmacological experiments
indicated that MeOH extract, its partially purified fraction VI and the protopine
derivatives constrictosine 1-5, significantly reduced, in a dose dependent
manner, the electrical, acetylcholine, and histamine contractions of the isolated
guinea-pig ileum.
PMID- 9392876
TI - Triterpenoid saponins from Trevesia sundaica.
AB - Six new bisdesmosidic saponins 1-6, along with four known triterpenoid saponins
were isolated from the aerial parts of Trevesia sundaica (Araliaceae). Their
structures were determined by 1H-1H correlation spectroscopy (COSY, TOCSY, ROESY)
and 1H-13C heteronuclear correlation (HSQC, HMBC) NMR experiments, FABMS, and
chemical data.
PMID- 9392877
TI - Isolation, synthesis, and antiplatelet aggregation activity of resveratrol 3-O
beta-D-glucopyranoside and related compounds.
AB - Resveratrol 3-O-beta-D-glucopyranoside (1) has been isolated from the seeds of
Erythrophleum lasianthum (Caesalpinioidae, Leguminosae), a South African plant
used in traditional medicine, and has shown antiplatelet aggregation activity.
The synthesis of 1, related hydroxystilbenes, and their glucosides has been
undertaken to provide larger quantities, for further biological evaluation, and
has been accomplished via Wittig reactions followed by glucosylation under phase
transfer catalysis.
PMID- 9392878
TI - Isolation of a novel Kunitz family protease inhibitor in association with Tethya
hemolysin from the sponge Tethya ingalli.
AB - Aqueous extracts from the New Zealand sponge Tethya ingalli (Hadromerida)
displayed potent cytotoxicity in the NCI's 60-cell-line human tumor panel.
Fractionation of the extract by ammonium sulfate precipitation, gel filtration,
ultrafiltration, and both hydrophobic interaction and reversed-phase
chromatography resulted in the isolation of two biologically active proteins. The
first protein, Tethya protease inhibitor (TPI), which was purified to
homogeneity, inhibited trypsin with an EC50 of 65 nM. TPI had a molecular mass of
11,431 Da, and an isoelectric point of 8.2. A partial N-terminal amino acid
sequence determined for TPI showed significant homology with protease inhibitors
of the Kunitz family. The second isolated protein displayed potent cytotoxicity,
with pronounced selectivity for certain tumor cell lines (e.g., ovarian, renal,
CNS, and breast). The latter protein, which had an apparent molecular weight of
21 kDa (SDS-PAGE), also lysed human red blood cells (EC50 of 39 nM) and was
similar to a hemolysin previously isolated from the sponge Tethya lycinurium.
PMID- 9392879
TI - Antitumor agents. 180. Chemical Studies and cytotoxic evaluation of
cumingianosides and cumindysoside A, antileukemic triterpene glucosides with a
14,18-cycloapotirucallane skeleton.
AB - Treatment of cumingianosides and cumindysoside A, which possess a 14,18
cycloapotirucallane skeleton, with p-toluenesulfonic acid in CH2Cl2 yielded new
triterpene glucosides. Cumingianoside A (1) gave 10 and 11, along with
cumingianoside Q (5). The structures of 10 and 11 were determined on the basis of
spectral examination and contained a dammar-13(17)-ene and a 17(R),23(R)
epoxydammarane skeleton, respectively. Cumingianoside C (2) afforded, together
with cumingianoside P (6), products 12 and 13, which were similar to 10 and 11,
respectively. With a short reaction time at room temperature, cumingianoside E
(3) yielded cumingianoside D (4). In contrast, when 3 was treated with p
toluenesulfonic acid in CH2Cl2 overnight at 5 degrees C, it gave two products, 9
and 14. Extensive spectroscopic examination revealed that 9 possessed a dammar-12
ene skeleton, while 14 was a pentacyclic tetranortriterpene glucoside with a
novel skeleton. Cumindysoside A (8) gave a product (15) similar to 14. The
cytotoxicities of 9-15 were evaluated against a panel of 58 human tumor cell
lines. Compounds 11-15 exhibited potent cytotoxicity with log GI50 values ranging
from -7.11 to -4.94, especially against leukemia and colon-tumor cell lines.
PMID- 9392880
TI - Sesquiterpenoids of the drimane class from a sponge of the genus Dysidea.
AB - Ten sesquiterpenoids, including seven new ones, have been isolated from an
undescribed sponge of the genus Dysidea. Compounds 1-8 are sesquiterpenoids of
the drimane class, while 9 and 10 are 12-norsesquiterpenoids of the same
structural class. The structures of novel compounds have been determined by
combined spectroscopic methods. These compounds exhibited moderate antimicrobial
and enzyme inhibitory (Na+/K(+)-ATPase and PLA2) activities.
PMID- 9392882
TI - New cembranoid diterpenes and a geranylgeraniol derivative from the common
Caribbean sea whip Eunicea succinea.
AB - A recent collection and extraction of the common Caribbean sea whip Eunicea
succinea from Puerto Rico has produced four previously undescribed
representatives of the cembrane family of diterpenes (2, 3, 4, and 6). A new
geranylgeraniol derivative, 8, was also isolated as a minor constituent. The
chemical structures of the new compounds were carefully established by
spectroscopic and chemical methods in addition to detailed NMR spectral
comparisons with known cembranoid models from Eunicea.
PMID- 9392881
TI - Oxidations of vincristine catalyzed by peroxidase and ceruloplasmin.
AB - The dimeric Catharanthus alkaloid vincristine (1) is oxidized to the same ring
fission product in incubations with either horseradish peroxidase or the human
serum copper oxidase ceruloplasmin. Horseradish peroxidase-catalyzed oxidation of
vincristine requires hydrogen peroxide, whereas ceruloplasmin-catalyzed oxidation
of vincristine requires chlorpromazine as a "shuttle oxidant". Preparative-scale
incubations allowed for the production, isolation, structural characterization,
and biological evaluation of the metabolite. The metabolite was identified as the
heterocyclic ring cleavage product N-formylcatharinine (5). N-Formylcatharinine
was 118 times less active than vincristine in an in vitro test against a human T
cell leukemic cell line. Therefore, these enzyme-catalyzed reactions lead to
bioinactivation of vincristine.
PMID- 9392883
TI - Zanhasaponins A and B, antiphospholipase A2 saponins from an antiinflammatory
extract of Zanha africana root bark.
AB - A MeOH extract from Z. africana was examined for topical antiinflammatory
activity and proved to be active against arachidonic acid (AA) acute edema, 12-O
tetradecanoylphorbol 13-acetate (TPA)-induced chronic inflammation, and oxazolone
delayed-type hypersensitivity in mice. The extract also showed significant
inhibitory activity of Naja naja phospholipase A2 when a polarographic method was
used. Two oleanane-type triterpene saponins, zanhasaponins A (1) and B (2), and
the cyclitol pinitol (4), isolated from the extract, were active as inhibitors of
PLA2. A further saponin, zanhasaponin C (3) was inactive in this assay.
PMID- 9392884
TI - Saniculoside N from Sanicula europaea L.
AB - Extracts from the aerial parts of Sanicula europaea L. were investigated for
their anti-HIV activity, and the 50% ethanolic extract was shown to exhibit the
highest activity. A new triterpene saponin glycoside, 21 beta-(angeloyloxy)-3-O
[beta-D-arabinopyranosyl(1-->4)-beta- D-glucopyranosyl (1-->3)-beta-D
glucuronopyranosyl propyl ester]-3 beta,15,16,22 alpha,28 beta-pentahydroxy
delta(12)-oleanene, saniculoside N (1), in addition to the known phenolic acids,
rosmarinic acid (2), and caffeic acid (3) were isolated as major components.
Rosmarinic acid was established as the principal active substance.
PMID- 9392885
TI - A new steroidal glycoside from a Caribbean gorgonian, Eunicea sp.1.
AB - A new saponin possessing a pregnene-derived aglycon (1) has been isolated from
the Caribbean gorgonian octocoral Eunicea sp. The structure of the new compound
was assigned on the basis of chemical and spectral studies.
PMID- 9392886
TI - Multidrug-resistance modulators from Stephania japonica.
AB - An alkaloidal extract of the vines of Stephania japonica showed multidrug
resistance-reversing activity as demonstrated by the bicinchoninic acid assay.
Two known bisbenzylisoquinoline alkaloids, isotrilobine (1) and trilobine (2),
were isolated by bioassay-directed fractionation and separation. Isotrilobine (1)
was shown to be as active as verapamil (3) in reversing doxorubicin resistance in
human breast cancer cells.
PMID- 9392887
TI - Four new cytotoxic germacranolides from Carpesium divaricatum.
AB - In a bioassay-guided search for cytotoxic compounds from higher plants of South
Korea, four new sesquiterpenes of the germacranolide type, named cardivins A (1),
B (2), C (3), and D (4), have been isolated from the aerial parts of Carpesium
divaricatum. Structures of these compounds were elucidated on the basis of
spectroscopic techniques. Compounds 1, 2, 3, and 4 showed cytotoxicity to the
human tumor cells, A-549 (nonsmall cell lung), SK-OV-3 (ovary), SK-MEL-2 (skin),
XF-498 (central nervous system), and HCT-15 (colon).
PMID- 9392888
TI - New phomopsolides from a Penicillium sp.
AB - Investigation of the bioactive compounds from a Penicillium sp. isolated from the
inner bark of the Pacific yew, Taxus brevifolia, led to the isolation of the
known furanone 1, and a series of phomopsolides. The phomopsolide fractions
contained phomopsolides A and B, which have previously been described, and three
new phomopsolides. The structures of the new phomopsolides were deduced by
comparison of their NMR spectra to those of the known compounds.
PMID- 9392890
TI - Values of hypercompetitive and personal development competitive individuals.
AB - The value systems of hypercompetitive and personal development competitive
individuals were examined in a sample of university undergraduates. As expected,
people higher in hypercompetitiveness and in personal development competitiveness
were both more likely to endorse values related to self-contained individualism
such as achievement, hedonism, and a striving for an exciting and challenging
life, but only hypercompetitives endorsed the value of power and control over
others. Moreover, the data indicated that people higher in personal development
competitiveness were more prone to endorse values related to ensembled
individualism. In particular, they strongly endorsed values associated with
social concern, that is, with caring about the well-being of others and with
treating them with respect and as equals, whereas hypercompetitives expressed a
lack of such concern. Discussion centered on the socialization process and how it
can foster the development of different competitive orientations.
PMID- 9392889
TI - Antimycobacterial polyynes of Devil's Club (Oplopanax horridus), a North American
native medicinal plant.
AB - Two new (3 and 5), as well as three known (1, 2, and 4), polyynes were isolated
from Devil's Club (Oplopanax horridus; Araliaceae), a medicinal plant of North
America. The structures were established by 1H and 13C NMR. The absolute
configurations of 2 and 5 were determined by application of Mosher's method. All
the polyynes exhibited significant anti-Candida, antibacterial, and
antimycobacterial activity, with an ability to kill Mycobacterium tuberculosis
and isoniazid-resistant Mycobacterium avium at 10 micrograms/disk in a disk
diffusion assay.
PMID- 9392891
TI - Confirmatory factor analysis of the personality disorder subscales from the
Inventory of Interpersonal Problems.
AB - The purpose of this study was to identify the best fitting hierarchical factor
structure of the subscales for personality disorders developed from the Inventory
of Interpersonal Problems (IIP). In earlier work, 5 subscales associated with a
diagnosis of personality disorder (PD) had been developed. With data collected
from 5 additional samples at 4 sites (N = 1004), relations among the IIP-PD
subscales were investigated using confirmatory factor analysis. Several competing
models were tested, and a second-order model with 1 second-order factor and 5
first-order factors provided the best fit to the data. The results support the
hypothesis of a single latent construct reflecting general personality
dysfunction. Measures of this construct may be useful for screening patients into
yes versus no PD groups.
PMID- 9392893
TI - Stability of a Q-sort model of optimal mental health.
AB - This study explores clinicians' conceptions of optimal mental health as a
function of target age and asks whether contemporary conceptions of optimal
mental health differ from Block's (1961) earlier Q-sort model. Ten experienced
clinicians from Northwestern University described the personality characteristics
of optimally adjusted 25- and 50-year-old targets using the California Q-set.
Item scores from these Q-sorts were aggregated to form 25-year-old, 50-year-old,
and composite templates of optimal mental health. Using the Spearman-Brown
formula, the reliability of the 10-judge composite was .97. The 3 templates were
very highly correlated with each other and with Block's original template. Q-sort
descriptions of optimal mental health are remarkably stable over 2 generations of
clinicians and between young adulthood and mid-life.
PMID- 9392892
TI - Relations of five-factor model antagonism facets with personality disorder
symptomatology.
AB - The Five-Factor Model of Personality (FFM) has been used to conceptualize
personality disorders as maladaptive variants of normal personality traits. This
study assessed the convergence of 6 lower order traits, or facets, of FFM
agreeableness versus antagonism (trust, straightforwardness, altruism,
compliance, modesty, and tender-mindedness) with antisocial, borderline,
narcissistic, paranoid, and passive-aggressive personality traits. Interview
based scores for all of the antagonism facets except compliance demonstrated the
expected relations with these personality disorder traits. Results for self
reported facet scores were less clearly supportive, only yielding convergence for
straightforwardness and altruism with respect to antisocial traits. It is
suggested that future investigations of the FFM, or other normal personality
trait models, and personality disorder symptomatology include analyses at the
lower order trait level.
PMID- 9392894
TI - Comparison of the big-five factor structure across samples of Chinese and
American adults.
AB - We compared the factor structure of Goldberg's (1992) 50-item Bipolar Rating
Scale (50-BRS) in samples of Chinese (n = 198) and American (n = 303) students.
Results confirmed the hypothesized five-factor pattern for the U.S. sample, and a
simultaneous multisample confirmatory factor analysis showed that the same five
factor pattern fit the item covariances in the Chinese sample. High levels of
internal consistency were found within each sample, and a high degree of
congruency of corresponding item factor loadings was obtained across samples.
Overall, results supported the potential utility of the Five-Factor Model and the
50-BRS for assessing personality dimensions in Chinese culture.
PMID- 9392895
TI - Manic indices on the Rorschach.
AB - This study examined signs of mania on the Rorschach, specifically whether manic
inpatients (n = 24) produce different thematic content and thought disorder than
comparison groups of paranoid schizophrenic (n = 27) and schizoaffective (n = 25)
inpatients. Rorschach protocols were scored by a trained rater for the Thought
Disorder Index and the Schizoid-Affective Rating Scale. Results indicated that
all 3 groups had moderate levels of thought disorder, but the manic inpatients
produced significantly more combinatory thinking and affective content responses
than the other 2 groups. The paranoid schizophrenic and schizoaffective patients
did not produce significantly more schizoid content and were not different on any
other types of thought disorder than the manic patients. These findings are
discussed in terms of the contribution of thought disorder and affective thematic
content in making the diagnosis of mania on the Rorschach.
PMID- 9392896
TI - Motivational distortion of the 16PF by welfare recipients.
AB - The effectiveness of the Sixteen Personality Factor (16PF) motivational
distortion correction procedures was investigated with a sample of 212 welfare
recipients who completed the 16PF while participating in a mandatory welfare-to
work program. A multiple regression analysis showed that the motivational
distortion (MD) score was significantly related to most of the preselected
Personality factors. The regression analysis also revealed that primary E
(Dominance) was associated with MD, although the manual does not require MD
adjustments for this factor. Based on comparisons of mean differences at the
various MD correction levels, findings indicated general support for the MD
correction procedures described in the manual; however, the magnitude of the
correction procedures should be used cautiously as this may overcorrect for MD on
some of the 16PF primaries. The relevance of the findings also are discussed in
terms of evidence for Cattell's (1968, 1973, 1986) trait-view theory as it
applies to response distortions.
PMID- 9392897
TI - Self-report differentiation of anxiety and depression in chronic pain.
AB - The psychometric distinctiveness of self-reported anxiety and depression in
patients with chronic pain was investigated. The item-level responses of 220
patients with heterogeneous pain conditions from the Beck Depression Inventory
and State--Trait Anxiety Inventory State--Anxiety scale were submitted to common
factor analysis. Three first-order factors were identified: depression, anxiety
absent, and anxiety-present. One second-order factor of negative affect was also
identified. Correlations of first-order factor scores with other psychometric
measures suggested only minor distinctiveness. The findings indicated that it is
possible to distinguish anxiety and depression psychometrically in patients with
chronic pain but suggested that negative affect may be the primary underlying
construct of the affective experience of these patients.
PMID- 9392899
TI - Second-order motion perception in peripheral vision: limits of early filtering.
AB - Spatial and temporal analysis of contrast-modulated sine-wave gratings reveals
that the second-order motion stimulus contains two sidebands, with equal energy
but moving in opposite directions, flanking a stationary carrier. Any early
linear spatial filtering process in the visual system that attenuates one
sideband more than the other will be detrimental to the balance between the two
sidebands, so that the perceived direction of the carrier might be opposite to
that of the envelope motion. We tested this hypothesis by using contrast
modulated gratings presented centrally or at 20 deg in the horizontal nasal field
with a two-alternative forced-choice staircase paradigm. We found that when the
envelope frequency was close to that of the carrier, a second-order stimulus
whose envelope motion direction was correctly identified in the fovea appeared to
drift in the opposite direction in the periphery. Further increasing the envelope
spatial frequency resulted in a reversed motion percept in both central and
peripheral viewing conditions. For subjects to identify correctly the direction
of motion of the envelope, the spatial frequency ratio of the carrier to the
envelope had to be more than 2 in the fovea and more than 6 in the periphery.
These phenomena in second-order motion perception can be explained by a linear
model of motion detection with an early spatial filtering process. Further
experiments and computer simulation show that undersampling of the carrier has
little effect on second-order motion perception in the periphery, as long as the
carrier is detectable.
PMID- 9392898
TI - A hostility scale for the California Psychological Inventory: MMPI, observer Q
sort, and big-five correlates.
AB - Using two samples, we developed and validated a hostility scale that can be
scored from the California Psychological Inventory (CPI) and serves as an
alternate for the Cook-Medley Hostility Scale (Ho; Cook & Medley, 1954). The CPI
Hostility (H) scale consists of 33 items that are either duplicates or close
equivalents of specific Ho items, and the two scales correlate at least .90 in
samples differing in sex. The H and Ho scales show a similar pattern of
correlations with conceptually relevant MMPI scales and with observer-rated
personality attributes tapping Barefoot, Peterson, et al.'s (1991) five hostility
categories of Hostile Affect, Cynicism, Aggressive Responding, Social Avoidance,
and Hostile Attributions. These findings provide evidence for the equivalence of
the two hostility scales, as well as external validation for those personality
characteristics that are purported to underlie the construct of hostility as
tapped by both the original Ho scale and the new CPI H scale.
PMID- 9392900
TI - Geometry of shadows.
AB - Shadows provide a strong source of information about the shapes of surfaces. We
analyze the local geometric structure of shadow contours on piecewise smooth
surfaces. Particular attention is paid to intrinsic shadows on a surface: that
is, shadows created on a surface by the surface's own shape and placement
relative to a light source. Intrinsic shadow contours provide useful information
about the direction of the light source and the qualitative shape of the
underlying surface. We analyze the invariants relating surface shape and light
source direction to the shapes and singularities of intrinsic shadow contours.
The results suggest that intrinsic shadows can be used to directly infer
illuminant tilt, qualitative global surface structure, and, at intersections with
surface creases, the concavity/convexity of a surface. We show that the results
obtained for point sources of light generalize in a straightforward way to
extended light sources, under the assumption that light sources are convex.
PMID- 9392901
TI - Does the photon-diffusion coefficient depend on absorption?
AB - We investigate the controversy over the precise form of the photon diffusion
coefficient and suggest that it is largely independent of absorption, i.e., Do =
v/3mu(s)'. After presentation of the general theoretical arguments underlying
this assertion, Monte Carlo simulations are performed and explicitly reveal that
the absorption independent diffusion coefficient gives better agreement with
theory than the traditionally accepted photon diffusion coefficient, D(mu)a =
v/3(mu(s) + mu(a)). The importance of resolving this controversy for the proper
characterization of the material optical properties is discussed.
PMID- 9392902
TI - Use of four mirrors to rotate linear polarization but preserve input-output
collinearity. II.
AB - We report on the design, construction, and testing of a four-mirror reflective
polarization rotator, proposed by Smith and Koch [J. Opt. Soc. Am. A 13, 2102
(1996)], that rotates by an angle phi the input linear polarization while
preserving the input-output beam collinearity. We correct errors in the previous
work that led to an incorrect design for a phi = pi/2 rotator. This type of pure
rotator is simple and inexpensive, and it is a direct application of the concept
of the nonadiabatic geometric phase to polarization rotation. We also present
measurements of the polarization rotation for the case of three metallic mirrors
with antiparallel input and output beams, a test of geometric phase in
polarization optics not done before.
PMID- 9392903
TI - Decorrelation of L- and M-cone signals.
AB - For a large sample of broadband lights reflected from natural and man-made
objects, the correlation between L- and M-cone absorptions was found to be 0.99.
The correlation between L + M and L - M signals was 0.21. The early recombination
of cone signals in the visual system thus leads to a substantial decorrelation.
PMID- 9392904
TI - Secular rates of twinning in Asia: recent observations and review of literature.
AB - OBJECTIVE: To study the rates of twinning in Asian countries using the most
recent data available. METHOD: A Medline search was performed and all primary and
secondary references obtained. RESULTS: Data was obtained from 5 Asian countries
from reports published between 1983 and 1993. Total twinning rates varied.
CONCLUSION: Twinning among Asians is much more variable than had been reported
previously. Further documentation in this area is indicated.
PMID- 9392905
TI - Ectopic pregnancy in uterosacral ligament.
AB - Two cases of ectopic pregnancy in the uterosacral ligament are presented. The
cases are reported not only because of its rarity but also to arouse the thought
of primary aetiology. With the increasing incidence of ectopic pregnancy due to
assisted reproduction, gynaecologists are posed with the diagnostic challenge.
The golden rule of management in extra-tubal pregnancy is to maintain high index
of suspicion.
PMID- 9392907
TI - Hydatid cyst of Morgagni: any impact on fertility?
AB - On laparoscopy in 3 patients with primary infertility, the only pathology found
was hydatid cysts of Morgagni that were excised. In one patient with monolateral
hydatid cyst, pregnancy failed to be achieved. Despite prior failure of repeated
trials of ovulation induction and intrauterine insemination in the other 2
patients, a spontaneous pregnancy was achieved within 2-3 months following
laparoscopic extirpation of hydatid cysts of Morgagni. The hydatid cysts were
bilateral in one case; and monolateral (in relation to the only present tube with
a unicornuate uterus) in the other case. It is concluded that hydatids of
Morgagni, as a single pelvic pathology, might hinder fertility. Laparoscopic
extirpation of these cysts would improve ovum pick-up and enhance fertility.
PMID- 9392906
TI - A study of tubo-ovarian and ovarian abscesses, with a focus on cases with
endometrioma.
AB - OBJECTIVE: To determine the incidence and causes of endometrioma-associated tubo
ovarian abscesses (TOAs) and ovarian abscesses. METHODS: The medical records of
6,557 gynecologic inpatients were reviewed, and the data were analyzed using the
median test and chi 2 test. RESULTS: The incidence of TOAs was 2.3% (5/218) in
patients with endometrioma, and 0.2% (11/6,339) in patients without endometrioma
(p = 0.0001). Among the TOA cases (n = 16), no significant differences in age,
parity, history of pelvic surgery, or isolated organisms were observed between
the subgroups with (n = 5) and without endometrioma (n = 11). There were only 2
cases of ovarian abscess, and both were associated with endometrioma. The causes
of the abscesses in the 7 cases with endometrioma were contamination during
surgery (1 case), contamination during a transvaginal endometrioma aspiration (1
case), and ascending infection (1 case), and unknown in 4 cases. CONCLUSIONS: The
presence of endometrioma is a risk factor for the development of a TOA or an
ovarian abscess.
PMID- 9392908
TI - Diffuse cystic change of a term placenta with a normal newborn.
AB - We recently encountered a case of term placenta with a diffuse cystic lesion of
the villi. A 19-year-old primipara at 36 weeks of gestation underwent cesarean
section due to breech presentation with premature rupture of the membranes; she
delivered a mature male baby of 2,502 g with an Apgar score of 9/9. The placenta
was 940 g in weight and 29 x 20 x 3 cm in size, and macroscopically had multiple
cystic lesions (3-8 mm in diameter) that resembled hydatidiform moles. However,
histopathological examination revealed that the severe hydropic change was
localized in the stem villi but not remarkable in the terminal chorionic villi.
Moreover, abnormal proliferation of the trophoblast was not observed. However,
the hypertrophic change was observed in the vascular wall of stem villi, in which
hyperplasia of smooth muscle-like cells was present. The urinary hCG levels at 1
month and 2 months after delivery were less than 50 IU/l. These findings indicate
that the multiple cystic lesions of the placenta in this case are essentially
different from those of a trophoblastic disease, and that the diffuse cystic
lesion of the villi might have been secondary to changes in the local
circulation.
PMID- 9392909
TI - Spontaneous resolution of a postcesarean arteriovenous fistula of the uterine
cervix: the usefulness of transvaginal color Doppler scanning.
AB - We encountered in a woman at the 28th day after cesarean delivery the transient
appearance of a uterine cervical mass with a prominent blood flow, that was
revealed to be an acquired arteriovenous fistula. The size and blood flow of the
mass were monitored using transvaginal color Doppler scanning and magnetic
resonance imaging (MRI). Based on these findings, the arteriovenous fistula was
managed conservatively without any adverse complications.
PMID- 9392910
TI - Dengue hemorrhagic fever during pregnancy: antepartum, intrapartum and postpartum
management.
AB - Dengue hemorrhagic fever is a common tropical disease in Thailand that nowadays
has an increasing incidence during adulthood. We managed three cases of dengue
hemorrhagic fever during pregnancy which developed during the antepartum,
intrapartum and postpartum periods. We diagnosed dengue hemorrhagic fever during
pregnancy with clinical pictures of fever, hemoconcentration and thrombocytopenia
with serological proof in all cases. All cases were treated conservatively except
for the second one, in which cesarean delivery was inevitable due to severe
preeclampsia with unfavorable cervix. All patients and their babies were in good
condition before discharge. With increasing incidence during adulthood, more
cases of dengue hemorrhagic fever in pregnancy can be found. Conservative
treatment should be conducted in all cases. We believe that this is the first
case report of intrapartum dengue hemorrhagic fever during pregnancy.
PMID- 9392911
TI - Spontaneous rupture of the liver in an uncomplicated pregnancy.
AB - Spontaneous liver rupture has been reported during pregnancy secondary to severe
pregnancy-induced hypertension, eclampsia or syndrome of hemolysis, elevated
liver enzymes, and low platelet count (HELLP). Here we report a case diagnosed
using CO2 intra-arterial digital subtraction angiography in an uncomplicated
pregnancy. A 33-year-old Chinese woman at 39 weeks' gestation underwent a second
caesarean delivery. Her pregnancy course had been uneventful. In the immediate
postpartum period, she developed clinical signs of hepatic infarction or
hematoma. After a blood transfusion and the use of vasoactive agents, her
hemodynamic condition became stable. A hepatic angiography was performed before
an emergent laparotomy. CO2 intra-arterial digital subtraction angiography
revealed a small extravasation that was not found by the conventional method
using an ionized medium. This disease should be considered when there occur pain
in the upper part of the abdomen and signs of hemorrhagic shock, even in the case
of an uncomplicated pregnancy.
PMID- 9392912
TI - Prenatal diagnosis of Duchenne muscular dystrophy in the Japanese population by
fluorescent CA repeat polymorphisms analysis.
AB - OBJECTIVE: To investigate the efficacy of CA repeat analysis using fluorescence
labeled primers in the prenatal diagnosis of Duchenne muscular dystrophy in the
Japanese population. METHODS: Allelic frequencies of polymorphic loci in the
Duchenne muscular dystrophy gene were ascertained, and the polymorphic
information content (PIC) was calculated. CA repeat analysis of 21 Japanese
families with Duchenne muscular dystrophy was then performed. RESULTS: The STR 49
locus had the highest PIC, followed in decreasing order by the loci of STR 44,
STR 45, STR 50, DYS III, DYS II, DYS I, and 3' CA. The diagnostic applicability
increased to 0.999 when the PICs of all 8 loci were combined. When the highest
PIC from each of the 5' end, exons near the 3' end and the 3' end were combined,
the diagnostic applicability increased to 0.988. Of the 7 males examined
prenatally, 1 was diagnosed as normal, and 6 were affected, while of the 9
females examined, 5 were diagnosed as carriers, and 4 as non-carriers.
CONCLUSION: CA repeat analysis using fluorescence-labeled primers is useful in
the prenatal diagnosis of Duchenne muscular dystrophy in the Japanese population.
PMID- 9392913
TI - The immunotherapy during in vitro fertilization and embryo transfer cycles in
infertile patients with endometriosis.
AB - OBJECTIVE: To investigate if the immunotherapy with corticosteroids would improve
the pregnancy rate in infertile patients with endometriosis who undergo in vitro
fertilization and embryo transfer (IVF-ET). METHODS: Forty-two infertile patients
with endometriosis plus tubal factor and 87 pure tubal infertility patients who
underwent IVF-ET in our unit were allocated randomly to the corticosteroid
treatment group and the control group. RESULTS: The prevalence of autoantibodies
(antinuclear antibody, lupus anticoagulant, anticardiolipin antibody, rheumatoid
factor) was elevated significantly in patients with endometriosis plus tubal
factor compared with pure tubal infertility patients (38.1% vs 2.3%). Twenty-one
patients with endometriosis plus tubal factor underwent 54 cycles of IVF-ET,
receiving corticosteroids. Forty-three patients with pure tubal factor underwent
81 cycles of IVF-ET, receiving corticosteroids. Twenty-one patients with
endometriosis plus tubal factor who underwent 57 cycles of IVF-ET and 44 patients
with pure tubal factor who underwent 84 cycles of IVF-ET served as controls, not
receiving corticosteroids. In patients with endometriosis plus tubal factor,
there was a significantly higher clinical pregnancy rate per cycle in the
treatment group, with 42.6% (23/54) compared with 22.8% (13/57) in the control
group but no differences between 2 groups in spontaneous abortion rate (21.7% vs
15.4%) and multiple pregnancy rate (17.4% vs 15.4%). In patients with pure tubal
infertility, there were no significant differences between the treatment group
and control group in clinical pregnancy rate (40.7% vs 34.5%), spontaneous
abortion rate (12.1% vs 10.3%) or multiple pregnancy rate (18.2% vs 10.3%). In
the endometriosis plus tubal infertility group with autoantibodies, the clinical
pregnancy rate per cycle was significantly higher in the treatment group at 40.9%
compared with 14.8% in the control group. In endometriosis plus tubal infertility
group without autoantibodies, there was no significant difference between 2
groups with respect to the clinical pregnancy rate per cycle (43.8% vs 30.0%).
CONCLUSIONS: This study suggests that immunotherapy with corticosteroids could
improve the clinical pregnancy rate in endometriosis patients undergoing IVF-ET
and may be more effective in patients with positive autoantibodies.
PMID- 9392914
TI - A study of gamma-aminobutyric acid (GABA) in amniotic fluid.
AB - OBJECTIVE: The purpose of the study was to evaluate the role of gamma
aminobutyric acid (GABA), an inhibitory neurotransmitter, in amniotic fluid (AF)
during fetal distress, because it has been reported that several
neurotransmitters, e.g. norepinephrine, are affected by GABA. METHODS: AF was
obtained during elective cesarean section (CS, n = 11) and cesarean section due
to fetal distress without labor pain (FD, n = 7). Maternal and umbilical-cord
blood, as well as the first urine of the neonates, also were collected. GABA,
norepinephrine (NE), and epinephrine (EP) concentrations were measured using
HPLC. RESULTS: The GABA concentration was higher in the AF than in either
maternal or fetal circulation, or in the first urine of neonates. The GABA
concentrations in the AF and in the first urine of neonates were significantly
higher in the FD group than in the CS group (p < 0.05). Furthermore, significant
positive correlations were observed between the NE and GABA concentrations and
between the EP and GABA concentrations in the AF. GABA was produced in a time
dependent manner in cultured amnion cells. CONCLUSION: The highest concentration
of GABA was found in the AF. The GABA in the AF appeared to be derived from both
the amniotic membrane and the fetal urine. The increase in the GABA concentration
in cases of fetal distress might be partially derived from the fetus via fetal
urine. The positive correlations between the concentrations of GABA and those of
NE and EP in the AF, suggest that GABA, NE, and EP might play important roles
during fetal distress.
PMID- 9392915
TI - Effects of fibrin glue on postsurgical adhesions after uterine or ovarian surgery
in rabbits.
AB - OBJECTIVE: To evaluate the prophylaxis with fibrin glue on postoperative
adhesions following uterine or ovarian surgery in rabbits. STUDY DESIGN: The
uterine horns of 10 rabbits were exteriorized and electrocauterized by monopolar
coagulation. Fibrin glue was applied to one uterine horn and the other was left
untreated as a control (Experiment 1). Multiple ovulation was induced in 12
rabbits with hCG, and wedge resection was performed on both ovaries of each
animal. One ovary was treated with fibrin glue and the other was untreated as a
control (Experiment 2). Second-look laparotomy was performed to assess adhesion
formation 2 weeks after the initial operation. RESULTS: The use of fibrin glue
resulted in significant decrease in postoperative adhesions compared with the
control side, in the uterine horns and the ovaries (p < 0.02 and p < 0.01,
respectively). CONCLUSION: Fibrin glue was useful in preventing postoperative
adhesions of the reproductive organs in rabbits.
PMID- 9392916
TI - Integrin adhesion molecules in the endometrial glandular epithelium in patients
with endometriosis or adenomyosis.
AB - OBJECTIVE: To assess the role of beta 1-integrin and E-cadherin molecules in the
eutopic glandular epithelium in patients with endometriosis or adenomyosis. STUDY
DESIGN: Twenty-four patients with endometriosis, and 22 patients with adenomyosis
diagnosed histologically were selected as subjects. The controls consisted of 29
fertile women. Eutopic endometria were obtained by curettage or immediately after
the operation. The samples were immunohistochemically examined for the expression
of very late activation antigen-2 (VLA-2), VLA-3, VLA-4, VLA-5, VLA-6, and E
cadherin. RESULTS: The expression of each VLA molecule and E-cadherin except VLA
4, VLA-5, and VLA-6 was significantly increased throughout the menstrual cycle in
endometria in both the endometriosis and adenomyosis groups. In contrast, the
expression of VLA-4 in the adenomyosis group was significantly reduced in the
secretory phase. CONCLUSION: Altered expression of beta 1-integrins and E
cadherin was observed throughout the menstrual cycle in patients with
endometriosis and adenomyosis, suggesting the defective microenvironment of the
endometrium.
PMID- 9392917
TI - False-positive urine drug screen: beware the poppy seed bagel.
PMID- 9392918
TI - Postural hypotension from topical glyceryl trinitrate ointment for anal pain.
PMID- 9392919
TI - Assessment and knowledge in palliative care in second year family medicine
residents.
AB - Inadequate physician knowledge, particularly in areas of pain assessment and use
of analgesics, has been identified as a major factor contributing to poor pain
management in cancer patients. In most medical schools, teaching in Palliative
Care at both the undergraduate and postgraduate levels is limited or nonexistent.
Baseline knowledge and changes in knowledge in areas relevant to Palliative Care
were assessed by the use of 2 16-question examinations (Exams A and B) in 78
second-year Family Medicine Residents from the University of Alberta Family
Medicine Residency Program. The residents participated in a two-week rotation on
the Acute Palliative Care Unit at the Edmonton General Hospital or Grey Nuns
Community Health Centre between September 1991 and February 1996. The residents
were randomly assigned on their first day (Time 1) to complete either Exam A or B
and were subsequently crossed over on their final day of the rotation to complete
the alternate Exam (Time 2). Six domains were represented in the Exams as
follows: pain assessment, opioid use, adjuvant medications, delirium, urinary
catheterization, and hydration. Improvements were noted in the mean percentage
results in Time 2 compared with Time 1 for Exams A, B, and A and B combined. Mean
global percentage results were 53 +/- 15 versus 73 +/- 13 (p < 0.001) at Times 1
and 2, respectively. There were significant improvements for domains in Time 2
compared to Time 1 (p < or = 0.05) for combined A and B Exam except for urinary
catheterization. Despite these documented improvements in scores, serious
deficiencies were identified particularly in the areas of pain assessment and
opioid use, namely opioid sude effects and issues involving dependence,
addiction, and tolerance. Examinations, such as the two used in this study, can
be a useful aid in assessing physician knowledge in addition to structuring
teaching in Palliative Care. Examination content will require updating as
knowledge in Palliative Care evolves.
PMID- 9392920
TI - A role model program to promote institutional changes for management of acute and
cancer pain.
AB - This report describes an 18-month project to make acute and cancer pain
management an institutional priority in Southeastern Wisconsin health-care
facilities. Facility-based teams, each of which included a nurse in a leadership
position, were recruited to participate in a project based on the Cancer Pain
Role Model Program. The project was conducted in three stages: (a) a 1-day
conference focusing on basic pain management issues and clinical standards, (b) a
preceptorship at the Medical College of Wisconsin, and (c) a follow-up conference
focusing on institutional change. Participants completed an Action Plan,
outlining activities aimed at changing practice in their facility. Participants
from 17 of the 32 participating facilities partially or completely met their
Action Plan goals. Lack of ongoing facility commitment, staff turnover and
facility closures were cited as reasons for failure to meet goals. Nurses in key
positions, provided with strong institutional commitment and given suitable
educational training and nurturing, are ideally suited to help facilitate changes
in institutional pain practices.
PMID- 9392922
TI - Backlash in the treatment of cancer pain: use of opioid analgesics in a Finnish
general hospital in 1987, 1991, and 1994.
AB - Finland belongs to the group of countries in which the consumption of strong
opioids is low. This seems to reflect the general quality of cancer pain
treatment. During the last 10 years, many efforts have been made to improve the
treatment of cancer pain in Finland. To assess one parameter of change, the
present study compared the quantity of opioid and nonopioid analgesics used in
the treatment of terminal cancer pain in a Finnish general hospital in 1987,
1991, and 1994. Specifically, the records of all patients who died of cancer in
Kymenlaakso Central Hospital (KCH) in 1991 and in 1994 and during the last 6
months of 1987 were reviewed to acquire information about the use of analgesic
medication. The total proportion of cancer patients receiving analgesic
medication on a regular basis was 39% in 1987, 63% in 1991, and 52% in 1994. The
mean daily dose of strong opioids changed from 24 mg in 1987 to 58 mg in 1991,
and to 43 mg in 1994. These data suggest a possible backlash in prescribing
practices during recent years. In spite of various efforts to improve the
treatment of cancer pain, the medical records demonstrate a decline in
prescribing of the drugs needed for this treatment.
PMID- 9392921
TI - Graduating medical students' competencies and educational experiences in
palliative care.
AB - Palliative care involves an interdisciplinary approach to patient care and
specific clinical skills. Little prior research on palliative care education has
involved medical students, and the few reported studies focus mainly on student
attitudes. This study describes a needs assessment of senior medical students
based on a newly developed competency-based palliative care curriculum. Prior to
graduation, 102 senior students were mailed an anonymous survey with four parts:
a self-assessment of attitudes, knowledge, and skills; adequacy of instruction;
exposure to specific clinical experiences; and demographic information. The
response rate was 47%. While attitudinal goals were strongly endorsed by
students, they were less confident with regards to knowledge and skills. Ratings
varied across the five content areas of the curriculum. The results suggest a
need for educational efforts more focused on specific clinical competencies as
well as systematic evaluation of student competencies.
PMID- 9392923
TI - Assessment of satisfaction with treatment for chronic pain.
AB - The purpose of this study was to develop an instrument to assess satisfaction
with treatment of chronic pain, evaluate the reliability and validity of this
instrument, and then examine predictors and consequences of satisfaction. The
Pain Service Satisfaction Test (PSST) is the result of this effort. Fifty adult
patients receiving services for chronic pain in a university pain clinic
completed the PSST as part of a survey mailed to their homes. Findings supporting
the validity of the PSST included significant positive correlations with a
general measure of treatment satisfaction, patient ratings of global treatment
satisfaction and effects of treatment, and physician ratings of patient
satisfaction with treatment. Regression analyses of predictors of satisfaction
highlighted significant contributions of confidence and trust in the provider,
pain reduction, and waiting in the clinic. These predictors together accounted
for 60% of satisfaction with treatment. Treatment satisfaction was negatively
correlated with depression, reported number of physicians consulted, and number
of physician visits for pain in the past 12 months; and there was a trend toward
a negative correlation with disability. Results of the present study support the
importance of satisfaction with treatment as a predictor and possible determinant
of later health, function, and service utilization.
PMID- 9392924
TI - Nurses' perceptions of factors influencing the use of a pain program.
AB - Factors that, according to nurse participants, influenced the application of what
was learned in a pain program were explored by means of qualitative interviews.
Participants indicated that the correspondence between the program and their
personal view on pain management, attitudes toward the program and innovations in
general, self-efficacy perceptions, and (un)familiarity and taboos with respect
to program items influenced what they put into practice. In addition,
participants indicated that interactions with colleagues, nursing managers,
patients, and physicians affected their application of the program. Furthermore,
organizational factors, such as limited time and lack of formal program
implementation, were mentioned as influential.
PMID- 9392925
TI - Intractable nausea and vomiting due to gastrointestinal mucosal metastases
relieved by tetrahydrocannabinol (dronabinol).
AB - Four years following resection of a Clark's level IV malignant melanoma, a 50
year-old man developed widespred metastatic disease involving the liver, bones,
brain, gastrointestinal mucosa, and lungs. One week after whole brain radiation
therapy, he was admitted to the hospital for nausea, vomiting, and pain. He was
treated with several antiemetic drugs, but it was not until dronabinol was added
that the nausea and vomiting stopped. Dronabinol was an effective antiemetic used
in combination with prochlorperazine in nausea and vomiting unresponsive to
conventional antiemetics.
PMID- 9392926
TI - STDs surprisingly prevalent--diagnosis should be pursued aggressively.
PMID- 9392927
TI - Sexually transmitted diseases: a review.
PMID- 9392928
TI - The approach to treatment of invasive pneumococcal disease in the 1990s.
AB - Streptococcus pneumoniae is the most common cause of pediatric invasive
infections and an important cause of morbidity and mortality. In the past, S.
pneumoniae responded universally to penicillin until nonsusceptible isolates were
first noted in the 1960s. Before 1990, penicillin-nonsusceptible isolates
remained a minor component of all reported isolates. Since that time, 20-30% of
isolates in many centers in the United States and up to 50% of isolates in some
other countries are penicillin-nonsusceptible. Of greater concern has been the
development of isolates which are nonsusceptible to more than one antimicrobial
agent. This review presents data on pediatric invasive pneumococcal disease in
Arkansas and outlines the new treatment recommendations which have been developed
in response to these problems. Streptococcus pneumoniae is an important pathogen
worldwide and is considered the most common etiology of bacterial sinusitis,
otitis media, pneumonia, meningitis and bacteremia. Before 1990, 95-96% of
pneumococcal isolates were susceptible to penicillin. The first report of
penicillin-nonsusceptible S. pneumoniae was made by Hansman and Bullen in 1967,
who identified the strain in the sputum of a patient with hypogammaglobulinemia.
Soon thereafter, penicillin-nonsusceptible pneumococci were reported in New
Guinea and Australia as well. Over the last several years, the incidence of
penicillin-nonsusceptible isolates has greatly increased. Of particular concern
is the concomitant increase in the number of organisms that are nonsusceptible to
more than one antimicrobial agent. Due to the development of such isolates,
clinicians are having to approach patients with invasive disease due to
pneumococci more cautiously. In an attempt to clarify confusion with terminology,
the Centers for Disease Control and Prevention (CDC) have recommended the same
nomenclature be used to classify resistance for all organisms: nonsusceptible
organisms are those with an MIC (minimal inhibitory concentration) greater than
or equal to that defined for the intermediate category of resistance and the term
resistant should be reserved for those organisms with an MIC greater than or
equal to that defined for the resistant category. Therefore, resistant isolates
are a subgroup of the nonsusceptible isolates.
PMID- 9392929
TI - Hindsight--20/20.
PMID- 9392930
TI - Acute aortic dissection.
PMID- 9392931
TI - Rabies in Arkansas.
PMID- 9392932
TI - Results of the Kentucky high school football knee injury survey.
AB - The study attempted to: 1) determine knee injury and reinjury incidence of
Kentucky high school football players; 2) relate results to initial care
provider, treatment following initial physician exam, time lost from injury,
injury type, player position, and team size; and 3) assess coaches opinions and
practices about lateral prophylactic knee brace (LPKB) usage and effectiveness. A
post season, mail-in coaches' survey (50.2% return, 101/201) collected these
data. Returned surveys represented 4690 players with average team size (x +/- SD)
of 43 +/- 13. Two hundred fifty seven reported knee injuries yielded .055 knee
injuries/player with .04 knee injuries/player being "new" and .015 knee
injuries/player recurring (27% of reported knee injuries) during the season.
Games accounted for 56.4% (56/101) of reported knee injuries. Coaches generally
believed that LPKB usage prevented knee injuries (56.4%, 56/101) and allowed LPKB
usage (92.1%, 93/101), however only 8.3% (8/101) required their wear (interior
linemen 50%, linebackers 25%, entire team (25%). Interior linemen had the
greatest number of knee injuries, followed by offensive backs and linebackers.
Most knee injuries (81%, 208/257) were out 3-6 weeks or less, 64% (164/257)
involved sprains or contusions, 38% (97/257) were treated surgically (alone or
with rehabilitation) and 36% (92/257) were treated solely with rehabilitation.
Total knee injury and reinjury incidence were under-estimated compared to
existing reports. Improved injury recording methods, and post-symposia coaches
evaluation are recommended.
PMID- 9392933
TI - Prolymphocytic leukemia: diagnosis and treatment. A case report.
AB - A patient with B-cell prolymphocytic leukemia (PLL) who has had a prolonged
survival is presented. The patient was diagnosed incidentally while asymptomatic,
but later developed progressive disease. He was refractory to alkylating agents
and fludarabine, but responded to treatment with cyclophosphamide, doxorubicin,
vincristine, and prednisone. This patient's prolonged survival may be due partly
to his diagnosis at an indolent phase, possibly representing the early phase of
the natural course of the disease. Diagnosis, clinical course, and treatment
options for PLL are discussed.
PMID- 9392934
TI - Interprofessional code. Kentucky Medical Association and Kentucky Bar
Association.
PMID- 9392935
TI - The coming plague.
PMID- 9392936
TI - Audits, investigations, and serious trouble.
PMID- 9392938
TI - Direction of medical care--one physician's view.
PMID- 9392937
TI - Committee to investigate changing trends in medicine. Report on fraud and abuse
laws.
PMID- 9392939
TI - Toxic Pfiesteria and human health.
AB - Toxic activity of a Pfiesteria-like organism occurred for much of 1997 in the
waters of the lower Pocomoke River on Maryland's Eastern Shore. Maryland's
experience with these toxic blooms of dinoflagellates, current knowledge of their
potential human health effects, and the actions taken by state government
agencies in response to a potential public health threat are reviewed. A medical
diagnostic team commissioned by the Department of Health and Mental Hygiene
evaluated a group of persons with intense exposures to lesioned fish or the
waters from which they came and/or prominent symptoms following exposure to
affected waters or lesioned fish. The principal findings of the team included
consistent complaints of memory problems, acute burning of the skin following
direct contact with water, and respiratory irritation. Findings on examination
were limited to neurocognitive deficits in short-term memory and learning
difficulties. Physicians and citizens are asked to continue to report, through
their local health departments, illnesses thought to be related to exposure to
lesioned fish or the waters from which they are taken. Persons with questions or
wishing to report finding lesioned fish should call the state Pfiesteria hotline
at 1-888-584-3110.
PMID- 9392940
TI - Diagnosis of Pfiesteria-human illness syndrome.
AB - The first case reports of human illness caused by exposure to Pfiesteria
piscicida toxin(s) acquired outside of a laboratory are reported. Though
Pfiesteria, a toxin-forming dinoflagellate, is responsible for killing billions
of fish in estuaries in North Carolina, its role in human illness has remained
controversial, in part due to lack of identification of the toxin. A recent fish
kill in the rivers of the lower Eastern Shore has permitted careful investigation
and identification of a distinct clinical syndrome resulting from exposure to the
Pfiesteria toxin--Pfiesteria human illness syndrome (PHIS). Patients have memory
losses, cognitive impairments, headaches, skin rashes, abdominal pain, secretory
diarrhea, conjunctival irritation, and bronchospasm. Not all patients have all
elements of the syndrome.
PMID- 9392941
TI - A 74-year-old man with persistent fevers.
AB - An elderly man with a history of extensive world travel presents with a chronic
illness and fevers. The febrile illness has been present for eight years, and no
diagnosis has been made despite extensive evaluation and testing. The
differential diagnosis of this unusual case of fever of unknown origin is
discussed.
PMID- 9392942
TI - Ankle sprains: evaluation, treatment, rehabilitation.
AB - Ankle sprains are a common, costly, and potentially disabling problem. The proper
history and physical examination will determine the need for radiological
evaluation and treatment. Complications of ankle trauma like osteochondral
fractures, peroneal tendon injuries, fracture of the os trigonum, synovial
impingement, tarsal tunnel syndrome, Achilles tendon inflammation or rupture, and
nerve injury are reviewed. The treatment of ankle sprains is based on the
severity of the injury. Treatment begins with rest, ice, compression, and
elevation. Casting and orthotics may be needed to facilitate healing. Primary
rehabilitation, functional rehabilitation, and performance testing and the
assessment of efficacy for each of these modalities are critical parts of proper
treatment for ankle sprains.
PMID- 9392943
TI - Heroic medicine, bloodletting, and the sad fate of George Washington.
AB - Bloodletting was an established medical treatment for more than two millennia,
yet its greatest impact in the United States is undoubtedly the role it played in
the treatment of President George Washington. The theoretical justification for
bloodletting is provided, followed by a detailed description of the treatment
Washington received, reflecting the role played by heroic medicine in the
American president's demise. The arguments of bloodletting's critics emerge as
well founded; indeed, Washington and many others might have suffered less had
heroic medicine not been applied.
PMID- 9392944
TI - Interviews with women medical society leaders.
PMID- 9392945
TI - New recommendations for screening infants and children for tuberculosis.
PMID- 9392946
TI - Reader reflects on caring for the terminally ill.
PMID- 9392947
TI - Domestic abuse: a social ill in need of a cure.
PMID- 9392948
TI - Curing cancer takes more than medicine.
PMID- 9392949
TI - Dr. Walter Kempner and the Rice Diet program: another reason why Durham is the
City of Medicine.
PMID- 9392950
TI - Next generation telemedicine. The future is now.
PMID- 9392951
TI - Oral contraceptive pills. Prevention of ovarian cancer and other benefits.
PMID- 9392952
TI - Postmenopausal hormone replacement therapy. Information for effective patient
counseling.
PMID- 9392953
TI - For patients: hormone replacement therapy.
PMID- 9392954
TI - Investor-owned or not-for-profit health care. A conundrum for communities.
PMID- 9392956
TI - Environmental tobacco smoke: the smoke that's around you.
PMID- 9392955
TI - Some thoughts on keeping our noble profession professional and noble.
PMID- 9392957
TI - Gastroesophageal reflux disease. Pill, blade, or laparoscope?
PMID- 9392958
TI - Psychosocial factors and coronary disease. A national multicenter clinical trial
(ENRICHD) with a North Carolina focus.
AB - In addition to traditional risk factors (cigarette smoking, high blood pressure,
and elevated cholesterol) psychosocial factors (depression, social isolation, and
low socioeconomic status) have an adverse impact on prognosis of patients with
CAD. Several studies of psychosocial and behavioral treatments provide
encouraging evidence for the clinical efficacy of psychosocial interventions in
CAD patients. A new, multicenter clinical trial now underway (see sidebar) will
evaluate the impact of psychosocial interventions (compared to usual care) on all
cause mortality and nonfatal MI in post-MI patients with depression or perceived
low levels of social support or both.
PMID- 9392959
TI - "Children are not supposed to die." Combined pediatric and radiation oncology
grand rounds addresses severe illness and death.
PMID- 9392960
TI - How to open a free medical clinic.
PMID- 9392961
TI - The health and health care utilization of people in Buncombe County.
PMID- 9392962
TI - "Boldly they rode ... into the mouth of hell". Pennyroyal oil toxicity.
PMID- 9392963
TI - Automobile hood ornament as penetrating missile.
PMID- 9392965
TI - Acheson revisited: public health medicine ten years after the Acheson Report.
AB - The issue of communicable disease control and the role of public health medicine
is once more of considerable concern, particularly in the light of recent
outbreaks and NHS reorganisations. Ten years ago, following similar concerns, the
Acheson Report highlighted several issues with striking parallels to the present
day. These included uncertainty over the future and role of public health
medicine following repeated Health Service reorganisations. The Report
recommended the expansion of the specialty in both communicable disease control
and public health medicine in general, and a more clearly defined role for public
health medicine. Successive health authority mergers and the specialty's
inclusion as part of management costs have meant that the Report's findings have
yet to be fully implemented. In fact, the establishment of public health medicine
consultants (CsPHM) has fallen by a quarter since 1992. A further review of the
public health function is required if the specialty is not to fragment, and if
able doctors are not to be deterred from entering the specialty. Such a review
should include the removal of the specialty from management costs, and the
clarification & standardisation of the roles of the Director of Public Health
(DPH), CPHM and other members of the multi-disciplinary public health team, as
well as identifying possible organisational locations for the public health
function.
PMID- 9392964
TI - Health professionals--do we have enough?
PMID- 9392966
TI - Organ transplanting in Japan: the debate begins.
AB - OBJECTIVES: Japan is currently considering changing its long-standing policy of
banning most organ transplants. This paper reviews the current state of organ
transplantation in Japan and presents results from a recently conducted survey
regarding attitudes toward the removal of organs from brain-dead donors, and
potential methods of allocating those organs in a fair manner. METHODS: Survey
data were collected by the Research Project Team on Network Systems for Organ
Transplants funded by the Japanese Ministry of Health and Welfare. The sample
consisted of 1093 randomly selected citizens. Predictors of attitudes supporting
organ transplantation were analyzed using logistic regression. RESULTS: Although
many Japanese people support organ transplantation, few are willing to donate
their organs. General knowledge of transplantation was the best predictor of
support for such a program and willingness to donate organs. In addition, younger
respondents and male respondents were more likely to support programs and donate
organs. Implications of these results are discussed.
PMID- 9392967
TI - A serological survey of measles vaccine in a rural region of Eskisehir in Turkey.
AB - We designed this longitudinal study as a response to measles outbreaks which
occur occasionally in Eskisehir in Turkey to investigate the incidence of primary
and secondary vaccine failure. The investigation was conducted over two periods
(December 1993 to October 1994 and April 1995 to October 1995). Two study groups
were involved, infants aged 9-11 months and children aged 18 months to 9 y.
During December 1993 to October 1994 prevaccination sera was collected from 35
infants aged 9-11 months and tested to determine if maternally derived antibodies
were present. The infants were vaccinated and subsequently the 31 infants who
could be traced were retested 30-40 d later to determine their response to
vaccination. The following was done to determine whether seropositivity rates
alter over time. The second group, a randomised sample of 117 children aged
between 18 months to 9 y was chosen; all of whom had been previously vaccinated
and who had no history of measles. Sera was taken and tested during December 1993
to October 1994 in order to determine whether seropositivity rates varied with
time. During April 1995 to October 1995 out of all the children in both groups
123 children were retested. All sera samples were studied by an enzyme-lined
immunosorbent assay (ELISA). Out of the 35 infants in group 1 only four (11.4%)
had maternal antibody against measles on initial testing. Out of 31 infants
followed up 30-40 d after vaccination (61.3%) were found to be seropositive for
measles. In the second group, of the 117 previously vaccinated children ninety
three (71.5%) had measles IgG antibody. Seropositivity rates did not show
significant difference with time after vaccination. There was no association
between first and second screening seropositivity rates. We conclude that the
presence of maternal antibody reduces the success of vaccination. These results
suggest the vaccination policy in Turkey should be re-examined with a view to
revision.
PMID- 9392969
TI - Maternal serum screening for Down's syndrome: a survey of midwives' views.
AB - The lack of consensus regarding the implementation of maternal serum screening,
has led to a widespread variation in practice. The importance of the role of
midwives within the service has been recognised. All maternity units in the
Northern region now have a designated 'co-ordinator' in an attempt to improve
service delivery, professional liaison and training. This study was designed to
obtain midwives' views about maternal serum screening in principle and to assess
whether any changes had occurred since the introduction of co-ordinators. Semi
structured, postal questionnaires were sent to all midwives in one health
authority for them to complete and return. Within this authority, one maternity
unit offered universal screening whereas the other maintained a selective policy.
Responses were obtained from 90 out of 133 (67.7%). There was almost unanimous
support for the principle of screening 86 out of 90 (95.5%) and most midwives
considered the offer of screening should be an NHS service, independent of age 78
out of 90 (86.7%). Half of the respondents 46 out of 90 (51.2%) reported that the
introduction of a co-ordinator had been successful in improving staff education
but requests for further training and updating were made by 69 out of 90 (76.6%)
despite having had this organized training input: although those midwives who
were regularly involved with screening made significantly fewer requests 27 out
of 45 (60%). These findings confirmed our previous recommendation that ongoing
responsibility for such provision would be required. The results of the study
provided a useful contribution towards the review of screening policy undertaken
by the health authority, as well as evidence upon which to base further
development of the role of the co-ordinators in their support of midwives.
PMID- 9392968
TI - Use of contraception in women who present for termination of pregnancy in inner
London.
AB - OBJECTIVES: To describe the contraceptive usage of women undergoing termination
of pregnancy in order to identify problems with contraception, and therefore
suggest ways in which contraceptive services can be improved. DESIGN: Prospective
study of attenders for NHS termination of pregnancy over a three month period.
SETTING: Community based assessment clinics for NHS termination of pregnancy in
inner London. SUBJECTS: Two hundred and sixty-nine women asking for assessment
for NHS termination of pregnancy. MAIN OUTCOME MEASURES: Source of contraception,
method used around time of conception, and problems experienced. RESULTS:
Respondents tell into three groups: those using contraception around the time
they became pregnant; those who had ceased to use contraception; and those that
had never used contraception. The method of contraception used by the majority of
the first group was the condom and the main source of the method was the chemist
shop. The second group had most commonly used oral contraceptives in the past and
had ceased use in many cases as a result of side effects. The majority of the
third group did not speak English and had limited knowledge of methods of
contraception. CONCLUSIONS: High usage of chemists means women avoid service
providers who could offer help and advice. Women were prepared to put themselves
at risk of unwanted pregnancy rather than return for further help and the lack of
knowledge about emergency birth control was of some concern. The needs of black
and ethnic minority women requires detailed work to improve access and
acceptability of contraceptive services.
PMID- 9392970
TI - How good is the evidence relating to the frequency of childhood sexual abuse and
the impact such abuse has on the lives of adult survivors?
AB - Concerns relating to the methodological rigour of studies examining the frequency
and effects of childhood sexual abuse (CSA) have comforted those who dismiss the
results as scaremongering. This review highlights the difficulties to be overcome
in interpreting the epidemiological data currently available, and the lack of
consensus regarding the true frequency of CSA and the impact such abuse has on
the lives of adult survivors. However, it concludes that the rates of reporting
and disclosing a history of CSA are increasing, and that the health service needs
to recognise and respond to this changing clinical picture.
PMID- 9392971
TI - Somatic morbidity in schizophrenia--a case control study.
AB - Several studies have stated that rates of premature mortality of schizophrenic
patients are increased. Morbidity, however, is less often examined. In the
present study we have compared the number of hospitalizations due to different
somatic diseases in 775 schizophrenic patients with their sex- and age-matched
controls. The total number of patients hospitalized due to somatic diseases was
significantly greater among the schizophrenics than among the controls. In the
former group, 523 out of 775 and in the latter 373 out of 775 had been admitted
at least once during a 15 y period. If the schizophrenic patients who also had
been diagnosed as substance abusers at least once were excluded from the analysis
there was still a significant difference between the remaining patients and their
controls. The patients exhibited an over-morbidity in almost all diagnostic
groups, the most prominent excess morbidity appeared in the groups of injuries
and symptoms, signs and ill-defined conditions, when compared with the controls.
Even if there are confounding factors which should be taken into consideration
when interpreting morbidity data, the pattern of excess morbidity among
schizophrenic patients found in this study is so definite that it cannot be
considered merely coincidental.
PMID- 9392972
TI - Public views on community involvement in local health services in South Africa.
AB - An analysis of the information collected in a nation-wide health survey shows
that the South African public favours the involvement of communities in local
public health services. There are variations in the support for community
involvement in four aspects of health services examined, namely decision on
opening times of clinics, determination of patient-provider relationship,
recruitment of staff and determination of service charges. Multivariate analysis
indicates that the level of support for community involvement is significantly
low for Whites relative to other races, lower for rural residents than for city
dwellers and high for people with a very good health status. Further focused
research is required for improved understanding of the problems and policy
options in community involvement in public health programmes. Since 1994 the new
government has consistently expressed a strong commitment to involve communities
in the design and implementation of health policies and programmes. However,
considerable amount of uncertainty remains on how to translate such commitment
into practical action at the local level.
PMID- 9392973
TI - Approaches to community concerns: applied public health.
AB - Public health workers are challenged to address community health concerns
believed to be related to environmental exposures. The challenge is heightened
when there are multiple potential exposures and numerous health concerns. In a
community in Washington State, we employed different approaches depending on the
specificity of diagnosis and the relation of the disease to environmental
exposures. For diseases with specific diagnoses and questionable associations
with environmental exposures, we began by determining whether rates of disease
were higher than expected. Different approaches were needed for three different
health concerns. Major limitations were estimating community population counts
and obtaining comparison rates from published literature. Despite limitations,
epidemiologic data developed at a relatively low cost were useful in assisting
the community in understanding its health status.
PMID- 9392974
TI - Supply of in-patient medical services for elderly people and geographical
variation in medical admissions in a health district in England.
AB - Geographical variation in the utilisation of in-patient medical services for
elderly people in a health district in England was examined in relation to supply
of in-patient geriatric medical care and indicators of need. An ecological study
design based on electoral wards was used. The health district had a resident
population of 67,919 aged 65 y or more and was divided into three localities,
each with a different supply of in-patient medical services for elderly people.
Locality A had a traditional model of geriatric medical care, Locality B an
integrated model and Locality C an age-related model. Localities A and C also had
a high provision of general practice hospital beds. The main outcome measure was
the age and sex standardised hospital admission ratio for people aged 65 y or
more admitted under geriatric medicine, general medicine or general practice in
April 1991-March 1992. There were 8829 admissions in 1991/2, 48% in general
medicine, 40% in geriatric medicine and 12% in general practice, giving an
overall unadjusted admission rate of 130 per 1000 population aged 65 y or more
for the three specialties combined. Locality A had the highest, and Locality B
the lowest, unadjusted admission rate for the three specialties combined. This
rate remained highest in Locality A if second and subsequent admissions in the
same period were excluded. Lengths of stay in geriatrics were longest in this
locality but lengths of stay for the three specialties combined were similar in
the three localities. Multiple regression was used to examine the effect of three
indicators of need, the Jarman score, standardised mortality ratio and prevalence
of limiting long-term illness, on standardised admission ratios at the electoral
ward level. Jarman score had a significant independent association with the
standardised admission ratio but adjustment for this factor did not alter the
ranking of the three localities, with the standardised admission ratio remaining
highest in Locality A. Subject to the limitations of the study, the results
suggest that factors related to the supply of in-patient medical services may be
associated with geographical variation in medical admissions for elderly people.
PMID- 9392975
TI - Introducing managed care in Switzerland: impact on use of health services.
AB - The objectives of this study were to assess changes in the self-reported use of
health care services after gatekeeping by general practitioners and a global
budget were introduced in the health insurance plan for students at the
University of Geneva, Switzerland, in October 1992. A random sample of 336
members of the University plan answered questions about their use of health care
services during the year before (1992) and the year after (1993) the introduction
of managed care. Similar data were collected among a random sample of 300 members
of a comparison plan. All participants were 18-44 y old in 1992, spoke French and
lived in Geneva. The proportion of insurees who visited specialists decreased by
10% in the University plan between 1992 and 1993 and remained unchanged in the
comparison group. The proportion of insurees who visited general practitioners
increased by 12% in the University plan and remained unchanged in the comparison
group. No effects on the total number of health care visits, on hospitalisations
or on use of medications were detected. The introduction of gatekeeping and of a
global budget managed by physicians was associated with a transfer of patient
visits from specialists to general practitioners.
PMID- 9392976
TI - Cellular phones and traffic accidents.
AB - Cellular phone use in motor vehicles is becoming an increasing world-wide
phenomenon. Using data obtained from traffic accidents reported between 1992 and
1995 in the state of Oklahoma, USA, this study examined statistical rate-ratios
of accident characteristics between drivers with or without cellular phones.
Rates were calculated between cellular phone involvement and reported accident
causes, types of collision, driver actions immediately prior to the accident,
location of the accident, the extent of fatalities, and age and gender of
drivers. Results indicated a significant increased rate among drivers with
cellular phones for inattention, unsafe speed, driving on wrong side of road,
striking a fixed object, overturning their vehicle, swerving prior to the
accident, and running off the roadway. People with phones stood an increased risk
of being killed in an accident over persons without phones. Males with phones had
a significantly higher rate than females for many of accident characteristics
mentioned above. Rate-ratios of some accident characteristics and fatalities
increased as age increased, with the exception of drivers under age 20 yrs, who
had the highest fatality rate. Limitations of the study and possible prevention
alternatives are discussed.
PMID- 9392977
TI - A medical cause of death validation study of adult aboriginal deaths in the
Northern Territory of Australia in 1992.
AB - Judged on the criterion of equity, premature adult Aboriginal mortality is the
most serious public health problem faced in Australia today. There have been a
number of published epidemiological studies that have analysed Aboriginal cause
of death data, but this is the first study to formally validate such data. The
study sample included all adult Aboriginal people who lived and died in the
Northern Territory in 1992, excluding residents of the Alice Springs region. The
appropriateness of underlying cause of death codes was assessed by a single
reviewer in light of death certificates, medical records, postmortem records and
interviews with key health professional informants. Data were collected on 220
deaths. 8% (17 out of 220) of deaths were classified erroneously at the ICD-9
chapter level. Errors in death certification accounted for 64% (11 out of 17) of
the chapter errors and diagnostic and coding errors for 18% (3 out of 17) each.
The overall impact on mortality statistics was less severe because some cross
chapter classification errors cancelled each other out. Misclassification errors
aggregated mainly in chapter VII (circulatory diseases) of the ICD-9
classification which was overcounted by 3.2%, and chapter VIII (respiratory
diseases) which was overcounted by 1.3%. Before correction for misclassification
error, circulatory diseases were judged to cause the highest proportion of
deaths, whereas after correction, respiratory diseases accounted for the highest
proportion. Despite this, the overall quality of the medical cause of death
statistics was of a sufficiently good standard from a public health perspective
to broadly inform health policy. Future attempts to improve the validity of
medical cause of death statistics for Australian Aboriginal people should focus
on the education of medical practitioners about the purpose and process of death
certification.
PMID- 9392978
TI - Expanded programme on immunization (EPI). Progress towards global measles control
and elimination.
PMID- 9392979
TI - AIDS-related disseminated histoplasmosis in San Francisco, California.
AB - The published reports of patients with the acquired immunodeficiency syndrome
(AIDS) with disseminated histoplasmosis come mostly from institutions located in
endemic areas for histoplasmosis, where disease is thought to occur by either
primary infection or reactivation. The characteristics of reactivation disease
are not well delineated. We describe the clinical features of reactivation
disseminated histoplasmosis in 46 residents of San Francisco, California, with
AIDS who did not report recent travel to an area endemic for histoplasmosis.
Patients presented with illness lasting days to months, manifested most
frequently by fever, chills, sweats, cough or dyspnea, gastrointestinal
complaints, malaise, and weight loss. Physical examination and imaging studies
were notable for hepatosplenomegaly, lymphadenopathy, or abnormal pulmonary
findings in more than half of patients. Laboratory studies revealed a high rate
of cytopenia, elevated serum lactate dehydrogenase levels, abnormal liver
function test values, respiratory alkalosis with hypoxemia, and a median CD4
lymphocyte count of 36 x 10(9) per liter. The clinical presentation of
reactivation disseminated histoplasmosis in patients with AIDS living in San
Francisco is similar to that of disseminated histoplasmosis reported in patients
with AIDS living in endemic areas. Reactivation disseminated histoplasmosis
should be considered in any AIDS patient with a low CD4 lymphocyte count, a
febrile illness, and a history of travel or residence in an endemic area.
PMID- 9392980
TI - Intramuscular high-dose triamcinolone acetonide in the treatment of severe
chronic asthma.
AB - We describe our experience with administering intramuscular triamcinolone
acetonide to 22 steroid-dependent patients with asthma. These patients represent
the minority of those with asthma whose disease is characterized by frequent
emergency department visits, hospital admissions, and long-term dependency on
oral corticosteroid therapy. The participants were randomly assigned to 2
treatment groups, one group receiving 120 mg of intramuscular triamcinolone
acetonide, the second receiving 360 mg as a series of three 120-mg daily doses.
We determined relative efficacy by comparing peak expiratory flow rates and
incidents of emergency department visits, hospital admissions, and ventilatory
failure of the study and during the 12 months before enrollment. Peak expiratory
flow rates improved significantly in both groups. The mean (+/- standard
deviation [SD]) monthly percentage of predicted peak expiratory flow on the study
was 88.6 +/- 3.7% and 91.2 +/- 3.9% compared with 63 +/- 15.1% and 64 +/- 14.5%
at entry in patients receiving 120 and 360 mg, respectively (P < 0.02). Patients
receiving 120 mg required 8 hospital stays and 8 emergency department visits
compared with 27 hospital stays and 72 emergency department visits in the
previous year (P < 0.05). Patients receiving 360 mg required 5 hospital stays and
5 emergency department visits compared with 33 hospital stays and 34 emergency
department visits in the previous year (P < 0.05). The average monthly interval
(+/- SD) between exacerbations was 2.7 +/- 2.3 and 7.8 +/- 3.5 for patients
receiving 120 mg and 360 mg, respectively. A total of 25 intubations was required
in the previous year and only 1 during the study. The incidence of cushingoid
facies, weight gain, and hypertension was reduced in both groups (P < 0.05).
Total steroid use was reduced in both groups (P < 0.02). A dose of 360 mg
produced a longer exacerbation-free period than 120 mg (P < 0.02).
PMID- 9392981
TI - Geographic distribution, supply, and need for generalist physicians in Alaska.
AB - This study provides the first comprehensive description of Alaska's geographic
distribution of generalist physicians relative to population. All 443 generalist
care physicians (family, general, general internal medicine, and pediatric) or
their office managers were questioned about their specialties, ZIP codes,
employers, populations served, and hours spent per week offering direct patient
care. The results indicated a 30% overall shortage of generalist physicians for
the state, representing roughly 141 full-time-equivalent generalists relative to
national practice patterns and trends of health maintenance organizations. Of 17
primary health care areas, including the Anchorage area, 15 showed a need for
additional generalist physicians. Most areas had a 20 to 40% shortage. Concerns
about transportation and financial barriers to access to care, especially in
remote regions, were raised. Other needs emphasized included knowledge of
contributions of midlevel health care professionals, Alaska Native versus non
Native care, efforts to train and retain physicians in Alaska, and the need for
longitudinal tracking of practice patterns.
PMID- 9392982
TI - Closer to home (or home alone?) The British Columbia long-term care system in
transition.
AB - Finding ways to organize and deliver long-term care that provides for quality of
life at an affordable price is of increasing importance as the population ages,
family size decreases, and women enter the workforce. For the past 2 decades,
British Columbia has provided a model system that has apparently avoided
disruptive conflicts. Although formal users' complaints are rare, this study-
based on focus groups and interviews with users, their families, and advocates-
identified problems users encountered toward resolving concerns about the
structure, process, and outcome of long-term care. We present these findings in
the context of British Columbia's current devolution from provincial to regional
control that aims to save costs and keep disabled elderly persons in the
community. British Columbia may be continuing to lead the way in meeting the
needs of its burgeoning elderly population for long-term care. Study findings
have implications for the development of US long-term care policy by pointing to
the value of obtaining users' views of long-term care to identify both obvious
and more subtle trouble spots.
PMID- 9392983
TI - Recommendations for immunizations in HIV-infected individuals.
PMID- 9392984
TI - Drug reactions in HIV/AIDS.
PMID- 9392985
TI - Latex allergy--the latest insights.
PMID- 9392986
TI - Antileukotrienes--1997 and beyond.
PMID- 9392987
TI - Combination therapy for HIV disease.
PMID- 9392988
TI - Advances in allergic rhinitis pharmacotherapy.
PMID- 9392989
TI - Treatment of chronic urticaria.
PMID- 9392990
TI - Inhaled corticosteroids for asthma therapy.
PMID- 9392991
TI - Intravenous immune globulin in neuromuscular disorders.
PMID- 9392992
TI - Paralytic shellfish poisoning in Kodiak, Alaska.
PMID- 9392993
TI - Resolution of propylthiouracil-induced hepatic failure after treatment of
thyrotoxicosis.
PMID- 9392994
TI - Trimethoprim-sulfamethoxazole associated with hyperkalemia.
PMID- 9392995
TI - Treatment of chronic severe asthma.
PMID- 9392998
TI - Schistosomiasis: the cleanup continues.
AB - During the past 40 years immense progress has been made in the control of
schistosomiasis in China. The authors consider how the 100 million people in the
country who are still at risk from the disease can be protected.
PMID- 9392997
TI - Ethics, equity and renewal of WHO's health-for-all strategy.
AB - The renewal of WHO's strategy for health for all raises questions about human and
societal values that have to be fully taken into account. Discussions to date
have highlighted the principle of equity in the context of ethics and human
rights.
PMID- 9392999
TI - Cardiovascular disease stoppable in developing countries?
AB - The author discusses factors with a bearing on cardiovascular disease which are
shared by many developing countries, and outlines the difficulties that have to
be overcome if significant prevention is to be achieved.
PMID- 9393000
TI - Assessing risk factors for chronic diseases.
AB - A pilot survey of men aged 35 and over in Buenos Aires indicated that many had
one or more risk factors for chronic diseases. A low response rate hampered the
investigation: on average it proved necessary to visit several homes in order to
obtain one interview. Furthermore, at the cost of US$ 10 incurred per interview,
large prospective investigations would be precluded in most developing countries,
but case-control studies assessing tobacco use and other risk factors
retrospectively would be a good alternative.
PMID- 9393001
TI - Health sector reform: priorities and packages.
AB - Measures of health sector reform have been adopted in Chile, Colombia and Mexico.
The extent to which they promote equitable access to appropriate health services
is considered below.
PMID- 9393002
TI - Health information systems--making them work.
AB - A health services model based on different concentration levels between the
centre and the periphery, each with particular resources, responsibilities and
management functions, provides a framework on which health information systems
can be built or rebuilt so as to accelerate progress towards the health-for-all
goals.
PMID- 9393004
TI - Reducing maternal mortality in St Petersburg.
AB - Following the entry of St Petersburg into Europe's Healthy Cities Project in 1991
it was decided that the highest priority should be given to reducing the city's
maternal mortality ratio, then standing at approximately 70 deaths per 100,000
live births. Preventing deaths from unsafe, illegal abortion became the main
focus of attention. The use of modern contraceptive methods was promoted,
information was disseminated to improve the utilization of family planning
services, special outreach services for teenagers were established, and providers
were given opportunities for education and training. The maternal mortality ratio
and the abortion rate have now declined and contraceptive use appears to be
increasing. These achievements are attributable in large measure to the
commitment of a broad spectrum of St Petersburg society as well as to outside
support.
PMID- 9393005
TI - Training in district health management.
PMID- 9393003
TI - Sociocultural aspects of haemorrhage in pregnancy.
AB - The knowledge, attitudes and practices of rural women in southern Nigeria are at
least as important as the availability of modern obstetric care in the fight
against haemorrhage in pregnancy. Community-based interventions taking this into
account are necessary if the considerable mortality associated with the condition
is to be significantly reduced.
PMID- 9393006
TI - Medical negligence: a return to trust.
PMID- 9393007
TI - What food for the heart?
PMID- 9393008
TI - Medical aid for refugee camps.
PMID- 9393009
TI - Management of Bartholin's abscess.
PMID- 9393010
TI - Female health workers boost primary care.
AB - Women residing in villages in three districts of Pakistan were recruited, trained
to deliver primary care and mobilize their communities for health, assigned to
limited catchment areas, provided with supervisory and managerial support, and
remunerated. Their comprehensive activities substantially reduced infant, child
and maternal mortality within a year and generated positive perceptions of family
planning in the communities. The programme was cost-effective and appeared
suitable as a model for reforming the organization and provision of health care
services.
PMID- 9393012
TI - AIDS prevention with local implementors--overcoming obstacles.
PMID- 9393011
TI - Partnership for primary care.
AB - A project for improving primary health care in an underserved rural area of Osun
State, Nigeria, involved the creation of a partnership between the local
government, the community and a medical college. Joint administrative and
technical committees were established, and community mobilization was fostered.
The evidence so far indicates that partnership designs can accelerate the
development of primary health care in an affordable manner.
PMID- 9393013
TI - Improving the performance of health centres in district health systems. Report of
a WHO Study Group.
AB - Health centres are in the front line of health care provision. Located within
communities and usually easily accessible, health centres are in a key position
not only to contribute to improved health for the individual but also to foster
the development of the community as a whole. This report of a WHO Study Group
looks at how health centres function in different parts of the world, at the
range of services they provide, and how they can be made both more efficient and
more effective. The report covers political and legal issues, management,
resources and personnel, finance, and the provision of high-quality health care
that matches clients' needs. It describes how health centres can design their
activities to suit the health profile and priorities of the communities they
serve. The report acknowledges past drawbacks and future challenges. The health
centre's role is a changing one but, as this report shows, it is a role of
growing importance for the future as individuals and communities take on
increased responsibility for their own health and well-being.
PMID- 9393014
TI - Why complementary medicine is so popular.
PMID- 9393015
TI - Abortion law matures.
PMID- 9393016
TI - Back to nature.
PMID- 9393017
TI - A shot in the arm for public health.
PMID- 9393018
TI - Unfinished business.
PMID- 9393019
TI - The nurses helped the family do the right thing.
PMID- 9393020
TI - The mental health service user movement.
PMID- 9393021
TI - Clinical supervision: a hornet's nest.
PMID- 9393023
TI - Addiction. The vice of fame.
PMID- 9393022
TI - Clinical supervision: a hornet's nest? ... or honey pot?
PMID- 9393025
TI - A time to die.
PMID- 9393026
TI - The electronic campus.
PMID- 9393024
TI - Practical procedures for nurses. 4.2. Respiration technique and observation--2.
PMID- 9393027
TI - Lung cancer specialist and respiratory registrar. Interview by Alison Whyte.
PMID- 9393028
TI - The management of fluid balance.
AB - This is the sixth part in the series Care is Critical, which looks at the more
complex interventions nurses now have to deal with on general wards and in the
community. This article looks at the clinical assessment and management of fluid
balance disturbances.
PMID- 9393029
TI - Alginate dressings in wound care management.
PMID- 9393030
TI - Self-esteem and stress in mental health nurses.
PMID- 9393031
TI - Lean times for skin care.
PMID- 9393032
TI - Dermatology: the forgotten subject?
PMID- 9393033
TI - Know how. Wet wraps in atopic eczema.
AB - Wet wraps play an important part in the management of children with eczema that
does not respond to first-line treatment. They are used in hospitals and in the
community, and provide great relief and comfort, but the procedure requires
considerable input from the health team until the parents are confident of their
technique.
PMID- 9393034
TI - Take three experts. Interview by Adam Legge.
PMID- 9393035
TI - The assessment of patients with malignant fungating wounds--a holistic approach:
Part 1.
PMID- 9393036
TI - Advances in laser technology make this an exciting time in plastic surgical
nursing.
PMID- 9393037
TI - Laser physics and physiology.
AB - Laser light begins when an excited and unstable electron moves from its unstable
state back to a more stable state producing energy in the form of a photon. Laser
light is coherent which means that the light waves move in phase together in
space and time. Laser light is monochromatic which means it is comprised of only
one color or wavelength. Laser light is also collimated which means it is
perfectly parallel and travels in a single direction with very little divergence.
Medical lasers fall in the infrared and visible as well as ultraviolet portion of
the electromagnetic spectrum and are available at different wavelengths. The
wavelength of each laser partially determines the effect it will have on tissue.
A specific wavelength or color can be used to selectively target a specific
tissue such as hemoglobin, water, or melanin. Heat is produced by the laser,
destroying the targeted tissues.
PMID- 9393038
TI - Laser blepharoplasty.
AB - Laser blepharoplasty was introduced in 1984 by Sterling Baker and although there
are few disadvantages, several advantages as compared to traditional
blepharoplasty have been assessed. These advantages include an improved scar, a
shorter operating time, and a more rapid recovery time in most patients. Methods
include laser resurfacing of the periorbital area or full face with excision of
the upper eyelid skin and fat, as well as excision of the lower eyelid fat
through a transconjunctival incision alleviating the need for a lower eyelid
scar. In some cases, an upper eyelid excision may not be necessary following
resurfacing of this area. Excellent results have been achieved in over 150 cases
with comparisons of scarring in scalpel versus laser incisions.
PMID- 9393039
TI - Laser resurfacing of the face.
AB - Pulsed mode carbon dioxide laser allows precise ablation of fine facial tissue
while minimizing thermal damage to the skin. Changes in the structure of dermal
collagen may account for the overall tightening effect observed. Preoperative
preparation of the skin is important to prevent postoperative pigment changes.
Prophylactic antivirals are used to reduce the risk of Herpes infection. The
carbon dioxide laser produces pain when applied to the skin and various
anesthetic techniques may be used. After lasing, the face can be dressed with
occlusive dressings or left open. Sunscreens are required after reepithelization.
PMID- 9393040
TI - Complications of laser resurfacing.
AB - The laser demonstrates significant benefits over traditional resurfacing and
incisional techniques. Serious complications of laser surgery are easily
avoidable provided practitioners and support staff receive proper education and
training. The following article describes the more common complications of laser
resurfacing followed by a brief discussion of avoidance techniques.
PMID- 9393041
TI - Hair removal with the ruby laser (694 nm).
AB - Hair removal with the ruby laser is one of the newest uses of laser technology.
The laser seeks melanin in the hair shaft, and melanin content is highest during
the growth phase of the hair follicle. Nursing care focuses on preparing the
patient for the procedure, maintaining a safe operative environment, and teaching
the patient skin care after the laser therapy.
PMID- 9393042
TI - Confidentiality--An analysis of the issue.
AB - Today, in the high-tech, fast-paced health care arena in which professionals
practice, confidential information and the right to privacy in one's personal
life have become very basic concerns of society. Among the general public, a
genuine interest exists about potential invasions of privacy and the undermining
of confidentiality. Members of society are more educated concerning rights as the
result of multimedia and education presented by health care professionals. New
challenges for the professional attending to the health needs of society will be
encountered as the complexity of health care increases (Pohlman, 1988). One must
remember that the most intensely private and personal moments of an individual's
life are revealed in hospital settings. Health care professionals have a duty at
all times to diligently protect the confidence of each patient unless specific
criteria is met so that disclosure is warranted. Dilemmas encountered often are
complex and require a certain degree of expertise for resolution to occur. If
ethical theory and principles are used in combination with some of the specific
guidelines apropos to resolving confidentiality issues, creative solutions can be
devised. Professionals, by the very nature of their experience and education,
possess the talent to achieve this goal. Consequently, when guidelines for
confidential treatment of information are followed, public trust of professionals
will be ensured. Once trust is established, a significant step will have been
taken toward the solution of problems of confidentiality in modern day health
care.
PMID- 9393043
TI - Research critique of pulsed dye laser treatment of port-wine stains: a patient
questionnaire.
PMID- 9393044
TI - Laser safety guidelines for plastic surgical nurses. AORN.
PMID- 9393045
TI - To lease or not to lease.
PMID- 9393046
TI - Laser surgery: sample patient education materials for plastic surgical nurses.
PMID- 9393047
TI - Use of a semipermeable dressing (Biobrane) following laser resurfacing of the
face.
AB - Biobrane provides a suitable, reliable method of postoperative wound coverage for
the laser resurfaced patient. Pain and drainage are minimized.
PMID- 9393048
TI - Expanding practice and obtaining consent.
AB - The Scope of Professional Practice liberates nurses, midwives and health visitors
from previous role constraints, while keeping the focus on the patient. Some of
the adjustments to the scope of practice require the individual practitioner to
obtain explicit verbal or written consent.
PMID- 9393049
TI - Performing peripheral intravenous cannulation.
AB - Nurses need to be aware of their level of accountability when performing i.v.
cannulation. Nurse cannulation should be incorporated into practice as part of
holistic patient care. When introducing nurse cannulation into a department, a
commitment is required from the individual nurse and the organisation. i.v.
cannulation is a skilled technique, best performed as a staged process.
PMID- 9393050
TI - Pressure-relief mattresses and patient comfort.
AB - The ideal pressure-relieving support system is comfortable, relieves pressure and
prevents tissue damage. In order to ensure patient compliance with the choice of
mattress, patient comfort and quality of sleep should be among the most important
factors involved in the decision-making process.
PMID- 9393051
TI - Parkinson's disease.
PMID- 9393052
TI - Parenteral nutrition.
AB - Patients with a non-functioning gastrointestinal tract, those who require bowel
rest or cannot receive enteral nutrition will be considered for parenteral
feeding. This Update looks at indications, venous access, administration and
complications.
PMID- 9393053
TI - Creating an education model for cardiac patients.
AB - Patient education is important in reducing the risk of recurrence of myocardial
infarction. Education should be specific to patients' individual needs. Patients
need motivating to achieve the required behaviour changes. A multidisciplinary,
multifactorial approach to education is most effective.
PMID- 9393054
TI - Nursing and the law.
PMID- 9393055
TI - Professional negligence.
AB - The rules on which the law of negligence is based derive from judgements and
judicial statements contained in medical and non-medical cases. The principles
documented in these cases apply equally to nurses and it is therefore important
for nurses to be aware of them.
PMID- 9393056
TI - Liability in negligence.
AB - The nurse has two forms of liability, first for the action he or she took and,
second, for the harm that resulted. Nurses can take several simple measures to
protect themselves against liability for negligence.
PMID- 9393057
TI - Sterilising solutions for heat-sensitive instruments.
AB - Disinfectants should be used only to decontaminate heat-sensitive medical
equipment. A COSHH risk assessment is required to ensure the safe use of
disinfectants. Equipment and processing manufacturers should be consulted before
using any of the alternatives to glutaraldehyde.
PMID- 9393058
TI - Peri-operative nursing.
PMID- 9393059
TI - [ICN's representatives meet in Vancouver].
PMID- 9393060
TI - [ICN Congress].
PMID- 9393061
TI - [Goodness in nurse's heart matters. What is goodness in nursing practice?].
AB - Manifestation of goodness in nursing has been researched very little contrary to
good care. This article is based on a Master's thesis the aim of which is to
describe goodness in nursing as it is experienced by a nurse. The research is
qualitative and based on the phenomenological philosophy of science in which the
truth is understood through an individual experience. The research method is
developed by Paterson and Zderad. There were 15 nurses who participated in the
research and the following results were derived from their essays. Life
experience and prevailing values of society influence on the nurse's values which
are reflected in nursing practice. The nurse's sensitivity, maturity,
flexibility, hardiness and ability to grow combined with technical skills
facilitate goodness. Goodness is an open relationship with another people. In
this constantly living relationship closeness, listening by heart and willingness
to bring good to the other people exist simultaneously.
PMID- 9393062
TI - [Depression in humans--experience with being helped].
PMID- 9393063
TI - [Cipramil project--recruitment wrong from the start].
PMID- 9393064
TI - [Falck problem--3,880 ambulances only arrive after 20 minutes].
PMID- 9393065
TI - [Narcotics Council--county's methadone treatment is inadequate].
PMID- 9393066
TI - [Psychiatry--in a hospital bed outside the hospital. Interview by Grethe
Kjaergaard].
PMID- 9393067
TI - [Sexuality discontinued specifically in education].
PMID- 9393068
TI - [ADDH children suffer from distorted hearing].
PMID- 9393069
TI - [Supervisory nurses are indispensable].
PMID- 9393070
TI - [Quality development--passport to project pitfalls. Interview by Susanne Block
Kjeldsen].
PMID- 9393071
TI - [Psychiatry--case manager for Helle].
PMID- 9393072
TI - [Patient information--ageism or care?].
PMID- 9393073
TI - [Emergency medicine--new alarm system can save human lives].
PMID- 9393074
TI - [Psychiatry--greatest advantage with open day facilities. Interview by Grethe
Kjaergaard].
PMID- 9393075
TI - [Psychiatry--here in our house. Interview by Grethe Kjaergaard].
PMID- 9393076
TI - [Misuse of syringes--clean syringes should limit the harm. Interview by Jesper
Berg].
PMID- 9393077
TI - [Fetal monitoring as a service available to everyone].
PMID- 9393078
TI - [Romania--poverty forces children into an institutionalized life].
PMID- 9393079
TI - [Basic nursing care].
PMID- 9393080
TI - [Latex allergy--a current threat].
PMID- 9393081
TI - [Health care: observation of infants].
PMID- 9393083
TI - [Rogaland psychiatric hospital takes violence seriously].
PMID- 9393082
TI - [Relatives: lack of confidence in the system].
PMID- 9393084
TI - [Intensive care--mostly for active 30-year-olds].
PMID- 9393085
TI - [Viewpoint from the housekeeper. Interview by Marit Fonn].
PMID- 9393086
TI - [Part-time work--every third one wants longer working hours].
PMID- 9393087
TI - [Equality--male applicants get preference. Interview by Kari Anne Aase].
PMID- 9393088
TI - [Closeup Anders Vege, leader of the Nominating Committee in Norwegian Nurses'
Association. Start of the hunt. Interview by Marit Fonn].
PMID- 9393089
TI - [My workplace: emergency admissions unit, Haukeland Hospital, Bergen. Where time
is both friend and enemy. Interview by Erik Dale].
PMID- 9393090
TI - [From earlier times. A national conference in equal rights spirit].
PMID- 9393091
TI - [The aged--love is ageless. Interview by Erik Dale].
PMID- 9393092
TI - [Clinical nursing--taking care of eyes. Interview by Kjell Arne Bakke].
PMID- 9393093
TI - [Russia--the goal is independence. Interview by Marit Fonn].
PMID- 9393095
TI - [Professional Ethics Council: ethics, staffing and budget].
PMID- 9393094
TI - [Femidom started in fight against AIDS].
PMID- 9393096
TI - [Elderly immigrants--fear old age in Norway].
PMID- 9393097
TI - [Drug dependence is not always an addiction problem].
PMID- 9393098
TI - [Sexual assault--examination should not be another kind of assault].
PMID- 9393099
TI - [Minister Borst on the cutting nurse].
PMID- 9393100
TI - [The shadow disciplinary tribunal meets].
PMID- 9393101
TI - [The new nursing scientist. Interview by Tonny van de Pasch].
PMID- 9393102
TI - [Flexible child care important for health care sector].
PMID- 9393103
TI - ['Nurses: remain at the bedside'].
PMID- 9393104
TI - [Palliative Center Ghent straightens out the last winding road].
PMID- 9393105
TI - [Terminal dehydration].
PMID- 9393106
TI - [LCVV starts training program for young management talent (leadership for experts
in nursing and health care)].
PMID- 9393107
TI - [From the diary of a district nurse].
PMID- 9393108
TI - [Advanced nursing practice].
PMID- 9393109
TI - [Universities develop Master's education advanced nursing practice. Master or
doctorandus?].
PMID- 9393110
TI - [Sense and nonsense of protective isolation].
PMID- 9393111
TI - [Council BIG ceases to exist (professions in individual health care). Inspired
across the finish line].
PMID- 9393112
TI - [Flexible child care].
PMID- 9393113
TI - [Malnutrition in the hospital].
PMID- 9393114
TI - [The soul of caring].
PMID- 9393115
TI - [Diagnosis in nursing: the patient and his family].
PMID- 9393116
TI - [Ground-breaking nursing].
PMID- 9393117
TI - [AZR (Academic Hospital Rotterdam) determines restricted procedures. Interview by
Corina de Feijter].
PMID- 9393118
TI - [Nursing care and quality assurance. Interview by Tonny van de Pasch].
PMID- 9393119
TI - [Moving forward in AIDS care. 9th annual ANAC Conference in Chicago (Association
of Nurses in AIDS Care)].
PMID- 9393120
TI - [Nursing and self-regulation. Interview by Petra Nijdam].
PMID- 9393121
TI - [Norwegian research].
PMID- 9393122
TI - [Clinical supervision--experience of 10 nurses of a 2-year process-oriented
supervision].
AB - Many patients in swedish hospital care today are older, more physically and
mentally ill and in need of much care. Despite this there is a strong urge for
higher cost-effectiveness and shorter hospital stays. Both these trends are often
reported to be important sources of stress and burn-out among nurses. One way of
reducing such effects among nurses could be clinical supervision. The present
study is a result of one two-year long process-oriented supervision programme for
nurses, led by the authors. The method in this study consisted of semi-structured
interviews of 10 nurses joining the programme. The main questions in the
interviews concerned; a) what knowledge they had acquired through the programme;
b) if the programme had contributed to their understanding of others' feelings
and reactions and; c) whether the programme had influenced their cooperation with
others. The main conclusion from the interviews was that the programme had given
them more courage and a more pronounced experience of support from colleagues. It
was also found that the programme had improved their sense of professionalism and
their self-image. These results point to the value of offering nurses
possibilities for supervision, giving opportunities for both personal and
professional development and thus preventing burn-outs.
PMID- 9393123
TI - [We do not create values, but uphold them--a contribution to nursing's value
theory].
AB - This article argues how the nature of nursing is anchored in a realist conception
of moral value. This moral ontology claims that phenomena like suffering, pain
and human distress have a distinct moral character that is independent of
individual human perception and empathic responsiveness. This position of moral
realism is evident in the ethics of KE. Logstrup, Kari Martinsen and Nel
Noddings. However, these influential theories are in need of a philosophical
theory of moral agency which establish a role for moral sensitivity. Moreover,
and trying to bridge the gap between analytical moral philosophy and
fenomenologist analysis in ethics, the article's final part illuminates how the
encounter with the moral realities of immediate human suffering inhabits a
significant normative claim. This normative claim of compassion and mercy
restricts an impartial, justice-based morality and has significant implications
on nurse's perceptions of prioritizing dilemmas.
PMID- 9393124
TI - [How do nurses attend to their educational function and how do patients
experience this? A field study in an orthopedic department].
AB - Patient teaching is an essential component of patient care. Even if patient
education has been given much attention the last year--both in research and
textbooks for health professionals, some patients still complain about too little
information and support when they are in the hospital. The purpose of this study
was to find out how nurses fulfil their teaching responsibility in practice. Why,
what and how do they teach patients? How do they document their teaching? What do
patients think is the most important in relation to patient teaching? The study
was performed as a field study in an orthopaedic ward. Participation, open
observation and semistructured interviews were used as methods. Notes from
observation, interviews and written nurse documentation are the data in the
study. The results showed that the nurses were teaching the patients while they
were doing some practical things at the same time. Nurses did not plan the
teaching, and in hectic periods less information was given. Most of the teaching
was information about facts. Patients were told little about what they actually
would feel or sense (sensory information)--even if this is what several patients
said they wanted to know about. The patients wanted to meet fewer people and they
often felt that the nurses signalized business so they hesitated to ask them
questions. A standard teaching program was not used. Most of the teaching was
given orally, but written materials and a video were also used sometimes. The
nurses did not document their teaching.
PMID- 9393125
TI - Urinary incontinence among a 65-year old Swedish population: medical history and
psychosocial consequences.
AB - Urinary incontinence (UI) is a disability caused by an impairment, which can lead
to a handicap of importance for nursing care. This means that UI is not only a
practical-medical concern but also a socio-economic problem. The purpose of the
study was to determine the prevalence of UI among 65 year-olds in a Swedish
Health Care District and to compare gender differences concerning medical history
and psychosocial consequences. In a Primary Health Care District, a questionnaire
pertaining to UI was mailed to all women and men 65 years of age (N = 458). A
total of 91% (n = 419) was sufficient for data analysis, which was performed by
descriptive and inferential statistics. It was found that 28% (n = 61) of the
women and 9% (n = 21) of the men were afflicted with UI. Women reported
significantly more urge incontinence (p < .05) as well as stress incontinence (p
< .05). Information from the health service about UI had been given to 46% (n =
28) of the women and 33% (n = 7) of the men. The strongest reason reported, both
in women (42%, n = 26) and men (40%, n = 8), for not seeking help from the health
service was that UI was a normal condition for people of their age. Most of the
women had to urinate at least twice per night (42%) compared to once per night
(44%) for the men. It is important to establish a UI clinic at every main Primary
Health Care Centre which builds on nursing care and whose aim is to inform the
general public that UI is a common problem, that it leads to psychosocial
consequences, and that the health service can offer active rehabilitation
interventions.
PMID- 9393126
TI - [Letting family participate in care. A study on relatives' experience with a
palliative geriatric care department].
AB - An evaluation was made of relatives' experiences of the care of the patient and
the treatment of themselves at a geriatric ward where elderly patients dying of
cancer were nursed. A questionnaire was sent to 100 relatives after they had
agreed on telephone to participate. 86 relatives answered the questions. The
results shows that the majority of the relatives were satisfied with the care of
the patient and the treatment of themselves as relatives. Most of them thought
that they had been able to influence the care of their next-to-kin. However,
elderly ladies and younger men were uncertain whether they had had the
possibility to influence the care. Most of the relatives had been given the
opportunity to talk enough to the doctor, the nurses and the social-worker.
However; they required a more active approach from the staff in the ward. They
also desired more information about the patient's disease, prognosis and medical
treatment. The findings of this study suggest that relatives need information
repeated at several occasions in order to understand the message. They also need
support and invitation to get the courage to ask questions and to participate in
the care of their dying next-of-kin. We need deepen our knowledge of what kind of
information the relatives demands and what information needs to be repeated.
Evaluations of routines to make contact easier between patients, their relatives
and hospital staff should be done continuously.
PMID- 9393127
TI - [Tell me what you are like--a study of mentorship conferences in health and
social work graduate studies].
AB - The purpose of this study was to investigate educational systems with regard to
mentoring practice in two Schools of Health and a School of Social Work. Student
mentor interaction, notably mentor receptiveness, was studied through
storytelling and discourse analysis from a practical/theoretical perspective. The
study revealed that clinical mentors competencies are insufficient. As would be
expected, clinical mentors, however, are superior to college teachers in
practical mentoring situations. The study is based on observations of six
different mentoring situations in three different groups/contexts.
PMID- 9393128
TI - [Health status of the elderly over 67 years old in a community, and their need of
nursing care. A survey with descriptive analysis. Health status in the light of
life style].
AB - The purpose of this descriptive study was to explore the problems of community
dwelling persons 67 years and older, in meeting their self-care requisites, and
the factors in living arrangements associated with these problems. Community
nurses in both administration and practice can use the results in planning
curative and preventive interventions for all the elderly or for groups of
elderly according to living arrangements. These groups were those living alone,
living with a spouse or living with other family members. A standardized
questionnaire revised from Dr. Agnes Bjorns interview guide used in Denmark, was
mailed to 893 persons 67 years and older residing in their own homes in an
Eastern Norwegian community. To analyse the data, Dorothea Orems categories of
self-care requisites was used. The method was usefull to find the health status
among the elderly. Many elderly were satisfied with their lifestyle even if they
had health problems. Memory problems was the biggest area of problems, 59%
mentioned this. An average of 30% were dissatisfied with each of 10 specified
bodily functions. The data totally affirmed greater problems among those elderly
living alone or with a family member, than among those elderly living with a
spouse. The literature says little or nothing about basic need problems among
elderly living with a family member.
PMID- 9393129
TI - [A long and rocky road in a Swedish community. Interview by Anders Olsson].
PMID- 9393130
TI - [Many fine words but little action].
PMID- 9393131
TI - [The profession needs us, immigrants. Interview by Maria Ejd].
PMID- 9393132
TI - [Communities learn ever more about health care--thanks to our nurses. Interview
by Kaj Nyman].
PMID- 9393133
TI - ["Take over home care". District nurses write a letter to the community].
PMID- 9393134
TI - [Employers refuse to explain wage differences].
PMID- 9393135
TI - [Can faith move mountains?].
PMID- 9393136
TI - [Tough fight for Swedish registration].
PMID- 9393137
TI - [Fishing for votes and pulling the wool over someone's eyes].
PMID- 9393138
TI - [Tests which can prevent thrombosis. "They are too expensive", say physicians].
PMID- 9393139
TI - [Nurses should stick out their chin themselves. Interview by Birgitta Dalenstam].
PMID- 9393140
TI - [In memory of a child. Interview by Ingela Bjorck].
PMID- 9393141
TI - [Life situation in children with cancer. Questionnaire helps in determining
quality of life].
PMID- 9393142
TI - [Many seek new education in cytology].
PMID- 9393143
TI - ["How do I do that?" Action provides relatives quick contact with health care].
PMID- 9393144
TI - [Chief physician cautioned for lack of management responsibility].
PMID- 9393145
TI - [Take dizziness seriously. Interview by Bodil Sundvall].
PMID- 9393146
TI - ["We do not put up vendettas". Members do not always get legal assistance from
the association].
PMID- 9393147
TI - [New vision will guide association. "We want to describe how it will be in 10
years. Interview by Kaj Nyman].
PMID- 9393148
TI - [Petra will look after association's students' issues. Interview by Jan
Thomasson].
PMID- 9393149
TI - The importance of patient registration and processing.
PMID- 9393150
TI - Radiation dosimetry in diagnostic radiology.
PMID- 9393151
TI - A database program for the management of staff scheduling in a radiology
department.
AB - OBJECTIVE: Our objective is to report how an inexpensive computer database
program (Filemaker Pro, version 3.0, for Macintosh) can be used to manage work
schedules and optimize staff use in a radiology department. CONCLUSION: Using
this report in conjunction with the manufacturer's documentation, one can adapt
this database program to any scheduling situation.
PMID- 9393152
TI - Contrast-enhanced CT of intrahepatic and hilar cholangiocarcinoma: delay time for
optimal imaging.
AB - OBJECTIVE: The purpose of this study was to determine the optimal time for
obtaining delayed images with contrast-enhanced CT in patients who have
intrahepatic or hilar cholangiocarcinoma. SUBJECTS AND METHODS: CT studies were
performed in 25 consecutive patients with proven cholangiocarcinoma, including
six patients who had undergone radiotherapy or chemotherapy. Dynamic images of
the liver were obtained after 150 ml of IV contrast material was administered at
3 ml/sec. Delayed CT images were then obtained at 10, 20, and 30 min. Tumor-liver
attenuation difference was determined quantitatively for each time period. Images
were qualitatively evaluated by three observers for attenuation of the tumor
(hypoattenuating, isoattenuating, or hyperattenuating) relative to the liver.
Observer confidence for tumor detection was graded on a four-point scale. Dynamic
and delayed images were compared for tumor conspicuity. RESULTS: On dynamic
images, 18 tumors (72%) were hypoattenuating, six (24%) were isoattenuating, and
one was heterogeneous. On delayed images, 15 (60%) of these 25 tumors were
isoattenuating and nine (36%) were hyperattenuating compared with the liver.
Tumor-liver attenuation difference was greatest on dynamic studies (p < .01) and
did not differ significantly among the three delay times (p > .20). All tumors
seen on delayed images were also seen on dynamic images; however, in three
patients (12%), the confidence level for presence of tumor was better on delayed
than on dynamic images. Confidence levels for presence of tumor did not vary
significantly among the three delay times. Attenuation values on dynamic and
delayed images did not differ for the groups of patients who had or had not
undergone prior radiotherapy or chemotherapy (p > .05). CONCLUSION: In the
evaluation of hilar or intrahepatic cholangiocarcinoma, delayed CT images are
helpful for tumor characterization and may improve observer confidence for the
presence of tumor. The optimal time for acquisition of delayed images is 10-20
min after contrast media injection.
PMID- 9393153
TI - HASTE MR cholangiography in the evaluation of hilar cholangiocarcinoma.
AB - OBJECTIVE: The objective of this study was to determine the usefulness of MR
cholangiography using the half-Fourier acquisition single-shot turbo spin-echo
sequence in the examination of patients with hilar cholangiocarcinoma.
CONCLUSION: Half-Fourier acquisition single-shot turbo spin-echo MR
cholangiography is a useful, noninvasive adjunct to other imaging techniques,
particularly MR imaging, in the evaluation of hilar cholangiocarcinoma. MR
cholangiography allows rapid visualization of the biliary tract without
instrumentation and, therefore, without the risk of inducing sepsis in a patient
with ductal obstruction. In the six patients presented. MR cholangiography
allowed for determination of the proximal extent of disease and assessment of
resectability and delineated the duct both proximal and distal to the stricture
and isolated ductal obstructions. MR cholangiography provides three-dimensional
images of the biliary tract that facilitate planning of surgery, palliative
drainage, and radiation therapy.
PMID- 9393154
TI - Detection of hepatocellular carcinoma in patients with cirrhosis: MR imaging
versus angiographically assisted helical CT.
AB - OBJECTIVE: The purpose of our study was to compare the combination of
conventional spin-echo, phase-shift gradient-recalled echo (GRE), and triple
phasic dynamic GRE MR imaging with the combination of helical CT hepatic
arteriography (CTA) and CT performed during arterial portography (CTAP) in the
preoperative detection of hepatocellular carcinoma (HCC). MATERIALS AND METHODS:
Thirty-seven patients with cirrhosis underwent MR imaging and angiographically
assisted CT imaging. Paired T1- and T2-weighted spin-echo images, paired in-phase
and out-of-phase GRE images, triple-phasic dynamic GRE images, the combined MR
images, and the paired CTA and CTAP images were retrospectively and independently
reviewed by three radiologists. Image review was done on a segment-by-segment
basis. Of the 280 liver segments, 58 segments contained 79 HCCs that were 0.5-8.0
cm (mean, 2.0 cm) in diameter. The diagnostic value of each pair of images was
rated by means of receiver operating characteristic curve analysis. RESULTS: The
diagnostic accuracy of combined CTA and CTAP (mean area under the receiver
operating characteristic curve [Az] = 0.94) was significantly better than that of
spin-echo (Az = 0.86, p < .0001), phase-shift GRE (Az = 0.83, p < .0001), dynamic
GRE (Az = 0.85, p < .0001), and all combined (Az = 0.91, p < .001) MR imaging.
The relative sensitivity of combined CTA and CTAP (89%) was also significantly (p
< .0005) better than that of the combined MR imaging (75%). CONCLUSION:
Angiographically assisted helical CT imaging was superior to MR imaging combined
with conventional spin-echo, phase-shift GRE, and triple-phasic dynamic GRE
techniques in the detection of HCC in patients with cirrhosis. The noninvasive
dedicated combined MR imaging could not obviate invasive angiographically
assisted CT imaging. Combined CTA and CTAP is recommended, especially in the
preoperative examination of patients with HCC.
PMID- 9393155
TI - Placement of metallic stents for treatment of postoperative biliary strictures:
long-term outcome in 25 patients.
AB - OBJECTIVE: This study was undertaken to evaluate the results of our 7-year
experience with Gianturco-Rosch metallic stents, used for the management of
postoperative biliary strictures. SUBJECTS AND METHODS: From January 1989 to
April 1995, self-expanding Gianturco-Rosch metallic stents were placed in 25
patients with postoperative bile duct stenosis. All patients had a history of
bile duct injury during cholecystectomy. Twenty-four patients had a conventional
open cholecystectomy and one patient had a laparoscopic cholecystectomy. Eight
patients had stenosis at the level of the common bile duct. The other 17
patients, who had undergone surgical repair of the bile duct, had a stricture at
the level of the hepaticojejunostomy. These anastomotic strictures recurred after
simple cholangioplasty. Patients were monitored for 9-84 months (mean, 55
months). Treatment was considered successful if the initial stenosis did not
recur. Treatment was considered a failure if the initial stenosis recurred within
the stent. RESULTS: Two patients had early complications: one had bile pleural
effusion, treated with percutaneous drainage, and the other had arterial
hemobilia, treated with embolization. Eighteen (72%) of 25 patients had no
recurrence of the initial strictures. Among these patients, 11 had no further
symptoms of biliary obstruction and seven, all with strictured
hepaticojejunostomies, had recurrent episodes of cholangitis caused by secondary
sclerosing cholangitis or intrahepatic stone formation. Seven (28%) of 25
patients had recurrence of the initial stenoses, causing repeated episodes of
cholangitis. Among these seven patients, six had common bile duct stenoses and
one had an anastomotic stricture. Recurrent biliary obstruction was treated
surgically or with percutaneous methods, despite the presence of the metallic
stent. CONCLUSION: Gianturco-Rosch stent placement should be considered in
patients with postoperative bile duct stenoses in whom another operation is not
indicated and cholangioplasty has failed. The results are better in patients who
have hepaticojejunostomy strictures rather than common bile duct strictures.
Overall, a long-term recurrence rate of cholangitis of more than 50% of patients
was seen because of recurrence of the original stenosis or intrahepatic bile duct
obstruction.
PMID- 9393156
TI - Benign biliary strictures associated with recurrent pyogenic cholangitis:
treatment with expandable metallic stents.
AB - OBJECTIVE: The purpose of this study was to determine the long-term effectiveness
of expandable metallic stents in benign biliary strictures associated with
recurrent pyogenic cholangitis and the differences in primary patency of the
various types of stents deployed. SUBJECTS AND METHODS: During a 20-month period,
26 metallic stents (19 Gianturco-Rosch Z stents and seven Strecker stents) were
used to treat benign biliary strictures associated with recurrent pyogenic
cholangitis in 23 patients (11 men and 12 women; mean age, 42 years; range, 30-78
years). Insertion routes were percutaneous transhepatic biliary drainage tracts
for 16 stents, T-tube tracts for seven stents, and retrograde endoscopic routes
for three stents. The deployed locations were common hepatic or common bile ducts
for 11 stents, right or left hepatic ducts for 10 stents, and segmental ducts for
five stents. RESULTS: The initial technical success rate was 100%. Two stents in
one patient migrated spontaneously. Primary stent patency for the remaining 24
stents was 34 months (range, 3-58 months). Primary stent patency of the Gianturco
Rosch Z and Strecker stents was 50 and 10 months, respectively (p < .05). Primary
stent patency for the intrahepatic and extrahepatic ducts was 50 and 18 months,
respectively (p = .05). Primary patency rates for all stents at 6, 12, 24, and 36
months were 92%, 75%, 67%, and 46%, respectively. The causes of stent obstruction
were recurrent stone or sludge in eight stents and epithelial hyperplasia in five
stents. CONCLUSION: We believe that metallic stent placement is not an effective
long-term treatment technique for benign biliary stricture associated with
recurrent pyogenic cholangitis.
PMID- 9393157
TI - Dissecting room.
PMID- 9393158
TI - Displaced metallic biliary stents: technique and rationale for interventional
radiologic retrieval.
AB - OBJECTIVE: We investigated the spontaneous course and the possibility of
transhepatic removal of displaced biliary stents. MATERIALS AND METHODS:
Displaced biliary stents were observed in 11 patients (13-75 years old) between
October 1988 and August 1996. Stent types included the Palmaz stent (n = 3),
Wallstent (n = 3), and the Strecker stent (n = 5). Reasons for stent displacement
included primary misplacement (n = 4), dislocation due to transhepatic endoscopy
with biopsy (n = 2), dislocation resulting from a recanalization maneuver in
stent occlusion (n = 3), and unknown causes (n = 2). In three cases, the stent
was displaced into the proximal bile duct system. Seven patients had primary
malignancy. RESULTS: Eight of 11 displaced biliary stents were removed
transhepatically. Extraction was performed using either a wire loop (n = 4) or
forceps (n = 4). No complications occurred. In the remaining three patients,
whose stents were displaced into the intestine, no invasive action was taken. In
one of these patients, a Palmaz stent was passed spontaneously after 1 week. In
the second of these patients, a 6 cm Wallstent remained innocuously at a position
in the right lower abdomen, and the patient died as a result of malignancy. In
the third patient, who had a 10-cm Wallstent, an abscess developed in the stent
region 4 months after displacement and resulted in formation of an ileocutaneous
fistula. CONCLUSION: Transhepatic extraction of displaced biliary stents is
technically possible, even in the case of rigid stents such as the Palmaz stent.
Because of the risk of intestinal perforation, displaced stents should be
removed.
PMID- 9393159
TI - Outcome of 17 patients with portal venous gas detected by CT.
AB - OBJECTIVE: Portal venous gas has historically been associated with a poor
prognosis. The clinical outcomes of 17 patients with portal venous gas detected
by CT were reviewed. CONCLUSION: Portal venous gas seen on CT was associated with
a 71% survival rate. Patients with a history of vascular surgery or bowel
obstruction may have a higher mortality, and careful clinical evaluation is
mandatory in this patient population.
PMID- 9393160
TI - Solitary hepatic lesions with a hypoechoic rim: value of color Doppler
sonography.
AB - OBJECTIVE: A hypoechoic rim around a focal liver lesion as revealed by
conventional sonography may be present in malignant liver lesions as well as in
benign liver lesions. This study evaluated the potential of color Doppler
sonography in differentiating various focal liver lesions with a hypoechoic rim.
CONCLUSION: Color Doppler sonography may be helpful in distinguishing focal
nodular hyperplasia (FNH) from other focal liver lesions. The characteristic
finding of blood flow within the hypoechoic rim of FNH is most likely caused by
small vessel abnormalities that have previously been described for FNH.
PMID- 9393161
TI - Successful transjugular intrahepatic portosystemic shunt creation in a patient
with polycystic liver disease.
PMID- 9393162
TI - Multiplanar helical CT enterography in patients with Crohn's disease.
AB - OBJECTIVE: The purpose of this study was to assess the feasibility and usefulness
of helical CT with multiplanar reformations in revealing complications in
patients with Crohn's disease. SUBJECTS AND METHODS: Twenty-two patients with
Crohn's disease and clinically suspected complications underwent helical CT
enterography. The imaging protocol began with the administration of a large
volume (1600 ml) of oral contrast material followed by helical scanning with
axial and multiplanar two-dimensional coronal projections. Three independent
observers assessed the adequacy of bowel opacification and the contribution of
two-dimensional coronal projections to the interpretation of axial images. CT
enterography was compared with conventional barium studies in 14 patients.
Statistical analysis included repeated measures analysis of variance, the
Wilcoxon signed-rank test, and the McNemar test. RESULTS: The large oral contrast
medium dose was well tolerated and provided optimal bowel opacification in 21 of
22 patients. The addition of multiplanar to conventional axial images did not
reveal additional abnormalities; however, multiplanar imaging significantly
improved observers' confidence in their interpretation of imaging and in their
assessment of the extent of bowel wall thickening (p < .01). Interobserver
agreement was 78%. Findings on helical CT were comparable with those on barium
studies in nine of 14 patients, superior to those on barium studies in four
patients, and inferior in one patient. CONCLUSION: CT enterography is a useful
technique for bowel imaging. In patients with complicated Crohn's disease,
multiplanar imaging improves confidence in assessing the presence and extent of
disease. CT enterography is complementary and often superior to conventional
barium studies.
PMID- 9393163
TI - Percutaneous radiologic and endoscopic gastrostomy: a 3-year institutional
analysis of procedure performance.
AB - OBJECTIVE: The study was designed to evaluate the safety, efficacy, and
usefulness of the performance of percutaneous radiologic (PRG) and endoscopic
(PEG) gastrostomy. MATERIALS AND METHODS: This study involved a retrospective
review of 182 percutaneous gastrostomy procedures (68 PRG, 114 PEG) performed
over a 3-year period. Parameters analyzed included technical success, procedure
duration, anesthetic requirements, incidental findings on endoscopy, and
complications. RESULTS: The success rate for tube placement was higher for PRG
than for PEG (100% versus 95%). PRG was subsequently performed in four of six
patients in whom PEG procedures failed. Mean procedure duration was shorter for
PRG than for PEG (32.9 min versus 39.1 min, p < .05). PRG was performed without
conscious sedation (i.e., local anesthesia only) more frequently than was PEG
(25% versus 0%, p < .001). The mean volume of doses of midazolam hydrochloride
administered during PRG was two thirds of the volume of doses used during PEG.
Incidental abnormalities were detected in 32 (30%) of the successful PEG
procedures, 11 (10%) of which resulted in biopsy or medical therapy. No biopsy
specimen showed evidence of malignancy. One (0.9%) patient received treatment
other than gastric acid medication. Three (3%) major postprocedural complications
occurred immediately after PEG and none (0%) occurred after PRG. CONCLUSION: The
significant advantages of PRG over PEG included higher success rates, shorter
procedure duration, and less conscious sedation required. PRG was also successful
with patients for whom PEG failed.
PMID- 9393164
TI - The role of parity and hysterectomy on the development of pelvic floor
abnormalities revealed by defecography.
AB - OBJECTIVE: The purpose of our study was to assess the role of multiparity and
pelvic surgery, especially hysterectomy, on pelvic floor dysfunction as diagnosed
on defecography. MATERIALS AND METHODS: Three hundred fifty-four women who
underwent defecography between 1986 and 1996 were asked to provide information
regarding obstetric history and pelvic surgery. Responses were obtained from 272
women (response rate, 77%). Their presenting symptoms ranged from incontinence to
constipation and obstructed defecation. Historical data were correlated with
incidence of defecographic abnormalities that included rectocele, enterocele,
rectal prolapse, incontinence, excessive pelvic floor descent, and dyskinetic
puborectal muscle. RESULTS: Women with three or more birth deliveries were more
likely to have incontinence (48% versus 36%, p = .05) and excessive pelvic floor
descent (26% versus 17%, p = .07) than women who had delivered fewer children.
Women undergoing hysterectomy before defecography were more likely to have
enterocele (40% versus 25%, p = .009) and excessive pelvic floor descent (25%
versus 15%, p = .04) than women who had never undergone hysterectomy. CONCLUSION:
Our findings confirm the common belief that trauma from childbirth or
hysterectomy contributes to the development of defecation disorders.
PMID- 9393166
TI - Double-contrast examination of the colon without decubitus films.
PMID- 9393165
TI - Sonography of intraabdominal gas collections.
PMID- 9393167
TI - Characteristic angiographic appearance of inverted Meckel's diverticulum.
PMID- 9393169
TI - The use of unenhanced helical CT to evaluate suspected renal colic.
PMID- 9393168
TI - Dual-phase helical CT of the kidney: value of the corticomedullary and
nephrographic phase for evaluation of renal lesions and preoperative staging of
renal cell carcinoma.
AB - OBJECTIVE: Our objective was to evaluate early-phase unenhanced and late-phase
contrast-enhanced helical CT in revealing renal lesions and staging renal cell
carcinomas. SUBJECTS AND METHODS: Contrast-enhanced helical CT of the kidneys was
performed in 145 patients who also underwent unenhanced CT. Contrast-enhanced CT
was performed in the corticomedullary phase (CMP) and nephrographic phase (NP). A
total of 173 lesions in 96 patients were proven histologically or cytologically.
The performance of helical CT in the three study groups was compared: unenhanced
and CMP enhancement, group 1; unenhanced and NP enhancement, group 2; unenhanced,
CMP enhancement, and NP enhancement, group 3. Among the parameters evaluated were
the sensitivity for helical CT of all 173 renal lesions and the sensitivity and
specificity for the 90 malignant tumors. Also, the preoperative CT staging of the
76 renal cell carcinomas was correlated with the pathologic specimens. RESULTS:
The sensitivity for detection of all renal lesions in group 1 (84%) was
significantly less than in groups 2 and 3 (97% and 100%). The specificity and
accuracy of helical CT in revealing renal cell carcinomas were significantly
higher (p < .05) in group 3 (95% and 95%, respectively) than in groups 1 (93% and
92%, respectively) and 2 (89% and 91%, respectively). Two renal cell carcinomas
were overlooked by the interpreters of the helical scans in group 1. The accuracy
of preoperative CT staging of renal cell carcinomas was significantly better (p <
.05) in group 3 (91%) than in groups 1 (82%) and 2 (86%). CONCLUSION: When
patients underwent unenhanced helical CT, CMP helical CT, and NP helical CT, we
achieved a better rate of detection and characterization of renal lesions and
better preoperative staging of renal cell carcinomas than when we used either CMP
helical CT or NP helical CT alone.
PMID- 9393170
TI - Unilateral tubular obstruction: an unusual complication of urographic contrast
media.
AB - OBJECTIVE: Our purpose was to report our experience with four patients with renal
colic who had a rare unilateral complication from urographic contrast media, with
a dense and striated nephrogram affecting only the healthy kidney. All cases were
reversible. CONCLUSION: An unusual complication of urography with a
characteristic radiologic appearance is presented. This complication was
transient and reversible in our patients. Unilateral tubular blockage induced by
a contrast agent must be considered when the contralateral kidney shows evidence
of ureteral obstruction.
PMID- 9393171
TI - Radiologic insertion of subcutaneous nephrovesical stent for inoperable ureteral
obstruction.
PMID- 9393172
TI - Comparison of real-time virtual and fiberoptic bronchoscopy in patients with
bronchial carcinoma: opportunities and limitations.
AB - OBJECTIVE: Both helical CT and fiberoptic bronchoscopy are used in the staging of
pulmonary tumors for therapeutic decision making. The improved resolution offered
by helical CT has led to the clinical use of three-dimensional reconstruction
techniques such as virtual bronchoscopy. We tested this new simulated endoscopic
view of inner organ surfaces and compared it with corresponding fiberoptic
examinations of the tracheobronchial system. SUBJECTS AND METHODS: Twenty
patients with malignancies of the lung and mediastinum were examined with both
virtual bronchoscopy and fiberoptic bronchoscopy. Both examinations were reviewed
by radiologists and surgeons familiar with fiberoptic bronchoscopy. Virtual
bronchoscopy was calculated and reconstructed from the cross-sectional images on
a separate workstation. Stenoses and tumor infiltration were classified from the
fiberoptic examination. These results were compared with the virtual bronchoscopy
findings. RESULTS: Virtual bronchoscopy of diagnostic quality was achieved in 19
of 20 patients. High-grade stenoses were revealed equally well with virtual and
fiberoptic techniques. Virtual bronchoscopy offered the advantage of being able
to visualize areas beyond even high-grade stenoses. However, on virtual
bronchoscopy discrete infiltration or extraluminal impression was not visible in
five patients. In another patient, strong heart pulsation produced motion
artifacts that prevented evaluation of the reconstruction. CONCLUSION: Virtual
bronchoscopy represents a new noninvasive method for evaluating helical CT
findings. In comparison with fiberoptic bronchoscopy, virtual bronchoscopy offers
the advantage of being able to visualize areas beyond even high-grade stenoses.
In addition to the limited view of fiberoptic bronchoscopy, extraluminal causes
of lumen compressions can be analyzed in the cross-sectional images and evaluated
together with the virtual representation. However, it was not possible to detect
small infiltrations with virtual bronchoscopy. This new representation of helical
CT data might be helpful for postoperative follow-up examinations, such as after
stent implantation, and can be carried out without additional risk to the
patient. Radiologists do need special fiberoptic bronchoscopy knowledge and
experience with three-dimensional-reconstructions to differentiate between real
stenoses and artificial stenoses that might be caused by pulsation artifacts.
PMID- 9393173
TI - Altered intravascular contrast material flow dynamics: clues for refining
thoracic CT diagnosis.
AB - The ability of helical thoracic CT to acquire data rapidly has enabled
radiologists to use the dynamics of contrast medium flow more effectively to
diagnose subtle abnormalities. In general, these abnormal flow dynamics manifest
in two ways: diverted hyperdense venous opacification and an altered temporal
relationship of vascular opacification. When observed, these findings serve as
clues for the detection of elusive anatomic and physiologic abnormalities.
PMID- 9393174
TI - Sonographic guidance of mediastinal biopsy: an effective alternative to CT
guidance.
AB - OBJECTIVE: Our objective was to determine the diagnostic and cost efficacy of
sonographically guided mediastinal biopsy as an alternative to CT-guided
mediastinal biopsy and to review our biopsy triage experience in switching from
CT to sonography. CONCLUSION: Sonography is as safe and accurate as CT and is 25%
less costly than CT. Sonography proved particularly valuable for identifying
vessels and perfused tissue and for permitting upright biopsy positions in
dyspneic patients. When using our triage criteria, radiologists should find
sonographically guided mediastinal biopsy to be an attractive alternative to CT
guided mediastinal biopsy in most patients.
PMID- 9393175
TI - Detection of pulmonary nodules with helical CT: comparison of cine and film-based
viewing.
AB - OBJECTIVE: The purpose of our study was to determine whether cine viewing of
helical CT scans of the chest improves the detection of pulmonary nodules in
patients with known extrathoracic malignancy. SUBJECTS AND METHODS: Identical
helical CT studies of the chest of 60 patients with known extrathoracic
malignancy were reviewed for detection of pulmonary nodules. Four radiologists
interpreted the helical CT studies. Pulmonary nodules were divided into four
groups according to maximum diameter: group 1, nodules smaller than or equal to 5
mm; group 2, nodules larger than 5 mm but smaller than or equal to 10 mm; group
3, nodules larger than 10 mm but smaller than or equal to 20 mm; group 4, nodules
larger than 20 mm. Interpreters also assigned a lesion conspicuity score of
pulmonary nodules based on a four-point scale: one point for poor visibility, two
points for adequate visibility, three points for good visibility, and four points
for excellent visibility. Static film-based images printed on a laser printer
were viewed on a light box. Cine viewing of helical CT scans from the same
examinations was done on a commercially available workstation. The number,
diameter, and conspicuity scores of pulmonary nodules detected at lung window
settings were documented. RESULTS: Interpreters saw 266 nodules on cine viewing,
whereas 237 nodules were seen with static film-based viewing. A significantly
higher percentage of nodules that were smaller than or equal to 5 mm in diameter
was found with cine viewing (n = 106) than with static film-based viewing (n =
81) (p < .05). Cine viewing (n = 105) also allowed a slightly but not
significantly higher detection rate of nodules that were larger than 5 mm but
smaller than or equal to 10 mm in diameter than did static film-based viewing (n
= 101). We found no differences between cine (n = 55) and static film-based
viewing (n = 55) in the detection of pulmonary nodules that were larger than 10
mm in diameter. The mean conspicuity score of nodules was significantly higher
with cine viewing (2.9 +/- 0.2) than with film-based viewing (2.4 +/- 0.2) (p <
.05). CONCLUSION: Cine viewing of helical CT scans significantly increases the
detection rate of pulmonary nodules that are smaller than or equal to 5 mm in
diameter. However, we found no significant difference between cine and film-based
viewing in the detection rate of pulmonary nodules that were larger than 5 mm in
diameter. The advantages of cine viewing may be attributed to both the larger
image size and the ability to scroll through images for improved differentiation
between vessels and nodules.
PMID- 9393176
TI - Interventional drainage of appendiceal abscesses in children.
AB - OBJECTIVE: This study was undertaken to validate the outcome of interventional
drainage and IV antibiotics for the treatment of appendiceal abscesses in
children. MATERIALS AND METHODS: Between March 1991 and March 1995, 46 children
with one or more intraabdominal appendiceal abscesses were seen at a tertiary
care referral center. The children received IV antibiotics and underwent
interventional drainage of their collections. All procedures were performed in
the radiology intervention suite using IV sedation and, in one patient, a general
anesthetic. All patients were followed up for at least 1 year. RESULTS: The 46
patients underwent 64 procedures. These included the insertion of 34 percutaneous
drainage catheters, the insertion of 25 transrectal drainage catheters, and five
needle aspirations. Four patients did not respond to their initial treatment and
required surgery. One patient developed a colonic fistula that resolved
spontaneously. CONCLUSION: Successful treatment of 42 patients (91%) justifies
image-guided drainage and IV antibiotics as appropriate management for
appendiceal abscesses in children.
PMID- 9393177
TI - Fat necrosis after trauma: a benign cause of palpable lumps in children.
AB - OBJECTIVE: Our objective is to describe the clinical entity and MR imaging
appearance of fat necrosis after trauma, a benign cause of palpable soft-tissue
lesions in children. A related objective is to establish MR imaging criteria that
can be used reliably to differentiate this entity from other more serious causes
of soft-tissue masses. CONCLUSION: Fat necrosis after trauma is a common cause of
palpable lumps in children and has a benign course on long-term follow-up. When
characteristic MR imaging findings are seen, conservative therapy is appropriate.
PMID- 9393179
TI - Endodermal sinus tumor of the vagina.
PMID- 9393178
TI - Spectrum of imaging findings in pediatric hydatid disease.
PMID- 9393181
TI - Sonography of the breast: controversies and opinions.
PMID- 9393180
TI - Comparison of duodenal intubation techniques during conversion of gastrostomy to
gastrojejunostomy tubes in children.
PMID- 9393182
TI - Metallic particles on mammography after wire localization.
PMID- 9393183
TI - Granulocytic sarcoma (chloroma) of the breast: sonographic findings.
PMID- 9393184
TI - Posterolateral stabilizers of the knee: anatomy and injuries assessed with MR
imaging.
PMID- 9393185
TI - Carpal tunnel syndrome: are the MR findings a result of population selection
bias?
AB - OBJECTIVE: Previous descriptions of MR imaging of carpal tunnel syndrome used
limited study populations and volunteers as controls. We reevaluated these
descriptions to determine their sensitivity and specificity when applied to a
large consecutive clinical series in which the incidence of carpal tunnel
syndrome was small. SUBJECTS AND METHODS: In 196 consecutive wrists for which
supplemental axial conventional spin-echo T1-weighted and fast spin-echo T2
weighted images were obtained at 1.5 T with a dedicated wrist coil, 165 studies
were available for review. Previously described signs of carpal tunnel syndrome
such as proximally increased size, flattening of the median nerve, increased
median nerve signal intensity, flexor tenosynovitis, retinacular bowing,
decreased deep tendon fat, and deep palmar bursitis were retrospectively and
independently evaluated by two observers who were unaware of patient diagnosis.
RESULTS: None of the previously described signs was sensitive for the diagnosis
of carpal tunnel syndrome. However, specificity was high for retinacular bowing
(94%), median nerve flattening (97%), and deep palmar bursitis (95%). CONCLUSION:
Most previously described MR imaging signs of carpal tunnel syndrome are
insensitive and nonspecific. Exceptions include retinacular bowing, median nerve
flattening, and deep palmar bursitis, which in our study proved to have
specificities greater than or equal to 94%.
PMID- 9393186
TI - A comparison of whole-body turboSTIR MR imaging and planar 99mTc-methylene
diphosphonate scintigraphy in the examination of patients with suspected skeletal
metastases.
AB - OBJECTIVE: This study was undertaken to compare whole-body turbo short inversion
time inversion recovery MR imaging and 99mTc-methylene diphosphonate planar
scintigraphy in the examination of patients with suspected skeletal metastases.
SUBJECTS AND METHODS: Twenty-five patients with known or suspected skeletal
metastatic disease underwent both whole-body turbo short inversion time inversion
recovery MR imaging and whole-body 99mTc-methylene diphosphonate scintigraphy.
RESULTS: MR imaging revealed metastases at 57 of 175 possible sites (sensitivity,
96.5%, specificity, 100%; positive predictive value, 100%). Scintigraphy revealed
metastases at 43 of 175 possible sites (sensitivity, 72%; specificity, 98%;
positive predictive value, 95%) (McNemar test, 0.01; p = .016). Discrepancies in
skeletal evaluation by whole-body MR imaging and scintigraphy were observed in
six (24%) of 25 patients. Soft-tissue abnormalities were identified in 13 (52%)
of 25 patients with MR imaging alone. CONCLUSION: Preliminary results suggest
that whole-body MR imaging is an effective method of examining patients with
suspected skeletal metastases, with better sensitivity than conventional planar
99mTc-methylene diphosphonate scintigraphy.
PMID- 9393187
TI - FDG PET in head and neck cancer.
AB - In our extensive experience with FDG PET imaging in head and neck cancer, we have
found the technique to be of high accuracy but of limited usefulness. This
seeming paradox arises from several causes. Competing techniques such as CT, MR
imaging, and even clinical examination already have good accuracy. In addition,
high-resolution studies such as CT and MR imaging provide information required
for treatment planning that is unavailable from FDG PET images. The high cost of
FDG PET militates against its use in this setting, in which only a small marginal
gain can be expected. In the special problem areas in which FDG PET might be
expected to offer unique advantages, such as screening for second primary
lesions, searching for unknown primary lesions, or differentiating benign
salivary rumors from malignant lesions, the results of FDG PET have been
disappointedly poor. Of these special problem areas, only the question of
accuracy in finding occult primary lesions appears unresolved and in need of
further study. The single application in which FDG PET appears to be advantageous
is the posttherapy setting. In this setting, the technique is definitely superior
to alternative methods of determining tumor recurrence and differentiating
posttherapy sequelae such as radiation necrosis from tumor recurrence. We believe
that considerable opportunity remains for further research on the use of FDG PET
in head and neck cancer. Other agents such as 11C-methionine for example, might
improve the diagnostic accuracy of FDG PET in some of the problem areas that we
have identified, such as the early postirradiation period. We currently have such
a study under way. Also, because FDG PET offers a unique way to measure tumor
metabolism, further investigation of the use of FDG PET tracers to evaluate
various biologic parameters such as proliferation rates or tumor hypoxia are
needed. Such studies could provide a noninvasive technique to identify which
fractionation schemes or combinations of therapy might be useful for individual
patients. A final caveat is in order. Although our findings of the usefulness
(and lack thereof) of FDG PET in head and neck cancer may be disappointing to
many, these results should not be generalized to other applications of FDG PET in
oncology. Each tumor type and setting presents its own specific problems, and in
some instances FDG PET offers unique advantages over other imaging techniques. A
good example is the setting of primary lung cancer, in which FDG PET appears
clearly superior to all other methods of pretherapy screening [19-20].
PMID- 9393188
TI - Comparison of double-phase 99mTc-sestamibi with 123I-99mTc-sestamibi subtraction
SPECT in hyperparathyroidism.
AB - OBJECTIVE: Our purpose was to compare double-phase 99mTc-sestamibi single-photon
emission computed tomography (SPECT) and simultaneous 123I-99mTc-sestamibi
subtraction SPECT for preoperative localization of hyperfunctioning parathyroid
tissue in patients with primary hyperparathyroidism. SUBJECTS AND METHODS:
Fifteen patients with primary hyperparathyroidism underwent preoperative double
phase 99mTc-sestamibi SPECT and simultaneous 123I-99mTc-sestamibi subtraction
SPECT imaging. At surgery, the location, weight, and histopathologic evaluation
of all identified parathyroid glands were recorded. RESULTS: At surgery, 17
parathyroid adenomas and 37 normal parathyroid glands were identified. The
sensitivity, specificity, and diagnostic accuracy for the detection of
parathyroid adenomas were 88%, 97%, and 94%, respectively, for simultaneous 123I
99mTc-sestamibi subtraction SPECT and 53%, 86%, and 76%, respectively, for double
phase 99mTc-sestamibi SPECT. The differences in sensitivity and diagnostic
accuracy were statistically significant (p = .031 and p = .016, respectively).
CONCLUSION: Compared with double-phase 99mTc-sestamibi SPECT, simultaneous 123I
99mTc-sestamibi subtraction SPECT is a superior imaging study for the
preoperative localization of hyperfunctioning parathyroid tissue.
PMID- 9393189
TI - Whole-body positron emission tomography: normal variations, pitfalls, and
technical considerations.
PMID- 9393190
TI - Can radiologists accurately predict preepiglottic space invasion with MR imaging?
AB - OBJECTIVE: The purpose of this study was to evaluate whether observers of MR
imaging can accurately predict invasion of the preepiglottic fat (PEF) in
patients with oropharyngeal and supraglottic laryngeal squamous cell carcinoma.
MATERIALS AND METHODS: For 41 patients with pathologically proven squamous cell
carcinoma of the oropharynx and supraglottic larynx, we retrospectively analyzed
their MR images for the presence or absence of PEF neoplastic invasion.
Unenhanced T1-weighted, fat-suppressed T2-weighted, and contrast-enhanced fat
suppressed T1-weighted scans were analyzed independently by two neuroradiologists
who were unaware of the surgical findings. Proof of diagnosis was determined by
pathologic analysis, intraoperative assessment, or both. RESULTS: Sixteen
patients had neoplastic infiltration of the PEF. All infiltration was correctly
predicted by the two observers of MR imaging, resulting in a sensitivity of 100%.
Twenty-five patients had no invasion of the PEF by pathologic or surgical
evaluation or both. Of these patients, negative findings were correctly predicted
on MR imaging in 21 patients, whereas positive findings were incorrectly
predicted on MR imaging in the remaining four patients, resulting in a
specificity of 84% and an accuracy of 90%. In two of the four false-positive
cases, effacement of the fat in the preepiglottic space by large tumors was
mistaken for invasion. In a third patient, spread to the paraglottic space was
mistaken for PEF extension. In the fourth false-positive case, glandular tissue
along the ventral epiglottis may have been mistaken for tumor. The observers
believed that unenhanced sagittal and axial T1-weighted scans were particularly
useful because fat saturation artifacts may degrade T2-weighted and contrast
enhanced T1-weighted scans. CONCLUSION: Unenhanced T1-weighted MR images are
highly sensitive for neoplastic infiltration of the preepiglottic space in
patients with oropharyngeal and supraglottic laryngeal carcinoma who are at risk
for such spread. Identification of PEF invasion is important because it affects
prognosis and may affect surgical management.
PMID- 9393191
TI - Postoperative radiographic assessment of the Combi 40 cochlear implant.
AB - OBJECTIVE: The aims of this study were to establish a plain radiographic
technique for the assessment of the postoperative appearance, position, and
insertion depth of the Combi 40 cochlear implant and to correlate the radiologic
findings with surgical reports. SUBJECTS AND METHODS: In an experimental study,
an electrode of the Combi 40 device was inserted into the cochlea of a cadaveric
skull. Digital radiographs were obtained in a modified Chausse III projection, in
which the skull was placed supine on the radiography table with the
infraorbitomeatal line strictly perpendicular to the film cassette. The skull was
then rotated 30 degrees away from the side to be examined, and the central X-ray
beam was angled 15 degrees cephalad to the infraorbitomeatal line. On these
radiographs, the point of cochleostomy was marked by a needle tip and was
projected inferior to the vestibule and on a line drawn through the superior
semicircular canal and the vestibule. The appearance and position of the
electrode was evaluated. An electrode was defined as completely inserted if all
electrode contacts projected medial to the line drawn through the superior
semicircular canal and the vestibule. We also studied cochlear implant insertion
of the Combi 40 device in 37 patients. Postoperative digital radiographs of these
patients were obtained and analyzed for the criteria as defined in the cadaveric
study. In addition, the insertion depth of the electrode and the angle of
insertion were measured on the radiographs. This depth was correlated with depth
of insertion as estimated at surgery. RESULTS: The cadaveric study showed that
the completely inserted electrode was seen on radiographs as a nonoverlapping
spiral within the cochlea. All electrode contacts projected medial to the line
drawn through the superior semicircular canal and the vestibule. In all 37
patients, the electrode could be seen without overlapping. According to our
criteria, a completely inserted electrode was seen in 32 patients. In these
patients, the insertion depth ranged from 21 to 34 mm and the angle of insertion
ranged from 350 degrees to 810 degrees. In two patients, we saw a completely
inserted electrode with a bend. In three patients, an incompletely inserted
electrode was seen. Excellent correlation existed between the radiologic and
surgical results with regard to insertion depth (r = .92). CONCLUSION: Digital
radiographs obtained in the modified Chausse III projection allow clear depiction
of the electrode and avoid overlapping. Such radiographs enable a reliable and
accurate assessment of the position and insertion depth of the electrode of this
new cochlear implant. Such images can serve as a baseline for further
radiographic examinations when extrusion or slippage of the electrode is
clinically suspected.
PMID- 9393192
TI - Sonography of peripheral nerve tumors of the neck.
AB - OBJECTIVE: Peripheral nerve tumors (PNTs) of the neck are uncommon and are
frequently mistaken for lymph nodes. The purpose of this study is to describe the
sonographic appearance of PNTs in the neck and determine features useful in
differentiating PNTs from lymph nodes. CONCLUSION: PNTs of the neck have features
that should alert the sonographer to the correct diagnosis. Features of value in
differentiating PNTs from lymph nodes include a solitary, oval, hypoechoic mass
with posterior enhancement and absence of an echogenic hilum. These features
should lead to a careful search for the associated nerve to confirm the
diagnosis. In addition, schwannomas have a vascular pattern indicating marked
hypervascularity that can be obliterated with light pressure from the probe.
PMID- 9393193
TI - Cerebral venography: comparison of CT and MR projection venography.
AB - OBJECTIVE: The purpose of the study was to show equivalence or superiority of CT
venography compared with the existing test of choice--MR venography--in the
evaluation of dural sinus thrombosis and in the identification of cerebral veins
and dural sinuses. MATERIALS AND METHODS: Twenty-four patients underwent both CT
and MR venography of the intracranial venous circulation. Seventeen patients were
examined for suspected dural sinus thrombosis. Four patients underwent projection
venography to assess tumor invasion of a major dural sinus. The remaining three
patients were examined for cavernous sinus thrombosis, arteriovenous
malformation, and an elevated jugular bulb. Without knowledge of the patients'
case histories, two radiologists evaluated each CT venogram and MR venogram. The
radiologists then arrived at a consensus regarding the absence or presence of
dural sinus thrombosis. Later, the radiologists conducted a second interpretation
with knowledge of the patients' clinical histories during which time MR and CT
venograms were compared with regard to the advantages and disadvantages of each
imaging technique. In addition, the venograms were assessed for the presence of
12 different venous structure. Projection venograms were displayed using a
maximum-intensity-projection (MIP) algorithm, and the individual source images
were also evaluated. The CT venograms were also displayed using shell-MIP and
integral display algorithms. RESULTS: Using MR venography, the two radiologists
diagnosed dural sinus thrombosis in eight of the 17 patients with suspected dural
sinus thrombosis. In these eight patients, the diagnosis was also made with CT
venography. The diagnosis was confirmed by follow-up CT in four patients and by
follow-up MR imaging in two patients. The MIP algorithm did not allow direct
visualization of thrombus by either the CT or the MR imaging technique; however,
the CT integral display algorithm enabled direct visualization of thrombus on the
three-dimensional projection venograms. The systematic comparison of imaging
techniques showed that CT venography reliably reveals all cerebral veins and
sinuses when they are seen with MR venography. In addition, CT venography more
frequently visualizes sinuses or smaller cerebral veins with low flow as compared
with MR venography. CONCLUSION: Cerebral CT venography is superior to MR
venography in the identification of cerebral veins and dural sinuses and is at
least equivalent in the diagnosis of dural sinus thrombosis. CT venography is a
viable alternative to MR venography in the examination of patients with suspected
dural sinus thrombosis.
PMID- 9393194
TI - Optic neuritis: imaging with magnetization transfer.
AB - OBJECTIVE: Our objective was to prospectively examine the optic nerves in
patients with clinically severe unilateral optic neuritis, using routine spin
echo and magnetization transfer MR imaging. SUBJECTS AND METHODS: For 39 patients
with such lesions, we calculated the magnetization transfer ratio along the
involved intraorbital optic nerve and along the asymptomatic contralateral optic
nerve in a mirror-image location. Magnetization transfer ratios were correlated
with the imaging findings on routine spin-echo MR imaging. RESULTS: Magnetization
transfer ratios were decreased in 33 of the 39 clinically symptomatic optic
nerves, including 12 of the 18 clinically symptomatic optic nerves in which no
abnormality was seen on routine spin-echo MR images obtained before and after
administration of gadopentetate dimeglumine. CONCLUSION: Magnetization transfer
imaging reveals intraorbital optic nerve abnormalities in patients with optic
neuritis even when such lesions are otherwise occult on routine magnetization
transfer imaging.
PMID- 9393195
TI - MR imaging of intramedullary and intradural-extramedullary spinal cysticercosis.
AB - OBJECTIVE: The purpose of our study was to retrospectively review the MR imaging
findings in a group of patients with clinically proven cysticercosis involving
the spinal cord, the spinal subarachnoid space, or both. MATERIALS AND METHODS:
We retrospectively reviewed images of 16 patients with clinically diagnosed
spinal cysticercosis to summarize the imaging characteristics. All patients
underwent T1- and T2-weighted sagittal, axial, or both sagittal and axial MR
imaging before i.v. administration of paramagnetic contrast media. Thirteen
patients also underwent sagittal, axial, or both sagittal and axial T1-weighted
MR imaging after i.v. gadolinium administration. In addition, all patients
underwent cranial CT, MR imaging, or both to reveal possible evidence of cranial
cysticercosis. RESULTS: MR imaging revealed isolated intradural-extramedullary
involvement (n = 9), isolated intramedullary involvement (n = 3), combined
intradural-extramedullary and intramedullary involvement (n = 3), and/or
syringomyelia caused by infection and associated with chronic spinal
arachnoiditis (n = 2). Evidence of intradural-extramedullary disease included
cystic structures within the subarachnoid space or homogeneous sheetlike
enhancement within the subarachnoid space over the surface of the spinal cord.
Evidence of intramedullary disease included focal cystic lesions or syringomyelic
cavitation of the spinal cord. All patients had evidence of simultaneous
intracranial cysticercosis as shown on cranial CT, MR imaging, or both.
CONCLUSION: In the absence of scolex visualization, cysticercotic involvement of
the spinal cord or spinal subarachnoid space has a nonspecific appearance on MR
imaging. On the basis of the findings in this group of patients, we believe that
spinal cysticercosis is most often accompanied by intracranial disease.
PMID- 9393196
TI - Endoscopic treatment of symptomatic spinal subarachnoid cysts.
PMID- 9393197
TI - Normal lower limb venous Doppler flow phasicity: is it cardiac or respiratory?
AB - OBJECTIVE: The purposes of this study were to determine the origin and nature of
normal lower limb venous Doppler flow phasicity and to assess normal and
respiratory variations. SUBJECTS AND METHODS: The common femoral veins of 12
healthy volunteers (three men and nine women; age range, 21-50 years; mean, 29
years) were evaluated by detailed spectral Doppler examinations with simultaneous
ECG and respirometric tracings. The examinations were performed using a 5- or 7
MHz linear-array transducer with breath held in mid respiration, at the end of
deep expiration, at the end of deep inspiration, during Valsalva's maneuver, and
during quiet and deep breathing. The tracing obtained during breath-hold in mid
respiration was considered the baseline. Tracings obtained during the other
respiratory phases were analyzed for changes from the baseline. Doppler tracings
were analyzed for phasicity, waveform frequency, components, velocities, velocity
ratios, and presence of retrograde flow, all in correlation with simultaneous ECG
and respirometric tracings. Tracings were analyzed independently by two observers
to assess interobserver variability. RESULTS: With breath-hold in mid
respiration, the common femoral vein Doppler tracings consisted of multiphasic
waveforms that had a frequency similar to that of the heart rate. Each waveform
consisted of systolic, v, diastolic, and a waves. The systolic wave occurred 0.4
sec later than the QRS complex of the ECG and was always antegrade. The v wave
was always retrograde without flow reversal. The diastolic wave was always
antegrade. The a wave was always retrograde but showed flow reversal in nine of
12 subjects. The systolic:diastolic velocity ratio ranged from 0.9 to 1.5 (mean,
1.1). The minimum:maximum velocity ratio ranged from -0.4 to 0.2 (mean, -0.15).
With breath-hold at the end of expiration, the waveforms became slightly damped,
becoming biphasic in five subjects and remaining multiphasic in seven. With
breath-hold at the end of inspiration, the waveforms became nonphasic or biphasic
in nine and decreased in velocity in 12. With Valsalva's maneuver, flow stopped.
With normal respiration, cardiac waveforms were modulated by higher amplitude and
less frequent biphasic respiratory waves. The plasticity was equal in two,
dominantly cardiac in six, and dominantly respiratory in four. Flow velocity
increased with expiration and decreased with inspiration. With deep breathing,
the respiratory waves further increased, while the cardiac ones decreased in
amplitude. The latter continued to modulate the respiratory phasicity in 10
subjects. CONCLUSION: During quiet respiration, lower limb venous Doppler
tracings consisted of both cardiac and respiratory waveforms. Although
respiratory waveforms disappeared when patients held their breath, Doppler
tracings continued to be multiphasic and cardiac. Therefore, cardiac phasicity in
lower limb venous Doppler tracings does not necessarily indicate cardiac disease.
Other respiratory phases can modulate this basic cardiac pattern. Decrease in or
loss of phasicity in these waveforms does not always mean proximal obstruction,
because it can be caused by respiratory factors. Finally, the presence of minimal
cyclic retrograde flow that is 5 cm/sec or less does not necessarily indicate
cardiac disease.
PMID- 9393198
TI - Encephalopathy after transjugular intrahepatic portosystemic shunting: analysis
of incidence and potential risk factors.
AB - OBJECTIVE: Our purpose was to estimate the incidence of encephalopathy after
transjugular intrahepatic portosystemic shunting (TIPS) related primarily to the
diversion of portal vein blood flow and to identify periprocedural factors to
predict patients at risk. MATERIALS AND METHODS: All patients who underwent TIPS
with at least 1 month of clinical observation after the procedure were monitored
for clinically evident encephalopathy. Other variables that could individually
induce encephalopathy were retrospectively analyzed for interrelationships with
spontaneous or worsened encephalopathy. RESULTS: Of the 150 patients, 68 (45%)
suffered from encephalopathy after TIPS, but in only 33 (22%) was it new or worse
than baseline measurements obtained before TIPS; in 18 of these 33 patients, an
underlying medical cause was implicated. Fifteen (10%) of the 150 patients
developed mental dysfunction, usually mild and well controlled, thought to be
related only to TIPS and not to any underlying morbidity. Low portal vein
pressures after TIPS were found to be interrelated with new or worsened
spontaneous encephalopathy (p = .04). Like-wise, advanced age (> 59 years old)
weakly corresponded to the development of encephalopathy after TIPS. CONCLUSION:
TIPS causes an acceptably low rate of encephalopathy that is usually mild. No
specific variables exist for predicting the development or progression of
encephalopathy after TIPS.
PMID- 9393199
TI - Percutaneous revision of excess length from an implanted long-term central venous
access device.
PMID- 9393200
TI - Coarctation of the aorta: collateral flow assessment with phase-contrast MR
angiography.
AB - OBJECTIVE: The purpose of this report is to describe a new use of MR imaging in
coarctation of the aorta. The specific question addressed was how well collateral
blood flow in intercostal arteries, as determined by phase-contrast MR
angiography, correlated with findings during surgery or catheterization in
patients with coarctation of the aorta. CONCLUSION: Phase-contrast MR angiography
is an excellent technique for detecting the presence or absence of collateral
blood flow in the intercostal arteries of patients with coarctation of the aorta.
Knowing whether collateral blood flow is present in patients with narrowing of
the juxtaductal aorta should help assess the clinical hemodynamic significance of
the coarctation.
PMID- 9393201
TI - Endovascular repair of posttraumatic thoracic pseudoaneurysm with a stent graft.
PMID- 9393202
TI - Intrathoracic extension of retroperitoneal disease: is it purely lymphatic spread
or do some potential interfascial pathways exist?
PMID- 9393203
TI - Helical CT angiography in gastrointestinal bleeding.
PMID- 9393204
TI - Needle characteristics related to headaches after myelograms.
PMID- 9393205
TI - Color Doppler sonography of renal artery aneurysm.
PMID- 9393206
TI - The importance of being where? Balancing the perspective on practice coverage.
PMID- 9393207
TI - Langerhans' cell histiocytosis of the synovium.
PMID- 9393208
TI - MR imaging and CT appearances of aggressive angiomyxoma.
PMID- 9393209
TI - Rupture of the right atrium-superior vena cava junction from blunt thoracic
trauma: helical CT diagnosis.
PMID- 9393210
TI - Migration of translumbar inferior vena cava catheter into the right ureter.
PMID- 9393211
TI - CT and MR imaging of nasoethmoid schwannoma with intracranial extension.
PMID- 9393212
TI - Ion channels.
PMID- 9393213
TI - The health of gypsies.
PMID- 9393214
TI - The use or uselessness of annual public health reports.
PMID- 9393215
TI - Screening for fragile X syndrome: a model for genetic disorders?
PMID- 9393216
TI - Replacing the NHS market.
PMID- 9393217
TI - GMC accused of prejudicing doctors' defence.
PMID- 9393218
TI - Court confirms right to palliative treatment for mental distress.
PMID- 9393219
TI - Cancer in the offspring of radiation workers: a record linkage study.
AB - OBJECTIVES: To test the "Gardner hypothesis" that childhood leukaemia and non
Hodgkin lymphoma can be caused by fathers' exposure to ionising radiation before
the conception of the child, and, more generally, to investigate whether such
radiation exposure of either parent is a cause of childhood cancer. DESIGN: Case
control study. SETTING: Great Britain. SUBJECTS: 35,949 children diagnosed as
having cancer, together with matched controls. MAIN OUTCOME MEASURES: Parental
employment as radiation worker as defined by inclusion in the National Registry
for Radiation Workers and being monitored for external radiation before
conception of child; cumulative dose of external ionising radiation for various
periods of employment before conception; dose during pregnancy. RESULTS: After
cases studied by Gardner and colleagues were excluded, fathers of children with
leukaemia or non-Hodgkin lymphoma were significantly more likely than fathers of
controls to have been radiation workers (relative risk 1.77, 95% confidence
interval 1.05 to 3.03) but there was no dose-response relation for any of the
exposure periods studied; indeed, the association was greatest for those with
doses below the level of detection. No increased risk was found for fathers with
a lifetime preconception dose of 100 mSv or more, or with a dose in the 6 months
before conception of 10 mSv or more. There was no increased risk for the group of
other childhood cancers. Mothers' radiation work was associated with a
significant increase of childhood cancer (relative risk 5.00, 1.42 to 26.94;
based on 15 cases and 3 controls). Only four of the case mothers and no controls
were radiation workers during pregnancy. CONCLUSIONS: These results do not
support the hypothesis that paternal preconception irradiation is a cause of
childhood leukaemia and non-Hodgkin lymphoma; the observed associations may be
chance findings or results from exposure to infective or other agents. If there
is any increased risk for the children of fathers who are radiation workers, it
is small in absolute terms: in Britain the average risk by age 15 years is 6.5
per 10,000; our best estimate, using all available data, is that the increase is
5.4 per 10,000. For mothers, the numbers are too small for reliable estimates of
the risk, if any, to be made.
PMID- 9393220
TI - Birth weight of offspring and mortality in the Renfrew and Paisley study:
prospective observational study.
AB - OBJECTIVE: To investigate the association between birth weight of offspring and
mortality among fathers and mothers in the west of Scotland. DESIGN: Prospective
observational study. PARTICIPANTS: 794 married couples in Renfrew district of the
west of Scotland. MAIN OUTCOME MEASURES: Mortality from all causes and from
cardiovascular disease over 15 year follow up. RESULTS: Women who had heavier
babies were taller, had higher body mass index and better lung function, and were
less likely to be smokers than mothers of lighter babies. Fathers of heavier
babies were taller and less likely to be smokers than fathers of lighter babies.
Mortality was inversely related to offspring's birth weight for both mothers
(relative rate for a 1 kg lower birth weight 1.82 (95% confidence interval 1.23
to 2.70)) and fathers (relative rate 1.35 (1.03 to 1.79)). For mortality from
cardiovascular disease, inverse associations were seen for mothers (2.00 (1.18 to
3.33)) and fathers (1.52 (1.03 to 2.17)). Adjustment for blood pressure, plasma
cholesterol, body mass index, height, social class, area based deprivation
category, smoking, lung function, angina, bronchitis, and electrocardiographic
evidence of ischaemia had little effect on these risk estimates, although levels
of statistical significance were reduced. CONCLUSIONS: Birth weight of offspring
was related inversely to mortality, from all causes and cardiovascular disease,
in this cohort. The strength of this association was greater than would have been
expected by the degree of concordance of birth weights across generations, but an
extensive range of potential confounding factors could not account for the
association. Mortality is therefore influenced by a factor related to birth
weight that is transmissible across generations.
PMID- 9393221
TI - Impact of new antiretroviral combination therapies in HIV infected patients in
Switzerland: prospective multicentre study. Swiss HIV Cohort Study.
AB - OBJECTIVES: To examine trends in disease progression and survival among patients
enrolled in the Swiss HIV cohort study during 1988-96 and to assess the influence
of new antiretroviral combination therapies. DESIGN: Prospective multicentre
study, with follow up visits planned at six monthly intervals. SETTING: Seven HIV
units at university centres and cantonal hospitals in Switzerland. PATIENTS: 3785
men (mean age 35.0 years) and 1391 women (30.3 years) infected with HIV. 2023
participants had a history of intravenous drug misuse; 1764 were men who had sex
with men; 1261 were infected heterosexually; and 164 had other or unknown modes
of transmission. 601 participants had had an AIDS defining illness. RESULTS:
During more than 15,000 years of follow up, there were 1456 first AIDS defining
diagnoses and 1903 deaths. Compared with those enrolled during 1988-90, the risk
of progression to a first AIDS diagnosis was reduced by 18% (relative risk 0.82
(95% confidence interval 0.73 to 0.93)) among participants enrolled in 1991-2, by
23% (0.77 (0.65 to 0.91)) among those enrolled in 1993-4, and by 73% (0.27 (0.18
to 0.39)) among those enrolled in 1995-6. Mortality was reduced by 19% (0.81
(0.73 to 0.90)), 26% (0.74 (0.63 to 0.87)), and 62% (0.38 (0.25 to 0.97))
respectively. Compared with no antiretroviral treatment, the risk of an initial
AIDS diagnosis after CD4 lymphocyte counts fell to < 200 cells x 10(6)/1 was
reduced by 16% (0.84 (0.73 to 0.97)) with monotherapy, 24% (0.76 (0.63 to 0.91))
with dual therapy, and 42% (0.58 (0.37 to 0.92)) with triple therapy. Mortality
was reduced by 23% (0.77 (0.68 to 0.88)), 31% (0.69 (0.60 to 0.80)), and 65%
(0.35 (0.20 to 0.60)) respectively. CONCLUSIONS: The introduction of
antiretroviral combination therapies outside the selected patient groups included
in clinical trials has led to comparable reductions in disease progression and
mortality.
PMID- 9393222
TI - Helicobacter pylori infection and mortality from ischaemic heart disease:
negative result from a large, prospective study.
AB - OBJECTIVE: To determine whether there is an independent association between
Helicobacter pylori infection of the stomach and ischaemic heart disease. DESIGN:
Prospective study with measurement of IgG antibody titres specific to H pylori on
stored serum samples from 648 men who died from ischaemic heart disease and 1296
age matched controls who did not (nested case-control design). SUBJECTS: 21,520
professional men aged 35-64 who attended the British United Provident Association
(BUPA) medical centre in London between 1975 and 1982 for routine medical
examination. MAIN OUTCOME MEASURE: Death from ischaemic heart disease. RESULTS:
The odds of death from ischaemic heart disease in men with H pylori infection
relative to that in men without infection was 1.06 (95% confidence interval 0.86
to 1.31). In a separate group of 206 people attending the centre, plasma
fibrinogen was virtually the same in those who were positive for H pylori (2.62
g/l) and those who were negative (2.64 g/l). CONCLUSIONS: A study that by its
size and design minimised both random error and socioeconomic bias found no
relation between H pylori infection and ischaemic heart disease. The validity of
the study was shown by its confirmation of the recognised association between H
pylori infection and stomach cancer (odds ratio 4.0 (1.9 to 8.2); P < 0.001).
Eradication of H pylori infection may greatly reduce the incidence of stomach
cancer, one of the most common causes of death from cancer worldwide, but it
cannot be expected to have any effect in preventing ischaemic heart disease.
PMID- 9393223
TI - What investigations and procedures do patients in hospices want? Interview based
survey of patients and their nurses.
PMID- 9393224
TI - Aseptic meningitis associated with high dose immunoglobulin: case report.
PMID- 9393225
TI - Dentists' agreement on treatment of asymptomatic impacted third molar teeth:
interview study.
PMID- 9393226
TI - Why are babies getting heavier? Comparison of Scottish births from 1980 to 1992.
PMID- 9393227
TI - Prospective case-control study of role of infection in patients who reconsult
after initial antibiotic treatment for lower respiratory tract infection in
primary care.
AB - OBJECTIVE: To assess direct and indirect evidence of active infection which may
benefit from further antibiotics in adults who reconsult within 4 weeks of
initial antibiotic management of acute lower respiratory tract infection in
primary care. DESIGN: Observational study with a nested case-control group.
SETTING: Two suburban general practices in Arnold, Nottingham, over 7 winter
months. SUBJECTS: 367 adults aged 16 years and over fulfilling a definition of
lower respiratory tract infection and treated with antibiotics. 74 (20%) patients
who reconsulted within 4 weeks for the same symptoms and 82 "control" patients
who did not were investigated in detail at fallow up. MAIN OUTCOME MEASURES:
Direct and indirect evidence of active infection at the time of the
reconsultation or the follow up visit with the research nurse for the controls.
Investigations performed included sputum culture, pneumococcal antigen detection,
serial serology for viral and atypical pathogens and C reactive protein, throat
swabs for detecting viral and atypical pathogens by culture and polymerase chain
reaction, and chest radiographs. RESULTS: Demographic and clinical features of
the groups were similar. Two thirds of the 74 patients who reconsulted received
another antibiotic because the general practitioner suspected continuing
infection. Any evidence of infection warranting antibiotic treatment was uncommon
at reconsultation. The findings for the two groups were similar for the
occurrence of identified pathogens; chest x ray changes of infection (present in
13%); and C reactive protein concentrations, which had nearly all fallen towards
normal. Only three patients in the reconsultation group had concentrations > or =
40 mg/l. Pathogens identified at follow up in the 156 patients in both groups
included ampicillin sensitive bacteria in six. Atypical infections diagnosed in
27 (Chlamydia pneumoniae in 22) and viral infections in 54 had probably been
present at the initial presentation. CONCLUSION: Our study suggests that active
infection, which may benefit from further antibiotics, is uncommon in patients
who reconsult after a lower respiratory tract infection, and a repeat antibiotic
prescription should be the exception rather than the rule. Other factors, such as
patients' perception of their illness, may be more important than disease and
infection in their decision to reconsult.
PMID- 9393228
TI - Influence of patients' expectations on antibiotic management of acute lower
respiratory tract illness in general practice: questionnaire study.
AB - OBJECTIVE: To assess patients' views and expectations when they consult their
general practitioner with acute lower respiratory symptoms and the influence
these have on management. DESIGN: General practitioners studied consecutive,
previously well adults and recorded clinical data, the certainty regarding their
prescribing decision, and the influence of non-clinical factors on that decision.
Patients completed a questionnaire at home after the consultation. SETTING: 76
doctors from suburban, inner city, and rural practices. SUBJECTS: 1014 eligible
patients entered; 787 (78%) returned the questionnaire. MAIN OUTCOME MEASURES:
The views of the patient, the views of and antibiotic prescription by the doctor.
RESULTS: Most patients thought that their symptoms were caused by an infection
(662) and that antibiotics would help (656) and had both wanted (564) and
expected (561) such a prescription. 146 requested an antibiotic, 587 received
one. Of the 643 patients who thought they had an infection, 582 wanted an
antibiotic and thought it would help. Severity of symptoms did not relate to
wanting antibiotics. For those prescribed antibiotics, their doctor thought they
were definitely indicated in only 116 cases and not indicated in 126. Patient
pressure most commonly influenced the decision to prescribe even when the doctor
thought antibiotics were not indicated. Doctors considered antibiotics definitely
indicated in only 1% of the group in whom patient pressure influenced the
prescribing decision. Patients who did not receive an antibiotic that they wanted
were much more likely to express dissatisfaction. Dissatisfied patients
reconsulted for the same symptoms twice as often as satisfied patients.
CONCLUSION: Patients presenting with acute lower respiratory symptoms often
believe that infection is the problem and antibiotics the answer. Patients'
expectations have a significant influence on prescribing, even when their doctor
judges that antibiotics are not indicated.
PMID- 9393229
TI - Recent advances. Care of near term infants with respiratory failure.
PMID- 9393230
TI - ABC of palliative care. Anorexia, cachexia, and nutrition.
PMID- 9393231
TI - Case finding for the fragile X syndrome and its consequences.
PMID- 9393232
TI - Life span: conception to adolescence.
PMID- 9393233
TI - The real ethics of rationing. Purchasers, not surgeons, control waiting lists.
PMID- 9393234
TI - The real ethics of rationing. Doctors should not be penalised for doing private
work in spare time.
PMID- 9393235
TI - The real ethics of rationing. Conflict between private and national interests
within NHS needs scrutinising.
PMID- 9393236
TI - Death rates from childhood leukaemia near nuclear sites. Numbers of observed
deaths were closer to those expected after known risk factors were allowed for.
PMID- 9393237
TI - Death rates from childhood leukaemia near nuclear sites. Other studies showed
that radiation levels in Newbury area were low.
PMID- 9393238
TI - Death rates from childhood leukaemia near nuclear sites. Epidemiological studies
must define their cohort objectively.
PMID- 9393239
TI - Death rates from childhood leukaemia near nuclear sites. Findings were probably
due to chance fluctuations in small numbers of deaths.
PMID- 9393240
TI - Death rates from childhood leukaemia near nuclear sites. Place of residence at
diagnosis and at death may be different.
PMID- 9393241
TI - Death rates from childhood leukaemia near nuclear sites. Number of deaths in
Newbury area is not increased.
PMID- 9393242
TI - In screening for breast cancer, clinical examination is as effective as
mammography.
PMID- 9393243
TI - Incidence of gastrointestinal side effects due to alendronate is high in clinical
practice.
PMID- 9393244
TI - Communication between GPs and cooperatives is poor for terminally ill patients.
PMID- 9393245
TI - Geriatric depression scale can be used in older people in primary care.
PMID- 9393246
TI - Is the clinical course of HIV infection changing? Finding is disheartening.
PMID- 9393247
TI - Is the clinical course of HIV infection changing? Exclusion of people not
followed up for 12 months may have biased results.
PMID- 9393248
TI - Is the clinical course of HIV infection changing? Study's censoring strategy may
be source of bias.
PMID- 9393249
TI - Through the looking glass: backwards.
PMID- 9393250
TI - Therapeutic modification of nuclear factor kappa B binding activity and tumor
necrosis factor-alpha gene expression during acute biliary pancreatitis.
AB - The role of cytokines has been well documented in the pathogenesis of acute
pancreatitis. Antibodies against specific cytokines have been used to treat
pancreatitis, with mixed results. The transcription factor nuclear factor (NF)
kappa B is a pleiotropic regulator of many genes involved in stress and
inflammatory responses. The aim of this study was to prevent the NF-kappa B
binding activity and tumor necrosis factor (TNF)-alpha gene overexpression as a
possible therapeutic intervention for acute pancreatitis. Reversible acute
biliary pancreatitis was induced in male Sprague Dawley rats as established in
this laboratory. The animals were sacrificed at 0, 5, 15, 30 min and 1, 2, 3, 4,
6, 8, 10, 12, and 24 hours after the induction of pancreatitis. NF-kappa B
binding activity was determined by electrophoretic mobility shift assay, and TNF
alpha gene expression was assayed by reverse transcription-PCR. NF-kappa B
binding activity was markedly higher around 4 hours and persisted up to 24 hours
after pancreatitis induction in animals with acute pancreatitis, whereas TNF
alpha mRNA levels peaked at 24 hours. When amobarbital (to block NF-kappa B
activation) was given (60 mg/kg body weight, I.P.) 3 hours before induction of
pancreatitis, the activation of NF-kappa B and the overexpression of TNF-alpha
gene was prevented, with significantly decreased severity of pancreatitis as
assessed by amylase and clinical recovery. We conclude that 1) preventing the
activation of NF-kappa B eliminates the induced overexpression of inflammatory
cytokines (TNF-alpha) in acute pancreatitis, 2) such intervention correlates with
clinical improvement in pancreatitis, and 3) this genetic modification offers a
possible therapeutic intervention in acute pancreatitis.
PMID- 9393251
TI - Small molecule inhibition of tumor necrosis factor gene processing during acute
pancreatitis prevents cytokine cascade progression and attenuates pancreatitis
severity.
AB - The morbidity and mortality associated with acute pancreatitis are primarily a
result of pancreatic parenchymal necrosis and the development of marked pulmonary
dysfunction. Recent evidence suggests that both of these conditions are
propagated by interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha,
which are produced in large quantities within these organs. Because the
generation of these cytokines occurs in a predictable manner early in the
development of acute pancreatitis, we aimed to determine whether cytokine gene
processing could be inhibited in vivo and what effects this would have on
pancreatitis severity. Mild [caerulein, 50 micrograms/kg/hour intraperitoneally
(IP) x 4; n = 40] or severe (choline-deficient diet; n = 40) necrotizing
pancreatitis was induced in NIH swiss mice. Animals were randomly given a novel
small molecule (CNI-1493; 10 mg/kg IP) known to inhibit macrophage production of
TNF and IL-1 in vitro by inhibiting translation of TNF mRNA into protein. Control
animals received IP vehicle. All animals with acute pancreatitis showed dramatic
up-regulation of the IL-1 beta and TNF-alpha genes. Those animals receiving CNI
1493 demonstrated attenuated production of both species of mRNA in pancreatic as
well as pulmonary tissue (P < 0.01). Markers of pancreatitis severity such as
serum amylase and lipase, as well as pancreatic necrosis, were decreased in
animals treated with CNI-1493 (all P < 0.05). Posttranscriptional blockade of TNF
production precludes induction of the proinflammatory cytokine cascade that
normally occurs during acute pancreatitis. This lack of cytokine gene processing
in the pancreas and lungs results in dramatic reductions in tissue damage and
pancreatitis severity, which is not model dependent. This is the first time that
a small molecule has been shown to influence this disease.
PMID- 9393252
TI - Prospective evaluation of selective lymph node biopsy for cutaneous malignant
melanoma.
AB - Some patients presenting with cutaneous malignant melanoma without palpable
adenopathy have regional metastatic disease. We have applied the technique of
gamma probe-directed selective lymph node biopsy and used the results to direct
further therapy. The results of a prospective nonrandomized clinical study are
presented. Between November 1993 and December 1996, 63 patients with a diagnosis
of primary cutaneous malignant melanoma underwent lymphoscintigraphy with
technetium sulfur colloid followed by gamma probe-guided lymph node biopsy. There
were 32 (51%) women and 31 (49%) men with a mean age of 51.1 years (median, 50;
range, 13-87). Mean Breslow thickness was 2.13 mm (range, 0.5-15.0 mm; median,
1.56 mm). Primary locations were head and neck in 8 (13%), trunk in 24 (38%),
upper extremity in 13 (21%), and lower extremity in 18 (29%). Selective lymph
node biopsy was done on an outpatient basis with local anesthesia in 49 cases
(78%) and in the operating room with general anesthetic in 14 patients (22%). One
lymph node site was biopsied in 46 patients (73%), two sites in 16 (25%), and
three in 1 (2%), for a total of 81 selective lymph node biopsy sites, mean 1.29
per patient. The mean number of labeled lymph nodes removed per site per patient
was 1.64 (range, 1-5). Seroma or infection occurred in 6 patients (10%).
Micrometastatic disease was identified in nine selective lymph node biopsy sites
in eight patients. Of eight patients undergoing lymph node dissection, 5 (63%)
had no additional pathological lymph node involvement. With a mean follow-up of
579 days from selective lymph node biopsy (median, 594; range, 36-1157), 59 (94%)
have no evidence of disease. Three patients have died, 2 with systemic disease
(475 and 1149 days) and 1 from a myocardial infarction (380 days). No patient has
failed with regional-only recurrence. Gamma probe-directed selective lymph node
biopsy is a straightforward procedure that can be done in the outpatient setting
and facilitates management of patients with cutaneous malignant melanoma.
PMID- 9393253
TI - Quality assessment of intraoperative blood salvage and autotransfusion.
AB - Intraoperative blood salvage and autotransfusion are commonly used to minimize
exposure to banked blood. Although this technique has been used widely for years,
data vary regarding the quality of autotransfused blood. Salvaged blood may
contain plasma, residual heparin, and free hemoglobin released from damaged
cells. All of these factors may contribute to the adverse sequelae sometimes seen
with autotransfusion. For these reasons, we have monitored autotransfused blood
to assess its quality. Intraoperative blood salvage was used during most cardiac
procedures and at the discretion of the surgeon in other specialties. Blood was
collected through a double lumen catheter that was anticoagulated with heparin,
filtered, centrifuged, and washed with saline. A sample of the blood was removed
for analysis, which included hematocrit, heparin assay, fibrinogen, and free
hemoglobin levels. Over a 6-year period, 1593 patients had intraoperative blood
salvage with quality assessment. The majority of patients underwent cardiac
operations (941 patients, 59%), whereas 243 had orthopedic (15%) and 208 had
vascular (13%) procedures. Additionally, there were 127 pediatric patients (8%)
and 74 miscellaneous procedures (5%). The highest average yield of salvaged blood
was during vascular procedures (1073 +/- 76 mL), whereas orthopedic cases had the
lowest yield (378 +/- 19 mL) and hematocrit (39%). There was minimal residual
heparin activity, even in patients requiring systemic anticoagulation (0.3 to 0.5
units/mL). Patients undergoing pediatric procedures had the lowest concentration
of free hemoglobin (476 mg/L), whereas all adult patients had higher free
hemoglobin levels, especially vascular operations (990 mg/L). Intraoperative
salvaged blood has minimal heparin activity, even in procedures requiring
systemic anticoagulation. Fibrinogen, a marker of residual plasma, was
undetectable in the majority of cases. These data indicate that intraoperative
blood salvage generally results in a high-quality product (good hematocrit, low
heparin, minimal plasma), although there are significant differences in free
hemoglobin levels depending on the operative procedure.
PMID- 9393254
TI - Mesh inguinal herniorrhaphy: a ten-year review.
AB - Inguinal herniorrhaphy remains one of the most common surgical operations, with
approximately 10 to 20 per cent performed for recurrence. Reviews by specialized
hernia centers show mesh repair has a recurrence rate of 0.2 per cent. Detractors
of this repair include increased cost, technical difficulty, and risk for
infection. The purpose of this study was to compare mesh versus nonmesh inguinal
herniorrhaphy at a large teaching institution. From 1985 to 1994, 892 patients
underwent primary repair for inguinal hernia at the Veterans Administration
Hospital at Memphis, TN. Patients were stratified by repair [Lichtenstein (Mesh),
open anterior (Bassini, Marcy, McVay, and Shouldice), laparoscopic (Lap), and
preperitoneal (Post)]. Operative time for Mesh repair (111 +/- 2 minutes) was
longer than for Bassini or McVay (91 +/- 2 and 98 +/- 2 minutes; P < 0.05), and
Lap repairs were longer than all others (192 +/- 16 minutes; P < 0.05). Hospital
stay averaged 2.2 +/- 0.1 days for Mesh versus 2.6 +/- 0.1 days for all repairs
combined (P = not significant). Mesh patients developed four wound infections
(1.0%), none requiring mesh removal, versus nine infections (1.8%) in other
groups (P = not significant). One Mesh patient (0.3%) developed recurrence,
compared with 16 (3.5%) with open anterior repair (P < 0.01). Inguinal
herniorrhaphy using an open mesh repair technique provides superior recurrence
rates without increasing risk for infection, length of stay, or technical
difficulty.
PMID- 9393255
TI - Image-guided core biopsy has advantages over needle localization biopsy for the
diagnosis of nonpalpable breast cancer.
AB - Image-guided core biopsy (IGCB) of nonpalpable mammographic abnormalities has
gained attention as an alternative to needle-localized breast biopsy (NLB). This
study evaluated IGCB in the diagnostic workup of patients with nonpalpable
mammographic lesions suspicious for cancer. Eighty-six patients who underwent
IGCB were compared to 85 patients who underwent NLB for the diagnosis of
mammographic lesions suspicious for cancer. The incidence of positive margins was
less in patients who subsequently underwent needle-localized resection in the
IGCB group than in the NLB group (29 and 65%; P < 0.0001). The volume of excision
was greater for patients in the IGCB group than for the NLB group (106 cm3 and 52
cm3; P < 0.0001). Patients in the IGCB group averaged 1.1 operative procedures
compared with patients in the NLB group, who required an average of 1.9 operative
procedures. The mean charge for an IGCB was $1011 compared to $2975 for a NLB.
Subset analysis of 32 spiculated masses from the IGCB group and 21 from the NLB
group showed similar advantages of IGCB over NLB. The preoperative use of IGCB
for mammographically suspicious lesions can reduce the incidence of positive
surgical margins and the number of surgical procedures required. The use of IGCB
allows for a more efficient diagnostic workup and less expense to the patient.
PMID- 9393256
TI - Ductal carcinoma in situ of the breast: correlation of pathologic and
mammographic features with extent of disease.
AB - Optimal treatment of ductal carcinoma in situ (DCIS) of the breast requires an
improved understanding of its pathologic extent and propensity for local
recurrence. This study was performed to analyze mammographic and pathologic
features of DCIS that might predict the extent of disease within the breast and
facilitate treatment selection between lumpectomy alone, lumpectomy and
radiotherapy, and mastectomy. At our institution, 60 cases of DCIS were diagnosed
in 59 patients from June 1985 to February 1995 and form the basis of this
retrospective study. Demographic and treatment-related information was obtained
from hospital and tumor registry records. Mammograms were reviewed and size
estimates of the abnormalities were determined. Pathologic slides from all cases
were reviewed and classified according to size group, focality, nuclear grade,
necrosis, and histologic subtype. DNA ploidy status and proliferation indices
were available for 28 patients. Pathologically, 43 (72%) cases were < 15 mm, 14
(23%) were 16 to 40 mm, and 3 (5%) were > 40 mm. Five (8%) of the lesions were
multicentric, 28 (47%) focal, and 27 (45%) multifocal. Thirty-three (55%)
patients were treated by mastectomy, 16 (27%) by lumpectomy alone, and 11 (18%)
by lumpectomy and radiation therapy. Mammographic size, histologic grade,
presence or absence of necrosis, histologic subtype, DNA ploidy, and
proliferative index were compared with pathologic size and focality by chi 2
analysis. Mammographic size correlated significantly with pathologic size (chi 2
= 11.3; P = 0.02) but underestimated the extent of disease in 9 cases. Although
focality correlated significantly with pathologic size (chi 2 = 15.8; P = 0.003),
the remaining histopathologic features did not significantly correlate with
pathologic size or focality. Histopathologic features, including DNA studies, do
not reliably predict the pathologic extent of DCIS, but mammographic size and
focality do significantly correlate with pathologic size. Nevertheless, most
cases of DCIS are small focal or multifocal lesions that are amenable to breast
conservation approaches; further studies are needed to determine the appropriate
use of lumpectomy, radiation therapy, and mastectomy in the treatment of DCIS.
PMID- 9393257
TI - Utility of fine-needle aspiration cytology and frozen-section examination in the
operative management of thyroid nodules.
AB - Fine-needle aspiration cytology has a high sensitivity for the diagnosis of
solitary thyroid nodules. Certain diagnoses involving follicular histologies
often cannot be made with needle biopsy alone. The utility of frozen-section
examination of thyroid nodules, with particular regard to those lesions with
follicular histologies, is also limited. We examined the correlation of fine
needle aspiration cytology and frozen-section examination in solitary thyroid
nodules to determine the contribution of frozen-section examination to the
operation. We reviewed the fine-needle aspiration cytology, frozen-section
examination, and final pathology of 100 consecutive patients undergoing
thyroidectomy for a solitary solid thyroid nodule in an 4-year period. The
diagnoses were classified as indeterminant, benign, or malignant. The utility and
impact of the diagnosis from fine-needle aspiration or frozen section on the
operative procedure performed was analyzed. Fine-needle aspiration cytology as a
diagnostic test for thyroid nodules demonstrated an indeterminant rate of 23 per
cent, with a diagnostic accuracy of 77 and 92 per cent for benign and malignant
disease, respectively. In all patients with inaccurate benign diagnosis on fine
needle aspiration cytology, follicular neoplasm was misinterpreted for follicular
adenoma or multinodular goiter. In comparing frozen-section results, the
indeterminant, benign, and malignant rates were 7, 96, and 64 per cent,
respectively. Of the 23 patients with indeterminant results on fine-needle
aspiration cytology, the intraoperative frozen-section diagnosis on 4 patients
was deferred to permanent section; 18 received accurate cytological diagnosis;
and in 1 patient, carcinoma was missed. Overall, the decision about the extent of
surgical thyroid resection was changed in only 2 patients based on the frozen
section results. Preoperative evaluation with fine-needle aspiration cytology can
accurately and appropriately define the extent of thyroid surgery in most
patients with a diagnosis of malignant neoplasm or benign disease. Intraoperative
frozen-section examination may be helpful if fine-needle aspiration cytology
results are inderminant and in cases of follicular histology as an adjunct for
evaluation of the thyroid nodule, but overall, frozen section does not contribute
to the management of the thyroid lesion at the time of surgery.
PMID- 9393258
TI - Delayed ulcer recurrence after gastric resection: a new postgastrectomy syndrome?
AB - Recurrent ulceration following gastrectomy for peptic ulcer disease typically
occurs within the first several years postoperatively. Since 1990, we have
managed 20 patients who had undergone previous gastrectomy for peptic ulcer and
developed ulcer recurrence more than 10 years postoperatively. Mean age at
recurrence was 64 years, and the average time from original surgery to recurrent
ulceration was 21 years (range, 10-36 years). All patients had undergone vagotomy
and antrectomy (17 patients) or subtotal gastrectomy (3 patients). Presenting
symptoms included gastric outlet obstruction (70%) and bezoar formation (60%).
Endoscopic findings in this group of patients included a stenotic gastric outlet
(70%) and marginal ulcerations (80%). Thirteen of 15 patients tested (87%) were
Helicobacter pylori positive. Reoperation included partial resection of the
gastric pouch and exploration for persistent vagus nerve. Twelve patients
underwent Roux-en-Y reconstruction, whereas eight patients had Bilroth II
reconstruction. Three of the latter group also had Braun enteroenterostomy
performed. Good to excellent clinical results were obtained in 80 per cent of
patients. The four patients with poor outcomes shared the following
characteristics: 1) H. pylori-positive status, 2) presence of a preoperative
bezoar, 3) Roux-en-Y reconstruction. Our current approach is to avoid Roux-en-Y
construction in favor of Braun enteroenterostomy. Further prospective analysis of
long-term postgastrectomy patients is needed to determine whether this clinical
picture represents a new postgastrectomy syndrome.
PMID- 9393259
TI - Cost utility of routine imaging with Tc-99m-sestamibi in primary
hyperparathyroidism before initial surgery.
AB - Tc-99m-sestamibi has been shown to localize parathyroid adenomas effectively, but
controversy continues as to the use of this scan before initial surgery for
primary hyperparathyroidism. We analyzed the cost utility of obtaining this study
before initial surgery for primary hyperparathyroidism. Twenty-two consecutive
patients with primary hyperparathyroidism underwent dual-phase Tc-99m-sestamibi
scan before initial bilateral neck exploration. Surgical findings were correlated
with the results of sestamibi scan. There were 15 women and 7 men, with a mean
age of 50.5 years (range, 22-76). Preoperative mean total calcium was 11.74 mg/dL
(range, 10-15), ionized calcium was 6.19 mg/dL (range, 5.2-7.7), and intact
parathyroid hormone was 153.5 pg/mL (range, 83.1-551). Postoperative mean ionized
calcium was 4.56 mg/dL (range, 4.1-5.57). Twenty sestamibi scans had a positive
localization, and 2 scans had no localization. At surgery, 18 solitary adenomas,
3 diffuse hyperplasias, and 1 patient with four normal parathyroid glands were
found. Sixteen sestamibi scans were true positive (solitary adenoma), 4 scans
were false positive (2 diffuse hyperplasia, 1 wrong side, and 1 lymph node), 1
negative scan was true negative (diffuse hyperplasia), and 1 negative scan was
false negative (adenoma). One patient (four normal glands) at the second
operation had a supernumerary fifth gland adenoma excised from the mediastinum.
Preoperative Tc-99m-sestamibi scan did not offer any advantage when a complete
bilateral neck exploration is performed. Sixteen of (84%) adenomas were correctly
localized, but 18 of 19 adenomas were in the neck and were easily found. The 1
ectopic adenoma was not found by scanning or with initial surgery. The 4 of 22
(18%) false-positive localizations and the 2 of 22 (9%) negative scans
contributed nothing to the surgery. Of the 22 localizing sestamibi scans, surgery
was not altered to affect the outcome. At a cost of $550 per sestamibi scan and
with the error inherent in the scan, it is not cost effective to obtain Tc-99m
sestamibi scan before initial surgery for primary hyperparathyroidism.
PMID- 9393260
TI - Vacuum pack technique of temporary abdominal closure: a four-year experience.
AB - The purpose of this review is to present a 4-year experience with the vacuum pack
technique of temporary abdominal closure. From April 1992 to December 1996, 171
vacuum packs were performed on 93 patients. Eighty-seven vacuum packs were
performed on 38 general surgical patients, and 84 vacuum packs were performed on
55 trauma patients. Overall hospital mortality was 32 per cent. Methods of
achieving permanent wound closure varied in 73 patients. Four patients (4.3%)
developed enterocutaneous fistulae; four patients developed intra-abdominal
abscesses (4.3%). There were no eviscerations. Management of the complicated
intra-abdominal process is discussed: 1) the decision to manage the abdomen in an
open fashion; 2) which method of temporary closure to use; 3) subsequent
explorations; 4) when the abdomen should be closed; 5) which type of closure to
use; and 6) when the abdominal wall should be revised (herniorrhaphy). The vacuum
pack is the method of choice for open abdomen management and temporary abdominal
closure at our institution. With careful subsequent management, good patient
outcome can be achieved.
PMID- 9393261
TI - Prolonged abdominal packing for trauma is associated with increased morbidity and
mortality.
AB - Abdominal packing and planned reoperation is a lifesaving technique for temporary
control of hemorrhage in severely injured patients. Morbidity and mortality in
this group of patients, however, remain significant. It is unclear whether the
duration of packing impacts upon outcome. The purpose of this study is to
evaluate the abscess, sepsis, and mortality rates associated with duration of
abdominal packing. The records of 35 patients treated with abdominal packing
between July 1994 and December 1995 who survived to reoperation were
retrospectively reviewed. Evaluation included age; sex; mechanism; injuries;
Abdominal Trauma Index; duration of packing; survival; and presence of abscess,
sepsis or other infections. Patients packed for a total of 72 hours or less had
lower abscess, sepsis, and mortality rates than those packed for more than 72
hours. The differences in abscess rate and mortality were statistically
significant (P < 0.05). The Abdominal Trauma Index and mechanism of injury were
similar for the two groups. Based on these results, we conclude that although
abdominal packing is a useful technique in the severely injured patient, it is
associated with greater morbidity and mortality when the duration of packing
exceeds 72 hours.
PMID- 9393262
TI - Nonoperative therapy for acute necrotizing pancreatitis.
AB - Acute necrotizing pancreatitis is a highly morbid and lethal condition. We
performed a retrospective study of all patients admitted to Louisiana State
University Medical Center between 1980 and 1995 with a diagnosis of pancreatitis
(N = 617) and specifically examined those (N = 26) who developed acute
necrotizing pancreatitis. During the period 1980 to 1989, there were 7 patients
who progressed to acute necrotizing pancreatitis. Six of these seven patients
died (mortality, 86%). These patients were managed with multiple operations for
debridement and necrosectomy. The age ranged from 31 to 86 years in this group,
with a mean of 58.5. The patients' total hospital days ranged from 2 to 125 days
with a mean of 63.5 days. In 1989, we adopted an initial nonoperative approach to
necrotizing pancreatitis and began using CT-guided catheter drainage for this
condition. During this time period, 19 patients have progressed to necrotizing
pancreatitis. The range of hospital days was from 13 to 90 days, with a mean of
43.8 days. There were 2 deaths in this last group, resulting in a mortality rate
of 10.5 per cent. All of these patients were treated nonoperatively in the acute
phase of their illness. Two patients (15.8%) subsequently underwent laparotomy
and drainage when the collections were not amenable to CT-guided drainage.
Morbidity in this population approached 70 per cent; however, the mortality was
only 10 per cent compared to 86 per cent in the previous group. Although
nonoperative therapy has its associated morbidity, and although we understand the
controversy surrounding the management of this condition, it appears at least in
this population to have much less mortality than those who were treated
operatively in the acute phase.
PMID- 9393263
TI - Surgical management of chronic pain from chronic pancreatitis.
AB - Chronic pain from chronic pancreatitis remains a difficult clinical problem. We
present the results of surgical attempts to control this pain. For the past 3
years, all patients with chronic pancreatitis and pain requiring high-dose
narcotics or hospitalization for pain control were evaluated by the following
algorithm. Any anatomic pathology causing ductal dilatation was surgically
addressed first (Puestow's procedure, pseudocyst drainage, or sphincteroplasty).
If there was no evidence of ductal dilatation, or if pain recurred
postoperatively, denervation procedures were performed (splenopancreatic flap,
thorascopic sympathectomy, or resection). Pain recurrence was defined as the need
for further hospitalization or reoperation. Data were analyzed by comparison of
two proportions. Follow-up averaged 26 months. Thirty-seven patients underwent 44
operations solely in an attempt to control pain; 62 per cent were male, and 70
per cent had chronic alcoholic pancreatitis. Our results show that surgical
management provides relief in 68 per cent of patients, and no one procedure is
clearly superior to others.
PMID- 9393264
TI - Stereotactic core biopsy of the breast: results of one-year follow-up of 101
patients.
AB - Stereotactic core biopsy (SCB) is being used as a cost-effective alternative to
needle localized biopsy (NLB). However, an area of concern is the potential for
sampling error, with sparse surgical data available concerning follow-up and
failure rates. We therefore reviewed our results in patients undergoing SCB for
mammographically detected breast abnormalities. Between January 1994 and February
1995, 128 patients underwent SCB. Average age was 56.4 years. Nine patients
(7.0%) had histologic evidence of malignancy, with 111 (86.7%) benign diagnoses
requiring no further initial intervention. Eight patients (6.3%) proceeded
directly to NLB, five because of technical failure of SCB and three because of
suspicious initial histology. One of the latter patients had ductal carcinoma in
situ. The remaining 111 SCB patients were evaluated at 6 months and 1 year by
mammographic and physical examination. Ten patients were lost to follow-up. Of
the remaining 101 patients, 98 (97%) had stable mammograms and normal physical
examinations. Three patients (3.9%) required subsequent NLB due to progression of
the mammographic lesion. Two cases were histologically benign, and 1 patient had
ductal carcinoma in situ adjacent to the previous SCB biopsy site. An additional
patient underwent NLB for a new radiographic abnormality at a separate location
in the ipsilateral breast, which was invasive ductal carcinoma. SCB appears to be
an effective alternative to NLB for the majority of patients deemed eligible.
Careful mammographic follow-up is warranted for these patients given the small,
but real, possibility of sampling error.
PMID- 9393266
TI - Parotid pleomorphic adenoma.
PMID- 9393265
TI - Helicobacter pylori and peptic ulcer surgery.
PMID- 9393267
TI - Preventing postoperative recurrence of Crohn's disease.
AB - BACKGROUND AND METHODS: Risk factors for recurrence of Crohn's disease and the
evidence for progress in reducing recurrence following resection were reviewed. A
Medline based literature review was carried out. RESULTS AND CONCLUSION: Only
smoking has been confirmed as a significant adverse risk factor for recurrence.
Evidence for differing recurrence rates in fibrostenosing disease and perforating
disease is inconclusive, but such a classification along with the endoscopic
findings of recurrence may have a place in the analysis of therapeutic trials.
Minimal resectional surgery with clearing of only macroscopic disease seems to be
justified, with no clear benefits from different anastomotic techniques. Recent
trials offer encouraging evidence of the usefulness of 5-aminosalicylic acid,
particularly higher-dose regimens started early after resection, although the
long-term benefits are uncertain. The oral steroid, budesonide, offers a potent
treatment with minimal side-effects, but evidence of its prevention of recurrence
is presently weak.
PMID- 9393268
TI - Rational approach to combined carotid and ischaemic heart disease.
AB - BACKGROUND: The management of patients with concomitant coronary and carotid
artery disease remains a controversial subject. The aim of this review was to
develop a rational plan for the management of such patients based on a review of
the literature. METHOD AND RESULTS: A retrospective review was carried out of
relevant papers derived from the Medline database from 1964 to 1996. CONCLUSION:
The management of patients with concomitant coronary and carotid artery disease
has not yet been put to the test in a properly designed and randomized
multicentre trial. It is suggested that, until the results of such a trial are
available, the rational approach to combined symptomatic disease is combined
carotid endarterectomy and coronary artery bypass grafting (CABG). Combined
surgery is also appropriate for patients with symptomatic carotid artery disease
and significant but asymptomatic cardiac disease. At present there is inadequate
evidence to promote carotid endarterectomy for asymptomatic disease in
combination with CABG.
PMID- 9393269
TI - Monoclonal antibody treatment of colorectal cancer.
AB - BACKGROUND: The recent development of adjuvant monoclonal antibody immunotherapy
for patients suffering from colorectal cancer has led to a re-evaluation of the
role of these molecules in the treatment of solid tumours. In particular,
interest has been directed at identifying appropriate candidates for therapy,
evaluating treatment schedules and developing new molecules of therapeutic
potential. METHODS: This is a review of published data on patients undergoing
antibody therapy. In addition, current theories of the mechanism of action of
antitumour monoclonal antibodies are presented, along with potential future
therapeutic approaches. RESULTS AND CONCLUSION: Monoclonal antibody-based
adjuvant therapy of colorectal cancer appears to be effective; international
multicentre trials continue. The development of new molecules, such as chimaeric
antibodies, offers the potential of increased tumour targeting with reduced
toxicity. Such molecules may be used alone or in combination with agents such as
chemotherapy or cytokines.
PMID- 9393270
TI - Long-term oral administration of branched chain amino acids after curative
resection of hepatocellular carcinoma: a prospective randomized trial. The San-in
Group of Liver Surgery.
AB - BACKGROUND: Live cirrhosis is a state of protein calorie malnutrition which may
induce various complications. This study aimed to elucidate if long-term
nutritional support with branched chain amino acids (BCAAs) is effective after
hepatic resection for hepatocellular carcinoma (HCC). METHODS: Between 2 and 3
weeks after operation, 75 patients were randomized to receive oral BCAAs
(Aminoleban EN) 100 g per day for 1 year, and another 75 patients were assigned
to a control group. Mean follow-up times were 35.8 months and 36.0 months
respectively. RESULTS: Flapping tremor was less common, body-weight was greater
and performance status was better in the BCAA-treated group throughout the 1-year
period. BCAA treatment significantly increased red blood cell and serum albumin
level in patients with Child grade B and C disease. Substantially similar effects
were observed in those with major hepatic resection. Higher Fischer molar ratios
were maintained in the treated group. However, there were no differences in
cumulative tumour recurrence and survival rates. CONCLUSION: Long-term oral
nutritional support with BCAAs after resection of HCC is beneficial in improving
clinical features and laboratory data without increasing the rate of tumour
recurrence, particularly in patients with advanced cirrhosis or after major
hepatic resection.
PMID- 9393271
TI - Prognostic scoring systems to predict outcome in peritonitis and intra-abdominal
sepsis.
AB - BACKGROUND: Early classification of patients presenting with peritonitis and
intra-abdominal sepsis by means of objective scoring systems is desirable to
select patients for 'aggressive' surgery and to compare results of different
treatment regimens. However, none of the existing scoring systems has fulfilled
all expectations. METHODS: Evaluation of the value of various scoring systems
(Acute Physiology And Chronic Health Evaluation (APACHE) II, Simplified Acute
Physiology Score, Sepsis Severity Score, Multiple Organ Failure, Mannheim
Peritonitis Index (MPI), Ranson and Imrie) was performed in 50 patients.
Additionally, scoring systems were combined to obtain a 'combined score' for the
prediction of peritonitis-related in-hospital death. Hazard ratios were
calculated in a univariate and multivariate analysis. RESULTS: In the univariate
analysis all scoring systems, except Ranson and Imrie, predicted the primary
outcome. In the multivariate analysis, only the APACHE II score (hazard ratio
6.7) and the MPI (hazard ratio 9.8) contributed independently to the prediction
of outcome. All patients with an APACHE II score of 20 or more and a MPI of 27 or
more died in hospital. CONCLUSION: Combination of the APACHE II and the MPI
provides the best scoring system fitting clinical goals.
PMID- 9393272
TI - Randomized controlled trial of prophylactic chest physiotherapy in major
abdominal surgery.
AB - INTRODUCTION: This randomized controlled study evaluated the clinical benefit and
physiological effects of prophylactic chest physiotherapy in open major abdominal
surgery. METHODS: A group of 174 patients received chest physiotherapy including
breathing with pursed lips, huffing and coughing, and information about the
importance of early mobilization. In addition high-risk patients were given
resistance training on inspiration and expiration with a mask. The resistance
used during inspiration was -5 cmH2O and that during expiration +10 cmH2O. The
control group (194 patients) received no information or treatment unless a
pulmonary complication occurred. RESULTS: Oxygen saturation on postoperative days
1-3 was significantly greater in the treatment group. Treated patients were
mobilized significantly earlier. No difference was noted in peak expiratory flow
rate or forced vital capacity. Postoperative pulmonary complications occurred in
6 per cent of patients in the treatment group and in 27 per cent of controls (P <
0.001). In high-risk patients the numbers with pulmonary complications were six
of 40 and 20 of 39 respectively. Pulmonary complications were particularly common
in patients with morbid obesity. CONCLUSION: Preoperative chest physiotherapy
reduced the incidence of postoperative pulmonary complications and improved
mobilization and oxygen saturation after major abdominal surgery.
PMID- 9393273
TI - Acquired immune deficiency syndrome-related intussusception in adults.
PMID- 9393274
TI - Hand-held Doppler as a screening test in primary varicose veins.
AB - BACKGROUND: Hand-held Doppler is in common use for evaluating varicose veins, but
its accuracy in identifying the exact sites of venous reflux is inferior to that
of duplex scanning. It has been suggested that duplex should be used to
investigate all varicose veins, but this is currently impractical, and should be
unnecessary if hand-held Doppler examination were shown to be an adequate
screening test. METHODS: Eighty-five patients (122 legs) with primary varicose
veins were evaluated using a hand-held Doppler in the outpatient clinic,
according to a protocol. Patients then had venous duplex imaging. RESULTS:
Different methods of assessing the long saphenous vein (LSV) (tourniquet and
tapping tests, and examination at and below the groin) had similar sensitivities
for detecting reflux (75-86 per cent), and together detected 91 per cent of
cases. Six of the nine missed had a competent saphenofemoral junction, and five
had low-velocity reflux. Hand-held Doppler assessment missed 11 cases of
popliteal fossa reflux; only four involved the short saphenous vein (SSV), and
most had low-velocity popliteal vein reflux. CONCLUSION: Hand-held Doppler
examination missed LSV or SSV incompetence in 11 per cent of legs, but these
included cases with short-duration and low-velocity reflux of dubious clinical
importance.
PMID- 9393275
TI - Lateral rectal ligaments contain important nerves.
PMID- 9393276
TI - Population-based study of the treatment and prognosis of carcinoma of the rectum.
AB - BACKGROUND: Few population-based studies address the issue of treatment of
carcinoma of the rectum (15 cm or less from the anal verge) both from surgical
and epidemiological aspects. METHODS: Some 827 patients were analysed in the
cancer registry of the Cote-d'Or (Burgundy, France) from 1976 to 1990 (493,931
inhabitants). RESULTS: Resection for cure increased from 57.2 per cent before
1981 to 77.0 per cent after 1985 (P < 0.001), and the proportion of Dukes A and B
cases from 35.8 to 52.5 per cent (P < 0.001). Among patients resected for cure,
continence-preserving resections were performed more frequently during the 1986
1990 period (48.0 per cent) than during the two previous 5-year periods (20.0 per
cent; P < 0.001), more often in women, in the upper half of the ampulla and for
tumours of less than 45 mm. The operative mortality rate after curative surgery
decreased from 13.9 to 3.7 per cent (P < 0.001) between the first and the last
period whereas the 5-year crude survival rate rose from 25.8 to 42.6 per cent (P
< 0.001). Age, stage of disease and period of diagnosis were independent
prognostic factors of death in a relative survival model. CONCLUSION: This study
indicates that significant advances have been achieved at a population level in
the treatment of rectal cancer in terms of diagnosis, continence-preserving
procedures and survival.
PMID- 9393277
TI - Bone assessment in patients with ileal pouch-anal anastomosis for inflammatory
bowel disease.
AB - BACKGROUND: Patients with ulcerative colitis are at risk of low bone mineral
density (BMD). Proctocolectomy with ileal pouch-anal anastomosis (IPAA) for
ulcerative colitis diminishes the risk of bone disease. The aims of this study
were to assess the mechanism of low BMD and to measure bone density changes after
IPAA. METHODS: Twenty patients with IPAA for ulcerative colitis, of mean(s.d.)
age 38(9) (range 21-58) years, had measurements of lumbar spine and femoral neck
BMD by dual energy X-ray absorptiometry, a mean(s.d.) 28(23) (range 3-84) months
after proctocolectomy. Serum levels of calcium, phosphate, parathyroid hormone,
osteocalcin and 25-hydroxy vitamin D were determined. Fifteen patients were
followed for 28(12) (range 8-50) months. RESULTS: At baseline, six patients had
spine BMD more than two standard deviations below the normal value, and three had
vertebral crush fractures. Mean vitamin D values were normal and no patient had
osteomalacia. BMD increased with time elapsed since IPAA (spine: r = 0.71, P =
0.005). During follow-up, mean(s.d.) changes in bone density were +2.3(3.8) and
+2.1(5.6) per cent per year at the spine and femoral neck respectively.
CONCLUSION: These results suggest that in patients with IPAA for ulcerative
colitis, low BMD is not associated with vitamin D malabsorption and may be
reversible after surgery.
PMID- 9393278
TI - Magnetic resonance imaging of the pelvic floor in patients with obstructed
defaecation.
AB - BACKGROUND: Evacuation proctography and measurements of anorectal physiology are
frequently used to clarify the pathophysiology of obstructed defaecation. In some
patients these tests are normal, despite convincing clinical evidence of
defaecatory difficulty. The aim of this study was to determine whether magnetic
resonance imaging (MRI) could reveal pelvic floor abnormality in patients with
obstructed defaecation. METHODS: Eleven women with obstructed defaecation, in
whom evacuation proctography and anorectal physiology were normal, were examined
by MRI, using a fast gradient echo sequence. Measurements of pelvic visceral and
muscular descent were taken at rest and during straining, and compared with those
obtained from 13 asymptomatic volunteers. RESULTS: Patients with obstructed
defaecation had significantly greater pelvic visceral descent (P < 0.05), levator
muscle descent (P = 0.04), levator plate angle change (P = 0.003) and increase in
the area of the pelvic floor hiatus (P = 0.0002) than asymptomatic volunteers.
CONCLUSION: MRI demonstrated marked pelvic visceral and levator muscle descent in
women with obstructed defaecation, despite normal evacuation proctography and
anorectal physiology. MRI should be considered if these examinations have been
normal.
PMID- 9393279
TI - Tumour bed positivity predicts outcome after breast-conserving surgery.
AB - BACKGROUND: Local recurrence after breast-conserving surgery is associated with a
short distant disease-free survival, particularly if it occurs early. Early
recurrence is caused by residual disease left at the time of surgery. Previous
studies have demonstrated that disease in the tumour bed is a common finding
after breast-conserving surgery. METHODS: The follow-up (mean 4.4 years) of 300
patients who had tumour bed analysis performed by the cavity shaving technique
following breast-conserving surgery is presented. Postoperative radiotherapy was
administered to all patients. RESULTS: The incidence of tumour bed positivity was
39.3 per cent. With a selective re-excision policy the local recurrence rate was
2.0 per cent and distant recurrence rate 10.4 per cent. Multivariate analysis
identified lymphovascular invasion, oestrogen receptor status and tumour bed
status as independent predictors of time to distant recurrence. CONCLUSION: A low
rate of local recurrence can be achieved using this technique of margin
assessment. Tumour bed status may be a useful prognostic factor following breast
conserving surgery.
PMID- 9393280
TI - Pathological appearance of the stomach after endoscopic mucosal resection for
early gastric cancer.
AB - BACKGROUND: The pathological findings of the resected stomach after endoscopic
mucosal resection (EMR) for early gastric cancer were reviewed. EMR was indicated
when a lesion consisting of well or moderately differentiated adenocarcinoma had
a diameter of less than 2 cm. METHODS: Of 39 patients with early gastric cancer
were treated with EMR between 1990 and 1995, 11 required additional surgery.
RESULTS: Malignant tissue in the gastric wall was completely removed in four
patients, while cancer cells remained in the mucosa adjacent to the scar in five
and infiltrated into the submucosa in two. Most of these residual cancers were
characterized by a lesion with a diameter exceeding 15 mm and by the location in
the body or cardia of the stomach. Lymph node metastases were observed in one
patient whose carcinoma invaded the deeper submucosal layer. Assessment of the
depth of entire invasion from the endoscopically-resected specimen was correct
for six of 11 patients. CONCLUSION: Gastric carcinomas to be resected by EMR
should be smaller, especially if located in the body or cardia. Accurate
diagnosis of the width and depth of invasion is indispensable before proceeding
to EMR. Surgery may be the treatment of choice when there is submucosal invasion.
PMID- 9393282
TI - Laparoscopic fenestration of symptomatic non-parasitic cysts of the liver.
PMID- 9393283
TI - Colour flow duplex imaging of occlusive arterial disease of the lower limb.
PMID- 9393281
TI - Risk factors for surgical treatment in the Dutch Gastric Cancer Trial.
AB - BACKGROUND: A multicentre randomized study of surgical treatment of gastric
cancer has shown increased mortality and morbidity rates in patients having D2
resection. The aim of this report is to analyse risk factors in these patients.
METHODS: In a prospective randomized trial, comparing two types of
lymphadenectomy for curable gastric cancer, risk factors for hospital death and
morbidity in 711 patients treated with curative intent were evaluated by
multivariate analysis using stepwise regression analysis. RESULTS: Age greater
than 65 years and male sex were the most important risk factors for death
(relative risk (RR) 4.35 (95 per cent confidence interval (c.i.) 2.07-9.15) and
2.51 (95 per cent c.i. 1.24-5.08) respectively). The extent of nodal dissection
was also a significant risk factor for death (RR 2.13). For overall
complications, splenectomy was the most important risk factor (RR 2.13 (95 per
cent c.i. 1.44-3.16)), while pancreatectomy and type of gastrectomy were the only
factors significantly influencing the occurrence of major surgical complications.
CONCLUSION: The cumulative mortality risks of these factors should be considered
carefully when planning surgery for individual patients.
PMID- 9393284
TI - Intragastric endoscopic surgery using the transanal endoscopic microsurgery
technique.
PMID- 9393285
TI - One-wound laparoscopic cholecystectomy.
PMID- 9393286
TI - One-wound laparoscopic cholecystectomy.
PMID- 9393287
TI - One-wound laparoscopic cholecystectomy.
PMID- 9393288
TI - Antisperm antibodies and male subfertility.
AB - The outcome of treatment for couples with male immunological infertility must be
considered in conjunction with the risks, costs and time to success involved.
Reversible factors should be treated. Steroid treatment is a good option but its
failure in two-thirds of patients should add impetus to attempts to predict
responders before or soon after starting treatment. The treatment options are not
mutually exclusive [48]. The success of IUI may be enhanced further by new sperm
preparation techniques. If severe immunological infertility exists or other
infertility factors are present, IVF or ICSI may be considered from the outset.
PMID- 9393289
TI - Prognostic implications of cytogenetic findings in kidney cancer.
AB - OBJECTIVE: To evaluate the prognostic impact of cytogenetic findings in renal
cell carcinoma (RCC). PATIENTS AND METHODS: Tumour cytogenetics, histomorphology,
DNA ploidy and S-phase fraction, stage, size, and grade were related to survival
in 50 consecutive patients with RCC. The mean follow-up was 3.9 years (median
4.2, range 0-8.8). RESULTS: The predictive probability for recurrence-free
survival at 5 years (5-year RFS) for all 50 patients was 0.54. There was a
significant association between the degree of cytogenetic complexity and
survival, in that patients with five or less aberrations had a better prognosis
than those with more than five changes (5-year RFS 0.71 and 0.43, respectively; P
< 0.05). Patients with del(8p)/-8, +12, and +20 had a significantly worse
prognosis compared with those without these aberrations. Of the well-known
prognostic variables grade and stage, the former was far better for predicting
prognosis. A Spearman correlation test showed a significant covariation of grade
with the S-phase fraction, T-stage, and cytogenetic complexity. CONCLUSION: The
degree of cytogenetic complexity and recurrent cytogenetic abnormalities affect
the prognosis in RCC, although grade was the most reliable independent prognostic
factor predicting disease recurrence.
PMID- 9393290
TI - Clinical review of 100 consecutive surgically treated patients with upper urinary
tract transitional tumours.
AB - OBJECTIVE: To determine the outcome of conservative or radical treatment in a
retrospective study of 100 consecutive patients with upper urinary tract tumours.
PATIENTS AND METHODS: From 1965 to 1995, 100 patients (78 men and 22 women, mean
age 65 years, range 27-82) with upper urinary tract tumours were treated
surgically, using nephroureterectomy with excision of a cuff of bladder in 53 and
organ-sparing treatment in 47. The outcome was assessed as survival and
recurrence during a follow-up of up to 15 years. RESULTS: After radical and organ
sparing treatment, the 15-year cancer-specific survival was 69% and 25%,
respectively; metastases developed in 17% and 19% and global recurrence in 40%
and 70%, respectively. While locoregional and bladder recurrences were similar in
the two groups (9% vs 8% and 30% vs 38%, respectively), ureteric-stump recurrence
in the conservative group was 23%. There were no significant differences in
survival rates between patients with single or multiple presentation, or for
localization, while the grading of the lesions proved to be an accurate
prognostic indicator. CONCLUSION: This experience of urothelial neoplasia of the
upper tract highlights the difficulty in diagnosing this pathology and in
entrusting screening to a non-invasive technique such as urinary cytology. The
percentage recurrence observed after organ-sparing therapy indicates that this
treatment should be used cautiously.
PMID- 9393291
TI - Using the ICSOoL to measure the impact of lower urinary tract symptoms on quality
of life: evidence from the ICS-'BPH' Study. International Continence Society-
Benign Prostatic Hyperplasia.
AB - OBJECTIVE: To present and describe the validity and reliability of the
International Continence Society-Benign Prostatic Hyperplasia study quality-of
life (ICSQoL) instrument, a new set of questions to assess the impact of lower
urinary tract symptoms (LUTS) on quality of life (QoL) in middle-aged and elderly
men. PATIENTS AND METHODS: The study comprised 1271 consecutive men over the age
of 45 years, attending urology departments in 12 countries, with LUTS and
possible benign prostatic obstruction who were recruited to the ICS-'BPH' study
(the clinic group); 423 ambulant men were recruited from a general practice in
the UK to provide a community group. Each individual completed the ICS-'BPH'
study questionnaire which includes six items addressing general and specific
aspects of QoL (the ICSQoL). Content and construct validity were assessed by
interviews with patients and by testing hypotheses within the study groups, e.g.
the relationships with age, individual LUTS (as measured on the ICSmale
questionnaire) and generic health status, as measured by the Short Form (SF-36)
and EuroQol instruments. Reliability was assessed by measures of internal
consistency and a test-retest analysis. RESULTS: The ICSQoL items were easily
understood by patients, were completed with low levels of missing data, and
address some (but not all) concerns about the impact of LUTS on QoL. The ICSQoL
items have good construct validity, showing expected differences between
community and clinic samples, and expected relationships with each other and
individual LUTS. Items had good test-retest reliability, but their internal
consistency was poor, confirming that ICSQoL questions should not be combined
into a score. General ICSQoL items were closely related with most domains of the
SF-36 and the EuroQol. CONCLUSION: ICSQoL items may be used individually or as a
group in research studies or in clinical practice.
PMID- 9393292
TI - Construction and validation of a short-form benign prostatic hypertrophy health
related quality-of-life questionnaire. BPH Group in General Practice.
AB - OBJECTIVE: To construct and validate a short-form benign prostatic hypertrophy
(BPH) health-related quality-of-life (HRQL) questionnaire which is more practical
in use and as informative as the 20-item visual analogue scale questionnaire
(QOL20) previously validated in French. PATIENTS AND METHODS: From the factorial
structure of the QOL20, a nine-item questionnaire (QOL9) was constructed using
stepwise linear regression and factorial analysis. The feasibility and
reliability of the QOL9 were analysed in a cross-sectional case-control study and
a longitudinal cohort study, including symptomatic patients with BPH treated for
6 months with an alpha 1-blocker (alfuzosin). RESULTS: The reduction of the QOL20
to QOL9 showed a minimal loss of information (90-95% of the variance of QOL20 was
explained by QOL9) and lead to a three-dimensional structure: well being,
patients' perceived sexual-life status, and BPH interference with activities. The
QOL9 was practical in use (completion rate 87-100%; duration of completion at
inclusion 11.6, SD 2.0 min), consistent (Cronbach's alpha > 0.7), reliable
(intraclass correlation coefficient > 0.80) and responsive (effect-size index
0.9, SD 0.01 in the longitudinal study). CONCLUSIONS: The QOL9 is a good BPH HRQL
questionnaire, including an assessment of patients' perceived sexual-life status;
it easy to administer, accurate, reproducible and responsive to change with
treatment. We suggest that the QOL9 be substituted for the QOL20 and administered
in addition to the International Prostate Symptom Score to obtain a better
assessment of the patients' perception of their disease.
PMID- 9393293
TI - The influence of colonic enema irrigation on urodynamic findings in patients with
neurogenic bladder dysfunction.
AB - OBJECTIVE: To evaluate whether colonic enema irrigation influences the urodynamic
characteristics of patients with spina bifida, an overactive bladder and detrusor
sphincter dyssynergia (DSD). PATIENTS AND METHODS: Since 1991, 83 patients with
spina bifida at our institution have treated their bowel dysfunction by colonic
irrigation every 24-48 h. In 12 patients (seven boys and five girls, mean age 7.7
years, range 0.7-13.8) with an overactive bladder and DSD, urodynamic studies of
the bladder before and after enema treatment were available with no intercurrent
changes in urological therapy. RESULTS: There were no significant changes overall
in bladder capacity, leak-point pressure, bladder compliance and bladder
instability in the selected group of children. CONCLUSION: Although enema therapy
for bowel treatment in patients with spina bifida gave good results for faecal
incontinence, with good patient compliance, no favourable effect on bladder
function should be expected in most patients with a high-risk urinary tract
dysfunction. Further study is needed to determine factors in patients who will
benefit urologically from enema treatment.
PMID- 9393294
TI - Acute suppression of idiopathic detrusor instability with magnetic stimulation of
the sacral nerve roots.
AB - OBJECTIVE: To assess the effect of magnetic stimulation of the S3 nerve root on
unstable contractions in patients with idiopathic detrusor instability. PATIENTS
AND METHODS: Twelve patients with idiopathic instability were studied. The S3
nerve root was localized by mapping the response of the toe flexor muscles and
anal sphincter to magnetic stimulation at different sites. Unstable contractions
were provoked by rapidly infusing saline into the bladder and the effect of
magnetic stimulation of S3 on contractions was assessed. RESULTS: Magnetic
stimulation relieved the sensation of urinary urgency and reduced the duration
and amplitude of provoked contractions in all patients. Stimulation reduced the
area under the pressure/time curve by 80-98%. In some patients there was a
shortlived residual suppressive effect lasting up to 90 s. CONCLUSIONS: Magnetic
stimulation of S3 acutely abolishes unstable contractions in patients with
idiopathic detrusor instability.
PMID- 9393295
TI - Kinetics of peptide-induced release of inflammatory mediators by the urinary
bladder.
AB - OBJECTIVE: To investigate the release of inflammatory mediators by the urinary
bladder in response to exposure to pro-inflammatory peptides. MATERIALS AND
METHODS: Isolated guinea pig urinary bladder was incubated with 10 mumol/L each
of substance P (SP), neurokinin A (NKA), calcitonin gene-related peptide (CGRP),
vasoactive intestinal peptide (VIP), octreotide acetate (a long-acting analogue
of somatostatin, SOM), or bradykinin (BK), and the release of histamine,
prostaglandin (PG) E2, PGF2 alpha and leukotriene B4 (LTB4) was determined during
0-5, 5-30 and 30-120 min after addition. RESULTS: Substance P, NKA, VIP and BK
stimulated the release of histamine, while CGRP and SOM suppressed the release to
below the spontaneous rates. All peptides, except CGRP and SOM, stimulated the
release of PGE2 between 0 and 30 min, and only VIP failed to stimulate the
release of PGF2 alpha within 5 min of exposure. Substance P, NKA, VIP and BK
stimulated the release of LTB4 and this required > 5 min of exposure. CONCLUSION:
These results indicate that the peptides evaluated induce an immediate and
transient release of histamine and activation of cyclooxygenase and delayed
activation of 5-lipoxygenase. These actions may directly regulate the
participation of these peptides in the pathogenesis of cystitis.
PMID- 9393296
TI - Management of the long-term urinary catheter in the asymptomatic patient in the
Accident and Emergency department.
AB - OBJECTIVE: To determine the management of long-term urinary catheters in the
asymptomatic patient in the Accident and Emergency (A&E) Department. PATIENTS AND
METHODS: Using data obtained from patient records, a retrospective study was
undertaken of 41 patients who presented to the A&E department of a large district
general hospital, on a total of 80 occasions in a 6-month period, with blocked or
bypassing long-term urinary catheters, but who were otherwise asymptomatic.
RESULTS: In 78% of presentations, patients had one or more investigations
performed on their urine, which in 15% was on urine aspirated through an old,
unchanged catheter. In 23% of presentations, patients were discharged only having
had their catheters flushed, and in only 41% was the catheter changed as the
first line of management. Finally, in 63% of episodes, patients were discharged
with antibiotics, despite having no symptoms of a urinary tract infection.
CONCLUSIONS: All patients with long-term urinary catheters will have bacteriuria
and performing investigations on this urine if the patient is asymptomatic is a
waste of resources. Long-term urinary catheters which become blocked usually do
so by encrustation on the luminal surface of the catheter. Flushing these
catheters may dislodge some of these encrustations, but ideally the catheter
should be changed. The prescribing of antibiotics to asymptomatic patients with
bacteriuria has no proven benefit, but on the contrary it may cause harmful side
effects and also selects for antibiotic-resistant bacteria. These patients should
be managed in the A&E department with a simple catheter change.
PMID- 9393297
TI - Preliminary experience with a urinary control device in the management of women
with genuine stress incontinence.
AB - OBJECTIVE: To evaluate the efficacy and acceptability of the FemAssist urinary
control device (Insight Medical UK Ltd). PATIENTS AND METHODS: Twenty-seven women
with cystometrically confirmed genuine stress incontinence performed a perineal 1
h pad-test; the pad test was then repeated with the FemAssist device in place and
the difference in pad weights compared with and without the device in place.
Patients were given 100 mm visual analogue scales (VAS) to measure discomfort,
acceptability and embarrassment associated with using the device. RESULTS: The
median (range) loss with and without the FemAssist device was 4.9 (0-65) mL and
21 (1-94), respectively (P < 0.01); 20 patients were less wet when using the
device. The median (range) VAS scores were; discomfort 35 (4-93), embarrassment
11 (0-75), and acceptability 65 (3-100). Discomfort was greater among the women
with a greater loss. The acceptability correlated negatively with discomfort (r =
-0.53) and negatively with embarrassment (r = -0.39); 15 patients (56%) reported
that they would use the device in the long-term. CONCLUSION: The FemAssist device
produced a significant reduction in urine loss. The magnitude of benefit could
not be predicted for an individual and the device was ineffective in some women.
The use of the device was influenced by discomfort and associated embarrassment.
The device has a role in the management of stress incontinence but patients must
be assessed individually for suitability.
PMID- 9393298
TI - Collagen for female genuine stress incontinence after a minimum 2-year follow-up.
AB - OBJECTIVE: To evaluate the medium-term outcome of gluteraldehyde cross-linked
(GAX) collagen in the treatment of genuine stress incontinence in women. PATIENTS
AND METHODS: The study comprised 111 women (age range 33-90 years) with genuine
stress incontinence who were treated with para-urethral collagen injections
between 1990 and 1995. The patients were followed prospectively and their
clinical outcome documented. Pre- and post-operative urodynamic data were
examined to determine any prognostic indicators. RESULTS: The overall results at
a minimum 2-year follow-up (mean 3.3) showed 25% of patients to be dry and a
further 40% improved. Although there were significant changes in some urodynamic
values, no predictive factors of success were identified. Previous surgery for
stress incontinence did not influence the final outcome. CONCLUSION: Para
urethral collagen injection is a safe and relatively simple procedure with
acceptable results at the medium-term follow-up. It could be offered as a primary
or secondary procedure to women with genuine stress incontinence who are unable
or unwilling to undergo surgical treatment. Objective urodynamic assessment
revealed no factors of prognostic significance.
PMID- 9393299
TI - Tumour progression and survival in patients with T1G3 bladder tumours: 15-year
outcome.
AB - OBJECTIVE: To evaluate tumour progression and survival of patients with T1G3
bladder tumours who were followed for 15 years. PATIENTS AND METHODS: A subset of
48 patients with T1G3 bladder tumours was entered into a randomized trial of
transurethral resection (TUR) or TUR plus bacille Calmette-Guerin (BCG) therapy
and followed for a minimum of 15 years. Thirty-nine (81%) patients received one
or more courses of BCG. The endpoints of the study were stage progression
(defined as muscle invasion of metastasis) and disease-specific survival.
RESULTS: Of the 48 patients, 25 (52%) progressed and 15 (31%) died from the
disease; 33 patients (69%) survived, including 24 (50%) with an intact bladder.
The median progression-free survival time was 151 months. Tumour progression
occurred in 35% of the patients within the first 5 years, in 16% after 5-10 years
and in 12% of those followed for 10-15 years. Deaths from cancer occurred in 25%
of the patients in the first 5 years and in 10% of patients at risk from 5 to 15
years. CONCLUSIONS: Patients with T1G3 bladder tumours who are treated
conservatively are at life-long risk of having a muscle-invasive tumour and dying
from bladder cancer.
PMID- 9393300
TI - Soluble urinary CD14 after intravesical bacille Calmette-Guerin immunotherapy for
carcinoma in situ.
AB - OBJECTIVE: To characterize the production of the monocyte activation marker,
soluble CD14 (sCD14), after bacille Calmette-Guerin (BCG) immunotherapy for
superficial bladder cancer. PATIENTS AND METHODS: Nineteen patients with
carcinoma in situ were treated with a standard regimen of intravesical BCG. Urine
samples were collected after each instillation and analysed; the levels of
soluble CD14 were determined by an enzyme-linked immunosorbent assay, the
molecular weight confirmed by Western blotting and the possible cell source
investigated using immunohistochemistry. RESULTS: The mean levels of sCD14 were
higher in patients with persistent carcinoma (designated as failures) than in
those who had successful complete responses (responders) to BCG immunotherapy.
The differences were statistically significant, with P = 0.034 at instillation 4
and P = 0.027 at instillation 5 for the total mass of sCD14, and P = 0.049 at
instillation 4 for the concentration of sCD14. The predominant type of sCD14 in
urine was the 48 kDa form, although in most patients there was a minor band of
reactivity at 54 kDa. A panel of human bladder cancer cell lines did not react
with the anti-CD14 monoclonal antibodies 3C10, 5C5 and BA8, and the antibodies
also failed to react with malignant epithelial cells in frozen sections of
untreated bladder tumour. Furthermore, sCD14 was not secreted by cultured bladder
tumour cells. The source of urinary sCD14 is likely to be the resident and
infiltrating macrophages in the bladder wall. Freshly isolated peripheral blood
monocytes secreted sCD14 in response to BCG in a manner analogous to stimulation
with bacterial lipopolysaccharide. CONCLUSION: A soluble form of CD14 is secreted
into the urine of patients who receive intravesical BCG. The measurement of
soluble urinary CD14 could be of prognostic significance for the response to
immunotherapy.
PMID- 9393301
TI - Effect of oral administration of prostaglandin E1 on erectile dysfunction.
AB - OBJECTIVES: To investigate the effect of limaprost, an oral prostaglandin E1
(PGE1) derivative, on erectile dysfunction and to compare the effects of
limaprost with a Chinese herbal drug, gosyajinki-gan. PATIENTS AND METHODS: The
study comprised 50 consecutive patients with mild erectile dysfunction who showed
a good erectile response to intracavernosal injection with 20 micrograms of PGE1.
Limaprost was administered to the first 25 patients (30 micrograms three times
daily) and gosyajinki-gan (7.5 g three times daily) to the next 25 patients, for
8 consecutive weeks. Patients were evaluated by their ability to achieve vaginal
penetration and by a subjective assessment of erectile function (penile rigidity
and maintenance of erection) before and after the treatment, using a self
administered questionnaire. Objective measurements (nocturnal penile tumescence,
NPT, values) were also evaluated. RESULTS: Eleven of the 24 patients who received
limaprost without interruption and four of the 24 taking gosyajinki-gan succeeded
in vaginal penetration; the difference in the positive response rate was
significant. The mean increment of NPT was significantly higher with limaprost
treatment. However, all positive responders in both groups did not experience a
full erection. There were no side-effects in any patient except one in the
limaprost group who developed a facial flush. Thus the treatment was mild enough
to be tolerated. CONCLUSION: Limaprost was more effective for mild erectile
dysfunction than was gosyajinki-gan.
PMID- 9393302
TI - Variability in penile appearance and penile findings: a prospective study.
AB - OBJECTIVE: To document prospectively variation in penile morphology and clinical
findings in children. PATIENTS AND METHODS: The study comprised a consecutive
sample of 468 boys whose consultation with a physician included a genital
examination in a primary-care paediatric practice in rural northern Wisconsin.
RESULTS: Circumcised boys under 3 years of age were significantly more likely to
have a partially or completely covered glans, a reddened meatus, balanitis, or
trapped epithelial debris, and less likely to have a fully exposed glans than
were circumcised boys of 3 years or older. Among the 238 boys under 3 years,
those circumcised were significantly more likely to have non-cosmetic problems,
including coronal adhesions, trapped epithelial debris, a reddened meatus,
preputial stenosis (phimosis) and balanitis, than were boys with a foreskin.
Findings in the circumcised group under 3 years included: fully exposed glans (n
= 78, 35.6%), partially covered glans (n = 67, 30.6%), adhesions (25.6%),
completely covered glans (20.1%), entrapped desquamated epithelial debris
(24.7%), reddened meatus (19.1%), balanitis (15.5%), and preputial stenosis
(0.9%). Only two genital examinations in boys with foreskins revealed pertinent
findings. Coronal adhesions develop in circumcised boys at 2-6 months of age and
usually resolve by 24 months. The degree of skin covering the glans after
neonatal circumcision peaks at 6 months of age. CONCLUSIONS: There are
significant variations of appearance in circumcised boys; clinical findings are
much more common in these boys than previously reported in retrospective studies.
The circumcised penis requires more care than the intact penis during the first 3
years of life. Parents should be instructed to retract and clean any skin
covering the glans in circumcised boys, to prevent adhesions forming and debris
from accumulating. Penile inflammation (balanitis) may be more common in
circumcised boys; preputial stenosis (phimosis) affects circumcised and intact
boys with equal frequency. The revision of circumcision for purely cosmetic
reasons should be discouraged on both medical and ethical grounds.
PMID- 9393303
TI - Histological evidence of decreased contralateral testicular blood flow during
ipsilateral testicular torsion.
AB - OBJECTIVE: To evaluate contralateral testicular blood flow by histological
examination of arterioles during ipsilateral testicular torsion. MATERIALS AND
METHODS: The study comprised two groups of 20 male albino rats (weight 250-270
g). The control group underwent a sham operation, while in the second group the
left testes were twisted clockwise by 720 degrees. All rats underwent bilateral
orchidectomy 24 h after the initial intervention. Three slides for each testis (n
= 240) were evaluated randomly while unaware of treatment to determine the total
number of arterioles, the percentage of collapsed and open arterioles, the
diameter of open arterioles and the presence or absence of blood cells in the
lumen. Differences were assessed using t-tests for paired and independent
samples. RESULTS: Very few arterioles were collapsed in both testes of the
control group and in the ipsilateral testes of the torsion group, but half the
arterioles in the contralateral testes of the torsion group were collapsed. The
difference between the contralateral testes of the two groups and between the
ipsilateral and contralateral testes in the torsion group were significant. The
diameter of uncollapsed arterioles did not differ significantly among either
testes of the control and torsion groups and either testes in each group. Both
testes in the torsion group had significantly more arterioles containing blood
cells than those in the control group. The difference between the testes in the
torsion group was also significant, but was not in the control group. CONCLUSION:
There was histological evidence of decreased blood flow in the contralateral
testis during unilateral testicular torsion; contralateral testicular damage
during unilateral testicular torsion may result from hypoxia caused by decreased
blood flow.
PMID- 9393304
TI - The agreement among urological experts on the diagnostic management of patients
with common urological problems.
AB - OBJECTIVE: To assess the level of agreement among randomly selected international
urologists on the diagnostic management of patients with prostate cancer, bladder
cancer, urinary stones or lower urinary tract symptoms (LUTS) arising from benign
prostatic hyperplasia (BPH). METHODS: A computer program was used to provide an
unbiased format of 53 simulated patients, comprising 13 with prostate cancer, 10
with bladder cancer, 10 with stones in the upper urinary tract and 20 with LUTS
from BPH. For each case, the history was provided to the user while information
from 60 diagnostic tests could be chosen interactively. Thirty-three university
based urologists participated in the study. The probability that a certain test
was used by them in a certain patient [P(test)] and the related costs (Swedish
1995 prices) were recorded. The probability that two urologists would agree
(relative measure of agreement, RMA) on whether or not to use one particular test
in a certain case was RMA(test) = P(test)2 + [1-P(test)]2 and the mean of this
RMA(test) for a certain patient [RMA(case)] was used as a measure of the inter
individual agreement among the urologists on the diagnostic management. The
significance levels of the generalized kappa statistic, KG, were also calculated.
The correlation between the RMA(case) and the diagnostic groups was analysed.
RESULTS: The KG was statistically significant for all cases; the RMA(case) was
significantly correlated with the diagnostic groups (rs = 0.86). The agreement in
the diagnostic management was the strongest for stones, then for bladder cancer
and prostate cancer, and the weakest for BPH. The mean cost for the diagnostic
evaluation for one case varied from $455 to $1771 (mean 898) and varied in the
diagnostic groups, i.e. $1718 for prostate cancer, $947 for bladder cancer, $400
for stones and $594 for BPH. CONCLUSION: The diagnostic management of urological
patients varies greatly among urological experts from the industrial world. As a
consequence, the related diagnostic costs might vary by about 400% if prices were
similar everywhere. The agreement on the diagnostic management of cases is
strongly correlated to the diagnosis. LUTS from BPH seems to be managed with the
poorest agreement.
PMID- 9393305
TI - The natural history of pelvi-ureteric junction obstruction in children presenting
clinically with the complaint.
AB - OBJECTIVE: To determine the natural history of untreated pelvi-ureteric junction
(PUJ) obstruction in children presenting clinically with the complaint. PATIENTS
AND METHODS: The study comprised 42 children with anatomical PUJ obstruction
(three with bilateral lesions) who were managed expectantly in the first
instance, who had no immediately troublesome symptoms and differential function
in the affected kidney(s) of > 40%. They were followed by serial ultrasonography
and dynamic diuresis renography. Pyeloplasty was advised for those with
persistent symptoms or where differential renal function fell below 40%. RESULTS:
Only 15 children had presented with clearly relevant symptoms (loin pain or
febrile urinary infection). Thirty-four kidneys showed obstructive renographic
curves initially and 38 had moderate or severe hydronephrosis. During the follow
up (range 14-120 months, mean 56) patients remained asymptomatic except for four
of the nine presenting with loin pain. Renographic curves were apt to change,
with 'obstruction' increasing or decreasing with time, in the latter instance
usually with lessening or resolution of hydronephrosis. Eleven patients underwent
pyeloplasty, five for symptoms and six because of deteriorating renal function.
Renal function did not decline in any patient with mild hydronephrosis and/or a
non-obstructive renographic curve at presentation, but did so disproportionately
in those with severe hydronephrosis or a Type IV renographic curve. CONCLUSIONS:
Patients effectively asymptomatic at presentation are likely to remain so.
Expectant management is appropriate for patients with mild hydronephrosis and/or
non-obstructive renographic curves at the outset. Conversely, pyeloplasty may be
advisable for those with severe hydronephrosis or Type IV renographic curves.
Otherwise, for most the natural history of the complaint remains to be
determined.
PMID- 9393306
TI - Paediatric ureteroscopy for ureteric calculi: a 4-year experience.
AB - OBJECTIVE: To study the efficacy and safety of ureteroscopy in the management of
paediatric ureteric calculi at various levels. PATIENTS AND METHODS: The records
of 50 ureteroscopic procedures performed on 43 children (age range 6 months-12
years) for primary ureteric calculi or ureteric fragments after electrohydraulic
shockwave lithotripsy (EHWL) were analysed retrospectively. The distribution of
the calculi was in nine in the upper upper, seven in the mid and 30 in the lower
ureter, with a mean stone burden of 1.26 cm. Ureteroscopy was performed with the
8.5/9.5/11.5 F Wolf ureteroscopes, and EHL was used as the primary method of
fragmentation. Intravenous urograms were available in 34 children (79%) and
micturating cystography (MCUG) was performed in 23 children (54%) during the
follow-up. RESULTS: An overall stone-free status was achieved in 40 children
(93%) after performing 47 ureteroscopies (94%). Stones were completely cleared in
78%, 100% and 97% of the procedures in the upper, mid and lower ureters,
respectively. In three children the procedure failed and they were salvaged by
uretero-lithotomy. During the procedures, an upper ureteric perforation occurred
in one patient and a lower perforation in another. MCUG revealed low grade vesico
ureteric reflux in 17% of the patients, but close follow-up showed the reflux to
be sterile and clinically insignificant. CONCLUSION: Ureteroscopy was safe and
effective for the management of mid and lower ureteric calculi but the results
for upper ureteric calculi were marginally inferior. Ureteroscopy must be
performed judiciously to minimize ureteric injury in children. The incidence of
vesico-ureteric reflux after mechanical dilatation of the intramural ureter was
infrequent and clinically insignificant.
PMID- 9393307
TI - The use of a multipurpose stent in children.
AB - OBJECTIVES: To assess the use of a multipurpose stent (the 'Blue stent', Angiomed
Urosoft Pyeloplasty Stent, Bard, UK) in children undergoing pyeloplasty and
ureteric reimplantation. PATIENTS AND METHODS: Between August 1994 and August
1996, the Blue stent was used in 50 renal units in 46 children aged 2 months to
12 years and 6 months. Twenty-five children underwent pyeloplasty, 11 had
ureteric reimplantation for vesico-ureteric reflux (VUR), eight had ureteric
reimplantation with remodelling for obstructed megaureters and in two patients it
was used during the removal of stones. The mean follow-up was 18 months (range 6
30 months). RESULTS: After pyeloplasty, 22 patients (88%) had improved renal
function and drainage with a decrease in hydronephrosis; two patients had a
decrease in hydronephrosis only, one had an anastomotic leak and needed a repeat
pyeloplasty and four developed a urinary tract infection (UTI). After ureteric
reimplantation, VUR was not detected in any patient. Two patients had no change
in drainage after remodelling and reimplantation of a megaureter, one was later
diagnosed as having a neuropathic bladder and one child developed a UTI after
ureteric reimplantation. The hospital stay was 3 days after pyeloplasty and 5
days after reimplantation. CONCLUSION: The design of the multipurpose Blue stent
provides versatility; it can be used as a stent, and both an internal and
external drain. Its use does not prolong the hospital stay. Insertion causes
minimal trauma to the renal parenchyma, and removal is easy, pain-free and
requires no anaesthesia. The complication rates in the present series compare
favourably with other reported series.
PMID- 9393308
TI - Evaluation of the utility of video-urodynamics in children with urinary tract
infection and voiding dysfunction.
AB - OBJECTIVE: To assess the use of video-urodynamic studies (VUDS) in children with
urinary tract infection (UTI) and symptoms of voiding dysfunction (frequency,
urgency, incontinence), to ascertain whether VUDS significantly assists in
diagnosis and deciding treatment. PATIENTS AND METHODS: Over a 16-month period,
all children seen at our centre with a UTI in conjunction with previous symptoms
suggestive of voiding dysfunction underwent free and pressure-flow VUDS. Forty
two children underwent VUDS and 38 (mean age 9 years, range 4-16, 15 male, 23
female) had sufficient information to be included in the study. RESULTS: All
children had a prior history of voiding dysfunction (mean 55 months). Only five
patients were found to have reflux and three of these had associated detrusor
instability. In addition, 24 of 33 patients who did not have reflux had
abnormalities on urodynamic study, the most common problem being detrusor
instability in 17 of 24 patients. Other abnormalities included sphincter
dyssynergia (five patients), poor bladder compliance (two) and hypersensitivity
on bladder filling (three). CONCLUSION: VUDS can provide information about the
aetiology of UTI and voiding dysfunction in children that cannot be obtained from
any other source. The results of VUDS can be used to select specific treatments,
to avoid inappropriate therapy and to identify children who may benefit from
follow-up studies despite normal findings on voiding cystourethrography. From
these results, we believe that VUDS should be considered for children with UTI
and voiding dysfunction.
PMID- 9393309
TI - A possible explanation of wet and dry nights in enuretic children.
AB - OBJECTIVE: To clarify the relationship between nocturnal urine production and the
occurrence of both wet and dry nights in patients with nocturnal enuresis and to
estimate the effect on nocturnal urine production of treatment with the
antidiuretic hormone desmopressin in a group of enuretics with none or only a
partial reduction in the number of wet nights in response to desmopressin
treatment. PATIENTS AND METHODS: The nocturnal urine production of 60 children
with monosymptomatic nocturnal enuresis was measured for 14 nights with no
treatment (baseline) and for 14 nights with desmopressin treatment. Sixteen
children having both wet and dry nights in the two periods were chosen for the
subsequent analysis. RESULTS: There was significantly less nocturnal urine
production during desmopressin treatment (202 mL/night) than during the baseline
period (279 mL/night; P < 0.001) and a corresponding decrease in the number of
wet nights, from 10 during baseline to five during desmopressin treatment. When
expressed as mL/kg body weight per hour, the urine production during baseline was
0.89 on wet and 0.625 on dry nights (P < 0.001), and during desmopressin
treatment was 0.716 and 0.535, respectively (P < 0.01). CONCLUSION: In this group
of enuretics there was a clear reduction in the number of wet nights and in
nocturnal urine production during desmopressin treatment, even though none became
totally dry on desmopressin. There was a markedly higher nocturnal urine
production on wet nights during both the baseline period and during desmopressin
treatment. The higher urine production on wet nights could explain the enuretic
episode, with urine production exceeding bladder capacity.
PMID- 9393310
TI - Surgery for cavoatrial extension of renal malignant tumours using a veno-venous
shunt.
PMID- 9393311
TI - Autoaugmentation in the paediatric neurogenic bladder: report of a method.
PMID- 9393312
TI - Ureteroscopic salvage of a uretero-vaginal fistula.
PMID- 9393313
TI - Neonatal bladder rupture due to anterior urethral valves.
PMID- 9393314
TI - Ectopic labium in a newborn: a successful surgical transposition treatment.
PMID- 9393315
TI - Glomus tumour of the testicle.
PMID- 9393316
TI - Urodynamic evaluation of profound microcephaly in children.
PMID- 9393317
TI - Caval leiomyosarcoma.
PMID- 9393318
TI - Massive splenomegaly complicating left percutaneous renal surgery.
PMID- 9393319
TI - Cardiac metastases from a transitional cell carcinoma: an unusual clinical
manifestation.
PMID- 9393320
TI - Extragonadal germ cell tumour involving the urinary bladder.
PMID- 9393321
TI - Uretero-uterine fistula as a complication of caesarean section: successful
ureteroscopic management.
PMID- 9393322
TI - Comparison of real-time ultrasonography and magnetic resonance imaging in the
assessment of urinary bladder volume.
PMID- 9393323
TI - Fantasies and facts of testes.
PMID- 9393324
TI - Congenital fistula of the penile urethra.
PMID- 9393325
TI - British urological surgery practice: prostate cancer.
PMID- 9393326
TI - A modified in vitro technique to evaluate human detrusor muscle.
PMID- 9393327
TI - Urinary drainage systems to prevent intraluminal spread of bacteria.
PMID- 9393328
TI - A standard protocol for the evaluation of laser treatment of the prostate. ICS
'BPH' Study Group.
PMID- 9393329
TI - Assessing the odds.
PMID- 9393330
TI - Still more questions on pertussis vaccines.
PMID- 9393331
TI - New therapies for severe meningococcal disease but better outcomes?
PMID- 9393332
TI - Balanced view of risks of oral contraceptives.
PMID- 9393333
TI - Ultrasonography vs cystourethrography to exclude vesicoureteric reflux in babies.
PMID- 9393334
TI - Risks and prevention of Dupuytren's contracture.
PMID- 9393335
TI - Randomised controlled trial of two-component, three-component, and five-component
acellular pertussis vaccines compared with whole-cell pertussis vaccine. Ad Hoc
Group for the Study of Pertussis Vaccines.
AB - BACKGROUND: Trials in Italy and Sweden showed high efficacy for three-component
and five-component pertussis vaccines, and poor efficacy for a whole-cell vaccine
licensed in the USA and a two-component vaccine. We compared the efficacy of
three acellular vaccines with a UK whole-cell vaccine. METHODS: We enrolled
82,892 babies aged 2-3 months. Babies were vaccinated at age 3 months, 5 months,
and 12 months, or age 2 months, 4 months, and 6 months. They were randomly
assigned a two-component acellular diphtheria-tetanus-pertussis (DTP) vaccine (n
= 20,697), a three-component acellular DTP vaccine (n = 20,728), a five-component
acellular DTP vaccine (n = 20,747), or a UK whole-cell DTP vaccine (n = 20,720).
We collected data for all reported cases of culture-confirmed pertussis during 3
years of follow-up. The treatment status of the two-component-vaccine group had
to be made known midway through the trial for boosting because of poor efficacy.
We included data for the two-component vaccine in the analysis of safety and
immunogenicity, and data up its unmasking in secondary analyses of relative
efficacy. Analyses were by intention to treat. FINDINGS: During follow-up from
the third dose (mean 22 months), in the 3 months, 5 months, 12 months schedule,
there were 15 cases of culture-confirmed pertussis with at least 21 days of
paroxysmal cough in the whole-cell group, relative risk 1.00, compared with 13 in
the five-component group (0.85 [95% CI 0.41-1.79]), and 21 in the three-component
group (1.38 [0.71-2.69]). For culture-confirmed pertussis, with or without cough,
there were 19 cases in the whole-cell group (1.00). 27 in the five-component
group (1.40 [0.78-2.52]), and 49 in the three-component group (2.55 [1.50-4.33]).
In the intention-to-treat analyses, from the first dose in the 3 months, 5
months, 12 months schedule the whole-cell vaccine was significantly more
protective than the three-component vaccine against typical pertussis. Between
the second and the third doses, culture-confirmed pertussis with any cough and
with at least 21 days of paroxysmal cough was significantly more frequent in the
two-component group than in the three-component group, and in the three-component
group than in the five-component and the whole-cell groups, respectively. The
serological response of the acellular vaccines in the 2 months, 4 months, 6
months schedule were similar to those previously reported. The whole-cell vaccine
was highly immunogenic for fimbriae, pertactin, and filamentous haemagglutinin,
but had a low antipertussis toxin response. Hypotonic hyporesponsiveness occurred
significantly more frequently in the whole-cell group (p < 0.05) and was more
frequent in the acellular groups than previously reported. High fever and
seizures occurred more frequently after whole-cell vaccine than after any of the
acellular vaccines (p < 0.001). INTERPRETATIONS: The efficacy of the UK whole
cell vaccine and the five-component and three-component vaccines was similar
against culture-confirmed pertussis with at least 21 days of paroxysmal cough.
The lower efficacy of the three-component vaccine against mild disease suggests
that fimbriae have a role in protection against infection. The efficacy of
acellular vaccines depends on the number of components, and different whole-cell
vaccines have variable efficacies.
PMID- 9393336
TI - Lay diagnosis and health-care-seeking behaviour for chest pain in south Asians
and Europeans.
AB - BACKGROUND: South Asian people in the UK experience greater delays than Europeans
in obtaining appropriate specialist management for heart disease, but the causes
are not known. We investigated whether south Asians and Europeans interpret and
act upon anginal symptoms differently. METHODS: We randomly selected 2000 people
from general practitioners' (family physicians) lists in London, UK, to receive a
questionnaire that included a short fictional case history of an individual with
possible anginal pain and asked how respondents would react to experiencing it. A
second questionnaire seeking information on medical history, attitudes to health,
and demography was sent later. The main outcome measure was the proportion who
said they would seek immediate care (hospital emergency department or general
practitioner) for the pain described in the case scenario. FINDINGS: The rate of
response to both questionnaires was 60.2% (903 of 1500 who received both), 553
responders were of European origin, 124 were Hindu, and 235 were Sikh. There were
no differences between the ethnic groups in the proportion identifying the pain
as cardiac, but south Asians would be more anxious about the pain than would
Europeans. Of the men, 55 (23%) Europeans, 20 (38%) Hindus, and 52 (47%) Sikhs
said they would seek immediate care (p < 0.0001 for heterogeneity); of women, 77
(24%), 25 (35%), and 58 (46%), respectively, would seek immediate care (p <
0.0001). After adjustment for confounding variables the odds ratio for seeking
immediate care in Hindus compared with Europeans was 2.67 (95% CI 1.49-4.73) and
that for Sikhs compared with Europeans was 3.18 (1.98-5.12). INTERPRETATION:
Hindus and Sikhs reported a greater likelihood of seeking immediate care for
anginal symptoms than Europeans; this finding indicates that barriers to
cardiology services for south Asians are unrelated to difficulties in
interpretations of symptoms or willingness to seek care. Improvement of awareness
of heart disease may not decrease delays in obtaining care. Service-related
explanations must be explored, such as general practitioners' difficulties in
arriving at a diagnosis or differences in management because of ethnic origin.
PMID- 9393337
TI - Origins of health inequalities in a national population sample.
AB - BACKGROUND: Explanations for social inequalities in health are often explored but
remain largely unresolved. To elucidate the origins of health inequalties, we
investigated the extent to which adult-disease risk factors vary systematically
according to social position over three decades of early life. METHODS: We used
the 1958 birth cohort (all children born in England, Scotland, and Wales on March
3-9, 1958) with data up to age 33 years from parents, teachers, doctors, and
cohort members (n = 11,407 for age 33 interview). FINDINGS: Social class of
origin was associated with physical risk factors (birthweight, height, and adult
body-mass index); economic circumstances, including household overcrowding, basic
amenities, and low income; health behaviour of parents (breastfeeding and
smoking) and of participants (smoking and diet); social and family functioning
and structure, such as divorce or separation of participants or their parents,
emotional adjustment in adolescence, social support in early adulthood; and
educational achievement and working career, in particular no qualifications,
unemployment, job strain, and insecurity. With few exceptions, there were strong
significant trends of increasing risk from classes I and II to classes IV and V.
Self-perceived health status and symptoms were worse in participants with lower
class origins. INTERPRETATION: An individual's chance of encountering multiple
adverse health risks throughout life is influenced powerfully by social position.
Social trends in adult-disease risk factors do not emerge exclusively in mid
life, but accumulate over decades. Investment in educational and emotional
development is needed in all social groups to strengthen prevention strategies
relating to health behaviour, work-place environment, and income inequality.
PMID- 9393338
TI - Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus
induced purpura fulminans.
AB - BACKGROUND: Inflammatory and coagulation processes are both affected in
meningococcaemia. Severe acquired protein-C deficiency in meningococcaemia is
usually associated with substantial mortality: in survivors, skin grafts,
amputation, and end-organ failure are not uncommon. Protein C is a natural
anticoagulant and also has important anti-inflammatory activity. We assessed the
effects of early replacement therapy with protein-C concentrate together with
continuous veno-venous haemodiafiltration and conventional treatment in
meningococcaemia. METHODS: 12 patients aged between 3 months and 27 years with
meningococcaemia and severe acquired protein-C deficiency (mean 0.20 IU/mL) were
studied. All patients had septic shock, widespread purpura, skin necrosis, and
disseminated intravascular coagulopathy. After a test dose of protein-C
concentrate, patients received a continuous infusion with the dose adjusted daily
to keep the plasma concentration between 0.8 and 1.2 IU/mL. 11 patients were
given unfractionated intravenous heparin (10-15 IU kg-1 h-1). Nine patients had
haemodiafiltration and one had peritoneal dialysis. The Glasgow meningococcal
septicaemia prognostic score and the paediatric risk of mortality score predicted
a minimum mortality of 80% and 57%, respectively. FINDINGS: No patient died. No
adverse reactions to the treatment were seen. Two patients had lower-limb
amputations, one of whom had a thrombotic cerebrovascular accident; both patients
had received the protein-C concentrate and heparin later than the rest of the
group (60 h [16.97] vs 12 h [3.13]). One patient developed chronic renal failure
despite receiving protein-C infusion 15 h after admission. INTERPRETATION: The
acquired severe deficiency of protein C in meningococcaemia contributes to the
pathogenesis of the thrombotic necrotic lesions in the skin and other organs and
probably has an important role in the inflammatory response. Protein-C therapy is
merely one approach to improve the host response in this syndrome. We suggest
that a double-blind, randomised, controlled multicentre trial is needed to
confirm our results.
PMID- 9393339
TI - An infant with encephalitis.
PMID- 9393340
TI - Early computed-tomography abnormalities in acute stroke.
PMID- 9393341
TI - Benign symmetric lipomatosis associated with protease inhibitors.
PMID- 9393342
TI - Spontaneous neutralising antibodies to interferon--alpha and interleukin-12 in
thymoma-associated autoimmune disease.
PMID- 9393343
TI - El Nino and diarrhoea and dehydration in Lima, Peru.
PMID- 9393344
TI - Melatonin in feverfew and other medicinal plants.
PMID- 9393345
TI - Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma.
PMID- 9393346
TI - Decreased circulating adrenomedullin in pre-eclampsia.
PMID- 9393347
TI - Constrictive pericarditis after high-dose chemotherapy.
PMID- 9393348
TI - Compatibility of insulin pens and cartridges.
PMID- 9393349
TI - Bartonella-like erythrocyte inclusions in thrombotic thrombocytopenic purpura.
PMID- 9393350
TI - World Bank oil-pipeline project designed to prevent HIV transmission.
PMID- 9393351
TI - AIDS cost takes its toll in Canada.
PMID- 9393352
TI - Jet-lag.
PMID- 9393353
TI - What is required of an HIV vaccine?
AB - Mounting evidence suggests that the early dissemination of HIV in human beings
evokes an immune response that is responsible for containment of the infection
during the long symptom-free period. Loss of this immune control coincides with a
final escalation of the viraemia and the terminal failure of the immune system.
Other studies imply that pre-emptive vaccination of monkeys with attenuated forms
of simian immunodeficiency virus (SIV) produces a substantial degree of
resistance to superinfection with fully virulent viruses. Here we consider how
observations from natural and experimental systems might influence thought as to
what is required to produce safe induced immunity against HIV. We concentrate on
three questions: what is the nature of the immune response that contains the
infection? How does this response fail? How could a vaccine enhance protective
immunity so that it exceeds the efficacy of this natural response?
PMID- 9393354
TI - Literature in the education of the doctor.
PMID- 9393355
TI - Malarone-donation programme in Africa.
PMID- 9393356
TI - Imperial Cancer Research Fund and the Lancet.
PMID- 9393357
TI - Imperial Cancer Research Fund and the Lancet.
PMID- 9393358
TI - Imperial Cancer Research Fund and the Lancet.
PMID- 9393359
TI - Hormone replacement therapy and breast cancer.
PMID- 9393360
TI - Hormone replacement therapy and breast cancer.
PMID- 9393361
TI - Malarone-donation programme.
PMID- 9393362
TI - Fetal nuchal translucency test for Down's syndrome.
PMID- 9393363
TI - Fetal nuchal translucency test for Down's syndrome.
PMID- 9393364
TI - Fetal nuchal translucency test for Down's syndrome.
PMID- 9393365
TI - Fetal nuchal translucency test for Down's syndrome.
PMID- 9393366
TI - Fetal nuchal translucency test for Down's syndrome.
PMID- 9393367
TI - Treatment of hypertension in elderly patients.
PMID- 9393368
TI - Treatment of hypertension in elderly patients.
PMID- 9393369
TI - Treatment of hypertension in elderly patients.
PMID- 9393370
TI - Obesity.
PMID- 9393371
TI - Acts of violence against Rwandan refugees.
PMID- 9393372
TI - Illegal drug use and HIV-1 infection in Columbia.
PMID- 9393373
TI - Quality of drug advertisements in medical journals.
PMID- 9393374
TI - How reliable is peer review? An examination of operating grant proposals
simultaneously submitted to two similar peer review systems.
AB - To determine level of agreement and correlation between two similar but separate
peer review systems, proposals simultaneously submitted during the same funding
year to two agencies using the same scoring system were identified and analyzed
(n = 248). There was a direct linear relationship between the scores of the two
agencies (r = 0.592, p < 0.001). Raw agreement within whole-digit ranges was
moderate (53%) but a Cohen's kappa indicated that agreement beyond chance was
only fair (kappa = 0.29, 95% CI = 0.198, 0.382). When proposals were arbitrarily
categorized as being "clearly fundable" (on a 0-5 scale, score > or = 3.0) or
"not clearly fundable" (score < 3.0), raw agreement was 73% and agreement beyond
chance was moderate (kappa = 0.444, 95% CI = 0.382, 0.552). In cases where there
was inter-agency disagreement on the fundability of the project, the difference
in scores was greater than in those in which there was agreement. In a subsample
of 128 pairs, variables describing the application and the applicant (i.e.,
principal investigator) were coded, but none explained inter-agency agreement on
the "fundability" of proposals.
PMID- 9393375
TI - Asymptomatic microscopic hematuria--is investigation necessary?
AB - Microscopic hematuria is common in asymptomatic adults, but the benefit of
screening the general population for blood in the urine has not been established.
On the other hand, most studies of referred patients with putatively asymptomatic
microscopic hematuria have reported a 2-11% prevalence of urothelial
malignancies, leading to the recommendation that all patients with microscopic
hematuria be thoroughly investigated. Urinalysis is inexpensive and highly
acceptable to the general population, but is neither a sensitive, nor specific
test, and has poor predictive value for urothelial malignancies, and
nephrological diseases. Furthermore the benefits of early detection of such
diseases has not been established. We conclude that screening urinalysis cannot
be recommended. Studies are needed to determine which constellation of findings
primary physicians use to select patients for referral to centers with urological
and nephrological expertise.
PMID- 9393376
TI - Problems in defining cutoff points of continuous prognostic factors: example of
tumor thickness in primary cutaneous melanoma.
AB - Continuous prognostic factors are often categorized by defining optimized cutoff
points. One component of criticism of this approach is the problem of multiple
testing that leads to an overestimation of the true prognostic impact of the
variable. The present study focuses on another crucial point by investigating the
dependence of optimized cutoff points on the observed distribution of the
continuous variable. The continuous variable investigated was the vertical tumor
thickness according to Breslow, which is known to be the most important
prognostic factor in primary melanoma. Based on the data of 5093 patients,
stratified random samples were drawn out of six artificially created
distributions of tumor thickness. For each of these samples, Cox models were
calculated to explore optimized cutoff points for tumor thickness together with
other prognostic variables. The optimized cutoff points for tumour thickness
varied considerably with the underlying distribution. Even in samples from the
same distribution, the range of cutoff points was amazingly broad and, for some
of the distributions, covered the whole region of possible values. The results of
the present study demonstrate that optimized cutoff points are extremely data
dependent and vary notably even if prerequisites are constant. Therefore, if the
classification of a continuous prognostic factor is necessary, it should not be
based on the results of one single study, but on consensus discussions including
the findings of several investigations.
PMID- 9393377
TI - Comparing dichotomous screening tests when individuals negative on both tests are
not verified.
AB - Two dichotomous screening tests are often compared by performing both tests in a
sampled population, and submitting positive results on either test to
verification by the reference standard. Unbiased estimates of the true positive
and false positive rates of each test cannot be estimated directly. However,
unbiased estimates of the relative true positive and relative false positive
rates may be obtained. When one test has a higher true positive rate at the
expense of a higher false positive rate, the trade-off is represented by the
ratio of extra false positives detected to extra true positives detected. A 95%
confidence interval for this ratio is derived. This ratio is prevalence dependent
and only applies to the sampled population. For target populations of different
prevalence, estimates of the ratio may be obtained if one of the following
applies: (i) the test characteristics of one test are known; (ii) the relative
prevalence is known; and (iii) certain assumptions are made.
PMID- 9393378
TI - A logistic regression model when some events precede treatment: the effect of
thrombolytic therapy for acute myocardial infarction on the risk of cardiac
arrest.
AB - When outcomes occur in clinical trials before treatment can be given, neither
intent-to-treat nor according-to-protocol analyses give optimal estimates of the
treatment effect. A better approach employs a time-dependent variable for
treatment. Intent-to-treat analyses are conservative, biasing against treatment;
according-to-protocol analyses bias in favor of treatment. We show how to measure
the effect of a time-dependent variable in a logistic regression using person
time intervals as units of measurement and describe appropriate methods for
reporting model performance. The method is applied to develop a model to predict
the probability that a patient with a myocardial infarction will have a sudden
cardiac arrest within 48 hours of presentation to emergency medical services both
when treated with thrombolysis and when not treated. We use a time-dependent
treatment variable because many patients went into cardiac arrest while awaiting
treatment. This technique has been programmed into an electrocardiograph for real
time use in an emergency department.
PMID- 9393379
TI - Predicting outcomes in HIV-infected veterans: I. Progression to AIDS.
AB - This article and the following article (Parts I and II) report the development of
two clinical staging systems for HIV-infected individuals. The objective of the
research reported here (Part I) was to construct a clinical staging system to
predict progression to AIDS. We analyzed data from VA Cooperative Study Number
298, a multicenter, double-blind, randomized trial that compared immediate versus
deferred zidovudine therapy in 338 HIV-infected individuals who did not have AIDS
at enrollment. Baseline variables were tested in univariate Cox regression for
their relationship to progression to AIDS, and those that appeared predictive
were examined in multivariable analysis. Based on these analyses, we constructed
a new clinical staging system based on CD4+ cell count, age, hemoglobin, oral
hairy leukoplakia or oral thrush, and fever. The stages of the system were
significant predictors of progression to AIDS (p = 0.0001, log-rank test). In
conclusion, simple, valid, clinical staging systems for HIV-infected patients can
be constructed using information that is readily available in clinical practice
settings. Such systems provide better prognostic distinction than CD4+ cell count
alone by taking into account the known prognostic effects of other variables.
PMID- 9393380
TI - Predicting outcomes in HIV-infected veterans: II. Survival after AIDS.
AB - This article (Part II) and the preceding article (Part I) report the development
of two clinical staging systems for HIV-infected individuals. The objective of
the research reported here (Part II) was to construct a clinical staging system
to predict survival in patients with AIDS. We analyzed data from VA Cooperative
Study Number 298, a multicenter, double-blind, randomized trial that compared
immediate versus deferred zidovudine therapy in HIV-infected individuals.
Baseline variables obtained at the onset of AIDS in 204 individuals were tested
in univariate Cox regression for their relationship to survival, and those that
appeared predictive were examined in multivariable analysis. Based on these
analyses, we constructed a new AIDS Clinical Staging System. The system is based
on age, CD4+ cell count, type of first AIDS-defining condition, and functional
status. The stages of the system were significant predictors of survival (p =
0.0001, log-rank test). In conclusion, valid, simple clinical staging systems for
patients with AIDS can be developed based on a few variables that are readily
available in clinical settings.
PMID- 9393381
TI - The effect of estrogen replacement therapy on cognitive function in women: a
critical review of the literature.
AB - OBJECTIVE: To conduct a review of the available clinical trials to determine
whether sufficient evidence exists to support the conclusion that estrogen
replacement therapy has a beneficial effect on cognitive performance in post
menopausal women and in women with Alzheimer's disease. Studies were identified
through a MEDLINE search of all English-language publications between 1970 and
1996 in which the words estrogen and cognition or estrogen and memory appeared.
DATA EXTRACTION: Data were extracted for each study, including features of
subjects and eligibility criteria, duration of follow-up, and treatment regimen.
Baseline characteristics were evaluated, including age; menopausal status;
follicle-stimulating hormone, luteinizing hormone, and estradiol levels; mood;
and measures of cognitive function. Psychological tests were evaluated for
construct validity. RESULTS: Nineteen studies were reviewed, including 10
randomized trials of estrogen replacement therapy versus placebo. Extreme
heterogeneity among subjects and variability in the use of cognitive measures
across the studies precluded performing a quantitative summary. Of the 10
randomized trials, eight claimed therapeutic benefits for estrogen therapy, three
of which reported significant improvements in memory and two of which showed
improvements in attention. These studies did not control for potential confounds
such as depression and vasomotor symptoms. Of the nine observational studies,
five found a significant association between estrogen use and cognitive function.
CONCLUSION: Although several observational studies provide encouraging evidence
for the beneficial effect of estrogen on cognitive function, there is currently
inadequate evidence available from randomized, controlled trials to support the
conclusion that estrogen replacement therapy improves cognitive function in post
menopausal women or women with Alzheimer's dementia.
PMID- 9393382
TI - Use of physician services among family caregivers of elderly persons with
dementia.
AB - It is well known that there is an excess of physical and psychological health
problems among family caregivers of elderly persons with Alzheimer's disease and
other dementias. The objective of this study was to determine whether the higher
level of morbidity translates into a higher level of medical care utilization.
Data from a previously completed longitudinal study of caregivers for elderly
persons with dementia were merged with data on physician visits obtained from the
computerized records of the Quebec Health Insurance Board. Utilization of
physician care (adjusted for age, sex, number of chronic diseases, and
depression) was no higher for family caregivers of elderly patients with
Alzheimer's disease and other dementias than for comparable family members of
older persons without dementia. The annual cost of physician care was almost
identical among caregivers and noncaregivers. However, the pattern of utilization
for the two groups was somewhat different: there was a significantly higher
frequency of physician utilization among caregivers for services billed by
psychiatrists and internal medicine specialists. In multivariate analysis,
physician utilization was significantly associated with having more than one
chronic condition and with increased age. Future studies should focus on
determining whether caregivers neglect their own health care needs as a result of
the exigencies of the caregiving role.
PMID- 9393384
TI - Interpretation and bias in case-crossover studies.
AB - The case-crossover design is an innovative epidemiologic technique with distinct
strengths and limitations. We review the fundamental logic of this self-matching
non-randomized design and direct attention to 15 concerns related to the
available data, unavailable data, analytic technique, quantitative statistics,
and etiologic model. Implications for each concern are discussed in the context
of a recent report on whether cellular telephone calls are associated with an
increased risk of a motor vehicle collision. We suggest that an understanding of
the case-crossover design may help investigators explore selected questions in
behavioral medical research.
PMID- 9393383
TI - Statistical evaluation of the role of Helicobacter pylori in stress gastritis:
applications of splines and bootstrapping to the logistic model.
AB - Stress gastritis is a serious problem in the intensive care unit population. The
recent discovery of the causal nature of Helicobacter pylori (H. pylori) in the
development of gastric ulcers led us to examine its relationship with stress
gastritis. We investigated this relationship in 874 veterans admitted to
intensive care units who were tested for the presence of H. pylori and followed
for 6 weeks for the development of stress gastritis. We fit spline models to
assess functional relationships and used the logistic model to determine the
association between H. pylori and stress gastritis. The predictive ability of the
model was assessed with receiver operating characteristic (ROC) curve analysis
and validated with the bootstrapping technique. Increased anti-H. pylori
immunoglobulin A concentrations were found to be an important predictor of stress
gastritis independent of other known risk factors.
PMID- 9393385
TI - Ethnicity and conditional breast cancer survival in Hawaii.
AB - The conditional survival experience of 4502 female breast cancer cases diagnosed
in Hawaii between 1960 and 1983 was studied. The calculation of conditional
survival is based on patients who have already survived for a specified time
period. Cox proportional hazards models were used to examine the effect of
ethnicity, stage at diagnosis, and menopausal, marital, and socioeconomic
statuses on conditional survival prognosis. Native Hawaiian and Filipino women
showed a significantly higher risk of dying from breast cancer than any other
ethnic group, followed by Chinese and Caucasian women, while Japanese women had
the lowest risk. The ethnic pattern of breast cancer survival changed and ethnic
survival differences decreased from 17 to 4% as time progressed. Conditional
survival varied greatly with stage at first diagnosis. For localized, regional,
and distant disease, the conditional survival rate increased from 92, 71, and 24%
after diagnosis to 95, 85, and 65% 5 years after diagnosis, respectively,
indicating that stage at diagnosis becomes less important in determining survival
as time progresses. Being married and of a high socioeconomic status increased
survival probability. These results suggest that considering time effect, the
conditional survival rate is an informative tool to assess clinical outcome of
breast cancer among ethnic groups over a long follow-up period.
PMID- 9393386
TI - Antibiotic noncompliance and waste in upper respiratory infections and acute
diarrhea.
AB - A prospective cohort study was conducted to analyze factors associated with
antibiotic noncompliance and waste among patients suffering acute respiratory
infection (ARI) and acute diarrhea (AD). The study took place in four primary
health care clinics in Mexico City, two belonging to the Ministry of Health (MoH)
and two to the Mexican Social Security Institute (IMSS). Two hundred twenty-two
patients with ARI and 155 with AD were included. Data about study variables and
the assessment of compliance were obtained through patient interviews and direct
observation. Factors associated with noncompliance were assessed through a
multiple logistic regression procedure. Noncompliance was 60% for ARI and 55.5%
for AD in both health care systems. Prescription of an antibiotic was justified
only in 13.5% of cases. Associated factors were: increased duration of illness
(OR 2.95; 95% CI, 1.17-7.41); complexity of the treatment: 3 or more doses per
day (OR 2.47; 95% CI, 1.56-3.92), and treatment for more than 7 days (OR 1.94;
95% CI, 1.16-3.26); younger age of patient (OR 1.89; 95% CI, 1.18-3.02); and an
inadequate physician-patient relationship (OR 1.87; 95% CI, 1.16-3.02).
Antibiotic waste was higher in IMSS (ARI 39.3%, AD 32.6%), than in the MoH (ARI
21.2%, AD 16.4%). Educational strategies to modify physician prescribing
practices and strengthen physician-patient relationships might improve compliance
and decrease drug waste.
PMID- 9393387
TI - Quantification and the quest for medical certainty.
PMID- 9393388
TI - Neural networks and logistic regression: analysis of a case-control study on
myocardial infarction.
PMID- 9393389
TI - Obsessive-compulsive disorder: the hidden epidemic.
PMID- 9393390
TI - Epidemiology of obsessive-compulsive disorder: a world view.
AB - The worldwide prevalence of obsessive-compulsive disorder (OCD) is approximately
2% of the general population. Symptoms of OCD include fear of contamination by
dirt or germs; constant checking; repetitive, intrusive thoughts of a somatic,
aggressive, or sexual nature; extreme slowness; and an inordinate concern with
orderliness and symmetry. Differential diagnosis is sometimes complicated by the
overlap between OCD and obsessive-compulsive personality disorder (OCPD). The
most common complication of OCD is depression. However, while both serotonergic
and nonserotonergic antidepressants are effective in treating patients with
depression, only serotonergic medications are effective in treating OCD patients.
Because OCD patients often attempt to conceal their symptoms, it is incumbent on
clinicians to screen for OCD in every mental status examination, since
appropriate treatment can often result in improved quality of life.
PMID- 9393391
TI - Update on pharmacologic management of OCD: agents and augmentation.
AB - A preponderance of patients with obsessive-compulsive disorder (OCD) experience
little or no improvement in their symptoms when treated with serotonin reuptake
inhibitors (SRIs). It is hypothesized that SRI-refractory patients may have
altered serotonin neurotransmission different from patients responsive to SRIs,
or that they may have abnormalities in their dopamine function. When drugs
affecting serotonin function (e.g., tryptophan, fenfluramine, lithium, buspirone)
are added to SRI therapy in SRI-refractory patients, results are mixed and not
consistently encouraging. However, when drugs affecting dopamine function (e.g.,
pimozide, haloperidol, risperidone) are added to SRI therapy in SRI-refractory
OCD patients, individuals with either a personal history or family history of
tics experience a reduction in their symptoms.
PMID- 9393392
TI - Pharmacologic treatment of obsessive-compulsive disorder: comparative studies.
AB - The predominant hypothesis about obsessive-compulsive disorder (OCD)
pathophysiology implicates abnormal serotonergic function regulation.
Pharmacologic agents with potent serotonin reuptake-inhibiting properties have
demonstrated effectiveness in treating OCD. In short-term clinical trials
compared by meta-analysis, clomipramine and serotonin selective reuptake
inhibitors (SSRIs) were found superior to placebo in improving symptoms of OCD.
In one-to-one comparative studies, clomipramine has been found as efficacious as
fluoxetine and fluvoxamine, and in a comparative trial of clomipramine with
sertraline, there was a statistically superior response to sertraline after 16
weeks of treatment; moreover, discontinuation rate in patients taking
clomipramine was more than twice that in patients taking sertraline (26% vs.
11%). In contrast to patients receiving clomipramine who showed poor tolerance in
long-term use, patients maintained on fluoxetine for 24 weeks after an acute
phase well tolerated the medication. In another study, patients responding to 12
weeks of sertraline treatment also showed improved tolerance during an additional
40-week period, with 75% completing the continuation phase. With long-term or
even lifelong treatment appearing necessary for people with OCD, those agents
that result in better tolerance will prove preferable.
PMID- 9393394
TI - Implantology 1997--do we have all the answers?
PMID- 9393393
TI - An interactive computer-administered self-assessment and self-help program for
behavior therapy.
AB - Behavior therapy for obsessive-compulsive disorder (OCD) is extremely effective
and usually conveys lasting benefits. Unfortunately, behavior therapy is not
widely available and is usually quite costly in the few settings where it can be
obtained. The essential features of effective behavior therapy are identifying
triggers of obsessions, rituals, and discomfort; designing personalized exposure
and ritual prevention (E & RP) goals; and encouraging and monitoring E & RP
sessions of sufficient frequency and duration for habituation to occur. A
computer program (BT STEPS) was designed to assist OCD sufferers in carrying out
self-assessment and self-help behavior therapy. The program has nine clinical
steps, 12 computer-controlled interactive voice response (IVR) telephone calls
(some used repeatedly), and more than 1000 digitized voice files that depend on
the progress that patients report during calls. BT STEPS has been studied in two
trials at three sites with a total of 65 patients. In both trials, patients who
experienced behavior therapy had substantial reductions in OCD severity as
assessed by the Yale-Brown Obsessive Compulsive Scale. Approximately two thirds
of those who participated in two or more E & RP sessions were much or very much
improved. Patients liked using the program, and 71% thought their lives improved
as a result. BT STEPS makes behavior therapy for OCD patients potentially
available to anyone with a touch-tone telephone. It is intended for use under the
supervision of a clinician and can be used in conjunction with pharmacotherapy.
PMID- 9393395
TI - Breathing patterns and levels of consciousness in children during administration
of nitrous oxide after oral midazolam premedication.
AB - PURPOSE: The combination of midazolam and nitrous oxide is commonly used to
achieve sedation and analgesia during pediatric oral procedures, yet there are
few, if any, data that illustrate the ventilatory effects of N2O in children,
especially when used in combination with additional central nervous system (CNS)
depressants. It was hypothesized that the addition of N2O inhalation to oral
midazolam premedication would enhance the sedative effects of the midazolam and
add analgesia without causing significant respiratory depression. The purpose of
this study was to test this hypothesis. MATERIALS AND METHODS: Thirty-four
healthy children about to undergo restorative dental treatment under general
anesthesia were premedicated with oral midazolam, 0.7 mg/kg, and were then
exposed to 40% N2O for 15 minutes after a 5-minute control period. The effect of
adding N2O on SpO2, respiratory rate, PETCO2, VT, and VT/TI was examined and the
levels of consciousness (conscious vs deep sedation) before and during N2O
inhalation were determined. RESULTS: During the course of the study, no child
developed hypoxemia (SpO2 < 92%) nor clinically significant upper airway
obstruction. Four children who did not develop hypoventilation (defined as PETCO2
> 45 mm Hg) during the control period did so after initiation of N2O. Overall,
there were no significant differences in SpO2, PETCO2, VT, or VT/TI between the
control and study periods. However, respiratory rates were significantly higher
in the first 10 minutes of N2O inhalation when compared with the control period.
Before starting N2O administration, 14 children were not clinically sedated, 19
children met the criteria for conscious sedation, and one child met the criteria
for deep sedation. At the end of 15 minutes of N2O inhalation, 12 children were
not clinically sedated, 17 children met the definition of conscious sedation,
three were deeply sedated, and one child had no response to IV insertion,
implying a state of general anesthesia. There were no differences in sedation
scores between the control and study periods (P = .6). Overall, seven children
had an increase in their sedation score while breathing N2O, four had a decrease
in their sedation score, and 22 had no change. CONCLUSIONS: The addition of 40%
N2O to oral midazolam, 0.7 mg/kg, did not result in clinically meaningful
respiratory depression nor upper airway obstruction, but did, in some children,
cause an increase in the level of sedation beyond simple conscious sedation.
PMID- 9393396
TI - Recommendations for management of trigeminal nerve defects based on a critical
appraisal of the literature.
AB - PURPOSE: Management of trigeminal nerve injuries continues to challenge oral and
maxillofacial surgeons. The purpose of this review article is to apply the
principles of evidence-based medicine (E-BM) to determine the optimal operative
technique for managing defects involving the inferior alveolar (IAN) or lingual
nerves when direct (ie, primary) repair is not feasible. METHODS: To address the
research purpose, the four steps of the E-BM critical appraisal process were
applied: 1) identify the clinical problem, 2) efficiently search the literature,
3) select relevant articles and apply rules of evidence, and 4) apply the
findings to patient care. Parameters for the literature search included using
Medline to identify English language articles, publication dates from 1986
through 1996, and studies involving human subjects. RESULTS: The studies reviewed
showed that the clinical literature on operative management of trigeminal nerve
injuries is sparse, preoperative and postoperative neurosensory examinations are
poorly documented, and the data are derived completely from reports using case
series methods. Given these limitations, the available literature suggests that
1) tension-free, primary (direct) suture repair of an injured nerve, if possible,
provides optimal results; 2) if direct repair is not possible, autogenous nerve
grafts should be used for acute injuries, for example, immediate nerve repair
after tumor resection or at the time of acute repair after traumatic injury; and
3) if direct repair is not possible, autogenous nerve grafts or hollow conduits
(entubulization) to bridge the defect are equally successful for delayed
reconstruction of gaps of 3 cm or smaller. CONCLUSIONS: Based on the weakness of
the current literature, recommendations for future research include 1) better
standardization and documentation of sensory deficits resulting from nerve
injuries and their recovery, 2) using multicenter studies to accumulate large
samples of patients rapidly, 3) using case series or prospective cohort study
designs to assess the value of operative management of nerve injuries, and 4)
progressing to randomized clinical trials to ascertain the optimal operative
management of nerve injuries.
PMID- 9393397
TI - Diagnosis and management of blunt carotid artery injury in oral and maxillofacial
surgery.
AB - PURPOSE: Traumatic occlusion of the internal carotid artery (ICA) is a rare
complication of maxillofacial trauma or surgery. This investigation evaluated
patient demographics, diagnostic methods, and effective therapeutic modalities
associated with blunt carotid injury (BCI). PATIENTS AND METHODS: This was a
retrospective analysis of patient records with an ICD-9-CM diagnosis of carotid
injury conducted at MetroHealth Medical Center during the 24-month period between
August 1993 and July 1995. Carotid injuries attributable to penetrating trauma
were excluded. Age, gender, cause of injury, Glasgow Coma Scale score, Injury
Severity Score, type and location of injury, concomitant injury, diagnostic
methods, treatment modalities, and outcome were identified, recorded, and
analyzed. RESULTS: During the 24-month period, 12 patients (seven males and five
females) suffered BCI. These patients were divided into two groups based on cause
of the problem. In group I, there were 3,214 blunt trauma patients admitted
during the 2-year study, of which 10 patients had BCI, representing 0.31% of
blunt trauma patients, and 1.2% of patients with head injuries. Seven patients
presented with hemiplegia, two with cranial nerve palsy, and one with perceptual
neglect. Ninety percent of the patients had associated injuries. Two patients had
surgical intervention, three received anticoagulation, and five had only
supportive care. Four of the 10 patients died, four had moderate neurologic
deficits, and two survived with only minor neurologic deficits. In group II, two
patients developed BCI after surgery. A 52-year-old woman had a carotid injury
after right total temporomandibular joint replacement, and a 48-year-old man who
underwent surgical removal of a third molar became hemiplegic postoperatively.
The first patient recovered after anticoagulation, whereas the second patient,
who received only supportive care, has severe neurologic deficits. CONCLUSIONS:
BCI is an uncommon entity. It is usually recognized when a patient develops an
unexplained neurologic deficit, most often hemiplegia, subsequent to trauma or
surgery of the head, face, or neck. In the early stages, the diagnosis can be
missed by carotid ultrasound or computed tomography. The injury is unrelated to
Glasgow Coma Scale score. Symptoms may not develop for days after injury in 50%
of patients. Anticoagulation appears to be the most beneficial therapeutic
modality.
PMID- 9393398
TI - Reconstruction of the severely resorbed maxilla with a combination of sinus
augmentation, onlay bone grafting, and implants.
AB - PURPOSE: A new method of reconstruction of the atrophic maxilla by combining a
bilateral sinus floor elevation and cancellous bone graft with buccal and labial
onlay graft using L-shaped corticocancellous blocks from the posterior iliac
crest is presented. PATIENTS AND METHODS: Seventeen patients were treated with
this procedure. One hundred one IMZ implants were placed in 14 patients, and 22
Branemark implants were placed in three patients. Patients were observed for 6
months after prosthetic rehabilitation. RESULTS: All patients were fully
rehabilitated with fixed bridges except one, who preferred an overdenture. Only
two implants were lost at the time of the abutment connection. Some bone
resorption was seen around six implants. The success rate with this procedure was
92.7% 6 months after prosthetic rehabilitation if implants with bone resorption
were considered failures. CONCLUSIONS: These preliminary results indicate that
this surgical procedure is suitable for reconstruction of most atrophic maxillas.
PMID- 9393399
TI - Treatment of mandibular fractures with rigid osteosynthesis: using the AO system.
AB - PURPOSE: This study evaluated the results achieved in the surgical treatment of
all mandibular fractures at two university centers using the 2.7 AO mandibular
system. PATIENTS AND METHODS: A total of 227 patients presenting with 180 single
fractures and 47 with double fractures (274 osteosyntheses) were included in this
prospective study. RESULTS: During a mean follow-up of 27.5 months (minimum, 12
months), an overall complication rate of 7% was observed. No infection justified
early removal of the osteosynthesis material. CONCLUSIONS: The systematic use of
the technique recommended by AO for treating mandibular fractures, performed by
thoroughly experienced operators on a compliant population, results in a low rate
of complications and an early return to normal function.
PMID- 9393400
TI - Use of activator appliances in pediatric patients treated with costochondral
grafts for temporomandibular joint ankylosis: analysis of 13 cases.
AB - PURPOSE: The long-term outcomes and clinical results of costochondral transplants
used for the treatment of condylar ankylosis of the mandible in children with and
without application of postoperative activator appliances are evaluated and
compared. MATERIALS AND METHODS: A nonrandomized, retrospective clinical study of
13 cases of condylar ankylosis (16 joints) of the mandible surgically treated
during a 9-year period from 1988 to 1997 was performed. All 13 patients were
treated by condylectomy and immediate costochondral rib grafts. Nine of these
patients underwent long-term postoperative therapy using removable activator
appliances. Four patients did not undergo activator therapy postoperatively.
Casts, radiographs, photographs, computed tomography (CT) scans, magnetic
resonance imaging (MRI) and 99Tc bone scans were used postsurgically to evaluate
graft take, condylar growth and function, occlusion, and facial and condylar
symmetry. RESULTS: The postoperative and long-term clinical results in both
groups showed costochondral growth center transplants to be effective in
restoring mandibular growth of the affected side. However, symmetry, arch
coordination, correction of occlusal canting, mandibular deviation, facial
growth, and prevention of reankylosis were obtained and better controlled only in
those cases that underwent long-term orthodontic activator therapy
postoperatively and were followed closely. CONCLUSIONS: Children with long
standing condylar ankylosis of the mandible and its resultant facial asymmetry
and occlusal canting (secondary to a nonfunctional joint and maxillary
compensation) treated with condylectomy and immediate costochondral rib graft
reconstruction of the affected joint were treated more favorably when activators
were used postsurgically. The patients that failed to comply with or continue
activator therapy postsurgically developed complications relating to mandibular
deviation, occlusal dysharmony, asymmetry and, in one case, reankylosis of the
temporomandibular joint (TMJ).
PMID- 9393401
TI - The free fibula bone graft for salvaging failed mandibular reconstructions.
AB - PURPOSE: The purpose of this study was to determine the efficacy of vascularized
free fibula bone grafts for mandibular salvage reconstruction. PATIENTS AND
METHODS: Seven patients had fibula grafts after failed attempts at mandibular
reconstruction. The prior attempts involved 20 operative procedures. Four of the
seven patients (57%) had a history of radiation to the affected mandible. Bony
defects averaged 10.2 cm (range, 4.5 to 24 cm), and the associated soft tissue
defects averaged 6 x 12 cm. Average follow-up was 16 months. Cosmetic (facial
symmetry) and functional (speech quality, oral continence, deglutition, donor
site morbidity, dental rehabilitation) results were evaluated by questionnaire
and clinical examinations. RESULTS: Soft tissue coverage and mandibular
restoration were successful in all patients, and flap survival was 100%. Five of
the seven patients (70%) achieved good or excellent functional results, and five
of seven (70%) achieved good or excellent esthetic results. Complications were
minimal, and the average hospital stay was 14 days. CONCLUSIONS: When the initial
attempt at mandibular reconstruction is unsuccessful, mandibular function and
esthetics can be salvaged with reliable vascularized soft tissue and bone flaps.
As long as appropriate flap options are considered and the patient is medically
stable, successful mandibular reconstruction should be achievable despite the
number or cause of prior failed attempts.
PMID- 9393402
TI - Experimental study of epithelialization of the muscle-only flap in the oral
cavity.
AB - PURPOSE: The purpose of this study was to observe the epithelialization process
of the muscle-only flap used for reconstruction of the oral mucosal defects.
MATERIALS AND METHODS: Forty-three male adult Japanese rabbits were used. A
superiorly based cleidomastoid muscle flap was designed after vascular
assessment. The flap was transferred into the oral cavity to cover a
mucoperiosteal defect made in the mandibular alveolus. Epithelialization of the
flap was histologically evaluated at designated intervals. RESULTS: The flaps
survived without ischemic necrosis. By 8 days postoperation, the flap was
infiltrated by acute inflammatory cells and being replaced by granulation tissue
originating from the adjacent tissues. The oral epithelial cells advanced onto
this granulating muscle flap, with eventual coverage by 21 days. The granulation
tissue matured to fibrous tissue with significant contraction by 2 months. At 6
months postoperation, abnormally hyperkeratinized epithelium was seen on the
flap. This differed from the surrounding parakeratinized oral epithelium.
CONCLUSIONS: The muscle-only flap in the oral cavity epithelializes after the
granulation process.
PMID- 9393403
TI - Skeletal and dental movements after anterior maxillary advancement using implant
supported distraction osteogenesis in dogs.
AB - PURPOSE: This study evaluated skeletal and dental relapse in the dog after
anterior maxillary advancement using an implant-anchored distraction osteogenesis
device. MATERIALS AND METHODS: After the placement of implants into the palate,
four dogs had a skeletally anchored distraction device fabricated and an anterior
maxillary osteotomy performed. The distraction device was activated 0.5 mm two
times each day to advance the anterior segment 10 mm in 10 days. The dental and
skeletal changes were measured and compared for 26 weeks after distraction was
completed. RESULTS: Tooth and radiographic measurements indicated that on the
10th day of distraction the average tooth advancement was 6.83 mm +/- 1.75 mm SD,
and the average skeletal advancement, based on radiographs, was 8.67 mm +/- 1.25
mm SD. After 10 weeks, the average tooth advancement was 4.0 +/- 1.73 mm, and the
average skeletal advancement was 8.67 +/- 3.59 mm. After 26 weeks, the average
tooth advancement was 3.65 +/- 1.69 mm, and the average skeletal advancement was
8.0 +/- 1.98 mm. Bone healing occurred in all animals. The skeletal advancement
26 weeks after distraction was 85% of the initial advancement. The teeth adjacent
to the distraction site initially moved 68% of the advancement, but the distance
between the teeth subsequently decreased, with a resultant 36% advancement
compared with the initial advancement. CONCLUSION: This study showed that
skeletal fixation will result in bone movement greater than dental movement,
indicating the need for skeletal anchorage to advance the maxilla.
PMID- 9393404
TI - Repair of craniofacial defects with hydroxyapatite cement.
AB - PURPOSE: The objective of this study was to evaluate the course of healing of
craniofacial bone defects when filled with hydroxyapatite cement and to determine
whether adding various percentages by weight of demineralized bone powder to the
cement will result in enhanced bone formation. MATERIALS AND METHODS: The model
for the study was the canine calvarium. The implants were placed into cranial
defects and harvested at 3 or 6 months for qualitative evaluation by light
microscopy, microradiography, and quantitative histomorphometry. RESULTS: The
implantation of hydroxyapatite cement resulted in characteristic replacement of
the material with new bone ingrowth. The addition of demineralized bone powder to
the hydroxyapatite cement appeared to improve the handling characteristics of the
cement; however, improvement in the replacement of the material by bone was not
observed. The implantation of only allogeneic demineralized bone showed limited
new bone formation within the defect site. CONCLUSIONS: Hydroxyapatite cement
formed an effective osseoconductive scaffold for bone replacement. The addition
of demineralized bone powder to the cement to serve as a carrier of
osseoinductive factors did not result in additional bone being formed.
PMID- 9393405
TI - Alcohol withdrawal syndrome: current management strategies for the surgery
patient.
AB - PURPOSE: As advances in the therapeutic management of alcohol withdrawal syndrome
occur, oral and maxillofacial surgeons should be aware of the current treatment
philosophies and modalities. This article provides a comprehensive review of
alcohol withdrawal syndrome and presents some of the current management
strategies that can be used for these patients, whether it be in the office or in
the hospital.
PMID- 9393406
TI - Mixed radiolucent/radiopaque lesion of the mandible.
PMID- 9393408
TI - Melanoma of the tongue: case report.
PMID- 9393407
TI - Adenoid cystic carcinoma originated from an anterior lingual minor salivary
gland: immunohistochemical and ultrastructural studies and review of the
literature.
PMID- 9393409
TI - Bone-forming pleomorphic adenoma of the upper lip: report of a case.
PMID- 9393410
TI - Orbital root blow-in fracture: report of a case.
PMID- 9393411
TI - Disseminated intravascular coagulation associated with parotitis: a case report
and review.
PMID- 9393412
TI - Numb chin syndrome leading to a diagnosis of acute lymphoblastic leukemia: report
of a case.
PMID- 9393413
TI - Pseudoaneurysm of the internal maxillary artery and Frey's syndrome after blunt
facial trauma.
PMID- 9393415
TI - Osteoplasty and advancement genioplasty for widening of the chin.
PMID- 9393414
TI - Crestal window technique for anterior iliac crest graft procurement.
PMID- 9393416
TI - Ligation of the descending palatine artery: pro and con.
PMID- 9393417
TI - Going back to our roots.
PMID- 9393418
TI - The debate about debris.
PMID- 9393419
TI - Clinical factors of importance to successful implant therapy. Preface.
PMID- 9393420
TI - Clinical factors of importance to successful implant therapy. Introduction.
PMID- 9393421
TI - Positive effect of surgical experience with implants on second-stage implant
survival.
AB - This Dental Implant Clinical Research Group study defined a learning curve for
dental implant placement. Implants placed by inexperienced surgeons (< 50
implants) failed twice as often as those placed by experienced surgeons (> or =
50 implants). Implants placed during the first 6, 8, 10, 12, and 16 cases were
compared with all others. The greatest difference was seen between the first nine
cases and all others (P = .001), with later cases failing significantly less
often. Inexperienced surgeons had more failures in the first nine cases (5.9%)
than more experienced surgeons (2.4%). Surgeons with little or no previous
experience must expect a definite learning curve. Previous experience may
transfer and result in a shallower learning curve for subsequent systems.
PMID- 9393422
TI - The influence of preoperative antibiotics on success of endosseous implants up to
and including stage II surgery: a study of 2,641 implants.
AB - According to the American College of Surgeons, complex oral surgical procedures,
including the transoral placement of endosseous implants, are of the type that
may require prophylactic antibiotics. However, the routine use of prophylactic
antibiotics in the field of dental implantology continues to be controversial,
and their utilization varies widely. No data from a randomized prospective
clinical study of the prophylactic use of antibiotics in implant surgery have
been previously published. As part of the comprehensive Dental Implant Clinical
Research Group clinical implant study, the preoperative or postoperative use of
antibiotics, the type used, and the duration of coverage was left to the
discretion of the surgeon. These data were recorded and correlated with failure
of osseointegration during healing (stage I) and at stage II surgery
(uncovering). The results showed that significantly fewer failures occurred when
preoperative antibiotics were used.
PMID- 9393423
TI - The influence of 0.12% chlorhexidine digluconate rinses on the incidence of
infectious complications and implant success.
AB - The effect of perioperative chlorhexidine on the frequency of infectious
complications through stage II was examined. Chlorhexidine was used
perioperatively in 54.6% of patients (52.5% of implants) in a Dental Implant
Clinical Research Group study with a database of 2,641 implants (595 patients).
With chlorhexidine, there was a significant reduction in the number of infectious
complications (4.1% vs 8.7%). Two percent of implants failed in the absence of an
infectious complication, whereas 12% with infectious complications failed. This
sixfold difference is highly significant. Chlorhexidine may reduce microbial
complications when used in the immediate perioperative period.
PMID- 9393424
TI - The influence of type of incision on the success rate of implant integration at
stage II uncovering surgery.
AB - In 1991, the Dental Implant Clinical Research Group comprising 30 Department of
Veterans Affairs medical centers and two dental schools initiated a long-term
clinical study to investigate the clinical performance of implants within the
Spectra-System (Core-Vent Corporation, Las Vegas, NV). This article focuses on a
portion of the study database related to incision type, implant success rates,
and response of crestal bone up to the time of surgical uncovering. The crestal
incision was used for 1,705 implants (381 patients) and the remote incision for
593 implants (141 patients). No statistically significant difference (P = .092
chi-square statistic) was found in implant integration or the response of crestal
bone.
PMID- 9393425
TI - Distribution of bone quality in patients receiving endosseous dental implants.
AB - Knowledge of the distribution of bone quality in the various jaw regions assists
the clinician in dental implant treatment planning. Bone quality was assessed
with radiographs and tactile sensation for 2,839 implants at the time of
placement into four anatomic regions of the jaw. The Lekholm-Zarb classification
system was used. Overall, bone quality types 1 and 4 were found much less
frequently than types 2 and 3. Although variations in density existed in each
region, quality 2 bone dominated the mandible, and quality 3 bone was more
prevalent in the maxilla. For both anterior and posterior jaw regions, types 2
and 3 bone predominated. The anterior mandible had the densest bone, followed by
the posterior mandible, anterior maxilla, and posterior maxilla.
PMID- 9393426
TI - Bone quality and implant design-related outcomes through stage II surgical
uncovering of Spectra-System root form implants.
AB - Failure rates at second-stage surgery were reported for the ongoing Dental
Implant Clinical Research Group studies of the Spectra-System (Core-Vent
Corporation, Las Vegas, NV) implants. As of May 1995, 69 implants failed out of
2,633 placed and uncovered. The overall failure rate was 2.6%, with 3.6% in bone
quality 1 (BQ-1), 2.4% in BQ-2, 2.5% in BQ-3, and 3.1% in BQ-4. HA-coated
cylinders had the lowest number of failures and titanium alloy baskets the
highest. The basket design failed more often in the posterior jaw areas; 9 of 32
clinical centers (28%) accounted for 72% of these failures.
PMID- 9393428
TI - Radiographic assessment of peri-implant vertical bone loss: DICRG Interim Report
No. 9.
AB - Vertical bone loss is being assessed radiographically as part of the Dental
Implant Clinical Research Group studies through direct measurements on study
radiographs taken longitudinally at surgery and recall appointments. Preliminary
results and trends for the period between implant placement and 6 months after
implant uncovering show more bone loss in implants that are 1) not coated with
hydroxyapatite; 2) placed in the maxilla; 3) placed in anterior regions of the
jaws; 4) in completely edentulous cases; and 5) placed in bone scored as having
lower quality. Confounding relationships between predictor variables will require
controlled statistical analyses when data collection is completed.
PMID- 9393427
TI - The influence of bone quality on Periotest values of endosseous dental implants
at stage II surgery.
AB - Periotest values (Periotest, Siemens AG, Bensheim, Germany) were recorded as a
baseline variable at surgical uncovering in the ongoing multicenter, prospective
clinical studies of the Dental Implant Clinical Research Group, which uses
implants from the Spectra-System (Core-Vent Corporation, Las Vegas, NV). For
2,212 osseointegrated implants, the mean Periotest value (PTV) of mandibular
implants was -4.14 (anterior, -4.22; posterior, -4.06) versus -3.24 for maxillary
implants (anterior, -2.91; posterior, -3.91). Implants in the densest bone
(quality 1) had the lowest mean PTV (-4.13), followed by quality 2 (-4.00),
quality 3 (-3.58), and quality 4 (-2.64).
PMID- 9393429
TI - Changes in patient screening for a clinical study of dental implants after
increased awareness of tobacco use as a risk factor.
AB - Independent external monitoring committees are an important part of scientific
clinical trials. They monitor patient safety, study progress, investigators'
performance, and accurate interpretation/reporting of the study data. Data trends
observed by a study monitoring committee detected a change in the pattern of
patient screening by investigators after an increased awareness that tobacco use
could directly compromise the osseointegration of root-form dental implants. This
increased awareness is believed to have altered the number of active smokers
accepted into a multicenter prospective dental implant study. Recent data
analyses indicate that the success ratios were improved by alterations in this
discretionary inclusion-exclusion criterion.
PMID- 9393431
TI - Relationships between H-NS, sigma S, SpvR and growth phase in the control of
spvR, the regulatory gene of the Salmonella plasmid virulence operon.
AB - The sigma S-regulated gene spvR of Salmonella typhimurium encodes an
autoregulatory protein required for transcriptional activation of the virulence
operon spvABCD. A mutation in the histone-like protein H-NS, which negatively
controls the sigma S level, has been reported to increase spv gene expression in
S. typhimurium strain LT2. In agreement with this, we found that transcription of
spvR and spvABCD was derepressed in hns strains of Escherichia coli and S.
typhimurium. Moreover, levels of spv gene expression in hns rpoS double mutants
were higher than expression levels in mutants deficient in rpoS alone, and were
close to those measured in wild-type strains. This demonstrates that H-NS
contributes to spv gene regulation independently of its function in controlling
the sigma S level. Since the same start site was used for spvR gene transcription
in wild-type as in hns and hns rpoS mutant strains, it is likely that the spvR
promoter. spvRp1, can be recognized efficiently by an RNA polymerase containing
sigma 70. The spvR promoter region shows an intrinsic DNA curvature that might be
a determinant in H-NS- and/or sigma S-mediated control. A single amino acid
substitution, Leu to Pro at position 265, abolished the regulatory function of
SpvR in E. coli and Salmonella, implicating the C-terminal domain of SpvR in its
structure and/or regulatory function. The spvR265 allele is not transcribed at
detectable levels in hns or hns rpoS strains, suggesting that activation of
spvRp1 in these strains remains dependent on SpvR. Thus, we propose a model for
spvR gene regulation in which SpvR acts as a co-regulator of an RNA polymerase
containing either sigma 70 (in the absence of H-NS) or sigma S, to induce
transcriptional initiation at spvRp1. Moreover, growth-phase regulation of spv
gene expression was maintained in hns and hns rpoS strains, indicating that an
additional element, besides sigma S, is involved in the growth-phase regulation
in rich medium.
PMID- 9393430
TI - Success of multiple endosseous dental implant designs to second-stage surgery
across study sites.
AB - A multicenter clinical study of dental implants is being conducted by the Dental
Implant Clinical Research Group to investigate the influence of implant design,
application, and site on clinical performance and crestal bone. This article
reports on the percentage of success up to implant uncovering for different
implant designs and the distribution of failures across study sites. Data from
2,847 implants placed at 32 study sites were analyzed. Percentages of success up
to implant uncovering were calculated for study implants overall, by implant
design, by implant design within study strata, and according to individual study
sites and quartile groupings of sites based on success. Comparisons were made,
with chi-square and exact tests employed where appropriate. Differences were
found between the different implant designs for the study overall, and between
implant designs within the different study strata. Although some implant designs
were found to have generally high success across study sites, some study sites
designated as having surgeons with less experience tended to have higher failure
levels, and one implant design failed at higher rates in a subset of study sites.
The percentage and distribution of implant failures varied across study sites and
by implant design. These differences appeared to be in part related to the level
of experience of the surgeons. Further investigation should focus on
identification of factors that contribute to higher success in implant placement
with different implant designs.
PMID- 9393432
TI - Transposition-mediated transcriptional overexpression as a mechanism of
insecticide resistance.
AB - It has been proposed that amplification of genes for esterase that provide
resistance to insecticides may originate from transposition events. To test this
hypothesis, we have constructed a minigene coding for a soluble
acetylcholinesterase under the control of a nontissue-specific promoter (hsp70).
When introduced into Drosophila, the gene is expressed in all tissues and the
extra acetylcholinesterase produced confers a low level of insecticide resistance
(twofold). The minigene was mobilized by crossing the initial transformant with a
strain providing a source of P-element transposase. After 34 generations of
exposure to the organophosphate parathion, we obtained a strain with a higher
resistance (fivefold). This strain had only one extra Ace gene, which
overexpressed acetylcholinesterase. Thus, following transposition, resistance
resulted from the overexpression of a single copy of the gene and not from gene
amplification.
PMID- 9393433
TI - Cloning of the gene encoding the catalytic subunit of casein kinase II from the
yeast Yarrowia lipolytica.
AB - Casein kinase II from the yeast Yarrowia lipolytica is a heterotetramer of the
form alpha alpha' beta 2. We report on the cloning and sequencing of a partial
cDNA and of the complete genomic DNA coding for the catalytic alpha subunit of
the casein kinase II from this yeast species. The sequence of the gene coding for
this enzyme has been analyzed. No intron was found in the gene, which is present
in a single copy. The deduced amino acid sequence of the gene shows high
similarity with those of alpha subunit described in other species, although,
uniquely, Y. lipolytica CKII alpha lacks cysteines. We find that the alpha
subunit sequence of Y. lipolytica CKII is shown greater homology with the
corresponding protein from S. pombe than with that from S. cerevisiae. We have
analyzed CKII alpha expression and CKII alpha activity. We show that expression
of this enzyme is regulated. The catalytic subunit is translated from a single
mRNA, and the enzyme is present at a very low level in Y. lipolytica, as in other
yeasts.
PMID- 9393434
TI - Mutational analysis of Cak1p, an essential protein kinase that regulates cell
cycle progression.
AB - In Saccharomyces cerevisiae, entry into S phase requires the activation of the
protein kinase Cdc28p through binding with cyclin Clb5p or Clb6p, as well as the
destruction of the cyclin-dependent kinase inhibitor Sic1p. Mutants that are
defective in this activation event arrest after START, with unreplicated DNA and
multiple, elongated buds. These mutants include cells defective in CDC4, CDC34 or
CDC53, as well as cells that have lost all CLB function. Here we describe
mutations in another gene, CAK1, that lead to a similar arrest. Cells that are
defective in CAK1 are inviable and arrest with a single nucleus and multiple,
elongated buds. CAK1 encodes a protein kinase most closely related to the Cdc2p
family of protein kinases. Mutations that lead to the production of an inactive
kinase that can neither autophosphorylate, nor phosphorylate Cdc28p in vitro are
also incapable of rescuing a cell with a deletion of CAK1. These results
underscore the importance of the Cak1p protein kinase activity in cell cycle
progression.
PMID- 9393435
TI - Identification of the Saccharomyces cerevisiae genes STB1-STB5 encoding Sin3p
binding proteins.
AB - The yeast SIN3 gene functions as a transcriptional repressor, despite the fact
that Sin3p does not bind DNA directly. We have conducted a two-hybrid screen to
look for proteins that interact with Sin3p, using the PAH2 domain of Sin3p as
bait. Five new genes, STB1-STB5 were identified, as well as the STB6 gene, which
is similar to STB2. STB1, STB2, STB3, and STB6 are novel genes, and STB4 and STB5
encode C6 zinc cluster DNA-binding proteins. None of these genes is essential for
viability, and several of these genes may encode transcriptional activators.
Several special problems were encountered in using a transcriptional repressor in
a two-hybrid screen. For example, the STB genes will interact with a LexA
Sin3(PAH2) fusion protein containing a region of Sin3p, but a LexA-Sin3p fusion
protein containing full-length Sin3p, along with a STB clone, does not produce
two-hybrid activation of a transcriptional reporter. In addition, a sin3 mutation
reduces the transcriptional activation by two-hybrid partners, suggesting that a
sin3 mutation reduces the transcriptional efficiency of the Gal4p and VP16
activation domains. We have shown previously that Sin3p is part of a large
multiprotein complex, and we show here that Stb1p and Stb2p are present in this
complex.
PMID- 9393436
TI - Transposon-like structure of a new plasmid-encoded restriction-modification
system in Rhizobium leguminosarum VF39SM.
AB - Total DNA isolated from Rhizobium leguminosarum VF39SM cells is resistant to
cleavage by the restriction endonuclease PstI. Plasmid curing and transfer
studies localized this phenotype to pRleVF39b, the second smallest of six
plasmids found in this bacterium. In vitro selection for vector modification was
employed to isolate a presumptive methylase gene (M.Rle39BI) from a plasmid gene
library. Total and plasmid DNAs isolated from E. coli containing M.RleBI were
resistant to digestion by PstI. Sequence data suggested that a putative
restriction endonuclease (R.Rle39BI) was also encoded on the same fragment. The
two genes were flanked by identical copies of a putative insertion sequence,
which was also present in several copies elsewhere in the VF39SM genome. The
presence of this element in other strains examined suggested that this element is
indeed an insertion sequence. The differences in G/C content between the DNA
coding for the R/M system and that of the IS element suggest that this DNA region
may have been acquired by horizontal transfer.
PMID- 9393437
TI - Clustered amino acid substitutions in the yeast transcription regulator Pdr3p
increase pleiotropic drug resistance and identify a new central regulatory
domain.
AB - In the yeast Saccharomyces cerevisiae mutations in the genes encoding the
transcription factors Pdr1p and Pdr3p are known to be associated with pleiotropic
drug resistance mediated by the overexpression of the efflux pumps Pdr5p, Snq2p,
and Yor1p. Mutagenesis of PDR3 was used to induce multidrug resistance phenotypes
and independent pdr3 mutants were isolated and characterized. DNA sequence
analysis revealed seven different pdr3 alleles with mutations in the N-terminal
region of PDR3. The pdr3 mutants were semidominant and conferred different drug
resistance patterns on host strains deleted either for PDR3 or for PDR3 and PDR1.
Transactivation experiments proved that the mutated forms of Pdr3p induced
increased activation of the PDR3, PDR5, and SNQ2 promoters. The amino acid
changes encoded by five pdr3 mutant alleles were found to occur in a short
protein segment (amino acids 252-280), thus revealing a regulatory domain. This
region may play an important role in protein-DNA or protein-protein interactions
during activation by Pdr3p. Moreover, this hot spot for gain-of-function
mutations overlaps two structural motifs, MI and MII, recently proposed to be
conserved in the large family of Zn2Cys6 transcription factors.
PMID- 9393438
TI - Molecular and phenotypic characterization of yeast PDR1 mutants that show
hyperactive transcription of various ABC multidrug transporter genes.
AB - Mutations at the yeast PDR1 transcriptional regulator locus are responsible for
overexpression of the three ABC transporter genes PDR5, SNQ2 and YOR1, associated
with the appearance of multiple drug resistance. The nucleotide sequences of 13
alleles of PDR1, comprising 6 multidrug resistance mutants, 1 intragenic
suppressor and 6 wild types, have been determined. Single amino acid
substitutions were shown to result from the mutations pdr1-2 (M308I), pdr1-3
(F815S), pdr1-6 (K302Q), pdr1-7 (P298A) and pdr1-8 (L1036 W), whereas the
intragenic suppressor mutant pdr1-100 is deleted for the two amino acids L537 and
A538. An isogenic series of strains was constructed containing the mutant alleles
pdr1-3, pdr1-6 and pdr1-8 integrated into the genome. We found that the levels of
resistance to cycloheximide, oligomycin, 4-nitroquinoline-N-oxide and
ketoconazole were increased in all three mutants. The increase was more
pronounced in the pdr1-3 than in the pdr1-6 and pdr1-8 mutants. Studies of the
activity of the promoters of the ABC genes PDR5, SNQ2 and YOR1 demonstrated that
the combination of the PDR5 promoter and the pdr1-3 mutation resulted in the
highest level of promoter induction. Concomitantly, the level of PDR5 mRNA, of
Pdr5p protein, and of its associated nucleoside triphosphatase activity, was
strongly increased in the plasma membranes of the PDR1 mutants. Again, the pdr1-3
allele was associated with a stronger effect than the pdr1-8 and pdr1-6 alleles.
The locations of the mutations in the PDR1 gene indicate that at least three
different regions distributed throughout the Pdr1p transcription factor may be
mutated to generate a Pdr1p with considerably increased transcriptional
activation potency. These gain-of-function mutations support the concept,
recently proposed, that in members of the large family of yeast Zn2Cys6
transcription factors a central inhibitory domain exists (delineated by the pdr1
7, pdr1-6 and pdr1-2 mutations). This domain may interact in a locked
conformation with a putative, more C-terminally located inhibitory domain
(mutated in pdr1-3), and with the putative activation domain (mutated in pdr1-8).
PMID- 9393439
TI - SigX of Bacillus subtilis replaces the ECF sigma factor fecI of Escherichia coli
and is inhibited by RsiX.
AB - Analysis of the Bacillus subtilis genome sequence revealed two open reading
frames, designated sigX and ypuN (now termed rsiX), that are homologous to fecI
and fecR, respectively, of Escherichia coli. fecI encodes a sigma 70-type factor
that is necessary for transcription of the ferric citrate transport genes
fecABCDE. fecR encodes a cytoplasmic transmembrane protein that is required for
the induction of fec transport gene transcription by ferric citrate binding to
the FecA outer membrane receptor protein. Investigation of the SigX and RsiX
activities disclosed that they are not involved in ferric citrate utilization-
since ferric citrate did not serve as an iron source for B. subtilis SG64--or in
the regulation of any other ferric siderophore transport system tested. Strains
deleted for sigX or rsiX displayed no phenotype under aerobic or anoxic
conditions. However, cloned sigX complemented an E. coli fecI mutant, and the Fur
box upstream of sigX responded to the E. coli iron regulatory protein Fur. The
purified SigX protein was required for in vitro transcription of a sigX
containing DNA fragment by the E. coli RNA polymerase core enzyme. Autoregulation
of sigX was also found in vivo using a sigX'-lacZ gene fusion. RsiX inhibited
SigX activity in vivo and in vitro and stabilized the SigX protein. RsiX was
localized in the membrane fraction. When RsiX is present, SigX is found in the
membrane fraction; in the absence of RsiX, some SigX is detectable in the
cytoplasm. We conclude that SigX is a sigma factor that belongs to the ECF
(extracytoplasmic function) sigma 70-factor family. It is not known which
promoters are recognized by SigX in B. subtilis. SigX may be involved in the
regulation of iron metabolism, as evidenced by its activity in E. coli.
PMID- 9393440
TI - Fil1, a G-protein alpha-subunit that acts upstream of cAMP and is essential for
dimorphic switching in haploid cells of Ustilago hordei.
AB - A constitutive mutation, fil1, that causes filamentous growth in the haplophase
of the dimorphic smut fungus Ustilago hordei, was previously shown to be
genetically associated with a 50-kb deletion within a 940-kb chromosome.
Physiological studies suggested that a gene that functions upstream of adenylyl
cyclase was deleted in the mutant. Representational difference analysis of
isolated chromosomes was used to obtain deletion-specific DNA probes and
corresponding genomic cosmid clones. Complementation analysis identified a cosmid
clone and subsequently a 2.1-kb insert that converted transformants of the mutant
strain 10.1a(fil1) from the filamentous to the sporidial cell type. A single open
reading frame of 354 codons that encodes a putative alpha-subunit of the
heterotrimeric G-proteins was identified. Fil1 displayed a high degree of
sequence identity to Gpa1 from the basidiomycete Cryptococcus neoformans and CPG
2 from the ascomycete Cryphonectria parasitica. FIL1, when introduced on a self
replicating vector, was found to suppress filamentous growth of starved haploid
wild-type strains and restore normal mating response to the fil1 mutant, but did
not suppress sexual dimorphism of either strain. Fil1 appears to function
analogously to mammalian G alpha proteins, which are coupled to cAMP production
via adenylyl cyclase, to regulate dimorphic switching in U. hordei.
PMID- 9393441
TI - Genetic and molecular characterization of Neurospora crassa mus-23: a gene
involved in recombinational repair.
AB - A newly isolated mutant, mus-23, of Neurospora crassa was found to be highly
sensitive to a wide variety of mutagens, including UV light, methyl
methanesulfonate, 4-nitroquinoline 1-oxide, N-methyl-N'-nitro-N-nitrosoguanidine
and tert-butyl hydroperoxide. This mutant was originally isolated as a mutant
that could not grow on medium containing histidine. Meiosis and sporulation were
defective in homozygous crosses between mus-23 haploids. The mus-23 gene is
located on the right arm of LGII, between fl and trp-3. Analyses of epistasis
between mus-23 and other mutations that cause defects in DNA repair indicated
that the mus-23 gene belongs to the same DNA repair group as mei-3, which is the
Neurospora homolog of the Saccharomyces cerevisiae gene RAD51. The double mutant
carrying mus-23 and uvs-3 mutations was lethal. The mus-23 gene was cloned by
complementation of the MMS-sensitive phenotype of the mus-23 mutant. The gene
contained an open reading frame of 1578 bp and did not contain any introns. The
molecular weight of the predicted mus-23 gene product was 60.4 kDa. Computer
analyses revealed that the MUS23 protein has significant homology to Mre11p,
which is known to be involved in recombinational repair in S. cerevisiae. The
level of mus-23 transcripts increased significantly within 60 min of treatment
with UV or MMS and then gradually decreased. The role of MUS23 protein in
recombinational repair is discussed.
PMID- 9393442
TI - Isolation and analysis of functional homologues of the secretion-related SAR1
gene of Saccharomyces cerevisiae from Aspergillus niger and Trichoderma reesei.
AB - The Aspergillus niger and Trichoderma reesei genes encoding the functional
homologues of the small GTP-binding protein SAR1p, which is involved in the
secretion pathway in Saccharomyces cerevisiae, have been cloned and
characterised. The A. niger gene (sarA) contains five introns, whereas the T.
reesei gene (sar1) has only four. In both cases the first intron is at the same
position as the single S. cerevisiae SAR1 intron. The encoded proteins show 70
80% identity to the SAR1 protein. Complementation of S. cerevisiae sar1 and sec12
mutants by expression vectors carrying the A. niger sarA and T. reesei sar1 cDNA
clones confirmed that the cloned genes are functional homologues of the S.
cerevisiae SAR1 gene. Three mutant alleles of the A. niger sarA gene (D29G,
E109K, D29G/E109K), generated by site-directed mutagenesis, revealed a
thermosensitive dominant-negative phenotype in the presence of the wild-type sarA
allele. This result contrasts with the situation in S. cerevisiae, where similar
mutations have a thermosensitive phenotype. Taken together, our results indicate
that the sarA gene is involved in an essential function in A. niger.
PMID- 9393443
TI - Gene activation at a distance and telomeric silencing are not affected by yeast
histone H1.
AB - Until recently, it was believed that the budding yeast Saccharomyces cerevisiae
has no histone H1 gene. However, a search of the yeast genome database revealed a
possible H1 homologue of 258 amino acids, termed yeast histone H1 (HHO1). The
protein shows 36% identity to the human H1 core domain over a stretch of 93 amino
acids. Unlike other H1 proteins, Hho1p has a second possible core domain which
shows 43% identity to the first core domain. Since vertebrate H1 histone had been
implied in gene repression as well as gene activation at a distance, we tested
the effect of deleting the yeast H1-like gene on remote activation of a modified
GAL1 promoter, which contains a synthetic GAL4 binding site close to the TATA
box, and the natural UASG, consisting of four GAL4 binding sites. Different
spacing up to 1.8 kb between the proximal binding site and the distal UASG
enhancer revealed no differences in gene activation between wild-type and
knockout strains. Overexpression of a heterologous histone H1 from sea urchin
showed an overall inhibition of gene activation by the GAL1 promoter, whereas
overexpression of the yeast histone H1 had no effect. Also, the expression of A1,
ALPHA2 or SUC2 genes, all of which are known to be responsive to an altered
chromatin structure, was unchanged in HHO1 knockout or HHO1-overexpressing
strains when compared to wild-type cells. We also considered the possibility that
HHO1 was involved in forming the heterochromatin at telomeres. On testing for
telomeric silencing of a URA reporter gene introduced 1.3 kb away from the
chromosomal end, we again observed no differences between wild-type and knockout
strains. Thus, the yeast histone H1-like gene appears to have no role in gene
activation at a distance or in silencing under the conditions tested. It remains
to be seen whether the yeast H1 histone is a gene-specific regulator rather than
a general chromatin-associated protein.
PMID- 9393444
TI - Antisense suppression of the putative ribosomal protein S3A gene disrupts ovarian
development in Drosophila melanogaster.
AB - The Drosophila melanogaster homologue of the Anopheles gambiae C3 cDNA has been
isolated and characterized by sequence analysis. The encoded protein was
localized by immunochemical and immunocytochemical methods. The Drosophila C3
protein is highly similar to homologues of disputed function, which have
previously been identified in fungi, plants and animals. The protein is
ubiquitous and localized in the cytoplasm. Cell fractionation followed by
detection with a specific antibody preparation shows that the protein is
associated with the 40S ribosomal subunit. The C3 gene is located in section 101F
of chromosome 4. Antisense transgenic analysis shows that this gene is essential
for oogenesis. The most prominent phenotype resulting from antisense depletion of
C3 RNA is disappearance of the follicular cells of the ovary (where the
concentration of C3 protein is normally high) and abnormalities of the associated
germline derivatives, leading to failure of egg production.
PMID- 9393445
TI - Differential activation of two ACC oxidase gene promoters from melon during plant
development and in response to pathogen attack.
AB - ACC (1-aminocyclopropane-1-carboxylate) oxidase genes are differentially
expressed in melon during development and in response to various stresses. We
investigated the molecular basis of their transcription by analyzing the 5'
untranslated regions of the ACC oxidase genes CM-ACO1 and CM-ACO3. In order to
determine how their temporal and spatial expression patterns were established, we
fused the promoter regions of CM-ACO1 (726 bp) and CM-ACO3 (2260 bp) to the beta
glucuronidase (GUS) reporter gene and examined their regulation in transgenic
tobacco plants. The CM-ACO1 promoter was able to drive GUS expression in response
to wounding, and to treatment with ethylene or copper sulfate. It was also
rapidly induced (8-12 h postinoculation) in tobacco leaves inoculated with the
hypersensitive response (HR)-inducing bacterium Ralstonia solanacearum.
Expression was also observed during compatible interactions but was delayed. In
contrast, the CM-ACO3 promoter was not expressed in response to infection, but
was up-regulated during flower development. Both promoters were regulated during
leaf senescence but in different patterns. The CM-ACO1-driven GUS activity
increased sharply concomitantly with the onset of chlorophyll breakdown, while
the CM-ACO3 promoter drove strong GUS expression in green, fully expanded leaves
and this declined at the onset of senescence. This result is consistent with the
expression patterns of these two genes in senescent melon leaves. These data
suggest that the regulation of expression of CM-ACO1 is related preferentially to
stress responses, whereas CM-ACO3 seems to be associated with developmental
processes. The possible role of ethylene is discussed, particularly in the
regulation of the CM-ACO1 gene in response to stress and during senescence.
PMID- 9393446
TI - Dap (Defective aleurone pigmentation) mutations affect maize aleurone
development.
AB - Dap (Defective aleurone pigmentation) is the designation for mutations in maize
that give rise to a characteristic dappled endosperm phenotype, consisting of
patches of purple tissue, of variable size and shape, on a yellow background.
Features shared by all Dap mutants are: dominant expression when they are
maternally derived, lack of expression or transmission when they originate from
pollen, failure to recover homozygous Dap genotypes, reduced frequency of Dap
seeds in the progeny of outcrosses of Dap/+ females, association of the dappled
phenotype with reduction in seed size. The mutants so far tested, six in all, can
be grouped into two classes, one including male-transmissible (MT) isolates not
expressed in the endosperm if their contribution is paternal, and a second class
of isolates (NMT) that are permanently lost following paternal transmission. We
suggest that the NMT mutations are on a chromosome that carries an intercalary
deletion. Assuming linkage between the mutant and the deletion, selection against
the deficient chromosome during male gametogenesis would account for the failure
to recover Dap seeds in the progeny of Dap/+ male parents. We have obtained
genetic evidence supporting this hypothesis. This interpretation, however, does
not apply to MT alleles. For these, other mechanisms, such as imprinting and/or
dosage effects may be proposed. The mutable pattern in the endosperm to which all
Dap mutants give rise is an intriguing phenotype which remains to be clarified.
An unexpected finding is that aleuronic and subaleuronic cells corresponding to
the colourless areas are abnormal in shape and anthocyanin biosynthesis is
blocked in these cells. This finding calls for further investigation in light of
a possible connection between flavonoid precursors and cell shape.
PMID- 9393447
TI - Genetic analyses of the formation of the serrated margin of leaf blades in
Arabidopsis: combination of a mutational analysis of leaf morphogenesis with the
characterization of a specific marker gene expressed in hydathodes and stipules.
AB - Developmental control of the formation of the serrated margin of leaf blades was
investigated. First, the expression was characterized of a marker gene encoding
beta-glucuronidase in strain #1-35-38, a transgenic strain of Arabidopsis
thaliana (L.) Heynh, derived by the use of a previously described transposon
tagging system. In strain #1-35-38, expression of the marker gene was tissue
specific, being restricted to stipules and the toothed margins of laminae. Using
this transgenic marker gene, we examined the development of leaf blade margins in
Arabidopsis. We compared the pattern of expression of the marker gene in the
leaves of the wild-type plant with that in plants carrying the asymmetric leaves1
(as1) mutation, which causes dramatic changes in leaf-blade morphology in
Arabidopsis. The as1 mutant showed normal morphology of early leaf primordia. The
mutation affected the development of leaf segmentation in Arabidopsis without any
change in the number or morphology of cells in laminae. The as1 mutation affected
leaf morphology independently of mutations in other genes known to affect leaf
morphogenesis, such as the acaulis1 mutation and the angustifolia mutation. Based
upon these results, the development of the morphology of leaf margins in
Arabidopsis is discussed.
PMID- 9393448
TI - Analysis of seven genes from the eryAI-eryK region of the erythromycin
biosynthetic gene cluster in Saccharopolyspora erythraea.
AB - The gene cluster (ery) governing the biosynthesis of the macrolide antibiotic
erythromycin A by Saccharopolyspora erythraea contains, in addition to the eryA
genes encoding the polyketide synthase, two regions containing genes for later
steps in the pathway. The region 5' of eryA, and lying between eryA and the gene
eryK, which is known to encode the C-12 hydroxylase, has been sequenced and shown
to contain seven additional open reading frames (ORFs 13-19). On the basis of
sequence similarities, roles are proposed for several of these ORFs in the
biosynthesis of the deoxysugar mycarose and the deoxyaminosugar desosamine. A
chromosomal mutant carrying a deletion in ORF15 has been constructed and shown to
accumulate 3-O-mycarosylerythronolide B, as expected for an eryC mutant.
Similarly, a chromosomal mutant carrying a deletion in ORF16 has been constructed
and shown to accumulate erythronolide B, as expected for an eryB mutant.
PMID- 9393449
TI - A germline restricted, highly repetitive DNA sequence in Paramyxine atami: an
interspecifically conserved, but somatically eliminated, element.
AB - In some species of hagfish, the phenomenon of chromosome elimination occurs
during embryogenesis. However, only two repetitive DNA families are known to be
represented in chromosomes that are eliminated from somatic cells of the Japanese
hagfish Eptatretus okinoseanus. Using molecular analyses, another germ line
restricted, highly repetitive DNA family has been detected in another Japanese
hagfish, Paramyxine atami. The repeat unit of this family, which is 83 bp long,
has been designated "EEPa1", for Eliminated Element of P. atami 1. DNA filter
hybridization using EEPa1 as a probe revealed that this family is shared among
several species and is conserved in the germline DNA. Although eliminated,
repetitive DNA that is shared interspecifically has not been reported in hagfish
species, cases of chromatin diminution and chromosome elimination processes have
been described previously in other organisms. The patterns and intensities of
hybridization signals suggest that members of the repetitive DNA family defined
by EEPa1 have undergone concerted molecular evolution.
PMID- 9393450
TI - Three members of the S multigene family are linked to the S locus of Brassica.
AB - Two self-incompatibility genes in Brassica, SLG and SRK (SLG encodes a
glycoprotein; SRK encodes a receptor-like kinase), are included in the S
multigene family. Products of members of the S multigene family have an SLG-like
domain (S domain) in common, which may function as a receptor. In this study,
three clustered members of the S multigene family, BcRK1, BcRL1 and BcSL1, were
characterized. BcRK1 is a putative functional receptor kinase gene expressed in
leaves, flower buds and stigmas, while BcRL1 and BcSL1 are considered to be
pseudogenes because deletions causing frameshifts were identified in these
sequences. Sequence and expression pattern of BcRK1 were most similar to those of
the Arabidopsis receptor-like kinase gene ARK1, indicating that BcRK1 might have
a function similar to that of ARK1, in processes such as cell expansion or plant
growth. Interestingly, the region containing BcRK1, BcRL1 and BcSL1 is
genetically linked to the S locus and the physical distance between SLG, SRK and
the three S-related genes was estimated to be less than 610 kb. Thus the genes
associated with self-incompatibility exist within a cluster of S-like genes in
the genome of Brassica.
PMID- 9393451
TI - Ectopic anthocyanin pigmentation in maize as a tool for defining interactions
between homologous regulatory factors.
AB - The duplicated R and Sn genes are involved in the regulation of the maize
anthocyanin biosynthetic pathway, encoding tissue-specific products that are
homologous to the helix-loop-helix transcriptional activators. Sn determines the
pigmentation of the mesocotyl, leaf basis and pericarp, while R determines
pigmentation in various tissues, but not in the mesocotyl. In the progeny derived
from test-crosses of R/Sn heterozygous plants, a high frequency of R plants
exhibiting mesocotyl pigmentation was observed; these derivatives were defined as
R*. In R* plants, the presence of this novel trait was not accompanied by the
acquisition of Sn or by gross DNA rearrangements in the R profile. Accordingly,
RT-PCR analysis showed that mesocotyl pigmentation in R* was attributable to the
resident R gene. The occurrence of R* was observed with all R alleles tested, and
was enhanced when a P component was present. The heritability of R* was shown
only in the case of the standard R-r allele, which carries a functional P
component. In addition, we observed that R* can influence other R alleles,
transferring the ability to pigment the mesocotyl. R* is unstable, showing a
tendency to return to its original state after a few generations. In R* plants
there was a correlation between observed ectopic pigmentation and an increase in
the level of A1 transcript but, surprisingly, not in the accumulation of R
transcript. The results obtained from the analysis of test crosses of rSn/r delta
plants suggest that an unlinked genetic factor accounts for the ectopic
pigmentation. Concomitant occurrence of epigenetic events might explain the
observed instability and reversibility noted above. Further study of this
phenomenon might help to elucidate the basis of the interaction between
homologous and non-homologous regulators.
PMID- 9393452
TI - Genetic analysis of mutagenesis in aging Escherichia coli colonies.
AB - Bacteria live in unstructured and structured environments, experiencing feast and
famine lifestyles. Bacterial colonies can be viewed as model structured
environments. SOS induction and mutagenesis have been observed in aging
Escherichia coli colonies, in the absence of exogenous sources of DNA damage.
This cAMP-dependent mutagenesis occurring in Resting Organisms in a Structured
Environment (ROSE) is unaffected by a umuC mutation and therefore differs from
both targeted UV mutagenesis and recA730 (SOS constitutive) untargeted
mutagenesis. As a recB mutation has only a minor effect on ROSE mutagenesis it
also differs from both adaptive reversion of the lacI33 allele and from iSDR
(inducible Stable DNA Replication) mutagenesis. Besides its recA and lexA
dependence, ROSE mutagenesis is also uvrB and polA dependent. These genetic
requirements are reminiscent of the untargeted mutagenesis in lambda phage
observed when unirradiated lambda infects UV-irradiated E. coli. These mutations,
which are not observed in aging liquid cultures, accumulate linearly with the age
of the colonies. ROSE mutagenesis might offer a good model for bacterial
mutagenesis in structured environments such as biofilms and for mutagenesis of
quiescent eukaryotic cells.
PMID- 9393453
TI - Role of Escherichia coli cspA promoter sequences and adaptation of translational
apparatus in the cold shock response.
AB - A shift in growth temperature from 37 degrees C to 15 degrees C leads to a
dramatic increase in the level of CspA, the major cold shock protein of
Escherichia coli. To investigate the molecular basis of this induction, we
considered the relevance of transcriptional and posttranscriptional controls by
analyzing the steady-state levels of transcripts and the expression of reporter
genes in cells carrying a set of cspA promoter fragments of variable length fused
to lacZ or cat genes. We demonstrate that: (i) the core cspA promoter (from -40
to +16) responds to cold shock and a mutation at -36 increases the relative
activity of the promoter at low temperature by threefold; (ii) the sequences
upstream of -40 have a positive effect on expression at 37 degrees C, but no
effect on the cold shock response; (iii) by virtue of their influence on mRNA
stability, the downstream sequences (from +81 to +165) reduce expression at 37
degrees C and increase the intensity of the cold shock response; (iv) mutations
in the GCACATCA and CCAAT motifs, present at +1/-4 and between the -10 and -35
elements, respectively, do not affect the cold shock response of the cspA
promoter; (v) following cold shock, a modification of the protein synthetic
machinery takes place that allows preferential translation of cspA mRNA relative
to the non-cold shock cat and lacZ mRNAs. The quantitatively modest
transcriptional activation shown by the core promoter of cspA following cold
shock suggests that transcriptional activation can significantly contribute to
cold shock induction only when coupled to posttranscriptional controls, such as
alterations in mRNA stability and the translational apparatus.
PMID- 9393454
TI - Genetic basis of the MbrC "ploidy" phenotype in Escherichia coli.
AB - The mbrC17 mutation in Escherichia coli had been shown to cause conditional
growth defects and an increase in the quantity of DNA per cell. The present work
was aimed at identifying the mutation. Sequencing showed that the MbrC17
phenotype does not involve glr (murI), as previously suggested. P1 transduction
data indicated that the mbrC17 mutation is closely linked to rpoB, and allele
exchange showed it to lie within the secE-nusG operon. A single change relative
to wild type was found in the secE-nusG region from the mbrC17 strain, a G-->A
mutation 23 bp upstream of the secE coding sequence. This mutation causes a two
fold increase in the concentration of secE-nusG mRNA.
PMID- 9393455
TI - Allelic variation at a hypervariable compound microsatellite locus in the
ascomycete Ascochyta rabiei.
AB - The genome of the fungal chickpea pathogen Ascochyta rabiei was screened for
polymorphisms by microsatellite-primed PCR. While ethidium-bromide staining of
electrophoretically separated amplification products showed only limited
polymorphism among 24 Tunisian A. rabiei isolates, Southern hybridization of
purified PCR fragments to restriction digests of fungal DNA revealed polymorphic
DNA fingerprints. One particular probe that gave rise to a hypervariable single
locus hybridization signal was cloned from the Syrian isolate AA6 and sequenced.
It contained a large compound microsatellite harbouring the penta- and decameric
repeat units (CATTT)n, (CATTA)n, (CATATC-ATTT)n and (TATTT)n. We call this locus
ArMS1 (Ascochyta rabiei microsatellite 1). Unique flanking sequences were used to
design primer pairs for locus-specific microsatellite amplification and direct
sequencing of additional ArMS1 alleles from Tunisian and Pakistani isolates. A
high level of sequence variation was observed, suggesting that multiple
mutational mechanisms have contribute to polymorphism. Hybridization and PCR
analyses were performed on the parents and 62 monoascosporic F1 progeny derived
from a cross between two different mating types of the fungus. Progeny alleles
could be traced back to the parents, with one notable exception, where a longer
than expected fragment was observed. Direct sequencing of this new length allele
revealed an alteration in the copy number of the TATTT repeat [(TATTT)53 to
(TATTT)65], while the remainder of the sequence was unchanged.
PMID- 9393456
TI - In vivo and in vitro studies on interactions between the components of the
hemolysin (HlyA) secretion machinery of Escherichia coli.
AB - The glycopeptide antibiotic vancomycin blocks cell wall synthesis in Escherichia
coli only when it can reach its target site in the periplasm. In vivo,
sensitivity to vancomycin is enhanced in the presence of the hemolysin (hly)
determinant of E. coli or its translocator portion hlyBD. Two different mutations
in hlyD alter the cell's susceptibility to vancomycin: mutations in the tolC
homologous region of hlyD increase vancomycin resistance, whereas mutations at
the 3'-terminus of hlyD lead to hypersensitivity to vancomycin and to the
accumulation of large periplasmic and cytoplasmic pools of this antibiotic in E.
coli. These effects are only observed in the presence of functional HlyB and
TolC, the two other components of the hemolysin secretion machinery. A defect in
TolC causes hyperresistance to vancomycin, even when present together with a
mutant HlyD protein which in the presence of TolC renders E. coli hypersensitive
to vancomycin. Lipid bilayer experiments in vitro revealed specific interactions
between TolC and vancomycin or HlyD protein. Second-site suppressor mutations in
hlyD and hlyB were obtained, which abolish the hypersensitive phenotype caused by
the 3'-terminal mutations in hlyD. Our results are compatible with the idea that
(a) TolC, together with the TolC-homologous part of HlyD, forms a pore in the
outer membrane through which hemolysin is released and vancomycin taken up; and
(b) the C-terminal sequence of HlyD interacts with periplasmic loop(s) of HlyB to
form a closed channel spanning the periplasm.
PMID- 9393457
TI - Repression of beta-actin synthesis and persistence of ribosomal protein synthesis
after infection of HeLa cells by herpes simplex virus type 1 infection are under
translational control.
AB - Synthesis and assembly of ribosomal proteins into mature ribosomes persist late
after infection of cells with herpes simplex virus type 1, while synthesis of
beta-actin is drastically shut off. Since mRNAs encoding ribosomal proteins and
beta-actin undergo concomitant degradation in infected HeLa cells, we have
advanced the hypothesis that translation of the remaining mRNAs is differentially
controlled after infection. The behaviour of mRNAs for three ribosomal proteins
and for beta-actin was investigated during the course of infection. In uninfected
cells, beta-actin mRNAs are associated with large polyribosomes, while only a
part of ribosomal protein mRNAs are present in polyribosomes. In the course of
infection, beta-actin mRNAs are released from the ribosomes and are sequestered
with 40S ribosomal subunits. Simultaneously, ribosomal protein mRNAs become
associated with an increased number of ribosomes, even late in infection. In
addition, virally induced phosphorylation of ribosomal protein S6 is more
efficient in pre-existing ribosomes than in newly assembled ribosomes. These
results indicate that in infected cells (i) translation of beta-actin mRNA is
selectively inhibited at a step necessary for binding the 60S ribosomal subunits;
(ii) the rate of initiation of translation of ribosomal protein mRNAs increases
after infection; and (iii) it is likely that translation of ribosomal protein
mRNAs takes place preferentially on pre-existing ribosomes.
PMID- 9393458
TI - Temperature regulates expression of the Drosophila vestigial gene only in mutant
wing discs.
AB - All Vestigial mutants in Drosophila melanogaster display a thermosensitive
phenotype, with the exception of two which disrupt an intronic wing-specific
enhancer element. Here we report a very unusual transcriptional regulation;
temperature changes are associated with alterations in the level of vg expression
only in the wing disc of thermosensitive mutant flies and not in the brain. No
effect is observed in the wild-type strain. The tissue specificity of the
temperature effect indicates an involvement of the intronic wing-specific
enhancer element in determining the thermosensitivity of mutants.
PMID- 9393459
TI - Distraction osteogenesis for lengthening of the hard palate: Part I. A possible
new treatment concept for velopharyngeal incompetence. Experimental study in
dogs.
AB - Many procedures have been described to correct velopharyngeal incompetence.
Significant complications can occur, and the results may not be satisfactory. If
the short soft palate has satisfactory muscle function and if it could be moved
toward the posterior pharyngeal wall by distraction osteogenesis of the hard
palate, an entirely new concept of treatment for velopharyngeal incompetence
would be available. The object of the present study was to explore the
possibility of osteogenesis occurring in the hard palate in dogs after gradual
distraction (callus distraction). Six adult, mix-bred dogs were anesthetized, and
the palatal mucosa was elevated. A midpalatal transverse osteotomy and two
lateral osteotomies were performed. Tantalum bone markers for cephalometric
analysis were placed, and an individually fabricated, orthodontic-like
distraction device with an expansion screw in the sagittal direction was
inserted. The device was stabilized on the premolars and fixed to the palatal
bone with titanium miniscrews. Gradual distraction began after a latency period
of 10 to 18 days. The rate of the distraction varied from 0.25 to 0.75 mm per
day. The device was left in place for 6 to 8 weeks after expansion to allow for
bony consolidation. Assessment was by direct examination, cephalograms, computed
tomography, and histology with bone labeling. Impressions of the jaws were taken
preoperatively and after device removal to examine plaster cast changes in the
dental occlusion. Cephalometric and computed tomographic scan analysis
demonstrated a distraction of up to 8 mm. All gaps were filled with de novo
osteogenesis. Comparison of the plaster casts revealed no change in the
occlusion. At 1 month after distraction, the computed tomographic scan showed the
first signs of ossification of the experimental gap from the anterior and
posterior bone ends. After 4.5 months ossification was almost complete with a
small translucent zone in the middle of the experimental gap. After 7 months
ossification was complete.
PMID- 9393460
TI - Distraction osteogenesis for lengthening of the hard palate: Part II.
Histological study of the hard and soft palate after distraction.
AB - To correct velopharyngeal incompetence, a new treatment concept was proposed in
Distraction Osteogenesis for Lengthening of the Hard Palate: Part I (using
lengthening of the hard and soft palate by distraction osteogenesis).
Cephalometry and computed tomography showed successful elongation of the
posterior hard palate with gradual calcification. Here the sequential use of
fluorochrome markers (oxytetracycline, xylenol orange, DCAF [2,4-bis-N-N'
dicarboxymethyl aminomethyl fluorescein], and alizarin complexone) during the
distraction and retention period is reported together with the histologic
investigations using light and laser scan microscopy without prior
demineralization. The experimental gap showed de novo osteogenesis in all dogs.
The new bone was always in continuity with the original anterior and posterior
palatal bone margins. It either bridged the experimental gap fully or left a
small central zone of fibrous tissue, in which eventual ossification occurred.
Several distinct zones could be distinguished: A small central zone was found
with parallel strains of collagen fibers, oriented longitudinally in the
direction of the distraction. Next to this zone a layer of undifferentiated
mesenchymal precursor cells was seen in direct contact to newly formed bone. The
next zone was coarse woven bone, showing a transition to mature lamellar bone
through remodeling. No evidence of endochondral bone formation was found, i.e.,
all dogs showed exclusively intramembranous bone formation. The soft tissues
showed no signs of alteration: in particular, there was no necrosis or scar
formation. The soft tissues were not thinned but appeared to have followed the
longitudinal displacement. In conclusion, gradual distraction osteogenesis of the
hard palate could be a possible method for lengthening the palate to treat
velopharyngeal incompetence.
PMID- 9393461
TI - Perception of postpalatoplasty speech differences in school-age children by
parents, teachers, and professional speech pathologists.
AB - The aims of this study were twofold: (1) to test the ability of parents and
teachers to discriminate the speech of children with repaired cleft palate from
that of their unaffected peers and (2) to compare these lay assessments of speech
acceptability with the critical perceptual assessments of expert clinicians. The
subjects for this study were 20 children of school age (age range, 8 to 12 years)
who were drawn from a large population (n = 1282) of patients. All subjects had
been referred for palatoplasty to the same tertiary cleft center between 1978 and
1991. There were 16 matched controls. The listening team included parents of
subjects (n = 32) and teachers of age-matched school children (n = 12).
Randomized master audiotape recordings of the study group were presented in
blinded fashion to both groups of the adult raters, who were inexperienced in the
evaluation of patients with speech dysfunction. An experienced panel of three
extramural speech pathologists evaluated the same recordings. In all parameters
rated, both parents and teachers showed a consistent tendency to give the subject
children more negative ratings than the control children. Expert raters were
sensitive to differences in resonance and intelligibility in the control and
cleft palate groups. Results of this study differ from similar previous research,
indicating that naive peer raters (similar-age children) were insensitive to
speech differences in the cleft palate and control groups.
PMID- 9393462
TI - Vascular lip enlargement: Part I. Hemangiomas--tenets of therapy.
AB - Vascular lesions involving the lips pose a difficult problem for both the surgeon
and patient. Their removal by surgery may result in greater disfigurement and
impairment than the original lesion. When nonsurgical modalities fail, using a
well-planned strategy of sequential procedures can provide excellent results.
Many hemangioma patients require judicious serial debulking of excess tissue
mass, whereas enlargement from port-wine lesions may require direct aggressive
surgery. Over a 10-year period, 38 patients underwent surgery for treatment of
vascular lip enlargement. In 27 patients, the lip deformities were caused by
hemangiomas. The remaining 11 patients had macrocheilia associated with port-wine
vascular malformations. This paper specifically addresses hemangiomas of the
lips, tenets for their removal, and reduction strategies. Of the 27 patients with
hemangiomas involving the lips, 12 had had some form of previous treatment
including corticosteroids (4 patients), embolization (3 patients), laser (3
patients), and interferon (2 patients). All 12 of these patients had
unsatisfactory results. Specific tenets for the surgical management of these
patients are presented. The distribution of the facial hemangiomas was as
follows: 15 patients had isolated involvement of the upper lip, 7 lesions
involved the lower lip alone and 5 involved both upper and lower lips.
Additionally, 10 of these lesions involved the cheek(s), nose, or chin to some
degree. Six patients experienced some form of functional impairment before our
evaluation including difficulty with eating or drinking, visual obstruction, and
psychosocial problems. All operations were performed following several principles
established by the senior surgeon (B.M.Z.). By following the tenets presented in
this report, he has achieved near-normal lip form, giving the patient marked
improvement in appearance and function.
PMID- 9393463
TI - Vascular lip enlargement: Part II. Port-wine macrocheilia--tenets of therapy
based on normative values.
AB - Port-wine (capillary) vascular malformations that enlarge the lips (port-wine
macrocheilia) are challenging reconstructive problems which, as a result, often
go untreated. The surgical management of these lesions is not straightforward.
Scarification by laser to diminish the discoloration has been performed with good
results in some cases. However, laser treatment does little to correct three
dimensional tissue deformities such as macrocheilia, which must be addressed
surgically. We present our experience with the treatment of port-wine
macrocheilia in 11 patients over the 10-year period between 1983 and 1994. Basic
principles for surgical and nonsurgical treatment of these patients are also
discussed. Normative data about lip dimensions are important to surgical
planning. We used 40 male and female volunteers, all less than 30 years of age,
as a source for measuring normal lip dimensions, thereby creating a normative
database. Preestablished points in the labial and perioral region were marked.
Measurements were taken and then averaged. This information was used as a guide
for surgical excision of large defects in some patients. In addition, in both the
lower and the upper lip, if the opposite side is uninvolved, this database could
serve as a template for reconstruction of the affected side. Between 1983 and
1994, 11 patients underwent surgery for port-wine macrocheilia. Of the 11
patients, 1 had previous treatment consisting of laser scarification. Four
patients had port-wine vascular malformations involving the upper lip alone, four
involved the lower lip alone, and three involved both lips. In six patients,
other areas of the face and body were also involved. Our experience has led us to
perform earlier surgical intervention than has previously been described for
these patients. Basic reconstructive surgical principles and planning based on
normative data and templates can lead to excellent results.
PMID- 9393464
TI - The mental V-Y island advancement flap in functional lower lip reconstruction.
AB - Various flap procedures for the reconstruction of lower lip defects have been
described to achieve the basic requirements of a functional repair, namely muscle
function and sensation. Flaps elevated from the upper lip or the adjacent cheek
may provide a solution, but for larger lower lip defects, preservation of
function is difficult. In this article, a new functional lower lip reconstruction
technique that includes the transfer of a myocutaneous flap based on the mental
neurovascular bundle and on the branches of the facial artery is described. The
principle of this reconstructive procedure is to advance the tissues from both
sides of the chin as myocutaneous flaps upward to the lip defect, reorienting the
muscles of the flap for sphincteric function, and preserving the mental nerve for
sensation. The depressor anguli oris and remnants of the orbicularis muscle
together with their motor nerve branches are included in the V-Y advancement
flap.
PMID- 9393465
TI - A re-evaluation of hypopharyngeal reconstruction: pedicled flaps versus
microvascular free flaps.
AB - Reconstruction of hypopharyngeal defects can be accomplished with the use of
pedicled myocutaneous flaps or with microvascular free flaps. The authors
contrast their results using the trapezoidal paddle pectoralis major myocutaneous
flap with the reported results of two published series of free jejunal flaps. The
severity of the defects, preprocedure irradiation, and mix of primary and
secondary reconstruction were comparable between series. The benefits,
complications, and functional results of either technique also seem to be
comparable. However, the authors recommend the trapezoidal paddle pectoralis
major myocutaneous flap for its ease of performance, rapidity of surgery, and
absence of intraperitoneal approach. With the current effort to achieve
comparable results with shorter procedures, and with greater conservation of
patient and public resources, the pedicled flap should be reconsidered.
PMID- 9393466
TI - Spiral CT angiography: an alternative vascular evaluation technique for head and
neck microvascular reconstruction.
AB - Facial trauma and head and neck oncologic patients are often destined for
extensive reconstructive procedures with microvascular free flaps due to ablative
injuries or postoperative defects. The integrity and competence of the
vasculature in the head and neck recipient site must be imaged and evaluated
preoperatively as an essential prerequisite for the success of the reconstructive
transfer. In a prospective study of five patients, we compared conventional
angiography, the traditional technique, with a new vascular imaging modality-
spiral computed tomographic (CT) angiography. One patient suffered from an
extensive, ablative facial trauma, and the other four had undergone
mandibulectomy as part of their oncologic therapy. In contrast to conventional
angiography, spiral CT angiography is a noninvasive imaging technique, which we
found to be characterized by much shorter patient examination time, avoidance of
selective cannulation with its attendant risks, improved perception of anatomy,
and the ability to rotate the reconstructed images in any plane to obtain the
best view of any vessel in question. Disadvantages of spiral CT angiography in
imaging vessels include the need for relatively large amounts of contrast medium,
great dependence on the skill and experience of the operator, and the need for
optimizing the timing of the contrast bolus and the scan.
PMID- 9393467
TI - A new design of the iliac crest microsurgical free flap without including the
"obligatory" muscle cuff.
AB - The iliac crest free flap has undergone a gradual evolution to provide more
functional and cosmetic oromandibular reconstructions. The soft-tissue cutaneous
component has largely resisted refinement and currently constitutes the flap's
principal drawback. Conventionally, the cutaneous vessel's soft-tissue encasement
and a protective cuff of abdominal muscle are harvested to ensure skin perfusion.
These protective measures, however, produce a bulky flap that is tethered to the
bone and difficult to inset into complex three-dimensional defects. A series of
anatomic and clinical investigations has confirmed that in 30 percent of
individuals, the skin island can be elevated on a dominant cutaneous branch from
the deep circumflex iliac artery. Harvesting the skin as an axial pattern flap
greatly increases its independence from the bone, improving maneuverability. A
small collar of abdominal muscle is incised around the pedicle, obviating the
need for the customary 2.5-cm protective muscle cuff. Exclusion of the abdominal
muscular component reduces the flap's volume, decreases the need for secondary
debulking, and reduces the donor site morbidity.
PMID- 9393468
TI - Quantitative facial motion analysis after functional free muscle reanimation
procedures.
AB - The purpose of this study was to evaluate the success of functional free muscle
transfer in patients with chronic facial paralysis using a recently developed
quantitative method known as the maximum static response assay of facial motion.
A retrospective review of a single surgeon series of six patients with
longstanding facial paralysis was performed. The maximum static response assay
was performed on all patients preoperatively and serially during the
postoperative period. Twenty-seven patients (54 sides) with normal facial
function were also evaluated and served as controls. The contralateral normal
side in those patients with unilateral facial paralysis (n = 4) also served as a
control. Movement of the modiolus during smile was recorded in the x axis and y
axis. To determine net smile movement, the vector of movement was calculated by
means of the Pythagorean theorem. Vectors were then defined mathematically by
calculating direction and magnitude. The average direction of the vector during
smile for the normal control population was 58.3 degrees (range 32.5 to 83.1
degrees) from the horizontal through the modioli, and the average magnitude was
10.6 mm (range 4.2 to 20.1 mm). The average preoperative direction for the
reanimated sides was 176.8 degrees with a range of 83.3 to 225 degrees. Patients
with bilateral paralysis (n = 2) were excluded for calculation of the vectors on
the normal contralateral side. The average preoperative direction for the normal
contralateral side in patients with facial paralysis was 58.3 degrees with a
range of 48.2 to 68.4 degrees. Postoperatively, the average direction of the
vector during smile for the reanimated sides improved to a value of 77.6 degrees
with a range of 45.7 to 113.8 degrees. The average change in direction of the
preoperative reanimated side compared with the postoperative reanimated side was
significant (p = 0.01). Postoperatively, the average direction of the vector for
the contralateral normal sides was 43 degrees with a range of 11 to 57.2 degrees.
The change in direction for the contralateral normal side was not significant (p
= 0.18). The average magnitude of the reanimated side improved from a non
anatomic 2.8 mm preoperatively (range 0.8 to 6.8 mm) to an anatomic 4.9 mm
postoperatively (p = 0.02). The contralateral normal side magnitude decreased
from 9.4 mm (range 7.3 to 11.6 mm) preoperatively to 5.7 mm (range 3.8 to 7.7 mm)
postoperatively (p = 0.006). More specifically, the absolute change in movement
on the reanimated side during smile for the x axis and y axis was 2.3 mm (p =
0.05) and 4.0 mm (p = 0.002), respectively. This corresponded to an absolute
change in the magnitude of the vector of 4.6 mm in an anatomic direction. On the
contralateral side the absolute change in magnitude during smile from
preoperative to postoperative for the x axis and y axis decreased by 1.5 mm (p =
0.13) and 5.3 mm (p = 0.05), respectively. This reflected an absolute change in
the magnitude of the vector of 5.5 mm. Functional free muscle transfer in
patients with chronic facial paralysis resulted in anatomic recovery of motion in
the majority of patients in this series. The maximum static response assay can be
used to objectively assess the results of facial reanimation.
PMID- 9393469
TI - Life span of silicone gel-filled mammary prostheses.
AB - The discussion on possible side effects of implanted silicone has resulted in a
growing number of patients inquiring whether or not their mammary prostheses are
intact and when failure of the prostheses is to be expected. Between November
1988 and May 1995, 182 patients had their silicone mammary prostheses replaced,
repositioned, or removed one to three times. Capsular contraction, dislocation,
pain paresthesia, and/or suspected rupture were common indications for surgery.
To try and be able to provide an indication as to the correlation of implant age
and integrity, we recorded the status of all 426 prostheses observed during
secondary surgery. In this selected group of patients, approximately 50 percent
of the mammary prostheses with an implant age of 7 to 10 years showed gel bleed
or rupture. Applying the survival Kaplan-Meier curve, 50 percent of implants may
be expected to bleed or be ruptured at the age of 15 years. Rupture was observed
more frequently than gel bleed. It seems that there is no chronologic relation
between gel bleed and rupture.
PMID- 9393470
TI - Textured surface, nonsilicone gel breast implants: four years' clinical outcome.
AB - Since the development of smooth silicone breast implants in 1962, more than 1
million women throughout the world have opted for breast augmentation surgery.
Although initially successful, smooth implants are prone to develop surrounding
scar capsules that may harden and contract, resulting in discomfort, weakening of
the shell with rupture, asymmetry, and patient dissatisfaction. This phenomenon
has been shown to occur in as many as 70 percent of implanted patients over time.
We have reviewed all of our patients and the Medical Device Reporting System for
Bioplasty, Inc. (Minneapolis, Minn.) for the history of this device. At 18
months, more textured implants remain soft than the smooth group. After an
additional 30 months of follow-up, for a total of 48 months maximum and 18 months
minimum, most textured implants still remain soft. Since 1990 we have used AU24K,
bio-oncotic hydrogel filling material in molecular impact surface textured
implants (MISTI) that is similar to breast tissue in color, radiodensity, and
viscosity. Complications have been late leaks, infection, and capsular
contracture. Several asymptomatic implants were removed because of anxiety over
the FDA controversy. Our experience so far indicates that such a breast implant
is a reasonable alternative to the prior art. The longer-term performance of
these implants must await the availability of further clinical outcome data.
PMID- 9393471
TI - Influence of underfilling on breast implant deflation.
AB - The authors report a series of 407 patients with a total of 709 saline breast
implants (average follow-up, 7.1 years). In this retrospective series, the
overall deflation rate was 6.6 percent (47 of 709). Initial comparison of the
deflation rates for smooth (8.8 percent) versus textured (1.8 percent) implants
suggested a significant difference between the implant types. However, further
analysis of the data revealed that smooth implants had a longer average follow-up
period and tended to have lower fill volumes. These data were re-examined using
Kaplan-Meier survival analysis plots, which corrected for differences in follow
up times, and log rank tests performed to determine significance. Implant type
was found to have a non-significant association with rupture rate. In contrast,
the percent fill (implant fill volume per minimum recommended fill volume x 100)
was significantly associated with the spontaneous ruptures; a mean difference of
13.9 percent (89.2 percent versus 103.1 percent) was found between the series of
deflated implants and the nondeflated implants (p < 0.0001). These data suggest
that underfilling is a major cause of deflation.
PMID- 9393472
TI - The vertically based deep fascia turnover flap of the leg: anatomic studies and
clinical applications.
AB - Although fasciocutaneous turnover flaps are a simple and fast method for covering
soft-tissue defects of the lower leg, many reconstructive surgeons have their
doubts about them. They revolve around the lack of criteria for safely designing
these random-pattern flaps and around the risk of donor site problems. A
vertically based deep fascia turnover flap with a paratibial or parafibular
pedicle is presented. Anatomic studies of 36 injected lower limbs showed the deep
fascia to be supplied by a mean of 61 vessels. As musculofascial, septofascial,
and periosteofascial branches, these contribute to a richly anastomosing vascular
network within the deep fascia. Along the deep transverse septum at the medial
tibial border, the anterior and posterior peroneal septa, and between the
anterior tibial and extensor muscles, the fascia is supplied by segmental vessels
in a clearly defined arrangement. Pedicled on these vessels, the deep fascia is a
useful candidate tissue for transversely oriented turnover flaps. These are
particularly well suited for covering pretibial or prefibular soft-tissue
defects. Unlike adipofascial turnover flaps, the transversely oriented deep
fascia turnover flap keeps its subcutaneous layer with its intact vascular plexus
so that the overlying skin is adequately perfused even in patients with sizable
flaps or an extremely thin skin. Clinical experience with the vertically based
paratibial or parafibular deep fascia turnover flap in six patients confirmed its
usefulness for covering small to medium-sized soft tissue defects of the lower
leg.
PMID- 9393473
TI - Island adipofascial flap based on distal perforators of the radial artery: an
anatomic and clinical investigation.
AB - Reconstruction of soft-tissue defects of the hand with exposed tendons, joints,
and bone represents a challenge to the plastic surgeon, and such defects
necessitate flap coverage to preserve hand function and to protect its vital
structures. Reported here is the study of an island adipofascial flap based
solely on the distal five to eight septocutaneous perforators of the radial
artery and their venae comitantes. Designing the flap in the form of an island
with skeletonization of the distal perforators of the radial artery ensures its
vascular pattern from these perforators alone with no connection to the ulnar
artery perforators or posterior interosseous artery perforators, as is the case
with fascial pedicled flaps. Furthermore, designing the flap as an island
facilitates the arc of rotation and avoids the pedicle kink when the flap is
turned 180 degrees. Preservation of the radial artery, as well as the mild
thickness of the flap are further advantages. The drawbacks of such a flap
include temporary impaired sensation at the donor site, the obvious scar in the
forearm, and loss of hair. Eleven fresh and fixed cadaver upper extremities were
dissected to delineate the vascular pattern and to define the arc of rotation of
the flap. Also, a clinical approach was conducted on two patients who sustained
extension scar contracture with tendon adhesions of the dorsum of the hands, on
two patients who sustained first web space contracture, and on two patients who
had full-thickness soft-tissue loss over the palm; and finally on two patients
who sustained traumatic soft-tissue loss over the dorsum of their hands with
exposed tendons and metacarpal bones.
PMID- 9393474
TI - The effect of ischemic preconditioning on the recovery of skeletal muscle
following tourniquet ischemia.
AB - It has been well documented that ischemic preconditioning limits ischemic
reperfusion injury in cardiac muscle, but the ability of ischemic preconditioning
to limit skeletal muscle injury is less clear. Previous reports have emphasized
the beneficial effects of ischemic preconditioning on skeletal muscle structure
and capillary perfusion but have not evaluated muscle function. We investigated
the morphologic and functional consequences of ischemic preconditioning, followed
by a 2-hour period of tourniquet ischemia on muscles in the rat hindlimb. The 2
hour ischemia was imposed without preconditioning, or was preceded by three brief
(10 minutes on/10 minutes off) preischemic conditioning intervals. We compared
muscle morphology, isometric contractile function, and muscle fatigue properties
in predominantly fast-twitch, tibialis anterior muscles 3 (n = 8) and 7 (n = 8)
days after ischemia-reperfusion. Two hours of ischemia, followed by reperfusion,
results in a 20 percent reduction of muscle mass (p < 0.05) and a 33 percent
reduction in tetanic tension (p < 0.05) when compared with controls (n = 8) at 3
days. The same protocol, when preceded by ischemic preconditioning, results in
similar decreases in muscle mass and contractile function. Neuromuscular
transmission was also impaired in both ischemic groups 7 days after ischemia.
Nerve-evoked maximum tetanic tension was 69 percent of the tension produced by
direct muscle stimulation in the ischemia group and 65 percent of direct tension
in the ischemic preconditioning/ischemia group. In summary, ischemic
preconditioning, using the same protocol reported to be effective in limiting
infarct size in porcine muscle, had no significant benefit in limiting injury or
improving recovery in the ischemic rat tibialis anterior. The value of ischemic
preconditioning in reducing imposed ischemic-reperfusion-induced functional
deficits in skeletal muscle remains to be demonstrated.
PMID- 9393475
TI - Primary critical ischemia time in the hairless mouse ear.
AB - The primary critical ischemia time of the hairless mouse ear was determined using
a probit analysis. An atraumatic clamp was used across the pedicle base of the
ear to induce total ischemia at 0, 2, 4, 6, 7, 7.5, 8.0, 8.5, 9.0, 9.5, and 12
hours of normothermic ischemia. Seventy-seven ears were examined 7 days after the
ischemic interval for evidence of necrosis. The median critical ischemia time was
determined to be 8.2 hours with 95 percent fiducial limits of 7.74 hours and 8.69
hours.
PMID- 9393476
TI - Reverse flow as an option in microvascular recipient anastomoses.
AB - This study was designed to investigate the retrograde arterial pressures in the
distal ends of the superior thyroid (n = 20) and facial arteries (n = 8). These
pressures were compared with mean systemic arterial pressure (n = 20) as well as
retrograde pressure in the radial artery (n = 8). The mean retrograde arterial
pressure in the radial artery was 50 to 60 percent of normal arterial pressure.
Similar pressures were recorded from the distal ends of both the superior thyroid
and facial arteries. Because we know that the radial artery can support a skin
flap through retrograde or reverse flow (reverse radial forearm flap), it was
concluded that both the superior thyroid and facial arteries could also support
flaps based on reverse flow. This has proved to be the case clinically. In
circumstances where pedicle geometry favors it and in the presence of pulsatile
flow from the distal ends of either of these arteries, a retrograde anastomosis
is now the practice of the authors in selected cases.
PMID- 9393477
TI - Tissue response to suture materials implanted subcutaneously in a rabbit model.
AB - We compared the tissue response to a nonabsorbable monofilamented suture made of
expanded polytetrafluoroethylene (ePTFE), which has recently been introduced for
use in plastic surgery, with the response to 10 other commercially available
absorbable sutures and nonabsorbable monofilamented and multifilamented sutures.
The sutures were used to secure a patch of ePTFE implanted in the dorsum of adult
New Zealand White rabbits. At 30, 60, and 120 days after implantation, the tissue
response to the sutures was assessed with respect to the number of foreign-body
giant cells present, the thickness of the fibrous capsule that developed, and the
general inflammatory response (n = 4 for each suture for each time period).
Analysis of variance revealed that specific suture type was significantly
associated with foreign-body giant cell count and fibrous capsule thickness.
Tevdek had a significantly higher value for mean number of foreign-body giant
cells. Silk and Tevdek had significantly thicker fibrous capsules, and ePTFE
suture had a significantly thinner capsule. Absorbable sutures and nonabsorbable
multifilamented sutures evoked a more extensive tissue response than
monofilamented sutures; the differences between nonabsorbable monofilamented and
nonabsorbable multifilamented sutures were significant for capsule thickness. In
general, suture made of ePTFE produced a minimal tissue response. It should be a
good choice for use in facial plastic surgery, in which excellent functional and
aesthetic results are critical.
PMID- 9393478
TI - The kleeblattschadel anomaly in Apert syndrome: intracranial anatomy, surgical
correction, and subsequent cranial vault development.
AB - We present a case of Apert syndrome in which intracranial anomalies of the
cranial base were localized to the lesser wings of the sphenoid and sphenoid
ridge. The lesser wings of the sphenoid were displaced superiorly to follow the
fused coronal sutures bilaterally, where they met at a single point on the skull
vertex. Careful preoperative study of the intracranial anatomy in the
kleeblattschadel anomaly led to a surgical plan for early correction of the
anomaly. The present report indicates that an aggressive approach to the
correction of the kleeblattschadel anomaly beginning early in infancy can result
in normalization of the trilobar skull configuration. Although this approach can
correct the kleeblattschadel anomaly, 3.5-year follow-up in this patient with
Apert syndrome demonstrates progressive turricephaly despite repeated cranial
vault remodeling. Although the trilobar skull configuration can be corrected
through early surgical intervention, the long-term correction of progressive
turricephaly in patients with Apert syndrome remains an unsolved problem.
PMID- 9393479
TI - Chronic orbital hematic cysts: a case for craniofacial correction.
AB - Chronic hematic cysts are rare conditions that usually present to the ophthalmic
surgeons with displacement of the globe. There is usually no, or minimal, bone
involvement. Two patients with unusual presentations of chronic orbital hematic
cysts are reported. These cysts resulted in significant expansion and erosion of
the bony orbits. The presentation, operative findings, and reconstruction are
reported and discussed.
PMID- 9393481
TI - Tensor fasciae latae flap: alternative donor as a functioning muscle
transplantation.
AB - The functioning tensor fasciae late muscle was used for a patient with both a
complete defect of the deltoid muscle and a defect of overlying skin. The
configuration of the tensor fasciae latae including the length of the muscle
belly as well as the muscle fiber arrangement was similar to that of the deltoid.
In addition, the spatial relationship between the muscle, donor vessels, and
motor nerve fulfilled the requirements for the recipient site of deltoid
reconstruction. The transferred muscle successfully replaced the function of the
deltoid and provided sufficient strength for elevation of the arm. Simultaneous
skin coverage was also satisfactory. The case report here clearly indicates that
the tensor fasciae latae muscle is a promising candidate for functioning muscle
transplantation, and can also be applied for other disorders. However, several
points such as limited motor nerve length should be considered when tensor
fasciae latae is used as a functioning muscle.
PMID- 9393480
TI - Congenital leukemia cutis: an unusual manifestation of a rare disease.
AB - This paper discusses a case of congenital leukemia cutis of lymphoblastic type
presenting as a solitary frontonasal tumor. The presentation is unusual when
compared with other reported cases of neonatal leukemia and represents the only
reported case with comparable presenting features to the authors' knowledge. The
differential diagnosis with other frontonasal tumors is discussed.
PMID- 9393482
TI - Endoscopic harvesting of the gracilis muscle for reinnervated free-muscle
transfer.
AB - Reinnervated functioning free-muscle transfer has proven to be invaluable in
numerous reconstructive procedures. However, one problem that remains unsolved
after transferring the muscle is the presence of a long and cosmetically
unacceptable scar at the donor site. This scar has undermined patients'
satisfaction with the procedure despite its excellent functional results. In an
attempt to resolve this problem, the authors harvested the gracilis muscle
endoscopically and now report their technique and results. To create an optical
cavity in harvesting the gracilis muscle endoscopically, they devised a lifting
apparatus, which is described. Comparative study showed that endoscopic
harvesting of the gracilis produced a significantly shorter scar, but took 1.5
times longer than conventional method.
PMID- 9393483
TI - Are patients satisfied with results from residents performing aesthetic surgery?
AB - An 8-year survey of patient satisfaction in an academic aesthetic surgery clinic
at the University of Toronto was carried out by means of a mailed questionnaire.
A total of 265 questionnaires were mailed; 131 completed questionnaires (49.4
percent) were returned. Of these, 93.1 percent would recommend this clinic (88.1
percent in the first year of operation and 95.4 percent in the subsequent 7
years), and 92.9 percent would undergo the same procedure again, if required
(88.3 percent in the first year and 95.0 percent in the next 7 years). The
highest patient satisfaction (10 of 10) was seen in augmentation mammoplasty
(average, 9.1); blepharoplasty (average, 9.0); rhytidectomy (average, 7.8), and
rhinoplasty (average, 6.9). The results obtained compared favorably with recently
published data of more experienced surgeons.
PMID- 9393484
TI - SMAS fixation to the facial skeleton: rationale and results.
AB - The trend in modern facial rejuvenation surgery is to reposition the ptosis of
the superficial soft-tissue mass relative to the facial skeleton. The logical
method of supporting the superficial tissue is to reattach it to the underlying
skeleton, thereby replicating the function of the retaining ligaments. Five
hundred consecutive face lifts involving deep fixation of the submucosal
aponeurotic system flap to the periosteum of the zygoma were reviewed for
complications and side effects. Expected complications, such as irregularities,
dimpling, and palpable sutures, occurred in fewer than 1 percent of cases,
confirming the safety of this method. The conclusion from this experience is
relevant to all methods of deep-layer facial rejuvenation surgery, including the
endoscopic approach.
PMID- 9393485
TI - Full face and neck laser skin resurfacing.
AB - Since the inception of laser skin resurfacing for the removal of facial rhytides,
laser surgeons have avoided laser resurfacing of the neck. The purpose of this
paper is to demonstrate that the accuracy and precision of the Ultrapulse carbon
dioxide laser allows the laser surgeon to safely laser skin resurface the neck as
well as the full face. This series includes 40 patients who have undergone laser
skin resurfacing of the neck at the time of full-face laser skin resurfacing.
Three subgroups are defined. Thick-skinned patients, thin-skinned patients, and
patients who otherwise would have medical contraindications to face and neck lift
are included in this study group. Patients between the ages of 40 and 60 who do
not have a lot of excessive neck skin or prominent platysma bands are candidates
for full face and neck laser skin resurfacing. Successful tightening for thick
skinned patients occurs by using 300 mJ at 60 W. a density of 6, and one pass.
For thinner-skinned patients, the upper half of the neck is treated with 300 mJ,
60 W, a density of 6, and one pass. The lower half of the neck in these patients
is treated with 125 mJ and 20 W, a density of 6, and one pass. In some patients
who otherwise have medical contraindications for face and neck lift, the laser
may be an indicated procedure because there is minimal bruising, lack of
bleeding, minimal edema, minimal to absent use of adrenaline, and nonincisional
surgery with a speedy recovery. The Ultrapulse laser delivers high energy with
high speed, precision, and control. Therefore, the laser surgeon can successfully
laser skin resurface the neck at the time of full face laser skin resurfacing.
Immediate tightening of the face and neck, from the photothermal effect, and the
neocollagenesis effectively tighten the neck in the properly selected patient.
PMID- 9393486
TI - Postoperative care following CO2 laser resurfacing: avoiding pitfalls.
AB - Facial skin resurfacing using the carbon dioxide laser has become an increasingly
popular procedure. Improvements in carbon dioxide laser technology have made the
procedure simpler and more reliable. However, difficulties in the postoperative
period can lead to patient morbidity and physician anxiety. Common problems such
as prolonged erythema, hyperpigmentation, acne, milia, dermatitis, and infection
can be controlled or avoided with proper postoperative care. Less common sequela
such as hypertrophic scarring and prolonged healing are often a results of errors
committed in the postoperative period. The authors have performed laser
resurfacing in almost 2100 patients in the last 4 years. Changes in the
postoperative regimen to include no pretreatment, use of semipermeable dressings,
antiviral and antibacterial prophylaxis, and early treatment with sunscreens and
bleaching agents have made for a smoother recovery with more predictable results.
PMID- 9393487
TI - Use of preoperative subcutaneous "wetting solution" and epidural block anesthesia
for liposuction in the office-based surgical suite.
AB - Uniform saturation of subcutaneous fat using the "wetting solution" formula
described by Klein for his "tumescent technique" has been shown to decrease
operative blood loss associated with liposuction procedures and to eliminate the
requirement for general anesthesia for selected patients. However, we found this
infusate provided an inadequate level of anesthesia for many of our patients. We
use preoperative infusion of Klein's epinephrine and lidocaine containing wetting
solution in our lipoplasty practice only for control of blood loss and
postoperative pain. Our anesthetic of choice for liposuction is the epidural
block technique, which provides consistent intraoperative comfort for the
patient. We report our experience with 85 consecutive lipoplasty patients who
underwent liposuction under epidural anesthesia after subcutaneous fat perfusion
with Klein's wetting solution. Our epidural block technique uses the rapidly
metabolized local anesthetic agent, chloroprocaine, which has the lowest systemic
toxicity risk of any local anesthetic agent. Chloroprocaine's anesthetic
characteristics are particularly well suited for the outpatient surgery patient
with few undesirable side effects.
PMID- 9393488
TI - Advances in hair restoration surgery.
PMID- 9393489
TI - A simple technique for correction of male nipple hypertrophy: the "sinusoidal"
nipple reduction.
PMID- 9393491
TI - The art of miscommunication.
PMID- 9393490
TI - Complications of the tumescent formula for liposuction.
PMID- 9393492
TI - Gore-Tex facial implants. Plastic Surgery Educational Foundation DATA Committee.
PMID- 9393493
TI - Vitamin E and wound healing. Plastic Surgery Educational Foundation DATA
Committee.
PMID- 9393494
TI - External fatty tissue massage (the "endermologie" and "silhouette" procedures).
Plastic Surgery Educational Foundation DATA Committee.
PMID- 9393495
TI - Computer imaging/surgical simulation. Plastic Surgery Educational Foundation DATA
Committee.
PMID- 9393499
TI - Fat trapper.
PMID- 9393496
TI - Advances in assessing outcome of surgical repair of cleft lip and cleft palate.
PMID- 9393497
TI - Physiopathology of the dynamic muscular sphincter of the pharynx.
PMID- 9393498
TI - Influence to the development of cleft lip, palate, or both by fertilized ovum
transfer in A/J strain mice.
PMID- 9393500
TI - Task force on ultrasound-assisted lipoplasty.
PMID- 9393501
TI - Correction of the elevated nasal ala after Millard's repair in unilateral cleft
lip.
PMID- 9393502
TI - Subcutaneous infiltration in suction-assisted lipoplasty.
PMID- 9393503
TI - A new transconjunctival retractor.
PMID- 9393504
TI - Saphenous vein injection in the rat: a simple and time efficient technique.
PMID- 9393505
TI - Temporalis muscle flap revisited on its centennial: advantages, newer uses, and
disadvantages.
PMID- 9393506
TI - Gluteal fasciocutaneous V-Y advancement flap.
PMID- 9393507
TI - Function of the infrahyoid muscle flap.
PMID- 9393508
TI - Device for easy inflation of expanders used in breast reconstruction.
PMID- 9393509
TI - On call.
PMID- 9393510
TI - Method for middle vault reconstruction in primary rhinoplasty: upper lateral
cartilage bending.
PMID- 9393511
TI - High-resolution imaging of the musculoskeletal system.
PMID- 9393512
TI - Human immunodeficiency virus infection and hepatitis: biosafety in radiology.
AB - Radiologists frequently perform invasive diagnostic and therapeutic procedures
involving needles and/or vascular access, and often they do so in darkened rooms.
Therefore, they are at risk of exposure to blood-borne pathogens. The risk of HIV
infection with a single sharp injury is low (0.3%), and on average 99.7% of
exposures will not result in infection. However, this seroconversion rate is
increased when a high volume of blood or a high concentration of virus is
inoculated, and it is decreased by 79% when postexposure prophylaxis is used. An
estimated 800,000 needle-stick injuries and other injuries from sharp objects to
health care workers occur annually in the United States (25). Approximately
16,000 of these involve HIV-contaminated blood, and even more are contaminated
with HBV or HCV (46). Needle-stick injury therefore poses the single greatest
risk to health care workers regarding occupational transmission of HIV. Because
most patients in the radiology department have an unknown HIV or hepatitis
serostatus, all patients should be regarded as potentially infectious, and
precautions should be universal. In fact, the 1991 OSHA ruling made compliance
with the CDC Universal Precautions Guidelines the enforceable national standard.
Real-time oral communication among all members of the radiology team and
scrupulous attention to safe technique are absolutely essential. Radiologists are
not in agreement regarding the use of precautions against injury with a sharp
object and splashing (47-50). Many have adapted some of their habits to conform
well to the CDC and OSHA guidelines regarding universal precautions, but some
remain skeptical regarding the risk of exposure to themselves. Consequently, in
some areas resistance to the above recommendations persists. However, the data to
date provide a compelling argument for protection against occupational exposure
to blood either by percutaneous sharp injury or splashing on mucous membranes or
interrupted skin. A number of resources were made available in early 1997 for
easy access to the most current data regarding occupational transmission of HIV
or hepatitis. For instance, the CDC has a World Wide Web site
(http://www.cdc.gov) and a facsimile information service through the Hospital
Infections Program directory (telephone 404-332-4565). Also, the National AIDS
Clearinghouse can be reached by telephone (800-458-5231), as can the HIV/AIDS
Treatment Information Service (800-448-0440). The postexposure prophylaxis
protocol used at the University of California, San Francisco, can be reviewed by
visiting its World Wide Web site at http://epi-center.ucsf.edu. And up-to-date
information is available to both Veterans Administration and other health care
staff worldwide by J. Michael Howe, MSLS, of the AIDS Information Center, a
service of the VA HIV/AIDS National Training Program, located at the Veterans
Administration Medical Center, San Francisco, University of California, San
Francisco (hivinfo@itsa.ucsf.edu).
PMID- 9393513
TI - Imaging squamous cell carcinomas of the upper aerodigestive tract: what
clinicians need to know.
PMID- 9393514
TI - Valediction: sweet sorrow.
PMID- 9393515
TI - Duplex sonography: can it be used to evaluate carotid artery stents?
PMID- 9393516
TI - Improving radiology research methods: what is being asked and who is being
studied?
PMID- 9393517
TI - Traumatic thoracic aortic aneurysm: treatment with endovascular stent-grafts.
AB - PURPOSE: To demonstrate the feasibility and safety of endovascular stent-graft
placement for treatment of traumatic aortic aneurysm. MATERIALS AND METHODS: Ten
patients with traumatic aortic aneurysm were treated with endovascular stent
grafts. Three patients had an acute traumatic aneurysm; seven had a chronic
aneurysm. Stent-grafts were constructed from modified Z-stents covered with woven
polyester or expanded polytetrafluoroethylene graft material and were deployed
through a 20-24-F delivery sheath in an exposed artery located remotely from the
lesion. RESULTS: Stent-graft placement and thrombosis of the aneurysmal sac were
successful in all patients. Major complications were encountered in three
patients after endovascular treatment. One patient had a peri-graft leak;
complete thrombosis of the aneurysmal sac was achieved after coil embolization of
the leak. Transposition of the left subclavian artery was necessary to relieve
left arm ischemia in another patient. In the third patient, stent placement in
the left main stem bronchus was needed to relieve left lung atelectasis. All
patients were alive and without complications during the follow-up period (mean,
15 months). CONCLUSION: Transluminal placement of endovascular stent-grafts is a
technically feasible method for treatment of traumatic thoracic aortic aneurysm
and may be an effective alternative to open-chest surgery.
PMID- 9393518
TI - Percutaneous biliary drainage: clinical trial of analgesia with interpleural
block.
AB - PURPOSE: To determine the analgesic efficacy and safety of interpleural block for
percutaneous biliary drainage. MATERIALS AND METHODS: In this double-blind study,
34 age- and sex-matched patients who were to undergo percutaneous biliary
drainage because of malignant biliary obstruction were randomly assigned to the
true-block group (30 mL 0.5% bupivacaine block) or placebo-block group; all had
access to a patient-controlled analgesia (fentanyl) pump. Self medication, pain
reports, blood pressure, heart rate, and oxygen saturation were monitored during
and until 8 hours after drainage. The McGill Pain Questionnaire was administered
1 hour after biliary drainage. RESULTS: Patients in the placebo group self
administered statistically significantly more fentanyl than did patients in the
true-block group (P = .008). Peak pain scores (10-point scale) and McGill Pain
Questionnaire scores were statistically significantly higher for the placebo
group patients (P = .017 and P = .001, respectively). There were no differences
between groups in terms of blood pressure, heart rate, and oxygen saturation. Two
patients had pneumothorax caused by the interpleural block. CONCLUSION:
Interpleural block was effective in decreasing pain and opioid requirements
during and after percutaneous biliary drainage and did not compromise the
cardiopulmonary status of the patient. However, the rate of pneumothorax was
higher than previously reported.
PMID- 9393519
TI - Radiologically guided placement of pull-type gastrostomy tubes.
AB - PURPOSE: To evaluate percutaneous placement of pull-type gastrostomy tubes that
has traditionally necessitated endoscopic guidance. MATERIALS AND METHODS: From
September 1995 through March 1997, 63 pull-type gastrostomy tubes were placed in
64 patients. Retrograde catheterization of the esophagus was performed through
the stomach. Then the gastrostomy tube was pulled through from the mouth into the
stomach. RESULTS: Gastrostomy tube placement was successful in 63 (98%) of 64
patients in 65 attempts. One procedure was stopped when the patient reported
chest pain after gastric insufflation, and a second placement attempt was
initially unsuccessful. Major complications occurred in three (5%) patients: exit
site infection necessitating tube removal (n = 2) and prolonged bleeding
necessitating transfusion (n = 1). Minor complications occurred in six (9%)
patients: failure of placement (n = 2), exit site infection (n = 1), leakage
around the tube (n = 1), tube migration (n = 1), and inadvertent tube removal (n
= 1). There were no cases of peritonitis, tract disruption, or gastrostomy
related death. CONCLUSION: Percutaneous placement of a pull-type gastrostomy tube
was performed with a minimum risk of tract disruption and peritonitis. The tube
was safely and effectively placed by radiologists.
PMID- 9393520
TI - Rapid thrombectomy with a hydrodynamic catheter: results from a prospective,
multicenter trial.
AB - PURPOSE: To evaluate efficacy and safety of a hydrodynamic rheolytic thrombectomy
device for rapid percutaneous treatment of acute thromboembolic occlusions of
native lower-extremity arteries and bypass grafts. MATERIALS AND METHODS: In 50
patients, thrombectomy was performed with the rheolytic catheter at four centers.
Patients had acute occlusions of native lower-extremity arteries (n = 39) or
acute thrombosis of lower-limb bypass grafts (n = 11). Estimated occlusion age
was 5 days +/- 5. Mean thrombus length was 15 cm +/- 11. Clinical success was
measured on a scale of -3 (deterioration) to +3 (improvement) with established
criteria. RESULTS: With the thrombectomy catheter, the majority of thrombus
material was removed and antegrade blood flow was reestablished in 45 (90%)
patients. Technical success (residual luminal narrowing < 50%) was 52% with use
of the device alone. Adjunctive therapy was performed in 45 patients. Clinical
improvement after intervention was +3 in 25 (50%) patients, +2 in 10 (20%), +1 in
six (12%), and 0 (no improvement) in nine (18%). Clinically unimportant
complications related to use of the device were one (2%) distal embolization and
two (4%) dissections. Laboratory analysis revealed hemolysis without clinical
sequelae. Primary patency rates were 76% after 30 days, 74% after 3 months, and
69% after 1 year. CONCLUSION: The hydrodynamic catheter appears to be safe and
effective for rapid thrombectomy.
PMID- 9393521
TI - PTFE-encapsulated endovascular stent-graft for transjugular intrahepatic
portosystemic shunts: experimental evaluation.
AB - PURPOSE: To evaluate the safety and efficacy of a stent-graft designed for a
transjugular intrahepatic portosystemic shunt (TIPS), assess angiographic and
hepatic biologic responses to polytetrafluoroethylene (PTFE)-encapsulated stents,
and compare with a bare stent. MATERIALS AND METHODS: Twelve TIPS (eight with
flexible PTFE-encapsulated balloon-expandable stent-grafts and four control TIPS
with bare Wallstents) were created in 12 pigs. Shunt venography was performed at
1-month intervals and necropsy of graft-containing animals at 1, 2, 3, 4, and 5
months. Control animals were sacrificed at 6 weeks. Detailed histopathologic
analyses were performed. RESULTS: The stent-grafts were readily deployed in all
cases. Seven of eight graft TIPS remained fully patent during the follow-up
period without luminal encroachment. Typical myofibrolasts proliferated on the
abluminal surface of the graft, without extension into the lumen. No inflammatory
reaction was present. Cellular overgrowth from the hepatic vein occluded the end
of one graft at 3 months, partly related to rapid axial growth of that animal.
The endoluminal surface of this shunt was otherwise patent. At 4-6 weeks, one
control TIPS was occluded and the other three showed 45%-85% stenoses. No bile
staining was seen in any case. CONCLUSION: This PTFE-encapsulated stent-graft is
biocompatible and safe to place. It markedly improves TIPS patency, providing
almost uninterrupted, unimpeded patency in this model.
PMID- 9393522
TI - Renal artery stenosis: evaluation with breath-hold, three-dimensional, dynamic,
gadolinium-enhanced versus three-dimensional, phase-contrast MR angiography.
AB - PURPOSE: To compare breath-hold, three-dimensional, gadolinium-enhanced magnetic
resonance (MR) angiography with three-dimensional, phase-contrast MR angiography
in the evaluation of renal artery stenosis. MATERIALS AND METHODS: Fifty-five
consecutive adult patients with clinical suspicion of renovascular disease were
prospectively examined with three-dimensional, phase-contrast MR angiography and
breath-hold, three-dimensional MR angiography with injection of a standard dose
of gadopentetate dimeglumine to evaluate the number of renal arteries and the
presence and degree of stenosis. The standard of reference was intraarterial
digital subtraction angiography. RESULTS: Gadolinium-enhanced MR angiography
depicted all 105 main renal arteries, whereas phase-contrast MR angiography
depicted 104. The number of accessory renal arteries depicted was significantly
higher with gadolinium-enhanced (17 of 18) than with phase-contrast (11 of 18)
studies (P = .04). Both techniques depicted 27 of the 29 stenoses (sensitivity,
93%; P > .05). Sensitivities, specificities, and accuracies in the diagnosis of
hemodynamically significant stenosis (> 50% narrowing) were, respectively, 94%,
96%, and 96% for phase-contrast and 100%, 97%, and 98% for gadolinium-enhanced MR
angiography (P > .05). CONCLUSION: Gadolinium-enhanced MR angiography is superior
to phase-contrast MR angiography in accessory renal artery depiction. No
statistically significant difference in the assessment of stenosis has been found
between the two techniques.
PMID- 9393523
TI - Coronary artery calcification in women with syndrome X: usefulness of double
helical CT for detection.
AB - PURPOSE: To determine the usefulness of double-helical computed tomography (CT)
for detection of diseased coronary arteries in women with anginal pain, positive
exercise stress test results, and angiographically normal coronary arteries
(syndrome X). MATERIALS AND METHODS: Double-helical CT of the coronary arteries
was performed in 81 consecutive women who were referred for coronary angiography
for evaluation of chest pain. Patients were classified into three groups
according to stress test and angiographic results: normal (normal exercise test
results and angiographically normal coronary arteries), syndrome X (abnormal
exercise test results and angiographically normal coronary arteries), and
coronary artery disease (at least one diseased vessel seen at angiography).
RESULTS: The prevalence of coronary calcification in the syndrome X group was 63%
(10 of 16 patients) compared with 96% (45 of 47 patients) in the coronary artery
disease group (P = .002) and 22% (four of 18 patients) in the normal group (P =
.02). The lowest total coronary calcification score and logarithmic transformed
data were found in the normal group (2.9 +/- 0.7), statistically significantly
higher values were found in the syndrome X group (4.3 +/- 1.5), and the highest
values were found in the coronary artery disease group (5.1 +/- 2.0; for trend, P
= .03). CONCLUSION: Double-helical CT may be useful in detection of
atherosclerosis in women with syndrome X who demonstrate normal coronary arteries
at angiography.
PMID- 9393524
TI - Visualization of colorectal polyps with spiral CT colography: evaluation of
processing parameters with perspective volume rendering.
AB - PURPOSE: To evaluate two key processing steps for detection of colon polyps with
spiral computed tomographic (CT) colography with perspective volume rendering
(PVR): image reconstruction and opacity assignment of the attenuation data.
MATERIALS AND METHODS: Spiral CT was performed in 10 patients with known polyps
confirmed at colonoscopy, and detailed quantitative analyses were performed of
data obtained in four. First, anatomic fidelity of three-dimensional (3D) images
generated from two-dimensional (2D) source images with equal voxel dimensions
(87%-90% overlap) was compared with 3D images generated from 2D source images
with unequal voxel dimensions (0%-80% overlap). Next, the relative dimensions of
colorectal polyps to adjacent structures were evaluated for various opacity
threshold settings. Then, step and sigmoidal opacity functions were compared with
respect to image smoothness and edge sharpness. RESULTS: PVR images generated
after interpolation of image data reconstructed with at least 60% overlap were
equivalent in image quality to PVR images generated from source images with equal
voxel dimensions. Relative polyp-to-haustral fold dimensions demonstrated
substantial distortions with opacity thresholds below -700 HU. The 3D PVR images
generated with the sigmoidal opacity function were significantly smoother than
those generated with the step opacity function (paired t test, P < .02), with
small differences noted in edge sharpness. CONCLUSION: Use of highly overlapping
source images (87%-90%) was not necessary to generate 3D PVR images of colorectal
polyps. Image artifacts were suppressed with use of an appropriate opacity
threshold and a sigmoidal opacity function without substantial loss in edge
sharpness.
PMID- 9393525
TI - Hypervascular liver metastases: do unenhanced and hepatic arterial phase CT
images affect tumor detection?
AB - PURPOSE: To evaluate the relative roles of unenhanced and hepatic arterial phase
(HAP) computed tomographic (CT) imaging in the detection of hypervascular liver
metastases. MATERIALS AND METHODS: Eighty-four patients with biopsy-proved liver
metastases from hypervascular primary tumors other than hepatocellular carcinoma
underwent unenhanced and HAP and portal venous phase (PVP) helical CT studies.
Three blinded radiologists evaluated each series of images separately for the
number, size, and enhancement characteristics of lesions. Sixty-nine patients had
follow-up imaging proof of tumor burden. RESULTS: The three readers detected 381
402 lesions on the PVP images and 397-416 lesions on the unenhanced images.
Unenhanced images allowed detection of 72%-80% of the lesions seen on PVP images.
They detected 94-137 additional lesions on unenhanced but not PVP images. On the
HAP images, 375-395 lesions were identified. HAP images allowed detection of 81%
90% of the lesions seen on PVP images. Forty-five to 78 additional lesions were
detected on HAP but not on PVP images. In the 69-patient subset, maximal
detection of tumor foci occurred in 94% of patients with unenhanced plus PVP
images and in 78% with HAP plus PVP images. Unenhanced plus PVP images allowed
detection of 96% of the 322 tumors in the subset population. CONCLUSION:
Unenhanced plus PVP CT images allow detection of statistically significantly more
hypervascular liver metastases than do HAP plus PVP images or imaging only in the
PVP.
PMID- 9393526
TI - Colorectal cancer: diagnostic potential of CT measurements of hepatic perfusion
and implications for contrast enhancement protocols.
AB - PURPOSE: To assess changes in hepatic perfusion in patients with colorectal
cancer with computed tomography (CT), diagnostic potential of CT perfusion
measurements, and implications for design of contrast enhancement protocols.
MATERIALS AND METHODS: In 27 patients with colorectal cancer, arterial and portal
perfusion were calculated from temporal changes in attenuation after intravenous
administration of contrast material. RESULTS: Arterial perfusion greater than
0.25 mL/min/mL was seen in nine (82%) of the 11 patients with overt metastases
versus six (38%) of the 16 patients with no overt metastases (P < .05). Portal
perfusion of 0.25 mL/min/mL or less was found in five (46%) of the patients with
overt metastases versus three (19%) of the patients with no overt metastases.
Follow-up imaging showed progressive metastatic disease in three patients, all of
whom had decreased portal perfusion. CONCLUSION: Increased arterial perfusion
appears to be an indicator of liver metastases, whereas reduced portal perfusion
may indicate progressive disease. Contrast enhancement protocols that are based
on experience with normal livers may not be optimal for patients with metastases.
PMID- 9393528
TI - Small (1.5 cm or less) liver metastases: US-guided biopsy.
AB - PURPOSE: To determine the techniques used for and the success of ultrasound (US)
guided biopsy of hepatic metastases 1.5 cm in diameter or smaller. MATERIALS AND
METHODS: A computer search of radiology reports identified 29 patients who
underwent US-guided biopsy of 30 hepatic masses 1.5 cm in diameter or smaller
suspected to be metastases. All 30 lesions were sampled for biopsy with the free
hand technique. Parameters assessed were lesion size and location, needle size,
transducer type, number of passes made, cytologic or histologic analysis, and
final histologic diagnosis. Biopsies were considered successful if a positive
histologic diagnosis of metastasis was made. RESULTS: The mean lesion diameter
was 1.3 cm (range, 0.9-1.5 cm). Lesion depth was 3-9 cm (mean, 5 cm). Twenty
biopsies were performed with a 22-gauge aspirating needle and analyzed
cytologically. An average of 2.7 passes were made per lesion. Phased-array sector
transducers were used in 23 lesions. In 28 (93%) lesions and 28 (96%) patients,
an adequate specimen was obtained to establish the histologic diagnosis of
metastatic disease. CONCLUSION: US appears to be an effective guidance technique
for biopsy of small liver metastases.
PMID- 9393527
TI - Hepatocellular carcinoma: evaluation with dynamic and static gadobenate
dimeglumine-enhanced MR imaging and histopathologic correlation.
AB - PURPOSE: To analyze the potential of gadobenate dimeglumine-enhanced magnetic
resonance (MR) imaging for the characterization and diagnosis of hepatocellular
carcinoma (HCC) by using static and dynamic sequences. MATERIALS AND METHODS:
Twenty-eight patients with histopathologically proved HCC were evaluated with T1-
and T2-weighted spin-echo and static and dynamic gradient-echo sequences before,
during, and after intravenous administration of 0.1 mmol/kg gadobenate
dimeglumine (0.5 mol/L). RESULTS: During the perfusion phase of the dynamic
sequence, all 16 nodular well-differentiated HCC lesions showed a rapid increase
in signal intensity 10-30 seconds after injection followed by a progressive
decrease in signal intensity. The nine poorly differentiated HCC lesions showed
no rapid increase in signal intensity. All eight large (> 3 cm), nodular, well
differentiated HCC lesions showed a hypointense rim before injection and both
hypo- and hyperintense rims (double-ring sign) immediately after injection,
compared with normal liver parenchyma. About 55 seconds after injection,
substantial single-rim enhancement was detected in 21 of the 28 HCC lesions.
CONCLUSION: Dynamic gadobenate dimeglumine-enhanced MR imaging allows improved
characterization of HCC lesions, which show rapid increase in signal intensity
during the early, arterial phase in well-differentiated HCC lesions and a double
ring sign in large well-differentiated nodular HCC lesions.
PMID- 9393529
TI - Gastrointestinal submucosal tumors: evaluation with endoscopic US.
AB - PURPOSE: To describe the endoscopic ultrasound (US) features of benign versus
malignant submucosal tumors throughout the gastrointestinal tract. MATERIALS AND
METHODS: One hundred nine patients aged 24-81 years suspected to have submucosal
tumors (11 esophageal, 41 stomach, 24 duodenal, and 33 colorectal tumors) at
barium studies or endoscopy underwent endoscopic US. The layer of origin,
internal echo pattern, and lesion margin were analyzed by means of consensus and
independent interpretation by three radiologists. RESULTS: Endoscopic US findings
revealed several distinct patterns among various submucosal tumors. Sixteen (94%)
of the 17 homogeneous lesions with histopathologic findings of malignancy were
hypoechoic, although 29 (43%) of the 68 homogeneous lesions with histopathologic
findings of benignity were similarly hypoechoic. Homogeneous lesions that were
anechoic, of intermediate echogenicity, or hyperechoic were almost exclusively
benign (39 [98%] of 40). In contrast, 23 (96%) of the 24 malignant lesions were
heterogeneous (n = 7) or homogeneously hypoechoic (n = 16). The sizes of benign
and malignant lesions were significantly different (P < .05). There was no
significant difference in the echo pattern (i.e., homogeneous versus
heterogeneous), but there was a significant difference in the proportion of
hypoechoic versus nonhypoechoic lesions (anechoic, hyperechoic, or of
intermediate echogenicity; P < .001). CONCLUSION: The differential diagnosis of
gastrointestinal submucosal tumors is assisted with endoscopic US.
PMID- 9393530
TI - Cystic dystrophy of the duodenal wall: radiologic findings.
AB - PURPOSE: To determine the radiologic characteristics of cystic dystrophy of the
duodenal wall. MATERIALS AND METHODS: Ten patients with cystic dystrophy of the
duodenal wall and chronic pancreatitis underwent ultrasonography (US) (n = 10),
computed tomography (CT) (n = 10), endoscopic US (n = 5), and endoscopic
retrograde cholangiopancreatography (ERCP) (n = 9). Cystic dystrophy of the
duodenal wall was classified as either cystic or solid. The imaging findings were
retrospectively analyzed and compared with findings at pancreatoduodenectomy (n =
10). RESULTS: The more frequent cystic type (n = 7) of cystic dystrophy of the
duodenal wall was characterized by the presence of easily recognizable cystic
lesions (diameter, more than 1 cm), located within the thickened wall of the
second portion of the duodenum. The solid type (n = 3) of cystic dystrophy of the
duodenal wall demonstrated fibrous thickening of the duodenal wall within which
small cysts (diameter, less than 1 cm) were present. The intraduodenal cysts were
usually elongated or bilobate with a thick wall. The thickening of the duodenal
wall appeared as a solid layer between the duodenal lumen and the pancreas,
hypoechoic at US, isoattenuating at unenhanced CT, and hypoattenuating in the
early phase (after initiation of infusion of contrast material) and
isoattenuating in the late phase (after completion of infusion) at contrast
material-enhanced CT. Findings at retrospective analysis of CT and endoscopic US
images were characteristic. CONCLUSION: Imaging modalities, notably CT and
endoscopic US, helped establish the diagnosis of cystic dystrophy of the duodenal
wall.
PMID- 9393531
TI - Carotid artery stents: early and intermediate follow-up with Doppler US.
AB - PURPOSE: To determine whether ultrasound (US) is a sensitive follow-up method
after placement of a carotid artery stent for the detection of significant
stenosis, occlusion, and other complications at early and intermediate follow-up.
MATERIALS AND METHODS: Doppler US examinations were performed after stent
placement in 170 carotid arteries in 119 patients with angiographic correlation.
Prospective diagnostic US criteria for stenosis were peak-systolic velocity
greater than 1.25 m/sec, internal carotid artery (ICA) to common carotid artery
(CCA) peak-systolic velocity ratio of greater than or equal to 3:1, and
intrastent doubling of peak-systolic velocity. Retrospective criteria for
stenosis were also applied: peak-systolic velocity greater than 1.7 m/sec, ICA
end-diastolic velocity greater than 0.4 m/sec, ICA/CCA peak-systolic velocity
ratio greater than 2.0, and ICA/CCA end-diastolic velocity ratio greater than
2.4. RESULTS: Eighty-seven immediate and 83 intermediate (average, 7.3 months)
follow-up US examinations were performed. Two stent occlusions were detected. One
or more prospective US criteria were abnormal in 26 arteries with a stent. One or
more retrospective criteria were positive in 47 arteries. Angiography showed
corresponding findings, with only one significant stenosis (63%) in the ICA
stents. Moderate collapse of a CCA stent was depicted at US. CONCLUSION: Only one
significant recurrent stenosis was detected, and no significant stenoses were
missed at US. US successfully depicted carotid artery stent occlusion and a
moderate stent collapse. Sensitivity in the detection of intrastent stenosis is
promising. Further study to refine US criteria in a study with longer term follow
up is needed owing to the lack of significant recurrent stenosis in the
intermediate follow-up group.
PMID- 9393532
TI - Normalizing fractional moving blood volume estimates with power Doppler US:
defining a stable intravascular point with the cumulative power distribution
function.
AB - PURPOSE: To normalize the power Doppler ultrasound (US) signal to the expected
signal from 100% blood in the calculation of a fractional moving blood volume
estimate. MATERIALS AND METHODS: To locate the signal from flowing blood with a
consistent backscatter coefficient, the authors estimated the knee of the
cumulative Doppler power distribution function. They used a flow-tube phantom to
test the use of this knee to locate a radial position that would fall into a
region of high shear stress and minimal rouleaux formation. They also studied how
well the method normalized fractional moving blood volume estimates of the right
renal cortex in a volunteer when simulating different body habitus and in a group
of six healthy volunteers to estimate variability. RESULTS: Over five flow
velocities and over undersaturated to severely oversaturated receiver gains, the
calculated flow-tube area was a mean 89% +/- 7 (+/- standard deviation) of a
standard. In humans, the technique normalized the fractional moving blood volume
estimates over an 8-dB receiver gain variation; the mean +/- standard deviation
of fractional moving blood volume estimates for the six volunteers was 37.6% +/-
3.6. CONCLUSION: Vascularity estimates with power Doppler US are feasible with a
normalization scheme based on the cumulative Doppler power distribution function.
PMID- 9393533
TI - Renal cancer: preoperative evaluation with dual-phase three-dimensional MR
angiography.
AB - PURPOSE: To evaluate the use of dual-phase three-dimensional magnetic resonance
(MR) angiography in the preoperative staging of renal cancer. MATERIALS AND
METHODS: MR angiography was performed in 18 patients before performance of
partial (n = 7), radical (n = 10), or laparoscopic (n = 1) nephrectomy to treat
renal cancer. Dynamic, three-dimensional MR angiograms were obtained with
gadoteridol enhancement, breath holding, and a three-dimensional spoiled gradient
echo sequence. Images were obtained at 15-second intervals to achieve
opacification of arteries and veins. Source, maximum intensity projection, and
multiplanar reconstruction images were evaluated. Imaging results were compared
with surgical findings. RESULTS: Renal arterial phase MR angiograms depicted 30
of 31 (97%) surgically confirmed renal arteries, with one false-positive result
(an artery that arose from an early-branching single main renal artery,
interpreted as a separate accessory artery). Renal venous phase MR angiograms
depicted all seven instances of renal vein involvement, including extension to
the inferior vena cava in two patients. Collateral vessels around the tumor,
including prominent gonadal veins in three patients, were demonstrated.
Additional findings included adenopathy and adrenal and pulmonary metastases.
CONCLUSION: Dual-phase MR angiography of the kidney may be a useful technique in
depicting renal vessels before nephrectomy.
PMID- 9393534
TI - Placenta accreta: evaluation with color Doppler US, power Doppler US, and MR
imaging.
AB - PURPOSE: To determine the value of transabdominal ultrasound (US), transvaginal
US, color Doppler US, power Doppler US, and magnetic resonance (MR) imaging in
the diagnosis of placenta accreta. MATERIALS AND METHODS: Nineteen patients in
the third trimester of pregnancy who were at risk for placenta accreta underwent
color Doppler and power Doppler US; 18 patients also underwent MR imaging. Images
were interpreted prospectively for signs of accreta by two reviewers. The
reviewers' confidence in their diagnosis was graded on a five-point scale.
RESULTS: Outcomes at delivery were as follows: normal placenta (n = 11),
hysterectomy owing to uncontrollable bleeding (n = 1), and placenta accreta (n =
7). Five cases of lower-uterine-segment placenta accreta were diagnosed with a
high level of confidence with vaginal and power Doppler US. In one patient with a
posterior placenta who had previously undergone myomectomy, MR imaging enabled
the diagnosis of placenta accreta, which was not well depicted at US. CONCLUSION:
In patients with a history of uterine scars, vaginal US with power Doppler US
performed well in the evaluation of lower-uterine-segment placenta accreta. MR
imaging depicts posterior placenta accreta.
PMID- 9393535
TI - Medial border of the perirenal space: CT and anatomic correlation.
AB - PURPOSE: To explore the mode of spread of disease between the perirenal space and
the perivascular central retroperitoneum and to determine the anatomy along the
medial border of the perirenal space. MATERIALS AND METHODS: Anatomic dissection,
injection of latex, and observation of cross sections of the abdomen were
performed in nine cadavers. Attention was paid to the juncture of the central
prevertebral, perivascular, and extraperitoneal regions, and the perirenal space.
Anatomic findings were correlated with observations made at computed tomography
(CT) in 82 patients with retroperitoneal hemorrhage (n = 24), inflammation (n =
37), and neoplasia (n = 21) involving the perirenal spaces or the central
retroperitoneum. RESULTS: Along most of the length of each kidney, no apparent
fascia separates the perirenal space from the central retroperitoneum. At this
location, septa between fat lobules form a fenestrated multitier barrier. These
septa were imperceptible on CT scans obtained in healthy individuals. After
injection of latex in cadavers, this potential barrier was seen. In the clinical
study, spread of disease was allowed in only 38 (30%) of 128 instances of
potential spread. Spread was facilitated along the renal vessels and the
interlobular septa. CONCLUSION: Beyond the kidneys, the renal fascia is closed,
forming a cone superiorly and an inverted cone inferiorly. A network of
interlobular septa acted as a barrier or pathway to the free spread of disease
from the perirenal space to the central retroperitoneum or from the central
retroperitoneum to the perirenal space.
PMID- 9393536
TI - Balloon dacryocystoplasty: indications and contraindications.
AB - PURPOSE: To define the indications and contraindications for balloon
dacryocystoplasty. MATERIALS AND METHODS: Eighty-five patients with severe
epiphora due to partial (n = 47) or complete (n = 38) obstruction of the
nasolacrimal duct (NLD) were treated with balloon dacryocystoplasty (DCP).
Steerable micro-guide wires with flexible tips were used. Success rates of DCP
were evaluated clinically and dacryocystographically during the acute phase and
at 6- and 12-month follow-up. Failures and recurrences were correlated with
clinical and dacryocystographic indications for treatment. RESULTS:
Recanalization was successful in 35 (92%) of 38 patients with isolated focal
stenoses (n = 20) or short-distance occlusions (n = 18) of the NLD. Among all 85
patients, recanalization was successful in 25 patients (66%) with complete and 37
patients (79%) with partial obstructions. In the absence of the main predictors
for recurrent obstructions (ie, active inflammation, filling defects due to
calculi, long-distance occlusions, and posttraumatic lesions), 12-month patency
rates were 89% (17 of 19 focal stenoses) and 94% (15 of 16 focal occlusions).
Otherwise, reobstruction rate was 46% (12 of 26 cases). CONCLUSION: Balloon
dacryocystoplasty is successful only in select cases. To achieve results
comparable to those of operative treatment, the indication should be limited to
patients with circumscribed focal stenoses or occlusions of the NLD. Active
dacryocystitis, dacryocystolithiasis, and posttraumatic lesions are the main
contraindications.
PMID- 9393537
TI - Obstructed nasolacrimal duct system in epiphora: long-term results of
dacryocystoplasty by means of balloon dilation.
AB - PURPOSE: To evaluate the long-term results of balloon dacryocystoplasty in the
treatment of epiphora due to obstruction of the nasolacrimal ducts. MATERIALS AND
METHODS: One hundred eyes in 84 patients with complete or incomplete obstruction
of the lacrimal sac and duct were selected for dacryocystoplasty. A catheter with
a balloon diameter of 3 mm was used. Follow-up was 5-48 months. No stents were
placed. A Kaplan-Meier analysis was used to evaluate patency. RESULTS: The long
term primary patency rate was 70% +/- 7 (+/- standard error). Repeat
dacryocystoplasty was successful in 10 of the 11 cases with initial failure or
reobstruction during follow-up, which yielded a long-term secondary patency rate
of 81% +/- 7. There was no association between the length of the obstruction or
the duration of symptoms before dacryocystoplasty and the initial and long-term
success. Initial and long-term success was statistically significantly higher in
dacryocystoplasty for an incomplete obstruction rather than for a complete
obstruction. CONCLUSION: The long-term results of dacryocystoplasty, followed if
necessary by repeat dacryocystoplasty, are good. Dacryocystoplasty is a safe and
simple procedure and could become the treatment of choice for epiphora due to
obstruction of the nasolacrimal ducts. Dacryocystorhinostomy is indicated when
dacryocystoplasty or repeat dacryocystoplasty fails or when dacryocystoplasty is
contraindicated (e.g., in anatomic malformations in the lacrimal duct or bony
canal).
PMID- 9393538
TI - Brain capillary telangiectasia: MR imaging appearance and clinicohistopathologic
findings.
AB - PURPOSE: To demonstrate the clinical and magnetic resonance (MR) imaging findings
of brain capillary telangiectasia and compare them with postmortem specimens.
MATERIALS AND METHODS: MR images obtained in and clinical histories of 18 adult
patients with a presumed diagnosis of capillary telangiectasia examined within 3
years were retrospectively reviewed. All patients had undergone MR imaging with
conventional T1- and T2-weighted spin-echo sequences and gadolinium-enhanced T1
weighted and susceptibility-sensitive gradient-echo (GRE) sequences. No biopsies
had been performed. Fourteen patients had undergone clinical and MR imaging
follow-up (median, 11 months). Postmortem tissues from three cases of
histopathologically confirmed capillary telangiectasia were imaged. RESULTS: All
lesions were small, homogeneously enhancing, and hypo- to isointense on T1
weighted images and iso- to slightly hyperintense on proton-density- and T2
weighted images. None was hypointense on proton-density- or T2-weighted images.
All lesions showed marked GRE signal loss. None had changed at follow-up. Two
patients had multiple classic cerebral cavernous angiomas. The three specimens
showed no abnormal susceptibility and contained no hemosiderin at tissue
analysis. CONCLUSION: Capillary telangiectasia has mild contrast material
enhancement but is otherwise undetectable on conventional MR images. It lacks the
"hemosiderin rim" of cavernous angioma and demonstrates increased susceptibility
only on GRE images, likely owing to blood oxygen-level-dependent contrast. GRE is
essential in diagnosing brain capillary telangiectasia, which could otherwise be
misdiagnosed as neoplasia, subacute infarction, or demyelination.
PMID- 9393539
TI - Intracranial tumor in children: MR imaging findings within 24 hours of
craniotomy.
AB - PURPOSE: To evaluate whether very early magnetic resonance (MR) imaging enables
distinction of residual tumor from benign postoperative change in children.
MATERIALS AND METHODS: Forty-six postoperative MR examinations were performed in
43 children with intracranial tumors within 24 hours of the completion of surgery
during a 2-year period. These examinations were categorized according to whether
residual tumor could be definitely identified or excluded, or whether the
diagnosis was uncertain. RESULTS: Contrast enhancement occurred in 33 of 46 MR
examinations performed within 24 hours of surgery. In 18 instances, this was
associated with obvious residual tumor. In 15 patients, only small amounts of
linear or patchy enhancement were seen. Of these, seven patients (46%) were
disease-free for an average of 4.5 years. Assessment for postoperative
enhancement was hampered in seven patients because of the presence of
methemoglobin in the tumor bed. Contrast enhancement was not observed in two
patients before surgery. CONCLUSION: Surgically induced, MR-detectable contrast
enhancement and extracellular methemoglobin formation occurs within 24 hours of
the completion of intracranial surgery. This can interfere with the detection of
small amounts of residual tumor.
PMID- 9393540
TI - Fetal cerebral ventriculomegaly: misidentification of the true medial boundary of
the ventricle at US.
AB - PURPOSE: To investigate the implications of mistaking the medial surface of the
cerebral hemisphere for the medial wall of the lateral ventricle at antenatal
ultrasonography (US) and to identify US clues that might help avoid this
interpretive error. MATERIALS AND METHODS: In 50 second- and third-trimester
fetuses, a directed attempt was made to demonstrate the medial surface of the
cerebral hemisphere and the medial wall of the lateral ventricle on images that
depicted the lateral wall of the ventricle. In each fetus, measurements of the
diameter of the false ventricular atrium were compared with the true diameter of
the lateral ventricle to assess the potential magnitude of error. RESULTS: The
average diameter measured with the medial surface of the cerebral hemisphere was
10.7 mm, compared with the true mean ventricular diameter of 6.2 mm. This value
was greater than or equal to 10 mm (the generally accepted upper limit of normal
for the ventricular diameter) in all 15 third-trimester fetuses and in 16 (46%)
of 35 second-trimester fetuses. The parietal occipital fissure was demonstrated
along the medial surface of the cerebral hemisphere in 36 (72%) of 50 fetuses,
and the medial surface of the cerebral hemisphere could be traced posteriorly
around the occipital lobe in 45 (90%). CONCLUSION: When ventriculomegaly is
suspected, the examiner should make a direct attempt to find the medial wall of
the ventricle and distinguish it from the medial boundary of the cerebral
hemisphere. Correct identification of the anatomic interfaces is facilitated by
demonstrating that the cerebral interface contains the parietal occipital fissure
and can be traced posteriorly around the occipital lobe.
PMID- 9393541
TI - Pneumonia in children: decreased parenchymal contrast enhancement--CT sign of
intense illness and impending cavitary necrosis.
AB - PURPOSE: To determine if computed tomographic (CT) findings of decreased contrast
material enhancement are predictive of more intense illness and of the
development of cavitary necrosis in children with pneumonia. MATERIALS AND
METHODS: Contrast-enhanced CT scans in 44 children with pneumonia who did not
respond appropriately to therapy were compared with precontrast CT scans to
evaluate enhancement of consolidated lung parenchyma. Enhancement was correlated
with admission to the intensive care unit, length of hospital stay, cavitary
necrosis in the lung at follow-up CT, and frequency of lung resection. RESULTS:
Parenchymal enhancement was decreased in 21 children; pneumonia was enhanced in
the other 23 children. Decreased enhancement was associated with increased
admission to intensive care (14 of 21 [67%] vs five of 23 [22%] children; P =
.0026), increased length of hospital stay (15 vs 10 days; P = .0615), increased
frequency of cavitary necrosis at follow-up CT (seven of seven [100%] vs none of
three children; P = .0086), and increased frequency of resection (two of 21 [10%]
vs none of 23 children). At histopathologic examination, diffuse cavitary
necrosis was present in resected lobes in two patients. CONCLUSION: Decreased
parenchymal enhancement at CT is a predictor of more intense illness and may
herald the development of cavitary necrosis in children with pneumonia.
PMID- 9393542
TI - Vesicoureteral reflux in older children: concordance of US and voiding
cystourethrographic findings.
AB - PURPOSE: To determine if a negative renal sonogram is reliably predictive of the
absence of vesicoureteral reflux at voiding cystourethrography (VCUG) in children
aged 5 years or older. MATERIALS AND METHODS: Imaging studies in 70 children aged
5 years or older who underwent renal ultrasound (US) and VCUG on the same day
were reviewed. These children had initially undergone evaluation because of a
urinary tract infection. RESULTS: Five of 70 children had abnormal sonograms; two
(40%) of the five had reflux at VCUG. One had mild pelvicalyceal dilatation, and
one had a small kidney. The other three (without reflux) had a pelvic kidney, a
calyceal diverticulum, or a renal stone. Of 65 children with a negative sonogram,
19 (29%) had reflux at VCUG; 46 (71%) did not. Altogether, of the 70 children, 21
had reflux, 19 (90%) of whom had no sonographic abnormality. CONCLUSION: Children
with abnormal screening renal sonograms often have vesicoureteral reflux, but a
normal sonogram does not reliably exclude the condition even in children aged 5
years or older. Therefore, VCUG must be performed even in older children,
regardless of US findings, if clinical decisions are influenced by documentation
of the presence of VUR.
PMID- 9393543
TI - Detection of malignant and benign breast lesions with an automated US system:
results in 120 cases.
AB - PURPOSE: To evaluate clinically an automated ultrasound (US) system for detecting
benign and malignant breast lesions. MATERIALS AND METHODS: A prototype automated
US system was used to examine 119 patients: 38 patients with 39 proved malignant
breast lesions (7-50 mm), 41 patients with 41 proved benign breast lesions (8-40
mm), and 40 patients without breast lesions. The device yields a three
dimensional set of B-mode scans and reconstructed US images comparable to
mammograms. All patients had undergone mammography. Four radiologists who had not
performed the examinations independently assessed the mammograms and US images to
detect benign and malignant breast lesions. RESULTS: Each of the four readers did
not recognize one to three detectable malignant lesions on mammograms, one to two
detectable malignant lesions on US images, two to four detectable benign lesions
on mammograms, and five to seven detectable benign lesions on US images. All
readers identified the 39 cancers with at least one of the modalities. The 40
cases without lesions were diagnosed correctly more frequently on the US images
by three readers and on the mammograms by one reader. CONCLUSION: Depiction of
breast lesions at automated US is reproducible. Automated US is complementary to
mammography.
PMID- 9393544
TI - Metastatic breast carcinoma in axillary lymph nodes: in vitro US detection.
AB - PURPOSE: To establish the ultrasonographic (US) characteristics of benign versus
metastatic lymph nodes. MATERIALS AND METHODS: One hundred fifty-eight axillary
lymph nodes in 40 patients (age range, 31-73 years) surgically treated for breast
cancer have been studied in vitro with a 7.5-MHz US probe in a water bath. The
long-to-short axis ratio and the hilar and cortical characteristics were
evaluated; the US findings were correlated with the histopathologic findings. To
estimate the long-to-short axis ratio, all lymph nodes were measured. RESULTS: Of
the 158 lymph nodes, 45 showed histopathologic evidence of metastasis; 38 of the
45 revealed US signs of malignancy. The signs that caused malignancy to be
suspected were a long-to-short axis ratio of less than 1.5, absence of a hilus,
and disruption of the cortical zone. The most specific sign for the diagnosis of
metastasis was absence of the hilus. The increase in the long-to-short axis ratio
was the finding that caused the most false-negative interpretations. Signs of
malignancy were more accurate in lymph nodes 10 mm or larger than they were in
lymph nodes smaller than 10 mm. CONCLUSION: Findings of in vitro US studies of
axillary adenopathy provide the basis for the evaluation of lymph node metastasis
in vivo before surgery, especially in those lymph nodes 10 mm or larger.
PMID- 9393545
TI - Dynamic echo-planar imaging of the breast: experience in diagnosing breast
carcinoma and correlation with tumor angiogenesis.
AB - PURPOSE: To correlate quantitative echo-planar magnetic resonance (MR) imaging
measures of gadopentetate dimeglumine tumor uptake with histologic diagnoses and
microvessel density (MVD) and to compare dynamic echo-planar imaging of breast
lesions with conventional dynamic MR imaging techniques. MATERIALS AND METHODS:
The study group comprised 63 patients (aged 13-70 years) with 71 breast lesions
who underwent conventional and echo-planar MR imaging. The T1 values, change in
gadopentetate dimeglumine concentration, and extraction-flow products were
calculated with the echo-planar imaging data and were correlated with histologic
findings and MVD estimates. Extraction-flow product data normalized to pectoral
muscle gadopentetate dimeglumine concentration in invasive cancers was also
correlated with MVD. RESULTS: On average, cancer T1 values were shorter than
benign values, but there was substantial overlap between the two groups. Cancers
had higher extraction-flow products than benign lesions (P < .001). Sensitivity,
specificity, positive predictive value, and negative predictive value were 83%,
79%, 67%, and 90%, respectively. Receiver operating characteristic analysis
showed improved performance with extraction-flow products than with percentages
of signal intensity change. Among the invasive cancers, there was no significant
correlation between extraction-flow product and MVD. CONCLUSION: The T1 value
remains important in more precise quantitative estimation of gadopentetate
dimeglumine uptake in breast tumors, which helps improve the specificity of
dynamic imaging. Tumor MVD affects the contrast medium enhancement of breast
lesions, but other factors contribute.
PMID- 9393546
TI - Functional anatomy of the thoracic outlet: evaluation with spiral CT.
AB - PURPOSE: To determine the anatomic characteristics of the thoracic outlet before
and after dynamically induced modifications. MATERIALS AND METHODS: Fifty-two
volunteers (24 women; 28 men; mean age, 42 years) with no clinical or
radiographic indications of thoracic outlet syndrome underwent spiral computed
tomography (CT) of the apexes at full inspiration with the arms alongside the
body and then with the dominant arm in hyperabduction, with a contralateral
rotation of the head. RESULTS: After elevation of the dominant arm, (a) no
statistically significant difference was found in median value of the
costosubclavian and costoclavicular distances; (b) the median distance between
the posterior border of the smaller pectoral muscle and the anterosuperior chest
wall was 12 mm in all subjects; (c) the subclavian artery in 18 (75%) women and
in 20 (71%) men and/or the subclavian vein in three (12%) women and in three
(11%) men were identified in the costoclavicular space. The median angles of
rotation, retraction, and upward displacement of the clavicle were 22 degrees, 32
degrees, and 7 degrees, respectively, in women and 25 degrees, 31 degrees, and 11
degrees, respectively, in men. CONCLUSION: Spiral CT is expected to be useful for
determining the complex pathophysiologic processes that underlie thoracic outlet
syndrome.
PMID- 9393547
TI - The breast: in-plane x-ray protection during diagnostic thoracic CT--shielding
with bismuth radioprotective garments.
AB - PURPOSE: To evaluate the ability of thin overlying bismuth radioprotective
shielding to reduce the x-ray dose to radiosensitive superficial organs during
diagnostic computed tomography (CT). MATERIALS AND METHODS: A variety of patient
and phantom studies were performed with four thicknesses of bismuth
radioprotective latex over the breast. Dose savings were determined with
thermoluminescent dosimeters. A prototype and then a final manufactured
radioprotective brassiere was constructed and tested for radiation dose savings
to the breast during diagnostic chest CT. Preliminary studies were also performed
to evaluate shielding of the thyroid, orbit, and testes. RESULTS: The use of
bismuth radioprotective latex saved an average 57% of the radiation dose to the
breast from thoracic CT, decreasing the radiation level from an average 2.2 rad
(0.022 Gy) to 1.0 rad (0.010 Gy) (P < .001). Preliminary tests of shielding other
superficial radiosensitive organs frequently included at diagnostic CT (eyes,
thyroid gland, and testes) were performed with the same thickness of overlying
bismuth radioprotective latex, with similar results. Radiation to the thyroid
gland was reduced by 60% (from 0.0573 to 0.0229 Gy) and radiation to the eye and
testes was reduced by 40% (from 0.0256 to 0.0154 Gy) and 51% (from 0.0463 to
0.0229 Gy), respectively. CONCLUSION: The use of in-plane overlying bismuth
radioprotective latex manufactured into form-fitting garments did not affect the
diagnostic CT image but reduced the amount of radiation to radiosensitive
superficial structures.
PMID- 9393549
TI - Scaphopisocapitate alignment: criterion to establish a neutral lateral view of
the wrist.
AB - PURPOSE: To determine whether a "true" neutral lateral view of the wrist is
necessary for accurate capitolunate angle measurement, to compare two standards
of diagnostic adequacy for neutral lateral wrist views (distal radioulnar overlap
[RUO] and scaphopisocapitate [SPC] relationship), and to confirm positional
reproducibility and measurement precision of the SPC criterion. MATERIALS AND
METHODS: Capitolunate angles were measured on neutral lateral and supine
pisotriquetral views of 10 normal wrists. Two hundred neutral lateral wrist views
were classified by each standard (RUO and SPC) as excellent, acceptable, or
unacceptable. In two subgroups, capitolunate angles were measured on the lateral
views to determine SPC practicality and sensitivity. RESULTS: Compared with
neutral lateral positioning, supinated off-lateral views showed an apparent
increase in lunate dorsiflexion of up to 30 degrees. Diagnostically unacceptable,
excellent, and acceptable pronosupination was present on 118, 22, and 60 of 200
views by using the RUO criterion and on 40, 79, and 81 of 200 views by using the
SPC criterion, respectively. The capitolunate angle did not show a significant
difference between each of the two subgroups (P > .05). CONCLUSION: A true
neutral lateral view of the wrist is necessary for accurate measurement of the
capitolunate angle on the basis of a comparison with off-lateral views. SPC
relationship provides a diagnostically reproducible standard for a neutral
lateral wrist view and should reduce the need for repeat lateral radiographs.
PMID- 9393548
TI - Accuracy of bedside chest hard-copy screen-film versus hard- and soft-copy
computed radiographs in a medical intensive care unit: receiver operating
characteristic analysis.
AB - PURPOSE: To compare the clinical diagnostic accuracy of hard-copy readings of
screen-film bedside chest radiographs and both hard- and soft-copy readings of
bedside chest computed radiographs obtained in a medical intensive care unit.
MATERIALS AND METHODS: Two samples of 95 cases were assembled from chest images
obtained in 541 patients with either screen-film radiography or computed
radiography. The cases were stratified according to the clinical problem for
which the examination was ordered; the corresponding diagnosis was verified by a
panel of two or three radiologists. Four radiologists blindly read the hard-copy
images obtained with screen-film or computed radiography. Six months later, the
radiologists read the computed radiographs by using an 8-bit, 1,684 x 2,048-pixel
display. The data were analyzed by using multireader-multicase receiver operating
characteristic (ROC) analysis of variance. RESULTS: No statistically significant
differences in the area under the ROC curve were found between any of the
methods. CONCLUSION: The results provide some justification for using bedside
chest computed radiography and for reading soft-copy images from a high-quality
display.
PMID- 9393550
TI - Soft-tissue sarcoma involving bone or neurovascular structures: MR imaging
prognostic factors.
AB - PURPOSE: To determine if magnetic resonance (MR) imaging findings of soft-tissue
sarcoma involving bone or neurovascular structures allow prediction of local
recurrence, distant metastasis, or disease-specific survival. MATERIALS AND
METHODS: Preoperative MR images of 46 patients with soft-tissue sarcoma were
reviewed for tumor involving bone or major vessels or nerves. MR imaging findings
were correlated with local recurrence, distant metastasis, and disease-specific
survival after surgery and chemotherapy and/or radiation therapy. Primary tumors
were predominantly in the lower extremity (n = 35 [76%]), deep (n = 44 [96%]),
and high-grade (n = 35 [76%]). RESULTS: On MR images, bone invasion occurred in
12 patients (26%), major-vessel encasement in five patients (11%), and major
nerve encasement in seven patients (15%). In patients with (n = 12) and those
without (n = 34) bone invasion, frequencies of disease-related death (in nine
[75%] and 12 [35%] patients, respectively) were significantly different (P =
.02); frequencies of local recurrence or distant metastasis were not
significantly different. In patients with and those without major-vessel or major
nerve encasement, there were no significant differences between frequencies of
local recurrence, distant metastasis, or disease-specific survival. CONCLUSION:
In soft-tissue sarcoma, bone invasion on MR images was predictive of decreased
disease-specific survival. MR imaging findings of bone or neurovascular
involvement otherwise appear to be more important for tailoring surgery than for
predicting local recurrence, distant metastasis, or survival.
PMID- 9393551
TI - Bell's palsy and herpes simplex virus.
AB - Bell's palsy, which is defined as idiopathic peripheral facial paralysis of
sudden onset, accounts for > 50% of all cases of facial paralysis. Different
theories on the etiology of Bell's palsy have been proposed and investigated.
Various clinical studies have suggested an etiological link between Bell's palsy
and herpes simplex virus (HSV). In addition, animal experiments have shown the
ability of HSV to induce facial paralysis. In our opinion, the possible link
between Bell's palsy and HSV can only be explored properly by studying the human
facial nerve, and especially the geniculate ganglion itself. Different groups
have tried to detect hypothetically reactivated and hypothetically latent HSV in
the facial nerves of Bell's palsy patients and control patients, respectively.
The isolation of infectious HSV from facial nerve tissue by conventional cell
culture methods appeared to be very difficult, also when Bell's palsy patients
were tested. Instead, modern molecular methods, such as in situ hybridization and
the polymerase chain reaction (PCR) could easily detect HSV DNA in geniculate
ganglia. The detection of HSV-specific latency-associated transcripts in the
ganglia of control patients provided further evidence for the hypothetically
latent state of HSV in the geniculate ganglia in these patients. Recent PCR
experiments performed by a Japanese group strongly suggest that the area adjacent
to the geniculate ganglia does not usually contain any HSV at all, except in
patients with Bell's palsy. This well-controlled study provides conclusive
evidence that reactivation of HSV genomes from the geniculate ganglia is the most
important cause of Bell's palsy. Consequently, it has been suggested that "Bell's
palsy" be renamed as "herpetic facial paralysis".
PMID- 9393552
TI - Normal interleukin-12 production in individuals with antibodies to Helicobacter
pylori.
AB - It is increasingly recognized that the inability of the immune system to clear H.
pylori infection is caused by an inadequate immune response and is associated
with chronic gastric inflammation. To further investigate the cellular immune
response to H. pylori, we studied PBMC from 31 H. pylori antibody-negative and 16
H. pylori antibody-positive individuals for H. pylori-induced DNA synthesis,
secretion of the Th1-type cytokine IFN-gamma and secretion of IL-12, a cytokine
produced by bacteria-stimulated monocyte/macrophages and a potent inducer of
antibacterial immune responses and Th1-type T cells. All experiments were
performed using Y. enterocolitica 03 as control. Our results demonstrate that DNA
synthesis, IFN-gamma production and IL-12 production induced by H. pylori or Y.
enterocolitica 03 did not differ significantly between H. pylori antibody
positive and H. pylori antibody-negative individuals. However, in the H. pylori
positive group there was a tendency, although not statistically significant, to
produce less IFN-gamma in response to H. pylori but not Y. enterocolitica. These
results demonstrate that monocyte/macrophages from H. pylori-positive individuals
secrete normal amounts of IL-12 upon bacterial challenge and suggest that the
decreased production of IFN-gamma in H. pylori-positive individuals observed in
previous studies is selective for H. pylori and not caused by decreased IL-12
secretion.
PMID- 9393553
TI - Hemagglutination ability and adherence to the Buffalo green monkey kidney cell
line of uropathogenic Escherichia coli.
AB - The hemagglutination ability and adherence capacity to the Buffalo green monkey
(BGM) kidney cell line of 160 wild-type strains of Escherichia coli isolated from
bacteriuric patients were investigated. It was found that P-fimbriated E. coli
strains adhered significantly better to BGM cells than did strains in which P
fimbriae were not detected, which is in accordance with the capacity of P
fimbriated strains to cause unobstructive pyelonephritis and with receptor
distribution for P-fimbriae in the urinary tract. The strains which exhibited
other adhesions, alone or simultaneously, showed reduced adherence to BGM cells,
while non-agglutinating strains, mostly isolated from urine of patients with
asymptomatic bacteriuria, did not adhere at all or adhered poorly to the utilized
cell line. The BGM cells served as a good experimental model for investigation of
uropathogenic E. coli adherence; because these cells originate from the upper
urinary tract, they are viable and not coated with Tamm-Horsfall protein.
PMID- 9393554
TI - Chronic Pseudomonas aeruginosa lung infection is more severe in Th2 responding
BALB/c mice compared to Th1 responding C3H/HeN mice.
AB - The chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) is
characterized by a pronounced antibody response and microcolonies surrounded by
numerous polymorphonuclear neutrophils (PMN). Poor prognosis is correlated with a
high antibody response to P. aeruginosa antigens. An animal model of this
infection was established in two strains of mice: C3H/HeN and BALB/c, generally
known as Th1 and Th2 responders, respectively, which were challenged with
alginate-embedded P. aeruginosa. Mortality was significantly lower in C3H/HeN
compared to BALB/c mice (p < 0.025). P. aeruginosa was cleared more efficiently
in C3H/HeN mice and significantly more C3H/HeN mice showed normal lung
histopathology (p < 0.02), and we found significantly fewer microabscesses in
C3H/HeN mice than in BALB/c mice (p < 0.005). In supernatants from P. aeruginosa
antigen and concanavalin A-stimulated spleen cells from the two strains of mice,
the interferon-(IFN-) gamma levels were higher, whereas IL-4 levels were lower in
C3H/HeN mice than in BALB/c mice. The implications of these findings for CF
patients with chronic P. aeruginosa lung infection are discussed.
PMID- 9393555
TI - Improved ELISA for determination of anti-diphtheria and/or anti-tetanus antitoxin
antibodies in sera.
AB - Double-antigen ELISAs for detection and quantification of anti-tetanus or anti
diphtheria antibodies in serum have been developed. The assays showed good
correlations with established toxin neutralizing assays and were functionally
specific for IgG antibodies. The double-antigen set-up allows specific antibodies
to bind to antigen-coated microtitre wells with one arm and the free arm to bind
to biotin-labelled antigen. The amount of antibodies able to bind labelled
antigen was assessed by adding enzyme-conjugated streptavidin and colour
substrate followed by measurement of the colour using an ELISA reader. The double
antigen principle makes it possible to compare samples of different species on
the same plate, permitting the direct use of existing international references of
animal or human origin. The double-antigen ELISAs showed a detection limit of
0.00002 IU/ml for both antibodies and were suitable for quantifying antibodies in
blood samples collected on filter paper as well as in serum. The assays required
no special equipment compared to traditional ELISA.
PMID- 9393556
TI - Antibiotic susceptibility of blood culture isolates of Enterobacteriaceae from
six Norwegian hospitals 1991-1992.
AB - From August 1991 to February 1992, each of the six largest hospitals throughout
Norway collected 84 to 107 consecutive blood culture isolates of
Enterobacteriaceae, altogether 571 isolates. The distribution of various species
and genera at the different hospitals was uniform; Escherichia coli being most
prevalent (57-67%), followed by Klebsiella spp. (12-18%) and Proteus mirabilis (7
11%). Twenty-one and 4% of E. coli isolates were resistant to ampicillin and
cefuroxime, respectively, and 11% of Klebsiella isolates were cefuroxime
resistant. Five Enterobacter isolates and one Citrobacter isolate were resistant
to ceftazidime, and one Salmonella isolate was resistant to imipenem. All
isolates were susceptible to ciprofloxacin and tobramycin. These results were
compared with the antibiotic consumption in each hospital region. Although
hospitals in the regions with the highest consumption of ampicillin tended to
have a higher percentage of isolates resistant to this agent, no significant
differences were found. There was no significant difference between hospitals
regarding prevalence of cefuroxime-resistant isolates.
PMID- 9393557
TI - Mice overexpressing human lecithin: cholesterol acyltransferase are not protected
against diet-induced atherosclerosis.
AB - Lecithin: cholesterol acyltransferase (LCAT) (EC 2.3.1.43) is generally assumed
to participate in reverse cholesterol transport, i.e., cholesterol transport from
peripheral tissues to the liver. LCAT is secreted by the liver and transported in
plasma mostly associated with high density lipoprotein. It catalyzes the
esterification of cholesterol, mainly high density lipoprotein cholesterol, and
produces cholesteryl ester and lysolecithin. Transgenic mice overexpression human
LCAT on a C57BL/6 background have elevated high density lipoprotein cholesterol
and markedly reduced low and very low density lipoprotein cholesterol and
triglyceride levels in plasma, suggesting that such mice may be less susceptible
to diet-induced atherosclerosis than isogenic nontransgenic controls. To
determine if the apparent anti-atherogenic lipoprotein profile of the LCAT
transgenics reduced their susceptibility to atherogenesis, the atherosclerotic
lesions developing in transgenic LCAT mice and controls when fed an atherogenic
diet were compared by histology and morphometry. Histological examination of the
aortas from mice fed a high fat diet for 12, 17 and 22 weeks revealed that the
aortic lesions were no smaller or less developed in the transgenic LCAT mice than
in the C57BL/6 controls. After 17 weeks there were significantly more "fatty
streaks" in the transgenic mice than in the controls. Thus, overexpression of
human LCAT in transgenic mice, in spite of their very favourable blood
lipoprotein and lipid profile, does not protect against development of
atherosclerosis.
PMID- 9393558
TI - Electron microscopic study of milk sediments. Qualitative and quantitative
observations.
AB - Sediment of milk from ovine mammary glands infected experimentally with coagulase
negative staphylococci was examined by transmission electron microscopy. The
proportions, of the various particles and cells present in milk and of
macrophages and neutrophils involved in phagocytosis were determined 6 h, 18 h
and 49 days after infection. All cell types together predominated over
cytoplasmic bodies in approximately 54% of normal milk samples. The proportion of
macrophages in normal milk was higher than that of neutrophils in approximately
69% of samples examined. After infection and in the early phase of inflammation,
the proportion changed in favour of neutrophils. In both the early and late
phases of infection, greater numbers of macrophages (3-27.2%) than neutrophils (0
2.7%) contained phagocytized cocci. Moreover, greater numbers of cocci were
observed in macrophages than in neutrophils (mean values 8.1 vs 1.2), indicating
the importance of the macrophage in the maintenance of ovine subclinical mastitis
caused by coagulase negative staphylococci.
PMID- 9393559
TI - The antifungal effect of lactoferrin and lysozyme on Candida krusei and Candida
albicans.
AB - Lactoferrin and lysozyme (muramidase) are non-immune defence factors present in
various exocrine secretions, including saliva. Previous studies have shown that
both proteins, either singly or in combination, are bactericidal in nature and
their combined activity is synergistic. As little is known of their interactions
with Candida species, 20 oral isolates of C. krusei and 5 isolates of C. albicans
were studied for their susceptibility to human apo-lactoferrin and lysozyme,
either singly or in combination, using an in vitro assay system. The two species
exhibited significant interspecies differences in susceptibility to lactoferrin
(p < 0.05), but not for lysozyme; C. krusei being more sensitive to lactoferrin
(c 1.4 times) than C. albicans. Both species revealed significant intraspecies
differences in their susceptibility to lysozyme (p < 0.05), but not for
lactoferrin. No synergistic antifungal activity of the two proteins on either
Candida species was noted. The results imply that the variable expression of the
fungicidal activity of lactoferrin and lysozyme on Candida species may modulate
the oral carriage of yeasts in a complex manner.
PMID- 9393560
TI - Antibodies against human papillomavirus type 6 capsids are elevated in men with
previous condylomas.
AB - Serum samples from 47 men with current condylomas, 32 men with a history of
condylomas and from 205 men with no history of genital wart disease, who were
attending sexually transmitted disease (STD) clinics at two different hospitals
in Stockholm, were analyzed for the presence of immunoglobulin G (IgG) and A
(IgA) antibodies to capsids of human papillomavirus types 6 and 11. IgG to HPV
type 6 was found among 35% of patients with a history of condylomas compared to
10% of controls (p = 0.0003), but only among 27% of patients with current
condylomas. Antibodies to HPV 6 and to HPV 11 showed a very limited correlation,
suggesting that the antibodies are HPV-type restricted. The results strengthen
conclusions from a previous serological study indicating that IgG antibodies
against HPV 6 develop late during condylomatous disease and mostly reflect
previous exposure to the virus.
PMID- 9393561
TI - Optimization of a battery using nine immunocytochemical variables for
distinguishing between epithelial mesothelioma and adenocarcinoma.
AB - A battery of immunocytochemical analyses, previously established to distinguish
between malignant mesothelioma and metastatic adenocarcinoma, was extended by
analysing the same cases with three other commercially available antibodies.
Altogether, 11 antibodies were studied in mesotheliomas diagnosed by other means,
using 14 different immunocytochemical parameters. Logistic regression analysis
indicated that the following parameters were of importance for this diagnostic
problem: vimentin reactivity in epithelial cells (1), cytokeratin (CAM 5.2)
reactivity in spindle-shaped (fibrous) cells (2), cell membrane-associated
reactivity of EMA (3), HBME-1 (4) and thrombomodulin (5), and absence of
reactivity to CEA (6), CD15 (7), BerEp4 (8) and Sialyl-TN (9). The analysis gave
an algorithm with which a specific diagnosis of mesothelioma could be made in 80%
of the cases-i.e., some improvement compared to the 55% sensitivity using the
previous battery.
PMID- 9393563
TI - CD73 (ecto-5'-nucleotidase) on blood mononuclear cells. Regulation of ecto-5'
nucleotidase activity and antigenic heterogeneity of CD73 on blood mononuclear
cells from healthy donors and from patients with immunodeficiency.
PMID- 9393562
TI - The pituitary-gonadal function in postmenopausal women with epithelial ovarian
tumors.
PMID- 9393564
TI - The need for a multidisciplinary approach in the treatment of advanced colorectal
cancer: a critical review from a medical oncologist and surgeon.
AB - Over the last 10 years important advances have been made in the treatment of
patients with advanced colorectal cancer, particularly with surgery either alone
or in combination with radiotherapy. Furthermore, despite early scepticism,
several chemotherapy studies have now reported significant clinical benefits with
5-FU-based regimens and promising results have also been reported with newer
agents such as raltitrexed and irinotecan. Taken together these advances now
enable a significant proportion of patients to undergo treatment which will
improve their quality of life, prolong survival and even result in cure in
certain cases. Patients with advanced colorectal cancer can only benefit from
these important advances, however, if a truly multidisciplinary approach to
patient care is adopted which requires integration of the roles of the surgeon,
medical oncologist and radiotherapist.
PMID- 9393565
TI - Lymphatic mapping and selective lymphadenectomy for melanoma: not yet standard
therapy.
PMID- 9393566
TI - A one-year audit of 255 operable breast cancers.
AB - The publications 'Guidelines for Surgeons in the Management of Symptomatic Breast
Disease' and 'QA Guidelines for Surgeons in Breast Cancer Screening' by the BASO
Breast Specialty Group set standards for audit which were aimed at good,
achievable practice. Data from 251 patients with operable breast cancers, under
the age of 70 years and treated in 1994 at Nottingham City Hospital's
Professorial Unit of Surgery, were audited according to 12 of the quality
objectives and outcomes measures specified. The questions addressed included:
waiting time for first appointment; number of attendances in diagnostic clinic;
time for results to be given; pre-operative diagnosis; waiting time for surgery;
localization biopsy reports; and number of therapeutic operations. Six outcome
measures achieved the targets, four were close and required minimal action for
correction, while two were not achieved. As a result of this audit corrective
action has been taken with regard to the latter two quality objectives.
PMID- 9393567
TI - Percutaneous self-expandable metallic stents and malignant biliary strictures.
AB - Thirty-five patients with malignant obstructive jaundice received palliative
treatment using percutaneous self-expandable metallic stents. Cholangiocarcinoma
was the most frequent cause of the biliary obstruction. In more than 50% of
cases, the stricture was located in the hilum. Adequate biliary drainage was
achieved in 97% of cases. Median survival was 182 days, and 11% of patients died
within 30 days. Early complications occurred in 31% of patients, and 25% of
patients showed recurrent jaundice after an average of 180 days. Percutaneous
self-expandable metallic stents are an efficient means of palliatively treating
malignant biliary strictures, particularly high biliary obstructions.
PMID- 9393568
TI - Palliative and adjuvant regional chemotherapy in pancreatic cancer.
AB - To improve the dismal prognosis of patients (pts) with pancreatic cancer we
treated 32 patients with non-resectable (UICC III, 17 pts; UICC IV, 15 pts--group
1) and 20 patients with resected (UICC I, 1 pt; UICC II, 3 pts; UICC III, 16 pts-
group 2) pancreatic cancer with palliative (group I) and adjuvant post-operative
(group II) coeliac axis intra-arterial cyclic infusions (CAI). CAI consisted of
mitoxantrone 10 mg/m2 on day 1, folinic acid 170 mg/m2 and 5-FU 600 mg/m2 during
days 2-4, and cis-platinum 60 mg/m2 on day 5 for up to 11 (group I) or six (group
II) cycles. In a total of 211 cycles toxicities at the level of WHO III occurred
in 0-6% and of WHO IV in 0%. The median survival times, compared with
institutional historical controls (treated vs controls), were 12 vs 4.8 months in
UICC III (P < 0.006) and 4 vs 2.9 months in UICC IV (P < 0.05) group I pts, and
21 vs 9.3 months in group II (P < 0.0003). Hepatic disease progression appeared
to be suppressed with CAI, which also appears to be effective for palliative and
adjuvant treatment in non-resectable and resected pancreatic cancer.
PMID- 9393569
TI - Expression of p53 in recurrent nodal metastasis from nasopharyngeal carcinoma
(NPC).
AB - This study reports the incidence of p53 expression in 40 patients with recurrent
nodal metastasis from nasopharyngeal carcinoma (NPC) and its prognostic value in
this group of patients. Immunohistochemical staining using monoclonal antibody
specific for human p53 protein was performed on the tumour-bearing nodes from 40
patients. The results were divided into four grades (I, negative; II, < 10% of
cells positive; III, 10-50% of cells positive; and IV, > 50% of cells positive).
The staining scores were correlated with histological tumour types, subsequent
recurrence and survival. All patients had undergone neck irradiation. Lymph node
specimens from six patients (15%) showed positive staining of nuclear p53
protein. The distribution among the different grades was: three (7.5%) for II,
two (5%) for III and one (2.5%) for IV. Patients with p53-overexpressed tumours
had a significantly higher number of tumour-bearing lymph nodes. There was no
correlation of p53 expression with histological tumour types, second tumour
recurrence and survival. Expression of p53 appears to be uncommon in patients
with recurrent nodal metastases in NPC. It did not have prognostic value in this
particular series of patients.
PMID- 9393570
TI - The use of biliary CEA measurements in the diagnosis of recurrent colorectal
cancer.
AB - To assess the usefulness of biliary CEA determinations in the diagnosis of
recurrent tumour, gallbladder bile was sampled in patients who underwent
laparotomy for proven or suspected recurrent colorectal cancer and in control
patients. Biliary CEA concentrations in controls were < 5 ng/ml, whereas
significantly elevated CEA concentrations were found in the bile of all patients
with tumour recurrence. Serum concentrations in these patients were elevated in
77% only. In a series of 12 patients with (a) suspicious lesion(s) on liver
imaging but normal serum CEA concentration during follow-up, biliary CEA
determination differentiated clearly between metastases and benign lesions.
Biliary CEA determination seems to aid detection of tumour recurrence at an early
stage and may preclude unnecessary surgery in patients with undefined liver
lesions.
PMID- 9393571
TI - Resection of pulmonary metastases from colorectal carcinoma.
AB - A retrospective study was made on 22 patients who underwent surgery (28
operations) for lung metastases of colorectal origin from 1986 to 1995 at the
Department of Surgery II, Padova University. The overall 5-year survival (OS)
following pulmonary resection was 62% and the 5-year disease-free interval after
metastasectomy (DFIM) 45%. The median survival was 23.6 months and the median
DFIM 15.3 months. Univariate (Mantel Cox) and multivariate (Cox's model) analyses
were used to identify any prognostic factors significant for OS and DFIM. Site
and stage of primary colorectal carcinoma, number of pulmonary metastases at
presentation, disease-free intervals between treatment of primary tumour and
diagnosis of lung metastases (DFIP) appeared to have no influence on OS and DFIM.
However, patients who underwent radical resection for metastases had a
significantly longer DFIM than those who underwent 'non-radical' resections (P =
0.02), but radical resection had no significant positive effect on OS. A short
DFIP, multiple and/or bilateral lesions, lung metastases occurring after liver
resection with a curative aim are not contraindications to surgery in patients
with pulmonary metastases from colorectal cancer, the main criterion for
selection of patients being the possibility of performing 'radical' resection.
PMID- 9393572
TI - Endocavitary Ir-192 radiation and laser treatment for palliation of obstructive
rectal cancer.
AB - Endoscopic laser therapy (ELT) either alone or combined with endocavitary Ir-192
radiation is performed for advanced, inoperable rectal cancer and when patients
are ineligible for surgery due to severe concomitant medical illness. During the
period from January 1984 to January 1997 we treated 81 patients (51 males, 30
females). Sixty-seven patients had ELT only using a ND-Yag Laser system. Twenty
five patients (average age: 80.5 years) were ineligible for surgery (Group I).
Forty-two patients (74.1 years) had an advanced locally inoperable tumour (Group
II). Fourteen patients (76.5 years) underwent a combined therapeutic regime with
endocavitary Ir-192 afterloading following ELT (Group III). Adequate
desobliteration was achieved in 100% (groups I and III) and 97% (group II) of the
patients. The average interval to aftertreatment was 8.4 weeks in group I and 9.4
weeks in group II, compared to 11.5 weeks in group III. Serious complications
(perianal abscess, rectovaginal fistula) occurred in 3.7%, minor complications
(laser-induced bleedings, unclear fever) in 12.3%. All laser-induced bleedings
could be dealt with using laser therapy. The frequency of treatment was governed
by tumour mass and the patient's survival. The results suggest that additional
endocavitary radiation significantly prolongs the maintenance of normal bowel
function compared with laser therapy alone.
PMID- 9393573
TI - Lung carcinomas composed of rhabdoid cells.
AB - Rhabdoid tumours form a distinctive morphological entity that is associated with
aggressive biological behaviour. They have been described in several sites and
tumour types. This paper presents three new cases of rhabdoid lung cancers. Lung
cancers were analysed for the presence of cells with the rhabdoid phenotype:
eccentric vesicular nuclei and abundant eosinophilic cytoplasm. Cells displaying
this morphology were then subjected to immunohistochemistry and electron
microscopy. The relevant clinical data on these cases were then accessed. Three
cases conforming to the morphological, immunophenotypic and ultrastructural
characteristics of rhabdoid cells were identified. Two of the cases were
associated with foci of adenocarcinoma and the remaining case was a large cell
neuroendocrine carcinoma. Two of the cases showed rapid clinical courses with the
patients dying of disease within 6 months. Lung tumours with a rhabdoid phenotype
are uncommon but are noteworthy because of their aggressive behaviour and, hence,
poor prognosis.
PMID- 9393574
TI - Carbon dioxide laser for cutaneous melanoma metastases: indications and
limitations.
AB - A total of 469 in-transit or satellite lesions were treated by carbon dioxide
(CO2) laser vaporization in 15 patients. The treatment was performed mostly on an
outpatient basis, under local anaesthesia. The technique was easily mastered and
quickly performed. Wound healing and patient acceptance were good. A major
drawback, however, proved to be the unexpected high incidence of recurrences at
the lasered sites. In our opinion CO2 laser treatment may be considered as a
palliative option in patients with a moderate to extensive amount of cutaneous
metastases, whose lesions preferably are < 10 mm and in whom local excision is
not feasible anymore. For extremity lesions this treatment may have a place after
failure of isolated limb perfusion. CO2 laser treatment cannot be considered a
first-line option unless the issue of local recurrences is solved.
PMID- 9393575
TI - Tissue toxicity of doxorubicin in first and second hyperthermic isolated limb
perfusion--an experimental study in dogs.
AB - The aim of this experimental study in dogs was to assess the tissue toxicity of
doxorubicin (DOX) and the impact of dose and pharmacokinetics after double
isolated limb perfusion (ILP). Fifteen beagle dogs were assigned to three groups
of five animals each. In the first ILP 0.75 mg/kg bodyweight (bw) DOX was given
to all animals. In the second perfusion after an interval of 6 to 8 weeks the
dosage was 0.5 mg/kg bw in group I, 0.75 mg/kg bw in group II, and 1.0 mg/kg bw
in group III. At the same dosage tissue toxicity increased in comparison to the
first ILP. At the second ILP there was a dose-toxicity relationship. At a dose of
0.75 mg/kg bw pharmacokinetics of DOX in the perfusate showed no significant
differences between first and second perfusion. The mean muscle tissue levels
during the second ILP were lower than during the first perfusion. However, in
contrast to the first perfusion, they showed a further increase after perfusate
eluation. A disturbed microcirculation caused by intima proliferations in
arteries and arterioles fter the first ILP may impair the removal of DOX from the
intravasal and interstitial compartment and can be assumed as a reason for
increased tissue toxicity. Therefore, we recommend a reduction of DOX dose in the
second ILP for clinical use.
PMID- 9393576
TI - New technology in the analytical cell sciences: the laser scanning cytometer.
AB - New technologies are making a major contribution to progress in applied clinical
research in surgical oncology. The laser scanning cytometer is a new machine
which combines the analytical capabilities of flow cytometry with the ability to
inspect and visualize labelled cells and particles. This substantially reduces
the uncertainty associated with assays in a wide range of surgical oncology
research applications. This article introduces this new technology.
PMID- 9393577
TI - Sister Joseph's nodule: a case report and review.
AB - The history of Sister Joseph and a pathological review of the nodule named after
her.
PMID- 9393578
TI - Leiomyosarcoma of the renal vein.
PMID- 9393579
TI - Biphasic sarcomatoid carcinoma of the lung: report of 5 cases and review of the
literature.
PMID- 9393580
TI - Lymph node recurrence of gallbladder carcinoma successfully managed by systemic
chemotherapy with 5-fluorouracil and mitomycin C: report of a 5-year survivor.
AB - Although gallbladder cancer (GBC) is believed to be chemoresistant, the
effectiveness of chemotherapy against lymph node metastasis has been reported. We
report a 70-year-old woman with advanced GBC in whom isolated, widespread lymph
nodal recurrence after a radical resection responded completely to systemic
chemotherapy with mitomycin C and 5-fluorouracil. This patient remains symptom
free with no evidence of disease at 6 years after surgery (5 years after the
initiation of chemotherapy). Both our case and a literature review suggest that
nodal disease appears more chemosensitive than the primary lesion in GBC.
Chemotherapy may provide long-term palliation for selected patients with isolated
nodal recurrence.
PMID- 9393581
TI - Haemangiopericytoma of the heart: report of a case with combined modality
treatment.
PMID- 9393582
TI - Cystic mesothelioma of the peritoneum.
AB - A 48-year-old man presented with a 3-month history of weight loss and progressive
right lower quadrant abdominal pain. His medical history was notable for
appendectomy at age 17. Ultrasonography and computed tomography of the abdomen
revealed a 12 cm multicystic mass in the right paracolic space. At laparotomy a
large serous cyst was found arising from the lateral wall of the cecum, and four
additional small cysts were found on the small bowel mesentery, greater omentum,
liver capsule, and right hemi-diaphragm. Complete removal of the tumor was
accomplished by right colectomy with extraperitoneal dissection of the large cyst
and simple excision of the four smaller cysts. Final pathology with
immunohistochemical staining confirmed cystic mesothelioma of the peritoneum. In
this report we discuss the diagnostic workup and treatment of this rare disease.
PMID- 9393583
TI - Plexosarcoma of the bladder.
AB - Plexosarcomas are rare soft tissue sarcomas, previously reported in association
with gastrointestinal autonomic nerve (GAN) plexi. We report the first case
arising from the autonomic nerve plexus of the bladder.
PMID- 9393584
TI - Is small tumour size alone enough for omitting axillary clearance?
PMID- 9393585
TI - The administration of paclitaxel without prophylaxis for the prevention of
hypersensitivity reactions: is this a rationale and safe therapeutic strategy?
PMID- 9393586
TI - Differential expressions of cyclin A and the retinoblastoma gene product in
histological subtypes of lung cancer cell lines.
AB - Cell-cycle-dependent phosphorylation of the tumor-suppressor protein product of
the retinoblastoma gene (RB) is mediated by a family of cyclin-dependent kinases
and cyclins. We examined the expressions of RB protein and cyclin A protein in 13
small-cell lung cancer (SCLC) lines and 14 non-small-cell lung cancer (NSCLC)
lines by immunoblotting. RB protein was not present or was of a mutant type in
77% of the SCLC lines (10/13) but was present in all the NSCLC lines. Cyclin A
was expressed in 38% of the SCLC lines (5/13) and in 86% of the NSCLC lines
(12/14). A positive correlation (P = 0.0034) between expression of cyclin A and
wild-type RB protein was found by Fisher's exact probability test. Densitometric
analysis of the expression of RB protein in RB(+) lung cancer lines showed that
the phosphorylated form was predominant in 2/3 of the SCLC and 8/14 of the NSCLC
lines. The positive correlation between the expressions of RB protein and cyclin
A suggests that RB protein in most RB(+) lung cancer cell lines is a target of
cyclin-A-dependent kinase and that the tumor-suppressor function may be
inactivated by phosphorylation.
PMID- 9393587
TI - Diagnostic and prognostic usefulness of N1,N8-diacetylspermidine and N1,N12
diacetylspermine in urine as novel markers of malignancy.
AB - Recently, we found N1,N8-diacetylspermidine (Ac2Spd) and N1,N12-diacetylspermine
(Ac2Spm) in human urine, and noted that their amount increased significantly in
patients with urogenital malignancies. Previous findings that simultaneous
reference to these diacetylpolyamines is useful in distinguishing cancer patients
from healthy persons were confirmed by more recent analytical data on urine
samples from several cancer patients. Further examination revealed that urinary
Ac2Spm and Ac2Spd tended to decrease when cancer patients were treated and
entered partial remission. In cases where the Ac2Spm and Ac2Spd levels were
normal or near-normal after treatments, the prognosis of the patients was
generally good. In contrast, when their level remained far above the normal
limits after apparently effective treatment, the prognosis of the patients was
poor. When a patient is in remission for more than 3 years, urinary levels of
both Ac2Spm and Ac2Spd are stabilized and stay below the normal limits, with rare
exceptions. The recurrence of a cancer as well as the complication of a second
one during the period of follow-up examination was accompanied by elevation of
urinary diacetylpolyamines. These observations indicate that urinary Ac2Spm and
Ac2Spd are useful as prognostic indicators after treatment and during follow-up
examination of cancer patients.
PMID- 9393588
TI - Decreased levels of topoisomerase II alpha in human renal cell carcinoma lines
resistant to etoposide.
AB - Renal cell carcinoma (RCC) displays strong resistance against many
chemotherapeutic drugs. Overexpression of P-glycoprotein (Pgp) appears to be part
of this resistance. The involvement of another resistance mechanism, involving
the decreased activity of DNA topoisomerase II (topoII), remains uncertain. By
culturing the human RCC lines RC2 and RC21 in the presence of increasing
concentrations of etoposide, we derived the variant sublines RC2E, RC21A and
RC21E, that had acquired approximately 30-, 60- and 90-fold resistance to this
drug respectively. RC2E, RC21A and RC21E were approximately 50-, 5- and 400-fold
cross-resistant to doxorubicin respectively. RC2E and RC21E also showed cross
resistance (approximately 200- and 3500-fold respectively) to vinblastine.
Quantitative differences in MDR1 and Pgp expression (elevated in RC2E and RC21E)
and topoII alpha (reduced in RC21E and RC21A) were demonstrated using Western
blotting and the reverse transcriptase/polymerase chain reaction. Decreased
amounts of topoII alpha were reflected in a reduced activity of RC21A and RC21E
as measured by unknotting phage P4 DNA. Qualitative changes of the topoII alpha
gene, such as point mutations in the motif B/DNBS and DNA-binding regions, or
differences in methylation status of the promoter gene of RC21E, were not found.
These cell lines represent a model of a solid tumor in which overexpression of
Pgp, a combination of increased Pgp and decreased topoII alpha, and a decrease of
topoII alpha are represented.
PMID- 9393589
TI - A prospective study on the prognostic significance of urokinase-type plasminogen
activator levels in breast cancer tissue.
AB - Urokinase-type plasminogen activator (u-PA), which cleaves plasminogen to yield
plasmin, is a serine protease of fibrinolysis and is presumed to play a key role
in extracellular proteolysis and facilitate the migration of cancer cells. This
study was conducted prospectively to evaluate the prognostic significance of u-PA
antigen level in breast cancer tissues. u-PA concentrations in the cytosol of 226
breast cancer tissues were determined prospectively by enzyme-linked
immunosorbent assay using cytosol fractions prepared for steroid hormone assay.
The median follow-up period of the patients was 60 months. Various prognostic
factors were evaluated by univariate analysis or multivariate analysis using the
Cox proportional-hazards method. Patients with primary breast cancer containing
high levels of u-PA had a significantly shorter disease-free survival than
patients with low levels of u-PA antigens. In multivariate analysis, a high level
of u-PA was an independent risk factor for disease-free survival, being
independent of age, axillary node status, and estrogen receptor status. Among the
major prognostic factors, a high u-PA antigen level, lymph node involvement, and
a positive estrogen receptor status were the most important for predicting
relapse-free survival (P = 0.044, P < 0.0001, P = 0.0039). This first prospective
study confirmed the prognostic significance of the u-PA antigen level in
association with other major prognostic factors. The results of our present study
suggest that u-PA in breast cancer tissue might be involved in breast cancer
invasion and metastasis.
PMID- 9393590
TI - Leukaemia and lymphoma of the appendix presenting as acute appendicitis or acute
abdomen. Four case reports with a review of the literature.
AB - Leukaemic and lymphomatous infiltration of the appendix is rare and even rarer is
acute appendicitis as the initial manifestation. From our routine biopsy material
we collected four cases of haematological malignancies presenting as acute
appendicitis or acute abdomen, caused or accompanied by tumoral infiltration of
the appendix. Appendicitis was the initial manifestation that allowed diagnosis
of the underlying disease. The clinical histories and histological examinations
of the appendices and of one autopsy are described. We report the first detailed
description of acute myeloid leukaemia involving the appendix, and three cases of
lymphomatous infiltration of the appendix presenting with appendicitis, and give
an overview of the literature. In these days of budgetary cuts in national health
services, where one may be tempted not to have seemingly commonplace cases of
appendicitis histologically verified, our cases emphasize that careful
histopathological examination of all appendectomy specimens should be mandatory.
Despite the fact that leukaemia and lymphoma of the appendix are rare, our cases
illustrate that these must be included in the differential diagnosis of acute
appendicitis and that physicians and surgeons have to be aware of these
conditions.
PMID- 9393591
TI - p53 nuclear immunoreactivity as a predictor of response and outcome following
chemotherapy for metastatic bladder cancer.
AB - p53 nuclear immunoreactivity was determined in primary bladder tumours from 50
patients who developed metastatic bladder cancer. We investigated the
relationship between p53 nuclear immunoreactivity and the response and outcome
following chemotherapy. p53 nuclear accumulation was detected in 48% of the
primary tumours using the PAb1801 antibody in archival paraffin-embedded tissue
sections. All patients received platinum-based combination chemotherapy including
methotrexate for metastatic disease. The response to chemotherapy did not relate
to the prevalence of p53 nuclear overexpression: 50% of the patients expressing
p53 nuclear reactivity achieved a response compared to 27% of those without p53
expression (P = 0.14); overall, 38% of the patients responded. The median
survival after chemotherapy was 5.9 months; 8.4 months for patients with p53
nuclear reactivity compared to 5.2 months for those without (P = 0.38).
Multivariate analysis showed that performance status but not p53 nuclear status
was an independent prognostic factor for survival following chemotherapy. The
results indicate that patients with p53 nuclear immunoreactivity in the primary
bladder tumour do not have a lower response rate or poorer outcome following
chemotherapy for metastatic disease than do patients without p53 nuclear
reactivity.
PMID- 9393592
TI - Increased number of cancer cells in bronchial washing fluid detected by combining
conventional cytology and high-resolution flow cytometry.
AB - The present study was performed to improve early lung cancer diagnosis in
bronchial washing fluid, thereby increasing the diagnostic sensitivity of
bronchoscopy by means of high-resolution flow cytometry (FC). We combined dual
parameter DNA/protein FC and conventional cytology in bronchial washing fluid
samples from 112 patients with neoplastic and non-neoplastic lung diseases and
found 43% of histologically confirmed tumor cases to be cytologically positive;
63% of the tumor samples were aneuploid, 52% of the aneuploid cases were
cytologically positive and 48% were negative. In the negative cases, FC was an
independent diagnostic factor. In 32% of the cases, FC also failed to detect
abnormalities. However, the combination of both techniques increased the
sensitivity in detecting neoplastic cells to 73%. Furthermore, simultaneous
DNA/protein analysis allowed the recognition of aneuploid cell lines not
detectable by single DNA measurement. Identification of aneuploid subpopulations
by dual-parameter analysis in cytologically negative one-parameter FC "diploid"
samples assumes an important diagnostic value. Dual-parameter DNA/protein FC is a
valuable technique that increases the diagnostic yield of bronchoscopy with no
risk for the patient and a low additional cost.
PMID- 9393593
TI - Deficiency of neutrophilic granule membrane glycoproteins in the myelodysplastic
syndromes: a common deficiency in 216 patients studied by the Cancer and Leukemia
Group B.
AB - Previous studies on neutrophils in patients with the myelodysplastic syndromes
(MDS) have indicated deficiencies in the contents of primary and secondary
granules. However, the granule membrane remains virtually unstudied despite its
essential role in the dynamic function of the cytoplasmic granules. In this
study, we examined the membrane glycoproteins of primary and secondary granules
of peripheral blood and/or bone marrow neutrophils using the monoclonal antibody
H36/71 to CD15 glycoproteins. In addition, myeloperoxidase activity and antigen,
elastase and lactoferrin were also studied using cytochemical and
immunocytochemical stains. A total of 216 patients were included. Deficiencies of
granule membrane glycoproteins were the most common, detected in 49%, followed by
myeloperoxidase activity (17%), elastase (16%), myeloperoxidase antigen (9%), and
lactoferrin (8%). Multiple deficiencies always included granule membrane
deficiency. We conclude that granule membrane defects are common in MDS, may
provide a common mechanism for multiple granule deficiencies, and may prove to be
an additional abnormality associated with granulocyte dysfunction.
PMID- 9393594
TI - Synthesis of quantitation standards for nested competitive PCR for the
determination of minimal residual disease in B-lineage acute lymphoblastic
leukaemia.
AB - Quantitative PCR-based assays of leukaemic cells in remission marrow hold promise
for therapeutic guidance, but are not yet sufficiently reliable for clinical
application. For B-lineage ALL, these assays usually involve PCR of clonal
somatic gene rearrangements of the immunoglobulin heavy chain gene. The most
accurate quantification can be achieved by competitive PCR. Here we present a
novel approach for the production of reference standards for use in nested
competitive PCR of these gene rearrangements, which might enable more reliable
assessment of MRD for prognosis and selection of patients for individualised
therapy.
PMID- 9393596
TI - Allelic loss in childhood acute lymphoblastic leukemia.
AB - Acute lymphoblastic leukemia (ALL) is the most frequent cancer encountered in
children. Little is known about the molecular basis of childhood ALL, although
the clinical, pathological, and immunophenotypic features have been well
documented. To understand the role of tumor suppressor genes (TSGs) in the
development of this disease, we performed a detailed allelotype analysis. Twenty
nine patients (24 pre-B and 5 of T-cell lineage) were investigated for loss of
heterozygosity (LOH), using 49 highly polymorphic markers distributed over 13
chromosomal arms which are known or postulated to contain TSGs. The highest rates
of allelic losses were observed in chromosomes 9p and 12p which were deleted in
29 and 32% of the informative patients, respectively. These are among the most
frequent alterations found in childhood ALL. Other losses were found at a lower
frequency in chromosomes 6p, 6q, 9q, 17p, and 17q. No LOH was found at
chromosomes 3p, 5q, 11p, 11q, 13q and 18q in any patient. These results suggest
that many TSGs may be involved in the development of childhood ALL.
PMID- 9393595
TI - Salvage therapy for relapsed or refractory childhood acute lymphocytic leukemia
by alternative administration a lymphoid- and myeloid-directed chemotherapeutic
regimen consisting of dual modulation of ara-C, hydroxyurea, and etoposide.
AB - Risk-directed chemotherapeutic regimens in recent use have improved the prognosis
of children with acute lymphocytic leukemia (ALL). However, many patients relapse
during or shortly after cessation of the initial continuation chemotherapy. Since
achievement of a second complete remission (CR) is the initial step in successful
retreatment effort, it is important to develop salvage protocols for children
with relapsed or refractory ALL. In the present study, we developed a new salvage
protocol (MLL-93) and applied the concept of dual chemical modulation of
cytarabine, hydroxyurea, and etoposide with the alternative administration of
high doses of myeloid- and lymphoid-directed agents. We also planned to perform
allogeneic bone marrow transplantation (BMT) following a CR if patients had HLA
identical donor(s). The six patients treated with the MLL-93 protocol achieved a
second CR. One patients in CR died of interstitial pneumonia after an unrelated
allogeneic BMT. The other five patients have been in CR for 12-41 months. We
suggest that the concepts of alternative administration of lymphoid- and myeloid
directed drugs and biochemical modulation are useful in the treatment of children
with relapsed or refractory ALL.
PMID- 9393597
TI - Quantification of P-glycoprotein in chronic lymphocytic leukemia by flow
cytometry.
AB - The P-glycoprotein (P-gp) was investigated in 40 patients with chronic
lymphocytic leukemia by immunological, functional and quantitative assays. The
proportion of positive cases with the anti-Pgp McAb UIC2 was 30% and increased to
64% after neuraminidase treatment (p = 0.002). Fifty-six per cent of cases were
positive with the functional test with rhodamine 123 and verapamil. A negative
correlation was found between the number of cells stained with the McAb and the
functional test (p = 0.006). The mean of P-gp molecules was 2509 +/- 2805
molecules per cell; these values were higher than in the control K562 cell line
in the majority of cases. The number of positive cases and P-gp molecules were
higher in treated than in untreated patients (p = 0.01 and 0.07). There were no
significant differences with respect to response to treatment, but a higher
number of P-gp molecules was found in non-responders. When the results of the
functional test were put together with the quantification assay this allowed the
detection of 71% non-responders. Our findings suggest that quantification of the
P-gp could be of value in the assessment of possible drug resistance in CLL.
PMID- 9393598
TI - C/EBP-epsilon: chromosomal mapping and mutational analysis of the gene in
leukemia and preleukemia.
AB - We and others have cloned a novel human gene CCAAT/enhancer-binding protein
epsilon (C/EBP-epsilon) encoding a member of the C/EBP gene family. It is
exclusively expressed in myeloid and T-lymphoid cells and appears to have an
important role in inducing expression of several myeloid-specific genes. We used
a polymerase chain reaction (PCR)-based technique to examine DNA from 93
hamster/human radiation hybrid clones in order chromosomally to map C/EBP-epsilon
to 14q11.2 (between D14S264 and D14S275) which is telomeric to the T-cell
receptor alpha and delta genes and centromeric to several other myeloid gene
products including Cathepsin G (CTSG) and Chymase-1 (CMA1). To determine whether
C/EBP-epsilon behaves as an altered tumor-suppressor gene, samples from patients
with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) evolving
to AML were studied for loss of heterozygosity (LOH) using microsatellite
sequences that we identified within 0.2 kb of the amino-terminus of the human
C/EBP-epsilon gene. Allelic loss of the C/EBP-epsilon gene was detected in four
out of 20 (20%) evolving MDS cases and in none of the 17 AML and 17 T-cell
leukemia cases. Mutational analysis of the gene was performed using PCR-SSCP on
37 AML and 40 MDS cases including those with LOH at the gene. No abnormalities
were found suggesting that the altered gene in this region is not C/EBP-epsilon.
Also, C/EBP-epsilon was examined by Southern blot analysis on DNA samples from 20
AML patients and 10 AML cell lines. No rearrangements or amplifications of the
gene were detected. Taken together, we have mapped C/EBP-epsilon to 14q11.2, a
region containing other myeloid and T-lymphoid specific genes. Furthermore, no
structural alterations were detected in the C/EBP-epsilon gene.
PMID- 9393599
TI - Differential phosphorylation of lamin B2 in normal and leukemic cells.
AB - Lamins constitute the nuclear lamina, which underlie the inner membrane of the
cell nucleus. Phosphorylation of lamins is a key factor in the regulation of
nuclear structure during the cell cycle and of gene transcription. Since an
uncontrolled cell cycle and altered gene transcription are major characteristics
of neoplasms, we looked for differences in lamin B2 phosphorylation between PBMC,
ALL and AML cells. Using different lamin B2-specific antibodies, we detected two
different lamin B2 species termed lamin B2 and B2A. Although phosphorylation of
lamin B2 in leukemic cells was reminiscent of resting cells, the majority of ALL
and AML samples showed significantly higher and more altered lamin B2A
phosphorylation compared to PBMC. It remains to be elucidated which mechanism
leads to these alterations and whether it could explain the extended G1-phase
frequently observed in ALL cells.
PMID- 9393600
TI - Growth factor stimulation of hematopoietic cells leads to membrane translocation
of AKT1 protein kinase.
AB - AKT1 is the human homolog of the v-akt oncogene. AKT1 has two distinct protein
domains, one serine/threonine kinase domain and one pleckstrin homology (PH)
domain. We studied the expression and activity of AKT1 in hematopoietic cell
lines. The expression of AKT1 was constitutive in hematopoietic cells of various
stages of development. In the growth factor dependent MO7e cells, serum and
growth factor starvation resulted in an early 50% fall in activity which was
maintained over 24 h. Treatment of cells which growth factors or agents which
induce differentiation activated AKT1. The subcellular localization of AKT1 in
MO7e cells was altered as it was activated. High AKT1 kinase activity was
associated with membrane fractions in stimulated cells, in contrast to the much
lower AKT1 activity in membranes of cells starved of serum and growth factor for
1 h. These results demonstrate AKT1 kinase activity and its regulation by
extracellular signaling factors in vivo in hematopoietic cells, and suggest that
the activation of AKT1 involves intracellular translocation of the kinase from
cytosol to membrane.
PMID- 9393601
TI - The influence of recombinant human tumor necrosis factor alpha and its muteins
used alone or in combination with 2-chlorodeoxyadenosine on normal and leukemic
hematopoiesis in vitro.
AB - We investigated the influence of TNF alpha and its muteins III, V and VI on the
colony growth of normal and CML CFU-GM cells as well as on CFU-L clonogenic
blasts from AML patients in cultures in vitro. The muteins were constructed using
a synthetic cDNA fragment substituting nucleotides coding for the N-terminal
amino acids in the chain of native TNF alpha. We observed that TNF alpha and
mutein VI inhibited the growth of colonies formed by both types of CFU-GM and CFU
L cells in a greater degree than muteins III and V. In addition, the percentage
of colony growth inhibition after the use of mutein VI was the greatest. These
observations were the basis for the evaluation of interaction between 2-CdA and
TNF alpha and between 2-CdA and mutein VI. We have confirmed that 2-CdA used
together with mutein VI acts synergistically on CFU-GM and CFU-L cells, whereas 2
CdA and TNF alpha show the additive effect.
PMID- 9393602
TI - Effect on cell kill of addition of multidrug resistance modifiers cyclosporin A
and PSC 833 to cytotoxic agents in acute myeloid leukaemia.
AB - Multidrug resistance (MDR) mediated by the drug efflux pump P-glycoprotein (Pgp),
may cause remission failure and relapse in patients with acute myeloid leukaemia
(AML) by extruding cytotoxic agents such as anthracyclines from leukaemic cells
thus allowing them to survive. Cell line data suggest that reversal of MDR is
possible using modifying drugs such as cyclosporin A (CSA) and its analogue PSC
833. We have investigated the effects on cell kill of the addition of CSA and PSC
833 to daunorubicin, idarubicin, mitozantrone, etoposide and cytarabine in 52
fresh cell samples from AML patients using an MTT assay. Pgp status was
determined by using monoclonal antibodies JSB-1 and MRK-16 and by assessment of
rhodamine efflux. Although overall each cytotoxic-modifier combination produced
significant improvements in cell kill compared to cytotoxic alone (P values
ranged from P < 0.001 to P = 0.017), modifiers also produced significant
cytotoxicity in their own right, and no consistent difference was seen between
responses in Pgp-positive and negative groups. Up to one in three Pgp-positive
samples failed to show any improvement in cell kill with the addition of CSA or
PSC 833, possibly owing to co-expression of alternative resistance mechanisms not
affected by the MDR modifiers. The best responses were seen when PSC 833 was
added to idarubicin, with 7 out of 22 Pgp-positive cases (32%) showing five-fold
improvements in cell kill or better compared to idarubicin alone. Comparison of
equimolar concentrations of the two modifiers in the Pgp positive group failed to
show a significant difference in cell kill, though PSC 833 was markedly superior
to CSA in a minority of highly responsive samples which demonstrated clear
evidence of MDR reversal. Our in vitro data suggest that MDR modifiers such as
CSA and PSC 833 could play an important role in the therapy of AML and indicate
the need for prospective randomised trials to assess their clinical efficacy.
PMID- 9393603
TI - Bufalin reduces the level of topoisomerase II in human leukemia cells and affects
the cytotoxicity of anticancer drugs.
AB - When human leukemia HL-60 cells were treated with 10(-7) M bufalin, the amounts
of both topoisomerase (topo) II alpha and II beta and the activity of topo II
decreased markedly and were almost undetectable 18 h after the start of
treatment. The level of topo II mRNA started to decrease immediately after the
start of treatment with bufalin, with a subsequent decrease in the amount of topo
II alpha protein. These changes preceded the fragmentation of DNA, a typical
feature of apoptosis. The results suggest that bufalin caused a marked decrease
in the steady-state level of topo II alpha mRNA, which led to a decrease in the
amount and activity of the enzyme and to the induction of apoptosis. A reduction
in the level of topo II alpha by bufalin was also observed in other lines of
human leukemia cells such as ML1 and U937. The results were exploited to
potentiate the effects of cisplatin and retinoic acid (RA) on HL-60 cells:
pretreatment of HL-60 cells with 10(-7) M bufalin for 6 h increased the
inhibitory effects of cisplatin and RA on cell growth and enhanced the induction
of cell death.
PMID- 9393604
TI - A case-control study of reproductive factors and risk of lymphomas and myelomas.
AB - The relationship between reproductive factors and risk of lymphoid neoplasms was
investigated in a hospital-based case-control study conducted in northern Italy
on women with histologically confirmed incident Hodgkin's disease (HD) (n = 68),
non-Hodgkin's lymphomas (NHL) (n = 180) and multiple myelomas (MM) (n = 71), and
448 controls admitted to hospitals, for acute, non-neoplastic, non-immunological
and non-gynecological conditions. The odds ratios (OR) of HD were 0.6 for > or =
3 pregnancies compared to nulligravidae, and 0.5 for > or = 1 total (spontaneous
and induced) abortions compared to women reporting no abortions. Compared to
nulliparae, the OR of HD was 0.9 in parae and 0.3 in those with first birth when
aged < 20 years. The OR of NHL and MM in relation to number of pregnancies,
abortions and births, age at first birth and time since last birth were close to
unity. Results were similar for the relation between reproductive factors and HD
in women younger than 50 years. The OR of NHL was above unity (OR 2.2, 95% CI 1.0
to 4.9) for women aged < 50 years reporting one or more pregnancies as compared
to nulliparae, and for women reporting the last birth since less than 10 years
(OR 2.9, 95% CI 1.1 to 7.4). Early events in pregnancy, including changes in
immunological status, rather than exposure to female sex hormones are likely
mechanisms for the protection of pregnancies and abortions on the risk of HD.
PMID- 9393605
TI - Chronic myelomonocytic leukemia in a patient with antiphospholipid syndrome:
first case report.
PMID- 9393606
TI - Continuous hemofiltration in the management of 'retinoic acid syndrome'.
PMID- 9393607
TI - Lymphocytes with cerebriform nuclei in chronic B-cell lymphoproliferative
diseases.
AB - Two patients with chronic lymphoproliferative diseases, a splenic marginal zone
lymphoma and hairy cell leukaemia variant, were reported. In both diseases a B
immunophenotype was demonstrated but a variable percentage of lymphoid cells (30
and 52%) showed a highly irregular nuclear outline, sometimes mimicking the
nuclei of Sezary cells.
PMID- 9393608
TI - Secondary amyloidosis in the course of idiopathic myelofibrosis.
AB - Secondary amyloidosis without a known cause, diagnosed antemortem in a patient
with idiopathic myelofibrosis, is reported here. This is the first such case, to
our knowledge. Amyloid deposits were seen in the bone marrow, renal glomeruli and
jejunum. Reasons for investigating for amyloidosis were hypogammaglobulinemia,
proteinuria and recurrent diarrhea.
PMID- 9393609
TI - Indo-French symposium on apoptosis and multidrug resistance.
PMID- 9393610
TI - Detection of mineral-dust-induced DNA damage in two mammalian cell lines using
the alkaline single cell gel/comet assay.
AB - It has been estimated that over three million workers in the USA are potentially
exposed to silica or other mineral dusts. Results of epidemiological studies
evaluating whether silica or glass fibers increase lung cancer risk to the
exposed workers are inconclusive. Detection of DNA damage in cells exposed to
genotoxic agents is being used to assess the carcinogenic potential of
environmental agents. The alkaline (pH > 13) single cell gel/comet (SCG) assay
was used to determine and compare DNA damage in cultured Chinese hamster lung
fibroblasts (V79 cells) and human embryonic lung fibroblasts (Hel 299 cells)
exposed to crystalline silica (Min-U-Sil 5), amorphous silica (Spherisorb),
carbon black, and glass fibers (AAA-10). V79 or Hel 299 cells were exposed to
these mineral dusts for 3 h at various concentrations. Min-U-Sil 5 and AAA-10, at
almost all concentrations tested, caused a significant increase in DNA migration
measured as tail length in both V79 and Hel 299 exposed cells. However, the
increase was much higher in V79 then in Hel 299 cells for Min-U-Sil 5. Tail
length was also increased relative to controls after amorphous silica treatment,
but not to the same extent as that induced by crystalline silica. Exposure to
carbon black did not induce DNA migration at any of the concentrations tested.
These results indicate that silica and glass fibers, but not carbon black, can
induce DNA damage in mammalian cells, and that crystalline silica has a higher
DNA-damaging activity than amorphous silica. For glass fibers, induction of DNA
damage in both V79 and Hel 299 cells was observed even at a concentration 10
times lower than silica and the response was similar in both cell lines. These
results suggest that the SCG/comet assay is useful for the detection of DNA
damage caused by occupationally related dusts/particles.
PMID- 9393611
TI - Genetic toxicity studies of 1,2,3,4-tetrahydro-9-acridinamine (tacrine).
AB - The mutagenicity and clastogenicity of 1,2,3,4-tetrahydro-9-acridinamine
(tacrine) were studied in vitro using the Salmonella mutagenicity test and the
induction of chromosome aberrations in Chinese hamster ovary (CHO) cells, and in
the mouse bone marrow micronucleus test in vivo. This chemical is currently being
used to treat dementia arising from Alzheimer's Disease. Tacrine was mutagenic in
Salmonella but did not produce chromosome damage in CHO cells or in mouse bone
marrow cells. A clear mutagenic response was seen in strain TA97 with rat and
hamster liver S9; inconsistent results were obtained without S9. No mutagenicity
was seen in strains TA98 and TA100 without S9, and inconsistent results were seen
with S9. There was no induction of chromosome aberrations in cultured CHO cells
with or without S9. Oral administration to mice of tacrine daily for three days
did not result in the induction of micronuclei in their bone marrow cells. The
mutagenic response in Salmonella, and the structure of the molecule, suggests
that tacrine may be carcinogenic when tested in rodents. This information must be
considered when preparing benefit-risk determinations for medical uses of this
substance.
PMID- 9393612
TI - Benzidine-DNA adduct levels in human peripheral white blood cells significantly
correlate with levels in exfoliated urothelial cells.
AB - In a cross-sectional study of 33 workers exposed to benzidine and benzidine dyes
and 15 non-exposed controls, we previously reported that exposure status and
internal dose of benzidine metabolites were strongly correlated with the levels
of specific benzidine-DNA adducts in exfoliated urothelial cells. We also
evaluated DNA adduct levels in peripheral white blood cells (WBC) of a subset of
18 exposed workers and 7 controls selected to represent a wide range of adducts
in exfoliated urothelial cells. Samples were coded and then DNA was analyzed
using 32P-postlabeling, along with n-butanol extraction. One adduct, which co
chromatographed with a synthetic N-(3'-phospho-deoxyguanosin-8-yl)-N'
acetylbenzidine standard, predominated in those samples with adducts present. The
median level (range) of this adduct in WBC DNA was 194.4 (3.2-975) RAL x 10(9) in
exposed workers and 1.4 (0.1-6.4) in the control subjects (p = 0.0002, Wilcoxon
Rank Sum Test). There was a striking correlation between WBC and exfoliated
urothelial cell adduct levels (Pearson r = 0.84, p < 0.001) among exposed
subjects. In addition, the sum of urinary benzidine, N-acetylbenzidine and N,N'
diacetylbenzidine correlated with the levels of this adduct in both tissues. This
is the first study in humans to show a relationship for a specific carcinogen
adduct in a surrogate tissue and in urothelial cells, the target for urinary
bladder cancer.
PMID- 9393613
TI - Induction of micronuclei in human, goat, rabbit peripheral blood lymphocytes and
mouse splenic lymphocytes irradiated in vitro with gamma radiation.
AB - The frequencies of gamma-ray-induced micronuclei (MN) in cytokinesis-blocked (CB)
lymphocytes at several doses were measured in three donors of four species
(human, goat, rabbit, mouse). Measurements performed after irradiation showed a
dose-related increases in MN frequency in each of the donors studied. The
relative sensitivity of mouse in spleen lymphocytes (SLs), goat in peripheral
blood lymphocytes (PBLs) and rabbit PBLs compared with human PBLs was estimated
by best fitting linear-quadratic model based on the radiation-induced MN data
over the range from 0 to 400 cGy. In the case of MN frequency with 0.2, the
relative sensitivities of mouse SLs, goat PBLs and rabbit PBLs were 1.67, 0.98
and 0.39, respectively. These data indicate that the induction of MN in CB cells
following irradiation is similar in human and goat PBLs, and PBLs from rabbit
were much less sensitive to the MN induction effects of gamma-radiation than
those from human. Compared with the radiation-induced MN formation in the PBLs of
human, the SLs of mouse were more radiosensitive.
PMID- 9393614
TI - Differential induction of adaptive responses by paraquat and hydrogen peroxide
against the genotoxicity of methyl mercuric chloride, maleic hydrazide and ethyl
methane sulfonate in plant cells in vivo.
AB - Induction of adaptive response by conditioning doses of paraquat (PQ) and
hydrogen peroxide (H2O2) in embryonic shoot cells of Hordeum vulgare and root
meristem cells of Allium cepa was tested against the genotoxicity of challenge
doses of methyl mercuric chloride (MMCl), maleic hydrazide (MH) or ethylmethane
sulfonate (EMS). Plant tissue fixed at different recovery hours following the
challenge treatments was analysed for cells with genotoxicity markers that
include spindle or chromosome aberrations and micronuclei. The results provided
clear-cut evidence that whereas H2O2 induced adaptive response for the chromosome
damage caused by MMCl and MH, PQ induced the same for MMCl and EMS, but not for
damage caused by MH. The findings pointed to the differences in the underlying
mechanisms of oxidative responses induced by H2O2 and O2-.
PMID- 9393615
TI - Quercetin and myricetin protect against hydrogen peroxide-induced DNA damage
(strand breaks and oxidised pyrimidines) in human lymphocytes.
AB - The effects of the flavonoids quercetin and myricetin, and the antihepatotoxic
agent silymarin, on hydrogen peroxide-mediated DNA damage in human lymphocytes
were determined using alkaline single-cell gel electrophoresis (the comet assay).
Treatment with hydrogen peroxide increased the levels of DNA strand breaks and
oxidised pyrimidine bases in these cells. Quercetin was protective at
concentrations above 10 microM and myricetin decreased oxidant-induced DNA strand
breakage at concentrations of 100 microM. Cellular metabolism may alter the
antioxidant efficacy of the flavonoids. Silymarin had no protective effect at any
of the concentrations tested. None of these flavonoids was itself genotoxic.
Neither alpha-tocopherol nor beta-carotene decreased hydrogen peroxide-induced
DNA breakage. The differences in effectiveness of these dietary compounds against
oxidative DNA damage may be explained by differences in their chemical structure
or location within the cell.
PMID- 9393616
TI - Construction of mutants of Salmonella typhimurium deficient in 8-hydroxyguanine
DNA glycosylase and their sensitivities to oxidative mutagens and nitro
compounds.
AB - 8-Hydroxyguanine (8-OH-G) DNA glycosylase is an enzyme involved in repair of
oxidative DNA damage, e.g., 8-OH-G in DNA. In order to assess the roles of 8-OH-G
in spontaneous and chemically-induced mutagenesis, the mutMST gene encoding 8-OH
G DNA glycosylase of Salmonella typhimurium was disrupted in several Ames tester
strains, i.e., S. typhimurium TA1535 (hisG46, uvrB-, rfa), TA1975 (hisG46, uvr+,
rfa) and TA102 (hisG428, uvr+, rfa). The spontaneous mutation frequencies were
increased 2.4 and 1.6 times, respectively, by the mutMST deletions in strains
TA1535 and TA1975, which are spontaneously reverted to His+ by mutations mainly
at G:C base pairs. The resulting strains YG3001 (TA1535 delta mutMST) and YG3002
(TA1975 delta mutMST) were 2 to 8 times more sensitive to the mutagenicities of
methylene blue plus visible light, neutral red plus visible light and 2
nitrofluorene than the parent strains. The strain YG3002 but not YG3001 was about
30 times more sensitive to the mutagenicity of 4-nitroquinoline N-oxide than the
parent strain TA1975. Neither hydrogen peroxide nor phenazine methosulfate was
mutagenic in the mutMST-deletion strains as well as in the parent strains. In
contrast, the mutMST deletion did not affect the spontaneous mutation frequency
of strain TA102, which has an A:T base pair at the critical site for reversion.
The sensitivities of strain TA102 to the chemicals were not enhanced by the
mutMST deletion except for hydrogen peroxide. These results suggest that 8-OH-G
in DNA plays important roles in spontaneous mutagenesis occurring at G:C base
pairs in S. typhimurium, and some nitro aromatics such as 4-nitroquinoline N
oxide or 2-nitrofluorene as well as the photosensitizers plus visible light can
produce 8-OH-G in DNA, thereby inducing mutations. In the case of 4
nitroquinoline N-oxide, 8-OH-G rather than DNA adducts seems to play major roles
in mutagenesis in uvr+ background. The new strains could be useful for the
evaluation of the roles of 8-OH-G in mutagenesis in S. typhimurium and permit the
efficient detection of some oxidative mutagens in the environment.
PMID- 9393617
TI - Metabolism of galangin by rat cytochromes P450: relevance to the genotoxicity of
galangin.
AB - The mutagenicity of flavonols seems to depend on the number and position of
hydroxyl groups in the B ring. Galangin is a flavonol that does not have any
hydroxyl group in the B ring and has been suggested to be a substrate of
cytochromes P450 which, through the hydroxylation of the B ring, could metabolise
it to more genotoxic products. The present study was undertaken to test this
hypothesis. Using high performance liquid chromatography we show that glangin is
sequentially transformed to kaempferol and then to quercetin by a mechanism
dependent on cytochrome P450 reactions. The metabolites of galangin are
responsible for its mutagenicity in Salmonella typhimurium reversion assay and
for the induction of chromosomal aberrations in V79 cells.
PMID- 9393618
TI - Sister chromatid exchange analysis in patients exposed to low dose of iodine-131
for thyroid scintigraphy.
AB - To determine the genotoxic risk associated with diagnostic exposure to low doses
of iodine 131 (131I), sister chromatid exchange (SCE) analysis was performed in
lymphocytes of 18 non-smoking women who received 370 kBq (10 microCi) intravenous
131I sodium iodide as an adjuvant for scintigraphy for diagnosing thyroid
nodularity. SCE frequencies were measured before and after 131I administration.
SCE results in the pre-treated phase were regarded as control. Although SCE
values 24 h after 131I administration did not show a significant increment (p >
0.05), there was a significant increase 72 h after treatment (p < 0.05). These
results indicate that genetic damage might be induced by low dose of 131I.
PMID- 9393619
TI - Evaluation of the mutagenicity of acetochlor to male rat germ cells.
AB - Male rat dominant lethal (DL) assays conducted on the herbicide acetochlor are
described. Single dose studies conducted at the maximum tolerated dose (MTD, < or
= 1000 mg/kg) produced no effects on any of the DL assay parameters at any of the
ten weekly sampling periods. It is concluded that acetochlor is non-mutagenic to
rat germ cells. Due to initial limited knowledge of the MTD of acetochlor it was
also evaluated in the DL assay at a dose level of 2000 mg/kg. At this high dose
level severe bodyweight loss and some deaths occurred among the treated animals.
In addition, reduced implantations and reduced pregnancy rates were observed at
the third sampling period (18-25 days post dosing) in the absence of an increase
in early post-implantation deaths. These results indicated that the use of supra
MTD doses of acetochlor had reduced the fertility of the treated males leading to
the production of a pseudo-DL assay response, as alerted to and defined by
Ehling. Although several such pseudo-DL assay responses have been described, none
have been explained mechanistically. It was therefore decided to pursue the
effects seen in the DL assay when using supra-MTD doses of acetochlor. Ova
analysis of female rats mated with male rats exposed to 2000 mg/kg acetochlor
revealed unfertilized ova at the critical third sampling time. Normal
fertilization of ova was observed at the first and fifth sampling period and, for
a dose of 200 mg/kg acetochlor, at the third sampling period. The magnitude and
temporal nature of these effects confirmed the induction of a pseudo-DL assay
response, and studies were then undertaken to probe its genesis. Rats treated
with 2000 mg/kg acetochlor had normal testicular and epididymal pathology and
normal sperm numbers and sperm motility at the critical third sampling period.
Despite a small reduction in testicular and epididymal glutathione levels 12 h
after exposure to 2000 mg/kg acetochlor, testicular LDH and LDH-X enzyme levels
were unaffected. Further, no reduction in the level of free sulphydryl groups (
SH) were observed in epididymal caput sperm heads isolated 0.5, 7 or 14 days
after treatment of male rats with 2000 mg/kg acetochlor. The only sperm parameter
affected by treatment with 2000 mg/kg acetochlor was an increase in epididymal
cauda sperm with head abnormalities. The non-specific nature of this effect was
considered inadequate to explain fully the high dose fertility effects seen in
the DL assays, which therefore remain unexplained. The present data establish
that acetochlor is non-mutagenic to rat germ cells. They also confirm the
importance of segregating mutagenic and fertility effects in the DL assay, and
emphasize the need for appropriate dose-setting studies prior to the conduct of
rodent genetic toxicity assays.
PMID- 9393620
TI - Chromosomal aberrations and micronuclei in lymphocytes of workers at a phosphate
fertilizer factory.
AB - The frequencies of chromosomal aberrations (CA) and micronuclei (MN) in
peripheral blood lymphocytes of 40 workers at a phosphate fertilizer factory in
North China, were studied. HF and SiF4 are the main air pollutants and small
amounts of dust containing fluoride, NH3 and SO2 were also present in the
factory. It was shown that the chemicals caused an increase in both CA and MN.
The mean frequencies per 100 metaphase of major CA type (chromosome rings,
translocations, and dicentrics) of the workers and the non-exposed controls were
0.91 and 0.24 (p < 0.01), respectively. The average percentages of lymphocytes
with MN of the workers and the controls were 1.55 +/- 0.71 and 0.62 +/- 0.54 (p <
0.01), respectively. Both CA frequency and MN frequency of the workers increased
with length of the chemical exposure period up to 10 years.
PMID- 9393621
TI - Lack of emodin genotoxicity in the mouse micronucleus assay.
AB - The study was performed to investigate the potential of emodin (1,3,8-trihydroxy
6-methylanthraquinone) to induce micronuclei in polychromatic erythrocytes
(PCEs). Mice of both genders received a single oral dose of 2000 mg emodin/kg and
were killed 24 and 48 h later. Bone marrow cells were collected from 5 males and
5 females and 2000 PCEs per animal were scored for the presence of micronuclei.
There was no enhancement in the frequency of micronuclei at both preparation
intervals when compared to the negative controls. Blood level examinations
confirmed the systemic availability of emodin. Plasma levels of up to 190
micrograms emodin/ml represented concentrations being in the concentration range
that induced positive responses in several genotoxicity cell culture assays.
PMID- 9393622
TI - Development of a novel CHL/IU cell line with an incorporated gpt shuttle vector
for concurrent analysis of gene mutations and chromosome aberrations.
AB - A cosmid shuttle vector containing the target gene of Escherichia coli gpt coding
xanthine-guanine phosphoribosyl transferase was constructed. The shuttle vector
was designed to be rescued into the gpt-deficient Escherichia coli from Chinese
hamster CHL/IU cells through an in vitro packaging method. Mutations occurred at
the target gene can be detected with a selective agent, 6-thioguanine (6-TG). The
shuttle vector was stably transfected into CHL/IU cells to give several cell
lines containing copies of the shuttle vector in the chromosomes. Each cell line
exhibited a characteristic rescue efficiency (0 to 1.9 x 10(5) CFU/microgram of
genomic DNA) of the shuttle vector and spontaneous mutation frequency (3.9 x 10(
5) to over 10(-2)) at the 6-TG selection. One transgenic cell line (KN63), which
showed a higher rescue efficiency and a low spontaneous mutation frequency, was
selected and tested for the ability to respond to a genotoxic agent, N-methyl-N'
nitro-N-nitrosoguanidine (MNNG). MNNG increased both the mutation frequency at
the target gene and the number of the cells with chromosome aberrations. DNA
sequence analysis of 6-TG mutants showed that predominant mutations (10/14) were
identified as G:C to A:T transitions in MNNG-induced mutants, whereas
transversions were predominant (5/9) in spontaneous mutants. These results
suggest that this transgenic CHL/IU cell line can be a useful tool for analyzing
the relation between gene mutations and chromosome aberrations.
PMID- 9393623
TI - Suppression of aflatoxin B1- or methyl methanesulfonate-induced chromosome
aberrations in rat bone marrow cells after treatment with S-methyl
methanethiosulfonate.
AB - The suppressive effect of S-methyl methanethiosulfonate (MMTS) on aflatoxin B1
(AFB1)- or methyl methanesulfonate (MMS)-induced chromosome aberrations (CA) in
rat bone marrow cells was studied. MMTS significantly suppressed CA induced by
both AFB1 (an indirect-acting carcinogen) and MMS (a direct-acting carcinogen).
Suppression was observed at all periods (6, 12, 18, 24 and 48 h) after AFB1 or
MMS treatment and in all doses of AFB1 (5, 10 and 20 mg/kg) or MMS (50, 75 and
100 mg/kg) investigated. AFB1-induced CA was potently suppressed by MMTS given
between 2 h before and 6 h after the AFB1 injection. The suppression of AFB1
induced CA by MMTS paralleled the dose of MMTS when MMTS was given in a dose
range of 1-20 mg/kg body weight. MMS-induced CA was potently suppressed by MMTS
given between 2 h before and 2 h after the MMS injection. The suppressive effect
of MMTS on MMS-induced CA paralleled the dose of MMTS when MMTS was given in a
dose range of 1-15 mg/kg body weight. Diphenyl disulfide, which modifies -SH
groups in proteins like MMTS, also significantly suppressed both AFB1- and MMS
induced CA. Although other mechanisms are not excluded, the suppression of
carcinogen-induced CA by MMTS may result from the ability of MMTS to modify -SH
groups in proteins. The juices of cabbage and onion, which contain considerable
amounts of MMTS and S-methyl-L-cysteinesulfoxide (the precursor of MMTS), also
significantly suppressed AFB1- or MMS-induced CA. These results suggest that MMTS
is a possible chemopreventive agent against cancer.
PMID- 9393624
TI - The Nobel Lectures in Immunology. The Nobel Prize for Physiology or Medicine,
1996. Cellular immune recognition and the biological role of major
transplantation antigens.
PMID- 9393625
TI - Tumour immunology: alternative perspectives.
PMID- 9393626
TI - A novel mycobacterial antigen relevant to cellular immunity belongs to a family
of secreted lipoproteins.
AB - The gene sequence of a novel 24.1 kDa Mycobacterium tuberculosis protein was
identified within the Sanger Centre (UK) M. tuberculosis genome database (cosmid
MTCY24G1) by searching with a 126 bp DNA sequence isolated from a genomic M.
leprae lambda gt11 library with M. leprae reactive human T cell clones as probes.
The 24.1 kDa antigen is common to the vaccine strain Mycobacterium bovis BCG, as
well as Mycobacterium leprae. The 699 bp open reading frame encodes a 233 amino
acid long precursor protein with a signal peptide sequence for secretion and a
consensus motif for lipid conjugation, which suggests that the mature protein is
an exported lipoprotein antigen. The molecular mass of the mature protein antigen
from M. leprae sonicate was shown to correspond to the deduced size of the M.
tuberculosis protein by T cell Western analysis. Homology searches revealed two
other similarly sized hypothetical secreted mycobacterial lipoproteins within the
M. tuberculosis genome database.
PMID- 9393627
TI - Release of cytokines and soluble cell surface molecules by PBMC after activation
with the bispecific antibody CD3 x CD19.
AB - Bispecific antibodies (BsAb) consist of two different heavy and light chains and
may bind to two different antigens present on different cell types. With their
dual specificity BsAb may recognize effector cells (e.g. T cells) on one hand and
tumour cells (e.g. malignant B cells) on the other hand. The authors analysed
whether T cell activation and subsequent killing of malignant B cells mediated by
the bispecific antibody CD3 x CD19 was reflected by the release of cytokines. In
addition, the authors investigated whether the in vitro cytokine release was
similar to that observed in vivo in the patients treated with BsAb. The in vitro
release of cytokines into the supernatant of cell cultures of peripheral blood
mononuclear cells (PBMC) and malignant B cells was measured after incubation with
either the bispecific antibody CD3 x CD19 or the monospecific anti-CD3 (aCD3)
antibody in the presence or absence of interleukin (IL)-2. Release of tumour
necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-6, IL-8, IL
10, soluble (s) CD4, sCD8 and sCD25 by PBMC was equal under both conditions and
could be used as an indicator for T cell activation. However, the cytokine
pattern and level did not correlate with the cytotoxic capacity, which was 4 logs
higher with BsAb + IL-2 compared to aCD3 + IL-2. The in vitro pattern of cytokine
release was similar to that observed in vivo in the serum of patients treated
with BsAb and IL-2, indicating the possibility of predicting cytokine release in
future patients with other therapeutic regimens.
PMID- 9393628
TI - Effect of treatments with cyclosporin A and anti-interferon-gamma antibodies on
the mechanisms of immune tolerance in staphylococcal enterotoxin B primed mice.
AB - The authors were interested to investigate the effect of Cyclosporin A (CsA),
known to block interleukin-2 (IL-2) production, or of anti-interferon-gamma
antibodies (anti-IFN-gamma Abs) in a model of T cell tolerance induced by the
injection of the superantigen Staphylococcal Enterotoxin B (SEB) in BALB/c mice.
After SEB immunization, tolerance was mainly achieved through deletion and anergy
of SEB-reactive V beta 8+ T cells. Association of CsA treatment with SEB led to a
greater decrease of the percentage of V beta 8+ CD4+ lymphocytes in the spleen
and an abolition of clonal energy. In contrast, treatment of SEB primed mice with
anti-IFN-gamma Abs resulted in an increased percentage of V beta 8+ CD4+ cells
without affecting the induction of clonal anergy. The authors found that 1-2 h
after SEB priming, splenic mRNA levels of IFN-gamma and IL-4 were decreased by
either CsA and anti-IFN-gamma Abs, whereas FasL, Bcl-2, p. 53, and c-myc levels
were not influenced by either treatment. However, SEB-induced IL-2 and IL-10 mRNA
expression was suppressed only by CsA, whereas tumour necrosis factor-alpha (TNF
alpha) was decreased only by anti-IFN-gamma Abs. To investigate whether the
effect of CsA on the tolerance mechanisms was related to suppression of IL-2, CsA
was administered together with recombinant IL-2. Whereas anergy was not
influenced, the decreased percentage of V beta 8+ CD4+ cells seen in CsA-treated
animals in the second week after SEB injection was partially corrected by the
administration of IL-2. Experiments involving bromodeoxiuridine incorporation
revealed that the latter effect of IL-2 was mainly due to a correction of the
defective proliferation of V beta 8+ T cells after SEB injection in CsA-treated
mice. These results suggest that the effect of CsA and anti-IFN-gamma Abs on
tolerance mechanisms are in part explained by their action on cytokines.
PMID- 9393629
TI - Increased mortality and impaired clonal deletion after staphylococcal enterotoxin
B injection in old mice: relation to cytokines and nitric oxide production.
AB - In the present study peripheral T cell tolerance and the occurrence of shock were
evaluated in young and old mice after injection of Staphylococcal enterotoxin B
(SEB). In young mice SEB immunization leads to tolerance based on deletion and
anergy of SEB-reactive V beta 8+ T cells. With aging, mice developed resistance
to SEB-induced deletion of V beta 8+ T cells as well as a high sensitivity to
toxic shock. Compared to young mice, older mice injected with SEB showed
increased serum levels of interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and
IL-4. These results were confirmed by reverse transcription-polymerase chain
reaction (RT-PCR), as splenic mRNA levels taken 2 h after SEB injection showed
higher values of IL-2, IL-4, and IFN-gamma in old mice. In contrast, mRNA levels
for FasL and tumour necrosis factor-alpha (TNF-alpha) were lower. No difference
in IL-10 mRNA was found. Compared to young mice, old mice showed a high, but
statistically not significantly different (P = 0.20), production of nitric oxide
(NO). Blocking of IFN-gamma with antibodies or reducing IFN-gamma by depletion of
natural killer (NK) cells resulted, respectively, in a complete or partial
protection against mortality in aged mice. Suppressing the NO production by the
NO synthase inhibitor N-nitro-L-arginine methylester (L-NAME) increased the
mortality in both young and old mice, and abrogated clonal deletion in the
surviving young mice. In conclusion, in young mice NO production is a key factor
in the protection against mortality and the development of clonal deletion after
SEB injection. The higher mortality seen in older mice is mainly related to the
elevated production of IFN-gamma and occurs despite a sufficient production of
NO. The decreased clonal deletion of old mice may be related to their decreased
expression of Fas ligand or TNF-alpha after SEB injection.
PMID- 9393630
TI - Selective cytotoxicity of two rodent T cell lymphomas to rat yolk sac tumours
involves a retroviral envelope protein expressed by the lymphoma.
AB - A Gross virus induced rat T cell lymphoma G1-Tc1 and a Moloney virus induced
mouse T cell lymphoma YAC-1 are shown to exert a strong cytotoxic activity
against rat yolk sac tumours but not to various types of rat, mouse or human
normal cells or tumour cell lines including carcinomas, sarcomas, lymphomas and
gliomas. Both lymphomas are CD3+, CD4-, CD8- and T-cell receptor (TCR) alpha beta
+. The cytotoxicity was not MHC restricted or dependent on the density of MHC
class I of the target cells, and the mouse lymphoma killed the rat yolk sac
tumour target. The cytotoxic action was fast and up to 80% specific killing was
observed in 4-h 51Cr release assays. A rat B cell hybridoma was established from
a Wistar/Furth (WF) rat immunized with the syngeneic lymphoma G1-Tc1 producing an
immunoglobulin (Ig)G2c monoclonal antibody (MoAb) 1F2. This binds to the
lymphomas G1-Tc1 and YAC-1 and also to a murine non-cytolytic Rauscher lymphoma
RMA, but not to any other of several rat, mouse or human cell types tested. The
1F2 completely inhibited the killing of rat yolk sac tumours by the two cytolytic
lymphomas, but did not interfere with the killing mediated by natural killer (NK)
cells or cytolytic lymphokine-activated killer (LAK) cells. Immunochemical
analysis of solubilized cell membranes of the lymphoma G1-Tc1 demonstrates that
the 1F2 antibody recognizes an epitope on a retroviral gp 70 envelope protein.
This indicates that a retroviral protein is involved in the lytic activity of the
two lymphomas.
PMID- 9393631
TI - Linomide enhances apoptosis in CD4+CD8+ thymocytes.
AB - Linomide, a quinoline-3-carboxamide, has a pleiotropic immune modulating capacity
and inhibits development as well as progression of disease in animal models of
autoimmunity. Linomide treatment of mice resulted in a dramatic, dose-dependent
decrease of the thymic cell number shortly after the start of administration.
Flow cytometric analysis revealed that the major thymocyte subset, the early
immature type CD4+CD8+ thymocytes, were reduced in number by 75%, mature CD4+CD8-
or CD4-CD8+ thymocytes were less sensitive to treatment. The polyclonal T cell
activator Con A (Concanavalin A) was used together with IL-2 to evaluate the
potential proliferative responsiveness of ex vivo thymocytes. Thymocytes from
mice treated with Linomide exhibited a more vigorous proliferation than control
cultures. An effect shown to not only be due to the enrichment of mature
thymocytes in the cultures from Linomide treated animals, but also when purified,
mature thymocytes (CD4+CD8- and CD4-CD8+) were cultured with Con A and IL-2,
these cells responded with a significantly enhanced proliferation. In vivo
Linomide treatment did not result in increased plasma concentrations of
corticosterone and treatment of adrenalectomized mice resulted in a reduction of
thymocytes which was comparable to the effect in intact mice, indicating that
glucocorticoids (GC) are not major mediators of Linomide-induced thymocyte
deletion. In addition to this, and supporting a glucocorticoid independent mode
of action, Linomide treatment of thymocytes in vitro resulted in a significant
increase in the number of apoptotic cells, specifically in the CD4+CD8+ subset,
implicating apopotosis as one component in the course of thymocyte reduction. In
addition to this, in vivo treatment with Linomide resulted in an identical
pattern to that seen in vitro in that there was significantly increased apoptosis
only in the CD4+CD8+. These data indicate that Linomide modifies thymocyte
development using a glucocorticoid independent pathway and results in the
increased apoptosis of the CD4+CD8+ subset.
PMID- 9393632
TI - Interferon-gamma production by human T cells and natural killer cells in vitro in
response to antigens from the two intracellular pathogens Mycobacterium
tuberculosis and Leishmania major.
AB - Acquired resistance to both mycobacteria and Leishmania is primarily mediated by
interferon-gamma (IFN-gamma), which triggers mechanisms leading to the death of
the microorganism in macrophages. In this study, cell activation and IFN-gamma
production was investigated in human peripheral blood mononuclear cells (PBMC)
from individuals previously sensitized to tuberculin and without known exposure
to Leishmania parasites. Immune staining for intracellular IFN-gamma and surface
markers allowed flow cytometric identification of the cellular sources of IFN
gamma in cell cultures incubated with purified protein derivative of tuberculin
(PPD) and Leishmania antigens. It was found that IFN-gamma was produced in
response to both PPD and Leishmania stimulant by T cells in the cultures.
Activation of IFN-gamma producing natural killer (NK) cells was demonstrated only
in some cultures, and only with concomitant T cell activation.
PMID- 9393633
TI - Down-regulatory effect of Mycobacterium leprae cell wall lipids on phagocytosis,
oxidative respiratory burst and tumour cell killing by mouse bone marrow derived
macrophages.
AB - The authors have previously demonstrated that lipids from Mycobacterium leprae
cell walls inhibit macrophage functions and are endowed with anti-inflammatory
properties in vivo. To investigate these observations further, the authors
describe here the influence of dead M. leprae or of the lipids extracted from the
cell wall of the mycobacterium, enclosed in liposomes, on the phagocytic,
oxidative respiratory burst and tumouricidal ability of bone marrow derived
macrophages in vitro. Dead M. leprae or its cell wall lipids abrogated the
oxidative respiratory burst and phagocytic ability of mouse bone marrow derived
macrophages. A dose-dependent inhibitory effect of the bacterial lipid extract on
tumour cell killing by lipopolysaccharide (LPS)-activated bone marrow derived
macrophages was demonstrated. However, when delipidated M. leprae was added to
cultures of bone marrow derived macrophages, immune phagocytosis and superoxide
production was up-regulated. Mycobacterium leprae or its lipids did not appear to
be toxic to those cells assayed by the MTT (methyl thiazol tetrazolium) test.
These data, added to our preceding observations, support the hypothesis that the
down-regulatory activity of M. leprae wall lipids on macrophage function might be
one of the evasive mechanisms of the bacterium to enable it to perpetuate itself
in the host tissues.
PMID- 9393634
TI - Nasal lymphoid tissue (NALT) as a mucosal immune inductive site.
AB - Intranasal (i.n.) immunization is a very effective route for inducing mucosal
immunity, but the cellular mechanism responsible for regulating and disseminating
these responses is not fully understood. The authors studied the role of nasal
lymphoid tissue (NALT) as a mucosal inductive site by using highly purified NALT
cells obtained by a new method of mechanical isolation. The NALT cells, like
Peyer's patch (PP) cells, were smaller in size and less granular than lymphocytes
from salivary glands (SG) and small intestinal lamina propria (LP). The NALT
cells isolated from i.n. immunized mice contained antigen-specific antibody
secreting cells (ASC) predominantly of immunoglobulin (Ig)A isotype, similar to
those also recovered from salivary glands in a time course study. However, the
higher proportion of smaller sized sports formed by NALT cells in ELISPOT assays
suggested that these cells were less differentiated precursors of those found in
salivary glands. This was supported by the fact that after i.n. immunization, IgA
ASC appeared in NALT, as well as in mucosal effector sites SG and LP, but none or
very few in another mucosal inductive site, PP. In contrast, after intragastric
(i.g.) immunization, IgA ASC were detected in PP, along with the SG and LP, but
none or very few in NALT. Furthermore, after i.n. immunization, lymphocytes from
NALT but not PP proliferated in response to the specific antigen in culture.
These findings imply that NALT served as an inductive site for IgA antibody
responses at mucosal effector sites.
PMID- 9393635
TI - How to diagnose chronic rejection. A study in porcine intestinal allografts.
AB - Porcine small bowel allografts were followed for 18 weeks during
immunosuppression with cyclosporine-A (CyA), azatioprine and prednisone. The
mucosal alterations noted at the 12th week were epithelial vacuolation and loss
of Goblet cells. Moderate infiltration of inflammatory cells, mainly lymphocytes,
was found in the lamina propria. In addition, a few grafts exhibited oedema and
fibrosis. Vessels already showed endothelial swelling and intimal proliferation
at the 12th week. In the submucosa, the infiltration of inflammatory cells was
not present till the 18th week. Further changes in the mucosa at the 18th week
were the blunting of villi, cuboidal epithelium, crypt abscesses and epithelial
atrophy. The histological alterations of mucosa and lamina propria existing in
the full thickness biopsies were mostly also detectable in mucosal biopsies,
provided that multiple biopsies were taken. Thus these parameters analyzed from
mucosal biopsy material are suitable for the diagnosis and monitoring of chronic
small bowel rejection. In autopsy, the most prominent features were in the
mesenterial arteries: intimal proliferation, vasculitis, proliferation of media
and endothelial alterations. The activity of the mucosal disaccharidases maltase
and sucrase remained near the initial level till the 12th week and had decreased
markedly by the 18th week.
PMID- 9393636
TI - T-cell receptor BJ gene segment expression in human umbilical cord blood CD4+ and
CD8+ T-cell subsets.
AB - By employing RT-PCR-based technology, followed by Southern-blot analysis,
patterns of relative TRC BJ gene segment usage in human CD4+ and CD8+ umbilical
cord blood T cells (UCT) from ten children were determined in relation to seven
recombined TCR BV gene (sub) families (BV 3, 5S1, 6S1-3, 8, 9, 12 and 18). Normal
frequency of usage of individual BJ members was observed to be extremely
nonrandom. BJ usage in association with each BV was ranked and mean ranking
values were calculated for individual BJs. Moreover, BJ family usage and family
ranges as well as individual BJ over-representations were determined. In all
these aspects of BJ exon expression, CD4+ and CD8+ UCT displayed similar
distribution patterns. Comparisons of BJ usage in UCT subpopulations and in the
adult peripheral blood lymphocyte (PBL) counterparts were performed and many
similarities were observed. However, discrepancies in two parameters were
recorded; contrary to observations in PBL, individual BJ over-representations
were virtually absent in UCT, and significantly less wide BJ family ranges were
demonstrated in CD8+ UCT relative to CD8+ PBL T cells. These differences support
the notion that UCT are in a less dynamic state than are PBL T cells. Hence,
despite the fact that PBL T cells are subjected to continuous antigenic
challenge, the striking resemblance of PBL and UCT with regard to the overall
individual relative usage, ranking, mean ranking and family utilisation of BJ
gene segments, irrespective of the choice of recombined BV exons, may suggest a
relatively nondiscriminatory role for the BJ gene product in antigen recognition
as compared to those encoded by the BV, (N) and BD gene segments.
PMID- 9393637
TI - Cloning and molecular analyses of the Arabidopsis thaliana plastid pyruvate
dehydrogenase subunits.
AB - Herein we report the first molecular description of the pyruvate dehydrogenase
component of the higher plant plastid pyruvate dehydrogenase complex. The full
length cDNAs for the E1 alpha (1530 bp) and E1 beta (1441 bp) subunits of the
Arabidopsis thaliana plastid pyruvate dehydrogenase contain open reading frames
that encode polypeptides of 428 and 406 amino acids, respectively, with
calculated molecular weight values of 47,120 and 44,208. The deduced amino acid
sequences for Arabidopsis plastid E1 alpha and E1 beta have 61% and 68% identity
to the odpA and odpB genes of the red alga Porphyra purpurea, respectively, but
only 31% and 32% identity to the plant mitochondrial counterparts. Results of
Southern analyses suggest that each subunit is encoded by a single gene. Northern
blot analyses indicate expression of mRNAs of the appropriate size in Arabidopsis
leaves.
PMID- 9393638
TI - Patch clamp investigation into the phosphate carrier from Saccharomyces
cerevisiae mitochondria.
AB - After heterologous expression in E. coli, functionally active phosphate carrier
(PIC) from Saccharomyces cerevisiae mitochondria was purified and reconstituted
into giant liposomes and used for patch clamp experiments. Single channel
currents across excised patches revealed an anion channel function of the PIC
protein. Besides the three transport modes known to date, namely
phosphate/phosphate exchange, phosphate/OH exchange and mercurial-induced
unidirectional transport, this channel activity represents the fourth transport
mode of the PIC. The PIC channel activity was sensitive towards phosphate as its
physiological substrate. Phosphate (10 mM) blocked in a specific but reversible
manner the PIC channel, suggesting a phosphate-dependent conformational change of
the protein into the carrier mode. Furthermore, the current through the channel
and its gating activity were affected by divalent cations. In the presence of
Ca2+ and Mg2+, the channel displayed a mean conductance of 25 +/- 5 pS whereas 40
+/- 10 pS was observed in the absence of divalent cations. Also, the dwell times
in either the open or closed state of the PIC channel appeared to be prolonged in
the presence of Ca2+ and Mg2+. The observed PIC channel characteristics are
discussed with respect to previously reported electrophysiological in situ
measurements on anion channels of the inner mitochondrial membrane. Similarities
of the PIC channel to the inner mitochondrial anion channel (IMAC) have been
found.
PMID- 9393639
TI - Intramolecular oxidation of cytochrome c by covalently attached sulfoaromatic
molecules.
AB - Two photosensitive molecules, 1-maleimidopyrene-3,6,8-trisulfonate (MPTS) and N
acetylaminoethyl-1-aminonaphthalene-5-sulfonate (AEDANS), are employed to drive
the intramolecular oxidation of the heme residue in cytochrome c. Intense pulse
illumination (60-120 MW cm-2) of MPTS and AEDANS in the aqueous solution by the
third harmonic frequency of Nd-Yag laser drives a two successive-photon process
of the dyes. The oxidized products originating from the dyes react with variety
of electron donors. MPTS and AEDANS residues were covalently linked the
Saccharomyces cerevisiae iso-1-cytochrome c by labeling of its single sulfhydryl
group. When pulsed by intensive laser beam the heme of the labeled
ferrocytochrome c undergoes fast oxidation. Transient absorption spectroscopy was
used to directly measure the rate constants for the photoinduced electron
transfer reaction from the ferros heme group to the oxidized dyes. The rate
constant was found to be (3.6 +/- 0.4) x 10(4) s-1 for MPTS derivative. The rate
of the heme oxidation in AEDANS derivative was faster than response time of our
detection system (20 ns). Rapid photooxidation of cytochrome c makes it a useful
tool for fast initiation of electron transfer in oxidized direction within
complexes of cytochrome c with the other redox proteins.
PMID- 9393640
TI - The role of the membrane-spanning and extra-membranous regions of the iron-sulfur
protein in its assembly into the cytochrome bc1 complex of yeast mitochondria.
AB - The assembly of six deletion mutants of the Rieske iron-sulfur protein into the
cytochrome bc1 complex was investigated by immunoprecipitation from detergent
solubilized mitochondria with specific antisera against either the iron-sulfur
protein or the intact cytochrome bc1 complex. After import, the mutant proteins
lacking residues 41-55 or 66-78, located at the membrane-spanning region of the
protein, and residues 182-196 located at the C-terminus of the protein, were
assembled in vitro into the bc1 complex approximately 50% as effectively as the
wild type iron-sulfur protein suggesting that these regions of the iron-sulfur
protein may not be critical for the assembly. By contrast, only trace amounts of
the mutant proteins lacking residues 80-95, 122-135, 138-153 located in the extra
membranous region of the iron-sulfur protein were assembled into the bc1 complex.
After import in vitro into mitochondria isolated from a cytochrome b-deficient
yeast strain, the mutants lacking residues 41-55 and 182-196 were assembled as
efficiently as the wild type; however, the mutants lacking residues 55-66 and 66
78 were assembled less efficiently in the absence of cytochrome b suggesting that
the hydrophobic membrane-spanning region, residues 55-78, of the iron-sulfur
protein, may interact with cytochrome b during the assembly of the bc1 complex.
PMID- 9393641
TI - Binding of MOA-stilbene to the mitochondrial cytochrome bc1 complex is affected
by the protonation state of a redox-Bohr group of the 'Rieske' iron-sulfur
protein.
AB - MOA-stilbene is a specific inhibitor of the ubihydroquinone oxidation center
(center P or o) of cytochrome bc1 complex. Binding of this inhibitor does not
require the 'Rieske' iron-sulfur protein, but is affected by the redox-state of
the cytochrome bc1 complex. We have analyzed the pH dependence of the apparent
dissociation constant for MOA-stilbene. A 2.5 fold change in affinity between pH
6.0 and 9.5 was observed for oxidized bovine cytochrome bc1 complex. The pH
profile could be simulated by assuming a single protonable group with pKA = 7.7.
This pKA was not observed after partial or complete reduction of the enzyme or
after removal of the iron-sulfur protein. We conclude that this protonable group
was identical to the redox-Bohr group with the same pKA that has been reported to
be associated with the 'Rieske' iron-sulfur cluster. Fully reduced cytochrome bc1
complex exhibited an additional binding site for MOA-stilbene. As this second
binding site was abolished by the center P inhibitor stigmatellin, but not by
antimycin, an inhibitor of ubiquinone reduction at center N, we conclude that it
is also located at center P.
PMID- 9393642
TI - Effect of nitroso compounds on Na/K-ATPase.
AB - Thiol containing NO.-derivatives were found to inhibit the activity of brain and
kidney Na/K-ATPase. S-Nitrosogluthatione demonstrated only minor inhibiting
activity, while dinitrosyl iron complexes (DNIC) with cysteine or glutathione
were much more effective. Brain Na/K-ATPase is more vulnerable to inhibiting
action than kidney Na/K-ATPase. Inhibition of the activity is accompanied by a
decrease in amount of protein thiol groups and a change in the substrate
dependence curve of the enzyme. Restoration of Na/K-ATPase activity by SH-reagent
dithiothreitol or cysteine is accompanied by restoration of SH-groups of the
enzyme. This suggests that blockade of SH-groups of Na/K-ATPase is responsible
for the inhibition. The possibility that this blockade results in disordering of
interprotomer interactions within the oligomeric complexes of Na/K-ATPase is
suggested. Possible regulatory meaning of the effect of NO. derivatives is
discussed.
PMID- 9393643
TI - ATPase and phosphatase activities are differentially inhibited by photo-oxidation
of the sarcoplasmic reticulum Ca(2+)-ATPase.
AB - We have already described that photo-oxidation of the sarcoplasmic reticulum
Ca(2+)-ATPase with the halogenated dye erythrosin B produces inhibition of the
ATPase activity (J.A. Mignaco et al., Biochemistry 35 (1996) 3886-3891). We now
show that the Ca(2+)-dependent and Ca(2+)-independent p-nitrophenylphosphatase
activities are also inhibited by this treatment. Modification of rapidly (< 10
min) oxidized residue(s) is responsible for the major loss of ATPase activity,
whereas photo-inhibition of the phosphatase activities occurs more slowly (t1/2
20-30 min). Here we have focused on photo-inhibition of the Ca(2+)-independent
pNPPase activity, and the counteracting effects of ATP and FITC. Following photo
oxidation, the Ca(2+)-independent pNPPase activity decreases monotonically. ATP
partially protects against the inactivation of the pNPPase, whereas labeling the
enzyme with FITC does not. However, the protective effect of ATP is completely
abolished by the attached FITC. These data are interpreted in terms of two
different sites that are susceptible to photo-oxidation and are involved in
different events related to substrate hydrolysis.
PMID- 9393644
TI - Microbiological observations in the anoxic basin Golfo Dulce, Costa Rica.
AB - Our basic microbiological studies of the water column and the sediment of Golfo
Dulce, Costa Rica, were focused on aerobic and denitrifying sulfur-oxidizing
bacteria and anaerobic sulfate-reducing bacteria. We observed no increasing
numbers of total bacterial counts within the water column. Although no oxygen was
present hydrogen sulfide was only detectable close to the sediment. The highest
numbers of sulfate-reducing bacteria measured by Most-Probable-Number counts were
found in or close to the sediment. In the anoxic bottom water sulfide-oxidizing
bacteria typically containing large sulfur globules were observed
microscopically. They were identified as free-swimming Thiovulum and Thiospira
species. At one station large vacuolated forms of the filamentous colourless
sulfur bacterium Beggiatoa were noted. Together with these sulfur containing
bacteria there were long free swimming rods showing no sulfur inclusions of
unknown character. The microscopic observations showed good correlation with Most
Probable-Number-counts and molecular biological techniques for sulfate-reducing
bacteria.
PMID- 9393645
TI - Polychaete worms (Annelida) collected in Golfo Dulce, during the Victor Hensen
Costa Rica expedition (1993/1994).
AB - A total of forty seven species of benthic polychaetes belonging to twenty five
families have been identified from bottom samples taken in Golfo Dulce, Costa
Rica, by the RV Victor Hensen. Only those stations collected in waters less than
100 m depth contained polychaetes. The major feeding type of these polychaete
species was surface deposit feeding with slightly fewer species recognized as
carnivores. Comparison of the species identified from the RV Victor Hensen
material with those of the RV. T.V. Thompson material collected in 1969 reveals
very few that are common to the two studies, indicating that the polychaetes of
Golfo Dulce are probably quite diverse and poorly known. An estimated total of
eighty five species of polychaetes have been identified from Golfo Dulce in the
two studies.
PMID- 9393646
TI - Annotated list of species of marine crustaceans (Decapoda and Stomatopoda) from
Golfo Dulce, Costa Rica.
AB - The present study is an annotated list of the marine crustaceans (Decapoda and
Stomatopoda) from Golfo Dulce, Costa Rica, collected during the RV Victor Hensen
Cruise 1993-1994, at depths ranging from 20 to 260 m. Stomatopoda was represented
by one family and two species. Decapoda was represented by 12 families and 21
species. Two new records for Costa Rica, Cancer johngarthi and Lysmata
californica are reported. This increases the reported marine crustaceans of Golfo
Dulce to three species of Stomatopoda and sixty-six of Decapoda (a complete
checklist in included). A list of species reported in the literature from the
gulf is also included.
PMID- 9393647
TI - Checklist of crustaceans (Decapoda and Stomatopoda), collected during the Victor
Hensen Costa Rica expedition (1993/1994).
AB - A checklist of the marine crustaceans (Decapoda and Stomatopoda) from the Pacific
coast of Costa Rica collected by trawling during the RV Victor Hensen Cruise
(1993-1994) is presented. A total of 117 species were identified, 10 stomatopods
and 107 decapods.
PMID- 9393648
TI - Checklist of copepods from Gulf of Nicoya, Coronado Bay and Golfo Dulce, Pacific
coast of Costa Rica, with comments on their distribution.
AB - A list of 54 copepod species (Crustacea) in 23 families is presented for the
Pacific coast of Costa Rica. Identifications are from zooplankton samples of the
Victor Hensen Expedition during December 1993 and February 1994. Samples were
taken with a Bongo net (0.60 m net opening, 2.50 m net length) with 200 microns
mesh size. Oblique hauls were done from the surface to the ground at a towing
speed of aprox. 1 knot. 37 species (68.5%) were found in the Gulf of Nicoya, 36
in Golfo Dulce (66.6%) and 17 (31.4%) species were common to both gulfs, while
only twelve species (22.2%) were found in Coronado Bay. Four species (7.4%) were
distributed along the coast and were common to the three regions: Paracalanus
parvus, Euchaeta sp., Oithona plumifera and O. similis. Eleven species of
calanoids found normally in the Costa Rica Dome show the influence of typical
oceanic waters principally at the mouth of Gulf of Nicoya. Differences were
observed in the composition and presence of the copepod species when the inner
and outer (upper and lower) parts of both gulfs were compared. Gulf of Nicoya was
dominated in its upper part by typical neritic estuarine species like Acartia
lilljenborgii, Paracalanus parvus and, Hemyciclops thalassius as well as species
of Pseudodiaptomus. On the other hand a more oceanic composition of copepods was
observed in the lower part of the gulf. Both small species, like Oncaea venusta,
as well as larger species, such as Pleuromamma robusta, Eucalanus attenuatus, E.
elongatus and Rhincalanus nasutus, were typical of these waters. Oithona
plumifera and O. similis were found in the lower part too; and both species are
typical from oceanic water. Coronado Bay was characterized by the presence of
typical oceanic species like Neocalanus gracilis, Euchaeta longicornis, Eucalanus
attenuatus and Haloptilus ornatus with more transitional species like
Clausocalanus pergens and C. furcatus near the coast. In the Golfo Dulce
differences in copepod composition were also observed, but the separation of the
species was not so evident. Outer stations were represented by oceanic species
like Paracalanus aculeatus, Pleuromamma gracilis, Lucicutia ovalis, Candacia
catula, Euchaeta wolfendeni and Oncaea mediterranea, while the inner station,
located at the upper part of the Gulf, was more characterized by a mixed copepod
group, with both neritic species like Pseudodiaptomus wrigthi, Acartia danae, A.
clausi, Canthocalanus pauper as well as oceanic species like Scolicithricella
marginata, Saphirina nicromaculata or Oncaea conifera. Two species of Coryceaus,
C. flaccus and C. speciosus, were identified in the outer stations of Golfo
Dulce, while C. brehmi was found in inner stations of Gulf of Nicoya. The
majority of copepods found are typical of the east Pacific. This paper
constitutes an additional work about the copepods in the Gulf of Nicoya and the
first report of copepod species for Coronado Bay and Golfo Dulce.
PMID- 9393649
TI - Demersal crustacean assemblages along the Pacific coast of Costa Rica: a
quantitative and multivariate assessment based on the Victor Hensen Costa Rica
expedition (1993/1994).
AB - During the first cruise leg with the RV Victor Hensen to the Pacific coast of
Costa Rica in December 1993 (end of the rainy season) the crustacean fauna found
in the demersal collections revealed an unexpected species richness and biomass.
The Crustacea collections were analyzed qualitatively and quantitatively during
the fourth leg (February 1994, dry season) in the three study areas Golfo Dulce
(GD), Bahia Coronado in the Sierpe-Terraba-estuary (ST) and Golfo de Nicoya (GN).
Qualitative data were available for comparison from the first leg in december
1993. A total of 24 beamtrawl and ten ottertrawl sample collections were done on
an area of 860.000 m2 yielding a total of 119 species with a biomass of 37.8 kg
(10275 specimens). Despite the smaller area covered by the beamtrawl, it
collected a higher number of species and more biomass than the ottertrawl due to
the smaller mesh size (0.8 cm). Judging from the shape of the species -per-area
curves, the crustacean fauna appeared as representatively sampled for the study
area. As compared with the GN (biomass 0.36 g +/- 0.26, SR = 97) and the ST (0.41
g +/- 0.27, SR = 59) and according to the results of the log-series-plots
constructed from the abundance data, the GD seems to be a depauperated area with
significantly lower biomass (0.05 g +/- 0.07) and species richness (45 sp.). No
crustaceans were found in the center of the deep basin of the GD put parts of the
interior gulf with adjacent mangrove areas seem to be important as nursery area
for some commercially important penaeid shrimp species. The ST-estuary revealed
the highest mean species number per station in the whole study area, but the GN
had the highest total number of species. Biomass seems to be regularly
distributed and not depth-depending within the GN, while species abundance varies
clearly, confirming previous results. In contrast, abundance and biomass
correlated well in the ST. Based on the results of the multivariate analysis,
seven station groups of particular species assemblages can be distinguished in
the study areas. Despite a high variability between stations in abundance and
biomass, the following four areas of characteristic species assemblages can be
identified which are also confirmed by an independent study on demersal fishes:
(1) the interior part of the GN, characterized by juvenile shrimps (Sicyonia
disdorsalis, Trachypenaeus fuscina), several patchily distributed anomurans,
brachyurans and other predator species like portunids (especially Portunus asper)
and pre-adult stomatopods (Squilla spp.); (2) the exterior part of the GN with
high amounts of caridean (Pantomus affins, Plesionika spp.) and penaeid shrimps
(Sicyonia picta, Solenocera mutator), the highly abundant Iliacantha hancocki and
some specimens of the stomatopod Hemisquilla stylifera and the deep water
portunid Portunus iridescens; (3) a transition zone between 60 and 120 m water
depth with a heterogeneous faunal composition, located in the ST and east of Isla
Tortugas in the GN, and (4) the oxygen-depleted shelf edge area, dominated by the
galatheid Pleuroncodes monodon. Mass occurrence of this species takes place off
the GD and to a lesser extent off the ST-estuary, associated with high numbers of
Solenocera spp. There seems to be a general trend of species groupings along
abiotic gradients (depth, temperature, oxygen saturation) interrupted by small
scale variations in habitat type, current regime, food availability and other
factors not identified in this study. Neither total abundance and biomass nor
biotic summary parameters like diversity, dominance or species richness
correlated well with the abiotic factors measured during this survey.
PMID- 9393650
TI - Comparative biomass spectra and species composition of the zooplankton
communities in Golfo Dulce and Golfo de Nicoya, Pacific coast of Costa Rica.
AB - This study is based on a subset of plankton samples obtained during an expedition
of the German RV Victor Hensen to the Pacific coast of Costa Rica in 1993/94. It
aims at the identification of the main plankton taxa for a general description
and comparison of the plankton communities of the gulf systems Golfo de Nicoya
(GN) and Golfo Dulce (GD) and the analysis of biomass spectra at inshore and
offshore stations at the end of the rainy season and during the dry season.
Inshore plankton biomass was significantly higher in GN than GD and exceeded
offshore biomass several times, while in the GD area the reverse was found. In
the rainy season, inshore biomass spectra of GN and GD were discontinuous with
biomass concentrations at small sizes (around 0.06 mg) suggesting little
developed communities, with highest production and energy use occurring in the
small organisms. From the rainy to the dry season inshore species richness
increased in both gulf systems and a shift was observed towards the larger size
groups resulting in more continuous biomass spectra. In GN, bivalve larvae,
foraminifers, ostracods, mysids and nauplii increase heavily in abundance and
some gelatinous specimens occur. In GD, gelatinous zooplankton appears in
enormous abundance and dominate the community biomass, followed by large
chaetognaths and ostracods. In GD, inshore plankton has neritic and oceanic
elements and differs less from the offshore plankton, whereas in GN, inshore
plankton in largely neritic. The high abundance of fish eggs and invertebrate
larvae suggest that this area is an important spawning ground. While in the rainy
season inshore biomass was about 15 times higher in GN compared to GD, this
difference was reduced to 3-4 times in the dry season due to the appearance of
the large predators mentioned above. The changes from the rainy to the dry season
at the offshore stations of both gulf systems are less pronounced in terms of
total biomass, shape of the biomass spectra and taxonomic composition of the
community. The differences-relatively continuous biomass spectra with an
increasing slope and a high total biomass in GD versus flat and shorter spectra
due to the absence of large chaetognaths and medusa in the GN-suggest that
conditions in the former area allow for a better development of a
trophodinamically tightly structured plankton community.
PMID- 9393651
TI - Distribution and biomass of arrow worms (Chaetognatha) in Golfo de Nicoya and
Golfo Dulce, Costa Rica.
AB - The chaetognath species guild was analyzed from samples collected during the
cruise of the German RV Victor Hensen to the Pacific coast of Costa Rica in
December 1993 and February, 1994, finding the following ten species of the genera
Sagitta and Krohnitta: S. enflata, S. hexaptera, S. pacifica, S. neglecta, S.
regularis, S. bedoti, S. friderici, S. popovicii, S. pulchra and K. pacifica.
Because of their distributional patterns in the study area these species were
ascribed to the following ecological groups: neritic, semi-neritic and oceanic. A
strong gradient in species richness from offshore to inshore waters (8 to one
respectively) was found in both gulf systems. Inshore chaetognaths were dominated
by juveniles and adults of S. friderici in Golfo de Nicoya and by S. popovicii in
Golfo Dulce. Biomass spectra were more continuous and of wider range in the Golfo
Dulce area showing a dominance of larger chaetognaths, suggesting a more general
developed pelagic system in Golfo Dulce, where larger chaetognaths might
structure the plankton community by strong grazing pressure from above.
PMID- 9393652
TI - Ichthyoplankton assemblages in the Gulf of Nicoya and Golfo Dulce embayments,
Pacific coast of Costa Rica.
AB - Ichthyoplankton surveys were conducted in December (rainy season), 1993 and
February (dry season), 1994, during the RV Victor Hensen German-Costa Rican
Expedition to the Gulf of Nicoya and Gulfo Dulce, Costa Rica. Samples from the
inner, central, and outer areas of each gulf were collected in oblique tows with
a bongo net of 0.6 m mouth diameter, 2.5 m long and 1000-micron mesh. A total of
416 fish larvae of 22 families were sorted out of 14 samples. Stations of both
the maximum (11) and the minimum (1) family richness were located in Golfo Dulce.
Mean total larval abundances were 124.9 and 197.2 individuals 10 m-2 for the Gulf
of Nicoya and Golfo Dulce, respectively, while mean larval densities ranged from
95.3 larvae 10 m-2 in December to 236.7 larvae 10 m-2 in February. However, no
statistical differences between gulfs or seasons were detected, due to the high
within-group variability. Cluster Analysis, Multi-Dimensional Scaling (MDS), and
non-parametric tests showed two well-defined major groups: (1) the Gulf of Nicoya
neritic assemblage, represented by Engraulids, Sciaenids, and Gobiids (inner and
central stations), and (2) the oceanic assemblage, dominated by Myctophids,
Bregmacerotids, Ophiidids, and Trichiurids (outer stations off the Gulf of Nicoya
and Golfo Dulce). A third, although less defined group, was an Ophichthid
dominated assemblage (typical in areas nearby coral or rocky reefs). These
assemblages closely resemble the clusters based upon adult fish data of the
beamtrawl catches of the same cruise. This publication is the first to report on
the ichthyoplankton community of Golfo Dulce.
PMID- 9393653
TI - Fishes collected during the Victor Hensen Costa Rica expedition (1993/1994).
AB - A list is presented of 242 species of fishes taken in the Golfo de Nicoya, Golfo
Dulce and on the Pacific continental shelf of Costa Rica. The specimens were
collected using dredges and bottom trawls during December 1993 and February 1994.
The Golfo Dulce revealed the lowest diversity with only 75 species represented;
118 species were collected in the Golfo de Nicoya and 129 species in offshore
waters. It is presumed that low fish diversity in Golfo Dulce is due to the deep,
unproductive waters in that embayment. The checklist includes presence-absence
data for each locality.
PMID- 9393654
TI - Demersal fish assemblages along the Pacific coast of Costa Rica: a quantitative
and multivariate assessment based on the Victor Hensen Costa Rica expedition
(1993/1994).
AB - During two cruise legs with the RV Victor Hensen (December 1993, February 1994),
the demersal fish assemblages of the Golfo de Nicoya (GN), Bahia Coronado-Sierpe
Terraba (ST) and Golfo Dulce (GD) areas were assessed from nearshore
(approximately 20 m) to shelf edge (approximately 200 m) waters. 44 Beam- and 29
otter trawl collections were made on an area of 2,119,405 m2, yielding a total of
242 species of fish. Despite the lower number of samples taken, more species were
collected by the otter trawl (189 compared to 160), due to a wider area swept. As
revealed by the species-area curve and a longnormal-curve constructed from the
pooled (log) abundance data, the fish assemblage appeared as well sampled and a
theoretical species richness (SR) of-306 was estimated for the whole area. Mean
species number per collection and mean biomass per area were much lower in the GD
area (9.3 species, 0.36 g/m2) compared to the ST (15.4, 0.81 g/m2) and GN (17.3,
0.74 g/m2) areas, indicating a depauperate fish assemblage in the former. Lowest
species numbers and biomass were found in the central deep part of GD with
increasing values towards the sill area at the opening of the gulf and towards
the shallow stations above the thermocline. Average biomass was an order of
magnitude higher in the interior part of GN compared to the other areas with
values up to 18.1 g/m2. Based on results of a multivariate analysis of the
collections, the GN area can be divided into (1) an interior shallow area above
the thermocline (< 50 m) characterized by scianids, sea carfishes, stingrays,
flatfishes, sea robins, (2) an outer part (> 100 m) characterized by cods,
scorpionfishes, gobies, cutlassfishes, serranids, anglerfishes and flatfishes and
(3) a transition zone of the central and lateral parts with a mixed species
assemblage with carangids, pufferfish, snappers, several flatfish species and the
lizardfish as common elements. Characteristic for the deep basin of GD were small
species of the genera Cynoscion and Porichthys. These occurred in low densities,
suggesting a reduced carrying capacity of this deep basin for fish biomass in
terms of food and oxygen. Species occurring at the shallow stations of GD are
also found at a similar depth in the other areas, but many species are missing,
namely ariids and many scianids found in the GN area. The species assemblage of
the ST area resembles that of GN. Ariids, however, are missing here too. Biotic
station parameters like species richness, biomass, abundance and production were
not significantly correlated with abiotic parameters (temperature, oxygen,
nutrients) suggesting that other habitat factors not evaluated in this study like
habitat heterogeneity, distance to the open ocean, current regime and food
availability probably are important factors for the structure of the fish
assemblage.
PMID- 9393655
TI - D-dimer levels detected DVT in patients hospitalized for stroke rehabilitation.
PMID- 9393656
TI - Viral gastroenteritis associated with eating oysters -- Louisiana, December 1996
January 1997.
AB - Viral gastroenteritis outbreaks caused by caliciviruses (i.e., Norwalk-like
viruses or small round-structured viruses) have been associated with eating
contaminated shellfish, particularly oysters (Crassostrea virginica). This report
describes the findings of the investigation of an outbreak of oyster-associated
viral gastroenteritis in Louisiana during the 1996-97 winter season and
implicates sewage from oyster harvesting vessels as the probable cause of
contaminated oysters.
PMID- 9393657
TI - Progress toward poliomyelitis eradication -- Western Pacific Region, January 1,
1996-September 27, 1997.
AB - In 1988, the World Health Assembly adopted the goal of global poliomyelitis
eradication by 2000, which was endorsed in each of the six regions of the World
Health Organization (WHO). In the Western Pacific Region (WPR), where the last
known case of polio associated with isolation of wild poliovirus occurred in
March 1997, the reported number of cases decreased from 5963 in 1990 to 197 in
1996. This report documents progress toward polio eradication in WPR from January
1, 1996, through September 27, 1997, in countries where polio is endemic
(Cambodia, China, Laos, Papua New Guinea, Philippines, and Vietnam) or recently
was endemic (Malaysia and Mongolia) and describes the routine and supplemental
vaccination activities necessary to interrupt wild poliovirus transmission in the
region.
PMID- 9393658
TI - Surveillance for fetal alcohol syndrome using multiple sources -- Atlanta,
Georgia, 1981-1989.
AB - Fetal alcohol syndrome (FAS) is caused by heavy alcohol consumption during
pregnancy and is characterized by specific anomalies of the face; prenatal and
postnatal growth deficits; and a variety of central nervous system (CNS)
abnormalities, including mental retardation. Children with either full or partial
FAS often incur severe and costly secondary disabilities. Despite the importance
of surveillance for establishing the magnitude of FAS and in monitoring trends in
the occurrence of this disease, population-based surveillance for FAS has been
difficult because the syndrome can be diagnosed only by clinical observation and
often is not recognized until after the child reaches school age. Although most
FAS surveillance has been based on diagnoses among newborns, most (89%) cases
(full FAS and partial FAS) are diagnosed after the age of 6 years. To develop a
more accurate estimate of the prevalence of FAS in a defined population, in 1997
CDC linked data from the Metropolitan Atlanta Congenital Defects Program (MACDP)
and the Metropolitan Atlanta Developmental Disabilities Surveillance Program
(MADDSP) for children born in Atlanta during 1981-1989 (the most recent birth
year for which data were available for 3-10-year-olds). This report presents a
multiple-source method for FAS surveillance that is more complete than previous
methods and that enables comparison of rates between states.
PMID- 9393659
TI - Youth Risk Behavior Surveillance: National College Health Risk Behavior Survey-
United States, 1995.
AB - PROBLEM/CONDITION: Colleges and universities are important settings for
delivering health promotion education and services to many young adults. However,
before this national college-based survey was conducted in 1995, the prevalences
of health-risk behaviors among college students nationwide had not been well
characterized. REPORTING PERIOD: January through June 1995. DESCRIPTION OF THE
SYSTEM: The Youth Risk Behavior Surveillance System (YRBSS) monitors six
categories of priority health-risk behaviors among youth and young adults:
behaviors that contribute to unintentional and intentional injuries, tobacco use,
alcohol and other drug use, sexual behaviors, unhealthy dietary behaviors, and
physical inactivity. The YRBSS includes a) national, state, and local school
based surveys of high school students conducted biennially since 1991, b) a
household-based survey conducted in 1992 among a national sample of youth aged 12
21 years, whether enrolled in school, and c) the national college-based survey
conducted in 1995. This report summarizes results from the national college-based
survey-the National College Health Risk Behavior Survey (NCHRBS)-and describes
priority health-risk behaviors among college students nationwide and health
promotion programs on college campuses. RESULTS AND INTERPRETATION: Data from the
1995 survey indicated that many college students throughout the United States
engage in behaviors that place them at risk for serious health problems. Almost
one third (29.0%) of college students were current cigarette smokers. One third
(34.5%) of college students reported episodic heavy drinking during the 30 days
preceding the survey, 27.4% reported drinking alcohol and driving during the 30
days preceding the survey, and 30.5% of students who had gone boating or swimming
during the 12 months preceding the survey had drunk alcohol while boating or
swimming. One in five (20.4%) female college students had been forced to have
sexual intercourse during her lifetime. Only 29.6% of students who had had sexual
intercourse during the 3 months preceding the survey had used a condom at last
sexual intercourse, and 34.5% had used birth control pills. Approximately one in
five (20.5%) college students was overweight. Survey results indicated that three
fourths (73.7%) of students had failed to eat five or more servings of fruits and
vegetables on the day preceding the survey, 21.8% had eaten three or more high
fat foods on the day preceding the survey, and few students had engaged in
vigorous (37.6%) or moderate (19.5%) physical activity at recommended levels.
ACTIONS TAKEN: The NCHRBS data will be used to measure progress toward achieving
28 national health objectives related to the health-risk behaviors of college
students and two national health objectives related to the availability and
characteristics of health promotion programs for college students. These data
also will be used nationwide by college health and education officials to improve
health policies and programs designed to reduce risks associated with the leading
causes of mortality and morbidity among college students.
PMID- 9393660
TI - Secondary ischemic tolerance improved by administration of L-NAME in rat flaps.
AB - Nitric oxide (NO) under basal conditions is an important regulator of vascular
tone. Under ischemic conditions, however, NO can combine with superoxide anion to
produce the damaging hydroxyl free radical. The current project observes the
effect of inhibiting NO production (L-Nitro-amino-methyl-arginine, L-NAME) on
flaps rendered ischemic by secondary (2 degrees) venous obstruction. Eighty rats
had 3 x 6 cm skin flaps based on the epigastric vessels. Primary (1 degree)
ischemia was produced by arteriovenous occlusion for 2 hours; (2 degrees) venous
ischemia was induced by clamping the vein, alone for either 3 or 5 hours. Thirty
minutes prior to 2 degrees ischemia, rats received either L-NAME (30 mg/kg) or
saline buffer. Flap survival was assessed 7 days later and Chi-square analysis
was used. At 3 hours of ischemia, treatment improved survival from 55% to 85% (P
< 0.05). Treatment also improved survival at 5 hours of ischemia from 5% to 35%
(P < 0.04). Although under resting conditions, NO is a potent vasodilator, during
2 degrees venous obstruction it may contribute to flap necrosis.
PMID- 9393661
TI - A new method of applying fibrin glue at the microvascular anastomotic site: the
"paintbrush" technique.
AB - Fibrin glue has been used by several researchers to seal microvascular
anastomoses sites. Usually the glue is delivered at the site with a syringe and
needle. However, this technique can result in excess deposition of glue, which
can cause intravascular thrombosis and can harden the vessel wall. We describe a
new technique that avoids both these problems. We designed a "paintbrush" by
inserting a suture through the syringe needle and then using the suture tip as a
brush to apply the fibrin glue. End-to-side anastomoses were performed between
the femoral artery and femoral vein in ten rats. Only two sutures were used to
perform the anastomosis, the rest of the anastomosis being completed by sealing
the gaps with fibrin glue. All the anastomoses were patent after 2 weeks, and no
thromboses occurred. This is a new method for applying fibrin glue that delivers
an adequate amount of fibrin glue without causing thrombosis.
PMID- 9393662
TI - Results of interfascicular nerve grafting for radial nerve lesions.
AB - During the 10 year interval 1979-1989, 20 patients underwent nerve grafting of a
radial nerve lesion, 13 high radial and 7 posterior interosseous. Average follow
up was 38 months (range 12 months-10 years). Overall 72% of patients achieved a
Highet Scale rating of M3 or better function and 44% M4 or better recovery. Age
of the patient and length of the nerve graft did not seem to influence outcome.
Time from initial injury to nerve grafting did affect outcome, with 85% of
patients grafted within 6 months obtaining M3 or better recovery. No patient
grafted 12 months after injury recovered any useful function. Lesions of the
posterior interosseous nerve had a consistently superior recovery. Power grip
strength in the affected hand of patients averaged 60% of the unaffected hand
while key pinch averaged 74%. There was good correlation between the Highet Scale
rating of recovery and the ultimate power grip or key pinch strength obtained.
Hand dexterity, as assessed by the turning and displacing tests of the Minnesota
Rate of Manipulation Test, displayed a wide range of scores in both affected and
unaffected hands. Nevertheless, a relative score derived from the results
obtained in the displacing test did show correlation with the Highet Scale
rating. All patients with M4 or better recovery obtained relative scores for the
affected hand that were in the middle of the range of scores considered an
average performance for a normal population. Patients who achieved M4 or better
nerve recovery following radial nerve grafting also obtained a functional hand as
evidenced by the results of grip, key pinch strength, and hand dexterity testing.
Lesser degrees of recovery were accompanied by poorer strength and dexterity
ratings reflecting inferior function.
PMID- 9393663
TI - Warm ischaemia time in a model for small bowel transplantation.
AB - Intestinal transplantation is associated with high rates of mortality and
morbidity. This paper details our initial experience with 82 heterotopic small
bowel transplants based upon the original rat model described by Monchik and
Russell (Surgery 70:693-702, 1971). A key issue associated with mortality was a
warm ischaemia time of more than 40 min (P < 0.01). Sixty-eight percent of the
recipients (44/65) survived for more than 24 hr when the warm ischaemia time of
the donor bowel was reduced to less than 40 min. Investigators establishing an
animal model of heterotopic small bowel transplantation should pay particular
attention to the warm ischaemia time of the donor bowel.
PMID- 9393664
TI - Assessment of nerve ultrastructure by fibre-optic confocal microscopy.
AB - Fibre-optic technology combined with confocality produces a microscope capable of
optical thin sectioning. In this original study, tibial nerves have been stained
in a rat model with a vital dye, 4-(4-diethylaminostyryl)-N-methylpyridinium
iodide, and analysed by fibre-optic confocal microscopy to produce detailed
images of nerve ultrastructure. Schwann cells, nodes of Ranvier and longitudinal
myelinated sheaths enclosing axons were clearly visible. Single axons appeared as
brightly staining longitudinal structures. This allowed easy tracing of multiple
signal axons within the nerve tissue. An accurate measurement of internodal
lengths was easily accomplished. This technique is comparable to current
histological techniques, but does not require biopsy, thin sectioning or tissue
fixing. This study offers a standard for further in vivo microscopy, including
the possibility of monitoring the progression of nerve regeneration following
microsurgical neurorraphy.
PMID- 9393665
TI - Latissimus dorsi free flap for sacral wound closure: the world's longest vein
grafts for free tissue transfer.
AB - In 1983, Salibian et al. reported the use of a two-stage latissimus dorsi free
tissue transfer to cover a sacral radiation ulcer using 28-centimeter
thoracodorsal interposition vein grafts. In 1985, Nahai and Hagerty reported a
similar case in which the procedure was performed in one stage with 25-centimeter
vein grafts. We present a case in which a large sacral osteoradionecrosis ulcer
is closed using this one-stage technique with 46-centimeter vein grafts, the
longest ever reported for free tissue transfer.
PMID- 9393666
TI - Ischemia increases the angiogenic potency of basic fibroblast growth factor (FGF
2).
AB - The aim of this study was to investigate the angiogenic response to exogenously
administered basic fibroblast growth factor (FGF-2) in normal and ischemic skin,
using the hairless mouse ear microcirculatory model. The hairless mouse ear is a
well-established model for in vivo studies of skin microcirculation. Using this
model, angiogenesis- and angiogenesis-associated changes in the microcirculation
can be directly and continuously viewed and quantified in a variety of different
experimental settings. To create ischemia in the mouse ear, all but one of the
three to four feeding vessels nourishing the ear were ligated 3 days prior to a
local subdermal injection of FGF-2 (9.3 + 1-0.5 mm/mm2) or saline into the dorsum
of the ears. Angiogenesis was quantified by direct observation, at high
magnification, of the injection site where increases in total vessel length (TVL)
were measured repeatedly over 18 days following injection. We found a significant
(P < 0.01) increase in TVL in normal and ischemic ears injected with FGF-2.
Saline injection also induced a significant increase in TVL in ischemic ears.
However, the angiogenic response to FGF-2 in ischemic ears was significantly
stronger than saline alone in ischemic ears or saline or FGF-2 in normal ears.
This response could be used clinically to accelerate angiogenesis and thus
increase perfusion in ischemic tissue.
PMID- 9393667
TI - Vascularized bone grafts for congenital pseudarthrosis of the tibia.
AB - Eight vascularized fibula grafts and two vascularized rib grafts were used for
the treatment of 10 Boyd's Type II congenital pseudarthrosis of the tibia. All
but one vascularized fibula graft united within 4 months. The two vascularized
rib grafts did not unite until receiving a conventional bone graft. Nine
spontaneous fractures were seen in four patients; all were subsequently treated
successfully with cast or conventional bone graft. Corrective osteotomies were
done in two patients. Follow-up averaged 8 years and 5 months (range, 5 years and
1 month to 14 years and 4 months). Average age at end of follow-up was 13 years
and 6 months (range, 7 years and 10 months to 20 years and 4 months). After bony
union was achieved, shortening of the affected leg averaged 3.8 centimeters,
flexion deformity averaged 20 degrees, and valgus deformity averaged 24 degrees.
In three patients, whose leg discrepancy averaged 4.9 centimeters, the leg was
lengthened at an average patient age of 13 years and 9 months (age range, 11
years and 7 months to 15 years and 2 months). The resulting limb length
discrepancy averaged 2.2 centimeters. Vascularized bone grafting is a reliable
technique for achieving bony union in congenital pseudarthrosis of the tibia.
Residual shortening may be corrected later by limb lengthening.
PMID- 9393668
TI - Application of a new sleeve anastomosis technique to graft rearterialization in
rat liver transplantation.
AB - A new rearterialized orthotopic liver transplant (OLT) model in the rat is
described. The model involved performing a novel sleeve anastomosis technique for
graft rearterialization which consisted of three extraluminal suture anastomoses
between the recipient's proper and the donor's common hepatic artery. The total
surgical time and in particular the time required to perform the arterial
anastomosis was significantly reduced with the utilization of this technique.
Hepatic artery patency was 100% and the 4-week survival rate was greater than
90%. Applying this novel sleeve anastomosis technique not only simplifies the
rearterialized rat OLT but also ensures that blood flow to all vascular beds is
undisturbed.
PMID- 9393669
TI - New strategies for chemokine inhibition and modulation: you take the high road
and I'll take the low road.
AB - Chemokines are low molecular weight cytokines that induce extravasation,
chemotaxis, and activation of a wide variety of leukocytes. Members of the
different chemokine families are defined by the orientation of specific critical
cysteine residues, and are designated as C-X-C (e.g. interleukin-8), C-C (e.g.
regulated upon activation normally T cell expressed and secreted, RANTES), or C
(lymphotactin). All chemokines bind to members of a G-protein coupled serpentine
receptor superfamily that span the leukocyte cell surface membrane seven times
and mediate the biological activities of the individual ligands. Most chemokines
possess two major binding surfaces: a high affinity site responsible for specific
ligand/receptor interactions and a lower affinity site, also called the heparin
binding or glycosaminoglycan-binding domain, believed to be responsible for the
establishment and presentation of chemokine gradients on the surface of
endothelial cells and within the extracellular matrix. Although chemokines are
clearly beneficial in wound healing, hemopoiesis, and the clearance of infectious
organisms, the continued expression of chemokines is associated with chronic
inflammation. Therefore, this class of cytokines are attractive targets for the
creation of antagonists that abrogate one or more chemokine functions. It is
envisioned that such antagonists could serve as a new class of anti-inflammatory
drugs. In this commentary, we will discuss two different but related strategies
for antagonizing chemokine-induced functions, namely, disruption of the low and
high affinity binding sites.
PMID- 9393670
TI - Inhibition of inducible nitric oxide synthase gene expression and enzyme activity
by epigallocatechin gallate, a natural product from green tea.
AB - Chronic inflammation has been implicated as the underlying factor in the
pathogenesis of many disorders. In the past decade, inflammation-related
endogenous production of reactive nitrogen species, similar to oxygen free
radicals, has also been suggested as a risk factor for cancer, in addition to the
well-studied exogenous nitroso compounds. Epidemiological, in vitro, and animal
model studies have implicated green tea to be protective against nitroso compound
induced and inflammation-related cancer. Therefore, we investigated the effect of
epigallocatechin-3-gallate (EGCG), one of the known biologically active catechins
contained in green tea, on the production of nitric oxide (NO.). We have shown
previously that EGCG reduces NO. production as measured by nitrite accumulation
in the culture medium. Expanding on this finding, in this report we show that
EGCG may do so by two mechanisms: reduction of inducible nitric oxide synthase
(iNOS) gene expression and inhibition of enzyme activity. Addition of 1-10 microM
EGCG to lipopolysaccharide- and interferon-gamma-activated mouse peritoneal cells
reduced iNOS mRNA expression concentration dependently, to 82-14%, as measured by
relative reverse transcription-polymerase chain reaction. Addition of 50-750
microM EGCG, in a concentration-dependent manner, inhibited the enzyme activity
of iNOS, to 85-14%, and neuronal nitric oxide synthase (nNOS), to 93-56%, as
measured by citrulline formation. EGCG competitively inhibited binding of
arginine and tetrahydrobiopterin, and the gallate structure is important for this
action.
PMID- 9393671
TI - Sustained increase in intracellular free calcium and activation of cyclooxygenase
2 expression in mouse hepatoma cells treated with dioxin.
AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a non-genotoxic environmental
pollutant that causes multiple adverse effects in experimental animals and in
humans. We show here that TCDD treatment of mouse hepatoma cells causes a rapid
mobilization of intracellular calcium both in wild type Hepa-1 cells and in its
c2 variant, a cell line that has highly reduced levels of functional aromatic
hydrocarbon (Ah) receptor (AHR). In wild type cells, but not in the c2 variant,
TCDD treatment leads to a sustained elevation of cytosolic free calcium. TCDD
also induces elevated levels of cyclooxygenase-2 (COX-2) mRNA in wild type and in
c37, a CYP1A1-deficient cell line, but not in c2 cells. Induction of Cox-2 is in
fact dependent on the presence of a functional Ah receptor, since it can be
blocked by antisense oligonucleotides to Ah receptor mRNA. Most likely as a
consequence of Cox-2 induction, we find a significant increase in the level of 12
hydroxyheptadecatrienoic acid (12-HHT) secreted from TCDD-treated Hepa-1 cells.
In addition, we observe elevated levels of 6-keto prostaglandin F1alpha in c2
cells and high levels of secreted prostaglandin F2alpha in c2, c37 and c4, the
variant cell line lacking aromatic hydrocarbon nuclear translocator protein.
These data suggest that Cox-2 activation by TCDD leads to the release of
prostaglandins, eicosanoids and other mediators which may have an important role
in the biological and toxic effects of TCDD.
PMID- 9393672
TI - Emergence of different mechanisms of resistance in the evolution of multidrug
resistance in murine erythroleukemia cell lines.
AB - We examined the genetic and biochemical bases for drug resistance and the order
of appearance of different mechanisms underlying the increasingly more resistant
murine erythroleukemia cell lines established in Adriamycin (ADR). In the first
step low-level resistant cell line PC4-A5 (able to grow in 5 ng/mL ADR), there
was a 2-fold reduction in topoisomerase IIalpha and topoisomerase IIbeta mRNA
levels, as well as topoisomerase IIalpha protein and activity levels as compared
with the parental cell line. The topoisomerase IIalpha activity levels remained
reduced as the cells became increasingly more resistant. In contrast, the
topoisomerase II mRNA and protein levels returned to approximately the parental
levels in resistant cells growing in higher drug concentrations (40-160 ng/mL).
Parental cells expressed the multidrug resistance protein (MRP), but beginning
with PC4-A5 MRP expression decreased and remained reduced in increasingly
resistant cell lines. At high levels of ADR resistance, the cells expressed the
mdr3 gene concomitant with the appearance of vincristine resistance and energy
dependent daunomycin and vincristine efflux. Glutathione levels, internal pH, and
expression of the major vault protein (MVP) remained unchanged in all cell lines.
Fluorescence microscopy revealed no alterations in daunomycin distribution or
vesicle numbers between the parental and resistant cell lines. Different
resistance mechanisms emerge sequentially as cells become more resistant to ADR;
the mechanisms are retained during the development of multidrug resistance (MDR).
In intermediate-level MDR cell lines (PC4-A10 and PC4-A20), resistance involves
an as yet undetermined mechanism(s).
PMID- 9393673
TI - Dinitrosyl-dithiol-iron complexes, nitric oxide (NO) carriers in vivo, as potent
inhibitors of human glutathione reductase and glutathione-S-transferase.
AB - Human glutathione reductase (GR) and rat liver glutathione-S-transferases (GSTs)
had been shown to be inhibited by the nitric oxide (NO) carrier S-nitroso
glutathione (GSNO). We have now extended these studies by measuring the effects
of dinitrosyl-iron complexed thiols (DNIC-[RSH]2) on human GR, GST and
glutathione peroxidase. DNIC-[RSH]2 represent important transport forms of NO but
also of iron ions and glutathione in vivo. Human GR was found to be inhibited by
dinitrosyl-iron-di-glutathione (DNIC-[GSH]2) and dinitrosyl-iron-di-L-cysteine
(DNIC-Cys2) in two ways: both compounds were competitive with glutathione
disulfide (GSSG), the inhibition constant (Ki) for reversible competition of DNIC
[GSH]2 with GSSG being approximately 5 microM; preincubating GR for 10 min with 4
microM DNIC-[GSH]2 and 40 microM DNIC-Cys2, respectively, led to 50% irreversible
enzyme inactivation. More than 95% GR inactivation was achieved by incubation
with 36 microM DNIC-[GSH]2 for 30 min. This inhibition depended on the presence
of NADPH. Absorption spectra of inhibited GR showed that the charge-transfer
interaction between the isoalloxazine moiety of the prosthetic group flavin
adenine dinucleotide (FAD) and the active site thiol Cys63 is disturbed by the
modification. Cys2 and FAD could be ruled out as sites of the modification.
Isolated human placenta glutathione-S-transferase and GST activity measured in
hemolysates were also inhibited by DNIC-[GSH]2. This inhibition, however, was
reversible and competitive with reduced glutathione, the Ki being 20 nM. The
inhibition of GST induced by GSNO was competitive with reduced glutathione (GSH)
(Ki = 180 microM) and with the second substrate of the reaction, 1-chloro-2,4,
dinitrobenzene (Ki = 170 microM). An inhibition of human glutathione peroxidase
by GSNO or DNIC-[RSH]2 was not detectable. Inactivation of GR by DNIC-[GSH]2 is
by two orders of magnitude more effective than modification by GSNO; this result
and the very efficient inhibition of GST point to a role of DNIC-[RSH]2 in
glutathione metabolism.
PMID- 9393674
TI - Synthesis and characterization of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene
(BODIPY)-labeled fluorescent ligands for the mu opioid receptor.
AB - A series of opioid ligands utilizing the 4,4-difluoro-4-bora-3a,4a-diaza-s
indacene (BODIPY) fluorophores 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s
indacene++ +-3-propionic acid or 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora
3a,4a-diaza- s-indacene-3-propionic acid were synthesized and characterized for
their ability to act as a suitable fluorescent label for the mu opioid receptor.
All compounds displaced the mu opioid receptor binding of [3H]Tyr-D-Ala-Gly
(Me)Phe-Gly-ol in monkey brain membranes with high affinity. The binding of
fluorescent ligands to delta and kappa receptors was highly variable. 5,7
Dimethyl-BODIPY naltrexamine, "6-BNX," displayed subnanomolar affinities for the
mu and kappa opioid receptors (Ki 0.07 and 0.43 nM, respectively) and nanomolar
affinity at the delta (Ki 1.4 nM) receptor. Using fluorescence spectroscopy, the
binding of 6-BNX in membranes from C6 glioma cells transfected with the cloned mu
opioid receptor was investigated. In these membranes containing a high receptor
density (10-80 pmol/mg protein), 6-BNX labeling was saturable, mu opioid
specific, stereoselective (as determined with the isomers dextrorphan and
levorphanol), and more than 90% specific. The results describe a series of newly
developed fluorescent ligands for the mu opioid receptor and the use of one of
these ligands as a label for the cloned mu receptor. These ligands provide a new
approach for studying the structural and biophysical nature of opioid receptors.
PMID- 9393675
TI - Pretranslational and posttranslational regulation of rat hepatic CYPs 3A2 and 2E1
by disulfiram.
AB - The aldehyde dehydrogenase inhibitor disulfiram (DS) has been used to deter
drinking in alcoholics, but it also precipitates pharmacokinetic interactions
with coadministered drugs. From previous experiments conducted in vitro, it has
been proposed that the ethanol-inducible cytochrome P450 2E1 (CYP2E1) is the
major target for inhibition by DS, but the inference from reported drug
interactions is that the drug inhibits multiple CYPs. The aim of the present
study was to evaluate the inhibition of major constitutive CYPs in rat liver by
DS. Thus, the effects of DS on activities mediated by CYPs 2A1/2, 2C11, 2E1, and
3A, which constitute approximately 80% of total CYPs in male rat liver, were
evaluated. It was found that CYP2E1-mediated aniline 4-hydroxylase activity was
weakly inhibited by DS in vitro, but that preincubation of the drug with NADPH
supplemented microsomes to generate metabolites of DS enhanced the extent of
inhibition somewhat. In contrast, constitutive testosterone hydroxylases were
inhibited effectively at low concentrations of DS (20 microM decreased the
activities of all hydroxylation pathways to 40-60% of control), and a
preincubation step between DS and NADPH-fortified microsomes enhanced the
inhibition of CYP2C11 and 3A2 activities. In vivo studies were undertaken in
which a single dose of DS (100 mg/kg, i.p.) was administered to rats; 24 hr
later, CYP2E1-mediated aniline 4-hydroxylase activity was decreased to about 50%
of the activity in untreated control rats. CYP2E1 apoprotein and mRNA were also
decreased to 38% of the respective control, and CYP3A apoprotein and CYP3A2 mRNA
responded similarly. In contrast, CYP2C11 apoprotein was decreased to 66% of
control after DS administration, and CYP2A1 expression was unchanged. These
findings establish that multiple CYPs are targets for inhibition by DS and
provide a basis for clinically significant drug interactions involving CYPs other
than 2E1. In addition, the in vivo modulation of CYP function by DS
administration is not restricted to enzyme inactivation and may also include down
regulatory effects mediated at a pretranslational level.
PMID- 9393676
TI - The hydrolysis of phosphatidyl-alcohols by phospholipases A2: effect of head
group size and polarity.
AB - The ability of a variety of secretory phospholipases A2 (sPLA2: EC 3.1.1.4) to
bind to and hydrolyse a series of phosphatidyl-alcohol substrates, in the absence
of detergent, was explored by both fluorescence-based kinetic and interfacial
binding assays. The enzymes used were sPLA2 from porcine pancreas, Naja naja
venom and a recombinant human non-pancreatic enzyme. Four dioleoyl phosphatidyl
alcohols were used with different headgroups, methanol, ethanol, propanol and
butanol. Comparative kinetic analyses with dioleoyl phosphatidyl-choline,
dioleoyl phosphatidyl-glycerol and wheat germ phosphatidyl-inositol are also
described. With the phosphatidyl-alcohol series, as the headgroup acyl-chain
length increased the susceptibility to hydrolysis decreased. This effect was much
more pronounced with the human non-pancreatic and the Naja naja venom enzymes
than with the pancreatic enzyme. Maximum activity in this assay system was
observed with porcine pancreatic sPLA2 and dioleoyl phosphatidyl-methanol (1440
+/- 167 micromol/min/mg). We demonstrate that the slow rate of hydrolysis of
dioleoyl phosphatidyl-propanol by the human non-pancreatic secretory enzyme (4.56
+/- 0.90 micromol/min/mg) is not due to a lack of interfacial binding. The
hydrolysis of mixtures of dioleoyl phosphatidyl-choline and dioleoyl phosphatidyl
propanol in various molar proportions by Naja naja sPLA2 suggests good mixing of
the two phospholipids with minimal phospholipid domain formation under these
assay conditions. We present strong evidence for a stimulation of hydrolysis of
phosphatidyl-choline by human non-pancreatic sPLA2 in the presence of as little
as 1 mol% phosphatidyl-methanol (<40 fold total rate enhancement). Overall, the
results demonstrate that the rates of hydrolysis of anionic phospholipids by
sPLA2 vary considerably with the different enzymes from this close structurally
related family. The tight binding of the human enzyme to poorly hydrolysable
anionic phospholipid vesicles provides a novel mechanism of enzyme inhibition by
interfacial sequestration.
PMID- 9393677
TI - Renal cellular transport, metabolism, and cytotoxicity of S-(6
purinyl)glutathione, a prodrug of 6-mercaptopurine, and analogues.
AB - The disposition of S-(6-purinyl)glutathione (6-PG) and its metabolites, including
the antitumor agent 6-mercaptopurine (6-MP), was characterized in freshly
isolated renal cortical cells from male F344 rats to assess the ability of the
kidney to convert 6-PG to 6-MP. The intracellular transport and accumulation of 6
PG and 6-MP, the metabolism of 6-PG to 6-MP, and the potential cytotoxicity of 6
MP, 6-thioxanthine (6-ThXan), and 6-thioguanine (6-ThGua) were determined. 6-PG
and 6-MP were accumulated by renal cortical cells by time- and concentration
dependent processes, reaching maximal levels of 14.2 and 1.52 nmol/10(6) cells,
respectively, with 1 mM concentrations of each compound. Treatment with acivicin,
an inhibitor of 6-PG metabolism by gamma-glutamyltransferase, increased
accumulation of 6-PG, and treatment with alpha-keto-gamma-methiolbutyrate, a keto
acid cosubstrate that stimulates activity of the cysteine conjugate beta-lyase
(beta-lyase), which generates 6-MP, decreased accumulation of 6-PG. Incubation of
renal cells with 10 mM 6-PG generated 6-MP at a rate of 2.4 nmol/min per 10(6)
cells, demonstrating that the beta-lyase pathway forms the desired product from
the prodrug within the intact renal cell. Preincubation of cells with acivicin or
aminooxyacetic acid, an inhibitor of the beta-lyase, decreased the net formation
of 6-MP, demonstrating further the function of the beta-lyase. 6-MP, 6-ThXan, and
6-ThGua exhibited approximately equivalent cytotoxicity (45-55% release of
lactate dehydrogenase with 1 mM at 2 hr) in isolated renal cells. Based on the
known antitumor potency of these agents, this suggests that cytotoxicity and
antitumor activity occur by distinct mechanisms. The high amount of accumulation
of 6-PG and its subsequent metabolism to 6-MP, as compared with the relatively
low amount of accumulation of 6-MP, in renal cells suggest that 6-PG can function
as a prodrug and is a more effective delivery vehicle for 6-MP to renal cells
than 6-MP itself. Administration of 6-PG may be an effective means of treating
renal tumors or suppressing renal transplant rejection.
PMID- 9393678
TI - Receptor-stimulated phospholipase C activity in human umbilical artery cultured
endothelial cells grown in a low oxygen environment.
AB - Endothelial cells of the human umbilical blood vessels are widely cultured in an
oxygen tension (21%) far above that in which they exist in vivo (3%). This study
investigates the effect of the long term culture (ca. 1 month) of human umbilical
artery endothelial cells in a reduced oxygen environment (3%: HUAEC3) in
comparison to cells grown in a 'normoxic' environment (21%: HUAEC21). Despite
reports of altered metabolic pathways and reduced membrane integrity in other
cell types, the characteristics of HUAEC3 were found to be similar to those of
HUAEC21 with respect to morphology, immunocytochemical profile and in vitro
growth rates. Cellular glutathione was maintained in these cells although ATP
levels in HUAEC3 were found to be significantly lower than those observed in
HUAEC21. The phosphoinositide responses of the HUAEC3 to a variety of agonists
were also found to be of similar magnitude to those observed in HUAEC21. In
addition, the pharmacological characteristics of the phospholipase C-linked
histamine H1 and P2y2 (P2U) receptors were not changed by culture of cells in a
low oxygen environment.
PMID- 9393679
TI - Monoamine oxidase inhibitory properties of some methoxylated and alkylthio
amphetamine derivatives: structure-activity relationships.
AB - The monoamine oxidase (MAO) inhibitory properties of a series of amphetamine
derivatives with different substituents at or around the para position of the
aromatic ring were evaluated. In in vitro studies in which a crude rat brain
mitochondrial suspension was used as the source of MAO, several compounds showed
a strong (IC50 in the submicromolar range), selective, reversible, time
independent, and concentration-related inhibition of MAO-A. After i.p. injection,
the compounds induced an increase of serotonin and a decrease of 5
hydroxyindoleacetic acid in the raphe nuclei and hippocampus, confirming the in
vitro results. The analysis of structure-activity relationships indicates that:
molecules with amphetamine-like structure and different substitutions on the
aromatic ring are potentially MAO-A inhibitors; substituents at different
positions of the aromatic ring modify the potency but have little influence on
the selectivity; substituents at the para position such as amino, alkoxyl,
halogens, or alkylthio produce a significant increase in the activity; the para
substituent must be an electron donor; bulky groups next to the para substituent
lead to a decrease in the activity; substituents located at positions more
distant on the aromatic ring have less influence and, even when the substituent
is a halogen (Cl, Br), an increase in the activity of the compound is obtained.
Finally, the MAO-A inhibitory properties of some of the compounds evaluated are
discussed in relation to: (a) potential antidepressant activity, and (b) their
reported hallucinogenic, neurotoxic, or anxiolytic effects.
PMID- 9393680
TI - High sensitivity of leukemic peripheral blood lymphocytes to triethyllead action.
AB - In a previous study we reported that triethyllead (Et3Pb+) inhibits cell
proliferation of normal human lymphocytes. To further characterize this
interaction, we studied herein the effects of Et3Pb+ on the cell viability of
normal and leukemic human lymphocytes and analysed the expression and dynamics of
the monomer/polymer equilibrium of tubulin in these cells. Short- and long-term
cell culture experiments demonstrated significantly different dose-dependent
effects of Et3Pb+ on cell viability of leukemic compared to normal lymphocytes.
Indeed, in the presence of increasing concentrations of Et3Pb+ (10(-12)-10(-5)
M), primary cultures of chronic lymphocytes (CLL) and acute lymphoblastic (ALL)
leukemic human Lymphocytes were much more sensitive to Et3Pb+ treatment when
compared to normal peripheral blood lymphocytes (PBL). The IC50 values were
approximately 5 x 10(-6) M for PBL and 8 x 10(-10) M for both CLL and ALL
respectively, when cells were preincubated for 3 h with this agent. These
experiments revealed a 1000-fold higher responsiveness of leukemic cells to
Et3Pb+ treatment. Quantitative immunoblot analysis showed that leukemic cells
express up to 4-fold higher total tubulin amounts. However, the proportion of
polymerized tubulin in leukemic compared to normal lymphocytes increased only
slightly (up to 1.4-fold). These findings reveal a significant decrease in the
polymeric to total tubulin ratio in leukemic lymphocytes, indicating important
modifications in tubulin dynamics and reorganization of the microtubular
structures. Our results demonstrate that leukemic cells are much more sensitive
than normal lymphocytes to Et3Pb+ action. This effect may be due to the altered
monomer/polymer dynamic equilibrium of tubulin shown in leukemic cells. It is,
therefore, worthwhile exploring future applied uses of Et3Pb+ as a potential
suppressor of leukemic cell growth.
PMID- 9393681
TI - Transcriptional and translational control of the genes for the mating pair
formation apparatus of promiscuous IncP plasmids.
AB - The trb operon of broad-host-range plasmid RK2 encodes most of the genes required
for formation of mating-pair apparatus and is thus essential for the promiscuous
spread of this plasmid. Only two promoters, lying upstream of trbA and trbB, have
been identified for this operon. trbB encodes a protein belonging to a large
family of proteins which function in the assembly of apparatuses associated with
the cell surface. trbA encodes a repressor protein, one of whose targets is the
trbB promoter. trbAp is arranged as a face-to-face divergent promoter with trfAp,
the strongest of the three promoters in this region. trfAp completely inhibits
trbAp unless it is repressed by the KorA protein, a key regulator encoded in the
plasmid's central control operon. We show that when trfAp is firing
constitutively, it also appears to interfere with trbBp, but that trbBp activity
increases when trfAp activity is decreased by repression or mutation. A second
global regulator encoded in the central control operon, KorB, represses trbBp,
trfAp, and trbAp. The results presented here show that both KorB and TrbA are
necessary for full repression of trbBp. The region between trbA and trbB encodes
a large inverted repeat which has been proposed to modulate translation of trbB
on transcripts which are initiated at trbAp but not trbBp. Using translational
fusions to lacZ, we show that translation of trbB is completely blocked when
transcripts incorporate the inverted repeat upstream of trbB but proceeds with
reasonable efficiency when deletions remove the sequences predicted to sequester
the ribosome binding site. Results from both transcriptional fusion and direct
measurement of transcript size and intensity by Northern blot analysis show that
most trbA transcripts are monocistronic and serve to express only trbA, although
some transcription continues into trbB. The monocistronic trbA transcript appears
to be the result of transcription termination downstream of trbA. Thus, trbAp and
trbA appear to form an operon distinct from the trbB-trbP operon. Consequently,
trbA and the switch that controls its expression help to provide the sequential
steps which allow efficient expression of transfer genes during plasmid
establishment but tight repression once the plasmid is established.
PMID- 9393682
TI - The Candida albicans CDR3 gene codes for an opaque-phase ABC transporter.
AB - We report the cloning and functional analysis of a third member of the CDR gene
family in Candida albicans, named CDR3. This gene codes for an ABC (ATP-binding
cassette) transporter of 1,501 amino acids highly homologous to Cdr1p and Cdr2p
(56 and 55% amino acid sequence identity, respectively), two transporters
involved in fluconazole resistance in C. albicans. The predicted structure of
Cdr3p is typical of the PDR/CDR family, with two similar halves, each comprising
an N-terminal hydrophilic domain with consensus sequences for ATP binding and a C
terminal hydrophobic domain with six predicted transmembrane segments. Northern
analysis showed that CDR3 expression is regulated in a cell-type-specific manner,
with low levels of CDR3 mRNA in CAI4 yeast and hyphal cells, high levels in WO-1
opaque cells, and undetectable levels in WO-1 white cells. Disruption of both
alleles of CDR3 in CAI4 resulted in no obvious changes in cell morphology, growth
rate, or susceptibility to fluconazole. Overexpression of Cdr3p in C. albicans
did not result in increased cellular resistance to fluconazole, cycloheximide,
and 4-nitroquinoline-N-oxide, which are known substrates for different
transporters of the PDR/CDR family. These results indicate that despite a high
degree of sequence conservation with C. albicans Cdr1p and Cdr2p, Cdr3p does not
appear to be involved in drug resistance, at least to the compounds tested which
include the clinically relevant antifungal agent fluconazole. Rather, the high
level of Cdr3p expression in WO-1 opaque cells suggests an opaque-phase
associated biological function which remains to be identified.
PMID- 9393683
TI - Synergistic roles of HslVU and other ATP-dependent proteases in controlling in
vivo turnover of sigma32 and abnormal proteins in Escherichia coli.
AB - Production of abnormal proteins during steady-state growth induces the heat shock
response by stabilizing normally unstable sigma32 (encoded by the rpoH gene)
specifically required for transcription of heat shock genes. We report here that
a multicopy plasmid carrying the hslVU operon encoding a novel ATP-dependent
protease inhibits the heat shock response induced by production of human
prourokinase (proUK) in Escherichia coli. The overproduction of HslVU (ClpQY)
protease markedly reduced the stability and accumulation of proUK and thus
reduced the induction of heat shock proteins. In agreement with this finding,
deletion of the chromosomal hslVU genes significantly enhanced levels of proUK
and sigma32 without appreciably affecting cell growth. When the deltahslVU
deletion was combined with another protease mutation (lon, clpP, or ftsH/hflB),
the resulting multiple mutations caused higher stabilization of proUK and
sigma32, enhanced synthesis of heat shock proteins, and temperature-sensitive
growth. Furthermore, overproduction of HslVU protease reduced sigma32 levels in
strains that were otherwise expected to produce enhanced levels of sigma32 due
either to the absence of Lon-ClpXP proteases or to the limiting levels of FtsH
protease. Thus, a set of ATP-dependent proteases appear to play synergistic roles
in the negative control of the heat shock response by modulating in vivo turnover
of sigma32 as well as through degradation of abnormal proteins.
PMID- 9393684
TI - Characterization of the Rhizobium (Sinorhizobium) meliloti high- and low-affinity
phosphate uptake systems.
AB - Genetic studies have suggested that Rhizobium (Sinorhizobium) meliloti contains
two distinct phosphate (Pi) transport systems, encoded by the phoCDET genes and
the orfA-pit genes, respectively. Here we present data which show that the ABC
type PhoCDET system has a high affinity for Pi (Km, 0.2 microM) and that Pi
uptake by this system is severely inhibited by phosphonates. This high-affinity
uptake system was induced under Pi-limiting conditions and was repressed in the
presence of excess Pi. Uptake via the OrfA-Pit system was examined in (i) a phoC
mutant which showed increased expression of the orfA-pit genes as a result of a
promoter-up mutation and (ii) a phoB mutant (PhoB is required for phoCDET
expression). Pi uptake in both strains exhibited saturation kinetics (Km, 1 to 2
microM) and was not inhibited by phosphonates. This uptake system was active in
wild-type cells grown with excess Pi and appeared to be repressed when the cells
were starved for Pi. Thus, our biochemical data show that the OrfA-Pit and
PhoCDET uptake systems are differentially expressed depending on the state of the
cell with respect to phosphate availability.
PMID- 9393686
TI - Glycolytic flux is conditionally correlated with ATP concentration in
Saccharomyces cerevisiae: a chemostat study under carbon- or nitrogen-limiting
conditions.
AB - Anaerobic and aerobic chemostat cultures of Saccharomyces cerevisiae were
performed at a constant dilution rate of 0.10 h(-1). The glucose concentration
was kept constant, whereas the nitrogen concentration was gradually decreasing;
i.e., the conditions were changed from glucose and energy limitation to nitrogen
limitation and energy excess. This experimental setup enabled the glycolytic rate
to be separated from the growth rate. There was an extensive uncoupling between
anabolic energy requirements and catabolic energy production when the energy
source was present in excess both aerobically and anaerobically. To increase the
catabolic activity even further, experiments were carried out in the presence of
5 mM acetic acid or benzoic acid. However, there was almost no effect with
acetate addition, whereas both respiratory (aerobically) and fermentative
activities were elevated in the presence of benzoic acid. There was a strong
negative correlation between glycolytic flux and intracellular ATP content; i.e.,
the higher the ATP content, the lower the rate of glycolysis. No correlation
could be found with the other nucleotides tested (ADP, GTP, and UTP) or with the
ATP/ADP ratio. Furthermore, a higher rate of glycolysis was not accompanied by an
increasing level of glycolytic enzymes. On the contrary, the glycolytic enzymes
decreased with increasing flux. The most pronounced reduction was obtained for
HXK2 and ENO1. There was also a correlation between the extent of carbohydrate
accumulation and glycolytic flux. A high accumulation was obtained at low
glycolytic rates under glucose limitation, whereas nitrogen limitation during
conditions of excess carbon and energy resulted in more or less complete
depletion of intracellular storage carbohydrates irrespective of anaerobic or
aerobic conditions. However, there was one difference in that glycogen dominated
anaerobically whereas under aerobic conditions, trehalose was the major
carbohydrate accumulated. Possible mechanisms which may explain the strong
correlation between glycolytic flux, storage carbohydrate accumulation, and ATP
concentrations are discussed.
PMID- 9393685
TI - Host cell phospholipids are trafficked to and then modified by Chlamydia
trachomatis.
AB - There is little information on the trafficking of eukaryotic lipids from a host
cell to either the cytoplasmic membrane of or the vacuolar membrane surrounding
intracellular pathogens. Purified Chlamydia trachomatis, an obligate
intracellular bacterial parasite, contains several eukaryotic
glycerophospholipids, yet attempts to demonstrate transfer of these lipids to the
chlamydial cell membrane have not been successful. In this report, we demonstrate
that eukaryotic glycerophospholipids are trafficked from the host cell to C.
trachomatis. Phospholipid trafficking was assessed by monitoring the
incorporation of radiolabelled isoleucine, a precursor of C. trachomatis specific
branched-chain fatty acids, into host-derived glycerophospholipids and by
monitoring the transfer of host phosphatidylserine to chlamydiae and its
subsequent decarboxylation to form phosphatidylethanolamine. Phospholipid
trafficking to chlamydiae was unaffected by brefeldin A, an inhibitor of Golgi
function. Furthermore, no changes in trafficking were observed when C.
trachomatis was grown in a mutant cell line with a nonfunctional, nonspecific
phospholipid transfer protein. Host glycerophospholipids are modified by C.
trachomatis, such that a host-synthesized straight-chain fatty acid is replaced
with a chlamydia-synthesized branched-chain fatty acid. We also demonstrate that
despite the acquisition of host-derived phospholipids, C. trachomatis is capable
of de novo synthesis of phospholipids typically synthesized by prokaryotic cells.
Our results provide novel information on chlamydial phospholipid metabolism and
eukaryotic cell lipid trafficking, and they increase our understanding of the
evolutionary steps leading to the establishment of an intimate metabolic
association between an obligate intracellular bacterial parasite and a eukaryotic
host cell.
PMID- 9393687
TI - Expression of a stress- and starvation-induced dps/pexB-homologous gene is
controlled by the alternative sigma factor sigmaB in Bacillus subtilis.
AB - SigmaB-dependent general stress proteins (Gsps) of Bacillus subtilis are
essential for the development of glucose-starvation-induced cross-resistance to
oxidative challenge. However, the proteins directly involved in this nonspecific
resistance to oxidative stress have to be identified. We found that one prominent
Gsp displayed strong sequence similarity to the previously characterized
oxidative-stress-inducible MrgA protein of B. subtilis and to the starvation
induced Dps/PexB protein of Escherichia coli. We therefore designated this
prominent Gsp Dps. While MrgA belongs to the peroxide-stress-inducible proteins
needed for the H2O2-inducible adaptive response to oxidative stress, Dps belongs
to the proteins induced by heat, salt, or ethanol stress and after starvation for
glucose but not by a sublethal oxidative challenge. Primer extension experiments
identified two overlapping promoters upstream of the coding region of dps, one
being sigmaB dependent (PB) and the other being sigmaB independent (P1). Both
promoters contribute to the basal level of dps during growth. After stress or
during entry into the stationary phase, transcription from PB strongly increased
whereas transcription from P1 decreased. Mutant strains lacking Dps completely
failed to develop glucose-starvation-induced resistance to oxidative stress.
These results confirm our suggestion that sigmaB-dependent general stress
proteins of B. subtilis are absolutely required for the development of
nonspecific resistance to oxidative stress.
PMID- 9393688
TI - A gene (plsD) from Clostridium butyricum that functionally substitutes for the sn
glycerol-3-phosphate acyltransferase gene (plsB) of Escherichia coli.
AB - The sn-glycerol-3-phosphate acyltransferase (plsB) of Escherichia coli is a key
regulatory enzyme that catalyzes the first committed step in phospholipid
biosynthesis. We report the initial characterization of a novel gene (termed
plsD) from Clostridium butyricum, cloned based on its ability to complement the
sn-glycerol-3-phosphate auxotrophic phenotype of a plsB mutant strain of E. coli.
Unlike the 83-kDa PlsB acyltransferase from E. coli, the predicted plsD open
reading frame encoded a protein of 26.5 kDa. Two regions of strong homology to
other lipid acyltransferases, including PlsB and PlsC analogs from mammals,
plants, yeast, and bacteria, were identified. PlsD was most closely related to
the 1-acyl-sn-glycerol-3-phosphate acyltransferase (plsC) gene family but did not
complement the growth of plsC(Ts) mutants. An in vivo metabolic labeling
experiment using a plsB plsX plsC(Ts) strain of E. coli confirmed that the plsD
expression restored the ability of the cells to synthesize 1-acyl-glycerol-3
phosphate. However, glycerol-3-phosphate acyltransferase activity was not
detected in vitro in assays using either acyl-acyl carrier protein or acyl
coenzyme A as the substrate.
PMID- 9393689
TI - Analysis of the fnrL gene and its function in Rhodobacter capsulatus.
AB - The fnr gene encodes a regulatory protein involved in the response to oxygen in a
variety of bacterial genera. For example, it was previously shown that the
anoxygenic, photosynthetic bacterium Rhodobacter sphaeroides requires the fnrL
gene for growth under anaerobic, photosynthetic conditions. Additionally, the
FnrL protein in R. sphaeroides is required for anaerobic growth in the dark with
an alternative electron acceptor, but it is not essential for aerobic growth. In
this study, the fnrL locus from Rhodobacter capsulatus was cloned and sequenced.
Surprisingly, an R. capsulatus strain with the fnrL gene deleted grows like the
wild type under either photosynthetic or aerobic conditions but does not grow
anaerobically with alternative electron acceptors such as dimethyl sulfoxide
(DMSO) or trimethylamine oxide. It is demonstrated that the c-type cytochrome
induced upon anaerobic growth on DMSO is not synthesized in the R. capsulatus
fnrL mutant. In contrast to wild-type strains, R. sphaeroides and R. capsulatus
fnrL mutants do not synthesize the anaerobically, DMSO-induced reductase.
Mechanisms that explain the basis for FnrL function in both organisms are
discussed.
PMID- 9393690
TI - The TolB protein interacts with the porins of Escherichia coli.
AB - TolB is a periplasmic protein of the cell envelope Tol complex. It is partially
membrane associated through an interaction with the outer membrane lipoprotein
PAL (peptidoglycan-associated lipoprotein), which also belongs to the Tol system.
The interaction of TolB with outer membrane porins of Escherichia coli was
investigated with a purified TolB derivative harboring a six-histidine tag. TolB
interacted with the trimeric porins OmpF, OmpC, PhoE, and LamB but not with their
denatured monomeric forms or OmpA. These interactions took place both in the
presence and in the absence of lipopolysaccharide. TolA, an inner membrane
component of the Tol system, also interacts with the trimeric porins via its
central periplasmic domain (R. Derouiche, M. Gavioli, H. Benedetti, A. Prilipov,
C. Lazdunski, and R. Lloubes, EMBO J. 15:6408-6415, 1996). In the presence of the
purified central domain of TolA (TolAIIHis), the TolB-porin complexes disappeared
to form TolAIIHis-porin complexes. These results suggest that the interactions of
TolA and TolB with porins might take place in vivo and might be concomitant
events participating in porin assembly. They also suggest that the Tol system as
a whole may be involved in porin assembly in the outer membrane.
PMID- 9393691
TI - Cloning and characterization of the aru genes encoding enzymes of the catabolic
arginine succinyltransferase pathway in Pseudomonas aeruginosa.
AB - The arginine succinyltransferase (AST) pathway is the major arginine and
ornithine utilization (aru) pathway under aerobic conditions in Pseudomonas
aeruginosa. A 26-kb DNA fragment of the P. aeruginosa PAO1 chromosome carrying
the regulatory argR gene and the aru structural gene cluster was cloned.
Complementation tests and nucleotide sequence data established the locations of
the argR, aruC, aruF, aruG, aruD, aruB, and aruE genes, in that order. The aruR,
aruC, aruD, aruB, and aruE genes specify the ArgR regulatory protein, N2
succinylornithine 5-aminotransferase, N-succinylglutamate 5-semialdehyde
dehydrogenase, N2-succinylarginine dihydrolase, and N-succinylglutamate
desuccinylase, respectively, and the aruF and aruG genes encode the subunits
(AruAI and AruAII) of arginine and ornithine N2-succinyltransferases.
Furthermore, in vivo analysis of transcriptional aru fusions and of polar
insertion mutations located at different sites in the aru cluster indicated the
presence of three transcriptional units which are controlled by ArgR. The
aruCFGDB genes appear to form an operon transcribed from a promoter upstream of
aruC, whereas aruE has its own promoter. The argR gene, which is located upstream
of the aruCFGDB operon, is a member of another (aot) operon coding for arginine
transport genes. The deduced amino acid sequences of the AST enzymes were
compared to those of homologous proteins of Escherichia coli specified by the ast
genes lying in the chromosome region from 39.2 to 39.5 min (Kohara clone 327;
GenBank/EMBL/DDJB accession no. D90818). The overall organization of the aru and
ast genes in both organisms is similar, with the exception that E. coli appears
to have a single AST gene.
PMID- 9393692
TI - Mutational analysis of the R64 oriT region: requirement for precise location of
the NikA-binding sequence.
AB - Conjugative DNA transfer of IncI1 plasmid R64 is initiated by the introduction of
a site- and strand-specific nick into the origin of transfer (oriT). In R64 oriT,
17-bp (repeat A and B) and 8-bp inverted-repeat sequences with mismatches are
located 8 bp away from the nick site. The nicking is mediated by R64 NikA and
NikB proteins. To analyze the functional organization of the R64 oriT region,
various deletion, insertion, and substitution mutations were introduced into a 92
bp minimal R64 oriT sequence and their effects on oriT function were
investigated. This detailed analysis confirms our previous prediction that the
R64 oriT region consists of an oriT core sequence and additional sequences
necessary for full oriT activity. The oriT core sequence consists of the repeat A
sequence, which is recognized by R64 NikA protein, and the nick region sequence,
which is conserved among various origins of transfer and is most probably
recognized by NikB protein. The oriT core sequence is sufficient for NikAB
mediated oriT-specific nicking. Furthermore, it was shown that the repeat A
sequence is essential for localization to a precise position relative to the nick
site for oriT function. This seems to be required for the formation of a
functional ternary complex consisting of NikA and NikB proteins and oriT DNA. The
repeat B sequence and 8-bp inverted repeat sequences are suggested to be required
for the termination of DNA transfer.
PMID- 9393693
TI - Transcriptional regulation of type 4 pilin genes and the site-specific
recombinase gene, piv, in Moraxella lacunata and Moraxella bovis.
AB - Moraxella lacunata and Moraxella bovis use type 4 pili to adhere to epithelial
tissues of the cornea and conjunctiva. Primer extension analyses were used to map
the transcriptional start sites for the genes encoding the major pilin subunits
(tfpQ/I) and the DNA invertase (piv), which determines pilin type expression.
tfpQ/I transcription starts at a sigma54-dependent promoter (tfpQ/Ip2) and, under
certain growth conditions, this transcription is accompanied by weaker upstream
transcription that starts at a potential sigma70-dependent promoter (tfpQ/Ip1).
piv is expressed in both M. lacunata and M. bovis from a putative sigma70
dependent promoter (pivp) under all conditions assayed. Sigma54-dependent
promoters require activators in order to initiate transcription; therefore, it is
likely that tfpQ/Ip2 is also regulated by an activator in Moraxella. Primer
extension assays with RNA isolated from Escherichia coli containing the subcloned
pilin inversion region from M. lacunata showed that pivp is used for the
expression of piv; however, tfpQ/Ip2 is not used for the transcription of tfpQ/I.
Transcription from tfpQ/Ip2 was activated in E. coli when the sensor (PilS) and
response regulator (PilR) proteins of type 4 pilin transcription in Pseudomonas
aeruginosa were expressed from a plasmid. These results suggest that the
expression of the type 4 pilin in M. lacunata and M. bovis is regulated not only
by a site-specific DNA inversion system but also by a regulatory system which is
functionally analogous to the PilS-PilR two-component system of P. aeruginosa.
PMID- 9393694
TI - Cloning, sequencing, and expression of the gene encoding Clostridium
paraputrificum chitinase ChiB and analysis of the functions of novel cadherin
like domains and a chitin-binding domain.
AB - The Clostridium paraputrificum chiB gene, encoding chitinase B (ChiB), consists
of an open reading frame of 2,493 nucleotides and encodes 831 amino acids with a
deduced molecular weight of 90,020. The deduced ChiB is a modular enzyme composed
of a family 18 catalytic domain responsible for chitinase activity, two
reiterated domains of unknown function, and a chitin-binding domain (CBD). The
reiterated domains are similar to the repeating units of cadherin proteins but
not to fibronectin type III domains, and therefore they are referred to as
cadherin-like domains. ChiB was purified from the periplasm fraction of
Escherichia coli harboring the chiB gene. The molecular weight of the purified
ChiB (87,000) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS
PAGE) analysis, was in good agreement with the value (86,578) calculated from the
deduced amino acid sequence excluding the signal peptide. ChiB was active toward
chitin from crab shells, colloidal chitin, glycol chitin, and 4
methylumbelliferyl beta-D-N,N'-diacetylchitobioside [4-MU-(GlcNAc)2]. The pH and
temperature optima of the enzyme were 6.0 and 45 degrees C, respectively. The Km
and Vmax values for 4-MU-(GlcNAc)2 were estimated to be 6.3 microM and 46
micromol/min/mg, respectively. SDS-PAGE, zymogram, and Western blot analyses
using antiserum raised against purified ChiB suggested that ChiB was one of the
major chitinase species in the culture supernatant of C. paraputrificum. Deletion
analysis showed clearly that the CBD of ChiB plays an important role in
hydrolysis of native chitin but not processed chitin such as colloidal chitin.
PMID- 9393695
TI - In vitro Tn7 mutagenesis of Haemophilus influenzae Rd and characterization of the
role of atpA in transformation.
AB - Haemophilus influenzae Rd is a gram-negative bacterium capable of natural DNA
transformation. The competent state occurs naturally in late exponential growth
or can be induced by a nutritional downshift or by transient anaerobiosis. The
genes cya, crp, topA, and sxy (tfoX) are known to function in the regulation of
competence development. The phosphoenolpyruvate:carbohydrate phosphotransferase
system functions to maintain levels of cyclic AMP necessary for competence
development but is not directly involved in regulation. The exact signal(s) for
competence and the genes that mediate the signal(s) are still unknown. In an
effort to find additional regulatory genes, H. influenzae Rd was mutated by using
an in vitro Tn7 system and screened for mutants with a reduced ability to induce
the competence-regulatory gene, comA. Insertions in atpA, a gene coding for the
alpha subunit of the F1 cytoplasmic domain of the ATP synthase, reduce
transformation frequencies about 20-fold and cause a significant reduction in
expression of competence-regulatory genes, while the expression of constitutive
competence genes is only minimally affected. In addition, we found that an
insertion in atpB, which encodes the a subunit of the F0 membrane-spanning
domain, has a similar effect on transformation frequencies.
PMID- 9393696
TI - Pectate lyase PelI of Erwinia chrysanthemi 3937 belongs to a new family.
AB - Erwinia chrysanthemi 3937 secretes five major isoenzymes of pectate lyases
encoded by the pel4, pelB, pelC, pelD, and pelE genes and a set of secondary
pectate lyases, two of which, pelL and pelZ, have been already identified. We
cloned the pelI gene, encoding a ninth pectate lyase of E. chrysanthemi 3937. The
pelI reading frame is 1,035 bases long, corresponding to a protein of 344 amino
acids including a typical amino-terminal signal sequence of 19 amino acids. The
purified mature PelI protein has an isoelectric point of about 9 and an apparent
molecular mass of 34 kDa. PelI has a preference for partially methyl esterified
pectin and presents an endo-cleaving activity with an alkaline pH optimum and an
absolute requirement for Ca2+ ions. PelI is an extracellular protein secreted by
the Out secretory pathway of E. chrysanthemi. The PelI protein is very active in
the maceration of plant tissues. A pelI mutant displayed reduced pathogenicity on
chicory leaves, but its virulence did not appear to be affected on potato tubers
or Saintpaulia ionantha plants. The pelI gene constitutes an independent
transcriptional unit. As shown for the other pel genes, the transcription of pelI
is dependent on various environmental conditions. It is induced by pectic
catabolic products and affected by growth phase, oxygen limitation, temperature,
nitrogen starvation, and catabolite repression. Regulation of pelI expression
appeared to be dependent on the three repressors of pectinase synthesis, KdgR,
PecS, and PecT, and on the global activator of sugar catabolism, cyclic AMP
receptor protein. A functional KdgR binding site was identified close to the
putative pelI promoter. Analysis of the amino acid sequence of PelI revealed high
homology with a pectate lyase from Erwinia carotovora subsp. carotovora (65%
identity) and low homology with pectate lyases of the phytopathogenic fungus
Nectria haematococca (Fusarium solani). This finding indicates that PelI belongs
to pectate lyase class III. Using immunoblotting experiments, we detected PelI
homologs in various strains of E. chrysanthemi and E. carotovora subsp.
carotovora but not in E. carotovora subsp. atroseptica.
PMID- 9393697
TI - The cold shock response of the psychrotrophic bacterium Pseudomonas fragi
involves four low-molecular-mass nucleic acid-binding proteins.
AB - The psychrotrophic bacterium Pseudomonas fragi was subjected to cold shocks from
30 or 20 to 5 degrees C. The downshifts were followed by a lag phase before
growth resumed at a characteristic 5 degrees C growth rate. The analysis of
protein patterns by two-dimentional gel electrophoresis revealed overexpression
of 25 or 17 proteins and underexpression of 12 proteins following the 30- or 20
to-5 degrees C shift, respectively. The two downshifts shared similar variations
of synthesis of 20 proteins. The kinetic analysis distinguished the induced
proteins into cold shock proteins (Csps), which were rapidly but transiently
overexpressed, and cold acclimation proteins (Caps), which were more or less
rapidly induced but still overexpressed several hours after the downshifts. Among
the cold-induced proteins, four low-molecular-mass proteins, two of them
previously characterized as Caps (CapA and CapB), and heat acclimation proteins
(Haps) as well as heat shock proteins (Hsps) for the two others (TapA and TapB)
displayed higher levels of induction. Partial amino acid sequences, obtained by
microsequencing, were used to design primers to amplify by PCR the four genes and
then determine their nucleotide sequences. A BamHI-EcoRI restriction fragment of
1.9 kb, containing the complete coding sequence for capB, was cloned and
sequenced. The four peptides belong to the family of small nucleic acid-binding
proteins as CspA, the major Escherichia coli Csp. They are likely to play a major
role in the adaptative response of P. fragi to environmental temperature changes.
PMID- 9393698
TI - A cysG mutant strain of Rhizobium etli pleiotropically defective in sulfate and
nitrate assimilation.
AB - By its inability to grow on sulfate as the sole sulfur source, a mutant strain
(CTNUX8) of Rhizobium etli carrying Tn5 was isolated and characterized. Sequence
analysis showed that Tn5 is inserted into a cysG (siroheme synthetase)-homologous
gene. By RNase protection assays, it was established that the cysG-like gene had
a basal level of expression in thiosulfate- or cysteine-grown cells, which was
induced when sulfate or methionine was used. Unlike its wild-type parent (strain
CE3), the mutant strain, CTNUX8, was also unable to grow on nitrate as the sole
nitrogen source and was unable to induce a high level of nitrite reductase.
Despite its pleiotropic phenotype, strain CTNUX8 was able to induce pink,
effective (N2-fixing) nodules on the roots of Phaseolus vulgaris plants. However,
mixed inoculation experiments showed that strain CTNUX8 is significantly
different from the wild type in its ability to nodulate. Our data support the
notion that sulfate (or sulfite) is the sulfur source of R. etli in the
rhizosphere, while cysteine, methionine, or glutathione is supplied by the root
cells to bacteria growing inside the plant.
PMID- 9393699
TI - A null mutation in the Bacillus subtilis aconitase gene causes a block in Spo0A
phosphate-dependent gene expression.
AB - The citB gene of Bacillus subtilis encodes aconitase, the enzyme of the Krebs
citric acid cycle, which is responsible for the interconversion of citrate and
isocitrate. A B. subtilis strain with an insertion mutation in the citB gene was
devoid of aconitase activity and aconitase protein, required glutamate for growth
in minimal medium, and was unable to sporulate efficiently in nutrient broth
sporulation medium. Mutant cells failed to form the asymmetric septum
characteristic of sporulating cells and were defective in transcription of the
earliest-expressed spo genes, that is, the genes dependent on the Spo0A
phosphorelay. However, this early block in sporulation was partially overcome
when cells of the citB mutant were induced to sporulate by resuspension in a poor
medium. Accumulation of citrate in the mutant cells or in their culture fluid may
be responsible for the early block, possibly because citrate can chelate divalent
cations needed for the activity of the phosphorelay.
PMID- 9393700
TI - A study of iterative type II polyketide synthases, using bacterial genes cloned
from soil DNA: a means to access and use genes from uncultured microorganisms.
AB - To examine as randomly as possible the role of the beta-ketoacyl and acyl carrier
protein (ACP) components of bacterial type II polyketide synthases (PKSs),
homologs of the chain-length-factor (CLF) genes were cloned from the
environmental community of microorganisms. With PCR primers derived from
conserved regions of known ketosynthase (KSalpha) and ACP genes specifying the
formation of 16- to 24-carbon polyketides, two CLF (KSbeta) genes were cloned
from unclassified streptomycetes isolated from the soil, and two were cloned from
soil DNA without the prior isolation of the parent microorganism. The sequence
and deduced product of each gene were distinct from those of known KSbeta genes
and, by phylogenetic analysis, belonged to antibiotic-producing PKS gene
clusters. Hybrid PKS gene cassettes were constructed with each novel KSbeta gene
substituted for the actI-ORF2 or tcmL KSbeta subunit genes, along with the
respective actI-ORF1 or tcmK KSalpha, tcmM ACP, and tcmN cyclase genes, and were
found to produce an octaketide or decaketide product characteristic of the ones
known to be made by the heterologous KSalpha gene partner. Since substantially
less than 1% of the microorganisms present in soil are thought to be cultivatable
by standard methods, this work demonstrates a potential way to gain access to a
more extensive range of microbial molecular diversity and to biosynthetic
pathways whose products can be tested for biological applications.
PMID- 9393701
TI - An exo-poly-alpha-D-galacturonosidase, PehB, is required for wild-type virulence
of Ralstonia solanacearum.
AB - Ralstonia solanacearum, which causes bacterial wilt disease of many plant
species, produces several extracellular plant cell wall-degrading enzymes that
are suspected virulence factors. These include a previously described
endopolygalacturonase (PG), PehA, and two exo-PGs. A gene encoding one of the exo
PGs, pehB, was cloned from R. solanacearum K60. The DNA fragment specifying PehB
contained a 2,103-bp open reading frame that encodes a protein of 74.2 kDa with a
typical N-terminal signal sequence. The cloned pehB gene product cleaves
polygalacturonic acid into digalacturonic acid units. The amino acid sequence of
pehB resembles that of pehX, an exo-PG gene from Erwinia chrysanthemi, with 47.2%
identity at the amino acid level. PehB also has limited similarity to plant exo
PGs from Zea mays and Arabidopsis thaliana. The chromosomal pehB genes in R.
solanacearum wild-type strain K60 and in an endo-PG PehA- strain were replaced
with an insertionally inactivated copy of pehB. The resulting mutants were
deficient in the production of PehB and of both PehA and PehB, respectively. The
pehB mutant was significantly less virulent than the wild-type strain in eggplant
virulence assays using a soil inoculation method. However, the pehA mutant was
even less virulent, and the pehA pehB double mutant was the least virulent of
all. These results suggest that PehB is required for a wild-type level of
virulence in R. solanacearum although its individual role in wilt disease
development may be minor. Together with endo-PG PehA, however, PehB contributes
substantially to the virulence of R. solanacearum.
PMID- 9393702
TI - Bacillus subtilis RNase III gene: cloning, function of the gene in Escherichia
coli, and construction of Bacillus subtilis strains with altered rnc loci.
AB - The rnc gene of Bacillus subtilis, which has 36% amino acid identity with the
gene that encodes Escherichia coli RNase III endonuclease, was cloned in E. coli
and shown by functional assays to encode B. subtilis RNase III (Bs-RNase III).
The cloned B. subtilis rnc gene could complement an E. coli rnc strain that is
deficient in rRNA processing, suggesting that Bs-RNase III is involved in rRNA
processing in B. subtilis. Attempts to construct a B. subtilis rnc null mutant
were unsuccessful, but a strain was constructed in which only a carboxy-terminal
truncated version of Bs-RNase III was expressed. The truncated Bs-RNase III
showed virtually no activity in vitro but was active in vivo. Analysis of
expression of a copy of the rnc gene integrated at the amy locus and transcribed
from a p(spac) promoter suggested that expression of the B. subtilis rnc is under
regulatory control.
PMID- 9393703
TI - Differential translocation of protein precursors across SecY-deficient membranes
of Escherichia coli: SecY is not obligatorily required for translocation of
certain secretory proteins in vitro.
AB - SecY, a component of the protein translocation system in Escherichia coli, was
depleted at a nonpermissive temperature in a strain which had a temperature
sensitive polar effect on the expression of its secY. Membrane vesicles prepared
from these cells, when grown at the nonpermissive temperature, contained about 5%
SecY and similarly low levels of SecG. As expected, translocation of alkaline
phosphatase precursors across these SecY-deficient membranes was severely
impaired and appeared to be directly related to the decrease of SecY amounts.
However, despite such a dramatic reduction in SecY and SecG levels, these
membranes exhibited 50 to 70% of the wild-type translocation activity, including
the processing of the signal peptide, of OmpA precursor (proOmpA). This
translocation activity in SecY-deficient membranes was still SecA and ATP
dependent and was not unique to proOmpA, as lipoprotein and lambda receptor
protein precursors were also transported efficiently. Membranes that were
reconstituted from these SecY-depleted membranes contained undetectable amounts
of SecY yet were also shown to possess substantial translocation activity for
proOmpA. These results indicate that the requirement of SecY for translocation is
not obligatory for all secretory proteins and may depend on the nature of
precursors. Consequently, it is unlikely that SecY is the essential core channel
through which all precursors traverse across membranes; rather, SecY probably
contributes to efficiency and specificity.
PMID- 9393704
TI - Interaction of Bacillus subtilis purine repressor with DNA.
AB - A purine repressor (PurR) mediates adenine nucleotide-dependent regulation of
transcription initiation of the Bacillus subtilis pur operon. This repressor has
been purified for the first time, and binding to control site DNA was
characterized. PurR binds in vitro to four operons. Apparent Kd values for
binding were 7 nM for the pur operon, 8 nM for purA, 13 nM for purR, and 44 nM
for the pyr operon. In each case, DNase I footprints exhibited a pattern of
protected and hypersensitive sites that extended over more than 60 bp. A GAAC-N24
GTTC sequence in the pur operon was necessary but not sufficient for the PurR-DNA
interaction. However, this motif, which is conserved in the four binding sites,
was not required for binding of PurR to purA. Thus, the common DNA recognition
element for binding of PurR to the four operons is not known. Multiple PurR-pur
operon DNA complexes having a binding stoichiometry that was either approximately
two or six repressor molecules per DNA fragment were detected. The results of a
torsional constraint experiment suggest that control site DNA forms one right
handed turn around PurR.
PMID- 9393705
TI - The arginine deiminase pathway in Rhizobium etli: DNA sequence analysis and
functional study of the arcABC genes.
AB - Sequence analysis upstream of the Rhizobium etli fixLJ homologous genes revealed
the presence of three open reading frames homologous to the arcABC genes of
Pseudomonas aeruginosa. The P. aeruginosa arcABC genes code for the enzymes of
the arginine deiminase pathway: arginine deiminase, catabolic ornithine
carbamoyltransferase (cOTCase), and carbamate kinase. OTCase activities were
measured in free-living R. etli cells and in bacteroids isolated from bean
nodules. OTCase activity in free-living cells was observed at a different pH
optimum than OTCase activity in bacteroids, suggesting the presence of two
enzymes with different characteristics and different expression patterns of the
corresponding genes. The characteristics of the OTCase isolated from the
bacteroids were studied in further detail and were shown to be similar to the
properties of the cOTCase of P. aeruginosa. The enzyme has a pH optimum of 6.8
and a molecular mass of approximately 450 kDa, is characterized by a sigmoidal
carbamoyl phosphate saturation curve, and exhibits a cooperativity for carbamoyl
phosphate. R. etli arcA mutants, with polar effects on arcB and arcC, were
constructed by insertion mutagenesis. Bean nodules induced by arcA mutants were
still able to fix nitrogen but showed a significantly lower acetylene reduction
activity than nodules induced by the wild type. No significant differences in
nodule dry weight, plant dry weight, and number of nodules were found between the
wild type and the mutants. Determination of the OTCase activity in extracts from
bacteroids revealed a strong decrease in activity of this enzyme in the arcA
mutant compared to the wild-type strain. Finally, we observed that expression of
an R. etli arcA-gusA fusion was strongly induced under anaerobic conditions.
PMID- 9393707
TI - Alkyl hydroperoxide reductase, catalase, MrgA, and superoxide dismutase are not
involved in resistance of Bacillus subtilis spores to heat or oxidizing agents.
AB - Only a single superoxide dismutase (SodA) was detected in Bacillus subtilis, and
growing cells of a sodA mutant exhibited paraquat sensitivity as well as a growth
defect and reduced survival at an elevated temperature. However, the sodA
mutation had no effect on the heat or hydrogen peroxide resistance of wild-type
spores or spores lacking the two major DNA protective alpha/beta-type small, acid
soluble, spore proteins (termed alpha(-)beta(-) spores). Spores also had only a
single catalase (KatX), as the two catalases found in growing cells (KatA and
KatB) were absent. While a katA mutation greatly decreased the hydrogen peroxide
resistance of growing cells, as found previously, katA, katB, and katX mutations
had no effect on the heat or hydrogen peroxide resistance of wild-type or alpha(
)beta(-) spores. Inactivation of the mrgA gene, which codes for a DNA-binding
protein that can protect growing cells against hydrogen peroxide, also had no
effect on spore hydrogen peroxide resistance. Inactivation of genes coding for
alkyl hydroperoxide reductase, which has been shown to decrease growing cell
resistance to alkyl hydroperoxides, had no effect on spore resistance to such
compounds or on spore resistance to heat and hydrogen peroxide. However, Western
blot analysis showed that at least one alkyl hydroperoxide reductase subunit was
present in spores. Together these results indicate that proteins that play a role
in the resistance of growing cells to oxidizing agents play no role in spore
resistance. A likely reason for this lack of a protective role for spore enzymes
is the inactivity of enzymes within the dormant spore.
PMID- 9393706
TI - Fis, an accessorial factor for transcriptional activation of the mar (multiple
antibiotic resistance) promoter of Escherichia coli in the presence of the
activator MarA, SoxS, or Rob.
AB - Transcription of the multiple antibiotic resistance marRAB operon increases when
one of the sequence-related activators, MarA, SoxS, or Rob, binds to the "marbox"
centered at -61.5 relative to the transcriptional start site. Previous deletion
analyses showed that an adjacent upstream "accessory region" was needed to
augment the marbox-dependent activation. To analyze the roles of the marbox and
accessory regions on mar transcription, thirteen promoters, each with a different
5-bp transversion of the -96 to -32 sequence, were synthesized, fused to lacZ,
and assayed for beta-galactosidase production in single-copy lysogens with
appropriate genotypes. The accessory region is shown here to be a binding site
for Fis centered at -81 and to bind Fis, a small DNA-binding and -bending
protein, with a Kd of approximately 5 nM. The binding of MarA to the marbox and
that of Fis to its site were independent of each other. MarA, SoxS, and Rob each
activated the mar promoter 1.5-to 2-fold when it had a wild-type marbox but Fis
was absent. In the presence of MarA, SoxS, or Rob, Fis further enhanced the
activity of the promoter twofold provided the promoter was also capable of
binding Fis. However, in the absence of MarA, SoxS, or Rob or in the absence of a
wild-type marbox, Fis nonspecifically lowered the activity of the mar promoter
about 25% whether or not a wild-type Fis site was present. Thus, Fis acts as an
accessory transcriptional activator at the mar promoter.
PMID- 9393708
TI - Physical and genetic map of the Clostridium acetobutylicum ATCC 824 chromosome.
AB - A physical and genetic map of the Clostridium acetobutylicum ATCC 824 chromosome
was constructed. The macrorestriction map for CeuI, EagI, and SstII was created
by ordering the 38 restriction sites by one- and two-dimensional pulsed-field gel
electrophoresis (PFGE) and by using an original strategy based on the CeuI enzyme
and indirect end labelling by hybridization on both sides of the CeuI sites with
rrs (16S RNA) and 3' rrl (23S RNA) probes. The circular chromosome was estimated
to be 4.15 Mb in size, and the average resolution of the physical map is 110 kb.
The chromosome contains 11 rrn loci, which are localized on 44% of the chromosome
in a divergent transcriptional orientation regarding the presumed location of the
replication origin. In addition to these 11 rrn operons, a total of 40 identified
genes were mapped by hybridization experiments with genes from C. acetobutylicum
and from various other clostridia as probes. The genetic map of C. acetobutylicum
was compared to that of the three other endospore-forming bacteria characterized
so far: Bacillus subtilis, Clostridium beijerinckii, and Clostridium perfringens.
Parodoxically, the chromosomal backbone of C. acetobutylicum showed more
similarity to that of B. subtilis than to those of the clostridia.
PMID- 9393709
TI - Genetic requirements and mutational specificity of the Escherichia coli SOS
mutator activity.
AB - To better understand the mechanisms of SOS mutagenesis in the bacterium
Escherichia coli, we have undertaken a genetic analysis of the SOS mutator
activity. The SOS mutator activity results from constitutive expression of the
SOS system in strains carrying a constitutively activated RecA protein (RecA730).
We show that the SOS mutator activity is not enhanced in strains containing
deficiencies in the uvrABC nucleotide excision-repair system or the xth and nfo
base excision-repair systems. Further, recA730-induced errors are shown to be
corrected by the MutHLS-dependent mismatch-repair system as efficiently as the
corresponding errors in the rec+ background. These results suggest that the SOS
mutator activity does not reflect mutagenesis at so-called cryptic lesions but
instead represents an amplification of normally occurring DNA polymerase errors.
Analysis of the base-pair-substitution mutations induced by recA730 in a mismatch
repair-deficient background shows that both transition and transversion errors
are amplified, although the effect is much larger for transversions than for
transitions. Analysis of the mutator effect in various dnaE strains, including
dnaE antimutators, as well as in proofreading-deficient dnaQ (mutD) strains
suggests that in recA730 strains, two types of replication errors occur in
parallel: (i) normal replication errors that are subject to both exonucleolytic
proofreading and dnaE antimutator effects and (ii) recA730-specific errors that
are not susceptible to either proofreading or dnaE antimutator effects. The
combined data are consistent with a model suggesting that in recA730 cells error
prone replication complexes are assembled at sites where DNA polymerization is
temporarily stalled, most likely when a normal polymerase insertion error has
created a poorly extendable terminal mismatch. The modified complex forces
extension of the mismatch largely at the exclusion of proofreading and polymerase
dissociation pathways. SOS mutagenesis targeted at replication-blocking DNA
lesions likely proceeds in the same manner.
PMID- 9393711
TI - Purification and properties of serine hydroxymethyltransferase from Sulfolobus
solfataricus.
AB - Serine hydroxymethyltransferase (SHMT) catalyzes the reversible cleavage of
serine to glycine with the transfer of the one-carbon group to tetrahydrofolate
to form 5,10-methylenetetrahydrofolate. No SHMT has been purified from a
nonmethanogenic Archaea strain, in part because this group of organisms uses
modified folates as the one-carbon acceptor. These modified folates are not
readily available for use in assays for SHMT activity. This report describes the
purification and characterization of SHMT from the thermophilic organism
Sulfolobus solfataricus. The exchange of the alpha-proton of glycine with solvent
protons in the absence of the modified folate was used as the activity assay. The
purified protein catalyzes the synthesis of serine from glycine and a synthetic
derivative of a fragment of the natural modified folate found in S. solfataricus.
Replacement of the modified folate with tetrahydrofolate did not support serine
synthesis. In addition, this SHMT also catalyzed the cleavage of both allo
threonine and beta-phenylserine in the absence of the modified folate. The
cleavage of these two amino acids in the absence of tetrahydrofolate is a
property of other characterized SHMTs. The enzyme contains covalently bound
pyridoxal phosphate. Sequences of three peptides showed significant similarity
with those of peptides of SHMTs from two methanogens.
PMID- 9393712
TI - Purification and biochemical characterization of a hydroxyneurosporene desaturase
involved in the biosynthetic pathway of the carotenoid spheroidene in Rhodobacter
sphaeroides.
AB - Hydroxyneurosporene desaturase is involved in the carotenoid biosynthetic pathway
of Rhodobacter species. The gene encoding this enzyme was expressed in
Escherichia coli, purified, and biochemically characterized. The resulting
protein contained an N-terminal six-histidine extension which derived from the
cloning vector; this allowed for a one-step purification of the enzyme to
homogeneity after solubilization with Nonidet P-40. The hydrogen acceptor in the
C-3,4 desaturation reaction was molecular oxygen. NAD+, NADP+, and flavin adenine
dinucleotide had no influence on enzymatic activity. Different acyclic 1
hydroxycarotenoids were tested as substrates. Very good conversion was achieved
with 1-hydroxyneurosporene and 1-hydroxylycopene, whereas 1-hydroxy-gamma
carotene and 1,1'-dihydroxylycopene were much less effective. From 1'-hydroxy-3,4
didehydrolycopene only trace amounts of product were obtained, and 1
methoxyneurosporene was not converted by purified hydroxyneurosporene desaturase.
A Km of 13.4 microM was determined for 1-hydroxyneurosporene.
PMID- 9393710
TI - NtrC is required for control of Klebsiella pneumoniae NifL activity.
AB - In response to molecular oxygen and/or fixed nitrogen, the product of the
Klebsiella pneumoniae nitrogen fixation L (nifL) gene inhibits NifA-mediated
transcriptional activation. Nitrogen regulation of NifL function occurs at two
levels: transcription of the nifLA operon is regulated by the general Ntr system,
and the activity of NifL is controlled by an unknown mechanism. We have studied
the regulation of NifL activity in Escherichia coli and Salmonella typhimurium by
monitoring its inhibition of NifA-mediated expression of a K. pneumoniae
phi(nifH'-'lacZ) fusion. The activity of the NifL protein transcribed from the
tac promoter is regulated well in response to changes of oxygen and/or nitrogen
status, indicating that no nif- or K. pneumoniae-specific product is required.
Unexpectedly, strains carrying ntrC (glnG) null alleles failed to release NifL
inhibition, despite the fact that synthesis of NifL was no longer under Ntr
control. Additional evidence indicated that it is indeed the transcriptional
activation capacity of NtrC, rather than its repression capacity, that is needed,
and hence it is a plausible hypothesis that NtrC activates transcription of a
gene(s) whose product(s) in turn functions to relieve NifL inhibition under
nitrogen-limiting conditions.
PMID- 9393713
TI - Cloning and genetic analysis of the UV resistance determinant (uvr) encoded on
the Enterococcus faecalis pheromone-responsive conjugative plasmid pAD1.
AB - The conjugative pheromone-responsive plasmid pAD1 (59.6 kb) of Enterococcus
faecalis encodes a UV resistance determinant (uvr) in addition to the hemolysin
bacteriocin determinant. pAD1 enhances the UV resistance of wild-type E. faecalis
FA2-2 and E. faecalis UV202, which is a UV-sensitive derivative of E. faecalis
JH2-2. A 2.972-kb fragment cloned from between 27.7 and 30.6 kb of the pAD1 map
conferred UV resistance function on UV202. Sequence analysis showed that the
cloned fragment contained three open reading frames designated uvrA, uvrB, and
uvrC. The uvrA gene is located on the pAD1 map between 28.1 and 29.4 kb. uvrB is
located between 30.1 and 30.3 kb, and uvrC is located between 30.4 and 30.6 kb on
the pAD1 map. The uvrA, uvrB, and uvrC genes encode sequences of 442, 60, and 74
amino acids, respectively. The deduced amino acid sequence of the uvrA-encoded
protein showed 20% homology of the identical residues with the E. coli UmuC
protein. Tn917 insertion mutagenesis and deletion mutant analysis of the cloned
fragment showed that uvrA conferred UV resistance. A palindromic sequence, 5'
GAACNGTTC-3', which is identical to the consensus sequence found within the
putative promoter region of the Bacillus subtilis DNA damage-inducible genes, was
located within the promoter region of uvrA. Two uvrA transcripts of different
lengths (i.e., 1.54 and 2.14 kb) which terminate at different points downstream
of uvrA were detected in UV202 carrying the deletion mutant containing uvrA. The
longer transcript, 2.14 kb, was not detected in UV202 carrying the deletion
mutant containing both uvrA and uvrB, which suggests that uvrB encodes a
terminator for the uvrA transcript. The uvrA transcript was not detected in any
significant quantity in UV202 carrying the cloned fragment containing uvrA, uvrB,
and uvrC; on the other hand, the 1.54-kb uvrA transcript was detected in the
strain exposed to mitomycin C, which suggests that the UvrC protein functions as
a regulator of uvrA.
PMID- 9393715
TI - Structure and evolution of NGRRS-1, a complex, repeated element in the genome of
Rhizobium sp. strain NGR234.
AB - Much of the remarkable ability of Rhizobium sp. strain NGR234 to nodulate at
least 110 genera of legumes, as well as the nonlegume Parasponia andersonii,
stems from the more than 80 different Nod factors it secretes. Except for nodE,
nodG, and nodPQ, which are on the chromosome, most Nod factor biosynthesis genes
are dispersed over the 536,165-bp symbiotic plasmid, pNGR234a. Mosaic sequences
and insertion sequences (ISs) comprise 18% of pNGR234a. Many of them are
clustered, and these IS islands divide the replicon into large blocks of
functionally related genes. At 6 kb, NGRRS-1 is a striking example: there is one
copy on pNGR234a and three others on the chromosome. DNA sequence comparisons of
two NGRRS-1 elements identified three types of IS, NGRIS-2, NGRIS-4, and NGRIS
10. Here we show that all four copies of NGRRS-1 probably originated from
transposition of NGRIS-4 into a more ancient IS-like sequence, NGRIS-10.
Remarkably, all nine copies of NGRIS-4 have transposed into other ISs. It is
unclear whether the accumulation of potentially mutagenic sequences in large
clusters is due to the nature of the IS involved or to some selection process.
Nevertheless, a direct consequence of the preferential targeting of transposons
into such IS islands is to minimize the likelihood of disrupting vital functions.
PMID- 9393714
TI - Negative regulation of mutS and mutH repair gene expression by the Hfq and RpoS
global regulators of Escherichia coli K-12.
AB - The MutS, MutL, and MutH proteins play major roles in several DNA repair
pathways. We previously reported that the cellular amounts of MutS and MutH
decreased by as much as 10-fold in stationary-phase cultures. Consequently, we
tested whether the amounts of MutS, MutL, and MutH were regulated by two global
regulators, RpoS (sigma38) and Hfq (HF-I [putative RNA chaperone]), which are
involved in stationary-phase transition. We report here that mutations in hfq and
rpoS reversed the stationary-phase down-regulation of the amounts of MutS and
MutH. hfq regulation of the amount of MutS in stationary-phase cultures was
mediated by RpoS-dependent and -independent mechanisms, whereas hfq regulation of
the amount of MutH was mediated only through RpoS. Consistent with this
interpretation, the amount of MutS but not MutH was regulated by Hfq, but not
RpoS, in exponentially growing cells. The amount of MutL remained unchanged in
rpoS, hfq-1, and rpoS+, hfq+ strains in exponentially growing and stationary
phase cultures and served as a control. The beta-galactosidase activities of
single-copy mutS-lacZ operon and gene fusions suggested that hfq regulates mutS
posttranscriptionally in exponentially growing cultures. RNase T2 protection
assays revealed increased amounts of mutS transcript that are attributed to
increased mutS transcript stability in hfq-1 mutants. Lack of Hfq also increased
the amounts and stabilities of transcripts initiated from P(miaA) and P1hfqHS,
two of the promoters for hfq, suggesting autoregulation, but did not change the
half-life of bulk mRNA. These results suggest that the amounts of MutS and MutH
may be adjusted in cells subjected to different stress conditions by an RpoS
dependent mechanism. In addition, Hfq directly or indirectly regulates several
genes, including mutS, hfq, and miaA, by an RpoS-independent mechanism that
destabilizes transcripts.
PMID- 9393716
TI - The 2microm-plasmid-encoded Rep1 and Rep2 proteins interact with each other and
colocalize to the Saccharomyces cerevisiae nucleus.
AB - The efficient partitioning of the 2microm plasmid of Saccharomyces cerevisiae at
cell division requires two plasmid-encoded proteins (Rep1p and Rep2p) and a cis
acting locus, REP3 (STB). By using protein hybrids containing fusions of the Rep
proteins to green fluorescent protein (GFP), we show here that fluorescence from
GFP-Rep1p or GFP-Rep2p is almost exclusively localized in the nucleus in a cir+
strain. Nuclear localization of GFP-Rep1p and GFP-Rep2p, though discernible, is
less efficient in a cir(0) host. GFP-Rep2p or GFP-Rep1p is able to promote the
stability of a 2microm circle-derived plasmid harboring REP1 or REP2,
respectively, in a cir(0) background. Under these conditions, fluorescence from
GFP-Rep2p or GFP-Rep1p is concentrated within the nucleus, as is the case in cir+
cells. This characteristic nuclear accumulation is not dependent on the
expression of the FLP or RAF1 gene of the 2microm circle. Nuclear colocalization
of Rep1p and Rep2p is consistent with the hypothesis that the two proteins
directly or indirectly interact to form a functional bipartite or high-order
protein complex. Immunoprecipitation experiments as well as baiting assays using
GST-Rep hybrid proteins suggest a direct interaction between Rep1p and Rep2p
which, in principle, may be modulated by other yeast proteins. Furthermore, these
assays provide evidence for Rep1p-Rep1p and Rep2p-Rep2p associations as well. The
sum of these interactions may be important in controlling the effective cellular
concentration of the Rep1p-Rep2p complex.
PMID- 9393717
TI - Escherichia coli cells expressing a mutant glyV (glycine tRNA) gene have a UVM
constitutive phenotype: implications for mechanisms underlying the mutA or mutC
mutator effect.
AB - Transfection of M13 single-stranded viral DNA bearing a 3,N4-ethenocytosine
lesion into Escherichia coli cells pretreated with UV results in a significant
elevation of mutagenesis at the lesion site compared to that observed in
untreated cells. This response, termed UVM, for UV modulation of mutagenesis, is
induced by a variety of DNA-damaging agents and is distinct from known cellular
responses to DNA damage, including the SOS response. This report describes our
observation, as a part of our investigation of the UVM phenomenon, that E. coli
cells bearing a mutA or mutC allele display a UVM-constitutive phenotype. These
mutator alleles were recently mapped (M. M. Slupska, C. Baikalov, R. Lloyd, and
J. H. Miller, Proc. Natl. Acad. Sci. USA 93:4380-4385, 1996) to the glyV (mutA)
and glyW (mutC) tRNA genes. Each mutant allele was shown to arise by an identical
mutation in the anticodon sequence such that the mutant tRNAs could, in
principle, mistranslate aspartate codons in mRNA as glycine at a low level.
Because a UVM-constitutive phenotype resulting from a mutation in a tRNA gene was
unexpected, we undertook a series of experiments designed to test whether the
phenotype was indeed mediated by the expression of mutant glycine tRNAs. We
placed either a wild-type or a mutant glyV gene under the control of a
heterologous inducible promoter on a plasmid vector. E. coli cells expressing the
mutant glyV gene displayed all three of the following phenotypes: (i) missense
suppression of a test allele, (ii) a mutator phenotype measured by mutation to
rifampin resistance, and (iii) a UVM-constitutive phenotype. These phenotypes
were not associated with cells expressing the wild-type glyV gene or with cells
in which the mutant allele was present but was not transcriptionally induced.
These observations provide strong support for the idea that expression of mutant
tRNA can confer a mutator phenotype, including the UVM-constitutive phenotype
observed in mutA and mutC cells. However, our data imply that low-level
mistranslation of the epsilon subunit of polymerase III probably does not account
for the observed UVM-constitutive phenotype. Our results also indicate that mutA
deltarecA double mutants display a normal UVM phenotype, suggesting that the mutA
effect is recA dependent. The observations reported here raise a number of
intriguing questions and raise the possibility that the UVM response is mediated
through transient alteration of the replication environment.
PMID- 9393718
TI - Identification and characterization of the niddamycin polyketide synthase genes
from Streptomyces caelestis.
AB - The genes encoding the polyketide synthase (PKS) portion of the niddamycin
biosynthetic pathway were isolated from a library of Streptomyces caelestis NRRL
2821 chromosomal DNA. Analysis of 40 kb of DNA revealed the presence of five
large open reading frames (ORFs) encoding the seven modular sets of enzymatic
activities required for the synthesis of a 16-membered lactone ring. The
enzymatic motifs identified within each module were consistent with those
predicted from the structure of niddamycin. Disruption of the second ORF of the
PKS coding region eliminated niddamycin production, demonstrating that the cloned
genes are involved in the biosynthesis of this compound.
PMID- 9393719
TI - Nested DNA inversion of Campylobacter fetus S-layer genes is recA dependent.
AB - Wild-type strains of Campylobacter fetus are covered by a monomolecular array of
surface layer proteins (SLPs) critical for virulence. Each cell possesses eight
SLP gene cassettes, tightly clustered in the genome, that encode SLPs of 97 to
149 kDa. Variation of SLP expression occurs by a mechanism of nested DNA
rearrangement that involves the inversion of a 6.2-kb sapA promoter-containing
element alone or together with one or more flanking SLP gene cassettes. The
presence of extensive regions of identity flanking the 5' and 3' ends of each SLP
gene cassette and of a Chi-like recognition sequence within the 5' region of
identity suggests that rearrangement of SLP gene cassettes may occur by a
generalized (RecA-dependent) homologous recombination pathway. To explore this
possibility, we cloned C. fetus recA and created mutant strains by marker rescue,
in which recA is disrupted in either S+ or S- strains. These mutants then were
assessed for their abilities to alter SLP expression either in the presence or
absence of a complementary shuttle plasmid harboring native recA. In contrast to
all previously reported programmed DNA inversion systems, inversion in C. fetus
is recA dependent.
PMID- 9393721
TI - Methylmalonyl coenzyme A selectivity of cloned and expressed acyltransferase and
beta-ketoacyl synthase domains of mycocerosic acid synthase from Mycobacterium
bovis BCG.
AB - Methyl-branched fatty acids and polyketides occur in a variety of living
organisms. Previous studies have established that multifunctional enzymes use
methylmalonyl coenzyme A (CoA) as the substrate to generate methyl-branched
products such as mycocerosic acids and polyketides. However, we do not know which
of the component activities show selectivity for methylmalonyl-CoA in any
biological system. A comparison of homologies of the domains of the
multifunctional synthases that selectively use malonyl-CoA or methylmalonyl-CoA
suggested that the acyltransferase (AT) and beta-ketoacyl synthase (KS) domains
might be responsible for the substrate selectivity. To test this hypothesis, we
expressed the AT and KS domains of the mycocerosic acid synthase (MAS) gene from
Mycobacterium bovis BCG in Escherichia coli and examined whether they confer to
synthases that normally do not use methylmalonyl-CoA the ability to incorporate
methylmalonyl-CoA into fatty acids. Both the AT and the KS domains of MAS showed
selectivity for methylmalonyl-CoA over malonyl-CoA. Acyl carrier protein (ACP)
dependent elongation of the n-C12 acyl primer mainly by one methylmalonyl-CoA
unit was catalyzed by an E. coli fatty acid synthase preparation only in the
presence of the expressed MAS domains. An ACP-dependent elongation of the n-C20
acyl primer by one methylmalonyl-CoA extender unit was catalyzed by fatty acid
synthase from Mycobacterium smegmatis only in the presence of the expressed MAS
domains. These results show methylmalonyl-CoA selectivity for the AT and KS
domains of MAS. These domains may be useful in producing novel polyketides by
genetic engineering.
PMID- 9393720
TI - A quorum-sensing system in the free-living photosynthetic bacterium Rhodobacter
sphaeroides.
AB - Rhodobacter sphaeroides is a free-living, photoheterotrophic bacterium known for
its genomic and metabolic complexity. We have discovered that this purple
photosynthetic organism possesses a quorum-sensing system. Quorum sensing occurs
in a number of eukaryotic host-associated gram-negative bacteria. In these
bacteria there are two genes required for quorum sensing, the luxR and luxI
homologs, and there is an acylhomoserine lactone signal molecule synthesized by
the product of the luxI homolog. In R. sphaeroides, synthesis of a novel
homoserine lactone signal, 7,8-cis-N-(tetradecenoyl)homoserine lactone, is
directed by a luxI homolog termed cerI. Two open reading frames immediately
upstream of cerI are proposed to be components of the quorum-sensing system. The
first of these is a luxR homolog termed cerR, and the second is a small open
reading frame of 159 bp. Inactivation of cerI in R. sphaeroides results in mucoid
colony formation on agar and formation of large aggregates of cells in liquid
cultures. Clumping of CerI mutants in liquid culture is reversible upon addition
of the acylhomoserine lactone signal and represents a phenotype unlike those
controlled by quorum sensing in other bacteria.
PMID- 9393723
TI - Terminal inverted repeats of insertion sequence IS30 serve as targets for
transposition.
AB - In the present study, we demonstrate that the terminal inverted repeats of the
Escherichia coli insertion sequence IS30 are functional target sites for the
transposition of the (IS30)2 dimer, which represents an intermediate structure in
the transposition of IS30. Comparative analysis of various target regions
revealed that the left and right ends differ in their "attractivity." In our
experiments, the joined left and right ends, i.e., the (IS30)2 intermediate
structure, was found to be the most preferred target. It was also shown that
flanking sequences can influence the target activity of the terminal repeats. The
functional part of the target region was localized in the inverted repeats by
means of mutational analysis, and it corresponds to the binding site of IS30
transposase. Insertion of 1 bp into the right inverted repeat resulted in unusual
target duplication accompanied by gene conversion. The choice of the terminal
inverted repeats as targets in transposition leads to the reconstruction of the
(IS30)2 structure, which may induce a cascade of further rearrangements.
Therefore, this process can play a role in the evolution of the genome.
PMID- 9393722
TI - Conserved motifs II to VI of DNA helicase II from Escherichia coli are all
required for biological activity.
AB - There are seven conserved motifs (IA, IB, and II to VI) in DNA helicase II of
Escherichia coli that have high homology among a large family of proteins
involved in DNA metabolism. To address the functional importance of motifs II to
VI, we employed site-directed mutagenesis to replace the charged amino acid
residues in each motif with alanines. Cells carrying these mutant alleles
exhibited higher UV and methyl methanesulfonate sensitivity, increased rates of
spontaneous mutagenesis, and elevated levels of homologous recombination,
indicating defects in both the excision repair and mismatch repair pathways. In
addition, we also changed the highly conserved tyrosine(600) in motif VI to
phenylalanine (uvrD309, Y600F). This mutant displayed a moderate increase in UV
sensitivity but a decrease in spontaneous mutation rate, suggesting that DNA
helicase II may have different functions in the two DNA repair pathways.
Furthermore, a mutation in domain IV (uvrD307, R284A) significantly reduced the
viability of some E. coli K-12 strains at 30 degrees C but not at 37 degrees C.
The implications of these observations are discussed.
PMID- 9393724
TI - Characterization of the acc operon from the nopaline-type Ti plasmid pTiC58,
which encodes utilization of agrocinopines A and B and susceptibility to agrocin
84.
AB - The acc locus from the Ti plasmid pTiC58 confers utilization of and chemotaxis
toward agrocinopines A and B (A+B), as well as susceptibility to a highly
specific antiagrobacterial antibiotic, agrocin 84. DNA sequence analyses revealed
that acc is composed of eight open reading frames, accR and accA through accG.
Previous work showed that accR encodes the repressor which regulates this locus,
and accA codes for the periplasmic binding protein of the agrocinopine transport
system (S. Beck Von Bodman, G. T. Hayman, and S. K. Farrand, Proc. Natl. Acad.
Sci. USA 89:643-647, 1992; G. T. Hayman, S. Beck Von Bodman, H. Kim, P. Jiang,
and S. K. Farrand, J. Bacteriol. 175:5575-5584, 1993). The predicted proteins
from accA through accE, as a group, have homology to proteins that belong to the
ABC-type transport system superfamily. The predicted product of accF is related
to UgpQ of Escherichia coli, which is a glycerophosphoryl diester
phosphodiesterase, and also to agrocinopine synthase coded for by acs located on
the T-DNA. The translated product of accG is related to myoinositol 1 (or 4)
monophosphatases from various eucaryotes. Analyses of insertion mutations showed
that accA through accE are required for transport of both agrocin 84 and
agrocinopines A+B, while accF and accG are required for utilization of the opines
as the sole source of carbon. Mutations in accF or accG did not abolish transport
of agrocin 84, although we observed slower removal of the antibiotic from the
medium by the accF mutant compared to the wild type. However, the insertion
mutation in accF abolished detectable uptake of agrocinopines A+B. A mutation in
accG had no effect on transport of the opines. The accF mutant was not
susceptible to agrocin 84 although it took up the antibiotic. This finding
suggests that agrocin 84 is activated by AccF after being transported into the
bacterial cell.
PMID- 9393725
TI - Specificities of FemA and FemB for different glycine residues: FemB cannot
substitute for FemA in staphylococcal peptidoglycan pentaglycine side chain
formation.
AB - The femAB operon codes for two nearly identical approximately 50-kDa proteins
involved in the formation of the staphylococcal pentaglycine interpeptide bridge.
Sequencing and analysis of the femA region of mutants isolated by chemical
mutagenesis and selection for lysostaphin resistance revealed point mutations
leading to the expression of truncated FemA proteins. These femA mutants,
although still producing an intact FemB, exhibited a phenotype identical as that
described for femAB double mutants. Thus, FemA seems to be essential for the
addition of glycine residues 2 and 3 only, whereas FemB is involved in the
attachment of exclusively glycine residues 4 and 5. Although FemB has 39%
identity with FemA, it cannot substitute for FemA. The FemA and FemB proteins
seem to be highly specific in regard to the position of the glycine residues that
they attach.
PMID- 9393726
TI - Essential role of the consensus nucleotide-binding site of PtlH in secretion of
pertussis toxin from Bordetella pertussis.
AB - PtlH is a member of a specialized set of transport proteins that is essential for
secretion of pertussis toxin (PT) from Bordetella pertussis. Previously, PtlH was
shown to contain a consensus nucleotide-binding motif. Here, we demonstrate that
introduction of plasmids containing mutant forms of ptlH, altered in the putative
nucleotide-binding region, into a wild-type strain of B. pertussis resulted in
inhibition of PT secretion. Thus, this region of PtlH appears to be essential for
protein function. Moreover, the observed dominant negative phenotype suggests
that PtlH either functions as a multimer or interacts with another component
necessary for secretion of PT.
PMID- 9393727
TI - A gene (wbbL) from Serratia marcescens N28b (O4) complements the rfb-50 mutation
of Escherichia coli K-12 derivatives.
AB - A cosmid-based genomic library of Serratia marcescens N28b was introduced into
Escherichia coli DH5alpha, and clones were screened for serum resistance. One
clone was found resistant to serum, to bacteriocin 28b, and to bacteriophages
TuIa and TuIb. This clone also showed O antigen in its lipopolysaccharide.
Subcloning and sequencing experiments showed that a 2,124-bp DNA fragment
containing the rmlD and wbbL genes was responsible for the observed phenotypes.
On the basis of amino acid similarity, we suggest that the 288-residue RmlD
protein is a dTDP-L-rhamnose synthase. Plasmid pJT102, containing only the wbbL
gene, was able to induce O16-antigen production and serum resistance in E. coli
DH5alpha. These results suggest that the 282-residue WbbL protein is a
rhamnosyltransferase able to complement the rJb-50 mutation in E. coli K-12
derivatives, despite the low level of amino acid identity between WbbL and the E.
coli rhamnosyltransferase (24.80%). S. marcescens N28b rmlD and wbbL mutants were
constructed by mobilization of suicide plasmids containing a portion of rmlD or
wbbL. These insertion mutants were unable to produce O antigen; since strain N28b
produces O4 antigen, these results suggest that both genes are involved in O4
antigen biosynthesis.
PMID- 9393728
TI - Role of NifS in maturation of glutamine phosphoribosylpyrophosphate
amidotransferase.
AB - Glutamine phosphoribosylpyrophosphate amidotransferase from Bacillus subtilis is
synthesized as an inactive precursor that requires two maturation steps:
incorporation of a [4Fe-4S] center and cleavage of an 11-residue NH2-terminal
propeptide. Overproduction from a multicopy plasmid in Escherichia coli leads to
the formation of soluble proenzyme and mature enzyme forms as well as a small
fraction of insoluble proenzyme. Heterologous expression of Azotobacter
vinelandii nifS from a compatible plasmid increased the maturation of the soluble
proenzyme three- to fourfold without influencing the content of the insoluble
fraction. These results support a role for NifS in heterologous Fe-S cluster
assembly and enzyme maturation.
PMID- 9393729
TI - The rpoN (sigma54) gene from Listeria monocytogenes is involved in resistance to
mesentericin Y105, an antibacterial peptide from Leuconostoc mesenteroides.
AB - To gain insight into the mode of action of mesentericin Y105, a bacteriocin
bactericidal agent against Listeria monocytogenes, we undertook to identify the
listerial factors mediating this susceptibility by using a genetic approach.
Transposon mutants resistant to the bacteriocin were obtained. One of them
corresponded to a transposon insertion in a gene (rpoN) encoding a putative
protein (447 amino acids) with strong homologies to alternative transcriptional
sigma54 factors, including that of Bacillus subtilis (38% identity).
Complementation experiments with the wild-type rpoN gene demonstrated that the
insertion in rpoN was responsible for the resistance phenotype in L.
monocytogenes. Moreover, expression of the L. monocytogenes rpoN gene in an rpoN
mutant strain of B. subtilis promoted transcription of a sigma54-dependent operon
in the presence of the associated regulator. These results demonstrate that the
L. monocytogenes rpoN gene encodes a new sigma54 factor.
PMID- 9393730
TI - Proteins induced in Escherichia coli by benzoic acid.
AB - Proteins induced by benzoic acid in Escherichia coli were observed on two
dimensional electrophoretic gels (2-D gels). Cultures were grown in glucose-rich
medium in the presence or absence of 20 mM benzoate at an external pH of 6.5,
where the pH gradient (deltapH) is large and benzoate accumulates, and at an
external pH of 8.0, where deltapH is inverted and little benzoate is taken up.
Radiolabeled proteins were separated on 2-D gels and were identified on the basis
of the index of VanBogelen and Neidhardt. In the absence of benzoic acid, little
difference was seen between pH 6.5 and pH 8.0; this confirms that the mechanisms
of protein homeostasis in this range are constitutive, including the transition
between positive and inverted deltapH. Addition of benzoate at pH 6.5 increased
the expression of 33 proteins. Twelve of the benzoate-induced proteins were
induced at pH 8.0 as well, and nine of these matched proteins induced by the
uncoupler dinitrophenol. Eighteen proteins were induced by benzoate only at pH
6.5, not at pH 8.0, and were not induced by dinitrophenol. One may be the iron
and pH regulator Fur, which regulates acid tolerance in Salmonella spp. The other
13 proteins had not been identified previously. The proteins induced by benzoate
only at a low pH may reflect responses to internal acidification or to
accumulation of benzoate.
PMID- 9393731
TI - Mutational analysis of amiloride sensitivity of the NhaA Na+/H+ antiporter from
Vibrio parahaemolyticus.
AB - The activity of the NhaA Na+/H+ antiporter of Vibrio parahaemolyticus is
inhibited by amiloride. We found an amino acid sequence in the NhaA that was
identical to a putative amiloride binding domain of the Na+/H+ exchanger in
mammalian cells. We constructed mutant NhaAs that had amino acid substitutions in
the putative amiloride binding domain by site-directed mutagenesis. These include
V62L (Val62 replaced by Leu), F63Y, F64Y, and L65F. Most mutant NhaAs showed
decreased sensitivity for amiloride. Among these, the F64Y mutant NhaA showed the
least amiloride sensitivity, with a Ki value 7 to 10 times greater than that in
the wild type. Thus, the sequence between residues V62 and L65 in NhaA,
especially F64, is very important for the inhibitory effect of amiloride on the
antiporter.
PMID- 9393732
TI - Contribution of glucose kinase to glucose repression of xylose utilization in
Bacillus megaterium.
AB - The glk gene from Bacillus megaterium, which encodes glucose kinase, was isolated
and analyzed. Disruption by a transcriptional glk-luxAB fusion indicated that glk
is the only glucose kinase gene in that strain but did not affect growth of that
mutant on glucose. Determination of luciferase activity under various growth
conditions revealed constitutive transcription of glk. Expression of a xylA-lacZ
fusion was repressed by glucose in the strain with the glk disruption about
twofold less efficiently than in the wild type. The potential contribution of glk
expression to glucose repression is discussed.
PMID- 9393733
TI - Functional domains of a zinc metalloprotease from Vibrio vulnificus.
AB - Vibrio vulnificus, an opportunistic human pathogen causing wound infection and
septicemia, secretes a 45-kDa metalloprotease (V. vulnificus protease; VVP). A
plasmid which carries the entire vvp gene subcloned into pBluescriptIIKS+ was
transformed into Escherichia coli DH5alpha for overproduction of the protease.
The 45-kDa recombinant protease (rVVP) was isolated from the periplasmic fraction
of the transformant by ammonium sulfate precipitation followed by column
chromatography on phenyl Sepharose. Biochemical characterization of the isolated
rVVP showed that the recombinant protease was identical to that produced by V.
vulnificus. When rVVP was incubated at 37 degrees C, a 35-kDa fragment was
generated through autoproteolytic removal of the C-terminal peptide. This 35-kDa
fragment (rVVP-N) was found to have sufficient proteolytic activity toward
oligopeptides and soluble proteins but had markedly reduced activity toward
insoluble proteins. Lineweaver-Burk plot analysis indicated increased Km values
of rVVP-N for all of the protein substrates. rVVP, but not rVVP-N, was shown to
agglutinate rabbit erythrocytes, bind to the erythrocyte ghosts, and digest the
ghost membrane proteins. These results strongly suggest that rVVP (and VVP)
consists of at least two functional domains: an N-terminal 35-kDa polypeptide
mediating proteolysis and a C-terminal 10-kDa polypeptide which may be essential
for efficient attachment to protein substrates and erythrocyte membranes.
PMID- 9393734
TI - Carcinoma-associated expression of core 2 beta-1,6-N
acetylglucosaminyltransferase gene in human colorectal cancer: role of O-glycans
in tumor progression.
AB - Recently, it was demonstrated that an increased level of NeuNAc alpha2-3Gal beta1
4(Fuc alpha1-3)GlcNAc beta-R (sialyl Le(x)) and NeuNAc alpha2-3Gal beta1-3(Fuc
alpha1-4)GlcNAc beta-R (sialyl Le(a)) expression on the surface of colorectal
cancer cells is positively correlated with progression of the disease. It has not
been determined, however, which type of glycans, N- or O-glycans, is more closely
associated with progression when cancer cells express those oligosaccharides. To
address this problem, we have examined expression of sialyl Le(a) and sialyl
Le(x), those oligosaccharides in O-glycans, and core 2 beta-1,6-N
acetylglucosaminyltransferase (C2GnT) transcripts in colorectal cancer specimens
from 46 patients and compared those results with clinicopathological variables.
C2GnT is a glycosyltransferase that is responsible for the core 2 branch, which
is critical for biosynthesis of sialyl Le(a) and sialyl Le(x) in O-glycans.
Sialyl Le(a) and sialyl Le(x) were determined by immunohistochemistry, and C2GnT
transcripts were detected by reverse transcription-PCR. Sialyl Le(a) or sialyl
Le(x) in O-glycans was assessed by combining immunohistochemistry for sialyl
Le(a) or sialyl Le(x) with reverse transcription-PCR for C2GnT. Sialyl Le(a),
detected on cancer cells in 74% of patients, was well correlated with lymph node
metastasis, whereas sialyl Le(a) and sialyl Le(x) in O-glycans, which were
specifically detected in cancer tissues of 50 and 61% of patients, respectively,
were closely associated with lymphatic and venous invasion. In addition, C2GnT,
which was specifically detected in cancer tissues of 63% of patients, was closely
correlated with the vessel invasion, as well as depth of tumor invasion. These
results strongly suggest that sialyl Le(a) and sialyl Le(x) in O-glycans and
C2GnT, expressed in cancer cells, may play important roles in tumor progression
through vessel or direct invasion.
PMID- 9393735
TI - Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene
abnormalities.
AB - Genomic alterations and abnormal expression of the FHIT gene at 3p14.2 have been
observed in cell lines and primary tumors of the lung. To correlate FHIT locus
DNA and RNA lesions with effects on Fhit protein expression, we have analyzed 11
lung cancer cell lines, 15 small cell lung carcinomas, and 38 pairs of non-small
cell primary tumors and bronchial mucosa specimens by molecular genetic and
immunocytochemical methods. Using specific antibodies against the Fhit protein,
we observed concordance between RNA abnormalities and lack of Fhit protein
expression in lung tumors and cell lines. In addition, absence of Fhit protein in
some precancerous dysplastic lesions suggested that FHIT inactivation may occur
at an early phase of lung carcinogenesis.
PMID- 9393736
TI - Patterns of chromosomal alterations in metastasizing and nonmetastasizing primary
head and neck carcinomas.
AB - In an attempt to define chromosomal alterations that are associated with the
metastatic phenotype, we investigated a total of 29 metastasizing (pN+) and 19
non-metastasizing (pN0) head and neck squamous cell carcinomas by comparative
genomic hybridization (CGH). The analysis indicated that the pN0 tumors carried
preferentially overrepresentations of chromosomes 5p, 6p, and 7p and that the pN+
tumors were frequently characterized by deletions on chromosomes 7q, 10q, 11p,
11q, 15q, and 20p and overrepresentations of the chromosomes 19q and 20q. In
particular, the use of difference histograms and statistical analysis indicated
that the deletions on chromosomes 10q25-q26 and 11p13-p14 were highly significant
for metastasizing carcinomas. The findings on chromosome 10q were supported by
loss of heterozygosity analysis in the primary tumors and eight synchronous lymph
node metastases using four microsatellite polymorphisms. The data suggest that
distinct patterns of genetic lesions are responsible for the metastatic phenotype
of head and neck squamous cell carcinomas.
PMID- 9393737
TI - Intracellular localization of p53 tumor suppressor protein in gamma-irradiated
cells is cell cycle regulated and determined by the nucleus.
AB - DNA damage leads to the stabilization of p53 protein and its translocation to the
nucleus, resulting in activation or suppression of p53-responsive genes. However,
a significant proportion of cell nuclei remain negative for p53 and p53-inducible
cyclin-dependent kinase inhibitor p21waf1 after a single dose of gamma
irradiation. Quantitation of DNA content in p53-positive and -negative nuclei 4-6
h after 10 Gy of gamma-irradiation of human breast carcinoma MCF7 cells,
fibrosarcoma HT1080 cells, and diploid skin fibroblasts showed that p53 and
p21waf1 nuclear accumulation occurs predominantly in the G1 phase and at the
beginning of the S phase of the cell cycle. The majority of the nuclei in late S
phase and in G2-M phase remained p53- and p21waf1-negative. This suggests that
there is a cell cycle window during which p53 can accumulate in the nucleus and
activate expression of p21waf1. To determine whether cell cycle-dependent
distribution of p53 is caused by cytoplasmic modifications of p53 protein or by
properties of the nucleus, p53 localization was analyzed in multinucleated cells
obtained by polyethylene glycol-mediated cell fusion. Dramatic differences in p53
accumulation were found among the nuclei in individual multinucleated cells.
Distribution of p53-positive and -negative nuclei among the phases of the cell
cycle was similar to that observed in a regular cell population. These results
suggest that the observed differences in p53 accumulation in the nuclei of
irradiated cells are determined by cell cycle-dependent nuclear functions. In
contrast to p53, p21waf1 was equally distributed among the nuclei of
multinucleated cells regardless of the stage of the cell cycle, indicating that
the observed phenomenon is specific for p53.
PMID- 9393738
TI - MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines.
AB - A candidate tumor suppressor gene, MMAC1/PTEN, located in human chromosome band
10q23, was recently identified based on sequence alterations observed in several
glioma, breast, prostate, and kidney tumor specimens or cell lines. To further
investigate the mutational profile of this gene in human cancers, we examined a
large set of human tumor specimens and cancer cell lines of many types for 10q23
allelic losses and MMAC1 sequence alterations. Loss of heterozygosity (LOH) at
the MMAC1 locus was observed in approximately one-half of the samples examined,
consistent with the high frequency of 10q allelic loss reported for many cancers.
Of 124 tumor specimens exhibiting LOH that have been screened for MMAC1
alterations to date, we have detected variants in 13 (approximately 10%) of these
primary tumors; the highest frequency of variants was found in glioblastoma
specimens (approximately 23%). Novel alterations identified in this gene include
a missense variant in a melanoma sample and a splicing variant and a nonsense
mutation in pediatric glioblastomas. Of 76 tumor cell lines prescreened for
probable LOH, microsequence alterations of MMAC1 were detected in 12
(approximately 16%) of the lines, including those derived from astrocytoma,
leukemia, and melanoma tumors, as well as bladder, breast, lung, prostate,
submaxillary gland, and testis carcinomas. In addition, in this set of tumor cell
lines, we detected 11 (approximately 14%) homozygous deletions that eliminated
coding portions of MMAC1, a class of abnormality not detected by our methods in
primary tumors. These data support the occurrence of inactivating MMAC1
alterations in multiple human cancer types. In addition, we report the discovery
of a putative pseudogene of MMAC1 localized on chromosome 9.
PMID- 9393740
TI - Evidence that the multidrug resistance protein (MRP) functions as a co
transporter of glutathione and natural product toxins.
AB - The MRP (multidrug resistance protein) gene, a member of the ubiquitous
superfamily of ATP-binding cassette transporters, is associated with the
multidrug resistance of mammalian cells to natural product anticancer agents. We
have previously shown that abrogation of MRP expression by gene targeting leads
to hypersensitivity to several drugs. In two independently produced MRP double
knockout clones, the baseline export of glutathione (GSH) was one-half that of
wild-type embryonic stem (ES) cells. The export of GSH from wild-type ES cells,
but not from the MRP double knockout clones, increased in the presence of
etoposide (VP-16) and sodium arsenite, accompanied by equivalent decreases in
intracellular levels of GSH. In the two MRP double knockout clones, the
intracellular steady-state concentration of etoposide was twofold greater than
that in wild-type cells. Depletion of intracellular GSH by D,L-buthionine
sulfoximine increased the intracellular accumulation of radiolabeled etoposide in
parental ES cells up to the level present in the two MRP knockout clones but did
not change etoposide levels in the MRP knockout clones. These observations
provide evidence that: (a) MRP exports GSH physiologically, presumably in
association with an endogenous compound(s); (b) baseline MRP expression protects
cells from the toxic effects of xenobiotics by effluxing the xenobiotics and GSH
from the intracellular compartment into the extracellular medium by a co
transport mechanism; and (c) disruption of the gene encoding MRP abrogates the
cotransport of xenobiotics and GSH.
PMID- 9393739
TI - Expression of PACE4 in chemically induced carcinomas is associated with spindle
cell tumor conversion and increased invasive ability.
AB - Gene expression changes associated with the conversion of squamous cell carcinoma
(SCC) to a more advanced malignant spindle cell carcinoma (SPCC) were determined
by differential display. Using an animal model of human SCC progression, we
provide evidence of increased PACE4 expression in SPCC cell lines and primary
tumors induced by chemical carcinogenesis protocols, thus implicating this
proprotein convertase in the process of tumor progression. Exogenous
overexpression of PACE4 cDNA in mouse SCC cells of low invasive ability resulted
in enhanced tumor cell invasiveness that was absent in parental or mock
transfected SCC cells. In addition, the PACE4-transfected cells acquired the
ability to process prostromelysin 3 into its active enzyme form. Taken together,
these results show that up-regulation of PACE4 expression is associated with SCC
conversion to SPCC and suggests that activation of essential PACE4 substrates,
such as the metalloproteinase stromelysin 3, is required for tumor cell invasion.
PMID- 9393741
TI - Disruption of the murine MRP (multidrug resistance protein) gene leads to
increased sensitivity to etoposide (VP-16) and increased levels of glutathione.
AB - The mrp (multidrug resistance protein) gene has been associated with the
multidrug resistance of cancer cells in vitro and in vivo. To gain information on
its physiological role, embryonic stem cells were used to generate mice
homozygous for a disruption of the mrp gene, resulting in complete abrogation of
mrp expression. No physiological abnormalities were observed, at least up to 4
months of age. Viability, fertility, and a range of histological, hematological,
and serum-chemical parameters were similar in mrp(+/+) and mrp(-/-) mice. mrp(-/
) mice displayed an increased sensitivity to etoposide phosphate (2-fold)
accompanied by greater bone marrow toxicity, whereas the acute toxicity of sodium
arsenite was equivalent in mrp(+/+) and mrp(-/-) mice. Tissue levels of
glutathione (GSH) were elevated in breast, lung, heart, kidney, muscle, colon,
testes, bone marrow cells, blood mononuclear leukocytes, and blood erythrocytes
of mrp(-/-) mice and were unchanged in organs known to express little if any mrp,
such as the liver and small intestine. The increase in GSH was not due to an
increase in the activity of gamma-glutamylcysteine synthetase, the rate-limiting
enzyme for GSH synthesis. The findings demonstrate that mrp is dispensable for
development and growth but exerts a role in drug detoxification and GSH
metabolism.
PMID- 9393742
TI - NADH dehydrogenase deficiency in an apoptosis-resistant mutant isolated from a
human HL-60 leukemia cell line.
AB - An apoptosis-resistant mutant (VC-33) was selected from HL-60 by alternating
exposure to camptothecin and etoposide. VC-33 cells demonstrated resistance to
apoptosis as induced not only by camptothecin and etoposide but by a variety of
other agents as well, including 1-beta-D-arabinofuranosylcytosine, hydroxyurea,
calcium ionophore (A23187), cycloheximide, and UV irradiation. In an effort to
identify the mechanism of such apoptosis resistance, a mRNA differential display
analysis was used. Among a total of 12 bands with reduced expression in VC-33
cells, 1 cDNA clone was isolated that was hybridized to the wild-type transcript
but not to the VC-33 transcript on Northern blotting. Partial sequence of this
gene revealed 98% homology to mitochondrial NADH dehydrogenase subunit 5. When
cell growth and intracellular ATP levels under glucose starvation were measured,
VC-33 cells were found to be more sensitive than wild-type cells. Thus, NADH
dehydrogenase deficiency may contribute, at least in part, to the mechanism of
resistance to apoptosis in VC-33 cells.
PMID- 9393743
TI - Liposomal doxorubicin circumvents PSC 833-free drug interactions, resulting in
effective therapy of multidrug-resistant solid tumors.
AB - Conventional methods that are used to overcome multidrug resistance (MDR) often
involve the coadministration of chemosensitizers and anticancer drugs. The
cyclosporin analogue SDZ PSC 833 [(3'-keto-Bmt1)-(Val2)-cyclosporin] (PSC 833)
has been shown to possess powerful chemosensitization properties in vitro, in
addition to being intrinsically nontoxic. However, coadministration of PSC 833
with anticancer drugs, such as daunorubicin, doxorubicin (DOX), and Taxol, have
resulted in the exacerbation of anticancer drug toxicity, which is due to altered
anticancer drug pharmacokinetics. Here, we hypothesized that optimization of the
anticancer drug delivery, using liposomal carriers, may, by avoiding these
adverse interactions, offer a significant advantage over nonencapsulated drugs.
Toxicity studies were conducted in normal BDF1 mice, with i.v. DOX (free or
liposome encapsulated) administration and p.o. PSC 833 in single and multiple
dosage regimens over a 15-day study period. p.o. administration of PSC 833, at a
dose of 100 mg/kg, reduced the maximum tolerated dose (MTD) of i.v administered
free drug by 2.5-3-fold, in single- and multiple-dose regimens. In contrast, PSC
833 administration resulted in only a 20% reduction of the MTD for DOX
encapsulated in 100-nm 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol
liposomes (55:45 molar lipid ratio) in a single-dose regimen and had no effect on
the liposomal DOX MTD for the day 1, 5, and 9 treatment schedule. Modest
modulation of P-glycoprotein-mediated MDR was observed in the murine P388/ADR
solid tumor model when PSC 833 was administered with free DOX at the MTD. In
contrast, liposomal DOX combined with PSC 833 resulted in tumor growth inhibition
that was comparable to that observed for drug-sensitive P388/WT tumors. This
efficacy of P388/ADR tumors treatment was dependent on PSC 833 because treatment
with liposomal DOX alone provided significantly less antitumor activity.
Pharmacokinetic and tissue distribution data demonstrated that DOX encapsulated
in 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol liposomes exhibited
comparable plasma elimination and tissue distribution properties in the presence
and absence of PSC 833, whereas free DOX displayed reduced plasma elimination
rates and altered tissue distribution in the presence of PSC 833. These results
provide evidence that PSC 833 can induce P-glycoprotein modulation and
chemosensitize MDR tumors in the absence of altered DOX pharmacokinetics when
liposomal carriers are used. This suggests that the improved tumor selectivity of
anticancer drugs that are administered in liposomal formulations may avoid the
complications that are associated with free drug-MDR-reversing agent combinations
and enhance the therapy of multidrug-resistant tumors.
PMID- 9393744
TI - PTEN/MMAC1 mutations and EGFR amplification in glioblastomas.
AB - Loss of heterozygosity (LOH) from chromosome 10 is a hallmark of glioblastoma,
the most malignant (grade IV) form of glioma. A candidate tumor suppressor gene,
PTEN/MMAC1, that may be targeted for deletion in association with chromosome 10
LOH has recently been identified. Here we have investigated 63 glioblastomas for
PTEN/MMAC1 alterations and identified DNA sequence changes that would affect the
encoded protein in 17 (27%) tumors. Microsatellite analyses of normal-tumor DNA
pairs were performed on 14 of these cases and revealed LOH at locations flanking
and/or near PTEN/MMAC1 in all but 1 instance, suggesting that deletion of the
remaining wild-type allele had occurred in the large majority of tumors with
PTEN/MMAC1 mutations. Competitive PCR assays were developed to address the
possible occurrence of PTEN/MMAC1 homozygous deletions in glioblastomas, and this
analysis identified three samples having loss of both PTEN/MMAC1 alleles. EGFR
amplification was determined to occur at similar frequencies among cases with or
without PTEN/MMAC1 homozygous deletions or mutations, suggesting that a growth
promoting effect resulting from amplification-associated increases in epidermal
growth factor receptor signaling is not necessarily dependent on the inactivation
of PTEN/MMAC1.
PMID- 9393745
TI - The use of exfoliative cell samples to map clonal genetic alterations in the oral
epithelium of high-risk patients.
AB - Although it is widely accepted that clonal genetic alterations are an essential
component of tumor progression, little is known of the distribution of such
changes in high-risk lesions or how such clones are altered over time. We
explored the feasibility of using exfoliative cells collected by scraping the
mucosal surface to detect allelic loss in oral lesions of 22 patients (14
squamous cell carcinomas, 2 carcinomas in situ, and 6 dysplasias). The data show
that the patterns of allelic loss observed in these samples closely represent
those observed in biopsies of the same region. Furthermore, early indications are
that this approach can be used to detect recurrent outgrowth of clones of altered
cells in patients after therapy.
PMID- 9393746
TI - Human tumor blood flow is enhanced by nicotinamide and carbogen breathing.
AB - Perfusion insufficiency and the resultant hypoxia are recognized as important
mechanisms of resistance to anticancer therapy. Modification of the tumor
microenvironment to increase perfusion and oxygenation of tumors may improve on
the efficacy of these treatments. Using laser Doppler probes to measure
microregional RBC flux, this study examines the influence of nicotinamide and
carbogen on human tumor perfusion. Ten patients with advanced cancers were
studied. Nicotinamide (80 mg/kg) was given p.o., and 60 min later, up to six
probes were inserted into the tumor. Readings were taken for 1 h, followed by 10
min of carbogen breathing and 10 additional min of breathing room air. Results
were compared with those from a similar group of eight control patients who were
not given nicotinamide, but who breathed carbogen. In 44 microregions analyzed,
33 (73%) showed perfusion fluctuations of 50% or more, and 20 (44%) by 100% or
more. This compared with the control group in whom 62% and 27% of microregions
varied by 50% or more and 100% or more, respectively. Perfusion increases
outweighed decreases by 30% with nicotinamide and 20% in the controls. On
breathing carbogen, patients pretreated with nicotinamide showed an increase in
tumor perfusion of 17% at 5 min and 22% at 10 min, compared with only 0% and 1%
in the control group. Pretreatment with nicotinamide made little difference to
the random blood flow fluctuations seen in controls. However, when carbogen was
introduced, tumor perfusion increased compared with the control group. This may
have important therapeutic implications by improving response to treatment and
allowing better delivery of systemically administered agents.
PMID- 9393747
TI - Overexpression of manganese superoxide dismutase selectively modulates the
activity of Jun-associated transcription factors in fibrosarcoma cells.
AB - Manganese superoxide dismutase (MnSOD) is reduced in a variety of tumor cells and
has been proposed to be a new type of tumor suppressor gene. The mechanism(s) by
which MnSOD suppresses cancer development is currently unknown. However,
expression of this antioxidant might play a significant role in maintaining
cellular redox status. The relationship between MnSOD expression and modulation
of DNA-binding activity and transcriptional activation of redox-sensitive
oncoproteins and tumor suppressor proteins was studied in a murine fibrosarcoma
cell line (FSa-II). Electrophoretic mobility shift assay and transcriptional
activation studies revealed an inverse correlation between MnSOD expression and
activity of c-jun-associated transcription factors, activator protein 1 and
cyclic AMP-responsive element binding protein. Furthermore, expression of an
activator protein 1 target gene, bcl-xL, was decreased in MnSOD-transfected cell
lines. The results suggest that overexpression of MnSOD may exert its tumor
suppressor activity, in part, by modulation of specific oncogenes.
PMID- 9393748
TI - Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of
Bcl-2 family.
AB - Galectin-3, a beta-galactoside-binding protein, has been shown to be involved in
tumor progression and metastasis. Here, we demonstrate that expression of
galectin-3 in human breast carcinoma BT549 cells inhibits cis
diamminedichloroplatinum (cisplatin)-induced poly(ADP-ribose) polymerase
degradation and apoptosis, without altering Bcl-2, Bcl-X(L), or Bax expressions.
Galectin-3 contains the NWGR amino acid sequence highly conserved in the BH1
domain of the bcl-2 gene family, and a substitution of glycine to alanine in this
motif abrogated its antiapoptotic activity. Our findings demonstrate that
galectin-3 inhibits apoptosis through a cysteine protease pathway and highlight
the functional significance of the NWGR motif in apoptosis resistance of a non
Bcl-2 protein.
PMID- 9393749
TI - Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo.
AB - Angiostatin inhibits angiogenesis and metastatic tumor growth; however, its
usefulness in treating primary nonmetastasizing tumors is less well understood.
We now report the effectiveness of human angiostatin administration in a mouse
hemangioendothelioma model. Human angiostatin was administered to mice with s.c.
hemangioendothelioma and associated disseminated intravascular coagulopathy
(Kasabach-Merritt syndrome). Angiostatin significantly reduced tumor volume in
comparison to nontreated controls, increased survival, and prevented the profound
thrombocytopenia and anemia of Kasabach-Merritt syndrome. Apoptosis of tumor
cells was induced by angiostatin, but tumor cell proliferation was not inhibited.
These data suggest angiostatin as a novel treatment for nonmetastasizing vascular
tumors and for Kasabach-Merritt syndrome.
PMID- 9393750
TI - Vascular endothelial growth factor is a predictor of relapse and stage
progression in superficial bladder cancer.
AB - Tumor development is angiogenesis dependent, and vascular endothelial growth
factor (VEGF) is a key growth factor in this process. We demonstrate that high
expression of VEGF mRNA in 55 superficial bladder cancers was associated with
earlier recurrence (P = 0.001; hazard ratio, 3.09) and progression to a more
invasive phenotype (P = 0.02; hazard ratio, 5.33). VEGF mRNA expression
correlated with protein levels in superficial tumors (r = 0.59, P = 0.003) and
normal bladder (r = 0.65, P < 0.05), although the ratio of VEGF protein to mRNA
was elevated in tumors compared to normal bladder (P = 0.004), suggesting
posttranscriptional regulation. In this study, VEGF is implicated as a major
downstream mediator of the effects of the p53 tumor suppressor gene by the
association between high p53 protein (determined immunochemically) and high VEGF
protein and mRNA expression (P < 0.02), although in cases without high p53
protein expression, high VEGF mRNA also predicts a poor prognosis. The
relationship between VEGF and early tumor recurrence suggests that seeding via
angiogenesis may be a major mechanism in the pathogenesis of recurrence. These
studies indicate that VEGF can predict the behavior of superficial bladder tumors
and is a therapeutic target for intravesical therapy.
PMID- 9393751
TI - Murine susceptibility to radiation-induced pulmonary fibrosis is influenced by a
genetic factor implicated in susceptibility to bleomycin-induced pulmonary
fibrosis.
AB - From evidence of interpatient variability in normal tissue sensitivity to
radiotherapy and from radiation studies using inbred mouse strains, it is
hypothesized that individual variation in susceptibility to radiation-induced
pulmonary fibrosis is genetically controlled. A genetic model has been developed
from the fibrosis-prone C57BL/6J and the fibrosis-resistant C3Hf/Kam mouse
strains. Inheritance of the fibrotic phenotype was characterized in F1 and F2 (F1
intercross) generations derived from the parental strains. Genetic mapping was
used to determine whether the quantitative trait loci (QTL), which influence
susceptibility to bleomycin-induced lung fibrosis in these progenitor strains,
could be implicated in susceptibility to radiation-induced lung fibrosis. Mice
were treated with 14 or 16 Gy (60Co) to the whole thorax. The doses were selected
to investigate the response at the LD50 and LD100 of C3Hf/Kam mice. The animals
were sacrificed 33 weeks after treatment or when moribund. The percentage of lung
with fibrosis for each mouse was quantified with image analysis of a histological
section of the lung. For both the 14- and 16-Gy data sets, heritability was
estimated at 38 +/- 11%, and the number of genetic factors influencing
susceptibility to pulmonary fibrosis was estimated to be one or two. Two hundred
fifty-five F2 intercross mice were genotyped with markers at the bleomycin loci
on chromosomes 11 and 17 (chromosome 17 marker is at the major histocompatibility
complex). Genetic linkage was established for the marker on chromosome 17 (P =
3.0 x 10(-6)), which accounts for 6.6% of the F2 phenotypic variance but not for
the markers surrounding the QTL on chromosome 11 (P = 0.37). The inheritance data
suggested that susceptibility to radiation-induced pulmonary fibrosis is a
heritable trait controlled by two genetic loci, and through genomic mapping, a
QTL on chromosome 17 was identified as one of the loci.
PMID- 9393752
TI - Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by
1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in
human glioma cells.
AB - Treatment of human glioma A172 cells with 1-(4-amino-2-methyl-5
pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), an alkylating
antitumor agent the primary target of which has been thought to be DNA, resulted
in elevated expression of mRNA for multidrug resistance-associated protein (MRP)
within the first 2 h and then a decrease in expression 24 h after the treatment.
Western blot analyses revealed that levels of MRP in these ACNU-treated cells
paralleled mRNA levels. Membrane vesicles prepared from ACNU-treated cells also
displayed elevated transport activities for leukotriene C4, a known substrate for
MRP. Gamma-glutamylcysteine synthetase (gamma-GCS) mRNA expression was coinduced
with MRP by ACNU. Because gamma-GCS is the rate-limiting enzyme involved in the
de novo biosynthesis of glutathione, increases in glutathione were also
transiently induced by ACNU. These results demonstrate for the first time that
the expression of functional MRP and gamma-GCS can be transiently coinduced by
ACNU. Multiple short exposures (1 h) of ACNU following a long duration (1 week)
of drug-free conditions resulted in the development of an ACNU-resistant
population (designated A172R) that overexpressed MRP/gamma-GCS mRNA and had
elevated transport activities for leukotriene C4. A172R exhibited cross
resistance to the antitumor drug doxorubicin and heavy metal sodium arsenate but
not to cisplatin. Our results also demonstrate that intermittent treatments of
human glioma cells with ACNU can lead to the development of MRP-related multidrug
resistance. These results, taken together, reveal a possible new mechanism of the
development of drug resistance for the antitumor nitrosoureas.
PMID- 9393753
TI - The protein kinase C activators phorbol esters and phosphatidylserine inhibit
neutral sphingomyelinase activation, ceramide generation, and apoptosis triggered
by daunorubicin.
AB - To address the role of protein kinase C (PKC) in the regulation of ceramide
production, we evaluated the impact of the PKC activators 12-O
tetradecanoylphorbol-13-acetate and phosphatidylserine on the apoptotic signaling
pathway triggered by the chemotherapeutic drug daunorubicin. Treatment of U937
and HL-60 cells with 0.5-1 microM daunorubicin induced a greater than 30%
activation of neutral sphingomyelinase activity within 4-10 min with concomitant
sphingomyelin hydrolysis and ceramide generation. Activation of PKC by 12-O
tetradecanoylphorbol-13-acetate and phosphatidylserine inhibited daunorubicin
induced neutral sphingomyelinase activation, sphingomyelin hydrolysis, ceramide
generation, and apoptosis. The apoptotic response could be restored by the
addition of 25 microM cell-permeant C6-ceramide. In conclusion, PKC emerges as a
potentially critical negative regulator of the anthracycline-activated
sphingomyelin-ceramide apoptotic pathway.
PMID- 9393754
TI - Intravenous administration of irinotecan elevates the blood beta-glucuronidase
activity in rats.
AB - 7-Ethyl-10-hydroxycamptothecin (SN-38) is the active metabolite of an anticancer
drug, irinotecan (CPT-11). Severe late diarrhea is the dose-limiting toxic effect
of CPT-11. This diarrhea has been examined regarding biliary excretion and
deconjugation of SN-38 glucuronide by the enzyme beta-glucuronidase (beta-GL) in
intestinal microflora. Prompted by the enzymological and structural similarity of
CPT-11 to organophosphorus and carbamate insecticides, we studied the effect of
CPT-11 on blood beta-GL activity in rats. The i.v. injection of CPT-11 in rats
significantly elevated their plasma beta-GL activity (with phenolphthalein
glucuronide as a substrate) at doses of 10 and 40 mg/kg, with peak activity
observed 2-3 h after administration. SN-38 lactone and carboxylate had no effect
on the plasma beta-GL level. The enhancement of the activity was also observed in
serum using SN-38 glucuronide as a substrate. The serum beta-GL levels showed a
close correlation between these substrates. The enhancement of plasma (serum)
beta-GL activity is suggested to be a result of the release of beta-GL from liver
microsomes. Serum and microsomal carboxylesterase were not significantly affected
by CPT-11 administration.
PMID- 9393755
TI - Improved treatment of medullary thyroid cancer in a nude mouse model by combined
radioimmunochemotherapy: doxorubicin potentiates the therapeutic efficacy of
radiolabeled antibodies in a radioresistant tumor type.
AB - Whereas in advanced metastatic medullary thyroid cancer (MTC), a variety of
chemotherapeutic regimens have achieved only limited success clinically, more
recently, radioimmunotherapy (RIT) with 131I-labeled anti-carcinoembryonic
antigen (CEA) monoclonal antibodies (MAbs) has shown promising results. The aims
of this study were to compare, in an animal model, the therapeutic efficacy of
RIT to clinically used "standard" chemotherapeutic regimens and to evaluate
whether combination strategies of both modalities may be feasible and may help to
improve therapeutic results in this rather radioresistant tumor type. Nude mice,
bearing s.c. xenografts of the human MTC cell line, TT, were treated either with
the 131I-labeled anti-CEA MAb, F023C5 IgG, or were administered chemotherapeutic
regimens that had shown promising results in patients with metastatic MTC
(doxorubicin and cisplatinum monotherapy, combinations of both agents, and a 5
fluorouracil/dacarbazine/streptozotocin scheme). Control groups were left
untreated or were injected with an irrelevant radiolabeled antibody at equitoxic
dose levels. The maximum tolerated dose (MTD) of each agent was determined.
Combinations of chemotherapy and RIT were evaluated as well. Toxicity and tumor
growth were monitored at weekly intervals. From the chemotherapeutic agents and
schemes tested, doxorubicin monotherapy was the most effective; combination
therapies did not result in an increased antitumor efficacy, but they did result
in more severe toxicity. At equitoxic doses, no significant difference was found
between the therapeutic efficacy of doxorubicin and that of RIT. Myelotoxicity
was dose limiting with radiolabeled MAbs (MTD, 600 microCi), as well as with
chemotherapeutic regimens containing alkylating agents (cisplatinum, dacarbazine,
or streptozotocin). At its MTD (200 microg), doxorubicin caused only mild
myelotoxicity, and despite signs of cardiac toxicity, gastrointestinal side
effects were dose limiting. Accordingly, bone marrow transplantation (BMT)
enabled dose intensification with RIT (MTD with BMT, 1100 microCi), which led to
further increased antitumor efficacy, whereas BMT was unable to increase the MTD
of doxorubicin. Due to the complementarity of toxic side effects but an
anticipated synergism of antitumor efficacy, combinations of RIT with doxorubicin
were tested. Administrations of 500 microCi of 131I-labeled anti-CEA and, 48 h
later, 200 microg of doxorubicin (i.e., 83 and 100% of the respective single
agent MTDs), were the highest doses that did not result in an increased
lethality; with bone marrow support, 1000 microCi of 131I-labeled anti-CEA could
be combined with 200 microg of doxorubicin (i.e., 90 and 100% of the individual
MTDs). Therapeutic results of this combined radioimmunochemotherapy were superior
to equitoxic monotherapy with either agent, and indication for synergistic
antitumor effects is given. At its respective MTD, radioimmunochemotherapy led to
a 36% cure rate if it was given without bone marrow support and to a 85%
permanent cure rate if it was given with bone marrow support. The animal model,
as presented in this study, seems to be useful for the preclinical testing of
therapeutic agents for the systemic treatment of MTC. At equitoxic doses, RIT
with radiolabeled anti-CEA antibodies seems to be equally as effective as
chemotherapy with doxorubicin. Combination of RIT and doxorubicin chemotherapy
seems to have synergistic therapeutic efficacy, which may be due to a
radiosensitizing effect of doxorubicin.
PMID- 9393756
TI - T-cell receptor repertoire in matched MART-1 peptide-stimulated peripheral blood
lymphocytes and tumor-infiltrating lymphocytes.
AB - Characterization of tumor-associated antigens (TAAs) recognized by CTLs makes the
consideration of therapeutic strategies based on peptide stimulation of
peripheral blood lymphocytes (PBLs) feasible. Several such approaches are
adoptive transfer of peptide-stimulated PBLs, ex vivo peptide stimulation of
dendritic cells, and direct vaccination with TAA-derived peptides. A critical
component of any of these peptide-based strategies is the requirement that the
patient's PBLs are able to react productively against the presented TAA. The
purpose of this study, through the study of T-cell receptor (TCR) usage, was to
evaluate the T-cell response in matched MART-1(27-35) peptide-stimulated PBLs and
tumor-infiltrating lymphocytes (TILs). MART-1(27-35)-reactive PBL and TIL
cultures were generated from three patients by in vitro stimulation with an
immunodominant peptide of MART-1 (MART-1(27-35)). All cultures had a human
leukocyte antigen A2-restricted, MART-1(27-35)-specific CTL response. The TCR
usage of each was assessed by the DNA sequence analysis of 50 TCR beta clones
obtained by rapid amplification of cDNA ends per culture. TCR analysis suggests a
TCR repertoire that differed from patient to patient (8-16 subfamilies were used)
and a predominant usage of a different variable beta chain (BV) by each of these
MART-reactive T cells. These predominant BV rearrangements were derived from
multiple clonotypes because different variable, diversity, and junctional regions
were observed. However, a similar pattern of expansion was present for both PBLs
and TILs; the relative usage of each prevailing BV was more marked in TILs (36,
50, and 78% of TILs versus 26, 20, and 24% of PBLs, respectively), a broader TCR
repertoire was used by PBLs (P > 0.05), and similar TCR subfamily usage was noted
when TIL and PBL cultures from the same patient were compared (8 of 11, 7 of 9,
and 7 of 8 for patients 1, 2, and 3, respectively). Furthermore, the exact same
clonotypes derived from predominant TCR subfamilies in the PBLs and TILs were
present in each patient, suggesting peptide-stimulated expansion in both
biological compartments. These studies suggest that there will not be a limited
and predictable TCR subfamily response to a specific TAA, although reproducible
patterns of PBL and TIL expansion are present from patient to patient.
Additionally, identical T-cell clonotypes having the same potential for antigen
driven expansion were present in a patient's PBLs and TILs. As such, our data
support the conceptualization of approaches using adoptive transfer or
vaccination based on TAA-derived peptide stimulation of PBLs.
PMID- 9393757
TI - V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription
of genes encoding vascular endothelial growth factor and enolase 1: involvement
of HIF-1 in tumor progression.
AB - Adaptation to hypoxia represents an important aspect of tumor progression.
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates
essential homeostatic responses to cellular and systemic hypoxia by activating
transcription of multiple genes including those encoding glycolytic enzymes and
vascular endothelial growth factor (VEGF). In this report, we demonstrate that
whereas C-SRC expression is not required for expression of HIF-1 or
transcriptional activation of genes encoding VEGF and enolase 1 (ENO1), cells
expressing the v-Src oncogene have increased expression of HIF-1, VEGF, and ENO1
under both hypoxic and nonhypoxic conditions. Expression of V-SRC was associated
with increased transcription of reporter genes containing cis-acting hypoxia
response elements from the VEGF and ENO1 genes, and this transcriptional
activation required an intact HIF-1 binding site. When three rat hepatoma
subclones that differed with respect to the level of HIF-1 expression were
injected into nude mice, tumor growth correlated with HIF-1 expression,
suggesting that HIF-1 may be generally involved in tumor progression. These
studies link an oncogene to the induction of HIF-1 expression, thus providing a
mechanism for hypoxic adaptation by tumor cells.
PMID- 9393758
TI - Low frequency of p16/CDKN2A methylation in sporadic melanoma: comparative
approaches for methylation analysis of primary tumors.
AB - Methylation of the 5' CpG island of the p16 tumor suppressor gene represents one
possible mechanism for inactivation of this cell cycle regulatory gene that is
also a melanoma predisposition locus. We have investigated the potential
contribution of somatic silencing of the p16 gene by DNA methylation in 30 cases
of sporadic cutaneous melanoma. The methylation status of the 5' CpG island of
p16 was initially determined by Southern analysis and then reevaluated (in a
blinded manner) using methylation-specific PCR, methylation-sensitive single
nucleotide primer extension, and bisulfite genomic sequencing. All methodologies
yielded concordant results, and significant levels of methylation were observed
in 3 of the 30 (10%) melanoma DNAs analyzed. Of the three tumors found to be
methylated, two were also positive for LOH on 9p21 (where the p16 gene resides),
implying that both p16 alleles were inactivated, one via deletion and the other
via methylation-associated transcriptional silencing. The association between
methylation and transcriptional silencing of p16 was also further supported by
inducing p16 expression with a DNA demethylating agent (5-aza-2'-deoxycytidine)
in a melanoma cell line known to harbor a methylated p16 allele. Although
methylation-associated gene silencing does not represent a common mechanism for
p16 inactivation in sporadic melanoma, our findings provide support that PCR
based techniques, such as methylation-specific PCR and methylation-sensitive
single nucleotide primer extension, can be reliably used for the accurate
detection and quantitation of aberrant levels of DNA methylation in tumor
specimens.
PMID- 9393759
TI - Enforced expression of the Mr 33,000 Pim-1 kinase enhances factor-independent
survival and inhibits apoptosis in murine myeloid cells.
AB - Expression of the Mr 33,000 human Pim-1 protein is induced in hematopoietic cells
by a variety of growth factors and cytokines. We have introduced the human pim-1
cDNA via retroviral transduction into interleukin (IL)-3-dependent FDC-P1 cells
and examined the resulting phenotype. Compared with cells infected with a neo
encoding retrovirus (FD/neo), cells infected with a pim-1-transducing virus
(FD/hpim) showed longer survival or autonomous growth in suspension culture in
the absence of IL-3, as well as IL-3-independent clonogenic growth in semisolid
medium. The unique murine Mr 44,000 Pim-1 protein, as well as human proteins with
short C- or N-terminal truncations, also was biologically active. This effect of
Pim-1 expression was associated with a decrease in apoptotic cells and an
increase in G0/G1-phase cells, and the increase in G0/G1-phase cells caused by
enforced expression of Pim-1 was due to a decrease in apoptosis rather than to a
decrease in transit of the G1-S-phase checkpoint. The Pim-1 kinase appears to
function primarily as a survival factor in factor-dependent FDCP-1 cells
subjected to either cytokine withdrawal or exposure to cytotoxic agents.
PMID- 9393760
TI - Genomic organization and mutation analysis of Hel-N1 in lung cancers with
chromosome 9p21 deletions.
AB - Allelic loss of chromosome 9p21 is common in small cell lung cancer (SCLC), but
inactivation of the tumor suppressor gene CDKN2a is rare, implying the existence
of another target gene at 9p21. A recent deletion mapping study of chromosome 9p
has also identified a site of deletion in non-small cell lung cancer (NSCLC)
centered around D9S126. The Hel-N1 (human elav-like neuronal protein 1) gene
encodes a neural-specific RNA binding protein that is expressed in SCLC. We have
mapped this potentially important gene in lung tumorigenesis to within 100 kb of
the D9S126 marker at chromosome band 9p21 by using homozygously deleted tumor
cell lines and fluorescence in situ hybridization to normal metaphase spreads.
Hel-N1 is, therefore, a candidate target suppressor gene in both SCLC and NSCLC.
We have determined the genomic organization and intron/exon boundaries of Hel-N1
and have screened the entire coding region for mutations by sequencing 14 primary
SCLCs and cell lines and 21 primary NSCLCs preselected for localized 9p21
deletion or monosomy of chromosome 9. A homozygous deletion including Hel-N1 and
CDKN2a was found in a SCLC cell line, and a single-base polymorphism in exon 2 of
Hel-N1 was observed in eight tumors. No somatic mutations of Hel-N1 were found in
this panel of lung tumors. Hel-N1 does not appear to be a primary inactivation
target of 9p21 deletion in lung cancer.
PMID- 9393761
TI - Role of O6-methylguanine-DNA methyltransferase in the resistance of pancreatic
tumors to DNA alkylating agents.
AB - Pancreatic adenocarcinomas rarely respond to radiation or chemotherapy,
indicating that a large percentage of these tumors possess complex mechanisms of
resistance. The failure of alkylating agents, such as carmustine [1,3-bis(2
chloroethyl)-1-nitrosourea; BCNU], lomustine [1-(2-chloroethyl)-3-cyclohexyl-1
nitrosourea; CCNU], and streptozotocin, to yield consistent therapeutic results
further suggests that one of these mechanisms may be the high expression of O6
methylguanine-DNA methyltransferase (MGMT). All 12 human pancreatic ductal
adenocarcinomas assayed for MGMT activity showed unusually high levels, implying
that these malignancies are efficient in repairing genotoxic O6-alkylguanine
lesions induced by methylating (streptozotocin) and 2-chloroethylating (BCNU and
CCNU) chemotherapeutic genotoxic agents. Immunohistochemical analysis of an
additional 15 pancreatic tumors showed that high levels of MGMT protein reside in
the nucleus and the cytoplasm of malignant cells. Both nuclear and cytoplasmic
staining were absent in hyperplastic duct epithelium, but staining was invariably
present in moderate to highly dysplastic foci and especially strong in invasive
components of the tumor. With the exception of lymphocytes that were MGMT
positive, acinar, ductal, and islet cells did not stain for MGMT in
histologically normal pancreata. These data indicate that MGMT activity is up
regulated in dysplastic epithelium, and its expression increases during tumor
progression, reaching the highest levels in the invasive components of the tumor.
Resistance of pancreatic tumor cells to alkylating agents was verified with four
pancreatic tumor cell lines. CAPAN-2, CFPAC-1, PANC-1, and MIAPaCa-2, having MGMT
levels of 1800, 987, 700, and 880 fmol/mg protein, respectively, were resistant
to BCNU, but their resistance declined sharply following pretreatment with the
MGMT inhibitor O6-benzylguanine (O6-BG). On the other hand, PANC-1 and MIAPaCa-2
could not be eradicated with N-methylnitrosourea (MNU) at concentrations as high
as 2 mM, even when pretreated with O6-BG. These two lines were shown to be
modified genetically in microsatellite sequences by MNU and are believed to have
a defective mismatch repair system, which may explain their resistance to
methylating agents. Failure of pancreatic tumors to respond to nitrosoureas is
related to high levels of MGMT expression and in some cases to genomic
instability. However, these tumors can be sensitized to chloroethylating drugs
and eradicated following the elimination of MGMT activity by O6-BG or homologous
MGMT inhibitors.
PMID- 9393762
TI - Fibroblast growth factor receptor 2 limits and receptor 1 accelerates
tumorigenicity of prostate epithelial cells.
AB - Progressive loss of the differentiated phenotype and communication with stroma
accompanies the transition of nonmalignant rat prostate epithelial cells to
anaplastic, malignant tumors. Here we show that cell surface expression of the
fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase is reduced in
malignant tumor cell populations (type II) and undetectable at the mRNA level in
30% of cells. This is in addition to the irreversible loss by splice switching of
the FGFR2 ectodomain that abrogates response to FGF-7 and homologues from the
stroma. One hundred % of type II malignant cells express FGFR1, which is normally
expressed in the stroma. Expression of the FGFR1 kinase in premalignant type I
tumor epithelial cells by transfection accelerated progression to the malignant
phenotype. In contrast to the FGFR2 kinase fused to the ectodomain of FGFR1, the
FGFR1 kinase failed initially to support a mitogenic response to FGF-2 in type I
tumor cells. However, the FGFR1-transfected cells acquired a mitogenic response
after extensive proliferation of the cell population. Resident FGFR2 and ectopic
FGFR1 appeared to be partitioned in the type I cells, because neither full-length
nor truncated isoforms of FGFR1 affected the mitogenic response of the other.
Restoration of the FGFR2IIIb kinase to malignant cells expressing FGFR1 depressed
tumor growth rates, restored responsiveness to stromal cells, and restored
epithelial cell differentiation. These observations reveal that homologous FGFR1
and FGFR2 kinases play very different roles in cell growth and differentiation
and in development and support of the malignant phenotype.
PMID- 9393763
TI - Molecular evidence that most but not all carcinosarcomas of the uterus are
combination tumors.
AB - The pathogenesis of carcinosarcoma is still a subject of controversy. In the
present study, molecular techniques were applied to determine the pathogenesis of
uterine carcinosarcomas. The patterns of chromosome X inactivation were analyzed,
targeting a portion of exon 1 of the human androgen receptor (HUMARA) in
malignant epithelial and mesenchymal components. The presence of p53 and K-ras
mutations were also analyzed. H&E-stained sections of paraffin-embedded, formalin
fixed tissues were microdissected to obtain both epithelial and nonepithelial
lesions from 25 carcinosarcomas, and DNAs were extracted by proteinase K
digestion. Following treatment with methylation-sensitive restriction
endonuclease (HhaI or HpaII), PCR amplification was performed using nested
primers targeted to the HUMARA locus. Mutations in the p53 gene and K-ras gene
were found in eight (32%) and six (24%) tumors, respectively. The patterns of
chromosome X inactivation were different between the carcinomatous and
sarcomatous components of three carcinosarcomas, indicating that these three
tumors represent collision tumors. By contrast, the patterns of chromosome X
inactivation, K-ras sequence, and p53 sequence were identical in both
carcinomatous and sarcomatous components in 21 carcinosarcomas, indicating that
these 21 tumors represent combination tumors. One case produced equivocal results
that precluded determination of whether it represented a collision or combination
tumor. These observations show that although most carcinosarcomas are combination
tumors, some develop as collision tumors. The determination of histogenesis in
individual cases of carcinosarcoma using molecular markers may be worthwhile,
because the result could help predict the prognosis of individual cases and help
guide clinical management.
PMID- 9393764
TI - The osteoclast-associated protease cathepsin K is expressed in human breast
carcinoma.
AB - Human cathepsin K is a novel cysteine protease previously reported to be
restricted in its expression to osteoclasts. Immunolocalization of cathepsin K in
breast tumor bone metastases revealed that the invading breast cancer cells
expressed this protease, albeit at a lower intensity than in osteoclasts. In situ
hybridization and immunolocalization studies were subsequently conducted to
demonstrate cathepsin K mRNA and protein expression in samples of primary breast
carcinoma. Expression of cathepsin K mRNA was confirmed by reverse transcription
PCR and Southern analysis in a number of human breast cancer cell lines and in
primary human breast tumors and their metastases. As this protease is known to
degrade extracellular matrix, including bone matrix proteins, it is possible that
cathepsin K may contribute to the invasive potential of breast cancer cells,
including those that metastasize to bone. Thus, cathepsin K may be a potential
target leading to the design of novel drugs for cancer therapy.
PMID- 9393765
TI - Met and hepatocyte growth factor/scatter factor expression in human gliomas.
AB - Using double immunofluorescence staining and quantitative confocal laser scan
microscopy, we show that the intensity of hepatocyte growth factor/scatter factor
(HGF/SF) and Met staining in human primary brain tumors increases with the grade
of malignancy and is prevalent in both the infiltrating tumor cells and
endothelial hyperplastic areas. HGF/SF and Met also are expressed in vitro in
glioblastoma multiforme cell lines as well as in normal human astrocyte (NHA)
cells. Moreover, HGF/SF stimulates tyrosine phosphorylation of Met in both glioma
cell lines and NHA cells, but only the glioma cell lines proliferate and become
motile and invasive in response to HGF/SF, whereas the NHA cells are
nonresponsive. These results implicate autocrine/paracrine Met-HGF/SF signaling
in glioma tumorigenesis and suggest that HGF/SF signaling through Met is
negatively regulated in NHA cells.
PMID- 9393766
TI - Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters
cell adhesion in vitro, enhances metastatic behavior in vivo, and activates Jun
kinase.
AB - Point mutations, deletions, and recombinations of the RET proto-oncogene are
associated with several inherited human diseases of neural crest-derived cells:
Hirschsprung's disease, familial medullary thyroid carcinoma, and the multiple
endocrine neoplasia (MEN) syndromes, types 2A and 2B. RET expression is
restricted to normal and malignant cells of neural crest origin, such as human
neuroblastoma cells. To better understand the role of the activated RET oncogene
in neural crest cells, we transfected two adherent human neuroblastoma tumor cell
lines with oncogenic MEN2 mutant RET cDNAs. Transfectant clones from both cell
lines overexpressing MEN2B RET demonstrated a marked increase in the cell
fraction growing in suspension. Both control and MEN2B cells formed tumors at the
site of injection in all cases. However, mice injected with MEN2B cells developed
lung metastases at a much higher frequency than control mice. Only RET protein
derived from MEN2A transfectant cells had increased autokinase activity, whereas
MEN2B transfectant cells demonstrated selective activation of the mitogen
activated protein kinase, Jun kinase-1 (Jnk1). These results indicate a
biochemical signaling pathway that may link oncogenic RET with the metastatic
process.
PMID- 9393767
TI - Methyl-p-hydroxyphenyllactate-esterase activity in breast cancer: a potentially
new prognostic factor in short-term follow-up.
AB - We assayed methyl-p-hydroxyphenyllactate esterase (MeHPLAase) activity in 48
cases of primary breast cancer. MeHPLAase activity did not show significant
correlation with estrogen receptor and progesterone receptor levels. No
significant relationship was found between enzymatic activity and tumor diameter,
lymph node status, mitotic activity, degree of nuclear differentiation, and
proportion of the S-phase fraction. During the follow-up period (median, 18.8
months; range, 6-69 months), recurrences were observed in 18 of 48 (37%) cases.
The Weibull survival regression model using the enzymatic activity as a
continuous covariate showed that levels of enzymatic activity were directly
associated with the risk of recurrence (P = 0.02). Assuming the mean value of
enzymatic activity as the cutoff value, we found a statistically significant
relationship between high MeHPLAase activity and shorter recurrence-free
survival. On multivariate analysis, MeHPLAase activity proved to be an
independent factor for predicting a short period of recurrence-free survival.
PMID- 9393768
TI - Epidermal growth factor regulates protein kinase A activity in murine
fibrosarcoma cells: differences between metastatic and nonmetastatic tumor cell
variants.
AB - The interplay between cyclic AMP (cAMP)-dependent protein kinase A (PKA)- and
p21ras-mediated signaling pathways is expected to determine further loss,
maintenance, or modulation of differentiation and proliferation of a particular
cell. Therefore, the relationship and nature of the cross-talk between these two
major signaling systems are of utmost importance to the understanding of these
processes in both normal and neoplastic cells. In view of their paramount
physiological importance, one would expect the existence of a well-controlled
bidirectional interaction between these pathways, which would be more appropriate
and in agreement with basic principles of cellular homeostasis. However, based on
the discovery that activated PKA may inhibit ras-mediated translocation of c-Raf
1 to the plasma membrane, it is generally accepted that the cross-talk between
cAMP/PKA and p21ras-mediated signal transduction pathways is unilateral, i.e.,
that the activation of PKA regulates growth factor receptor protein tyrosine
kinase-mediated signaling. To challenge the validity of a unilateral approach, we
decided to test the possible existence of cross-talk of a bidirectional nature
between the aforementioned signaling pathways at different stages of malignant
differentiation. For that purpose, we investigated the nature of the cross-talk
existing between a known receptor protein tyrosine kinase-epidermal growth factor
receptor (EGFR) and PKA in highly metastatic and nonmetastatic cloned variants of
a murine fibrosarcoma (T-10). Our study revealed the existence of principal
differences in PKA activity between metastatic and nonmetastatic cloned
fibrosarcoma variants that may be due to the differential expression and membrane
translocation of the p21(Ki-ras) small mass G-protein. Most importantly, our
experiments have demonstrated the existence of a novel character of interactions
between EGFR and PKA, because the ligation of the EGFR by epidermal growth factor
in the metastatic variant induced a high activity of PKA. These findings are of
prime importance, because they reveal the existence of a new relationship between
two major signal transduction pathways in mammalian cells, i.e., the existence of
a bilateral interaction between the ras- and cAMP/PKA-mediated signal
transduction pathways. Furthermore, the fact that two tumor cell variants
originating in the same tumor and differing in their metastatic capacity differ
as well in the nature of the cross-talk between major signal generation systems
imposes new challenges for the future use of biological response modulators to
cure cancer and restrict metastatic spread.
PMID- 9393769
TI - Fibronectin secretion from human peritoneal tissue induces Mr 92,000 type IV
collagenase expression and invasion in ovarian cancer cell lines.
AB - Our previous study showed that human peritoneal conditioned medium (CM) increased
the matrix metalloproteinase-9 (MMP-9) secretion and invasiveness of ovarian
cancer cells (NOM1). In an effort to identify this MMP-9-stimulating factor, we
examined the effects of extracellular matrix components, such as type IV
collagen, laminin, and fibronectin, on ovarian cancer cells. We found that
fibronectin increased the MMP-9 activity of NOM1 cell CM in a concentration
dependent manner and that the peritoneal CM contained high level of fibronectin.
An increase of MMP-9 activity in NOM1 cell CM by the peritoneal CM was almost
completely blocked by 20 microg/ml of anti-integrin alpha5/FnR antibody and RGD
polypeptides. Furthermore, after immunoprecipitation by antifibronectin antibody
supernatant of the peritoneal CM did not increase MMP-9 activity in NOM1 cells.
Fibronectin and the peritoneal CM also increased MMP-9 activity and expression in
NOM1 cell lysate, and these effects were blocked by anti-integrin alpha5/FnR
antibody. Invasiveness of NOM1 cells was enhanced by fibronectin and the
peritoneal CM in a concentration-dependent manner, and anti-integrin alpha5/FnR
antibody blocked these effects. These results suggested that fibronectin secreted
from peritoneum increased MMP-9 activity and expression, and, in turn,
invasiveness of ovarian cancer cells.
PMID- 9393770
TI - Vascular endothelial growth factor up-regulates its receptor fms-like tyrosine
kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial
cells.
AB - The growth of solid tumors and the formation of metastases are dependent on
neoangiogenesis. One of the most important factors in inducing the formation of
new blood vessels is the vascular endothelial growth factor (VEGF), which acts
specifically on endothelial cells. VEGF is expressed and secreted by almost all
solid tumors. The molecular mechanisms leading to enhanced production of this
angiogenic mitogen are manyfold and have been elucidated to some degree. Two VEGF
receptors, fms-like tyrosine kinase 1 (FLT-1) and KDR, have been identified
almost specifically on human endothelial cells. They are expressed preferentially
in the proliferating endothelium of vessels lining and/or penetrating solid
tumors, whereas they are almost undetectable by convenient methods in vessels of
healthy tissue. However, the underlying mechanisms are not understood. We could
show that media conditioned by various cancer cell lines grown under hypoxic
conditions were able to up-regulate expression of FLT-1 mRNA and protein but not
of KDR mRNA. Furthermore, up-regulation of a shorter mRNA species was observed
that most probably codes for the soluble variant of FLT-1. These effects were
completely inhibited by VEGF-neutralizing extracellular VEGF receptor domains.
The effect could be mimicked by adding recombinant VEGF instead of conditioned
cancer cell medium to the endothelial cell cultures. Both mutant VEGF, which
activates only KDR, and placenta growth factor, which activates only FLT-1, were
able to enhance FLT-1 expression. VEGF-stimulated FLT-1 mRNA expression was
inhibited by actinomycin D. These data suggest that VEGF itself is the main
factor secreted by tumor cells that is able to enhance the expression of its
receptor FLT-1 and of a soluble variant of FLT-1 in endothelial cells.
PMID- 9393771
TI - Posttranscriptional regulation of protein expression in human epithelial
carcinoma cells by adenine-uridine-rich elements in the 3'-untranslated region of
tumor necrosis factor-alpha messenger RNA.
AB - Eukaryotic mRNAs contain 3'-untranslated regions (UTR) that are involved in
posttranscriptional control of gene expression. AU-rich octanucleotide repeats,
UUAUUUAU, present in the 3'-UTR of mature lymphokine and other cytokine
transcripts, have been implicated in the regulation of mRNA stability and
translational efficiency. For example, previous evidence suggests that the AU
rich element (ARE) present in the 3'-UTR of murine tumor necrosis factor-alpha
(TNF-alpha) can affect the posttranscriptional regulation of murine TNF-alpha
gene expression in hematopoietic cells. Although cytokines are produced in
epithelial cells, little is known about the regulation of TNF-alpha and other
cytokine gene expression by 3'-UTR elements in human malignant epithelial cells.
To better understand the function of the 3'-UTR of the human TNF-alpha gene in
the regulation of TNF-alpha protein production in human epithelial cancer cells,
a series of luciferase reporter constructs with portions of the 3'-UTR of human
TNF-alpha was transfected into human breast carcinoma cell lines ZR-75-1 and ZR
75-1R (which overexpresses TNF-alpha). The 3'-UTR of TNF-alpha markedly
suppressed luciferase activity in both cell lines, and the suppression of
activity was reversed by deletion of the AU-rich sequences. This suppression was
quantitative, with six repeats causing more inhibition than two repeats.
Increased levels of luciferase activity were observed 3 h after TNF-alpha
stimulation in ZR-75-1 cells transfected by constructs containing AU-rich
repeats. In addition, cytoplasmic extracts from both cell lines were assayed for
factors that bind to the 3'-UTR of human TNF-alpha mRNA. RNA-protein binding
activities were found in both cell lines. Competition studies showed that these
proteins specifically bound to AU-rich repeats present in the 3'-UTR of TNF
alpha. No binding activity was observed when the AU-rich repeats were deleted.
TNF-alpha exposure markedly increased activity of several RNA-binding proteins,
especially a novel Mr 50,000-55,000 RNA-binding protein. The binding activity in
untreated ZR-75-1R was higher than that in untreated ZR-75-1 cells, suggesting
that the level of RNA-protein binding correlates with the expression level of TNF
alpha in human epithelial cancer cells and that the RNA-binding proteins may
control expression of TNF-alpha in ZR-75-1 cells. We conclude that the AU-rich
repeats in the 3'-UTR of human TNF-alpha mRNA may regulate gene expression in
human epithelial cancer cells by binding to AU sequence-specific proteins,
including a previously undescribed Mr 50,000-55,000 protein not observed in
hematopoietic cells.
PMID- 9393772
TI - Correspondence re: J. S. DeFrank et al., p53-null cells are more sensitive to
ultraviolet light only in the presence of caffeine. Cancer Res., 56: 5365-5368,
1996.
PMID- 9393774
TI - Role of gamma interferon in natural clearance of Bordetella pertussis infection.
AB - Using a mouse model of Bordetella pertussis infection, we have analyzed the role
of gamma interferon (IFN-gamma) in bacterial clearance from the respiratory
tract. Adult BALB/c mice began to clear a respiratory infection within 3 weeks
postinfection, with complete resolution of infection 6 to 8 weeks postinfection.
In contrast, neither adult SCID mice (which lack mature B and T lymphocytes) nor
adult nude mice (which lack mature T lymphocytes) controlled B. pertussis
infection, and both strains died within 3 to 5 weeks postinfection. Short-term T
cell lines generated from the draining lymph nodes of the lungs of infected
BALB/c mice were found to be CD4+ and produced IFN-gamma but no detectable
interleukin-4. Analyses of IFN-gamma mRNA induction in the lungs of mice
following B. pertussis infection showed that in both BALB/c and C57BL/6 mice, IFN
gamma mRNA levels increased sharply by 1 week postinfection and then subsequently
declined. Further exploration of a potential role for IFN-gamma demonstrated that
infection of adult BALB/c mice depleted of IFN-gamma in vivo with anti-IFN-gamma
monoclonal antibodies resulted in greater numbers of bacteria recovered from the
lungs than in infected, control BALB/c mice, although IFN-gamma-depleted mice
could subsequently clear the infection. Infection of mice which have a disrupted
IFN-gamma gene resulted in bacterial clearance with a time course similar to
those seen with IFN-gamma-depleted mice. These results indicate that IFN-gamma
plays a role in controlling B. pertussis infection.
PMID- 9393773
TI - Interleukin-12 is critical for induction of nitric oxide-mediated
immunosuppression following vaccination of mice with attenuated Salmonella
typhimurium.
AB - Studies from our laboratory have shown that infection of mice with an attenuated
strain of Salmonella typhimurium causes a marked suppression in the capacity of
splenocytes to generate an in vitro plaque-forming cell (PFC) response to sheep
erythrocytes. The suppression has been shown to be mediated by mature, adherent
macrophages (Mphis) and nonadherent, precursor Mphis. Nitric oxide has been
identified as the suppressor factor. The present study investigated the role of
interleukin-12 (IL-12) in the generation of nitric oxide-mediated
immunosuppression in this model. Salmonella inoculation resulted in marked
suppression of PFC responses and high levels of nitrite production. When mice
were treated with anti-IL-12 prior to inoculation, nitrite levels in splenocyte
cultures were reduced by 75% and the suppression of PFC responses was prevented.
The nonadherent splenocyte fraction from Salmonella-inoculated mice, which
contains precursor Mphis and is weakly immunosuppressive, was treated with IL-12
in vitro. IL-12 augmented the capacity of this fraction to suppress PFC responses
by normal splenocytes in a coculture system. Additionally, IL-12 induced nitrite
and gamma interferon (IFN-gamma) production in a dose-dependent manner. Treatment
with anti-IFN-gamma blocked nitrite production and suppression, indicating that
IFN-gamma is an important intermediary in the pathway of IL-12-induced
immunosuppression. These results indicate that IL-12 is critical for the
induction of nitric oxide-mediated immunosuppression following S. typhimurium
inoculation and, through its ability to stimulate IFN-gamma production, can
induce nitric oxide-producing suppressor Mphis.
PMID- 9393775
TI - A gene homologous to Saccharomyces cerevisiae SNF1 appears to be essential for
the viability of Candida albicans.
AB - The SNF1 gene of Saccharomyces cerevisiae (ScSNF1) is essential for the
derepression of catabolic repression. We report here the isolation and
characterization of an SNF1 homolog from Candida albicans (CaSNF1) which is
apparently essential for the viability of this organism. The putative amino acid
sequence of CaSNF1 has 68% identity with that of ScSNF1 and can restore the S.
cerevisiae snf1 delta mutant's ability to utilize sucrose. Disruption of one of
the CaSNF1 alleles resulted in morphological changes and decreased growth rates
but did not modify the carbon source utilization pattern. Repetitive unsuccessful
attempts to generate a snf1/snf1 homozygote by disruption of the second allele,
using various vectors and approaches, suggest the lethal nature of this mutation.
Integration into the second allele was possible only when a full-length
functional SNF1 sequence was reassembled, further supporting this hypothesis and
indicating that the indispensability of Snf1p prevented the isolation of
snf1/snf1 mutants. The mutant bearing two disrupted SNF1 alleles and the SNF1
functional sequence maintained its ability to utilize sucrose and produced
stellate colonies with extensive hyphal growth on agar media. It was demonstrated
that in a mouse model, the virulences of this mutant and the wild-type strain are
similar, suggesting that hyphal growth in vitro is not an indicator for higher
virulence.
PMID- 9393776
TI - A strategy for rational design of fully synthetic glycopeptide conjugate
vaccines.
AB - The present study describes a strategy to rationally design fully synthetic
glycopeptide conjugate vaccines. Glycopeptide immunogens were constructed by
coupling synthetic oligosaccharides comprising repeating units of synthetic 3
beta-D-ribose-(1-1)-D-ribitol-5-phosphate (sPRP) to synthetic peptides containing
potent T-helper cell determinants and B-cell epitopes of the Haemophilus
influenzae type b (Hib) outer membrane proteins (OMPs) P1, P2, and P6. Rabbit
immunogenicity studies revealed that some of these fully synthetic
glycoconjugates were capable of eliciting high titers of both anti-PRP and anti
OMP immunoglobulin G antibodies. In addition, we systematically investigated the
factors which could influence their immunogenicity. We observed that the
magnitude of the anti-PRP antibody response markedly depended on the relative
spatial orientation of sPRP and T-cell epitopes, the anti-PRP antibody response
was enhanced when a multiple antigenic peptide was used as a carrier, the anti
PRP antibody response was optimal for three PRP repeating units, and lipidation
of peptide-PRP conjugates had a minimal effect on the magnitude of the anti-PRP
antibody response. The results of this study clearly demonstrate that coupling a
carbohydrate hapten to a peptide can provide T-cell help and convert it into a T
cell-dependent antigen. The antisera raised against these conjugates were also
found to be protective against Hib infection in the infant rat model of
bacteremia.
PMID- 9393777
TI - Murine model of recurrent group G streptococcal cellulitis: no evidence of
protective immunity.
AB - Despite the well-known tendency of cellulitis due to beta-hemolytic streptococci
to recur, little is known regarding the mechanisms of human immunity to this
infection. We established cellulitis in mice by using a strain of group G
streptococcus (1750) originally isolated from the bloodstream of a patient with
acute cellulitis. This strain, which has been studied extensively in our
laboratory, expresses M protein structurally and functionally analogous to that
of group A streptococci, and we have cloned and sequenced the gene encoding this
protein (emmMG1). Mice injected with 5 x 10(7) CFU of strain 1750 developed
nonlethal necrotic skin and soft tissue infections that healed spontaneously
after 14 to 16 days. After healing, the mice were repetitively reinoculated three
times with the same challenge dose of 1750. Lesion size did not decrease in
severity, size, or time to healing after repetitive challenge. The maximum lesion
size and tissue concentration of microorganisms increased between the first and
fourth challenges. Pretreatment of 1750 cells with opsonic antisera to MG1
diminished neither the maximum lesion size nor the time course of evolution of
the lesions. Thus, in the mouse model used here, there was no evidence of
acquired protective immunity to experimentally induced cellulitis.
PMID- 9393778
TI - Bacterial phospholipase C upregulates matrix metalloproteinase expression by
cultured epithelial cells.
AB - Phospholipase C (PLC) is a putative virulence factor of several pathogenic
bacteria. We studied if exogenous PLC would perturb epithelial behavior in
infected tissues. Gelatin and casein zymography of cell culture medium indicated
that the broad-spectrum PLC of Bacillus cereus induced matrix metalloproteinase
(MMP) production in epithelial cells of human skin (NHEK), human gingiva (HGE),
and porcine periodontal ligament (PLE). In all three cell types, the strongest
increase (ninefold) at 0.1 U/ml was seen in the MMP-9 (92-kDa gelatinase)
activity, and the effect was dose dependent in the range of 0.1 to 1.0 U/ml. A
relatively weaker increase (twofold) in MMP-2 (72-kDa gelatinase) was also
observed in each cell type. PLC induction of MMP-3 (48-kDa stromelysin) was also
seen in NHEK and HGE on gelatin and more sensitively for PLE by casein zymography
(fivefold). Total gelatinolytic activity as measured by degradation of 14C
labeled denatured type I collagen increased by about 18-fold (NHEK), 12-fold
(HGE), and 14-fold (PLE). Northern analysis showed a clear increase in the MMP-9,
and a minor increase in MMP-3 mRNA levels but no significant increase in MMP-2
mRNA levels. Further studies with PLE revealed that MMP-9 induction by PLC
progressively increased with the length of cell culture time in the absence of
serum. PLC induction of MMPs was polar, with MMP-9 and MMP-3 secreted primarily
in the apical direction and MMP-2 secreted mainly in the basal direction. The PLC
effect was blocked by neomycin, an inhibitor of the phosphoinositol signal
pathway. No significant effects were observed in MMP expression with the calcium
ionophore A23187 or phospholipase A2. Morphologically, PLC treatment resulted in
reduced contacts between the cultured cells and loss of the cell surface
microvilli. These results suggest that PLC secreted by bacterial pathogens may
disrupt epithelium of infected tissue and increase the subepithelial tissue
destruction through induction of MMPs.
PMID- 9393779
TI - Identification of N-acetylneuraminic acid and its 9-O-acetylated derivative on
the cell surface of Cryptococcus neoformans: influence on fungal phagocytosis.
AB - Sialic acids from sialoglycoconjugates present at the cell surface of
Cryptococcus neoformans yeast forms were analyzed by high-performance thin-layer
chromatography, binding of influenza A and C virus strains, enzymatic treatment,
and flow cytofluorimetry with fluorescein isothiocyanate-labeled lectins. C.
neoformans yeast forms grown in a chemically defined medium contain N
acetylneuraminic acid and its 9-O-acetylated derivative. A density of 3 x 10(6)
residues of sialic acid per cell was found in C. neoformans. Sialic acids in
cryptococcal cells are glycosidically linked to galactopyranosyl units as
inferred from the increased reactivity of neuraminidase-treated yeasts with
peanut agglutinin. N-Acetylneuraminic acids are alpha-2,6 and alpha-2,3 linked,
as indicated by using virus strains M1/5 and M1/5 HS8, respectively, as
agglutination probes. The alpha-2,6 linkage markedly predominated. These findings
were essentially confirmed by the interaction of cryptococcal cells with the
lectins Sambucus nigra agglutinin and Maackia amurensis agglutinin. We also
investigated whether the sialyl residues present in C. neoformans are involved in
the fungal interaction with a cationic solid-phase substrate and with mouse
resident macrophages. Adhesion of yeast cells to poly-L-lysine was mediated, in
part, by sialic acid residues, since the number of adherent cells was markedly
reduced after treatment with bacterial neuraminidase. The enzymatic removal of
sialic acids also made C. neoformans yeast cells more susceptible to endocytosis
by macrophages. The results show that sialic acids are components of the
cryptococcal cell surface that contribute to its negative charge and protect
yeast forms against phagocytosis.
PMID- 9393780
TI - Role of receptor binding in toxicity, immunogenicity, and adjuvanticity of
Escherichia coli heat-labile enterotoxin.
AB - The role of receptor binding in the toxicity, immunogenicity, and adjuvanticity
of the heat-labile enterotoxin of Escherichia coli (LT) was examined by comparing
native LT and LT(G33D), a B-subunit receptor binding mutant, with respect to the
ability to bind to galactose and to GM1, toxicity on mouse Y-1 adrenal tumor
cells, the ability to stimulate adenylate cyclase in Caco-2 cells, enterotoxicity
in the patent mouse model, and oral immunogenicity and adjuvanticity. In contrast
to native LT, LT(G33D) was unable to bind to the galactosyl moiety of Sepharose
4B or GM1 but did retain the lectin-like ability to bind to immobilized galactose
on 6% agarose beads. LT(G33D) had no enterotoxicity in the patent mouse model but
exhibited residual toxicity on mouse Y-1 adrenal tumor cells and had an ability
equivalent to that of native LT to stimulate adenylate cyclase in Caco-2 cells
(5,000 versus 6,900 pmol per mg of protein). In addition, LT(G33D) was unable to
serve as an effective oral adjuvant for induction of immunoglobulin G or A
directed against a coadministered antigen. Furthermore, LT(G33D) elicited
negligible serum and mucosal antibody responses against itself. These data
indicate that the toxicity, immunogenicity, and oral adjuvanticity of LT are
dependent upon binding of the B subunit to ganglioside GM1.
PMID- 9393781
TI - MTC28, a novel 28-kilodalton proline-rich secreted antigen specific for the
Mycobacterium tuberculosis complex.
AB - Proteins that are actively secreted by Mycobacterium tuberculosis serve as major
targets of immune responses in the infected host. To identify and purify novel
proteins in the filtrates of M. tuberculosis cultures, a bacteriophage lambda
library of M. tuberculosis H37Rv DNA was immunoscreened by using an anti-culture
filtrate rabbit antiserum. Of 20 positive clones isolated, 6 were analyzed and
found to express the genes for two known components of the early culture
filtrate, the secreted 45/47-kDa antigen complex and the KatG protein, and two
novel genes. Here we report the molecular cloning and nucleotide sequence of one
of the new genes encoding a culture filtrate protein of 310 amino acid (aa)
residues. We called this gene mtc28. The deduced polypeptide sequence contained
an NH2-terminal, highly hydrophobic 32-aa region having properties of a secretion
signal peptide. The putative 278-aa mature MTC28 protein was characterized at its
NH2 and COOH termini by a high content of proline and alanine residues organized
in an (AP)n motif. Thus, MTC28 is a new member of a group of proline-rich
antigens found in M. tuberculosis and Mycobacterium leprae. As shown by DNA
hybridization experiments, the mtc28 gene was present only in species of the M.
tuberculosis complex. Purified recombinant MTC28 antigen evoked strong delayed
type hypersensitivity and antibody responses in guinea pigs immunized with
Mycobacterium bovis BCG, but not in guinea pigs immunized with Mycobacterium
avium. The strong immunological activity of MTC28 and the absence of B- and T
cell epitopes cross-reactive with a common environmental mycobacterial species,
such as M. avium, make this novel antigen an attractive reagent for
immunodiagnosis of tuberculosis.
PMID- 9393782
TI - Characterization of B-cell responses to Chlamydia trachomatis antigens in humans
with trachoma.
AB - The circulating B-cell responses to Chlamydia trachomatis of 60 children and 34
adults in The Gambia were characterized in a cross-sectional study of different
grades of trachoma, using the enzyme-linked immunospot (ELISPOT) assay. Antibody
secreting cells (ASCs) specific to chlamydial major outer membrane protein
(MOMP), heat shock protein 60, and whole elementary bodies were detected in
children with no evidence of ocular disease, and the immunoglobulin (IgA)
response was significantly increased in those with follicular trachoma. In marked
contrast, children with the most intense ocular inflammation paradoxically had an
almost completely absent B-cell response of all isotypes and to all chlamydial
antigens, but with normal serum IgG and IgA responses, which was even lower than
in the group with no ocular inflammation. Adults with or without evidence of
trachomatous scarring had equivalent numbers of circulating B cells, principally
IgA, to all chlamydial antigens. Plasmablasts secreting antibodies to MOMP were
present in the urine of children in the absence of urogenital infection
detectable by PCR, and relative numbers were 8 to 25 times higher than in blood,
suggesting site-specific homing within a common mucosal immune system. These
results suggest that ELISPOT assay of ongoing B-cell responses detects
suppression of chlamydia-specific IgA ASCs during the proinflammatory response to
ocular chlamydial infection seen in intense trachoma, which may play a role in
tissue damage leading to trachomatous scarring.
PMID- 9393783
TI - Expression of the superantigen Mycoplasma arthritidis mitogen in Escherichia coli
and characterization of the recombinant protein.
AB - Mycoplasma arthritidis mitogen (MAM), is a soluble protein with classical
superantigenic properties and is produced by an organism that causes an acute and
chronic proliferative arthritis. Unfortunately, the process of obtaining purified
MAM from M. arthritidis culture supernatants is extremely time-consuming and
costly, and very little material is recovered. Thus, our laboratory has expressed
MAM in Escherichia coli by using a protein fusion expression system. The
construction and expression of recombinant MAM (rMAM), as well as a comparison of
the biological properties of rMAM to those of native MAM, are discussed. Briefly,
conversion of the three UGA codons to UGG codons was required to obtain full
length expression and mitogenic activity of rMAM. Antisera to native MAM
recognized both rMAM and the fusion protein. The T-cell receptor Vbeta and major
histocompatibility complex class II receptor usages by rMAM and the fusion
protein were identical to that of native MAM. In addition, the ability to induce
suppression and form the superantigen bridge could also be demonstrated with
rMAM. Importantly, dose-response experiments indicated that homogeneous native
MAM and rMAM were of equal potency. Thus, MAM has been successfully expressed in
E. coli, thereby creating a viable alternative to native MAM.
PMID- 9393784
TI - Identification and characterization of a two-component regulatory system involved
in invasion of eukaryotic cells and heavy-metal resistance in Burkholderia
pseudomallei.
AB - Burkholderia pseudomallei is the causative agent of melioidosis, a disease
increasingly recognized as an important cause of morbidity and mortality in many
regions of the world. B. pseudomallei is a facultative intracellular pathogen
capable of invading eukaryotic cells. We used Tn5-OT182 mutagenesis to generate
mutants deficient in the ability to invade a human type II pneumocyte cell line
(A549 cells). One of these mutants, AJ1D8, exhibited approximately 10% of the
ability of the parental strain, 1026b, to invade A549 cells. There was no
difference in the abilities of 1026b and AJ1D8 to resist killing by RAW
macrophages or the human defensin HNP-1. The nucleotide sequence flanking the Tn5
OT182 integration in AJ1D8 was determined, and two open reading frames were
identified. The predicted proteins shared considerable homology with two
component regulatory systems involved in the regulation of heavy-metal resistance
in other organisms. AJ1D8 was 16-fold more sensitive to Cd2+ and twofold more
sensitive to Zn2+ than was 1026b but was not sensitive to any of the other heavy
metals examined. The B. pseudomallei two-component regulatory system, termed
irlRS, complemented the invasion-deficient and heavy-metal-sensitive phenotype of
AJ1D8 in trans. There was no significant difference between the virulence of
AJ1D8 and that of 1026b in infant diabetic rats and Syrian hamsters, suggesting
that the irlRS locus is probably not a virulence determinant in these animal
models of acute B. pseudomallei infection.
PMID- 9393786
TI - Production of Vibrio cholerae accessory cholera enterotoxin (Ace) in the yeast
Pichia pastoris.
AB - Accessory cholera enterotoxin (Ace) is a recently identified toxin of Vibrio
cholerae. Preliminary studies using crude toxin extracts in animal models
indicate that Ace increases transcellular ion transport, which is proposed to
contribute to diarrhea in cholera. The lack of purified toxin has hindered
elucidation of the mechanism of action of Ace. In this study, ace was cloned and
was expressed in and secreted by the methylotrophic yeast Pichia pastoris.
Secreted toxin constituted 50% of the total supernatant protein from Pichia
pastoris. Presumed monomer and dimer forms with molecular masses of 9 and 18 kDa,
respectively, were observed. The 18-kDa form predominated. Biological activity
was assayed by studying ion fluxes across epithelial membranes in Ussing
chambers. Among the characteristics of Ace was the unusual property of staining
with silver but not Coomassie blue stain. To our knowledge this is the first
report of a biologically active bacterial toxin produced with the P. pastoris
system. The purified protein may now be used in studies of the mechanism of
action of Ace in physiologic systems.
PMID- 9393785
TI - Progression of visceral leishmaniasis due to Leishmania infantum in BALB/c mice
is markedly slowed by prior infection with Trichinella spiralis.
AB - We investigated in BALB/c mice the influence of the immunological environment
created by the nematode Trichinella spiralis on the course of visceral
leishmaniasis due to Leishmania infantum. On the day of Leishmania inoculation
(day 0), mice, T. spiralis infected 7 days earlier, presented increased gamma
interferon (IFN-gamma), interleukin-4 (IL-4), and IL-5 mRNA levels locally and
systemically and increased the potential of spleen cells to synthesize IFN-gamma
and IL-4 after activation in vitro. Eighteen days after Leishmania inoculation
(day 18), corresponding to the acute phase of leishmaniasis, the hepatic
amastigote burden in mice coinfected with L. infantum and T. spiralis (LT mice)
was significantly lower (P < 0.001) than that in mice infected with L. infantum
only (L mice). IFN-gamma and IL-4 mRNAs were overexpressed in livers of LT and L
mice. On day 70, corresponding to the chronic phase, the splenic amastigote load
was significantly lower (P = 0.004) in LT mice than it was in L mice. Splenic IFN
gamma transcripts were overexpressed in both L and LT mice. After Leishmania
specific in vitro stimulation, cytokine production was enhanced in both groups,
but spleen cells from L mice produced significantly more IFN-gamma than did
spleen cells from LT mice. Our data (i) generalize previous results indicating
the lack of a clear-cut correlation between the outcome of murine visceral
leishmaniasis and the type of cytokine pattern and (ii) demonstrate that in LT
mice, leishmaniasis takes a markedly milder course than it does in L mice,
providing information on the potential consequences of coinfection in a mammalian
host.
PMID- 9393787
TI - Isolation, cloning, and expression of a 70-kilodalton plasminogen binding protein
of Borrelia burgdorferi.
AB - Surface receptors for plasminogen are expressed by many gram-positive and gram
negative bacteria and may play a role in the dissemination of organisms by
binding plasminogen, which upon conversion to plasmin can digest extracellular
matrix proteins. Two plasminogen binding proteins have been identified for
Borrelia burgdorferi, outer surface protein A and a 70-kDa protein (BPBP). We
purified BPBP by plasminogen affinity chromatography and obtained its amino acid
sequence by Edman degradation of a tryptic digest. The gene coding for BPBP was
isolated from a lambda-ZAP II genomic library with probes developed from
sequenced portions of the protein. This gene was expressed in Escherichia coli;
the recombinant product was seen by antibody raised against native BPBP and also
bound 125I-labeled plasminogen. The experimentally derived amino acid sequences
corresponded to the predicted sequence encoded by the BPBP gene. The deduced
amino acid sequence for BPBP revealed significant similarity to p30, a 30-kDa
protein of B. burgdorferi (54% identity and 65% similarity), to a 60-kDa protein
in Borrelia coriaceae (66% identity and 80% similarity), to oligopeptide binding
protein A of E. coli (34% identity and 57% similarity), and, more generally, to
the periplasmic oligopeptide binding family of proteins.
PMID- 9393788
TI - Therapeutic intragastric vaccination against Helicobacter pylori in mice
eradicates an otherwise chronic infection and confers protection against
reinfection.
AB - Chronic infection of the gastroduodenal mucosae by the gram-negative spiral
bacterium Helicobacter pylori is responsible for chronic active gastritis, peptic
ulcers, and gastric cancers such as adenocarcinoma and low-grade gastric B-cell
lymphoma. The success of eradication by antibiotic therapy is being rapidly
hampered by the increasing occurrence of antibiotic-resistant strains. An
attractive alternative approach to combat this infection is represented by the
therapeutic use of vaccines. In the present work, we have exploited the mouse
model of persistent infection by mouse-adapted H. pylori strains that we have
developed to assess the feasibility of the therapeutic use of vaccines against
infection. We report that an otherwise chronic H. pylori infection in mice can be
successfully eradicated by intragastric vaccination with H. pylori antigens such
as recombinant VacA and CagA, which were administered together with a genetically
detoxified mutant of the heat-labile enterotoxin of Escherichia coli (referred to
as LTK63), in which the serine in position 63 was replaced by a lysine. Moreover,
we show that therapeutic vaccination confers efficacious protection against
reinfection. These results represent strong evidence of the feasibility of
therapeutic use of VacA- or CagA-based vaccine formulations against H. pylori
infection in an animal model and give substantial preclinical support to the
application of this kind of approach in human clinical trials.
PMID- 9393789
TI - Transient control of interleukin-4-producing natural killer T cells in the livers
of Listeria monocytogenes-infected mice by interleukin-12.
AB - Unconstrained development of gamma interferon (IFN-gamma)-secreting natural
killer (NK) cells and T helper (Th) 1 cells is central to protection against
Listeria monocytogenes. In contrast, interleukin 4 (IL-4) is considered harmful.
IL-12 produced by infected macrophages promotes, and IL-4 interferes with,
protective antilisterial immunity. The liver NK T lymphocytes, which are a potent
source of IL-4, are downregulated at an intermediate stage of listeriosis. Here
we demonstrate that endogenous IL-12 participates in the control of IL-4
producing liver NK T lymphocytes during listeriosis. The effects of L.
monocytogenes infection on IL-4-producing liver NK T lymphocytes were reversed by
antibody neutralization of IL-12 but not of IFN-gamma or tumor necrosis factor
alpha (TNF-alpha). IL-4 production by liver NK T lymphocytes was virtually
unaffected by heat-killed L. monocytogenes (HKL). Viable L. monocytogenes
markedly increased the numbers of IL-12 producers in livers in parallel with an
increase in macrophage numbers, whereas HKL failed to do so with similar
efficiency. These results indicate that in the liver endogenous IL-12 improves
protective immunity against listeriosis by downregulating IL-4-producing NK T
lymphocytes. Moreover, our findings that HKL have a low level of IL-12-inducing
activity and fail to control IL-4-producing NK T lymphocytes in the liver are
consistent with the lesser protective capacity of HKL compared to that of live
listeriae.
PMID- 9393790
TI - The acylated form of protein D of Haemophilus influenzae is more immunogenic than
the nonacylated form and elicits an adjuvant effect when it is used as a carrier
conjugated to polyribosyl ribitol phosphate.
AB - The nonacylated form of protein D (PDm) of Haemophilus influenzae has been shown
to induce the production of antibodies that are bactericidal to homologous and
heterologous nontypeable H. influenzae (NTHi) strains. In this study,
immunization of rats with lipoprotein D (LPD) induced higher levels of anti
protein D immunoglobulin G and A serum antibodies than immunization with PDm, and
the bactericidal activities of sera from LPD-immunized rats were greater than
those of sera from PDm-immunized rats. Immunization with LPD or PDm did not
prevent the development of acute otitis media (AOM) when rats were challenged
with 10(4) CFU of an NTHi strain. However, on the eighth day of bacterial
challenge, 50% (5 of 10) of LPD-immunized rats had recovered from otitis media
and 30% (3 of 10) had negative middle ear cultures, whereas only 30% (3 of 10) of
PDm-immunized rats had recovered, though none was culture positive. Immunization
with an inactivated homologous bacterial strain elicited 70% protection (i.e., 7
of 10 rats) in the rat otitis media model. LPD and PDm were also conjugated to
the H. influenzae type b (Hib) capsular polysaccharide, polyribosyl ribitol
phosphate (PRP), to test protein D-conjugated PRP vaccine's potential for
protection against Hib infection. When two LPD-conjugated and two PDm-conjugated
PRP vaccines, each containing a different protein concentration, and a tetanus
toxoid-conjugated vaccine (ACT-HIB) were tested in the experimental model of rat
otitis induced with a Hib strain (Minn A), both of the LPD-conjugated and one of
the PDm-conjugated vaccines induced significant protection from AOM, the level of
protection being highest in animals given the vaccine with the highest LPD
content. Sera from these rats also manifested the highest anti-PRP and anti-LPD
antibody levels and the highest bactericidal activities against a Hib strain and
an NTHi strain.
PMID- 9393791
TI - Variable number of tandem repeats in clinical strains of Haemophilus influenzae.
AB - An algorithm capable of identifying short repeat motifs was developed and used to
screen the whole genome sequence available for Haemophilus influenzae, since some
of these repeats have been shown to affect bacterial virulence. Various di- to
hexanucleotide repeats were identified, confirming and extending previous
findings on the existence of variable-number-of-tandem-repeat loci (VNTRs).
Repeats with units of 7 or 8 nucleotides were not encountered. For all of the 3-
to 6-nucleotide repeats in the H. influenzae chromosome, PCR tests capable of
detecting allelic polymorphisms were designed. Fourteen of 18 of the potential
VNTRs were indeed highly polymorphic when different strains were screened. Two of
the potential VNTRs appeared to be short and homogeneous in length; another one
may be specific for the H. influenzae Rd strain only. One of the primer sets
generated fingerprint-type DNA banding patterns. The various repeat types
differed with respect to intrinsic stability as well. It was noted for separate
colonies derived from a single clinical specimen or strains passaged for several
weeks on chocolate agar plates that the lengths of the VNTRs did not change. When
several strains from different patients infected during an outbreak of lung
disease were analyzed, increased but limited variation was encountered in all
VNTR sites analyzed. One of the 5-nucleotide VNTRs proved to be hypervariable.
This variability may reflect the molecular basis of a mechanism used by H.
influenzae bacteria to successfully colonize and infect different human
individuals.
PMID- 9393792
TI - Natural proteoglycan receptor analogs determine the dynamics of Opa adhesin
mediated gonococcal infection of Chang epithelial cells.
AB - Many bacterial pathogens possess a complex machinery for the induction and/or
secretion of factors that promote their uptake by mammalian cells. We searched
for the molecular basis of the 60- to 90-min lag time in the interaction of
Neisseria gonorrhoeae carrying the heparin-binding Opa adhesin with Chang
epithelial cells. Infection assays in the presence of chloramphenicol
demonstrated that the Opa-mediated gonococcal infection of Chang cells required
bacterial protein synthesis when the microorganisms were derived from GC agar but
not when grown in liquid media. Further analysis indicated that contact with agar
ingredients rather than the growth state of the microorganisms determined the
infection dynamics. DEAE chromatography of GC agar extracts and sodium dodecyl
sulfate-polyacrylamide gel electrophoresis analyses and testing of collected
fractions in infection assays identified negatively charged high-molecular-weight
polysaccharides in the agar as inhibitors of the cellular infection. Electron
microscopy showed that agar-grown gonococci were surrounded by a coat of alcian
blue-positive material, probably representing accreted polysaccharides. Similar
antiphagocytic material was isolated from bovine serum, indicating that in
biological fluids gonococci producing the heparin-binding Opa adhesin may become
covered with externally derived polysaccharides as well. Binding assays with
gonococci and epithelial proteoglycan receptors revealed that polysaccharides
derived from agar or serum compete with the proteoglycans for binding of the
heparin-binding Opa adhesin and thus act as receptor analogs. Growth of gonococci
in a polysaccharide-free environment resulted in optimal proteoglycan receptor
binding and rapid bacterial entry into Chang cells. The recognition that
gonococci with certain phenotypes can recruit surface polysaccharides that
determine in vitro infection dynamics adds a different dimension to the well
recognized biological significance of genetic variation for this pathogen.
PMID- 9393793
TI - Structural and antigenic types of cell wall polysaccharides from viridans group
streptococci with receptors for oral actinomyces and streptococcal lectins.
AB - Lectin-mediated interactions between oral viridans group streptococci and
actinomyces may play an important role in microbial colonization of the tooth
surface. The presence of two host-like motifs, either GalNAc beta1-->3Gal (Gn) or
Gal beta1-->3GalNAc (G), in the cell wall polysaccharides of five streptococcal
strains accounts for the lactose-sensitive coaggregations of these bacteria with
Actinomyces naeslundii. Three streptococcal strains which have Gn-containing
polysaccharides also participate in GalNAc-sensitive coaggregations with strains
of Streptococcus gordonii and S. sanguis. Each Gn- or G-containing polysaccharide
is composed of a distinct phosphodiester-linked hexa- or heptasaccharide
repeating unit. The occurrence of these polysaccharides on 19 additional viridans
group streptococcal strains that participate in lactose-sensitive coaggregations
with actinomyces was examined. Negatively charged polysaccharides that reacted
with Bauhinia purpurea agglutinin, a Gal and GalNAc binding plant lectin, were
isolated from 17 strains by anion exchange column chromatography of mutanolysin
cell wall digests. Results from nuclear magnetic resonance and immunodiffusion
identified each of 16 polysaccharides as a known Gn- or G-containing structural
type and one polysaccharide as a new but closely related Gn-containing type.
Unlike the reactions of lectins, the cross-reactions of most rabbit antisera with
these polysaccharides were correlated with structural features other than the
host-like motifs. Gn-containing polysaccharides occurred primarily on the strains
of S. sanguis and S. oralis while G-containing polysaccharides were more common
among the strains of S. gordonii and S. mitis examined. The findings strongly
support the hypothesis that lectin-mediated recognition of these streptococci by
other oral bacteria depends on a family of antigenically diverse Gn- and G
containing cell wall polysaccharides, the occurrence of which may differ between
streptococcal species.
PMID- 9393794
TI - A specific cell surface antigen of Streptococcus gordonii is associated with
bacterial hemagglutination and adhesion to alpha2-3-linked sialic acid-containing
receptors.
AB - A Ca2+-independent lectin activity for alpha2-3-linked sialic acid-containing
receptors is associated with Streptococcus gordonii DL1 (Challis) but not with a
spontaneous mutant, strain D102, that specifically lacks hemagglutinating
activity. Comparison of crossed-immunoelectrophoresis patterns of parent and
mutant sonicated cell extracts identified a unique antigen (Hs antigen) in the
parent cell extract that was purified by DEAE Sephacel column chromatography and
by a wheat germ agglutinin (WGA) lectin affinity column. The purified antigen
formed a single arc in crossed immunoelectrophoresis with anti-DL1 serum and
migrated as a diffuse band above the 200-kDa marker in sodium dodecyl sulfate
polyacrylamide gel electrophoresis. Immunoelectron microscopy with specific anti
Hs antibody revealed labeling of structures in the fibrillar layer of strain DL1
and no labeling of fibrillar structures on strain D102. Rabbit anti-DL1 serum and
anti-Hs Fab inhibited the hemagglutinating activity of strain DL1, and the
inhibition was specifically neutralized by purified Hs antigen. Anti-Hs Fab did
not inhibit the hemagglutinating activities of several heterologous S. gordonii
strains; however, these bacteria were agglutinated by anti-Hs immunoglobulin G
and also by WGA. In contrast, two S. gordonii strains that lacked
hemagglutinating activity did not react with anti-Hs antibody or with WGA. These
findings associate the sialic acid-binding lectin activity of S. gordonii DL1
with a specific fibrillar antigen, which is composed of protein and WGA reactive
carbohydrate, and indicate that cross-reactive antigens occur on other strains of
this species that possess hemagglutinating activity.
PMID- 9393795
TI - Protection against Pneumocystis carinii pneumonia by antibodies generated from
either T helper 1 or T helper 2 responses.
AB - To determine whether different antibody isotypes associated with T helper 1 (Th1)
or Th2 responses are protective against Pneumocystis carinii, mice with disrupted
interleukin 4 genes (IL-4(-/-) mice) or gamma interferon genes (IFN-gamma(-/-)
mice) along with wild-type C57BL/6 mice were immunized intratracheally against P.
carinii, depleted of T cells in vivo by use of monoclonal antibodies, and
rechallenged intratracheally with 10(7) viable P. carinii organisms. Nearly all
immunized mice resolved their lung P. carinii infections (limit of detection,
log10 4.06) within 21 days of challenge even though they were depleted of T
cells. Unimmunized mice depleted of T cells had significant lung infections
(>log10 5.5) at day 21 post-P. carinii challenge. IFN-gamma(-/-) and wild-type
mice developed P. carinii-specific immunoglobulin primarily of the immunoglobulin
G1 (IgG1) subclass with relatively little P. carinii-specific IgG2a, IgG2b, or
IgG3 in their sera, characteristic of a Th2-type response. In contrast, IL-4(-/-)
mice had primarily an IgG2b P. carinii-specific antibody response in their sera
with very little IgG1. Although IgG2b was the predominant isotype in IL-4(-/-)
mice, optical density values of IgG2a and IgG3 were significantly higher in these
mice (two and three times, respectively) than in IFN-gamma(-/-) mice,
characteristic of a Th1-type response. Together, these data indicate that
resolution of P. carinii infection can be mediated by specific antibody responses
and that the antibody response can be either a predominantly Th1 or Th2 type.
Furthermore, although wild-type mice mounted a Th2-like antibody response, IL-4(
/-) mice could resolve P. carinii pneumonia, indicating that resistance to P.
carinii can occur in the absence of IL-4.
PMID- 9393796
TI - Characterization of a new region required for macrophage killing by Legionella
pneumophila.
AB - In a previous study, a collection of 55 Legionella pneumophila mutants defective
for macrophage killing was isolated by transposon mutagenesis. In this study,
nine of these mutants that belong to the same DNA hybridization group (group 3)
were characterized. A wild-type DNA fragment that covers this DNA hybridization
group was cloned and sequenced. This region was found to contain six new genes
(designated icmT, icmS, icmR, icmQ, icmP, and icmO), five of which contain at
least one transposon insertion. No transposon insertion was found in icmS.
However, this gene was found to be required for macrophage killing, since a
kanamycin resistance cassette introduced into icmS by gene replacement resulted
in a mutant that was attenuated for macrophage killing. A plasmid containing the
DNA fragment that covers this region complements all the mutants for macrophage
killing, although various levels of complementation were observed for mutants in
different genes. Complementation tests were also performed with plasmids
containing one or two of these genes, as well as with plasmids containing
nonpolar in-frame deletions. The results from these complementation tests
indicated that all six genes located in this region are needed for macrophage
killing and that they are probably arranged as two transcriptional units (icmTS
and icmPO) and two genes (icmR and icmQ). A region upstream of the coding
sequence of several icm genes may contain a potential promoter and/or regulatory
site. Homology searches show that icmP and icmO bear significant homology to the
trbA and trbC genes from the Salmonella R64 plasmid, respectively. The sequences
of the other four genes do not show significant homology with any entries in
sequence databases.
PMID- 9393797
TI - Cryptosporidium parvum infection of human intestinal epithelial cells induces the
polarized secretion of C-X-C chemokines.
AB - Cryptosporidium parvum infects intestinal epithelial cells and does not invade
deeper layers of the intestinal mucosa. Nonetheless, an inflammatory cell
infiltrate that consists of neutrophils and mononuclear cells is often present in
the lamina propria, which underlies the epithelium. This study investigated the
host epithelial cell response to C. parvum by assessing in vitro and in vivo the
expression and production of proinflammatory cytokines by intestinal epithelial
cells after infection. The human colon epithelial cell lines HCT-8 and Caco-2 and
human intestinal xenografts in SCID mice were infected with C. parvum. The
expression and secretion of the C-X-C chemokines interleukin-8 (IL-8) and
GROalpha were determined by reverse transcription-PCR analysis and enzyme-linked
immunosorbent assay. Our results demonstrate that upregulated expression and
secretion of IL-8 and GROalpha after C. parvum infection of intestinal epithelial
cells first occurred 16 to 24 h after infection and increased over the ensuing 1
to 2 days. The kinetics of C-X-C chemokine production by C. parvum-infected
epithelial cells contrast markedly with the rapid but transient expression of C-X
C chemokines by epithelial cells infected with invasive enteric bacteria. C-X-C
chemokine secretion in C. parvum-infected epithelial cells occurred predominantly
from the basolateral surface in polarized monolayers of Caco-2 cells grown in
Transwell cultures, whereas cell lysis occurred at the apical surface. The
basolateral secretion of IL-8 and GROalpha from C. parvum-infected epithelial
cells suggests that C-X-C chemokines produced by those cells contribute to the
mucosal inflammatory cell infiltrate in the underlying intestinal mucosa.
PMID- 9393798
TI - Invasion of brain microvascular endothelial cells by group B streptococci.
AB - Group B streptococci (GBS) are the leading cause of meningitis in newborns.
Although meningitis develops following bacteremia, the precise mechanism or
mechanisms whereby GBS leave the bloodstream and gain access to the central
nervous system (CNS) are not known. We hypothesized that GBS produce meningitis
because of a unique capacity to invade human brain microvascular endothelial
cells (BMEC), the single-cell layer which constitutes the blood-brain barrier. In
order to test this hypothesis, we developed an in vitro model with BMEC isolated
from a human, immortalized by simian virus 40 transformation, and propagated in
tissue culture monolayers. GBS invasion of BMEC monolayers was demonstrated by
electron microscopy. Intracellular GBS were found within membrane-bound vacuoles,
suggesting the organism induced its own endocytic uptake. GBS invasion of BMEC
was quantified with a gentamicin protection assay. Serotype III strains, which
account for the majority of CNS isolates, invaded BMEC more efficiently than
strains from other common GBS serotypes. GBS survived within BMEC for up to 20 h
without significant intracellular replication. GBS invasion of BMEC required
active bacterial DNA, RNA, and protein synthesis, as well as microfilament and
microtubule elements of the eukaryotic cytoskeleton. The polysaccharide capsule
of GBS attenuated the invasive ability of the organism. At high bacterial
densities, GBS invasion of BMEC was accompanied by evidence of cellular injury;
this cytotoxicity was correlated to beta-hemolysin production by the bacterium.
Finally, GBS demonstrated transcytosis across intact, polar BMEC monolayers grown
on Transwell membranes. GBS invasion of BMEC may be a primary step in the
pathogenesis of meningitis, allowing bacteria access to the CNS by transcytosis
or by injury and disruption of the endothelial blood-brain barrier.
PMID- 9393799
TI - T-cell immunity to peptide epitopes of liver-stage antigen 1 in an area of Papua
New Guinea in which malaria is holoendemic.
AB - Liver-stage antigen 1 (LSA1) is one of several pre-erythrocytic antigens
considered for inclusion in a multiantigen, multistage subunit vaccine against
falciparum malaria. We examined T-cell proliferation and cytokine responses to
peptides corresponding to amino acids 84 to 107, 1813 to 1835, and 1888 to 1909
of LSA1 in asymptomatic adults living in an area of Papua New Guinea where
malaria is holoendemic. Whereas T cells from North Americans never exposed to
malaria did not respond to any of the peptides, those from 52 of 55 adults from
the area where malaria is endemic had vigorous proliferation responses to one or
more of the LSA1 peptides (mean stimulation indices of 6.8 to 7.2). Gamma
interferon (IFN-gamma) production driven by LSA1 peptides ranged from 34 to more
than 3,500 pg/2 x 10(6) cells, was derived primarily from CD8+ cells, and was
dissociated from T-cell proliferation. The frequencies of IFN-gamma response to
the amino acid 1819 to 1835 and 1888 to 1909 peptides were significantly greater
than that to the amino acid 84 to 107 peptide (87 and 88% versus 33% of subjects;
P < 0.0001). In contrast to proliferation and IFN-gamma, interleukin 4 (IL-4)
and/or IL-5 responses to LSA1 peptides were detected in only 18% of the subjects.
These data show that T-cell immunity to epitopes in the N- and C-terminal regions
of LSA1 are common in persons living in this area of Papua New Guinea where
malaria is endemic. The dominance of type 1 CD8 cell IFN-gamma responses is
consistent with a role for this T-cell population in immunity to liver-stage
Plasmodium falciparum in humans.
PMID- 9393800
TI - Escherichia coli cytolethal distending toxin blocks the HeLa cell cycle at the
G2/M transition by preventing cdc2 protein kinase dephosphorylation and
activation.
AB - Cytolethal distending toxins (CDT) constitute an emerging heterogeneous family of
bacterial toxins whose common biological property is to inhibit the proliferation
of cells in culture by blocking their cycle at G2/M phase. In this study, we
investigated the molecular mechanisms underlying the block caused by CDT from
Escherichia coli on synchronized HeLa cell cultures. To this end, we studied
specifically the behavior of the two subunits of the complex that determines
entry into mitosis, i.e., cyclin B1, the regulatory unit, and cdc2 protein
kinase, the catalytic unit. We thus demonstrate that CDT causes cell accumulation
in G2 and not in M, that it does not slow the progression of cells through S
phase, and that it does not affect the normal increase of cyclin B1 from late S
to G2. On the other hand, we show that CDT inhibits the kinase activity of cdc2
by preventing its dephosphorylation, an event which, in normal cells, triggers
mitosis. This inhibitory activity was demonstrated for the three partially
related CDTs so far described for E. coli. Moreover, we provide evidence that
cells exposed to CDT during G2 and M phases are blocked only at the subsequent G2
phase. This observation means that the toxin triggers a mechanism of cell arrest
that is initiated in S phase and therefore possibly related to the DNA damage
checkpoint system.
PMID- 9393801
TI - Virulence characteristics of oral treponemes in a murine model.
AB - This study was designed to investigate the virulence characteristics of Treponema
denticola, T. socranskii, T. pectinovorum, and T. vincentii following challenge
infection of mice. These microorganisms induced well-demarcated, dose-dependent,
raised subcutaneous (s.c.) abscesses which were similar in time of onset, lesion
progression, and duration of healing. Only viable cells were capable of inducing
these characteristic s.c. abscesses. Histological examination of the skin lesion
3 and 5 days postinfection revealed abscess formation in the s.c. tissues, and
abundant spiral organisms were demonstrated to be present in the abscess. Host
resistance modulation by dexamethasone (neutrophil alteration) and
cyclophosphamide (neutrophil depletion) pretreatment had a minimal effect on the
virulence expression by any of these treponemes. The T. denticola isolates
demonstrated significant trypsin-like protease (TLPase) activity, while both T.
socranskii and T. vincentii were devoid of this activity. Interestingly, T.
pectinovorum strains were heterogeneous with respect to TLPase as high producers,
low producers, and nonproducers. However, no differences in lesion formation were
noted regardless of whether the species expressed this proteolytic activity or
whether treatment with N alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) and
dithiothreitol was performed. These results showed that (i) a murine model may be
used to evaluate virulence expression by oral treponemes; (ii) while TLPase
activity varies among the oral treponemes, this protease does not appear to
participate in abscess induction in the mouse model; and (iii) T. pectinovorum
strains show variation in TLPase activity.
PMID- 9393802
TI - Oligoclonality of serum immunoglobulin G antibody responses to Streptococcus
pneumoniae capsular polysaccharide serotypes 6B, 14, and 23F.
AB - Serum antibodies (Abs) specific for the capsular polysaccharides of Streptococcus
pneumoniae provide protection against invasive pneumococcal disease. Previous
studies indicate that Abs to pneumococcal polysaccharide (PPS) serotypes 1 and 6B
have limited clonal diversity. To determine if restricted diversity was a feature
common to other PPS specificities, we examined the light (L)-chain expression and
isoelectric heterogeneity of type 6B, 14, and 23F Abs elicited in 15 adults
following PPS vaccination. At the population level, both PPS-6B and PPS-14 Abs
expressed kappa and lambda chains, although 6B Abs more frequently expressed
lambda chains lambda and 14 Abs more frequently expressed kappa chains. In
individual sera, Abs were generally skewed towards either kappa or lambda
expression. 23F-specific Abs had predominantly kappa chains. Isoelectric focusing
analyses showed that sera contained one or at most a few immunoglobulin G Ab
spectrotypes to all three respective capsular serotypes, a result indicative of
oligoclonality. A sequence analysis of a purified PPS-14-specific Ab having a
single spectrotype gave uniform amino-terminal sequences for both the heavy chain
(V(H)III subgroup) and the L chain (kappaIII-A27 V region). From these results we
conclude that within individual adults, serum Ab responses to PPS serotypes 6B,
14, and 23F derive from a small number of dominant B-cell clones, and
consequently variable-region expression is probably individually limited as well.
Oligoclonality appears to be a general characteristic of human PPS-specific Ab
repertoires, and we suggest that this property could lead to individual
differences in Ab fine specificity and/or functional activity against
encapsulated pneumococci.
PMID- 9393804
TI - A mutation of F47 to A in staphylococcus enterotoxin A activates the T-cell
receptor Vbeta repertoire in vivo.
AB - The bacterial superantigen staphylococcal enterotoxin A (SEA) binds with high
affinity to major histocompatibility complex (MHC) class II molecules and
subsequently activates T cells bearing particular T-cell receptor (TCR) Vbeta
chains. Structural and mutational studies have defined two distinct MHC class II
binding sites located in the N-terminal and C-terminal domains of SEA. The N
terminal F47 amino acid is critically involved in a low-affinity interaction to
the MHC class II alpha-chain, while the C-terminal residues H187, H225, and D227
coordinate a Zn2+ ion and bind with moderate affinity to the beta-chain. In order
to analyze whether the SEA-MHC class II alpha-chain interaction plays a role in
dictating the in vivo repertoire of T-cell subsets, we studied distinct Vbeta
populations after stimulation with wild-type SEA [SEA(wt)] and SEA with an F47A
mutation [SEA(F47A)]. Injections of SEA(wt) in C57BL/6 mice induced cytokine
release in serum, strong cytotoxic T-lymphocyte activity, expansion of T-cell
subsets, and modulated expression of the T-cell activation antigens CD25, CD11a,
CD44, CD62L, and CD69. SEA-reactive TCR Vbeta3+ and Vbeta11+ T cells were
activated, while TCR Vbeta8+ T cells remained unaffected. The SEA(F47A) mutant
protein induced a weaker T-cell response and failed to induce substantial
interleukin-6 production compared to SEA(wt). Notably, SEA(F47A) failed to
activate TCR Vbeta11+ T cells, whereas in vivo expansion and modulation of T-cell
activation markers on TCR Vbeta3+ T cells were similar to those for SEA(wt). A
similar response to SEA(F47A) was seen among CD4+ and CD8+ T cells. Activation of
TCR Vbeta3+ and TCR Vbeta11+ T-cell hybridomas confirmed that SEA(F47A) activates
TCR Vbeta3+ but not TCR Vbeta11+ T cells. The data support the view that the SEA
N-terminal MHC class II alpha-chain interaction defines a topology that is
required for engagement of certain TCR Vbeta chains in vivo.
PMID- 9393803
TI - Isolation and characterization of a pigmentless-conidium mutant of Aspergillus
fumigatus with altered conidial surface and reduced virulence.
AB - Aspergillus fumigatus is an important pathogen of immunocompromised hosts,
causing pneumonia and invasive disseminated disease with high mortality. The
factors contributing to the predominance of A. fumigatus as an opportunistic
pathogen are largely unknown. Since the survival of conidia in the host is a
prerequisite for establishing disease, we have been attempting to identify
factors which are associated with conidia and, simultaneously, important for
infection. Therefore, an A. fumigatus mutant strain (white [W]) lacking conidial
pigmentation was isolated. Scanning electron microscopy revealed that conidia of
the W mutant also differed in their surface morphology from those of the wild
type (WT). Mutant (W) and WT conidia were compared with respect to their
capacities to stimulate an oxidative response in human phagocytes, their
intracellular survival in human monocytes, and virulence in a murine animal
model. Luminol-dependent chemiluminescence was 10-fold higher when human
neutrophils or monocytes were challenged with W conidia compared with WT conidia.
Furthermore, mutant conidia were more susceptible to killing by oxidants in vitro
and were more efficiently damaged by human monocytes in vitro than WT conidia. In
a murine animal model, the W mutant strain showed reduced virulence compared with
the WT. A reversion analysis of the W mutant demonstrated that all phenotypes
associated with the W mutant, i.e., altered conidial surface, amount of reactive
oxygen species release, susceptibility to hydrogen peroxide, and reduced
virulence in an murine animal model, coreverted in revertants which had regained
the ability to produce green spores. This finding strongly suggests that the A.
fumigatus mutant described here carries a single mutation which caused all of the
observed phenotypes. Our results suggest that the conidium pigment or a
structural feature related to it contributes to fungal resistance against host
defense mechanisms in A. fumigatus infections.
PMID- 9393805
TI - Prohibitin, a putative negative control element present in Pneumocystis carinii.
AB - Little is known about the molecules involved in the regulation of Pneumocystis
carinii replication and development in vitro and in vivo. We describe in this
report the identification of a P. carinii gene encoding the P. carinii prohibitin
protein. In mammals, the prohibitin gene product has been shown to negatively
regulate cell proliferation. A cDNA clone encoding the P. carinii prohibitin gene
was isolated from a P. carinii cDNA library and identified on the basis of amino
acid sequence homology with prohibitin from mammalian sources. Southern blot
analysis confirmed that the prohibitin cDNA clone was of P. carinii origin.
Western blot analysis of total P. carinii protein indicated that the prohibitin
gene is transcribed and translated in vivo. The P. carinii prohibitin gene was
expressed in vivo in human fibroblasts and shown to arrest the cell cycle in the
G1 phase. The results obtained suggest a potential role for P. carinii prohibitin
in the regulation of P. carinii proliferation and development.
PMID- 9393806
TI - Induction of neutrophil chemoattractant cytokines by Mycoplasma hominis in
alveolar type II cells.
AB - Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature infants
who are mechanically ventilated due to respiratory distress. The disease consists
of an initial inflammatory influx of neutrophils to the lungs, followed by long
term chronic fibrosis of the lung tissue. The antigenic repertoire that initiates
the inflammatory component of BPD has not been defined. Furthermore, the
repertoire of cytokines responsible for attracting neutrophils to the lung and
the mediators of pathogenesis in BPD have not been characterized. Mycoplasmas
such as Mycoplasma hominis and Ureaplasma urealyticum have been isolated from the
lungs of infants that developed BPD and yet have not been widely recognized as
potential initiators of the inflammatory component of BPD. In the studies
described here, we examined the ability of both viable and heat-killed Mycoplasma
hominis to elicit type II epithelial cell production of cytokines that are
chemotactic for polymorphonuclear leukocytes (PMNs), particularly interleukin-8
(IL-8) and epithelial cell-derived neutrophil-activating peptide (ENA-78). The
results of these studies demonstrate that M. hominis and M. hominis antigen are
potent stimulators of type II epithelial cell-derived IL-8 and ENA-78. Thus,
these data strongly suggest that the presence of M. hominis in the lungs of
premature infants may initiate the inflammatory component of BPD by inducing
epithelial cell production of cytokines chemotactic for PMNs. Furthermore, these
data suggest that the onset of the inflammatory component of BPD likely precedes,
and is independent of, the recruitment and activation of alveolar macrophages.
PMID- 9393807
TI - Internalin B promotes the replication of Listeria monocytogenes in mouse
hepatocytes.
AB - The uptake of Listeria monocytogenes by a variety of cell types in vitro is
facilitated by the protein products of the inlAB (internalin) operon expressed by
the organism. In the case of mouse hepatocytes, the extent to which inlAB
expression influenced the uptake of Listeria in vitro was markedly dependent upon
the ratio of bacteria to cells. At a ratio of 100:1, greater than 40-fold fewer
transposon-induced inl4B mutant listeriae entered hepatocytes compared to the
isogenic wild-type control; the difference was only fourfold, however, in
cultures inoculated at a 1:1 ratio. Similarly, the uptake of in-frame inlB or
inlAB deletion mutants differed only fourfold from the uptake of wild-type or
inlA mutant Listeria at a 1:1 multiplicity of infection. Mutations affecting inlB
or inlAB, on the other hand, resulted in a marked decrease in the capacity of
Listeria to proliferate within mouse hepatocytes in vivo and in vitro. Electron
micrographs of Listeria-infected hepatocytes demonstrated the impaired capacity
of inlB mutants to escape from endocytic vacuoles and to enter the cytoplasm
where proliferation occurs. These findings indicate that the protein product of
inlB exerts a significant effect on the intracellular replication of Listeria.
PMID- 9393808
TI - Contact-dependent disruption of the host cell membrane skeleton induced by
Trichomonas vaginalis.
AB - This report presents evidence showing that the pathogenetic process of the
protozoan parasite Trichomonas vaginalis involves degradation of the target cell
membrane skeleton; spectrin, the most representative protein within this
structure, has been identified as the main molecular target. Degradation of the
target cell spectrin is accomplished only upon contact with the parasite, and
immunochemical and immunofluorescence studies performed with the erythrocyte as a
model demonstrate that degradation of the protein takes place before target cell
lysis. A preliminary characterization of the effectors involved has led to the
identification of a nonsecreted 30-kDa proteinase which is characterized by a
high specificity for spectrin. This molecule is suggested as the main effector
responsible for cytoskeletal disruption.
PMID- 9393809
TI - Induction of gamma interferon production in human alveolar macrophages by
Mycobacterium tuberculosis.
AB - Gamma interferon (IFN-gamma) is a cytokine which plays a critical role in
resistance to Mycobacterium tuberculosis infection. While T lymphocytes and
natural killer cells are a major source of IFN-gamma, previous demonstrations
that it can be produced by murine macrophages prompted us to examine the capacity
of human alveolar macrophages to express IFN-gamma. Here we report that in vitro
infection of alveolar macrophages with M. tuberculosis induces both the release
of IFN-gamma protein and a transient increase in IFN-gamma mRNA levels. The IFN
producing cells were shown to be macrophages by reverse transcription-in situ
PCR. We also observed that M. tuberculosis stimulation resulted in IFN-gamma
dependent expression of the chemokines IFN-gamma-inducible protein 10 and
monokine induced by IFN-gamma, suggesting that macrophage-derived IFN-gamma can
function in an autocrine and/or paracrine manner. The existence of a positive
regulatory loop was suggested by the observation that exogenous IFN-gamma protein
could induce IFN-gamma mRNA expression in uninfected alveolar macrophages.
Interleukin-12 was also found to be a potent inducer of IFN-gamma production, and
M. tuberculosis-induced IFN-gamma production appears to be mediated, at least in
part, by IL-12. In contrast, M. tuberculosis-induced IFN-gamma production by
alveolar macrophages could be blocked by exogenous interleukin-10. These studies
are the first to demonstrate an autoregulatory role for IFN-gamma produced by
alveolar macrophages infected in vitro with M. tuberculosis.
PMID- 9393810
TI - Invasion of dentinal tubules by oral streptococci is associated with collagen
recognition mediated by the antigen I/II family of polypeptides.
AB - Cell surface proteins SspA and SspB in Streptococcus gordonii and SpaP in
Streptococcus mutans are members of the antigen I/II family of polypeptides
produced by oral streptococci. These proteins are adhesins and mediate species
specific binding of cells to a variety of host and bacterial receptors. Here we
show that antigen I/II polypeptides are involved in the attachment of oral
streptococci to collagen and that they also determine the ability of these
bacteria to invade human root dentinal tubules. Wild-type S. gordonii DL1
(Challis) cells showed heavy invasion of tubules to a depth of approximately 200
microm, whereas the abilities of cells of isogenic mutant strains OB220 (sspA)
and OB219 (sspA sspB) to invade were 50 and >90% reduced, respectively. Likewise,
wild-type S. mutans NG8 cells invaded dentinal tubules, whereas cells of isogenic
mutant strain 834 (spaP) did not. The invasive abilities of strains OB220 and
OB219 were restored by heterologous expression of S. mutans SpaP polypeptide in
these strains. The extents of tubule invasion by various wild-type and mutant
strains correlated with their levels of adhesion to type I collagen, a major
component of dentin. Furthermore, S. gordonii DL1 cells exhibited a growth
response to collagen by forming long chains. This was not shown by ssp mutants
but was restored by the expression of SpaP in these cells. The production of SspA
polypeptide by S. gordonii DL1, but not production of SspB polypeptide by strain
OB220 (sspA), was enhanced in the presence of collagen. These results are the
first to demonstrate that antigen I/II family polypeptides bind collagen and
mediate a morphological growth response of streptococci to collagen. These
antigen I/II polypeptide activities are critical for intratubular growth of
streptococci and thus for establishment of endodontic infections.
PMID- 9393812
TI - Passive protection by polyclonal antibodies against Bacillus anthracis infection
in guinea pigs.
AB - The protective effects of polyclonal antisera produced by injecting guinea pigs
with protective antigen (PA), the chemical anthrax vaccine AVA, or Sterne spore
vaccine, as well as those of toxin-neutralizing monoclonal antibodies (MAbs)
produced against PA, lethal factor, and edema factor, were examined in animals
infected with Bacillus anthracis spores. Only the anti-PA polyclonal serum
significantly protected the guinea pigs from death, with 67% of infected animals
surviving. Although none of the MAbs was protective, one PA MAb caused a
significant delay in time to death. Our findings demonstrate that antibodies
produced against only PA can provide passive protection against anthrax infection
in guinea pigs.
PMID- 9393811
TI - The interleukin 1beta-converting enzyme, caspase 1, is activated during Shigella
flexneri-induced apoptosis in human monocyte-derived macrophages.
AB - Shigella, the etiological agent of bacillary dysentery, rapidly kills human
monocyte-derived macrophages in vitro. Wild-type Shigella flexneri, but not a
nonvirulent derivative, induced human macrophage apoptosis as determined by
morphology and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end
labeling (TUNEL). Shigella-mediated macrophage cell death was blocked by the
peptide inhibitors of caspases, acetyl-Tyr-Val-Ala-Asp-aldehyde (acetyl-YVAD-CHO)
and acetyl-Tyr-Val-Ala-Asp-chloromethylketone (acetyl-YVAD-CMK). Protection from
apoptosis by YVAD was observed in monocytes matured in the presence or absence of
colony-stimulating factors (CSF) like macrophage-CSF or granulocyte-macrophage
CSF. Furthermore, lipopolysaccharide (LPS) or gamma interferon (IFN-gamma)
rendered human macrophages partially resistant to Shigella cytotoxicity.
Macrophages stimulated with either LPS or IFN-gamma were also protected by YVAD
from Shigella-induced cell death. During Shigella infections of human
macrophages, interleukin-1beta (IL-1beta) was cleaved to the mature form. IL
1beta maturation was severely retarded by YVAD, indicating that IL-1beta
converting enzyme (ICE; caspase 1) is activated in Shigella-induced apoptosis.
The finding that Shigella induces apoptosis in human macrophages by activating
ICE supports the hypothesis that the acute inflammation characteristic of
shigellosis is initially triggered by apoptotic macrophages which release mature
IL-1beta during programmed cell death.
PMID- 9393813
TI - Altered cytokine production by cystic fibrosis tracheal gland serous cells.
AB - Human submucosal tracheal glands are now believed to play a major role in the
physiopathology of cystic fibrosis (CF). We successfully developed techniques for
culturing human tracheal gland serous cells from normal individuals (HTGS cells)
and from CF patients (CF-HTGS cells) and have shown that the cultured cells have
retained most of their in vivo epithelial and secretory characteristics. In order
to determine to what extent the serous cells may participate in the lung defense
against infection, we examined the effects of the lipopolysaccharide (LPS) of
Pseudomonas aeruginosa on HTGS and CF-HTGS cells, with special reference to tumor
necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and IL-8 secretion. HTGS
cells showed a daily basal secretion of IL-6 (1.68 +/- 0.14 ng/10(6) cells) and
IL-8 (9.6 +/- 1.3 ng/10(6) cells) and no constitutive secretion of TNF-alpha.
Treatment with P. aeruginosa LPS resulted in a significant increase in the basal
production of IL-6 (increase of 200% +/- 12%) and IL-8 (525% +/- 40%) as well as
a rapid production of TNF-alpha (250 +/- 38 pg/10(6) cells). The LPS-induced
secretion of IL-6 and IL-8, but not that of TNF-alpha, was inhibited by
glucocorticoids. CF-HTGS cells showed a much higher basal secretion of IL-6 (13.2
+/- 0.5 ng/10(6) cells) and IL-8 (45.6 +/- 7.2 ng/10(6) cells) than normal cells.
Treatment with the LPS of P. aeruginosa induced increased production of IL-6
(increase of 100% +/- 8%) and IL-8 (55% +/- 18%) but did not induce the secretion
of TNF-alpha. Neither intracellular TNF-alpha nor TNF-alpha transcripts were
found in CF-HTGS cells, whereas they were found in normal HTGS cells. In
addition, dexamethasone was found to stimulate IL-6 and IL-8 secretion (in the
presence or absence of LPS) but did not induce any secretion of TNF-alpha. All
these data indicate that HTGS cells are responsive to P. aeruginosa LPS, which
results in an increased secretion of IL-6, IL-8, and TNF-alpha, the secretion of
which appeared to be impaired in CF-HTGS cells.
PMID- 9393814
TI - Human B- and T-cell responses after immunization with a hexavalent PorA
meningococcal outer membrane vesicle vaccine.
AB - The PorA protein from Neisseria meningitidis, a potential vaccine candidate,
induces human bactericidal antibodies which are serosubtype specific. We
developed a hexavalent PorA outer membrane vesicle vaccine based on reference
strain H44/76. This vaccine contains the six most prevalent PorA serosubtypes as
found in many countries. We previously reported on the immune responses of 20
adult volunteers after a single immunization with this vaccine. In this study,
the B- and T-cell responses in three adult volunteers were studied after three
consecutive immunizations (0, 2, and 11 months). The first immunization induced a
strong B-cell response resulting in high immunoglobulin G levels in an outer
membrane vesicle enzyme-linked immunosorbent assay. At least a fourfold increase
in bactericidal activity was observed against the majority (four to six) of the
vaccine antigens compared to prevaccination titers. Immunodominance was observed
for one or two of the PorAs in the bactericidal assay with a set of six isogenic
H44/76-derived PorA target strains. These strains carry the individual PorAs as
present in the vaccine. The second and third immunizations did not induce a
further increase in the immune responses. A decline in time with respect to PorA
specific antibodies was observed after each immunization. These observations were
reflected by the T-cell proliferation responses. Two additional sets of isogenic
H44/76-derived mutant strains were used to study the specificity and/or cross
reactivity of the induced bactericidal antibodies. These target strains differ
only in expressing mutant family variants of either PorA P1.7,16 or P1.5,10, both
present in the PorA vesicle vaccine. The bactericidal antibody responses found
were directed predominantly against the P1.7 (loop 1 of P1.7,16) and the P1.10
(loop 4 of P1.5,10) epitopes. This indicates that different portions of PorA were
involved in the induction of bactericidal antibodies depending upon the PorA
serosubtype.
PMID- 9393815
TI - Systemic infection of mice by wild-type but not Spv- Salmonella typhimurium is
enhanced by neutralization of gamma interferon and tumor necrosis factor alpha.
AB - The spv genes of the virulence plasmid of Salmonella typhimurium and other
nontyphoidal serovars of S. enterica are involved in systemic infection by
increasing the replication rate of the bacteria in host tissues beyond the
intestines. We considered the possibility that the Spv virulence function is to
evade suppression by the host response to infection. To examine this possibility,
gamma interferon (IFN-gamma) and/or tumor necrosis factor alpha (TNF-alpha) were
neutralized in BALB/c mice by intraperitoneal administration of monoclonal
antibodies. Neutralization of IFN-gamma and/or TNF-alpha resulted in increased
splenic infection with wild-type salmonellae after oral inoculation; however, Spv
salmonellae were defective at increasing splenic infection in cytokine-depleted
mice. The use of a temperature-sensitive marker plasmid, pHSG422, indicated that
neutralization of IFN-gamma caused less killing of wild-type S. typhimurium,
while neutralization of TNF-alpha resulted in an increased in vivo replication
rate for wild-type salmonellae. These results demonstrate that the Spv virulence
function is not to evade suppression of bacterial infection normally mediated by
IFN-gamma or TNF-alpha.
PMID- 9393817
TI - Differential induction of Th1 versus Th2 cytokines by group A streptococcal toxic
shock syndrome isolates.
AB - The majority of group A streptococcal (GAS) isolates from patients with
streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis (NF) express
numerous virulence factors, including several superantigens (SAgs). Purified SAgs
are potent inducers of inflammatory (Th1) cytokines that contribute to the
pathogenesis of severe infections. However, GAS-infected individuals are likely
to be exposed to a mixture of GAS SAgs as well as other virulence factors
produced by the bacteria, and therefore, our goal was to characterize the
mitogenic and cytokine induction profiles of this mixture. All GAS isolates
tested had brisk mitogenic activity and induced potent cytokine responses, with
higher frequencies of Th1 than Th2 cytokine-producing cells. The mitogenic
activity produced in culture supernatants of three selected clinical GAS isolates
was significantly different, but no marked difference was found in their overall
cytokine induction profiles. However, significant differences (P < 0.0062) were
noted in the induction of Th2 cytokines between GAS supernatants and recombinant
streptococcal pyrogenic exotoxin A (rSpeA), suggesting that the presence of other
SAgs and/or the production of additional virulence factors may alter the overall
cytokine induction profile of SAgs. A significant individual variation in the
level of proliferative and cytokine responses to the same GAS culture
supernatants or to rSpeA was noted. Individuals with higher frequencies of cells
producing Th2 cytokines mounted lower levels of Th1 cytokine responses, and vice
versa. Furthermore, quantification of the intensity and cell area of interleukin
1beta (IL-1beta)-producing cells by image analysis revealed that individuals with
higher Th2 responses had significantly lower IL-1beta production (P < 0.0001)
than the individual with a strong Th1 response. Differences in the ability to
induce Th1 versus Th2 cytokines, as well as the individual variations in cytokine
responses to streptococcal SAgs, may play a central role in determining the
severity of invasive GAS infections.
PMID- 9393816
TI - Identification of homing receptors that mediate the recruitment of CD4 T cells to
the genital tract following intravaginal infection with Chlamydia trachomatis.
AB - Murine genital infection induced with the mouse pneumonitis biovar of Chlamydia
trachomatis (MoPn) elicits a short-lived protective immunity mediated primarily
by Th1 CD4 cells. To understand the development of local cell-mediated immunity
against C. trachomatis infection, we investigated the mechanism(s) which mediates
CD4 lymphocyte migration to the genital mucosa by identifying molecules that
could support this process. We found that primarily CD4 cells were recruited to
the genital tract (GT) during primary and challenge MoPn infection. Peak levels
were found 21 days after primary inoculation (15.4% +/- 2.7%) and 7 days (31.3%
+/- 8.5%) after challenge but diminished after resolution of infection. The CD4
cells appeared to be recruited to the GT in response to infection since these
cells expressed the profile of activated, or memory, cells. We also observed up
regulation of homing receptors containing LFA-1 (CD11a) and alpha4 (CD49d) on GT
CD4 cells over the course of infection. Furthermore, the mucosal homing receptor
chain, beta7, but not the peripheral homing receptor chain beta1 (CD29), was
detected on GT CD4 cells. MoPn-infected GT tissue expressed the endothelial cell
ligands vascular cell adhesion molecule 1 (VCAM-1), intracellular adhesion
molecule 1 (ICAM-1), and mucosal vascular addressin cell adhesion molecule 1
(MAdCAM-1), which correspond to the homing receptors on GT CD4 cells.
Interestingly, VCAM-1 and MAdCAM-1 were not expressed in the GTs of uninfected
mice but were temporarily induced following infection, indicating that expression
of endothelial ligands in the GT are regulated by chlamydial infection. These
data suggest that recruitment of CD4 cells to the GT is mediated through LFA
1:ICAM-1 and alpha4beta7:MAdCAM-1-VCAM-1 interactions.
PMID- 9393818
TI - Immunogenicity and protective efficacy of the alpha C protein of group B
streptococci are inversely related to the number of repeats.
AB - Infection by group B streptococci (GBS) is an important cause of bacterial
disease in neonates. Alpha C protein is a protective cell surface-associated
protein of GBS. This protein contains a repeat region flanked by N and C termini.
Variable expression of tandem repeating units of alpha C proteins had been found
among clinical isolates of GBS. We examined the effect of the number of repeats
on the immunogenicity of the alpha C protein and its ability to elicit protection
from GBS infection in a neonatal mouse model. Mice were immunized with purified
alpha C proteins of constructs containing various numbers of repeats (n = 1, 2,
9, and 16) and the N- and C-terminal regions. Both the N-terminal and the repeat
regions contain protective and opsonic epitopes. Antibody responses to the alpha
C protein constructs with various numbers of repeats were tested with enzyme
linked immunosorbent assay plates coated with either native, nine-repeat alpha C
protein or "repeatless" N-terminal antigen. An inverse relationship was found
between the number of repeats and the immunogenicity of the alpha C protein; this
effect was most pronounced on titers of antibody to the N-terminal region. An
inverse relationship was also observed between the number of repeats and
protective efficacy, i.e., mouse dams immunized with 5 microg of one- or nine
repeat alpha C protein transferred protective immunity to 65 or 11% of their
pups, respectively (P < 0.0001). Thus, the presence of multiple repeats appears
to lessen the antibody response to the complete alpha C protein, and especially
the antibody response to its N-terminal region, and suggests a mechanism whereby
repeat elements contribute to the evasion of host immunity.
PMID- 9393820
TI - Identification of a Fusobacterium nucleatum PK1594 galactose-binding adhesin
which mediates coaggregation with periopathogenic bacteria and hemagglutination.
AB - Attachment of Fusobacterium nucleatum to various oral surfaces is mediated by
several adhesins anchored on its outer surface. Monoclonal antibodies (MAbs) were
prepared and used to identify the putative galactose-binding adhesin of F.
nucleatum PK1594. Four unique MAbs, 8G7, 26B9, 28G11, and 29D4, were isolated on
the basis of their ability to inhibit coaggregation of F. nucleatum PK1594 with
Porphyromonas gingivalis PK1924. All four MAbs were also capable of inhibiting
galactose-inhibitable interactions of F. nucleatum PK1594 with other oral gram
negative bacteria and with erythrocytes. Preincubation of F. nucleatum PK1594
with MAb 26B9 or its Fab fragments at concentrations lower than 1 microg/ml
resulted in complete inhibition of coaggregation with P. gingivalis PK1924 or
hemagglutination. F. nucleatum PK1594 surface components prepared by mild
sonication or by extracting whole cells with detergents were subjected to Western
blot analysis. None of the MAbs were able to recognize any polypeptide in these
experiments. Therefore, detergent extracts of F. nucleatum PK1594 surface
components were subjected to three experimental procedures: (i) separation by ion
exchange chromatography and testing of fractions for reaction with MAb 26B9 in an
enzyme-linked immunosorbent assay (ELISA), (ii) lactose-Sepharose affinity
chromatography and testing of the lactose eluate in ELISA with MAb 26B9, and
(iii) immunoseparation with either MAb 26B9 or 8G7. Collectively, the results
suggest that the putative adhesin is a 30-kDa outer membrane polypeptide which
mediates the coaggregation with P. gingivalis PK1924 as well as other galactose
sensitive interactions of F. nucleatum PK1594.
PMID- 9393819
TI - Identification and characterization of a K88- and CS31A-like operon of a rabbit
enteropathogenic Escherichia coli strain which encodes fimbriae involved in the
colonization of rabbit intestine.
AB - Initiation of attaching-effacing lesions, which characterize infections with
rabbit enteropathogenic Escherichia coli (REPEC), requires bacteria to adhere to
the intestinal epithelium. This adherence is reflected in vitro by the affinity
of these E. coli strains for various types of eukaryotic cells. TnphoA mutants of
REPEC 83/39 (O15:H-) which had lost the ability to adhere to HEp-2 epithelial
cells, guinea pig ileal brush borders, and mouse erythrocytes were generated. DNA
sequencing of the region surrounding the inactivating transposon insertions
within a 95-kb plasmid, designated pRAP for REPEC adherence plasmid, revealed
extensive homology between that region and the structural genes of
enterotoxigenic E. coli operons encoding the K88 and CS31A fimbrial adhesins and
the genes for the afr2 adhesin from REPEC B10 (O103:H2). Seven genes of the ral
operon (for REPEC adherence locus), including three putative minor fimbrial
subunit genes (ralC, ralF, and ralH), a major fimbrial subunit gene (ralG), a
gene of unknown function (ralI), and genes for two fimbrial subunit chaperones
(ralD and ralE), were sequenced. When inoculated perorally into weanling rabbits,
a mutant with a TnphoA insertion in the ralE gene showed a 10-fold reduction in
colonizing ability, with only 1 of 10 rabbits excreting bacteria compared to all
5 of those infected with the wild-type parent strain (P = 0.002). The severity of
the diarrheal illness caused by the mutant strain was also reduced. Western
blotting of surface protein extracts of strain 83/39 with hyperimmune anti-83/39
antiserum, adsorbed with the ralE mutant, revealed a 32-kDa protein which was
absent from protein extracts of two nonadherent mutants. The adsorbed antiserum
also bound to the surface of strain 83/39 but not to nonadherent mutants, as
detected by immunogold labeling. These results indicate that the ral operon of
REPEC 83/39 contains genes necessary for the biosynthesis of fine fimbriae which
are responsible for in vitro adherence of the bacteria and play a role in their
colonization of, and hence virulence for, rabbits. The putative major fimbrial
subunit is a protein with an observed molecular size of approximately 32 kDa
which, when assembled, appears to form a capsule of fimbriae surrounding the
bacterium similar to that described for CS31A.
PMID- 9393821
TI - Pathogenicity and protective effect of rough mutants of Salmonella species in
germ-free piglets.
AB - In this study, two stable, rough, streptomycin-sensitive Salmonella mutants with
different types of genetic defects were used to colonize groups of germ-free (GF)
piglets. The lipopolysaccharide (LPS) of Salmonella typhimurium SF 1591 was of
the Ra chemotype (complete core), whereas the LPS of the S. minnesota mR 595 deep
rough mutant contained only lipid A and 2-keto-3-deoxyoctulosonic acid (Re
chemotype). Both strains readily colonized the intestinal tracts of GF piglets
and were stable during the whole experiment. All animals survived, and only
transient fever was observed in some piglets colonized with the SF 1591 strain.
Finally, streptomycin and virulent, smooth, streptomycin-resistant S. typhimurium
LT2 were administered perorally 1 week later. All piglets colonized previously
with the deep-rough mutant mR 595 died of sepsis, in contrast to piglets infected
with the LT2 strain and colonized with the SF 1591 mutant, all of which survived.
This difference is explained by the penetration of the mesenteric lymph nodes,
spleen, and liver by great numbers of live bacteria in the latter case, resulting
in prominent systemic and local immune responses. On the other hand, live
bacteria were found only rarely in the mesenteric lymph nodes of animals
colonized with the mR 595 strain and a negligible antibody response was observed.
PMID- 9393822
TI - Cellular changes and cytokine expression in the ilea of gnotobiotic piglets
resulting from peroral Salmonella typhimurium challenge.
AB - Two stable rough mutants of Salmonella spp. were studied as live peroral
vaccines. The SF1591 mutant of S. typhimurium (Ra chemotype) protected germ-free
piglets against subsequent infection with virulent smooth S. typhimurium LT2,
whereas a deep-rough mutant of S. minnesota mR595 (Re chemotype) did not. We
investigated cytokine and leukocyte profiles in the ilea of gnotobiotic piglets
colonized for 1 week either with rough mutants alone or with rough mutants
followed by S. typhimurium LT2. The ileal mucosae of piglets associated with
strain SF1591 alone were not inflamed. Villi contained activated macrophages, and
enterocytes expressed transforming growth factor beta (TGF-beta). Subsequent
infection of piglets with S. typhimurium LT2 resulted in immigration of alphabeta
T cells and immunoglobulin A (IgA) response. In contrast, the ileal mucosae of
piglets associated with strain mR595 alone expressed heat shock proteins and
inflammatory cytokines but not TGF-beta. Acellular villi contained numerous
gammadelta T cells but no alphabeta T cells. After subsequent challenge with the
LT2 strain, most piglets died of sepsis. Intestinal mucosae contained IgG but no
IgA. These findings suggest the importance of cytokine signals in the regulation
of intestinal responses against Salmonella infection.
PMID- 9393823
TI - Mapping of antigenic determinant regions of the Bor56 protein of Orientia
tsutsugamushi.
AB - The 56-kDa protein (Bor56) of Orientia tsutsugamushi is an immunoprotective
antigen and is the target molecule of neutralizing antibodies. This antigen is
recognized by almost all of the serum antibodies produced by patients in the
convalescence phase of scrub typhus. We expressed the Bor56 open reading frame in
Escherichia coli and generated from it a series of deletion constructs as MalE
fusion proteins. Antibody-binding domains were characterized by using patient
sera, mouse monoclonal antibodies (MAbs), and Bor56-immunized-mouse sera. None of
the antibodies bound to a fusion protein containing the carboxy-terminal 140
amino acids (aa) of the Bor56 protein, suggesting that the carboxy-terminal
domain of Bor56 is not exposed on the surface of the molecule. Human
immunoglobulin M (IgM) antibodies predominantly bound to antigenic domain I (AD
I; amino acids [aa] 19 to 113) and AD III (aa 243 to 328). Human IgG antibodies
also showed preferential binding to AD I. The epitope recognized by strain
specific MAb (KI4) or group-specific MAb (KI57) was mapped to AD II (aa 142 to
203). Mouse serum antibodies, elicited by immunization with deletion mutants,
consistently bound to AD III. Moreover, the carboxy-terminal 140 aa of the Bor56
protein did not elicit an antibody response in C3H/HeDub mice. A model of the
antigenic structure of Bor56 is presented and discussed. These results suggest
that antigenic fragments from AD I and AD III are useful in the induction of
humoral immunity against O. tsutsugamushi. These antigenic analyses provide an
important foundation for further analyses of the neutralizing-antibody responses
generated during rickettsial infections. They also provide potential peptide
substrates for diagnostic assays and vaccine strategies.
PMID- 9393824
TI - Calcium dependence and binding in cultures of Histoplasma capsulatum.
AB - Histoplasma capsulatum is a pathogenic fungus with two distinct morphologies and
lifestyles. The saprophytic form of this organism, a mold, thrives in soil and is
especially abundant in the Ohio and Mississippi River valleys. Its parasitic
counterpart, a yeast, colonizes phagolysosomes of mammalian macrophages. We have
observed a major difference in the calcium requirements of the two forms of
Histoplasma, potentially implicating the phagolysosome as a calcium-limiting
compartment. Deprivation of calcium by the addition of EGTA to culture media
inhibited the growth of mycelial H. capsulatum but had no effect on yeast growth
in vitro. In addition, yeasts released a calcium-binding protein (CBP) detectable
by a 45CaCl2 blotting technique. CBP was a major component of yeast culture
supernatant and was also detectable by ruthenium red staining, another assay for
calcium-binding activity. Conversely, mycelial H. capsulatum did not produce CBP,
a finding that correlates with the dependence of mycelia on calcium for growth.
We also describe here the purification of CBP from yeast culture supernatant by
reversed-phase high-pressure liquid chromatography.
PMID- 9393825
TI - Apoptosis of human monocytes and macrophages by Mycobacterium avium sonicate.
AB - Mycobacterium avium is an intracellular organism which multiplies predominantly
within human macrophages. This organism has previously been shown to induce
apoptosis in human macrophages. With a view to identifying M. avium components
that induce cell death in infected host cells, sonicated extracts of M. avium as
well as individual components isolated from the M. avium sonicate were tested in
various assays with a human monocytic cell line (THP-1). THP-1 cells incubated
with M. avium sonicate showed significantly reduced viability after a 2-day
exposure compared to control cells incubated with media alone. This effect was
dose dependent, with only 6.6% +/- 5.2% and 48.8% +/- 10.3% of the cells being
viable by trypan blue exclusion at 600 and 300 microg/ml, respectively. Control
cells, on the other hand, exhibited a viability of 98.8% +/- 1.0%. In addition,
an 80% ammonium sulfate fraction of the M. avium sonicate and the previously
characterized 68-kDa protein were found to have similar effects on THP-1 cells.
In both cases, the reduction in viability was due to apoptosis characterized by
chromatin condensation, DNA fragmentation by agarose gel electrophoresis, or
terminal deoxynucleotidyl transferase-mediated d-UTP nick end labeling (TUNEL)
and release of nuclear matrix protein (NMP) into the culture medium. M. avium
sonicate-induced apoptosis of THP-1 cells was completely inhibited by the
commonly used antioxidants pyrrolidinedithiocarbamate (PDTC) and butylated
hydroxyanisole (BHA), indicating that the generation of free oxygen radicals may
be responsible for inducing cell death. M. avium sonicate was found to induce
apoptosis of monocyte-derived macrophages (MDMs) as well. This effect was not
reversed in the presence of PDTC and was not accompanied with DNA fragmentation
when determined by agarose gel electrophoresis, as seen in the case of THP-1
cells. However, these MDMs were found to contain fragmented DNA by TUNEL. These
findings suggest that the mechanism of cell death in MDMs may be different from
that observed with THP-1 cells. Furthermore, these results provide new insight
into the effect of M. avium components on host cell responses during M. avium
infection.
PMID- 9393827
TI - Comparison of inducible nitric oxide synthase expression in the brains of
Listeria monocytogenes-infected cattle, sheep, and goats and in macrophages
stimulated in vitro.
AB - The expression of inducible nitric oxide synthase (iNOS) was studied in the
brains of cattle, sheep, and goat that succumbed to a natural infection with
Listeria monocytogenes. The lesions in infected brains are characterized by
microabscesses, perivascular cuffs, gliosis, glial nodules, and large areas of
malacia. Using immunocytochemistry, we detected bacteria in microabscesses,
particularly in sheep and goats, and in areas without signs of inflammation, but
not in perivascular infiltrates. iNOS was expressed by macrophage (Mphi)-type
cells of microabscesses and glial nodules but rarely by Mphi in areas of malacia,
as determined by immunohistochemistry with iNOS-specific antibodies. iNOS was not
detected in perivascular cuffs. Major histocompatibility complex class II
molecules (MHC-II), another marker of cell activation, showed a different pattern
of distribution. Perivascular cuffs contained high numbers of MHC-II-positive
cells, including some with Mphi characteristics. Microabscesses in sheep and
goats showed low expression of MHC-II, particularly in iNOS-expressing cells. In
cattle, the expression of markers for activated or recruited phagocytes, the
calcium-binding proteins S100A8 and S100A9 (formerly called MRP-8 and MRP-14,
respectively), was largely restricted to cells showing weak or undetectable iNOS
expression; iNOS-positive Mphi showed a low expression of S100A8 and S100A9.
Thus, iNOS is expressed by a restricted subset of Mphi in listeric encephalitis.
In cultured sheep and goat Mphi, a low proportion of cells expressed iNOS upon
activation by L. monocytogenes and gamma interferon, resulting in nitrite
generation at least 1 order of magnitude lower than that in similarly treated
cattle Mphi. Since these species differences were much less obvious in vivo, it
appears that the well-known species variation in iNOS expression by Mphi could
reflect an in vitro phenomenon.
PMID- 9393826
TI - Effects of mycobacteria on regulation of apoptosis in mononuclear phagocytes.
AB - Since apoptosis is observed in tuberculous granulomata, we investigated the
molecular mechanisms underlying the apoptotic pathway in an in vitro model of
mycobacterial infection of mononuclear phagocytes. We postulated that
Mycobacterium tuberculosis could trigger the apoptotic pathway in macrophages,
resulting in death of the microorganism by modulating the expression of bcl-2,
bax, bcl-xL, and bcl-xS. We found that the mRNA of bcl-2, an inhibitor of
apoptosis, was downregulated in peripheral blood monocytes (PBM) between 2 and 6
h following infection with M. bovis BCG or induction with heat-killed M.
tuberculosis H37Ra. Western analysis showed a downregulation of the Bcl-2
protein, with a half-life of 24 h. At the same time points, there was no change
in the expression of Bax or Bcl-xS, inducers of apoptosis, but Bcl-xL, another
inhibitor of apoptosis, was minimally upregulated by BCG. To determine if
apoptosis could be a mechanism for growth inhibition in vivo, we obtained
alveolar macrophages by bronchoalveolar lavage from involved sites in patients
with active pulmonary tuberculosis. Using the TUNEL (terminal
deoxynucleotidyltransferase mediated nick end labeling) technique, we observed
significantly more apoptosis in involved segments of five tuberculosis patients
(14.8 +/- 1.9%) than in those of normal controls (<1%, P = 0.02) or in uninvolved
segments (4.3 +/- 0.9%, P < 0.05). We conclude that apoptosis of mononuclear
phagocytes induced by M. tuberculosis occurs in vivo and that in an in vitro
model of mycobacterial infection, apoptosis may be mediated by downregulation of
Bcl-2.
PMID- 9393828
TI - Expression, cloning, and characterization of a Candida albicans gene, ALA1, that
confers adherence properties upon Saccharomyces cerevisiae for extracellular
matrix proteins.
AB - Adherence of Candida albicans to host tissues is a necessary step for maintenance
of its commensal status and is likely a necessary step in the pathogenesis of
candidiasis. The extracellular matrix (ECM) proteins are some of the host tissue
and plasma proteins to which C. albicans adheres through adhesins located on the
fungal cell surface. To isolate genes encoding ECM adhesins, an assay was
developed based on the ability of yeast cells to adhere to magnetic beads coated
with the ECM protein fibronectin, type IV collagen, or laminin. A C. albicans
genomic library was constructed by cloning XbaI-partially-digested and size
selected fragments into pAUR112, an Escherichia coli-yeast low-copy-number
shuttle vector. The C. albicans library was transformed into Saccharomyces
cerevisiae YPH 499, and clones capable of adherence were selected by using ECM
protein-coated magnetic beads. A plasmid containing an approximately 8-kb insert
was isolated from 29 adherent clones. These clones exhibited adherence to all ECM
protein-coated magnetic beads and to human buccal epithelial cells. The ALA1 gene
(for agglutinin-like adhesin) was localized by subcloning it into a 5-kb XbaI
fragment which retained the adherence phenotype in both orientations. The
complete DNA sequence of the 5-kb insert was determined, and an open reading
frame (ORF) encoding 1,419 amino acid residues was identified. Deletions from the
5' and 3' ends extending into the DNA sequence encoding the 1,419-amino-acid ORF
product inactivated the adherence phenotype, suggesting that it is the coding
region of the ALA1 gene. A database search identified ALA1 to be similar to the
C. albicans ALS1 (for agglutinin-like sequence 1) protein and the S. cerevisiae
agglutinin protein (AG alpha1), although the homology at the primary amino acid
sequence level is limited to the first half of each of these proteins. ALA1
contains a central domain of six tandem repeats of 36 amino acids. We discuss the
significance of various predicted ALA1 structural motifs and their relationships
to function in the adherence process.
PMID- 9393829
TI - A highly adherent phenotype associated with virulent Bvg+-phase swine isolates of
Bordetella bronchiseptica grown under modulating conditions.
AB - The ability of Bvg(-)-phase and Bvg(+)-phase Bordetella bronchiseptica swine
isolates, grown under modulating or nonmodulating conditions, to adhere to swine
ciliated nasal epithelial cells was determined. When virulent strains were
cultivated at 37 degrees C in the Bvg+ phase, numerous adherent bacteria
(approximately eight per cell, depending on the strain used) were observed.
However, when such strains were grown under modulating conditions (23 degrees C),
a significant increase in the level of attachment was seen, suggesting that B.
bronchiseptica produces a Bvg-repressed adhesin under these conditions. bvg
mutant strains, including an isogenic bvgS mutant, adhered minimally. Western
blots indicated that two putative B. bronchiseptica adhesins, filamentous
hemagglutinin and pertactin, were not detectable in cultures displaying the
highly adherent phenotype. Several proteins apparent in Western blots obtained by
using bacterial extracts enriched in outer membrane proteins derived from B.
bronchiseptica grown at 23 degrees C were not present in similar extracts
prepared from an isogenic bvgS mutant grown at 23 degrees C or from the parent
strain grown at 37 degrees C. Adherence of bacteria cultivated at 23 degrees C
was almost completely abolished by pretreatment of organisms at 60 degrees C;
adherence was reduced by 57% when bacteria were pretreated with pronase E.
Temperature shift experiments revealed that the heightened level of adhesion that
occurs following growth at 23 degrees C was maintained for up to 18 h when
bacteria were subsequently incubated at 37 degrees C. We propose that a Bvg
repressed adhesin, expressed only by modulated bvg+ strains of B. bronchiseptica,
may play a key role in the initial colonization of naturally infected swine.
PMID- 9393830
TI - Infection with Chlamydia trachomatis alters the tyrosine phosphorylation and/or
localization of several host cell proteins including cortactin.
AB - Infection of epithelial cells by two biovars of Chlamydia trachomatis results in
the tyrosine phosphorylation of several host proteins. The most prominent change
in host protein tyrosine phosphorylation involves a complex of proteins with
molecular masses of 75 to 85 kDa (pp75/85) and 100 kDa (pp100). The C.
trachomatis-induced tyrosine phosphorylation of pp75/85 and pp100 is observed in
several cell lines, including epithelial cells, fibroblasts, and macrophages.
Subcellular fractionation and detergent solubility properties of pp75/85 are
consistent with its association with the cytoskeleton. Phosphoamino acid analysis
demonstrates that the pp75/85 complex is phosphorylated on both tyrosine and
serine residues. Immunofluorescence studies of chlamydia-infected cells by using
fluorescein isothiocyanate-phalloidin and antibodies to phosphotyrosine and
cortactin demonstrate that tyrosine-phosphorylated proteins, as well as
cortactin, are localized to the chlamydial vacuole and that this process is
facilitated by actin.
PMID- 9393831
TI - Internalin of Listeria monocytogenes with an intact leucine-rich repeat region is
sufficient to promote internalization.
AB - Listeria monocytogenes can use two different surface proteins, internalin (InlA)
and InlB, to invade mammalian cells. The exact role of these invasiveness factors
in vivo remains to be determined. In cultured cells, InlA is necessary to promote
Listeria entry into human epithelial cells, such as Caco-2 cells, whereas InlB is
necessary to promote Listeria internalization in several other cell types,
including hepatocytes, fibroblasts, and epithelioid cells, such as Vero, HeLa,
CHO, or Hep-2 cells. We have recently reported that the InlA receptor on Caco-2
cells is the cell adhesion molecule E-cadherin and demonstrated that
nonpermissive fibroblasts become permissive for internalin-mediated entry when
transfected with the gene coding for LCAM, the chicken homolog of the human E
cadherin gene. In this study, we demonstrate for the first time that the
internalin protein alone is sufficient to promote internalization into cells
expressing its receptor. Indeed, internalin confers invasiveness to both
Enterococcus faecalis and internalin-coated latex beads. As shown by transmission
electron microscopy, these beads were phagocytosed via a "zipper" mechanism
similar to that observed during the internalin-E-cadherin-mediated entry of
Listeria. Moreover, a functional analysis of internalin demonstrates that its
amino-terminal region, encompassing the leucine-rich repeat (LRR) region and the
inter-repeat (IR) region, is necessary and sufficient to promote bacterial entry
into cells expressing its receptor. Several lines of evidence suggest that the
LRR region would interact directly with E-cadherin, whereas the IR region would
be required for a proper folding of the LRR region.
PMID- 9393832
TI - Expression of thin aggregative fimbriae promotes interaction of Salmonella
typhimurium SR-11 with mouse small intestinal epithelial cells.
AB - The factors that mediate binding of Salmonella typhimurium to small intestinal
epithelial cells have not been fully characterized. In this paper we demonstrate
that elimination of production of thin aggregative fiber by a transposon
insertion within the gene encoding the subunit protein of the fiber reduced
binding of S. typhimurium SR-11 to a conditionally immortalized proximal small
intestinal epithelial cell line established from transgenic mice. This binding
defect could be overcome by transcomplementation with a wild-type allele. The
conditionally immortalized cell line should prove useful in identifying the
epithelial cell receptor for bacterial attachment since expression of its
bacterial binding activity can be induced by manipulating the line's
proliferative status.
PMID- 9393833
TI - A nonamer peptide derived from Listeria monocytogenes metalloprotease is
presented to cytolytic T lymphocytes.
AB - Listeria monocytogenes is an intracellular bacterium that secretes proteins into
the cytosol of infected macrophages. Major histocompatibility complex (MHC) class
I molecules bind peptides that are generated by the degradation of bacterial
proteins and present them to cytolytic T lymphocytes (CTL). In this study we have
investigated CTL responses in L. monocytogenes-immunized mice to peptides that
(i) derive from the L. monocytogenes proteins phosphatidylinositol-specific
phospholipase C, lecithinase (most active on phosphatidylcholine),
metalloprotease (Mpl), PrfA, and the ORF-A product and (ii) conform to the
binding motif of the H2-Kd MHC class I molecule. We identified a nonamer peptide,
Mpl 84-92, that is presented to L. monocytogenes-specific CTL by H2-Kd MHC class
I molecules. Unlike other motif-conforming peptides derived from the secreted Mpl
of L. monocytogenes, Mpl 84-92 is bound with high affinity by H2-Kd. Mpl 84-92 is
the fourth L. monocytogenes-derived peptide found to be presented to CTL by the
H2-Kd molecule during infection and demonstrates the importance of high-affinity
interactions between antigenic peptides and MHC class I molecules for CTL
priming.
PMID- 9393834
TI - The role of Legionella pneumophila-infected Hartmannella vermiformis as an
infectious particle in a murine model of Legionnaire's disease.
AB - Legionella pneumophila is a bacterial parasite of many species of freshwater
protozoa and occasionally an intracellular pathogen of humans. While protozoa are
known to play a key role in the persistence of L. pneumophila in the environment,
there has been limited research addressing the potential role of L. pneumophila
infected protozoa in the pathogenesis of human infection. In this report, the
potential role of an L. pneumophila-infected amoeba as an infectious particle in
replicative L. pneumophila lung infection was investigated in vivo with the
amoeba Hartmannella vermiformis, a natural reservoir of L. pneumophila in the
environment. L. pneumophila-infected H. vermiformis organisms were prepared by
coculture of the amoebae and virulent L. pneumophila cells in vitro. A/J mice,
which are susceptible to replicative L. pneumophila lung infection, were
subsequently inoculated intratracheally with L. pneumophila-infected H.
vermiformis organisms (10(6) amoebae containing 10(5) bacteria), and
intrapulmonary growth of the bacteria was assessed. A/J mice inoculated
intratracheally with L. pneumophila-infected H. vermiformis organisms developed
replicative L. pneumophila lung infections. Furthermore, L. pneumophila-infected
H. vermiformis organisms were more pathogenic than an equivalent number of
bacteria or a coinoculum of L. pneumophila cells and uninfected amoebae. These
results demonstrate that L. pneumophila-infected amoebae are infectious particles
in replicative L. pneumophila infections in vivo and support the hypothesis that
inhaled protozoa may serve as cofactors in the pathogenesis of pulmonary disease
induced by inhaled respiratory pathogens.
PMID- 9393835
TI - CD8+ T cells are activated during the early Th1 and Th2 immune responses in a
murine Lyme disease model.
AB - T-helper responses following Borrelia burgdorferi infection in mice determine
susceptibility to Lyme arthritis. The ratio of interleukin 4-positive, CD4+ to
gamma interferon (IFN-gamma)-positive, CD4+ T cells was significantly greater in
infected BALB/cJ mice than in infected C3H/HeJ mice. Increased numbers of IFN
gamma-producing cells predicted greater arthritis severity, and CD8+ T cells were
the main source of IFN-gamma in both strains.
PMID- 9393836
TI - A systemic downregulation of gamma interferon production is associated with acute
shigellosis.
AB - Production of cytokines by peripheral blood mononuclear cells from Shigella
infected patients was assessed. The frequencies of tumor necrosis factor alpha
(TNF-alpha), TNF-beta, and transforming growth factor beta mRNA-expressing cells
were persistently upregulated during the course of shigellosis in comparison to
those of healthy controls. In contrast, the frequency of gamma interferon (IFN
gamma) mRNA-expressing cells was significantly reduced during the acute stage
compared to that during the convalescent stage and to that of healthy Bangladeshi
controls (P < 0.01). Constitutive IFN-gamma production in Bangladeshi controls
was significantly upregulated compared to that in Swedish controls.
PMID- 9393837
TI - The role of complement, antibody, and tumor necrosis factor alpha in the killing
of Plasmodium falciparum by the monocytic cell line THP-1.
AB - Killing of Plasmodium falciparum blood forms by the differentiated human
myelomonocytic THP-1Mo cell line was studied by a radiometric assay. Results
showed that parasite killing was promoted by complement, antimalarial antibody,
and the cytokines tumor necrosis factor alpha and gamma interferon.
Differentiated THP-1Mo appears to be a useful monocytic cell line for the study
of mechanisms of immunity to Plasmodium.
PMID- 9393838
TI - Interference of peptides and specific antibodies with the function of the
Actinobacillus pleuropneumoniae transferrin-binding protein.
AB - Multiple-antigenic peptides (MAPs) containing transferrin-binding domains of the
Actinobacillus pleuropneumoniae serotype 7-derived transferrin-binding protein
(TfbA) (K. Strutzberg, L. von Olleschik, B. Franz, C. Pyne, M. A. Schmidt, and G.
F. Gerlach, Infect. Immun. 63:3846-3850, 1995) were constructed. It was found
that the MAPs inhibited transferrin binding of the recombinant TfbA protein,
whereas antibodies directed against transferrin-binding domains failed to do so.
PMID- 9393839
TI - Experimental infection of C3H mice with avian, porcine, or human isolates of
Serpulina pilosicoli.
AB - C3H/HeJ (lps(d)/lps(d)) and C3H/HeOuJ (lps(n)/lps(n)) mice were infected via
gastric intubation with avian, porcine, or human isolates of weakly hemolytic
spirochetes classified as Serpulina pilosicoli. Upon histopathological
examination of cecal tissue from mice infected with avian or porcine isolates,
colonization of spirochetes attached end-on to the apical surface of enterocytes
was observed. There were no apparent differences in severity of cecal lesions
between the lipopolysaccharide (LPS)-responsive (C3H/HeOuJ) and LPS
hyporesponsive (C3H/HeJ) mouse strains infected with these isolates. Transmission
electron microscopy showed spirochetes invaginated into the host cell membrane
with resultant effacement of microvilli and loss of the glycocalyx. End-on
attachment of the human isolate S. jonesii was not observed in the present
studies, although weakly hemolytic spirochetes were reisolated from mice infected
with S. jonesii. Moreover, results of Western immunoblot experiments showed mice
developed serum antibody responses to the S. pilosicoli isolates examined. Thus,
the present results indicate that specific isolates of S. pilosicoli can colonize
mice and exhibit end-on attachment to cecal enterocytes.
PMID- 9393840
TI - A monoclonal antibody to Candida albicans enhances mouse neutrophil candidacidal
activity.
AB - A monoclonal antibody (MAb) to Candida albicans (MAb B6.1) that protects against
candidiasis and the nonprotective MAb B6 were compared for ability to support
neutrophil (polymorphonuclear leukocyte [PMN]) candidacidal activity. Both MAbs
are immunoglobulin M, and each recognizes distinct C. albicans mannan cell wall
determinants. PMN candidacidal activity was assessed by transmission electron
microscopy and by an in vitro killing assay. The results indicated that MAb B6.1,
but not MAb B6, enhances ingestion and killing of yeast cells by PMN in the
presence of serum complement.
PMID- 9393841
TI - Identification of shuA, the gene encoding the heme receptor of Shigella
dysenteriae, and analysis of invasion and intracellular multiplication of a shuA
mutant.
AB - shuA encodes a 70-kDa outer membrane heme receptor in Shigella dysenteriae.
Analysis of the shuA DNA sequence indicates that this gene encodes a protein with
homology to TonB-dependent receptors of gram-negative bacteria. Transport of heme
by the ShuA protein requires TonB and its accessory proteins ExbB and ExbD. The
shuA DNA sequence contains a putative Fur box overlapping the -10 region of a
potential shuA promoter, and the expression of shuA is repressed by exogenous
iron or hemin in a Fur-dependent manner, although hemin repressed expression to a
lesser extent than iron salts. Disruption of this open reading frame on the S.
dysenteriae chromosome by marker exchange yielded a strain that failed to use
heme as an iron source, indicating that shuA is essential for heme transport in
S. dysenteriae. However, shuA is not essential for invasion or multiplication
within cultured Henle cells; the shuA mutant invaded and produced normal plaques
in confluent cell monolayers.
PMID- 9393842
TI - Characterization of lipoprotein IRP1 from Corynebacterium diphtheriae, which is
regulated by the diphtheria toxin repressor (DtxR) and iron.
AB - The Corynebacterium diphtheriae irp1 gene is negatively regulated by DtxR and
iron. The nucleotide sequence of irp1 revealed that it has homology with genes
involved in iron acquisition. Expression of the irp1 gene showed that it encodes
a lipoprotein (IRP1) with a predicted size of 38 kDa. Northern blot experiments
indicated that transcription from the irp1 promoter is repressed in high-iron
medium and suggested that irp1 is part of an iron-regulated operon.
PMID- 9393843
TI - Association of Leishmania heat shock protein 83 antigen and immunoglobulin G4
antibody titers in Brazilian patients with diffuse cutaneous leishmaniasis.
AB - Diffuse cutaneous leishmaniasis (DCL) is characterized by the presence of
numerous nonulcerated nodules and plaques containing large numbers of Leishmania
amazonensis parasites and few lymphoid elements. The immune responses of DCL
patients reflect severe antigen-specific T-cell deficiencies, while the antibody
response to Leishmania antigens is often accentuated. We report herein on the
Leishmania antigen-specific antibody subclass distribution in DCL patients and
demonstrate that a dominant antigen contributing to the biased immunoglobulin G4
antibody subclass in sera of DCL patients is Leishmania heat shock protein 83.
PMID- 9393845
TI - Quantification of conserved antigens in Helicobacter pylori during different
culture conditions.
AB - In this study, we raised monoclonal antibodies (MAbs) against three conserved
Helicobacter pylori antigens, i.e., the N-acetylneuraminyllactose-binding
fibrillar hemagglutinin, HpaA; the flagellin subunits, FlaA and FlaB; and a
species-specific 26-kDa protein. The MAbs were used for the development of
sensitive inhibition enzyme-linked immunosorbent assays for quantification of
these antigens in H. pylori during various culture conditions. The quantities of
these antigens varied considerably (up to 8-fold) during different culture
procedures and between strains (up to 10-fold).
PMID- 9393844
TI - The transcriptional regulator SoxS is required for resistance of Salmonella
typhimurium to paraquat but not for virulence in mice.
AB - In Escherichia coli, the SoxRS regulon is required for resistance to redox
cycling agents which elevate cytosolic superoxide levels, as well as for
resistance to nitric oxide-dependent macrophage killing. In Salmonella
typhimurium, SoxS is also required for enhanced expression of Mn-superoxide
dismutase and resistance to paraquat, but not for resistance to nitric oxide
donor compounds in vitro, resistance to macrophage killing, or virulence in mice.
Differences in other antioxidant defense systems or compensation by homologous
regulons may account for species-specific differences in the role of SoxS.
PMID- 9393846
TI - Characterization and immunogenicity of Salmonella typhimurium SL1344 and UK-1
delta crp and delta cdt deletion mutants.
AB - S. typhimurium SL1344 and UK-1 mutants with deletions of the crp (cyclic AMP
receptor protein) and cdt (colonization of deep tissues) genes have been
constructed and characterized, and their levels of virulence and immunogenicity
have been determined for BALB/c mice. All Crp- Cdt- and Crp+ Cdt- mutants were
avirulent, as mice survived oral doses of 10(9) cells without illness. All the
mutants colonized the gut-associated lymphoid tissue efficiently, but capacities
to colonize deeper tissues, such as those of the spleen and liver, and blood were
significantly reduced for the Crp- Cdt- and Crp+ Cdt- mutants compared with the
Crp- Cdt+ mutant and the wild-type parent strain. The Crp- Cdt- and Crp+ Cdt-
SL1344 strains induced complete protection, as all mice immunized with the
mutants survived challenge with approximately 10(4) times the 50% lethal dose of
the wild-type SL1344 strain. The Crp- UK-1 strain was least attenuated yet
induced the highest level of protective immunity against challenge with the wild
type UK-1 strain. The Crp+ Cdt- and Crp- Cdt- strains, although totally
attenuated, differed in immunogenicity to challenge with the highly virulent UK-1
parent, with the apparently hyperattenuated Crp- Cdt- strain inducing a lower
level of protective immunity than the Crp+ Cdt- strain. Nevertheless, these UK-1
Crp- Cdt- and Crp+ Cdt- strains induced complete protective immunity to challenge
with the less-virulent SL1344 wild-type strain. Taken collectively, the results
indicate that the attenuation of a highly virulent S. typhimurium strain can
yield a vaccine that induces excellent protective immunity to challenge with less
virulent S. typhimurium strains.
PMID- 9393847
TI - Splicing into senescence: the curious case of p16 and p19ARF.
PMID- 9393848
TI - Cytochrome c: can't live with it--can't live without it.
PMID- 9393849
TI - Protein translocation in the three domains of life: variations on a theme.
PMID- 9393850
TI - Biogenesis of the gram-negative bacterial envelope.
PMID- 9393851
TI - Membrane protein biogenesis: regulated complexity at the endoplasmic reticulum.
PMID- 9393852
TI - Impaired maternal behavior in mice lacking norepinephrine and epinephrine.
AB - The roles of norepinephrine (NE) and epinephrine in behavior were investigated by
targeted disruption of the dopamine beta-hydroxylase (Dbh) gene, thereby
eliminating these compounds in vivo. Most heterozygous pups born to Dbh-/-
females died within several days of birth and were often found scattered within
the bedding. Potential causes including deficits in olfaction and lactation were
not apparent. A deficit in maternal behavior was confirmed by the lack of pup
retrieval exhibited by Dbh-/- virgin females. Restoration of NE shortly before
but not after birth induced females that previously abandoned their litters to
act maternally. Our results suggest that NE is responsible for long-lasting
changes that promote maternal behavior during both development and parturition in
mice.
PMID- 9393853
TI - Complex polymorphisms in an approximately 330 kDa protein are linked to
chloroquine-resistant P. falciparum in Southeast Asia and Africa.
AB - Chloroquine resistance in a P. falciparum cross maps as a Mendelian trait to a 36
kb segment of chromosome 7. This segment harbors cg2, a gene encoding a unique
approximately 330 kDa protein with complex polymorphisms. A specific set of
polymorphisms in 20 chloroquine-resistant parasites from Asia and Africa, in
contrast with numerous differences in 21 sensitive parasites, suggests selection
of a cg2 allele originating in Indochina over 40 years ago. One chloroquine
sensitive clone exhibited this allele, suggesting another resistance component.
South American parasites have cg2 polymorphisms consistent with a separate origin
of resistance. CG2 protein is found at the parasite periphery, a site of
chloroquine transport, and in association with hemozoin of the digestive vacuole,
where chloroquine inhibits heme polymerization.
PMID- 9393854
TI - Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic
cells.
AB - Invasion of human mucosal cells by N. gonorrhoeae via the binding to
heparansulfate proteoglycan receptors is considered a crucial event of the
infection. Using different human epithelial cells and primary fibroblasts, we
show here an activation of the phosphatidylcholine-specific phospholipase C (PC
PLC) and acidic sphingomyelinase (ASM) by N. gonorrhoeae, resulting in the
release of diacylglycerol and ceramide. Genetic and/or pharmacological blockade
of ASM and PC-PLC cause inhibition of cellular invasion by N. gonorrhoeae.
Complementation of ASM-deficient fibroblasts from Niemann-Pick disease patients
restored N. gonorrhoeae-induced signaling and entry processes. The activation of
PC-PLC and ASM, therefore, is an essential requirement for the entry of N.
gonorrhoeae into distinct nonphagocytic human cell types including several
epithelial cells and primary fibroblasts.
PMID- 9393855
TI - Regulation of Golgi structure through heterotrimeric G proteins.
AB - We have previously shown that ilimaquinone (IQ), a marine sponge metabolite,
causes complete vesiculation of the Golgi stacks. By reconstituting the IQ
mediated vesiculation of the Golgi apparatus in permeabilized cells, we now
demonstrate that this process does not require ARF and coatomers, which are
necessary for the formation of Golgi-derived COPI vesicles. We find that IQ
mediated Golgi vesiculation is inhibited by G alpha(s)-GDP and G alpha(i3)-GDP.
Interestingly, adding betagamma subunits in the absence of IQ is sufficient to
vesiculate Golgi stacks. Our findings reveal that IQ-mediated Golgi vesiculation
occurs through activation of heterotrimeric G proteins and that it is the free
betagamma, and not the activated alpha subunit, that triggers Golgi vesiculation.
PMID- 9393856
TI - Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria.
AB - Mitochondrial physiology is disrupted in either apoptosis or necrosis. Here, we
report that a wide variety of apoptotic and necrotic stimuli induce progressive
mitochondrial swelling and outer mitochondrial membrane rupture. Discontinuity of
the outer mitochondrial membrane results in cytochrome c redistribution from the
intermembrane space to the cytosol followed by subsequent inner mitochondrial
membrane depolarization. The mitochondrial membrane protein Bcl-xL can inhibit
these changes in cells treated with apoptotic stimuli. In addition, Bcl-xL
expressing cells adapt to growth factor withdrawal or staurosporine treatment by
maintaining a decreased mitochondrial membrane potential. Bcl-xL expression also
prevents mitochondrial swelling in response to agents that inhibit oxidative
phosphorylation. These data suggest that Bcl-xL promotes cell survival by
regulating the electrical and osmotic homeostasis of mitochondria.
PMID- 9393857
TI - Avian hairy gene expression identifies a molecular clock linked to vertebrate
segmentation and somitogenesis.
AB - We have identified and characterized c-hairy1, an avian homolog of the Drosophila
segmentation gene, hairy. c-hairy1 is strongly expressed in the presomitic
mesoderm, where its mRNA exhibits cyclic waves of expression whose temporal
periodicity corresponds to the formation time of one somite (90 min). The
apparent movement of these waves is due to coordinated pulses of c-hairy1
expression, not to cell displacement along the anteroposterior axis, nor to
propagation of an activating signal. Rather, the rhythmic c-hairy mRNA expression
is an autonomous property of the paraxial mesoderm. These results provide
molecular evidence for a developmental clock linked to segmentation and
somitogenesis of the paraxial mesoderm, and support the possibility that
segmentation mechanisms used by invertebrates and vertebrates have been
conserved.
PMID- 9393858
TI - Tumor suppression at the mouse INK4a locus mediated by the alternative reading
frame product p19ARF.
AB - The INK4a tumor suppressor locus encodes p16INK4a, an inhibitor of cyclin D
dependent kinases, and p19ARF, an alternative reading frame protein that also
blocks cell proliferation. Surprisingly, mice lacking p19ARF but expressing
functional p16INK4a develop tumors early in life. Their embryo fibroblasts (MEFs)
do not senesce and are transformed by oncogenic Ha-ras alone. Conversion of
ARF+/+ or ARF+/- MEF strains to continuously proliferating cell lines involves
loss of either p19ARF or p53. p53-mediated checkpoint control is unperturbed in
ARF-null fibroblast strains, whereas p53-negative cell lines are resistant to
p19ARF-induced growth arrest. Therefore, INK4a encodes growth inhibitory proteins
that act upstream of the retinoblastoma protein and p53. Mutations and deletions
targeting this locus in cancer cells are unlikely to be functionally equivalent.
PMID- 9393859
TI - Identification of clonogenic common lymphoid progenitors in mouse bone marrow.
AB - The existence of a common lymphoid progenitor that can only give rise to T cells,
B cells, and natural killer (NK) cells remains controversial and constitutes an
important gap in the hematopoietic lineage maps. Here, we report that the Lin(
)IL-7R(+)Thy-1(-)Sca-1loc-Kit(lo) population from adult mouse bone marrow
possessed a rapid lymphoid-restricted (T, B, and NK) reconstitution capacity in
vivo but completely lacked myeloid differentiation potential either in vivo or in
vitro. A single Lin(-)IL-7R(+)Thy-1(-)Sca-1loc-Kit(lo) cell could generate at
least both T and B cells. These data provide direct evidence for the existence of
common lymphoid progenitors in sites of early hematopoiesis.
PMID- 9393860
TI - MAP kinases with distinct inhibitory functions impart signaling specificity
during yeast differentiation.
AB - Filamentous invasive growth of S. cerevisiae requires multiple elements of the
mitogen-activated protein kinase (MAPK) signaling cascade that are also
components of the mating pheromone response pathway. Here we show that, despite
sharing several constituents, the two pathways use different MAP kinases. The
Fus3 MAPK regulates mating, whereas the Kss1 MAPK regulates filamentation and
invasion. Remarkably, in addition to their kinase-dependent activation functions,
Kss1 and Fus3 each have a distinct kinase-independent inhibitory function. Kss1
inhibits the filamentation pathway by interacting with its target transcription
factor Ste12. Fus3 has a different inhibitory activity that prevents the
inappropriate activation of invasion by the pheromone response pathway. In the
absence of Fus3, there is erroneous crosstalk in which mating pheromone now
activates filamentation-specific gene expression using the Kss1 MAPK.
PMID- 9393861
TI - The MinE ring: an FtsZ-independent cell structure required for selection of the
correct division site in E. coli.
AB - E. coli cell division is mediated by the FtsZ ring and associated factors.
Selection of the correct division site requires the combined action of an
inhibitor of FtsZ ring formation (MinCD) and of a topological specificity factor
that somehow prevents MinCD action at the middle of the cell (MinE). Here we show
that a biologically active MinE-Gfp fusion accumulates in an annular structure
near the middle of young cells. Formation of the MinE ring required MinD but was
independent of MinC and continued in nondividing cells in which FtsZ function was
inhibited. The results indicate that the MinE ring represents a novel cell
structure, which allows FtsZ ring formation at midcell by suppressing MinCD
activity at this site.
PMID- 9393862
TI - Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt
1 receptor.
AB - Vascular endothelial growth factor (VEGF) is a homodimeric hormone that induces
proliferation of endothelial cells through binding to the kinase domain receptor
and the Fms-like tyrosine kinase receptor (Flt-1), the extracellular portions of
which consist of seven immunoglobulin domains. We show that the second and third
domains of Flt-1 are necessary and sufficient for binding VEGF with near-native
affinity, and that domain 2 alone binds only 60-fold less tightly than wild-type.
The crystal structure of the complex between VEGF and the second domain of Flt-1
shows domain 2 in a predominantly hydrophobic interaction with the "poles" of the
VEGF dimer. Based on this structure and on mutational data, we present a model of
VEGF bound to the first four domains of Flt-1.
PMID- 9393863
TI - Metals, motifs, and recognition in the crystal structure of a 5S rRNA domain.
AB - Two new RNA structures portray how non-Watson-Crick base pairs and metal ions can
produce a unique RNA shape suitable for recognition by proteins. The crystal
structures of a 62 nt domain of E. coli 5S ribosomal RNA and a duplex dodecamer
encompassing an internal loop E have been determined at 3.0 and 1.5 A,
respectively. This loop E region is distorted by three "cross-strand purine
stacks" and three novel, water-mediated noncanonical base pairs and stabilized by
a four metal ion zipper. These features give its minor groove a unique hydrogen
bonding surface and make the adjacent major groove wide enough to permit
recognition by the ribosomal protein L25, which is expected to bind to this
surface.
PMID- 9393864
TI - Effect of high-energy phosphates and free radical scavengers on replant survival
in an ischemic extremity model.
AB - In replantation surgery, preoperative and intraoperative ischemia can lead to
irreversible changes that prevent reperfusion during the subsequent re
establishment of circulation. These changes are termed the no-reflow phenomenon.
Ischemic phase damage was addressed by comparing the dose-response effects of
controls vs. five different high-energy phosphate compounds on replanted limb
survival. Reperfusion damage was evaluated via comparisons of controls with
superoxide dismutase (SOD). Ischemic hindlimbs treated with high-energy
phosphates displayed improved survival compared with controls. Limbs treated with
SOD demonstrated no change in survival at 4 hours and improved survival at 8
hours. Combining adenosine and SOD had no improved effect on survival. Adenosine
was the most effective high-energy phosphate in limiting ischemic damage. The
free radical scavenger (SOD) was beneficial only at the later stages of ischemia.
In this experimental model, there appears to be a role for both phosphates and
free radical scavengers in enhancing ischemic tissue survival.
PMID- 9393865
TI - Application of hemodilution in microsurgical free flap transplantation.
AB - The intra-operative hemodilution and blood auto-transfusion is a blood-saving
technique that can be performed when major blood loss is expected. The effects of
this technique were studied in 30 microsurgical free flap transplantation
patients. Between 400-600 ml blood was collected from the patients before
surgery. The patients received dextran, a balanced salt solution, and glucose
with the ratio of 3:1 to the collected blood volume, bleeding, and urine before
the blood auto-transfusion. There were no significant changes in RBC, HCT, MCV,
blood pressure, or heart rate. Of the 30 free flaps, 28 were successful with a
93.3% survival rate. The safety of intra-operative hemodilution and autologous
blood transfusion in microsurgery as well as the effect of hemodilution on
transplanted flap survival are discussed in this study.
PMID- 9393866
TI - Effect of anastomosis and geometry of vessel curvature on blood flow velocity and
patency in microvessels.
AB - The effect of the geometry of the vessel and the number of anastomoses on the
blood flow was studied. Four different shapes of the vessel were constructed by
using a 6-cm-long double vein graft model with three anastomoses: (1) an alpha
loop, (2) an omega loop, (3) a sigmoid curve, and (4) straight. Blood flow was
measured by an ultrasound Doppler flowmeter. The result showed no alternation in
blood flow across different geometry and through three patent microanastomoses.
However, six out of seven vein grafts were thrombosed at 24 hr postoperative due
to vascular kinks. This model demonstrates potential sites of kinking at the
dissection end of the femoral artery, the microanastomoses, the side branches of
the vein graft, and the adventitial adhesions. This model is recommended to
microvascular trainees for the study of kinking and the management of redundant
pedicles and vein grafting.
PMID- 9393867
TI - Actions of glucocorticosteroids on ischemic-reperfused muscle and cutaneous
tissue.
AB - Ischemia-reperfusion injury represents a complex series of vascular and cellular
events that resembles an acute inflammatory reaction within the reperfused
tissue. This article provides an overview of glucocorticosteroid effects on cells
and tissues involved in inflammatory reaction following ischemia-reperfusion of
muscle and cutaneous tissue. Glucocorticosteroids exert a variety of effects that
influence the microcirculation. These effects include leukocyte recruitment,
reduction of vascular permeability, inhibition of formation of cytokines or other
mediators, and modulation of enzyme systems involved in inflammation. The current
view is that glucocorticosteroids act through cytoplasmic receptors by
controlling the transcription of certain genes encoding regulatory proteins, but
the exact mechanisms of glucocorticoid action on ischemia-reperfusion are not
completely understood. Potential mechanisms may involve modulation of neutrophil
and endothelial function, inhibition of formation of arachidonic acid products,
and attenuation of lipid peroxidation of biological membranes through membrane
stabilization and scavenging of toxic free radicals.
PMID- 9393868
TI - Free posterior tibial perforator flap: anatomy and a report of 6 cases.
AB - Anatomy of cutaneous perforators of the posterior tibial artery were studied in
20 limbs of 10 cadavers. The majority of the perforators (n = 74, 61%) were
located in the middle two quarters of the leg, at an average of 18.6 cm (s.d. 4.5
cm; range 10.5-26 cm) from the medial malleolus, or around 54% (s.d 16%) of the
length of the leg. There were usually 3 or 4 perforators in this region, with an
average caliber of 1.5 mm (s.d. 0.2 mm; range 1-2 m.m.) and an average length
from the posterior tibial artery to the skin of 4.0 cm (s.d. 1.3 cm; range 2.5-6
c.m.). A free fasciocutaneous skin flap based on one of these perforators (the
posterior tibial perforator flap, PTP flap) was successfully transplanted in 6
cases. This modified technique of the posterior tibial flap enables the surgeon
to retain the posterior tibial artery when the skin of the medial aspect of the
leg is chosen to be used as skin flap donor.
PMID- 9393869
TI - Effect of vein grafting on the survival of microvascularly transplanted muscle
flaps.
AB - Since vein grafting is often required during transplantation of free muscle flaps
but is associated with a higher failure rate than those flaps transplanted with
primary anastomoses, we sought to compare primary repair with the use of vein
grafting in an experimental setting. We transplanted the gracilis muscle to the
contralateral side in 98 rats using four different methods of vessel repair. In
the Control group (n = 28), both femoral vessels were anastomosed primarily. In
Experimental Group 1 (n = 25), the femoral artery was anastomosed with an
epigastric vein graft and the femoral vein was anastomosed primarily. In
Experimental Group 2 (n = 25), the femoral vein was anastomosed with a femoral
vein graft and the femoral artery was anastomosed primarily. In Experimental
Group 3 (n = 20), both femoral vessels were anastomosed with vein grafts. The
Control and Experimental Groups 1-3 survival rates were 89.3, 76.0, 84.0, and
70.0%, respectively; none of the experimental group survival rates was
significantly different from that of the control (P < 0.5). This study
demonstrates that the use of size-matched, interpositional vein grafts in the
arterial or venous pedicle of the rat gracilis muscle flap during transplantation
did not significantly decrease flap survival as compared to primary arterial or
venous anastomoses. If the observed failure rate persisted with expansion of the
study groups to 60-100 animals each, the failure rate of flaps with vein grafts
would be significantly lower and comparable to failure rates reported in some
clinical series. The large numbers necessary to significantly show this decrease
make this model impractical for further studies.
PMID- 9393870
TI - Influence of postischemic administration of oxyradical antagonists on ischemic
injury to rabbit skeletal muscle.
AB - The aim of this study was to determine whether the administration of free radical
antagonists, immediately before and during the early minutes of reperfusion,
improves muscle survival 24 hr after a period of ischemia. Rabbit rectus femoris
muscles were isolated, made ischemic for 3 1/2 hr and treated with either
desferrioxamine (DFX), an Fe3+ chelator, superoxide dismutase and catalase (SOD &
CAT), which quench superoxide and hydrogen peroxide, or allopurinol, an inhibitor
of xanthine oxidase (XO). After 24 hr reperfusion, muscle viability (+/-s.e.m.),
measured by the nitro blue tetrazolium (NBT) vital staining technique, was 41.6
+/- 11.3% for saline-treated ischemic controls, 30.6 +/- 7.6% for DFX-treated,
46.7 +/- 10.3% for SOD & CAT-treated, and 43.3 +/- 9.5% for allopurinol-treated
muscles. None of the treated groups differed significantly from the ischemic
control group. Tissue myeloperoxidase, ATP and reduced glutathione levels, and
plasma lactate dehydrogenase (LDH) and aspartate transaminase (AST) levels were
increased by ischemia and reperfusion in all groups, but the changes did not
differ between the treatment groups. Levels of XO in the rabbit muscle were
determined and found to be very low in both normal and postischemic muscle. As XO
is the target enzyme of allopurinol, its absence provides a basis for the lack of
effect of this agent. However, it is not clear why DFX and SOD & CAT had no
protective effect.
PMID- 9393871
TI - The multiple endocrine neoplasia type 2B point mutation switches the specificity
of the Ret tyrosine kinase towards cellular substrates that are susceptible to
interact with Crk and Nck.
AB - The RET proto-oncogene encodes a Tyrosine Kinase Receptor (RTK) which plays an
important function in the proliferation and/or differentiation of neuroectodermic
cells. Germline mutation of a methionine to a threonine within the RET TK domain
predisposes to the Multiple Endocrine Neoplasia type 2B (MEN 2B). It has been
demonstrated that, unlike c-Ret, the MEN 2B mutated Ret displays constitutive TK
activity, tyrosine autophosphorylation and transforms fibroblasts. However, this
oncoprotein is more than a fully activated wild-type (WT) Ret TK since it also
displays modified substrate specificity. Change in substrate specificity leads to
the tyrosine autophosphorylation of MEN 2B Ret on new sites as well as the
phosphorylation of several novel downstream targets. But, none of these
substrates have been identified and the ability of MEN 2B Ret phosphoprotein to
interact with Src Homology 2 (SH2) domain containing molecules has been poorly
investigated. In this report, using a constitutively activated Ret TK form, Ret
ptc 2, we demonstrate that the MEN 2B as the activated WT Ret TK binds to several
SH2 signalling proteins such as Shc, Grb-2, Phospholipase Cgamma, Crk and Nck.
However, in contrast to the activated WT form, expression of the MEN 2B mutated
Ret-ptc 2 results in the tyrosine phosphorylation of a panel of proteins which
interestingly interact with Crk and Nck. We identified Paxillin, a cytoskeletal
protein as one of the Crk associated proteins that is dramatically phosphorylated
in MEN 2B but not in WT Ret expressing cells. These data suggest that MEN 2B
mutated Ret triggers distinct signalling pathways that might be related to its
transforming power.
PMID- 9393872
TI - Activation of p65 NF-kappaB protein by p210BCR-ABL in a myeloid cell line
(P210BCR-ABL activates p65 NF-kappaB).
AB - The chimeric tyrosine kinase p210BCR-ABL is involved in the pathogenesis of
chronic myelogenous leukemia. It transforms immature hematopoietic cells in vitro
and abrogates IL-3-dependent growth. The mechanisms by which p210BCR-ABL mediates
its oncogenicity are not well elucidated. Identifying transcription factors
targeted by the chimeric protein may help to clarify these mechanisms. We have
analysed the effect of p210BCR-ABL expression on NF-kappaB activity in DA1 cells
(an IL-3-dependent murine myeloid progenitor cell line). A specific stimulation
of NF-kappaB activity by kinase-active wild-type p210BCR-ABL has been evidenced
by transcriptional activation assays. Electrophoretic mobility supershift assays
revealed the presence of p65 protein (RelA) DNA binding activity in p210BCR-ABL
transformed DA1 cells but not in parental DA1 cells. Activation of RelA in
transformed DA1 cells may occur by protein stabilization. Experiments using
oligonucleotides antisense to RelA showed that p210BCR-ABL transfected cells
failed to survive after IL-3 removal. Moreover, inhibition of cellular growth was
shown following treatment of p210BCR-ABL transformed DA1 cells by p65 antisense
oligonucleotides. This study suggests that p65 NF-kappaB may be an effector for
p210BCR-ABL and probably contributes to its induced transformation process.
PMID- 9393873
TI - JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases.
AB - The function of the tumor suppressor protein p53 is modulated by post
translational events, primarily by phosphorylation. p53 is phosphorylated at
multiple sites by a variety of protein kinases depending on the cellular
environment. It has been suggested that serine 34 of mouse p53 is specifically
phosphorylated by a stress-activated protein kinase in response to ultraviolet
radiation. Since serine 34 is a major site of phosphorylation of mouse p53 in
vivo and its specific protein kinase is still not definitively identified yet, we
have examined the c-Jun N-terminal kinase 1 (JNK1) activity on p53 by expressing
JNK1 in 293T cells. We show here that activated JNK1 phosphorylates mouse p53
specifically at serine 34 in vitro, while a dominanant-negative JNK1 mutant does
not phosphorylate p53. More importantly, JNK1 associates with p53 in vivo, with
or without activation, confirming that JNK1 is indeed a p53 kinase.
Interestingly, activated JNK2 and JNK3 also phosphorylate serine 34 of mouse p53.
Furthermore, JNK2 and JNK3 also associate with p53 in vivo, indicating that not
only JNK1, but also JNK2 and JNK3 are p53 N-terminal serine 34 kinases.
Phosphorylation of p53 by JNKs may play an important role in nuclear signal
transduction in response to environmental stress or tumorigenic agents.
PMID- 9393874
TI - Choline kinase inhibitors as a novel approach for antiproliferative drug design.
AB - Recent progress in deciphering the molecular basis of carcinogenesis is of utmost
importance to the development of new anticancer strategies. To this end, it is
essential to understand the regulation of both normal cell proliferation and its
alterations in cancer cells. We have previously demonstrated that in ras
transformed cells there is an increased level of phosphorylcholine (PCho)
resulting from a constitutive activation on choiline kinase (ChoK). The
importance of ChoK for the regulation of cell proliferation has also been
proposed since an inhibitor for this enzyme, hemicholinium-3 (HC-3), drastically
reduces entry into the S phase after stimulation with growth factors. Here we
report the synthesis of several new compounds which are highly specific
inhibitors for ChoK, with up to 1000-fold or 600-fold increased inhibitory
activity, compared to HC-3 under ex vivo or in vitro conditions respectively.
These novel compounds also drastically reduce entry into the S phase after
stimulation with specific growth factors. A more profound inhibition of cell
proliferation was observed in ras-, src- and mos-transformed cells in the
presence of ChoK inhibitors, compared to their parental, untransformed NIH3T3
cells. By contrast, this effect was not observed in fos-transformed cells. While
ras, src and mos transformation is associated with elevated levels of ChoK
activity, fos-induced transformation does not affect ChoK activity. The
inhibitory effect on proliferation of the new compounds correlates with their
ability to inhibit the production of phosphorylcholine in whole cells, a proposed
novel second messenger for cell proliferation. These results strongly support a
critical role of choline kinase in the regulation of cell growth and makes this
enzyme a novel target for the design of new antiproliferative and anticancer
drugs.
PMID- 9393875
TI - AU-rich mRNA instability elements on human papillomavirus type 1 late mRNAs and c
fos mRNAs interact with the same cellular factors.
AB - Expression levels of human papillomavirus type 1 late genes are determined in
part by an AU-rich inhibitory sequence in the 3' untranslated region on the late
mRNAs. Fine mapping of the AU rich inhibitory sequence revealed that it mapped to
a 57 nucleotide sequence, consisting of an AU-rich region containing two AUUUA
motifs and a U-rich region containing three UUUUU motifs. An internal deletion
showed that the U-rich region was required for inhibition. Point mutations in the
AUUUA- and UUUUU-motifs inactivated the inhibitory sequence. Analysis of the
stability of mRNAs containing the AU-rich sequence in sense or anti-sense
orientation showed that mRNAs containing the AU-rich sequence in sense
orientation had reduced half life. Analysis of RNA-protein interactions revealed
that binding to the inhibitory sequence of three poly(U) binding proteins (38, 44
and 46 kDa) correlated with inhibition and that the same proteins bind to the AU
rich mRNA instability element in the 3' untranslated region on the human c-fos
mRNA. We speculate that the human papillomavirus late mRNAs, produced from
several hundred copies of the virus genome present in infected cells, compete
with the c-fos mRNAs for destabilizing cellular factors and that this may lead to
elevated Fos protein levels in human papillomavirus infected cells.
PMID- 9393876
TI - Effects of the inhibition of p38/RK MAP kinase on induction of five fos and jun
genes by diverse stimuli.
AB - The ERK, JNK/SAPK and p38/RK MAP kinase subtypes are differentially activated by
physiological, pharmacological and stress stimuli; all three subtypes are
implicated in immediate-early (IE) gene induction by these agents. Here, we have
asked whether inhibition of a single MAP kinase subtype under these conditions
would generally alter induction of several IE genes in a similar way or whether
this would differentially up- and down-regulate particular IE genes, an issue
which bears on the question of whether individual MAP kinases are strictly
targeted to specific IE genes, or whether they might catalyse phosphorylation
events that affect several IE genes in the same way. SB 203580, an inhibitor of
p38/RK, has been used to analyse the role of this kinase in the induction of five
IE genes (c-fos, fosB, c-jun, junB and junD) under diverse conditions of
stimulation. In C3H 10T1/2 cells, p38/RK and its downstream kinase MAPKAP K-2 are
activated by all stimuli used with the exception of TPA. The specificity of SB
203580 as a p38/RK inhibitor in these cells is demonstrated; it does not affect
ERKs or JNK/SAPKs but does result in a small increase in the activity of the
upstream kinase MKK6, the principal p38/RK activator in these cells. We find that
inhibition of p38/RK under these conditions produces general effects on all five
IE genes as a group in three ways. First, induction of all five genes in response
to okadaic acid or tumour necrosis factor-alpha (TNF-alpha) is not significantly
altered by SB 203580. Second, in cells stimulated with anisomycin or U.V.
radiation, SB 203580 potently inhibits all of the induced IE genes. Finally, SB
203580 enhances induction of all five IE genes in EGF-treated cells; these
enhanced mRNA levels are not due to stabilisation of labile mRNA transcripts. The
significance of these results to current thinking on the relationship between
distinct MAP kinase subtypes and specific IE genes is discussed.
PMID- 9393877
TI - The Bcr-Abl tyrosine kinase activates mitogenic signaling pathways and stimulates
G1-to-S phase transition in hematopoietic cells.
AB - Bcr-Abl is a constitutively active tyrosine kinase that is expressed in
Philadelphia chromosome (Ph1)-positive human leukemias. Bcr-Abl has been shown to
inhibit apoptosis and cause anchorage independent growth. However, its ability to
activate mitogenic signaling pathways is controversial. Here we show that Bcr-Abl
signaling prevents down-regulation of cyclin-dependent kinase activity and cell
cycle arrest after growth factor deprivation of hematopoietic progenitor cells.
Using an inducible system to regulate Bcr-Abl expression, we also demonstrate
that Bcr-Abl expression is sufficient to induce G1-to-S phase transition, DNA
synthesis, and activation of cyclin-dependent kinases in cells that were arrested
in G0 by growth factor deprivation. Furthermore, Bcr-Abl activates Ras, Erk, and
Jnk pathways as a primary consequence of expression. These data show that Bcr-Abl
is one of a select group of oncogenes that is capable of both inhibiting
apoptosis and deregulating cell proliferation. The combination of these
activities is likely to be important for the progression of CML.
PMID- 9393878
TI - Regulation of DNA-dependent protein kinase activity in leukemic cells.
AB - The DNA-dependent protein kinase (DNA-PK) complex is composed of a catalytic (DNA
PKcs), and a regulatory subunit (Ku70/Ku86 heterodimer). The expression and
function of DNA-PK subunits was investigated in purified blood lymphocytes
obtained from patients with chronic lymphocytic leukemia (CLL) either refractory
to chemotherapy or untreated. Variations in DNA-PK activity were found amongst
CLL samples by comparison to human cell lines. It was noticeable that the low DNA
PK activity was associated with samples from untreated patients that exhibited a
sensitivity phenotype, determined in vitro, to the radiomimetic agent
neocarcinostatin by comparison to samples from refractory patients. The
regulation in DNA-PK activity was associated with Ku heterodimer expression while
DNA-PKcs was unaffected. Moreover, the presence of an altered form of the Ku86
subunit was identified in samples with low DNA-PK activity. These results suggest
a regulation process of the DNA-PK activity in fresh human cells.
PMID- 9393879
TI - Retinoic acid enhances the expression of interferon-induced proteins: evidence
for multiple mechanisms of action.
AB - Retinoic acid (RA) and interferons (IFNs) are negative regulators of cell
proliferation. In vitro and in vivo, their combination leads to a more potent
growth inhibition. However, the molecular mechanisms by which RA and IFNs
potentiate each other are not fully understood. As some IFN-induced gene products
regulate cell growth and/or antiviral activity, we analysed the effects of RA on
their expressions. RA increases the level of 2'5'oligoadenylate synthetase, p68
kinase, the promyelocytic leukemia protein (PML) and Sp100 in both HL-60 and WISH
cells. Moreover, RA and IFN act cooperatively to increase the expression of these
proteins. RA also inhibits vesicular stomatitis virus replication and induces a
higher antiviral state and growth inhibition when combined with IFN. RA
stimulates the IFN regulatory factor 1 (IRF-1) gene expression directly through
the GAS motif and causes the induction and secretion of IFNalpha. Additional
mechanisms could be involved as RA increases the level of signal transducing
activators of transcription (STAT) proteins, and enhances the IFN-induced STAT
activation, suggesting that cooperative effects by RA and IFN are mediated
through multiple pathways.
PMID- 9393880
TI - Praja1, a novel gene encoding a RING-H2 motif in mouse development.
AB - As part of a cloning strategy to identify genes involved in early mouse liver
development we have isolated Praja1, a gene with similar sequences to the
Drosophila melanogaster gene goliath (gl) which is involved in the fate of
mesodermal cells ultimately forming gut musculatures, fat body, and the heart.
Praja1 is a 2.1 kb gene encoding a putative 396 amino acid ORF and includes a
COOH-terminal RING-H2 domain. Using the Jackson Laboratory BSS panel, we have
localized Praja1 on chromosome X at 36 cM, which may be a candidate gene for
mouse sla (sex linked sideroblastic anemia), near the X inactivation center gene,
Xist. Northern blot analysis demonstrated three transcripts (3.1, 2.6 and 2.1 kb)
in mRNA from adult mouse tissues brain, liver, and kidney as well as in mRNA from
developing mouse embryos (days 7, 11, 15 and 17 post coitus, p.c.). In vitro
transcription/translation yielded a product with an Mr of 59 kD.
Immunohistochemical staining of in vitro liver explant cultures using a
heterologous antibody against praja1 demonstrated cytoplasmic staining of
cuboidal cells that have hepatocyte morphology and organization. The presence of
the RING-H2 domain, a proline-rich region at the COOH-end, and regions rich in
acidic amino acids, leads to the hypothesis that the Praja1 product is possibly
involved in mediating protein-protein interactions, possibly as part of a protein
sorting or transport pathway. This is strengthened by the similarity of Praja1 to
rat Neurodap1, whose product has been shown to localize to the endoplasmic
reticulum and golgi in brain.
PMID- 9393881
TI - Deletional remodeling of c-myc-deregulating chromosomal translocations.
AB - Evidence is presented for the existence of a novel remodeling-by-deletion
mechanism that alters the fine structure of c-myc-deregulating chromosomal
translocations in t(12;15)-positive BALB/c plasmacytomas. DNA sequence analysis
of the t(12;15) in five primary tumors revealed the co-existence of precursor
cells harboring genetic recombinations between the immunoglobulin heavy-chain mu
locus (Igh mu) and c-myc with clonally related progenitors containing
rearrangements between the immunoglobulin heavy-chain alpha locus (Igh alpha) and
c-myc. Clonal relatedness was based upon unique junction fragments between the
switch region of Igh mu and c-myc. S mu/c-myc junctions are thus useful
clonotypic markers for monitoring the conversion of Igh mu/c-myc-positive tumor
precursor clones into Igh alpha/c-myc-positive plasmacytomas. Aberrant isotype
switch recombination appears to be the most likely mechanism effecting this
conversion event (other possibilities are discussed) which may help to explain
the preferred usage of the Igh alpha locus in recombinations with c-myc in
t(12;15)-positive plasma cell tumors in BALB/c mice.
PMID- 9393883
TI - Neuroprotection.
PMID- 9393882
TI - The phosphatidylinositol polyphosphate 5-phosphatase SHIP and the protein
tyrosine phosphatase SHP-2 form a complex in hematopoietic cells which can be
regulated by BCR/ABL and growth factors.
AB - We report here that interleukin-3 (IL-3) and erythropoietin (EPO) induce
formation of a complex composed of two SH2-containing phosphatases, the tyrosine
phosphatase SHP-2 and the SH2 containing inositol 5-phosphatase (SHIP). Both SHP
2 and SHIP are known to be involved in growth factor signal transduction, but
their potential interaction in the same pathway is novel. SHIP has previously
been shown to associate with SHC, and potentially to be involved in regulating
apoptosis. In contrast, in some model systems, SHP-2 has been demonstrated to
positively regulate cell growth. Both phosphatases in the complex were tyrosine
phosphorylated, and the amount of SHIP coprecipitating with SHP-2 was inversely
related to the amount of SHIP coprecipitating with SHC. In hematopoietic cells
transformed by the BCR/ABL oncogene, this phosphatase complex was found to be
constitutively present with both components heavily tyrosine phosphorylated.
Also, other proteins were detected in the complex, including BCR/ABL itself and c
CBL. However, transformation by BCR/ABL was associated with a reduced SHIP
protein expression, which could further affect the accumulation of various
inositol polyphosphates in these leukemic cells. These data suggest that the
function of SHIP and SHP-2 in normal cells are linked and that BCR/ABL alters the
function of this signaling complex.
PMID- 9393885
TI - Ischaemic cerebral injury, intrauterine growth retardation, and placental
infarction.
AB - Two hundred and twenty-five consecutive autopsies performed on fetuses >20 weeks'
gestation were reviewed, and 37 growth-retarded stillborn fetuses without
multiple congenital abnormalities or evidence of intrauterine infection were
identified. Histological evidence of ischaemic cerebral injury was found in 31 of
the 37 cases and placental infarction was seen in 26 of 36 placentas. Of the 31
cases with cerebral ischaemia, 24 had placental infarcts. Twenty-six of 27
stillborn fetuses >26 weeks' gestation showed histological evidence of cerebral
ischaemia. It was concluded that in the group of growth-retarded fetuses studied,
there was a high incidence of both cerebral and placental ischaemic abnormality.
PMID- 9393884
TI - Relation of deranged neonatal cerebral oxidative metabolism with
neurodevelopmental outcome and head circumference at 4 years.
AB - Cerebral oxidative metabolism was studied using phosphorus magnetic resonance
spectroscopy during the first week of life and neurodevelopmental outcome was
assessed at 4 years in 62 infants who had clinical and/or biochemical evidence
consistent with birth asphyxia (critically impaired intrapartum gas exchange).
Twenty-one died and the neurodevelopmental status of the 41 who survived was
assessed by a range of tests at age 4 years. The minimum recorded values for the
cerebral phosphocreatine:inorganic phosphate concentration ratio (an index of
oxidative metabolism) were related to outcome. The results showed significant
relations between the extent of derangement of neonatal oxidative metabolism and
a range of adverse outcomes, including death, and at 4 years reduced head growth
and the presence and severity of neuromotor impairments, overall
neurodevelopmental impairments, and cognitive functioning. Strong correlations
between the extent of derangement of neonatal oxidative metabolism and outcome at
1 and 4 years were also shown. We conclude that the severities of adverse
outcomes at 1 and 4 years of age were closely related to the extent of cerebral
energy derangement in the first week of life, and we also conclude that primary
intrapartum hypoxic-ischaemic cerebral injury was generally responsible for the
events that led to death, microcephaly, and impaired
PMID- 9393886
TI - The effect of seizure type and medication on cognitive and behavioral functioning
in children with idiopathic epilepsy.
AB - Antiepileptic drugs have been reported to have a variety of adverse effects on
behavior and performance in children with epilepsy. Previous studies
investigating these side effects, however, have not controlled for the baseline
status of the child (e.g. underlying neurological condition, seizure type,
socioeconomic status, family variables), making it difficult to determine whether
changes in function are attributable to the use of medication. We investigated
the cognitive and behavioral profiles of 43 children, aged from 4 to 16 years,
with new onset, idiopathic seizures. Twenty-six of these children participated in
a 6-month follow-up study, and 12 in a 12-month follow-up study, investigating
the effects of antiepileptic medications on psychological functioning. The
children were of average intelligence (mean IQ 108) and had not previously been
treated with antiepileptic medication. Children were classified as having either
generalized convulsive, generalized non-convulsive (absence), simple partial, or
complex partial seizures. Prior to the initiation of treatment, children with
partial seizures were found to perform better than children with generalized
seizures on measures of cognitive functioning. Children with convulsive seizures
obtained significantly higher cognitive scores than those with non-convulsive
seizures. Children with generalized non-convulsive seizures had lower cognitive
scores than subjects with other types of seizure. No differences were found
between groups at baseline prior to the initiation of antiepileptic medications.
Analysis of subjects' performance after 6 and 12 months of antiepileptic therapy
showed no significant deterioration attributable to medication. The differences
in cognitive performance of the four seizure groups at baseline were not apparent
at the time of follow-up. These results indicate that intrinsic and environmental
variables may play a more significant role in predisposing certain children to
cognitive and learning problems than do antiepileptic medications.
PMID- 9393887
TI - Covert orienting of visuospatial attention in children with developmental
coordination disorder.
AB - It is still unclear whether impairments in visuospatial processing in children
with developmental coordination disorder (DCD) are a consequence of their motor
deficits or are independent of them. In two experiments, 20 children with DCD and
20 matched controls were tested on the covert orienting of a visuospatial
attention task (COVAT). Experiment 1 used a COVAT with peripheral cues and an 80%
probability that targets would appear at the cued location. While the results
suggested a deficit in the disengage operation of orienting covert attention for
the DCD group, they were difficult to reconcile with models of covert orienting
and the results of past research. Experiment 2 tested subjects on two new
versions of the COVAT: the first used peripheral cues and no probability
information (exogenous mode), and the second used central cues and an 80%
probability that targets would appear at the cued location (endogenous mode). The
DCD group displayed attentional orienting deficits only for the endogenous mode.
These results suggest that impairments in the endogenous control of visuospatial
attention are independent of motor deficits in DCD.
PMID- 9393888
TI - Caregivers' perceptions following gastrostomy in severely disabled children with
feeding problems.
AB - Feeding difficulties are common in neurologically impaired children, often
leading to great distress and frustration in the child and family. A gastrostomy
may be advocated if oral intake is inadequate causing poor weight gain or when
there is significant aspiration during feeding, or if feeding is very
distressing. To find out if caregivers were happy with the outcome of gastrostomy
(with fundoplication, when indicated), a 35-item questionnaire was developed and
sent to 38 of them. Twenty-nine replies were received and appeared to be
representative of the whole group. Coughing, choking, and vomiting improved in
most cases. Weight gain improved in all in whom it had been a problem. In the
majority, it became easier to give the children their medications although
control of epilepsy was unchanged overall. Time spent feeding the child was
reduced and many caregivers had more time to devote to other children and
themselves. Only one parent regretted the operation. In children with severe
disability and feeding problems, a gastrostomy (with fundoplication if there is
significant reflux) can reduce symptoms of vomiting, coughing, and choking, help
growth and improve quality of life in the child, when patients are properly
selected.
PMID- 9393889
TI - Correlates of maladaptive behavior in individuals with 5p- (cri du chat)
syndrome.
AB - This study examined the range, distinctiveness, and correlates of maladaptive
behavior in 146 subjects with 5p- (cri du chat) syndrome using the Aberrant
Behavior Checklist as a standardized measure. Hyperactivity was the most
significant and frequent problem in the sample. Subjects with 5p- syndrome also
showed aggression, tantrums, self-injurious behavior, and stereotypies; some of
these problems were more pronounced in individuals with lower cognitive-adaptive
levels, as well as in those with histories of previous medication trials.
Autistic-like features and social withdrawal were more characteristic of
individuals with translocations as opposed to deletions, even when controlling
for the lower adaptive level of the translocation group. These findings encourage
further research on the behavior of individuals with 5p- syndrome.
PMID- 9393890
TI - Families of children with 5p- (cri du chat) syndrome: familial stress and sibling
reactions.
AB - This research examined family stress and sibling reactions in families of
children with 5p- (cri du chat) syndrome aged 1 to 18 years who were living at
home. In Study 1, 99 parents reported on themselves and their child with 5p-, as
well as on family demographics, social supports, and stress. The best predictor
of familial stress was the child's amount of maladaptive behavior, accounting for
12 to 38% of the variance across different stress measures. In Study 2, sibling
concerns were examined in 44 unaffected siblings. The major finding was that
parents and siblings disagreed on the extent of the siblings' interpersonal
concerns. Parents reported that siblings felt ignored and misunderstood, whereas
siblings themselves rated these concerns at much lower levels.
PMID- 9393891
TI - Neurobrucellosis in childhood: six new cases and a review of the literature.
AB - Neurobrucellosis accounts for <1% of cases of brucellosis in children. Six new
cases of neurobrucellosis are presented and data from 39 previously published
cases are analysed. The incidence is equal in males and females, and the source
of infection is likely to be unpasteurised milk. Clinical presentation varies
from severe meningoencephalitis or peripheral neuropathy/radiculopathy to
behavioural disturbance. Diagnostic certainty requires isolation of the organism
from the CSF, but as this is rarely possible serological diagnosis can be
performed with the Coombs test on the CSF. Treatment requires combination
antibiotic therapy and should continue for at least 8 weeks.
PMID- 9393892
TI - Fast-wave periodic complexes in a mentally retarded child who later developed
subacute sclerosing panencephalitis: a modification of a classic EEG by
preexisting brain damage?
AB - The EEG of a 12-year-old girl with stage II subacute sclerosing panencephalitis
(SSPE), who had also suffered from a non-progressive mental retardation of
unknown aetiology since early childhood, revealed periodic generalised
stereotyped fast wave bursts synchronous with myoclonic jerks. The background
activity was nearly normal. The diagnosis of SSPE was established by raised serum
and measles antibody titres, raised CSF IgG, and brain biopsy. This rare type of
periodic complex has only once been described in the literature, again in a
mentally retarded child who had developed SSPE. We suggest a mechanism of origin
of this type of periodic complex drawn from observations in these two cases, and
discuss its significance.
PMID- 9393893
TI - Absence of alpha-sarcoglycan and novel missense mutations in the alpha
sarcoglycan gene in a young British girl with muscular dystrophy.
AB - An 11-year-old white female presented with progressive proximal muscle weakness
and marked calf hypertrophy. Muscle biopsy showed severe dystrophy with normal
expression of dystrophin. There was complete absence of the 50kDa dystrophin
associated glycoprotein (alpha-sarcoglycan). DNA analysis showed novel point
mutations (one missense and one splicing) in the alpha-sarcoglycan gene at
chromosomal location 17q21, confirming the diagnosis of limb-girdle muscular
dystrophy type 2D (LGMD-2D). We believe this is one of the first confirmed white
cases of primary alpha-sarcoglycanopathy identified in the UK. This case supports
the assumption of a wide geographic prevalence of severe childhood onset
autosomal recessive muscular dystrophy and genetic heterogeneity. In the future,
with improved diagnostic accuracy it is likely that more cases demonstrating
primary or secondary deficiency of alpha-sarcoglycan will be identified. We would
recommend staining for dystrophin-associated glycoproteins (sarcoglycans) in all
new cases of muscular dystrophy with normal dystrophin, and confirmation with DNA
analysis where possible.
PMID- 9393895
TI - Epilepsy and prejudice with particular relevance to childhood.
PMID- 9393894
TI - Myositis ossificans complicating severe Guillain-Barre syndrome.
AB - We report myositis ossificans occurring in a 13-year-old boy with severe and
rapidly progressive Guillain-Barre syndrome. This complication should be
considered when severe musculoskeletal pain is experienced by such patients.
Disodium etidronate may be of benefit in this condition.
PMID- 9393896
TI - The Worster-Drought syndrome: a severe test of paediatric neurodisability
services?
PMID- 9393897
TI - Thromboprophylaxis in elective orthopaedic surgery -- what is the purpose?
PMID- 9393898
TI - Fracture of the femur in children.
PMID- 9393899
TI - Planovalgus and cavovarus deformity of the hind foot. A functional approach to
management.
PMID- 9393901
TI - Total hip arthroplasty with an uncemented femoral component. Excellent results at
ten-year follow-up.
AB - We followed 138 patients (145 hips) who had had uncemented total hip arthroplasty
using the Taperloc femoral component for a mean of ten years (8 to 12.5). No
patient was lost to follow-up; 31 (31 hips) died before the minimum time of eight
years for inclusion in the study, and 30 of these still had their femoral
component in place. One well-fixed prosthesis had been exchanged at the time of
acetabular revision. Of the remaining 114 hips, one femoral component required
revision for aseptic loosening and one for sepsis. Three other well-fixed femoral
components were removed during acetabular revision. Complete clinical and
radiological follow-up was obtained in the 109 hips which had not had revision.
Clinically, 94 (87%) were rated good or excellent, eight (7%) fair and seven (6%)
poor. The average Harris hip score increased from 48 before operation to 88 at
the time of the last follow-up. Radiologically, 103 hips (94%) had fixation by
bone ingrowth, three (3%) showed stable fibrous ingrowth and three (3%) were
unstable. Osteolysis of the fomoral cortex was seen in seven hips (6%), with
major lysis in only one. At a mean follow-up of ten years, the results of the
Taperloc femoral component are comparable with those of modern techniques of
cementing in primary total hip arthroplasty.
PMID- 9393900
TI - Mortality and fatal pulmonary embolism after primary total hip replacement.
Results from a regional hip register.
AB - We calculated the rates for perioperative mortality and fatal pulmonary embolism
(PE) after primary total hip replacement in a single UK health region, using a
regional arthroplasty register and the tracing service of the Office of National
Statistics. During 1990, there were 2111 consecutive primary replacements in 2090
separate procedures. Within 42 days of operation a total of 19 patients had died
(0.91%, 95% CI 0.55 to 1.42). Postmortem examination showed that four deaths
(0.19%, 95% CI 0.05 to 0.49) were definitely due to PE. The overall perioperative
mortality and fatal PE rates are low and in our study did not appear to be
altered by the use of chemical thromboprophylaxis (perioperative mortality rate:
one-tailed Fisher's exact test, p = 0.39; fatal PE rate: one-tailed Fisher's
exact test, p = 0.56). The routine use of chemical thromboprophylaxis for primary
THR is still controversial. The issue should be addressed by an appropriate
randomised, prospective study using overall mortality and fatal PE rate as the
main outcome measures, but the feasibility of such a study is questioned.
PMID- 9393902
TI - The cement mantle in femoral impaction allografting. A comparison of three
systems from four centres.
AB - An analysis of the cement mantle obtained with the Exeter impaction allografting
system at one centre showed that it was either deficient or absent in almost 47%
of Gruen zones. We therefore examined the mantle obtained using this system at
another hospital and compared the results with those from the CPT and Harris
Precoat Systems at other centres. The surgical indications for the procedure and
the patient details were broadly similar in all four hospitals. There was some
variation in the frequency of use of cortical strut allografts, cerclage wires
and wire mesh to supplement the impaction allograft. Analysis of the cement
mantles showed that when uncertain Gruen zones were excluded, the incidence of
zones with areas of absence or deficiency of the cement was 47% and 50%,
respectively, for the two centres using the Exeter system, 21% for the CPT system
and 18% for the Harris Precoat system. We measured the difference in size between
the proximal allograft impactors and the definitive prosthesis for each system.
The Exeter system impactors are shorter than the definitive prosthesis and taper
sharply so that the cavity created is inadequate, especially distally. The CPT
proximal impactors are considerably longer than the definitive prosthesis and are
designed to give a mantle of approximately 2 mm medially and laterally and 1.5 mm
anteriorly and posteriorly. The Harris Precoat proximal impactors allow for a
mantle with a circumference of 0.75 mm in the smaller sizes and 1 mm in the
larger. Many reports link the longevity of a cemented implant to the adequacy of
the cement mantle. For this reason, femoral impaction systems require careful
design to achieve a cement mantle which is uninterrupted in its length and
adequate in its thickness. Our results suggest that some current systems require
modification.
PMID- 9393903
TI - Continuous passive motion after primary total knee arthroplasty. Does it offer
any benefits?
AB - We report a prospective randomly controlled trial to examine the effectiveness of
continuous passive motion (CPM) in improving postoperative function and range of
movement after total knee arthroplasty (TKA). We allocated 53 patients (57 knees)
to one of three postoperative regimes: no CPM (n = 19); CPM at 0 to 40 degrees (0
to 40 CPM; n = 18); and CPM at 0 to 70 degrees (0 to 70 CPM; n = 20). Those in
the CPM groups had CPM for 48 hours and all patients had an identical regime of
physiotherapy. There was an even distribution of various cemented and cementless
TKAs in each group. Patients were assessed preoperatively and at one week and at
one year postoperatively. At one week, there was a statistically significant
increase in the range of flexion and total range of movement in the 0 to 70 CPM
group compared with the no-CPM group. At one year we found no significant
differences in mean flexion, overall range of movement, fixed flexion deformity
or functional results in the three groups. Those who had CPM had a significant
increase in analgesic requirement (p = 0.04). There was an increased mean blood
drainage postoperatively in those who had 0 to 70 CPM (1558 ml) compared with
those with no CPM (956 ml) (t = 2.96, p = 0.005) and with 0 to 40 CPM (1017 ml)
(t = 2.62, p = 0.01). Our findings show that CPM had no significant advantage in
terms of improving function or range of movement, and that its use increased
blood loss and analgesic requirements.
PMID- 9393904
TI - Synovectomy of the elbow and radial head excision in rheumatoid arthritis.
Predictive factors and long-term outcome.
AB - We carried out a survival analysis of elbow synovectomy (ES) and excision of the
radial head (RHE) performed on 171 rheumatoid elbows. The failure criteria were
revision surgery (performed or desired) and/or the presence of significant or
severe pain. The cumulative survival was 81% at one year which thereafter
decreased by an average of 2.6% per year. The strongest predictor for success was
a low preoperative range of supination-pronation when corresponding survival
curves were compared. A low range of flexion-extension also predicted failure.
Combining both factors gave better prediction (failure: 6.3% v 67%), but a long
duration of elbow symptoms before surgery predicted failure (72%, p = 0.04). At
review, there was a mean gain of 50 degrees in supination-pronation and 11
degrees in flexion-extension; both correlated with success. Failure correlated
with recurrence of synovitis, elbow instability, ulnar neuropathy, poor general
mobility and poor upper-limb function. The last was independently affected by the
severity of RA in the ipsilateral shoulder. Our findings show that although the
short-term result of ES and RHE in rheumatoid arthritis is good, the long-term
outcome is poor except in a subgroup with more than 50% limitation of forearm
rotation.
PMID- 9393905
TI - Forequarter amputation for high-grade malignant tumours of the shoulder girdle.
AB - We reviewed 20 patients after forequarter amputation performed for high-grade
malignant tumours of the shoulder girdle (Enneking grades IIB to III). The
operations were classified as palliative or curative according to the resection
margins and the presence of disseminated disease at the time of the surgery.
There were five palliative and 15 curative procedures. Two patients died from
unrelated causes, septicaemia and suicide. Eight died in the first two years,
four of whom had had a palliative operation. Four died between two and five years
after surgery, one after a palliative operation. Five patients are alive, at a
mean of 89.4 months after surgery, four of whom are free from disease. The median
survival after a palliative amputation was 20.6 months. Our overall five-year
survival (palliative and curative cases) was 21.2%, for curative cases it was
30.2%. None of the patients use an artificial prosthesis. Despite the
disfigurement which results from this operation, it still has a useful role to
play in the management of high-grade malignant tumours of the upper limb.
PMID- 9393906
TI - Stanmore custom-made extendible distal femoral replacements. Clinical experience
in children with primary malignant bone tumours.
AB - The use of extendible distal femoral replacements is a relatively new treatment
alternative for malignant bone tumours in growing individuals. Although their
appearance was widely appreciated, questions about functional practicality and
longevity remain unclear. With longer follow-up, advantages of immediate
functional restoration and beneficial psychological aspects seem to be
overshadowed by an increase in complications such as aseptic loosening, infection
or prosthetic failure. We have reviewed 18 children with such tumours who were
treated between 1983 and 1990 by custom-made Stanmore extendible distal femoral
replacements. Four died from metastatic disease within 2.5 years of operation and
two required amputation for local recurrence or chronic infection. The remaining
12 patients were followed for a mean of 8.7 years (6 to 13.2). A mean total
lengthening of 5.2 cm was achieved, requiring, on average, 4.3 operations. Using
the Musculoskeletal Tumor Society rating score the functional result at review
was, on average, 77% of the expected normal function, with seven patients
achieving > or = 80%. Revision of the prosthesis was required in ten patients, in
six for aseptic loosening, at a mean of 6.2 years after the initial procedure.
PMID- 9393907
TI - Growth after extendible endoprosthetic replacement of the distal femur.
AB - We report our results in 24 children with malignant primary bone tumours of the
distal femur treated with a Stanmore extendible endoprosthesis (SEER). This
consists of a femoral component that can be lengthened, a constrained knee and an
uncemented sliding tibial component which crosses the proximal tibial physeal
plate perpendicularly. The average age of the patients at diagnosis was ten years
and the mean follow-up was 4.7 years (2.5 to 7.9). The mean growth of the
affected tibia was 76% (18 to 136) and of the fibula 83% (15 to 750) of the
growth of the unaffected limb. Measurement of growth arrest lines showed that the
mean growth of the proximal tibial physis on the affected side was 69% (43 to
100) of that of the normal side. The great variability in the growth of the
physis cannot yet be explained.
PMID- 9393908
TI - Far lateral lumbar disc herniation. The key to the intertransverse approach.
AB - Of a total of 330 patients requiring operation on a lumbar disc, 20 (6.1%) with
lateral disc prolapse had a new muscle-splitting, intertransverse approach which
requires minimal resection of bone. There were 16 men and 4 women with a mean age
of 52 years. All had intense radicular pain, 15 had femoral radiculopathy and 19
a neurological deficit. Far lateral herniation of the disc had been confirmed by
MRI. At operation, excellent access was obtained to the spinal nerve, dorsal root
ganglion and the disc prolapse. The posterior primary ramus was useful in
locating the spinal nerve and dorsal root ganglion during dissection of the
intertransverse space. At review from six months to four years, 12 patients had
excellent results with no residual pain and six had good results with mild
discomfort and no functional impairment. Two had poor results. There had been
neurological improvement in 17 of the 20 patients. We report a cadaver study of
the anatomy of the posterior primary ramus. It is readily identifiable through
this approach and can be traced down to the spinal nerve in the intertransverse
space. We recommend the use of a muscle-splitting intertransverse approach to far
lateral herniation of the disc, using the posterior primary ramus as the key to
safe dissection.
PMID- 9393909
TI - Neurological deterioration after posterior wiring of the cervical spine.
AB - Posterior cervical wiring is commonly performed for patients with spinal
instability, but has inherent risks. We report eight patients who had
neurological deterioration after sublaminar or spinous process wiring of the
cervical spine; four had complete injuries of the spinal cord, one had residual
leg spasticity and three recovered after transient injuries. We found no relation
between the degree of spinal canal encroachment and the severity of the spinal
cord injury, but in all cases neurological worsening appeared to have been caused
by either sublaminar wiring or spinous process wiring which had been placed too
far anteriorly. Sublaminar wiring has substantial risks and should be used only
at atlantoaxial level, and then only after adequate reduction. Fluoroscopic
guidance should be used when placing spinous process wires especially when the
posterior spinal anatomy is abnormal.
PMID- 9393910
TI - Sparing of sensation to pin prick predicts recovery of a motor segment after
injury to the spinal cord.
AB - We have reviewed 59 patients with injury to the spinal cord to assess the
predictive value of the sparing of sensation to pin prick in determining motor
recovery in segments which initially had MRC grade-0 power. There were 35
tetraplegics (18 complete, 17 incomplete) and 24 paraplegics (19 complete, 5
incomplete), and the mean follow-up was 29.6 months. A total of 114 motor
segments initially had grade-0 power but sparing of sensation to pin prick in the
corresponding dermatome. Of these, 97 (85%) had return of functional power (> or
= grade 3) at follow-up. There were 479 motor segments with grade-0 power but no
sparing of sensation to pin prick and of these only six (1.3%) had return of
functional power. Both of the above associations were statistically significant
(chi-squared test, p < 0.0001). After injury to the spinal cord, the preservation
of sensation to pin prick in a motor segment with grade-0 power indicated an 85%
chance of motor recovery to at least grade 3.
PMID- 9393911
TI - Lengthening of short great toes by callus distraction.
AB - We lengthened seven first metatarsals in four patients with short great toes by
callus distraction using an external fixator. Good clinical and cosmetic results
were obtained. Bone lengthening is effective in patients with short great toes
not only for cosmesis, but also to relieve pain and callosities on the plantar
aspect of the second and third metatarsal heads. Excessive lengthening of the
first metatarsal resulted in limitation of the range of movement of the
metatarsophalangeal joint of the great toe. To prevent this the amount of
lengthening should not exceed 40% of the preoperative length of the metatarsal.
PMID- 9393913
TI - The fibula-flexor hallucis longus osteomuscular flap.
AB - Limb salvage after loss of bone and soft tissue may require many operations to
obtain soft-tissue cover and bony continuity. We describe a fibula-flexor
hallucis longus osteomuscular flap which can provide both soft tissue and bone in
a single stage. The flap is based on the peroneal vessels and is covered by a
split-thickness skin graft. We report the results in five patients with an
average bone defect of 8.3 cm and soft-tissue and skin loss. All regained a
normal gait on the donor side; four had clinical and radiological union with
excellent soft-tissue cover, but one required later amputation due to diffuse
coagulopathy. The flap provides free vascularised bone with muscle cover. It has
a dependable, long pedicle with minimal morbidity at the donor site, and allows
monitoring of the vascularity of the fibular graft.
PMID- 9393912
TI - Does indomethacin reduce heterotopic bone formation after operations for
acetabular fractures? A prospective randomised study.
AB - We have studied prospectively the effect of indomethacin on the development of
heterotopic ossification (HO) after the internal fixation of acetabular
fractures. After operation 107 patients randomly received either a six-week
course of indomethacin or no treatment against HO. Plain radiographs of 101
patients at a mean of 7.9 months after surgery showed HO in 47.4% of the 57
patients who received indomethacin and in 56.8% of the 44 who did not. This
difference was not statistically significant. Heterotopic ossification of Brooker
class II or more was seen in four patients (7%) with prophylaxis and in one
without (p = 0.51). Measurements of the volume of HO on 3-D CT reconstructions
showed a median value of 1.5 cm3 in patients with indomethacin and 4.0 cm3 in
those without (p = 0.28). When only the 57 patients in whom the operation was
carried out through either a Kocher-Langenbeck or an extended iliofemoral
approach were included the indomethacin group showed a median volume of 1.7 cm3
compared with 3.6 cm3. On plain radiographs Brooker class II or above was seen in
9.4% of the patients receiving indomethacin and in 4.8% of those who did not.
Indomethacin was therefore not effective in preventing ectopic bone formation
after surgery for acetabular fractures. There was a significant association of
male gender with volume of HO using a non-parametric analysis of variance.
PMID- 9393914
TI - Awareness of tip-apex distance reduces failure of fixation of trochanteric
fractures of the hip.
AB - We compared the results of the surgical treatment of trochanteric hip fractures
before and after surgeons had been introduced to the tip-apex distance (TAD) as a
method of evaluating screw position. There were 198 fractures evaluated
retrospectively and 118 after instruction. The TAD is the sum of the distance
from the tip of the screw to the apex of the femoral head on anteroposterior and
lateral views. This decreased from a mean of 25 mm in the control group to 20 mm
in the study group (p = 0.0001). The number of mechanical failures by cut-out of
the screw from the head decreased from 16 (8%) in the control group at a mean of
13 months to none in the study group at a mean of eight months (p = 0.0015).
There were significantly fewer poor reductions in the study group. Our study
confirms the importance of good surgical technique in the treatment of
trochanteric fractures and supports the concept of the TAD as a clinically useful
way of describing the position of the screw.
PMID- 9393915
TI - A more accurate method of measurement of angulation after fractures of the tibia.
AB - Accurate measurement of the alignment of the tibia is important both clinically
and in research. The conventional method of measuring the angle of malunion after
a fracture of the shaft of the tibia is potentially inaccurate because the
mechanical axis of the normal bone may not pass down the centre of the medullary
canal. An alternative method is described in which a radiograph of the opposite
tibia is used as a template. A sample of 56 sets of standard radiographs of
healed fractures of the shaft of the tibia was evaluated. The 95% limits of
agreement between this and the conventional method were wide, being -6.2 degrees
to +5.5 degrees for coronal angulation and -6.7 degrees to +8.1 degrees for
sagittal angulation. These results suggest that the conventional method is
inaccurate. The new method has good inter- and intraobserver reliability.
PMID- 9393916
TI - External fixation or flexible intramedullary nailing for femoral shaft fractures
in children. A prospective, randomised study.
AB - We report the outcome of 19 children aged 5.2 to 13.2 years with 20 fractures of
the femoral shaft requiring surgery, who were randomly assigned to have external
fixation (EF) or flexible intramedullary nailing (FIN) (10 fractures each). The
duration of the operation averaged 56 minutes for the EF group with 1.4 minutes
of fluoroscopy, compared with 74 minutes and 2.6 minutes, respectively, for the
FIN group. The early postoperative course was similar, but the FIN [corrected]
group showed much more callus formation. The time to full weight-bearing, full
range of movement and return to school were all shorter in the FIN group. The FIN
complications included one transitory foot drop and two cases of bursitis at an
insertion site. In the EF group there was one refracture, one rotatory malunion
requiring remanipulation and two pin-track infections. At an average follow-up of
14 months two patients in the EF group had mild pain, four had quadriceps
wasting, one had leg-length discrepancy of over 1 cm, four had malalignment of
over 5 degrees, and one had limited hip rotation. In the FIN group, one patient
had mild pain and one had quadriceps wasting; there were no length discrepancies,
malalignment or limitation of movement. Parents of the FIN group were more
satisfied. We recommend the use of flexible intramedullary nailing for fractures
of the femoral shaft which require surgery, and reserve external fixation for
open or severely comminuted fractures.
PMID- 9393917
TI - Different methods of treatment related to the bilateral occurrence of Perthes'
disease.
AB - We treated 98 consecutive patients with Perthes' disease by a unilateral brace in
external rotation, flexion and abduction and a further consecutive 110 by a
bilateral cast with the hips in internal rotation and abduction. During treatment
in the unilateral brace, six (6.1%) hips on the opposite side developed evidence
of Perthes' disease and one developed this after the brace had been removed. In
children managed in bilateral casts, no contralateral Perthes' disease was seen.
Adequate containment of the femoral head may prevent subsequent changes in the
opposite hip.
PMID- 9393918
TI - Primary subacute haematogenous osteomyelitis of the tarsal bones in children.
AB - Primary subacute haematogenous osteomyelitis (PSHO) of the small bones of the
foot is a rare and infrequently considered cause of a limp in children. We
describe 11 patients with PSHO, of whom nine were under three years of age, who
had a limp with few symptoms. The talus was involved in 36%. Bone scans were
positive in all patients and led to localisation of the lesion in two. The
radiological features included soft-tissue swelling, an osteolytic lesion in the
talus and the calcaneus and a sclerotic appearance of the cuboid and the
navicular bones. All patients except one were cured with antibiotics.
PMID- 9393919
TI - Regulation of bone cells by particle-activated mononuclear phagocytes.
AB - Bone loss around replacement prostheses may be related to the activation of
mononuclear phagocytes (MNP) by prosthetic wear particles. We investigated how
osteoblast-like cells were regulated by human MNP stimulated by particles of
prosthetic material. Particles of titanium-6-aluminium-4-vanadium (TiAIV)
stimulated MNP to release interleukin (IL)-1beta, tumour necrosis factor
(TNF)alpha, IL-6 and prostaglandin E2 (PGE2). All these mediators are implicated
in regulating bone metabolism. Particle-activated MNP inhibited bone cell
proliferation and stimulated release of IL-6 and PGE2. The number of cells
expressing alkaline phosphatase, a marker associated with mature osteoblastic
cells, was reduced. Experiments with blocking antibodies showed that TNFalpha was
responsible for the reduction in proliferation and the numbers of cells
expressing alkaline phosphatase. By contrast, IL-1beta stimulated cell
proliferation and differentiation. Both IL-1beta and TNFalpha stimulated IL-6 and
PGE2 release from the osteoblast-like cells. Our results suggest that, particle
activated mononuclear phagocytes can induce a change in the balance between bone
formation and resorption by a number of mechanisms.
PMID- 9393920
TI - Age variations in the properties of human tibial trabecular bone.
AB - We tested in compression specimens of human proximal tibial trabecular bone from
31 normal donors aged from 16 to 83 years and determined the mechanical
properties, density and mineral and collagen content. Young's modulus and
ultimate stress were highest between 40 and 50 years, whereas ultimate strain and
failure energy showed maxima at younger ages. These age-related variations
(except for failure energy) were non-linear. Tissue density and mineral
concentration were constant throughout life, whereas apparent density (the amount
of bone) varied with ultimate stress. Collagen density (the amount of collagen)
varied with failure energy. Collagen concentration was maximal at younger ages
but varied little with age. Our results suggest that the decrease in mechanical
properties of trabecular bone such as Young's modulus and ultimate stress is
mainly a consequence of the loss of trabecular bone substance, rather than a
decrease in the quality of the substance itself. Linear regression analysis
showed that collagen density was consistently the single best predictor of
failure energy, and collagen concentration was the only predictor of ultimate
strain.
PMID- 9393921
TI - Synthetic osteochondral replacement of the femoral articular surface.
AB - We have studied damage to the tibial articular surface after replacement of the
femoral surface in dogs. We inserted pairs of implants made of alumina, titanium
and polyvinyl alcohol (PVA) hydrogel on titanium fibre mesh into the femoral
condyles. The two hard materials caused marked pathological changes in the
articular cartilage and menisci, but the hydrogel composite replacement caused
minimal damage. The composite osteochondral device became rapidly attached to
host bone by ingrowth into the supporting mesh. We discuss the clinical
implications of the possible use of this material in articular resurfacing and
joint replacement.
PMID- 9393922
TI - Fresh osteochondral allografts for post-traumatic osteochondral defects of the
knee.
AB - We used fresh small-fragment osteochondral allografts to reconstruct post
traumatic osteochondral defects in 126 knees of 123 patients with a mean age of
35 years. At a mean follow-up of 7.5 years (2 to 20), 108 knees were rated as
successful (85%) and 18 had failed (15%). The factors related to failure included
age over 50 years (p = 0.008), bipolar defects (p < 0.05), malaligned knees with
overstressing of the grafts, and workers' compensation cases (p < 0.04). Collapse
of the graft by more than 3 mm and of the joint space of more than 50% were seen
more frequently in radiographs of failed grafts. Our encouraging clinical results
for fresh small-fragment osteochondral allografts show that they are indicated
for unipolar post-traumatic osteochondral defects of the knee in young active
patients.
PMID- 9393923
TI - Lower-limb lengthening in short stature. An electrophysiological and clinical
assessment of peripheral nerve function.
AB - We assessed peripheral nerve function during and after lower-limb lengthening by
callotasis in 14 patients with short stature, using motor conduction studies.
Four patients with short stature of varying aetiology showed unilateral and one
showed bilateral weakness of foot dorsiflexion. Both clinical and
electrophysiological abnormalities consistent with involvement of the peroneal
nerve were observed early after starting tibial callotasis. There was some
progressive electrophysiological improvement despite continued bone distraction,
but two patients with Turner's syndrome had incomplete recovery. A greater
percentage increase in tibial length did not correspond to a higher rate of
peroneal nerve palsy. The function of the posterior leg muscles and the
conduction velocity of the posterior tibial nerve were normal throughout the
monitoring period. The F-wave response showed a longer latency at the end of the
bone distraction than in basal conditions; this is probably related to the
slowing of conduction throughout the entire length of the nerve.
PMID- 9393924
TI - Length and torsion of the lower limb.
AB - Corrective osteotomies are often planned and performed on the basis of normal
anatomical proportions. We have evaluated the length and torsion of the segments
of the lower limb in normal individuals, to analyse the differences between left
and right sides, and to provide tolerance figures for both length and torsion. We
used CT on 355 adult patients and measured length and torsion by the Ulm method.
We excluded all patients with evidence of trauma, infection, tumour or any
congenital disorder. The mean length of 511 femora was 46.3 +/- 6.4 cm (+/-2SD)
and of 513 tibiae 36.9 +/- 5.6 cm; the mean total length of 378 lower limbs was
83.2 +/- 11.4 cm with a tibiofemoral ratio of 1 to 1.26 +/- 0.1. The 99th
percentile level for length difference in 178 paired femora was 1.2 cm, in 171
paired tibiae 1.0 cm and in 60 paired lower limbs 1.4 cm. In 505 femora the mean
internal torsion was 24.1 +/- 17.4 degrees, and in 504 tibiae the mean external
torsion was 34.9 +/- 15.9 degrees. For 352 lower limbs the mean external torsion
was 9.8 +/- 11.4 degrees. The mean torsion angle of right and left femora in
individuals did not differ significantly, but mean tibial torsion showed a
significant difference between right (36.46 degrees of external torsion) and left
sides (33.07 degrees of external torsion). For the whole legs torsion on the left
was 7.5 +/- 18.2 degrees and 11.8 +/- 18.8 degrees, respectively (p < 0.001).
There was a trend to greater internal torsion in femora in association with an
increased external torsion in tibiae, but we found no correlation. The 99th
percentile value for the difference in 172 paired femora was 13 degrees; in 176
pairs of tibiae it was 14.3 degrees and for 60 paired lower limbs 15.6 degrees.
These results will help to plan corrective osteotomies in the lower limbs, and we
have re-evaluated the mathematical limits of differences in length and torsion.
PMID- 9393925
TI - The effects of mechanical forces on bones and joints. Experimental study on the
rat tail.
AB - We have used an experimental model employing the bent tail of rats to investigate
the effects of mechanical forces on bones and joints. Mechanical strain could be
applied to the bones and joints of the tail without direct surgical exposure or
the application of pins and wires. The intervertebral disc showed stretched
annular lamellae on the convex side, while the annulus fibrosus on the concave
side was pinched between the inner corners of the vertebral epiphysis. In young
rats with an active growth plate, a transverse fissure appeared at the level of
the hypertrophic cell layer or the primary metaphyseal trabecular zone.
Metaphyseal and epiphyseal trabeculae on the compressed side were thicker and
more dense than those of the distracted part of the vertebra. In growing animals,
morphometric analysis of hemiepiphyseal and hemimetaphyseal areas, and the
corresponding trabecular bone density, showed significant differences between the
compressed and distracted sides. No differences were observed in adult rats. We
found no significant differences in osteoclast number between compressed and
distracted sides in either age group. Our results provide quantitative evidence
of the working of 'Wolff's law'. The differences in trabecular density are
examples of remodelling by osteoclasts and osteoblasts; our finding of no
significant difference in osteoclast numbers between the hemiepiphyses in the
experimental and control groups suggests that the response of living bone to
altered strain is mediated by osteoblasts.
PMID- 9393926
TI - Management of gunshot wounds of the limbs.
PMID- 9393927
TI - Radio-opaque agents in bone cement increase resorption.
PMID- 9393928
TI - Thromboprophylaxis and death after total hip replacement.
PMID- 9393929
TI - Trauma management.
PMID- 9393930
TI - Recurrent rotational deformity of the femur after static locking of
intramedullary nails.
PMID- 9393931
TI - Physical examination is sufficient for the diagnosis of sprained ankles.
PMID- 9393932
TI - Management of fibular hemimelia.
PMID- 9393933
TI - Articular penetration in Garden-I fractures of the hip.
PMID- 9393934
TI - Rat natriuretic peptide receptor genes are regulated by glucocorticoids in vitro.
AB - The effects of glucocorticoids on NPR-A and NPR-B mRNA transcription and
natriuretic peptides ANP and CNP mediated cGMP production by intact vascular
smooth muscle cells (VSMC) were studied in rat. Cultured VSMC were prepared from
rat mesenteric arteries of 12-week-old Sprague-Dawley rats by enzymatic
digestion. Dexamethasone-induced NPR-A mRNA increase was detectable early in the
incubation periods and reached a plateau after 48 hours of glucocorticoid
administration. This mRNA increase was mimicked by cortisol and inhibited by the
glucocorticoid receptors antagonist RU 38,486. The levels of NPR-B mRNA remained
unchanged during all the periods of stimulation. However, cGMP generated by both
receptors in dexamethasone treated cells was higher than in control cells and
this production was mimicked by cortisol and also blocked by RU 38,486.
Desoxycorticosterone acetate (DOCA) had no effect on the levels of cGMP
production. The results suggest that glucocorticoids have transcriptional and
posttranscriptional effects on rat mesenteric arteries cells through
glucocorticoid receptors.
PMID- 9393935
TI - Prevention of hypoxemia-induced renal dysfunction by perindoprilat in the rabbit.
AB - The role of angiotensin II, a potent postglomerular vasoconstrictor, in the
hypoxemia-induced renal changes is still controversial. The ability of
perindoprilat, an angiotensin converting-enzyme inhibitor, to prevent the acute
renal effects of hypoxemia was assessed in 22 anesthetized-ventilated rabbits. In
8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure
(MBP) (-12 +/- 2%), glomerular filtration rate (GFR) (-16 +/- 3%) and renal blood
flow (RBF) (-12 +/- 3%) with a concomittant increase in renal vascular resistance
(RVR) (+18 +/- 5%) and urine flow rate (+33 +/- 14%), and without any changes in
filtration fraction (FF) (-4 +/- 2%). This suggests the occurrence of glomerular
vasoconstriction during the hypoxemic stress. In 7 normoxemic rabbits,
intravenous perindoprilat (20 microg/kg) induced an increase in urine flow rate
(+17 +/- 4%) and RBF (+17 +/- 4%), and a decrease in MBP (-6 +/- 1%), RVR (-14 +/
3%) and FF (-11 +/- 2%) without a significant change in GFR. The drop in FF and
the increase in RBF suggests preferential postglomerular vasodilatation. In 7
rabbits, perindoprilat prevented the occurence of the hypoxemia-induced changes
in RBF and RVR without improving MBP. FF decreased significantly (-18 +/- 2%),
while the drop in GFR (-7 +/- 2%) was partially blunted and the increase in urine
flow rate (+25 +/- 9%) was confirmed. These results could be explained by the
inhibition of the angiotensin-mediated efferent vasoconstriction and by the
inhibition of bradykinin degradation by perindoprilat. These data confirm the
ability of converting-enzyme inhibitors to prevent the renal hypoperfusion
induced by acute hypoxemia.
PMID- 9393936
TI - Spinal mu, delta and kappa opioids alter chemical, mechanical and thermal
sensitivities in amphibians.
AB - Previously we demonstrated the use of chemical (topical acetic acid), thermal
(radiant heat) and mechanical (von Frey filament) stimuli as quantifiable
behavioral response assays in the northern grass frog, Rana pipiens. Furthermore,
response thresholds in all of these sensory modalities are significantly elevated
by systemic morphine injections, which can be antagonized by naltrexone. The
present study employed these three sensory assays to assess changes in chemical,
mechanical and thermal sensitivities following spinal administration of mu, delta
and kappa opioids. Significant elevations were observed across all three sensory
modalities in each subtype category and these effects were abolished by prior
systemic administration of naltrexone. However, naltrexone antagonism of morphine
produced hyperalgesia in both the mechanical and thermal modalities. The results
support other recent work demonstrating that the spinal site for opioid analgesia
is present in amphibians and that the thermal, mechanical and acetic acid assays
are measures of true nociceptive activity in the amphibian.
PMID- 9393937
TI - Antagonism to noradrenaline-induced lethality in rats is related to affinity for
the alpha1A-adrenoceptor subtype.
AB - The potency of several alpha1-adrenoceptor antagonists in preventing the
noradrenaline-induced lethality in conscious rats, their binding affinity for the
native alpha1A- and alpha1B-adrenoceptors, the recombinant animal alpha1a-,
alpha1b- and alpha1d-adrenoceptor subtypes, as well as their functional affinity
for the alpha1L-adrenoceptor subtype were evaluated. The potency of the tested
compounds as antagonists of noradrenaline-induced lethality was correlated with
the affinity for the alpha1A- (and alpha1a-) adrenoceptor subtype, but not with
the affinity for the other subtypes. On the contrary, the hypotensive effects of
the compounds, assessed in anesthetized rats, were not clearly related with the
affinity for any of the alpha1-subtypes. These results suggest that the alpha1A
subtype plays a determining role in preventing lethality induced by noradrenaline
in the rats, and that this activity is unrelated to the hypotensive effect of the
compounds, which cannot be clearly correlated with affinity for a particular
alpha1-adrenoceptor subtype.
PMID- 9393938
TI - The changes in pulmonary C-fiber activity and lung mechanics induced by vagal
stimulation in rabbits.
AB - The effect of unilateral stimulation of the vagus nerve on pulmonary C-fiber
activity, total lung resistance (R(L)) and dynamic lung compliance (Cdyn) was
studied in anesthetized, artificially ventilated rabbits. Vagal stimulation (4-30
Hz) increased both pulmonary C-fiber activity and R(L) but decreased Cdyn, and
these changes were frequency-dependent. Atropine (2 mg/kg) blocked the responses
of pulmonary C-fiber, R(L) and Cdyn to vagal stimulation at 4-30 Hz. Stimulation
of pulmonary C-fiber activity by the higher volume-induced lung inflation was not
significantly altered by atropine (2 mg/kg). A selective SP antagonist [D-Pro2, D
Try(7,9)]-SP (0.5 mg/kg) inhibited bronchoconstrictor responses to vagal
stimulation at 30 Hz but had no significant effect on those to the stimulation at
4-17 Hz. These results suggest that excitation of the rabbit pulmonary C-fiber
activity by unilateral vagus nerve stimulation would occur as a result of the
mechanical stimuli via a cholinergic neurotransmission and that during the
stimulation at 30 Hz this excitation partly involves the local release of
substance P (SP) to promote acetylcholine outflow.
PMID- 9393940
TI - Role of enzymatic activity in the antiplatelet effects of a phospholipase A2 from
Ophiophagus hannah snake venom.
AB - A phospholipase A2 (OHV A-PLA2) from the venom of Ophiophagus hannah (King cobra)
is an acidic protein exhibiting antiplatelet activity. In in vitro tests, OHV
APLA2 showed a marked inhibitory effect on platelet aggregation induced by ADP,
collagen and arachidonic acid in both human whole blood and platelet-rich plasma
in a dose-dependent manner. The antiplatelet effects of OHV A-PLA2 did not
increase when preincubation times of platelets and OHV A-PLA2 were prolonged
indicating phospholipid hydrolysis did not significantly contribute to the
antiplatelet effects. Alkylation of active site His residue using p-bromophenacyl
bromide resulted in the complete loss of enzymatic activity, but the modified
enzyme retained more than 30% of its antiplatelet effects. These results indicate
that the antiplatelet effects of OHV A-PLA2 appear to be independent of its
enzymatic activity, and there are separate sites responsible for the catalytic
and antiplatelet activities.
PMID- 9393939
TI - Nitric oxide synthase inhibition attenuates signs of ethanol withdrawal in rats.
AB - The effects of N(G)-nitro arginine methyl ester (L-NAME) and 7-nitroindazole (7
NI), nitric oxide synthase inhibitors, and L-arginine, a nitric oxide precursor,
on ethanol withdrawal signs were investigated in rats. Ethanol (7.2% v/v) was
given to rats by a liquid diet for 16 days. L-NAME (30 and 60 mg/kg), 7-NI (40
and 80 mg/kg), L-arginine (100 mg/kg), a combination of L-arginine (100 mg/kg)
and 7-NI (40 mg/kg), and saline or vehicle were injected to rats
intraperitoneally 30 min before ethanol withdrawal. A second series of injections
was given at 6 hour after the first one, and subjects were then tested for
audiogenic seizures. 7-NI (40 mg/kg), vehicle and saline were also administered
to naive rats. 7-NI (40 mg/kg) did not produce any significant change in
locomotor activity in naive rats. Both L-NAME and 7-NI significantly inhibited
locomotor hyperactivity from the 2nd to the 6th hour of the withdrawal period.
They also reduced the total ethanol withdrawal score from the 30th min to the 6th
hour, and they significantly decreased audiogenic seizures. Neither drug
increased locomotor activity nor total ethanol withdrawal score, which were
increased significantly by L-arginine (100 mg/kg); however, L-arginine (100
mg/kg) prevented the inhibitory effects of 7-NI (40 mg/kg) on increased locomotor
activity, total ethanol withdrawal score, and audiogenic seizure. Our results
suggest that nitric oxide synthase inhibition by L-NAME and 7-NI alleviates the
signs of ethanol withdrawal. The data also support the hypothesis that nitric
oxide may take part in the neuroadaptation that develops during chronic ethanol
ingestion in rats.
PMID- 9393941
TI - Amphetamine induces hydroxyl radical formation in the striatum of rats.
AB - Amphetamine-induced hydroxyl radical formation in the striatum of rats was
investigated in this study. With the utilization of the microdialysis and HPLC
ECD, the striatal dopamine (DA) release and the formation of 2,3-dihydroxybenzoic
acid (2,3-DHBA), derived from the reaction of hydroxyl radicals (.OH) and
salicylate in perfusion, were monitored and detected during desipramine and/or
amphetamine (AMPH) administration. Our data revealed that after desipramine
treatment AMPH injections not only amplified striatal DA release and 2,3-DHBA
formation, but also intensified the stereotyped behaviors induced by AMPH.
Furthermore, we discovered that alpha-methyl-para-tyrosine (alpha-MT)
pretreatment prevented the onset of the above responses. In desipramine-treated
rats, the tissue homogenization study demonstrated that a single dose of AMPH
produced long-term depletion of striatal DA; this was not seen in saline-treated
rats. Moreover, striatal DA depletion could be lessened by pretreatment with
mannitol, a .OH scavenger. These results indicate that AMPH-induced striatal .OH
formation might be DA-related in desipramine-treated rats, and suggest that .OH
formation might be correlated with AMPH-induced neurodegeneration.
PMID- 9393942
TI - Iron binding capacity of didox (3,4-dihydroxybenzohydroxamic acid) and amidox
(3,4-dihydroxybenzamidoxime) new inhibitors of the enzyme ribonucleotide
reductase.
AB - Ribonucleotide reductase is the rate limiting enzyme of deoxynucleoside
triphosphate synthesis and is considered to be an excellent target of cancer
chemotherapy. Didox and amidox are newly synthesized compounds, which inhibit
this enzyme and have in vitro and in vivo antitumor activity. We have now
investigated the capability of didox and amidox to interfere with the iron
metabolism. We show by photometric and polarographic methods, that didox and
amidox are capable of forming an iron complex. However, their cytotoxic action
cannot be completely circumvented by addition of Fe-ammoniumcitrate, indicating
that the iron complexing capacity may not be responsible for the mechanism of
action of these compounds. When L1210 leukemia cells were incubated with the
didox-iron or amidox-iron complex itself, changes of the 50% growth inhibitory
capacity of the complex in comparison with didox or amidox alone could be shown.
We conclude, that didox and amidox are capable of forming iron complexes, but in
contrast to other agents, the anticancer activity cannot be contributed to this
effect alone. Future studies will have to elucidate the molecular mechanism of
action of these new and promising anticancer agents.
PMID- 9393943
TI - With aging in humans the activity of the hypothalamus-pituitary-adrenal system
increases and its diurnal amplitude flattens.
AB - There is compelling evidence for feedback disturbances in the hypothalamus
pituitary-adrenal system associated with human aging as assessed by challenge
tests. However, reports about age-related changes in human basal activity are
ambiguous and to date little is known about changes in the pulsatile features of
the HPA system. To investigate these changes we studied twenty-two healthy male
and eleven healthy female subjects ranging from 23 to 85 and 24 to 81 years
respectively. 24-hour blood sampling with 30 minute sampling intervals was
performed. From 18.00 to 24.00 hours blood was sampled every 10 minutes for
analysis of pulsatile features of HPA activity. Statistical analysis revealed
that age in particular had major effects upon basal HPA-system activity: there
was a significant age-associated increase in minimal (p < 0.0001) and mean (p <
0.02) cortisol plasma concentrations, but no alteration in pulsatile features. We
found no age-cortisol correlation during daytime, but were able to demonstrate a
strong impact of age upon cortisol plasma levels from 20.00 to 1.30 hours. The
diurnal amplitude of cortisol (p < 0.005) and ACTH (p < 0.006), relative to the
24-hour mean of the hormones, showed an age-associated decline. Additionally, the
evening cortisol quiescent period (p < 0.01) was shortened in the elderly,
suggesting increasingly impaired circadian function in aging. Our results suggest
an increased basal activity and a flattened diurnal amplitude of the HPA system
in the elderly.
PMID- 9393944
TI - The effect of metabolic acidosis and alkalosis on the H+-ATPase of rat cerebral
microvessels.
AB - To determine the role of the proton translocating adenosine triphosphatase (H+
ATPase) of the blood-brain barrier, the density of the 31 Kd subunit of the
vacuolar type H+-ATPase was quantitated in isolated rat cerebral microvessels
with immunoblotting techniques. To establish the tissue specificity of the
findings, synaptosomal membranes were also studied. Metabolic acidosis was
induced with 1.5% ammonium chloride in drinking water for five days. Metabolic
alkalosis was induced with 2.35% NaHCO3 in drinking water and daily injections of
10 mg/Kg furosemide intraperitoneally for 5 days. The quantity of the 31 Kd
subunit (in arbitrary units) in cerebral microvessels was significantly increased
in acidosis (3.98 +/- 0.45) (p<0.05) and was significantly decreased in metabolic
alkalosis (0.49 +/- 0.16) (p<0.00) compared to controls (1.77 +/- 0.73). In
synaptosomal membranes, metabolic alkalosis was associated with significant
decrease in the quantity of the 31 Kd subunit-H+-ATPase (0.62 +/- 0.12 vs 0.92 +/
0.01) p<0.05. The increase in the 31 Kd subunit in synaptosomal membranes with
acidosis did not reach statistical significance. It is concluded that the
quantity of vacuolar H+-ATPase in the blood-brain barrier is modulated by blood
H+ or HCO3- content. These changes may be relevant to the physiology of the acid
base balance in the central nervous system.
PMID- 9393945
TI - Cyclosporine A-induced contraction of isolated rat aortic smooth muscle cells.
AB - The mechanisms by which the immunosuppressive drug cyclosporine A (CsA) induces
hypertension and nephrotoxicity are still not fully understood. Although smooth
muscle cell (SMC) contraction is probably the mechanism of vasoconstriction, the
direct contractive effect of CsA on SMCs has not yet been demonstrated. Thus, it
was the purpose of this study to evaluate the direct effects of CsA in cultured
SMCs through interactive image analysis. In aortic SMCs, CsA at the
concentrations of 0.01, 0.1 and 1 microM, caused a concentration-dependent
decrease of the planar cross-sectional area (PCSA) after 30 min and 60 min of
treatment. The PCSA decreases were statistically significantly different from
control at all concentrations. No cytotoxicity was observed under these
conditions. Ten minutes preincubation of SMCs with a monoclonal antibody against
endothelin-1 (ET-1) significantly prevented the CsA effects at 1 microM. When the
same antibody was heat inactivated or an unspecific antibody (anti-desmin
immunoglobulin G) was applied, the CsA-induced contractions were not affected.
These data suggest that CsA can cause a direct contractive effect on vascular
SMCs. This effect is partly mediated by ET-1.
PMID- 9393946
TI - Characterization of methadone receptor subtypes present in human brain and lung
tissues.
AB - In addition to their use in pain control, opioids can function as regulators of
tumor cell growth. We have found that the therapeutic opioid, methadone,
significantly inhibits the in vitro and in vivo growth of human lung cancer
cells, and this effect appears to be mediated by specific, high affinity, non
conventional opioid binding sites. The present study indicates the existence of
multiple subtypes of binding sites mediating the peripheral and central nervous
system actions of this drug. Pharmacological and biochemical characterizations of
the methadone binding sites expressed in human brain and normal lung tissues
indicate that these sites are distinct from each other and from other opioid
receptor types present on human and rat brain membranes, as well as those
expressed in human lung cancer cells. The identification of distinct methadone
receptor types in the different tissues could lead to the development of more
selective and less toxic drugs targeted toward the tumor cells.
PMID- 9393947
TI - The role of estrogen receptor mutations in tamoxifen-stimulated breast cancer.
AB - During the past 20 years, the hormonal therapy of choice for the treatment of
breast cancer has been the antiestrogen, tamoxifen. The use of tamoxifen has been
proved to produce a favorable response and survival advantage in patients whose
tumors are classified as estrogen receptor-positive (ER+)/progesterone receptor
positive (PR+). Additionally, tamoxifen is the only drug known to reduce the
incidence of contralateral disease. This drug produces relatively few harmful
side effects, while exhibiting several beneficial effects such as maintaining
bone density and reducing the incidence of myocardial infarction in the
postmenopausal woman. However, tumors eventually acquire a tamoxifen-resistant or
tamoxifen-stimulated phenotype, resulting in disease recurrence. Several
mechanisms have been proposed to account for tamoxifen-resistant breast cancer,
in the hope of developing a more effective first-line or perhaps second-line
treatment strategy. One popular theory is the occurrence of a mutation in the
estrogen receptor, the drug target. A plethora of studies have reported the
detection of estrogen receptor mRNA splice variants, and it has been suggested
that the accumulation of these variant mRNAs are responsible for the development
of tamoxifen-resistant breast cancer. In this review, several questions will be
posed to address the suitability of both laboratory and clinical evidence to
support this hypothesis. Although there is adequate data generated in the
laboratory, there is, as yet, no compelling evidence to suggest that mutation of
the estrogen receptor is the molecular mechanism producing tamoxifen-stimulated
growth in human breast and endometrial cancer.
PMID- 9393948
TI - Trans-retinoic acid and glucocorticoids synergistically induce transcription from
the mouse mammary tumor virus promoter in human embryonic kidney cells.
AB - Human embryonic kidney (K293) cells transfected with a mouse mammary tumor virus
(MMTV) promoter-luciferase reporter construct (pHH-Luc) were utilized to
investigate the potential effects of trans-retinoic acid (tRA), either by itself
or in combination with glucocorticoid (GC) hormones, on a well-characterized, GC
sensitive transcriptional response. tRA or the synthetic GC hormone dexamethasone
induced transcription from the MMTV promoter in a dose-dependent manner, with 1
micromol tRA and 1 micromol dexamethasone alone causing a four- to six-fold and a
40-fold induction of basal transcription, respectively. Simultaneous treatment
with 1 micromol dexamethasone and 1 micromol tRA resulted in a synergistic
transcriptional response that was 120-fold higher than basal level and 2.5 times
the predicted response, based on a simple additive effect of both agonists. tRA
does not appear to mediate this synergistic transcriptional response by enhancing
GC receptor (GR) binding capacity, affinity, or nuclear translocation. tRA was
unable to potentiate GC-induced transcriptional activity from a minimal GC
response element (GRE), and GC were unable to potentiate tRA-induced
transcriptional activity from a minimal retinoic acid response element (RARE).
These data rule out direct protein-protein interactions between GC and retinoid
receptors as a mechanism for the observed synergism. tRA also synergized with
aldosterone-induced, mineralocorticoid receptor (MR)-mediated, transcriptional
activation of the MMTV promoter, resulting in a response that was 1.7 times the
predicted additive response. The MMTV GRE located between -187 and -165 was
required for GC-induced and synergistic activation of the MMTV promoter, whereas
sequences located within -151 to +5 were sufficient for tRA-induced transcription
from the MMTV promoter. Mutation of a consensus RARE half-site (CCAAGT)
identified at position -65 to -60 within the MMTV-LTR did not affect either tRA
induced transcriptional activation or synergism with GC. We propose that the tRA
induced transcriptional response from the MMTV promoter, as well as synergism
with GC, may be mediated by the activation or induction of a factor(s) that
either directly binds to the MMTV promoter or indirectly stabilizes binding of
another transcription factor to these sequences.
PMID- 9393949
TI - Identification of two estrogen receptor transcripts with novel 5' exons isolated
from a MCF7 cDNA library.
AB - Two novel transcripts of human estrogen receptor (ER) have been identified that
differ in the 5' untranslated sequence. It has previously been determined that an
alternate ER transcript is generated from transcription initiated upstream of the
main ER cap site (P1), and utilizes a splice acceptor site at +163. Here we
report the isolation of 21 ER clones from a MCF7 cDNA library. Eleven of these
clones correspond to transcripts that initiate at the P1 cap site, whereas the
remaining 10 clones are derived from two previously unidentified ER transcripts
(designated E and H) that both utilize the +163 splice acceptor site. A panel of
breast and endometrial carcinoma cell lines were screened by reverse
transcriptase-polymerase chain reaction (RT-PCR) for expression of the E and H
transcripts. It was found that all ER-positive cell lines expressed both of the
novel transcripts. In addition, 10 primary human breast cancers were analyzed, of
which six expressed the E transcript and five abundantly expressed the H
transcript. These data indicate that expression of ER in human breast cancers can
be dependent upon an alternate promoter at least 20 kb upstream of the primary
cap site for ER.
PMID- 9393950
TI - Auto-regulation of the estrogen receptor promoter.
AB - The presence or absence of estrogen receptor (ER) plays a key role in the
diagnosis and treatment of breast tumors. It is known that patients with breast
tumors classified as ER-positive have a better prognosis. Observations such as
this have led us to explore the question of what makes some breast tumors
overexpress ER whereas others express either very low levels or none at all. To
begin a study of ER regulation, we first chose to examine a 200 bp region of the
ER promoter located immediately upstream from the transcribed sequence of the
human ER gene. We found that this region of the ER promoter contained basal
activity when transiently transfected into ER-negative HeLa cells. ER promoter
activity was further increased by co-transfection of a wild-type ER expression
vector, and this increased activity was hormone-dependent. Several ER deletion
mutant constructs were also able to increase the activity of the ER promoter
fragment, but none could support equivalent activity as was seen with the full
length ER. Therefore, we conclude that the ER can contribute to its own
expression, and we hypothesize that this auto-regulation may contribute to its
overexpression in some breast tumors.
PMID- 9393951
TI - A reporter gene assay for fungal sterol biosynthesis inhibitors.
AB - Acetoacetyl-CoA thiolase (ACoAT) catalyses the condensation of two acetyl-CoA
molecules, the first step in the sterol biosynthetic pathway. We constructed a
yeast strain containing a fusion of the promoter of the Saccharomyces cerevisiae
ACoAT gene to a reporter gene (Escherichia coli beta-galactosidase). Reporter
gene activity in this strain can be induced by a variety of inhibitors of sterol
biosynthesis. These results suggest that the ACoAT gene is feedback regulated at
the transcriptional level by products of the sterol biosynthetic pathway. The
reporter gene approach described here may be used to screen chemical collections
for compounds which inhibit fungal sterol biosynthesis.
PMID- 9393952
TI - Neutral mutations to three acidic AF2 residues in the mouse estrogen receptor
confer agonist activity to A-ring isomers of estradiol.
AB - The ability of the estrogen receptor (ER) to function as a ligand-mediated
transcription factor involves the activation function-2 (AF2) in the hormone
binding domain (HBD). Although several types of ligand bind to the ER, AF2
functions selectively, as it is activated by estradiol (E2) but not by
antiestrogens. The mechanism used by AF2 to interpret the chemical and structural
information encoded in the bound ligand, and to transfer this information to
other transcriptional regulatory proteins on the promoters of estrogen-regulated
genes, is unknown at present. To address this issue, we have examined the
activities of two mouse ERs with mutations in the AF2 region. One incorporated
changes in three acidic residues (pJ3MOR, D542N/E546Q/D549N) on the polar face of
the putative AF2 alpha-helix, whereas the other contained alterations in two
hydrophobic amino acids (pJ3MOR, L543D/L544A) on the non-polar face.
Transcriptional activity was measured with chloramphenicol acetyltransferase
(CAT) reporter genes including a minimal (JA12) or a complex (pS2tkCAT) promoter.
In transient cotransfection assays using COS-1 cells, it was found that A-ring
isomers of E2, which are inactive or behave as antagonists with the wild-type ER,
acted as agonists when the neutral AF2 mutant ER and the pS2tkCAT promoter were
tested. On the other hand, when the mutant ER with changes in key hydrophobic
residues was used with this same promoter, the estrogen antagonist, ICI 164,384,
acted as an agonist. The findings in this report establish a role for acidic AF2
amino acids, and confirm the contributions made by hydrophobic residues, in the
interpretation of ligand identity and in the transmission of this information to
the transcriptional regulatory apparatus. Critical residues on both sides of the
AF2 alpha-helix are, therefore, likely to be involved in distinguishing between
ligands with either extensive or subtle alterations in structure, and in
mediating this information to the regulatory proteins on estrogen-responsive
genes.
PMID- 9393953
TI - The effect of chorion-uterine interaction upon free progesterone metabolism
during advanced gestation in the guinea pig.
AB - The in vitro fate of [3H]progesterone was studied after incubation with guinea
pig tissues at 58/59 days (before pubic symphysis relaxation) and in the final
week (post relaxation) of gestation. Buffered steroid was added to the fetal
surface of chorion attached to the uterus or to the uterus alone. Neither the
amount of recovered progesterone nor its metabolites (6.2% average conversion)
differed between the two stages when only uterus was incubated. With chorion
present, conversion averaged 28.3% at 58/59 days and 63.4% at the late stage. A
4.6-fold decrease in progesterone concentration, and 3.0-, 2.4- and 3.1-fold
increases in the concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one, 3beta
hydroxy-5alpha-pregnan-20-one and 5alpha-pregnane-3,20-dione, respectively, were
found in the uterus in the late stage vs 58/59 days. Also, 2.8- and 6.4-fold
decreases in progesterone concentration occurred in the myometrium and
endometrium, respectively, from 58/59 days to the late stage. In endometrium, the
concentrations of the 3alpha- and 3beta-isomers, and 5alpha-pregnane-3,20-dione,
increased 2.6-, 2.6- and 5.0-fold, respectively. The above changes were all
significant at P < 0.05 or better. Changes in the 3alpha-, 3beta- isomers and
dione in the myometrium were not significant. The chorion-uterine interaction and
gestation time thus affect the degree of progesterone conversion, and the amounts
of metabolites reaching the uterus in the chorion-uterine in vitro system.
PMID- 9393954
TI - Metyrapone is a competitive inhibitor of 11beta-hydroxysteroid dehydrogenase type
1 reductase.
AB - The present study was designed to examine the effects of metyrapone in vitro on
the activities of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2,
the two intracellular enzymes responsible for the metabolism of glucocorticoids.
Enzymatic activities of 11beta-HSD1 and 2 were determined by a radiometric
conversion assay using cortisol and cortisone as physiological substrates. The
enzyme activity assays were carried out in the absence and presence of metyrapone
using sheep liver and kidney microsomes as the source of 11beta-HSD1 and 2,
respectively. It was found that metyrapone inhibited the reductase activity of
11beta-HSD1 in a dose-dependent manner with an apparent Ki of 30 microM.
Moreover, this inhibition was competitive because the Km for cortisone was
increased in the presence of metyrapone. In contrast, metyrapone showed biphasic
effects on the dehydrogenase activity of 11beta-HSD1, in that it increased the
activity at concentrations lower than 100 microM but decreased it at higher
concentrations. However, under similar conditions, metyrapone had little effect
on the unidirectional dehydrogenase activity of 11beta-HSD2. In conclusion, the
present results provide the first direct evidence that metyrapone is a
competitive inhibitor of 11beta-HSD1 reductase, and that it also exerts biphasic
effects on 11beta-HSD1 dehydrogenase activity. These findings indicate that
metyrapone influences peripheral glucocorticoid metabolism through its regulation
of 11beta-HSD1 activity, in addition to its classic inhibitory effects on adrenal
steroid biosynthesis. It is therefore imperative that this novel extra-adrenal
effect of metyrapone be considered when this drug is used in the diagnosis and
treatment of adrenocorticoid-related diseases.
PMID- 9393955
TI - Second messengers and the control of progesterone production from first trimester
trophoblast.
AB - Basal progesterone production from first trimester placental cells in culture was
high during the first 24 h of culture and fell to less than 30% of the initial
level after 96 h in vitro. 22(R)-Hydroxycholesterol had a similar effect on
progesterone production at all incubation times, indicating that the decline in
basal steroidogenesis was not due to a loss of mitochondrial or post
mitochondrial enzymes. Continuous stimulation with dibutyryl (db) cyclic AMP
maintained progesterone synthesis at a relatively constant high level despite the
fall in basal progesterone production, and the optimum concentration of db cyclic
AMP was 1.0 mM. The calcium ionophore A23187 had no effect on progesterone
incubation during short-term cultures (<4 h), and inhibited steroidogenesis after
24 h. Repeated addition of A23187 during 96 h of culture also inhibited
progesterone production. These findings indicate that progesterone production in
human trophoblast is supported by a local factor which maintains a high level of
steroid production through a cyclic AMP-dependent mechanism. The inhibitory
effects of calcium ionophore in trophoblast differ from the stimulatory effects
of this compound in other steroidogenic cells, but the reasons for the difference
are not known at present.
PMID- 9393956
TI - Inhibition of steroidogenesis in rat adrenal cells by 18
ethynyldeoxycorticosterone: evidence for an alternative pathway of aldosterone
biosynthesis.
AB - The effect of the mechanism-based inhibitor 18-ethynyldeoxycorticosterone (18-E
DOC) on the late steps of the aldosterone biosynthetic pathway was examined in
freshly isolated cells of the zona glomerulosa (ZG) and fasciculata (ZF) from rat
adrenal glands. ZG synthesis of aldosterone was inhibited by 18-E-DOC in a time-
and concentration-dependent manner with a Ki of approximately 0.05 microM. The
maximal degree of inhibition of ZG production of aldosterone and 18
hydroxycorticosterone (18-OH-B) was approximately 80%. ZF cells, perhaps
surprisingly, were found to secrete 18-OH-B at levels approximately one-third to
one-fourth those of ZG cells and the Ki of 18-E-DOC inhibition of 18-OH-B
secretion was approximately 10 microM for ZF cells, 200-fold higher than for ZG
cells. The inhibitor had no effect on the secretion of corticosterone by either
ZG or ZF, and the secretion of 18-hydroxydeoxycorticosterone (18-OH-DOC) by both
the ZG and ZF was inhibited only to a minor degree. 18-E-DOC inhibited the
biosynthesis of aldosterone by ZG cells incubated with 10 microM added DOC or 18
OH-DOC by approximately 75%, similar to the degree of inhibition of aldosterone
biosynthesis from endogenous substrate, whereas ZF biosynthesis of 18-OH-B from
either substrate was inhibited by less than 40%. ZF cells do not express
aldosterone synthase, the only enzyme known to convert 18-OH-DOC into 18-OH-B.
Incubation of MA-10 cells stably transfected with the cDNA of the rat aldosterone
synthase with 18-E-DOC resulted in a complete inhibition of the conversion of DOC
to aldosterone with a Ki of approximately 0.02 microM. In addition, transfected
cells expressing 11beta-hydroxylase convert DOC to 18-OH-B in very small
quantities only and cannot convert 18-OH-DOC to 18-OH-B. These data suggest that
neither 11beta-hydroxylase nor aldosterone synthase are responsible for the
biosynthesis of 18-OH-B by ZF cells from DOC or 18-OH-DOC, that 20% of
aldosterone synthesis appears not to be attributable to the actions of
aldosterone synthase and that an unknown CYP11B enzyme is also involved in the
biosynthesis of 18-OH-B.
PMID- 9393957
TI - Steroid productions by co-cultures of granulosa cells with inner and outer theca
cells in preovulatory follicles of gonadotropin stimulated calves.
AB - Granulosa, interna and externa theca cells were isolated from large follicles of
equine-chorionic-gonadotropin (eCG)-primed calves and co-cultured during 3 days
in the absence or in the presence of dehydroepiandrosterone (DHEA). Co-cultures
were performed by adding defined numbers of theca and/or granulosa cells which
represented 0, 10, 20, 50 or 100% of total cells per well. Secretion of
oestradiol-17beta (E2), androstenedione (A4) and progesterone (P4) depended on
the type of theca cells (P < 0.001), on the percentage of seeded granulosa cells
(P < 0.001) and on the day of culture (P < 0.001). DHEA increased (P < 0.001) E2
and A4, but not P4 (P > 0.05) productions. Interactions existed between these
factors (P < 0.01). On day 1, A4 production was nil in granulosa cells alone. E2
production was negligible in theca cells alone but it increased when granulosa
cells were added. E2 and A4 varied in an opposite manner according to the
percentage of granulosa cells and with the type of theca cells. On day 3, without
DHEA, E2 and A4 were low. On day 3 with DHEA, E2 production was maintained in
granulosa cells alone but not with any combination of theca cells. In these
conditions, A4 production was maintained in the presence of theca cells but not
in granulosa cells alone. Granulosa cells alone secreted more P4 than theca
cells. P4 increased as a function of the percentage of granulosa in co-cultures
with externa but not interna theca cells with which it remained low. In
conclusion, theca cells in culture have two effects in relation to the granulosa
cells, which differ according to the steroid concerned and to the cell
combination. Both types of theca cells have an inhibitory effect on E2 secretion
whereas only interna theca cells are able to alter P4 production.
PMID- 9393958
TI - Induction of cytochrome P450 1B1 and catechol estrogen metabolism in ACHN human
renal adenocarcinoma cells.
AB - The catechol estrogen metabolites of 17beta-estradiol (E2), 2-hydroxyestradiol
(OHE2) and 4-OHE2, differ in hormonal properties and carcinogenic potential. In
Syrian hamster kidney, 4-OHE2 induces clear-cell carcinoma whereas 2-OHE2 does
not, and an E2 4-hydroxylase appears to be involved in E2-induced carcinogenesis
in these animals. Specific E2 4-hydroxylase activity has been observed in
extrahepatic tissues from several species. In humans, cytochrome P450 1B1
(CYP1B1) appears to be an extrahepatic E2 4-hydroxylase under the regulatory
control of the aromatic hydrocarbon receptor (AhR). As an initial approach to
investigating CYP1B1 expression and E2 4-hydroxylase activity in human kidney, we
used the ACHN cell line, derived from a human renal adenocarcinoma. In untreated
ACHN cells, a very low level of CYP1B1 mRNA expression was observed and CYP1B1
protein could not be detected; however, in ACHN cells exposed to the high
affinity AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), CYP1B1 mRNA
levels were elevated 28-fold, and the CYP1B1 protein was detected by immunoblot
analysis. Exposure of ACHN cells to TCDD resulted in minimal induction of the
CYP1A1 mRNA, and the CYP1A1 protein was not detectable prior to or after exposure
to TCDD. E2 hydroxylase activity could not be detected with microsomes from
untreated ACHN cells, although activities at C-4 and, to a lesser extent, at C-2
of E2 were observed with microsomes from TCDD-treated ACHN cells. In experiments
with intact ACHN cells, elevated rates of formation of 4-methoxyestradiol (MeOE2)
and 2-MeOE2 were observed in response to treatment with TCDD. The EC50 for
induction of the CYP1B1 mRNA was 1.5 nM TCDD; EC50s for the stimulation of 2- and
4-MeOE2 formation were 0.68 and 1.1 nM TCDD. These results indicate that the ACHN
cell line may be a useful in vitro model system to study the regulation of CYP1B1
expression and the cytotoxic effects associated with E2 4-hydroxylation.
PMID- 9393960
TI - Identification and characterization of polymorphisms in the promoter region of
the human Apo-1/Fas (CD95) gene.
AB - Apo-1/Fas (CD95) is a transmembrane protein expressed on the cell surface that is
involved in apoptosis and plays an important role in the function and regulation
of the immune system. Aberrant expression of the Apo-1/Fas gene product has been
reported in a number of immune-related disorders, such as autoimmune
lymphoproliferative syndrome and systemic lupus erythematosus in humans.
Mutations in the coding sequence of the Apo-1/Fas gene have been reported in the
former condition, whereas no abnormalities of the gene have been found to account
for the increased gene expression noted in SLE. We screened the whole 5' flanking
region of the Apo-1/Fas gene encompassing over 2000 bp for
mutation(s)/polymorphism(s) using multiplex PCR, single-strand conformation
polymorphism (SSCP) analysis and sequencing techniques, and identified two
polymorphisms in this region. The first polymorphism is a CG-->CA substitution at
-1377 nucleotide position within the silencer region, which neither creates or
deletes any restriction enzyme sites but alters the transcription factor SP-1
binding site. This polymorphism is noted in 20% of normal Caucasians. The second
polymorphism is an GA-->GG substitution at -670 nucleotide position in the
enhancer region that creates a MvaI restriction fragment length polymorphism
(RFLP) and abolishes the binding site of nuclear transcription element GAS. The
MvaI RFLP is polymorphic with heterozygosity of 52% and the frequency of G and A
alleles are 0.49 and 0.51, respectively. The identification and characterisation
of these two new polymorphisms, particularly the MvaI RFLP marker, provides new
genetic markers and may prove useful for further studies on the regulation of
apoptosis mediated by the Apo-1/Fas gene on human chromosome 10q23.
PMID- 9393959
TI - Synthetic lipopeptides incorporated in liposomes: in vitro stimulation of the
proliferation of murine splenocytes and in vivo induction of an immune response
against a peptide antigen.
AB - Amphiphilic lipopeptides, such as Pam3CysAlaGly and Pam3CysSerSer, were
synthesized and incorporated into liposomes, and their ability to induce the
proliferation of BALB/c mouse splenocyte was tested in vitro. When compared to
monophosphoryl lipid A (MPL) the following potency order was found: liposomal
lipopeptides > liposomal MPL > free (emulsified) lipopeptides. These results
strongly depend on the size of the vesicles used: a mitogenic effect was observed
only with lipopeptides incorporated within vesicles of diameter < or = 100 nm
while lipopeptides in larger vesicles (diameter approximately 300 nm) gave no
response. This may be related to the necessity for the liposome-associated
lipopeptides to be endocytosed to reach putative intracellular targets. As
immunoadjuvanticity seems to be linked to B-lymphocyte activation, the
lipopeptides represent attractive alternatives to MPL for the realization of
completely synthetic liposome-based peptide vaccine formulations. This was borne
out by showing that Pam3CysAlaGly and Pam3CysSerSer, when incorporated in small
unilamellar vesicles carrying a covalently conjugated synthetic peptide of
sequence IRGERA, corresponding to an epitope of the C-terminal region of histone
H3, were able to induce a potent and long-lasting immune response.
PMID- 9393961
TI - Isolation and N-terminal sequence determination of a novel gamma/delta T cell
surface antigen.
AB - An antigen complex unique for porcine gamma/delta T cells has previously been
identified using the monoclonal antibodies MAC319 and MAC320. Here we use
digestion with the proteolytic enzyme bromelain to selectively release the MAC319
antigen as a soluble fragment, for further characterisation. A cytofluorometric
inhibition assay was developed to follow the purification of this fragment, as
the conformation sensitivity of the MAC319 epitope prevented the use of
immunoblotting techniques. The antigen has been purified using a combination of
anion-exchange and hydrophobic-interaction columns, followed by separation on a
size-exclusion column. Fractions from the size-exclusion column containing the
antigen consisted of one major band at Mr 95,000. This species was shown to be
specifically absorbed onto MAC319-coupled Sepharose, thereby identifying the
MAC319 antigen. N-terminal amino acid sequencing of this band has revealed a
previously unidentified sequence. This fragment was also shown to be
glycosylated, most likely with a single sugar moiety. Enzymatic removal of the
sugars showed that they did not appear to be necessary for binding of the
polypeptide to the MAC319 antibody.
PMID- 9393962
TI - Glycosylation is influential in murine IgG3 self-association.
AB - In mice and humans, antibodies of the IgG3 isotype are unique in that they
spontaneously self-associate. A consequence is the formation of cryoglobulins
from some, but not all IgG3 molecules. Little is known about the structural basis
of murine IgG3 self-association. A region of the CH3 domain that is unique to
IgG3 antibodies is the presence of an extra glycosylation site at residues 471
473. It is known that glycosylation greatly influences solubility. It has also
been shown by X-ray crystallography that glycosylated residues (specifically
sialic acid) are influential in the contacts of the CH1 to CH2 as well as the CH2
to CH2 domains in a human IgG1 antibody. These findings provided evidence that a
direct interaction exists between the glycosylated residues and other residues
within the constant and/or variable domains. It was, therefore, important to
determine whether the glycosylated residue in the CH3 domain of the IgG3 constant
region is influential in self-association. We have found that removing the
glycosylation site by site-directed mutagenesis of an IgG3 RF significantly
reduced the self-associating ability of this antibody.
PMID- 9393963
TI - Tandem repeats of T helper epitopes enhance immunogenicity of fusion proteins by
promoting processing and presentation.
AB - Empirical findings have shown that recombinant chimeric proteins may be made more
immunogenic if T helper epitopes are incorporated as tandem repeats. In the
present study we investigated the mechanisms responsible for the enhanced
immunogenicity of fusion proteins composed of the heat-stable enterotoxin of
enterotoxigenic E. coli (STa) linked to multiple copies of the ovalbumin323-339 T
helper epitope (ova) and a connecting dimer of an Ig-binding region of
Staphylococcus aureus protein A (ZZ), which were previously shown to stimulate
strong anti-STa titres in mice. We used B cell and macrophage cell lines as APC
and IL-2 production by ova-specific T cells as our read-out system. Fusion
proteins containing four repeated T helper epitopes were found to be the most
immunogenic and resulted in 50-fold higher IL-2 production than constructs with a
single T helper epitope. Under limiting APC conditions the construct with four
epitopes was the best inducer of IL-2, indicating that this construct was most
effectively processed by the APC. Analysis of IL-2R alpha expression by flow
cytometry confirmed that four copies gave the highest frequency of activated T
cells in culture, indicating a direct correlation between ability to activate T
cells and IL-2 production in culture. Also in vivo, the fusion protein with four
epitopes exhibited the strongest T cell priming effect. Moreover, both in vitro
and in vivo, the ZZ construct was found to serve as an efficient means for
targeting of the fusion proteins to B cells, thereby allowing access to the Ig
receptor uptake pathway for Ag. The present study provides direct evidence that
fusion proteins can be constructed to optimize processing in the individual APC
and enhance activation of clonal T cells.
PMID- 9393964
TI - Cloning of anti-Gal Fabs from combinatorial phage display libraries: structural
analysis and comparison of Fab expression in pComb3H and pComb8 phage.
AB - Anti-Gal is the most abundant natural antibody in humans. It interacts
specifically with the carbohydrate epitope Gal alpha1-3Galbeta1-4GlcNAc-R (termed
the alpha-galactosyl epitope). In an attempt to characterize the Ig genes
encoding anti-Gal, two combinatorial phage display libraries in phagemid pComb3H
were screened for anti-Gal Fabs. For this purpose, phages were incubated with
biotinylated BSA coupled with alpha-galactosyl epitopes (designated alpha-Gal
BSA). Subsequently, phages complexed with alpha-Gal-BSA were isolated by
streptavidin-coupled magnetic beads. Because of the low affinity of this
antibody, a characteristic shared with other anti-carbohydrate antibodies, only
two clones displaying anti-Gal activity were isolated. Clone G9 contained the VH
gene V3-43 and VL gene DPK15, whereas clone P19 contained the VH gene V3-15 and
VL gene DPL16. Both clones contained between five and 14 mutations in their H and
L chain V genes. The affinity of clone G9 was found to be higher than that of
clone P19, as only the former could bind to solid-phase alpha-galactosyl epitopes
in an enzyme-linked immunosorbent assay. This interaction could be increased by
expressing Fabs in phagemid pComb8 grown in the presence of IPTG. Under such
conditions, the IPTG-activated Lac-Z promoter induces an increased expression of
Fabs that are linked to phage envelope protein VIII, resulting in multiple Fab
display on the phage. The data suggest that screening combinatorial phage display
libraries for anti-carbohydrate antibodies may be more effective with pComb8
phage grown in the presence of IPTG.
PMID- 9393965
TI - Molecular cloning, expression and characterization of Pru a 1, the major cherry
allergen.
AB - A high percentage of birch pollen allergic patients experiences food
hypersensitivity reactions after ingestion of several fruits and vegetables.
Previous work demonstrated common epitopes on an allergen of Mr 18,000 from sweet
cherry (Prunus avium) and Bet v 1, the major allergen from birch pollen. N
terminal amino acid sequencing showed a sequence identity of 67% with Bet v 1.
Here we report the cloning and cDNA sequencing of this cherry allergen. The
entire deduced amino acid sequence described a protein of Mr 17,700 with 59.1%
identity to Bet v 1. High degrees of identity in the range of 40 to 60% were also
found with related allergens from other kinds of tree pollen and plant foods as
well as with stress-induced proteins from food plants such as parsley, potato and
soya. The coding DNA of the cherry protein was cloned into vector pET-16b and
expressed in E. coli strain BL21(DE3) as a His-tag fusion protein. As shown by
SDS-PAGE, the apparent molecular masses of the nonfusion protein and the natural
allergen were identical. The fusion protein showed high IgE binding potency when
sera from patients allergic to cherry were tested by immunoblotting and enzyme
allergosorbent tests. Moreover, it cross-reacted strongly with IgE specific for
the natural counterpart and for Bet v 1. The high biological activity of the
recombinant fusion protein was further confirmed by the induction of a strong
histamine release in basophils from cherry-allergic patients. Since sera from
17/19 of such patients contained IgE against this allergen it was classified as a
major allergen and named Pru a 1. Recombinant Pru a 1 mimics most of the
allergenic potency of cherry extract and hence could be a useful tool for
studying the molecular and immunological properties of pollen related food
allergens.
PMID- 9393966
TI - Structure and organization of the immunoglobulin M heavy chain genes in Atlantic
salmon, Salmo salar.
AB - To determine the structure and organization of the germline immunoglobulin M
heavy chain (IgH) genes in Atlantic salmon, Salmo salar, relevant clones from a
genomic library (of one individual fish) have been characterized. Two closely
related IgH constant region genes, CHA and CHB, have been sequenced completely.
In addition, an allotypic variant of CHA was identified and partially sequenced.
Five joining (JH) elements were found in a distance of 0.5-1.6 kb upstream of the
first constant exon (CH1), in both CHA and CHB, substantiating the hypothesis
that the entire gene complex is duplicated; possibly a remnant of a tetraploid
event in the salmonid ancestor. An octamer motif (ATGTATTT, and its reverse
complementary sequence) was found to be dispersed in the JH-CH1 region, but not
elsewhere, signifying a role in these loci. Four closely related variable (VH)
genes which were subcloned from three distinct lambda clones showed the classical
structure of a two exon unit split by a 100 bp intron. The split-intron and a few
hundred base pairs of the flanking sequences of the genes were highly similar.
Three of the four genes were interrupted by stop codons and/or frame shifts,
indicating a high proportion of VH-pseudogenes in this species. Based on the
present results, and comparison with sequences of rainbow trout, Oncorhynchus
mykiss, it is likely that the IgH loci have remained tetrasomicly inherited
throughout the radiation of the genus Salmo and Oncorhynchus, and that the
duplicated loci have gone into a disomic inheritance pattern in the comparatively
recent past.
PMID- 9393967
TI - A single predominantly expressed polymorphic immunoglobulin VH gene family,
related to mammalian group, I, clan, II, is identified in cattle.
AB - In order to understand the generation of antibody diversity in cattle, seven
cDNAs, from heterohybridomas secreting bovine IgM and IgG1 antibodies, were
cloned and structurally analyzed for rearranged bovine VDJ genes. All of the
seven bovine VH genes, together with four available bovine VH gene sequences,
shared a high nucleotide sequence homology (84.2-93.5%). Based upon the criteria
of nucleic acid homology > or =80%, all of the bovine VH gene sequences isolated
from the expressed antibody repertoire constitute a single VH gene family, which
we have designated as bovine VH1 (Bov VH1). An analysis of 44 bovine IgM
secreting mouse x cattle heterohybridomas, originating from polyclonally
activated PBLs from bovine leukemia virus-infected cattle, revealed that all of
these expressed Bov VH1 (100%) based upon DNA sequencing and Northern dot blot.
The bovine VH genes showed highest DNA sequence similarity, ranging between 81.5
and 87.6%, with a single sheep VH gene family (related to human VH4) and are,
thus, closest to the VH genes from another ruminant species. The Bov VH1 gene
family is most homologous to the murine VH Q-52 (71.8-78%) and human VH4 (67.4
69.8%) gene families, which belong to mammalian group, I, clan, II, VH genes. The
CDR3 length of rearranged bovine VDJ genes is characteristically long (15-23
amino acids). The bovine JH gene segments were most homologous to human JH4 (82.1
87.2%) and JH5 (84.6-89.7%) genes, suggesting the existence of at least two JH
gene segments. An analysis of CDRs provides evidence that somatic hypermutations
contribute significantly to the generation of antibody diversity in cattle.
Southern blot analysis of BamH I, EcoR I and Hind III digested genomic DNA from
four cattle breeds (Holstein, Jersey, Hereford and Charolais) revealed three RFLP
patterns; the genomic complexity of Bov VH1 ranged between 13 and 15 genes. These
observations provide evidence for polymorphism at the bovine Ig-VH locus, similar
to that seen in mice and humans.
PMID- 9393968
TI - Genomic organization of the TcR beta-chain diversity (Dbeta) and joining (Jbeta)
segments in the rainbow trout: presence of many repeated sequences.
AB - This work describes a 5.5 kb genomic sequence of the rainbow trout T-cell
receptor beta-chain locus. It includes, from 5' to 3', a Dbeta gene, 10 Jbeta
genes and the 5'-end of the first Cbeta exon. The trout Dbeta-Jbeta-Cbeta locus
is about the same size as the mouse, rat and human homologous loci, but it is
less compact and contains 10 Jbeta segments instead of the 6-7 found in mammals.
The trout Dbeta coding sequence is identical to those of the mouse, rat and human
Dbeta, and the Dbeta recombination signal sequences (RSS) are also very well
conserved. Each trout Jbeta segment is flanked in 5' by a 7-mer RSS, which
matches with the canonical conserved 7-mer sequences of all RSS. However, 6 of
the 10 Jbeta segments have no characteristic 9-mer RSS, although at least some of
them are well expressed (Jbeta1 and Jbeta2). The Jbeta region of the trout
TcRbeta locus contains numerous micro/minisatellite repeated DNA sequences; some
of these repeats contain heptamer RSS-like sequences that could interfere with
Jbeta expression. Knowledge of the germline boundaries of the trout Dbeta and
Jbeta ends makes it possible to evaluate precisely the exonuclease activity and N
nucleotide addition at the Dbeta-Jbeta junctions of the rearranged TcRbeta chain
genes. Many (40%) of the Dbeta-Jbeta junctions in the adult trout have no N
nucleotides, compared to 26.4% in adult mice, and 37% of the adult trout TcRbeta
transcripts are out of frame. Thus, there may be major differences in the T-cell
developmental kinetics and selection in fish and mammals.
PMID- 9393969
TI - Distinct tissue and cellular distribution of two major isoforms of calcineurin.
AB - The protein phosphatase calcineurin is known to be an essential intracellular
signal transducer involved in the TCR-mediated signal transduction pathway and is
the common target of the immunosuppressive drugs cyclosporin A (CsA) and FK506.
The catalytic subunit of calcineurin exists in multiple isoforms, but their
functional differences are not known. It has been assumed that the alpha isoform
of calcineurin is the relevant isoform mediating TCR signaling. Recently,
calcineurin alpha was knocked out in mice, but no defect in the TCR-mediated IL-2
production was observed, suggesting that another isoform of calcineurin mediates
the TCR signal transduction pathway. We have generated specific polyclonal
antibodies against the alpha and the beta2 isoforms of calcineurin and examined
their distribution in murine tissues and immune cells by immunohistochemical
staining and Western blot analysis. We found that the beta2 isoform of
calcineurin is predominant in T and B lymphocytes as well as in thymus compared
to the alpha isoform, suggesting that the beta2 isoform may play a key role in
TCR signaling. Furthermore, we observed that the two isoforms exhibit distinct
expression patterns in both kidney and thymus, indicating that the two isoforms
of calcineurin have distinct cellular functions. Together, these findings raise
the possibility that the nephrotoxicity associated with CsA and FK506 can be
reduced by designing novel inhibitors of calcineurin that target specific
isoforms of the enzyme.
PMID- 9393970
TI - Probing the structure of C1 with an anti-C1s monoclonal antibody: the possible
existence of two forms of C1 in solution.
AB - Anti-human C1s monoclonal antibody H1532, a mouse gamma-1-immunoglobulin elicited
by a C1r2C1s2 immunogen, appeared to bind to the beta-domain of C1s by electron
microscopy. In agreement with this observation, Western blotting demonstrated
good binding to unreduced C1s, but no binding to the alpha or gamma-B domains.
When added to solutions of the C1r2C1s2 tetramer, HI532 converted the 8.7 S
tetramer into an 18 S complex, which was seen by electron microscopy to be a
dimer of parallel C1s x C1r x C1r x C1s molecules cross-linked by two bivalent
monoclonal antibodies. If increasing amounts of HI532 were added to C1r2C1s2
followed by addition of equivalent C1q, there was a progressive loss of hemolytic
activity, which became zero when two equivalents of antibody HI532 were added.
When two equivalents of HI532 were added to serum or C1 reconstituted overnight
from purified subcomponents, there was an immediate loss of approximately 50% of
the hemolytic activity; thereafter, activity decayed slowly and even after 24 hr,
10-30% of the activity remained. The rapid loss of only 50% of the activity would
be readily explained by the existence of two conformations of C1, one of which
was rapidly disassembled by antibody, and the other was resistant to disassembly.
These two conformations may correspond to two previously proposed structures for
the C1 complex.
PMID- 9393971
TI - Wnt-10b directs hypermorphic development and transformation in mammary glands of
male and female mice.
AB - Wnt-10b is expressed during the formation of the mammary rudiment in mouse
embryos and its expression continues through puberty when the mammary ductal
pattern is established under control of ovarian steroids. Recently, viral
activation of the Wnt-10b locus has linked its overexpression to mammary tumor
formation, suggesting a role for Wnt-10b in patterning and growth-regulation of
the mammary gland. To test this notion, we created lines of transgenic mice that
express elevated levels of Wnt-10b under the control of the MMTV
promoter/enhancer. Overexpression of this gene resulted in profound developmental
alterations in the mammary gland, including expanded glandular development and
the precocious appearance of alveoli in virgin females. Moreover, transgenic male
mice also exhibited dramatic mammary development involving highly branched
mammary ducts and gynecomastia. Aberrant expression of Wnt-10b in the mammary
rudiments of males evidently bypasses the normal requirement for ovarian hormonal
control in stimulating mammary ductal growth and the repressive effects of
androgens. In addition to these developmental effects, transgenic mice of both
sexes were highly susceptible to the development of mammary adenocarcinomas. Such
tumors arose in a solitary manner indicating that Wnt-10b is a proto-oncogene
which provides a necessary, but insufficient signal for oncogenesis. Relevant to
this, there was no evidence of amplified expression of FGF mRNAs in these tumors
though the Fgf's are a class of genes often implicated as collaborators in Wnt
mediated tumor formation. Indeed, co-expression of MMTV-Wnt-10b and MMTV-FGF
3/int-2 resulted in sterile offspring with highly disorganized mammary
epithelium, demonstrating a potent interaction between their respective
developmental pathways. These results suggest that Wnt-10b, or other Wnt genes
expressed early in mammary development, play a role in regulating sexual
dimorphism and show potent transforming activity when overexpressed.
PMID- 9393972
TI - A novel brain-specific p53-target gene, BAI1, containing thrombospondin type 1
repeats inhibits experimental angiogenesis.
AB - The genetic alteration of p53 is associated with neovascularization during
progression of glioma to its more malignant form, glioblastoma. Hence, one or
more of the genes transactivated by p53 is likely to function as an angiogenesis
inhibitors. We isolated a novel p53-inducible gene that encodes a 1584-amino-acid
product containing five thrombospondin type 1 (TSP-type 1) repeats and is
specifically expressed in the brain. A recombinant protein corresponding to the
TSP-type 1 repeats of this gene product inhibited in vivo neovascularization
induced by bFGF in the rat cornea. The expression of this gene, designated BAI1
(brain-specific angiogenesis inhibitor 1) was absent or significantly reduced in
eight of nine glioblastoma cell lines, suggesting BAI1 plays a significant role
in angiogenesis inhibition, as a mediator of p53.
PMID- 9393973
TI - Dominant-negative abrogation of connexin-mediated cell growth control by mutant
connexin genes.
AB - Connexin genes exert negative growth control when transfected into various types
of tumor cell lines. We previously demonstrated that connexin 26 (Cx26)
suppresses in vitro and in vivo growth of HeLa cells. In this study, we have
examined whether certain Cx26 mutants can abrogate cell growth control and the
gap junctional intercellular communication (GJIC) capacity of such Cx26
transfected HeLa cells. For this purpose, we transfected three mutated Cx26 genes
(C60F, P87L and R143W) into HeLa cells already containing the wild-type Cx26
gene, which are GJIC-competent and non-tumorigenic. Transfection of P87L and
R143W mutants enhanced the tumorigenicity of the HeLa Cx26 cells in nude mice
without any change in GJIC capacity. On the other hand, transfection of the C60F
mutant reduced the GJIC capacity of HeLa Cx26 cells without affecting their
growth in vivo. Immunostaining studies demonstrated that the Cx26 proteins were
localized mainly at cell-cell contact areas in the HeLa Cx26 cells both before
and after transfection of mutated Cx26 genes. These results suggest that certain
mutant Cx26 proteins exert a dominant-negative effect on Cx26-regulated growth of
HeLa cells and that such effects may be independent of the effect on GJIC
ability. It is proposed that wild-type and mutant Cx26 proteins produce
heteromeric connexons and that such heteromeric connexons may exert different
effects on growth control from those of homomeric connexons.
PMID- 9393974
TI - Suppression of anchorage-independent growth and matrigel invasion and delayed
tumor formation by elevated expression of fibulin-1D in human fibrosarcoma
derived cell lines.
AB - Using differential display, we identified an mRNA that is markedly down-regulated
in cell line 6A/SB1, derived from a fibrosarcoma formed in an athymic mouse
following injection of carcinogen-transformed MSU-1.1 cells. The nontumorigenic
parental cell strain, MSU-1.1, expresses high levels of this mRNA. Sequencing of
the corresponding cDNA fragment revealed that it corresponded to an expressed
sequence tag, which ultimately led to its identification as the fibulin-1D gene.
Fibulin-1 is a cysteine-rich, calcium-binding extracellular matrix and plasma
protein, which has four isoforms, A-D, derived from alternative splicing.
Northern and Western blotting analysis of 16 cell lines established from tumors
formed in athymic mice by MSU-1.1-derived cell strains independently transformed
in culture showed that 44% exhibited low level or lack of expression of fibulin
1D mRNA and protein. In a similar analysis of 15 malignant cell lines derived
from patients, 80% showed low level or no expression. To study the role of
fibulin-1D in transformation, we transfected 6A/SB1 cells and a human
fibrosarcoma-derived cell line (SHAC) with a fibulin-1D cDNA expression
construct. Transfectants displaying high levels of fibulin-1D were isolated and
characterized. Elevated expression of fibulin-1D led to reduced ability to form
colonies in soft agar and reduced invasive potential as tested in a matrigel in
vitro invasion assay. Furthermore, expression of fibulin-1D resulted in a
markedly extended latency in tumor formation in athymic mice. These results
indicate that low expression of fibulin-1D plays a role in tumor formation and
invasion.
PMID- 9393975
TI - p38 MAP kinase activation by vascular endothelial growth factor mediates actin
reorganization and cell migration in human endothelial cells.
AB - Vascular endothelial growth factor (VEGF) is a potent chemotactic agent for
endothelial cells. Yet the signalling pathways that modulate the motogenic
effects of VEGF in vascular endothelial cells are still ill defined. In the
present study, we found in primary cultures of human umbilical vein endothelial
cells (HUVEC) that VEGF increased cell migration and induced a marked
reorganization of the microfilament network that was characterized by the
formation of stress fibers and the recruitment of vinculin to focal adhesions.
VEGF also stimulated the mitogen activated protein (MAP) kinases ERK
(extracellular signal-regulated kinase) and p38 (stress activated protein kinase
2), but not SAPK1/JNK (stress activated protein kinase-1/c-Jun NH2-terminal
kinase). Activation of p38 resulted in activation of MAP kinase activated protein
kinase-2/3 and phosphorylation of the F-actin polymerization modulator, heat
shock protein 27 (HSP27). Inhibiting the VEGF-induced activation of ERK with
PD098059 did not influence actin organization or cell migration but totally
inhibited the VEGF-induced incorporation of thymidine into DNA. Inhibition of p38
activity by the specific inhibitor SB203580 led to an inhibition of HSP27
phosphorylation, actin reorganization and cell migration. The results indicate
that the p38 pathway conveys the VEGF signal to microfilaments inducing
rearrangements of the actin cytoskeleton that regulate cell migration. By
modulating cell migration, p38 may thus be an important regulator of
angiogenesis.
PMID- 9393976
TI - Inactivation of the small GTPase Rho disrupts cellular attachment and induces
adhesion-dependent and adhesion-independent apoptosis.
AB - Rho small GTPases regulate a variety of cellular signaling pathways involved in
cell growth and transformation. In this study, we examined potential roles for
Rho in adhesion-dependent and -independent pathways regulating apoptosis. Rho
GTPases are specifically inactivated by exoenzyme C3 (C3) of Clostridium
botulinum. Using a novel Sindbis virus-based gene expression system, we created a
double subgenomic recombinant (dsSIN:C3) capable of expressing active C3 in
intact cells. Infection of L929 fibroblasts with dsSIN:C3 caused essentially
complete ADP-ribosylation of intracellular Rho within 1 h. dsSIN:C3-infected
cells also became rounded within 1-2 h and detached by 5 h post-infection.
Infection of L929 in suspension with dsSIN:C3 disrupted the ability for normal
cellular attachment and spreading. Infection of primary cell explants of chicken
embryo fibroblasts (CEF) and rat aortic smooth muscle cells (RSM) with dsSIN:C3
caused cytoskeletal effects similar to those seen in L929. We also observed that
C3 markedly decreased the basal phosphorylation state of focal adhesion kinase
(FAK). Most intriguingly, we found that dsSIN-based expression of C3 or loss of
function mutants of Rho could each induce apoptosis and, in RSM, this effect was
observed to be adhesion-independent. Rho GTPases, therefore, appear to regulate
signal pathways that are required for cell survival and growth that are separate
from, but likely overlap with, Rho-dependent pathways involved in cellular
adhesion.
PMID- 9393977
TI - A functional analysis of p53 during early development of Xenopus laevis.
AB - p53 is a nuclear protein that acts like a tumor suppressor and is involved in
regulation of cellular growth. In Xenopus, the p53 protein is highly expressed
during oogenesis and is strictly cytoplasmic in the oocyte. We have analysed its
participation in DNA replication and transcription during early development,
using the egg and oocyte as model-systems. The injection of sperm nuclei into
Xenopus eggs is followed by DNA replication and mitotic events. We show that the
endogenous p53 enters the nuclei and moves through a series of discrete sub
nuclear loci whose distribution is S-phase specific. A specific peripheral
nuclear localization of p53 is observed before entry into S-phase, followed by an
internal localization which is strictly dependent on ongoing DNA synthesis. At no
stage in the cell cycle, however, did we observe any co-localization with RPA or
PCNA, which were used as initiation or elongation markers for DNA replication. We
also show that injection into the nucleus of the oocyte of small amounts of
either Xenopus or human p53 - less than 10% of the cytoplasmic storage - is
sufficient to block RNA polymerase II-dependent transcription from a coinjected
TATA-box-containing reporter plasmid. Transcription is rescued by microinjection
of the TATA-box binding protein (TBP), suggesting that nuclear exclusion of p53
during oogenesis may be necessary for transcription of maternal genes. These
characteristics are discussed in relation to the regulation of nuclear activities
during early embryogenesis.
PMID- 9393978
TI - Tumor suppressor protein p53 binds preferentially to supercoiled DNA.
AB - Wild type human tumor suppressor protein p53 (expressed in insect cells) binds
strongly to negatively supercoiled (sc) plasmid DNA at a native superhelix
density, as evidenced by electrophoretic retardation of scDNA in agarose gels and
imaging by scanning force microscopy (SFM). The binding occurs both in the
presence and absence of the p53 consensus sequence. At relatively low p53/DNA
ratios, binding of p53 to scDNA results in the appearance of several retarded DNA
bands on the gels, similar to a conventional topoisomer ladder generated
enzymatically. However, after removal of p53 by deproteination, the original
mobility of the scDNA is recovered, indicating that the reduction of torsional
stress accompanying p53 binding does not reflect changes in linking number. In
DNA samples partially relaxed by topoisomerase I p53 binds preferentially to the
scDNA molecules with the largest negative superhelix density. SFM imaging of the
p53/scDNA complex reveals a partial or total relaxation of the compact scDNA, the
degree of which increases with the number of bound p53 molecules. Competition
assays with linear DNA reveal a preference of p53 for scDNA. In addition, scDNA
induces dissociation of p53 from a preformed complex with a DNA fragment (474 bp)
containing the consensus sequence. We conclude that the affinity of p53 for
negatively supercoiled DNA is greater than that for the consensus sequence in
linear fragments. However, thermally denatured linearized plasmid DNA is
efficient in competing for the binding of p53 to scDNA, although the first
retarded band (presumed to contain one bound p53 molecule) is retained in the
case of the plasmid containing the consensus sequence. Thus, it appears that
interactions involving both the core domain and the C-terminal domain regulate
the binding of p53 to scDNA. The above results are not restricted to human p53;
the wild type rat p53 protein also results in the retardation of scDNA on agarose
gels. The biological implications of the novel DNA binding activities of p53 are
discussed.
PMID- 9393979
TI - Mouse fibroblast growth factor 10: cDNA cloning, protein characterization, and
regulation of mRNA expression.
AB - Fibroblast growth factor 7 (FGF-7) or keratinocyte growth factor (KGF), is a
potent and specific mitogen for epithelial cells. We have recently identified a
novel human FGF-7 homologue, named FGF-10. To study the expression of this new
FGF family member and its regulation in wound repair, we cloned the mouse FGF-10
(mFGF-10) cDNA. The encoded protein is 92% identical to human FGF-10 and 91%
identical to rat FGF-10. When expressed in mammalian 293 cells, the mFGF-10
protein was glycosylated but remained cell- or extracellular matrix-associated.
Upon addition of heparin, mFGF-10 protein was released into the media. mRNA
encoding mFGF-10 was relatively abundant in lung, skin, brain and heart. In the
skin, both FGF-7 and mFGF-10 were expressed in the dermal, but not the epidermal
compartment. In contrast to FGF-7, mFGF-10 expression was not induced during
cutaneous wound repair. In cultured fibroblasts, expression of mFGF-10 was
strongly repressed by transforming growth factor beta and tumor necrosis factor
alpha, whereas epidermal growth factor and interleukin-1beta had no effect. These
results demonstrate a differential regulation of mFGF-10 and FGF-7 expression in
vitro and during the wound healing process.
PMID- 9393980
TI - Reduced ability of transforming growth factor-alpha to induce EGF receptor
heterodimerization and downregulation suggests a mechanism of oncogenic synergy
with ErbB2.
AB - The epidermal growth factor receptor (EGFR) is activated by a variety of ligands
including EGF and transforming growth factor-alpha (TGFalpha), whereas no ligand
for the homologous ErbB2 oncoprotein has yet been identified. Here we use both an
ErbB2 phosphoantibody (aPY1222) and an activation-specific EGFR antibody to show
that low concentrations of EGF induce more efficient tyrosine phosphorylation of
ErbB2 in A431 cells than does equimolar TGFalpha, while EGFR is more potently
activated by TGFalpha. Co-precipitation studies confirm that heterodimerization
of activated EGFR and transphosphorylated ErbB2 is readily induced by EGF but not
TGFalpha. EGFR downregulation is also more efficiently induced by EGF, suggesting
that ligand-dependent modification of ErbB2 may be required to terminate EGFR
signalling in cells expressing both receptor types. These findings indicate that
EGF and TGFalpha differ in their abilities to induce tyrosine phosphorylation and
heterodimerization of ErbB2, and raise the possibility that ErbB2 exerts its
oncogenic effect in part by impairing TGFalpha-dependent EGFR downregulation.
PMID- 9393981
TI - Among genes involved in the RB dependent cell cycle regulatory cascade, the p16
tumor suppressor gene is frequently lost in the Ewing family of tumors.
AB - The pRB cell cycle regulatory cascade is frequently perturbed in neoplasia by
overexpression of a component of the pRB-phosphorylating cyclin D1/CDK4 complex
or by inactivation of pRB or the CDK4 inhibitors p16 and p15. We investigated the
status and expression of p16, p15, CCND1, CDK4 and RB genes in the Ewing family
of tumors. P16 loss was observed in 8 of 27 tumors (30%) and in 12 of 23 (52%)
tumor cell lines from unrelated patients. There were no discrepancies in the p16
status between primary tumors and the corresponding cell lines and between cell
lines established from consecutive tumor samples. p15 was codeleted in most cases
but p15 mRNA was absent also in cell lines retaining the gene. In addition,
posttranscriptional p16 inactivation was observed in two cases. Although no
evidence for CDK4 or CCND1 amplification was obtained, expression of these genes
varied considerably in the cell lines in a case specific manner. In wild-type p16
cell lines, pRB expression was lost in one case. Our data indicate that, despite
the absence of cytogenetically detectable 9p21 chromosomal aberrations, p16
deletions constitute the most frequent secondary molecular aberration in Ewing
tumors so far. These results are discussed in the context of the stage of disease
and the clinical outcome of the patients. The potential prognostic impact of
these findings remains to be further evaluated.
PMID- 9393982
TI - Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in
papillary renal cell carcinoma.
AB - We demonstrate that the cytogenetically defined translocation t(X;1)(p11.2;p34)
observed in papillary renal cell carcinomas results in the fusion of the splicing
factor gene PSF located at 1p34 to the TFE3 helix-loop-helix transcription factor
gene at Xp11.2. In addition we define an X chromosome inversion inv(X)(p11.2;q12)
that results in the fusion of the NonO (p54nrb) gene to TFE3. NonO (p54nrb), the
human homologue of the Drosophila gene NonAdiss which controls the male courtship
song, is closely related to PSF and also believed to be involved in RNA splicing.
In each case the rearrangement results in the fusion of almost the entire
splicing factor protein to the TFE3 DNA-binding domain. These observations
suggest the possibility of intriguing links between the processes of RNA
splicing, DNA transcription and oncogenesis.
PMID- 9393983
TI - A fluorescent p53GFP fusion protein facilitates its detection in mammalian cells
while retaining the properties of wild-type p53.
AB - Tumor progression is often characterized by the cumulative loss of crucial cell
cycle control genes and the concomitant loss of genome stability. Progressed
tumors are often resistant to conventional therapies. Gene-transfer of key growth
regulatory genes, such as the p53 gene, is one potential approach to treating
advanced tumors. To this end, we have produced high-titer retroviruses, based on
the pCL vector system, which encode a chimeric protein consisting of human wild
type p53 and the green fluorescent protein (wtp53GFP). The fluorescent wtp53GFP
protein and the wild-type p53 protein are recognized equally by several
monoclonal p53-specific antibodies, have similar half-lives and function
comparably in transactivating a p53-responsive element as well as in suppressing
the growth of tumor cells. Additionally, due to its fluorescent nature, wtp53GFP
facilitates the direct identification of cells expressing the p53 fusion protein.
Combining the features of the pCL retroviral production system with the highly
visible green fluorescent protein provides a potent tool for the delivery of p53
into cells and the subsequent detection of the protein, both in vitro and in
vivo.
PMID- 9393984
TI - v-Abl protein tyrosine kinase (PTK) mediated suppression of apoptosis is
associated with the up-regulation of Bcl-XL.
AB - We demonstrated previously that the activation of v-Abl protein tyrosine kinase
(PTK) in IC.DP murine pre-mast cells resulted in suppression of apoptosis after
withdrawal of interleukin 3 (IL-3), that protein kinase C (PKC) translocated to
the nucleus 6 h after v-Abl PTK activation and that inhibition of PKC restored
apoptosis after IL-3 deprivation in the presence of v-Abl PTK activity. Here we
demonstrate that v-Abl PTK activation is followed by an approximately twofold
increase in mRNA level of Bcl-XL by 6 h and a corresponding increase in Bcl-XL
protein level by 24 h. Bcl-xL RNA and protein decreased in IL-3 deprived cells in
the absence of v-Abl PTK activity. Exposure of cells with v-Abl PTK active to the
PKC inhbitor calphostin C (125 ng/ml) prevented the increase in Bcl-xL protein
and resulted in apoptosis. No changes in Bax or Bcl-2 protein level were noted
after IL-3 withdrawal and/or activation of v-Abl PTK. Bak was barely detectable
and Bad protein level decreased in cells undergoing apoptosis. The data suggest
that suppression of apoptosis by v-Abl PTK in the absence of IL-3 is associated
with PKC signalling and the upregulation of Bcl-xL in IC.DP cells.
PMID- 9393985
TI - Preprints and Nature.
PMID- 9393986
TI - Transgenic patents a step closer in Europe.
PMID- 9393987
TI - Germany tightens grip on misconduct...
PMID- 9393988
TI - Female scientists wanted -- apply to UK research councils.
PMID- 9393989
TI - Canadian inquiry calls for 'safety first' blood agency.
PMID- 9393990
TI - European grants to face ethics scrutiny.
PMID- 9393991
TI - US air base in Japan increases monitoring of local dioxin threat.
PMID- 9393992
TI - No evidence of sexism in peer review.
PMID- 9393993
TI - The enzyme at the end of the food chain.
PMID- 9393994
TI - Do males rely on female hormones?
PMID- 9393995
TI - Poor prospects for oiled birds.
PMID- 9393996
TI - No 'nanofossils' in martian meteorite.
PMID- 9393997
TI - TGF-beta signalling from cell membrane to nucleus through SMAD proteins.
AB - The recent identification of the SMAD family of signal transducer proteins has
unravelled the mechanisms by which transforming growth factor-beta (TGF-beta)
signals from the cell membrane to the nucleus. Pathway-restricted SMADs are
phosphorylated by specific cell-surface receptors that have serine/threonine
kinase activity, then they oligomerize with the common mediator Smad4 and
translocate to the nucleus where they direct transcription to effect the cell's
response to TGF-beta. Inhibitory SMADs have been identified that block the
activation of these pathway-restricted SMADs.
PMID- 9393998
TI - A conserved RNA-binding protein that regulates sexual fates in the C. elegans
hermaphrodite germ line.
AB - The nematode Caenorhabditis elegans has two sexes, males and hermaphrodites.
Hermaphrodites Initially produce sperm but switch to producing oocytes. This
switch appears to be controlled by the 3' untranslated region of fem-3 messenger
RNA. We have now identified a binding factor (FBF) which is a cytoplasmic protein
that binds specifically to the regulatory region of fem-3 3'UTR and mediates the
sperm/oocyte switch. The RNA-binding domain of FBF consists of a stretch of eight
tandem repeats and two short flanking regions. This structural element is
conserved in several proteins including Drosophila Pumilio, a regulatory protein
that controls pattern formation in the fly by binding to a 3'UTR. We propose that
FBF and Pumilio are members of a widespread family of sequence-specific RNA
binding proteins.
PMID- 9394000
TI - Radial optic flow induces vergence eye movements with ultra-short latencies.
AB - An observer moving forwards through the environment experiences a radial pattern
of image motion on each retina. Such patterns of optic flow are a potential
source of information about the observer's rate of progress, direction of heading
and time to reach objects that lie ahead. As the viewing distance changes there
must be changes in the vergence angle between the two eyes so that both foveas
remain aligned on the object of interest in the scene ahead. Here we show that
radial optic flow can elicit appropriately directed (horizontal) vergence eye
movements with ultra-short latencies (roughly 80 ms) in human subjects.
Centrifugal flow, signalling forwards motion, increases the vergence angle,
whereas centripetal flow decreases the vergence angle. These vergence eye
movements are still evident when the observer's view of the flow pattern is
restricted to the temporal hemifield of one eye, indicating that these responses
do not result from anisotropies in motion processing but from a mechanism that
senses the radial pattern of flow. We hypothesize that flow-induced vergence is
but one of a family of rapid ocular reflexes, mediated by the medial superior
temporal cortex, compensating for translational disturbance of the observer.
PMID- 9393999
TI - A role for oestrogens in the male reproductive system.
AB - Oestrogen is considered to be the 'female' hormone, whereas testosterone is
considered the 'male' hormone. However, both hormones are present in both sexes.
Thus sexual distinctions are not qualitative differences, but rather result from
quantitative divergence in hormone concentrations and differential expressions of
steroid hormone receptors. In males, oestrogen is present in low concentrations
in blood, but can be extraordinarily high in semen, and as high as 250 pg ml(-1)
in rete testis fluids, which is higher than serum oestradiol in the female. It is
well known that male reproductive tissues express oestrogen receptors, but the
role of oestrogen in male reproduction has remained unclear. Here we provide
evidence of a physiological role for oestrogen in male reproductive organs. We
show that oestrogen regulates the reabsorption of luminal fluid in the head of
the epididymis. Disruption of this essential function causes sperm to enter the
epididymis diluted, rather than concentrated, resulting in infertility. This
finding raises further concern over the potential direct effects of environmental
oestrogens on male reproduction and reported declines in human sperm counts.
PMID- 9394001
TI - Defective limbic system in mice lacking the tailless gene.
AB - The gene tailless is a member of the superfamily of genes that encode
transcription factors of the ligand-activated nuclear receptor type, and is
expressed in the invertebrate and vertebrate brain. In mice, its transcripts are
restricted to the periventricular zone of the forebrain, the site of origin of
neurons and glia. Here we use homologous recombination to generate mice that lack
a functional tailless protein. Homozygous mutant mice are viable at birth,
indicating that tailless is not required for prenatal survival; however, adult
mutant mice show a reduction in the size of rhinencephalic and limbic structures,
including the olfactory, infrarhinal and entorhinal cortex, amygdala and dentate
gyrus. Both male and female mice are more aggressive than usual and females lack
normal maternal instincts. These animals therefore enable a molecular approach to
be taken towards understanding the genetic architecture and morphogenesis of the
forebrain.
PMID- 9394002
TI - Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock.
AB - Anandamide, an endogenous cannabinoid ligand, binds to CB1 cannabinoid receptors
in the brain and mimics the neurobehavioural actions of marijuana. Cannabinoids
and anandamide also elicit hypotension mediated by peripheral CB1 receptors. Here
we report that a selective CB1 receptor antagonist, SR141716A, elicits an
increase in blood pressure in rats subjected to haemorrhagic shock, whereas
similar treatment of normotensive rats or intracerebroventricular administration
of the antagonist during shock do not affect blood pressure. Blood from
haemorrhaged rats causes hypotension in normal rats, which can be prevented by
SR141716A but not by inhibition of nitric oxide synthase in the recipient.
Macrophages and platelets from haemorrhaged rats elicit CB1 receptor-mediated
hypotension in normotensive recipients, and incorporate arachidonic acid or
ethanolamine into a product that co-elutes with anandamide on reverse-phase high
performance liquid chromatography. Also, macrophages from control rats stimulated
with ionomycin or bacterial phospholipase D produce anandamide, as identified by
gas chromatography and mass spectrometry. These findings indicate that activation
of peripheral CB1 cannabinoid receptors contributes to haemorrhagic hypotension,
and anandamide produced by macrophages may be a mediator of this effect.
PMID- 9394003
TI - Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium
channels.
AB - Leptin, the protein encoded by the obese (ob) gene, is secreted from adipose
tissue and is thought to act in the central nervous system to regulate food
intake and body weight. It has been proposed that leptin acts in the
hypothalamus, the main control centre for satiety and energy expenditure.
Mutations in leptin or the receptor isoform (Ob-R[L]) present in hypothalamic
neurons result in profound obesity and symptoms of non-insulin-dependent
diabetes. Here we show that leptin hyperpolarizes glucose-receptive hypothalamic
neurons of lean Sprague-Dawley and Zucker rats, but is ineffective on neurons of
obese Zucker (fa/fa) rats. This hyperpolarization is due to the activation of a
potassium current, and is not easily recovered on removal of leptin, but is
reversed by applying the sulphonylurea, tolbutamide. Single-channel recordings
demonstrate that leptin activates an ATP-sensitive potassium (K[ATP]) channel.
Our data indicate that the K(ATP) channel may function as the molecular end-point
of the pathway following leptin activation of the Ob-R(L) receptor in
hypothalamic neurons.
PMID- 9394004
TI - RGS8 accelerates G-protein-mediated modulation of K+ currents.
AB - Transmembrane signal transduction via heterotrimeric G proteins is reported to be
inhibited by RGS (regulators of G-protein signalling) proteins. These RGS
proteins work by increasing the GTPase activity of G protein alpha-subunits (G
alpha), thereby driving G proteins into their inactive GDP-bound form. However,
it is not known how RGS proteins regulate the kinetics of physiological responses
that depend on G proteins. Here we report the isolation of a full-length
complementary DNA encoding a neural-tissue-specific RGS protein, RGS8, and the
determination of its function. We show that RGS8 binds preferentially to the
alpha-subunits G(alpha)o and G(alpha)i3 and that it functions as a GTPase
activating protein (GAP). When co-expressed in Xenopus oocytes with a G-protein
coupled receptor and a G-protein-coupled inwardly rectifying K+ channel
(GIRK1/2), RGS8 accelerated not only the turning off but also the turning on of
the GIRK1/2 current upon receptor stimulation, without affecting the dose
response relationship. We conclude that RGS8 accelerates the modulation of G
protein-coupled channels and is not just a simple negative regulator. This
property of RGS8 may be crucial for the rapid regulation of neuronal excitability
upon stimulation of G-protein-coupled receptors.
PMID- 9394005
TI - Pore-forming segments in voltage-gated chloride channels.
AB - The ability to differentiate between ions is a property of ion channels that is
crucial for their biological functions. However, the fundamental structural
features that define anion selectivity and distinguish anion-permeable from
cation-permeable channels are poorly understood. Voltage-gated chloride (Cl-)
channels belonging to the ClC family are ubiquitous and have been predicted to
play important roles in many diverse physiological and pathophysiological
processes. We have identified regions of a human skeletal muscle ClC isoform that
contribute to formation of its anion-selective conduction pathway. A core
structural element (P1 region) of the ClC channel pore spans an accessibility
barrier between the internal and external milieu, and contains an evolutionarily
conserved sequence motif: GKxGPxxH. Neighbouring sequences in the third and fifth
transmembrane segments also contribute to isoform-specific differences in anion
selectivity. The conserved motif in the Cl- channel P1 region may constitute a
'signature' sequence for an anion-selective ion pore by analogy with the
homologous GYG sequence that is essential for selectivity in voltage-gated
potassium ion (K+) channel pores.
PMID- 9394006
TI - Ammonia mediates communication between yeast colonies.
AB - Under certain growth conditions unicellular organisms behave as highly organized
multicellular structures. For example, the fruiting bodies of myxobacteria and of
the slime mould Dictyostelium discoideum form structures composed of non-dividing
motile cells. Although non-motile, yeasts can create organized structures,
colonies in which cells communicate and act in a coordinated fashion. Colony
morphologies are characteristic for different species and strains. Here we
describe that, in addition to short-range intracolony cell-cell communication,
yeasts exhibit long-distance signals between neighbouring colonies. The volatile
alkaline compound ammonia, transmitted by yeast colonies in pulses, has been
identified as a substance mediating the intercolony signal. The first alkaline
pulse produced by neighbouring colonies is non-directed and is followed by
acidification of the medium. The second pulse seems to be enhanced and is
oriented towards the neighbour colony. Ammonia signalling results in growth
inhibition of the facing parts of both colonies. This phenomenon is observed in
different yeast genera. The presence of amino acids in the medium is required for
ammonia production. Colonies derived from the yeast Saccharomyces cerevisiae shr3
mutant, defective in localization of amino-acid permeases, do not produce
detectable amounts of ammonia and do not exhibit asymmetric growth inhibition.
PMID- 9394008
TI - RagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1
GTPase pathway.
AB - Human RagA and RagB is reported to be 52% identical to a putative GTPase of
Saccharomyces cerevisiae, Gtr1p. According to the reported nucleotide sequence,
we amplified human RagA and RagBs cDNAs from the human B cell cDNA library with
PCR. Both cDNAs rescued a cold sensitivity of S. cerevisiae, gtr1-11.
Furthermore, we introduced into the cloned human RagA cDNA, the mutation 'T21L'
corresponding to the gtr1-11 mutation which has been reported to suppress not
only all of rcc1-, temperature-sensitive mutants of Ran/Gsp1p GTPase GDP/GTP
exchanging factor, but also rna1-1, a temperature-sensitive mutant of Ran/Gsp1p
GTPase-activating protein. The resulting RagAgtr1-11 cDNA partially, but
significantly, suppressed both rcc1- and rna1-1 mutations. These results
indicated that RagA and RagBs are functional homologues of S. cervisiae Gtr1p.
Interestingly, while wild-type human RagA and RagBs were localized within the
cytoplasm, similar to S. cerevisiae Gtr1p, the mutated human RagAgtr1-11
corresponding to a dominant negative form of RagA was distributed in discrete
speckles in the nucleus, being localized side by side with SC-35, a non-snRNP of
the splicing complex. In contrast, a dominant positive form of RagA, Q66L was
localized in the cytoplasm. Thus, RagA was suggested to shuttle between the
cytoplasm and the nucleus, depending on the bound nucleotide state.
PMID- 9394007
TI - Sphingolipid organization in biomembranes: what physical studies of model
membranes reveal.
AB - Recent cell biological studies suggest that sphingolipids and cholesterol may
cluster in biomembranes to form raft-like microdomains. Such lipid domains are
postulated to function as platforms involved in the lateral sorting of certain
proteins during their trafficking within cells as well as during signal
transduction events. Here, the physical interactions that occur between
cholesterol and sphingolipids in model membrane systems are discussed within the
context of microdomain formation. A model is presented in which the role of
cholesterol is refined compared to earlier models.
PMID- 9394009
TI - Analysis of Toxoplasma gondii stably transfected with a transmembrane variant of
its major surface protein, SAG1.
AB - We have genetically engineered Toxoplasma gondii so that its major surface
antigen SAG1 is anchored by a human transmembrane domain (SAG1-TM) instead of its
natural GPI anchor (SAG1-GPI) in order to initiate studies to address the
function of this protein anchor in parasitic protozoa as well as to get insights
into the functional role of SAG1. Our results show that SAG1-TM is correctly
folded (at least as judged by the presence of conformationally dependent
epitopes) and targeted to the surface of the parasite, indicating that the GPI
anchor does not determine its localization nor overall three-dimensional
structure. No significant difference was seen in any aspect of the growth of the
SAG1-TM mutant. However, compared to the natural SAG1-GPI, SAG1-TM does not form
strong associations with itself and/or other molecules in high molecular weight
complexes suggesting that allowing such complexes to form may be one role of the
GPI anchor. The in vitro half-life of SAG1-TM of extracellular parasites is
significantly lower than that of SAG1-GPI suggesting a stabilizing function of
the glycolipid anchor against degradation and/or membrane release. Antibodies to
SAG1 are shed from SAG1-TM parasites as they invade, just as they are stripped
from SAG1-GPI bearing parasites. The stripping, therefore, is unlikely to be
driven by the action of lipases.
PMID- 9394010
TI - A quantitative analysis of connexin-specific permeability differences of gap
junctions expressed in HeLa transfectants and Xenopus oocytes.
AB - Gap junctions provide direct intercellular communication by linking adjacent
cells with aqueous pores permeable to molecules up to 1 kDa in molecular mass and
8-14 A in diameter. The identification of over a dozen connexins in the mammalian
gap junction family has stimulated interest in the functional significance of
this diversity, including the possibility of selectivity for permeants as seen in
other channel classes. Here we present a quantitative comparison of channel
permeabilities of different connexins expressed in both HeLa transfectants (rat
Cx26, rat Cx32 and mouse Cx45) and Xenopus oocytes (rat Cx26 and rat Cx32). In
HeLa cells, we examined permeability to two fluorescent molecules: Lucifer Yellow
(LY: anionic, MW 457) and 4',6-diamidino-2-phenylindole, dihydrochloride (DAPI,
cationic, MW 350). A comparison of the kinetics of fluorescent dye transfer
showed Cx32, Cx26 and Cx45 to have progressively decreasing permeabilities to LY,
but increasing permeabilities to DAPI. This pattern was inconsistent with
selection based on physical size of the probe, nor could it be accounted for by
the differences between clones in the electrical conductance of the monolayers.
In Xenopus oocytes, where electrical and dye coupling could be assessed in the
same cells, Cx32 coupled oocytes showed an estimated 6-fold greater permeability
to LY than those coupled by Cx26, a comparable result to that seen in HeLa cells,
where an approximately 9-fold difference was seen. The oocyte system also allowed
an examination of Cx32/Cx26 heterotypic gap junction that proved to have a
permeability intermediate between the two homotypic forms. Thus, independent of
the expression system, it appears that connexins show differential permeabilities
that cannot be predicted based on size considerations, but must depend on other
features of the probe, such as charge.
PMID- 9394012
TI - Targeted gene disruption reveals a role for vacuolin B in the late endocytic
pathway and exocytosis.
AB - Cells of Dictyostelium discoideum take up fluid by macropinocytosis. The contents
of macropinosomes are acidified and digested by lysosomal enzymes. Thereafter, an
endocytic marker progresses in an F-actin dependent mechanism from the acidic
lysosomal phase to a neutral post-lysosomal phase. From the post-lysosomal
compartment indigestible remnants are released by exocytosis. This compartment is
characterised by two isoforms of vacuolin, A and B, which are encoded by
different genes. Fusions of the vacuolin isoforms to the green fluorescent
protein associate with the cytoplasmic side of post-lysosomal vacuoles in vivo.
Vacuolin isoforms also localise to patches at the plasma membrane. Since
vacuolins have no homologies to known proteins and do not contain domains of
obvious function, we investigated their role by knocking out the genes
separately. Although the sequences of vacuolins A and B are about 80% identical,
only deletion of the vacuolin B gene results in a defect in the endocytic
pathway; the vacuolin A knock-out appeared to be phenotypically normal. In
vacuolin B- mutants endocytosis is normal, but the progression of fluid-phase
marker from acidic to neutral pH is impaired. Furthermore, in the mutants post
lysosomal vacuoles are dramatically increased in size and accumulate endocytic
marker, suggesting a role for vacuolin B in targeting the vacuole for exocytosis.
PMID- 9394011
TI - Localization of three human polypeptide GalNAc-transferases in HeLa cells
suggests initiation of O-linked glycosylation throughout the Golgi apparatus.
AB - O-glycosylation of proteins is initiated by a family of UDP-N
acetylgalactosamine:polypeptide N-acetylgalactos-aminyltransferases (GalNAc-T).
In this study, we have localized endogenous and epitope-tagged human GalNAc-T1,
T2 and -T3 to the Golgi apparatus in HeLa cells by subcellular fractionation,
immunofluorescence and immunoelectron microscopy. We show that all three GalNAc
transferases are concentrated about tenfold in Golgi stacks over Golgi associated
tubular-vesicular membrane structures. Surprisingly, we find that GalNAc-T1, -T2
and -T3 are present throughout the Golgi stack suggesting that initiation of O
glycosylation may not be restricted to the cis Golgi, but occur at multiple sites
within the Golgi apparatus. GalNAc-T1 distributes evenly across the Golgi stack
whereas GalNAc-T2 and -T3 reside preferentially on the trans side and in the
medial part of the Golgi stack, respectively. Moreover, we have investigated the
possibility of O-glycan initiation in pre-Golgi compartments such as the ER. We
could not detect endogenous polypeptide GalNAc-transferase activity in the ER of
HeLa cells, neither by subcellular fractionation nor by situ glycosylation of an
ER-retained form of CD8 (CD8/E19). However, upon relocation of chimeric GalNAc-T1
or -T2 to the ER, CD8/E19 is glycosylated with different efficiencies indicating
that all components required for initiation of O-glycosylation are present in the
ER except for polypeptide GalNAc-transferases.
PMID- 9394013
TI - The role of NuMA in the interphase nucleus.
AB - NuMA is an essential protein for the formation of spindle poles in mitosis.
During interphase, NuMA is transported into the nucleus where it resides until
prometaphase of the next mitotic cycle. We tested for a potential function of
NuMA in interphase nuclei that were assembled from human sperm DNA using frog egg
extract immunodepleted of NuMA. Despite the absence of NuMA, nuclei formed
without visible changes of the chromatin structure, surrounded by an intact
nuclear membrane containing pores and nuclear lamins. These nuclei were fully
competent to import nuclear substrates and to replicate their DNA. By screening
tissue sections of various organs, absence of NuMA from the nucleus was observed
in a number of cell types, including sperm, granulocytes in the blood, and
differentiated smooth and skeletal muscle fibers. Experiments on cultured
myoblasts indicated that NuMA is degraded during muscle cell differentiation. The
absence of NuMA in interphase nuclei of the tissues tested correlated with a non
spherical, elongated or beaded nuclear morphology, suggesting that during
interphase NuMA may act as a non-essential nucleoskeletal element.
PMID- 9394014
TI - Identification of intracellular sites of superoxide production in stimulated
neutrophils.
AB - In this study, we show that superoxide production is carried out within
intracellular compartments of human neutrophils and not at the plasma membrane
following stimulation with phorbol myristate acetate. Oxidant production was not
observed in unstimulated cells. Stimulated cells exhibited superoxide production
in two distinct types of intracellular organelles. Initially, activity was
detected in slender rod-shaped granules and in spherical or elliptical granules.
The oxidant-producing granules fused directly with the plasma membrane or fused
to form larger intracellular vesicles which then became associated with the
plasma membrane. Longer periods of stimulation with PMA resulted in a decrease in
the number of vesicles containing oxidant reaction product only, and an increase
in structures containing both the oxidant-reaction product and ferritin
particles; the latter was used herein as a marker for endocytosis. Thus a complex
pattern of intracellular vesicular trafficking occurs in stimulated neutrophils.
Alkaline phosphatase activity, a marker enzyme for a type of intracellular
neutrophil granule was co-localized in the oxidant reaction-positive
intracellular compartments. The time course of up-regulation of alkaline
phosphatase activity to the cell surface parallelled the release of superoxide
from stimulated cells. Results from this study demonstrate for the first time
cytochemical and morphological evidence that superoxide is released from
stimulated neutrophils through exocytosis of an oxidant-producing intracellular
granule.
PMID- 9394015
TI - Unidirectional movement of fluorescent microtubules on rows of dynein arms of
disintegrated axonemes.
AB - Tetramethylrhodamine-labelled microtubules were observed to move on rows of
dynein arms of sea urchin sperm axonemes exposed by elastase-induced sliding
disintegration. The microtubules moved towards the flagellar tip at a velocity of
3.1+/-2.1 microm second-1 (mean +/- s.d., n=53) in the presence of 0.1 mM ATP at
22 degrees C, but none moved towards the sperm head. We also examined the
polarity of microtubule binding to axonemal doublet microtubules in the absence
of ATP by using microtubules brightly labelled at their minus-ends. In 140 of 210
microtubules studied, they bound to axonemal microtubules with a parallel
polarity. These results suggest that tightly packed dynein arms on the outer
doublet microtubules of sperm axoneme preferentially bind microtubules to
themselves with the same polarity as that of the axoneme and that they generate a
force to move only these microtubules in the direction away from the sperm head.
PMID- 9394016
TI - T cell syncytia induced by HIV release. T cell chemoattractants: demonstration
with a newly developed single cell chemotaxis chamber.
AB - A chemotaxis chamber has been developed to analyze both the velocity and the
directionality of individual T cells in gradients of high molecular mass
molecules over long periods of time. Employing this chamber, it is demonstrated
that syncytia induced by HIV in SUP-T1 cell cultures release two T cell
chemoattractants with approximate molecular masses of 30 and 120 kDa. Neither
uninfected single cells nor polyethylene glycol-induced syncytia release
detectable chemoattractant, suggesting that these chemoattractants are linked to
HIV infection. Soluble gp120 functions as a T cell chemoattractant and the
addition of anti-gp120 antibody to syncytium-conditioned medium blocks the high
molecular mass chemoattractant activity but not the low molecular mass activity.
The addition of anti-CD4 antibody to syncytium-conditioned medium also blocks the
high molecular mass chemoattractant activity but not the low molecular mass
activity. These results demonstrate that HIV-induced T cell syncytia release a
low and a high molecular mass T cell chemoattractant, and suggest that the high
molecular mass factor is gp120 and that it functions through the CD4 receptor.
PMID- 9394017
TI - Platelet-derived growth factor (PDGF)-induced actin rearrangement is deregulated
in cells expressing a mutant Y778F PDGF beta-receptor.
AB - Platelet-derived growth factor-stimulated actin rearrangement and edge ruffle
formation have previously been shown to be dependent on activation of
phosphatidylinositol 3'-kinase, the activity of which also is important for
directed migration of cells. This lipid kinase binds to phosphorylated tyrosine
residues Y740 and Y751 in the kinase insert of the human platelet-derived growth
factor ss-receptor. We examined the role of two other tyrosine residues in the
kinase insert of this receptor, Y775 and Y778, for ligand-induced actin
rearrangement. Both were shown to be phosphorylation sites; Y775 was only
marginally phosphorylated in cells expressing the wild-type ss-receptor, whereas
Y778 was phosphorylated at higher stoichiometry. Mutant receptors Y775F, Y778F
and Y775/778F were active kinases and mediated proliferative responses when
expressed in porcine aortic endothelial cells. Fluorescence staining of actin in
platelet-derived growth factor-stimulated PAE cells revealed that Y778 is
involved in regulation of the actin cytoskeleton since the cells contained, apart
from edge ruffles and circular ruffles, a novel type of giant ruffle on the
dorsal side of the cell, which consisted of irregular multilayered actin
structures. Mutation at Y778 had no effect on activation of phosphatidylinositol
3'-kinase, nor on the GTPase activating protein of Ras and phospholipase
C(gamma), and the extent of directed migration towards platelet-derived growth
factor of these cells was not changed. We conclude that actin rearrangement is
regulated in part by Y778 in the platelet-derived growth factor ss-receptor,
potentially through binding of a novel signaling molecule to this site.
PMID- 9394018
TI - In vivo association of lamins with nucleic acids in Drosophila melanogaster.
AB - A 32P-labeling strategy was developed to study the interaction(s) in tissue
culture cells between proteins and nucleic acids. Interphase and mitotic nuclear
lamins were studied in Drosophila Kc cells. After bromodeoxyuridine incorporation
and in vivo photo-crosslinking with 366 nm light, it was found that interphase
lamins were associated with nucleic acid. Interactions with DNA as well as RNA
were detected. In contrast, interaction of nucleic acids with mitotic lamin was
not observed. Photo-crosslinking in the presence of antibiotics distamycin and/or
chromomycin suggested that interphase lamins interacted with both A-T-rich DNA
and G-C-rich DNA; interactions with G-C-rich DNA predominated. These results have
implications for understanding the interphase organization of the higher
eukaryotic cell nucleus as well as the transition of cells from interphase to
mitosis. A model of nuclear organization, consistent with our results, is
proposed.
PMID- 9394019
TI - Mutational analysis of regulated exocytosis in Tetrahymena.
AB - Genetic analysis of regulated exocytosis can be accomplished in ciliates, since
mutants defective in stimulus-dependent secretion of dense-core vesicles can be
identified. In Tetrahymena thermophila, secretion in wild-type cells can result
in their encapsulation by the proteins released from vesicle cores. Cells with
defects in secretion were isolated from mutagenized homozygous cells that were
generated using a highly efficient method. Screening was based both on a visual
assay for encapsulation, and on a novel panning step using differential
centrifugation to take advantage of the selective mobility of mutants that fail
to encapsulate upon stimulation. 18 mutants with defects in several ordered steps
have been identified. Defects in a set of these could be localized to three
stages: granule formation, transport to cell surface docking sites, and
exocytosis itself. Mutants with defects in this last stage can be ordered into
successive steps based on several criteria, including their responsiveness to
multiple secretagogues and Ca2+ ionophores. The results of both somatic and
genetic complementation on selected pairs also help to characterize the defective
factors.
PMID- 9394021
TI - Oral bioavailability and first-pass effects.
AB - Existing experimental strategies for the in vivo evaluation of factors affecting
oral bioavailability have been reviewed. Based on concepts that have evolved, an
integrated set of strategies emerges that appears capable of providing estimates
of the individual contributions attributable to absorption, losses in the gut
lumen, and first-pass elimination in the gut wall and the liver. The only
assumptions are linear pharmacokinetics and constant clearance between
treatments. These methods are also suitable for the assessment of metabolite
bioavailability after drug administration and the quantitative determination of
sites of biotransformation and metabolite formation in vivo.
PMID- 9394020
TI - Degradation of phagosomal components in late endocytic organelles.
AB - Phagosomes are formed when phagocytic cells ingest particles such as bacteria,
viruses or synthetic beads of different kinds. The environment within the
phagosome gradually changes to generate degradative conditions. These changes
require multiple interactions between the maturing phagosomes and the endocytic
and the biosynthetic pathway. The phagosomes probably communicate with endocytic
organelles by a transient fusion event, often referred to as the 'kiss-and-run'
hypothesis. We have studied the role of endocytic organelles in the phagocytic
pathway of J774 cells, a mouse macrophage cell line. We have used magnetic
Dynabeads coated with 125ITC-IgG and 125ITC-OVA as phagocytic probes and were
able to isolate the phagosomal fraction by means of a magnet. To separate
lysosomes from other organelles in the endocytic pathway we allowed the cells to
endocytose a pulse of colloidal gold particles complexed with ovalbumin. By
combining this density shift technique with subcellular fractionation of a
postnuclear supernatant in Percoll gradients we could isolate three endocytic
fractions corresponding to early endosomes (the light Percoll fraction), late
endosomes (the dense Percoll fraction) and lysosomes (the gold fraction). We
observed that the proteins linked to the ingested beads are initially cleaved in
the phagosomes. This cleavage is inhibited by leupeptin, a thiol-protease
inhibitor, and requires an acidic environment. However, efficient communication
between the phagosomes and the endocytic pathway leads to the transfer of
dissociated phagocytosed peptides of different sizes to late endosomes and
lysosomes for further processing. Consequently, the late endosomes and the
lysosomes may be involved in the degradation of phagocytosed compounds.
PMID- 9394022
TI - Effects of probenecid on brain-cerebrospinal fluid-blood distribution kinetics of
E-Delta 2-valproic acid in rabbits.
AB - E-Delta 2-valproic acid (E-Delta 2-VPA), a major active metabolite of VPA, has
been proposed as an alternative to VPA because it is less hepatotoxic and is
nonteratogenic. In rodents, VPA and E-Delta 2-VPA have a brain tissue/free plasma
concentration ratio less than unity, which suggests rapid removal of the
alkanoate anticonvulsants from the central nervous system. This study in rabbits
employed a simultaneous iv infusion-ventriculocisternal (VC) perfusion technique
to investigate the steady-state kinetics of E-Delta 2-VPA transport at the blood
brain barrier, the blood-cerebrospinal fluid (CSF) barrier, and the neural cell
membrane. Probenecid (PBD) was coadministered to probe the mediation of transport
by organic anion transporter(s). Rabbits in the control group (N = 6) received an
iv infusion of E-Delta 2-VPA to achieve a steady-state plasma concentration of 50
to 60 microg/ml. Blood and cisternal outflow of mock CSF perfusate were
continuously sampled. Midway through the experiment, the VC perfusate was
switched to one containing [3H]E-Delta 2-VPA. At 225 min, the rabbits were
sacrificed, and each brain was removed and dissected into ten regions. Rabbits in
the PBD group (N = 9) received an iv infusion and VC perfusion as in the control
group as well as concomitant iv infusion of the inhibitor. The mean steady-state
VC extraction ratio for [3H]E-Delta 2-VPA did not differ between the control and
PBD groups (63.7 +/- 8.3% vs. 60. 6 +/- 9.6%), indicating the lack of a
significant PBD-sensitive transport at the choroidal epithelium. Coadministration
of PBD elevated brain concentration of cold E-Delta 2-VPA in the absence of a
significant change in total or free steady-state plasma concentration. Mean E
Delta 2-VPA brain tissue/free plasma concentration ratios in the various brain
regions were 3.5- to 5.2-fold higher in PBD-treated animals than in the controls.
Significant increases (3.0- to 4.5-fold) in the mean brain tissue/cisternal
perfusate concentration ratios were also observed. Compartmental modeling of the
steady-state distribution data suggested that clearance of E-Delta 2-VPA from the
brain parenchyma is governed jointly by efflux transporters at the neural cell
membrane and brain capillary endothelium. Moreover, PBD-induced elevation of E
Delta 2-VPA tissue concentrations is attributed primarily to inhibition of E
Delta 2-VPA efflux transport at the neural cell membrane, resulting in both
intracellular trapping and greater tissue retention of E-Delta 2-VPA.
PMID- 9394023
TI - The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha
acetylmethadol (LAAM), norLAAM, and methadone.
AB - The N-demethylation of LAAM, norLAAM, and methadone has been investigated in
human liver microsomes and microsomes containing cDNA-expressed human P450s. Gas
chromatography/mass spectrometry methods allowed detection of norLAAM and
dinorLAAM formation from LAAM, dinorLAAM formation from norLAAM, and EDDP and
EMDP formation from methadone. The rates of N-demethylation varied 4- to 7-fold
in microsomes from four different donors with activities for LAAM and norLAAM
consistently greater (5- to 14-fold) than for methadone. The N-demethylation of
LAAM, norLAAM, and methadone were significantly inhibited by ketoconazole. IC50s
could be determined for ketoconazole inhibition of LAAM and norLAAM N
demethylation of 1.6 and 1.1 microM, respectively. The ability of ketoconazole to
reduce methadone N-demethylation below 40% varied in regard to liver donor. No
other P450-selective inhibitors reduced the average activities more than 43%.
cDNA-expressed P450 3A4 N-demethylated LAAM, norLAAM, and methadone at greater
rates than the other cDNA-expressed P450s studied (1A2, 2C9, 2D6, or 2E1). P450
3A N-demethylation of LAAM, norLAAM, and methadone exceeded the next most active
P450, respectively, by at least 2.5, 9.6, and 13.4 times when expressed per
milligram protein and by 18.2, 6.0, and 6.1 times when expressed per nanomole
P450. These results suggest that P450 3A4 is the primary site of N-demethylation
of LAAM, norLAAM, and methadone in human liver. Although other enzymes may also
be capable of N-demethylating these compounds, identification of specific
enzymes, except P450 3A4, has yet to be established. Knowledge of these enzymatic
pathways is essential for assessment of the impact of metabolic drug-drug
interactions on therapeutic success and/or adverse events.
PMID- 9394024
TI - Cytochrome P450 isozymes involved in lisofylline metabolism to pentoxifylline in
human liver microsomes.
AB - We describe the kinetics of pentoxifylline formation from lisofylline in human
liver microsomes using selective inhibitors of cytochrome P450 isozymes,
correlation studies with specific isozyme activities, and cDNA-expressed human
CYP1A2 and 2E1. A biphasic model fitted the data best for the formation of
pentoxifylline, Km1 = 0.282 +/- 0.135 microM, Vmax1 = 0.003 +/- 0.001 nmol/min/mg
protein, Km2 = 158 +/- 42.6 microM and Vmax2 =0.928 +/- 0.308 nmol/min/mg (N =
4). Pentoxifylline formation by the low Km isoform (200 microM lisofylline)
required NADPH, was not inhibited by any isozyme-specific P450 inhibitor, and was
inhibited only 10% and 20%, respectively, by aminobenzotriazole and N
octamylamine. We concluded that the low Km enzyme was not a cytochrome P450. At 5
microM of lisofylline the CYP1A2 inhibitor, furafylline, inhibited pentoxifylline
formation by 58.8%, and the nonspecific CYP2E1 inhibitor, diethyldithiocarbamate,
inhibited pentoxifylline formation by 21.7%. When preincubated with furafylline
plus diethyldithiocarbamate, inhibition of pentoxifylline formation was increased
71.4%. Microsomal CYP1A2 activity correlated with pentoxifylline formation (r2 =
0.870, p < 0.001). However, CYP2E1 activity did not correlate with pentoxifylline
formation (r2 = 0.143, p = 0.181). Baculovirus insect cell expressed human CYP1A2
formed pentoxifylline at 0.987 nmol/min/nmol cytochrome P450 at 5 microM
lisofylline. cDNA expressed CYP2E1 did not catalyze formation of pentoxifylline.
Diethyldithiocarbamate inhibited pentoxifylline formation by 85.7% in cDNA
expressed CYP1A2. We conclude that CYP1A2 is the high affinity enzyme catalyzing
pentoxifylline formation from lisofylline.
PMID- 9394025
TI - Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic
clearance to hepatic clearance as assessed through examination of warfarin,
imipramine, and propranolol.
AB - The nonspecific, noncovalent binding of three drugs, imipramine, warfarin, and
propranolol, to pooled human and animal liver microsomes has been determined
using equilibrium dialysis in conditions where no cofactor (NADPH) was included
in the incubation. The binding of warfarin was dependent upon both protein and
drug concentration, whereas the binding of propranolol and imipramine was also
dependent upon protein concentration but generally independent of drug
concentration. At a microsomal protein concentration of 1.0 mg/ml and a warfarin
concentration of 10 microM, the free fraction (fu(mic)) was 0.85. The
corresponding values for propranolol and imipramine were 0.41 and 0.16,
respectively. Thus, although all three drugs exhibit high binding in plasma
(fu<0.1) the acidic drug warfarin differs from the basic drugs propranolol and
imipramine in the extent to which each binds to microsomal protein. The binding
of all three drugs to liver microsomes obtained from commonly studied animal
species (rat, dog, and monkey) was almost identical to that observed in human.
Additionally, the binding of warfarin and propranolol to microsomes obtained from
insect cells used in baculovirus cytochrome P450 expression systems was similar
to that exhibited in liver microsomes, when equal protein concentrations were
compared. The enzyme kinetics of propranolol, imipramine, and warfarin oxidative
metabolism were determined in pooled human liver microsomes, and the intrinsic
clearance values obtained were used in scaling up to project human in vivo
clearance. The values obtained by incorporating microsomal binding were compared
with those in which this factor is ignored. The findings suggest that the
parameter fu(mic) is important to obtain when attempting to relate in vitro
intrinsic clearance to in vivo clearance. Also, this value is important to
consider when comparing substrates with respect to enzyme specificity, since
measured apparent KM values should be converted to true "free KM" values by
correcting for the free fraction in the in vitro incubation. Furthermore, the
extent of nonspecific binding to microsomes is likely an important parameter to
consider when attempting to relate Ki values measured in vitro to observations of
drug-drug interactions (or the lack thereof) in vivo.
PMID- 9394026
TI - Species differences in metabolism of panomifene, an analogue of tamoxifen.
AB - In vitro metabolism of panomifene (E-1,2-diphenyl-1--4-(2-(2-hydroxyethyl-amino)
ethoxy)-phenyl--3,3,3- trifluoropropene), a novel antiestrogen against hormone
dependent tumors, has been investigated using liver microsomes from mouse, rat,
dog, and human. Hydroxylation and side chain modifications were the routes of
panomifene metabolism. Microsomal biotransformation showed some qualitative
similarities, but several differences were observed in the metabolic profiles of
the four species tested. Seven metabolites were detected in the incubation
mixtures analyzed by thin layer chromatography and autoradiography, although
there was only one produced by all species that had lost the side chain. Among
the side chain shortened metabolites, the compound that had lost the hydroxyethyl
amino group was formed by the microsomal system of rodents, whereas the one that
had lost the hydroxyethyl group was detected in the incubation mixtures with rat,
dog, and human microsomes. Three metabolites (M1, M3, and M4) were produced
exclusively by the dog. The structure of M3 was identified by mass spectroscopy
as 4-hydroxy-panomifene. Furthermore, human liver microsomes formed a metabolite
(M8) that was not detectable in the mixtures with mouse, rat, or dog microsomes.
Its structure is suspected to be an oxidized form of panomifene with a double
bound in the side chain. The structure of panomifene is analogous to tamoxifen,
an antiestrogen currently used as a therapeutic agent against breast cancer, and
there are some similar routes in their metabolism. The main difference is that
the rate of tamoxifen biotransformation seems faster than that of panomifene. On
the other hand, 4-hydroxy-panomifene is produced by only dog, while 4
hydroxylated derivative is one of the main metabolites of tamoxifen that has
potent antiestrogenic activity and is considered to be responsible for the
formation of DNA-adducts.
PMID- 9394027
TI - Metabolism of clozapine by cDNA-expressed human cytochrome P450 enzymes.
AB - The metabolism of clozapine was studied in vitro using cDNA-expressed human
cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6, and 2E1. CYP1A2, 3A4,
2C9, 2C19, and 2D6 were able to N-demethylate clozapine. N-Oxide formation was
exclusively catalyzed by CYP3A4. CYP2E1 did not metabolize clozapine. With regard
to quantitative relationships, CYP1A2, 2C9, 2C19, and 2D6 displayed KM values
ranging from 13 to 25 microM, whereas CYP3A4 had a 5-10 times higher KM value.
CYP2C19 and 2D6 had the highest Vmax values (149-366 mol/hr/mol CYP). Taking into
account the typical relative distribution of amounts of CYP enzymes in the liver,
a simulation study suggested that at therapeutic concentrations CYP2C19 and
CYP3A4 each accounted for about 35% of the metabolism. At toxic concentrations,
the relative importance of CYP3A4 increased.
PMID- 9394028
TI - In vitro biotransformation and identification of human cytochrome P450 isozyme
dependent metabolism of tazofelone.
AB - Tazofelone is a new inflammatory bowel disease agent. The biotransformation of
tazofelone in human livers and the cytochrome P450 responsible for the
biotransformation has been studied. Two metabolites of tazofelone were formed in
vitro. A sulfoxide metabolite was identified by cochromatography with authentic
standards, and a quinol metabolite of tazofelone was identified by mass
spectrometry and proton NMR. Sulfoxidation was catalyzed by a single enzyme
system while formation of the quinol metabolite was catalyzed by a two enzyme
system. The Km and Vmax values for sulfoxidation were 12.4 microM and 0.27
nmol/min/mg protein, respectively. The high affinity Km and Vmax values for the
formation of the quinol metabolite were 7.5 microM and 0.17 nmol/min/mg protein,
respectively. Tazofelone was incubated at 20 microM concentration with human
microsomes to determine which of the cytochrome P450 isozyme(s) is involved in
the oxidation of tazofelone. A strong correlation was found between the
immunoquantified concentrations of CYP3A and the rates of formation of the
sulfoxide and quinol metabolites of tazofelone. Similarly, significant
correlations were observed between the formation of midazolam 1'-hydroxylation
and the rates of formation of both metabolites of tazofelone. Inhibition studies
have indicated that triacetyloleandomycin, a CYP3A specific inhibitor, almost
completely inhibited the formation of both of these tazofelone metabolites.
Incubations with specific cDNA expressed microsomes indicated that the formation
of both the sulfoxide and quinol metabolites was highest with CYP3A4 containing
microsomes. The correlation data was confirmed by inhibition studies and cDNA
expressed cytochrome P450 systems demonstrating that the biotransformation of
tazofelone to its metabolites is primarily mediated by CYP3A.
PMID- 9394029
TI - Glucuronidation of opioids, carboxylic acid-containing drugs, and hydroxylated
xenobiotics catalyzed by expressed monkey UDP-glucuronosyltransferase 2B9
protein.
AB - UDP-glucuronosyltransferase (UGT) 2B9, isolated from a cynomolgus monkey liver
cDNA library, is 89% identical to human UGT2B7 in primary amino acid sequence,
and the two expressed enzymes were previously shown to catalyze the
glucuronidation of many common endogenous substrates. The purpose of the present
study was to characterize the reactivity of expressed UGT2B9 with important
therapeutic agents and other xenobiotics. UGT2B9, stably expressed in human
embryonic kidney 293 cells, catalyzes the 3-O- and 6-O-glucuronidation of
morphine and the 6-O-glucuronidation of codeine. A number of other morphinan
(e.g. naloxone, naltrexone, and nalorphine) and oripavine (e.g. buprenorphine)
derivatives are substrates for this enzyme. In general, morphinan derivatives are
glucuronidated at higher rates, compared with oripavines; however,
glucuronidation efficiency values (Vmax/KM) for the compounds are similar. Stably
expressed UGT2B9 also catalyzes the glucuronidation of profen nonsteroidal anti
inflammatory drugs, fibrate hypolipidemic agents, and straight-chain fatty acids
at the carboxylic acid moiety. Monoterpenoid alcohols and propanolol are
glucuronidated at aliphatic hydroxyl positions. Expressed UGT2B9 exhibits
enantioselective glucuronidation for (R/S)-ibuprofen, (R/S)-propanolol, and (+)/(
)-menthol. The data suggest that monkey UGT2B9 and human UGT2B7 are functionally
similar.
PMID- 9394030
TI - Metabolism and excretion of a new antianxiety drug candidate, CP-93,393, in
cynomolgus monkeys: identification of the novel pyrimidine ring cleaved
metabolites.
AB - The metabolism and excretion of a new anxiolytic/antidepressant drug candidate,
CP-93,393, ((7S, 9aS)-1-(2-pyrimidin-2-yl-octahydro-pyrido[1, 2-a]-pyrazin-7-yl
methyl)-pyrrolidine-2,5-dione) were investigated in cynomolgus monkeys after oral
administration of a single 5 mg/kg dose of 14C-CP-93,393. Urine, bile, feces, and
blood samples were collected and assayed for total radioactivity, parent drug,
and metabolites. Total recovery of the administered dose after 6 days was 80%
with the majority recovered during the first 48 hr. An average of 69% of the
total radioactivity was recovered in urine, 4% in bile, and 7% in feces. Mean
Cmax and AUC(0-infinity) values for the unchanged CP-93,393 were 143.2 ng/ml and
497.7 ng.hr/ml, respectively, in the male monkeys and 17.2 ng/ml and 13.7
ng.hr/ml, respectively, in the female monkeys. HPLC analysis of urine, bile,
feces, and plasma from both male and female monkeys indicated extensive
metabolism of CP-93,393 to several metabolites. The identification of metabolites
was achieved by chemical derivatization, beta-glucuronidase/sulfatase treatment,
and by LC/MS/MS, and the quantity of each metabolite was determined by
radioactivity detector. CP-93,393 undergoes metabolism by three primary pathways,
aromatic hydroxylation, oxidative degradation of the pyrimidine ring, and
hydrolysis of the succinimide ring followed by a variety of secondary pathways,
such as oxidation, methylation, and conjugation with glucuronic acid and sulfuric
acid. The major metabolites, oxidation on the pyrimidine ring to form 5-OH-CP
93,393 (M15) followed by glucuronide and sulfate conjugation (M7 and M13),
accounted for 35-45% of the dose in excreta. Two metabolites (M25 and M26) were
formed by further oxidation of M15 followed by methylation of the resulting
catechol intermediate presumably by catechol-O-methyl transferase. A novel
metabolic pathway, resulting in the cleavage of the pyrimidine ring, was also
identified. The metabolites (M18, M20, and M21) observed from this pathway
accounted for 8-15% of the dose. Aliphatic hydroxylation of the succinimide ring
was a very minor pathway in monkey. 5-Hydroxy-CP-93,393 (M15, 37-49%), its
sulfate and glucuronide conjugates (M7 and M13, approximately 34%), and the
pyrimidine ring cleaved product (M18, approximately 8%) were the major
metabolites in monkey plasma. The identified metabolites accounted for
approximately 90, 93, 97, and 92% of the total radioactivity present in urine,
bile, plasma, and feces, respectively. The major in vivo oxidative metabolites
were also observed after in vitro incubations with monkey liver microsomes.
PMID- 9394031
TI - Mechanism-based inactivation of human liver cytochrome P450 2A6 by 8
methoxypsoralen.
AB - The P450 2A6 catalyzed 7-hydroxylation of coumarin proceeded with a mean Km of
0.40 (+/-0.13) microM and Vmax of 6.34 nmol/nmol P450/min (36-fold variation) in
microsomal preparations from a panel of 12 human livers. Substrate depletion was
avoided during the kinetic determinations. 8-Methoxypsoralen (8-MOP) is a potent
mechanism-based inactivator of human liver P450 2A6 and reconstituted purified
recombinant P450 2A6 based on the following evidence: 1) 8-MOP causes time,
concentration, and NADPH-dependent loss of P450 2A6 activity that is not reversed
by potassium ferricyanide or extensive dialysis, 2) loss of P450 2A6 activity is
associated with a loss of spectrally observable P450, 3) addition of nucleophiles
or reactive oxygen scavengers to the incubations does not prevent inactivation of
P450 2A6, and 4) 8-MOP-dependent P450 2A6 inactivation is inhibited
(concentration dependent) by the addition of a competitive inhibitor
(pilocarpine). Inactivation is selective for P450 2A6 at low concentrations of 8
MOP (2.5 microM) after short incubation time periods (3 min) and was
characterized by a KI of 0.8 and 1.9 microM in a reconstituted and microsomal
system, respectively, and a kinact of 1 min-1 and 2 min-1 in a reconstituted and
microsomal system, respectively. A substrate depletion partition ratio of 21 was
calculated for the inactivation of recombinant P450 2A6. Potency and selectivity
suggest that 8-MOP could be a useful tool in vitro for evaluating P450 2A6
activity in various enzyme preparations.
PMID- 9394032
TI - Gadolinium chloride inhibition of rat hepatic microsomal epoxide hydrolase and
glutathione S-transferase gene expression.
AB - The effects of gadolinium chloride, a Kupffer cell toxicant, on the constitutive
and inducible expression of hepatic microsomal epoxide hydrolase (mEH) and
glutathione S-transferase (GST) genes were examined in rats. Northern blot
analysis showed that treatment of rats with GdCl3 caused suppression of mEH and
GST gene expression. mEH mRNA levels were decreased in a time-dependent manner
after a single injected dose of GdCl3 (10 mg/kg, iv), resulting in 95, 55, 17,
36, and 69% of the levels in untreated animals at 6, 12, 18, 24, and 48 hr after
treatment, respectively. A maximal reduction in GST Ya, Yb1/2, and Yc1 mRNA
levels was also noted at 18 hr after treatment with GdCl3, followed by a gradual
return to levels in untreated rats at later time points. Whereas treatment of
rats with thiazole, allyl disulfide, propyl sulfide, oltipraz, or clotrimazole
caused 2-13-fold increases in mEH mRNA levels at 18 hr after treatment,
concomitant GdCl3 treatment caused 30-70% reductions in the increases in mEH mRNA
levels. The chemical-inducible mRNA levels for GST Ya, Yb1/2, and Yc1 were also
significantly inhibited by GdCl3 at 18 hr after treatment. Rats treated with
GdCl3 (10 mg/kg/day, iv) for 3-5 consecutive days exhibited 40-90% decreases in
mEH, GST Ya, and GST Yb1/2 mRNA levels, relative to control, whereas the Yc1 mRNA
level was suppressed at early times and returned to levels in untreated animals
at day 5 after treatment. The mRNA levels for mEH and GST Ya in rats treated
daily with both allyl disulfide (25 mg/kg, po) and GdCl3 for 3 consecutive days
were 20-30% of those in rats treated with allyl disulfide alone. Western
immunoblotting showed that mEH and GST Ya protein expression was decreased at 1-3
days after consecutive daily treatment with GdCl3. Whereas treatment of rats with
GdCl3 at a dose of 1 mg/kg suppressed constitutive hepatic mEH gene expression by
85% at 18 hr, rats treated with CaCl2 (10 mg/kg, iv) in combination with GdCl3 (1
mg/kg, iv) showed 45% suppression of the mEH mRNA level, compared with untreated
animals. GdCl3-induced suppression was also significantly reversed for GST Ya
mRNA by excessive CaCl2 administration. These results demonstrate that GdCl3
effectively inhibits constitutive and inducible mEH and GST expression, with
decreases in their mRNA levels. GdCl3 suppression of detoxifying enzyme
expression may be associated with its blocking of intracellular Ca2+ influx,
which affects signaling pathways for the expression of the genes.
PMID- 9394033
TI - In vitro and in vivo effects of the arylamine human immunodeficiency virus
protease inhibitor 4R-(4alpha,5alpha,6beta, 7beta)-1-[(3-(1
imidazoylcarbamoyl)phenyl)methyl]-3-[(3-aminophenyl)m ethyl]hexahydro-5,6
dihydroxy-4,7-bis(phenylmethyl)-2H-1, 3-diazepin-2-one (SD894) on rat hepatic
cytochrome P450 2B and 3A.
AB - The human immunodeficiency virus-1 protease inhibitor SD894 was evaluated as an
inhibitor and inducer of cytochromes P450 (CYPs) in rats. After addition of 10
microM SD894 and 2 mM NADPH to liver microsomes from dexamethasone-treated rats,
a type II spectrum appeared. Within 2 min, it was replaced by a type III
spectrum, with absorbance maxima at 426 and 456 nm, similar to those observed
with alkylamines (SKF-525A) and arylamines (p-chloroaniline). Preincubation of
microsomes from dexamethasone-treated rats with SD894 and NADPH resulted in a
time-dependent inhibition of testosterone 6beta-hydroxylation (CYP 3A1/2
activity), which was decreased to 25% of controls after 30 min. Testosterone
16beta-hydroxylation (CYP 2B1/2 activity) was unaffected under these conditions.
Testosterone 6beta-hydroxylation rates in liver microsomes from pregnenolone
16alpha-carbonitrile-treated rats incubated with 10 microM SD894 and NADPH,
washed, and reisolated by ultracentrifugation were reduced by 71%, whereas 16beta
hydroxylation was unaffected by SD894. Immunoblots of liver microsomes from rats
dosed iv with SD894 or ip with TAO displayed increased CYP 2B1 and CYP 3A1
levels, respectively. Testosterone 6beta-hydroxylase activity in microsomes from
TAO-treated rats was greater than controls. Preincubation of these microsomes
with potassium ferricyanide produced an additional 50% increase, consistent with
disruption of a metabolite-CYP complex. Microsomes from SD894-treated rats
displayed a 3-fold increase in testosterone 16beta-hydroxylation. Potassium
ferricyanide preincubation did not increase activity. Thus, although SD894
appears to inhibit CYP in vitro in a manner typical of other amine-containing,
mechanism-based inhibitors, in vivo induction by 10 mg/kg daily doses of SD894
affects a different isozyme than does inhibition. The mechanism of induction is
unknown.
PMID- 9394034
TI - Human lymphocyte cytochrome P450 2E1, a putative marker for alcohol-mediated
changes in hepatic chlorzoxazone activity.
AB - Cytochrome P450 (CYP) 2E1 is implicated in a variety of chemically initiated
hepatotoxicities, including alcoholic liver disease. These pathological
conditions arise from increased production of reactive intermediates caused by
elevated enzyme concentrations. Thus, the ability to detect enhanced CYP2E1
levels would aid in identifying individuals at high risk for xenobiotic-promoted
liver injury. With this in mind, the present investigation assessed in vivo
chlorzoxazone metabolism and compared pharmacokinetic parameters with CYP2E1
expression in blood. Twenty-two subjects were recruited and divided into two
groups, control subjects and alcohol abusers, based on responses to two screening
questionnaires. Those individuals with higher survey scores, i.e. those who
consumed alcohol more frequently, exhibited higher rates of chlorzoxazone
metabolism. Indeed, a correlation (r = 0.66, p < 0.01) was obtained when scores
were compared with the pharmacokinetic parameter AUC for chlorzoxazone.
Lymphocyte microsomes isolated from blood samples obtained from these same
individuals were subjected to immunoblot analyses to detect CYP2E1 levels. That
lymphocytes contained CYP2E1 was confirmed by reverse transcription-polymerase
chain reaction and sequence analysis of the cDNA. Quantification of
immunoreactive bands revealed that levels of this P450 were 2.3-fold higher in
alcoholics than in control subjects. This increase in lymphocyte CYP2E1 content
in alcoholic subjects coincided with a 2.1-fold increase in chlorzoxazone
clearance and a 2-fold decrease in the AUC for chlorzoxazone. Importantly, a
correlation (r = 0.62, p < 0.01) was observed between CYP2E1 content in
lymphocytes and chlorzoxazone clearance rates. Thus, monitoring lymphocyte CYP2E1
expression may provide a substitute for estimating hepatic activity of this P450.
PMID- 9394035
TI - Relative contribution of human erythrocyte aldehyde dehydrogenase to the systemic
detoxification of the oxazaphosphorines.
AB - Detoxification of cyclophosphamide is effected, in part, by hepatic class 1
aldehyde dehydrogenase (ALDH-1)-catalyzed oxidation of aldophosphamide, a pivotal
aldehyde intermediate, to the nontoxic metabolite, carboxyphosphamide. This
enzyme is found in erythrocytes as well. Detoxification of aldophosphamide may
also be effected by enzymes, viz. certain aldo-keto reductases, that catalyze the
reduction of aldophosphamide to alcophosphamide. Such enzymes are also found in
erythrocytes. Not known at the onset of this investigation was whether the
contribution of erythrocyte ALDH-1 and/or aldo-keto reductases to the overall
systemic detoxification of circulating aldophosphamide is significant. Thus, NAD
linked oxidation and NADPH-linked reduction of aldophosphamide catalyzed by
relevant erythrocyte enzymes were quantified. ALDH-1-catalyzed oxidation of
aldophosphamide (160 microM) to carboxyphosphamide occurred at a mean (+/- SD)
rate of 5.0 +/- 1.4 atmol/min/rbc (red blood cell). Aldo-keto reductase-catalyzed
reduction of aldophosphamide (160 microM) to alcophosphamide occurred at a much
slower rate, viz. 0.3 +/- 0.2 atmol/min/rbc. Thus, at a pharmacologically
relevant concentration of aldophosphamide, viz. 1 microM, estimated aggregate
erythrocyte ALDH-1-catalyzed aldophosphamide oxidation, viz. 2.0 micromol/min,
was only about 3% of estimated aggregate hepatic enzyme-catalyzed aldophosphamide
oxidation, viz. 72 micromol/min; however, this rate is greater than the estimated
flow-limited rate of aldophosphamide delivery to the liver by the blood, viz. 1.5
micromol/min. These observations/considerations suggest an important in vivo role
for erythrocyte ALDH-1 in systemic aldophosphamide detoxification. Erythrocyte
ALDH-1-effected oxidation of other aldehydes to their corresponding acids, e.g.
retinaldehyde to retinoic acid, may also be of pharmacological and/or
physiological significance since a wide variety of aldehydes are known to be
substrates for ALDH-1.
PMID- 9394037
TI - 9,13-Dicis-retinoic acid as an isomerization product of 9-cis-retinoic acid.
PMID- 9394036
TI - Induction of rat hepatic cytochrome P450 2B subfamily by azidophenobarbital, as a
possible photoaffinity probe for the putative phenobarbital receptor: comparative
study with modified phenobarbitals with different functional groups.
AB - To study the specific target to which phenobarbital (PB) binds, resulting in the
induction of cytochrome P450, we prepared two azido-PBs (AZPBs) as photoaffinity
ligands. The azido substituent was introduced at the para- or meta-position of
the PB aromatic ring. In this study, we estimated the utility of these compounds
by examining their inducing activities in vivo in rats. Induction was assessed by
immunoblotting with anti-CYP2B1/2 antibody and measuring testosterone
metabolizing activity, using hepatic microsomes. Administration of p-AZPB to rats
increased hepatic CYP2B1/2 protein and testosterone 16beta-hydroxylase activity,
although the effects were less than those of unmodified PB. m-AZPB showed no
effect in the induction of CYP2B1/2. To assess the specificity of the effects of
substituents, we compared the inducing activities of p/m-nitro-PBs, p/m-amino
PBs, and p/m-hydroxy-PBs with those of AZPBs. The results showed that p-nitro-PB,
m-amino-PB, and p-hydroxy-PB were also potent inducers for CYP2B1/2, with lower
activity than that of unmodified PB, whereas the other three isomers had no
effect. These results suggest that 1) the absence of any substituents on the
aromatic ring of PB is needed for maximal inducing activity and 2) substitution
at the meta-position of the PB aromatic ring tends to reduce effectiveness as an
inducer more than does substitution at the para-position. Because p-amino-PB and
p-acetylamino-PB, the minor and major metabolites of p-AZPB, respectively, were
without effect in the induction of CYP2B1/2, the effect of p-AZPB was considered
to be due to the unchanged compound itself. The present study demonstrates that,
based on the weak but positive ability to induce CYP2B1/2, p-AZPB may be a useful
tool for identifying the putative PB receptor.
PMID- 9394038
TI - Tissue engineering: generation of differentiated artificial tissues for
biomedical applications.
AB - A new field in biomedical science has been established. Cell biologists,
engineers, and surgeons now work within a team. Artificial connective,
epithelial, or neuronal tissues are being constructed using living cells and
different kinds of biomaterials. Numerous companies and laboratories are
presenting dynamic developments in this field. Prognoses predict that, at the
beginning of the coming century, the industry of tissue engineering will reach
the importance of the present genetic technology. An enormous demand for organ
and tissue transplants motivates research activities and drives the acquisition
of innovative techniques and creative solutions. At the front of this development
is the creation of artificial skin for severely burned patients and the
generation of artificial cartilage for implantation in articular joint diseases.
Future challenges are the construction of liver organoids and the development of
an artificial kidney on the basis of cultured cells. In this paper we show
strategies, needs, tools, and equipment for tissue engineering. The
presupposition for all projects is the induction, development, and maintenance of
differentiation within the tissue under in vitro conditions. As experiments in
conventional culture dishes continued to fail, new cell and tissue culture
methods had to be developed. Tissues are cultured under conditions as close as
possible to their natural environment. To optimize adherence or embedding, cells
are grown on novel tissue carriers and on individually selected biomatrices or
scaffolds. The tissues are subsequently transferred into different types of
containers for permanent perfusion with fresh culture medium. This guarantees
constant nutrition of the developing tissue and prevents the accumulation of
harmful metabolites. An organo-typical environment for epithelial cells, for
example, is obtained in gradient containers, which are permanently superfused at
the apical and basal sides with different media. Long term experiments result in
cultured tissues in a quality thus far unreached.
PMID- 9394039
TI - Differential expression of the TFF-peptides xP1 and xP4 in the gastrointestinal
tract of Xenopus laevis.
AB - TFF-peptides (formerly P-domain peptides, trefoil factors) represent major
secretory products of the mammalian gastrointestinal tract. A molecular cloning
approach revealed the existence of two TFF-peptides, xP1 and xP4, also in the
stomach of Xenopus laevis. Here, the localization of these two peptides by
Western blot analysis as well as immunohistochemistry is presented. xP1 is found
predominantly in the surface mucous cells of the stomach, whereas xP4 is mainly
localized to a specific population of goblet cells in the esophagus, to mucous
neck cells of the stomach, and to closely resembling cells in antral glands. xP4
in the esophagus and in the stomach differ by their N-glycosylation patterns.
Compared to mammalian TFF-peptides, xP1 obviously represents the frog homologue
of human TFF1 (formerly pS2) and xP4 seems to be the amphibian equivalent of
human TFF2 (formerly hSP).
PMID- 9394040
TI - High-affinity glutamate transporters in the rat retina: a major role of the glial
glutamate transporter GLAST-1 in transmitter clearance.
AB - Glutamate is the major excitatory neurotransmitter of the mammalian retina and
glutamate uptake is essential for normal transmission at glutamatergic synapses.
The reverse transcriptase-polymerase chain reaction (RT-PCR) has revealed the
presence of three different high-affinity glutamate transporters in the rat
retina, viz. GLAST-1, GLT-1 and EAAC-1. No message has been found in the retina
for EAAT-4, a transporter recently cloned from human brain. By using membrane
vesicle preparations of total rat retina, we show that glutamate uptake in the
retina is a high-affinity electrogenic sodium-dependent transport process driven
by the transmembrane sodium ion gradient. Autoradiography of intact and
dissociated rat retinae indicates that glutamate uptake by Muller glial cells
dominates total retinal glutamate transport and that this uptake is strongly
influenced by the activity of glutamine synthetase. RT-PCR, immunoblotting and
immunohistochemistry have revealed that Muller cells express only GLAST-1. The Km
for glutamate of GLAST-1 is 2.1+/-0.4 microM. This study suggests a major role
for the Muller cell glutamate transporter GLAST-1 in retinal transmitter
clearance. By regulating the extracellular glutamate concentration, the action of
GLAST-1 in Muller cells may extend beyond the protection of neurons from
excitotoxicity; we suggest a mechanism by which Muller cell glutamate transport
might play an active role in shaping the time course of excitatory transmission
in the retina.
PMID- 9394041
TI - Estrogen receptor and progesterone receptor-immunoreactive cells are not co
localized with gonadotropin-releasing hormone in the brain of the female mink
(Mustela vison).
AB - The distribution of gonadal steroid (estrogen, progesterone) receptors in the
brain of the adult female mink was mapped by immunocytochemistry. Using a
monoclonal rat antibody raised against human estrogen receptor (ER), the most
dense collections of ER-immunoreactive (IR) cells were found in the
preoptic/anterior hypothalamic area, the mediobasal hypothalamus (arcuate and
ventromedial nuclei), and the limbic nuclei (amygdala, bed nucleus of the stria
terminalis, lateral septum). Immunoreactivity was mainly observed in the cell
nucleus and a marked heterogeneity of staining appeared from one region to
another. A monoclonal mouse antibody raised against rabbit uterine progesterone
receptor (PR) was used to identify the PR-IR cells in the preoptic/anterior
hypothalamic area and the mediobasal hypothalamus (arcuate and ventromedial
nuclei). This study also focused on the relationship between cells containing sex
steroid receptors and gonadotropin-releasing hormone (GnRH) neurons on the same
sections of the mink brain using a sequential double-staining immunocytochemistry
procedure. Although preoptic and hypothalamic GnRH neurons were frequently in
close proximity to perikarya containing ER or PR, they did not themselves possess
receptor immunoreactivity. The present study provides neuroanatomical evidence
that GnRH cells are not the major direct targets for gonadal steroids and
confirms for the first time in mustelids the results previously obtained in other
mammalian species.
PMID- 9394042
TI - Transient axonal side branches in the developing mammalian optic nerve.
AB - Optic axons were labelled with horseradish peroxidase to establish the presence
of side branches and examine their distribution and morphology in the developing
optic nerve of the quokka wallaby, Setonix brachyurus, the cat and rat at stages
when axon numbers are at their peak. In each species, three quarters of the axons
were essentially straight and lacked side branches. The remaining axons took
significantly longer paths and bore side branches, mostly at points where axons
undulated or changed direction. Side branches occurred at intervals of 28-43
micron, had lengths of 2-3 micron and were usually simple rather than branched. A
minority (1%) of the axons crossed diagonally between fascicles and two thirds of
these had more side branches (interval: 10-18 microm) on the interfascicular
portion than were found on the forward-directed axons. A small number of axons
(0.01%) doubled back to grow retrogradely towards the eye, these axons also bore
relatively more side branches (interval: 8-22 micron), especially at points where
the axons changed direction. Ultrastructural reconstruction showed that side
branches resembled small axonal profiles and constituted 2% of the total axon
number. It is suggested that side branches are involved in the fine-tuning of
growth cone navigation. Most side branches are lost by adulthood, indicating
their transient nature. The absence of retrogradely-directed axons from adults
suggests that cells with such axons are removed by naturally occurring cell
death.
PMID- 9394043
TI - Co-localization of nitric oxide synthase I (NOS I) and NMDA receptor subunit 1
(NMDAR-1) at the neuromuscular junction in rat and mouse skeletal muscle.
AB - Nitric oxide synthase I (NOS I) has been localized to the skeletal muscle
sarcolemma in a variety of vertebrate species including man. It is particularly
enriched at neuromuscular junctions. Recently, the N-methyl-D-aspartate (NMDA)
receptor subunit 1 (NMDAR-1) has been detected in the postjunctional sarcolemma
of rat diaphragm, providing a clue as to the possible source of Ca2+ ions that
are necessary for NOS I activation. To address this possibility, we studied the
distribution of NMDAR-1 and NOS I in mouse and rat skeletal muscles by
immunohistochemistry and enzyme histochemistry. NMDAR-1 and NOS I were closely
associated at neuromuscular junctions primarily of type II muscle fibers. NOS I
was also present in the extrajunctional sarcolemma of this fiber type.
Dystrophin, beta-dystroglycan, alpha-sarcoglycan, and spectrin were found
normally expressed in both the junctional and extrajunctional sarcolemma of both
fiber types. By contrast, in the muscle sarcolemma of MDX mice, dystrophin and
dystrophin-associated proteins were reduced or absent. NOS I immunoreactivity was
lost from the extrajunctional sarcolemma and barely detectable in the junctional
sarcolemma. NOS I activity was clearly demonstrable in the junctional sarcolemma
by NADPH diaphorase histochemistry, especially when the two-step method was used.
NMDAR-1 was not altered. These data suggest that different mechanisms act to
attach NOS I to the junctional versus extrajunctional sarcolemma. It may further
be postulated that NMDA receptors are involved not only in the regulation but
also sarcolemmal targeting of NOS I at neuromuscular junctions of type II fibers.
The evidence that glutamate may function as a messenger molecule at vertebrate
neuromuscular junction is discussed.
PMID- 9394044
TI - Pituitary adenylate cyclase activating polypeptide (PACAP) in the
gastrointestinal tract of the rat: distribution and effects of capsaicin or
denervation.
AB - The expression of pituitary adenylate cyclase activating polypeptide (PACAP) was
studied in the gastrointestinal tract (GI-tract) of normal rats using
radioimmunoassay, chromatography, immunocytochemistry, and in situ hybridization.
PACAP-38, PACAP-27, and PACAP-related peptide were demonstrated in all parts of
the GI-tract, PACAP-38 being the predominant form confirmed by chromatography.
PACAP-immunoreactive nerve fibers and nerve cell bodies were found in the
myenteric ganglia throughout the GI-tract. PACAP-containing nerve cell bodies
were also demonstrated in the submucous ganglia of the small and large intestine.
The synthesis of PACAP in intrinsic neurons was confirmed by in situ
hybridization. Double immunostaining showed that PACAP is present in calcitonin
gene-related peptide-containing sensory nerve fibers as well as in vasoactive
intestinal polypeptide (VIP)- or VIP/gastrin-releasing peptide (GRP)-containing
(intramural) nerve fibers in the upper GI-tract and in anally projecting,
intrinsic VIP-and VIP/nitric oxide syntase-containing nerve cell bodies and nerve
fibers in the small and large intestine. Neonatal treatment with capsaicin
significantly reduced the concentration of PACAP-38 in the esophagus, stomach,
and colon. Extrinsic denervation decreased the PACAP-38 concentration in the
stomach, while no change was observed in the small intestine. These results
indicate that PACAP- immunoreactive nerve fibers in the GI-tract originate from
both intrinsic (enteric) and extrinsic (presumably sensory) sources suggesting
that PACAP may have diverse gastrointestinal functions.
PMID- 9394045
TI - Calbindin D28k-like immunoreactivity in the developing and regenerating
circumvallate papilla of the rat.
AB - The distribution of calbindin D28k (CB)-like immunoreactivity (-LI) in the
circumvallate papilla (CVP) was examined during development and regeneration
following bilateral crush injury to the glossopharyngeal nerve in the rat. In the
adult CVP, CB-like immunoreactive (-IR) nerve fibers were observed in the
subgemmal region and some penetrated into the taste buds. CB-LI was also detected
in the cytoplasm of the spindle-shaped gustatory cells in the lower half of the
trench epithelium, which contained numerous synaptic vesicles and bundles of
intermediate filaments. These CB-IR gustatory cells made synapse-like contacts
with CB-IR nerve terminals. Some CB-IR nerve terminals made contacts with the
gustatory cells negative for CB-LI. At least three developmental stages were
defined with regard to the developmental changes in the distribution of CB-LI:
(1) Stage I (embryonic day (E) 18-postnatal day (P)5): CB-IR nerve fibers
appeared in the lamina propria just beneath the newly-formed CVP at E18, but the
gustatory epithelium of the CVP contained no CB-IR structures. Taste buds with
taste pores appeared at P1. (2) Stage II (P5-10): thin CB-IR nerve fibers began
entering the trench epithelium, but no CB-IR cells were observed. (3) Stage III
(P10-adult): in addition to the intragemmal and perigemmal CB-IR nerve fibers,
very few CB-IR cells appeared in the taste buds around P10, and their numbers
increased progressively. The changes in the distribution of taste buds and CB-LI
following glossopharyngeal nerve injury were similar to those observed during
development. On post-operative day (PO) 4, the taste buds and CB-IR cells
decreased markedly in number. These CB-IR cells became round in shape, and the
number of CB-IR nerve fibers decreased markedly. On PO8, both taste buds and CB
IR cells disappeared completely. The regenerated taste buds were first observed
on PO12, increased rapidly in number by PO20, and increased slowly thereafter. CB
IR nerve fibers accumulated at the subgemmal region and began penetrating into
the trench wall epithelium around PO16. CB-IR cells appeared between PO20 and
PO24, and their numbers increased progressively and reached the normal level on
PO40. The topographical localizations of the taste buds and CB-IR cells during
development and regeneration were comparable to those of normal animals. The
delay of the time courses for appearance of CB-IR nerve fibers and CB-IR cells
compared to the appearance of taste buds during development and regeneration
suggests that CB in the gustatory epithelium may participate in the survival of
the taste bud cells rather than in the induction of the taste buds.
PMID- 9394046
TI - Reversibility of omeprazole-evoked changes in the ultrastructure of ECL cells in
the rat stomach.
AB - The ECL cells are histamine- and peptide hormone-producing endocrine cells in the
rat oxyntic mucosa. They are rich in secretory vesicles and also contain
microvesicles and electron-dense granules. They operate under the control of
circulating gastrin. In the present study, we examined the ECL-cell
ultrastructure after long term treatment with omeprazole, which is known to
induce hypergastrinemia, and after withdrawal of the drug. Rats received
omeprazole (400 micromol/kg per day, orally) for 16 days and were killed 1, 5,
20, or 40 days after the last dose of the drug. Oxyntic mucosal specimens were
processed for electron microscopy. Electron micrographs of ECL-cell profiles were
analyzed planimetrically. The ECL-cell profile area increased promptly in
response to omeprazole, the secretory vesicles and granules were reduced in
number and volume density, the microvesicles were unchanged in number but reduced
in volume density, and vacuoles appeared. Within a week after stopping the
omeprazole treatment, the numbers and volume densities of secretory vesicles and
microvesicles returned to pre-stimulation values. Also, the vacuoles disappeared
promptly. The ECL-cell profile area decreased below the pre-stimulation level
within five days after stopping treatment, while, in contrast, the granules
increased in number and volume density. Somewhat surprisingly, the cell size and
the granule compartment did not return to normal until 40 days after stopping
treatment.
PMID- 9394047
TI - Occurrence of a terminal vascularisation after experimental myocardial
infarction.
AB - Physiological data indicate a residual vascularisation within ischemic myocardial
regions where necrosis of most cells have been reported to occur after myocardial
infarction. We therefore studied, by means of immunohistochemistry, computer
assisted morphometry, and electron microscopy, the terminal vascularisation in
correlation to cardiomyocytes in ten canine hearts 1 and 3 weeks after occlusion
of the left anterior descending (LAD) coronary artery. In comparison to non
infarcted myocardium we found the following alterations in infarcted myocardium:
(1) the area density of cardiomyocytes decreased from 98% (control) to 7.9% (1
week after occlusion) and to 2.7% (3 weeks after occlusion); (2) the number of
capillaries was diminished to 11.6% and to 2.6%; respectively; (3) smooth muscle
alpha-actin was induced in endothelial (EC) cells of the microvessels; and (4)
terminal resistance vessels increased 11-fold and 20-fold in number,
respectively. Our findings confirm the necrosis of the vast majority of
cardiomyocytes and capillaries within the first 3 weeks after myocardial
infarction. Besides a small number of capillaries, many terminal resistance
vessels, however, seem to persist in the scarring infarcted tissue. The
occurrence of these microvessels is supposed to be important for the granulation
tissue as well as for the control and regulation of a residual blood supply
during scar formation.
PMID- 9394048
TI - CD57, a marker for B-cell activation and splenic ellipsoid-associated reticular
cells of the chicken.
AB - We have demonstrated that the ellipsoid-associated reticular cells of chicken
spleen express CD57, a marker for B-cell activation. These cells are
characterised by their spindle-shaped morphology, tissue distribution and the
absence of certain leucocyte-specific markers. They are phagocytotic and possess
high endogenous non-specific esterase activity. Previous reports failed to detect
CD57 expression on ellipsoid-associated reticular cells, probably because the
tissue sections were differently treated before immunohistochemistry. CD57 is
also expressed by a small number of T-cells in the spleen and the caecal tonsils.
This number is highly variable between individual chickens depending on the
activation state of the immune system. Moreover, CD57 is expressed by bursal
lymphocytes (90% or more) but not by B-cells of the peripheral blood. More
interestingly, we have been able to discriminate and quantify three B-cell
populations of the secondary lymphoid organs, i.e. resting B-cells, germinal
centre B-cells and plasma cells, based on their expression levels of CD57 and Bu
1 (a pan B-cell marker). Thus, CD57 should be considered as a B-cell activation
marker, rather than as a marker for bursal B-cells; it is also a valuable marker
for the immunohistochemical study of ellipsoid-associated reticular cells of
chicken spleen.
PMID- 9394049
TI - Dynamics of monocytes/macrophages and T lymphocytes in acutely rejecting rat
renal allografts.
AB - We examined the infiltration of acutely rejecting renal allografts (DA-->LEW) by
ED1+ and ED2+ macrophages and T lymphocytes at intervals of 24 h after
transplantation. Donor and recipient macrophages were differentiated by MHC class
II antigen expression in double-staining experiments with ED1. Proliferation was
assayed after pulse-labelling with BrdU. We subdivided allograft infiltration
into three consecutive phases: 1) During phase I on days 1 to 2 after allogeneic
kidney transplantation, perivascular infiltrates developed that contained
numerous donor and recipient macrophages. Allograft rejection could already be
diagnosed 24 h after transplantation by perivascular infiltration of T
lymphocytes, whereas T cells were rarely found in isografts. 2) Phase II of
allograft rejection from day 3 to 4 was characterized by massive propagation of
the infiltrate. About equal numbers of interstitial donor and recipient
macrophages were counted. Both macrophages and T lymphocytes proliferated in situ
and macrophages outnumbered T cells until complete rejection. 3) During phase III
the allograft was destroyed. Large intravascular monocytes surprisingly expressed
the ED2 antigen. In the interstitium of viable graft regions, the population of
recipient macrophages grew, whereas the population of donor macrophages and of T
lymphocytes decreased.
PMID- 9394050
TI - Expression of the mouse histone gene H1t begins at premeiotic stages of
spermatogenesis.
AB - The gene encoding H1t, a testicular variant of histone H1, is expressed in
mammals during spermatogenesis. Northern blot and in situ hybridization has
detected H1t mRNA only at the stage of pachytene spermatocytes. We have extended
this analysis to more sensitive approaches and demonstrate, by RNase protection
and electron-microscopic in situ hybridization, that H1t mRNA is detectable even
in spermatogonia. Just a faint H1t band is seen in Western blots of nuclear
protein from 9-day-old mice. This indicates that the H1t gene is expressed at
premeiotic stages, albeit at a low level. In contrast to H1t mRNA, the H1t
protein has not been detected in spermatogonia by electron microscopy after
immunogold staining.
PMID- 9394051
TI - Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and
their inhibitors (TIMP) during trophoblast invasion in the human placenta.
AB - The invasion of extravillous trophoblast cells into the maternal endometrium is
one of the key events in human placentation. The ability of these cells to
infiltrate the uterine wall and to anchor the placenta to it as well as their
ability to infiltrate and to adjust utero-placental vessels to pregnancy depends,
among other things, on their ability to secrete enzymes that degrade the
extracellular matrix. Most of the latter enzymes belong to the family of matrix
metalloproteinases. Their activity is regulated by the tissue inhibitors of
matrix metalloproteinases. We have studied the distribution patterns of matrix
metalloproteinases-1, -2, -3, and -9 and their inhibitors TIMP-1 and TIMP-2 as
compared to the distribution of their substrates along the invasive pathway of
extravillous trophoblast of 1st, 2nd, and 3rd trimester placentas by means of
light microscopy on paraffin and cryostat sections as well as at the
ultrastructural level (only 3rd trimester placenta). The comparison of different
methods proved to be necessary, since the immunohistochemical distribution
patterns of these soluble enzymes are considerably influenced by the pretreatment
of tissues. All three methods revealed immunoreactivities of both, proteinases
and their inhibitors, not only intracellularly in the extravillous trophoblast
but also extracellularly in its surrounding matrix, the distribution patterns
depending on the stage of pregnancy and on the degree of differentiation of
trophoblast cells along their invasive pathway. Within the extracellular matrix,
immunolocalization of matrix metalloproteinases as well as their inhibitors
showed a specific relation to certain extracellular matrix molecules.
PMID- 9394052
TI - Cognitive late effect factors related to decision making and risk behaviors of
cancer-surviving adolescents.
AB - The purpose of this correlational study was to examine factors related to
cognitive late effects of treatment that may be predictors of decision making and
risk behaviors for cancer-surviving adolescents. A convenience sample of 52
survivors (ages 14-19 years, disease-free for 5 years, no treatment for 2 years,
and with all types of cancer except primary brain tumors) participated in this
study at two regional survivor follow-up clinics. A medical record review, a
semistructured interview with the teen, and intelligence testing on a separate
day were used to collect data. A history of cancer therapy threatening cognitive
function (defined as > or = 18 gy of radiotherapy, intrathecal or high-dose
systemic methotrexate, or both) was a marginally significant predictor of poorer
quality decision making in the first regression model. Poorer-quality decision
making was a significant predictor of one or more risk behaviors in the second
model. Younger age at initial treatment and lower cognitive ability (full-scale
IQ) were not significant predictors for either of the models. There were no
significant differences for the Wechsler IQ subtests related to abstract and
analytic ability by cognitive threat status. Post hoc analysis indicated that
lack of sensitivity to change of the Wechsler IQ measure may have affected
outcomes. Abstract and/or analytic ability may be important links for decision
making and risk behaviors of teen survivors, thus warranting further examination
within a larger sample. Intervention to improve decision making needs to be
provided for teen survivors; this may be true especially when there is a history
of therapy threatening cognitive function.
PMID- 9394053
TI - Predicting mammography and breast self-examination in African American women.
AB - Breast cancer mortality is significantly greater in African American women than
in their Caucasian counterparts. The purpose of this study was to identify
variables associated with the breast cancer screening behaviors of mammography
utilization and breast self-examination (BSE) in a convenience sample of low
income African American women. A total of 328 African American women, living in a
large midwestern metropolitan area, who were at < or = 150% of poverty level, and
between the ages of 45 and 64 years were included in this study. Data were
collected over a period of 18 months. Predisposing, enabling, and need variables
from Anderson's theoretical framework included perceived susceptibility,
benefits, barriers, confidence, knowledge, physician recommendation, demographic
characteristics, and past experiences, as well as health-care and insurance
information. Variables that significantly predicted mammography utilization
included perceived barriers, mammography suggested by health-care professionals,
recent thoughts about mammography, and a regular medical doctor. Variables that
significantly predicted either frequency or proficiency of BSE included
susceptibility, benefits, confidence, knowledge, barriers, and a regular
physician. Implications for clinical practice include (a) recognizing predictors
of screening among low-income African American women; (b) addressing culturally
specific barriers, e.g., cancer fatalism, in order to increase compliance with
screening; (c) establishing consistency in primary care providers; and (d)
increasing confidence and knowledge through education.
PMID- 9394054
TI - Enhancing breast cancer screening in the university setting.
AB - Mammography, physical examination by a health care professional, and breast self
examination (BSE) may increase the probability of detection of breast cancer at
an early stage and thus increase long-term survivor rates. The purpose of this
study was to investigate the effectiveness of supportive coaching as an
intervention to enhance compliance with these breast cancer screening guidelines.
The following research questions were identified: (a) what are the attitudes of
women toward breast cancer screening? (b) what are the barriers to compliance
identified by women in breast cancer screening? and (c) what are the effects of
supportive interventions by a professional nurse and of compliance with breast
cancer screening in women? A quasi-experimental design was used to study the
research questions. The population chosen for the study included female employees
in a state university setting. Participants were randomly assigned to one of two
groups. All participants were asked to complete a prestudy questionnaire
measuring attitudes and beliefs, gathering demographic and health information,
and surveying breast cancer screening practices. The experimental group then
received coaching and supportive interventions over the course of the academic
year. The remainder of the sample served as a control group. A poststudy
questionnaire was then sent to the entire sample to identify behaviors related to
breast cancer screening. A variety of beliefs and attitudes were observed in the
groups. No significant difference was found between the experimental and control
groups on compliance with mammography and the clinical breast examination. A
difference was noted on compliance with BSE by the experimental group evidencing
more compliance.
PMID- 9394055
TI - Stories of being a hospice nurse: a journey towards finding one's footing.
AB - This article sheds light on the meaning of the lived experience of being a
hospice nurse, as interpreted from in-depth interviews with 18 hospice nurses.
The nurses' stories were analyzed using a phenomenologic-hermeneutic approach
inspired by the philosophy of Ricoeur. Findings were synthesized into two themes:
pursuing meaningful hospice care and pursuing spiritual integrity. Results
indicated that it was the nurses' conceptions of "ideal" hospice practice that
seemed to be the lens through which the nurses experienced and interpreted "real"
practice as being either vitalizing or devitalizing. Results also indicated that
being a hospice nurse means being visible as a person, in the sphere between the
sacred and the profane and on the border between eternity and the finite. In
narrating these experiences, the nurses used metaphors pointing towards "the
sacred" and a "consciousness of fault." The tension between "ideal" and "real"
hospice practices, and the nurses' vitalizing and devitalizing experiences and
their use of metaphors in narrating these experiences are interpreted in the
light of Bauman's two "life strategies" of deconstructing mortality and
immortality, and Ricoeur's Symbolism of Evil.
PMID- 9394056
TI - Relaxation to reduce nausea, vomiting, and anxiety induced by chemotherapy in
Japanese patients.
AB - The purpose of this study was to examine the effectiveness of progressive muscle
relaxation (PMR) in reducing the nausea, vomiting, and anxiety induced by
chemotherapy in Japanese patients. Subjects comprised 60 cancer chemotherapy
patients who were hospitalized in a cancer center. These subjects were randomly
assigned to either the experimental or control group. In addition to routine
nursing care, subjects in the experimental received PMR training, while those in
the control received contact with the investigator. Results from this study
verified the effectiveness of PMR in reducing total scores used to measure
nausea, vomiting, and retching; subscale scores of nausea; and subjective
feelings of anxiety. The efficacy of PMR to reduce subscale scores of vomiting
was not verified, partly due to an extremely low incidence of vomiting.
PMID- 9394057
TI - Intervening with the psychosocial needs of patients and families: perceived
importance and skill level.
AB - Although nurses claim that psychosocial aspects of care are an important part of
their practice, it is not clear that the psychosocial aspects of care is evident
in clinical practice. This raises the question as to whether a gap exists between
the theoretical literature and what is occurring at the bedside. This survey was
designed as a means to examine (a) the importance staff nurses place on
intervening with patient and family members' psychosocial needs, and (b) nurses'
perceived skill level in meeting those psychosocial needs. The questionnaire,
psychosocial interventions: perceived importance and skill level, was developed
for this study. Questionnaires were distributed to 310 nurses, and 112
questionnaires were returned (37%). Data analyses included the use of descriptive
statistics, independent t-tests, and analysis of variance. Nurses noted that each
psychosocial need identified was quite important when providing care to patients
with cancer and their families. However, nurses identified a moderate skill level
for intervening with these aspects of care. A variety of individuals and factors
were identified as promoting psychosocial care. Time was identified as the number
one barrier to psychosocial care. Implications include the need for continuing
education and preceptorship models that can be used to enhance nurses' skill in
intervening with psychosocial needs of patients and their families.
PMID- 9394058
TI - Clinical applications of genetic technologies to cancer care.
PMID- 9394059
TI - Sexually transmitted diseases among teenagers in England and Wales.
AB - A profile of sexually transmitted diseases (STDs) and HIV infections among
teenagers in England and Wales was obtained from reports of newly diagnosed STDs
among teenagers attending genitourinary medicine (GUM) clinics in 1995,
laboratory reports of newly diagnosed HIV infections between 1985 when reporting
began and the end of 1995, and the prevalence of HIV (unlinked anonymous
programme) among teenagers attending genitourinary medicine clinics and antenatal
clinics in 1994 and 1995. STD reports were analysed by sex, age group, and place
of residence of patients--whether in the NHS Thames regions or elsewhere in
England and Wales. High rates of STDs were reported in teenagers, particularly in
girls. The incidences of gonorrhoea, chlamydia infection, and first attack
genital wart infections were higher in teenage girls than in any other age group.
Boys under 16 years of age had substantially higher rates of infection with all
STDs in the Thames regions than elsewhere. Rates of gonorrhoea in teenagers of
both sexes in the Thames regions were more than twice those in the rest of the
country. Infection rates for genital herpes, and chlamydia in girls, were also
higher in the Thames regions, although the geographical differences were less
marked. The seroprevalence of HIV among heterosexual teenagers was very low. In
contrast, 226 HIV infections among teenage boys had probably been acquired
through sexual intercourse with other males. Unlinked anonymous testing revealed
HIV antibody in 7.5% of routinely collected serology specimens taken from teenage
homosexual or bisexual males attending GUM clinics in London. The high rates of
STDs among teenage girls and all teenagers in the Thames regions make these
groups a high priority for sexual health promotion, with special consideration
given to homo/bisexual male teenagers. Detailed surveillance of risk factors for
STDs, and further studies of teenage sexual behaviour will help to effectively
target resources to improve the sexual health of teenagers in England and Wales.
PMID- 9394060
TI - CD4 cell counts of 200 x 10(6)/1 or below in natural history studies and
surveillance: is one enough or are two better?
AB - A retrospective cohort study was performed to examine the extent and clinical
significance of misclassification associated with using the current United States
AIDS case defining category of an initial CD4 count < or = 200 cells x 10(6)/l (<
or = 200) compared with a definition requiring two consecutive counts below this
level. The main outcomes examined were the probability of subsequent CD4 counts >
200 x 10(6)/l (> 200) and progression times to AIDS and death. Of the 2025
predominantly male homosexual HIV-positive patients attending two hospital based
HIV clinics with initial CD4 cell counts < or = 200, 1524 (75%) subsequently had
consecutive counts < or = 200, but only half did so at the next CD4 count. Ten
per cent had either no further or only non-consecutive counts < or = 200, and 15%
had only one CD4 count available for analysis. The cumulative proportion of
patients with a CD4 count > 200 at one year after a first count of < or = 200 was
about twice (39%) that observed among the subgroup with at least two consecutive
counts < or = 200 (19%). The times from the initial counts of < or = 200 to AIDS
and death were also shorter by six months and two months, respectively, in the
subgroup with two or more consecutive counts < or = 200. A significant proportion
of patients will be prematurely classified as having a CD4 cell count < or = 200
if a single CD4 count below this level is accepted. A definition of two
consecutive counts < or = 200 should be adopted in preference to a single count <
or = 200 for natural history studies and clinical trials, in which precise
estimates of the time to or from a defined CD4 threshold are important. In
surveillance programmes, however, such an approach may be impractical because of
missing or infrequent serial CD4 counts, although adjustments can be made based
on these estimates of premature misclassification.
PMID- 9394061
TI - Leptospirosis in the Republic of Ireland: 1985 to 1996.
AB - Official government statistics and serological laboratory data provide limited
information about the incidence of leptospirosis in the Republic of Ireland. The
mean annual notified incidence in the Republic of Ireland from 1985 to 1996 was
1.3/million. The incidence according to hospital discharge diagnosis was higher
at 4.9/million. One hundred and seventy-five serologically confirmed cases of
leptospirosis were reported from 1986 to 1996, giving a mean annual incidence of
4.5/million. The true incidence of leptospirosis in the Republic of Ireland is
probably higher, as hospital discharge data are incomplete and full serological
testing was not always performed. Our data indicate that leptospirosis is an
underestimated public health problem with only 26% of cases being notified. A
national communicable disease surveillance centre in the Republic of Ireland
would facilitate better monitoring and understanding of this disease.
PMID- 9394062
TI - Outbreak of cryptosporidiosis associated with a swimming pool in Andover.
AB - An outbreak of eight cases of cryptosporidiosis in Hampshire over a period of
eight weeks in the summer of 1996 was linked to use of one swimming pool.
Cryptosporidial oocysts were not isolated from samples of backwash, but the
presence of enterobius ova indicated faecal contamination and a case control
study including the first four primary cases suggested an association with
immersion in the pool. Even in small outbreaks case control studies can provide
useful supportive evidence as to the possible source of infection.
PMID- 9394063
TI - Vero cytotoxin producing Escherichia coli O157.
PMID- 9394064
TI - Changes in medical education: examinations under scrutiny.
PMID- 9394066
TI - A survey of Irish palliative care services.
AB - There has been no national policy directing the development of palliative care
services in Ireland. Over the last 25 years different palliative care services
have been established around the country, due largely to a strong and concerted
effort on the part of voluntary groups. A study was carried out to determine the
structure and process of all adult palliative care services in Ireland, to
determine, where possible, the costs of providing these services and to assess
the need for palliative care services in Ireland. All adult palliative care
services (24 home care services, three inpatient services and one acute hospital
service) in existence at the end of 1993 were circulated and 26 returns received
(response rate 93 per cent). Twenty-five counties were covered by palliative care
services, serving approximately three-quarters of the national population. Less
than 10 per cent of patients had non-cancer diagnoses. Wide variation in staffing
levels, workload, travelling, assessment of need and finance arrangements was
reported. There is a need for further debate on the breadth and scope of
palliative care services that should ideally be provided in Ireland, and how they
should be funded in the future.
PMID- 9394065
TI - The role of surgery and laser ablation in oesophageal carcinoma.
AB - Between January 1990 and December 1994 oesophagectomy was carried out in 42
patients and comparison made with 38 who had palliative laser therapy. Apart from
six patients referred after being unresectable at surgical exploration there were
no agreed selection criteria, although the laser patients were in general older
(mean 64 V 73 year) with a higher proportion of cardiorespiratory co-morbidity
(14 per cent V 18 per cent). Lateral margins were involved in 14 per cent of
known palliative resections with 50 per cent having positive nodes. The mean
operating time was three hours and two chest drains inserted electively were
removed after 3.6 days with mean drainage of 817 ml. The mean ICU stay was 5.4
days and 3 had radiological leaks; all but one settled conservatively. The 90 day
mortality was 11.9 per cent for surgery and 34 per cent for laser patients.
Twenty-three patients (61 per cent) required further courses of laser-therapy for
benign anastomotic stenosis. Including the initial treatment of both groups 6.0
procedures per patient year were required in the laser groups compared with 1.1
for surgery. The 1, 2 and 3 year survival was 60 per cent, 31 per cent, 39 per
cent for surgery compared with 24 per cent, 8 per cent, 3 per cent for laser--12
surgical patients are still alive and well at mean of 29 months (range 16-68).
Surgery where possible with acceptable morbidity and mortality offers good
palliation and long-term survival is possible; selection criteria for palliation
only need to be defined.
PMID- 9394067
TI - Irish surgeons and the Victoria Cross.
PMID- 9394068
TI - Mucin-like carcinoma associated antigen (MCA) at presentation with breast cancer.
AB - The usefulness of serum measurements of mucin-like carcinoma associated antigen
(MCA) in 100 women at presentation with breast cancer was evaluated. Peripheral
venous blood was drawn and MCA values determined by radioimmunoassay. Twenty
women presenting with benign breast disease and 20 normal women served as
controls. There was no difference in the MCA values between the benign breast
disease group and the normal group: 4.1 +/- 0.9 units/ml versus 5.0 +/- 0.75
units/ml (mean +/- sem). The following were the MCA values for patients by stage;
stage 1: 11.2 +/- 1.02, stage 2: 11.0 +/- 1.29, stage 3: 20.2 +/- 6.7, stage 4:
31 +/- 5.0. Statistical analysis of stage versus controls showed significant
elevations only in stage 3 and 4 disease (p < 0.05). We conclude that MCA may be
a useful serum tumour marker only in advanced breast cancer but is unreliable in
detection of early breast cancer.
PMID- 9394069
TI - Video-assisted thoracic surgery (VATS) for spontaneous pneumothorax.
AB - Video-assisted thoracic surgery (VATS) involves using a thoracoscope with a
camera chip attached to a video monitor which allows certain thoracic procedures
to be performed with limited incisions. Using VATS, 170 procedures have been
performed on 158 patients including 42 procedures on 39 patients with spontaneous
pneumothorax. There were 24 males and 15 females with age ranging from 17 to 84
yr (mean 36.7). Indication for operation included recurrent pneumothorax in 20
(51 per cent), persistent pneumothorax in 16 (41 per cent) and bilateral
pneumothorax in 3 (8 per cent). The main therapeutic strategies were apical
pleurectomy, in all (42) and blebectomy/bullectomy in 38 (90 per cent). There was
one hospital death (hospital mortality 2.5 per cent) in an elderly patient who
developed multi organ failure post bullectomy and persistent air leak. One
patient (2.5 per cent) required conversion to formal thoracotomy. Mean post
operative chest tube duration was 2.7 days and mean post-operative hospital stay
was 5.1 days. There has been no recurrence of pneumothorax in this series during
short term follow up (mean 18 months). Our experience indicates an expanding role
for video-assisted thoracic surgery in the management of patients with
spontaneous pneumothorax.
PMID- 9394070
TI - Dietary intakes in Ireland of a healthy elderly population.
AB - The aim of this paper is to assess the adequacy of the diet of individuals over
60 yr of age, participating in the 1990 Irish National Nutritional Survey. A
nationwide random sample based on the most recently updated electoral register
was used. Demographic information was collected. Anthropometric measurements were
taken and nutrient intake was assessed using the 7-day dietary history method.
The randomly selected sample of 1213 subjects was considered to be representative
of the Irish population. Of those selected, 163 individuals were over 60 yr of
age, 79 of whom were male and 84 female. Mean energy intakes including alcohol
for males and females were 9.55 +/- 3.09MJ and 7.07 +/- 2.39MJ respectively. The
main sources of energy were bread, meat and meat products, potatoes and milk. As
percentage energy, protein, fat and carbohydrate intakes were 14.90 per cent,
33.97 per cent and 48.22 per cent for men and 15.39 per cent, 34.09 per cent and
49.37 per cent for women respectively. Except for vitamin D and folate,
micronutrient intakes were adequate. The body mass index (BMI [weight/height2]
kg/m2) for men was 25.6 and for women 26.4. Fewer than 27.8 per cent of the males
and 20.2 per cent of females take part in regular physical activity. In
conclusion, the diet of a healthy elderly population in Ireland is nutritionally
adequate with macronutrient intake in keeping with the recommended guidelines.
Overall energy intakes are lower than those of a younger age group and may
account for the lower intakes of certain micronutrients. An increase in fruit and
vegetable consumption would improve vitamin and mineral intake. In order to allow
for a higher energy intake an increase in physical activity is desirable.
PMID- 9394071
TI - Evaluation of lifestyle, food consumption and nutrient intake patterns among
Irish teenagers.
AB - Lifestyle, food consumption and nutrient intake patterns from a randomly selected
group of 390 secondary pupils aged between 12-18 were evaluated. Demographic
information and anthropometric measurements included weight, height, and skinfold
thickness were taken. Nutrient intake was assessed using the 7-day dietary
history method, using a photographic atlas as an aid. Mean energy intakes for
boys and girls aged 12-15 and 15-18 were 11.3MJ and 14MJ and 9.1MJ and 8.9MJ
respectively. As percentage energy, protein fat and carbohydrate intakes varied
little between the different age-sex groupings and were approximately 13.7-14.5,
35.4-37 and 46.8-50 per cent respectively. For boys micronutrient intake for iron
and folate achieving only 83 and 78 per cent and 98 and 90 per cent of the
recommended nutrient intake (R.N.I.) for ages 12-15 and 15-18 respectively. Mean
dietary fibre intakes were approximately 19.6-25g/day for boys aged 12-18 and
17g/day for girls of a similar age. The main sources of energy were bread, meat
and meat products, potatoes/chips, confectionery and preserves. Fruit and
vegetable consumption was low for all groups. The majority of those surveyed
consumed the traditional main meals. Snacking was also common practice. The snack
foods consumed were generally of a high fat/high sugar content. 1.1 per cent boys
and 2.6 per cent of girls aged 12-15 and 5.5 per cent and 8.2 per cent of boys
and girls aged 15-18 respectively had a BMI greater than 26 indicating a risk of
overweight. Greater than 68 per cent of girls and 79.5 per cent of boys surveyed
participated in some form of sport. Boys were more physically active than girls
and older girls less active than younger. In conclusion, changes from present day
practices would be beneficial to reduce incidence of chronic disease for present
day teenagers.
PMID- 9394072
TI - Acute bacterial meningitis in adults: analysis of 218 episodes.
AB - A retrospective study was conducted to examine the laboratory, clinical features
and outcome of 206 adult acute bacterial meningitis patients (218 episodes)
during the years 1985-1996. Pneumonia (8.7 per cent), head trauma (7.8 per cent)
and chronic otitis media (6.0 per cent) were identified as the main predisposing
factors for acute bacterial meningitis. Aetiology was described only in 61
episodes (28.0 per cent). Streptococcus pneumonia was the most commonly
identified pathogen overall, causing 33 of the 218 episodes (15.2 per cent).
Antibiotic treatment before admission was given to 48.4 per cent of patients. On
admission, the following symptoms of meningitis were predominant: 83 per cent had
neck stiffness, 81 per cent had a headache and 73 per cent had fever. Case
fatality rate was 27.1 per cent (59 patients). The important factors in mortality
were as follows: old age, a long duration of symptoms before admission, a lack of
neck stiffness, obtunded mental state on admission, low glucose levels in first
CSF, low CSF/blood glucose ratio, and abnormality in computerised tomography
scanning.
PMID- 9394073
TI - HIV risk behaviour in Irish intravenous drug users.
AB - The aim of the study was to measure HIV prevalence and risk behaviour in 185
Irish Intravenous Drug Misusers. Information was obtained by application of a
standardised WHO questionnaire covering HIV risk behaviour in the preceding 6
months. HIV serostatus was obtained by saliva/blood sample testing. One hundred
and 3 (55.7 per cent) shared and 114 (61.6 per cent) lent used injecting
equipment in the previous 6 months. 97 (94.2 per cent) of those who shared always
cleaned the needles before use but only 48 (49.5 per cent) of these always
cleaned in an efficient manner. One hundred and 14 (79.2 per cent) males and 28
(68.3 per cent) females reported heterosexual activity in the preceding 6 months.
On examination sexual risk behaviour was found to be high. 50.5 per cent of males
and 63 per cent of females never used condoms with regular partners. 32.6 per
cent of males never used condoms with casual partners. The large majority of
partners of male I.D.U'.s (both regular and casual) were non injectors. Therefore
there is potential for sexual spread of HIV into the non-injecting heterosexual
population. Conversely the vast majority of partners of female IDU's were
injectors. This suggests that female IDU's are at higher risk of HIV infection
than their male counterparts. HIV prevalence in the study group was 8.4 per cent.
Implications of results for future intervention are discussed.
PMID- 9394074
TI - Carbimazole induced agranulocytosis: rescue with human recombinant granulocyte
colony stimulating factor.
AB - We report on a 25 yr old woman with primary autoimmune hyperthyroidism who was
treated with carbimazole. Forty-three days later she developed agranulocytosis
(64 x 10(6)/l). With 4 days treatment with recombinant human Granulocyte Colony
Stimulating factor the granulocyte count rose to normal--4,350 cells x 10(6)/l.
This is considerably faster than the rate of spontaneous recovery which usually
takes one to 2 weeks.
PMID- 9394075
TI - Dermatitis Herpetiformis: a review of fifty-four patients.
AB - A review of 54 patients with dermatitis herpetiformis presenting between 1984
1993 to The Regional Centre of Dermatology, Mater Misericordiae Hospital was
undertaken. All patients had skin lesions clinically and histologically typical
of dermatitis herpetiformis. Deposition of granular IgA at the dermoepidermal
junction on direct immunofluorescence was present in each case. The average age
of onset was 41.8 yr, patients having symptoms for an average of 1.6 yr before
diagnosis. Six patients had a prior history of coeliac disease. Two patients had
a family history of dermatitis herpetiformis, a father and son who were both
propositi in this study. Small bowel biopsy was performed on 35 patients, 71.4
per cent of them showing evidence of villous atrophy. All patients were
controlled on a gluten free diet or by dapsone or a combination of these. None of
the patients experienced serious adverse effects of therapy, nor did any develop
lymphoma of the small bowel with a mean follow up period of 4.2 yr (range 1-10
yr).
PMID- 9394076
TI - Renal transplantation performed across a positive crossmatch: a single centre
experience.
AB - The importance of certain positive crossmatches (CM+) in kidney transplantation
remains controversial. Fifty consecutive kidney transplants were performed across
a CM+ between Jan. 1990-April 1994. In 19 cases there was an isolated B-cell CM+
(Group I), in 24 an historic T-cell IgM CM+ (Group II) and in 7 an historic T
cell IgG CM+ (Group III). Comparing groups I:II:III: early acute rejection
affected 32%, 42%, 57% of grafts; mean serum creatinine at 3 months was 166, 150,
229 umol/l (p < 0.05); 1 yr graft survival was 95 per cent, 96 per cent, 71 per
cent (p = 0.09). In group III both graft losses were in the setting of an
additional current B-cell CM+. CONCLUSIONS: Transplantation performed in either
the presence of an isolated B-cell CM+ or in the presence of an historic T-cell
IgM CM+ was associated with acceptable outcomes at 1 yr. An historic T-cell IgG
CM+ was confirmed as a contraindication to transplantation in most circumstances,
especially when coupled with a current B-cell CM+.
PMID- 9394078
TI - The Melkersson Rosenthal syndrome--a differential diagnosis of facial
sarcoidosis.
PMID- 9394077
TI - A comparison of regular with intermittent bronchodilators in asthma patients on
inhaled steroids.
AB - The aim of this study was to compare the effect of regular versus intermittent
(p.r.n.) bronchodilators on bronchial reactivity and asthma control in patients
on concomitant inhaled corticosteroids. We studied 12 patients with asthma in a
prospective, randomised, single-blind, single-dummy, three-period crossover trial
comparing placebo (2 puffs t.d.s.), salbutamol (200 micrograms t.d.s.) and
oxitropium bromide (200 micrograms t.d.s.) for 28 days each. Computerised
spirometry and bronchial reactivity to histamine were obtained on entry and after
each treatment period. Symptom scores, use of rescue bronchodilator and peak
expiratory flow rates were recorded daily. There were no significant differences
in bronchial hyperreactivity between the salbutamol, oxitropium and placebo
treatment periods. There were no significant differences in baseline FEV1, FEF25
75%, symptom scores, use of rescue bronchodilator or morning and evening PEFR
between treatment periods. Intermittent beta agonist therapy is as effective as
regular therapy in terms of asthma control and bronchial hyperreactivity in
patients on concomitant inhaled corticosteroid therapy. Since intermittent
therapy achieves similar results with significantly lower beta agonist
consumption, the data support current recommendations that beta agonists should
be taken on a p.r.n. basis in asthma patients on inhaled steroids.
PMID- 9394079
TI - Long-term efficacy of cyclical etidronate therapy in postmenopausal osteoporosis.
AB - Sixty-two women (mean age 68.7 +/- 0.9 yr) with postmenopausal spinal
osteoporosis were treated with cyclical etidronate therapy (400 mg for 2 weeks
alternating with 12 weeks of 1 gm elemental calcium and 400 IU Vitamin D3) for a
minimum of 2 yr. Bone mineral density (BMD) of the lumbar spine (g/cm2) increased
significantly (p < 0.0001) after yr 1 (4.1 +/- 0.5 per cent) and yr 2 compared
with yr 1 (2.2 +/- 0.5 per cent). The response rate was 89 per cent after yr 1
and 84 per cent after yr 2. BMD of the hip (30 patients) increased by 1.5 +/- 0.9
per cent after yr 1 and 5.5 +/- 1.1 per cent (p < 0.0001) after yr 2 when
compared with baseline. The response rate was 63 per cent after yr 1 and 80 per
cent after yr 2. Smaller numbers of patients continued with treatment up to 4 yr
with no adverse long-term effects.
PMID- 9394080
TI - Efficacy of combination therapy in non-insulin dependent diabetes mellitus.
AB - Secondary failure of oral hypoglycaemic agents raises the dilemma of whether to
institute therapy with insulin alone, or in combination. We reviewed our
experience of combination therapy following secondary failure of oral
hypoglycaemic therapy. Seventeen subjects were receiving combination therapy for
6 months or more. Such treatment was associated with a significant fall in HbA1C-
from 10.7 +/- 0.38 per cent to 8.3 +/- 0.35 per cent (p < 0.01) after 6 months
and remained significantly reduced at 12 months (8.7 +/- 0.34 per cent (p <
0.01)). Mean body weight, systolic and diastolic blood pressure were unchanged
during treatment with adjuvant insulin therapy. Insulin therapy is a useful
adjunct in the daily management of subjects with NIDDM who experience secondary
failure of oral hypoglycaemic agents.
PMID- 9394082
TI - Familial adenomatous polyposis registry in South Carolina.
PMID- 9394081
TI - Non-admitted elderly in the accident and emergency department.
AB - The aim of the study was to identify the functional disabilities and support
needs of elderly people who presented but were not admitted to a Dublin Accident
& Emergency (A & E) department within a 1 month period. Semi-structured
interviews were conducted with 19 per cent (100/532) of the non-admitted elderly
within 2 weeks of the A & E visit. Injury related complaints were apparent in 51
per cent of the patients with 3 per cent requiring hospital admission within 2
weeks of the A & E visit. Increased dependency in 1 or more Activities of Daily
Living (ADL) occurred in 10 per cent while 28 per cent had increased dependency
in 1 or more Instrumental Activities of Daily Living (IADL). Increased family
support following discharge was received by 45 per cent of the elderly. The most
commonly needed statutory service which was not provided was the home-help
service. This study provides baseline data on the non-admitted elderly in one
Dublin A & E department and should assist planning of future service.
PMID- 9394083
TI - Percutaneous method for internal jugular venous introduction and retroclavicular
placement of permanent endocardial leads.
PMID- 9394084
TI - Oocyte donation program: initial experiences at Southeastern Fertility Institute.
AB - From March 1994 to February 1996, 28 infertile couples participated in the oocyte
donation program in 33 treatment cycles at the Southeastern Fertility Institute.
Of the 31 cycles with embryo transfer, 15 cycles (48.4 percent) resulted in a
clinical pregnancy with fetal heart beat by ultrasound. The spontaneous first
trimester abortion rate was 3/15 (20 percent), multiple pregnancy rate 3/15 (20
percent), live birth rate 11/15 (73.3 percent) and delivery rate 12/15 (80
percent). It is recommended that oocyte donation procedure is a highly successful
treatment option for women with ovarian failure or repeated unsuccessful trials
of assisted reproductive technologies.
PMID- 9394085
TI - The origin of hemodialysis in South Carolina.
PMID- 9394086
TI - Complexity in health: race, gender, social support, and campus culture.
PMID- 9394087
TI - The effect of family and social support on feelings and past acts of violence
among African American college men.
AB - A sample of 1,874 male undergraduates in 11 predominantly African American
colleges and universities was surveyed to explore the effect of social support
and family factors on feelings and past acts of violence. The health of the
students' interpersonal relationships in the family during adolescence, as well
as the informational and emotional support from the students' mothers and
significant others, were found to be significantly associated with feelings of
violence and past acts of violence. Various strategies for reducing violence
among African American men, including violence-prevention programs at the college
level, for families, and for the community, are discussed. Changes in public- and
private-sector programs to reduce and prevent violence in American communities
are called for.
PMID- 9394088
TI - Health behaviors of students attending historically black colleges and
universities: results from the National College Health Risk Behavior Survey.
AB - The National College Health Risk Behavior Survey was administered to a
convenience sample of students at 8 historically Black colleges and universities
in 7 states. Analyses showed major differences in the men's and women's
responses. The men were significantly more likely than the women to be current
smokers. Also, they more frequently reported heavy drinking, drinking and driving
in the past days 30 days, and carrying a weapon. The women were significantly
more likely to view themselves as overweight, and more than one third reported
they were trying to lose weight. More than one third of the students had not
exercised or participated in sports activities for more than 20 minutes in the
past 7 days. Because historically Black colleges and universities educate the
majority of undergraduate Black college students, multidimensional programs to
promote disease prevention and health promotion for Black college students must
be expanded and evaluated.
PMID- 9394089
TI - How sleep deprivation affects psychological variables related to college
students' cognitive performance.
AB - The effects of sleep deprivation on cognitive performance psychological variables
related to cognitive performance were studied in 44 college students.
Participants completed the Watson-Glaser Critical Thinking Appraisal after either
24 hours of sleep deprivation or approximately 8 hours of sleep. After completing
the cognitive task, the participants completed 2 questionnaires, one assessing
self-reported effort, concentration, and estimated performance, the other
assessing off-task cognitions. As expected, sleep-deprived participants performed
significantly worse than the nondeprived participants on the cognitive task.
However, the sleep-deprived participants rated their concentration and effort
higher than the nondeprived participants did. In addition, the sleep-deprived
participants rated their estimated performance significantly higher than the
nondeprived participants did. The findings indicate that college students are not
aware of the extent to which sleep deprivation negatively affects their ability
to complete cognitive tasks.
PMID- 9394090
TI - College women's perceptions regarding resistance to sexual assault.
AB - College women's perceptions about resistance to sexual assault were examined.
Twenty-one percent of the 334 women surveyed stated that they had been sexually
assaulted. The vast majority of participants had changed their lifestyles to
prevent a sexual assault. Less than 1 woman in 5 of those surveyed had taken a
self-defense class. Participants believed that resisting sexual assault by a
stranger with a weapon was more likely than resisting an unarmed attacker to
increase their chances of being physically harmed, raped, or murdered. Twenty-two
percent of the participants said they were "very likely" to resist sexual assault
by a stranger with a weapon; 52% would resist a stranger without a weapon. The
findings indicate the need for an increase in the number of women taking self
defense classes and a revision in women's perceptions about resisting sexual
assault.
PMID- 9394091
TI - Cessation related perceptions and behavior of former and current smokeless
tobacco users.
AB - Four hundred fourteen former and 73 current users of smokeless tobacco were
questioned about their experiences in giving up smokeless tobacco. Their
responses were compared with those of 463 ex-smokers to determine whether former
smokeless tobacco users differed from former smokers in using specific cessation
techniques. Of the smokeless tobacco users, 77% were interested in quitting, but
only 7% wanted to quit "now." Seven percent of the daily users reported that a
college-based health or fitness professional had advised them to quit. Former
smokeless tobacco users were significantly more likely than former smokers to
report that smoking cigarettes was related to their efforts to give up smokeless
tobacco than former smokers were to report using smokeless tobacco as a strategy
to stop smoking, Former smokeless tobacco users were also significantly more
likely than former smokers to report current tobacco use. Smokeless tobacco
cessation programs based on the transtheoretical approach to behavior change are
recommended.
PMID- 9394092
TI - Health discussions between college students and parents: results of a Delphi
study.
AB - College students' perspectives on health discussions with parents were examined
in a survey of students from 5 US universities. Topics important for promoting
students' and parents' health as well as guidelines for promoting productive
discussions between college students and their parents were identified, using the
Delphi technique to reach consensus. Sex, drugs, alcohol, and HIV/AIDS ranked as
the most important discussion topics related to students' health; family
relationships, physical fitness, and stress management ranked as most important
topics dealing with parental health. Guidelines for profitable discussion were
that the individual be honest, open, respectful of others' opinions, and a good
listener. Parent education, health education activities that promote student
parent discussion, and further research on the topic are suggested.
PMID- 9394093
TI - Frank B. Cerra, MD.
AB - Though the effects of managed care can be seen all across the country, the state
of Minnesota has clearly been in the forefront of change. While this has
presented an opportunity to be on the leading edge of health reform, it has also
had a revolutionary impact on all previously held ways of doing business. A long
time faculty member at the University of Minnesota Frank Cerra was named Dean of
the medical school in May of 1995, a time which found the University of Minnesota
Hospital in a precarious position. The day-to-day financial workings of the
institution soon became his major focus and in 1997 he became the Senior Vice
President for Health Sciences. In this position much of the restructuring and
strategic planning of the school is now under his supervision, and he has dealt
with several daunting challenges both within the school and the state.
Interviewed in his office in Minnesota, Cerra candidly reflected on the power of
market-based health reform the frustrations involved in turning a slow moving
public institution towards the future.
PMID- 9394094
TI - Ethical and regulatory challenges in a randomized control trial of adjuvant
treatment for breast cancer in Vietnam.
PMID- 9394095
TI - Cyclic AMP-mediated signal transduction in heart failure: molecular
pathophysiology and therapeutic implications.
PMID- 9394096
TI - Testosterone suppression of the HPT axis.
AB - BACKGROUND: Although studies have demonstrated the suppression of normal gonadal
function in the experimental setting, the specific mechanisms by which androgenic
anabolic steroids impact male gonadal function remain ill defined. Following 2
consecutive weekly injections of an identically appearing testosterone cypionate
(TC) placebo, subjects were randomized to a TC dose of 100 mg/wk, 250 mg/wk, or
500 mg/wk. Following the last weekly injection of active agent the subjects
received 12 consecutive weeks of TC placebo injections. RESULTS: Spermatogenesis
was impaired by each of the doses of TC employed in this study, but the observed
decreases in, sperm count were neither strictly dose dependent nor consistent
between individuals treated with the same dose. Basal leuteinizing hormone (LH)
and follicle stimulating hormone (FSH) became undetectable 2 weeks after the
start of 250 and 500 mg/wk TC injections and were lost within 5 to 6 weeks of
starting 100 mg doses. Pituitary gonadotropin responses to leutinizing hormone
releasing hormone (LHRH) disappeared more slowly with FSH responses being lost 1
to 3 weeks after the loss of basal FSH activity. Leuteinizing hormone responses
to LHRH appeared to be suppressed last, disappearing 4 to 6 weeks after FSH
responses to LHRH. CONCLUSIONS: Exogenous testosterone-mediated inhibitory
influences on the hypothalamic-pituitary-testicular axis were reversed following
the cessation of drug treatment.
PMID- 9394097
TI - SPECT-evaluation of the monoamine uptake site ligand [123I](1R)-2-beta
carbomethoxy-3-beta-(4-iodophenyl)-tropane ([123I]beta-CIT) in untreated patients
with suspicion of Parkinson disease.
AB - BACKGROUND: For a few years, data on SPECT-imaging of dopamine transporters with
the cocaine derivate [123I](1R)-2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane
([123I] beta-CIT) have been reported mostly in healthy subjects or animals. This
study reflects our preliminary results with SPECT-imaging of dopamine
transporters using the cocaine analogue 123-beta-CIT in patients with untreated
(de novo) parkinsonism. METHODS: In 33 patients with clinical suspicion of
Parkinson disease and 5 healthy controls, SPECT-imaging of dopamine transporters
was performed 1, 4, and 24 hours after injection of 180 MBq of 123I-beta-CIT,
which was generated by iododestannylation. None of the patients or controls had
been treated before with neuroleptical drugs or any other pharmaceuticals with
known binding to the dopamine transporters. Clinical symptoms were staged by the
scales Hoehn-Yahr (HYS), Unified Parkinson Disease Rating Scale (UPDRS), and the
self-rating scale of Beck depression inventory (BDI). For evaluation,
striatal/cerebellar ratios were calculated to every time point. RESULTS:
Significant correlations of 123I-beta-CIT uptake could be stated compared to
UPDRS, HYS, and BDI values (Spearman correlation, p < 0.05). The symptoms of
rigor and akinesia showed a significant correlation with the beta-CIT uptake,
whereas the symptom of tremor failed, which may be caused by the location of
tremor symptoms out of the striatum. Comparing the controls, a significant (p <
0.01) decrease of tracer uptake in parkinsonian patients is stated on the images
at 24 hours p.i. In our patients, tracer uptake does not depend significantly on
duration of disease and age. CONCLUSION: 123I-beta-CIT seems to be a promising
tool in imaging of untreated parkinsonian patient.
PMID- 9394099
TI - Immunophenotyping as a diagnostic tool to differentiate lichen planus from
chronic graft-versus-host disease: diagnostic observations on two patients.
AB - BACKGROUND: Lichen planus (LP) and the lichenoid variant of chronic graft-versus
host disease (cGVHD) can present with similar clinical and histological findings.
The distinction, although difficult, is important both prognostically and
therapeutically. The mechanism and effector cell phenotypes have also shown to
differ between the 2 entities. While the lichenoid infiltrate of LP is
predominantly T lymphocytes helper/inducer cell phenotype, the
suppressor/cytotoxic subset appears to play a major role in cGVHD. The aim of
this study is to determine whether the immunophenotypic character of the
lichenoid infiltrate can aid in distinguishing the 2 entities. METHODS: Biopsies
were obtained from 2 patients with lichenoid papules and a history of
transplantation. Light microscopy revealed lichenoid inflammation in both cases
characterized by a band-like lymphohistiocytic infiltrate at the dermal-epidermal
junction. Immunochemistry was performed on fresh tissue using a panel of
monoclonal antibodies including anti-CD1a, CD3, CD4, CD8, CD16, CD20, CD28, and
CD68. Results were quantitated using computer-assisted image analysis. RESULTS:
We found that in both cases the majority of cells stained with pan T cell marker
CD3+. One case demonstrated predominantly CD4+ T cells and increased numbers of
CD1a positive Langerhans cells, while the lymphokine natural killer cell activity
(LAK) markers anti-CD16 and anti-CD28 were largely nonreactive. Conversely, the
second case contained predominately CD8+ lymphocytes and very few CD1a positive
Langerhans cells with abundant LAK cell anti-CD16 and anti-CD28 reactivity.
CONCLUSIONS: Based on these findings, the former was classified as lichen planus
and the latter as lichenoid cGVHD. The diagnoses are substantiated with clinical
history and follow-up information. We conclude that immunophenotypic
characteristics of the infiltrate can be a useful tool in differentiating
lichenoid cGVHD from lichen planus.
PMID- 9394098
TI - Cardiac high-energy phosphate metabolism in patients with aortic valve disease
assessed by 31P-magnetic resonance spectroscopy.
AB - BACKGROUND: The purpose of this work was to determine the clinical and
hemodynamic correlates of alterations in cardiac high-energy phosphate metabolism
in patients with aortic stenosis and with aortic incompetence. METHODS: Fourteen
volunteers, 13 patients with aortic stenosis, and 9 patients with aortic
incompetence were included. Patients underwent echocardiography and left and
right heart catheterization. 31P-MR spectra from the anterior myocardium were
obtained with a 1.5 Tesla clinical MR system. RESULTS: Aortic stenosis and aortic
incompetence patients had similar New York Heart Association (NYHA) classes (2.77
+/- 0.12 vs 2.44 +/- 0.18), ejection fractions (normal), left ventricular (LV)
end-diastolic pressures, and LV wall thickness. In volunteers,
phosphocreatine/adenosine triphosphate (ATP) ratios were 2.02 +/- 0.11. For all
patients, phosphocreatine/ATP was significantly reduced (1.64 +/- 0.09; *p =
0.011 vs volunteers). Phosphocreatine/ATP decreased to 1.55 +/- 0.12 (*p = 0.008)
in aortic stenosis, while in aortic incompetence, phosphocreatine/ATP only showed
a trend for a reduction (1.77 +/- 0.12; p = 0.148). For all patients,
phosphocreatine/ATP decreased significantly only with NYHA class III (1.51 +/-
0.09; *p = 0.001), but not with NYHA classes I and II (phosphocreatine/ATP 1.86
+/- 0.18). In aortic stenosis, phosphocreatine/ATP ratios decreased (1.13 +/-
0.03; *p = 0.019) only when LV end-diastolic pressures were > 15 mm Hg or when LV
diastolic wall stress was > 20 kdyne cm-2 (1.13 +/- 0.03; *p = 0.024).
CONCLUSIONS: For a similar clinical degree of heart failure in human myocardium,
volume overload hypertrophy does not, but pressure overload does, induce
significant impairment of cardiac high-energy phosphate metabolism. In aortic
valve disease, alterations of high-energy phosphate metabolism are related to the
degree of heart failure.
PMID- 9394100
TI - The need for inotropic support in a subgroup of infants with severe life
threatening respiratory syncytial viral infection.
AB - BACKGROUND: We experienced an unusual complication of life-threatening
respiratory syncytial viral disease cardiovascular compromise. Life-threatening
respiratory syncytial virus (RSV) infection has predominancy involved with
ventilatory support for respiratory distress and/or failure. We performed a
retrospective chart review of 20 consecutive infants admitted to the pediatric
intensive care unit (PICU) for impending respiratory failure. METHODS: Seventeen
required ventilatory support. As part of the infants' initial assessment, blood
pressure, distal perfusion [capillary refill time (CRT) > or = 3 sec], decreased
peripheral pulses, and peripheral mottling were used to determine cardiovascular
compromise. These infants received volume resuscitation either at the referring
facility or the PICU until euvolemia was obtained, as determined by central
venous pressure (CVP) monitoring (between 3 to 7 cm H20). Nine of the 20 infants
did not respond to volume resuscitation alone and required vasopressor support in
the form of: Dopamine (7 patients, 5-10 micrograms/kg/min), Dobutamine (2
patients, 5-7 micrograms/kg/min), and one who expired required both Epinephrine
(600 ng/kg/min) and Dopamine (10 micrograms/kg/min). The mean ages of these 9
patients were 6.2 +/- 3.4 weeks (range 3-12 weeks), the mean duration of
ventilation was 7.2 +/- 4.1 days (range 4-12 days). The mean duration of
pharmacologic support was 69.7 +/- 47 hours (range 14-168 hours). The mean ages
of RSV+ infants not requiring inotropic support was 19.4 +/- 27.4 weeks (range 1
90 weeks), and mean duration of ventilation was 5.5 +/- 5.9 days (range 2-20
days). RESULTS: The inotrope treated patients were weaned from pharmacologic
support prior to extubation, without any hemodynamic deficits. Our experience
with this rather high incidence of hemodynamic complications during this RSV
epidemic was unexpected. CONCLUSION: These results substantiate the fact that
younger patients with RSV disease are at both greater risk for pulmonary
complications and cardiovascular deterioration and may thus benefit from
pharmacologic support.
PMID- 9394101
TI - Interleukin-1 response to arterial antigen, lipopolysaccharide, and oxidized low
density lipoprotein in ischemic heart disease.
AB - Monocytes responding to oxidized low density lipoprotein (LDL) or other antigens
may initiate atherogenesis through production of interleukin-1 (IL-1) and
additional cytokines. Interleukin-1 is chemotactic for circulating leukocytes,
can stimulate growth of fibroblasts or smooth muscle cells, and causes activation
of T- and B-lymphocytes. METHODS: Peripheral blood mononuclear cells (PBMCs) were
isolated from 42 patients with angiographically verified ischemic heart disease
(IHD) and 35 age-matched control subjects without a history of cardiac disease.
Rates of proliferation and production of IL-1 beta were measured after peripheral
blood mononuclear cells were cultured for 7 days in the presence of mitogens,
arterial antigen, lipopolysaccharide, or native and oxidized forms of LDL.
RESULTS: In patients with IHD, proliferation in response to arterial antigen was
either diminished or unchanged from control values. Peripheral blood mononuclear
cells from IHD and control patients had similar levels of proliferation after
treatment with different mitogens. Levels of IL-1 beta, produced after
stimulation with arterial antigen or lipopolysaccharide, also did not differ for
PBMCs obtained from control and IHD patients. For patients with either a stable
angina pattern or no history of cardiac disease, PBMC cultured in the presence of
native and oxidized forms of LDL released similar amounts of IL-1 beta. In
contrast, PBMCs from 4 patients with unstable angina had increased levels of IL-1
beta after culture in the presence of oxidized LDL (group means +/- standard
deviation of 1.63 +/- 1.08 pg/mL for 17 control patients, 0.96 +/- 0.23 pg/mL for
4 cases with stable angina, and 4.02 +/- 5.91 pg/mL, for 19 cases with unstable
angina). These values reflect a greater than 5-fold increase in variability for
IL-1 beta produced on exposure to oxidized LDL for patients with unstable angina
relative to control patients. CONCLUSIONS: Effects of in vitro stimulation with
mitogens or lipopolysaccharide are similar for PBMC obtained from normal or IHD
patients. The response to arterial antigen is also not increased in cells from
patients with IHD. However, PBMCs obtained from a subset of patients with
unstable angina produce greater levels of IL-1 beta after treatment with
oxidized, but not native, LDL.
PMID- 9394102
TI - Gastric myoelectrical activity, gastric emptying and correlations with dyspepsia
symptoms in patients with gastroesophageal reflux.
AB - BACKGROUND: Delayed gastric emptying is a mechanism that contributes to the
pathogenesis of gastroesophageal reflux. Electrogastrogram changes, gastric
emptying rates, and Helicobacter pylori status were investigated, and a
correlation was sought with dyspepsia symptoms in gastroesophageal reflux disease
patients. METHODS: Fifty patients (27 females; mean age 43) with gastroesophageal
reflux were studied. Electrogastrographic recordings were obtained 30 minutes
before and simultaneously with a 2-hour radionuclide gastric-emptying test using
an isotope-labeled solid meal. Symptoms of nausea, abdominal bloating, abdominal
pain, and early satiety were graded from 0 to 5. RESULTS: Thirty-six percent of
patients had delayed gastric eliminating. Thirty-eight percent (19/50) patients
had abnormal electrogastrograms, and 11 of these 19 also had delayed gastric
emptying. There was a significant difference in the electrogastrographic
parameter of postprandial power change in patients with delayed versus normal
gastric emptying (0.20 +/- 0.8 dB vs 3.17 +/- 0.8 dB, p < 0.05). In patients with
an abnormal electrogastrogram, the mean symptom score was significantly higher
than in patients with a normal electrogastrogram (2.18 +/- 0.26 vs 1.35 +/- 0.16,
p < 0.05). Twenty-one percent (7/33) of patients were positive (+) for
Helicobacter pylori overall, but this did not seem to affect electrogastrogram
and gastric emptying findings. CONCLUSIONS: Fifty-two percent of gastroesophageal
reflux disease patients have gastric motor or myoelectrical abnormalities that
contribute to the pathogenesis of this entity and also help explain the high
prevalence of dyspepsia in the clinical presentation of gastroesophageal reflux
disease.
PMID- 9394103
TI - Differences in the course of alcohol withdrawal in women and men: a Polish
sample.
AB - A retrospective study compared the course of alcohol withdrawal, including
delirium tremens, in women and men hospitalized in the Nowowiejski Hospital in
Warsaw from 1973 to 1987. Medical records pertaining to 1179 patients were
analyzed; 13.8% of these patients were women and 86.2% were men. The study showed
that women began intensive alcohol drinking later than men (p < 0.0001), but the
period between the onset of alcohol abuse and the first occurrence of alcohol
withdrawal was shorter in women than in men (p < 0.0001). In the period of heavy
drinking before hospitalization, women consumed significantly less alcohol then
men (p < 0.0001); moreover, women drank nonbeverage alcohol less frequently than
men (p < 0.05). Women were hospitalized substantially longer than men (p <
0.0001), whereas the duration of alcohol withdrawal symptoms at the time of
hospitalization was comparable in both groups. Withdrawal seizures were
significantly more frequent among men than among women (p < 0.001). Significant
differences in the patients' somatic conditions were not noted between the
groups, with the exception of anemia and decreased potassium concentration, which
were more frequently observed in women (both p < 0.0001), and of increased
concentration of ALT and hypoproteinemia, which were more frequent in men
(respectively, p < 0.05 and p < 0.01). Co-existing personality disorders,
depressive disorders, and anxiety disorders--as well as abuse of benzodiazepines
and barbiturates--were more frequently observed in women (p < 0.0001). The period
between the first hospitalization due to alcohol withdrawal and the time of death
was significantly shorter in men than in women (p < 0.05). The results point to
differences in the conditions and the course of alcohol dependence and alcohol
withdrawal between women and men.
PMID- 9394104
TI - Association analysis of a regulatory variation of the serotonin transporter gene
with severe alcohol dependence.
AB - The present study tested the hypothesis that the short, low activity variant of a
biallelic polymorphism in the 5' regulatory region of the human serotonin
transporter (5-HTT) gene confers susceptibility to severe alcohol dependence
marked by severe withdrawal symptoms. Applying a phenotype-genotype strategy, our
population-based association analysis included 216 German controls and an extreme
sample of 103 severely affected alcoholics who were selected from 315 German
alcohol-dependent subjects by a history of alcohol withdrawal seizure or
delirium. The frequency of the short allele (S) was significantly increased in
the severely affected alcoholics, compared with that in the controls (X2 = 3.87,
df = 1, nominal p = 0.049). The post-hoc exploration indicated that this allelic
association resulted exclusively from a significant excess of the S/S genotype in
the severely affected alcoholics (p = 0.035), suggesting a recessively acting
effect. Consistently, we found a weak but significant correlation (p = 0.013)
between the frequency of the S/S genotype and severity of withdrawal symptoms
(WDS): no WDS [18.3%, odds ratio (OR) = 1.16], vegetative WDS only (21.8%, OR =
1.44), and severe WDS with either withdrawal seizure only or delirium only
(25.0%, OR = 1.69), and both withdrawal seizure and delirium (30.8%, OR = 2.30).
Further studies are required to test whether the tentative genotype-phenotype
relationship occurred by chance or reflects a real genotypic association between
a recessively modifying effect of the short variant of the functional 5-HTT
promoter polymorphism and alcohol withdrawal vulnerability.
PMID- 9394105
TI - Gastric ethanol metabolism and gastritis: interactions with other drugs,
Helicobacter pylori, and antibiotic therapy (1957-1997)--a review.
AB - The stomach provides some protection against the penetration of ethanol into the
body by contributing to the metabolism of ethanol. The latter is attenuated by
various drugs and, although the magnitude of this effect is still the subject of
debate, patients should be warned of the corresponding possible increase in blood
alcohol levels. Furthermore, oxidation of ethanol generates acetaldehyde, a toxic
metabolite. In addition, chronic alcohol abuse seems to favor colonization by
Helicobacter pylori, which produces ammonia that also contributes to the commonly
associated chronic gastritis. Because antibiotics were shown over the last 4
decades to effectively eliminate gastric ammonia, they should be considered for
the routine treatment of such chronic gastritis in the way they are now being
used for ulcer therapy.
PMID- 9394106
TI - Effect of treatment with paromomycin on endotoxemia in patients with alcoholic
liver disease--a double-blind, placebo-controlled trial.
AB - The results of experimental and clinical studies support the hypothesis that gut
derived endotoxins might be of relevance for the development and course of
alcoholic liver disease. The aim of this study was to test the effect of a
nonabsorbable, broad-spectrum antibiotic on endotoxemia in patients with
alcoholic liver disease. Fifty patients with alcoholic liver disease (27 with
cirrhosis, 23 without cirrhosis) were randomly assigned to receive either
paromomycin sulfate (3 x 1 g/day) or placebo in a double-blind fashion for at
least 3 weeks, and if possible 4 weeks. Endotoxin concentration, liver function
tests, and other laboratory parameters were determined in weekly intervals.
Endotoxin concentration was also determined in 15 healthy controls. Groups
receiving paromomycin or placebo were similar for clinical and biological items
collected initially. Mean initial endotoxin concentrations were significantly
elevated in both groups (mean +/- SEM; paromomycin, 16.7 +/- 5.3 pg/ml; placebo,
17.5 +/- 6.9 pg/ml; healthy controls, 2.3 +/- 0.4 pg/ml). Although the mean
endotoxin concentration was lower in the verum group after 1 week (paromomycin,
8.0 +/- 1.9 pg/ml; placebo, 14.6 +/- 3.5 pg/ml; p > 0.05), paromomycin treatment
had no significant effect on endotoxin concentration or liver function tests
during the 4-week period. The beneficial effect of paromomycin treatment on
endotoxemia in cirrhotics reported in earlier studies could not be reproduced
under the conditions of this trial in patients with alcoholic liver disease.
PMID- 9394107
TI - Which relapse criteria best predict the mortality risk of treated alcoholics?
AB - We examined which relapse criteria best predict the mortality risk of treated
male alcoholics. The subjects were 172 male alcoholics who had previously been
hospitalized. Using three criteria which defined relapse as failure to maintain
abstinence from alcohol, alcohol abuse, or dependence, the relapse of each
subject had been evaluated during a previous 3-year outcome study. Relative
mortality risks in the next 3 years classified by the three relapse criteria were
compared. The follow-up rate was 93.6% and 31 subjects died. The age-corrected
relative mortality risk for subjects failing to maintain abstinence compared with
abstainers was 5.32, while the relative mortality risks for the group abusing
alcohol and for the group suffering alcohol dependence were 2.23 and 2.56,
respectively. These results suggest that relapse defined as failure to maintain
abstinence predicts a higher relative mortality risk than do criteria defining in
terms of alcohol abuse and alcohol dependence.
PMID- 9394108
TI - Predicting problem drinking: a test of an interactive social learning model.
AB - This study tested a social learning model and explored the direct and interactive
relationships between personality and environment in predicting problem alcohol
use. We used longitudinal data from a nonclinical sample of males and females
first tested in adolescence and followed into young adulthood. Hierarchial
regression analyses were used to test main effects and interaction models. The
cross-sectional data supported an interactive social learning model. Both
personality and environment variables significantly predicted problem drinking.
Two interactions between heavy drinking peer groups and personality variables
were significant. Contrary to our hypothesis, the direction of the interaction
was negative. In contrast, the longitudinal analyses did not provide strong
support for our interactive model. Personality variables were significant
predictors longitudinally, but in only one analysis did an environment variable
significantly predict problem drinking. Furthermore, none of the interactions was
significant predictors over time. Overall, the findings suggest that social
learning models based on the interaction of personality and environmental
influences may be more appropriate for predicting concurrent, as opposed to
future problems, and that future research should include person-environment
interactions. In addition, cultural tolerance of heavy drinking may be an
important determinant of the role of psychological vulnerability in the
development of problem drinking.
PMID- 9394109
TI - Comparison of screening instruments for alcohol problems between black and white
emergency room patients from two regions of the country.
AB - A number of brief screening instruments to identify alcohol dependence exist, but
the validity of these instruments across ethnic groups or regions of the country
is not well established. The sensitivity and specificity of a number of standard
screening instruments (CAGE, brief MAST, AUDIT, TWEAK, and RAPS), as well as
other measures (History of Trauma Scale, breathalyzer reading, self-reported
drinking before the event, and consuming five or more drinks at a sitting at
least monthly) are compared against ICD-10 and DSM-IV criteria for alcohol
dependence between probability samples of Black and White emergency room patients
in Santa Clara County, CA (n = 716) and in Jackson, MS (n = 1330). Variability in
the sensitivity of screening instruments among current drinkers was found to be
greater between samples for both Blacks and Whites, than for Blacks compared with
Whites within the same sample. The AUDIT, TWEAK, and RAPS seemed to perform well
by gender and injury status for both Blacks and Whites in the two samples, and no
significant differences were found in the performance of these instruments across
sample sites. To evaluate the influence of regional differences in alcohol
dependence on differences found in the performance of screening instruments,
using logistic regression with the simultaneous entry of demographic variables
(age, gender, ethnicity, injury status, and site) and drinking variables
(breathalyzer reading, self-reported drinking before the event, and drinking five
or more drinks at a sitting at least monthly) to predict alcohol dependence in a
merged sample of these patients (Jackson vs. Santa Clara) site was not found to
be significant. Data suggest that, whereas region of the country may not be
important in predicting alcohol dependence in emergency room populations,
regional differences in the performance of screening instruments for alcohol
dependence may exist, even when ethnicity is taken into account. Given distinct
regional differences in drinking patterns and problems in the U.S., further
research on commonly used screening instruments is needed to determine those
screeners most efficient for identifying problem drinking.
PMID- 9394110
TI - Neurophysiological correlates of response production and inhibition in
alcoholics.
AB - Scalp recordings of the P300 component of the event-related potential were made
from a group of medication-free, chronic male alcoholics and a control group,
participating in a visual Go/No Go reaction time paradigm. Subjects were
presented with large and small forms of the letters T and V. The large forms (Go
stimuli) required a button press with either the left or right hand, whereas the
small forms (NO Go stimuli) required response inhibition. Recordings were made
from 31 electrodes that, for statistical analyses, were grouped into five
regions: frontal, central, parietal, occipital, and temporal. The results
indicated that, in each of the five regions, both Go and NO Go response
amplitudes were larger in the controls than in the alcoholics. No group
differences in latency were observed in any region. Surface energy (Wang et al.,
Brain Topogr. 6:193-202, 1994) magnitudes paralleled P300 amplitudes and in the
controls, compared with the alcoholics, were larger during both Go and No Go
trials. Our findings suggest that abstinent, chronic alcoholics differ electro
physiologically from control individuals. These differences are manifested as
widespread reductions in P300 amplitudes during the performance of a simple
information processing paradigm. The reduced amplitudes may reflect a deficiency
in an inhibitory mechanism proposed to underlie P300 generation.
PMID- 9394111
TI - Voices of the afflicted.
AB - Over the past 10 years, I have been privileged to conduct educational forums for
audiences containing many recovering alcoholics or otherwise chemically dependent
persons. In these forums about the addictive diseases and their treatment and
research possibilities, significant interaction with the audience members occurs.
During these interactions, certain anecdotal phenomena seem to predominate. The
repetitive nature of these reports suggests the need for systematic
investigation. As with editorial comments in major medical journals, observed
phenomena and unanswered questions from those afflicted can be valuable in the
generation of testable hypotheses. Perhaps the ideas presented herein will be
useful in the development of future research on alcohol abuse and alcohol
dependence.
PMID- 9394112
TI - Effects of ethanol on rat Sertoli cell function: studies in vitro and in vivo.
AB - Chronic alcohol administration to male animals is associated with testicular
atrophy and gonadal failure. The Sertoli cell seems to be the first testicular
cell injured as a result of alcohol exposure. To investigate the adverse effects
of ethanol on testicular and particularly Sertoli cell function, the consequences
of in vivo and in vitro ethanol exposure on rat Sertoli cell mRNA and protein
levels of transferrin and ornithine decarboxylase were investigated. In vivo,
ethanol exposure enhanced the levels of both hepatic and testicular (Sertoli
cell) transferrin protein and mRNA. Ethanol exposure also enhanced testicular,
but not hepatic, levels of ornithine decarboxylase protein and mRNA. These in
vivo findings were confirmed when isolated Sertoli cells were studied in vitro.
Specifically, ethanol exposure increased Sertoli cell transferrin protein and
mRNA levels. Ethanol exposure increased Sertoli cell ornithine decarboxylase mRNA
and protein when cultured in serum-free media, but not when cultured in the
presence of serum. These studies demonstrate that ethanol exposure of rat Sertoli
cells is associated with alterations in the levels of mRNA and protein that are
known to be important in the process of spermatogenesis. These findings add to
the body of evidence that suggests that, within the testes, the Sertoli cell may
be an important target for ethanol-induced gonadal injury.
PMID- 9394113
TI - Fetal alcohol exposure and temporal vulnerability regional differences in alcohol
induced microencephaly as a function of the timing of binge-like alcohol exposure
during rat brain development.
AB - In humans, microcephaly (small head for body size) is a common feature of fetal
alcohol syndrome. An analogous measure, termed microencephaly (small brain for
body size), can be used for evaluating the detrimental effects of the
differential timing of alcohol exposure on brain development in animal model
systems. Timed-pregnant rats were exposed to binge-like alcohol during either the
first 10 days (first trimester equivalent) or second 10 days of gestation (second
trimester equivalent), or the combination of first and second trimesters
equivalent for prenatal treatments. Offspring from some of the animals exposed to
alcohol during the combined first and second trimesters equivalent were raised
artificially from postnatal day (P) 4 through P9 (part of the third trimester
equivalent), and also received binge-like alcohol during this period, producing
animals that were exposed to alcohol during all three trimesters equivalent.
Offspring from untreated dams were also raised artificially and received alcohol
only from P4 to P9, thus creating animals that were exposed to alcohol only
during part of the third trimester equivalent. All pups were perfused on P10.
Appropriate controls (nutritional and normally reared) were used for every
alcohol treatment combination. Peak blood alcohol concentrations were not
different among the treatment groups for a given sampling time. Significant
somatic growth deficits occurred in offspring exposed to alcohol for the
equivalent of all three trimesters, compared with offspring exposed to alcohol
during other periods. Brain growth in offspring also was significantly affected
by the timing of alcohol exposure. The whole brain, forebrain, and cerebellum to
body weight ratios of pups exposed to alcohol during the third trimester had more
significant brain growth deficits than pups in groups exposed to alcohol during
other times of brain development. Although alcohol exposure during the third
trimester had a significant detrimental impact on overall brain growth,
significant differences in temporal vulnerability were also found for the
brainstem to body weight ratios. Offspring of dams exposed to alcohol during the
first trimester had the same magnitude of deficit as those exposed to alcohol
during the third trimester, and those two groups were significantly deficient
compared with the groups exposed to alcohol at other times, suggesting some
differential vulnerability of this region to alcohol-induced injury at different
times of development. This study is the first thorough examination of
microencephaly and gross regional vulnerability of the developing brain as
related to temporal factors of alcohol exposure in an animal model system, and
the results support and expand on the findings of the available clinical
literature. Furthermore, our results substantiate claims that the cessation of
alcohol before the third trimester can lessen the severity of some alcohol
related birth deficits.
PMID- 9394114
TI - Ethanol feeding causes inactivation of both state 1 and state 2 rat hepatic
asialoglycoprotein receptors.
AB - Previous studies have shown that ethanol feeding in rats causes inactivation and
redistribution of approximately 50% of the total asialoglycoprotein receptors
(ASGPRs) in hepatocytes (Tworek et al., J. Biol. Chem. 271:2531, 1996), and that
two equal populations of hepatic ASGPRs mediate ligand uptake and processing via
two functionally different pathways (Weigel in Glycoconjugates: Composition,
Structure and Function, Marcel Dekker, 1992, p. 421). The purpose of this study
was to determine if ethanol feeding causes preferential inactivation of only one
of these two ASGPR populations, which have been designated state 1 and state 2
ASGPRs. The state 2, but not state 1, ASGPRs are inactivated in isolated
hepatocytes by a variety of drugs and inhibitors. State 2 ASGPRs can also be
inactivated in permeable cells by ATP treatment and then reactivated by treatment
with fatty acyl coenzyme As. In the present study, permeable cell assays for
state 2 ASGPR inactivation and reactivation were used to assess whether
hepatocytes from ethanol-fed rats contain inactive state 2 ASGPRs. The results
show that preferential inactivation of one ASGPR population does not occur after
ethanol feeding. That inactive ASGPRs could not be reactivated by treatment with
palmitoyl-coenzyme A to a greater extent in ethanol-fed versus control cells
indicates there is not a larger pool of inactivated state 2 ASGPRs in treated
cells. We conclude that ethanol feeding causes equal inactivation of both state 1
and state 2 ASGPRs. Ethanol feeding may represent the first treatment found to
inactivate state 1 ASGPRs.
PMID- 9394115
TI - Combination of naltrexone and fluoxetine on rats' propensity to take alcoholic
beverage.
AB - Naltrexone (NTX) and fluoxetine (FLU) are useful for treating alcoholism and
depression, respectively. Furthermore, these afflictions covary. Given the
possibility that people might be prescribed NTX and FLU concurrently, we assessed
the effects of these two agents on rats' propensity to drink an alcoholic
beverage. Rats were given 65 days of access to a sweetened alcoholic beverage and
water for 2 hr daily. At first, they took little ethanol, but after 20 days, they
took on average 2.0 to 2.5 g/kg of ethanol, daily during the 2-hr session. They
also took sufficient water to maintain their health. After 30 days, they were
divided into four groups to receive, 30 min before the drinking session, 1 of 4
different kinds of injections. For the next 20 days, one group received placebo
daily. Another group received 5 mg/kg of NTX daily and another 5 mg/kg of FLU
daily. The fourth group received both 5 mg/kg of NTX and 5 mg/kg of FLU daily.
After 20 days, the doses of NTX and FLU were doubled across an additional 10
days. Both NTX and FLU reduced rats' intake of alcoholic beverage. The
combinations of NTX and FLU, however, were no more effective in reducing rats'
intake of alcoholic beverage than either alone. Also, the small dose of NTX
seemed to lose its effectiveness with repeated administrations. A second
experiment confirmed the conclusion that small doses of NTX lose their
effectiveness in suppressing intake of alcoholic beverage across repeated
administrations. In summary, data provide no support for the idea that FLU and
NTX would act synergistically to reduce propensity to take alcoholic beverages.
PMID- 9394116
TI - The effect of cold stress on lymphocyte proliferation in fetal ethanol-exposed
rats.
AB - Prenatal ethanol exposure and stress have each been shown to have significant
effects on the immune system. This study examined the possible interactive
effects of prenatal ethanol exposure and exposure to stress later in life on the
immune system. Differential vulnerability to these challenges in female and male
offspring was assessed. At 5 to 6 months of age, female and male offspring from
prenatal ethanol-exposed (E), pair-red (PF), and ad libitum-fed control (C)
conditions were exposed to 0, 1 or 3 days of cold (4 degrees C). At the end of
the cold period, the proliferative response of splenic lymphocytes to the
mitogens concanavalin A (Con A) and pokeweed mitogen (PWM) was assessed. The data
demonstrate a significant interactive effect between prenatal ethanol exposure
and cold stress in female offspring. After 1 day of cold stress, E females had
significantly increased PWM-induced lymphocyte proliferation compared with PF and
C females, and significantly increased Con A-induced lymphocyte proliferation
compared with PF females. There were no differences in PWM or Con A-induced
lymphocyte proliferation among E, PF, and C females after 0 or 3 days of cold
stress, nor among E, PF, and C males on any test day. Regardless of prenatal
treatment, females exposed to 1 or 3 days of cold had significantly greater basal
plasma corticosterone levels than females not exposed to cold. In contrast, only
E males exposed to 1 or 3 days of cold had significantly increased basal plasma
corticosterone levels, compared with E males not exposed to cold; PF and C males
showed no significant change in basal corticosterone after cold stress. These
data demonstrate that, in response to the challenge of cold stress, changes in
lymphocyte proliferation to PWM and Con A may occur selectively in E females.
Moreover, the interactive effects of prenatal ethanol and cold stress may result
in enhanced rather than suppressed immune responsiveness.
PMID- 9394117
TI - Selective inhibition of alcohol intake in diverse alcohol-preferring rat strains
by the 5-HT2A antagonists amperozide and FG 5974.
AB - The present studies sought to elucidate the role of 5-HT2A receptor antagonists
in suppressing alcohol intake by comparing the effects of amperozide and FG 5974
on alcohol, food, and water intake in strains of alcohol-preferring rats: P, Alko
Alcohol (AA), and Fawn-Hooded (FH). Both amperozide and FG 5974 have 5-HT2A
receptor antagonist properties, but FG 5974 also shows presynaptic 5-HT1A
receptor agonist activity. After establishment of stable baselines for intake
measures in a two-bottle continuous access paradigm, rats (n = 10) were injected
with 1 of 5 doses (0, 2.5, 5.0, and 10.0 mg/kg, sc) of amperozide or FG 5974 at
weekly intervals. Amperozide dose-dependently reduced alcohol intake, total fluid
intake, and alcohol preference in all three strains under continuous access
conditions, whereas FG 5974 was less effective. Food intake was also suppressed
by amperozide at higher doses, whereas it was increased by FG 5974. Amperozide
also dose-dependently reduced alcohol intake when it was available for only 1
hr/day, but FG 5974 tended to increase it. After oral administration, amperozide
was also more effective than FG 5974 in reducing alcohol intake. Despite these
differences in efficacy in suppressing alcohol intake, both compounds produced
taste aversion to a novel saccharin solution. These complex findings suggest that
biochemical properties other than 5-HT2A receptor antagonism (e.g., 5-HT1A
receptor agonism) may be involved in the effects of amperozide and FG 5974 on
alcohol intake and other consummatory behaviors.
PMID- 9394118
TI - Content of dynorphins and kappa-opioid receptors in distinct brain regions of
C57BL/6 and DBA/2 mice.
AB - Differences in the activity of various components of the endogenous opioid system
under basal conditions and after ethanol exposure have been reported between
strains and lines of animals showing either high or low ethanol consumption. The
objective of the present studies was to investigate the presence of differences
in (a) the density of kappa-opioid binding sites, (b) the content of prodynorphin
mRNA, and (c) the content of dynorphin peptides in distinct brain regions between
the C57BL/6 (ethanol-preferring) and the DBA/2 (ethanol-avoiding) mice. Results
indicated that the C57BL/6 mice have a higher content of kappa-opioid binding
sites and dynorphin A 1-13 in the amygdala, and dynorphin A 1-8 in the ventral
tegmental area, whereas the DBA/2 mice presented a significantly higher content
of kappa-opioid binding sites, prodynorphin mRNA, as well as dynorphin A 1-13 and
dynorphin A 1-8 peptides in the nucleus accumbens and septum. In addition, the
DBA/2 mice presented a higher content of kappa-opioid receptors in the
periaqueductal gray and dynorphin A 1-13 and dynorphin A 1-8 in the caudate
putamen. Because enhanced stimulation of the kappa-opioid receptors at the level
of the nucleus accumbens has been associated with decreased dopamine release and
aversive states, the higher content of kappa-opioid receptors, pro-dynorphin
mRNA, and dynorphin peptides (the endogenous ligand of k-binding sites) in
regions of the limbic system of the DBA/2 mice may play an important role in
determining their low alcohol consumption.
PMID- 9394119
TI - Effects of chronic ethanol on the mobilization of arachidonate and
docosahexaenoate stimulated by the type 2A serotonin receptor agonist (+/-)-2,5
dimethoxy-4-iodoamphetamine hydrochloride in C6 glioma cells.
AB - We studied the effects of chronic ethanol exposure on the mobilization of
polyunsaturated fatty acids stimulated by activation of the type 2A serotonin
receptor in C6 glioma cells. In our in vitro model, we prelabeled cells with
[3H]arachidonate and [14C]docosahexaenonate and subsequently stimulated with the
type 2A serotonin receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine
hydrochloride. In as early as 10 days of exposure to 20 or 50 mM ethanol, the (+/
)-2,5-dimethoxy-4-iodoamphetamine hydrochloride-simulated mobilization of
[3H]arachidonic acid [[3H]AA) and [14C]docosahexaenoic acid ([14C]DHA) was
significantly inhibited, and this inhibition was accompanied by decreased
mobilization of intracellular [Ca2+]i. Exposure to ethanol did not alter
significantly the release of [3H]AA and [14C]DHA stimulated by the calcium
ionophore A23187 nor the incorporation of [3H]AA and [14C]DHA into cellular
lipids. Decreased mobilization of polyunsaturated fatty acids and calcium in
astroglia may contribute to neurotoxicity caused by chronic ethanol exposure.
PMID- 9394120
TI - Ethanol increases surface-localized fibrinolytic activity in cultured endothelial
cells.
AB - Epidemiological studies demonstrated a positive association between moderate
alcohol consumption and reduced cardiovascular mortality that may be mediated, in
part, through increased fibrinolysis. These studies were conducted to determine
whether low concentrations of alcohol (0.025 to 0.1%, v/v) directly affected the
surface-localized versus secreted/solution phase fibrinolytic activity in live
cultured endothelial cell (EC) types. Confluent live cultured ECs [human
umbilical vein ECs (HUVECs), human saphenous vein ECs (HSVECs), and porcine
aortic ECs (PAECs)] were preincubated (0 to 20 min, 4 degrees C) in the absence
or presence of varying concentrations of alcohol (0 to 0.1%, v/v), in the
presence of saturating levels of 125I-labeled Glu-plasminogem (2 microM) and 125I
Plasmin M(r) 20-kDA light-chain formation quantitated by phosphorimaging
autoradiography analysis. Endogenous plasminogen activator (PA)-mediated
fibrinolytic activity was time- and dose-dependent; reached a maximum
approximately 5- to 10-fold increase at 0.05% alcohol in HUVECs, HSVECs, and
PAECs; was completely inhibited by anti-t-PA IgG in HUVECs; and partially
inhibited by both anti-t-PA (approximately 40%) and anti-u-PA IgG (approximately
60%) in HSVECs. Complete inhibition of alcohol-induced (0.05%) fibrinolytic
activity in cultured HUVECs by 2 mM tranexamic acid (an antagonist of plasminogen
binding) indicated that the increased fibrinolytic activity was receptor-bound
and localized to the EC surface, rather than present in or secreted into the
medium (solution phase). Finally, the alcohol-induced increased fibrinolytic
activity in cultured HUVECs returned to essentially normal control levels in
approximately 1 hr. These studies have demonstrated a direct effect of low
alcohol on EC fibrinolytic activity that may contribute, in part, to the
decreased risk for thrombosis, coronary artery disease, and myocardial infarction
associated with moderate alcohol consumption.
PMID- 9394121
TI - The density of monoamine oxidase B sites is not altered in the postmortem brain
of alcoholics.
AB - The status of the enzyme monoamine oxidase B (MAO-B) was directly evaluated in
the postmortem brain from 20 alcoholics and 23 matched controls. The density of
MAO-B sites was quantified by the specific binding of the selective inhibitor
[3H]Ro 19-6327 (lazabemide) (8 nM) to cortical membranes. A positive correlation
between age at death and MAO-B density was observed in the total sample (r =
0.37, p = 0.015). The density of MAO-B in alcoholics (Bmax = 1,263 +/- 131
fmol/mg of protein) was not different form that in control (Bmax = 1,131 +/- 96
fmol/mg of protein). Ethanol in vitro inhibited [3H]Ro 19-6327 binding, with
similar potency in membranes form alcoholics (Ki = 280 +/- 13 mM) and controls
(Ki = 338 +/- 84 mM). The present results in brain tissue contrast with previous
reports of decreased MAO-B enzymatic activity in platelets of alcoholics, but
strongly agree with recent genetic studies on MAO-B status in alcoholism.
PMID- 9394122
TI - Regional restriction of alcohol/retinol dehydrogenases along the mouse
gastrointestinal epithelium.
AB - The gastrointestinal tract is a major site of alcohol dehydrogenase (ADH)
activity in humans and rodents. Because class I ADH (ADH-I) and class IV ADH (ADH
IV), but not class III ADH (ADH-III), function as retinol dehydrogenases in vitro
and may thus participate in retinoid signaling needed for epithelial
differentiation, the aim of this study was to determine the localization of these
enzymes along the gastrointestinal tract. Specific antibodies were used to
examine the tissue distribution of all three known classes of mouse ADH by
Western blotting, and cellular localization was determined by
immunohistochemistry. ADH-I was detected primarily in the intestine, liver,
kidney, adrenal, and uterus, with detection of ADH-III in all tissues examined,
and detection of ADH-IV primarily in the esophagus, stomach, adrenal, skin,
ovary, and epididymis. Along the gastrointestinal tract, ADH-III was not
specifically localized, whereas ADH-I was localized exclusively in the villus
epithelium of the small intestine and absorptive epithelium of the large
intestine, with ADH-IV being localized exclusively in the basal and suprabasal
epithelial cells of the esophagus and gastric pit surface epithelium of the
stomach. The ADH localization patterns observed are consistent with ADH-I and ADH
IV, but not ADH-III, functioning physiologically in retinol metabolism needed for
epithelial differentiation. Our results further suggest that the functions of ADH
I and ADH-IV are regionally restricted to the lower and upper components,
respectively, of the gastrointestinal epithelium, a finding that may relate to
the different efficiencies of these two enzymes for retinol oxidation, as well as
to the different susceptibilities of the upper and lower digestive tracts for
ethanol-induced cancers.
PMID- 9394123
TI - Differences in free-choice ethanol acceptance between taste aversion-prone and
taste aversion-resistant rats.
AB - Taste aversion (TA)-prone (TAP) and TA-resistant (TAR) rats were tested for
naive, nonforced acceptance of ethanol. Ethanol acceptance had played no role in
line development. Rather, the lines had been developed via bidirectional,
nonsibling matings based on susceptibility to develop cyclophosphamide-induced
conditioned TAs to a 0.1% saccharin solution (at cyclophosphamide doses of 12.5
mg/kg for males and 15.0 mg/kg for females, i.p.). Rats from the 23rd selectively
bred generations, with no prior exposure to ethanol, were given 24-hr access to a
two-bottle choice between plain tap water and a solution of ethanol in water.
Rats were initially given access to 1% ethanol in water, and the ethanol
concentration was increased by 1% every 3 days to a maximum of 10%. Ethanol
consumption (g ethanol consumed/kg body weight) and preference scores (volume
ethanol solution consumed/total fluid intake) were determined by daily bottle
weighings. At 1% ethanol concentration, there were no differences between the rat
lines in terms of ethanol consumption or preference. At concentrations of 2 to
10%, TAP rats consumed less ethanol and showed a decreased preference for the
ethanol solutions than TAR rats. Maximum ethanol consumption was reached at the
6% concentration for both lines. The mean (+/- SE) values of consumption at 6%
ethanol were 1.8 (+/- 0.8) and 5.6 (+/- 0.5) g of ethanol/kg body weight for TAP
and TAR rats, respectively. Mean (+/- SE) preference scores at 6% ethanol were 26
(+/- 12) and 76 (+/- 6) for TAP and TAR rats, respectively. These findings
indicate that differences in TA conditionability may be associated with the
propensity of rats to be high or low consumers of ethanol. Based on these data,
it is hypothesized that high susceptibility for TA conditionability may deter
many individuals from consuming the high levels of ethanol that usually precede
alcohol tolerance and dependence.
PMID- 9394124
TI - Genetics ethanol and the Fos response: a comparison of the C57BL/6J and DBA/2J
inbred mouse strains.
AB - The effect of ethanol (0.25 to 4 g/kg) on the number of Fos-like immunoreactive
(Fos-li) neurons was studied in the C57BL/6J (B6) and DBA/2J (D2) inbred mouse
strains. The brain regions emphasized in the analysis were from the basal ganglia
and some associated limbic nuclei. The question addressed was whether or not the
D2 and B6 strains differed in these regions in a way that could explain the
marked psychomotor stimulation of the D2, but not the B6, strain over the dose
range of 1 to 2 g/kg of ethanol. Over the dose range of 0.25 to 2 g/kg, ethanol
caused a modest increase in the number of Fos-li neurons within the caudate
putamen (dorsolateral and dorsomedial) and the nucleus accumbens (core and
shell), but there were no marked strain effects. There was no significant effect
in either strain of ethanol treatment (0.25 to 2 g/kg) in the globus pallidus,
ventral pallidum, and subthalamic nucleus. However, at 4 g/kg, there was a
dramatic (> 100%) increase of Fos-li neurons in the D2 but not B6 strain. A
similar effect was noted in the entopeduncular nucleus, the substantia nigra zona
reticulata (and compacta), but not the ventral tegmental area. A marked and
substantial (> 200%) Fos response was seen in the central amygdaloid nucleus
(CeA) of the D2 strain over the entire dose range; in contrast, a substantial Fos
response in the B6 strain was seen only at the 4 g/kg dose. The paraventricular
thalamic nucleus, in general, paralleled data in the CeA; but, the Fos response
was more modest, and the results for the D2 strain were significant only at the 2
g/kg dose. Overall, data suggest that ethanol at low to moderate doses induces
significant, strain-dependent Fos responses in some limbic structures, but not in
the basal ganglia. The possibility is considered that activation of some neurons
in the CeA are permissive for expression of the ethanol-induced increase in motor
activity.
PMID- 9394125
TI - NMDA receptor binding in adult rat brain after several chronic ethanol treatment
protocols.
AB - The amino acid L-glutamate is a major excitatory neurotransmitter that is
involved in many CNS functions, including learning, memory, long-term
potentiation, and synaptic plasticity. Acute exposures to ethanol (50 to 200 mM)
have been shown to inhibit NMDA receptor responses, whereas chronic exposure to
ethanol leads to adaptive supersensitivity thought to be involved in ethanol
dependence and tolerance. To investigate the effects of chronic ethanol exposure
on glutamate receptor density, we examined the binding of both NMDA and non-NMDA
ligands in rat brain after several chronic ethanol treatment protocols using a
number of different rat strains. No increases in the binding of [3H]MK-801,
[3H]CGP 39653, or the polyamine specific competitive antagonist, [3H]ifenprodil,
were seen after two well-used chronic ethanol treatments. These included the 2
week liquid diet developed by Frye et al. (J. Pharmacol. Exp. Ther. 216:306-314,
1981) and the 4-day binge treatment developed by Majchrowicz (Psychopharmacologia
43:245-254, 1975). However, small increases in the binding of both the NMDA
noncompetitive antagonist [3H]MK-801, as well as the competitive NMDA antagonist
[3H]CGP 39653, were seen in select frontal brain regions after 3 weeks of the
Walker-Freund chronic ethanol liquid diet. When this chronic liquid diet
treatment was extended to a period of 6 weeks, these increases in receptor
binding were diminished to nonsignificant levels. The binding of the non-NMDA
ligands [3H]AMPA and [3H]kainate were not significantly affected by either length
of Walker-Freund liquid diet exposure. When rats were treated chronically with
ethanol for 30 days using the paradigm developed by Tsukamoto et al. (Hepatology
5:224-232, 1985), small, but significant, increases in the binding of [3H]MK-801
were seen in the CA1 and dentate gyrus regions of the hippocampus. These studies
indicate that robust increases in NMDA receptor binding do not occur with several
chronic ethanol treatment protocols, and suggests that NMDA receptor
supersensitivity during the development of tolerance and dependence to ethanol
may not simply be due to changes in the density of NMDA receptors, but may
involve other mechanisms.
PMID- 9394126
TI - Chronic ethanol exposure alters leukocyte subsets in repopulating spleens, but
does not alter negative selection in thymuses of sublethally irradiated mice.
AB - Results from previous in vitro experiments in this laboratory suggested that
ethanol may affect selection processes in the thymus. To determine whether
ethanol allows escape of potentially autoreactive T-cell clones from negative
selection, we fed ethanol to sublethally irradiated, young, adult C57BR mice
during the time of thymic and splenic repopulation as a new model of human third
trimester fetal alcohol exposure. The mice received a whole-body, sublethal dose
(6 Gy) of gamma irradiation at 5 to 6 weeks of age. Feeding of a liquid diet
providing 25% of calories as ethanol (EDC) or an isocaloric control liquid diet
was begun 3 days after irradiation and was continued for 5 weeks. Each EDC mouse
had 2 weight- and age-matched controls, 1 pair-fed (PF), and 1 fed ad libitum (AD
LIB). Average blood alcohol concentrations (90 to 440 mg/100 ml) were higher than
those reported previously for neonatal mice exposed to ethanol through lactation.
At 5 weeks after irradiation, the EDC mice had lower total thymocyte numbers (p <
0.05) and a higher proportion of CD4-CD8-thymocytes than either the PF or AD LIB
mice (p < 0.05), which is consistent with findings using in utero models of
ethanol exposure. Ethanol exposure also altered the proportion of leukocyte
subsets in repopulating spleens. B cells were the most sensitive to the
detrimental effects of ethanol and, as a percentage of total nucleated cells in
the spleen, B cells were decreased in the EDC group, compared with both the PF
and AD LIB groups (p < 0.05). C57BR mice normally delete by negative selection
thymocytes bearing v beta 17 T-cell receptors. There was no discernible effect of
ethanol exposure during thymic and splenic repopulation on the expression of V
beta 17a on thymocytes and splenic T lymphocytes, indicating that ethanol does
not affect negative selection.
PMID- 9394127
TI - Chronic alcohol ingestion enhances tumor necrosis factor-alpha expression and
salivary gland apoptosis.
AB - We investigated the extent of induction in sublingual salivary gland cells
apoptosis and tumor necrosis factor-alpha (TNF-alpha) expression with chronic
ethanol ingestion. The experiments were conducted on rats pair-fed for 8 weeks
with alcohol-containing and control liquid diet. The animals were killed, their
sublingual glands dissected, and the glandular tissue used for quantization of
TNF-alpha expression and the assays of acinar cells apoptosis employing sandwich
enzyme immunoassay for histone-associated DNA fragments. The mean value for TNF
alpha in sublingual gland of the control group was 22.3 pg/mg of protein and
showed a 1.6-fold increase in the chronic ethanol diet group to 36.5 pg/mg of
protein. In comparison with the controls, the sublingual gland of the chronic
ethanol diet group also exhibited a 3.4-fold enhancement in acinar cell
apoptosis. These findings suggest that chronic ethanol ingestion causes the
enhancement in TNF-alpha expression and leads to the induction in salivary gland
acinar cells apoptosis. Thus, the diminished secretion of saliva in alcoholics
may be a direct result of increased salivary gland apoptosis.
PMID- 9394128
TI - Effects of prenatal ethanol exposure on phospholipase C-beta 1 and phospholipase
A2 in hippocampus and medial frontal cortex of adult rat offspring.
AB - Previous studies in our laboratory using a rat model of fetal alcohol exposure
(FAE) suggest that FAE-induced behavioral deficits are, in part, linked to
neurochemical and electrophysiological deficits in long-term potentiation (LTP)
in the entorhinal cortical perforant path projection to the hippocampal
formation. Several findings suggest that signal-activated phospholipase C (PLC)
and phospholipase A2 (PLA2) are critical to the induction and maintenance of LTP.
Thus, alterations in phospholipid metabolism may play a significant role in the
LTP deficits observed in FAE offspring. To test this hypothesis, we measured PLC
beta 1 and PLA2 activities in the hippocampus and medial frontal cortex of adult
rats prenatally exposed to ethanol. PLC-beta 1 activities were significantly
decreased by 20 to 30% in both the hippocampus and medial frontal cortex of FAE
rats, compared with ad libitum and pair-fed controls. Total Ca(2+)-dependent PLA2
activity was 25% lower in the medial frontal cortex of FAE rats, but did not
significantly differ from controls in the hippocampal formation. Approximately
30% of the measured activity in both the medial frontal cortex and hippocampal
formation of ad libitum and pair-fed animals was associated with an 85 kDa
cytosolic PLA2 form. Cytosolic PLA2 activities were significantly reduced in both
the medial frontal cortex and hippocampal formation of FAE rats, compared with
controls. These changes in Ca(2+)-dependent PLA 2 and PLC-beta 1 activities,
coupled with reports of FAE-induced deficits in protein kinase C activity,
indicate that prenatal exposure to moderate quantities of ethanol causes profound
and long-lasting deficits in the cellular signaling mechanisms associated with
activity-dependent synaptic plasticity and memory formation.
PMID- 9394129
TI - Fetal alcohol exposure augments the blunting of tumor necrosis factor production
in vitro resulting from in vivo priming with lipopolysaccharide in young adult
male but not female rats.
AB - We previously reported altered responses of thymocytes and splenocytes to mitogen
stimulation in fetal alcohol-exposed (FAE) male Sprague-Dawley rats. We also
reported enhanced neuroendocrine responses to stressful stimuli in these animals.
The experiments we describe herein aimed at testing whether young adult FAE rats
manifest a notable dysregulation in the neuroendocrine-immune response to
pathogen administration. We tested the effect of in vivo priming of the animal
with a low dose of endotoxin [lipopolysaccharide (LPS), 5 micrograms/kg],
considered to be suboptimal from the perspective of mounting detectable levels of
circulating monokines several hours after administration, upon the production of
immunoreactive tumor necrosis factor (TNF-alpha) in response to a further in
vitro challenge of peripheral blood mononuclear cells with 2.5 micrograms/ml of
LPS 90 min after priming. We show that the response to the LPS pathogen in vitro
after priming is significantly blunted (p < 0.01) in male rats exposed prenatally
to alcohol, compared with control male animals. FAE female rats and FAE
ovariectomized female rats do not show significant differences in the priming
response, compared with control animals. We also show that there is no
correspondence between plasma corticosterone levels and TNF-alpha production
after priming in any of the groups tested.
PMID- 9394130
TI - Alcohol-induced expression of the CD14 endotoxin receptor protein in rat Kupffer
cells.
AB - Gut-derived endotoxins (lipopolysaccharide, LPS) are believed to contribute to
alcohol-induced liver disease (ALD) by stimulating Kupffer cells, the resident
liver macrophages, to release proinflammatory cytokines. This activation is
largely mediated by CD14, a high-affinity membrane-anchored receptor for LPS. We
observed, by chemiluminescence-enhanced detection, an increase in immunoreactive
CD14 protein in Kupffer cells isolated from rats treated with ethanol for 2
weeks. Immunocytofluorescence experiments confirmed that this increase was
confined to the membranes of Kupffer cells from the alcohol-treated rats. The
increase was regulated pretranslationally: a 3-fold elevation (p < 0.01) in the
hepatic level of CD14 mRNA was observed. The marked increase in CD14 expression
suggests a new mechanism by which alcohol increases the LPS-mediated cytokine
signaling by the liver macrophages, thus promoting the interaction between
alcohol and endotoxins in the development of liver damage.
PMID- 9394131
TI - "Big" versus "little" science: comparative analysis of program projects and
individual research grants.
AB - Controversy about the amount and nature of funding for mental retardation
research has persisted since the creation of NICHD. An issue that has aroused
considerable debate, within the mental retardation research community as well as
beyond, is distribution of funds between large group research grants, such as the
program project (PO1) and the individual grant (RO1). Currently within the Mental
Retardation and Developmental Disabilities Branch, more money is allocated to the
PO1 mechanism than the RO1. We compared the two types of grants, focusing on
success rates, productivity, costs, impact, publication practices, and outcome
and conducted a comparative analysis of biomedical and behavioral research. Other
related issues were considered, including review processes and cost
effectiveness.
PMID- 9394132
TI - Maladaptive behavior in children with Prader-Willi syndrome, Down syndrome, and
nonspecific mental retardation.
AB - Although some genetic, mental retardation syndromes have well-described
behavioral features, comparative studies have not yet assessed the relative
uniqueness of these so-called phenotypes. Maladaptive behavior of 43 children
with Prader-Willi syndrome was compared to age- and gender-matched children with
Down syndrome and with nonspecific mental retardation. The Prader-Willi group
showed more frequent and severe internalizing, externalizing, and total problem
behaviors on the Child Behavior Checklist. Some problems were elevated in all
groups, and 12 behaviors were significantly elevated in Prader-Willi subjects
relative to both comparison groups. Seven behaviors predicted membership into the
Prader-Willi group with 91% accuracy. Implications were discussed for research on
behavioral phenotypes in general and for dual diagnosis in particular.
PMID- 9394133
TI - Intensive behavioral treatment for preschoolers with severe mental retardation
and pervasive developmental disorder.
AB - From archival records, we assessed outcomes achieved by preschoolers with both
severe mental retardation and autistic features: (a) an experimental group (n =
11), which received intensive behavioral treatment, and (b) a comparison group (n
= 10), which received minimal treatment. At intake (mean CA = 3.08 years), the
groups did not differ significantly on any variable. At follow-up children in the
experimental group obtained a higher mean IQ and evinced more expressive speech
than did those in the comparison group. Behavior problems diminished in both
groups. Results indicate that intensively treated children achieved clinically
meaningful gains relative to the comparison group but remained quite delayed.
PMID- 9394135
TI - Fathers and mothers of school-age children with developmental disabilities:
parental stress, family functioning, and social support.
AB - Thirty pairs of fathers and mothers who had school-age children with mental
retardation and other disabilities were compared with each other and with 32
father and mother pairs of parents of children without disabilities. Responses to
family scales indicated that fathers and mothers of children with developmental
disabilities did not differ from each other nor from fathers and mothers of
children without disabilities in parental stress, family social support, or
family functioning. However, parents of children with disabilities experienced a
disproportionately greater level of stress relating to their children than did
those of children without disabilities. Fathers' and mothers' stress was
associated with aspects of family functioning as perceived by themselves and
their spouses.
PMID- 9394134
TI - Disaggregating parental depression and family stress in assessing families of
children with developmental disabilities: a multisample analysis.
AB - The psychometric properties of a 5-item subcomponent (DEP5) of Factor 1, Parent
and Family Problems, of the Friedrich Questionnaire on Resources and Stress were
examined to determine whether these items formed a depression subcomponent of the
larger family stress factor. Data were pooled from two samples numbering more
than 450 respondents. Internal analyses established that the DEP5 had adequate
internal reliability and stability over 2 years. Furthermore, confirmatory factor
analyses indicated that the DEP5 measured depressive reactions as distinct from
other parent and family problems. These results should be useful to researchers
who want to reanalyze the Questionnaire on Resources and Stress data specifically
for depressive reactions. Also, the technique for disaggregating global
instruments can be applied to other variables.
PMID- 9394136
TI - Reliability of ratings of consumers with mental retardation and their staff on
multiple measures of social support.
AB - Reliability of self-reports of social support with staff ratings was compared
through determining the internal consistency of the measures, consistency across
measures, and consistency across raters. Fifty adults with mild mental
retardation and their staff in supported living residential settings were
interviewed. Self-report ratings had moderate internal consistency, were
consistent across rating scales, and were significantly correlated with staff
ratings, although staff members tended to agree more with each other than with
consumers. Results suggest that individuals with mild mental retardation can be
reliable reporters about their own social support. Further, examining self
informant agreement for specific support sources can illuminate discrepancies
between self- and informant-obtained ratings.
PMID- 9394137
TI - Generalized identity matching of two-dimensional forms by individuals with
moderate to profound mental retardation.
AB - The classic literature suggests that individuals with MAs of less than 5 years
may fail tasks that require same/different judgments. In Study 1 we used an
assessment procedure that provided minimal instructional programming to determine
whether 17 adults with MAs ranging from 2 years, 5 months to 4 years, 11 months
would show accurate identity matching-to-sample. Stimuli were letter-like
nonsense forms. Eight participants showed highly accurate matching. Eight of the
9 who failed were available for further study. Of these, 5 ultimately
demonstrated highly accurate matching after training with standard fading
procedures. These data suggest that a greater proportion of individuals with low
MAs can exhibit generalized identity matching than previously documented in the
literature.
PMID- 9394138
TI - Differences in social signals produced by children with developmental delays of
differing etiologies.
AB - Clarity of referential looks (either a focus on parent's face or other focus)
produced by preschool children with delays of differing etiologies and children
without delays was examined. Adults (with and without experience with children
with delays) viewed videotaped segments in which children's looks did or did not
occur. Adults judged whether a look occurred and rated their confidence in each
judgment; latency to respond was measured. Adults' experience with children with
delays did not influence outcome measures. When viewing looks focusing on
parents' faces, participants were more accurate and more confident judging looks
by children with typical development, less accurate when viewing face-directed
looks of children with developmental delays, and least accurate when viewing
children with Down syndrome. Discriminability of social looks differed by
etiological group, and judges' decision criteria, confidence, and speed of
responding also differed.
PMID- 9394139
TI - Therapist-child interaction in the middle minutes of sensory integration
treatment.
AB - The purpose of this study was to describe the management of challenge during
therapist-child interaction in sensory integration treatment. This descriptive
and relational study of the middle minutes of treatment sessions partially
replicated an earlier study of the beginning minutes. One-minute videotape clips
taken from the middle minutes of 38 treatment sessions were shown to therapist
judges who rated qualities of therapist and child behavior. Two patterns emerged
from the correlations of ratings: work and playfulness. Work for the child
involved trying hard, cooperating and seeking assistance, whereas work for the
therapist involved assisting and guiding the child. Play for the child included
enjoying the activity, being successful and confident, and trying hard. For the
therapist, play involved being creative and behaving playfully. Patterns of work
and play were different across different levels of challenge to the child.
PMID- 9394140
TI - Clinical interpretation of "Therapist-child interaction in the middle minutes of
sensory integration treatment".
PMID- 9394141
TI - Symbolic play language during sensory integration treatment.
AB - OBJECTIVE: Clinical writings on sensory integration treatment and theory have
long professed that play serves as an important means of implementing treatment
goals. However, to date, there has been little research that examines this aspect
of the intervention. With the use of play language as an indicator for the
occurrence of play, this study examined the frequency and characteristics
associated with symbolic play language that therapists and children use during
sensory integration therapy. This study is part of an ongoing research program
designed to examine therapist-child interactions. METHOD: The frequency of
symbolic play language observed in 41 videotaped treatment sessions of therapist
child dyads (21 children, 12 therapists) was recorded with the Challenge Coding
System. The presence of symbolic play language was recorded if the child or
therapist used language that incorporated the child, therapist, equipment, or
activity into a symbolic or pretend play theme. The frequency of symbolic play
language and percentage of time spent using play language were calculated.
Associations among frequency of play language, child age, and behavior during the
session (e.g., seeking assistance, cooperation) were also examined. RESULTS:
Symbolic play language proved to be a major feature of sensory integration
treatment sessions. It also correlated with child age and with some features
associated with therapeutic interactions (i.e., child tries hard, child seeks
assistance, therapist assists child, therapist modifies activity, therapist
structures activity). CONCLUSION: The results suggest that these therapists used
play language frequently and that this usage may support children in sensory
integrative therapy to successfully accomplish activities.
PMID- 9394142
TI - The Interest Checklist: a factor analysis.
AB - OBJECTIVE: The purpose of this study was to determine whether the 80 items on the
Interest Checklist empirically cluster into the five categories of interests
described by Matsutsuyu, the developer of the tool. METHOD: The Interest
Checklist was administered to 367 subjects classified in three subgroups:
students, working adults, and retired elderly persons. An 80-item correlation
matrix was formed from the responses to the Interest Checklist for each subgroup
and then used in a factor analysis model to identify the underlying structure or
domains of interest. RESULTS: Results indicated that the Social Recreation
theoretical category was empirically independent for all three subgroups; the
Physical Sports and Cultural/Educational theoretical categories were empirically
independent for only the college students and working adults; and the Manual
Skills theoretical category was empirically independent for only the working
adults. CONCLUSION: Although therapists should continue to be cautious in their
interpretation of patients' Interest Checklist scores, the tool is useful for
identifying patients' interests in order to choose meaningful activities for
therapy.
PMID- 9394143
TI - Forced use of the upper extremity in cerebral palsy: a single-case design.
AB - OBJECTIVE: Muscle imbalance and poor control of movement can have an impact on
the daily occupational functioning of children with cerebral palsy. When one side
of the body functions better than the other, children will often prefer to use
the less-involved upper extremity for completion of play and self-care activities
because they have learned that the other hand does not function as effectively.
This study examined a method purported to overcome this learned nonuse of the
affected upper extremity by directing the child's attention to this extremity and
increasing his or her motivation to use it. The research hypothesis was that
restriction of the less-involved hand with a resting splint would result in
increased use of the more-involved hand in a child with spastic cerebral palsy.
METHOD: Initially, two children with cerebral palsy participated in this single
subject, ABA design study, but only one subject complied with the splint-wearing
schedule and completed the study. This subject was a 2-year-old girl with greater
involvement of the right side than the left. During the experimental phase, she
wore a resting splint on her less-involved hand for most of the waking hours of
the day to restrict its use. Data were collected over a 7-week period (2 weeks
presplinting, 3 weeks splinting, 2 weeks postsplinting) and at a 6-month follow
up. Use of the more-involved extremity was measured through analysis of her
performance during 15-min videotaped sessions of free play, administration of
items from the Peabody Developmental Fine Motor Scales, and completion of a daily
finger-feeding task. RESULTS: An improvement in quality, quantity, and variety of
use of the more-involved extremity after splinting, with some continuing
improvement evident at follow-up, was found. The subject had increased voluntary
control of her more-involved arm and hand and used them more spontaneously for
completion of daily occupations. CONCLUSIONS: Although the results of this single
case design are encouraging, further research with a randomized, controlled
design is necessary to determine the effectiveness of the forced-use technique
with a larger population.
PMID- 9394144
TI - Development of a post-offer screening tool for patient support services.
AB - OBJECTIVES: The purpose of our project was to develop a post-offer screening tool
that demonstrates interrater reliability, predictive validity, and face validity
and that accurately represents the physical demands of the patient support
services (lifting team) job at our health care facility. METHODS: The screening
tool, which consists of 11 static and dynamic tasks, was developed, using the 13
incumbent staff members of the patient support services department, to determine
whether the criteria established for each task matched the physical abilities of
at least 80% of the total group tested. Test-retest design was used for this
study. Intraclass correlation coefficients and the Kappa statistic were used to
calculate interrater reliability. Face validity was determined through the Job
Similarity Questionnaire completed by all subjects. RESULTS: Subjects did not
meet criteria established for the static knee pull and the knuckle-to-elbow lift
tasks, resulting in modification of these two criteria. Interrater reliability
ranged from .22 for the maximum static pull wall task to .94 for the left-hand
grip strength task. Face validity ranged from 53.9% to 92.4%. CONCLUSION:
Although face validity of the Job Similarity Questionnaire represented a wide
range, we believe that the results were homogeneous enough to continue with the
screening tool unchanged, except for lowering the expected outcome on two tasks.
Interrater reliability was established for 75% of the tasks. The lack of
variation of data for the other 25% prevented statistical analysis of those tasks
but confirmed that all members met the physical criteria.
PMID- 9394145
TI - The use of service learning in client environments to enhance ethical reasoning
in students.
AB - OBJECTIVES: This study examined the effects of two service-learning experiences
on the psychosocial and moral reasoning development of occupational therapy
students. The assumption was that ethical reasoning ability can be facilitated
through participation in value-laden experiences. METHOD: Participants visited
older adults in nursing homes (n = 19) or interacted with persons with
disabilities in community settings (n = 33). All participants reflected on their
experiences through weekly journals. Psychosocial and moral reasoning development
were measured at the beginning and end of the experiences with the Student
Development Task and Lifestyle Inventory and the Sociomoral Reflection Measure
Short Form. RESULTS: Participants in both groups exhibited a significant time
related increase in psychosocial development but no increase in moral reasoning.
Participants interacting with persons with disabilities exhibited a decrease over
time in moral reasoning compared with the participants interacting with older
adults. CONCLUSION: Service learning effected a change in the participants'
psychosocial development indicative of developing an appreciation for dignity,
equality, and justice. These are core concepts in occupational therapy and are
viewed as important in ethical reasoning. The lack of advancement and current
level of moral reasoning in these undergraduate students raises a question as to
their readiness to engage in ethical reasoning as entry-level practitioners.
PMID- 9394146
TI - Cross-training concept paper.
PMID- 9394147
TI - Statement--sensory integration evaluation and intervention in school-based
occupational therapy.
AB - Based on the educational team recommendations, school-based occupational therapy
practitioners provide interventions to students who are eligible for special
education services under IDEA and who need occupational therapy to benefit from
their education program. The occupational therapist develops an intervention plan
based on the student's needs and the therapist's professional knowledge base.
When students demonstrate deficits in sensorimotor performance components that
contribute to a significant and documented discrepancy in their skills within
their educational program, the use of sensory integrative approach may be one
frame of reference for intervention chosen by the occupational therapist.
PMID- 9394148
TI - Statement--fundamental concepts of occupational therapy: occupation, purposeful
activity, and function.
AB - Deriving from the philosophical basis of the profession, occupation is the core
concept of the profession of occupational therapy. However, in the occupational
therapy literature, the term occupation is used in a variety of ways. Occupation,
a collection of activities that people use to fill their time and give life
meaning, is organized around roles or in terms of activities of daily living,
work and productive activities, or pleasure, for survival, for necessity, and for
their personal meaning. It is the individualized, unique combination of
activities that comprises an individual's occupations. Purposeful activities have
been described in many different ways: as something all people engage in; as
tools or media that therapists use to enhance or facilitate performance; and
vehicles for bringing about change. Purposeful activities are seen as part of the
process of occupational therapy. Purposeful activities are subset of occupations
in that they are goal directed and serve as a major tool in the process of
occupational therapy. The term function, viewed as the ability to perform
activities required in one's occupations has become increasingly important to
society in describing the performance or change in individuals. This societal
shift in ideas has prompted the concept of function, viewed as a product, to
become more important than the process of bringing about change. Occupational
therapy practitioners typically have viewed the process as being just as
important as the product. When working to improve function, occupational therapy
practitioners use purposeful activities that are meaningful to the person in
relation to his or her occupational history, preferences, personal goals, and
needs. Occupational therapy practitioners need to keep the individual's
occupations in the forefront of their thoughts when using any purposeful activity
and to plan interventions toward improving the individual's ability to function
within his or her occupations. In the interest of the profession, it is important
to concentrate on occupation. Furthermore, it is essential that we study our
interventions' relationship to occupation and function, and how purposeful
activities are used toward supporting the individual's ability to engage in
occupation.
PMID- 9394150
TI - Physical agent modalities position paper.
PMID- 9394149
TI - The psychosocial core of occupational therapy position paper.
PMID- 9394151
TI - Occupational therapy's link to vocational reeducation, 1910-1925.
AB - The development of occupational therapy is rooted in early 20th century medical
reform. During the early 1910s, several members of the medical profession, human
service workers, and the larger American society were increasingly disturbed by
medical practices that did not consider the individual's personal experience of
disability. Occupational therapy was developed, in part, out of this desire to
provide persons with treatment that helped them to function in their communities
despite their disability. Early occupational therapy leaders envisioned the
fledgling profession as a societal service capable of assisting persons with
disabilities to return to both work and community life. Vocational reeducation
was initially considered to be an integral component of occupational therapy in
the years from 1910 to 1920. However, the profession's early link to vocational
reduction was challenged by vocational technical trainers during World War I. To
prevent occupational therapy from being subsumed by vocational technical
training, the early occupational therapy leaders implemented several strategies:
adoption of physician prescription for all occupational therapy services,
delivery of occupational therapy services primarily within hospital settings, and
dissociation from vocational reeducation services. Reasons accounting for why the
early occupational therapy leaders abandoned their initial commitment to
vocational reeducation are explored. Suggestions about how this decision has
affected present-day practice are also offered.
PMID- 9394152
TI - Identifying best practice in the occupational therapy assistive technology
evaluation: an analysis of three focus groups.
PMID- 9394153
TI - Positioners for wheelchairs in long-term-care facilities.
PMID- 9394155
TI - Impact of promotion of occupational therapy campaign.
PMID- 9394156
TI - Professional values: diversity versus disintegration.
PMID- 9394154
TI - Spirituality issue provides needed voice.
PMID- 9394157
TI - Reversible oligohydramnios in a pregnancy with angiotensin-converting enzyme
inhibitor exposure.
AB - The use of angiotensin-converting enzyme inhibitors during pregnancy has been
associated with poor fetal outcomes, including oligohydramnios, renal tubular
dysplasia, cranial malformations, and fetal death. A 35-year-old woman with
chronic hypertension was treated with the angiotensin-converting enzyme inhibitor
benazepril until 27 weeks' gestation, when severe oligohydramnios was noted.
After hospitalization for bed rest, fetal surveillance, and discontinuation of
the agent, amniotic fluid rapidly reaccumulated, and a healthy infant was
delivered at term. Although the use of angiotensin-converting enzyme inhibitors
should be avoided during pregnancy, patients whose fetuses are inadvertently
exposed in utero need not be given a uniformly poor prognosis. Oligohydramnios
induced by the use of angiotensin-converting enzyme inhibitors during pregnancy
may be reversible if the agent is discontinued. This case underscores the need
for obstetricians to review carefully the medication regimens of all pregnant
women and to be familiar with generic and proprietary names of medications to
avoid the use of potentially harmful agents during pregnancy.
PMID- 9394158
TI - Relative humidity under radiant warmers: influence of humidifier and ambient
relative humidity.
AB - The effects of humidifier air temperature and flow, and ambient relative humidity
(RH(amb)) on RH and air temperature under a radiant warmer (RW) were determined
in stable and unstable conditions, using an infant surrogate. Mean supplemented
RH under the RW was 36.3% at 14% RH(amb) and 67.6% at 55% RH(amb). Humidifier
temperature of 38 degrees C and air flow of 10 LPM produced highest RHs (74.5%
and 43.1% in high and low RH(amb), respectively). RH(amb) was highest in summer
and lowest in winter in this midwest U.S. hospital, and could be predicted by
calendar date (r = 0.58). Humidification equipment capabilities and limitations
must be known when using this method to limit evaporative water loss.
PMID- 9394159
TI - Ilio-psoas abscess in a neonate.
AB - A full-term, small-for-gestational-age, neonate was born 4 days after rupture of
the membranes. On the 5th day of life, she developed sepsis due to Klebsiella
pneumoniae. On the 18th day of life, the right hip was noted swollen with limited
range of motion, but it was painless on passive movements. Ultrasonography
revealed abscess of the right ilio-psoas muscle with normal appearance of the
right hip joint. Surgical incision and drainage and antibiotic administration
resulted in a gradual full recovery. Ultrasonography can confirm the diagnosis of
this exceptional clinical entity in neonates, which is difficult to differentiate
from septic arthritis of the hip.
PMID- 9394160
TI - The risk of neonatal death and respiratory distress syndrome in relation to birth
weight of preterm infants.
AB - The aim of this study was to determine the risk of respiratory distress syndrome
(RDS) and neonatal death (NND) in relation to birth weight in preterm neonates. A
group of 255 singleton preterm neonates born at 22-36 weeks were examined. The
mean birth weight for each gestational week was estimated from a fitted curve.
Each birth weight was recalculated as a multiple of the mean. This approach
allowed description of a range of birth weight for the whole population of
preterm infants. As expected, the incidence of neonatal death and respiratory
distress syndrome was higher among the less mature infants. However, there were
no significant differences in outcome (NND, severe RDS) between infants whose
birth weight was above or below the mean for gestational age, and no excess of
"growth retardation" (birth weight below the 5th centile) in babies with NND or
RDS. We conclude that, in our population, the risk of RDS and neonatal death does
not appear to be related to the birth weight of preterm neonates but is, of
course, related to gestational age.
PMID- 9394161
TI - Vaginal delivery is associated with occult disruption of the anal sphincter
mechanism.
AB - Childbirth is thought to be an important cause of pelvic floor dysfunction.
Heretofore, this has been thought due to pudendal denervation. Endovaginal
sonography allows thorough assessment of the anorectum and in this study was used
to assess nulliparous women and women before and after delivery. Two groups were
studied. Thirty-two nulliparous subjects without complaints of incontinence were
studied once. Thirty-four pregnant women were studied before and after delivery.
Endovaginal sonography was used to assess integrity of internal and external anal
sphincters, thickness of the levator bundle, internal and external sphincters,
anal length, and the angle between the levator bundles. Delivery was associated
with disruption of the internal and external sphincters. No nulliparous women
(nonpregnant or pregnant) had sphincter disruption demonstrated. Episiotomy in
the index delivery was associated with increased thickness in the external
sphincter and a smaller angle between the levator bundles. Vaginal delivery is
associated with occult disruption of the anal sphincters.
PMID- 9394162
TI - The effects of essential fatty acids preparation in the treatment of intrauterine
growth retardation.
AB - A treatment of intravenous infusion of glucose, amino acids, and emulsion
enriched in essential fatty acids (EFAs), linoleic, and linolenic acids were
given to 30 pregnant women with intrauterine growth retardation (IUGR) and 28 non
EFAs treated cases as controls. There was a marked gain in fetal biparietal
diameter (BPD) and in the estimated weight of the treated group over the control
group. The mean birth weight was significantly different in the two groups. Fetal
BPD increased much more in patients treated with EFAs at 28-34 gestational weeks
than those at 34 1/7-37 weeks, which indicates that early initiate complement of
n-3 and n-6 fatty acids to IUGR mothers may correct pregnancy-induced EFAs
deficiency and maternal-fetal malnutrition, which demonstrates a fetal catch-up
of growth in the brain and the whole body.
PMID- 9394163
TI - Growth and growth factors in premature infants receiving dexamethasone for
bronchopulmonary dysplasia.
AB - Physical growth and the serum growth factors, insulin growth factor 1 (IGF1) and
its binding protein (IGFBP3) were measured weekly during dexamethasone treatment
and for 3 weeks after stopping therapy in 10 ventilated babies [median (range)
birth weight 860 g (640-1210); median (range) gestational age 26 weeks (24-29)]
with bronchopulmonary dysplasia (BPD). The mean (+/- SE) rates of change of all
physical measures except crown-rump length (CRL) increased significantly after
stopping dexamethasone: weight gain 13.2 (+/- 1.5) on versus 1.0 (+/- 1.9) g/day
off treatment; occipital-frontal circumference 0.7 (+/- 0.1) cm/week; CRL 0.5 (+/
0.1) versus 0.7 (+/- 0.1) (TBL) 0.7 (+/- 0.1) versus 1.1 (+/- 0.1) cm/week; CRL
0.5 (+/- 0.1) versus 0.7 (+/- 0.1) cm/week, and knee-ankle length (KAL) 0.13 (+/-
0.02) versus 0.36 (+/- 0.04) cm/week. Mean serum IGF-1 (1.57 +/- 0.13 versus 3.56
+/- 0.41 nmol/L) and IGFBP3 (0.94 +/- 0.03 versus 1.12 +/- 0.05 mg/L) levels also
increased off treatment. The weekly dose of dexamethasone (mg/kg) was
significantly negatively correlated with all physical growth measures (P < 0.01),
but showed no correlation with growth factors. Protein intake (g/kg/day) was
significantly correlated (P < 0.01) with weight gain (r = 0.28), changes (TBL) (r
= 0.32), serum IGF1 levels (r = 0.60), and IGFBP3 levels (r = 0.37). All aspects
of physical growth are compromised during dexamethasone treatment for BPD. Poor
growth during steroid treatment is associated with lower IGF1 and IGFBP3 levels.
Further study is needed to examine the effect of varying dexamethasone dosage
regimes and nutritional intake on the growth process in BPD.
PMID- 9394164
TI - The effect of maternal glycemic control on fetal growth in diabetic pregnancies.
AB - In this prospective study, we examined the effect of maternal glycemic control on
fetal growth in pregnancies complicated by pregestational diabetes. One hundred
and sixty-five pregestational diabetic pregnancies were studied with serial
ultrasound scans and fetal growth was examined as a function of maternal glycemic
control. There was a significant, although small, reduction in fetal biparietal
diameter growth rate in the presence of poor maternal glycemic control during the
first half of the pregnancy. In the second half of pregnancy, maternal
hyperglycemia contributed to fetal macrosomia. We conclude that in pregnancies
with pregestational diabetes, maternal hyperglycemia affects fetal growth in a
biphasic manner. As a result of that, although babies born to diabetic mothers
appear of relatively overall normal size and weight, they may have smaller heads
than their potential and more fat.
PMID- 9394165
TI - Penicillin desensitization in the treatment of syphilis during pregnancy.
AB - The objective of this study was to compare patients' hospital course,
complications, and charges for oral and intravenous (i.v.) desensitization
regimens for the treatment of syphilis in the penicillin-allergic gravida. We
performed a retrospective search of medical records at two tertiary-level
teaching hospitals and reviewed the hospital course of penicillin-allergic
gravidas who underwent penicillin desensitization. Between August 1988 and
December 1995, 16 procedures for penicillin desensitization were carried out: 11
oral procedures, and 6 i.v. procedures. There were no significant differences
between the patients in the oral and i.v. desensitization groups with respect to
demographic characteristics, duration of time in a monitored bed, or length of
hospital stay. The oral regimen was less expensive than the i.v. regimen ($144.06
vs. $319.48). In our experience, oral and i.v. regimens provide effective
desensitization for the treatment of syphilis in penicillin-allergic gravidas.
However, the oral route offers ease of administration and substantial cost
savings, making it the preferred method.
PMID- 9394166
TI - Nuchal cord entanglements and gestational age.
AB - The purpose of this observational study was to investigate the relation between
nuchal cord entanglements and gestational age. Computerized data from our
hospital perinatal database were reviewed between January 1990 and December 1994.
Data from all deliveries > or = 20 weeks' gestation underwent either a Cochran
Mantel test for trend or Chi-square testing where appropriate. Of the 13,895
singleton deliveries, the finding of an entanglement increased significantly from
5.8% at 20 weeks to 29.0% at 42 weeks' gestation. The frequencies increased
linearly, regardless of whether the entanglement involved a single loop (p <
0.001) or multiple loops (p < 0.002). The risk of an antepartum stillbirth was
not increased in the presence of a nuchal cord entanglement, even after
controlling for other risk factors. These normative data should serve as a
reference for prenatal ultrasound examinations and for prospective studies
intended to evaluate the predictive value of reporting this finding prenatally.
PMID- 9394168
TI - Fetal acidemia in the absence of fluid observed at amniotomy.
AB - The objective of this study was to determine the rate of pathological fetal
acidemia in the absence of fluid observed at amniotomy. Thirty-nine consecutive
patients with no fluid observed at the time of amniotomy were prospectively
enrolled in this study. Ultrasound measurement of amniotic fluid index was
performed. Umbilical cord gases were performed on arterial and venous samples at
the time of delivery. Patient name and medical record number were noted and
delivery data were extracted from review of the medical record. The median
gestational age at admission was 41 weeks (range 38 to 42 weeks). Sixteen
patients (41%) were subsequently noted to have meconium at the time of delivery.
The median amniotic fluid index was 2.0 cm with a range of 0 to 9.0 cm. Thirty
patients (76.9%) had an amniotic fluid index of less than 5.0 cm. The median
umbilical artery pH in this patient population was 7.21 with a range of 6.75 to
7.42. Only one infant had an umbilical artery pH less than 7.00. The rate of
cesarean section for documented fetal distress was 2.6%. The absence of observed
fluid at amniotomy, while commonly associated with subsequent meconium at
delivery, is not predictive of fetal acidemia or operative delivery for fetal
distress.
PMID- 9394167
TI - Urinary cyclic GMP, endothelin, and prostaglandin E2 in normal pregnancy and
preeclampsia.
AB - Cyclic GMP, endothelin and prostaglandin E2 (PGE2) all have systemic vasoactive
properties (with cyclic GMP acting as a second messenger of nitric oxide).
Intrarenally they act as natriuretics and urinary levels reflect intrarenal
production. Cyclic GMP and PGE2 also act as important inhibitors of platelet
activation and thrombosis. The purpose of this study was to determine if urinary
levels of cyclic GMP, endothelin, and PGE2 differ in preeclamptic as compared to
normal pregnancies. Parameters were compared in 13 normotensive, nonpreeclamptic
pregnancies, and 32 preeclamptic pregnancies. Preeclamptic women had
significantly lower levels of urinary cyclic GMP (0.67 +/- 0.12 vs. 2.1 +/- 0.5
nmol/g creatinine), endothelin (0.88 +/- 0.09 vs. 3.75 +/- 1.4 ng/g creatinine),
and PGE2 (26 +/- 4 vs. 9 ng/g creatinine) as compared to normals (p < 0.05).
Intrarenal production of cyclic GMP, endothelin, and PGE2 are all disturbed in
preeclampsia and may have implications in the sodium retention, hypertension, and
intrarenal thrombosis and vasospasm of preeclamptic pregnancy.
PMID- 9394169
TI - The Cantrell-sequence: a result of maternal exposure to aminopropionitriles?
AB - The characteristic features of the Cantrell-sequence--anterior thoraco-abdominal
wall defect with ectopia cordis and diaphragm, sternum, pericardium, and heart
defects--have been observed in animals following maternal administration of beta
aminopropionitrile, a toxic amino-acid derivative. We report on an unusual case
of the Cantrell-sequence in a premature infant with associated dysmelia, aplasia
of the right kidney, cerebellar hypoplasia and circumscribed aplasia of the
cutis, which has not been reported previously. Maternal history suggested an
occupational exposure to aminopropionitriles prior to pregnancy. Prenatal
ultrasound, differential diagnosis, perinatal management, and the teratogenic
role of aminopropionitriles in this rare genetic disorder are discussed.
PMID- 9394170
TI - Liposomal amphotericin B in neonates with invasive candidiasis.
AB - Liposomal amphotericin B L-Amp B, a novel formulation of Amp B, is effective for
the treatment of invasive fungal infections in children and adults and is
associated with less toxicity than the conventional preparation. Data on the use
of L-Amp B in neonates is scarce. We describe the clinical course of two
premature infants who were treated with L-Amp B (one infant had candidemia, and
the other had candidemia and meningitis), and provide a summary of previously
published experience on this topic. L-Amp B may be an option for therapy of
invasive candidiasis in neonates who are at high risk of nephrotoxicity and other
amphotericin-related reactions, but clinical trials are necessary to document its
safety and efficacy in this age group.
PMID- 9394171
TI - Early-onset neonatal sepsis in Pakistan: a case control study of risk factors in
a birth cohort.
AB - We prospectively evaluated risk factors for early-onset neonatal (EON) sepsis in
a case-control study among inborn patients at the Aga Khan University Medical
Centre in Karachi between 1990-1993. A total of 38 cases with blood culture
proven bacterial sepsis were identified within 72 hr of birth (prevalence 5.6 of
1000 live births) and matched with two consecutive gender matched births with no
complications. The most common isolates were Staphylococcus aureus (18%), group B
Streptococci (13%), and Klebsiella pneumoniae (13%). Univariate analysis of
maternal risk factors revealed a significant association between maternal urinary
tract infection (UTI) (odds ratio [OR]20, 95% confidence interval [CI]2.4-166.9),
maternal pyrexia (P < 0.0001), vaginal discharge (P < 0.05), vaginal examinations
during labor (P = 0.03), and EON sepsis. The infected newborns also had
significantly lower apgar scores at birth (P < 0.0001) and a significantly
greater number were intubated at birth (Fisher's exact test P = 0.04). Infected
newborn infants were transferred out of the labor room earlier than noninfected
controls and significantly fewer received exclusive breastfeeds (OR 0.33, 95% CI
0.1-0.8). Our data suggest the possibility that both vertical transmission from
the mother as well as postnatal acquisition of infection from the environment may
be of importance in the pathogenesis of EON sepsis in Karachi. Preventive
measures should focus at recognition of high-risk infants, strict asepsis during
labor, and early institution of exclusive breastfeeding.
PMID- 9394172
TI - Exposure to pulsed magnetic fields in the treatment of plantar ulcers in leprosy
patients--a pilot, randomized, double-blind, controlled clinical trial.
AB - A pilot, randomized, double-blind, controlled clinical trial to study the effect
of exposure to pulsed magnetic fields (PMF) on the rate of healing of plantar
ulcers in leprosy patients was undertaken. Twenty patients were randomly
allocated to receive standard wound-care treatment (controls) and 20 others
received standard treatment plus exposure to PMF (sinusoidal form, 0.95 to 1.05
Hz, amplitude +/- 2400 nano Teslas) (study group) for four weeks. Assessment of
the outcome of treatment was based on the volume of ulcers, calculated from the
maximal length, breadth and depth of the ulcer recorded on the day of admission,
at one and two weeks and at the end of treatment. The analysis of the results was
based on 15 control patients and 18 PMF patients after deletion of four patients
due to irregularity in attendance and three others on account of suspected
malignancy of the ulcers. In the control group, the geometric mean volumes of the
ulcers were 2843 and 1478 cu mm on the day of admission and at the end of the
treatment (P = 0.03); the corresponding values in the PMF group were 2428 and 337
cu mm, respectively (P < 0.001). A decrease in the volume of 40% or more was
observed in 53% of control patients and 89% of PMF patients (P = 0.02); a
decrease of 80% or more was observed in none of the controls and in 33% of PMF
patients. These findings strongly suggest that exposure to PMF causes a
significantly more rapid healing of plantar ulcers in leprosy patients.
PMID- 9394173
TI - Semen biochemistry of leprosy patients.
AB - Studies have been made on the semen of three categories (borderline, borderline
tuberculoid and lepromatous) of leprosy patients to evaluate the seminal
biochemical constituents viz. fructose, glycerylphosphorylcholine and acid
phosphatase besides the physical properties viz. volume, pH, liquefaction time,
sperm density and sperm motility. In all categories of leprosy patients, seminal
pH, liquefaction time and sperm density underwent significant decline. The
decline in the seminal volume and sperm motility was significant only in
borderline leprosy. It was observed that seminal glycerylphosphorylcholine (GPC)
concentration and acid phosphatase activity declined in all categories of leprosy
patients but GPC showed a significant decline only in borderline tuberculoid and
acid phosphatase declined significantly only in borderline and lepromatous
leprosy.
PMID- 9394174
TI - Profile of leprosy in children: past and present.
AB - The profile of leprosy in children currently seen in a referral hospital is
compared with that of children with leprosy admitted in the 1970s. Children with
leprosy under the age of 15 years in 1974 and 1979 comprised one group (Group I)
while those during 1989 and 1994 constituted the second group (Group II) The
variables studied included age, sex, type of leprosy, deformity and contact
status. Multidrug therapy (MDT) was introduced in the treatment of leprosy in
1982. The probable change it has made in the presentation of leprosy in children
is discussed.
PMID- 9394175
TI - Concurrent leprosy and HIV infection: a report of three cases.
AB - Three cases of concurrent infection with HIV and leprosy are reported. One had
developed borderline lepromatous leprosy one year after identifying HIV
infection, while the other two had indeterminate leprosy and both conditions were
identified at the same time in these two patients. All three cases showed
satisfactory response to standard antileprosy multidrug therapy.
PMID- 9394176
TI - Shortening duration of treatment of multibacillary leprosy. Action Programme for
the Elimination of Leprosy, WHO.
PMID- 9394177
TI - Hidden cases of leprosy (in prison)
AB - Leprosy survey conducted in eight prisons in seven districts of Bihar State
revealed a prevalence of 13.3 per 1000 which was 12 times more than the recorded
prevalence of leprosy in the State. Thus this finding supports the view that
prisons could form a hyperendemic pocket for leprosy. Regular NLEP services need
to be extended to the inmates of the prisons.
PMID- 9394178
TI - Cauda equina syndrome masquerading as leprosy.
PMID- 9394179
TI - Profundus minus deformity in leprosy.
PMID- 9394180
TI - Building bridges and controlling parasites.
PMID- 9394181
TI - Australasian contributions to anti-parasite vaccines.
PMID- 9394182
TI - The Bancroft-Mackerras Oration. Livestock parasite treatment--a call for greater
interaction between research and industry sectors.
PMID- 9394183
TI - Livestock parasite treatment--a call for greater interaction between research and
industry sectors.
AB - During the past 2 decades, treatment of livestock parasitism has changed from a
situation of relative stability, particularly in the mid-late 1980s when the
macrocyclic lactone compounds were introduced, to the situation in many countries
now where control of sheep parasites is rapidly being lost. As serious as the
situation may be, now is not a time to wring our hands in despair but a time to
address some of the limitations and identify opportunities where a greater
integration of the efforts of research and industrial bodies might be directed to
maintaining parasite control in our livestock industry.
PMID- 9394184
TI - Molecular methods for diagnosis and epidemiological studies of parasitic
infections.
AB - Direct microscopy is widely used for the diagnosis of parasitic infections
although it often requires an experienced microscopist for accurate diagnosis, is
labour intensive and not very sensitive. In order to overcome some of these
shortcomings, molecular or nucleic acid-based diagnostic methods for parasitic
infections have been developed over the past 12 years. The parasites which have
been studied with these techniques include the human Plasmodia, Leishmania, the
trypanosomes, Toxoplasma gondii, Entamoeba histolytica, Giardia, Trichomonas
vaginalis, Cryptosporidium parvum, Taenia, Echinococcus, Brugia malayi,
Wuchereria bancrofti, Loa loa and Onchocerca volvulus. Early methods, which
involved hybridisation of specific probes (radiolabelled and non-radiolabelled)
to target deoxyribonucleic acid (DNA), have been replaced by more sensitive
polymerase chain reaction (PCR)-based assays. Other methods, such as PCR
hybridisation assays, PCR-restriction fragment length polymorphism (PCR-RFLP)
assays and random amplified polymorphic DNA (RAPD) analysis have also proved
valuable for epidemiological studies of parasites. The general principles and
development of DNA-based methods for diagnosis and epidemiological studies will
be described, with particular reference to malaria. These methods will probably
not replace current methods for routine diagnosis of parasitic infections in
developing countries where parasitic diseases are endemic, due to high costs.
However, they will be extremely useful for genotyping parasite strains and
vectors, and for accurate parasite detection in both humans and vectors during
epidemiological studies.
PMID- 9394185
TI - Designer vaccines for parasitic diseases.
AB - Conventional ways of developing vaccines against infections, either on pragmatic
grounds or by identifying protective antigens and attempting to mimic natural
immune responses, have largely been unsuccessful for parasitic-infections, mainly
because of the complexity of the immunological processes involved. It is clear
that a new approach is required and it is now known that the "immunological
environment" in which the immune response is initiated is as, or more, important
than the actual antigens used. CD4+ and CD8+ T1 cells, through the agency of IL-2
and IFN-gamma, direct the response towards cell-mediated immunity involving
cytotoxicity and macrophage activation, whereas T2 cells, through the agency of
IL-4 and IL-10, direct the response towards antibody production. The two poles
are counter-regulatory in that IFN-gamma inhibits antibody formation and IL-4 and
IL-10 inhibit macrophage activation. However, immune responses are not immutable
and can be artificially driven towards one or other pole, for example IFN-gamma,
IL-2 and IL-12 favour T1 responses, whereas IL-4 and IL-10 favour the T2 type.
With this knowledge, it is possible to design recombinant or nucleic acid
vaccines that include gene products or genes for desirable cytokines as well as
the appropriate antigen. For example, in experimental leishmaniasis, protective
immune responses can be induced by the incorporation of genes for IL-2 and IFN
gamma into recombinant Salmonella typhimurium vectors and nucleic acid vaccines.
A similar approach might be appropriate in experimental schistosomiasis, in which
exogenous IL-12 drives the immune response towards the T1 pole and ameliorates T2
mediated pathology. These approaches require novel delivery systems and these
have already begun to produce encouraging results. However, simply modifying the
nature and route of administration of the vaccine is not enough and attention has
now turned to the effector molecules involved, for example nitric oxide, and the
signaling systems that are modified by the presence of particular cytokines.
PMID- 9394186
TI - The importance of transmission-blocking immunity in the control of infections by
apicomplexan parasites.
AB - Transmission-blocking immunity may have great potential for use in the control of
diseases caused by apicomplexan parasites. In this review I will describe our
work on the application of transmission-blocking immunity to the control of the
Eimeria parasite and compare our results to those working on transmission
blocking immunity against Cryptosporidium and Plasmodium. Eimeria causes the
disease known as coccidiosis in domestic animals. Coccidiosis is particularly
problematic in the chicken industry, mainly due to the crowded rearing conditions
under which chicks are raised. In our work we identified, isolated and
characterized 3 major gametocyte antigens (230 kDa, 82 kDa and 56/54 kDa) of
Eimeria maxima. We used these native glycoproteins to immunize laying hens that,
via the egg yolk, provide large amounts of transmission-blocking maternal
antibodies to offspring chicks. We demonstrated that hatchlings from immunized
hens shed 60-80% fewer oocysts (i.e. the infective stage of the life-cycle of
Eimeria) than those from control hens. Such a reduction in oocyst output acts to
significantly reduce parasite numbers in the litter of chicks raised in floor
pens. This reduction in oocyst output is comparable to that seen using the most
effective coccidiostat drugs and is probably sufficient to control coccidiosis
under field conditions. Based on our results together with those of other groups
working on transmission-blocking immunity against Cryptosporidium and Plasmodium,
it appears that this immunological approach holds great promise for the control
of apicomplexan parasites that cause diseases in both animals and man.
PMID- 9394187
TI - Research collaboration in parasitology between Indonesia and Australia.
AB - Indonesia and Australia are close neighbours sharing agro-ecological zones and
common parasitological interests. Australia is an industrialised country and
Indonesia is both industrialising and a developing country. The types of
collaboration, contractual, collegiate, research collaboration and partnerships
are briefly described. All forms of collaboration have and continue to exist
between Australia and Indonesia. A survey of mammalian parasitology publications
over the last 23 years indicates that the bulk of papers have been by Indonesian
and non-Australian authors. Australian and Indonesian authors provided 4% of the
total number of publications. The rational for collaboration is suggested to be
the high degree of common multiple interests and the synergy of effort that can
be derived from research partnerships. The most difficult issues in research
collaboration are establishing the research priorities and, to a lesser extent,
funding. The globalisation of the international research centre, International
Livestock Research Institute, to include Asia will expand the opportunities for
research collaboration. Details of the Australian Centre for International
Agricultural Research mandate in supporting parasitology research collaboration
is briefly described. The past and current research collaborative activities are
reviewed and opportunities for future collaboration are listed.
PMID- 9394188
TI - Control of parasites in cultured marine finfishes in Southeast Asia--an overview.
AB - Mariculture in Southeast Asia began in the 1970s and expanded rapidly during the
1980s, with the commercial hatchery production of the seabass Lates calcarifer.
Other important cultured species were Epinephelus coioides, Epinephelus
malabaricus, Lutjanus johni, and Lutjanus argentimaculatus. Intensification in
the polyculture of these species and the large-scale international movement of
fingerlings or juveniles, as well as the rapid expansion and concentration of
fish farms, have caused severe problems resulting from parasitic infections.
Infections in maricultured fish are predominantly caused by monoxenous parasites,
in particular the capsalid and diplectanid monogeneans. Heteroxenous blood
parasites also successfully maintained transmission in the culture system despite
their requirement for an intermediate host. Prophylactic chemical treatments
helped to reduce parasitic infection but did not eliminate them and once
introduced into the floating netcage culture system, these parasites managed to
maintain their transmission successfully. Despite the current lack of information
regarding the biology of many parasites affecting cultured marine fishes, it
nevertheless is possible to develop methodologies to produce an integrated health
management system specifically designed to the needs of the mariculture practiced
in the Southeast Asian region. This system is important and should include a
sequence of prophylaxes, adequate nutrition, sanitation, immunization and an
effective system of marketing for farmed fishes.
PMID- 9394189
TI - Control of freshwater fish parasites: a Southeast Asian perspective.
AB - Parasites commonly found in freshwater fishes and other aquatic animals primarily
belong to Protozoa, Platyhelminthes, Acanthocephala, Nematoda, Hirudinea and
Crustacea. Most of these parasites are external parasites of the skin, fins or
gills, while few are internal parasites living in the epidermal intralamellar
gills, intestine or intramuscular tissues. Possible control measures involving
manual removal, cleaning by topical cleaners, management practices, nutritional
improvement, vaccination, chemoprophylaxis, chemotherapy, and quarantine and
certification, etc., are discussed.
PMID- 9394190
TI - Nematode parasite control of livestock in the tropics/subtropics: the need for
novel approaches.
AB - Because parasites are more abundant, small ruminants in the tropical/subtropical
regions of the world experience much greater ravages from internal parasitic
disease than those in the temperate regions. In the tropics/subtropics, the
limiting ecological factor influencing the severity of parasitism is rainfall, as
temperatures almost always favour hatching and development of the free-living
stages. Attempts to expand sheep and goat production by replacing traditional
village production systems, which rarely involve anthelmintic treatment, with
large-scale intensive commercial enterprises invariably induce complete reliance
on anthelmintics to control nematode parasites. This has led to the widespread
development of high level, multiple anthelmintic resistance throughout the
tropics/subtropics, and in certain regions this has reached the ultimate
disastrous scenario of total chemotherapeutic failure. Immediate concerted
efforts are needed to resolve this crisis. Significant benefits are likely to
emerge from research into non-chemotherapeutic approaches to nematode parasite
control, such as grazing management, worm vaccines, breed selection and
biological control. However, it is likely that none, in isolation or
collectively, will completely replace the need for effective anthelmintics. What
is needed is the integration of all methods of parasite control as they come to
hand, with the underlying aim of reducing the use and thus preserving the
effectiveness of anthelmintics. Although cheap and simple procedures, based on
sound epidemiological principles, can achieve dramatic benefits in worm control,
they have been poorly adopted by livestock owners. Clearly then, the greatest
need is for technology transfer and education programmes, but these activities
are generally found to be chronically under-resourced.
PMID- 9394191
TI - Basic and applied immunology in cestode infections: from Hymenolepis to Taenia
and Echinococcus.
AB - In larval cestode infections, it is well established that the intermediate
mammalian host infected with egg-derived metacestodes in the tissue becomes
completely immune to reinfection with eggs, whereas autoinfection has been
conceived to occur in Hymenolepis nana/mouse (and human) and Taenia solium/human
systems when these hosts are initially infected with metacestode-derived adult
tapeworms in the lumen. In this review paper, the first topic is immunobiology of
H. nana/mouse system on the reinfection immunity in order to get critical
information as to how the initially ingested parasite (eggs or metacestodes) can
develop into adult worms and how autoinfection does or does not occur in
immunocompetent mice, since H. nana can complete its whole life cycle in the
mouse intestinal tissue and lumen. When mice are infected with eggs (=
oncospheres) of H. nana, they become immune to challenge infections with eggs
within a few days (early response) and with cysticercoids within two weeks (late
response). The initially established adult worms are expelled later (worm
expulsion response). When mice are infected with cysticercoids, either derived
from beetles or mice, they become immune to challenge infection with
cysticercoids but not with eggs. Therefore, autoinfection occurs in the
intestinal tissue for the establishment of cysticercoids in the tissue but never
occurs in the intestinal lumen for the establishment of adult worms in
immunocompetent mice. The second topic is vaccination trial against challenge
infection with eggs of Asian Taenia in pigs. Pigs vaccinated with frozen
oncospheres of Asian Taenia from Taiwan or Korea or T. saginata showed very
strong resistance, whereas pigs vaccinated with those of T. solium showed partial
resistance only. It is suggested that Asian Taenia is much closer to T. saginata
than T. solium from the immunobiological viewpoint. The third topic is
immunodiagnosis of echinococcosis and cysticercosis. Immunoblot analysis has
revealed that Em18 (18 kDa component of crude antigens of Echinococcus
multilocularis protoscolex) and glycoproteins of T. solium cysticerci are highly
specific or unique to alveolar echinococcosis and cysticercosis, respectively.
The fourth topic is discussion on miscellaneous prospects including laboratory
animal models for echinococcosis and cysticercosis.
PMID- 9394192
TI - A vaccine against the Asian schistosome, Schistosoma japonicum: an update on
paramyosin as a target of protective immunity.
AB - Paramyosin from parasitic worms of the genus Schistosoma has shown promise as a
vaccine target and it is one of the candidates selected by WHO for the
development of a vaccine against schistosomiasis. Here we discuss the literature
of the past decade and report on different recombinant paramyosin constructs we
are using in our laboratory to develop a vaccine against the Asian schistosoma,
Schistosoma japonicum.
PMID- 9394193
TI - Immunological approaches for the control of fasciolosis.
AB - The immunological relationship between liver flukes and their mammalian hosts is
being unravelled by in vivo and in vitro studies. Vaccine studies in cattle and
sheep with purified antigens (fatty acid binding protein, FABP; glutathione S
transferase, GST; cathepsin L, CatL; hemoglobin) have shown that high reductions
in worm burdens (31-72%) and egg production (69-98%) can be achieved, raising the
realistic possibility that immunological control of Fasciola infection is a
commercially achievable goal. Combination vaccines may also be feasible since a
cocktail of CatL and hemoglobin elicits a significant 72% protection in cattle.
Analysis of immune responses to Fasciola during infection in ruminants suggests
that chronic infection correlates with a type 2 helper T cell response, implying
that type 1 helper T cell responses are down-regulated in fasciolosis. Recent
results studying the resistance of Indonesian Thin Tail (ITT) sheep to F.
gigantica have shown that this breed exhibits high innate (or rapidly acquired)
resistance to infection and acquires a higher level of resistance after a primary
challenge. Initial studies suggest that the resistance of ITT sheep to F.
gigantica may be determined by a major gene. Merino sheep also acquire resistance
to F. gigantica. In contrast, ITT and Merino sheep do not exhibit resistance to
F. hepatica. These results suggest that there are fundamental differences between
these two species of Fasciola in the biology of their interaction with the sheep
immune system. In vitro studies on immune mechanisms of killing of juvenile fluke
have shown that juvenile larvae of F. hepatica are susceptible to antibody
dependent killing by activated rat macrophages in vitro which is mediated by
nitric oxide. Future studies on the immune effector mechanisms expressed by
resistant sheep which control infection by F. gigantica will lead to new
knowledge which may allow the design of more effective vaccines for fasciolosis.
PMID- 9394194
TI - The biological basis of malarial disease.
AB - In this review we summarise the arguments that inflammatory cytokines, triggered
by material released from the parasite at schizogony (malarial toxin), might
induce the illness and pathology seen in malaria. These pro-inflammatory
cytokines can generate inducible nitric oxide synthase and cause nitric oxide to
be released, as can low concentrations of malarial toxin itself provided
interferon-gamma, which has only low activity in the absence of malarial toxin,
is present. We suggest here that recently described hypermetabolic functions of
these mediators provide a much more plausible explanation for malarial
hyperlactataemia and hypoglycaemia, the chief prognostic indicators in falciparum
malaria, than does hypoxia secondary to mechanical blockage of vessels by
sequestering parasites, which is the dominant current theory. We also review the
arguments that rationalise, through these mediators, the reversibility of the
coma of cerebral malaria. Although not yet tested at a cellular level, the
proposal that nitric oxide generated in cerebral vascular walls contributes to
this coma continues to gather indirect support. In addition, new evidence
incriminating nitric oxide in the mechanism of tolerance to endotoxin
rationalises the raised nitric oxide generation seen in malarial tolerance.
PMID- 9394195
TI - Tumour necrosis factor and associated cytokines in the host's response to
malaria.
AB - Tumour Necrosis Factor (TNF) is produced at the initiation of malaria infections
(pre-erythrocytic phase), as demonstrated by the release of bioactive TNF by
peripheral blood mononuclear cells from individuals residing in endemic areas
after stimulation with stage specific sporozoite antigens. During the
erythrocytic phase, TNF production is greatly augmented by parasite antigens at
the time of schizont rupture and merozoite release from infected erythrocytes.
Some of the strongest inducers of TNF synthesis and release are malaria toxins,
e.g. glycosylphosphatidylinositol moieties and malaria pigment. Because of TNF's
well-known cytotoxic activity it was originally hypothesized that it alone was
responsible for killing parasites directly or within host cells. Though earlier
reports of the capability of serum containing TNF to kill plasmodia supported
this idea, later experiments with recombinant TNF showed a lack of significant
parasiticidal activity. Recent studies investigating related factors showed that
they were involved with TNF in the control of infection. These factors included
ther cytokines, such as interleukin (IL)-1, IL-6, IL-12, interferon-gamma (IFN
gamma) as well as nitric oxide intermediates (NOI) and reactive oxygen
intermediates (ROI). This positioned TNF as a key regulator of the immune
response against the malaria parasite. However, it must be noted that TNF and its
associated factors are also responsible for the fever, aches and pains of acute
illness, as well as the hypoglycemia, shock, bleeding and reversible coma of
severe malaria seen in approximately 1 percent of individuals with malaria.
Therein lies the rub; factors important in the control of malaria also appear to
have detrimental properties. Research presented in this review characterizes TNF
and associated cytokines' importance in the immune response to malaria.
PMID- 9394196
TI - An international practitioner data bank as a quality tool.
AB - While international tort costs have not reached the level of those in the United
States, international medical employers, like their American counterparts, must
be able to ascertain updated objective information regarding the physicians they
are going to employ, in order to protect their patients and organizations from
the increasing risks in today's medical environment. The NPDB set up in the
United States by the United States Congress provides a structure that can record
and set standards for professional reviews. While the data bank established in
the United States can still be considered a new entity, and the exact impact it
has on quality, peer review and risk management is still being judged, it is the
first step towards an organized, objective governing body. We recommend that an
international committee convene to study the American model of a data bank and
decide how and which parameters could be used for setting international standards
and norms to be recorded in an international data bank. This data bank would be
an important addition to the increasing array of tools available to ensure
quality care.
PMID- 9394197
TI - Data bank--"1984 and all that".
PMID- 9394198
TI - International practitioner data bank as a quality tool: are we using behavior
control in the right environment?
PMID- 9394199
TI - Internationalizing the National Practitioner Data Bank.
PMID- 9394200
TI - International Practitioner Data Bank: false premise, false promise.
PMID- 9394201
TI - Improving health care quality. Is standardization the answer?
PMID- 9394202
TI - The policy implications of using hospital and physician volumes as "indicators"
of quality of care in a changing health care environment.
AB - There is growing interest in the quality of health care and in using quality
measures to direct patients to hospitals and providers offering high quality, low
cost health care. The dilemma is that, while there is an increasing need for
quality indicators as a result of a changing health care environment, this
changing environment has important implications for the use of some of these
measures. Since the 1970s, a growing body of research in the U.S. has addressed
the empirical relationship between the number of patients with a specific
diagnosis of surgical procedure and their outcomes after treatment in a
particular hospital or by a particular physician ("volume-outcome" studies). In
this paper, we examine the policy implications of using hospital and physician
volume information as an "indicator" of quality in a rapidly changing health care
environment with new players and new incentives. We begin by describing the
evolution of the use of volumes within both regulatory and market-oriented
contexts in the U.S. We then discuss policy considerations and cautions in using
volumes, along with suggestions for future research. Our purpose is to point out
potential problems and clarify confusions about the use of volumes, so that
policymakers and practitioners can be sensitive to the potential minefields they
are traversing.
PMID- 9394203
TI - Treatment adequacy for HIV-related pneumocystis pneumonia: quality measures for
inpatient care.
AB - To develop and evaluate severity-adjusted indicators of treatment timeliness and
adequacy for inpatient care of first episode of HIV-related pneumocystis
pneumonia, a retrospective cohort study (n = 414) using medical record review was
conducted in six California medical centers (1 January 1983-30 June 1987).
Measures included patient baseline characteristics and complexity, process-of
care indicators (delay in treatment initiation and proportion of adequate
treatment delivered), and overall survival of hospitalization and survival
without respiratory failure. Logistic regression models of severity were
developed among optimally treated patients and cross-validated. Exposure to
medication with pneumocystis activity within 30 days prior to admission was
protective. After controlling for pre-admission medication and severity, the
average proportion of adequate pneumocystis medication delivered during the first
7 and 30 days were significant predictors of outcome in all models. Delay in
treatment initiation, while not a statistically significant predictor, was
associated with baseline severity. Summary measures of treatment adequacy show
promise as process-of-care indicators.
PMID- 9394204
TI - Quality of STD care in Zambia. Impact of training in STD management.
AB - STUDY OBJECTIVE: To assess quality of care of sexually transmitted diseases
(STDs) and evaluate interactive training methods aimed at improving providers'
performance. DESIGN AND SETTING: This comparative study, with a baseline,
intervention, and evaluation phases was conducted at two urban health centers in
Zambia. The personnel at one health center were trained in STD management using
interactive training methods. The other health center acted as a control.
SUBJECTS AND METHODS: Two-hundred patients with STD were interviewed and their
interaction with health care providers observed before and after the training.
Another 200 interviews and observations were conducted at the control health
center. RESULTS: The proportion of patients being examined, given health
education and informed about partner notification increased significantly after
the intervention. The proportion of patients who had complaints about the health
care did not decrease. Long waiting time and lack of time to discuss the disease
were the main complaints. CONCLUSION: The training solved some, but not all,
problems of poor case management. This indicates the need for a more process
oriented approach for improving quality of care.
PMID- 9394205
TI - Patient satisfaction with emergency house calls.
AB - STUDY OBJECTIVES: To identify determinants of patient satisfaction with emergency
house calls and to assess the properties of a satisfaction measurement
questionnaire. DESIGN: Patient survey, combined with routinely collected
information on the circumstances of the house call. SETTING: Emergency house
calls provided by an independent emergency care organization (ECO) in Geneva,
Switzerland. PARTICIPANTS: Consecutive sample of 389 patients (67% response
rate). MAIN OUTCOME MEASURE: Patient satisfaction. PREDICTOR VARIABLES: patient
age and sex, type of medical problem, time of visit, waiting time, duration of
visit, perceived effectiveness of treatment. RESULTS: The satisfaction
questionnaire was easy to administer. Factor analysis identified 3 separate
dimensions of satisfaction, which pertained to the visit itself, to access and to
general attitude toward the ECO. Validation tests were consistent with
expectations. In multivariate analysis, older patient age and greater perceived
treatment effectiveness predicted independently all satisfaction scales. Presence
of a mixed physical and mental problem reduced satisfaction with the visit itself
only, a delay between the phone call and the visit exceeding one hour reduced
satisfaction with access and worsened the attitude toward the ECO. CONCLUSION:
The instrument used to measure patient satisfaction with emergency house calls
performed well. Overall levels of satisfaction were high. Perceived effectiveness
of treatment was the strongest correlate of patient satisfaction. Monitoring of
patient satisfaction in emergency settings may contribute to improvements of
quality of care.
PMID- 9394206
TI - Quality management savings: at Al-Hussein Hospital, Salt, Jordan.
PMID- 9394207
TI - Quality Assurance Project: the second five years.
PMID- 9394208
TI - Re: ISQua position paper.
PMID- 9394209
TI - Re: ISQua position paper.
PMID- 9394210
TI - "Every defect is a treasure".
AB - After seeing multiple providers for various complaints, a patient becomes
frustrated with the healthcare system. She is diagnosed with acromegaly secondary
to pituitary tumor when she transfers to another healthcare system.
PMID- 9394211
TI - Cold restraint-induced gastric lesions in individual- and group-stressed rats.
AB - The aim of the present study was to 1) determine the intensity of cold restraint
induced gastric lesions and core body temperature in single- and group-stressed
rats, and establish a correlation between them; and 2) determine the influence of
visual contact among animals during cold restraint on development of gastric
stress ulcer. Therefore, adult male Wistar rats were put into individual or group
restraint boxes (composed of two, three, six or nine single boxes) with or
without possibility of visual contact and then exposed 2 hr to the cold (4
degrees C). Core body temperature was measured just before and after cold
restraint using a digital rectal thermometer. The results showed that: 1) single
stressed animals expressed significantly higher ulcer index than those stressed
in group of three, six and nine rats; 2) there was no significant difference in
degree of hypothermia among rats exposed to various group paradigms; and 3) there
was no significant difference in ulcer index among animals stressed in conditions
with or without visual contact. An absence of significant difference in ulcer
index between single and paired stressed rats implies that three is the lowest
number of animals per group at which an influence of group size on behavioral and
adaptive mechanisms in rats exposed to cold restraint becomes manifest.
PMID- 9394212
TI - Learning and memory in nucleus basalis magnocellularis-lesioned rats after
transplantation of fetal frontal cortex.
AB - The effect of fetal frontal cortex transplantation on behaviour performance was
examined in adult male Wistar rats with lesions of the nucleus basalis
magnocellularis (NBM). Compared to intact and sham-operated controls, the rats
tested ten or twenty days after bilateral electrolytic lesions of NBM exhibited
the significant learning and memory impairments (acquisition and performance of
two-way active avoidance) whereas spontaneous motor activity was not
significantly altered. The animals which received allotransplants of fetal
frontal cortex (from 18-day gestational rat fetuses) into NBM, two ("early"
transplantation-NBM-ET) or ten ("delayed" transplantation-NBM-DT) days after
lesioning, respectively, manifested the complete amelioration of noticed
impairments when tested ten days after transplantation procedure. Corresponding
sham-transplants groups (NBM-SET and NBM-SDT) showed only slightly improvement of
acquisition but not performance of two-way active avoidance. The ability of the
transplants to restore learning and memory in the NBM lesioned rats suggests that
graft of fetal frontal cortex can functionally influence neuronal activity of the
lesioned host brain.
PMID- 9394213
TI - Ultrastructural study of NADPH-d positive neurons in laminae I and II of the rat
caudal spinal trigeminal nucleus.
AB - The present study investigated the ultrastructure of neurons in the caudal spinal
trigeminal nucleus. These neurons which are believed to function as interneurons
in the transmission of orofacial nonreflexive nociceptive information, measured
20 microns x 11 microns, and were nicotinamide adenine dinucleotide phosphate
diaphorase (NADPH-d) positive. The reaction product, formazan, was localized in
the nuclear envelope, mitochondria, rough endoplasmic reticulum, and
multivesicular bodies of these neurons. It was also localized in the membrane of
the smooth endoplasmic reticulum at the axon terminal. The neurons were contacted
by both axosomatic and axodendritic synapses formed by both NADPH-d positive and
NADPH-d negative axon terminals. Two types of NADPH-d positive axon terminals
could be recognized. The first was a large terminal containing many stained
mitochondria and unstained small round agranular vesicles mixed with some
slightly flattened ones. It formed asymmetrical axodendritic synapse. The second
type of axon terminals contained pleomorphic synaptic vesicles and formed
asymmetrical synapses upon both dendrites and soma. The sources of NADPH-d
positive axon terminals were discussed. Most of the unstained axon terminals
forming axosomatic and axodendritic synapses with stained cell bodies and
dendrites contained flattened vesicles. In addition to the above, complicated
synaptic configurations showing NADPH-d positive axoaxonic synapses in relation
to NADPH-d negative dendritic spines were also seen in which a NADPH-d negative
dendritic spine was completely contacted by a NADPH-d positive bouton which was
in turn contacted by another NADPH-d positive bouton.
PMID- 9394214
TI - Impaired temporal discrimination in Parkinson's disease: temporal processing of
brief durations as an indicator of degeneration of dopaminergic neurons in the
basal ganglia.
AB - Recent findings suggest that temporal processing of brief durations is a function
of dopaminergic neurotransmission in the basal ganglia. Furthermore, there is
preliminary evidence of abnormal timing functions in patients suffering from
idiopathic Parkinson's disease (PD). In the present study, temporal
discrimination of intervals in the range of milliseconds was investigated in 20
PD patients and 20 healthy controls matched for sex and age. Temporal
discrimination was significantly impaired in PD patients as compared to healthy
controls. For PD patients, additional correlational analyses did not yield any
significant relationship between performance on temporal processing and degree of
motor impairment or illness duration. However, impairment in temporal processing
was associated with dosage of L-dopa substitution and self-rated feelings of
depression. The overall pattern of results suggests that deficits in temporal
information processing observed in PD patients may represent a trait marker of
vulnerability to decreasing levels of dopaminergic activity in the basal ganglia
rather than a state-dependent indicator of the acute clinical symptomatology.
PMID- 9394215
TI - Reversal of cognitive impairment in an elderly parkinsonian patient by
transcranial application of picotesla electromagnetic fields.
AB - A 74 year old retired building inspector with a 15 year history of Parkinson's
disease (PD) presented with severe resting tremor in the right hand, generalized
bradykinesia, difficulties with the initiation of gait with freezing, mental
depression and generalized cognitive impairment despite being fully medicated.
Testing of constructional abilities employing various drawing tasks demonstrated
drawing impairment compatible with severe left hemispheric dysfunction. After
receiving two successive transcranial applications, each of 20 minutes duration,
with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla flux density and
frequencies of 5Hz and 7Hz respectively, his tremor remitted and there was
dramatic improvement in his drawing performance. Additional striking improvements
in his drawing performance occurred over the following two days after he
continued to receive daily treatments with EMFs. The patient's drawings were
subjected to a Reliability Test in which 10 raters reported 100% correct
assessment of pre- and post drawings with all possible comparisons (mean 2 = 5.0;
p < .05). This case demonstrates in PD rapid reversal of drawing impairment
related to left hemispheric dysfunction by brief transcranial applications of AC
pulsed picotesla flux density EMFs and suggests that cognitive deficits
associated with Parkinsonism, which usually are progressive and unaffected by
dopamine replacement therapy, may be partly reversed by administration of these
EMFs. Treatment with picotesla EMFs reflects a "cutting edge" approach to the
management of cognitive impairment in Parkinsonism.
PMID- 9394216
TI - Occurrences of electroencephalographic (EEG) patterns that resemble epileptiform
discharges in background EEG in epileptic patients.
AB - The relationships of background EEG to epileptiform discharge development were
studied in 9 epileptic patients having generalized spike and wave complexes
(SWCs) with a maximum at the frontal location on either side. The instantaneous
power spectrum of EEGs at F3, F4, C3, C4, P3, P4, O1, O2, T3 and T4 was estimated
with wavelet transform. Subsequently, the similarity of power spectra between
SWCs and background EEG was determined by use of Kullback-Leibler information and
artificial neural network in each patient. Both similarity measures revealed that
EEG patterns similar to SWCs occurred in the background activity just before SWCs
at frontal locations. These findings suggested that these SWC-like EEG events
occurred as poorly developed epileptiform discharges buried in the background
activity.
PMID- 9394217
TI - The Stroop's test evokes a negative brain potential, the N400.
AB - The Event Related Potential (ERP) of 8 french right handed subjects were recorded
with 5 active electrodes located in frontal (Fz), central (Cz), occipital (Oz)
and right/left parietal (RH, LH) sites while they were performing a modified
version of the test of Stroop. They had either to read the names of basic colors
(yellow, green, blue, red) written in the same colors (red written in red:
concordant stimuli) or in a different color (red written in blue: discordant
stimuli) or to name mentally the color in which was written the name of a color,
both colors being concordant or discordant. The ERPs for reading were similar for
concordant and discordant stimuli and showed no sign of a N400 wave, this was
also the case for the mental naming of a color associated to the written name of
the same color. A N400 wave with a Cz location was evident for the mental naming
of a color when it was associated to the written name of another color. In this
last case, the automatic reading of the name of a color would correspond to a
priming which interferes with the access to the target word: the name of another
color that the subject is required to evoke mentally.
PMID- 9394218
TI - Brain-stem auditory evoked potential monitoring. The increase of the stimulus
artifact in the development of brain death: a biological phenomenon?
AB - Brain-stem auditory evoked potentials (BAEPs) were recorded in 12 dead subjects
(mean age, 72.6 +/- 14.8 years), 30.6 +/- 19.5 hours (range 9-70) after abolished
systemic circulation. Death was due to cardiac failure (n = 10), intracerebral
hemorrhage (n = 1) and larynx cancer (n = 1). The presence and amplitude of the
stimulus artifact were evaluated. The mean (+/- SD) amplitudes of the stimulus
artifact was 0.03 +/- 0.02 microV on the left side and 0.01 +/- 0.02 microV on
the right side. These findings in accordance with previous studies on comatose
patients and brain dead subjects confirm that the increase of the stimulus
artifact in the development of brain death, in spite of stimulation with
alternating polarity, seems to reflect a biological phenomenon which is not found
in dead subjects after complete cessation of systemic circulation.
PMID- 9394219
TI - Electrophysiological analysis of expectancy: P3 in informed guessing.
AB - 18 healthy subjects had to guess, which of two nonequiprobable events would occur
next. Each trial was preceded by a cue which increased the probability of the
corresponding event as compared to its global probability. Event-related
potentials (ERPs) were recorded and then classified according to global
probability of events, their relation to the preceeding cue (valid versus invalid
cues) and to subject's prediction (predicted versus nonpredicted). Two late
positive waves (P350 and P550) with parietal maxima were distinguished. Both
waves had larger amplitudes in response to improbable events than to highly
probably events. Similarly, both had larger amplitudes following invalid cues
than following valid cues, and this difference was larger in those subjects who
tended to follow the cue than in those who tended to reject it. No difference in
terms of ERP component amplitudes was found between predicted and unpredicted
events; however, the latency of the P350 peak was longer following unpredicted
events. Taken together with data of the literature, the present results indicate
that ERP allow us to distinguish between two meanings of the word "expectancy":
(1) the rule-related expectancy as cognitive estimation of the likelihood or
"representativeness" of an event (based on grasping event contingencies), and (2)
the goal-related expectancy manifested in the subject's overt behavior. Only the
former "expectancy" affects the amplitude of the late positive wave ("P3"), while
the latter does not.
PMID- 9394220
TI - Reliability of dipole localization for the movement-evoked field component MEF I.
AB - The movement-evoked field I (MEF I) component is the largest and most stable
neuromagnetic component accompanying self-paced movements. In order to use MEG
for studying dynamic changes in the cortical organization of movements, data
about the reliability and variability of these neuromagnetic components for
individual subjects must be established during different sessions. For this aim,
three male subjects were requested to perform self-paced flexions of their index
finger and thumb in repeated sessions while the MEG was recorded by a 31 channel
system. The MEF I was identified for each session and a single equivalent dipole
was calculated for this component. The dipole localizations of the various
sessions were compared. The standard deviation of the localization for all
persons and all values amounts to 4.0-5.2 mm for the three spatial dimensions.
Our data suggest that the spatial distance between two single focal sources
fitted to the MEF I must be greater than 14 mm to be interpreted as distinct.
However, the neuromagnetic field structure and the resulting dipole localization
of the MEF I component are quite stable and could be used for the evaluation of
cortical plasticity.
PMID- 9394221
TI - Modulation of microglial form and immune function by factors released from
goldfish optic nerves.
AB - Activation of microglia is associated with neural damage and may aid repair of
the CNS. To begin to investigate their role, microglia purified from mouse brain
were grown in media conditioned (CM) by goldfish optic nerve (GFON), optic tectum
(GFOT), vagal lobe, telencephalon and cerebellum, and medium conditioned by rat
optic nerves (RON). Microglia maintained in GFON- or GFOT-CM assumed an ameboid
morphology, whereas microglia grown in media conditioned by the other neural
tissues produced long, crenellated processes that resembled the ramified
microglial form. Microglia maintained in all types of CM functioned as antigen
presenting cells in a MHC-restricted manner when tested on conalbumin-specific
Thelper (Th) cells, except for microglia maintained in GFON- and GFOT-CM. These
studies suggest that GFON, in contrast to RON, produces a substance(s) that
affects microglial morphology and immune reactivity, and may promote the vigorous
regeneration seen in GFON after damage.
PMID- 9394222
TI - Facial asymmetry in right- and left-handed men and women.
AB - A posteroanterior cephalometric radiographic study was performed on the right-
and left-handed men and women with normal occlusion. A posteroanterior
cephalometric radiography was conducted in these subjects. Method of
triangulation was used to measure various face areas. The surface areas of these
triangles were compared with their equivalents on the contralateral side. Sex and
its interactions with handedness and side were significant factors influencing
facial areas. Areas on the left were found to be significantly larger than those
on the right in right-handers. Left-handers were inconsistent in facial
asymmetry, but they tended to have larger facial areas on the right than the
left. Sex was especially significant for left-handers. It was suggested that an
asymmetric development in some brain regions may be responsible for the
development of asymmetric facial regions.
PMID- 9394223
TI - Case report: subependymal diffuse heterotopia. Clinical, EEG, and neuroimaging
findings.
AB - We report the case of a 41 year-old woman with a slight mental retardation and
epilepsy. MRI showed a diffuse subependymal heterotopia. The cognitive level
supports the view that the ectopic cells are probably not important for the
normal cortical functions but that they are likely able to maintain some of the
electric properties of normal neurons, even if with altered discharge modalities.
The genetic etiology of subependymal neuronal migration disorders is discussed.
This is the second reported case of diffuse subependymal heterotopia in a female
patient.
PMID- 9394224
TI - Effects of intrathecal monoamine antagonists on the nociceptive c-Fos expression
in a lesioned rat spinal cord.
AB - Effects of intrathecal (i.t.) administration of monoamine antagonists on formalin
induced neuronal c-Fos expression in two sides of the lumbar dorsal horn were
observed in rats with unilateral transection of the dorsolateral funiculus at T11
12 level. The results showed that: 1) pretreated with i.t. normal saline
(control) and then an equal volume of formalin was injected into the two
hindpaws, the number of Fos-like immunoreactive neurons were 44% lower on the
side of lumbar dorsal horn with intact dorsolateral funiculus (57 +/- 3.1 vs. 103
+/- 3.8). 2) Pretreatment with i.t. phentolamine (a non-selective alpha
adrenoceptor antagonist) caused an increase of Fos-like immunoreactive neurons on
the intact side so showing only a reduction rate of 23% to the lesioned side (p <
.01); 3) pretreatment with i.t. cyproheptadine (a 5-HT-receptor antagonist)
caused a similar reduction rate of 21% (p < .01) of Fos-like immunoreactive
neurons on the intact side; and 4) combined i.t. pretreatment with phentolamine
and cyproheptadine caused a reduction of Fos-like immunoreactive neurons of only
4% on the intact side, namely, the differences in the number of Fos-like
immunoreactive neurons on two sides of the lumbar spinal cord owing to the
unilateral dorsolateral funiculus lesion were nearly abolished by i.t.
coinjection of phentolamine and cyproheptadine. The results indicate that 1)
peripheral noxious inputs can provoke a spinally-descending inhibitory effect on
the spinal nociceptive transmission via the dorsolateral funiculus and 2) the
descending fibers in dorsolateral funiculus exert their action mainly through the
release of either norepinephrine or 5-HT at the spinal level.
PMID- 9394225
TI - Open field behavior in nucleus basalis magnocellularis-lesioned rats treated with
physostigmine and verapamil.
AB - The present study was done to investigate and compare the effect of
acetylcholinesterase inhibitor, physostigmine (0.030, 0.045, 0.060 and 0.075
mg/kg sc) and Ca-antagonist, verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg sc) on open
field behavior in male Wistar rats with bilateral electrolytic lesions of nucleus
basalis magnocellularis (NBM). NBM-lesions produced a significant increase and
decrease of ambulation and number of inner squares entered, and defecation,
respectively, with no influence on grooming in rats exposed to novel environment.
Physostigmine and verapamil in all tested doses, given 30 min before the test did
not affect the open field behavior in control animals. In contrast to that,
physostigmine (0.045, 0.060 and 0.075 mg/kg) and verapamil (2.5 and 5.0 mg/kg)
significantly reduced ambulation and number of inner squares entered in NBM
lesioned rats. Also, physostigmine in a dose of 0.060 mg/kg significantly
decreased defecation and in doses of 0.060 and 0.075 mg/kg the grooming, as well.
On the other hand, verapamil only in a dose of 2.5 mg/kg significantly increased
defecation. It could be concluded that lesions of NBM in rats induced
disturbances in the open field behavior, which might be successfully ameliorate
by physostigmine and verapamil treatment.
PMID- 9394226
TI - Treatment with AC pulsed electromagnetic fields improves the response to levodopa
in Parkinson's disease.
AB - A 52 year old fully medicated Parkinsonian patient with severe disability (stage
4 on the Hoehn & Yahr disability scale) became asymptomatic 10 weeks after he
received twice weekly transcranial treatments with AC pulsed electromagnetic
fields (EMFs) of picotesla flux density. Prior to treatment with EMFs, his
medication (Sinemet CR) was about 50% effective and he experienced end-of-dose
deterioration and diurnal-related decline in the drug's efficacy. For instance,
while his morning medication was 90% effective, his afternoon medication was only
50% effective and his evening dose was only 30% effective. Ten weeks after
introduction of treatment with EMFs, there was 40% improvement in his response to
standard Sinemet medication with minimal change in its efficacy during the course
of the day or evening. These findings demonstrate that intermittent, AC pulsed
applications of picotesla flux density EMFs improve Parkinsonian symptoms in part
by enhancing the patient's response to levodopa. This effect may be related to an
increase in the capacity of striatal DA neurons to synthesize, store and release
DA derived from exogenously supplied levodopa as well as to increased serotonin
(5-HT) transmission which has been shown to enhance the response of PD patients
to levodopa. Since decline in the response to levodopa is a phenomenon associated
with progression of the disease, this case suggests that intermittent
applications of AC pulsed EMFs of picotesla flux density reverse the course of
chronic progressive PD.
PMID- 9394227
TI - Drug induced double peak waveforms in the N20-component of somatosensory evoked
potentials.
AB - The double peak waveform of the N20 component of the early somatosensory evoked
potentials is a rare finding. In the present paper we investigated 9 patients
(mean age +/- SD: 31.3 +/- 11.3 years; range 18-52 years) with the phenomenon of
the two subcomponents of the primary cortical complex, after stimulation of the
median nerve in a retrospective analysis. The results of the heterogenous patient
group showed that the generation of the second subcomponent is not pathognomonic
for patients with severe head injury, that it could be reversible and that
pharmacological induced effects are presumably responsible for this phenomenon.
PMID- 9394228
TI - Involvement of brain dopaminergic structures in neuroimmunomodulation.
AB - Bilateral electrolytic destruction of the brain areas containing dopamine (DA)
cell bodies (nuclei A9 and A10) as well as terminal regions of the nigrostriatal
and mesolimbic DAergic systems (nuclei caudatus and accumbens) resulted in a
considerable decrease in the intensity of the immune response in rats immunized
with sheep red blood cells (SRBC). Administration of SRBC (5 x 10(8) i.p.) to
rats produced a marked rise in activity of central DAergic system at early stage
of the immune response formation. The most pronounced elevation in the
concentration of DA and its metabolites, measured by the method of high
performance liquid chromatography with electrochemical detection, was observed in
the terminal regions of the nigrostriatal and mesolimbic DAergic systems (nuclei
caudatus and accumbens), hypothalamus, hippocampus, amygdala within 20 min
following antigen inoculation. By 60 min after immunization DA metabolism has
been retained at a high level in all brain regions examined. The concentration of
DA returned to control level in the amygdala and hypothalamus 24 hours after
antigen administration and had a tendency to reach control values in the rest of
the structures. The present results indicate that nigrostriatal and mesolimbic
DAergic systems and DAergic structures of the hypothalamus are involved in the
mechanisms of neuroimmunomodulation.
PMID- 9394229
TI - Unilateral brain lesions and performance on Russell's version of the Wechsler
Memory Scale in an African American population.
AB - Studies of patients with unilateral lesions report hemisphere-specific and locus
specific impairments on Russell's (1975) Revision of the Wechsler Memory Scale
(RWMS). In the current investigation "race-homogeneous" and "race-comparative"
paradigms provide the context in which the generalizability of RWMS findings are
examined in a population of African Americans with unilateral lesions. The
performances of brain-damaged patients were impaired relative to normal controls
on five of the six RWMS measures. However, patients with left and right
hemisphere damage in our sample did not differ systematically on RWMS subtests.
Likewise, among patients with lesions confined to one of the quadrants in the
brain, there were no quadrant group differences in performance on RWMS subtests.
But, right posteriors were impaired relative to controls on immediate and delayed
VR subtests. The relative merits of the race-comparative and race-homogeneous
paradigms are considered in the context of these findings.
PMID- 9394230
TI - Attentional systems and the allocation of cerebral resources in reading and
grammatical tasks.
AB - To evaluate the possible role of attentional centers as modulators of neural
networks that mediate visual tasks involving reading and grammatical
manipulations of verbs, we measured cerebral blood flow (CBF) using positron
emission tomography (PET), and reaction times as subjects read verbs, "nonce
verbs" such as jelt or brep, and formed past tenses of regular, irregular and
nonce verbs after viewing their stems. Statistical parametric maps (SPMs) showed
significant activation of the pulvinar in the read verb irregular, and generate
nonce past tense tasks, compared to rest. This was confirmed by a post hoc ANOVA
of CBF values from a discrete locus in the pulvinar (p = .0000417). Functional
links between the pulvinar and other brain regions were shown by high
correlations of CBF in the pulvinar with CBF in brain regions known to have
anatomical connections to the pulvinar, particularly those mediating vision.
There was also a significant relationship between task-specific reaction times
and rest minus task CBF differences in a multiple regression analysis that
included CBF values from the pulvinar, superior colliculus plus reticular
formation, and the anterior cingulate, known attentional centers (p = .021, r2 =
0.99). Regression analyses relating reaction time to the amount of brain
activated (pixels in the SPMs) and the degree of activation of the pixels (mean Z
score) yielded p values of .078 and .074, respectively. Our data provide direct
experimental evidence to support the hypothesis that attentional centers are
activated in proportion to the complexity of visually mediated language tasks and
that the centers that mediate attention modulate the activity of task-specific
neural networks.
PMID- 9394231
TI - Evidence of altered cerebral blood-flow relationships in acute phobia.
AB - Functional cerebral guiding and integrating systems may be revealed by analyzing
the covariation of regional cerebral blood flow (rCBF). Positron emission
tomography (PET) was used to measure absolute rCBF in 14 volunteers with specific
phobia and 6 nonphobic controls, when exposed to videos containing phobia
relevant and neutral scenes. A fear reaction and increased covariation between
absolute rCBFs was observed during phobia-relevant as compared to neutral
stimulation in phobics only. In controls fear was not elicited and rCBF
covariation was not influenced by stimulus condition, being similar to the
pattern observed in phobics during neutral stimulation. We suggest the rCBF
correlative pattern during phobic fear to reflect fear-related activation of
distinct neuronal pathways that involves the amygdala, the thalamus, and the
striatum. We theorize that these pathways are activated also by uncontrolled
emotions in diverse conditions, like posttraumatic stress disorder, panic
disorder, and schizophrenia.
PMID- 9394232
TI - Clinical case report: memory functions after anterior communicating artery
aneurysm rupture.
AB - The case of a patient suffering from rupture of an aneurysm of the anterior
communicating artery is reported. The hematoma was located in the basal
forebrain, one of the anatomical regions associated with mnestic functions.
Memory and other cognitive functions were studied. The patient performed well on
all non-mnestic tests, but showed significant memory impairment. Anterograde
memory was deficient not only in recall, but also in recognition. Performance on
remote memory tests showed some differentiation. The patient remembered
autobiographical material and famous faces correctly, but presented deficits on a
Famous Events Test. This dissociation represents a difference in emotional
content or familiarity of the material; the performance in tests using material
with a higher emotional content was unremarkable. Lesions within the basal
forebrain seem to deteriorate anterograde and remote memory, but performance may
be inconspicuous if test material of high emotional content or familiarity is
used.
PMID- 9394233
TI - Encoding into working memory of spatial location, color, and shape:
electrophysiological investigations.
AB - Event-related potentials (ERP) were recorded while subjects memorized either the
location, the color or the shape of stimuli which could be located in 1 of 4
positions relative to a central fixation point (top, bottom, left or right), be
of 1 of 4 positions relative to a central fixation point (top, bottom, left or
right), be of 1 of 4 colors (white, green, red or blue), and present 1 of 4
shapes (triangle, cross, circle or square). These ERP were compared to ERP
recorded while subjects looked at the same stimuli but performed other control,
nonmemory tasks. Only ERP corresponding to the memorization of spatial location
showed a differential pattern which could be specifically attributed to memory
encoding processes. This reveals an important difference in ERP modulation
between a working memory subsystem for spatial location and other subsystem (or
subsystems) for color or shape, which would provide evidence supporting the
existence of different working memory subsystems for visual information in the
brain.
PMID- 9394234
TI - Visual organization test performance in an African American population with acute
unilateral cerebral lesions.
AB - Controversy abounds as to whether the Hooper Visual Organization Test (VOT) is a
measure of hemisphere-specific, region-specific, or non-specific brain damage.
The present study examines this issue in a group of African Americans with acute
unilateral brain damage and non-brain-injured controls. Consistent with the idea
that the VOT is a measure of "organic" cerebral pathology, non-brain damaged
controls earned significantly higher VOT scores than brain-damaged patients.
While other studies have noted that the VOT is primarily sensitive to damage in
the right parietal region of the brain, the present study shows that VOT
performance is especially vulnerable to acute lesions in the right anterior
quadrant of the brain. This latter finding supports the idea that VOT performance
is differentially sensitive to regional cerebral pathology, but challenges the
region specific claim of poorer VOT performance among patients with right
posterior cerebral damage.
PMID- 9394235
TI - [Clinical evaluation of faropenem against infections in pediatric fields].
AB - The recent increases in the prevalence of penicillin-resistant Streptococcus
pneumoniae becomes a point at issue clinically. We carried out a clinical study
in 40 cases in the pediatrics department, as faropenem (FRPM) was proved to have
an excellent antimicrobial activity against penicillin-resistant Streptococcus
pneumoniae. The study was planned to investigate in detail the movement of stools
that had been a problem in a clinical development studies out before. In this
study, an observation of the daily movement of stools was one of the principal
evaluation items, hence the patients were divided into two groups. One group (S
group) were administered FRPM only, the other group (E-group) were administered
FRPM in combination with a medicine for intestinal disorders (Enteronon-R). An
observed frequencies of any loose bowel movements were 94.7% in S-group, and
63.2% in E-group, hence the study suggested that the combination drug was
effective. The patients observed higher frequencies of development of the
movement of stools, all of them were recovered from in the course of
administration or within 4 days after administration, however whether or not
being treated symptomatic therapy. Clinical efficacy rates of FRPM on mainly
respiratory infections were 94.6%. In this study, 4 strains (patients) of
penicillin-resistant Streptococcus pneumoniae were isolated. Against penicillin
resistant Streptococcus pneumoniae, FRPM demonstrated more potent antibacterial
activity than the oral penicillins and cephems tested here except cefditoren.
Clinical efficacies was deemed effective in all of the 4 cases, and
bacteriologically, 3 organisms were eradicated. As for side effects including
diarrhea and loose stool, no serious side effects were observed. Based on the
above results, FRPM is effective against most infections in the pediatric field
which Streptococcus pneumoniae are isolated at high frequencies highly, and is
considered to cases in be useful an attention will have to be paid to stool
movement, however.
PMID- 9394236
TI - [Clinical and bacteriological effects of cefetamet pivoxil against community
acquired respiratory tract infections. Part II].
AB - We investigated clinical and bacteriological effects of cefetamet pivoxil (CEMT
PI) in community-acquired respiratory tract infections and obtained the following
findings. That method was approximately equal to that of investigation in 1994.
1. Of the 431 respiratory tract infection cases that were treated with CEMT-PI
according to a same protocol at a total of 41 institutions in Tokyo, Kanagawa
ken, Saitama-ken and Chiba-ken from January to the beginning of March 1996.
Outpatients accounted for 98.1% of the subjects. Regarding genders to patients,
slightly more females (52.6%) than males were included. Diagnoses given to these
patients included pharyngo-laryngitis (53.5%), tonsillitis (20.4%) and acute
bronchitis (19.1%). 2. We investigated clinical efficacy rates (the ratio of
those excellent + good) classified by diseases. The improvement rates of pharyngo
laryngitis, tonsillitis and acute bronchitis were more than 85.0%. Other cases
were small in number. That of chronic bronchitis-acute increasing change for the
worse was 66.7%, pneumonia was 50.0% and bronchiectasis infection was 16.7%. It
was not studied that clinical efficacy rates among those who were treated with 1
CEMT-PI tablet twice and among those who were given 2 tablets twice were
significant level. 3. For the bacteriological study, a written material
describing the method of collecting specimens, storage and transport in detail
was distributed to the above mentioned institutions. The isolation and
identification of suspected causative bacteria, determination of minimum
inhibitory concentrations (MICs) and investigation of beta-lactamase production
were conducted all together at section of studies, Tokyo Clinical Research
Center. Suspected causative bacteria were detected from 274 (63.6%) cases. They
included 88 strains of Haemophilus influenzae, 47 strains of Streptococcus
pneumoniae, 42 strains of Streptococcus pyogenes, 20 strains of Moraxella
subgenus Branhamella catarrhalis and 17 strains of Klebsiella pneumoniae subsp.
pneumoniae. Suspected causative bacteria classified by diseases were S. pyogenes
(tonsillitis), S. pneumoniae (acute bronchitis and secondary infection of chronic
respiratory infection) and H. influenzae (pharyngo-laryngitis), and the detection
frequency of those was high. The clinical efficacies (the ratio of improvement)
classified by suspected causative bacteria were 84.4% against organism that was
indicating CEMT and were 69.2% against organism that was not indicating CEMT.
PMID- 9394237
TI - [Recent trends in incidence of respiratory tract pathogens and antimicrobial
susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae and
Moraxella catarrhalis isolated in 1994 and 1995].
AB - The incidence of pathogenic bacteria in respiratory tract infections in 1994 and
1995 was investigated using quantitative cultures of sputa from patients with the
infections in our department. Haemophilus influenzae, Streptococcus pneumoniae
and Moraxella catarrhalis were isolated at high rates (70.5% in 1994 and 73.8% in
1995) from the specimens of out-patients, and the incident rates were similar to
the past data. The antimicrobial susceptibilities of these three pathogens were
examined with the agar dilution method. The incidence of penicillin (Pc)
resistant S. pneumoniae against which MIC of Pc-G was higher than 0.125
microgram/ml was markedly increased from 24% in 1994 to 34.9% in 1995. Most of
the Pc resistant isolates were also resistant to other antibiotics including
erythromycin, minocycline and tosufloxacin. Serotype of strains against which MIC
of Pc-G was higher than 1.0 microgram/ml was 19. The ratios of beta-lactamase
producing strains among H. influenzae isolated in 1994 and 1995 were 20 and
15.8%, respectively, which were slightly higher than those in the past. One
quinolone resistant strain was isolated in this study. Although the ratio of beta
lactamase-producing strains among M. catarrhalis was as high (96.7%) as in the
past, no increased resistance against the drugs examined was observed.
PMID- 9394238
TI - [Antimicrobial activities of clarithromycin against recent obtained clinical
isolates].
AB - In order to evaluate antimicrobial activities of clarithromycin (CAM), minimum
inhibitory concentrations (MICs) of CAM and control drugs were determined against
clinical isolates that were obtained from outpatients in 1994 and 1996. The
results are summarized as follows; 1. It was not showed that CAM-resistant
strains were increasing among Staphylococcus spp., beta-streptococci, Moraxella
subgenus Branhamella catarrhalis, Haemophilus influenzae, Bordetella pertussis,
Campylobacter jejuni subsp. jejuni, Chlamydia trachomatis and Mycoplasma
pneumoniae. It appeared that resistances to CAM and macrolides (MLs) were
increasing among Streptococcus pneumoniae and Peptostreptococcus spp. 2. The drug
susceptibility patterns to MLs were similar and detection frequencies of induced
resistant strains that were resistant to only 14-membered ring MLs including CAM
and constitutive resistant strains that were resistant to 14 and 16-membered ring
MLs were high among Streptococcus pneumoniae and Peptostreptococcus spp. It
appears that MLs-resistance systems are linked to each other, and that this was a
cause of increasing MLs-resistance among these bacterial species. 3.
Notwithstanding of antibiotic resistance problems, CAM is still useful since it
maintains strong antimicrobial activities against M. (B.) catarrhalis, B.
pertussis, C. jejuni subsp. jejuni, C. trachomatis and M. pneumoniae, and it
controls arginate producing abilities of mucoide strains of Pseudomonas
aeruginosa.
PMID- 9394239
TI - [Evaluation of reduced vancomycin susceptibility of MRSA strain Mu50 with various
conditions of antibiotic susceptibility tests].
AB - We evaluated a clinical strain of methicillin-resistant Staphylococcus aureus
(MRSA), Mu50, for vancomycin susceptibility. Mu50 was isolated from a patient
with infection of a surgical incision site which resisted vancomycin therapy.
Mu50 showed a decrease in susceptibility to vancomycin, but this strain did not
carry vanA or vanB or vanC genes as judged from PCR amplification. MICs of
vancomycin against Mu50 and vancomycin-susceptible S. aureus FDA209P, S. aureus
ATCC-29213, and MRSA H-1 were 8, 1, 1, and 1 microgram/ml, respectively by agar
dilution and macro-broth dilution methods according to NCCLS. MIC values with
agar dilution method using MHA + 20% horse serum, HIA, and BHIA agreed with the
MIC values with micro- and macro-broth dilution method. Population analysis
revealed that vancomycin concentration required for inhibition of ca. 10(7) cells
of Mu50, S. aureus FDA209P, S. aureus ATCC29213, and MRSA H-1 were 36, 2, 2, and
2 micrograms/ml, respectively. These results showed that the activity of
vancomycin against Mu50 was at least 8-fold decreased compared to that against S.
aureus FDA209P, S. aureus ATCC29213, and MRSA H-1.
PMID- 9394240
TI - [The in vitro antifungal activities of fluconazole against pathogenic yeasts
recently isolated from clinical specimens].
AB - The emergence of Candida albicans resistance to azole antifungal agents have been
reported in the U. S. and Europe. We examined the in vitro antifungal activities
of fluconazole against clinical isolates collected by seven investigators in
three years to examine if a tendency existed toward the development of azole
resistance among fungal isolates in Japan. The following results were obtained:
1. Sensitivities to fluconazole (FLCZ) were determined for yeast-like fungi,
including 113 strains isolated in 1993, 149 strains isolated in 1994 and 205
strains isolated in 1995. No significant differences in sensitivities in the
three years were detected. 2. Minimum inhibitory concentrations of FLCZ were 0.1
0.78 microgram/ml for C. albicans and 3.13-25 micrograms/ml for C. glabrata.
Strains with 25 micrograms/ml of FLCZ's MIC were detected; two strains of C.
krusei and one strain each of C. krusei, Trichospron beigelii and Hansenula
anomala. No strains with higher than 50 micrograms/ml MIC of FLCZ were detected.
3. In vitro activities of FLCZ were compared between clinical strains isolated
between 1993 and 1995 and clinical strains isolated before the marketing of FLCZ
(up to December 1987) or clinical yeasts isolated between 1991 and 1992. No
significant differences were observed, suggesting that no tendency existed toward
azole resistance among fungal strains examined.
PMID- 9394241
TI - Usage of T cell receptor (TCR) V beta gene in ulcerative colitis.
AB - Ulcerative colitis (UC) is an inflammatory disease of unknown etiology. In this
study, the expression of TCRV beta gene in UC patients was examined. The present
study included 11 consecutive Japanese patients with UC. The control group
comprised 10 healthy people. The usage of T Cell Receptor (TCR) V beta chain gene
segments in peripheral blood was examined using RT-PCR. In addition, HLA-DR DNA
typing was performed for the 11 patients with UC. The average of the positive
expression rates in the UC group was 0.617 +/- 0.126, which was significantly
higher than that of the control group (0.829 +/- 0.080) (p < 0.01). In the UC
group, the usage of V beta chain gene in the active phase was almost same as that
in the inactive phase. No specific distribution of V beta repertoire was observed
in the UC group. In UC patients, no distinct correlation was found between any
certain HLA-DR type and TCRV B gene usage. UC patients had a significantly lower
rate of the expression of TCR V beta genes compared to normal controls. There is
a possibility that the restricted usage of TCR V beta repertoire is possibly
related to the existence of oligoclonal TCR repertoire in UC patients.
PMID- 9394242
TI - Adjuvant activity of diesel exhaust particulates (DEP) in production of anti-IgE
and anti-IgG1 antibodies to mite allergen in mice.
AB - The present study indicates that diesel exhaust particulates (DEP) and pyrene
contained in DEP have an adjuvant activity on IgE and IgG1 antibody productions
in mice immunized intranasally with a mite allergen. The effect of pyrene on IgE
and IgG1 antibody productions in mice was investigated to clarify the relation
between mite allergy and adjuvancy of the chemical compounds in DEP. Der f II,
one of the major allergens of house dust mite (Dermatophagoides farinae), was
used as a mite allergen. Mice were grouped, and immunized with 5 micrograms of
Der f II alone, 5 micrograms of Der f II plus 200 micrograms of pyrene and 5
micrograms of Der f II plus 100 micrograms of DEP intranasally seven times at two
week intervals. The separate groups of mice were also immunized with 10
micrograms of Der f II plus the same dose of adjuvants in the same way. The IgE
antibody responses to Der f II in mice immunized with Der f II plus pyrene or Der
f II plus DEP were markedly enhanced compared with those immunized Der f II
alone. The anti-Der f II IgE antibody production increased with increasing the
dose of Der f II from 5 micrograms to 10 micrograms in mice immunized with Der f
II plus the same dose of adjuvants. The IgG1 antibody responses to Der f II in
mice immunized with 10 micrograms of Der f II plus 200 micrograms of pyrene or 10
micrograms of Der f II plus 100 micrograms of DEP were extremely higher than
those immunized with 10 micrograms of Der f II alone. In addition, when the
peritoneal macrophages obtained from normal mice were incubated with pyrene or
DEP in vitro, an enhanced interleukin-1 alpha production of the macrophages was
observed. When the spleen lymphocytes obtained from the mice immunized with 10
micrograms of Der f II plus 100 micrograms of DEP or 10 micrograms Der f II plus
200 micrograms of pyrene were stimulated with 10 micrograms of Der f II in vitro,
an enhanced IL-4 production of the lymphocytes was also observed compared with
those immunized with Der f II alone. These results suggest that the adjuvancy of
DEP and pyrene on the production of IgE and IgG1 antibodies to Der f II may be
one of the factors responsible for an incidence of asthma caused by house dust
mite.
PMID- 9394243
TI - Characterization of reactivity of monoclonal autoantibodies with renal antigens
in experimental lupus nephritis.
AB - Mice with chronic graft-versus-host disease (GvHD), induced by injection of DBA/2
lymphocytes into (C57BL10*DBA/2)F1 hybrids, develop a lupus-like syndrome with
immune complex glomerulonephritis. Circulating autoantibodies are reactive with
various self-antigens, including DNA, renal tubular epithelium (RTE), and laminin
1. To elucidate the reactivity of autoantibodies with renal antigens in
experimental lupus nephritis further, the reactivity of the autoantibodies was
studied in more detail by generating hybridomas from GvHD spleen cells.
Hybridomas were selected for reactivity with RTE and laminin-1 coated on
nitrocellulose sheets. Four stable clones were obtained (GV1-GV4). Monoclonal
antibody (mAb) GV1 showed no reactivity on kidney sections, while GV2 stained the
brush border of proximal tubular epithelial cells. Both GV1 and GV2 reacted only
with RTE in ELISA. GV3 showed a nuclear staining pattern, while GV4 stained
matrix structures on F1 kidney sections. GV3 and GV4 both reacted with RTE,
laminin-1, ssDNA, and dsDNA in ELISA. Growth of hybridomas in mice, but not
passive transfer of the mAbs, led to glomerular Ig binding for mAbs GV3 and GV4
without development of proteinuria. Our results show that in addition to anti
nuclear autoantibodies cross-reactive with renal antigens, autoantibodies
reactive with renal antigens and not with DNA are generated during chronic GvHD.
Based on these results, combined with those of earlier experiments, we conclude
that a combination of autoantibodies against multiple epitopes is necessary for
the induction of glomerular damage in this model for lupus nephritis.
PMID- 9394244
TI - The resurgence of selective contracting restrictions.
AB - As managed care has spread, so has legislation to force plans to contract with
any willing provider (AWP) and give patients freedom of choice (FOC). Managed
care organizations' selective networks and provider integration reduce patient
access to providers, along with provider access to paying patients, so many
providers have lobbied for AWP-FOC laws. In opposition are managed care
organizations (MCOs), which want full freedom to contract selectively to control
prices and utilization. This article comprehensively describes laws in all fifty
one jurisdictions, classifies their relative strength, and assesses the
implications of the laws. Most are relatively weak forms and all are limited in
application by ERISA and the federal HMO Act. The article also uses an
associative multivariate analysis to relate the selective contracting
environments to HMO penetration rates, rural population, physician density, and
other variables. States with weak laws also have higher HMO penetration and
higher physician density, but smaller rural populations. We conclude that the
strongest laws overly restrict the management of care, to the likely detriment of
cost control. But where market power is rapidly concentrating, not restricting
selective contracting could diminish long-term competition and patient access to
care. In the face of uncertainty about the impact of these laws, an intermediate
approach may be better than all or nothing. States should consider mandating that
plans offer point-of-service options, for a separate premium. This option expands
patient choice of plans at the time of enrollment and of providers at the time of
care, yet maintains plans' ability to control core providers.
PMID- 9394245
TI - Medicaid managed care and the family planning free-choice exemption: beyond the
freedom to choose.
AB - Family planning services represent one of the most common managed care services,
particularly in the case of Medicaid. In 1986, Congress enacted legislation
exempting family planning services from mandatory managed care requirements. The
effect of this legislation was to permit beneficiaries enrolled in mandatory
managed care plans to continue to obtain family planning benefits from the
providers of their choice, regardless of the providers' network status. The
purpose of the law was to assure that managed care would not impede individuals'
access to benefits. Subsequent experiences surrounding implementation of this
provision indicated that the Health Care Financing Administration failed either
to define the scope of the exemption or to provide guidance to states regarding
the various issues that would have to be resolved in exempting certain primary
care services from mandatory managed care. States, in turn, developed working
definitions of exempt family planning services that omitted treatment for
sexually transmitted diseases and also delegated to their managed care
contractors the responsibility to design implementation and payment arrangements.
This systematic failure to articulate the scope and functional elements of the
exemption consequently led to nonpayment of providers, and ultimately, to denial
of care in some cases. Moreover, plans and community providers alike relied on
the exemption to justify their failure to come to grips with the requirements and
challenges of managed care. We conclude that exempting primary care services from
managed care requirements may raise as many questions as it answers, and instead
recommend that states, plans, and community providers focus on developing managed
care systems that are responsive to patient needs.
PMID- 9394246
TI - Should health insurance cover IVF? Issues and options.
AB - An emotional debate has attended the question of whether health insurance should
cover the cost of in vitro fertilization (IVF) for infertile couples. Some
private health plans have opted to cover IVF, although most have not. Ten states
have mandated that it be included or offered as a standard benefit for private
health insurance plans. This article analyzes several key issues in the debate:
the impact of insurance coverage; the cost-effectiveness of IVF; valuing the
benefit of IVF; and adoption as an alternative. It recommends policy action in
several areas: more efficiently allocating resources for IVF (by giving priority
to couples with better chances of success, and by making more extensive use of
facilities with higher success rates); ensuring that clear and reliable
information about the effectiveness of IVF is available; and leveling the playing
field between IVF and adoption.
PMID- 9394247
TI - Social science and the public agenda: reflections on the relation of knowledge to
policy in the United States and abroad.
AB - It is tempting to oversell the practical value of applied research. A hard look
at the effects of U.S. social science on public policy in areas such as active
labor market policies (training, job creation, placement, etc.), crime
prevention, fiscal policy, poverty reduction, and health care reform suggests an
inverse relationship between social science consensus and policy and budgetary
decisions. Fragmented and decentralized political economies (e.g., the United
States) foster policy segmentation and isolated, short-run single-issue research-
often politicized and misleading. More corporatist democracies (such as Sweden,
Norway, Austria, and Germany) evidence a tighter relation between knowledge and
power in which a wider range of issues is connected, longer-range effects are
sometimes considered, and research is more often actually used for planning and
implementation. Even in less hospitable societies, however, social science does
make its way in the long run. Favorable conditions and examples are discussed.
PMID- 9394248
TI - Learning from others: shall the last be the first?
AB - The cross-national exchange of ideas and experience in health care reform has, in
recent years, reached epidemic proportions. Taking stock of this suggests the
need for critical caution. The various participants in the process have different
motives; models may be exported before they have been fully tested; information
may be sought chiefly as political ammunition; and selective perception often
distorts the evidence. A more helpful approach might be to concentrate on
evaluating the experience of countries over time, rather than concentrating on
the latest fashionable panacea, and to focus more on the process of introducing
change.
PMID- 9394250
TI - Institutions of reflective practice.
PMID- 9394249
TI - Funding by the Center for Indoor Air Research (CIAR)
PMID- 9394251
TI - Chitosan: properties, preparations and application to microparticulate systems.
AB - Chitosan, a hydrophilic biopolymer, is obtained industrially by hydrolysing the
aminoacetyl groups of chitin. It is a natural, non-toxic, biodegradable
polysaccharide available as solution, flake, fine powder, bead and fibre. The
sources, biochemical aspects, structure and chemical modification, physico
chemical and functional properties, and applications of chitosan have been
investigated extensively in the literature. In this paper, the attractive
properties and broad applications of chitosan-based microparticles, their
versatile properties, different preparation methods, and pharmaceutical and
biopharmaceutical applications are reviewed.
PMID- 9394252
TI - Comparison of two commercial brands of microcrystalline cellulose for extrusion
spheronization.
AB - Two commercial brands of microcrystalline cellulose, the widely used Avicel PH
101 and the newly available Pharmacel 101, were compared for aqueous extrusion
spheronization of a model mix with lactose. Based on the results of multi-level
experiments employing pellet size analysis by sieving and sphericity
determination by image analysis, Avicel was shown to be less adversely affected
by variation in added water or speed of spheronization. Physicochemical testing
of powder samples from both brands was carried out using laser particle sized
analysis, density determinations, differential scanning calorimetry and X-ray
diffraction studies. The results indicated that the improved ease of processing
with Avicel may be related to its smaller particle size with less aggregates,
improved flow, lower depolymerization temperature range and absence of traces of
cellulose II in its cellulose I content.
PMID- 9394253
TI - Preparation of polymeric microspheres by the solvent evaporation method using
sucrose stearate as a droplet stabilizer.
AB - Polymeric microspheres containing nicardipine hydrochloride (HCl) as a reference
drug were prepared with the acrylic polymers Eudragit RS and L by the solvent
evaporation method. Different concentrations of sucrose stearate as a droplet
stabilizer were used. Sucrose stearate affected the diffusion rate of the solvent
from the preliminary emulsion droplets to the outer phase for the formation of
microspheres. Increasing concentrations of sucrose stearate in the formulations
caused increasing porosity on the surface of the microspheres. However, a
correlation between the concentrations of sucrose stearate and diameters of
microspheres could not be assessed. From this point of view, during processing,
applied stirring rate was important.
PMID- 9394254
TI - Development of vegetable extracts by microencapsulation.
AB - The microencapsulation of essential oils offers protection against oxidation and
evaporation, and allows the concurrent utilization of several vegetable extracts.
Complex coacervation methods have been described for essential oils. Even though
microencapsulation involves wrapping the essential oils in shells, some
difficulties arise in the process of stabilizing the essential oils: oil may be
lost by evaporation and partial dissolution in the water-gelatin phase and this
will vary with the type of essential oil being encapsulated. In order to
investigate the efficacy of the gelatin-polyphosphate methods we analysed their
essential oil microcapsules peppermint and rosemary, in particular their
granulometric size distribution, oil content (%) and encapsulation yield (%). In
addition the essential oils were analysed by GC before and after
microencapsulation so as to investigate the loss of their components during the
process.
PMID- 9394255
TI - In vitro characterization of a controlled-release chlorpheniramine maleate
delivery system prepared by the air-suspension technique.
AB - Non-pareil cores were spray-coated with a chlorpheniramine maleate (an alkylamine
antihistamine) layer and a Eudragit NE30D overcoat in a Wurster air-suspension
apparatus. In vitro dissolution studies demonstrated that drug release was a
function of polymer membrane thickness. Polyethylene glycol 6000, as a
hydrophillic additive, increased the in vitro release of chlorpheniramine maleate
from the pellets. Pellets coated with 8.30% Eudragit NE30D, 0.50% talc and 1.00%
polyethylene glycol 6000 were found to display desirable controlled release
characteristics for chlorpheniramine maleate over the 8-h testing period, which
were also comparable with that of Dykatuss capsules. The controlled release
pellets exhibited first-order release characteristics for chlorpheniramine
maleate. Reproducibility of the manufacturing conditions employed in the study
were confirmed thus ensuring reproducibility of drug release characteristics
between batches of chlorpheniramine maleate pellets. Drug release from the
pellets was shown to be independent of the dissolution method and medium used.
Pellets displayed no significant change in drug release characteristics relative
to the initial drug release data when stored for 12 weeks at room temperature (20
+/- 2 degrees C) and for 8 weeks at a low temperature (5 +/- 1 degrees C).
However, pellets stored at 37 degrees C with 80% relative humidity and at 40 +/-
2 degrees C showed a slower in vitro drug release after 8-week storage and
therefore failed to maintain their initial drug release profile.
PMID- 9394256
TI - Encapsulation of calcitonin in liposomes depends on the vesicle preparation
method.
AB - Calcitonin-loading was studied in liposomes composed of phosphatidylcholine,
cholesterol and stearylamine in relation to the vesicle preparation method.
Liposomes entrapping calcitonin were prepared by extrusion, sonication or from
mixed micelles through the elimination of cholate by gel filtration. To
understand the mode of calcitonin encapsulation in the vesicles, riboflavin was
entrapped within the vesicles and taken as a simple model for the encapsulation
of molecules in the aqueous phase. Interactions of calcitonin with the liposomal
membranes were evaluated by studying the fixation of radiolabelled calcitonin to
the outer surface of empty liposomes, and by preparing calcitonin-loaded LDL-like
nanoparticles composed of phosphatidylcholine and cholesteryloleate. Calcitonin
entrapment in the vesicles depends largely on the vesicle preparation method.
When vesicles are prepared by removal of cholate from mixed micelles, relatively
little calcitonin entrapment in the liposomes is obtained. In this type of
vesicle, calcitonin is exclusively embedded in the vesicle bilayer. When vesicles
are prepared by extrusion or sonication, calcitonin is found both in the aqueous
and lipidic phases of the vesicles. Optimal calcitonin encapsulation was obtained
when the liposomes were prepared by sonication.
PMID- 9394257
TI - Microencapsulation of human insulin DEAE-dextran complex and the complex in
liposomes by the emulsion non-solvent addition method.
AB - Human insulin-DEAE (diethyl amino ethyl) dextran complex and human insulin DEAE
dextran complex in liposomes were encapsulated in cellulose acetate butyrate
(CAB) microcapsules by the emulsion non-solvent addition method. The ratio of
core-to-coat used was 1:1. The average diameters of the complex microcapsules and
the complex liposome microcapsules were 239.5 +/- 77.5 and 182.9 +/- 52.2 microns
respectively. In vitro dissolution studies of both types of microcapsules in
simulated intestinal fluid at pH 7.2 showed a sustained release of the complex
and the complex liposome microcapsules with t50 = 1.5 h and 4 h respectively.
This study can be applied to the further development of oral formulations of
human insulin liposomes for diabetic treatment.
PMID- 9394258
TI - Characterization of ciprofloxacin liposomes: derivative ultraviolet
spectrophotometric determinations.
AB - Neutral, (-) and (+) charged CF encapusulated liposome formulations prepared with
EPC:Chol and DPPC:Chol lipids were investigated for their loading capacity,
encapsulation % and release properties. CF amounts in the liposomes were
estimated using derivative UV spectroscopy. Among the liposome formulations
DPPC:Chol and EPC:Chol neutral formulations had a significantly higher loading
capacity and slowest release rate compared with (-) and (+) charged liposomes.
The derivative UV spectroscopy was found to be an easy and sensitive method for
direct estimation of CF in liposomes.
PMID- 9394259
TI - Stability of cyclosporine-loaded poly-sigma-caprolactone nanoparticles.
AB - The aim was to evaluate the long-term stability of cyclosporin A-loaded
nanoparticle suspensions, stored at 8 and 25 degrees C. The stability of freeze
dried samples was also investigated. Nanoparticles (NP) of poly-sigma
caprolactone (P sigma CL), a biodegradable polymer, were obtained by a modified
nanoprecipitation method. A central composite experimental design was used to
investigate the simultaneous effect of technological factors (temperature of the
aqueous phase and needle gauge) and formulation variables (volume of acetone and
the amount of polymer and surfactant). The effect of these variables on the
stability of the 100-220 nm particles obtained was evaluated. The percentage of
cyclosporin A (CyA) encapsulated in the NP suspensions stored at 8 and 25 degrees
C for at least 3 months remained unaltered. Moreover, there was no change in the
size of NP. After 4 months storage, the physical stability of the preparation was
affected. NP aggregates could be observed by light microscopy. Reconstituted
freeze-dried preparations showed a mean increase of 1% in the incorporated drug
and also a considerable increase in mean size and size distribution. Additional
experiments investigated the effect of freezing temperature (-70 and -196 degrees
C) and of 5, 10 and 20% (w/v) cryoprotector (mannitol, sorbitol, glucose and
threalose) on 100 nm particles. The addition of glucose and threalose at
concentrations > 10% permitted adequate reconstitution of the freeze-dried
product with conservation of the encapsulated CyA.
PMID- 9394260
TI - Depression and coronary heart disease: observations and questions.
AB - The evidence that depressive symptomatology precedes the onset of the acute
coronary syndromes and influences the course of disease after their manifestation
is accumulating. However, we still are far short of proof that depression has a
causal role in the etiology and pathogenesis of coronary heart disease (CHD).
Some unsolved questions concern the causes and the nature of the depression
preceding a first or recurrent cardiac event, the biological mechanisms relating
depression and CHD, the time window of the exposure-disease association, and the
power of therapy programs for depression to reduce the risk of a first or
recurrent cardiac event.
PMID- 9394261
TI - The psychological and behavioral management of angina.
PMID- 9394262
TI - Improving the effectiveness of routine care for somatization.
PMID- 9394263
TI - Liaison psychiatry and psychology in dentistry.
AB - Dentists are trained to provide treatment for patients with straightforward
problems that respond to routine therapy and do not recur. However, patients may
present to dentists and complain solely of physical symptoms such as toothache,
headache, and facial pain: only after much inappropriate treatment these symptoms
are revealed to be due to emotional disturbance. The dentist may spend hours
investigating such patients, in some of whom dental pathology may be present, but
the symptoms and ensuing disability cannot be satisfactorily explained as a
result. There are other patients who are preoccupied by physical symptoms or by
their appearance. In others, anxiety may manifest itself as a phobia, or a
dysmorphic concern about certain aspects of their appearance. This article
reviews the role of liaison psychiatry and psychology in dentistry.
PMID- 9394264
TI - Predictive genetic testing: psychological factors.
AB - Advances in medical technology such as those linked to the human genome project
are increasing the potential for predictive testing for a wide range of health
threats. There have not been comparable advances in understanding of the
psychological factors involved in such testing. These factors and issues relating
to them are examined, and it is suggested that a cognitive-behavioral approach to
the understanding and management of adverse reactions to testing is likely to be
particularly fruitful. The use of such an approach should result in the
development of effective pre- and posttest interventions to prevent, minimize,
and manage distress associated with screening.
PMID- 9394265
TI - Neurovegetative dystonia--psychiatric evaluation of 40 patients diagnosed by
general physicians in Brazil.
AB - The diagnosis of neurovegetative dystonia (NVD) is commonly made by general
physicians in Brazil, but its precise meaning is unclear. Anecdotal evidence
suggests that it is used to describe patients with a wide range of psychological
and physical symptoms and is often used pejoratively, in a similar way to
"crocks" in the USA. Forty patients who had been diagnosed as having NVD by
general physicians working in a triage department of a general public hospital
were compared with 40 non-NVD patients, matched for age and gender, from the same
department. Patients were evaluated by a psychiatrist who was blind to the
diagnosis that had been made. The assessment included a structured
sociodemographic questionnaire, the Clinical Interview Schedule (CIS), and a
routine psychiatric interview using DSM-III-R criteria. Using the CIS, the
"reported symptoms" that most distinguished NVD patients from controls were
somatic and anxiety, whereas for "manifest abnormality" NVD patients displayed
more anxiety, histrionic behavior, hypochondriasis, and depressive thoughts. A
total of 92.5% of NVD patients received diagnoses using DSM-III-R criteria
compared to 37.5% of controls. The relative risk of NVD patients subsequently
receiving a psychiatric disorder was 8.3 (95% CI = 2.5-43.1, p < 0.001). Although
general physicians correctly identify most patients with psychiatric disorder
they miss many others. Furthermore, they use an obsolete diagnostic category
which has no psychiatric currency. Medical students and residents need better
psychiatric training so that they can correctly identify patients in general
medical settings who are suffering from mental disorders and make a diagnosis
using accepted psychiatric terminology.
PMID- 9394266
TI - Medication misuse, abuse and dependence in chronic pain patients.
AB - We report the prevalence of drug use, misuse, abuse, and dependence in 125
chronic pain patients attending specialist pain clinics in South London. A total
of 110 patients (88%) were taking medications for their pain problem. Opioid
analgesics (69.6%), nonopioids (48%), antidepressants (25%), and benzodiazepines
(17.6%) were the drugs most frequently used. Psychoactive substance abuse or
dependence (DSM-III-R) was diagnosed in 12%. A total of 9.6% of the patients met
the DSM-III-R criteria for substance abuse or dependence in remission. Data are
also presented on the misuse and abuse of nonpsychoactive drugs, qualitative
information on how patients use drugs, and the information they have received
about medication.
PMID- 9394267
TI - Personality change following head injury: assessment with the NEO Five-Factor
Inventory.
AB - We evaluated personality change following head injury in 68 patients at 6 months
postinjury using the NEO Five-Factor Inventory to assess the five personality
dimensions of the Five-Factor Model of Personality. All items had to be rated
twice, once for the preinjury and once for the current status. Twenty-eight
trauma patients with injuries to other parts of the body than the head were used
as controls. For the head-injured group, 63 relatives also completed the
questionnaire. The results showed no differences between the ratings of head
injured patients and the ratings of trauma control patients. Both groups showed
significant change in the personality dimensions Neuroticism, Extraversion, and
Conscientiousness. Compared to their relatives, head-injured patients report a
smaller change in Extraversion and Conscientiousness. Changes were not reported
on the Openness and Agreeableness scales, by neither the head-injured or their
relatives, nor by the trauma controls.
PMID- 9394268
TI - Gender, self-reported depressive symptoms, and sleep disturbance among older
community-dwelling persons. FICSIT group. Frailty and Injuries: Cooperative
Studies of Intervention Techniques.
AB - The purposes of this report are: (1) to investigate the association between sleep
disturbances and depressive symptomatology in older adults; (2) to evaluate the
degree to which gender serves to mediate this relationship; and (3) to determine
whether several predefined covariates help to explain the association between
sleep disturbance and depressive symptoms. This is a retrospective and cross
sectional analysis of baseline data from 485 elderly adults enrolled in three of
the eight clinical sites participating in the Frailty and Injuries: Cooperative
Studies of Intervention Techniques (FICSIT) trials. FICSIT was a linked series of
randomized clinical trials which evaluated the impact of various exercise
interventions on several measures of frailty in older adults. Women reported more
depressive symptoms and more sleep disturbances than men. Sleep disturbances were
independently associated with depressive symptoms, bodily pain, a history of
falling, limited education, being married, and being female. Gender interactions
suggest that, although women reported more depressive symptoms and more chronic
health conditions than men, both may be more important predictors of sleep
disturbance in men. By contrast, being married may be more predictive in women.
Finally, the data suggest a stronger relationship between sleep disturbance and
depressive symptoms in men than in women.
PMID- 9394270
TI - Negative affect and the seeking of medical care in university students with
irritable bowel syndrome: a preliminary study.
AB - In a preliminary study using only self-report measures, university students
completed questionnaires about their bowel symptoms and trait anxiety. Results
showed that students with irritable bowel syndrome (IBS) reported higher trait
anxiety than asymptomatic controls. Among the students with IBS, there were no
significant differences in trait anxiety between those who had sought medical
care for IBS mostly from a primary care physician, and those who had not sought
care for IBS. Students who had sought medical care for IBS reported being more
bothered by the symptoms and were more concerned about their meaning than those
students who had not sought care. The results are compared to other research with
IBS patients referred to specialist clinics, and a distinction is made between
initial vs. continued care seeking for IBS.
PMID- 9394269
TI - Acute phase proteins in major depression.
AB - Extensive evidence exists associating depression with changes in the immune
system. The present study evaluates the levels of complement components C3 and
C4, C-reactive proteins, and IL-6 in patients who met DSM-III-R diagnostic
criteria for major depressive disorder, as well as controls. Whereas no
significant differences between the mean levels of C3 could be detected between
depressed patients and controls, the levels of C4, IL-6 (where detected), and C
reactive protein were significantly raised in the group with a depressive
disorder. Our study suggests an interaction between psychological state and
immune systems operative in host defenses.
PMID- 9394271
TI - The comorbidity, relationship and treatment implications of borderline
personality and obesity.
AB - Studies indicate that a significant minority of obese individuals in clinical
studies meet criteria for borderline personality. Although the relationship
between obesity and borderline personality remains unexplained, the following
article discusses the implications of treating obesity among individuals with
this personality disorder. Longitudinal intervention, normalizing or regulating
eating patterns, and reframing weight plateaus are emphasized.
PMID- 9394272
TI - An accurate method for computer-generating tungsten anode x-ray spectra from 30
to 140 kV.
AB - A tungsten anode spectral model using interpolating polynomials (TASMIP) was used
to compute x-ray spectra at 1 keV intervals over the range from 30 kV to 140 kV.
The TASMIP is not semi-empirical and uses no physical assumptions regarding x-ray
production, but rather interpolates measured constant potential x-ray spectra
published by Fewell et al. [Handbook of Computed Tomography X-ray Spectra (U.S.
Government Printing Office, Washington, D.C., 1981)]. X-ray output measurements
(mR/mAs measured at 1 m) were made on a calibrated constant potential generator
in our laboratory from 50 kV to 124 kV, and with 0-5 mm added aluminum
filtration. The Fewell spectra were slightly modified (numerically hardened) and
normalized based on the attenuation and output characteristics of a constant
potential generator and metal-insert x-ray tube in our laboratory. Then, using
the modified Fewell spectra of different kVs, the photon fluence phi at each 1
keV energy bin (E) over energies from 10 keV to 140 keV was characterized using
polynomial functions of the form phi (E) = a0[E] + a1[E] kV + a2[E] kV2 + ... +
a(n)[E] kVn. A total of 131 polynomial functions were used to calculate accurate
x-ray spectra, each function requiring between two and four terms. The resulting
TASMIP algorithm produced x-ray spectra that match both the quality and quantity
characteristics of the x-ray system in our laboratory. For photon fluences above
10% of the peak fluence in the spectrum, the average percent difference (and
standard deviation) between the modified Fewell spectra and the TASMIP photon
fluence was -1.43% (3.8%) for the 50 kV spectrum, -0.89% (1.37%) for the 70 kV
spectrum, and for the 80, 90, 100, 110, 120, 130 and 140 kV spectra, the mean
differences between spectra were all less than 0.20% and the standard deviations
were less than approximately 1.1%. The model was also extended to include the
effects of generator-induced kV ripple. Finally, the x-ray photon fluence in the
units of photons/mm2 per mR was calculated as a function of HVL, kV, and ripple
factor, for various (water-equivalent) patient thicknesses (0, 10, 20, and 30
cm). These values may be useful for computing the detective quantum efficiency,
DQE(f), of x-ray detector systems. The TASMIP algorithm and ancillary data are
made available on line at http:/(/)www.aip.org/epaps/epaps.html.
PMID- 9394273
TI - Three-dimensional reconstruction of curves from pairs of projection views in the
presence of error. I. Algorithms.
AB - We have previously described an approach to 3D intracerebral vascular
reconstruction that uses an MRA as a reconstruction base. Additional vessels seen
only by angiography are added by segmenting 2D curves from projection angiograms
and reconstructing these curves into 3D, building upon the MRA. Intracerebral
vascular reconstruction is difficult for at least two reasons. First, 2D curves
must be associated on projection images even when the human eye cannot do so.
Second, 3D curves must be reconstructed in the presence of errors such as
misregistration, image distortion, and misdefinition of 2D curves. This paper is
the first of two that address the specific issue of reconstruction of a 3D curve
from a given pair of 2D curves in the presence of error. The method explicitly
separates what can and cannot be determined from a pair of projection views. It
is also capable of recognizing interruptions produced by viewplane errors, of
continuing reconstruction beyond such interruptions, and of localizing and
estimating the magnitude of the interruptions. These measurements can also be
used to estimate the lengths of regional disparities between a pair of 2D curves,
leading to a quantitative estimate of the capacity of a pair of 2D curves to
combine to create a 3D object (match value). Match values can be used, in turn,
as part of the strategy for automatically associating pairs of 2D curves. This
paper provides methods for reconstructing a given pair of 2D curves into 3D in
the presence of error and for calculating match values. Error analysis is given
in the companion report.
PMID- 9394274
TI - Three-dimensional reconstruction of curves from pairs of projection views in the
presence of error. II. Analysis of error.
AB - We have previously described an approach to 3D intracerebral vascular
reconstruction that uses an MRA as a reconstruction base. Additional vessels seen
only by angiography are added by segmenting 2D curves from projection angiograms
and reconstructing these curves into 3D, building upon the MRA. This paper is the
second of two that discuss the specific problem of reconstructing a 3D curve from
a given pair of 2D curves in the presence of error. The method presented is
capable of detecting and handling many errors produced by misregistration, image
distortion, or misdefinition of 2D curves. The first paper gives an algorithm.
The current paper discusses factors affecting the accuracy of a reconstructed
curve, with emphasis upon registration error. We analyze the spatial accuracy of
a reconstructed point in terms of the relationships between pixel size, relative
viewing angle, 3D point location, and registration error. We provide a
theoretical framework that, given the known error properties of a registration
algorithm, allows optimization of the viewing geometry so as to produce the
highest precision of point reconstruction. A major focus is the effect of
registration error upon the reconstruction of a curve. We subdivide registration
error into two types, one of which produces smoothly continuous point placement
errors and the other of which produces pixel pairing errors. We test our ability
to reconstruct a 3D curve in the presence of both. Finally, we summarize
approaches to other sources of error. We conclude with a list of recommendations
to optimize reconstruction accuracy. When projection points are associated by the
rules of epipolar geometry, viewplane point displacements should not exceed 1.5-2
mm along the axis perpendicular to epipolar planes.
PMID- 9394275
TI - Computer simulation of time-gated transillumination and reflection of biological
tissues and tissuelike phantoms.
AB - A simulation technique is employed to explore the possibility of locating
millimeter-sized objects, immersed in turbid media, from time-gated measurements
of the transmitted or reflected light. The simulation results for tissuelike
phantoms are compared to experimental transillumination data and excellent
agreement is found. Simulations of time-gated reflection experiments show that it
is possible to detect objects of 1 mm diameter. This may open new possibilities
for medical diagnosis of breast cancer in an early stage.
PMID- 9394276
TI - A method for quantifying SPECT uniformity.
AB - Field uniformity is an important parameter for monitoring the performance of
SPECT imaging systems. However, it is difficult to apply objective measures of
uniformity because of the large variance associated with reconstructed images. In
the proposed method, annular sampling of the SPECT uniformity image is used to
reduce the noise level without decreasing the magnitude of uniformity artifacts.
The reconstructed uniformity image is sectioned into annular rings centered on
the center of rotation to match the expected distribution of uniformity
artifacts. Statistical fluctuations are reduced by averaging the counts within
the annular rings, allowing the use of objective measures of field uniformity
such as integral uniformity. Application of the annular sampling technique on
simulated and phantom uniformity images showed that the technique could reliably
quantify SPECT uniformity artifacts at acceptable count levels. As a result this
method can be used to objectively evaluate SPECT field uniformity in systems
which utilize parallel collimation and circular orbits.
PMID- 9394277
TI - The effect of gamma ray penetration on angle-dependent sensitivity for pinhole
collimation in nuclear medicine.
AB - The sensitivity of a pinhole collimator for gamma ray imaging in nuclear medicine
is dependent on the angle of incidence of the gamma rays. The effect of
penetration near the pinhole aperture on angle-dependent sensitivity was
investigated using experimental measurements and numerical modeling. Projection
data measurements were acquired with Tc-99m and I-131 point sources using
tungsten pinhole inserts with 1.0 to 4.0 mm diameter apertures. Curves of the
form sinx theta, where theta is the angle of the incident ray with the surface of
the detector crystal, were fit to sensitivity measurements from the projection
data. Experimentally measured x values were between 3.3 and 4.1 for Tc-99m and
between 5.1 and 7.2 for I-131. Penetration near the pinhole aperture was modeled
using (1) an expression for effective pinhole diameter that is a generalization
of Anger's formula for normally incident photons and (2) a photon transport
simulation code. Experimentally measured sensitivity exponents x from new and
previously reported experimental observations were modeled within 15% by the
numerical simulations. For modeling using the generalized expression for
effective diameter the average error was 1.4% and the standard deviation was
7.7%. For the photon transport simulation code the average error was 1.5% and the
standard deviation also was 7.7%. The effect of pinhole aperture design
parameters on angle-dependent sensitivity for high resolution pinhole apertures
was modeled using a photon transport simulation code. The sensitivity exponents x
were greater for 364 keV photons than for 140 keV photons and were greater for
small aperture diameters, small acceptance angles, and large aperture channel
heights. These results provide theoretical justification for incorporating sinx
theta sensitivity corrections, with x greater than the value of 3 for an
impenetrable pinhole, in filtered back projection and iterative reconstruction
algorithms for single photon emission computed tomography (SPECT) pinhole
imaging. Simulated I-131 SPECT studies for uniformly active cylinders showed that
activity concentrations were underestimated toward the outside of the cylinders
when a sin3 theta rather than the correct sinx theta sensitivity correction was
applied in image reconstruction.
PMID- 9394278
TI - Radiation doses in radiation therapy are not safe.
PMID- 9394279
TI - Calculating dose and output factors for wedged photon radiotherapy fields using a
convolution/superposition method.
AB - We have developed a convolution/superposition method to calculate dose
distributions in photon treatment fields with beam modifiers such as physical
wedges. The dose component due to wedge generated radiation was accounted for by
using an extended phantom model, which integrated a wedge, an air gap, and a
patient phantom as the calculation phantom. The inhomogeneities in the extended
phantom and the effect of beam hardening by the wedge were both corrected for in
the convolution dose calculation. The calculated dose was verified by Monte Carlo
simulation of the same extended phantom. A new dual photon source model was also
used in the convolution method to account for both primary photons from the
target and extra-focal photons from the primary collimator and flattening filter.
Thus, realistic photon energy fluence distributions in the extended phantom were
used for the dose calculation. The calculated dose distributions and the wedge
factors agreed with the measured data within 2% for a variety of treatment fields
including asymmetric fields. Our results showed that the wedge-generated
radiation could contribute a significant fraction of the total dose in patients.
This dose component depends on a specific field configuration, thus wedge factor
changes with photon energy, wedge angle, field size, depth, and patient phantom
SSD. The variation of the wedge factor can be predicted accurately by our
convolution approach with the extended phantom model, which allows for more
accurate dose or monitor unit computation for photon fields with beam modifiers.
PMID- 9394280
TI - Correcting kernel tilting and hardening in convolution/superposition dose
calculations for clinical divergent and polychromatic photon beams.
AB - To account for clinical divergent and polychromatic photon beams, we have
developed kernel tilting and kernel hardening correction methods for convolution
dose calculation algorithms. The new correction methods were validated by Monte
Carlo simulation. The accuracy and computation time of the our kernel tilting and
kernel hardening correction methods were also compared to the existing approaches
including terma divergence correction, dose divergence correction methods, and
the effective mean kernel method with no kernel hardening correction. Treatment
fields of 10 x 10-40 x 40 cm2 (field size at source to axis distance (SAD)) with
source to source distances (SSDs) of 60, 80, and 100 cm, and photon energies of
6, 10, and 18 MV have been studied. Our results showed that based on the relative
dose errors at a depth of 15 cm along the central axis, the terma divergence
correction may be used for fields smaller than 10 x 10 cm2 with a SSD larger than
80 cm; the dose divergence correction with an additional kernel hardening
correction can reduce dose error and may be more applicable than the terma
divergence correction. For both these methods, the dose error increased linearly
with the depth in the phantom; the 90% isodose lines at the depth of 15 cm were
shifted by about 2%-5% of the field width due to significant underestimation of
the penumbra dose. The kernel hardening effect was less prominent than the kernel
tilting effect for clinical photon beams. The dose error by using nonhardening
corrected kernel is less than 2.0% at a depth of 15 cm along the central axis,
yet it increased with a smaller field size and lower photon energy. The kernel
hardening correction could be more important to compute dose in the fields with
beam modifiers such as wedges when beam hardening is more significant. The kernel
tilting correction and kernel hardening correction increased computation time by
about 3 times, and 0.5-1 times, respectively. This can be justified by more
accurate dose calculations for the majority of clinical treatments.
PMID- 9394281
TI - Decision theoretic steering and genetic algorithm optimization: application to
stereotactic radiosurgery treatment planning.
AB - Treatment planning for stereotactic radiosurgery and fractionated radiotherapy is
currently a labor intensive, operator-dependent process. Many degrees of freedom
exist to make rigorous optimization intractable except by computationally
intelligent techniques. The quality of a given plan is determined by an aggregate
of clinical objectives, most of which are subject to competing tradeoffs. In this
work, we present an autonomous scheme that couples decision theoretic guidance
with a genetic algorithm for optimization. Ordinal ranking among a population of
viable treatment plans is based on a generalized distance metric, which promotes
a decreasing hyperfrontier of the efficient solution set. The solution set is
driven toward efficiency by the genetic algorithm, which uses the tournament
selection mechanism based on the ordinal ranking. Goals and satisficing
conditions can be defined to signal the ultimate and the minimum achievement
levels in a given objective. A conventionally challenging case in radiosurgery
was used to demonstrate the practical utility and the problem-solving power of
the decision theoretic genetic algorithm. Treatment plans with one isocenter and
four isocenters were derived under the autonomous scheme and compared to the
actual treatment plan manually optimized by the expert planner. Quality
assessment based on dose-volume histograms and normal tissue complication
probabilities suggested that computational optimization could be driven to offer
varying degrees of dosimetric improvement over a human-guided optimization
effort. Furthermore, it was possible to achieve a high degree of isodose
conformity to the target volume in computational optimization by increasing the
degree of freedom in the treatment parameters. The time taken to derive an
efficient planning solution was comparable and usually shorter than in the manual
planning process, and can be scaled down almost linearly with the number of
processors. Overall, the autonomous genetic algorithm scheme was found to be
powerful and versatile as a computationally intelligent counterpart to human
guided strategies in treatment optimization for stereotactic radiosurgery and
radiotherapy.
PMID- 9394282
TI - Inverse radiation treatment planning using the Dynamically Penalized Likelihood
method.
AB - In this paper we present a new method of solving the inverse radiation treatment
planning problem. The method is based on a Maximum Likelihood Estimator with
dynamically changing penalization terms. The resulting Dynamically Penalized
Likelihood (DPL) algorithm achieves a dose distribution of excellent uniformity
in a tumor volume and a much lower dose in regions containing sensitive volumes.
A simple model of a patient and of energy deposition has been used for the
initial results presented: a two-dimensional computer generated phantom and
monochromatic x rays, without scattering. Three two-dimensional problems are
solved with the DPL algorithm, corresponding to different size and spatial
relationships between the tumor and sensitive tissue volumes. The results show
that the DPL algorithm is robust and flexible; it only requires moderate
computation times and leads to promising solutions, even in rather difficult
problems. The results encourage the extension of the present work to more
realistic therapy situations.
PMID- 9394283
TI - A sector-integration method for calculating the output factors of irregularly
shaped electron fields.
AB - An empirical model is presented that uses a sector-integration method for
calculating the output factors of irregularly shaped electron fields. The sector
integration method accounts for changes in electron fluence, lateral scatter
equilibrium, and scatter from the edge of a cutout shield. This method is tested
for elliptical and rectangular fields with a ratio of the long-to-short axis as
great as 4 to 1. Differences between measured and calculated values for output
factors were less than +/- 1%. Comparisons were also carried out for a large
number of cutout shields that were used in the clinic and similar levels of
accuracy were obtained.
PMID- 9394284
TI - An equivalent square field formula for determining head scatter factors of
rectangular fields.
AB - A simple formula is derived for the calculation of an equivalent square field
that gives the same head scatter factor as a given rectangular field. This
formula is based strictly on the configuration of a medical linear accelerator
treatment head. The geometric parameters used are the distances between the
target and the top of each field-defining aperture. The formula accounts for both
the effect of field elongation and the collimator exchange effect. This method
predicts the output to within 1% accuracy for both open and wedged fields and
does not require any new measured data other than the field size dependence of
head scatter for a range of square field sizes. Interestingly, the formula we
derived has the same format as the formula that was empirically obtained by
Vadash and Bjarngard [Med. Phys. 20, 733-734 (1993)].
PMID- 9394285
TI - An approximation of central-axis absorbed dose in narrow photon beams.
AB - In narrow photon beams of therapeutic energy range, the absorbed dose derived
from experimental measurements is subject to a significant error. The error stems
from high dose gradients characteristic to small radiation fields and from finite
probe dimensions. In this study, a simple model for the narrow-beam absorbed dose
is described. It is shown that broad-beam dose data are sufficient to predict a
narrow-beam dose. The dose is calculated as a sum of primary and scatter
components given in the form of respective analytical functions. For both
functions, numerical coefficients are determined in broad-beam geometry. The
model is evaluated by comparing calculated dose values with the Monte Carlo
simulated narrow-beam dose data for 6 and 15 MV x rays.
PMID- 9394286
TI - Forward dose perturbation at high atomic number interfaces in kilovoltage x-ray
beams.
AB - High atomic number (Z) materials such as lead, used for field shaping and
shielding normal tissues in kilovoltage beams could produce significant dose
enhancement in the forward direction contrary to our normal belief with respect
to the attenuation of photon beams. Such a dose enhancement has not been studied
in kilovoltage beams, which is investigated in this study. Using a Siemens ortho
voltage unit (60-240 kVp) and a thin window (5 microns) parallel plate ion
chamber, forward dose perturbation factor (FDPF) was measured at interfaces
created by high- and low-Z materials. The FDPF is defined as the ratio of doses
with and without an interface (FDPF = Di/Dh; where Di is the dose at an interface
and Dh is the dose in a homogeneous medium). Results indicate that dose
enhancement (FDPF > 1) as high as 20-fold can be observed for a thin (> or = 0.02
mm) Pb sheet in contact with soft tissue. The magnitude of FDPF is relatively
independent of field size and falls off exponentially with Pb thickness. The
typical photon beam attenuation takes at a thickness > 1 mm. This intense dose
enhancement is localized within 250 microns of the interface. The FDPF is energy
dependent but saturates above 140 kVp, unlike the backscatter dose perturbation
that peaks around 200 kVp. The FDPF varies inversely with the thickness of high Z
and distance between the surface and high-Z medium. The FDPF falls off rapidly to
a level of photon transmission usually predicted by exponential attenuation when
distance is increased. In conclusion, with kilovoltage beam, a high-Z medium
placed in contact with soft tissue may not attenuate radiation dose unless
adequate thickness and proper distance between the surface and high-Z medium is
used. The localized intense dose enhancement (approximately 20-fold) created by
the high-Z interface could be exploited for clinical use.
PMID- 9394287
TI - The investigation of 32P wire for catheter-based endovascular irradiation.
AB - The dose distribution from a 32P source has been measured and calculated in order
to evaluate its application in endovascular irradiation. The source dimension was
27 mm in length and 0.3 mm in diameter and was embedded in the end of a Ni-Ti
wire. Dose measurements were performed using radiochromic film in several
specially designed tissue equivalent phantoms. Loevinger's point dose kernel was
used for the calculation. The approximate dose rate at a radial distance of 1.5
mm from the center of the source was found to be 6.75 cGy/s per GBq (0.25 cGy/s
per mCi), which allows the delivery of a therapeutic dose in a short time
interval with a satisfactory homogeneity without stepping the source. However,
the dose rate falls off almost exponentially along the radial distance. Therefore
it may not be suitable for treating large diameter vessel from a centrally
located source. The effect of a curved 32P wire source on the radial dose
distribution was also investigated. The results showed that for a maximum bend of
180 degrees the dose rate was increased by as much as 20% along the inner radial
distance but decreased by as much as 20% along the outer radial distance compared
to the dose along a straight wire. However, for curvatures normally encountered
in a clinical situation, the dose rate was changed less than 5%.
PMID- 9394288
TI - MarCell software for modeling bone marrow radiation cell kinetics.
AB - Differential equations were used to model cellular injury, repair, and
compensatory proliferation in the irradiated bone marrow. Recently, that model
was implemented as MarCell, a user-friendly MS-DOS computer program that allows
users from a variety of technical disciplines to evaluate complex radiation
exposure. The software allows menu selections for different sources of ionizing
radiation. Choices for cell lineages include progenitor, stroma, and malignant,
and the available species include mouse, rat, dog, sheep, swine, burro, and man.
An attractive feature is that any protracted irradiation can be compared with an
equivalent prompt dose (EPD) in terms of cell kinetics for either the source used
or for a reference such as 250 kVp x rays or 60Co. EPD is used to mean a dose
rate for which no meaningful biological recovery occurs during the period of
irradiation. For human as species, output from MarCell includes: risk of 30-day
mortality; risk of whole-body cancer and leukemia based either on radiation
induced cytopenia or compensatory cell proliferation; cell survival and
repopulation plots as functions of time or dose; and 4-week recovery following
treatment.
PMID- 9394289
TI - A method for measuring the ionization fraction due to the chamber wall (alpha)
and assessing its characteristics.
AB - To calibrate a megavoltage therapy beam using an ionization chamber, it is
necessary to know the fraction of the ionization arising in the chamber wall when
this is made of a material different than the medium. A method for measuring the
ionization fraction produced by electrons arising in the chamber wall (alpha) is
presented here. The method uses three measurements at the same point in a medium
in order to calculate alpha. These measurements are made using the examined
chamber with and without a buildup cap and one reference chamber of wall material
equivalent to the medium (i.e., in our case, A1 and A-150 were used as wall
materials for the examined and the reference chamber, respectively). Using this
method, it is possible to calculate alpha in the medium for a series of
irradiation conditions and assess its characteristics. Two main conclusions came
out of this assessment. The first one is the independence of alpha from the wall
material, even if this is aluminum (alpha is only dependent on wall thickness
expressed in g cm-2). The second one is that alpha depends on the irradiation
conditions; it increases with field size and depth.
PMID- 9394290
TI - What studies of fusion peptides tell us about viral envelope glycoprotein
mediated membrane fusion (review).
AB - This review describes the numerous and innovative methods used to study the
structure and function of viral fusion peptides. The systems studied include both
intact fusion proteins and synthetic peptides interacting with model membranes.
The strategies and methods include dissecting the fusion process into
intermediate stages, comparing the effects of sequence mutations,
electrophysiological patch clamp methods, hydrophobic photolabelling, video
microscopy of the redistribution of both aqueous and lipophilic fluorescent
probes between cells, standard optical spectroscopy of peptides in solution
(circular dichroism and fluorescence) and attenuated total reflection-Fourier
transform infrared spectroscopy of peptides bound to planar bilayers. Although
the goal of a detailed picture of the fusion pore has not been achieved for any
of the intermediate stages, important properties useful for constraining the
development of models are emerging. For example, the presence of alpha-helical
structure in at least part of the fusion peptide is strongly correlated with
activity; whereas, beta-structure tends to be less prevalent, associated with non
native experimental conditions, and more related to vesicle aggregation than
fusion. The specific angle of insertion of the peptides into the membrane plane
is also found to be an important characteristic for the fusion process. A shallow
penetration, extending only to the central aliphatic core region, is likely
responsible for the destabilization of the lipids required for coalescence of the
apposing membranes and fusion. The functional role of the fusion peptides (which
tend to be either nonpolar or aliphatic) is then to bind to and dehydrate the
outer bilayers at a localized site; and thus reduce the energy barrier for the
formation of highly curved, lipidic 'stalk' intermediates. In addition, the
importance of the formation of specific, 'higher-order' fusion peptide complexes
has also been shown. Recent crystallographic structures of core domains of two
more fusion proteins (in addition to influenza haemagglutinin) has greatly
facilitated the development of prototypic models of the fusion site. This latter
effort will undoubtedly benefit from the insights and constraints gained from the
studies of fusion peptides.
PMID- 9394291
TI - A novel family of channel-forming, autotransporting, bacterial virulence factors.
AB - Pathogenic bacteria produce virulence factors that cross the bacterial cell
envelope from the cytoplasm to the extracellular milieu where they promote
disease. The mechanisms of their export are poorly understood. We here
characterize a family of autotransporter (AT) protein domains present at the C
termini of several nonhomologous Gram-negative bacterial virulence factors. The
family consist of 18 sequenced protein domains, the functionally characterized
members of which catalyze export of (1) proteases, (2) virulence-related cell
adhesins, (3) mediators of actin-promoted bacterial motility, (4) cytotoxins and
(5) tissue invasion proteins. We (1) establish that these AT domains are
homologous, (2) multiply align their sequences, (3) derive an AT family-specific
signature sequence, and (4) define the evolutionary relationships between members
of the family. Secondary structural predictions as well as average hydropathy,
average similarity and average amphipathicity plots have allowed us to propose a
specific 14 beta-stranded barrel structural model that may be applicable to all
protein members of the AT family. We suggest that the AT domains became
associated with active virulence factor domains by interdomain fusion events that
occurred during the evolution of these complex proteins.
PMID- 9394293
TI - Assignment of the human serotonin 1F receptor gene (HTR1F) to the short arm of
chromosome 3 (3p13-p14.1).
AB - In the present study, we report the chromosomal localization of the human 5-HT1F
receptor gene (HTR1F) by the analysis of somatic cell hybrids. Based upon the
HTR1F cDNA sequence, a primer set that reacted with human genomic DNA but not
mouse or hamster genomic DNA was derived from the relatively nonconserved 5'
untranslated and coding region. Using monochromosomal hybrid cell lines of the
NIGMS Mapping Panel 2 we localized the HTR1F to human chromosome 3. To confirm
the localization on chromosome 3 and to further sublocalize the HTR1F gene, a set
of human cell hybrids regionally separating chromosome 3 into 7 regions was
similarly analysed. Analysis of this regional panel showed that the HTR1F gene
was located proximal to the 3p14.1 breakpoint in hybrid APH14 and distal to the
breakpoint in 3p13 in hybrid APH13. This localizes the HTR1F gene to human
chromosome 3p13-p14.1.
PMID- 9394292
TI - Phosphatidylserine exposure and aminophospholipid translocase activity in Rh
deficient erythrocytes.
AB - Endogenous phosphatidylserine (PS) exposure and lipid transport activity have
been investigated for seven unrelated cases of Rhnull erythrocytes. Endogenous PS
exposure was measured by prothrombinase activity. Out of six cases studied, two
Rhnull samples exhibited abnormal aminophospholipid exposure, as suggested by the
measurement of a lower Km of factor Xa for prothrombin. Aminophospholipid
translocase activity was measured through the transbilayer redistribution of spin
labelled analogues of phospholipids. Provided that incubation conditions allow
the maintainance of intracellular ATP level, no difference was observed between
Rhnull and control erythrocytes, clearly indicating that the aminophospholipid
translocase and Rh polypeptides are different molecular species.
PMID- 9394294
TI - Aggregation, fusion and aqueous content release from liposomes induced by
lysozyme derivatives: effect on the lytic activity.
AB - Chemically modified lysozymes, namely: N-succinyl lysozyme, glycine methyl ester
of N-succinyl lysozyme and oxoindole lysozyme have been prepared. Aggregation,
fusion and leakage of phospholipid vesicles induced by these derivatives have
been studied in comparison with the effect of the unmodified protein. The
experiments were carried out with negatively charges 9PC/PA, 9:1) and uncharged
(PC and PC/DOPE/Chol (10:5:5)) lipid vesicles of different packing. Fusion and
aggregation of negatively charged phospholipid vesicles in induced by proteins
positively charged at pH 7.0 involving electrostatic interactions, a similar
pattern on fusion and aggregation of the least stably packed lipid vesicles
points also to hydrophobic forces playing a role in the lipid-protein
interaction. A conformational change of the protein involved increasing beta
turns, loops and unordered structure at the expenses of beta-sheet without
affecting alpha helix content. The conformational effect is necessary to provoke
the effects studied, since one of the derivatives (N-succinyl lysozyme) neither
changes conformation nor causes aggregation and fusion of vesicles. However,
there is no relationship between lysozyme activity and fusion or aggregation of
lipid vesicles that catalytic and fusogenci sites of, indicating lysozyme are
topographically different.
PMID- 9394295
TI - Membrane proteins at the interface of erythrocytes fused by treatment with
polyethylene glycol.
AB - Fusion of human red cells through the action of polyethylene glycol gives rise to
pairs or higher clusters with a common membrane envelope, in which a barrier at
the position of the original interface can be seen in phase contrast. At early
times this septum contains lipids, as judged by labelling with a fluorescent
lipophile, and transmembrane protein; this was shown by the presence of the
preponderant component, band 3, detected by a fluorescent label, covalently
attached before fusion at an extracellular site, or by immunofluorescence with
anti-band 3 antibody. Ankyrin, which is bound to band 3, is also observed in the
septum. The lipid thereafter disappears from the interface, carrying most of the
band 3 with it. A continuous membrane skeletal network, defined by the presence
of spectrin (detected by immunofluorescent staining in epifluorescence and
confocal microscopy) appears to persist for long periods, but in many cells
interruptions develop in the septum. In other fused pairs, particularly at longer
times, the interface is seen to have vanished completely. Protease inhibitors
have no discernible effect on any of these observations. The results suggest a
model for the events that follow fusion. Covalent cross-linking of membrane
proteins beyond a critical level causes inhibition of fusion, suggesting that
proteins, probably the membrane skeletal network, regulate the fusion process.
The efficiency of fusion is strikingly dependent on the composition of the
isotonic medium, being relatively high at an orthophosphate concentration of 5 mM
and minimal at 20 mM.
PMID- 9394296
TI - Patenting inventions in the field of biology and chemistry: German and European
patent law and case law.
AB - Patent law is intended to provide protection for new and inventive achievements
in technology. Technical progress is considered to be the purpose and aim of
patent law. The main objective of patent law is to protect patentable results
according to the latest state of science and research. It is most important to
encourage the inventor to completely publish his knowledge. As a reward for this
the inventor is granted a right of exclusion which is limited in time: the
patent. It is not the purpose of patent law to enrich mere theory but to create
industrially applicable knowledge for the public. This contribution deals with
important problems to be considered by inventors in the patenting of inventions
in the field of biology and chemistry. Such questions are related particularly to
the accessibility of inventions and discoveries to patent protection, the various
kinds (categories) of patents, the requirement of novelty, complete disclosure of
the invention, patentability of DNA sequences and proteins, as well as inventive
step.
PMID- 9394297
TI - How to derive steady-state rate laws for enzyme-catalyzed reactions from
macroscopic probabilities.
PMID- 9394298
TI - Molecular intervention with antisense oligodeoxynucleotides (ODNs) in nephrology.
PMID- 9394299
TI - How does the macula densa sense tubule function?
PMID- 9394300
TI - Genetics of cardiovascular disease in type 1 (insulin-dependent) diabetes with
and without renal involvement.
PMID- 9394301
TI - Implications of the Systolic Hypertension in Europe (Syst-Eur) Trial for clinical
practice.
PMID- 9394302
TI - PTH--one can teach an old hormone new tricks.
PMID- 9394303
TI - Malnutrition is bad, but how can one detect malnutrition?
PMID- 9394304
TI - Apoptosis: background and possible role in secondary hyperparathyroidism.
PMID- 9394305
TI - Nephrology, dialysis and transplantation in Brazil.
AB - The European Renal Association welcomes this opportunity and feels that European
nephrologists should be informed about the state of nephrology in South America,
with which particularly our Latin colleagues maintain close cultural
relationships. The following report on Nephrology in Brazil is a welcome addition
to a series of reports designed to provide to European nephrologists a global
view of nephrology. It is hoped that this is not misconstrued as a violation of
nephrological Monroe doctrine.
PMID- 9394306
TI - Preservation of renal function: the spectrum of effects by calcium-channel
blockers.
AB - The vast majority of animal data derived from models of either remnant kidney or
diabetes demonstrate that dihydropyridine (nifedipine-like) calcium-channel
blockers (DHPCCBs) effectively reduce arterial pressure but do not significantly
affect proteinuria nor prevent development of glomerular scarring. Conversely,
the non-DHPCCBs such as diltiazem and verapamil blunt both the rise in
proteinuria as well as mesangial matrix expansion and subsequent glomerular
scarring in diabetes. Additionally, the non-DHPCCBs markedly attenuate
development of glomerular scarring in the remnant kidney model. The primary
reasons for these differences between subclasses of CCBs relates to a lack of the
following attributes by DHPCCBs: (1) they fail to reduce glomerular membrane
permeability which is increased in these models; (2) they fail to affect the
synthesis of certain key matrix proteins that perpetuate development of
glomerular scarring (this effect may be due to the differential expression of
calcium channels within the glomerular mesangium); and (3) the DHPCCBs totally
abolish renal autoregulation in these models, an effect not observed with non
DHPCCBs. Taken together with long-term (> 3 year) clinical studies, primarily in
diabetic nephropathy, it is clear that the non-DHPCCBs seem to offer protection
to the kidney not available with DHPCCBs alone, unless systolic arterial pressure
is reduced to levels of < or = 110 mmHg.
PMID- 9394307
TI - Organ donation in the UK: a survey by a British Transplantation Society working
party.
AB - BACKGROUND: During the past few years the number of organ donors in the UK has
declined after a slow but steady increase during the 1980s. Concern about the
decline led to a survey by the British Transplantation Society. The report of
this survey highlighted a number of reasons for the decline and this manuscript
presents and discuss the main items in the report. METHODS: Comprehensive
information relating to organ donation was obtained by a combination of
structured interviews during visits to intensive care units (ICUs) and
neurosurgical units, the use of detailed questionnaires sent to all UK ICUs, and
from the register held by the United Kingdom Transplant Support Service
Authority. RESULTS: The information obtained highlighted a number of reasons for
the decline in organ donor numbers and these are presented and discussed. The
pool of potential donors is shrinking as death rates from road traffic accidents
and intracranial haemorrhage decrease. Also the increasing use of modern imaging
techniques has improved predictive ability in patients with severe brain damage
with the result that more patients whose prognosis is assessed as hopeless are
not treated by ventilation. Inadequacies both in intensive care unit bed
provision and the resourcing of the transplant co-ordinator service were also
thought to be important. CONCLUSIONS: Eight recommendations have been made,
covering ICU bed provision, neurosurgical provision, transplant surgical
staffing, the transplant co-ordinator network, reimbursement to donor units,
asystolic donation, live donor transplantation, and interventional ventilation.
PMID- 9394308
TI - Intercellular adhesion molecule-1 mediated interactions and leucocyte
infiltration in IgA nephropathy.
AB - BACKGROUND: Mononuclear leucocytes have a role in IgA nephropathy (IgAN). Renal
leucocyte recruitment is mediated by adhesive interactions between leucocytes and
their ligands on renal cells. METHODS: We have assessed interstitial and
glomerular leucocytes by avidin-biotin-peroxidase with monoclonal antibodies (MA)
against leucocytes (CD45), beta 2-integrin (CD18), monocyte-macrophages (CD14), T
(CD3) and T-cell subsets (CD4, CD8), and intercellular adhesion molecule-1 (ICAM
1) (CD54), and analysed their relation with the abnormal expression of ICAM-1 on
proximal tubule epithelium in sequential renal sections from 48 patients with
IgAN stratified according to the severity of the interstitial cellular
infiltration observed by light microscopy. RESULTS: In IgAN without (n = 15) and
with (n = 7) interstitial cellular infiltration of 1+, ICAM-1 expression on
vascular endothelium was unchanged with respect to that observed in the normal
kidney; the proximal tubule epithelium was negative for this stain. In IgAN with
interstitial cellular infiltration of 2+ (n = 10), 3+ (n = 11), and 4+ (n = 5),
ICAM-1+ stain was observed on the proximal tubule epithelium, the median value of
its quantitative expression being 0.3, 0.1, and 0.2 (P = 0.0008), respectively.
The tubular ICAM-1 + stain was significantly associated with the interstitial
leucocytes identified by MA, and correlated with CD45+ (r = 0.59, P = 0.02),
CD14+ (r = 0.54, P < 0.02), and CD3+ (r = 0.51, P = 0.02) interstitial leucocytes
in IgAN with interstitial cellular infiltration. Interstitial ICAM-1+ and CD18+
leucocytes were correlated (r = 0.56, P < 0.001). Correlation was found between
the quantitative tubular expression of ICAM-1+ and the number of CD45+ (r = 0.98,
P < 0.0001), CD3+ (r = 0.48, P = 0.02), and CD8+ (r = 0.76, P < 0.02) glomerular
leucocytes. CONCLUSIONS: Our results suggest that tubular and interstitial ICAM
1+ cells may participate in adhesive interactions with interstitial leucocytes.
Interstitial T-cells and macrophages as well as glomerular T-cells bearing
predominantly CD8+ phenotype could play a role in the induction of the tubular
expression of ICAM-1 in IgAN.
PMID- 9394309
TI - Occurrence of anti-C1q antibodies in IgA nephropathy.
AB - BACKGROUND: The pathogenic mechanisms and the antigens involved in the
establishment and progress of IgA nephropathy are unknown. As antibodies against
C1q have been reported to correlate with SLE nephritis, we analysed the
occurrence of these antibodies in IgA nephropathy in order to investigate the
possibility of pathogenetic similarities in these renal disorders. METHODS: The
occurrence of IgA- and IgG anti-C1q antibodies (anti-C1q) were determined by
ELISA in patients with IgA nephropathy (n = 36) and SLE nephritis (n = 37),
diseases both known to be associated with circulating immune complexes. Levels of
these antibodies were also determined in two other glomerular diseases, i.e.
idiopathic membranous glomerulonephritis (n = 7) and minimal change disease (n =
2), in which circulating immune complexes are usually not present, and in 40
healthy controls. RESULTS: IgA anti-C1q was observed in increased titres in 11/36
of the patients with IgA nephropathy, in 2/37 of the patients with SLE nephritis
(both with proliferative disease) and in 1/9 of the patients with membranous and
minimal change disease (P < 0.001). Increased titres of IgG anti-C1q were
observed in 1/36 of the patients with IgA nephropathy, in 17/37 of the patients
with SLE nephritis and in 0/9 of the patients with membranous and minimal change
disease (P < 0.001). There were no correlations between the levels of anti-C1q
antibodies and clinical parameters such as degree of proteinuria, haematuria, or
renal function. Nor was there any correlation to the concentration of C3a and the
terminal complement complex (TCC) in patients with IgA nephropathy. CONCLUSIONS:
The occurrence of anti-C1q antibodies in both IgA nephropathy and SLE nephritis,
albeit of different predominating isotypes, indicates the possibility of a
similar pathogenic mechanism involved in these renal disorders. The occurrence of
IgA anti-C1q antibodies in patients with IgA nephropathy has to our knowledge not
previously been reported.
PMID- 9394310
TI - Properties of circulating IgA molecules in Henoch-Schonlein purpura nephritis
with focus on neutrophil cytoplasmic antigen IgA binding (IgA-ANCA): new insight
into a debated issue. Italian Group of Renal Immunopathology Collaborative Study
on Henoch-Schonlein purpura in adults and in children.
AB - BACKGROUND: The presence and the pathogenetic role of circulating IgA reacting
with neutrophil cytoplasmic antigens (IgA-ANCA) in patients with Henoch-Schonlein
purpura (HSP) is still debated. This study was aimed to investigate some
characteristics of serum IgA and macromolecular IgA in HSP patients, focusing on
IgA-ANCA. METHODS: Eighty-seven HSP patients with biopsy proved renal involvement
(51 adults and 36 children) enrolled in a multicentre study of the Italian Group
of Immunopathology were investigated. RESULTS: Significantly high levels of IgA
immune complexes were found in both adults (P < 0.05) and children (P < 0.01),
while the binding of IgA to jacalin, was significantly low in children with HSP
(P < 0.01) only. Two series of ELISA were done for IgA-ANCA, in two different
laboratories. Increased binding to PMN crude extracts (P < 0.01) without any
modification in IgA binding to proteinase 3 was found by either specific ELISA.
Conversely, the binding of IgA to myeloperoxidase (MPO) was found to be
significantly (P < 0.05) increased with positive values in 25% of patients by one
assay only. Three of four sera with positive IgA-MPO ANCA exhibited binding in
Western-blot studies with the MPO preparation used in ELISA to a 28-kDa species.
D-galactose and N-acetyl-glucosamine decreased the binding of serum IgA to MPO
more in HSP than in controls (P < 0.05). CONCLUSIONS: The conflicting reports on
IgA-ANCA may reflect some atypical characteristics of the reaction which can be
detected only by some ELISAs. We suggest that not an antigen-antibody reaction
but a lectinic interaction due to abnormal composition of IgA carbohydrate side
chains may account for the IgA-ANCA reaction in patients with HSP nephritis.
PMID- 9394311
TI - Long-term prognosis of Henoch-Schonlein nephritis in adults and children. Italian
Group of Renal Immunopathology Collaborative Study on Henoch-Schonlein purpura.
AB - BACKGROUND: The aim of this multicentre collaborative study was to compare the
progression of renal disease in children and adults with Henoch-Schonlein purpura
(HPS) nephritis selected on the basis of IgA-dominant renal deposits and biopsy
material available for review. METHODS: The analysis was performed in 152
patients (95 adults and 57 children < 16 years old at diagnosis) with a follow-up
(> or = 1 year up to 20 years (4.9 +/- 3.4 years in adults and 4.8 +/- 3.9 years
in children). RESULTS: Renal histology and clinical presentation were similar in
both age groups: crescents were found in 36% of adults and 34.6% of children (in
only 2.7% of adults and 1.9% of children involving > 50% of glomeruli), nephrotic
range proteinuria in 29.5% of adults and 28.1% of children and functional
impairment in 24.1% of adults and 36.9% of children. The outcome was similar for
both age groups (remission, 32.5% of adults and 31.6% of children; renal function
impairment, 31.6% of adults and 24.5% of children). Endstage renal disease was
observed in 15.8% of adults and in 7% of children. Renal function survival at 5
years was not significantly different in the two groups (85% in adults and 95% in
children) and at 10 years it was approximately 75% in both groups. None of the
children died and adult survival was 97% at 5 years. In adults at presentation,
renal function impairment (P < 0.02) as well as proteinuria higher than 1.5 g/day
(P < 0.02) and hypertension (P < 0.001) were negative prognostic factors.
Multivariate analysis stressed the main statistical relevance of proteinuria
(relative risk 2.37, P < 0.02). Conversely, in children no definite level of
proteinuria, hypertension or other data were found to be associated with poor
prognosis. CONCLUSIONS: Among patients with a clinical presentation which
warrants renal biopsy, HSP nephritis has a similar prognosis in children and
adults. The evolution is more predictable in adults than in children.
PMID- 9394312
TI - Neonatal presentation of autosomal dominant polycystic kidney disease with a
maternal history of tuberous sclerosis.
AB - BACKGROUND: Childhood presentation of polycystic kidney disease has been reported
with tuberous sclerosis complex (TSC). Recently some such cases have been shown
to be due to combined deletion of the PKD1 and TSC2 genes, which lie close
together on chromosome 16. The phenomenon of anticipation, whereby disease
presentation occurs at a progressively earlier age in each generation, has been
suggested to occur in autosomal dominant polycystic kidney disease (ADPKD). We
have carried out a genetic study of a family in which these issues became
clinically relevant. Neonatal presentation of polycystic kidneys occurred in an
individual with a maternal family history of epilepsy and features of TSC without
renal cystic disease. METHODS: Detailed historical and clinical profiles were
gathered for three generations of the maternal and paternal families. Both
parents underwent renal ultrasound scanning. Genomic DNA was obtained from
affected and unaffected individuals from the maternal family and used for linkage
analysis to gene loci for TSC. RESULTS: Renal cysts were not present in the
mother by ultrasound. Linkage to TSC2 was found for members of the maternal
family with clinical features of TSC. While a diagnosis of TSC was confirmed in
her mother the child was found not to have inherited the disease-related allele.
The father was found to have asymptomatic bilateral polycystic kidneys consistent
with ADPKD. The presence of ADPKD in other paternal relatives could not be
confirmed. CONCLUSIONS: The index case was found to have paternally inherited
ADPKD with unusually early presentation. While at risk for concomitant maternal
inheritance of TSC this diagnosis was ruled out by linkage analysis studies. The
ability to clarify the true nature of a complex inherited condition greatly
facilitates future management and counselling. The mechanisms underlying
phenotypic heterogeneity in ADPKD remain to be clearly defined and are the
subject of ongoing investigation.
PMID- 9394313
TI - Enalapril versus metoprolol in primary hypertension--effects on the glomerular
filtration rate.
AB - BACKGROUND: Hypertension is a significant cause of end-stage renal failure and
effective treatment of hypertensive will reduce the progression rate of chronic
renal failure in various kidney disorders. Different classes of drugs may be more
effective than others in this respect. In this study we compared the effects on
the glomerular filtration rate (GFR) of the ACE-inhibitor enalapril and the
betablocker metoprolol in patients with mild and moderate primary hypertension
during 6 years. METHODS: Patients with GFR in the normal range (> or = 80
ml/min/1.73 m2 BSA) were included after a placebo treatment period of 4-8 weeks
if diastolic blood pressure was 100-120 mm Hg. Target blood pressure was set to <
90 mm Hg diastolic. One hundred and thirty patients were randomized in an open
parallel study to receive either enalapril or metoprolol. No placebo group was
included. GFR was measured using the 51CR-EDTA clearance method and 81 patients
completed the study. RESULTS: At inclusion, there were no significant differences
regarding GFR or blood pressure between the groups. The blood pressure treatment
goal was reached in all patients and was maintained during the whole observation
period. A small but significant fall in GFR by 4 ml/min/1.73 m2 BSA was noted in
both groups after the first year of treatment but thereafter GFR decreased by
only 1 ml/min/year/1.73 m2 BSA, in both groups. Body weight, serum uric acid and
triglycerides increased slightly with metoprolol treatment but no other
differences between the two treatments were noted. CONCLUSIONS: With the blood
pressure maintained at the same level using either enalapril or metoprolol during
a 6-year study period, GFR decreased to the same extent in the two groups both
during the first year and thereafter. The overall magnitude of the GFR decline
approached that of the normal age-related decrease of kidney function, i.e. GFR
decreased only about 1 ml/min/year. Thus, treatment with an ACE-inhibitor,
enalapril, and a beta-blocker, metoprolol, protected the kidney function to the
same extent in this 6 year long study in mild and moderate primary hypertension.
PMID- 9394314
TI - A randomized, controlled study of sulodexide therapy for the treatment of
diabetic nephropathy.
AB - BACKGROUND: Glycosaminoglycans (GAGs) play an important role in the
physiopathology of diabetic nephropathy; they are essential for the maintenance
of glomerular charge selectivity and their administration can reduce albuminuria
in diabetic patients. METHODS: Following a randomized block design, controlled
versus placebo, we investigated, in insulin-dependent diabetic patients with
micro- or macroalbuminuria, whether GAG therapy can influence an altered albumin
excretion rate (AER). Thirty-six patients (18 micro- and 18 macroalbuminuric)
were randomized to receive, during 5 days/week for 3 weeks, either a daily dose
of 600 lipoproteinlipase releasing units (LRU) of sulodexide by the i.m. route (9
micro- and 9 macroalbuminuric patients), or a matching i.m. placebo (9 micro- and
9 macroalbuminuric patients). All patients were followed-up for further 6 weeks.
AER was evaluated before treatment, weekly during it and every 3 weeks during
follow-up. RESULTS: Seventeen of the 18 sulodexide-treated patients showed a
trend towards decrease in AER, more evident and statistically significant in
microalbuminurics (P < 0.01 after the first week). At the end of follow-up, AER
was still significantly reduced in microalbuminurics, while macroalbuminurics
showed again increased values. Placebo-treated patients evidenced no AER
variations during all the study period. No statistically significant differences
vs baseline, concerning blood pressure, haematological, haematochemical, and
coagulative tests, and urinalysis, were ever observed, apart from a clear-cut
decrease in blood cholesterol and triglycerides at the end of treatment, in a
subgroup of hyperlipidaemic, sulodexide-treated subjects. No adverse events were
registered. CONCLUSIONS: Our results suggest that the GAG sulodexide exerts a
positive activity in type I diabetic patients with micro- and macroalbuminuria,
by reducing the abnormally high AER levels.
PMID- 9394315
TI - An investigation of the effect of advancing uraemia, renal replacement therapy
and renal transplantation on blood pressure diurnal variability.
AB - BACKGROUND: Ambulatory blood pressure recordings have been shown to correlate
better with target organ damage than have isolated clinic blood pressure
readings. There have been some small studies demonstrating that abnormal blood
pressure diurnal rhythm is common in uraemia and in patients on renal replacement
therapy. Abnormal blood pressure diurnal rhythm itself may be a risk factor for
accelerated target organ damage. METHODS: We retrospectively studied 480
ambulatory blood pressure recordings in 380 patients with essential hypertension,
secondary hypertension, and on renal replacement therapy. We examined diurnal
blood pressure rhythm in each group. RESULTS: Abnormal blood pressure diurnal
rhythm (non-dipping) is significantly more prevalent in patients with underlying
renal disease, even with normal excretory renal function (53%) than in age-, sex
, and race-matched controls with essential hypertension ((30%), P < 0.01). In
patients with renal disease the prevalence of non-dipping rose with worsening
renal function, reaching statistical significance once plasma creatinine was
greater than 400 mumol/l. There was a direct correlation between plasma
creatinine and percent decline in blood pressure at night for both systolic (r =
0.23) and diastolic (r = 0.24) blood pressure in patients with underlying renal
disease and impaired excretory renal function. High prevalences of abnormal
diurnal BP rhythm are seen in patients on haemodialysis (82%), peritoneal
dialysis (78%), patients with plasma creatinine > 600 mumol/l (75%), and in renal
transplant recipients (74%). CONCLUSIONS: Abnormal blood pressure diurnal rhythm
('non-dipping') is significantly more common in secondary than in primary
hypertension, even with normal renal function. Abnormal blood pressure diurnal
rhythm becomes increasingly common with advancing uraemia. Once the plasma
creatinine is greater than 600 mumol/l the prevalence of non-dipping is the same
as that seen with renal replacement therapy. This phenomenon is not modulated by
successful renal transplantation.
PMID- 9394316
TI - Interdialytic weight gain and 48-h blood pressure in haemodialysis patients.
AB - BACKGROUND: Hypertension, which is often associated with hypervolaemia, is common
in haemodialysis patients and is a known determinant of target organ damage.
Interdialytic weight gain due to volume overload has also been associated with
mortality in haemodialysis patients. METHODS: We therefore studied 27 chronic
haemodialysis patients who underwent 48-h ambulatory blood pressure monitoring
between two midweek dialysis sessions, and 2D and M-mode echocardiography for
determination of left ventricular mass index. RESULTS: Left ventricular
hypertrophy (left ventricular mass index in men > 131 g/m2, women > 100 g/m2) was
present in 70% (19/27) patients despite a mean 48-h blood pressure of 132 +/-
19/81 +/- 15 mmHg. Mean interdialytic weight gain was 1.6 +/- 0.8 kg and was not
related to left ventricular mass index. Two patterns of interdialytic blood
pressure change were apparent: in group 1 (16 patients) 48-h blood pressure
increased (+19 +/- 12/13 +/- 9 mmHg), whereas in group 2 (11 patients) blood
pressure fell (-10 +/- 13/-8 +/- 10 mmHg P < 0.0001). In both groups the number
of hypertensive patients (group 1, 10/16; group 2, 6/11), the 48-h blood pressure
(132 +/- 20/80 +/- 15 vs 132 +/- 18/82 +/- 15 mmHg) and interdialytic weight gain
(+1.9 +/- 0.7 vs +1.3 +/- 0.7 kg) were similar. There was also no correlation
between interdialytic blood pressure change and weight gain in either group.
CONCLUSIONS: We conclude that interdialytic blood pressure changes cannot be
directly related to interdialytic fluid gain, even in apparent volume-dependent
hypertension, emphasizing the importance of additional factors in the control of
blood pressure in end-stage renal disease.
PMID- 9394317
TI - Erythropoietin and oxidative stress in haemodialysis: beneficial effects of
vitamin E supplementation.
AB - Oxidative stress can produce profound alterations to cellular membrane lipids,
impairing cell metabolism and viability. This phenomenon, previously observed in
haemodialysis patients, has been proposed as a significant factor in regard to
haemodialysis-related shortened red blood cells (RBC) survival. In the present
study, several parameters associated with oxidative stress were evaluated in a
group of haemodialysis patients either receiving erythropoietin therapy (n = 12,
mean erythropoietin dose 88 +/- 24 U/kg/week) or not receiving such therapy (n =
30), and in 38 controls. Malonyldialdehyde (MDA, nmol/ml), an end-product of
lipid peroxidation, and RBC antioxidant systems were measured, including RBC
alpha-tocopherol (RBC vitamin E, mg/l), RBC glutathione (GSH, nmol/mgHb), and RBC
superoxide dismutase activity (SOD, U/mgHb). Plasma vitamin E concentrations were
also evaluated. Finally, oral vitamin E supplementation (500 mg daily), an
exogenous antioxidant, was administered for 6 months to seven patients from the
dialysis group receiving erythropoietin while oxidative parameters were
repeatedly evaluated and erythropoietin requirements monitored, in order to
appreciate the therapeutic relevance of an antioxidant supplementation. An
elevation of serum MDA was observed in all haemodialysis patients and a
significant decrease in RBC vitamin E, despite normal serum vitamin E levels.
Furthermore, the reduction in RBC vitamin E was more important in patients
treated with erythropoietin. Vitamin E supplementation resulted in a significant
increase in RBC vitamin E (from 0.3 +/- 0.1 to 1.2 +/- 0.2 mg/l of pellet) and a
reduction in erythropoietin dose (from 93 +/- 24 to 74 +/- 26 U/kg/week) while
maintaining stable haemoglobin concentrations. These results suggest that the
oxidative stress could be one of the resistance factors to erythropoietin
response in haemodialysis and that vitamin E supplementation could have a sparing
effect on erythropoietin dosage requirement.
PMID- 9394318
TI - Increased plasma leptin/fat ratio in patients with chronic renal failure: a cause
of malnutrition?
AB - BACKGROUND: Protein-energy malnutrition occurs in patients with chronic renal
failure primarily due to loss of appetite. The ob gene protein, leptin, which is
secreted by adipocytes, regulates body composition by lowering food intake. We
have measured plasma leptin in undialysed and dialysed patients and in controls
and the concentrations have been related to body composition, dietary intake, and
biochemistry. METHODS: Plasma leptin was measured by radioimmunoassay in 93
individuals in groups of undialysed, peritoneal dialysed, and haemodialysed
patients and controls. Body composition was determined by DEXA. RESULTS: Protein
energy malnutrition was evident in non-dialysed and dialysed patients from low
lean or fat tissues, plasma albumin and transferrin. A third of the dialysis
patients were eating less than prescribed intakes. Leptin relative to total fat
mass (ng/ml/kg) was significantly greater for patients than for controls,
particularly the dialysed patients. Leptin was highly correlated with total, arm,
leg, and all other fat measurements, e.g. r for leptin vsm % total fat was:
undialysed 0.88, PD 0.81, HD 0.93, and controls 0.83 (P < 0.0001 for all).
Dialysis patients with the highest leptin/fat mass ratio had low protein intakes
and significantly lower lean tissue mass. Leptin/fat ratio correlated inversely
with dietary intake e.g. with protein intake in g/day and marginally in g/kg of
ideal weight/day. Leptin concentration was unrelated to plasma creatinine or
residual renal function or to the protein 'nutritional indices', albumin and
transferrin. CONCLUSIONS: Our data suggests that leptin is markedly increased in
some patients with chronic renal failure. The association of increased leptin
with low protein intake and loss of lean tissue is consistent with leptin
contributing to malnutrition but a definitive role cannot be substantiated by
this study.
PMID- 9394319
TI - The impact of malnutrition in morbidity and mortality in stable haemodialysis
patients. Spanish Cooperative Study of Nutrition in Hemodialysis.
AB - BACKGROUND: When assessed by single biochemical measurements, malnutrition in
dialysis patients is associated with increased mortality, but there are few data
evaluating abnormalities in anthropometry or composite nutritional scores and
outcome. The aim of our study was to ascertain the prevalence and severity of
malnutrition in 761 stable patients from 20 haemodialysis centres and its
influence in morbidity and mortality after one year of follow-up. METHODS:
Malnutrition was estimated by scoring four anthropometric indexes; body mass
index (BMI), triceps skinfold thickness (TSF), mid-arm circumference (MAC), and
mid-arm muscle circumference (MAMC); three biochemical measurements; serum
albumin, serum transferrin and total lymphocyte count; and clinical examination.
Mortality and hospitalizations were collected prospectively during the year of
follow-up. RESULTS: A moderate/severe degree of malnutrition was presented by
51.6% of male and 46.3% of female patients. TSF was moderate-severely decreased
in 41% without differences between males and females. MAMC was moderately
decreased in 19.8% of males and in 8.1% of females (P < 0.001). Multiple logistic
regression analysis showed that the predictors of malnutrition were: age > 65
years (OR = 1.96, CI: 1.22-3.14), male sex (OR = 1.95, CI: 1.24-3.07),
comorbidity index (OR = 1.23, CI: 1.03-1.45), time on dialysis (OR = 1.13, CI:
1.08-1.18), duration of dialysis (OR = 0.73, CI: 0.63-0.85) and PCR related to
ideal body weight (OR = 0.17, CI: 0.06-0.50). After 1 year of follow-up, data
from 442 patients were available. A total of 68 patients died (15.4%) with
cardiovascular diseases being the most frequent cause of death (57.3% of the
cases). The predictors of mortality were: age (OR = 1.06, CI: 1.03-1.09),
cardiovascular disease (OR = 2.13, CI: 1.19-3.83), neurological disease (OR =
2.96, CI: 1.41-6.15), nephroangiosclerosis (OR = 2.34, CI: 1.10-4.98) and total
lymphocyte count (OR = 0.93, CI: 0.87-0.98). Hospitalization was needed in 44% of
patients. The comorbidity index, serum albumin and age were the predictive
factors of hospitalization. CONCLUSIONS: Protein-calorie malnutrition is frequent
in haemodialysis patients. Fat depletion predominated in both sexes. Duration of
dialysis and protein catabolic rate related to ideal body weight was the only
predictor which could be influenced by a nutritional intervention. Morbidity
appeared to be influenced by the comorbidity index and age was the strongest
predictor of mortality. The only nutritional measurements predictive of morbidity
and mortality were serum albumin and total lymphocyte count respectively.
Therefore, the influence of malnutrition in morbidity and mortality can not be
definitively stated.
PMID- 9394320
TI - Total, free, and protein-bound sulphur amino acids in uraemic patients.
AB - Fasting plasma concentrations of sulphur amino acids (sAA) were measured in nine
non-dialysed (ND) chronic uraemic patients on conservative treatment, 10 patients
on continuous ambulatory peritoneal dialysis (CAPD), nine patients on
haemodialysis (HD) treatment, and 10 healthy subjects (HS). Methionine and
taurine concentrations were significantly decreased in the CAPD and HD patients
and tended to be low in the ND patients. Cysteine sulphinic acid (CSA) levels
were significantly higher in all patient groups. Total (t), free (f), and protein
bound (pb) homocysteine (Hcy) and cysteine (Cys) were significantly increased in
all patient groups. Serine, a substrate for cystathionine synthesis from Hcy,
showed significantly lower concentrations in all patient groups. The percentages
of pbHcy were significantly higher in the CAPD and HD patients than in the ND
patients (P < 0.0001, P = 0.002 respectively) or in the HS (P < 0.0001, P = 0.008
respectively), whereas the percentages of pbCys in CAPD and HD patients were
significantly higher than in ND patients (P = 0.0006, P = 0.009 respectively) and
tended to be high without reaching statistical significance compared to the HS. A
single HD treatment decreased tHcy by 26%, fHcy by 39%, and pbHcy by 22%, as well
as tCys by 40%, fCys by 54%, and pbCys by 27%. The tHcy concentration, although
decreased by HD treatment, remained higher than in HS, whereas tCys was
normalized by the dialysis session. In addition, HD treatment significantly
decreased the plasma concentrations of methionine, CSA, taurine, and serine. We
conclude that, except for methionine and taurine, the plasma sAA in their
different forms are markedly increased in dialysed and non-dialysed uraemic
patients. The percentages of pbHcy and pbCys were significantly higher in
dialysed than in ND uraemic patients. HD treatment can normalize the tCys
concentration, and decrease the tHcy concentration but not normalize it. The
observed hyperhomocysteineaemia and low taurine levels may contribute to the high
incidence of cardiovascular disease in uraemic patients.
PMID- 9394321
TI - Free amino-acid levels simultaneously collected in plasma, muscle, and
erythrocytes of uraemic patients.
AB - BACKGROUND: Disturbances in amino acid (AA) metabolism in uraemia have mainly
been reported to occur in plasma and muscle. The erythrocytes (RBC) constitute a
large proportion of the free AA in blood and may play an important role in the
interogan transport of AA. This report presents the first data on AA levels
obtained simultaneously from three different compartments in uraemic patients.
METHODS: Muscle biopsy and blood samples were obtained from 38 haemodialysis
(HD), 22 continuous peritoneal dialysis (CPD) and 10 end-stage renal failure
patients for determination of free amino acids by reversed-phase HPLC. The
results are compared to data obtained from 27 healthy subjects under the same
conditions. RESULTS: For a number of non-essential AA (alanine, glycine,
asparagine, arginine) and for lysine, elevated concentrations were present
simultaneously in RBC and in muscle but not in plasma. On the other hand, low
concentration of some essential AA (leucine, valine, phenylalanine, tyrosine)
were observed in RBC and in plasma, while the concentrations in muscle were
normal. Most of the non-essential AA (NEAA), especially taurine and glutamine,
had much higher muscle/plasma gradients than RBC/plasma gradients, although an
accumulation in RBC of glycine, serine, arginine, asparagine, ornithine,
glutamate and taurine was observed. Most of the essential AA (EAA) showed higher
muscle/plasma gradients, whereas the RBC/ plasma gradients were approximately
1.0. CONCLUSION: Our findings are in agreement with studies that have shown that
RBC and plasma play independent and opposing roles in AA interorgan transport.
The results indicate that there are several AA abnormalities in all three
compartments in uraemic patients. They also suggest that there may be some
specific common changes of selected transport systems for both RBC and muscle in
uraemia. Determination of AA in RBC should be considered when undertaking
metabolic and clinical studies of AA disturbances.
PMID- 9394322
TI - Individualized anticoagulation with dermatan sulphate for haemodialysis in
chronic renal failure.
AB - BACKGROUND: Dermatan sulphate (DS) is a selective thrombin inhibitor with
antithrombotic properties and low bleeding potential. In preliminary studies it
was reported to be effective for preventing clot formation in the haemodialysis
circuit. METHODS: Ten patients on maintenance haemodialysis for chronic renal
failure underwent three consecutive investigation phases. In phase 1 (individual
dose titration), repeated dialyses were performed with increasing doses of DS
until successful dialysis was obtained in two sessions at the same dose. In phase
2, individualized DS doses were validated by a randomized crossover comparison
with the individual heparin dose of each patient. In phase 3, each patient
underwent 24 consecutive dialyses with DS over 8 weeks. Successful dialysis was
defined as completion of the procedure without visible clot formation in the
bubble traps and lines or a greater than 20% decrease in dialyser capacity.
Dialysis efficiency (decrease in serum urea and creatinine, Kt/V), APTT
prolongation, bleeding time, and DS plasma concentrations were also assessed.
RESULTS: Phase 1: successful dialysis was achieved in nine patients with 4 mg/kg
DS as a predialysis intravenous bolus followed by continuous infusion of 0.65
mg/kg/h. One patient required 5 mg/kg plus 1.3 mg/kg/h. Phase 2: no statistically
significant differences were found between DS and heparin in any of the
investigated variables. Residual dialyser capacity and dialysis efficiency
indexes indicated equivalent efficacy. Phase 3: residual dialyser capacity and
dialysis efficiency did not change with time. There was no accumulation of DS in
plasma. No bleeding or thrombocytopenia were observed. CONCLUSIONS: The dose of
DS can be individually titrated to suppress clot formation during haemodialysis
as efficiently as with individualized heparin. Such an individualized DS regimen
maintains its anticoagulant efficacy and is safe in prolonged use.
PMID- 9394323
TI - Plasma hypercoagulability in haemodialysis patients: impact of dialysis and
anticoagulation.
AB - BACKGROUND: Thrombotic complications are common in patients with endstage renal
disease and contribute substantially to the morbidity and mortality in this
population. The aim of the present study was to: i) determine the prevalence and
the extent of hypercoagulability in patients undergoing dialysis treatment by
measuring parameters that directly reflect thrombin concentrations; ii) assess
changes in coagulation status during haemodialysis (HD); iii) quantify the
relative impact of heparin, dialysis and their combined effects on coagulation
status and iv) detect factors that modify coagulation haemostasis in dialysis
patients. METHODS: A total of 39 patients (HD: n = 29, CAPD: n = 10) was analysed
for procoagulatory and fibrinolytic activity determined by measurements of
partial thromboplastin time, prothrombin fragments F1 + 2, thrombin-antithrombin
complexes and D-dimer concentrations. HD patients were investigated prior to and
during dialysis. A subgroup of patients was infused heparin alone without
dialysis or was dialysed without heparin administration. Furthermore, subgroup
and correlation analyses were performed for the type of dialysis (HD vs CAPD),
dialyzer and shunt, Kt/V, underlying disease and treatment with recombinant
erythropoietin (rhEPO). RESULTS: Baseline levels of all parameters-procoagulatory
and fibrinolytic--were substantially elevated in all patients, but to a higher
degree among those on CAPD. Moreover, haemodialysis treatment increased
procoagulatory markers even further, suggesting stimulated coagulation and/or
insufficient anticoagulation during dialysis. However, after 3 h of dialysis
thrombin concentrations, determined by quantification of prothrombin fragments,
were inversely correlated with Kt/V. Selective heparin infusion diminished
procoagulatory activity only slightly and incompletely, whereas HD without
heparin resulted in excess thrombin accumulation. Finally, subgroup analyses
revealed more pronounced thrombin formation among patients treated with
polysulfon dialyzers, whereas erythropoietin dosage was positively related with
lower procoagulatory activity. CONCLUSION: A majority of patients on dialysis are
in a hypercoagulable state, which is further aggravated by the haemodialysis
procedure itself and may not be sufficiently controlled with current
anticoagulation regimens. Intensified heparin treatment and the use of rhEPO are
likely to improve coagulation haemostasis, whereas the type of dialyzer should be
considered as a relevant procoagulatory factor.
PMID- 9394324
TI - Dissociation between beta-2 microglobulin and IL-1 production in hemodialyzed
patients.
AB - BACKGROUND: beta-2 microglobulin is predominant in amyloid deposits in patients
undergoing long term hemodialysis. Amyloid accumulation has been ascribed to
dialysis membranes, endotoxin contamination of the dialysate, uremia and chronic
systemic inflammation associated with enhanced monocytic cytokine production in
hemodialyzed patients. Interleukin-1 has been proposed to play a critical role in
the induction of beta-2 microglobulin synthesis and release. METHODS: We examined
if monocytes contribute to beta-2 microglobulin production upon stimulation with
inflammatory mediators that are generated during hemodialysis and investigated
the production of beta-2 microglobulin by cells from patients, with and without
clinical signs of amyloidosis, at the time when patients' monocytes contained
maximal intracellular accumulation of IL-1. RESULTS: We demonstrated that only
monocytes are able to release increased levels of beta-2 microglobulin upon
stimulation by IL-1, TNF alpha, C5a and LPS. Increased levels of beta-2
microglobulin were associated with increased levels of beta-2 microglobulin mRNA.
Before dialysis session, 20-60% of circulating CD14+ monocytes from patients
contained IL-1. At the time when maximal IL-1 production was detected, we showed
by RT-PCR increased transcription of IL-1 gene in patients' monocytes. We
observed that monocytes from patients with amyloidosis contained higher amounts
of IL-1 as compared to monocytes from patients without clinical signs of
amyloidosis, but could not secrete increased amounts of beta-2 microglobulin upon
LPS-stimulation. CONCLUSIONS: Our data indicated that chronic inflammation, as
demonstrated by increased intracellular IL-1 expression, is not associated with
increased production of beta-2 microglobulin by monocytes from patients on
hemodialysis.
PMID- 9394325
TI - The required dose of erythropoietin during renal anaemia treatment is related to
the degree of impairment in erythrocyte deformability.
AB - BACKGROUND: Renal anaemia is rapidly corrected by recombinant human
erythropoietin (rHuEpo) therapy, but the dose required varies greatly. Since
impaired erythrocyte deformability may be one factor contributing to the
development of renal anaemia, the interrelationship between that variable and the
rHuEpo requirement was examined. METHODS: Twenty-five patients treated with
hemodialysis and rHuEpo for at least 6 months were included in the study. The Hb
value had been stable and the rHuEpo dose unchanged the last two months. Using a
rotational viscometer, the fluidity of erythrocytes, separated from plasma and re
suspended in isotonic buffered saline to a standardized haematocrit, was taken as
a measure of erythrocyte deformability. RESULTS: The average weekly dose of s.c.
epoetin alpha was 186 +/- 93 U/kg body weight (range 56-370). The dose was
correlated to the reticulocyte fraction (R = 0.69, P = 0.0001). When the rHuEpo
dose was used as dependent variable and blood haemoglobin concentration, serum
(S) albumin, S ferritin, S aluminium, S PTH, S urea, Kt/V/week, erythrocyte
fluidity, and plasma viscosity were used as independent variables in a stepwise
multiple regression analysis, only erythrocyte fluidity remained significantly
negatively correlated to the rHuEpo dose (R = 0.5, P = 0.01). Despite a tendency
towards higher doses of rHuEpo in patients with a C-reactive protein
concentration exceeding 20 mg/l, the Hb was lower in these patients. CONCLUSIONS:
We conclude that the interindividual differences in bone marrow response to
rHuEpo were small in these patients. Impaired erythrocyte deformability and
inflammation seem to be factors associated with increased rHuEpo requirement.
PMID- 9394326
TI - GBV-C/HGV infection in renal dialysis and transplant patients.
AB - BACKGROUND: Recently a new human virus (GBV-C/HGV) was identified. With the use
of the polymerase chain reaction (PCR) the possibility of a high prevalence of
the GBV-C/HGV infection in haemodialysis patients was demonstrated. The aim of
the present study was to use a combination of the PCR and a new diagnostic test
for antibodies to the viral envelope protein E2 to assess the prevalence of the
GBV-C/HGV infection in German patients with renal failure. METHODS: RT-PCR and
ELISA were used to detect GBV-C/HGV RNA and antiviral antibodies (anti-E2) in the
sera of 31 patients on a maintenance haemodialysis (HD)), 25 patients on a
perioneal dyalisis (CAPD), and 92 renal transplant patients (RT). RESULTS: A
statistical trend was noted for a higher rate of the GBV-C/HGV RNA in the whole
group of patients with renal failure (11.5%) than in the control group of organ
donors (5.5%); The difference between GBV-C/HGV RNA prevalence in RT patients
(15.2%) and in organ donors (5.5%) was found to be significant. Anti-E2, which
are considered as an indicator of a past GBV-C/HGV infection, were detected in
12.9% of HD patients, in 20.0% of CAPD patients, in 10.9% of RT patients, in
11.1% of organ donors, and in 10.9% of blood donors. These differences were not
significant. Time on haemodialysis was significantly longer in GBV-C/HGV infected
patients compared to uninfected patients and all patients with the GBV-C/HGV RNA
have a history of blood transfusions. CONCLUSIONS: Patients with renal failure
treated with dialysis or subjected to renal transplantation are at increased risk
of aquiring the GBV-C/HGV infection. Higher rates of the GBV-C/HGV RNA and a
similar prevalence of anti-E2 in patients with renal failure as compared to
donors suggest that the rate of GBV-C/HGV infection resolution in
immunosuppressed patients with renal failure might be lower than in
immunocompetent patients.
PMID- 9394327
TI - Rejection rates in kidney transplant patients with and without IgA nephropathy.
AB - BACKGROUND: Based on graft survival rates it has been claimed that patients with
IgA nephropathy have a reduced risk of rejection after kidney transplantation. We
wanted to evaluate this hypothesis. METHODS: Certified IgA nephropathy was the
original disease in 70 of 874 consecutive kidney transplant patients (8.0%).
Eighty per cent of the patients were men. Median age was 37 years, range 9-64.
Fifty-three per cent had living donors and 20% of the transplantations were pre
emptive. Non-diabetic patients matched for age, sex, type of donor, and
transplant number served as controls. Median follow-up time was 68 months.
Duration of treatment for rejection during the first year post-transplant and
graft loss due to rejection was recorded. RESULTS: The fraction of patients
treated for rejection during the first year was 53% versus 54% of controls and
the number of days when any antirejection treatment was given was 5.0 +/- 7.5
versus 5.5 +/- 7.4. Actual 3-year graft survival was 81% versus 80% and the
number of grafts lost due to rejection was 9 versus 11. CONCLUSIONS: Rejection
rates were not reduced in patients with IgA nephropathy and survival of grafts
and patients not better than for matched controls.
PMID- 9394328
TI - Colchicine myopathy in renal transplant recipients on cyclosporin.
AB - Few data are available about the muscle status in renal transplant recipients.
Moreover, the list of myotoxic drugs is growing longer and some of them are
likely to be prescribed in renal transplant patients. These conditions may act as
confounding factors in case reports of both cyclosporin and colchicine
myopathies. Moreover no study has evaluated the frequency of myopathy in patients
on both colchicine and cyclosporin. We conducted a retrospective study including
all renal transplant recipients followed in our unit in whom colchicine was
prescribed since January 1994. Clinical and biological data of patients on both
colchicine and cyclosporin were analysed. Secondly case subjects were compared
with matched controls not receiving colchicine but cyclosporin. Ten patients
received colchicine in association with cyclosporin. Five patients (50%)
experienced muscular symptoms and when performed, muscular histology showed
vacuolar myopathy. All five patients improved after colchicine withdrawal. Cases
with and without muscular symptoms did not differ in age, transplant duration,
and serum creatinine level. Mean duration of colchicine therapy was 12.2 +/- 4.4
months in cases with muscular symptoms and 6.8 +/- 4.6 months in cases without
muscular symptoms (P < 0.05). No control complained of either muscular pain nor
weakness (P < 0.0005). Only one patient (3.3%) had elevated serum creatine
phosphokinase concentration (P < 0.0005). We conclude that myopathy is very
frequent in patient on both colchicine and cyclosporin. Muscular symptoms improve
in all patients after colchicine withdrawal.
PMID- 9394329
TI - Parathyroidectomy after renal transplantation: a retrospective analysis of long
term outcome.
AB - BACKGROUND: Advanced hyperparathyroidism refractory to active vitamin D continues
to be a problem and frequently forces the nephrologist to resort to
parathyroidectomy. One particular aspect is persisting advanced
hyperparathyroidism after renal transplantation. Published information on this
point is fragmentary. DESIGN: Retrospective analysis. PATIENTS: Between 1983 and
1995 a total of 456 patients with renal secondary hyperparathyroidism were
subjected to parathyroidectomy (PTX) of whom 103 were transplanted or had at
least a history of renal transplantation. The present analysis concerns 37
patients who had a functional renal graft at the time of PTX and were followed
for up to 13 years. PTX was performed after an average of 36.7 months after renal
transplantation. OUTCOME: Thirteen patients experienced rejection and became
dialysis-dependent. Twenty-four patients had stable function of the renal graft.
Seven patients died during follow-up. Hypoparathyroidism post-PTX developed in
4/37 patients, but could be overcome by replantation of cryoconserved parathyroid
tissue. FREQUENCY ESTIMATE: A total of 2632 renal transplants were performed in
the catchment area. As a minimum estimate 3.91% of patients with a functional
graft required PTX. RECOMMENDATION: Parathyroidectomy should be considered early
in cases with advanced secondary renal hyperparathyroidism, since renal
transplantation does not necessarily guarantee reversibility of parathyroid
overactivity.
PMID- 9394330
TI - The influence of bicarbonate supplementation on plasma levels of branched-chain
amino acids in haemodialysis patients with metabolic acidosis.
AB - BACKGROUND: It has been hypothesized that correction of metabolic acidosis might
improve the nutritional state of acidotic haemodialysis (HD) patients partly
because of a reduced oxidation of branched-chain amino acids (BCAA). AIM: We
investigated whether bicarbonate (Bic) supplementation in acidotic HD patients
results in increased plasma levels of BCAA. METHODS: In a longitudinal study (run
in period, 2 months; study period, 6 months), the effect of Bic supplementation
on plasma levels of BCAA was studied in 12 acidotic HD patients (7 men, 5 women,
mean age 54 +/- 18 years) with a predialysis bicarbonate (Bic) concentration
smaller or equal to 22 mmol/l. Bic was supplemented by increasing Bic
concentration of the dialysate and by oral Bic supplementation. RESULTS:
Predialysis Bic increased significantly during the study period (18.7 +/- 2.7 vs.
23.1 +/- 11.5 mmol/l). There was no change in nutritional parameters. However,
plasma levels of the BCAA valine, leucine, and isoleucine increased
significantly. CONCLUSIONS: In haemodialysis patients with metabolic acidosis,
Bic supplementation over a 6-months period resulted in an increase in plasma
levels of BCAA. Further study is needed to elucidate the mechanisms behind, and
the clinical importance of the observed changes in plasma BCAA levels.
PMID- 9394331
TI - Cyclosporin A therapy in frequently relapsing nephrotic syndrome and IgA
nephropathy.
PMID- 9394332
TI - Membranoproliferative glomerulonephritis (MPGN) and pulmonary carcinoid tumour.
PMID- 9394333
TI - Treatment of idiopathic retroperitoneal fibrosis with tamoxifen.
PMID- 9394334
TI - Stretching of renal artery in a functionally solitary kidney: an unusual case of
ischaemic nephropathy.
PMID- 9394335
TI - Acute interstitial nephritis secondary to omeprazole.
PMID- 9394336
TI - Functional renal recovery after spontaneous renal embolization in a sole kidney.
PMID- 9394337
TI - Renal amyloidosis and renal failure--a novel complication of the SAPHO syndrome.
PMID- 9394338
TI - Heparin-induced systemic inflammatory response syndrome with progressive skin
necrosis in haemodialysis.
PMID- 9394339
TI - Relapsing bacteraemia due to Micrococcus luteus in a haemodialysis patient with a
Perm-Cath catheter.
PMID- 9394340
TI - Recurrence of lecithin cholesterol acyltransferase deficiency after kidney
transplantation.
PMID- 9394341
TI - Tacrolimus treatment for steroid- and cyclosporin-resistant minimal-change
nephrotic syndrome.
PMID- 9394342
TI - Immune thrombocytopenic purpura presenting in an immunosuppressed patient after
renal transplantation.
PMID- 9394343
TI - Retropharyngeal abscess in a renal transplant recipient.
PMID- 9394344
TI - Recurrence of lipoprotein glomerulopathy after renal transplantation.
PMID- 9394345
TI - A transplanted child with severe hypercalcaemic hyperparathyroidism despite only
modest bone lesions.
PMID- 9394346
TI - Bacillus cereus peritonitis in a patient being treated with continuous ambulatory
peritoneal dialysis.
PMID- 9394347
TI - Doppler ultrasound in renal transplantation.
PMID- 9394348
TI - A calcareous calamity.
PMID- 9394349
TI - The alcoholic patient with an acute nephrotic syndrome and resistance to
diuretics.
PMID- 9394350
TI - Ultrasonographic evaluation of parathyroid hyperplasia.
PMID- 9394351
TI - Sulphonamides in vasculitides: which mechanism?
PMID- 9394352
TI - Calcifying panniculitis or 'simple' inflammation? Biopsy is better than a bone
scan.
PMID- 9394353
TI - Interleukin-6 production by endothelial cells: effect of corticosteroids.
PMID- 9394354
TI - ANCA in Behcet's disease.
PMID- 9394355
TI - Anti-beta 2-glycoprotein I and anti-prothrombin antibodies in haemodialysis
patients.
PMID- 9394356
TI - Hepatitis G virus infection in haemodialysis patients.
PMID- 9394357
TI - Mycophenolate mofetil toxicity in an anorexic kidney transplant patient treated
with sulphinpirazone.
PMID- 9394358
TI - [Derivative advantages of autologous blood transfusion].
PMID- 9394359
TI - [Bone morphogenetic protein receptors].
PMID- 9394360
TI - [Free radicals and joint destruction].
PMID- 9394362
TI - A case of parathyroid carcinoma visualized on Tc-99m-sestamibi scintigraphy.
AB - Recent studies indicate that Tc-99m-Sestamibi (MIBI, DuPont Pharma) is a useful
tracer for detecting parathyroid adenomas. We present a patient with focal Tc-99m
MIBI uptake in parathyroid carcinoma which has only been described once before
(1). Tc-99m-MIBI scintigraphy may be considered for diagnosing pathological
parathyroid tissue. But presently the histopathological examination only allows
the differentiation between adenoma and carcinoma.
PMID- 9394361
TI - Evaluation of pentavalent Tc-99m DMSA scintigraphy in small cell and nonsmall
cell lung cancers.
AB - AIM: The purpose of this study was to evaluate the clinical usefulness of Tc-99m
(V) DMSA in patients suspected of lung cancer and determine whether this agent
may have value in differentiation between small cell (SCLC) and non-small cell
(NSCLC) lung carcinoma. METHODS: Thirty-six patients with clinical and
radiological suspicion of primary lung carcinoma were injected 450-600 MBq of Tc
99m (V) DMSA intravenously. Whole body and planar anterior, posterior thorax
images were obtained 4-5 h after injection of the radioactive complex. RESULTS:
Histopathological results confirmed 23 NSCLC, 10 SCLC and 1 metastatic lung
carcinoma and 2 lung abscess. Nineteen of the 23 (82%) NSCLC and all of the 10
(100%) SCLC cases showed Tc-99m (V) DMSA uptake. Single metastatic lung cancer
also accumulated radiotracer. Lung abscess did not show uptake. Lesion/Nonlesion
(L/N) ratio of SCLC (1.59 +/- 0.32) and NSCLC (1.43 +/- 0.19) tumour types did
not show statistical difference (p > 0.05). Tc-99m (V) DMSA whole body imaging
also showed bone metastases. CONCLUSION: Tc-99m (V) DMSA is a noninvasive and
cheap imaging method to detect malignant lung cancers and their bone metastases
but, differentiation of SCLC and NSCLC is not possible.
PMID- 9394363
TI - Clinical experience with gemcitabine in pancreatic carcinoma.
AB - The treatment of advanced pancreatic carcinoma has been viewed with pessimism.
Because of the lack of activity of commonly used agents, there is no consensus
regarding a standard chemotherapy regimen. Assessment of response is neither
uniform nor reproducible. Debilitating tumor-related symptoms, including pain,
anorexia, weight loss, and impaired performance status, are common. Many studies
have failed to evaluate the palliative benefit of treatments, although many
patients consider such benefit to be of the utmost importance. Tools have been
developed to uniformly assess tumor-related symptoms, and the concept of clinical
benefit response has been developed as an end point to quantify symptomatic
improvement utilizing these tools. Clinical benefit response incorporates
palliative measures, such as pain control, analgesic consumption, performance
status, and weight gain. In early phase I and II trials, gemcitabine (Gemzar) has
shown activity in patients with chemotherapynaive advanced pancreatic carcinoma.
In addition to producing some responses and symptomatic benefit, gemcitabine has
a favorable toxicity profile. Two recent trials using clinical benefit response
as the primary end point have demonstrated that gemcitabine significantly
improves disease-related symptoms in approximately one-quarter of patients. These
trials also showed improved survival with gemcitabine, as compared with
fluorouracil. Additional studies are required to fully assess the role of
gemcitabine in both adjuvant and advanced disease settings.
PMID- 9394364
TI - Clinical status and optimal use of topotecan.
AB - Topotecan (Hycamtin) is a promising new topoisomerase I-targeting anticancer
agent that first entered clinical trials in 1989 under National Cancer Institute
sponsorship in collaboration with SmithKline Beecham. In 1996, it was approved
for use by the United States Food and Drug Administration (FDA) for previously
treated patients with advanced ovarian cancer. For these patients, topotecan
provides another therapeutic option upon disease progression after initial
platinum-based chemotherapy. Topotecan also has activity in other tumor types,
including small-cell lung cancer, hematologic malignancies and pediatric
neuroblastoma and rhabdomyosarcoma. Topotecan combination regimens with
paclitaxel (Taxol), etoposide (VePesid), cisplatin (Platinol), and cytarabine and
with other treatment modalities, such as radiation therapy, are in development.
Studies evaluating topotecan combinations as initial treatment in such diseases
as ovarian and small-cell lung carcinoma are also underway. It is hoped that
earlier use of topotecan, with its novel mechanism of action, will prolong
survival and increase cure rates in patients with these chemoresponsive tumors.
Whether or not such hopes are realized, these important studies will help define
the role of topotecan in cancer chemotherapy.
PMID- 9394365
TI - Clinical status and optimal use of the cardioprotectant, dexrazoxane.
PMID- 9394366
TI - Clinical trials referral resource. Clinical trials in lung cancer.
PMID- 9394367
TI - Anastrozole: a new selective nonsteroidal aromatase inhibitor.
AB - Aromatase (estrogen synthetase) is the enzyme complex responsible for the final
step in estrogen synthesis--the conversion of androstenedione and testosterone to
estrone and estradiol, respectively. Inhibitors of this enzyme have been shown to
be clinically effective in the treatment of advanced breast cancer in
postmenopausal women, in whom the major source of estrogen production derives
from aromatization of adrenal androgens in peripheral tissues, such as muscle,
liver, and fat. The most widely used aromatase inhibitor has been
aminoglutethimide; however, it is nonselective and also inhibits
adrenocorticosteroid synthesis, necessitating hydrocortisone supplementation.
Aminoglutethimide is also associated with frequent and troublesome side effects.
Formestane, the first selective aromatase inhibitor to be developed, has an
improved safety profile and selectivity, but its use has been limited somewhat by
its inconvenient administration via intramuscular injection. In this article, the
preclinical and clinical data published to date on the new third-generation
aromatase inhibitor anastrozole (Arimidex) are presented in the context of
current endocrine therapies. Future applications of aromatase inhibitors, both as
monotherapy and in combination with other endocrine therapies, are discussed. The
use of aromatase inhibitors in advanced disease, the adjuvant setting, and as
possible chemopreventive agents are examined.
PMID- 9394368
TI - Progress and prospects in vaccine therapy for gynecologic cancers.
AB - Therapeutic and prophylactic vaccines that harness the potential of the immune
system against a number of gynecologic cancers are now being developed. The
therapeutic vaccines coerce the cellular components of the immune system to
attack malignant tissue. The prophylactic vaccines induce the production of
antibodies capable of neutralizing viral antigens before they infect host cells.
However, malignant tumors are usually a heterogeneous mixture of different
malignant cells, and it is likely that variant tumor clones within a tumor may
not express the target antigen or may possess defects in their antigen-presenting
mechanism. Ultimately, therapeutic vaccines may be better suited for the
treatment of preinvasive disease or for use as an adjuvant following primary
therapy. The prospects for developing efficacious vaccines to treat or prevent
cervical, ovarian, uterine, and other gynecologic cancers are promising, however.
This article describes the methodology of and rationale for these vaccines.
PMID- 9394369
TI - Technology versus biology--where are we headed?
PMID- 9394370
TI - Laser biopsy artifact.
PMID- 9394371
TI - Transalveolar screw.
PMID- 9394372
TI - Pigmented villonodular synovitis of the temporomandibular joint.
PMID- 9394373
TI - Ulcerated tumor mass involving the right base of the tongue.
PMID- 9394374
TI - Anatomic guidelines for the placement of external references for maxillary
repositioning.
AB - OBJECTIVE: External reference points, particularly Kirschner pins (K-wire),
placed in the region of the nasion have been shown to improve the accuracy of
maxillary vertical repositioning. Although no complications associated with this
technique have been reported, there is a potential for injury to the anterior
cranial fossa or frontal sinus. The purpose of this study was to measure the
shortest distance from the nasion to the anterior cranial fossa and from the
nasion to the frontal sinus. These measurements were used to establish anatomic
guidelines governing safe placement of external reference point pins. STUDY
DESIGN: Twenty-seven cadaver heads were sectioned in the midsagittal plane for
gross study. Using a Boley gauge, two specific measures were obtained: (1)
distance from deepest depression of nasion to the most anterior and inferior
projection of the anterior cranial fossa, and (2) distance from nasion to the
most inferior aspect of the frontal sinus. All measurements were made in the
midsagittal plane. RESULTS: The average distance from nasion to anterior cranial
fossa was 16.9 mm (range 13.0 to 20.0 mm) and the smallest distance, 13.0 mm, was
seen in two specimens. The average distance from nasion to the frontal sinus was
6.2 mm (range 2.0 to 10.0 mm) and the smallest distance, 2.0 mm, was seen in
three specimens. CONCLUSION: Based on our findings, we recommend the following:
(1) place pin to a depth of no more than 8 mm into bone, (2) place pin 5 to 10 mm
inferior to soft tissue nasion, and (3) place pin in an anterosuperior to
posteroinferior direction (i.e., roughly perpendicular to the nasal dorsum). When
these anatomic guidelines are followed, one would expect minimal morbidity
associated with the placement of ERP pins.
PMID- 9394377
TI - Intraoral morbidity following free buccal mucosal graft harvesting for
urethroplasty.
AB - Buccal mucosa is the preferred donor tissue for urethroplasty in many cases. This
study documents donor site morbidity associated with this technique in 12
patients. Nine patients had a transiently decreased parotid salivary flow for 1
week, and one patient reported transient nerve involvement (long buccal nerve).
Intraincisal opening returned to presurgical values within 6 weeks and in some
cases exceeded presurgical values. This appears to be a low morbidity technique
with high patient acceptance.
PMID- 9394376
TI - Predictors of postextraction complications in HIV-positive patients.
AB - OBJECTIVE: The purpose of this study was to identify factors associated with an
increased risk for post-tooth-extraction complications in a sample of HIV
positive patients. STUDY DESIGN: A cohort of HIV-positive patients who required
the extraction of one or more teeth was enrolled. The predictor variables were
grouped into the following sets: demographics; medical and social history;
preoperative clinical findings; preoperative laboratory measures (hematologic,
immunologic, and nutritional); and treatment. The outcome variable was defined as
the presence or absence of a complication following tooth extraction. Logistic
regression techniques were used to identify variables associated with an
increased risk for complications following tooth extraction. RESULTS: During the
enrollment period, 76 HIV-positive patients were enrolled into the study cohort.
Seventeen patients (22.4%) had postoperative complications. Based on the
bivariate statistical analyses, variables associated with the presence of
postoperative complications were red blood cell count, CD8 count, total number of
positive sites tested using cell-mediated immunity skin tests, and extraction
technique (p < or = 0.05). Using a stepwise logistic regression technique, the
variable identified as being predictive of postoperative complications was the
CD8 count (p = 0.02). The post-tooth-extraction complication rate of the HIV
positive patients in this study sample was greater than the rate reported in most
other studies (22% vs. 3%-5%). The complications, however, were minor and easily
treated. The variable consistently identified with an increased risk for
complications was the CD8 count: the lower the CD8 count, the higher the risk for
complications. The CD8 count, however, had poor predictive value. CONCLUSION: In
acute clinical situations--for example, in cases of patients with significant
dental pain--the results suggest that delaying treatment to obtain laboratory
studies may be of little clinical value. It may be appropriate to proceed with
suitable, definitive procedure(s) to alleviate symptoms.
PMID- 9394375
TI - Radiologic variables of clinical significance in the extraction of impacted
mandibular third molars.
AB - OBJECTIVE: To determine which radiologic variables have a clinical significance
in the extraction of impacted mandibular third molars. STUDY DESIGN: A
prospective study was carried out on 100 consecutive extractions of unilateral
impacted mandibular third molars (60 women and 40 men, mean age: 26.27 +/- 10.63
years). Fourteen radiologic variables were ordinally evaluated, establishing
their relation to the surgical intervention time. The Kruskal-Wallis test, a
multivariant analysis of the principal components, the Pearson correlation
coefficient, and logistical regression tests were carried out. RESULTS: Seven
variables (occlusal plane, relation to the second molar, depth, follicle,
periodontal ligament width, ramus of the mandible, and angulation) demonstrated a
statistically significant relation to the surgical intervention time (Kruskal
Wallis tests, p < 0.007). Two associated variables, depth and periodontal
ligament width, showed the most powerful and simple relation to the surgical
intervention time (r2 multiple = 0.307, p < 0.001). CONCLUSION: The model we
propose is a tool that may help the general practitioner to establish competence
in an extraction of the impacted mandibular third molar by measuring the
association of two radiologic variables: depth and periodontal ligament width.
PMID- 9394378
TI - Preserving the posterior superior synovial recess during allograft TMJ diskal
condylar transplantation in the adult goat.
AB - OBJECTIVE: The purpose of the study was to test the hypothesis that sparing the
posterior superior synovial recess during the resection of temporomandibular
joint condyle and disk would maintain a critical mass of synovium necessary to
predictably achieve a successful allograft joint reconstruction. STUDY DESIGN: A
group of 15 adult goats underwent unilateral resection of their temporomandibular
condyle and meniscus. The fossa and posterior superior synovial recess were left
intact. They were immediately reconstructed with cryogenically preserved
allograft mandibular condyles and temporomandibular joint disk harvested from 15
adult donor goats. The animals were evaluated clinically and radiographically at
6 and 12 months and histologically at 12 months. RESULTS: Of the 15 animals, 13
met all the criteria to be declared a success and retained the posterior superior
synovial recess. CONCLUSION: Immediate joint reconstruction using cryogenically
preserved mandibular condyles and temporomandibular joint disk can have a high
rate of success if the native posterior superior synovial recess remains intact.
PMID- 9394379
TI - Kindler syndrome: a rare cause of desquamative lesions of the gingiva.
AB - Kindler syndrome is a rare syndrome with cutaneous and intraoral manifestations.
It has been suggested that there is an overlap between this syndrome and another
called Weary syndrome. Only 68 cases of Weary and Kindler syndromes have been
reported, with fewer solely attributed to Kindler syndrome. The salient cutaneous
features are neonatal bullae, poikiloderma, photosensitivity, and acral atrophy.
This article presents the clinical intraoral findings of two siblings of
consanguineous descent diagnosed as having Kindler syndrome. Both had an
erythematous and erosive appearance of the gingiva; one sibling had poor oral
hygiene and a rapidly progressive form of periodontal disease; the other, whose
oral hygiene was acceptable, had no detectable bone loss.
PMID- 9394380
TI - Melanocanthoma: a rare cause of oral hyperpigmentation.
AB - The oral features of a black woman with melanocanthoma of the oral mucosa are
detailed, and the current literature of melanocanthoma of the oral mucosa is
briefly reviewed.
PMID- 9394381
TI - Spontaneous exfoliation of teeth following severe elemental mercury poisoning:
case report and histological investigation for mechanism.
AB - BACKGROUND: Although the spontaneous exfoliation of teeth and breakdown of oral
tissues from severe mercury intoxication have been noted for over a century,
there are no published reports investigating the mechanisms of these phenomena.
Severe mercury poisoning is rare in modern times, but it does occur. We present a
case report and a histopathologic investigation into the mechanism of the
associated tooth loss. METHODS: An exfoliated tooth and periodontal and gingival
tissues were obtained from a 15-month-old patient who had been severely
intoxicated with elemental mercury over a period of months and hospitalized for
severe neurologic and renal effects. The tissues were examined both by routine
hematoxylin and eosin stain and by autometallography specific for mercury. For
comparison, control tissue from an age-matched subject was examined with the
autometallography technique. RESULTS: Under light microscopy, the gingival tissue
showed evidence of moderate to severe acute and chronic inflammation. The tooth
pulp tissue showed evidence of moderate vascular dilatation and congestion, and
it was infiltrated by many neutrophils. The autometallographic sections showed
intense accumulations of mercury in the soft tissues of the mercury-exposed
subject, but not in the tissues of the control subject. The deposits were
primarily found in fibroblasts, which are essential to maintaining the integrity
of the oral tissues. CONCLUSIONS: Histopathologic and autometallographic
examination of the affected tissue indicates that the primary mechanism of the
spontaneous sloughing of tissue and loss of teeth may be the cytotoxic effects of
the accumulation of mercury in fibroblasts. Studies of additional cases would be
valuable to confirm this hypothesis.
PMID- 9394382
TI - An open clinical trial of a new mouth-PUVA variant in the treatment of oral
lichenoid lesions.
AB - OBJECTIVE: To investigate the feasibility of topical psoralen PUVA (sensitization
in photosensitizing psoralen drug + UVA radiation) treatment of oral lichenoid
lesions (OLL). STUDY DESIGN: A total of 16 patients with OLL were treated using a
0.01% trioxsalen ointment and UVA doses in the 0.09 to 1.80 J/cm2 range. The
average number of sessions was 8.7 and a mean cumulative irradiation dose was
4.25 J/cm2. RESULTS: A marked-to-complete healing occurred in 3 to 16 (19%)
patients immediately after therapy, in 4 of 14 (29%) after 3 months, and in 5 of
14 (38%) after 14 months, respectively. Of the 16 subjects with OLL, five were
diagnosed as oral lichen planus (OLP) and 11 were classified as oral lichenoid
reaction (OLR). Post-PUVA amelioration rate in patients with genuine OLP (4 of 5,
80%) was superior to that in patients with OLR (1 of 9, 11%). CONCLUSION: Topical
trioxsalen photosensitization can be used in mouth-PUVA treatment, and lichen
planus is a main indication for this therapy.
PMID- 9394383
TI - Orofacial pain with vascular-type features.
AB - OBJECTIVE: To examine whether a classifiable primary vascular-type craniofacial
pain subgroup exists that predominantly affects intraoral structures. STUDY
DESIGN: Fifty-five patients were chosen prospectively according to the following
inclusion criteria; periodic craniofacial pain that was unilateral, pulsatile,
severe, and that may wake the patient from sleep. Accompanying phenomena could
include local autonomic and/or systemic signs. Twenty-six cases could be further
classified into one of the categories of vascular craniofacial pain. The
remaining 29, all with predominantly intraoral pain, were not readily
classifiable. RESULTS: Of the 29 patients 70% were women, with an average onset
age of 42.6 years. All reported severe, episodic pain that was usually unilateral
and lasted minutes to hours. In all, 55% of patients had autonomic or systemic
signs, 48% had pulsatile pain, and 35.4% of patients were awakened by the pain.
CONCLUSION: Although clinical similarities were observed within these patients,
further studies are needed to confirm vascular orofacial pain as a clear
diagnostic category.
PMID- 9394384
TI - Evaluation of a new device for sterilizing dental high-speed handpieces.
AB - Dental high-speed turbines and handpieces can take up and expel microorganisms
during operation and thus need regular sterilization. This study established a
method for validating devices used to sterilize high-speed turbines and
handpieces. The air and water channels and turbine chambers were contaminated
with suspensions of Streptococcus salivarius or endospores of Bacillus
stearothermophilus. The effect of flushing and/or autoclaving performed by a new
device combining both procedures was evaluated by counting the number of viable
bacteria recovered from these devices. Further, the effect on clinically used
handpieces was evaluated. In an initial experiment, the device partially reduced
S. salivarius, and the endospores survived. In a second experiment, a 5 to 6 log
reduction of S. salivarius in air and water channels was obtained. No growth was
observed in clinically used high-speed handpieces, and both S. salivarius and
endospores were eliminated from the turbine chambers. Thus, the method of
validation proved capable of discriminating between different levels of bacterial
reduction.
PMID- 9394385
TI - Mucocutaneous features of autoimmune blistering diseases.
AB - This review will describe adult onset mucocutaneous/autoimmune diseases that
involve defects in cell-to-cell, cell-to-matrix, or cell-to-basement membrane
adhesion. Included in this group are pemphigus, cicatricial pemphigoid, linear
IgA bullous dermatosis, epidermolysis bullosa acquisita, and bullous systemic
lupus erythematous. Detection and treatment of blistering disorders that manifest
early in the oral cavity may prevent widespread involvement of skin. During the
past few years, targets of autoantibodies have been clarified and new targets
have been identified, allowing better understanding of the pathophysiology
involved in these diseases. New information about more effective regimens with
fewer side effects has also been obtained, presenting new treatment options.
Clinical manifestations and management of these disorders will be described as
well as histopathologic, ultrastructural, and immunopathologic studies that
distinguish each disorder and facilitate diagnosis and treatment.
PMID- 9394386
TI - Keratoameloblastoma of the maxilla. A case report and review of the literature.
AB - The keratoameloblastoma is a rare histologic variant of the ameloblastoma. Review
of the English language literature revealed five case reports of
keratoameloblastoma. We report the sixth case of this tumor. The tumor developed
in the right posterior maxilla of a 26-year-old African-American man and
demonstrated aggressive clinical behavior, analogous to conventional
ameloblastoma. The initial biopsy specimen showed extensive cyst formation, which
histologically resembled odontogenic keratocyst. However, the lining epithelium
varied in thickness and there was separation and edema between the basal cells
and the rest of the epithelium. The basal cells were strongly adherent to the
underlying stroma unlike the basal layer of the odontogenic keratocyst, where
cleavage often occurs in this area. Additionally, although the basal cells were
palisaded and demonstrated nuclear polarization in areas, they were cuboidal
rather than columnar. The excision specimen revealed more of a solid ameloblastic
component in addition to the cystic component seen on the initial biopsy.
Nevertheless, it is possible that the ameloblastoma had developed in an
odontogenic keratocyst. Alternatively, it can be postulated that the
keratoameloblastoma consists of both cystic and solid components, the former
being analogous to the cysts of the conventional ameloblastoma.
PMID- 9394387
TI - Distinguishing features of focal cemento-osseous dysplasia and cemento-ossifying
fibromas. II. A clinical and radiologic spectrum of 316 cases.
AB - The distinguishing histopathologic features of focal cemento-osseous dysplasia
(FCOD) (including lesions occurring in both anterior and posterior jaws) and
cemento-ossifying fibroma (COF) (ossifying fibroma and cementifying fibroma) were
demonstrated in our earlier work. The aim of the current study was to further
refine their clinical and radiographic features. We have assessed 18 clinical and
radiographic parameters by univariate comparisons (chi-squared and Student t
tests), and a multivariate assessment (logistic regression) in 241 cases of FCOD
and 75 of COF. These cases were diagnosed from a combination of clinical,
radiographic, and histopathologic information. FCOD was seen predominantly in
black women, with a peak incidence in the fourth and fifth decades, whereas COF
showed no female predilection except in the fourth decade (p < 0.005). COF
occurred in patients an average of 10 years younger than patients with FCOD (p <
0.0001). Most patients with FCOD were asymptomatic (62%); the average lesion size
was 1.8 cm. More than half of patients with COF displayed jaw expansion and a
considerably larger size lesion (mean 3.8 cm, p < 0.001). The mandible was the
most frequent site for both FCOD (86%) and COF (70%). Radiographically, a well
defined border was observed in 53% of cases of FCOD and 85% of cases of COF (p <
0.01). Cases of FCOD mostly demonstrated an irregularly mixed radio-opacity
(69%), whereas 53% of COFs presented as a radiolucency (p < 0.005). In FCOD,
there was a close association with tooth apices (70.6%, p < 0.0001) or with
previous extraction sites (21%, p < 0.05); however, the majority of COF cases
(86%) showed no relationship with either. Combining the radiographic feature of a
periapical location with the pathology of multiple curetted fragments and "ginger
root" bony trabeculae, allowed 90% sensitivity and 89% specificity in a logistic
regression model to predict the lesion to be an FCOD. These findings provide
guidelines not only to distinguish these two entities clinically, but also aid in
reaching an accurate diagnosis histopathologically.
PMID- 9394388
TI - A review of key research design and statistical analysis issues.
AB - This article highlights some basic principles of the design and use of
statistical tests, using a minimum of mathematics or statistical jargon. It is
not the intent to summarize all the possible details involved with performing
these tests, but instead to offer insight into evaluating the statistical methods
found in published articles. Historically, the number of scientific articles
published in which inappropriate statistical analyses were performed is alarming.
Only when the reader understands the problem and demands change will this
situation improve. The consequence of inaction is to be mired with an array of
poorly designed articles that, at the very least, do not advance the field of
study and, at worse, may influence practitioners not well versed in statistics to
expose patients to useless, unnecessary, or even harmful procedures.
PMID- 9394389
TI - Adenomatoid odontogenic tumor presenting as periapical disease.
AB - Adenomatoid odontogenic tumor commonly occurs in association with the crowns of
unerupted teeth. An extrafollicular variant, radiographically in relationship to
root apices, has been reported. However, clear association with the root apices
at surgery has not been demonstrated. We report a case of adenomatoid odontogenic
tumor in the anterior mandible in a 21-year-old woman that presented
radiographically at the root apices and at surgery as a radicular cyst. We
believe this represents the first reported case of adenomatoid odontogenic tumor
presenting as periapical disease both clinically and radiographically. The
diagnosis of adenomatoid odontogenic tumor should be considered when the
clinician is presented with a corticated radiolucency in the anterior jaw,
especially in teens and young adults.
PMID- 9394390
TI - Three-dimensional dental imaging by spiral CT. A progress report.
AB - OBJECTIVE: To demonstrate the feasibility of using spiral computed tomographic
data for three-dimensional image acquisition, display, and segmentation of dental
structures and lesions and to demonstrate the feasibility of metal artifact
suppression. STUDY DESIGN: Isolated extracted teeth, a dry mandible, cadaver
mandible, and cadaver head were scanned and reconstructed using spiral computed
tomography data. Algorithms for metal artifact reduction including extended
attenuation range and interpolation of missing projections were applied.
Volumetric rendering was performed to synthesize images comparable to
conventional intraoral dental radiographs. Serial examinations were obtained by
spiral computed tomographic tomography, registered by surface matching, and
interval change determined by three-dimensional subtraction. RESULTS: Metal
artifact reduction was successful in markedly reducing the streaks and star
patterns that usually accompany metallic restorations and intraoral appliances.
Voxel sum images were comparable to dental radiographs. Image segmentation could
successfully isolate dental structures, and simulated lesions could be detected
through three-dimensional subtraction. CONCLUSION: The results demonstrate the
feasibility of spiral volumetric computed tomography for quantitative study of
oral hard tissues in the presence of metal restorations.
PMID- 9394391
TI - Radiographic evaluation of possible etiology of diffuse sclerosing osteomyelitis
of the mandible.
AB - To examine the cause and site of origin of diffuse sclerosing osteomyelitis of
the mandible, we compared various radiographic findings for the mandibular
lesions in 20 patients with diffuse sclerosing osteomyelitis with those in 48
patients with osteomyelitis caused by bacterial infection. In osteomyelitis of
infectious origin, a typical radiographic feature was a radiolucent lesion
spreading in the cancellous bone, with cortical bone perforation and lamellated
periosteal reaction. In diffuse sclerosing osteomyelitis, intermingled sclerotic
and osteolytic lesions with solid periosteal reaction or external bone resorption
were a common finding, and in some patients the cortical bone was initially
affected by the fresh or recurrent lesion. Based on these distinct differences,
we suggest that the cause of diffuse sclerosing osteomyelitis is not bacterial
infection and that the site of origin is not in the bone but in the periosteum.
PMID- 9394392
TI - Submandibular gland duct endoscopy. Diagnostic value for salivary duct disorders
in comparison to conventional radiography, sialography, and ultrasonography.
AB - The purpose of this study is to evaluate the usefulness of endoscopy as a
procedure for the diagnosis of submandibular gland duct disorders. Endoscopy of
the submandibular glands was performed on 12 patients with symptoms of
obstructive sialoadenitis to identify the cause of obstruction. The endoscopic
findings were then compared to those of diagnostic procedures such as
conventional radiography, sialography, and ultrasonography. Six normal subjects
also underwent endoscopy to better understand the normal findings of the duct
system. Endoscopy demonstrated salivary gland calculus in 5 of 12 patients, which
was revealed as filling defects on sialograms and as strongly echogenic
structures on ultrasonograms in 4 of the patients. Endoscopy revealed secretion
plugs, secretion plaques, and/or stenosis, which could not be seen by any other
diagnostic procedures in 5 patients, as the cause of recurrent swelling in all 7
patients not demonstrating sialolith. Abnormal findings of the duct wall such as
vasodilatation, fibrosis, edema, or erythema were seen in four patients, three of
whom exhibited dilatation of the duct system on sialograms. In four patients, a
decreasing internal echo level of the gland was seen on ultrasonograms. Our
initial results for submandibular gland duct endoscopy thus appear to be
promising.
PMID- 9394393
TI - In vitro magnetic resonance imaging of rodent teeth.
AB - OBJECTIVE: The anatomic structure of rat teeth was studied and observed using
magnetic resonance imaging with high spatial resolution. STUDY DESIGN: The right
part of the low mandible of two rats of 3 and 12 weeks old were analyzed. Images
with different orientations were performed in a 2 Tesla magnetic field using the
spin-echo imaging technique. RESULTS: Highly spatially resolved images revealed
details of teeth, and anatomic differences between a young and an adult rat were
demonstrated. CONCLUSION: Magnetic resonance imaging is well suited to image the
buccal area and may be a useful tool for the diagnosis of dental diseases.
PMID- 9394395
TI - A new ozone-based method for virus inactivation: preliminary study.
AB - The nebulization technique reported here could be used to inactivate viruses with
ozone in large volumes of body fluids, such as plasma, partial blood and perhaps
whole blood in a short time. Coliphage MS2 was used as a model because it is
safe, easy to handle and more resistant to chemical disinfections than viruses
such as HIV. The theoretical curves and experimental points, describing ozone
inactivation of MS2, form a semi-sigmoid of congruent data. There was a > 7log10
reduction in MS2 viability and the possibilities of minimizing the ozone
concentration required to kill viruses are indicated. The analysis was expanded
to account for the interaction of ozone with a virus suspension in the shape of a
thin film from the experimental findings of Bolton et al. We again find a semi
sigmoid of congruent data for their case, i.e. describing ozone inactivation of
the influenza A virus (WSN strain) and the vesicular stomatitis virus versus
time. For the method of nebulization, the exposure time of droplets with ozone is
a few seconds, whereas for the thin film method the exposure time is measured in
hours.
PMID- 9394394
TI - Diffraction enhanced x-ray imaging.
AB - Diffraction enhanced imaging is a new x-ray radiographic imaging modality using
monochromatic x-rays from a synchrotron which produces images of thick absorbing
objects that are almost completely free of scatter. They show dramatically
improved contrast over standard imaging applied to the same phantom. The contrast
is based not only on attenuation but also the refraction and diffraction
properties of the sample. This imaging method may improve image quality for
medical applications, industrial radiography for non-destructive testing and x
ray computed tomography.
PMID- 9394396
TI - Reconstruction of 6 MV photon spectra from measured transmission including
maximum energy estimation.
AB - Photon spectra from a nominally 6 MV beam under standard clinical conditions and
at higher and lower beam qualities have been derived from narrow-beam
transmission measurements using a previously published three-parameter
reconstruction model. Estimates of the maximum photon energy present in each
spectrum were derived using a reduced number of model parameters. An estimate of
the maximum contribution of background, or room, scatter to transmission
measurements has been made for this study and is shown to be negligible in terms
of the quality index and percentage depth-dose of the derived spectra. Percentage
depth-dose data for standard beam conditions derived from the reconstructed
spectrum were found to agree with direct measurements to within approximately 1%
for depths of up to 25 cm in water. Quality indices expressed in terms of
TPR10(20) for all spectra were found to agree with directly measured values to
within 1%. The experimental procedure and reconstruction model are therefore
shown to produce photon spectra whose derived quality indices and percentage
depth-dose values agree with direct measurement to within expected experimental
uncertainty.
PMID- 9394397
TI - Comparison of graphite-to-water absorbed-dose transfers for 60Co photon beams
using ionometry and Fricke dosimetry.
AB - To derive the absorbed dose to water from a standard of absorbed dose to
graphite, the metrology laboratories which apply such a method usually make use
of cavity ionization chambers as transfer instruments. In addition, the BNM-LPRI
has tested, as such instruments, two types of Fricke dosimeter in its cobalt-60
beam. The two procedures are compared and their results are found to be in good
agreement (the difference is less than 0.1%). Both procedures are then taken into
account for the calculation of the reference value of absorbed dose to water.
PMID- 9394398
TI - Possibilities for tailoring dose distributions through the manipulation of
electron beam characteristics.
AB - The influence of the properties of an electron beam on resulting dose
distributions, and the potential benefits for dose conformity and optimizing dose
distribution characteristics by electron beam manipulation, are theoretically
examined. A simulated annealing routine is used to weight electron pencil beams
of discrete energies incident at discrete locations and angles on one side of a
phantom. The resulting optimal electron phase space provides a dose distribution
which most closely approaches a desired distribution on the basis of a physical
comparison. For simple desired distributions, intuitive results are obtained such
as the benefits of energy modulation for distributing dose with depth, of angular
and spatial modulation for overcoming disequilibrium effects and their
combination in boosting surface doses. For a complex desired dose distribution,
the optimization routine instigates a complex interplay of energy, angular and
spatial modulation in attempting to achieve dose conformity. A significant result
shows that, for a suitably selected beam energy, angular modulation can
compensate for the variation in the depth of the distal edge of a superficial
target. The effects of varying just energy for normally incident electrons are
compared with those of varying the distribution of incidence angle (for
monoenergetic electrons) and the combination of both, indicating the relative
merits of the manipulation of available degrees of freedom.
PMID- 9394399
TI - Optimization of 3D conformal electron beam therapy in inhomogeneous media by
concomitant fluence and energy modulation.
AB - The possibilities of using simultaneous fluence and energy modulation techniques
in electron beam therapy to shape the dose distribution and almost eliminate the
influences of tissue inhomogeneities have been investigated. By using a
radiobiologically based optimization algorithm the radiobiological properties of
the tissues can be taken into account when trying to find the best possible dose
delivery. First water phantoms with differently shaped surfaces were used to
study the effect of surface irregularities. We also studied water phantoms with
internal inhomogeneities consisting of air or cortical bone. It was possible to
improve substantially the dose distribution by fluence modulation in these cases.
In addition to the fluence modulation the most suitable single electron energy in
each case was also determined. Finally, the simultaneous use of several
preselected electron beam energies was also tested, each with an individually
optimized fluence profile. One to six electron energies were used, resulting in a
slow improvement in complication-free cure with increasing number of beam
energies. To apply these techniques to a more clinically relevant situation a
post-operative breast cancer patient was studied. For simplicity this patient was
treated with only one anterior beam portal to clearly illustrate the effect of
inhomogeneities like bone and lung on the dose distribution. It is shown that by
using fluence modulation the influence of dose inhomogeneities can be
significantly reduced. When two or more electron beam energies with individually
optimized fluence profiles are used the dose conformality to the internal target
volume is further increased, particularly for targets with complex shapes.
PMID- 9394400
TI - Correction factors for parallel-plate chambers used in plastic phantoms in
electron dosimetry.
AB - In electron beam dosimetry using parallel-plate chambers solid phantoms are
sometimes necessary. To obtain the dose to water from the ionization obtained in
the solid phantom, fluence correction factors and perturbation factors have to be
applied. In this study fluence factors in a perturbation free geometry have been
determined experimentally for common phantom materials. Wall perturbation factors
for simulated Attix, NACP, and Roos chambers have also been determined for the
same materials. Comparative Monte Carlo calculations have been performed using
the EGS4 Monte Carlo code. Comparison with data in newly published protocols such
as IAEA and IPEMB shows an agreement with the results obtained in this paper to
within 1%, demonstrating that the data published in these protocols may be used
with reasonable accuracy if recommended phantoms are used. The results also show
that if unsuitable phantom materials are used, the wall perturbation factors may
differ for different chambers and for different phantom materials by more than 3%
and perturbation factors have to be considered in order to obtain a high accuracy
in the dose determination.
PMID- 9394401
TI - Two-dimensional scatter integration method for brachytherapy dose calculations in
3D geometry.
AB - In brachytherapy clinical practice, applicator shielding and tissue
heterogeneities are usually not explicitly taken into account. None of the
existing dose computational methods are able to reconcile accurate dose
calculation in complex three-dimensional (3D) geometries with high efficiency and
simplicity. We propose a new model that performs two-dimensional integration of
the scattered dose component. The model calculates the effective primary dose at
the point of interest and estimates the scatter dose as a superposition of the
scatter contributions from pyramid-shaped minibeams. The approach generalizes a
previous scatter subtraction model designed to calculate the dose for axial
points in simple cylindrically symmetric geometry by dividing the scattering
volume into spatial regions coaxial with the source-to-measurement point
direction. To allow for azimuthal variation of the primary dose, these minibeams
were divided into equally spaced azimuthally distributed pyramidal volumes. The
model uses precalculated scatter-to-primary ratios (SPRs) for collimated
isotropic sources. Effective primary dose, which includes the radiation scattered
in the source capsule, is used to achieve independence from the source structure.
For realistic models of the 192Ir HDR and PDR sources, the algorithm agrees with
Monte Carlo within 2.5% and for the 125I type 6702 seed within 6%. The 2D scatter
integration (2DSI) model has the potential to estimate the dose behind high
density heterogeneities both accurately and efficiently. The algorithm is much
faster than Monte Carlo methods and predicts the dose around sources with
different gamma-ray energies and differently shaped capsules with high accuracy.
PMID- 9394402
TI - Dosimetry studies with TLDs for stereotactic radiation techniques for intraocular
tumours.
AB - Between March 1993 and January 1997, stereotactic radiation techniques were used
to irradiate 66 intraocular tumour patients with the Gamma Knife (Leksell Gamma
Knife, model B unit) at the University of Vienna, Austria. This study
investigates the dosimetry for stereotactic irradiation of ocular structures. For
the dosimetry program KULA 4.4, Gamma Knife stereotactic irradiation of the eye
represents an extreme frontal skull position. In addition, irradiation of the eye
may be performed in the usual supine position in exceptional cases only. With the
patient in the prone position, the dose planning program has to calculate with a
significantly large number of single-beam extrapolations. In our first experiment
we measured the isocentre dose for eight different gamma-angle positions, both in
prone and supine positions, using TLD measurements in an Alderson head phantom.
We found a maximum deviation of +/- 1.6% using these individually calibrated
TLDs. In the second experiment we examined the dose cross profiles for the two
most frequently used treatment positions (supine position, gamma = 65 degrees,
and prone position, gamma = 140 degrees). For this purpose we implanted a
specially designed TLD array into the orbit of a human cadaver head. We found
excellent agreement of the dose values measured for the isocentre as well as the
posterior part of the eye with orbit with deviations of less than -2.7%. However,
for the anterior part of the eye, deviations between computer-generated
calculations and the TLD measurements were found to range up to -30%. These
differences were noticed both for supine and prone positions. For the Gamma Knife
stereotactic irradiation of ocular tumours or pathologies, precautions should be
taken to avoid significant underdosage in the anterior part of the radiation
field.
PMID- 9394403
TI - The inverse problem of depth dose curve estimation.
AB - The inverse problem of the depth dose curve is formulated and a proposition for
its solution is presented. The solution is based on the approximation of the
observation equation with a numerical quadrature operator and the regularization
of this inverse problem with a smoothness side constraint. The problem
formulation is applicable for both the electron and the photon depth dose curve
estimation. Moreover, the method is equivalent for, for example, all energies,
field sizes and source-to-phantom distances. Simulations show that the estimation
error is smaller with the proposed method than with direct linear interpolation.
The main result of the paper, however, is the formulation of the problem that
allows feasible extensions and modifications for different measurement
situations.
PMID- 9394404
TI - An automated method for mapping human tissue permittivities by MRI in
hyperthermia treatment planning.
AB - This paper presents an automatic method to obtain tissue complex permittivity
values to be used as input data in the computer modelling for hyperthermia
treatment planning. Magnetic resonance (MR) images were acquired and the tissue
water content was calculated from the signal intensity of the image pixels. The
tissue water content was converted into complex permittivity values by monotonic
functions based on mixture theory. To obtain a water content map by MR imaging a
gradient-echo pulse sequence was used and an experimental procedure was set up to
correct for relaxation and radiofrequency field inhomogeneity effects on signal
intensity. Two approaches were followed to assign the permittivity values to fat
rich tissues: (i) fat-rich tissue localization by a segmentation procedure
followed by assignment of tabulated permittivity values; (ii) water content
evaluation by chemical shift imaging followed by permittivity calculation. Tests
were performed on phantoms of known water content to establish the reliability of
the proposed method. MRI data were acquired and processed pixel-by-pixel
according to the outlined procedure. The signal intensity in the phantom images
correlated well with water content. Experiments were performed on volunteers'
healthy tissue. In particular two anatomical structures were chosen to calculate
permittivity maps: the head and the thigh. The water content and electric
permittivity values were obtained from the MRI data and compared to others in the
literature. A good agreement was found for muscle, cerebrospinal fluid (CSF) and
white and grey matter. The advantages of the reported method are discussed in the
light of possible application in hyperthermia treatment planning.
PMID- 9394405
TI - A study of thyroid radioiodine monitoring by Monte Carlo simulations:
implications for equipment design.
AB - Monte Carlo simulations have been performed to evaluate the design of collimated
detectors used to measure 125I or 131I in the thyroid gland. Two detector sizes
were simulated for each radioisotope: (i) for 125I monitoring 2.54 cm diameter
and 7.62 cm diameter and 0.2 cm thickness and (ii) for 131I monitoring 2.54 cm
diameter, 3.2 cm thickness and 7.62 cm diameter, 6.4 cm thickness. The virtual
thyroid gland was 20 g. Activity was placed in both the gland and the remainder
of the body in varying amounts to assess the efficacy of collimation. The results
show that the detector should be sufficiently large so that its solid angle of
acceptance when placed 15 cm anterior to the skin surface will include the whole
of a moderately enlarged thyroid gland. Heavy collimation to reduce the
contribution of extrathyroidal radioiodine within the subject's body is not
normally required. It may be of more value as a positioning device and spacer
ensuring an appropriate and constant neck to detector distance than in cutting
down counts from extrathyroidal activity. In specifying a sensitive detector
system for monitoring intrathyroidal radioiodine, a wide angle of acceptance and
sufficient detector crystal thickness take precedence over collimation and
shielding.
PMID- 9394406
TI - Improving wedged field dose distributions.
AB - Dose profiles produced by wedge filters in the non-wedged direction can exhibit a
7% or greater dose reduction at the outer ends of the field compared with open
field profiles. However, many planning systems use open field profiles to model
wedged dose distributions. In the present work, wedges have been modified to
reproduce open field profile shapes. This modification involved removing varying
thicknesses of the wedge using a simple milling machine. The wedge thickness was
calculated using the assumption that dose is proportional to primary collision
kerma. The discrepancies in dose between wedged field and open field profile
shapes of up to 7% were reduced to less than 3% with the modifications, even for
varying depths and off-axis distances. The necessary measurements are simple to
perform, and hence this technique could be applied to improve wedged field dose
distributions in other radiotherapy departments.
PMID- 9394407
TI - An investigation into the effect of input function shape and image acquisition
interval on estimates of washin for dynamic cardiac SPECT.
AB - Dynamic cardiac SPECT and PET can be used to measure myocardial perfusion by
estimating the kinetic rate constant describing the washing of radioactive
labelled tracers from the blood to the extravascular myocardial tissue. Because
of differences in photon statistics and data acquisition techniques, protocols
which produce optimal estimates of the washin for dynamic cardiac PET may give
suboptimal estimates if applied in dynamic cardiac SPECT. Two important factors
in the estimation of washin are the shape of the tracer input function and the
image acquisition interval. This study uses computer simulations to investigate
the effect of varying the tracer infusion length and image acquisition interval
on the bias and variance of estimates of washin obtained with dynamic cardiac
SPECT and 99mTc-labelled teboroxime. Bias in parameter estimates can be
introduced by aliasing, integration of the time-varying radioactivity by the
detector, and detector motion. This bias can be reduced by decreasing the
acquisition interval and using a longer-duration input function. However, this
results in poor photon statistics, which generate large variance, and can also
introduce bias in the estimates of the washin. Our studies indicate that better
estimates of the washin are obtained by using an acquisition interval that is of
sufficient duration to obtain adequate photon statistics even if this is at the
expense of temporal resolution. The increase in bias caused by using a 10 or 20 s
acquisition interval instead of a 5 s acquisition interval is minimal when
compared with the reduction in variance. Variance in estimates is also reduced by
using a sharp input function, resulting in higher peak counts during washin. It
is also shown that the variance of estimates of the washin increases generally
when faster kinetics are observed. This variance can, however, be reduced by
using longer acquisition intervals.
PMID- 9394408
TI - Noise analysis of MAP-EM algorithms for emission tomography.
AB - The ability to theoretically model the propagation of photon noise through PET
and SPECT tomographic reconstruction algorithms is crucial in evaluating the
reconstructed image quality as a function of parameters of the algorithm. In a
previous approach for the important case of the iterative ML-EM (maximum
likelihood-expectation-maximization) algorithm, judicious linearizations were
used to model theoretically the propagation of a mean image and a covariance
matrix from one iteration to the next. Our analysis extends this approach to the
case of MAP (maximum a posteriori)-EM algorithms, where the EM approach
incorporates prior terms. We analyse in detail two cases: a MAP-EM algorithm
incorporating an independent gamma prior, and a one-step-late (OSL) version of a
MAP-EM algorithm incorporating a multivariate Gaussian prior, for which familiar
smoothing priors are special cases. To validate our theoretical analyses, we use
a Monte Carlo methodology to compare, at each iteration, theoretical estimates of
mean and covariance with sample estimates, and show that the theory works well in
practical situations where the noise and bias in the reconstructed images do not
assume extreme values.
PMID- 9394409
TI - Pre-processing variance reducing techniques in multispectral positron emission
tomography.
AB - Stochastic fluctuations and systematic errors severely restrict the potential of
multispectral acquisition to improve scatter correction by energy-dependent
processing in high-resolution positron emission tomography (PET). To overcome
this limitation, three pre-processing approaches which reduce stochastic
fluctuations and systematic errors without degrading spatial resolution were
investigated: statistical variance was reduced by smoothing acquired data in
energy space, systematic errors due to nonuniform detector efficiency were
minimized by normalizing the data in the spatial domain and the overall variance
was further reduced by selecting an optimal pre-processing sequence. Selection of
the best protocol to reduce stochastic fluctuations entailed comparisons between
four smoothing algorithms (prior constrained (PC) smoothing, weighted smoothing
(WS), ideal low-pass filtering (ILF) and mean median (MM) smoothing) and
permutations of three pre-processing procedures (smoothing, normalization and
subtraction of random events). Results demonstrated that spectral smoothing by
WS, ILF and MM efficiently reduces the statistical variance in both the energy
and spatial domains without observable spatial resolution loss. The ILF algorithm
was found to be the most convenient in terms of simplicity and efficiency.
Regardless of the position of subtraction of randoms in the sequence, reduction
of the systematic errors by normalization followed by spectral smoothing to
suppress statistical noise produced the best results. However, subtraction of
random events first in the sequence reduces computation load by half since the
need to pre-process this distribution before subtraction is removed. In summary,
normalizing data in the spatial domain and smoothing data in energy space are
essential steps required to reduce systematic errors and statistical variance
independently without degrading spatial resolution of multispectral PET data.
PMID- 9394411
TI - The optical properties of lung as a function of respiration.
AB - Lung consists of alveoli enclosed by tissue and both structures contribute to
volume-dependent scattering of light. It is the purpose of this paper to
determine the volume-dependent optical properties of lung. In vivo interstitial
fibre measurements of the effective attenuation coefficient mu eff at 632.8 nm
differed during inspiration (mu eff = 2.5 +/- 0.5 cm-1) from that during
expiration (mu eff = 3.2 +/- 0.6 cm-1). In vitro measurements on a piglet lung
insufflated with oxygen from 50 to 150 ml showed the effective attenuation
coefficient at 632.8 nm decreases as a function of oxygen volume in the lung (at
50 ml mu eff = 2.97 +/- 0.11 cm-1, at 100 ml mu eff = 1.50 +/- 0.07 cm-1, and at
150 ml mu eff = 1.36 +/- 0.15 cm-1). This was explained by combining scattering
of alveoli (Mie theory) with optical properties of collapsed lung tissue using
integrating sphere measurements. Theory and measured in vitro values showed good
agreement (deviation < or = 15%). Combination of these data yields the absorption
coefficient and scattering parameters of lung tissue as a function of lung
volume. We conclude that the light fluence rate in lung tissue should be
estimated using optical properties that include scattering by the alveoli.
PMID- 9394410
TI - In vitro double-integrating-sphere optical properties of tissues between 630 and
1064 nm.
AB - The optical properties (absorption and scattering coefficients and the scattering
anisotropy factor) were measured in vitro for cartilage, liver, lung, muscle,
myocardium, skin, and tumour (colon adenocarcinoma CC 531) at 630, 632.8, 790,
850 and 1064 nm. Rabbits, rats, piglets, goats, and dogs were used to obtain the
tissues. A double-integrating-sphere setup with an intervening sample was used to
determine the reflectance, and the diffuse and collimated transmittances of the
sample. The inverse adding-doubling algorithm was used to determine the optical
properties from the measurements. The overall results were comparable to those
available in the literature, although only limited data are available at 790-850
nm. The results were reproducible for a specific sample at a specific wavelength.
However, when comparing the results of different samples of the same tissue or
different lasers with approximately the same wavelength (e.g. argon dye laser at
630 nm and HeNe laser at 632.8 nm) variations are large. We believe these
variations in optical properties should be explained by biological variations of
the tissues. In conclusion, we report on an extensive set of in vitro absorption
and scattering properties of tissues measured with the same equipment and
software, and by the same group. Although the accuracy of the method requires
further improvement, it is highly likely that the other existing data in the
literature have a similar level of accuracy.
PMID- 9394412
TI - An electronic portal imaging device for transit dosimetry.
AB - An electronic portal imaging device has been designed and constructed. It
consists of an array of 128 CsI scintillation crystals coupled to photodiodes
which is scanned across the field in 4 seconds. The linac is operated at a dose
rate of 400 cGy min-1 and the dose delivered for image acquisition is
approximately 27 cGy. The data acquisition controller is a stand-alone STE
computer located within the scan arm. Sample images are presented showing
contrast and spatial resolution of the system together with a humanoid phantom
image and a clinical image of a breast cancer patient. The phantom images show
the detector has a contrast resolution of 0.3% (at 15 mm diameter) and a spatial
resolution of 2.5-3.2 mm. Images of uniform Perspex blocks have also been
calibrated for thickness, indicating the system can measure radiological
thickness to an accuracy of 2-3 mm of water. These results indicate the detector
may be used for transit dosimetry applications including compensator design.
PMID- 9394413
TI - Dosimetric comparison of an integrated multileaf-collimator versus a conventional
collimator.
AB - The dosimetric characteristics of both a conventional GE collimator (CC) and a GE
multileaf collimator (MLC) are compared for different photon beam energies. The
integrated GE MLC consists of 32 pairs of tungsten leaves, replacing the lower
pair of jaws of the conventional collimator. Measurements were performed with the
conventional collimator before this collimator was replaced by the MLC. All parts
of the accelerator except the collimator remained the same. Leakage and
transmission measurements show good agreement with the manufacturer's
specification, stating a leakage between leaves of less than 1% for all energies
and a transmission through leaves of less than 0.5%. The dosimetric
characteristics of both collimators are very similar for square and rectangular
fields. No significant change in beam quality, beam attenuation and depth of
maximum dose could be detected within the measurement accuracy. The MLC output
ratio variation is smaller than the one measured with the CC. The penumbra
difference in the Y direction is less than 0.5 mm at a depth of 5 cm in phantom;
in the X direction the penumbra is 1 mm larger for the MLC due to the rounded
leaf fronts. As the two leaf banks replace the lower pair of collimator jaws the
distance from the collimator end to the isocentre is similar for the two
collimators, therefore the MLC does not reduce the flexibility of the treatment
unit. For symmetrical and regular collimator settings the MLC can be treated as
the CC.
PMID- 9394414
TI - Output ratios in a miniphantom for asymmetric fields shaped by a multileaf
collimator.
AB - The integrated GE multileaf collimator (MLC) provides the ability to achieve
'double' asymmetric fields: each of the 64 leaves allow an over-axis travel of 10
cm and the Y-jaws allow 20 cm. A formalism has recently been proposed by the
authors to calculate the output ratio in a miniphantom for this type of MLC by
the product of independent leaf and jaw correction factors. The original proposed
formalism was restricted to regular or irregular fields including the collimator
rotational axis. Introducing 'reduced coordinates' for the correction factors in
the present work this formalism is extended to asymmetric fields where central
leaves or jaws overlap the collimator axis. The extended formalism is applied to
asymmetric square, rectangular and irregular fields. For all fields checked at a
given off-axis position, measured and calculated output ratios agree within 1%
for 6, 18 and 25 MV photon beams. To relate output ratios normalized to off-axis
points with output ratios on-axis, off-axis ratios are derived from film and
miniphantom measurements. Both off-axis ratios agree to within 1% for 6 and 25 MV
photon beams; a maximum deviation of 1.3% is observed at 18 MV. Calculated
products of output ratios and off-axis ratios derived from films are compared
with measurements for asymmetric square, rectangular and irregular fields, and
agree mostly within 1% for all energies checked; maximum deviations of 1.3 and
1.6% are observed for 6 and 18 MV photon beams.
PMID- 9394415
TI - Use of transgenic and gene-targeted mice to model the genetic basis of
hypertensive disorders.
AB - As both essential hypertension and hypertension associated with pregnancy (pre
eclampsia) have been determined to have strong genetic components, considerable
recent research has focused on identifying genes that may predispose to the
development of these disorders. Recent advances in molecular genetics and the
work of the Human Genome Project have facilitated the identification of genes
that may be linked to these hypertensive disorders. Although molecular genetic
studies performed in humans and animals can be used to link genes or mutations in
genes to hypertension (once identified), studies are needed to assess their
biochemical and physiologic importance. In this review, we discuss the ever
increasing importance and use of transgenic and gene-targeted mice in modeling
the genetic basis of hypertensive disorders.
PMID- 9394416
TI - Acute renal failure: growth factors, cell therapy, and gene therapy.
AB - The rapid understanding of the cellular and molecular basis of organ function and
disease will be translated during the next several decades into new therapeutic
approaches to a wide range of clinical disorders, including acute renal failure
(ARF). The development of the biotechnology for recombinant genetic engineering
has led to the prospect of using purified protein products for therapy. In this
regard, the repair of ischemic and toxic ARF is critically dependent on a
redundant, interactive cytokine network of growth factors to return kidney
function to near normal baseline function. Recombinant growth factors are being
tested both experimentally and clinically to accelerate the repair of kidney
tissue in this disorder. A newer strategy in biotechnology is the development of
cell therapy derivatives. Cell therapy is based on the ability to expand specific
cells in tissue culture to perform differentiated tasks and to introduce these
cells into the patient either in extracorporeal circuits or as implants as drug
delivery vehicles of a single protein or to provide physiological functions. Cell
therapy devices are being developed to replace components of renal function that
are lost during ARF and chronic renal failure and are not replaced with current
hemodialysis or hemofiltration. These new approaches may result in therapeutic
modalities that diminish the degree of renal failure and the time needed to
recover renal function in acute tubular necrosis. This article examines the
future prospects of these developing therapies in the treatment of ARF.
PMID- 9394417
TI - Genotyping by PCR-ELISA of a complex polymorphic region that contains one to four
copies of six highly homologous human VH3 genes.
AB - The Humhv3005 human VH gene is located in an intricate locus that encompasses for
each haplotype a combination of one to four copies of six highly homologous VH3
genes. To assess the complexity of this region, we developed a polymerase chain
reaction-enzyme-derived immunosorbent assay (PCR-ELISA) method capable of
detecting each of the VH3 genes. The method consisted of amplification of
selected germline VH3 genes with a biotinylated primer, covalent capture of the
amplicons onto streptavidin-coated wells, and quantitative typing of the bound
VH3 genes with diagnostic oligonucleotides. Pilot studies of two DNA samples with
known presence or absence of hv3005 [according to a characteristic BamH1
restriction fragment-length polymorphism (RFLP)] yielded the expected results.
Subsequent analysis of 100 additional DNA samples with the known EcoR1 RFLP of
hv3005 showed a complete match between the absence of the 9.4-kb hybridizing band
and lack of hv3005-like genes, as determined by PCR-ELISA. Importantly, the PCR
ELISA analyses of these 102 genomic DNA samples revealed two new haplotypes in
the complex hv3005 region. Combined, these data demonstrate the usefulness and
efficiency of this new technique to ascertain the presence or absence of six
highly homologous genes in an unusually heterogeneous duplication-insertion
deletion region. In the future, a similar strategy may be used to dissect other
similarly complex VH genetic loci.
PMID- 9394418
TI - Insulin receptor expression and clinical outcome in node-negative breast cancer.
AB - The insulin receptor (IR), a ligand-activated tyrosine kinase, is present in
breast cancers, but its relationship to patient survival is unknown. The IR was
measured in 584 tumor specimens from patients with node-negative breast carcinoma
by frozen-section immunohistochemistry and light microscopy. The immunostaining
signal was quantitated in relation to both the staining intensity and the
proportion of positive malignant epithelial cells. Analyses indicated that
patients with tumors with undetectable IR content in malignant epithelial cells
(260 cases) had a relatively lower predicted 5-year disease-free survival (DFS)
(69% +/- 3%) than did patients with tumors with detectable IR content (324 cases;
DFS 76% +/- 3%, p = .032). The significance of IR content in these breast
malignant epithelial cells was then analyzed along with patient age, tumor size,
progesterone and estrogen receptor status, p53 accumulation, and S-phase.
Multivariate analysis of these data revealed that after adjustment for these
other variables, IR content was the strongest independent predictive factor for
DFS (relative risk = 1.73, p = .005). Interestingly, in a small subset of
patients with very high IR content (n = 62), DFS was decreased. These data
indicate that IR content in node-negative breast cancers is a significant major
predictor of reduced DFS. Moreover, they raise the possibility that the
measurement of IR content might provide important information concerning breast
cancer biology.
PMID- 9394420
TI - The erythropoietin receptor gene is not linked with the polycythemia phenotype in
a family with autosomal dominant primary polycythemia.
AB - Primary familial and congenital polycythemia (PFCP or familial erythrocytosis) is
a rare hematological disorder with either autosomal-dominant inheritance or
sporadic occurrence. It is characterized by an increased proliferation of
erythroid precursors that results in an elevated red blood cell mass. In some of
the PFCP families, the disease phenotype is associated with mutations of the
erythropoietin receptor (EPOR). Mutations in other genes are likely to cause PFCP
as well, but no evidence so far has been provided to support this contention. In
this study, we present a family in which 6 of 15 family members were affected in
three generations. We screened exon VIII of the EPOR gene for mutations and found
a C-->T substitution (C6148T) in the maternal grandmother of the propositus. The
mutated allele of the affected grandmother was not passed to either of her two
affected children or to her one healthy child; thus, the disease phenotype was
not linked to the C6148T mutation in this family. Further examination of the
inheritance of the EPOR gene alleles and sequence analysis ruled out linkage
between the disease phenotype and the EPOR gene; therefore, an abnormality in
another gene must be the cause of PFCP in this particular family. In three
affected family members tested, erythroid progenitors were hypersensitive to EPO.
This in vitro behavior of the progenitors confirms the diagnosis of PFCP in these
subjects. Moreover, it suggests a dominant lesion of an as-yet unidentified gene,
either at the level of the EPOR-signaling pathway or another erythropoiesis
regulating pathway that may be responsible for enhanced proliferation of the
erythroid progenitors.
PMID- 9394419
TI - Media acidification inhibits TGF beta-mediated growth suppression in cultured
rabbit proximal tubule cells.
AB - Chronic metabolic acidosis induces both hyperplastic and hypertrophic renal
growth and is associated with progressive loss of renal function. These studies
examine the direct effect of media acidification on the growth of rabbit proximal
tubule cells in primary culture. The results demonstrate that media acidification
has a direct antiproliferative (hypoplastic) effect on both quiescent and mitogen
stimulated [epidermal growth factor (EGF)-stimulated] cells and does not induce
hypertrophy. This direct antiproliferative effect of acid is associated with
inhibition of EGF-induced phosphorylation of the retinoblastoma protein (pRB),
which maintains pRB activity and inhibits cell cycle progression from G1 to S
phase. Transforming growth factor-beta (TGF-beta) alone has an antiproliferative
effect in these cells. TGF-beta converts EGF-induced hyperplasia to hypertrophy
and inhibits EGF-induced pRB phosphorylation. Media acidification inhibits both
the antiproliferative effect of TGF-beta and the ability of TGF-beta to convert
EGF-induced hyperplasia to hypertrophy. This activity is associated with
inhibition of TGF-beta-mediated retention of pRB in the active,
hypophosphorylated state. These results demonstrate that metabolic acidosis has a
direct growth-suppressive effect on renal epithelial cells but inhibits the
growth-suppressive effects of TGF-beta. Inhibition of the antiproliferative
effect of cytokines, such as TGF-beta, may be responsible for acidosis-induced
hyperplasia in vivo.
PMID- 9394421
TI - Structures of RNA-binding proteins.
PMID- 9394422
TI - The Hofmeister series: salt and solvent effects on interfacial phenomena.
AB - Advances in experimental and computational methodologies have led to a recent
renewed interest in the Hofmeister series and its molecular origins. New results
are surveyed and assessed. Insights into the underlying mechanisms have been
gained, although deeper molecular understanding still seems to be elusive. The
principal reason appears to be that the Hofmeister series emerges from a
combination of a general effect of cosolutes (salts, etc.) on solvent structure,
and of specific interactions between the cosolutes and the solute (protein or
other biopolymer). Hence every system needs to be studied individually in detail,
a state of affairs which is likely to continue for some time. A deeper
understanding of the Hofmeister series can be an extraordinarily valuable guide
to designing experiments, including not only those probing the series per se, but
also those designed to elucidate the adsorption, aggregation and stabilization
phenomena which underlie so many biological events. The aim of this review is to
provide an up-to-date framework to guide such understanding, consolidating recent
advances in the many fields on which the Hofmeister series impinges.
PMID- 9394423
TI - [The impact of conjugal bereavement and the buffering effect of social support on
the health of elderly people].
AB - This study examined the impact of the spouse's death on the mental and physical
health of the elderly, sixty years and older, and the buffering effect of social
support against the impact. A three-year study was conducted of 1,087 people
whose spouses were alive at the time of the initial survey. Changes over the
three-year period were compared among the following three groups: (1) the spouse
died within a year prior to the second survey (N = 21); (2) the spouse died more
than a year before the survey (N = 47); and (3) the spouse was still alive (N =
901: the comparison group). Results were as follows: (1) Mental and physical
health declined more rapidly in the first group than the comparison group, while
no significant change was found for the second group. (2) Social support after
the spouse loss significantly helped buffer the negative effect on the mental
health, but support prior to the loss had no such effect. Social support had no
moderating effect on the physical health.
PMID- 9394424
TI - [Multiple goals in conflict resolution: their antecedents and effects upon
tactical preference].
AB - The multiple goals theory of conflict management (Ohbuchi & Tedeschi, in press)
postulated that participants in a conflict pursue to achieve resource goals
(economic and personal resources) and social goals (relationship, identity,
justice, and power-hostility). The hypotheses based on this theory were examined
by the episode method, in which 207 university students were asked to rate their
recent experiences of interpersonal conflicts in terms of participants'
attributes, goals, and tactics. More than 80% of the subjects answered that they
were motivated to achieve multiple goals in their attempts to resolve the
conflicts. Social goals were found to be more strongly activated, and economic
resource goals were least strongly activated. Regression analyses revealed that
the effects of participants' attributes on tactical preference were mediated by
goals.
PMID- 9394425
TI - [Does altruism reach beyond the in group?: a social orientation approach].
AB - The experiment of this paper studied the role social orientation would play in
double-dilemma situations. In a double-dilemma situation, social dilemmas exist
both between and within groups; a cooperation choice at the within-groups level
is considered a defection choice at the between-groups level, and vice versa.
Using such a situation, whether "others" in other-orientedness are limited to
those of the ingroup or include those of a competing group was examined. Each of
132 college students played both an ordinary social dilemma game and a double
dilemma game, with equivalent incentive structures. Subjects' social orientation
was measured a few days after the experiment. Results indicated that other
oriented subjects thought only about ingroup members, and did not care much about
the others. Furthermore, social orientation did not affect whether subjects acted
similarly or differently for the two dilemma situations. Therefore, social
orientation approach to intergroup conflicts apparently had its limitations.
PMID- 9394426
TI - [Explanation and estimation of subjective probability by generalized model of
Support Theory].
AB - The purpose of this paper is to develop a new model for describing the cognitive
process of decision making. Being of a generalization of Tversky and Koehler's
Support Theory, the proposed model firstly defines the choice probability among
several alternatives in terms of degree of "support." Secondly the model defines
the degree of support in terms of objective probability and representativeness.
Thirdly, this model specifies the integration process by which one reaches the
probability of an event utilizing the already assessed subevents. This model was
applied to and tasted by, real experimental data. In the experiment, subjects
were asked to evaluate the proportions (a kind of probability) and the degrees of
representativeness of two objects. Compared to the estimates derived by a
Bayesian approach, the subjective probabilities estimated by the proposed model
were shown to be closer to those reported by the subjects.
PMID- 9394427
TI - [Relations of "self-oriented perfectionism" to depression and hopelessness].
AB - The purpose of this study was to construct a new multidimensional self-oriented
perfectionism scale (MSPS) and to examine the relationship of self-oriented
perfectionism to depression and hopelessness in college students. In Study 1, 26
original items of a new MSPS were administered to 132 students and factor
analysis revealed 4 solutions: desire for perfectionism (DP), personal standard
(PS), concern over mistakes (CM), and doubting of actions (D). Twenty items of
the final MSPS had high reliability and validity as an instrument of measuring
self-oriented perfectionism (Hewitt & Flett, 1991). In Study 2, 178 students
completed a questionnaire consisting of MSPS, stressor scale, depression scale,
and hopelessness scale. PS was negatively related to hopelessness, and CM and D
were positively related to both depression and hopelessness. Students with high
CM scores had higher depression than those with low CM scores, unrelated to the
degree of stress.
PMID- 9394428
TI - [Effects of self-touching behavior on the performance of lexical retrieval].
AB - In this study, effects of self-touching behavior on the performance of lexical
retrieval were investigated. In Experiment 1, 52 women were required to retrieve
Japanese idioms, and to recall them approximately 2 minutes after the retrieval.
The participants were randomly assigned into two groups; in one group, they were
tested with the restriction of their hand movement, whereas in the other group,
they were allowed to move their hands freely. Results revealed that when the
movement was restricted, their performance in the retrieval task was
significantly deteriorated. In Experiment 2, after the presentation of tape
recorded verbal stimuli, 26 women were required to recall them either with an
interval of 2 minutes or with an interval of 2 weeks. The self-touching behavior
was found to occur more often when the recall was performed with the interval of
2 weeks than when it took place immediately after the stimulus presentation. Thus
self-touching is considered to serve as a cue to retrieve information stored in
the long term memory.
PMID- 9394429
TI - [The effect of perceived social support and achievement motive on hopelessness].
AB - The purpose of this study was to investigate the effect of achievement motive on
the relationship between perceived social support and hopelessness in elementary
school children. Two surveys were administered. The first examined the
reliability and validity of an achievement motive scale with 273 4th through 6th
graders children. The second examined the joint effect of achievement motive and
perceived social support on the tendency to feel hopeless, with 410 children of
the same age group. Results confirmed that the two-factor structure was indeed
appropriate for an achievement motive scale, and that self-fulfillment
achievement motive was a moderating variable of the relationship between
perceived social support and hopelessness.
PMID- 9394430
TI - [Effects of imagery ability and speech anxiety on imagery vividness of imaginary
of speech scene].
AB - Effects of imagery ability and speech anxiety on imagery vividness of imaginary
of speech scene were examined. Subjects were divided into four groups in terms of
high and low scores of Scale of Mental Imagery-Short Form (SMI-S) and a speech
anxiety scale. They imagined themselves in neutral, action and speech scenes.
They were asked to rate valence, arousal, and dominance of associated emotion, as
well as imagery vividness, of each scene. An SMI-S effect was found on the
vividness for neutral and action scenes. For vividness of the speech scene,
however, speech anxiety had a stronger effect than imagery ability. The subjects
with high speech anxiety significantly decreased imagery vividness, and
experienced stronger arousal during imaginary speech. Good-imagery subjects with
high speech anxiety reported stronger arousal than poor-imagery subjects. These
results suggested that speech anxiety was a major determinant of imagery
vividness of imaginary of speech scene.
PMID- 9394431
TI - Congenital malformations in experimental diabetic pregnancy: aetiology and
antioxidative treatment. Minireview based on a doctoral thesis.
AB - Diabetes mellitus in pregnancy causes congenital malformations in the offspring.
The aim of this work was to characterize biochemical and morphologic anomalies in
the conceptus of an animal model of diabetic pregnancy. In addition, a preventive
treatment against diabetes-induced dysmorphogenesis was developed. Congenital
cataract was often found in the offspring of diabetic rats. The fetal lenses had
increased water accumulation, sorbitol concentration and aldose reductase
activity compared to control lenses. The results suggest that the cataracts form
via osmotic attraction of water due to sorbitol accumulation in the fetal lens.
Another set of malformations, with possible neural crest cell origin, occurred
frequently in offspring of diabetic rats. These included low set ears,
micrognathia, hypoplasia of the thymus, thyroid and parathyroid glands, as well
as anomalies of the heart and great vessels. Furthermore, diabetes caused
intrauterine death and resorptions more frequently in the late part of gestation.
When the pregnant diabetic rats were treated with the antioxidants butylated
hydroxytoluene, vitamin E or vitamin C, the occurrence of gross malformations was
reduced from approximately 25% to less than 8%, and late resorptions from 17% to
7%. This suggests that an abnormal handling of reactive oxygen species (ROS) is
involved in diabetes-induced dysmorphogenesis in vivo. Indeed, an increased
concentration of lipid peroxides, indicating damage caused by ROS, was found in
fetuses of diabetes rats. In addition, embryos of diabetic rats had low
concentrations of the antioxidant vitamin E compared to control embryos. These
biochemical alterations were normalized by vitamin E treatment of the pregnant
diabetic rats. The antioxidants are likely to have prevented ROS injury in the
embryos of the diabetic rats, in particular in the neural crest cells, thereby
normalizing embryonic development. These results provide a rationale for
developing new anti-teratogenic treatments for pregnant women with diabetes
mellitus.
PMID- 9394432
TI - A two-site delfia immunoassay for measurements of the N-terminal peptide of pro
atrial natriuretic peptide (nANP).
AB - A rapid, sensitive and reliable two-site immunoassay for measurements of the N
terminal peptide of pro-atrial natriuretic peptide (nANP) is presented. The
method uses one monoclonal antibody, directed against the N-terminal part of
nANP, as catcher antibody and another monoclonal antibody, directed against the C
terminal part of nANP, as detector antibody. The catcher antibody is biotinylated
and is bound to streptavidin pre-coated microtiter strips. The detector antibody
is labelled with Europium, which is measured in a Wallac DELFIA time-resolved
fluorometer. Blood collected in plain Vacutainer tubes gave same measured amounts
of nANP as blood collected in heparinised tubes. Blood collected in tubes
containing EDTA gave same measured amounts of nANP as the plain tubes, provided
that a 2-step assay protocol was used. Based upon 100 healthy blood donors, a
reference interval was calculated to < 450 pmol/L. Within the reference group
there was a significant increase of serum nANP with age. Based on 42 patients
with different degree of impaired renal function, a significant correlation of
nANP and serum creatinine was found. Assay performance, given as total assay
variation was 12%, 10% and 9% respectively at serum levels of 140, 970 and 3500
pmol/L. It is concluded that this method is fast, sensitive and reliable for
clinical measurements of nANP.
PMID- 9394433
TI - Trigger delay in infant ventilators.
AB - In an experimental study we determined the response trigger delay time of three
infant ventilators with a capacity to detect and support spontaneous breathing.
We measured this in anaesthetized cats as the time between the start of phrenic
nerve activity and the increase in airway pressure caused by the subsequent
inflation. Two modes of ventilatory support were used, namely Assist/Control
(A/C) and synchronised intermittent mandatory ventilation (SIMV). We found that
ventilators equipped with flow sensors close to the free end of the endotracheal
tube had a shorter trigger delay than a ventilator which detected breathing with
an abdominal sensor. Further, the trigger delay was shorter in SIMV mode than in
A/C mode of operation. A higher set sensitivity reduced the response time. We
conclude that triggered ventilation may be used in infants, at least when the
spontaneous breathing rate is below 60 breaths per minute. This mode of
ventilation could be useful when infants are to be weaned off the ventilator.
PMID- 9394434
TI - Clinical characteristics of insulin-dependent diabetes mellitus in children at
diagnosis.
AB - The clinical characteristics of 60 consecutive children < 16 years in a Swedish
county with newly diagnosed diabetes mellitus, are described. Twenty-four of them
were 5.0-9.9 years old. The fathers of 12% had diabetes. There was no seasonal
variation in the onset of diabetes. Presenting symptoms were polyuria and
polydipsia in more than 90% of the cases. School children had a longer duration
of symptoms than pre-school children. Most of the children were in a good state
of health, and none were unconscious on admission. HbA1C was a good indicator of
diabetes duration (R2 = 0.32). Patients with Coxsackie B IgM antibodies had lower
blood glucose than those without such detectable antibodies.
PMID- 9394435
TI - HLA-A and -B antigens and larynx carcinoma in Greeks.
AB - The frequency of HLA antigens in 30 Greek larynx carcinoma patients was more
prominent for the A21, A28 and B17 antigens compared to 400 healthy unrelated
controls from the same population. It is suggested that immunogenetic factors may
contribute to the pathogenesis of this neoplasia.
PMID- 9394436
TI - Determination of dissociation constants of loop diuretics in acetonitrile-water
mixtures.
AB - The dissociation pK values of the representative loop diuretics furosemide,
bumetanide and ethacrynic acid in 10, 30, 40, 50 and 70% (w/w) acetonitrile-water
mixtures at 298.15 K were determined, according to the rules and procedures
endorsed by IUPAC. The variation in pK values over the whole composition range
studied can be explained by tacking into account the preferential solvation of
ionizable substances in acetonitrile-water mixtures. With a view to determining
the pK values of the loop diuretics studied in any of the binary solvent
acetonitrile-water mixtures, correlations of pK values and different bulk
properties of the solvent were examined, and the linear solvation energy
relationships method, LSER, has been applied. The pK values were then correlated
with the pi*, alpha and beta solvatochromic parameters of acetonitrile-water
mixtures. The resulting equations allowed us to calculate pK values for the loop
diuretics in any acetonitrile-water mixture up to 70% (w/w) acetonitrile.
PMID- 9394437
TI - Analysis of some herbal plants from India used in the control of diabetes
mellitus by NAA and AAS techniques.
AB - Elemental analysis of some herbal plants used in the control of diabetes has been
done by the techniques of Neutron Activation Analysis (NAA) and Atomic Absorption
Spectroscopy (AAS). The elements Mn, Na, K, Cl, Al, Cu, Co, Pb, Ni, Cr, Cd, Fe,
Ca, Zn and Hg are found to be present in different plants in various proportions.
PMID- 9394438
TI - Multivariate calibration for quantitative analysis of EDXRD spectra from a bone
phantom.
AB - Phantoms have been constructed to simulate trabecular bone mineral loss and
cortical bone thinning which consist of a mixture of hydroxylapatite powder and
animal fat in various quantities, surrounded by a varying thickness of dural
sleeve. Energy dispersive X-ray diffraction (EDXRD) spectra have been recorded,
and multivariate calibration has been performed on the spectra from the bone
phantoms. The multivariate technique of partial least squares (PLS) was used to
predict the hydroxylapatite content of the phantoms and the dural thickness for
measurement times of 250, 50 and 5 s. The calibration phantoms consisted of 10
hydroxylapatite densities ranging from 0.5852 g cm-3 to 0.3703 g cm-3
representing a loss of hydroxylapatite of approx. 40% in 4% intervals. Each
phantom had four dural sleeves of thickness 0.5, 1.0, 1.5 and 2.0 mm. Nine test
phantoms were constructed with a range of densities that were inside the
calibration range. For a measurement time of 250 s the average accuracy of
prediction for hydroxylapatite content was approx. +/- 3% while for a measurement
time of 5 s this fell to approx. +/- 8%. The dural thickness was predicted to
within approx. +/- 0.25 mm for a measurement time of 250 s. The results show that
multivariate calibration is a useful technique for obtaining quantitative data of
a desired variable from EDXRD measurements which may otherwise be masked or
corrupted by other variables.
PMID- 9394439
TI - Reinvestigation of a physiological eluate of the 52Fe/52mMn generator.
AB - We have achieved a significant step forward in the potential application of
52mMn2+ (T1/2 = 0.35 h, beta + = 97%) as a myocardial imaging agent with positron
emission tomography (PET) by the introduction of a 5% (physiological) glucose
solution as an eluent for the 52Fe/52mMn generator. Our experiments have
demonstrated the favourable properties of a glucose solution with minimal
breakthrough (< 0.3%) of 52Fe and yields of up to 90% 52mMn2+. Although it has
been shown that lower 52Fe breakthrough is attainable using other eluents, due to
the short half life of 52Fe (8.27 h) breakthrough up to 1% would not appear to
significantly alter the efficacy of the 52mMn eluted with this 5% glucose
solution. The primary advantage of this approach lies in its convenience of
application, in that a 5% glucose solution may be administered directly into
patients thereby circumventing the major problem of non-injectable eluates
previously associated with this generator.
PMID- 9394440
TI - A ring model for spatiotemporal properties of simple cells in the visual cortex.
AB - A neural model is proposed for the spatiotemporal properties of simple cells in
the visual cortex. In the model, several cortical cells are arranged on a ring,
with mutual excitatory or inhibitory connections. The cells also receive
excitatory inputs either from lagged and nonlagged cells of the lateral
geniculate nucleus in one setting or from nonlagged cells in the other. Computer
simulation shows that the cortical cells have spatiotemporally inseparable
receptive fields in the former setting and separable fields in the latter;
spatial profiles at a given time in the spatiotemporal fields are described with
a Gabor function whose phase parameter varies regularly from 0 to 2 pi with
rotation along the ring; the inseparable cells have directional selectivity as
observed physiologically.
PMID- 9394441
TI - Episodes of low-dimensional self-organized dynamics from electroencephalographic
alpha-signals.
AB - Self-organized neuronal dynamics revealed by cortical alpha-rhythms occur as
episodes, which are rarely observed without extraction of the alpha-band from the
other spectral components. Three episodes of an unusually long duration of 10 s,
two with no signal processing after data recording at the clinic, are described
and show evidence of low-dimensional alpha-dynamics. The evidence is gained from
an analysis of scaled structures appearing in families of slope curves of the
correlation integrals and is checked against time reparametrization. The data for
the two unprocessed 10-s episodes are used for a test of the methodology, as well
as a re-examination of the adequacy of the model of an autonomous dynamic system
in steady state and of the concept of an attractor in brain dynamics
investigations. Striking evidence for the model's inadequacy is provided by the
episode of subject S1. In this example five consecutive overlapping 6-s sections
do show evidence for low-dimensional dynamics, whereas the 10-s section
containing those sections does not. The episode of subject 1 provides an example
of alpha-activity which may involve self-organized dynamics extending down to low
frequencies. The system (the neuronal network) showing episodes of attractor
ruled dynamics, under conditions of blurred and smoothly fading out evidence that
it stays on an attractor, is designated as being ruled by a 'shadow-attractor'.
This concept is compared with that of a 'quasi-attractor' introduced by H. Haken
in studies of physiological systems. One possible mechanism for the observed
episodes is proposed, based on a time-dependent number of enslaved sub-systems.
PMID- 9394442
TI - Non-linear analysis of the electroencephalogram in Creutzfeldt-Jakob disease.
AB - Creutzfeldt-Jakob disease is a rare, neurological, dementing disorder
characterised by periodic sharp waves in the electroencephalogram (EEG). Non
linear analysis of these EEG changes may provide insight into the abnormal
dynamics of cortical neural networks in this disorder. Babloyantz et al. have
suggested that the periodic sharp waves reflect low-dimensional chaotic dynamics
in the brain. In the present study this hypothesis was re-examined using newly
developed techniques for non-linear time series analysis. We analysed the EEG of
a patient with autopsy-proven Creutzfeldt-Jakob disease using the method of non
linear forecasting as introduced by Sugihara and May, and we tested for non
linearity with amplitude-adjusted, phase-randomised surrogate data. Two epochs
with generalised periodic sharp waves showed clear evidence for non-linearity.
These epochs could be predicted better and further ahead in time than most of the
irregular background activity. Testing against cycle-randomised surrogate data
and close inspection of the periodograms showed that the non-linearity of the
periodic sharp waves may be better explained by quasi-periodicity than by low
dimensional chaos. The EEG further displayed at least one example of a sudden,
large qualitative change in the dynamics, highly suggestive of a bifurcation. The
presence of quasi-periodicity and bifurcations strongly argues for the use of a
non-linear model to describe the EEG in Creutzfeldt-Jakob disease.
PMID- 9394443
TI - Manuo-ocular coordination in target tracking. I. A model simulating human
performance.
AB - During eye tracking of a self-moved target, human subjects' performance differs
from eye-alone tracking of an external target. Typical latency between target and
eye motion onsets is shorter, ocular smooth pursuit (SP) saturation velocity
increases and the maximum target motion frequency at which the SP system
functions correctly is higher. Based on a previous qualitative model, a
quantitative model of the coordination control between the arm motor system and
the SP system is presented and evaluated here. The model structure maintains a
high level of parallelism with the physiological system. It contains three main
parts: the eye motor control (containing a SP branch and a saccadic branch), the
arm motor control and the coordination control. The coordination control is
achieved via an exchange of information between the arm and the eye sensorimotor
systems, mediated by sensory signals (vision, proprioception) and motor command
copy. This cross-talk results in improved SP system performance. The model has
been computer simulated and the results have been compared with human subjects'
behavior observed during previous experiments. The model performance is seen to
quantitatively fit data on human subjects.
PMID- 9394444
TI - Manuo-ocular coordination in target tracking. II. Comparing the model with human
behavior.
AB - Several studies have shown that humans track a moving visual target with their
eyes better if the movement of this target is directly controlled by the
observer's hand. The improvement in performance has been attributed to
coordination control between the arm motor system and the smooth pursuit (SP)
system. In such a task, the SP system shows characteristics that differ from
those observed during eye-alone tracking: latency (between the target-arm and the
eye motion onsets) is shorter, maximum SP velocity is higher and the maximum
target motion frequency at which the SP can function effectively is also higher.
The aim of this article is to qualitatively evaluate the behavior of a dynamical
model simulating the oculomotor system and the arm motor system when both are
involved in tracking visual targets. The evaluation is essentially based on a
comparison of the behavior of the model with the behavior of human subjects
tracking visual targets under different conditions. The model has been introduced
and quantitatively evaluated in a companion paper. The model is based on an
exchange of internal information between the two sensorimotor systems, mediated
by sensory signals (vision, arm muscle proprioception) and motor signals (arm
motor command copy). The exchange is achieved by a specialized structure of the
central nervous system, previously identified as a part of the cerebellum.
Computer simulation of the model yielded results that fit the behavior of human
subjects observed during previously reported experiments, both qualitatively and
quantitatively. The parallelism between physiology and human behavior on the one
hand, and structure and simulation of the model on the other hand, is discussed.
PMID- 9394445
TI - Evaluation of a self-consistent method for calculating muscle parameters from a
set of isokinetic releases.
AB - A new method for calculating parameters describing the force-velocity
relationship of the contractile element and the force-extension relationship of
the series elastic element of skeletal muscle from a set of isokinetic release
contractions is evaluated using experimental and numerical techniques. The method
calculates from the set of isokinetic releases those force-velocity and force
extension relationships that give a self-consistent description of the data set.
The self-consistent calculation method is applied to data obtained from the
gastrocnemius medialis muscle of the rat, since for such an animal model both
relationships can be independently derived from a set of isotonic release
contractions. For the two animals studied, the force-velocity and force-extension
relationships calculated by the self-consistent method were in good agreement
with the ones derived from isotonic releases performed on the same muscle. The
statistical properties of the estimates obtained by the calculation method were
investigated using a Monte Carlo technique. The method was found to yield results
which were biased by less than 2% and which possessed a coefficient of variation
smaller than 5%. These findings indicate that the proposed calculation method can
be a useful tool for determining the contractile properties of skeletal muscle as
reflected in the force-velocity and force-extension relationships.
PMID- 9394446
TI - Nonlinear principal components analysis of neuronal spike train data.
AB - Many recent approaches to decoding neural spike trains depend critically on the
assumption that for low-pass filtered spike trains, the temporal structure is
optimally represented by a small number of linear projections onto the data. We
therefore tested this assumption of linearity by comparing a linear factor
analysis technique (principal components analysis) with a nonlinear neural
network based method. It is first shown that the nonlinear technique can reliably
identify a neuronally plausible nonlinearity in synthetic spike trains. However,
when applied to the outputs from primary visual cortical neurons, this method
shows no evidence for significant temporal nonlinearities. The implications of
this are discussed.
PMID- 9394447
TI - Modeling neural activity using the generalized inverse Gaussian distribution.
AB - Spike trains from neurons are often used to make inferences about the underlying
processes that generate the spikes. Random walks or diffusions are commonly used
to model these processes; in such models, a spike corresponds to the first
passage of the diffusion to a boundary, or firing threshold. An important first
step in such a study is to fit families of densities to the trains' interspike
interval histograms; the estimated parameters, and the families' goodness of fit
can then provide information about the process leading to the spikes. In this
paper, we propose the generalized inverse Gaussian family because its members
arise as first passage time distributions of certain diffusions to a constant
boundary. We provide some theoretical support for the use of these diffusions in
neural firing models. We compare this family with the lognormal family, using
spike trains from retinal ganglion cells of goldfish, and simulations from an
integrate-and-fire and a dynamical model for generating spikes. We show that the
generalized inverse Gaussian family is closer to the true model in all these
cases.
PMID- 9394448
TI - Commentary on the application of (Q)SAR to the toxicological evaluation of
existing chemicals.
AB - For ethical and financial reasons it is impossible to perform thorough
toxicological testing for all of the more than 100,000 substances registered in
the European Inventory of Existing Substances. It was therefore investigated
whether the application of (quantitative) structure-activity relationships (QSAR)
with commercially available computer programs could predict the toxicological
profile and help identify those substances requiring priority toxicological
testing. Whereas predictions with respect to complex endpoints such as
carcinogenicity, chronic toxicity and teratogenicity are still disappointing,
more reliable predictions should be forthcoming in the immediate future for
sensitisation, mutagenicity and genotoxicity endpoints.
PMID- 9394449
TI - The toxic effect of the antibiotic metronidazole on aquatic organisms.
AB - The acute toxicity of metronidazole was tested on freshwater and marine
organisms. The tests showed effect on Chlorella sp. and Selenastrum
capricornutum. 72-hr EC10 of 2.03 mg/l and 19.9 mg/l respectively and 72-hr EC50
values of 12.5 mg/l and 40.4 mg/l respectively were among the results obtained.
No acute lethal effect was observed on Acartia tonsa or Brachydanio rerio. The
study demonstrates the potential ecotoxic effect of metronidazole, suggesting the
need for further investigations of the environmental exposure of medicinal
substances.
PMID- 9394450
TI - Ela 1.0--a framework for life-cycle impact assessment developed by the Fraunhofer
Gesellschaft. Part A: The conceptual framework.
AB - The Fraunhofer-Gesellschaft has sponsored the development of a conceptual and
flexible, computer aided tool to perform the impact assessment within LCA (life
cycle assessment) for technical products and processes. The developed general
framework "Ela 1.0" (environmental loads analysis) consists of four elements: the
selection of appropriate impact categories, the categorization of emissions and
wastes leaving the systems as well as of resource and energy consumption, the
characterization and an analysis of the results of the impact assessment. The
latter compares the product-based emissions with the total of emissions of a
region such as Germany, the EU or OECD countries. The framework Ela 1.0 considers
the environmental categories: global warming, ozone depletion, resource and
energy consumption, wastes, eutrophication (including COD and BOD as measured
parameters), acidification, ecotoxicity, ozone formation and human toxicity. The
latter categories are handled by listing of precursors for ozone formation, and
by listing of emissions scored according to their human hazard potential. The
options, possibilities and limitations of the conceptual framework are presented
in part A of a series of publications.
PMID- 9394451
TI - Assessment of the environmental behaviour of antioxidants in folios. Comparative
risk analysis for the use of folios in agriculture.
AB - The objective of the reported study has been to assess and evaluate as
comprehensively as possible the environmental impact of Octadecyl 3(3,5-di-tert
butyl-4-hydroxyphenyl) propionate (CAS no: 2082-79-3, Irganox 1076, Ciba
Specialty Chemicals Inc., Additives), which is used as an antioxidant. The
potential impact on the compartments soil, groundwater and surface water is to be
considered. For comparative purposes, additionally, other chemical compounds
being currently under environmental discussion are also taken into account. These
comprise pesticides and phthalates which are ubiquitously distributed
plasticizers as well as a complexing agent. Since the data basis for each of the
compounds under consideration is different, a tiered approach comprising various
methodologies of impact assessment has been chosen to achieve the best possible
comprehensiveness. The tiers are: 1. Tier: hazard assessment using a scoring
system 2. Tier: comparative risk assessment. When interpreting the results of
each method, system boundaries as well as underlying assumptions were taken into
consideration. Both methodologies showed, that-as compared to the reference
substances-there is no relevant environmental and toxicological concern due to
low environmental and human hazard from Octadecyl 3(3,5-di-tert-butyl-4
hydroxyphenyl) propionate.
PMID- 9394452
TI - Multinucleated giant cells recruited by implantation of octacalcium phosphate
(OCP) in rat bone marrow share ultrastructural characteristics with osteoclasts.
AB - The ultrastructural characteristics of multinucleated giant cells (MNGCs) on
octacalcium phosphate (OCP) and hydroxyapatite (HA) were investigated in
comparison with those of osteoclasts, when the synthetic OCP and HA were
implanted in rat bone marrow. The morphological difference in the MNGCs were
shown between OCP and HA implants in 2 weeks after implantation. The MNGC on the
implanted OCP (i-OCP) developed the ruffled border-like structure and the clear
zone-like structure. The i-OCP was frayed where it was in contact with the
ruffled border-like structure. The MNGC on the implanted HA (i-HA) developed the
clear zone-like structure, whereas no ruffled border was seen. The surface of i
HA associated with the MNGC was smooth and not frayed. Bone formed directly on
the OCP or HA implants. The interface between the i-OCP and bone matrix
interdigitated, whereas that between the i-HA and bone matrix was comparatively
smooth. The present study suggested that the i-OCP could be resorbed by the MNGCs
which share some ultrastructural characteristics with osteoclasts.
PMID- 9394453
TI - Substructures of the acinar basement membrane of rat submandibular gland as shown
by alcian blue staining and cryo-fixation followed by freeze-substitution.
AB - The ultrastructure of the epithelial basement membrane was studied in the acinar
cells of adult rat submandibular glands after: (i) immersion fixation in 0.1 M
sodium cacodylate buffer (CB, pH 7.2) containing 2.5% glutaraldehyde (GA) and
alcian blue (0.5%) in conjunction with microwave irradiation, (ii) perfusion
fixation with 2.5% GA in CB, (iii) rapid freezing followed by freeze-substitution
(RF-FS) with 1% GA in acetone, and (iv) RF-FS with 2% OsO4 in acetone. The
specimens were post-fixed with 1% OsO4 in CB after methods (i) and (ii) but not
(iii) and (iv). Fixed specimens were embedded in epoxy resin and the ultrathin
sections were cut, stained with both lead and uranium, and observed under a
transmission electron microscope. Various substructural components could be seen
in the acinar basement membrane. In the specimens processed by method (iv), a
clear meshwork structure could be found just beneath the basal plasma membrane.
This meshwork could not be seen in the specimens processed by method (iii) but
thin filaments of approximately 100 nm in length extending from the epithelial
base toward the connective tissue space were evident. By methods (i) and (ii), an
electron dense 30-75 nm layer could be seen subjacent to basal cell membranes. By
method (ii), particularly, thick threads connecting this layer to collagen fibres
in the connective tissue were stained with alcian blue. Lamina lucida was not
identified.
PMID- 9394454
TI - Ultrastructural study of capillary and myocytic changes in the masseter and heart
of KK-Ay mice.
AB - We studied the capillaries and myocytes of masseter and cardiac muscles of
diabetic KK-Ay mice, using light microscopy, transmission electron microscopy and
scanning electron microscopy. The following changes were observed for diabetic
masseters: capillary tortuosity, diversity of capillary caliber, endothelial cell
swelling accompanied by luminal narrowing, widening of the pericapillary space
and pericapillary fibrosis, and subsarcolemmal accumulation of myocytic
mitochondria in areas adjacent to capillaries. In addition, attenuated capillary
segments were largely covered by pericytes with profuse processes. In contrast,
cardiac muscles of KK-Ay mice exhibited subsarcolemmal accumulation of myocytic
mitochondria in areas contiguous to capillaries, and degenerative changes of
myocytes such as disarrangement of myofilaments, disappearance of Z-bands and
clustering of lipid-like vacuoles, although conspicuous changes of capillaries
were not noted. Microvascular and myocytic changes described above may suggest
the presence of microangiopathy and myopathy in the masseter and heart of KK-Ay
mice.
PMID- 9394455
TI - Electron microscopy of biological specimens by the plasma-polymerization rapid
freeze replica method.
AB - The plasma-polymerization replica method is a unique replica technique for
transmission electron microscopy. In the present study, we used this method in
combination with a rapid-freeze technique to observe T4 bacteriophages and
hepatitis B virus core particles. The heads of T4 bacteriophages appeared
hexagonal and measured approximately 110 nm in length. Striations in their tails
were also visible, indicating that the resolution of the present method is better
than 4 nm. The images corresponded well with those obtained by ice-embedding and
negative staining methods, with respect to both morphology and size of the phage
particle. Hepatitis B virus core particles observed by the present method
appeared round, approximately 30 nm in diameter, with hollow centres. Again, the
morphology and size of the particles corresponded well with those obtained by ice
embedding, negative staining, and ultrathin sectioning. From these results, we
conclude that the plasma-polymerization rapid-freeze replica method provides a
useful technique for observation of biological specimens in a natural state and
at high resolution.
PMID- 9394456
TI - Detection of Epstein-Barr virus DNA in virus-infected cells by electron
microscopic in situ hybridization.
AB - We describe a procedure for in situ hybridization using a biotinylated Epstein
Barr virus (EBV) sequence with detection at the light and electron microscopic
levels. In situ hybridization using an immunogold-silver staining detection
system was used to identify biotinylated DNA probes in cell smears and in
Lowicryl K4M-embedded EBV-infected and -noninfected cell lines. At the light
microscopic level, the reaction product of hybridized EBV DNA sequence seemed to
be located mainly in the nuclei. The labelling was dependent on the cell strains.
However, at the electron microscopic level, the reaction product was evident as
spots or clusters distributed not only in the nuclei of EBV-infected cells but
also in the cytoplasm and extracellular particles. These findings suggest that
immature particles in the cytoplasm contain EBV DNA. This procedure can be
applied to the observation and identification of virus infection.
PMID- 9394457
TI - Electron microscopic observations of the stichosome during the normal development
of Trichinella spiralis from muscle larvae to adult worms in BALB/c mice.
AB - The exocrine granules of the stichosome of Trichinella spiralis contain excretory
and secretory (ES) products that may alter host cell physiology in such a way
that T.spiralis can establish parasitism in the host [1,2]. The stichosome is the
most intriguing but still mysterious exocrine organ. This paper describes
ultrastructural changes of the stichosome during the normal development from
muscle larvae to adult worms. Stichocyte granules of the muscle larva stage were
excreted by 14 h post-infection (PI). Then the stichosome synthesized a new type
of granules, which disappeared from the stichosome by 30 h PI. These transient
granules were morphologically different from granules of muscle larva and adult
stages.
PMID- 9394458
TI - Ultrastructure of a well-preserved lymphocyte from a mummified human.
AB - A well-preserved lymphocyte was found during the electron microscopic examination
of the cerebral material recovered from a naturally preserved male mummy from
northern Chile dating back over 500 years. The cytoplasmic structures were easily
recognizable. This study represents one of the best ultrastructural analyses of
mummified human peripheral blood elements.
PMID- 9394459
TI - Acquisition of the mental state verb know by 2- to 5-year-old children.
AB - The production of the cognitive internal state word know by four 2- to 5-year-old
children and their parents was examined. The levels of meaning of cognitive words
can be categorized hierarchically along the dimensions of conceptual difficulty
and abstractness (see Booth & Hall, 1995). The present study found that children
and their parents expressed low levels of meaning less frequently, whereas they
expressed high levels of meaning more frequently as a function of age. The
children's use of know was also correlated positively with (1) their number of
different words produced suggesting that cognitive words are related to more
general semantic processes, and (2) with parental use of those same cognitive
words suggesting that parental linguistic input may be an important mechanism in
cognitive word acquisition. Finally, young children tended to use know more to
refer to themselves than to refer to others, whereas their parents tended to use
know equally to refer to self and others. The importance of cognitive words in a
theory of language acquisition is discussed.
PMID- 9394460
TI - Social structure of the mound-building mouse Mus spicilegus revealed by genetic
analysis with microsatellites.
AB - The Mound-building mouse Mus spicilegus possesses a unique behaviour amongst
mice. It constructs large earthen mounds and associated nesting chambers which
serve to store food for immature individuals during the winter nesting period. We
have used genetic analysis of four autosomal and four X-linked microsatellite
loci to determine relationships between individuals inhabiting 40 mounds in
Bulgaria. We show that, in almost all cases, individuals in a mound are the
product of multiple parentage. We estimate the minimum number of males and female
parents contributing offspring to each mound and demonstrate that at least two
male and two female parents contribute offspring to a minimum of seven mounds.
Analyses of relatedness coefficients and allele sharing values demonstrate that
parents of different sibships within mounds are more related than if they had
been chosen at random from the population and suggest that it is the female
parents that contribute this excess relatedness. These results suggest that the
mechanism by which individuals congregate to build mounds is kin-based and that
the evolution of mound building and communal nesting in M. spicilegus is due in
part to kin selection. This study represents a novel approach to the study of
mammalian behavioural ecology. We have used a genetic dataset to construct an
outline of social structure in the absence of behavioural data. These inferences
can now be used to direct further work on this species.
PMID- 9394461
TI - A genomic polymorphism located downstream of the gcvP gene of Escherichia coli
that correlates with ecological niche.
AB - Current evolutionary theory proposes that niche-adapted microbial populations
might evolve through selection for favoured genotypes followed by clonal
expansion (Maynard-Smith, 1991). Possible correlations between genomic variation
and ecological niche in Escherichia coli isolates derived from human and animal
sources were investigated by randomly amplified polymorphic DNA (RAPD) analysis.
A 1.6-kb polymorphic marker was identified which was present in 60% of isolates
from human clinical specimens but was present in less than 5% of isolates derived
from ovine and bovine faeces. The marker maps to a region of the chromosome
located immediately downstream from the gene encoding the glycine decarboxylase P
protein (gcvP). DNA sequences from marker-positive and marker-negative isolates
exhibit an abrupt loss of homology immediately downstream from the transcription
termination point of the gene which extends for at least 130-base pairs beyond
the gcvP transcription terminator. Sequences spanning this region in marker
negative isolates exhibit similarity to the cognate sequence from E. coli K-12,
while the corresponding region in marker-positive isolates bears no similarity to
any other published sequence. The utility of the marker for investigating the
occurrence of human-derived E. coli in the environment was studied in a rural
stream. Although the stream carried a high background of animal-derived E. coli,
the marker could only be detected in isolates obtained downstream of the human
faecal input. The polymorphism therefore shows promise for identification of
human-derived E. coli within environments containing isolates from multiple and
diverse sources. The methods described here could be used to generate further
markers suitable for investigating microbial population ecology.
PMID- 9394462
TI - Matriarchal genetic population structure of North American beluga whales
Delphinapterus leucas (Cetacea: Monodontidae).
AB - The North American beluga whale Delphinapterus leucas population has been divided
into a number of putative geographical stocks based upon migration routes and
areas of summer concentration. Nucleotide sequences of the mitochondrial DNA
(mtDNA) control region were used to assess whether these geographical stocks are
genetically distinct. Beluga whale samples from 25 sites were collected primarily
from aboriginal subsistence hunts across North America from 1984 to 1994. Thirty
nine mtDNA haplotypes were identified in 628 beluga samples. No differences were
found in the distribution of haplotypes between male and female beluga whales at
any sampling site. These haplotypes segregated into two distinct assemblages in
both a haplotype network and a neighbour-joining tree. The haplotype assemblages
and a geographically disjunct distribution that suggests postglacial
recolonization of the North American Arctic from two different refugia. An
analysis of molecular variance based on haplotype relationships and frequency
indicated genetic heterogeneity among beluga whale summering groups (P < or =
0.001). Sequence divergence estimates between sampling sites also indicated
geographical differentiation, particularly between samples taken at east Hudson
Bay or St Lawrence River and the western or central Arctic. The results of this
study show a high degree of philopatry to specific summering areas by this highly
mobile animal.
PMID- 9394463
TI - Intron variation in marbled murrelets detected using analyses of single-stranded
conformational polymorphisms.
AB - Combination of the targeted amplification of nuclear introns and the analysis of
single-stranded conformational polymorphisms has the potential to provide an
inexpensive, rapid, versatile and sensitive genetic assay for evolutionary
studies and conservation. We are developing primers and protocols to analyse
nuclear introns in vertebrates, and are testing them in a population genetic
study of marbled murrelets Brachyramphus marmoratus. Here we present protocols
and results for introns for aldolase B, alpha-enolase, glyceraldehyde-3-phosphate
dehydrogenase and lamin A. Results suggest that this approach presents a
potentially powerful method for detecting genetic variation within and among
local populations and species of animals: (i) a variety of genes can be surveyed,
including genes of special interest such as those involved in disease resistance;
(ii) assays are rapid and relatively inexpensive; (iii) large numbers of genes
can be assayed, enabling accurate estimation of variation in the total genome;
(iv) almost any mutation can be detected in the genes amplified; (v) the exact
nature of variation can be investigated by sequence analysis if desired; (vi)
statistical methods previously developed for proteins and/or sequence data can be
used; (vii) protocols can be easily transferred to other species and other
laboratories; and (viii) assays can be performed on old or degraded samples,
blood or museum skins, so that animals need not be killed. Results of analyses
for murrelets support earlier evidence that North American and Asiatic subspecies
represent reproductively isolated species, and that genetic differences exist
among murrelets from different sites within North America.
PMID- 9394464
TI - Genetic structure of an aphid studied using microsatellites: cyclic
parthenogenesis, differentiated lineages and host specialization.
AB - In a previous study, samples of the grain aphid Sitobion avenae (F.) were
collected from wheat and adjacent cocksfoot hosts in a population thought to be
primarily parthenogenetic, and DNA from individual aphids was analysed with a
multilocus technique. Here we have applied single-locus microsatellites and a
mitochondrial DNA marker to a subset of the same DNA extracts, and have made
several additional inferences about important genetic and population processes in
S. avenae. Microsatellite analysis indicated very high levels of genic and
genotypic variation. S. avenae fell into three genotypic groups inferred to be
almost noninterbreeding, while analysis of linkage and Hardy-Weinberg equilibria
suggested high levels of sexual recombination within each genotypic group. Host
specialization was evident: one lineage was found only on wheat, and one (bearing
many alleles inferred to be introgressed from the blackberry-grass aphid S.
fragariae (Walker)) was found only on cocksfoot. The third group of interrelated
genotypes was found commonly on both hosts. Although most genotypes were found
only once, some were much more numerous in the sample than expected from the
frequency of the alleles they contained. This, and rapid temporal changes in
genotypic composition of samples, indicates strong selective differences between
genotypes and lineages. In the major genotypic group, the commonest genotypes
were significantly more homozygous than were rare ones: thus these data may help
to explain the frequent observation of homozygous excess in aphid allozymes. The
genotype group showing S. avenae-like as well as S. fragariae-like alleles also
carried S. fragariae-like mitochondrial DNA in at least 25/31 cases, indicating
gender-asymmetrical hybridization.
PMID- 9394465
TI - Techniques for application of faecal DNA methods to field studies of Ursids.
AB - We describe methods for the preservation, extraction and amplification of DNA
from faeces that facilitate field applications of faecal DNA technology.
Mitochondrial, protein encoding and microsatellite nuclear DNA extracted and
amplified from faeces of Malayan sun bears and North American black bears is
shown to be identical to that extracted and amplified from the same individual's
tissue or blood. A simple drying agent, silica beads, is shown to be a
particularly effective preservative, allowing easy and safe transport of samples
from the field. Methods are also developed to eliminate the risk of faecal DNA
contamination from hair present in faeces.
PMID- 9394466
TI - Developing microsatellites when they are rare: trinucleotide repeat loci in the
northern mockingbird Mimus polyglottos.
AB - The great value of microsatellite loci to population studies spurs their
development. However, finding loci is difficult when microsatellites are uncommon
in the genome. Because trinucleotide-repeat loci are rare in northern
mockingbirds Mimus polyglottos, we sought a new method for developing a suite of
loci. Here we show that a bacterio-phage cloning vector, Lambda Zap Express
(Stratagene, La Jolla, CA, USA) has several features which make it suitable for
this purpose. Using this vector, we made a library of 150,000 size-selected
clones and screened with an AAT10 probe; 97 positives were identified. From
these, 12 pairs of PCR primers were developed, nine of which amplify polymorphic
loci. Certain combinations of these primer pairs enable simultaneous
amplification of up to three loci.
PMID- 9394467
TI - Characterization of microsatellite loci for a co-operatively breeding honeyeater.
PMID- 9394468
TI - Learning in the development of infant locomotion.
AB - Infants master crawling and walking in an environment filled with varied and
unfamiliar surfaces. At the same time, infants' bodies and skills continually
change. The changing demands of everyday locomotion require infants to adapt
locomotion to the properties of the terrain and to their own physical abilities.
This Monograph examines how infants acquire adaptive locomotion in a novel task-
going up and down slopes. Infants were tested longitudinally from their first
week of crawling until several weeks after they began walking. Everyday locomotor
experience played a central role in adaptive responding. Over weeks of crawling,
infants' judgments became increasingly accurate, and exploration became
increasingly efficient. There was no transfer over the transition from crawling
to walking. Instead, infants learned, all over again, how to cope with slopes
from an upright position. Findings indicate that learning generalized from
everyday experience traveling over flat surfaces at home but that learning was
specific to infants' typical method of locomotion and vantage point. Moreover,
learning was not the result of simple associations between a particular locomotor
response and a particular slope. Rather, infants learned to gauge their abilities
on-line as they encountered each hill at the start of the trial. Change in
locomotor responses and exploratory movements revealed a process of
differentiation and selection spurred by changes in infants' everyday experience,
body dimensions, and locomotor proficiency on flat ground.
PMID- 9394470
TI - Towards a chemical etiology of nucleic acid structure.
AB - In the sequel of some general remarks on a chemical etiology of nucleic-acid
structure, the paper presents a reproduction of the sequence of slides which were
shown in the author's lecture 'Pyranosyl-RNA' at the 8. ISSOL Conference in
Orleans. Each slide figure is accompanied by a short explanatory comment.
PMID- 9394469
TI - 30 years later--a new approach to Sol Spiegelman's and Leslie Orgel's in vitro
evolutionary studies. Dedicated to Leslie Orgel on the occasion of his 70th
birthday.
AB - The conditions necessary for evolution are amplification, mutagenesis and
selection. Here we describe the evolutionary response of an in vitro replicating
system to the selection pressure for fast growth and show what happens to the
amplified molecules within this replication system. Our emphasis is on
methodology, on the monitoring and the automation of experiments in molecular
evolution. In order to perform in vitro studies on the evolution of RNA
molecules, a modified self-sustained sequence replication (3SR) method was used.
In the first step of the 3SR reaction, the RNA template is reversely transcribed
by HIV-1 reverse transcriptase, followed by a second strand synthesis and the
transcription of the resulting dsDNA by T7 RNA polymerase. The selection pressure
(fast growth) was achieved by applying the principle of serial transfer pioneered
in the laboratories of Sol Spiegelman and Leslie Orgel. At the end of the
exponential growth phase of the 3SR reaction, an aliquot of the reaction mixture
is transferred into a new sample containing only buffer, nucleotides and enzymes
while RNA template molecules are provided by the transfer. The conditions in the
exponential growth phase allow the RNA molecules to be amplified in a constant
environment; all enzymes (HIV-1 reverse transcriptase and T7 RNA polymerase) and
nucleotides are present in large excess. Therefore, transferring reproducibly
within the exponential growth phase is equivalent to selecting for fast growth;
those molecules which can replicate faster will displace others after several
transfers. The experiments were performed using a serial transfer apparatus (STA)
which allows the nucleic acid concentration to be monitored on-line by measuring
the laser-induced fluorescence caused by intercalation of thiazole orange
monomers into the RNA/DNA amplification products. The serial transfer experiments
were carried out with an RNA template (220b RNA) that represents a 220-base
segment of the HIV-1 genome and comprises the in vivo primer binding site (PBS)
for the HIV-1 reverse transcriptase. It could be shown that after only two serial
transfers two RNA species (EP1 and EP2) emerged that were much shorter. EP1 (48b)
and EP2 (54b) were formed by deletion mutations within the original 220b RNA
template in the very beginning of the serial transfer experiment; due to their
higher replication rate (calculated from the growth curves derived on-line) these
two deletion mutants displaced the original 220b RNA template in the course of
the following thirty transfers. We assume that these two RNA species evolved
independently of each other. Their formation was probably induced by a strand
transfer reaction of HIV-1 reverse transcriptase. Sequence analyses of these two
evolution products seem to confirm such a presented pathway. 30 years after
Spiegelman's experiment, the study described here is another answer to the
question he posed: 'How do molecules evolve if the only demand is the biblical
injunction: multiply?'. The answer, derived from a modified 3SR amplification
system (mimicking a part of the HIV-1 replication cycle in vitro), is the same as
thirty years ago: The RNA molecules adapt to the new conditions by throwing away
any ballast not needed for fast replication. Clearly, this is only one aspect of
molecular evolution; however, it shows that we should be careful in designating
unidentified genetic material as 'junk DNA'.
PMID- 9394471
TI - Four-stranded DNA formed by isoguanine quartets: complex stoichiometry, thermal
stability and resistance against exonucleases.
AB - Single stranded DNA-fragments containing short runs of isoguanine such as
d(T4iG4T4) (5) or d(iG4T4) (6) form quartet structures by self-assembly of the
isoguanine residues. The stoichiometry of the complexes is deduced from mixed
aggregates formed between d(T4iG4T4) and d(iG4T4). The iGd-tetrads are more
stable with regard to their thermal denaturation and to their resistance against
enzymatic phosphodiester hydrolysis than those formed by dG.
PMID- 9394472
TI - The evolutionary design of error-rates, and the fast fixation enigma.
AB - Genetic and non-genetic error-rates are analyzed in parallel for a lower and a
higher organism (E. coli and man, respectively). From the comparison of mutation
with fixation rates, contrasting proposals are made, concerning the arrangement
of error-rates in the two organisms. In E. coli, reproduction is very
conservative, but genetic variability is high within populations. Most mutations
are discarded by selection, yet single mutational variants of a gene have, on
average, little impact on fitness. In man, the mutation rate per generation is
high, the variability generated in the population is comparatively low, and most
mutations are fixed by drift rather than selection. The variants of a gene are in
general more deleterious than in E. coli. There is a discrepancy in the published
mutation rates: the rate of mutation fixations in human populations is twice or
four times higher than the individual rate of mutation production, a feature
which is not consistent with current population genetics models. Two, not
mutually exclusive, hypotheses may explain this 'fast fixation enigma': (i)
Mutation rates have substantially decreased in recent human evolution and (ii) A
substantial fraction of the fixed mutations were generated in a process-such as
gene conversion-that violates the principle of independence of mutation events.
PMID- 9394473
TI - Melatonin: pathway from obscure molecule to international fame.
PMID- 9394474
TI - Why I changed my mind about water fluoridation.
PMID- 9394475
TI - On the causation of edema: a lymphologic perspective.
PMID- 9394476
TI - Emerging pathogens: threat and opportunity.
PMID- 9394477
TI - Rene J. Dubos and Fred L. Soper: their contrasting views on vector and disease
eradication.
PMID- 9394478
TI - Levels of heavy metals in seals of Lake Ladoga and the White Sea.
AB - Between 1990 and 1993 samples of hair, liver, kidney and muscle were collected
from 28 ringed seals from Lake Ladoga, Phoca hispida ladogensis, 20 ringed seals,
Phoca hispida hispida, and three bearded seals, Erignathus barbatus, from the
White Sea for heavy-metal residue analyses in tissues. The concentration of Hg,
Cd, Pb, Cu, Ni and Zn were determined by atomic absorption spectrometry (AAS).
The samples of hair and liver contained the highest mean levels of the elements
analysed and the muscle contained the lowest mean heavy-metal concentrations. Age
and sex differences in the accumulation of pollutants were found. Tissues of
Ladoga ringed seal were to a greater extent contaminated with the heavy metals
studied than the tissues of the White Sea pinnipeds.
PMID- 9394479
TI - Angular and fibrous particles in lung are markers of job categories.
AB - INTRODUCTION: The lung concentration of angular and fibrous particles has been
measured when cases are stratified into their job categories; 21 miners (metallic
mines such as gold, zinc and copper), 18 iron foundrymen, 22 non-iron foundrymen,
four welders, three sand-blast workers, four construction workers, three
technicians and professionals, seven workers in other trades excluding welding.
Twelve asbestos miners representing a positive exposure to asbestos and 20 people
representing a background population were added to the previous groups. MATERIAL
AND METHODS: Particles, both angular and fibrous, were extracted from lung
parenchyma by a bleach digestion method, mounted on copper microscopic grids by a
carbon replica technique and analyzed by transmission electron microscopy (TEM)
and energy dispersive spectroscopy (EDS). Quartz concentration was also
determined by X-ray diffraction (XRD) on a silver membrane filter after the
extraction from the lung parenchyma. RESULTS: (1) The highest concentrations of
quartz were found in mines (metallic mines), iron foundrymen and sand-blast
workers. Notable amounts quartz were found in welders and professionals. (2) The
highest concentrations of short fibres were found in non-iron foundrymen,
asbestos miners and construction workers. (3) The highest concentrations of long
fibres were found in non-iron foundry men and asbestos miners. (4) The highest
concentrations of ferruginous bodies were found in non-iron foundrymen and
asbestos miners. (5) The non-iron foundrymen were exposed to ceramic fibres and
asbestos fibres. CONCLUSION: The results of the study may not be representative
of the broad spectrum of workers in the industrial activities in which they have
been involved. However, the detailed composition of the retained particles of our
workers is explained both qualitatively and quantitatively by their work
histories. Finally, the broad range of particle types identified in the lungs of
these workers illustrate the complexity or trying to determine disease origins in
these occupational settings.
PMID- 9394480
TI - A model of the distribution and retention of tungsten in the human body.
AB - Expanding industrial and military uses of tungsten could result in substantially
increased levels of this metal in the environment in the next few years. Although
occupational experiences and available toxicological studies on laboratory
animals suggest that tungsten may have a relatively low order of toxicity, the
data are weak and inconclusive. There is a need not only for more systematic
studies of the behavior and effects of tungsten in different animal species but
also for a reliable, biologically realistic biokinetic model for tungsten in man
that can be used to relate concentrations of this metal in environmental media to
concentrations in tissues of exposed persons and translate results of
experimental studies into terms of environmental exposures. This paper is
intended as a first step toward development of such a biokinetic model.
Information related to the biokinetics of tungsten in mammalian species is
examined, a biologically meaningful compartmental model structure is proposed,
provisional transfer rates between compartments are selected, areas are
identified where additional biokinetic data on tungsten are most needed and
suggestions are made for further research into the biokinetics of tungsten.
PMID- 9394481
TI - Modeling methane emissions from cattle in Mexico.
AB - Modeling methane emissions from cattle requires data on herd size, herd
distribution by weight and use, and distribution by climate. In this article, it
is shown how empirical and semi-empirical models were obtained for these data in
Mexico. Some shortfalls in the Tier 2 approach of the 1994 IPCC's methodology for
emissions from enteric fermentation are discussed and an intermediate procedure
is proposed. These methods could also be applied in other countries.
PMID- 9394482
TI - Environmental pollution and child health in the Aral Sea region in Kazakhstan.
AB - The deterioration of human health with increasing infant mortality rate,
declining life expectancy at birth and increasing prevalence of serious
infectious diseases in Russia and other former Soviet Republics is thought to be
due to a combination of several factors such as inadequate nutrition, poor
sanitation, collapse of the health care system and pollution from Soviet
agriculture and industries. In the Aral Sea region in Kazakhstan, the
environmental problems are of near catastrophic proportions. As a result of the
implementation of a massive irrigation scheme to support the cotton fields in the
former desert land, the water flow to the Aral Sea was reduced to less than half.
Industrial pollutants such as PCB-compounds and heavy metals, but also the use of
large quantities of pesticides to control parasites and weeds have accumulated
not only in water, but also in soil and have been deposited over large areas by
atmospheric transport to enter the food chain leading to humans. In a study of 15
children and of an additional 12 children referred from the region of the Aral
Sea to the National Children's Rehabilitation Center in Almaty with symptoms and
signs of 'ecological disease', we have found that the concentration of PCB
compounds in the blood lipids is elevated in relation to healthy Swedish
children. In addition, the blood lipid concentration of the beta-isomer of the
hexachlorocyclohexanes was extremely high and of DDT-compounds was elevated up to
20 times. The concentrations of lead in red blood cells was moderately elevated
and that of cadmium slightly elevated compared to the findings in Stockholm
children. To study the role of these pollutants in the diseases found in children
from the Aral Sea region accurate epidemiological studies have to be performed.
PMID- 9394483
TI - Response of vehicular lead to the presence of street dust in the atmospheric
environment of major roads.
AB - Size fractionated particulate samples were collected from the roadside atmosphere
of three major roads within the Brisbane Metropolitan area, using a high volume
sampler fitted with an Anderson impactor. Street dusts were also sampled at these
sites. Deposition samples were collected simultaneously with those of atmospheric
particulates from periods with and without rainfall. All types of samples were
quantitatively analysed for lead and various anions and cations. The pH and
electrical conductivity for street dusts and deposition samples together with
total solids content of deposition samples were also determined. Results showed
that at sites where the process of street dust resuspension was at a minimum, the
bromide-to-lead ratios were comparable to the reported ratio in uncombusted
petrol. However, the relatively higher bromide-to-lead ratios observed at sites
with active street dust resuspension indicate the existence of a process by which
fine lead particulates are removed from the atmosphere by resuspended coarse dust
particles.
PMID- 9394485
TI - Disposal of chemical weapons in the Baltic Sea.
AB - Large quantities of chemical warfare agents were dumped in the Baltic Sea after
World War II (WWII). This included 32,000 t of chemical munitions containing
approximately 11,000 t of chemical warfare agents which were dumped into the
Bornholm Basin and 2000 t of chemical munitions containing approximately 1000 t
in the Gotland Basin. Because this material was contained in wooden crates, it
was distributed throughout the Baltic. The long-term environmental impact of
these agents is unknown.
PMID- 9394484
TI - Lead and fluoride content in human bone and hair in the Gdansk region.
AB - The post-mortem lead and fluoride content in the rib bone and hair of 59 persons
from the Gdansk region was determined. Fluoride was estimated potentiometrically
using a fluoride-specific electrode. Lead was determined by atomic absorption
spectrometry. The mean lead concentration in bone was 3.0 micrograms/g and 5.2
micrograms/g in hair. The mean fluoride concentrations were 625.7 micrograms/g
and 1.4 micrograms/g in bone and hair, respectively. A positive correlation
between the lead content in bone and hair was found in this study (r = 0.308, P <
0.05), no such correlation was observed between the fluoride content in bone and
hair. A positive correlation between the fluoride and lead contents in bones and
the age of the investigated persons was found. The results obtained correspond
well with the comparably moderate exposure to lead and fluoride in the Gdansk
region.
PMID- 9394486
TI - Neurotransmitter transporters: new insights into structure, function and
pharmacology.
AB - Neurotransmitter transporters on neurons and glial cells catalyze the uptake of
neurotransmitter, and may serve to limit the activation of receptors during
synaptic signaling. Over the past few years significant progress has been made
toward a molecular understanding of neurotransmitter transporters in the CNS. The
plasma membrane neurotransmitter carriers are comprised of two structurally- and
mechanistically-distinct gene families, the Na+ and Cl(-)-dependent transporters
that include the carriers for most of the classical CNS neurotransmitters and
several additional carriers for amino acids and other substrates outside the
nervous system. A second structurally distinct family of Na(+)-dependent carriers
encompasses the excitatory amino acid transporters. For both carrier families the
transport of substrate is coupled to the cotransport of sodium ions down a
concentration gradient. Electrophysiological studies of neurotransmitter
transporters indicate that many of the carriers are electrogenic and may operate
in some ways similar to ion channels. In addition, emerging data indicate that
these carriers not only function in the uptake of neurotransmitter, but also that
as a consequence of their ability to alter the membrane potential they may have a
broader role in regulating neuronal excitability and signaling mechanisms.
PMID- 9394487
TI - Developmental strategies underlying the elaboration of cortical circuits.
AB - The mammalian cerebral cortex is organized in layers and columns, which are
reflected in the local intrinsic connections and in the projections to and from
the cortex. It is well established that the development of the columnar
architecture is under the influence of neuronal activity, but little is known
about the mechanisms that control the laminar specificity of cortical circuits.
Here we review some recent studies which show that diffusible and membrane
associated molecules provide sufficient information to reconstruct layer-specific
intrinsic and extrinsic cortical circuits under in vitro conditions.
PMID- 9394488
TI - Heterogeneity of median and lateral midbrain radial glia and astrocytes.
AB - In the developing mammalian midbrain, radial glial cells are divided into median
formations and lateral radial systems with differential properties including rate
and timing of cell proliferation, expression of cytoskeletal and calcium-binding
proteins, storage of glycogen and relations to afferent fiber systems. To test
the hypothesis that radial glial cells of median and lateral midbrain sectors
and/or their derivatives are heterogeneous in their relations with local neurons,
an in vitro system has been developed and has also been characterized in terms of
extracellular matrix (ECM) components. Confluent astrocyte cultures, derived from
median (M) or lateral (L) embryonic mouse midbrain sectors, were used as
substrates for culturing dissociated cells from median (m) or lateral (l) sectors
of embryonic midbrains. In spite of the morphological invariance of glial
substrates at confluency, cells that were plated onto these substrates and that
were immunoreactive for neuronal markers (MAP2, polysialylated N-CAM or beta III
tubulin) showed differences in the aggregation of somata and in the length,
caliber and branching of neurites. These differences, which depend mostly on the
sector of origin of astrocytes (L: permissive, M: non-permissive for neuronal
growth), suggest that the substrates may differ in adhesiveness and/or their
carrying of growth-promoting vs. growth-interfering molecules. Indeed, L and M
cultures differ in laminin deposition patterns (L: fibrillar, M: punctate
pattern). Furthermore, sulfated glycosaminoglycans (s-GAGs) isolated from the
pericellular (P), intracellular (I) and extracellular (E) compartments of these
sectoral cultures also showed correlations with the ability to support neurite
growth. The total amount of s-GAGs in M cultures was twice that in L cultures and
was particularly high in the P compartment, with about 3 times as much heparan
sulfate (HS) and about 15 times as much chondroitin sulfate (CS) in this fraction
of M than in the corresponding compartment of L glia. Our results indicate that
cultured astrocytes have heterogeneous properties including different
organization of their extracellular matrix that reflect the roles played by their
parent radial glia in regions favorable to axonal growth or barrier regions of
the developing brain.
PMID- 9394489
TI - Macroglia cells of the macaque monkey retina.
AB - There are two types of macroglia cells in the macaque monkey retina: Muller cells
and astrocytes. Both cell types are in close contact with neuronal structures as
well as with the retinal vasculature and are thus well suited for their many
physiological tasks. Muller cells ubiquitously traverse the whole thickness of
the retina whereas astrocytes are only found in the ganglion cell and nerve fiber
layers of vascularized retinal regions. In the adult, astrocytes are very scarce
in the central 4 mm around the fovea, a region coinciding with peak Muller cell
densities. During development this area is transiently occupied by astrocytes
which then disappear during the first postnatal weeks at least in part through
apoptosis. Possible reasons for this transiency will be discussed.
PMID- 9394490
TI - Regeneration of cat's optic nerve and its functional recovery.
AB - The optic nerve of adult mammals can regenerate when a permissive environment is
provided with a peripheral nerve (PN) graft. Using this method of PN
transplantation, we have studied regeneration of the optic nerve in adult cats.
Number of retinal ganglion cells (RGCs) which regenerated their axons through the
PN graft corresponds to 3-4% of the total RGC population. The RGCs with
regenerated axons distributed widely from central to peripheral retinas. Of the
known cell types of cat's RGCs, alpha, beta, gamma and other cells, alpha cells
revealed the greatest capacity to regenerate their axons. Dendritic field
diameters of most RGCs with regenerated axons were preserved. These regenerated
axons were, however, mostly unmyelinated when surveyed by electron microscopy at
two months after the transplantation surgery. The regenerated axons revealed
normal physiological properties in response to visual stimuli and were
classifiable into Y, X or W cells. In accordance with morphological data, Y cells
(morphological alpha cells) were more frequently sampled than in normal retinas,
whereas the occurrences of X cells (morphological beta cells) and other cells
were unchanged or decreased. These results suggest that RGCs retain their
physiological function during axonal regeneration, and RGCs with large soma and
large dendritic field (Y or alpha cells) have the greatest capacity to regenerate
their axons.
PMID- 9394491
TI - Natriuretic peptides in the rat olfactory system.
AB - The olfactory system plays an important role in the mobilization of animal
behaviour, along with the sense of taste. These functions are mediated by a
complex olfactory structure composed of peripheral (olfactory epithelium) and
central (olfactory bulb) components. Several neuropeptides are synthesized in the
olfactory system and are believed to be involved in olfactive processing.
Recently, another bioactive substance, atrial natriuretic peptide (ANP), has been
demonstrated in the olfactory system. ANP is a potent diuretic, natriuretic and
vasorelaxant hormone which, originally, was isolated from mammalian atria, but
its gene is expressed in many loci. ANP is only one member of the natriuretic
peptide (NP) family, which includes two other peptides, BNP (brain natriuretic
peptide) and CNP (C-type natriuretic peptide) derived from different genes. All
three peptides show many common features. A high concentration of ANP
immunoreactive varicose fibers has been detected in the rat olfactory nerve layer
and glomerular layer of the olfactory bulb (OB). An important group of perikarya
and thin varicose fibers has been observed in the olfactory tubercle. We have
demonstrated the presence of both ANP precursor and ANP gene transcript in the
rat olfactory bulb. In addition to synthesizing ANP, the OB contains ANP
transducing receptors coupled to guanylyl-cyclase system. The immunoreactive ANP
has also been detected in the rat olfactory mucosa (OM), where ANP has been
localized in secretory cells of Bowman's gland and in the cells of the epithelial
layer. The relatively low concentration of ANP in OM (2.5 ng/mg protein) suggests
a local role for ANP, a hypothesis which is strengthened by the presence of ANP
high affinity receptors in this tissue. Although the role of ANP in the olfactory
system is not yet clear, ANP has been shown to modulate olfactory bulb
mitochondrial membrane activity and to be involved in the olfactive function.
PMID- 9394492
TI - Death in a dish: controls of apoptosis within the developing retinal tissue.
AB - Studies of programmed cell death in the developing retina in vitro are currently
reviewed. The results of inhibiting protein synthesis in retinal explants
indicate two mechanisms of apoptosis. One mechanism depends on the synthesis of
positive modulators ('killer proteins'), while a distinct, latent mechanism
appears to be continuously blocked by negative modulators. Extracellular
modulators of apoptosis include the neurotrophic factors NT-4 and BDNF, while
glutamate may have either a positive or a negative modulatory action on
apoptosis. Several protein kinases selectively modulate apoptosis in distinct
retinal layers. Calcium and nitric oxide were also shown to affect apoptosis in
the developing retinal tissue. The protein c-Jun was found associated with
apoptosis in various circumstances, while p53 seems to be selectively expressed
in some instances of apoptosis. The results indicate that the sensitivity of each
retinal cell to apoptosis is controlled by multiple, interactive, cell type- and
context-specific mechanisms. Apoptosis in the retina depends on a critical
interplay of extracellular signals delivered through neurotrophic factors,
neurotransmitters and neuromodulators, several signal transduction pathways, and
the expression of a variety of genes.
PMID- 9394493
TI - The role of nitric oxide (NO) in control of hypothalamic-pituitary function.
AB - Neurons containing neural nitric oxide synthase (nNOS) are found in various
locations in the hypothalamus and, in particular, in the paraventricular and
supraoptic nuclei with axons which project to the median eminence and extend into
the neural lobe where the highest concentrations of NOS are found in the rat.
Furthermore, nNOS is also located in folliculostellate cells and LH gonadotropes
in the anterior pituitary gland. To define the role of NO in the release of
hypothalamic peptides and pituitary hormones, we injected an inhibitor of NOS, Ng
monomethyl-L-arginine (NMMA) or a releasor of NO, nitroprusside (NP) into the
third ventricle (3V) of conscious castrate rats and determined the effect on the
release of various pituitary hormones. In vitro, we incubated medial basal
hypothalamic (MBH) fragments and studied inhibitors of NO synthase and also
releasors of NO. The results indicate that NOergic neurons play an important role
in stimulating the release of corticotrophin-releasing hormone (CRH), luteinizing
hormone releasing-hormone (LHRH), prolactin-RH's, particularly oxytocin, growth
hormone-RH (GHRH) and somatostatin, but not FSH-releasing factor from the
hypothalamus. NO stimulates the release of LHRH, which induces sexual behavior,
and causes release of LH from the pituitary gland. The intrahypothalamic pathway
by which NO controls LHRH release is as follows: glutamergic neurons synapse with
noradrenergic terminals in the MBH which release nonepinephrine (NE) that acts on
alpha 1 receptors on the NOergic neuron to increase intracellular free Ca++ which
combines with calmodulin to activate NOS. The NOS diffuses to the LHRH terminal
and activates guanylate cyclase (GC), cyclooxygenase and lipoxygenase causing
release of LHRH via release of cyclic GMP, PGE2 and leukotrienes, respectively.
Alcohol and cytokines can block LHRH release by blocking the activation of
cyclooxygenase and lipoxygenase without interfering with the activation of GC.
GABA also blocks the response of the LHRH neurons to NO and recent experiments
indicate that granulocyte macrophage colony-stimulating factor (GMCSF) blocks the
response of the LHRH neuron to NP by activation of GABA neurons since the
blockade can be reversed by the competitive inhibitor of GABAa receptors,
bicuculine.
PMID- 9394494
TI - Patterns of nitric oxide synthase expression in the developing superior
colliculus.
AB - Nitric oxide (NO) is synthesized in cells of both the central and peripheral
nervous system and has been implicated in several forms of synaptic plasticity.
The enzyme that produces NO, nitric oxide synthase (NOS), can be visualized in
the brain by the reduced nicotinamide adenine dinucleotide phosphate diaphorase
histochemistry technique (NADPH-d). We have used NADPH-d activity to detect the
presence of NOS-positive cells in the developing rat superior colliculus. Our
results showed that NOS is present in cells and neuropil in the developing and
adult rat superior colliculus. The first NOS-positive cells appeared at postnatal
day 7 and were weakly stained. The number and intensity of the NOS-positive cells
increased progressively during the following days reaching a maximum at postnatal
day 15. By the end of the third postnatal week, both the number and intensity of
stained cells showed an adult-like pattern. The NOS-positive cells showed a Golgi
like morphology and we have found that all cell types present in the superior
colliculus express the enzyme. The expression of NOS by tectal cells parallels
the functional development of the retino-collicular and cortico-tectal
projections and suggest that nitric oxide synthase-positive cells might be
involved in this process. In this review we highlighted some of the recent
descriptions of the expression of NOS in the mammalian visual system with
emphasis in the superior colliculus and correlate these findings with several
developmental events taking place in this structure.
PMID- 9394495
TI - Effects [correction of Effecs] of the thyroid hormone (T3) on astrocytes.
AB - Thyroid hormones have profound effects on growth and development. In the brain L
3,5,3'-triiodothyronine (T3), the bioactive hormone, is involved with the
harmonious development acting in neuronal and glial cell differentiation. T3 acts
on the cells by interacting with nuclear receptors that can regulate the
expression of several genes. Astrocytes also show receptors to the hormone. We
reported herein data on the effects of T3 on astrocytes. We have verified that T3
has a morphological effect on cultured cortical astrocytes with rearrangement of
GFAP filaments, and induces proliferation in the cultured cerebellar astrocytes
of newborn rats. We discuss here the effects of T3 on astrocytes, considering the
possibility that thyroid hormone prepares the astrocytes to interact with
neurons.
PMID- 9394497
TI - Development of nitric oxide synthase in the avian retina.
AB - Nitric oxide is an important intercellular messenger in the central nervous
system. Our previous work showed the presence of NADPH-diaphorase activity, that
partially corresponded to nitric oxide synthase, in the chick embryo retina. In
the present study, we have demonstrated the presence of nitric oxide synthase in
the chick retina measuring the conversion of 3(H)arginine to 3(H)citrulline. We
found that the enzyme is dependent on the presence of calcium, calmodulin and
NADPH and is inhibited by the arginine analog L-NG-nitroarginine. The enzyme
activity was higher at 8-day-old embryonic retinas, decreased at 13-14 days and
attained minimal levels at 15 days up to the post-hatching period. Glutamate
stimulated nitric oxide synthase activity approximately 4 fold, an effect that
was blocked by the NMDA antagonist MK-801. The results indicate that the
glutamate/nitric oxide system has important functions during retinal development.
PMID- 9394496
TI - Neurotransmitter release in aggregate cultures of chick embryo retina cells.
AB - The study of neurotransmitter release using aggregate cell cultures has been
limited by the fact that cell aggregates are obtained only when cells are
maintained in suspension with rotatory agitation. In this report we describe a
simple and easy method that uses aggregate cell cultures to study the release of
neurotransmitters. The results demonstrate that this relatively simple technique
can be of great value to address the problem of neurotransmitter release and
study the mechanisms of action of natural and synthetic compounds on the
differentiation of functional synapses in the CNS.
PMID- 9394498
TI - Monoamines and acetylcholine in primate cerebral cortex: what anatomy tells us
about function.
AB - In primates, cholinergic and monoaminergic axons that innervate the cerebral
cortex originate almost exclusively from subcortical nuclei in the brainstem and
basal forebrain. These projections are thought to modulate cortical activity
during arousal, attention and memory formation. Physiological and anatomical
evaluations of these ascending projections suggest that they have overlapping but
somewhat distinctive synaptic targets in the cortex. This review compares the
anatomical organization of acetylcholine-, dopamine-, norepinephrine-, and
serotonin-containing axon systems in the monkey and human cerebral cortex.
Analysis of the distributions of axons, receptors, and synapses suggests that
each system is likely to have a differential role in modulating cortical
function.
PMID- 9394499
TI - Release and uptake of glutamate as related to excitotoxicity.
AB - It has been established that neurons exposed to high concentrations of glutamate
or other excitatory amino acids degenerate and die. Neuronal damage appears to be
due to the activation of different types of glutamate receptors, among which the
ionotropic N-methyl-D-aspartate (NMDA) type seems particularly involved, since
its channel is permeable to Ca2+ and an increase in the cytoplasmic concentration
of this cation promotes a chain of events leading to cell death. The mechanism of
such glutamate receptor-mediated neurodegeneration has been defined as
excitotoxicity, and several pieces of evidence suggest that this mechanism might
contribute to the neuronal death associated with certain neurological disorders,
such as ischemia, cerebral trauma and some chronic neurodegenerative diseases. A
relevant question is whether the origin of endogenous extracellular glutamate is
important for the induction of excitotoxicity. An excess of glutamate release, or
a deficiency in its clearance from the synaptic cleft, which depends mainly on
its transport by high affinity carriers, are potential sources for the
accumulation of extracellular glutamate. In the present article some experimental
results from our laboratory, aimed at obtaining information on this question, are
reviewed. These experiments include the use of 4-aminopyridine, a convulsant drug
that enhances the release of glutamate, and of some inhibitors of glutamate
transport, in vivo and in neuronal cell cultures. The results obtained indicate
that an increase of endogenous extracellular glutamate due to these procedures is
not sufficient to induce neuronal death, at least under the experimental
conditions used.
PMID- 9394500
TI - Subcellular localisation of neurotrophins and neurotrophin receptors:
implications for synaptic plasticity.
AB - A growing body of recent evidence indicate that neurotrophins can act as
mediators of neuronal plasticity. In the context of a more detailed,
comprehensive understanding of the function of neurotrophins it is essential to
characterize where neurotrophins are synthesised and stored and from where they
are released. Here we present evidence that the mRNAs for NGF, trkB and BDNF but
not trkA are localised in the dendrites of rat neurons, thus implying that
neurotrophins and their receptors can be synthesised at locations close to their
sites of function, with particular regard to the dendritic synapses. The
significance of this finding and its possible implications for synaptic
plasticity are discussed within the theoretical framework of the synapse-specific
control of individual synapses of a given neuron.
PMID- 9394501
TI - The opossum photoreceptors--a model for evolutionary trends in early mammalian
retina.
AB - The topography and spectral characteristics of mammalian photoreceptors correlate
with both, the present ecological demands and the evolutionary history. The South
American Opossum is a marsupial mammal with unspecialized habitus and crepuscular
lifestyle. A sparse population of cones (max. = 3000/mm2) can be differentiated
into four subtypes by morphological, topographical and immunocytochemical
criteria. In spite of this unusual diversity the cone types can be split into two
functional groups: The population of single cones labeled by antibody OS-2 for
short wavelength sensitive pigments was ubiquitous but at very low densities
(200/mm2). The single cones labeled by antibody (COS-1) against long wavelength
sensitive pigments constitute the dominant population in the area centralis
(2300/mm2). These two single cone types correlate with the pair typically present
in placental mammals. Discrimination of spatial and color contrast may be
provided by this "modern" set. The COS-1 labeled double and single cones bearing
an oil droplet, display a different pattern by being restricted to the inferior
(non-tapetal) half of the retina (max = 800/mm2). This additional set of cones
with oil droplets and long wavelength pigments is a conservative feature of the
opossum retina and other marsupials. As an accessory cone system it is possibly
providing enhanced sensitivity at mesopic conditions. During the early evolution
of nocturnal mammals with its prominent expansion of rod vision these cone types
were conserved but then were lost in placental mammals. Thus the unique features
of mammalian retinas are the result of two evolutionary steps: first a reduction
of cone based vision, followed by a secondary differentiation of photopic vision
and behaviour relying on the remaining set of cones.
PMID- 9394502
TI - Intrinsic projections of Cebus-monkey area 17: cell morphology and axon
terminals.
AB - Metric features of the axon terminals and cell morphology of intrinsic
projections of area 17 were studied in the Cebus apella. Anterograde and
retrograde labeled cell appendages were obtained using saturated pellets and
iontophoretic injections of biocytin in the operculum. Details of the
histological and histochemical procedures have been described elsewhere (Amorim
and Picanco-Diniz, 1996). We distinguished three labeled cell types: pyramidal,
star pyramidal and stellate cells and three distinct morphologies of axon
terminals were found: Ia, Ib and II, located at supragranular layers. Axon
terminals of the group I innervate larger extent of striate cortex through longer
intermediate segments, and acute branching angles compared to group II. Group II
present on average similar characteristics of the smooth neurons axon terminals.
The results taken together with the occurrence of only two types of synapses (I
and II) from Gray's ultrastructural studies, seem to give an additional support
to extend to the Cebus apella the major subdivision of neocortical neuronal
morphology that classified them as smooth and spine neurons.
PMID- 9394503
TI - ANP as a neuroendocrine modulator of body fluid homeostasis.
AB - The role played by the central nervous system (CNS) in the control of body fluid
homeostasis has been demonstrated by several authors. The AV3V plays a key role
in central control of sodium excretion since its cholinergic, adrenergic,
angiotensinergic and osmotic stimulation enhances and its destruction blocks
sodium excretion in rats and goats. Cholinergic stimulation of the AV3V induced
an increase in plasma ANP as well as a marked elevation in content of the peptide
in medial basal hypothalamus, neuro and adenohypophysis. On the other hand, a
decline in plasma ANP after AV3V lesions was accompanied by dramatic declines in
content of ANP in these same structures. Our previous work has also indicated the
essential role of the AV3V region and its ANPergic neurons in the control of ANP
release in response to volume expansion (BVE) and indicated that alpha-adrenergic
and muscarinic receptors are critical in mediating these responses. Lesions of
the AV3V region, or of the median eminence or posterior lobe of pituitary gland
blocked the increase in plasma ANP concentration in response to BVE. That this
effect is related to blockage of the activity of the brain ANPergic neurons is
supported by findings in sheep and in rats that the injection of the antiserum
directed against ANP into the AV3V region at least partially blocked the BVE
induced release of ANP. We and others have also previously shown that denervation
of baroreceptors inhibits ANP release induced by BVE. Activation of the ANP
neurons also cause release of ANP from the anterior and neural lobe of pituitary
gland. ANP neurons may activate oxytocinergic neurons in the supraoptic and
paraventricular, which projects to neural lobe. Oxytocin would circulate to the
atria and may directly activate release of ANP from the atrial myocytes, since
i.v. or i.p. injection of oxytocin increases sodium excretion as well as elevates
plasma ANP. Oxytocin is present in the neural lobe in large quantity, which could
reach the atria myocytes in high concentration and release ANP that circulate to
the kidneys and evokes natriuresis to return circulating blood volume to normal.
PMID- 9394504
TI - Preoptic-periventricular tissue (AV3V): central cholinergic-induced hydromineral
and cardiovascular responses, and salt intake.
AB - The periventricular tissue of the anterior ventral portion of the third ventricle
(AV3V) is an important area for the control of hydromineral balance and of
cardiovascular function. The present work discusses the importance of the
integrity of the AV3V for multiple responses to central cholinergic activation
(water intake, hypertension, natriuresis, salivation) and for the control of salt
intake.
PMID- 9394505
TI - The primate frontal eye field and the generation of saccadic eye movements:
comparison of lesion and acute inactivation/activation studies.
AB - The frontal eye field (FEF) of monkeys has been repeatedly implicated in the
generation of saccadic eye movements by various experimental approaches.
Electrical stimulation of most of the FEF produces saccadic eye movements, many
cells have activities related to saccades, and it has anatomical connections with
many other oculomotor areas. Surprisingly, complete lesions of the FEF have
remarkably little effect on oculomotor behavior. Only when more cognitive aspects
are tested is a deficit clearly detected. In contrast, acute inactivation of the
FEF of monkeys with the GABA agonist muscimol produced much more severe
oculomotor impairment. This difference is probably due to the acute nature of the
muscimol effect, which does not allow time for reorganization of the control of
eye movements before testing begins. In addition, acute activation of the FEF
with the GABA antagonist bicuculline caused the monkey to make irrepressible
saccades of the same dimensions as those electrically elicited at the site. These
experiments further confirm the strong involvement of the FEF in the control of
saccadic eye movements and fixation.
PMID- 9394506
TI - Responses of cells in the superior colliculus during performance of a spatial
attention task in the macaque.
AB - Previous studies have reported that superficial layer cells in the superior
colliculus (SC) give an enhanced response to a stimulus when it is the target for
an eye movement. However, in a peripheral detection paradigm, no such enhancement
was found when a stimulus was attended, in the absence of an eye movement.
Inasmuch as behavioral studies have found attention deficits in the absence of
eye movements following SC lesions or deactivation, we investigated this issue in
a paradigm that is very sensitive to effects of attention. In a matching-to
sample paradigm, a sample stimulus was presented at one location followed by a
brief test stimulus at that (relevant) location and a distracter at another
(irrelevant) location. While maintaining fixation, the monkey indicated whether
the sample and the test stimulus matched, ignoring the distracter. The relevant
and irrelevant locations were switched from trial to trial. SC cells in the
superficial layers tended to give enhanced responses when the attended test
stimulus was inside the receptive field compared to when the (physically
identical) distracter was inside the field. We found that responses to attended
targets in the receptive field were larger than to physically identical, but
ignored, distracter stimuli. These effects were found only in an "automatic"
attentional cueing paradigm, in which a peripheral stimulus explicitly cued the
animal as to the relevant location in the receptive field. No attentional effects
were found in a "central" or "cognitive" cueing paradigm, in which the monkey had
to learn the relevant location in a given block of trials. The larger responses
to attended targets in the automatic cueing paradigm appeared to be due to a
sustained elevation of cells' baseline activity when attention was directed to
the receptive field, as well as a transient enhancement of the target response.
Thus, responses of SC cells appear to be modulated by directed attention, even in
absence of eye movements, probably reflecting the properties of cortical cells
projecting to the SC.
PMID- 9394507
TI - Interaction between facilitatory and inhibitory effects due to voluntary and
automatic covert orienting of attention.
AB - Covert orienting of attention to one spatial location improves the processing of
signals occurring at this location at the expenses of the processing of signals
occurring at other spatial positions. According to the premotor theory of visual
attention, the voluntary orienting of attention to a peripheral position
corresponds to the programming of a saccadic eye movement towards this position.
A similar mechanism has been proposed to explain the inhibitory effects elicited
by a non-informative peripheral cue. This review discusses some neural mechanisms
involved in the facilitatory and inhibitory effects due to covert orienting of
attention.
PMID- 9394508
TI - Malnutrition and brain function: experimental studies using the phenomenon of
cortical spreading depression.
AB - Depending on its intensity and duration, nutritional deficiency can disrupt the
structure and function of the nervous system of humans and other mammals, with
consequences more or less devastating for the whole organism, particularly in the
early postnatal life, when body growth is very rapid and the need for proteins,
calories and other nutrients is greatest. In this review, electrophysiological
data are presented regarding the use of the phenomenon of cortical spreading
depression (CSD) to study effects of malnutrition on the brain. Several
conditions of clinical importance and that are known to alter brain function are
shown also to influence CSD features in experimental animals. Some of these
conditions, (e.g., pharmacological manipulation of neurotransmitter systems,
dietary treatment with Lithium, acute hyperglycemia, hypothyroidism, aging and
environmental stimulation) decrease CSD susceptibility, while other conditions
increase it, as, for example, systemic reduction of extracellular chloride
levels, deprivation of REM-sleep, acute hypoglycemia, treatment with diazepam,
consumption of ethanol and malnutrition. Particular emphasis is laid on the
effect of early environmental enrichment on CSD in normal and malnourished
animals. Our results suggest that such effect is more evident in the malnourished
brain, as compared to the well-nourished one. The data also show that
malnutrition alters the brain responsivity to some CSD-facilitatory or inhibitory
agents. The underlying mechanisms to explain the observed effects are discussed.
PMID- 9394509
TI - Comparative neurobiology of the optokinetic reflex in mammals.
AB - Mammals have developed almost perfect functional adaptations of their eyes,
central visual system and oculomotor system for high resolution and stable
vision. This performance is subserved by stabilizing reflexes like the
optokinetic and the vestibular ocular reflex. Visual information about retinal
image slip is relayed through the nucleus of the optic tract in the pretectum and
the terminal nuclei of the accessory optic system to the visual motor system.
Retinal and more importantly cortical information is integrated in these nuclei
to optimize visual control of gaze stabilization during ego-motion.
PMID- 9394510
TI - What comparative studies of neocortex tell us about the human brain.
AB - There are several ways in which comparative studies of brain organization and
function can be informative in attempts to understand the human brain. Often
investigators study a favorable and sometimes specialized species in order to
reveal features that may reflect general or widespread principles. The example
used here is that the cortical representation of the unique and highly
specialized receptor sheet of the nose of the star-nosed mole provides further
evidence that the receptor sheet instructs the development of cortex. Comparative
studies are also used to reconstruct the evolution of brain systems. As an
example, comparative studies suggest that the visual area MT in the upper
temporal lobe of primates evolved from a visual area along the border of V2. A
third and very important use of comparative studies is to provide another level
of evaluation of theories developed from a particular species. Since the brains
of different mammals are modifications of an ancestral plan, conclusions about
brain organization in any given species should be consistent with those for other
species, within the framework of evolutionary change. When current proposals for
how visual cortex is organized in rats and humans are considered from a
comparative point of view, key concepts are clearly challenged.
PMID- 9394511
TI - Parallel pathways in the retina of Old and New World primates.
AB - Old-world simians are all trichromats, but in most new-world primates there is a
polymorphism; males are dichromats but most females are trichromats. In the old
world simian, luminance and red-green chromatic channels defined by
psychophysical experiments have as a basis parasol ganglion cells of the
magnocellular (MC) pathway and midget ganglion cells of the parvocellular (PC)
pathway respectively. Small bistratified ganglion cells provide a basis for a
blue-yellow chromatic channel, which should probably be considered a separate
entity. In both dichromatic and trichromatic new-world animals, the MC pathway
and the small bistratified, blue-yellow system seem anatomically and
physiologically similar to those in their old-world relatives. The midget
ganglion cells of the parvocellular pathway in trichromats are anatomically and
physiologically similar to the old-world pattern. In dichromatic animals, they
are anatomically similar and physiologically resemble those of trichromatic
animals, except for the lack of chromatic opponency. We conclude that these three
systems may from a basic pattern for the visual pathway of primates. However, the
results from dichromats indicate that the evolution of trichromacy may be found
to be more complex than presently supposed.
PMID- 9394512
TI - Some aspects of the pineal gland function.
AB - Rhythmic production of melatonin by the mammalian pineal gland occurs in response
to noradrenergic stimulation which produces a cascade of biochemical events
within the pinealocyte. Melatonin is involved in a wide range of physiological
processes, including seasonal reproduction and diurnal activity rhythms. It was
recently discovered that melatonin is a very potent hydroxyl radical scavenger,
reinforcing its relationship with the aging process and the immune system.
PMID- 9394513
TI - Joint entropy loci of M and P cells: a hypothesis for parallel processing in the
primate visual system.
AB - The M and P neurons connect the retinal inner plexiform layer to the
magnicellular and parvicellular layers of the lateral geniculate nucleus and to
layer 4 of the primary visual cortex. The M and P pathways transmit visual
signals with different six-dimensional joint entropy for space, spatial
frequency, time and temporal frequency. Beyond V1 layer 4, M and P influences mix
in information processing streams which connect different visual cortical areas.
Some visual cortical cells perform better than it is possible for linear filters,
regarding to simultaneous spatial and spatial frequency localization of their
response. This can be explained by nonlinear combination of M and P input on such
cells.
PMID- 9394514
TI - On the purinergic regulation of hormonal secretion from the anterior pituitary
gland.
AB - Purinergic regulation of hormonal secretion from the anterior pituitary may be
characterized by effects with biphasic secretory response. This response may be
started by activation of different subtypes of membrane prurinergic receptors (A1
and/or A2). A putative autocrine mechanism has been proposed to explain the
action of adenosine on pituitary hormonal secretion. This mechanism may be
dependent on adenosine degradation by the enzyme adenosine deaminase into the
extracellular space. The regulation of AMPc and calcium levels in cytoplasm may
be part of putative intracellular mechanisms involved in purinergic action.
Additionally, hypophysiotrophic effects induced by hypothalamic substances may be
modulated by adenosine. The mechanisms involved in this modulatory effects,
however, remain elusive.
PMID- 9394515
TI - The nucleus of the optic tract of the opossum.
AB - This paper reviews anatomical and electrophysiological data on the nucleus of the
optic tract (NOT) of the opossum, a nucleus in the afferent branch of the
horizontal optokinetic reflex. It is proposed that subcortical routes are
essential for responses from the two eyes: a direct retinal projection from the
contralateral eye and a commissural pathway between the two NOTs for the
ipsolateral eye. In the latter case there's evidence that the commisural axons
have a relay on inhibitory neurones. This circuit accounts for the differences in
response pattern under monocular condition: temporo-nasal motion of the visual
stimulus elicits excitation in the contralateral NOT, resulting in inhibition of
the ipsolateral nucleus, while naso-temporal motion promotes inhibition in the
contralateral nucleus, releasing the ipsolateral nucleus from the commissural
input.
PMID- 9394516
TI - The retinal ganglion cell classes of New World primates.
AB - In the primate retina there are distinct ganglion cell classes, exhibiting
particular morphologies and central projections, each responsible for conveying
particular types of visual information to the brain. The chief retinal inputs to
the cortex arise from specific ganglion cell classes, M-ganglion cells,
responsible for carrying the luminance signal, and P-ganglion cells, that convey
the red-green color opponent signal, as well as high contrast luminance signal.
There are other ganglion cell classes, such as small-field bistratified cells,
exhibiting dendrites that stratify at two different levels in the inner plexiform
layer, which convey the blue-yellow color opponent signal. Most published data
concerning primate retinal ganglion cell anatomy and physiology have been
obtained from Old World species. Studies on New World monkeys have recently
become of interest since they differ from the Old World monkeys with respect to
the color vision inheritance pattern. On reviewing retinal ganglion cell layer
organization in New World monkeys, it seems that there are more similarities than
differences in relation to the Old World monkeys. Diurnal genera of New World
monkeys exhibit a well-developed fovea centralis and ganglion cell density peak,
as well as peripheral density values which are in the range reported for Old
World monkeys and human. Moreover, all the major ganglion cell classes identified
in Old World monkeys are also present in New World primates. Up to now, no
obvious anatomical differences between dichromats and trichromats have been
reported. The only genus that is significantly different from the others is the
Aotus. It exhibits lower ganglion cell density in the central retina, and
apparently lacks the small-field bistratified cells.
PMID- 9394517
TI - Virulence parameters in the characterization of strains of Entamoeba histolytica.
AB - Differences in virulence of strains of Entamoeba histolytica have long been
detected by various experimental assays, both in vivo and in vitro. Discrepancies
in the strains characterization have been arisen when different biological assays
are compared. In order to evaluate different parameters of virulence in the
strains characterization, five strains of E. histolytica, kept under axenic
culture, were characterized in respect to their, capability to induce hamster
liver abscess, erythrophagocytosis rate and cytopathic effect upon VERO cells. It
was found significant correlation between in vitro biological assays, but not
between in vivo and in vitro assays. Good correlation was found between
cytopathic effect and the mean number of uptaken erythrocytes, but not with
percentage of phagocytic amoebae, showing that great variability can be observed
in the same assay, according to the variable chosen. It was not possible to
correlate isoenzyme and restriction fragment pattern with virulence indexes since
all studied strains presented pathogenic patterns. The discordant results
observed in different virulence assays suggests that virulence itself may not the
directly assessed. What is in fact assessed are different biological
characteristics or functions of the parasite more than virulence itself. These
characteristics or functions may be related or not with pathogenic mechanisms
occurring in the development of invasive amoebic disease.
PMID- 9394518
TI - Immune responses induced by a Leishmania (Leishmania) amazonensis recombinant
antigen in mice and lymphocytes from vaccinated subjects.
AB - In the search for Leishmania recombinant antigens that can be used as a vaccine
against American Cutaneous Leishmaniasis, we identified a Leishmania (Leishmania)
amazonensis recombinant protein of 33 kD (Larp33) which is recognized by
antibodies and peripheral blood leukocytes (PBL) from subjects vaccinated with
Leishvacin, Larp33 was expressed in Escherichia coli after cloning of a 2.2 kb
Sau3 digested genomic fragment of L. (L.) amazonensis into the pDS56-6 His
vector. Immunoblotting analysis indicated that Larp33 corresponds to an
approximately 40-kD native protein expressed in promastigotes of L. (L.)
amazonensis and L. (Viannia) braziliensis. Northern blots of total RNA also
demonstrated that the gene coding for this protein is expressed in promastigotes
of the major lineages of Leishmania causing American Cutaneous Leishmaniasis.
Larp33 induced partial protection in susceptible mouse strains (BALB/c and
C57BL/10) against L. (L.) amazonensis after vaccination using Bacille Calmette
Guerin (BCG) as adjuvant. In vitro stimulation of splenocytes from BALB/c
protected mice with Larp33 elicited the secretion of IL-2 and IFN-gamma,
suggesting that a Th1 cell-mediated protective response is associated with the
resistance observed in these mice. As revealed by its immunogenic and antigenic
properties, this novel recombinant antigen is a suitable candidate to compose a
vaccine against cutaneous leishmaniasis.
PMID- 9394519
TI - Detection and identification of dengue virus isolates from Brazil by a simplified
reverse transcription-polymerase chain reaction (RT-PCR) method.
AB - We show here a simplified RT-PCR for identification of dengue virus types 1 and
2. Five dengue virus strains, isolated from Brazilian patients, and yellow fever
vaccine 17DD as a negative control, were used in this study. C6/36 cells were
infected and supernatants were collected after 7 days. The RT-PCR, done in a
single reaction vessel, was carried out following a 1/10 dilution of virus in
distilled water or in a detergent mixture containing Nonidet P40. The 50
microliters assay reaction mixture included 50 pmol of specific primers
amplifying a 482 base pair sequence for dengue type 1 and 210 base pair sequence
for dengue type 2. In other assays, we used dengue virus consensus primers having
maximum sequence similarity to the four serotypes, amplifying a 511 base pair
sequence. The reaction mixture also contained 0.1 mM of the four deoxynucleoside
triphosphates, 7.5 U of reverse transcriptase, 1U of thermostable Taq DNA
polymerase. The mixture was incubated for 5 minutes at 37 degrees C for reverse
transcription followed by 30 cycles of two-step PCR amplification (92 degrees C
for 60 seconds, 53 degrees C for 60 seconds) with slow temperature increment. The
PCR products were subjected to 1.7% agarose gel electrophoresis and visualized by
UV light after staining with ethidium bromide solution. Low virus titer around
10(3, 6) TCID50/ml was detected by RT-PCR for dengue type 1. Specific DNA
amplification was observed with all the Brazilian dengue strains by using dengue
virus consensus primers. As compared to other RT-PCRs, this assay is less
laborious, done in a shorter time, and has reduced risk of contamination.
PMID- 9394520
TI - In vivo and in vitro Plasmodium falciparum resistance to chloroquine, amodiaquine
and quinine in the Brazilian Amazon.
AB - In order to study the chemoresistance of Plasmodium falciparum to commonly used
antimalarial drugs in Brazil the authors have studied ten patients with
falciparum malaria, acquired in the Brazilian Amazon region. Patients were
submitted to in vivo study of drug sensitivity, after chemotherapy with either 4
aminoquinolines (chloroquine or amodiaquine) or quinine. Adequate drug absorption
was confirmed by standard urine excretion tests for antimalarials. Eight patients
could be followed up to 28 days. Among these in vivo resistance (R I and R II
responses) was seen in all patients who received 4-amino-quinolines. One patient
treated with quinine exhibited a R III response. Peripheral blood samples of the
same patients were submitted to in vitro microtests for sensitivity to
antimalarials. Out of nine successful tests, resistance to chloroquine and
amodiaquine was found in 100% and resistance to quinine in 11.11% of isolates.
Probit analysis of log dose-response was used to determine effective
concentrations EC50, EC90 and EC99 to the studied drugs. Good correlation between
in vivo and in vitro results was seen in six patients. The results emphasize high
levels of P. falciparum resistance to 4-aminoquinolines and suggest an increase
in resistance to quinine in the Brazilian Amazon region, reinforcing the need for
continuous monitoring of drug sensitivity to adequate chemotherapy according to
the most efficacious drug regimens.
PMID- 9394521
TI - Water-contact patterns and risk factors for Schistosoma mansoni infection in a
rural village of northeast Brazil.
AB - Schistosomiasis mansoni in the Serrano village, municipality of Cururupu, state
of Maranhao, Brazil, is a widely spread disease. The PECE (Program for the
Control of Schistosomiasis), undertaken since 1979 has reduced the prevalence of
S. mansoni infection and the hepatosplenic form of the disease. Nevertheless
piped water is available in 84% of the households, prevalence remains above 20%.
In order to identify other risk factors responsible for the persistence of high
prevalence levels, a cross-sectional survey was carried out in a systematic
sample of 294 people of varying ages. Socioeconomic, environmental and
demographic variables, and water contact patterns were investigated. Fecal
samples were collected and analyzed by the Kato-Katz technique. Prevalence of S.
mansoni infection was 24.1%, higher among males (35.5%) and between 10-19 years
of age (36.6%). The risk factors identified in the univariable analysis were
water contacts for vegetable extraction (Risk Ratio--RR = 2.92), crossing streams
(RR = 2.55), bathing (RR = 2.35), fishing (RR = 2.19), hunting (RR = 2.17),
cattle breeding (RR = 2.04), manioc culture (RR = 1.90) and leisure (RR = 1.56).
After controlling for confounding variables by proportional hazards model the
risks remained higher for males, vegetable extraction, bathing in rivers and
water contact in rivers or in periodically inundated parts of riverine woodland
(swamplands).
PMID- 9394522
TI - Evaluation of the schistosomicidal efficacy of liposome-entrapped oxamniquine.
AB - Oxamniquine (OXA) was successfully encapsulated in small unilamellar vesicles
using a pH gradient method. This procedure led to a high drug encapsulation
efficiency (> 85%) at a drug to lipid molar ratio of 1/10. Moreover, these
liposomes were found to retain encapsulated OXA efficiently under dialysis
conditions at 37 degrees C. Liposome-entrapped OXA (LOXA), OXA, and empty
liposomes were tested against Schistosoma mansoni in a murine model. LOXA
produced a significant reduction of the worm burden compared to the other
preparations, when inoculated by subcutaneous route (s.c.) with 10 mg OXA/kg
animal one day before the infection, and 3, 7, and 14 days after. However, LOXA
was not effective when given 7 days before, or 35 days after infections. OXA, in
the free form, was effective in relation to the untreated group, only when
administered 3 days after the infection. Maximum effect of LOXA, with 97%
reduction of the parasite number, was observed when the preparation was given
s.c. one day before the infection. On the other hand, LOXA inoculated
intraperitoneally one day before the infection didn't show any reduction of the
parasite count. It can be concluded that LOXA is more effective than OXA for the
treatment of experimental schistosomiasis, particularly when administered
subcutaneously at a time close to the infection.
PMID- 9394523
TI - Resistance to oxamniquine of a Schistosoma mansoni strain isolated from patient
submitted to repeated treatments.
AB - A strain of Schistosoma mansoni (R1) was isolated from patient previously
submitted to four treatments with oxamniquine, and to another one with
praziquantel. The results obtained with chemotherapeutic test, by using
oxamniquine in mice infected with the strains R1 and LE (standard), showed an
evident resistance to the drug in worms of the strain R1. Thus, at the dose of
250 mg/kg oxamniquine, all mice (17) infected with the LE strain did not show
surviving worms, whereas 12 out of 17 mice infected with the R1 strain presented
surviving worms. At the dose of 200 mg/kg, the LE strain showed recovery rates of
1.06% and 20.58%, whereas the R1 strain presented 18.57% and 61.14%, for male and
female worms, respectively. At the dose of 100 mg/kg, the recovery of male worms
was 2.6% for the LE strain, and 29.9% for the R1 strain. At the same dose, the
recovery of females did not show statistically significant differences between
the two strains (LE = 76.38%, R1 = 79.12%). Praziquantel showed similar
antischistosomal activity against both studied strains, when administered at the
dose of 500 mg/kg.
PMID- 9394524
TI - Human infection with Trypanosoma cruzi in Nasca, Peru: a seroepidemiological
survey.
AB - We estimated the proportion of seropositivity for infection with Trypanosoma
cruzi (Chagas' disease) in a sample of the rural population of the Province of
Nasca, Department of Ica, southwestern Peru. Although Triatoma infestans, the
only vector species identified in the Department of Ica, is often found in
domestic environments, data of the extent of human infection with T. cruzi are
scant. This study comprised 446 houses, known to be infested with triatomines,
distributed in 19 rural localities. While visiting those houses we collected
filter paper bloodspots from 864 occupants (of both sexes, aged one year or
over). By means of the indirect fluorescent antibody test (IFAT), we detected
anti-T. cruzi IgG antibodies in samples from 178 individuals (20.6%).
Seropositivity was significantly more frequent in females (23.8%) than in males
(17.5%). Among the 410 individuals in the 1- to 10-year-old age group (47.5% of
the population sample), 85 (20.7%) were found seropositive, which is indicative
of an early acquisition of the infection. Within this group no significant
differences in seropositivity were associated with sex.
PMID- 9394525
TI - Epidemiological and clinical aspects of snakebite in Belo Horizonte, southeast
Brazil.
AB - Epidemiologic and clinical aspects of 310 hospitalized snakebite patients and 310
matched controls were described, over a seven years period, from an emergency
hospital in Belo Horizontal, Southeast Brazil. The diagnosis was based upon
clinical picture or actual snake identification. Fifty six percent of victims
were bitten by the snakes of genus Bothrops, 32.0% by Crotalus, 1.0% by Lachesis
and 10.0% undetermined. During the study period, stable number of cases and
marked seasonal variation were noted. In comparing cases of snakebite and
controls, those from a rural area or who were involved in agricultural labor
activity were identified as a high risk group, with an odds ratio (OR) of 14.7
and 6.7, respectively, in favor of being bitten. Upon treatment, snakebite
patients were 13.5 times more likely to have had early anaphylactic reactions
than their controls, with a higher association in the age group > or = 20 years
(OR = 30.3). Increased risks were also detected for pyrexia (OR = 11.7), with a
marked association in the group under 19 years old (OR = 16.6). Severe cases of
snakebite are an important treatable cause of morbidity in Brazil but therapy may
be potentially life threatening. The higher case-fatality ratio encountered,
compared to national statistics may be due the representativeness of the more
severe cases who sought hospitalization. Preventing snakebite and early referral
of those who are bitten is proposed.
PMID- 9394526
TI - Effect of beta-propiolactone treatment on the complement activation mediated by
equine antisera.
AB - Reduction of complement activation through an alteration of the Fc fragment of
immunoglobulins by beta-propiolactone treatment was carried out in equine
antisera raised against rabies virus, Bothrops venoms and diphtherial toxin.
Results were evaluated by means of an anaphylactic test performed on guinea-pigs,
and compared to the ones obtained with the same sera purified by saline
precipitation (ammonium sulfate), followed or not by enzymatic digestion with
pepsin. Protein purity levels for antibothropic serum were 184.5 mg/g and 488.5
mg/g in beta-propiolactone treated and pepsin-digested sera, respectively. The
recovery of specific activity was 100% and 62.5% when using antibothropic serum
treated by beta-propiolactone and pepsin digestion, respectively. The
antidiphtherial and anti-rabies sera treated with beta-propiolactone and pepsin
presented protein purity levels of 5,698 and 7,179 Lf/g, 16,233 and 6,784 IU/g,
respectively. The recovery of specific activity for these antisera were 88.8%,
77.7%, 100% and 36.5%, respectively. beta-propiolactone treatment induced a
reduction in complement activation, tested "in vivo", without significant loss of
biological activity. This treatment can be used in the preparation of
heterologous immunoglobulins for human use.
PMID- 9394527
TI - Bertiellosis in man: a review of cases.
AB - The presence of Bertiella mucronata and Bertiella studeri (Cestoda:
Anoplocephalidae) in humans is reviewed, and international infection rates and a
bibliography included. Taxonomic, biological, epidemiological, pathological,
diagnostic, control, prevention and therapeutic aspects of the zoonosis are
analyzed, and the increase in zoonotic potentiality of the parasitosis is
discussed.
PMID- 9394528
TI - A focus of favus due to Trichophyton schoenleinii in Rio Grande do Sul, Brasil.
PMID- 9394529
TI - Description of the egg of Anopheles (Anopheles) intermedius (Peryassu, 1908)
(Diptera: Culicidae) by scanning electron microscopy.
AB - The egg of Anopheles (Anopheles) intermedius (Peryassu, 1908) is described and
illustrated with scanning electron micrographs. Literature data on An. (Ano.)
maculipes (Theobald, 1903) is provided.
PMID- 9394530
TI - Immunostimulation as adjuvant for the chemotherapy of experimental
schistosomiasis.
AB - Immunosuppressed animals respond poorly to schistosomal chemotherapy and a proper
response can be restored by the administration of immune serum. Present study
attempts to search whether immunological stimulation would increase drug
effectiveness. Swiss mice infected with 50 S. mansoni cercariae were later
treated with complete Freund's adjuvant. Treatment with oxamniquine was made with
100 mg/kg.b.w., 25 mg/kg.b.w. and 50 mg/kg.b.w., the last two doses representing
a fourth and a half of the recommended curative dose. Appropriate controls for
the drug, the adjuvant and the infection were also studied. The serum-level of
anti-S. mansoni antibodies (ELISA) and recovery of worms by perfusion of the
portal vein system were the evaluated parameters. Statistical analysis of the
results failed to reveal significant differences in worm recovery between
adjuvant-stimulated animals treated with oxamniquine and any of the treated
controls receiving the same amount of the drug. Although total lack of immunity
interferes with curative treatment the usual immune response seems to be
sufficient to allow for curative drug action in schistosomiasis and thus
apparently does not need to be artificially stimulated.
PMID- 9394531
TI - Immunogenicity of low-dose intramuscular and intradermal vaccination with
recombinant hepatitis B vaccine.
AB - The study is a randomized trial using recombinant DNA vaccine to determine
whether an intramuscular 10 micrograms dose or intradermal 2 micrograms induces
satisfactory anti-HBs levels compared to the standard dose of intramuscular 20
micrograms. Participants were 359 healthy medical and nurse students randomly
allocated to one of the three groups: Group I-IM 20 micrograms; Group II-IM 10
micrograms; Group III-ID 2 micrograms at 0, 1 and 6 months. Anti-HBs titres were
measured after complete vaccine schedule by ELISA/Pasteur. Baseline variables
were similar among groups and side effects were mild after any dose. Vaccines in
the IM-10 micrograms group had seroconversion rate and geometric mean titre (GMT
2344 IU L-1), not significant different from the IM-20 micrograms group (GMT 4570
IU L-1). On the contrary, 21.4% of the ID-2 micrograms recipients mount antibody
concentration below 10 IU L-1 and GMT of 91 IU L-1, a statistically significant
difference compared with the standard schedule IM-20 micrograms (p < 0.001). A
three dose regimen of half dose IM could be considered an appropriate schedule to
prevent hepatitis B in young health adults which is of relevance to the expansion
of hepatitis B vaccine programme.
PMID- 9394532
TI - Evaluation of a rapid screening assay for bacterial identification (Dot-ELISA) in
fecal samples from children.
AB - With the objective of standardizing a Dot Enzyme-Linked Immunosorbent Assay (Dot
ELISA) to detect antigens of fecal bacterial enteropathogens, 250 children, aged
under 36 months and of both sexes, were studied; of which 162 had acute
gastroenteritis. The efficacy of a rapid screening assay for bacterial
enteropathogens (enteropathogenic Escherichia coli "EPEC", enteroinvasive
Escherichia coli "EIEC", Salmonella spp. and Shigella spp.) was evaluated. The
fecal samples were also submitted to a traditional method of stool culture for
comparison. The concordance index between the two techniques, calculated using
the Kappa (k) index for the above mentioned bacterial strains was 0.8859, 0.9055,
0.7932 and 0.7829 respectively. These values express an almost perfect degree of
concordance for the first two and substantial concordance for the latter two,
thus enabling this technique to be applied in the early diagnosis of diarrhea in
infants. With a view to increasing the sensitivity and specificity of this
immunological test, a study was made of the antigenic preparations obtained from
two types of treatment: 1) deproteinization by heating; 2) precipitation and
concentration of the lipopolysaccharide antigen (LPS) using an ethanol-acetone
solution, which was then heated in the presence of sodium EDTA.
PMID- 9394533
TI - Hemagglutination test for the diagnosis of human neurocysticercosis: development
of a stable reagent using homologous and heterologous antigens.
AB - A hemagglutination (HA) test was standardized using formalin- and tannin-treated
gander red blood cells sensitized with a total salt extract of C. cellulosae (HA
Cc) and an antigenic extract of Cysticercus longicollis (HA-Cl) vesicular fluid.
A total of 61 cerebrospinal fluid (CSF) samples were assayed, 41 from patients
with neurocysticercosis and 20 from a control group which were, respectively,
reactive and non-reactive to ELISA using C. cellulosae. The CSF samples from the
control group did not react and 35 (85.4%) and 34 (82.9%) CSF samples from
patients were reactive to the HA-Cc and HA-Cl tests, respectively. The reagents
ready for use were stable up to 6 months when stored at 4 degrees C in 50%
glycerol. The present results confirm that the reagent using Cysticercus
longicollis stabilized with glycerol can be used as an alternative in the
immunological diagnosis of neurocysticercosis.
PMID- 9394534
TI - Reactivity of anti-gp43 antibodies from Paracoccidioides brasiliensis antiserum
with extracts from cutaneous lesions of Lobo's disease. Preliminary note.
AB - We demonstrated through several immunochemical tests the presence of gp43 from P.
brasiliensis in extracts of cutaneous lesions from Jorge Lobo's disease. This
glicoprotein is one of the immunodominant antigens in this species, and is used
to identify it. The demonstration of gp43 tissues infected by the agent of Jorge
Lobo's disease is an additional evidence for classifying it in the genera
Paracoccidioides, species loboi.
PMID- 9394535
TI - Preliminary report of the use on adults of a recombinant yeast-derived hepatitis
B vaccine manufactured by Instituto Butantan.
AB - Three 10 micrograms of the recombinant hepatitis B vaccine, manufactured by
Instituto Butantan by original technology, were administered in an adult
population, mean age 30 years old, following the 0, 1 and 6 months schedule
immunization. The clinical trial was considered satisfactory in terms of
immunogenicity (anti-HBs titers between 17.5-29500 IU/ l, seroconversion 95.3%)
and reactogenicity (no incapacitating side effects).
PMID- 9394536
TI - Subcutaneous phaeohyphomycosis caused by Phoma cava. Report of a case and review
of the literature.
AB - We report a case of subcutaneous phaeohyphomycosis observed in a male patient
presenting pulmonary sarcoidosis and submitted to corticosteroid treatment. He
presented nodular erythematous-violaceous skin lesions in the dorsum of the right
hand. Histopathological examination of the biopsied lesion revealed dematiaceous
hyphae and yeast-like cells, with a granulomatous tissual reaction. The isolated
fungus was identified as Phoma cava. A review of the literature on fungal
infection caused by different Phoma species, is presented. The patient healed
after therapy with amphotericin B. followed by itraconazole.
PMID- 9394537
TI - Presence of anti-Toxocara antibodies in children selected at Hospital
Universitario, Campo Grande, MS, Brazil.
PMID- 9394539
TI - Chronic chagasic cardiopathy: the product of a turbulent host-parasite
relationship.
AB - The pathogenesis of chronic chagasic cardiopathy is still a debated matter. In
this review, the main theories raised about it since the first description of the
disease in 1909 by Carlos Chagas, are considered. The scarcity of T.cruzi
parasites into the myocardium and the apparent lack of correlation between their
presence and the occurrence of myocardial inflammatory infiltrate, have
originated many theories indicating that chronic Chagas' cardiopathy is an
autoimmune disease. Recently however, papers using immunohistochemical technique
or PCR have demonstrated a strong association between moderate or severe
myocarditis and presence of T.cruzi Ags, indicating a direct participation of the
parasite in the genesis of chronic chagasic myocarditis. Different patterns of
cytokine production seem to have important role in the outcome of the disease.
Participation of the microcirculatory alterations and fibrosis as well as the
relationship with the parasite are also emphasized. Finally, the author suggests
that the indeterminate form of the disease occurs when the host immunological
response against the parasite is more efficient while the chronic cardiopathy
occurs in patients with hyperergic and inefficient immune response.
PMID- 9394538
TI - Possible role of Lutzomyia maranonensis and Lutzomyia robusta (Diptera:
Psychodidae) as vectors of human bartonellosis in three provinces of region nor
Oriental del Maranon, Peru.
PMID- 9394540
TI - Effect of tannin-rich plant (Acacia nilotica) on some nutritional and
bacteriological parameters in goats.
AB - The effects of A. nilotica (tannin-rich plants) on the digestion coefficient of
nutrients and its antibacterial properties were "in-vivo" investigated in this
study. Twenty five male baladi goats aged 3-4 years and weighing 19-21 kg were
randomly classified into five groups (5 per each). Each animal group was fed on
one of the experimental diets containing different levels of A. nilotica leaves
(0%, 5%, 10%, 15% & 20%). Chemical analysis of A. nilotica leaves revealed that
its content of crude protein, crude fiber, ash were 12.1%, 30.5%, 13.2%,
respectively, while the total soluble tannins were 34%. The digestion coefficient
of dry matter (DM), crude protein, crude fiber and nitrogen free-extract (NFE) in
the control group were better than those of the experimental diets. However,
digestion coefficient of most nutrients were significantly decreased (P < 0.01)
with increasing levels of A. nilotica in the goat's diets. Absorbed and retained
nitrogen (g/day) were decreased with increasing levels of A. nilotica. Concerning
nitrogen balance, all animals of the experimental groups showed positive nitrogen
balance. Colony forming units (CFU) were drastically reduced in both faecal und
ruminal juice samples. This reduction was directly proportional to levels of A.
nilotica in the ingested feed. The CFU were reduced in the faecal samples from
5.9 x 10(8)/g (control group) to 2.8 x 10(4) (fifth group) (that received 20%
Acacia nilotica). On the other hand, the CFU/ml of ruminal juice samples were
reduced from 5.8 x 10(6) (control group) to 1.8 x 10(3) (fifth group). On the
other hand, Cl. perfringens count was reduced from 1.0 x 10(4) to 6.3 x 10/g in
the faecal samples while their count was reduced from 6.2 x 10(2) to 4.4 x 10/ml
in case of ruminal samples. The reduction of total bacterial and Cl. perfringens
counts were directly proportional to the levels of A. nilotica in the diets of
goats.
PMID- 9394541
TI - Differentiation of proteinase (minor toxin lambda) in Clostridium perfringens
strains from sheep and goats in Iran.
AB - 17 Clostridium perfringens strains isolated post mortem from sheep and goats in
Iran were examined by biochemical tests and by enzyme immuno assay (EIA). 7 of
the C. perfringens strains belonged to type B, 8 strains were type D, one strain
was type A, one strain was untypable by EIA. The isolated strains were examined
for presence of Minor Toxin Lambda (proteinase) to identify the Iran subtype of
C. perfringens type B. The results are compared to characteristics of Clostridium
perfringens reference strains. The differentiation technique for proteinase
(Minor Toxin Lambda) is discussed.
PMID- 9394542
TI - [Atopic myelitis: a novel clinical entity].
PMID- 9394543
TI - [Studies on the taste perceptive threshold for 4 basic taste qualities at various
sites of lingual surface].
AB - Using filter-paper-disk method for 20 approximately 23 year-old 60 healthy
females, taste perceptive thresholds for 4 basic taste qualities (sweetness,
saltiness, sourness and bitterness) were measured detailedly at various sites of
the lingual surface (lingual apex, lingual center, lingual margin, lingual
radix). Sucrose, sodium chloride, sodium tartarate and quinine hydrochloride as
taste-producing substances were used for the sweetness, saltiness, sourness and
bitterness, respectively. The results revealed the apical site to be most
sensitive to all of the sweetness, saltiness and sourness (and especially to the
saltiness) and to be followed by marginal and radical sites in sensitiveness. The
radical site was revealed to be most sensitive only to the bitterness, and the
central site was remarkably hyposensitive to all of these taste qualities. These
experimental results differ, in many respects, from those results of study which
have been published by Kiesow in 1894 and are already established today (lingual
sensitivity to taste qualities is found separately by site: sweetness, sourness
and bitterness and highly perceptible at apical, marginal and radical sites,
respectively, and saltiness is not very differently perceptible by site),
indicating that further detailed reexamination will be needed to know how taste
perceptive thresholds for 4 basic taste qualities are distributed in the lingual
surface.
PMID- 9394544
TI - [Regional pulmonary function by 133Xe gas and 99mTc-MAA in 11 cases with
lymphangiomyomatosis (LAM)].
AB - The evaluation of the regional distribution of ventilation and perfusion was
performed by 133Xe gas and 99mTc-MAA in 11 patients with LAM. We divided the lung
images into six lung regions, the upper, middle, and lower lung fields of the
left and right lungs, and classified the ventilation distribution pattern as one
of three types according to the washout time. Prolongation of mean transit time
(MTT) predominantly in the lower lung field was classified as type a,
predominantly in the middle and upper lung fields as type b, and diffuse
prolongation of MTT throughout the lung as type c. The classification included 16
cases of type b, four of type a, and two of type c. The 133Xe washout was
predominantly delayed in the middle and upper lung fields in 73% of LAM cases.
Pulmonary perfusion was reduced in the middle lung field and relatively increased
in the lower lung field in comparison with healthy controls. A follow-up study of
133Xe gas lung scan was performed in three cases of type b. All the cases
deteriorated and presented obstructive and restrictive disturbances without
changes in the distribution pattern. These findings suggested that the washout
type did not change with the progress of the stage of the disease.
PMID- 9394545
TI - [Scatter correction with an off-peak triple energy window method in thallium-201
imaging].
AB - For scatter correction using the triple energy window (TEW) acquisition in 201Tl
imaging, we propose an off-peak TEW (OFPTEW) method. This OFPTEW method employs a
wide main energy window of 34 keV centered at 73 keV and two 5.1 keV sub-energy
windows and uses the scatter correction factor of 0.55. To assess scatter
correction using the OFPTEW method in 201Tl imaging, phantom studies for planar
and SPECT imaging were performed and the data with the OFPTEW method were
compared with those by the conventional TEW method using the trapezoidal formula
with the 20% main energy window centered at 70 keV and two 4.9 keV sub-energy
windows. The planar images corrected by both methods were visually similar. The
OFPTEW method, however, estimated the true primary counts and the contrast value
in the cold lesion accurately, while the conventional TEW method underestimated
the primary counts by 30% and gave wrong contrast values. For the myocardial
SPECT imaging, the short-axis images by both methods were very similar, but the
images by the OFPTEW method had 1.46 times more counts than those corrected by
the conventional TEW method. In conclusion, the OFPTEW method can correct scatter
in 201Tl imaging accurately and increase the primary counts effectively compared
with the conventional TEW method.
PMID- 9394546
TI - [123I-MIBG lung uptake in patients with diabetes mellitus].
AB - The purpose of this study is to clarify the relationship between 123I-MIBG lung
uptake and silent myocardial ischemia (SMI), cardiac autonomic neuropathy (AN) or
clinical characteristics. For the quantitative analysis, lung to upper
mediastinum uptake ratio (L/M) and heart to upper mediastinum uptake ratio (H/M)
were obtained from chest planar image. In addition, both lung washout ratio (%WR
L) and heart washout ratio (%WR-H) were calculated from early and delayed images.
Each indices were compared in both diabetic and control groups. Mean values of
H/M in diabetes with complication were significantly lower than those of control
group. Particularly, AN(+)SMI(+) group showed lowest value. Similarly, mean
values of %WR-H in diabetes with complication were significantly higher than
those of control group and AN(+)SMI(+) group showed highest value. Although mean
value of L/M in each diabetic group was significantly higher than that of control
group, there was no statistical significance among each diabetes except AN(+)SMI(
) group on early image. Mean value of %WR-L in AN(+) or SMI(+) group was also
significantly higher than that of control group, but there was no statistical
significance among each diabetic group. The current study suggested that high
pulmonary 123I-MIBG uptake in diabetes was independent of the complication of SMI
or AN. Pulmonary endothelial dysfunction related with severity of diabetes
mellitus was considered to be the most important factor.
PMID- 9394547
TI - [Clinical significance of 123I-MIBG myocardial scintigraphy in patients with
hypertrophic cardiomyopathy].
AB - We studied the abnormality of myocardial sympathetic nervous system in patients
with hypertrophic cardiomyopathy using 123I-metaiodobenzylguanidine (MIBG)
myocardial scintigraphy in comparison with the parameters of other clinical
examinations. In 50 patients with HCM, the heart to mediastinum 123I-MIBG uptake
ratio (H/M) was significantly low and washout rate (WR) of 123I-MIBG was
significantly high respectively compared with normal subjects (n = 8). H/M was
negatively correlated with serum norepinephrine level, wall thickness of left
ventricle, left ventricular mass index, left ventricular end diastolic pressure
respectively, and WR was positively correlated with those parameters
respectively. On the other hand, LF/HF calculated by spectral analysis in holter
electrocardiogram was positively correlated with H/M, and negatively correlated
with WR. In HCM, H/M in patients with subjective symptoms was significantly lower
than that without subjective symptoms, and WR in patients with paroxysmal atrial
fibrillation was significantly higher than that without paroxysmal atrial
fibrillation. This study revealed that H/M and WR reflected the severity and the
difference of disease type in HCM. In conclusion, 123I-MIBG contributes to
evaluating more details in diagnosis and pathophysiology of HCM.
PMID- 9394548
TI - [Oligomelanotic malignant melanoma in the nasal cavity diagnosed by IMP
scintigraphy].
AB - MRI, 67Ga scintigraphy, and 123I-IMP-SPECT were performed in the patient with
oligomelanotic malignant melanoma in the nasal cavity which is not confirmed
pathologically at first. MRI failed to diagnose the tumor as malignant melanoma.
It was difficult to differentiate malignant melanoma from malignant lymphoma in
67Ga scintigraphy. The remarkable accumulation of 123I-IMP was consistent with
the tumor localization in the nasal cavity. This tumor uptake was thought to be
oligomelanotic or amelanotic melanoma since the accumulation was more distinctive
at the delayed image and since the tumor was not visibly melanotic. Finally the
tumor was confirmed to be oligomelanotic melanoma by immunohistochemical
examination; which was in accordance with IMP-SPECT findings. Oligomelanotic or
amelanotic melanoma occurs in nasal cavity with high frequency. We report here
the oligomelanotic melanoma case where IMP-SPECT was rather useful to make a
pathological diagnosis than other imaging modalities.
PMID- 9394549
TI - [A case of an adult neuroblastoma with bone-marrow metastases: 131I-MIBG
scintigraphy in comparison with MRI].
AB - To detect a primary neuroblastoma lesion and its metastases, 131I-MIBG
scintigraphy was performed for a 24-year-old woman who had a high level of serum
catecholamine. 131I-MIBG scintigrams showed high radioactivity in the left upper
quadrant, pelvic bone, and vertebral bodies. A biopsy of the pelvic bone revealed
metastasis from the neuroblastoma. After four chemotherapy courses, the
accumulation of 131I-MIBG decreased after each course; however, scintigraphy
performed after the last chemotherapy course showed focal mild uptake in the
right sacroiliac. The presence of residual tumor in the sacroiliac was confirmed
histologically. On the other hand, T1-weighted and T2-weighted MR images
performed before the treatment showed low signal intensity and high signal
intensity in the pelvic bone, respectively. After the fourth chemotherapy course,
T2-weighted MR images showed low signal intensity in the pelvic bone; however, it
was difficult to determinate whether it should improve. To assess the effect of
treatment of neuroblastoma, 131I-MIBG scintigraphy was considered more useful
than MRI.
PMID- 9394551
TI - [Experimental study on the location of energy windows for scatter correction by
the TEW method in 201Tl imaging].
AB - To investigate validity of scatter correction by the TEW method in 201Tl imaging,
we performed an experimental study using the gamma camera with the capability to
perform the TEW method and a plate source with a defect. Images were acquired
with the triple energy window which is recommended by the gamma camera
manufacturer. The result of the energy spectrum showed that backscattered photons
were included within the lower sub-energy window and main energy window, and the
spectral shapes in the upper half region of the photopeak (70 keV) were not
changed greatly by the source shape and the thickness of scattering materials.
The scatter fraction calculated using energy spectra and, visual observation and
the contrast values measured at the defect using planar images also showed that
substantial primary photons were included in the upper sub-energy window. In TEW
method (for scatter correction), two sub-energy windows are expected to be
defined on the part of energy region in which total counts mainly consist of
scattered photons. Therefore, it is necessary to investigate the use of the upper
sub-energy window on scatter correction by the TEW method in 201Tl imaging.
PMID- 9394550
TI - [Evaluation of 123I-MIBG clearance from the myocardium; comparison of two methods
-SPECT & planar methods].
AB - In 123I-metaiodobenzylguanidine (MIBG) scintigram, MIBG clearance from the heart
is used to evaluate the severity of various heart diseases. There are two methods
for calculating MIBG clearance. One involves planar images (planar method) and
the other uses a bull's eye map (SPECT method). In 158 patients and 10 normal
subjects, we compared these two methods. Fifteen minutes and 4 hours after
intravenous injection of 111 MBq MIBG, planar images and SPECT images were
obtained. Then clearance from the heart was calculated by each method. Abnormal
increase was defined as present if clearance was more than the mean + standard
deviation of 10 normal subjects. Then, we examined the sensitivity with which
each method could detect clearance abnormality in 158 patients. Thirty-two
patients showed abnormality only on SPECT images, while planar images alone
showed abnormalities in only 5 patients. The reason the SPECT method was more
sensitive than the planar method may be as follows; in the case of decreased MIBG
clearance from the lung, for example, in congestive heart failure, clearance by
planar method is apparently decreased. Thus, the SPECT method can detect
clearance abnormality more sensitively than the planar method, and if we evaluate
MIBG clearance from the heart by the planar method, we must take into account
MIBG clearance from the lung.
PMID- 9394552
TI - [Typical normal cases and normal cases with abnormal image pattern in every
myocardial SPECT radiopharmaceutical].
AB - Working group of cardiac nuclear medicine was made as a Japanese part of society
of international cardiac nuclear medicine under the cooperation between Japanese
society of nuclear medicine and Japanese society of cardiology. We investigated
typical normal cases and normal cases with abnormal image pattern in every
myocardial SPECT radiopharmaceutical as one of the research activity of working
group. From 11 faculties, 16 T1 cases, 14 BMIPP cases, 8 MIBG cases, 8 MIBI cases
and 14 tetrofosmin cases were submitted as typical normal cases, and 12 T1 cases,
5 BMIPP cases, 12 MIBG cases, 10 MIBI cases and 5 tetrofosmin cases were
submitted as normal cases with abnormal image pattern. We summarized the
condition of SPECT data acquisition of each faculties. And we added the
discussion from literature about how to discriminate normal cases with abnormal
image pattern from abnormal cases. In MIBG, patterns of typical normal cases and
normal cases with abnormal image pattern were slightly different from other 4
pharmaceuticals. In other 4 pharmaceuticals, diaphragmatic attenuation, breast
attenuation, apical thinning and others were presented as normal cases with
abnormal image pattern.
PMID- 9394554
TI - [Evaluation of effective treatment drugs against Acanthamoeba cyst].
AB - Cysts of 2 isolates of Acanthamoeba from the cornea of 2 patients with confirmed
Acanthamoeba keratitis were tested in vitro for sensitivity to antimycotic agents
such as fluconazole, miconazole, amphotericin-B, pimaricin, antiprotozoal agents
such as pentamidine isetionate and antiseptics which could be use in the
ophthamological region. Pimaricin was the most successful cysticidal agent
against the two strains. Sensitivity to pentamidine isetionate showed variation.
Fluconazole, miconazole and amphotericin-B were resistant against cysts with
concentration of eye drops that have been used in the treatment of Acanthamoeba
keratitis. It was supposed that 5% pimaricin eye drops could be use in the
treatment of Acanthamoeba keratitis in addition to keratomycosis. Pentamidine
isetionate which belong to the diamidine family, is not yet clear as to the side
effects to corneal epithelium cell, but we believe that this drug could be
expected as a new therapeutic agent for Acanthamoeba keratitis.
PMID- 9394553
TI - [Trend of bacterial meningitis in children over a 14 year period (1981 through
1994) in Japan--an analysis based on studies in 27 institutions].
AB - We observed 266 children with purulent meningitis in 27 institutions in Japan
during the 14 years from 1981 on dividing these years into 3 periods, 1981-1985,
1986-1990 and 1991-1994, and studied the trend of causative organisms identified
in 254 among the 266 patients. Their ages were less than 3 months after birth in
50 children and 3 months or older in 216: there were 141 boys and 125 girls. The
causative organisms were H. influenzae in 134 patients and S. pneumoniae in 50,
most of them being aged 3 months or older. Next to the above bacteria ranked S.
agalactiae in 29 and E. coli in 12, many of the patients were aged less than 3
months. Staphylococcus spp. was found in 7 patients and about 70% of them were
aged 3 months or older. L. monocytogenes was found in 4 patients and N.
meningitidis in 3 and they were aged 3 months or older in both patient groups. S.
pyogenes, Enterococcus spp., Peptostreptococcus spp., P. Mirabilis and
Enterobacter spp. were detected each in 1 patient. The causative organism was
unknown in 21 patients and there was no double infection. H. influenzae were
detected in 18 patients in 1981-1985 period (36.7%), in 56 in 1986-1990 (54.9%)
and in 60 in 1991-1994 (63.8%) showing an increasing tendency, but S. pneumoniae
exhibited neither an increasing nor decreasing tendency. There was a decreasing
tendency with S. agalactiae and E. coli, but the details were not clear because
there were few patients aged less than 3 months. Although the period of
coexistence of 4 main bacterial species was not made clear in this study.
Listeria is considered to develop mainly in the early childhood, and we believe
that the conventional way of using a cephem preparation and ampicillin combined
for patients under 6 years need not be altered. However, panipenem (phonetic) is
likely to be effective for insensible S. pneumoniae for the time being.
PMID- 9394555
TI - [Clinical features of Japanese children infected with Cryptosporidium parvum
during a massive outbreak caused by contaminated water supply].
AB - A massive outbreak of cryptosporidiosis occurred at a local town of Saitama
Prefecture, in 1996. During this outbreak, we investigated the clinical features
of children seen at Saitama Medical School. Cryptosporidium parvum (C. parvum)
was detected from 10 out of 28 (36%) children with diarrhea during June and
August, 1996. The average ages of the children who were positive and negative for
C. parvum were 6.5 and 5 year old, respectively. Among the children infected with
C. parvum, colic pain was observed in 3 children and 4 children had vomiting.
However, none of the children showed fever over 38.0 degrees C nor bloody stools.
Family members of children infected with C. parvum also had diarrhea and/or
vomiting (5/6). C. parvum was repeatedly detected from 2 out of 3 children. All
infected children had an improvement of abdominal symptoms in 4 to 10 days. C.
parvum should be included as a pathogen which causes enterocolitis in Japanese
children.
PMID- 9394556
TI - [Distribution of serogroups of Vibrio cholerae non-O1 non-O139 with specific
reference to their ability to produce cholera toxin, and addition of novel
serogroups].
AB - A total of 1898 strains of Vibrio cholerae non-O1 non-O139, which had been
collected worldwide for the past 3 year period of 1994-1996, were serogrouped.
The strains were also examined for presence of cholera toxin (CT) gene (ctx) and
NAG-ST gene, and strains which carried to ctx were further analyzed for their
ability to produce CT. In addition, attempts were made to establish novel
serogroups for those serologically untypable strains. Of those examined, 1,774
strains of V. cholerae non-O1 non-O139 was classified into 128 known serogroups
while 50 strains were found to belong to R type, and the rest of the 74 strains
could not be serotyped. Distribution of the serogroups did not seem to correspond
to either the strains geographic distribution or sources of isolation. Of those
serologically untypable strains, 38 novel serogroups (O156-O193) were established
and added to our reference of V. cholerae antigenic schema. It was also found
that antisera raised against many V. cholerae strains included R antibodies. This
indicates that any V. cholerae antisera for diagnostic purpose should be absorbed
with the reference R strains, CA385, before use. There were luminescence
producing strains among those sucrose and VP reaction negative strains.
Subsequent DNA/DNA homology analysis revealed that they were identified as V.
cholerae. This points to a possibility that strains tentatively identified as
Vibrio mimicus by conventional biochemical tests may have included luminescent
strains of V. cholerae. It is thus highly recommended that strains in question
should be tested for the luminescence production in order to differentiate V.
cholerae from V. mimicus. Of those 1989 strains examined, 37 strains (ca. 2%)
were found to produce CT. Interestingly, CT producing strains were prevalent in
serogroup O141; 10 strains out of 16 strains (63%) were positive for CT. The
evidence calls for a caution to possible occurrence of cholera-like diarrhea
caused by V. cholerae O141 in the future.
PMID- 9394557
TI - [Diagnosis of neonatal enterovirus meningitis by reverse transcription-polymerase
chain reaction].
AB - We evaluated the potential clinical utility of a reverse transcription-polymerase
chain reaction (RT-PCR) for neonatal enterovirus meningitis, comparing the
results with viral culture and white blood cell (WBC) counts in the cerebrospinal
fluid (CSF). Of the 41 cases of enteroviral infection, 31 cases (76%) were
finally diagnosed as meningitis by either viral culture, CSF WBC count or RT-PCR.
Of those with culture positive and negative, the RT-PCR positive rates were 10
(100%) and 6/13 (46%), respectively. Of those with and without WBC increase in
the CSF, the RT-PCR positive rates were 18/20 (90%) and 5/14 (36%), respectively.
There was one RT-PCR positive case (1/6, 17%) among those with culture negative
and no WBC increase in the CSF. RT-PCR performed on CSF is a sensitive and
specific method for the diagnosis of neonatal enterovirus meningitis.
PMID- 9394558
TI - [Effect of the prior influenza vaccination on serum antibody titer induction by
subsequent inactivated influenza vaccine in the elderly].
AB - In order to investigate the effects of prior influenza vaccination on subaequent
annual influenza vaccination in the geriatric population, we analyzed serum
hemagglutinine inhibition antibody tirers (HI titer) before and after vaccination
with inactivated influenza vaccine in elderly inpatients. A total of 163
inpatients of 60 years or older were enrolled with informed consent. They were
classified by vaccination status in the previous year, 53 patients had
inactivated vaccine (inactivated). 52 patients had genetically assorted cold
adapted influenza live attenuated vaccine (cold-adapted), and 53 had no influenza
vaccine history during the past year. The HI titer was higher in the inactivated
group than in the cold-adapted and non-vaccinated groups, suggesting residual
immunological effects of inactivated influenza vaccine from the previous year
vaccination. The HI titer after the inactivated vaccine in 1993 was higher in
both the inactivated and cold-adapted groups than in the non-vaccinated group.
The number of patients with HI titers of 2(7) or higher, which is the putative
protective HI titer level for influenza infection, was significantly higher in
both the inactivated and cold-adapted groups than the non-vaccinated group. These
results suggest that continuous annual influenza vaccination does not impair the
effects of vaccination, and may actively promote elevated HI titers.
PMID- 9394559
TI - eaeA genes in Escherichia coli derived from Japanese patients with sporadic
diarrhea.
AB - To investigate the prevalence of attaching and effacing Escherichia coli, we
examined 364 strains isolated from the feces of 9,684 patients with diarrhea at
the Anjo Kosei Hospital in Japan for the presence of eaeA. Twenty-nine (8%) of
the strains were eaeA positive. Of enteropathogenic E. coli (EPEC), 11 of the 87
(13%) strains were for the positive eaeA gene. The serotypes and the numbers of
eaeA-positive strains among the strains tested were as follows: O26:H-(2/3),
O55:H7 (4/4), O55:H-(2/ 2) and O128:H2(3/3). Two enterohemorrhagic E. coli (EHEC)
strains (Verotoxin positive O157:H7) were also eaeA positive. Among 260 non-EPEC
strains that were not categorized as diarrheagenic E. coli, 16 (6%) were eaeA
positive. Those serotypes were as follows: O15:H2, O20:H6, O28:H28, O63:H6.
O153:H7, O28:H6, O153:H19 and O157:H45. EPEC strains including O18:H7 and six
other serotypes, enteroinvasive E. coli (EIEC), and enterotoxigenic E. coli
(ETEC) were all eaeA negative.
PMID- 9394560
TI - [Toxic shock-like syndrome after acupuncturation].
AB - A 80-year-olkd male was admitted to our hospital because of severe pain and
swelling on his left lower leg on January 23, 1996. He had received an
acupuncture to both legs because of intermittent claudication once a week from
July, 1995 to January 18, 1996. On the next day of the last acupuncture, pain and
swelling on his left leg appeared. On admission, his left leg showed diffuse
swelling and redness with blisters. We diagnosed this patient as toxic shock-like
syndrome (TSLS), based on the rapid exacerbation of the skin changes, necrotizing
superficial fasciitis, multiple organ failure with shock, and the detection of
group A streptococcus from culture samples obtained from both skin blister and
necrotic fascia. He recovered from the disease by amputation of the involved leg
and antibiotic therapy. Acupuncture could have been the cause of streptococcal
infection.
PMID- 9394561
TI - [Campylobacter jejuni enteritis in three patients with HIV infection].
AB - Gatrointestinal symptoms, which include diarrhea, are as common as respiratory
symptoms in patients with HIV infection. Gastrointestinal symptoms may result
from infections, neoplasma, HIV enteropathy or drug toxicity. Three HIV-infected
patients admitted to our hospital complaining of diarrhea and fever. We confirmed
their diagnosis as Campylobacter jejuni enteritis by bacteriological examination
of their feces. All of them had eaten inadequately cooked meat in restaurants
before the onset of their enteritis. Their symptoms immediately improved after
the administration of antimicrobial agents. One strain of C. jejuni isolated in
our cases, however, was resistant to ofloxacin. This case report suggests that we
must counsel HIV-infected patients to avoid inadequately cooked food and observe
resistant patterns of C. jejuni to antimicrobial agents in Japan in the future.
PMID- 9394562
TI - [A case of cat scratch disease identified by an elevated Bartonella henselae
antibody level using enzyme immunoassay].
AB - A 68-year-old male was admitted to our hospital because of fever and a 2-week
history of inguinal adenomegaly. Since he owned a cat, cat scratch disease was
suspected. But it was necessary to distinguish cat scratch disease from lymphoma
type adult T-cell leukemia because he showed a high level of antibody against
HTLV-1. An excisional biopsy of the inguinal node was performed. Histopathologic
examination revealed abscess-forming granulomatous lymphadenitis compatible with
cat scratch disease. A Warthin-Starry silver stain showed pleomorphic bacilli in
the lymph node. So we confirmed a serological response to Bartonella henselae,
the causative agent of cat scratch disease, using enzyme immunoassay (EIA). The
IgG antibody level to B. henselae was positive at 42 EIA Unit before treatment.
After treatment with intravenous cefepime and oral tosufloxacin, his physical
symptoms improved and the antibody level decreased to less than 12 EIA Unit. EIA
was very useful for diagnosis of this case. Serology to B. henselae may replace
traditional diagnostic criteria for cat scratch disease.
PMID- 9394563
TI - [Acute respiratory failure associated with G-CSF-induced leukocyte recovery in
three patients with preceding infection].
AB - Acute respiratory failure (ARF) occurred at the time of leukocyte recovery
promoted by granulocyte colony-stimulating factor (G-CSF) in three patients with
the preceding infection (S. aureus pneumonia, varicella zoster, and P. aeruginosa
bacteremia, respectively) which had developed during leukopenia after cancer
chemotherapy. G-CSF was used for 4 to 6 days, and the leukocyte counts at onset
of ARF were 19,300/microliter, 11,300/microliter, and 4,100/microliter,
respectively. All of the three patients received high-dose methylprednisolone and
the artificial respiration was used in two. Consequently two patients responded
well and survived, but one died of respiratory failure 2 weeks after occurrence
of ARF. Autopsy of the dead case revealed mild interstitial pneumonia in the both
lungs together with bacterial pneumonia in the right lobe. These cases indicate
that G-CSF-induced leukocyte recovery can cause severe ARF in patients with
precending infection. Therefore, G-CSF should be administered very carefully to
granulocytopenic patients with infection.
PMID- 9394564
TI - [Case report: lung abscess caused by Streptococcus agalactiae].
AB - Streptococcus agalactiae is a well-recognized cause of neonatal sepsis and
meningitis. In adults, infections by S. agalactiae are rare. We report an adult
case of lung abscess and pyogenic spondylitis caused by S. agalactiae. A 51-year
old male was admitted to our hospital because of an abnormal shadow in the chest
and lumbago on May 25, 1995. He was diagnosed as lung abscess from the chest
roentgenogram and CT scan and the subcutaneous pus was aspirated. The pus culture
was only positive for S. agalactiae. He was treated with IPM/CS 1 g/day and CLDM
1.2 g/day and the abscess was drained. MRI showed his lumbago was caused by
pyogenic spondylitis. The underlying disease of this case was diabetes mellitus.
He recovered from the infections with in about 10 weeks of antibiotic treatment.
PMID- 9394565
TI - DNA diagnosis of Plasmodium falciparum malaria by single-tube PCR.
PMID- 9394566
TI - [An evaluation of computed radiography in contrast-enhanced imaging of the
gastric area].
AB - The usefulness of computed radiography (CR) in contrast-enhanced imaging of the
stomach was evaluated. First, the spatial resolution and density resolution of CR
under the conditions of contrast-enhanced imaging of the digestive tract were
examined. Spatial resolution was lower, but density resolution was similar, in
comparison with those of conventional film screen (FS). Both were better in CR at
a low dose. Evaluation of processing conditions for CR using a gastric phantom
indicated that the use of N for gamma type (GT) and T for response type (RT) in
the left image and the use of A for GT and F for RT in the right image is
recommended. Evaluation of the relationship between the stomach segment and
response enhancement (RE) showed that RE should not be very strong in cases where
segments to be visualized are limited to the lower part of the stomach. With an
optimal RE, the image quality of the gastric segment was better in CR than in FS.
When dynamic-range control processing was performed in an area overlapped by
colon gas, obscure parts became visually recognizable. CR is considered to be
useful also for contrast-enhanced imaging of the digestive tract.
PMID- 9394567
TI - [Evaluation of therapeutic effect using enhanced MRI in lung cancer: evaluation
of methods in terms of necrosis].
AB - To evaluate therapeutic effect in terms of necrosis or cavity, enhanced MRI was
performed in 40 lung cancer patients treated by conservative therapy. We provided
the reduction ratio of the viable tumor as calculated by a volume method and a
cross-sectional method. In the volume method, the volume of necrosis was
subtracted from the volume of the tumor, and in the cross-sectional method, the
product of the longest diameter and widest perpendicular diameter of necrosis was
subtracted from the product of the longest diameter and widest perpendicular
diameter of the tumor. We then examined whether we could substitute the cross
sectional method for the volume method. The reduction ratios of viable tumor
calculated by the two methods were in good correlation. The limits of agreement
of each method and their repeatability coefficients were considered small enough
for clinical use. Therefore, we concluded that the cross-sectional method could
be used in place of the volume method for clinical purposes. In evaluating
therapeutic effect in terms of necrosis when using contrast-enhanced MR imaging,
the reduction ratio of the viable tumor determined by the cross-sectional method
can be substituted for that determined by the volume method.
PMID- 9394568
TI - [Usefulness of photon counting X-ray radiography for diagnostic imaging of the
thorax: experimental and clinical studies].
AB - To evaluate the usefulness of photon counting X-ray radiography (quantum
radiography, QR) for diagnostic imaging of the thorax, comparative studies
between QR and the conventional screen-film system (SF) were performed. Exposure
dose, spatial resolution and density resolution on QR were evaluated in the
experimental study. The ability of QR to describe normal structures and several
kinds of abnormal shadows was evaluated in the clinical study. The relative
exposure dose of QR was lower than that of SF, while the spatial resolution of QR
was slightly inferior to that of SF. However, the density resolution of QR was
superior to that of SF. Clinically, QR was superior to SF in the description of
normal structures and several kinds of abnormal shadows. In conclusion, it was
considered that QR is useful for diagnostic imaging of the thorax.
PMID- 9394569
TI - [Radiation therapy for adrenal metastases].
AB - PURPOSE: To evaluate the role of radiation therapy for adrenal metastases.
MATERIALS AND METHODS: Fourteen patients, 13 with primary lung carcinoma and one
with primary unknown carcinoma, received radiation therapy for adrenal metastases
from 1984 to 1995 at the Hyogo Medical Center for Adults. Total dose ranged from
16 Gy to 60 Gy, and fractional dose from 1.6 Gy/ Fr to 3 Gy/Fr. RESULTS: Partial
response of the local tumor was recognized in 2 of 7 patients by CT imaging. Pain
relief was obtained in 7 of 8 patients. Median survival was 3 months, and 6-month
survival was 28.6% in all patients. Among patients in the symptomatic group, who
had complaints of pain due to adrenal mass, survival was even worse (12.5% at 6
months). There were no severe complications, but 4 patients (29%) had
gastrointestinal symptoms. CONCLUSION: Radiation therapy is useful for the
purpose of pain relief in adrenal metastases.
PMID- 9394570
TI - [Radionuclear estimation with 99mTc-N-pyridoxyl-5-methyl-tryptophan (PMT)
scintigraphy of recurrent hepatocellular carcinoma after non-surgical treatment].
AB - 99mTc-N-pyridoxyl-5-methyl-tryptophan (PMT) scintigraphy, which exhibits highly
specific for the diagnosis of primary hepatocellular carcinoma (HCC), was
performed for recurrent HCC following non-surgical treatment. Eighty-four
patients (total 351 examinations) were selected for the study. The ability of PMT
scintigraphy to diagnose recurrent HCC after treatment was compared with that of
computed tomography, ultrasonography and angiography. The results showed that 1)
sixty-three (75%) of 84 cases demonstrated positive findings during our follow-up
period, 2) most of the tumors initially showing positive findings remained PMT
positive when they recurred and 3) PMT studies shortly after treatment
demonstrated wider tracer uptake rather than the actual tumor area. In
conclusion. PMT scintigraphy for patients with HCC after non-surgical treatment
exhibited high accuracy in identifying viable HCC only for tumors indicating
positive findings.
PMID- 9394571
TI - [CT-guided lung needle biopsy using a new supporting implement].
AB - We contrived a new supporting implement to increase the hit rate of CT-guided
needle biopsy (CTNB) for localized pulmonary lesions. Using this implement,
twenty-two CTNB examinations for localized pulmonary lesions were performed. In
21 out of the 22 examinations (95%), the lesions were hit, and specimens
appropriate for cytological or histological diagnosis were obtained. The course
of needle insertion, which was difficult to define in the past, has become to be
easier and more precise with this method. Using this new implement, CTNB is now
applicable to smaller and deeper lesions.
PMID- 9394572
TI - [Radioresistant CD4+ T cells in normal, unprimed mice: with verification of the
Bergonie-Tribondeau law].
AB - This is the first report on radioresistant CD4+ T cells found in normal, unprimed
mice. After sublethal whole body irradiation, regular CD4+ as well as primitive
NK1.1 + CD4+ T cells were enriched in the spleen. Since it has been well
established that virgin T and B cells are highly radiosensitive, these cells were
once assumed to be a unique lymphocyte population for which radiosensitivity does
not follow the general law of radiation sensitivity for mammalian cells (Bergonie
Tribondeau law). These cells exhibited higher proliferative response to accessory
cells than the non-irradiated control cells in the syngeneic mixed leukocyte
reaction (SMLR). This indicated that virgin CD4+ T cells sensitized to, and
readily respond to self-MHC class II molecules are radioresistant, and that their
radioresistance, as activated cells, is consistent with the Bergonie-Tribondeau
law.
PMID- 9394573
TI - [Cardiac surgery in patients with chronic renal failure on maintenance dialysis].
AB - From July 1988 through August 1996, 54 patients with chronic renal failure (CRF)
on maintenance dialysis (50 hemodialysis = HD, and 4 continuous ambulatory
peritoneal dialysis) have undergone some sort of surgical procedure requiring the
use of extra corporeal circulation (ECC); 42 patients underwent isolated coronary
artery bypass grafting (CABG), 8 valve replacement, 3 combined procedures and 1
correction of a congenital heart defect. The protocol called for maintenance
dialysis on the day before surgery, large volume hemofiltration (HF) during the
ECC period, postoperative K+ management with dextrose-insulin if required, and
resumption of whatever preoperative maintenance dialysis 24 hours after the
operative procedure. The mean diafiltrate volume of HF was 7963 +/- 2688 ml which
was replaced with 6342 +/- 2748 ml. No patient required emergency HD before the
resumption of the maintenance dialysis, although in 40% of the early patients HD
was added on the second postoperative day. However as experience was gained, in
the latter 60% of patients resumption of maintenance dialysis (HD 3 times a week)
was thought to be sufficient. The incidence of calcification in patients with CRF
is higher not only of involved coronary artery segments (4.5 +/- 2.3 segments;
AHA coronary classification) than its counterpart without CRF, but also of the
ascending aorta which mandated modifications of the technique in 6 patients
(operation under ventricular fibrillation, cannulation access other than
ascending aorta). The use of arterial in situ conduits for CABG was also thought
to be advantageous, and the left internal thoracic artery combined to the gastro
epiploic artery was used in 11 patients (26.2%). Four patients died) (7.4%): 2
from arrhythmia, one from intestinal necrosis and one from multiple cerebral
infarction. Thus we conclude that the outlined protocol is quite effective in
controlling fluid and electrolyte balance in patients on maintenance dialysis
allowing to undertake surgical procedures requiring the use of extra corporeal
circulation relatively safely.
PMID- 9394574
TI - [Glutamate neurotoxicity during spinal cord ischemia--development of a delayed
onset paraplegia model].
AB - The incidence and severity of spinal cord dysfunction are related to both the
depth and duration of the resulting ischemic state. Evidence is accumulating that
glutamate, a major neurotransmitter, has potent neurotoxic activity during
ischemia. In our laboratory, it has been confirmed that exogenous glutamate has
detrimental effects on spinal cord neurons during brief ischemia in vivo. We
hypothesized that glutamate neurotoxicity is associated with delayed-neuronal
dysfunction. Delayed-onset paraplegia is defined as a neurologic deficit which
develops after initial recovery. Infrarenal aortic segments from 12 New Zealand
white rabbits, were isolated for 5 minutes and perfused at a rate of 2 ml/min.
Group I (n = 6) received normothermic saline (39 degrees C). Group II (n = 6)
received normothermic L-glutamate (20 mM). Neurologic function was assessed at 6,
24, and 48 hours after surgery according to the modified Tarlov scale. After 48
hours, the rabbits were euthanized and their spinal cords were harvested for
histologic examination. The neurologic function of all group I was fully intact,
whereas three rabbits in group II showed acute paraplegia and the other three
showed delayed-onset paraplegia. Histologic examination of spinal cords from
rabbits in group I revealed no evidence of cord injury, whereas spinal cords from
those in group II had evidence of moderate spinal cord injury with central gray
matter and adjacent white matter necrosis and axonal swelling. These results
indicate that dose-dependent glutamate neurotoxicity is associated with delayed
neuronal dysfunction following ischemia in vivo. The severity of the ischemic
event, i.e., extracellular glutamate overload, is suspected to be the etiology of
delayed-onset paraplegia which, in turn, is thought to be the result of
borderline ischemia. This model may allow a pharmacologic approach to the
prevention of ischemic spinal cord injury.
PMID- 9394575
TI - [Radial artery for coronary artery bypass graft].
AB - Early postoperative results were studied in 50 cases of coronary artery bypass
graft (CABG) using a radial artery (RA). The patients ranged in age from 37 to 81
years, with the mean age of 61 years. Of them, 49 were male. An average of RA was
17.6 cm at completion of detachment and 15.6 cm when the graft was cut for use.
The internal diameter before anastomosis an average of 3.7 mm on the proximal
side and an average of 2.8 mm on the distal side. RA was anastomosed with
ascending aorta in 47 cases, with the left internal thoracic artery in 2 cases
and with the right internal thoracic artery in one case on the proximal side. RA
was anastomosed with the left anterior descending branch area in 6 cases, with
the left circumflex branch area in 40 cases and with the right coronary artery
area in 4 cases on the distal side. There was no case of operative death, but one
patient died while in hospital. The cumulative patency rate of the RA grafts was
95% (n = 40). Early postoperative results of the RA graft were satisfactory,
therefore the RA graft were satisfactory, therefore the RA graft was an excellent
alternative conduit for myocardial revascularization.
PMID- 9394576
TI - [Brain damage after surgery for thoracic aortic aneurysm].
AB - We analyzed cases with brain damage after surgery for thoracic aortic aneurysm in
our institution and investigated the causes, risk-factors and preventive measures
for this disastrous postoperative complication. Irreversible brain damage was a
complication in 25 out of 184 operative cases (13.6%) over a 21-year period. The
cause of brain damage was determined to be embolism by manipulation of the aorta
in six cases, clamping of the left subclavian artery in four cases, technical
problems of separate cerebral perfusion (SCP) in four cases, severe shock in
three cases, embolism unrelated to operative maneuver in three cases, stenosis of
a branch of the arch with aortic dissection in two cases, and air embolism,
circulatory arrest with insufficient hypothermia and hypoperfusion of a temporary
bypass to the left carotid artery in one case each. The neurological symptom
improved in eight cases and was unchanged in 17 cases. Eighteen cases died in the
hospital. In the univariate analysis, age (p = 0.048), a portion of the aneurysm
(p = 0.035), preoperative brain complication (p = 0.003), emergency operation (p
= 0.033) and clamping of the arch (p = 0.001) were found to be prominent risk
factors for brain damage. In the multivariate analysis, clamping of the arch (p =
0.0310), SCP (p = 0.0327) and emergency operation (p = 0.0223) were prominent. To
prevent postoperative brain damage, the arch should not be clamped, appropriate
operative techniques to avoid bleeding and to shorten SCP time should be
employed, and proper and prompt management of the emergency operation and caution
in clamping the left subclavian artery are considered to be necessary.
PMID- 9394577
TI - [Carinal resection for primary lung cancer--with special attention to a modified
double-barrel method].
AB - Carinal resection for primary lung cancer was clinically evaluated. Carinal
resection was performed in 18 patients, 17 males and one female, with a mean age
of 64 years. Nine patients underwent carinal reconstruction and the other 9
sleeve or wedge pneumonectomy. The carinal reconstruction was of the montage type
in one patient, the one-stoma type in 2, and the modified double-barrel method in
6. The modified double-barrel method is a technique that we developed by adding
bronchial end-to-side anastomosis to the tracheobronchial end-to-end anastomotic
site. A pedicled intercostal muscle flap was used for covering the anastomotic
site. The postoperative respiratory complications after carinal reconstruction
were anastomosis failure in 4 patients (pin-hole in 3) and respiratory failure in
2. However, no anastomosis stricture occurred, and recovery was satisfactory.
There were no respiratory complications after pneumonectomy. One patient had
renal failure before surgery and died of multiple organ failure 23 days after a
montage type carinal reconstruction. The other 17 patients did well and could be
discharged from the hospital and the overall mortality rate was 5.6%. No
anastomosis stricture occurred in the modified double-barrel method. By carinal
reconstruction covering of the anastomotic site is mandatory to prevent fatal
postoperative complications.
PMID- 9394578
TI - [Extra-anatomic bypass from the ascending aorta to the supraceliac abdominal
aorta--surgical option applied to reoperation for aortic coarctation or
interruption].
AB - The optimal approach for reoperation following repair of aortic coarctation (CoA)
or interruption (IAA) remains controversial. Four patients underwent extra
anatomic bypass for restenosis after repair of CoA or IAA. The age ranged from 4
to 12 years. The initial repairs for two CoA, one type A-IAA, and one type B-IAA
consisted of two grafting, one subclavian arterial turning-down aortoplasty, and
one subclavian flap aortoplasty. All of them underwent during infancy.
Preoperative right arm systolic pressure ranged from 140 to 190 mmHg ar rest.
Through a midline sternotomy and an upper laparotmy incision, an extra-anatomic
bypass from the ascending aorta to the supraceliac abdominal aorta was employed
using a 12 to 18 mm tube graft. All patients survived surgeries, and their
hypertension markedly improved. Our experience confirms safety and effectiveness
of this option in selected young patients with re-stenosis of following repair of
CoA or IAA.
PMID- 9394579
TI - [Composite valve graft replacement in patients with type A aortic dissection--a
modified cabrol procedure].
AB - Composite valve graft replacement of the ascending aorta and aortic valve is
indicated for a variety of conditions affecting the aortic root. However, a major
drawback in this operation is bleeding from the proximal suture line and coronary
anastomosis especially in patient with friable root tissue involved by aortic
dissection. We describe here a modified technique to take advantage of the aortic
button and cabrol techniques to reattach the coronary artery ostia. We have
experienced seven patients with the aortic root replacements for type A
dissection using the described technique over the past two years. In view of our
favorable experience, we recommend this technique especially for patient with
acute dissection involving nondilated aortic annulus, in addition to the patients
with Marfan syndrome or annulo-aortic ectasia.
PMID- 9394580
TI - [Lymph node dissection during a video-assisted lobectomy is inferior to that in a
standard lobectomy].
AB - The indications for a video-assisted lobectomy are currently ill-defined.
Clinicians recommend based on the extent of lymph node involvement. Fifty-nine
patients with clinical stage I non-small cell lung cancer underwent lobectomies
with systemic lymph node dissections through a standard thoracotomy (Group C),
and 26 patients underwent lobectomies with lymph node dissections using the video
assisted procedure (Group V). The number of dissected lymph nodes at all node
levels were compared between the two groups. There was no significant difference
between groups in the total number of dissected lymph nodes in patients with
right lung cancer. The number of dissected hilar and interlobar lymph nodes,
however, was less in Group V than that in Group C (hilar: 1.2 +/- 0.4 vs. 2.8 +/-
0.6, interlobar: 1.1 +/- 0.4 vs. 2.1 +/- 0.4). The total number of dissected
lymph nodes in patients with left lung cancer was significantly less in Group V
than that in Group C (18.5 +/- 0.3 vs. 28.7 +/- 2.4). In addition, the number of
dissected lymph nodes in pratracheal, pretracheal, tracheobronchial, subcarinal,
hilar, and interlobar lymph nodes were significantly less in the group V than
those in Group C. Although there was no significant difference in the actual
survival rates between the groups in this preliminary study, a sufficiently small
number of dissected lymph nodes in the video-assisted lobectomy may have resulted
in inaccurate staging and poor prognosis in these patients.
PMID- 9394581
TI - [Effects of aprotinin on blood loss reduction in children undergoing repair of
tetralogy of Fallot].
AB - The effect of aprotinin on the blood loss reduction was studied in children
undergoing repair of tetralogy of Fallot. We administered aprotinin to
consecutive 21 patients during the repair of tetralogy of Fallot and examined the
blood loss and operative time in comparison with that in a control group of 20
patients. 30,000 KIU/kg of aprotinin was infused as the initial cardiopulmonary
bypass (CPB) dose and 10,000 KIU/kg/hr was continuously administered as the
maintenance dose during CPB. There was no resternotomy case due to bleeding and
no operative death in both groups. Blood loss after CPB during operation and
total blood loss during operation were significantly lower in aprotinin group
than in control group. There were no differences between two groups in the volume
of chest tube drainage in the postoperative 24 hours and the duration of chest
tube drainage. Time from cessation of CPB to skin closure and total operative
time were significantly shorter in aprotinin group than in control group. In
conclusion, aprotinin was effective on the reduction of blood loss and the
shortening of operative time in children undergoing repair of tetralogy of
Fallot.
PMID- 9394582
TI - [A prospective study on the timing of discontinuation of aspirin before coronary
artery bypass grafting].
AB - The effects of the timing of discontinuation of aspirin before coronary artery
bypass grafting (CABG) on postoperative blood loss and blood requirements were
examined in 22 patients undergoing elective CABG, who were randomly assigned into
two groups. In Group I (11 patients), aspirin was discontinued two days before
the operation and in Group II (11 patients), aspirin was continued up to the
operation. The other 40 patients, who did not take aspirin for at least seven
days before the operation, served as a control Group. There were no differences
in preoperative data including the platelet count and the hemoglobin
concentration, nor in operative variables such as operation time, cardiopulmonary
bypass duration and aortic crossclamp time among the groups. Although
postoperative blood loss (six hours' loss; Group I 218 ml, Group II 183 ml and
control Group 172 ml) and red blood cells transfusion requirements were not
different among the groups, platelet concentrates transfusion was more frequently
required in Group II (54.5%) as compared with control Group (7.5%) and Group I
(9.1%). The difference between Group II and the control Group reached statistical
significance (p < 0.01), but there was no significant difference between Group I
and control Group. This fact suggests that preoperative two days' discontinuation
of aspirin works as effectively as seven days' discontinuation.
PMID- 9394583
TI - [A clinical application of histidine buffered cardioplegia].
AB - Blood cardioplegia has been widely accepted due to better oxygen delivery, pH
buffering and free radical scavenge. We have found that a crystalloid
cardioplegia solution formulated to accelerate anaerobic glycolysis with high
buffering capacity. To conserve blood cardioplegia, we formulated a crystalloid
cardiopletia containing 100 mM histidine for buffering. This cardioplegia (HBS)
was compared to cold blood cardioplegia in patients requiring open heart surgery.
Eighty patients including HBS (n = 28), and CBC (n = 40) were involved in this
study. Left ventricular end-systolic elastance (Emax; mmHg/cm3) was evaluated pre
and postoperatively. Cardiac index and inotropic requirement were also monitored
at 1, 3, and 12 hours after cardiopulmonary bypass. There was no death in either
group. All hearts returned to previous rhythm in HBS group, whereas total 12 DC
cardioversions were requested in 6 patients. Emax was significantly higher in HBS
group (5.2 +/- 0.6 mmHg/cm3) than in CBC group (3.4 +/- 0.4 mmHg/cm3). Cardiac
index was also significantly higher in HBS group postoperatively than in CBC
group with lower inotropic requirements. We conclude that histidine containing
crystalloid cardioplegia provides excellent recovery of cardiac performance with
lower inotropic requirements in open heart surgery. The ease of use, and lack of
blood are other important advantages of this crystalloid cardioplegia.
PMID- 9394584
TI - [Assessment of right gastroepiploic artery grafts by thallium scintigraphy].
AB - From 1990 to 1996 we performed coronary artery bypass grafting using only
arterial grafts. Both pre- and post-operative thallium-201 exercise myocardial
scintigraphy were evaluated in 68 cases (161 grafts). The rate of improvement (%)
was defined as follows: (number that showed improvement of perfusion of thallium
on post-operative scintigraphy/number that showed decreased perfusion of thallium
on pre-operative scintigraphy) x 100. Examination was made separately regarding
cases of ischemia (102 grafts) and infarction (54 grafts). For ischemic cases,
the rate of improvement using left internal thoracic artery (LITA), right
internal thoracic artery (RITA) and right gastroepiploic artery (RGEA) was 80%
(12/15), 70% (7/10) and 71% (5/7) respectively. For infarction cases, the rate of
improvement using LITA, RITA and RGEA was 54% (7/13), 60% (6/10) and 53% (9/17)
respectively. Among these three groups no significant differences were noted. As
a result, RGEA is thought to have usefulness equivalent to LITA and RITA.
PMID- 9394585
TI - [Thickness of the muscle layer of the gastroepiploic artery and the internal
mammary artery--a presumable factor of flow instability in GEA during the
perioperative period].
AB - Recently the right gastroepiploic artery (RGEA) is often used for coronary bypass
grafting. Although patency rate of the RGEA is as high as that of the IMA,
instability of blood flow through the RGEA during the perioperative period is
reported. We assumed that the RGEA is more predisposed to spasm than the internal
mammary artery (IMA). This study was carried out to verify the following two
points. 1. The GEA has a smaller internal diameter and thicker muscle layer than
the IMA. 2. The contractile force of the muscle layer of the GEA are stronger
than those of the IMA under the same transmural pressure due to the greater
thickness o the muscle layer of the GEA. METHODS: The RGEA was obtained at its
full length from gastorectomy cases due to gastric cancer (n = 25). The distal
section of the IMA was obtained from the left IMA during bypass grafting (n =
23). All specimens were stained by the Masson-trichrome method and examined
microscopically. The thickness of the smooth muscle layer of the media and the
internal radius were compared between the RGEA and the IMA. RESULTS: The
thickness of the muscle layer was 274.0 +/- 13 microns in the RGEA, and 169.1 +/-
8 microns in the IMA (p < 0.01) that is the thickness in the GEA was 1.62 times
greater in the IMA. Although a significant difference was not obtained, the
internal radius of GEA (563.7 +/- 21.8 microns) was smaller than that of IMA
(583.1 +/- 12.0 microns). Based on the internal diameter-elastic wall tension
relationship and the Laplace law, internal diameter and elastic tension in both
arteries were obtained at the same blood pressure. Mean elastic tension and
internal diameter in the GEA were considered to be smaller than than those in the
IMA. The values of the internal diameter of the arteries obtained from the
theoretical view point were correlated well with those obtained by the
histometoric methods. As the muscle layer of the arterial wall of the GEA is
thicker than that o the IMA, and the internal diameter of the GEA tends to be
smaller than that of the IMA, the stronger contraction o the muscle layer, when
induced, would reduce the blood flow in much greater extent in the GEA than the
IMA. CONCLUSION: These results support the assumption that the RGEA reacts
strongly than the IMA to constructor agents and physical stimuli, thereby
inducing a greater instability of blood flow. Therefore, RGEA grafts should be
carefully handled during bypass grafting.
PMID- 9394586
TI - [Four cases of adrenal tumor discovered through examination before surgery for
lung cancer].
AB - Preoperative CT and Ultrasonography (US) showed adrenal tumors in four patients
with lung cancer. Although metastasis of the cancer to the adrenal gland was
suspected, a definitive diagnosis could not be made by CT and US alone. MRI is as
ineffective as CT and US. Needle biopsy is useful if tumor cells are detected,
but not unless they are discovered. Surgery, therefore, is necessary to establish
the final diagnosis. (Adrenalectomy was performed on all cases, one of which had
metastasis). No particular complications occurred after adrenalectomy.
Adrenalectomy was considered unavoidable to determine stage and treatment
policies in patients suspected of metastasis in imaging diagnosis.
PMID- 9394587
TI - [Rupture of the papillary muscle after percutaneous transvenous mitral
commissurotomy (PTMC)--a case report].
AB - We experienced a rare case of the mitral regurgitation due to papillary muscle
rupture after percutaneous transvenous mitral commissurotomy (PTMC). This case
was a seventy years old female who underwent PTMC. The cardiac tamponade and
mitral regurgitation occurred after PTMC. Pericardial drainage was done
immediately, and the next day the emergency operation was required. Rupture of
the posterior papillary muscle was found at the operation, and mitral valve
replacement was performed. Her postoperative course was uneventful and she
discharged on the 26th day after the operation. We should take the papillary
muscle rupture into consideration if there are severe sub-valvular lesion and
shorting of the chorda.
PMID- 9394588
TI - [Right-sided intrathoracic bypass grafting for a coarctation of the aorta in an
advanced aged woman].
AB - A sixty-two years old woman with a successful bypass grafting for coarctation of
the thoracic aorta (Co-A) is presented. She has been suffering from hypertension
since her thirties. Preoperative cardiac catheterization demonstrated Co-A with a
pressure gradient of 100 mmHg. Angiography revealed the hypoplastic aortic arch
with marked calcification and well developed collateral circulation. Right-sided
intrathoracic bypass grafting using a 16 mm woven Dacron graft was placed between
the ascending and descending aorta via a right sixth intercostal space. The
patient had a good postoperative course with reduced pressure gradient of 10
mmHg. We recommend this procedure to be a safe and simple technique that can
avoid injury to the collateral circulation to our knowledge, this is the most
aged patient who underwent a successful surgical treatment for the Co-A in Japan.
PMID- 9394589
TI - [A case of ruptured thoracoabdominal aortic aneurysm with aortitis syndrome-
operation with selective cold visceral arteries perfusion].
AB - We report a successful result of treatment for a ruptured thoracoabdominal aortic
aneurysm with aortitis syndrome. A 43-year-old male suffered sudden low back
pain, that was diagnosed as a ruptured thoracoabdominal aortic aneurysm based on
abdominal computed tomography. Preoperative angiography revealed a
thoracoabdominal aortic aneurysm with occlusion of the superior mesenteric
artery, and well developed Riolan's archade. The aneurysm was replaced by a
prosthetic graft with partial femoro-femoral bypass in conjunction with selective
cold perfusion for the visceral arteries. Total extracorporeal circulation time,
and aortic clamptime, was 187 minutes and 132 minutes, respectively. The
postoperative courses of liver and renal function were excellent. The patient
recovered from surgery uneventfully. It was suggested that selective cold
visceral perfusion was effective for prevention of renal and liver dysfunction
associated with a ruptured thoracoabdominal aneurysm.
PMID- 9394590
TI - [Successful two-stage approach to treating excessive hemorrhage from pulmonary
arterial stump in post-lobectomy bronchopleural fistula].
AB - A 62-year-old man underwent right lower lobectomy for adenocarcinoma (pT2N0M0)
and nine days later, a bronchopleural fistula with empyema was evident. Six weeks
following the lobectomy, excessive hemorrhage from the site of chest drainage and
hemoptysis were noted. The bleeding and empyema were controlled by a two-stage
approach. Anterior transpericardial approach was first made through the median
sternotomy to clamp the right main pulmonary artery and then postero-lateral
thoracotomy was conducted for the bronchopleural fistula with empyema. The right
bronchial stump was covered with a pedicled muscle flap and pseudomonas
aeruginosa, always positive in drainage effusion, consequently disappeared. The
patient was discharged with a closed bronchus 4 months following the operation.
PMID- 9394591
TI - [Successful emergency surgical management following cardiac massage in a patient
with acute myocardial infarction due to total obstruction of the left main
trunk].
AB - The prognosis in patients manifesting shock following acute myocardial infarction
due to total occlusion of the left main trunk (LMT) is usually very poor and so
is the lifesaving rate. Accurate judgement and rapid response are key to the
successful management of this disease. We experienced a successful case with
emergency coronary artery bypass grafting (CABG) on the 14 the day after initial
attack. The patient, who had total occlusion of LMT, underwent a PTCA
(percutaneous transluminal coronary angioplasty) during the initial attack under
cardiac massage. We think in situations where patients have cardiac arrest,
shock, elevated CPK levels suggesting devastation of myocardium due either to LMT
or severe triple vessels disease, early catheter intervention rather than
emergency CABG would be much more tolerable as long as hemodynamic situation
allows. Our previous experience taught us that immediate surgical intervention
with CABG usually resulted in poor outcome. Further refinements regarding the
surgical procedure, technique, assist circulatory supports, cardioplegia, etc.,
are indispensable before trying to have a successful emergency CABG.
PMID- 9394592
TI - [Repair of aortic arch aneurysm protruding to the retrobronchial space--a case
report].
AB - A case of pseudoaneurysm of the aortic arch which protruded to the retrobronchial
space is reported. A 73-year-old female complaining of severe chest pain was
transferred to our hospital, CT showed an abnormal mass which occupied the
retrobronchial space and displaced the esophagus toward righ, associated with
left pleural effusion. A pseudoaneurysm of the aortic arch was suspected.
Angiography revealed an aortic arch aneurysm protruding to the retrobronchial
space. Emergent total arch replacement was performed. We diagnosed it as an
impending rupture of the aortic arch aneurysm with a specific shape.
PMID- 9394593
TI - [Successful surgical correction of incomplete endocardial cushion defect in a 65
year-old female].
AB - We report a case of surgical correction of a 65-year-old female. She presented
severe congestive heart failure and preoperative cardiac catheterization showed
massive left to right shunt (87%), mild mitral regurgitation, severe tricuspid
regurgitation and pulmonary hypertension. The operative procedure consisted of
annuloplasty of mitral valve (Kay's method), patch closure of the ostium primum
defect and annuloplasty of tricuspid valve. Postoperative examination showed
complete competence of mitral valve and improved functional capacity. This is the
fourth successful case report of surgical correction of incomplete endocardial
cushion defect in patients older than 65-year-old in Japan to our knowledge.
Surgical correction of incomplete endocardial cushion defect should be
recommended even in elder patients.
PMID- 9394594
TI - [An surgical case of right pulmonary coccidioidomycosis--with subcutaneous
coccidiomycosis in the left wrist].
AB - Coccidioides is an afferent fungus disease. In Japan, there have been only a few
surgical reports on coccidioides disease. We report a 39-year-old male who was
diagnosed as having coccidioides disease by biopsy of subcutaneous nodules in the
left wrist. The patient also showed a tumor image (1.5 x 1.0 cm) in S4 in the
right lung. He had previously lived in Fresno, California on business between
1988 and 1993. After biopsy of the subcutaneous nodules, Itraconazole (200 mg),
an anti-fungal drug, was orally administered for the lesion in the right lung for
about 6 months. Since the tumor image revealed no improvement through this
treatment, the tumor was resected. Histopathological examination by Grocott
staining demonstrated the spherical form Coccidioides, i.e., endospores. Only 5
cases of resected pulmonary coccidioidal lesions have been reported in Japan
including this case. We must be careful when handling coccidioidal culture
because of its strong infectiosity.
PMID- 9394595
TI - [An adult case of aortic coarctation associated with two thoracic aneurysms].
AB - A 57-year-old woman in whom an abnormality was detected on the chest X-ray
presented with no signs or symptoms other than hypertension. Several examinations
revealed that she had aortic coarctation of the isthmus with two aneurysm in the
arch. One aneurysm was located in the root of the left subclavian artery, another
was just distal of the first aneurysm. For prevention of rupture of the aneurysms
and treatment of hypertension, aortic arch reconstruction was performed with the
aid of selective cerebral perfusion. The postoperative course was uneventful and
she was discharged 19 days after the operation with normalization of her blood
pressure. At the operation in this case, the combination of the two approaches,
median sternotomy and left 4th thoracotomy, was useful.
PMID- 9394596
TI - [Minimally invasive approach for mitral valve, aortic valve, and atrial septal
defect surgery].
AB - We successfully introduced minimally invasive cardiac surgery (MICS) to japan by
performing thoracoscopic clipping of a patent ductus arteriosus in July 1992.
MICS via a small right parasternal incision (Cosgrove procedure) was applied for
one patients with severe rheumatic mitral stenosis, one with severe aortic
regurgitation, and one with atrial septal defect (ASD). Mitral valve replacement
(MVR), aortic valve replacement (AVR), and direct closure of the ASD were
performed successfully by MICS for the the first time in Japan. All three
patients required no blood transfusion and had no complications postoperatively,
being discharged from hospital at 15, 13, and 9 days after their operations. MICS
was satisfactory for mitral valve and ASD operations, but AVR by this approach
took much longer than by standard midline sternotomy due to the poor surgical
field obtained via the small right parasternal incision. A minimally invasive
approach for surgery on the aortic valve and ascending aorta may require
transection of the sternum or some other method. MICS has several advantages,
including less trauma and pain, faster patient recovery, shorter ICU and hospital
stays, a lower cost, and a better cosmetic outcome. Therefore, it is better for
the patient when it is feasible. MICS should develop and be applied to more
patients with cardiovascular disease in the future. Some of the standard
cardiovascular operations may soon be replaced by MICS.
PMID- 9394597
TI - [A successful surgical treatment for huge left circumflex artery-right ventricle
fistula using the fistula occlusion test].
AB - A surgical case of rare coronary artery fistula between the left circumflex
artery and right ventricle was reported. A 46-year-old woman had suffered from
exertional dyspnea and palpitation for three years. Pan systolic heart murmur was
heard through the left 4th inter costal space. The chest X-ray film demonstrated
cardiac enlargement and lung congestion, and the electrocardiograms showed atrial
fibrillation and left ventricular hypertrophy when she was admitted to our
hospital. Preoperative catheterization revealed a huge coronary artery fistula
originating from the left circumflex artery and opening into the right ventricle
through the posterior wall of the heart. The left-to-right shunt ratio was 60%
and Qp/Qs was 2.47. At operation, the dilated circumflex artery fistula was
carefully dissected and the tape was passed around the fistula as a tourniquet
under extra corporeal circulation on the beating heart. To estimate myocardial
ischemia, the fistula occlusion test was performed by tightening the previously
placed tourniquet. Monitoring of electrocardiograms, transesophageal
echocardiography, and hemodynamics were useful to detect myocardial ischemia. The
occlusion test was performed under ECC for 5 minutes. No ischemic changes were
observed. The fistula was interrupted under cardiac arrest at the point of the
occlusion test.
PMID- 9394598
TI - [Localized lesions on MRI in the globus pallidus, subthalamic nuclei and
hippocampus in patients with severe intellectual and motor disabilities].
AB - We examined the clinical picture of eight patients with severe intellectual and
motor disabilities, who had experienced prolonged and severe neonatal jaundice,
and showed localized lesions in the globus pallidus, subthalamic nuclei and
hippocampus on MRI. All patients had athetoid tetraplegia, and five patients
showed disturbed ocular movements and seven showed dysphagia. Five patients could
communicate with others or utter words, and all showed mental retardation.
Auditory brainstem responses were abnormal in seven, and the percentage of REM
sleep on all-night polysomnography was reduced in three. Neither CT nor T1
weighted MR images could detect any changes in the pallidum or subthalamic
nuclei, while T2-weighted MR images disclosed bilateral high signals in the
pallidum, especially in the internal segment, in all patients. Five of the 7
patients, in whom coronal T2-weighted MR imagings were obtained, showed high
signals in the subthalamic nuclei. The hippocampus showed atrophy and/or T2
prolongation in seven patients. In one autopsy case, these MRI changes were
concordant with pathological lesions. In patients with athetoid cerebral palsy,
brainstem dysfunctions, and abnormal ABR, localization of MRI lesions to the
pallidum and subthalamic nuclei is evidence for neonatal bilirubin
encephalopathy.
PMID- 9394599
TI - [Clinico-etiological study of forty-five cases of children with severe motor and
intellectual disabilities of postnatal origin].
AB - The aim of this study is to analyze causes of severe brain damages of postnatal
origin in children and to search for strategies to prevent them. The patients
group consists of forty-five children with severe motor and intellectual
disabilities sampled at several hospitals and special schools in a part of Tokyo.
Twenty-four out of 45 cases (53%) were due to infectious diseases of the central
nervous system (meningitis, encephalitis, and acute encephalopathy including Reye
syndrome). Nine cases (20%) were due to brain damage related to medical services
(complications of heart surgery, hypoglycemic encephalopathy, and so on).
Accident-related brain damages accounted for 8 cases (18%) and 4 out of 8 were
anoxic encephalopathy due to asphyxia (hanging and near drowning in two cases
each). We conclude that intensive prevention and treatment of infectious diseases
and accidents in children can reduce large part of the incidence of postnatally
acquired severe brain damages in children.
PMID- 9394600
TI - [Mismatch negativity of patients with hydranencephaly].
AB - We examined auditory evoked potentials and passive event-related potentials in
two patients with hydranencephaly. In the middle latency response, a Na component
was observed in both cases. Mismatch negativity was elicited in response to tone
bursts and three patterns of vowel sounds in Patient 1, and three patterns of
vowel stimuli in Patient 2. These results implicate the subcortical components of
the auditory system in the generation of mismatch negativity.
PMID- 9394601
TI - [Proinflammatory cytokine levels in cerebrospinal fluid from children with acute
encephalitis].
AB - We investigated interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor
necrosis factor-alpha (TNF-alpha), and soluble TNF receptor 1 (sTNF-R 1) during
the acute stage in the cerebrospinal fluid (CSF) from children with acute
encephalitis by means of a sandwich enzyme immunoassay. We divided the 24
children with acute encephalitis into two groups: those who survived without
neurological sequelae (Group 1, n = 15), and those who died or were left with
sequelae (Group 2, n = 9). The IL-1 beta, IL-6, TNF-alpha and sTNF-R 1 levels in
CSF in the two groups were significantly higher than those in control subjects (n
= 23). The CSF sTNF-R 1 levels in Group 2 were significantly higher than those in
Group 1. Our findings suggest that the IL-1 beta, IL-6 and TNF-alpha in CSF are
related to the pathogenesis of acute encephalitis, and that the CSF level of sTNF
R1 during the acute stage of encephalitis is an important index for predicting
the neurological outcome.
PMID- 9394602
TI - [Moyamoya disease presenting initially with mental disturbance].
AB - Moyamoya disease usually presents itself in children as recurrent episodes of
transient cerebral ischemia, such as acute motor and sensory deficits, speech
disturbance, headache and seizures. Its initial symptoms rarely include mental
disturbance. We experienced a nine-year-old girl with Moyamoya disease who showed
choreic involuntary movements of the left upper and lower limbs. In spite of
mental disturbance which began around the age of four, she had never visited
hospital. CT and MRI detected multiple ischemic lesions in the frontal, parietal
and occipital areas. SPECT demonstrated low perfusion of these regions as well as
of the right corpora striata, which appeared to be normal in MRI. She underwent
right and left superficial temporal artery-middle cerebral artery (STA-MCA)
anastomoses with an interval of three months. The choreic movement completely
disappeared but her intelligence showed no improvement. The cerebral blood flow
increased, but there was no change in the infarction area. Moyamoya disease
should be considered in the differential diagnosis of mental disturbance in young
children.
PMID- 9394603
TI - [A case of pacemaker implantation for complete atrioventricular block associated
with Duchenne muscular dystrophy].
AB - We report here a case of Duchenne muscular dystrophy (DMD) who underwent
pacemaker implantation for complete atrioventricular block. This 30 year-old male
had the deletion of exon 45-52 in the dystrophin gene and complained of
palpitation and precordial oppression. Because his electrocardiogram showed
complete atrioventricular block, a permanent pacemaker was implanted. He has been
doing well for 15 months after implantation. There have been few reports about
pacemaker implantation for patients with DMD. As these patients survive longer by
mechanical ventilation with chest respirators or nasal intermittent positive
pressure ventilators, an increasing number of cases may require pacemaker
implantation.
PMID- 9394604
TI - [A case of postencephalitic intractable partial epilepsy with multiple brain
lesions demonstrated by MRI].
AB - We encountered a case of focal encephalitis. A 5-year-old boy developed high
fever and he was admitted to our hospital on the third day with generalized tonic
clonic convulsions. Cerebrospinal fluid showed slight pleocytosis. CT showed
diffuse low-density area in the left temporal, parietal and occipital regions. T2
weighed MRI showed swelling and hyperintense regions in the left temporal,
parietal and occipital cortex. With the disappearance of generalized convulsion,
the cortical swelling improved. But aphasia and intractable complex partial
seizures appeared. On MRI, the atrophic findings of the left hippocampus and
temporal lesion became developed. We considered this case corresponds to focal
encephalitis related to "a peculiar type of post-encephalitic/encephalopathic
epilepsy" reported by Awaya et al.
PMID- 9394605
TI - [A case of PEHO (progressive encephalopathy with edema, hypsarrhythmia and optic
atrophy) syndrome: changes in clinical and neuroradiological findings].
AB - We reported serial clinical, radiological, and neurophysiological findings of a
patient with PEHO (progressive encephalopathy with edema, hypsarrhythmia and
optic atrophy) syndrome. The case was a 4-year-and-8-month-old boy. He had no
apparent problems during pregnancy, but after his birth severe hypotonia and
developmental delay were evident. Infantile spasms appeared at 3 months of age,
and progressive opisthotonic posture and loss of his visual acuity at 8 months.
Eye fixation was lost, and optic atrophy was observed. Seizures and progressive
atrophy of the cerebellum and brainstem developed during the same period. These
findings of our case support the hypothesis that brainstem lesions are related to
infantile spasms.
PMID- 9394606
TI - [Fulminant subacute sclerosing panencephalitis: clinical and neuropathological
observations].
AB - We describe a 3-year-old boy with subacute sclerosing panencephalitis (SSPE) who
died 4 months after its onset. His initial symptoms were drowsiness and left
hemiplegia. He became comatose in 10 days, and developed a decortical posture
after 45 days. He suffered from multiple cerebral hemorrhage and infarction 3
months later. Oligodendrocytes were positively stained by immunocytochemical
stain with a complement-fixing measles antibody. Light microscopy revealed glial
nodules, perivascular cuffing and reactive gliosis. Small arteries showed intimal
thickening with resultant occlusion and occasional recanalization. These findings
suggested vascular involvement in SSPE. This case illustrates the difference
between the fulminant and chronic forms of SSPE.
PMID- 9394607
TI - [A 10-year-old case with idiopathic oculomotor nerve palsy].
AB - We reported a 10-year-old girl with acquired left oculomotor nerve palsy.
Neurologic and radiological examinations failed to reveal the etiology. Following
administration of corticosteroid and vitamin B6, diplopia improved within 6
weeks, and mydriasis has been improving over the past 9 months. Idiopathic
acquired oculomotor nerve palsy is a very rare condition in childhood, and
prognosis of the disease is sometimes good.
PMID- 9394608
TI - [Female autopsy case of Seitelberger's connatal form of Pelizaeus-Merzbacher
disease].
AB - We report here an autopsy case of connatal Pelizaeus-Merzbacher disease, the
second from Japan. Her clinico-pathological findings were essentially the same as
those of the first case that we reported previously. The clinical course of this
patient was 19 years in duration. Pathologically myelin had disappeared from the
entire central nervous system, whereas that of the peripheral nervous system was
preserved. Axons appeared also intact except for torpedo formation in the
cerebellum. Demyelinated areas showed isomorphic gliosis. Recent studies have
revealed impairment of proteolipid protein synthesis in classical Pelizaeus
Merzbacher disease, the causative gene of which being located on the X
chromosome. Thus, this disease is inherited as an X-linked recessive trait.
However we report herein a sporadic female case in a non-consanguineous family.
Therefore, we propose that this disease might have another causative gene and/or
another mode of inheritance.
PMID- 9394609
TI - [A case of floppy infant with diffuse cerebral calcification, atresia ani, mental
retardation and epilepsy].
PMID- 9394610
TI - Histamine and eicosanoid levels in plasma and peripheral blood leucocyte cultures
during experimental infection of cattle with bluetongue virus serotype 11.
AB - Three calves were sensitized with three doses of inactivated BTV-11 UC8 strain
and then experimentally infected with the homologous virus. In addition, four BTV
seronegative heifers were also experimentally infected with BTV-11. Granulocyte
rich fractions of peripheral blood leucocyte (PBL-GRF) cultures from BTV
sensitized/infected calves and from control unexposed cattle were exposed in
vitro with BTV-11. Histamine, leukotriene (LT) C4 and prostaglandin (PG) D2 were
assayed in supernatant fluids. Plasma histamine levels increased in BTV-infected
heifers from 10.1 +/- 2 ng/ml at Day 0 to 23.1 +/- 6.6 ng/ml at Day 12 following
virus exposure. In addition, in this experimental group the concentration of PGF2
alpha (mean 551.97 +/- 243.54 pg/ml) increased significantly (P < or = 0.05)
compared with control cattle (mean 467.3 +/- 73.9 pg/ml). Bluetongue virus
induced histamine and LTC4 release after in vitro infection of PBL-GRF. Release
of LTC4 was significantly (P < or = 0.05) higher in PBL-GRF cultures from
sensitized and control animals than in unexposed PBL-GRF cultures. In contrast to
these results, PGD2 was not released after BTV infection of PBL-GRF in vitro. The
histamine release caused by BTV was virus-specific and mainly mediated by an
immunological reaction, since the release was significantly reduced by removal of
cell surface immunoglobulins.
PMID- 9394611
TI - Experimental infection of swine and cat central nervous systems by the pig
paramyxovirus of the blue eye disease.
AB - This study analyses whether the pig paramyxovirus of blue eye disease (PPBED)
infects the central nervous system (CNS) utilizing anterograde and retrograde
peripheral nerve transport systems. The virus was injected into muscle and skin,
and inoculated per nasum. The presence of PPBED was detected by an
immunohistochemical method using polyclonal mouse antibodies against the whole
inactivated virus, and was revealed with polyclonal rabbit antibodies against
mouse immunoglobulin G (IgG) labelled with peroxidase. The PPBED injected into
the pig medial gastrocnemius (MG) muscle was detected in a terminal branch
innervating the MG muscle, in neural fibres of the sciatic nerve, in fibres of
the ventral and dorsal spinal roots and in ventral horn neurones of the spinal
cord. When PPBED was injected into the skin area innervated by the sural nerve,
it was detected in neural fibres of the sural and sciatic nerves and in spinal
cord dorsal horn neurones. The per nasum inoculum rapidly invaded the CNS through
the olfactory nerve. The study concluded that, in order to invade the CNS, PPBED
was transported retrogradely by peripheral cutaneous and muscular nerves, and
anterogradely by the olfactory nerve. No PPBED was detected in either cat
peripheral nerves or in cat CNS.
PMID- 9394612
TI - Monoclonal antibody characterization of rabies virus strains isolated in the
River Plate Basin.
AB - In this study, 91 strains isolated in the River Plate Basin, South America, were
examined from the epidemiological standpoint and with monoclonal antibodies
(MAbs) to the nucleocapsid of rabies virus. Such strains reacted to MAbs in
accordance with nine different patterns (antigenic variants). Rabies virus was
isolated from 49 cattle, 21 dogs, 11 non-haematophagous bats, four vampire bats,
two foxes, two horses, one buffalo, and one human. Five of the variants had not
been described previously. It was also found that two cases of rabies in wild
foxes (Cerdocyon thous) which had attacked persons in the Province of Chaco,
Argentina, had been caused by variants from dog and vampire bat, while two cases
in frugivorous bats (Artibeus lituratus) from Argentina and Brazil, had been
infected by vampire bat variants. In addition, symptoms shown by cattle infected
with strains which reacted as originating in canine vectors, differed from those
observed in bovines from which the variants isolated corresponded to vampire
bats.
PMID- 9394613
TI - Immunopotentiating activities of polysaccharide fraction from pine seed shell
extract.
AB - The function of polysaccharide (PSE) extracted from pine seed shells as a
immunopotentiator was investigated. The phagocytosis and chemotaxis of mouse
peritoneal macrophages (MP) were augmented by oral administration of PSE. The
incorporation of 3H-thymidine by Con A-stimulated mouse splenic cells was
significantly intensified by administration of PSE but the adherent-cells (MP)
eliminated splenic lymphocytes was not increased. It is shown that the existence
of activated MP is needed for the activation (proliferation) of T lymphocytes.
The responsiveness of mouse T cells to alloantigen was also augmented by
administration of PSE. The number of anti-SRBC plaque-forming cells in the spleen
of mouse and chicken was also significantly increased. The results indicate that
MP are first activated by oral administration of PSE and that the activation of T
cells is then initiated indirectly by humoral factors (cytokines) produced by
activated MP.
PMID- 9394614
TI - Partial purification and characterization of a murine malaria parasite,
Plasmodium berghei specific aldolase.
AB - Cell-free P. berghei contains 26.1 times more aldolase activity as compared to
normal mouse erythrocytes. Subcellular fractionation of cell-free parasite showed
maximum enzyme activity in the soluble fraction. The parasite enzyme was active
in a narrow pH range of 7.8-8.0. Of the enzyme activity 90% was lost within 2
weeks at 4 degrees C. Slight inhibition was observed with specific inhibitors
ATP, pyrophosphate (PPi) and PEP. The F1, 6DP Km was 0.025 mM.
PMID- 9394615
TI - Intestinal manifestations of experimental SIV-infection in rhesus monkeys (Macaca
mulatta): a histological and ultrastructural study.
AB - Intestinal lesions were studied in 32 rhesus monkeys experimentally infected with
different strains of simian immunodeficiency virus SIVmac (251/32H, 251/32H-SPL
and 251/MPBL) by light microscopy, transmission and scanning electron microscopy.
A spectrum of primary and secondary manifestations of SIV-infection were
detected. Primary changes included 'SIV-enteropathy' in 12 monkeys and virus
induced syncytial giant cell formation (GCF) of the intestine in two animals. A
primary virus-induced enteropathy occurred both as only histologically visible
'SIV-enteropathy' and as 'AIDS-enteropathy' accompanied by clinical signs of
enteritis. Secondary opportunistic infections (Balantidium coli, Cryptosporidium,
Trichuris, Trichomonas, Spironucleus, Mycobacteria and Cytomegalovirus) were
identified in 27 animals and three monkeys developed malignant lymphomas
involving the intestinal tract. Compared to intestinal lesions in HIV-infected
patients, differences were found concerning the incidence of GCF and the range of
opportunistic infections, with cryptosporidium, cytomegalovirus and mycobacteria
occurring in both SIV-infected macaques and AIDS patients. The present
observations revealed that SIV-infected rhesus monkeys provide an excellent model
both for studies on the pathogenesis of HIV-enteropathy and opportunistic
infections and for the development of therapies against cryptosporidial,
cytomegalovirus and mycobacteria infection. Comparison of three SIV-strains
revealed differences in primary and secondary lesions observed: SIVmac251/MPBL
was correlated with severe primary SIV-induced pathologic changes and SIVmac251
SPL-infected animals showed a higher incidence of malignant lymphomas.
PMID- 9394616
TI - The chromosomal signal for sex determination in Caenorhabditis elegans.
AB - In Caenorhabditis elegans, sex is determined by the number of X chromosomes
which, in turn, determines the expression of the X-linked gene xol-1. Recent work
has shown that xol-1 expression is controlled by least two distinct regulatory
mechanisms, one transcriptional and another post-transcriptional. The
transcriptional regulator is a repressor acting in XX embryos; although the
specific gene has not been identified, the chromosome region has been defined. A
previously defined regulator of xol-1, known as fox-1, maps to a different region
of the X chromosome and works post-transcriptionally, consistent with the
identification of the fox-1 gene product as a putative RNA binding protein.
PMID- 9394617
TI - Zyxin: zinc fingers at sites of cell adhesion.
AB - Zyxin is a low abundance phosphoprotein that is localized at sites of cell
substratum adhesion in fibroblasts. Zyxin displays the architectural features of
an intracellular signal transducer. The protein exhibits an extensive proline
rich domain, a nuclear export signal and three copies of the LIM motif, a double
zinc-finger domain found in many proteins that play central roles in regulation
of cell differentiation. Zyxin interacts with alpha-actinin, members of the
cysteine-rich protein (CRP) family, proteins that display Src homology 3 (SH3)
domains and Ena/VASP family members. Zyxin and its partners have been implicated
in the spatial control of actin filament assembly as well as in pathways
important for cell differentiation. Based on its repertoire of binding partners
and its behavior, zyxin may serve as a scaffold for the assembly of multimeric
protein machines that function in the nucleus and at sites of cell adhesion.
PMID- 9394618
TI - Root development: signaling down and around.
AB - Because of its elegant simplicity, the Arabidopsis root has become a model for
studying plant organogenesis. In this review we focus on recent results
indicating the importance of signaling in root development. A role for positional
information in root cell specification has been demonstrated by ablation
analyses. Through mutational analysis, genes have been identified that play a
role in radial pattern formation. The embryonic phenotypes of these mutants
raised the possibility that division patterns in post-embryonic roots are
dependent on signaling that originates during embryonic development. Analysis of
expression of the SCARECROW gene indicates that it may play a role in this 'top
down' signaling process. Characterization of root epidermis development has led
to the identification of negative regulators of root-hair formation. These appear
to set up a prepattern which is reinforced by signaling by plant hormones.
PMID- 9394619
TI - Proliferating cell nuclear antigen: more than a clamp for DNA polymerases.
AB - DNA metabolic events such as replication, repair and recombination require the
concerted action of several enzymes and cofactors. Nature has provided a set of
proteins that support DNA polymerases in performing processive, accurate and
rapid DNA synthesis. Two of them, the proliferating cell nuclear antigen and its
adapter protein replication factor C, cooperate to form a moving platform that
was initially thought of only as an anchor point for DNA polymerases delta and
epsilon. It now appears that proliferating cell nuclear antigen is also a
communication point between a variety of important cellular processes including
cell cycle control, DNA replication, nucleotide excision repair, post-replication
mismatch repair, base excision repair and at least one apoptotic pathway. The
dynamic movement of proliferating cell nuclear antigen on and off the DNA renders
this protein an ideal communicator for a variety of proteins that are essential
for DNA metabolic events in eukaryotic cells.
PMID- 9394620
TI - Multifunctional plasma membrane redox systems.
AB - All the biological membranes contain oxidoreduction systems actively involved in
their bioenergetics. Plasma membrane redox systems seem to be ubiquitous and they
have been related to several important functions, including not only their role
in cell bioenergetics, but also in cell defense through the generation of
reactive oxygen species, in iron uptake, in the control of cell growth and
proliferation and in signal transduction. In the last few years, an increasing
number of mechanistic and molecular studies have deeply widened our knowledge on
the function of these plasma membrane redox systems. The aim of this review is to
summarize what is currently known about the components and physiological roles of
these systems.
PMID- 9394621
TI - Budding of enveloped viruses from the plasma membrane.
AB - Many enveloped viruses are released from infected cells by maturing and budding
at the plasma membrane. During this process, viral core components are
incorporated into membrane vesicles that contain viral transmembrane proteins,
termed 'spike' proteins. For many years these spike proteins, which are required
for infectivity, were believed to be incorporated into virions via a direct
interaction between their cytoplasmic domains and viral core components. More
recent evidence shows that, while such direct interactions drive budding of
alphaviruses, this may not be the case for negative strand RNA viruses and
retroviruses. These viruses can bud particles in the absence of spike proteins,
using only viral core components to drive the process. In some cases the spike
proteins, without the viral core, can be released as virus-like particles.
Optimal budding and release may, therefore, depend on a 'push-and-pull' concerted
action of core and spike, where oligomerization of both components plays a
crucial role.
PMID- 9394622
TI - Signaling activation and repression of RNA polymerase II transcription in yeast.
AB - Activators of RNA polymerase II transcription possess distinct and separable DNA
binding and transcriptional activation domains. They are thought to function by
binding to specific sites on DNA and interacting with proteins (transcription
factors) binding near to the transcriptional start site of a gene. The ability of
these proteins to activate transcription is a highly regulated process, with
activation only occurring under specific conditions to ensure proper timing and
levels of target gene expression. Such regulation modulates the ability of
transcription factors either to bind DNA or to interact with the transcriptional
machinery. Here we discuss recent advances in our understanding of these
mechanisms of transcriptional regulation in yeast.
PMID- 9394623
TI - Calpains: intact and active?
AB - Calpains are a family of calcium-dependent thiol-proteases which are proposed to
be involved in many physiological processes as well as pathological conditions.
Calpains are likely to be involved in processing of numerous enzymes and
cytoskeletal components, thereby linking their activity to a variety of
intracellular events. Although widely studied, the precise mechanism(s) involved
in calpain activation and activity in vivo remain poorly understood. Initial
studies suggested that calpain exists primarily as an inactive proenzyme that
required autolytic cleavage for activation. It was also hypothesized that calpain
associated with membrane phospholipids, serving to increase calcium sensitivity,
facilitating autolytic conversion and thus activating the enzyme. These
hypotheses, however, have not been universally accepted and there is increasing
evidence that intact, non-autolyzed calpain is the physiologically active calpain
form.
PMID- 9394624
TI - Antimicrobial peptide defense in Drosophila.
AB - Drosophila responds to a septic injury by the rapid synthesis of antimicrobial
peptides. These molecules are predominantly produced by the fat body, a
functional equivalent of mammalian liver, and are secreted into the hemolymph
where their concentrations can reach up to 100 microM. Six distinct antibacterial
peptides (plus isoforms) and one antifungal peptide have been characterized in
Drosophila and their genes cloned. The induction of the gene encoding the
antifungal peptide relies on the spatzle/Toll/cactus gene cassette, which is
involved in the control of dorsoventral patterning in the embryo, and shows
interesting structural and functional similarities with cytokine-induced
activation of NF-kappa B in mammalian cells. An additional pathway, dependent on
the as yet unidentified imd (for immune-deficiency) gene, is required for the
full induction of the antibacterial peptide genes. Mutants deficient for the Toll
and imd pathways exhibit a severely reduced survival to fungal and bacterial
infections, respectively. Recent data on the molecular mechanisms underlying
recognition of non-self are also discussed in this review.
PMID- 9394625
TI - Does sex determination start at conception?
AB - Recent molecular studies of mammalian sexual determination have been focused on
gene expression in the gonadal ridge at the time of appearance of sexual
dimorphism: the critical time defined by the 'Jost principle'. Three lines of
evidence suggest that, instead, sex determination may start shortly after
conception: (1) the XY preimplantation embryo usually develops more rapidly than
the XX preimplantation embryo (this phenotype has been linked to the Y chromosome
and will be termed 'Growth factor Y'); (2) the gene for testis determination,
SRY/Sry, and the closely linked genes ZFY/Zfy and Smcy, are transcribed in the
preimplantation embryo; and (3) male and female preimplantation embryos are
antigenically distinguishable, indicating sex differences in gene expression. The
data to support these assertions are reviewed. Possible relationships of these
three phenomena to each other and to sex differentiation are discussed.
Similarities in mechanisms of sexual determination between marsupial and
eutherian mammals are hypothesized. Problems with interpreting male sexual
differentiation as being solely due to testosterone and Mullerian inhibiting
substance (MIS) are discussed.
PMID- 9394626
TI - Plastids in parasites of humans.
AB - It has recently emerged that malarial, toxoplasmodial and related parasites
contain a vestigial plastid (the organelle in which photosynthesis occurs in
plants and algae). The function of the plastid in these obligate intracellular
parasites has not been established. It seems likely that modern apicomplexans
derive from photosynthetic predecessors, which perhaps formed associations with
protists and invertebrates and abandoned autotrophy in favour of parasitism.
Recognition of a third genetic compartment in these parasites proffers
alternative strategies for combating a host of important human and animal
diseases. It also poses some fascinating questions about the evolutionary biology
of this important group of pathogens.
PMID- 9394627
TI - Evolving rodent dentition.
PMID- 9394628
TI - Cross-modal equivalence of visual and auditory scatterplots for exploring
bivariate data samples.
AB - The equivalence of visual and auditory scatterplots was examined in two
experiments. Experiment 1 examined the relationship between actual Pearson's r
and visual and auditory judgments of direction and magnitude of correlation for
24 bivariate data samples. Experiment 2 directly evaluated visual and auditory
perceptual sensitivity to outliers by examining changes in perceived magnitude
and direction of correlation estimates for scatterplots from Experiment 1 that
were altered by the addition of outlier points. Results suggest that the
information conveyed by visual and auditory scatterplots is used very similarly
by the two modalities. Both visual and auditory scatterplots are quite efficient
in conveying sign and magnitude of correlation, and the effect of outliers on
judged magnitude of correlation is similar for the two types of data display.
PMID- 9394629
TI - Artificial looming yields improved performance over lateral motion: implications
for stereoscopic display techniques.
AB - In the natural world, a number of visual cues indicate that an item is quickly
approaching the perceiver. Binocular disparity is one cue for depth, and it has
been demonstrated that abrupt changes in disparity, artificially unaccompanied by
correlated depth cues, are capable of causing the perception of looming for the
observer. An experiment involving 38 undergraduates, using a computer-controlled
stereoscopic display, examined the ability of above-threshold changes in
disparity (artificial looming) to facilitate response time and accuracy for
observers engaged in an object-enumeration task within a cluttered display.
Compared with performance using the same stimuli without disparity information
(lateral motion), participants were more accurate regardless of the disparity
level (9, 12, 24, or 48 minutes of arc) and faster at the two lowest levels of
disparity. Participants showed the classic subitizing function, suggesting that
target stimuli presented with motion information were segregated from otherwise
identical distractor items. It is proposed that binocular disparity information
can act as a valid location cuing method in stereoscopic computer displays in
which form and color information are to be preserved.
PMID- 9394630
TI - The effects of spatial frequency on binocular fusion: from elementary to complex
images.
AB - Factors limiting binocular fusion were studied using 2-dimensional difference of
Gaussian (2D-DOG) stimuli. The proportion of fused stimuli and observer's
response time were determined for stimuli that varied in spatial frequency
composition between 0.22 and 4.8 cycles per degree. At small disparities, mean
fusion response times were short and relatively stable but increased rapidly once
the disparity reached a certain critical value. This 2-phase function implies the
existence of 2 separate fusional mechanisms: a rapid neurally based fusional
process, which operates at small disparities, and a second mechanism involving
reflexive vergence movements operating at disparities 2 to 3 times larger. Both
mechanisms are highly influenced by spatial frequency, being 4 to 5 times more
effective at low spatial frequencies. Additional experiments demonstrated that
with compound stimuli, the fusion limit is not determined by the highest spatial
frequency components (as had been reported previously) but, rather, can take
advantage of the additional fusional range associated with low spatial
frequencies. Such cooperation may be obvious only in the case of 2-dimensional
stimuli.
PMID- 9394631
TI - Visual accommodation and virtual images: do attentional factors mediate the
interacting effects of perceived distance, mental workload, and stimulus
presentation modality?
AB - A study was conducted to examine the effect on the visual accommodation response
of processing information presented either visually or aurally while viewing a
real-world scene. A number of different conditions were tested in which a mental
processing task, a virtual image overlaying the real world (as is the case with
head-up displays), or both were present. These manipulations provided two factors
that have previously been demonstrated to have some influence on the
accommodation response: mental effort and perceived distance. They also allowed
the investigation of the influence of the source modality of the information to
be processed. The results suggested that these influences may have a cumulative
effect on the visual accommodation response, possibly mediated by attentional
factors.
PMID- 9394632
TI - Multiaccommodative stimuli in VR systems: problems & solutions.
AB - Virtual reality environments can introduce multiple and sometimes conflicting
accommodative stimuli. For instance, with the high-powered lenses commonly used
in head-mounted displays, small discrepancies in screen lens placement, caused by
manufacturer error or user adjustment focus error, can change the focal depths of
the image by a couple of diopters. This can introduce a binocular accommodative
stimulus or, if the displacement between the two screens is unequal, an unequal
(anisometropic) accommodative stimulus for the two eyes. Systems that allow
simultaneous viewing of virtual and real images can also introduce a conflict in
accommodative stimuli: When real and virtual images are at different focal
planes, both cannot be in focus at the same time, though they may appear to be in
similar locations in space. In this paper four unique designs are described that
minimize the range of accommodative stimuli and maximize the visual system's
ability to cope efficiently with the focus conflicts that remain: pinhole optics,
monocular lens addition combined with aniso-accommodation, chromatic bifocal, and
bifocal lens system. The advantages and disadvantages of each design are
described and recommendation for design choice is given after consideration of
the end use of the virtual reality system (e.g., low or high end, entertainment,
technical, or medical use). The appropriate design modifications should allow
greater user comfort and better performance.
PMID- 9394633
TI - A methodology for optimally designing console panels for use by a single
operator.
AB - A seven-step methodology is presented to determine a dimensionally correct
optimal layout of a console panel for a single operator. This methodology
integrates the steps in the layout design process and uses a mathematical
optimization model from facility design to obtain the optimal panel layout. A
major difference in this methodology from previous work is that the mathematical
optimization model incorporates factors that are only partially included in
previous mathematical models. In addition, it includes the areas of the panel
components as a new factor. This methodology is illustrated by the design of a
nuclear power plant console panel.
PMID- 9394634
TI - Competition and performance on a computer-based complex perceptual-motor task.
AB - Employees of temporary agencies practiced Space Fortress, a complex video game
task, for 10 sessions, each consisting of 8 practice and 2 test games of 3 min
each. Trainees practiced individually, in dyads, or in tetrads, and they were
classified as having high or low aptitude based on computer attitude scores and
baseline performance. Competition for monetary prizes was introduced early in
training, late in training, or not at all. Competition facilitated high-aptitude
trainees but not low-aptitude trainees. Group size and the timing of competition
instructions had no main effects or interactions. The results are discussed in
terms of social facilitation theory, according to which competition facilitates
dominant responses, which helps high-skill trainees but not low-skill trainees.
PMID- 9394635
TI - Framing of task performance strategies: effects on performance in a
multiattribute dynamic decision making environment.
AB - It is well documented that the way a static choice task is "framed" can
dramatically alter choice behavior, often leading to observable preference
reversals. This framing effect appears to result from perceived changes in the
nature or location of a person's initial reference point, but it is not clear how
framing effects might generalize to performance on dynamic decision making tasks
that are characterized by high workload, time constraints, risk, or stress. A
study was conducted to examine the hypothesis that framing can introduce
affective components to the decision making process and can influence, either
favorably (positive frame) or adversely (negative frame), the implementation and
use of decision making strategies in dynamic high-workload environments. Results
indicated that negative frame participants were significantly impaired in
developing and employing a simple optimal decision strategy relative to a
positive frame group. Discussion focuses on implications of these results for
models of dynamic decision making.
PMID- 9394636
TI - Aging and decision making: driving-related problem solving.
AB - We examined age-related effects on decision making in a task environment familiar
to most younger and older adults. Participants made route-selection decisions in
real time. Participants received information about traffic density and expected
speed limits of main and alternative routes, from which they determined the
optimality of their present route versus alternative routes. The experiment
evaluated the effects of information type, amount of congestion, alternative
route speed limit, and age on speed and quality of decision making. Measures of
optimal route selection revealed main effects of alternative route speed limit,
congestion level, and message type, but there was not a main effect of age, and
age did not interact with any variable. In terms of decision speed (but not
quality of decision making), older participants were slower, and age interacted
with alternative route speed and with message type. The data are interpreted in
relation to previous data examining everyday problem solving and aging.
PMID- 9394638
TI - Stability limits in extreme postures: effects of load positioning, foot
placement, and strength.
AB - Although injuries related to postural stability are prevalent, ergonomic job
analyses traditionally have not addressed stability issues. In this research
functional stability limits are quantified for persons standing in extreme
postures under various external load and foot positioning conditions.
Participants were asked to lean and displace their center of gravity (COG) as far
as possible in eight directions to the sides and front of the body. Stability
measures based on these COG displacements were calculated. All controlled
variables significantly affected the stability measures. When standing unladen,
participants extended their COG to within 99% of their theoretical maximum.
Movement was much more restricted when handling a load (89%), especially when
holding it with one hand on the shoulder (84%). On average, increased separation
of the feet in a particular direction resulted in larger COG displacements in
that direction. The results are discussed relative to their effects on balance
and stability modeling.
PMID- 9394637
TI - The influence of flooring on standing balance among older persons.
AB - This study investigated the effects of flooring on balance during quiet standing
in healthy young and older participants. Seven flooring conditions were examined,
including a hard tile floor and combinations of low-pile and high-pile carpet
with urethane foam and rubber padding. The resulting floors provided a variety of
compliant surfaces, ranging from very soft to hard. Participants stood during
three separate visual conditions: eyes open, eyes closed, and looking at a moving
visual surround. Three measures of postural sway were calculated using center of
pressure recordings during the trails. The results showed that the amplitude of
sway was higher in the older than in the younger participants, particularly in
the moving visual surround condition. Flooring compliance was found to have an
effect on sway during moving visual environments, with the largest effects found
among the older participants. Softer floors increased the amount of sway in the
older participants. These results suggest that floor compliance influences
standing postural stability in older people, particularly in destabilizing visual
environments.
PMID- 9394639
TI - Evaluation of the probability of spinal damage caused by sustained cyclic
compression loading.
AB - A sensitivity analysis of two alternative models predicting damage to vertebral
motion segments (VMS) in cyclic compression was performed to evaluate the
relative probability of damage occurring when peak compression force, loading
frequency, or duration in a lifting task is changed. The first model is based on
the assumption that fatigue failure is the mechanism underlying damage to the VMS
in cyclic compression. The second model is based on the assumption that the VMS
damage in cyclic compression is determined by the viscoelastic deformation of the
segment and that the instant of failure can be predicted on the basis of the
energy stored in this process. With both models, we estimated the percentage of
the population likely to incur a VMS injury when performing a repetitive lifting
task with peak compression forces ranging from 1500 to 4100 N, frequencies from 2
to 12 min-1, and durations between 30 and 120 min. The results indicate a
dominant influence of the peak compression force on this outcome over the domain
studied. This conclusion holds qualitatively for both models, suggesting that for
a comparative analysis they can be considered interchangeable. However, a
considerable quantitative difference in the absolute outcomes of the two models
was found, which stresses the importance of further study on the validity of
these models.
PMID- 9394640
TI - Effects of team size on the maximum weight bar lifting strength of military
personnel.
AB - Teamwork is an essential element in the majority of critical Army lifting tasks.
Therefore, an understanding of the relationship between individual and team
lifting capacity is of great tactical importance. Twenty-three male and 17 female
U.S. Army soldiers were randomly assigned to single- and mixed-gender teams of
two, three, and four persons. Individual lifting strength was the one-repetition
maximum (1RM) load lifted from floor to knuckle height using a weight bar. A
square-shaped bar was used for two- and four-person lifting, and a triangular
shaped bar was used for three-person lifting. Team lifting strength as a
percentage of the sum of individual lifting strength (%sum) did not change with
team size. The %sum for teams of men (87.3%) was less than for teams of women
(91.1%, p < 0.05). The %sums for both single-gender teams (all men and all women)
were greater (p < 0.01) than for mixed-gender teams (80.2%). The number of people
lifting a large object was increased to four with no decrease in the
effectiveness of the individual lifter beyond that found for two persons. The 1RM
loads presented in this paper were lifted under ideal conditions by young
soldiers and do not represent norms for an industrial population.
PMID- 9394641
TI - The effect of valve handwheel type, operating plane, and grasping posture on peak
torque strength of young men and women.
AB - An experiment was designed to assess the factors affecting the operation of valve
handwheels. Forty volunteers (20 men and 20 women) participated in this study. A
nested-factorial experimental design was employed. Handwheel type (smooth,
curved, or knurled rim), operating plane (sagittal, frontal, or transverse
plane), grasping posture (power or precision grasp), and operating direction
(clockwise or counterclockwise) were found to have significant effects on the
(maximum volitional torque exertion [MVTE]). A power grasp exerted more force
than did a precision grasp. A smooth-rim handwheel oriented in the frontal plane
resulted in the least MVTE. Counterclockwise torque exertion was significantly
greater than clockwise torque exertion, but the difference was not very large.
MVTE for women (7.9 Nm) was about 66% of that for men (12.0 Nm).
PMID- 9394642
TI - A dynamic mechanical model for hand force in right angle nutrunner operation.
AB - A deterministic mechanical model based on physical tool parameters was used for
estimating static and dynamic hand forces from kinematic measurements. We
investigated the effects of target torque (25, 40, and 55 Nm) and threaded
fastener joint hardness (35-, 150-, 300-, 500-, and 900-ms torque buildup time)
on hand force. Estimated hand force was affected by target torque and joint
hardness. Peak and average dynamic hand force was least for the hard joint (35-ms
buildup) and greatest for the medium hardness joint (150-ms buildup). Tool
inertia played the major role in reducing hand reaction force. Estimated hand
force decreased when the inertial force component increased. Inertial force
decreased by 366% when buildup time increased from 35 to 300 ms. Static modeling
overestimated hand force; the error ranged from 10% for a soft joint to 40% for a
hard joint. Results from direct hand force measurements using a strain gauge
dynamometer showed that the dynamic model overestimated peak hand force by 9%.
However, average hand force and force impulse were not significantly
overestimated.
PMID- 9394643
TI - Health risk assessment of fluctuating concentrations using lognormal models.
AB - A mathematical model is proposed for assessing health risk rates of fluctuating
concentrations. Each time-averaged concentration may be regarded as a dose that,
when applied to the dose-response curve, produces a risk of an adverse effect. A
theoretical derivation shows that the dose-response pattern is a cumulative
lognormal curve because of the diversity of the individuals in the exposed
population. Similarly, the concentration pattern is a log-normal distribution
because of the diversity of emission sources and dispersive processes. The health
risk is produced by the overlapping of the right tail of the concentration
distribution and the left tail of the dose-response curve. The evaluation of the
joint probability in this region has been performed by numerical integration by
computer in terms of two generalized parameters. One represents the geometric
standard deviation of the concentration distribution relative to that of the dose
response curve, and the other represents the distance between the geometric mean
concentration and the concentration producing an adverse response in 50% of the
exposed population. These results are presented graphically and in tabular form.
If the two parameters of the dose-response curve are known, the health risk of
the concentration pattern may be calculated conveniently for any geometric mean
and geometric standard deviation values.
PMID- 9394644
TI - The origin and development of diagnostic radiology as illustrated by postage
stamps.
AB - This is a brief account of the scientific history of radiology and its use in
medical imaging. The approach is untraditional as the narrative is highlighted
with reproductions of selected postage stamps. These illustrations add a new
dimension to the presentation of important events leading to the discovery and
development of diagnostic radiology.
PMID- 9394645
TI - The origin of the word Stent.
AB - In 1856, the English dentist Charles Stent developed a thermoplastic-like
material for taking impressions of toothless mouths. This "Stent mass" was later
used as a device or mould for keeping a skin graft in place; it was also used to
provide support for anastomosis. A hundred years after the inventor's death in
1885, the word stent has been adopted all over the world in interventional
radiology but today it is understood to mean percutaneous tubular structures that
induce or maintain lumen patency. The true origin of the word stent is not found
in many dictionaries. In most references, the wrong dentist is given credit for
the discovery. Dictionaries also refer to the obsolete English and Scottish words
stent and stint which mean, among other things, "to extend". The true origin of
the word is therefore somewhat unclear.
PMID- 9394646
TI - MR imaging of the central nervous system in diving-related decompression illness.
AB - PURPOSE: This investigation was conducted to determine whether MR imaging showed
cerebral or spinal damage in acute diving-related decompression illness, a term
that includes decompression sickness (DCS) and arterial gas embolism (AGE).
MATERIAL AND METHODS: A total of 16 divers with dysbaric injuries were examined
after the initiation of therapeutic recompression. Their injuries comprised:
neurological DCS II n = 8; AGE n = 7; combined cerebral-AGE/spinal-DCS n = 1. T1-
and T2-weighted images of the brain were obtained in 2 planes. In addition, the
spinal cord was imaged in 7 subjects. The imaging findings were correlated with
the neurological symptoms. RESULTS: MR images of the head showed ischemic
cerebrovascular lesions in 6/8 patients with AGE but showed focal
hyperintensities in only 2/8 divers with DCS. Spinal cord involvement was
detected in 1/7 examinations, which was the combined cerebral-AGE/spinal-DCS
case. There was agreement between the locations of the documented lesions and the
clinical manifestations. CONCLUSION: MR readily detects cerebral damage in AGE
but yields low sensitivity in DCS. A negative MR investigation cannot rule out
AGE or DCS. However, MR is useful in the examination of patients with
decompression illness.
PMID- 9394648
TI - Proton (1H) MR spectroscopy for routine diagnostic evaluation of brain lesions.
AB - PURPOSE: To describe the introduction and performance of proton MR spectroscopy
(1H-MRS) in the daily routine of a modern standard MR unit. MATERIAL AND METHODS:
Over an 8-month period, 52 patients with brain lesions were studied with 1H-MRS,
using SE and STEAM sequences for chemical-shift imaging and single-volume
spectroscopy. The quality of the spectra was graded from 1 (best) to 3, and the
main factors influencing the quality of the spectra were evaluated. RESULTS: Of
the measurements: 85% were graded as 1; 12% as 2; and 3% as 3. The main reasons
for poor spectral quality were: the unfortunate positioning of the VOI;
hemorrhage; and/or postoperative changes within the VOI. Of 40 patients with a
final diagnosis: MRS provided an increased confidence in MR diagnosis in 18
cases; MRS contributed significantly to preoperative diagnosis in 3 cases; and
the spectra were not specific (n = 10) or were difficult to evaluate (n = 9)
owing to reduced quality (grade 2 or 3) in 19 cases. CONCLUSION: MRS of the brain
can provide a high percentage of interpretable spectra and frequently can
increase confidence in the MR diagnosis of brain lesions in clinical routine.
PMID- 9394647
TI - Supratentorial primary intra-axial tumors in children. MR and CT evaluation.
AB - PURPOSE: To evaluate the MR and CT features of pediatric supratentorial intra
axial tumors with respect to differential diagnosis and the role of each
investigation modality. MATERIAL AND METHODS: MR and CT findings in 40 children
with 12 types of pathologically proven histological tumors were reviewed.
RESULTS: The location of tumors might be one clue to differential diagnosis. In
our material, cysts (60%), calcifications (45%), and intratumoral hemorrhages
(27%) were found in the tumors. Characteristic features noted in some lesions
included: peritumoral hemosiderin deposition in cavernous angiomas; intratumoral
flow void in a choroid plexus carcinoma and in glioblastomas; and hemicerebral
atrophy in germinomas. A comparison between malignant and benign tumors showed
perifocal edema and a mass effect to be significantly more common in malignant
lesions. Homogeneous enhancement suggested a benign tumor and an inhomogeneous
pattern represented malignancy, while the lack of obvious enhancement did not
always suggest benignity. Intratumoral calcium deposition was a not uncommon
finding in malignant tumors. CONCLUSION: In most cases, the exact diagnosis
should be made by histological examination but it is important for treatment
planning that the appropriate depiction of tumor extension and tissue
characterization be made by MR and CT.
PMID- 9394649
TI - The perfusion fraction in volunteers and in patients with ischaemic stroke.
AB - The fractional volume of capillary blood, i.e. the perfusion fraction f, was
measured with the aid of an echo-planar imaging protocol originally designed for
the measurement of water diffusion. In healthy volunteers, reasonable f values
were obtained. In patients with cerebral ischaemic stroke, a marked decrease in
the f value was seen in the infarcted region as compared with corresponding
values in the contralateral hemisphere. We suggest that perfusion-fraction
measurements may add to the diagnostic value of water-mobility examinations in
patients with ischaemic disease.
PMID- 9394650
TI - Detection of normal mediastinal lymph nodes by ultrasonography.
AB - PURPOSE: The detection by US (in contrast to CT) of lymph nodes of any size in
the mediastinum is usually considered to be a pathological finding. The aim of
this study was to find out whether it was possible to detect normal lymph nodes
by high-resolution mediastinal US. MATERIAL AND METHODS: Six different
mediastinal regions in 80 healthy asymptomatic volunteers and in 20 human
cadavers were examined by means of US (with colour Doppler imaging) to assess US
access to the respective regions and to demonstrate the number and size of
detectable lymph nodes. All the cadaveric lymph nodes that were detected were
examined histologically to exclude inflammatory or malignant infiltration.
RESULTS: In almost all subjects, we obtained US access to the supra-aortic
(100%), paratracheal (95%), prevascular (99%), and pericardial (98%) regions, and
to the aorticopulmonary window (98%). US access to the subcarinal region was more
difficult (75%). In the healthy subjects, lymph nodes were detected in the
paratracheal region (in 35% of these subjects, mean lymph-node diameter 12 x 7
mm), in the aorticopulmonary window (45%, 14 x 8 mm), and in the subcarinal
region (13%, 13 x 7 mm). In the cadavers, histologically normal lymph nodes were
detected frequently in the paratracheal region (85%, mean size 11 x 6 mm) and in
the aorticopulmonary window (90%, 11 x 5 mm). CONCLUSION: These results indicate
that normal lymph nodes (and not only pathological lymph nodes) can be
demonstrated by high-resolution mediastinal US.
PMID- 9394651
TI - Abdominal CT features and survival in acquired immunodeficiency.
AB - PURPOSE: HIV-infected patients show a high incidence of abdominal disease. This
investigation was made to determine whether abdominal CT provided prognostically
relevant information in these patients. MATERIAL AND METHODS: Images from 533
abdominal CT examinations in 339 HIV-infected patients were retrospectively
reviewed for signs of abdominal disease, and correlated with clinical data and
survival rates. The Kaplan-Meier analysis and rank testing of survival, and
proportional hazards regression were used to define prognostic clinical and
imaging findings. RESULTS: Of the 339 patients, 278 (82%) showed abnormal
abdominal findings on CT. Median survival was 29 months. Of the imaging findings,
hepatic masses (n = 11), pathologically enlarged lymph nodes (n = 48), and
ascites (n = 7) were associated with poor survival, giving a median survival of
respectively 13 months, 15 months, and less than 1 month. These three features
showed no association with CD4(+)-T-lymphocyte count or CDC category. Main
determinants of survival were a low CD4(+)-T-lymphocyte count, and certain
abnormal CT findings. Splenomegaly (n = 147), hepatomegaly (n = 144), and
lymphadenopathy (n = 111) were the most common abdominal findings on CT but
lacked prognostic relevance. CONCLUSION: Abdominal CT offered prognostic
implications in HIV-infected patients and might serve in risk stratification in
selected patients. CT features such as hepatic masses, grossly enlarged lymph
nodes, or ascites indicate advanced immunosuppression.
PMID- 9394652
TI - CT-guided core-needle biopsy in omental pathology.
AB - PURPOSE: To assess the accuracy and clinical usefulness of CT-guided core-needle
biopsy in the diagnosis of omental pathology. MATERIAL AND METHODS: We
retrospectively reviewed the results of CT-guided percutaneous core biopsies in
25 patients with focal (n = 2) or diffuse (n = 23) omental pathology. These
results were compared to the final diagnoses as determined by laparotomy (n =
15), laparoscopic biopsy (n = 3), endoscopic biopsy (n = 1), or by the results of
percutaneous biopsy and clinical-radiological and bacteriological modalities (n =
6). The final diagnoses showed 4 patients with isolated omental pathology and 21
with widespread peritoneal involvement. The CT-guided biopsies were performed
with 1.0-1.8-mm Surecut core-needles. RESULTS: In 16 patients, the final
diagnosis was metastatic adenocarcinoma--with the primary tumor sites in the
ovary (n = 3), stomach (n = 1), appendix (n = 2), and unknown (n = 10). In the
remaining 9 patients, the final diagnosis was hepatocellular carcinoma, lymphoma,
and mesothelioma in 1 patient each; tuberculosis in 5; and actinomycosis in 1.
Sufficient histological (n = 16) or cytological (n = 8) material was obtained by
CT biopsy in 24/25 (96%) cases; the specimen was insufficient for diagnosis in 1
case. In differentiating benign from malignant disease, CT-guided biopsy showed a
sensitivity, specificity and accuracy of respectively 89.5%, 100% and 92%. It
gave a specific diagnosis in 78.9% (15/19) of patients with malignant conditions
and in 50% (3/6) of patients with benign disorders. There were no biopsy-related
complications. CONCLUSION: CT-guided percutaneous core-needle biopsy of the
omentum is a safe, useful and highly accurate procedure for diagnosing malignant
omental pathology.
PMID- 9394653
TI - Morphometric measurement of abdominal organs. Comparison of ultrasound and spiral
CT.
AB - PURPOSE: To determine interobserver variability in the morphometric measurement
of abdominal organs with US and spiral CT, and to compare the results obtained
with these two modalities. MATERIAL AND METHODS: US and spiral CT examinations of
the abdomen were performed in 25 patients. In each patient, 13 defined distances
were measured in the liver, spleen and both kidneys with US and spiral CT by two
pairs of radiologists in a blinded manner. The interobserver variations of these
measurements were evaluated for the US and CT examinations, and the data of both
modalities were compared with one another. RESULTS: The measurement of distances
in the abdomen with US and spiral CT is subject to considerable interobserver
variability in both modalities. The relative interobserver variations showed
marked differences, according to which distance was measured. The average
interobserver variations were higher in US than in CT. A direct comparison of US
and spiral CT revealed that distances obtained with CT frequently exceeded those
obtained with US. CONCLUSION: Morphometric measurements of abdominal organs with
US and with spiral CT showed considerable differences. The follow-up examinations
should therefore be performed with the same imaging modality as used in the
original examination.
PMID- 9394654
TI - Diagnosis of liver metastases from colorectal adenocarcinoma. Comparison of
spiral-CTAP combined with intravenous contrast-enhanced spiral-CT and SPIO
enhanced MR combined with plain MR imaging.
AB - PURPOSE: The purpose of this study was to determine whether MR with and without
SPIO (AMI-25) could replace spiral-CTAP in the staging of colorectal
adenocarcinoma. MATERIAL AND METHODS: Thirty-five patients were studied
prospectively by means of i.v. contrast-enhanced spiral-CT, spiral-CTAP, and MR
of the liver. MR imaging was performed before and after infusion of AMI-25.
Diagnoses were compared to intraoperative findings (n = 35) which included
intraoperative ultrasound (n = 21), and follow-up CT (n = 18). RESULTS AND
CONCLUSION: Fifteen patients were found to have a total number of 53 liver
metastases and 43 benign lesions were detected. Evaluation was performed in four
different ways: 1) i.v. contrast-enhanced spiral-CT; 2) i.v. contrast-enhanced
spiral-CT + spiral-CTAP; 3) plain MR; 4) plain MR + SPIO-enhanced MR. I.v.
contrast-enhanced spiral-CT, spiral-CTAP and SPIO-enhanced MR identified patients
with liver metastases with equal sensitivity. However, owing to its significantly
higher sensitivity, based on a lesion-by-lesion analysis, spiral-CTAP cannot be
replaced by SPIO-enhanced MR in patients who are to undergo liver resection. A
limitation in spiral-CTAP is its relatively low specificity.
PMID- 9394655
TI - Single-session alcohol sclerotherapy in benign symptomatic hepatic cysts.
AB - PURPOSE: To evaluate the results of single-session alcohol sclerotherapy in
benign symptomatic liver cysts. MATERIAL AND METHODS: Ten cysts (volume 200-4,800
ml) in 10 patients were treated by percutaneous catheterization and injection of
96% ethanol at a dose of 10% of the cyst volume but never more than 100 ml. The
treatment was applied for a maximum of 20 min, after which the alcohol and
catheter were removed. RESULTS: A satisfactory reduction in cyst volume was
achieved in all patients. In 8 patients there was a re-accumulation of fluid
during the first period after therapy, followed by a significant reduction in
volume on later follow-up examinations. Except for pain, there were no
complications. CONCLUSION: Sclerotherapy as a single-session procedure resulted
in a significant reduction in cyst volume in all 10 patients. The postprocedural
re-accumulation of fluid seen in 8 patients proved to be temporary. It was not
necessary to repeat the sclerotherapy procedure in any patient.
PMID- 9394656
TI - Human hepatic carbohydrate metabolism. Dynamic observation using 13C MRS without
proton decoupling.
AB - PURPOSE: Dynamic natural-abundance 13C MR spectroscopy (MRS) studies without
proton decoupling were performed in the human liver using commercial 1.5 T MR
equipment. MATERIAL AND METHODS: A single tuned custom-made circular surface coil
with an OD of 20 cm operating at 16.04 MHz was used for the 13C study. Seventy
five grams of glucose dissolved in water was administered for the natural
abundance 13C-MRS dynamic study which lasted for approximately 40 to 60 min. Data
acquisition was broken into 20-min and 1.7-min blocks. Localized proton shimming
with a whole-body coil was performed with sufficient volume to include the
observing area of the surface coil; the line width of the water signal was less
than 20 Hz. RESULTS AND CONCLUSION: The glucose and glycogen spectra were clearly
visible at 80 to 120 ppm after oral administration of the glucose solution. These
data demonstrate that dynamic hepatic carbohydrate metabolism can be observed
with commercially available MR equipment. Given that the human hepatic glycogen
pool reaches maximum level within less than 10 min, this technique should provide
a direct diagnosis of hepatic carbohydrate metabolic disorders.
PMID- 9394657
TI - CT with different doses of the hepatocyte-specific contrast medium FP 736-03.
Evaluation in a nude-rat model of experimental metastases.
AB - PURPOSE: To study the dose-response relationship in FP 736-03 (48 mg I/ml),
hepatocyte-specific contrast medium for CT of the liver. MATERIAL AND METHODS: A
nude-rat model of experimental hepatic metastases was used. CT of the liver was
performed before and after i.v. injection of FP 736-03 at 4 different doses:
0.25, 0.5, 1.0 and 2.0 ml/kg b.w. Attenuation in the normal liver parenchyma and
in the metastases was measured and plotted as a function of time. RESULTS: The
enhancement of the normal liver parenchyma increased in the dose range studied.
No increase was found in the metastases: the attenuation here remained constant
during the observation period. The maximum enhancement values at doses of 0.25,
0.5, 1.0 and 2.0 ml/kg b.w. were (mean +/- SD) 13.5 +/- 2.7, 30.1 +/- 4.2, 33.2
+/- 4.5 and 59.7 +/- 13.1 HU respectively.
PMID- 9394658
TI - Choledochoduodenal fistula secondary to duodenal peptic ulcer. A case report.
AB - Spontaneous choledochoduodenal fistula (CDDF) is a rare form of biliary enteric
fistula which usually occurs as a complication of duodenal peptic ulcer disease.
The more common form is cholecystoduodenal fistula (CCDF) which is generally
associated with gallbladder disease. We report on a case of ulcerogenic CDDF
diagnosed by upper gastrointestinal barium study, ultrasonography, and
gastroduodenal endoscopy.
PMID- 9394659
TI - Absorbed dose and image quality in examinations of the colon with digital and
analogue techniques.
AB - PURPOSE: Image quality and the absorbed dose to the patient are issues of primary
interest in the change-over from the conventional analogue technique to the
digital technique in the examination of the colon by means of fluoroscopy. The
aim of this study was to compare the incident radiation and to evaluate the image
quality in two different X-ray equipment types, one digital and one analogue.
MATERIAL AND METHODS: A kerma-area product meter was used to measure the incident
radiation to the patient. Both fluoroscopy and total-examination times were
measured as was the number of images. An evaluation of image quality was made and
statistically analysed. RESULTS AND CONCLUSION: No significant difference in the
irradiation dose was observed between the two techniques. The fluoroscopy time
was significantly lower with the conventional technique but the total-examination
time decreased by 18% with the digital technique. The total number of images
taken was higher with the digital technique (25 images compared to 19) owing to
the limited field of the image intensifier. Significantly more noise and less
sharpness were observed with the digital system but there was no significant
difference in contrast or image quality in the various anatomical structures.
Although the change-over to the digital system produced a reduction in sharpness
and an increase in noise, and no significant dose saving was measured, the
digital system was faster to work with and could well be used for diagnostic
purposes.
PMID- 9394660
TI - Unusual imaging presentations in renal transitional cell carcinoma.
AB - PURPOSE: To report on unusual imaging presentations in renal transitional cell
carcinoma (TCC). MATERIAL AND METHODS: Imaging studies of 140 cases of
pathologically proven renal TCC were retrospectively studied with the focus on
unusual presentations. RESULTS: Unusual imaging manifestations were found in 20
cases (14.3%). These findings were classified into 5 categories: perirenal
abscesses or perirenal hematomas in 6 cases; parenchymal masses in 5; undue
thickening of the hydronephrotic wall in 4; "tuberculoid" pyelograms in 3; and
tumors with massive necrosis in 2. CONCLUSION: Deceptive imaging presentations
may occur in renal TCC. Recognition of these presentations may help to prevent
delay in diagnosis.
PMID- 9394661
TI - Recurrent varicocele. Demonstration by 3D phase-contrast MR angiography.
AB - This is a report on an initial experience with Gd-enhanced 3D phase-contrast MR
angiography in 4 patients with recurrent varicocele. The examinations were
performed with the patients prone, and a coronal imaging volume was used. The
scrotal part of the varicocele was demonstrated in 3 cases and the spermatic vein
in 2 cases. This technique could be an alternative to spermatic venography in the
radiological mapping of dilated spermatic veins.
PMID- 9394662
TI - Pelvic pain syndrome caused by ovarian varices. Treatment by transcatheter
embolization.
AB - PURPOSE: The aim of this study was to evaluate the clinical effect of therapeutic
embolization in the pelvic congestion syndrome caused by ovarian varices.
MATERIAL AND METHODS: Six women, aged 25-40 years, with pelvic pain syndrome and
marked left (n = 5) or bilateral (n = 1) ovarian varicocele were treated by
transcatheter retrograde venous embolization. RESULTS: The pelvic pain syndrome
disappeared in all patients within 4 weeks, and there was regression of the
periodic pain in 2 women with dysmenorrhoea. The patients were free of symptoms
during the 1-4-year follow-up. CONCLUSION: Marked ovarian varices may cause a
pelvic pain syndrome. Percutaneous embolization improves both the chronic pain
and the dysmenorrhea in these patients. Transcatheter treatment could be
considered as an alternative to surgical or laparoscopic ligation in ovarian
varicocele.
PMID- 9394663
TI - Resistive index of the intrascrotal artery in scrotal inflammatory disease.
AB - PURPOSE: To investigate the utility of the resistive indices (RIs) of the
epididymal and intratesticular arteries, and to establish diagnostic criteria for
scrotal inflammatory disease on the basis of quantitative color Doppler
sonography. MATERIAL AND METHODS: We prospectively examined 29 consecutive
patients with scrotal pain, and 15 normal control subjects. The RIs of the
intratesticular and epididymal arteries were obtained from color Doppler
sonographs. RESULTS: The RIs of the testicular artery in epididymoorchitis were
significantly lower than those in normal control subjects and in epididymitis (p
< 0.01) while the RIs of the testicular artery in epididymitis and control
subjects were similar (p > 0.5). With a cut-off value of RI = 0.5, sensitivity,
specificity, accuracy, and positive and negative predictive values were 91%, 94%,
94%, 83%, and 77% respectively. The mean RI of the epididymal arteries in
epididymitis and epididymoorchitis was 0.49 +/- 0.11. A high level of diagnostic
accuracy in scrotal inflammatory disease was achieved when the RIs of the
intratesticular and epididymal arteries were less than 0.5 and 0.7 respectively.
CONCLUSION: The RI of the intrascrotal artery would give a more objective
evaluation than subjective assessment and could provide diagnostic criteria for
scrotal inflammatory disease.
PMID- 9394664
TI - A case of hyperoxaluria. Radiological aspects.
AB - PURPOSE: Oxalosis is an unusual pathological condition with calcium oxalate
deposits in soft tissue and bone, recognized as osteosclerosis on radiography.
Osteosclerotic bone changes in patients treated with hemodialysis are in most
cases due to secondary hyperparathyroidism, but several other diagnoses have to
be considered. MATERIAL, METHODS AND RESULTS: We describe the case of a young
woman with advanced renal failure treated with hemodialysis since her youth. She
had skeletal pain and radiological examination showed: osteosclerosis with
sclerotic vertebral bodies; irregular sclerosis and unsharp periostal outline in
the tubular bones of the extremities; and acrolysis and calcifications of
vascular and soft tissue in the hands. Histological examination showed changes
typical of oxalosis. A liver biopsy excluded primary oxalosis type I, and she
probably had a secondary oxalosis due to renal failure. This condition (as
opposed to primary oxalosis) can be treated with renal transplantation.
CONCLUSION: Oxalosis is a rare condition but it should be considered in patients
with radiological skeletal changes and chronic renal failure and should not be
misinterpreted as renal osteodystrophy. The classification of oxalosis as primary
or secondary is important for further treatment.
PMID- 9394665
TI - Evaluation of the post-operative lumbar spine with MR imaging. The role of
contrast enhancement and thickening in nerve roots.
AB - PURPOSE: Two new signs of lumbar nerve-root affection have been reported in
recent years on the basis of MR examinations, namely: thickening in nerve roots;
and contrast enhancement in nerve roots. The aim of this study was to assess
contrast enhancement in nerve roots in a standardised way, and to evaluate the
clinical significance of contrast enhancement and of nerve-root thickening in the
symptomatic post-operative lumbar spine. MATERIAL AND METHODS: A total of 121
patients (who had previously been operated on for lumbar disc herniation)
underwent 152 MR examinations, mainly on a 1.5 T system. Focal nerve-root
enhancement was identified by visual assessment. Intradural enhancement was also
quantified by pixel measurements that compared the affected nerve roots before
and after contrast administration. Non-affected nerve roots were used as
reference. RESULTS: Enhanced nerve roots in the dural sac increased at least 40
50% in signal intensity after contrast administration compared to pre-contrast
images and also compared to non-affected nerve roots. Intradural nerve-root
enhancement was seen in 10% of the patients and focal enhancement in the root
sleeve was seen in a further 26%. Nerve-root thickening was seen in 30%. Good
correlation with clinical symptoms was found in 59% of the patients with
intradural enhancement, in 84% with focal enhancement, and in 86% with nerve-root
thickening. The combination of thickening and enhancement in the nerve root
correlated with symptoms in 86% of the patients. CONCLUSION: Nerve-root
enhancement (whether focal or intradural) and thickening in the nerve root are
significant MR findings in the post-operative lumbar spine. In combination with
disc herniation or nerve-root displacement, these two signs may strengthen the
indication for repeat surgery. However, root enhancement within 6 months of
previous surgery may be a normal post-operative finding.
PMID- 9394666
TI - Cine-MR imaging of the shoulder.
AB - PURPOSE: Shoulder lesions are usually examined with the joint in only one or two
positions. We examined the shoulder with the joint in a variety of positions. We
also assessed the application of cine-MR to the detection of instability and
impingement. MATERIAL AND METHODS: The cine-MR examinations were performed in 30
patients and 15 healthy volunteers. We used an open 0.2 T system and a closed 1.0
T system. Spoiled gradient echo 2D T1-weighted images and turbo spin-echo T1- and
T2-weighted images were obtained with a field of view of 180 mm. The examinations
were videotaped and evaluated later. RESULTS: Normal variations of the
glenohumeral joint were easy to recognize. Sub-luxations and luxations of the
humeral head as well as rupture of the labrum were identified. It was also
possible to identify the labrum with a signal change after arthroscopic
refixation. And we were able to objectively assess distances between the osseous
structures during dynamic movement. CONCLUSION: Unlike static MR, cine-MR would
appear to be useful in visualizing the capsular ligament complex of the gleno
humeral joint in impingement and instability. It also provides information on
dynamic changes and may thus prove to be an important tool for shoulder
diagnostics. The method may provide an early diagnosis in the sub-acromial
impingement syndrome.
PMID- 9394667
TI - MR-guided joint puncture and real-time MR-assisted contrast media application.
AB - OBJECTIVE: To develop, in MR arthrography of the shoulder joint, an MR-guided
technique for localizing the needle puncture and confirming the intracapsular
needle-tip position by visualization of the contrast media inflow. MATERIAL AND
METHODS: Three unfixed human shoulder specimens were examined on a 1.0 T MR unit.
On the basis of MR-compatible markers, the optimal entrance point for puncturing
the joint was determined. The precise localization of the needle tip (MR
compatible 0.7-mm needle) in the shoulder joint was determined with rapid
localizer GRE sequences in 2 orthogonal planes. To confirm the intracapsular
position of the needle tip, diluted Gd-DTPA was applied via a long connecting
tube and contrast medium inflow into the joint space was controlled on an LCD
screen in real-time MR imaging (local-look technique). RESULTS: MR-compatible
markers on the skin allowed the rapid determination of the optimal entrance point
for needle puncture. An adequate localization of the intra-articular needle-tip
position was possible in all specimens although significant artifacts were
present on rapid localizer GRE sequences which resulted in an increase in the
apparent width of the needle shaft. Real-time MR imaging of the contrast medium
inflow was made possible by the local-look technique and LCD screen on the MR
unit and this allowed confirmation of the intracapsular position. CONCLUSION: In
MR arthrography of the shoulder, an MR-guided technique in conjunction with the
LCD screen and real-time MR imaging would seem to be a practical alternative to
conventional fluoroscopic guidance.
PMID- 9394668
TI - MR imaging of the wrist in carpal tunnel syndrome.
AB - PURPOSE: To determine whether specific parameters measured on MR images
correlated to electrophysiological changes in carpal tunnel syndrome (CTS).
MATERIAL AND METHODS: Prospective clinical examinations were made of 20 patients
with suspected CTS. We performed bilateral electrophysiological examinations of
the median nerve and bilateral MR imaging of the wrists. RESULTS: The
electrophysiological examination suggested median nerve entrapment in 18 wrists.
These wrists were compared to the remaining 22 electrophysiologically normal
wrists. In addition, we compared both wrists in 12 patients with unilateral
symptoms of CTS without reference to the electrophysiological findings. We found
no difference in specific MR parameters between the 2 groups. CONCLUSION: Neither
symptoms nor electrophysiological findings in CTS were related to specific MR
parameters.
PMID- 9394669
TI - A simple device for the stereoscopic display of 3D CT images.
AB - We describe a simple device for creating true 3D views of image pairs obtained at
3D CT reconstruction. The device presents the images in a slightly different
angle of view for the left and the right eyes. This true 3D viewing technique was
applied experimentally in the evaluation of complex acetabular fractures.
Experiments were also made to determine the optimal angle between the images for
each eye. The angle varied between 1 degree and 7 degrees for different observers
and also depended on the display field of view used.
PMID- 9394670
TI - A new radiographic method for evaluating the degree of sliding in devices used in
hip-fracture surgery.
AB - PURPOSE: To find a practical method for estimating the degree of sliding that
occurs in screw-plate devices used in hip-fracture surgery. Greater understanding
of the sliding mechanisms in different fracture types should improve surgical
technique and reduce the failure rate. METHODS AND RESULTS: In dynamic screw
plate devices, the lag screw slides inside the barrel of the plate. A recent
innovation allows the barrel-plate to slide inside a side-plate, thus making
possible a combined fracture compression along the neck and the shaft of femur.
The lengths of the different parts and the angle of a device in vivo, measured on
a radiograph, depend on the position of the femur relative to the photographic
film and the roentgen source. We obtained these measurements with a ruler and a
protractor from sequential a.p. radiographs of the hip and implemented them in a
special computerized program that used the principles of the scaled orthographic
and the central projection models. These calculations provided the correct amount
of sliding by the lag screw and by the barrel-plate within the side-plate.
CONCLUSION: The method presented here can establish the real degree of sliding in
screw-plate devices from standard a.p. radiographs independently of the position
of the hip.
PMID- 9394671
TI - Postero-anterior radiogram of the knee in weight-bearing and semiflexion.
Comparison with MR imaging.
AB - PURPOSE: The purpose was four-fold: to assess the reproducibility of p.a. weight
bearing radiograms of the knee and the minimal joint-space (MJS) width
measurements in these radiograms; to compare the MJS with MR-detected cartilage
defects; to evaluate the location of these cartilage defects; and to estimate the
relation between meniscal abnormalities and joint-space narrowing. MATERIAL AND
METHODS: Fifty-nine individuals, aged 41-58 years (mean 50), with chronic knee
pain were examined by means of p.a. weight-bearing radiograms in semiflexion with
fluoroscopic guidance of the knee joint. The MJS was measured with a standard
ruler. On the same day MR imaging was performed with proton-density- and T2
weighted turbo spin-echo on a 1.0 T imager. Meniscal abnormalities and cartilage
defects in the tibiofemoral joint (TFJ) were noted. RESULTS AND CONCLUSION: The
p.a. view of the knee and the MJS measurements were reproducible. MJS of 3 mm is
a limit in diagnosing joint-space narrowing in knees with MR-detected cartilage
defects. There was a high proportion (p < 0.001) of meniscal abnormality within
the narrowed compartments in comparison with those that were not narrowed. A
larger number of the cartilage defects (p < 0.05) was found in the medial femoral
condyle than in any of the other condyles of the TFJ. The defects had a dorsal
location (p < 0.001) as shown in the weight-bearing radiograms of the knee in
semiflexion.
PMID- 9394673
TI - Correlation of T1 and T2 relaxation rates in normal bone-marrow water with serum
ferritin concentration.
AB - PURPOSE: This study was made to clarify the paramagnetic effect of iron stored in
the hematopoietic tissue of bone marrow. MATERIAL AND METHODS: The T1 and T2
relaxation times of bone-marrow water in the L1-3 vertebrae of 20 healthy
individuals were measured by MR imaging with a 1.5 T magnet. The chemical shift
misregistration effect was used to isolate the bone-marrow water. The results
were compared with the serum ferritin concentration. RESULTS AND CONCLUSION:
Although no correlation between the T1 relaxation rate of the water fraction and
the serum ferritin concentration was evident, the T2 relaxation rate of the water
fraction showed strong linear correlation with the serum ferritin concentration
(r = 0.87, p < 0.0001). Thus, T2 of bone-marrow water accurately reflects the
amount of iron in normal bone marrow. This finding may be useful in the
evaluation of the characteristics of hematopoietic tissue in bone marrow.
PMID- 9394672
TI - Magnetization transfer and spin lock MR imaging of patellar cartilage
degeneration at 0.1 T.
AB - PURPOSE: To investigate magnetization transfer (MT) parameters and rotating frame
relaxation time T1 rho in patellar cartilage at different levels of degeneration.
MATERIAL AND METHODS: Thirty cadaveric patellae were examined at 0.1 T using the
time-dependent saturation-transfer MT technique and the spin lock (SL) technique.
In an SL experiment, nuclear spins are locked with a radiofrequency (RF) field,
and the locked nuclear magnetization relaxes along the magnetic component of the
locking RF field. The specimens were divided into three groups according to the
level of cartilage degeneration. MT parameters and T1 rho were measured. RESULTS:
The MT effect was greater in degenerated cartilage than in normal cartilage. T1
rho was longer in advanced cartilage degeneration than in intermediate cartilage
degeneration. CONCLUSION: The results suggest that more studies are needed to
fully establish the value of SL imaging in cartilage degeneration.
PMID- 9394674
TI - Urine viscosity after injections of iotrolan or iomeprol.
AB - PURPOSE: Previous observations in rats caused us to speculate whether the
injection of iotrolan, a nonionic dimeric contrast medium (CM), would increase
urine viscosity enough to obstruct urine outflow in the collecting duct. MATERIAL
AND METHODS: The urine viscosity in dogs was measured directly with a
viscosimeter after injections of iotrolan or of iomeprol, a nonionic monomeric
CM. RESULTS AND CONCLUSION: The injection of iotrolan increased urine viscosity
considerably whereas iomeprol had little effect on this variable. The osmolality
dependent adverse reactions of CM have previously been emphasized but viscosity
dependent adverse reactions must also be considered when the CM is a polymer with
a low osmolality.
PMID- 9394675
TI - An in vitro 1H-MRS model of oncogene transfection. The spectral feature of c-erbB
2 and c-Ha-ras transfected NIH3T3 fibroblast cells.
AB - PURPOSE: Malignancy is an abnormality of cell division and differentiation based
on abnormal expression of oncogenes. This note describes the in vitro 1H-NMR
spectral features of oncogene-transfected NIH3T3 fibroblast cells compared to non
transfected cells. MATERIAL AND METHODS: 1H-NMR spectra of cultured NIH3T3 cells
and c-erbB-2 or c-Ha-ras gene-transfected cells were obtained by 400 MHz high
resolution NMR. The peaks were assigned by 2D HOHAHA spectra of the cell
suspension and the spectral changes were evaluated in 1D and 1D differential
spectra. RESULTS: The 1H spectra obtained from both transfected cell lines were
broadened over all peaks, suggesting reduced mobility in plasma membrane lipid
molecules. No other differential spectra for characterizing metabolic change was
detected. CONCLUSION: Broadened 1H spectra observed after c-erbB-2 or c-Ha-ras
transfection suggest changes of plasma membrane viscosity, which may be related
to the oncogene expression.
PMID- 9394676
TI - Combinations of nonlabeled, 125I-labeled, and anti-idiotypic antiplacental
alkaline phosphatase monoclonal antibodies at experimental radioimmunotargeting.
AB - PURPOSE: Placental alkaline phosphatase (PLAP) is a membrane-bound oncofetal
antigen that can be used for radioimmunotargeting. Preinjection of nonlabeled
monoclonal anti-PLAP antibody (H7) and postinjection of monoclonal anti-idiotypic
anti-PLAP antibody (alpha H7) were used in order to improve the localization
efficacy of 125I-labeled H7. MATERIAL AND METHODS: A human cervix adenocarcinoma
cell line (HcLa Hep 2) was inoculated subcutaneously in 24 nude mice. Repeated
quantitative radioimmunoscintigraphic recordings were performed on 27 occasions
in each of the 24 mice during the observation period which lasted for nearly 3
months. The tumor and nontumor doses were calculated according to the Medical
International Radiation Dose Committee formula on the basis of the scintigraphic
data. RESULTS: All tumors were clearly visualized as early as one day after
injection of 125I-labeled H7. The remaining radioactivity was exclusively located
in the tumors at days 30-81. As much as 12-16% of the injected dose/g accumulated
in the tumors during the first 2 days after injection, and remained stable at
this high level for approximately 10 days in all investigated groups.
Radioactivity in the whole body was rapidly eliminated during the same time
period. The highest tumor/nontumor dose ratio was obtained after a single
injection of 125I-labeled H7. CONCLUSION: Neither a preinjection of nonlabeled H7
nor a postinjection of alpha H7 nor a combination of both strategies resulted in
improved tumor/nontumor dose ratios compared to a single injection of labeled H7.
The monoclonal antibody H7 has a rapid and high uptake, combined with a prolonged
retention time in the tumors. The kinetic properties of H7 are different from
antibodies targeting intracellular tumor antigens.
PMID- 9394677
TI - Bioavailability of folic acid in fortified food.
PMID- 9394678
TI - Retinoids and alcoholic liver disease.
PMID- 9394679
TI - Complementary medicine: a review of immunomodulatory effects of Chinese herbal
medicines.
AB - Popular demand for and scientific interest in complementary or alternative
medicine, particularly medicinal botanicals, has increased considerably in recent
years. The medicinal botanicals with the longest tradition, and for which
extensive data are available, are Chinese herbal medicines and their Japanese
counterparts--Kampo medicines. This review focuses on some representative
examples of studies examining the effects of some traditional Chinese medicines
on various aspects of the immune response. In vitro as well as in vivo studies
are cited, the latter including not only animal experiments but also clinical
trials. Although by no means exhaustive, this review attempts to show that much
research has focused on the specific beneficial effects of Chinese herbal
medicines. Studies examining the mechanisms by which they exert their
immunomodulatory actions, however, are found much less frequently. Nonetheless,
even the limited number of mechanistic experiments presented here reveal that
numerous mechanisms are likely involved in the various actions of even a single
medicine. It will be the elucidation of such mechanisms that will provide the
scientific basis for establishing the efficacy and safety of not only Chinese
herbal medicines but all forms of medicinal botanicals.
PMID- 9394680
TI - New definitions in nutritional disciplines: will the public be damned or saved?
PMID- 9394681
TI - Changes in total body fat during the human reproductive cycle as assessed by
magnetic resonance imaging, body water dilution, and skinfold thickness: a
comparison of methods.
AB - Total body fat and fat-free mass were assessed by magnetic resonance imaging
(TBFMRI and FFMMRI) in 11-16 healthy Swedish women before pregnancy and 5-10 d
and 2, 6, and 12 mo after delivery. On these occasions, TBF was also measured by
the body water dilution (TBFBWD) and skinfold-thickness (TBFSFT) techniques. The
results were used to compare changes in TBFSFT and TBFBWD during reproduction
with changes in TBFMRI. TBFBWD was 1.5-4.0 kg higher than TBFMRI and at all
postpartum measurements the difference between these estimates increased
significantly with increased body fat content. This difference was also
significantly higher 6 mo after delivery than it was 2 and 12 mo postpartum. The
possibility that this was due to variations in the degree of hydration of FFM
postpartum was considered. TBFSFT was 1.7-3.1 kg higher than TBFMRI and this
difference increased with increasing body fat content. The agreement between
changes in TBFMRI and TBFSFT was different during different times in the
reproductive cycle and was also influenced by the amount of fat lost or gained.
The findings thus suggest that there is a risk for bias when changes in TBF
during reproduction are estimated by the skinfold-thickness technique as well as
by isotope dilution.
PMID- 9394682
TI - Body composition of a young, multiethnic, male population.
AB - The study objective was to establish the range of total body-composition values
for a young, multiethnic, healthy male population (aged 3-18 y) by using dual
energy X-ray absorptiometry (DXA). Results for 297 males in three ethnic groups
[European American (white), n = 145; African American (black), n = 78; and
Mexican American (Hispanic), n = 74] are reported. Bone mineral content (BMC),
lean tissue mass (LTM), body fat mass, and percentage fat are presented as
functions of age. Analysis of variance with age, weight, and height as covariates
was used to evaluate differences among the three ethnic groups. BMC and LTM were
higher in black than in white males, but no difference in BMC or LTM was evident
between the white and Hispanic groups. The relation between total-body BMC and
LTM was linear (r = 0.985, P < 0.0001) and independent of age or ethnic
classification. The Hispanic males had higher body fat values than the white
group, whereas the black males generally had lower values than the white group.
When adjusted for body size, the Hispanic males continued to have significantly
higher body fat and percentage fat than the white or black males. Ethnic-specific
equations for the prediction of body composition as a function of age, weight,
and height were derived. The results for the white males in the present study
were compared with DXA-derived reference data reported in other countries for
young white males. We conclude that reference values of total body composition
for young healthy males need to be ethnic specific.
PMID- 9394683
TI - Effect of high-fat and low-fat diets on voluntary energy intake and substrate
oxidation: studies in identical twins consuming diets matched for energy density,
fiber, and palatability.
AB - There remains controversy over the effects of dietary fat content on voluntary
energy intake. Additionally, the question of whether there is a genetic
susceptibility to overeating high-fat diets has not been resolved. To address
these issues, we designed two diets: a low-fat diet providing approximately 20%
of energy as fat and a high-fat diet with approximately 40% of energy as fat. The
diets were matched for energy density, fiber, and palatability. In a two-phase,
18-d intervention study, voluntary energy intakes and macronutrient oxidation
rates during the fasting and fed states were determined in seven pairs of
identical male twins. In contrast with results of previous intervention studies,
in which low-fat and high-fat diets were not matched for energy density and other
associated variables, we observed no significant difference in voluntary energy
intake between the low-fat and high-fat phases, and mean daily intakes were
similar (10.3 and 10.7 MJ/d, respectively). Postprandial rates of fat oxidation
tended to reflect fat intakes in the two dietary phases, thus helping to explain
the lack of a difference in mean energy intakes. There was also a significant
twin-pair similarity in differences in energy intakes between dietary phases (P =
0.013). These results suggest that dietary fat content does not have a major
influence on voluntary energy intake when dietary variables usually associated
with fat are controlled for and that there may be a familial influence on the
effects of dietary fat content on energy intake.
PMID- 9394684
TI - Leptin concentration in women is influenced by regional distribution of adipose
tissue.
AB - Leptin concentrations in humans are increased with obesity, and women have higher
leptin concentrations than men. This sex difference reflects the greater fat mass
of women. However, there is evidence that factors other than the size of the
adipose tissue mass contribute to serum leptin concentrations. This study was
undertaken to determine whether anthropometric factors influenced leptin
concentrations in our population. Leptin concentrations were measured in 375
persons from a population study of hypertension and diabetes for whom body
composition data (bio-electrical impedance analysis and anthropometry) were
available. Serum leptin concentrations were more than four times higher in women
than in men (18.5 +/- 13.9 compared with 3.8 +/- 3.6 ng/L, P < 0.0001). In
individuals with comparable body mass indexes, these differences persisted after
adjustment for either percentage fat (P < 0.05) or fat mass (P < 0.0001) by
multivariate-regression analysis. After fat mass was adjusted for, the serum
leptin concentration in both men and women was independent of waist circumference
but in women was associated with hip circumference. Hip circumference is a proxy
measure of peripheral fat and these results suggest that the larger hips of women
may contribute to the sex difference in serum leptin concentration.
PMID- 9394685
TI - Intraabdominal adipose tissue and anthropometric surrogates in African American
women with upper- and lower-body obesity.
AB - It is well established that visceral adipose tissue (VAT) is associated with
increased morbidity and mortality in white women. In a recent study, we found
that African American women had smaller depots of VAT. To test the relation of
VAT to the commonly used anthropometric surrogates for fat patterning, including
waist-to-hip ratio (WHR), waist circumference, subscapular skinfold thickness,
and ratio of triceps to subscapular skinfold thickness, we recruited 48
normotensive African American women > 120% of ideal body weight on the basis of
WHRs > 0.85 [upper-body obesity (UBO); n = 23] and < 0.76 [lower-body obesity
(LBO); n = 25]. There were no differences between groups in age, height, weight,
body mass index, or percentage of body fat. VAT was determined by magnetic
resonance imaging at L4-5; percentage of fat was determined by dual-energy X-ray
absorptiometry. Women with UBO had significantly larger mean (+/- SEM) depots of
VAT at L4-5 than did women with LBO (0.26 +/- 0.02 compared with 0.19 +/- 0.02
L). Waist circumference was the single best predictor of VAT at L4-5 in both
groups of women whereas WHR was significantly associated with VAT at L4-5 only in
women with UBO. In African American women, waist circumference is a better
surrogate for VAT than is WHR.
PMID- 9394686
TI - Effects of fasting and glucose infusion on basal and overnight leptin
concentrations in normal-weight women.
AB - The plasma concentration of leptin is reduced in association with chronic energy
restriction and weight loss in humans, but little is known about the acute
effects of fasting and glucose infusion on leptin. In this study, plasma leptin,
insulin, glucose, and fatty acid concentrations were measured daily in 14
healthy, normal-weight, female volunteers aged 24 +/- 4 y with a body mass index
(kg/m2) of 24.2 +/- 3.6 during a 4-d fast. The mean plasma leptin concentration
decreased by 54 +/- 8% with fasting (P = 0.0006, ANOVA). In a stepwise-regression
model, the change in leptin concentration with fasting correlated most
significantly with the change in insulin (R2 = 0.48, P = 0.0057) and to a lesser
extent with the change in body fat by bioimpedance analysis (R2 = 0.19, P =
0.03). Plasma leptin concentrations measured every 20 min from 2000 to 0800 on
the fourth night of the fast did not show a time-dependent rise. A continuous
intravenous infusion of 5% glucose providing 1414 +/- 323 kJ/d (338 +/- 78
kcal/d) was begun after 4 d of fasting in seven subjects who continued to fast
for an additional 6 d. Within 24 h of the glucose infusion, leptin concentrations
increased significantly by 80 +/- 52% (P < 0.05). These data show the sensitivity
of plasma leptin concentrations to small changes in energy supply and suggest a
basic role of substrate metabolism in the short-term regulation of leptin.
PMID- 9394687
TI - Three-month nutritional supplementation in Indonesian infants and toddlers
benefits memory function 8 y later.
AB - Does short-term supplementary feeding during infancy and childhood have long
lasting effects? In 1986, 334 children aged 6-60 mo living on rural tea
plantations in West Java, Indonesia, participated in a 3-mo randomized trial to
test the effects of a dietary supplement providing approximately 1672 kJ (400
kcal) energy/d, with about the same nutrient density as local foods. We returned
to the same communities in 1994 and enrolled 231 (125 supplemented, 106 control)
of the original subjects in a follow-up study of the long-term effects of
supplementation. We assessed these subjects by using several measures:
anthropometry, iron status, information processing, Peabody Picture Vocabulary
Test, word fluency, and an arithmetic test. The supplemented group showed no
differences from those in the control group. However, when the analysis was
limited to subjects who had received the supplement before the age of 18 mo (n =
73), the supplemented children performed better than control children on the
Sternberg test of working memory (decision time intercept: probe absent, P =
0.002; probe present, P = 0.053). After considering possible confounders, we
concluded that the supplementation during infancy was responsible for the
difference. This finding shows that supplementation can have long-lasting effects
on a specific domain if the child receives it at the appropriate stage of
development.
PMID- 9394688
TI - Clinical outcome of geriatric patients in the United States receiving home
parenteral and enteral nutrition.
AB - In this study the use of home parenteral and enteral nutrition (HPEN) therapy in
geriatric patients and the effect of aging on the clinical outcome of HPEN
therapy was assessed between 1985 and 1992. Data were obtained from Medicare
(part B) parenteral and enteral nutrition workload statistics, Blue Cross and
Blue Shield of South Carolina, and the North American HPEN Patient Registry. On
the basis of these data it was estimated that in 1992 there were 40,000 HPN
patients and 152,000 HEN patients nationwide. One-quarter to one-third of the HPN
group was aged > or = 65 y, depending on the underlying diagnosis. Geriatric HPN
patients had a generally good outcome but did not do as well as their younger
counterparts; however, they had fewer therapy-related complications than
children. In the HEN group, 44% of cancer patients and 69% of patients with
neuromuscular swallowing disorders were geriatric. Geriatric HEN patients with
swallowing disorders had a poorer outcome (i.e., lower survival, poorer
rehabilitation, and fewer resumed full oral nutrition) than younger patients
after 1 y of follow-up. In conclusion, although aging was associated with a
poorer outcome for HPN patients, it was still reasonably good; therefore, age per
se should not exclude geriatric subjects from therapy. For HEN, the poorer
outcome in geriatric dysphagic patients raises concern regarding the
appropriateness of this therapy.
PMID- 9394689
TI - Maternal obesity and breast-feeding success in a rural population of white women.
AB - Maternal obesity interferes with the initiation and maintenance of lactation in
animal models but it has not been investigated widely in women. We reviewed
medical records from a white population to examine the relation between
prepregnant overweight [body mass index (BMI; in kg/m2) 26.1-29.0] and obesity
(BMI > 29.0) on initiation and duration of breast-feeding. Logistic regression
revealed that of those who ever put their infants to the breast (n = 810), women
who were overweight [odds ratio (OR) = 2.54, P < 0.05] or obese (OR = 3.65, P <
0.0008) had less success initiating breast-feeding than did their normal-weight
counterparts (BMI < 26.1). Proportional-hazards regression revealed higher rates
of discontinuation of exclusive breast-feeding in overweight (RR = 1.42, P <
0.04) and obese (RR = 1.43, P < 0.02) women and higher discontinuation of breast
feeding to any extent in overweight (RR = 1.68, P < 0.006) and obese (RR = 1.73,
P = 0.001) women. Controlling for parity, socioeconomic status, maternal
education, and other factors that often covary with maternal obesity and breast
feeding did not change these results. These results suggest that excessive
fatness in the reproductive period may inhibit lactational performance in women.
PMID- 9394690
TI - Changes in vitamin B-6 status indicators of women fed a constant protein diet
with varying levels of vitamin B-6.
AB - Changes in vitamin B-6 status indicators were evaluated in vitamin B-6-replete
subjects. Ten young women consumed diets providing 85 g protein/d and 1.03, 1.33,
1.73, and 2.39 mg vitamin B-6/d for 12 or 15 d during four successive diet
periods; in a second study, six women were fed diets providing 85 g protein/d and
0.84, 1.14, and 2.34 mg vitamin B-6/d for 10 or 12 d during three successive diet
periods. Vitamin B-6 status indicators showing significant differences among
intakes included urinary excretion of 4-pyridoxic acid and total vitamin B-6,
pyridoxal 5'-phosphate and total vitamin B-6 in plasma, and xanthurenic acid
excretion after a 2-g L-tryptophan load. Significant correlations were found
between vitamin B-6 intake and 4-pyridoxic acid, total vitamin B-6, plasma
pyridoxal 5'-phosphate, plasma total vitamin B-6, erythrocyte alanine
aminotransferase percentage stimulation and postload excretion of xanthurenic
acid and volatile amines (kynurenine plus acetylkynurenine). Depending on the
indicator, between 20% and 70% of the subjects had inadequate values for 4
pyridoxic acid, total vitamin B-6, plasma pyridoxal 5'-phosphate, and erythrocyte
alanine aminotransferase percentage stimulation at a vitamin B-6 intake of 1.33
mg/d (0.016 mg vitamin B-6/g protein). A ratio of dietary vitamin B-6 to protein
> 0.016 mg/g is required for adequate vitamin B-6 status in women.
PMID- 9394691
TI - Absorption of folate from fortified cereal-grain products and of supplemental
folate consumed with or without food determined by using a dual-label stable
isotope protocol.
AB - The absorption of folic acid in fortified white and whole-wheat bread, rice, or
pasta or in solution was evaluated in human subjects with use of a single-dose,
dual-label, stable-isotope protocol that did not involve prior loading of
subjects with nonlabeled folate. In each of five sequential trials, 14 adults
received a single oral dose of [13C5]folic acid in one of the four fortified
cereal-grain products or in water concurrently with an intravenous injection of
[2H2]folic acid. In two additional trials, subjects received oral [13C5]folic
acid with or without a light breakfast meal. In all trials, urine was collected
24-36 h postdosing and the isotopic labeling of urinary folates determined.
Isotope excretion ratios of urinary folates (% [13C5]folate dose/% [2H2]folate
dose), which were used as criteria of absorption, indicated no significant
differences among the various fortified foods and the control (P = 0.607).
Because statistical power was sufficient to have detected a 50% difference from
the control, these results suggest that [13C5]folic acid in these fortified
cereal-grain foods was highly available. This study also suggests that
fortification will contribute effectively to the folate status of the population.
Consuming [13C5]folic acid after a light breakfast meal led to a small reduction
in absorption relative to the control without food (P < 0.085). Between-subject
variation in this protocol exceeded that observed in previous studies conducted
using prior saturation of subjects with nonlabeled folic acid. We recommend that
either prior saturation or multiple doses be used in future applications of this
technique to improve precision.
PMID- 9394692
TI - Field-study screening of blood folate concentrations: specimen stability and
finger-stick sampling.
AB - We describe optimized procedures for field studies of blood folate concentrations
by using finger-stick blood sampling and include relevant studies on blood folate
stability. We introduce whole-blood folate adjustment using sample hemoglobin
(folate/hemoglobin, nmol/g) as a novel and practical tool yielding accurate and
precise results when blood volume or dilution is unknown. Red cell folate
concentrations (nmol/L) of 11,887 Americans correlated well with hemoglobin
corrected whole-blood folate concentrations (r2 = 0.993; red cell folate = 0.347
x hemoglobin folate + 1 nmol/L), which supports the approach of using the mean
cell hemoglobin concentration (g/L) to interconvert red cell and hemoglobin
folate data. Folate concentrations in capillary (finger stick) and venous blood
samples from 28 normal donors were similar (P > 0.87), correlating closely (r =
0.98, P < 0.001). Whole-blood samples (collected into K2-EDTA-containing
evacuated tubes) in field studies are best stored intact at 4 degrees C until
they can be processed and frozen (-20 degrees C). Specific knowledge of blood
folate stability is essential in planning and designing field studies.
PMID- 9394693
TI - A 14-mo zinc-supplementation trial in apparently healthy Chilean preschool
children.
AB - Apparently healthy preschool children (46 boys, 52 girls) aged 27-50 mo from low
socioeconomic conditions who attended daycare centers in Santiago participated in
a 14-mo long double-blind zinc supplementation trial. Unlike most previous
studies, no additional inclusion criteria such as short stature or slow growth
rate were considered. Subjects were pair matched according to sex and age and
randomly assigned to two experimental groups: the supplemented group, which
received 10 mg Zn/d, and the placebo group. Selected anthropometric, clinical,
dietary, biochemical, and functional indexes were determined at the beginning of
the study and after 6 and 14 mo of intervention. Actual dietary zinc intake was
66% of the recommended dietary allowance. Height gain after 14 mo was on average
0.5 cm higher in the supplemented group (P = 0.10). The response, however, was
different between sexes. Boys from the supplemented group gained 0.9 cm more than
those in the placebo group (P = 0.045). No effect was seen in girls. Although no
significant differences were observed in the rest of the variables studied,
trends (0.05 < P < 0.10) in the supplemented group compared with the placebo
group for increased midarm muscle area in boys, improved response to tuberculin,
and reduced rates of parasite reinfestation were noted. We conclude that in
preschool children of low socioeconomic status, zinc is a limiting factor in the
expression of growth potential.
PMID- 9394694
TI - Association between dietary fiber intake and the folate status of a group of
female adolescents.
AB - The main objective of this study was to assess the association between dietary
fiber intake and the folate status of Canadian female adolescents. We also
assessed dietary folate intakes and evaluated the prevalence of biochemical
folate deficiency in these subjects. Female adolescents aged 14-19 y (n = 224)
were recruited and fasting blood samples were collected. Dietary intakes (3-d
food record) were recorded and participants were classified as
lactoovovegetarians, semivegetarians, or omnivores on the basis of food
consumption patterns assessed with food-frequency questionnaires. Fourteen
percent, 17%, and 26% of lactoovovegetarians, semivegetarians, and omnivores,
respectively, had dietary folate intakes below their predicted requirements; 1%,
4%, and 23%, respectively, had serum folate concentrations indicative of
deficiency. Despite low dietary folate intakes and serum folate concentrations,
few subjects had homocysteine concentrations indicative of deficiency, suggesting
that the degree of folate depletion had not yet produced functional consequences.
Most important, results suggest that the consumption of nonstarch polysaccharide
is significantly associated with serum folate concentrations (P < 0.001). For
each 1-g increase in nonstarch polysaccharide intake, a 1.8% increase in serum
folate concentration is expected. In summary, we propose that an increase in
nonstarch polysaccharide intake may promote the intestinal biosynthesis of
folate, providing a complementary strategy to enhance the folate nutriture of
humans.
PMID- 9394695
TI - Effect of intestinal parasite treatment on the efficacy of oral iodized oil for
correcting iodine deficiency in schoolchildren.
AB - Oral supplementation with iodized oil for correction of iodine deficiency in a
population has advantages over intramuscular injection but the duration of effect
is shorter. The relation of intestinal parasite treatment and efficacy of oral
iodized oil was examined in an intervention study in 8-10-y-old schoolchildren in
Malawi. Severely iodine-deficient schoolchildren with a single parasitic
infestation of Ascaris lumbricoides (n = 44), hookworm (n = 42), or Entamoeba
histolytica (n = 24) were randomly allocated to receive or not receive treatment
before taking a 1-mL oral supplement (490 mg I) of iodized ethyl esters from
poppy seed oil. The urinary iodine concentration was measured at various time
points after supplementation to define the time intervals before urinary iodine
concentrations returned to 0.40 mumol/L, indicating moderate iodine deficiency.
Treatment with metronidazole for E. histolytica increased the protection period
from 2.0 to 21.0 wk (P < 0.05). For all untreated children together, the duration
of effect was 9.2 wk shorter (P < 0.001) than that for their treated peers (16.8
wk). We conclude that intestinal parasitic infestations reduce the efficacy of
oral supplementation with iodized ethyl esters by interfering with absorption.
PMID- 9394696
TI - Sex differences in response to dietary manipulation in rats with hypertension and
myocardial hypertrophy.
AB - Studies of the effect of sex on the metabolic state of rats with chronic
hypertension and concomitant myocardial hypertrophy were conducted. Female and
male spontaneously hypertensive rats (SHRs) with early myocardial hypertrophy
(5.5 mo old) were used. Serum fatty acids, liver glycogen, and myocardial
glycogen were measured at baseline and after the rats were deprived of food for
24 h. The metabolic effects of progressive myocardial hypertrophy in females were
assessed in additional groups of female SHRs (5.5 or 12 mo old) under the
following conditions: control, food deprived, or food deprived and refed with
equienergetic lipid-rich (38.9% of total energy) or carbohydrate-rich (76.5% of
total energy) diets. Despite no differences in serum fatty acids, females had
significantly higher baseline myocardial glycogen and liver glycogen
concentrations than males. In response to food deprivation, females continued to
have significantly higher myocardial glycogen and fatty acid concentrations than
males, whereas there were no sex differences in liver glycogen, which was
depleted in both males and females. Older hypertensive females had higher
baseline fatty acid concentrations and lower liver glycogen concentrations than
younger females, whereas there were no differences in myocardial glycogen. Food
deprivation doubled fatty acid concentrations, depleted liver glycogen, and
increased myocardial glycogen in both age groups. In both age groups, fatty acid
concentrations and liver glycogen did not return to baseline values after food
deprivation and refeeding. In both age groups, fatty acid concentrations
increased further after the lipid-rich diet whereas liver glycogen concentrations
returned to approximately 50% of baseline values after the carbohydrate-rich
diet. Refeeding with either diet did not significantly increase myocardial
glycogen further. Thus, the metabolic response to dietary manipulation was
influenced by both sex and, in females, progressive pathology.
PMID- 9394697
TI - Body composition in adults with cerebral palsy by dual-energy X-ray
absorptiometry, bioelectrical impedance analysis, and skinfold anthropometry
compared with the 18O isotope-dilution technique.
AB - The aim of this study was to determine in adults with cerebral palsy the accuracy
and practicality of standard methods used to estimate body composition. The
sample consisted of 20 adults (13 men and 7 women) aged 20-55 y with various
degrees of cerebral palsy. Percentage body fat was estimated from skinfold
thickness, bioelectrical impedance analysis (BIA), and dual-energy X-ray
absorptiometry (DXA), and compared with the reference measure of percentage body
fat from total body water by 18O dilution. Values derived from use of BIA and
skinfold thickness, estimated by using the Jackson-Pollock equation, were
significantly different from those derived with use of 18O dilution (P < 0.001
and P < 0.001, respectively). There was no significant difference between
percentage body fat measured with DXA and that measured with 18O. There was
favorable agreement between DXA and 18O (mean difference: 0.06 +/- 9.6%), but not
between skinfold thickness (mean difference: 6.33 +/- 12.3%) or BIA (mean
difference: -6.55 +/- 13.6%) and 18O. Although DXA was the best measure for
predicting percentage body fat in the sample, its high cost prohibits its use as
a practical method. The best-fitting regression equation specific for this sample
by using anthropometric measures to predict percentage body fat was as follows:
8.76 - (7.34 x sex) + (0.32 x weight) + (0.38 x biceps skinfold) (R2 = 0.84, P <
0.001, SEE = 4.85). This equation needs to be cross-validated in an independent
sample of adults with cerebral palsy.
PMID- 9394698
TI - Effects of lowering fat and increasing dietary fiber on fasting and postprandial
plasma lipids in hypercholesterolemic subjects consuming a mixed Mediterranean
Western diet.
AB - The aim of this study was to evaluate the cholesterol-lowering effects of
reducing fat and increasing or not increasing dietary fiber in subjects consuming
a mixed Mediterranean-Western diet. Thirty-one free-living, mildly
hypercholesterolemic subjects were randomly allocated to two groups. Subjects in
both groups first shifted for 4 wk to a low-fat, low-fiber diet (LFLFD). For an
additional 4-wk period, subjects in group 1 continued consuming the LFLFD whereas
subjects in group 2 consumed a low-fat, high-fiber diet (LFHFD). Most dietary
fatty acids were monounsaturated (38-41%) and fibers, when provided (up to 35
g/d), came from unrefined cereals, legumes, and soluble-fiber-enriched ready-to
eat cereals. After period 1 of the LFLFD, mean serum and low-density-lipoprotein
(LDL)-cholesterol concentrations of subjects in groups 1 (-12.5% and -15.5%,
respectively) and 2 (-10.5% and -15.5%, respectively) decreased significantly
from baseline (P < 0.05). After period 2, mean serum and LDL-cholesterol
concentrations of subjects consuming the LFLFD (group 1) were still lower (by
8.8% and 9.2%, respectively, from baseline) whereas in subjects consuming the
LFHFD (group 2) these values decreased further to significantly lower values
(14.2% and 17.6% from baseline, respectively). Fasting high-density-lipoprotein
(HDL) cholesterol, apolipoprotein A-I, glycemia, and insulinemia did not change
significantly. In seven men, postprandial lipemia transiently increased more
after a breakfast test meal at the completion of the LFHFD period than after the
LFLFD period. In conclusion, an LFHFD more comparable with the traditional
Mediterranean diet may improve the dietary management of moderate
hypercholesterolemia.
PMID- 9394699
TI - Hormonal implications of the hypocholesterolemic effect of intake of field beans
(Vicia faba L.) by young men with hypercholesterolemia.
AB - This study examined the hypocholesterolemic effect and hormonal changes resulting
from 30 d of supplementation with Vicia faba L. (field bean) flour of diets of
young men (aged 18-21 y; n = 40) with borderline-high or high serum cholesterol
values. All subjects (groups A-D) consumed the same basic diet. Additionally,
volunteers in the control group (A) consumed 90 g control flour/d whereas those
in the three bean groups received either 90 g cooked field bean flour (groups B
and C) or 90 g raw field bean flour (group D) daily. Groups A and B included
volunteers with borderline-high cholesterol values [5.2-6.2 mmol total
cholesterol/L and 3.4-4.1 mmol low-density-lipoprotein (LDL) cholesterol/L].
Subjects in groups C and D had high serum cholesterol concentrations (total
cholesterol > 6.2 mmol/L and LDL cholesterol > 4.1 mmol/L). After 30 d, serum
glucose, insulin, triacylglycerol, total, LDL-cholesterol, and very-low-density
lipoprotein (VLDL)-cholesterol values were significantly lower than initial
values in all subjects who consumed diets containing field bean flour (P < or =
0.0001, except for LDL-cholesterol concentrations in group C, for which P < or =
0.0007). Legume intake also resulted in a significant increase (P < or = 0.0001)
in glucagon and high-density-lipoprotein cholesterol. Neither cortisol nor
thyroid hormone values changed significantly. The results suggest that the
hypocholesterolemic effect of field bean intake depends at least partly on a
concomitant increase in glucagon and decrease in insulin values. The more marked
reduction in triacylglycerol and VLDL-cholesterol concentrations in subjects who
consumed raw field beans indicates a coparticipation of their thermolabile
components.
PMID- 9394700
TI - beta-Carotene beadlets potentiate hepatotoxicity of alcohol.
AB - Administration of beta-carotene in beadlets to baboons potentiates alcohol
induced liver injury. To determine whether this also occurs in other species, and
whether the beadlet carrier itself contributes to the toxicity, rats were given
for 2 mo vitamin A (1.4 U/J), beta-carotene (4.8, 12.0, and 24.0 U/J, with or
without beadlets), or corresponding amounts of beadlets without beta-carotene, in
diets containing either carbohydrates or equivalent amounts of ethanol.
Isoenergetic substitution of ethanol (36% of total energy) for carbohydrates
reduced hepatic vitamin A by 80%, and such a depletion was also observed with
beta-carotene as vitamin A precursor. By contrast, ethanol raised hepatic beta
carotene, which was further increased by beadlets. Thus, whereas alcohol promoted
hepatic depletion of vitamin A, it had the opposite effect on beta-carotene.
Ethanol seems to affect the homeostasis of beta-carotene. Furthermore, the
ethanol-induced oxidative stress, assessed by an increase in hepatic 4
hydroxynonenal and F2-isoprostanes (measured by gas chromatography-mass
spectrometry), was not improved despite a concomitant rise in hepatic
antioxidants (beta-carotene and vitamin E). Moreover, beadlets resulted in
proliferation of the smooth endoplasmic reticulum and in leakage of the
mitochondrial glutamate dehydrogenase into the plasma, reflecting mitochondrial
injury (both documented by electron microscopy). Thus, in rats given ethanol,
beta-carotene is not an efficient vitamin A precursor. Its bioavailability was
improved by beadlets, but the ethanol-induced oxidative stress was not attenuated
and there was associated hepatotoxicity that now needs to be assessed in humans.
PMID- 9394701
TI - Low dietary fiber and high protein intakes associated with newly diagnosed
diabetes in a remote aboriginal community.
AB - The high prevalence of diabetes mellitus in North American aboriginal populations
may be due to recent changes in lifestyle, including the adoption of a high-fat,
low-fiber diet. To determine whether fat or fiber intakes were associated with
new cases of diabetes, we studied 72% (728/1018) of residents aged > 9 y from a
remote aboriginal community in northern Ontario using the 75-g oral-glucose
tolerance test and 24-h dietary recall. The mean fat intake of this population
(36% of energy) was typical for North America, but fiber intake (1.2 g/MJ) was
very low. Logistic-regression analysis, adjusted for age, sex, and body mass
index, showed that a 1-SD increase in fiber intake reduced the risk of having
diabetes by 39% (P = 0.026) whereas the same increase in protein intake increased
the risk by 38% (P = 0.027). There was no significant effect of energy, fat,
starch, or simple sugars. These data support Trowell's original dietary-fiber
hypothesis that "... dietary fiber depleted starchy foods are conducive to the
development of diabetes mellitus in susceptible human genotypes."
PMID- 9394702
TI - Coffee consumption and plasma homocyst(e)ine: results from the Atherosclerosis
Risk in Communities Study.
PMID- 9394703
TI - Truly quantitative dietary studies have stringent requirements.
PMID- 9394704
TI - Vitamin B-12 and folic acid supplementation.
PMID- 9394706
TI - Race, ethnicity, and health: how can greater understanding be attained?
PMID- 9394705
TI - Unmetabolized folic acid and masking of cobalamin deficiency.
PMID- 9394707
TI - Iron stores related to iron absorption.
PMID- 9394708
TI - Methodologic issues, theoretical considerations, and design criteria for
experimental animal and cell culture experiments.
AB - This article provides background information that is important when evaluating
the relevance to humans of particular animal or in vitro experiments designed to
assess the relations between fatty acids and cancer. Considerations in designing
carcinogenesis studies to assess the relation between dietary fatty acids and
human cancer include selection of the animal model and design of the experimental
diets. Animal carcinogenesis models are generally best for evaluating the early
phases of cancer development: the initiation and promotion of cancer.
Transplantation protocols have been developed for evaluating the effect of diet
on the growth and metastasis of partially or fully transformed cells. The
variables that are important in such models are the origin and biology of the
cell line, the animal host used for the implantation, the site of
transplantation, whether the primary tumor is excised after a period of time to
allow for metastasis, and when the diets are fed relative to the different phases
of tumor growth and metastasis. Studies in cultured cells have been particularly
useful for assessing the mechanisms by which fatty acids affect cancer.
Considerations in designing studies with cultured cells include selection of the
cell line, cell culture conditions, selection of biological endpoints that are
relevant to human cancer, and in vivo confirmation of the mechanisms observed in
vitro. Design considerations for each of these experimental approaches are
discussed and the contributions of each approach are summarized.
PMID- 9394709
TI - Effects of dietary fatty acids on breast and prostate cancers: evidence from in
vitro experiments and animal studies.
AB - Linoleic acid, an n-6 polyunsaturated fatty acid, is essential for normal mammary
tissue development, at least in part because it provides the metabolic precursor
required for the biosynthesis of key eicosanoids. A similar requirement applies
to the growth of estrogen-independent but apparently not to estrogen-dependent
rodent mammary and human breast carcinoma cells in vitro. By way of lipoxygenase
products, n-6 fatty acids also regulate expression of the invasive phenotype.
High-fat, linoleic acid-rich diets promote chemically induced rat mammary
carcinogenesis, virally induced mouse mammary tumor development, and the growth
and metastasis of estrogen-independent human breast cancer cells in athymic nude
mice. In contrast, saturated fatty acids have no discernible effects on mammary
carcinogenesis or progression. Most mechanistic studies have focused on the
cyclooxygenase and lipoxygenase products of n-6 fatty acid metabolism, and
support is accumulating for interactions between these eicosanoids and growth
factors and oncogenes. The investigation of dietary fatty acids in prostate
cancer is at an early stage and has been handicapped by a lack of satisfactory
animal models. However, there are indications that the n-6 fatty acids perform
functions in experimental prostate cancer progression similar to those described
for breast cancer.
PMID- 9394710
TI - Review of the effects of trans fatty acids, oleic acid, n-3 polyunsaturated fatty
acids, and conjugated linoleic acid on mammary carcinogenesis in animals.
AB - I review the effects of trans fatty acids, oleic acid, n-3 polyunsaturated fatty
acids, and conjugated linoleic acid on mammary carcinogenesis in animals. The
goal is not to provide an exhaustive survey of all the publications on these
topics; such a Herculean effort has been accomplished by previous reviews, which
are cited in the text. Instead, the emphasis is on the consistency or lack of
consistency of information regarding each of the above fatty acids, confounding
factors that may help to reconcile discrepancies in the database, a perspective
of the history of the research, and certain unique or exciting opportunities that
are worthy of special attention in evaluations of the relations between specific
fatty acids and cancer. This review arrives at four conclusions: 1) There is
little evidence that trans fatty acids have an adverse effect on carcinogenesis.
2) The data on cancer protection by oleic acid are not convincing. An inhibitory
effect attributed to an increased intake of oleic acid could be due to an
inadequate supply of linoleic acid. 3) Although a suppressive response to n-3
polyunsaturated fatty acids is observed in most cases, the availability of
linoleic acid is likely to be a confounding factor in determining the final
outcome. 4) Conjugated linoleic acid is unique in the sense that concentrations <
or = 1% are sufficient for producing significant cancer protection and that this
effect seems to be independent of the other fatty acids.
PMID- 9394711
TI - Fatty acids and colon cancer in experimental models.
AB - Experimental models have several advantages in the study of colon cancer. They
can be used to tightly control diet, examine putative intermediate markers, test
hypotheses about mechanisms of carcinogenesis, and quantify development of tumors
in a short time. Dietary issues that have been studied in animal models but are
unresolved include the concept of the effects of total fat compared with energy
intake, composition of the basal diet, linoleic acid requirements, and
interactions of fat with other nutrients. Intermediate markers that have been
probed in animal or in vitro studies include cytokinetics, aberrant crypt foci,
eicosanoids and hydroxyoctadecadienoic acids, ornithine decarboxylase, tyrosine
kinase, protein kinase C, and gene expression. Colon cancer is studied in animals
primarily with use of chemicals that are relatively specific inducers of these
tumors, but transplantable models and transgenic animals are also used. Total
dietary fat is generally thought to affect colon tumorigenesis, but there does
not appear to be any specific fatty acid that promotes the development of colon
cancer. Several studies indicate that n-3 fatty acids from marine sources alter a
variety of biological intermediates and inhibit colonic tumorigenesis; this is
probably mediated via the eicosanoid pathway. Although there are undoubtedly
multiple cellular changes elicited by certain fatty acids, our current knowledge
of this area suggests that specific fatty acid metabolites or their targets are
the likely mediators in this sequence.
PMID- 9394712
TI - Animal studies: summary, gaps, and future research.
AB - Animal models are essential in cancer research but investigators should recognize
the limits of the models they use. Because there is no ideal animal model,
researchers should use the biological and biochemical diversity among the models
to experimental advantage. The differences can tell us as much as the
similarities. Fatty acid metabolism seems to play a role in hormone-dependent and
hormone-independent cancers, and cell culture experiments have yielded much
information on possible mechanisms. However, a knowledge gap exists between these
studies and a full understanding of mechanisms in vivo. Mechanisms must be
understood before the possible relevance of the findings to humans can be
confidently assessed. There is little evidence to suggest that either trans fatty
acids or oleic acid has any specific effect on carcinogenesis and it is unlikely
that further study will reveal something important but heretofore overlooked. By
contrast, there appear to be notable gaps in our understanding of n-3 fatty
acids, linoleic acid, and conjugated linoleic acid in relation to possible
effects on cancer in humans. The major knowledge gap, and our greatest challenge,
is relating promising data from animal models and cell culture studies to the
prevention of cancer in humans.
PMID- 9394713
TI - Issues in the design and interpretation of studies of fatty acids and cancer in
humans.
AB - The methods used in nutritional epidemiology to study the relations between fatty
acids and cancer risk include ecologic studies, case-control studies, cohort
studies, and intervention trials examining either intermediate markers of cancer
risk or cancer incidence. Each type of study design has its particular strengths
and weaknesses. The inaccuracy of estimates of fatty acid intake from the use of
dietary questionnaires linked to nutrient databases is a major limitation in
nutritional epidemiology. Information on the concentrations of fatty acids in the
circulation or in adipose tissue can complement estimations of dietary intake.
Cancer prevention studies now underway are designed to test whole-diet effects on
neoplasia and will not be able to separate the effects of specific fatty acids
from those of other nutrients in the diet. The development of better intermediate
markers of cancer risk could enable the use of experimental methods to assess the
relation between specific fatty acids and cancer. Research findings as described
in the literature are complicated both by the multiple hypotheses that can be
tested when assessing fatty acid effects and by the uncertainties of multivariate
adjustment. Although there are substantial obstacles to understanding the
relations between fatty acid intakes and cancer risk, there is no better species
than humans for inference about diet and cancer risk in people.
PMID- 9394714
TI - Biomarkers of fatty acid exposure and breast cancer risk.
AB - Study of the effects of most individual biologically active dietary fatty acids
on human disease requires the use of biomarkers of long-term intake in well
designed epidemiologic studies. Several small studies of tissue taken from women
undergoing surgery for breast abnormalities have compared fatty acid profiles of
women with ascertained metastatic breast cancer with those with other
abnormalities. These studies, although often flawed in design and generally of
inadequate statistical power to determine significant differences, provide some
evidence. Human studies are generally consistent with animal models suggesting a
protective effect of n-3 fatty acids, a detrimental effect of high n-6 fatty
acids, and the possible importance of the ratio of these two classes of dietary
fatty acids on both breast cancer incidence and recurrence. High intakes of
monounsaturated fatty acid were also often negatively associated with breast
cancer. The effects of trans fatty acids have rarely been studied, but there are
some indications that they may enhance risk. In general, the study of individual
fatty acids is in its infancy. Larger well-designed studies with diverse
population and modern analyses of individual fatty acids are needed.
PMID- 9394715
TI - Specific fatty acids and risks of breast and prostate cancer: dietary intake.
AB - Although international comparisons have suggested positive associations between
consumption of total or saturated fat and risk of breast cancer, these relations
have not been supported in large prospective studies in which confounding factors
were minimized. There is no suggestion from international comparisons, case
control, or cohort studies that monounsaturated fat (the most abundant fat in the
US diet) increases risk of breast cancer, and there is some evidence that higher
intake, particularly in the form of olive oil, might actually reduce risk. The
available epidemiologic evidence provides little support for any important
relation between intake of either linoleic acid or extra-long-chain n-3 fatty
acids from fish and risk of breast cancer. However, high consumption of linoleic
acid is a relatively recent phenomenon in Western societies and continued
evaluation of its relation with breast cancer risk is warranted because of animal
data suggesting possible adverse effects. Ecologic, case-control, and cohort
studies all support a positive relation between consumption of animal fat and
risk of prostate cancer, but current evidence suggests that vegetable fat is not
related to risk of this cancer. Although relevant data are limited, neither
linoleic acid nor extra-long-chain n-3 fatty acid consumption appears to be
related to risk of prostate cancer. Because of the strong evidence that some
aspect of foods high in animal fat increases risk of prostate cancer, further
studies of specific dietary fatty acids in relation to the occurrence of this
malignancy are likely to be particularly valuable.
PMID- 9394716
TI - The role of fat, fatty acids, and total energy intake in the etiology of human
colon cancer.
AB - A high correlation between national per capita disappearance of fat and national
rates of colon cancer led to the hypothesis that consumption of fat, especially
from animal sources, increases risk for colon cancer. Over the past two decades,
this hypothesis has been tested in numerous case-control and cohort studies. In
general, neither case-control nor cohort studies find that the total fat
composition of the diet increases risk of colon cancer. Case-control studies
frequently find that total energy consumption is related to a higher risk of
colon cancer, but this result is difficult to interpret because physical activity
appears to be protective whereas obesity increases risk. In contrast with the
results for total fat, epidemiologic data regarding the role of specific fatty
acids are sparse. Nonetheless, useful information regarding major fatty acids may
be inferred from the numerous studies that have examined major source of various
fats in relation to colon cancer. Intake of red meat or beef has been related to
colon cancer risk in most case-control and cohort studies, whereas dietary fat
from sources other than red meat, including dairy, poultry, and vegetable oils,
does not increase risk of colon cancer. The apparent influence of red meat does
not appear to be mediated through its total lipid content, suggesting that other
factors such as heterocyclic amines formed during cooking may be critical.
Mechanisms whereby fat or red meat may influence colon carcinogenesis are
discussed, although none appear compelling.
PMID- 9394717
TI - Bridging animal and human studies: what are the missing segments in dietary fat
and prostate cancer?
AB - Epidemiologic investigations have suggested an association of dietary fat intake
with prostate cancer risk, especially risk of advanced prostate cancer. However,
supporting evidence from animal studies is limited. Segments that would bridge
animal and human studies on dietary fat and prostate cancer--which would
determine the future directions of research--are missing. Such segments include
1) well-designed animal studies to evaluate whether dietary fat or fatty acid
modulation, particularly by reducing dietary fat and supplementing n-3 fatty
acids, reduces the progression of prostate cancer; 2) in vivo identification of
intermediate biomarkers that are responsive to dietary fat and fatty acid
treatment and may serve as surrogate endpoints in future clinical studies; 3)
elucidation of mechanisms by which dietary fat or fatty acid modulation could
prevent prostate cancer progression; 4) further epidemiologic studies to estimate
dietary exposure more precisely to establish the correlation between dietary fat
and risk of prostate cancer; 5) randomized clinical intervention trials
evaluating whether dietary fat reduction combined with dietary n-3 fatty acid
supplementation delays the recurrence of prostate cancer and improves survival in
patients with clinical disease after therapeutic treatment, and whether it
prevents or reduces the progression to clinically significant disease in men with
latent disease; and 6) studies validating intermediate biomarkers as surrogate
endpoints.
PMID- 9394719
TI - It's a jungle out there: biodiversity and the physician-scientist.
PMID- 9394718
TI - Human studies on the effects of fatty acids on cancer: summary, gaps, and future
research.
AB - Both the goal of understanding the basic biology of cancer development as well as
the practical considerations involving public health, marketing, and nutrition
education have stimulated interest on the effects of individual fatty acids on
cancer. Data on diet-disease relations must meet the standard of significant
scientific agreement based on the totality of publicly available scientific
evidence. The process of arriving at significant scientific agreement begins by
collecting data accumulated from epidemiologic associations, animal studies, and
clinical trials. This supplement represents one useful effort toward that end.
Questions raised include: 1) What stage of the disease is being studied, what are
the relevant characteristics of the study participants, how well characterized
was the diet, and were appropriate experimental designs used; 2) Is there is a
significant role for markers of disease and, if so, are the markers available; 3)
Is there consistency, strength, and quality of evidence for establishing basic
scientific relations; 4) Do dose-response relations, biological plausibility, and
temporal relations (with special attention to clinical trials) exist; 5) What is
the level of specificity of the data for the health claim or posited relation;
and 6) What are the effective amounts of fatty acids in foods and diet? More
complete food-composition data with respect to fatty acids and more comprehensive
food tables are needed, as are better methods for measuring fat intakes, better
markers of progression, and more definitive epidemiologic and clinical studies.
At present there is insufficient evidence to conclude that specific fatty acids
are associated with cancer development in humans.
PMID- 9394720
TI - Image of the month. Cronkhite-Canada syndrome.
PMID- 9394721
TI - Risk and significance of endoscopic/radiological evidence of recurrent Crohn's
disease.
AB - BACKGROUND & AIMS: The aim of this study was to determine the risk of
endoscopic/radiological recurrence of Crohn's disease postoperatively and the
long-term outcome. METHODS: A randomized placebo-controlled trial was performed
to determine the effectiveness of mesalamine in preventing recurrent Crohn's
disease postoperatively. Patients in the control group were examined
endoscopically/radiologically before entry into and annually during the trial.
Findings were classified as minimal or severe. RESULTS: There were 76 patients
(49 men and 37 women; mean age, 37.1 +/- 13.2 years). Fifty (61.7%) had terminal
ileal resections. Overall, 55 endoscopic/radiological recurrences were observed
in 51 patients (67.1%). Expressed actuarially, the recurrence rate was 27.5% at 1
year (95% confidence interval [CI], 15.8%-37.6%), 60.8% at 2 years (95% CI, 46%
71.3%), and 77.3% at 3 years (95% CI, 62.7%-86.3%). Nineteen (37%) were
symptomatic and 12 (24%) were initially asymptomatic but later became symptomatic
(mean, 13.0 +/- 8.8 months), whereas 20 (39%) remained asymptomatic (mean, 16.9
+/- 17.4 months). Patients with severe endoscopic/radiological disease were
significantly more likely to be or become symptomatic than those with minimal
disease (23 of 32 vs. 8 of 19, respectively; P = 0.0437). CONCLUSIONS: This study
suggests that postoperative endoscopic/radiological recurrences occur later than
previously reported. Furthermore, many of these patients, especially with minimal
disease, will remain asymptomatic.
PMID- 9394722
TI - Antineutrophil cytoplasmic antibodies in T-cell receptor alpha-deficient mice
with chronic colitis.
AB - BACKGROUND & AIMS: Antineutrophil cytoplasmic antibodies (ANCAs) have been
detected in approximately 60% of sera from patients with ulcerative colitis. The
aim of this study was to examine the presence of ANCAs and distribution of ANCA
producing B cells in the lymphoid tissue of T-cell receptor alpha-deficient (TCR
alpha-/-) mice that develop chronic colitis resembling human ulcerative colitis.
METHODS: Sera from 87 TCR-alpha-/- mice were tested for the presence of ANCAs by
enzyme-linked immunosorbent assay against a human neutrophil extract and selected
antigens and by immunofluorescence study using human neutrophils. Enzyme-linked
immunospot assay was used for detecting ANCA-producing cells from spleen,
mesenteric lymph node (MLN), or colon. RESULTS: Approximately 70% of sera from
TCR-alpha-/- mice showed reactivity against human neutrophil extracts by enzyme
linked immunosorbent assay. Sixty percent of ANCA-positive sera showed a
perinuclear reaction pattern. By enzyme-linked immunospot, ANCA-producing cells
were detected in MLN and colon and less often in the spleen of TCR-alpha-/- mice
with chronic colitis. The predominant immunoglobulin isotype of these
autoantibodies was immunoglobulin A in the colon but not in the MLN and spleen.
CONCLUSIONS: TCR-alpha-/- mice produce ANCAs. The ANCA (immunoglobulin A isotype)
producing B cells exist primarily in the diseased colonic mucosa of TCR-alpha-/-
mice.
PMID- 9394723
TI - Regulation of gastric epithelial cell growth by Helicobacter pylori: offdence for
a major role of apoptosis.
AB - BACKGROUND & AIMS: Helicobacter pylori may affect the normal balance between
gastric epithelial cell proliferation and epithelial cell death, thus interfering
with the maintenance of gastric mucosal integrity. The aim of this study was to
investigate the effect of H. pylori on cell growth, DNA synthesis, induction of
apoptosis, and viability of human gastric epithelial cells in vitro. METHODS: H.
pylori was incubated with a differentiated human gastric cancer cell line for up
to 72 hours, and the effects on cell numbers (cell counts and WST-1 assay), DNA
synthesis (5-bromo-2'-deoxyuridine assay and [3H]thymidine incorporation), and
DNA fragmentation (DNA fluorochrome staining, transmission electron microscopy,
and histone enzyme-linked immunosorbent assay) were assessed. RESULTS: Incubation
of gastric epithelial cells with H. pylori led to a time- and concentration
dependent reduction of epithelial cell growth and a concomitant induction of DNA
fragmentation. At high bacteria-cell ratios (> 100), inhibition of cell growth
was associated with a reduction in DNA synthesis. Treatment of gastric cells with
tumor necrosis factor alpha, a receptor-activating CD95/APO-1/Fas antibody, and
interferon gamma markedly potentiated H. pylori-induced DNA fragmentation.
CONCLUSIONS: H. pylori affects gastric epithelial cell growth by direct induction
of apoptosis and inhibition of DNA synthesis and indirectly by sensitization of
epithelial cells for apoptosis induced by proinflammatory stimuli.
PMID- 9394724
TI - Murine CD4 T-cell response to Helicobacter infection: TH1 cells enhance gastritis
and TH2 cells reduce bacterial load.
AB - BACKGROUND & AIMS: Previous findings suggest that TH1 cellular immune responses
contribute to Helicobacter-associated gastritis. To further investigate this
issue, interleukin 4 gene targeted mice were infected with Helicobacter felis,
and a series of adoptive transfer experiments was performed to evaluate the role
of both TH1 and TH2 cells. METHODS: Antigen-specific spleen cells from
immunized/challenged or nonimmunized/infected mice or CD4+ T-cell lines were
transferred adoptively into naive recipients before live bacterial challenge.
RESULTS: Transfer of cells from both groups of donors as well as TH1 or TH2 cell
lines exacerbated gastric inflammation in the recipients. No effect on bacterial
load was observed in recipients of bulk spleen cells from infected mice or
recipients of TH1 cell lines. In contrast, when either a TH2 cell line or bulk
cells from immunized challenged mice were transferred adoptively, recipients
showed a dramatic reduction in bacterial load. Increased numbers of bacteria were
also noted in interleukin 4-deficient mice. CONCLUSIONS: These data suggest a
differential contribution of TH1 and TH2 cell-mediated immune responses in
Helicobacter infection: one associated with the pathogenesis of disease (TH1
phenotype) and the other associated with protection from or control of infection
(TH2 phenotype).
PMID- 9394725
TI - Roles of hepatocyte growth factor and its receptor Met during gastric ulcer
healing in rats.
AB - BACKGROUND & AIMS: It is unclear which growth factors are primarily responsible
for stimulating gastric ulcer healing. The roles of hepatocyte growth factor
(HGF) and Met/HGF receptor during gastric ulcer healing were studied in rats.
METHODS: HGF and Met/HGF receptor were located and quantified by in situ
hybridization and immunohistochemistry during experimental gastric ulcer healing.
The in vivo effects of exogenous recombinant human HGF on cell proliferation and
ulcer healing were assessed and compared with those of placebo and omeprazole
treatment. RESULTS: Compared with intact oxyntic mucosa, messenger RNA (mRNA) of
HGF and met was substantially greater in the ulcerated region on days 3 and 15.
HGF mRNA was located in stromal cells between the regenerative glands and in the
arterial vessels of submucosal tissue, whereas met mRNA was located in the
epithelial cells of the regenerative glands. After cryoinjury, immunoreactivity
for the Met/HGF receptor was absent on day 3, reappeared on day 8, and was
overexpressed on day 15. Exogenous recombinant human HGF had no effect on the
ulcer healing parameters over days 3-8, but it did increase epithelial cell
proliferation in the ulcer margin over days 8-15. CONCLUSIONS: These data suggest
that HGF mediates specific tissue interactions between mesenchyme and epithelia
during gastric ulcer healing.
PMID- 9394726
TI - Enteropathogenic Escherichia coli-induced myosin light chain phosphorylation
alters intestinal epithelial permeability.
AB - BACKGROUND & AIMS: Infection of epithelial cells with enteropathogenic
Escherichia coli (EPEC) induces phosphorylation of the 20-kilodalton myosin light
chain (MLC20). The physiological consequence of this biochemical observation,
however, has not been discerned. The aim of this study was to determine if EPEC
induced phosphorylation of MLC20 was involved in the associated perturbation of
intestinal epithelial barrier function. METHODS: Cultured intestinal epithelial
cells, T84, were infected with EPEC. The effects of protein kinase inhibitors on
EPEC-induced perturbation of barrier function were assessed using
electrophysiological techniques. Alterations in MLC20 phosphorylation were
correlated with functional responses. RESULTS: Inhibition of myosin light chain
kinase, but not protein kinase C or tyrosine kinase, prevented the decrease in
resistance caused by EPEC infection and significantly diminished EPEC-induced
MLC20 phosphorylation. Epithelial cell monolayers genetically manipulated to
constitutively increase MLC20 phosphorylation were relatively resistant to the
effects of EPEC on barrier function. CONCLUSIONS: For the first time, these data
show that a physiological consequence of the long-recognized increase in MLC20
phosphorylation by EPEC is perturbation of intestinal epithelial barrier
function, which probably contributes to the diarrhea associated with this
infection.
PMID- 9394727
TI - A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed
rat intestinal epithelial cells.
AB - BACKGROUND & AIMS: Constitutive expression of cyclooxygenase 2 (COX-2) has been
found in 85% of colorectal cancers. Ras mutations are found in 50% of colorectal
adenocarcinomas. The aim of this study was to determine the role of COX-2 in ras
induced transformation in rat intestinal epithelial (RIE) cells. METHODS: Cell
growth was determined by cell counts. The expression of COX-2 was examined by
Northern and Western analyses. For tumorigenicity assays, cells were inoculated
into dorsal subcutaneous tissue of athymic nude mice. DNA-fragmentation assays
were performed to detect apoptosis. RESULTS: The expression of COX-2 was
increased in RIE-Ras cells at both messenger RNA (9-fold) and protein (12-fold)
levels. Prostaglandin I2 levels were elevated 2.15-fold in RIE-Ras cells. Serum
deprivation further increased COX-2 expression 3.8-fold in RIE-Ras cells.
Treatment with a selective COX-2 antagonist (SC58125) inhibited the growth of RIE
Ras cells through inhibition of cell proliferation and by induction of apoptosis.
SC-58125 treatment reduced the colony formation in Matrigel by 83.0%.
Intraperitoneal administration of SC-58125 suppressed RIE-Ras tumor growth in
nude mice by 60.3% in 4 weeks. SC-58125 treatment also induced apoptosis in RIE
Ras cells as indicated by increased DNA fragmentation. CONCLUSIONS:
Overexpression of COX-2 may contribute to tumorigenicity of ras-transformed
intestinal epithelial cells. Selective inhibition of COX-2 activity inhibits
growth of ras-transformed intestinal epithelial cells and induces apoptosis.
PMID- 9394728
TI - A K-ras oncogene increases resistance to sulindac-induced apoptosis in rat
enterocytes.
AB - BACKGROUND & AIMS: Mutations of c-K-ras occur commonly in colonic neoplasms. The
aim of this study was to determine how c-K-ras mutations alter the responses to
the chemopreventive agent sulindac. METHODS: The parental rat intestinal cell
line IEC-18 and c-K-ras-transformed derivatives were treated with sulindac
sulfide. Cell cycle distribution was determined by flow-cytometric analysis
(fluorescence-activated cell sorter), apoptosis by DNA fragmentation (laddering),
flow cytometry, and microscopy, and changes in gene expression by immunoblotting.
RESULTS: Sulindac sulfide inhibited cell growth and induced apoptosis in a time-
and dose-dependent manner more rapidly in and at lower concentrations in parental
cells than ras-transformed cells. Expression of the sulindac sulfide arrested
cells in G0/G1, but cells entered apoptosis throughout the cell cycle.
Proapoptotic protein Bak was relatively high in untreated parental cells and
increased markedly after sulindac sulfide but was low in untreated ras
transformed cells and did not increase after sulindac sulfide. Expression of
other Bcl-2 family members was unchanged after sulindac sulfide. However,
sulindac sulfide reduced levels of cyclin D1 protein and cyclin E- and cyclin D1
associated kinase activity. CONCLUSIONS: c-K-ras-transformed enterocytes are
relatively resistant to sulindac sulfide-induced growth inhibition and apoptosis,
which may result from specific reduction of bak expression.
PMID- 9394729
TI - Bile regulates the expression of major histocompatibility complex class II
molecules on rat intestinal epithelium.
AB - BACKGROUND & AIMS: Major histocompatibility complex (MHC) class II molecules are
expressed on intestinal epithelial cells, and the intensity of this expression is
regulated. The aim of this study was to test the hypothesis that bile regulates
the expression of MHC class II molecules on intestinal epithelium. METHODS: Rats
were deprived of intestinal bile by external drainage for 24 or 48 hours, and
their intestines were collected, sectioned, and stained with the anti-MHC class
II monoclonal antibodies OX4 and OX6. For one group of rats, bile flow was
deviated from its usual entry point to the ileum. RESULTS: Compared with intact
animals, MHC class II expression was observed to be diminished within 24 hours
and totally absent after 48 hours of bile drainage. For the group in which bile
flow was deviated to the ileum, staining was only observed in the region distal
to the entry point. Analysis by bioassay and enzyme-linked immunosorbent assay of
bile showed the presence of tumor necrosis factor and interferon gamma,
respectively. CONCLUSIONS: It is concluded that the presence of bile is required
for the expression of MHC class II molecules on gut epithelium and that the
cytokine components of bile may be the inducing agents.
PMID- 9394730
TI - Differential expression of galectin 3 and galectin 1 in colorectal cancer
progression.
AB - BACKGROUND & AIMS: Galectins are beta-galactoside-binding proteins possibly
involved in tumor progression. The aim of this study was to determine the pattern
of galectin 3 and galectin 1 expression and involvement in colorectal cancer
progression. METHODS: Galectin 3 expression was examined immunohistochemically in
39 samples of normal mucosae, 25 adenomas, 87 carcinomas, and 39 lymph node
metastases. Galectin 1 was analyzed in 25 samples of mucosae, 15 adenomas, 25
carcinomas, and 11 metastases. Western blot analysis was also performed. RESULTS:
All normal mucosae showed strong nuclear galectin 3 expression, which was down
regulated in the neoplastic progression, because only 60% of adenomas, 48% of
carcinomas, and 44% of metastases were strongly positive (P < 0.0001).
Cytoplasmic expression was down-regulated in adenomas (16%) but increased again
in carcinomas (64%) (P < 0.0001). Galectin 1 expression was mainly detected in
stromal cells and correlated with tumor progression from normal mucosae to
adenomas and carcinomas (P < 0.0001). CONCLUSIONS: Galectin 3 expression is down
regulated in the initial stages of neoplastic progression, whereas a dissociated
cytoplasmic expression increases in later phases of tumor progression. Galectin 1
in colorectal mucosa is predominantly a stromal product whose overexpression is
associated with the neoplastic progression of colorectal cancer.
PMID- 9394731
TI - The neurochemical coding and projections of circular muscle motor neurons in the
human colon.
AB - BACKGROUND & AIMS: Enteric neurons can be characterized by their chemical coding,
projections, and morphology. The aim of this study was to describe the different
classes of human colonic circular muscle motor neurons. METHODS: Human colonic
circular muscle motor neurons were identified by retrograde tracing with 1,1'
didodecyl 3,3,3',3'-indocarbocyanine perchlorate (Dil) applied to the circular
muscle layer. Whole-mount preparations of the myenteric plexus were then double
labeled with antisera to choline acetyltransferase (ChAT) and/or nitric oxide
synthase (NOS), or NOS and vasoactive intestinal peptide (VIP), and the position
and immunoreactivity of Dil-filled neurons were recorded. RESULTS: Fifty-two
percent of all Dil-filled neurons were ChAT immunoreactive, and 86% of these
projected up to 11 mm orally, with 14% projecting short distances anally. Forty
eight percent of the Dil-filled neurons were NOS immunoreactive, and 77% of these
projected up to 19 mm anally, with 23% projecting no more than 6 mm orally. A
subpopulation of these NOS-immunoreactive motor neurons were also VIP
immunoreactive. A small population of myenteric neurons was immunoreactive for
both ChAT and NOS, but none projected to the circular muscle. NOS-immunoreactive
motor neurons projected for longer distances than those with ChAT
immunoreactivity and were larger. CONCLUSIONS: There are two classes of human
colonic motor neurons: one is excitatory (ChAT-immunoreactive) and mainly
projects orally and the other is inhibitory (NOS +/- VIP immunoreactive) and
projects preferentially anally.
PMID- 9394732
TI - Corticosteroids repress the interleukin 1 beta-induced secretion of collagenase
in human intestinal smooth muscle cells.
AB - BACKGROUND & AIMS: The cytokine interleukin (IL)-1 beta induces collagenase
expression and inhibits collagen expression in human intestinal smooth muscle
(HISM) cells. Corticosteroids cause transrepression of certain genes, including
the collagenase gene. The aim of this study was to determine if corticosteroids
repress the induction of collagenase expression and the inhibition of collagen
secretion by IL-1 beta in HISM cells. METHODS: HISM cells were exposed to IL-1
beta (1-100 pmol/L) for 24 hours in the presence or absence of dexamethasone (10(
6) mol/L). Collagenase messenger RNA (mRNA) levels were determined by
ribonuclease protection assay. Collagenase and tissue inhibitor of
metalloproteinase protein secretion were determined by enzyme-linked
immunosorbent assay of culture medium. Procollagen and collagen secretion were
determined by polyacrylamide slab gel analysis of radiolabeled proteins in
culture medium. RESULTS: A 30-fold induction of collagenase mRNA and collagenase
protein secretion by IL-1 beta was completely abrogated by dexamethasone.
Dexamethasone at 10(-6) mol/L also reduced basal levels of collagenase mRNA by
50% and blocked the IL-1 beta-induced inhibition of collagen secretion.
CONCLUSIONS: Corticosteroids repress the collagenolytic action of IL-1 beta on
HISM cells in vitro and therefore should promote healing in the inflamed
intestine.
PMID- 9394733
TI - Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: a
preliminary study.
AB - BACKGROUND & AIMS: Cirrhotic patients with a prolonged prothrombin time (PT) are
known to have low levels of factor VII. Because the current modalities to correct
this problem are not ideal, recombinant factor VIIa (rFVIIa) may be useful in
correcting the prolonged PT observed in the coagulopathy of cirrhosis. The aim of
this study was to evaluate the effectiveness of rFVIIa in nonbleeding volunteer
patients with the coagulopathy of cirrhosis. METHODS: A preliminary, single
center, dose-escalation trial was performed. Cirrhotic patients with a PT of > 2
seconds above the upper limit of the reference value received an intramuscular
injection of vitamin K. Ten patients whose PT did not correct to within 2 seconds
above the control of the upper limit of the reference value were given three
successive dosages of rFVIIa (5, 20, and 80 micrograms/kg) during a 3-week
period. RESULTS: The mean PT transiently corrected to normal in all three dosage
groups. No adverse effects were noted. There was no evidence of the induction of
disseminated intravascular coagulation. CONCLUSIONS: This preliminary trial shows
rFVIIa to be effective in transiently reversing the prolonged PT in a select
group of nonbleeding cirrhotic patients. These preliminary observations support
conducting a large-scale efficacy trial.
PMID- 9394734
TI - Vesicle movement in rat hepatocytes is reduced by ethanol exposure: alterations
in microtubule-based motor enzymes.
AB - BACKGROUND & AIMS: Ethanol is known to alter vesicle-mediated protein trafficking
in hepatocytes by undefined mechanisms. In this study, the effects of long- and
short-term ethanol exposure on vesicle movements were measured in isolated
hepatocytes, and alterations in the function of the microtubule-associated motor
enzymes dynamin, kinesin, and dynein, which are believed to support the transport
and/or budding of vesicles along microtubules, were tested. METHODS: Vesicular
movements in isolated hepatocytes exposed to short- and long-term ethanol
treatment were measured. Motor adenosine triphosphatase activities and their
association with specific membrane organelles were assessed in response to long
term administration of ethanol in vivo or acetaldehyde in vitro. RESULTS:
Hepatocytes exposed to short- or long-term ethanol treatment showed a significant
reduction in the number of motile vesicles. No alterations in the levels of motor
messenger RNA, protein, or enzymatic activity were observed. Interestingly,
ethanol had no effect on the association of dynein and kinesin with membranes,
whereas there was a significant increase in the amount of dynamin associated
specifically with Golgi membranes. CONCLUSIONS: Long- and short-term ethanol
exposure markedly reduces hepatocellular vesicle transport by a mechanism
apparently independent of any alteration in the enzymatic activity of molecular
motors, possibly involving a change in the function of dynamin.
PMID- 9394735
TI - Quantitative estimations of the contribution of different bile acid pathways to
total bile acid synthesis in the rat.
AB - BACKGROUND & AIMS: Cholesterol degradation to bile acids occurs via "classic" or
"alternative" bile acid biosynthetic pathways. The aim of this study was to
assess the contributions of these two pathways to total bile acid synthesis in
vivo. METHODS: Rats with biliary fistulas were infused with squalestatin for 24
and 48 hours; specific activities of cholesterol 7 alpha-hydroxylase (C7 alpha H)
and sterol 27-hydroxylase (S27H) and rates of bile acid synthesis were
determined. RESULTS: Continuous squalestatin infusion (15 micrograms/h) decreased
C7 alpha H specific activities to 4% and 12% of paired biliary fistula controls
at 24 and 48 hours, respectively (P < 0.05) without any changes in S27H specific
activities (82% and 95% of controls). At 24 hours, bile acid synthesis decreased
to 43% (P < 0.05) but returned to 87% at 48 hours (P = NS). Cholic acid synthesis
decreased at 24 hours but returned to control levels at 48 hours. Similar changes
in C7 alpha H, S27H, and bile acid synthesis were observed in primary rat
hepatocytes after addition of squalestatin (1.0 mumol/L). CONCLUSIONS: In the
face of persistent suppression of C7 alpha H and the classic pathway, an
alternative pathway becomes a main pathway of bile acid synthesis capable of
generating cholic and chenodeoxycholic acids. The observed induction of bile acid
synthesis via an alternative pathway or pathways represents an important
mechanism for maintenance of cholesterol homeostasis in the rat.
PMID- 9394736
TI - Increased bile acid pool inhibits cholesterol 7 alpha-hydroxylase in cholesterol
fed rabbits.
AB - BACKGROUND & AIMS: Cholesterol feeding unexpectedly inhibits cholesterol 7 alpha
hydroxylase in rabbits. The aim of this study was to explore the mechanism.
METHODS: Twenty male New Zealand white rabbits were fed regular chow with and
without 2% cholesterol for 10 days followed by 7 days of bile drainage. The
activities of hepatic cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase
that control bile acid synthesis in classic and alternative pathways were related
to the size and composition of bile acid pool. RESULTS: After feeding
cholesterol, plasma and hepatic cholesterol concentrations increased, the bile
acid pool doubled (from 254 +/- 44 to 533 +/- 51 mg; P < 0.001), cholesterol 7
alpha-hydroxylase activity decreased 68% (P < 0.01), but sterol 27-hydroxylase
activity increased 66% (P < 0.05) with increased cholic acid synthesis (P <
0.01). Bile drainage in the cholesterol-fed rabbits depleted the bile acid pool
and stimulated down-regulated cholesterol 7 alpha-hydroxylase activity 11.4-fold
(P < 0.001), although hepatic cholesterol remained elevated. Hepatic sterol 27
hydroxylase activity was unaffected. CONCLUSIONS: Feeding cholesterol increased
hepatic cholesterol and stimulated sterol 27-hydroxylase and alternative bile
acid synthesis, which expanded the bile acid pool and inhibited cholesterol 7
alpha-hydroxylase in rabbits. In distinction, hepatic sterol 27-hydroxylase was
insensitive to changes in the bile acid pool.
PMID- 9394737
TI - Chemokine gene expression in rat pancreatic acinar cells is an early event
associated with acute pancreatitis.
AB - BACKGROUND & AIMS: The molecular mechanisms underlying pancreatitis are largely
unknown. The goal of this study was to identify an early genetic event that
correlated with pancreatitis. METHODS: Differential display of messenger RNAs
(mRNAs) was conducted on normal pancreas vs. those of animals with secretagogue
induced pancreatitis. Northern blots from normal animals and animals with
experimental acute pancreatitis were probed with cloned complementary DNAs for
chemokines. Pancreatitis was induced with cerulein and by retrograde injection of
bile salts. Immunocytochemistry was used to identify the source of chemokine
expression. Pyrrolidine dithiocarbamate was tested for effects on chemokine
expression and pancreatitis. RESULTS: A differentially amplified band was
consistently observed early after cerulein hyperstimulation. This band was
identified as a portion of the mob-1 gene, an alpha-chemokine. Northern analysis
indicated that mRNAs for mob-1 and another chemokine, mcp-1, were induced after
cerulein hyperstimulation in vivo. mob-1 mRNA was also induced by retrograde
injection of bile salts and by cerulein in acinar cells in vitro. mob-1 protein
was localized to exocrine cells in pancreata of diseased animals. Pyrrolidine
dithiocarbamate inhibited both chemokine gene expression and early inflammatory
characteristics of pancreatitis. CONCLUSIONS: Chemokines are induced in acinar
cells by treatments that induce pancreatitis and may play an important role in
the early stages of the disease.
PMID- 9394739
TI - Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric
cancer: a model.
PMID- 9394738
TI - A preS mutation isolated from a patient with chronic hepatitis B infection leads
to virus retention and misassembly.
AB - A preS mutation derived from a patient with chronic hepatitis B virus (HBV)
infection who had HBV reinfection with fibrosing cholestatic hepatitis after
orthotopic liver transplantation was characterized. Sequence analysis of the HBV
genome revealed two deletions and a point mutation in the regulatory CCAAT
element of the S promoter. To investigate the particular preS mutation for
replication competence and viral assembly in functional experiments, the mutant
preS region was introduced into a replication competent HBV plasmid. Functional
studies were performed by transfecting this plasmid into hepatoma cells. Analysis
of the mutant HBV strain revealed an inverse ratio of S-gene products in
comparison to wild-type HBV that leads to intracellular viral retention. An
atypical intracellular distribution of HBV proteins and an enhanced nuclear
localization of HBV DNA was also detected. Additionally, a major fraction of the
extracellular viral particles was malformed. The association of intracellular
accumulation of viral proteins with cirrhosis and fibrosing cholestatic hepatitis
has been described recently. In this study, we show that the particular preS
mutation accounted for the viral retention, which may have contributed to a more
progressive form of liver disease found in this HBV-positive patient after liver
transplantation.
PMID- 9394740
TI - Nonsteroidal anti-inflammatory drugs and colorectal cancer: evolving concepts of
their chemopreventive actions.
PMID- 9394741
TI - NSAIDs to prevent colorectal cancer: a question of sensitivity.
PMID- 9394742
TI - Galectins: multipurpose carbohydrate-binding proteins implicated in tumor
biology.
PMID- 9394743
TI - Bile salt biosynthesis: an alternate synthetic pathway joins the mainstream.
PMID- 9394744
TI - The gatekeeper has many keys: dissecting the function of the APC gene.
PMID- 9394745
TI - By their scars ye shall know them.
PMID- 9394746
TI - Lansoprazole, H. pylori, and atrophic gastritis.
PMID- 9394747
TI - Gastroesophageal reflux after cure of H. pylori infection.
PMID- 9394748
TI - H. pylori eradication in gastroesophageal reflux disease.
PMID- 9394749
TI - Reflux esophagitis and H. pylori.
PMID- 9394750
TI - Therapeutic placebo in ulcerative colitis: fact or fiction?
PMID- 9394751
TI - Cost of endoscopy in economic evaluation.
PMID- 9394752
TI - Proceedings of the American Digestive Health Foundation International Update
Conference on Helicobacter pylori. McLean, Virginia, USA, February 13-16, 1997.
PMID- 9394753
TI - How is Helicobacter pylori transmitted?
AB - Helicobacter pylori is one of the world's most common pathogens. It colonizes
about 60% of the world's population, causes gastritis and peptic ulcer, and is
strongly associated with gastric adenocarcinoma and lymphoma. However, most
individuals never develop clinical disease. Thirteen years after the culture of
H. pylori by Marshall and Warren, we still do not know its major mode of
transmission. Childhood represents the major period of acquisition of infection
in the third world, but infection is rare in children in the developed world.
Possible routes of infection include either oral-oral or fecal-oral, iatrogenic
spread with inadvertent use of unsterile pH probes and endoscopes, and vectorial
spread by flies. Evidence to support each route of transmission is provided, but
there is no predominant route. The only significant reservoir of infection
appears to be humans themselves. The organism has been found in some domestic
cats and in nonhuman primates, but the opportunities for human interaction with
the latter are rare, making infection from this source an unlikely possibility.
The organism has the propensity to become a coccoid form. This may represent a
persistent form in which H. pylori can exist in the environment, but it has yet
to be shown that it can revert to the replicative form.
PMID- 9394754
TI - What are the host factors that place an individual at risk for Helicobacter
pylori-associated disease?
AB - Helicobacter pylori infection is associated with duodenal and gastric ulcer
disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma.
Although more than half the world's population harbors H. pylori, only a
proportion will develop clinically significant disease. The specific clinical
outcome of an individual can be examined as the modulation of host factors by H.
pylori infection. Host acid-secretory status and sensitivity to gastrin can be
modulated by H. pylori infection. Once H. pylori has established itself in the
stomach, virtually everyone develops gastritis, and variations in gastritis
patterns have been associated with different gastric acid responses to H. pylori
infection. The patterns of gastritis are important because they seem to determine
disease outcome. Blood group antigens have been implicated in studies of ulcer
disease. Receptors to Lewis antigens in gastric mucosa indicate that host mucosal
factors influence H. pylori attachment. Conversely, H. pylori strains express
Lewis antigen-like molecules, suggesting an autoimmune component for some H.
pylori-associated diseases. HLA genotypes may influence the host response to H.
pylori infection, and those of H. pylori-infected individuals have been
correlated with histological features. The clinical outcome of H. pylori
infection is most likely a result of complex interactions among host, bacterial,
and environmental factors. The mechanisms by which these diverse factors
influence the pathogenesis of different clinical outcomes remain under
investigation.
PMID- 9394755
TI - Helicobacter pylori factors associated with disease development.
AB - Although certain factors appear to predispose the host to infection by
Helicobacter pylori, clearly the bacterium possesses a well-defined battery of
virulence factors that allow the organism to: (1) colonize the gastric mucosa
(urease, flagella, adhesins, acid-inhibitory protein, iron acquisition proteins,
and heat shock proteins); (2) evade host defense (shedding of surface proteins,
catalase, superoxide dismutase, and poorly reactive lipopolysaccharide); and (3)
damage host tissue (vacuolating cytotoxin, protease, CagA-related factors,
inducers of cytokines, and chemotaxins). Together these factors allow H. pylori
to persist in the host, establishing a chronic infection. Although many of these
virulence factors are produced by all strains of H. pylori, there are also well
defined pathogenicity islands (contiguous stretches of chromosomal DNA) present
in some strains that encode additional proteins including CagA that potentiate
virulence. Strains possessing these "virulence cassettes" are isolated more
frequently from patients with the more serious clinical manifestations associated
with duodenal ulcer than from patients with gastritis alone or nonulcer
dyspepsia.
PMID- 9394756
TI - Commentary: Helicobacter pylori transmission, host factors, and bacterial
factors.
PMID- 9394757
TI - How does Helicobacter pylori cause mucosal damage? Direct mechanisms.
AB - Helicobacter pylori-associated gastritis is characterized by an abundant
inflammatory response and gastric epithelial cell injury. Adherence of H. pylori
to gastric epithelial cells seems to be required for bacterial colonization of
the gastric mucosa. Attachment of the bacterium to polarized gastric epithelial
cells causes damage to microvilli and stimulates actin polymerization, which is
associated with adherence pedestal formation. Studies suggest that H. pylori
directly contributes to the injury of gastric epithelial cells by the elaboration
of cytotoxic factors. The first toxin identified from H. pylori strains, known as
vacuolating cytotoxin, induces vacuole formation in eukaryotic cells. Elaborated
enzymes by H. pylori may also contribute directly to epithelial cell injury.
Ammonia produced through urease activity may be toxic to gastric epithelial
cells. H. pylori protease and lipase degrade gastric mucus and disrupt the
phospholipid-rich layer at the apical epithelial cell surface, allowing for cell
injury from back diffusion of gastric acid. This cell injury may lead to cell
death, believed to result from induction of apoptosis. There are sufficient data
to suggest that H. pylori, through direct pathogenic mechanisms, contributes
significantly to the gastric mucosal injury associated with this infection, and
may enhance the susceptibility of gastric epithelial cells to carcinogenic
conversion.
PMID- 9394758
TI - How does Helicobacter pylori cause mucosal damage? The inflammatory response.
AB - The role for Helicobacter pylori in the pathogenesis of disease provides the
conundrum that only a subset of subjects infected with H. pylori will ever
develop peptic ulcer or gastric cancer. Thus, variation in strain as well as
environmental or host factors converge in the gastroduodenal milieu and control
the final outcome of infection. The host immune and inflammatory response is
emerging as an important element in the pathogenesis of these gastric diseases.
The ideal host response provides protection to clear an infection without causing
excessive amounts of inflammation that could compromise the integrity and
function of host cells. This review will cover four main questions: (1) What are
the mucosal immune/inflammatory responses that confer protection without damaging
the host? (2) How do the gastric immune responses during infection with H. pylori
differ from this ideal scenario? (3) Do these responses contribute to autoimmune
mediated damage to gastric tissue? (4) Can immunomodulation through vaccination
enhance protective, nondestructive responses that prevent or treat infection or,
at least, attenuate inflammation?
PMID- 9394759
TI - How does Helicobacter pylori cause mucosal damage? Its effect on acid and gastrin
physiology.
AB - Helicobacter pylori infection increases gastric acid secretion in patients with
duodenal ulcers but diminishes acid output in patients with gastric cancer and
their relatives. Investigation of the basic mechanisms may show how H. pylori
causes different diseases in different persons. Infection of the gastric antrum
increases gastrin release. Certain cytokines released in H. pylori gastritis,
such as tumor necrosis factor alpha and specific products of H. pylori, such as
ammonia, release gastrin from G cells and might be responsible. The infection
also diminishes mucosal expression of somatostatin. Exposure of canine D cells to
tumor necrosis factor alpha in vitro reproduces this effect. These changes in
gastrin and somatostatin increase acid secretion and lead to duodenal ulceration.
But the acid response depends on the state of the gastric corpus mucosa. The net
effect of corpus gastritis is to decrease acid secretion. Specific products of H.
pylori inhibit parietal cells. Also, interleukin 1 beta, which is overexpressed
in H. pylori gastritis, inhibits both parietal cells and histamine release from
enterochromaffin-like cells. H. pylori also promotes gastric atrophy, leading to
loss of parietal cells. Factors such as a high-salt diet and a lack of dietary
antioxidants, which also increase corpus gastritis and atrophy, may protect
against duodenal ulcers by decreasing acid output. However, the resulting
increase of intragastric pH may predispose to gastric cancer by allowing other
bacteria to persist and produce carcinogens in the stomach.
PMID- 9394760
TI - Helicobacter pylori, inflammation, mucosal damage, and apoptosis: pathogenesis
and definition of gastric atrophy.
AB - Much of what is currently accepted on the natural history of Helicobacter pylori
induced gastritis and its relationship with gastric adenocarcinoma rests on the
assumption that atrophic gastritis can be correctly identified and reproducibly
recognized. Recently, several studies have indicated that pathologists have a low
level of agreement on this topic, and the terms "gastric atrophy" and "atrophic
gastritis" remain imprecisely defined and, therefore, poorly understood.
Furthermore, the genesis and progression of the atrophic changes taking place in
the gastric mucosa of some, but not all, subjects infected with H. pylori are
incompletely characterized. This review has three aims: (1) to briefly reexamine
our current knowledge of the mechanisms involved in the injury and repair of
gastric glands; (2) to present a hypothesis on the development of gastric
atrophy; and (3) to propose a new, stringent definition of gastric atrophy that
may be usefully applied in the clinical research arena.
PMID- 9394761
TI - What role does Helicobacter pylori play in gastric cancer?
AB - Several lines of evidence support an association between Helicobacter pylori
infection and gastric cancer. The natural history of H. pylori-associated
gastritis is inexorable progression ultimately leading to gastric atrophy. In
general, this process requires between 20 and 40 years to complete. Atrophic
gastritis is widely considered to be a precursor lesion of the intestinal type of
gastric cancer. Moreover, areas with a high prevalence of H. pylori infection
also have a high prevalence of gastric cancer. Strong evidence from three
prospective studies shows the risk of gastric cancer to be increased fourfold in
H. pylori-positive persons. Several retrospective studies have also confirmed
that H. pylori infection is associated with development of gastric cancer,
especially in the younger generation, early gastric cancer, and noncardiac
gastric cancer. H. pylori alone is not likely responsible for gastric cancer.
Rather, it may provide a suitable environment, including chronic gastritis and
intestinal metaplasia, for neoplastic change. Recognition of an association
between H. pylori infection and gastric cancer has led to a major shift in
emphasis on the cause of the disease. Research into H. pylori has focused
attention on the importance of chronic inflammation and impaired host defense
mechanisms as factors in the development of gastric cancer. H. pylori infection
leads to changes in many factors that are important to the pathogenesis of
gastric cancer, including vitamin C content of gastric juice, reactive oxygen
metabolites, and epithelial cell proliferation. Eradication of the organism may
reverse these changes. Therefore, eradication of H. pylori in infected persons
might be a route to preventing gastric cancer, although many questions still
remain as to the effectiveness of this strategy.
PMID- 9394762
TI - What role does Helicobacter pylori eradication play in gastric MALT and gastric
MALT lymphoma?
AB - The concept of mucosa-associated lymphoid tissue (MALT) has been introduced to
differentiate biological functions from behavior of nonnodal vs. nodal lymphoid
tissues. Lymphomas arising from MALT also behave differently than typical nodal
lymphomas. In contrast to other tissues, MALT in the stomach is almost
exclusively a result of Helicobacter pylori infection. Thus, MALT is part of the
host defense against the pathogen H. pylori. Consequently, lymphomas arising from
gastric MALT may be a clonal evolution starting from the infection. In low-grade
gastric MALT lymphoma, cure of the infection may induce complete histological
remission in the majority of patients. Investigators have recently reported that
complete remission rate is between 70% and 80%. In an extended analysis, we have
treated 84 patients with low-grade gastric MALT lymphoma in stage El, using a
dual regimen to eradicate H. pylori. Complete remission was observed in 68 (80%)
patients; a partial remission was found in 4 patients. In contrast, 12 patients
showed no change and were referred to alternative treatment. In patients in
complete remission, a polymerase chain reaction assay for the rearranged
immunoglobulin heavy-chain gene remained positive in many cases. Together with
data from the literature, these data suggest that the majority of patients with
low-grade gastric MALT lymphomas in stage El respond to eradication of H. pylori.
Longer follow-up investigations are necessary to determine if remissions indicate
a cure from the disease.
PMID- 9394763
TI - Commentary: role of Helicobacter pylori on gastric mucosal damage, gastric
cancer, and gastric MALT lymphoma.
PMID- 9394764
TI - What role does Helicobacter pylori play in dyspepsia and nonulcer dyspepsia?
Arguments for and against H. pylori being associated with dyspeptic symptoms.
AB - A major role for Helicobacter pylori gastritis in nonulcer dyspepsia (NUD) is
controversial. Gastroduodenal dysfunction may be associated with H. pylori
infection, but there is little evidence for a causal link with dyspepsia.
Population-based studies with appropriate methodology have generally failed to
confirm an association between H. pylori and NUD. Furthermore, no definite
association between subgroups of NUD (ulcer-like, dysmotility-like, reflux-like,
and nonspecific) and H. pylori has been identified however the subgroups have
been defined, and no specific symptom pattern characterizes patients with H.
pylori infection. Whether H. pylori-induced alterations of gastric physiology can
explain NUD remains open to debate while we await the results of more specific
experiments. Although acid secretion in response to gastrin-releasing peptide may
be increased in a subset of NUD patients who are infected with H. pylori,
uninfected patients with NUD have not been assessed and the results require
confirmation. Most studies suggest no association between H. pylori and
gastroduodenal motor or sensory dysfunction in NUD. Treatment trials have been
unconvincing. The trials with bismuth therapy have not been adequately blinded.
Furthermore, some studies suggest that H. pylori-negative patients with NUD may
respond to bismuth treatment, although the results have not been uniform.
Therapies aimed at curing H. pylori infection have produced mixed results, with
small positive and negative trials. The trials that have used adequate outcome
measures have more often than not been negative. Based on current evidence, H.
pylori is not established to be of causal importance in NUD.
PMID- 9394765
TI - What is the role of Helicobacter pylori in complicated ulcer disease?
AB - The role of Helicobacter pylori in the pathogenesis of duodenal and gastric ulcer
and ulcer recurrence is widely known. Bleeding, perforation, and obstruction
represent the most serious, potentially life-threatening manifestations of ulcer
disease (hemorrhage in 15%-20%). The lifetime prevalence of perforation and
obstruction is much lower (approximately 5% and 2%, respectively). Despite
improved diagnostic and therapeutic options, bleeding-related mortality rates
remain at 6%-7% in the United States and between 4% and 14% in Europe. H. pylori
and nonsteroidal anti-inflammatory drugs are now recognized as the two primary
causes of ulcer disease. Eradication of H. pylori in patients with uncomplicated
ulcers results in recurrence rates of < 10%, suggesting that eradication of H.
pylori in patients with bleeding ulcers may virtually prevent recurrence of both
the disease and its complications. Although the prevalence of H. pylori infection
is almost 100% in duodenal and 80%-90% in gastric ulcer patients not using
nonsteroidal anti-inflammatory drugs, the prevalence of the organism in bleeding
duodenal and gastric ulcers does not reach 70% and 60%, respectively, which may
be due to false-negative test results.
PMID- 9394766
TI - Relationship between nonsteroidal anti-inflammatory drug use, Helicobacter
pylori, and gastroduodenal mucosal injury.
AB - With the realization that Helicobacter pylori is the main etiologic factor for
peptic ulcer disease, recent studies have explored a potential relationship
between H. pylori and nonsteroidal anti-inflammatory drug (NSAID)-related
gastroduodenal mucosal injury. Using serology and/or histology to detect H.
pylori, case-control studies have shown no meaningful differences in H. pylori
prevalence in both arthritis and nonarthritis NSAID users and controls. Placebo
controlled short-term trials of NSAIDs have also shown no change in the frequency
of detection of H. pylori by gastric mucosal biopsy specimens after 7-30 days of
NSAID ingestion. A number of studies have shown that the histological gastritis
identified in NSAID users is caused by H. pylori infection, whereas the reactive
(chemical) gastritis can be caused by NSAID use. Although the overall
relationship between H. pylori gastritis and dyspepsia remains controversial,
there is no evidence from well-controlled studies using either serology or
histology that this gastritis predisposes to NSAID-related dyspepsia. The effect
of H. pylori on NSAID-related gastroduodenal mucosal injury may be best
established by evaluating the ulcer recurrence rate after H. pylori eradication
and rechallenge with NSAIDs. To date, only one such study has examined this
question, and in this small study, the ulcer recurrence rate at 6 months was not
reduced by H. pylori eradication.
PMID- 9394767
TI - Commentary: bleeding ulcers, interaction between NSAIDs and Helicobacter pylori
infection, and nonulcer dyspepsia.
PMID- 9394768
TI - How should Helicobacter pylori infection be diagnosed?
AB - The ideal approach for the initial diagnosis of Helicobacter pylori infection is
to perform an endoscopy to obtain biopsy specimens for histology and culture.
Histology allows classification of any gastritis lesions present and may have
prognostic value, and culture enables susceptibility testing of antimicrobial
agents to direct proper treatment. Biopsy specimens must also be taken from the
corpus if the patient was pretreated with proton pump inhibitors. The cost of
these tests and the delay in receiving results limits their use in clinical
practice. Therefore, the urease test, a quick and inexpensive test, is used to
detect the presence of H. pylori and constitutes the basic invasive test for H.
pylori. A new urease test based on a strip instead of an agar disk may be the
test of choice in the future, because of its increased sensitivity and 2-hour
delay (instead of 24 hours) in obtaining the result. In some countries, because
of the cost, endoscopy will be used in selected patients only, either because of
alarm symptoms or age > 45 years, which is considered a threshold for gastric
cancer risk. In other patients, the noninvasive tests will be used. The cost of
serology makes it more attractive compared with the urea breath test. Currently,
there are accurate enzyme-linked immunosorbent assay tests that can be performed
in any laboratory and that provide precise and quick diagnoses. In the event of a
doubtful result, an immunoblot can be performed, as is the case for other
infections. Patient follow-up after treatment provides a different situation
because bacterial load is usually lower. A noninvasive test should be performed,
and only the urea breath test can be used within the timing originally proposed
to test eradication efficacy (i.e., 4-6 weeks after treatment). If the result is
positive, susceptibility testing is required before administering a second course
of treatment. The increasing use of antimicrobial agents to treat H. pylori is
likely to result in antimicrobial resistance, requiring that bacteriologic
surveillance programs be implemented. There are numerous research projects
ongoing in this area, and one can expect that improved methods, such as
colorimetric polymerase chain reaction (PCR) and improved antibody tests, will
also be used in the future.
PMID- 9394770
TI - For what conditions is there evidence-based justification for treatment of
Helicobacter pylori infection?
AB - Evidence-based medicine combines clinical expertise and the best available
evidence from systematic research to aid decision making in patient care. Levels
of evidence can be graded from I to V, with level I, the strongest, coming from
large randomized controlled trials (RCTs). When a definitive RCT has not been
performed, or is impracticable or inappropriate, lesser grades of evidence are
used. There is level I evidence supporting the treatment of Helicobacter pylori
infection in patients with duodenal or gastric ulcers. Prospective RCTs have
shown that cure of the infection is associated with ultimate cure of the ulcer
diathesis. Therefore, this is a "grade A" recommendation for treatment. In
nonulcer dyspepsia, numerous RCTs have yielded conflicting results regarding the
benefits of treatment. Although there are methodological problems with many
reported studies, there is some evidence (level II at best) to support treatment-
a grade B recommendation. In early gastric cancer and gastric mucosa-associated
lymphoid tissue lymphoma, the best available evidence supporting treatment of H.
pylori infection is of low quality, i.e., levels III and V. Although these carry
only grade C treatment recommendations, treatment is safe and carries at least
some evidence of efficacy. It is therefore indicated based on the current best
available evidence. No evidence exists to support treating the infection in
patients receiving long-term proton pump inhibitors for gastroesophageal reflux
disease or in patients with any of the nongastrointestinal conditions that have
been tentatively linked to H. pylori.
PMID- 9394769
TI - Who should be treated for Helicobacter pylori infection? A review of consensus
conferences and guidelines.
AB - The publication of the National Institutes of Health Consensus Development
Conference guidelines on management of Helicobacter pylori infection in 1994 set
a precedence. At present, at least eight European countries have produced
national guidelines, and, more recently, the European Helicobacter pylori Study
Group also outlined guidelines based on the strength of available evidence. It is
generally agreed that H. pylori should be eradicated in peptic ulcer disease. In
nonsteroidal anti-inflammatory drug (NSAID)-related ulcers, most countries that
considered the issue suggested discontinuing NSAIDs when possible and eradicating
H. pylori. The prophylactic eradication of H. pylori was not recommended. A
number of panels felt that there was not enough evidence available to recommend
eradication of H. pylori in functional dyspepsia, whereas other groups felt that
nonulcer dyspepsia, particularly after investigation and with severe or recurrent
symptoms, was an indication for eradication therapy. Other conditions (i.e.,
gastroesophageal reflux disease [GERD] and mucosa-associated lymphoid tissue
[MALT] lymphoma) have emerged in this short time as possible indications for H.
pylori eradication. There is no evidence that H. pylori infection has a role in
the pathogenesis of GERD, but there is evidence suggesting that patients with H.
pylori infection who require long-term acid suppression may be at risk of
developing atrophic gastritis. The European Helicobacter pylori Study Group has
suggested that eradication therapy should be offered to infected family members
of patients with gastric cancer. It also recommended that eradication therapy was
"strongly recommended" on the basis of "supportive" evidence in gastritis with
severe abnormalities and after early resection of early gastric cancer. An
"uncertain" recommendation with "equivocal" evidence was given for asymptomatic
subjects, extra-alimentary tract disease, the prevention of gastric cancer in the
absence of risk factors, and in pediatric patients with recurrent abdominal pain.
Despite considerable advances, further research studies are needed to provide
definite direction for the treatment of many conditions.
PMID- 9394771
TI - Can therapy even be denied for Helicobacter pylori infection?
AB - Helicobacter pylori infection is a transmissible bacterial infection of the
gastric mucosal surface that causes progressive damage with eventual destruction
of the stomach. In the United States, the presence of H. pylori infection in
patients carries a lifetime risk of developing peptic ulcer of at least 16% and a
1%-3% risk of developing gastric cancer. An infected individual is also a risk to
the community because the infection can be transmitted. A review of the data
shows that H. pylori is the only treatable infectious disease with such a high
rate of morbidity and mortality that is not the subject of an all-out program to
eradicate it from the population. The risk of a serious outcome of untreated
asymptomatic H. pylori infection is great, or greater, than with asymptomatic
syphilis or tuberculosis. H. pylori infection is a serious public health problem,
and thus the presence of H. pylori infection justifies treatment. The question is
not whom to treat, but whom to test. The gastroenterology community appears to
have been unduly influenced by the fact that H. pylori infection is widespread
and often asymptomatic, as well as by the costs and complications of current
treatment. H. pylori infection is a serious, worldwide infectious disease with
tremendous and unacceptable morbidity and mortality. Although there are no
emotional reasons to treat H. pylori infection, there are logical and persuasive
scientific reasons to treat. If the tools are available, screening the population
for the presence of H. pylori infection with the goal of preventing all H. pylori
related diseases is recommended. Our goal should be to totally eliminate H.
pylori from the face of the earth, just as we eliminated smallpox.
PMID- 9394772
TI - Commentary: how, in whom, and when to diagnose Helicobacter pylori.
PMID- 9394773
TI - What are the treatment goals for Helicobacter pylori infection?
AB - The goals of therapy of Helicobacter pylori are commonly viewed as either
clinical (e.g., avoid further morbidity, mortality, or prevent disease from
occurring) or economic (e.g., save healthcare dollars by avoiding further
expenditure of resources). However, when viewed globally, these goals are not
incongruent but are inexorably linked. Prevention of disease or avoidance of
further morbidity and mortality by curing H. pylori infection is obviously an
improved clinical outcome, but it also concurrently avoids further utilization of
healthcare resources and is "cost-effective," resulting in improved economic
outcome as well. The more clinically effective an H. pylori treatment is, the
more economically effective it is as well. When comparing regimens, the cost
effectiveness is determined by efficacy of the regimen, not its cost. Put more
simply, "The most expensive therapy is the one that doesn't work!" Therefore, the
goals of the therapy are simple: avoid further morbidity, mortality, and prevent
disease while minimizing further utilization of healthcare resources, thus saving
money. The most clinically effective therapy is also the most cost-effective
therapy. Regimens used should have demonstrated greater than 90% efficacy or
effectiveness in the population being treated for H. pylori infection. The
regimens should be simple and well tolerated. It is clinically and economically
inappropriate to use a regimen not meeting these criteria.
PMID- 9394774
TI - Current FDA-approved treatments for Helicobacter pylori and the FDA approval
process.
AB - U.S. Food and Drug Administration (FDA) approval of new drugs expands treatment
options and serves as a "safety net" of well-documented efficacy and safety. The
information provided in the package insert facilitates physician education and
provides some assurance that marketing information is accurate. As of February
1997, three Helicobacter pylori regimes have been FDA-approved for eradication of
H. pylori in infected patients with active duodenal ulcers. Regimen 1, omeprazole
+ clarithromycin (O/C), was supported by two multicenter, controlled studies with
a 6-month follow-up. Eradication rates were 74% (n = 53; 95% confidence interval
[CI], 62-85) and 64% (n = 61; 95% CI, 52-76). Twenty-five of 26 patients with
failed eradication therapy who were taking O/C with clarithromycin-susceptible
strains before treatment and who had pretreatment and posttreatment
susceptibility tests performed developed clarithromycin resistance after
treatment. Regimen 2, ranitidine-bismuth-citrate + clarithromycin, was supported
by two multicenter, placebo-controlled studies with a 6-month follow-up.
Eradication rates were 84% (n = 19; 95% CI, 60-96) and 73% (n = 22; 95% CI, 50
88). Insufficient pretreatment and posttreatment susceptibility data were
collected to assess antimicrobial resistance. Regimen 3, bismuth subsalicylate +
metronidazole + tetracycline + an H2-receptor antagonist, was supported by two
pivotal literature-based studies. Eradication rates in patients with duodenal
ulcer were 82% (n = 51; 95% CI, 70-92) and 77% (n = 39; 95% CI, 61-89),
respectively. When extrapolating the results of these three FDA-approved regimens
to the clinical setting, particular aspects of the clinical trial should be kept
in mind. These include the type of controls, primary end points used, population
studied, and number and type of dropouts.
PMID- 9394775
TI - What other regimens are under investigation to treat Helicobacter pylori
infection?
AB - The most common infection in the world, Helicobacter pylori infection, is very
specific, and present experience in treating infectious diseases is not
applicable in general for this infection. Animal models (e.g., mouse and ferret)
are thus far inadequate as reliable screening models. Old-fashioned trial-and
error treatment of infected humans is still the screening model and the gold
standard in the evaluation of regimens aimed at eradication of H. pylori. A
variety of studies on treatment of H. pylori infection have been performed with
varying results. This pooled analysis of the following therapeutic combinations:
proton pump inhibitor (PPI) plus two antibiotics or antimicrobials, quadruple
therapies, and nonantibiotic regimens is an attempt to make a fair comparison of
tested therapeutic strategies aimed at eradicating H. pylori. Data from treatment
groups including specified drug combinations are pooled, regardless of dose or
duration. Search methods are: MEDLINE 1984-1996, Digestive Disease Week 1988
1996, United European Gastroenterology Week 1992-1996, European Helicobacter
pylori Study Group 1988-1996, Asia Pacific Congress 1996, H. pylori International
Workshop Hong Kong 1996, and miscellaneous. Eradication rates (efficacy) are
presented as intention-to-treat data (i.e., worst-case analysis). Separate
subanalyses with regard to study quality, dose, and duration are performed for
some groups. A general cost-efficacy analysis is performed based on pooled
efficacy data. Convenience data are presented as total number of tablets, total
number of intake occasions, and duration of therapy. Drugs evaluated in the
analysis are bismuthdicitrate, tetracycline, amoxicillin, nitroimidazoles,
macrolides, H2-receptor antagonists, PPIs, sucralfate, and sofalcone. The most
effective and convenient drug combinations are the PPI-based triple therapies. No
significant difference was observed between the three PPIs. The cure rate did not
improve after addition of bismuth. Cost-effectiveness is closely associated with
efficacy.
PMID- 9394776
TI - What is the role for vaccination in Helicobacter pylori?
AB - Helicobacter pylori has been implicated in the etiology of peptic ulcer disease,
chronic gastritis, gastric carcinoma, and gastric mucosa-associated lymphoid
tissue lymphoma. Although significant progress has been made in treating this
infection with combinations of either antimicrobial agents or antimicrobial
agents plus proton pump inhibitors, these antimicrobial-based treatments continue
to be suboptimal. Over the past few years it has become increasingly recognized
that direct mucosal immunization can induce protection from infection at mucosal
surfaces. Therefore, prevention of H. pylori infection by oral immunization is an
alternative approach for the control of H. pylori disease. Using the Helicobacter
felis mouse model or H. pylori mouse model, both prophylactic and therapeutic
oral immunizations have been shown to be effective against H. pylori. In
addition, several H. pylori proteins have been identified as potential candidate
vaccines, and a phase 1 clinical trial has been completed that demonstrates the
safety and tolerability of urease as a vaccine antigen. Such antigens in
combination with a safe mucosal adjuvant could be used in the form of an oral
vaccine administered during childhood before exposure to H. pylori to prevent
infection. In addition, therapeutic immunization alone or as an adjunct to
antimicrobial therapy may be capable of achieving a cure rate approaching 100%.
PMID- 9394777
TI - Commentary: treatment of Helicobacter pylori.
PMID- 9394778
TI - What remaining questions regarding Helicobacter pylori and associated diseases
should be addressed by future research? View from the Far East.
AB - Based on the findings of several epidemiological studies, it is believed that
Helicobacter pylori infection is closely associated with gastric cancer. Because
some abnormalities, such as severe inflammation in the gastric mucosa, impaired
secretion of vitamin C, and increased gastric cell proliferation, improve after
cure of the infection, anti-H. pylori therapy may reduce the incidence of gastric
cancer. In Japan, the odds ratios for the development of atrophic gastritis and
gastric cancer in H. pylori-positive patients are not as high as those reported
in Europe and the United States. These findings suggest that factors other than
H. pylori may exert a considerable influence on the development of atrophic
gastritis and gastric cancer in Japan. It is not known whether atrophy and
intestinal metaplasia, possible precursors of gastric cancer, are reversible. H.
pylori infection is associated with a "gastritis, intestinal metaplasia, and
gastric cancer sequence," but it remains obscure whether the infection is
directly associated with the development of gastric cancer. We do not know which
age group of patients should be given anti-H. pylori therapy for the prevention
of gastric cancer. To elucidate whether the eradication of H. pylori can prevent
gastric cancer, a Japanese intervention trial is now in progress.
PMID- 9394779
TI - What remaining questions regarding Helicobacter pylori and associated diseases
should be addressed by future research? View from Europe.
AB - A variety of questions regarding Helicobacter pylori need to be addressed by
future research. Further investigations are needed on the relationship between H.
pylori and gastric cancer. In particular, the mechanism of the interaction
between H. pylori infection and host genetic factors and dietary factors that
lead to the cancer need to be unraveled. Also, the reversibility of cancer
associated abnormalities (e.g., hypochlorhydria, atrophy, and intestinal
metaplasia) by eradication of H. pylori needs to be determined. Noninvasive means
of identifying H. pylori-positive subjects at high risk of developing gastric
cancer are required for such subjects to be targeted for eradication therapy.
Further studies are also required on the interactions between H. pylori and
proton pump inhibitor therapy that might predispose to cancer. There is
considerable interest in the possibility of noninvasive H. pylori testing
replacing endoscopy in determining management of nonelderly patients with
uncomplicated dyspepsia unassociated with nonsteroidal anti-inflammatory drugs
(NSAIDs). Randomized studies comparing endoscopy vs. noninvasive H. pylori
testing in this situation are required with comprehensive outcome measures.
Improvement in eradication therapy is required and will depend on the development
of more effective and specific antibiotics and therapeutic vaccines. Wide-scale
elimination of the infection will depend on preventing its spread from person to
person. Achieving this will require further knowledge of its mode of
transmission, particularly in childhood, and the development of prophylactic
vaccines. Further studies are required to define the role of H. pylori infection
in other diseases, including predisposition to enteric infection in the
developing world as a result of H. pylori-induced chronic hypochlorhydria,
nonulcer dyspepsia, pernicious anemia, atherosclerosis, and NSAID-related ulcer
disease. Finally, we need to know whether H. pylori infection may be beneficial
in certain circumstances and whether eradicating the infection may be
disadvantageous to some subjects.
PMID- 9394780
TI - What remaining questions regarding Helicobacter pylori and associated diseases
should be addressed by future research? View from North America.
AB - Several areas regarding Helicobacter pylori that need improvement or
clarification in the United States include treatment of dyspepsia, physician
education on disease associations with H. pylori, and evidence from U.S. studies
that 7-day H. pylori eradication regimens are more effective than current
regimens. Dyspepsia, a ubiquitous condition in the United States, is routinely
managed on the basis of a positive H. pylori serology without other
investigations. This approach has been fostered by cost-effectiveness studies of
various approaches to duodenal ulcer and dyspeptic patients. Serology-directed
therapy was the most cost-effective option vs. endoscopy-directed management. The
option of not obtaining endoscopy had broad appeal to primary care physicians. In
addition, a recent survey suggests that even gastroenterologists routinely
attempt H. pylori eradication in infected patients with nonulcer dyspepsia,
despite a number of negative efficacy studies. Finally, the option of not
eradicating a World Health Organization-defined carcinogen in the litigious
United States is unappealing to clinicians. Eradication of H. pylori in patients
with dyspepsia despite more negative trials is likely to continue. There is
evidence that U.S. physician awareness of the H. pylori-disease associations and
the best therapies are improving rapidly, but further improvement is needed.
Discrepancy of awareness of H. pylori between gastroenterologists and family
physicians exists. In a recent survey, 94% and 72% of gastroenterologists
regarded H. pylori as a causative agent in duodenal and gastric ulcer,
respectively, vs. 68% and 68% of family physicians, and only 9% of family
physicians believed there was a definite relationship between H. pylori infection
and gastric cancer vs. 21% of gastroenterologists. One hundred three different H.
pylori regimens were being used; 31% of family physicians and 11% of
gastroenterologists used ineffective regimens or regimens of unknown
effectiveness. Although 1-week proton pump inhibitor triple therapy is promising,
there is skepticism that U.S. studies will yield the optimistic results that have
characterized the European studies. Unlike in Europe, the U.S. standard is to use
double diagnostics to prove eradication rather than just the urea breath test and
to use intent-to-treat rather than assessable patient analyses. Both approaches
reduce apparent eradication rates.
PMID- 9394781
TI - Commentary: Helicobacter pylori and future research.
PMID- 9394782
TI - Conditioned immunomodulation: investigations of the role of endogenous activity
at mu, kappa, and delta opioid receptor subtypes.
AB - The present investigations were designed to determine the role of activity at mu,
kappa, and delta opioid receptor subtypes in conditioned immunomodulation by
evaluating the effects of selective opioid receptor antagonists on conditioned
stimulus-induced alterations in immune status. Lewis rats were exposed to an
aversive conditioned stimulus that was developed through pairings with electric
footshock. This aversive conditioned stimulus induces a reduction in splenic
natural killer cell activity, splenocyte proliferation in response to mitogens,
and diminished levels of interferon-gamma (IFN-gamma) production by splenocytes.
Intracerebroventricular (i.c.v.) administration of the opioid antagonist
naltrexone or the mu 1-selective antagonist naloxonazine blocked conditioned
alterations of immune status, indicating that activity at mu-opioid receptors is
involved in conditioned immunomodulation. Further support for the involvement of
mu-opioid receptors within the central nervous system is provided by data showing
that peripheral administration of naloxonazine, at doses shown to be effective
when administered i.c.v., had no effect on conditioned alterations of immune
status. Ventricular administration of the kappa receptor antagonist nor
binaltorphimine (nor-BNI) did not antagonize the immunomodulatory effects of the
conditioned stimulus. Administration of the delta receptor antagonist naltrindole
also did not antagonize the conditioned alterations of immune status.
Collectively, the results of this study indicate that the alterations of immune
status produced by an aversive conditioned stimulus require activity at mu-opioid
receptors, possibly mu 1, within the central nervous system.
PMID- 9394783
TI - Treatment with intact anti-B7-1 mAb during disease remission enhances epitope
spreading and exacerbates relapses in R-EAE.
AB - PLP139-151-induced experimental autoimmune encephalomyelitis in the SJL mouse is
a Th1-mediated inflammatory demyelinating disease characterized by a relapsing
remitting clinical course (R-EAE). Clinical relapses are mediated by T cells
specific for a non-cross reactive secondary PLP epitope (PLP178-191) induced by
epitope spreading. We have previously shown that B7-1 expression is upregulated
in SJL mice undergoing R-EAE and in vivo treatment during remission with F(ab)
fragments of anti-B7-1 mAb, blocked epitope spreading and disease progression. In
contrast, the present study shows that treatment with intact anti-B7-1 mAb
exacerbated clinical disease relapses and enhanced CNS demyelination. Anti-B7-1
treated mice showed enhanced in vivo delayed-type hypersensitivity (DTH) to the
relapse-associated PLP178-191 epitope and responses to the immunodominant MBP84
104 epitope which are absent in the controls. Thus, ligation of B7-1 by intact
mAbs has effects opposite to those of anti-B7-1 F(ab) fragments suggesting that
the mAb is directly signaling through B7-1 expressed on T cells and/or APCs.
PMID- 9394784
TI - Inhibition of allergic encephalomyelitis in marmosets by vaccination with
recombinant vaccinia virus encoding for myelin basic protein.
AB - A primary demyelinating form of experimental allergic encephalomyelitis (EAE)
resembling human multiple sclerosis (MS) occurs in Callithrix jacchus marmosets
following immunization with human white matter. Participation of a T-cell immune
response against myelin basic protein (MBP) in this disease model is supported by
observations of increased reactivity against MBP in PBMC and of adoptive transfer
of an inflammatory form of EAE by MBP-reactive T-cells. To evaluate the effects
of ectopic presentation of MBP on marmoset EAE, animals were vaccinated prior to
induction of EAE by subcutaneous injection of attenuated strains of vaccinia
virus genetically engineered to contain either the entire coding sequence for
human MBP (vT15) or the equine herpes virus glycoprotein gH gene (vAbT249).
Vaccination with vT15 was followed by transient cytoplasmic and surface membrane
expression of MBP in circulating PBMC (15-45 days). The onset of clinical EAE
after immunization (pi) was markedly delayed in vT15-vaccinated animals (37-97
days pi, n = 4) compared to vAbT249-vaccinated controls (14-18 days pi, n = 3).
Proliferative responses against MBP but not against vaccinia antigens or
phytohemagglutinin were suppressed in protected animals. Thus, development of
attenuated live viruses carrying genes for myelin antigens could be useful for
induction of immunologic tolerance and for modulation of autoimmune
demyelination.
PMID- 9394785
TI - Modulation of experimental autoimmune neuritis in Lewis rats by oral application
of myelin antigens.
AB - Experimental autoimmune neuritis (EAN) in Lewis rats is a T cell-mediated disease
and serves as an animal model of human inflammatory demyelinating neuropathies.
EAN can be induced by immunization with complete bovine peripheral nerve myelin
(BPM), the myelin protein P2 or its neuritogenic peptide, each emulsified in
complete Freund's adjuvant (CFA). The present study evaluates the effect of oral
tolerization with BPM or P2 protein on the development of actively induced EAN.
Oral administration of BPM strongly suppressed clinical and histological signs of
EAN subsequently induced by BPM/CFA, but feeding of P2 protein alone did not
affect its course. In contrast, feeding of BPM did not mitigate the course of EAN
subsequently induced by immunization with neuritogenic P2 peptide/CFA. Oral
therapy with BPM after onset of myelin-induced EAN only slightly ameliorated the
further course of disease, but significantly reduced lethality of this severe
form of disease. The findings suggest that immunogenicity of the antigens fed
determine strength of tolerance, that downregulation of EAN occurs at the site of
immunization and not in the nerve, and that active suppression rather than
specific anergization is operative in mediating resistance to EAN. However, only
partial tolerance to myelin-induced EAN was achieved in naive animals by transfer
of spleen/LN cells from rats orally tolerized with BPM. Although methodic factors
may have limited the effect of the cells, the result is suggestive of some
contribution of anergy to oral tolerance in the present model. Cholera toxin and
LPS were identified as oral adjuvants for BPM and prolonged the state of
tolerance. However, LPS exhibited proinflammatory properties if EAN was induced
early after BPM/LPS-feeding. Thus, oral application of a mixture of myelin
components in combination with cholera toxin may be a useful treatment for
chronic inflammatory neuropathies considered autoimmune in nature.
PMID- 9394786
TI - Synergism between sirolimus and 1,25-dihydroxyvitamin D3 in vitro and in vivo.
AB - The active form of vitamin D, 1 alpha, 25-(OH)2D3, displays immunomodulatory
effects in vitro and in vivo at pharmacological levels. We evaluated the dose
effect relationship of 1,25(OH)2D3 and sirolimus (rapamycin, RAP) in vitro, on
the inhibition of PHA-stimulated PBMC proliferation, by using the median effect
analysis. Pharmacological concentrations of 1,25(OH)2D3 (between 10(-9) and 3 x
10(-6) M) interacted synergistically with RAP (combination index value of 0.01
for 50% suppression of PBMC proliferation). In vivo, the effect of 1,25(OH)2D3
and RAP combinations on the evolution of experimental allergic encephalomyelitis
in SJL mice was analyzed. 1,25(OH)2D3, given i.p., in monotherapy, at a dose of 2
micrograms/kg every two days, from day -3 until day +19 after disease induction,
or RAP, injected daily at a dose of 0.3 mg/kg for the same period, decreased EAE
incidence (paralysis in 70 and 55% of the animals, respectively, versus 98% in
the placebo treated group, p < 0.001). The combination treatment using the two
drugs in these subtherapeutical doses provided near-total clinical (8% paralysis,
p < 0.001 compared to monotherapy with 1,25(OH)2D3 or RAP) and histological
protection, comparable to that obtained with RAP in monotherapy at a threefold
higher dose (1 mg/kg/d). When the two drugs were given using an alternate day
administration schedule (RAP at 0.6 mg/kg and 1,25(OH)2D3 at 2 micrograms/kg,
each given on alternate days from day -3 to 19), near total protection was again
obtained (13% paralysis, p < 0.001 versus control). These in vitro and in vivo
data support the existence of synergistic interactions between 1,25(OH)2D3 and
RAP. Considering the narrow therapeutic windows of both RAP and vitamin D-related
compounds in autoimmune disease models, combinations of these drugs could find
clinical application in reducing their individual therapeutically efficient doses
to non-toxic levels.
PMID- 9394787
TI - Embryonic expression of the mRNA for the rat homologue of the fusin/CXCR-4 HIV-1
co-receptor.
AB - We have previously cloned a human receptor recently shown to be a cofactor for
entry of T-tropic HIV-1 strains into CD4+ cells, now named fusin. Stromal derived
factor-1 (SDF-1) is an endogenous ligand for fusin, also called CXCR-4. Here we
show the distribution of fusin/CXCR-4 mRNA during ontogeny in the rat. The onset
of mRNA expression is around embryonic day 9 and the mRNA expression is high in
the thymus as well as proliferative areas of the brain during development. Our
results suggest: (1) that fusin/CXCR-4 might have a dual role in both brain
development and the immune system; (2) that SDF-1 has a role in brain development
or that additional physiological ligands exist for this receptor; (3) co
expression of CD4 and fusin/CXCR-4 may make fetuses susceptible to HIV infection
during development.
PMID- 9394788
TI - Compartmentalization of antigen specific cytokine responses to the central
nervous system in CNS borreliosis: secretion of IFN-gamma predominates over IL-4
secretion in response to outer surface proteins of Lyme disease Borrelia
spirochetes.
AB - The neurological manifestations of Lyme disease have been proposed to be partly
due to cytokine-mediated immunopathological mechanisms. In this study, the number
of Borrelia-specific cells secreting interferon-gamma and interleukin-4 was
determined in blood and cerebrospinal fluid from patients with CNS borreliosis (n
= 23), other neurological diseases (n = 20), and in blood from healthy controls
(n = 10), utilizing an ELISPOT-assay. Elevated specific secretion of IFN-gamma
was found in CNS borreliosis, most pronounced in cerebrospinal fluid, whereas
secretion of IL-4 was strikingly low. This may indicate that symptoms are due to
side effects of the immune response, since IFN-gamma secretion in the absence of
corresponding levels of IL-4 may be associated with tissue destruction.
PMID- 9394789
TI - Dissociation of microglial activation and neuropathic pain behaviors following
peripheral nerve injury in the rat.
AB - Peripheral nerve injury commonly leads to neuropathic pain states fostered, in
part, by neuroimmunologic events. We used two models of neuropathic pain (L5
spinal nerve cryoneurolysis (SPCN) and chronic constriction injury (CCI)) to
assess the role of spinal glial activation responses in producing pain behaviors.
Scoring of glial responses subjectively encompassed changes in cell morphology,
cell density and intensity of immunoreactivity with specific activation markers
(OX-42 and anti-glial fibrillary acidic protein (GFAP) for microglia and
astrocytes, respectively). Glial responses were compared with tactile sensitivity
(mechanical allodynia) at 1, 3 or 10 days following SPCN and with thermal
hyperalgesia at 10 days in the CCI group. Neuropathic pain behaviors preceded and
did not closely correlate with microglial responses in either model. Perineural
application of bupivacaine prior to SPCN prevented spinal microglial responses
but not pain behaviors. Spinal astrocytic responses to SPCN were early, robust
and not altered by bupivacaine. The current findings support the use of
bupivacaine as a tool to suppress microglial activation and challenge the
putative role of microglia in initiating or potentiating pain behaviors which
result from nerve injury.
PMID- 9394790
TI - Thymocytes and cultured thymic epithelial cells express transcripts encoding
alpha-3, alpha-5 and beta-4 subunits of neuronal nicotinic acetylcholine
receptors: preferential transcription of the alpha-3 and beta-4 genes by immature
CD4 + 8 + thymocytes.
AB - Thymic tissues express transcripts encoding the alpha-3, alpha-5 and beta-4
subunits of nicotinic neuronal acetylcholine receptors (AcChRs) suggesting that
neuronal AcChRs similar to those expressed in ganglia are expressed in the
thymus. Transcription occurs in both isolated thymocytes and thymic epithelial
cells. RT-PCR analyses of thymocyte subsets indicate that immature CD4 + 8 +
thymocytes express higher levels of the alpha-3 and beta-4 transcripts than more
mature thymocytes. Compared to freshly isolated thymocytes, peripheral blood
lymphocytes do not express alpha-3 and beta-4 AcChR subunit transcripts. Cultured
thymocytes rapidly down-regulate transcription of the alpha-3 and beta-4 AcChR
subunit genes by a process that is not reversed by stimulation with
phytohemagglutinin and IL-2. Thus our results indicate that there is
transcriptional regulation of neuronal AcChR subunit genes during the process of
thymocyte maturation and that factors within the thymic microenvironment
influence expression of the alpha-3 and beta-4 AcChR subunit genes by developing
T cells.
PMID- 9394791
TI - Oligoclonal expansion of muscle infiltrating T cells in inclusion body myositis.
AB - Inclusion body myositis (IBM) is the most common muscle disease affecting
individuals over 50 years of age. An important feature of IBM is invasion of
muscle fibers by T cells. The muscle infiltrating T cells show a restricted usage
of variable (V) alpha/beta gene families. In this study we have investigated the
clonality of T cells using two of the predominant V beta families i.e. V beta 3
and V beta 8 in three patients with IBM. The study was performed by reverse
transcription and polymerase chain reaction (RT-PCR) analysis, followed by
cloning and sequencing of the T cell receptor complementarity determining region
3. We found oligoclonal expansion of V beta 3 bearing muscle infiltrating T cells
in two patients and of V beta 8 in one patient, supporting the concept that
antigen stimulated T cells are important in the pathogenesis of IBM. Results of
HLA typing indicated a genetic predisposition for the disease by the presence of
DR3, DR52 and DQB1*0201/0202 in all three patients.
PMID- 9394792
TI - Ia expression and antigen presentation by glia: strain and cell type-specific
differences among rat astrocytes and microglia.
AB - Astrocytes from experimental allergic encephalomyelitis (EAE)-susceptible Lewis
rats expressed higher levels of Interferon-gamma-inducible Ia than astrocytes
from EAE-resistant Brown Norway (BN) rats, whereas BN microglia expressed higher
Ia than Lewis at both mRNA and protein levels. Lewis astrocytes induced
proliferation of MBP-specific T cells selected on Lewis background as efficiently
as Lewis thymocytes, whereas BN astrocytes were much less efficient in
stimulating T cells selected in the presence of BN thymocytes. Microglia,
irrespective of strain, induced only weak proliferative responses of these T
cells despite the high expression of Ia. Antigen-stimulated T cells underwent
apoptosis in the presence of microglia but not astrocytes. Thus, astrocyte
mediated proliferation of MBP-specific T cells may contribute to the development
of EAE, while microglia-induced T cell apoptosis may downregulate
immunopathological processes in the brain.
PMID- 9394793
TI - Paraneoplastic anti-Hu serum: studies on human tumor cell lines.
AB - Patients with low titers of anti-Hu, the paraneoplastic encephalomyelitis/sensory
neuronopathy (PEM/PSN) antibody, have a better tumor prognosis that those who do
not harbor these antibodies. Accordingly, we examined the effects of serum from
patients with anti-Hu antibodies on human tumor cell lines, in order to
determine: (1) if the serum was toxic (growth inhibition or cytolysis) to tumor
cells with or without complement, and (2) if anti-Hu antibodies contributed to
tumor toxicity. The serum of 14 patients with anti-Hu associated PEM/PSN, 22
patients with small-cell lung cancer (SCLC) without anti-Hu antibodies, and 20
normal individuals were studied. Three cell lines (NT-2, BE(2)-C, and SH.SY5Y)
that express Hu proteins, and one cell line (SAOS-2) that does not, were studied.
We examined the effects of whole serum, IgG-depleted serum, and purified IgG in
the presence or absence of complement. A higher percentage of anti-Hu sera were
toxic (71%) compared with sera from anti-Hu negative SCLC patients (23%) (p <
0.0001). No correlation existed between the titer of anti-Hu antibodies and
toxicity. The toxic effects were observed in all tumor cell lines including the
cell line that does not express Hu antigens. Toxicity persisted in serum depleted
of IgG. Purified anti-Hu IgG in the presence and absence of complement, was not
toxic. Our findings indicate that anti-Hu serum is toxic for human tumor cell
lines, but this toxicity does not appear to be mediated by anti-Hu antibodies.
PMID- 9394794
TI - The restraint stress-induced reduction in lymphocyte cell number in lymphoid
organs correlates with the suppression of in vivo antibody production.
AB - In this study, we examined the effects of restraint stress on some immune
parameters such as the in vivo antibody levels, cytokine production, and
lymphocyte cell number in the spleen or mesenteric lymph node (MLN). BALB/c mice
were thus injected intraperitoneally 2-times with OVA absorbed into alum on days
0 and 21. Before the first injection, the animals were either restrained for 12 h
(stress group) or returned to their home cage (control group). Exposure to stress
resulted in a reduction in the serum levels of anti-OVA IgE, IgG1, and IgG2a. In
addition, stress also caused a decrease in the IL-4 and IFN-gamma levels in the
spleen or mesenteric lymph node cell culture supernatants. Furthermore, exposure
to stress resulted in a decrease in the splenic and mesenteric lymphocyte cell
number when examined immediately after the cessation of stress. This decrease
persisted for at least 12 h after the termination of stress and thereafter
disappeared 24 h after stress. The stress-induced reductions in antibody and
cytokine production occurred only when antigen was given either immediately or 6
h after stress, but not when antigen was given 24 h post stress. These results
thus suggest that the restraint stress-induced change in lymphocyte cell number
in the spleen or MLN closely correlates with the altered antibody and cytokine
levels.
PMID- 9394795
TI - A re-evaluation of the effects of X-linked immunodeficiency (xid) mutation on B
cell differentiation and function in the mouse.
AB - CBA/N (xid) mice have a point mutation in Bruton's tyrosine kinase (btk), which
results in their failure to respond to T-independent type 2 (TI-2) antigens, and
to several B cell mitogens [most notably anti-immunoglobulin (Ig)] in vitro. They
have reduced numbers of peripheral (B2) B cells, which are regarded as being
phenotypically and functionally immature. We show here that adult CBA/N mice in
fact have two distinct B cell populations: some 60% of the cells are CD23+ HSAlo
sIgDhi and hence resemble recirculating, follicular (RF) B cells from normal
mice, except that they are sIgMhi. The remaining 40% of xid B cells are CD23-
HSAhi sIgD-/lo and resemble immature transitional (TR) B cells. TR B cells from
xid mice do not synthesize DNA when cultured with lipopolysaccharide (LPS),
whereas those from normal mice do so. Only the RF cells from either xid or normal
mice proliferate in response to ligation of CD40. In neonatal normal mice the
emergence of mitogen responsiveness followed the chronological sequence LPS-
>anti-CD40-->anti-Ig approximately anti-CD38. The same developmental sequence was
seen with B cells from xid mice (for LPS and anti-CD40), but it occurred at a
significantly slower tempo and this correlated with the later appearance of RF
type cells. TR xid B cells express very low levels of bcl-2 and we conclude that
these cells resemble very immature (bone marrow) B cells, rather than normal
transitional cells. We, therefore, propose that the xid mutation imposes a
multistage brake on B cell differentiation in the mouse. The available data
suggest that btk is required for the positive selection of B cells throughout
their differentiation in the periphery. This in turn implies that low level
signaling via surface Ig is needed throughout this process in order for
peripheral B cells to become functionally mature.
PMID- 9394796
TI - A role for the VLA-4 integrin in the activation of human memory B cells.
AB - It is generally recognized that activation through membrane effector molecules
such as CD40 or the B cell receptor (BCR) is mandatory to allow B cells to
proliferate and differentiate into antibody (Ab)-secreting cells in response to
cytokines. We show here that purified tonsillar B cells can be stimulated
directly by a cytokine combination to proliferate and secrete immunoglobulins
when cultures are performed at high cell density. The contact-mediated activation
of B cells in this experimental system is strongly inhibited both by anti-very
late antigen (VLA)-4 monoclonal Ab and by a peptide containing the LDV sequence
specifically recognized by the alpha 4 integrin binding site. These reagents also
significantly suppressed the B cell responses elicited by engagement of the BCR
or CD40. Our data reveal that memory B cells but not virgin or germinal center B
cells are sensitive to the direct stimulatory effect of cytokines in high-density
cultures. Finally, we found that the dual expression of the alpha and beta chains
of VLA-4 is a distinctive feature of the memory B cell population. Collectively,
our findings support the notion that VLA-4-dependent homotypic B cell
interactions can mediate a co-stimulatory signal to human memory B cells and
might participate in the B cell activation triggered through the BCR and CD40.
PMID- 9394797
TI - In vitro cell death of activated lymphocytes in Omenn's syndrome.
AB - Omenn's syndrome (OS) is characterized by erythrodermia, hepatosplenomegaly,
lymphadenopathy, hypereosinophilia and elevated IgE levels associated with
increased susceptibility to severe infections. Peripheral blood T cells, though
usually present in normal number, show an activated phenotype (including an
increased expression of CD95/Fas), a Th2 pattern of cytokine secretion and
defective proliferative response to mitogens. In this report, we demonstrate that
T cells from patients with OS undergo an excessive cell death in vitro resulting
from two mechanisms. First, a substantial number of peripheral blood lymphocytes
from OS patients die in unstimulated cultures (p = 0.009 vs. healthy controls).
This spontaneous apoptosis is associated with reduced expression of bcl-2 gene
product (p < 0.05) and can be prevented by addition of interleukin (IL)-2 (which
also prevents down-modulation of bcl-2), while is independent from CD95
signaling. Second, lymphocytes from OS patients are highly susceptible to
activation-induced cell death (AICD) induced with mitogens. This mechanism is
largely independent from IL-2, while it can be significantly inhibited blocking
CD95 with an IgG2b monoclonal antibody (mAb). The dependence of AICD from signals
transduced via CD95 was confirmed showing that cross-linking CD95 with an IgM mAb
induces a higher cell death in purified CD4+ CD45R0+ cells from OS patients than
in controls (comparable for CD95 expression). Both mechanisms of cell death
observed in this study result from lymphocyte hyperactivation occurring in vivo
in these patients and may contribute to functional T cell defects of OS.
PMID- 9394798
TI - Activation induces apoptosis in Herpesvirus saimiri-transformed T cells
independent of CD95 (Fas, APO-1).
AB - Signaling via the T cell receptor (TCR)/CD3 complex of pre-activated T cells
induces apoptosis. Such an activation-induced cell death (AICD) is thought to
play an important role in the regulation of cellular immune responses. In this
study we analyzed pathways of AICD by using human T cells transformed by
Herpesvirus saimiri. These growth-transformed T cells show the phenotype of
activated mature T cells and continue to express a functionally intact TCR. We
show that human H. saimiri-transformed T cell clones readily undergo cell death
upon signaling via the TCR/CD3 complex or via phorbol 12-myristate 13-acetate
(PMA) + ionomycin. The AICD in H. saimiri-transformed T cells was detectable a
few hours after activation and it was not affected by the presence of interleukin
(IL)-2 or by anti-CD4 cross-linking. However, AICD required tyrosine
phosphorylation, since it could be blocked by herbimycin A. Cyclosporin A (CsA)
did not block the development of AICD, but other consequences of activation in H.
saimiri-transformed T cells like the production of interferon-gamma.
Surprisingly, the development of AICD was not reduced by neutralizing antibodies
to tumor necrosis factor (TNF)-alpha or blocking antibodies directed to CD95
(Fas, APO-1), although H. saimiri-transformed T cells were sensitive to CD95
ligation. To confirm that this form of AICD is really independent of CD95, we
have established an H. saimiri-transformed T cell line from a patient with a
homozygous deletion in the CD95 gene. This CD95-deficient T cell line was as
sensitive to AICD as other CD95-expressing H. saimiri-transformed T cells. In
conclusion, we describe here a type of AICD in H. saimiri-transformed T cells
that is independent of CD95 and TNF-alpha, not sensitive to CsA, but requires
tyrosine phosphorylation. This system should be useful for the investigation of
CD95-independent forms of AICD.
PMID- 9394799
TI - Rapamycin inhibits proteasome activator expression and proteasome activity.
AB - Rapamycin (RAPA) is a potent immunosuppressive drug, and certain of its direct or
indirect targets might be of vital importance to the regulation of an immune
response. In this study, we used differential hybridization to search for human
genes whose expression was sensitive to RAPA. Seven RAPA-sensitive genes were
found and one of them encoded a protein with high homology to the alpha subunit
of a proteasome activator (PA28 alpha). This gene was later found to code for the
beta subunit of the proteasome activator (PA28 beta). Activated T and B cells had
up-regulated PA28 beta expression at the mRNA level. Such up-regulation could be
suppressed by RAPA, FK506, and cyclosporin A. RAPA and FK506 also repressed the
up-regulated PA28 alpha messages in phytohemagglutinin (PHA)-stimulated T cells.
At the protein level, RAPA inhibited PA28 alpha and PA28 beta in the activated T
cells according to immunoblotting and confocal microscopy. Probably as a
consequence, there was a fourfold increase of proteasome activities in the
peripheral blood mononuclear cell lysate after the PHA activation. RAPA could
inhibit the enhanced part of the proteasome activity. Considering the critical
role played by the proteasome in degrading regulatory proteins, our data suggest
that the proteasome activator is a relevant and important downstream target of
rapamycin, and that the immune response could be modulated through the activity
of the proteasome.
PMID- 9394800
TI - Comparison of the effects of interleukin-1 alpha, interleukin-1 beta and
interferon-gamma-inducing factor on the production of interferon-gamma by natural
killer.
AB - Interferon-gamma inducing factor (IGIF) is a recently identified cytokine which
stimulates the production of interferon-gamma (IFN-gamma) by T cells and enhances
natural killer (NK) cell cytolytic activity. Protein fold recognition, structure
prediction and comparative modeling have revealed that IGIF is a member of the
interleukin (IL)-1 cytokine family and has prompted the designation IL-1 gamma.
Here we report functional similarities between members of the IL-1 family by
comparing the effects of IL-1 alpha, IL-1 beta and IGIF on NK cell production of
IFN-gamma. All three IL-1 types enhanced NK cell production of IFN-gamma when
induced by IL-2 or IL-12, although at high concentrations (> 10 ng/ml), IGIF was
five- to tenfold more potent than IL-1 alpha or IL-1 beta. This effect correlated
with enhanced levels of mRNA for IFN-gamma when NK cells were stimulated with
IGIF plus IL-12. In contrast to IL-12 and IL-2, the ability of IGIF to stimulate
NK cell production of IFN-gamma was not increased by IL-1 alpha or IL-1 beta. The
ability of IGIF to enhance IFN-gamma production was independent of the type I and
type II IL-1 receptors or the IL-1R accessory protein. Together, these results
identify IGIF as a potent stimulator of NK cell production of IFN-gamma and
demonstrate that the effect of IGIF on NK cell production of IFN-gamma is similar
to that of IL-1 alpha and IL-1 beta but distinct from that of IL-12.
PMID- 9394801
TI - Rho prevents apoptosis through Bcl-2 expression: implications for interleukin-2
receptor signal transduction.
AB - Here we describe a Rho-mediated apoptosis suppression pathway driven by Bcl-2
expression in the interleukin (IL)-4- or IL-2-dependent murine T cell line TS1
alpha beta. IL-2, but not IL-4, induces Bcl-2 expression through RhoA activation
which is inhibited by the specific Rho family inhibitor, Clostridium difficile
Toxin B, as well as by a dominant negative RhoA mutant. Using transient
transfections of RhoA mutants tagged with the vesicular stomatitis virus
glycoprotein, we show that a constitutively active RhoA mutant induces Bcl-2
expression and prevents apoptosis upon IL-4 withdrawal. Finally, we have
identified the signaling pathway involved together with RhoA in Bcl-2 induction
and show compelling evidence for the implication of phosphatidylinositol 3 kinase
and protein kinase C.
PMID- 9394802
TI - Involvement of nuclear factor-kappa B in platelet-activating factor-mediated
tumor necrosis factor-alpha expression.
AB - Tumor necrosis factor (TNF)-alpha and platelet-activating factor (PAF) are
important mediators of inflammatory reactions, and their release is controlled by
a positive feedback network. However, the regulatory mechanisms underlying the
interaction of these two molecules are unknown. Within 10 min of the injection of
lipopolysaccharide (LPS) into C57BL/6 mice, effects inducible by PAF such as
anaphylactic shock-like symptoms, disseminated intravascular coagulation, and
hemorrhage in renal medullae were observed, and all these pathological changes
were prevented by the PAF antagonist, BN 50739. The plasma level of PAF after LPS
injection reached a peak at 5 min. TNF-alpha gene expression was evident 20 min
after LPS injection and was maximal at 40 min, and the level of serum TNF-alpha
reached a peak at 1 h. Pretreatment with BN 50739 inhibited LPS-induced TNF-alpha
gene expression and protein synthesis in a dose-dependent manner. Injection of
PAF or treatment of the macrophage cell line, J774A.1, with PAF activated the
transcription factor, nuclear factor (NF)-kappa B, which is essential for
inducible TNF-alpha transcription. The activation of NF-kappa B by PAF preceded
the LPS-mediated TNF-alpha gene expression. Pretreatment with BN 50739 inhibited
LPS-induced mobilization of NF-kappa B in a dose-dependent manner in vivo as well
as in vitro. These data suggest that PAF, which is released immediately or
shortly after LPS injection, induces the expression of TNF-alpha through the
activation of NF-kappa B.
PMID- 9394803
TI - Extracellular HIV-1 Tat protein activates phosphatidylinositol 3- and Akt/PKB
kinases in CD4+ T lymphoblastoid Jurkat cells.
AB - The biological basis for the pleiotropic activity of extracellular human
immunodeficiency virus (HIV)-1 Tat protein on lymphoid T cell survival is not
well understood. We have here demonstrated that the addition in culture of 0.1-10
nM Tat protein to 36-h serum-starved lymphoblastoid Jurkat T cells rapidly
stimulates the catalytic activity of phosphatidylinositol 3-kinase (PI 3-K). The
peak of activation was observed 30 min after Tat addition. Extracellular Tat also
stimulated the catalytic activity of the Akt/PKB kinase, a major target of PI 3-K
lipid products. Pretreatment of serum-starved Jurkat cells with 100 nM wortmannin
(WT) or 10 microM LY294002, two unrelated pharmacological inhibitors of PI 3-K,
markedly suppressed the catalytic activity of both PI 3-K and Akt/PKB in Jurkat
cells. Moreover, at low concentrations (0.1-1 nM), extracellular Tat showed a
small but reproducible protection of Jurkat cells from apoptosis induced by serum
deprivation (p < 0.05), while the combination of Tat plus 100 nM WT significantly
(p < 0.05) increased the percentage of apoptosis with respect to cells left
untreated or treated with Tat alone. Taken together, these data suggest that the
anti-apoptotic activity of low concentrations of Tat protein on Jurkat cells is
mediated by a PI 3-kinase/Akt pathway.
PMID- 9394804
TI - Control of self-reactive cytotoxic T lymphocytes expressing gamma delta T cell
receptors by natural killer inhibitory receptors.
AB - The majority of peripheral blood gamma delta T cells in human adults expresses T
cell receptors (TCR) with identical V regions (V gamma 9 and V delta 2). These V
gamma 9 V delta 2 T cells recognize the major histocompatibility complex (MHC)
class I-deficient B cell line Daudi and broadly distributed nonpeptidic antigens
present in bacteria and parasites. Here we show that unlike alpha beta or V gamma
9- gamma delta T cells, the majority of V gamma 9V delta 2 T cells harbor natural
killer inhibitory receptors (KIR) (mainly CD94/NKG2A heterodimers), which are
known to deliver inhibitory signals upon interaction with MHC class I molecules.
Within V gamma 9V delta 2 T cells, KIR were mainly expressed by clones exhibiting
a strong lytic activity against Daudi cells. In stark contrast, almost all V
gamma 9V delta 2 T cell clones devoid of killing activity were KIR-, thus
suggesting a coordinate acquisition of KIR and cytotoxic activity within V gamma
9V delta 2 T cells. In functional terms, KIR inhibited lysis of MHC class I
positive tumor B cell lines by V gamma 9V delta 2 cytotoxic T lymphocytes (CTL)
and raised their threshold of activation by microbial antigens presented by MHC
class I-positive cells. Furthermore, masking KIR or MHC class I molecules
revealed a TCR-dependent recognition by V gamma 9V delta 2 CTL of ligands
expressed by activated T lymphocytes, including the effector cells themselves.
Taken together, these results suggest a general implication of V gamma 9V delta 2
T cells in immune response regulation and a central role of KIR in the control of
self-reactive gamma delta CTL.
PMID- 9394805
TI - Requirement of a second signal via protein kinase C or protein kinase A for
maximal expression of CD40 ligand. Involvement of transcriptional and
posttranscriptional mechanisms.
AB - High levels of CD40 ligand (CD40L) protein expression are induced on native T
cells by increasing the intracellular Ca2+ concentration. In the present study we
have shown that ionomycin induces CD40L gene transcription leading to mRNA
accumulation which translates to high levels of protein expression. Conversely,
agents which increase the intracellular levels of cyclic AMP (cAMP), such as
prostaglandin E2 (PGE2) or dibutyryl cyclic AMP (dbcAMP), were unable to induce
CD40L expression on T lymphocytes. Cell activation by phorbol 12-myristate 13
acetate (PMA) treatment had a slight effect on increasing CD40L mRNA and protein
levels. However, PMA and dbcAMP synergized with ionomycin to significantly
increase and to prolong the CD40L expression. Nuclear run-on assays revealed that
PMA, but not dbcAMP, increased threefold the CD40L gene transcription rate
induced by ionomycin. This effect was independent of de novo protein synthesis.
In addition, at a posttranscriptional level, both reagents synergized with the
Ca2+ ionophore to prolong the CD40L mRNA half-life by a mechanism which was also
independent of de novo protein synthesis. Moreover, when transcription was
blocked with actinomycin D, an increment of the CD40L transcript levels induced
by PMA or dbcAMP on ionomycin-treated cells was observed in the presence of
cycloheximide. This probably means that newly synthesized protein may contribute
to the CD40L mRNA destabilization. In summary, these data show that PMA and
dbcAMP synergized with ionomycin to increase the CD40L mRNA and protein levels.
The up-regulatory effect of PMA was accomplished at a transcriptional and
posttranscriptional level, whereas dbcAMP exerted its synergistic effect
exclusively at a posttranscriptional level.
PMID- 9394806
TI - Induction of heat shock protein 72 synthesis by endogenous tumor necrosis factor
via enhancement of the heat shock element-binding activity of heat shock factor
1.
AB - Endogenous tumor necrosis factor (enTNF) acts as a resistance factor against
cytotoxicity caused by heat by inducing manganous superoxide dismutase (MnSOD),
thereby scavenging reactive oxygen free radicals. On the other hand, it is also
well known that heat shock proteins (HSP) which are induced by heat stress behave
as cytoprotective factor against this stress. However, the relationship of these
two resistance factors is not elucidated yet. In the present study, we therefore
proposed the possibility that enTNF enhances HSP72 expression. Heat-sensitive L-M
(mouse tumorigenic fibroblast) cells, which normally do not express enTNF, were
transfected with a nonsecretory-type human TNF-alpha expression vector to produce
enTNF. Stable transfectants showed resistance to heat treatment and an increase
of HSP72 expression. Conversely, when HeLa (human uterine cervical cancer) cells,
which normally produce an appreciable amount of enTNF, were transfected with an
antisense TNF-alpha mRNA expression vector to inhibit enTNF synthesis, their heat
sensitivity was enhanced and HSP72 expression was reduced by half. Although enTNF
caused no difference in the level of heat shock factor (HSF) 1 in these cells,
enTNF expression correlated well with the binding activity of HSF-1 to a 32P
labeled synthetic oligonucleotide containing the human heat shock element (HSE).
These results indicate that enTNF participates not only in intrinsic resistance
against heat via induction of MnSOD but also via enhancement of the HSE-binding
activity of HSF 1 followed by augmentation of HSP72 expression.
PMID- 9394807
TI - Cloning of NKG2-F, a new member of the NKG2 family of human natural killer cell
receptor genes.
AB - The NKG2 family of genes encodes at least four different type II transmembrane
molecules (NKG2-A, NKG2-B, NKG2-C and NKG2-E) which contain a C-lectin domain.
These proteins have been shown to be covalently associated with CD94, another C
type lectin member. The heterodimers are involved in natural killer cell-mediated
recognition of different HLA-allotypes. Here we describe the cloning of a new
NKG2-related gene, termed NKG2-F, localized 25 kb from NKG2-A as well as its
relationship with the previously described NKG2-D cDNA. Despite the similarities
with the other NKG2 genes, NKG2-F encodes a putative protein which does not
contain any lectin domain. However, a conserved 24-amino acid sequence, present
in all members of the NKG2 family, suggests that NKG2-F is also able to form
heterodimers with CD94.
PMID- 9394808
TI - The central nervous system environment controls effector CD4+ T cell cytokine
profile in experimental allergic encephalomyelitis.
AB - In experimental allergic encephalomyelitis (EAE), CD4+ T cells infiltrate the
central nervous system (CNS). We derived CD4+ T cell lines from SJL/J mice that
were specific for encephalitogenic myelin basic protein (MBP) peptides and
produced both Th1 and Th2 cytokines. These lines transferred EAE to naive mice.
Peptide-specific cells re-isolated from the CNS only produced Th1 cytokines,
whereas T cells in the lymph nodes produced both Th1 and Th2 cytokines.
Mononuclear cells isolated from the CNS, the majority of which were microglia,
presented antigen to and stimulated MBP-specific T cell lines in vitro. Although
CNS antigen-presenting cells (APC) supported increased production of interferon
(IFN)-gamma mRNA by these T cells, there was no increase in the interleukin (IL)
4 signal, whereas splenic APC induced increases in both IFN-gamma and IL-4. mRNA
for IL-12 (p40 subunit) was up-regulated in both infiltrating macrophages and
resident microglia from mice with EAE. We have thus shown that a Th1 cytokine
bias within the CNS can be induced by CNS APC, and that IL-12 is up-regulated in
microglial cells within the CNS of mice with EAE. Microglia may therefore control
Th1 cytokine responses within the CNS.
PMID- 9394809
TI - Influence of complement on the allospecific antibody response to a primary
vascularized organ graft.
AB - The induction of antibody responses against T cell-dependent antigens has been
reported to be influenced by complement. We therefore asked if the primary
induction of alloantibodies against transplantation antigens, an important
determinant of transplant outcome, is complement sensitive and whether this has
functional implications. We transplanted rat kidney allografts into fully major
histocompatibility complex-mismatched recipients, in which complement activation
was inhibited by daily injection of soluble recombinant human complement receptor
type 1 (sCR1). Control allograft recipients were injected with saline. Animals in
the control group showed a marked antibody response against donor-specific
antigens and an increase in the proportion of activated B and T splenocytes by
day 5 after transplantation. Complement-inhibited rats showed a reduced level of
antibody binding on target cells sharing the same histocompatibility antigens as
the donor strain (p < 0.001), and a reduced level of activated splenic B (p <
0.01) and T (p < 0.01) cells. In a functional assay, the plasma of complement
inhibited rats showed reduced cytotoxic activity against donor-specific cells,
and their grafts contained less bound antibody than controls. Analysis beyond 6
days was obscured due to the development of antibodies against sCR1. We conclude
that complement activation facilitates the induction of the alloantibody
response. Sparing of vascular injury and prolongation of graft survival,
previously reported in complement-inhibited rats (Pratt J. R. et al., Am. J.
Path. 1996, 149: 2055), could therefore be due to down-regulation of the B cell
response as well as reduced complement-dependent cytotoxicity. Inhibition of
complement may provide an ancillary approach to the prevention of allospecific
antibody formation and the prolongation of allograft survival in primary kidney
grafting.
PMID- 9394810
TI - Analysis of susceptibility of NOD mice to spontaneous and experimentally induced
thyroiditis.
AB - Beside diabetes, non-obese diabetic (NOD) mice develop sporadic lymphoid
infiltration of the thyroid gland, mimicking Hashimoto's thyroiditis. We have
examined the prevalence of those manifestations in NOD mice, the influence of the
major histocompatibility complex (MHC) and the association with autoantibodies.
The incidence at 1 year is of 14.3% in wild-type NOD mice versus 19.6% in
congenic NOD.H2k mice. The moderate, but statistically significant difference,
based on the analysis of 161 NOD and 169 NOD.H2k mice, suggests that MHC genes
partially control spontaneous NOD thyroiditis. Autoantibodies against
thyroglobulin (Tg) are mouse specific and their presence correlates closely with
thyroiditis. The strong correlation between cellular and humoral anomalies
therefore resembles Hashimoto's thyroiditis. NOD and NOD.H2k mice actively
immunized against Tg develop severe chronic lesions with epithelium necrosis and
interstitial tissue fibrosis. Most interestingly, those lesions do not regress
spontaneously as in CBA/J mice. Paradoxically, the response to Tg of lymph node
cells from NOD mice is weaker both in proliferation and cytokine production. The
defect is most evident for interferon-gamma-producing T cells and is reflected in
the marked deficit in IgG2a antibodies. Thus a moderate anti-Tg response seems to
favor chronicity of thyroiditis. In conclusion, NOD and NOD.H2k mice offer a
unique opportunity of analyzing the factors leading to immune chronicity in a
genetic context which promotes autoimmune endocrinopathies.
PMID- 9394811
TI - Nitric oxide and the immunomodulation of experimental allergic encephalomyelitis.
AB - Previous studies examining the effect of nitric oxide synthase (NOS) inhibition
on the course of experimental allergic encephalomyelitis (EAE) have yielded
conflicting results. This may relate to the use of nonspecific inhibitors and to
differences between active and adoptive EAE. We examined the effect of treatment
with L-N-(1-iminoethyl)lysine (L-NIL), a selective inhibitor of the cytokine
inducible isoform of NOS, on the clinical course of active and adoptive EAE in
Lewis rats. We find that while L-NIL treatment of recipients is protective in
adoptive EAE, treatment of active EAE with L-NIL leads to a marked accentuation
of disease expression. In L-NIL-treated animals treated with myelin basic
protein/complete Freund's adjuvant (MBP/CFA), disease onset is accelerated and
clinical symptoms are more severe. Accentuation of integrated disease scores is
seen even if L-NIL treatment is started 5 days following immunization. The
histological findings in involved spinal cords from L-NIL-treated animals with
active EAE are similar to those from untreated animals with similar clinical
scores. L-NIL treatment of MBP/CFA-immunized animals does not prevent recovery
from clinical symptoms, nor does it allow for reinduction of disease in animals
previously immunized with MBP/CFA. Treatment of F344 rats, a strain which is
relatively nonsusceptible for EAE, with L-NIL results in consistent evidence of
EAE following immunization with MBP/CFA. These findings, together with our
previous work on interstitial nephritis, support a role for endogenously
generated NO in immunoregulation of T cell responses following immunization with
antigen in CFA, and suggest that inducibility of NOS expression may be an
important susceptibility factor for autoimmunity.
PMID- 9394812
TI - In vivo evidence for a functional role of both tumor necrosis factor (TNF)
receptors and transmembrane TNF in experimental hepatitis.
AB - The significance of tumor necrosis factor receptor 1 (TNFR1) for TNF function in
vivo is well documented, whereas the role of TNFR2 so far remains obscure. In a
model of concanavalin A (Con A)-induced, CD4+ T cell-dependent experimental
hepatitis in mice, in which TNF is a central mediator of apoptotic and necrotic
liver damage, we now provide evidence for an essential in vivo function of TNFR2
in this pathophysiological process. We demonstrate that a cooperation of TNFR1
and TNFR2 is required for hepatotoxicity as mice deficient of either receptor
were resistant against Con A. A significant role of TNFR2 for Con A-induced
hepatitis is also shown by the enhanced sensitivity of transgenic mice
overexpressing the human TNFR2. The ligand for cytotoxic signaling via both TNF
receptors is the precursor of soluble TNF, i.e. transmembrane TNF. Indeed,
transmembrane TNF is sufficient to mediate hepatic damage, as transgenic mice
deficient in wild-type soluble TNF but expressing a mutated nonsecretable form of
TNF developed inflammatory liver disease.
PMID- 9394813
TI - Expression of the Ly49A gene in murine natural killer cell clones is
predominantly but not exclusively mono-allelic.
AB - The Ly49 family of natural killer (NK) cell receptors are major
histocompatibility complex (MHC) class I-specific inhibitory receptors that are
distributed to overlapping NK cell subsets. Extending earlier studies of
polyclonal NK cell populations, we have employed an analysis of short-term NK
cell clones from Ly49A heterozygous mice, to demonstrate that the Ly49A gene is
usually expressed from one or the other allele in each Ly49A+ cell. However, we
also detected a small percentage of clones that expressed both Ly49A alleles. The
possibility that the colonies exhibiting bi-allelic Ly49A gene expression had
been inoculated with more than one cell was ruled out by parallel analysis of
clones isolated from mixtures of NK cells from Ly49A homozygous mice. The
frequency of bi-allelic Ly49A+ clones suggested that the two Ly49A alleles in an
NK cell are chosen for expression independently. These data are consistent with
the proposal that mono-allelic Ly49A gene expression may arise as a consequence
of a stochastic Ly49 gene activation mechanism. Analysis of Ly49A+ clones from
MHC-different mice demonstrated that class I-deficient mice harbored a greater
number of bi-allelic Ly49A+ cells than did H-2d mice, which express a Ly49A
ligand. Although the numbers were insufficiently large for a clear assignment, H
2b mice may harbor an intermediate number of bi-allelic Ly49A+ NK cells. The
effects of MHC expression on the prevalence of bi-allelic Ly49A+ cells suggest
that an MHC-dependent education process modifies the Ly49 repertoire.
PMID- 9394814
TI - Interleukin-15 preferentially promotes the growth of intestinal intraepithelial
lymphocytes bearing gamma delta T cell receptor in mice.
AB - Several cytokines including stem cell factor (SCF) and interleukin (IL)-7 are
known to be required for development of gamma delta T cell receptor (TCR)
intestinal intraepithelial lymphocytes (i-IEL) in mice. We show here the effects
of IL-15 on the proliferation and maintenance of murine gamma delta i-IEL in
vitro. gamma delta i-IEL constitutively expressed a high level of IL-15 receptor
alpha mRNA and proliferated in response to IL-15 more vigorously than alpha beta
i-IEL. V gamma/delta repertoire analysis revealed that IL-15, like IL-2, induced
polyclonal expansion of gamma delta i-IEL, whereas gamma delta i-IEL responding
to IL-7 showed a V gamma/delta repertoire skewed towards V gamma 1/V delta 4, V
delta 5. IL-15 efficiently prevented gamma delta i-IEL from apoptosis induced by
growth factor deprivation. This rescue was accompanied by up-regulation of Bcl-2
expression. These results suggest that IL-15 plays important roles in
proliferation and maintenance of gamma delta i-IEL.
PMID- 9394815
TI - The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions
through the chemokine receptors CCR1 and CCR3.
AB - Eosinophils are predominant effector cells not only in allergic diseases but also
in connective tissue diseases. The recruitment of eosinophils to the site of
inflammation and release of reactive oxygen species leading to tissue damage and
propagation of the inflammatory response are mediated by chemokines. Thus, agents
that would be able to inhibit or antagonize chemokine-induced eosinophil
activation are interesting as therapeutical agents. We describe the effect of a
chemokine receptor antagonist, Met-RANTES, on human eosinophil effector functions
in response to RANTES, monocyte chemoattractant protein (MCP)-3 and eotaxin. Met
RANTES was able to inhibit dose-dependently [Ca2+]i transients in eosinophils
following stimulation with RANTES, MCP-3 and eotaxin. Whereas maximal and half
maximal inhibitory effect of Met-RANTES following stimulation with RANTES and MCP
3 were observed at 2 micrograms/ml and 1 microgram/ml, respectively, maximal and
half-maximal inhibitory effects of Met-RANTES in response to eotaxin were
detected at 10 micrograms/ml and 3 micrograms/ml. Moreover, eotaxin-induced
[Ca2+]i transients were only half reduced at a Met-RANTES concentration at which
RANTES and MCP-3 were completely blocked. Besides its effect on [Ca2+]i
transients, Met-RANTES dose-dependently inhibited actin polymerization in
eosinophils following chemokine stimulation. Whereas Met-RANTES totally inhibited
RANTES- and MCP-3-induced actin polymerization at 5 micrograms/ml, the eotaxin
induced response was only reduced by 50%. However, Met-RANTES inhibited dose
dependently the release of reactive oxygen species in response to RANTES, MCP-3
and eotaxin. Again, eotaxin-induced release of reactive oxygen species, however,
was only half reduced at a Met-RANTES concentration (10 micrograms/ml) at which
RANTES and MCP-3 were completely blocked. The results of this study show that (1)
Met-RANTES is an effective and powerful antagonist of effector functions of human
eosinophils following stimulation with RANTES, MCP-3 and eotaxin; (2) Met-RANTES
seems to be able to antagonize the response of eosinophils through chemokine
receptor 1 (CCR1) preferentially to CCR3; (3) Met-RANTES antagonizes eosinophil
but not neutrophil effector functions and might be therefore of interest for a
new therapeutical approach to prevent the invasion and destructive power of
eosinophils in diseases that are accompanied by eosinophil infiltration such as
allergic asthma and connective tissue diseases.
PMID- 9394816
TI - Expression of epsilon germ-line gene transcripts and mRNA for the epsilon heavy
chain of IgE in nasal B cells and the effects of topical corticosteroid.
AB - We have studied the expression of the gene encoding the epsilon heavy chain of
IgE in nasal B cells of hayfever patients. We developed probes to detect
transcripts of the epsilon germ-line gene and the rearranged gene by in situ
hybridization of biopsy sections from the nasal mucosa. We compared tissue from
hayfever patients out of season with that of normal controls, and also of
hayfever patients treated with topical corticosteroid (fluticasone propionate) or
placebo for 6 weeks and then challenged with antigen. epsilon chain mRNA was
expressed in an unexpectedly high proportion of nasal B cells of both hayfever
patients and normal subjects. However, although similar numbers of B cells were
found in both groups, the proportion of cells that express epsilon chain mRNA was
several times higher in the hayfever patients. No transcripts of the epsilon germ
line gene were detected in either group before allergen challenge. When hayfever
patients were administered antigen locally, early (10-30 min) and late (1-24 h)
symptoms ensued. After 24 h, coincident with an increase in the number of cells
expressing mRNA for IL-4 in the tissue, epsilon germ-line gene transcripts
appeared in the nasal B cells. The induction by allergen of IL-4 mRNA and epsilon
germ-line gene transcripts was suppressed by fluticasone propionate treatment.
Our results suggest that local IgE synthesis and cytokine regulation of heavy
chain switching to IgE occur in the nasal mucosa.
PMID- 9394817
TI - Nitric oxide pathway is induced by Fc epsilon RI and up-regulated by stem cell
factor in mouse mast cells.
AB - Murine stem cell factor (SCF) induces the differentiation of mucosal mast cells
(MMC) into connective tissue mast cells (CTMC) and potentiates mediator release
induced by aggregation of high-affinity IgE receptors (Fc epsilon RI). In the
present work, we investigated the effect of Fc epsilon RI aggregation on nitric
oxide (NO) pathway induction in the different subsets of mast cells, as well as
the contribution of SCF in this induction. Inducible NO synthase (iNOs)
expression was not evidenced in non-stimulated MMC obtained by culture of
hematopoietic progenitors in the presence of interleukin-3, whereas IgE-antigen
stimulated MMC expressed iNOs mRNA and protein and synthesized nitrites. Long
term treatment of MMC with SCF, allowing them to differentiate into CTMC, induced
iNOs expression in non-stimulated cells and up-regulated iNOs expression and
generation of NO derivatives induced by IgE-antigen stimulation. Thus, NO
derivatives generated by mast cells could participate in inflammatory reactions
during allergic stimulation.
PMID- 9394818
TI - The roles of complement receptors type 1 (CR1, CD35) and type 3 (CR3, CD11b/CD18)
in the regulation of the immune complex-elicited respiratory burst of
polymorphonuclear leukocytes in whole blood.
AB - The binding of immune complexes (IC) to polymorphonuclear leukocytes (PMN) and
the consequent respiratory burst (RB) were investigated in whole blood cell
preparations suspended in 75% human serum, using flow cytometry. Blockade of the
complement receptor (CR)1 receptor sites for C3b on whole blood cells using the
monoclonal antibody (mAb) 3D9 resulted in a 1.9-fold increase in the IC-elicited
PMN RB after 5 min of incubation, rising to 3.1-fold after 40 min. This
enhancement was not due to increased IC deposition on PMN. Blockade of CR3
abrogated the mAb 3D9-induced rise in RB activity and inhibited the IC binding to
PMN in a whole blood cell preparation, with or without mAb 3D9, by approximately
40% from 15-40 min while reducing their RB over 40 min to approximately one
third. Blockade of CR1 on either erythrocytes (E) or leukocytes, before mixing
the populations, revealed that the potentiation of the RB by mAb 3D9 was
associated with abrogation of E-CR1 function, whereas blockade of leukocyte-CR1
had a diminishing effect. Exposure to IC at high concentrations induced release
of both specific and azurophilic granule contents from PMN. The latter was CR3
dependent in that blockade of the receptor inhibited the lactoferrin release by
one third during 40 min of incubation. In conclusion, CR3 plays a significant
role in the IC-mediated generation of an RB and release of specific granules by
PMN, while CR1 on whole blood cells, primarily E CR1, restricts the IC-elicited
RB in PMN. We propose that CR1 in whole blood promotes the degradation of IC
bound iC3b to C3dg, thereby rendering the IC inaccessible for binding to CR3.
PMID- 9394819
TI - Structural analysis of human gamma 3 intervening regions and switch regions:
implication for the low frequency of switching in IgG3-deficient patients.
AB - High and low serum concentrations of IgG3 are associated with the human G3m(b)
and G3m(g) allotypes, respectively. In the present study, we analyzed the
structure of the S gamma 3 and I gamma 3, the switch frequency, switch
breakpoints and the levels and initiation sites of I gamma 3 transcripts both in
normal blood donors expressing (b) or (g) allotypes as well as IgG3-deficient (D)
patients. A low switch frequency to gamma 3 was found in the (g) allotype IgG3D
patients which may be caused in part by the allotype-associated mutations in the
S gamma 3 region and in part by additional individual mutations observed in the A
(SNAP) and B (SNIP/ NF-kappa B) sites in the S gamma 3 repeat region. A higher I
gamma 3 germ-line (GL) transcriptional rate was seen in cells from the IgG3D
patient, suggesting that low levels of GL I gamma 3 transcripts are not a major
contributing factor to the defect. However, individual mutations in the I gamma 3
region and differential splicing of GL I gamma 3 transcripts were found which may
affect the switching process.
PMID- 9394820
TI - Relapsing and remitting experimental allergic encephalomyelitis: a focused
response to the encephalitogenic peptide rather than epitope spread.
AB - The progression of experimental allergic encephalomyelitis (EAE) in certain mouse
strains has been reported to involve a broadening of the response to myelin
antigens, apparently resulting from priming to endogenous determinants of the
myelin sheath. The phenomenon has been termed determinant spread. Interest in
this effect has centered on the mechanism it offers to explain the progressive,
relapsing and remitting course of EAE and indeed of multiple sclerosis. We have
conducted a systematic, longitudinal study in SJL mice to look for determinant
spread during relapsing and remitting EAE, correlating epitope recognition and
cytokine production with disease severity. Disease was induced using three of the
four encephalitogenic proteolipid protein or myelin basic protein epitopes, and
responses to each of four epitopes recognized by SJL T cells were tracked through
acute disease, remission and relapse. The responses of lymph node cells,
splenocytes and central nervous system (CNS)-infiltrating T cells were analyzed.
While marginal, transient responses to secondary epitopes were detectable in
splenocytes, CNS-infiltrating cells showed a dominant response to the original
disease-inducing epitope without evidence of a shift to other determinants during
relapse. Disease relapse was correlated with an increase in CNS-infiltrating
cells and a high proliferative and interferon (IFN)-gamma response to the disease
inducing peptide. During remission, there was a decrease in numbers of cells
infiltrating the CNS. These cells were down-regulated, showing low if any
response to the myelin peptides tested as measured by proliferation, production
of IFN-gamma or production of IL-4. Our findings argue strongly against a causal
role for determinant spread in disease relapse as observed in these models of
EAE.
PMID- 9394821
TI - In vivo rolling and endothelial selectin binding of mononuclear leukocytes is
distinct from that of polymorphonuclear cells.
AB - In inflammation, rolling of leukocytes along the microvascular endothelium is a
precondition for subsequent integrin-mediated firm adhesion and extravasation.
Rolling characteristics of polymorphonuclear leukocytes (PMNL) and mononuclear
leukocytes (MNL) in small venules (15-25 microns) of the rat mesentery were
studied by intravital fluorescence microscopy under basal conditions and after
intravenous treatment with an anti-rat neutrophil serum (ANS). The baseline
rolling fraction of the venular total leukocyte flux was 36 +/- 15% (mean +/-
SD). The PMNL fraction of the systemic leukocyte count was 27 +/- 9%. Treatment
with ANS resulted in total depletion of circulating PMNL and reduced the
leukocyte rolling fraction to 12 +/- 5%, in this situation represented only by
MNL. In rats treated intraperitoneally with interleukin (IL)-1 beta for 4 h, the
leukocyte rolling fraction was 53 +/- 13% and was reduced to 33 +/- 11% after ANS
treatment. These data indicated that most, if not all, circulating PMNL rolled
along the venular endothelial lining in the rat mesentery prepared for intravital
microscopy, whereas MNL rolling was minor (approximately 10%) under the same
basal condition. In cytokine-activated tissue, on the other hand, the number of
rolling MNL was greatly increased. While PMNL rolling is known to be entirely
selectin dependent, the increased MNL rolling after IL-1 stimulation was likely
mediated by alpha 4 integrins, inasmuch as the rolling fraction of isolated
peripheral blood lymphocytes injected into the microcirculation of the cytokine
stimulated mesentery was reduced from 31 +/- 14% to 6 +/- 2% by pretreatment of
the cells with a monoclonal antibody against the rat integrin alpha 4 chain. In
accordance with the in vivo rolling characteristics of the two cell populations,
binding of soluble P- or E-selectin (selectin/IgG chimeras) was less intense for
blood lymphocytes than for granulocytes, as determined by flow cytometric
analyses of rat and human leukocytes. Taken together, our findings in vivo
indicate that the adhesive interactions responsible for rolling of PMNL and MNL,
respectively, are distinct in terms of receptor occupancy, and may help explain
the temporal selectivity in recruitment of different leukocyte subpopulations in
inflammatory or immune reactions.
PMID- 9394822
TI - T helper cell priming of mice to Borrelia burgdorferi OspA leads to induction of
protective antibodies following experimental but not tick-borne infection.
AB - Antibodies to the outer surface lipoprotein A (OspA) of Borrelia burgdorferi
confer protection to SCID mice against subsequent tick-borne or experimental
infection. However, OspA-specific antibodies are hardly detectable in naturally
infected humans, dogs, hamsters and mice. This is most probably due to limited
expression of OspA on spirochetes transmitted from the vector to the host. Here
we have tested whether T cell priming of mice would lead to the induction of
protective OspA-specific antibodies upon infection. It is shown that AKR/N mice,
previously immunized with either a single T helper cell peptide of OspA, or a
mixture of 27 peptides spanning the entire molecule, develop OspA-specific IgM or
IgG antibodies, including those to a prominent protective B cell epitope of OspA.
LA-2, within 7 days of infection with low doses (10(3)) of culture-derived
spirochetes. In marked contrast, the same groups of pre-sensitized mice failed to
generate any detectable OspA-specific antibodies after tick-borne infection for
more than 40 days after infection. All mice, irrespective of their state of T
cell immunity to OspA or the mode of infection, produced similar levels of OspC
specific IgM and IgG antibodies as early as day 14 after infection. None of the
mice previously immunized with OspA peptides were protected against experimental
infection, in spite of the appearance of protective antibodies. It is clear from
these data that, in contrast to culture-derived spirochetes, the naturally
transmitted pathogen fails to express OspA within the mammalian host at levels
sufficient for induction of B cell responses, even in the presence of pre
activated T helper cells. Together with the fact that OspA-specific antibodies
are mainly operative by eliminating spirochetes from the vector during
infestation, the data suggest that OspA-vaccination for T helper cell immunity
alone is not sufficient to prevent Lyme disease.
PMID- 9394823
TI - Alpha beta lineage-committed thymocytes can be rescued by the gamma delta T cell
receptor (TCR) in the absence of TCR beta chain.
AB - Commitment of the alpha beta and gamma delta T cell lineages within the thymus
has been studied in T cell receptor (TCR)-transgenic and TCR mutant murine
strains. TCR gamma delta-transgenic or TCR beta knockout mice, both of which are
unable to generate TCR alpha beta-positive T cells, develop phenotypically alpha
beta-like thymocytes in significant proportions. We provide evidence that in the
absence of functional TCR beta protein, the gamma delta TCR can promote the
development of alpha beta-like thymocytes, which, however, do not expand
significantly and do not mature into gamma delta T cells. These results show that
commitment to the alpha beta lineage can be determined independently of the
isotype of the TCR, and suggest that alpha beta versus gamma delta T cell lineage
commitment is principally regulated by mechanisms distinct from TCR-mediated
selection. To accommodate our data and those reported previously on the effect of
TCR gamma and delta gene rearrangements on alpha beta T cell development, we
propose a model in which lineage commitment occurs independently of TCR gene
rearrangement.
PMID- 9394824
TI - Hypermutation, diversity and dissemination of human intestinal lamina propria
plasma cells.
AB - In this work we have microdissected lamina propria plasma cells and used
polymerase chain reaction and sequencing to investigate immunoglobulin (Ig) gene
rearrangements and mutations in human intestine. In addition, specific primers
were designed for individual Ig gene rearrangements to analyze the distribution
of related B cell and plasma cell clones at different sites along the bowel.
Confirming our earlier work, intestinal IgVH genes were highly mutated in plasma
cells from older individuals (> 30 years). IgVH genes were significantly less
mutated in samples taken from patients aged 11-30 years, and there were fewer
mutations again in samples from young children (< 11 years). In age-matched
specimens the number of mutations was equivalent in the duodenum and colon. Using
complementarity-determining region 3 primers to amplify specific Ig gene
rearrangements, evidence was also found for the existence of related lamina
propria plasma cells along the small bowel and colon, although these were quite
scarce. In addition, analysis of the numbers of related clones in a random
sampling from discrete areas of lamina propria indicates that the local
population is diverse. These results suggest that the highly mutated IgVH genes
in adult intestinal plasma cells are a consequence of chronic antigen exposure
with age. Duodenal plasma cells are as highly mutated as colonic plasma cells,
despite the fact that the upper bowel has no indigenous microbial flora (the
stimulus for intestinal plasma cells). They also show that the plasma cell
population is diverse and can be widely disseminated along the bowel.
PMID- 9394825
TI - Expression and function of NKRP1A molecule on human monocytes and dendritic
cells.
AB - In this study, we analyzed the expression and function of the lymphocyte surface
lectin NKRP1A on peripheral blood monocytes (Mo) or Mo and dendritic cells (DC)
derived from thymic and bone marrow precursors. De novo expression of NKRP1A and
CD14 molecules was detected upon culture of CD2- CD3- CD14- CD16- CD1a- NKRP1A-
immature thymic precursors for 7 days in the presence of granulocyte-macrophage
colony-stimulating factor (GM-CSF). Under these culture conditions, by day 21, a
fraction of cells had lost CD14 and acquired both CD80 (B7.1) and CD86 (B7.2)
molecules. These cells displayed a DC-like morphology and were surface NKRP1A
positive. CD34+ NKRP1A- CD14- precursors, isolated from bone marrow and cultured
in the presence of GM-CSF, also expressed both NKRP1A and CD14: these antigens
were newly expressed on about one third of cells which had lost the CD34
precursor marker. In addition, NKRP1A was constitutively present on resting CD14+
peripheral blood Mo. When these cells were cultured in the presence of GM-CSF,
the resulting DC population retained the expression of NKRP1A and acquired CD80,
while they lost the CD14 antigen. Functional analysis revealed that the
engagement of NKRP1A molecule leads to a strong intracellular calcium ([Ca2+]i)
increase both in resting peripheral blood Mo and in vitro-derived DC. [Ca2+]i
increase was mainly due to extracellular calcium influx, as it was completely
abrogated by the addition of EGTA. More importantly, the engagement of the NKRP1A
molecule induced interleukin (IL)-1 beta and IL-12 production by resting Mo and
DC, respectively. Altogether these data indicate that NKRP1A lectin is present at
the surface of Mo and DC and may play a relevant role in the activation and
function of both cell types.
PMID- 9394826
TI - Analysis of the tyrosine phosphorylation and calcium fluxing of human CD6
isoforms with different cytoplasmatic domains.
AB - CD6 is a cell surface glycoprotein that functions both as a co-stimulatory and
adhesion receptor on T cells. Recently we have described CD6 isoforms (CD6a, b,
c, d, e) that arise via alternative splicing of exons encoding the cytoplasmic
region of the molecule. CD6 becomes phosphorylated on tyrosine (Tyr) residues
following stimulation through the T cell receptor (TCR) complex. Since the
phosphorylation of Tyr residues renders some cell surface receptors competent for
interactions with proteins of intracellular signaling pathways, we wanted to
determine which region(s) and residues in the cytoplasmic domain of CD6 were
important for phosphorylation on Tyr residues. We engineered and stably expressed
chimeric receptors that consisted of the extracellular region of mouse CD6 and
the cytoplasmic regions of either naturally occurring isoforms of human CD6,
truncated proteins, or point mutants. We were able to demonstrate that of the
nine Tyr residues in the cytoplasmic domain of the largest isoform CD6a, the two
C-terminal Tyr residues (Tyr 629/662) are critical for the phosphorylation of CD6
following TCR cross-linking. Isoform CD6e, which is missing a region that
contains two proline-rich motifs, is not phosphorylated. We further analyzed the
ability of the different CD6 isoforms and truncated receptors to mobilize
intracellular calcium after CD6/TCR co-ligation. All CD6 isoforms, including
CD6e, as well as the truncation mutant delta 555, which is missing approximately
the C-terminal half of the cytoplasmic domain, are able to increase Ca2+ influx.
Taken together, these results suggest that the region of CD6 which is critical
for Ca2+ mobilization is located N-terminal from amino acid 555 and is therefore
different from the region located at the C terminus of CD6, which is necessary
for tyrosine phosphorylation.
PMID- 9394827
TI - Identification of a homolog of the C alpha 3'/hs3 enhancer and of an allelic
variant of the 3'IgH/hs1,2 enhancer downstream of the human immunoglobulin alpha
1 gene.
AB - Although four regulatory elements are known downstream of the mouse IgH alpha
gene, a single enhancer homologous to hs1,2 has been thus far described
downstream of each human alpha gene (Chen, C. and Birshtein, B. K., J. Immunol.
1997. 159: 1310). We characterized a 10-kb region downstream of the human alpha 1
gene. Two B cell-specific regulatory elements homologous to the murine C alpha
3'/hs3 and hs1,2,3' enhancers were found, which are duplicated downstream of
alpha 2. The hs1,2 element is in inverted orientation by comparison with a
recently reported alpha 1 hs1,2 element: it appears as a common allelic variant
carrying an internal tandem repeat insertion and its prevalence in the human
population is 60%. As in the mouse, the human hs1,2 enhancer is flanked with long
inverted repeats which may have promoted inversion events through homologous
recombination. Although the palindromic organization of the region is maintained
in human, sequence identity with rodents focuses on core enhancer elements rather
than on flanking repeats. Concerted divergence of both sides of the dyad symmetry
suggests that inverted repeats are not just evolutionary remnants but rather play
an architectural role in the LCR function.
PMID- 9394828
TI - Thymic T cell export is not influenced by the peripheral T cell pool.
AB - The peripheral T cell pool is maintained both by export of naive T cells from the
thymus and by post-thymic expansion of activated/memory T cells. However, it is
not known whether the thymus can alter its output following peripheral T cell
depletion. Using intrathymic injection of fluorescein isothiocyanate to detect
recent thymic emigrants (RTE), we directly tested whether the thymus is able to
alter the number of RTE or the CD4:CD8 ratio of RTE emigrating to the periphery
in response to in vivo depletion of total peripheral T cells or CD4 T cells,
respectively. Depletion of peripheral T cells was achieved with anti-Thy-1 or
anti-CD4, at doses that did not affect thymocyte numbers. Depletion of greater
than 70% of peripheral T cells by treatment with anti-Thy-1 in vivo did not alter
the number or cell cycle status of RTE trafficking to lymph nodes or spleen
during the peripheral reconstitution phase (6, 9, 12 days). Similarly, depletion
of the majority of CD4 T cells, which significantly reduced the peripheral
CD4:CD8 T cell ratio, did not alter the total number or the proportion of CD4+
CD8- RTE in peripheral lymphoid organs. These data clearly indicate that thymic
output is not influenced by downstream alterations in peripheral T cell pool size
or CD4:CD8 ratio. Rather we contend that thymic T cell export is internally
regulated by as yet undefined mechanisms.
PMID- 9394829
TI - Immune complexes are potent inhibitors of interleukin-12 secretion by human
monocytes.
AB - We have studied the effect of immune complexes (IC) on interleukin (IL)-12
secretion by human monocytes in vitro. Two experimental models of IC were used.
IC formed of tetanus toxoid and polyclonal anti-tetanus toxoid antiserum as well
as heat-aggregated human serum IgG almost completely inhibited IL-12 (p70 and
p40) secretion induced by interferon-gamma and lipopolysaccharide in human blood
derived monocytes. Neutralizing anti-IL-10 antibodies plus indomethacin restored
IL-12 secretion in the presence of IC to a high extent, indicating that IL-10 and
prostaglandin (PG) partially mediate the IC-induced inhibition of IL-12
secretion. However, neutralization of tumor necrosis factor (TNF)-alpha by
specific antibodies also incompletely restored IL-12 secretion. Indeed, monocytes
secrete high levels of TNF-alpha upon stimulation by IC. We found that
exogenously added TNF-alpha caused a profound inhibition of monocytic IL-12
secretion in the absence of IC, again mediated via the induction of IL-10 and PG.
In summary, IC inhibit IL-12 secretion via TNF-alpha-induced IL-10 and PG
synthesis. We conclude that IC, typically appearing in the course of chronic
inflammatory processes, may influence the balance between Th1 and Th2 responses
and may thus contribute to a deprivation of cell-mediated immune responses.
PMID- 9394830
TI - Interactions between membrane IgM and the cytoskeleton involve the cytoplasmic
domain of the immunoglobulin receptor.
AB - Cross-linking induced interactions between the membrane form of immunoglobulin
(mIg) and the cytoskeletal matrix have been described by several groups. To date,
the function of mIgM association with the cytoskeleton is not yet understood.
Delineation of the molecular basis of these interactions will be instrumental in
elucidating their function. We have previously shown that the Ig alpha/beta
heterodimer is not required for ligand-induced mIgM binding to the cytoskeleton.
In this study, we have investigated the role of other B cell-specific proteins in
mediating these interactions. For this, we expressed mIgM in the non
hematopoietic human cervical carcinoma cell line HeLa S3 and verified the
capacity of the surface-expressed IgM to interact with the cytoskeletal matrix
upon cross-linking with anti-mu chain antibodies. We show here that only the mIgM
molecule itself and no other B cell-specific protein(s) is required in mediating
mIgM interactions with actin filaments. In an attempt to determine the
cytoskeleton-binding site of mIgM we investigated the role of the cytoplasmic
tail of mIgM (KVK) in binding the receptor to actin-based microfilaments. Using
mutated forms of mIgM expressed in J558L cells, we show here that KVK plays a
role in mediating these interactions. The absence of KVK did not, however,
completely abrogate mIgM-cytoskeletal interactions, suggesting that there are
additional molecular requirements for the ligand-induced mIgM binding to the
cytoskeletal matrix.
PMID- 9394831
TI - Analysis of immunoreceptor tyrosine-based activation motif (ITAM) binding to ZAP
70 by surface plasmon resonance.
AB - The signaling function of the T cell antigen receptor (TCR) is mediated via CD3
polypeptides, the cytoplasmic sequences of which bear conserved immunoreceptor
tyrosine-based activation motifs (ITAM). ITAM are defined by two YxxL/I sequences
separated by a six-eight amino acid long spacer. Upon antigen recognition, ITAM
become phosphorylated on both tyrosine residues, creating a high affinity binding
site for the tandem SH2 domains found in the protein tyrosine kinase ZAP-70.
Using surface plasmon resonance, we further dissected the sequences required for
the binding of ZAP-70 to each TCR-associated ITAM. First, we generated protein
tyrosine phosphatase-resistant ITAM peptide analogs, in which
difluorophosphonomethyl phenylalanyl (F2p) replaced both phosphotyrosines, and
showed that those protein tyrosine phosphatase-resistant analogs bind ZAP-70 with
high affinity, establishing a rational strategy for the design of novel
pharmacological tools capable of interfering with TCR signaling function. Second,
we substituted the five amino acids separating the two YxxL/I sequences of the
CD3 zeta 1 ITAM with a non-peptidic linker made up of gamma-amino butyric acid
units and demonstrated that the length of this intervening sequence rather than
its chemical composition is essential for high affinity binding of phosphorylated
ITAM to the ZAP-70 SH2 domains.
PMID- 9394832
TI - Thiol modulation inhibits the interleukin (IL)-1-mediated activation of an IL-1
receptor-associated protein kinase and NF-kappa B.
AB - The interleukin-1 receptor type I (IL-1RI) is associated with other proteins thus
forming a complex system by which IL-1 exerts its various signals. The initiating
event is still uncertain, but activation of a recently described receptor
associated protein kinase is one of the earliest events detectable (Martin et
al., Eur. J. Immunol. 1994. 24: 1566). IL-1 signaling is commonly accompanied by
oxidative processes and is thought to be subject to redox regulation. We
therefore investigated whether the activation of the IL-1RI-associated protein
kinase could be a target for redox regulation and whether an altered activity of
the kinase could influence IL-1-mediated NF-kappa B activation. A murine T cell
line, EL4, was stimulated with IL-1 with and without pretreatment with different
compounds known to influence the cellular redox status. Thiol modifying agents
like diamide, menadione, pyrrolidine dithiocarbamate (PDTC), diethyl
dithiocarbamate or phenylarsine oxide inhibited the IL-1-induced activation of
the IL-1RI-associated protein kinase. N-Acetylcysteine, alpha,alpha'-dipyridyl,
aminotriazole or nitrofurantoin did not show any effect. The inhibition by PDTC
was reversible unless glutathione synthesis was blocked by buthionine
sulfoximine. The described conditions which inhibited or prevented the activation
of the IL-1RI-associated kinase similarly impaired the activation of NF-kappa B
in EL4 cells. From these observations we conclude that free thiols in the IL-1RI
complex are essential for the activation of the IL-1RI-associated protein kinase
and that this process is mandatory for IL-1 signaling leading to NF-kappa B
activation.
PMID- 9394833
TI - Molecular mechanisms regulating induction of interleukin-6 gene transcription by
interferon-gamma.
AB - The multifunctional cytokine interleukin-6 (IL-6) plays a central role in host
defence mechanisms and hematopoiesis. Furthermore, dysregulation of IL-6 gene
expression is associated with the pathogenesis of various immunologically related
diseases such as myeloma, systemic lupus erythematosus, rheumatoid arthritis,
psoriasis and Kaposi's sarcoma. The regulation of IL-6 gene expression occurs
mainly at transcriptional level, although mechanisms of post-transcriptional
regulation have also been described. In the present study we demonstrate that in
HeLa cells, induction of IL-6 by interferon-gamma (IFN-gamma) is
transcriptionally controlled, as shown by run on assays and analysis of the IL-6
mRNA stability. Gel-retardation experiments using antibodies specific for factors
of the IRF family identified four protein-DNA complexes, which bind to the
interferon regulatory factor (IRF) binding site at position -267 to -254, in
nuclear extracts from IFN-gamma treated cells. Furthermore, transient
transfection analyses of the 5'-flanking region of IL-6 gene linked to the
chloramphenicol acetyltransferase (CAT) reporter gene demonstrated that the -267
to -254 IRF site is necessary for IL-6 induction by IFN-gamma. However,
transfection experiments in which IRF-1 and I kappa B alpha were overexpressed
show that full-scale transcriptional activation of the IL-6 promoter directing
CAT expression requires the co-operation between IRF-1 and NF-kappa B at a low
constitutive level.
PMID- 9394834
TI - Dendritic cells differently respond to haptens and irritants by their production
of cytokines and expression of co-stimulatory molecules.
AB - After application of haptens to the skin, Langerhans cells (LC), i.e. immature
dendritic cells (DC) in the skin, move to secondary lymphoid organs to sensitize
naive T cells. During this process, LC become mature DC with augmented expression
of various co-stimulatory molecules and MHC class II antigens. In this scenario,
however, critical questions remain as to what kind of chemicals can induce this
maturation process through what kind of mechanisms. To clarify these questions,
we used monocyte-derived CD1a+ DC instead of LC since LC maturated spontaneously
in vitro culture. After we confirmed that monocyte-derived DC showed at least
phenotypic characteristics and a response to TNF-alpha similar to LC, we added
various chemicals, i.e., dinitrochlorobenzene (DNCB), trinitrochlorobenzene
(TNCB), NiCl2, ZnCl2, sodium dodecyl sulfate (SDS), or benzalkonium chloride
(BC), to a culture of purified monocyte-derived CD1a+ DC. Of these chemicals,
only NiCl2 and DNCB significantly increased the surface expression of CD54, CD86,
HLA-DR antigen, and interleukin (IL)-1 beta production, while SDS, BC, or ZnCl2
could not augment them, except for weak augmentation of CD86 expression by SDS.
The increase in the expression of CD86 induced by NiCl2 or DNCB was most
remarkable, being observed in DC from almost all the subjects we examined. TNCB
could also induce responses similar to those induced with DNCB, but the number of
subjects whose DC responded to it was far less than that of subjects whose DC
responded to NiCl2 or DNCB. In spite of the augmented CD86 expression on DC
treated with DNCB or NiCl2, these chemicals induced different responses of DC in
their expression of CD54 and HLA-DR and the production of IL-6 and tumor necrosis
factor (TNF)-alpha. In addition, the up-regulation of CD86 expression on DC
treated with DNCB was significantly suppressed by either anti-IL-1 beta or anti
TNF-alpha antibody, while that by NiCl2 was relatively insensitive to these
antibody treatments. Finally, the protein kinase C inhibitor, H7, but not
staurosporine, could suppress the augmentation of CD86 expression on DC induced
either by NiCl2 or by DNCB. These data suggest that DC respond to some haptens by
changing their expression of several co-stimulatory molecules and their
production of cytokines with a resultant change in antigen-presenting function.
They also suggest that these chemicals stimulate DC by different mechanisms. By
these responses, DC may modulate the final immune response to chemicals.
PMID- 9394835
TI - Separately expressed T cell receptor alpha and beta chain transgenes exert
opposite effects on T cell differentiation and neoplastic transformation.
AB - Two aspects of T cell differentiation in T cell receptor (TCR)-transgenic mice,
the generation of an unusual population of CD4-CD8-TCR+ thymocytes and the
absence of gamma delta cells, have been the focus of extensive investigation. To
examine the basis for these phenomena, we investigated the effects of separate
expression of a transgenic TCR alpha chain and a transgenic TCR beta chain on
thymocyte differentiation. Our data indicate that expression of a transgenic TCR
alpha chain causes thymocytes to differentiate into a CD4-CD8-TCR+ lineage at an
early developmental stage, depleting the number of thymocytes that differentiate
into the alpha beta lineage. Surprisingly, expression of the TCR alpha chain
transgene is also associated with the development of T cell lymphosarcoma. In
contrast, expression of the transgenic TCR beta chain causes immature T cells to
accelerate differentiation into the alpha beta lineage and thus inhibits the
generation of gamma delta cells. Our observations provide a model for
understanding T cell differentiation in TCR-transgenic mice.
PMID- 9394836
TI - Conservation of a master hematopoietic switch gene during vertebrate evolution:
isolation and characterization of Ikaros from teleost and amphibian species.
AB - The generation of T, B and NK lymphocyte lineages from pluripotent hematopoietic
stem cells is dependent upon the early expression of the Ikaros locus which by
means of alternative splicing produces a variety of zinc finger DNA binding
transcription factors. We assessed the general biological importance of Ikaros by
studying its conservation and expression in teleost fish and amphibians. Portions
of Ikaros cDNA from rainbow trout and Xenopus were amplified by reverse
transcription-polymerase chain reaction (RT-PCR). They show roughly 75%
conservation of the amino acid sequence with mammalian Ikaros. The trout fragment
was then used to isolate full-length Ikaros clones from a trout thymocyte cDNA
library. In mice and humans, Ikaros produces six alternatively spliced isoforms,
but in trout two additional novel splice variants designated Ik-7 and Ik-8 were
also found. Ik-7 is expressed in a similar fashion to Ik-1 and Ik-2, the
predominant isoforms expressed in mammalian lymphocytes. In trout and zebrafish,
as in mammals, Ikaros is a single-copy gene, but in Xenopus segregation analysis
demonstrates that Ikaros has been duplicated, most likely a result of
polyploidization. We then examined the expression of Ikaros in trout and Xenopus
tumor T cell lines via Northern blot, RT-PCR, immunofluorescence and Western blot
analysis. Overall, Ikaros is expressed in a lymphoid-specific fashion similar to
that found in mice and humans. In addition Ikaros is expressed early in trout
ontogeny, beginning roughly at days 3-4 in the yolk sac and at day 5-6 in the
embryo proper. The conservation of Ikaros structure and expression confirms it as
a master switch of hematopoiesis.
PMID- 9394837
TI - Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein
(MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is
directed against three main regions.
AB - Our previous analysis of the T cell reactivity to myelin antigens in a group of
24 patients with multiple sclerosis (MS) and 16 control individuals revealed that
the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) predominates
in MS over that to myelin basic protein (MBP), proteolipid protein or myelin
associated glycoprotein, suggesting a prevalent role for the autoimmune response
to MOG in the pathogenesis of MS. Using a recombinant human MOG (rhMOG)
preparation corresponding to the extracellular immunoglobulin-like domain of the
MOG molecule, we have now analyzed another group of 52 MS patients and 49 control
individuals for reactivity of their peripheral blood lymphocytes (PBL) to rhMOG
and to MBP concomitantly. Of the 52 MS patients tested 24 responded to MOG and 10
out of 49 responded to MBP, whereas only 5 MOG-reactive and 4 MBP-reactive
control individuals were detected out of the 49 tested. These results are
therefore highly confirmatory of the predominant reactivity to MOG in MS. The
analysis of the primary proliferative response to 11 synthetic overlapping
peptides (phMOG) spanning the extracellular domain of human MOG by PBL from 9 MS
patients and 15 control individuals (9 healthy controls and 6 patients with
neurological diseases other than MS) further supports a prevalent role for the
autoimmune response to MOG in MS, as only 1 of the 15 controls tested showed
reactivity to any of the phMOG, whilst 5 out of the 9 patients studied reacted to
at least 1 of the phMOG. PBL from 10 MS patients, and from 4 controls, were
selected in vitro with each of the phMOG. Of the 10 patients studied 7 reacted to
at least 1 phMOG upon secondary stimulation and the reactivity was mostly
directed to epitopes localized within three main regions (amino acids 1-22, 34-56
and 64-96), as was observed for the primary response of PBL. The predominant
response to MOG of PBL from MS patients as demonstrated in two separate studies
using native MOG and rhMOG as antigens, and the high incidence of reactivity of
these PBL compared to the lack of response to phMOG by control PBL, emphasize the
relevance of MOG in MS pathogenesis and support a primary role for the autoimmune
T cell response to MOG in disease development.
PMID- 9394839
TI - A T cell receptor (TCR) antagonist competitively inhibits serial TCR triggering
by low-affinity ligands, but does not affect triggering by high-affinity anti-CD3
antibodies.
AB - It has been demonstrated that modified peptides which fail to induce detectable T
cell responses can act as T cell receptor (TCR) antagonists when presented
together with agonist by the same antigen-presenting cell (APC). We report that a
TCR antagonist competitively inhibits TCR triggering induced by low-affinity
ligands such as agonistic peptides or bacterial superantigens. However, the same
antagonist cannot inhibit TCR triggering and T cell activation induced by high
affinity anti-CD3 antibodies that engage most TCR at once. These results indicate
that TCR antagonists inhibit T cell responses by interfering with the ongoing
process of serial triggering, rather than by delivering an inhibitory signal to T
cells.
PMID- 9394838
TI - Sequence analysis of rat integrin alpha E1 and alpha E2 subunits: tissue
expression reveals phenotypic similarities between intraepithelial lymphocytes
and dendritic cells in lymph.
AB - The integrin alpha OX-62 subunit is defined by the OX-62 monoclonal antibody that
was raised against rat dendritic cells in lymph (veiled cells) and shows
properties similar to those of human alpha E2 that is predominantly expressed on
intraepithelial lymphocytes. To clone alpha OX-62, rat probes generated using
primers specific for the human alpha E sequence were used to screen rat T cell
cDNA libraries. cDNA clones encoding two similar but not identical alpha subunits
that are closely related to but distinct from human alpha E were isolated. alpha
E1 is predicted to be the rat homolog of mouse alpha M290 and alpha E2
corresponds to rat alpha OX-62. Immunofluorescence analysis revealed that mouse
alpha E1 and rat alpha E2 are expressed in dendritic epidermal T cells in the
skin, intraepithelial lymphocytes in the small intestine and in cells with a
dendritic morphology present at sites where gamma delta T cells occur in lymphoid
organs. Unexpectedly, alpha E2 is co-expressed with intracellular CD3-delta and a
33-kDa CD3 chain but not the T cell receptor in veiled cells. These findings
suggest that veiled cells may be derived from a lymphoid precursor. Furthermore,
veiled cells show phenotypic similarities to intraepithelial lymphocytes.
PMID- 9394841
TI - Medical oncology as a discipline.
AB - Medical oncology has become a major subspecialty discipline of internal medicine
within only 25 years. The special skill of oncologists is judgement in matters
relating to cancer. This specialty brought the necessary expertise for cancer
management into the community, improved care of patients with cancer worldwide,
and provided a significant impact on cancer education and cancer research.
Current manpower needs have been met but the ultimate in desired services are not
apparent. Attempts to merge hematology and oncology are unwarranted. The future
for medical oncology will be challenging, especially to meet the expanding needs
of geriatric oncology.
PMID- 9394840
TI - The low-grade lymphoproliferative disorders.
AB - Rapid advances in our understanding of the biology and pathology of
lymphoproliferative disorders, permitted mainly by new diagnostic tools,
constantly change our approach to this heterogenous group of disorders. In this
review of the more indolent subgroup of lymphoproliferative disorders, some of
the recent advances are highlighted, and treatment options discussed.
PMID- 9394842
TI - The relationship of shape of tumor invasion to depth of invasion and cervical
lymph node metastasis in squamous cell carcinoma of the tongue.
AB - Several investigators have suggested that there is a strong correlation between
tumor depth and lymph node involvement in tongue carcinoma. The purpose of this
study was to investigate the relationship between the shape of tumor, tumor
depth, and lymph node metastasis in tongue carcinoma. Fifty-four patients with T1
abd T2 tongue carcinomas who underwent surgical treatment were included in this
study. Tumors were divided into four categories according to their shape of
invasion: superficial, exophytic, endophytic, and a combination of endophytic and
exophytic. Forty cases of endophytic and combination types were divided into two
groups according to the shape of invasion: (1) reductive bottom of invasion (n =
17) and (2) expansive bottom of invasion (n = 23). Tumors with a reductive bottom
of invasion showed a variety of tumor depths and had low lymph node involvement
(4/17, 23.5%). However, tumors with an expansive bottom of invasion showed deeper
invasion and a high incidence of lymph node metastasis (16/23, 69.6%). These
results suggested that the macroscopic shape of invasion is a feature that may
provide important information about the prognosis of the primary tumor especially
in relation to cervical lymph node involvement.
PMID- 9394843
TI - A case-control study on risk factors for local recurrences or distant metastases
in breast cancer patients treated with breast-conserving surgery.
AB - A case-control study was conducted on 143 case-control sets recruited from the 18
key hospitals/ institutes in Japan to identify risk factors for local recurrences
and distant metastases after breast-conserving surgery in breast cancer patients:
(1) positive surgical margin was a risk factor for local recurrences (relative
risk (RR) = 16.70, p < 0.001) but not for distant metastases, (2) positive p53
immunostaining was a risk factor for both local recurrences (RR = 5.62, p =
0.003) and distant metastases (RR = 3.11, p = 0.034), (3) lymph node metastasis
was a risk factor for distant metastases (RR = 9.28, p = 0.001) but not for local
recurrences, (4) radiation therapy reduced local recurrences (RR = 0.13, p =
0.004) and (5) adjuvant chemotherapy (RR = 0.27, p = 0.120), endocrine therapy
(RR = 0.21, p = 0.037), and chemoendocrine therapy (RR = 0.05, p = 0.013) reduced
local recurrences.
PMID- 9394844
TI - Tissue expression and serum levels of HER-2/neu in patients with breast cancer.
AB - We have analyzed serum levels of soluble HER-2/neu in 42 primary breast cancer
patients prior to any therapy and studied the relationship between the
overexpression and amplification of HER-2/neu in the primary tumor after surgical
excision and data obtained by pathohistological staging. In addition, we have
investigated the sera of 62 patients with stage IV breast cancer. Using an enzyme
linked immunosorbent assay, we observed elevated serum HER-2/neu levels in 6/42
(14.2%) preoperative patients. In 42.8% of the patients with HER-2/neu tumor
expression/amplification serum levels were increased. In contrast, only 8.5% of
the patients without HER-2/neu expression/amplification in the primary tumor
presented with elevated serum levels. There was a significant correlation between
serum concentrations of soluble HER-2/neu and tumor size (p < 0.0001) or axillary
lymph node involvement (p < 0.0001). In patients with stage IV disease, 27 of 62
(43.5%) had elevated soluble HER-2/neu serum levels. A highly significant
correlation between soluble HER-2/ neu and CA 15-3 (p < 0.002) was observed. The
correlation of serum concentrations of HER-2/neu with estrogen and progesterone
receptor status of the primary tumor was not significant in both groups. In
conclusion, the measurement of serum HER-2/neu levels at diagnosis defines a
small subgroup of breast cancer patients with a relatively advanced stage of
disease. Its strong correlation with tumor load in patients with stage II disease
and the high prevalence in patients with stage IV disease could make it a
promising tool for the assessment of disease activity and biologic behavior in
breast cancer.
PMID- 9394845
TI - Relationship of serum testosterone level with proliferating cell nuclear antigen
and nm23 protein in human prostatic carcinoma tissue.
AB - OBJECTIVE: To elucidate the biological significance of proliferating cell nuclear
antigen (PCNA) and nm23 immunoreactivity in prostatic carcinoma (PC) tissue, both
expressions were immunohistochemically analyzed, and the results were compared
with the change of the serum testosterone (T) level. METHODS: The paraffin
embedded materials obtained from 49 untreated PC and 16 hormonally refractory PC
(hr-PC) were used. Of the 49 untreated PC, 35 received luteinizing hormone
releasing hormone (LH-RH) analogue treatment, while 14 received a cisplatin-based
chemotherapy. The immunohistochemistry of PCNA and nm23 protein was performed
using an anti-PCNA monoclonal antibody (PC-10) and an antihuman nm23 polyclonal
antibody (OA-11-890), respectively. The serum T level was measured by means of
radioimmunoassay. RESULTS: In both untreated PC and hr-PC, the immunoreactivity
of nm23 protein significantly correlated with the PCNA expression. Both PCNA
expression and nm23 protein immunoreactivity were higher in poorly differentiated
PC than those observed in well-differentiated PC, while no significant difference
in the serum T level was observed between poorly and well-differentiated PCs. On
the other hand, both PCNA expression and nm23 protein immunoreactivity were
significantly higher in hr-PC than those observed in untreated PC, whereas the
serum T level was significantly lower in hr-PC. In 35 PCs treated with LH-RH
analogue, no significant difference in both PCNA expression and nm23 protein
immunoreactivity was found between those specimens obtained before and at 3
months after the treatment, while a significant reduction of the serum T level
was noted at 3 months after the treatment. Similarly, in 14 PCs treated with a
cisplatin-based chemotherapy, the same change of PCNA expression and nm23 protein
immunoreactivity as observed in LH-RH analogue treatment was found, while no
significant difference of the serum T level was found. CONCLUSIONS: These
findings appear to indicate that (1) nm23 protein immunoreactivity is
interrelated with cellular proliferation in PC tissue and (2) alteration of the
serum T level during a short period was not enough to explain the essential
change of cellular proliferation of PC tissue, but might reflect other aspects of
tumor growth such as apoptosis.
PMID- 9394846
TI - Adrenocortical carcinoma: experience in 45 patients.
AB - Forty-five patients with adrenocortical carcinoma (13 nonfunctioning and 32
functioning carcinomas) were retrospectively studied. Five-year survival rate was
29% overall; for patients at stage I-II (n = 15) it was 70%, and for patients at
stage III-IV (n = 30) it was 12%. In patients given mitotane + chemotherapy
survival rate was similar to that observed in patients given chemotherapy alone,
and significantly longer than in patients given mitotane alone (p < 0.05). There
were no differences in disease-free interval and survival between adjuvant
mitotane and no treatment. Optimization of therapeutic protocols in addition to
early recognition may improve prognostic aspects of this type of malignancy for
which treatment outcome is still unsatisfactory.
PMID- 9394847
TI - Serum steroids in relation to benign prostatic hyperplasia.
AB - In order to investigate the endocrine etiology of benign prostatic hyperplasia
(BPH), we conducted a case-control study in Athens, Greece using 52 patients with
histologically confirmed BPH and 52 healthy controls matched according to age and
town of residence. Blood samples were collected from all participants and
analyzed blindly in Boston, Mass. regarding testosterone (T),
dihydrotestosterone, estradiol (E2), sex hormone-binding globulin, and
dehydroepiandrosterone sulfate (DHEAS). Results from logistic regression models,
adjusting for age, height, body mass index, years of schooling, and mutually
among the measured hormones, indicate that DHEAS is significantly positively
associated with the risk of BPH [odds ratio = 3.10 per standard deviation (60
micrograms/dl), 95% confidence interval (1.28,7.50)]. T and E2 were not
significantly related to the risk of BPH.
PMID- 9394848
TI - Relaxation of insulin-like growth factor-II gene imprinting in human gynecologic
tumors.
AB - To test for the existence of genomic imprinting in human gynecologic tumors, we
analyzed the allelic expression of human insulin-growth factor-II (IGF-II) genes.
Genomic imprinting is the parental allele-specific expressions of genes, and
recently imprinting of IGF-II gene has demonstrated that parental IGF-II was
monoallelically expressed. To study whether IGF-II gene imprinting occurs in
human gynecologic tumors, we examined allele-specific expression using an ApaI
polymorphism in the 3' untranslated region of IGF-II gene exon 9. We used 19
gynecologic tumor cell lines, and 66 human gynecologic tumors. Four of 19 cell
lines (21%) were informative, and three of these four cell lines (75%) revealed
loss of imprinting (LOI). For gynecologic tumors, 24 of 66 were informative
(36%), and 5 of the 24 (21%) had LOI. We have reported here that the IGF-II gene
is expressed biallelically in some gynecologic tumors. We suggest that LOI of the
IGF-II gene is involved in the development of some gynecologic tumors.
PMID- 9394849
TI - Expression of p16 and cyclin-dependent kinase 4 proteins in primary breast
carcinomas.
AB - The immunolocalization of the p16 and cdk4 proteins was investigated in 65
retinoblastoma gene product (pRB)-positive and 20 pRB-negative breast carcinomas.
These proteins were expressed in similar lesions in 84.6% of the pRB-positive and
100% of the pRB-negative carcinomas. Diffuse expression of p16 was observed in
73.8 and 70.0% of the pRB-positive and -negative cases, respectively. cdk4 and
p16 expression was significantly more heterogeneous in tumors of larger sizes
and/or at higher stages. These findings suggest that p16 can be induced
regardless of pRB status and Rb gene function in primary breast carcinoma and
that it modulates the cell cycle progression in association with cdk4.
PMID- 9394850
TI - Survival with chronic myelogenous leukemia.
PMID- 9394851
TI - Octreotide for the treatment of hypercalcemia related to B cell lymphoma.
PMID- 9394852
TI - A review of endocrine options for the treatment of advanced breast cancer.
AB - It is now 100 years since it was first recognised that altering the endocrine
environment can be valuable in patients with inoperable breast cancer. Various
ablative endocrine and other treatments have since been developed, but few have
resulted in a substantial improvement in clinical efficacy, and the response
rates to endocrine manoeuvres remain at about 30%. The benefits of more recent
therapies, such as the new generation of aromatase inhibitors, appear to relate
to better tolerability and more convenient administration. It is now recommended
that the majority of patients with advanced breast cancer should receive
endocrine therapy as their first mode of treatment, although it is postmenopausal
patients who are likely to gain most benefit from this approach. Tamoxifen is
currently the first choice of treatment in the majority of postmenopausal women,
although most eventually experience progression of disease, possibly because of
the partial oestrogen agonist activity of tamoxifen. Second-line therapy is
usually then either an aromatase inhibitor or a progestin. The new-generation
selective, non-steroidal aromatase inhibitors are effective and can offer major
clinical benefits in terms of fewer side-effects.
PMID- 9394853
TI - The relevance of preclinical models to the treatment of postmenopausal breast
cancer.
AB - The predictive value of test results in animals when selecting a compound for
potential therapeutic human use depends upon the relevance of the animal model to
the human disease and the comparative pharmacokinetics of the compound in animals
and man. The development of the aromatase inhibitor, anastrozole (Arimidex),
illustrates the importance of these factors. In postmenopausal women with breast
cancer, aromatase activity in the peripheral tissues is the main source of
oestrogen for tumour growth. Only one form of the human enzyme is known, which is
not subject to strong feedback control. Inhibition of aromatase therefore simply
reduces oestrogen production. This situation is mimicked by assays of acute
inhibition of ovulation in rats, chronic inhibition of androstenedione-induced
uterine hypertrophy in sexually immature rats, and chronic inhibition of
peripheral aromatase in monkeys. In all these assays, maximum anastrozole
activity was consistently achieved at an oral dose of about 0.1 mg/kg, and the
clearance half-life of 7-16 h indicated that once-daily dosing would be possible
in humans. The clearance half-life in postmenopausal women is about 50 h, and
with once-daily dosing the dose of anastrozole required for maximal inhibition is
1 mg/day. The rat 7,12-dimethylbenzanthracene tumour model, in contrast, is
supported by ovarian oestrogen and chronic inhibition provokes positive feedback
loops that try to restore oestrogen production, masculinise the animals and
decrease the clearance half-life of anastrozole. Higher doses (10 mg/kg) of
anastrozole are therefore needed. Variations in the dose of aromatase inhibitor
required in different models, therefore, can be explained in terms of
pharmacokinetics and do not reflect the effectiveness of anastrozole as an
aromatase inhibitor.
PMID- 9394854
TI - Anastrozole--a new generation in aromatase inhibition: clinical pharmacology.
AB - Use of the aromatase inhibitor aminoglutethimide is limited by its lack of
selectivity for aromatase and its toxicity. Newer agents are more selective, but
do not always offer improved inhibition of aromatase. Indirect comparison of
their activity in inhibiting aromatase and suppressing plasma oestrogens
indicates that aminoglutethimide, rogletimide, formestane, and fadrozole
inhibited aromatase activity by 74-91%, with reported falls in oestradiol level
of 58-76%. In contrast, the new-generation oral once-daily aromatase inhibitors
anastrozole (Arimidex) and letrozole were of a similar activity, inhibiting
aromatase activity by over 96%, with a concomitant fall in oestradiol and
oestrone levels of at least 80%. Anastrozole at the recommended clinical dose of
1 mg daily also suppressed oestrone sulphate levels by 93.5%; activity with
anastrozole 10 mg daily was not statistically significantly different. The new
generation of aromatase inhibitors, as typified by anastrozole, thus offers
effective and convenient aromatase inhibition which correlates well with
decreases in the levels of plasma oestrogens.
PMID- 9394855
TI - Clinical overview of anastrozole--a new selective oral aromatase inhibitor.
AB - The efficacy and tolerability of the new selective aromatase inhibitor,
anastrozole (Arimidex), was compared with megestrol acetate in the treatment of
advanced breast cancer in postmenopausal women. In two independent prospective
randomised trials, patients who progressed after prior tamoxifen therapy received
anastrozole 1 or 10 mg once daily, or megestrol acetate, 40 mg q.i.d. The two
studies were designed to allow the data to be combined to increase the
statistical power of the analyses. It is the data from these combined analyses
that are considered in further detail. After 6 months of follow-up, the
proportion of patients gaining clinical benefit (complete response + partial
response + stable disease > or = 24 weeks) was approximately one third of
patients in all three groups. No significant difference was observed between
either dose of anastrozole and megestrol acetate in the time to disease
progression (130-153 days). All three treatments were generally well tolerated,
but significantly more patients on megestrol acetate gained weight, and the
weight gain in this group continued up to at least 9 months of follow-up. At a 12
month update of tolerability, of the commonly observed adverse events, a greater
than 2-fold difference between treatment arms was observed for hypertension,
weight gain, dyspnoea, vaginal haemorrhage, sweating and diarrhoea (all higher on
megestrol acetate except for diarrhoea). Anastrozole is effective and well
tolerated and on the basis of these data, 1 mg once daily is the recommended
clinical dose in postmenopausal women with advanced breast cancer.
PMID- 9394856
TI - A randomised comparison of oestrogen suppression with anastrozole and formestane
in postmenopausal patients with advanced breast cancer.
AB - The relative efficacy and tolerability of the aromatase inhibitors anastrozole
(Arimidex) and formestane are assessed in a direct comparative trial in
postmenopausal women with advanced breast cancer. Final results are available and
reported here only for oestradiol suppression. Patients were randomised to
receive either oral anastrozole, 1 mg once daily, or formestane, 250 mg every 2
weeks intramuscularly. In the anastrozole group, mean serum oestradiol levels
fell from 32.1 pmol/l at baseline to 6.5 pmol/l at week 1, and similar levels of
suppression were maintained over the next 3 weeks. In the formestane group, mean
serum oestradiol levels fell from 31.0 pmol/l at baseline to 9.5 pmol/l at the
week 1 assessment. In this group, serum oestradiol levels tended to rise by the 2
and 4-week measurements, i.e. immediately before the next injection was due.
Based on the 2- and 4-week measurements, the mean falls in oestradiol levels were
79 and 58% in the anastrozole and formestane groups, respectively (p = 0.0001).
More effective and consistent suppression of oestradiol was achieved with
anastrozole at the therapeutic dose of 1 mg once daily, orally, than with
formestane at the standard dose of 250 mg every 2 weeks, intramuscularly.
PMID- 9394857
TI - Tolerability of endocrine treatment for advanced breast cancer: results of an
international survey.
AB - In contrast with cytotoxic therapy, the impact of hormonal therapy for advanced
breast cancer in postmenopausal women is poorly documented. Two recent surveys of
the impact of hormonal therapy in this patient group found that side-effects had
an adverse impact on patients' quality of life which needed to be taken into
account when discussing treatment options. Patients were perceived to be more
comfortable discussing treatment-related problems with nurses rather than
doctors, who tended to underestimate the distress caused to patients by the side
effects of treatment. A need was identified for better lines of communication
between patients and medical professionals, and for a simple, more widely
applicable tool for assessment of side-effects. As a result of these findings, a
simple checklist, Checklist for Patients on Endocrine Therapy (C-PET), has been
developed to be completed by patients before a physician appointment, to form a
basis for discussion. A pilot study has indicated that C-PET is easy and quick
for patients to complete and aids communication between patients and healthcare
professionals. C-PET has now been formally launched to nurses, oncologists, and
other cancer physicians.
PMID- 9394858
TI - The role of selective non-steroidal aromatase inhibitors in future treatment
strategies.
AB - The major role of endocrine therapy in the treatment of early and advanced breast
cancer should not be forgotten as an increasing number of new and potentially
more exciting agents are introduced. Endocrine therapy generally has a more
powerful effect than cytotoxic therapy in the treatment of breast cancer.
Alternatives to tamoxifen, such as anastrozole (Arimidex), are now being
considered, both in advanced disease and as adjuvant therapy, whether as single
agents or in combination. Anastrozole has a low side-effect profile and is
becoming a drug of choice for second-line therapy in postmenopausal women with
advanced breast cancer. The present use of anastrozole in postmenopausal women
with advanced breast cancer includes second-line treatment after tamoxifen and
first-line treatment after tamoxifen has been used as an adjuvant treatment. It
may also be used when tamoxifen is not tolerated. The future potential of
anastrozole is currently being investigated in a programme of clinical trials in
postmenopausal women, including first-line treatment of advanced disease and as
an adjuvant treatment for early breast cancer.
PMID- 9394859
TI - Cerebral blood flow and energy metabolism in the newborn.
AB - In normal newborn term and preterm infants CBF is relatively low corresponding to
a low metabolic rate for oxygen, whereas cross-brain oxygen extraction is similar
to that in adults. This provides for a considerable reserve capacity to deal with
decreased CBF or decreased oxygen content in arterial blood. CBF reactivity to
CO2 is normal, and the evidence is that pressure-flow autoregulation is present,
even in very preterm infants. Absence of autoregulation and CBF-CO2 reactivity
has been documented in severely asphyxiated infants, and in preterm infants who
went on the develop severe intracranial hemorrhage. A number of methods are
available to study CBF and brain metabolism in newborn infants. Several of them
involve ionizing radiation, which has limited their use, even though it is
unlikely that the associated risks are particularly high. Magnetic resonance
spectroscopy has demonstrated a delayed disturbance of energy metabolism
following severe asphyxia. Doppler ultrasound has rarely been helpful to obtain
quantitative data. Near infrared spectrocopy has now been in use for more than 10
years. It has been slow to fulfill its promise as a continuous monitor of
cerebral circulation and of oxygen sufficiency of neurons.
PMID- 9394860
TI - Cerebral hemodynamics and oxygenation in the fetus. The role of intrapartum near
infrared spectroscopy.
AB - Current methods of intrapartum surveillance have made little impact on fetal
mortality and morbidity while leading to increased caesarean section rates. Near
infrared spectroscopy is a powerful new technique that can continuously measure
changes in fetal cerebral oxygenation and hemodynamics during labor. Data are
presented suggest that near-infrared spectroscopy has potential as a new form of
fetal monitoring. However, further technical developments and testing in clinical
trials are necessary before its introduction into clinical practice.
PMID- 9394861
TI - Brain injury in the premature infant. Neuropathology, clinical aspects,
pathogenesis, and prevention.
AB - There are two principal lesions that underlie brain injury and the neurologic
manifestations in the premature infant: periventricular hemorrhagic infarction
and periventricular leukomalacia. Both of these lesions may be potentially
preventable: periventricular hemorrhagic infarction by preventing germinal matrix
IVH, and periventricular leukomalacia by detecting impaired cerebrovascular
regulation with near-infrared spectroscopy, preventing the impaired cerebral
blood flow and interrupting the cascade to oligodendroglial cell death, perhaps
by such agents as free-radical scavengers. Prenatal magnesium sulfate also may be
valuable. The greatest progress toward prevention has been made regarding
periventricular hemorrhagic infarction, but the advent of new technologies,
especially near-infrared spectroscopy, and of new insights into the cellular
basis for oligodendroglial vulnerability provide hope for prevention of
periventricular leukomalacia.
PMID- 9394862
TI - Intraventricular hemorrhage and posthemorrhagic hydrocephalus. Current and
potential future interventions.
AB - Enhanced survival of very premature infants may be regarded as the most striking
demonstration of the major improvements in perinatal medicine during the last two
decades. This article discusses recent perinatal interventions in the context of
the pathogenesis and know risk factors for intraventricular hemorrhage (IVH). In
addition, controversies related to the evolution and management of
posthemorrhagic hyrdocephalus (PHH) are examined, and current concepts concerning
potential brain injury to PHH are reviewed.
PMID- 9394863
TI - Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical
aspects, and neuroimaging.
AB - Hypoxic-ischemic cerebral injury in the full-term infant results in a variety of
neurologic manifestations. The pathogenetic events resulting in this central
nervous system injury may occur throughout the prenatal period. Several clinical
patterns of signs and symptoms of hypoxic-ischemic cerebral injury have been
identified in the term infant. Further, characteristic neuroradiologic patterns
of this injury can be discerned. Information derived from the term infant's
clinical course and neuroimaging data convey useful neurodevelopmental prognostic
information. Several potential and promising therapeutic agents exist may
attenuate the sequelae of hypoxic-ischemic cerebral injury to the term infant.
PMID- 9394864
TI - Hypoxic-ischemic brain injury in the newborn. Cellular mechanisms and potential
strategies for neuroprotection.
AB - Recent advances have delineated many of the complex cellular mechanisms of
cerebral hypoxic-ischemic injury. These developments have created opportunities
for the design of rational "mechanism-based" strategies that target specific
injurious processes. A number of neuroprotective agents have entered adult
clinical trial and practice. For the newborn infant, progress in this areas has
been judiciously delayed by toxicity concerns. Central to those safety concerns
is the close relationship between mechanisms of hypoxic-ischemic cellular injury
and normal developmental processes. These cellular mechanisms and the dilemmas
facing the advance of this field are discussed. The likelihood of an effective
single "magic bullet" neuroprotective strategy emerging in the near future
appears remote. Rather more likely is the development of "cocktail" therapies
that seek to exploit synergistic antagonism at multiple levels in the complex
concentration of cellular events mediating hypoxic-ischemic cellular injury.
However, such combination therapies will require elucidation of the complex inter
relationships between mechanisms of cellular injury, brain development, and the
combination of therapies envisioned.
PMID- 9394866
TI - Recent advances in neonatal cranial ultrasound and Doppler techniques.
AB - Use of new scanning approaches, such as the mastoid fontanelle and new signal
processing techniques, such as power Doppler and spectral Doppler during
fontanelle compression, have dramatically improved our ability to image both the
structure and hemodynamics of blood flow in the neonatal brain. Continuing
development of US contrast agents hold promise for creation of regional cerebral
blood-flow maps at the cribside in critically ill newborns.
PMID- 9394865
TI - Cerebrovascular complications and neurodevelopmental sequelae of neonatal ECMO.
AB - A total of 355 infants have been treated with ECMO at our hospital between 1985
and 1996, 271 of whom have been enrolled in an ongoing prospective study; of the
271 infants enrolled, 223 (82%) survived, and most function within the normal
range of development. Nevertheless, handicapping sequelae, including spastic
forms of CP, hearing loss, and cognitive deficiencies at school age, have been
noted in a significant minority of ECMO-treated survivors. The need for RCCA
cannulation during venoarterial ECMO may increase the risk of a cerebrovascular
injury, and lateralized CBF abnormalities have been noted on CDI and pulsed
Doppler ultrasound studies during and after venoarterial bypass; however, post
ECMO CT scans, HUS, MR images, or clinical evaluations have not indicated
selective or greater injury to the right, compared with the left, cerebral
hemisphere in our survivors, nor was there a significant predilection for right,
rather than left, cerebral hemispheric EEG abnormalities during or following
venoarterial bypass. Although we routinely repair the RCCA following venoarterial
ECMO, the long-term consequences of a permanently ligated artery have not as yet
been demonstrated. We have noted the ominous predictive value of two or more
recordings that disclose ES and BS EEG abnormalities before or during
venoarterial ECMO and found that the need for vigorous CPR before or during RCCA
cannulation significantly increased the risk of these two markedly abnormal
bioelectric patterns. Because 85% of infants with severe respiratory failure have
moderate to marked EEG abnormalities (including 23% who have BS or ES patterns)
before ECMO, we believe that fetal and neonatal complications related to the
occurrence and treatment of severe cardiorespiratory failure are responsible in
large part for the neurologic sequelae in ECMO survivors. The risk for CP was
significantly increased in survivors of neonatal venoarterial ECMO treated at our
hospital who required CPR or who independently had a systolic BP below 39 mm Hg
before or during ECMO. We also noted that the risk for hearing loss was increased
significantly in surviving neonates who had a PaCO2 below 14 mm Hg before ECMO.
The possibility that undetected confounding variables were, in part, responsible
for the neurologic, audiologic, and cognitive sequelae in ECMO survivors could
not be excluded entirely by our data analyses. Although the pathogenesis of
severe brain damage has not been defined fully in neonates treated with ECMO,
focal, multifocal, or diffuse cerebral ischemia is the most likely final common
pathway; thrombosis, infarction, or hemorrhage may follow and contribute to the
brain injury. The cause of isolated SNHL is unknown in most affected ECMO
survivors, but in some very likely is associated with the complications and
treatment of severe cardiorespiratory failure, including profound hypocarbia
prior to ECMO. The results of our studies to date are consistent with the
following conclusions: (1) hypotension before or during ECMO and the need for CPR
before ECMO contribute to the pathogenesis of CP, probably through the mechanism
of cerebral ischemia; (2) profound hypocarbia before ECMO and delayed ECMO
treatment are associated with a significantly increased risk of hearing loss; (3)
hypoxemia without hypotension does not result in CP; (4) the type and severity of
neurologic and cognitive sequelae in ECMO survivors depends, in part, on the
primary cause of the neonatal cardiorespiratory failure; (5) early
neurodevelopment, except for severe deficits, may not predict school-age
performance; and (6) abnormally low or borderline WPPSI-R IQ scores and academic
deficiencies at early school age, without evidence of a congenital abnormality of
brain or CP or SNHL, remain unexplained. The criteria for initiating ECMO in the
neonate with severe cardiorespiratory failure include decreasing oxygenation
despite mechanical hyperventilation with 100% oxygen. (ABSTRACT TRUNCATED)
PMID- 9394867
TI - Magnetic resonance techniques in the evaluation of the newborn brain.
AB - MR imaging provides unequaled sensitivity as compared with US or CT scanning for
evaluating developmental changes and pathologic processes in the newborn brain.
Myelination can be assessed qualitatively and quantitatively using newer 3D-MR
imaging methods. MR imaging provides a much clearer delineation of many
developmental disorders, including anomalies of migration and organization, as
well as a variety of metabolic disorders and congenital infections. Neonatal
intracranial hemorrhage is detected in all its locations by MR imaging. The
timing of the hemorrhage is a unique feature of MR imaging. Venous thrombosis
also can be identified by MR imaging and confirmed with MR angiography. HIE is
the major cause of potentially preventable or reversible brain injury that
results in considerable long-term neurologic morbidity. Early detection is
crucial for interventions aimed at preventing or reversing ongoing injury. DWI
can show early changes at the cellular level that are not detectable by any other
imaging modality. MR spectroscopy has further opened the possibility of studying
the metabolic mechanisms that define the pathophysiologic events taking place in
neonatal brain injury. Both 31P-MR spectroscopy, as a marker of the acute changes
in energy metabolism, and 1H-MR spectroscopy, with the measurement of lactate and
the excitotoxic aminoacids glutamate and glutamine, have enabled us to study the
early and late effects of insults to the newborn brain in a noninvasive fashion.
Studies performed to determine the predictive value of MR spectroscopy for later
neurodevelopmental outcome after HIE have shown promising results but need
further evaluation on larger patient samples. The potential use of these methods
in the evaluation of early neuroprotective treatment regimens in the newborn
remains to be determined.
PMID- 9394868
TI - Radiographic patterns of pulmonary disease.
AB - Pulmonary radiographs are essential adjuncts to the evaluation and diagnosis of
suspected pulmonary disease. In the intensive care unit, radiographs are useful
to confirm correct positioning of diagnostic and therapeutic devices. Patterns
seen on the radiograph may be within broadly normal limits or may be interpreted
as abnormal, especially when placed in the clinical context of a specific
patient's problem. The description abnormal can be related to both nonspecific
and specific radiographic patterns of disease. Nonspecific radiographic patterns
of disease include location of disease, temporal course of disease, pleural
abnormalities, hyperinflation, extra-alveolar air, atelectasis, bronchiectasis,
and vascular disease. Specific radiographic patterns of disease are discrete
anatomic structures seen on a radiograph, for example, cavitary and cystic
disease. The interpretation of nonspecific and specific radiographic patterns is
useful in diagnosis, selection of treatment, and monitoring of the course of
disease and the patient's response to treatment.
PMID- 9394869
TI - CRF/NPY interactions: a potential role in sleep dysregulation in depression and
anxiety.
AB - Neuropeptide Y (NPY) has neuromodulatory actions on multiple brain functions
including endocrine, behavioral, and circadian processes and has been implicated
in the pathophysiology of both anxiety and depression. Behavioral studies suggest
that NPY is a potent anxiolytic, whereas CRF is anxiogenic, thus it seems that a
balance of these two peptides may exert important influences on behavioral state
regulation. However, little is known about how the NPY/CRF balance affects
general arousal, attention, and/or sleep states. The present study evaluated the
effects of CRF alone, and co-administered with NPY, on spontaneous brain activity
as well as on auditory processing using electrophysiological measures.
Electroencephalographic (EEG) and event-related potentials (ERPs) were obtained
in rats following intracerebroventricular administration of CRF (0.5 microgram)
and CRF (0.5 microgram)/NPY (5.0 or 15 micrograms). Auditory processing, as
assessed by ERPs, was affected most significantly in the frontal cortex where CRF
produced increases in the N1 and P3 components of the ERP, and NPY/CRF co
administration produced significant decreases. These data are consistent with a
role for CRF in hyperarousal, and further suggest that NPY may be capable of
reversing such states. Administration of CRF also produced a significant increase
in the time to sleep onset and a decrease in the amount of time spent in non
rapid eye movement (NREM) sleep as quantified by scoring the EEG paper records.
Co-administration of NPY with CRF reversed the effects of CRF on sleep duration
and sleep onset in a dose-dependent fashion. Spectral analysis revealed that CRF
produced quantitative changes in the EEG that were similar to what has previously
been reported. CRF-induced increases in fast frequency activity were found to be
reversed by co-administration of NPY. Taken together these data suggest that
"dysregulation" of sleep and arousal states in depression and anxiety may be
consistent with an upset of the balance between hypothalamic neuropeptide
systems.
PMID- 9394870
TI - Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: a meta-analysis.
AB - In this analysis we examined studies of tricyclic antidepressants (TCAs) and
selective serotonin reuptake inhibitors (SSRIs) to compare efficacy and drop-out
rates. Frequency of reported side effects was also studied. Using Medline, we
located 36 clinical trials of TCAs and SSRIs in a double-blind comparison. We
performed a meta-analysis on these studies and on a subgroup of 21 studies that
had more uniformly defined outcome criteria. The main outcome measures were
efficacy for treatment completers and for the intention-to-treat group; drop-out
rates due to adverse reactions and lack of efficacy; and reported side effects.
Overall, the response rate to treatment for patients who completed a trial was
63.2% for SSRIs and 68.2% for TCAs (P = 0.038). For the intention-to-treat
groups, these rates dropped to 48.0 and 48.6% (P, NS), respectively.
Significantly more TCA-treated than SSRI-treated subjects dropped out due to
either lack of efficacy or adverse reactions (30.0 vs. 24.7%, P = 0.01). Patients
taking SSRIs experienced significantly more gastrointestinal problems and sexual
dysfunction, whereas treatment with TCAs produced significantly more complaints
of sedation, dizziness, and anticholinergic symptoms.
PMID- 9394871
TI - Dexamethasone suppression test identifies a subset of elderly depressed patients
with reduced platelet serotonin transport and resistance to imipramine inhibition
of transport.
AB - Dysregulation of the hypothalamus-pituitary-adrenal axis (HPA) is more common in
elderly patients with depression than in younger depressed patients, and
glucocorticoids are known to influence serotonergic function. Elderly depressed
patients are also reportedly more resistant to therapeutic effects of
antidepressants. In the current study, we measured platelet serotonin transporter
binding sites and transport function in young and elderly depressed patients and
determined the relationship to HPA status as assessed with the dexamethasone
suppression test (DST). The density and affinity of transporter molecules showed
no differences between young and elderly depressed patients, regardless of DST
results. Nevertheless, transporter function showed a substantial interaction of
aging with DST: elderly DST suppressors showed a deficit in [3H]serotonin uptake
capabilities and resistance to imipramine inhibition of uptake. No such defects
were seen in the young depressed cohort, regardless of DST status, nor in elderly
depressed DST non-suppressors. These results are consistent with the view that
depression in the elderly exhibits basic biological differences from depression
in earlier life, and that such distinctions may account in part for therapeutic
ineffectiveness of antidepressants in specific subgroups, associated with the
presence or absence of appropriate HPA regulation.
PMID- 9394872
TI - Effect size of efficacy measures comparing divalproex, lithium and placebo in
acute mania.
AB - Effect size (ES) is a statistical concept that can be used to improve the
interpretation of results from psychopharmacological studies. ES may aid
interpretation of results when sample size is unbalanced or small or when units
or levels of baseline measures differ across items. Usually, an investigator can
define a threshold value for a clinically meaningful ES based on published data
and clinical judgment or by resorting to conventions, e.g., a medium ES = 0.5
S.D., which can usually be discerned by the trained clinician. In the present
study, we apply ES analysis to results from a study comparing the effectiveness
of divalproex (DIVAL), lithium (LI), and placebo (PLA) in hospitalized, acutely
manic patients. One hundred seventy-six patients were randomly assigned to DIVAL,
LI, or PLA in a 2:1:2 ratio, with drug administered in a double-blind, parallel
group design for 21 days. The primary efficacy measure was the Mania Rating Scale
from the Schedule for Affective Disorders and Schizophrenia, composed of the
Manic Syndrome Score (MSS) from items that are relatively specific to the manic
state, and the Behavior and Ideation Score (BIS), which reflects severe but
nonspecific psychopathology. Improvement of the MSS after 5 days of treatment was
difficult to interpret based on percentage change (DIVAL = 19%, LI = 13.5%, PLA =
8.5%). However, the corresponding effect sizes of 0.79, 0.55, and 0.35 indicated
a medium to marked ES for DIVAL, a medium ES for LI, and a small ES for PLA at
this early point in treatment. Similarly, the ES for change on the MSS at the end
of treatment indicated a large, readily observable improvement with both DIVAL
(ES = 1.01) and LI (ES = 0.79) vs. an ES of 0.37 for PLA. ES analysis also
indicated that the BIS is a less robust indicator of change to either drug. The
ES at the end of treatment for the BIS was 0.67 for DIVAL-, 0.62 for LI-, and
0.25 for PLA-treated patients.
PMID- 9394873
TI - Fluoxetine and concomitant centrally acting medication use during clinical trials
of depression: the absence of an effect related to agitation and suicidal
behavior.
AB - Concomitant use of psychoactive medications is a common practice in most clinical
trials of antidepressant medications. However, the relative therapeutic impact of
such use on trial results has not been the subject of much attention. We
conducted a meta-analysis to determine whether concomitant use of psychoactive
medications confounded the efficacy or safety results of a series of fluoxetine
trials. Data were evaluated from 25 randomized, double-blind clinical trials
comparing fluoxetine with placebo or a tricyclic antidepressant (TCA) in 4,016
patients with major depression. We compared incidence rates of concomitant use of
anxiolytics, sedatives, and antipsychotics between treatments. In addition, we
compared the change in total score for the 21-Item Hamilton Depression Rating
Scale (HAMD21): incidence rates of any worsening, emergence, or improvement in
psychomotor agitation; and incidence of suicidal acts and any worsening,
emergence, or improvement in suicidal ideation between treatment groups among
patients taking/not taking a sedative. Anxiolytic and antipsychotic drug use was
uncommon (8.3% and 0.9% overall use, respectively) and did not substantially
increase over time. Sedative drugs were used most often (29.6% overall), but only
29.8% of the fluoxetine-treated patients took one or more doses. Regarding
efficacy, fluoxetine was superior to placebo in decreasing HAMD21 total scores
among patients taking/not taking sedatives. Effects on safety were assessed by
examining agitation and suicidal ideation. Use of sedatives did not affect the
change in the HAMD agitation score; scores were similar in patients receiving
fluoxetine, placebo, and TCAs. In all treatment groups, anxiolytic use tended to
increase as the HAMD anxiety score increased. Fluoxetine was superior to placebo
in treating suicidal ideation, and the concomitant use of sedatives did not
influence this effect. Overall, concomitant use of psychotropic medications in
the fluoxetine depression clinical trials was uncommon. Our meta-analysis
demonstrated that the clinical efficacy and safety of fluoxetine were not
confounded by the concomitant use of medications.
PMID- 9394874
TI - Psychotic versus nonpsychotic depression in hospitalized adolescents.
AB - One hundred fifty adolescent inpatients with major depression were systematically
assessed for demographic and clinical differences between psychotic and
nonpsychotic depression. Delusions and/or hallucinations were present in 10% of
the subjects. The psychotic group had significantly more frequent and severe
suicidal ideation. Posttraumatic stress disorder was also more frequent in the
psychotic group.
PMID- 9394877
TI - The issue of extralabel drug use.
PMID- 9394878
TI - Help wanted: ultrasonographers.
PMID- 9394879
TI - Peer review of case management skills in clinical veterinary medicine--is it
time?
PMID- 9394880
TI - Clinical relevance of intestinal reperfusion injury in horses.
PMID- 9394881
TI - What is your diagnosis? Avulsion fracture of the proximal suspensory ligament and
the third metacarpus.
PMID- 9394882
TI - Myocardial necrosis and sudden death after an episode of aggressive behavior in a
dog.
PMID- 9394883
TI - Animal behavior case of the month.
PMID- 9394884
TI - Multimedia case-simulation computer program for teaching veterinary nutrition.
PMID- 9394885
TI - Communicating with clients--informed consent.
PMID- 9394886
TI - How important is intestinal reperfusion injury in horses?
PMID- 9394887
TI - Concentration of ionized calcium in plasma from cats with urethral obstruction.
AB - OBJECTIVE: To measure ionized calcium concentration in plasma from cats with
urethral obstruction and to correlate these values with results of clinical
biochemical analyses and physical examinations. DESIGN: Prospective study.
ANIMALS: 24 male cats. PROCEDURE: Blood samples were obtained from each cat on
admission, and PCV, pH, and concentrations of ionized calcium, total calcium,
glucose, total solids, sodium, potassium, BUN, creatinine, chloride, magnesium,
albumin, and phosphorus were determined. Mentation, tissue perfusion, and ECG
recordings were also assessed. RESULTS: 18 (75%) cats had low ionized calcium
concentrations (reference range, 2.4 to 2.8 mEq/L). Hypocalcemia was considered
mild (2.0 to 2.36 mEq/L) in 9 (37.5%) cats, moderate (1.6 to 1.98 mEq/L) in 6
(25%), and severe (< 1.6 mEq/L) in 3 (12.5%). Significant positive correlations
were found between ionized calcium concentration and heart rate, pH, and
concentrations of sodium, chloride, and total calcium. Significant negative
correlations were found between ionized calcium concentration and concentrations
of potassium, BUN, creatinine, and phosphorus. CLINICAL IMPLICATIONS: Most cats
with urethral obstruction had a low concentration of ionized calcium. This may
contribute to cardiac electrical and mechanical dysfunction in some severely
affected cats. Although effects of i.v. administration of calcium were not
evaluated, results of this study strengthen the rationale for its use in cats
with urethral obstruction.
PMID- 9394888
TI - Measurement of serum total thyroxine, triiodothyronine, free thyroxine, and
thyrotropin concentrations for diagnosis of hypothyroidism in dogs.
AB - OBJECTIVE: To determine whether measurement of baseline serum concentrations of
total thyroxine (T4), and triiodothyronine (T3), free T4, and thyrotropin
(thyroid-stimulating hormone; TSH) would aid in the diagnosis of hypothyroidism
in dogs. DESIGN: Prospective case series. ANIMALS: 54 dogs with hypothyroidism,
54 euthyroid dogs with nonthyroidal disease initially suspected to have
hypothyroidism, and 150 clinically normal dogs. PROCEDURE: In the 54 dogs with
hypothyroidism, diagnosis was established on the basis of clinical signs, results
of routine laboratory and TSH stimulation tests, exclusion of concurrent
nonthyroidal disease, and a good clinical response to treatment with L-thyroxine.
Blood samples were collected from all dogs and were tested for thyroid hormone
and TSH concentrations. Reference ranges for hormone concentrations were
established on the basis of results for the 150 clinically normal dogs. RESULTS:
Of the 54 hypothyroid dogs, 48 (89%) had low total T4 concentrations, 3 had low
normal concentrations, and 3 had high concentrations because of T4
autoantibodies. In contrast, only 10 (18%) euthyroid dogs had low total T4
concentrations. Only 3 of 31 (10%) hypothyroid dogs had low T3 concentrations; 23
had concentrations within the reference range, and 5 had high concentrations
because of T3 autoantibodies. Only 3 of 38 euthyroid dogs had low T3
concentrations. Of the hypothyroid dogs, 53 (98%) had low free T4 concentrations
and 1 had a low-normal concentration. Only 4 (7%) euthyroid dogs had low free T4
concentrations. Of the hypothyroid dogs, 41 (76%) had high TSH concentrations,
and 13 had TSH concentrations within the reference range. Of the euthyroid dogs,
only 4 (8%) had high TSH concentrations. Of all single hormone measurements
evaluated, measurement of free T4 concentration had the highest sensitivity
(0.98), specificity (0.93), and accuracy (0.95) as a test for hypothyroidism;
measurement of total T4 concentration had a lower sensitivity (0.89), specificity
(0.82), and accuracy (0.85). Compared with measurement of total or free T4
concentration, measurement of TSH concentration had a lower sensitivity (0.76)
and accuracy (0.84) but specificity (0.93) equal to that for measurement of free
T4 concentration. When T4 (total or free) and TSH concentrations were evaluated
together, specificity was higher than when T4 or TSH concentration was evaluated
alone. Only 1 euthyroid dog had low T4 (total and free) and high TSH
concentrations. CLINICAL IMPLICATIONS: Results indicate that measurement of serum
free T4 and TSH concentrations is useful for diagnosis of hypothyroidism in dogs.
About a quarter of the dogs with confirmed hypothyroidism, however, will have
serum TSH concentrations within reference limits.
PMID- 9394889
TI - Regional anesthesia of the infraorbital and inferior alveolar nerves during
noninvasive tooth pulp stimulation in halothane-anesthetized dogs.
AB - OBJECTIVE: To document that regional anesthesia of the infraorbital and inferior
alveolar nerves would abolish reflex-evoked muscle action potentials (REMP) in
the digastricus muscle during noninvasive stimulation of tooth pulp in halothane
anesthetized dogs. DESIGN: Prospective study. ANIMALS: 9 healthy female dogs
between 2 and 6 years old. PROCEDURE: Dogs were anesthetized using halothane. An
alligator clip anodal electrode was attached to the tooth to be stimulated, and a
platinum needle cathodal electrode was inserted in adjacent gingival mucosa. The
cathodal and anodal electrodes were moved to the left upper and lower canine,
fourth premolar, and first molar teeth for sequential stimulation. Baseline
recording of REMP was made for each tooth. Catheters were inserted percutaneously
in the infraorbital and mandibular canals. Saline (0.9% NaCl) solution was
injected at each catheterized site in 3 control dogs, and chloroprocaine
hydrochloride was injected at each catheterized site in 6 test dogs. Each tooth
was stimulated every 10 minutes for 90 minutes (test dogs) or every 10 minutes
for 30 minutes and at 90 minutes (control dogs), and REMP was recorded. RESULTS:
REMP was abolished within 10 minutes in all test dogs, except during stimulation
of the lower first molar in 1 dog. In 4 dogs, duration of blockade was less than
90 minutes. The REMP was not restored within 90 minutes for the upper teeth in 1
dog and within 2 hours for all teeth in another dog. At 24 hours, REMP was
restored for all teeth except the lower left canine in 1 dog. The REMP was
restored for the lower left canine in that dog at 96 hours. The REMP was not
abolished at any time in control dogs. CLINICAL IMPLICATIONS: Regional anesthesia
of the infraorbital and inferior alveolar nerves may effectively provide
analgesia for dental procedures in dogs.
PMID- 9394890
TI - Risk factors for acquired megaesophagus in dogs.
AB - OBJECTIVE: To identify risk factors associated with acquired megaesophagus in
dogs. DESIGN: Case-control study. ANIMALS: 136 dogs with acquired megaesophagus
(case dogs); 272 dogs from the general hospital population and 151 dogs that
underwent thyroid-stimulating hormone response tests (control dogs). All dogs
were more than 6 months old. PROCEDURE: Medical records of dogs in which
megaesophagus was diagnosed during a 10-year period were reviewed. Inclusion
criteria included regurgitation or vomiting, onset of clinical signs at more than
6 months of age, and radiographic evidence of generalized esophageal dilatation.
Dogs with intra- or extraesophageal obstructive disease, brain stem disease, or
neck trauma were excluded from analyses. Statistical analyses included odds
ratios, 95% confidence intervals, and two-tailed t-tests. Control dogs were
frequency matched to case dogs on the basis of year of diagnosis. RESULTS: Dogs
with megaesophagus ranged from 0.75 to 18 years old (mean, 8.1 years) and were
significantly older and heavier than control dogs. More males than females were
affected, but sex and reproductive status were not associated with megaesophagus.
German Shepherd Dogs, Golden Retrievers, and Irish Setters were at increased risk
for developing megaesophagus. Peripheral neuropathies, laryngeal paralysis,
acquired myasthenia gravis, esophagitis, and chronic or recurrent gastric
dilatation with or without volvulus were associated with an increased risk of
developing megaesophagus. Hypothyroidism was not associated with megaesophagus.
CLINICAL IMPLICATIONS: Dogs with acquired megaesophagus should be evaluated for
peripheral neuropathies, laryngeal paralysis, acquired myasthenia gravis,
esophagitis, and chronic or recurrent gastric dilatation with or without
volvulus. These dogs may be evaluated for hypothyroidism; however, this study did
not reveal a clear association between hypothyroidism and acquired megaesophagus.
PMID- 9394892
TI - Complete deletion of factor IX gene and inhibition of factor IX activity in a
labrador retriever with hemophilia B.
AB - Hemophilia B is a heritable bleeding disorder caused by mutations in the gene
coding for coagulation factor IX. The defect has been identified in purebred and
mixed-breed dogs. Management of affected dogs requires transfusion of canine
blood products supplying active factor IX. Production of inhibitors to factor IX
is a complication of transfusion therapy that has been documented as affecting
human patients. Risk for producing coagulation inhibitors is greatest for
patients having large factor IX gene deletions. To our knowledge, this is the
first report of canine factor IX inhibitor production in dogs. The affected dog
had clinically severe hemophilia B caused by complete deletion of the factor IX
gene and developed resistance to transfusion. Comprehensive evaluation of
hemophilic dogs, including assays of specific factor activity, concentration, and
factor inhibition, enhances diagnosis and management of this bleeding disorder.
Characterization of the molecular defect causing hemophilia is useful for genetic
counseling and identifying individuals at highest risk for producing coagulation
inhibitors.
PMID- 9394891
TI - Multicenter clinical comparison of sedative and analgesic effects of medetomidine
and xylazine in dogs.
AB - OBJECTIVE: To evaluate analgesic and sedative effects of medetomidine
hydrochloride in dogs and to compare effects with those of xylazine
hydrochloride. DESIGN: Randomized, controlled trial. ANIMALS: 184 dogs that
required sedation or analgesia for completion of minor diagnostic or therapeutic
procedures. PROCEDURE: Dogs were sedated with medetomidine, i.v. (750
micrograms/m2 of body surface area) or i.m. (1,000 micrograms/m2) or with
xylazine, i.v. (1.1 mg/kg 10.5 mg/lb] of body weight) or i.m. (2.2 mg/kg [1
mg/lb]). Sedative effects were measured by scoring posture and response to noise.
Durations of effects were determined by measuring time intervals between drug
administration and changes in posture. Analgesic effects were measured by
determining toe-pinch pressure needed to elicit a withdrawal response. Clinicians
rated sedative and analgesic effects and ease with which diagnostic or
therapeutic procedures could be performed. RESULTS: Posture and response to noise
scores were significantly higher for dogs given medetomidine, i.m., than for dogs
given xylazine, i.m., and for dogs given medetomidine, i.v., than for dogs given
xylazine, i.v. Time to regaining sternal recumbency and time to regaining ability
to stand were longest after i.m. administration of medetomidine. Toe-pinch
pressures were not significantly different among groups. Clinicians rated overall
analgesic and sedative effects as excellent significantly more often after
administration of medetomidine than after administration of xylazine. Prevalence
of adverse effects did not differ among groups. CLINICAL IMPLICATIONS:
Medetomidine and xylazine, at doses tested, were effective and safe, but results
of subjective measurements indicated that medetomidine provided better sedation
and analgesia than did xylazine. Specific alpha 2-adrenergic antagonists
(atipamezole, yohimbine) are available for control of adverse cardiovascular
effects.
PMID- 9394893
TI - Evaluation of prognostic factors for dogs with primary lung tumors: 67 cases
(1985-1992).
AB - OBJECTIVE: To determine associations between clinical and histologic factors in
dogs with primary lung tumors and outcome and to develop a histologic grading
method for primary lung tumors. DESIGN: Retrospective study. ANIMALS: 67 dogs
undergoing thoracotomy and lobectomy for primary lung tumors. PROCEDURE: Medical
records and histologic sections were reviewed to evaluate factors of prognostic
importance. Association of these factors with disease-free interval (DFI) and
survival time was evaluated, using the Cox proportional hazards model. Median DFI
and survival time were determined, using the Kaplan-Meier product-limit method.
RESULTS: Clinical and histologic factors significantly associated with prognosis
were histologic score, detection of clinical signs, and metastasis to regional
lymph nodes. On the basis of histologic score, a histologic grading method was
developed. Dogs with well-differentiated tumors had significantly longer survival
time and DFI (median DFI, 493 days) than dogs with moderately (median DFI, 191
days) or poorly (median DFI, 0 days) differentiated tumors. Dogs with clinical
signs or metastasis to regional lymph nodes had shorter survival times and DFI
than dogs in which lung masses were discovered as an incidental finding. CLINICAL
IMPLICATIONS: Dogs with well-differentiated, nonmetastasized, primary lung tumors
that do not have clinical signs associated with the tumor have a favorable
prognosis. Dogs with more advanced disease or aggressive tumors histologically
may require treatment, such as chemotherapy in combination with surgery. The
grading method proposed here for primary lung tumors may be useful in other dogs
with primary lung tumors.
PMID- 9394894
TI - Risk factors for acquired myasthenia gravis in dogs: 1,154 cases (1991-1995).
AB - OBJECTIVE: To determine frequency of initial clinical signs and risk factors for
acquired myasthenia gravis (MG) in dogs. DESIGN: Retrospective study. SAMPLE
POPULATION: 1,154 dogs residing within the United States from 1991 to 1995 with a
confirmed diagnosis of acquired MG and 7,176 dogs with other neuromuscular
disorders, including generalized weakness, megaesophagus, and dysphagia (control
group). PROCEDURE: Records were retrieved from a database containing results of
serum samples tested for acetylcholine receptor antibodies. Signalment, breed,
age, state of origin, and month of onset of clinical signs were obtained. An
antibody titer > 0.6 nmol/L was diagnostic for acquired MG. Unconditional
logistic regression was used for statistical analysis. RESULTS: In comparison
with mixed-breed dogs, dogs with the highest risk of acquired MG were Akitas,
terrier group, Scottish Terriers, German Shorthaired Pointers, and Chihuahuas.
Rottweilers, Doberman Pinschers, Dalmatians, and Jack Russell Terriers had low
relative risks. Sexually intact males and dogs less than 1 year old had some
protection from risk. Generalized weakness with megaesophagus and megaesophagus
alone were the most common initial clinical signs. CLINICAL IMPLICATIONS: Breed
predispositions for acquired MG were demonstrated. Age and sex were contributing
factors. Although most dogs had generalized clinical signs, a substantial
proportion of dogs had focal signs.
PMID- 9394895
TI - Renal transplants in cats: 66 cases (1987-1996).
AB - OBJECTIVE: To document the morbidity and survival time after renal transplants in
cats with end-stage renal failure. DESIGN: Retrospective case series. ANIMALS: 66
cats that had renal transplants. PROCEDURE: Information regarding signalment,
history, diagnostic testing, and postoperative morbidity and mortality was
retrieved from medical records of cats with renal failure that had renal
transplants at the University of California School of Veterinary Medicine between
1987 and 1996. RESULTS: 47 of 66 (71%) cats that had renal transplants survived
until discharge. Nineteen cats died in the perioperative period. Most common
causes of death were seizure-related complications (7 cats) and renal pedicle
complications (4). One discharged cat was unavailable for follow-up monitoring.
Of the 46 cats discharged and available for follow-up monitoring, 28 died. Most
common causes of death in these cats were renal complications (9 cats) and death
related to immunosuppression (8; mean and median survival times, 15 and 12
months, respectively). Of the 18 cats that were still living at the time this
report was written, mean and median survival times were 26 and 22 months,
respectively. CLINICAL IMPLICATIONS: Renal transplantation resulted in long-term
survival of many cats that would have otherwise died from, or have been
euthanatized as a result of, renal failure. Problems with ureteral obstruction
can be minimized. Postoperative CNS disorders were the most prevalent
complication.
PMID- 9394896
TI - Mechanisms of intestinal mucosal repair.
PMID- 9394897
TI - Respiratory function parameters in infants using inductive plethysmography.
AB - A signal processing technique has been developed to determine respiratory
function parameters by processing displacement data obtained from the abdomen and
the rib cage of infants using respiratory inductive plethysmography. The
technique transforms time-variant signals into the frequency domain, where they
are filtered to reduce unwanted signal components. The phase relationship between
the abdominal displacement and the rib cage displacement is determined from the
phases of the filtered signals. Flow-volume loops, which are currently of great
interest in respiratory medicine, are obtained from waveforms representing
respiratory tidal flow and respiratory tidal volume. The index of respiratory
timing is determined from a waveform representing respiratory tidal flow. The
technique has been verified by statistical comparison with data simultaneously
obtained using pneumotachography in a clinical study involving 49 infants.
PMID- 9394898
TI - Estimating the effective Young's modulus of soft tissues from indentation tests-
nonlinear finite element analysis of effects of friction and large deformation.
AB - A nonlinear finite element model was developed to investigate the biomechanics of
indentation, particularly the influence of friction and large deformation on the
calculation of the effective Young's modulus from the cylindrical, flat-ended
indentation test of soft tissues. A new kappa table was given for calculation of
the effective Young's modulus to account for the effects of layered geometry with
consideration of the larger deformation. The results indicate that the effect of
friction on the calculation of Young's modulus becomes significant with a large
aspect ratio and with a large Poisson's ratio. It is found that the factor kappa
increases almost proportionally to the increase of the indentation depth,
especially obvious with a larger Poisson's ratio v and a larger aspect ratio a/h.
PMID- 9394899
TI - A stiffness-varying model of human gait.
AB - We report on a conceptual two degrees of freedom (2 DOF) human gait model, which
incorporates nonlinear joint stiffness as a stabilizing agent. Specifically,
muscle spring-like property provides inherent stability during gait movement
using a nonlinear angular spring and dash pot at each joint. The instability
problem of the gait model in direct dynamic analysis is overcome by simulating
the human co-contraction muscle function. By developing dynamic system stability
requirements and hypothesizing a minimum joint stiffness criterion, we determine
time-varying joint stiffness. Optimum joint stiffnesses are present for varying
gait pattern, stride lengths and cadences. We conclude that nonlinear joint
stiffness can be incorporated into gait models to overcome stability problems
inherent in such linkage models.
PMID- 9394901
TI - Modelling and simulation of the hand grasping using neural networks.
AB - In this paper we present preliminary results of a study on the use of artificial
neural networks to model and simulate the hand grasping. Results of this study
will provide a basic understanding of the co-ordination and control of multiple
degrees of freedom upper limb prosthetic devices and robotic end effectors when
interacting with the environment. We assumed the hand to be a black box with the
inputs being the object and simulation time sequence, whilst the output is the
grasping postures over time. We trained the network with samples of key postures
of the hand grasping several object shapes and sizes. The back-propagation
technique was used to update the weights of the network. We found that the neural
network is able to reproduce the postures of the hand grasping objects of
different shapes and sizes from a single set of neural network weights.
PMID- 9394900
TI - Apparatus and methods for studying artificial feedback-control of the
plantarflexors in paraplegics without interference from the brain.
AB - Apparatus has been built to explore the practical feasibility of using automatic
control with electrical stimulation of paralysed legs to restore function. The
experiments are performed with paraplegics with the aim of achieving a realistic
postural task: to see whether the body may be maintained upright by stimulation
of the plantarflexors when the other joints are braced. Significantly, the intact
upper body, under natural control of the brain, cannot interfere with the
automatic control. The "Wobbler" apparatus allows measurement of the ankle muscle
properties in isometric conditions or in sinusoidal motion. Using the
biomechanical properties of the body, which are also measured, controllers for
stabilising the body can be designed. Controllers can be dynamically tested,
imitating anterior-posterior sway, while the body is held upright, before "actual
standing" is attempted.
PMID- 9394902
TI - Comparison of loads on internal spinal fixation devices measured in vitro and in
vivo.
AB - The loads on internal spinal fixation devices were measured using modified,
telemeterized AO-Dick internal fixators. The implants allow measurement of the
three force components and the three moments acting on the implant. The modified
fixators were mounted on cadaver spines, and the implant loads were measured in
the intact and postcorpectomy spines for different loading modes, including axial
compression force, flexion, extension, lateral bending, and torsion. The in vitro
experiment did not consider muscle forces. Modified fixators were also implanted
in three patients, and the implant loads were determined before and after
anterior interbody fusion with autologous iliac-crest bone grafts. The results
for different in vitro loading modes were compared with those in vivo in order to
demonstrate the extent to which the in vitro loads represent the real situation
in patients. In several cases, the implant loads in the in vitro experiment
differed strongly from those measured in patients. For flexion and lateral
bending, a tensile axial force occasionally was measured in the in vitro
experiment, while in the patients the axial force was always compressive.
Extension was predominantly associated with extension bending moments in the in
vitro study but with flexion bending moments in the patients. When muscle forces
are not considered in the in vitro experiment, the loads on the fixators may
differ significantly from the situation found in patients.
PMID- 9394903
TI - A model study of periodic breathing, stability of the neonatal respiratory
system, and causes of sudden infant death syndrome.
AB - A mathematical model of the neonatal respiratory system has been modified and
used to examine the system under various physiological conditions at different
stages of maturity. The respiratory responses in hypoxia, periodic breathing and
following a sign have been analyzed. The effects of different respiratory
parameters on the stability of the system for normal and premature infants have
been investigated. The causes of periodic breathing, apnea spells and sudden
infant death syndrome for full-term and premature infants have been studied, and
the results compared with the available experimental findings. The response of
the infant respiratory system has been found to be highly sensitive to several
parameters of the system, as indicated by the results of this study. These
significant parameters are sensitivity factor of central receptors to carbon
dioxide, sensitivity factor of arterial receptors to carbon dioxide, sensitivity
factor of arterial receptors to oxygen, functional residual capacity of the
lungs, the alveolar-arterial oxygen difference and the lungs shunt ratio. It has
been shown that different parts of the respiratory controller have antagonistic
effects on hypoxic periodic breathing and apnea of infancy.
PMID- 9394904
TI - Predicting the leakage performance of small bodyworn disposable incontinence pads
using laboratory tests.
AB - An international multi-centre project has been run to create an international
standard for measuring the leakage performance of small, disposable incontinence
pads for lightly incontinent women. One hundred and thirteen women tested batches
of nine different incontinence pads of widely differing designs and noted the
severity with which each individual used pad had leaked so that leakage
performance could be determined as a function of urine weight. In addition,
testers rated the overall leakage performance of each of the nine products on a
five-point scale. These clinical data were compared with laboratory data from 153
different pad measurements, each of which was evaluated by seeing how well the
data it yielded correlated with the clinical test data. A wetback test emerged as
the clear winner. It usually predicted the clinical leakage performance of pads
to an accuracy of +/- 10%. It involved applying 25 ml of 1% w/v saline to a pad
and measuring how much escaped into a filter paper held against the wet pad for 1
min under a pressure of 1.5 kPa. Pads which released the least test fluid into
the filter paper leaked least in the user tests. The method will be published as
an ISO standard during 1997.
PMID- 9394905
TI - Data compression of fetal Doppler ultrasound audio signals using zero-crossings
analysis.
AB - This paper outlines a method of reducing the data rate for transmitting fetal
Doppler ultrasound audio signals. A specific application is cited where
compression of the fetal Doppler signal is required to transmit information to
cardiotocographs (CTGs) using radio telemetry. The method involves splitting the
signal into amplitude and frequency components. The amplitude is represented by
samples of the signal envelope whilst the frequency information is represented by
the number of zero-crossings within fixed intervals (windows). With a careful
choice of window size, it is shown that this method can be used to reproduce the
signal with no audible difference when compared with the original waveform. A
reduction in data rate of 15:1 is achieved.
PMID- 9394906
TI - Time-frequency distribution of heart rate variability below 0.05 Hz by Wigner
Ville spectral analysis in congestive heart failure patients.
AB - The Wigner-Ville spectral analysis was utilized to demonstrate a high-resolution
time-frequency distribution of heart rate variability below 0.05 Hz. There are
different time-frequency characteristics between the normal subject and the
patient with severe congestive heart failure. The former consists of multiple and
broad-band spectral peaks, while the latter presents unique spectral peaks. Based
on Bayes theory, a classifier for the unique spectral peaks was developed. After
the beneficial improvement with low-dose beta-blockers, the unique spectral peaks
had disappeared or the time of occurrence was reduced in most patients.
PMID- 9394907
TI - Three-dimensional stress analysis of polypropylene leaflets for prosthetic heart
valves.
AB - The effect of changing the modulus and thickness of the material in the leaflets
of an artificial heart valve has been investigated. This has been achieved with a
finite element model of the valve having approximately 2300 thin shell elements.
The valve motion and the resulting stresses are modelled dynamically during
closure, and subsequent pressurisation. The stresses decrease as the leaflets are
made thicker and the modulus is increased. Local and global thickening has been
investigated. The highest stresses appear at the tops of the stent posts in the
regions of the commissures. When the modulus is too low, or the leaflets are too
thin, the valve prolapsed.
PMID- 9394908
TI - High-risk superficial bladder cancer: transurethral resection alone in selected
patients with T1 tumor.
PMID- 9394909
TI - High-risk superficial bladder cancer: intravesical therapy for T1 G3 transitional
cell carcinoma of the urinary bladder.
AB - The ideal treatment for T1 G3 transitional cell carcinoma (TCC) of the urinary
bladder remains controversial. Therapeutic options after the initial
transurethral (TUR) resection are observation, intravesical therapy, a repeat
resection, radiation therapy, and cystectomy. Because more than half of patients
with T1 G3 TCC of the urinary bladder do not progress, initial cystectomy can
represent overtreatment. However, observation alone following TUR for T1 G3 TCC
of the urinary bladder is associated with a progression rate of 48%. Intravesical
immunotherapy has been shown to decrease recurrence and progression in high-grade
Ta carcinoma in situ and T1 bladder cancer. When patients with T1 G3 tumors are
well selected, intravesical therapy following the initial TUR can significantly
improve survival and quality of life. Persistence or recurrence of high-grade
tumor mandates consideration of cystectomy.
PMID- 9394910
TI - Early cystectomy for clinical stage T1 transitional cell carcinoma of the
bladder.
AB - Early radical cystectomy for a high-grade tumor invading the lamina propria (T1)
remains controversial. In 1997, we cannot identify accurately which of these high
risk tumors will progress to muscle-invasive disease and metastases. In the near
future, urologists may be able to use the presence of genetic alterations, such
as p53 mutations, to help make therapeutic decisions. Previous reports on
superficial bladder cancer treated with intravesical bacillus Calmette-Guerin
immunotherapy have demonstrated a decrease in recurrence and progression.
Unfortunately, there is no reliable method to predict which patients with a high
grade T1 tumor will fail to respond to intravesical therapy. Failure of
intravesical therapy to control these aggressive tumors is associated with a
significant rate of pathological upstaging and metastases. Radical cystectomy
will cure a high percentage of these T1 tumors with acceptable morbidity and low
mortality. In an era of nerve-sparing cystectomy and orthotopic neobladder
reconstruction, early radical cystectomy is an alternative that should be
discussed with the patient before instituting intravesical therapy.
PMID- 9394911
TI - The case for radiotherapy with or without chemotherapy in high-risk superficial
and muscle-invading bladder cancer.
AB - The standard treatment for superficial high-grade bladder cancer is transurethral
resection with or without subsequent intravesical therapy. Although a few series
have reported good local control rates for T1 tumors, using either external beam
irradiation or brachytherapy, this does not represent the standard of care in the
United States. External beam radiation may be attempted in patients whose tumors
cannot be resected transurethrally and who refuse cystectomy. The case for
radiotherapy with or without chemotherapy is far stronger in muscle-invading
cancers. Overall survival rates around 50% have been reported in larger series
from a number of major centers. Most of these 5-year survivors retain their
native bladders. The bladder morbidity of such an approach is very low. There are
several studies currently active to determine the most appropriate sequence and
combination of drugs and radiation.
PMID- 9394912
TI - Superficial bladder cancer: the role of molecular markers in the treatment of
high-risk superficial disease.
AB - The use of molecular markers to guide decision making in the treatment of high
risk superficial disease is in its infancy. At present, p53 expression and
epidermal growth factor receptor expression have been studied in greatest depth.
The abundance of potential markers and our greater understanding of cellular
pathophysiology suggest that molecular markers with significant stratifying power
beyond that provided by standard histology shall be identified in the near
future.
PMID- 9394913
TI - Continent cutaneous urinary diversion.
AB - Using the case history of a 57-year-old woman with a G3 T1 bladder cancer as a
reference point, general considerations on tumor biology and therapeutic choices
are reviewed. Options for urinary tract diversion or reconstruction are
presented. This author recommends radial cystectomy for this patient with
continent cutaneous urinary diversion, the Indiana pouch. Important technical
points of the surgical procedure are emphasized.
PMID- 9394914
TI - Orthotopic diversion in women.
AB - An orthotopic neobladder has quickly become the preferred diversion after
cystectomy in most women. The decision to proceed with a cystectomy for high
grade, superficially invasive transitional cell carcinoma is frequently difficult
for the patient and physician alike. The availability of an orthotopic diversion
to provide an excellent voiding pattern and continence may tip the scale toward
earlier cystectomy with anticipated excellent cancer control.
PMID- 9394915
TI - Comparison of the ileal conduit to the continent cutaneous diversion and
orthotopic neobladder in patients undergoing cystectomy: a critical analysis and
review of the literature.
AB - In recent years, many investigators have devised innovative urinary diversions to
improve the quality of life of patients requiring urinary diversions after
cystectomy. In this article, we report a literature review in which we compare
the outcomes of patients receiving an ileal conduit to those receiving either a
continent cutaneous diversion or an orthotopic neobladder. In this discussion, we
analyze the data in the literature that pertains to quality of life, incontinence
rates, and metabolic complications. We conclude that although the newer urinary
diversions are promising, randomized prospective trials comparing patients
receiving these diversions to those receiving an ileal conduit need to be
performed.
PMID- 9394916
TI - Nursing issues in the management of urinary diversions in women.
AB - Cancer and urinary diversion via orthotopic or cutaneous stomas in women result
in significant physiological and psychosocial issues. Patient counseling,
education, and follow-up care are best achieved by the intervention of a
multidisciplinary health care team. Urologic and enterostomal therapy nursing
support in these endeavors can contribute to facilitating a positive outcome.
PMID- 9394917
TI - Role of Rab GTPases in membrane traffic.
AB - Small GTPases of the Rab subfamily have been known to be key regulators of
intracellular membrane traffic since the late 1980s. Today this protein group
amounts to more than 40 members in mammalian cells which localize to distinct
membrane compartments and exert functions in different trafficking steps on the
biosynthetic and endocytic pathways. Recent studies indicate that cycles of GTP
binding and hydrolysis by the Rab proteins are linked to the recruitment of
specific effector molecules on cellular membranes, which in turn impact on
membrane docking/fusion processes. Different Rabs may, nevertheless, have
slightly different principles of action. Studies performed in yeast suggest that
connections between the Rabs and the SNARE machinery play a central role in
membrane docking/fusion. Further elucidation of this linkage is required in order
to fully understand the functional mechanisms of Rab GTPases in membrane traffic.
PMID- 9394918
TI - Lignification in plant cell walls.
AB - Cell wall lignification is a complex process occurring exclusively in higher
plants; its main function is to strengthen the plant vascular body. This process
involves the deposition of ill-defined phenolic polymers, the so-called lignins,
on the extracellular polysaccharidic matrix. These polymers arise from the
oxidative coupling of three cinnamyl alcohols in a nonrandom reaction, in which
cell wall polysaccharides appear to influence the freedom of cinnamyl alcohol
radicals, giving rise to a highly orchestrated process. This review is focused on
the most recent advances in the chemical, biochemical, cytological,
physiological, and evolutive aspects of cell wall lignification. As we shall see
throughout this review, there are still some open questions to be answered which
may serve as the basis of future endeavors.
PMID- 9394919
TI - Functional interactions among cytoskeleton, membranes, and cell wall in the
pollen tube of flowering plants.
AB - The pollen tube is a cellular system that plays a fundamental role during the
process of fertilization in higher plants. Because it is so important, the pollen
tube has been subjected to intensive studies with the aim of understanding its
biology. The pollen tube represents a fascinating model for studying interactions
between the internal cytoskeletal machinery, the membrane system, and the cell
wall. These compartments, often studied as independent units, show several
molecular interactions and can influence the structure and organization of each
other. The way the cell wall is constructed, the dynamics of the endomembrane
system, and functions of the cytoskeleton suggest that these compartments are a
molecular "continuum," which represents a link between the extracellular
environment and the pollen tube cytoplasm. Several experimental approaches have
been used to understand how these interactions may translate the pollen-pistil
interactions into differential processes of pollen tube growth.
PMID- 9394920
TI - Biology of the postsynaptic glycine receptor.
AB - Glycine is one of the major inhibitory neurotransmitters, and upon binding to its
receptor it activates chloride conductances. Receptors are accumulated
immediately opposite release sites, at the postsynaptic differentiations, where
they form functional microdomains. This review describes recent advances in our
understanding of the structure-function relationships of the glycine receptor, a
member of the ligand-gated ion channel superfamily. Following purification of the
receptor complex and identification of its integral and peripheral membrane
protein components, molecular cloning has revealed the existence of several
subtypes of the ligand-binding subunit. This heterogeneity is responsible for the
distinct pharmacological and functional properties displayed by the various
receptor configurations that are differentially expressed and assembled during
development. This review also focuses on the molecular aspects of glycinergic
synaptogenesis, highlighting gephyrin, the peripheral component of the receptor.
The role of this cytoplasmic protein in anchoring and maintaining the channel
complex in postsynaptic clusters is discussed. The glycine receptor recently
moved into the spotlight as a paradigm in the approach to cell biology of the
formation of the postsynaptic membrane.
PMID- 9394921
TI - Cell fate specification by localized cytoplasmic determinants and cell
interactions in ascidian embryos.
AB - Tadpole larvae of ascidians show the basic body plan of chordates. An ascidian
larva consists of only a few types of cells and has a relatively small number of
cells. Cell lineages are invariant among individuals and have been described in
detail. These advantages facilitate the analysis of how the fate of each
blastomere becomes specified during development. Over a century of research on
ascidian embryogenesis has uncovered many interesting features concerning
cellular mechanisms responsible for the fate specification. During embryogenesis,
the developmental fate of a blastomere is specified by one of three different
mechanisms: localized maternal cytoplasmic determinants, inductive interactions,
or lateral inhibition in an equivalence cell group.
PMID- 9394922
TI - Distribution of Na+,K(+)-ATPase in photoreceptor cells of insects.
AB - Light stimulation of insect photoreceptors causes opening of cation channels and
an inward current that is partially carried by Na+ ions. There is also an efflux
of K+ ions upon photostimulation. Na+ and K+ gradients across the photoreceptor
membrane are reestablished by the activity of the enzyme Na+,K(+)-ATPase. About
two-thirds of the total amount of ATP consumed in response to a light stimulus is
attributed to the activity of this ion pump, demonstrating the importance of this
enzyme for photoreceptor function. Insect photoreceptor cells are polarized
epithelial cells; their plasma membrane is organized into two domains having a
distinct morphology, molecular composition, and function. The visual pigment
rhodopsin and the molecular components of the transduction machinery are
localized in the rhabdomere, an array of densely packed microvilli, whereas
Na+,K(+)-ATPase resides in the nonrhabdomeric membrane. Comparative
immunolocalization studies on compound eyes of diverse insect species have
demonstrated subtle variations in the distribution patterns of Na+,K(+)-ATPase.
These may be accounted for by differences in the mechanisms responsible for
Na+,K(+)-ATPase positioning.
PMID- 9394923
TI - Infertility and in vitro fertilization. A growing need for consumer-oriented
regulation of the in vitro fertilization industry.
PMID- 9394924
TI - Civil liability against prison officials for prescribing and dispensing
medication and drugs to prison inmates.
PMID- 9394925
TI - Medicine on trial. Physicians' attitudes about expert medical witnesses.
PMID- 9394927
TI - Sudden (un)explained death.
PMID- 9394926
TI - Tragic life or tragic death. Mandatory testing of newborns for HIV--mothers'
rights versus children's health.
PMID- 9394928
TI - Threshold stimulus ECT.
PMID- 9394929
TI - Are insurance agencies making treatment decisions?
PMID- 9394930
TI - Safety of combined pharmacotherapy.
PMID- 9394931
TI - Safety of combined pharmacotherapy.
PMID- 9394932
TI - Munchausen by proxy.
PMID- 9394933
TI - Forensic child and adolescent psychiatry: a review of the past 10 years.
AB - OBJECTIVE: To review important developments in child and adolescent forensic
psychiatry from 1987 through 1996. METHOD: Major changes in the law and
developments in research and practice were surveyed in the areas of the legal
regulation of psychiatry, family law (divorce and child abuse), consultation to
juvenile and criminal courts, civil litigation, and the development of the
subspecialty. RESULTS: There has been a large increase in research based on
quantifiable descriptive data of forensic populations, although studies using
comparison or control groups remain relatively rare. While managed care has
heavily influenced treatment practice, legal liability remains largely with the
clinician. Issues regarding techniques of evaluation for sexual abuse have been
scrutinized by the courts and by researchers. Legislative responses to rising
rates of juvenile violence have been in the direction of treating violent
adolescent offenders as criminally responsible adults. There has been a major
move toward setting standards for forensic evaluations, training, and
credentials. CONCLUSIONS: Child and adolescent forensic psychiatry remains an
area encompassing diverse clinical issues. It remains unclear the extent to which
it will develop into a formal subspecialty.
PMID- 9394934
TI - Posttraumatic stress disorder in children: a review of the past 10 years.
AB - OBJECTIVE: To review current knowledge about the clinical presentation,
assessment, and treatment of posttraumatic stress disorder (PTSD) in children.
METHOD: The literature on PTSD in children is examined. RESULTS: Over the past 10
years, PTSD has been described in children exposed to a variety of traumatic
experiences. Little is known about the epidemiology of the disorder in children.
Partial symptomatology and comorbidity are common. A variety of factors influence
response to trauma and affect recovery. They include characteristics of the
stressor and exposure to it; individual factors such as gender, age and
developmental level, and psychiatric history; family characteristics; and
cultural factors. Since the condition is likely to occur after disaster
situations, much of the literature describes the child's response to disaster and
interventions tend to include efforts within schools and/or communities. A number
of clinical approaches have been used to treat the condition. CONCLUSIONS: While
assessment has been studied extensively, the longitudinal course of PTSD and
treatment effectiveness have not been. Biological correlates of the condition
also warrant greater attention.
PMID- 9394935
TI - Microanalysis of adolescent suicide attempters and ideators during the acute
suicidal episode.
AB - OBJECTIVE: To compare psychological and event-related contingencies that
characterize and differentiate adolescent suicidal ideation and attempts. METHOD:
Thirty-five ideators and 32 attempters (aged 12 to 17 years) consecutively
referred to the suicide disorders clinic were evaluated with a semistructured
interview about current and past emotional, cognitive, and behavioral states.
RESULTS: Before the precipitant stressor (baseline), attempters reported
significantly more hopelessness than ideators (odds ratio [OR] = 4.2, p < .05).
During the suicidal episode, attempters, relative to ideators, spent more time
ideating (OR = 4.3, p < .05), were more likely to isolate themselves (OR = 5.8, p
< .01), and were less likely to tell anyone what they were thinking (OR = 4.5, p
< .05). In contrast, ideators reported significantly more residual anger after
the episode than did attempters (OR = 4.0, p < .05). All the episodes of ideation
and attempts were preceded by a stress event. No differences were found between
the groups on Beck Depression inventory scores. CONCLUSIONS: Preexisting
hopelessness, a tendency toward isolation, not talking about ideation, and longer
length of time ideating during suicidal episodes discriminated suicide attempters
from suicide ideators. Knowledge of these factors may be helpful in preventive
and treatment efforts with suicidal adolescents.
PMID- 9394936
TI - Suicidal adolescents and ego defense mechanisms.
AB - OBJECTIVES: To identify defense mechanisms that characterize adolescents with a
range of suicidal behaviors and to differentiate them from nonsuicidal
adolescents. METHODS: Fifty-five suicidal adolescent inpatients admitted for a
definite suicide attempt were compared with 87 adolescent inpatients who had no
history of suicide attempt or ideation and 81 nonpatients. Defense mechanisms
were assessed by the Ego Defense Scale (EDS) which is part of a larger
semistructured interview, the Child Suicide Potential Scale (CSPS), and by a self
report questionnaire, the Life Style Index (LSI). The CSPS was also used to
quantity violent and suicidal behaviors. RESULTS: On the LSI suicidal adolescent
patients scored higher on denial, displacement, repression, and total defenses
than the nonpatients. On the EDS they scored higher on regression, denial,
projection, introjection, repression, and total defenses and lower on
sublimation. LSI scores on displacement (higher) and on compensation (lower)
distinguished suicidal from nonsuicidal inpatients. Denial and regression
correlated positively and sublimation correlated negatively with both suicidal
and violent behaviors. Introjection and repression correlated with suicidal
behavior only. CONCLUSIONS: Overuse of displacement is connected with increased
risk for suicidal and aggressive behaviors, while sublimation is probably a
protective factor. In addition, several immature ego defenses possibly amplify
aggression, which then is directed against the self by the maladaptive overuse of
introjection, displacement, and repression.
PMID- 9394937
TI - Suicidal ideation and behavior and noncompliance with the medical regimen among
diabetic adolescents.
AB - OBJECTIVE: To examine (1) the 1-year and lifetime prevalence of suicidal thoughts
and behavior among adolescents with insulin-dependent diabetes mellitus (IDDM),
(2) the relationship between suicidal thoughts and serious noncompliance with the
medical regimen, and (3) factors including psychiatric disorder, self-efficacy
expectations, and hopelessness that might mediate the relationship between
suicidal thoughts and noncompliance. METHOD: Semistructured and structured
interview instruments and self-report questionnaires were used to determine
history of suicidal thoughts and behavior, serious noncompliance with the medical
regimen, current psychiatric disorder, hopelessness, and self-efficacy
expectations among 91 adolescents attending outpatient clinic appointments.
RESULTS: The rate of suicidal ideation among the diabetic adolescents was higher
than expected, but the rate of suicide attempts was comparable with that reported
for the general population. Suicidal thoughts were strongly associated with
serious noncompliance with the medical regimen. Duration of IDDM and psychiatric
diagnosis were related to both suicidal ideation within the previous year and
lifetime suicidal ideation. Diagnosable psychiatric disorder and not living in a
two-parent home were related to noncompliance with medical treatment.
CONCLUSIONS: Suicidal thoughts and serious noncompliance with the medical regimen
are strongly associated among diabetic teenagers, and psychiatric disorder is a
common correlate of both.
PMID- 9394938
TI - Epidemiology of youth suicide in Israel.
AB - OBJECTIVE: This study examined sociodemographic correlates and temporal trends in
suicide among young Jews, Moslem Arabs, Druzes, and Christian Arabs in Israel.
METHOD: The average yearly rates (1975 through 1989) for suicide and
undertermined causes of death were calculated for children, adolescents, and
subjects of army age. Rates were examined by gender, national/religious
affiliation, and place of residence for all groups and, in addition, by ethnic
origin among the jews. Logistic regression was used to ascertain the statistical
differences. Temporal changes were examined by plotting the rates over the 15
year period and fitting a regression line. RESULTS: Among the young, differences
by gender, national/religious, and ethnic origin did not consistently follow the
pattern found in adults. Male Jews and Druzes of army age, facing a period of
enhanced stress and availability of weapons, showed increased risk for suicide.
Temporal trends for suicide differed from the worldwide pattern of increasing
risk; these changes, however, were not homogeneous across all groups.
CONCLUSIONS: The suicide rates among the youth in Israel, as in adults, are among
the lowest in the world. Army service may be a period of enhanced risk,
justifying preventive action. The almost worldwide trend of increasing suicide
among the young is only partially present.
PMID- 9394939
TI - Precipitating factors and life events in serious suicide attempts among youths
aged 13 through 24 years.
AB - OBJECTIVE: Precipitating factors and life events associated with medically
serious suicide attempts were examined in young people making serious suicide
attempts and control subjects. METHOD: Using a case-control design, the authors
contrasted 129 young people making serious suicide attempts with 153 randomly
selected community controls on a series of life event occurrences within the
preceding year. Precipitating factors for serious suicide attempts were also
examined. RESULTS: The most common precipitants of serious suicide attempts were
relationship breakdowns, other interpersonal problems, and financial
difficulties. However, one third of those attempting suicide were unable to
describe any precipitating factor. Individuals who made serious suicide attempts
had elevated rates of life events which were associated principally with
interpersonal difficulties, work issues, financial difficulties, and legal
problems. When due allowance was made for intercorrelations between life event
measures and antecedent social, family, and personality factors, interpersonal
losses and conflicts and legal problems remained significant risk factors for
serious suicide attempts. CONCLUSIONS: Important proximal occurrences for serious
suicide attempts among young people include a series of life events associated
principally with interpersonal conflicts, relationship difficulties, and legal
problems.
PMID- 9394940
TI - Mania in children with pervasive developmental disorder revisited.
AB - OBJECTIVE: Although a small literature of case reports suggests that mania co
occurs with pervasive developmental disorder (PDD), little is known about this
overlap. The authors systematically investigated the overlap between mania and
PDD in a consecutive sample of referred youths, examining its prevalence and
correlates. It was hypothesized that children with PDD plus manic features have
both disorders. METHOD: Subjects were consecutively referred children meeting
diagnostic criteria on structured interview for PDD without mania (n = 52), the
comorbid condition PDD + mania (n = 14), and mania without PDD (n = 114). All
subjects were evaluated using a comprehensive diagnostic battery that included
assessment of psychopathology (structured diagnostic interview and Child Behavior
Checklist), cognition, and functioning. RESULTS: Of the 727 referred children, 52
met criteria for PDD, 114 met criteria for mania, and 14 met criteria for both.
The 14 children with both PDD + mania represented 21% of the PDD subjects and 11%
of all manic subjects. Clinical characteristics of PDD were similar in PDD
subjects with and without mania, and manic features were similar in manic
children with and without PDD. CONCLUSIONS: Children with PDD and mania may
suffer from two disorders. Comorbid mania among patients with PDD may be more
common than previously thought. Identification of the comorbid condition may have
important therapeutic and scientific implications.
PMID- 9394941
TI - Autism and associated medical disorders in a French epidemiological survey.
AB - OBJECTIVE: To estimate the prevalence of autism, to assess the strength of its
association with specific medical disorders, and to test for a secular increase
in its incidence. METHOD: An epidemiological survey was conducted among 325,347
French children born between 1976 and 1985 and living in three different French
departements. Diagnosis, educational level, and associated medical conditions
were abstracted from the records of children known to local educational
authorities. Data were also pooled with those from another similar survey.
RESULTS: One hundred seventy-four children (mean age: 11.6 years) with autism
were identified. The prevalence rate was 5.35/10,000 (16.3/10,000 if other
pervasive developmental disorders are included), with no difference according to
geographical area or social class. Rates of medical conditions were as follows:
1.1% for tuberous sclerosis, 2.9% for chromosomal abnormalities including fragile
X, 2.9% for cerebral palsy, 4.6% for sensory impairments, 0.6% for
neurofibromatosis, 0.6% for congenital rubella, and 1.7% for Down syndrome. In
the combined sample of 328 children with autism, the level and pattern of medical
correlates were comparable, with tuberous sclerosis having a consistently strong
association with autism. Prevalence rates were similar in successive birth
cohorts. CONCLUSION: Medical disorders (excluding epilepsy and sensory
impairments) accounted for fewer than 10% of the cases of autism. No secular
increase in the prevalence of autism was found.
PMID- 9394942
TI - Naltrexone in young autistic children: replication study and learning measures.
AB - OBJECTIVE: This study expanded upon previous work on naltrexone efficacy and
safety in young autistic children and assessed performance on learning measures.
METHOD: Eleven children with autistic disorder, aged 3.0 to 8.3 years, were
studied in home, school, and outpatient laboratory, bringing to 24 the combined
study sample. Naltrexone, 1.0 mg/kg, was given daily in a randomized, double
blind, crossover design. Dependent measures were parent and teacher Clinical
Global Impressions (CGI) and Naltrexone Side Effects Rating Scale (SE), Conners
Parent Impulsivity/Hyperactivity Factor, Teacher Hyperactivity Factor, laboratory
CGI, and analysis of videotaped behavior. Learning measures were the Early
Intervention Developmental Profile-Language and paired-associate learning.
RESULTS: Comparisons between naltrexone and baseline, but not naltrexone and
placebo, on parent and teacher ratings showed statistical significance. Three of
11 subjects improved in two or more settings. Side effects were mild.
Administering naltrexone was a challenge. The combined study sample showed
improvement on all parent measures and on Teacher CGI and SE-Restlessness
compared with baseline and placebo. Eleven of the 24 children improved in two or
more settings. Scores on learning measures did not change across conditions.
CONCLUSIONS: Naltrexone was associated with modest improvement of behavior in 11
of 24 children, but learning did not improve.
PMID- 9394944
TI - WISC profiles in child psychiatric diagnosis: sense or nonsense?
AB - OBJECTIVE: WISC factor structure, the specificity of WISC factors, and diagnostic
correlates of WISC profiles were studied to investigate the contribution of WISC
profile analysis to child psychiatric diagnosis. METHOD: The fit of various
factor models was tested and differences between various clinical groups
regarding three WISC patterns were studied, using the WISC-RN (the Dutch version
of the WISC-R) scores of a group of 465 Dutch children (mean age 11.2 years)
referred to a psychiatric clinic. RESULTS: The traditional factor models were
replicated in this study. However, most of the variance in the factors could be
explained by an underlying factor, "general intelligence," suggesting that WISC
factors measure specific cognitive abilities only to a limited degree. Another
important finding is that the various DSM-III-R and Child Behavior Checklist
diagnoses could not be distinguished on the basis of WISC profiles. CONCLUSION:
The data demonstrate that the relationship between WISC factors and specific
cognitive abilities and neuropsychological functions needs further clarification
in order to improve the validity of the traditional use of WISC profiles as a
source of diagnostic information.
PMID- 9394943
TI - Neurological soft signs: one-year stability and relationship to psychiatric
symptoms in boys.
AB - OBJECTIVE: This study had two main objectives: (1) to examine the 1-year
stability of neurological soft signs and (2) to examine the longitudinal
relationship between soft signs and psychiatric symptoms in young boys. METHOD: A
consecutive series of 56 boys from a high-risk sample received standardized
psychiatric and soft sign assessments at study intake. Approximately 1 year
later, 48 (86%) of these boys received a reassessment of their psychiatric and
soft sign status. RESULTS: Soft signs exhibited marked stability across the 1
year period (intraclass correlation = .70, p < .001). Symptoms of both
internalizing and externalizing disorders correlated with poor performance on the
soft sign examination. For both internalizing and externalizing symptoms, the
association with soft signs occurred primarily among individuals with
persistently high scores on symptom scales across the two assessments.
CONCLUSIONS: Performance on a standardized neurological soft sign examination is
stable over a 1-year period. Soft signs measured with this examination relate to
both internalizing and externalizing symptoms in young boys, particularly when
symptoms are relatively stable over time. Further research should consider the
clinical significance of childhood soft signs.
PMID- 9394945
TI - Traumatic brain injury in a child psychiatry inpatient population: a controlled
study.
AB - OBJECTIVE: To extend our findings from child psychiatry outpatients to child
psychiatry inpatients regarding the similarity of children with a history of
traumatic brain injury (TBI), particularly mild TBI, to matched children without
such a history. METHOD: This is a chart review of patients consecutively admitted
to a child psychiatry inpatient unit over a 5-year period. Children with TBI were
matched by age, sex, race, and social class to children with no history of TBI.
Axis I and II diagnoses and diagnostic clusters and use of special education
services and IQ scores were compared. RESULTS: Fifty-six (8.1%) of 694
consecutive patients admitted had a definite TBI. Not one of more than 50
variables compared between TBI and control subjects was significantly different.
CONCLUSION: In a child psychiatry inpatient unit, patients with a history of TBI
were virtually indistinguishable from matched children without TBI. Caution
should be exercised before attributing the child's problems, especially long-term
problems, to the TBI unless the injury was severe or the child is exhibiting
related phobic or posttraumatic stress symptomatology.
PMID- 9394946
TI - Case study: trauma-related hallucinations.
AB - Proper differential diagnosis of psychiatric disorders with psychotic symptoms is
imperative, as the treatment implications of the various conditions are quite
different. A case study of a 5-year-old abused child with posttraumatic stress
disorder is presented to illustrate some of the characteristic features of
psychotic symptoms in traumatized children. Literature reviewed suggests that
trauma-related hallucinations frequently contain content which is related to
children's life experiences, are exacerbated by "triggers" and safety concerns,
resolve with psychotherapy or psychosocial interventions, and are resistant to
standard neuroleptic treatments. They are also associated with unique clinical,
familial, developmental, and psychobiological correlates, and they require
multifaceted treatment interventions.
PMID- 9394947
TI - Case study: neuropsychiatric symptoms associated with the antimalarial agent
mefloquine.
AB - The development of acute neuropsychiatric symptoms in a 10-year-old boy
subsequent to his return from travel abroad in Africa, where he had taken the
antimalarial agent mefloquine (Lariam), is reported. A 4-week course of cognitive
behavioral therapy was used to effectively treat this substance-induced anxiety
disorder, which had been caused by treatment with mefloquine. A review of the
literature about adverse neuropsychiatric effects of mefloquine and the
differential diagnosis of malaria is provided. In an age in which international
travel is occurring with increasing frequency, it is important to obtain travel
histories, including exposure to prophylactic medication, when patients present
with acute-onset psychiatric symptoms.
PMID- 9394948
TI - Adolescents with psychiatric disorders and the risk of HIV.
AB - OBJECTIVE: To review literature relevant to human immunodeficiency virus (HIV)
associated risk behaviors among adolescents with psychiatric disorders and
psychological influences on risk behaviors. METHOD: This report is based on
review of 66 articles, which comprise all of the relevant literature in the
English language. RESULTS: Although the seroprevalence of HIV in adolescents with
psychiatric disorders is unknown, studies indicate that adolescents with
psychiatric disorders are at greater risk than their peers because of increased
rates of unsafe sexual practices, impulsivity, self-destructive attitudes,
cognitive immaturity, high rates of substance use, self-cutting behavior, and the
sequelae of sexual abuse. CONCLUSION: Directions are proposed for the design of
developmentally appropriate, clinically oriented HIV prevention interventions
based on the relationships between psychological dysfunction, social stressors,
and HIV risk behaviors.
PMID- 9394949
TI - Tourette's syndrome and psychopathology in a child psychiatry setting.
AB - Prior investigations of psychopathology among children with Tourette's syndrome
(TS) have rarely used child psychiatry samples and sophisticated personality
instruments. OBJECTIVE: To produce an objectively derived composite TS
personality profile and to determine the rate of particular problems in a TS
psychiatry sample compared with children with out TS from the same clinical
practice. METHOD: Children (n = 33) referred to child psychiatrists because of
emotional and behavior problems who were subsequently also found to meet DSM-III
R criteria for TS were assessed by the Personality Inventory for Children.
RESULTS: Children with TS expressed high rates of psychopathology overall
(composite 2.7 SD elevated) with depression, anxiety, and peculiar behavior
having the highest values; depression occurred most frequently (73%), and
attention-deficit hyperactivity disorder (55%) was no more common than among
comparison group children and conduct problems (18%) were rarer. "Depression,
anxiety, tension, and excessive worry" were characteristic of the actuarially
derived modal TS personality. CONCLUSIONS: The prevalence and manifestations of
psychopathology of children with TS in a child psychiatry practice are not
identical with those reported in the literature. Child psychiatrists should be
particularly vigilant of depressive symptoms and expect to encounter relatively
few conduct problems compared with children without TS. Establishing "local
prevalence rates" for children with TS seeking psychiatric evaluation can help
guide the diagnostician and make diagnosis more assured.
PMID- 9394950
TI - Hopelessness in inpatient youths: a closer look at behavior, emotional
expression, and social support.
AB - OBJECTIVE: To examine the individual and family characteristics of children and
adolescents with high levels of hopelessness. METHOD: One hundred inpatient
youngsters participated in the study. Several measures, including the
Hopelessness Scale for Children, Problem Behavior Scale of the Scales of
Independent Behavior, Social Support Questionnaire-Revised, Pediatric Anger
Expression Scale, and Differential Emotions Scale, were used to compare
differences between youngsters who scored high or low on hopelessness. RESULTS:
The results indicated that youngsters with high hopelessness scores tended to
perceive their families and peers as providing little support, to express their
anger overtly and aggressively, and to demonstrate more negative emotions than
youngsters with low hopelessness scores. CONCLUSIONS: Hopelessness in youths
appears to be associated with a specific pattern of behavioral and emotional
problems. Clinical implications of the findings include integrating anger
management, emotional expression interventions, and involving the family in
treatment to enhance the social support network of youngsters with high levels of
hopelessness.
PMID- 9394951
TI - Treating anorexia nervosa patients in the era of managed care.
PMID- 9394952
TI - Altered kidney matrix gene expression in early stages of experimental diabetes.
AB - The expression of mRNA and distribution of alpha 1(IV), alpha 3(IV) chains of
type IV collagen, matrix metalloproteinase 2 (MMP-2), and tissue inhibitor of
metalloproteinase 1 (TIMP-1) were examined in kidneys from streptozotocin
diabetic rats, 2.5 months after administration of the drug, an early time point
when specific diabetic glomerular changes were still minimal. Ten age-matched
Sprague-Dawley rats were assigned to control and diabetic groups. Compared to the
controls, the diabetic rats had a significantly lower body weight, higher kidney
weight and serum glucose levels, but no significant changes of glomerular surface
area and urine albumin were observed. Northern blot analysis, using whole kidney
mRNA, revealed that diabetic rat kidneys expressed 113.5% more alpha 1(IV), 46.5%
more alpha 3(IV), 54.8% less MMP-2 and 246% more TIMP-1 (in all instances: p <
0.05). These results were corroborated by in situ hybridization for RNA
expression. A quantitative analysis of the data indicated the following changes
in glomeruli: (1) 74.6% more alpha 1(IV), (2) 103.8% more alpha 3(IV), (3) 40.7%
less MMP-2 and (4) 80.9% more TIMP-1. Similar changes were observed in tubular
(proximal and distal) cells. We conclude that an increased synthesis and
decreased degradation of renal extracellular matrix components occur early after
induction of experimental diabetes, before the onset of typical structural
changes in the kidneys, and represent changes of specific gene expression at the
transcriptional level. All the cell types in the glomerulus as well as the
proximal and distal tubules appear to be involved in this alteration of
expression, and this is a novel finding.
PMID- 9394953
TI - Dynamics of endothelium-muscle cell contacts in the coronary artery of the dog in
ontogeny.
AB - The myo-endothelial area in the coronary artery conduit was described in 3
developmental stages: in fetuses, newborns, and adult dogs. Transmission and
scanning electron microscopy were used for the study, and morphometry was used
for quantitative evaluation. In all three stages, the internal elastic lamina was
found to be fenestrated. Endothelial cells and smooth muscle cells (SMC)
approached the fenestrae, and protrusions of one or both cells entered into the
fenestrae. In some places contacts between endothelial and SMC were found. The
patterns of mutual approaches of smooth muscle and endothelial cells, as well as
the entering into the fenestrae were similar in all three stages. The myo
endothelial contacts were counted per 100 microns inner circumference of the
coronary artery and the numbers observed, i.e. 5.17 +/- 0.50 in fetuses, 1.94 +/-
0.17 in newborns and 0.33 +/- 0.09 in adult animals, proved clearly that the
frequency of myo-endothelial contacts, highest in fetuses, decreases with age.
With regard to the dual control of the coronary smooth muscle and/or diameter, it
is noteworthy that an opposite trend can be observed in the development of
innervation of the coronary artery: the autonomic nerve fibres with varicosities
are missing in the coronary wall 1 week before birth, while after birth their
number keeps increasing. Remarkable enough is also the difference in distances
between the endothelium and SMC on the one hand and nerve varicosities and SMC on
the other. The above facts indicate a prevalence of endothelial control of
coronary diameter.
PMID- 9394954
TI - Organization of the lamina propria mucosae of rat intestinal mucosa, with special
reference to the subepithelial connective tissue.
AB - Light microscopy, scanning electron microscopy and transmission electron
microscopy have been used to delineate the structure and function of the lamina
propria mucosae in the rat jejunum. In silver-impregnated sections, the
adepithelial surface of the lamina propria mucosae was framed by a sheet of
reticular fibers (reticular sheet). Short-term (3-hour) immersion of jejunal
tissues in 2 N NaOH solution enabled us to simultaneously view networks of
reticular fibrils and fibroblasts residing in the subepithelial connective tissue
under a scanning electron microscope. The reticular fibrils, which measured about
40 nm in diameter and were interwoven in dense networks, formed a sheet 2-3
microns thick. In the villi, this sheet contained numerous foramina ranging from
3 to 7 microns in diameter, through which lymphocytes, macrophages, basal
extensions of epithelial cells and fat particles traversed. The reticular sheet
in the domes of isolated lymphoid nodules was markedly porous, and many
lymphocytes migrated into or out of the epithelium through the foramina. The
formaina of the reticular sheet may participate in the communication between the
intestinal epithelium and the lamina propria mucosae. It was noted that the
foramina of the reticular sheet in the villi were surrounded by end feet of the
cytoplasmic processes of fibroblasts. In addition, these fibroblasts were
combined with lymphocytes or dendritic cells in the lamina propria mucosae.
PMID- 9394955
TI - Long-term effects of core decompression by drilling. Demonstration of bone
healing and vessel ingrowth in an animal study.
AB - Avascular necrosis of the femoral head is associated with bone marrow
hyperpression. Although core decompression by drilling is an accepted treatment
regimen, until today no experimental results exist concerning the physiological
effects of this procedure. Published clinical data are controversial. In an
animal study marrow decompression was carried out by drilling of both hips in 18
healthy male sheep. In the right hip of each animal a resorbable stent was
implanted in order to prolong the duration of core decompression. Over a time
period of 24 weeks the effects were studied by measurement of the intraosseous
pressure, by the plastination method and by morphological examination with light
and electron microscopy. Bone drilling is a procedure of high short-time efficacy
in decompressing the bone marrow. But decompression lasts only for a short time
period. Three weeks postoperatively the drill channel is sealed by hematoma and
fibrous tissue in both hips (with/without stent) and no significant decompressive
effect is measured. Ingrowth of vessels along the drill channel is found in all
hips after a time period of 3 weeks. These vessels originate from the periosteum
as well as from the bone marrow and form temporary anastomoses between the
periostal-diaphyseal-metaphyseal and the epiphyseal-physeal circulatory system.
In conclusion, for the first time an anastomosis induced by drilling between both
circulatory systems of bone is demonstrated and the importance of the periosteum
is confirmed. The time of decreased core pressure induced by drilling is too
short for substitution of a necrotic area and could be the explanation of the
inferior clinical results of the procedure.
PMID- 9394956
TI - Quantitative analysis of incongruity, contact areas and cartilage thickness in
the human hip joint.
AB - Joint incongruity and cartilage thickness have been shown to determine the
contact stresses and the load partitioning between the solid and fluid phases of
articular cartilage. Matrix stresses, which are relevant in the development of
osteoarthrosis, can, however, not be determined experimentally but must be
calculated using numerical methods. The aim of the present study was to quantify
the incongruity and cartilage thickness of the human hip, in order to allow for
the construction of morphologically accurate finite element models. Twelve
cadaveric specimens (34-86 years), two fresh and ten fixed, were investigated.
The loading configuration was based on in vivo measurements of hip joint forces
during midstance. The incongruity and contact areas were determined using a
polyether casting technique, in the minimally and the fully loaded state. The
cartilage thickness was measured at identical coordinate points with an A-mode
ultrasonic system. Generally, the contact started at lower loads at the edge of
the lunate surface, and the joint space increased towards its central aspects. In
some specimens the contact started in the acetabular roof, leaving a joint space
of up to 2 mm in the horns of the lunate surface. In others, the initial contact
was observed in the anterior and posterior horns of the lunate surface with a
joint space width of up to 0.75 mm in the acetabular roof. The size of the
contact areas increased from about 20% of the lunate surface to 98% at higher
loads. The articular cartilage thickness ranged from 0.7 to 3.6 mm, the maxima
being located in the ventral aspects of the femoral head and acetabulum. These
quantitative data on joint space width, contact, and cartilage thickness in the
human hip joint may be used to construct and validate finite element models which
are required to elucidate the mechanical factors involved in osteoarthrosis.
PMID- 9394957
TI - Blebs in the mouse cerebellar granular layer as a sign of structural
inhomogeneity. 1. Anterior lobe vermis.
AB - The cerebellum is a modular structure. However, the size of the fundamental
compartments is uncertain, with anatomical methods showing a parasagittal band
arrangement but electrophysiological mapping suggesting a finer subdivision into
microzones and patches. A new anatomical way to demonstrate compartmentation is
described. The cerebellum is fixed by perfusion with 70% ethanol, paraffin
embedded and sectioned. When the sections are rehydrated the granular layer
pleats into an elaborate array of blebs. These blebs are seen in both transverse
and sagittal sections, found in all lobules of both the vermis and the
hemispheres, symmetrical about the midline, reproducible between neighboring
sections and between individuals, and bear a constant relationship to the
Purkinje cell bands as revealed by zebrin II immunocytochemistry. The data
suggest that the granular layer of the adult mouse cerebellum is divided into
several thousand modules. These modules may reflect the mossy fiber topography,
and may be the anatomical equivalents of the tactile receptive field patches.
Such a profound compartmentation has important implication for theories of
cerebellar structure and development.
PMID- 9394958
TI - Magnetic resonance imaging of cerebral associative white matter bundles employing
fast-scan techniques.
AB - Rapid scan techniques have introduced new sequence parameters as well as novel
contrast concepts into everyday magnetic resonance imaging (MRI). In particular
contrast characteristics of fast-spin echo (FSE) sequences showed some
significant differences when compared to conventional spin echo images. The
purpose of this work was to demonstrate the capabilities of FSE MRI in
identifying and characterizing the in vivo anatomy of the main cerebral
associative systems. Between March and November 1995, 20 healthy adult volunteers
(12 males, 8 females, mean age 35 years) were submitted to a cranial MRI
examination (1.5 Philips Gyroscan NT). In all cases axial and coronal 2
dimensional FSE T2-weighted and 2-dimensional inversion recovery FSE T1-weighted
images were obtained. All MRI images were examined by a neuroradiologist (G. Dal
Pozzo) for the depiction of the following compact white matter fiber bundles:
anterior commissure, corpus callosum, superior fronto-occipital fasciculus,
cingulum, fornix, mammillothalamic tract, uncinate fasciculus, superior and
inferior longitudinal fasciculus. All these associative pathways could be well
identified on T2-weighted images due to a lower signal intensity with respect to
the surrounding white matter. On T1-weighted images only the corpus callosum, the
anterior commissure and the fornix could always be identified. Correlation with
myelin-specific colorations (Luxol fast blue stains) in anatomic atlases and a
review of the literature on the myelinization process during infancy indicate
that the short T2 relaxation times of the aforementioned cerebral associative
systems may be due to heavy myelination and high fiber density. The correct
visualization of interintrahemispheric associative white matter fiber bundles may
play an important role in white matter disorders like dys- and demyelinating
diseases and in the spreading of vasogenic edema and/or tumor being useful for
their staging.
PMID- 9394959
TI - Anterior tympanic artery: course, ramification and relationship with the
temporomandibular joint.
AB - The anterior tympanic artery, a branch of the maxillary artery, ascends through
the retroarticular region dividing into anterior branches that spread through the
posterior part of the temporomandibular joint, and posterior branches that
contribute to the vascularization of the external acoustic meatus and the
tympanic cavity. The arrangement of the anterior tympanic artery was studied
bilaterally in 18 adult cadavers. In some cases, the anterior tympanic artery
branches off from the superficial temporal artery. The relationships of the
anterior tympanic artery with the posterior part of the temporomandibular joint
were analyzed.
PMID- 9394960
TI - The management of malignant melanoma revisited.
PMID- 9394961
TI - Bacterial contamination of pneumoperitoneum gas in peritonitis and controls: a
prospective laparoscopic study.
AB - There is a theoretical risk that the pneumoperitoneum gas could carry bacteria in
aerosol form and spread infection throughout the peritoneal cavity during
laparoscopy for infective conditions such as appendicitis. The aim of this study
was to attempt to culture bacteria from the pneumoperitoneum gas during
laparoscopy for potentially infected cases and a group of controls. A total of 53
consecutive laparoscopies were studied, of which 21 were potentially infected and
32 served as controls. A lavage of the operative site was positive for pathogenic
bacteria in almost 30% of the potentially infected group and only 3% of the
control group. The pneumoperitoneum gas was bubbled through blood culture medium
at the beginning and the end of the procedure, but only one of the 106 bottles
grew any bacteria, and the specimen was a likely contaminant. In conclusion, we
were unable to grow any significant bacteria from any of our cases despite using
a sensitive method and demonstrating pathogenic bacteria in the peritoneal
lavages. The pneumoperitoneum itself is unlikely to disperse bacteria.
PMID- 9394962
TI - Caecostomy in the management of acute left colonic obstruction.
AB - In the management of acute left colonic obstruction there is a tendency to
perform immediate resection with anastomosis. We evaluated 27 consecutive
patients (mean age 73.8 years) with acute left colonic obstruction and gross
dilatation of the proximal colon treated by the "traditional" staged procedure.
After caecostomy, no further resection was performed in two patients. In 25
patients, the obstructing tumour was resected after a median period of 14 days.
In 17 (68%) patients the caecostomy was closed simultaneously. In 8 patients this
was done at a third stage. Histologic examination revealed diverticular disease
in 6 and adenocarcinoma in 19 patients. No deaths occurred after caecostomy nor
was there major morbidity. After colonic resection, one in-hospital, nonprocedure
related, death occurred (mortality rate 4%). In 21 patients with an anastomosis
no dehiscence occurred. Other postoperative complications occurred in 5 patients
(morbidity rate 20%). The median hospital stay for patients with a two-stage
procedure was 32 days and with a three-stage procedure 39.5 days. The staged
procedure in the management of acute colonic obstruction is still a safe and
acceptable procedure in elderly patients with acute large bowel obstruction. To
shorten the hospital stay the period between caecostomy and colonic resection
should be reduced and it is best to close the caecostomy simultaneously.
PMID- 9394963
TI - Carotid chemodectomas. Experience with nine cases with reference to preoperative
embolization and malignancy.
AB - The medical records of nine patients (five female and four male, mean age 58 +/-
5 years) presenting with a carotid chemodectoma between 1983 and 1995 were
reviewed. In two cases (22%) the diagnostic was not suspected at the time of
initial presentation. The most common complaint was a swelling in the
anterolateral region of the neck. One patient (11%) presented with a preoperative
peripheral nerves deficits (vagus and hypoglossal palsies and Horner's syndrome).
Two tumours were embolized preoperatively with polyvinyl alcohol particles.
Complete surgical excision was possible in each patient and the plane of
resection was adventitial. In three cases, early ligation of the external carotid
artery facilitated the resection. In two patients, the vagus nerve was sacrificed
because of tumour involvement. No operative mortality was observed and no
vascular complication occurred. In addition to the patient with preoperative
neurologic symptoms, three patients developed peripheral nerve deficits (vagus
and hypoglossal nerves) postoperatively. Two of these deficits were transient.
These peripheral neurologic complications were observed with the largest tumour
sizes. Two cases were malignant (lymph nodes and bony metastases). These two
patients received postoperative radiotherapy. The mean follow-up period 63 +/- 19
months. No patient developed local recurrence during the follow-up. Two patients
died during the follow-up, one for condition unrelated to their disease and the
second from metastatic dissemination. In conclusion, carotid chemodectomas may be
safely resected. The best way to minimize the rate of complications is to operate
them at an early stage of evolution.
PMID- 9394964
TI - Thrombangiitis obliterans (Buerger's disease): still a limb threatening disease.
AB - A series of 29 well-documented and properly analysed patients with thrombangiitis
obliterans (Buerger's disease) is presented. The diagnosis of Buerger's disease
was based on following criteria: smoking history, onset before the age of 50
years, infrapopliteal arterial occlusive disease, either upper limb involvement
or phlebitis migrans, absence of atherosclerotic risk factors other than smoking.
In the last 10 years (1986-1996), we identified 29 patients who met these rigid
criteria. There were 24 men and 5 women, aged 32.4 years at the moment of the
disease first clinical symptom. The cumulative tobacco use averaged 16 pack-years
for each patient. The initial symptom was limited gangrene of a toe (n = 9) or a
finger (n = 2), foot claudication (n = 6), calf claudication (n = 3), rest pain
(n = 3), migratory superficial phlebitis (n = 4), and Raynaud phenomenon (n = 2).
Angiography and/or Doppler ultrasound revealed digital, pedal and calf artery
involvement in all patients, with proximal extension in ten patients
(femoropopliteal in ten, including three cases with external iliac artery
involvement). Seven patients had also evidence of upper limb involvement.
Histologic proof was available in only seven patients. Only nine patients
completely stopped smoking. Treatment was exclusively medical in five cases.
Twenty-four underwent sympathectomy (20 at lumbar, and four at thoracic level),
with good immediate result in 16. In 11 patients a vascular reconstruction was
done (eight femorocrural and three iliofemoral bypasses), with a patency rate of
only 36% at two years. Amputation was required in 16 patients (a mean of 2.7
amputations per patient) at one or more levels: toe (n = 19), forefoot (n = 5),
below knee (n = 8), above knee (n = 2), finger (n = 3). Two patients ended up
with bilateral leg amputation. Overall, 23% (7/30) of the patients required major
leg amputation during the course of the disease. Disease progression was
moderately related to continued tobacco use. Buerger's disease still entails
considerable risk of major amputation. Complete abstinence from tobacco use is
crucial to expect stabilization of the process. However, in advanced stages of
the disease and despite cessation of smoking recurrent episodes of ischaemia or
tissue loss are not excluded.
PMID- 9394965
TI - Surgical approaches to the humeral shaft.
AB - Open fractures, transverse, short oblique and spiroid fractures of the humeral
shaft, as well as comminuted fractures with radial palsy or vascular injury,
mostly lead to bad end-results if treated conservatively. The same is valid in
the case of bilateral humeral shaft fractures, multiple injuries, polytrauma,
pathologic fractures and pseudarthrosis. Good end-results and a low rate of
complications in the operative procedure require an adequate approach to the
fractured limb as well as a meticulous care of the soft tissues. In plate
osteosynthesis, the anterolateral approach for the proximal third of the shaft,
the anterolateral approach with radial exposure for the middle third of the shaft
and the posterior approach for the distal third of the shaft seem to offer the
best pathway for reposition and fixation, respecting the biologic requirements
for a successful osteosynthesis. The approaches for external fixation demand a
thorough knowledge of the course of the axillary and radial nerves. Unreamed
intramedullary nailing can be done in an anterograde and in a retrograde way. In
anterograde nailing, damage of the rotator cuff must be avoided, in retrograde
nailing, the elbow capsule should be left closed and untouched.
PMID- 9394966
TI - The diagnosis by fine needle aspiration biopsy of hydatid cyst of the pancreas.
AB - We describe a case of pancreatic hydatid cyst in which the definitive diagnosis
was made at fine needle aspiration cytology. The most common site of hydatid cyst
is the liver (65%), followed by the lungs (25%). The hydatid cyst of the pancreas
is rare since it accounts for less than 1% of the various sites of hydatid
disease. The diagnosis may be difficult when the presentation is that of an
unexplained epigastric mass or cyst, despite suggestive radiological and
ultrasonographic features. Modern serology tests are positive in up to 80% of the
abdominal hydatid cysts. It is mandatory to obtain a fine needle aspiration
biopsy for definite diagnosis and for appropriate treatment planning. Surgical
removal of the hydatid cyst still remains the most effective treatment.
PMID- 9394967
TI - Mesenteric venous thrombosis. Diagnostic and therapeutic approach.
AB - Mesenteric venous thrombosis is an infrequent but distinct form of intestinal
ischaemia. We report a case of acute mesenteric venous thrombosis diagnosed by
computed tomography. Laparoscopy permitted to establish the extent of the
ischaemia. Initially, high doses streptokinase were administered for 6 hours,
followed by heparinotherapy for 10 hours, with the aim to reduce the length of
bowel to be resected. One day later, intestinal resection was carried out,
followed by postoperative anticoagulation.
PMID- 9394968
TI - Spinal ischaemia after surgery for abdominal infrarenal aortic aneurysm.
Diagnosis with nuclear magnetic resonance.
AB - A 76-year-old man underwent surgery for an infrarenal aortic aneurysm reaching 6
cm in maximal transverse diameter. The aorta was crossclamped below the level of
the renal arteries. A tube graft was interposed and tend between the infrarenal
aorta and the aortic bifurcation. Due to leakage on the suture line two
consecutive episodes of crossclamping for a total duration of 40 min. were
required. No hypotension was noted during or after the procedure. After
operation, the patient complained of difficulties to move both legs and
neurologic examination demonstrated paraparesis, with mild sensory deficit.
Faecal and urinary incontinences were also noted and urodynamic testing
demonstrated sphincterovesical palsy. Nuclear magnetic resonance imaging detected
an ischaemic zone in the spinal cord at the level of T11. Faecal incontinence and
motor deficit partially resolved but no bladder function recovery was observed.
Spinal ischaemia is a rare complication after abdominal aortic surgery. Several
risk factors have been suggested which include level and duration of the aortic
crossclamping, possible interruption of the spinal cord blood supply via the
greater medullary artery (the so-called artery of Adamkiewicz), presence of intra
or postoperative episodes of hypotension, atheromatous embolization, underlying
occlusive arteriosclerosis of spinal arteries, and respect or not of the
hypogastric circulation. In our case, the duration of the crossclamping and
interruption of the blood flow in lumbar arteries probably supplying the distal
spinal cord were likely contributive factors.
PMID- 9394969
TI - Ulnar artery false aneurysm: temporary ultrasound-guided compression closure in
an unusual case.
AB - A case of traumatic false aneurysm located in an unusual portion of the ulnar
artery is presented and the clinical findings, diagnosis and treatments are
considered. The authors report the first use of ultrasound-guided compression
closure, as an alternative to surgical management of ulnar artery false
aneurysms.
PMID- 9394970
TI - Osteosarcoma of the proximal fibula: report of 3 cases.
AB - Osteosarcoma of the proximal fibula represents about 2% of all osteosarcomas. The
complexity of anatomical structures in this region led in the past to low
transfemoral amputation in order to achieve local control. Three patients aged
14, 13 and 14 were treated in our institution and surgical margins were free of
tumour after a wide en bloc resection. To achieve that, the lateral wall of the
tibia and the anterior tibial artery were taken out with the proximal fibula. All
three patients are alive without evidence of disease. The functional results are
evaluated according to Enneking system recommended and adopted by the Musculo
Skeletal-Tumor Society (M.S.T.S). Overall functional results were 80, 100 and
100%.
PMID- 9394971
TI - Non-invasive in vivo techniques to differentiate photodamage and ageing in human
skin.
AB - It is important to differentiate skin changes due to the intrinsic ageing process
from those due to chronic photodamage in the development of therapies to assist
the latter condition, and in this study we have used instrumental techniques to
differentiate between changes in a range of properties of skin due to ageing and
those due to photodamage, especially with regard to elasticity. We measured three
sites of differing sun exposure in a group of younger and in a group of older
subjects. A pulsed A-scan ultrasound system was used to measure skin thickness,
and a uniaxial extensometer was employed to assess elastic properties. Skin
surface roughness measurements were made using silicone rubber impressions and a
stylus profilometer. We demonstrated significant differences in skin roughness
between young and old subjects at every site and differences between sun-exposed
and sun-protected sites only in the older group. Parameters of the elastic
properties of skin differed between the groups, and also between sites of most
different sun exposure. The uniaxial extensometer can demonstrate a loss of the
skin's elasticity predominantly by photodamage, and the roughness of the skin
surface can be shown to increase mostly by chronological ageing but to decrease
modestly by photodamage. This demonstrates that differences between the two
processes can be quantified, and indeed they should be.
PMID- 9394972
TI - Quantification and specificity of the repeated open application test (ROAT). A
methodological study using cobalt and colophony in guinea pigs.
AB - The repeated open application test is used to assess the clinical relevance of
positive patch test reactions to ingredients of formulated products. The great
variation in outcome is usually claimed to be related to the concentration of the
allergen responsible. We have here studied the quantitative aspects, specificity
and effect of patch testing on the outcome of the repeated open application test
in an animal model, using guinea pigs sensitized with cobalt chloride or
colophony. Thresholds of sensitivity were determined before and after the topical
treatments. Clear dose-response relationships were established. The reactivity in
sham-treated controls and to the vehicles was minimal. The concordance between
patch test results and outcome of the use tests was concentration-dependent and
at low concentrations < 50%. The repeated open application test is a useful
method, but some of the basic issues need further evaluation. This animal model
will hopefully serve this purpose.
PMID- 9394973
TI - Flow cytometric DNA content analysis of ultraviolet light-induced squamous cell
carcinomas: a comparative study of squamous cell carcinomas of the lip and those
arising from other sites of sun-damaged skin.
AB - The development of squamous cell carcinoma (SCC) of the lip is considered to be
mainly related to excessive sun exposure. However, its higher metastatic rate is
distinct from that of SCCs arising from other sites of sun-damaged skin. Flow
cytometric DNA content analysis, using paraffin-embedded specimens, was performed
on 15 SCCs of the lip and 32 SCCs arising from other sites of sun-damaged skin. A
significantly lower incidence of DNA-aneuploidy was observed in SCCs of the lip
(2/15) than in those of sun-damaged skin (15/32) (p < 0.05). The mean age of
patients with SCC of the lip (66.7 +/- 11.6 years; mean +/- SD) was significantly
lower than that of the other patients (78.1 +/- 11.1 years) (p < 0.01). There was
no significant difference between the mean diameter size of tumors on the lip
(19.5 +/- 5.7 mm) and that of tumors on other sites of sun-damaged skin (30.7 +/-
20.5 mm). These results suggest that additional carcinogenic factors besides
ultraviolet light may be involved in the development of SCC of the lip.
PMID- 9394974
TI - Keratinocytes cultured under hyperthermal conditions secrete factor(s) which can
modulate dermal fibroblast proliferation and extracellular matrix production.
AB - We have studied how keratinocytes cultured under hyperthermal conditions modulate
skin fibroblast growth potential and their biosynthetic phenotypes in vitro. When
keratinocytes were cultured at 30, 34, 37 or 39 degrees C, the conditioned medium
of the keratinocytes cultured at 39 degrees C showed a greater inhibitory
activity for fibroblast proliferation and greater synthetic activities of
collagen and glycosaminoglycans than those incubated at 30, 34, or 37 degrees C.
Transforming growth factor (TGF) beta 1 production in skin fibroblasts was also
stimulated by the keratinocyte conditioned medium cultured at 39 degrees C. The
stimulating activity of collagen and glycosaminoglycan syntheses of keratinocyte
conditioned medium may be explained at least partly by enhanced TGF beta 1
production. The results indicate that keratinocytes cultured at a higher
temperature (39 degrees C) may secrete factor(s) which modulate both fibroblast
growth and matrix synthesis. This may provide evidence that under hyperthermal
conditions epidermis can influence the functions of skin fibroblasts.
PMID- 9394975
TI - Evaluation of scratch movements by a new scratch-monitor to analyze nocturnal
itching in atopic dermatitis.
AB - Itching is very important in atopic dermatitis, but the details of itching or
scratch movements, especially during sleep at night, have not yet been fully
comprehended. We designed a new, simple device, the Scratch-Monitor (SM), to
evaluate scratch movements at night and assessed the usefulness of this device by
a comparison involving 26 patients and 17 healthy controls. The SM, a box
weighing only 25 g with a pressure sensor on the bottom, is attached to the back
of each hand under a cotton glove and records the number as scratch movements per
minute in the case of more than three successive changes of pressure. The SM
indicated that patients with atopic dermatitis scratched more frequently and
suffered more severe sleep disturbance than healthy controls. Although the SM had
several problems related to specificity and sensitivity, we conclude that the SM
is a useful tool for evaluating nocturnal itching.
PMID- 9394976
TI - Inducible nitric oxide synthase demonstrated in allergic and irritant contact
dermatitis.
AB - Eight allergic patch test reactions, eight irritant skin reactions induced by 3%
sodium lauryl sulphate and six normal controls were biopsied. Biopsies were
immunohistochemically stained with a mouse monoclonal antibody to inducible
nitric oxide synthase (iNOS), and staining was quantified by computerised image
analysis. Human chondrocytes induced to express iNOS were used as a positive
control. A significant increase in iNOS was found in both irritant and allergic
contact dermatitis. There were no differences in the distribution of expression
of iNOS. The antibody used was confirmed by Western blotting not to cross-react
with the endothelial isoform of nitric oxide synthase (NOS) but did cross-react
with a 150 kDa protein, which may be neuronal NOS or an isoform of neuronal NOS.
PMID- 9394977
TI - Upregulation of CD40 and CD40 ligand expression in IgE-associated cutaneous
diseases.
AB - In order to better understand the immunological processes connected with IgE
associated cutaneous disease, we have examined the expression of CD40 and its
ligand CD40L, required for the induction of IgE synthesis in B-cells, as well as
of IgE and its receptors in various dermatoses (atopic dermatitis (AD), scabies,
chronic recurrent urticaria) versus normal skin, and in one dermopathic lymph
node versus normal lymphatic tissue by immunohistochemistry. Compared to normal
skin, cells expressing IgE, Fc epsilon RI, Fc epsilon RII, CD40, CD40L and L26
were increased in the dermis, partly also in the epidermis, from patients with AD
and scabies, but not in chronic urticaria. CD40 and CD40L were detected on
numerous cells in lymphatic tissue from both normal donors and a patient with AD,
whereas large numbers of IgE- and Fc epsilon RI-positive cells were only found in
the dermopathic lymph node from the AD patient, in contrast to very few in normal
lymphatic tissue. These results with selectively increased IgE/Fc epsilon RI and
associated CD40/CD40L expression in the skin of AD and scabies suggest that
cutaneous tissue, in addition to dermopathic lymphatic tissue, might contribute
to IgE synthesis.
PMID- 9394978
TI - Sleep patterns in children with atopic eczema.
AB - Following routine appointments in a paediatric dermatology clinic, the parents of
44 young children with atopic eczema and 18 with other skin conditions were
interviewed regarding sleep patterns. Sleep disorders were more prevalent in the
eczema children than in the control group and normal populations. "Night waking"
problems were particularly common in the eczema children, whereas settling
problems were not. An association was found between scratching habits and "night
waking"--the more the children scratched, the greater the likelihood of their
waking at night. Consideration is given to the management of the sleep problems
of eczematous children.
PMID- 9394979
TI - Topical application of a platelet-activating factor (PAF) antagonist in atopic
dermatitis.
AB - Platelet-activating factor (PAF acether) is a lipid mediator with a potent
proinflammatory activity. Results derived both from in vitro and in vivo studies
suggest a possible role of this substance in the pathophysiology of atopic
dermatitis. A double-blind, randomized, multi-center, within-patient study was
performed to evaluate the efficacy of a topically applied PAF antagonist (RO-24
0238) in 36 patients with atopic dermatitis. Over a period of 28 days, 0.25 ml of
the PAF antagonist and the vehicle (placebo) were applied twice daily on opposite
sites of symmetrical lesions (measuring 10 to 20 cm2 each). The overall
assessment of the therapeutic efficacy did not demonstrate a superior effect of
the PAF antagonist in comparison to placebo, and this was the same with the
individual study parameters erythema, scaling, induration and exudation. For
reducing pruritus, as assessed by the patient using a visual analogue scale, a
statistically significant action was documented during the first 2 weeks of the
study (p < 0.04; Wilcoxon rank sum test), with a continued, yet not statistically
significant efficacy after weeks 3 and 4. The exact role of the pathological
events of atopic dermatitis that might be influenced by a PAF antagonist remains
to be determined, but the anti-pruritic component of this substance especially
deserves further scientific interest.
PMID- 9394980
TI - Treatment of refractory cases of atopic dermatitis with acidic hot-spring
bathing.
AB - The incidence of refractory atopic dermatitis has increased in teenagers and
young adults. The purpose of this study was to control the skin symptoms of such
patients in daily life. Seventy patients repeatedly took a 10-min 42 degrees C
acidic hot-spring bath twice daily. The skin symptoms were improved in 76% of
cases. In 30 of 42 responders examined Staphylococcus aureus, detected on the
skin surface, disappeared or decreased through balneotherapy. In contrast, S.
aureus remained unchanged in 8 of 10 non-responders examined. Thus, the
balneotherapy using acidic hot-spring water may be useful for controlling the
skin symptoms of acute flares of refractory cases of atopic dermatitis.
PMID- 9394981
TI - Evaluation of a self-reported questionnaire on hand dermatosis in secondary
school children.
AB - The purpose of this study was to investigate the reliability and validity of a
self-reported questionnaire for estimating the prevalence of hand eczema and
other hand dermatoses. All pupils in grades 1 and 3 from the secondary schools in
Vaxjo, in southern Sweden, were invited to participate in the study, which
consisted of two parts, a questionnaire and a clinical examination. Of those
invited, 2572 (98.6%) responded to the questionnaire. Of the respondents, 2535
pupils (98.5%) were clinically examined. The kappa value for the questionnaire
findings, compared with the diagnosis from the clinical examination, was 0.79,
indicating good agreement. The sensitivity of the questionnaire findings was 73%
(95% confidence interval [CI]: 0.6425-0.7975), and the specificity was 99% (95%
confidence interval [CI]: 0.9860-0.9940). The self-reported questionnaire was
suitable for detecting hand dermatosis in a population of secondary school
children and may be used as a cost-effective and reliable method of investigating
the prevalence of hand dermatosis in epidemiological studies.
PMID- 9394982
TI - Plaque-type blue nevus. Review and an unusual Case.
AB - A 31-year-old male presented with a 13-15-mm blue-black plaque tumor on his left
forearm, which had existed since birth. Histological examination showed a common
blue nevus. Its small size and its location are unusual. A review of plaque-type
blue nevus is given.
PMID- 9394983
TI - Improvement of vitiligo after oral treatment with vitamin B12 and folic acid and
the importance of sun exposure.
AB - The aim of this 2-year study was to test the hypothesis that folic acid, vitamin
B12 and sun exposure could be helpful in treating vitiligo. One hundred patients
with vitiligo were treated with oral folic acid and vitamin B12 after being
informed that sun exposure might enhance repigmentation. They were requested to
keep a record of sun exposure in summer and UVB irradiation in winter. The
minimal treatment time suggested was 3-6 months but should be longer if
improvement was achieved. Clear repigmentation occurred in 52 patients, including
37 who exposed their skin to summer sun and 6 who used UVB lamps in winter.
Repigmentation was most evident on sun-exposed areas, where 38% of the patients
had previously noted repigmentation during summer months. Total repigmentation
was seen in 6 patients. The spread of vitiligo stopped in 64% of the patients
after treatment. Folic acid and vitamin B12 supplementation combined with sun
exposure can induce repigmentation better than either the vitamins or sun
exposure alone. Treatment should continue as long as the white areas continue to
repigment. Further studies are needed to determine ideal minimal dosages of
vitamins and UV exposure, as well as treatment time.
PMID- 9394984
TI - Epidermal sheet grafts for repigmentation of vitiligo and piebaldism, with a
review of surgical techniques.
AB - Thin epidermal sheets, obtained by a high-speed air-driven dermatome, were used
to repigment white areas in 19 patients with vitiligo and one boy with
piebaldism. In the depigmented skin to be treated the epidermis was removed by a
rotating diamond fraise under topical and/or local anaesthesia injections. The
method was used on most parts of the body, including the eyelids and genitalia.
The maximum total area treated on each occasion was 190 cm2. Excellent results
could be obtained if the vitiligo had been stable and had not increased anywhere
during the last 2 years. Lack of immobilization could explain a poor result in
some areas. The donor area on the buttocks healed quickly without depigmentation.
In the transplanted area milia were observed in the first 6 months. No scarring
was seen. The technique has a niche in the treatment of depigmented skin,
especially in larger areas.
PMID- 9394985
TI - Factors influencing participation among melanoma screening attenders.
AB - We surveyed the demographic profile and motives prompting to participate among
people attending voluntary melanoma screening clinics in Southern Limburg, the
Netherlands, in June 1993. Precampaign public announcements addressed only
melanoma and its precursor lesions. All attendees completed a detailed
questionnaire addressing demographic particulars and specific fixed choice
questions on their motivation to attend. There were 4,146 persons attending the
screening clinics. Most attendees opted for examination of a specific lesion
(71%). More females than males participated. Fear of having skin cancer was an
important reason to participate (27%). Of all attenders, 16% had to be convinced
by relatives or friends to attend the screens, and 33% would not have visited a
physician on their own initiative when there had not been a free screening.
Females were more concerned about skin cancer than males. The local and regional
newspapers formed the most important precampaign publicity channel. Free melanoma
screenings attract large numbers of people. Males are underrepresented. They are
less aware of the risk profile of melanoma. Future screenings should target the
male population.
PMID- 9394986
TI - Pinch grafting of leg ulcers. A retrospective study of 412 treated ulcers in 146
patients.
AB - In a retrospective study of 412 leg ulcers in 146 patients treated with pinch
grafting, with a mean duration of follow-up of 32 months (range 2-84), the
overall healing rate was 38%. The healing rate was best in the vasculitic ulcers
(56%), followed by venous ulcers (38%), arteriosclerotic ulcers (33%), mixed
ulcers (33%) and "other ulcers" (20%). In the series as a whole, the mean
duration of ulcer problems was 8 years, and that of the 412 ulcers treated 2.5
years; the mean recurrence rate was 28%, and the mean remission time 12.5 months.
In the ulcers that were still healed at close of the study (comprising 27%
(112/412) of the series), the remission time was > or = 26.6 months. Thus we
consider pinch grafting to be a successful complement to conservative therapy in
most types of ulcers.
PMID- 9394988
TI - Widespread cutaneous cryptococcosis occurring in an immunocompromised patient
treated with high doses of fluconazole for oro-pharyngeal candidosis.
PMID- 9394987
TI - Morphology of endogenous flare-up reactions in contact allergy to gold.
AB - In a double-blind study, 20 patients with contact allergy to gold were given an
intramuscular injection of gold sodium thiomalate or placebo, inducing a clinical
and histological flare-up of healed patch test sites in the gold-injected but not
in the placebo group. The test area of the placebo group showed some perivascular
lymphocytic foci (UCHL-1+) and vascular endothelial ELAM-1 staining. The gold
group, with flare-up, showed larger and more extensive lymphocytic foci with ELAM
1+ endothelium as well as lymphocytic epidermotropism. CD1a+ LC cells were
downgraded, tryptase+ mast cells accumulated and CD68+ monocytes/macrophages
markedly increased. Probably, a significant part of the tissue priming as a
result of patch testing comprises memory T-cells and endothelial ELAM-1
upgrading, but blood-borne CD68+ monocytes may also be instrumental in the flare
up.
PMID- 9394989
TI - Koebner phenomenon in classic Kaposi's sarcoma.
PMID- 9394990
TI - A pleomorphic liposarcoma imitated a subcutaneous cyst.
PMID- 9394991
TI - Lithium therapy associated with hidradenitis suppurativa.
PMID- 9394992
TI - Erythema multiforme major in a female with acute systemic meningococcal disease.
PMID- 9394993
TI - Linear atrophoderma of Moulin.
PMID- 9394994
TI - Acquired perforating collagenosis in a patient with carcinoma of the prostate.
PMID- 9394995
TI - Cutaneous larva migrans detected by epiluminescent microscopy.
PMID- 9394996
TI - Lichen planus and Crohn's disease.
PMID- 9394997
TI - Epidermal growth factor concentration in the sera of male psoriatic patients.
PMID- 9394998
TI - A case of dermatomyositis triggered by tegafur.
PMID- 9394999
TI - Zosteriform lichen planus without evidence of herpes simplex virus or varicella
zoster virus by polymerase chain reaction. Report of two cases.
PMID- 9395000
TI - Lupus erythematosus as an occupational disease.
PMID- 9395001
TI - Malignant epithelioid schwannoma with melanocytic differentiation: a rare tumour
with an unusual feature.
PMID- 9395003
TI - CO2 laser treatment causes local tattoo allergic reaction to become generalized.
PMID- 9395002
TI - Low doses of low molecular weight heparin in vivo do not inhibit delayed-type
hypersensitivity.
PMID- 9395004
TI - The role of leukotriene A4 hydrolase/aminopeptidase in transcellular leukotriene
B4 synthesis in human epidermis.
PMID- 9395006
TI - Respiratory allergy to Cupressus sempervirens in Rome.
AB - Mediterranean Cypress pollen is the major aerospore component in winter and early
spring. Several recent studies have assessed the incidence of respiratory allergy
to this pollen. A personal series of patients encountered in 1994-96 revealed a
9.33% incidence of positive prick-test responses to Cypress pollen among a
population with atopical status. That series included 16 (19.05%) single and 68
(80.95%) multiple allergy sufferers. Among the former the symptoms encountered
were rhinitis (62.5%) and asthma (37.5%). Given the ever-increasing incidence of
Cypress pollen allergy, there is a need to restrict the planting of the tree for
ornamental purposes, especially in areas with a high pollen count.
PMID- 9395005
TI - Clinical efficacy and tolerance of two year Lolium perenne sublingual
immunotherapy.
AB - Last years, in spite of increasing use of sublingual immunotherapy (SLIT), not
enough clinical studies have been published and its efficacy ought to be
documented still more. For that purpose, 54 patients suffering seasonal
rhinoconjunctivitis--with or without asthma--were allocated to either six month
preseasonal SLIT with Lolium perenne extract (n = 35) or to a control group (n =
19). In the following year, thirty from previously treated patients and 12 from
former control group, received a nine-month pre-coseasonal SLIT. Skin (SPT) and
conjunctival (CPT) allergen response were monitorized several times along the
study. Either seric antibodies or intraseasonal eosinophil cationic protein
(ECP), as symptom, medication scores and peak nasal inspiratory flow (PNIF) were
also assessed, fifty-five adverse reactions were recorded (0.7% doses), although
only four required treatment. No main changes in CPT, SPT and antibodies were
detected. Nevertheless, during the first pollen season, treated patients needed
less medication than their control counterparts (p < 0.05). In the second season,
the twelve ex-control subjects also required fewer drugs than in the first one (p
< 0.01). Moreover, the whole forty-two treated patients showed a lesser
intraseasonal ECP than a reference set of grass-allergic individuals (p < 0.05).
We conclude that Lolium perenne SLIT is well tolerated and induces fewer drug
requirements during pollen season, being eosinophil activation additionally
reduced.
PMID- 9395007
TI - Lodoxamide versus spaglumic acid: a comparative double-blind trial on patients
suffering from seasonal allergic conjunctivitis induced by Parietaria pollen.
AB - In order to evaluate the efficacy and tolerability of lodoxamide in the treatment
of allergic conjunctivitis, the authors conducted a double-blind trial with
intrapatient comparison on 32 patients, using lodoxamide versus spaglumic acid in
the course of two conjunctival provocation tests performed with specific
allergens. The patients received one drop of lodoxamide in one eye and one drop
of spaglumic acid in the other; 15 minutes later, 25 microliters of allergen
extract at a pre-established concentration was instilled. After 10 minutes, the
signs and symptoms of the allergic response were evaluated and recorded. Six
hours later, the instillation of the allergen extract in both eyes was repeated
following the same procedure, to establish the duration of the effect of the two
drugs. The results, obtained by evaluating the main clinical signs and symptoms
(itching, lacrimation, hyperaemia, palpebral oedema and chemosis), demonstrate
with statistically significant differences that lodoxamide inhibits the
conjunctival response to exposure to the allergen with greater efficacy than
spaglumic acid, and for a longer duration. The two drugs provided similar and
satisfactory tolerability. In view of these results, lodoxamide can definitely be
considered and effective drug in the treatment of allergic conjunctivitis.
PMID- 9395008
TI - Modulation of TCR usage in HIV-1 infection is regulated by IL-7 and sCD23.
AB - The purpose of this study is to elucidate the effect of interleukin-7 (IL-7) and
soluble CD23 (sCD23) on Phorbol12 Myristate13 Acetate (PMA) activated CD4+ TCR
alpha beta+ cells of HIV-1 infected subjects. CD23 and IL-7R were detectable on
activated CD4+ T cells of these subjects by FACS. Addition on IL-7 (1000 U/ml),
at the onset of cultures, resulted in a significant increase of CD23 expression.
We also demonstrated that T cells proliferation and CD23 expression in the
presence of exogenous IL-7 occur in an IL-2 independent manner. Addition of IL-7
and sCD23 to activated CD4+ cells of HIV-1 infected subjects induced a
proliferative response of TCR alpha beta cells. In contrast, addition of either
sCD23 or IL-7 to activated CD4+ T cells did not result in an increase of TCR
alpha beta expression. The data provide direct evidence that sCD23 in combination
with IL-7 induce proliferation of activated CD4+ T cells of HIV-1 infected
subjects to augment TCR alpha beta expression. These results support the
possibility that IL-7 plus sCD23 might play an important role in the modulation
of TCR alpha beta expression in HIV infection.
PMID- 9395009
TI - Fixed drug eruption from amoxycillin.
AB - We present a case of fixed drug eruption on the genital mucosa induced by
amoxycillin. Topical provocation was carried out, applying amoxycilin (10% pet)
on the glans penis. No reaction was observed. Oral challenge with amoxycillin was
followed by pruritic erythema on the glans penis 6 hours after the intake of 125
mg. The study of cross-reactivity to other betalactams showed good tolerance of
phenoxymethyl-penicillin, which shares an identical nuclear structure with
amoxycillin. The patient also tolerated cephadroxil, a cephalosporin with a side
chain identical to that of amoxycillin. On reviewing the literature we have only
found three reports of fixed drug eruption fue to amoxycillin.
PMID- 9395010
TI - Platelet-activating factor antagonists.
AB - Platelet-activating factor (PAF), identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3
phosphorylcholine, exhibits potent proinflammatory properties. PAF is produced by
numerous cell types, including endothelial cells, neutrophils, monocytes,
macrophages, basophils, eosinophils and mastocytes. Since the discovery and
identification of the chemical structure of PAF, a large variety of specific PAF
receptor antagonists, both natural and synthetic compounds, have been described.
Intensive research has been conducted and development programs set up by more 25
pharmaceutical companies world-wide, studying the therapeutic interest of more
than 50 PAF-receptors antagonists in various pathophysiological conditions.
Medline (1966-1996), Embase (Excerpta Medica; 1974-1996), and other biomedical
and drug directory databases were searched to identify English-language articles
(basic science, clinical trial research, and review articles) and abstracts of
conference proceedings on PAF receptor antagonists and related terms. The most
important PAF receptor antagonists are reviewed with their effectiveness in
various experimental tests. Fundamentally, PAF antagonists may be divided in two
groups: natural and synthetic compounds. Natural (Ginkgolides, Kadsurenone,
Chantancin, Phomactin, Swietemohonin A, Prehispalone, THC-7-oic acid, Aglafoline,
FR 900452, PCA 4248 and SCH 37370), and synthetic antagonists (CV-3988, CV-6209,
SRI 63-072, SRI 63-441, UR-10324, UR-11353, E-5880, CL 184005, 6-Mono and Bis
aryl phosphate antagonists, TCV-309, Ro-74719, WEB 2086, Y 24180, BN 50726, BN
50727, BN 50730, BN 50739, Ro 24-4736, Ro 24-0238, RP 55778, RP 59227, RP 66681,
YM 264, YM 461, SM 10661, SR 27417, UK 74505, BB 182, BB 823, BB 654, SDZ 64-412,
SDZ 65-123, L 652731, L 659898, L 668750, L 671284, L680573, L 680574, CIS 19,
ABT-299 and Pinusolide) have a great variability in their chemical structure that
might have importance in their different pharmacological profile. The great
majority of these drugs are under development, and only a few have undergone
clinical trials.
PMID- 9395011
TI - Noncutaneous cavernous hemangiomas of the head and neck.
PMID- 9395013
TI - Laryngeal reconstruction with free nonvascularized grafts from the buccal mucosa.
AB - PURPOSE: This study was designed to investigate the suitability of
nonvascularized healthy buccal mucosal graft in reconstruction of subglottic
defects. PATIENTS AND METHODS: The study was conducted over an 11-year period
from 1985 to 1995. Seven nonvascularized healthy buccal mucosal grafts were used
to provide coverage for subglottic defects. The indications for surgery included
chondrosarcoma of the cricoid including two recurrent tumors and one patient with
recurrent subglottic benign laryngeal stenosis. No stenting was used. Period of
follow-up ranged from 1 to 10 years. RESULTS: Graft take was successful in all
cases without complications. CONCLUSION: Healthy nonvascularized buccal mucosal
graft is suitable for reconstruction of subglottic defects. Stenting is not
required.
PMID- 9395012
TI - Using polymerase chain reaction to human papillomavirus in oral and
pharyngolaryngeal carcinomas.
AB - PURPOSE: Increasingly, evidence has shown that human papillomavirus (HPV) plays a
role in the induction of certain carcinomas. The presence of HPV sequences in 56
previously untreated oral and pharyngolaryngeal carcinomas was examined by the
polymerase chain reaction (PCR). MATERIALS AND METHODS: After DNA extraction,
samples underwent 40 replication cycles with specific oligonucleotide primers
corresponding to sequences from the E6 open-reading frame of HPV-6b, HPV-16, and
HPV-18. To determine the E6 genomic integration, positive samples were processed
with specific primers for the corresponding HPV L1 genes. Genomic HPV DNA clones
into PBR 322 was used as positive control. RESULTS: HPV E6 DNA of the 6b and 16
types was detected in 14 patients (25%). The L1 gene was not present. CONCLUSION:
Detected HPV E6 DNA might be integrated into the cell genome in the positive
cases as indicated by the absence of the L1 gene-coding for the viral capside.
Histological and survival rates, were unrelated to the presence of HPV.
PMID- 9395015
TI - Surgical treatment for pulmonary metastases of squamous cell carcinoma of the
head and neck.
AB - PURPOSE: As locoregional control of head and neck cancer has improved, distant
metastases have become increasingly common problems. PATIENTS AND METHODS: To
determine the role of surgical treatment, we reviewed 32 patients with squamous
cell carcinoma (SCC) of the head and neck who underwent thoracotomy for pulmonary
metastases. RESULTS: The overall 5-year survival rate was 32%. The 5-year
survival rate of the patients with SCC of the oral cavity was significantly
poorer than that of the patients with other primary site (15.4% v 45.2%; P =
.01). In the patients with single nodule, extent of the tumor was a significant
prognostic factor (P = .007). Mediastinal lymph node involvement (P = .004) and
pleural invasion (P = .04) also correlated with survival. CONCLUSION: TNM
classification of the primary tumor did not have an impact on survival in this
study. Further studies of a large series should be performed to determine the
indications and modalities of the surgical treatment for pulmonary metastases of
the SCC of head and neck.
PMID- 9395014
TI - Supracricoid partial laryngectomy with cricohyoidoepiglottopexy for "early"
glottic carcinoma classified as T1-T2N0 invading the anterior commissure.
AB - PURPOSE: "Early" glottic squamous cell carcinoma classified as T1-T2N0 with
anterior commissure invasion is conventionnaly managed with vertical partial
laryngectomy (VPL) or radiation therapy (RT). At our insitution, in the early
1980s, vertical partial laryngectomy was progressively replaced by supracricoid
partial laryngectomy with cricohyoidoepiglottopexy (SCPL-CHEP). The medical files
and operative charts of 62 patients with "early" glottic carcinoma classified as
T1-T2N0 invading the anterior commissure, consecutively managed with
cricohyoidoepiglottopexy, were retrospectively reviewed to ascertain whether any
conclusions could be drawn regarding this treatment modality. MATERIALS AND
METHODS: Survival, local control, nodal recurrence, distant metastasis, and
metachronous second primary tumor estimate was analyzed using the Kaplan-Meier
life table method. RESULTS: The 3- and 5-year actuarial survival estimate was
93.3% and 86.5%, respectively. The 3- and 5-year actuarial local control estimate
was 98.2%. The only patient with local recurrence was successfully salvaged with
RT resulting in an overall 100% local control rate and laryngeal preservation
rate. The 3- and 5-year actuarial nodal recurrence estimate was 1.8%. The 3- and
5-year actuarial distant metastasis estimate was 0% and 2%, respectively.
Aspiration related completion total laryngectomy and permanent tracheostomy never
occurred. CONCLUSION: The present retrospective study suggests that
cricohyoidoepiglottopexy for glottic carcinoma classified as T1-T2 invading the
anterior commissure resulted in higher local control rates and overall laryngeal
preservation rate when compared with historical series using either VPL or RT.
Further series are warranted to confirm our results.
PMID- 9395017
TI - Fine-needle aspiration of head and neck masses in children.
AB - PURPOSE: Head and neck masses in children are common. Suspicious or persistent
masses are referred to the otolaryngologist who is faced with the dilemma of
deciding which ones require surgical excision. Fine-needle aspiration (FNA) in
adults helps distinguish lesions requiring excision from those that do not. Few
reports exist of its use in children PATIENTS AND METHODS: Between January 1991
and December 1994, 67 FNAs were performed on children, 29 of which (43%) were for
head and neck masses. Based on the FNA findings, 16 patients underwent surgery.
RESULTS: In 13 patients, the final pathology was consistent with the FNA
findings: granulomatous diseases (3), branchial cysts (3), acute/chronic
lymphadenitis (3), thyroglossal cyst, hemangioma, Hodgkin's lymphoma, and
Castleman's disease (one each). There was one misdiagnosis, no false positives,
and two nondiagnostic specimens. Based on the results of FNA, surgery was not
performed in the remaining 10 patients. The cytology was: cervical
lymphadenopathy (7), abscess formation (1), lymphangioma (1), and leukemia (1).
CONCLUSION: We conclude that FNA in an extremely useful tool in the management of
head and neck masses in children. It is very well-tolerated by children, and we
did not encounter any complications.
PMID- 9395016
TI - Update on intraoperative analysis of mandibular margins.
AB - PURPOSE: Assessing the adequacy of the surgical resection during composite
resection of carcinoma is limited by the ability to evaluate the bone margins.
The standard pathologic evaluation of bone is by decalcification. PATIENTS AND
METHODS: A method of analysis was devised based on histologically proven methods
of cortical invasion and subsequent spread. Frozen-section analysis of cancellous
bone was investigated as a rapid method of evaluating adequacy of the mandibular
resection. This report is an update of previously published results and includes
an increase in the sample size as well as the analysis of additional pathology.
Subjects consisted of 66 patients undergoing full thickness mandibular resection
with 30 cases of histologically proven mandibular invasion qualifying for
evaluation. Results on frozen section were then compared to the permanent section
analysis on the cancellous bone and to the decalcified specimen. RESULTS:
Complete correlation was found between frozen and permanent section results.
Frozen section analysis was able to correctly predict adequacy of resection in 60
of 61 margins. CONCLUSION: Based on these results, the oncologic surgeon can
evaluate bone margins at the time of the resection and adjust the amount of
excision required to eradicate the disease.
PMID- 9395019
TI - Cortical activity of a patient with Usher's syndrome using a cochlear implant.
PMID- 9395018
TI - Eosinophil expression of transforming growth factor-beta and its receptors in
nasal polyposis: role of the cytokines in this disease process.
AB - PURPOSE: Nasal polyposis (NP) is characterized by an increase in inflammatory
processes including fibrosis. Because transforming growth factor beta (TGF-beta)
has been proven to induce fibrosis, we hypothesize that TGF-beta and its
receptors are present in NP and influence polyp development. MATERIALS AND
METHODS: To test this hypothesis, we evaluated distribution
(immunohistochemistry) of TGF-beta isoforms (TGF-beta 1, TGF-beta 2, and TGF-beta
3) and its receptors [(TGF-beta(RI) & TGF-beta(RII)] in NP from 36 NP patients
and in five normal sinus tissue specimens obtained from septoplasty/inferior
turbinectomy. Tissue levels of TGF-beta 1 and TGF-beta 2 levels were determined
by enzyme-linked immunosorbent assay (ELISA) and protein content was determined
by Bio Rad assay (Bio Rad, Richmond, CA). All tissue levels of TGF-beta were
normalized and expressed as pg of TGF-beta per mg of total protein (pg/mg TP).
RESULTS: Immunohistochemical studies showed eosinophils as the major cells
positively staining for TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta(RI), and TGF
beta. In fibrotic sections, increased staining of eosinophils, fibroblast, and
mononuclear cells was found for all three isoforms and both receptors. Evaluation
of tissue levels indicated mean levels of TGF-beta 1 in the NP were 11.64 +/-
22.12 pg/mg TP versus normal control mean 44.36 +/- 22.12 pg/mg TP.TGF-beta 2
mean levels were 11.46 +/- 23.73 pg/mg TP versus normal control mean of 2.03 +/-
1.13 pg/mg TP. NP showed decreased expression of TGF-beta 1 and enhanced
expression of TGF-beta 2 isoforms with presence of their receptors. Higher levels
of TGF-beta 2 correlated with an increase in previous polypectomies perhaps
indicative of severity of disease (P < or = .0001). CONCLUSION: Our studies show
the presence of the TGF-beta isoforms and receptors in NP tissue. The results
support our hypothesis that the eosinophil continues to be a pivotal inflammatory
cell in NP, a differential regulation may govern the activity of TGF-beta in NP,
and hence, the TGF-beta family of cytokines and receptors likely play a key role
in controlling NP formation.
PMID- 9395020
TI - Endonasal endoscopic management in fibrous dysplasia of the paranasal sinuses.
PMID- 9395021
TI - Maxillary sinus ossifying fibroma.
PMID- 9395022
TI - Bone spur presenting as a submandibular mass following free fibula reconstruction
of the mandible.
PMID- 9395023
TI - Candida epiglottitis: clinical implications.
PMID- 9395024
TI - Endoscopic cranionasal resection of anterior skull base tumor.
PMID- 9395025
TI - Alcohol-related traffic fatalities involving children--United States, 1985-1996.
AB - Motor-vehicle-related injuries are the leading cause of death for persons aged 1
24 years in the United States. Although the relation between alcohol use and
motor-vehicle-related deaths involving teenagers is well established,
understanding of the role of alcohol in such deaths among younger children is
limited. To characterize the involvement of alcohol in motor-vehicle-related
deaths of U.S. children aged <15 years during 1985-1996, CDC analyzed data from
the Fatality Analysis Reporting System (FARS) of the National Highway Traffic
Safety Administration (NHTSA). This report summarizes the results of that
analysis, which indicate that approximately one fourth of all traffic deaths
among children aged <15 years involved alcohol and that in nearly two thirds of
passenger deaths involving a legally drunk driver, the child was in the car
driven by the legally drunk driver.
PMID- 9395026
TI - Abortion surveillance: preliminary analysis--United States, 1995.
AB - For 1995, CDC received data about legal induced abortions from the 50 states, New
York City, and the District of Columbia. This report presents preliminary data
for 1995; final abortion data for 1995 will be published during spring 1998.
PMID- 9395027
TI - Use of clinical preventive services by Medicare beneficiaries aged > or = 65
years--United States, 1995.
AB - Delivery of clinical preventive services to older adults can reduce premature
morbidity and mortality while preserving function and enhancing overall quality
of life . Until recently, the use of such services has been low among older
adults because Medicare coverage has not been extended to many preventive
services (3). Medicare coverage now includes four clinical preventive services: a
single lifetime pneumococcal polysaccharide vaccination (vaccine plus any
required revaccination and administration) (since 1981); annual influenza
vaccination (vaccine and administration) (since 1993); and forwomen, biennial
mammography screening (since 1991) and Papanicolaou smear screening every 36
months (since 1990). To assess current state-specific levels of use of these
services among Medicare beneficiaries, CDC and the Health Care Financing
Administration (HCFA) analyzed data from the 1995 Behavioral Risk Factor
Surveillance System (BRFSS). This report summarizes the findings of this
analysis, which indicate that, despite Medicare coverage of these preventive
services, many U.S. adults aged > or = 65 years did not receive such services in
1995, and state-specific use of these services varied substantially.
PMID- 9395028
TI - Efforts to quit smoking among persons with a history of alcohol problems--Iowa,
Kansas, and Nebraska, 1995-1996.
AB - In 1991, approximately 13.8 million adults in the United States met diagnostic
criteria for alcohol abuse, alcohol dependence, or both. In addition, at least
80% of persons in this group were likely to be daily tobacco smokers and,
therefore, at increased risk for oral and pharyngeal cancers. In Minnesota, among
adult smokers with a history of alcohol abuse during 1972-1983, the number of
tobacco-related deaths was higher than the number of alcohol-related deaths. To
assess rates of smoking cessation among adults with a history of alcohol
problems, the University of Nebraska Medical Center conducted an intervention
study with 1 year of follow-up during 1995-1996 in 12 residential alcohol
treatment centers in Iowa, Kansas, and Nebraska. This report summarizes the
findings, which suggest that a substantial proportion of adults recently treated
for alcoholism attempted to quit smoking, even though actual quit rates were low.
PMID- 9395029
TI - Alcohol involvement in fatal motor-vehicle crashes--United States, 1995-1996.
AB - The table and figure on page 1155 compare alcohol involvement in fatal motor
vehicle crashes for 1995 and 1996. A fatal crash is considered alcohol-related by
the National Highway Traffic Safety Administration (NHTSA) if either a driver or
non-occupant (e.g., pedestrian) had a blood alcohol concentration (BAC) of > or =
0.01 g/dL in a police-reported traffic crash. Because BACs are not available for
all persons in fatal crashes, NHTSA estimates the number of alcohol-related
traffic fatalities based on a discriminant analysis of information from all cases
for which driver or nonoccupant BAC data are available.
PMID- 9395030
TI - Long-term follow-up of patients with newly diagnosed acute myeloid leukemia
treated at the University of Texas M.D. Anderson Cancer Center.
AB - BACKGROUND: Chemotherapy is known to cure a small minority of patients with acute
myeloid leukemia (AML). Less is known about the risk of such patients developing
subsequent cancers or about their ability to return to work. METHODS: The authors
analyzed outcomes among 1892 patients who received treatment for newly diagnosed
AML at the University of Texas M. D. Anderson Cancer Center from 1965 to May
1995. RESULTS: Because failure rates declined to relatively low levels after a
first or later complete remission of > or = 3 years' duration, such patients
comprised a "potentially cured" cohort. The criterion for entry into this cohort
was fulfilled by 215 patients (10.7%; 203 in first complete remission and 12 in
second remission). At a median of 6.2 years after entry into the cohort (i.e.,
9.2 years from complete remission), 163 patients (76%) remain alive and in
complete remission. Approximately 9% and 5% of the 1892 patients have been in
complete remission for > 5 years and > 10 years, respectively. The pretreatment
prognostic importance of cytogenetics is still apparent even after 5 years in
complete remission. On average, members of the potentially cured cohort were not
observed to be at increased risk of subsequent invasive malignancies compared
with a normal population. Furthermore, two-thirds of those in the potentially
cured cohort who were working full time before diagnosis of AML claimed to have
returned to full-time work. Of those not working, only 10% cited physical
limitation as the reason. CONCLUSIONS: The major threat to the life and well
being of the patient with AML is clearly the disease and not its treatment.
PMID- 9395031
TI - Long-term follow-up of three randomized trials comparing idarubicin and
daunorubicin as induction therapies for patients with untreated acute myeloid
leukemia.
AB - BACKGROUND: Most clinical trials for acute leukemia have reported results after 2
3 years of follow-up. Comparisons between the original data and longer-term
follow-up data may be of interest, particularly with regard to promising new
therapies. METHODS: In 1996, survival data were updated from three prospective,
randomized comparisons of idarubicin and daunorubicin that began in 1984 and
1985. These were trials of the Memorial Sloan-Kettering Cancer Center (MSKCC),
the U.S. Multicenter Study Group, and the Southeastern Cancer Study Group (SEG).
The original results of these trials were reported in 1991 and 1992. RESULTS: The
original results of the SEG trial demonstrated no significant difference between
idarubicin and daunorubicin. The updated survival analysis showed similar
results. The MSKCC trial revealed a significant advantage of idarubicin compared
with daunorubicin in both the original and the updated analyses. The U.S.
Multicenter trial found a significant difference favoring idarubicin in the
original analysis, but the difference was not significant in the updated
analysis. CONCLUSIONS: It is essential that the median length of follow-up be
clearly stated in any clinical trial. When the results obtained with a
particularly promising new drug or procedure are presented early in the course of
study (within 1-2 years), the investigators should strongly consider a repeat
evaluation after an additional 3-5 years of follow-up.
PMID- 9395032
TI - Long-term survival of patients with acute myeloid leukemia: updated results from
two trials evaluating postinduction chemotherapy.
AB - BACKGROUND: Although the prospect of long-term disease free survival (LFS) after
chemotherapy for acute myeloid leukemia (AML) is widely accepted, few studies
have reported long-term survival data. The authors therefore updated results from
a 1981 report on a study conducted by the University of Minnesota Masonic Cancer
Center (UMMCC) and a 1989 report on a study conducted by the North American
Marrow Transplant Group (NAMTG). METHODS: Minimum follow-up of 21.6 years for
living patients was obtained for 26 patients who received weekly cytarabine and 6
thioguanine maintenance therapy after achieving complete remission (CR) in the
UMMCC study. Minimum follow-up of 7.7 years was obtained on 87 patients treated
with high dose cytarabine intensification in first remission in the NAMTG study.
RESULTS: In the UMMCC study, the LFS rate was 28% and the overall survival rate
was 15%. Nineteen percent of patients died in first CR at 1.3-12 years. Three
patients remain alive in initial CR at >20 years. In the NAMTG study, the LFS
rate was 49% and the overall survival rate was 45%. A total of 38 patients (44%)
remain alive in initial CR at a median of 11.4 years after diagnosis. An
additional patient is alive in second CR at 8.6 years after diagnosis. In both
studies, relapses after 3 years were relatively uncommon (11-12%). CONCLUSIONS:
Chemotherapy alone is curative in more than 40% of AML patients who achieve CR.
Short-term, high dose cytarabine intensification appeared more efficacious,
without increased toxicity, compared with low dose, prolonged cytarabine-based
maintenance. However, for patients who cannot receive intensification, prolonged,
low dose maintenance therapy is an acceptable alternative for achieving cure. A
minimum follow-up of 3 years is a reasonable predictor of long-term survival and
should be obtained in studies evaluating therapeutic outcome in cases of AML.
PMID- 9395033
TI - Long-term survival of patients with acute myeloid leukemia: a third follow-up of
the Fourth International Workshop on Chromosomes in Leukemia.
AB - BACKGROUND: In 1982, the Fourth International Workshop on Chromosomes in Leukemia
reviewed data prospectively collected on 716 patients with acute myeloid leukemia
(AML) diagnosed between 1980 and 1982. The present study examined the extended
follow-up on these patients. METHODS: The analyses included cytogenetic and
clinical data, with a median follow-up of 14.7 years, from 54 patients with
treatment-associated AML and 628 with de novo AML. Of these patients, 291
received induction therapy that would be considered standard by today's criteria;
no patient received high-dose cytarabine (HiDAC) intensification. RESULTS: Among
the patients with treatment-associated AML, the only long-term survivor in
retrospect appears to have had de novo AML. Among the patients with de novo AML,
achievement of complete remission and survival varied significantly based on
cytogenetic classification among all 628 patients as well as among those who did
and did not receive standard induction therapy. The remission rate and survival
were significantly better with standard induction therapy for patients with
t(15;17) and normal cytogenetics. Multivariate analyses showed that karyotype was
an independent predictor of survival for all patients and those receiving
standard induction therapy. Only 8.9% of patients were alive 5 years following
diagnosis, but 5 years of continuous remission was synonymous with cure. Even
among 5-year survivors who had suffered a previous relapse, 41% appeared to be
cured. Survival among patients in continuous remission for > or = 10 years varied
significantly by cytogenetic classification. In the absence of HiDAC
intensification, no complete responders with t(8;21) and only 7% with normal
cytogenetics survived continuously 10 years disease free. CONCLUSIONS: Cure of
AML following specific therapies must be evaluated in the context of
cytogenetics. A meta-analysis incorporating cytogenetic data is indicated for
patients with > or = 10 years of follow-up.
PMID- 9395034
TI - Long-term survival after chemotherapy for acute myeloid leukemia: the experience
of the Southwest Oncology Group.
AB - BACKGROUND: Reports on outcomes of chemotherapy trials in acute myeloid leukemia
(AML) have rarely included results of long-term follow-up beyond 10 years. The
authors therefore chose to review long-term follow-up data from 3 studies
conducted by the Southwest Oncology Group (SWOG) between 1978 and 1990. METHODS:
The analysis included data on 2083 patients enrolled in SWOG studies S7823,
S8124, and S8600. The results were based on data available as of November 15,
1996. RESULTS: The probability of survival 8 years after entry was 9% in Study
S7823, 14% in S8124, and 15% in S8600. For patients age < 50 years, the
probabilities were 14%, 24%, and 20%, respectively. For patients ages 50-64
years, the probabilities were 7%, 8%, and 8%, respectively. For those age < 50
years who achieved complete remission, the 8-year probability of disease free
survival was 17% in Study S7823, 28% in S8124, 17% with standard dose cytarabine
in S8600, and 26% with high dose cytarabine in S8600. Relapse was the major
reason for failure after complete remission in all three studies. When the
results of the 3 studies were combined, most of the 743 relapses had occurred by
Year 3 and nearly all the rest by Year 5. Among the prognostic factors
universally available for study, three were highly associated with survival in
all three studies: age, French-American-British disease classification, and white
blood cell count at diagnosis. CONCLUSIONS: In view of the fact that most deaths
occurred during the first 3 years, it is appropriate to report the results of
clinical trials after patients have been followed for 4 years. Despite modest
gains, the results of chemotherapy for AML remain disappointing, especially in
the treatment of older patients.
PMID- 9395036
TI - Long-term follow-up of Cancer and Leukemia Group B studies in acute myeloid
leukemia.
AB - BACKGROUND: During the past 3 decades, the Cancer and Leukemia Group B (CALGB)
has conducted numerous large clinical trials in adult patients with acute myeloid
leukemia. METHODS: Updated data were obtained for 9 trials initiated by the CALGB
between 1974 and 1992. The updated data were compared with the original published
results. RESULTS: It was apparent from all the studies that hazard rates for
death and relapse are greatest in the first year, decrease substantially between
Years 1 and 2, then decrease further between Years 2 and 3. Rates of death and
relapse are quite low after 3-4 years. Large numbers of patients are long-term
disease free survivors. Overall, these patients have excellent function and a
normal quality of life. CONCLUSIONS: Patients with AML who are in complete
remission for 3-4 years can be assured that late relapse and death are relatively
uncommon events. It is inadvisable to publish results of large studies until this
minimal level of follow-up has been reached.
PMID- 9395035
TI - Long-term survival in acute myeloid leukemia: the Eastern Cooperative Oncology
Group experience.
AB - BACKGROUND: The data base of the Eastern Cooperative Oncology Group (ECOG)
provides access to data on a large adult patient population drawn from more than
25 major university institutions and hundreds of participating hospitals.
Extensive medical files are maintained at the ECOG Coordinating Center and are
updated regularly. METHODS: Data on 1414 eligible patients with acute myeloid
leukemia (AML), treated on 6 ECOG protocols during the period 1976-1994, were
reviewed to determine the number of long-term survivors (LTS) and to identify
factors that predicted LTS. Disease free survival and factors impacting quality
of life were examined as well. RESULTS: Of the 1414 patients, 274 survived for >
or = 3 years and were considered LTS. A logistic regression analysis revealed
that factors predicting LTS included age < 55 years, female gender, treatment
between 1985 and 1990, white blood cell count < 10,000 cells/mm3, and hemoglobin
> 10 g/dL. Disease free survival improved with escalating intensity of therapy.
Quality-of-life data showed that infections were fairly common. Significant graft
versus-host disease occurred in 6 of 40 patients who received allogeneic bone
marrow transplantation and contributed to the deaths of 4 individuals.
Information on employment, insurance, social or marital difficulties, and
psychosocial issues was more difficult to obtain. CONCLUSIONS: Prognosis in AML
is a complex interaction involving the cellular origin of the malignant clone,
morphology, and evolving therapeutic strategies. The most recent ECOG studies
incorporate these variables and should provide additional insights into factors
affecting LTS in patients with AML.
PMID- 9395037
TI - Conclusions regarding leukemia long-term survival.
PMID- 9395039
TI - Mechanical valve closing dynamics: relationship between velocity of closing,
pressure transients, and cavitation initiation.
AB - In this study, the closing dynamics of mechanical heart valves was experimentally
analyzed with the valves mounted in the mitral position of an in vitro flow
chamber simulating a single closing event. The average linear velocity of the
edge of the leaflet during the final 2.065 degrees of the traverse before closing
was measured using a laser sweeping technique, and the negative pressure
transients at 2 mm from the leaflet inflow surface in the fully closed position
was recorded at the instant of valve closure. The cavitation number was computed
for the various mechanical valves at a range of load at valve closure. The data
were correlated with cavitation bubble visualization previously obtained with the
same experimental set up. Cavitation incipience with mechanical valves was found
to be independent of the flexibility of the valve holder. For the same loading
rate at valve closure, valves with flexible (polyethylene) leaflets were found to
close with comparable velocity to those with rigid (pyrolytic carbon) leaflets,
but the negative pressure transients did not reach magnitudes close to the vapor
pressure for the fluid with flexible leaflets. For the same leaflet closing
velocity (and hence the cavitation number), valves with a seat stop or a seating
lip in the region of maximum leaflet velocity were observed to cavitate earlier,
suggesting that the effect of "squeeze flow" may be an important factor in
cavitation incipience.
PMID- 9395038
TI - Thin layer flows due to surface tension gradients over a membrane undergoing
nonuniform, periodic strain.
AB - Measurements of surface tension in the lung have shown that a time-mean gradient
exists with the potential to generate clearance flows toward the mouth in the
thin liquid layer that lines the airways. A model is developed to explore this
phenomenon in the simple case of a membrane with linear variation in strain along
its length, coupled with the unique properties of pulmonary surfactant. The
evolution equations are solved numerically for liquid layer thickness and
surfactant concentration during a single oscillatory cycle, and the net volume
exchanged is computed. The parameters governing the flow are shown to be time
scales for viscous effects, tau(v), surface diffusion, tau(DS), surfactant
adsorption, tau(A), surfactant desorption, tau(D), oscillation, tau(o), and the
average membrane strain epsilon. The volume pumped toward the less compliant end
on the initial cycle is maximized when tau(o)/tau(v) approximately O(1) and is
relatively insensitive to tau(DS). Rapid adsorption generally augments liquid
transport for tau(o)/tau(D) < O(1). Pumping drops precipitously if tau(o)/tau(D)
> O(1). Effects of strain amplitude are reported as well. For parameter values
approximating those in the lung, pumping rates are near optimal; the mean surface
velocity is approximately 0.05 mm/sec, compared with 0.2 mm/sec produced by the
action of cilia on the mucus layer. This mechanism might therefore be important
in assisting clearance from the lung or maintaining a liquid layer over alveolar
facets.
PMID- 9395040
TI - Velocity measurements within confined turbulent jets: application to
cardiovalvular regurgitation.
AB - An expression for centerline mean velocity distributions for circular and
noncircular confined turbulent jets has been obtained by assuming self
preservation of flow downstream of the jet potential core. It was assumed that
the velocity decay was not only dependent on the streamwise distance x in terms
of x/d, as in the case of free jets, but also on the ratio of the orifice
diameter d to the confining pipe diameter D. To validate the expression and to
determine the empirical constants, measurements of the centerline velocities
within the confined jets issuing from different size circular orifices and
various noncircular orifices of different shapes were conducted. The results
indicate that the validity of the expression is restricted to d/D < or =0.25 and
is weakly dependent on the particular orifice shape. It is suggested that, as for
the case of free turbulent jets reported earlier, that this expression may be
used potentially to predict the valvular lesion size or to estimate the volume of
valvular regurgitation for confined jets provided the value of D, which
corresponds to the "atrial diameter," is known or statistically available.
PMID- 9395041
TI - The role of spatial interactions in creating the dispersion of transmembrane
potential by premature electric shocks.
AB - Strong electric shocks applied during the refractory period can initiate or
terminate cardiac arrhythmias. To elucidate the underlying mechanism, Knisley et
al. used rabbit papillary muscle in vitro to scan the refractory period of an
action potential with shocks of different strengths. The resulting map of the
shock-induced changes in the transmembrane potential (Vm) illustrates the
substrate for the creation of rotors. Our study uses computer simulations to
reproduce this experimental map. Three models (a space-clamped membrane, a single
cell, and a one-dimensional fiber) were used to determine whether the observed
map was caused by (i) the intrinsic dynamics of the membrane, (ii) the
simultaneous depolarization and hyperpolarization of the opposite ends of each
cell, or (iii) spatial interactions involving the whole muscle strand. The
results show that the membrane and single cell models cannot reproduce the
experimental map. The fiber model reproduces the shock-induced changes in Vm and
demonstrates that they are caused by a propagating disturbance, which, depending
on the coupling interval and the shock strength, can be a new action potential or
an electrotonus and can arrive from the depolarized end or from both depolarized
and hyperpolarized ends of the fiber. These results indicate that the induction
of rotors in the heart may not be a direct effect of the electric field.
PMID- 9395043
TI - Time-frequency coherence analysis of atrial fibrillation termination during
procainamide administration.
AB - A time-frequency coherence estimator is developed and applied to study changes in
signal characteristics as atrial fibrillation converts to sinus rhythm during
administration of procainamide. A coherence spectrogram (CS) using multiple
sinusoidal tapers is used in this study to assess phase relations between
electrogram recordings at multiple atrial sites of seven patients who received
procainamide to terminate atrial fibrillation. CSs are calculated (0 to 60 Hz)
with 1 sec time resolution and 6.2 Hz frequency resolution. In agreement with
previous studies, CSs generally exhibit low coherence during atrial fibrillation.
Conversion to sinus rhythm is concomitant with an increase in coherence and
emergence of structured time-frequency topography. Transition from atrial
fibrillation to sinus rhythm is associated with a variety of time-frequency
dynamics. Both gradual and abrupt increases in coherence coincide with
conversion. Results suggest transient electrical organization in the atria during
atrial fibrillation not seen in previous low-resolution coherence studies. CSs
permit investigation of rhythm organization with unparalleled time and frequency
resolution and thus are useful for studying transient changes in cardiac rhythms
that may reflect underlying mechanisms.
PMID- 9395042
TI - Mechanisms by which thrombolytic therapy results in nonuniform lysis and residual
thrombus after reperfusion.
AB - A transport-reaction model describing penetration of plasmin by diffusion and
permeation into a dissolving fibrin gel was solved numerically to explore
mechanisms that lead to the formation and growth of dissolution fingers through
blood clots during thrombolytic therapy. Under conditions of fluid permeation
driven by arterial pressures, small random spatial variations in the initial
fibrin density within clots (+/-4 to 25% peak variations) were predicted by the
simulation to result in dramatic dissolution fingers that grew in time. With in
vitro experiments, video microscopy revealed that the shape of the proximal face
of a fibrin gel, when deformed by pressure-driven permeation, led to lytic
breakthrough in the center of the clot, consistent with model predictions of
increased velocities in this region leading to cannulation. Computer simulation
of lysis of fibrin retracted by platelets (where more permeable regions are
expected in the middle of the clot due to retraction) predicted cannulation of
the clot during thrombolysis. This residual, annular thrombus was predicted to
lyse more slowly, because radial pressure gradients to drive inner clot
permeation were quite small. In conjunction with kinetic models of systemic
pharmacodynamics and plasminogen activation biochemistry, a two-dimensional
transport-reaction model can facilitate the prediction of the time and causes of
clot cannulation, poor reperfusion, and embolism during thrombolysis.
PMID- 9395044
TI - A comprehensive simulator of the human respiratory system: validation with
experimental and simulated data.
AB - A comprehensive model of oxygen (O2) and carbon dioxide (CO2) exchange,
transport, and storage in the adult human is presented, and its ability to
provide realistic responses under different physiological conditions is
evaluated. The model comprises three compartments (i.e., lung, body tissue, and
brain tissue) and incorporates a controller that adjusts alveolar ventilation and
cardiac output dynamically integrating stimuli coming from peripheral and central
chemoreceptors. A new realistic CO2 dissociation curve based on a two-buffer
model of acid-base chemical regulation is included. In addition, the model
explicitly considers relevant physiological factors such as buffer base, the
nonlinear interaction between the O2 and CO2 chemoreceptor responses, pulmonary
shunt, dead space, variable time delays, and Bohr and Haldane effects. Model
simulations provide results consistent with both dynamic and steady-state
responses measured in subjects undergoing inhalation of high CO2 (hypercapnia) or
low O2 (hypoxia) and subsequent recovery. An analysis of the results indicates
that the proposed model fits the experimental data of ventilation and gas partial
pressures as some meaningful simulators now available and in a very large range
of gas intake fractions. Moreover, it also provides values of blood
concentrations of CO2, HCO3-, and hydrogen ions in good agreement with more
complex simulators characterized by an implicit formulation of the CO2
dissociation curve. In the experimental conditions analyzed, the model seems to
represent a single theoretical framework able to appropriately describe the
different phenomena involved in the control of respiration.
PMID- 9395045
TI - Nonparametric block-structured modeling of rat lung mechanics.
AB - The quasistatic and dynamic pressure volume characteristics of the lungs were
measured in five anesthetized, paralyzed open-chest rats. Psuedo-random volume
perturbations over a frequency range of 0.25 to 25 Hz and having peak-peak
amplitudes of 1 to 4 ml were applied after the lungs were allowed to expire
against 0.2, 0.4, 0.6, and 0.8 kPa positive end-expiratory pressure (PEEP). The
lung mechanics were partitioned in two ways: a linear dynamic block followed by a
static nonlinearity (Wiener model) and a static nonlinearity ahead of a linear
dynamic block (Hammerstein model). It was found that a Hammerstein model
featuring a third-order polynomial static nonlinearity and a linear impulse
response function of 1-sec duration accounted for the greatest amount of the
output variance (98.8 +/- 0.6%, mean +/- SD from perturbations of 4 ml amplitude
and PEEP = 0.8 kPa). The static nonlinear behavior matched the measured
quasistatic pressure volume behavior obtained at the same amplitude and at the
same level of PEEP, provided that all direct current gain of the model was
located within the static nonlinearity. Under these conditions, the linear
resistance was inversely dependent on the PEEP, whereas little PEEP or amplitude
dependence of the linear compartment elastance was observed. Thus, of the two
block-structured models tested, the Hammerstein model accounted better for the
large amplitude nonlinear mechanical behavior. However, neither model could
account for the dependence of the linear block resistance on PEEP.
PMID- 9395046
TI - Experimental and numerical analyses of indentation in finite-sized isotropic and
anisotropic rubber-like materials.
AB - Indentation tests perpendicular to the major plane of a material have been
proposed as a means to index some of its in-plane mechanical properties. We
showed the feasibility of such tests in myocardial tissue and established its
theoretical basis with a formulation of small indentation superimposed on a
finitely stretched half-space of isotropic materials. The purpose of this study
is to better understand the mechanics of indentation with respect to the relative
effects of indenter size, indentation depth, and specimen size, as well as the
effects of material properties. Accordingly, we performed indentation tests on
slabs of silicone rubber fabricated with both isotropic, as well as transversely
isotropic, material symmetry. We performed indentation tests in different
thickness specimens with varying sizes of indenters, amounts of indentation, and
amounts of in-plane stretch. We used finite-element method simulations to
supplement the experimental data. The combined experimental and modeling data
provide the following useful guidelines for future indentation tests in finite
size specimens: (i) to avoid artifacts from boundary effects, the in-plane
specimen dimensions should be at least 15 times the indenter size; (ii) to avoid
nonlinearities associated with finite-thickness effects, the thickness-to-radius
ratio should be >10 and thickness to indentation depth ratio should be >5; and
(iii) we also showed that combined indentation and in-plane stretch could
distinguish the stiffer direction of a transversely isotropic material.
PMID- 9395047
TI - Extraction forces and tissue changes during explant of CWRU-type intramuscular
electrodes from rat gastrocnemius.
AB - Intramuscular electrodes are currently in use for clinically implementing several
electrotherapeutic and neuroprosthetic protocols. A decrease in motor recruitment
is often reported in these systems due to movement of the electrode tip from the
initial implant site. In the study reported here, multistrand intramuscular
electrodes of the CWRU design were implanted aseptically in the gastrocnemii of
adult rats under anesthesia. These electrodes were explanted immediately after
implant in one group and after periods of 1 and 4 hr; 1, 3, and 5 days; 1 week;
10 days; and 2 and 4 weeks in others. Force as a function of displacement was
recorded during explantation. Analysis of the results showed that there was a
significant increase in the force required to dislodge the electrode tip between
5 and 7 days of implant. Electrodes seemed to be vulnerable to movement in the
first 5 days when the barb provided the only fixation. Histology of muscles from
which electrodes had been explanted did not show any increase in the area of
tissue changes, compared with control muscles in which the electrode remained in
situ. These results indicated that electrode removal occurred within the
encapsulation tissues, and the surrounding muscle was mainly unaffected by the
explant process.
PMID- 9395048
TI - Segmentation of depth-EEG seizure signals: method based on a physiological
parameter and comparative study.
AB - The analysis of stereoelectroencephalographic (intracerebral recording) signals
provides information on the electrical activity of brain structures implied in
epileptic seizures. A simple nonparametric adaptive segmentation method, based on
a physiologically relevant parameter, is presented and compared with three
methods reported in the literature. The comparative frame allows us to
objectively test methods for their performances on the same basis. Results show
that the proposed method is robust with respect to the types of change studied
and easier to conduct, even if it is less accurate about the estimation of
instants of change than another method presented in this study. Signals are
segmented throughout the duration of seizures without parameter readjustment and
generate instants of change in accordance with those interactively delimited by
the clinician.
PMID- 9395049
TI - An artificial neural network-based controller for the control of induced
paralysis using vecuronium bromide.
AB - This study presents an artificial neural network-based controller for regulating
the level of induced paralysis during surgery using vecuronium bromide. The
controller uses the myogram of a rapid muscle contractions (called twitch) to
generate the appropriate infusion rate. The controller is self-adjusting and can
accommodate inter- and intrapatient drug response variations. It also withstands
changes in the pure time delay and nonlinear pharmacokinetic parameters of the
response. Another feature of the controller is that it does not depend on a
priori knowledge of the patient response model. Computer simulations using
pharmacokinetic and pharmacodynamic models showed negligible steady-state error
and maximum percent undershoot averaged to 6.24%. The average infusion rate for
90% paralysis was 1.22 (microg x kg(-1) x min[-1]).
PMID- 9395050
TI - Do increased electrogastrographic frequencies always correspond to internal
tachygastria?
AB - This study was undertaken to investigate the possible origin of some cutaneously
recorded higher frequency electrogastrographic signals. Computer modeling of
gastric electrical uncoupling was performed using previously described conoidal
dipole model. Cutaneous electrogastrograms were simulated after uncoupling was
introduced. In separate, real-life experiments, 6 pairs of bipolar electrodes
were inserted into the gastric wall (3 anterior, 3 posterior) of 15 anesthetized
dogs at laparotomy to record 6 channels of internal gastric electrical activity
(GEA). Eight-channel bipolar cutaneous electrogastrography (EGG) was
simultaneously recorded. Three separate 1/2-hr recordings were made from each dog
in the basal state and after each of two circumferential cuts of all gastric
muscle. Distal stomach was surgically divided into three equal-sized areas, each
with an electrode pair in its anterior and posterior walls. Gastric electrical
activity and EGG were digitized, bandpass-filtered and analyzed in frequency
domain using the fast Hartley transform. The phenomena of tachygastria and
tachyarrhythmia were quantitatively compared in internal and cutaneous
recordings. Computer modeling indicated that it is possible to record cutaneous
"tachygastric" or "tachyarrhythmic" signals without them being present
internally. Real experiments on dogs showed higher percentage of tachyarrhythmia
in EGG than in the internal signal in the basal state. After the first
circumferential cut, the periods of tachygastria and tachyarrhythmia increased,
with EGG signals showing again a higher percentage. This tendency persisted after
the second circumferential cut. A similar pattern was observed when monitoring
the percentage of uncorresponding tachygastrias/tachyarrhythmias. Our findings
indicate that gastric electrical uncoupling can be another possible reason for
abnormal frequency characteristics of EGG. Not all cutaneously recognized
tachygastrias and/or tachyarrhythmias could be related to objectively existing
internal tachygastric events.
PMID- 9395051
TI - Automatic segmentation of intravascular ultrasound images: a texture-based
approach.
AB - Extraction of blood vessel boundaries from intravascular ultrasound images is
essential in the quantitative analysis of cardiovascular functions. In this
study, we are presenting a completely automated procedure for determining blood
vessel borders. This approach uses textural operators to separate different
tissue regions and morphological processing to refine extracted contours. The
method was tested in a set of 29 intravascular ultrasound images obtained in
vivo. To assess the performance of the method, we have compared the automatically
processed images with the manual tracings, using three different criteria:
correlation coefficient, match ratio, and relative error of computed shape
parameters. In both contour detection and shape parameters estimation, the
proposed method yielded consistently good results. Due to its robustness and
accuracy, this approach is appropriate for clinical use, whereas computational
efficiency of the method facilitates low-cost implementation.
PMID- 9395052
TI - Controlling receptor-ligand contact to examine kinetics of T cell activation.
AB - A method for controlling the contact of cell-surface receptors with immobilized
ligands has been developed. Cells are trapped in an asymmetric liquid film that
can be quantitatively thinned by reducing the film's capillary pressure. Ligands
adsorbed to the liquid-solid interface are forced into increasingly tighter
contact with the cells as the air-liquid interface is drawn down. Controlling the
degree of thinning allows study of repulsive forces, and controlling its time
course produces a definite time 0 for analyzing signal transduction. This system
was tested by examining the time course of calcium mobilization in T cells upon
activation with anti-CD3 antibody at different dilutions and ionic strengths. The
averaged calcium transient of the responding cells was essentially the same for
each condition. However, the fraction of responding cells decreased with anti-CD3
dilution, and indicated that the critical ligand density for T cell activation
lies between approximately 35 and 70 molecules of anti-CD3 per microm2.
Decreasing the medium's ionic strength from the normal value of 157 mM to 57 mM
did not affect either the average calcium response profile or the fraction of
responding cells, but strongly affected receptor-ligand contact, decreasing the
percent of spontaneous activation from 38% to 5%. Such an imposed decrease sets
the stage for film thinning to impose much greater control of receptor-ligand
contact.
PMID- 9395053
TI - Three-component laser Doppler velocimetry measurements in the regurgitant flow
region of a Bjork-Shiley monostrut mitral valve.
AB - Three-dimensional laser Doppler velocimetry measurements were acquired in a mock
circulatory loop proximal to a Bjork-Shiley monostrut valve in the mitral
position, and synchronous ensemble-averaging was applied to form an "average"
beat. Two axial locations in the regurgitant flow region of the valve (in the
minor orifice) were mapped, and maximum Reynolds shear stresses were calculated.
A large spike in regurgitant flow was noted at the beginning of systole, which
may be the squeeze flow phenomenon computed by other researchers. A region of
sustained regurgitant flow 50 msec later was the focus of this study. Maximum
velocities of approximately 3.7 mps were noted, and maximum Reynolds shear
stresses of approximately 10,000 dyne/cm2 were calculated. Comparisons were made
of two-dimensional (ignoring tangential component) versus three-dimensional shear
stresses, and, in this case, in regions of high stress, the differences were
insignificant. This suggests that the tangential component of velocity can
probably be ignored in similar measurements where the tangential velocity is
likely to be small.
PMID- 9395054
TI - Advances and pitfalls in the diagnosis of Lyme disease.
PMID- 9395055
TI - Aggregation-promoting factor in human vaginal Lactobacillus strains.
AB - A total of 60 Lactobacillus sp. strains were examined for expression of auto
aggregation and cell surface hydrophobicity. Isolates were obtained from the
vagina of healthy women (n = 20). The results obtained showed that the occurrence
of cell surface hydrophobicity correlated with auto-aggregative activity in 12
homofermentative Lactobacillus sp. strains. The aggregation mechanism was
mediated by the presence of an aggregation promoting factor (APF) in one
Lactobacillus sp. strain, HV 142. APF was confirmed by DNA hybridisation with a
1.3 kb PstI DNA fragment of recombinant plasmid pFDS containing the reading open
frame of the APF gene derived from Lactobacillus plantarum 4B2. Coaggregation
activity was seen in three strains of auto-aggregative human vaginal lactobacilli
and five strains of P-fimbriated uropathogenic Escherichia coli. Moreover, one of
four Lactobacillus sp. strains (HV 389) aggregated with two of five E. coli
tested. These results suggest that APF producing lactobacilli could represent a
further mechanism in the interaction of commensal microflora with strains of
uropathogenic E. coli.
PMID- 9395056
TI - Epitope mapping Candida albicans proteinase (SAP 2).
AB - The continuous epitopes of Candida albicans proteinase SAP 2 were derived by
epitope mapping with sera from patients with oral candidiasis (n = 3), necropsy
proven disseminated candidiasis (n = 5), paired sera from patients who had
recovered from blood culture-proven disseminated candidiasis (n = 3) and
infection due to Candida parapsilosis (n = 2) and Candida tropicalis (n = 2). In
C. albicans infection, IgM identified epitopes in amino acid positions 57-61
(QAVPV), 146-151 (SQGTLY) and 346-351 (PYDKCQ) and IgG at position 386-390
(VKYTS). For C. tropicalis IgM and IgG were positive for the same epitopes whilst
IgG also detected epitopes at 78-83 (SNNQKL) and 159-164 (GVSIKN). For C.
parapsilosis, IgM was positive for SNNQKL and IgG detected no epitopes.
Reactivity of two of the epitopes as peptides KTSKRQAVPVTL and SLAQVKYTSASSI was
confirmed in an indirect ELISA. At a cut-off optical density of 0.4, IgM against
either peptide was associated with survival but present in only about half of the
sera (n = 60) from patients who recovered from disseminated candidiasis whilst
IgG levels were disappointing. Human recombinant antibodies from a patient who
had recovered from disseminated candidiasis against either of these peptides had
no activity in a lethal mouse model of candidal infection.
PMID- 9395057
TI - Differentiation between Debaryomyces hansenii/Candida famata complex and Candida
guilliermondii by polymerase chain reaction.
AB - Primers for the differentiation of the Debaryomyces hansenii/Candida famata
complex were designed from large subunit ribosomal DNA base sequences. With these
primers, a polymerase chain reaction test amplified DNAs from all the species of
the Debaryomyces hansenii/Candida famata complex and distinguished this complex
from Candida guilliermondii.
PMID- 9395058
TI - Enhanced production of inducible nitric oxide synthase by beta-glucans in mice.
AB - We have already demonstrated that various activities including NO (nitric oxide)
synthesis in vivo and in vitro significantly differ between triple helical (SPG)
and single helical (alkaline-treated SPG, SPG-OH) beta-glucans. It was previously
suggested that the single helical conformer of beta-glucan (SPG-OH) was dominant
in cytokine production and subsequent NO synthesis in vitro. In this study, we
analyzed production of inducible nitric oxide synthase (iNOS) induced by beta
glucans in vitro and in vivo. The iNOS production was enhanced in proteose
peptone-induced peritoneal macrophages (PMs) cultured with SPG-OH in the presence
of IFN-gamma for 24 h, and SPG-OH-induced PMs. Moreover, SPG-OH was effective for
iNOS production not only in isolated macrophages but also in tissue macrophages,
whereas SPG was less effective. These findings suggest that a single helical
conformer is essential for iNOS production, and that NO synthesis by beta-glucans
is closely related to iNOS production.
PMID- 9395059
TI - Cloning and characterization of a Campylobacter jejuni 72Dz/92 gene encoding a 30
kDa immunopositive protein, component of the ABC transport system; expression of
the gene in avirulent Salmonella typhimurium.
AB - Three gene libraries of Campylobacter jejuni 72Dz/92 DNA were prepared using
lambda gt11, pSupercos and pWSK129 cloning vectors. Screening of the libraries
with Escherichia coli absorbed antiserum generated against whole C. jejuni
revealed several immunoreactive clones of apparent molecular masses 19, 28, 30
and 50 kDa. The most commonly isolated clones expressed 30 kDa protein. The
nucleotide sequence of the 1768 bp C. jejuni DNA yielded one complete (ORF2) and
two partial open reading frames (ORF1 and ORF3). ORF2 encoded CjaA protein
exhibits relevant overall homology to several prokaryotic solute binding proteins
(family 3), components of the ABC transport system, while the product of the
truncated ORF3 (CjaB protein) shows extensive homology to Gram-negative bacterial
proteins, members of the sugar transporter family. The genetic organization of
the putative cjaAB operon was studied. The cjaA gene fragment (616 bp) was
amplified from three C. jejuni strains isolated from patients with acute bloody
diarrhea, whereas it was not amplified from strains which caused acute diarrhea
with no blood in the stools. The gene was introduced into avirulent Salmonella
typhimurium vaccine strain where it is expressed at a reasonably high level.
PMID- 9395060
TI - Simultaneous detection of Streptococcus pneumoniae and Haemophilus influenzae by
nested PCR amplification from cerebrospinal fluid samples.
AB - Haemophilus influenzae and Streptococcus pneumoniae are often the cause of
serious diseases such as meningitis. We designed a nested PCR assay to identify
these pathogens from cerebrospinal fluid samples. The first-step PCR was able to
detect eubacterial rRNA genes with a unified set of universal primers. In the
second-step PCR, the identification primers, HI I and II and SP I and II, could
detect H. influenzae and S. pneumoniae respectively through amplification of the
rRNA spacer between the 16S and 23S rRNA genes. We suggest that the two-step PCR
assay can be used as a novel method for the immediate and retrospective diagnosis
of bacterial meningitis caused by H. influenzae and S. pneumoniae.
PMID- 9395061
TI - Analysis of the human Ig isotype response to individual transferrin binding
proteins A and B from Neisseria meningitidis.
AB - Subcapsular antigens, including transferrin binding proteins, are being
considered as potential vaccines against serogroup B meningococci. This study
examined the human isotype antibody responses in cases of meningococcal disease
to meningococcal TbpA (transferrin binding protein A) and TbpB (transferrin
binding protein B) from two strains (SD and B16B6) expressing high and low
molecular mass TbpB respectively. TbpA isolated from both strains were recognised
more frequently and higher durable ELISA absorbance values were detected than
those detected against TbpB from either strain. These antibody responses to Tbps
were independent of the infecting meningococcal strain type. The antibody
response to the four proteins was highly variable between individuals and
differed significantly against all four antigens. The variability of immune
responses to each Tbp from the two strains suggests that a successful vaccine
would need to include TbpA and TbpB from a number of strains.
PMID- 9395062
TI - Interleukin-4 suppresses antifungal activity of human mononuclear phagocytes
against Candida albicans in association with decreased uptake of blastoconidia.
AB - Pathogenesis of invasive candidiasis may involve regulatory activities of Th2
immunity on phagocytic host defenses. The effects of interleukin (IL)-4 on
antifungal capacity of human mononuclear phagocytes against Candida albicans were
studied. Incubation of adherent mononuclear leukocytes from healthy donors with
IL-4 (1-5 ng ml(-1)) at 37 degrees C for 2-4 days suppressed uptake of C.
albicans blastoconidia in the presence of human serum (P < or = 0.01), and anti
IL-4 inhibited its suppressive effect. The effect of IL-4 was protein synthesis
dependent. Interferon-gamma (0.25-25 ng ml(-1)), granulocyte-macrophage colony
stimulating factor (CSF, 20 ng ml(-1)), macrophage-CSF (15 ng ml(-1)) but not IL
10 (100 ng ml(-1)) somewhat counteracted the suppressive effect of IL-4. In
contrast, mannose receptor-mediated uptake of blastoconidia in the absence of
serum was increased by IL-4. Killing of conidia was decreased after incubation of
morphonuclear leukocytes with IL-4 for 2 days (P < 0.05). While superoxide anion
production in response to phorbol myristate acetate was decreased by IL-4 (P <
0.05), it was not altered in response to blastoconidia and pseudohyphae.
Morphonuclear leukocyte-induced pseudohyphal damage also remained unaltered.
These findings suggest that IL-4 plays its detrimental role in invasive
candidiasis by predominantly suppressing uptake and killing of blastoconidia by
morphonuclear leukocytes. Anti-IL-4, IFN-gamma, GM-CSF and M-CSF appear to
counteract suppression of morphonuclear leukocyte phagocytic activity suggesting
new approaches to the management of disseminated candidiasis.
PMID- 9395063
TI - Alu sequences.
AB - Alu sequences are frequently encountered during study of human genomic nucleic
acid and form a major component of repetitive DNA. This review describes the
origin of Alu sequences and their subsequent amplification and evolution into
distinct subfamilies. In recent years a number of different functional roles for
Alu sequences have been described. The multiple influences of Alu sequences on
RNA polymerase II-mediated gene expression and the presence of Alu sequences in
RNA polymerase III-generated transcripts are discussed.
PMID- 9395064
TI - SHP-1 is involved in neuronal differentiation of P19 embryonic carcinoma cells.
AB - Accumulating evidence suggests that tyrosine phosphorylation plays an important
role in the development of the central nervous system and in the differentiation
of neuronal cells. To identify protein tyrosine phosphatases (PTPs) that might
regulate signaling events leading to neuronal cell differentiation, we cloned PTP
genes from the murine P19 embryonic carcinoma cell line and examined the change
of their expression during differentiation. P19 cells are known to be pluripotent
and the aggregate formation and subsequent replating in the presence of retinoic
acid (RA) induce growth arrest and neuronal differentiation. The results
demonstrated that among several PTP genes expressed in P19 cells, a cytosolic Src
homology region 2 domain-containing PTP, SHP-1, is expressed highly in
undifferentiated P19 cells, but is reduced to an undetectable level at day 3
after replating in the presence of RA. Further, SHP-1 was tyrosine-phosphorylated
and activated at day 1 after replating. When ectopic SHP-1 was constitutively
expressed, P19 cells continued to proliferate and failed to differentiate upon
stimulation with RA. Collectively, these results suggest that the regulated
expression and activity of SHP-1 may be involved in the neuronal differentiation
of P19 cells.
PMID- 9395065
TI - Overexpression of hIGF-1 exclusively in skeletal muscle increases the number of
dihydropyridine receptors in adult transgenic mice.
AB - The number of dihydropyridine receptors (DHPR) and sarcoplasmic reticulum (SR)
Ca2+ release channels (RyR1) and their interaction determine the efficacy of the
sarcolemmal excitation-SR Ca2+ release-contraction coupling (ECC). Both receptors
play a central role in ECC as demonstrated in various animal species and muscle
subtypes. In the present work we studied the effect of transgenic overexpression
of human insulin-like growth factor 1 (hIGF-1) on the levels of these two Ca2+
channels in extensor digitorum longus (EDL) (fast-twitch), soleus (slow-twitch)
and pool of fast- and slow-twitch muscles from adult C57BL/6 mice. Muscles from
hIGF-1 transgenic mice showed a significant increase in IGF-1 concentration (20
30-fold) and in the number of DHPR (52% increase) whereas no significant change
in RyR1 binding sites was detected. The differential effect on DHPR and RyR1
resulted in a 30% increase in DHPR/RyR1 ratio. Fast- and slow-twitch muscles
showed 50 and 70% increase in the number of DHPR and 30 and 80% increase in
DHPR/RyR1, respectively. These results support the concept that the increased
autocrine/paracrine secretion of hIGF-1 exerts potent stimulatory effects on DHPR
alpha1 subunit expression in adult skeletal muscle.
PMID- 9395066
TI - Increased expression of alpha-enolase in c-jun transformed rat fibroblasts
without increased activation of plasminogen.
AB - Two-dimensional gel electrophoresis was used to identify polypeptides
differentially expressed between normal and c-jun transformed rat fibroblasts.
The level of a 49 kDa polypeptide was 3-fold elevated in c-jun transformed cells.
Sequence analysis by ion trap mass spectrometry identified the polypeptide as rat
alpha-enolase. Enolase functions as a cell surface receptor for plasminogen,
suggesting that upregulation may increase plasminogen activation and cell surface
proteolysis important for tumor growth. However, no difference was observed
between normal and transformed cells in formation of plasmin, suggesting that
upregulation of alpha-enolase may contribute to an increased metabolic capacity,
but not to increased plasminogen activation.
PMID- 9395067
TI - Functional assessment of the yeast Rvs161 and Rvs167 protein domains.
AB - Mutations in RVS161 and RVS167 yeast genes induce identical phenotypes associated
to actin cytoskeleton disorders. The whole Rvs161 protein is similar to the amino
terminal part of Rvs167p, thus defining a RVS domain. In addition to this domain,
Rvs167p contains a central glycine-proline-alanine rich domain and a SH3 domain.
To assess the function of these different domains we have expressed recombinant
Rvs proteins in rvs mutant strains. Phenotype analysis has shown that the RVS and
SH3 domains are necessary for phenotypical complementation, whereas the GPA
domain is not. Moreover, we have demonstrated that the RVS domains from Rvs161p
and Rvs167p have distinct roles, and that the SH3 domain needs the specific RVS
domain of Rvs167p to function. These results suggest that Rvs161p and Rvs167p
play distinct roles, while acting together in a common function.
PMID- 9395069
TI - Expression of Reticulomyxa filosa tubulins in Pichia pastoris: regulation of
tubulin pools.
AB - We expressed the alpha2- and beta2-tubulin isoforms of the giant freshwater
amoeba Reticulomyxa filosa in the methylotrophic yeast Pichia pastoris. Single
expression lead to little or no detectable material. Coexpression of both
tubulins, however, resulted in a significant increase of expressed proteins. At
the same time, the detectable internal tubulins of the host yeast cell were
downregulated. This finding indicates the functionality of the expressed amoeba
tubulins. Further regulation phenomena were observed on the level of equilibrium
between the two R. filosa tubulin isoforms and on the level of the total tubulin
pool. The P. pastoris/R. filosa system therefore seems to be an accessible system
for the simultaneous study of the various mechanisms involved in tubulin
regulation.
PMID- 9395068
TI - A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity
blockade of the human cardiac potassium channel HERG.
AB - Cisapride (Propulsid) is a gastrointestinal prokinetic agent commonly used to
treat nocturnal heartburn as well as a variety of other gastrointestinal
disorders. The use of cisapride has been associated with acquired long QT
syndrome and ventricular arrhythmias such as torsades de pointes which produces
sudden cardiac death. These cardiotoxic effects can be due to blockade of one or
more types of K+ channel currents in the human heart. For this reason we compared
the effects of cisapride on two cloned human cardiac K+ channels, Kv1.5 and the
human ether-a-go-go-related gene (HERG) stably transfected into mammalian cells.
Using patch clamp electrophysiology, we found that cisapride was a potent
inhibitor of HERG displaying an IC50 value of 44.5 nmol/l when tail currents at
40 mV were measured following a 2 s test depolarization to +20 mV. When HERG
currents were measured at the end of prolonged (20 s) depolarizing steps to +20
mV, the apparent affinity of cisapride was increased and measured 6.70 nmol/l.
The main effect of cisapride was to enhance the rate of HERG current decay
thereby reducing current at the end of the voltage clamp pulse. Furthermore, the
potency of cisapride for the HERG channel was similar to that observed for the
class III antiarrhythmic agent dofetilide (IC50 = 15.3 nmol/l) and the
nonsedating antihistamine terfenadine (IC50 = 56.0 nmol/l). In contrast to its
effects on HERG, cisapride inhibited Kv1.5 channel currents weakly displaying an
IC50 value of 21.2 micromol/l. It is concluded that cisapride displays specific,
high affinity block of the human cardiac K+ channel HERG. It is likely that this
interaction underlies the proarrhythmic effects of the drug observed under
certain clinical settings.
PMID- 9395070
TI - Ro31-8220 inhibits protein kinase C to block the phorbol ester-stimulated release
of choline- and ethanolamine-metabolites from C6 glioma cells: p70 S6 kinase and
MAPKAP kinase-1beta do not function downstream of PKC in activating PLD.
AB - The use of bisindolylmaleimide derivatives of staurosporine as selective
inhibitors of protein kinase C (PKC) is in doubt following the report by Alessi
[FEBS Lett. 402 (1997) 121-123] that Ro31-8220 and GF109203X are potent in vitro
inhibitors of p70 S6 kinase and mitogen-activated protein kinase-activated
protein kinase-1beta, as well as of PKC. Here we show that the phorbol ester
stimulated release of choline- and ethanolamine-metabolites from C6 glioma cells
due to phospholipid hydrolysis by phospholipase D (PLD) is not inhibited by
rapamycin or PD98059, specific inhibitors respectively of p70 S6 kinase and MAPKK
(MEK) and thus of MAPKAP kinase-1beta but is still completely blocked by Ro31
8220. We conclude therefore that p70S6k and MAPKAP kinase-1beta as well as MAPK
are not involved in signalling pathways downstream of PKC that regulate phorbol
ester-stimulated phospholipid turnover and that the inhibitory action of Ro31
8220 occurs by blocking PKC which regulates at least one pathway to PLD
activation. The PI-3 kinase inhibitor, wortmannin, inhibits the phorbol ester
stimulated release of ethanolamine- but not choline-metabolites from C6 cells
suggesting that different PLD isoforms regulate the turnover of PtdEth and PtdCho
in C6 cells. Both PLD isoforms are activated via PKC but the PtdEth-PLD is also
regulated via a wortmannin-sensitive pathway.
PMID- 9395071
TI - Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation.
AB - Rectification of HERG is due to a rapid inactivation process that has been
labeled C-type inactivation and is believed to be due to closure of the external
mouth of the pore. We examined the effects of mutation of extracellular residues
that remove C-type inactivation on binding of the intracellularly acting
methanesulfonanilide drug E-4031. Removal of inactivation through mutation
reduced drug affinity by more than an order of magnitude. Elevation of [K+]o in
the wild-type channel reduces channel affinity for E-4031. Elevation of [K+]o
also interferes with the extracellular pore mouth closure associated with C-type
inactivation through a 'foot in the door' mechanism. We examined the possibility
that [K+]o elevation reduces drug binding through inhibition of C-type
inactivation by comparing drug block in the wild-type and inactivation-removed
mutant channels. Elevation of [K+]o decreased affinity in both channel constructs
by a roughly equal amount. These results suggest that [K+]o alters drug binding
affinity independently of its effects on C-type inactivation. They further
suggest that inhibition of pore mouth closure by elevated [K+]o does not have
same effect on drug affinity as mutations removing C-type inactivation.
PMID- 9395072
TI - Genome methylation of the marine annelid worm Chaetopterus variopedatus:
methylation of a CpG in an expressed H1 histone gene.
AB - Hydrolysis by methylation-dependent restriction enzymes shows that the genomic
DNA of the polychaete annelid worm Chaetopterus variopedatus is methylated.
Electrophoretic analyses of the digestion products indicate that the degree of
methylation is lower in adult tissues than in sperm and embryonic DNA. 5
Methylcytosine was identified by HPLC, absorption spectroscopy and mass
spectrometry analyses of free bases obtained by acid hydrolysis of the DNA. An
average value of 1.6% methylated cytosines was determined in sperm DNA. Partial
methylation was also found in an actively expressed H1 histone gene. This is the
first time that genomic DNA methylation is demonstrated to occur in a worm.
PMID- 9395073
TI - Expression of messenger RNA for the prostaglandin D receptor in the leptomeninges
of the mouse brain.
AB - The localization of prostaglandin D receptor in the mouse brain was examined by
in situ hybridization histochemistry. The autoradiography showed significant
hybridization signals of mRNA for prostaglandin D receptor in the leptomeninges
covering the surface of the brain, but not in neurons or glia in the brain
parenchyma. This finding was confirmed by Northern blot analysis using mRNA
prepared from either the whole brain with the leptomeninges, brain parenchyma
without the leptomeninges or the leptomeninges alone. A weak signal corresponding
to the major 3.5-kbp transcript was detected in the whole brain. This band was
significantly enriched in the leptomeninges, but was not detected in the brain
parenchyma. These results suggest that prostaglandin D receptor is most highly,
if not exclusively, expressed in the leptomeninges of the mouse brain.
PMID- 9395074
TI - Regulatory phosphorylation of plant phosphoenolpyruvate carboxylase: role of a
conserved basic residue upstream of the phosphorylation site.
AB - In order to mimic regulatory phosphorylation of the Ser-15 of maize C4-form
phosphoenolpyruvate carboxylase (PEPC), we replaced Ser-15 and Lys-12 with Asp
(S15D) and Asn (K12N), respectively, by site-directed mutagenesis. Although both
mutant enzymes were catalytically as active as the wild-type PEPC, they showed
much less sensitivity to malate, an allosteric inhibitor, similarly to the
phosphorylated wild-type PEPC. A maize protein kinase of 30 kDa which is known to
be specific to PEPC (PEPC-PK), phosphorylated K12N as well as the wild-type PEPC
but not S15D. The phosphorylation of K12N further diminished the sensitivity to
malate. Thus, a positive charge of the conserved Lys-12 is not required for the
recognition by PEPC-PK but contributes to the intrinsic sensitivity to malate
inhibition.
PMID- 9395075
TI - Nef protein of HIV-1 induces apoptotic cytolysis of murine lymphoid cells
independently of CD95 (Fas) and its suppression by serine/threonine protein
kinase inhibitors.
AB - The Nef protein of HIV-1 is suggested to play a role in depletion of uninfected
CD4+ T cells leading to the development of AIDS. The recombinant soluble Nef
protein was shown to bind to cell surfaces of various murine lymphoid cell lines,
including T and B lymphocytes, mastocytoma cells and macrophages. Cross-linking
of the cell-bound Nef protein with anti-Nef antibodies induced apoptotic
cytolysis of the cells. Although primary lymphocytes from young mice resisted Nef
binding and Nef-induced cytolysis, treatment of the cells with concanavalin A or
phytohemagglutinin made them susceptible to these activities, indicating that
cellular activation is required for the apoptosis. The Nef-induced apoptosis also
occurred with murine cells not expressing CD95 (Fas). These findings were quite
similar to those obtained for human blood cells, suggesting that the mouse is
applicable for analysis of Nef activities. The Nef-induced apoptosis was
efficiently suppressed by serine/threonine protein kinase inhibitors, H7, fasudil
hydrochloride and M3, which did not inhibit CD95 (Fas)-mediated apoptosis. On the
other hand, bisindolylmaleimide, a protein kinase C inhibitor which inhibits CD95
(Fas)-mediated apoptosis, did not affect Nef-induced apoptosis. These results
suggest that the Nef-induced apoptosis of murine cells involved a
serine/threonine protein kinase-dependent signal transduction pathway distinct
from the CD95 (Fas)-mediated system.
PMID- 9395076
TI - The human alpha3b is a 'full-sized' laminin chain variant with a more widespread
tissue expression than the truncated alpha3a.
AB - We report the molecular cloning of the human laminin alpha3b chain variant and
its mRNA expression pattern in adult human tissues when compared to the alpha3a
variant. The mRNA encoding for the alpha3b variant is about 11 kb and the
predicted translation product carries the complete set of domains typical for a
'full-sized' laminin alpha chain. Apart from the similar domain structure of
alpha3b also the sequence of alpha3 resulted more closely related to the alpha5
than to the alpha4 chain. Quantitative analysis of the RNA expression in a broad
panel of adult human tissues indicated that the alpha3b variant is more widely
distributed than the alpha3a shorter variant.
PMID- 9395077
TI - Synthesis of a new zinc finger peptide; comparison of its 'code' deduced and
'CASTing' derived binding sites.
AB - Using two synthetic oligonucleotides, we have constructed a new gene containing
three zinc finger motifs of the Cys2-His2 type. We named this artificial gene
'Mago'. The Mago nucleotide triplets encoding the amino acid positions, described
to be crucial for DNA binding specificity, have been chosen on the basis of the
proposed recognition 'code' that relates the zinc finger's primary structure to
the DNA binding target. Here we demonstrate that Mago protein specifically binds
the 'code' DNA target, with a dissociation constant (Kd) comparable to the Kd of
the well known Zif268 protein with its binding site. Moreover, we show that the
deduced Mago 'code' and the 'experimental' selected DNA binding sites are almost
identical, differing only in two nucleotides at the side positions.
PMID- 9395078
TI - Kinetics of the inhibition of mitochondrial respiration by NO.
AB - The kinetics of the inhibition of mitochondrial respiration by NO was examined in
isolated mitochondria (here obtained from rat brown adipose tissue). The Ki of NO
for the inhibition was approximately 27 nM; the IC50 of NO increased in
proportion to the square of an increase in O2 tension. The Km of O2 for
respiration was approximately 16 microM; in the presence of NO, the dependence of
respiration on O2 tension had a Hill coefficient of approximately 2. The unusual
kinetics is probably related to the ability of cytochrome c oxidase to use 2 NO
or 1 O2 as electron acceptor. The interaction between NO and O2 in the control of
respiration could be described by the formula VO2(O2, NO) = VO2max x ([O2]2/((16
microM x (1 + [NO]/27 nM))2 + [O2]2)). Thus, the kinetics is such that
respiration in the presence of physiological levels of NO is very sensitive to
decreasing O2 tension.
PMID- 9395079
TI - Insulin and cyclic AMP act at different levels on transcription of the L-type
pyruvate kinase gene.
AB - We previously demonstrated that, in hepatocytes in primary culture, the role of
insulin on induction of L-type pyruvate kinase (L-PK) gene expression was mainly
to induce glucokinase synthesis, needed for glucose phosphorylation to glucose 6
phosphate. However, we show here that when hepatocytes have been isolated from
rats starved for 72 h, glucose and constitutive glucokinase expression was not
sufficient to fully stimulate the L-PK promoter, low insulin concentrations being
still required. In addition, activation remains sensitive to cAMP inhibition, but
cannot be reproduced in the absence of insulin by a competitive cAMP antagonist.
We propose that both insulin and cAMP act on expression of the L-PK gene at, at
least, two levels: positive and negative regulation of glucokinase gene
expression, and more downstream levels.
PMID- 9395080
TI - The macrophage migration inhibitory factor MIF is a phenylpyruvate tautomerase.
AB - A macrophage migration inhibitory factor (MIF), originally described as a product
of activated lymphocytes, has been defined as a 12 kDa protein, expressed in a
wide variety of tissues. Here MIF is identified as a phenylpyruvate tautomerase
(EC 5.3.2.1) having p-hydroxyphenylpyruvate and phenylpyruvate as its natural
substrates. The definition of MIF as an enzyme may yield insight into the
mechanism of action of this proinflammatory and immunomodulating cytokine.
PMID- 9395081
TI - Generation and characterization of transgenic mice expressing a human mutant
alpha-galactosidase with an R301Q substitution causing a variant form of Fabry
disease.
AB - Transgenic mice expressing a human mutant alpha-galactosidase with an R301Q
substitution, which was found in a patient with a variant form of Fabry disease,
were established. The mice transcribed a sufficient amount of alpha-galactosidase
mRNA, but the steady-state levels of the enzyme protein were decreased in liver,
kidney and heart, only residual activity being detected in these tissues. The
mice will be useful for the clarification of the defective regulation of the
structurally altered enzyme protein expressed by the mutant gene at the organ or
individual level as well as for the evaluation of drugs that stabilize and/or
activate the mutant alpha-galactosidase.
PMID- 9395082
TI - Populating the equilibrium molten globule state of apomyoglobin under conditions
suitable for structural characterization by NMR.
AB - Conditions have been determined under which the equilibrium molten globule state
of apomyoglobin is stable and remains monomeric for periods of time sufficient
for the application of three-dimensional heteronuclear NMR experiments. The
quality of initial two-dimensional NMR spectra suggests that sequence-specific
assignments can be made for a majority of the protein resonances under these
conditions. A pH titration of the protein followed using two-dimensional 1H-15N
correlation experiments indicates that the equilibrium intermediate undergoes
fast exchange on the chemical shift time scale with the unfolded state and
intermediate time scale exchange with the native state, and suggests a strategy
to assist with backbone resonance assignments. The conditions and techniques
described may be applicable to the characterization of other equilibrium folding
intermediates.
PMID- 9395083
TI - Thermodynamic characterizations of an intramolecularly hydrogen bonded C5
structure across proteinogenic residue.
AB - Thermodynamic investigations of a smallest possible intramolecularly hydrogen
bonded C5-structure, across a Thr residue, in model peptides Boc-Xxx-Thr-NH2 (Xxx
= Ile, 1 or Leu, 2), indicated unusual thermal stability of the structure in non
polar medium. An analysis of van't Hoff plots, constructed from variable
temperature 1H NMR data, yielded the thermodynamic parameters of a hydrogen
bonded five-membered ring. The non-significance of the spatial organizations of
the preceding CdeltaH3 bearing hydrophobic proteinogenic residue on the thermal
stability of the C5-structure has been observed. The results revealed that the
contribution of this element of secondary structure is quantifiable and the
stability appeared to be roughly comparable to other intramolecularly hydrogen
bonded reverse turn structures frequently observed in polypeptides and proteins.
PMID- 9395084
TI - Involvement of integrins and the cytoskeleton in modulation of skeletal muscle
glycogen synthesis by changes in cell volume.
AB - Muscle glycogen synthesis is modulated by physiologically relevant changes in
cell volume. We have investigated the possible involvement of integrin
extracellular matrix interactions in this process using primary cultures of rat
skeletal muscle subject to hypo- or hyper-osmotic exposure with integrin binding
peptide GRGDTP to disrupt integrin actions and the inactive analogue GRGESP as
control. Osmotically induced increases (77%) and decreases (34%) in glycogen
synthesis (D-[14C]glucose incorporation into glycogen) were prevented by GRGDTP
(but not GRGESP) without affecting glucose transport. Cytoskeletal disruption
with cytochalasin D or colchicine had similar effects to GRGDTP. Osmotically
induced modulation of muscle glycogen synthesis involves integrin-extracellular
matrix interactions and cytoskeletal elements, possibly as components of a cell
volume 'sensing' mechanism.
PMID- 9395085
TI - Cloning of two novel human importin-alpha subunits and analysis of the expression
pattern of the importin-alpha protein family.
AB - The import of many proteins into the nucleus is mediated by the importin
alpha/beta heterodimer. While only one importin-beta gene has been found, several
forms of importin-alpha have been described. In addition to the three human
importin-alphas already identified, we report here the primary structure of two
new human importin-alpha proteins. The five known human importin-alpha subunits
can be classified into three subfamilies that appear conserved in higher
eukaryotic organisms. We show by immunoblotting that the different importin-alpha
subfamilies are expressed in a variety of human tissues and mammalian cell lines.
PMID- 9395086
TI - Proteins interacting with the molecular chaperone hsp70/hsc70: physical
associations and effects on refolding activity.
AB - We investigated several hsp70/hsc70 interacting proteins and established by two
independent techniques that hsp40 and Hop/p60 specifically interact with the 257
residue carboxy-terminal domain of hsp70 while Hap-46 and Hip/p48 bind the 383
residue amino-terminal ATP binding domain. Hap-46 and Hip/p48 competed for
binding to hsc70, while Hap-46 had no effect on the binding of either Hop/p60 or
hsp40 to hsc70. Hap-46 inhibited the refolding of thermally denatured firefly
luciferase in an hsc70 and hsp40 dependent assay, and this effect was largely
compensated by Hop/p60. These interacting proteins thus appear to cooperate in
affecting the chaperoning activity of hsp70/hsc70.
PMID- 9395087
TI - Identification of the yeast ACR1 gene product as a succinate-fumarate transporter
essential for growth on ethanol or acetate.
AB - The protein encoded by the ACR1 gene in Saccharomyces cerevisiae belongs to a
family of 35 related membrane proteins that are encoded in the fungal genome.
Some of them are known to transport various substrates and products across the
inner membranes of mitochondria, but the functions of 28 members of the family
are unknown. The yeast ACR1 gene was introduced into Escherichia coli on an
expression plasmid. The protein was over-produced as inclusion bodies, which were
purified and solubilised in the presence of sarkosyl. The solubilised protein was
reconstituted into liposomes and shown to transport fumarate and succinate. Its
physiological role in S. cerevisiae is probably to transport cytoplasmic
succinate, derived from isocitrate by the action of isocitrate lyase in the
cytosol, into the mitochondrial matrix in exchange for fumarate. This exchange
activity and the subsequent conversion of fumarate to oxaloacetate in the cytosol
would be essential for the growth of S. cerevisiae on ethanol or acetate as the
sole carbon source.
PMID- 9395088
TI - Photoaffinity labelling of P-glycoprotein catalytic sites.
AB - Photoaffinity labelling of hamster P-glycoprotein was carried out after trapping
of radioactive Mg-8-azido-ADP in the catalytic sites by vanadate or beryllium
fluoride. With either trapping agent the same labelled peptide was obtained in
homogeneous form, with the sequence -FNEVVFNxPTRPDI-, corresponding to residues
1034-1037 in the C-terminal nucleotide binding site. The missing residue 'x'
corresponds to Tyr-1041, which is therefore a primary reaction target of 8-azido
ADP. This tyrosine is conserved in all hamster, mouse and human P-glycoproteins.
A second major labelled peptide fraction was also identified. The major sequence
in this fraction was -NIHFSxPSR-, corresponding to residues 393-401 of hamster P
glycoprotein, where 'x' corresponds to Tyr-398 in the N-terminal nucleotide
binding site. Therefore Tyr-398, which is also conserved in other P
glycoproteins, is also a reaction target for 8-azido-ADP. In sequence alignment
of the two nucleotide binding sites, Tyr-398 exactly corresponds to Tyr-1041. The
data indicate that these two tyrosines lie close to the adenine ring of bound
substrate MgATP in the respective catalytic sites of P-glycoprotein.
PMID- 9395089
TI - Influence of a NH2-terminal extension on the activity of KTX2, a K+ channel
blocker purified from Androctonus australis scorpion venom.
AB - A cDNA encoding a short polypeptide blocker of K+ channels, kaliotoxin 2 (KTX2),
from the venom of the North African scorpion Androctonus australis was expressed
in the periplasmic space of Escherichia coli. KTX2 was produced as a fusion
protein with the maltose binding protein followed by the recognition site for
factor Xa or enterokinase preceding the first amino acid residue of the toxin.
The fully refolded recombinant KTX2 (rKTX2) was obtained (0.15-0.30 mg/l of
culture) and was indistinguishable from the native toxin according to chemical
and biological criteria. An N-extended analogue of KTX2 exhibiting three
additional residues was also expressed. This analogue had 1000-fold less affinity
for the 125I-kaliotoxin binding site on rat brain synaptosomes than KTX2.
Conformational models of KTX2 and its mutant were designed by amino acid
replacement using the structure of agitoxin 2 from Leiurus quinquestriatus as
template, to try to understand the decrease in affinity for the receptor.
PMID- 9395090
TI - The 5'-untranslated region of the human muscle acylphosphatase mRNA has an
inhibitory effect on protein expression.
AB - The cDNA of the human muscle type acylphosphatase was isolated and characterized.
The mRNA presents a very long 5'-untranslated region, covering the first half of
the molecule: 175 bases of this part were cloned and prediction of the possible
secondary structure showed that a very stable stem-loop structure could be formed
in that region. Moreover, an additional AUG triplet was found upstream of the
start codon of the protein, defining an open reading frame of 60 codons which
overlapped that of acylphosphatase. The possible regulatory effect on translation
of this part of the mRNA molecule was studied by means of transient transfection
experiments: a 10-fold decrease in the expression of a reporter protein and a
dramatic decrease in the corresponding mRNA was observed, due to the presence of
the 5'-untranslated region of acylphosphatase mRNA. Mutagenesis of the upstream
AUG triplet eliminated mRNA instability, leading to the hypothesis that the
product of the upstream open reading frame could play a role in this mechanism.
PMID- 9395091
TI - Modulation of membrane activity of amphipathic, antibacterial peptides by slight
modifications of the hydrophobic moment.
AB - Starting from the sequences of magainin 2 analogs, peptides with slightly
increased hydrophobic moment (mu) but retained other structural parameters were
designed. Circular dichroism investigations revealed that all peptides adopt an
alpha-helical conformation when bound to phospholipid vesicles. Analogs with
increased mu were considerably more active in permeabilizing vesicles mainly
composed of zwitterionic lipid. In addition, the antibacterial and hemolytic
activities of these analogs were enhanced. Correlation of permeabilization and
binding indicated that the activity increase is predominantly caused by an
increased membrane affinity of the peptides due to strengthened hydrophobic
interactions.
PMID- 9395092
TI - Design of mu selective opioid dipeptide antagonists.
AB - We have recently designed potent delta selective opioid antagonist dipeptides on
the basis of a simple conformational analysis. Following a similar procedure we
found a mu selective dipeptide antagonist, 2,6-dimethyl-Tyr-D-Phe-NH2. Although
its selectivity is not as high as those of the quoted delta selective dipeptides
it has good in vitro activity and looks very promising for further development
since the 2,6-dimethyl-Tyr-D-Phe message, like the delta selective 2,6-dimethyl
Tyr-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid counterpart, seems able to
impart antagonism to longer peptides.
PMID- 9395093
TI - An electrospray ionisation mass spectrometry (ESI-MS) study to probe the metal
ion binding site in the DNA binding domain of the yeast transcriptional activator
GAL4.
AB - Electrospray ionisation mass spectrometry (ESI-MS) is used to detect metal ions
and their stoichiometry of binding in the DNA binding domain of GAL4. In this
analysis, the mass spectra of the apo- and metallo-proteins differ by both mass
and charge, precluding the possibility of random adduct formation. Deuterium
exchange NMR experiments of Zn(II)-GAL4(7-49) indicate that the binuclear metal
ion structure, which is shown to have a net negative charge of -2, is the
recipient of several hydrogen bonds, notably from the main-chain amide protons of
the ligating cysteine residues, indicating the charge is stabilised in this
manner.
PMID- 9395094
TI - New biomarker evidence of oxidative DNA damage in patients with non-insulin
dependent diabetes mellitus.
AB - Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been reported to serve as a
sensitive biomarker of oxidative DNA damage and also of oxidative stress. We have
investigated oxidative DNA damage in patients with non-insulin-dependent diabetes
mellitus (NIDDM) by urinary 8-OHdG assessments. We determined the total urinary
excretion of 8-OHdG from 24 h urine samples of 81 NIDDM patients 9 years after
the initial diagnosis and of 100 non-diabetic control subjects matched for age
and gender. The total 24 h urinary excretion of 8-OHdG was markedly higher in
NIDDM patients than in control subjects (68.2 +/- 39.4 microg vs. 49.6 +/- 37.7
microg, P = 0.001). High glycosylated hemoglobin was associated with a high level
of urinary 8-OHdG. The increased excretion of urinary 8-OHdG is seen as
indicating an increased systemic level of oxidative DNA damage in NIDDM patients.
PMID- 9395095
TI - FT-IR study of the Ca2+-binding to bovine alpha-lactalbumin. Relationships
between the type of coordination and characteristics of the bands due to the Asp
COO- groups in the Ca2+-binding site.
AB - Fourier-transform infrared spectroscopy (FT-IR) was applied to examine
relationships between the type of coordination and the COO- antisymmetric and
symmetric stretches of the COO- groups in the Ca2+-binding site of bovine alpha
lactalbumin. The peaks at 1593, 1578, 1425, and 1403 cm(-1) were assigned to the
COO- groups of Asp-82, 87, and 88 coordinating to Ca2+ in the pseudo bridging
mode, according to the results of X-ray crystallography. The bands due to the COO
groups were quite similar to each other between alpha-lactalbumin and EDTA which
is the model compound for the pseudo bridging state.
PMID- 9395097
TI - Cognitive-behavioral profiles among different categories of orofacial pain
patients: diagnostic and treatment implications.
AB - Psychological homogeneity in temporomandibular disorders (TMD) is not conclusive.
The multidimensional pain inventory (MPI) has previously identified 3 cognitive
behavioral profiles in TMD and chronic pain patients. Our aims were to replicate
these findings in another cultural setting and relate the profiles to the
diagnosis and to the treatment demand and outcome. The MPI was administered to
112 referrals comprising 6 categories of patients diagnosed with TMD or
intractable orofacial pain. Dysfunctional profiles (high in pain and distress)
were most common in patients with orofacial pain of obscure origin and more
common in myofascial pain patients than in patients with other TMD diagnoses.
Interpersonally-distressed profiles were found in all categories. Among patients
with disk displacement, the 3rd profile (adaptive copers with low pain and
distress and high control and activity) was most common in earlier successfully
diskectomized patients and least common in those about to undergo invasive
interventions. A dysfunctional profile was associated with treatment failure,
conservative or surgical, and with the demand for radical therapy. Some support
for a cyclical causality between pain and psychological factors was found. It is
concluded that the robustness of the MPI as a relevant assessment instrument was
further strengthened.
PMID- 9395096
TI - Molecular cloning and characterization of a human brain ryanodine receptor.
AB - We have cloned and sequenced the cDNA of the human brain ryanodine receptor
(RyR3), which is composed of 4866 amino acids and shares characteristic
structural features with the rabbit RyR3. Northern blot analysis shows that the
human RyR3 mRNA is abundantly expressed in hippocampus, caudate nucleus and
amygdala as well as in skeletal muscle. The human RyR3 mRNA is also detected in
several cell lines derived from human brain tumors. Functional expression of RyR3
and a chimeric RyR suggests that RyR3 forms a calcium-release channel with a very
low Ca2+ sensitivity.
PMID- 9395098
TI - Psychological characteristics of patients applying for treatment in a dental fear
clinic.
AB - The aim of the present study was to assess psychological characteristics of
highly anxious dental patients. Subjects were 321 patients (203 women) applying
for treatment at a dental fear clinic in The Netherlands. Patients filled out
several questionnaires to assess the amount of psychological complaints (Dutch
version of the Symptom Checklist 90-Revised; SCL-90) and dental anxiety (Dental
Anxiety Scale, Short version of the Dental Anxiety Inventory) approximately 4
months prior to their first appointment. The total mean score on the SCL-90 for
the highly anxious patients was 142.7 (SD=47.2) for men and 166.5 (SD=64.3) for
women. The SCL-90 total score and the mean scores of all subscales were
significantly higher, and above the 80th percentile for most of the subscales,
than the mean scores of the Dutch general population. The results indicate that
patients who apply for treatment at a dental fear clinic are not just dentally
anxious; they show complaints on a wide range of other psychological dimensions.
PMID- 9395099
TI - "Checkerboard" versus culture: a comparison between two methods for
identification of subgingival microbiota.
AB - The present study compared the "checkerboard" DNA-DNA hybridization methodology
with culture techniques for the analysis of the composition of the subgingival
microbiota. 70 subjects, presenting with a variety of periodontal conditions,
contributed with a total of 283 subgingival plaque samples analyzed with respect
to the following species: Porphyromonas gingivalis, Prevotella
intermedia/Prevotella nigrescens, Fusobacterium nucleatum, Campylobacter rectus,
Eikenella corrodens, Bacteroides forsythus, Actinobacillus actinomycetemcomitans,
Streptococcus sanguis and Streptococcus mutans. Species identification and
quantification was performed by (i) the checkerboard method, using whole genomic,
digoxigenin labeled DNA probes; and (ii) culture, including non-selective and
selective media in combination with routine biochemical testing using commercial
test panels. We found that the checkerboard technology resulted in higher
prevalence figures for half of the species tested when compared to culture data.
If the latter were used as the reference, checkerboard detection sensitivities
ranged from 0.17 to 0.86, specificities from 0.17 to 1.0, and diagnostic
accuracies from 0.51 to 0.81, depending on bacterial species. The use of the
checkerboard data as the reference resulted in detection sensitivities for the
culture procedures between 0.24 and 1.0 and specificities between 0.21 and 0.87.
The checkerboard methodology resulted in statistically significant higher
bacterial counts for the majority of the species. It was further observed that,
for most species, the higher the total number colony-forming units in the sample,
the higher the discrepancy between the results obtained by the two techniques.
PMID- 9395100
TI - Expression of T-cell receptor Vbeta2, 6 and 8 gene families in chronic adult
periodontal disease.
AB - Substantial evidence exists to suggest a role for T-cells in periodontal disease.
As yet, however, the T-cell receptors remain to be characterised at the molecular
level. The expression and the nucleotide sequence of genes from the T-cell
receptor beta variable (TCRBV) gene families 2, 6 and 8 were analyzed in
periodontal tissue from 24 patients with chronic adult periodontal disease (CAPD)
and peripheral blood lymphocytes (PBL) of 16 of these patients. A restriction in
the expression of these TCRBV gene families was detected in periodontal tissue
from 14/24 patients with CAPD, and the pattern of gene expression was often
different between individual patients; however there was no restriction in TCRBV
gene expression in matched PBL samples from 8 of these 14 patients. Quantitative
RT PCR analysis of samples from 5 CAPD patients who expressed all 3 TCRBV gene
families in their periodontal tissues did not reveal any significant differences
in the levels of gene expression in periodontal tissue and PBL. In contrast to
the findings with some CAPD patients, genes from all 3 TCRBV families were always
expressed in periodontal tissue and PBL from disease-free control subjects. PCR
products from both the PBL and periodontal tissue of CAPD patients were cloned
and sequenced; analysis of the nucleotide sequence revealed diversity with
respect to the expression of TCRB joining (TCRBJ) and TCRB diversity (TCRBD)
genes and the sequence of the junctional region in all samples analysed. In
conclusion, in CAPD, the pattern of TCRBV gene expression in periodontal tissue
is often but not always different from that in PBL and healthy periodontal
tissue, which may indicate, in some cases, a local influence on particular T-cell
subsets which is relevant to the pathogenesis of periodontal disease. However,
the expressed TCRB genes are heterogeneous at the nucleotide level, emphasising
the underlying complexity at the molecular level in the local T-cell response in
CAPD.
PMID- 9395101
TI - Dentin sialoprotein (DSP) transcripts: developmentally-sustained expression in
odontoblasts and transient expression in pre-ameloblasts.
AB - Dentin sialoprotein (DSP), a 53 kDa glycoprotein, is believed to be present
exclusively in dentin. Using rat and mouse digoxigenin labeled (DIG)-DSP and 35S
DSP riboprobes, and in situ hybridization techniques, we have studied the
presence of DSP mRNA at specific developmental stages of dentinogenesis. In mouse
and rat molars and incisors, DSP transcripts were localized in young odontoblasts
associated with early stages of predentin formation, as well as in mature
odontoblasts, cells with cytoplasmic extensions embedded in the forming dentin.
No DSP transcripts were detected in dental pulp, enamel organ, ameloblasts,
epithelial root sheath, Meckel's cartilage, alveolar bone or tibia. Furthermore,
no DSP mRNA was observed in other soft tissues including heart, lung, kidney,
intestine, eye, and muscle. In addition to the intense and prolonged expression
by odontoblasts, DSP mRNA was transiently expressed by pre-ameloblasts in both
developing molars and incisors. These observations are consistent with the
results of previous immunohistochemical studies (1). The transient expression of
DSP in pre-ameloblasts across from young odontoblasts suggests an involvement of
DSP in epithelial-mesenchymal interactions that are crucial to later stages of
tooth development.
PMID- 9395102
TI - Closing of dentinal tubules by Gluma desensitizer.
AB - Gluma Dentin Bond is an adhesive system, where the primer contains 5%
glutaraldehyde and 35% hydroxyethyl methacrylate. Practitioners have reported a
strong desensitizing effect of the Gluma system on dentin. This study, thus,
sought to evaluate the effect of this system on dentin using various microscopic
techniques. 12 non-restored human molars extracted for prosthodontic reasons were
used. Prior to extraction the buccal cusps were removed such that a 2 mm x 2 mm
wide dentin surface was exposed. The surfaces were treated in 6 ways: (1)
application of Gluma 2 cleanser, Gluma 3 primer to which 0.1% w/v fluorescein was
added, and Gluma 4 sealer; (2) as in (1) but treatment with H2O/0.1% w/v
fluorescein instead of the Gluma 3; (3) as in (1) but without Gluma 2; (4) as in
(1) but with application of 5% glutaraldehyde instead of Gluma 3; (5) as in (1)
but without Gluma 4; (6) as in (1) but with application of 35% HEMA/0.1% w/v
fluorescein instead of Gluma 3. Following extraction, 1 tooth per procedure was
prepared for confocal laser scanning microscopy. The remaining teeth were fixed
and prepared for SEM and TEM evaluation. In specimens of procedures (1) and (5),
tubular occlusions could be seen to a depth of 200 microm. In specimens of
procedure (4) tubular occlusions were found only to a depth of 50 microm. Such
occlusions were not seen in control specimens (2), in specimens where the smear
layer had not been removed (3), or following application of HEMA alone (6). It is
concluded that glutaraldehyde can intrinsically block dentinal tubules. The septa
in the tubules may counteract the hydrodynamic mechanism for dentinal
sensitivity.
PMID- 9395103
TI - Transmission electron microscopic study of in vivo pellicle formation on dental
restorative materials.
AB - This electron microscopic investigation was performed to examine the
ultrastructure of the in vivo formed salivary pellicle on 15 different dental
materials. Test pieces of amalgam alloys, casting alloys, titanium, ceramics,
resins, composite resins, glass polyalkenoate cement, and bovine enamel were
attached to the buccal and lingual surfaces of the upper first molars in three
adults using removable intraoral splints. The splints were carried over periods
of 2 and 6 h. Pellicle-like structures could be identified on all tested material
surfaces by transmission electron microscopic analysis. The pellicle layer showed
a high degree of similarity on different kinds of surfaces with regard to the
ultrastructural appearance. However, distinct differences could be detected in
the ultrastructural pattern and thickness of the pellicle layer formed on
buccally and lingually mounted specimens. Pellicles adsorbed on buccally carried
test pieces were characterized by a heterogeneous, globular appearance and a
thickness ranging from 500 to 1,000 nm after 6 h. In contrast, all lingually
mounted test pieces were covered by a granular pellicle of about 100 nm thickness
after 6 h. It is concluded that the ultrastructural pattern and extent of
salivary pellicle formation are influenced by locally available salivary
biopolymers and locally effective shearing forces rather than by material
dependent parameters.
PMID- 9395104
TI - Improved efficacy of dentin-bonding agents.
AB - Dentin cavities, prepared in extracted human teeth, were treated with various
proprietary dentin-bonding agents and then filled with a light-cured restorative
resin for posterior use. All bonding agents were either treated in accordance
with the manufacturers' instructions or combined with Gluma, which is an aqueous
solution of glutaraldehyde and HEMA, a hydrophilic monomer. 10 min after
polymerization, the width and the extent of the marginal contraction gap was
measured approximately 0.1 mm below the free surface of the filling, using a
light microscope. With nearly all dentin-bonding agents, the marginal contraction
gap could be significantly reduced if Gluma was used after conditioning of the
dentin. The reason for this improvement may be that glutaraldehyde cross-links
the collagen fibers and thereby strengthens the organic part of the hybrid layer,
however, other mechanisms might also play a role in the improvement found.
PMID- 9395105
TI - Chondroitin sulfate isomers in synovial fluid of healthy and diseased human
temporomandibular joints.
AB - Synovial fluid was collected from the superior articular cavity of the
temporomandibular joint in patients with unilateral internal derangement and
joint pain whose contralateral joint was healthy. Glycosaminoglycans were
liberated by digestion with pronase E, and precipitated with cetylpyridinium
chloride and ethanol. Unsaturated disaccharide isomers of chondroitin sulfate,
obtained following chondroitinase ACII digestion, were analyzed by high
performance liquid chromatography. Analytic data indicated that deltaDi-0S and
deltaDi-6S were often found in chondroitin sulfate from the fluid of the diseased
joints. The amounts of deltaDi-0S and deltaDi-6S differed significantly between
synovial fluid samples from the diseased and healthy joints. Comparison of the
relative proportions of the unsaturated disaccharides in the synovial fluid with
previously reported values for several tissues, indicated that the chondroitin
sulfate originated from articular cartilage, with possibly some contributions
from soft connective tissues and serum present in the synovial fluid. These
results suggest that chondroitin sulfate in the synovial fluid provides a useful
indicator of the degree of internal derangement of the temporomandibular joint.
PMID- 9395106
TI - Irradiation effects on microhardness of fluoridated and non-fluoridated bovine
dentin.
AB - The objective of this study was to evaluate the effects of irradiation on
microhardness of dentin. Dentin blocks from the cervical region of bovine
incisors were treated as follows: (1) no irradiation; (2) irradiation of
specimens up to 60 Gy (2 Gy/day, 5 days/week); (3) no irradiation, but
fluoridation of specimens for 5 min/d; (4) irradiation of specimens and daily
fluoridation. Knoop hardness number (KHN) of the control specimens was 62.63+/
14.75 (mean+/-SD). This was significantly different from the irradiated dentin
samples (8.74+/-2.59 KHN). Hardness of the fluoridated dentin specimens was
11.19+/-1.95 KHN in the non-irradiated group and 10.03+/-2.76 KHN in the
irradiated groups, respectively. Within the limitations of an in vitro study, it
is concluded that dentin is severely affected by irradiation. This could be an
explanation for the frequently observed side-effects of irradiation like loss of
enamel, gap formation at the amelodentinal junction, and caries of the cervical
region. Fluoridation with acidic gels decreases microhardness of dentin surface,
and does not prevent softening due to radiation, when saliva is absent.
PMID- 9395107
TI - Research revisited: Gunnar Rolla's contribution to oral health.
AB - Gunnar Rolla's contributions to oral science cover an enormous range. They
include research into the basic understanding of pellicle and plaque formation,
to mechanisms for the prevention of oral diseases. Rolla has collaborated with
over 100 persons from many different countries and thus his influence on dental
research has been global.
PMID- 9395108
TI - On the value of research in health care.
AB - This paper describes 3 important myths that reduce the political impact of
academic research in healthcare and reviews data on the social return of such
research. The myths are (i) scientists' interest in pursuing issues without
concern for value to society; (ii) industry and private investors should fund
more of society's basic research; (iii) Academic research can be improved by
better administration. A recent study on return on investment in academic
research in general is discussed as well as more specific studies on research
related to healthcare. Examples include the BCG and Polio vaccines that today
saves Norway more in healthcare costs than the entire public bill for drugs. Some
factors that explain why research is undervalued are reviewed, notably rapid
changes making benchmarking difficult, insufficient routines in accounting,
changing goals, and unpredictable outcomes.
PMID- 9395109
TI - The end of science?
PMID- 9395110
TI - Review on fluoride, with special emphasis on calcium fluoride mechanisms in
caries prevention.
AB - Low concentrations of fluoride have a beneficial effect on enamel and dentin de-
and remineralization. After fluoride treatments, such as topical applications,
rinses or dentifrices, salivary fluoride concentrations decrease exponentially in
a biphasic manner to very low concentrations within a few hours. For treatments
to be effective over periods longer than the brushing and the following salivary
clearance, fluoride needs to be deposited and slowly released. Calcium fluoride
(or like) deposits act in such a way, owing to a surface covering of phosphate
and/or proteins, which makes the CaF2 less soluble under in vivo conditions than
in a pure form in inorganic solutions. Moreover, due to the phosphate groups on
the surface of the calcium fluoride globules, fluoride is assumed to be released
with decreasing pH when the phosphate groups are protonated in the dental plaque.
PMID- 9395111
TI - Fluoride-induced precipitates on enamel surface and subsurface areas visualised
by electron microscopy and confocal laser scanning microscopy.
AB - The present study examined the enamel surface after in vitro topical treatments
with a neutral 2% NaF solution. For minimising the risk of artefacts, samples
were inspected without pre-treatment as fresh, naturally wet specimens by
complementary techniques: variable pressure electron microscopy (VP-SEM) and
confocal laser scanning microscopy (CLSM). VP-SEM provided information on the
surface morphology, whereas CLSM allowed non-destructive visualisation of
subsurface areas. Neutral NaF solutions induced globular precipitates on the
enamel surfaces. If the globules formed may be described as "calcium fluoride
like material", the additional information of this experiment is that, after
interaction with neutral solutions, they also contain considerable amounts of
NaF. When the NaF solutions were soaked on pellets and then were brought into
contact with the enamel surfaces, NaF crystallites of cubic shape are formed.
Confocal optical tomographies of subsurface enamel after treatments with neutral
NaF solutions revealed partly coroded enamel structures, whereas VP-SEM showed
intact surfaces. In between the coroded areas, a fine granulate precipitate could
be observed. This is evidence that fluoride induces the formation of sub-surface
precipitates only when applied during demineralisation. The precipitate could be
readily removed by 24-h contact with a KOH solution.
PMID- 9395112
TI - The resistance of titanium tetrafluoride-treated human enamel to strong
hydrochloric acid.
AB - The acid resistance of TiF4-treated enamel was investigated to establish a
possible treatment modality for endogenous dental erosion. Enamel slabs were
prepared from human molars and treated with solutions of TiF4. Scanning electron
microscopy (SEM) and microhardness testing were used to examine the effects of
the exposure of the treated enamel to strong acid. SEM micrographs showed the
presence of heavy deposits on enamel surfaces. The surface coating, formed
following TiF4 application, appeared to be resistant to severe acid attacks.
Microhardness measurements showed that TiF4 treatment inhibited enamel softening.
It is concluded that topical TiF4 application may be effective in prevention of
dental erosion caused by hydrochloric acid from the stomach in patients with
frequent vomiting or gastroesophageal reflux.
PMID- 9395113
TI - Fluoride in plaque fluid and saliva after NaF or MFP rinses.
AB - A micro-analytic method, capable of measuring the fluoride concentration in 5 nl
of plaque fluid, was used to follow changes in fluoride concentration in saliva
and plaque fluid at 6 single tooth-sites in 6 subjects for 180 min after a 0.048
M fluoride rinse as a NaF or MFP (sodium monofluorophosphate) solution. The
maximum fluoride concentrations in saliva after NaF was 13x higher than with MFP.
About 5% of the total amount of fluoride following the 20 ml NaF rinse was
retained in the oral cavity. The corresponding figure followig MFP was <1%. The
saliva/plaque fluid fluoride ratios for upper molars and lower incisors were
significantly higher than for the upper incisors and lower molars. There was a
tendency for a decline in the ratios with respect to time for all sites. To
characterize the plaque fluid fluoride intra-oral single-site distribution and
clearance, fluoride concentration versus time (AUC) was calculated from 10 to 60
min after a rinse. The NaF AUC followed the order: upper incisor, lower molar,
upper molar and lower incisors reflecting a different exposure and clearance
pattern due to the different access of the plaque to saliva. The MFP AUC values
varied more, but were all significantly lower than the NaF AUC values. Analysis
of plaque fluid fluoride curves at various sites revealed an exponential decline
in most cases. With NaF, the baseline plaque fluid fluoride levels were not
reached within 3 h. It is concluded that NaF solutions result in a significantly
higher intra-oral fluoride exposure than MFP solutions. The fluoride distribution
and clearance of fluoride from different sites in the oral cavity are linked to
salivary access to these sites. These site-specific differences may have clinical
consequences with regard to the dynamics of fluoride in the de- and
remineralization processes.
PMID- 9395114
TI - On the role of human salivary micelle-like globules in bacterial agglutination.
AB - The hypothesis to be tested in this in vitro study was that the salivary micelle
like globules (SMGs) have a role in the agglutination of some oral bacteria. An
attempt to determine the mechanisms for the interactions involved was also
carried out. 4 laboratory and 4 native streptococci strains were tested. Human
whole (HWS) and parotid (HPS) saliva was collected from 4 subjects, and SMGs were
isolated from both salivas, and agglutination was recorded in the various
bacterial suspensions over time. HPS, HWS and SMGs isolated from HPS and HWS
caused typical agglutination patterns for the mutans strains. Salivary
supernatants (without SMGs) caused a much delayed or no agglutination. Electron
microscopy showed SMG-like structures on the surface of the agglutinated
bacteria. Addition of pyrophosphate to HPS prevented agglutination, whereas
guanidine HCl prevented normal agglutination of a sanguis strain, and urea had no
obvious effect. Together, these results indicate that the SMGs are important in
the agglutination of streptococci, and that both calcium-dependent, electrostatic
and hydrophobic interactions may be involved.
PMID- 9395115
TI - Fractionation of salivary micelle-like structures by gel chromatography.
AB - Globular structures have been demonstrated in human parotid saliva by
transmission electron microscopy and photon correlation spectroscopy. The aim of
this study was to fractionate these salivary globular structures for analytical
and preparative purposes using a gel-filtration material capable of separating
spherical particles up to 300-400 nm in diameter. Freshly obtained parotid saliva
was applied to a Sephacryl S-1000 column. Peak fractions were collected and
prepared for transmission electron microscopy (TEM) or for amino acid analysis.
Bovine milk was included as the casein micelles by TEM appear to be similar to
the salivary aggregates and their elution profiles are known. The salivary
globular structures were eluted in one major peak. TEM of negatively stained
samples from the peak fractions demonstrated globular protein aggregates
consistent with the salivary structures in parotid saliva. Amino acid analysis
showed characteristic amino acid profiles with unusual high levels of proline, 40
45%. The casein micelles were eluted in one major peak and separated from the
whey proteins. This study indicates that the salivary globular structures can be
isolated by gel chromatography. The amino acid analysis indicates that proline
rich proteins may be an important fraction of the salivary globular structures.
PMID- 9395116
TI - Chemical agents for the control of plaque and plaque microflora: an overview.
AB - This presentation provides an overview of the technologies available for the
chemical control of plaque. It is generally accepted that the formation of dental
plaque at the interfaces of tooth/gingiva is one of the major causes of gingival
inflammation and dental caries. Several therapeutic approaches have been used to
control dental plaque and supragingival infections. These include fluoride
preparations such as stannous fluoride, oxygenating agents, anti-attachment
agents, and cationic and non-cationic antibacterial agents. Among the fluoride
preparations, stable stannous fluoride pastes and gels have been shown to reduce
supragingival plaque, gingivitis, hypersensitivity and caries. The effect of the
oxygenating agents on the supragingival plaque has been equivocal, but recent
data indicate that a stable agent which provides sustained active oxygen release
is effective in controlling plaque. A polymer, PVPA, which reduced attachment of
bacteria to teeth was shown to significantly reduce plaque formation in humans. A
new generation of antibacterials includes non-ionics such as triclosan, which in
combination with a special polymer delivery system, has been shown to reduce
plaque, gingivitis, supragingival calculus and dental caries in long-term studies
conducted around the world. Unlike the first generation of agents, the
triclosan/copolymer/sodium fluoride system is effective in long-term clinicals
and does not cause staining of teeth, increase in calculus, or disturbance in the
oral microbial ecology.
PMID- 9395117
TI - Dental calculus: recent insights into occurrence, formation, prevention, removal
and oral health effects of supragingival and subgingival deposits.
AB - Dental calculus, both supra- and subgingival occurs in the majority of adults
worldwide. Dental calculus is calcified dental plaque, composed primarily of
calcium phosphate mineral salts deposited between and within remnants of formerly
viable microorganisms. A viable dental plaque covers mineralized calculus
deposits. Levels of calculus and location of formation are population specific
and are affected by oral hygiene habits, access to professional care, diet, age,
ethnic origin, time since last dental cleaning, systemic disease and the use of
prescription medications. In populations that practice regular oral hygiene and
with access to regular professional care, supragingival dental calculus formation
is restricted to tooth surfaces adjacent to the salivary ducts. Levels of
supragingival calculus in these populations is minor and the calculus has little
if any impact on oral-health. Subgingival calculus formation in these populations
occurs coincident with periodontal disease (although the calculus itself appears
to have little impact on attachment loss), the latter being correlated with
dental plaque. In populations that do not practice regular hygiene and that do
not have access to professional care, supragingival calculus occurs throughout
the dentition and the extent of calculus formation can be extreme. In these
populations, supragingival calculus is associated with the promotion of gingival
recession. Subgingival calculus, in "low hygiene" populations, is extensive and
is directly correlated with enhanced periodontal attachment loss. Despite
extensive research, a complete understanding of the etiologic significance of
subgingival calculus to periodontal disease remains elusive, due to inability to
clearly differentiate effects of calculus versus "plaque on calculus". As a
result, we are not entirely sure whether subgingival calculus is the cause or
result of periodontal inflammation. Research suggests that subgingival calculus,
at a minimum, may expand the radius of plaque induced periodontal injury. Removal
of subgingival plaque and calculus remains the cornerstone of periodontal
therapy. Calculus formation is the result of petrification of dental plaque
biofilm, with mineral ions provided by bathing saliva or crevicular fluids.
Supragingival calculus formation can be controlled by chemical mineralization
inhibitors, applied in toothpastes or mouthrinses. These agents act to delay
plaque calcification, keeping deposits in an amorphous non-hardened state to
facilitate removal with regular hygiene. Clinical efficacy for these agents is
typically assessed as the reduction in tartar area coverage on the teeth between
dental cleaning. Research shows that topically applied mineralization inhibitors
can also influence adhesion and hardness of calculus deposits on the tooth
surface, facilitating removal. Future research in calculus may include the
development of improved supragingival tartar control formulations, the
development of treatments for the prevention of subgingival calculus formation,
the development of improved methods for root detoxification and debridement and
the development and application of sensitive diagnostic methods to assess
subgingival debridement efficacy.
PMID- 9395118
TI - Oral mucosal side effects of cytotoxic chemotherapy of testicular cancer. A
retrospective study.
AB - Cancer chemotherapy often leads to injury of normal cells. Adverse effects on
oral mucosa have been documented for several cytotoxic treatment regimens. The
aim of the present retrospective study was to evaluate incidence and degree of
oral soft tissue side-effects of a cisplatin-based chemotherapy regimen used for
treating testicular cancer. The study was based upon a questionnaire mailed to 56
consecutive patients treated at the Norwegian Radium Hospital. A total of 39
individuals joined the study, as 2 patients refused and 15 did not reply. The
patients were divided into two groups, a case group (24 individuals) having
received 4 7 cycles of cisplatin-based chemotherapy in addition to surgery, and a
control group (15 individuals) treated with surgery alone. The study revealed
that 62% of the patients in the chemotherapy group developed adverse soft tissue
reactions, with mucositis and pain as chief complaints, whereas none in the
control group experienced any mucosal complications.
PMID- 9395119
TI - The influence of triclosan, zinc or propylene glycol on oral mucosa exposed to
sodium lauryl sulphate.
AB - Previous studies on triclosan treatment of skin exposed to sodium lauryl sulphate
(SLS) indicated a protective role of zinc and an irritant effect of propylene
glycol (PG). The aim was hence to examine whether zinc or PG also may affect SLS
induced oral mucosal reactions, and also to test the influence of zinc in
combination with triclosan. 15 healthy dental students participated in this
double-blind crossover study performed in 2 experimental series. They were
rinsing 2x daily with solutions containing (A) 1.5% SLS, (B) 1.5% SLS/0.5% zinc
citrate and (C) 1.5% SLS/PG (1:8) in experiment 1, and (D) 1.5% SLS/0.15%
triclosan/0.3% zinc citrate and (E) 1.5% SLS/0.15% triclosan in experiment 2.
Clinical evaluation by 2 examiners of degree of erythema and oral mucosal
desquamations was then performed. The critical micellar concentration was also
determined. SLS and SLS/PG, which were not different in effect, evoked
significantly more erythematous reactions than SLS/Tri/Zn. This solution was
numerically but not statistically better than SLS/Tri, and the latter also did
lead to significantly less erythema than SLS/PG. In conclusion, the present study
revealed no irritation of the oral mucosa due to PG, whereas a protective effect
of zinc as well as the anti-inflammatory effect of triclosan were confirmed.
PMID- 9395120
TI - On the transformation of sulfur-containing amino acids and peptides to volatile
sulfur compounds (VSC) in the human mouth.
AB - Halitosis is most often caused by oral conditions. Volatile sulfur compounds
(VSC), constituting the major components of oral malodor, are produced by
anaerobic, gram-negative bacteria retained mainly in periodontal pockets or on
the tongue dorsum. Sulfur-containing amino acids serve as substrate for these
bacteria. VSC have also been found to have unfavorable effect on the tissue. The
aim of this study was to examine whether normal, healthy individuals with no
history of halitosis were able to produce VSC from cysteine, when applied as a
mouthrinse. A further aim of the study was to investigate and compare the
potential of other sulfur-containing amino acids and peptides as substrates for
oral VSC production and to localize the odor-production sites. A portable sulfide
monitor was used for VSC registration. Results showed that all test subjects
produced high oral concentrations of VSC upon rinses with cysteine, which thus
seems to be a major substrate for VSC production. The other sulfur-containing
substrates had much less effect. It was found that the tongue was the major site
for VSC production, and that saliva per se caused low VSC production.
PMID- 9395121
TI - Neurological effects of microwave exposure related to mobile communication.
AB - Due to the wide and growing use of mobile communication, there is increasing
concern about the interactions of electromagnetic radiation with the human
organism, and, in particular, with the brain. In the present report, experimental
studies on putative electrophysiological, biochemical and morphological effects
of continuous or pulsed microwave radiation are briefly reviewed. Such effects
have been described in vitro and in vivo using animals and humans. Particularly,
effects on neuronal electrical activity, cellular calcium homeostasis, energy
metabolism, genomic responses, neurotransmitter balance and blood-brain barrier
permeability have been reported. However, some results have either been disputed,
since experimental replication led to contradictory findings, or been related to
procedural side effects. Since neurological disturbances induced by mobile
telephone devices would be of considerable interest for public health, the
authors recognize that further experimental studies, involving strict positive
and negative control conditions, will be required in the future. At the present
state of knowledge there is no positive evidence that pulsed or continuous
microwave exposure in the non-thermal range confers elevated risk to the health
of the brain.
PMID- 9395122
TI - Risk factors for microangiopathy-related cerebral damage in the Austrian stroke
prevention study.
AB - Microangiopathy-related cerebral damage (MARCD) represents a common incidental
MRI observation in the elderly. The risk factors of such findings are widely
unknown. We therefore performed MRI in 349 randomly selected volunteers (ages 50
to 70 years) without neuropsychiatric disease, and evaluated the association of
MARCD with conventional and recently suggested cerebrovascular risk factors such
as apolipoprotein E genotypes, plasma concentrations of essential antioxidants
and anticardiolipin antibody titres. MARCD was defined as evidence of early
confluent and confluent deep white matter hyperintensities and lacunes. It was
present in 71 (20.3%) subjects. Individuals with MARCD were older than those
without such findings (62.7 years vs 59.6 years; P=0.0001). They had a higher
rate of arterial hypertension (45.1% vs 28.1%; P=0.006) and cardiac disease
(50.7% vs 37.1%; P=0.04), higher systolic blood pressure readings at exam (144.4
mmHg vs 136.7 mmHg; P=0.004), and higher serum fibrinogen concentrations (327.1
mg/dl vs 292.5 mg/dl; P=0.001). Their levels of total cholesterol (217.6 mg/dl vs
231.2; P=0.009), apolipoprotein A-I (167.3 mg/dl vs 177.4 mg/dl, P=0.02),
lycopene (0.17 micromol/l vs 0.24 micromol/l; P=0.003), retinol (1.91 micromol/l
vs 2.10 micromol/l; P=0.02) and alpha-tocopherol (27.55 micromol/l vs 31.14
micromol/l; P=0.001) were significantly lower. Forward stepwise regression
analysis created a model of independent predictors of MARCD with age entering
first (odds ratio 2.01/10 years), fibrinogen second (odds ratio 2.45/100 mg/dl),
alpha-tocopherol third (odds ratio 0.55/10 micromol/l), and arterial hypertension
fourth (odds ratio 1.96). The association of MARCD with various treatable
clinical conditions may have preventive implications.
PMID- 9395123
TI - Serial brain CT in corticobasal degeneration: radiological and pathological
correlation of two autopsy cases.
AB - This report concerns serial brain computed tomography (CT) images in two patients
with corticobasal degeneration (CBD). The diagnosis of CBD was confirmed by
neuropathological examination. In one case, we obtained serial brain CT images
for one year and five months, and in the other, for three years and four months.
The CT images showed that the anterior portions of the cerebrum atrophied
progressively with the length of the disease. This was also seen in the CT images
with respect to the caudate nucleus. Regarding radiological and pathological
correlations, we consider that the progressive atrophy of the anterior portions
of the cerebrum, seen in brain CT images, is ascribed to neuronal loss and
gliosis in the anterior portions of the cerebrum. We also believe that the
observed caudate nucleus atrophy is due to loss of neurons and gliosis in this
structure, and also to the fibrillary gliosis of the cerebral white matter. The
progressive atrophy of the caudate nucleus detected in brain CT is a valuable
feature for the neuroradiological diagnosis of CBD.
PMID- 9395124
TI - Tolerance induction to myelin basic protein by intravenous synthetic peptides
containing epitope P85 VVHFFKNIVTP96 in chronic progressive multiple sclerosis.
AB - Peptide-based tolerance induction may be useful for antigen-specific
immunotherapy of human autoimmune diseases. Induction of tolerance to myelin
basic protein (MBP) was examined in a Phase I clinical trial in multiple
sclerosis (MS) patients with chronic progressive disease using a peptide that is
immunodominant for MBP specific T cells and B cells. Tolerance induction was
monitored by quantification of MBP specific autoantibodies in cerebrospinal fluid
(CSF). The route of peptide administration was important since only intravenous
but not intrathecal or subcutaneous injection induced tolerance to MBP. Following
a single intravenous injection of a peptide containing epitope P85VVHFFKNIVTP96,
MBP autoantibodies were undetectable for three to four months. Tolerance was more
prolonged following a second injection since autoantibodies were low or
undetectable after one year in the majority of patients. Duration of tolerance to
MBP depended on MHC class II haplotypes of patients; tolerance was long-lived in
all patients with disease associated HLA-DR2. No neurological or systemic side
effects were observed, regardless of the route of peptide administration. These
data demonstrate that intravenous administration of a soluble peptide can result
in long-lasting tolerance to an autoantigen in humans.
PMID- 9395125
TI - Normal human aging: factors contributing to cerebral atrophy.
AB - Factors that accelerate rates of 'normal' age-related cerebral atrophic and
degenerative changes are important because they may predispose to cognitive
declines. To determine characteristic patterns of normal aging, risk factors were
correlated with serial neurological-neuropsychological examinations, CT measures
of progressive cerebral atrophy, local tissue hypodensities, or perfusional
declines. Both cross-sectional and longitudinal designs were utilized. Ninety
four cognitively and neurologically normal aging volunteers, 15 with a history of
transient ischemic attacks (TIAs), were followed for mean intervals of 3.0+/-2.1
years. Results indicated that: (1) after age 60, cerebral atrophy, polio- and
leuko-araiosis doubled and cerebral perfusion decreased, with marked individual
variations; (2) risk factors independently accelerating cerebral atrophy and
cortico-subcortical perfusional declines included TIAs, hypertension, smoking,
hyperlipidemia, excessive alcohol consumption and male gender; (3) progressive
leuko-araiosis correlated directly with cortical atrophy and cortical perfusional
declines. We posit that: (1) cerebral atrophy and degenerative changes result
from neuronal shrinkage and/or loss, which are accelerated by TIAs, hypertension,
smoking, hyperlipidemia, excessive alcohol consumption and male gender; (2)
accelerated cerebral atrophic and degenerative changes identified by neuroimaging
should be considered as markers for depleted neuronal synaptic reserves, which
predispose to cognitive declines. Interventions available for controlling some of
these risk factors include control of TIAs, hypertension, and hyperlipidemia, as
well as tobacco and alcohol withdrawal.
PMID- 9395126
TI - Tumor necrosis factor alpha and its receptors in relapsing-remitting multiple
sclerosis.
AB - In the attempt to further characterize the extent and timing of tumor necrosis
factor (TNF)alpha-system activation during multiple sclerosis (MS), we performed
a cross-sectional and a longitudinal study in a total of 73 relapsing-remitting
MS patients. We assessed serum levels of soluble TNFalpha, soluble TNFalpha
receptor 1 (R1) and soluble TNFalpha receptor 2 (R2) in 65 relapsing-remitting MS
patients in different phases of disease. TNFalpha, R1 and R2 serum levels
measured in MS patients did not differ from those measured in healthy individuals
and did not correlate with (a) clinical relapses, (b) presence of gadolinium
enhancing brain-magnetic resonance imaging (MRI) lesions, and (c) bioactivity of
TNFalpha. We also measured in 8 additional relapsing-remitting MS patients
peripheral blood mononuclear cells (PBMC) mRNA levels of TNFalpha, R1 and R2
every 15 days for one year. In 4 of these patients we also measured levels of
soluble TNFalpha, R1 and R2 every 15 days for 5 months across a clinical
exacerbation. PBMC TNFalpha, R1 and R2 mRNA levels and serum levels of soluble R1
and R2, but not TNFalpha, fluctuated concordantly (P<0.05) and peaked a mean of 6
weeks before clinical and MRI evidence of disease activity. Moreover, we found a
significant positive correlation between cumulative TNFalpha and R2 mRNA levels
(measured during the follow-up period in the 8 MS patients studied serially) and
the number of clinical attacks recorded in these patients during the study. Our
data show that serum levels of soluble TNFalpha, R1, and R2 in MS patients do not
differ from those of healthy individuals. However, although within normal values,
the transcription and production rate of all these molecules fluctuate
concordantly in the peripheral blood during the course of the disease (with the
exception of soluble TNFalpha) and their maximal elevation significantly precedes
the occurrence of clinical exacerbations. It is not clear whether soluble
TNFalpha escapes recognition by commonly used assays or is simply not released in
its soluble form in MS patients. In any case, measurement of TNFalpha mRNA levels
and R1 and R2 mRNA and protein levels appears to be a better indicator of disease
fluctuations during the course of MS than assessments of soluble TNFalpha
protein.
PMID- 9395128
TI - Correlates of p53- and Fas (CD95)-mediated apoptosis in Alzheimer's disease.
AB - Apoptosis may be an important mechanism of cell loss in Alzheimer's disease (AD).
Experimentally, apoptosis is preceded by nuclear accumulation of p53, and
increased expression of Fas (CD95) antigen. In the present study, quantitative
Western blot analysis of postmortem frontal and temporal lobe tissue demonstrated
significantly higher mean levels of p53 and Fas in AD relative to age-matched
controls. Immunohistochemical staining and in situ apoptosis assays demonstrated
increased p53 and Fas expression and DNA fragmentation in overlapping populations
of cortical neurons, and cortical and white matter glial cells distributed in
regions damaged by neurodegeneration. Double-label immunohistochemical staining
studies revealed p53 immunoreactivity in: 1) cortical neurons without tau
immunoreactive neurofibrillary tangles; 2) numerous, but not all tau
immunoreactive neuropil neurites and white matter axons; 3) dystrophic fibrils
surrounding amyloid-beta-immunoreactive plaques; and 4) glial cells characterized
as A2B5+ protoplasmic astrocytes or oligodendrocytes. The prominent distribution
of dystrophic p53-immunoreactive processes around amyloid-beta-containing plaques
suggests that amyloid deposits are associated with local neuritic degeneration.
In addition, the results suggest that many tau-immunoreactive neuritic processes
originate from degenerating (p53) as well as regenerating neurons. Finally,
apoptosis of glial cells (A2B5+) required to maintain the functional integrity of
axons and dendrites may represent an important pathogenic mechanism of axonal
loss and synaptic disconnection in AD.
PMID- 9395127
TI - Impaired quantitative cerebral blood flow in scleroderma patients.
AB - Systemic Sclerosis (SSc) is a multisystem disease characterised by proliferation
of vascular tissue, obliterative microvascular lesions and diffuse organ
fibrosis. Despite widespread vascular disease, Central Nervous System complaints
are only infrequently reported and it is uncertain whether they merely derive
from systemic complications or whether they may be also caused by a primary
vascular process within the brain. Regional cerebral blood flow (rCBF) was
quantitatively measured by the 133Xenon clearance technique in twenty-seven
consecutive SSc patients without relevant systemic complications and with
different severity of vascular involvement, as staged by nailfold capillary
videomicroscopy (NCV). Absolute, percent, and asymmetry rCBF values were compared
(z-statistics) with age- and sex-matched healthy controls. Cerebral MRI and Mini
Mental State Examination (MMSE) were also performed. Doppler sonography of neck
vessels and Transcranial Doppler sonography (TCD) were performed in patients
presenting rCBF reduction. Cerebral hypoperfusion was found in the 52% of
patients, i.e.: in 33% of patients with the 'early' NCV pattern, in 56% of
patients with the 'active' pattern, and in 67% of patients with the 'late' NCV
pattern. Thirty percent were the MRIs showing focal and/or diffuse signal
abnormalities in the white matter of both hemispheres with the highest rate (44%)
in the 'late' NCV pattern. MMSE disclosed mild dementia in one patient in the
'late' NCV group and some mistakes in 6 more patients, in the 'active' or 'late'
NCV groups, whereas TCD failed to find significant stenosis of Willis' arteries.
Cerebral hypoperfusion is shown for the first time in a substantial part of SSc
patients without either neurological symptoms or relevant systemic complications.
It is suggested that the rCBF reduction might be related to the systemic
scleroderma microangiopathy although, probably due to the paucity of connective
tissue in cerebral vessels, the vast majority of patients remains in a
subclinical phase.
PMID- 9395129
TI - Normal auditory brainstem and cochlear function in extreme pediatric plumbism.
AB - Lead (Pb) intoxication in children has been associated with encephalopathy,
sensory and cognitive impairments. We investigated the prevalence and neuro
sensory effects of Pb exposure in children living in Andean villages of Ecuador
with high Pb contamination from discarded automobile batteries used in the local
ceramics glazing industry. Venous blood samples were collected from 107 children
in the Pb glazing area and from 39 children living in a geographically distant
area with no known Pb contamination and measured for blood lead (PbB) levels.
Auditory brainstem responses (ABR) and audiological/otological tests were
conducted on children in the Pb-Glazing Group. The median PbB level for children
in the Pb-Glazing Group was 40.0 microg per dl (range: 6.2-128.2 microg per dl)
and for the non Pb-Glazing Group 6.0 microg per dl (1.9-18.0 microg per dl). The
differences in PbB levels for children in the study and control areas were
statistically significant (t-test, P<0.0001). ABR tests on the Pb-Glazing Group
indicated normal wave latencies and neural transmission times, and no statistical
correlation between PbB level and interpeak latencies. Audiological tests showed
normal cochlear function and no statistical relation between auditory thresholds
and PbB level. Contrary to prevailing assumptions, elevated PbB levels in
children do not invariably impair auditory brainstem neural transmission or
sensory-neural cochlear function, both of which have been implicated as
significant contributors to the neurodevelopmental disabilities associated with
childhood plumbism.
PMID- 9395130
TI - The presence of autoantibodies to N-terminus domain of GluR1 subunit of AMPA
receptor in the blood serum of patients with epilepsy.
AB - We have analyzed the serum from patients with refractory epilepsy for the
presence of autoreactive antibodies to AMPA glutamate receptor subunits. The
presence and the level of autoantibodies were assessed using immunoblot and ELISA
with synthetic peptides specific for subregions of AMPA glutamate receptor
subunits. Patients with refractory epilepsy exhibited strong immunoreactivity to
GluR1 subunit compared to healthy donors and patients with Parkinson's disease
and Alzheimer's disease. Weak immunoreactivity to other AMPA glutamate receptor
subunits was also detected and the signal was diminished in the raw
GluR4>GluR3>GluR2. The occurrence of autoantibodies to specific neurotransmitter
subunits in the sera of patients with refractory epilepsy suggest that autoimmune
process may underlie this disorder.
PMID- 9395131
TI - GM1 gangliosidosis type 3 with severe jaw-closing impairment.
AB - The patient had adult GM1 gangliosidosis (type 3) with severe impairment of
mastication caused by dystonia of anterior digastric muscles (jaw-opener) on
clenching. This is the first report on jaw dystonia severe enough to cause the
masticatory impairment in adult GM1 gangliosidosis. The discordance of closing
and opening muscles during mastication might be caused by a basal ganglia lesion
in this disease.
PMID- 9395132
TI - Successful treatment of painful traumatic mononeuropathy with carbamazepine:
insights into a possible molecular pain mechanism.
AB - The delayed onset of painful paresthesias following trauma to a peripheral nerve
is a well recognized but poorly understood phenomenon. This report describes an
illustrative case of painful paresthesias in the territory of the ilioinguinal
nerve, 3 to 6 weeks after an otherwise routine herniorraphy, which subsequently
responded dramatically to carbamazepine. The case is considered in light of
recent studies which have determined molecular changes which occur in dorsal root
ganglion (DRG) neurons following axotomy and neuroma formation. Voltage-dependent
sodium (Na+) channels in DRG neurons undergo a change following axotomy, in which
there is significant up- and down-regulation of different subpopulations of Na
channels over a time frame measured in days to weeks. Such changes may render the
DRG neurons hyperexcitable, thus contributing to a neuropathic pain syndrome, yet
susceptible to treatment with a sodium channel blocker such as carbamazepine.
PMID- 9395133
TI - Confirmation that neither cyanide intoxication nor mutations commonly associated
with Leber's Hereditary Optic Neuropathy are implicated in Tanzanian Epidemic
Optic Neuropathy.
PMID- 9395134
TI - Amyotrophic lateral sclerosis and multifocal motor neuropathy with conduction
block.
PMID- 9395135
TI - Detection of tick-borne encephalitis virus by sample transfer, plaque assay and
strand-specific reverse transcriptase polymerase chain reaction: what do we
detect?
AB - Experimental inoculation of mice provides a well characterized model for studying
infection with tick-borne encephalitis virus (TBEV), a flavivirus pathogenic for
humans. Conflicting data on the kinetics of viremia and the development of virus
titers in the brain, however, were only recently shown to have resulted from the
use of assay systems with different levels of sensitivity in the titration of
TBEV, i.e. plaque assay or sample transfer into naive recipient mice.
Theoretically, RT-PCR could extend further the detectability to antibody
neutralized virus and when undertaken strand-specifically discriminate active
replication from the mere presence of TBEV. We have compared the conventional
methods for detection of TBEV with a newly devised RT-PCR method. As expected, RT
PCR, in contrast to the infectivity assays, detected antibody-neutralized virus.
Furthermore, the mere presence or active replication of the virus could be
differentiated by strand-specific RT-PCR. Plaque assay and sample transfer, in
contrast, both detected only infectious virus. However, whereas sample transfer
provides higher sensitivity for detection of TBEV from solid organs, the plaque
assay is less costly and considering animals welfare more convenient. Thus, the
newly devised method may allow the resolution of unanswered questions, while both
the traditional infectivity assays retain their benefits in certain situations.
PMID- 9395137
TI - Use of site-directed mutagenesis to generate a herpes simplex virus type 1 strain
17+ mutant lacking seven HindIII restriction endonuclease cleavage sites.
AB - The genome of herpes simplex virus type 1 (HSV-1) strain 17+ contains ten HindIII
and four XbaI restriction endonuclease (RE) cleavage sites. We have previously
reported the isolation of an HSV-1 mutant, 1702, devoid of all the four XbaI
sites. Here we report the isolation of HSV-1 mutants lacking seven of the HindIII
sites plus the four XbaI sites. In order to destroy the various HindIII sites,
mutagenic oligonucleotides were synthesized and introduced in to the plasmids
containing HSV-1 restriction endonuclease fragments spanning these HindIII sites.
All the seven HindIII sites were removed by site-directed mutagenesis. Two
methods of site-directed mutagenesis were used: 1) the HindIII site at 0.91 map
coordinates (mc) of HSV-1 strain 17+ genome was deleted using a gapped,
heteroduplex molecule of DNA, and 2) uracil-rich single-stranded DNA templates
were used in in vitro mutagenesis reactions to remove the HindIII sites at 0.08,
0.1, two at 0.18, 0.26 and 0.64 mc. These HindIII site deletions were then marker
transferred back in to the 1702 genome to generate virus mutants devoid of
specific HindIII sites. No other deletions and/or insertions were observed within
the viral genomes of mutant viruses as allowed by restriction endonuclease
analysis of their 32P-labelled DNAs. All the HindIII site-deletion mutants, 1721
1733, showed comparable growth properties and polypeptide profiles to those of
the parental 17+ and 1702 viruses.
PMID- 9395136
TI - Comparison of ELISA and RT-PCR for the detection of beet yellows closterovirus in
plants and aphids.
AB - A reverse-transcription polymerase chain reaction (RT-PCR) was developed to
detect beet yellows closterovirus (BYV) in plants and single aphids using primers
spanning the conserved regions of the published sequences of the coat protein
gene and open reading frames 7 and 8. Three total RNA extraction procedures were
examined and all were found to produce RNA of sufficient quality for RT-PCR,
although the RNA extraction kit supplied by Flowgen was found to be the most
versatile for the extraction of BYV from individual aphids. When 60 aphids, which
had fed on virus infected sugar beet were tested by RT-PCR, 55% of individuals
were found to contain BYV. Two groups of 36 individual aphids were tested by TAS
ELISA using a specific BYV monoclonal antibody; 53% gave positive absorbance
values when a substrate amplification system was used, but none was found to
contain virus when the system was replaced with the substrate p-nitrophenyl
phosphate. An immunocapture RT-PCR method was shown to detect BYV regardless of
whether the RNA had been extracted from the trapped particles or the reverse
transcription and PCR mixtures were added to the wells containing intact
particles. The RT-PCR method is now used to determine the numbers of BYV carrying
aphids migrating into sugar-beet crops.
PMID- 9395138
TI - Use of Doehlert matrices for study of poliovirus-1 adsorption.
AB - Experiments designed according to Doehlert matrices were carried out to study
poliovirus-1 adsorption to Na-montmorillonite in a complex aqueous environment.
Salt concentration and valence, virus load, clay concentration, and organic
matter concentration were included in the design as selected parameters for
possible or known involvement in viral adsorption in environmental waters. Use of
this experimental design not only allowed to detect and quantify direct influence
of the tested parameters upon the viral response, but also to reveal the
influence of interactions between these tested factors. Thus, beyond the
reassessment of the higher efficiency of multivalent cations on virus adsorption,
as opposed to monovalent ones, detection was enabled of a tannic acid/aluminium
specific interaction that seemed to be responsible for the nonavailability of
these elements for interaction with viruses. Such a statistical tool allows for a
gain in experimental accuracy beyond technical improvements and is particularly
suited for low-cost study of multifactorial phenomena.
PMID- 9395139
TI - Immunoassays to study prevalence of antibody against GB virus C in blood donors.
AB - Immunoassays were developed to determine the seroprevalence of antibody against
human GB virus C (GBV-C). The antigenic target in each assay was a 44.6-kDa
glycosylated protein representing the first 315 amino acids encoded by the GBV-C
E2 gene. Sera or plasma were assayed for E2 antibody using an anti-human EIA
format in which antigen-coated polystyrene beads were reacted with sample, and
bound antibody was detected by addition of enzyme labelled goat anti-human IgG.
The presence of anti-E2 antibody was confirmed using a sandwich EIA format in
which samples were reacted with antigen coated polystyrene beads, followed by
addition of solution phase biotinylated antigen. Detection of antibody captured
biotinylated E2 was accomplished by addition of enzyme-conjugated anti-biotin
antibody. Antibody against the E2 antigen was detected in 7.4 and 7.8% of 500
sera and 500 plasma, respectively, from US volunteers donating to a Wisconsin
blood center, and in approximately 10.7% of hepatitis and retrovirus marker
negative volunteer blood donors from a Missouri blood center. The rate in 1018
sera from US commercial donors at multiple US blood centers was 36.7%. These
results indicated a relatively high prevalence of GBV-C exposure in US volunteer
donors, and particularly in commercial donors. The clinical implication of the
high exposure rate is unclear. These immunoassays are being combined with nucleic
acid detection to assess prevalence of GBV-C world wide and to determine if GBV-C
plays a role as an etiologic agent.
PMID- 9395141
TI - Development of a RT-PCR test coupled with a microplate colorimetric assay for the
detection of a swine Arterivirus (PRRSV) in boar semen.
AB - Transmission of porcine reproductive and respiratory syndrome virus (PRRSV)
through boar semen has been demonstrated, stressing the need for a reliable semen
PRRSV detection test. A diagnostic assay was developed based on amplification of
the PRRSV RNA by reverse transcription and polymerase chain reaction (RT-PCR)
followed by detection of the amplification products by hybridization and
colorimetric assay in microwell plates. A highly reproducible and efficient
method of viral RNA isolation from semen samples was set up. A combined RT-PCR
procedure was performed, incorporating the use of uracil-N-glycosylase (UNG) in
combination with dUTP instead of dTTP to prevent false positive results due to
carry-over contamination. An RNA internal control was added during the RNA
isolation procedure to detect false negative results. The colorimetric detection
in microwell plates of amplification products from either PRRSV or IC RNA gave
specific and objective results and was automated. A cut-off value of 1000 RNA
copies or 10 TCID50 of PRRSV per ml of semen samples could be detected with this
assay. Semen samples collected from experimentally-infected boars were tested
with this assay and showed PRRSV excretion early after infection and for an
extended period.
PMID- 9395140
TI - Generation of a p10-based baculovirus expression vector in yeast with infectivity
for insect larvae and insect cells.
AB - A new, versatile baculovirus vector was developed for the generation of
recombinants in the yeast Saccharomyces cerevisiae and for the expression of
foreign proteins in both insect larvae and in insect cells. This vector is based
on Autographa californica multiple nucleocapsid nucleopolyhedrovirus (AcMNPV) and
exploits the 10-kDa protein promoter (p10) for the expression of the foreign
gene. The p10 locus was used for the insertion of a yeast-selectable marker
system (ARS-URA-URA3) and of a gene for screening and titration of recombinants
in insect cells (beta-galactosidase). The polyhedron-positive phenotype of this
vector is maintained allowing its use in insect larvae, by feeding polyhedra, and
in insect cells, by infecting with budded virus. The generation of this
baculovirus vector requires a single recombination step in yeast prior to
infection of insect cells, but has the advantage over the vector designed
previously (Patel et al., A new method for the isolation of recombinant
baculovirus, Nucleic Acids Research 20 (1992) 97-104) that these vectors can also
be used in insects.
PMID- 9395142
TI - Single-antibody in situ enzyme immunoassay for infectivity titration of hepatitis
A virus.
AB - Hepatitis A virus (HAV) establishes a persistent infection in cultured cells,
with minimal effect on host cell metabolism. As a result, the virus produces very
little, if any, cytopathic effect (CPE), even with cell culture-adapted strains.
This feature precludes the use of a plaque or standard endpoint assay (using CPE
as an indicator of infection) for the titration of infectious virus. The
radioimmunofocus assay (RIFA) is the standard method for HAV titration, though
this method is labour intensive and requires the use of radioisotopes. To this
end, a single-antibody in situ enzyme immunoassay (EIA) has been developed, using
binding of a perioxidase-labelled monoclonal antibody to fixed cell monolayers as
an indicator of infection. This novel assay is highly reproducible, can be read
by eye, and is suitable for high throughput situations. Furthermore, the assay
has been validated against the RIFA making it suitable for use in studies
validating the safety of therapeutic biologicals for human use.
PMID- 9395143
TI - Disinfection of cell-associated and extracellular HIV-1 by PUVA treatment.
AB - To inactivate cell-associated and extracellular HIV-1 while preserving cellular
surface antigens, a procedure was used based on PUVA treatment, i.e. addition of
psoralen to cell suspensions followed by irradiation with UVA light. T-lymphoid
MT-4 cells were infected with HIV-1 strain NL4-3, 4'-aminomethyl-4,5',8
trimethylpsoralen was added, and the cell suspension was irradiated with 20
mW/cm2 UVA light for 3, 4 and 5 min. To evaluate virus inactivation, cells and
supernatants were diluted serially and cocultured with uninfected MT-4 cells.
Infectious HIV-1 was detected by cytopathic effects, immunofluorescence and p24
antigen ELISA. UVA irradiation at 3.6 J/cm2 (3 min 20 mW/cm2) reduced the amounts
of both cell-associated and extracellular infectious HIV-1 by more than five
orders of magnitude. Even at more stringent conditions of PUVA treatment (10 min
20 mW/cm2 UVA irradiation), conformational cellular surface epitopes remained
detectable by flow cytometry.
PMID- 9395145
TI - Detection of antibodies against iridoviruses in the serum of the amphibian Bufo
marinus.
AB - Sera from the amphibian Bufo marinus (cane or marine toad) were investigated
using a newly-developed enzyme-linked immunosorbent assay for the detection of
antibodies to ranaviruses (Family Iridoviridae). Epizootic haematopoietic
necrosis virus (EHNV) or Bohle iridovirus (BIV) was affinity purified from cell
culture supernatants and simultaneously bound to the solid phase using specific
linker antibodies. After binding to antigen, antibodies in Bufo marinus serum
were then detected with a specific anti-immunoglobulin reagent. Of 21 Bufo
marinus sera, 3 contained antibodies against EHNV, BIV or related viruses in the
ranavirus group, at titres greater than 3200. Reactivity of cane toad antibodies
against BIV, an amphibian virus, was greater than that against similar
concentrations of EHNV, a piscine virus.
PMID- 9395144
TI - Rapid direct diagnosis of mumps meningitis by ELISA capture technique.
AB - ELISA capture technique (ELISAc) was carried out using a rabbit hyperimmune serum
attached to a solid phase for capturing mumps antigens in cerebrospinal fluid
(CSF) in patients with meningitis and/or in supernatants of infected Vero cells.
A biotin-labelled rabbit serum prepared from the previous serum was added and the
reaction was read by an enzymatic (avidine-peroxidase) reaction by automated
reading. The cut-off was calculated in 100 CSFs negative for viruses by
conventional diagnosis. The specificity was evaluated in Vero cells infected with
22 CSFs collected from vaccinated children (URABE AM9 attenuated vaccine) who
developed meningitis. A guinea pig hyperimmune serum confirmed the specificity.
Results in culture correlated with the ELISA capture technique (ELISAc). No cross
reactivity was observed with parainfluenza 1, 2, 3 human reference strains. At
least 2.5 ngs of purified mumps proteins were detected corresponding to 10(1.5)
infectious particles per ml. ELISAc applied directly to 14 CSFs collected from
unvaccinated children with meningitis diagnosed five positive cases, whereas in
four cases conventional diagnosis had to be undertaken twice. ELISAc permitted
the diagnosis of one additional patient. The test can be carried out in 3 h.
PMID- 9395146
TI - The development of the somatoform dissociation questionnaire (SDQ-5) as a
screening instrument for dissociative disorders.
AB - Using cases of dissociative disorder (n=50) and other DSM-IV diagnoses (n=50), a
somatoform dissociation self-report questionnaire was developed and its capacity
to function as a screening device for dissociative disorders was analysed. A list
of 75 items was constructed which, according to clinical experience and expert
judgement, could reflect instances of somatoform dissociation. Statistical
analyses revealed the 20 best discriminating items. Stepwise forward logistic
analysis detected five items which, as a group, provided optimal discrimination
between the two groups. At an estimated prevalence rate of dissociative disorders
of 10% among psychiatric patients the sensitivity would be 94%, the specificity
would be 96%, the positive predictive value would be 72%, and the negative
predictive value would be 99%. Cross-validation in an independent sample
(n=33/42) largely corroborated the initial findings. The SDQ-5 can be used as a
brief screening device for dissociative disorders.
PMID- 9395147
TI - First-trimester maternal gestational infection and cycloid psychosis.
AB - Using a structured interview, the mothers of patients with cycloid psychosis,
manic depression and controls (40 mothers in each case) were investigated in
order to assess the occurrence of maternal gestational infection and other
obstetric complications during pregnancy with the affected child. The cycloid
psychoses with low heritability and a good long-term prognosis were found to be
significantly associated with first-trimester respiratory infection (i.e.
influenza and febrile cold). Furthermore, maternal infection seems to predict an
early onset in cycloids. In manic depression, we failed to identify a significant
link with maternal gestational infection or other obstetric complications. These
findings are discussed in the light of our previous reports of an excess of
maternal gestational infections during the second trimester in chronic
schizophrenics. Our results suggest that the exogenously induced disturbances of
fetal brain maturation during the first trimester of gestation caused by maternal
respiratory infection via live virus or disturbed maternal immune response are
involved in the aetiology of cycloid psychoses.
PMID- 9395149
TI - Reasons for substance use in schizophrenia.
AB - Abuse of and dependence on drugs, alcohol and other substances in schizophrenia
are being increasingly recognized and well documented in the literature. It has
been suggested that up to 60% of patients with schizophrenia use illicit drugs. A
total of 41 subjects who fulfilled DSM-III-R criteria for schizophrenia and
substance abuse or dependence were asked to describe their reasons for using such
substances, the reasons why they might stop and the subjective effects of the
substances. Drugs were reportedly used to increase pleasure, to 'get high' and to
reduce depression. However, subjective effects of increased depression and
positive symptoms were also reported. These results are considered in the context
of potential treatment strategies.
PMID- 9395148
TI - The healthy control subject in psychiatric research: impulsiveness and volunteer
bias.
AB - Exciting and demanding biomedical experiments may attract a specific subgroup of
people as volunteers. In the present study of selection bias, subjects
volunteering in a psychobiological study that included a potentially painful
procedure (lumbar puncture) were compared with those who declined to participate,
with regard to scores on personality scales administered during a previous
investigation of the same subjects. Significant differences were found on the
Eysenck Personality Questionnaire and Karolinska Scales of Personality
Impulsiveness scale, suggesting an over-representation of impulsive individuals
among the volunteers. If the specific subject of investigation has implications
for the type of individual who will participate as a healthy volunteer in
biomedical research, variation will be introduced, affecting the independent
variable, and the conclusions that can be drawn from such research may be
questionable.
PMID- 9395150
TI - Electroconvulsive therapy vs. paroxetine in treatment-resistant depression -- a
randomized study.
AB - Failure to respond to adequate pharmacological treatment for major depression is
now the most common indication for the use of electroconvulsive therapy (ECT).
The advantages of ECT with respect to both speed and quality of response are
clinically important issues, but surprisingly few studies have examined the
efficacy of ECT in relation to newer antidepressant agents such as selective
serotonin reuptake inhibitors (SSRIs). A total of 39 subjects with major
depression and with at least two failed antidepressant trials (mean 4.9 trials)
were randomized to either paroxetine treatment (n=18) or right unilateral (RUL)
ECT (n=21). Up to the end of the study treatment we found a reduction in the HAMD
score of 59% for the ECT group and of 29% for the paroxetine group (P<0.001
paired t-test). In the ECT group, 71% of subjects fulfilled the response criteria
(at least a 50% decrease in total HAMD score). The present study found ECT to be
superior to paroxetine in medication-resistant major depression, in terms of both
degree and speed of response.
PMID- 9395151
TI - Citalopram in the treatment of obsessive-compulsive disorder: an open pilot
study.
AB - Obsessive-compulsive disorder (OCD) is a common anxiety disorder, which often
causes significant impairment of the affected individual's social, occupational
or interpersonal functioning. Previous reports suggest that the disorder may be
treated with the tricyclic antidepressant clomipramine, and also with the more
recently introduced selective serotonin reuptake inhibitors (SSRIs), such as
fluoxetine, fluvoxamine, sertraline and paroxetine. The present 24-week open
pilot study was designed to examine the efficacy, appropriate dose range, side
effects and clinical usefulness of citalopram in OCD. A total of 29 OCD patients
were included in the study, of whom 76% showed alleviation of symptoms as
evaluated by various self- and observer-rated scales, such as the Yale-Brown
Obsessive Compulsive Scale. In most cases the citalopram doses used were in most
cases 40 or 60 mg daily, and the treatment was well tolerated. The most commonly
experienced adverse events during the study were nausea, vomiting, increased
dreaming and decreased sleep. Diminished sexual desire and orgasmic dysfunction
were also reported. Despite having the limitations of an open study, our results
suggest that citalopram may be effective in the treatment of obsessive-compulsive
disorder.
PMID- 9395152
TI - Long-term outcome of depot neuroleptic maintenance treatment among chronic
psychotic patients.
AB - A total of 51 chronic psychotic out-patients, with a median age of 51 years and
median duration of psychosis of 23 years, treated with depot neuroleptics,
entered a 5-year follow-up study with assessments of symptoms, side-effects and
plasma concentration of the depot drug (follow-up (FU) patients). The outcome for
38 non-eligible (NE) patients was obtained from hospital case reports. The
relapse rate was higher for NE than for FU patients (71% vs. 50%). The mortality
rate was 9%, and the median age at death was 47 years. Half of the FU patients
completed 3 years of treatment uneventfully. Of the total of 89 patients, only
18% remained stable over a period of 5 years. The depot dose was approximately
the same after 3 years (median 255 mg, range 50-1018 mg chlorpromazine
equivalents).
PMID- 9395154
TI - Suicide attempts in a cohort of drug abusers: a 5-year follow-up study.
AB - A group of 125 drug abusers admitted consecutively for detoxification and short
term rehabilitation were followed up 5 years after discharge. They were asked
about possible suicide attempts in a semi-structured face-to-face interview.
Nearly half of the group (45%) reported having attempted suicide at some point in
their life. The most common reasons given were the loss of a person whom they
loved, and feelings of loneliness. Only three respondents reported using their
drug of choice in the attempt(s). The suicide attempters were more often found to
have been in child psychiatric treatment earlier, and to have experienced loss of
significant others in childhood, than those who did not report attempting
suicide. At follow-up the suicide attempters indicated that they experienced more
depressive moods and more severe psychological problems than those who had never
made a suicide attempt. The importance of assessing the risk of suicide attempts
among drug addicts in order to be able to take measures to prevent future
suicidal behaviour is emphasized.
PMID- 9395153
TI - Prediction of outcome and early vs. late improvement in OCD patients treated with
cognitive behaviour therapy and pharmacotherapy.
AB - In this study, follow-up results of cognitive-behaviour therapy and of a
combination of cognitive-behaviour therapy with a serotonergic antidepressant
were determined. The study also examined factors that can predict this treatment
effect, both in the long term and in the short term. In addition, it investigated
whether differential prediction is possible for cognitive-behaviour therapy vs. a
combination of cognitive-behaviour therapy with a serotonergic antidepressant. A
total of 99 patients were included in the study. Treatment lasted 16 weeks, and a
naturalistic follow-up measurement was made 6 months later. Of the 70 patients
who completed the treatment, follow-up information was available for 61 subjects.
Significant time effects were found on all outcome measures at both post
treatment measurement and follow-up. No differences in efficacy were found
between the treatment conditions. Effectiveness at post-treatment measurement
appears to predict success at follow-up. However, 17 of the 45 non-responders at
the post-treatment measurement had become responders by the follow-up. The
severity of symptoms, motivation for treatment and the dimensional score on the
PDQ-R for cluster A personality disorder appear to predict treatment outcome. No
predictors were found that related specifically to cognitive-behaviour therapy or
combined treatment. These results indicate that the effectiveness of cognitive
behaviour therapy or a combination of cognitive-behaviour therapy and fluvoxamine
at the post-treatment measurement is maintained at follow-up. However, non
response at post-treatment does not always imply non-response at follow-up.
Patients with more severe symptoms need a longer period of therapy to become
responders. Although predictors for treatment success were found, no evidence was
found to determine the choice of one of the treatment modalities.
PMID- 9395155
TI - Validation of the Bech-Rafaelsen Mania Scale using latent structure analysis.
AB - The essential criteria of internal validity have not been sufficiently evaluated
for any mania rating scale, although the fulfillment of such criteria is a
prerequisite for summing the item scores to give a total score reflecting the
severity of mania, and for comparing total scores across patient groups that
differ with regard to variables such as age and sex. This study investigated the
internal validity of the Bech-Rafaelsen Mania Scale (MAS), based on the ratings
of 100 consecutively admitted drug-free DSM-III-R manic patients. Application of
logistic latent structure models did not statistically confirm the additivity of
the MAS. However, a modified MAS (the MAS-M) arising from the analyses fulfilled
the measurement model. Transferability of the MAS-M across age and sex was also
confirmed. The MAS-M showed an acceptable concurrent validity and an adequate
sensitivity in discriminating between responders and non-responders among
patients participating in a drug trial. The MAS-M presented here is the first
mania rating scale that has been shown to fulfil statistical criteria for
internal validity.
PMID- 9395156
TI - Life events in childhood, adolescence and adulthood and the relationship to panic
disorder.
AB - The aim of this study was to explore the association between stressful life
events (SLE) and the development of panic disorder (PD) in an Israeli sample. A
total of 44 PD patients and a matched control group were studied with regard to
SLE over the life cycle (in childhood, adolescence, adulthood and the year
preceding the outbreak of the disorder). The major findings were as follows. (i)
With regard to the total number of life events experienced in childhood and
adolescence, the PD group had experienced significantly more life events than the
control group. (ii) No differences were detected in the total amount of SLE
between the PD group and the control group with regard to adulthood and the year
preceding the outbreak of the disorder, although the PD group had more life
events relating to loss in adulthood, whereas in the year before the outbreak of
PD life events relating to 'love and family', negative and loss events were more
prevalent. These results expand previous findings by demonstrating that SLE in
childhood and adolescence may contribute to the development of PD in adulthood.
PMID- 9395157
TI - Seizures and myoclonus associated with antidepressant treatment: assessment of
potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment
with CYP2D6 inhibitors.
AB - All adverse drug reaction reports labelled seizures or myoclonus during treatment
with antidepressants and stored in the Swedish national database for spontaneous
reporting of adverse drug reactions were reviewed in order to evaluate possible
risk factors. The reporting physicians were contacted and asked for complementary
information, and blood samples for determination of the CYP2D6 and CYP2C19
genotypes were obtained from patients available. In total, 25 cases of seizures
and 7 cases of myoclonus were studied. The drugs included were maprotiline (n=8),
mianserin (n=7), fluvoxamine (n=6), amitriptyline (n=3), clomipramine (n=3),
citalopram (n=2), paroxetine (n=2) and lofepramine (n=1). Previously suggested
predisposing factors were identified in all but four cases (87%). None of the 11
patients genotyped were found to be poor metabolizers with respect to the enzymes
CYP2D6 or CYP2C19. Thus, neither the CYP2D6 nor the CYP2C19 genotype were found
to be associated with the occurrence of seizures/myoclonus during treatment with
antidepressants. However, 15 patients (47%) were concomitantly treated with drugs
with potential inhibitory effects on CYP2D6, such as neuroleptics and
dextropropoxyphene, and the patients might thus have been converted from the
extensive metabolizer to the poor metabolizer phenotype during this treatment.
Concomitant treatment with drugs decreasing the seizure threshold and/or
inhibiting the metabolism of antidepressants appeared to be an important risk
factor for the occurrence of seizures/myoclonus.
PMID- 9395158
TI - Cortisol in light treatment of seasonal and non-seasonal depression: relationship
between melatonin and cortisol.
AB - The effect of bright light on cortisol and the relationship between melatonin and
cortisol were studied in 63 depressed patients (42 patients with a seasonal
pattern and 21 patients with a non-seasonal pattern). The patients were matched
for age, time of treatment and severity of depression. Before and after light
treatment the severity of the depression was rated with the Comprehensive
Psychopathological Rating Scale (23 items) and the Hamilton Depression Rating
scale (18 items), and serum cortisol and melatonin were drawn at nine time-points
between 20.00 and 08.00 hours. Two hours of light treatment (350 cd m-2) was
given daily for 10 days either in the morning (06.00-08.00 hours) or in the
evening (18.00-20.00 hours). As reported earlier, patients with a seasonal
pattern improved significantly more than patients with a non-seasonal pattern of
depression, and no significant differences were found between the treatment
efficacy of morning compared to evening light. A cosinor analysis showed that the
cortisol batyphase was significantly advanced by morning light, but was not
delayed by evening light. A delay in batyphase cortisol showed a weak significant
correlation with a decrease in the absolute and relative sum of scores. The
batyphase of cortisol occurred approximately 3 h earlier than the acrophase of
melatonin. Of the changes in the melatonin acrophase 43% were reflected in a
change of cortisol batyphase, indicating a hierarchical relationship with
melatonin as the co-ordinating hormone transducing part of the information of the
external light to the phase position of cortisol. No significant differences
between patients with a seasonal or a non-seasonal pattern were seen in mesor,
amplitude or batyphase of cortisol before treatment, and no significant changes
in mesor or amplitude were seen as a result of light treatment.
PMID- 9395159
TI - A comprehensive method of assessing routine CT scans in schizophrenia.
AB - Morphological brain abnormalities are common in schizophrenia, although the
aetiological and clinical significance of these findings is largely unknown.
Substantial between-subject variability suggests that large samples are needed to
study the full implications of brain pathomorphology. Computerized tomography
(CT) is frequently used routinely in schizophrenia, and large numbers of scans
are available for study. This article describes the development and statistical
properties of a rapid and simple method of assessing CT scans. The CT Rating
Scale for Schizophrenia (CTRSS) is minimally affected by variability in scanning
procedures, is reliable, and accurately estimates area and volumetric measures of
brain spaces. By promoting the comprehensive assessment of large numbers of
routinely obtained scans, the CTRSS would allow the investigation of variables
that may systematically affect results (e.g. gender and age) and variables with
low prevalence. The CTRSS provides a useful adjunct to technologically more
sophisticated methods of assessment such as magnetic resonance imaging (MRI).
PMID- 9395160
TI - Effects of child-rearing by schizophrenic mothers: a 25-year follow-up.
AB - We conducted a 25-year follow-up study of 50 children of schizophrenic mothers,
consisting of 25 children reared by their mothers and 25 children reared apart.
The children's adult psychiatric status was evaluated in a 3-h structured
interview employing a battery of syndrome check-lists and scales. A slightly
higher incidence of psychopathology (including schizophrenia-spectrum disorders)
was found among the reared-apart subjects. This may possibly be attributed to
their greater genetic predisposition, as suggested by their mothers' more severe
illnesses. Lifetime diagnoses do not provide evidence that psychopathology in
offspring at genetic risk is increased by rearing by a schizophrenic mother.
PMID- 9395161
TI - The impact of treatment resistance on depressive relapse following
electroconvulsive therapy.
PMID- 9395162
TI - Reproducibility of ventricular fibrillation characteristics in patients
undergoing implantable cardioverter defibrillator implantation.
AB - INTRODUCTION: The purpose of this study was to evaluate the immediate
reproducibility of local electrogram characteristics recorded during repeated
episodes of induced ventricular fibrillation (VF) in patients undergoing
implantable cardioverter defibrillator (ICD) implantation. METHODS AND RESULTS:
Power spectral analysis (using a fast Fourier transform algorithm) of
electrograms recorded during 3 seconds of VF were analyzed in 24 patients
undergoing ICD implantation using a Medtronic Transvene lead. Patients had 2 to 7
episodes of VF that were induced during defibrillation threshold testing. VF was
induced by burst pacing (n = 20) or T wave shock (n = 4). Simultaneous
electrograms during VF were recorded from a Medtronic Transvene lead with the
following configurations: (1) a narrow spaced (12 mm) dedicated bipole used
clinically for sensing; (2) a unipolar electrogram from the right ventricular
coil; and (3) a widely spaced (18.3 mm) integrated bipole using the distal tip
and the coil. Intraclass correlation coefficients (ICCs) were determined to
examine the reproducibility of these VF characteristics among VF episodes in each
patient. Recordings from both bipolar configurations had ICCs from 0.40 to 0.55,
whereas unipolar recordings ICCs were below 0.40. Reproducibility was similar for
dedicated and integrated recordings. CONCLUSIONS: Frequency characteristics of
repeated episodes of VF induced in the same subjects show fair-to-good but not
excellent reproducibility. Bipolar recordings were far more reproducible than
unipolar recordings, but both bipolar configurations had similar reproducibility.
These findings have implications for both the pathophysiology of induced VF and
the design of VF detection algorithms.
PMID- 9395163
TI - Carotid sinus hypersensitivity in patients undergoing coronary arteriography:
relation with the severity of carotid atherosclerosis and the extent of coronary
artery disease.
AB - INTRODUCTION: The purpose of the present investigation was to study the precise
relationship between carotid sinus hypersensitivity (CSH) and both the severity
of carotid atherosclerosis and the extent of coronary artery disease in patients
who were referred for evaluation for suspected ischemic heart disease. METHODS
AND RESULTS: Duplex echocardiography and coronary angiography were used to assess
carotid and coronary artery atherosclerosis in 130 consecutive patients. Carotid
sinus stimulation was performed before coronary arteriography with simultaneous
recordings of the ECG and aortic pressure. Coronary artery disease was present in
103 patients (79%). Thirty patients (23.08%) had one-vessel disease (1-VD), 31
(23.85%) had 2-VD, 29 (22.31%) had 3-VD, and 13 patients (10%) had left main
coronary artery disease. Carotid artery atherosclerosis was present in 100
patients (76.92%) and carotid disease (diameter stenosis > 50%) was present in 24
patients (18.46%). CSH was found in 33 patients (25%). The incidence of CSH was
9% in patients with carotid stenosis 1%-15%, 17% in patients with stenosis 16%
49%, 85% in patients with stenosis 50%-79%, and 100% in patients with stenosis >
or = 80%. The incidence of CSH was 11%, 17%, 23%, 34%, and 62% in patients with
no VD, 1-VD, 2-VD, 3-VD, and left main coronary artery disease, respectively.
Stepwise multiple logistic regression analysis revealed that carotid disease and
left main coronary artery disease were the most significant determinants of CSH
(P < 0.001 and P = 0.013, respectively). CONCLUSION: The incidence of CSH
increased in proportion to the severity of carotid and coronary atherosclerosis.
These data provide evidence that CSH is closely related to severe carotid
atherosclerosis or left main coronary artery disease in patients being evaluated
for suspected ischemic heart disease.
PMID- 9395164
TI - Comparison of the effects of regional ischemia and hyperkalemia on the membrane
action potentials of the in situ pig heart. Experimental Cardiology Group,
University of North Carolina at Chapel Hill.
AB - INTRODUCTION: This study was designed to determine the role of increased
extracellular potassium [K+]e on action potential duration (APD) in the in situ
porcine heart during acute regional no-flow ischemia. METHODS AND RESULTS: In
open chest, anesthetized swine, an arterial shunt from the carotid artery to the
mid-left anterior descending coronary artery was created through which a solution
of KCl was infused to raise [K+]e. Myocardial [K+]e was determined by potassium
sensitive electrodes, and transmembrane action potential was recorded by floating
glass microelectrode. During the first 2 minutes of ischemia, APD at 90%
repolarization (APD90) lengthened by 31.2 +/- 1.1 msec (P < 0.05). The comparable
increase in [K+]e alone shortened APD90. During the next 6 minutes of ischemia,
[K+]e rose to 11.3 +/- 0.3 mM and APD90 showed a decrease. However, the
comparable increase in [K+]e by infusion of KCl caused further shortening of
APD90 at similar levels of [K+]e. CONCLUSIONS: Acutely ischemic myocardium showed
a brief increase in APD90 during the first 2 minutes of ischemia, followed by a
fall in APD90 after 2 minutes of ischemia, but the shortening is less than
anticipated by the rise in [K+]e. Thus, we hypothesize that other component(s) of
ischemia may inhibit action potential repolarization.
PMID- 9395165
TI - Extracellular potassium and the action potential duration of the ischemic heart.
PMID- 9395166
TI - Differential effects of D-sotalol, quinidine, and amiodarone on dispersion of
ventricular repolarization in the isolated rabbit heart.
AB - INTRODUCTION: Increased dispersion of ventricular repolarization has been
suggested as a cause of proarrhythmic effects of Class IA or III antiarrhythmic
drugs, such as d-sotalol, quinidine, and amiodarone. METHODS AND RESULTS: The
influence of d-sotalol, quinidine, and amiodarone on the dispersion of monophasic
action potential (MAP) durations was studied in 55 isolated Langendorff-perfused
rabbit hearts at different pacing cycle lengths (CLs). MAP duration measured at
90% repolarization (APD90) was determined from 6 to 8 endocardial and epicardial
MAP recordings with dispersion of ventricular repolarization defined as the range
of APD90. The protocol was repeated 60 minutes after initiation of a perfusate
containing increasing concentrations of d-sotalol (n = 12, 10[-6] M, 10[-5] M,
and 5 x 10[-5] M) and quinidine (n = 8, 10[-6] M and 10[-5] M). Seventeen rabbits
were fed with an aqueous solution of amiodarone (50 mg/kg per day over 4 weeks).
The data of these experiments (n = 17) were compared with a series of 18
untreated control rabbits. Dispersion of ventricular repolarization was unchanged
with the low concentration of d-sotalol (10[-6] M) but was increased-particularly
at long CLs-with higher d-sotalol concentrations. With both concentrations of
quinidine, dispersion of ventricular repolarization was increased in a rate
independent manner. Amiodarone did not affect dispersion of ventricular
repolarization. CONCLUSIONS: Rate-dependent and concentration-dependent increases
in dispersion of ventricular repolarization by d-sotalol and quinidine in this
isolated rabbit heart model may help explain their proarrhythmic effects while
the absence of an increase in dispersion of ventricular repolarization with
amiodarone correlates with its clinically observed lower incidence of
proarrhythmia.
PMID- 9395167
TI - Importance of electrode conductive surface area and edge effects on ventricular
defibrillation efficacy.
AB - INTRODUCTION: The role of edge effects and electrode surface area of the right
ventricular (RV) transvenous lead (TVL) on defibrillation efficacy is unknown.
METHODS AND RESULTS: Defibrillation threshold (DFT) testing was conducted
randomly in 12 dogs using ring electrode leads in an RV/SVC (superior vena cava)
or RV/SVC/patch system. The leads (RV-4, RV-8t, RV-8, RV-15) had electrode
surface areas of 20%, 20%, 40%, and 70%, respectively. A computer model predicted
the magnitude of electrode surface current (RV-8t > RV-4 > RV-8 > RV-15) and the
potential distribution (PD) at four sites: electrode surface (site a) and at 2 mm
(b), 4 mm (c), and 8 mm (d) away from the surface. Despite different near-field
PDs (sites a, b, c), PDs were nearly identical at site d. Resistance decreased as
the surface area increased. DFT energy for the RV-15 lead was lower than the RV-4
and RV-8t. There was no difference between energy requirements for the RV-15 and
RV-8 leads. No difference was found in DFT current for each lead. Comparison of
the RV-8t and RV-4 leads showed no difference in DFT energy despite a lower
resistance and a greater number of edges. CONCLUSIONS: Increasing the RV TVL
surface area lowered the resistance. However, surface area coverages > or = 40%
did not lower DFT energy. No significant change in DFT current occurred despite
different predicted near-field current densities. PDs were nearly identical 8 mm
from the electrode surface. Thus, the far-field current density appears to play a
more important role in determining defibrillation success.
PMID- 9395168
TI - Critical atrial site for ablation of pacing-induced atrial fibrillation in the
normal dog heart.
AB - INTRODUCTION: Radiofrequency catheter ablation (RFA) has been used recently to
treat atrial fibrillation (AF). The purpose of this study was to investigate a
new approach to preventing AF by RFA. METHODS AND RESULTS: In open chest,
anesthetized dogs, AF (lasting > 30 sec) was induced after burst stimulation, and
electrophysiologic parameters were recorded before and after RFA. In group 1 (9
dogs) we performed selective and combined slow and fast pathway RFA, whereas in
group 2 (11 dogs) RFA was applied as a linear lesion at the mid-atrial septum
between the inferior vena cava and the fossa ovalis. After ablation, the
Wenckebach cycle length was significantly prolonged only in group 1 (194 +/- 23
vs 282 +/- 35 msec, P = 0.002), whereas the interval between the stimulus (S)
artifact applied at the high right atrium to the His bundle (H) (SH interval)
prolonged to the same extent in both groups (162 +/- 14 vs 146 +/- 45 msec, P =
NS); group 1 due to an A-H prolongation whereas in group 2 it was due to an intra
atrial conduction delay. In group 1 AF still remained inducible, although with a
longer mean R-R interval (215 +/- 16 vs 433 +/- 88 msec, P < 0.05). No instance
of complete AV block developed. In group 2, sustained AF was noninducible in 10
dogs and its duration was markedly shorter in the remaining one (8 sec). Gross
anatomy and histology did not reveal any damage inside of Koch's triangle, and
particularly to the compact AV node. CONCLUSION: These findings suggest that RFA
at the mid-atrial septum prevents AF in the normal dog heart. This approach might
also be successful in those clinical settings in which the atrial septum plays a
critical role in the maintenance of sustained AF.
PMID- 9395169
TI - Ablation of atrial fibrillation.
PMID- 9395170
TI - Chronic amiodarone reduces transmural dispersion of repolarization in the canine
heart.
AB - INTRODUCTION: Amiodarone is a potent antiarrhythmic agent used in the management
of both atrial and ventricular arrhythmias. In addition to its beta-blocking
properties, amiodarone is known to block the sodium, potassium, and calcium
channels in the heart. Its complex electropharmacology notwithstanding, the
reasons for the high efficacy of the drug remain unclear. Also not well
understood is the basis for the low incidence of proarrhythmia seen with
amiodarone relative to other agents with Class III actions. The present study was
designed to examine the effects of chronic amiodarone in epicardial, endocardial,
and M cells of the canine left ventricle. METHODS AND RESULTS: We used standard
microelectrode techniques to record transmembrane activity from endocardial,
epicardial, mid-myocardial, and transmural strips isolated from the canine left
ventricle. Tissues were obtained from mongrel dogs receiving amiodarone orally
(30 to 40 mg/kg per day) for 30 to 45 days or from untreated controls. Chronic
amiodarone produced a greater prolongation of action potential duration in
epicardium and endocardium, but less of an increase, or even a decrease at slow
rates, in the M region, thereby reducing transmural dispersion of repolarization.
In addition, chronic amiodarone therapy suppressed the ability of the IKr
blocker, d-sotalol, to induce a marked dispersion of repolarization or early
afterdepolarization activity. CONCLUSION: Our data demonstrate for the first time
a direct effect of chronic amiodarone treatment to differentially alter the
cellular electrophysiology of ventricular myocardium so as to produce an
important decrease in transmural dispersion of repolarization, especially under
conditions in which dispersion is exaggerated. These results may contribute to
our understanding of the effectiveness of amiodarone in the treatment of life
threatening arrhythmias as well as to our understanding of the low incidence of
proarrhythmia attending therapy with chronic amiodarone in comparison with other
Class III agents.
PMID- 9395172
TI - Retrograde supernormal conduction in concealed accessory atrioventricular pathway
following catheter ablation.
AB - A case is presented of a 63-year-old woman with a concealed accessory pathway
that exhibited retrograde supernormal conduction after radiofrequency catheter
ablation. Although ventricular pacing at a slow rate revealed no retrograde
conduction over the accessory pathway following ablation, the tachycardia
recurred 15 months later. During ventricular pacing there was retrograde 1:1
conduction over the accessory pathway at a fast rate while there was intermittent
VA dissociation with rare retrograde conduction at the slower rate. Ventricular
extrastimulus testing demonstrated a supernormal conduction zone of the coupling
interval. Thus, accessory pathways may exhibit supernormal conduction after
catheter ablation. Pacing should be performed at both slow and fast rates to
confirm the presence of conduction block following ablation.
PMID- 9395171
TI - Effects of sodium channel block with mexiletine to reverse action potential
prolongation in in vitro models of the long term QT syndrome.
AB - INTRODUCTION: Recent clinical studies have reported a greater effectiveness of
sodium channel block with mexiletine to abbreviate the QT interval in patients
with the chromosome 3 variant (SCN5A, LQT3) of the long QT syndrome (LQTS) than
those with the chromosome 7 form of the disease (HERG, LQT2), suggesting the
possibility of gene-specific therapy for the two distinct forms of the congenital
LQTS. Experimental studies using the arterially perfused left ventricular wedge
preparation have confirmed these clinical observations on the QT interval but
have gone on to further demonstrate a potent effect of mexiletine to reduce
dispersion of repolarization and prevent torsades de pointes (TdP) in both LQT2
and LQT3 models. A differential action of sodium channel block on the three
ventricular cell types is thought to mediate these actions of mexiletine. This
study provides a test of this hypothesis by examining the effects of mexiletine
in isolated canine ventricular epicardial, endocardial, and M region tissues
under conditions that mimic the SCN5A and HERG gene defects. METHODS AND RESULTS:
We used standard microelectrode techniques to record transmembrane activity from
endocardial, epicardial, mid-myocardial, and transmural strips isolated from the
canine left ventricle. d-Sotalol, an IKr blocker, was used to mimic the HERG
defect (LQT2), and ATX-II, which increases late Na channel current, was used to
mimic the SCN5A defect (LQT3). d-Sotalol (100 microM) preferentially prolonged
the action potential of the mid-myocardial M cell (APD90 increased from 340 +/-
65 to 623 +/- 203 msec) as did ATX-II (10 to 20 nM; APD90 increased from 325 +/-
51 to 580 +/- 178 msec; basic cycle length = 2000 msec), thus causing a marked
increase in transmural dispersion of repolarization (TDR). Mexiletine (2 to 20
microM) dose-dependently reversed the ATX-II-induced prolongation of APD90 in all
three cell types. Mexiletine also reversed the d-sotalol-induced prolongation of
the M cell action potential duration (APD), but had little effect on the action
potential of epicardium and endocardium. Due to its preferential effect to
abbreviate the action potential of M cells, mexiletine reduced the dispersion of
repolarization in both models. Low concentrations of mexiletine (5 to 10 microM)
totally suppressed early afterdepolarization (EAD) and EAD-induced triggered
activity in both models. CONCLUSIONS: Our results indicate that the actions of
mexiletine are both cell and model specific, but that sodium channel block with
mexiletine is effective in reducing transmural differences in APD and in
abolishing triggered activity induced by d-sotalol and ATX-II. The data suggest
that mexiletine's actions to reduce TDR and prevent the induction of spontaneous
and programmed stimulation-induced TdP in these models are due to a preferential
effect of the drug to abbreviate the APD of the M cell and to suppress the
development of EADs. The data provide further support for the hypothesis that
block of the late sodium current may be of value in the treatment of LQT2 as well
as LQT3 and perhaps other congenital and acquired (drug-induced) forms of LQTS.
PMID- 9395173
TI - A case of widely split double P waves with marked intra-atrial conduction delay.
AB - We report a 78-year-old man as the first documented case of double P waves
separated by 400 msec on 12-lead ECG. These P waves had different polarities on
lead V1. The first P wave represented activation of the lateral wall of the right
atrium, and the latter P wave represented activation of the medial right atrium
and the left atrium. Widely spaced double potentials were recorded craniocaudally
along the line, presumably corresponding to the crista terminalis during sinus
rhythm. For this to occur, conduction disturbance has to be present both in the
upper and lower right atrium. Conduction disturbance in the upper right atrium
would interrupt excitation from the sinus node to the medial wall, and conduction
disturbance in the lower right atrium would interrupt excitation spreading from
the lower lateral right atrium to the isthmus area where fragmented potentials
were recorded. These multiple discrete lesions appear to constitute a unique
electrical atriopathy in this patient.
PMID- 9395174
TI - Atypical atrioventricular nodal reentry tachycardia with atrioventricular block
mimicking atrial tachycardia: electrophysiologic properties and radiofrequency
ablation therapy.
AB - INTRODUCTION: Fast-intermediate form AV nodal reentry tachycardia (AVNRT)
sometimes may mimic atrial tachycardia or atrial flutter and render the diagnosis
difficult when the tachycardia rate is fast and AV block occurs during
tachycardia. METHODS AND RESULTS: A 45-year-old woman with paroxysmal
supraventricular tachycardia was referred to this institution. Initially, the
tachycardia was thought to be an atrial tachycardia because of: (1) a short cycle
length of the tachycardia with 2:1 and Wenckebach AV block; (2) a difference in
the atrial activation sequence during tachycardia and during ventricular pacing;
and (3) failure of burst ventricular pacing to affect the atrial rate and the
atrial activation sequence during tachycardia. An accurate diagnosis of fast
intermediate form AVNRT was subsequently made based on the finding that the
tachycardia was induced following delivery of a third ventricular extrastimulus,
which showed a sequence of V-A-H and a change on atrial activation sequence of
the induced beat. Successful radiofrequency ablation was achieved only after
accurate diagnosis of the tachycardia was made. CONCLUSION: Fast-intermediate
form AVNRT sometimes may masquerade as atrial tachycardia. Accurate diagnosis is
mandatory for successful ablation therapy.
PMID- 9395175
TI - Radiofrequency catheter ablation of ventricular tachycardia late after myocardial
infarction.
AB - Radiofrequency catheter ablation is a promising method for controlling
ventricular tachycardia (VT) due to prior myocardial infarction. Limitations of
mapping and ablation techniques have largely restricted its use to selected
patients who have hemodynamically tolerated sustained monomorphic VT that allows
catheter mapping. Multiple monomorphologies of VT, which are usually present,
often complicate the ablation procedure and interpretation of ablation effects.
Ablation is generally restricted to experienced centers and is usually reserved
for patients who have failed other therapies. Despite these difficulties,
successful ablation can be life-saving in patients with incessant VT and can
markedly improve quality of life with frequent shocks from implantable
defibrillators.
PMID- 9395176
TI - Management of the child with Wolff-Parkinson-White syndrome and supraventricular
tachycardia: model for cost effectiveness.
AB - In the next decade, "better" management will be defined by cost effectiveness
including morbidity, mortality, and cost. We used a cost-effectiveness model for
children with Wolff-Parkinson-White syndrome (WPW) and supraventricular
tachycardia (SVT) comparing medical, surgical, and catheter ablative treatment
between age 5 years (estimated average age at first recurrence after infancy) and
age 21. Charges were quantitated from actual hospital bills; mortality was
estimated from the literature; morbidity was assessed by estimating the number of
hours in SVT, hours in clinic, hours in routine hospital bed, and hours in
hospital intensive care; and the hours were then multiplied by a severity factor,
normalized to 1.0 for 1 hour of SVT (0.5 for 1 hour in clinic, 0.75 for routine
hospital, and 2.0 for intensive care). Overall charges (5 to 21 years old) for
catheter ablation ($17,236) were 39% of surgical management and 57% of medical
management; estimated mortality for catheter ablation (5 to 21 years old
including failures that reverted to medical management) was 0.15%, which was 10%
of medical management and 28% of surgical management; morbidity for catheter
ablation was 27.6 units, which was 32% of medical management and 36% of surgical
management. Sensitivity analysis demonstrated that the catheter ablation strategy
remained preferable throughout the range of plausible values of cost, mortality,
and morbidity (including a repeat procedure for initial failures). Therefore,
catheter ablation has lower cost, mortality, and morbidity than either medical
management or surgery and is the treatment of choice for the child 5 years of age
or older with WPW and SVT. This type of analysis can be used for other forms of
chronic disease in children.
PMID- 9395177
TI - Wide complex tachycardia in a critically ill patient: what is the rhythm?
PMID- 9395178
TI - Electrophysiology of the atrio-AV nodal inputs and exits in the normal dog heart:
radiofrequency ablation using an epicardial approach.
PMID- 9395180
TI - Detection of BCL-6 rearrangements and p53 mutations in Malt-lymphomas.
AB - Twenty-seven lymphomas of mucosa-associated lymphoid tissue (MALT) derived from
distinct anatomical sites were tested for the presence of genetic lesions
commonly involved in B-cell lymphomagenesis, including activation of proto
oncogenes (BCL-1, BCL-2, BCL-6, and c-MYC), disruption of tumor suppressor loci
(p53, 6q), and infection by viruses [Epstein-Barr virus (EBV), and Kaposi's
sarcoma-herpesvirus/human herpesvirus-8 (KSHV/HHV-8)]. Sixteen low-grade and 11
high-grade MALT-lymphomas were included in the study. The presence of genetic
lesions was tested by a combination of molecular approaches, including Southern
blot hybridization, polymerase chain reaction (PCR), and PCR-single strand
conformation polymorphism followed by DNA direct sequencing. Alterations of BCL
1, BCL-2, or c-MYC, as well as infection by KSHV/HHV-8, scored negative in all
MALT-lymphomas analysed. Conversely, rearrangements of BCL-6 and mutations of p53
clustered with a fraction of high-grade MALT-lymphomas. Deletions of 6q occurred
in selected cases of both low- and high-grade MALT-lymphomas, whereas a
monoclonal infection by EBV was restricted to one single patient. These data
corroborate the notion that the molecular pathogenesis of MALT-lymphomas differs
substantially from that of nodal B-cell lymphomas. Occasionally, however, a
proportion of high-grade MALT-lymphomas may harbor selected genetic lesions among
the ones commonly involved in nodal B-cell lymphomagenesis.
PMID- 9395179
TI - Cell behavior and signal molecule involvement in a case study of malignant
histiocytosis: a negative model of morphine as an immunoregulator.
AB - In a patient diagnosed with histiocytic medullary reticulosis (HM), we examined
immunocytes for their responsiveness towards known signaling molecules. Both the
granulocytes and monocytes were found to exhibit a high level of spontaneous
activation (96% compared to normal cells 7%; P < 0.001). These cells could not be
downregulated when exposed to morphine. Following patient treatment with
doxorubicin and cyclophosphamide, the immunocytes still exhibited a high
spontaneous activation. They responded to morphine exposure in vitro with a cell
rounding and becoming immobile for only 20 min whereas normal cells would remain
round and immobile for up to 1-2 h. An examination of the plasma from the HM
patient revealed that monocyte colony stimulating factor (MCSF) levels were
elevated (6.4 and 5.78 compared to a control range of 1-1.75 ng/ml). In the HM
patient, the immunocytes did not express the opiate selective and opioid peptide
insensitive receptor, mu3, supporting the lack of opiate action. Given this
finding, we incubated normal monocytes with MCSF and found that it significantly
reduced the mu3 Bmax. Given the role of intracellular calcium in the activation
process of immunocytes, we examined the action of various calcium channel
blockers for their ability to inhibit the activated HM monocytes. The agents
(nimodipine, cardiazem, and verapamil; 10[-9] M) were able to inhibit the HM
associated chemokinesis. Taken together, the data indicate that in the HM patient
the immunocytes appear to be overactivated because stimulatory molecules are high
and have the ability to downregulate the normal "braking" process. Additionally,
the data indicate that MCSF deregulation may be involved as an initiating factor
for this disorder.
PMID- 9395181
TI - Sequential mitoxantrone, daunorubicin, and cytosine arabinoside for patients with
newly diagnosed acute myelocytic leukemia.
AB - Mitoxantrone (M) is a synthetic aminoanthraquinone with anti-leukemic activity in
patients with daunorubicin (D) resistant acute leukemia. The Cancer and Leukemia
Group B (CALGB) has undertaken a limited access pilot study in which M, 12 mg/m2,
over 30 min, daily for 3 days, and cytosine arabinoside (Ara-C), 100 mg/m2/day by
constant infusion for 7 days were used for the induction of newly diagnosed
patients with AML. Responding patients were consolidated with daunorubicin, 45
mg/m2/day for 3 days, and 7 days of Ara-C. After a second consolidation identical
to induction, no further therapy was given. Twenty-nine patients with a median
age of 50 years (range 18-72) were entered in the study; 18 were males and 11
females. Twenty-four (83%) patients achieved CR, 1 patient achieved a PR, and 4
died in induction from leukemia-related causes. Two patients died in CR from
consolidation-related neutropenic sepsis and two additional patients died in CR.
Of 24 patients, 7 remain disease-free at a median follow-up interval of 8 years.
The regimen is active and well tolerated. The duration of disease-free survival
in responding patients is consistent with that seen in similar regimens using
intensification chemotherapy without prolonged maintenance.
PMID- 9395182
TI - Lymphoma with multi gene rearrangement on the level of immunoglobulin heavy
chain, light chains, and T-cell receptor beta chain.
AB - A unique case with diffuse mixed malignant lymphoma was investigated for gene
rearrangement on the level of T-cell receptor (TCR), heavy chain immunoglobulin
(Ig), and both light chains. Cell phenotype was examined with immunofluorescence
techniques using antibodies against surface immunoglobulins (SIg) and the kappa
and lambda light chains. Monoclonal antibodies were used against CD3, CD4, CD5,
CD8, CD10, CD19, CD22, HLA-DR, and TdT. Gene rearrangement analysis for
monoclonality determination was carried out with restricted DNA (EcoR I and Hind
III) hybridized with one of the following 32P-labelled probes: T-cell receptor
(TCR beta), immunoglobulin heavy chain (JH), k light chain, and lambda light
chain. Phenotyping of the cell population from the excised lymph node (LN)
revealed the presence of 66% B-cells and 35% T-cells. Most of the B cells (94%)
expressed mu heavy chain only. Expression of both light chains was negligible (k
= 7% and lambda = 2%). Gene rearrangement, which indicates monoclonality, was
positive on the level of TCR, Ig heavy chain, and both light chains. The data
obtained suggests a neoplastic transforming event in lymphoid stem cells, which
preceded the subsequent differentiation process into either B or T lymphoma.
PMID- 9395183
TI - MDS and AML with trisomy 8 as the sole chromosome aberration show different sex
ratios and prognostic profiles: a study of 115 published cases.
AB - A number of chromosome aberrations occur nonrandomly as the sole aberration in
malignant and premalignant hematological disorders. They imply very different
prognoses. For most of them the survival consequences have been established. For
trisomy 8, which is the most frequent numerical aberration in myeloid disorders,
the prognostic implications have not been investigated. In order to clarify
survival in patients with trisomy 8 as the sole aberration, the literature was
searched for such cases. In 115 patients survival data were available. In 103
(89.6%), a myeloid disorder had been diagnosed. Acute myeloid leukemia (AML) or a
myelodysplastic syndrome (MDS) occurred in 100 cases (87.0%). The median survival
was found to be 17.1 months. On multivariate survival analysis (Cox), age above
60 and a leukemic diagnosis were found to be independent adverse prognostic
indicators. MDS patients survived significantly longer (median 21 months) than
AML patients (median 15 months). In MDS age and in AML the trisomy 8 clonal size
was an independent prognostic factor. An unexpected observation was a clear male
preponderance in trisomy 8 MDS (about two-thirds of cases). In trisomy 8 AML an
approximate 1:1 ratio was found. Browsing of Mitelman's catalog confirmed these
ratios.
PMID- 9395184
TI - Serum methylmalonic acid and total homocysteine in patients with suspected
cobalamin deficiency: a clinical study based on gastrointestinal
histopathological findings.
AB - We compared the sensitivity and specificity of the two metabolite tests,
methylmalonic acid (MMA) and total homocysteine (Hcy) in serum, and serum
cobalamin (Cbl) in patients referred to our hospital because of suspected
cobalamin deficiency and a serum cobalamin value at the referring unit <200
pmol/L. All 111 patients included were investigated using upper gastrointestinal
endoscopy with biopsy specimens taken from the gastric and duodenal mucosa to
find a morphological basis for cobalamin malabsorption as well as the Schilling
test for the validation of the serum tests. All patients were treated with
cobalamin and new blood samples were taken after 4 weeks. We found no difference
in sensitivity and specificity between serum MMA, Hcy, and Cbl in identifying
patients with and without conditions compatible with cobalamin malabsorption.
Elevated serum MMA and Hcy were also found in about 15% of the group of patients
with normal Schilling tests and without a morphological basis for cobalamin
malabsorption. Moreover, most patients in this group responded with decreased
values of the metabolite tests following cobalamin treatment, suggesting that
neither elevated metabolites nor a decrease in these values following cobalamin
treatment are specific for cobalamin deficiency.
PMID- 9395185
TI - Dissection of the association status of two polymorphisms in the beta-globin gene
cluster with variations in F-cell number in non-anemic individuals.
AB - Expression of fetal hemoglobin (Hb F) is under polygenic control involving
determinants both linked and unlinked to the beta-globin gene cluster on
chromosome 11. Variations in the DNase I-hypersensitive site 2 of the locus
control region (LCR-HS2) and a C --> T change at position -158 from the Ggamma
gene (detected as an XmnI polymorphism) correlate with the high level of Hb F
expression in patients with sickle-cell anemia and beta-thalassemia.
Interpretation of data under these conditions of anemic stress is difficult
because the preferential survival of Hb F-containing erythrocytes (F-cells) may
not reflect the true status of Hb F expression. We investigated the relationship
between these markers and Hb F expression in terms of F-cell levels in 48
unrelated non-anemic AS heterozygotes from Sicily. The betaS-chromosome of all
these individuals was of the Benin haplotype and they differed only by their
betaA chromosomes. We demonstrate that F-cell expression is more strongly
associated with LCR-HS2 polymorphism than with XmnI polymorphism. The observed
association between XmnI polymorphism and Hb F expression is very likely to be
due to linkage disequilibrium with LCR-HS2 sequences.
PMID- 9395186
TI - Effects of hyperthermal stress on the ultrastructure of platelets with reference
to the localization of platelet peroxidase and fibrinogen in vivo.
AB - Ultrastructure of platelets with the localization of platelet peroxidase and
fibrinogen through 3-min 47 degrees C hot-spring bathing was investigated in
eight healthy volunteers. The mean sublingual temperature rose about 1.8 degrees
C 5 min after the start of bathing. The frequencies of fold, pseudopods,
vacuoles, and centralization were increased after bathing. Platelet peroxidase
activity was decreased after bathing. Furthermore, fibrinogen was decreased in
alpha-granules after bathing. Thus, hyperthermal stress in vivo may activate
platelets, resulting in consumption of platelet peroxidase and fibrinogen.
PMID- 9395187
TI - Parvovirus B19 quiescence during the course of human immunodeficiency virus
infection in persons with hemophilia.
AB - To detect and characterize parvovirus B19 infection during the course of
progressive immune deficiency from human immunodeficiency virus (HIV), ten
subjects enrolled in the Multicenter Hemophilia Cohort Study were followed for
6.4 to 15 years from HIV seroconversion through extreme immune deficiency. Four
to five sera or plasma samples from each subject, collected at predetermined CD4+
lymphocyte levels, were tested for immunoglobulin G (IgG) and M (IgM) B19
antibodies and DNA. All 42 samples were positive for B19 IgG antibodies, and
three were weakly positive for IgM antibodies. Only one sample, collected
coincident with HIV seroconversion, was unequivocally positive for B19 DNA. No
persistent hematologic adverse effects of B19 infection were observed. Thus,
although B19 IgG antibodies are highly prevalent among HIV-infected persons with
hemophilia or related disorders, B19 viremia and its hematologic consequences
were not detected, even with severe depletion of CD4+ lymphocytes. If primary B19
infection occurs after immune deficiency, however, the consequences may be more
adverse.
PMID- 9395188
TI - BFU-E colony growth in response to hydroxyurea: correlation between in vitro and
in vivo fetal hemoglobin induction.
AB - Patients with sickle-cell anemia treated with hydroxyurea may have significant
reduction in frequency and severity of pain episodes. However, previous clinical
trials show a variable response to hydroxyurea. Criteria which can be used to
select patients who are likely to respond to hydroxyurea treatment would be
useful. Our laboratory has previously demonstrated an inverse linear relationship
between the total number of burst-forming unit-erythroid (BFU-E) colonies and
fetal hemoglobin levels in sickle-cell patients treated with hydroxyurea. In the
present report, an in vitro cell culture system was established to evaluate the
effects of hydroxyurea on BFU-E colony growth and induction of fetal hemoglobin
production. Five Hb SS patients who were not previously treated with hydroxyurea
and three Hb SS patients who failed to respond to hydroxyurea treatment were
included in the study. The results show that the number of BFU-E colonies is
decreased from 153.7 to 7.2 per 3 x 10(5) mononuclear cells, whereas fetal
hemoglobin levels were increased from 5.1 to 19.4% in the presence of hydroxyurea
in vitro in cultured erythroid progenitors, which were derived from 5 patients
before treatment. The number of BFU-E colonies decreased from 153.7 to 2.0 per 3
x 10(5) mononuclear cells in the in vitro cultures obtained from serial
peripheral blood samples over a 9- to 20-week period of oral hydroxyurea therapy.
A simultaneous rise in fetal hemoglobin level from 10.2 to 28.6% in the
peripheral blood over the same period of hydroxyurea therapy was also observed.
Our results demonstrate that the increase in fetal hemoglobin levels in cells
treated with hydroxyurea in vitro is comparable to the rise of fetal hemoglobin
production following hydroxyurea therapy in these patients. On the contrary,
these findings were not observed in three previously non-responsive sickle-cell
patients. These results suggest that the changes in number of BFU-E colonies and
fetal hemoglobin levels after in vitro exposure to hydroxyurea may be a useful
approach to select sickle-cell patients who will respond to hydroxyurea therapy.
PMID- 9395189
TI - Release of adenosine triphosphate by adenosine diphosphate in whole blood and in
erythrocyte suspensions.
AB - In whole blood samples from thrombocytopenic patients, large amounts of ATP were
released by ADP, exceeding the level obtained with samples from normal persons by
far. Because we suspected that the high potential of ATP in erythrocytes would be
the main source for this phenomenon, the release of ATP by ADP was measured in
whole blood samples from normal, thrombocytopenic, and leukocytopenic persons and
in suspensions of washed erythrocytes. The release was recorded by a Whole Blood
Lumi-Aggregometer type 500 VS (Chrono-Log Corporation, Havertown, PA) using the
luciferin-luciferase system. Not only in samples from thrombocytopenic persons
but also with normal platelet count, increasing amounts of ATP were released with
increasing ADP concentrations, finally exceeding the ATP releasable from
thrombocytes by thrombin. The amounts of ADP required to match the ATP release of
thrombin were closely correlated with the platelet counts in the samples. With
lower platelet counts, the release mechanism from erythrocytes could be
stimulated more easily by low concentrations of ADP. The binding of ADP to
platelets occurred with ostensibly higher affinity. The phenomenon of
overshooting ATP release was also observed in samples from extremely
leukocytopenic patients. A very large release of ATP was also achieved in
suspensions of washed erythrocytes. In this way our hypothesis of ATP release
from erythrocytes by ADP was confirmed again. The mechanism of the release from
erythrocytes remains unclear. We speculate that its purpose is to regulate
extracellular nucleotides in the circulating blood.
PMID- 9395191
TI - Cyclic thrombocytopenia in a patient treated with cyclosporine for refractory
idiopathic thrombocytopenic purpura.
AB - Cyclic thrombocytopenia (CT) is a rare disorder with cyclic changes of the
platelet counts. Though the pathogenesis of this disorder has not been clarified,
recent reports suggest that periodic destruction and/or ineffective production of
platelets may be important causes of the disease. We report a case of a patient
with refractory idiopathic thrombocytopenic purpura (ITP) in whom CT developed
after cyclosporine A (CyA) therapy. There was an inverse relation between
platelet counts and the serum levels of platelet-associated immunoglobulin G
(PAIgG). The ploidy of bone marrow megakaryocytes also had an inverse relation
with platelet counts. When the platelet count was low, the ploidy of
megakaryocytes increased (P < 0.01). The number and area of bone marrow
megakaryocytes were unrelated to platelet counts. These results indicate the
possibility of platelet destruction caused by immunological mechanisms in CT.
Cyclosporine A could have certain but fluctuating regulatory effects against
antibody production for circulating platelets, which could lead to cyclic changes
of the platelet counts. This case also suggests that CyA can be effective in
severe refractory ITP. Regulatory mechanisms of platelet production and
destruction and appropriate doses of CyA should be further studied in autoimmune
mediated thrombocytopenias.
PMID- 9395190
TI - Telomere length in myelodysplastic syndromes.
AB - We have studied telomere length in the bone marrow cells or the granulocyte and
lymphocyte cell fractions of 54 patients with myelodysplastic syndromes (MDS) by
Southern blot hybridization using the (TTAGGG)4 probe. The average telomere
length expressed as the peak telomere repeat array (TRA) in the peripheral blood,
or bone marrow samples obtained from a group of 21 healthy age-matched controls
(26-89 years old, mean age 55), ranged between 7.5 and 9.5 kb (mean peak TRA 8.6
kb). Twenty-four patients with refractory anemia (RA) were studied; 10/24 (42%)
had telomere reduction (<7.5 kb) relative to age-matched controls and the mean
peak TRA was 7.5 kb (range 4.0-9.0 kb). Eleven patients with RA with excess
blasts (RAEB) were studied; 5/11 (45%) had reduced telomeres relative to age
matched controls and the mean peak TRA was 7.1 kb (range 5.0-9.0 kb). Eighteen
patients with MDS in transformation to AML, comprising 15 with RAEB in
transformation (RAEBt) and 3 with CMML in transformation (CMMLt), were also
studied. Thirteen of eighteen patients (72%) had telomere reduction relative to
age-matched controls and the mean peak TRA was 6.1 kb (range 3.5-9.0 kb). Thirty
six patients included in the study had either a normal karyotype or a simple
karyotype (1 karyotypic change) and 20/36 (55%) of these had telomere reduction
and the mean peak TRA was 7.1 kb (range 4.3-9.0 kb); 8 patients had a complex
karyotype (3 or more karyotypic changes) and 5/8 (62%) of these had telomere
reduction and the mean peak TRA was 6.1 kb (range 3.5-9.0 kb). We conclude,
firstly that there is heterogeneity of telomere length in MDS and that this is
observed throughout the spectrum of FAB-subtypes. Secondly, these data show that
a marked reduction in telomere length in MDS if often associated with leukemic
transformation and with the presence of complex karyotypic abnormalities.
PMID- 9395192
TI - Intra-mesenteric artery steroid administration relieved severe refractory gastro
intestinal graft-vs.-host disease in an allogeneic bone marrow transplantation
patient.
AB - We report a case of severe gastro-intestinal (G-I) graft-vs.-host disease (GVHD)
successfully treated with intra-mesenteric artery steroid administration. A 29
year-old man with severe aplastic anemia (SAA) was submitted to HLA-identical
unrelated allogeneic bone marrow transplantation (BMT) and was found to be
suffering from grade IV G-I GVHD. Although cyclosporine, steroid pulse therapy,
and FK506 proved ineffective, 30 mg of water-soluble prednisolone as administered
into each the superior and inferior mesenteric artery with remarkable effects.
This treatment was repeated two times, and the symptoms of G-I GVHD disappeared
completely.
PMID- 9395193
TI - Concomitant chronic lymphocytic leukemia and acute myeloid leukemia with an
uncommon immunophenotype.
AB - We report a case of simultaneous diagnosis of chronic lymphocytic leukemia (CLL)
and acute myeloid leukemia (AML), in which the use of flow cytometry analysis
allowed the demonstration of two different cell populations and the study of both
immunophenotyping patterns with a large panel of monoclonal antibodies (MoAbs).
CLL cells showed a typical immunophenotype with coexpression of B cell markers
with CD5, CD23, CD43, and weak surface immunoglobulin light chain restriction
expression, whereas the AML population had a very uncommon phenotype with
expression of myeloid markers and CD56 and lack of expression of other natural
killer (NK) antigens, CD34 and HLA-DR. After chemotherapeutic treatment of AML
with two induction courses, the patient achieved complete remission of the AML
with persistence of a CD19/CD5 positive population. After consolidation
chemotherapy, this latter population was no longer detectable despite the
presence of lymphoid nodules in a bone marrow biopsy. Six months after diagnosis,
the patient relapsed with AML and died shortly afterwards.
PMID- 9395194
TI - Multiple myeloma associated with diffuse osteosclerotic bone lesions: a clinical
entity distinct from osteosclerotic myeloma (POEMS syndrome).
AB - Multiple myeloma usually is characterized by the development of lytic bone
lesions. Osteosclerotic myeloma is a rare entity characterized by a single or
multiple osteosclerotic bone lesions and often accompanied by a demyelinating
polyneuropathy. Multiple myeloma associated with widespread osteosclerotic
lesions seen on radiographic studies is exceedingly rare. We describe 3 such
cases and review 12 other cases described in the literature. Overall, the
patients described herein had a clinical course that resembled multiple myeloma
more than osteosclerotic myeloma. However, some patients had features of both
diseases. Although rare, multiple myeloma should be included in the differential
diagnosis of widespread osteosclerotic bone lesions.
PMID- 9395195
TI - Acquired dysfibrinogenemia following allogeneic bone marrow transplantation.
PMID- 9395196
TI - Identification of a myeloma variant with aggressive biological and clinical
characteristics: "early" plasma cell meningitis.
PMID- 9395197
TI - Microparticles and coronary artery disease.
PMID- 9395198
TI - Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and
peroxisome proliferator Wy-14,643.
AB - Chronic administration of peroxisome proliferators to mice and rats results in
hepatomegaly and ultimately carcinogenesis. The mechanism underlying the
carcinogenic effect of nongenotoxic peroxisome proliferators is not well
understood. To determine whether nongenotoxic carcinogenesis is receptor
mediated, we evaluated the effect of the prototypical peroxisome proliferator Wy
14,643 on replicative DNA synthesis and carcinogenesis in the PPAR alpha-null
mouse line. Male mice (F4, Sv/129 ter) of both genotypes (+/+) and (-/-) were fed
either a control diet or one containing 0.1% Wy-14,643 for either 1 week, 5
weeks, or 11 months. Wild-type mice fed the Wy-14,643 diet for 1 or 5 weeks
showed increased hepatic labeling by bromodeoxyuridine (BrDU) compared to
untreated controls. In contrast, there was no increase in hepatic BrDU labeling
index in (-/-) mice fed the Wy-14,643 diet for the same time periods compared to
controls. After 11 months, 100% of the (+/+) mice fed the Wy-14,643 diet had
multiple hepatocellular neoplasms, including adenomas and carcinomas, while the (
/-) mice fed the Wy-14,643 diet were unaffected. This work demonstrates that the
effects of Wy-14,643 on replicative DNA synthesis and hepatocarcinogenesis are
mediated by PPAR alpha.
PMID- 9395199
TI - The carcinogenic potential of the gas phase of environmental tobacco smoke.
AB - Female strain A/J mice were exposed to unfiltered or HEPA-filtered environmental
tobacco smoke (ETS). Total suspended particulates (TSP) in the full smoke
exposure chamber was 78.5 mg/m3 and in the filtered smoke chamber 0.1 mg/m3;
nicotine concentrations in the full and filtered smoke chamber were 13.4 and 3.1
mg/m3, respectively. Animals exposed to filtered ETS (6 h a day, 5 days a week)
and killed after 5 months had a higher lung tumor incidence and multiplicity than
controls maintained in filtered air, although the differences were not
statistically significant. Animals exposed to filtered and full ETS and allowed
to recover in air for 4 months had an average of 1.2 +/- 0.3 tumors per lung and
1.3 +/- 0.3 tumors per lung, respectively. Air exposed control animals had an
average tumor multiplicity 0.5 +/- 0.1 tumors per lung. Increased immunostaining
for CYP 1A1 was not evident in the lung of animals exposed to filtered smoke.
Based on the chamber concentrations of selected nitrosamines and polycyclic
aromatic hydrocarbons, the possible maximum uptakes by the mice of NNK, NNN and
benzo[a]pyrene during the 5 months exposure period were three to six orders of
magnitude below doses reported in the literature to produce 1 lung tumor in
strain A/J mice. It was concluded that the gas phase of ETS is as carcinogenic as
is full ETS. The carcinogenicity of the gas phase may be due to some as yet
unidentified, yet highly potent carcinogens or by placing a substantial, possibly
free radical-mediated oxidative stress on the lung.
PMID- 9395200
TI - Emergence of undifferentiated rat tracheal cell carcinomas, but not squamous cell
carcinomas, is associated with a loss of expression of E-cadherin and of gap
junction communication.
AB - A series of cells representing normal, non-tumorigenic cell lines, as well as
differentiating neoplastic and undifferentiated neoplastic rat tracheal
epithelial cell populations were evaluated for their ability to establish
homologous and/or heterologous cell-cell gap junction communication in culture.
Gap junction communication was evaluated by flow cytometric quantitation of the
transfer of the fluorescent dye calcein from a donor to a recipient cell
population via gap junctions. The data indicate that normal primary cultures of
rat tracheal epithelial cells, as well as non-tumorigenic cell lines and squamous
cell carcinomas cell populations, retain the ability to establish both homologous
and heterologous gap junction communication. In all cases an average of >48% of
recipient cells had acquired calcein label during a 5-h interval of co-culture of
donor and recipient cells at confluent densities. Cells harvested directly from
squamous cell carcinoma tumors exhibited similar levels of cell-cell
communication. In contrast, cells giving rise to undifferentiated carcinomas, as
well as cells harvested from undifferentiated carcinomas, exhibited very low
levels or no homologous or heterologous cell-cell communication. Cell populations
exhibiting distinctly different communication phenotypes were evaluated by
Northern blot analysis for expression of connexins (Cx 26, 32 and 43) and E
cadherin. Neither communicating nor non-communicating cells expressed connexin
32. Those cell populations, which established functional gap junctions, expressed
E-cadherin as well as connexin 26 and/or 43. In contrast, those cell populations
that lacked the ability to communicate universally lacked expression of E
cadherin, and a quarter also lacked expression of detectable levels of connexin.
PMID- 9395201
TI - Mutagenicity of oxidative DNA damage in Chinese hamster V79 cells.
AB - We have investigated the mutagenicity of oxidative DNA damage induced in V79
Chinese hamster lung fibroblast, and measured 8-hydroxydeoxyguanosine (8OHdG)
levels as an indicator of this damage. A hydroxyl radical generator, N,N'-bis(2
hydroxyperoxy-2-methoxyethyl)-1,4,5,8-naphthalene-tetra -carboxylic-diimide (NP
III), induced 8OHdG in V79 upon irradiation with 366 nm ultraviolet light (UV)
for 15 min. 8OHdG was determined by HPLC with electrochemical detection after
anaerobic sample processing. The 8OHdG level in the cells treated without NP-III
was 0.49 per 10(5) dG, whereas levels in the cells treated with 5, 10 or 20
microM NP-III and UV irradiation were 1.84, 4.06 or 6.95 per 10(5) dG,
respectively. The 8OHdG induced by 20 microM NP-III with UV irradiation decreased
rapidly, and the half-life of the induced 8OHdG was approximately 6 h. NP-III
with UV irradiation also induced DNA strand breaks in all cells uniformly, as
determined by single cell gel assay. Mutant frequencies at the hypoxanthine
guanine phosphoribosyltransferase (hprt) locus in V79 were determined as the
number of 6-thioguanine-resistant cells per 10(6) cells. Mutant frequency of the
cells without NP-III was 8.0, and frequencies of the cells treated with 5, 10 or
20 microM NP-III and UV irradiation were 14.9, 20.6 or 24.7 respectively.
Treatment with 20 microM NP-III and UV irradiation decreased the cell number,
determined 3 days after the treatment, to 20.8%. These findings indicate that
acutely induced oxidative DNA damage including mutagenic 8OHdG is only weakly
mutagenic in V79.
PMID- 9395202
TI - Allelotype and replication error phenotype of small cell lung carcinoma.
AB - Allelotype and replication error (RER) phenotype analyses were performed to
clarify the pathogenetic significance of inactivation of tumor suppressor genes
and genomic instability in the genesis and progression of small cell lung
carcinoma (SCLC). We examined 37 cases of SCLC for loss of heterozygosity (LOH)
and microsatellite instability at 49 loci on all 39 nonacrocentric chromosomal
arms. LOH was frequently (>70%) detected on chromosomes 3p (29/32, 90.6%), 5q
(15/21, 71.4%), 13q (25/26, 96.2%), 17p (22/25, 88.0%), and 22q (24/33, 72.7%).
Frequent LOH (>70%) on these loci was observed even among seven cases of stage I
tumors. The incidence of LOH on all 39 nonacrocentric chromosomal arms was not
significantly different between primary tumors and metastases. These results
suggest that inactivation of multiple tumor suppressor genes accumulates
relatively early during progression of SCLC and it may be responsible for
clinically and biologically aggressive phenotype of SCLC. RER was observed in
6/37 (16.2%) of SCLC, however, RER at multiple loci was observed only in two
cases. Therefore, it was indicated that genomic instability is uncommon, but
might play a role in the genesis of a small subset of SCLC.
PMID- 9395203
TI - Stable overexpression of PML alters regulation of cell cycle progression in HeLa
cells.
AB - Our previous studies demonstrated that PML is a growth suppressor that suppresses
oncogenic transformation of NIH/3T3 cells and rat embryo fibroblasts. PML is a
nuclear matrix-associated phosphoprotein whose expression is regulated during the
cell cycle. Disruption of PML function by t(15;17) in acute promyelocytic
leukemia (APL) plays a critical role in leukemogenesis. To further study the role
of PML in the control of cell growth, we have stably overexpressed PML protein in
the HeLa cell line. This overexpression of PML significantly reduced the growth
rate of HeLa cells and suppressed anchorage-independent growth in soft agar. We
consequently investigated several parameters correlated with cell growth and cell
cycle progression. We found that, in comparison with the parental HeLa cells,
HeLa/PML stable clones showed proportionally more cells in G1 phase, fewer cells
in S phase and about the same number in G2/M phase. The HeLa/PML clones showed a
significantly longer doubling time as a result of a lengthening of the G1 phase.
No effect on apoptosis was found in HeLa cells overexpressing PML. This
observation indicates that PML suppresses cell growth by increasing cell cycle
duration as a result of G1 elongation. To further understand the mechanism of the
effect of PML on HeLa cells, expression of cell cycle-related proteins in
HeLa/PML and parental HeLa cells was analyzed. We found that Rb phosphorylation
was significantly reduced in PML stable clones. Expression of cyclin E, Cdk2 and
p27 proteins was also significantly reduced. These studies indicate that PML
affects cell cycle progression by mediating expression of several key proteins
that normally control cell cycle progression. These results further extend our
current understanding of PML function in human cells and its important role in
cell cycle regulation.
PMID- 9395204
TI - Presence and consequence of uracil in preneoplastic DNA from folate/methyl
deficient rats.
AB - Uracil can arise in DNA by misincorporation of dUTP into nascent DNA and/or by
cytosine deamination in established DNA. Based on recent findings, both pathways
appear to be promoted in the methyl-deficient model of hepatocarcinogenesis. A
chronic increase in the ratio dUTP:dTTP with folate/methyl deficiency can result
in a futile cycle of excision and reiterative uracil misincorporation leading to
premutagenic apyrimidinic (AP) sites, DNA strand breaks, DNA fragmentation and
apoptotic cell death. The progressive accumulation of unmethylated cytosines with
chronic methyl deficiency will increase the potential for cytosine deamination to
uracil and further stress uracil mismatch repair mechanisms. Uracil is removed by
a highly specific uracil-DNA glycosylase (UDG) leaving an AP site that is
subsequently repaired by sequential action of AP endonuclease, 5'
phosphodiesterase, a DNA polymerase and DNA ligase. Since the DNA polymerases
cannot distinguish between dUTP and dTTP, an increase in dUTP:dTTP ratio will
promote uracil misincorporation during both DNA replication and repair synthesis.
The misincorporation of uracil for thymine (5-methyluracil) may constitute a
genetically significant form of DNA hypomethylation distinct from cytosine
hypomethylation. In the present study a significant increase in the level of
uracil in liver DNA as early as 3 weeks after initiation of folate/methyl
deficiency was accompanied by parallel increases in DNA strand breaks, AP sites
and increased levels of AP endonuclease mRNA. In addition, uracil was also
detected within the p53 gene sequence using UDG PCR techniques. Increased levels
of uracil in DNA implies that the capacity for uracil base excision repair is
exceeded with chronic folate/methyl deficiency. It is possible that enzyme
induced extrahelical bases, AP sites and DNA strand breaks interact to negatively
affect the stability of the DNA helix and stress the structural limits of
permissible uracil base excision repair activity. Thus substitution of uracil for
thymine induces repair-related premutagenic lesions and a novel form of DNA
hypomethylation that may relate to tumor promotion in the methyl-deficient model
of hepatocarcinogenesis.
PMID- 9395205
TI - Induction of replicative DNA synthesis and PPAR alpha-dependent gene
transcription by Wy-14 643 in primary rat hepatocyte and non-parenchymal cell co
cultures.
AB - Peroxisome proliferators (PP) are known hepatocarcinogens in rats and mice. We
have investigated the ability of Wyeth-14 643 (Wy), a PP and potent rodent
carcinogen, to induce replicative DNA synthesis and to modulate the levels of
peroxisome proliferator activated receptor-alpha (PPAR alpha) transcriptionally
dependent genes in primary rat hepatocyte (HPC) cultures and
hepatocyte/nonparenchymal cell (HPC/NPC) co-cultures maintained on Matrigel. Four
days after plating, cells were treated with Wy and replicative DNA synthesis was
quantitated using [3H]thymidine incorporation and specific mRNA transcript levels
were determined by reverse-transcriptase polymerase chain reaction (RT-PCR). An
increase in HPC replicative DNA synthesis was detected at 48 h in both Wy-treated
HPC and HPC/NPC co-cultures relative to controls. This increase was approximately
3- and 6-fold in HPC and HPC/NPC cultures respectively, and was Wy concentration
dependent. The levels of PPAR alpha-transcriptionally dependent genes [cytochrome
P4504A1, acyl-CoA oxidase (AOxase), and liver-fatty acid binding protein (L
FABP)] transcripts were determined as indicators of PPAR alpha activation. These
transcripts increased dose-dependently at 48 h in HPC/NPC cultures up to 10
microM Wy. Similarly, RT-PCR product levels were also increased in HPC cultures
with 10 microM Wy at 48 h. In conclusion, we have investigated the transcription
of PPAR alpha-dependent genes and HPC replicative DNA synthesis by Wy in HPC/NPC
co-cultures. Results of this work are clearly more reflective of the known in
vivo effects of PP and suggest that HPC/NPC co-cultures are more appropriate than
HPC cultures for such studies. The effect of PP on human HPC/NPC co-cultures is
currently being investigated in our laboratory in an attempt to assess human
risks to these chemicals more directly.
PMID- 9395206
TI - Immortalized mouse mammary cells in vivo do not exhibit increased telomerase
activity.
AB - The acquisition of immortalization is an early and carefully documented event in
mouse mammary tumorigenesis. Activation of telomerase activity is one hypothesis
to explain the acquisition of immortalization. We examined the activity of
telomerase in well-defined immortalized, non-tumor cell populations of mouse
mammary tissue in vivo. The results indicated that normal virgin and mid-pregnant
mammary gland had low to moderate levels of telomerase activity, respectively. In
comparison with the levels detected in pregnant mammary gland, telomerase
activity was elevated in mammary tumors in situ and in established mammary cell
lines in vitro, both tumorigenic and nontumorigenic; however, hyperplastic
alveolar preneoplastic mammary outgrowths and non-tumorigenic ductal outgrowths,
both in vivo immortalized populations, had telomerase activity <12% of the levels
detected in normal pregnant mammary gland. These results suggest that elevated
telomerase activity is not necessary for the immortalization phenotype in in vivo
mouse mammary cell populations and that elevated telomerase activity occurs as a
late event in mammary tumorigenesis. Furthermore, the data suggest that low
levels of telomerase activity are characteristic for mouse mammary epithelial
cells and not sufficient for immortalization. These data suggest that other
factors play more important roles in the induction and/or maintenance of the
immortalization state in mammary cell populations.
PMID- 9395207
TI - Inhibition of tumor promoter activity toward mouse fibroblasts and their in vitro
transformation by tissue inhibitor of metalloproteinases-1 (TIMP-1).
AB - Tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of matrix
metalloproteinases (MMPs), is known to inhibit invasion and metastasis of tumor
cells. In the present study we examined anti-tumor promoter activity of TIMP-1
and its effect on in vitro cell transformation using BALB/3T3 cells in low serum
culture medium. In the dye transfer assay the tumor promoter 12-O
tetradecanoylphorbol-13-acetate (TPA) continuously blocked gap-junctional
intercellular communication (GJIC) of BALB/3T3 cells in confluent phase. TIMP-1
did not prevent transient inhibition of GJIC induced by TPA, but it quickly
restored the reduced GJIC level to the control level. The recovery of GJIC was
dependent on the concentration of TIMP-1 from 1 to 1000 ng/ml. In an in vitro two
stage transformation assay in which BALB/3T3 cells were treated with 0.5
microg/ml N-metyl-N'-nitro-N-nitrosoguanidine as initiator and 100 ng/ml TPA as
promoter, TIMP-1 at concentrations > 10 ng/ml inhibited the focus formation of
transformed cells by approximately 60%. TIMP-2 and a synthetic MMP inhibitor
showed a similar inhibitory activity on in vitro cell transformation.
Furthermore, zymographyic analysis showed that TPA treatment of BALB/3T3 cells
induced secretion of gelatinase B and stromelysin-1 into the culture medium.
These results indicate that TIMP-1 and TIMP-2 have inhibitory activity on in
vitro transformation of cells. It seems likely that TPA-inducible MMPs are
involved in carcinogenesis and TIMPs have a protective role against
carcinogenesis in vivo.
PMID- 9395208
TI - Assessment of the mutagenicity of dichloroacetic acid in lacI transgenic B6C3F1
mouse liver.
AB - Dichloroacetic acid (DCA) is a chlorination byproduct found in finished drinking
water. When administered in drinking water this chemical has been shown to
produce hepatocellular adenomas and carcinomas in B6C3F1 mice over the animal's
lifetime. In this study, we investigated whether mutant frequencies were
increased in mouse liver using treatment protocols that yielded significant tumor
induction. DCA was administered continuously at either 1.0 or 3.5 g/l in drinking
water to male transgenic B6C3F1 mice harboring the bacterial lacI gene. Groups of
five or six animals were killed at 4, 10 or 60 weeks and livers removed. At both
4 and 10 weeks of treatment, there was no significant difference in mutant
frequency between the treated and control animals at either dose level. At 60
weeks, mice treated with 1.0 g/l DCA showed a 1.3-fold increase in mutant
frequency over concurrent controls (P = 0.05). Mice treated with 3.5 g/l DCA for
60 weeks had a 2.3-fold increase in mutant frequency over the concurrent controls
(P = 0.002). The mutation spectrum recovered from mice treated with 3.5 g/l DCA
for 60 weeks contained G:C-->A:T transitions (32.79%) and G:C-->T:A transversions
(21.31%). In contrast, G:C-->A:T transitions comprised 53.19% of the recovered
mutants among control animals. Although only 19.15% of mutations among the
controls were at T:A sites, 32.79% of the mutations from DCA-treated animals were
at T:A sites. This is consistent with the previous observation that the
proportion of mutations at T:A sites in codon 61 of the H-ras gene was increased
in DCA-induced liver tumors in B6C3F1 mice. The present study demonstrates DCA
associated mutagenicity in the mouse liver under conditions in which DCA produces
hepatic tumors.
PMID- 9395209
TI - Dietary energy restriction does not inhibit pancreatic carcinogenesis by N
nitrosobis-2-(oxopropyl)amine in the Syrian hamster.
AB - Dietary energy restriction was previously shown to be effective in preventing a
wide range of experimentally induced cancers. Studies were conducted to assess
the influence on pancreatic carcinogenesis of dietary energy restrictions
(reduced fat and carbohydrate) of 10%, 20% or 40% in comparison with control in
Syrian hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Two
carcinogenesis studies were conducted. One used a single treatment with 20 mg
BOP/kg body weight and followed hamsters for 102 weeks following treatment, and
the other used three weekly treatments of 20 mg BOP/kg body weight and followed
hamsters for 45 weeks after treatment. Hamsters were fed control or energy
restricted diet beginning the week following the last BOP treatment. Pancreatic
carcinomas were induced in 9-18% of the hamsters in the first experiment and in
59-66% of the animals in the second. Dietary energy restriction did not influence
carcinoma incidence in either study, and in the second experiment the
multiplicity of tumors was higher in the 40% energy restriction (ER) group than
in control hamsters. Plasma corticosterone was suppressed by BOP treatment,
particularly in the 20% and 40% ER hamsters in the second experiment, and diet or
BOP treatment did not significantly alter plasma cortisol. Pancreatic protein
kinase Czeta measured by Western blot was highest in the cytosol and particulate
fractions of the 40% ER hamsters in the first experiment. These results indicate
that dietary energy restriction is not effective in the prevention of BOP induced
pancreatic carcinogenesis in the Syrian hamster.
PMID- 9395210
TI - Oltipraz stimulates the transcription of the manganese superoxide dismutase gene
in rat hepatocytes.
AB - Oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) (OPZ) is recognized as
a potent chemoprotective agent against chemical-induced carcinogenesis in several
animal models and is thought to act mainly by inducing phase II conjugating
together with inhibiting phase I detoxication enzymes. The present study was
undertaken to determine whether oltipraz can also influence expression of genes
encoding antioxidant enzymes. In rat hepatocytes in primary culture, this
compound was found to selectively induce the transcription of the manganese
superoxide dismutase (Mn-SOD) gene while it had no effect on copper/zinc-SOD and
glutathione peroxidase genes. Oltipraz increased Mn-SOD gene expression in a time
and dose-dependent manner by 2- to 3-fold and enhanced the binding activity of
the nuclear factor kappa B within 30 min. Moreover, the increase in Mn-SOD gene
transcription was associated with a 2- to 3-fold increase of free malondialdehyde
and conjugated dienes, two markers of lipid peroxidation, an index of oxidative
stress. These results suggest that in rat hepatocytes, oltipraz induced a
production of reactive oxygen species that probably acted as second messengers in
order to trigger the transcription of many genes. Such a mechanism of action of
OPZ and other dithiolethiones would account for the broad spectrum of action of
these anticarcinogenic compounds.
PMID- 9395211
TI - Prevention by retinoids of azoxymethane-induced tumors and aberrant crypt foci
and their modulation of cell proliferation in the colon of rats.
AB - Retinoids are proposed chemopreventive agents that inhibit cell proliferation and
induce differentiation. Their ability to prevent azoxymethane (AOM)-induced
aberrant crypt foci (ACF) and tumors and to modulate cell proliferation was
investigated in the colon of male F344 rats. Thirteen retinoids were evaluated
for prevention of ACF and two of them, 9-cis-retinoic acid (RA) and 4
(hydroxyphenyl)retinamide (4-HPR), were also evaluated for prevention of colon
cancer. The retinoids were administered continuously in the diet starting 1 week
prior to the first of two weekly 15 mg/kg i.p. injections of AOM and for a total
of either 5 or 36 weeks in order to evaluate their effect on colonic ACF and
tumors. At a concentration of 1 mmol/kg diet, 2-(carboxyphenyl)retinamide caused
the greatest reduction (57.7%) in the yield of ACF. 9-cis-RA was toxic at 1
mmol/kg so that it was evaluated at 0.1 mmol/kg, resulting in a 41.6% reduction
in ACF. The ability of the retinoids to reduce the proliferating cell nuclear
antigen (PCNA) labeling index in ACF and in non-involved crypts correlated with
their ability to prevent ACF. Both 9-cis-RA (0.1 and 0.2 mmol/kg diet) and 4-HPR
(1 and 2 mmol/kg diet) were highly effective in decreasing the yield of AOM
induced colon tumors. In summary, retinoids were demonstrated to reduce cell
proliferation and to prevent ACF and tumors in the colon, suggesting promise as
preventive agents for colon cancer.
PMID- 9395212
TI - A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of
breast cancer.
AB - Polymorphisms in the N-acetyltransferase 2 (NAT2) gene are determinants of the
rate of metabolic activation of carcinogenic compounds such as aryl aromatic
amines. Homozygosity for any combination of three variant alleles in Caucasians
defines 'slow' acetylators; presence of one or two wild-type alleles
characterizes 'rapid' acetylators. Although most previous studies have not
observed an overall elevation in risk of breast cancer among slow acetylators, a
recent study observed that cigarette smoking was associated with a large increase
in risk of breast cancer among slow acetylators. We assessed the relation between
NAT2 acetylation status and breast cancer risk, and its interaction with smoking,
in a prospective study of mainly Caucasian US women. Four hundred and sixty-six
incident cases who were diagnosed with breast cancer after giving a blood
specimen in 1989-90 were matched to 466 controls in a nested case-control study.
NAT2 genotype was determined using PCR-RFLP assays. The multivariate relative
risk (RR) comparing slow with rapid acetylators was 0.9 (95% CI 0.7-1.2). Among
slow acetylators, current smoking immediately prior to diagnosis was not
associated with a significant elevation in risk compared with never smoking rapid
acetylators (RR = 1.4, 95% CI 0.7-2.6). No significant association was seen
between pack-years of smoking and risk of breast cancer among either slow or fast
acetylators. A non-significant elevation in risk was observed among women who
smoked for > or = 5 years prior to first pregnancy and were rapid acetylators,
compared with never smoking rapid acetylators (RR = 1.5, 95% CI 0.9-2.6). In
analyses limited to 706 post-menopausal women, the elevated risks for current
smokers immediately prior to diagnosis who were slow acetylators compared with
never smokers who were fast acetylators were slightly stronger but still not
statistically significant. In summary, we observed little evidence of an
association between NAT2 genotype and breast cancer. In this prospective study,
cigarette smoking was not appreciably associated with breast cancer among either
slow or fast NAT2 acetylators.
PMID- 9395213
TI - Inhibition by N-(4-hydroxyphenyl)retinamide and all-trans-retinoic acid of
exogenous and endogenous development of putative preneoplastic, glutathione S
transferase placental form-positive lesions in the livers of rats.
AB - The effects of N-(4-hydroxyphenyl)retinamide (4-HPR) and all-trans-retinoic acid
(tRA) on the exogenous and endogenous models of rat liver carcinogenesis
respectively using diethylnitrosamine (DEN) and a choline-deficient, L-amino acid
defined (CDAA) diet were studied. For the exogenous study, male Fischer 344 rats,
6 weeks old, were given a single i.p. dose of 200 mg/kg body wt of DEN, partially
hepatectomized at week 3, administered 4-HPR at doses of 0, 0.04, 0.08 and 0.16%
or tRA at 0, 0.004, 0.008 and 0.015% in diet from week 2 for 6 weeks, and killed
at the end of week 8. For the endogenous study, rats were fed the CDAA diet
containing 4-HPR or tRA for 12 weeks and killed at the end of week 12. 4-HPR
decreased the numbers and sizes of the glutathione S-transferase placental form
positive foci, assayed as putative preneoplastic lesions, the levels of 8
hydroxyguanine (8-OHG), a parameter of oxidative DNA damage, and the
bromodeoxyuridine labeling indices (BrdU L.I.) by all three doses in the DEN
initiated case and, more prominently, in the CDAA diet-associated case. In
contrast, while tRA failed to exert inhibitory effects apparently on foci
development, 8-OHG formation or BrdU labeling in the DEN-initiated case, it
reduced the numbers and sizes of the foci, the 8-OHG levels and the BrdU L.I. by
all three doses in the CDAA diet-associated case. Furthermore, both 4-HPR and tRA
inhibited the CDAA diet-associated induction of hepatocyte necrosis and
connective tissue increase but not intrahepatocellular fat accumulation. These
results indicate that 4-HPR exerts chemopreventive effects against the exogenous
and endogenous rat liver carcinogenesis, while tRA can inhibit only the latter.
PMID- 9395214
TI - Chemopreventive activity of thiol conjugates of isothiocyanates for lung
tumorigenesis.
AB - A series of L-cysteine (L-Cys), glutathione (GSH), and N-acetyl-L-cysteine (NAC)
conjugates of phenethyl (PEITC), benzyl (BITC), and 6-phenylhexyl isothiocyanate
(PHITC) were studied for their inhibitory activity toward metabolic activation of
the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) in mouse lung microsomes. Selected compounds, PEITC, PEITC-GSH, PEITC-NAC
and PHITC-NAC, were also assayed for the potential chemopreventive activity
toward NNK-induced lung tumorigenesis in A/J mice. Results showed that PEITC and
its conjugates inhibited NNK metabolism with decreasing potency: PEITC < PEITC
GSH > PEITC-Cys > PEITC-NAC. PHITC and its GSH and NAC conjugates exhibited
nearly 10 times higher inhibitory activity toward NNK metabolism than the PEITC
counterparts. In the tumor bioassay, as expected, the conjugates exhibited
inhibitory activity against lung tumorigenesis induced by NNK. PEITC-GSH was not
inhibitory at 4 micromol/mouse, but it inhibited approximately 32% of lung tumor
multiplicity at 8 micromol/mouse. PEITC-NAC at 5 and 20 micromol/mouse both
inhibited approximately 30% tumor multiplicity. Among all the conjugates
examined, PHITC-NAC was the most potent. At a 5-micromol dose, it completely
inhibited tumor multiplicity and incidence to the background level observed in
the control group. These results revealed that the structure-activity
relationships of the conjugates are similar to those found with their parent
isothiocyanates (ITCs), i.e., the potency increased with the increasing alkyl
chain length from two to six carbons in arylalkyl ITCs, suggesting that a common
active species is involved. The inhibitory activity of ITC conjugates and the
expected low toxicity make thiol conjugates of ITC a promising new series of
chemopreventive agents.
PMID- 9395215
TI - Inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline-DNA adducts by indole-3
carbinol: dose-response studies in the rat colon.
AB - Indole-3-carbinol (I3C) inhibits the formation of colonic aberrant crypt foci and
DNA adducts in rats given heterocyclic amine colon carcinogens, such as 2-amino-3
methylimidazo[4,5-f]quinoline (IQ). Mechanism studies indicate that I3C induces
cytochromes P4501A1 and 1A2 (CYP1A1 and CYP1A2), isozymes that respectively
metabolize IQ via ring hydroxylation or activate the carcinogen by N
hydroxylation. The present study examined the dose-response for induction of
CYP1A1 versus CYP1A2 by I3C, and compared the profiles of induction with the dose
response for inhibition of IQ-DNA adducts in the colon of the F344 rat. Dietary
equivalent doses of I3C in the range 100-1000 p.p.m. increased in a dose-related
manner both ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O
demethylase (MROD) activities in the liver and colonic mucosa, and Western blots
showed a corresponding induction of CYP1A1 and CYP1A2 proteins. However, dietary
equivalent doses of I3C in the range 10-25 p.p.m. (i) reduced hepatic EROD and
MROD activities and CYP1A protein levels compared with controls, (ii) increased
the ratio of CYP1A2 versus CYP1A1, and (iii) activated IQ to a more potent
mutagen when liver microsomes from rats given I3C were used for metabolic
activation in the Salmonella assay. Rats given a single oral dose of I3C shortly
before administering IQ (5 mg/kg body wt, p.o.) exhibited dose-related inhibition
of colonic IQ-DNA adducts in the range 25-100 p.p.m. I3C, reaching 95% inhibition
at doses > or = 100 p.p.m. I3C, but IQ-DNA adducts were elevated slightly at the
lowest I3C dose as compared with the controls. The possible significance of the
low versus high dose effects of I3C are discussed in the context of human dietary
exposures to I3C and the reported chemopreventive mechanisms of I3C in vivo.
PMID- 9395216
TI - Citrus auraptene inhibits chemically induced colonic aberrant crypt foci in male
F344 rats.
AB - The modifying effect of dietary administration of auraptene isolated from the
peel of citrus fruit (Citrus natsudaidai Hayata) on the development of
azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in
rats. Male F344 rats were given s.c. injections of AOM (15 mg/kg body wt) once a
week for 3 weeks to induce ACF. They also received diets containing 100 or 500
p.p.m. auraptene for 5 weeks, starting 1 week before the first dose of AOM. At
termination of the study (week 5) dietary administration of auraptene caused a
significant reduction in the frequency of ACF in a dose-dependent manner (P <
0.05). Feeding of auraptene suppressed expression of cell proliferation
biomarkers (5-bromo-2'-deoxyuridine labeling-index, ornithine decarboxylase
activity, polyamine content and number of silver stained nucleolar organizer
region protein particles) in the colonic mucosa and the occurrence of micronuclei
caused by AOM. Also, auraptene increased the activities of phase II enzymes
(glutathione S-transferase and quinone reductase) in the liver and colon. These
findings might suggest that inhibition of AOM-induced ACF may be associated, in
part, with increased activity of phase II enzymes in the liver and colon and
suppression of cell proliferation in the colonic mucosa.
PMID- 9395217
TI - Inhibitory effect of black tea on the growth of established skin tumors in mice:
effects on tumor size, apoptosis, mitosis and bromodeoxyuridine incorporation
into DNA.
AB - Female CD-1 mice were initiated with a single topical application of 7,12
dimethylbenz[a]anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate.
Mice with established papillomas were then treated with black tea or
decaffeinated black tea (approximately 4 mg tea solids/ml) as the sole source of
drinking fluid for 11-15 weeks. In four separate experiments, oral administration
of black tea inhibited the growth of papillomas (increase in tumor volume/mouse)
by an average of 35%, 37%, 41% and 48%, respectively. Studies with decaffeinated
black tea gave inconsistent results. In one experiment, administration of
decaffeinated black tea inhibited papilloma growth (increase in tumor
volume/mouse) by 27%, but in two additional experiments papilloma growth was
stimulated by 14% and 193%, respectively. In a separate experiment, skin tumors
were generated by treating SKH-1 female mice with ultraviolet B light (UVB; 30
mJ/cm2) twice weekly for 22 weeks, after which UVB administration was stopped.
Tumors were allowed to develop during the following 13 weeks, and tumor-bearing
mice were then treated with black tea (6 mg/ml tea solids) as the drinking fluid
for 11 weeks. In this experiment, tumor growth (increase in tumor volume/mouse)
was inhibited by 70%. Histological examination revealed that tea-treated mice had
a 58% decrease in the number of nonmalignant tumors (primarily
keratoacanthomas)/mouse and a 54% decrease in the number of squamous cell
carcinomas/mouse. In addition, administration of black tea decreased the volume
per tumor by 60% for nonmalignant tumors and by 84% for carcinomas. Mechanistic
studies with tumors from these mice revealed that administration of black tea
decreased the bromodeoxyuridine labeling index in squamous cell papillomas,
keratoacanthomas and squamous cell carcinomas by 56%, 45% and 35%, respectively,
and the apoptosis index was increased by 44%, 100% and 95%, respectively.
Administration of black tea decreased the mitotic index in keratoacanthomas and
squamous cell carcinomas by 42% and 16%, respectively. The results indicate that
oral administration of black tea to tumor-bearing mice inhibited proliferation
and enhanced apoptosis in nonmalignant and malignant skin tumors.
PMID- 9395218
TI - Metabolic competence and susceptibility of intestinal epithelium to genotoxic
injury during regeneration.
AB - The carcinogenic potency of many mutagens is increased in conditions of tissue
regeneration. This involves fundamental changes of cellular division and
differentiation, in intestinal epithelium. However, effects on epithelial
capacity for carcinogen metabolism and susceptibility to genotoxic injury are
unknown. Using a novel rat model, this study assessed expression of cytochrome
P450 mono-oxygenases (Cyps), glutathione S-transferases (GSTs) and uridine
diphosphoglucuronosyl transferase (UGT) in intestinal epithelium during
sequential stages of regeneration. Enzyme induction and DNA adduct formation were
also assessed after benzo[a]pyrene (BaP) exposure. Control assays were carried
out in normal intestinal epithelium. Fewer phase I and II xenobiotic metabolizing
enzymes were expressed in regenerating intestinal epithelium than in normal
control intestinal epithelium (GSTA3, UGT in regeneration vs Cyp2B, GSTA1/2,
GSTA4, GSTP1, UGT in control). Benzo[a]pyrene induced GSTA3 and UGT in
regeneration vs Cyp1A, Cyp2B, GSTA1/2, GSTA3, GSTA4, GSTP1 and UGT in control
normal intestinal epithelium. Benzo[a]pyrene induced low levels of GSTA3 in early
regenerating intestinal epithelium but induction increased by >2-fold at late
stage regeneration. Higher levels of benzo[a]pyrene 7,8-diol-9,10-epoxide (BPDE)
DNA adducts were formed at early stages of regeneration, than at later stages.
Intestinal epithelium displayed reduced metabolic competence and differential
susceptibility to genotoxic injury from BaP, during regeneration.
PMID- 9395220
TI - DNA damage and mutagenesis induced by procarbazine in lambda lacZ transgenic
mice: evidence that bone marrow mutations do not arise primarily through
miscoding by O6-methylguanine.
AB - The DNA damaging and mutagenic activities of procarbazine, a methylating drug
employed in cancer chemotherapy and suspected of causing therapy-related
leukaemia, were investigated in the liver and bone marrow of lambda lacZ
transgenic mice (MutaMouse). The drug was administered using two different
protocols, a 'high-dose' one involving 5 daily doses of 200 mg/kg, expected to
cause depletion of the repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT)
and thus favour the selective accumulation of the premutagenic lesion O6
methylguanine (O6-meG) relative to other adducts, and a 'low-dose' one involving
10 daily doses of 20 mg/kg procarbazine. Substantial accumulation of O6-meG was
observed in both tissues examined 6 h after the end of the 'high-dose' treatment,
with the liver accumulating somewhat higher levels than the bone marrow (28.0 +/-
1.8 fmol/microg DNA and 18.5 +/- 1.1 fmol/microg DNA respectively). However,
significant increases in mutant frequency 10 days after the end of treatment were
observed only in the bone marrow, reaching a 16-fold increase over background
following the 5 x 200 mg/kg treatment. Sequence analysis of the mutations induced
after this treatment revealed a mixed spectrum, in which G:C-->A:T transitions
(characteristic of O6-meG miscoding) were only a secondary feature: Among 20
mutants analysed, only six such mutations were found, including three at CpG
sites, which might have arisen from deamination of 5-methylcytosine. The other
mutations observed included 1 A:T-->G:C transition, five transversions (one G:C-
>T:A, one double G:C-->C:G, two A:T-->T:A, one A:T-->C:G), five deletions and
three insertions. The mechanistic and clinical significance of these findings is
discussed.
PMID- 9395219
TI - Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S
transferases during the progressive hepatitis associated with Helicobacter
hepaticus.
AB - Mice naturally infected by Helicobacter hepaticus develop a chronic active
hepatitis leading to hepatocellular carcinoma. This mouse model of liver cancer
was used to examine the impact of bacterial infection on the hepatic expression
and activity of enzymes involved in carcinogen bioactivation (phase I enzymes)
and detoxification (phase II enzymes). No major differences in total cytochrome
P450 (CYP) content were found between control and infected mice during the course
of the study. The most striking modulations of individual isoenzymes were the
increases in immunohistochemical staining observed for CYP1A and CYP2A5 in
relation to increasing age and liver lesions. The increase in CYP2A5 in mice aged
over 12 months was confirmed by the observed increases in coumarin 7
hydroxylation (CYP2A5 substrate) in vitro and CYP2A5 mRNA levels by Northern blot
analysis. Immunoblotting confirmed the specific induction of CYP1A2 in infected
mice 12 and 18 months of age. Perfusion of liver with nitroblue tetrazolium, an
indicator for superoxide formation, demonstrated that in livers of infected mice,
hepatocytes often co-expressed CYP2A5 and formazan deposition. Concerning phase
II enzymes, an enhancement of glutathione S-transferase (GST) activities, related
to the disease process, was observed in infected mice. An age-specific increase
of GSTpi and A4.4 (early stage of disease) and GST YaYa (>9 months) expression
was also demonstrated by immunohistochemical staining. In contrast, catalase and
glutathione-peroxidase activities, as well as reduced glutathione content were
decreased in the early stages of disease (3-9 months) in infected mice compared
to age-matched control mice. Overall, these results suggest that alterations in
CYP and GST expression may contribute to the aetiology of tumour incidence due to
H. hepaticus infection via production of reactive oxygen species.
PMID- 9395221
TI - Intestinal and extra-intestinal tumor multiplicities in the Apc1638N mouse model
after exposure to X-rays.
AB - Seven-week-old Apc1638N mice were exposed to a single dose of 5 Gy total-body X
irradiation resulting in a 8-fold increase in the number of intestinal tumors and
a reduction of the lifespan to an average of 6 months. The distribution of tumors
along the intestinal tract as well as the adenoma/carcinoma ratio, were similar
between non-irradiated and irradiated animals. Semi-quantitative PCR analysis of
intestinal-tumor DNA revealed that 10 out of 14 tumors had lost the wild-type Apc
allele. However, in contrast to spontaneous Apc1638N intestinal tumors in which
the LOH event at the Apc locus involves the entire chromosome 18 (1), in 6 out of
10 tumors derived from X-irradiated animals the Apc loss is associated with only
a partial intrachromosomal deletion. The remaining tumors have lost all
chromosome 18 markers tested. In addition to the intestinal tumors, female
Apc1638N mice are susceptible to the development of mammary tumors. Upon X
irradiation, Apc1638N mice show a striking 15-fold increase in mammary tumors.
Moreover, Apc1638N mice spontaneously develop other extra-intestinal neoplasia,
such as desmoid-like lesions similar to those associated with familial
adenomatous polyposis (FAP), the human syndrome caused by germline mutations in
the APC gene. Spontaneous desmoid growth is sex-dependent, as male Apc1638N mice
develop 3-fold more desmoids than female mice. Interestingly, X-irradiation
seemed to increase the number of desmoids per animal nearly twofold only in
female Apc1638N mice. Five out of 9 desmoids found in Apc1638N mice exposed to X
ray displayed loss of the wild-type Apc allele.
PMID- 9395222
TI - DNA adducts in human nasal mucosa and white blood cells from smokers and non
smokers.
AB - The goal of the present study was to measure the levels of DNA adducts in human
nasal mucosa cells and in total white blood cells in relation to smoking. DNA was
isolated from samples of 20 healthy volunteers (six smokers and 14 non-smokers).
The levels of DNA adducts were measured by 32P-postlabelling assay. In smokers
the mean DNA adduct levels were 3.3 and 17.0 adducts/10(8) nucleotides in total
white blood cells and nasal mucosa cells respectively. The corresponding values
in non-smokers were 2.0 and 6.8 adducts/10(8) nucleotides. The mean adduct level
was significantly higher in nasal mucosa cells than in total white blood cells
both in smokers and non-smokers. The mean adduct levels in smokers' nasal mucosa
cells were significantly higher than those in non-smokers. Thus the nasal mucosa
cells constituted a sensitive tissue for the determination of cigarette smoking
induced DNA adducts. Combining the sensitivity of the 32P-postlabelling assay
with the specificity of the nasal mucosa to the airborne chemical exposures, the
DNA adduct analysis from human nasal mucosa cells represents a method of choice
in the assessment of exposure to airborne carcinogens.
PMID- 9395223
TI - Investigation of the formation and accumulation of liver DNA adducts in mice
chronically exposed to tamoxifen.
AB - Tamoxifen was administered to three strains of female mice (B6C3F1, C57BL/6 and
DBA/2) in short- and long-term studies to determine their ability to activate
tamoxifen and cause hepatic DNA damage. 32P-Postlabelling of liver DNA from mice
treated for 4 days showed a group of major adducts that increased in a dose
dependent manner and co-chromatographed with the major adducts detected in rat
liver. On cessation of dosing, the majority of adducts were cleared within 3
days. Binding of [14C]tamoxifen to DNA nucleotides was demonstrated by the use of
accelerator mass spectrometry. In long-term studies of 12 months to 2 years
duration, dependent on strain, tamoxifen was administered continuously in the
diet to give a daily dose of approximately 40 mg/kg. DNA adducts were detected
after 3 months, although the number of adducts decreased with time and by 2 years
were not detectable in the tamoxifen treated mice. None of the treated groups
showed a significantly increased incidence of liver tumours, with or without
phenobarbital promotion and there was no sustained liver cell proliferation.
Tamoxifen was detected in the mouse livers, but at levels 50 times lower than
those reported in a comparable rat study. These results suggest that, in contrast
to the rat, tamoxifen is non-carcinogenic in mice because it does not cause
sufficient cumulative DNA damage, or act as a promoter by causing cell
proliferation.
PMID- 9395224
TI - Dysregulation of ornithine decarboxylase activity, apoptosis and Bcl-2
oncoprotein in Syrian hamster embryo cells stage-exposed to di(2
ethylhexyl)phthalate and tetradecanoylphorbol acetate.
AB - Perturbations of cell proliferation and death are considered as essential events
in the process of carcinogenesis. Thus, two parameters, ornithine decarboxylase
(ODC), an enzyme closely related to cell proliferation and transformation, and
apoptotic phenomenon are profoundly modified. Using Syrian hamster embryo (SHE)
cells, we have examined in the framework of two-stage carcinogenesis (initiation
promotion) the effects of a non-genotoxic [diethylhexylphthalate (DEHP)] or
genotoxic [benzo[a]pyrene (BaP)] carcinogen or a non-carcinogenic compound
[phthalic anhydride (AP)] on these parameters. Immunoreactive Bcl-2 and Bcl-xL
proteins were also investigated following two-stage exposures. Whereas exposures
to BaP, DEHP or AP alone did not provoke any modification of ODC activity, the
phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), strongly increased it.
Using two-stage exposure protocol (xenobiotics first, then replacement by TPA
promoter), the ODC activity was higher than that obtained with TPA alone. This
superinduction of ODC activity was observed only with the carcinogenic compounds
DEHP and BaP. Following the same exposure protocol, spontaneous cellular
apoptosis was decreased. Furthermore, Bcl-2 oncoprotein was also upregulated
approximately 8- and 11-fold for BaP and DEHP respectively; meanwhile Bcl-xL
protein rate did not change. The non-carcinogenic compound AP slightly inhibited
spontaneous SHE cell death without ODC superinduction. Exogenous polyamines,
putrescine, spermidine and spermine diluted in the medium did not inhibit
spontaneous apoptosis. Although inhibition of apoptosis was not specific of
carcinogenic compound, both superinduction of ODC activity and inhibition of
apoptosis via Bcl-2 upregulation, may cooperate during early stages of the
carcinogenic process.
PMID- 9395225
TI - Determination of steady-state levels of oxidative DNA base modifications in
mammalian cells by means of repair endonucleases.
AB - The alkaline elution technique in combination with various repair endonucleases
(Fpg protein, endonuclease III, exonuclease III, T4 endonuclease V) was used to
quantify steady-state (background) levels of oxidative base modifications in
various types of mammalian cells. In human lymphocytes the number of base
modifications sensitive to Fpg protein, which include 8-hydroxyguanine, was 0.25
+/- 0.05 per 10(6) base pairs. Even lower levels (0.07 +/- 0.02 per 10(6) bp)
were observed in HeLa cells. The numbers of sites sensitive to the other repair
endonucleases were below the detection limit (0.05 per 10(6) bp). In a direct
comparison, the background level of Fpg-sensitive modifications determined by
alkaline elution was much lower than the background level of 8
hydroxydesoxyguanosine (8-oxodG) determined after enzymatic DNA hydrolysis by
HPLC and electrochemical detection. However, the number of additional Fpg
sensitive modifications induced by a photosensitizer plus light was similar to
the additional number of 8-oxodG residues determined by HPLC with electrochemical
detection. This indicates that the enzyme assay does not systematically
underestimate the number of lesions and points to an artefactual generation of 8
oxodG during DNA isolation and hydrolysis.
PMID- 9395226
TI - The mutagenic response at the ouabain resistance locus in T cells of mice exposed
to N-ethyl-N-nitrosourea parallels the response at the Hprt locus and correlates
with mutation target size.
AB - The lymphocyte Hprt gene has been used extensively as a reporter locus to monitor
the mutational effects of the exposure of animals to genotoxicants. Implicit in
this view of the function of a reporter gene is the assumption that its mutagenic
response is representative of that of other genes in the organism. As a test of
this hypothesis we compared the frequency of 6-thioguanine-resistant (TGr)
mutants at the Hprt locus with the mutant frequency (MF) induced at another
locus, the ouabain resistance (Oua) locus. The frequency of spontaneous OUA(R)
mutants was estimated to be 1.1x10(-7) (MF between <0.3 and 1.1x10(-7)), which
was approximately 30-fold less than the spontaneous TGr MF. Following treatment
with N-ethyl-N-nitrosourea (ENU), the induced OUA(R) MF at each of two dose
levels (50 and 150 mg/kg ENU) and two time points (3 and 6 weeks post-exposure)
was consistently 8- to 9-fold lower than the corresponding TGr MF. Thus the
mutagenic response of the Oua locus closely paralleled that of the Hprt locus,
indicating a similarity in their response to ENU. In addition, the Oua locus was
3-4 times more sensitive than the Hprt locus to the mutagenic effect of ENU, as
measured by the fold increase in MF over the background level. The number of ENU
mutable sites capable of resulting in a TGr or OUA(R) phenotype, otherwise known
as the mutation target size, was estimated to differ by an order of magnitude
between the two loci. This difference in target size correlates with, and
therefore may largely account for, the difference in induced MF between both
loci.
PMID- 9395227
TI - Analysis of tissue-specific lacZ mutations induced by N-nitrosodibenzylamine in
transgenic mice.
AB - N-Nitrosodibenzylamine (NDBzA) is a contaminant found frequently in rubber baby
bottle nipples and pacifiers. To evaluate more fully the mutagenic potential and
analyse the molecular nature of possible mutations induced in vivo, we have
studied the mutagenicity of NDBzA in vivo using the MutaMouse system. NDBzA,
suspended in olive oil, was administered orally once to male mice at different
doses (0, 30, 100, 425 and 750 mg/kg) and the mice were killed 30 and 90 days
after treatment. As a positive control, and to compare relative mutagenicity, N
nitrosodimethylamine (NDMA) was also administered to animals in the same
experiment at doses of 0, 2, 6 and 10 mg/kg. Mutant frequencies were increased in
both 30 and 90 day liver samples, but not in bone marrow, after both NDBzA and
NDMA treatment. However, NDBzA was >100 times less mutagenic than NDMA. A total
of 81 mutants obtained from liver samples of treated animals (750 mg/kg) were
characterized by DNA sequencing. While spontaneous mutations in transgenic mice
have been characterized previously by a preponderance of G:C-->A:T transitions,
mainly at 5'-CpG-3' dinucleotide sites, the predominant type of NDBzA-induced
mutation in this study was transversion, mainly G:C-->T:A changes. The molecular
characteristics of mutations induced by NDBzA indicate that they may arise from
specific unidentified DNA adducts and benzylation appears to be the primary
mechanism involved in formation of these DNA adducts.
PMID- 9395228
TI - Initiating activity of the anti-estrogen tamoxifen, but not toremifene in rat
liver.
AB - A striking difference between two structurally related anti-estrogen medicines is
that tamoxifen is strongly hepatocarcinogenic in the rat, whereas toremifene
lacks such activity. To study the basis for this difference, the initiating
potential of tamoxifen and toremifene were studied by measurement of rapid
induction of hepatocellular altered foci (HAF) that express placental-type
glutathione S-transferase in the livers of female Sprague-Dawley (S-D) rats and
female Fischer 344 (F344) rats. Both agents were administered by gavage at
equimolar doses up to a dose that produced marked weight gain suppression. In
rats given the high dose of 40 mg/kg per day tamoxifen continuously for 36 weeks,
75% of S-D rats developed liver neoplasms, in contrast to only 10% of F344 rats.
In the S-D strain, tamoxifen produced a tendency to increased HAF at 2 weeks at
the dose of 40 mg/kg per day and by 12 weeks, a dose-related increase was
evident. In contrast, toremifene induced no HAF even at the equimolar high dose
of 42.4 mg/kg per day for 12 weeks. The induction of HAF by tamoxifen was less in
the F344 rats. Neither agent elicited increases in hepatocellular proliferation
in S-D or F344 rats. When phenobarbital was administered for 24 weeks as a
promoting agent after the anti-estrogens, S-D rats given tamoxifen at 20 mg/kg
per day for 12 weeks, developed liver neoplasms, but not F344 rats or rats of
either strain given even a higher dose (42.4 mg/kg) of toremifene. Thus,
tamoxifen has initiating activity in these rat strains whereas toremifene does
not.
PMID- 9395229
TI - Functional characterization of the rat mdr1b encoded P-glycoprotein: not all
inducing agents are substrates.
AB - The multidrug resistance (mdr) genes encode P-glycoproteins, integral membrane
proteins which function as drug efflux transporters. Exposure of animals in vivo
and cells in vitro to a variety of xenobiotics leads to increased mdr1 gene
expression and higher levels of P-glycoprotein. This response may protect cells
from the cytotoxic effects of these compounds. In this investigation we
functionally expressed the rat mdr1b gene in NIH 3T3 cells and assessed the
ability of the encoded P-glycoprotein to protect these cells from the
cytotoxicity of xenobiotics known to induce mdr1b expression. In long-term colony
survival assays, stably expressed mdr1b conferred resistance to cytotoxic drugs
such as colchicine, vinblastine and doxorubicin, but not to 5-fluorouracil nor to
the carcinogens aflatoxin B1 and N-hydroxy-acetylaminofluorene. The mdr reversal
agent verapamil restored cytotoxicity of colchicine, doxorubicin, actinomycin D,
vinblastine and taxol, but had no effect on the sensitivity of these cells to 5
fluorouracil, aflatoxin B1 or N-hydroxy-acetylaminofluorene. In a competitive
transport assay, verapamil and, to a lesser extent, colchicine blocked the
increased efflux of the fluorescent dye rhodamine 123 from mdr1b-transfected
cells, whereas aflatoxin B1 did not compete for this export. These data
demonstrate that expression of the rat mdr1b encoded P-glycoprotein can protect
cells from a diverse group of compounds previously identified to be mdr
substrates, however, other effective inducers of mdr expression, such as
aflatoxin B1 and N-hydroxy-acetylaminofluorene, remain potent cytotoxins despite
high levels of P-glycoprotein. The fact that compounds which are not themselves
substrates can induce P-glycoprotein expression may have implications for
pharmacokinetic interactions and chemotherapy.
PMID- 9395230
TI - Development of esophageal metaplasia and adenocarcinoma in a rat surgical model
without the use of a carcinogen.
AB - In order to establish an animal model for studying the cause and prevention of
esophageal adenocarcinoma (EAC) and its frequent precursor, Barrett's esophagus
(BE), factors affecting the pathogenic processes were investigated in an
esophagoduodenal anastomosis model with rats. Experiments by us and others have
shown that surgical treatment produced reflux esophagitis with cell
hyperproliferation, but not EAC. Additional treatment with a carcinogen has been
shown to be necessary for the development of EAC, squamous cell carcinomas (SCC)
or EAC/SCC mixtures. We found that the surgically treated animals developed
anemia due possibly to reduced iron absorption. When the operated animals were
supplemented with iron, EAC occurred at a high rate (73%) after 30 weeks, and
treatment with N'-nitrosonornicotine did not enhance the rate of tumorigenesis.
Treatment with carcinogen, however, induced SCC in the group of rats killed after
22 weeks. The results suggest that iron overload, which is known to cause
oxidative damage, is an enhancing factor for adenocarcinogenesis. The
pathogenesis of EAC in the iron-supplemented, non-carcinogen treated group
resembles human esophageal adenocarcinogenesis in many features. All the BE was
the specialized type with goblet cells (containing sialomucin or sulfomucin) and
columnar cells (containing acid or neutral mucin) as well as an incompletely
developed brush border. Almost all of the BE was located at the bottom of the
esophagus and was continuous with the duodenal mucosa; dysplasia became more
frequent at later time points. All of the cancers were well-differentiated
mucinous EAC, and most of the EAC had an adjacent area of BE with dysplasia. The
results are consistent with the proposed human sequence for pathogenic events of
BE progression to 'BE with dysplasia' and then to EAC. Esophagoduodenal
anastomosis and iron treatment in rats produces a high rate of BE and EAC which
are morphologically similar to human BE and EAC; this may be a useful animal
model to study the development and prevention of EAC in humans.
PMID- 9395231
TI - Cyclic food restriction, insulin and mammary cell proliferation in the rat.
AB - We reported recently that weight cycling significantly increased the incidence of
mammary cancer in virgin female rats that were pretreated with N-methyl-N
nitrosourea. The present study investigated the effect of weight cycling on
mammary epithelial cell proliferation and its relationship to changes in plasma
insulin, estrogen, progesterone and urinary corticosterone in 30 female virgin
Sprague-Dawley rats. Animals were fed a modified AIN-76A diet containing 24.6%
corn oil by weight. Weight-cycled (WC) rats were food restricted daily by either
33% or 50% of non-restricted controls for 1 week followed by 3 weeks compensatory
refeeding and weight recovery over 18 weeks or 4.5 weight cycles. WC rats
consumed 6-10% less food than controls (P = 0.01) but showed a 71-89% greater
efficiency of food utilization for growth (P < 0.0001) than controls. There were
no differences in total weight gain during treatment. Mammary lobuloalveolar and
ductal cell proliferation of WC rats, measured by 5-bromo-2'deoxyuridine
labelling, increased in a dose-response fashion, P = 0.03, P = 0.06 respectively
in comparison to controls. Energy and substrate utilization measured by indirect
calorimetry indicated WC animals expended less energy (P = 0.005) and utilized
less glucose (P = 0.0001) and protein (P = 0.006) during restriction, and less
lipid during recovery (P = 0.05) than controls. There were no significant
differences in hormone levels between groups. Multiple regression analysis with
plasma insulin, estrogen, progesterone and urinary corticosterone as independent
variables (r = 0.947, r2 = 0.897, P = 0.003) showed that plasma insulin was the
only significant predictor (P < 0.01) of mammary cell proliferation. In accord
with this observation, tyrosine-phosphorylated activation of insulin receptor
substrate-1, detected by immunoprecipitation and Western immunoblot analysis in
mammary tumors of WC rats from our previous study, was 3-5 times greater than in
non-restricted controls (P < 0.01). Present findings suggest that weight cycling
in rats increases risk of breast cancer development via insulin stimulated
mammary cell proliferation.
PMID- 9395232
TI - Tumour necrosis factor alpha (TNF alpha) suppresses apoptosis and induces DNA
synthesis in rodent hepatocytes: a mediator of the hepatocarcinogenicity of
peroxisome proliferators?
AB - Peroxisome proliferators (PPs) are a class of non-genotoxic rodent
hepatocarcinogens that cause increased hepatocyte DNA synthesis, peroxisome
proliferation and liver enlargement. We have demonstrated previously that PPs
suppress both spontaneous rat hepatocyte apoptosis and that induced by the
physiological negative regulator of liver growth, transforming growth factor beta
(TGF beta1). Evidence suggests that the suppression of apoptosis by PPs is
mediated via activation of the peroxisome proliferator activated receptor-alpha
(PPAR alpha), a member of the nuclear hormone receptor superfamily. Here, we
investigate the effects of tumour necrosis factor alpha (TNF alpha) on cultured
rat or mouse hepatocytes to determine whether TNF alpha influences hepatocyte
growth in a manner analogous to that seen with PPs. Rat recombinant TNF alpha was
found to stimulate DNA synthesis and suppress apoptosis in isolated rat
hepatocyte monolayers (P < or = 0.01). These effects were seen in the range of
500-5000 U/ml with a maximum effect at 5000 U/ml. Similarly, mouse recombinant
TNF alpha was able to stimulate DNA synthesis in mouse hepatocyte monolayers (P <
or = 0.01) with a maximal effect at 1000 U/ml. Suppression of mouse hepatocyte
apoptosis by TNF alpha was not detected, possibly because of the low levels of
apoptosis under control conditions. However, when the levels of mouse hepatocyte
apoptosis were augmented using TGF beta1, TNF alpha caused a significant
suppression (P < or = 0.01). The neutralization of TNF alpha using anti-TNF alpha
antibodies abrogated significantly (P < or = 0.01) the suppression of apoptosis
by the PP, nafenopin. These data that suggest TNF alpha may mediate, at least in
part, the growth perturbation, liver enlargement and hepatocarcinogenesis seen in
response to the PP class of non-genotoxic hepatocarcinogens.
PMID- 9395233
TI - Artificial background and induced levels of oxidative base damage in DNA from
human cells.
AB - The pre-mutagenic oxidative DNA base damage of 8-hydroxy-guanine is present in
DNA isolated from cells and the amount present increases with exposure of cells
to oxidative stress. The oxidative DNA base damage may be present before
isolation of DNA or it may be produced during isolation and processing of DNA. We
have found that the amount of oxidative base damage measured in DNA can be
reduced to a stable lower level by adding increasing concentrations of the
antioxidants desferrioxamine, histidine and reduced glutathione immediately
before cell lysis. Inclusion of these antioxidants after cell lysis did not
affect the level of DNA damage. Oxidative DNA base damage produced by ultraviolet
A irradiation of human cells was also reduced by adding antioxidants after
irradiation and before cell lysis. Thus, unidentified oxidants induced by
ultraviolet A irradiation may damage DNA significantly during extractions of DNA
from cells subsequent to ultraviolet A irradiation.
PMID- 9395234
TI - Mutation and downregulation of the transforming growth factor beta type II
receptor gene in primary squamous cell carcinomas of the head and neck.
AB - In the present study, we analyzed 28 squamous cell carcinomas of the head and
neck (SCCHN) for mutations in the coding region of TbetaR-II using 'Cold' SSCP
and automatic DNA sequencing analyses. Twenty-one percent (6/28) of the SCCHN
examined contained TbetaR-II mutations compared with patient-matched normal
tissues. These alterations included five missense mutations (A:T-->G:C
transitions in codons 250, 401, 448 and 488, and a G:C-->T:A transversion in
codon 373), and a 38-bp deletion between nucleotides 1825 to 1862. In addition to
these code-altering mutations, one case exhibited a silent mutation (A:T-->G:C
transition in codon 451) and three cases contained one of two potential
population polymorphisms (codons 354 and 389). In contrast to colon and gastric
cancers exhibiting microsatellite instability (MI) or replication errors (RER+),
no 'indirect' frameshift mutations were identified within a 10-bp polyadenine
repeat present in the TbetaR-II coding sequence. All of the mutations in the
present study occurred within the highly conserved serine/threonine kinase domain
and represent the first report of such 'direct' TbetaR-II mutations in primary
human tumors. In addition, we analyzed a subset of SCCHN and corresponding normal
samples for TbetaR-II mRNA expression using semi-quantitative multiplex RT-PCR.
Expression of TbetaR-II was decreased by 24% to 74% in 20 of 23 SCCHN (87%)
compared with patient-matched normal tissues. Taken together, the results from
this study suggest that alterations in the nucleic acid sequence and mRNA
expression of TbetaR-II are prevalent events in the development of SCCHN, which
may deregulate cell cycle control.
PMID- 9395235
TI - Signaling through the ARK tyrosine kinase receptor protects from apoptosis in the
absence of growth stimulation.
AB - ARK (AXL) is the prototype of a distinctive family of receptor tyrosine kinases
which contain in their extracellular domains features reminiscent of cell
adhesion molecules. ARK is capable of homophilic binding, which results in a
degree of receptor activation, but can also be activated by a heterophilic
ligand, Gas6, a member of the family of vitamin K dependent proteins that is
preferentially expressed in quiescent cells. Since a number of tissues and cell
lines express both ARK and Gas6, we studied the effect of endogenous and
exogenous Gas6 on the phenotype of ARK expressing cells. Here we show that
constitutive expression of Gas6 in an NIH3T3 cell line that does not
spontaneously express this protein does not result in cell transformation or
uncontrolled growth, but protects from apoptosis induced by serum deprivation.
Recombinant exogenous Gas6 was also capable of protecting cells from apoptosis at
concentrations that did not result in significant induction of DNA synthesis.
Activation of ARK phosphorylation and a weak but significant induction of MAP
kinase activity accompanied the increased survival of cells treated with Gas6.
The antiapoptotic effect of ARK signaling was confirmed by studies using
fibroblasts from ARK knock-out mice, that showed that the absence of ARK resulted
in higher levels of serum deprivation-induced apoptosis, that could not be
rescued by the addition of Gas6. Interestingly ARK signaling protects from
apoptosis induced by serum deprivation, myc overexpression, or by TNF alpha but
not from u.v. irradiation or Staurosporine. These results suggest that a major
function of Gas6-ARK signaling is that of increasing cell survival under
conditions which do not allow cell proliferation.
PMID- 9395236
TI - Different HPV16 E6/E7 oncogene expression patterns in epithelia reconstructed
from HPV16-immortalized human endocervical cells and genital keratinocytes.
AB - Human papillomavirus type 16 (HPV16) E6/E7 oncogenes immortalize two types of
human genital epithelial cells in vitro, endocervical cells and ectocervical or
foreskin keratinocytes. Epithelia reconstructed in in vivo nude mouse implants or
in vitro organotypic raft cultures from immortalized endocervical cells form
higher grade dysplasia than those from keratinocytes. Here, we compared viral
E6/E7 mRNA expression in immortalized cell lines of the three cell types using
implants, rafts and in situ hybridization assays. Endocervical cells expressed
E6/E7 throughout their reconstructed epithelia. In contrast, oncogenes were
limited to basal cells for keratinocyte lower grade dysplasias. To study the role
of the HPV16 promoter/enhancer in this repression in the upper layers of
keratinocyte epithelia, new cell lines were established by immortalization with
E6/E7 controlled by the SV40 promoter. The oncogenes were shown to be controlled
from the SV40 elements after immortalization. Nevertheless, E6/E7 in the two cell
types had the same cell-specific expression pattern as that controlled from the
homologous HPV16 promoter. In addition, naturally occurring premalignant lesions
having integrated HPV16 DNA expressed E6/E7 extensively in the high-grade
dysplastic region of undifferentiated metaplasia. On the other hand, oncogene
expression was restricted to lower layers in the lower grade dysplastic region of
more mature differentiation. Our data suggest that keratinocytes have an inherent
HPV16 promoter-nonspecific mechanism of repression. Apparently this mechanism,
which can be acquired during maturation, is initially nonfunctional in in vitro
and in vivo epithelia derived from metaplastic endocervical cells.
PMID- 9395237
TI - Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton.
AB - During an attempt to elucidate regulatory mechanisms of skeletal muscle cell
differentiation, we cloned cDNAs encoding a novel small GTPase from cDNA
libraries of the mouse skeletal muscle cell line C2 and rat brain. It was
designated as M-Ras due to the structural similarity to Ras family proteins. M
Ras contained conserved motifs for GDP/GTP-binding and GTPase activities, whereas
it varied from the other Ras family proteins at several amino acids within the
extended effector domain. From the C-terminal sequence, M-Ras is presumed to be
anchored to the cell membrane with a geranylgeranyl group in combination with a
polybasic region. Bacterially expressed recombinant M-Ras exerted the GTP-binding
and GTPase activities. A mutant M-RasG22V was unable to hydrolyze bound GTP,
indicating that it serves as a constitutively active form. Epitope-tagging
experiments showed that M-Ras was concentrated on certain plasma membrane
associated structures. Transfection of M-Ras cDNA and microinjection of the M
RasG22V protein into fibroblasts induced formation of the peripheral microspikes.
In addition, the actin stress fibers disappeared and instead numerous actin foci
were formed in the injected cells. The transfected cells eventually exhibited
dendritic appearances with microspikes. Consequently, M-Ras is likely to
participate in reorganization of the actin cytoskeleton.
PMID- 9395238
TI - Transcription of the SCL gene in erythroid and CD34 positive primitive myeloid
cells is controlled by a complex network of lineage-restricted chromatin
dependent and chromatin-independent regulatory elements.
AB - The SCL gene (also known as TAL-1) encodes a basic helix-loop-helix transcription
factor that is essential for the development of all haematopoietic lineages, and
ectopic expression of which results in T cell leukaemia. SCL is expressed in
normal pluripotent haematopoietic stem cells and its expression is maintained
during differentiation along erythroid, mast and megakaryocytic lineages, but is
extinguished following commitment to other cell types. The mechanisms responsible
for this pattern of expression are poorly understood, but are likely to
illuminate the molecular basis for stem cell development and lineage commitment.
We have identified multiple lineage-restricted DNase I hypersensitive sites in a
45 kb region spanning the murine SCL locus. Committed erythroid cells and CD34
positive primitive myeloid cells exhibited both shared and unique DNase I
hypersensitive sites whereas none were found in T cells. The function of each
hypersensitive site was studied using both transient and stable reporter assays
in erythroid, primitive myeloid and T cells. Multiple positive and negative
regulatory elements were characterised and found to display lineage-specificity,
promoter-specificity and/or chromatin-dependence. These results represent the
first description of key components of a complex network of regulatory elements
controlling SCL expression during haematopoiesis.
PMID- 9395240
TI - Potentiation of apoptosis by low dose stress stimuli in cells expressing
activated MEK kinase 1.
AB - MEK kinases (MEKKs) are serine-threonine kinases that regulate sequential protein
phosphorylation pathways involving mitogen-activated protein kinases (MAPKs),
including members of the Jun kinase (JNK) family. MEKK1 is a 196 kDa protein that
when cleaved by caspase-3-like proteases generates an active COOH-terminal kinase
domain. Expression of the MEKK1 kinase domain is sufficient to induce apoptosis.
Mutation of MEKK1 to prevent its proteolytic cleavage protects cells from MEKK1
mediated cell death even though the JNK pathway is still activated, indicating
that JNK activation is not sufficient to induce cell death. The inducible acute
expression at modest levels of the activated MEKK1 kinase domain can be used to
potentiate the apoptotic response to low dose ultraviolet irradiation and
cisplatin. Similarly, in L929 fibrosarcoma cells inducible acute expression of
the kinase domain of MEKK1 markedly increased the cell death response to tumor
necrosis factor alpha (TNF alpha). The findings demonstrate that acute expression
of an active form of MEKK1 can potentiate the cell death response to external
stress stimuli. Manipulation of MEKK1 proteolysis and its regulation of signal
pathways involved in apoptosis has significant potential for anticancer therapies
when used in combination with therapeutic agents at doses that alone have little
or modest effects on cell viability.
PMID- 9395239
TI - p53-induced apoptosis in the human T-ALL cell line CCRF-CEM.
AB - The tumor suppressor p53 has been implicated in apoptosis induction and is
mutated in human T-ALL CCRF-CEM cells. To investigate possible consequences of
wild-type p53 loss, we reconstituted CEM-C7H2, a subclone of CCRF-CEM, with a
temperature-sensitive p53 allele (p53ts). Stably transfected lines expressed high
levels of p53ts and shift to the permissive temperature (32 degrees C) caused
rapid induction of p53-regulated genes, such as p21(CIP1/WAF1), mdm-2 and bax.
This was followed by extensive apoptosis within 24 h to 36 h, supporting the
notion that mutational p53 inactivation contributed to the malignant phenotype.
p53-dependent apoptosis was preceded by digestion of poly(ADP-ribose) polymerase,
a typical target of interleukin-1beta-converting enzyme (ICE)-like
proteases/caspases, and was markedly resistant to the ICE/caspase-1 and
FLICE/caspase-8 inhibitor acetyl-Tyr-Val-Ala-Asp.chloromethylketone (YVAD), but
sensitive to the CPP32/caspase-3 inhibitor benzyloxycarbonyl-Asp-Glu-Val
Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Ala
Asp.fluoromethylketone (zVAD), a caspase inhibitor with broader specificity. This
indicated an essential involvement of caspases, but argued against a significant
role of ICE/caspase-1 or FLICE/caspase-8. Actinomycin D or cycloheximide
prevented cell death, suggesting that, in this system, p53-induced apoptosis
depends upon macromolecule biosynthesis. Introduction of functional p53 into CEM
cells enhanced their sensitivity to the DNA-damaging agent doxorubicin, but not
to the tubulin-active compound vincristine. Thus, mutational p53 inactivation in
ALL might entail relative resistance to DNA-damaging, but not to tubulin
destabilizing, chemotherapy.
PMID- 9395241
TI - A novel epithelial-expressed ETS gene, ELF3: human and murine cDNA sequences,
murine genomic organization, human mapping to 1q32.2 and expression in tissues
and cancer.
AB - The ETS family of genes are implicated in cancers such as Ewings sarcoma, acute
myeloid leukemia and chronic myelomonocytic leukemia. Further, they have
important functions in embryonic development. Hence, identification and
characterization of members of this family are important. We identify a novel ETS
family member, ELF3, and report its human and murine cDNA sequences. The mouse
cDNA has an alternatively spliced transcript with an extra 60 bp inserted. Hence
we present the organization of the murine Elf3 gene together with its exon/intron
structure. This gene consists of 9 exons and 8 introns spanning 4.8 kb. ELF3
binds and transactivates ETS sequences and interestingly also shows the ability
to bind a GGAT-like purine core, a preferential ETS1/ETS2 type binding site. The
expression of ELF3, unlike most other ETS family members, is absent in
hematopoietic cells and hematopoietic organs in humans and mice. Intriguingly,
the gene is specifically expressed in cell lines of epithelial origin and in
organs such as lung, stomach, intestine, kidney that have specialized epithelial
cells. We localize the human gene to 1q32.2, a region that is amplified in
epithelial tumors of the breast, lung and prostate. Finally, we show that ELF3
expression is increased in a lung carcinoma and adenocarcinoma, as compared to
normal tissue. ELF3 is also expressed in cell lines derived from lung cancers.
These results suggest that this novel ETS gene may be involved in lung
tumorigenesis.
PMID- 9395243
TI - The human protein p19ARF is not detected in hemopoietic human cell lines that
abundantly express the alternative beta transcript of the p16INK4a/MTS1 gene.
AB - The p16/MTS1/CDKN2 gene on human chromosome band 9p21 encodes two unrelated
proteins: p16INK4a, a specific inhibitor of the cyclin D-dependent kinases CKD4
and CDK6, and the structurally unrelated p19ARF protein that arrests cell growth
in G1/S and also in G2/M. By use of polyclonal antibodies, the human p19ARF
(hp19ARF) protein has been identified in the nucleus of various cells including
normal cultured fibroblasts. The level of this protein did not fluctuate
throughout the cell cycle and was more elevated in fibroblasts with limited or
arrested growth, suggesting that p19ARF accumulated in presenescent or senescent
cells. Interestingly, hp19ARF was not detected in several hemopoietic tumor cell
lines (mainly of B-type lymphoid origin) that expressed abundant amounts of the
p16beta transcript. This finding indicates that in certain tumors, the expression
of hp19ARF RNA and protein may be uncoupled. Furthermore, it suggests that
disruption of a translational mechanism may be involved in the inactivation of
hp19ARF.
PMID- 9395242
TI - Cloning of two candidate tumor suppressor genes within a 10 kb region on
chromosome 13q14, frequently deleted in chronic lymphocytic leukemia.
AB - Previous studies have indicated the presence of a putative tumor suppressor gene
on chromosome 13q14, commonly deleted in patients with B-cell chronic lymphocytic
leukemia (B-CLL). We have previously defined a minimally deleted region of 130 kb
centromeric to the marker D13S272, and constructed a PAC and cosmid contig
encompassing this area. In the present study we have made a detailed restriction
and transcriptional map of the region of interest. Using these tools we have
screened a panel of 206 primary CLL clones and three cell lines. In five CLL
cases we found limited deletions defining the region of interest to an area of no
more than 10 kb. Two adjacent genes, termed Leu1 and Leu2 (leukemia-associated
gene 1 and 2), were mapped to the minimally deleted region, with several patients
showing deletion borders within these genes. The Leu1 and Leu2 genes show little
homology to previously published genes at the nucleotide and expected translated
amino acid sequence level. Mutational analysis of the Leu1 and 2 genes in 170 CLL
samples revealed no small intragenic mutations or point mutations. However, in
all cases of 13q14 loss examined, the first exon of both genes, which are only
300 bp apart, were deleted. We conclude that the Leu1 and Leu2 genes are strong
candidates as tumor suppressor gene(s) involved in B-CLL leukemogenesis.
PMID- 9395244
TI - Phosphorylated retinoblastoma protein stimulates DNA polymerase alpha.
AB - Human retinoblastoma (Rb) protein, immunopurified from an extract of recombinant
baculovirus infected cells, stimulated 10-100-fold the activity of DNA polymerase
alpha from calf thymus or human HeLa cells. Purified Rb protein is composed of
two electrophoretically distinguishable forms, i.e., partially phosphorylated and
under-phosphorylated forms. Dephosphorylation of Rb protein by protein
phosphatase 2A largely diminished its stimulatory effect. On the other hand, a
hyperphosphorylated Rb protein, obtained from insect cells overexpressing Rb
protein, cyclin E and cyclin-dependent kinase 2 simultaneously, stimulated DNA
polymerase alpha more strongly than the singly-expressed Rb protein. These
results indicate that the phosphorylation is crucial for the stimulation. Rb
protein isolated from human Burkitt lymphoma Raji cells also stimulated DNA
polymerase alpha. In contrast, Rb protein did not affect eukaryotic DNA primase
or Klenow fragment of Escherichia coli DNA polymerase I. By immunoprecipitation
using anti-DNA polymerase alpha antibody, Rb protein in nuclear extract of Raji
cells was co-precipitated with DNA polymerase alpha. This result indicates that
DNA polymerase alpha exists as a complex containing phosphorylated Rb protein in
cells. DNA polymerase alpha specifically bound to a purified Rb protein
immobilized Sepharose column. Rb protein also bound to DNA polymerase alpha
trapped to anti-DNA polymerase alpha antibody-Sepharose column, suggesting the
direct association of these two proteins. These observations suggest a new
function of phosphorylated Rb protein in the regulation of DNA replication.
PMID- 9395245
TI - Cross-talk in signal transduction: Ras-dependent induction of cAMP-responsive
transcriptional repressor ICER by nerve growth factor.
AB - The CREM gene encodes both activators and repressors of cAMP-induced
transcription. By virtue of an alternative, intronic promoter within the gene,
the ICER (Inducible cAMP Early Repressor) isoform is generated. ICER acts as a
dominant negative regulator and is cAMP-inducible in various neuroendocrine cells
and tissues. ICER negatively autoregulates its own expression, and appears to
participate in the molecular events governing oscillatory hormonal regulations.
Here we report that ICER is inducible with nerve growth factor (NGF). This is the
first example of cAMP-independent induction of ICER expression. Importantly,
induction by NGF occurs via a subset of the CREs present in the ICER promoter
which were previously shown to direct cAMP-inducibility. ICER induction
correlates with a NGF-mediated phosphorylation of CREB. Both CREB phosphorylation
and ICER inducibility require an intact Ras-dependent signalling pathway. We show
that increased ICER levels result in the attenuation of c-fos expression. The
activation of a powerful repressor of cAMP-responsive transcription by NGF, whose
transduction signalling is cAMP-independent, constitutes a notable example of
nuclear cross-talk and thus is likely to have relevant physiological
implications.
PMID- 9395246
TI - DNA-damage-inducible p53 activity in SV40-transformed cells.
AB - The biological state of the tumour suppressor proteins Rb and p53 is altered in
papillomavirus- and SV40-transformed cells, due to interaction with the DNA
tumour virus oncogene proteins E6/E7 and the tumour (T) antigen. Thus, the DNA
damage response function of p53, a crucial feature of the tumour suppressor p53,
might be considered as inactive. To investigate this subject, C57SV and VLM, two
SV40-transformed murine cell lines enharboring constitutively high nuclear p53
and SV40 large T antigen levels, were treated with mitomycin C. Mitomycin C is
known for its activity to elicit DNA damage, followed by nuclear accumulation of
biologically active p53. Surprisingly, the nuclear p53 level significantly
increased in mitomycin-C-treated C57SV cells and to a lesser degree in VLM cells.
In addition, expression of p21WAF1 protein was induced in C57SV and VLM cells.
This indicates a possible DNA-damage-elicited p53 activation. Finally, nuclear
extracts of mitomycin-C-treated C57SV and VLM cells, but not of untreated cells,
exhibited PAb421-enhanced specific DNA-binding activity of p53, as proven by gel
shift analysis. Thus, DNA damage induced essential biological functions typical
for wild-type p53 in the SV40-transformed cell lines examined so far.
PMID- 9395247
TI - Interdomain binding mediates tumor growth suppression by the NF2 gene product.
AB - The neurofibromatosis 2 (NF2) tumor suppressor gene encodes an intracellular
membrane-associated protein, called merlin (or schwannomin), that belongs to the
band 4.1 family of cytoskeleton-associated proteins. Inactivating NF2 mutations
occur in several sporadic tumor types and have been linked to the NF2 disease,
whose hallmark is the development of bilateral Schwann cell tumors (schwannomas)
of the eighth cranial nerve. Two major alternatively spliced NF2 variants are
expressed in normal tissues: 'NF2-17' lacking exon 16 and 'NF2-16' that contains
exon 16 and encodes a merlin protein truncated at the C-terminus. We report that
overexpression of NF2-17 in rat schwannoma cells inhibits their growth in vitro
and in vivo, while NF2-16 fails to influence schwannoma growth. Tumor growth
inhibition by merlin depends on an interdomain association occurring either in
cis or in trans between the N- and C-termini. This association does not occur in
the truncated NF2-16 protein nor in a mutant NF2-17 protein lacking C-terminal
sequences. These data indicate that merlin has a unique mechanism of tumor
suppression, inhibiting cell proliferation via self-association.
PMID- 9395248
TI - Nitric oxide and inflammatory arthritides.
AB - Nitric oxide (NO), first identified as endothelium-derived relaxing factor
(EDRF), is a free radical synthesized from L-arginine by NO synthases (NOS). NO
plays vital roles in biological responses, including regulation of vascular tone,
neurotransmission, anti-viral defense and immune response. There are two isoforms
in NOS; constitutive NOS (cNOS) and inducible NOS (iNOS). Inflammatory cytokines
such as interleukin-1(IL-1), interferon-gamma (IFN-gamma), tumor necrosis factor
alpha (TNF-alpha) induce iNOS expression in various cells including macrophages.
NO production is increased in inflammatory arthritides both in rodent models and
human. Enhanced NO production is observed in various compartment in vivo but
inflammatory synovium and cartilage are the major source of NO. The onset of
arthritis in rodent models is successfully blocked by the NOS inhibitor, NG
monomethyl-L-arginine (L-NMMA). These data suggest a possible involvement of NO
in the pathogenesis and tissue destruction in arthritis, and the significance of
up-regulated NO production is discussed.
PMID- 9395249
TI - Brain pharmacokinetics and in vivo receptor binding of 1,4-dihydropyridine
calcium channel antagonists.
AB - Brain pharmacokinetics of 1,4-dihydropyridine (DHP) calcium channel antagonists
and their in vivo receptor binding in mice were characterized. The area under the
concentration vs time curve (AUCbrain) for [3H]nifedipine, [3H]nimodipine and
[3H]PN 200-110 in mouse brain after intravenous injection was higher than that
for [3H]amlodipine. Brain/plasma concentration ratios (AUCbrain/AUCplasm) for
[3H]nimodipine and [3H]PN 200-110 were 3 to 5 times higher than those for [
H]nifedipine and [3H]amlodipine. Further, brain/heart concentration ratios
(AUCbrain/AUCheart) for [3H]nifedipine, [3H]nimodipine and [3H]PN 200-110 were
about 20 times higher than the ratio for [3H]amlodipine. A significant amount of
specific binding in particulate fractions of mouse brain was detected in vivo by
intravenous injection of [3H]nifedipine, [3H]nimodipine and [3H]PN 200-110 but
not [3H]amlodipine. These data suggest that [3H]nifedipine, [3H]nimodipine and
[3H]PN 200-110 are more extensively taken up into brain from plasma than
[3H]amlodipine and bind to the receptor sites in brain parenchymal cells in a
significant amount in vivo. In conclusion, the present simultaneous measurement
of pharmacokinetics and in vivo receptor binding in mouse brain suggests an
usefulness of calcium channel antagonists such as nimodipine in the
pharmacotherapy of brain diseases.
PMID- 9395250
TI - Prothymosin alpha promotes cell proliferation in NIH3T3 cells.
AB - Thymic hormones have immunomodulatory effects on T cells and hence have been used
clinically to restore the immunity of immunodeficient patients as well as to
enhance the cellular immunity of cancer patients. Prothymosin alpha, which is a
member of the thymic hormone family, has recently been suggested to act as a
nuclear protein participating in the stimulation of cell proliferation. To
characterize the biological activities ofprothymosin alpha in vitro, we
established NIH3T3 cell transformants that constitutively express higher
prothymosin alpha protein and its mRNA compared with the wild-type counterpart.
Cells that overexpressed prothymosin alpha increased the proliferative activity
assayed by the [3H]-thymidine incorporation or by the cell cycle analysis with
the fluorescent-activated cell sorter. The results provide direct evidence that
prothymosin alpha plays a role in cell proliferation by shortening the duration
of the G1 phase.
PMID- 9395251
TI - Comparative study of radical scavenger and antioxidant properties of phenolic
compounds from Vitis vinifera cell cultures using in vitro tests.
AB - Vitis vinifera cell suspensions were used to isolate and characterize the
flavonoids (anthocyanins, catechins) and non-flavonoids (stilbenes) found in red
wine. Furthermore, we showed that astringin is produced although this stilbene
has not previously been reported to be a constituent of V. vinifera or wine. The
ability of these compounds to act as radical scavengers was investigated using
1,1-diphenyl-2-picryl-hydrazyl (DPPH), a stable free radical. Antioxidant
activities were assessed by their capacity to prevent Fe2+-induced lipid
peroxidation in microsomes and their action on Cu2+-induced lipid peroxidation in
low-density lipoproteins. The results showed that astringin has an important
antioxidant effect similar to that of trans-resveratrol, and a higher radical
scavenger activity than the latter. Astringinin appeared to be more active. These
data indicate that phenolic compounds (stilbenes, catechins, anthocyanins)
exhibit interesting properties which may account in part for the so-called
"French paradox," i.e. that moderate drinking of red wine over a long period of
time can protect against coronary heart disease.
PMID- 9395252
TI - Expression of prostaglandin EP2 receptor mRNA in the rat spinal cord.
AB - RT-PCR and an in situ hybridization analyses demonstrated expression of
prostaglandin EP2 receptor mRNA in the subfield of the dorsal horn of the rat
spinal cord. The intensive signals from the cells labeled with digoxigenin-11
dUTP were scattered through this region and they corresponded to neurons. EP2
receptor-mediated signal transduction is expected to play roles in modulating
some neuronal functions such as transmission of nociceptive reaction or motor
reflex.
PMID- 9395253
TI - Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors:
binding affinities, brain penetration and activity in the neurogenic dural
inflammation model of migraine.
AB - LY344864 is a selective receptor agonist with an affinity of 6 nM (Ki) at the
recently cloned 5-HT1F receptor. It possesses little affinity for the 56 other
serotonergic and non-serotonergic neuronal binding sites examined. When examined
for its ability to inhibit forskolin-induced cyclic AMP accumulation in cells
stably transfected with human 5-HT1F receptors, LY344864 was shown to be a full
agonist producing an effect similar in magnitude to serotonin itself. After an
intravenous dose of 1 mg/kg, rat plasma LY344864 levels declined with time
whereas brain cortex levels remained relatively constant for the first 6 hours
after injection. Oral and intravenous LY344864 administration potently inhibited
dural protein extravasation caused by electrical stimulation of the trigeminal
ganglion in rats. Taken together, these data demonstrate that LY344864 is a
selective 5-HT1F receptor agonist that can be used to explore both the in vitro
and in vivo functions of this receptor.
PMID- 9395254
TI - Comparison of the Ca2+ movement by activation of alpha1-adrenoceptor subtypes in
HEK-293 cells.
AB - We studied the Ca2+ movement induced by activation of alpha1A-, alpha1B- and
alpha1D-adrenoceptor subtypes in transfected HEK-293 cells with the fura-2 probe.
All these alpha1-AR subtypes induced both Ca2+ release and Ca2+ entry. The effect
on Ca2+ release in alpha1b transfected HEK-293 cells was bigger than that in
alpha1a and alpha1d transfected HEK-293 cells, and the effects on Ca2+ entry were
the same in alpha1a, alpha1b and alpha1d transfected HEK-293 cells. The Ca2+
entry was inhibited by 1 mM NiSO4, but not by nifedipine. Cyclopiazonic acid
(CPA) produced a biphasic Ca2+ signal response in Ca2+ medium, and only induced a
transient response in Ca2+-free medium. After depletion of CPA-sensitive Ca2+
pool by 10 microM CPA in Ca2+-free medium, 10 microM adrenaline (Adr) still
transiently increased [Ca2+]i in three different alpha1-adrenoceptor subtype
transfected HEK-293 cells. However, after depletion of adrenaline-sensitive Ca2+
pool by 10 microM Adr, CPA transiently elevated [Ca2+]i only in alpha1a and
alpha1d transfected HEK-293 cells, not in alpha1b transfected HEK-293 cells.
U73122, a phospholipase C (PLC) inhibitor, inhibited both Ca2+ release and Ca2+
entry induced by activation of alpha1A alpha1B and alpha1D subtypes in
transfected HEK-293 cells. These results suggest that HEK-293 cell line contains
two functionally separate intracellular Ca2+ pools, CPA-sensitive and Adr
sensitive pools. Activation of alpha1B-AR stimulates Ca2+ release from both CPA
sensitive and Adr-sensitive Ca2+ pools. Alpha1A and alpha1D subtypes induce Ca2+
release only from Adr-sensitive Ca2+ pool.
PMID- 9395255
TI - Hemolytic effects of dehydroepiandrosterone in vitro.
AB - Dehydroepiandrosterone (DHEA), a major steroid secreted by the adrenal gland
which decreases with age after adolescence, is available as a over-the-counter
product. This study demonstrates that DHEA induced lysis of human red blood cells
(RBCs) in a concentration-dependent manner, with ca. 70% hemolysis at 2 mM DHEA
at 37 degrees C for 1 hr. Hemolysis induced by 2 mM DHEA was rapid and involved
neither hemoglobin oxidation nor lipid peroxidation. The hemolysis was also not
inhibited by addition of EDTA, catalase, superoxide dismutase, glucose or a
radical scavenger including mannitol, dimethylsulfoxide and alpha-tocopherol,
indicating a non-oxidative mechanism. RBCs stored overnight before incubation
with DHEA were hemolyzed to a lesser extent than the freshly prepared RBCs. Light
microscopy of the fresh RBCs following 1-h incubation with 2 mM DHEA revealed
thickened and cup-shaped deformity of the membranes, suggesting a change in the
membrane structure possibly due to the intercalation of the steroid into the
membranes.
PMID- 9395257
TI - Theoretical analysis of a morphine withdrawal phenotype in a cultured cell line.
AB - We have previously described a delta-opioid receptor-expressing cultured cell
line that proliferates in a defined medium and responds to chronic morphine
treatment with an inhibition of its rate of proliferation. To help provide an
explanation for this behavior, we have used computer simulation of cell cycle
kinetics to analyze the observed rates of proliferation of these cells in the
presence and absence of morphine, and after withdrawal of morphine treatment. We
questioned whether the difference in cell kinetics observed for the cell
populations under the different treatments could be due to changes in the length
of the cell cycle, withdrawal of cells from the cycle into a quiescent state, or
differences in cell renewal. This was investigated by comparing observed cell
numbers as a function of time with the results of different computer simulations
using different values for these parameters. We found that we can provide a
satisfactory explanation of the experimental observations on the basis of changes
in a small set of parameters: Untreated cells experience a slowdown of cell
proliferation at about the culture density where multiple cell-cell contacts are
made and, beginning then, a large fraction are shunted from G1 into a quiescent
state. Chronic morphine treatment inhibits proliferation by slowing passage
through G1, but the cells remain as sensitive to cell-cell contacts as the
untreated cells. After drug withdrawal following a 6 day treatment with morphine,
the cells exhibit a large temporary increase in their rate of proliferation
compared with control or chronically treated cells but about 48 hours after
withdrawal, when cell-cell contacts just begin to be made, the cells return to
almost their pre-treatment total cell cycle time and, as before, a large fraction
are shunted into a quiescent state. Taken in conjunction with previously
published results, the present ones indicate a possible interaction between
morphine-induced and insulin-induced nuclear signaling pathways to the nucleus.
PMID- 9395256
TI - Serotonin transporter gene-linked polymorphic region: allele distributions in
relationship to body weight and in anorexia nervosa.
AB - Several lines of evidence implicate a role for the serotonergic system in body
weight regulation and eating disorders. The magnitude and duration of
postsynaptic responses to serotonin (5-HT) is directed by the transport into and
release from the presynaptic neuron. Recently, a common polymorphism of a
repetitive element in the region of the serotonin transporter (5-HTT) gene-linked
polymorphic region (5-HTTLPR) was identified that results in a system of two
common alleles. The activity of the 5-HTT, as measured in in vitro assays and in
human lymphoblastoid cell lines, is dependent on the respective genotype. We thus
hypothesized that this polymorphism is relevant for weight regulation in general
and is possibly involved in the etiology of anorexia nervosa (AN). Allele
frequencies and genotypes were determined in a total of 385 unrelated obese
children, adolescents and adults, 112 underweight subjects and 96 patients with
AN. Furthermore, both parents of 98 obese children and adolescents and of 55
patients with AN, respectively, were genotyped, thus allowing to test for both
association and linkage. The comparison of allele frequencies between obese and
underweight probands provided no evidence for a major role of the 5-HTTLPR in
weight regulation. Patients with AN had allele frequencies not significantly
different to those observed for obese and underweight individuals.
PMID- 9395258
TI - Effect of Ca2+-channel blockers on isoprenaline-induced desensitization in rat
trachea.
AB - Isoprenaline-induced desensitization in vitro in rat trachea was studied in the
presence of the Ca2+-channel blockers (Ca2+-CBs) verapamil and nitrendipine. The
concentration-response curves for isoprenaline were determined in a noncumulative
manner using carbachol as contracting agent, and then desensitization was
achieved by 40-min incubation of the tracheal preparations with isoprenaline (1
microM). The effect of verapamil and nitrendipine was studied by the addition of
each Ca2+-CB to the desensitizing solution. Both verapamil and nitrendipine
reduced the isoprenaline-induced desensitization in the rat trachea.
PMID- 9395259
TI - Interaction mechanisms of imipramine and desipramine with enkephalin-degrading
aminopeptidases in vitro.
AB - In the last few years, considerable evidence has appeared concerning the
importance of the opioid systems in the action mechanism of some antidepressant
drugs. This action mechanism could be mediated through the inhibition of the
enzymes responsible for enkephalin degradation. In this sense, imipramine
treatment in vivo increases the enkephalin levels, and this effect is enhanced by
inhibitors of enkephalin-degrading enzymes. The present work shows the effects in
vitro of imipramine and its active metabolite desipramine on the activities of
two membrane-bound enkephalin-degrading aminopeptidases present in rat brain.
Imipramine and desipramine in vitro do not affect the aminopeptidase M activity,
but they reversibly inhibits the aminoeptidase MII. The enzyme kinetic analysis
shows that this enzyme molecule has two different binding sites for each drug,
which exert a mixed type enzyme inhibition.
PMID- 9395260
TI - Induction of the human sperm acrosome reaction with mannose-containing
neoglycoprotein ligands.
AB - In the interest of classifying cases of male factor infertility, we have paid
particular attention to the sugar ligand binding properties of the human sperm
surface and the functional capacity of the acrosome for exocytosis--key
parameters for assessing sperm fertilizing ability. Zona recognition and binding
involve the interactions of sperm surface mannose receptors (lectins) with
mannose ligands on the zona pellucida. Sperm surface mannose lectins can be
visualized by their ability to bind a synthetic model zona ligand, fluorescein
isothiocyanate (FITC)-conjugated mannosylated bovine serum albumin (BSA) (Man
FITC-BSA). We now report that Man-FITC-BSA biologically also mimics the effects
of solubilized authentic human zonae, in that binding of Man-FITC-BSA results in
a time-dependent receptor aggregation and the induction of acrosome exocytosis in
capacitated sperm populations from fertile donors. In our assay, the addition of
mM amounts of mannose monosaccharide to Man-FITC-BSA increases the number of
polyvalent mannose ligands bound by individual spermatozoa and increases the rate
of the acrosome reactions induced by Man-FITC-BSA, thereby increasing specimen
processing efficiency. We conclude that exposure of human spermatozoa to
polyvalent mannose ligands + D-mannose monosaccharide offers a new, convenient
and readily available system to study sperm capacity for induced acrosome loss.
PMID- 9395261
TI - Use of mannose ligands in IVF screens to mimic zona pellucida-induced acrosome
reactions and predict fertilization success.
AB - A predictive test for determining whether motile populations of human spermatozoa
will fertilize eggs in vitro has been an elusive goal of clinical research. We
have developed an assay for the ability of motile human spermatozoa to bind
fluorescein isothiocyanate-labelled mannosylated bovine serum albumin (Man-FITC
BSA) as a test for the presence of sperm surface receptors (lectins) for mannose
ligands. Mannosylated ligands are present on the human zona pellucida and are
involved in the species-specific binding of human spermatozoa to the zona
pellucida. We now demonstrate in prospective blinded analysis that the fractional
increase in acrosome loss following a mannose ligand challenge is highly
correlated with the rate of fertilization in vitro. Using an incremental increase
of acrosome exocytosis of >0.1 as a threshold to predict which specimens will
yield normal fertilization, the assay has a sensitivity of 97.8%, a specificity
of 83.3%, a positive predictive value of 95.7% and a negative predictive value of
90.7%. These data indicate that testing for a mannose-induced acrosome reaction
may be useful in assessment of sperm function prior to in-vitro fertilization in
order to assign males to conventional insemination or intracytoplasmic sperm
injection protocols.
PMID- 9395262
TI - Assisted reproductive technology and complex chromosomal rearrangements: the
limits of ICSI.
AB - Complex chromosomal rearrangements are very rare events in the human population.
According to our knowledge on the consequences of simple reciprocal
translocations for male fertility, translocations involving three or more
chromosomes are thought to lead to severe reproductive impairments in terms of
meiotic disturbance or chromosomal imbalance of gametes. We report the case of a
48 year old man whose sperm count revealed either oligozoospermia (<10(3)
spermatozoa/ml) or azoospermia. He was referred to the laboratory for in-vitro
fertilization after intracytoplasmic sperm injection. Cytogenetic investigations
showed a complex chromosomal rearrangement involving firstly a translocation
between the short arm of chromosome 7 and the long arm of chromosome 13 and
secondly a translocation between the short arm of the same chromosome 13 and the
short arm of chromosome 9. Diagnosis was ascertained by fluorescence in-situ
hybridization and staining of the nucleolar organizer regions. Theoretical study
of the translocated chromosomes predicted a 'chain' configuration of the
hexavalent at the pachytene stage of meiosis. In all, 32 modes of segregation
were considered and only one resulted either in a normal or a balanced gamete
karyotype. Genetic counselling and choice of appropriate artificial reproduction
technique are discussed.
PMID- 9395264
TI - Oocyte polarity and cell determination in early mammalian embryos.
AB - Knowledge on determination and differentiation in the mammalian embryo has not
kept pace with discoveries in other phyla. Current concepts overlook well
established pathways leading to polarity in oocytes and embryos of other phyla,
modern principles of totipotency in plants and animals, and axis formation in
lower vertebrates. Various models derived from invertebrates and frogs could be
relevant to the situation in eutherian mammals, and we explore the nature of
strict genetic controls in these species and its implications for early mammalian
differentiation. Concepts on totipotency and related phenomena in animal and
human embryos are examined and the possibility raised that two cell lines are
formed in early human embryos from the 2-4 cell stage. Clinical consequences are
assessed, including causes of the high incidence of chromosomal mosaicism in
human embryos. Our interpretations are obviously speculative, and must be
clarified by experimentation.
PMID- 9395263
TI - Analysis of P[gal4] insertion lines of Drosophila melanogaster as a route to
identifying genes important in the follicle cells during oogenesis.
AB - We report the analysis of a number of lines of Drosophila melanogaster containing
insertions of the yeast gal4 gene. By crossing a UAS-lacZ fusion gene as a
reporter into these lines, we analysed the expression patterns of beta
galactosidase during oogenesis. Since there is no expression of GAL4 in the germ
line in these experiments, this is an ideal system for the analysis of expression
patterns in sub-sets of follicle cells. These lines provide ideal markers for
sets of follicle cells, e.g. anterior or posterior polar cells for studying
genetic interactions in oogenesis; however, they can also be used in the same way
as conventional enhancer traps to clone nearby genes with similar expression
patterns. The advantages of this dual gal4/UAS system over conventional enhancer
trapping includes the possibility of GAL4-directed misexpression and antisense
expression studies to establish the function of the genes we identified during
follicle cell determination and differentiation. These studies could lead to the
isolation of homologous genes crucial in mammalian oogenesis. Understanding how
the somatic cells and germ cells interact to promote growth and maturation of the
mammalian follicle and oocyte could well be crucial for improving the fertility
of eggs used for in-vitro fertilization programmes, and could provide methods for
assessing the quality of eggs.
PMID- 9395265
TI - Cell surface carbohydrates and lectins in early development.
AB - Current knowledge on the development regulation of cell surface carbohydrates and
lectins in mammalian embryos is summarized. Much of this data comes from
observations on mouse embryos but information on the human embryo is included
where it is available. Over the last few years, numerous studies have indicated
that carbohydrates play a critical role in the cell-cell interactions of the pre-
and peri-implantation embryo. Functional tests suggest a role for terminal
fucosylated Galbeta1-3/4GlcNAc structures in the early steps of implantation. We
also now have clear evidence for the expression of lectins in the trophectoderm
just prior to implantation. Mouse mutants have been generated which lack
particular enzymes involved in glycosylation or particular lectins, but so far
they have not been informative about the role of glycoconjugates or lectins in
the very early embryo.
PMID- 9395266
TI - Cell death in the mammalian blastocyst.
AB - Cell death is a widespread feature in the blastocysts of many mammals. Isolated
cells in both the inner cell mass and the trophectoderm undergo cell death. These
dying cells appear morphologically to be undergoing apoptosis. In mouse
blastocysts, a wave of cell death is seen in vivo, suggesting that it plays an
important role in normal development. However, cell death is increased under
suboptimal culture conditions. There is evidence that levels of cell death are
regulated by 'survival' factors produced both by the embryo itself and by the
maternal reproductive tract. The role of cell death in development is unknown,
but could involve the elimination of abnormal cells, or a sublineage of cells
with an inappropriate developmental potential. Work in other systems has
demonstrated that cell death is regulated by the activity of apoptosis genes.
Whether these genes are implicated in blastocyst cell death, and the reasons for
apoptosis in the early embryo, remain to be determined.
PMID- 9395267
TI - Nikolaj Nikolajewitsch Anitschkow (1885-1964) established the cholesterol-fed
rabbit as a model for atherosclerosis research.
AB - The cholesterol-fed rabbit is a widely used model for experimental
atherosclerosis research. In regard to this, one name is periodically mentioned:
Nikolaj Nikolajewitsch Anitschkow. Those infrequent reminders of an important
name in modern medical history do not pay an adequate tribute to basic findings
concerning the pathology and pathogenesis of atherosclerosis. In contrast to
research groups at that time conducting experiments with protein enriched diets,
Anitschkow demonstrated, in 1913 in St. Petersburg, that it was cholesterol only
that caused these atherosclerotic changes in the rabbit arterial intima, which
was very similar to human atherosclerosis. By analysing the plaque's development
and histology, Anitschkow was able to identify the cell types, on which modern
atherosclerosis research is now focussing with a new set of immunohistochemical
methods: smooth muscle cells, macrophages and lymphocytes. He noted early (fatty
streaks) and advanced (atheromatous plaques) lesions and, by standardizing
cholesterol feeding, he discovered that the amount of cholesterol uptake was
directly proportional to the degree of atherosclerosis formation. His explanation
for this observation was what modern terminology calls 'response-to-injury'. With
modern immunohistochemical and molecular-biological methods, the cholesterol-fed
rabbit can be used to investigate the pathophysiological aspects which also
contribute to human atherosclerosis, such as lipoproteins, diabetes, mitogens,
growth-factors, adhesion molecules, endothelial-function, receptor-pathways or
platelets. This model can be combined with a number of other methods causing
endothelial dysfunction and injury, such as balloon denudation, electric
stimulation, cuff implantation, artificial hypertension, diabetes or infection.
Bred strains of hereditary hypercholesterolemic rabbits or those resistant to a
cholesterol-diet provide further possibilities to expand experimental designs.
PMID- 9395268
TI - Endothelial-derived nitric oxide preserves anticoagulant heparan sulfate
expression in cultured porcine aortic endothelial cells.
AB - Nitric oxide (NO) has been shown to inhibit platelet adhesion and aggregation,
but there are no reports on its interaction with the coagulation system. We
investigated the effect of the L-arginine analogues, N-nitro-L-arginine (LNA),
N(G)-nitro-L-arginine methyl ester (L-NAME), and N(G)-monomethyl-L arginine (L
NMMA), competitive inhibitors of NO production, on endothelial-surface heparan
sulfate. Addition of LNA to porcine aortic endothelial cells reduced 125I-labeled
antithrombin III binding to the cell surface heparan sulfate in a dose- and time
dependent fashion. Significant inhibition was observed with 1 mM LNA, and the
maximal suppression (-50% of control) occurred at 10 mM LNA after 12 h. L-NAME (1
mM) and L-NMMA (1 mM) also significantly inhibited the antithrombin III binding.
The iron chelator desferrioxamine significantly prevented the reduction of
antithrombin III binding to LNA-treated cells. We further investigated the effect
of L-NAME on intracellular oxidative stress of endothelial cells using a
hydroperoxide-sensitive fluorochrome, carboxy-dichloro-dihydrofluorescein
diacetate bisacetoxymethyl ester probe, and revealed that inhibition of NO
synthesis by L-NAME led to a marked increase in intracellular oxidative stress.
These results demonstrated that the prolonged inhibition of NO synthesis in
porcine aortic endothelial cells decreases the expression of anticoagulant
heparan sulfate on endothelial cells through the increase in intracellular
oxidative stress, perhaps comprising another mechanism by which NO affects the
coagulation system in the vasculature.
PMID- 9395270
TI - Analysis of the T cell receptor V beta repertoire in human aortic aneurysms.
AB - Human aortic aneurysm is commonly characterized by the presence of advanced
atherosclerosis associated with variable chronic adventitial inflammation.
Histological examination of human aortic aneurysmal specimens revealed the
presence of plasma cells and lymphoid aggregates in media and adventitia of the
vessels. Immunostaining further demonstrated that CD3-positive T lymphocytes are
present in follicles. Using a highly sensitive reverse transcription-polymerase
chain reaction amplification method, the T cell receptor (TCR) V beta gene
expression in aortic aneurysms was shown to be polyclonal. Furthermore. there was
no preferential expression of any TCR V beta gene in the aortic tissue as
compared with that in peripheral blood in aneurysmal patients. These results
indicate that the TCR repertoire in aortic aneurysm is not restricted.
PMID- 9395269
TI - Subendothelial smooth muscle cells of human aorta express macrophage antigen in
situ and in vitro.
AB - Cells bearing a smooth muscle cell marker--alpha-actin and a macrophage marker-
CD68 antigen were immunocytochemically identified on 'en face' preparations of
human aortic intima. Cells, expressing smooth muscle alpha-actin, macrophage CD68
antigen and both markers, i.e. smooth muscle cells possessing the macrophage
antigen, were identified both in grossly normal aortic areas and in
atherosclerotic lesions (fatty streaks and atherosclerotic plaques). CD68
positive smooth muscle cells were most common in the lipid-rich areas: fatty
streaks and atherosclerotic plaque shoulders. Cells expressing smooth muscle
alpha-actin and CD68 were also revealed in primary cultures prepared from grossly
normal and atherosclerotic intima. Cells expressing both antigens were found in
all examined cultures. The proportion of these cells in cultures from grossly
normal areas and atherosclerotic plaques was similar: 14.5 +/- 4.1 and 14.6 +/-
4.8%, respectively. Cultures from fatty streaks had a higher content of cells
expressing both antigens: 25.1 +/- 7.0%. Modified low density lipoprotein-induced
intracellular lipid accumulation in cells cultured from grossly normal intima led
to a three-fold increase in the number of cells sharing alpha-actin and CD68
antigen. Accumulation of latex beads by phagocytosis had a similar effect. It was
suggested that in atherosclerotic lesions intracellular lipid accumulation and
other stimulators of phagocytosis may provoke the expression of macrophage
associated antigen CD68 in settled cells of the subendothelial intima of human
aorta.
PMID- 9395271
TI - Effects of green tea, black tea and dietary lipophilic antioxidants on LDL
oxidizability and atherosclerosis in hypercholesterolaemic rabbits.
AB - The hypothesis that tea or dietary lipid-soluble antioxidants reduce
atherogenesis by lowering the oxidizability of low-density lipoprotein (LDL) was
investigated. Five groups of 20 female New Zealand white rabbits were fed a
restricted amount of a high-fat (30 en%) semipurified diet supplemented with
cholesterol (0.15%, w/w) for 21 weeks. The vitamin E content of the control diet
was 40 mg/kg diet. The animals received either green tea or black tea in their
drinking water or vitamin E (200 mg/kg diet) or beta-carotene (20 mg/kg). The
serum cholesterol concentrations (in the order of 18-23 mmol/l) were not
significantly different between the groups. Vitamin E was substantially increased
as compared to controls in vitamin E supplemented animals (3-fold within 8 weeks
in plasma and LDL; P < 0.01) and weakly (1.2-fold) by green and black tea (P <
0.05). Green tea consumption tended to reduce aortic lesion formation by 31% (24
+/- 3.2% versus 35 +/- 5.7% for control animals P = 0.11), while black tea,
vitamin E and beta-carotene had no effect. This was in contrast to the resistance
of isolated LDL to oxidation induced at high copper concentration. Green and
black tea induced a 13% and 15% (P < 0.05) prolongation of the lag phase,
respectively, with a correspondingly lower oxidation rate, while vitamin E
increased the lag phase by 63% (P < 0.01) with a concomitant diminution of the
oxidation rate and beta-carotene had no effect. Regression analysis showed that
there was no relationship between the extent of atherosclerosis and LDL
oxidizability or plasma malondialdehyde as marker of in vivo lipid peroxidation.
The results of the present study raise the question whether LDL oxidizability (at
least when tested at high induction rate ex vivo) is a primary causal mechanism
in atherosclerosis in the cholesterol-fed rabbit. The suitability of the
cholesterol-fed rabbit with extreme hypercholesterolaemia as a model to study
antiatherosclerotic properties of dietary antioxidants, such as the tested
polyphenols, is discussed.
PMID- 9395272
TI - N(G)-nitro-L-arginine- and indomethacin-resistant endothelium-dependent
relaxation in the rabbit renal artery: effect of hypercholesterolemia.
AB - Studies were designed to compare the N(G)-nitro-L-arginine- and indomethacin
resistant, endothelium-dependent relaxation to acetylcholine in isolated renal
artery rings from normal and cholesterol-fed rabbits. It was assumed that the
resistant part in response to acetylcholine is mediated by the endothelial
derived hyperpolarizing factor (EDHF). Rabbits were fed normal (n = 15) or
cholesterol enriched chow (n = 13, 1% cholesterol for 4 weeks, 0.5% for 12
weeks). In organ chamber experiments, renal artery rings were precontracted with
0.1-1 microM phenylephrine or 35 mM KCl, and relaxed with acetylcholine (0.001-10
microM) in the presence of 10 microM indomethacin. Studies were performed in the
presence or absence of: 100 microM N(G)-nitro-L-arginine (L-NOARG) to inhibit the
nitric oxide pathway, 100 nM charybdotoxin (CTX) or 1 mM tetrabutylammonium (TBA)
to inhibit Ca2+-activated K+ channels, and 100 microM SKF 525a to inhibit
cytochrome P450 monoxygenase pathway. In normal arteries, L-NOARG partially
inhibited acetylcholine-induced relaxation. The resistant part was almost
abolished when the arteries were depolarized with KCl, or when L-NOARG was
combined with either CTX, TBA or SKF 525a. In arteries from hypercholesterolemic
animals, the relaxation to acetylcholine was only slightly impaired as compared
to normal animals. However, in comparison to arteries from normal animals, the L
NOARG-resistant part of acetylcholine-induced endothelium-dependent relaxation
was enhanced. It is speculated that differences in the balance between nitric
oxide (NO)- and EDHF-mediated control of vascular tone may maintain acetylcholine
induced vasodilatation of the renal artery in hypercholesterolemia.
PMID- 9395273
TI - Beta-very low density lipoprotein induces triglyceride accumulation through
receptor mediated endocytotic pathway in 3T3-L1 adipocytes.
AB - To elucidate the mechanism of triglyceride (TG) accumulation in adipocytes
induced by TG-rich lipoproteins, we examined the effect of beta-very low density
lipoprotein (beta-VLDL) on TG accumulation in 3T3-L1 adipocytes. Beta-VLDL did
not induce TG accumulation in 3T3-L1 preadipocytes but in 3T3-L1 adipocytes. TG
accumulation was significantly inhibited by cytochalasin B, an inhibitor of
receptor mediated endocytosis. In contrast, cytochalasin B did not inhibit free
fatty acid induced TG accumulation in adipocytes. The binding of [125I]beta-VLDL
to preadipocytes was inhibited completely by both beta-VLDL and LDL. In sharp
contrast, the binding of [125I]beta-VLDL to adipocytes was inhibited completely
by beta-VLDL, but partially by LDL. The VLDL receptor mRNA was only expressed in
adipocytes. These results suggest that beta-VLDL induced TG accumulation in
adipocytes may be mediated through the VLDL receptor pathway.
PMID- 9395274
TI - Unrestricted usage of immunoglobulin heavy chain genes in B cells infiltrating
the wall of atherosclerotic abdominal aortic aneurysms.
AB - The aim of this study was to provide evidence for the hypothesis that the B cell
rich infiltrate concentrated in the adventitia of atherosclerotic abdominal
aortic aneurysms is an autoimmune response to specific tissue antigens. Detailed
histological examination of biopsies from 26 atherosclerotic abdominal aortic
aneurysms showed in the adventitia, the presence of lymphoid follicles in 7/26
(27%) and of plasma cells in all cases. DNA prepared from the outer aneurysm wall
(n = 25) was amplified using the polymerase chain reaction to investigate the
repertoire of the immunoglobulin heavy chain (VH) genes used. Amplification of
the VDJ region of VH, using both framework 2 and 3 primers, revealed unrestricted
usage of the VH gene in 24/25 cases. The only case where restricted usage of the
VH genes was observed, might have been attributable to severe virally-induced
tissue inflammation. These results indicate that, in the vast majority of
atherosclerotic abdominal aortic aneurysms, the B cell rich adventitial
infiltrates are not an autoimmune response to a limited repertoire of tissue
antigens.
PMID- 9395275
TI - The effect of hormone replacement therapy on the oxidation of low density
lipoprotein in postmenopausal women.
AB - The oxidative modification of low density lipoprotein (LDL) is important in the
pathogenesis of atherosclerosis, and oestrogen has been shown to inhibit copper
and cell mediated oxidation of LDL in vitro. We have investigated the effect of
oral and transdermal oestrogens (oestradiol valerate 1 mg, conjugated equine
oestrogens 0.625 mg and patches releasing 50 microg oestradiol daily), oestrogen
implants (oestradiol 50 mg) and oral combined oestrogen and progestogen
(oestradiol valerate 2 mg with medroxyprogesterone acetate 5 mg and oestradiol
valerate 2 mg with norethisterone acetate 1 mg), on the susceptibility of LDL to
oxidation in postmenopausal women (total n = 56). Oxidation of LDL was initiated
by the addition of copper ions, and monitored by measurement of conjugated
dienes. Changes in fasting serum levels of total cholesterol, LDL, HDL and
triglycerides were also evaluated, as were changes in LDL composition. Total
cholesterol decreased by 5.5% (P < 0.05) with CEE, 6.8% with oestradiol implants
(P < 0.05), 9.3% with oestradiol + MPA (P < 0.01) and 10% with oestradiol +
norethisterone (P < 0.05). There were reductions in LDL with oral oestradiol
valerate (7.8%) (P < 0.05), CEE (13.8%) (P < 0.01) and oestradiol combined with
MPA (12.7%) (P < 0.05). HDL increased by 7.1% (P < 0.01) and 6.3% (P < 0.05),
with oestradiol valerate and CEE respectively, and decreased by 9% (P < 0.05)
with implants and by 14.7% with oestradiol combined with norethisterone (P <
0.01). Triglycerides were significantly increased with CEE (14.9%) and reduced
with oestradiol implants (15.2%) (both P < 0.05). While there was no change in
the ratio of 'cholesterol ester' to 'free cholesterol' within LDL with any of the
HRT preparations, a reduction in total cholesterol and cholesterol ester content
of LDL occurred with transdermal oestradiol and a reduction in free cholesterol
occurred with oestradiol plus MPA. Although we found a small but significant
decrease in plasma hydroperoxide concentration four weeks after insertion of the
oestradiol implant from 1.17 +/- 0.06 to 1.03 +/- 0.04 micromol/l (P < 0.05), we
found no significant change in the lag time to oxidation, or in the maximum rate
of propagation of the reaction, after treatment with any of the above forms of
hormone replacement therapy. This study does not therefore support the role of
oestrogens as antioxidants in vivo.
PMID- 9395276
TI - Direct association between the hepatic secretion of very-low-density lipoprotein
apolipoprotein B-100 and plasma mevalonic acid and lathosterol concentrations in
man.
AB - Apolipoprotein B-100 (apo B) is the principal structural and functional protein
of the pro-atherogenic lipoproteins, but its homeostasis in man has not been
clearly established. The hepatic availability of cholesterol substrate may be a
determining factor. We examined whether there was a direct correlation between
plasma concentrations of mevalonic acid (MVA) and lathosterol (indices of in vivo
cholesterol synthesis) and hepatic secretion of very-low-density lipoprotein
(VLDL) apo B in 13 normolipidaemic, healthy male subjects. The secretion of VLDL
apo B was measured using a primed constant intravenous infusion of 1-[13C]
leucine (1 mg/kg per h) over 8 h. Gas-chromatography mass spectrometry (GCMS) was
used to derive isotopic enrichment of apo B and fractional turnover rate was
calculated using a monoexponential function. There was a highly significant
positive correlation between the absolute secretion rate (ASR) of VLDL apo B and
the plasma concentrations of mevalonic acid (r = 0.72, P = 0.005) and lathosterol
(r = 0.81, P = 0.001) and the lathosterol:cholesterol ratio (r = 0.79, P =
0.001). In multiple regression analysis, these correlations remained significant
after adjusting for waist circumference, age, apolipoprotein E genotype and
dietary fat intake. The data further support the notion that the availability of
cholesterol substrate regulates the hepatic secretion rate of apo B.
PMID- 9395277
TI - Red wine and fractionated phenolic compounds prepared from red wine inhibit low
density lipoprotein oxidation in vitro.
AB - The oxidative modification of low density lipoproteins (LDL) has been implicated
in the development of atherosclerosis. This study examined the effect of red
wine, ethanol and red wine stripped of phenols on copper-mediated and azo
initiated LDL oxidation. Red wine containing phenolic compounds (0.025-20 mg/l
gallic acid equivalents) increased the lag time of conjugated diene formation,
inhibited the generation of thiobarbituric acid reactive substances (TBARS) and
decreased the relative electrophoretic mobility of LDL in a concentration
dependent manner. These changes were not apparent in LDL incubated with ethanol
or red wine stripped of phenols. In other experiments, red wine (75 mg/l gallic
acid equivalents) was incubated with plasma at 37 degrees C for 3 h. The LDL
isolated from this plasma displayed a 60% increase in lag time following copper
mediated oxidation. Uptake of this LDL by cultured J774 macrophages was three
fold lower than control LDL. Red wine was fractionated into phenolic acids
(fraction 1), catechins and monomeric anthocyanidins (fraction 2), flavonols
(fraction 3) and polymeric anthocyanidins (fraction 4). All red wine fractions
prolonged the time before LDL oxidation. Fraction 2 displayed a significantly
greater antioxidant activity than fractions 3 and 4 (but not fraction 1) in at
least one pro-oxidant model. In conclusion we have shown that antioxidant
compounds in red wine can associate with LDL particles following an incubation in
whole plasma, can exert an antioxidant effect and, in so doing, can inhibit the
uptake of the lipoprotein by macrophages. This antioxidant effect of red wine was
apparent in most of the phenolic fractions separated from wine, particularly
catechins, monomeric anthocyanidins and phenolic acids.
PMID- 9395278
TI - Lymphocytes in human atherosclerotic plaque exhibit the elastin-laminin receptor:
potential role in atherogenesis.
AB - The purpose of this immuno-histochemical study was to investigate if lymphocytes,
present in the human atherosclerotic plaque, exhibit the elastin-laminin
receptor. We showed recently that human activated lymphocytes in vitro express
this receptor. Briefly, we demonstrated by immuno-localization experiments and by
flow cytometry that this receptor is available on the cell surface of human
activated lymphocytes, free to react with ligands and show capping. The
activation of this receptor by elastin peptides triggers several cellular
reactions of biological interest as shown previously such as chemotactic movement
to an elastin peptide gradient, modulation of the biosynthesis of connective
tissue macromolecules, increase of protease synthesis and release of free
radicals (O2-., NO.) from mononuclear and endothelial cells, modifications of ion
fluxes and also increase of cell proliferation. All these processes may
contribute to the development of the atherosclerotic lesion. Two of the
previously demonstrated cell reactions mediated by the receptor could be
demonstrated also on PHA-stimulated human lymphocytes namely stimulation of cell
proliferation and increase of elastase activity. We demonstrated in the present
immuno-histological study that about 50-60% of lymphocytes of the human
atherosclerotic plaque obtained by endarterectomy express the 67 kDa subunit of
the elastin-laminin receptor confirming that the above described phenomena could
contribute to the chronicity of the lesion.
PMID- 9395280
TI - Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA
reductase inhibitor.
AB - The pyridine derivative cerivastatin is a new entirely synthetic and
enantiomerically pure inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
reductase. As a sodium salt cerivastatin is present in the active, open ring
form. Cerivastatin inhibited the membrane-bound (non-solubilized) HMG-CoA
reductase of the native microsomal fraction isolated from rat liver with a Ki
value of 1.3 x 10(-9) M. The reference compound lovastatin was 100-fold less
potent and exhibited a Ki value of 150 x 10(-9) M. Cerivastatin inhibited the
cholesterol synthesis in the human hepatoma cell line HepG2 cells with a similar
IC50 value of 1.0 x 10(-9) M. In vivo studies reflected its high in vitro
activity. In both rats and dogs, cerivastatin inhibited the hepatic
[14C]cholesterol synthesis from [14C]acetate with an oral ED50 value of 0.002
mg/kg body weight, while lovastatin exhibited an oral ED50 value of 0.3 mg/kg in
rats, showing again the ratio of 100 or more between cerivastatin and lovastatin.
In the small intestine and testes, cerivastatin was at least 50-fold less active
with oral ED50 values higher than 0.1 mg/kg, which is indicative for a high liver
selectivity of cerivastatin. In cholestyramine-primed dogs cerivastatin dose
dependently lowered the serum cholesterol concentrations by up to 59% with 0.1
mg/kg after 20 days. Interestingly, the serum triglycerides were markedly reduced
by 53 and 76% with 0.03 and 0.1 mg/kg, respectively. In normal chow fed dogs the
low density lipoprotein (LDL) concentrations were reduced by up to 75% after 0.1
mg cerivastatin/kg. The ratio of HDL/LDL increased by 81% compared with a change
of only 14% in the placebo treated control group. The antiatherogenic effect of
cerivastatin was shown in rabbits fed a diet enriched with 0.2% cholesterol.
After 9 weeks on diet 0.1 mg cerivastatin/kg decreased the accumulation of
cholesterol ester in the arterial tissue by 73%. In summary, these data as
compared to published data on other HMG-CoA reductase inhibitors demonstrate
cerivastatin to be the most active compound in this class. Vastatins used in
therapy are effective in mg doses, while cerivastatin offers a new low dose
therapy in the microg range.
PMID- 9395279
TI - Cardiovascular prognosis in relation to apolipoproteins and other lipid
parameters in patients with stable angina pectoris treated with verapamil or
metoprolol: results from the Angina Prognosis Study in Stockholm (APSIS).
AB - Relationships between apolipoproteins and other lipid parameters and
cardiovascular (CV) prognosis were evaluated in the Angina Prognosis Study In
Stockholm (APSIS). Out of 809 patients with stable angina pectoris, lipid
variables were obtained in 786 patients at baseline, and after one month's double
blind treatment with metoprolol or verapamil, to evaluate treatment effects on
these lipid variables. During a median follow-up time of 3.3 years (2663 patient
years), 37 patients suffered a CV death, 30 suffered a non-fatal myocardial
infarction (MI) and 100 underwent a revascularization. Apolipoprotein (apo) A-I,
high-density lipoprotein cholesterol and triglycerides were predictors of CV
death or non-fatal MI in univariate analyses, but only apo A-I remained as an
independent predictor in multivariate analyses. All lipid variables except low
density lipoprotein cholesterol were related to the risk of revascularization in
univariate analyses, but only apo A-I and apo B were independent predictors of
such events. Triglycerides were weakly, but not independently, associated with
prognosis. Verapamil and metoprolol had differential short-term effects on
lipids, with a shift towards a more atherogenic profile in metoprolol treated
patients. However, there was no significant impact of the treatment given, or of
these treatment effects on the risk of CV events. Results of the present study
suggest that apolipoprotein levels were better predictors of CV events than other
lipid parameters in patients with stable angina pectoris.
PMID- 9395281
TI - Ras-like GTPases.
PMID- 9395282
TI - Tales of tails: Brachyury and the T-box genes.
PMID- 9395283
TI - Regulation and function of the JNK subgroup of MAP kinases.
PMID- 9395284
TI - TGF-beta receptor signaling.
PMID- 9395285
TI - The role of the bcl-2/ced-9 gene family in cancer and general implications of
defects in cell death control for tumourigenesis and resistance to chemotherapy.
AB - Cell production within an organ is determined by the rate of immigration,
proliferation, differentiation, emigration and death of cells. Abnormalities in
any one of these processes will disturb normal control of cell production,
thereby eliciting hyperplasia can be an early event in neoplasia. Cell death,
apoptosis, is a physiological process responsible for removing unwanted cells. It
is used in multi-cellular organisms for tissue remodelling during embryogenesis,
regulation of cell turnover and as a defence strategy against invading pathogens.
In this review article we describe the role of the bcl-2/ced-9 gene family in
cancer and discuss the general implications of defects in the apoptosis program
for tumourigenesis and resistance of cancer cells to chemotherapy in light of
current knowledge of the molecular mechanisms of cell death.
PMID- 9395286
TI - Functional role for the c-Abl protein tyrosine kinase in the cellular response to
genotoxic stress.
PMID- 9395287
TI - Targeted therapy of cancer with recombinant immunotoxins.
PMID- 9395288
TI - Alzheimer's alpha-secretase may be a calcium-dependent protease.
AB - Proteolytic processing of beta-amyloid precursor protein (APP) is believed to be
fundamental to the understanding of Alzheimer's disease. The identities and the
regulatory elements of the proteases involved in the process, known as
alpha/beta/gamma secretases, are unclear. In this study, by examining reported
data, we found some indications suggesting that the putative alpha-secretase may
be a calcium-dependent protease, and that this enzyme may play a primary role in
the regulation of APP processing. Based on this, we proposed a model for the
membrane orientations of the secretases for further discussions.
PMID- 9395289
TI - Purified HrpA of Pseudomonas syringae pv. tomato DC3000 reassembles into pili.
AB - Pseudomonas syringae pv. tomato DC3000 produces Hrp pili under inducing in vitro
conditions. A preparation of partially purified extracellular filaments contains
HrpA, flagellin and some minor contaminants. HrpA was separated from the major
contaminant, the flagellin, by gel filtration to a fraction containing HrpA as
well as its three N-terminally truncated forms. These were further separated by
two steps of reversed phase chromatography. HrpA and its degradation products
were each shown to reassemble into filament structures after denaturation and
renaturation showing that HrpA alone is sufficient for formation of filament
structures.
PMID- 9395290
TI - Activation of sphingosine kinase in pheochromocytoma PC12 neuronal cells in
response to trophic factors.
AB - Nerve growth factor (NGF), basic fibroblast growth factor (bFGF), dibutyryl cAMP
and forskolin, known differentiating agents for pheochromocytoma PC12 cells,
induced sustained activation of sphingosine kinase, the enzyme responsible for
the formation of the sphingolipid second messenger, sphingosine-1-phosphate,
which mediates the mitogenic effects of certain growth factors. In contrast,
epidermal growth factor and insulin-like growth factor-1, which stimulate
proliferation of PC12 cells, induced only small and transient increases in
sphingosine kinase activity. Of the growth factors examined, NGF was the most
potent activator of sphingosine kinase, inducing a 4-fold increase in Vmax.
Sphingosine kinase activity induced by NGF, but not FGF, was blocked by the
protein kinase inhibitor K252a when added simultaneously, with minimal effect
when added after 60 min. Thus, activation of sphingosine kinase may have an
important role in neural differentiation.
PMID- 9395291
TI - Cloning of a functional vesicular GABA and glycine transporter by screening of
genome databases.
AB - The unc-47 locus of Caenorhabditis elegans has been suggested to encode a
synaptic vesicle GABA transporter. Here we used hydropathy plot analysis to
identify a candidate vesicular GABA transporter in genomic sequences derived from
a region of the physical map comprising unc-47. A mouse homologue was identified
and cloned from EST database information. In situ hybridization in rat brain
revealed codistribution with both GABAergic and glycinergic neuronal markers.
Moreover, expression in COS-7 and PC12 cells induced an intracellular, glycine
sensitive GABA uptake activity. These observations, consistent with previous data
on GABA and glycine uptake by synaptic vesicles, demonstrate that the mouse clone
encodes a vesicular inhibitory amino acid transporter.
PMID- 9395292
TI - Early expression of a beta1-adrenergic receptor and catecholamines in Xenopus
oocytes and embryos.
AB - From a Xenopus stage 11 cDNA library, we have cloned a gene, termed X-beta1AR,
whose sequence is highly homologous to that of the human beta1-adrenergic
receptor. As shown by RT-PCR assay, X-beta1AR RNA is present in the mature
oocyte, decreases after fertilization up to stage 6 and then gradually increases
during gastrulation. Binding studies performed with radiolabeled ligands reveal
that X-beta1AR RNA is translated into the receptor protein. Furthermore,
noradrenaline and adrenaline are also detected in oocytes and early embryos. The
concomitant presence of beta1-adrenergic receptors and catecholamines suggest
that this ligand-receptor couple could play a role in the very early stages of
embryonic development.
PMID- 9395293
TI - C-terminally deleted fragments of 40-kDa earthworm actin modulator still show
gelsolin activities.
AB - C- and N-terminally truncated fragments of earthworm gelsolin were constructed,
cloned and expressed in Escherichia coli. G-actin-binding properties of these
fragments and their influences on the polymeric state of actin were investigated.
A construct lacking a large part of the third segment [E(1-295)] supports actin
nucleation similar to the complete protein and shows reduced actin fragmentation
property, but is no longer Ca2+-sensitive in its activity. The first and the
second segments (E1 and E2) each contain one actin-binding site. In contrast to
human gelsolin, E1 in combination with a short N-terminal region of E2 is not
sufficient for the F-actin-severing activity of the protein.
PMID- 9395294
TI - Inhibitory effect on curcumin on mammalian phospholipase D activity.
AB - Curcumin, the major yellow pigment of turmeric (Curcuma longa), has strong anti
carcinogenic and anti-inflammatory activities. We examined the effects of
curcumin on enzyme activities of the following phospholipases in a cell-free
system: G protein-mediated phospholipase D (PLD), phosphatidylinositol-specific
phospholipase C, and phospholipase A2 from mouse macrophage-like cell line J774.1
cells, sphingomyelinase from bovine brain, and phosphatidylcholine-phospholipase
C from Bacillus cereus. Curcumin inhibited several types of phospholipases, most
effectively PLD among those tested. It also inhibited 12-O-tetradecanoylphorbol
13-acetate-induced PLD activation in intact J774.1 cells in a dose-dependent
manner. These results suggest that the anti-inflammatory and anti-carcinogenic
action of curcumin is partly due to the inhibition of PLD.
PMID- 9395295
TI - Cationic lipids destabilize lysosomal membrane in vitro.
AB - Addition of cationic lipids to plasmid DNA considerably increases the efficiency
of transfection. The mechanism has not yet been elucidated. A possibility is that
these compounds destabilize biological membranes (plasma, endosomal, lysosomal),
facilitating the transfer of nucleic molecules through these membranes. We have
investigated the problem by determining if a cationic lipid N-(1-(2,3
dioleoxy)propyl)-N,N,N,-trimethylammonium methyl-sulfate (DOTAP, Boehringer,
Mannheim, Germany) affects the integrity of rat liver lysosomal membrane. We have
measured the latency of beta-galactosidase, a lysosomal enzyme, and found that
incubation of lysosomes with low concentrations of DOTAP causes a striking
increase in free activity of the hydrolase and even a release of the enzyme into
the medium. This indicates that lysosomal membrane is deeply destabilized by the
lipid. The phenomenon depends on pH, it is less pronounced at pH 5 than at pH
7.4. Anionic compounds, particularly anionic amphipathic lipids, can to some
extent prevent this phenomenon. It can be observed with various cationic lipids.
A possible explanation is that cationic liposomes interact with anionic lipids of
lysosomal membrane, allowing a fusion between the lipid bilayers which results in
a destabilization of the organelle membrane.
PMID- 9395296
TI - Degradation of the 74 kDa form of L-histidine decarboxylase via the ubiquitin
proteasome pathway in a rat basophilic/mast cell line (RBL-2H3).
AB - L-Histidine decarboxylase (HDC) is a dimer consisting of two identical 53 kDa
subunits. On the other hand, the size of HDC deduced from its cDNA sequence is
around 74 kDa, indicating that the translated 74 kDa form of HDC is subjected to
post-translational processing to generate the 53 kDa form. However, modification
of the translated 74 kDa form of HDC in histamine-forming cells is unknown. Here
we demonstrate that the 74 kDa form is translated in rat basophilic leukemia
cells, followed by conversion to the 53 kDa form, and that the 74 kDa form is a
short half-life protein because of the degradation mediated by the ubiquitin
proteasome pathway. Degradation of the 74 kDa form was stimulated in the presence
of an ATP-generating system, accompanied by ubiquitination, and inhibited by
specific proteasome inhibitors such as ZL3H and lactacystin. A significant amount
of proteasome activity was detected in RBL-2H3 cells.
PMID- 9395297
TI - Expression of B-type endothelin receptor gene during neural development.
AB - Mutations of the B-type endothelin receptor (ETRB) gene have been found to cause
defects in the development of enteric neurons, which resulted in aganglionic
megacolon in rodents and humans. To determine the distribution of ETRB mRNA
during neural development, mainly in the CNS, in situ hybridization was applied
at various developmental stages of rat. ETRB gene was abundantly expressed
prenatally in the ventricular and subventricular zones, as well as postnatally in
the ependymal and subependymal cells. ETRB mRNA was also strongly detected
prenatally in the dorsal root ganglia, as well as postnatally in the cerebellar
Bergmann glial cells and epithelial cells of choroid plexus. Our data suggest
that ETRB acts as a regulator in the differentiation, proliferation, or migration
of neural cells during development.
PMID- 9395298
TI - Characterization of nuclear tRNA(Tyr) introns: their evolution from red algae to
higher plants.
AB - We have previously isolated numerous intron-containing nuclear tRNA(Tyr) genes
derived from either monocotyledonous (Triticum) or dicotyledonous (Arabidopsis,
Nicotiana) plants by screening the corresponding genomic phage libraries with a
synthetic tRNA(Tyr)-specific oligonucleotide. Here we have characterized
additional tRNA(Tyr) genes from phylogenetically divergent plant species
representing red algae (Champia), brown algae (Cystophyllum), green algae (Ulva),
stonewort (Chara), liverwort (Marchantia), moss (Polytrichum), fern (Rumohra) and
gymnosperms (Ginkgo) using amplification of the coding sequences from the
corresponding genomic DNAs by polymerase chain reaction (PCR). All novel
tRNA(Tyr) genes contain intervening sequences of variable sequence and length
ranging in size from 11 to 21 bp. However, two features are conserved in all
plant pre-tRNA(Tyr) introns: they possess a uridine and less frequently an
adenosine at the 5' boundary and can adopt similar intron secondary structures in
which an extended anticodon helix of 4-5 bp is formed by base-pairing between
nucleotides of the intron and the anticodon loop. In order to elucidate the
potential role of the highly conserved uridine at the first intron position, we
have replaced it by all other nucleosides in an Arabidopsis pre-tRNA(Tyr) and
have studied in wheat germ extract its effect on splicing and on conversion of U
to psi in the GpsiA anticodon. Furthermore, we discuss the putative acquisition
of tRNA(Tyr) introns at an early step of evolution after the separation of
Archaea and Eucarya.
PMID- 9395299
TI - Mutants affected in the putative diacylglycerol binding site of yeast protein
kinase C.
AB - In an attempt to study the functional similarities between protein kinase C from
the yeast Saccharomyces cerevisiae and its human homologues we have started in
vitro mutagenesis to alter specific domains. Here we report on the exchange of
four cysteine residues by serines in yeast Pkc1p that have been shown to be
essential for diacylglycerol (DAG) binding and activation by this compound in
humans. The mutant yeast protein leads to sensitivity to caffeine and low
concentrations of SDS when expressed in a pkc1 deletion strain. However,
sensitivity to staurosporine was not affected. Our data indicate that the
conserved DAG binding domain serves an important function in yeast Pkc1p.
PMID- 9395300
TI - A stable intermediate product of the archaeal zinc-containing 7Fe ferredoxin from
Sulfolobus sp. strain 7 by artificial oxidative conversion.
AB - Irreversible conversion of the purified zinc-containing 7Fe ferredoxin from the
thermoacidophilic archaeon Sulfolobus sp. strain 7 was found to occur under
aerobic conditions at pH 5.0 and at 4 degrees C. This process accompanied a
substantial increase of the electron paramagnetic resonance signal attributed to
a [3Fe-4S]1+ cluster, and the converted form containing approximately 6 Fe/Zn
(mol/mol) had a net charge different from that of the native 7Fe ferredoxin.
These data provide evidence for the formation of a stable intermediate product of
the archaeal ferredoxin having two [3Fe-4S] clusters and a zinc center by
artificial oxidative degradation. This further explains the discrepancy that a
zinc center and two [3Fe-4S] clusters (but not a zinc center and one [3Fe-4S]
cluster plus one [4Fe-4S] cluster) are observed in the crystal structure at pH
5.0.
PMID- 9395301
TI - Glycosylation of RNA polymerase II from wheat germ.
AB - RNA polymerase II from wheat germ was analyzed for the presence of sugars. The
two largest subunits and the 27 and 25 kDa subunits were found to be glycosylated
by a variety of sugars. However, no N-acetylglucosamine was detected, which was
found by Kelly et al. (J. Biol. Chem. (1993) 268, 10416-10424) in the largest
subunit of RNA polymerase II from calf thymus. Thus it appears that the
regulatory function of this sugar, postulated by Kelly et al., is performed in
the wheat germ enzyme by other monosaccharides. Carbohydrate analysis of the two
largest subunits of the calf thymus enzyme also revealed the presence, beside N
acetylglucosamine, of other sugars. Some similarities in the features of
glycosylation of the two polymerases, isolated from very different organisms,
suggest that the sugar moieties have an important role in the structure and/or
function of these enzymes.
PMID- 9395302
TI - Activated human neutrophils rapidly break down nitric oxide.
AB - Isolated human neutrophils produced no detectable (< 10 nM) nitric oxide (NO)
before or after activation with phorbol 12-myristate 13-acetate (PMA) or a
chemotactic peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine. Physiological
levels of NO (1 microM) added before or after neutrophil activation had no effect
on their respiratory burst oxygen consumption. Neutrophils activated with PMA
caused very rapid breakdown of exogenously added NO. NO breakdown rates recorded
at 250 nM NO were 0.09 +/- 0.02 and 3.77 +/- 0.23 nmol NO/min/10(6) cells (n = 3)
before and after activation respectively and addition of copper-zinc superoxide
dismutase during activation significantly decreased this rate (1.06 +/- 0.09 nmol
NO/min/10(6) cells (n = 3)), suggesting that superoxide (O2-) production was
mainly responsible for the NO breakdown. These results suggest that activation of
human neutrophils in vivo will dramatically decrease surrounding NO levels,
potentially causing vasoconstriction, platelet aggregation and adhesion and
peroxynitrite (ONOO-) formation.
PMID- 9395303
TI - Insulin-like growth factor I reverses interleukin-1beta inhibition of insulin
secretion, induction of nitric oxide synthase and cytokine-mediated apoptosis in
rat islets of Langerhans.
AB - We have previously observed that treatment of rat islets of Langerhans with
interleukin-1beta for 12 h results in nitric oxide-dependent inhibition of
insulin secretion, while 48 h treatment increased rates of islet cell death by
apoptosis. Here, we demonstrate that interleukin-1beta-mediated nitric oxide
formation and inhibition of insulin secretion are significantly reduced by 24 h
pretreatment of rat islets of Langerhans with insulin-like growth factor I (IGF
I). IGF-I decreased cytokine induction of nitric oxide synthase in islets. Use of
an arginine analogue in culture or IGF-I pretreatment of islets were also
effective in protecting islets against cytokine-mediated apoptotic cell death. We
conclude that IGF-I antagonises inhibitory and cytotoxic effects of cytokines in
rat islets.
PMID- 9395304
TI - Folding of the Fab fragment within the intact antibody.
AB - At present it is not clear to which extent the Fab fragment and the Fc part of an
antibody interact in the intact immunoglobulin structure. To determine such
potential interactions the unfolding and refolding of an isolated Fab fragment
and the respective antibody MAK 33 (kappa/IgG1) are compared. It could be shown
that the proline independent renaturation kinetics of both an unfolding
intermediate and the fully denatured form of both proteins are identical. Upon
denaturation, the loss of antigen binding activity occurs with the same rate for
both the Fab fragment and the intact antibody. However, the complete structural
unfolding of the Fab part of the antibody is significantly slower than that of
the isolated Fab fragment. These kinetic data suggest that the structure of the
Fab fragment within the intact antibody is stabilized by interactions, presumably
with the Fc part, missing in the isolated Fab.
PMID- 9395305
TI - Binding of multiple ligands to pleckstrin homology domain regulates membrane
translocation and enzyme activity of beta-adrenergic receptor kinase.
AB - Pleckstrin homology (PH) domains are discrete structural modules present in
numerous proteins involved in signal transduction processes. In the case of the
beta-adrenergic receptor kinase (betaARK), PH domain-mediated binding of two
ligands, the betagamma subunits of heterotrimeric G proteins (Gbetagamma) and
phosphatidylinositol 4,5-bisphosphate (PIP2), has been shown to be required for
the kinase function. In this study, the ability of Gbetagamma and PIP2 to affect
membrane localization of betaARK is used to define the ligand binding
characteristics of the betaARK PH domain. The binding of these ligands to the PH
domain of the intact kinase is shown to be cooperative, Gbetagamma increasing the
affinity of the PH domain for PIP2. Notably, although PIP2-dependent membrane
association of betaARK is observed at high concentrations of this lipid, in the
absence of Gbetagamma, no receptor phosphorylation is observed. Peptides derived
from the receptor intracellular loop inhibit the receptor phosphorylation without
affecting the membrane translocation of the kinase complex, suggesting that
betaARK activity does not necessarily correlate with the amount of betaARK
associated with the membrane. These results point to a distinct role for each PH
domain ligand in betaARK-mediated receptor phosphorylation. Strikingly, the
ligand binding characteristics of the isolated betaARK PH domain fused to
glutathione S-transferase are very different from those of the PH domain of the
intact kinase. Thus, in contrast to the native protein, the isolated PH domain
binds Gbetagamma and PIP2 independently and with no apparent cooperativity. That
protein environment plays an important role in determining the ligand binding
characteristics of a particular PH domain highlights the potential risks of
inferring mechanisms from studies of isolated PH domains.
PMID- 9395306
TI - Hemin and related porphyrins inhibit beta-amyloid aggregation.
AB - Porphyrins related to the naturally occurring pigment heme were found to
effectively interfere with the aggregation of beta-amyloid peptides as determined
by an immunoassay configured for the detection of beta-amyloid oligomers.
Oligomerisation of beta-amyloid is believed to be a key event in the progression
of Alzheimer's disease. Inhibition of this aggregation is thus an important
strategy in combating this commonest form of senile dementia. Evidence was also
generated for hemin and hematin mediated protection of cultured cells against the
neurotoxic effects of beta-amyloid. These data are discussed with reference to
the known pathology of Alzheimer's disease and the chemistry of porphyrins.
PMID- 9395307
TI - Identification of potential ferric binding residues in the iron-binding protein
of pathogenic Neisseria meningitidis through structure-based multiple sequence
alignments.
AB - The ferric iron-binding proteins of pathogenic Neisseria display structural and
metal-binding properties characteristic of the transferrin family. In the absence
of structural data for the ferric iron-binding proteins, spacial folding
templates have been derived for the meningococcal protein from complete and
partial structure-based multiple sequence alignments with structurally related
proteins. The templates have been used to identify a number of potential iron
binding residues. These include four residues that are identical with the iron
coordinating ligands of transferrin, but only two reside within equivalent
structural elements.
PMID- 9395308
TI - The role of tyrosine phosphorylation in proliferation and maturation of erythroid
progenitor cells--signals emanating from the erythropoietin receptor.
AB - Red blood cells arise continuously from pluripotent stem cells which mature and
become functionally specialized upon commitment to the erythroid lineage. In
mammals, the key regulator of this process is the hormone erythropoietin (EPO).
Hormone binding to the cognate receptor, the erythropoietin receptor (EPO-R),
causes receptor homodimerization and transiently triggers tyrosine
phosphorylation within target cells. Although the EPO-R lacks intrinsic enzymatic
activity it couples, presumably sequentially, to the protein tyrosine kinase
receptor c-KIT and the cytosolic protein tyrosine kinase JAK2. Signaling through
the EPO-R is promoted by tyrosine phosphorylation of the cytosolic domain and the
recruitment of secondary signaling molecules such as the lipid kinase
inositolphospholipid 3-kinase (phosphatidylinositol 3-kinase) and protein
tyrosine phosphatase SHP-2 to the activated receptor. Complex formation of the
activated EPO-R with the protein tyrosine phosphatase SHP-1 terminates signaling.
In primary fetal liver cells redundant signals emanating from phosphotyrosine
residues in the EPO-R support formation of erythroid colonies in vitro. However,
since the last tyrosine residue in the cytosolic domain of the EPO-R, Y479,
uniquely supports in the absence of other tyrosine residues an almost normal
level of colony-forming unit-erythroid (CFU-E) colony formation, Y479 represents
one of the key residues required in vivo for erythroid proliferation and
differentiation. The signal emanating from Y479 involves sequential EPO-induced
recruitment of phosphoinositol lipid 3-kinase to the EPO-R and activation of
mitogen-activated-protein(MAP)kinase activity. The MAP-kinase signaling cascade
could serve as an intracellular switch integrating signals mediated by several
phosphotyrosine residues in the cytosolic domain of the EPO-R and provide a
possible explanation for partial redundancy in signaling.
PMID- 9395309
TI - Signal transduction in fibroblasts stably transformed by [Val12]Ras--the
activities of extracellular-signal-regulated kinase and Jun N-terminal kinase are
only moderately increased, and the activity of the delta-inhibitor of c-Jun is
not alleviated.
AB - Ras-transformed cells often show high levels of expression of activating protein
1 and Ets and of genes regulated by these transcription factors. In analogy with
the effects of transient stimulation of Ras, it is assumed that the increase in
transcription-factor transactivation in stably transformed cells is due to Ras
induced constitutive activation of mitogen-activated protein kinases. However,
this has not been extensively studied. Using specific substrate peptides, we have
examined here the activities of two types of mitogen-activated protein kinase,
extracellular-signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK), in
[Val12]Ras-transformed rat embryo fibroblast cell lines. These activities were
elevated 2-3-fold in Ras-transformed cells compared with non-transformed cells
with a similar growth rate. Increased ERK activity was not necessarily
accompanied by a similar increase in JNK activity. In transformed cells, ERK and
JNK activities could be stimulated fourfold and ninefold by phorbol ester and
ultraviolet-light treatment, respectively, indicating that only a fraction of
these enzymes were constitutively activated in these cells. It has been suggested
that inactive JNK downregulates c-Jun transcriptional activity by binding to the
c-Jun delta-domain. No decrease in delta-inhibitor activity could be demonstrated
in Ras-transformed cells compared with control cells, consistent with the
presence of mainly inactive JNK in transformed cells. Treatment of transformed
cells wih benzodiazepine 5B, an inhibitor of Ras farnesylation, decreased ERK and
JNK activities, and concomitantly caused morphological reversion, reduced growth
rate, and normalization of transformation-related gene expression. We conclude
that in stably Ras-transformed cells the moderately increased ERK/JNK activities
are not coregulated, and that ERK rather than JNK activity correlated with
transformation-related gene expression.
PMID- 9395310
TI - Transport of activated fatty acids by the peroxisomal ATP-binding-cassette
transporter Pxa2 in a semi-intact yeast cell system.
AB - In the yeast Saccharomyces cerevisiae, fatty acid beta-oxidation is restricted to
peroxisomes. Previous studies have shown two possible routes by which fatty acids
enter the peroxisome. The first route involves transport of medium-chain fatty
acids across the peroxisomal membrane as free fatty acids, followed by activation
within the peroxisome by Faa2p, an acyl-CoA synthetase. The second route involves
transport of long-chain fatty acids. Long-chain fatty acids enter the peroxisome
via a route that involves activation in the extraperoxisomal space, followed by
transport across the peroxisomal membrane. It has been suggested that this
transport is dependent upon the peroxisomal ATP-binding-cassette transporters
Pxa1p and Pxa2p. In this paper we investigated whether Pxa2p is directly
responsible for the transport of C18:1-CoA, a long-chain acyl-CoA ester. Using
protoplasts in which the plasma membrane has been selectively permeabilised by
digitonin, we show that C18:1-CoA, but not C8:0-CoA, enters the peroxisome via
Pxa2p, in an ATP-dependent fashion. The results obtained may contribute to the
elucidation of the primary defect in the human disease X-linked
adrenoleukodystrophy.
PMID- 9395311
TI - Comparative stability and clearance of [Met30]transthyretin and
[Met119]transthyretin.
AB - [Met119]Transthyretin has been described as a non-amyloidogenic transthyretin
variant. In Portugal, it has also been found in compound heterozygotic individual
carriers of [Met30]transthyretin, the most prevalent variant associated with
familial amyloidotic polyneuropathy. In these individuals, the evolution of the
disease seems to be more benign than in typical [Met30]transthyretin carriers,
suggesting a protective effect of [Met119]transthyretin on the pathogenic effects
of [Met30]transthyretin. To study the mechanisms of this protective effect, we
performed comparative in vivo clearance studies. Heterotetrameric
[Met119]transthyretin showed a slower clearance, whereas homotetrameric
[Met30]transthyretin presented a faster clearance. These data correlate with the
relative TTR levels present in carriers of these mutations. Comparative analyses
of the resistance to dissociation into monomers of serum transthyretin by 4M urea
isoelectric focusing suggested a higher tetrameric stability of transthyretin in
[Met119]transthyretin carriers, in contrast to a lower stability in
[Met30]transthyretin carriers. The compound heterozygotes presented a pattern
similar to the normal individuals. Our results suggest that the protective
clinical effect of the Met119 mutation possibly involves the stabilisation of the
tetrameric structure of transthyretin. Whether this behaviour correlates with the
different metabolism found for the two variants is not known. The approaches
reported here open some possibilities for the study and development of future
therapeutic agents of familial amyloidotic polyneuropathy.
PMID- 9395312
TI - Regulation of argininosuccinate synthetase mRNA level in rat foetal hepatocytes.
AB - Expression of the hepatic gene for argininosuccinate synthase (ASS), one of the
key enzymes of the urea cycle, was analysed during the perinatal period in the
rat. To this end, the amount of specific mRNA was measured in the liver at
various stages of development and in cultured foetal hepatocytes maintained in
different hormonal conditions. The ASS mRNA was first detected in 15.5-day
foetuses and its level increased concomitantly with a rise in the enzyme
activity, suggesting that the appearance of the ASS activity reflects the turning
on of specific gene transcription. This was demonstrated by run-on assay which
showed an enhanced rate of transcription of the ASS gene during the perinatal
period. When foetal hepatocytes were cultured with dexamethasone, a dose
dependent increase in ASS mRNA was measured, which was completely abolished by
actinomycin D addition. The transcription rate of the gene was increased about
twofold in the presence of the steroid, as measured by nuclear run-on assay. This
transcriptional action could additionally require a protein factor since it could
be inhibited by the simultaneous addition of puromycin. Insulin or glucagon
respectively repressed or enhanced the dexamethasone-induced accumulation of ASS
mRNA when added simultaneously with the steroid for 24 h. This developmental
regulation of the ASS mRNA by glucocorticoids, insulin and glucagon could account
for the modulation of the enzyme activity previously observed in vivo and in
vitro in the foetal liver.
PMID- 9395313
TI - 5' sequences direct developmental expression and hormone responsiveness of
tyrosine aminotransferase in primary cultures of fetal rat hepatocytes.
AB - Tyrosine aminotransferase (TyrAT) is one of several gluconeogenic enzymes which
appear postnatally in humans and rodents in response to increased glucocorticoid
and glucagon levels and decreased insulin. Primary cultured fetal rat hepatocytes
older than day 15 of gestation (>E15) transcribe the TyrAT gene in response to
the synergistic effect of dexamethasone and N6,2'-O-dibutyryl-adenosine 3',5'
monophosphate (Bt2cAMP), whereas less mature hepatocytes (E15 hepatocytes, and not 3)-alpha-D-ManpNAc
(1-->4)-beta-D-GlcpA-(1-->3)-beta-D-Ga lp-(1-->3)-beta-D-GlcpNAc-(1-->.
PMID- 9395324
TI - The role of subunit VIII in the structural stability of the bc1 complex from
Saccharomyces cerevisiae studied using hybrid complexes.
AB - The QCR8 genes encoding subunit VIII of the bc1 complex from Kluyveromyces lactis
and Schizosaccharomyces pombe partially complement the respiratory-deficient
phenotype of a S. cerevisiae QCR8-null mutant. This implies that the heterologous
Qcr8 subunits can be imported by S. cerevisiae mitochondria and that they
assemble to form a hybrid bc1 complex that is sufficiently active to support
growth. In contrast, the QCR8 gene from bovine heart, encoding the 9.5-kDa
subunit, is not able to restore respiratory function to the S. cerevisiae null
mutant. This lack of functional complementation is directly attributable to the
inability of S. cerevisiae mitochondria to import this protein as shown by in
vitro assays. However, a hybrid gene encoding the N-terminal 26 residues of S.
cerevisiae subunit VIII and the rest of the 9.5-kDa bovine heart homologue, was
able to functionally complement the QCR8-null mutant, albeit to a very low
extent. Successful import into S. cerevisiae mitochondria was confirmed by in
vitro import experiments. Surprisingly, although assembly of these hybrid
complexes is reduced to an extent that is proportional to the evolutionary
distance of the homologue to S. cerevisiae, the specific activities of the
assembled complexes are the same as for the wild-type bc1 complex. After
solubilisation of the mitochondrial membranes with the mild detergent dodecyl
maltoside, the wild-type enzyme can be inactivated by incubation at increased
temperature, independent of protease activity. The rate of inactivation can be
significantly increased by the addition of o-phenanthroline [Boumans, H.,
Grivell, L. A. & Berden, J. A. (1997) J. Biol. Chem. 272, 16753-16760]. The
hybrid complexes are much more sensitive to both types of treatment. We conclude
that substitution of subunit VIII by a homologous counterpart results in a
loosening of the structure of the bc1 complex on the intermembrane space side,
resulting in a less stable insertion of the Rieske Fe-S protein in vivo and
therefore a lower stability of the assembled enzyme under certain in vitro
conditions, but without an effect on catalytic activity.
PMID- 9395325
TI - The Na+-translocating NADH:ubiquinone oxidoreductase from Vibrio alginolyticus-
redox states of the FAD prosthetic group and mechanism of Ag+ inhibition.
AB - The FAD prosthetic group of the Na+-motive NADH:ubiquinone oxidoreductase (Na+
NQR) from Vibrio alginolyticus was investigated by ultraviolet-visible and
fluorescence spectroscopy. The reduction of Na+-NQR by excess NADH in the
presence of 6-13 microM O2 resulted in the formation of the blue flavosemiquinone
radical. If the concentration of dioxygen was further reduced to 0.1 microM O2,
neither the reduction of Na+-NQR by NADH nor its reoxidation with ubiquinone-1 (Q
1) yielded a stable flavosemiquinone in equilibrium with reductant or oxidant,
respectively, but the fully reduced (Fl(red)H2) or oxidized flavin (Fl(ox))
prevailed. During reoxidation of Fl(red)H2 with Q-1, the intermediate formation
of an absorbance band around 800 nm was observed, which was tentatively assigned
as the Fl(red)H(-)-NAD+ charge-transfer complex. Complete reoxidation of
Fl(red)H2 in Na+-NQR was achieved by a fivefold excess of Q-1 over NADH. These
results indicated that only a small fraction of FAD was in the flavosemiquinone
redox state during turnover to mediate the electron transfer between the hydride
donor, NADH, and the one-electron acceptor [2Fe-2S]. The titration of Na+-NQR
with Ag+, a specific inhibitor, was followed by the fluorescence emission spectra
of FAD (Fl(ox)). The addition of Ag+ resulted in a marked increase of the flavin
fluorescence (16% at 200 nM Ag+), with half-maximal saturation at approximately
50 nM Ag+, indicating dissociation of FAD from the enzyme. The increase in
fluorescence intensity correlated with the loss of enzyme activity. Gel
filtration of the Ag+-treated Na+-NQR confirmed that FAD had been displaced from
the holo-enzyme.
PMID- 9395326
TI - Flavin adenine dinucleotide and flavin mononucleotide metabolism in rat liver-
the occurrence of FAD pyrophosphatase and FMN phosphohydrolase in isolated
mitochondria.
AB - In order to gain some insight into mitochondrial flavin biochemistry, rat liver
mitochondria essentially free of lysosomal and microsomal contamination were
prepared and their capability to metabolise externally added and endogenous FAD
and FMN tested both spectroscopically and via HPLC. The existence of two novel
mitochondrial enzymes, namely FAD pyrophosphatase (EC 3.6.1.18) and FMN
phosphohydrolase (EC 3.1.3.2), which catalyse FAD-->FMN and FMN-->riboflavin
conversion, respectively, is shown. They differ from each other and from
extramitochondrial enzymes, as judged by their pH profile and inhibitor
sensitivity, and can be separated in a partial FAD pyrophosphatase purification.
Digitonin titration and subfractionation experiments show that FAD
pyrophosphatase is located in the outer mitochondrial membrane and FMN
phosphohydrolase in the intermembrane space. Since these enzymes can metabolise
endogenous FAD and FMN, which are made available by using both Triton X-100 and
the effector oxaloacetate, a proposal is made that FAD pyrophosphatase and FMN
phosphohydrolase play a major role in mitochondrial flavoprotein turnover.
PMID- 9395327
TI - Purification and characterization of tilapia (Oreochromis mossambicus)
deoxyribonuclease I--primary structure and cDNA sequence.
AB - DNase I of tilapia (Oreochromis mossambicus) was purified to homogeneity. Tilapia
DNase I is most active at pH 8.5 with Mg2+ as activator. The Ca2+/Mg2+ pair has a
synergistic effect on activation. The enzyme is readily inactivated by heating
above 55 degrees C, but is not inactivated by trypsin or 2-mercaptoethanol under
alkaline conditions, with or without CaCl2. Its isoelectric point is 6.0. The 258
amino-acid sequence of tilapia DNase I was derived from overlapping sequences of
tryptic, chymotryptic and CNBr peptides. The purified enzyme has two variants
differing by a single Lys-->Arg mutation at position 125. The polypeptide chain
has one disulfide bridge and one carbohydrate side chain. By mass spectrometry,
the purified enzyme shows many molecular mass forms differing by Lys/Arg
substitution and sugar-chain length. The major form has a molecular mass of
30,914 Da. A 1061-bp nucleotide sequence for the cDNA of tilapia DNase I,
obtained by gene cloning and DNA sequencing, contains an ORF coding for a
putative 26-residue transmembrane peptide and the mature DNase I polypeptide.
PMID- 9395328
TI - Interleukin-3 activates Syk in a human myeloblastic leukemia cell line, AML193.
AB - Protein-tyrosine kinases and phosphatases play an important role in cytokine
mediated cell growth. The proliferation of a human myeloid leukemia cell line,
AML193, is dependent on interleukin-3 (IL-3) or granulocyte colony-stimulating
factor. In the current study, we demonstrated that a non-receptor-type protein
tyrosine kinase, Syk, was immediately activated by the stimulation with IL-3 or
granulocyte colony-stimulating factor in AML193 cells. We further investigated
the relation of Syk with IL-3-mediated signaling and found that the IL-3 receptor
beta subunit was immunoprecipitated with Syk. Since the IL-3 receptor beta
subunit is known to mediate growth signaling, our results indicate that Syk may
be involved in the proliferation of myeloid cells.
PMID- 9395329
TI - Change in the mode of gene expression of the hypopharyngeal gland cells with an
age-dependent role change of the worker honeybee Apis mellifera L.
AB - Major proteins synthesized in the hypopharyngeal gland of the worker honeybee
change from bee-milk proteins to alpha-glucosidase in accordance with the age
dependent role change of the worker bee. Previously, we showed that the gene for
alpha-glucosidase is expressed specifically in the forager-bee gland [Ohashi, K.,
Sawata, M., Takeuchi, H., Natori, S. & Kubo, T. (1996) Biochem. Biophys. Res.
Commun. 221, 380-385]. Here, we describe the isolation and analysis of cDNAs for
two bee-milk 56-kDa and 64-kDa proteins. The 56-kDa protein was a glycoprotein
which shared 63.2% and 56.9% amino acid sequence identities with proteins encoded
by cDNA for royal-jelly-related protein 57-1 (pRJP57-1) and pRJP57-2. The 64-kDa
protein cDNA was identical to pRJP57-1. Thus, these bee-milk proteins seem to
form a structurally related protein family. The gene for the 64-kDa protein/RJP57
1 was expressed specifically in the nurse-bee gland, whereas that for the 56-kDa
protein was expressed in both the nurse-bee and forager-bee glands. mRNAs for the
56-kDa and 64-kDa proteins were detected by in situ hybridization in a whole
acinus of the nurse-bee gland, whereas mRNAs for the 56-kDa protein and alpha
glucosidase were detected in that of the forager-bee gland. Therefore, the
individual secretory cells of the acinus of the hypopharyngeal gland were shown
to express these genes differently with the age-dependent role change of the
worker bee.
PMID- 9395330
TI - Human endothelin receptors ET(A) and ET(B) expressed in baculovirus-infected
insect cells--direct application for signal transduction analysis.
AB - We expressed human endothelin receptors, ET(A) and ET(B), in insect Sf9 cells
infected by recombinant baculoviruses that contained the respective cDNAs. Ligand
binding experiments showed that the two expressed receptors have the same
affinities as observed for the receptors in mammalian cells, i.e. the ET(A)
receptor showed an affinity order of ET-1 > or = ET-2 >> ET-3, and the ET(B)
receptor remained nonselective for three isopeptide ligands. The ET(B) receptor
was purified by affinity chromatography with K9-biotinyl-ET-1 without losing the
ligand-binding activity from the membrane of infected Sf9 cells. Protein chemical
analysis of the purified ET(B) receptor showed that it is glycosylated, and that
the N-terminal 38-amino-acid peptide is susceptible to proteolytic digestion,
resulting in a small 35-kDa receptor like that found in the human placenta.
Surprisingly, the infected and unlysed cells showed a strong intracellular Ca2+
concentration increase ([Ca2+]i), which was generated by a unique signal
transduction pathway consisting of the insect GTP-binding protein and human
endothelin receptors expressed in the late phase of virus infection. Due mainly
to an efficient expression (over 200,000 receptors/cell), to a low background
owing to no endogenous homolog receptor in insect Sf9 cells, and to a sensitive
fluorescent reagent Fura-2, this insect Sf9 cell system can detect the [Ca2+]i
induced by picomolar levels of endothelin-receptor. We propose that this highly
sensitive system be used to screen for potential antagonists/agonists of
endothelin receptors.
PMID- 9395331
TI - Effects of brefeldin A on phosphatidylcholine phospholipase D and
inositolphospholipid metabolism in HL-60 cells.
AB - The involvement of the small GTP-binding protein ADP-ribosylation factor (ARF) in
guanosine 5'-[gamma-thio]triphosphate (GTP[S])-dependent activation of
phospholipase D (PLD) in HL-60 cells has been well established in vitro. In this
study, we tested the effect of brefeldin A, which prevents ARF activation by
inhibiting guanine-nucleotide-exchange activity, on PLD stimulation by receptor
agonists (formyl-Met-Leu-Phe and ATP) and by the phorbol ester phorbol 12
myristate 13-acetate (PMA) in differentiated HL-60 cells. However, brefeldin A
did not affect the activation of PLD at a time (1 h) when it eliminated the
activity of the trans-Golgi enzyme galactosyltransferase. It also did not inhibit
PLD activity in Golgi-enriched membranes treated with GTP[S] with or without ARF
in vitro. However, longer times of brefeldin A treatment (>6 h), progressively
and completely inhibited the activation of PLD by formyl-Met-Leu-Phe and partly
inhibited (approximately 50%) the activation by PMA. In contrast, long-term
brefeldin A treatment did not inhibit the effect of GTP[S] on PLD in
permeabilized HL-60 cells. Long-term brefeldin A treatment completely inhibited
inositol phosphate production in response to formyl-Met-Leu-Phe and ATP,
indicating that it affected inositolphospholipid-specific phospholipase C
activity. These data indicate that the rapid inhibitory effect of brefeldin A on
Golgi function is not associated with inhibition of receptor-mediated or PMA
mediated PLD activation in HL-60 cells. However, longer-term effects, presumably
arising from the disruption of the Golgi, lead to a total inhibition of agonist
activation of PLD and inositolphospholipid-specific phospholipase C. In summary,
these results do not support a role for brefeldin-A-sensitive ARF in agonist
regulation of PLD in HL-60 cells.
PMID- 9395332
TI - Characterization, gene cloning and expression of isocitrate lyase involved in the
assimilation of one-carbon compounds in Hyphomicrobium methylovorum GM2.
AB - Isocitrate lyase of an obligate methylotrophic bacterium, Hyphomicrobium
methylovorum GM2, was purified to homogeneity and characterized. The enzyme is a
homotetramer of identical 62-kDa subunits. After the enzyme had been incubated at
temperatures up to 25 degrees C for 30 min, no loss of activity was observed. The
enzyme was stable in the pH range of 7.5-9.0. Maximum activity was observed at pH
7.5 and around 45 degrees C. The Km value for Ds-isocitrate was 0.51 mM. The
activity required Mg2+ and was inhibited by oxalate, succinate and glycolate. The
gene encoding the isocitrate lyase and its flanking regions were isolated from H.
methylovorum GM2. Nucleotide sequencing of recombinant plasmids revealed that the
isocitrate lyase gene codes for a 540-amino-acid protein. The amino acid sequence
of the enzyme is similar to those of the enzymes from Escherichia coli (40%
identity) and cucumber (37% identity). The recombinant plasmid, which was
constructed by ligation of the cloned gene and an expression vector, pKK223-3,
was introduced into E. coli HB101. The transformed E. coli cells expressed
isocitrate lyase, which was indistinguishable from the purified H. methylovorum
GM2 isocitrate lyase on analysis by SDS/PAGE.
PMID- 9395333
TI - Neuronal cell nuclear factor--a nuclear receptor possibly involved in the control
of neurogenesis and neuronal differentiation.
AB - We have cloned from a cDNA library of neuronal derivatives of retinoic-acid
induced embryonic carcinoma cells a nuclear receptor that may be involved in the
control of late neurogenesis and early neuronal differentiation. The receptor
which is practically identical in sequence with germ cell nuclear factor, has
been designated neuronal cell nuclear factor (NCNF). NCNF is exclusively
expressed in the neuronal derivatives of PCC7-Mz1 cells, with the expression
beginning within hours of exposure to retinoic acid. In the developing mouse
brain, NCNF is expressed in the marginal zones of the neuroepithelium which are
known to contain young postmitotic neurons. NCNF binds to the DR0 sequence
thereby silencing transcription. Because NCNF does not recognize hormone response
elements of other nuclear receptors tested and does not heterodimerize with
these, it probably binds exclusively as a homodimer. NCNF may induce neuronal
differentiation by repressing the activity of genes that permit cell fates other
than the neuronal one.
PMID- 9395334
TI - Characterization and evolution of a gene encoding a Trimeresurus flavoviridis
serum protein that inhibits basic phospholipase A2 isozymes in the snake's venom.
AB - The proteins that bind phospholipase A2 (PLA2) isozymes of Trimeresurus
flavoviridis (habu snake, crotalinae) venom were fractionated from sera on four
columns, each conjugated with one of four PLA2 isozymes. Five proteins, termed
PLA2 inhibitors (PLI) I-V, were obtained as the binding components. The
combinations of the binding components differed depending on the PLA2 isozymes.
PLI-IV and PLI-V correspond to PLI-A and PLI-B, respectively, which were known to
bind to a major [Asp49]PLA2, PLA2, and contained a segment similar to the
carbohydrate-recognition domain of C-type lectins. PLI-I, which is a major
component of inhibitory proteins against three basic PLA2 isozymes, PLA-B (a
basic [Asp49]PLA2) and basic proteins I and II (both [Lys49]PLA2s), has been
isolated, and its partial amino acid sequence has been determined. A cDNA
encoding PLI-I was isolated from a T. flavoviridis liver cDNA library and
sequenced. PLI-I cDNA encoded 200 amino acid residues, including a signal peptide
of 19 amino acid residues. One sugar chain was predicted to occur at position
157. A gene coding for PLI-I was isolated. It is 9.6-kb long and consists of five
exons and four introns. Comparison of the exon-intron structure of the PLI-I gene
with those of genes encoding urokinase-type-plasminogen-activator receptor
(uPAR), Ly-6, CD59 and neurotoxins showed that they have characteristic unit
encoding approximately 90 amino acid residues, which is divided over two exons.
This strongly suggests that the PLI-I gene belongs to the uPAR, Ly-6, CD59 and
neurotoxin gene family. There are two types of structurally different inhibitors
against PLA2 isozymes in T. flavoviridis serum with different evolutionary
origins.
PMID- 9395335
TI - Inhibitory guanine-nucleotide-binding-regulatory protein alpha subunits in medaka
(Oryzias latipes) oocytes--cDNA cloning and decreased expression of proteins
during oocyte maturation.
AB - We have previously shown that pertussis-toxin-sensitive inhibitory guanine
nucleotide-binding-regulatory proteins (G proteins) are involved in the signal
transduction of steroidal maturation-inducing hormone (MIH) of rainbow trout
(Oncorhynchus mykiss) oocytes, 17alpha,20beta-dihydroxy-4-pregnen-3-one
(17alpha,20beta-DP) [Yoshikuni, M. & Nagahama, Y. (1994) Dev. Biol. 166, 615
622]. In this study, we obtained five different cDNA fragments of G protein alpha
subunits from medaka (Oryzias latipes) intact ovarian follicles (three subtypes
of G(i alpha), G(i alpha a), G(i alpha b) and G(i alpha c); two subtypes of G(s
alpha), G(s alpha d), and G(s alpha e)). Using a newly developed extraction
method for medaka oocyte RNA, we demonstrated that oocytes expressed both G(i
alpha a) and G(i alpha c), but not G(i alpha b). Full-length cDNA clones for G(i
alpha a) and G(i alpha c) were then isolated from a medaka ovarian follicle cDNA
library. The predicted amino acid sequences of G(i alpha a) and G(i alpha c)
exhibited significant similarity with G(i alpha1) and G(i alpha2) of other
species, respectively. Both G(i alpha a) and G(i alpha c) possessed a specific
Cys residue in the C-terminal region that was the site for ADP-ribosylation by
pertussis toxin. G(o alpha), another G protein that is ADP-ribosylated by
pertussis toxin, was not detected in oocytes, although it was expressed in brain
tissue. Western blot analyses using a specific antibody against G(i alpha1) and
G(i alpha2) subunit proteins revealed that in both medaka and rainbow trout G(i
alpha) subunit protein (40 kDa) contents were abundant in plasma membranes of
postvitellogenic immature oocytes, decreased in mature oocytes, and were absent
in ovulated eggs. Furthermore, specific 17alpha,20beta-DP binding to plasma
membranes was higher in postvitellogenic immature oocytes than in ovulated eggs.
Taken together, these results suggest that G(i alpha a) and/or G(i alpha c) may
be involved in the transduction of the signal from 17alpha,20beta-DP receptors
during oocyte maturation of fish oocytes.
PMID- 9395336
TI - Isolation and characterization of goldfish Y box protein, a germ-cell-specific
RNA-binding protein.
AB - Cyclin B is a regulatory subunit of maturation-promoting factor. In goldfish
(Carassius auratus) oocytes, cyclin B is synthesized de novo after stimulation by
17alpha,20beta-dihydroxy-4-pregnen-3-one (maturation-inducing hormone). In this
study, we examined goldfish oocyte proteins bound to cyclin B mRNA. Using
oligo(dT)-cellulose affinity chromatography and northwestern blotting analysis,
we identified a 54-kDa cyclin B mRNA-binding protein (p54). Southwestern blotting
analysis showed the binding of p54 to the Y box DNA element (CTGATTGGCCAA),
suggesting that p54 is a Y box protein in goldfish. We isolated two cDNA clones,
GFYP1 and GFYP2, the latter of which encodes a germ-cell-specific Y box protein.
An antibody against a GFYP2 protein recognized p54, suggesting that p54 is
identical or highly similar to GFYP2 protein. This is also supported by the
finding that a recombinant GFYP2 expressed in bacteria bound to both the Y box
DNA element and the goldfish cyclin B mRNA synthesized in vitro. These results
suggest that p54 is a germ-cell-specific Y box protein and is a potential masking
protein of cyclin B mRNA in goldfish oocytes.
PMID- 9395337
TI - Supramolecular assemblies from lysosomal matrix proteins and complex lipids.
AB - Most lysosomal hydrolases are soluble enzymes. Lamp-II (lysosome-associated
membrane protein-II) is a major constituent of the lysosomal membrane. We studied
the aggregation of a series of lysosomal molecules. The aggregation-sensitive
lysosomal marker enzymes were optimally aggregated at intralysosomal pH. A
similar pH dependence was recorded for aggregation of Lamp-II. The pH-dependent
loss of solubility of isolated Lamp-II required components of the lysosome
extract. Conditions of mild acid pH promoting aggregation triggered the formation
of complexes with lipids of lysosomal origin. We fractionated a membrane-free
lysosome extract by gel-filtration chromatography and could reconstitute
assemblies in vitro from separated fractions. We found some selectivity in the
lysosomal proteins binding to complex lipids, phosphatidylcholine, sphingomyelin,
and phosphatidylethanolamine being most effective. We propose that the formation
at pH 5.0 of such supramolecular assemblies between lysosomal proteins and lipids
occurs within the intralysosomal environment. Some possible consequences of such
an intralysosomal matrix formation on organelle function are discussed.
PMID- 9395338
TI - Analysis of the complex formed by Erythrina variegata chymotrypsin inhibitor with
chymotrypsin and properties of the peptides prepared from the inhibitor by a
limited proteolysis.
AB - The stoichiometry of Erythrina variegata chymotrypsin inhibitor (ECI) and
chymotrypsin interaction was previously estimated to be 1:2 by a titration of
inhibitory activity. In the present study, gel-permeation chromatography and
reverse-phase HPLC (RP-HPLC) were employed to analyze the complex formed by the
inhibitor and enzyme. The results showed that ECI and chymotrypsin molecules
undergo aggregation in the complex-forming buffer simultaneously with a binary
complex consisting of one ECI and one chymotrypsin molecules in a soluble form. A
mild lysylendopeptidase digestion of ECI produced two peptides in high yield,
which were separated by RP-HPLC and characterized in terms of their structures
and inhibitory activities. The N-terminal peptide, ECI-(1-107)-peptide,
containing the primary reactive site retained a slight inhibitory activity, while
the C-terminal peptide, ECI-(108-179)-peptide, exhibited no inhibitory activity.
The inhibitory potency of the ECI-(1-107)-peptide was enhanced by the presence of
the ECI-(108-179)-peptide in reconstituted mixture. Recovery of the native-like
structure of the reconstituted complex was further indicated by fluorescence
spectra, which showed strong conformational interaction between the two peptides;
their dissociation constant Kd was calculated to be 209 nM. Taken together with
the previous result obtained by chymotryptic digestion, it is suggested that the
primary binding loop in ECI interacts with chymotrypsin not only by a standard
mechanism but also by a non-substrate-like manner. Alternatively, ECI might have
an additional binding segment in the N-terminal region which interacts with
chymotrypsin by a non-substrate-like manner. Further, it is shown that the C
terminal region may support the native conformation of the binding loop(s) in the
N-terminal region as an intramolecular chaperone.
PMID- 9395339
TI - Comparative study of chicken and human parathyroid hormone-(1-34)-peptides in
solution with SDS.
AB - Molecular conformations of chicken [cPTH-(1-34)] and human [hPTH-(1-34)]
parathyroid hormone fragments in aqueous solutions with various concentrations of
SDS were investigated by CD, fluorescence and NMR spectroscopy techniques. In the
presence of SDS, chicken and human PTH-(1-34) adopt an a-helical structure making
up 32-38% of all the peptide amino acids. The process of the a-helical formation
of these two fragments is considerably different. The CD spectral change of hPTH
(1-34) was characteristic of a monotonous increase in the negative peak at 222 nm
with increasing SDS concentrations. However, for cPTH-(1-34) a beta-turn is
formed first, followed by alpha-helix formation upon an increase in SDS
concentrations. The change of the tryptophan fluorescence spectra of cPTH-(1-34)
is well correlated with the changes in CD spectra, suggesting that the side chain
of Trp23 is involved in the conformational change from random coil to alpha-helix
via beta-turn. The three-dimensional structure of cPTH-(1-34) with SDS micelle
was elucidated by 1H-NMR at pH 3.8 and 300 K, with the combined use of distance
geometry and restrained molecular dynamics calculations. NMR results indicated
that it contains two helices encompassing residues 7-12 and 24-30, respectively.
The C-terminal helix in the residue range of 24-30 is amphiphilic, which is
stabilized by the hydrophobic interactions among Trp23, Leu24 and Lys27.
PMID- 9395340
TI - Biochemical and immunological characterization of recombinant allergen Lol p 1.
AB - Pollen from perennial rye grass (Lolium perenne), a major cause of type-I allergy
worldwide, contains a complex mixture of allergenic proteins among which Lol p 1
is one of the most important. We describe the expression, purification and
characterization of a recombinant Lol p 1 overproduced in Escherichia coli. The
recombinant allergen, expressed in high yields and purified in milligram amounts,
bound to specific IgE antibodies from human sera, induced histamine release from
sensitized human basophils, and elicited rabbit antisera that recognize
specifically recombinant Lol p 1 and natural Lol p 1 of pollen extract.
Recombinant Lol p 1 was used to develop ImmunoCAP assays for analysis of 150 sera
that were Radioallergosorbent test positive to L. perenne pollen. In 130 of them
(87%) the assay detected a significant level of IgE antibodies to Lol p 1,
reaching on average 37% of the level obtained with a test for IgE to the whole
grass pollen extract. To map epitopes on Lol p 1, we produced three deletion
mutants [des-(116-240)-Lol p 1, des-(1-88)-Lol p 1 and des-(133-189)-Lol p 1],
which were efficiently expressed in bacteria. These all showed a strong
reactivity with the specific rabbit IgG antibodies, but lacked most or all the
allergenic properties of recombinant Lol p 1. A study of the antigenic structure
of Lol p 1 was performed using the three deletion mutants and a set of 17-18
residue overlapping synthetic peptides covering the whole allergen sequence. The
results indicate that human IgE and rabbit IgG antibodies bind to distinct
regions of Lol p 1, and that at least some important IgE epitopes are mainly
conformational. The findings suggest that recombinant allergens constitute useful
reagents for further development of serological diagnosis of allergy, and that it
should be possible to produce immunogenic fragments of allergenic proteins
without allergenic properties.
PMID- 9395341
TI - Structural properties of chimeric peptides containing a T-cell epitope linked to
a fusion peptide and their importance for in vivo induction of cytotoxic T-cell
responses.
AB - We have previously shown that when administered to mice without adjuvant, a
chimeric peptide consisting of the fusion peptide F from measles virus protein
linked at the C-terminus of a cytotoxic T-cell epitope from the M2 protein of
respiratory syncytial virus efficiently primes for an major histocompatibility
complex (MHC) class-I restricted cytotoxic T lymphocyte (CTL) response. In this
report, we demonstrated by microspectrofluorometry that the fusion-peptide moiety
bound to the plasma membrane of living cells. When the fusion peptide was linked
to the C-terminus of the CTL epitope, the chimeric peptide (M2-F) adopted a
marked beta-sheet conformation. In contrast, when the fusion peptide was linked
to the N-terminus of the T-cell epitope (F-M2), the chimeric peptide adopted an
alpha-helical conformation in the presence of trifluoroethanol. The
immunogenicity of the two chimeric peptides for class-I restricted CTL was also
significantly different, the one adopting the alpha-helical conformation being
more immunogenic. Probably due to its obvious conversion to an alpha-helical
conformation, the F-M2 peptide could have a higher propensity to insert into
membranes, as shown by microspectrofluorometry, with a resultant better
immunogenicity than the M2-F peptide.
PMID- 9395342
TI - The cell wall polymer of the extremely halophilic archaeon Natronococcus
occultus.
AB - The cell wall polymer of Natronococcus occultus (DSM 3396) consists of L
glutamate, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-galacturonic acid,
D-glucuronic acid and D-glucose in a molar ratio of 5:7:1:8:0.5:0.3. Partial acid
hydrolysis of the cell wall polymer produced soluble fragments that could be
separated by HPLC. A gamma-glutamyl dipeptide was isolated. In the intact cell
wall polymer, the glutamate residues form a poly-(gamma-glutamine) chain with a
length of about 60 monomers, which corresponds to a relative molecular mass of
approximately 7700 Da. Two other soluble dimeric fragments, composed of glutamate
and either glucosamine or galactosamine in a molar ratio of 1:1, were purified
from the hydrolysate, suggesting the presence of two different oligosaccharides
linked to the poly-(gamma-glutamine) chain of the intact polymer. The analysis of
additional fragments, which were composed of an amino sugar and galacturonic acid
or glucose indicated that one oligosaccharide consisted of a glucosamine pentamer
in an alpha-1,3 linkage at the reducing end and an oligomer with at least five
beta-1,4-linked galacturonic acid residues at the non-reducing end. The second
oligosaccharide was comprised of a galactosamine dimer in a beta-1,3 linkage at
the reducing end and a maltose unit at the non-reducing end. Both
oligosaccharides were linked to the alpha-amide group of the glutamine residues
of the poly-(gamma-glutamine) chain. The whole cell wall polymer, which
represents a novel type of natural glycoconjugate, has a relative molecular mass
of 54 kDa.
PMID- 9395343
TI - Overlay versus underlay tympanoplasty. Part I: historical review of the
literature.
AB - The history of otology is the history of the successful treatment of infections
of the middle ear and the eardrum. Otologists have sought to restore hearing lost
to infections of the eardrum since the 1600s. The development of instruments,
techniques, and materials to treat infection is fascinating because of the
serendipitous nature of the discoveries and the insight of the discoverers. This
historical review describes the history of the treatment of infections of the ear
and the development of modern techniques of ear surgery. Two contemporary methods
of tympanic membrane repair are then described.
PMID- 9395344
TI - Overlay versus underlay tympanoplasty. Part II: the study.
AB - This report compares two contemporary techniques of tympanic membrane repair. The
prospective comparison study included 712 cases over 9 years. Whether the
tympanic membrane was repaired by an underlay or an overlay technique, results
were reliable. By making a postauricular incision, greater visibility of the
operative site can be obtained. Larger perforations can be closed more reliably
when greater exposure is obtained. The placement of the graft above or below the
annulus is not the issue. Careful technique and precise work are the keys to
successful tympanoplasty. Thus otologic surgeons should cultivate effective
techniques, attempting to continuously improve their results to achieve
perfection.
PMID- 9395345
TI - Factors influencing the relapse of patients with inflammatory bowel disease.
AB - The management of relapse of inflammatory bowel disease (IBD) remains a clinical
challenge and a relatively neglected area of current research. Many factors
contribute to relapse, and the proper identification of the cause of each case
may influence optimal management. Often, relapse is related to the failure of
maintenance therapy. Mesalamine sensitivity is difficult to recognize and should
be considered when increased doses are associated with the worsening of symptoms.
An increase in eosinophil activity could explain seasonal relapses of IBD as a
result of exposure to allergens, but other eosinophil activation pathways also
will influence the course of IBD. Infection, either enteric or systemic, may
trigger a relapse by activating the gastrointestinal mucosal immune system.
Nonsteroidal anti-inflammatory drug use is a well-recognized cause of
exacerbation of disease. Smoking status is emerging as a complex factor in IBD,
and a change in smoking status may influence the course of IBD.
PMID- 9395346
TI - Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases.
AB - The inflammatory bowel diseases (IBDs) are characterized by intestinal
inflammation of unknown etiology. Two distinct disorders, Crohn's disease and
ulcerative colitis, have been identified. Three theories of IBD etiology are
currently under consideration: 1) reaction to a persistent intestinal infection,
2) existence of a defective mucosal barrier to luminal antigens, and 3) a
dysregulated host immune response to ubiquitous antigens. In each of these
theories, either pathogenic or resident luminal bacteria constantly stimulate the
mucosal and systemic immune systems to perpetuate the inflammatory cascade.
Chronicity of inflammation results from an interaction of the persistent stimulus
of microbial antigens with genetically determined host susceptibility factors
that determine the individual's immune response or mucosal barrier function. The
pathogenesis of IBD involves a series of steps, beginning with the breach of the
intestinal mucosal barrier by infectious agents or toxins. The defective barrier
exposes lamina propria immune cells to the continual presence of resident luminal
bacteria, bacterial products, or dietary antigens, which perpetuates the
inflammatory cascade. Many immunoregulatory abnormalities are noted in IBD,
including the ratio of proinflammatory to immunosuppressive cytokines, selective
activation of T(H) lymphocyte subsets, and abnormalities in epithelial antigen
presentation. When activated during the initial inflammatory process, macrophages
and T lymphocytes secrete a host of cytokines, which recruit other inflammatory
cell types, thereby continuing the process. Tissue injury is the net result of
the soluble products of the activated inflammatory cells. Knowledge of the
pathogenesis in IBD suggests that the ultimate goals of therapy should be to
block the proinflammatory mediators toward the proximal, rather than the distal,
end of the cascade, to decrease the constant antigenic drive of luminal bacteria,
and to correct the dysregulated immune response.
PMID- 9395347
TI - Optimizing therapy for inflammatory bowel disease.
AB - This review focuses on current developments in the major categories of therapy
used in the management of inflammatory bowel disease (IBD). Conventional
corticosteroids, although a mainstay of the acute treatment of IBD for many
years, have many drawbacks, including a variety of side effects--particularly
with chronic use. Budesonide appears to be relatively safe and at least
moderately effective in inducing remission in active distal ulcerative colitis
(UC) and Crohn's disease. Aminosalicylates, both oral and topical, have proven
useful in managing mild-to-moderate active UC and mild active Crohn's disease, as
well as in maintaining remission. Data from recent trials suggest that higher
doses of mesalamine are generally more efficacious than lower doses. In addition,
a combination of oral and rectal formulations may succeed when one route, alone,
is not successful. The immunomodulatory agents azathioprine, 6-mercaptopurine,
and methotrexate have been shown to be effective in the treatment of IBD and are
now widely accepted as valuable parts of the therapeutic armamentarium.
Cyclosporine, although effective, is associated with many toxicities, and
patients must be monitored closely in centers experienced with this agent.
Clinical trials of IL-10, IL-11, and anti-TNFalpha have also shown promise.
Antibiotics have been used empirically for many years in the treatment of IBD.
Larger clinical trials are warranted to explore the potential efficacy of
antibiotic therapy. This has been accomplished with metronidazole in Crohn's
disease, and other antibiotic trials are underway at this time. The
investigational agents acemannan, heparin, and transdermal nicotine have also
shown variable degrees of promise as possible therapies for IBD. Despite the
variety of agents available for the treatment of IBD, none is ideal or
universally accepted. Ongoing research into the well-established therapeutic
agents, as well as novel drugs with more precise targets, may contribute to the
design of a more nearly optimal regimen for IBD in the not-too-distant future.
PMID- 9395348
TI - Quality of life issues in patients with inflammatory bowel disease.
AB - The assessment of health-related quality of life (HRQOL) plays an increasingly
important role in the evaluation of therapeutic interventions in various chronic
diseases, including inflammatory bowel disease (IBD). There are three main types
of HRQOL instruments, each of which have specific strengths and limitations.
Global assessments provide a general impression of the patient's HRQOL, but they
do not identify specific domains of dysfunction. Generic instruments can be used
to show similarities or differences among groups or populations, but they may not
be sensitive to changes over time or after treatment in groups of patients with
specific diseases. Disease-specific instruments, which are derived from and
validated in particular disease groups, are the most sensitive indicators of
change in HRQOL over time or with treatment. There are several potential sources
of bias in HRQOL measurement, and certain instruments are more or less sensitive
and reliable than others in detecting impaired function in patients with IBD.
Despite differences between studies regarding specific HRQOL findings, as a
group, these assessments confirm that HRQOL can be impaired significantly in
patients with IBD. Reliable validated HRQOL instruments should be applied with
the same methodological rigor as other assessments in clinical trials of
different therapeutic strategies for patients with IBD.
PMID- 9395350
TI - Pediatric hospitalizations for croup (laryngotracheobronchitis): biennial
increases associated with human parainfluenza virus 1 epidemics.
AB - Croup is a common manifestation of respiratory tract infection in children, and
human parainfluenza virus 1 (HPIV-1) is the agent most commonly associated with
croup. In the United States, HPIV-1 produces a distinctive pattern of biennial
epidemics of respiratory illness during the autumn months of odd-numbered years.
National Hospital Discharge Survey data for croup hospitalizations among patients
<15 years old between 1979 and 1993 were examined along with laboratory-based
surveillance data on HPIV-1 activity in the United States. The mean annual number
of croup hospitalizations was 41,000 (range, 27,000-62,000/year). Ninety-one
percent of hospitalizations occurred among children <5 years of age. Minor peaks
in croup hospitalizations occurred each year in February, and major peaks
occurred in October of odd-numbered years, coincident with peak HPIV-1 activity.
Each biennial epidemic of HPIV-1 was associated with 18,000 excess croup
hospitalizations nationwide.
PMID- 9395349
TI - Effects of the neuraminidase inhibitor zanamavir on otologic manifestations of
experimental human influenza.
AB - Middle ear pressure (MEP) abnormalities are frequently observed during influenza
virus infection and may serve as surrogate markers for the risk of otitis media.
MEP abnormalities were evaluated in adult volunteers who were inoculated with
influenza A/Texas/36/91(H1N1) or B/Yamagata/88 virus and given the antiviral
zanamivir (GG167) intranasally as prophylaxis or early treatment in randomized,
double-blind, placebo-controlled trials. In the influenza A prophylaxis studies,
15% of 61 zanamivir recipients versus 61% of 33 placebo recipients showed
significant MEP abnormalities (P < .01). In the influenza A early treatment
trial, 32% of 31 infected zanamivir recipients versus 73% of 26 infected placebo
recipients developed MEP abnormalities (P < .01). In the influenza B prophylaxis
trial, 16% of 25 zanamivir versus 44% of 9 placebo recipients showed
abnormalities (P = .09). These findings indicate that the neuraminidase inhibitor
zanamivir, which is effective in reducing experimental influenza illness,
provides protection against the development of MEP abnormalities.
PMID- 9395351
TI - Evaluation of two live, cold-passaged, temperature-sensitive respiratory
syncytial virus vaccines in chimpanzees and in human adults, infants, and
children.
AB - Two live-attenuated, cold-passaged (cp), temperature-sensitive (ts) candidate
vaccines, designated cpts530/1009 and cpts248/955, were attenuated, genetically
stable, and immunogenic in chimpanzees and were highly attenuated for human
adults. In respiratory syncytial virus (RSV)-seropositive children, cpts530/1009
was more restricted in replication than cpts248/955. In seronegative children,
10(4) pfu of cpts248/955 was insufficiently attenuated, and a high titer of
vaccine virus was shed (mean peak titer, 10(4.4) pfu/mL), whereas 10(4) pfu of
cpts530/1009 was relatively attenuated and restricted in replication (mean peak
titer, 10(2.0) pfu/mL). At a dose of 10(5) pfu, cpts530/1009 was immunogenic in
seronegative children (geometric mean titer of RSV neutralizing antibodies,
1:724). Transmission of either vaccine to seronegative placebo recipients
occurred at a frequency of 20%-25%. Of importance, vaccine viruses recovered from
chimpanzees and humans were ts. In contrast to previous studies, this study
indicates that live attenuated RSV vaccines that are immunogenic and
phenotypically stable can be developed. Additional studies are being conducted to
identify a live RSV vaccine that is slightly more attenuated and less
transmissible than cpts530/1009.
PMID- 9395352
TI - Adverse effects of maternal enterovirus infection on the fetus and placenta.
AB - Gestational outcome in a murine model of congenital enterovirus infection was
evaluated. Pregnant mice were inoculated intravenously with Theiler's murine
encephalomyelitis virus (TMEV), a murine enterovirus, or with BHK 21 cell lysate
(control) at 6-7 days of gestation (early) and sacrificed 6 or 12 days later, and
their placentas and fetuses were studied. High rates of gross and histologic
abnormalities (50%-87%) were seen in placentas and fetuses from dams infected
with TMEV and sacrificed 6 days later. TMEV-infected dams sacrificed 12 days
after inoculation had lower rates of placental-fetal abnormalities (25%-57%) but
an additional 42% rate of complete pregnancy loss. Pregnancy loss (9%) and
placental-fetal abnormalities (4%-7%) were uncommon in control animals. Rates of
fetal abnormalities and placental infection in infected dams exceeded fetal viral
infection, suggesting that TMEV infection adversely affects pregnancy either
directly by fetal damage or indirectly by placental compromise.
PMID- 9395354
TI - Anti-interleukin-10 antibodies in patients with chronic active Epstein-Barr virus
infection.
AB - The Epstein-Barr virus (EBV) genome encodes a protein in its BamHI C restriction
fragment rightward open-reading frame-1 (designated BCRF1 or viral interleukin-10
[vIL-10]) that shares protein homology and biologic properties with human IL-10.
Several EBV disorders are characterized by prolonged active EBV infection.
Because continued EBV replication could allow for increased vIL-10, ELISA and
immunoprecipitation were used to determine whether vIL-10 expression during
chronic active EBV infection resulted in vIL-10 and IL-10 antibodies. IL-10
antibodies were assayed in patients diagnosed with chronic and acute infectious
mononucleosis (CIM, AIM), nasopharyngeal carcinoma (NPC), and EBV-associated
lymphoproliferative disease (LPD), as well as from healthy organ transplant
patients and EBV-negative or EBV-positive persons. Whether anti-IL-10 antibodies
could inhibit IL-10 biologic activity was determined. vIL-10 antibodies were
found in CIM, NPC, and LPD patients and antibodies reactive to IL-10 were found
in CIM patients. One CIM patient had IL-10 antibodies that neutralized IL-10
bioactivity in vitro.
PMID- 9395353
TI - Recombinant bacille Calmette-Guerin expressing the measles virus nucleoprotein
protects infant rhesus macaques from measles virus pneumonia.
AB - Measles virus infection continues to be a major cause of infant mortality. There
is a need for a measles vaccine that can be administered at birth in the presence
of maternal neutralizing antibody. Infant rhesus monkeys were immunized with
recombinant bacille Calmette-Guerin expressing the full-length measles virus
nucleoprotein (BCG-N) and subsequently challenged with measles virus.
Nucleoprotein-specific lymphocyte proliferative responses were detected in the
absence of anti-N antibody after vaccination. Vaccination with BCG-N did not
prevent systemic measles virus infection; however, there was a significant
reduction of lung inflammation after challenge. Virus titers in lymph nodes were
significantly lower, and the duration of nasopharyngeal viral shedding was
shorter in some vaccinated monkeys after challenge. These results suggest that
measles virus-specific T cells were primed by BCG-N vaccination and that they
prevented virus-induced lung pathology.
PMID- 9395355
TI - Posttransplant lymphoproliferative disease in primary Epstein-Barr virus
infection after liver transplantation: the role of cytomegalovirus disease.
AB - Epstein-Barr virus (EBV) plays a major role in the pathogenesis of posttransplant
lymphoproliferative disease (PTLD). Patients who undergo primary EBV infection
after transplantation are at greater risk of developing PTLD. In this
retrospective study, the incidence of EBV infection and associated PTLD in 40
consecutive adult recipients who were seronegative for EBV at the time of liver
transplantation were investigated, and risk factors for PTLD were analyzed. Of 37
patients with available timely posttransplant serum samples, 35 (95%) developed
primary EBV infection. Of the 40 patients, 13 (33%) developed PTLD a median of
126 days (range, 48-776) after liver transplantation. The factor significantly
associated with the development of PTLD was cytomegalovirus disease (relative
risk, 7.3; 95% confidence interval, 2.36-22.6; P = .0006). Cytomegalovirus
disease is a predictor for the development of PTLD in primary EBV infection after
liver transplantation, and it may be a target for prophylactic intervention.
PMID- 9395356
TI - Increased prevalence of infectious diseases and other adverse outcomes in human T
lymphotropic virus types I- and II-infected blood donors. Retrovirus Epidemiology
Donor Study (REDS) Study Group.
AB - Disease associations of human T lymphotropic virus types I and II (HTLV-I and
II) infection were studied in 154 HTLV-I-infected, 387 HTLV-II-infected, and 799
uninfected blood donors. Adjusted odds ratios (ORs) and 99% confidence intervals
(CIs) were derived from logistic regression models controlling for demographics
and relevant confounders. All subjects were human immunodeficiency virus type 1
seronegative. HTLV-II was significantly associated with a history of pneumonia
(OR, 2.6; 99% CI, 1.2-5.3), minor fungal infection (OR, 2.9; 99% CI, 1.2-7.1),
and bladder or kidney infection (OR, 1.6; 99% CI, 1.0-2.5) within the past 5
years and with a lifetime history of tuberculosis (OR, 3.9; 99% CI, 1.3-11.6) and
arthritis (OR, 1.8; 99% CI, 1.2-2.9). Lymphadenopathy (> or =1 cm) was associated
with both HTLV-I (OR, 6.6; 99% CI, 2.2-19.2) and HTLV-II (OR, 2.8; 99% CI, 1.1
7.1) infection, although no case of adult T cell leukemia/lymphoma was diagnosed.
Urinary urgency and gait disturbance were associated with both viruses. This new
finding of increased prevalence of a variety of infections in HTLV-II-positive
donors suggests immunologic impairment.
PMID- 9395358
TI - Interrelationships among quantity of human cytomegalovirus (HCMV) DNA in blood,
donor-recipient serostatus, and administration of methylprednisolone as risk
factors for HCMV disease following liver transplantation.
AB - Longitudinal analysis of 162 liver transplant recipients identified 51 patients
who were viremic. Virus load was determined in 47 of these patients using
quantitative-competitive polymerase chain reaction. Peak virus load was
significantly higher in 20 symptomatic patients than 27 asymptomatic patients (P
< .0001). Elevated virus load, donor seropositivity, and total methylprednisolone
dosage were risk factors for human cytomegalovirus (HCMV) disease (odds ratio
[OR], 2.22/0.25 log10 increase in virus load, P = .001; OR, 4.11, P = .05; OR,
1.30/1-g increment in methylprednisolone, P = .01). Methylprednisolone and virus
load were independent risk factors in a multivariate analysis (OR, 2.70/1-g
increase, P = .003; OR, 1.61/0.25 log10 increase, P = .03, respectively). Virus
loads of 10(4.75)-10(5.25) genomes/mL of blood were associated with an increased
disease probability; the latter was shifted to lower virus loads with increasing
quantities of methylprednisolone. These data illustrate the central role of virus
load in HCMV pathogenesis.
PMID- 9395357
TI - Distinguishing baboon cytomegalovirus from human cytomegalovirus: importance for
xenotransplantation.
AB - The severe shortage of human organs for transplantation is the driving force
behind xenotransplant research. Nonhuman primates, particularly baboons, are
potential sources of organs and tissues. Human cytomegalovirus (HCMV) is the most
common donor-associated infection after allotransplantation. Baboon
cytomegalovirus (BCMV) is endemic in baboon populations and therefore is a
potential cause of donor-associated disease after xenotransplantation.
Accordingly, the ability for BCMV to grow in human cells was determined and a
sensitive method to distinguish BCMV from HCMV was developed. Human fibroblasts
were permissive for BCMV, isolates exhibited cytopathology characteristic of
HCMV, and herpesvirus-like virions were observed by electron microscopy. BCMV and
HCMV could be distinguished by restriction fragment length polymorphism patterns
and by polymerase chain reaction with primers targeting the BCMV major immediate
early gene promoter. These methods can be used to evaluate BCMV pathogenicity in
laboratory and clinical xenotransplant trials.
PMID- 9395359
TI - Hepatitis G virus infection in American patients with cryptogenic cirrhosis: no
evidence for liver replication.
AB - It is unclear whether hepatitis G virus (HGV) can lead to chronic liver disease
and cirrhosis. Eighty-nine patients with end-stage liver disease undergoing liver
transplantation were studied: 50 were diagnosed as having cryptogenic cirrhosis
while 39 had nonviral chronic liver disease. Five (10%) in the former and 1
(2.6%) in the latter group (not significantly different) were positive for HGV
RNA in serum. All 6 HGV-infected patients were negative for the presence of the
HGV RNA minus strand in the liver when tested with a strand-specific Tth-based
reverse transcription-polymerase chain reaction, and 5 were positive for the
presence of the plus strand, albeit at low levels. This implies that the liver is
not the primary replication site for HGV, at least in a significant proportion of
patients. Absence of liver replication explains the reported lack of association
between HGV infection and liver pathology encountered in many clinical settings.
PMID- 9395360
TI - Varicella-zoster virus infection in children with underlying human
immunodeficiency virus infection.
AB - This article describes a prospective longitudinal study of varicella-zoster virus
(VZV) infections in human immunodeficiency virus (HIV)-infected children,
designed to determine their natural history of VZV infection and possible effects
of VZV on the progression of HIV infection. Varicella was usually not a serious
acute problem, and it did not seem to precede clinical deterioration. The rate of
zoster was high: 70% in children with low levels of CD4+ lymphocytes at the time
of development of varicella. It is predicted that immunization with live
attenuated varicella vaccine is unlikely to be deleterious to HIV-infected
children. Moreover, if they are immunized when they still have relatively normal
levels of CD4+ lymphocytes, they may have a lower rate of reactivation of VZV
than if they were allowed to develop natural varicella when their CD4+ cell
counts have fallen to low levels as a result of progressive HIV infection.
PMID- 9395361
TI - DNA vaccination as anti-human immunodeficiency virus immunotherapy in infected
chimpanzees.
AB - The role of the immune response in controlling human immunodeficiency virus type
1 (HIV-1) replication is controversial. Immunotherapeutic strategies that have
the ability to broaden immune responses might play a role in slowing disease
progression. DNA immunization was studied as immunotherapy in infected
chimpanzees. Two HIV-1-infected chimpanzees were vaccinated with DNA plasmid
vaccines, one with plasmid pCMN160, which expresses the envelope glycoprotein of
HIV-1MN and rev, and the other with a control plasmid. The chimpanzee immunized
with pCMN160 demonstrated enhanced humoral responses. Virus load was monitored.
Virus load in the chimpanzee receiving pCMN160 decreased at week 20 and has
remained at background levels. The control chimpanzee was subsequently vaccinated
with pCMN160. After immunization, the antibody responses increased and, as in the
first animal, the virus load decreased. These results indicate the potential of
the immune response to have a direct impact on HIV-1 replication in chimpanzees.
PMID- 9395362
TI - Human immunodeficiency virus infection impairs hemopoiesis in long-term bone
marrow cultures: nonreversal by nucleoside analogues.
AB - Hematologic abnormalities are often seen in patients infected with human
immunodeficiency virus (HIV). The effect of HIV infection of bone marrow stroma
on support of uninfected CD34 progenitor cells in long-term bone marrow culture
(LTBMC) was investigated. Results show that HIV-infected bone marrow stroma was
unable to adequately support CD34 progenitor cells in vitro. Zidovudine or
didanosine was added to cultures in an attempt to reverse the suppressive effects
exerted by HIV and to determine whether such suppression was mediated by transfer
of HIV infection to progenitor cells. Didanosine failed to reduce the suppressive
effects of HIV, whereas zidovudine compounded the observed suppression. HIV
infection of bone marrow stroma, while reducing the production of nonadherent
cells, did not increase apoptosis and cell death in such cells. In contrast,
zidovudine enhanced apoptosis and cell death in nonadherent cells produced by
both HIV-infected and control LTBMC.
PMID- 9395363
TI - The safety and efficacy of adefovir dipivoxil, a novel anti-human
immunodeficiency virus (HIV) therapy, in HIV-infected adults: a randomized,
double-blind, placebo-controlled trial.
AB - Adefovir dipivoxil is a novel nucleotide analogue with several promising in vitro
anti-human immunodeficiency virus (HIV) characteristics. To evaluate the safety
and efficacy of adefovir dipivoxil monotherapy, a randomized, double-blind,
placebo-controlled study was initiated involving 72 subjects with moderately
advanced HIV disease. Subjects were randomly assigned in a 2:1 ratio to receive
adefovir dipivoxil or placebo as a once-daily oral dose for 6 weeks, followed by
6 weeks of open-label adefovir dipivoxil. Two dose levels were studied (125 mg
and 250 mg). Adefovir dipivoxil was determined to be safe and well-tolerated when
administered for 12 weeks. At week 6, changes in absolute CD4 T cell levels and
HIV-1 RNA levels were significantly greater with adefovir dipivoxil than with
placebo. These effects were sustained through 12 weeks of treatment. As
determined by standard RNA sequencing techniques, only 1 of the 24 subjects who
received adefovir dipivoxil (125 mg/day) developed any genotypic change from
baseline.
PMID- 9395364
TI - Severe disease in children with trachoma is associated with persistent Chlamydia
trachomatis infection.
AB - The immediate study objective was to determine if variable disease severity in
children with trachoma could be attributable in part to host variation in the
ability to clear Chlamydia trachomatis infection. Identification of sibling
cohorts with these variant phenotypes would be useful for immunogenetic studies.
A weekly survey for 3 months in a trachoma-hyperendemic village using detection
of chlamydial DNA and grading of disease severity indicated that 62% (33/53) of
children had at least one infection episode. Of those, 64% (21/33) who were
persistently infected had both significantly higher mean chlamydial DNA loads and
more severe trachoma than did sporadically infected children. Of importance,
duration of infection differed between siblings in 60% (6/10) of families. The
results suggest that chlamydial load and duration of infection determine the
chronic nature of severe disease in trachoma and that host variable efficiency
for chlamydial clearance between siblings is in part determined by host
variation.
PMID- 9395365
TI - Delta-toxin from Staphylococcus aureus as a costimulator of human neutrophil
oxidative burst.
AB - Delta-toxin from Staphylococcus aureus is responsible for various
pathophysiologic effects. By studying different cell types in binding of delta
toxin in low, noncytotoxic concentrations, a specific binding of fluorescein
labeled delta-toxin to neutrophils and monocytes was found. Studying direct
effects of delta-toxin on neutrophils, a dose-dependent up-regulation of
complement receptor 3 expression was found. Oxygen radical production, as
determined by Luminol-enhanced chemiluminescence, was not directly induced by
delta-toxin, and this toxin was also unable to prime neutrophils for an enhanced
response to FMLP or complement-opsonized zymosan. However, the priming response
induced by lipopolysaccharide or tumor necrosis factor-alpha (TNF-alpha) was
significantly further enhanced in the presence of delta-toxin. Furthermore, as a
direct effect on human monocytes, delta-toxin induced TNF-alpha production. These
data provide evidence that delta-toxin has direct and indirect effects on the
activity of neutrophils and monocytes with regard to its proinflammatory
capacity.
PMID- 9395366
TI - Predicting bacteremia in patients with sepsis syndrome. Academic Medical Center
Consortium Sepsis Project Working Group.
AB - The goal of this study was to develop and validate clinical prediction rules for
bacteremia and subtypes of bacteremia in patients with sepsis syndrome. Thus, a
prospective cohort study, including a stratified random sample of 1342 episodes
of sepsis syndrome, was done in eight academic tertiary care hospitals. The
derivation set included 881 episodes, and the validation set included 461. Main
outcome measures were bacteremia caused by any organism, gram-negative rods, gram
positive cocci, and fungal bloodstream infection. The spread in probability
between low- and high-risk groups in the derivation sets was from 14.5% to 60.6%
for bacteremia of any type, from 9.8% to 32.8% for gram-positive bacteremia, from
5.3% to 41.9% for gram-negative bacteremia, and from 0.6% to 26.1% for fungemia.
Because the model for gram-positive bacteremia performed poorly, a model
predicting Staphylococcus aureus bacteremia was developed; it performed better,
with a low- to high-risk spread of from 2.6% to 21.0%. The prediction models
allow stratification of patients according to risk of bloodstream infections;
their clinical utility remains to be demonstrated.
PMID- 9395367
TI - Inhibition of virulent Mycobacterium tuberculosis by Bcg(r) and Bcg(s)
macrophages correlates with nitric oxide production.
AB - The Nramp1 gene controls macrophage resistance or susceptibility to several
intracellular microorganisms; however, there is conflicting evidence regarding
its role during infection with virulent Mycobacterium tuberculosis. Nitric oxide
(NO) is a potent antimycobacterial agent produced by macrophages, which is also
regulated by Nramp1. The in vitro ability of B10R (resistant) and B10S
(susceptible) murine macrophages to inhibit M. tuberculosis H37Rv and to produce
NO in response to infection and interferon-gamma (IFN-gamma) was compared.
Infected B10R macrophages inhibited [3H]uracil incorporation by M. tuberculosis
and produced higher amounts of NO than did B10S macrophages. IFN-gamma increased
the inhibitory activity of both cells. Inhibition of M. tuberculosis by IFN-gamma
activated B10R macrophages was reversed by N(G)-monomethyl-L-arginine (N(G)MMA).
L-arginine restored NO production and increased the antimycobacterial activity by
IFN-gamma-stimulated N(G)MMA-treated macrophages. The Bcg/Nramp1 gene may
regulate macrophage resistance or susceptibility to virulent M. tuberculosis by a
differential capability of these cells to produce NO.
PMID- 9395368
TI - Infection of swine with Mycobacterium bovis as a model of human tuberculosis.
AB - Swine were infected with Mycobacterium bovis to develop a model for pulmonary and
disseminated tuberculosis in humans. Pigs were inoculated with various doses of
M. bovis by intravenous (i.v.), intratracheal (int), or tonsillar routes. Animals
were euthanized between 17 and 60 days after inoculation, and tissues were
collected for culture and histopathologic examination. Lesions of disseminated
tuberculosis were found in pigs given 10(4) or 10(8) cfu of M. bovis i.v. or int;
localized pulmonary disease was found in pigs given 10(2) or 10(3) cfu of M.
bovis int. Lesions ranged from well-organized tubercles with coagulative
necrosis, epithelioid macrophages, and fibrosis to large expansive tubercles with
liquefactive necrosis and extracellular growth of M. bovis. Tuberculous
meningitis was observed in animals given M. bovis i.v. Swine infected with M.
bovis are a useful animal model for elucidating the mechanisms of pathogenesis
and host defense to tuberculosis in humans.
PMID- 9395370
TI - Aspergillus fumigatus conidia induce a Th1-type cytokine response.
AB - The response of human peripheral blood mononuclear cells (MNC) to Aspergillus
fumigatus in vitro was evaluated. In studies of the proliferative response of MNC
from 18 healthy donors to heat-killed A. fumigatus conidia, 15 displayed a
significant response, with a stimulation index (SI) between 4 and 193. In
contrast, all donors displayed a positive response to Candida albicans
blastoconidia (SI ranged from 10 to 224). Despite the variability in reactivity
to A. fumigatus conidia, the response of a particular individual was stable when
retested over periods of 1-2 weeks. Supernatant from cocultures of A. fumigatus
conidia with MNC contained increased levels of interferon-gamma, granulocyte
macrophage colony-stimulating factor, tumor necrosis factor-alpha, and
interleukin (IL)-2, compared with unstimulated cells, but not IL-10 or IL-4. In
addition, A. fumigatus induced lymphocyte surface expression of
adhesion/activation-associated molecules. These results suggest that lymphocytes
may contribute to host defense against Aspergillus by generating a Th1-type
response.
PMID- 9395369
TI - Mechanisms and target sites of damage in killing of Candida albicans hyphae by
human polymorphonuclear neutrophils.
AB - Target sites of fungal cell damage were studied to define mechanisms of
neutrophil-mediated killing of Candida albicans hyphae. Neutrophils induced
hyphal cell wall damage, as evidenced by release of cell wall glycoproteins and
confocal microscopic changes. Damage occurred in the presence of neutrophil
granule extracts and did not require oxidants. However, oxidation of hyphal
surface glycoproteins correlated strongly with parallel increments in fungicidal
activity, suggesting that oxidants did contribute to maximal cell wall damage.
Neutrophil oxidants also induced hyphal DNA fragmentation, primarily single
strand breakage, as shown by increased electrophoretic migration after nuclease
S1 DNA digestion at single-strand break sites. The onset of damage to hyphal cell
walls and DNA preceded detectable neutrophil-mediated fungicidal effects.
Likewise, hyphal amino acid and nucleotide turnover as well as ATP initially
rose, then declined as lethal effects became detectable. Thus, preceding
detectable fungal cell death, neutrophil oxidative and oxygen-independent
mechanisms damaged defined targets.
PMID- 9395371
TI - Pathologic and clinical findings in patients with cyclosporiasis and a
description of intracellular parasite life-cycle stages.
AB - Cyclospora cayetanensis has been observed in the feces of persons with prolonged
diarrhea. A description of the symptoms and histopathologic findings for patients
with cyclosporiasis is presented. The intracellular life-cycle stages of these
parasites in the enterocytes of patients will also be described. Seventeen
Peruvian patients positive for Cyclospora organisms were surveyed and underwent
endoscopy, and their symptoms were recorded. Patients presented with
gastrointestinal symptoms, including diarrhea, flatulence, weight loss, abdominal
discomfort, and nausea. Jejunal biopsies showed an altered mucosal architecture
with shortening and widening of the intestinal villi due to diffuse edema and
infiltration by a mixed inflammatory cell infiltrate. There was reactive
hyperemia with vascular dilatation and congestion of villous capillaries.
Parasitophorous vacuoles contained sexual and asexual forms. Type I and II
meronts, with 8-12 and 4 fully differentiated merozoites, respectively, were
found at the luminal end of epithelial cells. These findings demonstrate the
complete developmental cycle associated with host changes due to Cyclospora
organisms.
PMID- 9395373
TI - Fibronectin-derived fragments as inducers of adhesion and chemotaxis of Entamoeba
histolytica trophozoites.
AB - Active migration of Entamoeba histolytica trophozoites through extracellular
matrixes might play a role in host tissue destruction. Trophozoites degrade
soluble fibronectin (FN) bound to their surface and adhere to substrate-bound FN,
producing local degradation. FN proteolytic fragments were used to determine the
nature of adhesion and motility-promoting domains within the protein. The 70-kDa
fragment (amino-terminal end) promoted the highest adhesion, followed by the 120
kDa fragment, which contains the cell-binding domain. The 25-kDa fragment
(carboxy-terminal end of the A chain) promoted half the adhesion, while two Hep
II-binding fragments had no effect. The 70- and 120-kDa fragments also stimulated
directed migration and chemokinesis. Intact FN and the 25-kDa fragment showed
lower stimulation. The Hep II-binding fragments had no activity. Results support
previous evidence for distinct cell-surface components as mediators of adhesion
to FN and trophozoite motility and the potential importance of cell matrix
recognition and degradation in their invasive behavior.
PMID- 9395372
TI - Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate
synthase and epidemiologic patterns of pyrimethamine-sulfadoxine use and
resistance.
AB - To assess the relationship between mutations in Plasmodium falciparum
dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) and clinical
pyrimethamine-sulfadoxine resistance, polymerase chain reaction surveys and
analyses for new mutations were conducted in four countries with increasing
levels of pyrimethamine-sulfadoxine resistance: Mali, Kenya, Malawi, and Bolivia.
Prevalence of mutations at DHFR codon 108 and a new mutation at DHPS 540
correlated with increased pyrimethamine-sulfadoxine resistance (P < .05).
Mutations at DHFR 51, DHFR 59, and DHPS 437 correlated with resistance without
achieving statistical significance. Mutations at DHFR 164 and DHPS 581 were
common in Bolivia, where pyrimethamine-sulfadoxine resistance is widespread, but
absent in African sites. Two new DHFR mutations, a point mutation at codon 50 and
an insert at codon 30, were found only in Bolivia. DHFR and DHPS mutations occur
in a progressive, stepwise fashion. Identification of specific sets of mutations
causing in vivo drug failure may lead to the development of molecular
surveillance methods for pyrimethamine-sulfadoxine resistance.
PMID- 9395374
TI - Review: JC virus infection of lymphocytes--revisited.
AB - JC virus (JCV), the causative agent of the fatal human demyelinating disease
progressive multifocal leukoencephalopathy (PML), is an opportunistic papovavirus
that infects and destroys oligodendrocytes, the myelin-producing cells of the
central nervous system. Since its isolation from the brain of a PML patient, JCV
has long been classed as a neurotropic virus. Many studies, however, have
demonstrated that JCV can infect various other cell types, including immune
system cells. Moreover, several recent studies have focused specifically on
lymphocytes as a target of JCV. This review chronicles the association of JCV
with lymphocytes, including cell type localization, molecular regulation, and
viral sequences, and discusses clinical implications of these findings.
PMID- 9395375
TI - Hepatitis A virus infections in urban children--are preventive opportunities
being missed?
AB - To determine the prevalence of hepatitis A virus (HAV) infections in children in
a large urban center, a point prevalence survey was conducted using a novel,
ultrasensitive assay for HAV-specific IgG in saliva. A structured sample of 224
grade-six students (5.8% of grade registrants) was obtained from 23 schools
throughout Vancouver. All students provided saliva samples adequate for testing.
The anti-HAV prevalence rate was 7.1% (95% confidence interval, 4.1%-11.3%).
Among 167 Canadian-born students, only 5 (3%) were positive, whereas among 57
students born elsewhere, 11 (19.3%) were positive (P < .001), with circumstances
in the latter group supporting infection prior to emigration. No clustering of
positive persons was evident. The cumulative risk of HAV infection in Canadian
born children was low through age 11-12 years even in less affluent parts of the
city, speaking against a need for routine use of HAV vaccine in this setting.
PMID- 9395376
TI - High rate of hepatitis C virus clearance in hemodialysis patients after
interferon-alpha therapy.
AB - To gain insight into the long-term effect of interferon-alpha (IFN-alpha) therapy
on hepatitis C virus (HCV) RNA-positive hemodialysis patients, 23 subjects were
given 3 MU of IFN-alpha 3 times a week for 6 (n = 12) or 12 months (n = 11). They
were followed for 19 months after cessation of therapy. Sustained serum HCV RNA
clearance occurred in 42% of patients treated for 6 months and in 64% of those
treated for 12 months. HCV was eradicated from 6 of 13 patients infected with HCV
genotype 1b and from 2 of 6 patients also infected with hepatitis G virus. HCV
RNA remained undetectable in both serum and a liver biopsy of 2 patients who were
given cadaveric kidney transplants after IFN-alpha treatment. These data suggest
that HCV RNA-positive dialysis patients can be considered for treatment while
receiving dialysis, particularly those awaiting transplant.
PMID- 9395377
TI - Investigation of human urine for genomic sequences of the primate polyomaviruses
simian virus 40, BK virus, and JC virus.
AB - Recent reports of the detection of simian virus 40 (SV40) nucleotide sequences in
ependymomas, choroid plexus tumors, osteosarcomas, and mesotheliomas have raised
the possibility that SV40, which naturally infects Asian macaques, is circulating
among humans. This possibility was examined by performing polymerase chain
reaction assays on urine samples of 166 homosexual men, 88 of them human
immunodeficiency virus (HIV)-seropositive, for genomic sequences of SV40 as well
as of human polyomaviruses BK virus (BKV) and JC virus (JCV). Tests with masked
urine specimens spiked with SV40-transformed cells were included to monitor the
SV40 assay. SV40, BKV, and JCV sequences were identified, respectively, in 0,
14%, and 34% of the urine specimens. JCV viruria was far more common (37%) than
BKV viruria (5%) in HIV-seronegative persons. HIV infection and more severe
immunosuppression were associated with a higher frequency of BKV viruria. In
summary, SV40 viruria was not detected among homosexual men who shed human
polyomaviruses at a high frequency.
PMID- 9395378
TI - Plasma levels of monocyte chemoattractant protein-1 but not those of macrophage
inhibitory protein-1alpha and RANTES correlate with virus load in human
immunodeficiency virus infection.
AB - Plasma levels of proinflammatory cytokines, cytokine inhibitors, and the beta
chemokines RANTES, macrophage inhibitory protein (MIP)-1alpha, and monocyte
chemoattractant protein (MCP)-1 were studied in relationship with virus load in
40 patients exhibiting plasma levels of HIV RNA ranging between undetectable and
levels >10(6) copies/mL. Mean plasma levels of MCP-1 were increased in patients
with high virus load compared with HIV-seropositive subjects with undetectable
plasma viral RNA and healthy controls. MCP-1 levels were directly correlated with
plasma levels of HIV RNA. No correlation was observed between virus load and
plasma concentrations of MIP-1alpha and RANTES. The results suggest that low
rates of viral replication in vivo are not dependent on increased production of
the suppressive chemokines RANTES and MIP-1alpha. Since MCP-1 upregulates viral
replication in vitro, the results may suggest a role for MCP-1 in triggering
viral replication in HIV disease.
PMID- 9395379
TI - An outbreak of foodborne illness caused by Escherichia coli O39:NM, an agent not
fitting into the existing scheme for classifying diarrheogenic E. coli.
AB - An outbreak of gastrointestinal illness with clinical and epidemiologic features
of enterotoxigenic Escherichia coli (ETEC) occurred among patrons of a restaurant
during April 1991. Illnesses among several groups of patrons were characterized
by diarrhea (100%) and cramps (79%-88%) lasting a median of 3-5 days. Median
incubation periods ranged from 50 to 56 h. A nonmotile strain of E. coli (E. coli
O39), which was negative for heat-labile (LT) and heat-stable (STa, STb) ETEC
toxins, was isolated only from ill patrons. This organism produced
enteroaggregative E. coli heat-stable enterotoxin 1 and contained the
enteropathogenic E. coli gene locus for enterocyte effacement; it did not display
mannose-resistant adherence, but produced attaching and effacing lesions in the
absence of mannose on cultured HEp-2 cells. E. coli that are not part of highly
characterized but narrowly defined groups may be important causes of foodborne
illness.
PMID- 9395381
TI - Cytokine profiles in cerebrospinal fluid of human immunodeficiency virus-infected
patients with cryptococcal meningitis: no leukocytosis despite high interleukin-8
levels. University of Zimbabwe Meningitis Group.
AB - Cytokine levels were studied in the cerebrospinal fluid (CSF) of 16 adults with
cryptococcal meningitis (CM). Low levels of tumor necrosis factor (TNF)-alpha and
interferon-gamma, high levels of interleukin (IL)-1beta, IL-6, and IL-8, and the
presence of IL-10 were documented. There were no significant differences in
levels of TNF-alpha and interferon-gamma for CM and control patients. Mean CSF
levels of IL-1beta (139.5 pg/mL), IL-6 (346 pg/mL), IL-8 (1160 pg/mL), and IL-10
(9.27 pg/mL) were significantly (P < .01) elevated in CM patients compared with
levels in control patients. Despite the high CSF levels of IL-8, minimal
leukocytosis was seen. Significant correlations between cryptococcal antigen
titers and IL-10 levels (r = .8, P < .05), protein and cryptococcal antigen titer
(r = .9, P < .05), and protein and IL-10 levels (r = .8, P < .05) were found.
PMID- 9395380
TI - Presence of human immunodeficiency virus (HIV) type 1 subtype A infection in a
New York community with high HIV prevalence: a sentinel site for monitoring HIV
genetic diversity in North America. Centers for Disease Control and Prevention
Bronx Lebanon HIV Serosurvey Team.
AB - To determine whether US residents are infected with subtypes of human
immunodeficiency virus (HIV) type 1 other than subtype B (Western), the
predominant North American subtype with a unique GPGR genetic sequence in the V3
loop, viruses from 22 HIV-infected adults were serotyped and subtyped. Twenty
patients had subtype B (Western), of whom 15 had serotype B (Western), 3 had
serotype A/C, 1 had serotype B (Thai), and 1 had a nontypeable serotype. Two had
subtype A, both serotype A/C. Both subtype A-infected patients, only 1 of whom
had been outside the United States, reported sex with persons traveling abroad,
suggesting possible acquisition in the United States. Because US residents are
infected with non-subtype B (Western) strains, US surveillance for HIV-1
diversity is needed to elucidate subtype-specific transmission patterns and
pathogenesis and to guide evaluation and development of HIV diagnostic tests and
vaccines.
PMID- 9395382
TI - Staphylococcus aureus stimulates urokinase-type plasminogen activator expression
by bovine mammary cells.
AB - Staphylococcus aureus commonly causes bovine mastitis, but bovine strains, unlike
human isolates of S. aureus, do not produce the bacterial plasminogen activator,
staphylokinase. By use of bovine mammary epithelial and myoepithelial cell lines,
it was found that bovine S. aureus M60 and its culture filtrates induce a 3- to
10-fold increase in urokinase-type plasminogen activator activity in mammary cell
conditioned media and cellular lysates. Furthermore, transcytosis of S. aureus
M60 across a mammary epithelial cell monolayer was significantly enhanced by the
addition of bovine plasminogen and inhibited by aprotinin. These findings provide
evidence that S. aureus M60 can trigger superactivation of host plasminogen
activator production and may then utilize the plasminogen activator-plasmin(ogen)
system to facilitate tissue invasion without producing staphylokinase.
PMID- 9395383
TI - Risk for gastric lymphoma in persons with CagA+ and CagA- Helicobacter pylori
infection.
AB - Infection with Helicobacter pylori increases the risk for gastric non-Hodgkin's
lymphoma (GNHL). Strains that express CagA protein are thought to be particularly
virulent. It was determined whether CagA+ H. pylori infection increased the risk
for GNHL more than CagA infection. Thirty-two cases and 130 controls previously
tested for H. pylori antibodies were tested for CagA antibodies by ELISA. The
risk for GNHL was compared among CagA+, CagA-, and uninfected persons by use of
conditional logistic regression. CagA+ subjects had 8.2 times the risk for GNHL
than uninfected persons (95% confidence interval [CI], 2.5-26.7). CagA- subjects
had 4.4 times the risk for GNHL than uninfected persons (95% CI, 1.2-16.5). Among
infected subjects only, CagA+ infection was not associated with significantly
increased risk for GNHL when compared with CagA- infection (odds ratio, 2.1; 95%
CI, 0.8-5.4). This study does not support a major role for CagA in
lymphomagenesis.
PMID- 9395384
TI - Lymphocyte response to tetanus toxoid among Indonesian men immunized with tetanus
diphtheria during extended chloroquine or primaquine prophylaxis.
AB - Immune suppression, a potential side effect of long-term chemoprophylaxis, was
evaluated as part of a randomized, placebo-controlled trial that compared daily
primaquine against weekly chloroquine for malaria prevention. In the last month
of the year-long trial, baseline in vitro lymphoproliferative responses to
tetanus toxoid were measured, and a tetanus-diphtheria (Td) immunization was
administered. Proliferative responses to tetanus toxoid in each Td-immunized
group increased significantly over pre-Td baselines and those of the unvaccinated
control. Highest initial responses were measured in the primaquine group. The
proportion of responders and the magnitude of proliferation was consistently low
in the chloroquine group, and end point responses in this group were
significantly below those of the placebo. These results suggest that the
development and duration of the cellular response to tetanus immunization was
impaired by long-term weekly chloroquine prophylaxis, while daily primaquine
prophylaxis over the same time period had no inhibitory effect.
PMID- 9395385
TI - Gammadelta T cells are not essential for control of cutaneous Leishmania major
infection in genetically resistant C57BL/6 mice.
AB - As gammadelta T cells are believed to be involved in host defense against
Leishmania major, the role of gammadelta T cells in immunity against this
parasite was investigated. The growth of L. major was measured in alphabeta (T
cell receptor [TCR] alpha -/-) and gammadelta (TCR delta -/-) TCR-deficient
C57BL/6 mice and compared with growth in control (C57BL/6) mice. While TCR alpha
/- mice developed nonhealing lesions containing large numbers of parasites
following L. major infection, TCR delta -/- and C57BL/6 mice effectively
controlled the infection. Following in vitro stimulation, lymph node cells from
C57BL/6 mice produced significantly more interferon (IFN)-gamma than those from
TCR delta -/- mice during early and late phases of infection; however, both
produced similar levels of IFN-gamma at postinfection week 6. Culture
supernatants from both TCR delta -/- and C57BL/6 mice contained interleukin-4, at
postinfection week 2 only. These results indicate that gammadelta CD3 T cells are
not essential for mediating protection against cutaneous L. major infection in
C57BL/6 mice.
PMID- 9395386
TI - Construction crew discovers grave of "Tiny Tim".
PMID- 9395387
TI - An inverse compton process for the excess diffuse EUV emission from the virgo and
coma galaxy clusters
AB - The excess extreme-ultraviolet (EUV) emission detected in the Virgo and Coma
clusters is explained by inverse Compton scattering of cosmic microwave
background photons, which are scattered by the relativistic electrons that
account for the extended radio synchrotron emission of these clusters. The lower
limits of the average magnetic fields of these clusters estimated from the EUV
excess are close to the equipartition magnetic fields derived from radio
observations, indicating that the electron energies and magnetic field energies
might be close to equipartition. The excess emission suggests energy reservoirs
of approximately 10(61) and approximately 10(60) ergs for the Coma and Virgo
clusters, respectively.
PMID- 9395388
TI - A pulsar, the heliosphere, and pioneer 10: probable mimicking of a planet of PSR
B1257+12 by solar rotation
AB - Doppler data generated with the Pioneer 10 spacecraft's radio carrier wave
between 1987 and 1995 show a 25.3-day periodicity which is related to the solar
rotation. The timing data of the pulsar PSR B1257+12 also show a periodicity of
25.34 days, which has been explained as a signature of the pulsar's barycentric
motion in response to the existence of a small moon-like object. However, because
PSR B1257+12 is located close to the ecliptic and because the timing variations
are in the range of microseconds, it is likely that the pulsar signal is affected
by the same mechanism acting on the Pioneer 10 Doppler data. Hence, the
hypothesized inner planet around PSR B1257+12 is probably an artifact of the
heliosphere.
PMID- 9395389
TI - Radar detection of the nucleus and coma of comet hyakutake
AB - Radar observations of comet Hyakutake (C/1996 B2) made at the Goldstone Deep
Space Communications Complex in California have detected echoes from the nucleus
and from large grains in the inner coma. The nucleus of this bright comet was
estimated to be only 2 to 3 kilometers in diameter. Models of the coma echo
indicate backscatter from porous, centimeter-size grains ejected anisotropically
at velocities of tens of meters per second. The radar observations suggest that a
comet's activity may be a poor indicator of its size and provide evidence that
large grains constitute an important component of the mass loss from a typical
active comet.
PMID- 9395390
TI - Spontaneous formation of macroscopic chiral domains in a fluid smectic phase of
achiral molecules
AB - A smectic liquid-crystal phase made from achiral molecules with bent cores was
found to have fluid layers that exhibit two spontaneous symmetry-breaking
instabilities: polar molecular orientational ordering about the layer normal and
molecular tilt. These instabilities combine to form a chiral layer structure with
a handedness that depends on the sign of the tilt. The bulk states are either
antiferroelectric-racemic, with the layer polar direction and handedness
alternating in sign from layer to layer, or antiferroelectric-chiral, which is of
uniform layer handedness. Both states exhibit an electric field-induced
transition from antiferroelectric to ferroelectric.
PMID- 9395391
TI - "New view" of protein folding reconciled with the old through multiple unfolding
simulations.
AB - Twenty-four molecular dynamics trajectories of chymotrypsin inhibitor 2 provide a
direct demonstration of the diversity of unfolding pathways. Comparison with
experiments suggests that the transition state region for folding and unfolding
occurs early with only 25 percent of the native contacts and that the root-mean
square deviations between contributing structures can be as large as 15
angstroms. Nevertheless, a statistically preferred unfolding pathway emerges from
the simulations; disruption of tertiary interactions between the helix and a two
stranded portion of the beta sheet is the primary unfolding event. The results
suggest a synthesis of the "new" and the classical view of protein folding with a
preferred pathway on a funnel-like average energy surface.
PMID- 9395392
TI - Atomic and macroscopic reaction rates of a surface-catalyzed reaction
AB - The catalytic oxidation of carbon monoxide (CO) on a platinum (111) surface was
studied by scanning tunneling microscopy. The adsorbed oxygen atoms and CO
molecules were imaged with atomic resolution, and their reactions to carbon
dioxide (CO2) were monitored as functions of time. The results allowed the
formulation of a rate law that takes the distribution of the reactants in
separate domains into account. From temperature-dependent measurements, the
kinetic parameters were obtained. Their values agree well with data from
macroscopic measurements. In this way, a kinetic description of a chemical
reaction was achieved that is based solely on the statistics of the underlying
atomic processes.
PMID- 9395393
TI - Growth of SiO2 at room temperature with the use of catalyzed sequential half
reactions
AB - Films of silicon dioxide (SiO2) were deposited at room temperature by means of
catalyzed binary reaction sequence chemistry. The binary reaction SiCl4 + 2H2O -
> SiO2 + 4HCl was separated into SiCl4 and H2O half-reactions, and the half
reactions were then performed in an ABAB ellipsis sequence and catalyzed with
pyridine. The pyridine catalyst lowered the deposition temperature from >600 to
300 kelvin and reduced the reactant flux required for complete reactions from
approximately 10(9) to approximately 10(4) Langmuirs. Growth rates of
approximately 2.1 angstroms per AB reaction cycle were obtained at room
temperature for reactant pressures of 15 millitorr and 60-second exposure times
with 200 millitorr of pyridine. This catalytic technique may be general and
should facilitate the chemical vapor deposition of other oxide and nitride
materials.
PMID- 9395394
TI - Cleavage of the BMP-4 antagonist chordin by zebrafish tolloid.
AB - Dorsoventral patterning of vertebrate and Drosophila embryos requires bone
morphogenetic proteins (BMPs) and antagonists of BMP activity. The Drosophila
gene tolloid encodes a metalloprotease similar to BMP-1 that interacts
genetically with decapentaplegic, the Drosophila homolog of vertebrate BMP-2/4.
Zebrafish embryos overexpressing a zebrafish homolog of tolloid were shown to
resemble loss-of-function mutations in chordino, the zebrafish homolog of the
Xenopus BMP-4 antagonist Chordin. Furthermore, Chordin was degraded by COS cells
expressing Tolloid. These data suggest that Tolloid antagonizes Chordin activity
by proteolytically cleaving Chordin. A conserved function for zebrafish and
Drosophila Tolloid during embryogenesis is proposed.
PMID- 9395395
TI - Role of inositol 1,4,5-trisphosphate receptor in ventral signaling in Xenopus
embryos.
AB - The inositol 1,4,5-trisphosphate (IP3) receptor is a calcium ion channel involved
in the release of free Ca2+ from intracellular stores. For analysis of the role
of IP3-induced Ca2+ release (IICR) on patterning of the embryonic body,
monoclonal antibodies that inhibit IICR were produced. Injection of these
blocking antibodies into the ventral part of early Xenopus embryos induced modest
dorsal differentiation. A close correlation between IICR blocking potencies and
ectopic dorsal axis induction frequency suggests that an active IP3-Ca2+ signal
may participate in the modulation of ventral differentiation.
PMID- 9395396
TI - Crystal structure of the adenylyl cyclase activator Gsalpha.
AB - The crystal structure of Gsalpha, the heterotrimeric G protein alpha subunit that
stimulates adenylyl cyclase, was determined at 2.5 A in a complex with guanosine
5'-O-(3-thiotriphosphate) (GTPgammaS). Gsalpha is the prototypic member of a
family of GTP-binding proteins that regulate the activities of effectors in a
hormone-dependent manner. Comparison of the structure of Gsalpha.GTPgammaS with
that of Gialpha.GTPgammaS suggests that their effector specificity is primarily
dictated by the shape of the binding surface formed by the switch II helix and
the alpha3-beta5 loop, despite the high sequence homology of these elements. In
contrast, sequence divergence explains the inability of regulators of G protein
signaling to stimulate the GTPase activity of Gsalpha. The betagamma binding
surface of Gsalpha is largely conserved in sequence and structure to that of
Gialpha, whereas differences in the surface formed by the carboxyl-terminal helix
and the alpha4-beta6 loop may mediate receptor specificity.
PMID- 9395397
TI - Mediation of Sonic hedgehog-induced expression of COUP-TFII by a protein
phosphatase.
AB - A Sonic hedgehog (Shh) response element was identified in the chicken ovalbumin
upstream promoter-transcription factor II (COUP-TFII) promoter that binds to a
factor distinct from Gli, a gene known to mediate Shh signaling. Although this
binding activity is specifically stimulated by Shh-N (amino-terminal signaling
domain), it can also be unmasked with protein phosphatase treatment in the mouse
cell line P19, and induction by Shh-N can be blocked by phosphatase inhibitors.
Thus, Shh-N signaling may result in dephosphorylation of a target factor that is
required for activation of COUP-TFII-, Islet1-, and Gli response element
dependent gene expression. This finding identifies another step in the Shh-N
signaling pathway.
PMID- 9395398
TI - Spike synchronization and rate modulation differentially involved in motor
cortical function.
AB - It is now commonly accepted that planning and execution of movements are based on
distributed processing by neuronal populations in motor cortical areas. It is
less clear, though, how these populations organize dynamically to cope with the
momentary computational demands. Simultaneously recorded activities of neurons in
the primary motor cortex of monkeys during performance of a delayed-pointing task
exhibited context-dependent, rapid changes in the patterns of coincident action
potentials. Accurate spike synchronization occurred in relation to external
events (stimuli, movements) and was commonly accompanied by discharge rate
modulations but without precise time locking of the spikes to these external
events. Spike synchronization also occurred in relation to purely internal events
(stimulus expectancy), where firing rate modulations were distinctly absent.
These findings indicate that internally generated synchronization of individual
spike discharges may subserve the cortical organization of cognitive motor
processes.
PMID- 9395399
TI - Protein disulfide isomerase as a regulator of chloroplast translational
activation.
AB - Light-regulated translation of chloroplast messenger RNAs (mRNAs) requires trans
acting factors that interact with the 5' untranslated region (UTR) of these
mRNAs. Chloroplast polyadenylate-binding protein (cPABP) specifically binds to
the 5'-UTR of the psbA mRNA and is essential for translation of this mRNA. A
protein disulfide isomerase that is localized to the chloroplast and copurifies
with cPABP was shown to modulate the binding of cPABP to the 5'-UTR of the psbA
mRNA by reversibly changing the redox status of cPABP through redox potential or
adenosine 5'-diphosphate-dependent phosphorylation. This mechanism allows for a
simple reversible switch regulating gene expression in the chloroplast.
PMID- 9395400
TI - Sequence-specific and phosphorylation-dependent proline isomerization: a
potential mitotic regulatory mechanism.
AB - Pin1 is an essential and conserved mitotic peptidyl-prolyl isomerase (PPIase)
that is distinct from members of two other families of conventional PPIases,
cyclophilins and FKBPs (FK-506 binding proteins). In response to their
phosphorylation during mitosis, Pin1 binds and regulates members of a highly
conserved set of proteins that overlaps with antigens recognized by the mitosis
specific monoclonal antibody MPM-2. Pin1 is here shown to be a phosphorylation
dependent PPIase that specifically recognizes the phosphoserine-proline or
phosphothreonine-proline bonds present in mitotic phosphoproteins. Both Pin1 and
MPM-2 selected similar phosphorylated serine-proline-containing peptides,
providing the basis for the specific interaction between Pin1 and MPM-2 antigens.
Pin1 preferentially isomerized proline residues preceded by phosphorylated serine
or threonine with up to 1300-fold selectivity compared with unphosphorylated
peptides. Pin1 may thus regulate mitotic progression by catalyzing sequence
specific and phosphorylation-dependent proline isomerization.
PMID- 9395401
TI - Mechanism of transcription through the nucleosome by eukaryotic RNA polymerase.
AB - Nucleosomes, the nucleohistone subunits of chromatin, are present on transcribed
eukaryotic genes but do not prevent transcription. It is shown here that the
large yeast RNA polymerase III transcribes through a single nucleosome. This
takes place through a direct internal nucleosome transfer in which histones never
leave the DNA template. During this process, the polymerase pauses with a
pronounced periodicity of 10 to 11 base pairs, which is consistent with
restricted rotation in the DNA loop formed during transfer. Transcription through
nucleosomes by the eukaryotic enzyme and by much smaller prokaryotic RNA
polymerases thus shares many features, reflecting an important property of
nucleosomes.
PMID- 9395402
TI - NDR1, a pathogen-induced component required for Arabidopsis disease resistance.
AB - Plant disease resistance (R) genes confer an ability to resist infection by
pathogens expressing specific corresponding avirulence genes. In Arabidopsis
thaliana, resistance to both bacterial and fungal pathogens, mediated by several
R gene products, requires the NDR1 gene. Positional cloning was used to isolate
NDR1, which encodes a 660-base pair open reading frame. The predicted 219-amino
acid sequence suggests that NDR1 may be associated with a membrane. NDR1
expression is induced in response to pathogen challenge and may function to
integrate various pathogen recognition signals.
PMID- 9395403
TI - Conversion of Bcl-2 to a Bax-like death effector by caspases.
AB - Caspases are a family of cysteine proteases implicated in the biochemical and
morphological changes that occur during apoptosis (programmed cell death). The
loop domain of Bcl-2 is cleaved at Asp34 by caspase-3 (CPP32) in vitro, in cells
overexpressing caspase-3, and after induction of apoptosis by Fas ligation and
interleukin-3 withdrawal. The carboxyl-terminal Bcl-2 cleavage product triggered
cell death and accelerated Sindbis virus-induced apoptosis, which was dependent
on the BH3 homology and transmembrane domains of Bcl-2. Inhibitor studies
indicated that cleavage of Bcl-2 may further activate downstream caspases and
contribute to amplification of the caspase cascade. Cleavage-resistant mutants of
Bcl-2 had increased protection from interleukin-3 withdrawal and Sindbis virus
induced apoptosis. Thus, cleavage of Bcl-2 by caspases may ensure the
inevitability of cell death.
PMID- 9395404
TI - A dual effect of 1-methyl-4-phenylpyridinium (MPP+)-analogs on the respiratory
chain of bovine heart mitochondria.
AB - We examined effects of several compounds, structurally related to 1-methyl-4
phenylpyridinium (MPP+), on the NADH-dependent respiration of bovine heart
submitochondrial particles. 1-Methyl-4-(3 '-trimethylammoniophenyl)pyridinium
(analog 8) as well as MPP+ completely inhibited O2 consumption, reduction of
ubiquinone-10, and reduction of cytochrome b in a dose-dependent manner. The
production of superoxide (O2-) induced by MPP+ or analog 8 was to the same extent
as that by rotenone, an inhibitor of complex I of the mitochondrial respiratory
chain. Rotenone had no additive effect on the maximal production of O2- induced
by MPP+ or analog 8, suggesting that the production was mediated by the same way
as rotenone. 1-Methyl-4-(4'-nitrophenyl) pyridinium (analog 1) induced about 20
fold more production of O2 than MPP+ and the production was additively increased
by rotenone. Analog 1 only partially inhibited rotenone-sensitive O2 consumption.
Paraquat induced the production of O2- as much as analog 1. Paraquat, however,
did not inhibit rotenone-sensitive O2 consumption or reduction of cytochrome b.
These results suggest that MPP+ and its analogs interact with the mitochondrial
respiratory chain at two sites, the substrate side of the rotenone-binding site
and the rotenone-binding site. The analogs may be reduced to produce O2- at the
former site and inhibit the respiratory chain at the latter site.
PMID- 9395405
TI - Evolutionary motif and its biological and structural significance.
AB - We developed a method for multiple alignment of protein sequences. The main
feature of this method is that it takes the evolutionary relationships of the
proteins in question into account repeatedly for execution, until the
relationships and alignment results are in agreement. We then applied this method
to the data of the international DNA sequence databases, which are the most
comprehensive and updated DNA databases in the world, in order to estimate the
"evolutionary motif" by extensive use of a supercomputer. Though a few problems
needed to be solved, we could estimate the length of the motifs in the range of
20 to 200 amino acids, with about 60 the most frequent length. We then discussed
their biological and structural significance. We believe that we are now in a
position to analyze DNA and protein not only in vivo and in vitro but also in
silico.
PMID- 9395406
TI - Genome plasticity as a paradigm of eubacteria evolution.
AB - To test the hypotheses that eubacterial genomes leave evolutionarily stable
structures and that the variety of genome size is brought about through genome
doubling during evolution, the genome structures of Haemophilus influenzae,
Mycoplasma genitalium, Escherichia coli, and Bacillus subtilis were compared
using the DNA sequences of the entire genome or substantial portions of genome.
In these comparisons, the locations of orthologous genes were examined among
different genomes. Using orthologous genes for the comparisons guaranteed that
differences revealed in physical location would reflect changes in genome
structure after speciation. We found that dynamic rearrangements have so
frequently occurred in eubacterial genomes as to break operon structures during
evolution, even after the relatively recent divergence between E. coli and H.
influenzae. Interestingly, in such eubacterial genomes of high plasticity, we
could find several highly conservative regions with the longest conserved region
comprising the S10, spc, and alpha operons. This suggests that such exceptional
conservative regions have undergone strong structural constraints during
evolution.
PMID- 9395407
TI - Requirement for EGF receptor signalling in neural recruitment during formation of
Drosophila chordotonal sense organ clusters.
AB - BACKGROUND: Drosophila proneural genes act in the process of selecting neural
precursors from undifferentiated ectoderm. The proneural gene atonal is required
for the development of precursors of both chordotonal organs (stretch receptors)
and photoreceptors. Although these types of sensory element are dissimilar in
structure and function, they both occur as organized arrays of neurons. Previous
studies have shown that clustering of photoreceptors involves local recruitment,
and that signalling by the Drosophila epidermal growth factor receptor (DER)
pathway is involved in the recruitment process. We present evidence that a
similar mechanism is required for the clustering of embryonic chordotonal organs.
RESULTS: We have examined the expression patterns of atonal and genes of the DER
pathway in wild-type and mutant backgrounds. Expression of atonal was restricted
to a subset of the atonal-requiring chordotonal precursors, which we call founder
precursors. The remaining precursors required DER signalling for their selection.
Signalling by the founder precursors was initiated by atonal activating, directly
or indirectly, rhomboid expression in these cells. Signalling by these founder
precursors then provoked a response in the surrounding ectodermal cells, as shown
by the activation of expression of the DER target genes pointed and argos. The
signal and response then led to recruitment of some of the ectodermal cells to
the chordotonal precursor cell fate. DER hyperactivation by misexpression of
rhomboid resulted in excessive chordotonal precursor recruitment. CONCLUSIONS:
Increased numbers of chordotonal precursors are recruited by homeogenetic
induction involving signalling via DER from founder precursors to surrounding
ectodermal cells. We suggest that the reason chordotonal organs and
photoreceptors share a requirement for the proneural gene atonal is that this
gene activates a common pathway leading to neural aggregation.
PMID- 9395409
TI - Movement of nuclei along microtubules in Xenopus egg extracts.
AB - Microtubules are implicated in the movement and positioning of nuclei in many
cell types. Nuclei can be moved by forces acting on microtubules nucleated at the
spindle pole body, as in fungi [1], or microtubules nucleated at the centrosome,
as during migration of the male (sperm) pronucleus towards the centre of the
zygote after fertilization [2] [3] [4]. The dramatic movements of the female
pronucleus towards the male pronucleus potentially involve another mechanism:
movement along the microtubules of the sperm aster towards their slower growing,
attached or 'minus' ends [3] [5]. Here, we have reconstituted this last type of
nuclear movement in vitro. Synthetic nuclei assembled in cytoplasmic extracts
made from interphase Xenopus eggs move along microtubules towards their minus
ends. We provide strong experimental evidence that cytoplasmic dynein is the
motor for nuclear movement in this in vitro system, and discuss our results in
terms of current knowledge of motility of the endoplasmic reticulum.
PMID- 9395408
TI - Phospholipase D2, a distinct phospholipase D isoform with novel regulatory
properties that provokes cytoskeletal reorganization.
AB - BACKGROUND: Activation of phospholipase D (PLD) is an important but poorly
understood component of receptor-mediated signal transduction responses and
regulated secretion. We recently reported the cloning of the human gene encoding
PLD1; this enzyme has low basal activity and is activated by protein kinase C and
the small GTP-binding proteins, ADP-ribosylation factor (ARF), Rho, Rac and
Cdc42. Biochemical and cell biological studies suggest, however, that additional
and distinct PLD activities exist in cells, so a search was carried out for novel
mammalian genes related to PLD1. RESULTS: We have cloned the gene for a second
PLD family member and characterized the protein product, which appears to be
regulated differently from PLD1: PLD2 is constitutively active and may be
modulated in vivo by inhibition. Unexpectedly, PLD2 localizes primarily to the
plasma membrane, in contrast to PLD1 which localizes solely to peri-nuclear
regions (the endoplasmic reticulum, Golgi apparatus and late endosomes), where
PLD activity has been shown to promote ARF-mediated coated-vesicle formation.
PLD2 provokes cortical reorganization and undergoes redistribution in serum
stimulated cells, suggesting that it may have a role in signal-induced
cytoskeletal regulation and/or endocytosis. CONCLUSIONS: PLD2 is a newly
identified mammalian PLD isoform with novel regulatory properties. Our findings
suggest that regulated secretion and morphological reorganization, the two most
frequently proposed biological roles for PLD, are likely to be effected
separately by PLD1 and PLD2.
PMID- 9395411
TI - [Why not a meeting place for the readers of the L[kartidningen?].
PMID- 9395410
TI - [Impact of control measures on the course of an outbreak of methicillin-resistant
Staphylococcus aureus].
AB - BACKGROUND: Outbreaks of nosocomial infection by methicillin resistent
Staphylococcus aureus (MRSA) are a problem in many hospitals with the control
measures to be adopted being controversial. An outbreak of MRSA in a 550-bed
university hospital is herein described and the impact of the adopted control
measures on the evolution of the epidemic in the general hospitalization area
(GHA) was analyzed. PATIENTS AND METHODS: The adopted control measures in the GHA
were: microbiologic surveillance, cutaneous isolation measures, treatment of
nasal carrier, and the early discharge of the cases. Hand washing was reinforced
and a study of carriers was carried out on detection of sporadic cases (not
related to the ICU). A molecular study of 70 strains of MRSA was performed with
analysis of total plasmids, plasmid restriction pattern and chromosomic DNA
analysis by pulsed field gel electrophoresis (PFGE). RESULTS: From December 1990
to December 1993, 273 cases of MRSA were reported. One hundred seventy-two cases
originated in the ICU and 101 cases in the GHA (sporadic cases). The incidence of
MRSA in 1991-1993 was 13.6, 14.3, and 6.6% in the ICU and 0.17, 0.36, and 0.15%
in the GHA, respectively. Molecular study of MRSA isolates (1991 and 1992)
demonstrated two plasmid and two chromosomic patterns. The latter had a
similarity coefficient > 0.90, probably belonging to the same "clone".
CONCLUSIONS: Despite the control measures adopted in the GHA the outbreak of MRSA
originated in the ICU thereafter extending to the GHA. The rates of colonization
detected, however, remained stable during the 3 years studied. On the other hand,
the observation of a single "clone", responsible for the epidemic, suggest that
most of the sporadic cases were autoctonous and due to failure in fulfillment of
the established norms.
PMID- 9395412
TI - [Claves ilustradas para las subfamilias, tribus y generos de esfecidos
neotropicales (Apoidea: Sphecidae) [Illustrated clues for subfamilies, tribes,
and genera of neotropical Spheciade (Apoidea:Sphecidae)].
AB - 141 genera of Sphecidae, representing 1,628 species, are known from the
Neotropical Region. Illustrated keys to genera, tribes, and subfamilies are
presented in Spanish and English. These have been modified and updated from those
in Bohart & Menke's 1976 book, Sphecid Wasps of the World. The validity of a few
genera recognized by Bohart & Menke is now in question and the keys are annotated
to alert users to these problems. A list of neotropical genera and higher taxa is
included. Names in the list are appended with significant literature published
since 1976. The history and current status of subfamilies are reviewed. Ten
subfamilies are recognized. Family characters and biology are summarized.
Morphological terms are illustrated and a glossary provided.
PMID- 9395413
TI - [Directly addressing suicidal thoughts in crisis intervention. Interview by Dr.
rer. nat. Anita Schweiger].
PMID- 9395414
TI - [Infectious endocarditis at the National Institute of Cardiology "Ignacio
Chavez". Five year's experience (1990-1994)].
AB - BACKGROUND: Infective endocarditis (IE) is one of the most life threatening
infections in both medical and surgical practices. In the last few years, changes
in its epidemiology, diagnostic methods and therapeutical trends have appeared.
We analysed our experience in the diagnosis and treatment of IE. METHODS: The
clinical records of patients admitted to our hospital with definitive (Group I)
and highly probable (Group II) diagnosis of IE, during a period of five years
(1990-1994), were retrospectively reviewed. Age, sex, clinical features, risk,
factors, echocardiographic abnormalities, microbiologic and surgical findings, as
well as mortality were recorded. In addition, an evaluation was made of the
accuracy of the diagnostic criteria proposed by Von Reyn versus those brought
forward by Duke University. RESULTS: One hundred thirty one patients were
included, 99 in Group I and 32 in Group II. The mean age was 35 years. Native
valve endocarditis was present in 88 patients and prosthetic valve endocarditis
in 43 patients. Streptococcus sp. (48%) was the most frequently causative german
and 16.7% of cases were culture negative. The sensitivity of transesophageal
echocardiography was higher than transthoracic echocardiography in the diagnosis
of both vegetations (76% vs 55%) and abscesses (30% vs 16.5%), (p < 0.05).
Vegetations (95%) were the most frequent surgical finding followed by abscesses
(23%). Inpatient mortality was 22% in Group I and 45% in Group II (p < 0.05). The
sensitivity of Von Reyn's diagnostic criteria and that of Duke's University group
was 49% and 85.8% (p < 0.05). Mean follow up was 531 days. Two patients had a new
event of IE and no outpatient deaths were recorded. CONCLUSION: IE is a medical
and surgical emergency. Because of the high mortality rate, in the medically
treated group, surgery should be considered in all cases as early as possible in
the course of the disease.
PMID- 9395415
TI - [[HPLC-determination of tamoxifen dihydrogen citrate with the base selective
column UltraSep ES Pharm RP8 in tablets].
PMID- 9395416
TI - [The causes of perioperative mortality. A trial of the German "CEPOD study."].
AB - We performed a prospective multi-center study in order to determine the causes of
30-day perioperative mortality. METHODS: In accordance with the CEPOD-Study and
with the kind permission of Dr. N. Lunn, we forwarded two different
questionnaires to 135 hospitals. One questionnaire was to be answered by the
anaesthetist and the other one by the surgeon involved in cases o perioperative
death within the first 30 days after the operation. 12 out of 135 addressed
hospitals agreed to participate in the study. These included four small
hospitals, six medical centres of medium capacity (about 500 beds) and two
University hospitals. In order to obtain an exact description of the events
leading to perioperative death, the questionnaires consisted of approximately 60
questions for the collection of demographic data and the surgical as well as
anaesthesiological perioperative management. RESULTS: From 1989 to 1993 more than
300 cases of perioperative death were reported. Only 200 cases could be analyzed
due to incompletely answered or unreturned questionnaires. The mean risk
classification (ASA) was 3.46, mean age 74.6 years. Approximately 40 percent of
deaths occurred in patients older than 80 years. More than 80 percent of patients
had at least one pre-existing cardiovascular disease with prevalence of 41% for
pulmonary and gastrointestinal diseases. In the majority of cases abdominal
operations were performed, followed by hip-surgery and surgery of the aorta. In
86% of the cases, the surgeon was experienced and had performed the respective
operation more than 20 times. In 38.2% an anaesthetist in training was
responsible for anaesthesia, but only 11.6% were without supervision of a
specialist anaesthetist. The majority of patients received general anaesthesia
(78%) and 8.5% had a combination of EDA and general anaesthesia. Regional
anaesthesia was performed in 12.5%, local anaesthesia in only 1%. The average
blood loss was approximately 1.600 ml (with a very wide range) and 42.5% of the
patients needed a transfusion of blood components, primarily in the form of
packed red blood cells. Seventeen serious incidents occurred intraoperatively,
including three "exitus in tabula". Four patients died shortly after the
operation in the ICU, the other ten incidents were managed in the operating room.
In 11 of 17 incidents the patients suffered a cardiac arrest; nine patients were
resuscitated. Two patients were not resuscitated in view of pre-existing diseases
and inoperability. All of the hospitals had an ICU for postoperative care, but
two of the smaller hospitals had no recovery rooms. In 22 cases of emergency
operations, there was a delay due to a lack of personnel or to logistic problems.
In five of these cases, the delay was described as a possible cofactor of
perioperative mortality. The most frequent causes of perioperative death were
myocardial failure (33.7%) and multi-organ-failure (19.2%), followed by
respiratory insufficiency (13%) and septic shock in 9.3%. A necropsy was carried
out in only 28 of 200 perioperative deaths (14%); 13% of the cases were discussed
in a surgical and only 2.5% in an anaesthesiological mortality-conference. In 9
out of 12 hospitals no mortality-conferences were held. All surgeons and
anaesthetists were asked for self-assessment on the basis of an analog scale
ranging from 0 and 10 points. The average score was 8.52 points (surgical
management) and 9.36 points (anaesthesiological management respectively), which
is not always in correspondence with the information provided in the
questionnaires. CONCLUSIONS: In order to further reduce perioperative mortality
in critically ill patients, every hospital should aim to optimize the structure
of the surgical and anaesthesiological departments. A delay due to logistical or
personnel problems may be a co-factor in perioperative mortality. Recovery rooms
with experienced personnel should be the standard in postoperative
anaesthesiological care. (ABSTRACT TRUNCATED)
PMID- 9395417
TI - [Institutionalization of community programs: review of theoretical models and
proposal of a model-].
AB - Community-based health promotion programs to change lifestyle habits must remain
in their host organizations for extended periods of time in order to have impact.
Their effectiveness can be closely linked to their long term viability or
institutionalization. To remain viable, these programs must survive beyond
initial investment and support by external organizations. However, some programs
disappear when external investment is withdrawn. This can be costly and in
addition can generate resistance to the implementation of other health promotion
programs in the future. Recently, interest in the processes involved in the
institutionalization of these programs has increased. Based on 28 publications,
this article reviews selected conceptual models that highlight environmental,
organizational, community and marketing-related, variables possibly related to
the institutionalization process. A new model is proposed to link these diverse
models according to: characteristics of the program, characteristics of the host
organization, characteristics related to the adoption, implementation and
incorporation of the program, and finally characteristics related to the fit
(mutual adjustment) between the host and the program.
PMID- 9395418
TI - [[Brucellar orchiepididymitis with abscess].
AB - OBJECTIVE: To emphasize the need to consider Brucella infection in patients
presenting with acute scrotum of a possible inflammatory etiology, in endemic
areas, as in some Spanish regions. The abscess forming type, although rare,
should be considered. One such case is described herein and the literature
briefly reviewed. METHODS: A male patient consulted for subacute inflammation and
left testicular pain. He had systemic brucellosis four months earlier that had
completely remitted following specific therapy. The patient had a physical
examination, analytical, blood and urine analyses, specific serological tests and
testicular ultrasound evaluation. RESULTS: Physical examination disclosed left
testicular pain and inflammation suggesting epididimo-orchitis. The laboratory
findings were normal except for high titles against Brucella. Ultrasound
disclosed diffuse enlargement of the left testis with several well-defined
hypoechoic areas. The foregoing data suggested abscess forming orchitis, although
a neoplasm could not be discarded. Empirical antibiotic therapy was instituted
initially and specific therapy for Brucella was administered subsequently, but
unilateral orchidectomy was decided because of the poor response to therapy.
Histopathological analysis of the surgical specimen disclosed acute abscess
forming epididimo-orchitis with multifocal chronic granulomatous involvement.
CONCLUSION: Brucella epididimo-orchitis must be considered when making the
differential diagnosis in acute inflammatory scrotum, particularly in endemic
areas, even in the absence of suggestive clinical and/or US findings. Necrotizing
orchitis is a rare form of Brucella infection which must be distinguished from
necrotizing involvement arising from other pathogens (TB or Salmonella). Above
all, this condition must be distinguished from a tumor.
PMID- 9395419
TI - [Does breast feeding compromise the efficacy of sero-vaccination of infants borne
to mothers who are chronic carriers of hepatitis B antigens].
PMID- 9395420
TI - [Are the products of CD44 exons v5 and v6 markers for metastasis of laryngeal
carcinomas?].
AB - BACKGROUND: The transmembrane glycoprotein CD44 is referred to by many names,
which are related to the polymorphism of this molecule. There are at least 10
different versions of the CD44 molecule. This polymorphism results from the
insertion of extra domains into the extracellular part of the molecule and from
different glycolization. These extra domains are coded by variable exons in the
gene of CD44, which can be alternatively spliced. Some authors have postulated a
link between expression of whole CD44 or some special molecule versions (often
with the product of exon v6) on carcinoma cells and the potential of metastatic
spread. The aim of our investigation was to look for this connection in larynx
carcinomas. METHOD: We have tested 28 larynx carcinomas without metastases, 26
with metastases, and 20 lymph node metastases from larynx carcinomas with
antibodies against the products of exon v5 and v6 in immunohistochemical studies
of paraffin sections. RESULTS: In all cases we observed nearly the same staining
intensity of exon v5 and v6 products. There was no significant difference between
carcinomas with and without metastases or the lymph node metastases. However, a
strong difference of reaction was found between the carcinoma cells of the outer
proliferative tumor areas and the inner tumor areas, which were cornified in
parts. Whereas the first mentioned cells generally stained very intensively, the
latter showed only a slight reaction or none at all. CONCLUSIONS: In our opinion,
CD44 v5 and v6 appear to be valuable markers of proliferation although we could
not establish a strong connection to metastatic behavior.
PMID- 9395421
TI - [Chronic fatigue syndrome: study of the clinical course of 28 cases].
AB - BACKGROUND: Chronic fatigue syndrome (CFS) is an entity of unknown
etiopathogenesis without specific markers. The diagnosis is based on clinical
criteria. There are few studies evaluating the natural evolution and prognosis
related factors in CFS. OBJECTIVES: a) to evaluate the outcome of patients
suffering from CFS, and b) to detect predictive factors associated with a better
prognosis. MATERIAL AND METHODS: Clinical records of all patients diagnosed of
CFS between January 1986 and December 1992 were retrospectively reviewed. Of
these patients, we included those fulfilling the CDC criteria for CFS, with a
follow-up period greater than one year. We evaluated epidemiological, clinical
and evolutive data recorded by their usual physicians. Moreover, the patients
were interviewed in order to know their own appreciation with respect to their
current clinical status, as well as their present working situation. RESULTS:
Twenty-eight patients were included in the present study. Their mean age was 38
+/- 7. Seventy-five percent of them were women. The mean time of clinical follow
up was of 3.2 +/- 1.8 years. According to evaluation, 21% of patients improved or
became asymptomatic. A similar percentage (28%) of improvement was obtained from
the interview. Forty-eight percent of cases had transitory or definitive laboral
incapacity. Regarding to prognostic factors, we could not find any statistical
differences among the analyzed variables except for marital status. In this
variable, married patients had better outcome than unmarried patients.
CONCLUSION: CFS is an entity with a poor outcome, since it evolves towards to
chronicity in an important number of cases. In addition, strong functional
disability may be present, leading frequently to laboral incapacity.
PMID- 9395422
TI - Case records of the Massachusetts General Hospital. Weekly clinicopathological
exercises. Case 27-1997. A 38-year-old man with the acquired immunodeficiency
syndrome and cavitary pulmonary lesions.
PMID- 9395423
TI - [Pancreatic hydatid cyst: review of a case].
PMID- 9395424
TI - Guidelines for the management of nausea and vomiting in pregnancy.
PMID- 9395425
TI - [Diagnosis of achalasia using 99m-Tc pertechnetate scintigraphy].
AB - A 73-year-old patient presented a 99mTc scintiscan with a focal tracer
accumulation left and caudal of the thyroid gland. Further investigations with
sonography, CT, esophagoscopy and barium swallow provided the diagnosis of
achalasia as the reason for focal 99mTc retention caudal of the thyroid gland.
Explanation for 99mTc accumulation within the esophagus may be the nonspecific
accumulation of 99mTc not only in the thyroid gland but also in the salivary
glands. Excretion of the tracer follows with the saliva. Structural and motor
disorders of the esophagus can thus lead to focal tracer retention within the
esophagus simulating thyroid tissue.
PMID- 9395426
TI - [Gastric anisakiasis diagnosed by endoscopy].
AB - Anisakiasis is a parasitic infestation of increasing incidence in Spain. The case
of a 75-years-old male diagnosed with gastric anisakiasis by endoscopy is
presented. This case presents some peculiarities such as the previous ingestion
of undercooked microwaved fish and the posterior serologic study (determination
of IgE specific for Anisakis simplex) which confirmed the diagnosis. The
importance of the endoscopic techniques in the diagnosis and treatment of gastric
anisakiasis is emphasized.
PMID- 9395427
TI - [Distribution of natural parasites--fungi and microsporidia--in a population of
malarial mosquito larva (Diptera: Culicidae) before and after infection by the
entomopathogenic bacteria Bacillus thuringiensis israelensis].
AB - The distribution specificity of fungi and microsporidies in natural population of
Anopheles messeae Fall. and A. beklemishevi Stegny et Kab. and those which
survived after treatment them by Bacillus thuringiensis israelensis (Bti) were
observed. Parasitic fungus nonselectively affected individuals of both species
and all inversion genotypes of A. messeae. Microsporidia Parathelohania messeae
affected males and it has not species and genotypic specificity. The 4-th instar
larvae of both species infected by parasitic fungus after treatment them by Bti
did not survive. The level of microsporidian infection of A. messeae and A.
beklemishevi after Bti treatment was reduced from 1.1 +/- 0.5 to 0.5 +/- 0.3% and
from 1.3 +/- 1.3 to 0.7 +/- 0.5% accordingly. A. beklemishevi was registered as
Parathelohania messeae host for the first time. The harmonious relationships
between malaria mosquitoes and their parasites in natural populations may be
destructed by the Bti treatments.
PMID- 9395428
TI - Postoperative radiotherapy in high-risk premenopausal women with breast cancer
who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b
Trial.
AB - BACKGROUND: Irradiation after mastectomy can reduce locoregional recurrences in
women with breast cancer, but whether it prolongs survival remains controversial.
We conducted a randomized trial of radiotherapy after mastectomy in high-risk
premenopausal women, all of whom also received adjuvant systemic chemotherapy
with cyclophosphamide, methotrexate, and fluorouracil (CMF). METHODS: A total of
1708 women who had undergone mastectomy for pathological stage II or III breast
cancer were randomly assigned to receive eight cycles of CMF plus irradiation of
the chest wall and regional lymph nodes (852 women) or nine cycles of CMF alone
(856 women). The median length of follow-up was 114 months. The end points were
locoregional recurrence, distant metastases, disease-free survival, and overall
survival. RESULTS: The frequency of locoregional recurrence alone or with distant
metastases was 9 percent among the women who received radiotherapy plus CMF and
32 percent among those who received CMF alone (P<0.001). The probability of
survival free of disease after 10 years was 48 percent among the women assigned
to radiotherapy plus CMF and 34 percent among those treated only with CMF
(P<0.001). Overall survival at 10 years was 54 percent among those given
radiotherapy and CMF and 45 percent among those who received CMF alone (P<0.001).
Multivariate analysis demonstrated that irradiation after mastectomy
significantly improved disease-free survival and overall survival, irrespective
of tumor size, the number of positive nodes, or the histopathological grade.
CONCLUSIONS: The addition of postoperative irradiation to mastectomy and adjuvant
chemotherapy reduces locoregional recurrences and prolongs survival in high-risk
premenopausal women with breast cancer.
PMID- 9395429
TI - Nutritional benefits of neonatal screening for cystic fibrosis. Wisconsin Cystic
Fibrosis Neonatal Screening Study Group.
AB - BACKGROUND: Many patients with cystic fibrosis are malnourished at the time of
diagnosis. Whether newborn screening and early treatment may prevent the
development of a nutritional deficiency is not known. METHODS: We compared the
nutritional status of patients with cystic fibrosis identified by neonatal
screening or by standard diagnostic methods. A total of 650,341 newborn infants
were screened by measuring immunoreactive trypsinogen on dried blood spots (from
April 1985 through June 1991) or by combining the trypsinogen test with DNA
analysis (from July 1991 through June 1994). Of 325,171 infants assigned to an
early-diagnosis group, cystic fibrosis was diagnosed in 74 infants, including 5
with negative screening tests. Excluding infants with meconium ileus, we
evaluated nutritional status for up to 10 years by anthropometric and biochemical
methods in 56 of the infants who received an early diagnosis and in 40 of the
infants in whom the diagnosis was made by standard methods (the control group).
Pancreatic insufficiency was managed with nutritional interventions that included
high-calorie diets, pancreatic-enzyme therapy, and fat-soluble vitamin
supplements. RESULTS: The diagnosis of cystic fibrosis was confirmed by a
positive sweat test at a younger age in the early-diagnosis group than in the
control group (mean age, 12 vs. 72 weeks). At the time of diagnosis, the early
diagnosis group had significantly higher height and weight percentiles and a
higher head-circumference percentile (52nd, vs. 32nd in the control group;
P=0.003). The early-diagnosis group also had significantly higher anthropometric
indexes during the follow-up period, especially the children with pancreatic
insufficiency and those who were homozygous for the deltaF508 mutation.
CONCLUSIONS: Neonatal screening provides the opportunity to prevent malnutrition
in infants with cystic fibrosis.
PMID- 9395430
TI - Bacterial meningitis in the United States in 1995. Active Surveillance Team.
AB - BACKGROUND: Before the introduction of the conjugate vaccines, Haemophilus
influenzae type b was the major cause of bacterial meningitis in the United
States, and meningitis was primarily a disease of infants and young children. We
describe the epidemiologic features of bacterial meningitis five years after the
H. influenzae type b conjugate vaccines were licensed for routine immunization of
infants. METHODS: Data were collected from active, population-based surveillance
for culture-confirmed meningitis and other invasive bacterial disease during 1995
in laboratories serving all the acute care hospitals in 22 counties of four
states (total population, more than 10 million). The rates were compared with
those for 1986 obtained by similar surveillance. RESULTS: On the basis of 248
cases of bacterial meningitis in the surveillance areas, the rates of meningitis
(per 100,000) for the major pathogens in 1995 were Streptococcus pneumoniae, 1.1;
Neisseria meningitidis, 0.6; group B streptococcus, 0.3; Listeria monocytogenes,
0.2; and H. influenzae, 0.2. Group B streptococcus was the predominant pathogen
among newborns, N. meningitidis among children 2 to 18 years old, and S.
pneumoniae among adults. Pneumococcal meningitis had the highest case fatality
rate (21 percent) and in 36 percent of cases was caused by organisms that were
not susceptible to penicillin. From these data, we estimate that 5755 cases of
bacterial meningitis were caused by these five pathogens in the United States in
1995, as compared with 12,920 cases in 1986, a reduction of 55 percent. The
median age of persons with bacterial meningitis increased greatly, from 15 months
in 1986 to 25 years in 1995, largely as a result of a 94 percent reduction in the
number of cases of H. influenzae meningitis. CONCLUSIONS: Because of the vaccine
related decline in meningitis due to H. influenzae type b, bacterial meningitis
in the United States is now a disease predominantly of adults rather than of
infants and young children.
PMID- 9395431
TI - Surgical treatment for epilepsy: a retrospective Swedish multicenter study.
AB - The characteristics of patients suffering from drug resistant epilepsy, including
the results of the preoperative evaluation and epilepsy surgery were
retrospectively analyzed in a Swedish multicenter 10-year cohort of children and
adults. Altogether 152 patients (65 children and 87 adults) treated during the
period 1980-1990 in three epilepsy centers were included and followed-up 2 years
after surgery. Median age at onset of seizures was 4 years for the children and
12 years for the adults. A localization related epilepsy was present in 85% of
the children and in 95% of the adults. The mean number of seizure types in the
children was 1.7 (range 1-4) and in the adults 1.8 (range 1-4). The median
monthly seizure frequency was 52 and 15 for children and adults respectively.
Resective surgery was performed in 143 cases (94 temporal, 31 extratemporal, 9
multilobar and 9 major resection procedures) and palliative procedures in 16
cases (13 callosotomies and 3 stereotactic amygdalotomies). Postoperative
neurological deficits were detected in 9% of the patients after temporal lobe
resections and in 15% of the patients after extratemporal and multilobar
resection procedures. Two years after resective surgery 53% of the children and
49% of the adults were seizure free. Another 25% of the patients had a more than
50% reduction of seizure frequency. In the postoperative non seizure free group
of patients there was a negative correlation between decrease in weighted seizure
severity and decrease in seizure frequency. This finding stresses the need for
including other parameters than seizure frequency when evaluating the outcome of
epilepsy surgery.
PMID- 9395432
TI - [Dermatologic laser therapy].
PMID- 9395433
TI - DNA methylation directs a time-dependent repression of transcription initiation.
AB - BACKGROUND: The regulation of DNA methylation is required for differential
expression of imprinted genes during vertebrate development. Earlier studies that
monitored the activity of the Herpes simplex virus (HSV) thymidine kinase (tk)
gene after injection into rodent cells have suggested that assembly of chromatin
influences the methylation-dependent repression of gene activity. Here, we
examine the mechanism of methylation-dependent HSV tk gene regulation by direct
determination of nucleoprotein organization during the establishment of a
transcriptionally silenced state after microinjection of templates with defined
methylation states into Xenopus oocyte nuclei. RESULTS: The transcriptional
silencing conferred by a methylated DNA segment was not immediate, as methylated
templates were initially assembled into active transcription complexes. The
eventual loss of DNase I hypersenitive sites and inhibition of transcription at
the HSV tk promoter only occurred after several hours. Flanking methylated vector
DNA silenced the adjacent unmethylated HSV tk promoter, indicative of a dominant
transmissible repression originating from a center of methylation. The resulting
repressive nucleoprotein structure silenced transcription in the presence of
activators that are able to overcome repression of transcription by nucleosomes.
CONCLUSIONS: Silencing of transcription by DNA methylation is achieved at the
level of transcription initiation and involves the removal of transcriptional
machinery from active templates. This transcriptional repression can occur by
indirect mechanisms involving the time-dependent assembly of repressive
nucleoprotein complexes, which are able to inhibit transcription more effectively
than nucleosomes alone.
PMID- 9395434
TI - The lipid transfer activity of phosphatidylinositol transfer protein is
sufficient to account for enhanced phospholipase C activity in turkey erythrocyte
ghosts.
AB - BACKGROUND: The minor membrane phospholipid phosphatidylinositol 4, 5
bisphosphate (PIP2) has been implicated in the control of a number of cellular
processes. Efficient synthesis of this lipid from phosphatidylinositol has been
proposed to require the presence of a phosphatidylinositol/phosphatidylcholine
transfer protein (PITP), which transfers phosphatidylinositol and
phosphatidylcholine between membranes, but the mechanism by which PITP exerts its
effects is currently unknown. The simplest hypothesis is that PITP replenishes
agonist-sensitive pools of inositol lipids by transferring phosphatidylinositol
from its site of synthesis to sites of consumption. Recent cellular studies,
however, led to the proposal that PITP may play a more active role as a co-factor
which stimulates the activity of phosphoinositide kinases and phospholipase C
(PLC) by presenting protein-bound lipid substrates to these enzymes. We have
exploited turkey erythrocyte membranes as a model system in which it has proved
possible to distinguish between the above hypotheses of PITP function. RESULTS:
In turkey erythrocyte ghosts, agonist-stimulated PIP2 hydrolysis is initially
rapid, but it declines and reaches a plateau when approximately 15% of the
phosphatidylinositol has been consumed. PITP did not affect the initial rate of
PIP2 hydrolysis, but greatly prolonged the linear phase of PLC activity until at
least 70% of phosphatidylinositol was consumed. PITP did not enhance the initial
rate of phosphatidylinositol 4-kinase activity but did increase the unstimulated
steady-state levels of both phosphatidylinositol 4-phosphate and PIP2 by a
catalytic mechanism, because the amount of polyphosphoinositides synthesized
greatly exceeded the molar amount of PITP in the assay. Furthermore, when
polyphosphoinositide synthesis was allowed to proceed in the presence of
exogenous PITP, after washing ghosts to remove PITP before activation of PLC,
enhanced inositol phosphate production was observed, whether or not PITP was
present in the subsequent PLC assay. CONCLUSION: PITP acts by catalytically
transferring phosphatidylinositol down a chemical gradient which is created as a
result of the depletion of phosphatidylinositol at its site of use by the
concerted actions of the phosphoinositide kinases and PLC. PITP is therefore not
a co-factor for the phosphoinositide-metabolizing enzymes present in turkey
erythrocyte ghosts.
PMID- 9395435
TI - Human p21-activated kinase (Pak1) regulates actin organization in mammalian
cells.
AB - BACKGROUND: The Rho family GTPases Cdc42, Rac1 and RhoA regulate the
reorganization of the actin cytoskeleton induced by extracellular signals such as
growth factors. In mammalian cells, Cdc42 regulates the formation of filopodia,
whereas Rac regulates lamellipodia formation and membrane ruffling, and RhoA
regulates the formation of stress fibers. Recently, the serine/threonine protein
kinase p65(pak) autophosphorylates, thereby increasing its catalytic activity
towards exogenous substrates. This kinase is therefore a candidate effector for
the changes in cell shape induced by growth factors. RESULTS: Here, we report
that the microinjection of activated Pak1 protein into quiescent Swiss 3T3 cells
induces the rapid formation of polarized filopodia and membrane ruffles. The
prolonged overexpression of Pak1 amino-terminal mutants that are unable to bind
Cdc42 or Rac1 results in the accumulation of filamentous actin in large,
polarized membrane ruffles and the formation of vinculin-containing focal
complexes within these structures. This phenotype resembles that seen in motile
fibroblasts. The amino-terminal Pak1 mutant displays enhanced binding to the
adaptor protein Nck, which contains three Src-homology 3 (SH3) domains. Mutation
of a proline residue within a conserved SH3-binding region at the amino terminus
of Pak1 interferes with SH3-protein binding and alters the effects of Pak1 on the
cytoskeleton. CONCLUSIONS: These results indicate that Pak1, acting through a
protein that contains an SH3 domain, regulates the structure of the actin
cytoskeleton in mammalian cells, and may serve as an effector for Cdc42 and/or
Rac1 in promoting cell motility.
PMID- 9395436
TI - Ras signalling is required for inactivation of the tumour suppressor pRb cell
cycle control protein.
AB - Ras proteins act as molecular switches, responding to signals by entering the
active GTP-bound, rather than the inactive GDP-bound, state. The inhibition of
normal Ras proteins by microinjection of neutralizing antibody or expression of
dominant-negative mutants has shown that Ras signalling is required for growth
factors to stimulate DNA synthesis [1] [2], but the link between Ras and the cell
cycle machinery is not clear. Regulation of the phosphorylation state of the
retinoblastoma protein (pRb), the product of the tumour suppressor gene Rb, is a
key event in the progression of cells from G1 phase into S phase. In growth
arrested or early G1 cells, pRb is hypophosphorylated and binds to transcription
factors of the E2F family [3]. These pRb-E2F complexes act to suppress gene
transcription required for entry into DNA synthesis either by preventing E2F from
stimulating transcription or by actively repressing transcription [4]. During G1,
cyclin-dependent kinases (CDKs) become activated and phosphorylate pRb at
multiple sites, leading to the dissolution of pRb-E2F complexes and gene
transcription [5]. Here, we have tested the hypothesis that Ras signalling is
required for the inactivation of pRb. A neutralizing antibody directed against
p21Ras was microinjected into cells derived from mutant mouse embryos that lack
Rb or CDK inhibitors (CDKIs). Cells without pRb or the p16 CDKI were more
resistant to the inhibitory effects of the anti-Ras antibody. DNA synthesis in
some tumour cell lines was completely resistant to the anti-Ras injection,
indicating that p21Ras is required for pRb inactivation but also has other
functions in cell-cycle progression.
PMID- 9395437
TI - Images in clinical medicine. Werner's syndrome.
PMID- 9395438
TI - Interprovincial data requirements for local health indicators: the British
Columbia experience.
AB - Indicators based on the registration of vital events are used to determine the
health status of populations. The need for these indicators at the regional and
community levels has grown with the trend toward decentralization in the delivery
of health services. Such indicators are important because they affect funding and
the types of service that are provided. Health status indicators tend to be
associated with variables such as the level of urbanization or socioeconomic
status. According to four indicators-mortality ratios for all causes of death,
mortality ratios for external causes of death, infant mortality ratios, and low
birth weight live birth ratios-some areas of British Columbia, specifically along
the border with Alberta, have relatively good health, although the
characteristics of these regions suggest that this should not be the case.
However, a much different picture emerges when vital event data registered in
Alberta for residents of these areas of British Columbia are considered. This
article shows that for adequate health planning and program implementation, some
communities need data from neighbouring provinces. It illustrates the effect of
incorporating Alberta data into the development of health status indicators for
British Columbia. It also suggests that similar adjustments may be necessary for
data compiled in other provinces.
PMID- 9395439
TI - The Health Utility Index: measuring health differences in Ontario by
socioeconomic status.
AB - The positive relationship between socioeconomic status (SES) and longevity has
long been established. Comparable evidence exists for SES and morbidity, but
observations of this relationship tend to be limited to specific health
indicators. In this article, a comprehensive quantitative measure of health
status, the Health Utility Index (HUI), is applied to an analysis of the
relationship between SES and the health status of people aged 25 and over in
Ontario. The HUI, based on a set of questions included in the 1990 Ontario Health
Survey (OHS), provides a summary index of the health of each respondent. The OHS
data show that lower levels of education, income, and occupation are associated
with lower HUI values. Health status differences across SES groups are greater in
late middle-age than at younger or older ages, a pattern consistent with the
findings of other studies. The development of summary indicators like the HUI is
part of a larger effort to construct measures for monitoring the health of
Canadians.
PMID- 9395440
TI - Causes of death: how the sexes differ.
PMID- 9395441
TI - Accidents in Canada, 1988 and 1993.
AB - Using data from Statistics Canada's 1988 and 1993 General Social Survey (GSS),
this article examines the incidence and consequences of accidents in Canada and
the characteristics of respondents aged 15 and over who were involved in them. In
1993, an estimated 3.9 million Canadians reported that they had been involved in
4.8 million accidents in the previous 12 months. Motor vehicle accidents and
sports accidents were the most frequent, each accounting for about 27% of
incidents, followed by accidents at work (21%) and at home (14%). Accidents were
most common among young people, particularly men. However, from 1988 to 1993,
there was a decline in the proportion of adults reporting accidents, and the
sharpest drop was for the age group most at risk-15- to 24-year-olds. Most of the
downturn was attributable to a decrease in the motor vehicle accident rate. Since
alcohol is known to be associated with accidents, reduced consumption during the
same period may have been partly responsible for the decline in accident rates.
Other factors that may have contributed include stricter enforcement of impaired
driving legislation and speed limits, and improvements in automobile safety.
Nonetheless, despite the decline in accident rates, the toll taken by accidents
reported in 1993 was considerable: 80% of accidents caused personal injury, and
almost half of these resulted in medical attention in a hospital. Overall, 62% of
accidents resulted in activity-loss days, and 29% involved bed-disability days.
Hospital utilization costs associated with these accidents in 1993 were about
$1.5 billion. As well, about one-third of accidents involved out-of-pocket
expenses, totalling $791 million. Moreover, accidents continue to be the leading
cause of death among persons under age 44.
PMID- 9395442
TI - Mechanism of ion transport across membranes. Bacteriorhodopsin as a prototype for
proton pumps.
PMID- 9395443
TI - A caveolar complex between the cationic amino acid transporter 1 and endothelial
nitric-oxide synthase may explain the "arginine paradox".
AB - Immunohistochemistry of porcine pulmonary artery endothelial cells (PAEC) with
antibodies specific for caveolin, endothelial nitric-oxide synthase (eNOS), and
the arginine transporter (CAT1) demonstrates that all of these proteins co
localize in plasma membrane caveolae. When incubated with solubilized PAEC plasma
membrane proteins, eNOS-specific antibody immunoprecipitates CAT1-mediated
arginine transport. These results document the existence of a caveolar complex
between CAT1 and eNOS in PAEC that provides a mechanism for the directed delivery
of substrate arginine to eNOS. Direct transfer of extracellular arginine to
membrane-bound eNOS accounts for the "arginine paradox" and explains why caveolar
localization of eNOS is required for optimal nitric oxide production by
endothelial cells.
PMID- 9395444
TI - Expression cloning of a novel scavenger receptor from human endothelial cells.
AB - Scavenger receptors mediate the endocytosis of chemically modified lipoproteins,
such as acetylated low density lipoprotein (Ac-LDL) and oxidized LDL (Ox-LDL),
and have been implicated in the pathogenesis of atherosclerosis. The evidence
that endothelial cells possess scavenger receptor activity is substantial, and
this property is widely used in the isolation of endothelial cells from vascular
tissues. In the current study, we have isolated, by expression cloning, the cDNA
encoding a novel type of scavenger receptor expressed by endothelial cells
(SREC), which mediates the binding and degradation of Ac-LDL. The primary
structure of the molecule has no significant homology to other types of scavenger
receptors, including the recently cloned endothelial cell Ox-LDL receptor, a
member of the C-type lectin family. The cDNA encodes a protein of 830 amino acids
with a calculated molecular mass of 85, 735 Da (mature peptide). Chinese hamster
ovary cells stably expressing SREC bound 125I-labeled Ac-LDL with high affinity
(Kd = 3.0 microg/ml, approximately 1.7 nM) and degraded them via an endocytic
pathway. Association of DiII-Ac-LDL were effectively inhibited by Ox-LDL,
malondialdehyde-modified LDL, dextran sulfate, and polyinosinic acid, but not by
natural LDL and heparin. The cloned receptor has several characteristic domain
structures, including an N-terminal extracellular domain with five epidermal
growth factor-like cysteine pattern signatures and an unusually long C-terminal
cytoplasmic domain (391 amino acids) composed of a Ser/Pro-rich region followed
by a Gly-rich region.
PMID- 9395445
TI - Sarcospan, the 25-kDa transmembrane component of the dystrophin-glycoprotein
complex.
AB - The dystrophin-glycoprotein complex is a multisubunit protein complex that spans
the sarcolemma and forms a link between the subsarcolemmal cytoskeleton and the
extracellular matrix. Primary mutations in the genes encoding the proteins of
this complex are associated with several forms of muscular dystrophy. Here we
report the cloning and characterization of sarcospan, a unique 25-kDa member of
this complex. Topology algorithms predict that sarcospan contains four
transmembrane spanning helices with both N- and C-terminal domains located
intracellularly. Phylogenetic analysis reveals that sarcospan's arrangement in
the membrane as well as its primary sequence are similar to that of the tetraspan
superfamily of proteins. Sarcospan co-localizes and co-purifies with the
dystrophin-glycoprotein complex, demonstrating that it is an integral component
of the complex. We also show that sarcospan expression is dramatically reduced in
muscle from patients with Duchenne muscular dystrophy. This suggests that
localization of sarcospan to the membrane is dependent on proper dystrophin
expression. The gene encoding sarcospan maps to human chromosome 12p11.2, which
falls within the genetic locus for congenital fibrosis of the extraocular muscle,
an autosomal dominant muscular dystrophy.
PMID- 9395446
TI - Correlating Ca2+ responses and secretion in individual RBL-2H3 mucosal mast
cells.
AB - The role of Ca2+ in stimulus-response coupling in nonexcitable cells is still not
well understood. The Ca2+ responses of individual cells are extremely diverse,
often displaying marked oscillations, and almost nothing is known about the
specific features of these Ca2+ signals that are important for the functional
response of a cell. Using the RBL-2H3 mucosal mast cell as a model, we have
studied the temporal relationship between changes in intracellular Ca2+ and
serotonin secretion at the single-cell level using simultaneous indo-1 photometry
and constant potential amperometry. Secretion in response to antigen never occurs
until intracellular Ca2+ is elevated, nor is it seen during the first few
oscillations in Ca2+. Exocytotic events tend to be clustered around the peaks of
oscillations, but excellent secretion is also seen in cells with sustained
elevations in Ca2+. Ca2+ release from stores in the absence of influx fails to
elicit secretion. If refilling and continued release of Ca2+ from stores is
prevented with thapsigargin, Ca2+ influx can still trigger secretion, suggesting
that store-associated microdomains of Ca2+ are not required for exocytosis. Our
findings demonstrate the importance of an amplitude-encoded Ca2+ signal and Ca2+
influx for stimulus-secretion coupling in these nonexcitable cells.
PMID- 9395447
TI - An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1.
AB - Ral proteins constitute a family of small GTPases that can be activated by Ras in
cells. In the GTP-bound state, Ral proteins bind to RalBP1, a GTPase-activating
protein for CDC42 and Rac GTPases. We have used the two-hybrid system in yeast to
clone a cDNA for a novel approximately 85-kDa protein that can bind to an
additional site on RalBP1. This newly identified protein contains an Eps homology
(EH) domain, which was first detected in the epidermal growth factor (EGF)
receptor substrate Eps15. Recently, the EH domain of Eps15 has been shown to bind
to proteins containing an asparagine-proline-phenylalanine motif. Moreover, EH
domains have been found in proteins involved in endocytosis and/or actin
cytoskeleton regulation. The RalBP1 associated Eps-homology domain protein,
Reps1, is tyrosine-phosphorylated in response to EGF stimulation of cells. In
addition, Reps1 has the capacity to form a complex with the SH3 domains of the
adapter proteins Crk and Grb2, which may link Reps1 to an EGF-responsive tyrosine
kinase. Thus, Reps1 may coordinate the cellular actions of activated EGF
receptors and Ral-GTPases.
PMID- 9395448
TI - Characterization of substrate phosphorylation and use of calmodulin mutants to
address implications from the enzyme crystal structure of calmodulin-dependent
protein kinase I.
AB - Calcium/calmodulin (CaM) directly activates CaM-dependent protein kinase I
(CaMKI) by binding to the enzyme and indirectly promotes the phosphorylation and
synergistic activation of CaMKI by an exogenous kinase. We have evaluated the
initial CaM-dependent activation of the unphosphorylated form of CaMKI. The
kinetics of bacterially expressed human CaMKI show that the peptide syntide-2 is
a relatively poor substrate, whereas the synapsin site-1 peptide is 17-fold more
specific. The peptide ADR1G is 400-fold more specific than syntide-2, and its
catalytic rate is among the highest reported for a kinase peptide substrate. To
understand how CaM activates CaMKI, we have characterized the activation of the
enzyme by CaM mutants with substitutions at hydrophobic residues. The point
mutant M124Q located in the C-terminal domain of CaM produced a 57-fold increase
in the CaM activation constant for CaMKI and suggests the involvement of
methionine 124 in an important hydrophobic interaction with tryptophan 303 of
CaMKI. Substituting two, three, and five hydrophobic residues in the N-terminal
domain of CaM increased the CaM activation constant for CaMKI by 10-190-fold and
lowered the maximal enzyme activity by more than 80%. Two of these N-terminal
mutants of CaM do not affect the Km for peptide substrate but instead produce a 5
10-fold higher Km for ATP. This result demonstrates the critical role of the N
terminal domain of CaM in regulating the access of ATP to CaMKI.
PMID- 9395449
TI - COL1A1 transgene expression in stably transfected osteoblastic cells. Relative
contributions of first intron, 3'-flanking sequences, and sequences derived from
the body of the human COL1A1 minigene.
AB - Collagen reporter gene constructs have be used to identify cell-specific
sequences needed for transcriptional activation. The elements required for
endogenous levels of COL1A1 expression, however, have not been elucidated. The
human COL1A1 minigene is expressed at high levels and likely harbors sequence
elements required for endogenous levels of activity. Using stably transfected
osteoblastic Py1a cells, we studied a series of constructs (pOBColCAT) designed
to characterize further the elements required for high level of expression.
pOBColCAT, which contains the COL1A1 first intron, was expressed at 50-100-fold
higher levels than ColCAT 3.6, which lacks the first intron. This difference is
best explained by improved mRNA processing rather than a transcriptional effect.
Furthermore, variation in activity observed with the intron deletion constructs
is best explained by altered mRNA splicing. Two major regions of the human COL1A1
minigene, the 3'-flanking sequences and the minigene body, were introduced into
pOBColCAT to assess both transcriptional enhancing activity and the effect on
mRNA stability. Analysis of the minigene body, which includes the first five
exons and introns fused with the terminal six introns and exons, revealed an
orientation-independent 5-fold increase in CAT activity. In contrast the 3'
flanking sequences gave rise to a modest 61% increase in CAT activity. Neither
region increased the mRNA half-life of the parent construct, suggesting that CAT
specific mRNA instability elements may serve as dominant negative regulators of
stability. This study suggests that other sites within the body of the COL1A1
minigene are important for high expression, e.g. during periods of rapid
extracellular matrix production.
PMID- 9395450
TI - PKC-epsilon is required for mechano-sensitive activation of ERK1/2 in endothelial
cells.
AB - Mechano-sensitive regulation of endothelial cells (EC) function by shear stress
is critical for flow-induced vasodilation and gene expression. Previous studies
by our laboratory demonstrated that shear stress activates the 44- and 42-kDa
extracellular signal-regulated kinases (ERK1/2) in EC in a time- and force
dependent manner. ERK1/2 activation was inhibited by protein kinase C (PKC) down
regulation with phorbol 12,13-dibutyrate (1 microM for 24 h) but not by calcium
chelation with BAPTA-AM (acetoxymethyl ester of BAPTA) (75 microM for 30 min),
suggesting that a novel PKC isoform (delta, epsilon, eta, theta) mediates shear
stress-induced ERK1/2 activation. Western blotting with PKC isoform-specific
antibodies demonstrated expression of PKC-alpha, -epsilon, and -zeta isoforms in
EC. PKC-epsilon was specifically inhibited by transfection with antisense PKC
epsilon phosphorothioate oligonucleotides (1,000 nM for 6 h). Antisense treatment
decreased PKC-epsilon protein levels by 80 +/- 13% after 72 h and completely
inhibited shear stress-stimulated ERK1/2 activation. Scrambled PKC-epsilon
oligonucleotides and antisense PKC-alpha and PKC-zeta oligonucleotides had no
effect on ERK1/2 activity. PKC-epsilon appeared specific for mechano-sensitive
ERK1/2 activation, as antisense PKC-epsilon oligonucleotides did not inhibit
ERK1/2 activation by EGF or bradykinin but did inhibit ERK1/2 activation upon EC
adhesion to fibronectin. These results define a pathway for shear stress-mediated
ERK1/2 activation and establish a new function for PKC-epsilon as part of a
mechano-sensitive signal transduction pathway in EC.
PMID- 9395451
TI - Molecular and biochemical characterization of an endo-beta-1,3- glucanase of the
hyperthermophilic archaeon Pyrococcus furiosus.
AB - We report here the first molecular characterization of an endo-beta-1,3-glucanase
from an archaeon. Pyrococcus furiosus is a hyperthermophilic archaeon that is
capable of saccharolytic growth. The isolated lamA gene encodes an extracellular
enzyme that shares homology with both endo-beta-1,3- and endo-beta-1,3-1,4
glucanases of the glycosyl hydrolase family 16. After deletion of the N-terminal
leader sequence, a lamA fragment encoding an active endo-beta-1,3-glucanase was
overexpressed in Escherichia coli using the T7-expression system. The purified P.
furiosus endoglucanase has highest hydrolytic activity on the beta-1,3-glucose
polymer laminarin and has some hydrolytic activity on the beta-1,3-1,4 glucose
polymers lichenan and barley beta-glucan. The enzyme is the most thermostable
endo-beta-1,3-glucanase described up to now; it has optimal activity at 100-105
degrees C. In the predicted active site of glycosyl hydrolases of family 16 that
show predominantly endo-beta-1,3-glucanase activity, an additional methionine
residue is present. Deletion of this methionine did not change the substrate
specificity of the endoglucanase, but it did cause a severe reduction in its
catalytic activity, suggesting a structural role of this residue in constituting
the active site. High performance liquid chromatography analysis showed in vitro
hydrolysis of laminarin by the endo-beta-1,3-glucanase proceeds more efficiently
in combination with an exo-beta-glycosidase from P. furiosus (CelB). This most
probably reflects the physiological role of these enzymes: cooperation during
growth of P. furiosus on beta-glucans.
PMID- 9395452
TI - Purification and characterization of recombinant catalase-peroxidase, which
confers isoniazid sensitivity in Mycobacterium tuberculosis.
AB - The Mycobacterium tuberculosis katG gene encodes a dual-function enzyme called
catalase-peroxidase, which confers sensitivity in M. tuberculosis to isonicotinic
acid hydrazide. We have constructed a system for the high level expression of a
recombinant form of this enzyme by amplifying the katG gene from the pYZ56
construct (1) and subcloning into a vector suitable for expression in Escherichia
coli. The resulting plasmid, pTBCP, produced the catalase-peroxidase in large
quantities, corresponding to 30% of total cell protein. The enzyme has been
purified to homogeneity and appears to be a dimer in the native form. Using
either hydrogen peroxide or t-butyl hydroperoxide and 2,2'-azino-bis(3
ethylbenzthiazoline-6-sulfonic acid) as substrates, kcat and Km values have been
obtained for both catalatic and peroxidatic activities, respectively. The
availability of significant quantities of an active, folded, recombinant form of
M. tuberculosis catalase-peroxidase should thus facilitate future studies of its
role in drug activation and antibiotic resistance.
PMID- 9395453
TI - Muscarinic receptor-mediated dual regulation of ADP-ribosyl cyclase in NG108-15
neuronal cell membranes.
AB - Cyclic ADP-ribose (cADP-ribose) is an endogenous modulator of ryanodine-sensitive
Ca2+ release channels. An unsolved question is whether or not cADP-ribose
mediates intracellular signals from hormone or neurotransmitter receptors. The
first step in this study was to develop a TLC method to measure ADP-ribosyl
cyclase, by which conversion of [3H]NAD+ to [3H]cADP-ribose was confirmed in COS
7 cells overexpressing human CD38. A membrane fraction of NG108-15 neuroblastoma
x glioma hybrid cells possessed ADP-ribosyl cyclase activity measured by TLC.
Carbamylcholine increased this activity by 2.6-fold in NG108-15 cells
overexpressing m1 or m3 muscarinic acetylcholine receptors (mAChRs), but
inhibited it by 30-52% in cells expressing m2 and/or m4 mAChRs. Both of these
effects were mimicked by GTP. Pretreatment of cells with cholera toxin blocked
the activation, whereas pertussis toxin blocked the inhibition. Application of
carbamylcholine caused significant decreases in NAD+ concentrations in untreated
m1-transformed NG108-15 cells, but an increase in cholera toxin-treated cells.
These results suggest that mAChRs couple to ADP-ribosyl cyclase within cell
membranes via trimeric G proteins and can thereby control cellular function by
regulating cADP-ribose formation.
PMID- 9395454
TI - Differential regulation of the transcriptional activity of the orphan nuclear
receptor NGFI-B by membrane depolarization and nerve growth factor.
AB - The immediate-early gene NGFI-B (also called nur77) encodes an orphan nuclear
receptor that activates transcription through a unique response element (NBRE).
NGFI-B is rapidly induced and modified via phosphorylation by a variety of
stimuli that induce cells to differentiate or to proliferate. We have shown that
the in vitro phosphorylation of Ser350 located within the "A-box," a motif
necessary for DNA binding by NGFI-B, results in a decrease in the binding of NGFI
B to its response element (Hirata, Y., Kiuchi, K., Chen, H.-C., Milbrandt, J.,
and Guroff, G. (1993) J. Biol. Chem. 268, 24808-24812). We show here that nerve
growth factor (NGF)-induced changes in the in vivo phosphorylation of Ser350
accompany transcriptional deactivation of NGFI-B in PC12 cells, that membrane
depolarization and NGF treatment cause differential phosphorylation of NGFI-B,
and that the transcriptional activation caused by exogenous expression of NGFI-B
or membrane depolarization can be inhibited by NGF treatment. In addition, the
mutation of Ser350 to Ala abolished the inhibitory effect of NGF on the
transcriptional activation of NGFI-B in PC12 cells. These data could provide new
insights into the regulation of transcriptional activity required for some
neurons to switch from activity-dependent survival to neurotrophin-dependent
survival during development.
PMID- 9395455
TI - Heparan sulfate proteoglycans participate in hepatic lipaseand apolipoprotein E
mediated binding and uptake of plasma lipoproteins, including high density
lipoproteins.
AB - High density lipoprotein (HDL) particles and HDL cholesteryl esters are taken up
by both receptor-mediated and non-receptor-mediated pathways. Here we show that
cell surface heparan sulfate proteoglycans (HSPG) participate in hepatic lipase
(HL)- and apolipoprotein (apo) E-mediated binding and uptake of mouse and human
HDL by cultured hepatocytes. The HL secreted by HL-transfected McA-RH7777 cells
enhanced both HDL binding at 4 degrees C (approximately 2-4-fold) and HDL uptake
at 37 degrees C (approximately 2-5-fold). The enhanced binding and uptake of HDL
were partially inhibited by the 39-kDa protein, an inhibitor of low density
lipoprotein receptor-related protein (LRP), but were almost totally blocked by
heparinase, which removes the sulfated glycosaminoglycan chains from HSPG.
Therefore, HL may mediate the uptake of HDL by two pathways: an HSPG-dependent
LRP pathway and an HSPG-dependent but LRP-independent pathway. The HL-mediated
binding and uptake of HDL were only minimally reduced when catalytically inactive
HL or LRP binding-defective HL was substituted for wild-type HL, indicating that
much of the HDL uptake required neither HL binding to the LRP nor lipolytic
processing. To study the role of HL in facilitating the selective uptake of
cholesteryl esters, we used HDL into which radiolabeled cholesteryl ether had
been incorporated. HL increased the selective uptake of HDL cholesteryl ether;
this enhanced uptake was reduced by more than 80% by heparinase but was
unaffected by the 39-kDa protein. Like HL, apoE enhanced the binding and uptake
of HDL (approximately 2-fold) but had little effect on the selective uptake of
HDL cholesteryl ether. In the presence of HL, apoE did not further increase the
uptake of HDL, and at a high concentration apoE impaired or decreased the HL
mediated uptake of HDL. Therefore, HL and apoE may utilize similar (but not
identical) binding sites to mediate HDL uptake. Although the relative importance
of cell surface HSPG in the overall metabolism of HDL in vivo remains to be
determined, cultured hepatocytes clearly displayed an HSPG-dependent pathway that
mediates the binding and uptake of HDL. This study also demonstrates the
importance of HL in enhancing the binding and uptake of remnant and low density
lipoproteins via an HSPG-dependent pathway.
PMID- 9395456
TI - Bovine proenteropeptidase is activated by trypsin, and the specificity of
enteropeptidase depends on the heavy chain.
AB - Enteropeptidase, also known as enterokinase, initiates the activation of
pancreatic hydrolases by cleaving and activating trypsinogen. Enteropeptidase is
synthesized as a single-chain protein, whereas purified enteropeptidase contains
a approximately 47-kDa serine protease domain (light chain) and a disulfide
linked approximately 120-kDa heavy chain. The heavy chain contains an amino
terminal membrane-spanning segment and several repeated structural motifs of
unknown function. To study the role of heavy chain motifs in substrate
recognition, secreted variants of recombinant bovine proenteropeptidase were
constructed by replacing the transmembrane domain with a signal peptide. Secreted
variants containing both the heavy chain (minus the transmembrane domain) and the
catalytic light chain (pro-HL-BEK (where BEK is bovine enteropeptidase)) or only
the catalytic domain (pro-L-BEK) were expressed in baby hamster kidney cells and
purified. Single-chain pro-HL-BEK and pro-L-BEK were zymogens with extremely low
catalytic activity, and both were activated readily by trypsin cleavage.
Trypsinogen was activated efficiently by purified enteropeptidase from bovine
intestine (Km = 5.6 microM and kcat = 4.0 s-1) and by HL-BEK (Km = 5.6 microM and
kcat = 2.2 s-1), but not by L-BEK (Km = 133 microM and kcat = 0.1 s-1); HL-BEK
cleaved trypsinogen at pH 5.6 with 520-fold greater catalytic efficiency than did
L-BEK. Qualitatively similar results were obtained at pH 8.4. In contrast to this
striking difference in trypsinogen recognition, the small synthetic substrate Gly
Asp-Asp-Asp-Asp-Lys-beta-naphthylamide was cleaved with similar kinetic
parameters by both HL-BEK (Km = 0.27 mM and kcat = 0.07 s-1) and L-BEK (Km = 0.60
mM and kcat = 0.06 s-1). The presence of the heavy chain also influenced the rate
of reaction with protease inhibitors. Bovine pancreatic trypsin inhibitor
preferred HL-BEK (initial Ki = 99 nM and final Ki* = 1.8 nM) over L-BEK (Ki = 698
nM and Ki* = 6.2 nM). Soybean trypsin inhibitor exhibited a reciprocal pattern,
inhibiting L-BEK (Ki* = 1.6 nM), but not HL-BEK. These kinetic data indicate that
the enteropeptidase heavy chain has little influence on the recognition of small
peptides, but strongly influences macromolecular substrate recognition and
inhibitor specificity.
PMID- 9395457
TI - A novel white laccase from Pleurotus ostreatus.
AB - Two laccase isoenzymes (POXA1 and POXA2) produced by Pleurotus ostreatus were
purified and fully characterized. POXA1 and POXA2 are monomeric glycoproteins
with 3 and 9% carbohydrate content, molecular masses of about 61 and 67 kDa by
sodium dodecyl sulfate polyacrylamide gel electrophoresis, of about 54 and 59 kDa
by gel filtration in native conditions, and of 61 kDa by matrix-assisted laser
desorption ionization mass spectrometry (only for POXA1) and pI values of 6.7 and
4.0, respectively. The N terminus and three tryptic peptides of POXA1 have been
sequenced, revealing clear homology with laccases from other microorganisms,
whereas POXA2 showed a blocked N terminus. The stability of POXA2 as a function
of temperature was particularly low, whereas POXA1 showed remarkable high
stability with respect to both pH and temperature. Both enzymes oxidize
syringaldazine and ABTS (2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid))
together with a variety of different substituted phenols and aromatic amines with
the concomitant reduction of oxygen, but POXA1 is unable to oxidize guaiacol.
Both enzymes were strongly inhibited by sodium azide and thioglycolic acid but
not by EDTA. UV/visible absorption spectra, atomic adsorption, and polarographic
data indicated the presence of 4 copper atoms/mol of POXA2 but only one copper,
two zinc, and one iron atoms were found/mol of POXA1. The neutral pI and the
anomalous metal content of POXA1 laccase render this enzyme unique in its
structural characteristics. The lack of typical absorbance at 600 nm allows its
classification as a "white" laccase.
PMID- 9395458
TI - Effects of intravesicular H+ and extracellular H+ and Zn2+ on insulin secretion
in pancreatic beta cells.
AB - The effects of extracellular Zn2+ and pH and intravesicular pH on insulin and 5
hydroxytryptamine (5-HT) secretion from pancreatic beta cells were investigated.
Insulin and 5-HT secretion from single cells was detected by amperometry as a
series of current spikes corresponding to detection of multimolecular packets
secreted by exocytosis. Spike width was used as a measure of the kinetics of
clearance from the cell and the area of spikes as a measure of amount released.
Changes in extracellular pH from 6.9 to 7.9 caused insulin spikes to become
narrower with no change in area, whereas the same treatments had no effect on 5
HT secretion. Treatment of cells with Bafilomycin A1 or N-ethylmaleimide, both of
which are expected to increase intravesicular pH by inhibiting V-type H+-ATPase,
had no effect on 5-HT secretion but caused insulin spikes to become more narrow.
These results indicate that exposure to high pH, whether intravesicular or
extracellular, accelerates release of insulin during exocytosis without affecting
the amount of insulin released. Increasing extracellular Zn2+ concentration from
0 to 25 microM increased the width and decreased the area of insulin spikes
without affecting 5-HT secretion. Zn2+ effects were likely exerted through a
common-ion effect on Zn2+-insulin dissociation. It was concluded that
intravesicular storage conditions and extracellular ions can affect free insulin
concentration in the vicinity of beta cells during secretion.
PMID- 9395459
TI - Identification and cloning of the membrane-associated serine protease, hepsin,
from mouse preimplantation embryos.
AB - Previous studies have suggested the existence of a membrane-associated serine
protease expressed by mammalian preimplantation embryos. In this study, we have
identified hepsin, a type II transmembrane serine protease, in early mouse
blastocysts. Mouse hepsin was highly homologous to the previously identified
human and rat cDNAs. Two isoforms, differing in their cytoplasmic domains, were
detected. The tissue distribution of mouse hepsin was similar to that seen in
humans, with prominent expression in liver and kidney. In mouse embryos, hepsin
expression was observed in the two-cell stage, reached a maximal level at the
early blastocyst stage, and decreased subsequent to blastocyst hatching.
Expression of a soluble form of hepsin revealed its ability to autoactivate in a
concentration-dependent manner. Catalytically inactive soluble hepsin was unable
to autoactivate. These results suggest that hepsin may be the first serine
protease expressed during mammalian development, making its ability to
autoactivate critical to its function.
PMID- 9395460
TI - Activation of PKCalpha downstream from caspases during apoptosis induced by 7
hydroxystaurosporine or the topoisomerase inhibitors, camptothecin and etoposide,
in human myeloid leukemia HL60 cells.
AB - We previously demonstrated that the anticancer agent and protein kinase C (PKC)
inhibitor 7-hydroxystaurosporine (UCN-01) induces apoptosis independently of p53
and protein synthesis in HL60 cells. We now report the associated changes of PKC
isoforms. PKCalpha, betaI, betaII, delta, and zeta activities were measured after
immunoprecipitation of cytosols from UCN-01-treated HL60 cells. UCN-01 had no
effect on PKCzeta and inhibited kinase activity of PKCbetaI, betaII, and delta.
PKCalpha activity was initially inhibited at 1 h, and subsequently increased as
cells underwent apoptosis 3 h after the beginning of UCN-01 treatment.
Camptothecin (CPT) and etoposide (VP-16) also markedly enhanced PKCalpha activity
during apoptosis in HL60 cells. However, CPT did not affect PKCbetaI, betaII and
zeta, and activated PKCdelta. PKCalpha activation was not due to increased
protein levels or proteolytic cleavage but was associated with PKCalpha
autophosphorylation in vitro and increased phosphorylation in vivo. We also found
that not only PKC delta but also PKC betaI was proteolytically activated in HL60
cells during apoptosis. The PKCalpha activation and hyperphosphorylation were
abrogated by N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl)-fluoromethylketone (z-VAD
fmk) under conditions that abrogated apoptosis. z-VAD-fmk also prevented PKCdelta
and betaI proteolytic activation. Together these findings suggest that caspases
regulate PKC activity during apoptosis in HL60 cells. At least two modes of
activation were observed: hyperphosphorylation for PKCalpha and proteolytic
activation for PKC delta and betaI.
PMID- 9395461
TI - Exchange of subunit interfaces between recombinant adult and fetal hemoglobins.
Evidence for a functional inter-relationship among regions of the tetramer.
AB - The inter-relationship between the interior subunit interfaces and the exterior
diphosphoglycerate (DPG) binding region of the hemoglobin tetramer and the
effects of a specific N-terminal acetylation on tetramer assembly have been
evaluated. Tetrameric fetal hemoglobin F in the liganded state was found to
dissociate to dimers much less than previously appreciated, i.e. about 70 times
less than adult hemoglobin A (Kd = 0.01 microM and 0.68 microM, for HbF and HbA,
at pH 7.5, respectively) over the pH range 6.2-7.5, whereas HbF1, in which the N
termini of the gamma-chains are acetylated, dissociates like HbA. To determine
whether this feature of HbF could be transferred to hemoglobin A, the single
amino acid difference in their alpha1beta2/alpha1gamma2 interfaces and the 4
amino acid differences in their alpha1beta1/alpha1gamma1 interfaces have been
substituted in HbA to those in HbF. This pentasubstituted recombinant HbA/F had
the correct molecular weight as determined by mass spectrometry, the expected
mobility on isoelectric focusing, the calculated amino acid composition, and
normal circular dichroism properties, oxygen binding, and cooperativity. Although
HbA/F has the same amino acid side chains that bind DPG as HbA, its diminished
response to 2,3-DPG resembled that of HbF. However, its tetramer-dimer
dissociation constant (Kd = 0.14 microM) was between that of HbA and HbF despite
the fact that it was composed entirely of HbF subunit interfaces. The results
indicate that regions of the tetramer distant from the tetramer-dimer interface
influence its dissociation and, reciprocally, that the interfaces affect regions
involved in the binding of allosteric regulators, suggesting flexible long range
inter-relationships in hemoglobin.
PMID- 9395462
TI - The effect of apolipoprotein A-II on the structure and function of apolipoprotein
A-I in a homogeneous reconstituted high density lipoprotein particle.
AB - In this study we examined the effects of apoA-II on the structure and function of
apoA-I in homogeneous reconstituted HDL (rHDL). First, we measured the binding of
apoA-II to apoA-I-rHDL, containing dipalmitoylphosphatidylcholine or
palmitoyloleoylphosphatidylcholine, and the degree of apoA-I displacement at
various ratios of apolipoproteins. Using fluorescence methods, we determined that
apoA-II binding is rapid, irreversible, and associated with apoA-I displacement
only when the molar ratio of apoA-II/apoA-I is greater than 1:2. Next, we used
the stable apoA-II/apoA-I-rHDL complex at the apoA-II/apoA-I ratio of 1:2 to
examine its physical properties, apoA-I structure, and reactivity with
lecithin:cholesterol acyltransferase (LCAT). Using chemical cross-linking in
conjunction with fluorescence and electrophoretic methods, we demonstrated that
the conformation of apoA-I must be flexible to allow apoA-II binding to the apoA
I-rHDL particles and showed that the hybrid particles have an unchanged Stokes
diameter. Fluorescence and circular dichroism measurements revealed little or no
change in the secondary structure or in the N-terminal domain of apoA-I, but
showed a marked destabilization of apoA-I to denaturation by guanidine
hydrochloride. Limited tryptic digestion indicated that the central region of
apoA-I becomes accessible to proteolysis in the hybrid particles. Together, these
results suggest that amphipathic alpha-helices of apoA-II replace four central
helices of one apoA-I molecule (residues approximately 99-187) in the complex and
in the process destabilize apoA-I. Thus, apoA-II binding at physiologic ratios
may not completely displace apoA-I from HDL, but may provide a reservoir of
easily exchangeable apoA-I. Finally, we showed that the reaction of the hybrid
HDL with LCAT was inhibited 2-5-fold, relative to apoA-I-rHDL, due to a
corresponding increase in the apparent Km value. This suggests that LCAT binding
to the hybrid particles is sterically hindered by the excess protein (portions of
apoA-I and apoA-II not bound to lipid). Therefore, apoA-II can modulate the
reaction of HDL with LCAT by decreasing LCAT binding to hybrid particles and
making the enzyme available for reaction with other substrates.
PMID- 9395463
TI - Purification and specificity of beta1,2-xylosyltransferase, an enzyme that
contributes to the allergenicity of some plant proteins.
AB - The enzyme that transfers D-xylose from UDP-xylose to the beta-linked mannose of
plant N-linked oligosaccharides was purified about 51,000-fold to apparent
homogeneity from soybean microsomes. On SDS gels, two proteins of 56 and 59 kDa
were detected and both were labeled to the same extent by the photoaffinity
label, 5-N3-UDP-[32P]xylose. Labeling of both proteins was inhibited by cold UDP
xylose, but not by UDP-glucose. The amount of 5-N3-UDP-[32P]xylose that bound to
the two protein bands was greatly increased in the presence of oligosaccharide
acceptors. The best acceptor for xylose transfer and for stimulation of UDP
xylose binding was GlcNAc2Man3GlcNAc2-T, but GlcNAc1Man3GlcNAc2, with the GlcNAc
on the 3-branch, was also a good acceptor and a good stimulator. A number of
other N-linked oligosaccharides were poor acceptors, especially those with
galactose units at the nonreducing termini. Many of the properties of this enzyme
have been described, and the product of the reaction of UDP-xylose and
GlcNAc2Man3(GlcNAc)2 was characterized as GlcNAcbeta1, 2Manalpha1,
6(GlcNAcbeta1,2Manalpha1,3)(Xylbeta1,2)Manbeta1, 4GlcNA c2-T by chemical and NMR
methods.
PMID- 9395464
TI - Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of
triglyceride-rich lipoproteins to the lipolysis-stimulated receptor.
AB - ApoC-III overexpression in mice results in severe hypertriglyceridemia due
primarily to a delay in the clearance of triglyceride-rich lipoproteins. We have,
in primary cultures of rat hepatocytes, characterized a lipolysis-stimulated
receptor (LSR). The apparent number of LSR that are available on rat liver plasma
membranes is negatively correlated with plasma triglyceride concentrations
measured in the fed state. We therefore proposed that the primary physiological
role of the LSR is to contribute to the cellular uptake of triglyceride-rich
lipoproteins. We have now tested the effect of apoC-III on the binding of
triglyceride-rich lipoproteins to LSR. Supplementation of 125I-very low density
lipoprotein (VLDL) with apoC-III inhibited the LSR-mediated binding,
internalization, and degradation of 125I-VLDL in primary cultures of rat
hepatocytes. Studies using isolated rat liver plasma membranes showed that
enrichment of human VLDL and chylomicrons with synthetic or purified human apoC
III decreased their binding to the LSR by about 40%. Supplementation of
triglyceride-rich lipoproteins under the same conditions with human apoC-II had
no such inhibitory effect, despite the fact that this apoprotein bound as
efficiently as apoC-III to these particles. Preincubation of LDL with apoC-III
did not modify its binding to LSR. Partitioning studies using 125I-apoC-III
showed that this lack of effect was due to apoC-III's inability to efficiently
associate with LDL. Purified human apoC-III1 was as efficient as the synthetic
nonsialylated form of apoC-III in inhibiting binding of VLDL to LSR. However,
despite a 2-fold greater binding of apoC-III2 to VLDL, this isoform was a less
efficient inhibitor of the binding of VLDL to LSR than apoC-III1 or nonsialylated
apoC-III. Desialylation of apoC-III2 by treatment with neuraminidase increased
the inhibition of VLDL binding to LSR to a level similar to that observed with
apoC-III1 and nonsialylated apoC-III. We propose that apoC-III regulates in part
the rate of removal of triglyceride-rich particles by inhibiting their binding to
the LSR, and that the level of inhibition is determined by the degree of apoC-III
sialylation.
PMID- 9395465
TI - The carboxyl terminus of the human calcium receptor. Requirements for cell
surface expression and signal transduction.
AB - The G-protein-coupled calcium receptor plays a key role in extracellular calcium
homeostasis. To examine the role of the membrane-spanning domains and the
approximately 200-residue cytoplasmic carboxyl terminus of the calcium receptor
in cell-surface expression and signal transduction, we transfected HEK-293 cells
with a series of truncation and carboxyl-terminal missense mutants and analyzed
expression by immunoblotting, glycosidase digestion, intact cell immunoassay, and
extracellular calcium-stimulated phosphoinositide hydrolysis assay. Two
truncation mutants terminating at residues 706 and 802 within the second and
third intracellular loops, respectively, were not properly glycosylated, failed
to reach the cell-surface, and showed no calcium response, indicating that mutant
receptors with the full extracellular domain but only three or five transmembrane
domains are improperly folded and/or processed. Truncation mutants terminating at
residues 888 and 903 within the carboxyl terminus were equivalent to the wild
type in all assays, whereas mutants truncated at residues 865 and 874 showed no
response to calcium, despite only approximately 25% reduction in cell-surface
expression. Mutants with a full-length carboxyl terminus but with residues
between positions 874 and 888 replaced with alanines showed either no (Ala875,
Ala876, and Ala879) or significantly reduced (Ala881-Ala883) calcium response at
levels of cell-surface expression equivalent to those of the wild-type receptor.
These results indicate that deletion of the majority of the carboxyl terminus is
compatible with normal processing, cell-surface expression, and signal
transduction of the receptor. The truncation and alanine substitution mutants
identify a small region between residues 874 and 888 critical for normal signal
transduction by the receptor.
PMID- 9395466
TI - Identification and quantitation of the fatty acids composing the CoA ester pool
of bovine retina, heart, and liver.
AB - Several proteins found in retinal photoreceptor cells (guanylate cyclase
activating protein, protein kinase A, recoverin, and transducin) are N-terminally
modified with the fatty acids 12:0, 14:0, 14:1n-9, and 14:2n-6, whereas similar
proteins in other tissues contain only 14:0. It has been hypothesized that the
acyl-CoA pool of the retina contains amounts of 12:0, 14:1n-9, and 14:2n-6
elevated over 14:0, in comparison to other tissues, and this accounts for the
specificity of N-terminal fatty acylation. To test this hypothesis, we performed
fatty acid analysis on total acyl-CoAs purified from bovine retina (light
adapted), heart, and liver. We also examined the N- and S-linked fatty acid
composition of the total protein pools from these tissues. Acyl-CoAs were
prepared from heart, liver, and retina and separated by high performance liquid
chromatography (HPLC). Identities of peaks were based on HPLC of standard 12:0,
14:0, 14:1n-9, and 14:2n-6 CoAs. Total protein was subjected to base hydrolysis
followed by acidic methanolysis to release S- and N-linked fatty acids,
respectively, and fatty acid phenacyl esters were prepared for HPLC analysis.
Retina had levels of 12:0 (2.7 +/- 2.1%), 14:1n-9 (2.9 +/- 2.2%), and 14:2n-6
(1.6 +/- 0.7%) CoAs below that of 14:0 CoA (7.0 +/- 1.8%). Likewise, heart levels
of 14:2n-6 CoA (3.7 +/- 0.1%) were near and 12:0 (2.6 +/- 0. 6%) and 14:1n-9 (0.7
+/- 0.3%) CoAs were below that of 14:0 CoA (3.8 +/- 1.0%). Liver had levels of
12:0 (16.1 +/- 5.7%) and 14:2n-6 (8.1 +/- 1.2%) CoAs above and 14:1n-9 CoA (1.2
+/- 0.6%) below that of 14:0 CoA (5.9 +/- 0.8%). Fatty acid analysis of total
protein showed that all tissues contained S-linked 16:0, 18:0, and 18:1n-9.
Retina proteins contained N-linked 14:0, 14:1n-9, and 14:2n-6, whereas heart and
liver had only 14:0. Our findings do not support the hypothesis that the CoA
ester pool of the retina is enriched with 12:0, 14:1n-9, and 14:2n-6 over 14:0,
in comparison to other tissues. This suggests that alternative models must be
considered for the regulation of N-terminal fatty acylation of proteins in
photoreceptor cells.
PMID- 9395467
TI - cea5, a structurally divergent member of the murine carcinoembryonic antigen gene
family, is exclusively expressed during early placental development in
trophoblast giant cells.
AB - The carcinoembryonic antigen (CEA) gene family encodes a large family of
glycoproteins. Some are probably involved in the homeostasis/development of
epithelial cells and granulocyte activation, while others e.g. the pregnancy
specific glycoproteins, are expressed in the placenta and are essential for a
positive outcome of pregnancy. In this paper, we have characterized cea5, a
member of the murine CEA gene family. RNase protection and in situ hybridization
analyses revealed that Cea5 mRNA is exclusively synthesized in primary and
secondary trophoblast giant cells of the placenta only during early stages of
development. Full-length Cea5 cDNA was obtained by a reverse transcription
polymerase chain reaction using day 10.5 post-coitum placental RNA. The 1.6
kilobase pair (kb) Cea5 mRNA encodes a secreted glycoprotein with a predicted
size of 30 kDa. It is composed of a leader peptide (L), one immunoglobulin (Ig)
variable or N, and one Ig constant-like or A domain. This domain organization is
unique within the human and murine CEA families. Two overlapping cosmid clones
covering 54 kb of the cea5 gene locus were mapped. cea5 consists of three exons
(L, N, A/3'-untranslated region exon) located within a 4-kb region. rnCGM2, the
rat cea5 counterpart, exhibits the same restricted expression pattern. This
together with their exceptional conservation within the rat and murine CEA
families and their absence from the human CEA family suggests that cea5 and
rnCGM2 are of functional importance for rodent placental development.
PMID- 9395468
TI - Developmental regulation of the sulfation profile of chondroitin sulfate chains
in the chicken embryo brain.
AB - Developmentally regulated and cell type-specific expression of distinct sulfated
glycosaminoglycan structures on cell surface proteoglycans is increasingly
recognized as providing information relevant to cell-cell interactions and
differentiation in developing organisms. In this report, developmental regulation
of both the sulfation profile of chondroitin sulfate chains and activities of
chondroitin 4-sulfotransferase (C4ST) and chondroitin 6-sulfotransferase (C6ST)
were evaluated in embryonic chicken brain. The results revealed that the
sulfation profile and the sulfotransferase activities changed markedly with
development, and these alterations were precisely coordinated. Specifically, the
proportions of both chondroitin 6-sulfate to 4-sulfate and C6ST to C4ST
activities progressively decreased with development. In addition, the total
amounts of both chondroitin sulfate chains and the sulfotransferase activities
were highest during early embryonic stages and decreased sharply as the
development reached completion. The developmental expression of the C6ST gene was
also found to parallel the developmental down-regulation of both the C6ST
activity and the chondroitin 6-sulfate structure. These findings suggest that the
developmentally regulated expression of the sulfotransferases is a predominant
factor for stage-specific regulation of chondroitin sulfate structures.
PMID- 9395469
TI - The carboxyl terminus of the Saccharomyces cerevisiae succinate dehydrogenase
membrane subunit, SDH4p, is necessary for ubiquinone reduction and enzyme
stability.
AB - The succinate dehydrogenase (SDH) of Saccharomyces cerevisiae is composed of four
nonidentical subunits encoded by the nuclear genes SDH1, SDH2, SDH3, and SDH4.
The hydrophilic subunits, SDH1p and SDH2p, comprise the catalytic domain involved
in succinate oxidation. They are anchored to the inner mitochondrial membrane by
two small, hydrophobic subunits, SDH3p and SDH4p, which are required for electron
transfer and ubiquinone reduction. Comparison of the deduced primary sequence of
the yeast SDH4p subunit to SDH4p subunits from other species reveals the presence
of an unusual 25-30 amino acid carboxyl-terminal extension following the last
predicted transmembrane domain. The extension is predicted to be on the
cytoplasmic side of the inner mitochondrial membrane. To investigate the
extension's function, three truncations were created and characterized. The
results reveal that the carboxyl-terminal extension is necessary for respiration
and growth on nonfermentable carbon sources, for ubiquinone reduction, and for
enzyme stability. Combined with inhibitor studies using a ubiquinone analog, our
results suggest that the extension and more specifically, residues 128-135 are
involved in the formation of a ubiquinone binding site. Our findings support a
two-ubiquinone binding site model for the S. cerevisiae SDH.
PMID- 9395470
TI - The chicken genome contains two functional nonallelic beta1,4
galactosyltransferase genes. Chromosomal assignment to syntenic regions tracks
fate of the two gene lineages in the human genome.
AB - Two distinct but related groups of cDNA clones, CKbeta4GT-I and CKbeta4GT-II,
have been isolated by screening a chicken hepatoma cDNA library with a bovine
beta1,4-galactosyltransferase (beta4GT) cDNA clone. CKbeta4GT-I is predicted to
encode a type II transmembrane glycoprotein of 41 kDa with one consensus site for
N-linked glycosylation. CKbeta4GT-II is predicted to encode a type II
transmembrane glycoprotein of 43 kDa with five potential N-linked glycosylation
sites. At the amino acid level, the coding regions of CKbeta4GT-I and CKbeta4GT
II are 52% identical to each other and 62 and 49% identical, respectively, to
bovine beta4GT. Despite this divergence in amino acid sequence, high levels of
expression of each cDNA in Trichoplusia ni insect cells demonstrate that both
CKbeta4GT-I and CKbeta4GT-II encode an alpha-lactalbumin-responsive, UDP
galactose:N-acetylglucosamine beta4-galactosyltransferase. An analysis of
CKbeta4GT-I and CKbeta4GT-II genomic clones established that the intron positions
within the coding region are conserved when compared with each other, and these
positions are identical to the mouse and human beta4GT genes. Thus CKbeta4GT-I
and CKbeta4GT-II are the result of the duplication of an ancestral gene and
subsequent divergence. CKbeta4GT-I maps to chicken chromosome Z in a region of
conserved synteny with the centromeric region of mouse chromosome 4 and human
chromosome 9p, where beta4-galactosyltransferase (EC 2.4.1.38) had previously
been mapped. Consequently, during the evolution of mammals, it is the CKbeta4GT-I
gene lineage that has been recruited for the biosynthesis of lactose. CKbeta4GT
II maps to a region of chicken chromosome 8 that exhibits conserved synteny with
human chromosome 1p. An inspection of the current human gene map of expressed
sequence tags reveals that there is a gene noted to be highly similar to beta4GT
located in this syntenic region on human chromosome 1p. Because both the
CKbeta4GT-I and CKbeta4GT-II gene lineages are detectable in mammals, duplication
of the ancestral beta4-galactosyltransferase gene occurred over 250 million years
ago in an ancestral species common to both mammals and birds.
PMID- 9395471
TI - Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function
by mitogen-activated protein kinase.
AB - Increased serine phosphorylation of insulin receptor substrate-1 (IRS-1) has been
observed in several systems to correlate with a decreased ability of the insulin
receptor to tyrosine-phosphorylate this endogenous substrate and to inhibit its
subsequent association with phosphatidylinositol 3-kinase. In the present studies
we have examined the potential role of the mitogen-activated protein (MAP) kinase
in the increased serine phosphorylation of IRS-1 observed in human embryonic
kidney cells treated with an activator of protein kinase C, phorbol 12-myristate
13-acetate. First, recombinantly produced kinase was shown to phosphorylate
intact IRS-1 in a way that decreased the ability of isolated insulin receptor to
phosphorylate the tyrosines recognized by the SH2 domains of the
phosphatidylinositol 3-kinase. Second, an inhibitor of MAP kinase activation,
PD98059, blocked the phorbol 12-myristate 13-acetate-induced inhibition of the
insulin-stimulated increase in IRS-1 associated phosphatidylinositol 3-kinase.
Third, activation of MAP kinase in intact cells via a regulatable upstream
kinase, a RAF:estrogen receptor construct, could also inhibit the insulin
stimulated increase in IRS-1-associated phosphatidylinositol 3-kinase. Fourth, an
in gel kinase assay showed that MAP kinase was the primary renaturable kinase in
cell extracts capable of phosphorylating an IRS-1 fusion protein. Finally, IRS-1
was found to associate in coprecipitation studies with endogenous MAP kinase.
These studies implicate MAP kinase as one of the kinases capable of
phosphorylating and regulating IRS-1 tyrosine phosphorylation.
PMID- 9395472
TI - Thermodynamic analysis of the interaction between the 0.5beta Fv fragment and the
RP135 peptide antigen derived from the V3 loop of HIV-1 gp120.
AB - The Fv fragment of the 0.5beta monoclonal antibody has recently been constructed,
expressed, and purified. It binds with nanomolar affinity to the immunogenic
RP135 peptide that is derived from the principal neutralizing determinant of HIV
1 in the third hypervariable region of gp120. Here, we analyzed the temperature
dependence of binding of the 0.5beta Fv fragment to the RP135 peptide and a
series of mutants thereof. Our results show that there is almost complete
enthalpy-entropy compensation in the effects of mutations in the peptide on
binding to the Fv, indicating that the mutations do not change the binding
mechanism. There is good correlation, for residues within the antigenic epitope,
between mutational effects on DeltaCp and calculated values of DeltaDeltaCp based
on the extent of burial of polar and non-polar surface areas of amino acids. The
value of DeltaCp for the binding of the 0.5beta Fv fragment to the wild-type
RP135 peptide is found to be -5.0 (+/- 0.9) kcal K-1 mol-1 in the presence of
0.1% Tween-20 but only -0.1 (+/- 0.9) kcal K-1 mol-1 in its absence. This result
has important implications for the successful application of the structural
parameterization approach to predicting changes in heat capacity that accompany
binding reactions carried out in the presence of detergent or protein-stabilizing
agents.
PMID- 9395473
TI - Site-directed disulfide mapping of helices M4 and M6 in the Ca2+ binding domain
of SERCA1a, the Ca2+ ATPase of fast twitch skeletal muscle sarcoplasmic
reticulum.
AB - In an attempt to define the spatial relationships among SERCA1a transmembrane
helices M4, M5, M6, and M8, involved in Ca2+ binding, all six cysteine residues
were removed from predicted transmembrane sequences by substitution with Ser or
Ala. The cysteine-depleted protein retained 44% of wild type Ca2+ transport
activity. Pairs of cysteine residues were then reintroduced to determine whether
their juxtaposition would result in the formation of disulfide cross-links
between transmembrane helices. In initial studies designed to map the
juxtaposition of Ca2+ binding residues, Cys was substituted for Glu309 or Gly310
in transmembrane sequence M4, in combination with the substitution of Cys for
Glu771 in M5; for Asn796, Thr799, or Asp800 in M6; or for Glu908 in M8. These
double mutants all retained the capacity to form a phosphoenzyme intermediate
from Pi (but not from ATP in the presence of Ca2+), and in all but mutants
E309C/N796C and G310C/N796C, phosphoenzyme formation was insensitive to 100
microM Ca2+. These results support the view that both Glu309 and Asn796
contribute to Ca2+ binding site II, which is not required for conversion of E2,
the substrate for Pi phosphorylation, to E1. Cross-linking in mutants E309C/N796C
and G310C/D800C established reference points for the orientation of M4 and M6
relative to each other and provided the basis for the prediction of potential
additional cross-links. Strong links were formed with the pairs T317C/A804C and
T317C/L807C near the cytoplasmic ends of the two helices and with A305C/L792C and
A305C/L793C near the lumenal ends. These combined results support the conclusion
that M4 and M6 form a right-handed coiled-coil structure that forms part of the
pathway of Ca2+ translocation. In addition to providing a possible explanation
for the mutation sensitivity of several pairs of residues in these helices, the
proposed association of M4 and M6 supports a new model for the orientation of the
two Ca2+ binding sites among transmembrane helices M4, M5, and M6.
PMID- 9395474
TI - The molecular chaperone function of the secretory vesicle cysteine string
proteins.
AB - The "J" domains of eukaryotic DnaJ-like proteins specify interaction with various
Hsp70s. The conserved tripeptide, HPD, present in all J domains has been shown to
be important for the interaction between yeast and bacterial DnaJ/Hsp70 protein
pairs. We have characterized mutations in the HPD motif of the synaptic vesicle
protein cysteine-string protein (Csp). Mutation of the histidine (H43Q) or
aspartic acid (D45A) residues of this motif reduced the ability of Csp to
stimulate the ATPase activity of mammalian Hsc70. The H43Q and D45A mutant
proteins were not able to stimulate the ATPase activity of Hsc70 to any
significant extent. The mutant proteins were characterized by competition assays,
tryptic digestion analysis, and direct binding analysis from which it was seen
that these proteins were defective in binding to Hsc70. Thus, the HPD motif of
Csp is required for binding to Hsc70. We also analyzed the interaction between
Csp and a model substrate protein, denatured firefly luciferase. Both Csp1 and
the C-terminally truncated isoform Csp2 were able to prevent aggregation of heat
denatured luciferase, and they also cooperated with Hsc70 to prevent aggregation.
In addition, complexes of Csp1 or Csp2 with Hsc70 and luciferase were isolated,
confirming that these proteins interact and that Csps can bind directly to
denatured proteins. Csp1 and Csp2 isoforms must differ in some aspect other than
interaction with Hsc70 and substrate protein. These results show that both Csp1
and Csp2 can bind a partially unfolded protein and act as chaperones. This
suggests that Csps may have a general chaperone function in regulated exocytosis.
PMID- 9395475
TI - Two NFAT transcription factor binding sites participate in the regulation of CD95
(Fas) ligand expression in activated human T cells.
AB - Antigen receptor engagement on T lymphocytes activates transcription factors
important for stimulating cytokine gene expression. This is critical for clonal
expansion of antigen-specific T cells and propagation of immune responses.
Additionally, under some conditions antigen receptor stimulation initiates
apoptosis of T lymphocytes through the induced expression of CD95 ligand and its
receptor. Here we demonstrate that the transcription factor, NFAT, which is
critical for the inducible expression of many cytokine genes, also plays a
critical role in the regulation of T cell receptor-mediated CD95 ligand
expression. Two sites within the CD95 ligand promoter, identified through DNase I
footprinting, bind NFAT proteins from nuclear extracts of activated T cells.
Although both sites appear important for optimal expression of CD95 ligand in
activated T cells, mutational analysis suggests that the distal NFAT site plays a
more significant role. Furthermore, these sites do not appear to be required for
constitutive CD95 ligand expression in Sertoli cells.
PMID- 9395476
TI - Acyl-coenzyme A causes Ca2+ release in pancreatic acinar cells.
AB - The regulation of cytosolic Ca2+ is important for a variety of cell functions.
One non-inositol 1,4,5-trisphosphate (IP3) compound that may regulate Ca2+ is
palmitoyl-coenzyme A (CoA), a fatty acid-CoA that is reported to cause Ca2+
release from intracellular stores of oocytes, myocytes, and hepatocytes. To study
the role of palmitoyl-CoA in the pancreatic acinar cell, rat pancreatic acini
were isolated by collagenase digestion, permeablized with streptolysin O, and the
release of Ca2+ from internal stores was measured with fura-2. Palmitoyl-CoA
released Ca2+ from internal stores (EC50 = 14 microM). The palmitoyl-CoA
sensitive pool was distinct from, and overlapping with the IP3-sensitive Ca2+
pool. The effects of submaximal doses of IP3 or cyclic ADP-ribose plus palmitoyl
CoA were additive. Fatty acid-CoA derivatives with carbon chain lengths of 16-18
were the most potent and efficacious. Ryanodine and caffeine or elevated resting
[Ca2+] sensitized the Ca2+ pool to the actions of palmitoyl-CoA. Fatty acid-CoA
levels in pancreatic acini were measured by extraction with 2
propanol/acetonitrile, followed by separation and quantification using reverse
phase high performance liquid chromatography, and were found to be 10.17 +/- 0.93
nmol/mg protein. These data suggest the presence of an IP3-insensitive palmitoyl
CoA-sensitive Ca2+ store in pancreatic acinar cells and suggest that palmitoyl
CoA may be needed for Ca2+-induced Ca2+ release.
PMID- 9395477
TI - Positional preferences of ionizable residues in Gly-X-Y triplets of the collagen
triple-helix.
AB - Collagens contain a high amount of charged residues involved in triple-helix
stability, fibril formation, and ligand binding. The contribution of charged
residues to stability was analyzed utilizing a host-guest peptide system with a
single Gly-X-Y triplet embedded within Ac(Gly-Pro-Hyp)3-Gly-X-Y-(Gly-Pro-Hyp)4
Gly-Gly-NH2. The ionizable residues Arg, Lys, Glu, and Asp were incorporated into
the X position of Gly-X-Hyp; in the Y position of Gly-Pro-Y; or as pairs of
oppositely charged residues occupying X and Y positions. The Gly-X-Hyp peptides
had similar thermal stabilities, only marginally less stable than Gly-Pro-Hyp,
whereas Gly-Pro-Y peptides showed a wide thermal stability range (Tm = 30-45
degrees C). The stability of peptides with oppositely charged residues in the X
and Y positions appears to reflect simple additivity of the individual residues,
except when X is occupied by a basic residue and Y = Asp. The side chains of Glu,
Lys, and Arg have the potential to form hydrogen bonds with available peptide
backbone carbonyl groups within the triple-helix, whereas the shorter Asp side
chain does not. This may relate to the unique involvement of Asp residues in
energetically favorable ion pair formation. These studies clarify the dependence
of triple-helix stability on the identity, position, and ionization state of
charged residues.
PMID- 9395478
TI - Fibronectin type III repeats mediate RGD-independent adhesion and signaling
through activated beta1 integrins.
AB - Many cell-surface and extracellular matrix proteins contain multiple modular
domains known as fibronectin type III (FNIII) repeats. Cells adhere to the
extracellular matrix proteins fibronectin and tenascin in part by the interaction
of certain integrins with the Arg-Gly-Asp (RGD) sequence, displayed on specific
FNIII repeats. We have found that, after experimental activation of beta1
integrins, a number of cell types adhere and spread on FNIII repeats lacking RGD,
derived from extracellular matrix proteins and cytokine receptors. Interaction
between individual FNIII domains and beta1 integrins mediates focal adhesion
kinase phosphorylation and subsequent stress fiber and focal contact formation.
These data suggest that many FNIII-containing proteins may bind and signal
through activated beta1 integrins, dramatically expanding the potential for
integrin-dependent intercellular and cell-matrix communication.
PMID- 9395479
TI - Structural analysis of the human BIN1 gene. Evidence for tissue-specific
transcriptional regulation and alternate RNA splicing.
AB - BIN1 is a putative tumor suppressor that was identified through its interaction
with the MYC oncoprotein. To begin to identify elements of BIN1 whose alteration
may contribute to malignancy, we cloned and characterized the human BIN1 gene and
promoter. Nineteen exons were identified in a region of >54 kilobases, six of
which were alternately spliced in a cell type-specific manner. One alternately
spliced exon encodes part of the MYC-binding domain, suggesting that splicing
controls the MYC-binding capacity of BIN1 polypeptides. Four other alternately
spliced exons encode amphiphysin-related sequences that were included in brain
specific BIN1 species, also termed amphiphysin isoforms or amphiphysin II. The 5'
flanking region of BIN1 is GC-rich and lacks a TATA box but directs
transcriptional initiation from a single site. A approximately 0. 9-kilobase
fragment from this region was sufficient for basal transcription and
transactivation by MyoD, which may account for the high levels of BIN1 observed
in skeletal muscle. This study lays the foundation for genetic and epigenetic
investigations into the role of BIN1 in normal and neoplastic cell regulation.
PMID- 9395480
TI - Mints, Munc18-interacting proteins in synaptic vesicle exocytosis.
AB - Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for
synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting
proteins called Mint1 and Mint2 that may mediate the function of Munc18-1. Mint
proteins are detectable only in brain and are composed of an N-terminal sequence
that binds Munc18-1, a middle phosphotyrosine-binding domain, and two C-terminal
PDZ domains thought to attach proteins to the plasma membrane. In brain, Mint
proteins are part of a multimeric complex containing Munc18-1 and syntaxin that
likely functions as an intermediate in synaptic vesicle docking/fusion. The
phosphotyrosine-binding domain specifically binds to phosphatidylinositol
phosphates known to be produced during vesicle exocytosis (Hay, J. C., Fisette,
P. L., Jenkins, G. H., Fukami, K., Takonawa, T., Anderson, R. A., and Martin, T.
F. J. (1995) Nature 374, 173-177). Our data suggest a model whereby local
production of phosphatidylinositol phosphates may trigger the binding of vesicles
to the active zone via the Mint.Munc18-1 complex in conjunction with syntaxin 1.
PMID- 9395481
TI - Chicken ovalbumin upstream promoter-transcription factor interacts with estrogen
receptor, binds to estrogen response elements and half-sites, and inhibits
estrogen-induced gene expression.
AB - Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) was identified
as a low abundance protein in bovine uterus that co-purified with estrogen
receptor (ER) in a ligand-independent manner and was separated from the ER by its
lower retention on estrogen response element (ERE)-Sepharose. In gel mobility
shift assays, COUP-TF bound as an apparent dimer to ERE and ERE half-sites. COUP
TF bound to an ERE half-site with high affinity, Kd = 1.24 nM. In contrast, ER
did not bind a single ERE half-site. None of the class II nuclear receptors
analyzed, i.e. retinoic acid receptor, retinoid X receptor, thyroid receptor,
peroxisome proliferator-activated receptor, or vitamin D receptor, were
constituents of the COUP-TF.DNA binding complex detected in gel mobility shift
assays. Direct interaction of COUP-TF with ER was indicated by GST "pull-down"
and co-immunoprecipitation assays. The nature of the ER ligand influenced COUP-TF
ERE half-site binding. When ER was liganded by the antiestrogen 4
hydroxytamoxifen (4-OHT), COUP-TF-half-site interaction decreased. Conversely,
COUP-TF transcribed and translated in vitro enhanced the ERE binding of purified
estradiol (E2)-liganded ER but not 4-OHT-liganded ER. Co-transfection of ER
expressing MCF-7 human breast cancer cells with an expression vector for COUP-TFI
resulted in a dose-dependent inhibition of E2-induced expression of a luciferase
reporter gene under the control of three tandem copies of EREc38. The ability of
COUP-TF to bind specifically to EREs and half-sites, to interact with ER, and to
inhibit E2-induced gene expression suggests COUP-TF regulates ER action by both
direct DNA binding competition and through protein-protein interactions.
PMID- 9395482
TI - Phosphoenolpyruvate carboxykinase (GTP) gene transcription and hyperglycemia are
regulated by glucocorticoids in genetically obese db/db transgenic mice.
AB - The molecular mechanisms underlying increased hepatic phosphoenolpyruvate
carboxykinase (PEPCK) gene transcription and gluconeogenesis in type II diabetes
are largely unknown. To examine the involvement of glucocorticoids and the cis
acting insulin response sequence (IRS, -416/-407) in the genetically obese db/db
mouse model, we generated crosses between C57BL/KsJ-db/+ mice and transgenic mice
that express -460 or -2000 base pairs of the rat PEPCK gene promoter containing
an intact or mutated IRS, linked to a reporter gene. Transgenic mice expressing
the intact PEPCK(460)-CRP (C-reactive protein) transgene bred to near
homozygosity at the db locus were obese, hyperinsulinemic, and developed fasting
hyperglycemia (389 +/- 26 mg/100 ml) between 4 and 10 weeks of age. Levels of CRP
reporter gene expression were increased 2-fold despite severe hyperinsulinemia
compared with non-diabetic non-obese transgenic mice. Reporter gene expression
was also increased 2-fold in transgenic obese diabetic db/db mice bearing a
mutation in the IRS, -2000(IRS)-hGx, compared with non-obese non-diabetic
transgenic 2000(IRS)-hGx mice. Treatment of obese diabetic db/db transgenic mice
with the glucocorticoid receptor blocker RU 486 decreased plasma glucose by 50%
and reduced PEPCK, GLUT2, glucose-6-phosphatase, tyrosine aminotransferase, CRP,
and hGx reporter gene expression to levels similar to those of non-obese
normoglycemic transgenic mice. Taken together, these results establish that -460
bp of 5'-flanking sequence is sufficient to mediate the induction of PEPCK gene
transcription in genetically obese db/db mice during the development of
hyperglycemia. The results further demonstrate that the mechanism underlying
increased expression of gluconeogenic enzymes in the db/db mouse requires the
action of glucocorticoids and occurs independently of factors acting through the
PEPCK IRS (-416/-407) promoter binding site.
PMID- 9395483
TI - Heterodimerization-independent functions of cell death regulatory proteins Bax
and Bcl-2 in yeast and mammalian cells.
AB - The pro-apoptotic protein Bax can homodimerize with itself and heterodimerize
with the anti-apoptotic protein Bcl-2, but the significance of these protein
protein interactions remains unclear. Alanine substitution mutations were created
in a well conserved IGDE motif found within the BH3 domain of Bax (residues 66
69) and the resulting mutant Bax proteins were tested for ability to homodimerize
with themselves and to heterodimerize with Bcl-2. Correlations were made with
cell death induction by these mutants of Bax both in mammalian cells where Bax
may function through several mechanisms, and in yeast where Bax may exert its
lethal actions through a more limited repertoire of mechanisms perhaps related to
its ability to form ion channels in intracellular membranes. Two of the mutants,
Bax(D68A) and Bax(E69A), retained the ability to homodimerize but failed to
interact with Bcl-2 as determined by yeast two-hybrid assays and co
immunoprecipitation analysis using transfected mammalian cells. The Bax(E69A)
protein exhibited a lethal phenotype in yeast, which could be specifically
suppressed by co-expression of Bcl-2, despite its failure to dimerize with Bcl-2.
Both the Bax(D68A) and Bax(E69A) proteins induced apoptosis when overexpressed in
human 293 cells, despite an inability to bind to Bcl-2. Moreover, co-expression
of Bcl-2 with Bax(D68A) and Bax(E69A) rescued mammalian cells from apoptosis. In
contrast, a mutant of Bax lacking the IGDE motif, Bax(DeltaIGDE), was incapable
of either homodimerizing with itself or heterodimerizing with Bcl-2 and was
inactive at promoting cell death in either yeast or mammalian cells. Although
failing to interact with Bcl-2, the Bax(D68A) and Bax(E69A) mutants retained the
ability to bind to Bid, a putative Bax-activating member of the Bcl-2 family, and
collaborated with Bid in inducing apoptosis. When taken together with previous
observations, these findings indicate that (i) Bax can induce apoptosis in
mammalian cells irrespective of heterodimerization with Bcl-2 and (ii) Bcl-2 can
rescue both mammalian cells and yeast from the lethal effects of Bax without
heterodimerizing with it. However, these results do not exclude the possibility
that BH3-dependent homodimerization of Bax or interactions with Bax activators
such as Bid may either assist or be required for the cell death-inducing
mechanism of this protein.
PMID- 9395484
TI - Immunochemical visualization and quantitation of cyclic AMP in single cells.
AB - Adenosine 3':5'-cyclic monophosphate (cAMP) is a key second messenger in
signaling pathways governing many cellular processes. To define the subcellular
localization and relative abundance of cAMP, we developed a novel immunochemical
approach based on acrolein fixation to visualize cAMP within cells. We describe
here the fixation and immobilization of cAMP within cells and the production of
specific, high titer polyclonal antibodies that recognize cAMP. Relative levels
of cAMP immunofluorescence were quantitated in glial cells (oligodendrocytes,
astrocytes, Schwann cells, and glioma cells) that were either untreated or
treated with activators of endogenous adenylyl cyclase to raise cAMP levels. In
treated cells, cAMP immunofluorescence is strongly localized in the perinuclear
cytoplasm.
PMID- 9395485
TI - Cloning and targeted deletion of the mouse fetuin gene.
AB - We proposed that the alpha2-Heremans Schmid glycoprotein/fetuin family of serum
proteins inhibits unwanted mineralization. To test this hypothesis in animals, we
cloned the mouse fetuin gene and generated mice lacking fetuin. The gene consists
of seven exons and six introns. The cystatin-like domains D1 and D2 of mouse
fetuin are encoded by three exons each, whereas a single terminal exon encodes
the carboxyl-terminal domain D3. The promoter structure is well conserved between
rat and mouse fetuin genes within the regions shown to bind transcription factors
in the rat system. Expression studies demonstrated that mice homozygous for the
gene deletion lacked fetuin protein and that mice heterozygous for the null
mutation produced roughly half the amount of fetuin protein produced by wild-type
mice. Fetuin-deficient mice were fertile and showed no gross anatomical
abnormalities. However, the serum inhibition of apatite formation was compromised
in these mice as well as in heterozygotes. In addition, some homozygous fetuin
deficient female ex-breeders developed ectopic microcalcifications in soft
tissues. These results corroborate a role for fetuin in serum calcium
homeostasis. The fact that generalized ectopic calcification did not occur in
fetuin-deficient mice proves that additional inhibitors of phase separation exist
in serum.
PMID- 9395486
TI - Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and
endothelial cells. Regulation by tumor necrosis factor-alpha and doxycycline.
AB - Neutrophil collagenase (matrix metalloproteinase-8 or MMP-8) is regarded as being
synthesized exclusively by polymorphonuclear neutrophils (PMN). However, in vivo
MMP-8 expression was observed in mononuclear fibroblast-like cells in the
rheumatoid synovial membrane. In addition, we detected MMP-8 mRNA expression in
cultured rheumatoid synovial fibroblasts and human endothelial cells. Up
regulation of MMP-8 was observed after treatment of the cells with either tumor
necrosis factor-alpha (10 ng/ml) or phorbol 12-myristate 13-acetate (10 nM).
Western analysis showed a similar regulation at the protein level. The size of
secreted MMP-8 was 50 kDa, which is about 30 kDa smaller than MMP-8 from PMN.
Conditioned media from rheumatoid synovial fibroblasts contained both type I and
II collagen degrading activity. However, degradation of type II collagen, but not
that of type I collagen, was completely inhibited by 50 microM doxycycline,
suggesting specific MMP-8 activity. In addition, doxycycline down-regulated MMP-8
induction, at both the mRNA and protein levels. Thus MMP-8 exerts markedly wider
expression in human cells than had been thought previously, implying that PMN are
not the only source of cartilage degrading activity at arthritic sites. The
inhibition of both MMP-8 activity and synthesis by doxycycline provides an
incentive for further studies on the clinical effects of doxycycline in the
treatment of rheumatoid arthritis.
PMID- 9395487
TI - Disruption of the gene encoding the mitogen-regulated translational modulator
PHAS-I in mice.
AB - PHAS-I is the prototype of a group of eIF4E-binding proteins that can regulate
mRNA translation in response to hormones and growth factors. To investigate the
importance of PHAS-I in the physiology of the intact animal, we disrupted the
PHAS-I gene in mice. Tissues and cells derived from the knockout mice contained
no detectable PHAS-I protein. A related protein, PHAS-II, and eIF4E were readily
detectable in tissues from these animals, but neither appeared to be changed in a
compensatory manner. Mice lacking PHAS-I appeared normal at birth. However, male
knockout mice weighed approximately 10% less than controls at all ages, whereas
female weights were similar to those of controls. Both males and females were
fertile. Tissues from adult animals appeared to be normal by routine histological
staining techniques, as were routine blood cell counts and chemistries.
Fibroblasts derived from PHAS-I-deficient mouse embryos exhibited normal rates of
growth and overall protein synthesis, responded normally to serum stimulation of
ornithine decarboxylase activity and cell growth, and rapamycin inhibition of
cell growth. Under these experimental conditions, PHAS-I is apparently not
required for the normal development and reproductive behavior of female mice, but
is required for normal body weight in male mice; the mechanisms responsible for
this phenotype remain to be determined.
PMID- 9395488
TI - Role of translocation in the activation and function of protein kinase B.
AB - We have investigated the role of subcellular localization in the regulation of
protein kinase B (PKB) activation. The myristoylation/palmitylation motif from
the Lck tyrosine kinase was attached to the N terminus of protein kinase B to
alter its subcellular location. Myristoylated/palmitylated (m/p)-PKBalpha was
associated with the plasma membrane of transfected cells, whereas the wild-type
kinase was mostly cytosolic. The activity of m/p-PKBalpha was 60-fold higher
compared with the unstimulated wild-type enzyme, and could not be stimulated
further by growth factors or phosphatase inhibitors. In vivo 32P labeling and
mutagenesis demonstrated that m/p-PKBalpha activity was due to phosphorylation on
Thr308 and Ser473, that are normally induced on PKB following stimulation of the
cells with insulin or insulin-like growth factor-1 (IGF-1). A dominant negative
form of phosphoinositide 3-kinase (PI3-K) did not affect m/p-PKBalpha activity.
The pleckstrin homology (PH) domain of m/p-PKBalpha was not required for its
activation or phosphorylation on Thr308 and Ser473, suggesting that this domain
may serve as a membrane-targeting module. Consistent with this view, PKBalpha was
translocated to the plasma membrane within minutes after stimulation with IGF-1.
This translocation required the PH domain and was sensitive to wortmannin. Our
results indicate that PI3-K activity is required for translocation of PKB to the
plasma membrane, where its activation occurs through phosphorylation of the same
sites that are induced by insulin or IGF-1. Following activation the kinase
detached from the membrane and translocated to the nucleus.
PMID- 9395489
TI - Self-assembly of laminin isoforms.
AB - The alpha, beta, and gamma subunits of basement membrane laminins can combine
into different heterotrimeric molecules with either three full short arms (e.g.
laminins-1-4), or molecules containing one (laminins-6-9) or more (laminin-5)
short arm truncations. Laminin-1 (alpha1beta1gamma1), self-assembles through a
calcium-dependent thermal gelation requiring binding interactions between N
terminal short arm domains, forming a meshwork polymer thought to contribute to
basement membrane architecture (Yurchenco, P. D., and Cheng, Y. S. (1993) J.
Biol. Chem. 268, 17286-17299). However, it has been unclear whether other
isoforms share this property, and if so, which ones. To begin to address this, we
evaluated laminin-2 (alpha2beta1gamma1), laminin-4 (alpha2beta2gamma1), laminin-5
(alpha3Abeta3gamma2), and laminin-6 (alpha3Abeta1gamma1). The first two isoforms
were found to self-aggregate in a concentration- and temperature-dependent manner
and a close self-assembly relationship among laminins-1, -2, and -4 were
demonstrated by: (a) polymerization of all three proteins was inhibited by EDTA
and laminin-1 short arm fragments, (b) polymerization of laminin-1 was inhibited
by fragments of laminins-2 and -4, (c) laminin-2 and, to a lesser degree, laminin
4, even well below their own critical concentration, co-aggregated with laminin
1, evidence for co-polymerization. Laminin-5, on the other hand, neither
polymerized nor co-polymerized with laminin-1. Laminin-6 failed to co-aggregate
with laminin-1 at all concentrations evaluated, evidence for a lack of a related
self-assembly activity. The data support the hypothesis that all three short arms
are required for self-assembly and suggest that the short arm domain structure of
laminin isoforms affect their architecture-forming properties in basement
membranes.
PMID- 9395490
TI - A new mechanism-based radical intermediate in a mutant R1 protein affecting the
catalytically essential Glu441 in Escherichia coli ribonucleotide reductase.
AB - The invariant active site residue Glu441 in protein R1 of ribonucleotide
reductase from Escherichia coli has been engineered to alanine, aspartic acid,
and glutamic acid. Each mutant protein was structurally and enzymatically
characterized. Glu441 contributes to substrate binding, and a carboxylate side
chain at position 441 is essential for catalysis. The most intriguing results are
the suicidal mechanism-based reaction intermediates observed when R1 E441Q is
incubated with protein R2 and natural substrates (CDP and GDP). In a consecutive
reaction sequence, we observe at least three clearly discernible steps: (i) a
rapid decay (k1 >/= 1.2 s-1) of the catalytically essential tyrosyl radical of
protein R2 concomitant with formation of an early transient radical intermediate
species, (ii) a slower decay (k2 = 0.03 s-1) of the early intermediate
concomitant with formation of another intermediate with a triplet EPR signal, and
(iii) decay (k3 = 0.004 s-1) of the latter concomitant with formation of a
characteristic substrate degradation product. The characteristics of the triplet
EPR signal are compatible with a substrate radical intermediate (most likely
localized at the 3'-position of the ribose moiety of the substrate nucleotide)
postulated to occur in the wild type reaction mechanism as well.
PMID- 9395491
TI - Specific recognition of an rU2-N15-rU motif by VP55, the vaccinia virus poly(A)
polymerase catalytic subunit.
AB - VP55, the vaccinia poly(A) polymerase catalytic subunit, interacts with
oligonucleotide primers via two uridylate recognition sites (Deng, L., and
Gershon, P. D. (1997) EMBO J. 16, 1103-1113). Here, we show that the cognate RNA
sequence comprises a 5'-rU2-N15-rU-3' motif (where N = any deoxyribo or
ribonucleotide), embedded within oligonucleotide primers 29-30 nucleotides (nt),
or greater, in length. Nine residues separate the 3'-most ribouridylate of the
optimally positioned motif from the primer 3'-OH. A ribose sugar at the extreme
3'-terminal nucleotide of the primer is absolutely required for VP55's
adenylyltransferase activity, but not for stable VP55-RNA interaction. A ribose
at position -3 markedly stimulates both adenylyltransferase activity and stable
binding. The use of uridine analogs indicated (i) those functional groups of the
uracil base which contribute to stable VP55-primer interaction, and (ii) that
VP55's ability to discriminate uracil from cytosine stems largely from the
requirement for a protonated N3 nitrogen within the pyrimidine ring. The rU2-N15
rU motif was identified within the uridylate-rich 3' end of a naturally occurring
vaccinia mRNA. However, oligonucleotides whose only internal uridylates comprised
the motif supported only a 3-5-nt processive burst of oligo(A) tail addition, as
opposed to the approximately 30-35-nt burst observed with the naturally occurring
3' end.
PMID- 9395492
TI - Probing the G-protein regulation of GIRK1 and GIRK4, the two subunits of the KACh
channel, using functional homomeric mutants.
AB - In heart, G-protein-activated channels are complexes of two homologous proteins,
GIRK1 and GIRK4. Expression of either protein alone results in barely active or
non-active channels, making it difficult to assess the individual contribution of
each subunit to the channel complex. The residue Phe137, located within the H5
region of GIRK1, is critical to the synergy between GIRK1 and GIRK4 (Chan, K. W.,
Sui, J. L., Vivaudou, M., and Logothetis, D. E. (1996) Proc. Natl. Acad. Sci. U.
S. A. 93, 14193-14198). By modifying this residue or the matching residue of
GIRK4, Ser143, we have been able to generate mutant proteins that produced large
inwardly rectifying, G-protein-modulated currents when expressed alone in Xenopus
oocytes. The enhanced activity of the heterologous expression of each of two
active mutants, GIRK1(F137S) and GIRK4(S143T), was not caused by association with
an endogenous oocyte channel subunit, and these mutants did not display apparent
differences in the ability to localize to the cell surface compared with their
wild-type counterparts. When these functional mutant channels were compared
individually with wild-type heteromeric channels, they responded with only small
differences to a number of maneuvers involving coexpression with muscarinic
receptors, G-protein betagamma subunits, wild-type or mutated G-protein alpha
subunits, and active protomers of pertussis toxin. These experiments, which
confirmed the crucial, though not exclusive, role of Gbetagamma in regulating
channel activity, demonstrated that GIRK1(F137S) and GIRK4(S143T), and by
extrapolation their wild-type counterparts, interact in a qualitatively similar
way with G-protein subunits. These findings suggest that functionally important
sites of interaction with G-proteins are likely to be located within the
homologous regions of GIRK1 and GIRK4 rather than within the divergent terminal
regions. They also raise the question of the functional advantage of a
heteromeric over homomeric design for G-protein-gated channels.
PMID- 9395493
TI - beta-dystrobrevin, a new member of the dystrophin family. Identification,
cloning, and protein associations.
AB - Dystrophin, the protein disrupted in Duchenne muscular dystrophy, is one of
several related proteins that are key components of the submembrane cytoskeleton.
Three dystrophin-related proteins (utrophin, dystrophin-related protein-2 (DRP2),
and dystrobrevin) have been described. Here, we identify a human gene on
chromosome 2p22-23 that encodes a novel protein, beta-dystrobrevin, with
significant homology to the other known dystrobrevin (now termed alpha
dystrobrevin). Sequence alignments including this second dystrobrevin strongly
support the concept that two distinct subfamilies exist within the dystrophin
family, one composed of dystrophin, utrophin, and DRP2 and the other composed of
alpha- and beta-dystrobrevin. The possibility that members of each subfamily form
distinct protein complexes was examined by immunopurifying dystrobrevins and
dystrophin. A beta-dystrobrevin antibody recognized a protein of the predicted
size (71 kDa) that copurified with the dystrophin short form, Dp71. Thus, like
alpha-dystrobrevin, beta-dystrobrevin is likely to associate directly with
dystrophin. alpha- and beta-dystrobrevins failed to copurify with each other,
however. These results suggest that members of the dystrobrevin subfamily form
heterotypic associations with dystrophin and raise the possibility that pairing
of a particular dystrobrevin with dystrophin may be regulated, thereby providing
a mechanism for assembly of distinct submembrane protein complexes.
PMID- 9395494
TI - Role of asymmetric phosphate neutralization in DNA bending by PU.1.
AB - The PU.1 transcription factor is a member of the Ets family of DNA binding
proteins. PU.1 binds to DNA via a loop-helix-loop domain and functions in the
differentiation of hematopoietic cells. The structure of a PU.1-DNA complex was
recently reported (Kodandapani, R., Pio, F., Ni, C.-Z., Piccialli, G., Klemsz,
M., McKercher, S., Maki, R., and Ely, K. (1996) Nature 380, 456-460). The DNA in
this complex is deformed by 8 degrees as it curves around the protein. The
pattern of electrostatic contacts between PU.1, and its DNA binding site suggests
that laterally asymmetric phosphate neutralization accompanies PU.1 binding.
Because of our previous studies showing that such neutralization can induce
bending in naked DNA, we have explored the effect of phosphate neutralization by
substituting neutral methylphosphonate internucleoside linkages at relevant
positions within DNA containing the PU.1 binding sequence. Consistent with the
prediction that DNA will collapse toward its partially neutralized surface, DNA
neutralized at seven positions to simulate PU.1 binding is observed to bend by 28
degrees . The directions of DNA curvature are slightly different in the co
crystal versus the partially neutralized duplexes. The electrostatic component of
the binding energy appears more than enough to account for the DNA bending
observed in the PU.1-DNA complex.
PMID- 9395495
TI - G protein beta1gamma2 subunits promote microtubule assembly.
AB - alpha and betagamma subunits of G proteins are thought to transduce signals from
cell surface receptors to intracellular effector molecules. Galpha and Gbetagamma
have also been implicated in cell growth and differentiation, perhaps due to
their association with cytoskeletal components. In this report Gbetagamma is
shown to modulate the cytoskeleton by regulation of microtubule assembly.
Specificity among betagamma species exists, as beta1gamma2 stimulates microtubule
assembly, and beta1gamma1 is without any effect. Furthermore, a mutant
beta1gamma2, beta1gamma2(C68S), which does not undergo prenylation and subsequent
carboxyl-terminal processing on the gamma subunit, does not stimulate the
formation of microtubules. beta immunoreactivity was detected exclusively in the
microtubule fraction after assembly in the presence of beta1gamma2, suggesting a
preferential association with microtubules rather than soluble tubulin. Crude
microtubule fractions from ovine brain contain Gbetagamma, and electron
microscopy reveals a specific association with microtubules. The decoration of
microtubules by Gbetagamma appears to be strikingly similar to the periodic
pattern observed for microtubule-associated proteins, suggesting a similar site
of activation of microtubule assembly by both agents. It is suggested that
reformation of the cytoskeleton represents an additional cellular process
mediated by Gbetagamma.
PMID- 9395496
TI - Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial cell
proliferation by a peptide corresponding to the exon 7-encoded domain of VEGF165.
AB - Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial
cells (EC) in vitro and a major regulator of angiogenesis in vivo. VEGF121 and
VEGF165 are the most abundant of the five known VEGF isoforms. The structural
difference between these two is the presence in VEGF165 of 44 amino acids encoded
by exon 7 lacking in VEGF121. It was previously shown that VEGF165 and VEGF121
both bind to KDR/Flk-1 and Flt-1 but that VEGF165 binds in addition to a novel
receptor (Soker, S., Fidder, H., Neufeld, G., and Klagsbrun, M. (1996) J. Biol.
Chem. 271, 5761-5767). The binding of VEGF165 to this VEGF165-specific receptor
(VEGF165R) is mediated by the exon 7-encoded domain. To investigate the
biological role of this domain further, a glutathione S-transferase fusion
protein corresponding to the VEGF165 exon 7-encoded domain was prepared. The
fusion protein inhibited binding of 125I-VEGF165 to VEGF165R on human umbilical
vein-derived EC (HUVEC) and MDA-MB-231 tumor cells. The fusion protein also
inhibited significantly 125I-VEGF165 binding to KDR/Flk-1 on HUVEC but not on
porcine EC which express KDR/Flk-1 alone. VEGF165 had a 2-fold higher mitogenic
activity for HUVEC than did VEGF121. The exon 7 fusion protein inhibited VEGF165
induced HUVEC proliferation by 60% to about the level stimulated by VEGF121.
Unexpectedly, the fusion protein also inhibited HUVEC proliferation in response
to VEGF121. Deletion analysis revealed that a core inhibitory domain exists
within the C-terminal 23-amino acid portion of the exon 7-encoded domain and that
a cysteine residue at position 22 in exon 7 is critical for inhibition. It was
concluded that the exon 7-encoded domain of VEGF165 enhances its mitogenic
activity for HUVEC by interacting with VEGF165R and modulating KDR/Flk-1-mediated
mitogenicity indirectly and that exon 7-derived peptides may be useful VEGF
antagonists in angiogenesis-associated diseases.
PMID- 9395497
TI - MAGI-1, a membrane-associated guanylate kinase with a unique arrangement of
protein-protein interaction domains.
AB - Membrane-associated guanylate kinase (MAGUK) proteins participate in the assembly
of multiprotein complexes on the inner surface of the plasma membrane at regions
of cell-cell contact. MAGUKs are characterized by three types of protein-protein
interaction modules: the PDZ domain, the Src homology 3 (SH3) domain, and the
guanylate kinase (GuK) domain. The arrangement of these domains is conserved in
all previously known MAGUKs: either one or three PDZ domains in the NH2-terminal
half, followed by the SH3 domain, followed by a COOH-terminal GuK domain. In this
report, we describe the cDNA cloning and subcellular distribution of MAGI-1, a
MAGUK with three unique structural features: 1) the GuK domain is at the NH2
terminus, 2) the SH3 domain is replaced by two WW domains, and 3) it contains
five PDZ domains. MAGI-1 mRNA was detected in several adult mouse tissues.
Sequence analysis of overlapping cDNAs revealed the existence of three splice
variants that are predicted to encode MAGI-1 proteins with different COOH
termini. The longest variant, MAGI-1c, contains three bipartite nuclear
localization signals in its unique COOH-terminal sequence and was found
predominantly in the nucleus of Madin-Darby canine kidney cells. A shorter form
lacking these signals was found primarily in membrane and cytoplasmic fractions.
This distribution, which is reminiscent of that seen for the tight junction
protein ZO-1, suggests that MAGI-1 may participate in the transmission of
regulatory signals from the cell surface to the nucleus.
PMID- 9395498
TI - Suppression of neuronal and cardiac transient outward currents by viral gene
transfer of dominant-negative Kv4.2 constructs.
AB - To probe the molecular identity of transient outward (A-type) potassium currents,
we expressed a truncated version of Kv4.2 in heart cells and neurons. The rat
Kv4.2-coding sequence was truncated at a position just past the first
transmembrane segment and subcloned into an adenoviral shuttle vector downstream
of a cytomegalovirus promoter (pE1Kv4.2ST). We hypothesized that this construct
would act as a dominant-negative suppressor of currents encoded by the Kv4 family
by analogy to Kv1 channels. Cotransfection of wild-type Kv4.2 with a beta
galactosidase expression vector in Chinese hamster ovary (CHO)-K1 cells produced
robust transient outward currents (Ito) after two days (14.0 pA/pF at 50 mV, n =
5). Cotransfection with pE1Kv4.2ST markedly suppressed the Kv4.2 currents (0.8
pA/pF, n = 6, p < 0.02; cDNA ratio of 2:1 Kv4.2ST:wild type), but in parallel
experiments, it did not alter the current density of coexpressed Kv1.4 or Kv1.5
channels. Kv4.2ST also effectively suppressed rat Kv4.3 current when coexpressed
in CHO-K1 cells. We then engineered a recombinant adenovirus (AdKv4.2ST) designed
to overexpress Kv4.2ST in infected cells. A-type currents in rat cerebellar
granule cells were decreased two days after AdKv4. 2ST infection as compared with
those infected by a beta-galactosidase reporter virus (116.0 pA/pF versus 281.4
pA/pF in Ad beta-galactosidase cells, n = 8 each group, p < 0.001). Likewise, Ito
in adult rat ventricular myocytes was suppressed by AdKv4.2ST but not by Adbeta
galactosidase (8.8 pA/pF versus 21.4 pA/pF in beta-galactosidase cells, n = 6
each group, p < 0.05). Expression of a GFP-Kv4.2ST fusion construct enabled
imaging of subcellular protein localization by confocal microscopy. The protein
was distributed throughout the surface membrane and intracellular membrane
systems. We conclude that genes from the Kv4 family are the predominant
contributors to the A-type currents in cerebellar granule cells and Ito in rat
ventricle. Overexpression of dominant-negative constructs may be of general
utility in dissecting the contributions of various ion channel genes to
excitability.
PMID- 9395499
TI - Functional coupling of NKR-P1 receptors to various heterotrimeric G proteins in
rat interleukin-2-activated natural killer cells.
AB - NKR-P1 molecules constitute a family of type II membrane receptors in natural
killer (NK) cells that preferentially activate NK cell killing and release of
interferon-gamma from these cells. Here, we demonstrate that anti-NKR-P1 enhances
GTP binding in rat interleukin-2-activated NK cell membranes; GTP binding to
Gi3alpha, Gsalpha, Gq,11alpha, and Gzalpha increased noticeably in these cell
membranes after treatment with anti-NKR-P1. Western blot analysis of membrane
proteins prepared from interleukin-2-activated NK cells reveals the presence of
Gi1,2alpha, Gi3alpha, Goalpha, Gsalpha, Gq, 11alpha, Gzalpha, and G12alpha, but
not G13alpha. However, only alphai3, alphas, alphaq,11, and alphaz, but not
alphai1,2, alphao, alpha12, or alpha13 subunits when immunoprecipitated with the
appropriate anti-G protein antibodies, are associated with NKR-P1 when
immunoblotted with anti-NKR-P1. Reciprocally, NKR-P1 immunoprecipitated with anti
NKR-P1 is associated with alphai3, alphas, alphaq,11, and alphaz immunoblotted
with anti-G proteins. These results are the first to demonstrate the physical and
functional coupling of NKR-P1 to the heterotrimeric G proteins in NK cells.
PMID- 9395500
TI - Selective cytotoxicity of dermaseptin S3 toward intraerythrocytic Plasmodium
falciparum and the underlying molecular basis.
AB - The antimicrobial activity of various naturally occurring microbicidal peptides
was reported to result from their interaction with microbial membrane. In this
study, we investigated the cytotoxicity of the hemolytic peptide dermaseptin S4
(DS4) and the nonhemolytic peptide dermaseptin S3 (DS3) toward human erythrocytes
infected by the malaria parasite Plasmodium falciparum. Both DS4 and DS3
inhibited the parasite's ability to incorporate [3H]hypoxanthine. However, while
DS4 was toxic toward both the parasite and the host erythrocyte, DS3 was toxic
only toward the intraerythrocytic parasite. To gain insight into the mechanism of
this selective cytotoxicity, we labeled the peptides with fluorescent probes and
investigated their organization in solution and in membranes. In Plasmodium
infected cells, rhodamine-labeled peptides interacted directly with the
intracellular parasite, in contrast to noninfected cells, where the peptides
remained bound to the erythrocyte plasma membrane. Binding experiments to
phospholipid membranes revealed that DS3 and DS4 had similar binding
characteristics. Membrane permeation studies indicated that the peptides were
equally potent in permeating phosphatidylserine/phosphatidylcholine vesicles,
whereas DS4 was more permeative with phosphatidylcholine vesicles. In aqueous
solutions, DS4 was found to be in a higher aggregation state. Nevertheless, both
DS3 and DS4 spontaneously dissociated to monomers upon interaction with vesicles,
albeit with different kinetics. In light of these results, we propose a mechanism
by which dermaseptins permeate cells and affect intraerythrocytic parasites.
PMID- 9395501
TI - Heparin-binding properties of the amyloidogenic peptides Abeta and amylin.
Dependence on aggregation state and inhibition by Congo red.
AB - Aggregation and deposition of the 40-42-residue amyloid beta-protein (Abeta) are
early and necessary neuropathological events in Alzheimer's disease. An
understanding of the molecular interactions that trigger these events is
important for therapeutic strategies aimed at blocking Abeta plaque formation at
the earliest stages. Heparan sulfate proteoglycans may play a fundamental role
since they are invariably associated with Abeta and other amyloid deposits at all
stages. However, the nature of the Abeta-heparan sulfate proteoglycan binding has
been difficult to elucidate because of the strong tendency of Abeta to self
aggregate. Affinity co-electrophoresis can measure the binding of proteoglycans
or glycosaminoglycans to proteins without altering the physical state of the
protein during the assay. We used affinity co-electrophoresis to study the
interaction between Abeta and the glycosaminoglycan heparin and found that the
aggregation state of Abeta governs its heparin-binding properties: heparin binds
to fibrillar but not nonfibrillar Abeta. The amyloid binding dye, Congo red,
inhibited the interaction in a specific and dose-dependent manner. The "Dutch"
mutant AbetaE22Q peptide formed fibrils more readily than wild type Abeta and it
also attained a heparin-binding state more readily, but, once formed, mutant and
wild type fibrils bound heparin with similar affinities. The heparin-binding
ability of aggregated AbetaE22Q was reversible with incubation in a solvent that
promotes alpha-helical conformation, further suggesting that conformation of the
peptide is important. Studies with another human amyloidogenic protein, amylin,
suggested that its heparin-binding properties were also dependent on aggregation
state. These results demonstrate the dependence of the Abeta-heparin interaction
on the conformation and aggregation state of Abeta rather than primary sequence
alone, and suggest methods of interfering with this association.
PMID- 9395502
TI - Cloning, expression, and properties of the regulatory subunit of bovine pyruvate
dehydrogenase phosphatase.
AB - cDNA encoding the regulatory subunit of bovine mitochondrial pyruvate
dehydrogenase phosphatase (PDPr) has been cloned. Overlapping cDNA fragments were
generated by the polymerase chain reaction from bovine genomic DNA and from cDNA
synthesized from bovine poly(A)+ RNA and total RNA. The complete cDNA (2885 base
pairs) contains an open reading frame of 2634 nucleotides encoding a putative
presequence of 31 amino acid residues and a mature protein of 847 residues with a
calculated Mr of 95,656. This value is in agreement with the molecular mass of
native PDPr (95,800 +/- 200 Da) determined by matrix-assisted laser desorption
ionization mass spectrometry. The mature form of PDPr was expressed in
Escherichia coli as a maltose-binding protein fusion, and the recombinant protein
was purified to near homogeneity. It exhibited properties characteristic of the
native PDPr, including recognition by antibodies against native bovine PDPr,
ability to decrease the sensitivity of the catalytic subunit to Mg2+, and
reversal of this inhibitory effect by the polyamine spermine. A BLAST search of
protein data bases revealed that PDPr is distantly related to the mitochondrial
flavoprotein dimethylglycine dehydrogenase, which functions in choline
degradation.
PMID- 9395503
TI - The type of basal promoter determines the regulated or constitutive mode of
transcription in the common control region of the yeast gene pair GCY1/RIO1.
AB - The yeast genes, GCY1 and RIO1, are transcribed divergently from the 869-base
pair intergenic region. GCY1 is inducible by galactose about 25-fold due to Gal4p
binding to a single UASGAL, whereas RIO1 is constitutively expressed. GCY1 has a
TATA box obeying the consensus TATAAA, whereas the RIO1 5'-upstream region lacks
such a motif. In vitro mutagenesis of the TATA motif of GCY1, on the one hand,
and introduction of a TATA-element into the promoter of RIO1, on the other hand,
as well as inversion of the intergenic region have revealed that transcription of
GCY1 and RIO1 is only regulated by Gal4p when a consensus TATA motif is included
in their core promoters but not in its absence. The data imply that only
transcription complexes that assemble at a consensus TATA box are compatible with
specific transactivators, such as Gal4p. As a result, the adjacent gene is
subject to regulated expression. By contrast, if a consensus TATA sequence is
absent, the initiation complex does not respond to regulatory transcription
factors, and consequently, the respective gene is constitutively transcribed. On
the other hand, we show that two blocks of homo-oligomeric (dA.dT) sequences do
not function as boundary sequences that might confine regulatory action of Gal4p
to GCY1.
PMID- 9395504
TI - Hsp110 protects heat-denatured proteins and confers cellular thermoresistance.
AB - The 110-kDa heat shock protein (hsp110) has long been recognized as one of the
primary heat shock proteins in mammalian cells. It belongs to a recently
described protein family that is a significantly diverged subgroup of the hsp70
family and has been found in organisms as diverse as yeast and mammals. We
describe here the first analysis of the ability of hsp110 to protect cellular and
molecular targets from heat damage. It was observed that the overexpression in
vivo of hsp110 conferred substantial heat resistance to both Rat-1 and HeLa
cells. In vitro heat denaturation and refolding assays demonstrate that hsp110 is
highly efficient in selectively recognizing denatured proteins and maintaining
them in a soluble, folding-competent state and is significantly more efficient in
performing this function than is hsc70. hsp110-bound proteins can then be
refolded by the addition of rabbit reticulocyte lysate or hsc70 and Hdj-1,
whereas Hdj-1 does not itself function as a co-chaperone in folding with hsp110.
hsp110 is one of the principal molecular chaperones of mammalian cells and
represents a newly identified component of the primary protection/repair pathway
for denatured proteins and thermotolerance expression in vivo.
PMID- 9395505
TI - Negative regulation of the mouse aldolase A gene. A cell cycle-dependent DNA
binding activity functions as a silencer of gene transcription.
AB - The expression of aldolase A L-type mRNA is increased in growth-arrested mouse
NIH3T3 cells and remarkably down-regulated in actively proliferating cells.
Treatment of proliferating cells with cycloheximide abolished the down-regulation
of L-type mRNA expression, thus indicating that a protein factor acts as
repressor in proliferating cells. Transient transfection experiments in NIH3T3
cells showed that a negative regulatory cis-element (NRE) is involved in the
modulation of the transcriptional activity of the distal L promoter. The
repressor, which is a protein of approximately 97 kDa, binds the murine aldolase
A NRE, revealing a much more intense DNA-protein complex in proliferating NIH3T3
cells than in serum-deprived cells. Mutations in the negative regulatory cis
element showed that the GA-rich motif is required for protein binding and
silencer function. We conclude that the expression of L-type mRNA is modulated by
the interaction between a cell cycle-dependent DNA-binding protein and the murine
aldolase A NRE.
PMID- 9395506
TI - G protein-coupled receptors mediate two functionally distinct pathways of
tyrosine phosphorylation in rat 1a fibroblasts. Shc phosphorylation and receptor
endocytosis correlate with activation of Erk kinases.
AB - The Ras-dependent activation of Erk kinases by G protein-coupled receptors
(GPCRs) is thought to involve tyrosine phosphorylation of docking proteins that
serve as scaffolds for the plasma membrane recruitment of Ras guanine nucleotide
exchange factors, such as the Grb2-mSos complex. We have investigated the role of
two GPCR-regulated tyrosine phosphoproteins, p125(FAK) (FAK) and Shc, in the Ras
dependent activation of Erk kinases by endogenously expressed GPCRs in Rat 1a
fibroblasts. Several lines of evidence suggest that tyrosine phosphorylation of
FAK and Shc are independently regulated. The GPCRs for lysophosphatidic acid
(LPA), thrombin, and bombesin mediate equivalent increases in FAK tyrosine
phosphorylation and FAK-Grb2 association. In contrast, only LPA and thrombin
receptors significantly stimulate Shc tyrosine phosphorylation and Shc-Grb2
complex formation. Tyrosine phosphorylation of FAK is pertussis toxin
insensitive, can be mimicked by calcium ionophore, and is inhibited by treatment
with cytochalasin D, which depolymerizes the actin cytoskeleton. In contrast,
tyrosine phosphorylation of Shc is inhibited by pertussis toxin treatment, is not
induced by calcium ionophore, and is insensitive to cytochalasin D. In each case,
the rapid stimulation of Erk 1/2 correlates with tyrosine phosphorylation of Shc
but not of FAK. The dissociation of FAK-Grb2 complex formation from receptor
mediated activation of Erk 1/2 indicates that recruitment of Grb2-mSos to the
plasma membrane is not sufficient to mediate rapid Erk activation. Using four
mechanistically distinct inhibitors of clathrin-mediated endocytosis,
concanavalin A, hypertonic medium, depletion of intracellular potassium, and
monodansylcadaverine, we find that GPCR-mediated Erk 1/2 activation is also
endocytosis-dependent. Thus, we propose that an additional step involving vesicle
mediated endocytosis is required for the rapid, Ras-dependent activation of Erk
kinases in fibroblasts.
PMID- 9395507
TI - hsp27 as a switch between differentiation and apoptosis in murine embryonic stem
cells.
AB - Small stress proteins are developmentally regulated and linked to cell growth and
differentiation. The early phase of murine embryonic stem (ES) cell
differentiation, characterized by a gradual growth arrest, is accompanied with
hsp27 transient accumulation. This differentiation process also correlated with
changes in hsp27 phosphorylation and oligomerization. The role of hsp27 was
investigated in ES clones stably transfected with murine or human hsp27 genes,
placed in sense or antisense orientation. Several clones were obtained that
either underexpressed endogenous murine hsp27 or overexpressed murine or human
hsp27. Maintained undifferentiated, these clones showed similar growth rates. We
report here that hsp27 constitutive overexpression enhanced the differentiation
mediated decreased rate of ES cell proliferation but did not alter morphological
changes. In contrast, hsp27 underexpression, which attenuated cell growth arrest,
induced differentiation abortion because of an overall cell death by apoptosis.
Recently, we showed that hsp27 interfered with cell death probably because of its
ability to modulate intracellular glutathione. hsp27 accumulation during ES cell
differentiation was also correlated with an increase in glutathione, which was
attenuated by hsp27 down-expression. Hence, hsp27 transient expression seems
essential for preventing differentiating ES cells from undergoing apoptosis, a
switch that may be redox regulated.
PMID- 9395508
TI - Structural analyses of gp45 sliding clamp interactions during assembly of the
bacteriophage T4 DNA polymerase holoenzyme. I. Conformational changes within the
gp44/62-gp45-ATP complex during clamp loading.
AB - A multisubunit ring-shaped protein complex is used to tether the polymerase to
the DNA at the primer-template junction in most DNA replication systems. This
"sliding clamp" interacts with the polymerase, completely encircles the DNA
duplex, and is assembled onto the DNA by a specific clamp loading complex in an
ATP-driven process. Site-specific mutagenesis has been used to introduce single
cysteine residues as reactive sites for adduct formation within each of the three
subunits of the bacteriophage T4-coded sliding clamp complex (gp45). Two such
mutants, gp45S19C and gp45K81C, are reacted with the cysteine-specific
photoactivable cross-linker TFPAM-3 and used to track the changes in the relative
positioning of the gp45 subunits with one another and with the other components
of the clamp loading complex (gp44/62) in the various stages of the loading
process. Cross-linking interactions performed in the presence of nucleotide
cofactors show that ATP binding and hydrolysis, interaction with primer-template
DNA, and release of ADP all result in significant conformational changes within
the clamp loading cycle. A structural model is presented to account for the
observed rearrangements of intersubunit contacts within the complex during the
loading process.
PMID- 9395509
TI - Structural analyses of gp45 sliding clamp interactions during assembly of the
bacteriophage T4 DNA polymerase holoenzyme. II. The Gp44/62 clamp loader
interacts with a single defined face of the sliding clamp ring.
AB - The phage T4 gp45 sliding clamp is a ring-shaped replication accessory protein
that is mounted onto DNA in an ATP-dependent manner by the gp44/62 clamp loader.
In the preceding paper (Pietroni, P., Young, M. C., Latham, G. J., and von
Hippel, P. H. (1997) J. Biol. Chem. 272, 31666-31676), two gp45 mutants were
exploited to probe interactions of the sliding clamp ring with the gp44/62
loading machinery at various steps during the clamp loading process. In this
report, these studies are extended to examine the polarity of the binding
interaction between gp45 and gp44/62. Three different gp45 mutants containing a
single cysteine in three topographically distinct positions were used. Several
different reporter groups, including extrinsic fluorophores, a photo-cross
linker, and a biotin linker for use in a novel "streptavidin interference assay,"
were covalently attached to these cysteine residues. Since gp45 is a trimeric
protein, these three different mutations allowed us to probe up to nine distinct
local environments along the surface of the sliding clamp in the presence and
absence of other replication proteins. The results show that the gp44/62-ATP
clamp loader complex binds exclusively to the C-terminal (S19C) face of the gp45
ring.
PMID- 9395510
TI - Structural analyses of gp45 sliding clamp interactions during assembly of the
bacteriophage T4 DNA polymerase holoenzyme. III. The Gp43 DNA polymerase binds to
the same face of the sliding clamp as the clamp loader.
AB - In the preceding paper (Latham, G. J., Bacheller, D. J., Pietroni, P. , and von
Hippel, P. H. (1997) J. Biol. Chem. 272, 31677-31684), we demonstrated that the
T4 gp44/62-ATP clamp loader binds to the C-terminal face of the gp45 sliding
clamp. Here we extend these results by exploring the structural relationship
between the gp43 polymerase and the gp45 sliding clamp. Using fluorescence
intensity and polarization techniques, as well as photo-cross-linking methods, we
present evidence that gp43, like gp44/62, binds to the C-terminal face of gp45.
In addition, we show that g43 binds to the gp45 clamp in two distinct interaction
modes, depending on the presence or absence of template-primer DNA. When template
primer DNA is present, gp43 binds tightly to gp45 to form the highly processive
DNA polymerase holoenzyme. Gp43 also binds to gp45 in the absence of template
primer DNA, but this interaction is more than 100 times weaker than gp43-gp45
binding on DNA. Specific interactions between gp43 and the C-terminal face of
gp45 are maintained in both modes of binding. These results underscore the
pivotal role of template-primer DNA in modulating the strength of protein-protein
interactions during DNA synthesis and provide additional insight into the
structural requirements of the replication process.
PMID- 9395511
TI - A role for estrogen-related receptor alpha in the control of mitochondrial fatty
acid beta-oxidation during brown adipocyte differentiation.
AB - Little is known about the factors involved in the brown adipocyte gene regulatory
program. In contrast to the white adipocyte, the brown adipocyte is characterized
by abundant mitochondria and high level expression of mitochondrial fatty acid
beta-oxidation enzymes. Previous studies in transgenic mice have shown that the
brown adipose-enriched expression of a key beta-oxidation enzyme, medium chain
acyl-coenzyme A dehydrogenase (MCAD), requires cis-acting elements located within
the proximal promoter region of the MCAD gene. The levels of mRNA encoding MCAD
and several other beta-oxidation cycle enzymes were coordinately induced during
differentiation of brown adipocytes in culture. Expression of transgenes
comprised of MCAD gene promoter fragments fused to chloramphenicol
acetyltransferase reporters in differentiating brown adipocytes revealed that a
known nuclear receptor response element (NRRE-1) was required for the
transcriptional induction of the MCAD gene during brown adipocyte
differentiation. Electrophoretic mobility shift assays and antibody recognition
studies identified distinct brown adipocyte differentiation stage-specific, NRRE
1-protein complexes; the orphan nuclear receptors, chicken ovalbumin upstream
promoter transcription factors I and II, were identified as major the NRRE-1
binding proteins in the pre-adipocyte, whereas the estrogen-related receptor
alpha (ERRalpha) bound NRRE-1 in extracts prepared from differentiated brown
adipocytes. DNA binding studies performed with a series of NRRE-1 mutant probes
indicated that ERRalpha was capable of binding two distinct sites within NRRE-1,
each of which conform to the known ERRalpha monomeric binding consensus. The
expression of ERRalpha paralleled NRRE-1 binding activities and MCAD expression
during brown adipocyte differentiation, cardiac development, and among a variety
of adult mouse tissues. These results identify a new class of ERRalpha target
genes and implicate ERRalpha and chicken ovalbumin upstream promoter
transcription factor in the control of a pivotal metabolic pathway during brown
adipocyte differentiation.
PMID- 9395512
TI - Aggregated low density lipoprotein induces and enters surface-connected
compartments of human monocyte-macrophages. Uptake occurs independently of the
low density lipoprotein receptor.
AB - Aggregation of low density lipoprotein (LDL) stimulates its uptake by
macrophages. We have now shown by electron microscopic and chemical experiments
that aggregated LDL (produced by vortexing (VxLDL) or treatment with
phospholipase C) induced and became sequestered in large amounts within surface
connected compartments (SCC) of human monocyte-derived macrophages. This occurred
through a process different from phagocytosis. Formation of SCC and accumulation
of aggregated LDL in SCC are cell-mediated processes that were temperature
dependent (10 x greater cell association at 37 degrees C than at 4 degrees C) and
blocked by cytochalasin D but not by nocodazole. Because of the surface
connections of SCC, trypsin could release aggregated LDL from SCC. Degradation of
125I-VxLDL through the SCC pathway showed delayed and a lower rate of degradation
(10-55%) compared with nonaggregated 125I-acetylated LDL that did not enter SCC.
However, similar to 125I-acetylated LDL degradation, 125I-VxLDL degradation
occurred through a chloroquine-sensitive pathway. Uptake of VxLDL into SCC was
not mediated by the LDL receptor. Methylation of LDL prevents its binding to the
LDL receptor. However, methylated LDL still entered SCC after it was aggregated
by vortexing. On the other hand, degradation of 125I-VxLDL was substantially
decreased by methylation of LDL and by cholesterol enrichment of macrophages,
which decreases macrophage LDL receptor expression. The results suggest that
whereas uptake of aggregated LDL into SCC occurs independently of the LDL
receptor, movement of aggregated LDL from SCC to lysosomes may depend in part on
LDL receptor function. Sequestration into SCC is a novel endocytosis pathway for
uptake of aggregated LDL that allows the macrophage to store large amounts of
this lipoprotein before it is further processed.
PMID- 9395513
TI - Furin-mediated cleavage of Pseudomonas exotoxin-derived chimeric toxins.
AB - Pseudomonas exotoxin (PE) requires proteolytic cleavage to generate a 37-kDa C
terminal fragment that translocates to the cytosol and ADP-ribosylates elongation
factor 2. Cleavage within cells is mediated by furin, occurs between arginine 279
and glycine 280, and requires an arginine at both P1 and P4 residues. To study
the proteolytic processing of PE-derived chimeric toxins, TGFalpha-PE38
(transforming growth factor fused to the domains II and III of PE) and a mutant
form, TGFalpha-PE38gly279, were each produced in Escherichia coli. When assessed
on various epidermal growth factor (EGF) receptor-positive cell lines, TGFalpha
PE38 was 100-500-fold more toxic than TGFalpha-PE38gly279. In contrast to PE,
where cleavage by furin is only evident at pH 5.5, furin cleaved TGFalpha-PE38
over a broad pH range, while TGFalpha-PE38gly279 was resistant to cleavage.
TGFalpha-PE38 was poorly toxic for furin-deficient LoVo cells, unless it was
first pretreated in vitro with furin. Furin treatment produced a nicked protein
that was 30-fold more toxic than its unnicked counterpart. Using the single chain
immunotoxin HB21scFv-PE40 as a substrate, furin-mediated processing of an
antibody-based immunotoxin was also evaluated. HB21scFv-PE40, which targets cells
expressing the transferrin receptor, was cleaved in a similar fashion to that of
TGFalpha-PE38 and nicked HB21scFv-PE40 exhibited increased toxicity for LoVo
cells. In short-term experiments, the rate of reduction in protein synthesis by
furin-nicked immunotoxins was increased compared with unnicked protein,
indicating that cleavage by furin can be a rate-limiting step. We conclude that
furin-mediated cleavage of PE-derived immunotoxins is important for their
cytotoxic activity.
PMID- 9395514
TI - Specific interaction of eukaryotic translation initiation factor 5 (eIF5) with
the beta-subunit of eIF2.
AB - Eukaryotic translation initiation factor 5 (eIF5) interacts with the 40 S
initiation complex (40 S.mRNA. eIF3.Met-tRNAf.eIF2.GTP) and mediates hydrolysis
of the bound GTP. To characterize the molecular interactions involved in eIF5
function, we have used 32P-labeled recombinant rat eIF5 as a probe in filter
overlay assay to identify eIF5-interacting proteins in crude initiation factor
preparations. We observed that eIF5 specifically interacted with the beta subunit
of initiation factor eIF2. No other initiation factors including the gamma
subunit of eIF2 tested positive in this assay. Furthermore, both yeast and
mammalian eIF5 bind to the beta subunit of either mammalian or yeast eIF2.
Binding analysis with human eIF2beta deletion mutants expressed in Escherichia
coli identified a 22-amino acid domain, between amino acids 68 and 89, as the
primary eIF5-binding region of eIF2beta. These results along with our earlier
observations that (a) eIF5 neither binds nor hydrolyzes free GTP or GTP bound as
Met-tRNAf.eIF2.GTP ternary complex, and (b) eIF5 forms a specific complex with
eIF2 suggests that the specific interaction between eIF5 and the beta subunit of
eIF2 may be critical for the hydrolysis of GTP during translation initiation.
PMID- 9395516
TI - Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia
mediated down-regulation of endothelial nitric oxide synthase.
AB - Hypoxia induces vasoconstriction, in part, by down-regulating endothelial cell
nitric oxide synthase (ecNOS) expression. Previous studies indicate that 3
hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors improve
endothelium-dependent relaxation by increasing ecNOS activity. To determine
whether HMG CoA reductase inhibitors can prevent hypoxia-mediated down-regulation
of ecNOS function and expression, human endothelial cells were exposed to hypoxia
(3% O2) in the presence of HMG CoA reductase inhibitors simvastatin and
lovastatin for various durations (0-48 h). Hypoxia decreased ecNOS protein and
mRNA levels in a time-dependent manner, resulting in a 4- and 9-fold reduction
after 48 h, respectively. In a concentration-dependent manner, simvastatin, and
to a lesser extent, lovastatin, prevented the down-regulation of ecNOS expression
by hypoxia. Simvastatin-induced changes in ecNOS expression correlated with
changes in endothelial NO production and were reversed by treatment with L
mevalonate. Actinomycin D studies revealed that under hypoxic conditions,
simvastatin increased ecNOS mRNA half-life from 13 to 38 h. Nuclear run-on
studies showed that simvastatin had no effect on repression of ecNOS gene
transcription by hypoxia. These results indicate that HMG CoA reductase
inhibitors regulate ecNOS function and expression through changes in ecNOS mRNA
stability and suggest that treatment with HMG CoA reductase inhibitors may have
beneficial effects in patients with hypoxia-mediated pulmonary hypertension.
PMID- 9395515
TI - Nucleotide sequence context effect of a cyclobutane pyrimidine dimer upon RNA
polymerase II transcription.
AB - We have studied the role of sequence context upon RNA polymerase II arrest by a
cyclobutane pyrimidine dimer using an in vitro transcription system consisting of
templates containing a specifically located cyclobutane pyrimidine dimer (CPD)
and purified RNA polymerase II (RNAP II) and initiation factors. We selected a
model sequence containing a well characterized site for RNAP II arrest in vitro,
the human histone H3.3 gene arrest site. The 13-base pair core of the arrest
sequence contains two runs of T in the nontranscribed strand that impose a bend
in the DNA. We hypothesized that arrest of RNAP II might be affected by the
presence of a CPD, based upon the observation that a CPD located at the center of
a dA6.dT6 tract eliminates bending (Wang, C.-I., and Taylor, J.-S. (1991) Proc.
Natl. Acad. Sci. U. S. A. 88, 9072-9076). We examined the normal H3.3 sequence
and a mutant sequence containing a T --> G transversion, which reduces bending
and efficiency of arrest. We show that a CPD in the transcribed strand at either
of two locations in the arrest site is a potent block to transcription. However,
a CPD in the nontranscribed strand only transiently pauses RNAP II. The CPD in
concert with a mutation in the arrest site can reduce the extent of bending of
the DNA and improve readthrough efficiency. These results demonstrate the
potential importance of sequence context for the effect of CPDs within
transcribed sequences.
PMID- 9395517
TI - Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor
by cleavage at a specific juxtamembrane site.
AB - Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is
synthesized as a membrane-anchored precursor that is cleaved to release the
soluble mature growth factor. The two forms are active as juxtacrine and
paracrine/autocrine growth factors, respectively. The enzymes that process the HB
EGF transmembrane form are unknown. Accordingly, an in vitro assay was
established using a fusion protein in which alkaline phosphatase (AP) replaced
the transmembrane and cytoplasmic domains of HB-EGF (HB-EGF JM-AP). The fusion
protein was anchored to agarose beads coated with anti-AP antibodies. Several
matrix metalloproteinases (MMPs) were tested for the ability to release soluble
HB-EGF in the in vitro system. MMP-3 released soluble 12-kDa immunoreactive and
mitogenic HB-EGF within 30 min. On the other hand neither MMP-2 nor MMP-9 had any
cleavage activities. A non-cleavable mutant was prepared by replacing the
juxtamembrane (JM) region of HB-EGF with the JM region of CD4. The mutant HB-EGF,
which in its full-length form was as active a juxtacrine growth factor as was the
wild type HB-EGF in vivo, was not cleaved by MMP-3 in the in vitro assay. The C
terminal portion of the cleaved HB-EGF JM-AP that remained attached to the anti
AP beads was N-terminally sequenced and the MMP-3 cleavage site was determined to
be Glu151-Asn152, a site within the JM domain. MMP-3 treatment also released
soluble HB-EGF in vivo from MC2 cells expressing transmembrane HB-EGF precursor,
at a level of about 2-fold above control. It was concluded that MMP-3 cleaves HB
EGF at a specific site in the JM domain and that this enzyme might regulate the
conversion of HB-EGF from being a juxtacrine to a paracrine/autocrine growth
factor.
PMID- 9395518
TI - Cig30, a mouse member of a novel membrane protein gene family, is involved in the
recruitment of brown adipose tissue.
AB - We have identified a previously uncharacterized gene that is implicated in the
thermogenic function of brown adipose tissue of mice. This gene, termed Cig30, is
the first mammalian member of a novel gene family comprising several nematode and
yeast genes, such as SUR4 and FEN1, mutation of which is associated with highly
pleiotropic phenotypes. It codes for a 30-kDa plasma membrane glycoprotein with
five putative transmembrane domains. The Cig30 mRNA was readily detected only in
brown fat and liver. When animals were exposed to a 3-day cold stress, the Cig30
expression was selectively elevated in brown fat more than 200-fold. Similar
increases were brought about in two other conditions of brown fat recruitment,
namely during perinatal development and after cafeteria diet. The magnitude of
Cig30 mRNA induction in the cold could be mimicked by chronic norepinephrine
treatment in vivo. However, in primary cultures of brown adipocytes, a
synergistic action of norepinephrine and dexamethasone was required for full
expression of the gene, indicating that both catecholamines and glucocorticoids
are required for the induction of Cig30. We propose that the CIG30 protein is
involved in a pathway connected with brown fat hyperplasia.
PMID- 9395519
TI - Ccs1, a nuclear gene required for the post-translational assembly of chloroplast
c-type cytochromes.
AB - Nuclear genes play important regulatory roles in the biogenesis of the
photosynthetic apparatus of eukaryotic cells by encoding factors that control
steps ranging from chloroplast gene transcription to post-translational
processes. However, the identities of these genes and the mechanisms by which
they govern these processes are largely unknown. By using glass bead-mediated
transformation to generate insertional mutations in the nuclear genome of
Chlamydomonas reinhardtii, we have generated four mutants that are defective in
the accumulation of the cytochrome b6f complex. One of them, strain abf3, also
fails to accumulate holocytochrome c6. We have isolated a gene, Ccs1, from a C.
reinhardtii genomic library that complements both the cytochrome b6f and
cytochrome c6 deficiencies in abf3. The predicted protein product displays
significant identity with Ycf44 from the brown alga Odontella sinensis, the red
alga Porphyra purpurea, and the cyanobacterium Synechocystis strain PCC 6803 (25
33% identity). In addition, we note limited sequence similarity with ResB of
Bacillus subtilis and an open reading frame in a homologous operon in
Mycobacterium leprae (11-12% identity). On the basis of the pleiotropic c-type
cytochrome deficiency in the ccs1 mutant, the predicted plastid localization of
the protein, and its relationship to candidate cytochrome biosynthesis proteins
in Gram-positive bacteria, we conclude that Ccs1 encodes a protein that is
required for chloroplast c-type holocytochrome formation.
PMID- 9395520
TI - Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat
hepatoma H4IIE cells.
AB - We have investigated mechanisms of omeprazole (OME)-mediated induction of CYP1A1
and CYP3A, using the rat hepatoma H4IIE cell line, in comparison with mechanisms
exerted by traditional aryl hydrocarbon receptor (AhR) ligands such as
benso(a)pyrene (B(a)P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). OME did
not bind specifically to AhR, and it could not activate the AhR complex in rat
cytosol to a xenobiotic-responsive element (XRE)-binding form in vitro.
Genistein, a tyrosine kinase inhibitor, and daidzein, an inhibitor of casein
kinase II, efficiently inhibited OME-mediated but not B(a)P- or TCDD-mediated
induction of CYP1A1, as monitored at the transcriptional, mRNA, and protein
levels as well as by analysis of activation of XRE-luciferase reporter constructs
transfected into H4IIE cells. The protease inhibitor Nalpha-p-tosyl-L-lysine
chloromethyl ketone (TLCK) and lavendustin A also had similar OME-specific
effects. In addition, insulin pretreatment caused an almost complete inhibition
of OME-dependent CYP1A1 induction but only partially affected TCDD and B(a)P
mediated induction of CYP1A1. Staurosporine, an inhibitor of protein kinase C,
impaired the induction by both B(a)P and OME. OME caused an approximately 2-fold
increase in the level of CYP3A expression, but all inhibitors used were
ineffective in preventing this induction. Gel shift analysis with radiolabeled
XRE and specific peptide antibodies toward AhR and aryl hydrocarbon receptor
nuclear translocator protein (Arnt) revealed an OME-mediated translocation of the
AhR.Arnt complex into the nuclei. Genistein inhibited the specific nuclear XRE
binding caused by OME, but it potentiated the formation of the TCDD-induced
XRE.AhR complex. Although daidzein was able to effectively inhibit the OME
stimulated CYP1A1 gene transcription, it did not influence the OME-dependent
AhR.XRE complex formation. The data are consistent with a mechanism for OME
mediated induction of CYP1A1 that involves activation of the AhR complex via
intracellular signal transduction systems and that is distinct from induction
mediated by AhR ligands.
PMID- 9395521
TI - Role of metalloproteases in the release of the IL-1 type II decoy receptor.
AB - The IL-1 type II receptor (decoy RII) is a nonsignaling molecule the only
established function of which is to capture IL-1 and prevent it from interacting
with signaling receptor. The decoy RII is released in a regulated way from the
cell surface. Here, we reported that hydroxamic acid inhibitors of matrix
metalloproteases inhibit different pathways of decoy RII release, including the
following: (a) the slow (18 h) gene expression-dependent release from monocytes
and polymorphonuclear cells exposed to dexamethasone; (b) rapid release (minutes)
from myelomonocytic cells exposed to tumor necrosis factor, chemoattractants, or
phorbol myristate acetate; (c) phorbol myristate acetate-induced release from
decoy RII-transfected fibroblasts and B cells. Inhibition of release was
associated with increased surface expression of decoy RII. Inhibitors of other
protease classes did not substantially affect release. However, serine protease
inhibitors increased the molecular mass of the decoy RII released from
polymorphonuclear cells from 45 to 60 kDa. Thus, irrespective of the pathway
responsible for release and of the cellular context, matrix metalloproteases,
rather than differential splicing, play a key role in production of soluble decoy
RII.
PMID- 9395522
TI - Characterization and purification of human corneodesmosin, an epidermal basic
glycoprotein associated with corneocyte-specific modified desmosomes.
AB - Using monoclonal antibodies, we identified a new protein in mammalian epidermis,
which we called corneodesmosin. It is located in the extracellular part of the
modified desmosomes in the cornified layer of the tissue, and its proteolysis
(from 52-56 to 33 kDa) is thought to be a major prerequisite of desquamation. We
have now further characterized human corneodesmosin. Proteolysis of purified
cornified cell envelopes produced immunoreactive fragments, confirming the
covalent linkage of the protein to these structures. Sequential extraction of
epidermal proteins indicated that the 52-56-kDa precursor form of the protein
exists in two distinct pools, one extracted with a nondenaturing hypotonic
buffer, and the other with urea. Two-dimensional gel analysis and reactivity with
phosphoserine-specific antibodies showed that it is a basic phosphoprotein.
Deglycosylation experiments, reactivity with lectins, and chromatography on
concanavalin A-Sepharose indicated that corneodesmosin is N-glycosylated. Partial
sequences, 10 and 15 amino acids long, of the purified 52-56-kDa corneodesmosin
showed identity with sequences predicted from a previously cloned gene, proved to
be expressed in the epidermis and designated S. This indicates that
corneodesmosin is probably encoded by the S gene, the function of which was
unknown until now. A model of corneodesmosin maturation during cornification is
proposed.
PMID- 9395523
TI - A transcription activator with restricted tissue distribution regulates cell
specific expression of alpha1(XI) collagen.
AB - Different regulatory programs are likely to control expression of the alpha1(XI)
collagen (COL11A1) gene in cartilaginous and non-cartilaginous tissues and in
coordination with different collagen genes. Here, we report the identification of
a cis-acting element that is required for constitutive and tissue-specific
activity of the proximal COL11A1 promoter. The element binds an apparently novel
activator whose expression is restricted mostly, but not exclusively, to cells of
mesenchymal origin. Transient transfection experiments using wild-type and mutant
constructs demonstrated the critical contribution of a 45-base pair upstream
element (FP9) to promoter activity. The same functional tests and DNA binding
assays narrowed down the critical portion of FP9 to a 20-base pair sequence,
which consists of an imperfect palindrome with strong homology to the GATA
consensus motif. Despite being able to bind GATA proteins in vitro, FP9 is
actually recognized by a distinct approximately 100-kDa polypeptide (FP9C)
probably belonging to the zinc-finger family of transcription factors. FP9C
binding was mostly identified in nuclei from cells of mesenchymal origin,
including those actively engaged in COL11A1 transcription. A positive correlation
was also established between the level of FP9C binding and the degree of cell
differentiation in vitro. Thus, FP9C represents an unusual example of tissue
specific and differentiation-related transcription factor with overlapping
expression in hard and soft connective tissues.
PMID- 9395524
TI - Platelet factor 4 binds to glycanated forms of thrombomodulin and to protein C. A
potential mechanism for enhancing generation of activated protein C.
AB - Platelet factor 4 (PF4) is an abundant platelet alpha-granule heparin-binding
protein. We have previously shown that PF4 accelerates up to 25-fold the
proteolytic conversion of protein C to activated protein C by the
thrombin.thrombomodulin complex by increasing its affinity for protein C 30-fold.
This stimulatory effect requires presence of the gamma-carboxyglutamic acid (Gla)
domain in protein C and is enhanced by the presence of a chondroitin sulfate
glycosaminoglycan (GAG) domain on thrombomodulin. We hypothesized that cationic
PF4 binds to both protein C and thrombomodulin through these anionic domains.
Qualitative SDS-polyacrylamide gel electrophoresis analysis of avidin extracts of
solutions containing biotinylated PF4 and candidate ligands shows that PF4 binds
to GAG+ but not GAG- forms of thrombomodulin and native but not Gla-domainless
protein C. Quantitative analysis using the surface plasmon resonance-based
BIAcoreTM biosensor system confirms the extremely high affinity of PF4 for
heparin (KD = 4 nM) and shows that PF4 binds to GAG+ thrombomodulin with a KD of
31 nM and to protein C with a KD of 0.37 microM. In contrast, PF4 had no
measurable interaction with GAG- thrombomodulin or Gla-domainless protein C.
Western blot analysis of normal human plasma extracted with biotinylated PF4
demonstrates PF4 binding to protein C in a physiologic context. Thus, PF4 binds
with relative specificity and high affinity to the GAG- domain of thrombomodulin
and the Gla domain of protein C. These interactions may enhance the affinity of
the thrombin.thrombomodulin complex for protein C and thereby promote the
generation of activated protein C.
PMID- 9395525
TI - CCAAT/enhancer-binding protein delta activates insulin-like growth factor-I gene
transcription in osteoblasts. Identification of a novel cyclic AMP signaling
pathway in bone.
AB - Insulin-like growth factor-I (IGF-I) plays a key role in skeletal growth by
stimulating bone cell replication and differentiation. We previously showed that
prostaglandin E2 (PGE2) and other cAMP-activating agents enhanced IGF-I gene
transcription in cultured primary rat osteoblasts through promoter 1, the major
IGF-I promoter, and identified a short segment of the promoter, termed HS3D, that
was essential for hormonal regulation of IGF-I gene expression. We now
demonstrate that CCAAT/enhancer-binding protein (C/EBP) delta is a major
component of a PGE2-stimulated DNA-protein complex involving HS3D and find that
C/EBPdelta transactivates IGF-I promoter 1 through this site. Competition gel
shift studies first indicated that a core C/EBP half-site (GCAAT) was required
for binding of a labeled HS3D oligomer to osteoblast nuclear proteins.
Southwestern blotting and UV-cross-linking studies showed that the HS3D probe
recognized a approximately 35-kDa nuclear protein, and antibody supershift assays
indicated that C/EBPdelta comprised most of the PGE2-activated gel-shifted
complex. C/EBPdelta was detected by Western immunoblotting in osteoblast nuclear
extracts after treatment of cells with PGE2. An HS3D oligonucleotide competed
effectively with a high affinity C/EBP site from the rat albumin gene for binding
to osteoblast nuclear proteins. Co-transfection of osteoblast cell cultures with
a C/EBPdelta expression plasmid enhanced basal and PGE2-activated IGF-I promoter
1-luciferase activity but did not stimulate a reporter gene lacking an HS3D site.
By contrast, an expression plasmid for the related protein, C/EBPbeta, did not
alter basal IGF-I gene activity but did increase the response to PGE2. In
osteoblasts and in COS-7 cells, C/EBPdelta, but not C/EBPbeta, transactivated a
reporter gene containing four tandem copies of HS3D fused to a minimal promoter;
neither transcription factor stimulated a gene with four copies of an HS3D mutant
that was unable to bind osteoblast nuclear proteins. These results identify
C/EBPdelta as a hormonally activated inducer of IGF-I gene transcription in
osteoblasts and show that the HS3D element within IGF-I promoter 1 is a high
affinity binding site for this protein.
PMID- 9395526
TI - The recycling of ERGIC-53 in the early secretory pathway. ERGIC-53 carries a
cytosolic endoplasmic reticulum-exit determinant interacting with COPII.
AB - Further investigation of the targeting of the intracellular membrane lectin
endoplasmic reticulum (ER)-Golgi intermediate compartment-53 (ERGIC-53) by site
directed mutagenesis revealed that its lumenal and transmembrane domains together
confer ER retention. In addition we show that the cytoplasmic domain is required
for exit from the ER indicating that ERGIC-53 carries an ER-exit determinant. Two
phenylalanines at the C terminus are essential for ER-exit. Thus, ERGIC-53
contains determinants for ER retention as well as anterograde transport which, in
conjunction with a dilysine ER retrieval signal, control the continuous recycling
of ERGIC-53 in the early secretory pathway. In vitro binding studies revealed a
specific phenylalanine-dependent interaction between an ERGIC-53 cytosolic tail
peptide and the COPII coat component Sec23p. These results suggest that the ER
exit of ERGIC-53 is mediated by direct interaction of its cytosolic tail with the
Sec23p.Sec24p complex of COPII and that protein sorting at the level of the ER
occurs by a mechanism similar to receptor-mediated endocytosis or Golgi to ER
retrograde transport.
PMID- 9395527
TI - The Ca2+/calmodulin-dependent kinase type IV is involved in the CD5-mediated
signaling pathway in human T lymphocytes.
AB - The CD5 receptor on T lymphocytes is involved in T cell activation and T-B cell
interactions. In the present study, we have characterized the signaling pathways
induced by anti-CD5 stimulation in human T lymphocytes. In T lymphocytes, anti
CD5 co-stimulation enhances the phytohemagglutinin/anti-CD28-induced interleukin
2 (IL-2) mRNA accumulation 1.6-fold and IL-2 protein secretion 2. 2-fold, whereby
the up-regulation is mediated at both the transcriptional and post
transcriptional level. The CD5 signaling pathway up-regulates the IL-2 gene
expression by increasing the DNA binding and transactivation activity of
activator protein 1 but affects none of the other transcription factors like
nuclear factor of activated T cells, nuclear factor kappaB, Oct, and CD28
responsive complex/nuclear factor of mitogen-activated T cells involved in the
regulation of the IL-2 promoter activity. The CD5-induced increase of the
activator protein 1 activity is mediated through the activation of
calcium/calmodulin-dependent (CaM) kinase type IV, and is independent of the
activation of mitogen-activated protein kinases Jun N-terminal kinase,
extracellular signal-regulated kinase, and p38/Mpk2, and calcium/calmodul
independent kinase type II. The expression of a dominant negative mutant of CaM
kinase IV in T lymphocytes transfected with an IL-2 promoter-driven reporter
construct completely abrogates the response to CD5 stimulation, indicating that
CaM kinase IV is essential to the CD5 signaling pathway. In addition, it is
demonstrated that calcium/calmodulin-dependent kinase type IV is also involved in
the stabilization of the IL-2 transcripts, which is observed after co-stimulation
of phytohemagglutinin/anti-CD28 activated T lymphocytes with anti-CD5.
PMID- 9395528
TI - Interaction of STAT5 dimers on two low affinity binding sites mediates
interleukin 2 (IL-2) stimulation of IL-2 receptor alpha gene transcription.
AB - Stimulation of the interleukin 2 receptor alpha (IL-2Ralpha) gene by IL-2 is
important for the proliferation of antigen-activated T lymphocytes. IL-2
regulates IL-2Ralpha transcription via a conserved 51-nucleotide IL-2 responsive
enhancer. Mouse enhancer function depends on cooperative activity of three
distinct sites. Two of these are weak binding sites for IL-2-activated STAT5
(signal transducer and activator of transcription) proteins, and mutational
analysis indicates that binding of STAT5 to both sites is required for IL-2
responsiveness of the enhancer. The STAT5 dimers interact to form a STAT5
tetramer. The efficiency of tetramerization depends on the relative rotational
orientation of the two STAT motifs on the DNA helix. STAT5 tetramerization on
enhancer mutants correlates well with the IL-2 responsiveness of these mutants.
This provides strong evidence that interactions between STAT dimers binding to a
pair of weak binding sites play a biological role by controlling the activity of
a well characterized, complex cytokine-responsive enhancer.
PMID- 9395529
TI - Differential ubiquitin-dependent degradation of the yeast apo-cytochrome c
isozymes.
AB - The yeast Saccharomyces cerevisiae contains two forms of cytochrome c, iso-1- and
iso-2-cytochrome c, which are encoded by the nuclear genes CYC1 and CYC7,
respectively. The cytochromes c are synthesized in the cytosol, imported into
mitochondria, and subsequently modified by the covalent attachment of heme
through the action of cytochrome c heme lyase, which is encoded by CYC3. Apo-iso
2-cytochrome c but not apo-iso-1-cytochrome c was observed in cyc3(-) mutants.
Furthermore, pulse-chase experiments previously demonstrated that the lack of apo
iso-1-cytochrome c was due to its rapid degradation. We report herein that this
degradation of apo-iso-1-cytochrome c is dependent on ubiquitination and on the
action of the proteasome. Diminished degradation of apo-iso-1-cytochrome c was
observed in pre2-2 and pre1-1 mutants having altered proteasome subunits; in
ubc1, ubc4, and ubc5 strains lacking one or more of the ubiquitin-conjugating
enzymes; and in strains blocked in multi-ubiquitination by overproduction of the
abnormal ubiquitin-K48R ubiquitin. In addition, we have used epitope-tagged
ubiquitin to demonstrate that apo-iso-1-cytochrome c but not apo-iso-2-cytochrome
c is ubiquitinated. Furthermore, the degradation of apo-iso-1-cytochrome c was
diminished when the N-terminal region was replaced with the N-terminal region of
apo-iso-2-cytochrome c, indicating that this region may be the target for
degradation. We suggest that ubiquitin-dependent degradation of apo-iso-1
cytochrome c is part of the regulatory process controlling the preferential
expression of the iso-cytochromes c.
PMID- 9395530
TI - Variant exons v6 and v7 together expand the repertoire of glycosaminoglycans
bound by CD44.
AB - Isoforms of the glycoprotein CD44 are cell surface receptors for the
glycosaminoglycan hyaluronate. They have been implicated in many biological
processes, but their function in these is poorly understood and cannot be
explained solely by hyaluronate binding. In the present work we examine the
ligand binding properties of alternatively spliced CD44 variant isoforms which
are functionally involved in the immune system, embryonic development, and tumor
behavior. We show that these isoforms bind directly to the purified
glycosaminoglycans chondroitin sulfate, heparin, and heparin sulfate, in addition
to being able to bind to hyaluronate. Binding to this extended repertoire of
glycosaminoglycans by CD44 depends on the inclusion of peptide sequences encoded
by the alternatively spliced exons v6 and v7, and occurs both when the CD44 is
solubilized from the plasma membrane and when it is expressed on intact cells. A
single point mutation in the most N-terminal hyaluronate binding motif of CD44
ablates both hyaluronate and chondroitin sulfate binding, suggesting that
glycosaminoglycans are bound through a common motif, and that only one of the
hyaluronate binding motifs is responsible for the majority of glycosaminoglycan
binding by CD44 on the cell surface. Taken together, these observations indicate
that alternative splicing regulates the ligand binding specificity of CD44 and
suggest that structural changes in the CD44 protein have a profound effect on the
range of ligands to which this molecule can bind with potentially wide-ranging
functional consequences.
PMID- 9395531
TI - A mutation in the aryl hydrocarbon receptor (AHR) in a cultured mammalian cell
line identifies a novel region of AHR that affects DNA binding.
AB - Introduction of a retroviral expression vector for the aryl hydrocarbon receptor
(AHR) restores CYP1A1 inducibility to a mutant derivative of the Hepa-1 cell line
that is defective in induction of CYP1A1 by ligands for the receptor. An AHR
protein with normal ligand binding activity is expressed in the mutant but ligand
treatment of mutant cell extract fails to induce binding of the AHR. ARNT (aryl
hydrocarbon receptor nuclear translocator) dimer to the xenobiotic responsive
element (XRE). AHR cDNAs derived from the mutant encode a protein that is
unimpaired in ligand-dependent dimerization with ARNT, but the AHR.ARNT dimer so
formed is severely impaired in XRE binding activity. The mutant cDNAs contain a C
to G mutation at base 648, causing a cysteine to tryptophan alteration at amino
acid 216, located between the PER-ARNT-SIM homology region (PAS) A and PAS B
repeats. Introduction of the same mutation in the wild-type AHR sequence by site
directed mutagenesis similarity impaired XRE binding activity. Substitution with
the conservative amino acid, serine, had no effect on XRE binding. The tryptophan
mutation, but not the wild-type allele, was detectable in genomic DNA of the
mutant. The implication that an amino acid within the PAS region may be involved
in DNA binding indicates that the DNA binding behavior of AHR may be more
anomalous than previously suspected.
PMID- 9395532
TI - High affinity dimerization by Ski involves parallel pairing of a novel bipartite
alpha-helical domain.
AB - c-Ski protein possesses a C-terminal dimerization domain that was deleted during
the generation of v-ski, and has been implicated in the increased potency of c
ski in cellular transformation compared with the viral gene. The domain is
predicted to consist of an extended alpha-helical segment made up of two motifs:
a tandem repeat (TR) consisting of five imperfect repeats of 25 residues each and
a leucine zipper (LZ) consisting of six heptad repeats. We have examined the
structure and dimerization of TR or LZ individually or the entire TR-LZ domain.
Using a quenched chemical cross-linking method, we show that the TR dimerizes
with moderate efficiency (Kd = 4 x 10(-6) M), whereas LZ dimerizes poorly (Kd > 2
x 10(-5) M). However, the entire TR-LZ domain dimerizes efficiently (Kd = 2 x 10(
8) M), showing a cooperative effect of the two motifs. CD analyses indicate that
all three proteins contain predominantly alpha-helices. Limited proteolysis of
the TR-LZ dimer indicates that the two helical motifs are linked by a small loop.
Interchain disulfide bond formation indicates that both the LZ and TR helices are
oriented in parallel. We propose a model for the dimer interface in the TR region
consisting of discontinuous clusters of hydrophobic residues forming "leucine
buttons."
PMID- 9395533
TI - Regulation of leukotriene A4 hydrolase activity in endothelial cells by
phosphorylation.
AB - Endothelial cells contain leukotriene (LT) A4 hydrolase (LTA-H) as detected by
Northern and Western blotting, but several studies have been unable to detect the
activity of this enzyme. Since LTA-H could play a key role in determining what
biologically active lipids are generated by activated endothelium during the
inflammatory process, we studied possible mechanisms by which this enzyme may be
regulated. We find that LTA-H is phosphorylated under basal conditions in human
endothelial cells and in this state does not exhibit epoxide hydrolase activity
(i.e. conversion of LTA4 to LTB4). LTA-H purified from endothelial cells is
efficiently dephosphorylated by incubation with protein phosphatase-1 in the
presence of an LTA-H peptide substrate and not at all in the absence of
substrate. Under conditions that lead to dephosphorylation, protein phosphatase-1
activates the epoxide hydrolase activity of LTA-H. Using peptide mapping and site
directed mutagenesis, we have identified serine 415 as the site of
phosphorylation of LTA-H by a kinase found in endothelial cell cytosol. In
parallel, we have studied a human lung carcinoma cell line that expresses active
LTA-H. Although these cells have cytosolic kinases that phosphorylate recombinant
LTA-H, they do not target serine 415 and thus do not inhibit LTA-H activity. We
believe that LTA-H is regulated in intact cells by a kinase/phosphatase cycle and
further that the kinase in endothelial cells specifically recognizes and
phosphorylates a regulatory site in the LTA-H.
PMID- 9395534
TI - Identification of cysteine pairs within the amino-terminal 5% of apolipoprotein B
essential for hepatic lipoprotein assembly and secretion.
AB - There is growing evidence that the amino-terminal globular domain of
apolipoprotein B (apoB) is essential for lipoprotein particle formation in the
hepatic endoplasmic reticulum. To identify the structural requirements for its
function in lipoprotein assembly, cysteine (Cys) pairs required to form the seven
disulfide bonds within the amino-terminal 21% of apoB were replaced in groups or
individually by serine. Substitution of Cys pairs required for formation of
disulfide bonds 1-3 or 4-7 (numbered from amino to carboxyl terminus) completely
blocked the secretion of apoB28 in transfected HepG2 cells. To identify the
specific disulfide bonds required for secretion, Cys pairs were mutated
individually. Substitution of Cys pairs required for disulfide bonds 1, 3, 5, 6,
or 7 had little or no impact on apoB28 secretion or buoyant density. In contrast,
individual substitution of Cys pair 2 (amino acid residues 51 and 70) or 4 (218
and 234) severely inhibited apoB28 secretion and its capacity to undergo
intracellular assembly with lipid. The same assembly and secretion defects were
observed when these mutations were expressed as part of apoB50. These studies
provide direct evidence that the ability of the internal lipophilic regions of
apoB to engage in the recruitment and sequestration of lipid during translation
is critically dependent upon a structural configuration contained within or
affected by the amino-terminal 5% of the protein.
PMID- 9395535
TI - Yrb2p is a nuclear protein that interacts with Prp20p, a yeast Rcc1 homologue.
AB - A conserved family of Ran binding proteins (RBPs) has been defined by their
ability to bind to the Ran GTPase and the presence of a common region of
approximately 100 amino acids (the Ran binding domain). The yeast Saccharomyces
cerevisiae genome predicts only three proteins with canonical Ran binding
domains. Mutation of one of these, YRB1, results in defects in transport of
macromolecules across the nuclear envelope (Schlenstedt, G., Wong, D. H., Koepp,
D. M., and Silver, P. A. (1995) EMBO J. 14, 5367-5378). The second one, encoded
by YRB2, is a 327-amino acid protein with a Ran binding domain at its C terminus
and an internal cluster of FXFG and FG repeats conserved in nucleoporins. Yrb2p
is located inside the nucleus, and this localization relies on the N terminus.
Results of both genetic and biochemical analyses show interactions of Yrb2p with
the Ran nucleotide exchanger Prp20p/Rcc1. Yrb2p binding to Gsp1p (yeast Ran) as
well as to a novel 150-kDa GTP-binding protein is also detected. The Ran binding
domain of Yrb2p is essential for function and for its association with Prp20p and
the GTP-binding proteins. Taken together, we suggest that Yrb2p may play a role
in the Ran GTPase cycle distinct from nuclear transport.
PMID- 9395536
TI - The tryptase, mouse mast cell protease 7, exhibits anticoagulant activity in vivo
and in vitro due to its ability to degrade fibrinogen in the presence of the
diverse array of protease inhibitors in plasma.
AB - Mouse mast cell protease (mMCP) 7 is a tryptase of unknown function expressed by
a subpopulation of mast cells that reside in numerous connective tissue sites.
Because enzymatically active mMCP-7 is selectively released into the plasma of V3
mastocytosis mice undergoing passive systemic anaphylaxis, we used this in vivo
model system to identify a physiologic substrate of the tryptase. Plasma samples
taken from V3 mastocytosis mice that had been sensitized with immunoglobulin (Ig)
E and challenged with antigen were found to contain substantial amounts of four
34-55-kDa peptides, all of which were derived from fibrinogen. To confirm the
substrate specificity of mMCP-7, a pseudozymogen form of the recombinant tryptase
was generated that could be activated after its purification. The resulting
recombinant mMCP-7 exhibited potent anticoagulant activity in the presence of
normal plasma and selectively cleaved the alpha-chain of fibrinogen to fragments
of similar size as that seen in the plasma of the IgE/antigen-treated V3
mastocytosis mouse. Subsequent analysis of a tryptase-specific, phage display
peptide library revealed that recombinant mMCP-7 preferentially cleaves an amino
acid sequence that is nearly identical to that in the middle of the alpha-chain
of rat fibrinogen. Because fibrinogen is a physiologic substrate of mMCP-7, this
tryptase can regulate clot formation and fibrinogen/integrin-dependent cellular
responses during mast cell-mediated inflammatory reactions.
PMID- 9395537
TI - Dephosphorylation of the cadherin-associated p100/p120 proteins in response to
activation of protein kinase C in epithelial cells.
AB - Protein kinase C signaling pathways have been implicated in the disruption of
intercellular junctions, but mechanisms are not clear. p100 and p120 are members
of the Armadillo family of proteins and are localized to cellular adherens
junctions. In strain I Madin-Darby canine kidney cells, protein kinase C
activation leads to disruption of tight junctions and an increase in permeability
of cell monolayers. We show that this permeability increase is accompanied by
dephosphorylation of p100/p120 on serine and threonine residues. The
dephosphorylation of these proteins can also be induced by the kinase inhibitors
staurosporine, KT5926, and Go 6976. Treatment of cells with phosphatase
inhibitors induced hyperphosphorylation of p100 and p120. Thus, p100 and p120
participate in a regulatable cycle of serine/threonine phosphorylation and
dephosphorylation. Protein kinase C must act, directly or indirectly, by
perturbing this phosphorylation cycle, by inhibition of a p100/p120 kinase and/or
activation of a phosphatase. These data clearly show that p100 and p120 are
targets of a novel protein kinase C signaling pathway. Dephosphorylation of these
proteins precedes the permeability increase across epithelial cell monolayers
seen in response to phorbol esters, raising the possibility that this pathway may
play a role in the modulation of intercellular junctions.
PMID- 9395538
TI - Drosophila factor 2, an RNA polymerase II transcript release factor, has DNA
dependent ATPase activity.
AB - Drosophila factor 2 has been identified as a component of negative transcription
elongation factor (N-TEF) that causes the release of RNA polymerase II
transcripts in an ATP-dependent manner (Xie, Z. and Price D. H. (1996) J. Biol.
Chem. 271, 11043-11046). We show here that the transcript release activity of
factor 2 requires ATP or dATP and that adenosine 5'-O-(thiotriphosphate)
(ATPgammaS), adenosine 5'-(beta,gamma-imino)triphosphate (AMP-PNP), or other NTPs
do not support the activity. Factor 2 demonstrated a strong DNA-dependent ATPase
activity that correlated with its transcript release activity. At 20 microg/ml
DNA, the ATPase activity of factor 2 had an apparent Km(ATP) of 28 microM and an
estimated Kcat of 140 min-1. Factor 2 caused the release of nascent transcripts
associated with elongation complexes generated by RNA polymerase II on a dC
tailed template. Therefore, no other protein cofactors are required for the
transcript release activity of factor 2. Using the dC-tailed template assay, it
was found that renaturation of the template was required for factor 2 function.
PMID- 9395539
TI - The VRG4 gene is required for GDP-mannose transport into the lumen of the Golgi
in the yeast, Saccharomyces cerevisiae.
AB - In the yeast Saccharomyces cerevisiae, glycoproteins and sphingolipids are
modified in the Golgi by the addition of mannose residues. The critical mannosyl
donor for these reactions is the nucleotide sugar, GDP-mannose, whose transport
into the Golgi from the cytoplasm is required for mannosylation. This transport
reaction has been well characterized, but the nucleotide sugar transporter has
yet to be identified in yeast. VRG4 is an essential gene whose product is
required for a number of Golgi-specific functions, including glycosylation and
the organization of the endomembrane system. Here, data are presented that
demonstrate that the primary role of Vrg4p is in the transport of GDP-mannose
into the Golgi. The vrg4 mutation causes a general impairment in mannosylation,
affecting N-linked and O-linked glycoprotein modifications as well as the
mannosylation of sphingolipids. By using an in vitro assay, vrg4 mutants were
shown to be specifically defective in the transport of GDP-mannose into Golgi
vesicles. The Vrg4 protein localizes to the Golgi complex in a pattern that
suggests a wide distribution throughout the Golgi. Vrg4p displays homology to
other putative nucleotide sugar transporters, suggesting that the VRG4 gene
encodes a Golgi GDP-mannose transporter. As Vrg4p is essential, these results
suggest that a complete lack of mannosylation of glycoproteins in the Golgi leads
to inviability. Alternatively, the essential function of Vrg4p in yeast involves
its effect on sphingolipids, which would imply a critical role for
mannosylinositol phosphorylceramides or mannosyl diphosphoinositol ceramides on
growth and viability.
PMID- 9395540
TI - S100beta inhibits alpha1-adrenergic induction of the hypertrophic phenotype in
cardiac myocytes.
AB - In an experimental rat model of myocardial infarction, surviving cardiac myocytes
undergo hypertrophy in response to trophic effectors. This response involves gene
reprogramming manifested by the re-expression of fetal genes, such as the
previously reported isoform switch from adult alpha- to embryonic beta-myosin
heavy chain. We now report the transient re-expression of a second fetal gene,
skeletal alpha-actin in rat myocardium at 7 days post-infarction, and its
subsequent down-regulation coincident with the delayed induction of S100beta, a
protein normally expressed in brain. In cultured neonatal rat cardiac myocytes,
co-transfection with an S100beta-expression vector inhibits a pathway associated
with hypertrophy, namely, alpha1-adrenergic induction of beta-myosin heavy chain
and skeletal alpha-actin promoters mediated by beta-protein kinase C. The
induction of beta-myosin heavy chain by hypoxia was similarly blocked by forced
expression of S100beta. Our results suggest that S100beta may be an intrinsic
negative regulator of the hypertrophic response of surviving cardiac myocytes
post-infarction. Such negative regulators may be important in limiting the
adverse consequences of unchecked hypertrophy leading to ventricular remodeling
and dysfunction.
PMID- 9395541
TI - Activation by cyclic GMP binding causes an apparent conformational change in cGMP
dependent protein kinase.
AB - Cyclic nucleotide binding activates cyclic nucleotide-dependent protein kinases,
but the molecular mechanism is unknown. In the present studies, cGMP binding to
type Ialpha or type Ibeta cGMP-dependent protein kinase (PKG) caused (i) a large
electronegative charge shift of each enzyme on ion exchange chromatography, (ii)
an increase in the Stokes radius (>3 A) of each enzyme, and (iii) a decreased
mobility of type Ibeta PKG on native gel electrophoresis. These physical changes
were not detected in the monomeric form of type Ibeta PKG upon activation by
cGMP. However, the results of partial proteolysis of type Ialpha PKG revealed
some degree of cGMP-induced conformational change within the PKG-monomer, since
cGMP binding protects the PKG-monomer against chymotryptic cleavage. The altered
sensitivity to proteolysis occurs at Met-200, which is located between the B and
C alpha-helices in the high affinity site (site A), and implies that the cGMP
induced structural perturbations in this region may participate in activation of
dimeric PKG. The cGMP-induced conformational effects observed using the physical
separation methods are likely to reflect altered interactions within the dimeric
PKG that are caused by structural alterations within the subunits.
PMID- 9395542
TI - Progressive cyclic nucleotide-induced conformational changes in the cGMP
dependent protein kinase studied by small angle X-ray scattering in solution.
AB - Small angle scattering data from bovine lung type Ialpha cGMP-dependent protein
kinase (PKG) in the absence of cGMP show the protein to have a highly asymmetric
structure with a radius of gyration (Rg) of 45 A and a maximum linear dimension
(dmax) of 165 A. The addition of cGMP induces a marked conformational change in
PKG. The Rg and dmax increase 25-30%, and the protein's mass moves further away
from the center of mass; this results in an even more asymmetric structure.
Fourier transform infrared spectroscopy data suggest that the conformational
change induced by cGMP binding is primarily due to a topographical movement of
the structural domains of PKG rather than to secondary structural changes within
one or more of the individual domains. Each monomer of the dimeric PKG contains
one high and one low affinity cGMP-binding site. A prominent increase in the
asymmetry of PKG occurs with binding to high affinity cGMP-binding sites alone,
but the full domain movements require the binding to both sets of sites. These
conformational changes occurring in PKG with the progressive binding of cGMP to
both sets of cGMP-binding sites correlate with past data, which have indicated
that cGMP binding to both sets of sites is required for the full activation of
the enzyme. These results provide the first quantitative measurement of the
overall PKG structure, as well as an assessment of the structural events that
accompany the activation of a protein kinase upon binding a small molecular
weight ligand.
PMID- 9395543
TI - Ethnicity and health: the challenges ahead.
PMID- 9395544
TI - Coronary heart disease risk factors in black and white patients with non-insulin
dependent diabetes mellitus.
AB - OBJECTIVE: To determine possible racial differences in risk factors for coronary
heart disease (CHD) in black and white patients with noninsulin-dependent
diabetes mellitus (NIDDM). METHODS: Study of risk factors for coronary heart
disease among 308 subjects who met the WHO criteria for NIDDM. RESULTS: Both
black and white patients were found to have a high prevalence of hypertension,
obesity, low high density lipoprotein (HDL) cholesterol, low leisure-time
physical activity levels, and an atherogenic dietary profile. Black males were
more likely to have hypertension, reported a greater intake of dietary
cholesterol, and had lower triglycerides, higher HDL cholesterol levels, a lower
CHOL/HDL ratio, and a lower waist to hip ratio (WHR) than white males. Black
females had higher mean arterial and diastolic blood pressures, had lower
triglycerides, higher HDL cholesterol, a lower CHOL/HDL ratio, a higher
subscapular/triceps ratio and lower reported leisure-time energy expenditure
compared to white females. There were no racial differences found for obesity
level. CONCLUSION: Our results indicate that racial differences in CHD risk
factors exist among black and white patients with NIDDM. The complex genetic,
sociocultural and environmental interactions involving CHD risk factors that
contribute to the development of CHD may eventually provide clues to the etiology
of the disease.
PMID- 9395545
TI - Racial differences in the incidence of end-stage renal disease.
AB - OBJECTIVE: To examine trends in the incidence of treated end-stage renal disease
(ESRD) and variations between blacks and whites. DESIGN: Retrospective record
reviews of all new patients > or = 15 years starting chronic dialysis during 1980
1988 at the Piedmont Dialysis Center, Forsyth County, North Carolina. RESULTS:
The cumulative nine-year incidence rate for hypertensive ESRD was 570 per
million, and for diabetic ESRD 497 per million. Among men, hypertensive ESRD
accounted for the largest proportion of cases (39.2% and 28.4%, blacks and whites
respectively), while diabetic ESRD contributed 33.9% of black female cases and
24.4% of white female cases. Compared to whites, blacks were at significantly
increased risk, with an adjusted risk odds ratio (OR) of 4.4 (95% confidence
interval (CI) 3.5-6.0) for all causes combined, 6.0 (CI 3.9-9.0) for hypertensive
renal disease, 6.0 (CI 3.8-9.3) for renal disease due to insulin-dependent
diabetes mellitus, and 12.2 (CI 6.9-21.7) due to non-insulin dependent diabetes
mellitus (NIDDM). The greatest risk among blacks was seen in the 55-64 year age
group, with ORs of 9.1 for all causes combined and 30.6 for hypertensive renal
disease. The OR for renal disease due to NIDDM for black versus white women was
20.0 (CI 9.5-41.7). Compared to 1980, 1981, 1982 and 1983, increased incidence
rates were seen in each year after 1984. CONCLUSION: These findings show even
greater excess risk of ESRD among blacks than previously reported. The majority
of the excess risk is seen for ESRD due to hypertension and diabetes, especially
NIDDM. The reasons for the increased risk among blacks, and for the increasing
incidence rates of ESRD are not known.
PMID- 9395546
TI - Relationship of hypertension to socioeconomic status in a west African
population.
AB - OBJECTIVES: To determine whether hypertension rates were positively related to
socioeconomic status (SES) in males in urban northern Nigerian civil servants in
order to confirm this relationship previously observed in a southern Nigerian
civil servant population which differed in tribal origin, religious practices and
diet. METHODS: Civil servants were recruited from the Sokoto State ministries,
Sokoto, Nigeria. Professionals and administrators were designated as higher SES,
and clerks and laborers as lower SES. In addition to blood pressure, the height
and weight of individuals, as well as their urinary sodium- and potassium
creatinine, were also measured. RESULTS: The age-adjusted occurrence of
hypertension (systolic pressure > or = 140 mmHg or diastolic pressure > or = 90
mmHg or current use of hypertension medication) was similar in male higher (n =
155) and lower (n = 255) SES groups aged 25-54, 19.3% and 19.8%, respectively.
However, the age-adjusted rate of definite hypertension (systolic pressure > or =
160 mmHg or diastolic pressure > or = 95 mmHg or current use of hypertension
medication) was considerably higher in the higher SES than in the lower SES men,
11.2% versus 3.6%. Age-adjusted body mass index (BMI, kg/m2) was higher among the
higher than in the lower SES group, 21.4 versus 20.4. Over-night sodium excretion
did not differ. Among female civil servants (n = 73) aged 20-44, there were few
of higher SES (n = 19) precluding SES-specific analyses. Total and definite
hypertension rates among women were 17.2% and 5.5%, respectively. Mean BMI was
22.2. In logistic regression, definite hypertensive status was related to age
group, BMI tertile, sodium excretion and SES in men and to sodium excretion in
women. CONCLUSION: Even in this very lean population, the higher risk for
hypertension in males of higher SES was confirmed. This was explained, in part,
by higher BMI.
PMID- 9395547
TI - Ethnic differences in public health awareness, health perceptions and physical
exercise: implications for heart disease prevention.
AB - OBJECTIVES: To study whether the wide differences in heart disease incidence
amongst ethnic groups in the UK, with the higher mortality and morbidity in
peoples of south Asian descent, may be attributed to differences in public health
awareness and life-style. DESIGN: Questionnaire-based survey of women from
different ethnic groups attending an antenatal clinic in a city centre district
general hospital. RESULTS: We surveyed 232 housewives from 3 different ethnic
groups: 84 white (mean age 24.3 years +/- standard deviation (SD) 5.84), 76 Afro
Caribbean (mean age 24.7 years +/- SD 4.46) and 72 Asians (defined as people of
south Asian or Indian subcontinent descent; mean age 25.7 years +/- SD 5.5). The
proportions of smokers amongst the whites, blacks and Asians were 38.1%, 27.6%
and 2.8% respectively. Proportions consuming alcohol regularly were 31.0%, 10.5%
and 4.2% respectively. A higher proportion of blacks reported a change in dietary
fibre intake, whilst a higher proportion of whites reported a change in dietary
fat intake and sugar intake as a result of public health campaigns, publicity or
advertising. There was a significantly lower proportion of reported regular
exercise activity amongst the Asian women and their husbands or partners.
CONCLUSION: This study demonstrates that Asian families were the least likely to
take regular exercise, and had a lower awareness of cholesterol or dietary
content (fibre, sugar, salt) despite public health campaigns and publicity. They
were however the least likely to smoke cigarettes. These ethnic differences may
in part explain the higher prevalence of coronary heart disease amongst the Asian
population in the UK. This ethnic group should be targeted for intense public
health intervention, education and other preventative measures to reduce the
risks of heart disease.
PMID- 9395548
TI - Suicide patterns and trends in people of Indian subcontinent and Caribbean origin
in England and Wales.
AB - OBJECTIVES: To examine suicide rates and trends in people of Indian subcontinent,
east African and Caribbean origin using the latest mortality data available for
England and Wales. To compare suicide rates in these groups with the baseline and
target rates for suicide in the Health of the Nation strategy. METHODS: Suicide
data for England and Wales for 1988-1992, classified by the country of birth of
the deceased, and population denominators from the 1991 Census were used for the
analysis. Standardised mortality ratios (SMRs) for ages 15-64 and age-specific
ratios were computed, using the age-sex specific rates for England and Wales as
the standard. Trends over the preceding decade and suicide by burning were also
analysed. Directly age-standardised suicide rates were derived to facilitate
comparison with Health of the Nation baseline and target rates. RESULTS: Suicide
ratios were significantly low (SMRs 32, 52 and 55 respectively) in Bangladeshi,
Sri Lankan and Pakistani born men at all ages, but raised in young Indian and
east African men. Ratios were significantly high in Indian and east African women
(143 and 154), with a 2-3 fold excess at ages 15-34 years. Ratios were low in
Pakistani and Bangladeshi women overall, but elevated at 15-24 years. For the
Caribbean-born, ratios were low overall but raised at ages 25-34. 20% of Asian
female suicides were by burning. Indians are a high risk group in terms of the
Health of the Nation suicide targets. Suicide trends in the minority ethnic
groups reflect national trends. CONCLUSIONS: This study confirms previous
findings of high suicide rates in young Asian women. A new finding is the raised
suicide rate in young Caribbeans. High suicide risks among young people from some
ethnic minority communities are significant in the context of both the Health of
the Nation strategy and recent governmental concern about the need to tackle
health variations in the UK. Such deaths are indicative of larger numbers of
young ethnic minority adults at risk of mental distress and self harm.
PMID- 9395549
TI - Race, socioeconomic status and survival in three female cancers.
AB - OBJECTIVES: Although many studies have reported that socioeconomic status (SES)
and race affect cancer survival, researchers have not established whether SES and
race affect survival independently. The research reported here addresses this
question with special attention to cancers affecting large numbers of women in
the US. METHODS: The authors analyzed data on survival among patients in the
Centralized Cancer Patient Data System (CCPDS) with cancers of the breast (n =
6896), cervix (n = 2209) and uterine corpus (n = 1492). RESULTS: According to Cox
proportional hazards models, race predicted survival in all three cancers, while
socioeconomic status predicted survival for cancers of the breast and uterine
corpus. Interaction effects between race and SES were generally not statistically
significant. This study includes larger numbers of observations within specific
forms of cancer and covers a broader patient population than most previous
investigations. These features promote detectability of SES effects,
comparability among disease sites, and generalizability to cancer patients
throughout the US. CONCLUSIONS: Findings imply that SES and race affect cancer
mortality risk independently of each other, and that the impact of SES and race
may vary by malignancy. Survival disadvantages due to race-which may be more
pronounced among women than men-should remain a continuing concern.
PMID- 9395550
TI - Gender and ethnic differences in survival in a cohort of HIV positive clients.
AB - OBJECTIVES: The purpose of this study was to examine gender and ethnic
differences in survival of persons receiving treatment for HIV infection to
determine if differences existed, and if they did, to assess the possibility of
explaining these differences by examining other factors, such as age, disease
severity when beginning treatment, alcohol, illicit drugs, tobacco, educational
level, living arrangements, antiretroviral treatment, PCP prophylaxis, sexually
transmitted diseases, mode of transmission and opportunistic infections. DESIGN:
A retrospective cohort study of all clients receiving treatment at an HIV only
clinic from its opening in early 1988 until the end of May 1993. Statistical
methods used to examine the data included incidence density ratios, Kaplan-Meier
survival curves, Breslow (generalized Wilcoxon) tests of equality of survival
curves and Cox proportional hazards models both with and without time dependent
covariates. RESULTS: In the cohort (37% African American, 7% Hispanic American
and 25% female), 220 deaths occurred during 1223 person years of follow-up.
Compared to European American males, the following incidence density ratios were
observed: European American females: 0.50, Hispanic American females: 0.70,
Hispanic American males: 0.96, African American females: 1.28 and African
American males: 2.38. The differences were noted above for gender/ethnicity
groups were significant at the p < 0.0001 level. After adjusting for disease
stage (as measured by laboratory testing of CD4 positive T-lymphocytes),
educational level, and age, no differences in survival by gender or ethnicity
remained. Disease stage and educational level had the greatest prognostic
significance. CONCLUSIONS: European Americans entered treatment at a much earlier
disease stage (as measured by CD4 positive T-lymphocyte counts) and had higher
educational levels (a surrogate for socioeconomic status) than African Americans.
These factors may explain the longer survival in European Americans as compared
to African Americans in this cohort.
PMID- 9395551
TI - Race/ethnicity misclassification of persons reported with AIDS. The AIDS
Mortality Project Group and The Supplement to HIV/AIDS Surveillance Project
Group.
AB - OBJECTIVES: To examine differences in race/ethnicity classifications of persons
with AIDS among three reporting sources and to estimate the effect of these
differences on calculated AIDS rates. METHODS: We reviewed case reports from the
national AIDS surveillance database, interview (self-reported) data from 11
state/local health departments, and death certificate information from 16
state/local health departments for agreement in race/ethnicity coding among
persons reported with AIDS. RESULTS: Race/ethnicity coding inconsistencies with
AIDS case reports were greatest for persons identified as American Indians/Alaska
natives on death certificates (46% [47/102] disagreement) and by self-report (57%
8/14 disagreement). Agreement with AIDS case reports was highest either for
persons identified as white from death certificates (4% [1314/31,070]
disagreement) and white from self-reports (2% [26/1068] disagreement) or black
from death certificates (3% [440/13,592] disagreement) and black from self
reports (3% [21/736] disagreement). For other racial/ethnic groups, disagreement
with AIDS case reports was intermediate; for Asians/Pacific Islanders, 12%
[45/377] disagreement with death certificates and 33% 4/12 disagreement with self
reports; and for Hispanics, 14% [1151/8527] disagreement with death certificates
and 24% [59/249] disagreement with self-reports. CONCLUSION: For certain
racial/ethnic groups, classification by race/ethnicity can differ substantially
by surveillance data source. Because allocation of public health resources may be
determined by estimates of disease impact on different population groups,
periodic evaluations of the accuracy of race and ethnicity reporting are needed
to assure appropriate distribution of these resources.
PMID- 9395552
TI - Use of the terms 'race', 'ethnicity', and 'national origins': a review of
articles in the American Journal of Public Health, 1980-1989.
AB - OBJECTIVES: To assess the use of the categories of race, ethnicity, and national
origin in recent public health research. METHODS: We reviewed all research
articles on human populations published in the American Journal of Public Health
from January 1980 through December 1989. Articles were classified by (1) mention
of the categories, (2) use of the categories, (3) presence of explicit
definitions, and (4) definitional criteria. RESULTS: Specific categories (e.g.
'black', 'Chinese', 'Hispanic') or generic categories (e.g. 'race', 'ethnicity',
'national origin') were mentioned in 461 (50.4%) of 914 articles on human
populations. In most studies (65.1%), single categories (e.g. race or ethnicity)
were considered; in 1.3% of studies, two terms (e.g. both race and ethnicity)
were examined independently; in 1.3%, categories were used interchangeably; in
5.6% of the studies, combined categories (e.g. race-ethnicity) were used; and in
27.5% of the studies, specific population groups were named without reference to
a generic category. Explicit definitions of categories were present in only 8.4%
of the articles in which the categories were considered. Absence of explicit
definitions and use of combined and interchangeable categories suggest a lack of
clarity and conceptual consistency in research on race, ethnicity, and national
origin-related topics. CONCLUSION: To improve our assessment of differences in
health status among racial, ethnic, and national origin groups, research
involving these categories should assess their validity and should define
concepts clearly, explicitly, and consistently. Such research would minimize
misclassification, improve the interpretation of findings, facilitate comparison
among studies, and enhance the understanding of causes underlying differences in
health status among populations of different racial, ethnic, and national
origins.
PMID- 9395553
TI - Utilization of health care services by immigrants and other ethnic/cultural
groups in Ontario.
AB - OBJECTIVES: This study assesses the accessibility of health care services by
immigrants and other ethnic/cultural groups in Ontario, using the 1990 Ontario
Health Survey. METHODS: The population sample of 38,519 adults aged 16-64 is
weighted to represent the entire non-institutionalized population of the
province. Outcome measures were whether the study participants visited a general
practitioner's office, a specialist's office, or a hospital's emergency
department during the past 12 months. RESULTS: The results showed that while the
percentages of participants who ever visited a general practitioner's office
during the past 12 months were slightly higher in immigrants and other
ethnic/cultural groups, the rates of visits to the specialist's office were quite
similar, and the rates of hospital emergency department's visits were often lower
(except for aboriginals), than for Canadians. These differences in the
utilization of health services across different immigrant and ethnic/cultural
groups remained unchanged after controlling for health status (as measured by
self-reported health problems) and age differences. However, because the sample
sizes in some immigrant and ethnic/cultural groups were small, many of the
differences were not statistically significant. CONCLUSIONS: We conclude that
while immigrants and other ethnic/cultural groups in Ontario usually had equal
access to regular services (e.g., visits to general practitioner's office), they
often had lower utilization of hospital emergency departments. However, general
purpose surveys have limited utility in assessing reasons of health care
utilization amongst different ethnic/cultural groups.
PMID- 9395554
TI - Hypertension in African Americans: basic science initiatives of the National
Heart, Lung and Blood Institute.
PMID- 9395555
TI - Hereditary intermediate phenotypes in African American hypertension.
AB - OBJECTIVE: Essential hypertension is a heterogeneous and multifactorial disorder
and is at least twice as frequent among African Americans as in the general
population. Inheritance of high blood pressure is complex, with the gene(s)
responsible for hypertension still remaining elusive. A useful strategy for
investigating the heritability of hypertension is to evaluate 'intermediate
phenotypes'--simple Mendelian or monogenic traits that are associated with
hypertension. These intermediate steps may identify potential pathophysiological
factors that antedate the development of high blood pressure and suggest
candidate genes. We are attempting to identify and characterize several such
intermediate phenotypes, in particular as these might apply to hypertension in
African Americans. METHODS: We studied several physiological and biochemical
candidate intermediate phenotypes in untreated black and white patients with
essential hypertension and in their normotensive counterparts stratified by
genetic risk of hypertension. RESULTS AND CONCLUSIONS: Promising intermediate
phenotypes, which may be useful for studies in African American families, include
baroreceptor sensitivity to low and high pressure stimuli, cold pressor test
responses, and biochemical markers such as plasma chromogranin A, dopamine-beta
hydroxylase and urinary kallikrein excretion. Identification of genes involved in
complex traits such as hypertension may be facilitated by the intermediate
phenotype approach, combined with recent advances in quantitative genetics and
linkage mapping. Further studies are needed to pinpoint the nature of genes in
African American hypertension.
PMID- 9395556
TI - New methods for maintaining human renal epithelial cells and analyzing their ion
transport functions: potential analysis of genetic disease.
AB - OBJECTIVES: New methods are available to immortalize parenchymal cells from
exocrine glands and kidney with retention of differentiation. Adaptation of this
technology to small, single-donor biopsy material or surgical specimens could
provide genetically homogeneous cells for functional analyses and correlation
with genetic background and underlying biochemistry. To develop a methodology
useful for renal sodium metabolism, epithelial cell line generation was tested in
a hypertensive rat model with features similar to salt-sensitive hypertension in
humans. This form of hypertension has a large genetic component and is prevalent
in African Americans. DESIGN: Protocols were designed to immortalize primary
cultures of microdissected proximal tubule epithelial cells from spontaneously
hypertensive (SHR) and control, normotensive Wistar-Kyoto (WKY) rats.
Immortalization was based on a replication-defective retrovirus coding for SV40
large T-antigen as positive cell cycle regulator. Transport competent cells that
grow on porous filters to form confluent monolayers were selected. RESULTS:
Several proximal tubule cell lines have been developed from SHR and WKY rats. The
cells retain important differentiated features, such as epithelial polarity, low
monolayer conductance, and sodium-succinate cotransport. They are suitable for
analyses of electrolyte transport by electrophysiology or imaging of
intracellular fluorescent indicator dyes, such as sodium-binding benzofuran
isophthalate. CONCLUSION: Feasibility of generating epithelial cell lines from
defined renal segments was demonstrated. The cells retain important transport
function so that analyses of sodium metabolism and the influence of genetic
background on it are possible. The methodology is applicable to human specimens.
PMID- 9395557
TI - Intracellular cations and hypertension in blacks.
AB - Considerable attention has been focused in recent years on the role of
intracellular ions in the pathophysiology of hypertension in African Americans.
Following the identification of marked differences in red cell sodium content and
sodium-lithium counter-transport between blacks and whites, the hypothesis
emerged that cation metabolism at the cellular level might account for part of
the ethnic difference in susceptibility to hypertension. Unfortunately, findings
in the red cell have not significantly increased our understanding of the
physiologic pathways and may prove to be anomalous. Interest has recently shifted
to calcium metabolism, because of its greater physiologic relevance, and a new
series of questions are being defined. With the development of fluoroprobes to
measure sodium and calcium simultaneously, wider application of pharmacologic
agonists and the use of single cell techniques have provided a new direction for
this field. Whether the ethnic contrasts observed for sodium in the red cell can
be reproduced in platelets remains to be seen. It may be that the earlier red
cell differences were epiphenomena, unrelated to the control of blood pressure,
and that the more closely one approaches basic physiologic mechanisms, the
greater the cross-ethnic group similarity. Rather than drawing attention to
unusual phenotypic characteristics, the study of hypertension in blacks may be
more instructive for the insight it provides into the basic physiology of this
disorder, common to all ethnic groups.
PMID- 9395558
TI - The kidney in the hypertensive black.
AB - Evidence suggests that the incidence of end-stage renal disease due to essential
hypertension is five to six times more frequent in black than in white patients.
The reason for this greater susceptibility is not clear. Several possibilities
have been proposed, including socioeconomic factors, compliance with therapy,
renal hemodynamic differences and anatomic differences. In this review, we
propose that the greater propensity of black hypertensives to develop renal
failure as a consequence of hypertension may be due to abnormal hemodynamic
adaptation of the renal circulation to a rise in blood pressure caused by high
dietary sodium intake. This would make the renal circulation of hypertensive
blacks more susceptible to injury.
PMID- 9395559
TI - Excess admixture proportion of extended major histocompatability complex
haplotypes of Caucasian origin among rheumatoid arthritis associated haplotypes
in African Americans and Afro-Caribbeans.
AB - Several extended major histocompatability complex (MHC) haplotypes are associated
with susceptibility to autoimmune disease in Caucasian populations. It is known
that African Americans and Afro-Caribbeans are ethnic groups descended from west,
central and southern black African populations which are admixed with Caucasians.
To examine the possible association of some marker of Caucasian MHC genes and
susceptibility to rheumatoid arthritis (RA) in African Americans, we studied
extended MHC haplotypes (HLA-B, complement and DR) in a sample of 18 African
American and Afro-Caribbean probands with RA, their first degree relatives and in
15 non-RA families. We defined 36 disease-associated RA haplotypes among the
probands and 96 normal haplotypes in normal individuals. To obtain the most
conservative estimate, we excluded recognized Caucasian, DR4-bearing, extended
MHC haplotypes from the analysis. Admixture proportions for non-HLA-DR4 extended
MHC haplotypes of known Caucasian origin among RA-associated and normal
haplotypes were computed (0.40 versus 0.163 respectively). When we compared the
difference in proportions between RA and normal haplotypes, the proportion of
extended MHC haplotypes of known Caucasian origin was significantly increased
among RA-associated haplotypes (Z = 3.16, p (one sided) < 0.001, p (adjusted) <
0.008). Our results suggest that racial admixture with Caucasian MHC genes may
augment RA susceptibility and thus may be one mechanism to explain the higher
prevalence of RA in African Americans and Afro-Caribbeans than in black African
populations.
PMID- 9395560
TI - Ethnicity and use of obstetrical analgesia: do Pakistani women receive inadequate
pain relief in labour?
AB - OBJECTIVE: To study whether the use of analgesic treatment in labour is
influenced by ethnicity. DESIGN: A cross-sectional study of hospital patients.
Setting; the two municipal hospitals, Ulleval and Aker, in Oslo, Norway.
Subjects; a total of 137 obstetrical patients, 67 Pakistani women and 70
Norwegian women. Main outcome measure; use of analgesics in labour. RESULTS: 30%
of the Pakistani and 9% of the Norwegian women received no analgesia in labour.
Pethidine injection was the preferred analgesic administered to Pakistani women.
Women of Pakistani origin received epidural infusion or nitrous oxide and oxygen
gas less frequently than Norwegian women. They also received fewer combinations
of other analgesic methods. When adjusted for the mothers' age, parity and
duration of delivery, Pakistani origin was the only significant predictor for
receiving no analgesia in labour. CONCLUSION: Women of Pakistani origin were more
than three times as likely not to receive analgesia in labour as Norwegian women.
The health services offered to Pakistani women in labour were different from
those offered to Norwegian women. These results indicate that women of Pakistani
origin may be offered insufficient obstetrical analgesia, or that Norwegian women
received unnecessary pain relief in labour.
PMID- 9395561
TI - The prevalence of Helicobacter pylori positivity in asymptomatic children of
different ethnic backgrounds living in the same country.
AB - OBJECTIVE: To measure the prevalence of Helicobacter pylori seropositivity in a
population of apparently healthy children of different ethnic backgrounds,
matched for age and socioeconomic background, who were born and continue to
reside in the same country. DESIGN: The presence of Helicobacter pylori specific
IgG antibodies was determined during pre-surgery blood analysis in 883 symptom
free children, aged from 1 months to 17 years, who belong to different ethnic
populations and were admitted for elective minor surgery. The different groups
were matched for age and socioeconomic background. RESULTS: Seventy-two children
(8.2%) had a positive titer for Helicobacter pylori. We observed a significant
difference in the prevalence of Helicobacter pylori positivity between symptom
free Caucasian and non-Caucasian children (p < 0.001). However, no difference
could be observed between the non-Caucasian groups (p > 0.8). CONCLUSION: We
conclude that significant differences exist in the prevalence of Helicobacter
pylori infection between asymptomatic children of different ethnic backgrounds,
despite the fact that all investigated subjects were born in Belgium and have
been living in this country ever since. Whether this difference is caused by an
unknown environmental factor or an, until now, unrecognized genetic
predisposition still needs to be evaluated.
PMID- 9395562
TI - Sexually transmitted diseases: experience and risk factors among urban, low
income, African American and Hispanic youth.
AB - OBJECTIVES: The objectives of this study were to assess: (1) ethnic and gender
differences in reporting of diagnoses of sexually transmitted diseases (STDs),
symptoms related to STDs and sexual behavior and (2) behavioral risk factors for
STDs in a probability sample of low income African American and Hispanic youth.
METHODS: Data were analyzed from a household probability sample of youth. The
study collected data on self reported STDs, symptoms of STDs and sexual behavior.
The sample was drawn from households in low income areas of urban Detroit: 1435
African American and Hispanic low income youth age 15-24 living in Detroit were
interviewed face to face in 1991. RESULTS: Patterns of sexual activity as well as
experience with STDs differ by ethnicity and gender. Within ethnic groups, women
report more symptoms of STDs. Risk factors for diagnosed STDs included age, a
young age at first intercourse, numbers of sexual partners, oral intercourse and
anal intercourse. CONCLUSIONS: The data underscore the importance of development
of effective safer sex intervention programs for these youth as well as careful
assessment of STD risks in medical clinics serving these youth.
PMID- 9395563
TI - Body mass index and cardiovascular risk factors in Pacific Island Polynesians and
Europeans in New Zealand.
AB - OBJECTIVES: To examine relationships between body mass index (BMI) and
cardiovascular risk factors in 279 Europeans and 231 Polynesian Pacific Islanders
in New Zealand. METHODS: Participants were recruited from Seventh-Day Adventist
church meetings or camps, and were surveyed by self-administered questionnaire.
Blood pressure, weight and height were measured. Fasting blood samples were
analysed for lipids, glucose and fructosamine. RESULTS: Age-adjusted BMI was
higher in Pacific Islanders than in Europeans: 32.8(0.3) versus 25.6(0.3);
means(SE); p = 0.0001). In Europeans, BMI was positively associated with systolic
and diastolic blood pressures, triglycerides, total cholesterol, LDL cholesterol
and fasting blood glucose, and negatively associated with HDL cholesterol. In
Pacific Islanders, BMI was associated only with systolic and diastolic blood
pressures, and with HDL cholesterol. These associations were stronger in
Europeans than in Pacific Islanders. CONCLUSIONS: In this group of Pacific
Islanders, the association between BMI and cardiovascular risk factors was weaker
than in Europeans. This suggests that either BMI is a poor measure of adiposity
in Pacific Islanders, or that adiposity may be less strongly linked to
cardiovascular disease in Pacific Islanders.
PMID- 9395564
TI - Increased gallbladder-related mortality among Hispanics: does education play a
role?
AB - OBJECTIVE: Hispanics, particularly Mexican Americans, are known to have a higher
incidence of mortalities whose underlying cause is a gallbladder-related
disorder. These analyses evaluate the role of educational attainment in the
differential mortality experiences of these populations. METHODS: US mortality
data for 1989-1991 were examined to determine ethnically-specific death rates
using 'any mention' of the disease on the death certificate. RESULTS: Age
adjusted multiple cause mortality was found to be higher for all gallbladder
related disorders among Hispanics, particularly Mexican Americans. Mortality due
to gallbladder cancer, gallstones and 'other gallbladder diseases' were found to
be inversely proportional to educational attainment in all ethnic groups. When
both age and education were used to adjust mortality, the gallstone and other
gallbladder disease mortality among Hispanics was non-significantly higher than
white, non-Hispanics. However, mortality due to gallbladder cancer remained
significantly higher among Hispanics. CONCLUSION: Gallbladder cancer mortality is
elevated in Hispanic populations, especially Mexican Americans, independent of
educational attainment. However, increased mortality associated with gallstones
or other gallbladder diseases among Hispanics may be partially due to differences
in factors associated with educational attainment. Research and public health
efforts to address these educational-related factors may improve this mortality
pattern among Hispanics.
PMID- 9395565
TI - Black-white differences in factors influencing mammography use among employed
female health maintenance organization members.
AB - OBJECTIVE: This study examined racial differences in knowledge, attitudes and
practices related to breast cancer screening of black and white women health
maintenance organization members over age 40 who are employed at 75 worksites in
Pennsylvania and New Jersey in the US. DESIGN: Data are from telephone interviews
of 1677 women (20% black). The interviews queried background factors and concepts
from the Health Belief Model. RESULTS: Compared to whites blacks were younger and
less likely to be married or to have family history of breast cancer. They were
also more likely to underestimate their cancer risk and to fear radiation, and
less likely to have a doctor advise them to get mammograms. Black and white women
did not differ in terms of self-reported mammography use. The results of
multivariate modeling suggest that different set of knowledge and belief
variables may explain mammography adherence among black and white women.
CONCLUSION: These findings have implications for clinical prevention and for
patient and community health education in minority populations.
PMID- 9395566
TI - Barriers to follow-up of abnormal screening mammograms among low-income minority
women. Cancer Control Center of Harlem.
AB - OBJECTIVE: To describe factors related to compliance diagnostic follow-up among
minority women of low socioeconomic status with abnormal screening mammograms.
METHODS: A retrospective cross-sectional survey using a structured telephone
interview. Three cancer screening clinics at an urban inner-city public hospital.
All women with abnormal screening mammograms between September 1990 and January
1992 were eligible; women were interviewed in August 1992. Abnormal mammograms
were those requiring specific, non-routine clinical follow-up; non-compliance was
defined as delayed follow-up (four to six months after the date of the
mammogram), or no follow-up at the time of interview (more than 6 months after
abnormal). RESULTS: Sixty-two of 442 screened women had abnormal results; the
overall rate of non-compliance with follow-up was 50%. Among the 42 (68%) women
who agreed to be interviewed, non-compliers were less likely to state that they
had been told to receive follow-up than compliers (65% versus 100%; p = 0.008).
Non-compliant women were less likely to have suspicious mammography
interpretations (p = 0.05), and more likely to report barriers to follow-up, such
as cost of lost wages and medical care, system barriers, or fears, than compliant
women (61.9% versus 9%, p = 0.01). There were no differences between the two
groups for age, education, insurance, source of care, family history, knowledge
or attitudes. CONCLUSIONS: These preliminary results suggest that follow-up of
low income, minority women with abnormal screening mammograms could be enhanced
by improved communication of results. Future studies should extend these findings
with larger samples and in other settings and populations.
PMID- 9395567
TI - Estimating breast cancer incidence in Hispanic women in Connecticut, 1989-1991.
AB - OBJECTIVES: The objective of this study was to estimate incidence rates for
breast cancer, the most commonly occurring cancer in women, in the growing
Hispanic population of Connecticut. METHODS: The population-based Connecticut
Tumor Registry (CTR) routinely obtains only limited information on Hispanic
origin and maiden name. In this study, surnames of CTR breast cancer patients
diagnosed in 1989-1991 were matched with a list of Spanish surnames. To assess
misclassification, both surnames and maiden names (from death certificates) of
female Connecticut residents who had died in 1989-1991 from any cause of death at
20 years of age and older were matched with the Spanish-surname list. RESULTS:
Age-specific incidence rates (1989-1991) for 'Hispanic' women (with Spanish
surname) were lower than those for 'non-Hispanic' white women (with non-Spanish
surname) for age 35-39 years and older. Errors in these estimated rates were
probably small because among decedents the number with a Spanish surname differed
by only 9% from the number with a Spanish maiden name; false positives were
almost balanced by false negatives. CONCLUSION: Matching of surnames in the
cancer registry with a Spanish surname list provided reasonably accurate
estimates of cancer incidence rates in Hispanic women, although individual women
were misclassified as 'Hispanic' or 'non-Hispanic'.
PMID- 9395568
TI - Appendicitis: higher risk in Mexican Americans?
AB - OBJECTIVES: Mexican Americans (MAs), compared to white non-Hispanics (WNHs), have
higher rates of biliary disease, noninsulin dependent diabetes, and endstage
renal disease but lower rates of lung cancer, hip fractures, and mortality from
coronary heart disease. Relatively little research has been done to identify
other ethnic differences in disease incidence. We used surgical procedure rates
to confirm known ethnic differences and to explore our clinical suspicion that
MAs have higher rates of appendectomy than WNHs. METHODS: We used a registry of
surgical procedures at two teaching hospitals in South Texas to calculate
proportional operation ratios (PORs) for MAs versus WNHs. These two hospitals are
the primary source of acute hospital care for the indigent in the area. The POR
is arithmetically identical to proportional incidence and mortality ratios.
RESULTS: MAs underwent appendectomy proportionally more often than WNHs at both
hospitals (POR = 1.41 and 1.75, p < 0.0001). Other significant PORs were
consistent with known ethnic disease differences in biliary tract operations,
vascular access for chronic hemodialysis, lung cancer, and coronary artery
bypass. CONCLUSIONS: These findings support the hypothesis that MAs may undergo
appendectomy more often than WNHs and so may be at higher risk of appendicitis.
PMID- 9395569
TI - Cultural aspects of African American eating patterns.
AB - The high mortality from diet-related diseases among African Americans strongly
suggests a need to adopt diets lower in total fat, saturated fat and salt and
higher in fiber. However, such changes would be contrary to some traditional
African American cultural practices. Focus group interviews were used to explore
cultural aspects of eating patterns among low- and middle-income African
Americans recruited from an urban community in Pennsylvania. In total, 21 males
and 32 females, aged 13-65+ years were recruited using a networking technique.
Participants identified eating practices commonly attributed to African Americans
and felt that these were largely independent of socioeconomic status. They were
uncertain about links between African American eating patterns and African
origins but clear about influences of slavery and economic disadvantage. The
perception that African American food patterns were characteristically adaptive
to external conditions, suggest that, for effective dietary change in African
American communities, changes in the food availability will need to precede or
take place in parallel with changes recommended to individuals. Cultural
attitudes about where and with whom food is eaten emerged as being equivalent in
importance to attitudes about specific foods. These findings emphasize the
importance of continued efforts to identify ways to increase the relevance of
cultural context and meanings in dietary counseling so that health and nutrition
interventions are anchored in values as perceived, in this case, by African
Americans.
PMID- 9395570
TI - Risk-taking behavior among Native American adolescents in Minnesota public
schools: comparisons with black and white adolescents.
AB - OBJECTIVES: To examine rates of risk-taking behavior among native American
adolescents in comparison with blacks and whites, and then to compare our off
reservation native American sample to available national statistics on
reservation youth. METHODS: A secondary data analysis of a Minnesota public
school health survey. Contingency table analyses were performed on a 10% random
sample of over 6000 young people focussing on three categories of behavioral
risk: antisocial behavior, sexual behavior and substance use. Comparisons were
then made to a national convenience sample from reservations and adjacent rural
areas. RESULTS: In general, native American adolescents have a significantly
higher prevalence of risk behaviors across all indices of antisocial behavior and
substance use relative to white and black peers. Native American females
presented the most troubling picture. Comparisons to a national convenience
sample from reservation lands indicated that native American adolescents in the
sample often exceeded national rates of risk behavior. CONCLUSIONS: Residence and
attendance at public schools outside reservation lands may make native American
adolescents more likely to engage in risky behaviors which endanger their health.
PMID- 9395571
TI - Hypertension awareness, treatment and control rates for an Asian population:
results from a national survey in Korea.
AB - OBJECTIVE: This observational study was performed in order to determine the
hypertension awareness, treatment, and control rates for the country of Korea.
METHODS: Rates were determined in conjunction with a national blood pressure
survey in Korea in 1990. Through cluster sampling, individuals aged > 30 in
190/146,944 districts were selected for study. Among 25,567 eligible individuals,
21,242 had measurement of blood pressure (BP) and answered a standard
questionnaire. BP was recorded as the mean of two measurements with a standard
mercury manometer. Hypertension was defined either as BP > or = 160/95 mm Hg or
on treatment (n = 2628), or as BP > or = 140/90 mm Hg or on treatment (n = 4219).
Treatment was defined as any method of BP treatment, including dietary,
traditional, or medication. RESULTS: Rates for BP > or = 160/95 mm Hg or on
treatment: aware 1057 (40%), treated 696 (27%), controlled 367 (14%). Rates for
BP > or = 140/90 mm Hg or on treatment: aware 1069 (25%), treated 696 (16%),
controlled 221 (5%). CONCLUSIONS: Hypertension awareness, treatment, and control
rates are relatively low in Korea. Blood-pressure control programs, including
detection strategies, are needed here and worldwide.
PMID- 9395572
TI - Cellular calcium and sodium regulation, salt-sensitivity and essential
hypertension in African Americans.
AB - The predisposition of African Americans to the salt sensitive form of essential
hypertension may result from increased freely exchangeable Ca in intracellular Ca
stores and a higher cellular Ca turnover (i.e., enhanced Ca entry into and
accelerated Ca extrusion from the cytosol). These alterations entail higher
activities of Ca extrusion transport systems, including the Na+/Ca2+ exchanger
(NCE), which extrudes Ca in exchange for external Na+, and plasma membrane Ca
ATPase (PMCA) that extrudes Ca in exchange for external protons. The higher
activity of PMCA, coupled with a higher metabolic activity resulting from a rise
in freely exchangeable Ca, increase cellular acid load. Adaptive cellular
mechanisms must evolve under these conditions, whereby increased activity of the
Na/H exchanger (NHE-1) maintains normal cytosolic pH by enhancing the extrusion
of cytosolic protons in exchange for extracellular Na. Cells with increased
cellular Ca stores and enhanced Ca turnover may be particularly vulnerable to the
factors that inhibit the Na-pump. By inhibiting the Na-pump, these factors
diminish the transmembrane Na gradient and consequently inhibit the forward mode
of the NCE. Since cells from African Americans show increased Ca turnover, they
should retain more Ca upon exposure to Na-pump inhibitors; a heightened
sensitivity to Na-pump inhibitors could therefore underlie the propensity of
African Americans and other individuals with accelerated cellular Ca turnover
rate to the salt sensitive form of essential hypertension. Accelerated cellular
Ca turnover in African Americans also explains their better response to Ca
antagonists compared with other antihypertensive drugs.
PMID- 9395573
TI - Trends in motor vehicle traffic fatalities among Hispanics, non-Hispanic whites
and American Indians in New Mexico, 1958-1990.
AB - OBJECTIVE: New Mexico has had the highest motor vehicle fatality rate in the
nation for many years. Our objective was to examine ethnic differences and trends
in motor vehicle fatality rates. DESIGN: Using death certificate data from the
New Mexico Bureau of Vital Records and Health Statistics, we compiled age
adjusted motor vehicle-related mortality rates from 1958-1990 among the three
major ethnic groups in New Mexico--Hispanics, white non-Hispanics and American
Indians. RESULTS: Over the 33-year study period, American Indians of both sexes
had two to three times higher mortality rates than white non-Hispanics. Hispanic
males also had higher motor vehicle death rates than white non-Hispanic males.
During the 1970s fatality rates peaked, with age-adjusted death rates of
233/100,000 for American Indian males, 74.7 for Hispanic males and 49.3 for white
non-Hispanics for the period 1973-1977. Evaluation of successive 5-year birth
cohorts showed highest mortality rates for ages 15-29 years for each ethnic group
and both sexes, and a dramatic decline in most ethnic, sex and age-specific rates
during the last eight years of the study period. CONCLUSION: Although the recent
trends indicate favorable changes in motor vehicle fatality rates, our data
highlight the need for ethnic and age-specific interventions to further reduce
rates of motor vehicle-related mortality in this state.
PMID- 9395574
TI - Racial and ethnic disparities in self-assessed health status: evidence from the
National Survey of Families and Households.
AB - We examined racial and ethnic disparities in global health assessment and
functional limitations of daily activities among whites, blacks and Hispanics,
and within the Hispanic origin among Mexicans, Puerto Ricans, Cubans, and
'Others'. Logistic regression were employed to estimate the log odds of reporting
'poor health' and 'having functional limitations' among 12,814 respondents from
the 1987-1988 National Survey of Families and Households. Compared with whites,
blacks had an increased risk of reporting poor health and functional limitations.
Hispanics had even a higher risk of reporting poor health, but did not have an
increased risk of reporting functional limitations. Among Hispanics, Mexicans
were more likely than whites to report poor health, whereas Puerto Ricans were
more likely than whites to experience functional limitations. Both race and
ethnicity remain important factors in explaining the disparities in self-assessed
health status independent of socioeconomic status (SES). Meanwhile, the way self
assessed health status varies with ethnicity is importantly stratified by SES as
measured by income and education. These results suggest that future research
should analyze the interplay between ethnicity and SES rather than assuming
measuring either captures all the important variation.
PMID- 9395575
TI - Increased rates of obesity among African Americans confirmed, but the question of
why remains unanswered.
PMID- 9395576
TI - Obesity in inner-city African Americans.
AB - OBJECTIVE: Obesity, a risk factor for chronic diseases, has a high prevalence in
African Americans and low-income individuals. However, little is known about
perceptions of overweight, attempts to lose weight, and strategies used to lose
weight among African Americans in inner cities. DESIGN: A 1990 cross-sectional
telephone survey (n = 1445) of north St Louis and central Kansas City, USA.
RESULTS: Obesity was common (44%) in this sample of inner-city African Americans.
The obese perceived themselves as overweight (70%) and were trying to lose weight
(66%). The majority of the obese (68%) were both dieting and exercising to lose
weight. Smoking prevalence was not higher among the obese or those trying to lose
weight. Many of the obese had received medical advice recently on low-fat diets
(51%) and had been advised to lose weight (40%). Factors independently associated
with perception, attempts to lose weight and medical advice differed, but
included degree of obesity. CONCLUSIONS: These results corroborate US national
data that obesity is a public health problem in this population and that obese
inner-city African Americans perceive themselves as overweight and are trying to
lose weight, especially as degree of obesity increases. It also appears that
smoking is not being used as a weight loss strategy and that the obese, as a
group, are receiving some medical advice on low-fat diets. This information is
critical for designing culturally sensitive weight-control programmes.
PMID- 9395577
TI - Differences in weight gain in relation to race, gender, age and education in
young adults: the CARDIA Study. Coronary Artery Risk Development in Young Adults.
AB - OBJECTIVE: To assess ethnic differences in weight gain in young adults. DESIGN:
Five-year weight change was assessed in 4207 young adults initially aged 18-30
years at the CARDIA Study baseline examination (1985-1986). RESULTS: Weight gain
was significantly (p < 0.0001) greater in black versus white men (13.2 versus 9.1
lb) and in black versus white women (13.2 versus 7.4 lb). Baseline weight and
year-five weight in all race and gender groups were strongly associated,
suggesting a high degree of tracking of adiposity during young adulthood. Greater
weight gain was noted in participants reporting baseline education of high school
or less versus college graduates in black women (14.4 versus 10.0 lb, p < 0.05),
white women (10.2 versus 5.2 lb, p < 0.0001) and white men (10.2 versus 7.8 lb, p
< 0.001). Significantly greater weight gain was observed in younger (18-24 years)
versus older (25-30 years) men, but no age-related difference was seen in women.
The racial differences in weight gain remained after adjustment for age and level
of education. The above trends were confirmed for other measures of body size,
i.e. body mass index and skinfold thickness. CONCLUSION: These data indicate that
young adults are at high risk of weight gain, and that weight gain was greatest
among African Americans and among less educated participants. These high-risk
groups can be identified and targeted for primary prevention of adult obesity in
addition to population wide efforts that will be required to counteract the
secular trend of increased obesity observed in US adults.
PMID- 9395578
TI - Ethnic differences in body composition and their relation to health and disease
in women.
AB - Differences in body composition between black and white women have been well
established. Black women have more bone and muscle mass, but less fat, as a
percentage of body weight, than white women, after controlling for ethnic
differences in age, body weight, and height. In addition, black women have more
upper-body fat than white women. These ethnic differences in body composition
appear to be associated with disease risk in women. The greater skeletal and
muscle mass in black compared to white women appears to protect them from
osteoporosis. The relationship between fat distribution and cardiovascular
disease also appears to be influenced by ethnicity. This review has two purposes:
(1) To examine previous research investigating ethnic differences in body
composition between black and white women; and (2) To demonstrate the
relationship between body composition and disease in women as a function of
ethnicity.
PMID- 9395579
TI - Ethnicity, hypertension, coronary heart disease and renal diseases in South
Africa.
AB - This paper reviews the impact of race and environment upon hypertension, coronary
heart disease and renal diseases in South Africa. Inequalities of socioeconomic
status, lifestyle, and access to South African health care have produced striking
differences in the prevalence and complications of hypertension. Coronary heart
disease is 'epidemic' in the white and Indian population and is still relatively
uncommon in blacks. There are different histological patterns of
glomerulonephritis among the racial groups, which may lead to end-stage renal
disease. Hypertension is an important cause of end-stage renal disease in the
black population whilst analgesic nephropathy is important in the white
population. Efforts are now being made to comprehend these daunting realities and
to minimize the inequalities.
PMID- 9395580
TI - Stigmatization, discrimination and fear of AIDS in Greece: implications for
health policy.
AB - A prospective health-education research project about AIDS knowledge and
attitudes towards AIDS was conducted in Athens and nine adjacent municipalities
in west Attica, Greece. Socioeconomic and demographic data, AIDS knowledge, and
attitudinal information were collected from 1552 respondents and analysed
treating the attitudes of stigmatization, discrimination and fear towards AIDS as
the dependent variable. Statistically significant correlations were found between
each of the three attitudinal variables and the independent ones; specifically,
age, place of residence, marital status and level of AIDS knowledge. Our working
hypothesis--that the higher the level of AIDS knowledge, the lower the level of
discrimination and stigmatization--was supported by our data. The relationship
between AIDS knowledge and fear was less clear. Fear probably inhibits a rational
approach to screening for HIV, and more empirical research is needed about fear
and its interaction with stigmatizing and discriminatory attitudes and
behaviours. Such research should be aimed at identifying population groups 'at
risk' of expressing high levels of negative social attitudes about AIDS so that
educational programmes can be appropriately designed.
PMID- 9395581
TI - Differential survival in blacks and Hispanics with AIDS.
AB - OBJECTIVE: The object of this study was to investigate whether there are
differences in survival by ethnicity in people with AIDS. DESIGN: The CDC Public
Access Dataset was analysed. To estimate survival more accurately, a cohort of
individuals diagnosed in 1987 was chosen from the dataset. Using this analysis,
probabilities of survival were estimated. RESULTS: There were significant
differences in survival in blacks and Hispanics as compared to whites diagnosed
in 1987. Although there are differences in survival by transmission category,
survival differences by ethnicity persisted when analysed within specific
transmission categories. A model where the frequency distributions of survival
were log-transformed suggests that disease progression per se may not be the most
important factor, but time of diagnosis may be. In addition, in looking at median
survival by year of diagnosis, it is clear that blacks and Hispanics have not
shown the same magnitude of improvement in survival time, and lag behind whites.
CONCLUSIONS: This study clearly shows differences in survival with AIDS by
ethnicity. Differential access to health care may underlie such ethnic
differences in survival.
PMID- 9395582
TI - Language background and communication skills of medical students.
AB - OBJECTIVE: The increasing proportion of medical students whose primary language
is other than English and recent reports of poor communication skills of medical
graduates has generated community concern about the methods of selection of
students and their communication skills training. This paper examines the
relationship between language background and examination performance in oral
communication skills in Year 5 medical students. METHOD: Questionnaire data from
all Year 5 students in the 1992 general practice terms were matched to
examination results. RESULTS: Seventy percent of students responded. Most
students whose primary language was not English passed, although some required
remedial communication skills tuition. The most powerful predictors of poor
performance were recent arrival in Australia and living in an environment where
English was not spoken at home. CONCLUSION: Students with poor English oral
communication skills should be encouraged to speak English away from the medical
school and should be offered additional tuition so that their skills in other
languages are not lost to the health-care system.
PMID- 9395584
TI - Patterns of mortality among Bangladeshis in England and Wales.
AB - OBJECTIVES: To investigate the patterns of mortality among Bangladeshis living in
England and Wales. METHODS: An analysis of national mortality data, classified by
country of birth, for the latest period (1988-1992), using the method of indirect
standardization for deriving standardized mortality ratios (SMRs) with the age-
and sex-specific rates for England and Wales as the standard (= 100). The SMRs
were derived for Bangladeshi-born men and women aged 20-69 years for major
disease entities. RESULTS: The mortality among Bangladeshi men was significantly
higher (SMR 118 and 95% CI 111-126) than the levels prevalent in England and
Wales. In contrast, the mortality among Bangladeshi women was significantly lower
(SMR 71 and 95% CI 61-82). The cancer mortality overall was lower than expected
in both sexes, with the exception of cancer of the liver and gall bladder. The
mortality from breast cancer (SMR 16 and 95% CI 6-34) and cervical cancer (SMR 51
and 95% CI 14-131) was lower than expected. Bangladeshi men experienced high
mortality from diabetes (SMR 685 and 95% CI 529-874), coronary heart disease (SMR
148 and 95% CI 134-163) and cerebrovascular disease (SMR 267 and 95% CI 222-319);
they also experienced excess deaths from cirrhosis of the liver (SMR 254 and 95%
CI 175-357). CONCLUSIONS: The findings establish significant variations in the
recent health experiences of Bangladeshi men living in England and Wales, posing
a major challenge for purchasers of care. If the Health of the Nation strategy is
to ensure that equity in health and health care is to apply to all those living
in this country, the Bangladeshi population needs special targeting.
PMID- 9395585
TI - Cultural variation in health locus of control.
AB - OBJECTIVE: To compare health locus of control scores in women from different
ethnic backgrounds. METHOD: One-hundred and twenty-eight caucasian, South Asian
and Afro-Caribbean women completed written or orally presented versions of the
multidimensional health locus of control scale, as well as ratings of
religiousness, health status and occupational status. RESULTS: South Asian women
scored higher on 'chance' and 'powerful others' locus of control as predicted.
They also had higher scores on internality. The ethnic differences persisted
after controlling for occupation and health status. High religiousness among the
South Asians appeared to explain some, but not all, of their higher scores.
CONCLUSION: South Asians may differ from British caucasians in relation to their
beliefs about internal and external influences on health.
PMID- 9395586
TI - Has psychological distress among UK South Asians been under-estimated? A
comparison of three measures in the west of Scotland population.
AB - OBJECTIVES: Previous work has shown low levels of psychological distress among UK
South Asians, but some argue that the distress is under-reported. The present
paper assesses distress on one clinically validated measure (the 12-item General
Health Questionnaire), a psychosomatic measure and a self-report measure.
METHODS: Interviews of 159 South Asians in Glasgow aged 30-40 years, mean age 35
years and 319 from the general population, all aged 35 years. RESULTS: The three
distress measures were moderately correlated and at the thresholds chosen there
was no hierarchy of severity between them. Distress on the GHQ12 was at similar
levels for all the social groups assessed, but distress on the psychosomatic
measure and self-assessment was higher for women, Muslims and limited English
speakers. CONCLUSIONS: Clinical measures may have under-estimated distress in
several South Asian groups. The results may be due to a preference for a
particular language of emotion in the affected groups or to a higher frequency of
stressful situations which provoke distinctive reactions.
PMID- 9395587
TI - Why are African Americans under-represented in medical research studies?
Impediments to participation.
AB - OBJECTIVES: In accordance with the NIH Revitalization Act of 1993, the National
Institutes of Health and the Alcohol, Drug and Mental Health Administration
require grant applicants and cooperative agreement participants to include
minorities in human subject research. In an environment characterized by
diminishing research dollars, this mandate has increased the pressure on
investigators to determine factors that impede minority participation and to
develop strategies to overcome these impediments. METHODS: An extensive review of
the literature was conducted to identify the factors possibly responsible for the
low participation levels of African Americans in medical research studies and to
highlight areas for further research. The items examined included the historical
relationship between African Americans and medical researchers and the attitudes,
perceptions and beliefs of potential participants and researchers as they relate
to the low representation of African Americans in medical research. RESULTS: The
factors identified as possible impediments to African American participation
included distrust of the medical/scientific community, poor access to primary
medical care, the failure of researchers to recruit African Americans actively,
the alienation of minority health professionals, lack of knowledge about clinical
trials, language and cultural barriers. CONCLUSIONS: Well-designed, relevant,
ethical research in conjunction with an appreciation of the many barriers to
participation are paramount to increasing African American presence in clinical
research.
PMID- 9395588
TI - Lipoprotein (a) distribution in a Nigerian population.
AB - OBJECTIVES: To determine the distribution and determinants of lipoprotein (a)
(Lp(a)) concentration among Nigerians. METHODS: Subjects were recruited from
civil servants living in Benin City, Nigeria. The height and weight of the
individuals were measured and their use of alcohol and tobacco estimated by
questionnaire. Laboratory analyses of blood samples involved Lp(a), total
cholesterol (TC), high-density lipoprotein (HDLc), HDL2c, HDL3c, triglyceride
(TG) and insulin. RESULTS: The analyses indicate that the Lp(a) concentrations
are elevated among Nigerian populations and more skewed towards high levels than
is observed for caucasian and oriental groups. The median levels for Lp(a) were
24.0 mg dl-1 and 19.0 mg dl-1 for women and men, respectively. This difference
was significant (P < 0.05) but after stratifying by age, only the 45-54 year-old
group of women (30.1 mg dl-1) had significantly higher (p < 0.001) median
concentrations of Lp(a) than men (18.4 mg dl-1). Age, 20-64, had no influence on
Lp(a) levels in men but in women Lp(a) concentrations increased significantly
with age (p < 0.05). Among males alcohol consumption, smoking and body mass index
(BMI) were not related to Lp(a) concentrations but a significant effect (p <
0.05) was noted for waist-hip ratio (WHR). Among females no relationship was
observed between Lp(a) levels and alcohol consumption, BMI and WHR. All serum
lipids measured (TC, HDLc, HDL2c, HDL3c, low-density lipoprotein (LDLc), and TG)
were correlated with Lp(a) concentrations among men. A significant association
with TC and LDLc remained after correcting for Lp(a) cholesterol. Among women,
the Lp(a) levels were associated with TC, HDLc, HDL3c, and LDLc but not with
HDL2c, and TG. The correlations with TC and LDLc were not significant after
correcting for Lp(a) cholesterol. Insulin did not correlate with Lp(a) levels in
either men or women. CONCLUSIONS: Lp(a) concentrations are high in Nigerians,
particularly among women, and the association between the Lp(a) concentrations
and other lipoproteins is stronger than in white populations.
PMID- 9395589
TI - Knowledge, uptake and availability of health and social services among Asian
Gujarati and white elderly persons.
AB - OBJECTIVES: To investigate factors affecting the uptake of health and social
services by elderly Asian Gujarati. METHODS: Four hundred and five Hindu
Gujaratis and 381 whites aged 65 years and over residing in Leicester were
randomly sampled from the Leicestershire District FHSA list by a computerized
method based on linguistic analysis of the patient's name. One hundred and fifty
Hindu Gujaratis and 152 whites were interviewed with response rates of 72% for
the Asian Gujaratis and 80% for the white groups. The outcome measures were the
activities of daily living (ADLs), incontinence, auditory/ visual deficits,
cardiovascular disease, cognitive impairment (measured by the Mini-mental State
Examination), depression, use of GP and hospital services, knowledge of community
health and social services, willingness to use, suitability and cultural
accessibility. RESULTS: The poorer uptake of services by elderly Asian Gujarati
could not be explained by better health. They were significantly more likely to
be dependent in six of the 14 ADLs and had higher rates of diabetes and impaired
vision. Significantly more Asian Gujaratis than whites lived with others (84
versus 52%, p < 0.0001) with a greater availability of alternative sources of
help and support. The knowledge and understanding of services were significantly
poorer in the Gujarati group; fewer Asian Gujaratis knew how to apply for
services and of those applying, fewer had been successful. Where services had
been obtained, the levels of dissatisfaction were higher in the Gujarati group.
The literacy rates were low in the Gujarati sample with 79% being unable to read
or write in English and 27% unable to read or write in their mother tongue.
CONCLUSIONS: The lower uptake of services by elderly Asian Gujarati is not the
result of better health but may be explained by greater family support together
with a lack of knowledge of and dissatisfaction with what is available. Health
services will need to reappraise and revise some of their practices if they are
to cater adequately for this growing population with many needs as yet unmet.
PMID- 9395590
TI - Use of selected high-fat foods by Hispanic adults in the northeastern US.
AB - OBJECTIVE: To add to the limited information of dietary fat intake of US Hispanic
adults, in particular for subgroups other than Mexican Americans. METHODS: The
frequency of eating 13 high-fat food items commonly consumed in the US was
examined in 665 Hispanic adults 20-74 years old in Connecticut and Long Island,
New York, sampled from Spanish-surname telephone listings and surveyed by
telephone in 1992. RESULTS: Mean estimated fat intake from the 13 items was
significantly greater for the 357 men than the 308 women; the largest gender
differences were for hamburgers/cheeseburgers and french fries. Whole milk was an
important contributor to the fat intake of persons with the highest fat intakes.
In multiple linear regression analyses, age (negative association) and gender,
but not education and acculturation (based on language spoken, read and written),
were statistically significant predictors of fat intake from the 13 items.
CONCLUSIONS: Longitudinal studies using diet diaries are needed in these Hispanic
populations.
PMID- 9395591
TI - Epidemiology of self-reported past heavy drinking in Hispanic adults.
AB - OBJECTIVES: Self-reports of past heavy drinking correlate with the current
drinking practices and with risk of mortality in non-Hispanic males. The
prevalence of past heavy drinking has not been reported in Hispanic populations.
METHODS: Using data from the Hispanic Health and Nutrition Examination Survey
(HHANES) we (1) report on the prevalence, duration and severity of past heavy
drinking in three Hispanic groups, (2) compare the current alcohol consumption
patterns among past heavy drinkers and those who do not report a history of past
heavy drinking and (3) compare the risk factor profiles and health indicators in
these two groups. RESULTS: The prevalence of past heavy drinking among Mexican
American and Puerto Rican males ranged from 28-35% while the rates for Cuban
American males ranged from 7-16%. The rates for Hispanic women were much lower (1
8%). The average years of past heavy drinking ranged from 2.3-14.9 years, while
the alcohol consumption during the past heavy drinking period ranged from 24.4
44.0 drinks per week. Past heavy drinkers tended to consume more alcohol at
present than did never heavy drinkers with the greatest differences found for
Mexican American females. Comparisons of the risk factors and health indicators
by drinking status revealed a higher prevalence of smoking among past heavy
drinkers (50-60%) versus never heavy drinkers (34-43%). Past heavy drinking
Mexican American females also reported significantly more chronic conditions and
depressive symptoms than did never heavy drinkers. CONCLUSIONS: Prevalence rates
of past heavy drinking among Mexican American and Puerto Rican males are
approximately three times higher than rates reported for non-Hispanic male
populations.
PMID- 9395592
TI - Longitudinal effects of an HIV testing and counseling programme for low-income
Latina women.
AB - OBJECTIVES: The purpose of this study was to assess the effects of an HIV
antibody testing, counseling and education programme on the knowledge and
practices of low-income Los Angeles Latina women. METHODS: The study design was
prospective and longitudinal involving pre-test, post-test and retest measures
over a 2-year period. The study employed an experimental group and a comparison
group which did not receive the intervention. The study group was comprised of a
convenience sample of 508 low-income Latina women who were recruited from the
Public Health Service nutrition programme for women, infants and children (WIC).
The comparison group (n = 51) was recruited from the same setting. A battery of
instruments was selected to measure HIV knowledge and practices, the social
support received, self-esteem, the level of acculturation and sociodemographic
characteristics. The instruments were administered at pre-test, 2 weeks post-test
and 1 year retest. The HIV antibody serostatus was assessed at pre-test and
retest. An intervention protocol based on cultural competence, women as
traditional health care givers and the major transmission categories was provided
after the pre-test and was reinforced post-test. Finally, qualitative data were
collected from the focus group participants (n = 55) to evaluate the intervention
protocol. RESULTS: The participants in the study made significant improvements in
HIV knowledge and reported condom use practices from pre-test to post-test that
were retained on retest. The comparison group subjects did not make significant
pre-test-post-test improvements on these measures. CONCLUSIONS: It should be
noted that the changes in practices made by the study group did not necessarily
reduce their risk of HIV infection or transmission and were not related to the
demonstrated knowledge and skills improvement. Of special significance to
programme planners, educators and researchers, both the quantitative and
qualitative data revealed problem areas with the intervention protocol related to
cultural norms and the possible fragmentation of information based on the
behavioral transmission categories.
PMID- 9395593
TI - Public policy analysis of Indiana's minority health initiatives.
AB - Similar to national health trends in the US, racial/ethnic minorities in the
state of Indiana continue to experience disparities in poor health status from
preventable health conditions. To address this problem, people from minority
communities across the state mobilized a broad base of individuals and
organizations to facilitate the successful legislative enactment of a statewide
minority health initiative. A case study of the initiative is presented for
public policy analysis. The theoretical framework for the study is Etzioni's
Societal Guidance Theory. The findings show that minority health advocates were
able to impact favorably on public policy formulation and funding of the
initiative by increasing knowledge about minority health status among grass-roots
people, generating public consensus for public policy intervention, setting
mutual goals via a 5-year strategic minority health plan, creating organizational
structures to implement the plan and utilizing power to push the initiative
through the legislative process. The weaknesses of the initiative efforts include
a limited infrastructure development of minority health coalitions, restricted
effective use of the legislative process and varying degrees of linkages among
other advocacy groups. Improvements in these areas are discussed and
recommendations are made for the implementation phase of the initiative.
PMID- 9395594
TI - Racial differences in post-neonatal mortality in Chicago: what risk factors
explain the black infant's disadvantage?
AB - OBJECTIVES: To investigate the extent to which the place of residence affects the
black to white differential in post-neonatal (28-365 days) mortality, we
performed a univariate analysis and multivariate logistic regression of the 1982
1983 Illinois vital records. Chicago Police violent crime information and 1980 US
Census income data. METHODS: Four environmental predictors of post-neonatal death
were examined: a median family income of < $10,000 per year, a poverty prevalence
of > 50%, violent crime rates of > 11/1000 and limited community access to
primary medical care based on physician supply ratios. RESULTS: The post-neonatal
mortality rate of black (n = 50,765) infants was three times that of white (n =
50,690) infants: 10/1000 versus 3/1000, respectively. Thirty-six percent of the
white infants had none of the environmental risk factors, whereas only 13% of the
black infants had none of the risk factors. For black infants, the presence of
any one factor was associated with a slightly increased risk of post-neonatal
mortality (9/1000 as compared to 7/1000 with no risk factors), whereas the
presence of two or more risk factors was associated with a higher risk (11/1000).
When the number of these environmental risk factors were taken into account, the
OR for black infants declined from 3.0 (95% CI 2.5-3.6) to 1.7 (95% CI 1.5-1.9).
When the differences in maternal age, education, marital status and infant birth
weight were also taken into account the odds ratio of post-neonatal death for
blacks was 1.5 (95% CI 1.3-1.7). CONCLUSIONS: We conclude that a substantial
proportion of the black to white difference in post-neonatal mortality is
associated with specific environmental conditions.
PMID- 9395596
TI - Alternative and complementary medicine: part of human heritage.
PMID- 9395597
TI - The importance of alternatives to health care reform.
PMID- 9395595
TI - Cardiovascular and plasma catecholamine response to static exercise in
normotensive blacks and whites.
AB - OBJECTIVES: The objectives of the present study were (1) to evaluate the pressor
response to an isometric handgrip exercise in normotensive black and white males;
(2) to measure plasma catecholamine levels pre- and post-exercise, as an index of
sympathetic nervous system activity; and (3) to quantify the pressor response to
bolus intravenous injections of phenylephrine (an alpha-specific agonist).
METHODS: Cardiovascular and catecholamine responses to an isometric handgrip
exercise (3 minutes at 30% MVC) were measured in 15 normotensive blacks and
whites. In another phase of the study, pressor responses to bolus injections of
phenylephrine were assessed to evaluate alpha-adrenergic sensitivity. RESULTS:
The blood pressure in the blacks increased from 119/69 to 160/120 mm HG during
isometric exercise, while in the whites it increased from 118/67 to 153/110 mm
HG. The blacks exhibited a greater diastolic blood pressure reactivity, as
evidenced by a significant race x time interaction (p < 0.05). The heart rate
responses were not significantly different between the two groups. The plasma
levels of norepinephrine were similar at rest, but were 25% lower in the blacks
than in the whites following isometric exercise (p < 0.01). Black subjects also
demonstrated an increased pressor response to intravenous injections of
phenylephrine at rest (p < 0.05). CONCLUSIONS: The enhanced vascular sensitivity
to norepinephrine may have contributed to the greater exercise pressor response
in the blacks.
PMID- 9395598
TI - Assessment of plants as medicines: a tale of two tales.
PMID- 9395599
TI - The regulation of acupuncture needles by the United States Food and Drug
Administration.
PMID- 9395600
TI - An image of distant contact: a blind Japanese massage practitioner.
PMID- 9395601
TI - Social science theory and methods in the study of alternative and complementary
medicine.
AB - Anthropology is a holistic science with theory, data, and methods that can be of
great service to researchers on alternative medicine. In this paper useful models
and methodologic stances were identified that can help researchers to deal
creatively with the stresses imposed on science by worldview preferences that
differ among both scientists and healthcare systems. I have argued that rather
than prefer one paradigm over another, researchers should select techniques based
on a rationale featuring deep knowledge of the context of the healthcare issue
they want to study. This will not only produce the most accurate and useful data,
but should also help free science of its current strictures and allow expansion
into a wider conversation about human and medical realities.
PMID- 9395602
TI - Social context of complementary medicine in Western society, Part I.
PMID- 9395603
TI - A critical analysis of acupuncture in pulmonary disease: efficacy and safety of
the acupuncture needle.
AB - Criteria for therapeutic efficacy and safety include significant amelioration of
symptoms and, ideally, cure (i.e., patients' belief in effective improvement of
symptoms and quality of life, durable impact on symptoms, verifiable subjective
and objective changes); improved patient management (e.g., diminishing, or
ceasing medication, physiotherapy, and other interventions); safety for patient
and practitioner and an acceptable side effect profile; cost-effectiveness of the
therapy in practice and to teach to others. There is evidence that in bronchial
asthma, chronic bronchitis, and chronic disabling breathlessness the use of
acupuncture fulfills these to varying degrees. It can facilitate reducing
pharmacologic medication and is safe, suggesting that acupuncture as an adjuvant
in the treatment of respiratory disease might be safer than prolonged
pharmaceutical maintenance therapy alone. Its cost-effectiveness has yet to be
adequately researched. Twenty-one papers in English were obtained and 16 were
further evaluated; eight were double-blind, five single-blind, and three
unblinded. The remaining five, and most of the Chinese literature, were excluded
on account of their poor quality. Acupuncture was effective in four of eight of
the double-blind, three of five single-blind, and three of three unblinded
studies (i.e., 10 of 16 [62.5%] overall). A previously unreported confounding
variable was identified and concerned the designation of sham points. Most sham
points were believed to be inactive but, according to traditional Chinese
principles, many are active in pulmonary disease. Reappraised accordingly, the
unequivocally positive studies were summed with those in which "real" and "sham"
acupuncture were not significantly different but in which the combined effect of
all acupuncture (i.e., real + sham) on breathlessness was significantly different
from baseline. This yielded 13 of 16 (81%) [corrected] studies in which
acupuncture led to significant improvement. In most studies, current
pharmacologic treatment had a greater effect than acupuncture alone. However, in
the 11 studies in which it was evaluated, medication could be significantly
reduced by acupuncture in 10 (91%). Twenty-three of the 320 patients in the 16
studies (7%) reported minimal side effects, none requiring intervention. Current
published evidence reveals no reason to withhold acupuncture as a safe and
potentially effective treatment in patients with bronchial asthma and chronic
obstructive lung disease. Further, more appropriately designed studies are
urgently required. This would be facilitated in the United States by licensing
the acupuncture needle as a therapeutic agent and might lead to important new
insights and therapeutic opportunities.
PMID- 9395604
TI - Treatment of seasonal affective disorder with a high-output negative ionizer.
AB - This study was designed to evaluate the antidepressant effect of negative ions in
the ambient air as a potential treatment modality for seasonal affective
disorder. Twenty-five subjects with winter depression underwent a double-blind
controlled trial of negative ions at two exposure densities, 1 x 10(4) ions/cm3
or 2.7 x 10(6) ions/cm3, using an electronic negative ion generator with wire
corona emitters. Home treatments were taken in the early morning for 30 min over
20 days, followed by withdrawals. The severity of depressive symptoms
(prominently including the reverse neurovegetative symptoms of hypersomnia,
hyperphagia, and fatigability) decreased selectively for the group receiving high
density treatment. Standard depression rating scale assessments were corroborated
by clinical impressions. When a remission criterion of 50% or greater reduction
in symptom frequency/severity was used, 58% of subjects responded to high-density
treatment while 15% responded to low-density treatment (chi 2 = 5.00, df = 1, p =
0.025). There were no side effects attributable to the treatment, and all
subjects who responded showed subsequent relapse during withdrawal. Treatment
with a high-density negative ionizer appears to act as a specific antidepressant
for patients with seasonal affective disorder. The method may be useful as an
alternative or supplement to light therapy and medications.
PMID- 9395605
TI - Introducing alternative/complementary healing to allopathic medical students.
AB - We have designed a senior elective, Introduction to Alternative Medicine, to
prepare our students better to practice in multicultural environments, and to
expand their views of health and healing. We combined didactic lecture, films,
first-hand experience with some methods, and observation of alternative
practitioners in their offices/clinics. Students explored hypnosis, chiropractic,
therapeutic touch, meditation, biofeedback, acupuncture, homeopathy, naturopathy,
and massage therapy. Discussions of scientific efficacy, legal and ethical
considerations, and the role of spirituality in health and healing focused on
limitations of science-based approaches and reasons why alternative/complementary
methods are popular with patients and allopathic physicians. We conclude that
allopathic medical schools have an important role in reducing the isolation of
their students from alternative health beliefs, practices, and systems of care
that are common in our communities.
PMID- 9395606
TI - Characteristics of complementary medical systems: the ubiquitous use of plants.
PMID- 9395607
TI - Alternative medicine.
PMID- 9395608
TI - Incense over a medicine bundle: Hidatsa.
PMID- 9395609
TI - Plants, food and civilization: the lessons of indigenous Americans.
PMID- 9395610
TI - The role of plants in traditional medicine and current therapy.
AB - Recent years have witnessed a renewed interest in plants as pharmaceuticals in
the Western world. This interest is channeled into the discovery of new
biologically-active molecules by the pharmaceutical industry and into the
adoption of crude extracts of plants for self-medication by the general public.
In both of these areas some attention is being paid to the investigation and use
of ethnopharmacology, the traditional use of plants for medicinal purposes by
particular cultural groups. Ethnopharmacologic leads have resulted in the
introduction of new single molecule drugs but have a greater role to play if
crude extracts are accepted for clinical use in the West. The problems
confronting such usage are discussed. Considerable benefits for developing
countries are possible when the local medicinal plants are subjected to
scientific methods of validation of traditional use and quality control. This
approach has met with success in some parts of the world but is not always
appreciated by national governments and international agencies. Related areas of
concern such as conservation of ecology and culture must be integrated with any
such program. Plants used in traditional medicine therefore have an important
role to play in the maintenance of health in all parts of the world and in the
introduction of new treatments.
PMID- 9395611
TI - Results of five randomized studies on the immunomodulatory activity of
preparations of Echinacea.
AB - This article describes and discusses five placebo-controlled randomized studies
investigating the immunomodulatory activity of preparations containing extracts
of Echinacea in healthy volunteers. A total of 134 (18 female and 116 male)
healthy volunteers between 18 and 40 years of age were studied. Two studies
tested intravenous homeopathic complex preparations containing Echinacea
angustifolia D1 (study 1) and D4 (study 5). Two studies (2 and 3a) tested oral
alcoholic extracts of roots of E. purpurea, one study an extract of E. pallida
roots (study 3b), and one study an extract of E. purpurea herb (study 4). Test
and placebo preparations were applied for four (study 5) or five (studies 1-4)
consecutive days. The primary outcome measure for immunomodulatory activity was
the relative phagocytic activity of polymorphonuclear neutrophil granulocytes
(PNG), measured in studies 1 and 2 with a microscopic method and in studies 3, 4,
and 5 with two different cytometric methods. The secondary outcome measure was
the number of leukocytes in peripheral venous blood. Safety was assessed by a
screening program of blood and other objective parameters as well as by
documentation of all subjective side effects. In studies 1 and 2 the phagocytic
activity of PNG was significantly enhanced compared with placebo [maximal
stimulation 22.7% (95% confidence interval 17.5-27.9%) and 54.0% (8.4-99.6%),
respectively], while in the other studies no significant effects were observed.
Analysis of intragroup differences revealed significant changes in phagocytic
activity during the observation periods in five test and three control groups.
Leukocyte number was not influenced significantly in any study. Side effects due
to the test preparations could not be detected. Our studies provide evidence for
immunomodulatory activity of the homeopathic combination tested in study 1 and
the E. purpureae radix extract tested in study 2. The negative results of the
other three studies are difficult to interpret due to the different methods for
measuring phagocytosis, the relevant changes in phagocytic activity within most
placebo and treatment groups during the observation period, and the small sample
sizes. Future studies should be performed on patients rather than healthy
volunteers and use standardized or chemically defined monopreparations of
Echinacea.
PMID- 9395612
TI - Social context of complementary medicine in Western society, Part II: traditional
Chinese medicine and HIV illness.
PMID- 9395613
TI - A systems theory approach to an expanded medical model: a challenge for
biomedicine.
PMID- 9395614
TI - A model for a networked information resource on alternative medicine.
PMID- 9395615
TI - The NIH Methodology Conference: the methodology debate in the United Kingdom
during the past ten years.
PMID- 9395616
TI - Acupuncture and stroke rehabilitation.
PMID- 9395617
TI - Social science theory and methods in the study of alternative and complementary
medicine.
PMID- 9395618
TI - Women chiropractors, 1921.
PMID- 9395619
TI - Traditional health systems: policy, biodiversity, and global interdependence.
PMID- 9395620
TI - Phytomedicines: the greening of modern medicine.
AB - Although available in the United States for little more than 10 years,
phytomedicines represent an important class of natural therapeutics that possess
significant scientific literature as well as broad use and acceptance worldwide.
Until recently, such products were severely limited in the United States. Passage
of the DSHEA has opened important new opportunities to communicate the use and
benefits of phytomedicines as safe and useful natural health care products.
Broader dissemination of the extant scientific literature on phytomedicines can
and should have an important effect on the view of the conventional medical
community that plant extracts specifically, and natural products generally, offer
valuable and needed benefits to America's aging population, as well as to others.
Although used since ancient times, plants are enjoying a renaissance of interest
and use in the United States. As Pliny the Younger said, "Everything old is new
again."
PMID- 9395621
TI - An alternative medicine treatment for Parkinson's disease: results of a
multicenter clinical trial. HP-200 in Parkinson's Disease Study Group.
AB - The natural occurrence of antiparkinsonian drugs in plants--anticholinergics in
Datura stramonium, levodopa in Mucuna pruriens and Vicia faba, dopamine agonist
activity in Claviceps purpura, and MAO inhibitor activity in Banisteria caapi-are
known. Our study examined the efficacy and tolerability of HP-200, derived from
Mucuna prurient, in patients with Parkinson's disease. Sixty patients with
Parkinson's disease (46 male and 14 female) with a mean (+/- SD) age of 59 +/- 9
years were treated in an open study for 12 weeks. Of these, 26 patients were
taking synthetic levodopa/carbidopa formulations before treatment with HP-200,
and the remaining 34 were levodopa naive. HP-200, a powder (supplied as a 7.5 g
sachet), was mixed with water and given orally. The Unified Parkinson's Disease
Rating Scale (UPDRS) was used at baseline and periodically during the 12-week
evaluation. Statistically significant reductions in Hoehn and Yahr stage and
UPDRS scores were seen from baseline to the end of the 12-week treatment (p <
0.0001, t-test). The group mean (+/- SD) dose for optimal control of symptoms was
6 +/- 3 sachets. Adverse effects were mild and were mainly gastrointestinal in
nature. No adverse effects were seen in clinical laboratory reports. HP-200,
developed from an alternative medicine source, Ayurveda, was found to be an
effective treatment for patients with Parkinson's disease.
PMID- 9395622
TI - Electroacupuncture reduces morphine-induced emesis in ferrets: a pilot study.
AB - We treated morphine-induced emesis in ferrets with electroacupuncture (EA) for
five minutes at the acupuncture point Neiguan (P6) using two different
frequencies of stimulation: 1.0 Hz and 5.0 Hz (n = 5 ferrets per group). Both EA
treatments reduced the number of emetic episodes (39% reduction of episodes, p <
or = 0.05 at 1.0 Hz; 43% reduction of episodes, p < or = 0.05 at 5.0 Hz) and
prolonged the onset time of emesis as compared with control receiving no EA. This
model demonstrates that under these conditions EA is effective as an antiemetic
against morphine in the ferret and may allow for further studies on the
mechanisms of acupuncture and emesis.
PMID- 9395623
TI - Stress reduction and preventing hypertension: preliminary support for a
psychoneuroendocrine mechanism.
AB - Our objective was to identify endocrine-related mechanisms capable of mediating
preventive effects of stress reduction in hypertensive heart disease. Since
beneficial effects of stress reduction accrue over time, this cross-sectional,
descriptive study sought differences between healthy students not practicing a
systematic technique for reducing stress (the average stress, or AS, group, n =
33) and a similar group who for 8.5 years had practiced the Transcendental
Meditation (TM) technique, used widely to reduce stress (the low stress, or LS,
group, n = 22). The two groups of students, matched for age and area of study,
performed timed collections of urine that included (separately) the entire waking
and sleeping portions of 1 day. They also completed the Profile of Mood States
and the State-Trait Anxiety Inventory, self-report instruments sensitive to
subjective level of stress. Urine samples were analyzed for adrenocortical
steroids by radioimmunoassay, for Na+, K+, Mg2+, Ca2+, and Zn2+ by atomic
absorption spectrometry, and for neurotransmitter metabolites by reverse-phase,
high-performance, liquid chromatography, and spectrophotometry. The two groups
differed significantly on most measures. Specifically, the LS group was lower in
cortisol and aldosterone and higher in dehydroepiandrosterone sulfate (DS) and
the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Excretion of
sodium, calcium, zinc, and the norepinephrine metabolite, vanillylmandelic acid
(VMA), was also lower in this group, as were Na+/K+ ratio, mood disturbance, and
anxiety. In women practicing TM, cortisol correlated inversely and DS directly
with number of months of TM practice. The results identify improvements in mood
state, adrenocortical activity, and kidney function as probable factors in the
preventive and treatment effects of stress reduction. Because suboptimal levels
of these parameters result from chronic, subjective stress, the findings add
mechanistic support to the contention that hypertensive heart disease is
avoidable, even in modern industrialized societies.
PMID- 9395624
TI - The effects of self-hypnosis on quality of life following coronary artery bypass
surgery: preliminary results of a prospective, randomized trial.
AB - The effects of complementary techniques and alternative medicine on allopathic
therapies is generating much interest and research. To properly evaluate these
techniques, well controlled studies are needed to corroborate the findings
espoused by individuals practicing complementary medicine therapies. To this end,
we evaluated the role of one of these therapies, self-hypnosis relaxation
techniques, in a prospective, randomized trial to study its effects on quality of
life after coronary artery bypass surgery. Subjects were randomized to a control
group or a study group. Study group patients were taught self-hypnosis relaxation
techniques the night prior to surgery. The control group received no such
treatment. Patients then underwent routine cardiac management and care. The main
endpoint of our study was quality of life, assessed by the Profile of Moods
Scale. Results demonstrated that patients undergoing self-hypnosis the night
prior to coronary artery bypass surgery were significantly more relaxed than the
control group (p = 0.0317). Trends toward improvement were also noted in
depression, anger, and fatigue. This study demonstrates the beneficial effects of
self-hypnosis relaxation techniques on coronary surgery. This study also
identifies endpoints and a study design that can be used to assess complementary
medicine therapies. Results of this preliminary investigation are encouraging and
demonstrate a need for further well-controlled studies.
PMID- 9395625
TI - NIH Office of Alternative Medicine Conference: federal agencies explore the
potential role of botanicals in U.S. health care.
PMID- 9395626
TI - Homeopathic physician, 1855.
PMID- 9395627
TI - The power of dance: health and healing.
AB - Dance involves the culturally mediated body, emotion, and mind. So do illness and
pain. Dance may promote wellness by strengthening the immune system through
muscular action and physiological processes. Dance conditions an individual to
moderate, eliminate, or avoid tension, chronic fatigue, and other disabling
conditions that result from the effects of stress. Dance may help the healing
process as a person gains a sense of control through (1) possession by the
spiritual in dance, (2) mastery of movement, (3) escape or diversion from stress
and pain through a change in emotion, states of consciousness, and/or physical
capability, and (4) confronting stressors to work through ways of handling their
effects.
PMID- 9395628
TI - Hospital 2000: the interface of radiology within a combined "complementary
allopathic" medicine framework.
AB - The field of radiology can play a crucial role in the movement beyond allopathic
and complementary medicine to a true combination approach. Radiologists are
proponents of minimal invasiveness and are familiar with the overreliance on
diagnostic imaging tests. Their experience can be used to design appropriate
applications for technology and to plan research methods to explore the questions
raised by a combination medicine paradigm.
PMID- 9395629
TI - "Self" and addiction: the role of imagery in self-regulation.
AB - In this paper we discuss the role of self-regulation and self-perception in
sustaining addictive behavior. We suggest that self-regulation techniques are
unlikely to have a sustained positive effect on changing addictive behavior in
the absence of a change in "addict" self-perception. We describe treatment
approaches that emphasize the use of guided imagery for facilitating a shift in
self-perception that may be more compatible with self-regulation.
PMID- 9395630
TI - The health beliefs and behaviors of three groups of complementary medicine and a
general practice group of patients.
AB - Patients (n = 256), consulting either a general practitioner (GP) or one of three
complementary practitioners (osteopath, homeopath, or acupuncturist), completed a
seven-part questionnaire that looked at demographic data, medical history,
familiarization with complementary therapies, health beliefs and life-style,
health locus of control, scientific health beliefs, and their perceptions of the
consultation style of general and complementary practitioners. The four subject
groups did not differ significantly on the demographic variables of sex, years of
schooling, whether or not they had a degree, marital status, or income, but did
differ on age and number of children. The effects of both the significant
demographic variables and some aspects of patients medical history were
controlled for in subsequent analyses. Acupuncture patients stood out as having
the most different chronic medical history. They were also least satisfied with
their GP, had least confidence in prescribed drugs, and were most concerned with
leading a healthy life-style. The acupuncture patients were most skeptical about
orthodox medicine. The main finding was that patients of complementary
practitioners are not a homogeneous group, but do differ in their views on
satisfaction with GPs, healthy life-style, global environmental issues,
confidence in prescribed drugs, faith in medical science, importance of a
"healthy mind," harmful effects of medical science, and scientific methodology.
The results imply that patients consult different practitioners, general or
alternative, on the basis of a combination of their level of skepticism about
orthodox medicine, their life-style, and other health beliefs. To talk of
patients of complementary practitioners as a homogeneous group is fundamentally
wrong.
PMID- 9395632
TI - A patient-centered paradigm: a model for chiropractic education and research.
AB - Within the chiropractic profession there is concern over both the appropriate
paradigm for educating the student and the appropriate research model for
investigating health care and promotion. The purpose of this study was to
identify, interpret, and describe a paradigm for chiropractic education and
research. Chiropractic first principles and existing health care paradigms were
identified and integrated with the characteristics of chiropractic practice
described in sociological studies of the chiropractic profession. A patient
centered paradigm emerged, incorporating the principles of vitalism, holism,
humanism, conservatism, naturalism, and rationalism. Characteristics of a patient
centered paradigm that were identified were then subjected to an eight-member
consensus panel with representatives drawn from chiropractic education, research,
and sociology. The characteristics of a patient-centered paradigm agreed upon
include self-healing, recognition of the patient as a unified whole, respect for
the patient's values, beliefs, and dignity, involvement of the patient as a
partner in health promotion, and a natural and conservative approach to evidence
based care. Patient-centered research must reach beyond the randomized controlled
trial, involving designs where clinicians apply their own patient-centered
therapy in a "real world" assessment. A pluralism of methods, including both
qualitative and quantitative studies, needs to be designed and implemented.
Patient-centered research is a process that is pragmatic, realistic, and grounded
in the day-to-day experiences of both patients and chiropractors. A patient
centered paradigm offers a useful model to critically study what benefits
patients and to prepare chiropractic students to practice in the patient's
interest.
PMID- 9395631
TI - Inhibition of several strains of influenza virus in vitro and reduction of
symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of
influenza B Panama.
AB - A standardized elderberry extract, Sambucol (SAM), reduced hemagglutination and
inhibited replication of human influenza viruses type A/Shangdong 9/93 (H3N2),
A/Beijing 32/92 (H3N2), A/Texas 36/91 (H1N1), A/Singapore 6/86 (H1N1), type
B/Panama 45/90, B/Yamagata 16/88, B/Ann Arbor 1/86, and of animal strains from
Northern European swine and turkeys, A/Sw/Ger 2/81, A/Tur/Ger 3/91, and A/Sw/Ger
8533/91 in Madin-Darby canine kidney cells. A placebo-controlled, double blind
study was carried out on a group of individuals living in an agricultural
community (kibbutz) during an outbreak of influenza B/Panama in 1993. Fever,
feeling of improvement, and complete cure were recorded during 6 days. Sera
obtained in the acute and convalescent phases were tested for the presence of
antibodies to influenza A, B, respiratory syncytial, and adenoviruses.
Convalescent phase serologies showed higher mean and mean geometric
hemagglutination inhibition (HI) titers to influenza B in the group treated with
SAM than in the control group. A significant improvement of the symptoms,
including fever, was seen in 93.3% of the cases in the SAM-treated group within 2
days, whereas in the control group 91.7% of the patients showed an improvement
within 6 days (p < 0.001). A complete cure was achieved within 2 to 3 days in
nearly 90% of the SAM-treated group and within at least 6 days in the placebo
group (p < 0.001). No satisfactory medication to cure influenza type A and B is
available. Considering the efficacy of the extract in vitro on all strains of
influenza virus tested, the clinical results, its low cost, and absence of side
effects, this preparation could offer a possibility for safe treatment for
influenza A and B.
PMID- 9395633
TI - Exploring homeopathic resources on the Internet: HOMEOWEB.
AB - Electronic mail and other forms of communication on the Internet are especially
important for complementary medicine disciplines, like homeopathy, which lack an
efficient academic network for research purposes. The main advantages of using
the Internet for homeopathy are outlined in this article. The first step to
developing an electronic communications network was to create a Homeopathic
Internet Resources List, which is available on-line now, and is being updated
constantly. This references the great homeopathic libraries and reference
databases. Most of these have been made accessible electronically through the
Internet or by e-mail, although many homeopathic physicians are still unaware of
the power of Internet communication. Since the summer of 1995 the HOMEOWEB
webserver has tried to bring together scientific information on all aspects of
homeopathic therapy on the Internet. This service will be enlarged in the near
future, and the aim is to promote the Internet as the primary means of worldwide
communication among the homeopathic community, ensuring that homeopathy survives
into the next century.
PMID- 9395634
TI - Legal ramifications of homeopathy.
AB - The article addresses four regulatory challenges faced by practitioners of
homeopathy: (1) medical practice acts, which prohibit the unlicensed practice of
"medicine," (2) scope of practice limitations, which restrict nonmedical
providers' ability to diagnose and treat disease; (3) prohibitions against
"unprofessional conduct;" and (4) malpractice rules. The article concludes with
suggestions for regulatory reform.
PMID- 9395635
TI - National Institutes of Health Office of Alternative Medicine-Food and Drug
Administration Workshop on Acupuncture.
PMID- 9395636
TI - A short history of acupuncture.
PMID- 9395637
TI - Acupuncture techniques and devices.
PMID- 9395638
TI - Safety issues in acupuncture.
PMID- 9395639
TI - Educational and licensing requirements for acupuncturists.
PMID- 9395640
TI - Testimony to the Office of Alternative Medicine workshop on acupuncture.
PMID- 9395641
TI - Educational and licensing requirements for medical practitioners.
PMID- 9395642
TI - Clinical trials in support of medical devices.
AB - 1. Clearly specify the hypothesis to be investigated using clinically meaningful
objective endpoints. 2. Collect all patients' data in a reliable and consistent
manner. 3. Use statistically appropriate procedures to analyze the data. 4.
Conclusions should be able to support all claims of safety and effectiveness that
are to be made.
PMID- 9395643
TI - Scientific research into acupuncture for the relief of pain.
PMID- 9395644
TI - Auricular acupuncture in animals: effects of opiate withdrawal and involvement of
endorphins.
PMID- 9395646
TI - Review of medical and clinical literature.
PMID- 9395645
TI - Veterinary clinical applications of acupuncture.
PMID- 9395647
TI - On the evaluation of the clinical effects of acupuncture: a problem reassessed
and a framework for future research.
PMID- 9395648
TI - Acupuncture in the treatment of pain.
PMID- 9395649
TI - Overview of acupuncture in chronic pain clinical research.
PMID- 9395650
TI - Review of acute and chronic pain published studies.
PMID- 9395652
TI - Acupuncture as an antiemetic treatment.
PMID- 9395651
TI - Overview of substance abuse acupuncture treatment research.
AB - The research on the efficacy of acupuncture substance abuse treatment is
generally still in an early stage. The methodological weaknesses found in the
acupuncture research can be found in most substance abuse research. Sufficient
early trial, empirical findings suggest that there are positive treatment
effects. Certainly, use of the treatment is popular and widespread. Overall, the
research has progressed beyond early clinical trials, and the method has been
documented to be safe and potentially useful.
PMID- 9395653
TI - Acupuncture in asthma and pulmonary disease: an analysis of efficacy and safety.
PMID- 9395654
TI - Acupuncture in the treatment of paralysis due to central nervous system damage.
PMID- 9395656
TI - Adverse effects of acupuncture.
PMID- 9395655
TI - History of the Food and Drug Administration's regulation of acupuncture devices.
PMID- 9395657
TI - South Vietnamese healing ceremony.
PMID- 9395658
TI - U.S. patent documents on the Internet: an information resource for research in
alternative and complementary medicine.
AB - The US patent literature is a valuable source of information and research data
relevant to studies in alternative and complementary medicine. Many patent
publications contain detailed historical reviews, case reports, clinical trials,
pilot studies, and basic biological research, any of which may give scientific
insights, notwithstanding the controversies surrounding the issues of some
patents, such as those of products of traditional medicinal plants. Much of the
scientific, efficacy, and safety data necessary to obtain a patent is unpublished
elsewhere. This paper gives an account of the recent experiment to make the full
text of U.S. patents documents openly and freely available on the Internet, gives
an example of browsing such a document from the AIDS Patents database, and
provides examples of searching on-line on the Patents Abstracts database together
with a miscellany of recent abstracts relevant to alternative and complementary
medicine.
PMID- 9395659
TI - Beneficial effect of Aloe on wound healing in an excisional wound model.
AB - Recent evidence from in vitro and in vivo experiments suggests that topical
antimicrobials may be toxic to fibroblasts and keratinocytes and retard wound
healing. The purpose of this study was to determine the effects of Aloe, a
potential wound-healing agent, on wound contraction in excisional wounds treated
with topical antimicrobials. Sprague-Dawley rats were prepared with four 1.5 cm2
dorsal defects through the skin and panniculus. The animals were divided into
five groups (n = 10 per group): (1) Aloe, (2) NaOCl solution (0.025%), (3)
mafenide acetate, (4) mafenide acetate + Aloe, and (5) control. Wounds were
treated topically for 14 days 3 times a day. Serial standard photographs and
serial wound planimetry were performed weekly. Following healing, the breaking
strength of each resultant scar was determined using an Instron tensiometer.
Kruskal-Wallis, ANOVA, and multiple comparison methods were used for data
analysis. Aloe and NaOCl solution significantly accelerated wound contraction (p
< 0.05). In the mafenide acetate + Aloe group, contraction was similar to the
control, whereas the mafenide acetate alone retarded wound healing. The addition
of Aloe in combination and alone in wounds increased the breaking energy when
compared to controls (p < 0.05). Aloe appears to expedite wound contraction and
neutralize the wound retardant effect seen with the topical mafenide acetate
alone. This effect appears to be due to an increased collagen activity, which is
enhanced by a lectin, consequently improving the collagen matrix and enhancing
the breaking strength.
PMID- 9395661
TI - Adverse effects of acupuncture: a study of the literature for the years 1981
1994.
AB - This study presents the adverse effects of acupuncture as recorded in the Medline
database for the years 1981-1994. A total of 125 papers were localized by the
keywords acupuncture adverse effects. Articles without case reports were
excluded, and 78 reports forms the basis for the present paper. A total of 193
patients were reported with adverse effects of acupuncture in 14 years.
Pneumothorax is the most common mechanical organ injury, while hepatitis
dominates among infections. Acupuncture treatment is claimed to be responsible in
the death of three patients. One patient died from bilateral pneumothorax,
another got endocarditis, and died of complications. The third patient died of
severe asthma while under acupuncture treatment. Most adverse effects of
acupuncture seem to rely on insufficient basic medical knowledge, low hygienic
standard, and inadequate acupuncture education. The study confirms the adverse
effects of acupuncture under certain circumstances. Serious adverse effects,
however, are few, and acupuncture can generally be considered as a safe
treatment.
PMID- 9395660
TI - Characterization of differing effects caused by homeopathically prepared and
conventional dilutions using cytochrome P450 2E1 and other enzymes as detection
systems.
AB - Determination of cytochrome P450 2E1 activity was carried out via hydroxylation
of the synthetic substrate p-nitrophenol to p-nitrocatechol. Crude microsomal
preparation isolated from rat liver served as source for cytochrome P450 2E1.
Under assay conditions guaranteeing a linear course of the reaction the
cytochrome P450 2E1 was stimulated in the presence of a 10(-6) dilution of As2O3
corresponding to 0.915 microM final concentration compared with control. All
other concentrations of As2O3 used inhibited the enzyme activity more or less
drastically. Furthermore, we used this enzyme system to study the influence of
arsenicum album (As2O3) and potassium cyanatum (KCN) in homeopathically prepared
(i.e., by consecutive 1:10 steps) and conventional dilutions. We found
significant differences between the effects caused by homeopathic potencies (D)
and equally concentrated dilutions on catalytic activity of cytochrome P450 2E1.
Such differing effects were observed in the case of arsenicum album (As2O3)
between D4/10(-4) and D6/10(-6) and in the case of potassium cyanatum (KCN)
between D6/10(-6) and D12/10(-12). When we used glutathione-S-transferases and
uricase we also found different effects mediated by potencies and conventional
dilutions. The results obtained suggest that these three enzyme systems are
appropriate detection systems to hunt out differing effects of differently
prepared dilutions of specific test substances.
PMID- 9395662
TI - New developments in Cuban holistic medicine: a personal view.
PMID- 9395663
TI - Familiarization with complementary medicine: report of a new course for primary
care physicians.
AB - A course entitled "Familiarization in Complementary Medicine" has been
established at Exeter University. The syllabus of the course is presented,
together with significant issues for debate that were raised by the attending
primary care physicians. The delegates started with a positive but questioning
attitude toward complementary medicine (CM) and acknowledge that they gained
useful information, leading to increased confidence in discussing CM with
patients. The course to a large extent met their needs and expectations. Benefits
and draw-backs of integrating CM within general practice were explored. The main
advantage of CM, apart from the potential intrinsic value of the techniques
themselves, was identified as the time to establish a good therapeutic
relationship with the patient. The particular concerns about CM that were
expressed by the doctors included poor dialogue with CM practitioners, doubts
about competence, and lack of readily identifiable and recognized qualifications.
The risk of holding out unrealistic hope of cure was their greatest concern,
however, especially if patients were thereby denied an effective orthodox
treatment. The course was popular and will be repeated on a regular basis;
similar courses for other health professionals including nurses are being
planned.
PMID- 9395664
TI - At least 80% of the population of most developing countries relies on traditional
medicine as its primary source of health care.
PMID- 9395665
TI - Global initiative for traditional health systems.
PMID- 9395666
TI - Traditional medical practitioner in Vietnam.
PMID- 9395667
TI - An aqueous extract of the leaves of Chromolaena odorata (formerly Eupatorium
odoratum) (Eupolin) inhibits hydrated collagen lattice contraction by normal
human dermal fibroblasts.
AB - Chromolaena odorata (formerly Eupatorium odoratum) is used as a traditional
medicine in Vietnam (Nghiem, 1992), where its Vietnamese common name is "co hoi."
While it has been widely considered a weed by agriculturalists (Holm et al.,
1991), the aqueous extract and the decoction from the leaves of this plant have
been used throughout Vietnam for the treatment of soft tissue wounds, burn
wounds, and skin infections. A number of clinical studies done by Vietnamese as
well as foreign medical workers has demonstrated the efficacy of this extract on
the wound-healing process. In this article, the effect of the Eupolin extract on
hydrated collagen lattice contraction by human dermal fibroblasts, an in vitro
model of wound contraction, is described. The significant inhibition of collagen
gel contraction by Eupolin extract at 50 to 200 micrograms/ml is demonstrated in
various concentrations of collagen. When the extract at 50 to 150 micrograms/ml
was washed out of the lattices and replaced by fresh medium without Eupolin, the
contraction of collagen by cells was resumed. The visualization of cells in the
lattices by incubation in a tetrazolium salt for 2 h showed live cells at 50 to
150 micrograms/ml of extract. In contrast, all cells were killed in the higher
extract doses of 300 or 400 micrograms/ml. These preliminary results showing the
inhibitory effect of Eupolin extract on collagen contraction suggest that a
clinical evaluation of its effect on wound contraction and scar quality should be
made. This work illustrates that traditional remedies that are used by folk
practitioners to improve healing can be examined in a scientific manner using in
vitro wound-healing models. It could be that the synergistic properties of
components of the natural extract contribute to the positive effects demonstrated
on various wound-healing mechanisms.
PMID- 9395668
TI - Effect of honey versus thyme on Rubella virus survival in vitro.
AB - In this paper, we assess the antiviral properties of honey solutions and thyme
extracts at varying concentrations. This was done by testing these solutions in
vitro using monkey kidney cell cultures that were infected with the Rubella
virus. Our results indicated that honey had good anti-Rubella activity, while
thyme did not. These results may justify the continuing use of honey in
traditional medicines from different ethnic communities worldwide and in some
modern medications such as cough syrups.
PMID- 9395669
TI - Conserving the medicinal plants of India: the need for a biocultural perspective.
PMID- 9395670
TI - Ginkgo biloba L.: history, current status, and future prospects.
AB - In this paper, we describe the status of the exploration and use of the Ginkgo
biloba leaves in China. We emphasize the need for careful studies of the intra
specific genetic diversity of Ginkgo biloba since genetic variation within this
species may result in significant differences between the chemical and
pharmacological properties of the different sub-species. It is therefore
imperative that we catalog the intraspecific diversity of Ginkgo biloba L., and
we stress that it is important to conserve this diversity since different
subspecies may have different pharmacochemical properties resulting in
differential medical usages.
PMID- 9395671
TI - Research on medicinal plants and traditional medicine in Africa.
PMID- 9395672
TI - Bumetha Rukararwe: integrating modern and traditional health care in southwest
Uganda.
AB - Rukararwe-Bumetha in southwest Uganda is a community-based program which combines
the services of traditional medical practitioners with modern medical services in
providing sustainable rural health care. In five years, approximately 50,000
patients have been seen. The clinic is staffed by a trained nurse and a
pharmaceutical technician, and visited by doctors from nearby Mbarara University
Medical School, all of whom work with traditional herbalists in diagnosing,
standardizing dosage and consistency of medicines, and dispensing herbal
mixtures, many of which are cultivated in Rukararwe's medicinal plant garden.
Conservation of medicinal plants and education are central to the integrated
health care services at Bumetha. Community health education emphasizes hygiene
and the appropriate use of local medicinal resources. Traditional health
practitioners care for the emotional and spiritual, as well as the physical, well
being of their patients.
PMID- 9395673
TI - The formulation of a health research agenda by and for indigenous peoples:
contesting the Western scientific paradigm.
AB - The paper addresses concerns related to the impact of Western science and
technology upon indigenous communities in the face of current heightened
globalization trends. Elements of the Western scientific paradigm that are
antagonistic to indigenous ways of life and can result in detrimental cultural
disruption are identified. In examining the Andean health paradigm, conceptual
elements inherent to indigenous forms of knowledge generation are uncovered. The
paper offers recommendations for the formulation of a research agenda and health
promotion strategies aimed at maximizing the benefits of cultural interaction
while minimizing potential damage to indigenous peoples.
PMID- 9395674
TI - Physical activity.
PMID- 9395675
TI - The genesis of physical culture in America.
PMID- 9395676
TI - The antioxidant and antiatherogenic effects of MAK-4 in WHHL rabbits.
AB - Oxidized low-density lipoprotein (ox-LDL) plays an important role in
atherogenesis. Atheroma formation is reduced significantly in Watanabe heritable
hyperlipidemic (WHHL) rabbits by antioxidants such as probucol and vitamin E. The
herbal mixture Maharishi Amrit Kalash-4 (MAK-4) inhibits Cu+2 -induced LDL
oxidation, and enzymatic- and nonenzymatic-induced microsomal lipid peroxidation.
We tested the effect of MAK-4 on the development of atheroma in WHHL rabbits.
Eleven rabbits were divided into two groups: controls (n = 5) and a group fed 6%
(w/w) MAK-4 (n = 6). Blood was drawn for biochemical analysis every two months
and at necropsy, six months after the special diet was started. The aortas were
preserved in formalin. The percentage area of aortic arch covered with visible
plaque in the MAK-4 group (22.5 +/- 4.2%, mean +/- SE) was significantly reduced
(p < 0.01) compared to the control group (47.6 +/- 6.8%, mean +/- SE). The MAK-4
group showed a significant decrease (p < 0.05) in lipid peroxide, and a
significant increase (p < 0.05) in glutathione peroxidase and resistance of LDL
to endothelial cell-induced and cupric ion-catalyzed oxidation (4.5 h and 5 h lag
phase, respectively, for the MAK-4 group; 0 h lag phase for both for the
controls). These findings suggest MAK-4 reduces atheroma formation through its
antioxidant activity.
PMID- 9395677
TI - Physiological measures of right nostril breathing.
AB - This study was conducted to assess the physiological effects of a yoga breathing
practice that involves breathing exclusively through the right nostril. This
practice is called surya anuloma viloma pranayama (SAV). Twelve volunteers
(average age 27.2 years +/- 3.3 years, four males) were assessed before and after
test sessions conducted on two consecutive days. On one day the test session
involved practicing SAV pranayama for 45 minutes (SAV session). During the test
period of the other day, subjects were asked to breathe normally for 45 minutes
(NB session). For half the patients (randomly chosen) the SAV session was on the
first day and the NB session on the next day. For the remaining six patients, the
order of the two sessions was reversed. After the SAV session (but not after the
NB) there was a significant (P < .05, paired t test) increase in oxygen
consumption (17%) and in systolic blood pressure (mean increase 9.4 mm Hg) and a
significant decrease in digit pulse volume (45.7%). The latter two changes are
interpreted to be the result of increased cutaneous vasoconstriction. After both
SAV and NB sessions, there was a significant decrease in skin resistance (two
factor ANOVA, Tukey test). These findings show that SAV has a sympathetic
stimulating effect. This technique and other variations of unilateral forced
nostril breathing deserve further study regarding therapeutic merits in a wide
range of disorders.
PMID- 9395678
TI - Electrostimulation: addiction treatment for the coming millennium.
AB - At a period of fundamental review of the health care system, it is timely to re
assess one of medicine's most intractable problems--the treatment of addictions.
The apparently insoluble dilemmas posed by the acute and chronic withdrawal
syndromes underlie universally high drop-out and relapse rates. In a decade of
HIV and AIDS infection, poly-substance addiction, potent street drugs, and
ossified treatment strategies, it is urgent that policy formulators investigate
seriously a flexible system of non-pharmacological transcranial
electrostimulation treatment, based on its record of rapid, safe, and cost
effective detoxification in several countries, as one innovative contribution to
the challenges presented by addiction in the 1990s. This is a brief report of the
introduction of NeuroElectric Therapy (NET) into Germany, describing the
responses of the first 22 cases. The daily progress of a heroin addict and a
methadone addict are detailed: both were treated as outpatients for 8 hours
daily, for 7 and 10 days respectively.
PMID- 9395679
TI - Wound healing and complementary therapies: a review.
AB - A series of five innovative experiments conducted by Wirth et al. which examined
the effect of various complementary healing interventions on the
reepithelialization rate of full thickness human dermal wounds was assessed as to
specific methodological and related factors. The treatment interventions utilized
in the series included experimental derivatives of the Therapeutic Touch (TT),
Reiki, LeShan, and Intercessory Prayer techniques. The results of the series
indicated statistical significance for the initial two experiments and
nonsignificance or reverse significance for the remaining three studies. This
review article examines the methodological designs of the series of studies,
along with the TT practitioners' phenomenologically based journal reports, to
provide potential contributing correlative factors for the differential results
obtained. These factors include: (1) methodological design restrictions, (2) a
transference/inhibitory effect (3) the influence of experimental assistants, (4)
healer visualization /imagery techniques, (5) variations in subject populations,
and (6) a potential cancellation effect. While the placebo controlled double
blind methodological designs used in the series were as stringent as those used
in other fields of scientific inquiry, the overall results of the experiments
were inconclusive in establishing the efficacy of the treatment interventions for
accelerating the rate of reepithelialization of full thickness dermal wounds.
PMID- 9395680
TI - The integrative hospital explored via acupuncture.
AB - To integrate complementary and allopathic medicine within a single hospital
requires close attention to models of health care delivery, economics, and
medical philosophy. The practice of acupuncture can be used as a heuristic device
to examine these issues and how solutions may apply to other complementary
modalities in the creation of such a hospital facility.
PMID- 9395681
TI - Methodological issues in complementary and alternative medicine research: a
personal reflection on 10 years of debate in the United Kingdom.
AB - There are certain immediate and obvious problems in using conventional research
techniques for the evaluation of complementary and alternative medicine (CAM).
These have led some to argue that alternative medicine requires alternative
methodologies. The experience in the United Kingdom has been that existing
methodologies can be adapted and do not have to be discarded wholesale.
Conventional research has developed a set of powerful techniques for generating
reliable knowledge and these have been used with considerable success in a
variety of different settings. In retrospect, the call for new methodologies
appears to have been a reaction against the perceived dominance of the randomized
controlled trial (RCT). This stemmed from the misperception that the RCT
inevitably involves features, such as placebo controls or double-blinding, which
are not feasible in many CAM therapies. There was also a desire to ask questions
about medicine, the answers to which, it was felt, could not be decided by the
RCT. A variety of different research designs need to be used to answer the
variety of questions important in CAM. However, research designs do not have to
be reinvented: appropriate methodologies can normally be found in one or another
of the diverse branches of medical research. Successful research has been
conducted in CAM using conventional research techniques and this refutes the
claims that such techniques are inappropriate for CAM. Solving methodological
problems in CAM is a matter of following simple guidelines, not the creation of
complex and esoteric research designs.
PMID- 9395682
TI - The traditional use of maggots in wound healing, and the development of larva
therapy (biosurgery) in modern medicine.
PMID- 9395683
TI - Post modern medicine.
AB - Although there is general agreement that our current approach to health and
healing is undergoing substantial change, there has been a lack of critical
discussion regarding the extent, character, and direction of that change. It is
important for us to articulate the values that we would like expressed in a
reconfigured approach to health and healing, and to ensure that our efforts to
initiate change are aligned with these values. An overview of western history
suggests that the post-modern world view is characterized by four essential
values: multidimensional realism, intentionality, holism, and personal
authenticity. Our current efforts to change the direction of health care have
failed to produce fundamental change. This has resulted from the compelling
influence of existing perspectives and the promotion of parochial professional
and institutional interests. To assure fundamental change, values that are
consistent with a post-modern world must be articulated, fostered, and embedded
into innovative programs.
PMID- 9395684
TI - Challenges for the future: report on the First National Conference on Medical and
Nursing Education in Complementary Therapies.
PMID- 9395685
TI - Report of the National Workshop on Research Methodologies for Unconventional
Therapies, sponsored by the Canadian Breast Cancer Research Initiative (CBCRI),
held October 4-6, 1996, at the Delta Pacific Resort and Conference Center in
Richmond, B.C.
PMID- 9395686
TI - Report from the Cochrane Collaboration 4th International Colloquium, held in
Adelaide, Australia, October 20-24, 1996.
PMID- 9395687
TI - One man's meat is another man's poison: the challenge of psychic/intuitive
diagnosis to the diagnostic paradigm of orthodox medical science.
PMID- 9395688
TI - Phrenologist at work, 1856.
PMID- 9395689
TI - A comparative survey of leguminous plants as sources of the isoflavones,
genistein and daidzein: implications for human nutrition and health.
AB - Over 80 taxa of mostly agriculturally important legumes were surveyed as sources
of the metabolites, genistein and daidzein. Remarkably high concentrations (over
2 g.kg-1 dry weight) of the anticancer metabolite, genistein, were found in the
leaves of Psoralea corylifolia (Indian bread root). All other legumes, with the
exception of fermented soybean miso, had genistein levels < 400 mg.kg-1 dry
weight. Concentrations of over 1 g.kg-1 dry weight and 0.95 g.kg-1 dry weight of
the anticancer metabolite, daidzein, were found in the stems of the fava bean
(Vicia faba) and roots of kudzu vine (Pueraria lobata), respectively. From this
survey, our results indicate that the legumes, lupine (Lupinus spp.), fava bean,
(Vicia faba), soybeans (Glycine max), kudzu (Pueraria lobata), and psoralea
(Psoralea corylifolia), are excellent food sources for both genistein and
daidzein. Miso, a fermented soybean product, is also a rich source of both
isoflavones.
PMID- 9395690
TI - Microbiological screening of Indian medicinal plants with special reference to
enteropathogens.
AB - The World Health Organisation (WHO) has recommended that all member states
actively promote native medicines in their country. Ten Indian medicinal plants
were screened for antibacterial activity specific to enteropathogens. Diffusion
and dilution methods were used to measure the antibacterial activity. Allium
sativum, Camellia sinensis, and Chamaesyce hirta showed higher activity when
compared to the rest. They had a minimum bactericidal concentration (MBC) of <
100 micrograms/ml and gave inhibition zones of more than 2 cm. Among the
pathogens studied, Vibrio cholerae and Shigella flexneri were found to be highly
susceptible to the plant extracts.
PMID- 9395691
TI - Double-blind study of pulsing magnetic field effects on multiple sclerosis.
AB - We performed a double-blind study to measure the clinical and subclinical effects
of an alternative medicine magnetic device on disease activity in multiple
sclerosis (MS). The MS patients were exposed to a magnetic pulsing device
(Enermed) where the frequency of the magnetic pulse was in the 4-13 Hz range (50
100 milliGauss). A total of 30 MS patients wore the device on preselected sites
between 10 and 24 hours a day for 2 months. Half of the patients (15) randomly
received an Enermed device that was magnetically inactive and the other half
received an active device. Each MS patient received a set of tests to evaluate MS
disease status before and after wearing the Enermed device. The tests included
(1) a clinical rating (Kurtzke, EDSS), (2) patient-reported performance scales,
and (3) quantitative electroencephalography (QEEG) during a language task.
Although there was no significant change between pretreatment and posttreatment
in the EDSS scale, there was a significant improvement in the performance scale
(PS) combined rating for bladder control, cognitive function, fatigue level,
mobility, spasticity, and vision (active group -3.83 +/- 1.08, p < 0.005; placebo
group -0.17 +/- 1.07, change in PS scale). There was also a significant change
between pretreatment and posttreatment in alpha EEG magnitude during the language
task recorded at various electrode sites on the left side. In this double-blind,
placebo-controlled study, we have demonstrated a statistically significant effect
of the Enermed magnetic pulsing device on patient performance scales and on alpha
EEG magnitude during a language task.
PMID- 9395692
TI - Characteristics and complaints of patients seeking therapy at a hospital-based
alternative medicine clinic.
AB - BACKGROUND: Patient use of complementary and alternative medicine (CAM) is on the
rise. With millions of Americans using CAM, it has become imperative from the
public health point of view to undertake a coordinated research effort that will
thoroughly evaluate the role and effectiveness of CAM modalities. METHODS: We
developed a prospective data-collection system to capture presenting complaints,
patient health histories, and demographic information on the patients of a
hospital-based alternative medicine clinic. RESULTS: Of 760 patients in the
present cohort, 248 different complaints or complaint combinations were entered.
Of 16 major categories, the largest was musculoskeletal, followed by the
addictions, psychiatric, and nonspecific categories. Slightly more than one in
five patients requested treatment on the recommendation of their physician. Over
two-thirds of patients in this study group were female. CONCLUSIONS: Given the
growing interest and use of complementary and alternative therapies, a system
such as described can demonstrate the types of patients presenting for treatment,
a more detailed picture of their complaints, and, over time, measurable outcomes.
PMID- 9395693
TI - An experimental test of psychic diagnosis of disease.
AB - The authors, one a medical anthropologist and the other a medical doctor,
investigated the claims of three acquaintances who include psychic diagnosis in
the services they provide to clients. An experiment was designed that allowed
each of the three psychics to diagnose five volunteers, patients of S. K. H.
Aung, one at a time while hidden behind a screen. The results of the psychic
diagnoses were then compared with the medical records of the patients. Results
indicate some correspondence between the psychic diagnoses and the medical
records, but the correspondence was not sufficiently impressive to warrant
considering psychic diagnosis as a useful alternative method for diagnosing
disease. It would appear that patients relying solely on psychic diagnosis as the
basis for therapy are at risk of serious medical problems going undetected.
Future research, with a larger sample of patients and psychic diagnosticians, is
required to substantiate this conclusion.
PMID- 9395694
TI - A review of research on acupuncture for the treatment of lumbar disk protrusions
and associated neurological symptomatology.
AB - The association between acupuncture (AP) and pain relief is so strong that it has
tended to obscure any other potentially significant clinical results. This review
indicates the wealth of data from around the world on various aspects of AP
treatment for low back syndromes related to lumbar intervertebral disk prolapse
(PID). Although plentiful, the research is variable in quality, especially with
respect to design, consistency, and follow-up. Even so, the large number of
patients who appear to have been treated successfully (i.e., given a high degree
of symptomatic relief) supports a potential role for AP. This is further
supported by studies on patients who had previously had unsuccessful treatment
with conservative methods. The role envisaged for AP, in cases of lumbar PID and
sciatica, is at least of a supplementary therapy capable of reducing the
requirement of more invasive forms of treatment. No such role is envisaged in
cases of cauda equina compression where surgery must remain the treatment of
choice. AP should be explored more fully, using appropriate designs, so that this
discipline may achieve its full therapeutic potential in the West.
PMID- 9395696
TI - Redefining medicine for the 21st century: reflections on values and principles: a
personal view.
PMID- 9395695
TI - Two cases of hepatitis C treated with herbs and supplements.
AB - The treatment of two cases of hepatitis C using herbal medicine and nutritional
supplements is presented. The selection of medicinals was based upon both
biomedical findings and traditional Chinese medical diagnosis. The text describes
the course of each patient's illness documented both subjectively and objectively
using blood values and traditional Chinese medicine analysis as parameters.
Explanation and/or citations are given for each medicinal used. Both patients
improved during the course of treatment; subjective signs and symptoms
(especially fatigue) as well as liver enzyme levels demonstrated improvement.
PMID- 9395697
TI - Maryland massage therapy bill passes after 10 years.
PMID- 9395698
TI - Dramatic increase in the interest in, and, use of, alternative and complementary
medicine.
PMID- 9395699
TI - Hydrotherapy.
PMID- 9395700
TI - Multisite electromyographic analysis of therapeutic touch and qigong therapy.
AB - The influence of complementary healing treatment on paraspinal electromagnetic
activity at specific neuromuscular sites was examined in an exploratory pilot
study that used a multisite surface electromyographic (sEMG) assessment
procedure. The study was a replication and extension of previous research that
indicated that complementary healing had a significant effect in normalizing the
activity of the "end organ" for the central nervous system (CNS). Multisite sEMG
electrodes were placed on the frontalis, cervical (C4), thoracic (T6), and
lumbosacral (L3) paraspinals of 44 subjects who were divided into three groups:
(1) students/patients of a Qigong practitioner (n = 16); (2) students/patients of
a therapeutic touch (TT) practitioner (n = 14); and (3) nonbelievers in
complementary healing (n = 14). A traditional ABAC experimental design was used
with each subject evaluated for one 20-minute session that included four 5-minute
segments. The purpose of this study was to measure the variable energizing effect
of Qigong therapy along with the anecdotally and experimentally established
relaxation effect of TT therapy relative to patient belief and expectancy.
Treatment sessions consisted of Qigong and a modified form of TT intervention for
all three groups. Due to the double-blind nature of the study, however, group 1
subjects were aware of only the Qigong intervention; group 2 subjects were aware
of only the TT intervention, and group 3 subjects were informed that the study
was designed to assess the neuromuscular activity of individuals in a seated
position. The results indicated a statistically significant rise in
electromagnetic activity for group 1 during the Qigong intervention segment (p <
.024). Group 2 demonstrated a modest although overall nonsignificant decrease in
multisite sEMG levels for both treatment protocols, whereas group 3 exhibited
relatively consistent neuromuscular activity for both control and treatment
segments. The results of this study are considered preliminary in nature,
however, due to the potential influence of several confounds including
psychophysiological factors, established behavior patterns, and the possibility
for information transfer due to sensory cues.
PMID- 9395701
TI - Use of acupuncture by American physicians.
AB - OBJECTIVES: Little is known about the characteristics of American physicians who
currently practice acupuncture. We asked: (1) Do the demographics of physicians
practicing acupuncture differ from the general physician population? (2) Do these
physicians use or endorse other alternative therapies? (3) For which conditions
is acupuncture most commonly used? (4) For which conditions is acupuncture
perceived to be most efficacious? DESIGN: Mailed survey of physicians who
incorporate acupuncture into their practice. PARTICIPANTS: Membership of the
American Academy of Medical Acupuncture (AAMA). OUTCOME MEASURES: Demographic
information regarding physicians and practice characteristics; specific illnesses
treated, and perceived efficacy; use of other complementary modalities; personal
reasons for practicing acupuncture. RESULTS: Compared with national data,
respondents were more likely to be nonspecialists, in private practice, and age
35 to 54. There was an equal proportion of men and women. Most had been doing
acupuncture for < 5 years; most use it on < 25% of their patients. Endorsement or
use of other complementary methods (spinal manipulation, herbal medicine,
supplements, homeopathy) was common. Acupuncture was more commonly used for pain
conditions than general medical problems or addiction management. Reasons for use
included: efficacy of the technique, an alternative in cases of inadequacy of
standard medical approach, and a multidimensional approach to health care.
CONCLUSIONS: Physicians surveyed in this study who incorporate acupuncture into
their practice do so mainly to treat pain problems. They are more likely to be in
the 35 to 54 age group, nonspecialists, and in private practice when compared
with national averages. These physicians are also more likely to use or endorse
other complementary modalities.
PMID- 9395702
TI - Who seeks alternative health care? A profile of the users of five modes of
treatment.
AB - This article compares the social and health characteristics of patients of five
kinds of practitioners: family physicians (used as a baseline group);
chiropractors; acupuncturist/traditional Chinese medicine doctors; naturopaths;
and Reiki practitioners. The data were gathered in a large Canadian city during
the period 1994 to 1995. Face-to-face interviews were conducted with 300 patients
(60 from each type of treatment group). While the most striking social and health
differences occur between patients of family physicians and the patients of
alternative practitioners, significant differences are also evident between the
different groups of alternative patients. Reiki patients, for example, have a
higher level of education and are more likely to be in managerial or professional
positions than other alternative patients. The profiles presented here indicate
that users of alternative care should not be regarded as a homogeneous
population. The findings also show that almost all alternative patients also
consult family physicians. The pattern revealed is one of multiple use: patients
choose the kind of practitioner they believe can best help their particular
problem.
PMID- 9395703
TI - Researching complementary therapies: a Delphi study to identify the views of
complementary and orthodox practitioners.
AB - Twenty five participants were invited to a workshop looking at the role of
research and development in complementary therapies. These participants took part
in a modified Delphi study to ascertain a consensus from their broad spectrum of
views and see how those views changed over time. Opinions were sought about
respondents' perceptions of complementary therapies, the type and scope of
research needed, and how such research should be coordinated. The workshop,
arranged by the Regional Health Authority, included orthodox and complementary
practitioners, purchasers, providers and academics. Questionnaires were
administered at the beginning and end of the workshop and 6 months later. The
group was small and potentially positively biased, having both pre-existing
knowledge and interest in complementary therapies. In consensus, the more
mainstream complementary therapies of osteopathy, acupuncture, and homeopathy
were perceived to be the most beneficial to patients, and therefore, most likely
to be recommended as treatments. These were also felt to be the priority areas
for research. For some unknown reason homeopathy had lost its popularity in
ranking 6 months later. The respondents agreed that research into complementary
therapies was needed and ideally should be collaborative between practitioners,
professional bodies, and academics. The workshop appeared to produce some changes
in knowledge that were not always maintained over time. It was, however,
formative in the decision of the Regional Health Authority to allocate research
funding into complementary therapies.
PMID- 9395704
TI - Effect of the combination of Aloe vera, nitroglycerin, and L-NAME on wound
healing in the rat excisional model.
AB - PURPOSE: Many systemic and topical therapeutic agents such as growth hormone,
platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal
growth factor (EGF), and insulin-like growth factor (IGF) have been used as
vulnerary agents. However, the role of nitric oxide (NO) as a wound-healing
stimulant has been received with mixed reviews. NO is a potent vasodilator that
is thought to be an endothelium-dependent relaxing factor, and a regulator of
blood pressure and regional blood flow. It affects vascular smooth muscle
proliferation and inhibits platelet aggregation and leukocyte adhesion. Therefore
we compared the effects of several topical substances that have similar or
reverse properties. METHODS: Using the excisional rat wound model, we evaluated
the topical effects of Dermaide Aloe (D-Aloe, Dermaide Research Corp, Palos
Heights, IL), nitroglycerin, Aquaphor (Beuersdorf, Inc., Norwalk, CT) alone, with
D-Aloe with nitroglycerin, 2%, and L-NAME (NO inhibitor) with Aquaphor, and L
NAME with Aquaphor and D-Aloe for a 21-day period. All wounds were measured by
planimetry at 1, 7, 10, 13, 16, 18, and 21 days. RESULTS: At day 1, all wounds
had an average wound size of 2.27 cm2 (SD +/- 0.372) with no significant
difference in wound size among the groups. Topically applied D-Aloe appeared to
promote wound healing faster than the remaining other topicals (p < .05, Student
Newman-Keuls and Dunn's Method) over the study period. However, topicals combined
with D-Aloe, the vehicle Aquaphor, and L-NAME improved the wound healing process
when compared with nitroglycerin alone (p < .05). CONCLUSIONS: D-Aloe appears to
have a wound-healing advancement factor that can reverse the effects of
petrolatum- and nitroglycerin-based products as observed in the remaining groups
when compared with nitroglycerin alone. It appears that D-Aloe's effect of
preventing dermal ischemia by reversing the effects of thromboxane synthetase
(TxA2) may act synergistically with NO or could be an oxygen radical scavenger.
PMID- 9395705
TI - Successful treatment of herpetic infections by autohemotherapy.
AB - Herpes zoster (shingles) affects a significant number of individuals over age 50.
To date, no satisfactory treatment has been available. The clinician author (JHO)
witnessed a dramatic response of a shingles patient to autohemotherapy: the pain
was completely relieved and lesions gone within 5 days with no recurrence of
either. Treatment of other herpetic patients then began with autohemotherapy.
Twenty-five patients with herpes were given an autologous blood transfer of 10 mL
of blood from the antecubital vein into the gluteal bundle and followed for
clinical signs. A 100% favorable response occurred in 20 patients who received
autohemotherapy within 7 weeks of the onset of clinical signs and 1 other who
received autohemotherapy at a 9-week interval. No untoward signs or symptoms of
the treatment occurred. Autohemotherapy has been demonstrated to be effective in
elimination of clinical sequelae in these cases of herpes infections and these
results justify further rigorous clinical investigation.
PMID- 9395706
TI - When conventional treatment is not enough: a case of migraine without aura
responding to homeopathy.
AB - A case of migraine without aura is reported, unresponsive to five years of
treatment with very well indicated conventional therapies, which are listed in
detail. Consultation with a homeopathic physician, who also has extensive
experience in diagnosis and treatment of headache disorders, leads to the
prescription of a single homeopathic remedy which was absolutely effective for
the condition. This case is offered as an open, admittedly retrospective study,
comparing the best of conventional migraine therapy with appropriate homeopathic
therapy in the same patient.
PMID- 9395707
TI - Diarrhea and human immunodeficiency virus: Western and Eastern perspectives
[corrected].
AB - Sixty percent of patients with human immunodeficiency virus (HIV) in the United
States and 90% throughout the world will have diarrhea at some point in their
illness. This article provides an introductory exploration and discussion of
Western and Eastern perspectives of chronic diarrhea in patients with HIV.
Western etiologies and treatment approaches, as well as Eastern views from
traditional Chinese medicine pathogenesis and treatment principles involving
acupuncture and moxibustion are presented. Whereas their interpretations of the
causes of diarrhea are different, both the East and West have something to offer
patients with this distressing symptom. Further exploration and clinical research
is needed in this area.
PMID- 9395709
TI - Segment therapy: the effects of ultrasound and benzocaine spray in the treatment
of contractures and spasticity.
AB - According to Krusen's Handbook of Physical Medicine and Rehabilitation, topical
application of ultrasound exerts only an indirect and adjunctive effect as deep
heat treatment. In support of this idea the extensibility of an isolated tendon
in a heated water bath is described. The significance of this experiment as a
biological phenomenon has never been critically examined. In this article the
existence of a segmental reflex is proposed. Such a segmental paradigm is in
keeping with the segmental organization and evolution of the locomotor system. It
is further suggested that ultrasound and related therapy, if applied segmentally,
may have a curative effect.
PMID- 9395708
TI - HIV-related diarrhea: urgent need for a reasoned holistic response.
PMID- 9395710
TI - Directory of Databases for research into alternative and complementary medicine.
AB - This Directory of Databases with significant holdings of primarily bibliographic
references to complementary and alternative medicine research resources has been
compiled to facilitate access to the widely scattered data and literature. The
Directory is directly accessible from the Web site of the Richard & Hinda
Rosenthal Center for Complementary and Alternative Medicine at Columbia
University's CPMCNet (http://cpmcnet.columbia.edu/dept/rosenthal/). General
selection criteria and a brief description of content, access, or contact details
are given for each of the 56 databases. Thirty-five of the databases are
available online over the Internet and of these, 17 are freely, publicly
available. There are 13 search services and a further 8 databases available in a
variety of formats.
PMID- 9395711
TI - The Cochrane Collaboration and evidence-based complementary medicine.
PMID- 9395712
TI - Follistatin and its role as an activin-binding protein.
AB - Follistatin (FS), a specific binding protein for activin, neutralizes the diverse
actions of activin by forming an inactive complex with activin. FS is a monomer
derived from two polypeptide core sequences of 288 (FS-288) and 315 (FS-315)
amino acids originated from alternatively spliced mRNA. We purified six molecular
forms of FS from porcine ovaries. Their structural differences were caused by
truncation of the COOH-terminal region and/or the presence of carbohydrate
chains, resulting in the formation of FS-288, FS-315 and FS composed of 303 amino
acids (FS-303) in various forms of glycosylation on the two potential Asn-linked
glycosylation sites. All six molecular species have almost the same activin
binding activity (Kd = 540-680 pM). By contrast, the COOH-terminal truncated
form, FS-288, showed much higher affinity for heparan sulfate proteoglycans of
the cell surface than FS-303, whereas the intact form of FS, FS-315, had no
affinity. Furthermore, FS-288 more effectively blocked the suppression of
follicle-stimulating hormone (FSH) secretion from rat pituitary cells by activin.
This implies that activin binds to the cell surface through FS-288 which adheres
to the cell surface. To clarify the physiological role of cell-associated FS, we
then investigated the binding of activin to cell-associated FS and the fate of
cell surface-bound activin and FS using primary cultured rat pituitary and
ovarian granuloma cells. When the cells were incubated with 125I-activin A in the
presence of FS-288 or 315, the binding of activin A to the cell surface was
promoted much more markedly by FS-288 than by FS-315. The amounts of
radioactivity recovered in trichloroacetic acid-soluble fractions (degraded
activin) from the incubation medium were greatly increased by the addition of FS
288. This increase was abolished by heparan sulfate, monensin (an endocytosis
inhibitor), chloroquine (a lysosome function inhibitor) and several lysosomal
enzyme inhibitors. These results suggest that cell-associated FS-288 accelerates
the internalization of activin into the cells, leading to its degradation by
lysosomal enzymes, and that cell surface-associated FS therefore plays a role in
the clearance system of activin.
PMID- 9395713
TI - Tumor suppressor genes in human lung cancer.
AB - Lung cancer is the most common cause of cancer death in Japanese males, the
incidence having increased markedly in recent years. Carcinogen exposure such as
to tobacco-smoke and air pollution are associated with the probability of
developing lung cancer. Aquired somatic mutations play an important role in the
pathogenesis of environmentally induced lung cancers. Cytogenetic and molecular
analysis of lung tumors has made it possible to examine this hypothesis and to
search for candidate genes that may be targeted by chronic exposure to these
carcinogens. Early studies implicate several distinct chromosomal loci (3p, 9p,
13q, 17p, and others) and suggest sequential genetic events occur during the
initiation and progression of lung carcinogenesis. Several suppressor genes
including Rb (13q), P53 (17p), and P16 (9p) have been identified and cloned at
these chromosomal loci. The identification of putative tumor suppressor gene at
chromosome 3p is still under work. Understanding the interaction of P53, RB,
cyclins, and protein kinase inhibitors including P16 will be essential to the
development of the next generation of diagnostic and therapeutic studies for lung
cancer.
PMID- 9395714
TI - Peripheral blood stem cell transplantation; an update.
AB - Patients with a number of different malignancies have been treated with high-dose
chemotherapy and peripheral blood stem cell transplantation (PBSCT). PBSC already
replaced bone marrow as the source of autologous hematopoietic progenitor
support. This is due to ease of collection, rapid engraftment and less
possibility of tumor cell contamination in the graft. Furthermore, allogeneic
transplantation of granulocyte colony-stimulating factor (G-CSF) mobilized PBSC
is now being increasingly performed. Recent advance of clinical PBSCT and new
strategies are stressed in this review. New strategies include CD 34+cell
purification, ex vivo expansion of PBSC and PBSC as a target cell for gene
therapy. Major future advance may occur better understanding of the mechanism of
mobilization and the biology of PBSC.
PMID- 9395715
TI - Cathepsin B-inhibitor promotes the development of Th1 type protective T cells in
mice infected with Leishmania major.
AB - BALB/c mice are genetically susceptible to infection with Leishmania major (L
major). When such mice infected with L. major were treated with specific
inhibitors of cathepsin B, a lysosomal cysteine protease that digests exogenous
antigenic proteins, the mice acquired resistance against L. major infection. T
cells from these mice produced large amounts of IFN-gamma and low amounts of IL-4
as compared with those of untreated BALB/c mice. In addition, the mice treated
with cathepsin B inhibitor produced a high titer of IgG2a specific antibodies and
only low titers of IgG1 and IgE antibodies. This type of response is in contrast
with the high specific IgG1 or IgE antibody responses which are the usual
antibody responses in BALB/c mice infected with L. major. These findings indicate
that cathepsin B may be critically involved in processing antigens of L. major to
promote exclusively the development of Th2 type CD 4+T cell responses.
PMID- 9395716
TI - Visual evoked potential and electroencephalogram of healthy females during the
menstrual cycle.
AB - Flash visual evoked potential (VEP) and electroencephalogram (EEG) changes during
the menstrual cycle were studied using healthy females having regular
menstruation, with 21 at the follicular phase (FP) and 23 at the luteal phase
(LP). The following results were obtained. (1) The waveforms of Group Mean VEPs
of both groups had approximately similar triphasic contours, consisting of 16
components of P 1-N 8 up to 500 msec of latency. (2) Latencies tended to be
longer in LP. (3) Interpeak amplitudes tended to be larger in LP, and one VEP
interpeak amplitude (P 5-N 7) of long latency component was significantly larger
at LP after eliminating the effect of body height by ANCOVA for 2 CH. (4)
Quantitative analysis of EEGs between FP and LP resulted in a tendency for
increased alpha, and decreased beta power % at LP. Since estrogen increases the
VEP amplitude, and decreases the VEP latency and the alpha activity of EEGs, the
large VEP amplitude, the tendency for prolonged VEP latency, and the tendency for
increased alpha power % at LP observed in this study indicate that the VEP
amplitude at LP reflects the effect of estrogen, and that the VEP latency and
EEGs at LP reflect the effect of progesterone.
PMID- 9395717
TI - Bile-induced DNA strand breaks and biochemical analysis of bile acids in an
experimental model of anomalous arrangement of the pancreaticobiliary ducts.
AB - A canine experimental model for the anomalous arrangement of the
pancreaticobiliary ducts (APBD) was made to investigate the effects of bile acids
on carcinogenesis. Seven adult mongrel dogs underwent dorsal pancreatico
cholecystostomy to serve as a functional model for APBD, and six dogs underwent
the same procedure with the pancreatic duct ligated as a control group. Bile from
the gallbladder was taken 14 months after surgery for bile acid analysis by HPLC.
DNA strand breaks in HeLa cells induced by the bile were also investigated in
situ by nick translation method. As a result, the fraction of cholic acid tended
to be lower, and that of deoxycholic acid slightly higher in APBD-dogs (N.S.).
The ursodeoxycholic acid percentage in APBD-dogs significantly decreased compared
with that in the control and normal dogs (p < 0.05). Extremely high frequency of
DNA strand breaks was shown in only two out of seven APBD-dogs. In those two
dogs, the cholic acid percentage decreased and that of deoxycholic acid increased
extremely. These findings suggest that the alteration of the bile composition in
APBD caused frequent DNA strand breaks and repair which might lead to gene
mutation and biliary tract carcinoma.
PMID- 9395718
TI - Interleukin-8 in bronchoalveolar lavage fluid of patients with diffuse
panbronchiolitis or idiopathic pulmonary fibrosis.
AB - This study was designed to clarify the contribution of IL-8 as a specific
neutrophil chemotactic factor in the human respiratory tract in various pulmonary
diseases. The neutrophil chemotactic activity (NCA), neutrophil counts and IL-8
concentration in the bronchoalveolar lavage fluid (BALF) obtained from normal
volunteers (NV), control patients (CP), patients with diffuse panbronchiolitis
(DPB) and patients with idiopathic pulmonary fibrosis (IPF) were examined.
Neutrophil counts, NCA and IL-8 concentration in BALF obtained from patients with
DPB or IPF was significantly higher than that from NV or CP. The IL-8
concentration correlated with neutrophil count and also correlated with NCA in
BALF from patients with IPF, whereas there was no correlation between these
factors in BALF from DPB. These results suggest that the contribution of IL-8 to
neutrophil accumulation of the lower respiratory tract is different between IPF
and DPB.
PMID- 9395719
TI - Thrombin stimulates platelet-derived growth factor release by alveolar
macrophages in rats--significance in bleomycin-induced pulmonary fibrosis.
AB - Thrombin is a multifunctional enzyme generated at sites of vascular injury, and
is known to be increased in the lungs in some types of fibrotic lung disease. In
this study, to determine whether thrombin is associated with fibroblast growth
and pulmonary fibrosis in these disorders, we examined whether a growth factor
for fibroblasts (platelet-derived growth factor, PDGF) was released by thrombin
stimulated alveolar macrophages (AM). The culture supernatants of rat AM
stimulated with 1 or 10 U/ml of thrombin showed a significant increase in
fibroblast growth-stimulating activity (FGA). Pretreatment of the AM supernatant
with anti-PDGF-AA antibody significantly decreased the FGA, but pretreatment with
anti-PDGF-BB antibody did not. The supernatants of AM stimulated with thrombin
also increased the growth of fibroblasts from the lungs of rats with bleomycin
induced lung injury. These results indicate that thrombin stimulates AM to
release PDGF-AA, which is responsible, at least in part, for fibroblast growth
and the development of pulmonary fibrosis in some types of fibrotic lung disease.
PMID- 9395720
TI - Comparison of energy metabolism in insulin-dependent and non-insulin-dependent
diabetes mellitus.
AB - To compare the metabolic consequences of insulin-dependent diabetes mellitus
(IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), glycemic control and
energy metabolism were evaluated in 18 children displaying IDDM and 19 NIDDM
adult patients. With rising concentrations of fasting blood glucose (FBG),
hemoglobin A1C and free fatty acid, the percentage of the ratio of resting energy
expenditure (REE) to predicted REE expressed as %REE increased and the
respiratory quotient (RQ) decreased. The linear regression between RQ and FBG
showed the same gradient in IDDM and NIDDM although the RQ in IDDM was always
0.07 lower than that in NIDDM given various FBG concentrations. Those patients
whose RQ values were less than 0.7, indicating ketone body production, included 8
(44%) IDDM and 2 (11%) NIDDM patients. These results may explain the relatively
greater manifestation of ketoacidosis in IDDM.
PMID- 9395721
TI - Effect of K+ channel openers on K+ channel in cultured human dermal papilla
cells.
AB - Minoxidil sulfate and pinacidil, well-known activators of the ATP-sensitive K+
(KATP) channel, induce hair growth in clinical studies. The opening of K+
channels is thought to be an important mechanism in the regulation of hair
follicles. In the present study, we used the patch clamp technique to
characterize the K+ channels and tested the effect of K+ channel openers on K+
channels in cultured human dermal papilla cells. In dermal papilla cells, the
Ca(2+)-activated K+ (KCa) channel with large conductance (179.3 +/- 13.1 pS in
symmetrical 150 mM K+ solutions, n = 9) was dominant and we could not observe
KATP channels in cell-attached and inside-out patches. In addition, minoxidil and
pinacidil failed to activate KATP or KCa channels. In inside-out membrane
patches, the channel was blocked by 10 mM tetraethylammonium ion, 2 mM 4
aminopyridine to the cytosolic face of the membrane or by lowering Ca2+ using 10
mM EGTA, but not by glibenclamide. In the cell-attached patch configurations,
extracellular application of 1 mM sodium nitroprusside, a nitrovasodilator,
activated the KCa channel. Methylene blue (2 mM) inhibited channel activation by
sodium nitroprusside. Extracellular application of 20 mM dibutyryl cGMP activated
the KCa channel, suggesting that channel activation is mediated by cGMP.
Nitrovasodilators, which have no effect on hair growth, now appear to activate
KCa channels in dermal papilla cells. These results suggest that increased K+
permeability itself in dermal papilla cells may not be sufficient for promotion
of hair growth.
PMID- 9395722
TI - Effect of evodiamine on catecholamine secretion from bovine adrenal medulla.
AB - The effect of evodiamine on catecholamine secretion from bovine adrenal medulla
was investigated. Evodiamine, a bioactive component isolated from dry unripened
fruit of Evodia rutaecarpa Bentham, was found to stimulate the secretion of
catecholamine from perfused bovine adrenal medulla at a concentration of 10
microM and its effect persisted for at least 30 min. This stimulatory effect of
evodiamine was abolished by omission of Ca2+ from the perfusion fluid. Evodiamine
(0.1-10 microM) markedly enhanced the secretion of catecholamine from the adrenal
medulla induced by acetylcholine (100 microM or high K+(56 mM). The secretion of
catecholamine was promptly enhanced by acetylcholine or high K+, but returned to
the control level on treatment for 20 min. However, when evodiamine was added to
the perfusion fluid after acetylcholine or high K+ stimulation for 10 min, the
secretion of catecholamine again increased greatly. These results indicate that
evodiamine not only stimulated the secretion of catecholamine from bovine adrenal
medulla but also reversed insensitivity of these cells to acetylcholine or high
K+ stimulation.
PMID- 9395723
TI - Estimation of free calcium levels after thyroidectomy.
AB - Total calcium is routinely measured after thyroidectomy in a clinical setting,
while the measurement or calculation of the free calcium level is not generally
performed. We reviewed total and free calcium levels in patients who underwent
lobectomy (n = 15), subtotal thyroidectomy (n = 15) and total thyroidectomy (n =
15). Postoperative total calcium levels decreased significantly in comparison to
preoperative levels in all thyroidectomies (p < 0.01), and this fall was
significantly related to the extent of surgery (p < 0.01). In contrast, there was
no significant difference between preoperative and postoperative free calcium
levels in patients undergoing lobectomy, although we found a decrease in free
calcium levels after both subtotal and total thyroidectomy. Total protein levels
decreased regardless of the type of operation. Serum total calcium levels were
thought to be altered by serum protein levels through the change of protein-bound
calcium levels. When examined for free calcium levels, some patients were
administered unnecessary calcium supplementation because hypocalcemia had been
judged from the total calcium level. Since the wrong diagnosis may be given with
regard to hypoparathyroidism by measurement of total calcium levels alone, we
propose that free calcium levels should be routinely measured or calculated after
thyroidectomy.
PMID- 9395724
TI - Age-related increase of autoantibodies to interleukin 1 alpha in healthy Japanese
blood donors.
AB - Although autoantibodies to interleukin-1 alpha (IL-1 alpha autoantibodies) are
known to be present in sera of apparently healthy humans, their frequency of
occurrence and significance are unclear. To determine the prevalence of
detectable IL-1 alpha autoantibodies in normal human blood, we screened the
plasma of blood donors (6290 subjects: 3977 men and 2313 women, ages 16 to 64 yr)
by a radioimmununoassay which we developed using a method that could detect over
5 ng/ml. Moreover, we investigated immunoglobulin class of IL-1 alpha
autoantibodies and also their function. IL-1 alpha autoantibodies were detected
in 14.6% of the 6290 donors. Their frequency was higher in males than females
(16.6% vs. 11.2%, p < 0.01) and increased with age in both sexes. The proportion
of subjects with a high IL-1 alpha autoantibodies titers also increased with age.
We showed that IL-1 alpha autoantibodies were of the IgG class and that they had
neutralizing function to IL-1 alpha by receptor assay. Neutralizing activity was
only shown in plasma with concentration of IL-1 alpha autoantibodies, the level
of which was over 1000 ng/ml. The affinity of the IL-1 alpha autoantibodies in
plasma was between 2.1 x 10(-10) and 1.2 x 10(-9) M (mean 6.4 x 10(-10)M). Our
results provide a basis for comparison with IL-1 alpha autoantibodies prevalence
between healthy states and disease states, and suggest that IL-1 alpha
autoantibodies may play a significant role in modulating the effects of excessive
IL-1 alpha at local site or in systemic regions.
PMID- 9395725
TI - Two siblings with vitamin B6-nonresponsive cystathionine beta-synthase deficiency
and differing blood methionine levels during the neonatal period.
AB - We present two siblings with vitamin B6-nonresponsive homocystinuria due to a
deficiency of cystathionine beta-synthase who had different levels of methionine
in the blood during the neonatal period, even though they had the same genetic
defect. One of them was missed in the screening of newborns for homocystinuria.
Special care should be taken in screening neonates for homocystinuria using the
blood level of methionine.
PMID- 9395726
TI - Immunological functions of adult T cell leukemia cells of a patient complicated
with synchronous double primary gynecologic cancer.
AB - A patient with triple malignancies is reported, who presented cervical cancer,
vulvar cancer and adult T cell leukemia (ATL). ATL was diagnosed as a smouldering
type, because antibody to human T cell leukemia virus associated antigen (ATLA)
was positive with a titer of 1:160. Although her malignant cells had an OKT 4+8
3+Tac+ phenotype, the cells did not display helper T cell functions. Namely they
showed no response to Phytohemagglutinin (PHA) and Interleukin 2 (IL-2) and
suppressed the PWM driven IgG synthesis of B cells obtained from healthy donor.
They did not produce IL-2 by stimulation with PHA and phorbol myristate acetate
(PMA). Furthermore, these ATL cells were producing IL-2 inhibitor like factors.
As synchronous triple malignancies are extremely rare, two gynecologic cancers
seem to ascribe to the suppressing state of the immunosurveillance mechanism by
viral infection.
PMID- 9395727
TI - A case of episodic angioedema associated with eosinophilia.
AB - BACKGROUND: Gleich et al. first described 4 cases of episodic angioedema
associated with eosinophilia as a distinct entity in 1984. Since then, several
cases of this disorder have been reported in the United States, Europe and Japan.
OBSERVATIONS: We report a case of a 22-year-old pregnant Japanese woman with this
disorder. She had no fever and her general condition was good except the
angioedema which was limited to her limbs. During an acute episode, her white
blood cell count increased to 29,500/mm3 with 50% eosinophils, following an
elevated serum interleukin-5 (IL-5) level. Spontaneous resolution occurred in 1
month after the onset. In a 5 month follow-up, no evidence of cardiac or other
visceral organ involvement was found, and no recurrence occurred. CONCLUSIONS:
Our case, combined with those reported in the literature, suggests that Japanese
cases of episodic angioedema associated with eosinophilia differ from Caucasian
cases in clinical symptoms and some other points.
PMID- 9395728
TI - From molecular genetics to diagnosis and gene therapy.
PMID- 9395729
TI - Genes involved in oncogenesis.
PMID- 9395730
TI - Diagnostic molecular genetics.
PMID- 9395731
TI - Gene therapy for the hemophilias.
AB - There are many lines of evidence that suggest the eventual success of gene
therapy as a treatment strategy for hemophilia. Because current treatment
protocols using plasma-derived or recombinant proteins are far from ideal, the
safe and efficient substitution of the defective gene by a normal copy of the
gene, or at least its addition, would be of great benefit to the patient and may
even be a potential cure. However, the construction of efficient gene therapy
vehicles has proven quite difficult in the past and, so far, there is no system
that promises to have all the desired features without any serious disadvantages.
In general, either the levels of transgene expression are too low (because of the
low titers achieved during the generation of the virus) or shortlived (e.g.,
because of the specific shut-off of the transferred promoter) as is often seen
with retroviruses, or in the case of adenoviral vectors, expression is limited
because of a strong immune response of the host. Clearly, much work remains to be
done to optimize these promising though still imperfect vector systems. In the
case of adenovirus, the development of less immunogenic vectors or in vivo
modulation of the host immune system may hold promise for improvements. Reports
by Yang et al. (1995) and Kay et al. (1995) are promising steps in the direction
of immunomodulation. Both attenuate the immune reaction to the adenoviral vector
by simultaneous application of either an interleukin or an immunoglobulin,
respectively. When IL-2 was administered, the amounts of IgA were reduced and
successful administration of a second dose of virus was possible. When CTLA4-Ig,
an immunoglobulin that blocks the second signal during antigen presentation, was
administered, a markedly prolonged expression of the transgene resulted. In vivo
trials with AAV vectors have been carried out for some diseases (Flotte et al.,
1993; Kaplitt et al., 1994) but not for hemophilia. Advances in high-titer AAV
vector preparation will make this approach more feasible. The pace continues to
quicken in the development of nonviral modes of gene delivery (Perales et al.,
1994). Although these results are encouraging for the future of gene therapy as a
treatment for genetic diseases, much work remains to be done to make this
potential alternative a reality for treatment of hemophilia.
PMID- 9395732
TI - Genes controlling retroviral virulence.
PMID- 9395733
TI - Mapping animal genomes.
PMID- 9395734
TI - The canine genome.
PMID- 9395735
TI - The contribution of biological maturation to the strength and motor fitness of
children.
AB - The interrelationships among skeletal maturity, body size, strength and motor
fitness were examined in American children 7-12 years of chronological age (CA).
A total of 391 Black (184 boys, 207 girls) and 349 White (193 boys, 156 girls)
children participated in the study. Biological maturity was assessed by the
Tanner-Whitehouse II method, 20 bone skeletal ages (SA). Strength items included
right and left grip strength, and pushing and pulling strength of the shoulders.
Motor fitness items included a 35-yard dash, the standing long jump, and softball
throw for distance. The standardized residuals of SA on CA (AG) were used to
represent the effects of SA, independent of CA. Interaction terms were also
computed by multiplying standardized values of stature (ST), body mass (MA), and
AG together in all combinations. Regression analyses showed that the strongest
predictor of strength was MA, while AG was the best predictor of motor
performance. The interaction terms were also significant predictors of
performance, explaining between 2% and 9% of the variance in 19 of the 41
significant regressions. The results highlight the complexity of the
interrelationships among body size, biological maturation, strength and motor
fitness. The effects of SA in children 7-12 years of age are expressed mainly
through body size, but SA apparently influences motor fitness more so than
muscular strength.
PMID- 9395736
TI - Is there an independent association between parity and maternal weight gain?
AB - The independent associations between parity and maternal body mass index (BMI),
and between parity and maternal weight gain, were investigated using a
combination of cross-sectional and longitudinal analyses based on a
retrospective, repeat-pregnancy study that examined the change in maternal body
weight from the beginning of one pregnancy to the beginning of the next. A group
of 523 multiparous women who had been weighed regularly during pregnancy, and
none of whom had fallen pregnant less than 12 months after the birth of their
previous child, were examined. Sociodemographic, behavioural, medical, obstetric
and perinatal data, together with antenatal measurements of maternal body weight
and height, were abstracted from each mother's obstetric notes. Parity was found
to be independently associated with maternal BMI (p < 0.001), gestational weight
gain (p < 0.001) and interpregnancy weight gain (p = 0.032). Women of different
parities were found to be at differential risk of long-term weight gain for two
reasons. First, primiparous women are at risk of long-term weight gain because
they gain the most weight during pregnancy, and high gestational weight gain is
in itself a risk factor for long-term weight gain. Second, women of higher parity
(4+) are at risk of long-term weight gain because they gain more weight in
association with pregnancy, irrespective of the amount of weight they gain during
their pregnancies. For women of parity 3 or less, the association between
maternal body weight and parity appears to be the result of cumulative weight
gained during successive pregnancies. For women of greater parity, the
association between maternal body weight and parity is partly the result of
cumulative excess gestational weight gained during successive pregnancies, and
partly the result of gaining more weight from the beginning of one pregnancy to
the next at later pregnancies.
PMID- 9395737
TI - Nutritional status and age at menarche of Senegalese adolescents.
AB - Growth and maturation during adolescence has not been well described in rural
African populations, although it may represent the missing link between high
levels of preschool stunting and nearly 'normal' adult heights. In 1995 the homes
of subjects aged 10.3-17.5 years, living in a rural area of Senegal, were
visited, and all adolescents present, 1527 boys and 1126 girls, were included in
the analysis. A number of girls were absent because they worked in the capital
city Dakar. Resident girls (n = 705) had significantly higher means than boys for
all anthropometric variables (weight, body mass index, arm circumference and
muscle arm circumference, triceps and subscapular skinfolds), except for height
and head circumference. Girls who had just returned from seasonal migration to
Dakar (n = 415) were, on average, 2 kg heavier, but not taller, than resident
girls (p < 0.0001). The girls fell off in height from 11 to 13 years compared to
the NCHS reference and then 'caught up' until the age of 17, while boys fell off
during the entire age span. Mean age at menarche was estimated at 16.1 years (95%
fiducial CI: 15.8-16.4) from status quo data by probit analysis. No significant
difference was found between residents and migrants. Postmenarcheal girls had
better nutritional status than premenarcheal girls in terms of height, weight,
body mass index, percentage body fat and arm muscle circumference (p < 0.0001).
In conclusion, puberty, as assessed by age at menarche, is delayed by about 3
years in this population, probably due to malnutrition.
PMID- 9395738
TI - Body water distribution in highlanders versus lowlanders.
AB - Acute exposure to high altitude produces characteristic changes in body water
distribution from which acclimatized individuals seem to be spared. However, it
has been suggested that body water distribution may be different in highlanders
(HL) as compared to lowlanders (LL). We studied the distribution of total body
water (TBW) between extracellular water (ECW) and intracellular water (ICW) in a
group of 20 HL (3200 m above sea level) versus one of 20 LL (900 m above sea
level). Subjects were matched for ethnic group (Kirghiz), sex (male), weight
(Wt), height and body mass index. TBW:Wt and ECW:TBW were not different in HL as
compared to LL (mean +/- SD, 58.5 +/- 5.0% versus 56.0 +/- 4.2% and 40.5 +/- 4.2%
versus 40.7 +/- 2.2%; p = n.s. for both). This study does not support the
hypothesis that body water distribution is different in HL as compared to LL.
PMID- 9395739
TI - Methodological aspects of short-term knemometry in the assessment of exogenous
glucocorticosteroid-induced growth suppression in children.
AB - During recent years knemometry has been introduced for short-term assessment of
the growth-suppressive effect of exogenous glucocorticosteroids in children. The
aim of the present paper is to review methodological aspects of short-term
knemometry used for this purpose. Knemometry has proven a highly accurate and
reproducible method for assessment of short-term growth suppression in
populations of children treated with exogenous glucocorticosteroids. Randomized,
double-blind crossover and parallel designs applying consistent measurement
intervals can be used. Confounding influences on the growth results from possible
inter-group differences in spontaneous growth velocities are reduced in the
crossover design. Glucocorticosteroid-induced knemometric growth suppression
seems to reflect suppressive effects on soft tissue and bone components in the
lower leg. In children treated with systemic glucocorticosteroids a shortening of
the lower leg, which may be due to a reduction of the water content in the soft
tissue, may confound the growth assessment. Suppressed short-term growth rates
should be considered to have a poor correlation with long-term growth, though
prospectively planned, controlled studies of the relation are needed in
glucocorticosteroid-treated children.
PMID- 9395740
TI - Anaemia- and malaria-attributable low birthweight in two populations in Papua New
Guinea.
AB - We studied 7300 singleton births in the highlands and 4881 in coastal Papua New
Guinea in order to examine the separate contribution of anaemia or malaria to low
birthweight. The highland sample was selected from a non-malarious area (Goroka)
and the coastal sample from an area with perennial malaria transmission (Madang).
There was an approximately three-fold increased risk of low birthweight (< 2500
g) in live-births in Madang compared to Goroka. The prevalence of anaemia in the
two areas was strikingly different, with 29.2% of Goroka and 89.0% of Madang
women anaemic. There was a trend towards increased low birthweight with
decreasing haemoglobin levels in both areas, but this was significant only for
Madang. It was assumed that for a given haemoglobin level the increased low birth
weight percentage in Madang compared to Goroka was due to malaria exposure, and
on this basis relative risk values were estimated for the effect of malaria
exposure on low birthweight. Using this approach separate estimates for anaemia
and malaria population-attributable risk for low birth weight in Madang were
calculated. These indicated that up to 40% of low birthweight babies born in
malarious areas may be attributable to malaria and less than 10% attributable to
severe anaemia (Hb < 7.0 g dl-1). The magnitude of the malaria effect estimated
in this analysis places a high priority on malaria control in pregnancy as a
strategy for improving birthweight and child survival.
PMID- 9395741
TI - Weight, height and arm circumference of children under 5 in the district of
Mbarara, south-west Uganda.
AB - This paper describes the growth of weight, height and arm circumference (MUAC) in
children aged under 5 years and living in the south-west area of Uganda. The
survey was carried out in 1988 and was based on a random sample of 31 villages of
the Mbarara district. A total of 4320 children were measured by a team of 20
trained assessors. From these children a reference group was made up of the 3654
known to be still alive after 1 year. Growth charts were drawn by smoothing the
non-parametric percentiles of the distribution of height, weight and MUAC for age
and of weight for height. The anthropometric characteristics of children living
in south-west Uganda differ considerably from those of children on which the
FELS/NCHS/WHO references are based. Between 1 and 5 years of age, the median
difference between Mbarara and American children increases from 1.5 to 3 kg for
weight, from 4 to 7 cm for height, and from 1.5 to 2.5 cm for MUAC. These results
imply that the use of the international reference may lead to low specificity and
predictive values in screening malnourished children living in an underdeveloped
country such as Uganda. The charts here proposed may apply to populations with a
lifestyle similar to that of inhabitants of south-west Uganda, both from a
nutritional and socioeconomic viewpoint.
PMID- 9395742
TI - Longitudinal analysis of growth in children with idiopathic short stature.
AB - In this study the growth curves of 229 children (145 boys, 84 girls ) with
idiopathic short stature (ISS) were analysed in three ways: (1) we compared the
results of longitudinal modelling by means of Karlberg's ICP model with those of
a cross-sectional analysis; (2) we studied to what extent an individual changes
his/her height standard deviation score (SDS) position during childhood; and (3)
we constructed height velocity curves for children with ISS using Cole's LMS
method, and compared these with the British references. During childhood the
difference between the average longitudinal and the cross-sectional height curves
was less than 1 cm and the spread was almost identical. The average change in
height SDS during childhood was not different from zero, indicating that in
general growth of children with ISS was well canalized. The individual change in
height SDS position during childhood was within 0.6 SDS for a follow-up of 1
year, increasing to 1.9 SDS for a follow-up of 7 years. During childhood mean
height velocity was about 1 cm/year lower than that of the British reference.
With respect to the pubertal growth spurt the maximum height velocity took place
1 year later, and was 0.6 cm/year lower than the British reference in boys as
well as girls. We conclude that spontaneous growth of children with ISS
adequately described by a cross-sectional curve.
PMID- 9395743
TI - Age variations in sibling correlations for height, sitting height and weight.
AB - Familial correlations for height, sitting height and weight have been studied in
a sample of 1278 siblings for the Biscay province (Basque Country), aged 4+ to
24+ years. The data have been internally standardized according to sex and age of
individuals. The degree of resemblance among sibling has been expressed by
intraclass correlation coefficients. The total sample has been divided into three
age categories: < 12 years, 12-15 years, and > or = 15 years, in order to examine
the effect of age on sibling correlations. In general, changes with age have been
observed: sibling correlations for height show a clear upward trend through the
considered growth period, reaching a value of 0.48 from 15 years of age. Intra
correlations for weight show a slight downward trend with age. Sitting height
shows a rather low correlation before 12 years of age, but equally high values in
the other two ranges of age (0.48 and 0.47, respectively). This study confirms
that the sibling resemblance for the analysed trait fluctuated through the growth
period--height and sitting height showing similar patterns of variation with age-
and that, after puberty, the degree of genetic determination is higher for bone
measurements than for weight.
PMID- 9395744
TI - Pathophysiology of portal hypertension.
AB - Portal hypertension is a common clinical syndrome associated with chronic liver
diseases and is characterized by a pathological increase in portal pressure.
Increase in portal pressure is because of an increase in vascular resistance and
an elevated portal blood flow. The site of increased intrahepatic resistance is
variable and is dependent on the disease process. The site of obstruction may be:
pre-hepatic, hepatic, and/or post-hepatic. In addition, part of the increased
intrahepatic resistance is because of increased vascular tone. Another important
factor contributing to increased portal pressure is elevated blood flow.
Peripheral vasodilatation initiates the classical profile of decreased systemic
resistance, expanded plasma volume, elevated splanchnic blood flow and elevated
cardiac index. The elevated portal pressure leads to formation of portosystemic
collaterals and oesophageal varices. Pharmacotherapy for portal hypertension is
aimed at reducing both intrahepatic vascular tone and elevated splanchnic blood
flow.
PMID- 9395745
TI - Evaluation of patients with portal hypertension.
AB - Patients with suspected portal hypertension must first be evaluated by physical
examination, upper digestive endoscopy and ultrasonography with Doppler.
Moreover, the evaluation of patients with portal hypertension depends on the
cause of portal hypertension, the presence of complications and the specific
treatment considered. Haemodynamic assessment with measurement of the hepatic
venous pressure gradient is useful in confirming the origin of portal
hypertension. This technique is the 'gold-standard' for evaluating haemodynamic
treatments. Splanchnic and systemic circulation must also be measured.
Quantitative evaluation of the splanchnic territory by Doppler sonography and
other non-invasive investigations, may be performed. Further clinical studies
are, however, needed to determine their interest in portal hypertension.
PMID- 9395746
TI - Natural history. Clinical-haemodynamic correlations. Prediction of the risk of
bleeding.
AB - Promoting the development of oesophageal varices and ascites, portal hypertension
dominates the clinical course of cirrhosis. Varices appear in patients with
portal pressure gradient above 10 mmHg and enlarge in 10-20% within 1-2 years of
their detection. Bleeding occurs in patients with portal pressure gradient above
12 mmHg when the wall tension causes the rupture of varices, with an incidence of
about 10% per year. Indicators of bleeding risk are portal pressure gradient,
variceal pressure, large varices and liver dysfunction. Mortality per bleeding
episode is 30-50%. Among survivors 60% will rebleed and 30% will die in the
following year. The risk of rebleeding decreases in patients with spontaneous or
treatment induced reduction of portal pressure gradient or variceal pressure.
Ascites develops in almost all patients along the course of the disease. Median
survival after its appearance is less than 2 years. Less than 5% of cirrhotic
patients die without ascites or without a previous bleeding. Thus portal
hypertension is a major determinant of survival in cirrhosis.
PMID- 9395747
TI - Portal Hypertensive gastropathy.
AB - The term portal hypertensive gastropathy (PHG) defines a wide spectrum of diffuse
macroscopic lesions that appear in the gastric mucosa of patients with portal
hypertension. Histologically, these lesions correspond to dilated vessels in the
mucosa and submucosa in the absence of erosions or inflammation. Endoscopically,
the lesions are classified as mild when mosaic pattern or superficial reddening
are present, and severe when gastric mucosa appear with diffuse cherry red spots.
Mild lesions are highly prevalent (65-90%), whereas severe lesions are present in
only 10-25% of cirrhotic patients. The pathogenesis of PHG is not well known, but
both venous congestion related with raised portal pressure and increased gastric
blood flow seem to be crucial factors for its development. Variceal sclerosis may
contribute to the development or aggravation of the lesions. Bleeding is the
unique clinical manifestation of PHG, and occurs only in those patients with
severe lesions. During a 5-year follow-up, the risk of overt bleeding or chronic
bleeding, which induces anaemia, is 60 % and 90%, respectively, for patients with
severe PHG. Propranolol is the only pharmacological treatment that has been
proven useful in preventing bleeding from PHG. Porto-systemic shunts and liver
transplantation are also effective.
PMID- 9395748
TI - Pharmacological prevention of variceal bleeding. New developments.
AB - The introduction of pharmacological therapy has been one of the major advances in
the treatment of the complications of portal hypertension. Many drugs have been
shown to reduce portal hypertension in patients with cirrhosis. However, the most
widely used drugs and the only ones for which there is sufficient evidence, are
the beta-blockers. These drugs have been, up to now, the only accepted
prophylactic therapy for oesophageal variceal bleeding and are also an
alternative treatment to sclerotherapy or surgery to prevent variceal rebleeding.
A reduction in portal pressure gradient by beta-blockers below 12 mmHg or by more
than 20% of baseline values is associated with almost a total protection from
oesophageal bleeding. Such a marked response in portal pressure is only achieved
in some patients receiving propranolol. New pharmacological approaches with a
greater portal pressure reducing effect may improve the beneficial effect of
drugs in preventing variceal bleeding. The more promising approach is the
combined administration of beta-blockers and isosorbide-5-mononitrate, which has
been shown to potentiate the reduction in portal pressure and to be highly
effective in initial randomized clinical trials.
PMID- 9395749
TI - Endoscopic treatments for portal hypertension.
AB - Endoscopic treatments for bleeding gastro-oesophageal varices include injection
sclerotherapy, variceal obturation with tissue adhesives and variceal rubber band
ligation. Today, endoscopic treatments are not recommended for the primary
prophylaxis of variceal bleeding. Acute injection sclerotherapy remains a quick
and simple technique for the control of active bleeding from oesophageal varices.
Its efficacy may be improved by the early administration of vasoactive drugs.
Banding ligation is the optimal endoscopic treatment for the prevention of
rebleeding from oesophageal varices. The use of tissue adhesives and thrombin as
injectates to treat bleeding fundal gastric varices and oesophageal varices not
responding to vasoactive drugs or sclerotherapy is promising but needs further
assessment by means of randomized controlled trials.
PMID- 9395750
TI - Advances in drug therapy for acute variceal haemorrhage.
AB - Recent advances in the pharmacology of portal hypertension are reviewed, against
the background of existing knowledge and current clinical research. The most
recent trials are analysed, and conclusions made about the use of drugs in acute
variceal haemorrhage, as well as directions for further clinical trials and
research.
PMID- 9395751
TI - Transjugular intrahepatic portosystemic shunts (TIPS).
AB - Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure recently
introduced for the management of complications of portal hypertension. TIPS can
be placed in the liver with relative ease by a skilled radiologist with a low
risk of mortality. The major complications following the procedure are infection,
especially in patients undergoing emergency TIPS, intra-abdominal haemorrhage
from capsular punctures, and long-term problems related to encephalopathy and
stenosis of the shunt. Encephalopathy is more of a problem in older patients with
wide diameter shunts. Stenosis of the shunt is related to pseudo-intimal
hyperplasia, probably related to transection of bile ductules during placement of
the shunt. In view of the high rate of encephalopathy and stenosis following the
shunt, a careful follow-up of all patients, including ultrasonographic and
angiographic examination of the shunt, is mandatory. TIPS is used predominantly
for the control of acute variceal haemorrhage, prevention of recurrent variceal
bleeding, and refractory ascites when conventional treatment has failed. However,
the role of TIPS in the management of complications of portal hypertension still
awaits the outcome of clinical trials.
PMID- 9395752
TI - Surgery in portal hypertension.
AB - The role of surgery in portal hypertension remains a topic of debate. For the
past 100 years, various surgical procedures have been used to treat variceal
bleeding, refractory ascites, and end-stage liver disease. The past decade has
seen significant advances in pharmacotherapy, endoscopy, interventional
radiology, and surgery for the management of patients with portal hypertension.
Liver transplantation has come of age in the 1990s and is now an accepted therapy
for patients with end-stage liver disease. The wide array of management options
can complicate the decision making process and defines the need to evaluate these
patients fully. Factors such as the aetiology and extent of liver disease,
response to prior medical, endoscopic, and other interventional treatments, and
possibility of future liver transplantation must be considered. This manuscript
will review the history of surgical treatments of portal hypertension, describe
the surgical procedures with their advantages and disadvantages, and evaluate
their role in the elective and emergent settings.
PMID- 9395753
TI - Ascites and renal functional abnormalities in cirrhosis. Pathogenesis and
treatment.
AB - In the past few years, there have been important advances in the field of
pathogenesis and management of ascites and hepatorenal syndrome in cirrhosis. A
new pathogenic theory of ascites and renal dysfunction in cirrhosis has been
presented and previously ill-defined conditions, such as refractory ascites and
hepatorenal syndrome, have been defined precisely. The link between the diseased
liver and the disturbances in renal function and vasoactive systems is not
completely known, but a large body of evidence indicates that it consists of a
circulatory dysfunction that affects mainly the arterial circulation and is
characterized by an inability to maintain an effective arterial blood volume
within normal limits. The research on the mechanisms of this circulatory
dysfunction will give valuable information in the design of more
pathophysiologically oriented therapeutic approaches to the management of
ascites.
PMID- 9395754
TI - Hepatopulmonary syndrome: the paradigm of liver-induced hypoxaemia.
AB - The current chapter deals with the concept, clinical manifestations and
diagnostic tools of the hepatopulmonary syndrome (HPS) and highlights its most
salient pathophysiological, mechanistic and therapeutic aspects. Defined as a
clinical triad, including a chronic liver disorder, pulmonary gas exchange
abnormalities and generalized pulmonary vascular dilatations, in the absence of
intrinsic cardiopulmonary disease, this entity is currently growing in interest
with both clinicians and surgeons. The combination of arterial hypoxaemia, high
cardiac output with normal or low pulmonary artery pressure, and finger clubbing
in a patient with advanced liver disease should strongly suggest the diagnosis of
HPS. Its potential high prevalence together with failure of numerous therapeutic
approaches depicts a life-threatening unique clinical condition that may
dramatically benefit with an elective indication of liver transplantation (LT). A
better orchestration of the concepts of the pathophysiology of this lung-liver
interplay may foster our knowledge and improve the clinical management and
indications of LT.
PMID- 9395755
TI - Interferon therapy.
PMID- 9395756
TI - Atypical esophageal ulceration.
PMID- 9395757
TI - Kayexalate (sodium polystyrene sulphonate) in sorbitol associated with intestinal
necrosis in uremic patients.
AB - BACKGROUND: Kayexalate (sodium polystyrene sulphonate) in sorbitol is commonly
used to treat hyperkalemia in patients with renal insufficiency. Isolated case
reports and one recent large series have documented intestinal necrosis following
administration of kayexalate in sorbitol. METHODS: Two patients with luminal
kayexalate crystals associated with intestinal pathology were first identified in
the pathology department, and clinicopathological correlation was carried out.
RESULTS: Both patients were seriously ill, had prior cardiac surgery and were in
renal failure (uremic). Examination of autopsy and colonic resection showed
luminal kayexalate crystals associated with underlying mucosal necrosis,
submucosal edema and transmural inflammation. CONCLUSION: Although occurring in
complex clinical settings, the pathological findings provide additional evidence
that kayexalate in sorbitol may be associated with intestinal necrosis and
inflammation in uremic patients and that this may be a clinically and
pathologically under-recognized iatrogenic bowel injury.
PMID- 9395758
TI - A multicentre randomized controlled trial of recombinant interferon-alpha-2a in
the treatment of patients with chronic hepatitis C.
AB - Sixty-one chronic hepatitis C patients were randomly assigned to receive either 6
x 10(6) or 9 x 10(6) U of recombinant interferon-alpha-2a (IFN alpha-2a) six days
a week for the first two weeks of treatment, followed in both cases by 6 x 10(6)
U three days a week for the next 22 weeks. In the low dose group, 11 patients
showed a complete response maintained for at least six months, 12 responded but
then relapsed and nine did not respond; the corresponding figures in the high
dose group were 10, 15 and five patients, respectively. The differences between
groups are not statistically significant. Thus, this study provides no evidence
of therapeutic benefit from increasing the initial dose of IFN alpha-2a. In both
treatment groups, complete responders had significantly lower pretreatment viral
titres than nonresponders and were significantly more likely to be infected by
type 2a versus type 1b virus.
PMID- 9395760
TI - Helicobacter pylori: from bench to bedside.
AB - With the exponential increase in research in the field of Helicobacter pylori a
paradigm shift has occurred. It is now recognized that H pylori is a chronic
infection of the stomach causing inflammation. Some patients remain asymptomatic,
while others may develop dyspepsia, duodenal or gastric ulcer, gastric cancer or
a mucosa-associated lymphoid tissue lymphoma. However, the role of H pylori in
contributing to nonulcer dyspepsia or nonsteroidal anti-inflammatory drug
gastropathy remains controversial. An effective vaccine against H pylori is years
away. Major interest has focused on the questions "who should be investigated and
therefore treated" and "what is the latest gold standard for eradication of H
pylori"? In Europe, guidelines have been developed to help the practitioner
answer these important questions. Canadian guidelines will soon be available. For
persons with known peptic ulcer disease there should be unequivocal acceptance
that the good clinical practice of eradicating H pylori will result in
substantial savings in health care expenses. The original 'classical triple
therapy' (bismuth, metronidazole and tetracycline [BMT]) has now been surpassed
by the combination of a proton pump inhibitor (PPI) plus two antibiotics
(metronidazole plus clarithromycin; amoxicillin plus clarithromycin; or
amoxicillin plus metronidazole), each given twice a day for one week. In Canada,
the regimen of omeprazole plus one antibiotic (amoxicillin or clarithromycin) was
approved recently but gives an eradication rate that is lower than the current
target of 90%. According to the European (Maastricht) recommendations, if a
single treatment attempt with PPI plus two antibiotics fails, PPI plus BMT is
recommended.
PMID- 9395759
TI - Intravenous cyclosporine for severe attacks of ulcerative colitis: a survey of
Canadian gastroenterologists.
AB - A single randomized trial evaluated the use of intravenous cyclosporine treatment
for severe attacks of ulcerative colitis. The perceived efficacy and safety of
this intervention were measured through a survey of the membership of the
Canadian Association of Gastroenterology (CAG). METHODS: All CAG members were
mailed a survey with questions regarding their familiarity with the data
supporting the use of cyclosporine, their perception of the efficacy and toxicity
of the drug, and whether patients who fail conventional treatment should receive
this therapy. The proportion of respondents who had used cyclosporine to treat
severe ulcerative colitis was determined. RESULTS: One hundred and sixty-one
responses were received (34% response rate). Sixty-four per cent of respondents
were academic faculty members and 82% treated patients with severe colitis. Using
multivariate analyses, positive associations were found between the respondents'
age (P = 0.004) and subspecialty training in gastroenterology (P = 0.001), and
whether respondents treat patients with severe ulcerative colitis. Twenty-six per
cent of individuals had prescribed cyclosporine for this indication, of whom 88%
were in academic practice (P = 0.007). Over 90% of respondents believe that
further clinical trials are needed before cyclosporine becomes accepted as
standard therapy. CONCLUSIONS: Although the use of cyclosporine is measurable
among Canadian gastroenterologists, the majority believe that further clinical
trials are necessary before the drug is accepted as a standard therapy.
PMID- 9395761
TI - Osteomyelitis and osteonecrosis in inflammatory bowel disease.
AB - Osteomyelitis and osteonecrosis are skeletal disorders seen in patients with
inflammatory bowel disease (IBD). Osteomyelitis usually occurs in the pelvic
bones, especially in complicated Crohn's disease, presumably by direct extension
from a pelvic inflammatory mass, abscess or fistulous tract. Diagnosis of
osteomyelitis may be difficult and can lead to spinal extension of the septic
process with a resultant neurological deficit, including paraplegia.
Osteonecrosis or avascular necrosis has been reported in patients with either
ulcerative colitis or Crohn's disease, often, but not exclusively, during or
following steroid treatment. The disease is often multifocal, but its natural
history is unknown, especially if diagnosed early with modern imaging methods,
such as magnetic resonance. In IBD patients, the relationship between
osteonecrosis and steroid use is unknown. An adverse steroid effect on bones,
especially the femoral heads, may develop in some patients with IBD but, to date,
this hypothesis remains unproven. Critical evaluation of published data reveals
no consistent association between osteonecrosis and steroid treatment in IBD
patients.
PMID- 9395762
TI - Small bowel review: Part II.
AB - Significant advances have been made in the study of the small bowel. Part II of
this two-part review of the small bowel examines the early development and later
ageing of the small bowel; the effect of diabetes, alcohol, radiation and HIV on
the small bowel; enteral and parenteral nutrition; the brush border membrane and
enterocyte proliferation; and peptide hormones (including transforming growth
factors, motilin peptide YY and cholecystokinin).
PMID- 9395763
TI - Hans Selye, inflammatory bowel disease and the placebo response.
PMID- 9395764
TI - Colonic flora and fermentation: a new frontier for exploration.
PMID- 9395765
TI - Liposome uptake by human retinal pigment epithelial cells in culture.
AB - PURPOSE: To examine the internalization of liposomes containing various
phospholipids by human retinal pigment epithelial (RPE) cells in culture. The
internalization was compared to that exhibited by macrophages and fibroblast
cells. METHODS: The uptake into cells was monitored by using a non-degradable,
radioactive cholesterol-hexadecyl ether derivative and a pH-sensitive, water
soluble fluorescent dye. Variables tested to determine their effect on uptake
included time, phospholipid concentration, the presence or absence of serum in
medium and the presence or absence of cholesterol in the liposome bilayer. The
most avidly ingested liposome was tested to determine its ability to deliver a
liposome-dependent drug. RESULTS: Liposome uptake was time and concentration
dependent. Uptake for RPE was maximal in serum-free media, while the opposite was
true for the other cells tested. Cell survival following exposure to fluoroorotic
acid-containing liposomes correlated with the radioactive cholesterol-hexadecyl
ether and fluorescent dye uptake data. CONCLUSIONS: No single liposome carrier or
set of conditions tested appeared to be optimum for the delivery of a cytotoxic
agent to these three cell types. This bears consideration when designing
strategies for the prevention and treatment of intraocular proliferative diseases
such as proliferative vitreoretinopathy (PVR).
PMID- 9395766
TI - Quantitative study on regenerated retinal pigment epithelium and the effects of
growth factor.
AB - PURPOSE: To evaluate the integrity of damaged retinal pigment epithelium (RPE)
with normal neural retina in a rabbit model, and to examine the effects of basic
fibroblast growth factor (bFGF) on the damaged RPE. METHODS: A 3-port vitrectomy,
a retinotomy, and a retinal detachment were made in pigmented rabbit eyes. The
RPE was then abraded beneath the neural retina. In one group, 1 microgram(s) of
bFGF was injected into the vitreous cavity (bFGF applied group). Zero, 7, 14, 21,
and 28 days after the operation, fundus examination and fluorescein angiography
were performed. Thereafter, the rabbits were killed, the eyes were enucleated,
and the histological features were observed with light microscopy (LM), scanning
electron microscopy (SEM), and transmission electron microscopy (TEM). The number
of RPE cells in the treated area were counted in all experiments, and the effect
of bFGF on the number of regenerated RPE cells was analyzed. RESULTS:
Regeneration of the RPE was observed in the treated area at postoperative day 14.
The number of regenerated RPE cells showed a linear increase. Regenerated cells
observed by TEM were smaller than those of the normal RPE. The difference in the
number of regenerated RPE cells between the bFGF-applied and non-applied groups
was statistically significant on postoperative days 7 and 21. CONCLUSIONS: Repair
of the RPE occurred in a short period of time. Similar RPE repair may be seen in
humans. Intravitreal injection of bFGF increased the number of regenerated RPE in
this model.
PMID- 9395767
TI - Distribution of plasmalemmal Ca(2+)-pump and caveolin in the corneal epithelium
during the wound healing process.
AB - PURPOSE: Caveolae are small plasmalemmal invaginations which are assumed to play
various physiological functions. In the present study, distribution of two
caveolae-specific proteins, the plasmalemmal Ca(2+)-pump and caveolin, was
examined in the corneal epithelium in the normal state and after artificial
wounding. METHODS: A central epithelial ablation was made in the mouse cornea by
a razor blade. After various intervals, the corneas were excised, fixed, and
rapidly frozen. The specimens were subjected to immunofluorescence microscopy and
immunoelectron microscopy, using antibodies against the plasmalemmal Ca(2+)-pump
or caveolin. RESULTS: In the normal corneal epithelium, both plasmalemmal Ca(2+)
pump and caveolin were observed along the cell surface by immunofluorescence
microscopy, and were localized to caveolae by immunogold electron microscopy. In
the regenerating epithelium, 12-18 h after injury, plasmalemmal Ca(2+)-pump was
seen as many dots in the cytoplasm by immunofluorescence microscopy; in contrast,
caveolin persisted along the cell surface. Immunoelectron microscopy revealed
that the labeling for the plasmalemmal Ca(2+)-pump was located around membranous
structures in the cytoplasm and was scarce along the plasma membrane, while
caveolin remained in caveolae. The Ca(2+)-pump regained normal distribution when
the wound was closed. By quantitation in electron micrographs, the number of
caveolae per unit plasma membrane length was found to be decreased in the wounded
corneal epithelium. CONCLUSIONS: The present results indicate that caveolae
undergo compositional modification during the wound healing process of the
corneal epithelium. Considering putative caveolar functions, the phenomenon may
be related to possible fluctuations of the intracellular Ca(2+)-concentration in
the regenerating epithelium.
PMID- 9395768
TI - Computerized measurement of the three-dimensional distribution of optic disc
pallor.
AB - PURPOSE: To describe a method which provides quantitative measurements of the
surface area of pallor in each quadrant of the three-dimensional optic cup, using
photogrammetric measurements from simultaneous stereophotographs and computerized
image analysis. METHODS: Simultaneous stereophotographs of one normal subject and
two subjects with primary open angle glaucoma were digitized and analyzed for
depth measurements. The boundaries of the optic disc, optic cup and region of
pallor were identified. Pallor/disc and pallor/cup ratios were subsequently
calculated for the superior, temporal, inferior and nasal walls. RESULTS: A
digitized photograph and a Laplacian-filtered image were obtained for each eye to
be studied. After processing each stereo pair through a similarity sequential
detection-based algorithm, depth measurements are represented as a grey scale
image, a contour plot, and a wire mesh, with the boundaries of the optic disc,
optic cup and pallor superimposed. Ratios are given of the surface area of pallor
to the surface area of the disc and the surface area of pallor to the surface
area of the cup, by quadrant. CONCLUSIONS: Determination of surface area of
pallor to cup may be useful in detecting early visual field loss in glaucoma and
neurological disease.
PMID- 9395769
TI - Effect of topical beta-blockers on tissue blood flow in the human optic nerve
head.
AB - PURPOSE: To study the effect of topical 0.5% timolol and 2% carteolol on tissue
blood flow in the human optic nerve head (ONH). METHODS: Using a laser speckle
tissue blood flow analyzer, normalized blur (NB), a quantitative index of tissue
blood velocity, was measured every 0.125 s in the temporal site of the ONH free
of visible surface vessels and averaged over 3 cardiac pulses (NBONH). To serve
as a baseline, NBONH and intraocular pressure (IOP) in both eyes, blood pressure
(BP) and pulse rate (PR) were recorded in healthy volunteers before, 1.5, 3 and
4.5 hrs after a 30L instillation of the vehicle of timolol or carteolol. From the
following day and twice daily for 3 weeks, 30L of either 0.5% timolol or 2%
carteolol was instilled into one eye and the respective vehicle into the fellow
eye in a masked manner. NBONH, IOP, BP and PR were again recorded on the 21st and
last experiment day. IOP was also recorded on the 7th and 14th days. Carteolol
concentration in the plasma was also recorded after instillation of carteolol on
the 21st day. RESULTS: During the baseline experiments, all the parameters
recorded showed no significant change. After topical timolol, IOP was
significantly reduced bilaterally with more reduction in the timolol-treated eye.
Bilateral NBONH, BP and PR showed little change on the 21st day. After topical
carteolol, IOP was significantly reduced bilaterally with more reduction in the
carteolol-treated eyes on the 21st day. NBONH in the carteolol- and vehicle
treated eyes was significantly higher on the 21st day than recorded in the same
eye in the baseline experiment (P = 0.013 and 0.047), while BP and PR showed
little change. The maximum carteolol concentration in plasma at 3 hrs on the 21st
day averaged 1294 pg/ml. CONCLUSIONS: Results indicated that 3-week twice daily
topical timolol treatment had no deleterious effect on the ONH tissue blood flow
in the human eye, and that 3-week twice daily topical carteolol treatment may
increase the tissue blood flow in the human ONH.
PMID- 9395770
TI - Effect of shaking of corneal endothelial preservation.
AB - PURPOSE: To investigate the effect of shaking on corneal endothelial
preservation. METHODS: Thirty-six dog corneal buttons were obtained under
standard eye bank procedure, after the animals had been sacrificed for
cardiovascular experiments in the surgical department. They were equally divided
into two groups. In Group I, buttons were put in Dexsol preservative medium and
preserved at 4 degrees C. In Group II, buttons were put in Dexsol preservative
medium and shaken in a shaking incubator at a speed of 5 rpm. at 4 degrees C for
10 h. After shaking, they were returned to a 4 degrees C refrigerator until
examination. Three buttons from each group underwent specular microscopy,
scanning electron microscopy (SEM), and alizarin red with trypan blue stain
examinations on days 0, 1, 3, 5, 7 and 9, respectively. RESULTS: In Group I,
intercellular borders became blurred under specular microscopy, beginning on day
5. However, endothelial cell count did not change significantly until day 9.
Intercellular digitations and wrinkling of intercellular borders were seen under
alizarin red with trypan blue stain and SEM examination, beginning on day 3.
Pleomorphism and ill-defined intercellular junctions were seen under SEM on day
7. There was no obvious denudement of the endothelial sheet, but a few scattered
exfoliations were seen in Group I. In Group II, endothelial cell count did not
decrease on day 1, but an endothelial image could not be obtained by specular
microscopy 3 days after treatment. Alizarin red with trypan blue stain and SEM
examination revealed that the endothelial cells were denuded from the Descemet's
membrane three days after shaking. Severe stromal edema was seen under SEM five
days after shaking. CONCLUSIONS: The results showed that shaking had a
detrimental effect on endothelial cell preservation. Vigorous shaking should be
avoided during transportation of corneal buttons. It is advisable to perform
penetrating keratoplasty as soon as possible upon receiving transported donor
corneas.
PMID- 9395772
TI - Immunodetection of membrane skeletal protein 4.2 in bovine and chicken eye lenses
and erythrocytes.
AB - PURPOSE: Protein 4.2 is a major erythrocyte membrane skeletal protein, playing an
important role in maintaining the integrity and stability of the membrane. It is
a transglutaminase-like molecule with no enzymatic cross-linking activity.
Several protein 4.2-associated proteins (i.e. band 3, ankyrin, and protein 4.1)
and transglutaminase activities have been detected in the lens. The purpose of
this study is to find out if protein 4.2 is also expressed in lens fiber
membranes. METHODS: Western blot analysis of cell membranes isolated from bovine
and chicken lens fibers and erythrocytes, and immunocytochemistry of frozen
sections of bovine and chicken lens fibers were carried out using two protein 4.2
specific antibodies. These two peptide antibodies have been used to identify two
alternatively spliced protein 4.2 isoforms in human erythrocyte membranes: the
short (P4.2S, or hP4.2(691)) and the long (P4.2L, or hP4.2(721)) isoforms.
RESULTS: Western blot analysis using anti-P4.2(L) antibody demonstrated specific
immunoreactive polypeptides in bovine and chicken lens fiber membranes and
erythrocyte membranes, co-migrating with hP4.2(721). Immunofluorescence staining
of bovine and chicken lenses, using anti-P4.2(L) antibody, revealed specific
signals along the cell membranes of cortical fibers. The signals exhibited a
unique, patchy pattern along the cortical fiber cell membranes in both cross
sectional and longitudinal views. In cross sections, the labeling of anti-P4.2(L)
along the entire cell membranes gave an appearance of a hexagonal shape of fiber
cells. CONCLUSIONS: Protein 4.2, or its analogs, is present in the lens fiber
membranes. Its specific staining pattern in the lens fibers suggests that it
participates in the architecture of the lens fiber cell membranes, and may play a
role in the lens mechanics and pathology.
PMID- 9395771
TI - Inhibition of RPE cell-mediated matrix adhesion and collagen gel contraction by
crovidisin, a collagen-binding snake venom protein.
AB - PURPOSE: Cell-mediated collagen gel contraction plays an important role in the
pathogenesis of proliferative vitreoretinopathy (PVR). Anti-adhesion therapy has
been suggested as a promising strategy in the treatment of PVR. Crovidisin, a
snake venom protein isolated from Crotalus viridis, has been shown to bind
selectively to collagen and to inhibit collagen-induced platelet aggregation. In
the present study, the effectiveness of crovidisin in inhibiting the attachment
of retinal pigment epithelial (RPE) cells to collagen, and RPE cell-mediated
collagen gel contraction, was evaluated. METHODS: Fluorescein isothiocyanate
(FITC)-conjugated crovidisin was prepared and used to evaluate its binding
affinity for collagen type I, fibronectin, vitronectin, and laminin. The
inhibitory effect of crovidisin on RPE cell-mediated extracellular matrix
attachment and collagen gel contraction was evaluated by cell adhesion and type I
collagen gel contraction assays. The cytotoxic effect of crovidisin was examined
with a cell proliferation assay, using the Alamar blue method. Flavoridin, an Arg
Gly-Asp-containing peptide from viper venom, was used for comparison. RESULTS:
FITC-conjugated crovidisin bound selectively to collagen type I with high
affinity. It did not bind to other matrix proteins, including fibronectin,
vitronectin and laminin, nor to RPE cells. Crovidisin inhibited RPE cell
attachment to type I collagen in a dose-dependent manner. This inhibitory effect
was enhanced by the presence of flavoridin. Crovidisin also dose-dependently
inhibited RPE cell-mediated type I collagen gel contraction. Crovidisin was non
toxic to RPE cells. CONCLUSIONS: Crovidisin, a snake venom-derived collagen
binding protein, possessing an inhibitory activity on RPE cell-collagen
interaction and RPE cell-mediated collagen gel contraction, may be a useful tool
for studying cell-collagen interaction, and a potential anti-adhesion therapeutic
agent for ocular disorders in which cell-collagen interaction in involved, such
as PVR.
PMID- 9395773
TI - A correlation between computer-predicted changes in secondary structure and the
phenotype of retinal degeneration associated with mutations in peripherin/RDS.
AB - PURPOSE: To investigate a molecular understanding of how mutations can lead to
different phenotypes, we analyzed the relationship between altered secondary
structures predicted by missense mutations in the peripherin/RDS and clinical
severity of autosomal-dominant retinal degeneration. METHODS: We analyzed
thirteen different kinds of missense mutations in the second intradiscal loop of
peripherin/RDS, previously reported in peer review journals. Alteration of the
secondary structure of peripherin/RDS was predicted by computer-assisted protein
structure analysis. The number of amino acid residues that would be involved in
the secondary structural change produced by a given missense mutation was scored
as a grade of molecular change. Clinical severity was estimated by the impairment
based on electroretinographic recordings of rods and cones, and was scored
according to the severity of their recordings. Regression analysis was carried
out between both scores of molecular change and clinical severity. Effects of
patients' ages on clinical severity was also analyzed. RESULTS: Significant
correlation was found between scores of molecular change and those of clinical
severity (rods, r = 0.89, p < 0.001; cones, r = 0.76, p < 0.005) by regression
analysis. There was no correlation between clinical severity and patients' ages.
CONCLUSION: . These findings indicate that the degree of change in the secondary
structure of peripherin/RDS can explain in part the correlation between genotype
and phenotype in autosomal-dominant retinal degeneration associated with missense
mutations in the peripherin/RDS gene.
PMID- 9395774
TI - Radiation response of porcine RPE cells in vitro.
AB - PURPOSE: To investigate the antiproliferative effect of ionizing radiation on
retinal pigment epithelial (RPE) cells that are supposed to play a major role in
the pathogenesis of proliferative vitreoretinopathy (PVR). METHODS: RPE cells
from pig eyes were irradiated with doses ranging from 4 to 16 Gy (1 Gray = 1
Joule/kilogram). Cells were counted at 1, 2, 3, and 4 weeks (Experiment 1) or 1,
2, 4, and 6 weeks (Experiment 2) after treatment. In Experiment 3, cells were
trypsinized 24 h after radiation and seeded again. Colonies were counted 10 days
later, and the surviving fraction was determined. RESULTS: The numbers of cells
and colonies were inversely correlated to the doses applied. In Experiment 2,
cell numbers of radiated cultures remained stable during the time of follow-up,
whereas, in Experiment 1, significant proliferation occurred in treated cultures
as well as in controls. This may be due to the higher growing rate that was found
in the cultures of Experiment 2, compared to those of Experiment 1, at the time
of radiation. In Experiment 3, a D0 value of 0.72 Gy was found. CONCLUSIONS:
Proliferation of RPE cells can be suppressed by irradiation in a dose-dependent
manner. Therefore, radiotherapy may be useful in the treatment of PVR. Its effect
probably depends on the stage or activity of PVR at the time of radiation.
PMID- 9395776
TI - MHC-II but not MHC-I responses are required for vaccine-induced protection
against ocular challenge with HSV-1.
AB - PURPOSE: To determine the importance of major histocompatibility complex (MHC)
class-I versus MHC class-II immune responses in protecting naive versus
vaccinated mice against an ocular HSV-1 challenge. METHODS: Class-II deficient A
beta o/o (CD4-CD8+ T cells) knockout mice, which are effectively CD4+ T cells
negative, and class-I deficient beta(2)mo/o (CD4+CD8- T cells) knockout mice,
which are effectively CD8+ T cells negative, were either vaccinated or mock
vaccinated and examined for their ability to withstand HSV-1 ocular challenge.
RESULTS: Unvaccinated A beta o/o and beta(2)mo/o mice were both more susceptible
to lethal ocular HSV-1 infection than the parental wild type C57BL/6J mice,
indicating that both MHC-I and MHC-II were required for optimal protection of
naive mice against ocular HSV-1 challenge. Vaccinated beta(2)mo/o mice produced
significant neutralizing antibody titers, and following ocular challenge, these
mice were completely protected against death and corneal scarring. In contrast,
vaccinated A beta o/o mice developed no neutralizing antibody titers and
vaccination did not provide these mice with any protection against death or
corneal scarring. Passive transfer of anti-HSV-1 antibody into A beta o/o mice up
to 6 days post ocular challenge resulted in complete protection against death and
corneal scarring. CONCLUSIONS: Passive antibody transfer, but not vaccination,
protected A beta o/o mice against ocular challenge. In contrast, vaccination
completely protected beta(2)mo/o mice. These results suggest for a vaccine to
provide optimal protection against ocular HSV-1 challenge in this system, it is
not only sufficient, but it is also required, that the vaccine induce an
effective neutralizing antibody response.
PMID- 9395777
TI - Fluorescein as a marker for subretinal transplantation of human fetal neural
retina.
AB - PURPOSE: To investigate the effect of fluorescein on human fetal neural retina
and adult rat retina; and to use fluorescein to map the area of subretinal
transplantation. METHODS: In vitro: Human fetal neural retina (8 to 14 weeks
gestational age) was incubated in 0.03% fluorescein in Dulbecco's Modified Eagles
Medium (DMEM) or DMEM alone for 30 min. Viability was determined using the trypan
blue exclusion test, and results were compared. Effects of the fluorescein on
cell morphology were assessed by observation of primary cultures for 1 week. In
vivo: Human fetal neural retina was mechanically dissociated in 0.03% fluorescein
in DMEM and transplanted to the subretinal space of immunosuppressed rats. To
control for the effect of fluorescein on the grafted tissue, transplants were
also performed in DMEM only. After transplantation, indirect ophthalmoscopy and
true color fundus photography were performed to document the area covered by the
transplant. One month after transplantation, the appearance of grafts exposed to
fluorescein was compared to those that were not, at the light microscopic level.
RESULTS: In vitro: Exposure of human fetal neural retina to fluorescein had no
effect on viability. Similarly, in tissue culture, the fluorescein-exposed cells
exhibited the same phenotype as the controls. In vivo: Immediately after
transplantation the graft site was clearly outlined within the subretinal area
and fluoresced intensely. There were no traces of the dye 2 h after
transplantation. Cells that were transplanted with fluorescein survived
transplantation, and one month after transplantation could be seen forming
subretinal grafts. No differences were noted between these and control grafts.
CONCLUSIONS: Fluorescein is an effective dye for immediate and transient
localization of trans-scleral transplants to the subretinal space. It allows
mapping of the area covered by the injection without interfering with the
viability and differentiation of the transplanted cells. It allows unequivocal
photo- and video-documentation in both the albino and pigmented fundi. It is
already FDA approved for many other extra- and intraocular studies and now has
directly been shown to be non-toxic to both human fetal neural retina and adult
rodent retina.
PMID- 9395775
TI - Induction of rabbit cyclooxygenase 2 in the anterior uvea following glaucoma
filtration surgery.
AB - PURPOSE: This study was undertaken to evaluate for the presence of cyclooxygenase
2 (COX2) gene expression in the anterior uvea of rabbits following glaucoma
filtration surgery. METHODS: One of the following surgical procedures were
performed on the right eye of New Zealand white albino rabbits: (1) paracentesis
(2.5 mm limbal incision); (2) iridectomy through a 2.5 mm limbal incision; (3)
lamellar scleral flap formation or (4) full glaucoma filtration surgery. The
animals were sacrificed within 3 hours of post-surgery, and the anterior uveal
tissues were isolated. Polymerase chain reaction-based techniques were employed
to assay for the presence of COX2 transcript. RESULTS: A partial coding sequence
of the previously unreported rabbit COX2 gene was obtained. COX2 mRNA was
detected in the operated eyes of animals that underwent either full filtration
surgery or iridectomy through a limbal incision. CONCLUSIONS: In normal rabbit
anterior uveal tissue, there appears to be minimal expression of COX2 message.
After experimental glaucoma filtration surgery, there is rapid induction of COX2
message.
PMID- 9395778
TI - Physostigmine increases aqueous humor production in human eyes.
AB - PURPOSE: To investigate if part of the progressive reduction of intraocular
pressure (IOP), seen when physostigmine is applied on alternate hours, is due to
a reduced aqueous flow. METHODS: In a randomized, open study, one drop of
physostigmine salicylate, 8 mg/ml, was instilled at 7 AM in one randomly assigned
eye in each of twenty healthy volunteers. Instillations were repeated on
alternate hours throughout the day. Each subject's untreated eye served as
control. Fluorophotometry of the anterior segment was performed hourly between 7
Am and 8 PM and aqueous flow was calculated. Subsequently, the subjects underwent
tomography and tonometry. The change in anterior chamber depth and volume induced
by physostigmine was assessed separately. RESULTS: The mean aqueous flow during
the day was 25-28% higher in the physostigmine-treated eye than in the control
eye. The difference was statistically significant from 9 AM (p < 0.05-p < 0.001).
Each dose caused a further increase. The mean outflow facility increased by 0.14
microliters/min/mm Hg with 95% confidence interval (CI) 0.09-0.18. Although the
increase in outflow facility was small, there was a marked reduction of IOP with
a mean difference between treated and untreated eye of 3.2 mm Hg (95% CI: 2.3
4.0). CONCLUSIONS: Repeated administrations of physostigmine increase the aqueous
flow and outflow facility. The combined effect is a marked reduction of IOP.
PMID- 9395779
TI - Induction of donor-specific ACAID can prolong orthotopic corneal allograft
survival in "high-risk" eyes.
AB - PURPOSE: To examine the effect of donor-specific anterior chamber-associated
immune deviation (ACAID) induction on the survival of orthotopic corneal
allografts in neovascularized graft beds. METHODS: To induce donor-specific ACAID
in recipients, peritoneal exudate cells (PEC) from C57BL/6 mice were incubated
overnight with transforming growth factor (TGF)-beta. Cultured PEC were injected
intravenously (i.v.) into BALB/c mice, and, 1 week later, these animals received
orthotopic corneal allografts from C57BL/6 donors into neovascularized graft
beds. Control mice received i.v. injection of syngeneic (BALB/c) PEC, cultured
overnight with TGF-beta, and then received orthotopic corneal allografts from
C57BL/6 donors. RESULTS: All corneal allografts (15 out of 15) were rejected
within 2 weeks after grafting in the neovascularized graft beds of control
animals. However, only 6 out of 16 (37.5%) of corneal allografts were rejected in
recipients in which donor-specific ACAID had been induced by injection of
allogeneic PEC cultured with TGF-beta. CONCLUSION: Previous studies revealed that
rejection of orthotopic corneal allografts in neovascularized graft beds in mice
correlated with acquisition of donor-specific delayed hypersensitivity (DH). The
results of this study suggest that induction of donor-specific ACAID, which
selectively impairs DH responses to donor antigens, effectively prolongs corneal
allograft survival in "high-risk" eyes.
PMID- 9395780
TI - Myocardial contrast echocardiography.
AB - MCE has evolved from a laboratory tool to a clinical procedure. It would be wrong
to consider it merely another tool for imaging of myocardial perfusion. As
discussed, it allows physicians to bring physiology and pathophysiology to the
bedside, providing a better understanding of the underlying mechanisms of
abnormal findings in individual patients. MCE can provide quantitative
measurements that can be repeated as often as necessary in a patient. Because of
its complexity, large clinical studies are necessary to define the role of MCE in
the general clinical milieu. Advances in MCE continue at a very rapid pace, and
its potential for the study of endothelial function, site-specific targeting, and
local delivery of drugs appears promising. Its role will continue to evolve into
the early part of the next century. What we learn of the myocardium can be easily
applied to other organ systems accessible to ultrasound. The future of MCE
appears very exciting.
PMID- 9395782
TI - The diaphragm in chronic obstructive pulmonary disease: how useful is it?
PMID- 9395781
TI - Intestinal taurine transport: a review.
AB - Intestinal uptake of dietary taurine is an important contributor to taurine
homeostasis and may become crucial when taurine metabolism is impaired. This
review aims to assess the literature documenting taurine transport and review
what is currently known about the operation of the enterocyte taurine transport
protein. Sources included MedLine searches from the last 10 years and references
from original and review articles. The aim was to include human and animal
studies directly addressing the subject of taurine uptake by enterocytes.
Intestinal taurine transport has been well documented in in vivo studies using
many different animal models. The mechanistic/kinetic aspects of the transport
system have been extensively documented. However, little is known about what
regulates the system. The recent development of a cell culture model of
intestinal taurine transport will allow studies to explore the regulation of gut
taurine uptake, which promises to be a very exciting area.
PMID- 9395783
TI - Helicobacter pylori and non-Helicobacter pylori bacterial flora in gastric
mucosal and tumour specimens of patients with primary gastric lymphoma.
AB - There is an association between Helicobacter pylori (H. pylori) and gastric
mucosa-associated lymphoid tissue (MALT) and MALT lymphoma. Histologically,
mainly non-specific stains are used to detect H. pylori, such as haematoxylin
eosin (HE) or modified Giemsa (MG). In this study, both a MG and a specific
immunohistochemical stain (IMM) for H. pylori (Dako B471) were performed on
sequential slides of resected material containing tumour and non-tumorous gastric
mucosa from patients with primary gastric lymphoma (n = 52). Special attention
was paid to the presence of non-H. pylori bacterial flora diagnosed by a positive
MG (according to form and localization) and a subsequently negative IMM. On all
slides, bacterial density was scored semiquantitatively (grades 0, 1, 2, 3). In
total, 32 (61.5%) patients were H. pylori positive using IMM and 34 (65.4%) were
non-H. pylori positive using MG. In 24 out of the 34 patients, the non-H. pylori
flora consisted mainly of cocci in combination with rods in 15 patients, mostly
in minor quantities; in another 10 patients, high numbers of both cocci and
different types of rods were present. Most non-H. pylori bacteria were localized
superficially, although in 22 patients minor quantities of non-H. pylori were
also seen in the glandular lumina. After all of the patients had been analysed,
no differences in the density of H. pylori and of non-H. pylori flora were found.
Only when comparing patients who had a small-cell lymphoma with those who had a
large-cell lymphoma was a significantly higher density of H. pylori found in the
corpus mucosa of large-cell lymphomas and a higher prevalence of non-H. pylori
was found in tumours, in antrum or corpus, of patients with large-cell lymphomas.
In conclusion, with joint evaluation using MG and a H. pylori-specific
immunohistochemical stains, the proportion of H. pylori-positive gastric lymphoma
patients was lower than in most previous studies but other bacteria were found in
a relatively high proportion. The role of the non-H. pylori intragastric
bacterial flora identified in this study has to be further elucidated in the
aetiopathogenesis of primary gastric lymphoma.
PMID- 9395785
TI - Hyposensitivity to nerve stimulation in portal hypertensive rats: role of nitric
oxide.
AB - Portal hypertension goes along with vascular hyporeactivity, partly mediated by
nitric oxide (NO). Interactions between the adrenergic nervous system and NO in
portal hypertension are undetermined. We tested (1) whether superior mesenteric
arterial beds of portal hypertensive rats have an altered sensitivity to
periarterial nerve stimulation (PNS) and (2) the role of NO in modulating nerve
stimulated responses. Vasopressor responses to PNS (Hz, 2-32) were similar in
preparations of partial portal vein-ligated (PVL, n = 12) and control (CON, n =
12) rats (60.0 +/- 6.7 and 47.8 +/- 6.1 CmH2O respectively) for 24 Hz (NS), but
sensitivity of vessels of portal hypertensive animals displayed a significant
rightward shift [Hz needed for 50% of maximal response (HZ50) being 15.5 +/- 0.4
and 12.9 +/- 0.6 for PVL and CON respectively, P < 0.001]. NO formation
inhibition by N omega-nitro-L-arginine (10(-4) mol L-1) significantly increased
responses to PNS (P < 0.05), the absolute values for 24 Hz being 101.4 +/- 11.7
cmH2O for PVL (n = 8) and 86.4 +/- 11.4 cmH2O for CON (n = 7) (NS). NO formation
inhibition reversed the hyposensitivity in preparations of PVL, Hz50 being 13.9
+/- 0.5 and 13.2 +/- 0.2 for PVL and CON respectively (NS). Adrenergic receptor
antagonism with prazosin (10(-7) mol L-1) and yohimbine (10(-6) mol L-1)
inhibited PNS-mediated vasopressor reactivity (n = 6 per group, P < 0.001),
confirming the nervous origin of vasoconstrictor responses. It is concluded that
(1) portal hypertension goes along with a significant hyposensitivity to PNS and
(2) this hyposensitivity is reversed by NO-formation inhibition
PMID- 9395784
TI - Signal transduction pathways of membrane expression of proteinase 3 (PR-3) in
human endothelial cells.
AB - At present, the exact mechanism of the pathogenic effect of anti-PR-3 antibodies
remains unknown. Interaction of anti-neutrophil cytoplasmic antibodies (ANCAs)
with human umbilical vein endothelial cells (HUVECs) may play a key role.
Recently we were able to show that ANCAs recognize their target antigen, PR-3,
translocated into the membrane of HUVECs. The objective of this study was to
investigate regulation, i.e. signal transduction pathways, of PR-3 expression in
endothelial cells. HUVECs were isolated according to the method of Jaffe et al.
and cultured under standard conditions. A cyto-enzyme-linked immunosorbent assay
(ELISA) with unfixed cells was performed. Membrane-expressed PR-3 was detected by
affinity-purified and monoclonal anti-PR-3 Ab. Tumour necrosis factor alpha (TNF
alpha)-induced membrane expression of PR-3 could be blocked with the RNA
synthesis inhibitor actinomycin D, the protein kinase C (PKC) and proteinase A
(PKA) inhibitor staurosporine, the specific PKA inhibitor calphostin C, the c-AMP
dependent PKA inhibitor KT5720 and the tyrosine kinase inhibitor genistein in a
dose-dependent manner. The effect of calphostin C was the most significant. In
addition, the effect of phorbol 12-myristate 13-acetate (PMA), a mediator of
intracellular second messengers, was investigated. In our study, pretreatment of
cells with PMA for 48 h led to a down-regulation of PR-3 expression. This effect,
however, could be overridden by TNF-alpha stimulation, i.e. TNF-alpha-induced
membrane expression of PR-3 was resistant to down-regulation of PKC. In
conclusion, our data suggest that translocation of PR-3 in HUVECs is an active
process depending on protein synthesis. PR-3 expression by HUVECs may involve a
PKC reactive to cytokines such as TNF-alpha which induces PR-3 expression at a
transcriptional level.
PMID- 9395786
TI - Phyllanthus amarus suppresses hepatitis B virus by interrupting interactions
between HBV enhancer I and cellular transcription factors.
AB - The Phyllanthus amarus plant suppresses HBV mRNA transcription in vitro and
exhibits therapeutic potential in chronic HBV carriers, although further work is
necessary to define its mechanism of action. Analysis in HuH-7 cells with
transfected plasmids using a luciferase reporter showed that P. amarus
specifically inhibited HBV enhancer I activity. To identify the mechanism of this
HBV enhancer I inhibition, liver-enriched cellular transcription factors were co
expressed in HuH-7 cells. The C/EBP alpha and beta, as well as HNF-3 alpha and
beta transcription factors, significantly up-regulated the HBV enhancer I
activity. In contrast, co-transfection of HNF-I alpha or beta had no effect upon
the HBV enhancer I activity. Exposure to P. amarus inhibited C/EBP alpha- and
beta-mediated up-regulation of HBV enhancer I activity in a dose-dependent
manner, whereas HNF-3 alpha- and beta-mediated up-regulation of HBV enhancer I
was unaffected. In vitro gel shifts showed that P. amarus inhibited complexing of
C/EBP transcription factors to a consensus oligonucleotide sequence, whereas DNA
binding of AP-1 and SP-1 transcription factors was unaffected. As P. amarus down
regulates HBV mRNA transcription by a specific mechanism involving interactions
between HBV enhancer I and C/EBP transcription factors, purification and further
analysis of the active P. amarus component will advance insights into its
antiviral activity.
PMID- 9395787
TI - Circulating endothelial cell markers in peripheral vascular disease: relationship
to the location and extent of atherosclerotic disease.
AB - We examined the relationship between specific endothelial cell markers soluble E
selectin, von Willebrand factor and soluble thrombomodulin and the location or
extent of atherosclerosis by analysing plasma samples from 200 patients with
symptomatic peripheral vascular disease and 213 age- and sex-matched asymptomatic
control subjects. Using ELISAS, we found increased von Willebrand factor and
thrombomodulin (both P < 0.0001) in the patients relative to the control
subjects, but no significant change in soluble E-selectin. Soluble thrombomodulin
was increased in patients with disease at one locus (i.e. of the carotid or
iliac/femoral arteries), with an additional significant increase in patients with
disease at multiple loci (i.e. any combination of carotid, coronary or
iliac/femoral artery disease). No marker differentiated carotid artery disease
from iliac/femoral artery disease. We conclude that von Willebrand factor is a
marker of generalized atherosclerosis, but that soluble thrombomodulin is related
to the extent of disease. Further research into these endothelial cell products
are warranted to explore their diagnostic and/or prognostic potential.
PMID- 9395788
TI - Detection and quantification of the control proteins of the alternative pathway
of complement in 3T3-L1 adipocytes.
AB - The complement peptide C3a desarg is identical to acylation-stimulating protein
(ASP), a human plasma protein that potently stimulates adipocyte triacylglycerol
synthesis and glucose transport. Both human and murine adipocytes express mRNA
and/or protein for the complement components C3 and factors B and D (adipsin)
required to generate ASP. However, the regulatory mechanisms controlling this
process are unknown. We have established a semiquantitative reverse transcriptase
polymerase chain reaction (RT-PCR) technique to demonstrate the presence in mouse
3T3-L1 adipocytes of mRNA for all components of the alternative pathway,
including the control proteins factors I and H, CR1 and properdin. On
differentiation, mRNA for C3 (fivefold) and factor D (> 50-fold) increased,
whereas stimulation with tumour necrosis factor (TNF)-alpha and interleukin (IL)
1 beta led to eightfold increases in factor B mRNA. Metabolic labelling followed
by immunoprecipitation showed that factor B protein is normally present in small
quantities, and is greatly increased by cytokine stimulation. The larger
quantities of C3 and H proteins present were little affected, whereas levels of
C3a increased on cytokine stimulation. These results suggest that the rate
limiting step in the cytokine-induced production of ASP in adipocytes is factor B
synthesis.
PMID- 9395789
TI - The Asn-291-->Ser and Ser-477-->Stop mutations of the lipoprotein lipase gene and
their significance for lipid metabolism in patients with hypertriglyceridaemia.
AB - We examined 99 Finnish patients whose serum fasting triglycerides (TG) had
exceeded 6.0 mmol L-1 with special interest to their lipid, lipoprotein and post
heparin plasma lipase activities. The control group consisted of 75 healthy
individuals. We also determined the frequency of the Asn-291-->Ser and Ser-447-
>Stop mutations both in hypertriglyceridaemic (HTG) subjects and in control
subjects. A total of 51 of the original 99 hypertriglyceridaemic patients still
had TG > 6.0 mmol L-1 when measured a second time. They are referred to as
persistently hypertriglyceridaemic subjects (pHTG). The remaining 48 subjects had
TG < 6.0 mmol L-1 in the second measurement and are referred to as sporadically
hypertriglyceridaemic subjects (sHTG). The allelic frequencies of the Ser-447-
>Stop mutation in the total HTG and sHTG groups were similar to the frequencies
present in the control group, but lower in pHTG patients compared with the
control group (0.049 vs. 0.153, chi(2) = 6.63, P < 0.05). The Asn-291-->Ser
mutation was more frequent in HTG group than in the control group (0.0606 vs.
0.013, chi(2) = 4.86, P < 0.05). This difference was due to the higher frequency
of the minor allele of Asn-291-->Ser in the cohort with persistent
hypertriglyceridaemia compared with the control group (0.088 vs. 0.013, chi(2) =
8.00, P < 0.01). The highest frequency (0.114) of the minor allele of Asn-291-
>Ser was found in type 2 diabetic patients with persistent hypertriglyceridaemia.
The carrier status of Asn-291-->Ser or Ser-447-->Stop did not predict either post
heparin plasma lipoprotein lipase (LPL) activities or lipid and lipoprotein
levels in any of the groups studied. Our data suggest that overproduction of very
low-density lipoproteins (VLDL) is a more important cause of
hypertriglyceridaemia in the Finns than is the LPL deficiency.
PMID- 9395790
TI - The role of intravenous administration of dextran 70 in enteric bacterial
translocation after partial hepatectomy in rats.
AB - The aim of this study was to assess the effect of intravenous dextran on
bacterial translocation and intestinal vascular endothelial and epithelial
barrier function after experimental partial hepatectomy. We determined systemic
arterial pressure, enteric bacterial growth (proximal and distal small intestine
and colon) and bacterial translocation (BT) to mesenteric lymph nodes (MLN),
liver, lungs, spleen, kidneys and blood, as well as intestinal vascular
endothelial and epithelial barrier permeability, after sham operation or partial
hepatectomy (50% and 90%) with preoperative intravenous administration of saline,
albumin or dextran 70. Subtotal hepatectomy induced a significant decrease in
arterial pressure and an increase in the number of Escherichia coli in the distal
small intestine. BT was not observed in sham-operated animals or in rats with 50%
hepatectomy administered dextran. The number of positive cultures of enteric
bacteria was significantly increased after hepatectomy, whereas dextran treatment
decreased the number of animals with BT. Increased permeability of the intestinal
vascular endothelial and epithelial barriers was noted in hepatectomized animals,
while dextran prevented hepatectomy-induced vascular endothelial barrier injury.
Enteric bacterial translocation occurred following partial hepatectomy in the
rat, associated with bacterial overgrowth in the distal small intestine.
Intravenous administration of dextran 70 prevented bacterial overgrowth and
translocation, at least in part, by maintaining gut vascular endothelial barrier
integrity
PMID- 9395791
TI - High doses of hydroxyethyl starch and human albumin have similar effects on
monocyte function and oncotic pressure.
AB - The accumulation of hydroxyethyl starches (HES) in monocytes/macrophages has
raised concern over their potential detrimental effects on host defences. We
assessed prospectively the function of circulating monocytes isolated from
patients treated with plasma exchange (PE) using HES. The study was carried out
in the medical intensive care unit of a university hospital. Eight patients
underwent PE for neurological disorders. Each patient underwent three PEs, 48 h
apart. The total exchange volume was 4 L per PE. Only 4% human albumin was used
for the first PE. In the second and third PEs, the plasma substitute was 2 L of
HES (200,000/6%/0.62) and 2 L of albumin. Mononuclear cells were collected before
and immediately after each PE and 48 h after the last PE. They were placed in
suspension culture and incubated with lipopolysaccharide (LPS). Monocyte function
was assessed in terms of procoagulant activity (PCA) and tumour necrosis factor
alpha (TNF-alpha) production. LPS-stimulated PCA increased after the first PE (P
< 0.05). Stimulated TNF-alpha production increased, but not significantly so.
Similar effects were observed after the second and third PE (P < 0.05 for
stimulated TNF-alpha). Values 48 h after the last PE were similar to those
obtained before the second PE, suggesting that repeated infusions of HES had no
detrimental effect on monocyte function. Furthermore, plasma oncotic pressure was
preserved after PE with HES. These results support the partial replacement of
costly human albumin with HES during repetitive PE, and suggest that HES might be
a safe plasma expander in septic patients.
PMID- 9395792
TI - Specific activation of AP-1 but not Stat3 in regenerating liver in mice.
AB - Liver regeneration following partial hepatectomy is regulated by hepatotrophic
factors whose precise roles are still elusive. In cell culture studies, some of
them have been shown to activate members of the family of the signal transducers
and activators of transcription (Stat). To test this contention in vivo, nuclear
extracts were isolated from livers of partially hepatectomized and sham-operated
mice killed at 30 different time points between zero and 108 h after surgery.
Stat3 DNA binding is rapidly induced after surgery in both partially
hepatectomized and sham-operated mice. Maximum activation of Stat3 is achieved 4
6 h after resection, and elevated Stat3 activation is detected as late as 60 h
after surgery in both groups. Activated Stat5 is found sporadically in both sham
operated and resected mice but appears to be absent in the first 12 h after
partial hepatectomy. Neither Stat1, Stat2, Stat4 nor Stat6 is induced during the
time of observation. In contrast, AP-1 DNA binding activity is specifically
induced in regenerating mouse liver.
PMID- 9395793
TI - Rapid screening for amyloid-related variant forms of transthyretin is possible by
electrospray ionization mass spectrometry.
AB - We have used a new and rapid method to detect three variant forms of
transthyretin (TTR): methionine for valine at position 30 (Met-30), serine for
cysteine at position 6 (Ser-6) and methionine for leucine at position 111 (Met
111). By using an anti-transthyretin antibody and a centrifugal concentrator,
transthyretin was isolated from plasma samples and analysed for variant forms by
electrospray ionization mass spectrometry. Differentiation between homozygous and
heterozygous transthyretin Met-30 and Met-111 posed no problems. However, a clear
separation of transthyretin Ser-6 and Met-111 peaks in one patient with
concordant Ser-6 and Met-111 mutations could not be achieved. The present method
enables a quick and reliable detection of variant TTR. It can be used to screen
families or small populations for abnormal TTR. Knowledge of TTR polymorphism and
the variable expression of different amyloidogenic mutations should be taken into
consideration when applying the methods in clinical practice.
PMID- 9395794
TI - ATP-sensitive potassium channels mediate vasodilatation produced by calcitonin
gene-related peptide in human internal mammary but not gastroepiploic arteries.
AB - The purpose of this study was to elucidate the mechanism of action of calcitonin
gene-related peptide-induced vasodilatation of human gastroepiploic and internal
mammary arteries. Calcitonin gene-related peptide (0.1-100 nmol L-1) elicited
relaxations of preconstricted vessels, with a significantly greater effect in the
gastroepiploic artery (P < 0.05). This effect was independent of endothelium
derived vasodilating substances. The response of the internal mammary artery but
not the gastroepiploic artery to calcitonin gene-related peptide was attenuated
by glybenclamide (1.0 mumol L-1) (P < 0.05). In vitro autoradiography indicated
that [125I]-calcitonin gene-related peptide bound to the tunica media but not the
endothelial cells in both types of artery, with a significantly higher degree of
binding in the gastroepiploic artery. It is concluded that calcitonin gene
related peptide acts directly on vascular smooth muscle via specific binding
sites to induce vasodilatation. In addition, KATP channels are involved in the
action of calcitonin gene-related peptide in the internal mammary artery but not
in the gastroepiploic artery.
PMID- 9395795
TI - Contribution of nitric oxide to exercise-induced changes in healthy volunteers:
effects of acute exercise and long-term physical training.
AB - Endothelium plays a central role in the regulation of regional blood flow through
the release of certain vasoactive substances. We conducted this study to test
whether an increase in the production of nitric oxide (NO) metabolites, atrial
natriuretic peptide (ANP) and plasma and intraplatelet cyclic guanosine 3':5'
monophosphate (cGMP) is involved in the adaptation to chronic exercise in
physically trained people and in the vasodilatation induced by acute physical
exercise. We studied one group of 10 trained athletes and another group of 10
untrained people. We measured plasma levels of nitrites, nitrates and cGMP and
intraplatelet levels of cGMP, as an indicator of intracellular guanylate cyclase
activity, and ANP before and after a maximal treadmill test. Resting cardiac rate
(CR) and systolic blood pressure (SBP) were lower in the athlete group than in
the control group (73.8 +/- 3.6 vs. 92 +/- 5.9; P < 0.02 and 110 +/- 2.58 vs. 118
+/- 3.27; P < 0.02 respectively). SBP did not show differences between groups
after the exercise test. Diastolic blood pressure (DBP) at rest was lower in the
athlete group (71 +/- 1.79 vs. 80.5 +/- 3.53; P < 0.03) and the decrease after
maximal exercise was more pronounced in this group (64 +/- 2.67 vs. 74.5 +/- 3.2;
P < 0.02). Basal plasma nitrites were 4.9 +/- 0.8 in the athlete group and 1.9 +/
0.3 in the control group (P < 0.05). After exercise, test differences between
groups remained (P < 0.05). Nitrates were significantly higher in the group of
athletes and did not show exercise-related changes. Plasma levels of cGMP and ANP
increased in both groups after the treadmill test, with no differences between
groups. Among the athletes, cGMP increased from 1.11 +/- 0.1 to 2.6 +/- 0.4 (P <
0.001), whereas in the untrained group plasma cGMP rose from 1.14 +/- 0.09 to
1.86 +/- 0.2 (P < 0.01). There was a significant correlation between the
increases in plasma cGMP and the atrial natriuretic peptide in both groups (r =
0.91, P < 0.0002, for athletes; and r= 0.68, P < 0.04, for control group). The
intraplatelet concentration of cGMP did not show differences between groups and
did not change after exercise. In conclusion, we have found increased basal
levels of plasma nitrite and nitrate in trained subjects. Exercise does not
produce differences in the increments of these metabolites. Therefore, we
speculate the release of nitric oxide is not augmented by exercise in trained
athletes.
PMID- 9395796
TI - The impact of electronic publication and the E-journal on quality and the peer
review process.
PMID- 9395797
TI - Penetrating keratoplasty in the Singapore National Eye Centre and donor cornea
acquisition in the Singapore Eye Bank.
AB - We analyzed all penetrating keratoplasties performed in the Singapore National
Eye Centre from 1 January 1991 to 31 December 1995, using records of the
Singapore Eye Bank Registry, evaluating the indications, complications, causes of
graft failure, visual outcome and graft survival rate. We also looked into donor
cornea acquisition in the Singapore Eye Bank and its influence on the development
of corneal transplantation in the Singapore National Eye Centre. A total of 327
penetrating keratoplasties were performed during the 5-year period. Bullous
keratopathy was an indication in 26.3% of cases. Of these, aphakic bullous
keratopathy accounted for 11.6% of all cases, while pseudophakic bullous
keratopathy accounted for 11.3%. Other indications were regrafts (11.9%), corneal
dystrophies (10.4%), traumatic corneal scarring (10.1%) and keratoconus (9.8%).
Graft rejection was a complication in 20% of all cases. Of these, 40.9% led to
graft failure. Other major complications were raised intraocular pressure (18%),
epithelium-related problems (7.3%), wound dehiscence (4.3%), cataract (3.3%) and
microbial keratitis (3.1%). The main causes of graft failure were graft rejection
(8.2%), endothelial failure (2.4%), infection (2.4%) and glaucoma (2.1%). Of the
327 grafts, 40.3% achieved best corrected visual acuity of 6/12 or better; 70.8%
achieved vision of 6/24 or better. The overall graft survival rate was 82.3%
after a mean follow-up period of 2 years. Donor corneas for the penetrating
keratoplasties were obtained from foreign eye banks as well as locally, with the
local donation rate steadily increasing from 1991 to 1996, with the establishment
of proper eye banking facilities and the Singapore Eye Bank. These results show
that the indications and outcome of penetrating keratoplasty in the Singapore
National Eye Centre are similar and comparable to that of other centres with
established corneal grafting programmes. The establishment of the Singapore Eye
Bank has ensured the proper co-ordination of acquisition of donor material which
has been vital to the development of corneal transplantation in the Singapore
National Eye Centre.
PMID- 9395798
TI - Photorefractive keratectomy for the treatment of compound myopic astigmatism
using the ablatable mask.
AB - Eight eyes of 8 patients with compound myopic astigmatism were treated with
excimer laser photorefractive keratectomy (PRK) using a hand-held ablatable mask
in conjunction with the Summit excimer laser. The attempted correction ranged
from -1.25 to -400 dioptres (D) of astigmatism and 0 to -8.00 D of myopia. All
eyes had attained at least 6 months of postoperative follow-up. Five of the 8
eyes achieved an unaided visual acuity of 6/12 or better. Postoperative
refractions ranged from -0.50 to -3.50 D of refractive cylinder and from +0.50 to
-3.75 D of spherical error. Decentration of the ablation zone was encountered in
3 eyes due to shifts in patients' fixation. Technical difficulty with the use of
the hand-held ablatable mask limited the widespread application of this procedure
and it has now been superseded by newer excimer laser systems which can correct
astigmatism without having to employ a mask. Despite this, because of the
theoretical ability of the mask to correct any form of refractive error, the
concept of the mask shape transfer process will remain as a potential alternative
in refractive surgery, especially for correction of hyperopia and hyperopic
astigmatism.
PMID- 9395799
TI - Hydroxyapatite orbital implants--our local experience.
AB - Hydroxyapatite orbital implants were first introduced by Arthur Perry in 1985 and
approved by the Food and Drug Administration for general use in 1989. Since its
inception, it has become a popular orbital implant as it combines
biocompatibility with improved motility. At the Singapore National Eye Centre,
twenty consecutive patients underwent hydroxyapatite implantation from June 1993
to June 1996. Seventeen patients who had a follow-up time of more than 6 months
were analysed retrospectively. Sixteen had enucleation while one had evisceration
performed. The implant size used was either 18 or 20 mm. Seven primary and 10
secondary hydroxyapatite implants were performed in 17 patients ranging in age
from 20 to 65 years. Six consisted of coralline hydroxyapatite while the
remaining 11 were made of artificial hydroxyapatite. In the follow-up time of 6
to 16 months (mean 10.2 months), there have been no cases of infection, extrusion
or migration. Two patients who had implant exposure were managed surgically with
fascia lata grafts and have healed well. It appears that hydroxyapatite is the
implant of choice for an anophthalmic socket. It becomes incorporated by the
patients own tissues and once vascularised, it is less likely to migrate or
extrude. The complication rate is low and implant exposure, if it occurs, can be
easily managed.
PMID- 9395800
TI - Acute orbital cellulitis--a review of 17 cases.
AB - This is a retrospective study of 17 patients who were admitted for orbital
cellulitis between August 1989 and February 1994. The epidemiology, possible
source of infection, the causative organisms and effectiveness of treatment were
reviewed. The results showed that one-third of the cases occurred in the first
decade of life. Paranasal sinusitis was the main source of infection in 11 (65%)
patients. Thirteen patients (76.5%) developed orbital and periocular abscesses
requiring surgical drainage. Two out of 17 eyes lost vision despite intensive
treatment. Orbital cellulitis is a blinding ocular emergency associated with high
morbidity. Immediate treatment is necessary to avoid devastating complications
such as optic nerve compression, panophthalmitis or intracranial spread of
infections. Cases with abscess formation required early surgical drainage.
Combined orbito-otorhinolaryngologic approach is recommended for drainage of
orbital abscess with associated paranasal sinus infection.
PMID- 9395801
TI - Detection of low numbers of neuroblastoma cells in vitro.
AB - Neuroblastoma is a tumour derived from the sympathoadrenal progenitors of the
neural crest. It is one of the most malignant solid tumours in childhood with an
annual incidence of 9.4 per 10(6) children under 15 years of age. Recent studies
suggest that immunocytological detection of neuroblastoma cells in bone marrow
and circulating neuroblasts during treatment may predict clinical outcome and
correlate with tumour relapse. The present methods of diagnosing metastasis in
neuroblastoma include histological, biochemical and immunohistological analysis.
Morphological distinction between tumour cells and primitive lymphoblasts in bone
marrow is often difficult, and these methods may also not always be sensitive
enough for early detection of the residual and minimally circulating tumor cells.
A sensitive assay for detection of such residual cells using two tissue-specific
markers, NFM and SYN, by reverse transcriptase-polymerase chain reaction (RT-PCR)
is reported here. Analysis of the specificity of this assay in three
neuroblastoma cell lines, namely IMR 32, SK-N-SH and SY5Y showed positive
expression while control peripheral blood mononuclear cells (HL 60) were
negative. In reconstituted cell spiking tests, this method has the ability to
detect 1-10(3) neuroblastoma cell in 10(7) normal peripheral blood mononuclear
cells (PBMC), as shown by serial dilution and limiting dilution. The NFM marker
was found to be a more sensitive marker. The specificity and sensitivity of this
technique makes it suitable for future application in detection of minimally
disseminated tumour cells in neuroblastoma patients.
PMID- 9395802
TI - Group B streptococcus: maternal carriage rate and early neonatal septicaemia.
AB - Between January 1984 and December 1994, 30 cases of early neonatal group B
streptococcus (GBS) septicaemia were managed in the Neonatal Unit, University
Hospital, Kuala Lumpur. Two neonates were outborn and 28 were inborn, giving an
average annual incidence of neonatal GBS septicaemia of 0.4/1000 livebirths among
inborn babies. In a separate survey over a three-month period, GBS genital
carriage rate among 196 parturients was found to be 9.7%. Of the infants with GBS
septicaemia, the mean gestational age was 37.5 +/- 3.8 weeks and the mean
birthweight was 2540 +/- 716 g. Twelve (40%) were preterm infants and 14 (47%)
were low birthweight infants. Male and female infants were almost equally
affected. Prolonged rupture of membranes and maternal pyrexia accounted for only
5 (17%) and 3 (10%) of the cases respectively. Twenty-four (80%) neonates had
onset of symptoms within 6 hours of life and respiratory symptoms were observed
in 24 (80%) of the cases, while meningitis was uncommon. Six (20%) neonates died.
Preterm and low birthweight infants had higher mortality than their term
counterparts: 42% versus 6% and 36% versus 6% respectively. Of those who died, 4
(67%) required respiratory support right from birth and the mean time of onset of
symptoms was 4 hours (range 0 to 21 hours) and the duration of survival was only
28.8 hours (range 12 to 38 hours). As the incidence of neonatal GBS septicaemia
was low, mass screening and chemoprophylaxis for GBS were not recommended. All
the GBS isolates were sensitive to penicillin and ampicillin, thus one of these
antibiotics should be included in the antimicrobial therapy of septic neonates.
PMID- 9395803
TI - Preoperative versus postoperative pethidine for extraction of impacted third
molars.
AB - We have studied the pre-emptive analgesic effects of pethidine by comparing its
analgesic effects given before or immediately after operation in a randomized,
double-blind study of 40 patients undergoing removal of bilateral impacted third
molars under general anaesthesia. Group 1 patients received pethidine 50 mg as a
1 ml injection 1 to 2 hours before operation and normal saline 1 ml
intramuscularly immediately after surgery. Group 2 patients received normal
saline 1 ml intramuscularly before operation and pethidine 50 mg as a 1 ml
injection immediately after surgery. Outcome measures included perception of pain
on a visual analogue scale (VAS), the number of patients who required
postoperative pethidine, time to first postoperative pethidine injection and
total dose of pethidine given. Four patients in group 1 compared to 8 in group 2
required postoperative pethidine but this was not statistically significant. The
VAS scores, time to first postoperative pethidine injection and total dose of
pethidine also did not differ significantly between the 2 groups. We concluded
that preoperative administration of pethidine intramuscularly did not confer
additional analgesic effects compared with a similar dose given after surgery.
PMID- 9395804
TI - Preoperative prediction of intra and postoperative red blood cell transfusion in
surgical patients.
AB - Anaesthetists were asked to predict the need for intra and postoperative red
blood cell transfusion in 1706 patients before surgery. Each prediction was made
using only the individual patient's medical history and physical examination, the
results of routine preoperative laboratory investigations, and knowledge of the
proposed surgical procedure. Only 159 patients (9.3%) received red blood cell
transfusion. The sensitivity and specificity of this preoperative prediction were
85.5% and 96.6% respectively, whereas the positive and negative predictive values
were 72.3% and 98.5% respectively. Using a stepwise logistic regression model,
preoperative haemoglobin concentration, Surgical Table of the procedure, and age
of patients were found to significantly determine the need for intra and
postoperative red blood cell transfusion. It is recommended that type and screen
should replace group and crossmatch procedures in surgical patients where no
intra and postoperative red blood cell transfusion is predicted as necessary.
PMID- 9395805
TI - Thyroid stimulating hormone receptor antibody levels in Singaporean patients with
autoimmune thyroid disease.
AB - Stimulating thyrotrophin receptor antibodies (TRAbs) have been identified as the
antibodies responsible for the pathogenesis of Graves' disease (GD) while
blocking TRAbs have been implicated as the cause of hypothyroidism in some
patients with chronic lymphocytic thyroiditis (CLT). TRAb positivity in patients
with other thyroid disorders such as silent thyroiditis, toxic multinodular
goitre and subacute thyroiditis has been reported but the role of TRAb in these
disorders is unclear. A study was carried out to determine the prevalence of TRAb
positivity in Singaporean patients with a spectrum of thyroid diseases. TRAb
levels were measured in 181 patients with GD, 54 patients with CLT (37 goitrous
and 17 agoitrous), 16 patients with thyroid nodules, 11 patients with subacute
thyroiditis, 1 patient with hyperthyroidism due to a human chorionic
gonadotrophin (HCG)-secreting tumour, 2 patients with thyroid stimulating hormone
secreting tumours and 2 patients with amiodarone-induced dysthyroidism. Using a
cut-off of 10.0 U/L, TRAb levels were found to be positive in 79.0% of GD
patients, 9.2% of CLT patients (euthyroid and hypothyroid) and no patients with
other thyroid disorders. TRAb was a more sensitive marker of GD than anti
thyroglobulin antibodies (53.2%) but not anti-microsomal (78.3%) antibodies. TRAb
levels > 10.0 U/L appear to be highly specific for autoimmune thyroid disease.
PMID- 9395806
TI - Usefulness of bacteriologic cultures in choice of antibiotics in patients with
chemotherapy-induced neutropenic sepsis.
AB - Neutropenic sepsis is a potential problem in cancer patients undergoing cytotoxic
chemotherapy. Septic work-up including cultures from various sites is routinely
done for these patients. To assess the usefulness of these cultures, a
retrospective review of all patients admitted for neutropenic sepsis in the
period from June 1994 to August 1995 was conducted. All patients included in the
study had solid tumours which were being treated at our institution during the
study period. All had fever and documented neutrophil count of < 1 x 10(9)/l on
at least one occasion. There was a total of 41 patients with 52 episodes of
neutropenic sepsis. Of the 52 episodes, there were positive cultures in 14 (27%)
episodes, including 7 from blood, 2 from urine and 5 from skin. In the
bacteriologic cultures, gram-negative bacteria were isolated in 11 episodes and
gram-positive bacteria in 5 episodes (2 episodes had both gram-negative and gram
positive bacteria isolated, and 1 episode had two gram-negative bacteria).
Majority of the patients (96%) were treated with a third generation cephalosporin
with/without an aminoglycoside. This empirical treatment was effective with
resolution of fever in 39 (75%). Thirteen (25%) had change of antibiotics because
of deteriorating clinical state or drug resistance. Nine patients with unabated
sepsis had bacteriological cultures which grew organisms resistant to the
empirical antibiotics. Eight responded to the change of antibiotics. One patient
with pseudomonas bacteraemia failed to respond to empirical treatment with
ceftriaxone and died before antibiotics could be changed. Of the patients with
positive cultures, the results of drug sensitivity made a difference to
treatment. None of the patients with negative cultures died from sepsis. It
appears that even though the rate of positive culture is low (27%), it is still
useful as a guide when change of antibiotics is required.
PMID- 9395807
TI - Profile of patients seeking psychiatric treatment from the adult public mental
health services in Singapore.
AB - This study examined the characteristics of patients seeking help from public
mental health services and changes in the utilisation of the services over time.
The sample included 198 consecutive new referrals above the age of 15 years to
the adult psychiatric services provided by Woodbridge Hospital and the Institute
of Mental Health from 1 January 1995 and followed up over a one-year period. The
most common reason for seeking psychiatric treatment was for abnormal behaviour
(26%) and the most common diagnostic group was schizophrenia/paranoid disorder
(21.1%). The medical sector was the most common source of referral (56%). The
primary health care services referred significantly more patients with anxiety
disorders while the police and relatives/friends referred significantly more
patients with schizophrenia/paranoid disorder. About one-third of the sample made
their first contact with the services at the 24-hour Admission Room. One third
received inpatient treatment after their first consultation and those with
schizophrenia/paranoid disorders were more likely to be admitted (P < 0.05). At
the end of one year, 23.2% remained in the services. There were significantly
more elderly patients and those suffering from schizophrenia/paranoid disorder
maintaining contact with the services after one year.
PMID- 9395808
TI - Hypercholesterolaemia and its treatment in Singapore with implications for
screening.
AB - The National University of Singapore Heart Study is a cross-sectional survey of
the whole of Singapore from 1993 to 1995 with a random sample of 961 persons aged
30 to 69 years (response rate 71.2%). Serum lipids were measured enzymatically on
an autoanalyser (Ektachem, kodak). Hypercholesterolaemia was diagnosed if the
person was on lipid lowering drugs or had a serum cholesterol > or = 6.5 mmol/L
(250 mg/dL). Results for the 40 to 64 age group are presented. The proportion and
number in Singapore with hypercholesterolaemia were high, 23.7% and 186,544
persons respectively. However, they declined with the additional requirement of
coronary heart disease (CHD) or risk factors (i.e. cigarette smoking,
hypertension or diabetes mellitus), and were small if only hypercholesterolaemic
persons with CHD were included, 1.6% and 13,126 persons respectively. For both
genders, the proportions on drugs increased with the added options of CHD or risk
factors, so that for persons with hypercholesterolaemia and CHD the proportion on
drugs was very high i.e. 84.0%. However, 11.2% of persons with only
hypercholesterolaemia (i.e. without CHD or other risk factors) had been
prescribed drugs. The main conclusions were:1) The use of different criteria for
the screening and treatment of hypercholesterolaemia would involve large
differences in the number of Singaporeans on lipid lowering drugs and this should
be considered when deciding policy and 2) Medical practitioners currently to some
extent do consider the presence of CHD or other risk factors when prescribing
lipid lowering drugs for hypercholesterolaemia.
PMID- 9395809
TI - Predilection for supracondylar fractures in children with cubital recurvatum.
AB - It has been a common observation that children with supracondylar fracture of the
humerus tend to demonstrate hyperextensibility of their elbow joints. In this
study, we measured and compared the degree of hyperextension of the uninjured
elbow of children less than sixteen years old who sustained either a
supracondylar or a distal radial fracture. We concluded that children with higher
degree of hyperextension in the elbow are more likely to sustain a supracondylar
fracture than a distal radius fracture during a fall on the outstretched hand.
PMID- 9395810
TI - An epidemiological study of developmental dysplasia of the hip in infants in
Singapore.
AB - The incidence of congenital dislocation of the hip (CDH) in Singapore and
Malaysia has been reported as being lower than in the West. In our hospital, we
have seen an increasing number of congenital hip dislocation as well as
dysplastic hips. We undertook a prospective study from December 1989 to December
1994 of 20,000 live births. The neonates were all screened by a consultant
neonatologist and the findings were confirmed by a consultant paediatric
orthopaedic surgeon. All babies had plain X-rays at 3 months and an acetabular
index (AI) of 30 degrees or more was considered dysplastic. All babies with
positive signs were followed up for 1 year and again had radiographs taken at 1
year. Comparison of plain X-rays and ultrasound assessment in a subgroup of 130
neonates showed that 64% of patients with AI > 20 degrees had hip dysplasia by
ultrasonographic (alpha angle < 60 degrees) The incidence of dysplastic hips was
16.8 per 1000 live births. The overall incidence of neonates with dislocated hips
was 4.7 per 1000 live births. The Malays were most affected with an incidence of
5.4 per 1000 live births. The incidence of developmental dysplasia of the hip in
Singapore is higher than previously reported, with the Malays having the highest
incidence. A significant number of babies with clicking hips have radiological
evidence of acetabular dysplasia (AI > 30 degrees). One-third of the babies' hips
were still dysplastic at 1 year of age. A well-organised screening programme with
experienced examiners has proved to be useful in making early and accurate
clinical diagnosis.
PMID- 9395811
TI - Uncemented total hip replacements using the Mecron acetabular cup--a prospective
study.
AB - The uncemented threaded cup gained some popularity over the past decade, firstly
as a revision and then as a primary procedure. We elected to test the Mecron
acetabular threaded cup system as a routine hip replacement. As there was no
matched femoral component, we decided to use an uncemented femoral stem of the
Ring system of the hip prosthesis. All patients were logged on to the study at
the outset although this is not a controlled comparison with another system.
Patients were assessed annually for up to 4-years at the time of reporting. There
were 104 primary total hip replacements in 99 patients between 1987 and 1991. The
mean follow-up for this report was 22.5 months (range 12 to 48 months). The mean
age was 76.3 years (range 24 to 88 years) and the female to male sex ratio was
3.3:1. Within the study period, 5 hips required revision, all for acetabular
loosening. Patients were assessed by the modified Harris score annually and 60.6%
of the cases had an excellent or good short-term result. Poor results were
observed in 18.3% of cases. Radiographic studies of the acetabular component were
undertaken annually and measured. Migration and tilting of the acetabular cup was
observed in all cases. Heterotropic bone formation occurred in 10 patients. As a
result of these poor results, the prosthesis was abandoned in 1991. The cohort of
patients continues to be followed. Failure of the Mecron acetabular cup in our
series was mainly due to tilting and migration and not untwisting.
PMID- 9395812
TI - Pattern of proteinuria in tubular injury and glomerular hyperfiltration.
AB - Proteinuria is one of the bad prognostic indices in renal disease. This study
compares the pattern of protein excretion in 10 patients with IgA nephropathy
(IgAN), 10 patients with chronic glomerulonephritis approaching end-stage renal
failure (ESRF) who still had proteinuria and 10 other patients with diabetic
nephropathy (DN) with proteinuria but normal renal function. The pattern of
proteinuria was analysed by sodium dodecyl sulphate polyacrylamide gel
electrophoresis (SDS-PAGE), isoelectric focusing (IEF) and assayed for
orosomucoid, alpha-1-microglobulin, retinol-binding protein, lysozyme, beta-2
microglobulin and N-acetyl-beta-D-glucosaminidase activity. Our data showed much
similarity in the pattern of proteinuria between the DN and ESRF groups but
significant differences with the IgAN group. The pattern of proteinuria in the
IgAN group reflects glomerulonephritis whereas the similar pattern between the
ESRF and DN groups may reflect hyperfiltration as well as tubular injury.
PMID- 9395813
TI - Refractory seizures in a young army cohort.
AB - This survey covered male Singapore citizens born in 1974 who were medically
screened at the age of 18 years before enlistment for compulsory military
service. Suspected epileptics were referred to government hospitals for further
management. Out of 20,542 men, there were 121 epileptics, giving a cumulative
incidence of 5 per 1000 by age 18 years. We had information on 106 (87%) of these
individuals and were able to interview them and review their hospital records.
Seventy-three of the 106 (69%) epileptics had generalised seizures while 14 (13%)
had refractory seizures. There was no statistically significant racial bias
amongst these epileptics. Unprovoked afebrile seizures occurred early in these
patients, half of whom had seizures onset before 7 years of age. Nine refractory
epileptics had a history of febrile seizures, 4 of which were complex febrile
seizures. Magnetic resonance imaging identified mesial temporal sclerosis in 2
patients and a hypothalamic lesion in 1 patient. Computed tomographic scans
revealed focal cortical atrophy in 2 patients. Nine other patients had normal
imaging studies. Nine out of 14 (64%) patients with refractory epilepsy had
partial seizures; 4 (29%) had generalised seizures and 1 (7%) was unclassified.
This is in contrast to the distribution of the entire cohort of epileptics
studied. Two out of 9 patients with refractory partial seizures (gelastic
epilepsy and mesial temporal sclerosis) had undergone surgery while 6 of the
other 7 patients refused to consider surgery.
PMID- 9395814
TI - Surgical excision of intracranial arteriovenous malformations after preoperative
embolisation with N-butylcyanoacrylate.
AB - The aim of this study was to determine the usefulness of preoperative
embolisation of intracranial arteriovenous malformations (AVMs) with N
Butylcyanoacrylate (NBCA) since the introduction of this interventional
neuroradiology technique in March 1994 at Tan Tock Seng Hospital, Singapore.
Twenty-one patients who underwent complete surgical excision of their AVMs
(proven on postoperative angiograms) were studied. Eight patients had
preoperative embolisation with NBCA prior to surgical excision of their AVMs.
Thirteen patients had excision of their AVMs without preoperative embolisation
and these were used as the control group. The parameters studied were the
patient's AVM characteristics, the amount of blood loss and the length of
operative time. Statistically significant reduction in blood loss occurred in
Spetzler and Martin Grade 3 and 4 AVMs but not in Grade 1 and 2 AVMs undergoing
preoperative embolisation with NBCA. Operative time was reduced in Grade 3 and 4
AVMs but not in Grade 1 and 2 AVMs, although this was not statistically
significant. Preoperative embolisation of AVMs is hence a useful and important
adjunct in the management of patients with Grade 3 and 4 AVMs of the brain
undergoing conventional open microneurosurgery.
PMID- 9395815
TI - Glycoprotein IIb/IIIa platelet receptor inhibitors: a new dimension in
cardiology.
AB - Platelets play a key role in the pathogenesis of atherosclerosis, acute coronary
syndromes and ischaemic complications following percutaneous coronary
intervention. More recently, the platelet glycoprotein (GP) IIb/IIIa receptor has
been identified as the pivotal mediator of platelet aggregation, leading to
thrombus formation. This has led to the emergence of a novel class of potent
antiplatelet agent, the GP IIb/IIIa receptor antagonists. These agents show great
promise in reducing ischaemic complications of coronary angioplasty and acute
coronary syndromes. This review summarizes the current state of knowledge of the
biology of GP IIb/IIIa receptor, the different classes of GP IIb/IIIa receptor
antagonists, the results of the various trials, and their impact on current
clinical practice.
PMID- 9395816
TI - The epidemiology of obesity: a review.
AB - Obesity is a major public health problem worldwide contributing to increased
morbidity and mortality. There are several indices of obesity which include body
mass index, waist-hip circumference ratio and skinfold thickness. The prevalence
of obesity varies from 7% in France to 32.8% in Brazil. However, the comparison
of obesity across different countries is difficult as there are different age
structures of the population, measurement techniques are not the same and surveys
may not be population-based. Trends in developed and developing countries suggest
that the rates of obesity are increasing. This rising trend may be contributed by
factors such as low levels of physical activity, high calorie intake and long
hours of watching television. Cohort and cross-sectional studies have shown that
obesity may be linked to an increased risk of coronary heart disease,
hypertension, diabetes mellitus and gallstones. There is also a positive
association between obesity and cancer. The mortality of obese adults,
adolescents and children is higher than that of the general population. Multi
prolonged intervention strategies are needed to prevent obesity and its
associated complications.
PMID- 9395817
TI - Vocal cord dysfunction: two case reports.
AB - Vocal cord dysfunction is an uncommon condition characterised by adduction of
vocal cords that can masquerade as or coexists with bronchial asthma. The glottic
dysfunction is due to a functional (non-organic) cause. If unrecognised,
incorrect diagnosis may result in patients being unnecessarily treated as
refractory or severe asthma with high doses of corticosteroid. This may result in
unwarranted steroid toxicity. Clues that should raise clinical suspicion to the
diagnosis of vocal cord dysfunction include lack of response to bronchodilators,
poor reproducibility of spirometric indices due to inconsistent effort and
truncation of the inspiratory limb of the flow-volume loop. Definitive diagnosis
is made by direct visualisation of the vocal cords during an attack. We report
two patients with vocal cord dysfunction and review the literature on this
disorder.
PMID- 9395818
TI - A case of fluid embolism from transcervical endometrial resection.
AB - Hysteroscopic transcervical endometrial resection (TCER) using a urological
resectoscope offers an alternative to hysterectomy for some women with
menorrhagia. The advantages of this technique are a shorter operating time and a
rapid recovery and discharge. However, this procedure is not without risk of
complications and one of them is related to dilutional hyponatraemia from
absorption of the irrigation solution. This report describes a patient who
experienced such a problem.
PMID- 9395819
TI - Familial aplasia cutis congenita of the scalp: a case report and review.
AB - We report three cases of aplasia cutis congenita of the scalp affecting two
siblings and their mother, suggesting group 1, or autosomal dominant aplasia
cutis congenita not associated with multiple abnormalities. A review of the
clinical features and literature concerning this heterogenous and rare condition
is presented.
PMID- 9395820
TI - Familial papillary thyroid cancer: a case report.
AB - Familial occurrence of medullary thyroid cancer is well known in families as an
isolated malignancy or in association with multiple endocrine neoplasia syndrome
type II. Conversely, papillary thyroid cancer almost always presents sporadically
except for reports of familial clustering in individuals with radiation exposure,
inherited syndromes of colonic polyposis or multiple harmatomas, and rarely in
monozygotic twins. We report a case of papillary thyroid cancer diagnosed
incidentally in a 53-year-old woman who underwent surgery for excision of an
adenomatous nodule. It was noted that her mother suffered from a similar thyroid
malignancy some 33 years ago, and several of her maternal relatives had either
Graves' disease or hypothyroidism. The possible existence of this familial entity
and its likely genetic basis is discussed.
PMID- 9395821
TI - De novo interstitial deletion of chromosome 1p with absent corpus callosum--a
case report.
AB - Deletion of short arm of chromosome 1 is a rare clinical entity and there are no
clearly defined phenotype. We report a case of deletion of the short arm of
chromosome 1, which is believed to be the first case among the Chinese
population. This baby was also found to have some Robinow Syndrome-like features
as well as absent corpus callosum which have never been reported in deletion of
chromosome 1p.
PMID- 9395822
TI - Histoplasmosis in the head and neck.
AB - Histoplasmosis is a fungal infection which when disseminated can be potentially
fatal, especially in the immunocompromised patient. Disseminated histoplasmosis
can present with orolaryngeal manifestations which often mimic carcinoma or
tuberculosis. A high index of suspicion and diagnosis with biopsy is needed. Two
recent cases are presented and the literature reviewed. As the number of
immunocompromised patients increases, more cases of histoplasmosis in the head
and neck will be encountered. Early treatment can reduce morbidity and mortality.
PMID- 9395823
TI - Popliteal artery aneurysm: two case reports of acute lower limb ischaemia.
AB - Two cases of thrombosed popliteal artery aneurysm causing acute ischaemia were
described. This report emphasises the importance of early diagnosis and surgical
intervention of this condition. We then present a brief review of clinical
presentation and current management of popliteal artery aneurysm. Popliteal
artery aneurysm commonly first present as acute lower limb ischaemia secondary to
thrombo-embolism. Failure to recognise this limb-threatening condition can lead
to delay in treatment and even limb loss. It is therefore important to increase
awareness of this condition. Popliteal artery aneurysm warrants early surgical
intervention, even in an asymptomatic stage because of its potential for serious
complications.
PMID- 9395824
TI - Cholesterol and atherosclerosis: a contemporary perspective.
AB - Monumental advances in the field of lipid metabolism and its relationship to
atherosclerotic cardiovascular disease have been achieved during the last half
century. Epidemiologic studies have defined lipid disorders as highly significant
independent risk factors for coronary heart disease, along with diabetes
mellitus, hypertension and smoking. Primary and secondary prevention studies
including the Coronary Primary Prevention Trial, Helsinki Heart Study, and the
Coronary Drug Project have shown that lowering the atherogenic low density
lipoproteins (LDL) and very low density lipoproteins (VLDL) whilst raising the
high density lipoproteins (HDL) significantly decreases the risk for coronary
disease. Striking evidence that aggressive therapy (to sharply lower LDL and
raise HDL with newer drugs) prevents progression and induces regression of
coronary narrowing has been obtained in numerous recent studies using
quantitative coronary arteriography. An interesting and unexpected lesson learned
from these arteriographic studies was that a highly significant reduction within
months in several studies in coronary events was out of proportion to
improvements in luminal narrowing. Recently, three major clinical trials to
assess the effects of cholesterol reduction by the newly discovered HMG CoA
reductase inhibitors (statins) have been published. Pravastatin significantly
reduced coronary events in hypercholesterolemic patients [mean LDL-Chol. = 5.0
mM/L (192 mg/dl)] without a history of myocardial infarction. In a secondary
prevention study, simvastatin also reduced coronary complications in
hypercholesterolemic patients [mean LDL-Chol. = 4.9 mM/L (190 mg/dl)] with pre
existing coronary disease. Very recently, pravastatin treatment significantly
reduced coronary events and stroke in patients with a history of myocardial
infarction and average cholesterol levels [mean LDL-Chol. = 3.6 mM/L (139
mg/dl)], representing the majority of patients with coronary disease. In all
these studies, reduction in cardiovascular events was approximately one-third. In
subgroup analyses, men, women, elderly, smokers and hypertensives benefited from
cholesterol lowering. There was no significant increase in non-cardiovascular
causes of death. In the United States of America, the National Cholesterol
Education Program (NCEP) Adult Treatment Panel, representing major health
organizations, developed national guidelines on the detection, evaluation and
treatment of high blood cholesterol in adults. In a given patient, the Panel
recognizes the importance of weighing all cardiovascular disease risk factors
including age (men > 45 years, postmenopausal women), family history of premature
coronary disease, smoking, hypertension, diabetes and HDL-Cholesterol (< 35
mg/dl) in determining how aggressive therapy should be. The patient with manifest
coronary heart disease (CHD) is given a special position as such patients are at
highest risk for recurrent events. Major goals of therapy are to lower the LDL
Cholesterol to 2.6 mM/L (< 100 mg/dl) in the CHD patient. In non-CHD patients
with two or more risk factors, the LDL-Cholesterol goal is 3.4 mM/L (130 mg/dl).
In those with fewer risk factors, the goal is 4.2 mM/L (160 mg/dl). These
guidelines should be modified as appropriate for Singapore. Patients with
elevated triglycerides usually have low HDL-Cholesterol levels and often
represent a heterogeneous group who may have other concurrent abnormalities
including the presence of small dense LDL, insulin resistance, hypertension,
obesity, overt diabetes and combined hyperlipidemia. Such patients merit
individualized treatment. The prevalence of this syndrome may be more common in
Singapore and requires further investigation. Current therapeutic guidelines
emphasize the need for weight loss and dietary restriction of total and
especially saturated fat (< 7% to 10% total calories), cholesterol (< 200 to 300
mg/day), and exercise. (ABSTRACT TRUNCATED)
PMID- 9395825
TI - Joint lectureship of the Royal College of Surgeons of Edinburgh and the Academy
of Medicine, Singapore--accurate long-term documentation in surgical audit and
evaluation of outcomes.
AB - The purpose of a surgical audit is to allow a critical assessment of patient
care, carried out among peers and in an atmosphere of learning, open discussion,
free of recriminations. The results of a surgical unit will hopefully lead to
improvement in the quality of care of our patients by reducing the preventable
causes of mortality and morbidity. Data from surgical audit can also be used to
monitor the teaching programme in a department. It may even allow us to study the
cost effectiveness of certain procedures which is obviously very important in
this era of diminishing resources and cost containment.
PMID- 9395826
TI - Knowledge and beliefs about common eye diseases.
PMID- 9395827
TI - Intraocular lens materials and styles: a review.
AB - Biomaterial science has lead to the development of a variety of foldable
intraocular lens (IOL) biomaterials. This literature review examines these lenses
from both a basic science and a clinical perspective. By most parameters,
hydrogel, soft acrylic and silicone IOL are better than polymethylmethacrylate
(PMMA) lenses. Plate haptic silicone IOL have the lowest incidence of cystoid
macula oedema and posterior capsule opacification, but these lenses require an
intact anterior capsularhexis and posterior capsule. Yttrium aluminium garnet
(YAG) laser capsulotomy must be delayed at least 3 months to avoid posterior lens
dislocation. Silicone has the lowest threshold for YAG laser damage of all IOL
materials and also adheres irreversibly to silicone oil with subsequent optical
impairment. Three piece silicone IOL with polypropylene haptics have a higher
incidence of decentration, pigment adherence and capsule opacification compared
with PMMA haptics. Hydrogel lenses are very biocompatible and resistant to YAG
laser damage, but pigment adheres to the surface more readily than PMMA. Soft
acrylic IOL unfold slowly, resulting in controlled insertion, but it is possible
to crack the lens and some lenses develop glistenings due to water accumulation.
There are significant socioeconomic implications to the large differences in
posterior capsule opacification rates between the various biomaterials and the
lens styles.
PMID- 9395828
TI - Topical anaesthesia for cataract surgery.
AB - First, do no harm. We believe that the analgesia provided by topical anaesthetic
is adequate for small-incision cataract surgery and does not compromise the
safety of the surgery. In addition, the lack of amaurosis is ideal for day-case
surgery, which itself is increasingly popular. If preventable, why not prevented?
The greatest attraction of topical anaesthesia is its complete absence of the
complications described for injectional local anaesthetic techniques. We
therefore recommend that our colleagues consider topical anaesthetic for patients
undergoing small-incision cataract surgery under local anaesthesia. Our policy
for the past 3 years has been to use only topical or general anaesthetics for
cataract surgery.
PMID- 9395829
TI - Retrospective study of ocular surface squamous neoplasia.
AB - BACKGROUND: Ocular surface squamous neoplasia (OSSN) encompasses the conditions
of simple dysplasia to carcinoma in situ to invasive squamous cell carcinoma. It
has a high rate of recurrence after treatment and the potential to metastasize.
The present retrospective study was aimed at further defining the characteristics
and clinical course of OSSN. METHODS: With ethical approval, the records of all
major pathology laboratories in Queensland were surveyed. Two hundred and eighty
eight cases were identified: 155 dysplasia, 71 carcinomas in situ and 62 invasive
squamous cell carcinoma. The records were analysed and an attempt was made to
contact and re-examine the patients. RESULTS: Ocular surface squamous neoplasia
occurs mainly in males (78.5%) with a mean age of 60.1 years (range 20-88 years).
They present as irritation (40.1%) and are located usually at the limbus (87.8%).
The majority of OSSN are treated by simple excision (87.5%), after which there is
a high rate of recurrence (23.3%). The main predictors for recurrence include
histological grade of the lesion, corneal location and larger size (> 2 mm).
CONCLUSIONS: Management of OSSN requires adequate excision and careful follow up
to monitor any recurrence. As with other ultraviolet light-related conditions,
preventative measures must remain the key to disease control.
PMID- 9395830
TI - Acute posterior multifocal placoid pigment epitheliopathy: a long-term study.
AB - PURPOSE: To study the long-term visual outcome in patients with acute posterior
multifocal placoid pigment epitheliopathy (APMPPE). METHODS: Fifteen patients (28
eyes) with APMPPE were reassessed at Westmead Hospital Eye Clinic (Westmead, NSW,
Australia) up to 18 years (mean 6.4 years) after their initial presentation to
one of the authors (PM) or to their private ophthalmologist. Stereo retinal
photographs and visual acuities taken at the initial presentation were compared
with those obtained at the most recent follow-up visit. RESULTS: The last
recorded visual acuity was 6/6 or better in 16 eyes (57%), 6/9-6/18 in four eyes
(14%), 6/24-6/60 in five eyes (18%) and worse than 6/60 in three eyes (11%). Nine
patients (60%) were treated with oral prednisone during the acute episode with
little therapeutic effect observed. Six patients (40%) described a prodromal flu
like illness. CONCLUSION: This study suggests that the long-term visual outcome
following an acute episode of APMPPE may not be as favourable as initially
portrayed by Gass. It confirms other study findings suggesting that APMPPE may
not be a benign self-limiting disease. Older age at onset and initial foveal
involvement were associated with a worse visual outcome.
PMID- 9395832
TI - A review of 24 cases of Mohs surgery and ophthalmic plastic reconstruction.
AB - PURPOSE: Mohs surgery (micrographically controlled excision) has been advocated
as an effective method of dealing with infiltrative periorbital skin tumours. It
has been shown to have high rates of tumour clearance with minimal loss of normal
tissue, thus making oculoplastic reconstruction easier and functional
preservation better. The aim of the present study was to confirm this. Guidelines
for the selection of patients for Mohs surgery are discussed. METHODS: We
retrospectively reviewed 24 cases of primary (n = 18) and recurrent (n = 6)
periorbital basal and squamous cell carcinomas managed by Mohs micrographic
excision and plastic reconstruction who presented to the Royal Perth Hospital
between 1992 and 1996. RESULTS: Our high rate of tumour clearance (100%) was
similar to that of previous studies, although our follow-up period was only 14.6
months. The fact that 50% of our patients with lid involvement had an intact
posterior lamella after Mohs excision correlates with the high level of normal
tissue preservation. The low rate of postoperative symptomatic problems suggests
good maintenance of function. The infiltrative nature of these tumours was
highlighted by the substantial proportion of cases (37.5%) that had a much larger
excision defect than what was expected prior to excision. CONCLUSIONS: Our
analysis confirms that Mohs excision and subsequent oculoplastic reconstruction
is an effective method to use when managing periorbital infiltrative skin
tumours.
PMID- 9395831
TI - Knowledge and beliefs about common eye diseases.
AB - PURPOSE: To ascertain the level of knowledge of common causes of blindness in an
adult Australian population and to relate this to use of eye care services.
METHODS: A population-based study of common eye diseases in an urban population
aged 49 years or older was conducted. The questions were concerned with the
awareness and knowledge of and the ability to describe three common eye diseases,
namely cataract, glaucoma and age-related macular degeneration (AMD). RESULTS:
Awareness of cataract (98%) and glaucoma (93%) were high in this population, but
awareness of AMD was low (20%). Among people who were aware of the target eye
disease, only 29% showed some knowledge of glaucoma, 26% showed some knowledge of
AMD and 20% showed some knowledge of cataract; this was also low in people who
had previous eye treatment, such as cataract surgery. Knowledge was related to
education level, occupational prestige and knowledge of other eye diseases. After
excluding people with a previous eye disease diagnosis, those people who were
aware and had some knowledge of eye disease accessed eyecare services more
frequently. CONCLUSIONS: Knowledge of common eye diseases is generally lacking.
Age-related macular degeneration is the leading cause of blindness in Australia,
yet only 20% of the present study population had heard of it. As there are often
no early symptoms for glaucoma, community awareness of this disease and the need
for screening of people at risk may allow timely diagnosis and more effective
therapy before advanced visual field loss has occurred. An informed public is
more likely to present earlier with visual symptoms before irreversible visual
loss has occurred and is more likely to comply better with recommended therapy.
PMID- 9395833
TI - Georg Bartisch: Ophthalmodouleia, der Augendienst, 1583. A treatise on service of
the eyes and a review of the chapter on strabismus.
AB - In 1583, Georg Bartisch, oculist and cutter for bladder stones at the court of
Duke August I of Saxony, published at his own expense a 273 page textbook of
ophthalmology. It contained 91 wood cuts and, in the present volume, they are
presented in brilliant colour as they were in the original books prepared for
presentation. The book was one of the first medical treatises to be published in
the German vernacular instead of traditional Latin. It has been translated into
English and published in gothic type to simulate the original. Treatment of
diseases of the eye by medicines or surgery are reported in great detail. It
gives an account of ophthalmology at the time of the early Renaissance when
enlightenment was beginning to overtake the darkness of the Middle Ages.
PMID- 9395834
TI - Aeromonas sobria endophthalmitis.
AB - BACKGROUND: Aeromonas sobria causes a rare Gram-negative bacterial water-borne
infection. It has been found in waters of North Queensland and South-east Asia.
Of all Aeromonas species, A. sobria is the most virulent and invasive and has
been reported to cause soft tissue infection and corneal ulcer. METHODS: A 14
year-old Caucasian male from North Queensland presented following a penetrating
eye injury in which a water bird (cormorant species) had pecked his eye while he
was fishing. A fulminant endophthalmitis developed despite treatment with
intravenous, intravitreal and topical antibiotics and initial wound repair.
Enucleation was performed. RESULTS: Aeromonas sobria was isolated from the
vitreous aspirate. CONCLUSION: Aeromonas sobria infection should be suspected in
water-contaminated penetrating eye injuries. The prognosis in this case was poor.
PMID- 9395835
TI - Cast-forming Actinomyces israelii canaliculitis.
AB - BACKGROUND: Primary chronic canaliculitis is an uncommon disease usually caused
by Actinomyces israelii (streptothrix). Actinomyces israelii is a cast-forming
Gram-positive anaerobe that is difficult to isolate and identify. We present a
case that demonstrates the typical clinicopathological presentation of this
unusual condition and discuss management options. METHODS AND RESULTS: A 10-year
old girl presented with a 6 month history of intermittent 'conjunctivitis' and
discharge from her 'pouted' left lower punctum. Microbiology confirmed probable
A. israelii infection, but topical treatment failed. Exploration under
anaesthesia revealed a canalicular diverticulum and three canaliculiths.
Histological examination of the canaliculiths demonstrated that they consisted of
solid casts of Actinomyces. Punctoplasty, removal of the casts, and adjunct
antibiotic therapy resulted in resolution of the canaliculitis. CONCLUSIONS:
Primary chronic canaliculitis should be considered in any patient who presents
with chronic or recurrent conjunctivitis and the eyelid should be inspected for a
discharging and 'pouting' punctum. Failure of the condition to resolve on topical
treatment requires surgical exploration of the canalicular system and removal of
any casts. Extensive surgery is not always required.
PMID- 9395836
TI - The pharmacokinetics of bumetanide in the newborn infant.
AB - This study characterizes the pharmacokinetics of bumetanide after an intravenous
dose of 0.05 or 0.10 mg/kg to 14 neonates (weight range 820-4,000 g; gestational
age 26-40 weeks) during the first week of life. Blood samples and urine were
collected for up to 12 h after dosing. Estimated serum clearance was 0.2-1.0
ml/min.kg (range), volume of distribution was 0.22 l/kg (range 0.11-0.32 l/kg),
and the harmonic mean half-life was 6-7 h (range of 4-19 h). Nonrenal clearance
accounted for 58-97% of the serum clearance with the presence of certain
oxidative metabolites of bumetanide in the urine. These findings suggest higher
dosing requirements and prolonged intervals as compared to adults. Utilizing
these pharmacokinetic data, pharmacodynamic and ototoxicity studies should be
conducted to establish a safe and effective neonatal dose.
PMID- 9395837
TI - Interplay between glutathione-S-transferase and glucose-6-phosphate dehydrogenase
in neonatal cord blood.
AB - Three hundred neonatal cord blood samples were collected from two major cities in
Jordan and assayed for glutathione-S-transferase (GST), glutathione, and glucose
6-phosphate dehydrogenase (G6PD). A significant positive correlation between the
levels of G6PD and GST activities was detected. When the G6PD activity decreased,
the GST activity declined. A similar concurrent decrease in the concentration of
reduced glutathione was also observed. When the samples were divided into males
and female samples, some significant variations in the levels of the two enzymes
were observed. Female samples exhibited higher G6PD and GST activities as
compared with male samples. Moreover, the incidence of severe and moderate G6PD
deficiencies was higher in male as compared with female samples. Analyses of the
samples for total bilirubin, red blood cells, hematocrit, and hemoglobin were
also performed, and slight nonsignificant variations were noted.
PMID- 9395838
TI - Hematological features of fetal triploidy: a report of 11 cases.
AB - Using fetal blood sampling, the diagnosis of triploidy can be strongly suspected
on the basis of the peculiar hematological picture. Triploid fetuses present with
anemia, marked anisopoikilocytosis, and grossly increased mean corpuscular
volume, associated with thrombocytopenia and significant platelet anisocytosis.
These findings are of considerable immediate diagnostic value. They allow
physicians to immediately counsel parents about the prognosis of the fetus. In
case of fetal or neonatal distress, this information could orientate decisions
about obstetrical and pediatric management while waiting for the definitive
diagnosis.
PMID- 9395839
TI - Response of hepatic mitochondrial and peroxisomal beta-oxidation to increasing
palmitate concentrations in piglets.
AB - Responses of total, mitochondrial, and peroxisomal beta-oxidation to increasing
[1-14C]-palmitate concentrations (0.02-1.0 mM) were measured in liver homogenates
from neonatal pigs. Incubations were conducted in the absence (total beta
oxidation) or presence (peroxisomal beta-oxidation) of antimycin A and rotenone;
mitochondrial beta-oxidation was calculated as total minus peroxisomal oxidation.
Total and mitochondrial beta-oxidations were maximized at a palmitate
concentration of 0.05 mM, whereas peroxisomal beta-oxidation was maximized at
0.50 mM palmitate. Across concentrations, peroxisomal beta-oxidation contributed
40-47% of total beta-oxidation. An increased rate of CO2 production and a greater
ratio of CO2 production to total mitochondrial beta-oxidation as palmitate
concentration increased suggested that the limited capacity for mitochondrial
beta-oxidation was attributable primarily to limited ketogenic capacity.
Comparative observations in liver from adult rats showed that peroxisomal beta
oxidation was maximized at 0.1 mM palmitate, but total and mitochondrial beta
oxidation rates were not maximized even at 1 mM palmitate. At 1 mM palmitate,
peroxisomal beta-oxidation was 20% of total beta-oxidation in adult rats and 37%
in adult pigs. Therefore, the contribution of peroxisomal beta-oxidation to total
beta-oxidation is highly dependent on substrate concentration and appears to be
greater in adult pigs than in adult rats. The greater proportional contribution
of peroxisomal beta-oxidation in piglet liver might act as a compensatory
mechanism for piglets to oxidize milk fatty acids.
PMID- 9395840
TI - Chronic intermittent in utero exposure to morphine: effects on respiratory
control in the neonatal guinea pig.
AB - This study was done to determine if chronic intermittent in utero exposure to
morphine (MOR) during the last half of gestation results in hypoventilation and
decreased ventilatory sensitivity to CO2 in the neonate. Pregnant guinea pigs
were randomly assigned to once-daily treatment with saline and 1.5, 5.0, or 15.0
mg/kg MOR. Neonates were studied for 3 weeks. Prenatal exposure to 5.0 and 15.0
mg/kg MOR significantly increased neonatal minute ventilation and central
inspiratory drive on day 7 while breathing room air or 5% CO2. The increase in
minute ventilation was part of a withdrawal syndrome that included increased
locomotor activity, but was not due to an increase in metabolic rate or
sensitivity to CO2. We conclude that neonatal guinea pigs exposed once daily to
MOR during the last half of gestation hyperventilate during the 1st week after
birth. These changes are neither permanent nor followed by hypoventilation or
depressed sensitivity to CO2.
PMID- 9395841
TI - Combined effects of fetal beta agonist stimulation and glucocorticoids on lung
function of preterm lambs.
AB - We asked whether a single-dose fetal treatment strategy using betamethasone plus
either a long-acting beta 2 agonist (formoterol) or betamethasone plus agents
that elevate intracellular cyclic adenosine monophosphate (isobutyl
methylxanthine and dibutyryl-cyclic adenosine monophosphate) would augment the
effects of prenatal betamethasone on postnatal lung function. Preterm lambs were
treated with 0.5 mg/kg beta-methasone or betamethasone plus the other agents and
delivered 48 h after treatment. The postnatal lung function as assessed by
compliance, ventilatory efficiency, and lung volumes at 40 min of age was
improved by prenatal betamethasone and improved further by combination treatment,
although the augmented responses were not significantly greater than with
betamethasone alone. Fatty acid synthase protein and enzymatic activity were not
increased by betamethasone or combined treatments, in contrast to responses
reported for other animal models. There were no effects of glucocorticoids or the
combined treatments on surfactant. Stimulation of the beta 2 agonist system did
not augment postnatal lung function significantly above that noted for
betamethasone alone with the agents, doses, and duration of exposures tested.
PMID- 9395842
TI - Estrogen-regulated uterine vascularization modulates the guinea pig intrauterine
environment.
AB - The effects of experimentally-induced, uterine vascular restriction on uterine
blood flow (UBF) and uterine blood volume (UBV) capacity, as well as the
dependent intrauterine oxygen tension (IUpO2) measurements used as an indication
of luminal nutrient availability, were examined using ovariectomized, estrogen
(E)-treated guinea pigs. Following 3 days of E treatment, both UBF and UBV
measurements were found to be elevated and associated with a causally-related
increase in intraluminal uterine oxygen availability levels. Following the acute
clamping of the uterine arteries, both UBF and UBV levels decreased dramatically
and induced a rapid fall in associated intrauterine luminal oxygen tension
measurements. As a result of chronic (i.e., 6 h) restriction of segmental blood
flow to the uterus by vascular cauterization, both UBV and IUPO2 levels were
suppressed as compared with sham-operated control levels, whereas UBF rates were
not significantly altered. The results of the present studies are the first
quantitative demonstration that either acute or chronic reductions in uterine
vascular capacity or competency can induce rapid and dramatic changes in the
intrauterine nutritional environment recognized to be essential for the
initiation, support and maintenance of nidation and subsequent fetal-placental
development.
PMID- 9395843
TI - Assessment of endogenous nitric oxide formation in newborns: measurement of
urinary nitrite and nitrate concentrations.
AB - We measured the urinary nitrite and nitrate (NOx-) excretion, an index of
endogenous nitric oxide formation, in term and preterm newborns on the 1st and
4th days of age. In the infants of both groups, the urinary NOx- excretion
significantly increased from the 1st to the 4th day. The urinary NOx- excretion
in preterm infants was significantly higher as compared with term babies on both
days. Furthermore, the urinary NOx- excretion was significantly elevated in
preterm infants with respiratory distress syndrome as compared with those without
cardiopulmonary complications on the 4th day. These changes of urinary NOx-
excretion in newborns strongly suggest the presence of an active physiological
role for nitric oxide in the circulatory adaptation to extrauterine life.
PMID- 9395844
TI - Risk factors of sensorineural hearing loss in preterm infants. Biol Neonate
1997;71:1-10.
PMID- 9395845
TI - Interference between two concurrent tasks is associated with activation of
overlapping fields in the cortex.
AB - Interference between two concurrent tasks can be measured as an increased
reaction time during simultaneous performance compared to when each task is
performed alone. We tested the hypothesis that two tasks interfere because they
require activation of overlapping areas of the cerebral cortex. With positron
emission tomography we measured cortical activation as fields with significant
increase in regional cerebral blood flow during single task performance of an
auditory and a visual go/no-go task and an auditory and a visual short-term
memory (STM) task. In a separate experiment we measured the degree of
interference between the two go/no-go tasks and between the two STM tasks during
dual task performance. Both the two go/no-go tasks and the two STM tasks
activated overlapping parts of the cortex and interfered significantly during
dual task performance. The two STM tasks had a larger volume of overlap and also
significantly larger increase in reaction time during dual task performance,
compared to the go/no-go tasks. The results thus indicate that two concurrent
tasks interfere, with a resulting increase in reaction time, if they require
activation of overlapping parts of the cortex.
PMID- 9395846
TI - Visual evoked cortical magnetic fields to pattern reversal stimulation.
AB - We studied visual evoked magnetic fields to pattern reversal stimulation in six
healthy subjects. Similar to the N75-P100-N145 components in visual evoked
potentials, triphasic deflections, N75m-P100m-N145m, were clearly observed around
the midoccipital position. A very small component, P50m, was occasionally
observed preceding the N75m. Equivalent current dipoles (ECDs) of the main
deflection, P100m, to quadrant-field stimulation were estimated near or around
the calcarine fissure contralateral to the stimulation. The vertical ECD location
of the P100m to the upper quadrant-field stimulation was estimated significantly
lower (0.81 +/- 0.45 cm) than those to lower stimulation. These results were
compatible with the retinotopic organization of the visual cortex (cruciform
model) and suggested that the P100m originated in the striate cortex. The small
P50m, although only a small number of ECDs could be estimated reliably, was
located in the contralateral visual cortex. ECDs of the N75m were estimated
mainly near or around the contralateral calcarine fissure. ECDs of the N145m were
estimated also retinotopically, but with a greater vertical distance (2.90 +/-
1.09 cm) between upper and lower quadrant-field stimulation. MR-overlaid ECDs of
the N145m suggested that these originated in the extrastriate cortex. No ECD was
estimated when a probe was placed at the midfrontal position.
PMID- 9395847
TI - Operant performance and cortical acetylcholine release: role of response rate,
reward density, and non-contingent stimuli.
AB - The relationship between acetylcholine (ACh) efflux in medial prefrontal cortex
(mPFC) and performance in a visual discrimination task and a variable interval
(VI) schedule of reinforcement was studied in rats. Animals were pretrained in
one of the two tasks and then unilaterally implanted with microdialysis guide
cannula into the mPFC. Animals were then dialyzed, during 12 min collection
intervals, in the operant chambers prior to task onset and during and after task
performance. Each animal was dialyzed for a total of four sessions: two standard
task sessions, one session in which a houselight was flashed at 0.5 Hz during the
third 12 min block, and an extinction session (always the last session) in which
reinforcement was withheld during the final three blocks. Response accuracy in
the discrimination task was very high (> 95% correct) and stable across the four
blocks with a progressive increase in omissions. The flashing houselight did not
affect performance whereas the loss of reinforcement led to an increase in
omissions. VI performance was associated with a high number of lever presses and
a high reward rate that declined over the four blocks. Again, the flashing
houselight did not affect VI performance whereas lever pressing declined markedly
during the extinction session. ACh efflux did not change, relative to baseline,
during performance in either task, or with the presentation of the flashing
houselight or the loss of reinforcement. These data contrast with the changes in
cortical ACh efflux observed in situations characterized by the presentation of
novel stimuli or changing demands on attentional processing and, therefore,
assist in the specification of hypotheses on the cognitive functions of cortical
ACh.
PMID- 9395848
TI - How the brain processes complex words: an event-related potential study of German
verb inflections.
AB - Event-related brain potentials (ERPs) were recorded as German-speaking subjects
read verbs in correct and incorrect participle forms. The critical words were
presented in three different versions to three different groups of subjects, as
part of a simple sentence, in a word list, and embedded in a story; for each
version separate ERPs were recorded. Three types of verbs were investigated,
regulars, irregulars and nonce verbs. We compared correct regular and irregular
participles with incorrect ones; the latter had -(e)n on verbs that actually take
-t participles (* getanz-en), or -(e)t on verbs that require -(e)n (* gelad-et).
For the nonce verbs, we compared participles with the unexpected -(e)n ending
with the expected -t participle forms. The ERP responses were very consistent
across the three versions of the experiment: (i) incorrect irregular participles
(* gelad-et) elicited a left frontotemporal negativity; (ii) incorrect regulars
(* getanz-en) produced no differences to the correct ones; (iii) nonce verbs were
associated with an N400 component but did not show a difference between expected
and unexpected endings. We will interpret these findings with respect to
psycholinguistic models of morphological processing and argue that the brain
processes regularly inflected words differently from irregularly inflected ones,
the latter by accessing full-form entries stored in memory and the former by a
computational process that decomposes complex words into stems and affixes.
PMID- 9395849
TI - Encoding behavioral context in recurrent networks of the fronto-striatal system:
a simulation study.
AB - This research addresses the hypothesis that behavioral context is encoded in
recurrent networks of the fronto-striatal system. Behavioral context influences
the processing of subsequent brain events, including responses to sensory inputs,
thus providing a basis for context-dependent behavior. We define context
dependent behavior as the adaptive ability to produce the appropriate response to
a given stimulus, dependent upon the context in which it appears. Behavioral
context can change with a time-scale on the order of seconds to tens of seconds
or more. This suggests a flexible mechanism that encodes context via an ensemble
of neural activation that will appropriately influence the processing of
subsequent sensory stimuli. We present a functional model of context encoding in
recurrent connections of the fronto-striatal system with simulation results that
correspond closely to empirical data. Neuronal activity in monkeys that perform a
context-dependent task indicate that the prefrontal cortex and striatum
participate differentially in this kind of context encoding. Likewise, simulated
neurons in our model of the fronto-striatal system, which performs the context
dependent task, display task-related activity remarkably similar to that found in
monkey frontal cortex and striatum, supporting our hypothesis.
PMID- 9395850
TI - Loss of functional hemispheric asymmetry in Alzheimer's dementia assessed with
near-infrared spectroscopy.
AB - In a total of 10 patients with dementia of the Alzheimer-type (DAT) and in 10
healthy controls near-infrared spectroscopy (NIRS), a new non-invasive optical
method, was used to measure the changes of concentrations of oxy- (O2HB) and
deoxyhemoglobin (HHB) in left and right hemispheric prefrontal brain tissue areas
during performance of the Verbal Fluency Test (VFT). On a neuropsychological
level, the healthy subjects performed better in the VFT than patients with DAT.
Statistical analysis of the relative concentrations of O2HB and HHB measured with
NIRS during performance of the VFT revealed a significant interaction of the
hemispheric effects with the diagnosis. A possible interpretation of this finding
is that a good performance in the VFT relies on a predominantly left hemispheric
activation observed in controls, whereas a low number of correct responses is
associated with a loss of this asymmetric activation in patients with DAT.
Although both, patients and controls, performed better in the category version of
the VFT, the metabolic effects of this task were significantly less pronounced
than in the letter version. This indicates that different energy demands,
according to the type of access to the memory stores, may be interpreted as the
result of a less energy-demanding access to categorically stored information and
adds further evidence to the view that memory departments in humans are organized
according to categorical principles.
PMID- 9395851
TI - Comparative study of antifungal activity of sertaconazole, terbinafine, and
bifonazole against clinical isolates of Candida spp., Cryptococcus neoformans and
dermatophytes.
AB - The in vitro activity of sertaconazole was compared with that of terbinafine and
bifonazole against 180 Candida spp., Cryptococcus neoformans yeasts and 53
dermatophytes. Minimum inhibitory concentrations (MICs) were determined by a
microdilution method in Sabouraud's buffered liquid medium (pH 5.6).
Sertaconazole (arithmetic mean MIC 1.24 mg/l) was statistically more active than
bifonazole (MIC 6.54 mg/l) and terbinafine (MIC 12.61 mg/l) against yeasts
strains, MIC values for sertaconazole being generally and specifically lower for
each tested yeast species. MIC for C. parapsilosis (0.26 mg/l) demonstrated a
higher activity of sertaconazole against this species, in contrast to C.
tropicalis (MIC 1.49 mg/l). Against dermatophytes, MIC for terbinafine (0.05
mg/l) was lower than sertaconazole (MIC 0.41 mg/l) and bifonazole (MIC 1.04
mg/l). These results, obtained under the same experimental conditions, confirm
the good antifungal activity of sertaconazole against both yeasts and
dermatophytes with lower MICs obtained in the topical application. This in vitro
activity correlates with the clinical efficacy of sertaconazole compared with
other antifungal agents.
PMID- 9395852
TI - In vitro activity of biapenem against recent gram-negative and gram-positive
clinical isolates.
AB - The in vitro activity of biapenem, a new carbapenem, against 535 clinical recent
isolates was compared with those of other antibiotics. Biapenem showed broad
spectrum activity against gram-negative and gram-positive clinical isolates. The
new carbapenem was more active than imipenem against members of the family
Enterobacteriaceae with MIC90S ranging from 0.12 to 2 mg/l and from 0.25 to 4
mg/l, respectively. Moreover it was 2-fold more active than imipenem against
Pseudomonas aeruginosa (MIC90, 8 and 16 mg/l, respectively). Taken together,
these results indicate that biapenem shares the favorable in vitro activity
properties of imipenem and merits further study in the treatment of infections
caused by a wide range of pathogens.
PMID- 9395853
TI - Bacterial colonization of the upper respiratory tract of patients with primary
lung cancer and nonmalignant lung disease.
AB - We examined the bacterial colonization of the upper respiratory tract of 110
patients with primary lung cancer (PLC), 75 patients with nonmalignant lung
diseases (NMLD) and 45 healthy volunteers (HV), comparing the sensitivity of
expectorated sputum, and throat and nasal swabs. The frequency of bacterial
colonization of the upper respiratory tract was significantly higher in the PLC
patients (59.1%) than in NMLD patients (37.3%, p < 0.01) and HV (37.8%, p <
0.01). The frequency of gram-negative colonization was significantly higher in
PLC patients than in the other subjects (p < 0.01). Expectorated sputum and nasal
swab were the most sensitive for detection of whole bacteria and methicillin
resistant Staphylococcus aureus in the patients with PLC. Our results showed that
PLC patients are significantly more frequently colonized by bacteria in their
upper respiratory tracts and that a combination culture of expectorated sputum
and nasal swab is suitable to estimate the bacterial colonization of the upper
respiratory tract in the patients.
PMID- 9395855
TI - Protein kinase C inhibitors augment tumor-necrosis-factor-induced apoptosis in
normal human diploid cells.
AB - In this report we show augmentation of tumor necrosis factor (TNF)-induced
apoptosis by protein kinase C (PKC) inhibitors in human embryonic lung fibroblast
(HEL) cells. Staurosporine (STS) reportedly potentiates TNF-mediated cytotoxicity
in cancer cell lines via inhibition of PKC. We investigated whether STS or
another potent PKC inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7),
augmented TNF-induced apoptosis in normal human diploid cells and examined the
effects of the PKC inhibitors on the expression of endogenous TNF (enTNF) and
manganous superoxide dismutase (MnSOD) as possible cell resistance factors
opposing TNF-induced apoptosis. Both PKC inhibitors augmented TNF-mediated DNA
fragmentation in HEL cells, which are normally TNF resistant and constitutively
express high amounts of enTNF and MnSOD activity. Neither the number nor the
affinity of TNF receptors were altered by STS and H7. The expression of enTNF and
MnSOD was suppressed by the presence of STS or H7 along with TNF. The results
indicate that PKC inhibitors augment TNF-induced apoptosis not only in tumor
cells but also in normal cells by inhibitory effects on cellular resistance
factors such as enTNF and MnSOD.
PMID- 9395854
TI - Endogenous tumor necrosis factor functions as a resistant factor against
hyperthermic cytotoxicity in pancreatic carcinoma cells via enhancement of the
heart shock element-binding activity of heart shock factor 1.
AB - To elucidate the relationship between two distinct resistant factors, endogenous
tumor necrosis factor (enTNF) and heat shock proteins (HSPs), against
hyperthermia, we assessed whether enTNF enhances HSP72 expression. Although there
was a variability in the sensitivity of pancreatic carcinoma cell lines to heat,
enTNF and HSP72 expression as well as MnSOD activity correlated positively with
heat resistance. When MIAPaCa-2 pancreatic carcinoma cells, which had the lowest
enTNF expression and highest heat sensitivity, were transfected with a
nonsecretory-human TNF gene (pTNF delta pro), intracellular manganous superoxide
dismutase (MnSOD) activity, HSP72 expression, and heat resistance were
significantly increased. Furthermore, in these cells, enTNF expression correlated
with the binding activity of heat shock factor 1 (HSF 1) to an oligonucleotide
containing the human heat shock element. These results indicate that enTNF
participates in the intrinsic resistance against heat via induction of MnSOD,
enhances HSF1-binding activity, and augments of HSP72 expression. Therefore,
inhibition of enTNF expression in pancreatic carcinoma cells would improve the
efficacy of hyperthermia for pancreatic carcinoma.
PMID- 9395856
TI - Inhibition of motility and adherence of Proteus mirabilis to uroepithelial cells
by subinhibitory concentrations of amikacin.
AB - The effect of subinhibitory concentrations of amikacin on Proteus mirabilis
motility and adherence to human uroepithelial and to HeLa cells was compared with
that of gentamicin. In addition, the effect of both antibiotics on cell surface
hydrophobicity was also examined. Exposure of bacterial cells in the logarithmic
phase to one fourth of amikacin or gentamicin at one fourth of their respective
minimal inhibitory concentrations causes the inhibition of swarming and motility
of Proteus strains. Amikacin significantly reduced adhesion of Proteus strains to
human uroepithelial cells and gentamicin exerts the same effect to a lesser
extent. Such inhibitory concentrations of amikacin or gentamicin had no
significant effect on the attachment ability of these strains to HeLa cells
compared to the nontreated cells. Treatment of the bacterial cells with amikacin
or gentamicin changed significantly the cell surface hydrophobicity towards the
hydrophilic state compared to nontreated cells, and it was found to be strain
dependent. Since motility and attachment ability are considered as pathogenic
traits, these data indicate the impact of amikacin on the virulence factors
especially in urinary tract infections with Proteus strains.
PMID- 9395857
TI - Improvement of albendazole efficacy against enteral, but not against parenteral
stages of Trichinella spiralis by preparing solid dispersions in
polyvinylpyrrolidone.
AB - A comparison was made, in the Trichinella/mouse model, of the anthelmintic
effects of albendazole (ABZ) and ricobendazole (RBZ) formulated as solid
dispersions in polyvinylpyrrolidone with regard to ABZ formulated as a suspension
in carboxymethylcellulose. A solid dispersion significantly increased (p < 0.01)
the efficacy of the drugs against intestinal preadult but not against migrating
and muscle stages of the parasite. The anthelmintic efficacy of RBZ given as a
solid dispersion was equivalent to (against preadult and encysted larvae) or
significantly lower than (against migrating larvae) that of ABZ with the same
formulation. The pharmacokinetic profiles of ABZSO as measured by HPLC showed no
significant differences in the Cmax and AUC following administration of ABZ
formulated as a suspension or solid dispersion although the Tmax was
significantly lower for the dispersion.
PMID- 9395858
TI - Combination therapy with fluconazole and flucytosine for pulmonary
cryptococcosis.
AB - We investigated, in vitro, the combined effects of fluconazole (FLCZ) and
flucytosine (5-FC) against different strains of Cryptococcus neoformans, and
retrospectively analyzed the clinical efficacy of combination therapy of FLCZ and
5-FC in patients with pulmonary cryptococcosis. The minimum inhibitory
concentrations (MICs) of antifungal agents and drug interaction were determined
by the broth microdilution method and checkerboard titration. FLCZ and 5-FC
showed synergistic activity against 8 (32%) of 25 strains of C. neoformans. The
clinical efficacy of the 2 drugs when combined together was good in 9 (90%)
patients and fair in 1 (10%) patient with pulmonary cryptococcosis. Renal
dysfunction occurred in 1 patient. Our results suggest that a combination therapy
using FLCZ and 5-FC is clinically useful in patients with pulmonary
cryptococcosis who otherwise show a limited response to monotherapy.
PMID- 9395859
TI - Experience with once daily dosing of gentamicin: considerations regarding dosing
and monitoring.
AB - Plasma concentrations of gentamicin following a fixed dose of 240 mg once daily
to patients with normal renal function were measured. The purpose was to
establish guidelines to achieve a sufficiently high peak concentration with an
appropriately low risk of accumulation. In 40 patients, 1-hour concentrations of
plasma gentamicin had a median of 9.3 mg/l (range: 4.5-19.0 mg/l) and 9.7 mg/l
(range: 3.6-14.6 mg/l) on days 1 and 3 of gentamicin treatment, respectively.
Thirty-nine patients had 1-hour concentrations > 5 mg/l. The 1-hour
concentrations varied considerably intra- and interindividually but showed a
significant inverse correlation with body weight, surface area and the estimated
endogenous creatinine clearance. The plasma gentamicin elimination half-life
correlated significantly with age and inversely with body weight and creatinine
clearance. There was no increase in the mean plasma creatinine from day 0 to day
4. No patients showed signs of nephrotoxicity, although 2 patients, both elderly
and with low body weight, showed signs of beginning gentamicin accumulation. In
conclusion, gentamicin treatment with the dose of 240 mg once daily in 3 days to
adults with normal kidney function generally does not require adjustment or
monitoring. However, the dose should be increased in young patients with an
excessive body weight, and decreased doses are needed for old and underweight
patients. Monitoring of trough plasma gentamicin concentration is not necessary
with treatment duration of 3 days or less.
PMID- 9395860
TI - Improbability of selection for RIF resistance in Mycobacterium tuberculosis by
accidental exposure during short-course therapy with Cotrifazid.
PMID- 9395862
TI - Catastrophic metabolic encephalopathies in the newborn period. Evaluation and
management.
AB - The newborn who presents with neurologic symptoms such as seizures or lethargy
due to inborn error of metabolism is an important problem. Although each inborn
error that presents in this manner is rare, these conditions are not rare as a
group, and more than one in 1000 babies is affected with one of the more than 100
different inborn errors that are now known. Many of these conditions present with
much the same features seen in sepsis or asphyxia and, when untreated, can lead
rapidly to death or permanent neurologic damage. Early diagnosis and management
may prevent some or all of this morbidity, and also permits the parents to be
informed about the chances of having other affected children. Despite the large
number and complexity, most metabolic encephalopathies can be diagnosed by
applying a few simple clinical principles and laboratory tests. These principles,
and the typical features of some inborn errors that present in the neonate, are
detailed in this article.
PMID- 9395861
TI - Seizures in the newborn infant. Diagnosis, treatment, and outcome.
AB - Neonatal seizures remain an emergent clinical problem in the neonatal intensive
care unit that requires prompt diagnosis and treatment. The electroencephalogram
is the preferred tool by which a surface-recorded seizure can be documented.
While a number of etiologic possibilities may occur, overlapping mechanisms
result in a lower seizure threshold. The susceptibility to seizures shortly after
birth, efficacy of antiepileptic medications to control seizures, as well as the
prediction of outcome in patients with neonatal seizures remains controversial.
Prospective studies are required to assess interactions among maternal, fetal,
and neonatal conditions that contribute to the occurrence of neonatal seizures.
PMID- 9395863
TI - Infections of the central nervous system in the newborn.
AB - Safe, effective vaccines and potent antimicrobial agents have diminished
substantially the morbidity and mortality associated with neonatal infections of
the central nervous system (CNS), and new molecular methods, such as the
polymerase chain reaction, enable clinicians to detect micro-organisms rapidly.
Despite these advances, CNS infections remain an important cause of death and
neurodevelopmental sequelae. This article summarizes current concepts regarding
infections of the developing CNS.
PMID- 9395864
TI - Neurologic complications of cardiac disease in the newborn.
AB - Advances in the management of infants with congenital heart disease have lead to
a striking decrease in mortality. The most dramatic impact has been in the
newborn infant with complex and previously lethal heart disease. These heart
lesions have become amenable to corrective procedures in the newborn period
because of the development of support techniques such as low-flow cardiopulmonary
bypass and deep hypothermic circulatory arrest. However, these techniques have
demonstrated their own inherit risk for neurologic injury. Consequently, in
recent years there has emerged a growing population of infants surviving
congenital heart disease only to manifest subsequent neurologic complications
originating from injury in the hemodynamically unstable preoperative period or
periods of intraoperative hypoperfusion. The preservation of neurology function
has emerged as the next frontier in the management of congenital heart disease.
Finally, neurologic dysfunction in the newborn with cardiac disease may reflect
associated brain malformations or the combined cardiac and brain manifestations
of inherited metabolic disease. The clinical features and mechanisms of brain
injury are discussed for these structural and metabolic cardiac diseases
presenting in the newborn infant.
PMID- 9395865
TI - Neuromuscular disorders in the newborn.
AB - The main manifestations of neuromuscular disease in the newborn period are
hypotonia and weakness. Infants with severe hypotonia but only marginal weakness
usually do not have a disorder of the lower motor unit. These infants may have
genetic conditions, metabolic disturbances, congenital heart disease,
hypothyroidism, sepsis, or other systemic disorders. Early on, neonates with
central nervous system pathology may present with profound hypotonia, decreased
reflexes, and moderate to severe but transient weakness. However, they also tend
to have seizures, obtundation, cranial nerve signs, or history of perinatal
asphyxia.
PMID- 9395866
TI - Neurologic birth trauma. Intracranial, spinal cord, and brachial plexus injury.
AB - The variety of perinatal neurologic injuries described in this article suggests
that any region of the central or peripheral nervous system may be affected by
the birth process. Fortunately, these injuries are infrequent and, in many
instances, resolve without any intervention.
PMID- 9395867
TI - Brain death in the newborn. Current perspectives.
AB - Brain death can be diagnosed in the full-term newborn, even when less than 7 days
of age. An observation period of 48 hours is recommended to confirm the
diagnosis. If an EEG is isoelectric or if a CBF study shows no flow, the
observation period can be shortened to 24 hours. Although there are few cases of
preterm infants who are brain dead, it is likely that the same time frame would
be applicable. Based on available data, the risk of misdiagnosis appears
exceedingly low. There have been few instances of neonates or older infants who
showed minimal transient clinical or EEG recovery but with no meaningful
neurologic function and all died within brief periods of time.
PMID- 9395868
TI - The Castroviejo Lecture. Prolonged eyelid closure is a risk to the cornea.
AB - PURPOSE: The author introduces new concepts and summarizes published evidence
suggesting that prolonged eyelid closure puts the cornea at risk. METHODS:
Significant clinical and experimental publications are reviewed, and the author's
experience is applied relating to the pathogenesis and treatment of a variety of
clinical entities thought to be induced, to some degree, by prolonged eyelid
closure. RESULTS: Evidence from the scientific literature suggests that the
hypoxia or reduced tear volume or both that result after prolonged eyelid
closure, especially during sleep and when a soft contact lens is in place, serve
as risk factors in the "sucked-on" contact lens syndrome, recurrent corneal
erosion, chronic corneal deepithelialization, Pseudomonas keratitis, filamentary
keratitis, superior limbic keratoconjunctivitis, sterile midperipheral corneal
infiltrates, and corneal vascularization. The limbal stem cells under the upper
eyelid are subjected to continuous hypoxic stress and are at special risk to
other insults. CONCLUSIONS: Prolonged eyelid closure, such as in patching and in
sleep, is a risk factor in the pathogenesis of a variety of corneal conditions.
PMID- 9395869
TI - A study of 530 patients referred for rigid gas permeable scleral contact lens
assessment.
AB - PURPOSE: The purpose of this study was to analyse the current application of
scleral contact lenses in two specialist centres. METHODS: The case notes of 530
patients assessed for fitting or refitting with rigid gas permeable (RGP) scleral
lenses were retrospectively analysed to determine the indication for contact
lenses and the outcome. Scleral lenses had been offered as a conservative
management option in suitable cases for a variety of visual and medical
indications. RESULTS: Various types of primary corneal ectasia, ranging from low
grade to advanced, including keratoconus, keratoglobus, and pellucid marginal
degeneration, formed 53.0% of the total referred for assessment. The other
principal indications for contact lenses were corneal transplant (15.8%), aphakia
(10.3%), high myopia (8.9%), and various ocular surface disorders (8.2%). Sixty
percent continued to use scleral lenses, 42.9% RGP, and 17.1%
polymethylmethacrylate lenses. Twenty-two percent discontinued scleral lens wear
or failed a trial of scleral lenses, with 9.3% in progress at the time of
assessment and 8.7% lost to follow-up. CONCLUSIONS: In the authors' opinion,
scleral lenses have retained their traditional role in the management of complex
ametropia and ocular surface disease. That role has been further enhanced by the
application of gas permeable materials.
PMID- 9395870
TI - Indications for penetrating keratoplasty and associated procedures, 1989-1995.
AB - PURPOSE: To identify changing trends in indications for penetrating keratoplasty
and associated surgical procedures. METHODS: Review of charts from all patients
who underwent penetrating keratoplasty at Wills Eye Hospital from January 1, 1989
through December 31, 1995. RESULTS: A total of 2,442 corneal transplants were
performed in 2,186 patients. The leading indication for penetrating keratoplasty
was pseudophakic corneal edema, accounting for 634 cases (26.0%); 54.7% of them
were associated with anterior chamber intraocular lenses, 36.4% with posterior
chamber intraocular lenses, and 3.1% with iris-fixated intraocular lenses.
Regraft (17.8%), Fuchs' dystrophy (15.7%), and keratoconus (13.2%) followed
pseudophakic corneal edema in frequency. Cataract extraction, with or without
intraocular lens implantation, was combined with penetrating keratoplasty in 439
cases of 1,264 phakic eyes (34.7%). Intraocular lens exchange was performed in
285 of the 634 cases of pseudophakic corneal edema (44.9%). CONCLUSION:
Pseudophakic corneal edema was the leading indication for penetrating
keratoplasty, with an increasing number of cases associated with posterior
chamber intraocular lenses during the study period (p = 0.001). The number of
regrafts steadily increased between 1989 and 1995 (p = 0.001), being the second
most common indication for corneal transplantation since 1992.
PMID- 9395871
TI - Effects of artificial tear temperature on corneal sensation and subjective
comfort.
AB - PURPOSE: Cooling reduces acute inflammation and local nerve sensation. We
investigated the relationship between artificial tear temperature, ocular surface
sensation, and patient comfort. METHODS: We placed preservative-free artificial
tears and eye mask stored at four temperatures (36 degrees C, 25.2 degrees C, 4
degrees C, and -10 degrees C) in the right eyes of 24 normal subjects, whose left
eyes served as controls. Corneal and conjunctival sensations were measured and
corneal temperature was recorded. Comfort was reported on a 7-point scale.
RESULTS: Corneal temperature was significantly lowered with all temperature
artificial tears and frozen eye mask (p < 0.001 for each temperature relative to
the previous one). Aesthesiometer readings were inversely correlated with corneal
temperature (r = -0.45, p = 0.0005), decreasing with lower temperatures, reaching
2.0 +/- 1.3 g/mm2 (p = 0.001) for the mask. Conjunctival sensation reacted
similarly and was well correlated with both corneal temperature (r = 0.43, p =
0.0009) and corneal sensation (r = 0.39, p = 0.006). Treatments provided relief,
with the 4 degrees C tears being the most comfortable (p = 0.0001). CONCLUSION:
Although there may still be some biases, cooled artificial tears provide relief
to the eye by the mechanism of reduced corneal and conjunctival sensation.
PMID- 9395872
TI - Granular-lattice (Avellino) corneal dystrophy in Japanese patients.
AB - PURPOSE: To determine amyloid deposition in the corneas of granular corneal
dystrophy in Japanese patients. METHODS: Eight Japanese patients (10 eyes) with a
clinical diagnosis of granular corneal dystrophy were investigated clinically and
histologically. Each specimen obtained at surgery was stained with hematoxylin
eosin, Masson trichrome or Mallory, and Congo red stain. Amyloid deposit was
identified by birefringence and dichroism under cross-polarized light after
staining with Congo red. RESULTS: Seven (70%) of the 10 corneal buttons (six of
eight patients) had amyloid deposits, as shown by Congo red staining with
birefringence and dichroism. Of the six amyloid-positive patients, two patients
(who were siblings) showed discrete gray-white corneal deposits with additional
linear deposits. This finding is typical of Avellino corneal dystrophy. The
corneas of the remaining four patients showed the discrete deposits typical of
granular dystrophy. Some of them showed a few whitish fusiform and stellate
opacities in the mid stroma, suggestive of Avellino corneal dystrophy.
CONCLUSION: The high frequency of amyloid deposits in Japanese patients with
granular corneal dystrophy may be caused by an allelic heterogeneity of the gene.
PMID- 9395873
TI - Evaluation of central and peripheral corneal thickness with ultrasound
biomicroscopy in normal and keratoconic eyes.
AB - PURPOSE: Our study was designed to calculate central and peripheral corneal
thickness in patients affected with early stages of keratoconus and in normal
subjects using ultrasound biomicroscopy (UBM). To obtain an objective and
reliable assessment of the corneal thinning in affected eyes, we developed a
keratoconus index (KI) by means of the UBM measurements. METHODS: By means of the
commercial version of the ultrasound biomicroscope (system model 840; Zeiss
Humphrey Instruments, San Leandro, CA, USA) using a 50-MHz probe, we studied 30
normal and affected eyes. In keratoconic eyes, we measured the thinnest corneal
thickness (TCT) at the apex of the conus and at four peripheral sites at a
distance of 2.5 mm from the central site (peripheral corneal thickness: PCT). The
same procedure was performed in the normal eyes. To obtain an objective and
reliable assessment of the corneal thinning, we calculated the ratio between the
mean PCT and the mean TCT (Keratoconus Index: KI = PCT/TCT), in keratoconic eyes.
In normal eyes, the KI was calculated on the basis of the ratio between the mean
PCT and the mean central corneal thickness (CCT). RESULTS: In keratoconic eyes,
the mean corneal thickness at the thinnest part of the conus was significantly
different from the CCT in normal patients (Student's t test, p < 0.001). The
peripheral measurements were not significantly different from keratoconic and
normal eyes. The mean KI was 1.482 (SD, 0.095) in the keratoconic eyes, whereas
it was 1.189 (SD, 0.086) in the normal subjects. The statistical analysis of the
KI calculated on the basis of the UBM measurements showed that the KI values are
significantly different from healthy subjects and from keratoconic patients
(Student's t test, p < 0.001). CONCLUSIONS: UBM can be considered a useful tool
in the study of keratoconus. We believe that calculation of the KI by means of
UBM gives the possibility of obtaining an objective assessment of corneal
thinning. Therefore this parameter can be useful in the staging and in the follow
up of these patients.
PMID- 9395874
TI - Nasolacrimal stimulation of aqueous tear production.
AB - PURPOSE: Aqueous tear production decreases after anesthetizing the ocular
surface. Loss of the nasolacrimal reflex is a risk factor for neurotrophic
keratopathy and keratoconjunctivitis sicca. The purpose of this study was to
evaluate the effect of nasal mucosal anesthesia on aqueous tear production.
METHODS: Eleven healthy human volunteers with a normal ocular surface and
Schirmer I tear-test scores > 10 mm participated in this study. Schirmer I values
were obtained daily for 3 days to establish a normal baseline. On a separate day,
the right nasal mucosa was anesthetized with aerosolized 10% lidocaine
(Xylocaine). After a 10-min period to allow the anesthetic to take effect and
reflex tearing to subside, the Schirmer I test was repeated. A saline nasal spray
was used as a control. RESULTS: Baseline Schirmer I values for both eyes had a
mean of 22.98 +/- 1.05 mm (SEM). There was no difference in Schirmer scores
between the two eyes after nasal anesthesia (p > 0.6); however, when these were
compared with the baseline Schirmer I values, a significant decrease in tear
production was noted (p < 0.001). The mean Schirmer I value after nasal
anesthesia was 15.18 +/- 1.38 mm (SEM), a 34% decrease from baseline. The
difference between the baseline and the normal saline control values was not
significant (p = 0.160). There was a significant difference in Schirmer test
scores between the saline control and nasal anesthesia groups (p < 0.02).
CONCLUSIONS: In addition to sensory neural stimulation from the ocular surface,
sensory stimulation of the nasal mucosa also promotes aqueous tear production.
These results may help explain the decreased tear production observed in patients
who have nasal mucosal damage, disease, or denervation.
PMID- 9395875
TI - Relationship between tear-meniscus parameters and tear-film breakup.
AB - PURPOSE: Several flaws exist with the lipid-diffusion model for tear-film
breakup. The aim of this study was to test an alternative model of tear-film
rupture in which the negative hydrostatic pressure in each tear meniscus (related
to the tear-meniscus radius of curvature) is proposed to influence the formation
of breaks in the tear film. METHODS: Measurements of noninvasive breakup time
(NIBUT) and tear-meniscus radius of curvature, height, width, and cross-sectional
area (TMC, TMH, TMW, and XSA) were made for 15 aqueous-deficient dry-eye and 15
age-matched control subjects. An optic section of the inferior tear meniscus
(colored with a minute volume of fluorescein) was photographed at x120
magnification, and images were computer analyzed. RESULTS: A significant positive
correlation was found between log NIBUT and TMC (r2 = 0.141; p < 0.05).
Furthermore, all subjects with TMC < 0.340 mm had NIBUT < 15 s, and two thirds of
subjects with TMC > 0.340 mm had NIBUT > 15 s. There was a moderate linear
relationship between TMH and log NIBUT, indicating an association between tear
volume and tear stability. TMC, TMH, and tear meniscus XSA measurements all
showed good reliability. CONCLUSIONS: The association between highly curved tear
menisci and rapid tear-film breakup times is consistent with the meniscus model
of tear-film rupture. However, a causal relationship has yet to be established.
PMID- 9395876
TI - The antibacterial activity of topical anesthetics.
AB - PURPOSE: Topical anesthetics are commonly used prior to obtaining bacterial
cultures in ulcerative keratitis. We performed an in vitro study designed to test
both the bacteriostatic and bactericidal effects of commercially available
preserved topical anesthetic agents. METHODS: Proparacaine, tetracaine, cocaine,
and sterile water solutions were applied to filter paper disks, which were then
placed on Mueller-Hinton agar plates that had previously been inoculated with
known quantities of Pseudomonas aeruginosa and Staphylococcus aureus. After 24 h
of incubation, zones of inhibition were measured and recorded. RESULTS:
Proparacaine strongly inhibited the growth of S. aureus at all concentrations
(0.5%, 0.25%, 0.125%) and inhibited growth of P. aeruginosa at 0.5% and 0.25% but
not at 0.125% concentration. Tetracaine also inhibited S. aureus at 0.5% and
inhibited P. aeruginosa at 0.5% and 0.25% concentrations. Cocaine exhibited no
inhibition of S. aureus and exhibited mild inhibition of P. aeruginosa growth
only at the 4% concentration. CONCLUSIONS: The in vitro antibacterial effect of
topical anesthetics suggests one possible reason why bacterial culture yields in
clinical ulcerative keratitis are suboptimal. We propose that clinicians consider
the use of a 1% or 2% cocaine solution instead of standard commercial topical
anesthetics in the management of individual cases of ulcerative keratitis and in
future clinical bacterial keratitis studies.
PMID- 9395877
TI - Assessment of cornea viability by confocal laser scanning microscopy and MTT
assay.
AB - PURPOSE: Determination of excised cornea viability is of interest for transplant
storage evaluation, but also for in vitro diffusion-study design and ocular
toxicity assessment. By using simultaneous vital staining by calcein AM (CAM) and
ethidium homodimer-1 (EH-1), as "live" and "dead" probes, respectively, we
developed a confocal laser scanning microscopy (CLSM) assay to determine
epithelial and endothelial viability and estimate cornea thickness. METHODS: New
Zealand White rabbit corneas were stored in phosphate-buffered saline (PBS) or
Optisol at 4 degrees C or at room temperature. At various times, corneas were
stained with an EH-1/CAM solution and observed, without further treatment, by
CLSM. Storage effects on the cornea were also assessed by using an MTT assay.
RESULTS: Stromal swelling, shedding of the upper epithelial layers, and severe
endothelial damage were observed after 4 h in PBS at room temperature. After 8 h,
lower epithelial cell death was observed, along with loss of endothelial
structure. Corneas stored in similar conditions in Optisol were indistinguishable
from controls. Storage in Optisol at 4 degrees C affected the superficial layers
of the corneal epithelium similarly at both 7 and 14 days. Extensive epithelial
shedding and wing-cell death were observed at 25 days, but the basal layer
remained approximately 50% healthy. Significant endothelial cell loss was
observed at 25 days. MTT results were consistent with CLSM data in the medium
term storage study only. CONCLUSIONS: This CAM/EH-1 CLSM fluorescence assay is a
sensitive index of viability in cornea, and thus may prove useful in
investigations in which maintenance of vital functions in different cell layers
is critical.
PMID- 9395878
TI - Alterations of corneal extracellular matrix after multiple refractive procedures:
a clinical and immunohistochemical study.
AB - PURPOSE: To describe the clinical course and alterations of the corneal
extracellular matrix (ECM) and basement membrane (BM) in a cornea after hexagonal
keratotomy, transverse keratotomies, and keratomileusis. METHODS: Frozen sections
of this cornea and of 12 normal corneas were studied by immunofluorescence with
specific antibodies. The patient history was analyzed to allow a clinical
correlation. RESULTS: In the treated cornea, keratotomy scars and subepithelial
fibrosis with neovascularization were seen. Around and beneath the epithelial
plugs and along the keratotomy scars, deposits of types III, VI, VIII, and XIV
collagen; fibrillin-1; fibronectin; and tenascin-C were found, together with
short streaks of types IV (alpha 1-alpha 2) and VII collagen, laminin-1 and -5,
entactin, and perlecan. alpha 3-alpha 4 Type IV collagen chains were abnormally
absent from the BM around the epithelial plugs. At the edges of the
keratomileusis flap, subepithelial fibrosis areas were found, with abnormal
deposits of eight different collagen types, perlecan, fibronectin, fibrillin-1,
and tenascin-C. The major part of the flap interface did not show ECM
abnormalities. ECM alterations outside the scarred areas included the appearance
of tenascin-C in the stroma and of alpha 1-alpha 2 type IV collagen in the
epithelial BM, and the disappearance of fibronectin from Descemet's membrane.
CONCLUSION: Five years after surgery, the treated cornea still presented BM
abnormalities at sites of keratotomy scars and epithelial plugs. Several ECM
components were abnormally expressed outside the scarred areas, consistent with
an ongoing fibrosis in the treated cornea.
PMID- 9395879
TI - Screening donor corneas that have undergone PRK.
PMID- 9395880
TI - Posterior corneal protrusion after PRK.
PMID- 9395881
TI - Corneal topography of human cadaver eyes donated months after radial and
astigmatic keratotomy.
PMID- 9395882
TI - Superior keratoconus.
PMID- 9395883
TI - Delayed development of amiodarone keratopathy in a corneal graft.
PMID- 9395884
TI - Beauveria bassiana keratitis cured by deep lamellar dissection.
PMID- 9395886
TI - Analysis of DNA from subjects found to be heterozygous for the haptoglobin
Johnson alpha gene.
AB - We found two rare Hp Johnson variant families (Hp2-Johnson type and Hp1-Johnson
type) by PAGE. It was confirmed by SDS-PAGE that the haptoglobin molecules with
the Hp Johnson variant consisted of alpha-2 or alpha-1 and alpha-3 subunits.
Direct gene analysis of Hp Johnson heterozygous individuals using three
endonucleases: EcoRI, HindIII and BamHI, showed a three-fold tandem repeat of the
same 1.7-kb DNA fragment implicated in the Hp alpha-2 gene duplication, and this
Hp-Johnson-specific extension was identified in two generations of the Hp2
Johnson and Hp1-Johnson families.
PMID- 9395885
TI - Fluconazole in filamentous fungal keratitis.
PMID- 9395887
TI - Tumor necrosis factor-alpha gene polymorphism in psoriasis.
AB - Psoriasis, an inflammatory autoimmune disease, is characterized by increased
level and activity of the proinflammatory cytokine TNF-alpha in affected lesions.
Two promoter region polymorphisms of the TNF-alpha locus--one at position -308
and the other at -238--were examined in 99 Caucasian patients (64 with type I and
35 with type II psoriasis) and in 123 controls. A highly significant difference
in the distribution of the -238 polymorphism--the TNF (G,A) genotypes--was
detected between the type I psoriasis patients and controls: compared to the
controls, the frequency of the homozygous TNF-G genotype was decreased (55 vs.
91%; p = 0.0000000274; corrected p = 0.0000001644; odds ratio = 0.12), whereas
that of TNF-G,A heterozygotes was increased (41 vs. 8%; p = 0.000000264;
corrected p = 0.000001584; odds ratio = 7.73) in patients. No significant
differences were observed in the distribution of the TNF-A homozygotes. These
results suggest that homozygosity of the G allele is associated with a lower
relative risk (resistance), whereas heterozygosity at this locus is associated
with an increased risk (susceptibility) of type I psoriasis.
PMID- 9395888
TI - Isolation of scFv fragments to polymorphic and monomorphic HLA-DR epitopes from a
synthetic phage library.
AB - The possibility of producing human recombinant antibodies by the phage display
libraries technology has opened up new perspectives in the fields of
immunological research and therapeutic applications. Despite the interest for a
potential use of this technology in the HLA field, no information is so far
available about selection and screening of libraries with HLA antigens. In this
study we report our first experience with expression and characterization of
human single-chain antibody fragments (scFvs) against HLA-DR epitopes selected
from a synthetic phage library.
PMID- 9395889
TI - Studies of the 6.7 family of dispersed genomic fragments within the MHC class I
Region.
AB - Searches for MHC-encoded disease susceptibility genes have led to considerable
knowledge of the content of the class I region. In an effort to further
understand the nature of the five 6.7 family members previously mapped to this
region of the genome, we have further analyzed the cross-reactive members of the
family and have observed additional genomic instability within the HLA-A
subregion. Such genomic variation may underscore the slower evolutionary rates of
the HLA-A allelic family and the extended linkage disequilibrium of markers
distal to this locus. Moreover, one of the largest genes associated with a member
of the 6.7 family, the 3.8-1 gene found proximal to HLA-B, was found to
demonstrate limited, composite similarity to RAG2 and complement C4a gene
sequences. A pancreas-specific transcript embedded in a 6.7 cross-reactive
fragment was found distal to HLA-H and suggests that the fragments have remained
linked to transcriptionally active chromatin comprised of both a major class I
gene and a second novel coding sequence since the time of their dispersal. The
absence of a 6.7 fragment in the HLA-B subregions of higher nonhuman primates
lends credence to the possibility that the great apes have suffered a recent
deletion event within this region following the emergence of Homo sapiens.
PMID- 9395890
TI - Antibody to human MHC class I inhibits SIVsmmPBj1.9-induced proliferation of
pigtailed macaque lymphocytes.
AB - Previously we have shown that the simian immunodeficiency virus SIVsmmPBj1.9, a
molecular clone of SIVsmmPBj14, induces proliferation of human peripheral blood
mononuclear cells (PBMC). We have extended this observation to show that
SIVsmmPBj1.9 induces proliferation of PBMC from pigtailed macaques. This
proliferative response was markedly inhibited by mAbs against human class I MHC,
class II MHC and CD4 antigens, and partially inhibited by mAbs against integrin
beta 2 subunit (CD18) and LFA-1 (CD11a). However, these antibodies differed in
their ability to inhibit in vitro viral infectivity of PBMC. While anti-CD4, MHC
class II, and LFA-1 strongly inhibited viral infectivity, antibodies to MHC class
I demonstrated little effect on viral infectivity. A control antibody (PLM2)
against porcine CD18 inhibited neither virus-induced proliferation nor viral
infectivity. Based on these results, we suggest that SIVsmmPBj1.9-induced
proliferation requires the participation of class I MHC, class II MHC and CD4
molecules. In addition, the observation that anti-class I MHC Ab inhibited
proliferation of macaque PBMC induced by mitogen (PHA) and bacterial
superantigens, such as Staphylococcus enterotoxin A and toxin shock syndrome
toxin-1, suggests that SIVsmmPBj1.9 also contains a viral superantigen similar to
that previously demonstrated in SIVsmmPBj14.
PMID- 9395891
TI - HLA class I and II genes in relation to the genetic structure and epidemiology of
an Italian province.
AB - The genetic structure of Pavia province is studied separately with HLA class I
and II alleles. The analysis reveals that HLA class I genes reflect the same
geographic barriers to migration found also with surnames, while class II gene
distribution does not seem to be influenced by the presence of these barriers.
The independence of HLA class II allelic distribution from the genetic structure
of the area reinforces the hypothesis that environmental factors, rather than
genetic drift, influence the frequency of these alleles. An example may be the
significant correlation found between the distribution of the DR3-DQ2 haplotype
and the prevalence of celiac disease in the province's districts.
PMID- 9395892
TI - Tumor necrosis factor-alpha, interleukin-1-beta and immunoglobulin (GM and KM)
polymorphisms in leprosy. A linkage study.
AB - In order to determine the genetic components of susceptibility to leprosy in 6
multiplex French Polynesian families, linkage analysis was carried out between a
putative disease gene and 6 polymorphic loci: G1M, G2M, KM, IL-1 beta, TNF-alpha
(1, 2) and TNF-alpha (A, G) using the lod score method. The three modes of
inheritance, assuming a full penetrance value or reduced penetrance values (80
and 40%) for the susceptible allele, as well as with affected ones only, were
tested. The results of this study provide no evidence for linkage between leprosy
and the markers tested.
PMID- 9395893
TI - Nucleotide sequence comparison of the IgE constant region in patients with atopic
dermatitis and non-atopic individuals.
AB - In order to answer the question whether the Fc portion of the IgE molecule in
patients with atopic dermatitis is altered by somatic replacement mutations, we
amplified and sequenced the respective C epsilon 2 and C epsilon 3 domain genes.
Five patients with atopic dermatitis and 6 non-atopic individuals were studied.
Neither within the C epsilon 2 nor the C epsilon 3 domain could any common
nucleotide substitutions be detected. Therefore, the conclusion can be drawn
that, in patients with atopic dermatitis, there are no protein sequence
differences within the Fc part of the IgE which could be responsible for distinct
functional features with regard to Fc epsilon-receptor binding and signal
transduction or could account for the frequent occurrence of anti-IgE
autoantibodies in these individuals.
PMID- 9395894
TI - The SCID mouse mutant: definition and potential use as a model for immune and
hematological disorders.
AB - Mice homozygous for a SCID mutation (SCID mice) are severely deficient in T and B
lymphocytes. The absence of effector T and B cells has encouraged investigators
to attempt engraftment of SCID mice with human fetal tissues, mature lymphocytes,
hematopoietic progenitors and tumors. SCID mice can be reconstituted with human
lymphocytes and are of interest for studying normal and abnormal lymphocyte
development and function. SCID mice are also providing an in vivo model of
infectious diseases. In addition, SCID mice readily support normal and pathologic
human hematopoiesis differentiation and is useful for testing innovative
hematological disease therapy. SCID mice with a fully functional human immune or
hematopoietic system therefore seem to be extremely valuable for biomedical
research.
PMID- 9395895
TI - Sequential intravenous-oral ciprofloxacin plus amoxycillin/clavulanic acid
shortens hospital stay in infected non severe neutropenic patients.
AB - The objective of this study was to determine the efficacy and safety of the
combination ciprofloxacin plus amoxicillin/clavulanic acid as an empirical
treatment of infection in hematologic patients without severe neutropenia. These
drugs allowed us to carry out a sequential therapy, first intravenously and later
orally, so that the patient could be discharged as soon as there was a response.
Serum concentrations of ciprofloxacin were monitored in this study. Forty seven
of the sixty-six patients included (71%) responded to the treatment with no
differences between the dosages of ciprofloxacin employed (600-900 mg daily in
two or three divided doses). In the patients who responded, the signs and
symptoms of infection lasted only three days, which could allow a short hospital
stay (median of six days). In the first pre and post-dose serum samples,
ciprofloxacin concentrations were significantly higher when the drug was
administered every 8 h. Nevertheless, 72 h after the beginning of treatment, they
had leveled out in either 8 and 12 h schemes. The toxicity of the treatment was
very light, with only four cases with adverse effects, grades I and II. This data
suggests that the employed combination is effective and safe and can considerably
decrease costs incurred through the admission of hematologic patients with
serious infections but without severe neutropenia.
PMID- 9395896
TI - Fibrinolytic response to venous occlusion in patients with homozygous sickle cell
disease.
AB - The fibrinolytic potential was evaluated in 37 patients with homozygous sickle
cell disease and compared to a control group of 30 age- and sex-matched healthy
volunteers. In all individuals, the euglobulin clot lysis time and plasma antigen
levels of t-Pa and PAI-1 were measured before and after venous occlusion (v.o)
for 10 min. The global fibrinolytic activity was normal in 4 patients (good
responders to v.o), while it was decreased in 33 patients (poor responders to
v.o). Among the latter, 22 patients had significantly increased baseline levels
of PAI-1 Ag (82.6 +/- 27.5 ng/ml, p < 0.001) and a normal release of t-Pa Ag
after v.o. In contrast, 11 patients had basal values of PAI-1 Ag comparable to
those in controls with a defective release of t-Pa Ag after v.o (11.4 +/- 5.2
ng/ml, p < 0.01). These data provide evidence for reduced fibrinolytic capacity
resulting from either increased basal levels of PAI-1 or defective release of t
PA.
PMID- 9395898
TI - In vitro production of human antigen presenting cells issued from bone marrow of
patients with cancer.
AB - In the prospect of producing autologous antigen presenting cells (APC) to
actively immunize patients with cancer against their own tumor we were interested
in the in vitro generation of MC and/or dendritic cells. We observed that the
best yielding in CD14+ cells was obtained by adding SCF and GM-CSF into RPMI 1640
completed medium and by using Teflon bags as culture-containers. The others
growth factors tested (LIF, IL3 and M-CSF) were useless in term of production of
macrophages. After a month of culture we usually obtained an average of 80% of
CD14, CD33, CD64, CD11a, CD11b, CD11c and HLA-DR positive cells expressing the
MGG staining phenotype of MC. For DC the best association of growth factors
combined GM-CSF, IL-4 and SCF. Hence we could obtained at least 60% of CD1a+,
CD14-, CD54+, CD58+, CD80+ and HLA DR+ dendritic cells.
PMID- 9395897
TI - Red cell and platelet kinetics in chronic cytopenias following transplantation.
AB - Thirty seven patients with unexplained anemia and/or thrombocytopenia after bone
marrow, kidney, liver or heart transplantation were referred to the Department of
Nuclear Medicine for erythrocyte or platelet kinetic studies in order to
determine the mechanism of the cytopenia: accelerated destruction, or production
defect. We observed only one definite case of thrombocytopenia due to accelerated
autologous platelet destruction, while the life span was normal in the other 16
cases. Anemia was due to accelerated hemolysis in 7 cases, while the red blood
cell life-span was normal in 12 other cases. Kinetic studies can therefore be
useful, by demonstrating the mechanism of cytopenia observed after
transplantation, and by facilitating the choice of appropriate treatment.
PMID- 9395899
TI - Studies of T cell reconstitution after hematopoietic stem cell transplant.
AB - Hematopoietic stem cell (HSC) transplantation, whatever its conditions, is
associated with an increased risk of infections and tumoral complications,
because of a delayed immune reconstitution. T-cell regeneration has been mostly
investigated and appears to come more from graft and/or host mature T-cells,
rather than from the differentiation/maturation of reinfused progenitors. In
allogeneic setting, the immune defect is enhanced by the immune host/donor
conflict and the use of prophylactic or curative immunosuppressive therapy. The
tools used for studying post-transplant immunity are the following:
immunophenotyping (kinetics and alterations of lymphocyte subset reconstitution),
functional studies of T cell proliferation, cytokine production, cytotoxicity and
signal transduction, as well as studies of T cell repertoire diversity. The
CD4/CD8 cell immunophenotyping might be enough for routine clinical evaluation,
allowing an adapted prophylaxis of opportunistic infections in those immune
suppressed patients, while functional assays might be useful to evaluate the
persistence overtime of defects in immune reconstitution. These overall assays
are useful both for basic and clinical research and allow better understanding in
the mechanisms for T cell regeneration in the diverse types of HSC transplants
performed nowadays particularly after graft of purified HSC where immune
reconstitution remains a key question.
PMID- 9395900
TI - Immune reconstitution after blood cell transplantation.
AB - Immune clinical events and pattern of recovery of total lymphocytes, T cells and
CD4+/CD8+ T cell subsets, B cells and NK cells, were analysed after allogeneic
blood cell transplantation (BCT) for 12 months following transplant (n = 33).
Results were compared with immune recovery after allogeneic bone marrow
transplantation (BMT) (n = 15) and autologous blood cell transplantation (n =
19). Rates of acute GVHD were comparable in the two allotransplantation groups.
Fourteen out of 17 evaluable alloBCT group patients have presented an extensive
cGVHD. Total T cell, CD4+T cells and CD56+NK cell reconstitution were improved in
alloBCT group vs alloBMT group. CD4+/CD8+ ratio evolution were improved in
alloBCT group vs alloBMT and autoBCT groups. These results confirm that rapid
immune recovery is associated with allogeneic blood stem cell transplantation.
PMID- 9395901
TI - Immune reconstitution following transplantation of selected hematopoietic stem
cells.
AB - The use of selected stem cell grafts has recently entered the era of clinical
application. Its potential interest lies in the decreased contamination of the
graft by tumor cells in the autologous graft setting and in the depletion of T
lymphocytes from the graft in the allogeneic situation. Very few and only
phenotypic studies of immunologic recovery post selected stem cell transplant
have been performed. Most studies conclude an absence of influence of stem cell
selection on quantitative neutrophil, NK, B-lymphocyte and CD8+ T-lymphocyte
recovery. CD4+ T-lymphocyte recovery seems delayed in half of the studies,
particularly in the context of allogeneic unrelated donor or HLA-mismatched
transplants and this could explain viral infections frequently noted in this
situation. Additional follow-up and comparative studies with non selected grafts
including functional tests of immunity will be required to better assess the
relationship of immune recovery post graft to the age of the patient, the type of
donor and HLA compatibility between donor and recipient, the underlying pathology
and the number of reinfused stem cells and accessory cells.
PMID- 9395902
TI - Potential and limitations of HSV-TK-transduced donor peripheral blood lymphocytes
after allo-BMT.
PMID- 9395903
TI - [Usefulness of DNA ploidy, AgNORs, PCNA and c-erbB-2 as predictors of prognosis
in patients with renal cell carcinoma].
AB - Seventy one patients with renal cell carcinomas were examined for a variety of
markers associated with tumor malignancy: nuclear DNA ploidy, AgNORs, PCNA and c
erbB-2. Usefulness of the markers in predicting the prognosis was studied by
analyzing the relationship between each of these markers and the prognosis of the
patients with renal cell carcinomas. DNA ploidy was analyzed by flow cytometry.
AgNORs were stained by the silver colloid method. PCNA and c-erbB-2 were detected
by immunohistochemistry. In all the patients examined, DNA ploidy, AgNORs, PCNA
and c-erbB-2 were significant predictors of the prognosis. Of the patients with
grade 2 carcinomas, the survival rate was significantly higher in the patients
with the PCNA-positive cells of lower than 35.0% than in those with the positive
cells of more than 35.0%. The patients without the expression of c-erbB-2
exhibited a significantly higher survival rate than those with the expression. In
the patients with grade 2 carcinomas, however, neither DNA ploidy nor AgNoRs was
a significant predictor of the prognosis. These findings suggest that PCNA and c
erbB-2 provide more accurate information than the others to understand the
biological characteristics of the grade 2 carcinomas and are useful in predicting
the prognosis of the patients with grade 2 renal cell carcinomas.
PMID- 9395904
TI - [A clinical study of intermittent hydronephrosis].
AB - A clinical study was conducted on the intermittent hydronephrosis in children. Of
78 children with hydronephrosis due to ureteropelvic junction obstruction
operated between 1991 and 1995, 5 had intermittent hydronephrosis. All 5 patients
were boys between 6 months and 6 years of age. Presenting symptoms were
intermittent flank pain and vomiting. Ultrasonography performed during pain
attack demonstrated dilation of the renal pelvis in all patients. Diuretic
renography demonstrated obstruction in 4 of the 5 children and deterioration of
renal function on the affected side in 2. The cause of ureteropelvic junction
obstruction was aberrant vessels in 2 cases, fibrous band in 1, ureteral kinking
within adventitia in 1 and a ureteral polyp in 1. Postoperatively, all patients
have been relieved from the pain. In summary, ultrasonography at the time of
symptom attack as well as diuretic renography are useful for the diagnosis and
observation of intermittent hydronephrosis.
PMID- 9395905
TI - [A clinicopathological study on carcinoma of the renal pelvis and ureter].
AB - We investigated the clinicopathological features of 62 patients with transitional
cell carcinoma of the renal pelvis and ureter. Four patients had been treated for
bladder cancer. Among 58 patients without precedent bladder cancer, 6 had
coexistent bladder cancer and bladder cancer subsequently developed in 13. The 5
year cause-specific survival rate was 33% in cases with coexistent bladder
cancer, 75% in those with subsequent bladder cancer and 62% in patients without
association of bladder cancer. Distant metastases were found in 23 of 62 (37%)
cases, the most frequent site being lymph nodes. The site of the primary tumor
(renal pelvis and/or ureter) and the pathological findings such as grade, stage,
type of infiltration, venous and lymphatic invasion, were significantly
correlated to cause-specific survival. Multivariate analysis showed the most
influential factors to be the type of infiltration and the site of the primary
tumor. Therefore, patients with INF beta or gamma tumors both in the renal pelvis
and ureter had a poor prognosis. However, association of bladder cancer was not
related to survival.
PMID- 9395906
TI - Two types of micturitions of ileal neobladder.
AB - Eight patients were evaluated clinically, radiologically, and urodynamically to
determine the outcome of continent urinary diversion with ileal neobladder
performed to treat the recurrent superficial bladder cancer after cystectomy with
subcapsular prostatectomy. The mean age of the patients was 55.3 years. After
descending dissection of the urinary bladder without ligation or dissection of
Santorini's plexus, the prostate was cut to the bladder neck distally for 2 cm
under the subcapular prostatectomy. One patient who had a short 3 cm intestinal
segment between the pouch and the urethra, had severely prolonged micturition
with peristalsis in this short segment, and required a re-operation. Micturition
was good in the other seven patients, all with detubularized neobladder directly
to the prostate capsule in anastomosis. Pressure flow studies performed on these
seven patients revealed two types of micturition; "fast bladder" and
"intermittent flow", the latter resembling detrusor sphincter dyssynergia.
PMID- 9395907
TI - [Cystic renal cell carcinoma: report of four cases].
AB - We report 4 cases of cystic renal cell carcinoma (RCC), one of simple cystic type
(case 2) and three of multilocular cystic type (case 1, 3 and 4). All cases were
diagnosed preoperatively as malignant neoplasms on the basis of radiological
examinations, including CT scan and angiography. Pathological examination
revealed that intrinsic cystic growth was the probable cause in the three cases
of multilocular cystic RCC, while the simple cystic case was probably caused by
secondary cyst formation as a result of tumor necrosis. Radical nephrectomy was
performed in cases 1, 2 and 4 and partial nephrectomy in case 3. We recommend
nephron-sparing surgery as an option in the management of select cystic RCC,
given that many cystic RCCs are low grade and enveloped by distinct
pseudocapsules with fibrous tissues.
PMID- 9395908
TI - [A case of renal cell carcinoma found after skin metastasis].
AB - A case of renal cell carcinoma, found after skin metastasis is presented. A 76
year-old woman came to our hospital complaining of two painless subcutaneous
tumors in her left chest. Histopathological diagnosis was clear cell carcinoma.
She underwent left nephrectomy and histopathological findings revealed renal cell
carcinoma, alveolar type, clear cell subtype, grade 1. Lung metastasis was proved
soon after the operation. We removed skin metastasis several times after the
nephrectomy.
PMID- 9395909
TI - [Mucinous adenocarcinoma of the renal pelvis: a case report].
AB - A rare case of primary mucinous adenocarcinoma of the renal pelvis is reported. A
76-year-old woman was admitted to our hospital because of right abdominal
fullness. Physical examination revealed a melon-sized (22 cm in diameter) tumor
located in the middle and lower right quadrant of the abdomen. Computed
tomography and transabdominal sonography revealed hydronephrosis and a renal
stone. Retrograde pyelography was impossible because of ureteral obstruction on
the right side. A diagnosis of severe hydronephrosis was made and a right
nephrectomy was performed. The kidney measured 24 x 14 cm in size and contained
1,500 ml of mucinous material. The histological diagnosis was mucinous
adenocarcinoma of the renal pelvis. The patient has had neither recurrence nor
metastasis for 2 years following postoperative chemotherapy.
PMID- 9395910
TI - [Microscopic foci of urachal carcinoma in an incidentally detected urachal cyst:
a case report].
AB - A 33-year-old man who had been treated for chronic prostatitis was diagnosed to
have urachal cysts by transabdominal ultrasonography. Cystoscopy revealed
protuberance at the dome of the bladder. Computerized tomography scan and
magnetic resonance imaging showed the mass to be mostly cystic but partly solid.
Resection of the urachal cysts and partial cystectomy were performed.
Histopathologically, most cysts had a normal cylindrical epithelium with
retention of mucinous substance. However, several small cysts contained
epithelial cells resembling tubulo-villous adenoma and showing mitotic figures.
This case was concluded as urachal carcinoma detected in its very early stage.
PMID- 9395911
TI - [A case of locally advanced squamous cell carcinoma in bladder diverticulum
successfully treated by bladder-preserving therapy].
AB - A 62-year-old man visited our hospital with asymptomatic gross hematuria. On
cystoscopy, two diverticula were identified at the dome of the urinary bladder
and one of them was packed with a tumor. Biopsy showed squamous cell carcinoma
(SCC), G1, but malignancy was not detected in the rest of the vesical mucosa. We
selected bladder-preserving therapy. Pathological diagnosis after partial
cystectomy was SCC, G1 > G2, pT3b. Postoperatively, 3 courses of adjuvant
chemotherapy with methotrexate, bleomycin and cisplatin were performed. The
patient has remained free of recurrence for 4.5 years.
PMID- 9395912
TI - [Small cell carcinoma of the urinary bladder: a case report and review of the
Japanese literature].
AB - A 50-year-old man presented with asymptomatic gross hematuria which he had first
noticed 3 months earlier. Clinical examinations revealed a non-papillary, broad
based tumor on the left lateral wall of the urinary bladder with a clinical stage
of T3N0M0. The pathological diagnosis of a transurethral biopsy tissue specimen
was small cell carcinoma. Neoadjuvant intraarterial infusion chemotherapy using
cisplatin and adriamycin was initially administered but proved to be ineffective.
Thus, we performed a radical cystectomy. The tumor tissue was apparently
homogenous and composed of small cells arranged in sheets and solid patterns, and
was staged to be pT3bR1L2V0N0. An electron microscopic study confirmed small cell
carcinoma with neurosecretory granules. Postoperatively, 4 courses of adjuvant
chemotherapy consisting of cisplatin, etoposide and ifosfamide were administered.
The patient is alive without any evidence of tumor recurrence 26 months after the
operation.
PMID- 9395913
TI - [Adenocarcinoma occurring 37 years after augmentation ileocystoplasty for
tuberculous bladder atrophy: report of a case].
AB - A 55-year-old woman was admitted with urinary frequency. She had undergone
augmentation ileocystoplasty due to tuberculous bladder atrophy 37 years
previously. Cystoscopy revealed a tumor on the posterior wall which had been
augmented with the ileum. Partial cystectomy and bladder reconstruction using a
segment of ileum and ascending colon were performed. Gross inspection showed a 15
x 10 mm, papillary tumor on the ileal mucosa near the vesico-ileal anastomosis.
Histologically, moderately differentiated adenocarcinoma infiltrating into the
muscle layer was surrounded by the normal ileal mucosa. She has been free of
recurrence for 2 years postoperatively. This is the 8th case of adenocarcinoma
following augmentation ileocystoplasty reported in the Japanese literature.
PMID- 9395914
TI - [Bladder hemangioma in a child: a case report].
AB - We report a case of bladder hemangioma in a child. An 8-year-old girl was
referred to our hospital for the evaluation of painless hematuria. Neither pyuria
nor bacteriuria was detected. She had no dysuria. Intravenous pyelography showed
deformity of the bladder without dilation of the upper urinary tract. Voiding
cystourethrography revealed a filling defect of the bladder. Reddish blue masses
were seen cystoscopically at the right wall and the dome of the bladder. Partial
cystectomy was performed. From the histological findings, the diagnosis was
cavernous hemangioma of the urinary bladder. Her postoperative course was
uneventful and no recurrence was seen at the cystoscopical examination 3 months
postoperatively. This is the 15th case of bladder hemangioma in children reported
in Japan.
PMID- 9395915
TI - A case of prostate cancer presenting as a symptomatic abdominal mass.
AB - An 80-year-old man presented to our hospital complaining of an abdominal mass. On
physical examination, a hard fist-sized mass was noted in the right lower
abdomen. Needle biopsy of the prostate and abdominal mass showed moderately
differentiated adenocarcinoma. The chest roentgenogram revealed multiple lung
metastases. Clinical diagnosis was T3N3M1, stage D2. Serum prostate specific
antigen (PSA) level (8,600 ng/ml) normalized after 3 months of anti-androgen
therapy. Lung metastases disappeared after 11 months, while the abdominal mass
was reduced to 25% of the pretreatment size after followup of 30 months.
PMID- 9395916
TI - [Prostatic endometrioid carcinoma: a case report].
AB - An 89-year-old man presented with urinary retention. Digital rectal examination
was benign despite elevated serum prostate-specific antigen (PSA) level.
Suprapubic prostatectomy was performed under the diagnosis of benign prostatic
hyperplasia. Histopathological diagnosis was endometrioid carcinoma showing
positive immunohistochemical staining for PSA. Postoperatively, estrogen was
administered for 9 months. After 37 months, serum PSA level began to increase and
a palpable nodule was detected on digital rectal examination. Biopsy showed
coexistence of endometrioid carcinoma and acinar adenocarcinoma. Hormonal
treatment was resumed and the disease has been well controlled for 65 months
postoperatively.
PMID- 9395917
TI - [Statistics of the operation at Division of Urology, Shimada Municipal Hospital:
1992-1996].
PMID- 9395918
TI - High affinity human antibodies by phage display.
AB - The development of phage display has now made it possible to consider the
isolation of human antibodies directly without immunization. Recent advances in
the field of human immunogenetics and in phage technology have led to the
assembly of 'naive' human repertoires in vitro whose complexity approach that of
the natural immune system. Screening of these libraries has allowed the isolation
in one step of antibodies with affinities in the nanomolar range.
PMID- 9395919
TI - Chimeric immunoglobulin E reactive with tumor-associated antigen activates human
Fc epsilon RI bearing cells.
AB - Crosslinking of immunoglobulin E molecules that are bound to the Fc epsilon
receptors expressed on mast cells or basophils triggers activation of these
cells, resulting in the development of a type I hypersensitivity. Targeting this
potent immune reaction towards tumors by using IgE that reacts with a tumor
associated antigen, may induce a local inflammation at the tumor site, and may
therefore promote tumor regression. We have previously shown that murine IgE
bound to tumor cells can activate murine mast cells to release TNF-alpha and
histamine. To further investigate the therapeutic potential of IgE-mediated
immunotherapy of carcinomas, we have developed human/murine chimeric versions,
containing the murine variable regions and human constant regions, of both G250
and 323/A3 IgE. These chimeric IgEs are reactive respectively with the G250 renal
cell carcinoma antigen and the Ep-CAM molecule, which is highly expressed by most
carcinomas. Transfection of the respective chimeric heavy and light chain genes
into recipient Sp2/0 myeloma cells yielded chimeric IgE-producing clones.
Chimeric G250 and 323/A3 IgE reacted with tumor cells expressing the G250 antigen
or Ep-CAM, respectively. To generate a cell line that expresses Fc receptors for
human or chimeric IgE, the rat basophilic leukemia cell line RBL-7 was
transfected with the human Fc epsilon RI alpha chain (RBL-7TZ) and subsequently
tested for binding of chimeric IgE. Functional assays showed that both chimeric
IgEs activated RBL-7TZ cells to release TNF-alpha when cultured with tumor cells
that express the respective specific antigen. Furthermore, both chimeric IgEs
were able to activate freshly isolated human basophils.
PMID- 9395920
TI - Optimisation of human anti-tetanus toxoid antibody responses and location of
human cells in SCID mice transplanted with human peripheral blood leucocytes.
AB - A strategy for the production of human antibodies to tetanus toxoid (TT) is
described. Human peripheral blood lymphocytes (PBL) were injected into severe
combined immunodeficient (SCID) mice (termed hu-PBL-SCID) and the mice
subsequently immunised with purified TT. By using low immunising doses of
antigen, PHA activated PBL and PBL from donors who were recently immunised with
TT, we established ongoing antibody responses to TT with specific recall IgG
responses of up to 22 IU ml-1 in the murine plasma, which was greater than that
in the donors' serum. Total IgG concentrations of up to 6 mg ml-1 were detected
over a 32 week period. Lower levels of IgM and IgM anti-TT were also detected
over this time. Large cellular infiltrations of human CD45+ and CD20+ cells were
detected by immunocytochemistry in the mesenteric membranes, mesenteric lymph
nodes and the pancreas 5 weeks after PBL were engrafted into a SCID mouse. Human
cells were also observed in the lungs, liver, thymus and spleen. Cells isolated
from the tissues were cultured with Epstein-Barr virus and the resulting B-cell
lines produced Ig in vitro up to 7 weeks, with IgG and IgM anti-TT detected
transiently in a culture of cells from the mesenteric membranes.
PMID- 9395921
TI - Elevated expression levels of the 14-3-3 family of proteins in lung cancer
tissues.
AB - Immunochemical staining of lung cancer sections with a murine monoclonal anti-14
3-3 antibody showed a sharp discrimination of the cancer tissue from neighboring
normal counterparts in 88 of 121 primary lung cancer tissue specimens of all four
major lung cancer histologies; specifically, 32 of 48 adenocarcinomas, 36 of 44
squamous cell carcinomas, 10 of 13 large cell carcinomas, and 10 of 16 small cell
carcinomas, respectively, were stained positively. Sets of the 10,000 x g
supernatants of normal and cancerous lung tissue homogenates, each set prepared
from surgically dissected tissues of the cancer and its surrounding normal part,
were assayed for 14-3-3 proteins by the sandwich enzyme-linked immunosorbent
assay using two different monoclonal antibodies to 14-3-3 proteins. The results
of the assay demonstrated 7.2 times higher 14-3-3 protein content in the lung
cancer tissue (378 +/- 200 ng ml-1) as compared with the normal lung (54 +/- 35
ng ml-1). These results indicate that the 14-3-3 family of proteins can be an
effective marker for lung cancer diagnosis such as sputum cytodiagnosis and that
14-3-3 proteins might be involved in the development of lung cancers.
PMID- 9395922
TI - Cytokeratin 8 and 19 as antigens recognized by adenocarcinoma-reactive human
monoclonal antibody AE6F4.
AB - The human monoclonal antibody (MAb) AE6F4 is secreted by a human-human hybridoma
line established from the in vitro immunization of normal human peripheral blood
lymphocytes with the human lung adenocarcinoma cell line, A549. This MAb is
strongly reactive to lung cancer tissues. In the previous study, the antigens
recognized by the MAb AE6F4 were purified from A549 cells and identified as 14-3
3 protein and 31 kDa cytosolic phospholipase A2 (cPLA2). The MAb AE6F4 also binds
two kinds of antigens (53 kDa and 40 kDa), which are not related to 14-3-3
protein or 31 kDa cPLA2, in the human breast adenocarcinoma cell line, MCF-7. We
purified a 38 kDa antigen, which is a degradation product of 53 kDa antigen from
breast adenocarcinoma MCF-7 cells using ion-exchange and hydroxyapatite column
chromatography. Two partial amino acid sequences of the purified 38 kDa antigen
showed 95-100% homology to human cytokeratin 8 (CK8). Two-dimensional gel
electrophoresis and immunoblot analysis of intermediate filament fraction
separated from MCF-7 cells demonstrated that the 53 kDa and 40 kDa antigens were
CK8 and CK19, respectively. Antigenic determinants on CK8 and CK19 recognized by
the MAb AE6F4 were resistant to sodium periodate treatment, although antigenic
determinant on 31 kDa antigen (14-3-3 protein and(or) cPLA2) was sensitive to
this treatment. These results suggest that the MAb AE6F4 reacts with both
carbohydrate and peptide antigenic determinants.
PMID- 9395923
TI - Age differences in information-seeking among cancer patients.
AB - Studies examining patient populations have found that information-seeking
decreases with age. However, researchers usually define information-seeking as
involving only the medical establishment, while they neglect other sources of
information. The present study examined the use of two types of information
sources, non-medical establishment (newspaper, television, and friends) and
medical establishment (doctors and nurses), among seventy-five cancer patients
aged eighteen to eighty-one years. Patients responded to questionnaires asking
about information-seeking, desire for more cancer information, self-perception of
their knowledge about cancer, and actual knowledge of facts about cancer. For the
medical establishment source, information-seeking decreased with age; however, no
age differences existed for seeking non-medical establishment information. In
individuals with high levels of desire for information, older adults reported
more information-seeking from non-medical sources than did younger adults.
PMID- 9395924
TI - Relation between fluid intelligence and frontal lobe functioning in older adults.
AB - This study reports the relations among normal aging, intelligence, and frontal
lobe functioning. Intelligence tasks and frontal lobe functioning tasks were
administered to 107 adults from two age groups (25 to 46 years and 70 to 99
years). Intelligence measures were assessed with two crystallized tests (WAIS
Vocabulary and Information subtests), one fluid intelligence test (Cattell's
Matrices), and one mixed, crystallized and fluid test (WAIS Similarities
subtest). Frontal functioning was assessed using the Wisconsin Card Sorting Test
(WCST) and two tests of verbal fluency. Significant age differences in favor of
the young were found on the two intelligence tests with a fluid component and on
all measures of frontal lobe functioning. Correlational analyses examining the
relationship of intelligence measures to frontal variables indicated that these
last measures were significantly correlated with only fluid intelligence tests in
the elderly group. The implications for the relations among aging, fluid
intelligence, and frontal lobe functioning are discussed.
PMID- 9395925
TI - An exploration of attachment styles and personality traits in caregiving for
dementia patients.
AB - The present study examined the influence of caregivers' Attachment Styles
(Anxious-ambivalent and Avoidant factors) and personality traits (Neuroticism,
Extraversion, Agreeableness, and Conscientiousness) on their experiences of
caring for dementia dependents. A total of 126 caregiver-dependent pairs
participated in the study. Support was found for the contribution of the
attachment style factors in explaining aspects of caregiver experiences. Those
who chose to institutionalize dependents were higher on the Avoidance factor than
those choosing to maintain them in the community. Less Anxious-ambivalent
caregivers reported larger social support networks, and more satisfaction with
the support received than those lower on this factor. The caregiver
Anxious/ambivalence and Neuroticism dimensions seemed to function as generalized
responses reflected in perceptions and appraisals of the stressful situation.
PMID- 9395926
TI - Age differences in self-appraisal motivation.
AB - One hundred and eight young (mean age 29 years) and 108 older adults (mean age 69
years) participated in a laboratory investigation of self-appraisal motivation.
Participants were recruited via media advertisement to take part in a study of
two novel and different thinking abilities and randomly assigned to either a
similar others, dissimilar others, or temporal-self comparison referent
condition. Each participant was administered two tests purported to measure
different thinking abilities and received experimenter-controlled test feedback
intended to manipulate participants' level of uncertainty about these abilities.
Motivation to self-appraise was assessed via behavioral choice measures collected
following the inducement of uncertainty about ability status. Results indicated
that older adults were less likely than the young to initiate behaviors that
would reduce uncertainty about ability. Subsequent post-hoc analyses suggested
that self-appraisal motivation in young adulthood is not moderated by level of
perceived efficacy, while in later adulthood an attenuation of self-appraisal
motivation occurs as a result of low efficacy or heightened uncertainty about
one's capabilities.
PMID- 9395927
TI - An examination of the therapeutic benefits of focus groups on elderly worriers.
AB - This study examines the effects on elderly worriers, of a focus group discussion
about the topic of worry. All subjects (N = 21) were self-designated worriers,
and at least seventy years of age. Pretest and-Posttest measures included
questionnaires on worry, life satisfaction, and psychological symptom domains
unrelated to the focus group topic. The percentage of the day spent worrying
variable, which was the criterion variable for admittance into the groups, showed
a significant reduction from pre to post. The focus group participants also
evaluated the focus group experience as positive and beneficial. The value of
focus groups for therapeutic effectiveness and data collection with the elderly
are discussed.
PMID- 9395928
TI - Appreciating background and culture: the South Asian elderly and mental health.
AB - In the next decade there will be an increase in the number of elderly people from
a South Asian background. All too often minority groups are treated as
homogeneous, leading to inappropriate generalisations, unmet need, and unsuitable
treatment and management. In order to understand and manage a person's illness it
is necessary to appreciate the effects of their culture, experiences and
environment. The South Asian community is well established in the UK and the
attitudes of the growing elderly population towards mental illness, their
expressions of distress, and views on management and treatment are only now being
canvassed. Awareness of these issues is essential before epidemiological studies
of depression and dementia and use of health services by this group will provide
beneficial results.
PMID- 9395929
TI - The Caregiver Activity Survey (CAS): development and validation of a new measure
for caregivers of persons with Alzheimer's disease.
AB - BACKGROUND: Most instruments that measure the impairments associated with
Alzheimer's disease assess symptom severity. Little attention has been paid to
the illness's impact on the time formal and informal caregivers spend caring for
Alzheimer's individuals. A tool that measures the time spent caregiving would
help to determine the economic impact of the illness. The Caregiver Activity
Survey (CAS) was developed to measure the time caregivers spend aiding
Alzheimer's patients with their day-to-day activities. METHODS: The test-retest
reliability of the CAS was assessed during a 3-week study with 42 Alzheimer's
patients and their caregivers. The CAS was validated with the Alzheimer's Disease
Assessment Scale Cognitive Subscale (ADAS-Cog), the Mini Mental State Exam (MMSE)
and the Physical Self Maintenance Scale (PSMS). RESULTS: The final version of the
CAS consists of six items (communicating with the person, using transportation,
eating, dressing, looking after one's appearance and supervising the person). The
six-item CAS total score has high test-retest reliability, with ICC = 0.88
between weeks 1 and 3. The scale has strong convergent validity with the ADAS-Cog
(r = 0.61), MMSE (r = -0.57) and PSMS (r = 0.43). Efforts to include a dimension
that reflects caregiver burden were not successful, in part due to the reluctance
of caregivers to acknowledge that caregiving is bothersome. CONCLUSIONS: The CAS
provides a new tool that measures time spent caring for Alzheimer's individuals.
The instrument may be used to augment existing clinical assessments that measure
the efficacy of potentially therapeutic agents for persons with Alzheimer's
disease.
PMID- 9395930
TI - Psychogeriatrics in South-East Asia.
AB - A common phenomenon in South-East Asia is ageing of the population. This article
describes the various stages of development of psychogeriatrics in Hong Kong,
Singapore, Malaysia, Thailand, Indonesia and the Philippines. It is only in the
last few years that more systematic development of psychogeriatric services has
begun under the pressure of an ageing population. The model of service delivery
in Hong Kong can serve as an example of development of psychogeriatric services
in South-East Asia.
PMID- 9395931
TI - Cognitive impairment and social distress as different pathways to depression in
the elderly: a cross-sectional study.
AB - BACKGROUND: This study investigates the recent suggestion that some putative
aetiological factors for depression, such as cerebral deterioration and social
distress, may act differentially in the aetiology of depression in old age.
METHOD: In a cross-sectional study, a community sample of 654 elderly subjects
were interviewed with Short-CARE to assess the prevalence of depression and
cognitive impairment. Information was collected for a variety of potential risk
factors for depression such as exposure to social support deficit, threatening
life events, impairment, disability and handicap. RESULTS: The prevalence of
depression was 17% and that of a broad concept of cognitive impairment 23.9%.
This analysis found associations between depression and exposure to social
support deficits and threatening life events in the year prior to interview.
These associations were considerably stronger for those subjects with no
cognitive impairment than for those with cognitive impairment. We also found a
progressive lowering in the strength of these associations the higher the chance
of cognitive impairment measured as a longitudinal variable using both the
Dementia Diagnostic Scale (DDS) and the Organic Brain Syndrome Scale (OBS)
included in Short-CARE. CONCLUSIONS: The results of this theory-driven analysis
lend some support to the notion of at least two differential pathways to
depression in the elderly, one via social distress factors and another mediated
by cerebral deterioration clinically expressed as cognitive impairment.
PMID- 9395932
TI - Cognitive impairment in geriatric chronic schizophrenic patients: a cross
national study in New York and London.
AB - Severe cognitive impairment has been reported in large numbers of geriatric
chronic schizophrenic patients in the US, with this impairment also being related
to severe negative symptoms and adaptive deficits. It is not clear if this
impairment is related to the particular environment of the American state
hospitals and would not generalize to other countries. In this study, a sample
composed of geriatric (age > 70) chronic schizophrenic patients in London, who
were assessed by the Team for Assessment of Psychiatric Services (TAPS) (N =
137), and a group of geriatric chronic schizophrenic patients in a New York
psychiatric center (N = 86) were compared for the severity of cognitive
impairment and on measures of adaptive functioning. Patients received essentially
identical Mini-Mental State Examination (MMSE) scores, but differed on 3/4
measures of adaptive functioning. The correlations among all four aspects of
adaptive deficit and MMSE scores were very similar in the two samples, suggesting
that cognitive deficits and their relationship with adaptive impairments are
relatively invariant across different psychiatric systems of care, while adaptive
functioning deficits are more variable and possibly more influenced by
environmental factors. These data add to previous results suggesting that
cognitive impairment is a common feature in poor outcome geriatric patients with
schizophrenia.
PMID- 9395933
TI - Age- and education-specific reference values for the Mini-Mental and modified
Mini-Mental State Examinations derived from a non-demented elderly population.
AB - MAIN OBJECTIVE: To report age- and education-specific reference values for the
Mini-Mental State Examination (MMSE) and Modified Mini-Mental State (3MS)
Examination. DESIGN: Cross-sectional study. SETTING: Community and institutional
settings in five regions across Canada. PARTICIPANTS: 7754 subjects aged 65 and
over randomly chosen to take part in the Canadian Study of Health and Aging.
Subjects classified as cognitively impaired or demented following a clinical and
neuropsychological examination were excluded. MEASUREMENTS: Total scores on the
MMSE and 3MS, and the degree to which they are influenced by the age, sex,
education, mother tongue and living environment of the subject. RESULTS:
Reference values on the two tests are reported through various descriptive
statistics for five age groups and four education levels. These values decrease
with age and increase with years of schooling. Test scores are also influenced by
the subject's sex and mother tongue, albeit to a lesser extent. These
observations led to the development of predictive equations of the performance to
be expected from a 'normal' elderly subject, given his/her socio-demographic
characteristics. CONCLUSION: The use of the reference values and related
predictive equations will allow the clinician to interpret a patient's
performance on two widely used cognitive tests, in light of the value expected
from a group of 'normal' subjects with the same sociodemographic profile.
PMID- 9395934
TI - Clinical diagnoses and disability of cognitively impaired older persons as
predictors of stress in their carers.
AB - BACKGROUND: Aspects of the caring relationship are often promoted as more
important than the clinical features of the care recipient in predicting
caregiver wellbeing. However, studies of consequences of caring for cognitively
impaired people seldom include detailed measures of the diagnostic profile and
disability of the care recipient. METHODS: Ninety community-living elderly
persons with cognitive impairment were clinically assessed for severity on a
range of illnesses. Their disability was examined via informant reports.
Informants (88% of whom were primary carers) provided information on the
behaviour and personality of the subject and reports of their own (informant)
wellbeing. Using multiple regression, features of the subjects' clinical profile
(severity of diseases, disability, behavioural problems and personality change)
were examined as predictors of informant wellbeing. After controlling for subject
clinical profile, we explored the additional associations between informant
stress measures and other descriptors of the subject, caregiver and their
relationship. RESULTS: The subjects' clinical characteristics, in particular
disability and disturbed behaviour, were strong predictors of caregiver
wellbeing, accounting for most of the explained variance. After control for the
subjects' clinical profile, few of the sociodemographic, caregiver or
relationship variables examined had any influence on caregiver outcome measures.
The exceptions were caregiver time demands, older subject age and self
identification as primary carer. Coresidence was not associated with caregiver
distress. CONCLUSION: Clinical characteristics of the care recipient are
determinants of caregiver wellbeing, while socio-demographic, caregiver and
relationship characteristics are less influential.
PMID- 9395935
TI - Experience with a Swedish version of the Geriatric Depression Scale in primary
care centres.
AB - OBJECTIVE: The purpose of this study was to use a Swedish version of the
Geriatric Depression Scale (GDS-20) for diagnosis of depression in the elderly in
primary care. DESIGN: Elderly consecutive patients visiting two primary care
centres (> or = 65 years of age; N = 1189) were rated by educated nurses using
the GDS-20. SETTING: All elderly patients attending two primary care centres in
an urban-based community in the south of Sweden. PATIENTS: Of the 1189 patients
interviewed, 1002 were rated using the GDS-20. MEASURES: The GDS-20, and in 26
patients also the Geriatric Mental State Schedule--Depression Scale (GMSS-DS).
RESULTS: Of 1002 rated patients, 93 had scores of 5 or above on the GDS-20.
Further analysis showed that 158 (13.3%) suffered from affective disorders.
CONCLUSION: Depression in the elderly is underdiagnosed in primary care centres.
A screening instrument such as the GDS-20 is of value in identifying the
patients.
PMID- 9395936
TI - Concurrent validity of a telephone-administered version of the Gospel Oak
instrument (including the SHORT-CARE).
AB - OBJECTIVE: The aim of the study was to establish the concurrent validity of a
telephone-administered version of the survey measures utilized in the Gospel Oak
studies, the core of which was the SHORT-CARE. DESIGN: Comparisons were made
between data obtained by administering the interview in its conventional, face-to
face form with those generated by conducting it by telephone. SETTING: A UK
teaching hospital. PATIENTS: Elderly subjects of both sexes, recruited from
geriatric and psychogeriatric day hospitals. MEASURES: The Depression Diagnostic
Scale, Dementia Diagnostic Scale and Organic Brain Syndrome scale (all taken from
the SHORT-CARE) and the London Handicap Scale. RESULTS: For depressive
symptomatology, cognitive impairment, subjective memory impairment and handicap,
intraclass correlations were 0.86, 0.89, 0.83 and 0.70, respectively. The kappa
coefficient for agreement on case-level diagnosis of pervasive depression was
0.79. CONCLUSIONS: These results indicate that the instrument is broadly reliable
when administered by telephone.
PMID- 9395937
TI - Cognitive function in community-dwelling elderly with chronic medical conditions.
AB - OBJECTIVES: The aim of this study was to examine the effect of chronic medical
conditions on cognitive function in a sample of community-dwelling elderly (N =
4528). METHODS: A checklist of 18 chronic medical conditions was used to
determine whether respondents were suffering from specific disease states. The
Mini Mental Status Examination (MMSE) was administered to assess cognitive
functioning. RESULTS: Statistically controlling for the effects of age, education
and depression, respondents with asthma/bronchitis and stroke had a tendency to
perform worse on the MMSE than those without these conditions. None of the 18
medical conditions was associated with a greater proportion of respondents
scoring below the cutoff for cognitive dysfunction. CONCLUSION: It appears that-
with the possible exception of stroke and asthma/bronchitis-cognitive function in
community-dwelling elderly is not consistently affected by specific disease
states.
PMID- 9395938
TI - Ethical issues.
PMID- 9395939
TI - Depression in old age: questions concerning prevalence studies.
PMID- 9395940
TI - Current awareness in geriatric psychiatry.
PMID- 9395941
TI - Reperfusion injury: fact or myth?
PMID- 9395942
TI - Repair of coarctation of the aorta in neonates and young infants.
AB - In repair of coarctation in neonates or young infants, inadequate removal of
ductal tissue, failure to address hypoplasia of the aortic arch, and suture line
tension have been reported to be important factors of residual or early recurrent
stenosis at the coarctation repair site. In a consecutive series of neonates and
young infants with coarctation, who were all operated without delay with extended
resection, the clinical outcome regarding the development of restenosis and
hypertension was studied. In addition, the resected specimens were investigated
regarding the completeness of resection of ductal tissue. Twenty-five consecutive
neonates and young infants (median age 22 days, range 5 to 39 days) who underwent
surgical correction of coarctation were reviewed; the resected specimens were
examined histologically to document the extent of ductal tissue in the aortic
wall. Fifteen patients had a preductal coarctation with associated cardiovascular
anomalies including a hypoplastic aortic arch (n = 11). The remaining 10 patients
had a paraductal coarctation without associated intracardiac anomalies. In all
patients, the isthmus was bypassed and an end-to-side anastomosis was constructed
between the descending aorta and the undersurface of the proximal aortic arch (n
= 13) or the distal ascending aorta (n = 12). In 13 patients without marked
hypoplasia of the aortic arch, the coarctation repair was performed through a
left thoracotomy. In the remaining 12 patients, the coarctation was repaired
through a median sternotomy with CPB and hypothermic circulatory arrest, on the
basis of an associated hypoplastic aortic arch (n = 4), hypoplastic aortic arch
with intracardiac anomalies (n = 7), or a "bovine" innominate artery (n = 1).
There was no perioperative or late mortality. At a median follow-up of 15 months,
1 patient (4%) developed a recurrent stenosis at the coarctation repair site; in
the remaining 24 patients, echocardiography showed a widely patent anastomosis
with no evidence of a hemodynamically significant gradient. None of the patients
had hypertension. Histologic examination of the resected specimens demonstrated
the presence of ductal tissue in the descending aorta with maximal extension into
its lateral wall (mean 5.2 mm). In all specimens of the paraductal subtype, there
was also extension of ductal tissue into the lateral wall of tbe isthmus (mean
3.9 mm). We conclude that: (1) in the absence of marked hypoplasia of the
proximal aortic arch, coarctation can be repaired with low mortality and
morbidity via a left thoracotomy; (2) in the presence of marked hypoplasia of the
proximal aortic arch and/or if associated intracardiac defects also need to be
repaired, we advocate repair of the coarctation and associated defects through a
median sternotomy with circulatory arrest; (3) in view of the absence of
postoperative hypertension in this series, early repair of aortic coarctation is
recommended; and (4) because ductal tissue may extend not only into the
descending aorta but also into the isthmus, complete excision of the coarctation
and bypass of the isthmus are valuable techniques to avoid secondary constriction
of the aorta by ductal tissue.
PMID- 9395943
TI - Twenty-year follow-up of acute type a dissection: the incidence and extent of
distal aortic disease using magnetic resonance imaging.
AB - A persistent distal false lumen (PDFL) after surgical repair of type A aortic
dissection is the most important factor in determining long-term survival. It has
been suggested that changes in surgical technique reduce the incidence of distal
false lumen. We report the findings of a 20-year follow-up (mean 5.2 years) on 87
patients who have undergone surgical repair of type A aortic dissection with all
survivors undergoing magnetic resonance (MR) scanning of the entire aorta. Early
mortality was 27.5%, and actuarial 5-, 10-, and 15-year survival was 65%, 28% and
20% respectively. Early mortality had decreased to 18% in the last 5 years. The
most common cause of late death was related to distal aortic disease, accounting
for 47% of all late deaths with a peak incidence at 7-10 years after surgery. The
incidence of PDFL in survivors was 72%, despite the fact that 82% of all intimal
tears were resected at time of operation. Incidence was not affected by extension
of the repair into the aortic arch nor by the use of the open technique or
Gelatin-Resorcine-Formal tissue glue. In patients with a distal false lumen 6%
had reached a maximum aortic diameter of 6 cm in at least one plane on MR
scanning and 25% had reached 5 cm. We conclude that if dissection has extended
beyond the arch at time of presentation then the choice of surgical technique
does not prevent the persistance of a distal false lumen. MR scanning gives ideal
anatomical and functional assessment of distal aortic disease and provides the
surgeon with all the necessary information to plan the timing and indications for
further surgery.
PMID- 9395944
TI - Endarterectomy of the ascending aorta: an alternative method in patients with
extensively calcified (porcelain) aorta requiring aortic valve replacement.
AB - A variety of surgical techniques have been described to manage the extensively
calcified (porcelain) aortic root in patients requiring aortic valve replacement.
We report two cases in which endarterectomy of the proximal ascending aorta was
successfully performed. Endarterectomy of the left main coronary artery ostium
was also performed in the one patient, and aortic root enlargement with patch
aortoplasty in another. The technical aspects of the procedure and alternative
approaches are discussed.
PMID- 9395945
TI - Coronary artery bypass grafting in patients with chronic congestive heart
failure: a 10-year experience with 203 patients.
AB - From 1983 to 1992, 203 patients with chronic congestive heart failure and no
angina underwent primary coronary artery bypass. This represented 3% of patients
undergoing coronary artery bypass grafting. Ninety-two percent of the patients
were in New York Heart Association (NYHA) functional class III or IV prior to
undergoing coronary artery bypass grafting. Thallium perfusion imaging was
performed in 21% of the patients, with a reversible defect present in 88%. An
internal mammary artery graft was used in 70% of the patients. The hospital
mortality was 6.0% and the actuarial survival at 5 years was 59%. An improvement
in NYHA functional class occurred in 75% of the surviving patients with a mean
improvement of 1.6 +/- 0.6 functional classes. Univariate analysis identified
risk factors for hospital death as emergency operation, recent myocardial
infarction (< 30 days), and the need for an intra-aortic balloon pump. A trend
emerged for nonuse of an internal mammary artery to predict hospital death. A
positive thallium perfusion scan was not a predictor of early or late survival,
nor did it influence NYHA functional class. The use of the internal mammary
artery significantly enhanced late survival (p = 0.01), however, did not affect
the functional class of survivors. We conclude that coronary artery bypass
grafting is effective in ameliorating symptoms of chronic congestive heart
failure in patients suffering from chronic ischemic cardiomyopathy and can be
performed with acceptable early and late mortality.
PMID- 9395946
TI - Noninvasive nasal mask BiPAP management for prolonged respiratory failure
following cardiovascular surgery.
AB - The purpose of this study was to assess the efficacy of nasal mas bi-level
positive airway pressure (BiPAP) support in managing respiratory failure
following cardiovascular surgery. A total of 20 patients requiring postoperative
prolonged respiratory support of 72 hours or longer were studied. BiPAP support
was used for eight patients (BiPAP group); the other 12 patients were managed
using ordinary oxygen mask treatment (control group). The mean age of the BiPAP
group and control group was 65 and 58 years of age, respectively. The mean period
of postoperative endotracheal intubation of the BiPAP group and control group was
12 +/- 5 days and 7 +/- 1 days, respectively. Reintubation was necessary in two
patients of the control group. The BiPAP group patients required no reintubation.
BiPAP support was discontinued within 48 hours in 6 out of 8 patients. The
respiratory rates of control group increased (p < 0.1) 24 hours after extubation,
however, the respiratory rates of the BiPAP group remained unchanged. The values
of the respiratory index of the BiPAP group improved significantly (p < 0.01)
after BiPAP management (from 1.5 +/- 0.2 to 0.9 +/- 0.2). The values of the
control group, however, remained unchanged. A-aDO2 and Qs/Qt decreased (p < 0.1)
in the BiPAP group. There were no significant differences in central venous
pressure or circulatory status between the two groups. In conclusion, BiPAP
support is a noninvasive management technique for postoperative respiratory
failure and may also prevent prolonged endotracheal intubation.
PMID- 9395947
TI - Pulmonary valve reconstruction in absent pulmonary valve syndrome: a new
technique.
AB - BACKGROUND: In patients with absent pulmonary valve syndrome, the relief of the
pulmonary regurgitation at the time of primary repair improves both the early and
late results. Though homograft and heterograft valves and conduits have been used
for this purpose, both are not easily available and are known for late failure.
Monocusp and bicuspid semilunar valves made out of pericardium have their own
problems. Hence, a technique of reconstructing an autologous competent 3-cusp
valve from the native tissues was developed. METHODS: Two posterolateral
semilunar cusps were fashioned from the anterior wall of the main pulmonary
artery. The anterior cusp was made from autologous pericardium stitched to the
autologous pericardial patch used to widen the right ventricular outflow tract.
RESULTS: This method of reconstruction was used in two patients aged 9 and 22
years, respectively. Visual assessment and passive testing after reconstruction
revealed well functioning neopulmonary valves in both patients. The second
patient, who had an unevenful hospital course, showed only mild pulmonary
regurgitation at 5 years postreconstruction. CONCLUSIONS: As 2 of the 3 cusps are
fashioned from the pulmonary arterial wall as a pedicled graft, we believe that
they will retain their viability and grow with the pulmonary artery. Simultaneous
reduction in the size of the pulmonary arteries will relieve bronchial
compression when present. The anterior pericardial cusp, even if it eventually
shrivels up, is unlikely to produce serious hemodynamic derangements.
PMID- 9395948
TI - A new instrument for immobilization and hemostasis during minimally invasive
direct coronary artery bypass ("MIDCAB doughnut"): experimental study.
AB - A new instrument for the immobilization and hemostasis of an anastomotic site is
described for use during minimally invasive off-pump direct coronary artery
bypass (MIDCAB). The mechanism is based on air suction of the heart surface. The
instrument is unique in that it can avoid direct temporary of the distal end of
the coronary artery to control bleeding. With this instrument, anastomosis of
left internal thoracic artery to left anterior descending artery (LAD) was
successfully performed on three pigs. Additionally, in six patients the LAD could
be stably and securely immobilized in the beating heart by the present
instrument. The instrument is hereinafter referred as "MIDCAB doughnut," which
can make an operative field motionless and bloodless without distal snaring.
PMID- 9395949
TI - Influence of two blood conservation techniques (cardiotomy reservoir versus cell
saver) on biocompatibility of the heparin coated cardiopulmonary bypass circuit
during coronary revascularization surgery.
AB - Blood conservation during cardiac surgery is critically important because of the
inherent risks in homologous blood transfusions. Two techniques for the
intraoperative conservation of blood--retransfusion of the red cells using a cell
saver (CS), or retransfusion of the blood using a cardiotomy suction (CTR) system
-were compared using biocompatibility markers, granulocyte activation, and
production of oxygen-free radicals (OFR). In the CTR group, heparin coated
circuits with an uncoated cardiotomy reservoir were used. For the CS group,
identical heparin coated cardiopulmonary bypass (CPB) sets, without a cardiotomy
reservoir but with a CS, were used. In each group, eight patients had coronary
artery bypass grafting performed. The capacity of the whole blood and the
granulocytes to produce OFR was estimated by a chemiluminescence, and granulocyte
activation was measured as release of the granulocyte granule proteins
myeloperoxidase (MPO) and lactoferrin. A significantly reduced capacity to
produce OFR by the whole blood was noted at 45 minutes of CPB in the CTR group
(68% +/- 17% vs 94% +/- 16% in the CS group). MPO release was higher after 3
hours (p = 0.05) and 20 hours (p < 0.05), postoperatively, in the CTR group (417
+/- 77 micrograms/L and 257 +/- 31 micrograms/L vs 246 +/- 25 micrograms/L and
164 +/- 12 micrograms/L, respectively, in the CS group). We conclude that the
heparin coated CPB circuit with the uncoated cardiotomy reservoir may be less
biocompatible than the identical CPB set used together with the CS.
PMID- 9395950
TI - Jarcho-Levin syndrome associated with atrial septal defect and partial anomalous
pulmonary venous return: a case report.
AB - A 61-year-old woman suffering from Jarcho-Levin syndrome (JLS) was associated
with atrial septal defect and partial anomalous pulmonary venous return and
underwent corrective surgery. Pressure controlled postoperative ventilator
therapy is preferred in patients with JLS.
PMID- 9395951
TI - Simple method to improve the effectiveness of brain retrograde perfusion during
total circulatory arrest.
PMID- 9395952
TI - Valvular closure of atrial septal defect and its extended use.
PMID- 9395953
TI - [Measurement of plaque volume using three-dimensional intravascular ultrasound:
in vitro study].
AB - The usefulness of three-dimensional echocardiography using intravascular
ultrasound (3D-IVUS) for the measurement of plaque volume was evaluated by
comparing plaque volume derived from 3D-IVUS with that directly measured in 10
autopsied iliac or femoral plaque models (5-15 mm long). Using IVUS (3.5 F, 30
MHz), sequential cross-sectional images for three-dimensional datasets were
acquired with a motorized catheter pullback device connected to the three
dimensional reconstruction system. Three-dimensional reconstruction was performed
from the sum of the two-dimensional cross-sectional views. Plaque volumes were
calculated using a summation of disks algorithm based on the reconstructed
multiple short-axis cross-sections from the three-dimensional data. Three
dimensional IVUS demonstrated a good correlation with direct measurement of
plaque volume (y = 0.71x + 0.001, r = 0.80, SEE = 0.003 ml), so is useful for the
measurement of plaque volumes in the experimental models.
PMID- 9395954
TI - Hemodynamic effects of warm bathing in a Hubbard tank and exercise loading in
patients after myocardial infarction.
AB - Hemodynamic parameters were measured during bathing and exercise testing in 43
patients with myocardial infarction (mean age: 60.2 years) to investigate the
predictive parameters to determine when patients could safely resume bathing.
Patients took a fresh water bath at 42 degrees C in the supine position for 5 min
in a Hubbard tank. Group A showed an elevation of pulmonary capillary wedge
pressure (PCWP) during bathing of 10 mmHg or more (23 patients, mean age: 61.7
years) and group B showed an elevation of less than 10 mmHg (20 patients, mean
age: 60.5 years). Continuous multistep exercise tests were performed with a
bicycle ergometer in the supine position, and hemodynamic parameters were
measured at up to 50 W for 3 min on the day before the warm bathing test. There
were no significant differences in the changes of arterial pressure and heart
rate between the two groups. The PCWP at 3 min with a load of 50 W was
significantly higher in group A (26.9 +/- 9.0 mmHg) than in group B (16.7 +/- 9.1
mmHg, p < 0.01). The stroke index (SI) during exercise testing was significantly
lower in group A than in group B. The difference in the stroke index from
baseline values (delta SI) at 3 min with a load of 50 W was significantly lower
in group A (3.5 +/- 5.5 ml/m2/beat) than in group B (10.6 +/- 7.0 ml/m2/beat, p <
0.01). Similarly, delta CI and delta oxygen pulse during testing were
significantly lower in group A than in group B. The physical work capacity and
ejection fraction of the left ventricle of group A were significantly lower than
those of group B, whereas the left ventricular end-diastolic pressure was higher
in group A than in group B. CI, delta CI, SI, delta SI, METs, oxygen pulse, and
delta oxygen pulse were examined by regression analysis and multivariate analysis
to predict a significant elevation of delta PCWP during bathing. delta SI (p =
0.0032), delta CI (p = 0.0094), delta SI + METs (p = 0.0051), delta CI + METs (p
= 0.0061), delta CI + delta SI (p = 0.0084), and delta CI + delta SI + METs (p =
0.0093) showed the highest correlations with delta PCWP. These findings suggest
that changes in delta CI, delta SI, and METs are good predictive parameters for
determining when patients may safely resume bathing. We suggest that patients
with myocardial infarction, reduced cardiac function and a physical work capacity
of approximately 4.0 METs, delta SI: 5 ml/m2/beat and delta CI: 2.4 l/min/m2
resume bathing only after careful consideration.
PMID- 9395955
TI - [Mechanism of increase in exercise tolerance in patients with acute myocardial
infarction].
AB - The contribution of cardiac output reserve and the skeletal muscle to exercise
capacity was investigated in 24 patients with acute myocardial infarction.
Symptom-limited exercise tests with a cycle ergometer were performed at 1 week, 3
weeks, and 3 months after the onset of the first infarction. Ventilatory gas was
analyzed throughout the testing, and peak oxygen uptake (peak VO2) and anaerobic
threshold (AT) were determined. During the test, the cardiac index (CI) was
measured by the dye dilution method and the change in CI during exercise (delta
CI) was calculated as an index of cardiac output reserve. The cross-sectional
area of the thigh muscles (CSA) at the level of 10 cm above the patella was
measured using computed tomography. Peak VO2 and AT increased significantly from
1 week to 3 months after the onset of infarction. delta CI increased
significantly from 1 week to 3 weeks, and CSA increased significantly from 3
weeks to 3 months. Peak VO2 correlated significantly with both delta CI and CSA
at each measurement point, as was AT with delta CI and CSA. Change in peak VO2
correlated with change of delta CI from 1 week to 3 weeks, and also with both
delta CI and CSA from 3 weeks to 3 months. These results suggest that both
cardiac output reserve and peripheral factors contribute to the exercise capacity
up to 3 months after the onset of myocardial infarction. In particular,
peripheral factors such as muscle volume are important to improve exercise
capacity from 3 weeks to 3 months.
PMID- 9395956
TI - [Usefulness of magnetic resonance imaging for managing patients with prosthetic
carbon valve in the mitral position].
AB - The safety, findings and clinical usefulness of magnetic resonance (MR) imaging
were assessed in patients with a prosthetic carbon valve in the mitral position.
In vitro deflection, heating and image distortion due to the magnetic field of a
1.5 tesla MR machine were examined in three carbon valves (CarboMedics, St. Jude
Medical and Bjork-Shiley valves). In vivo MR imaging of the left ventricular
horizontal long-axis, vertical long-axis and short-axis views was performed by
electrocardiographically synchronized spin echo and field (gradient) echo
techniques in eight patients with prosthetic mitral carbon valves, consisting of
six CarboMedics valves, one St. Jude Medical valve and one Bjork-Shiley valve. No
deflection and significant heating was seen in all three valves in vitro.
Although little image distortion was shown in the CarboMedics and St. Jude
Medical valves, a small distortion toward the frequency encoded direction was
seen in the Bjork-Shiley valve but caused no difficulty in assessing the
surrounding images. Four of the eight patients had normal sinus rhythm and the
other four had atrial fibrillation. The prosthetic valves were depicted as signal
voids in the images taken by both spin echo and field echo techniques in vivo.
Clear structural information with little image distortion of the adjacent tissues
of the prosthetic valves were obtained in all patients, although the image of the
Bjork-Shiley valve which contained stainless steel in the frame had a slightly
stronger distortion than those of the CarboMedics and St. Jude Medical valves
which contained titanium. The stainless wire suture material used to close the
sternal incision was depicted as a signal void, and the areas of the signal loss
were larger in the images taken by the field echo technique than those by the
spin echo technique. The images taken by the spin echo technique in patients with
atrial fibrillation had reduced quality due to the irregularity of repetition
time. Cine MR imaging by the field echo technique showed physiological mitral
regurgitant jets as signal loss within the flowing blood, which appeared as high
signal intensity, bidirectionally in the bileaflet mechanical valve and
unidirectionally in the monoleaflet mechanical valve. An abnormal cavity was seen
behind the basal left ventricular myocardium in one patient with a CarboMedics
valve. The wall of the abnormal cavity was disrupted abruptly and the rest of the
wall consisted of pericardium and adjacent tissue in the image taken by the spin
echo technique. The image taken by the field echo technique showed an abnormal
jet flow from the basal part of the left ventricular cavity into the abnormal
cavity, which was compatible with left ventricular pseudoaneurysm. Two
dimensional echocardiography and Doppler color flow mapping disclosed the
abnormal cavity and the abnormal flow inside, but failed to show the connection
between the left ventricle and the cavity due to reverberation of the ultrasound
signal by the prosthetic valve. These findings suggest that MR imaging is a safe
and promising method to assess the complications and valvular function in
patients with a prosthetic carbon valve in the mitral position.
PMID- 9395957
TI - Antegrade or retrograde catheterization across a ventricular septal defect.
AB - The success rate and the most suitable catheter tip for crossing over various
types of ventricular septal defects (VSDs) were examined as a preliminary study
for transcatheter closure of VSD. The 18 consecutive patients with various types
of VSD were aged from 1 to 95 (mean [+/- SD] 13 +/- 22) months. Body weight was
3.7 to 25.0 (8.0 +/- 5.1) kg. Two-dimensional echocardiography showed that the
maximal diameter of the defects ranged from 1.0 to 12.0 (7.5 +/- 3.1) mm. There
were 10 patients with perimembranous defects, 4 with outlet defects, 2 with
muscular defects, and 2 with tetralogy of Fallot with perimembranous defects. An
angiographic balloon catheter, or an original or modified Judkins right coronary
catheter could be passed through the VSD antegradely or retrogradely in 16 of 18
patients. In only two patients, with a small VSD of 2.0 and 1.0 mm, the catheter
could not cross over the defect. The catheter entered the ascending aorta
antegradely in 12 cases. The Judkins right coronary catheter is most suitable for
crossing a VSD either antegradely or retrogradely.
PMID- 9395958
TI - [Evaluation of intramyocardial coronary flow velocity pattern before and after
surgical repair of Bland-White-Garland syndrome by pulsed Doppler
echocardiography].
AB - Anomalous origin of the left main coronary artery from the pulmonary artery
(Bland-White-Garland syndrome) is a rare congenital anomaly. Intramyocardial
coronary flow dynamics by pulsed Doppler echocardiography were studied in three
patients with this syndrome who underwent surgical repair by Hamilton's method.
Before surgery, the intramyocardial flow at the ventricular septum showed a
retrograde velocity pattern which had two peaks in systole and diastole in all
patients. After surgery, two patients with successful repair showed a biphasic
intramyocardial flow pattern which consisted of retrograde and antegrade flows in
systole and diastole, respectively. In contrast, one patient who had a residual
shunt between the left coronary artery and the pulmonary artery showed a biphasic
pattern which had antegrade flow in systole and retrograde flow in diastole.
These results may suggest that the evaluation of postoperative intramyocardial
coronary flow velocity pattern by pulsed Doppler echocardiography is useful for
detecting a residual shunt after surgical repair of Bland-White-Garland syndrome.
PMID- 9395959
TI - [Cardiovascular imaging in-a-month. A 60-year-old woman with systolic murmur
after repeat mitral valve replacement].
PMID- 9395960
TI - The range of provider/insurer configurations.
AB - In the past few years, health care providers have begun to seriously explore the
possibilities of forming various kinds of provider/insurer entities. As most
people in the health care industry now know, various states, as well as the
federal government, have been working on one form or another of legislation or
regulations that would permit health care providers to either (1) become insurers
in their own right or (2) at least be able to contract more directly with
consumers by taking on "full-risk" contracts from health maintenance
organizations and insurance companies while, commensurably, assuming additional
"delegated authorities" with respect to such contracts with minimal interference
from state insurance departments.
PMID- 9395961
TI - Physician equity in health care delivery systems: three alternative models.
AB - The 1990s have seen many health care organizations attempting to merge, acquire,
or affiliate with physician groups. Many have failed to provide physicians a
stake in the success of the newly formed enterprise, frequently resulting in
declining physician productivity, poor morale, and large operating losses. These
problems warrant a reexamination of the traditional acquisition model of growth
in favor of structures that retain a physician ownership component. This article
examines three models of health care organization in which physicians share in
the success of the enterprise and compares them in terms of ownership structure,
governance, and funds flow.
PMID- 9395962
TI - Doing it all in the public eye: a comparative analysis of California district
hospital affiliations.
AB - California contains 74 hospital districts, which are local governmental entities
with publicly elected boards. Historically, they have been responsible for
operating hospitals in remote areas to provide for the health care needs of their
communities. Because the health care market has become increasingly competitive
and because some of these once rural areas have grown into large cities, these
districts are seeking partners for their hospitals in hopes of preserving their
long-term financial viability. The terms reached in these transactions are
discussed in the article.
PMID- 9395963
TI - Merging HMOs into an all-payer system: a model to pursue?
AB - An almost unending debate over the future shape of America's health care system
increasingly focuses on the continuum between managed competition and government
regulations, and the question: What is right for the United States? The Maryland
all-payer, rate setting system for its 50 hospitals, where over a third of the
state's population is enrolled in managed care plans, is used as an example of
relatively successful blending of competitive and regulatory strategies. This
article concludes with the theme that given America's penchant for compromise,
competitive and regulatory approaches can coexist in a pluralistic health system
that constrains the use of services and costs, and enhances access and the
quality of patient care.
PMID- 9395964
TI - HMO quality and financial performance: is there a connection?
AB - Following the continuing expansion of managed care is a growing public interest
in the quality of care provided by managed care organizations. Public and private
organizations are actively developing systems for measuring and monitoring
quality of care with the intention of holding plans more accountable for quality
improvements and encouraging health care consumers to make responsible choices.
This article examines correlations between a prevention-based quality measure and
other commonly used measures of differentiating health plans, including financial
performance and profit status. The findings are instructive in efforts to develop
a quality measurement system that incorporates a variety of measures of plan
performance.
PMID- 9395965
TI - Unionism and professionalism--physician, do no harm: one person's view.
PMID- 9395967
TI - Advanced practice nurses.
PMID- 9395966
TI - Financing universal health care coverage for America's children.
AB - The Clinton administration is about to engage in finding a solution to the much
heralded bankruptcy of Medicare. Still, it is appropriate to consider that
millions of this nation's children lack health insurance. A plan to provide such
coverage through universal insurance would cover a set of defined benefits and be
means tested at the upper end of incomes. It would create a rational replacement
for a hodgepodge of entitlement programs based on actuarially sound principles.
It would derive funds from current Medicaid allocations and private employer
contributions for minor dependents.
PMID- 9395968
TI - Sore nipples.
PMID- 9395969
TI - Breastfeeding after early discharge.
PMID- 9395970
TI - Patient self-testing.
PMID- 9395971
TI - Electronic fetal heart rate monitoring: research guidelines for interpretation.
The National Institute of Child Health and Human Development Research Planning
Workshop.
AB - The purpose of the National Institutes of Health (NIH) research planning
workshops are to assess the research status of clinically important areas. This
article reports on a workshop, whose meetings were held between May 1995 and
November 1996, in Bethesda, MD, and Chicago, IL. Its specific purpose was to
develop standardized and unambiguous definitions for fetal heart rate (FHR)
tracings. Their recommendations for interpreting FHR patterns are being published
here, in JOGNN, and simultaneously by the American Journal of Obstetrics and
Gynecology.
PMID- 9395972
TI - What nurses should know about natural family planning.
AB - Two common natural family planning (NFP) methods are the ovulation method based
on characteristics of cervical mucus and the symptothermal method based on
changes in cervical mucus, basal body temperature, and the cervix. Both methods
are effective when used correctly. Nurses should understand the principles of NFP
and introduce these methods in discussions of family planning options. Interested
clients should be referred to a certified NFP instructor for education and
supervision.
PMID- 9395973
TI - Addressing couples' sexuality concerns during the childbearing period: use of the
PLISSIT model.
AB - During pregnancy, a couple may benefit from discussing sexuality concerns with a
nurse. Couples indicate they do not receive this support, and frequently nurses
state they do not have the knowledge, time, or skills to provide patient
education regarding sexuality. The PLISSIT model provides a framework for
developing and implementing interventions to assist clients in maintaining their
sexual relationship throughout the childbearing experience.
PMID- 9395974
TI - Development of a pacifier for low-birth-weight infants' nonnutritive sucking.
AB - Nonnutritive sucking can provide low-birth-weight infants with an opportunity to
organize their behavior, an important component of developmental care. A pacifier
specifically designed for low-birth-weight infants facilitates their nonnutritive
sucking to more fully meet their needs. The research and development of a
pacifier for low-birth-weight infants incorporated a naturalistic approach and
used the best model, the infant thumb, in the design. Clinical trials with
infants randomized to control and experimental groups were conducted to compare
the prototype pacifier to a commercially available pacifier. Observations using
the Anderson Behavioral State Scale demonstrated that infants using the prototype
pacifier more often were found to be in an alert state. This pacifier may
contribute to infants' state organization for optimum feeding and could be a
component in developmental care planning.
PMID- 9395975
TI - Caring for childbearing Korean women.
AB - This article examines the traditional and modern cultural elements that may
influence the health behaviors of the childbearing Korean woman and suggests ways
to provide culturally sensitive care. The first author, born and raised in Korea,
shares her reflections of culture and examples of clinical situations in Korea.
Implications for nursing care are addressed through specific cultural
prescriptions. Do's and don'ts are presented to foster culturally appropriate
care for Korean childbearing women.
PMID- 9395976
TI - The nurse-technology relationship: the case of ultrasonography.
AB - OBJECTIVE: To examine the nurse-technology relationship via a case study of
ultrasonography in women's health nursing practice. DESIGN: Exploratory case
study using ethnographic methods. SETTING: Outpatient obstetric and gynecology
clinic of a large teaching hospital. PARTICIPANTS: Three nurses, two technicians,
and one physician. RESULTS: Two of the nurses and the physician were very "nurse
like" in their use of the technology of ultrasonography to fulfill the
traditional nursing purposes of observation, teaching, and comforting. The third
nurse was nurse-like in talk, but at times "technician-like" in performance,
allowing the technology to pull her away from nursing purposes. CONCLUSIONS: The
expert nurses bent the technology to nursing purposes. Sonographers performed in
accordance with professional training and experience, rather than with gender
expectations. The subtle differences between expert nurse use and technical use
(by novice nurses or technicians) of ultrasonography may provide a strong
rationale against current efforts to substitute technically trained or
technically oriented personnel for expert nurses.
PMID- 9395977
TI - Social support, knowledge of infant development, and maternal confidence among
adolescent and adult mothers.
AB - OBJECTIVE: To explore the influence of social support and knowledge of infant
development on maternal confidence in performing infant care tasks among
adolescents and adults. DESIGN: Descriptive, exploratory. SETTING: A large urban
teaching hospital in the midwestern United States. PARTICIPANTS: 116 adolescent
mothers (ages 13 to 19 years); 101 adult mothers (ages 20 to 41 years). MAIN
OUTCOME MEASURES: Adult mothers reported higher levels of knowledge about infant
development than did adolescent mothers. For both adolescent and adult mothers,
social support and knowledge of infant development were significantly correlated
with confidence in providing infant care. For adolescents, knowledge of infant
development explained 15% of the variance in maternal confidence scores, and the
number of people in the adolescent's household explained an additional 5%. For
adults, parity explained 10%, social support explained 9%, and knowledge of
infant development explained 4% of the variance in maternal confidence scores.
CONCLUSIONS: An adolescent's knowledge of infant development significantly
affects her confidence in providing infant care. Given the learning needs of new
mothers and the time constraints for in-hospital postpartum teaching, nurses may
need to adjust content and teaching methods for all new mothers, but especially
to meet the needs of adolescent mothers.
PMID- 9395978
TI - In utero exposure to terbutaline: effects on infant behavior and maternal self
esteem.
AB - OBJECTIVE: Little is known about correlates of infant behavior after tocolytic
intervention. This study investigated three related questions: (a) Are there any
behavioral differences in infants exposed in utero to terbutaline and infants not
exposed? (b) Is the mother's perception of her infant influenced by group status?
(c) Is maternal self-esteem influenced by group status? DESIGN: Group comparison
over time of infants exposed in utero to terbutaline and infants not exposed.
Group mean cluster scores and recovery curves were compared. Mothers' responses
to a series of questionnaires were compared according to group status. The first
author remained blind to group status until all measures were completed on all
participants. SETTING: Recruitment and first administration of the Brazelton
Neonatal Behavioral Assessment Scale occurred in two regional hospitals, at
Minneapolis and St. Paul. Subsequent administrations took place in the infants'
homes. PARTICIPANTS: Forty-eight healthy, full-term (> or = 37 weeks gestational
age) neonates and their mothers, 16 of whom had been given terbutaline, and 32
control subjects. MAIN OUTCOME MEASURES: Brazelton Neonatal Behavioral Assessment
Scale was administered three times to each neonate. Mothers completed the Infant
Characteristics Questionnaires, the Neonatal Perception Inventories, and the
Maternal Self-Report Inventory. RESULTS: Significant differences were found
between the two groups of infants on the habituation cluster at Time 1 and the
autonomic stability cluster at Time 1 and Time 2. No significant group
differences were found in the mothers' responses to the questionnaires.
CONCLUSIONS: Nurses can assure parents that neonates exposed to terbutaline,
although they may exhibit initial difficulties with behavioral organization,
recover well over the course of the neonatal period. In addition, nurses can help
mothers discover methods that will help calm their newborns.
PMID- 9395979
TI - Strategies for designing a research utilization project with labor and delivery
nurses.
AB - The background and development of the second National AWHONN Research Utilization
Project on Second Stage Labor Management that was conducted in multiple sites
within the United States and Canada are presented. On the basis of the results of
the project, recommendations for designing other research utilization projects
are discussed.
PMID- 9395980
TI - The process for initiating nursing practice changes in the intrapartum: findings
from a multisite research utilization project.
AB - The process of implementing a research-based protocol (the Second Stage Labor
Nursing Management) at 40 sites in North America is described. Both positive and
negative factors involved in implementing and adhering to the protocol are
presented based on the reports of site coordinators. Key findings from the
process data are: (a) the term "research utilization" causes confusion, (b) it is
essential that nurses collaborate with other disciplines when attempting to
change practice, (c) administrative endorsement of research utilization is
important for practice change to occur, (d) nurses know their own practice sites
and how to facilitate protocol acceptance, and (e) practice change may not need
to occur all at once.
PMID- 9395981
TI - Pushing techniques during labor: issues and controversies.
AB - The lack of support for spontaneous bearing down versus directed pushing efforts,
varying opinions on the determination of readiness for pushing, and the
prevailing use of prolonged breath holding associated with pushing during labor
are aspects of second-stage labor management that continue to be areas of
contention among physicians and nurses. A discussion of current practice outcomes
surrounding these controversies from the AWHONN Second Stage Labor Research
Utilization Project conducted in 1994-1995 is presented in view of the available
research literature. In addition, recommendations for future nursing research are
identified.
PMID- 9395982
TI - Positioning during the second stage of labor: moving back to basics.
AB - The advantages of an upright position during labor are presented, with historic,
physiologic, and psychosocial aspects discussed. The influences of modern
obstetric practices such as electronic fetal monitoring and anesthesia practices
are discussed with findings related to the use of upright positions from the
Association of Women's Health, Obstetric, and Neonatal Nursing National Research
Utilization Project on Second Stage Labor Management integrated. Recommendations
for facilitating upright positions on the labor and delivery unit are presented.
PMID- 9395983
TI - Safe closure of therapeutic relationships with abuse survivors.
AB - 1 Safe closure of a therapeutic relationship is needed because neither healer nor
client can be a "stranger" again. 2 A "failed termination" may overshadow the
therapeutic gains that were made during the working phase, constituting a
"retraumatization." 3 Closure, as opposed to termination, involves a unique,
individualized mutual transformation of the therapeutic relationship into a "real
relationship."
PMID- 9395984
TI - Use of analogy to educate clients about the roles of neurotransmitters in
addictions.
AB - 1 The professional nurse who practices within the field of addictions is in an
ideal position to serve as an educational conduit and catalyst for promoting
understanding of the addictive process. 2 Historically, the use of analogy as a
teaching device can be seen in the readings of the Bible to as far back as Plato.
3 The client's level of functioning must be assessed by the professional nurse so
that any educational approach or intervention will be designed to meet the
appropriate level of the client.
PMID- 9395985
TI - Advanced practice psychiatric-mental health nursing in a community-based nurse
managed primary care program.
AB - In the evolving health care environment, advanced practice opportunities for
psychiatric-mental health nurses may lie in managed care models of community
oriented primary health care. As providers, care managers, health promoters and
educators, and client advocates with family systems expertise, psychiatric-mental
health advanced practice specialists are a necessary component of all primary
health care. This article describes the development of a community-based primary
care practice that integrates physical and mental health care on the same site.
PMID- 9395986
TI - Benefits of a nurse-psychiatrist collaborative practice in an anxiety disorders
unit.
AB - 1 Only one out of four people receives the appropriate therapy for anxiety
disorders, despite available and effective treatments. 2 Nurse-doctors
collaborative practice is a working relationship with a sharing of
responsibilities of the treatment program within the realm of respective roles. 3
Using an evidence-based care approach allowed the care providers to continually
monitor, assess and revise the treatment program which proved to be cost
effective and time efficient, yet provided premium patient care.
PMID- 9395987
TI - Religion/spirituality and health among elderly African Americans and Hispanics.
AB - 1 It is important to view elders in a multicultural sense and also understand
that there may be great heterogeneity within cultural or ethnic groups. 2
Knowledge of the impact of religion and spiritual beliefs for ethnic groups can
help health care professionals design interventions that are culture-specific to
the beliefs of individuals. 3 The psychiatric nurse is in a unique position to
encourage the patient to use healthy religious practices to deal with their
illness, whether mental or physical.
PMID- 9395988
TI - Relationship between tolerance/intolerance of ambiguity and perceived
environmental uncertainty in hospitals.
AB - 1 Many variables may contribute to a nurse's perceptions when working in a
changing health care environment, especially in the field of psychiatry. 2 While
this study did not find a relationship between tolerance for ambiguity and
perceived environmental uncertainty in hospitals, age and educational background
appear to be variable, which may warrant further study as ultimately impacting
nursing. 3 Research which explores those personality variables which underlie
perception would assist nurse administrators in designing interventions, opening
new lines of communication, and increasing sensitivity to individual nurse's need
in these changing times.
PMID- 9395989
TI - The aesthetic aspects of psychoanalysis.
PMID- 9395990
TI - In Electra's voice: Gilligan's debt to Freud.
PMID- 9395991
TI - Malignant eroticized countertransference.
AB - Gabbard (1994) divided the pathology of therapists, both male and female, who
commit sexual boundary violations into those who are psychotic, those who are
predatory psychopaths, those engaging in masochistic surrender, and those called
"the lovesick therapist." Lovesick therapists are the most common type and
manifest crucial narcissistic themes of "a desperate need for validation by their
patients, a hunger to be loved and idealized, and a tendency to use patients to
regulate their own self-esteem" (p. 127). Among the psychodynamic aspects of this
curiously circumscribed area of loss of reality testing that makes it difficult
for the therapist to see how self-destructive and harmful such enactment is, are
an unconscious reenactment of incestuous longings, a misperception of the
patient's wish for maternal nurturance as a sexual overture, enactments of rescue
fantasies, a projected idealization of the self of the therapist, a confusion of
the therapist's needs with the patient's needs, a fantasy that love is curative,
acting out disavowed rage at the patient, or rage at an organization, an
institute, or one's training analyst, a manic defense against mourning, a
narcissistic fantasy that their sexual affair is an exception, insecurity
regarding masculine identity, and assorted primitive preoedipal themes. Gabbard's
(1991) erotized countertransference is one variety of what I have termed
malignant eroticized countertransference. His variety is a development that
occurs under the pressure of the patient's preemptive and compelling expressions
of lust and love, the patient's erotic transference. But malignant eroticized
countertransference can also occur without the patient having offered any such
expressions; it can even occur on first meeting the patient when he or she walks
into the office! This is akin to the romantic "love-at-first-sight" theme so
favored in the movies and by novelists, but it is always pathological when it
occurs in the therapeutic situation. Countertransference enactments are a
creation between the patient and the therapist on a continuum from one pole,
where the patient has just walked into the office and contributes almost nothing
directly, to the other pole, where the therapist loses control of himself or
herself as a response to the unbearable pressure of the patient's lust. In the
treatment of malignant eroticized countertransference it seems clear from this
discussion that every case should be evaluated psychodynamically and the
treatment should be made to fit the patient, not the patient to the treatment.
Each situation should be studied in psychodynamic depth without preconceptions
based on generalizations or formulas. Therapists who are psychotic should of
course be treated with antipsychotic drugs and usually should not be allowed to
practice any further. Therapists who are psychopathic or sociopathic predators
should certainly never be allowed to practice. Some of the individuals who are
"lovesick," or, as I put it "love/lust obsessed," or those who have made a
masochistic surrender to a sadistic destructive patient, are in need of
reanalysis and have the potential to continue as effective therapists under
careful supervision. Therapists like this do not deserve to be summarily
dismissed from the profession but, like therapists who develop other serious
neurotic problems, should receive appropriate help from us.
PMID- 9395992
TI - Institutional countertransference: the matrix of social structure and psychic
structure.
PMID- 9395993
TI - Moral values: development and gender influences.
PMID- 9395994
TI - Time compressed: psychoanalysis in the days of HIV and AIDS.
PMID- 9395995
TI - The hospital ethics committee: a role for the contemporary psychoanalyst.
PMID- 9395996
TI - A model for dealing with countertransference in first-year psychiatric residents.
PMID- 9395997
TI - Interminable analysis?
PMID- 9395998
TI - Further reflections on creativity and personal growth: sculpture and poetry.
PMID- 9395999
TI - Preservation of pig liver allografts after warm ischemia: normothermic perfusion
versus cold storage.
AB - Warm ischemia is known to induce substantial damage to the liver parenchyma. With
respect to clinical liver transplantation, the tolerance of the liver to warm
ischemia and the preservation of these organs have not been studied in detail. In
isolated reperfused pig livers we proceeded according to the following concept:
Livers were subjected to 1 or 3 h of warm ischemia. Subsequently, these organs
were preserved by either normothermic perfusion or cold storage (histidine
tryptophan-alpha-ketoglutarate, HTK) for 3 h each. After storage, liver function
was assessed in a reperfusion circuit for another 3 h. Parameters under
evaluation were bile flow, perfusion flow, oxygen consumption, enzyme release
into the perfusate (creatine kinase, glutamic oxaloacetic transaminase (GOT),
lactic dehydrogenase, and glutamic pyruvic transaminase), and histomorphology.
Damage to the liver was lowest after warm ischemia of 1 h. The results after cold
storage were superior to those after normothermic perfusion (GOT: 3.2 +/- 0.3 and
2.6 +/- 0.2 U/g liver; cumulative bile production: 14.7 +/- 2.1 and 9.4 +/- 1 ml,
respectively; P < 0.05). In contrast, we found substantial damage at the end of
reperfusion in livers undergoing 3 h of warm ischemia under both preservation
techniques with severe hepatocellular pyknoses and essentially altered
nonparenchymal cells. The results suggest that pig livers undergoing 1 h of warm
ischemia and cold storage for 3 h with HTK solution may lead to functioning after
transplantation.
PMID- 9396000
TI - Survival in primary soft tissue sarcoma of the extremities and trunk.
AB - BACKGROUND: Soft tissue sarcomas (STS) of the extremities are rare. The purpose
of this study was to identify prognostic risk factors associated with survival in
patients with primary extremity and truncal STS. METHODS: Patient, tumor, and
pathologic data from 149 consecutive patients with localized primary STS of the
extremities and trunk were analyzed using Kaplan-Meier and Cox regression
techniques to identify univariate and multivariate risk factors. A subgroup
analysis was performed to compare factors predictive of survival in patients who
received treatment before (n = 50) and after (n = 99) treatment was standardized
in 1988. RESULTS: The 5-year survival rate was 76.5% with an average follow-up of
6 years. Local recurrence occurred in 23% of all patients, 40% before 1988 and
15% after 1988 (P < 0.0001). Risk factors associated with survival included
resection quality (R0 vs. R1; P < 0.0001), era of operation (P = 0.002), local
recurrence (P < 0.001), UICC stage (P < 0.0001), tumor size (P < 0.001), tumor
depth (P = 0.002), regional lymph nodes (P < 0.0001), and histology (P < 0.0001).
Multivariate analysis revealed that tumor size, tumor depth, and resection
quality were independent risk factors of survival. CONCLUSIONS: These results
indicate that management of STS in a specialized institution improves overall
survival. Resection quality is the most important risk factor of survival.
Therefore, effort should be made during primary treatment of STS to achieve wide,
tumor-free resection margins.
PMID- 9396001
TI - Quantitative measurements of released amines from individual exocytosis events.
AB - Chemical analysis of single cells is an area of great interest in the biological
sciences. Single-cell systems are being utilized as a model to understand in vivo
processes better. One method that is moving to the forefront in cellular analysis
is electrochemistry. Owing to their rapid response time and small dimensions,
voltammetric microelectrode techniques, such as amperometry and fast-scan
voltammetry, have made it possible to monitor minute amounts of biological
compounds and transiently occurring chemical events in cellular systems. The
application of these methods to the quantitation of individual vesicular release
events from single cells is overviewed here. The application of electrochemical
monitoring to several types of cultured cells, including bovine adrenal
chromaffin cells, rat pheochromocytoma (PC12) cells, beige mouse mast cells,
superior cervical ganglion neurons, and human pancreatic beta-cells, as well as
to the invertebrate systems, the leech Hirudo medicinalis, and pond snail
Planorbis corneus has provided a wealth of new information concerning exocytosis.
Results obtained from the studies highlight the potential of electrochemical
techniques in cellular analysis to contribute to our understanding of molecular
and pharmacological effects on exocytosis. This article overviews work done on
all the above cell types with an emphasis on PC12 cells.
PMID- 9396002
TI - Acetylcholine and associative memory in the piriform cortex.
AB - The significance of cholinergic modulation for associative memory performance in
the piriform cortex was examined in a study combining cellular neurophysiology in
brain slices with realistic biophysical network simulations. Three different
physiological effects of acetylcholine were identified at the single-cell level:
suppression of neuronal adaptation, suppression of synaptic transmission in the
intrinsic fibers layer, and activity-dependent increase in synaptic strength.
Biophysical simulations show how these three effects are joined together to
enhance learning and recall performance of the cortical network. Furthermore, our
data suggest that activity-dependent synaptic decay during learning is a crucial
factor in determining learning capability of the cortical network. Accordingly,
it is predicted that acetylcholine should also enhance long-term depression in
the piriform cortex.
PMID- 9396003
TI - Caffeine and the olfactory bulb.
AB - Caffeine, a popular CNS stimulant, is the most widely used neuroactive drug.
Present in coffee, tea, chocolate, and soft drinks as well as over-the-counter
and prescription medications, it influences millions of users. This agent has
achieved recent notoriety because its dependency consequences and addictive
potential have been re-examined and emphasized. Caffeine's central actions are
thought to be mediated through adenosine (A) receptors and monoamine
neurotransmitters. The present article suggests that the olfactory bulb (OB) may
be an important site in the brain that is responsible for caffeine's central
actions in several species. This conclusion is based on the extraordinarily
robust and selective effects of caffeine on norepinephrine (NE), dopamine (DA),
and particularly serotonin (5HT) utilization in the OB of mice. We believe that
these phenomena should be given appropriate consideration as a basis for
caffeine's central actions, even in primates. Concurrently, we review a rich
rodent literature concerned with A, 5HT, NE, and DA receptors in the OB and
related structures along with other monoamine parameters. We also review a more
limited literature concerned with the primate OB. Finally, we cite the literature
that treats the dependency and addictive effects of caffeine in humans, and
relate the findings to possible olfactory mechanisms.
PMID- 9396004
TI - Current issues in invertebrate phototransduction. Second messengers and ion
conductances.
AB - Investigation of phototransduction in invertebrate photoreceptors has revealed
many physiological and biochemical features of fundamental biological importance.
Nonetheless, no complete picture of phototransduction has yet emerged. In most
known cases, invertebrate phototransduction involves polyphosphoinositide and
cyclic GMP (cGMP) intracellular biochemical signaling pathways leading to opening
of plasma membrane ion channels. Excitation is Ca(2+)-dependent, as are adaptive
feedback processes that regulate sensitivity to light. Transduction takes place
in specialized subcellular regions, rich in microvilli and closely apposed to
submicrovillar membrane systems. Thus, excitation is a highly localized process.
This article focuses on the intracellular biochemical signaling pathways and the
ion channels involved in invertebrate phototransduction. The coupling of
signaling cascades with channel activation is not understood for any invertebrate
species. Although photoreceptors have features that are common to most or all
known invertebrate species, each species exhibits unique characteristics.
Comparative electrophysiological, biochemical, morphological, and molecular
biological approaches to studying phototransduction in these species lead to
fundamental insights into cellular signaling. Several current controversies and
proposed phototransduction models are evaluated.
PMID- 9396005
TI - Alcohol, astroglia, and brain development.
AB - Glial cells constitute one of the most common cell types in the brain. They play
critical roles in central nervous system (CNS) development. Recent evidence
demonstrates that glial cells are profoundly affected by prenatal alcohol
exposure, suggesting that alterations in these cells may participate in CNS
abnormalities associated with ethanol-induced teratogenesis. In vivo studies show
that prenatal exposure to alcohol hampers myelinogenesis and is associated with
neuroglial heterotopias and abnormal astrogliogenesis. Studies using primary
cultures of rat cortical astrocytes show that ethanol affects DNA, RNA, and
protein synthesis, decreases the number of mitotic cells, alters the content and
distribution of several cytoskeletal proteins including the astroglial marker,
glial fibrillary acidic protein (GFAP), and the levels of plasma-membrane
glycoproteins, reduces the capacity of astrocytes to secrete growth factors, and
induces oxidative stress. Furthermore, ethanol exposure during early
embryogenesis alters the normal development of radial glia cells (the main
astrocytic precursors), delays the onset of GFAP expression, and decreases mRNA
GFAP levels in fetal and postnatal brains and in radial glia and astrocytes in
primary culture. Recent evidence suggests that ethanol interferes with the
transcription process of GFAP, thus leading to a reduction in GFAP-gene
expression during astrogliogenesis. However, brief exposure of rats to high
levels of ethanol during the neonatal period (the period of astrocyte
differentiation) causes a transient gliosis, with an increase in GFAP and its
mRNA levels. These findings indicate that astroglial cells are an important
target of ethanol toxicity during central nervous system (CNS) development.
PMID- 9396006
TI - Signals that initiate myelination in the developing mammalian nervous system.
AB - The myelination of axons by oligodendrocytes in the central nervous system and
Schwann cells in the peripheral nervous system is essential for the establishment
of saltatory conduction. In the absence or destruction of the myelin sheath, as
seen in demyelinating diseases, impulse conduction is impeded resulting in severe
sensory and motor deficits. Axon myelination is the culmination of a sequence of
events that begins with the differentiation of glial cells and proceeds to the
transcription and translation of myelin genes, the elaboration of a myelin
sheath, and the recognition and ensheathment of axons. This review examines the
regulatory mechanisms for each of these steps and compares and contrasts the role
of the axon in initiating myelination in the central and peripheral nervous
system.
PMID- 9396007
TI - Nucleotide receptors in the nervous system. An abundant component using diverse
transduction mechanisms.
AB - Extracellular nucleotides achieve their role as cell-to-cell communicators by
acting at cell surface transmembrane receptors-the P2 receptors. Before molecular
cloning led to the isolation of any P2-receptor sequence, a small number of
receptor types had been proposed on the basis of pharmacological evidence. The
application of molecular biology to this field of receptor research has indicated
that a great underestimation of the number of receptor subtypes and of their
abundance had occurred. There are now known to be seven characterized P2Y (G
protein linked) receptors and the same number again of P2X receptors of the
transmitter-gated ion channel type. In this review, we discuss the properties of
these cloned receptors, their distribution within the nervous system, and their
methods of signal transduction.
PMID- 9396008
TI - RC3/neurogranin, a postsynaptic calpacitin for setting the response threshold to
calcium influxes.
AB - In this review, we attempt to cover the descriptive, biochemical and molecular
biological work that has contributed to our current knowledge about
RC3/neurogranin function and its role in dendritic spine development, long-term
potentiation, long-term depression, learning, and memory. Based on the data
reviewed here, we propose that RC3, GAP-43, and the small cerebellum-enriched
peptide, PEP-19, belong to a protein family that we have named the calpacitins.
Membership in this family is based on sequence homology and, we believe, a common
biochemical function. We propose a model wherein RC3 and GAP-43 regulate
calmodulin availability in dendritic spines and axons, respectively, and
calmodulin regulates their ability to amplify the mobilization of Ca2+ in
response to metabotropic glutamate receptor stimulation. PEP-19 may serve a
similar function in the cerebellum, although biochemical characterization of this
molecule has lagged behind that of RC3 and GAP-43. We suggest that these
molecules release CaM rapidly in response to large influxes of Ca2+ and slowly in
response to small increases. This nonlinear response is analogous to the behavior
of a capacitor, hence the name calpacitin. Since CaM regulates the ability of RC3
to amplify the effects of metabotropic glutamate receptor agonists, this activity
must, necessarily, exhibit nonlinear kinetics as well. The capacitance of the
system is regulated by phosphorylation by protein kinase C, which abrogates
interactions between calmodulin and RC3 or GAP-43. We further propose that the
ratio of phosphorylated to unphosphorylated RC3 determines the sliding LTP/LTD
threshold in concept with Ca2+/ calmodulin-dependent kinase II. Finally, we
suggest that the close association between RC3 and a subset of mitochondria
serves to couple energy production with the synthetic events that accompany
dendritic spine development and remodeling.
PMID- 9396013
TI - Decreased nocturnal secretion of melatonin in drug-free schizophrenics: no change
after subchronic treatment with antipsychotics.
AB - To evaluate the biosynthetic activity of the pineal gland in schizophrenia, the
circadian rhythm of plasma melatonin was investigated in 9 drug-free chronic
schizophrenics and in matched healthy subjects. In 7 of the patients, the 24-hour
secretory pattern of the pineal hormone was reassessed after 10 weeks of
treatment with antipsychotic drugs. In drug-free schizophrenics, the nocturnal
increase in plasma melatonin levels was significantly blunted as compared to
healthy subjects (p < 0.0001). Chronic treatment with antipsychotic drugs
significantly improved psychotic symptomatology, but did not change the secretory
pattern of melatonin. These data show that the biosynthetic activity of the
pineal gland is impaired in chronic schizophrenia and that successful treatment
with antipsychotic drugs does not go parallel with changes in the production of
melatonin.
PMID- 9396014
TI - Weak association between blood sodium, potassium, and calcium and intensity of
symptoms in major depressed patients.
AB - In previous reports, we showed that plasma and erythrocyte magnesium were
increased in many drug-free hospitalized depressed patients. Furthermore, we
observed that erythrocyte magnesium content was related to the intensity of the
symptoms. Highly depressed patients had the highest magnesium values. Today, we
report the results of plasma and erythrocyte sodium and potassium, and of total
and ultrafilterable plasma calcium in 66 hospitalized patients with major
depression compared to 58 healthy controls. No consistent differences in these
biochemical parameters are observed between patients when separated according to
intensity of anxiety, psychomotor retardation, and moral distress. Plasma sodium
is higher and plasma potassium lower in female patients of all subgroups as
compared to controls. Both male patients and controls have erythrocyte sodium and
potassium levels that are significantly different from those of females. This
clearly suggests a separation into genders in such studies. In conclusion--in
contrast to blood magnesium--sodium, potassium, and calcium levels do not seem to
be related to the intensity of the main clinical symptoms in hospitalized
patients with major depression.
PMID- 9396012
TI - Gene therapy for Parkinson's disease.
AB - Gene therapy is a potentially powerful approach to the treatment of neurological
diseases. The discovery of neurotrophic factors inhibiting neurodegenerative
processes and neurotransmitter-synthesizing enzymes provides the basis for
current gene therapy strategies for Parkinson's disease. Genes can be transferred
by viral or nonviral vectors. Of the various possible vectors, recombinant
retroviruses are the most efficient for genetic modification of cells in vitro
that can thereafter be used for transplantation (ex vivo gene therapy approach).
Recently, in vivo gene transfer to the brain has been developed using adenovirus
vectors. One of the advantages of recombinant adenovirus is that it can transduce
both quiescent and actively dividing cells, thereby allowing both direct in vivo
gene transfer and ex vivo gene transfer to neural cells. Probably because the
brain is partially protected from the immune system, the expression of adenoviral
vectors persists for several months with little inflammation. Novel therapeutic
tools, such as vectors for gene therapy have to be evaluated in terms of efficacy
and safety for future clinical trials. These vectors still need to be improved to
allow long-term and possibly regulatable expression of the transgene.
PMID- 9396009
TI - Vesicular neurotransmitter transporters. Potential sites for the regulation of
synaptic function.
AB - Neurotransmission depends on the regulated release of chemical transmitter
molecules. This requires the packaging of these substances into the specialized
secretory vesicles of neurons and neuroendocrine cells, a process mediated by
specific vesicular transporters. The family of genes encoding the vesicular
transporters for biogenic amines and acetylcholine have recently been cloned.
Direct comparison of their transport characteristics and pharmacology provides
information about vesicular transport bioenergetics, substrate feature
recognition by each transporter, and the role of vesicular amine storage in the
mechanism of action of psychopharmacologic and neurotoxic agents. Regulation of
vesicular transport activity may affect levels of neurotransmitter available for
neurosecretion and be an important site for the regulation of synaptic function.
Gene knockout studies have determined vesicular transport function is critical
for survival and have enabled further evaluation of the role of vesicular
neurotransmitter transporters in behavior and neurotoxicity. Molecular analysis
is beginning to reveal the sites involved in vesicular transporter function and
the sites that determine substrate specificity. In addition, the molecular basis
for the selective targeting of these transporters to specific vesicle populations
and the biogenesis of monoaminergic and cholinergic synaptic vesicles are areas
of research that are currently being explored. This information provides new
insights into the pharmacology and physiology of biogenic amine and acetylcholine
vesicular storage in cardiovascular, endocrine, and central nervous system
function and has important implications for neurodegenerative disease.
PMID- 9396010
TI - Nicotinic acetylcholine receptors in health and disease.
AB - Nicotinic acetylcholine receptors (AChRs) are a family of acetylcholine-gated
cation channels that form the predominant excitatory neurotransmitter receptors
on muscles and nerves in the peripheral nervous system. AChRs are also expressed
on neurons in lower amounts throughout the central nervous system. AChRs are even
being reported on unexpected cell types such as keratinocytes. Structures of
these AChRs are being determined with increasing precision, but functions of some
orphan subunits are just beginning to be established. Functional roles for
postsynaptic AChRs in muscle are well known, but in neurons the post-, peri-,
extra-, and presynaptic roles of AChRs are just being revealed. Pathogenic roles
of AChRs are being discovered in many diseases involving mechanisms ranging from
mutations, to autoimmune responses, to the unknown; involving cell types ranging
from muscles, to neurons, to keratinocytes; and involving signs and symptoms
ranging from muscle weakness to epilepsy, to neurodegenerative disease, to
psychiatric disease, to nicotine addiction. Awareness of AChR involvement in some
of these diseases has provoked new interests in development of therapeutic
agonists for specific AChR subtypes and the use of expressed cloned AChR subunits
as possible immunotherapeutic agents. Highlights of recent developments in these
areas will be briefly reviewed.
PMID- 9396011
TI - Neural roles of immunophilins and their ligands.
AB - The immunophilins are a family of proteins that are receptors for
immunosuppressant drugs, such as cyclosporin A, FK506, and rapamycin. They occur
in two classes, the FK506-binding proteins (FKBPs), which bind FK506 and
rapamycin, and the cyclophilins, which bind cyclosporin A. Immunosuppressant
actions of cyclosporin A and FK506 derive from the drug-immunophilin complex
binding to and inhibiting the phosphatase calcineurin. Rapamycin binds to FKBP
and the complex binds to Rapamycin And FKBP-12 Target (RAFT). RAFT affects
protein translation by phosphorylating p70-S6 kinase, which phosphorylates the
ribosomal S6 protein, and 4E-BP1, a repressor of protein translation initiation.
Immunophilin levels are much higher in the brain than in immune tissues, and
levels of FKBP12 increase in regenerating neurons in parallel with GAP-43.
Immunophilin ligands, including nonimmunosuppressants that do not inhibit
calcineurin, stimulate regrowth of damaged peripheral and central neurons,
including dopamine, serotonin, and cholinergic neurons in intact animals. FKPB12
is physiologically associated with the ryanodine and inositol 1,4,5-trisphosphate
(IP3) receptors and regulates their calcium flux. By influencing phosphorylation
of neuronal nitric oxide synthase, FKBP12 regulates nitric oxide formation, which
is reduced by FK506.
PMID- 9396016
TI - Differential development of the enhanced metabolic response during amphetamine
sensitization.
AB - Behavioral sensitization elicited by repeated administration of amphetamine does
not fully develop until a period after discontinuation of amphetamine, but then
persists undiminished for a long time. This experiment investigated the regional
metabolic changes in rats pretreated with amphetamine and challenged after
different abstinence periods (2, 7 and 28 days), using the 2-[14C]deoxyglucose
method. The results demonstrated that chronic amphetamine administration enhanced
rates of local cerebral glucose utilization in specific cerebral regions. The
magnitude and distribution of effects varied with the abstinence period. A
challenge dose of d-amphetamine 2 days after pretreatment was found to have no
more, or only mildly elevated, local cerebral glucose utilization compared with
that following a single acute dose. In rats challenged at the 7th and 28th day, a
supersensitive metabolic response was found in dopaminergic and non-dopaminergic
areas. This finding suggested regional differences in the development of
sensitization and underscored the importance of an abstinence period in the study
of sensitization and amphetamine psychosis.
PMID- 9396015
TI - Side effect profile of azathioprine in the treatment of chronic schizophrenic
patients.
AB - Various findings suggest auto-immune changes in schizophrenia. We have recently
demonstrated that platelets from schizophrenic patients bear autoantibodies (PAA)
which cross-react with brain antigens. Accordingly, treatment of schizophrenia
with an immunosuppressant might be of potential benefit. In a recent case study,
a chronic schizophrenic patient treated with azathioprine has demonstrated a
clear psychiatric improvement preceded by a decrease in PAA level. A phase I
study designed for assessing side-effects of short-term azathioprine treatment in
a group of schizophrenic patients is described here. From a group of 40 chronic
non-responsive patients, 14 patients demonstrating high PAA level have entered
the study and 11 have complied all along. Two groups were tested in parallel. In
the first (6 patients) 150 mg/day was given for 7 weeks while in the second (5
patients) the same regimen was given for two periods of 7 weeks with an interval
of 6 weeks. Blood biochemistry and cell count, as well as determination of PAA
were carried out weekly, starting 3 weeks before the trial and continuing up to 7
weeks after the treatment. Two out of 11 patients developed leucopenia in week 4.
No other side-effects were recorded in any of the patients. A substantial
reduction in PAA was observed in 3 out of 6 patients in group I and 4 out of 5 in
group II. Two patients showed improvement of psychiatric symptomatology. Our
results demonstrate that short-term azathioprine treatment induces transient
leucopenia in 18% of the patients receiving the drug, much alike the percentage
reported for other patient populations.
PMID- 9396018
TI - The effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on ethanol-induced sleep
time and ethanol elimination in inbred strains of mice with different alcohol
preference.
AB - 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) is a coenzyme for tyrosine,
tryptophan and phenylalanine hydroxylases. Male C57BL/6J and DBA/2J mice were
given 6R-BH4 (0, 12.5, 25.0 and 50.0 mg/kg of body weight, i.v.) or saline, and
then 4 h later, all animals were injected with ethanol (EtOH) (4.0 g/kg, i.p.),
which causes them to lose the righting reflex, to investigate the differences in
EtOH-induced sleeping time. 6R-BH4 pretreatment reduced EtOH-induced sleep time
in DBA/2J mice with lower alcohol preference (p < 0.05), which showed no changes
in the pharmacokinetics of blood EtOH. No changes in EtOH-induced sleep time were
observed in C57BL/6J mice with higher alcohol preference. These results indicate
that the sensitivity to EtOH in mice with lower alcohol preference was associated
with 6R-BH4 activity in the CNS.
PMID- 9396017
TI - Exercise avoidance and impaired endurance capacity in patients with panic
disorder.
AB - Exercise habits and indices of aerobic fitness as measured by spiroergometric
testing were examined in 38 patients with panic disorder and/or agoraphobia and
24 untrained healthy controls. Maximal oxygen consumption, maximal power output
and the power output at a lactate concentration of 4 mmol/l were significantly
reduced in the patient group when compared to untrained controls. Other
parameters like physical work capacity at a heart rate of 150/min, maximal
lactate concentration, vital capacity, subjective exertion at maximal work load,
and maximal heart rate did not differ between patients and controls. Patient
interviews revealed that aerobic exercise is avoided by the vast majority of
patients. Reduced aerobic fitness might contribute to the pathophysiology of
panic disorder and/or agoraphobia.
PMID- 9396019
TI - On the use of neural network techniques to analyse sleep EEG data. First
communication: application of evolutionary and genetic algorithms to reduce the
feature space and to develop classification rules.
AB - To automate sleep stage scoring, the system sleep analysis system to challenge
innovative artificial networks (SASCIA) has been developed and implemented. The
aims of our investigation were twofold: In addition to automatic sleep stage
scoring the hypothesis was tested that the information of only 1 EEG channel (C4
A2) should be sufficient to automatically generate sleep profiles which are
comparable with profiles made by sleep experts on the basis of at least 3-channel
EEG (C4-A2), EOG and EMG, as EOG and EMG are seen as epiphenomena during sleep
and the full information about the sleep stage should--according to our
hypothesis--be available in the EEG. The main components of the SASCIA sleep
analysis system are designed to meet the requirements of flexible adaptation to
the interindividual differences of the sleep EEG. The core of the SASCIA sleep
analysis system consists of neural networks. Supervised learning was implemented
and the experts' scorings were included into the learning set and test set. The
feature selections out of a large number (118) are performed by genetic
algorithms and the topologies of the networks are optimized by evolutionary
algorithms. Different mathematical procedures were used to evaluate and optimize
the efficiency of the system. The profiles generated by SASCIA are in reasonable
agreement with the sleep stages scored by experts according to RKR. The
development of the system is communicated in three parts: the first communication
deals with the application of the neural network techniques using evolutionary
and genetic algorithms and with the selection of feature space. The second
communication shows the training of these evolutionary optimized network
techniques with multiple subjects and the application of context rules, while the
third communication shows an improvement in the robustness by the simultaneous
application of 9 different networks obtained from 9 subject types which were used
in combination with context rules.
PMID- 9396020
TI - Melatonin effects in a patient with severe REM sleep behavior disorder: case
report and theoretical considerations.
AB - REM sleep behavior disorder (RBD) is so far a possibly underestimated yet well
described sleep disorder. Its major impact is the vigorous sleep behavior that
often results in injuries to the patient himself or to people sleeping nearby. We
treated a 64-year-old male with a clinically and polysomnographically confirmed
diagnosis of RBD with 3 mg melatonin, which led to a significant reduction of
motor activity during sleep, as measured by actigraphy (p < 0.0001 in all
analyzed movement parameters), and a full clinical recovery over a 5-month
treatment period. RBD phenomena gradually returned after melatonin administration
was stopped. After 2 months' treatment, polysomnography showed no major changes
except an increase of REM sleep (13 vs. 17% of sleep period time) and a better
preservation of REM-sleep-associated muscle atonia. Our results suggest that
melatonin might be able to reinforce REM sleep in RBD patients by enhancing its
active inhibition of motor activity.
PMID- 9396021
TI - [New aspects of the mechanism of Ca2+ entry in non-excitable cells].
AB - The capacitative Ca2+ entry has been accepted to play a crucial role in Ca2+
signaling in non-excitable cells, and the mechanisms linking the depletion of
intracellular Ca2+ stores to the activation of Ca2+ entry are presently the
subject of intensive investigation. There are two hypotheses to explain the
molecular mechanism of capacitative Ca2+ entry. One is that a diffusible second
messenger released from intracellular Ca2+ stores may activate a Ca2+ channel at
the plasma membrane. Numerous molecules, including CIF, cGMP, arachidonic acid,
and a small G-protein, are proposed as the candidates for the diffusible
messenger. In addition, the capacitative Ca2+ entry has been suggested to be
modulated by protein phosphorylation/dephosphorylation. Another hypothesis is
termed the "conformational coupling model". This model suggests that information
between the IP3 receptor and a plasma membrane Ca2+ channel may be transferred
directly through conformational protein-protein interactions. The plasma membrane
Ca2+ channel involved in the capacitative Ca2+ entry is still neither purified
nor cloned, but recent studies suggest that the mammalian homologue of the
Drosophila protein Trp may function as a capacitative Ca2+ entry channel.
PMID- 9396022
TI - [ATP receptors in the central nervous system].
AB - ATP receptors in the central nervous system (CNS) are divided into 2 major
classes, ionotropic (P2Xn) and G protein-coupled (P2Yn) ATP receptors. P2Xn
receptors, a member of the 2-transmembrane family, contain non-selective cation
channels that may play a role in rapid synaptic transmission. Seven subtypes of
P2Xn were reported so far. Although all of these subtypes are distributed in the
CNS, P2X4 and P2X6 are most abundantly and widely distributed. P2X3 is
distributed only in trigeminal ganglia neurons as well as in small-diameter DRG
neurons, suggesting their relation to pain. P2Yn receptors, a member of the 7
transmembrane superfamily, are coupled with Gq/11 to activate PLC beta. These
receptors are thought to play an important role in the modulation of synaptic
efficacy. Seven subtypes of P2Yn were reported so far. P2Y1, P2Y2, P2Y3 and P2Y4
are distributed in the CNS. Neither selective agonists nor antagonists to P2Xn
and P2Yn are known.
PMID- 9396023
TI - [Pharmacological approach to control American foulbrood of honeybees].
AB - In this review, I will describe honeybee biology from my prospective as a
veterinary pharmacologist and will provide a summary of my research project to
search for effective drugs to control American foulbrood, a bacterial disease of
honeybees. In conclusion, mirosamicin, a macrolide antibiotic, as a preventive
and glutaral, an alkylating agent, as a disinfectant were the most promising
drugs.
PMID- 9396024
TI - [Measurement of receptor-operated Ca2+ influx by microspectrofluometry combined
with the whole-cell patch clamp technique].
AB - Signal transduction from mouse bradykinin B2-receptors to Ca2+ influx was studied
in single control or v-Ki-ras-transformed NIH/3T3 (DT) fibroblasts.
Microspectrofluometry (fura-2) was combined with the whole-cell patch-clamp
technique to study bradykinin-activated Ca2+ influx. Cytosolic Ca2+ oscillations
observed at holding potentials of -20 to -80 mV were terminated by holding at -10
mV or more depolarized potentials. Bradykinin significantly enhanced the
hyperpolarization-induced increases in the intracellular free Ca2+ concentration
upon membrane hyperpolarization only in DT cells but not in control cells.
Internal application of 10 microM inositol 1,3,4,5-tetrakisphosphate (InsP4)
mimicked membrane potential-dependent Ca2+ entry. Activation of B2-receptors
resulted in a decrease of cellular fluorescence at the excitation wavelength of
340 or 360 nm after MnCl2 application in DT cells. This Mn2+ entry through the
Ca2+ influx pathway increased with membrane hyperpolarization below -20 mV. The
results suggest that bradykinin-induced cytosolic Ca2+ oscillations in ras
transformed NIH/3T3 cells are maintained by bradykinin-activated continuous Ca2+
influx, which may use Ins(1,3,4,5)P4 as an intracellular messenger.
PMID- 9396025
TI - [Evaluation of marble burying behavior: induced alteration of monoamine
metabolism in mouse brain].
AB - Evaluation of marble burying behavior (MBB) housing-induced alteration of
monoamine metabolism in mouse brain was performed by measuring metabolite levels
with HPLC-ECD. Isolated housing of mice, each in a cage (22 x 32 x 14 cm;
sawdust, 1-mm diameter; 5 cm in thickness) with 15 evenly spaced glass marbles on
the floor (2.5-cm diameter; control, without marbles) for 24-168 hr, 5-HIAA
contents were decreased in three regions: the midbrain, thalamus and
hypothalamus. 5-HT turnover was not inhibited except for in the hypothalamus due
to the decreases of 5-HT in the other two regions. On the other hand, DOPAC
content and DA turnover were decreased in four regions: striatum, midbrain,
thalamus, hypothalamus. The decrease in hypothalamic monoamine neurons was
observed notably after 72 hr of MBB housing. No alterations were observed in
feeding, water-drinking, spontaneous locomotor activity, number of buried
marbles, serum corticosterone and serum glucose concentrations during MBB keeping
compared with the control mice. These results suggested that the isolated mouse
housed in a cage with evenly spaced glass marbles for a long period may be a
model animal for alteration of monoamine metabolism in brain regions without
physical infringement.
PMID- 9396026
TI - [Constructional apraxia in right brain-damaged patients].
PMID- 9396027
TI - [Clinical study on air in epidural hematomas].
AB - Air in epidural hematoma has previously been reported by some authors. With the
advent of CT scan, the presence of air in epidural hematomas is not uncommon
findings. In our series, 27 of 78 (34.6%) cases with acute epidural hematoma had
air bubbles in epidural hematoma on CT scan. Acute epidural hematoma was located
in the temporal in 18, frontal in 3, occipital in 2, parietal in one and
posterior fossa in 3 cases. The air entrance was thought to be mastoid air cells
in 13, open fracture in 5, frontal sinus in 3, sphenoid sinus in 3, and unknown
in 3 cases. No patients in our series developed meningeal infection or tension
pneumocephalus. There was no statistical difference of overall outcome or risk of
increase in size of hematoma between acute epidural hematoma with and without
air.
PMID- 9396028
TI - [Electrophysiological evaluation of polyneuropathy in juvenile insulin dependent
diabetics].
AB - Thirty patients with juvenile insulin dependent diabetes mellitus (IDDM) were
electrophysiologically evaluated. In addition to the conventional motor and
sensory nerve conduction studies, intrafascicular microneurography was performed
in the median nerve. In this method a tungsten microelectrode was inserted into
the median nerve trunk at the elbow, and a compound nerve action potential (CNAP)
was recorded with supramaximal electrical stimulation at the wrist. The subjects'
age ranged from 8 to 31 years with an average (SD) of 15.4 (6.2) years; the
disease duration varied from 1 to 23 years with an average (SD) of 8.3 (5.8)
years. Polyneuropathy index (PNI), expressed as a mean percentage of the normal
for twelve indices over the four nerves obtained by motor conduction studies, was
93.9% on the average in patients with IDDM. The mean amplitude of CNAP obtained
by intrafascicular microneurography was 417 microV. These results indicate that
neuropathy in IDDM is milder than that in adult non-insulin dependent diabetes
mellitus (NIDDM). The mean value of PNI decreased at a rate of 0.56% per year;
the mean glycosylated hemoglobin (A1c) level was as high as 8.2 +/- 0.9%,
findings consistent with those of the previous analysis of adult patients with
NIDDM. The PNI value had a significant negative correlation with the duration of
diabetes mellitus (p < 0.001) and with mean glycosylated hemoglobin (A1c) level
(p < 0.01). CNAP amplitude had a tendency to correlate with duration of diabetes
mellitus (p < 0.1). In patients with IDDM we can tell exactly when the disease
occurred. Progression of neuropathy in juvenile IDDM was identical to that of
adult NIDDM. Careful management of diabetes mellitus is of importance to prevent
the progression of neuropathy.
PMID- 9396029
TI - [Mitochondrial redox change in gerbil hippocampus before and after transient
ischemia].
AB - To investigate the basis of neuronal vulnerability we studied mitochondrial redox
changes in gerbil hippocampus before and after 5 minutes forebrain ischemia. The
brain was frozen by in situ funnel freezing method, and grinned off coronally
until exposure of hippocampus. Relative value of regional redox ratio (NAD+/NADH)
was obtained from fluorescence signals of intrinsic fluorochromes, i.e., NADH
(PN) and flavoproteins (Fp), using a high resolution fluorometer. We calculated a
modified redox ratio MRR = FP/(Fp + PN). Each point is displayed in gray scales
ranged 16 degrees corresponding to the MRR value of the point; black represents a
low MRR value (reduced) and white represents a high value (oxidized). Pyramidal
cell layers and the granule cell layers were seen as linear areas of high MRR.
The stratum radiatum and stratum orience of the CA 1 subfield showed low MRR
compared with other hippocampal regions. During ischemic period, MRR in all
subfield of hippocampus had decreased but the decrease was more severe in CA 1
region than in another. Just after recirculation, MRR decreased transiently in
dentate and CA 3 areas but was fully recovered in all hippocampal areas with the
exception of CA 1 region, where the MRR decreased again 12 hours after
recirculation. These results suggest that CA 1 area suffers more pronounced
hyoxic condition (state V) than other less vulnerable regions during 5 minutes
ischemia. The irreversible reduction of MRR in CA 1 area may result from
continuing mitochondrial dysfunction, and this may cause lasting energy shortage
in CA 1 neurons that eventually results in slowly progressive cell death.
PMID- 9396030
TI - [Central nervous system involvement of leukemia and systemic lymphoma in
children: CT and MR findings].
AB - The purpose of this paper is to retrospectively evaluate CT and MR findings of
central nervous system (CNS) involvement of leukemia and systemic lymphoma in
children. Over a 12-year period, sixty-five patients with leukemia and fifteen
patients with systemic lymphoma underwent cerebral CT and/or MR imaging. Nine
patients (11.3%) were diagnosed as CNS involvement of leukemia and lymphoma. The
diagnostic criteria of CNS involvement were as follows; 1) Histological proof was
confirmed by surgery, 2) Tumor cells were found in the cerebrospinal fluid
examinations, 3) Increase in size of the lesion during observation without
specific treatment, and 4) Response to the treatment for leukemia or lymphoma.
All of nine patients fulfilled more than two criteria of 1)-4). The CT and MR
abnormalities in these patients were correlated with the findings of histology,
cerebrospinal fluid cytology, and/or treatment. The age of the patients ranged
from 0 to 15 years old. They consisted of 6 boys and 3 girls. The CT examinations
were performed before and after contrast administration. MR examinations were
performed on a 1.5-T unit, and T1-weighted, T2-weighted, and proton density
weighted images were obtained using spin-echo or fast spin-echo sequences. Tumor
masses were present in seven with leukemia (acute lymphoblastic leukemia 4; acute
myeloblastic leukemia 1; acute promyelocytic leukemia 1; acute monocytic leukemia
1), and in two with malignant lymphoma. On the CT scan, tumor masses were
hyperdense with contrast enhancement. On the MR images, their signals were
variable. In all of nine patients, tumor masses were contiguous with a meningeal
surface. Postcontrast T1 weighted images were valuable in demonstrating meningeal
infiltration. Tumoral hemorrhage was found in two patients. In a patient with
tumor at the superior sagittal sinus, venous infarct was observed. CNS leukemic
and lymphomatous masses are almost hyperdense on the CT and they are
characteristically contiguous with a meningeal surface. MR imaging was valuable
in demonstrating meningeal infiltration. Findings of CT and MR imaging,
cerebrospinal fluid examinations, and response to the treatment are useful in the
differentiation of CNS involvement of leukemia and lymphoma from other lesions
such as infectious diseases and leukoencephalopathy.
PMID- 9396031
TI - [Effect of arginine vasopressin (AVP) inhibitor in the inhibition of the
peritumoral edema].
AB - We investigated the effect of RU599 Arginine Vasopressin (AVP) inhibitor on
peritumoral edema of Wistar rats implanted with C6 glioma. C6 glioma was
implanted into the right caudoputamen of 3 week-old rat's brain. Five weeks after
the implantation, the changes of the brain water contents were measured by the
dry-weight method. RU599 (1 mg/ml/kg body weight) was administered into Wistar
rats via the tail vein every one hour (total 4 times), and the same dose of
saline was used as control. Rats were sacrificed 1 hour after the last
administration, and the brain of each rat was divided into 3 parts such as the
anterior part without a tumor, the middle part with a tumor and the posterior
part without a tumor. After that each part was separated into the right and left
parts. The tumor was removed from the brain. The water contents of the brain were
increased in the area around the tumor and the contralateral cerebral hemisphere
excluding the anterior part. RU599 could reduce the increased water contents
significantly in all areas except in the tumor itself and the area surrounding
the tumor. Tumor-origin brain edema includes not only localized one but also
diffuse one in the brain, and this study suggests RU599 has an effect of
inhibiting the diffuse brain edema.
PMID- 9396032
TI - [A Japanese family with Lesch-Nyhan syndrome resulting from a new point mutation
in hypoxanthine-guanine phosphoribosyltransferase gene].
AB - Lesch-Nyhan syndrome is associated with complete deficiency of hypoxanthine
guanine phosphoribosyltransferase (HPRT), characterized by hyperuricemia and
severe neurological signs. The HPRT gene has been mapped to the q26 region on the
long arm of the X-chromosome. We are taking care of a family of Lesch-Nyhan
syndrome. A 14-year-old male was noted the growth disturbance at the age of 7
months and self-mutilation behavior characterized by compulsive biting of his lip
and fingers at the age of 18 months. In 1987, at the age of 4, he was diagnosed
as Lesch-Nyhan syndrome from neurologic signs and hyperuricemia (9.8 mg/dl).
Neurological examination revealed mild mental and growth retardation, spasticity
and hyperreflexia of lower extremities, choreoathetoid movements of extremities,
and compulsive self-mutilation. The HPRT activity in erythrocytes of this patient
was 0.02 nmol/min/mg hemoglobin (control value 1.76 +/- 0.06), and adenine
phosphoribosyltransferase (APRT) activity was 1.08 nmol/min/mg hemoglobin
(control value 0.43 +/- 0.06). Using polymerase chain reaction (PCR) method
coupled with direct sequencing, we analyzed the nucleotide sequences of each exon
from the genomic DNA as well as the entire HPRT coding region of the cDNA by RT
PCR method. In the HPRT gene from the patient, a guanine to adenine substitution
at base position 209 in exon 3 was identified, which resulted in a single amino
acid substitution of glycine with glutamic acid at codon 70. The family studies
indicated that his mother, sister and grandmother were heterozygotes. PCR
restriction fragment length polymorphism (RFLP) utilizing Mnl I site which
created by the mutation, was useful for detection of the mutant gene. We have
identified a new missense mutation of the HPRT gene in a Japanese patient. This
mutation was reported at the same codon as foreign mutants and mighty be
indicative of a location of mutation activity in the HPRT gene.
PMID- 9396033
TI - [Ibudilast prevents oligodendroglial excitotoxicity].
AB - Previously we have demonstrated that cells of oligodendroglial lineage express
non-N-methyl-D-aspartate (NMDA) glutamate receptor (GluR) genes and are damaged
by kainate induced Ca2+ influx via non NMDA GluR channels of the alpha-amino-3
hydroxy-5-methyl 4 isoxazole propionate (AMPA) type, representing
oligodendroglial excitotoxicity. We here present the finding that ibudilast,
which is used clinically for treat patients with asthma and cerebrovascular
diseases, prevents oligodendroglia excitotoxicity. The oligodendrocyte like cells
(OLC), differentiated from the CG-4 cell line established from rat
oligodendrocyte-type 2 astrocyte (O-2A) progenitor cells, were exposed to 2 mM
kainate for 24 h and cell death was evaluated by measuring activity of lactate
dehydrogenase (LDH) released into the culture medium. Kainate induced cell death
was prevented by 10 to 100 microM ibudilast, which increased intracellular cAMP.
A 45Ca2+ influx study revealed that ibudilast attenuated kainate-induced Ca2+
influx. Inhibition of kainate-induced Ca2+ influx by ibudilast was decreased by H
89, a protein kinase A (PKA) inhibitor, but increased by okadaic acid, an
inhibitor of phosphatase 1 and 2A. Therefore, we concluded that ibudilast
prevented oligodendroglial excitotoxicity by a PKA-dependent phosphorylation
process resulting in decreased kainate-induced Ca2+ influx.
PMID- 9396034
TI - [A case of chronic encephalitis due to double infection with herpes simplex and
measles viruses].
AB - In a healthy 49-year-old man, a decrease in job efficiency was noticed along with
bizarre behavior. On admission, he was euphoric, childish, superficial and had
increased libido. Neurological findings were normal. There were no abnormal
findings on routine blood tests, hematochemistry or urine analysis. MRI showed no
abnormal findings. However, single photon emission CT (SPECT) showed diffuse
hypoaccummulation of tracer from the temporal to frontal regions. Lumbar puncture
showed clear cerebrospinal fluid (CSF) with pleocytosis and an elevated protein
level. Moreover, antibody IgG titers to herpes simplex virus (HSV) and measles
virus were elevated, according to EIA [serum HSV -1,202.2x, measles virus 47.1x:
CSF HSV-116.1x, measles virus 9.9x]. The ratio of serum to CSF antibody titers of
HSV and measles virus were 12.5 and 4.75, respectively. The antibody index values
of HSV and measles virus IgG titers were 8.42 and 22.22. The ratio of albumin was
105.7. Chronic, progressive HSV encephalitis is rare, and there have been very
few reports of encephalitis due to double infection by HSV and another virus. Our
patient was diagnosed as having encephalitis due to double infection with HSV and
measles virus, because the ratio of serum to CSF antibody titers was less than 20
and the antibody index values were over 1.91. Moreover, since the IgG index was
elevated and the ratio of albumin was not low, it was suggested that the blood
brain-barrier had not been disrupted, and antibodies were being produced
chronically in the medullary cavity. Hyperaccummulation of tracer on SPECT
studies has been reported in the early stages of HSV encephalitis. In our case,
while CT and MRI showed no abnormal findings, SPECT showed diffuse
hypoaccummulation. SPECT appears to be a useful tool in the diagnosis of this
disorder. In case of chronic, progressive personality change in middle-aged
adults, we must be aware of double virus infection of the brain as a possible
causal factor.
PMID- 9396035
TI - [Myotonic dystrophy with marked megacolon: report of a case].
AB - A 45-year-old woman was incidentally suspected to have megacolon. Chest X-rays
showed elevated left diaphragm due to colonic gas, and the heart was deviated to
the midline. Barium enema revealed marked dilation of the sigmoid colon,
confirming the diagnosis of megacolon. Maximal diameter of the sigmoid colon was
23 cm, but she had no gastrointestinal symptoms. During the work up for
megacolon, the presence of myotonic dystrophy was suspected. She had hatchet
face, but was not bald. Muscles of the neck and extremities were slightly
atrophic. There was percussion myotonia of the tongue and both hands, and grip
myotonia of the hands. Laboratory examinations showed impaired glucose tolerance
and low level of serum IgG. EMG showed myotonic discharges and myopathic units in
the limbs. Brain CT imaging revealed a thick skull. Cases of myotonic dystrophy
associated with marked megacolon are rare in Japan. Megacolon presents a high
risk for ileus, volvulus, and rupture, and myotonic dystrophy is associated with
a high operative and anesthesic risk. Megacolon, therefore, is an important
complication to look for in the management of myotonic dystrophy.
PMID- 9396036
TI - [A case of midbrain infarction with ipsilateral hand tremor].
PMID- 9396037
TI - [Venous angioma].
PMID- 9396038
TI - [(Neurological CPC-59). A 65-year-old man with a history of gastric cancer who
presented progressive loss of vision, memory loss and consciousness disturbance].
AB - We report a 65-year-old man with progressive loss of vision and consciousness
disturbance. The patient was well until his age of 63 when he was found to have a
gastric cancer. He was treated by the tumor resection and chemotherapy; he was
apparently well, but hepatic metastases were found in the next year (1996). In
June, 1996, he noted an onset of blurred vision more on the left. He was admitted
to the ophthalmology service of our hospital on July 14, 1996. His vision was 0.8
on the right and 0.15 on the left. He was treated with oral prednisolone with
slight improvement. He was also found to have IgM kappa-type monoclonal
gammopathy; Bence-Jones protein was positive and a bone marrow aspiration
revealed that approximately 10% of bone marrow cells were atypical plasma cells.
His vision had progressively got worse and he became blind by the end of October
1996. A chest X-ray and cranial CT scan revealed multiple abnormal nodular
densities. In the middle of November 1996, he became confused, disoriented and
agitated. His mental symptoms had progressively became worse, and a neurologic
consultation was asked on December 10, 1996. Neurologic examination revealed that
he was somnolent with decreased attention to his surroundings. He showed marked
disorientation and memory loss. Higher cerebral functions appeared intact. He was
able to recognize only light and dark. Pupils were moderately dilated with very
sluggish light reflex remained. Vertical gaze was moderately restricted and
horizontal nystagmus was noted upon left and right lateral gaze. The remaining of
the neurologic examination were unremarkable. General physical examination
revealed hepatosplenomegaly; the liver was palpable by 3 cm below the right
costal margin. Laboratory examination revealed anemia (Hb10.1 g/dl) and
thrombocytopenia (43,000/microliter). A cranial CT scan and MRI revealed a mass
lesion in involving the chiasmatic and bilateral hypothalamic areas. The tumor
showed intense homogeneous enhancement after Gd-DTPA infusion. The patient was
treated with dexamethasone and radiation. After 9 Gray radiation, he showed
deterioration in the sensorium; a cranial CT scan revealed a hydrocephalus of the
right ventricle with the midline shift towards left. The radiation was
discontinued. The subsequent clinical course was complicated by aspiration
pneumonia and thrombocytopenia. He expired on January 4, 1997. The patient was
discussed in a neurological CPC and the chief discussant arrived at the
conclusion that the patient had systemic malignant lymphoma with metastasis to
the brain judging from the characteristics of MRI and CT findings. Opinions were
divided between malignant lymphoma and metastatic brain tumor. Post-mortem
examination revealed plasmacytoid lymphocytic infiltration in the bone marrow.
Immunologically, these cells were positive for IgM and kappa-type light chain.
These plasmacytic infiltrations were seen in the lungs and lymph nodes. These
findings were consistent with the diagnosis of Waldenstrom's macroglobulinemia.
In the liver metastatic cancer tissues were seen; microscopic pictures were
essentially similar to those of resected gastric cancer. No local recidive was
noted in the stomach. In the central nervous system, a necrotic tissue was
involving the hypothalamic area bilaterally; no clear neoplastic cells were
found, however, lymphocytic and plasmacytic infiltrations were seen in the
perivascular space. In the optic nerves, loss of myelin and axons were seen.
These findings most likely mass formation from macroglobulinemia which underwent
necrotic change after radiation. Mass formation in the brain is rare for
Waldenstrom's macroglobulinemia, although it has been reported. The relation
between gastric cancer and macroglobulinemia in this patient is unclear.
PMID- 9396040
TI - Tamoxifen alters the localization of F-actin and alpha 5/beta 1-integrin
fibronectin receptors in human endometrial stromal cells and carcinoma cells.
AB - We have investigated F-actin and the integrin fibronectin receptor as possible
targets of tamoxifen (TAM) signaling in a cell-based model of the endometrium.
Normal human endometrial stromal cells and RL95-2 human endometrial
adenocarcinoma cells were treated for 1 h with TAM, a known antagonist of protein
kinase C (PKC), or with staurosporine or HA1004, two broad-spectrum protein
kinase antagonists capable of inhibiting PKC and PKA, respectively. We utilized
fluorescein-phalloidin and confocal microscopy to visualize the cellular
distribution of F-actin. Normal stromal cells and RL95-2 cells differed in the
arrangement of F-actin in control cells and in their response to TAM. In control
stromal cells, actin stress fibers were well organized throughout the cell, but
in RL95-2 cells, they were disorganized and present mainly at the cell periphery.
F-actin in RL95-2 cells treated with TAM (0.1 and 1.0 microM) or with
staurosporine (0.7 and 7.0 nM) exhibited a reorganization into stress fibers
consistent with a more stationary phenotype. In contrast, TAM- or staurosporine
treated normal stromal cells exhibited an increase in the amount of organized F
actin. Interestingly, in normal stromal cells treated with staurosporine but not
TAM or HA1004, these F-actin fibers appeared to terminate in dense plaques
proximal to the plasma membrane. The alpha 5/beta 1 integrin fibronectin receptor
mediates between the extracellular matrix and the actin cytoskeleton. TAM induced
clustering of the fibronectin receptor at the plasma membrane in normal stromal
cells, but not in carcinoma cells. This study supports the importance of plasma
membrane-cytoskeletal protein interactions in the response of normal and
carcinoma cells to TAM.
PMID- 9396039
TI - Long-term resistance to HIV infection in vertical HIV infection: cytokine
production, HIV isolation, and HIV phenotype define long-term resistant hosts.
AB - We analyzed immunologic (CD4 and CD8 slopes; interferon-gamma, interleukin-2,
interleukin-10, and chemokines production; concentration of IgE; beta 2
microglobulin) and virologic (p24; HIV isolability and phenotype; plasma viremia)
parameters in HIV vertically infected children > or = 8 years of age without
disease progression or mild symptoms and an absolute CD4+ count > or =
500/microliter with CD4+ percentage > or = 25%. The results were compared to
those of two control groups: (1) slow progressors, children > or = 8 years of age
with moderate symptomatology and/or moderate CD4 depletion, and (2) progressors,
children > or = 8 years of age with severe clinical disease and/or severe CD4
depletion. Pediatric long-term resistant hosts were characterized by higher
production of interleukin-2 and interferon-gamma and lower production of
interleukin-10, normal concentration of IgE, HIV isolates with a non-syncytium
inducing phenotype, and lower plasma viremia. This condition was not associated
with the concentration of beta 2-microglobulin, p24, and chemokines, or with HIV
isolability. The IL-10/IL-2 ratio best correlated with both CD4 counts and
disease progression. Thus, vertically infected children showing resistance to
disease progression are immunologically and virologically distinct from those in
whom progressive HIV infection is observed.
PMID- 9396041
TI - Stage I and stage II infiltrating ductal carcinoma of the breast analyzed for
chromosome 8 copy number using fluorescent in situ hybridization.
AB - We previously reported the results of 30 informative samples (from a total of 34
specimens gathered) of archival breast cancer tissue, including infiltrating
ductal carcinoma (NOS), ductal carcinoma in situ, lobular carcinoma, papillary
carcinoma and benign lesions of the breast. The study was conducted using
fluorescent in situ hybridization (FISH) and a chromosome 8 alpha-satellite
probe. Subsequently, a total of 34 cases of infiltrating ductal carcinoma of the
breast (NOS, 17 cases stage I and 17 cases stage II) were studied, again using
interphase cytogenetics. The aim of the present study is to confirm and extend
the results of our initial study of stage I and stage II disease. Towards this
end, 36 additional specimens of formalin-fixed paraffin-embedded breast cancer
tissue have been analyzed cytogenetically under blinded conditions for the
frequency of abnormal chromosome 8 copy numbers using FISH and the previously
described protocol optimized for our laboratory. Of these, 18 were stage I and 18
were stage II. The frequency of trisomy 8 among stage I tumors was found to be
28% (5 out of 18). The frequency of trisomy 8 among stage II tumors was found to
be 61% (11 out of 18). These results, while less striking, are consistent with
those reported in our initial study of stage I and stage II disease, where the
frequencies of trisomy 8 among stage I and stage II tumors were 24% (4 out of 17)
and 82% (14 out of 17). These results not only establish that chromosome 8
trisomy is a recurrent finding in breast cancer, but also confirm that a higher
frequency of trisomy 8 was observed with a higher clinical stage (stage II) than
with a lower stage (stage I). It will be of interest to extend the findings in
stage I and stage II breast cancer to other stages as well.
PMID- 9396042
TI - Luzindole, a melatonin receptor antagonist, suppresses experimental autoimmune
encephalomyelitis.
AB - Melatonin has immune-enhancing effects and can exacerbate autoimmunity.
Pinealectomy or light exposure, which suppress melatonin, inhibit T cell
autoimmunity. To investigate the involvement of melatonin in experimental
autoimmune encephalomyelitis (EAE), a T-cell-mediated autoimmune demyelinating
disease, we tested the effect of luzindole, a melatonin receptor antagonist, on
EAE. Luzindole-treated mice did not develop EAE after immunization with spinal
cord homogenate, whereas control mice developed EAE. This study suggests that
pharmacological inhibition of the immunoenhancing effects of melatonin may
prevent autoimmune demyelination.
PMID- 9396044
TI - 'Autoantibody dominance' pattern following idiotypic manipulation of naive mice
by immunization with anti-U1RNP antibodies.
AB - OBJECTIVE: To study the immune response and clinical findings in mice immunized
with different epitope-specific anti-U1RNP antibodies purified from the sera of
mixed connective tissue disease (MCTD) patients with various clinical
manifestations. METHODS: BALB/c mice were immunized with anti-U1RNP-IgG
preparations from 3 patients with MCTD. Group 1 was immunized with U1 70 kD A
positive IgG, group 2 with U1 70 kD-negative, U1A, U1C, B-B'-positive IgG and
group 3 with U1 70 kD, U1A, U1C-positive IgG. The induced autoantibody response
in the mice was studied by ELISA and immunoblots and the clinical findings of
MCTD in humans were assessed. RESULTS: Immunoblot assays showed that mice
immunized with different human anti-U1RNP antibodies developed predominantly
autoantibodies directed against U1 68-70 kD epitope. This 'autoantibody
dominance' pattern was not associated with clinical findings. CONCLUSIONS: The
restricted murine autoimmune response may provide clues to the diversified
autoantibody production in autoimmune diseases and explain in part the changing
patterns of clinical findings in individuals with MCTD.
PMID- 9396043
TI - Overexpression of protein tyrosine kinases in human esophageal cancer.
AB - Using a PCR-based cloning technique, we isolated a series of protein tyrosine
kinases (PTKs) expressed in a cell line of esophageal squamous cell carcinoma.
Sequence analysis revealed 10 different kinds of PTKs of the receptor type
[epidermal cell growth factor receptor, insulin-like growth factor I receptor,
fibroblast growth factor receptor 4, eck, erk, discoidin domain receptor
(DDR)/trkE/cell adhesion kinase (Cak), HEK2, HEK8, axl and sky] and one PTK of
the nonreceptor type (tyk2). Subsequently, we examined the expression of the
transcripts of these 11 genes in paired samples of normal and carcinomatous
esophageal tissues obtained from 12 cases of esophageal cancer. We found that all
11 gene transcripts were expressed in both carcinomatous and normal tissues, and
6 of them were significantly overexpressed in carcinomatous tissues relative to
adjacent normal tissues. Among these, the magnitude of mRNA expression of
DDR/trkE/Cak PTK was positively correlated with the proliferative activity of
carcinoma cells, but not with their degree of differentiation.
Immunohistochemically, DDR was expressed in both normal and cancerous esophageal
cells. The intensity of the expression was higher in cancer than normal tissue.
In addition, we confirmed the expression of two isoforms of DDR/trkE/Cak in
normal and cancerous esophagus. Our study suggests that DDR/trkE/Cak plays an
important role in the regulation of proliferation of esophageal cancer.
PMID- 9396045
TI - HLA-DQB1 markers associated with human immunodeficiency virus type I disease
progression.
AB - In a previous investigation, we demonstrated that certain human leukocyte
antigens (HLA) may be associated with human immunodeficiency virus type I (HIV-1)
infection or protection from infection among regional African Americans and
Caucasians. We demonstrated that HLA-DQB1*0605 was associated with a possible
increased risk of susceptibility to infection in African Americans and that
DQB1*0602 was associated with a possible increased risk of infection in
Caucasians. The present study was designed to demonstrate possible HLA
associations with HIV-1 disease progression and AIDS in regional African American
and Caucasian populations. To differentiate rapid from slow progressors, immune
parameters of the HIV-1-positive patient population were monitored over a mean
follow-up period of 23 +/- 2 months for African Americans (n = 30) and 25 +/- 5
months for Caucasians (n = 22). To determine significance, HLA allele frequencies
among rapid progressors were compared to those of slow progressors, separated by
race. Results were analyzed by chi 2 analysis, with Fisher's exact test where
applicable, linear logistic regression and Kaplan-Meier survival analysis. In the
HIV-1-positive African American group, a better prognosis was associated with HLA
DQB1*0602. In the HIV-1-positive Caucasian group, HLA-DQB1*0302 was associated
with rapid HIV disease progression, but no marker was associated with a more
favorable prognosis.
PMID- 9396047
TI - Translocation 2;19 in a patient with probable relapsed acute myeloid leukemia.
AB - We report the cytogenetic and hematopathologic results from a patient diagnosed
with acute myeloid leukemia. Although the initial specimen revealed an apparently
normal male karyotype, a translocation, t(2;19)(q21;p13), was detected in the
second specimen. It is not clear whether this was a primary or secondary and
possibly chemotherapy-induced abnormality. In an extensive search of the recent
medical literature database (Medline, 1966 to the present; CancerLit, 1983 to the
present, MDX Health Digest, 1988 to the present; HealthSTAR, 1975 to the present,
and CINAHL, 1982 to the present), we found no previous report of this specific
translocation. This case is of interest not only because of its cytogenetic
rarity and its unique clinical features, but also because of the fact that this
patient worked in construction management, performing offshore drilling in oil
fields for several years, and also worked with plastics and polymer film for
about 4 years, although this past history of possible genotoxic exposure may or
may not be of relevance. In addition, it is also of interest that one of the
translocation breakpoints, 19p13, is apparently identical to that found in the
1;19 translocation associated with pre-B cell acute lymphocytic leukemia.
PMID- 9396046
TI - Mature CD4 single positive thymocytes in human Thymoma: T cells may differentiate
in the thymic epithelial cell tumor.
AB - Human thymoma, which is occasionally associated with autoimmune disease, is a
thymic epithelial cell tumor and often contains a large number of lymphocytes. In
a previous study, we have shown that a proportion of CD4 single positive T cells
in human thymomas lack CD3, suggesting immaturity. In this study, we focused on
the rest of the CD4 single positive T cells in thymomas that expressed CD3/TcR
alpha beta and investigated the maturity of single positive T cells by analyzing
lymphocyte surface antigens and the cells' proliferative response to a mitogen.
CD4 single positive cells that expressed CD3 or TcR alpha beta also expressed
CD69 and had probably undergone positive selection in the tumor. Further,
isolated CD4 or CD8 single positive cells from the thymomas responsed to a
mitogen although at lower levels than the corresponding single positive cells in
the peripheral blood. These results indicate that thymomas contain single
positive T cells which have mature phenotype and proliferative ability, and
suggest that T cells may differentiate in thymoma.
PMID- 9396048
TI - Characterization of myomodulin-related peptides from the pulmonate snail Helix
aspersa.
AB - Three myomodulin-related peptides--pQLSMLRLamide, PMSMLRLamide, and SLGMLRLamide-
have been purified and sequenced from extracts of whole snails. The level of
immunoreactive myomodulin was shown by HPLC and RIA to be widely distributed
among 26 different snail tissues, with the highest levels (higher even than those
in the central ganglia) occurring in certain male reproductive organs. Synthetic
pQLSMLRLamide modified either the spontaneous rhythmic activity or the resting
tone of several isolated muscular organs: the aorta, ventricle, upper gut,
epiphallus, flagellum, and spermatheca; but the retractor muscles of the pharynx,
penis, and tentacle were unaffected.
PMID- 9396049
TI - Neutral endopeptidase-24.11 (NEP)-like activity in molluscan hemocytes.
AB - Using a spectrofluorimetric procedure, we found that the plasma membrane from
hemocytes of two freshwater snails, Planorbarius corneus and Viviparus ater,
shows neutral endopeptidase-24.11 (NEP)-like activity. Moreover, the addition of
ACTH(1-24) to the hemolymph provokes an increase in NEP-like activity. This
increased NEP-like activity is blocked by phosphoramidon, a potent inhibitor of
mammalian NEP. These findings suggest that this peptidase has been well conserved
in the course of evolution and plays an important role in immune-neuroendocrine
mechanisms.
PMID- 9396050
TI - Adrenomedullin binds with high affinity, elevates cyclic AMP, and stimulates c
fos mRNA in C6 glioma cells.
AB - The effects of adrenomedullin (ADM) on C6 glioma cells were investigated.
[125I]ADM bound with high affinity (Kd = 24 nM) to a single class of sites (Bmax
= 36,000/cell) in C6 cells. Specific [125I]ADM binding was inhibited with high
affinity by ADM (IC50 value of 10 nM) but not ADM(22-52) or pro-adrenomedullin N
terminal 20 peptide (PAMP). By RT-PCR, ADM receptors were detected in C6 cells.
ADM elevated cAMP (ED50 value of 10 nM) whereas PAMP and ADM(22-52) did not. ADM
stimulated transiently c-fos mRNA in a concentration-dependent manner. Monoclonal
antibody G6, which neutralizes ADM, significantly inhibited C6 proliferation and
decreased the ability of ADM to elevate c-fos mRNA. These data suggest that ADM
is a regulatory peptide of C6 cells.
PMID- 9396051
TI - Production and secretion of adrenomedullin from glial cell tumors and its effects
on cAMP production.
AB - The expression of adrenomedullin (ADM) and its mRNA was studied in human glial
cell tumors and cultured glioblastoma cell lines, T98G and A172. Northern blot
analysis showed that ADM mRNA was expressed in all brain tumors examined (three
anaplastic astrocytomas and two glioblastomas multiforme) and in the glioblastoma
cell lines. Immunoreactive (IR-) ADM was detectable in these brain tumors by
radioimmunoassay (0.31-2.0 pmol/g wet weight), except for one anaplastic
astrocytoma. Reverse phase high performance liquid chromatography of the tumor
extracts showed a single peak eluting in the position of ADM-(1-52). IR-ADM
concentrations in the cultured media of T98G cells were 205.5 +/- 8.4 fmol/10(5)
cells/24 h (mean +/- SEM, n = 5). Treatment of T98G cells with interferon gamma
or interleukin 1 beta increased the expression levels of ADM mRNA and the IR-ADM
concentrations in the cultured media, whereas tumor necrosis factor alpha
decreased them in a dose-dependent manner. Treatment with synthetic ADM-(1-52)
(10(-8) or 10(-7) mol/l) increased the cAMP concentrations in the cultured media
of T98G cells. These findings suggest that ADM is secreted from glial cell tumors
and is related to the pathophysiology of these tumors.
PMID- 9396052
TI - Specific adrenomedullin binding sites in the human brain.
AB - Binding sites for adrenomedullin in human brain were investigated and
characterized by radioligand binding. Specific binding sites for adrenomedullin
were present in every region of human brain (cerebral cortex, cerebellum,
thalamus, hypothalamus, pons and medulla oblongata) obtained at autopsy. Despite
the homology with calcitonin gene-related peptide (CGRP), CGRP was a poor
inhibitor of [125I]adrenomedullin binding (IC50 > 1 microM) compared with
adrenomedullin(1-52) (IC50 = 1.2 +/- 0.5 nM, mean +/- SEM, n = 3). Three
adrenomedullin fragments, adrenomedullin(1-12), adrenomedullin(22-52), and
adrenomedullin(13-52), were also poor inhibitors of the binding (IC50 = 0.3
microM), suggesting that the whole molecule of adrenomedullin(1-52) is required
for binding to the receptor. Scatchard plots of [125I]adrenomedullin binding in
human brain (cerebral cortex) gave a dissociation constant of 0.17 +/- 0.03 nM
and maximal binding of 99.3 +/- 1.9 fmol/mg protein (n = 5). These findings
suggest that specific adrenomedullin binding sites that differ from the CGRP
receptors exist in human brain. This indicates a possible novel
neurotransmitter/neuromodulator role for adrenomedullin in human brain.
PMID- 9396053
TI - Neurobehavioral development of neonatal mice following blockade of VIP during the
early embryonic period.
AB - Previous work has shown that blockade of VIP function in the early
postimplantation embryo results in growth retardation and microcephaly. In the
present work, the neurobehavioral development of neonatal mice was examined
following treatment of dams with a VIP antagonist during this period. Inhibition
of VIP functions during early embryogenesis impaired the performance of 5 of 10
developmental behaviors. These behaviors included developmental milestones (first
appearance of ear twitch and eye opening) and complex motor behaviors (negative
geotaxis, surface righting, and air righting). The retardation of neurobehavioral
development produced by inhibition of VIP action indicates that this peptide is
important to the progression of embryonic development.
PMID- 9396054
TI - Vasoactive intestinal polypeptide (VIP) innervation of rat spleen, thymus, and
lymph nodes.
AB - In the thymus, VIP-positive (+) fibers were found in the capsular/septal system,
cortex, and medulla. In the spleen, VIP+ nerves coursed along large arteries and
central arterioles, and in the white pulp, venous/trabecular system, and red
pulp. Splenic VIP innervation was more robust in Long-Evans hooded rats than in
Fischer 344 rats. VIP+ nerves in mesenteric lymph nodes were found in the cortex,
and along the cortical vasculature and medullary cords. No VIP innervation was
observed in popliteal lymph nodes. Immunocytes also were VIP+, suggesting that
both neural and cellular synthesis of VIP contributes to VIP concentration in
lymphoid organs. Surgical sympathectomy did not alter splenic or thymic VIP
content, respectively, and VIP innervation of these organs was not altered,
suggesting an origin for VIP+ nerves other than the sympathetic nervous system.
PMID- 9396055
TI - Vasoactive intestinal peptide stimulates p59fyn kinase activity in murine
thymocytes.
AB - The neuropeptide VIP has immunomodulatory properties, including the inhibition of
cytokine production (IL-2, IL-4, and IL-10) in T lymphocytes stimulated through
their TCR. The transduction pathways involved in the inhibitory effect of VIP on
IL-2 expression are not known. Here we investigate the effect of VIP on the T
cell-specific protein tyrosine kinases p56lck and p59fyn in resting and
stimulated thymocytes. VIP does not affect lck or fyn activity in stimulated
thymocytes and does not alter the general pattern of cellular tyrosine
phosphorylation. However, VIP stimulates p59fyn, but not p56lck, kinase activity
in resting thymocytes. The effect is dose dependent, exhibits a specific time
course, and is reproduced by other cAMP-inducing agents such as forskolin,
prostaglandin E2, and 8-bromo-cAMP, suggesting that cAMP may function as the
intracellular mediator.
PMID- 9396056
TI - Pretreatment with neurokinin substance P but not with cholecystokinin-8S can
alleviate functional deficits of partial nigrostriatal 6-hydroxydopamine lesion.
AB - The neuropeptide substance P (SP) has been implicated in the control of various
neuro-behavioral functions including reinforcement and learning processes. It
also exerts neurotrophic and regenerating effects in vitro and in vivo. A
previous study indicated a potential therapeutic effect of SP in rats with
partial 6-hydroxydopamine lesions of the nigrostriatal dopamine system when SP
was administered after the lesion. The purpose of the present study was to
determine whether prelesion treatment with SP would also interact with the
effects of unilateral 6-hydroxydopamine lesion of the substantia nigra. Thus, SP
(50 micrograms/kg) was administered i.p. on 8 consecutive days prior to
unilateral lesion of the substantia nigra. Furthermore, we investigated the
effects of prelesion treatment with cholecystokinin-8S (CCK; 1 microgram/kg),
another neuropeptide, which is closely related to dopaminergic neurons, and which
also can have neurotrophic and neuroprotective functions. Our results show that
animals with partial neostriatal dopamine depletions (residual dopamine levels of
more than 10%) did not show turning asymmetries when pretreated with SP, whereas
animals pretreated with vehicle exhibited an initial ipsiversive asymmetry from
which they recovered. In contrast, behavioral asymmetries were most pronounced in
animals which had been pretreated with CCK. These peptide treatments did not
affect the degree of neostriatal dopamine depletion; however,
dihydroxyphenylacetic acid/dopamine ratios were enhanced in the neurostriatum of
animals with partial dopamine damage after SP- and CCK-pretreatment, and in the
ventral striatum of SP-pretreated animals. These data provide evidence that
prelesion treatment with SP, but not with CCK, can alleviate functional deficits
induced by a partial nigro-striatal dopamine lesion. This effect may be related
to enhanced ventral striatal dopamine activity and/or to the peptide's known
effects on learning, motivation, and emotion.
PMID- 9396057
TI - Gastric and brain stem, effects of substance P on nucleus tractus solitarius
unitary responses.
AB - Subdiaphragmatic vagally evoked unitary responses were recorded in the medial
subnucleus of the nucleus tractus solitarius in an in vitro neonatal rat brain
stem-gastric preparation. Substance P was applied to the gastric compartment
and/or the brain stem compartment of the bath chamber to evaluate the peripheral
gastric and central brain stem effects of the peptide on the nucleus tractus
solitarius unitary activity. After substance P application to the gastric or
brain stem compartment, a concentration-related change in the nucleus tractus
solitarius unitary activity was observed. The gastric effects of substance P, at
a concentration of 30 nM (minimum concentration for maximum effect), produced a
31 +/- 6.5% (mean +/- SD) increase in neuronal discharge frequency compared to
the control recording. Both the proximal and the distal stomach were important in
the gastric effect of the peptide on subdiaphragmatic vagally evoked nucleus
tractus solitarius unitary responses. The brain stem effects of substance P. at a
concentration of 10 nM (minimum concentration for maximum effect), induced a 52
+/- 11.3% increase in discharge frequency. Application of the peptide into both
the gastric and brain stem compartments resulted in a subadditive response of 73
+/- 5.9%. This suggest that, peripherally and centrally, there are two different
mechanisms of substance P activation. Our results suggest that substance P may
play a role in regulating the ingestive process in neonates.
PMID- 9396058
TI - Orthodromic activation of peptidergic cells in the medial amygdala.
AB - Electrical recordings from vasopressin-containing cells in the medial amygdala
were obtained. Electrical stimulation of one major afferent structure, the
accessory olfactory bulb, invariably elicited single unit discharge in the
peptidergic cells and set up a field potential indicating widespread excitation
in the structure. Pheromonal stimuli, normally borne into the brain by the
accessory olfactory bulb, were ineffective in activating the medial amygdala.
These results in combination with preexisting research suggest that the accessory
olfactory bulb is an important influence, but not the only influence, on the
activity of the peptidergic cells.
PMID- 9396059
TI - Facilitation of AVP(4-8) on gene expression of BDNF and NGF in rat brain.
AB - In situ hybridization and Northern blot assay were used to evaluate the effects
of exogenous AVP(4-8) on the transcription of mRNAs for nerve growth factor
(NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in the
adult rat brain. NGF and BDNF expression was found to be significantly enhanced
by AVP(4-8) administration in the cerebral cortex and hippocampus, but NT-3
expression was not changed. In the same conditions, behavior-active arginine
vasopressin (AVP) showed a small effect and its behavior-inactive homologue,
oxytocin did not. Our results suggest that selective regulation of neurotrophin
gene expression by the peptides may be responsible for its memory-enhancing
function.
PMID- 9396060
TI - Naltrexone, naltrindole, and CTOP block cocaine-induced sensitization to seizures
and death.
AB - I.c.v. injection for 9 days of either naltexone (NTX) (5, 10, 20, 40
micrograms/rat) or a selective mu peptide (CTOP) (0.125, 0.25, 0.5, 1, 3, 6
micrograms/rat) or delta (naltrindole) (NLT) (5, 10, 20 micrograms/rat) subtype
opioid receptor antagonist affected sensitization to cocaine (COC) (50 mg/kg,
i.p.) administered 10 min after. NTX (5 and 40 micrograms/rat), NLT (10 and 20
micrograms/rat), and the peptide CTOP (0.25-0.5 microgram/rat) attenuated seizure
parameters (percent of animals showing seizures, mean score and latency) in a day
related manner. The DD50 (days to reach 50% of death) value for COC was 2.69,
whereas it was 9.67 and 7.27 for NTX 5 and 40 micrograms/rat, 8.59 for NLT (10
micrograms/rat), and 6.11, 5.95, and 4.30 for CTOP (0.25, 0.5, and 1
microgram/rat respectively). These findings suggest a concurrent involvement of
mu- and delta-opioid receptor subtype in COC-induced sensitization to toxic
effects.
PMID- 9396061
TI - Decreases in systemic arterial and hindquarters perfusion pressure in response to
nociceptin are not inhibited by naloxone in the rat.
AB - Nociceptin, the endogenous ligand for the ORL1 receptor, has been shown to
decrease systemic arterial and hindquarters perfusion pressures in the rat. The
present study was undertaken to determine if decreases in systemic arterial and
hindquarters perfusion pressures, in response to nociceptin, are mediated by a
naloxone-sensitive mechanism. Injections of nociceptin decreased systemic
arterial and hindquarters perfusion pressures in a dose-related manner. The
decreases in systemic arterial and hindquarters perfusion pressure in response to
nociceptin were not altered by the administration of naloxone in a dose of 2
mg/kg i.v. Met-enkephalin decreased systemic arterial and hindquarters perfusion
pressures and responses to the opioid receptor agonist were significantly reduced
by naloxone, whereas decreases in systemic arterial pressure in response to the
nitric oxide donor, DEA/NO, were not altered. The results of the present study
show that decreases in systemic arterial and hindquarters perfusion pressure in
response to nociceptin are not mediated by a naloxone-sensitive mechanism in the
rat.
PMID- 9396062
TI - Evaluation of chronic opioid receptor antagonist effects upon weight and intake
measures in lean and obese Zucker rats.
AB - Body weight and food intake are significantly reduced in rats during development
of dietary obesity following chronic central administration of mu (beta
funaltrexamine, BFNA), mu1 (naloxonazine), kappa1 (nor-binaltorphamine, NBNI),
delta1 ([D-Ala2,Leu5,Cys6]-enkephalin, DALCE) and delta2 (naltrindole
isothiocyanate, NTII) opioid receptor subtype antagonists. In contrast, rats made
obese by maintainance on a 'cafeteria' diet failed to display weight loss
following chronic mu1 receptor antagonism. To test the hypothesis that chronic
administration of opioid antagonists are less effective in controlling intake and
weight in obese animals, the present study assessed whether chronic, central
administration of either BFNA (20 micrograms), naloxonazine (50 micrograms), NBNI
(20 micrograms), DALCE (40 micrograms) or NTII (20 micrograms) altered weight and
intake in lean and obese Zucker rats over seven days. Body weight was reduced
following chronic mu (lean: 42 g; obese: 49 g), mu1 (lean: 71 g; obese: 38 g),
kappa1 (lean: 30 g; obese 14 g), delta1 (lean: 43 g; obese: 22 g) or delta2
(lean: 37.5 g; obese: 36 g) antagonism. Overall food intake was reduced following
chronic mu (lean: 8.8 g; obese: 16.1 g), mu1 (lean: 12.6 g; obese: 17.0 g),
kappa1 (lean: 6.5 g; obese 7.0 g), delta1 (lean: 9.7 g; obese: 11.1 g) or delta2
(lean: 9.4 g; obese: 14.3 g) antagonism. Therefore, both lean and obese Zucker
rats display weight loss and reduced intake following chronic central
administration of opioid receptor subtype antagonists.
PMID- 9396063
TI - Modulation of dopamine receptor agonist-induced rotational behavior in 6-OHDA
lesioned rats by a peptidomimetic analogue of Pro-Leu-Gly-NH2 (PLG).
AB - The present study was undertaken to determine if the previously reported in vitro
interactions of the Pro-Leu-Gly-NH2 (PLG) peptidomimetic analogue 3(R)-[(2(S)
pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacet amide (PAOPA) with the
dopaminergic system could be exhibited in an in vivo animal model using 6
hydroxydopamine (6-OHDA)-lesioned rats. In this model, PAOPA was found to
potentiate the contralateral rotational behavior induced by either apomorphine or
L-DOPA. PAOPA was 100-fold more potent than PLG, and produced a fourfold greater
response than PLG when administered i.p. PAOPA also potentiated contralateral
rotations induced by SKF-38393 and quinpirole. In summary, the results of this
study indicate that PAOPA, a conformationally constrained peptidomimetic analogue
of PLG, can modulate dopaminergic activity in vivo with higher potency and
efficacy than PLG.
PMID- 9396064
TI - The detection of thyrotropin-releasing hormone (TRH) and TRH receptor gene
expression in Siberian hamster testes.
AB - Thyrotropin-releasing hormone (TRH) from the hypothalamus is the major regulator
of TSH synthesis and secretion. Most recently, TRH and TRH receptors (TRH-R), as
well as their mRNAs, have been identified in rat testis. To expand our knowledge
on the testicular TRH and TRH receptor gene expression in different species, in
the present study the mRNA levels of testicular TRH and TRH-R were investigated
in Siberian hamsters. To further localize the cellular sites of the gene
expression, the animal model was treated with a single injection of ethylene
dimethane sulfonate (EDS) (i.p., 80 mg/kg body weight), a compound known as to
specifically eliminate testicular Leydig cells. The elimination of Leydig cells
induced by EDS treatment was confirmed by histological studies of the testis
sections and by serum hormonal analyses, which showed a dramatic reduction of
serum testosterone (T) levels and significantly elevated serum LH concentrations.
Messenger RNA levels of TRH and TRH-R in the testes were determined by Northern
blot analyses quantitated with densitometry scanning. The results showed that
specific TRH-R mRNA, 3.8 kb in size, was identified in Siberian hamster testes
and the mRNA levels were significantly elevated in the EDS-treated testes
compared to the controls (p < 0.01). Testicular TRH mRNA was also detected;
however, no significant differences in TRH mRNA levels were found between EDS
treated and control groups. The size of TRH mRNA was characterized as about 1.2
kb in hamster testes, which was smaller than that observed in the rat
hypothalamus (1.6 kb) and in the rat testis (2.0 kb). Further studies by RNase H
digestion revealed the presence of smaller TRH transcripts in the hamster testes
than those in the rat testis. No hybridization signal for TRH mRNA was detected
by RNase protection assay, when a rat TRH riboprobe was applied to hamster testis
RNA, suggesting the limited homology of TRH gene sequences between these two
species. Our results demonstrate that both TRH and TRH-R genes are expressed in
Siberian hamster testes, and a significant increase of TRH-R mRNA levels occurs
in the Leydig cell eliminated hamster testes. Unlike the rat testicular TRH mRNA
mainly detected in Leydig cells, in hamster TRH mRNA could also be detected in
other testicular compartment.
PMID- 9396065
TI - Comparative antipsychotic profiles of neurotensin and a related systemically
active peptide agonist.
AB - Several lines of evidence have shown that neurotensin can modulate dopamine
neurotransmission. It has been suggested that neurotensin has potential
antipsychotic activity because it reduces dopaminergic activity preferentially in
the nucleus accumbens. In the present study, the effects of neurotensin and NT1
(N alpha Me-Arg-Lys-Pro-Trp-TIe-Leu or Eisai hexapeptide), a metabolically stable
and systemically active neurotensin agonist, were examined in several models of
antipsychotic activity and side effect liability in mice; analgesic and
hypothermic effects of both compounds also were determined. Up to high doses,
neurotensin (5.0 and 10.0 micrograms, i.c.v.) and NT1 (10.0 and 20.0 mg/kg, i.p.)
did not produce catalepsy. A much lower dose of neurotensin (0.03 microgram,
i.c.v.) significantly reduced amphetamine- and phencyclidine-stimulated locomotor
activity; NT1 also diminished amphetamine- and phencyclidine-stimulated
locomotion with ED50 values of 0.3 and 0.4 mg/kg, i.p., respectively. Neurotensin
(0.01-0.3 microgram, i.c.v.) and NT1 (0.1-1.0 mg/kg, s.c.) also produced dose
dependent analgesia in the paw pressure test and decreased body temperature;
these effects were insensitive to pretreatment with naloxone (10.0 mg/kg, i.p.).
Together, the results support the hypothesis that neurotensin agonists have
antipsychotic and analgesic activity. Moreover, the data suggest that such
compounds may not produce extrapyramidal side effects.
PMID- 9396067
TI - About-half-weekly (circasemiseptan) component of the endothelin-1 (ET-1) chronome
and vascular disease risk.
AB - Plasma ET-1 was measured around the clock on different calendar dates in healthy
subjects and in subjects with diabetes and/or with high blood pressure and/or a
history of vascular complications (HVDR). A transverse approach, with each
subject contributing a single 24-h mean, assessed any about-weekly or half-weekly
variation in ET-1. A circasemiseptan component resolved by single cosinor for
nondiabetic (but not for diabetic) HVDR subjects (p = 0.010) differs in its
timing of overall high values (p < 0.050) from that found in healthy subjects (p
= 0.006). The results are aligned with circasemiseptan patterns in other
circulatory variables and morbidity/mortality statistics.
PMID- 9396066
TI - Synthesis of recombinant atrial natriuretic peptide (rANP) using hybrid fusion
protein-phage fr coat/ANP (CP/ANP).
AB - Recombinant atrial natriuretic peptide (rANP) was expressed in and isolated from
E. coli. rANP was purified using HPLC. Amino acid analysis, partial sequencing,
and molecular mass were determined. Fused protein was used to rise polyclonal
antibodies and to develop of immunoenzymatic assays of rANP and CP/ANP.
Experiments were designed to study rANP effects on isolated rabbit aortic strips
and to examine hypotensive, diuretic, and natriuretic activity, as well as renal
creatinine clearance, in an in vivo rat model. Identity of recombinant and
commercial ANP has been confirmed. Physiological activity of CP/ANP has allowed
the investigators to predict the conformation of CP/ANP, pro-ANP processing, and
the method by which fusion protein interacts with ANP receptors.
PMID- 9396068
TI - Expression of corticotropin-releasing factor (CRF) in peritoneum and pericardium
in the rat embryo by in situ hybridization histochemistry.
AB - Corticotropin releasing factor (CRF) mRNA expression in the thorax and abdomen
was studied by in situ hybridization in rat tissue sections obtained from
embryonic day 12 (E12) to E16. On E12 no signal was observed in any region. On
E13 the first signals were detected particularly in serous membranes such as
pericardium and peritoneum. By E14, the signal was strong in these membranes. On
E15 the signal markedly diminished, and on E16 no signal was evident in serous
membranes. This stage-specific expression of CRF mRNA in developing pericardium
and peritoneum suggests that this peptide acts in pericardial and peritoneal
development.
PMID- 9396069
TI - Comparison of the antisecretory effect of endogenous forms of peptide YY on fed
and fasted rat jejunum.
AB - It is intriguing that the antisecretory peptide YY is present in plasma in two
forms: PYY1-36 and PYY3-36. PYY3-36 has been found in human and rabbit blood
within 30 min of the beginning of the meal, when the peak of water and
electrolyte secretion occurs in the duodeno-jejunum. The aim of this study was
therefore to compare the antisecretory effect of PYY1-36 and PYY3-36 in fed and
fasted rat jejunum. The variations in electrolyte secretion were assessed by
measuring the variations in short-circuit current (delta Isc) and transepithelial
isotopic chloride fluxes in jejunal mucosa isolated from fed and fasted animal,
and mounted in Ussing Chambers. In fasted animals, 2 x 10(-7) M PYY3-36 induced a
reduction in Isc of -0.50 +/- 0.01 microEq/hr.cm2, which was not statistically
different from that induced by 2 x 10(-7) M PYY1-36 (-0.60 +/- 0.01 microEq/h
cm2). In contrast, in fed animals, 2 x 10(-7) M PYY3-36 did not trigger a
significant response on Isc and net chloride flux, while the response to PYY1-36
was present but blunted. The absence of response was probably not related to the
presence of secretory peptides because PYY3-36 was still able to induce a
reduction in Isc after stimulation by a series of 10 different secretory
peptides. After 10(-8) M PYY3-36 addition to an epithelium from the fasted
animal, response to 10(-7) M PYY3-36 was blunted for 30 min and returned to
control value after 60 min. Plasma concentration of PYY was higher in the fed
rats compared to fasted (213.78 +/- 38 vs. 53.62 +/- 11.47 pg/ml p < 0.01). After
incubation of crypt cells with or without 0.1 microM of unlabeled PYY for 60 min,
Scatchard analysis of equilibrium binding data show that binding capacity (Bmax)
of receptors was reduced when crypt cells were previously incubated with
unlabeled PYY without significant modification of dissociation constants. Bmax
were 183 +/- 27 in control vs. 56 +/- 11 fmol/mg protein. These results confirm
the antisecretory activity of PYY1-36 in the jejunum of fasted and fed rats. They
further indicate that PYY3-36 displays similar activity to PYY1-36 in fasted
animals, but lack of activity in fed animals. These results suggest that the two
circulating forms of PYY act as antisecretory peptides by two different
mechanisms, implying a C-terminal specificity.
PMID- 9396070
TI - Selective, physiological transport of insulin across the blood-brain barrier:
novel demonstration by species-specific radioimmunoassays.
AB - Insulin in blood is thought to cross the blood-brain barrier (BBB) to act within
the brain to help control appetite. We examined the ability of blood-borne
insulin to cross the BBB. Human insulin was infused for 48 h subcutaneously at
several doses into mice and the amount of human and murine insulin in serum and
brain measured with species-specific radioimmunoassays. For the exogenous human
insulin, both brain and blood concentrations increased with increasing doses of
infused insulin, whereas for the endogenous murine insulin, brain and blood
concentrations decreased. Since the mouse cannot make human insulin, blood was
the only source for the human insulin in brain, demonstrating that insulin does
indeed cross the BBB. The relationship between the concentrations of human
insulin in brain and blood was nonlinear, showing that passage is by a saturable
mechanism. Partial saturation of the transporter occurred at euglycemic
concentrations of serum insulin. Thus, insulin enters the brain by a saturable
transport system that is operational primarily at physiological levels of serum
insulin.
PMID- 9396071
TI - Leptin stimulates insulin secretion and synthesis in HIT-T 15 cells.
AB - Leptin, an ob gene product, corrects hyperinsulinemia in ob/ob mice. The leptin
receptor may exist in pancreatic islets. The present studies were undertaken to
determine the direct effect of 1-100 ng/ml recombinant leptin on insulin
secretion and synthesis in HIT-T 15 cells by using static culture system. The
addition of recombinant leptin significantly increased insulin secretion for 20
min at the highest concentration (100 ng/ml). The addition of recombinant leptin
dose-dependently increased insulin secretion for 24 h in the 7 mM glucose
containing F-12 K medium. The incubation with recombinant leptin for 24 h
increased preproinsulin mRNA expression, assessed with reverse transcription
polymerase chain reaction (RT-PCR) method. It was furthermore demonstrated that
HIT-T 15 cells possessed the specific binding site for [125I]-labeled leptin. The
present study demonstrated the existence of the leptin-specific binding sites
that mediate its stimulatory effect on insulin secretion and synthesis in HIT-T
15 cells.
PMID- 9396072
TI - Leptin: a potent inhibitor of insulin secretion.
AB - The hormone leptin is expressed and secreted by the adipose tissue and impacts on
the central nervous system. Leptin is involved in the regulation of energy
balance, satiety, and body composition. The lack of active leptin results in
obesity, high food intake, hyperglycemia, and hyperinsulinemia. We present data
supporting effects of leptin on the endocrine pancreas. We found the leptin
receptor to be expressed in insulin- and glucagon-secretin cells derived from
mouse, hamster, and rat pancreas. In the isolated perfused rat pancreas leptin is
a potent inhibitor of basal and glucose-induced insulin secretion, especially
during the first phase of the insulin response. At isolated mouse islets and
insulin-secreting INS-1 cells leptin reduced promptly and persistently the
intracellular Ca2+ levels. Cytoplasmic Ca2+ oscillation amplitude was decreased
and the oscillation frequency increased. These findings suggest functional active
receptors for leptin on insulin-secreting B-cells. Therefore, leptin is a
metabolic hormone and not only a signal to the brain indicating filled fat
stores. Our data suggest that leptin is also a signal back to the endocrine
pancreas that no more insulin is required to replenish fat stores. Thus, an
"adipo-insular axis" operating with two arms exists: insulin and glucagon are
signals to the adipocyte. This releases leptin, which could be the mediator of
the respective feedback to the pancreas. A defective leptin suppression of
insulin secretion could contribute to hyperinsulinemia and disturbances of
glucose metabolism.
PMID- 9396073
TI - Synergy between leptin and cholecystokinin (CCK) to control daily caloric intake.
AB - Both cholecystokinin (CCK), a short-term meal-related satiety signal, and the ob
protein leptin, a postulated long-term adiposity hormone, are thought to be
important signals in the multiple interacting systems that control appetite and
adiposity. We hypothesized that these hormones may synergistically interact to
suppress feeding. Following IP administration of leptin (two doses of 50
micrograms each) and CCK (2, 4, 8, or 16 micrograms) total daily caloric intake
was significantly reduced by leptin and CCK compared to leptin alone. These
results support the hypothesis that CCK and leptin may synergistically interact
to control long-term feeding.
PMID- 9396075
TI - Effects of acute and chronic administration of L-arginine on the antinociceptive
action of morphine-6-beta-D-glucuronide.
AB - Chronic administration of L-arginine (200 mg/kg i.p.) but not of D-arginine (200
mg/kg i.p.) twice a day for 4 days decreased the antinociceptive response to
subcutaneously administered morphine-6-beta-D-glucuronide (M6G), a potent
metabolite of morphine, in male Swiss-Webster mice as measured by the tail-flick
test. However, the antinociceptive response to intracerebroventricularly
administered M6G was unaffected by chronic treatment with L-arginine. The
decreased antinociceptive response to M6G (s.c.) was reversed by concurrent
administration of NG-nitro-L-arginine (5 mg/kg i.p.), an inhibitor of nitric
oxide synthase. Acute administration of L-arginine (200 mg/kg i.p.) had no effect
on M6G-induced antinociception, but higher doses (400 and 800 mg/kg i.p.)
decreased it. Since the antinociceptive response to centrally administered M6G
was unaffected by chronic L-arginine treatment, the decreased antinociceptive
response of peripherally administered M6G may be related to a decrease of M6G
entry into brain structures responsible for antinociceptive action.
PMID- 9396074
TI - Brain melanocortin receptors: from cloning to function.
AB - The cloning of brain melanocortin (MC) receptors, the mapping of their expression
pattern and the identification of MC receptor selective ligands have opened a new
avenue towards elucidating the role of the melanocortin system in the brain. MC
receptors have now been implicated in melanocortin-induced grooming behavior in
rats, in the melanocortin-induced lowering of blood pressure and in the control
of weight homeostasis. Functional opioid antagonism and the anti-pyretic and anti
inflammatory effects of melanocortins are probably also mediated via MC
receptors. However, the effects of melanocortins on avoidance behavior and the
effect of gamma 2-MSH on increasing blood pressure are not mediated via one of
the cloned brain MC receptors. The structure of brain MC receptors, their
expression pattern, the MC receptor selective ligands and the function of MC
receptors are briefly reviewed.
PMID- 9396076
TI - Anti-inflammatory action of methimazole.
AB - The anti-inflammatory activity of 1-methylimidazole-2-thiol (methimazole), the
most widely used antithyroid drug, was investigated. Methimazole had a marked
inhibitory action on prostaglandin H synthase (IC50 = 10 mumol/l), inhibiting the
peroxidase (IC50 = 330 mumol/l), although the cyclo-oxygenase was slightly
activated. Methimazole was less potent than indometacin (IC50 = 1.7 mumol/l) on
prostaglandin H synthase, but was more potent than acetylsalicylic acid (IC50 =
160 mumol/l). Methimazole has been found to trap superoxide (O2.-) radicals and
to decrease the level of blood prostaglandin E2.
PMID- 9396078
TI - Effect of mucosal resection on detrusor function in the disused rabbit bladder.
AB - A new rabbit model of disused bladder was developed. Disused bladders were
created by sagittal splitting of the bladders along the midline and closure of
one side (reservoir side), leaving the remaining side unclosed (disused). The
mucosa was dissected from some of the disused sides. Tissue elasticity and the
weight of the detrusor muscle were decreased by bladder disuse. The
responsiveness to field stimulation, bethanechol, ATP, KCl, or isoproterenol, was
decreased by disuse. Tissue elasticity and responsiveness to stimuli were
decreased to a lesser extent in disused tissue with intact mucosa. Results
suggest that the bladder mucosa helps to preserve the function of the disused
bladder.
PMID- 9396077
TI - Lysine14galanin(1-15)-NH2: a partial agonist at galanin receptors in rat isolated
gastric fundus.
AB - The study was undertaken to characterize the effects of the porcine galanin
[pGal(1-29)-NH2] analogue [Lys14]pGal(1-15)-NH2 on rat gastric fundus.
[Lys14]pGal(1-15)-NH2 is a less potent contractile agent than pGal(1-29)-NH2
(EC50 74.1 vs. 43.7 nmol/l, respectively) and shows a significantly lower maximal
response than pGal(1-29)-NH2. Concentration-contraction curves were constructed
for pGal(1-29)-NH2 alone (control) and pGal(1-29)-NH2 in the presence of 10, 100,
and 1,000 nmol/l of [Lys14]pGal(1-15)-NH2. [Lys14]pGal(1-15)-NH2 shifted the
concentration-contraction curves of pGal(1-29)-NH2 significantly to the right,
whereas their linear portions remained parallel to that for the pGal(1-29)-NH2
control. [Lys14]pGal(1-15)-NH2 markedly increased the EC50 of the respective
pGal(1-29)-NH2 concentration-contraction curves. It did not substantially change
the maximal response of the muscles to pGal(1-29)-NH2 and the form of the
respective concentration-contraction curves. Schild's plot gave a straight line
with a slope of 0.84. The pA2 value for [Lys14]pGal(1-15)-NH2 was 8.23.
[Lys14]pGal(1-15)-NH2 seems to be a partial Gal receptor agonist. Since the lack
of specific Gal receptor antagonists in the gastrointestinal tract makes a
precise characterization of its role as a motility modulator difficult, the
position 14 in the pGal(1-29)-NH2 molecule looks as an attractive target in the
search of a pure Gal receptor antagonist in the smooth muscles of the gut.
PMID- 9396079
TI - Effects of KW-3902, a selective and potent adenosine A1 receptor antagonist, on
renal hemodynamics and urine formation in anesthetized dogs.
AB - The purpose of the present investigation was to examine the effects of KW-3902 [8
(noradamantan-3-yl)-1,3-dipropyl-xanthine], a selective and potent adenosine A1
receptor antagonist, in order to clarify the role of adenosine in the control of
renal hemodynamics and urine formation in anesthetized dogs. KW-3902 was directly
infused into the renal artery to eliminate the systemic effects of the drug. KW
3902 (10 micrograms/kg/min) almost completely inhibited the renal
vasoconstriction induced by adenosine via A1 receptors. Intrarenal infusion of KW
3902 did not affect mean arterial pressure, renal blood flow, creatinine
clearance, or arterial plasma renin activity, but drastically increased urine
flow, urinary excretion of sodium, and osmolar clearance. Inhibition of the renin
angiotensin system using CV-11974 [2-ethoxy-1-((2'-(1-H-tetrazole-5-yl)biphenyl-4
yl) methyl)-1-H-benzimidazole-7-carboxylic acid], a selective AT1 antagonist, did
not affect the diuretic action of KW-3902. These data suggest that endogenous
adenosine does not play a significant role in the control of renal hemodynamics
in whole kidney, but that it plays an important role in preserving body fluid via
the A1 receptor independent of the renin-angiotensin system in anesthetized dogs.
PMID- 9396080
TI - Nitric oxide reduces myocardial contractility in isoproterenol-stimulated rat
hearts by a mechanism independent of cyclic GMP or cyclic AMP.
AB - Nitric oxide has been shown to decrease myocardial contractility and O2
consumption. This study was designed to evaluate the hypothesis that nitric oxide
mediated increases in cyclic GMP require elevated cyclic AMP to produce cardiac
depression. Using isolated, Langendorff-perfused rat hearts, we determined the
effects of intracoronary nitroprusside (NP, 1 and 10 mM) in the absence and
presence of isoproterenol (ISO, 10(-8) M) on cardiac function, O2 consumption,
cyclic GMP and cyclic AMP. ISO, with and without NP, increased cyclic AMP (from
287 +/- 21 to 477 +/- 33 pmol/g) without altering cyclic GMP. Left-ventricular
pressure increased from 97 +/- 12 to 178 +/- 9 mm Hg and dP/dtmax from 1,786 +/-
275 to 4,049 +/- 354 mm Hg/s. NP increased cyclic GMP (from 4 to 30 pmol/g) in
both the absence and presence of ISO, but NP did not alter cyclic AMP. Without
ISO, NP insignificantly altered left-ventricular pressure; however, in the
presence of ISO, NP significantly decreased left-ventricular pressure by -25 +/-
4 mm Hg and decreased dP/dtmax by -619 +/- 142 mm Hg/s. Isoproterenol increased
O2 consumption, but the changes with NP were not significant. When this study was
repeated in the presence of LY83583, a guanylate cyclase inhibitor, NP still
produced cardiac depression in the presence of ISO. Therefore, cardiodepressant
effects of NP were only observed against a background of inotropic stimulation
with ISO. However, effects of NP on contractility were unrelated to increases in
cyclic GMP or cyclic GMP-induced changes in cyclic AMP.
PMID- 9396081
TI - Moxonidine-induced inhibition of norepinephrine release in monkey and rabbit
ciliary bodies: role of cGMP.
AB - This study was designed to determine whether in isolated rabbits iris-ciliary
bodies and monkey ciliary bodies, cGMP plays a role in the action of moxonidine,
an alpha 2- and imidazoline (I1) receptor agonist. In field-stimulated rabbit
iris-ciliary bodies, dose-related inhibition of norepinephrine release was
induced by 8-Br-cGMP, moxonidine or sodium nitroprusside; 8-Br-cGMP in
combination with moxonidine did not enhance inhibition of norepinephrine release.
Sodium nitroprusside at intermediate and high concentrations stimulated cGMP
production in rabbit iris-ciliary bodies, whereas moxonidine stimulated cGMP
production modestly only at a high concentration. When iris-ciliary bodies were
pretreated with a low concentration of moxonidine, sodium nitroprusside
stimulated cGMP production was enhanced from 1.6 to 2.2 pmol/mg protein. In field
stimulated monkey ciliary bodies, both sodium nitroprusside and moxonidine
inhibited norepinephrine release. Pretreatment of electrically stimulated monkey
ciliary bodies with sodium nitroprusside enhanced the suppressive effect of
moxonidine on norepinephrine release. In monkey ciliary bodies, moxonidine raised
cGMP production more than sodium nitroprusside did, but there was no synergism in
cGMP production by combined treatment with moxonidine and sodium nitroprusside.
These results suggest that cGMP could play a role in the ocular action(s) of
moxonidine in ciliary bodies; however, involvement of cGMP in the action of
moxonidine in monkey ciliary bodies seems to be more pronounced than in rabbit
iris-ciliary bodies.
PMID- 9396082
TI - Intestinal fate of 5-aminosalicylic acid: regional and systemic kinetic studies
in relation to inflammatory bowel disease.
PMID- 9396083
TI - Effects of 3-deazaadenosine on apoptosis-related gene transcripts in HL-60 cells.
AB - The effect of the transmethylation inhibitor 3-deazaadenosine on transcription
levels of genes associated with apoptosis was investigated in HL-60 cells. After
incubation of HL-60 cells with 100 microM 3-deazaadenosine for 45 min., a
schedule known to perturb transmethylation metabolites and initiate apoptosis in
these cells, a 50% decrease in c-myc and a 50% increase in bcl-2 RNA steady-state
levels compared to control cells were observed. Transcription levels of c-myc
continued to decrease after extended exposure to 3-deazaadenosine, while bcl-2
mRNA levels dropped to 25% and 30% below those in control cells after 1.5 hr and
3 hr, respectively. The expression levels of the bcl-2 related bax gene, showed a
similar pattern as bcl-2; a 60% increase was initially measured, but after 1.5
and 3 hr, bax transcripts were 80% and 70% respectively, of those found in
untreated cells. Another bcl-2 related gene, bcl-x, was previously reported to
generate two transcripts in human cells. The long variant bcl-x1 acts as bcl-2,
while the short form bcl-xs induces apoptosis. We were unable to detect bcl-xs
transcripts in untreated and 3-deazaadenosine treated cells by the highly
sensitive reverse transcriptase polymerase chain reaction method. This suggests
that this gene product may not be involved in 3-deazaadenosine induced apoptosis
in HL-60 cells. Bcl-x1 mRNA levels, however, slowly decreased with about 50%
after 1.5 or 3 hr 3-deazaadenosine treatment. It is concluded that 3
deazaadenosine initiated apoptosis affects c-myc, bcl-2, bax and bcl-x1 mRNA
levels.
PMID- 9396084
TI - Analysis of native human plasma proteins and haemoglobin for the presence of
bityrosine by high-performance liquid chromatography.
AB - Generation of reactive oxygen species in vivo results in oxidative-damage to
cellular components, including proteins. Due to the relatively long half-lives of
several blood proteins the cumulative formation of oxidatively damaged proteins
might serve as a biomarker for reactive oxygen species formation. The most
prominent sources of reactive oxygen species in vivo are site-specific metal ion
catalyzed reactions of the Fenton and Haber-Weiss types and the H2O2/peroxidase
system. In vitro oxidation of L-tyrosine using a peroxidase or Cu++/H2O2 system
gives rise to the formation of a highly fluorescent substance, bityrosine. High
performance liquid chromatography (HPLC) analysis of acid hydrolyzed serum
albumin after oxidation with peroxidase/H2O2 or with Cu++/H2O2 showed that
bityrosine had been formed whereas oxidation of this protein with
Fe(III)/ascorbate did not result in the formation of bityrosine. Bityrosine could
not be detected in human plasma proteins or haemoglobin with the detection limit
of one pmol per mg protein.
PMID- 9396085
TI - Involvement of cholinergic and opioid receptor mechanisms in nicotine-induced
antinociception.
AB - In this work we have studied the influences of nicotinic agents on the
antinociception of morphine in formalin test. Nicotine (0.001-0.1 mg/kg) induced
antinociception in mice in a dose-dependent manner in the early phase of formalin
test, and also potentiated the morphine effect. The nicotinic receptor
antagonist, mecamylamine (0.5 mg/kg), but not hexamethonium decreased the
antinociception induced by nicotine (0.1 mg/kg) in both phases. The muscarinic
receptor antagonist atropine (5 and 10 mg/kg) also decreased the response of
nicotine. Mecamylamine, hexamethonium or atropine did not alter morphine
antinociceptive response, while naloxone decreased responses induced by nicotine
or morphine. The antagonists by themselves did not elicit any response in
formalin test, however, high does of mecamylamine tend to increase pain response.
It is concluded that central cholinergic and opioid receptor mechanisms may be
involved in nicotine-induced antinociception.
PMID- 9396086
TI - Forskolin potentiates isoprenaline-induced glycerol output and local blood flow
in human adipose tissue in vivo.
AB - The synergistic action of forskolin on beta-adrenoceptor-mediated glycerol output
and changes in local blood flow were investigated in situ, in human adipose
tissue of healthy subjects, by the use of microdialysis. The addition of
isoprenaline 0.1-1.0 microM or forskolin 10-100 microM to the perfusion solvent
caused a concentration-dependent, marked and sustained increase in the levels of
glycerol in the dialysate (lipolysis index) as compared to the solvent alone. On
a molar basis, isoprenaline was almost one thousand times more potent than
forskolin. Isoprenaline caused a rapid and concentration-dependent decrease in
the ethanol clearance ratio (index of local blood flow, i.e. a decrease in
ethanol ratio implies an increase in blood flow). Forskolin had no effect on the
ethanol ratio at either 1.0 microM or 10 microM, while forskolin at 100 microM
induced a significant decrease in the ethanol ratio. When adipose tissue was pre
treated with forskolin, the subsequent addition of isoprenaline to the
microdialysate resulted in a significantly higher glycerol output and a
significantly more prominent decrease in the ethanol ratio than with isoprenaline
alone. In conclusion, the data demonstrate that forskolin and the (beta
adrenoceptor-agonist both stimulate lipolysis and local blood flow in human
adipose tissue in vivo. Furthermore, forskolin, at concentrations that are
ineffective alone, potentiates the actions of isoprenaline on lipolysis and blood
flow.
PMID- 9396087
TI - Actions of spermicidal and virucidal agents on electrogenic ion transfer across
human vaginal epithelium in vitro.
AB - Human ectocervical tissue was removed at operation over the menstrual cycle
mounted as a sheet in vitro in an Ussing-style chamber and incubated in
bicarbonate saline. The net electrogenic ion transport was measured as the short
circuit current (Isc in muamps/cm2) and was characterised as mainly (60-86%) an
amiloride-sensitive electrogenic Na+ transport (lumen to serosa). Serosal
application of amiloride had no effect. Serosal application of ouabain, a
selective Na(+)-pump inhibitor, reduced the Isc to near zero but neither
theophylline (10 mM) nor furosemide (1 mM) had any action. The data are
compatible with a model ectocervical vaginal cell having an amiloride-sensitive
Na+ entry mechanism at the lumenal membrane and a Na(+)-pump at the basolateral
membrane removing the ion from the cell. The effects of the putative virucides,
chlorhexidine and benzalkonium chloride, were tested on the preparation.
Mucosally added chlorhexidine (2 mg/ml) had no effect on the Isc or tissue
resistance but benzalkonium chloride, at concentrations between 0.06-1.2%, caused
a rapid fall in the Isc. At the highest concentration this was only partly
reversible even after two washes with fresh buffer. At the lowest concentration
(0.03%) benzalkonium chloride sometimes caused an initial increase in the Isc
which then fell to zero. In all the tissues even after the Isc was reduced to
near zero, nigrosin left in contact with the tissue for 5 min. did not enter and
stain the cells, indicating the detergent had a selective membrane action rather
than causing a non-specific increase in permeability. The preparation allows
objective measurements to be made of the initial acute membrane actions of
putative spermicides and virucides on human vaginal ectocervical epithelial cells
and offers a new approach of assessing their pharmacological/toxicological
actions.
PMID- 9396088
TI - Comparison of key steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
neurotoxicity in rodents.
AB - Three steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity
were compared with the neurodegenerative effects of the toxin in mice and rats.
Firstly, we compared the neurotoxicity of MPTP, mediated by monoamine oxidase
(MAO)-B, to that of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'
CH3-MPTP), an analogue oxidized by MAO-A and MAO-B. Both toxins caused
degeneration of dopamine terminals in mice but not in rats. In NMRI mice
noradrenaline terminals were also affected by both toxins. Pretreatment with
deprenyl to prevent MAO-B-mediated oxidation in the capillary endothelium
enhanced dopamine toxicity to 2'-CH3-MPTP in nucleus accumbens but no
potentiation was seen in striatum and the olfactory tubercle. Secondly,
synaptosomal uptake of the 1-methyl-4-phenylpyridinium ion (MPP+) was studied.
Uptake in rats was not significantly different from that in the two mice strains.
Thirdly, no significant differences were found in MPP(+)-induced lactate
production in striatal slices or synaptosomes. We conclude that the lack of
effect of MPTP in rats is not due to mechanisms specific for MPTP but probably to
the ability of rat catecholamine neurons to cope with, and survive, impaired
energy metabolism.
PMID- 9396089
TI - Evaluation of three novel cholecystokinin-B/gastrin receptor antagonists: a study
of their effects on rat stomach enterochromaffin-like cell activity.
AB - Gastrin stimulates rat stomach enterochromaffin-like (ECL) cells via activation
of cholecystokinin-B/gastrin receptors. The stimulation is manifested in the
activation of the histamine-forming enzyme histidine decarboxylase and in the
secretion of histamine and pancreastatin, a chromogranin A-derived peptide. We
have examined the short-term effects of three novel cholecystokinin-B/gastrin
receptor antagonists (YF476, JB93182 and AG041R) on the ECL cells in intact
fasted rats. The drugs and/or gastrin were infused intravenously for 3 hr and the
oxyntic mucosal histidine decarboxylase activity and the serum pancreastatin
concentration were measured. We also studied the effects of the three drugs on
gastric emptying in mice, a cholecystokinin-A receptor-mediated response. YF476,
JB93182 and AG041R antagonized the gastrin-evoked histidine decarboxylase
activation in a dose-dependent manner. YF476, JB93182 and AG041R induced maximal
inhibition at 0.03, 0.1 and 0.1 mumol kg-1 hr-1, respectively; the corresponding
ID50 values were 0.002, 0.008, and 0.01 mumol kg-1 hr-1. YF476 was selected for
further analysis. It produced a rightward shift of the gastrin dose-response
curve, consistent with competitive inhibition. Moreover, it antagonized the
omeprazole-evoked histidine decarboxylase activation and the gastrin- and
omeprazole-induced rise in the circulating pancreastatin concentration. None of
the three drugs tested inhibited gastric emptying or prevented the
cholecystokinin-8s-induced inhibition of gastric emptying at the doses tested.
The results show that YF476, JB93182 and AG041R are potent and selective
cholecystokinin-B/ gastrin receptor antagonists, and that YF476 is 4-5 times more
potent than JB93182 and AG041R.
PMID- 9396090
TI - The effects of glyceryl trinitrate and nicotinic acid ointments during cold
exposure.
AB - The aim of the present experimental study was to examine the effects of local
application of glyceryl trinitrate and nicotinic acid on the cold-provoked
haemodynamic responses, pain and hand dexterity. Ten young healthy volunteers
participated in this randomized, cross-over study with three phases at least two
days apart. Five cm of 2% glyceryl trinitrate ointment, 10% nicotinic acid
ointment or placebo ointment was applied on the back of each subject's both hands
15 min. before the 7 min. cold exposure. Blood pressure and heart rate were
measured prior to, during and after the cold exposure. In addition, the effect of
cold on hand dexterity was evaluated by the Purdue pegboard test and the subjects
assessed the pain in their hands during the cold exposure. Pretreatment with
glyceryl trinitrate ointment counteracted the cold-induced haemodynamic response,
as evidenced by a significantly (P < 0.05) smaller mean increase in the systolic
blood pressure from the baseline compared with placebo. In contrast, the cold
induced increase in the systolic blood pressure observed after pretreatment with
nicotinic acid ointment did not differ from placebo. Both glyceryl trinitrate and
nicotinic acid alleviated the cold-induced pain, but neither of them prevented
the deterioration of hand dexterity. In conclusion, the haemodynamic response
provoked by a brief cold exposure could to some extent be counteracted by
pretreatment with glyceryl trinitrate ointment, but not with nicotinic acid
ointment, compared with placebo.
PMID- 9396091
TI - Combined oral treatment with racemic and meso-2,3-dimercaptosuccinic acid for
removal of mercury in rats.
AB - Racemic dimercaptosuccinic acid (DMSA) was found more efficient than the meso
isoform in enhancing the removal of mercury in rats. However, racemic-DMSA has
recently been found more toxic. The efficiency of combined oral treatment with
the two isoforms of DMSA for removal of mercury has now been evaluated. Female
albino rats were treated orally for four days with meso- (M) and/or racemic- (R)
DMSA (1 mmol/kg each), five days after a single intraperitoneal administration of
203Hg with 0.5 mg HgCl2/kg. The animals were divided into six groups according to
the number of treatments with each isomer: control (untreated), 4M, 1R + 3M, 2R +
2M, 3R + 1M, and 4R. Whole body, kidney, liver and brain mercury contents were
measured nine days after 203Hg administration. In all treated groups retention in
the whole body and kidneys was greatly reduced. The groups treated with racemic
DMSA, regardless of the number of doses, showed a greater removal of mercury than
the group treated with meso-DMSA alone (4M). All treatments were less efficient
in reducing liver retention, and the brain retention was not affected. It was
concluded that even a single application of the more toxic racemic-DMSA during a
four-day oral treatment regimen is sufficient to improve the removal by meso-DMSA
of mercury from rats.
PMID- 9396092
TI - Vancomycin removal by plasmapheresis.
PMID- 9396093
TI - Reducing tobacco harms among older adults: a critical agenda for tobacco control.
PMID- 9396094
TI - Back to basics: getting smoke-free workplaces back on track.
PMID- 9396095
TI - The Farmington consensus statement on editorial guidelines for addiction
journals.
PMID- 9396097
TI - Turkey: Camel gets through again.
PMID- 9396096
TI - The pack as advertisement.
PMID- 9396098
TI - India: tobacco toothpaste squeezed out.
PMID- 9396099
TI - Blaming the children.
PMID- 9396100
TI - Cigarette smoking and smoking cessation among older adults: United States, 1965
94.
AB - OBJECTIVE: To characterise patterns of cigarette smoking and smoking cessation
among older adults in the United States. DESIGN: Data from the National Health
Interview Surveys (NHIS) 1965-94 were analysed. The NHIS is a cross-sectional
survey using a representative national sample. SETTING: In most cases interviews
were conducted in the home; telephone interviews were conducted when respondents
could not be interviewed in person. PARTICIPANTS: Participants were from a
representative sample of the American civilian, non-institutionalised population
aged 18 and older. Sample sizes for the years analysed ranged from n = 19,738 to
n = 138,988 overall, and n = 3806 to n = 12,491 for those aged 65 years and
older. MAIN OUTCOME MEASURES: Using the NHIS data from 1965-94, trends in current
smoking and the prevalence of smoking cessation by demographic characteristics
among older adults (65 years and older) were assessed and compared with trends
among younger adults. A logistic regression analysis was conducted to determine
the demographic characteristics of former smokers compared with current smokers
among those aged 65 and older. RESULTS: The prevalence of current smoking among
65 year olds and older declined from 1965 to 1994 (17.9% to 12.0%). Although
smoking prevalence was lower among older adults than younger adults (aged 18-64),
the rate of decline in smoking was slower among older adults. Among older adults,
the prevalence of cessation rose with increasing educational attainment, and was
consistently higher for men than for women and for whites compared with blacks.
After adjustment for demographic factors among older adults who had ever smoked,
increasing age and educational attainment were strongly related to the likelihood
of being a former smoker. Although there were no racial differences among women,
older white (OR = 2.6) and Hispanic (OR = 3.67) men were significantly more
likely to be former smokers than older black men. Also, the gender difference in
smoking cessation was noted only for whites. CONCLUSIONS: Given the projected
increase in the elderly population, the medical and economic consequences of
smoking will become a greater burden in the next decades. Therefore, focusing
attention on cessation among the elderly is an immediate and urgent priority for
public health professionals and clinicians.
PMID- 9396101
TI - Predictors of smoking cessation among elderly smokers treated for nicotine
dependence.
AB - OBJECTIVE: To examine outcomes and predictors of smoking cessation among elderly
patients treated for nicotine dependence. DESIGN: Retrospective analysis of
patients aged 65-82 who received a nicotine dependence consultation at the Mayo
Medical Center between 1 April 1988 and 30 May 1992. Patients were contacted by
telephone by a trained interviewer six months after the consultation and were
sent a follow-up survey in August 1993. SETTING: Mayo Medical Center, Rochester,
Minnesota, United States. SUBJECTS: A total of 613 patients (310 men, 303 women)
with a mean age of 69.0 (SD 3.5) years were seen during the study period. MAIN
OUTCOME MEASURES: Point prevalence self-reported smoking status. Patients were
considered abstinent if they self-reported not smoking (not even a puff) during
the seven days before contact. RESULTS: At six-month follow up, 24.8% of the 613
patients reported abstinence from smoking. On multivariate analysis, smoking
abstinence was more likely if patients were hospitalised at the time of the
consultation, married to a non-smoking spouse, very motivated to stop smoking,
and reported their longest time of previous abstinence to be less than a day or
more than a month. The response rate to the mailed follow-up survey was 69.9%
(429 of 613). The mean duration of follow up was 40.0 +/- 13.2 months following
the consultation. Of the 429 patients, 103 (24.0%) reported abstinence from
smoking and 326 (76.0%) were smoking at six-month follow up. Patients who
reported abstinence at six months had a higher cessation rate at the last follow
up (76.0%) compared with patients who were smoking at six-month follow up (33.0%,
P < 0.001). For patients who were not smoking at six months, no factors were
found to significantly predict abstinence at last follow up. For patients who
were smoking at six months, factors associated with smoking cessation at last
follow up were: more than a year as the longest time off cigarettes before the
consultation; counsellor rating of less severe nicotine dependence; and older age
at first regular smoking. CONCLUSIONS: Several predictors of smoking cessation
were identified in this study which may be useful for tailoring smoking
interventions for the elderly.
PMID- 9396102
TI - Self-help interventions for older smokers.
AB - OBJECTIVE: To evaluate the relative effectiveness of two self-help smoking
interventions as adjuncts to a self-help manual and telephone support service
(hotline) for older smokers. DESIGN: Subjects were stratified on baseline
variables and randomised to one of two treatment conditions in a methods
development study. SUBJECTS: 177 community-dwelling smokers aged 60 years and
older. INTERVENTIONS: All subjects received a self-help manual and access to a
smokers' telephone hotline. Subjects also received either mailings (Letters
condition) or counselling telephone calls (Proactive condition) at four and eight
weeks after enrollment. MAIN OUTCOME MEASURES: Use of the hotline and prevalence
of abstinence lasting at least 48 hours (verified by a "significant other") were
assessed at three and six months for the full sample. Seven-day abstinence was
calculated for comparison with previous research. A subsample of 91 subjects was
followed up at 12 months. RESULTS: Overall abstinence rates for the two
conditions were in the range of typical self-help interventions. Men were more
likely to be abstinent than women at follow up at three and six months. A
significant gender x treatment interaction was found, with abstinence rates
higher for men in the Letters condition, and women in the Proactive condition.
Hotline use was high, with nearly half of subjects calling by 12 months.
CONCLUSION: Both interventions appear promising for older smokers, but may be
differentially effective for men and women. Older smokers will use a hotline;
whether Letters and Proactive interventions can improve on manual and hotline
effectiveness rates alone is being tested in a subsequent controlled trial.
PMID- 9396103
TI - Non-smoking policies, tobacco education, and smoking cessation programmes in
facilities serving the elderly in Michigan, United States.
AB - OBJECTIVE: To determine the extent of and impetus for smoke-free policies in
facilities serving Michigan's elderly, and the extent of tobacco education and
smoking cessation programmes for elders and staff of these facilities. DESIGN:
Telephone survey in February 1997 of three types of facilities serving Michigan's
elderly population. SUBJECTS: Area Agencies on Aging (n = 12), Councils and
Commissions on Aging (n = 31), and senior centres (n = 98) located in Michigan,
USA. MAIN OUTCOME MEASURES: Prevalence of smoke-free policies, tobacco education,
and smoking cessation programmes in facilities serving the elderly. RESULTS: 99%
(95% confidence interval (CI) = 97% to 100%) of 141 facilities surveyed have an
indoor smoke-free policy. Eighty-five per cent (95% CI = 79% to 91%) of these
policies prohibit all smoking inside the facility. Forty-five per cent (95% CI =
37% to 54%) cited a law as requiring the smoke-free policy, whereas 38% (95% CI =
30% to 46%) indicated the policy was adopted voluntarily for health reasons.
Forty-two per cent (95% CI = 34% to 50%) of the facilities provided some
education on the dangers of tobacco, while 11% (95% CI = 6% to 16%) arranged
smoking cessation programmes for staff or elders. CONCLUSIONS: In Michigan, a
very high percentage of non-institutional facilities serving the elderly have
smoke-free policies, which appear to increase participation at these facilities.
Tobacco education programmes are provided in less than half the facilities, and
very few arrange smoking cessation programmes for elders or staff.
PMID- 9396104
TI - Workplace smoking policies in the United States: results from a national survey
of more than 100,000 workers.
AB - OBJECTIVE: To determine the prevalence of smoking policies in indoor work
environments as reported by a nationally representative sample of workers in the
United States. DESIGN: Cross-sectional survey of households within the United
States. SETTING: All 50 state and the District of Columbia, 1992-93.
PARTICIPANTS: Currently employed indoor workers 15 years of age and older who
responded to the National Cancer Institute's Tobacco Use Supplement to the
Current Population Survey (n = 100,561). MAIN OUTCOME MEASURES: The prevalence
and restrictiveness of workplace smoking policies as reported by workers
currently employed in indoor workplaces in the United States. RESULTS: Most of
the indoor workers surveyed (81.6%) reported that their place of work had an
official policy that addressed smoking in the workplace; 46.0% reported that
their workplace policy did not permit smoking in either the public/common areas-
for example, restrooms and cafeterias--or the work areas of the workplace. The
reporting of these "smoke-free" policies varied significantly by gender, age,
race/ethnicity, smoking status, and occupation of the worker. CONCLUSIONS:
Although nearly half of all indoor workers in this survey reported that they had
a smoke-free policy in their workplace, significant numbers of workers,
especially those in blue-collar and service occupations, reported smoke-free
rates well below the national average. If implemented, the US Occupational Safety
and Health Administration's proposed regulation to require worksites to be smoke
free has the potential to increase significantly the percentage of American
workers covered by these policies and to eliminate most of the disparity
currently found across occupational groups.
PMID- 9396105
TI - A mass media programme to prevent smoking among adolescents: costs and cost
effectiveness.
AB - OBJECTIVE: To examine costs and cost-effectiveness ratios of a four-year mass
media programme previously shown to prevent the onset of smoking among
adolescents. DESIGN: A matched control design. SETTING: Two cities in Montana,
one in New York and one in Vermont, USA. SUBJECTS: Students in grades 10-12 (ages
15-18). INTERVENTION: A four-year mass media campaign to prevent the onset of
smoking. MAIN OUTCOME MEASURES: Cost per student potentially exposed to the mass
media campaign; cost per student smoker potentially averted; and cost per life
year gained. Cost estimates were also made for a similar campaign that would be
broadcast nationally in the United States. RESULTS: In 1996 dollars, the cost of
developing and broadcasting the mass media campaign was $759,436, and the cost
per student potentially exposed to the campaign (n = 18,600) was $41. The cost
per student smoker averted (n = 1023) was $754 (95% confidence interval (CI) =
$531-$1296). The cost per life-year gained discounted at 3% over the life
expectancy for young adult smokers was $696 (95% CI = $445-$1269). The estimated
cost of developing and broadcasting a similar four-year mass media campaign in
all 209 American media markets would be approximately $84.5 million, at a cost of
$8 per student potentially exposed to a national campaign, $162 per student
smoker averted, and $138 (95% CI = $88-$252) per life-year gained. CONCLUSION:
Estimates of the cost-effectiveness ratios of this mass media campaign in
preventing the onset of smoking showed it to be economically attractive and to
compare favourably with other preventive and therapeutic strategies.
PMID- 9396106
TI - Question 1 tobacco education expenditures in Massachusetts, USA.
AB - BACKGROUND: In 1992, voters in Massachusetts (United States) approved Question 1,
a state ballot initiative, which raised the state excise tax to provide funds for
tobacco education. OBJECTIVE: To examine Question 1 expenditures for tobacco
specific programmes in the 1994, 1995, 1996, and 1997 fiscal years. DESIGN: This
study examined trends in Question 1 expenditures. Data were collected from the
Massachusetts Department of Public Health and the Massachusetts Department of
Revenue for the 1994, 1995, 1996, and 1997 fiscal years. MAIN OUTCOME MEASURES:
The amount of spending on tobacco-specific programmes. RESULTS: Excluding the
1994 fiscal year because the state allocated 18 months of new revenues, from the
1995 fiscal year to the projected 1997 fiscal year, the state will have spent 22%
of Question 1 funds for tobacco-specific programmes. Question 1 expenditures for
tobacco-specific programmes have declined by 15%, whereas Question 1 expenditures
for the other programmes decreased only 0.4%. CONCLUSIONS: The legislature has
established a trend that has produced real reductions in Question 1 funding for
tobacco education, which appears contrary to the mandate of the voters when they
enacted Question 1 in 1992. These reductions undermine the effectiveness of
tobacco-specific programmes that are an integral part of the Massachusetts
Tobacco Control Programme. These results also highlight the fact that the initial
compromises made after initiatives such as Question 1 are adopted have important
long-term consequences for funding of tobacco control initiatives.
PMID- 9396107
TI - Review of the evidence that pH is a determinant of nicotine dosage from oral use
of smokeless tobacco.
AB - OBJECTIVE: To determine whether manipulation of the pH of moist-snuff products by
manufacturers could control the delivery of nicotine. DATA SOURCES: Medline
database 1966-97 using the following subject headings and keywords: nicotine,
absorption, mouth mucosa, skin, hydrogen-ion concentration, smokeless tobacco,
biological transport, and membranes; computer database of the tobacco
bibliography maintained by the US Centers for Disease Control and Prevention's
Office on Smoking and Health; bibliographies of pertinent journal articles,
books, and governmental reports; personal communications with experts in nicotine
pharmacology and addiction; and Brown & Williamson Tobacco Corporation documents
in the Tobacco Control Archives of the University of California, San Francisco.
STUDY SELECTION: Included all relevant animal studies, in-vitro studies, nicotine
replacement therapy trials, and human observational studies. DATA SYNTHESIS: We
found that the effects of pH on drug absorption have been well established in
animal models for nicotine and many other acidic or basic compounds. Increased
alkalinity promotes the absorption of nicotine and increases its physiological
effects. Human studies, which are more limited, confirm these processes. For
example, nicotine absorption is directly related to the pH when nicotine is
delivered in either tobacco smoke or nicotine polacrilex gum. CONCLUSIONS:
Although other factors could influence the rate of nicotine absorption from oral
tobacco, manipulating tobacco pH appears to be the primary means by which the
speed of nicotine absorption is determined in moist-snuff products.
PMID- 9396108
TI - Tobacco blindness.
PMID- 9396109
TI - "Vast sums of money ... to keep the controversy alive"--the 1988 BAT memo.
PMID- 9396110
TI - Cigar advertising: targeting "baby-boomers" and older adults.
PMID- 9396111
TI - Cigarette marketing in Senegal, West Africa.
PMID- 9396112
TI - Aussie facts, EZ-letters, blue mould, RJR's home page, and UST's "roar tour".
PMID- 9396113
TI - Final report of the Advisory Committee on Tobacco Policy and Public Health.
PMID- 9396114
TI - AHCPR smoking cessation guideline: its' goals and impact.
PMID- 9396115
TI - AHCPR smoking cessation guideline: a fundamental review.
PMID- 9396116
TI - Implementing smoking cessation protocols in medical and dental practices.
PMID- 9396117
TI - Implementing the AHCPR guideline in health management organisations.
PMID- 9396118
TI - Reaching the medically underserved with the AHCPR guideline.
PMID- 9396119
TI - Primary-care physicians.
PMID- 9396120
TI - Two pharmacy-practice models for implementing the AHCPR smoking cessation
guideline.
PMID- 9396121
TI - AHCPR smoking cessation guideline goals and impact: examples from the nursing
field.
PMID- 9396122
TI - Implications of the AHCPR guideline for psychological practice and research.
PMID- 9396123
TI - Smoking cessation initiatives in Minnesota.
PMID- 9396124
TI - Employers' and purchasers' roles in smoking cessation.
PMID- 9396125
TI - An American Medical Association perspective on smoking cessation guidelines.
PMID- 9396126
TI - Consumers and the AHCPR smoking cessation guideline.
PMID- 9396127
TI - Changing provider behaviour: provider education and training.
PMID- 9396128
TI - Changing physicians' practices.
PMID- 9396130
TI - Defining benefits and payment for smoking cessation treatments.
PMID- 9396129
TI - Healthcare report cards and tobacco measures.
PMID- 9396131
TI - Selling smoking cessation to the states.
PMID- 9396132
TI - Pregnant women, infants, and the cost savings of smoking cessation.
PMID- 9396133
TI - A managed-care perspective on the AHCPR guideline.
PMID- 9396134
TI - Lysosomal storage diseases of animals: an essay in comparative pathology.
AB - A wide variety of inherited lysosomal hydrolase deficiencies have been reported
in animals and are characterized by accumulation of sphingolipids, glycolipids,
oligosaccharides, or mucopolysaccharides within lysosomes. Inhibitors of a
lysosomal hydrolase, e.g., swainsonine, may also induce storage disease. Another
group of lysosomal storage diseases, the ceroid-lipofuscinoses, involve the
accumulation of hydrophobic proteins, but their pathogenesis is unclear. Some of
these diseases are of veterinary importance, and those caused by a hydrolase
deficiency can be controlled by detection of heterozygotes through the gene
dosage phenomenon or by molecular genetic techniques. Other of these diseases are
important to biomedical research either as models of the analogous human disease
and/or through their ability to help elucidate specific aspects of cell biology.
Some of these models have been used to explore possible therapeutic strategies
and to define their limitations and expectations.
PMID- 9396135
TI - Systemic AA amyloidosis in captive cheetahs (Acinonyx jubatus).
AB - Ongoing disease surveillance of necropsied captive cheetahs (Acinonyx jubatus) (n
= 141) revealed a high prevalence of renal amyloidosis (n = 54 [38%]; age 1 to 16
years). The prevalence increased from 20% in pre- 1990 necropsies to 70% of
cheetahs necropsied in 1995. In 74% of the cheetahs with amyloidosis, renal
failure was determined to be the sole or partial cause of death. Papillary
necrosis was seen only in affected cheetahs and involved 25% of these animals.
Amyloid was present predominantly in the medullary interstitium, with minimal
glomerular involvement. The amyloid deposits were immunohistochemically
identified as AA type using antisera to both human and canine protein AA. A high
percentage (52%) of animals with renal amyloid also had subsinusoidal hepatic AA
amyloid deposits. Inflammatory diseases were identified in 100% of affected
cheetahs. The most common inflammatory disease was chronic lymphoplasmacytic
gastritis. The prevalence and severity of gastritis was higher in cheetahs with
amyloidosis, and the prevalence of severe gastritis increased from 16% to 43%,
coinciding with the increase in prevalence of amyloidosis. These findings suggest
that cheetahs have a high prevalence of systemic amyloidosis in response to
inflammation and that renal amyloidosis is an increasingly significant cause of
morbidity and mortality in captive cheetah populations. Factors of potential
importance in the apparent high prevalence of AA amyloidosis in cheetahs are
currently being investigated in our laboratories.
PMID- 9396136
TI - Pathobiology of H5N2 Mexican avian influenza virus infections of chickens.
AB - To determine the association between specific structural changes in the
hemagglutinin gene and pathogenicity of avian influenza viruses (AIVs), groups of
4-week-old White Plymouth Rock chickens were inoculated intravenously or
intranasally with AIVs of varying pathogenicities isolated from chickens in
central Mexico during 1994-1995. Mildly pathogenic (MP) viruses had a common
hemagglutinin-connecting peptide sequence of Pro-Gln-Arg-Glu-Thr-Arg decreases
Gly and had restricted capability for replication and production of lesions in
tissues. The principle targets for virus replication or lesion production were
the lungs, lymphoid organs, and visceral organs containing epithelial cells, such
as kidney and pancreas. Death was associated with respiratory and/or renal
failure. By contrast, highly pathogenic (HP) AIVs had one substitution and the
addition of two basic amino acids in the hemagglutinin connecting peptide, for a
sequence of Pro-Gln-Arg-Lys-Arg-Lys-Thr-Arg decreases Gly. The HP AIVs were
pantropic in virus replication and lesion production ability. However, the most
severe histologic lesions were produced in the brain, heart, adrenal glands, and
pancreas, and failure of multiple critical organs was responsible for disease
pathogenesis and death. No differences in lesion distribution patterns or in
sites of AIV replication were evident to explain the variation in mortality rates
for different HP AIVs, but HP AIVs that produced the highest mortality rates had
more severe necrosis in heart and pancreas. The ability of individual HP AIVs to
produce low or high mortality rates could not be explained by changes in sequence
of the hemagglutinin-connecting peptide alone, but probably required the addition
of other undetermined genomic changes.
PMID- 9396137
TI - Immunohistochemical demonstration of African horse sickness viral antigen in
formalin-fixed equine tissues.
AB - The distribution of viral antigen was studied in various tissues of three ponies,
aged 3-4 years, infected experimentally with a virulent strain of African horse
sickness virus (AHSV) serotype 4. Tissues were collected from the animals in the
terminal stage of the peracute form of the disease and from one noninfected
horse, included as a control. A polyclonal antibody with specificity for AHSV,
plus the nonstructural protein NS2, was used in a sensitive avidin-biotin
peroxidase-complex (ABC) method performed on formalin-fixed, paraffin-embedded
tissue sections. AHSV antigen was located primarily in endothelial cells of
capillaries and small venous and arteriolar vessels, particularly of
cardiopulmonary tissues. Viral antigen was also identified in cells resembling
macrophages and in reticular cells of spleen and lymph nodes. The pattern of
viral antigen labeling in some lymph nodes along the mantle zone of lymphoid
follicles was compatible with the morphology of cellular processes of follicular
dendritic cells. In some tissues, viral antigen was detected occasionally in
circulating cells, probably monocytes, within the larger vessels. These findings
suggest that endothelial cells, and to a lesser extent mononuclear cells, are the
main target cells of AHSV infection during the late stage of the peracute form of
the disease.
PMID- 9396138
TI - Histopathologic and ultrastructural alterations of white liver disease in sheep
experimentally depleted of cobalt.
AB - Many cobalt-deficient sheep develop liver lesions known as ovine "white liver"
disease, but the etiology of these changes is controversial. It has been
suggested that cofactors are required for development of liver damage in cobalt
deficient sheep. In this study, one group of lambs (n = 5) was fed a diet low in
cobalt (4.5 micrograms/kg) while a group of control lambs (n = 4) received the
same diet after it had been supplemented with cobalt (1000 micrograms/kg). All
cobalt-depleted lambs had reduced growth rate, anorexia, lacrimation, and
alopecia, and they eventually became emaciated (mean body weight at end of study:
83% of initial body weight). Plasma concentrations of bilirubin and serum
activity of glutamate-oxaloacetate transferase were elevated in these animals,
while plasma concentrations of vitamin B12 were reduced (less than 220 pmol/L
from day 42). Fatty degeneration of the liver associated with reduced
concentrations of vitamin B12 (14.5 pmol/g) was seen in these animals at necropsy
at 196 days. Microscopic liver lesions included accumulation of lipid droplets
and lipofuscin particles in hepatocytes, dissociation and necrosis of
hepatocytes, and sparse infiltration by neutrophils, macrophages, and
lymphocytes. Ultrastructural hepatocytic alterations included swelling,
condensation and proliferation of mitochondria, hypertrophy of smooth endoplasmic
reticulum, vesiculation and loss of arrays of rough endoplasmic reticulum, and
accumulation of lipid droplets and lipofuscin granules in cytoplasm of
hepatocytes. No liver lesions were seen in control lambs. The results of this
study indicate that cofactors are not a prerequisite to development of hepatic
damage in cobalt-deficient sheep. Reduced activities of the vitamin B12-dependent
enzymes, methylmalonyl CoA mutase and methionine synthase, and lipid peroxidation
are of likely pathogenetic importance in the development of the lesions.
PMID- 9396139
TI - In situ hybridization demonstration of albumin mRNA in B6C3F1 murine liver and
hepatocellular neoplasms.
AB - In situ hybridization was used to detect albumin mRNA in normal liver and
hepatocellular neoplasms in 20 male B6C3F1 mice between 17 and 24 months of age.
Positive signals for albumin were observed consistently in the cytoplasm of
hepatocytes in normal liver, particularly in periportal areas. No signals were
observed in other cells, such as Kupffer's cells, mesenchymal cells, or bile duct
epithelium. Of hepatocellular adenomas, 11/11 (100%) stained positively for
albumin mRNA, whereas 14/15 (93%) of primary hepatocellular carcinomas showed
positive expression. Albumin mRNA was also detected in extrahepatic metastases of
hepatocellular carcinoma, including 9/15 (60%) of pulmonary neoplasms and 5/12
(42%) of metastases at other sites. The pulmonary metastases of hepatocellular
carcinoma frequently exhibited a glandular, papillary, or sarcomatous histologic
appearance. The presence of albumin in these tumors, lacking characteristic
hepatocellular phenotype, is a potential determinant of hepatic lineage. We
conclude that in situ hybridization for albumin mRNA in mice is a useful tool in
the differential diagnosis of hepatocellular carcinoma, particularly in the case
of pulmonary metastasis. This technique may also enable recognition of hepatocyte
differentiation in glandular structures with phenotypic features of biliary
cells, as seen in mixed hepatocellular-cholangial neoplasms.
PMID- 9396140
TI - Regression of pulmonary lesions produced by inhaled titanium dioxide in rats.
AB - Inhaled ultrafine particles of TiO2 (TiO2-D, 20 nm particle size) lead to a
greater pulmonary inflammatory response than larger pigment-grade particles (TiO2
F, 250 nm). Male Fisher 344 rats were exposed for 6 hours a day, 5 days a week,
for 3 months to 1) filtered air (control); 2) TiO2-F, 22.3 mg/m3; 3) TiO2-D, 23.5
mg/m3; or 4) crystalline SiO2, a positive control particle (approximately 800 nm
particle size, 1.3 mg/m3). Groups of 3-4 animals were sacrificed at 6 and 12
months following the completion of exposure. Pulmonary effects of exposure were
evaluated using standard hematoxylin and eosin-stain sections, histochemical
stains for collagen, and immunohistochemical assays for cell turnover. Six months
after animals were exposed to SiO2, they had moderate focal interstitial fibrosis
and moderately severe focal alveolitis. Animals exposed to TiO2-D had slightly
less fibrosis. The least fibrosis was seen in the TiO2-F group. At 1 year after
exposure, fibrosis was still present but decreased in the SiO2 group. The amount
of interstitial fibrosis in the TiO2-D- and TiO2-F-treated animals had largely
returned to untreated control levels, although an increased number of alveolar
macrophages persisted, usually with retained particles. There was discordance
between bromodeoxyuridine and proliferating cell nuclear antigen indices, most
probably due to cytokine elaboration in the areas of inflammation, which may have
altered the expression of proliferating cell nuclear antigens. There was no
detectable fibroblast labeling at the 6-month observation and only very low
levels at 12 months. Thus, although initially irritant, TiO2-induced lesions
regressed during a 1-year period following cessation of exposure.
PMID- 9396141
TI - Intercellular adhesion molecule-1 expression in dextran sodium sulfate-induced
colitis in rats.
AB - Orally administered dextran sodium sulfate (DSS) produces an acute colitis in
rodents. The pathogenesis is unknown but may relate to DSS-mediated toxicity of
colonic crypt epithelium and/or DSS-induced inflammation. The purpose of this
study was to determine when colonic mucosal inflammation, as indicated by
histopathology and intercellular adhesion molecule-1 (ICAM-1) expression, occurs
relative to crypt epithelial damage. Groups of eight adult male Wistar rats were
administered 5.0% DSS solution in the drinking water for 2-6 days. Clinical signs
at 3 days consisted of loose stool, progressing to marked rectal hemorrhage by
days 5 and 6 that correlated with marked intraluminal colonic hemorrhage at
necropsy. Histological lesions of predominantly the distal colon consisted of
multifocal areas of mucosal erosion, reduction in goblet cells, dilated crypts,
crypt collapse, increased lamina propria neutrophils, and submucosal edema on
days 2 and 3, progressing to locally extensive ulceration and marked mixed
inflammatory infiltrates by days 4-6. Enhanced expression of ICAM-1, demonstrated
by both immunohistochemical and northern blot analysis, was evident in colonic
mucosa as early as day 2, with consistent increases through days 3-6. Results
demonstrate that enhanced colonic mucosal endothelial cell ICAM-1 expression is
an early event in the inflammatory cascade of DSS-induced colitis.
PMID- 9396142
TI - Lesions of aryl-hydrocarbon receptor-deficient mice.
AB - We have analyzed the possible role of the aryl-hydrocarbon receptor (AHR) in the
aging process of mice using a homozygous null mouse (Ahr-/-) line as a model. We
studied 52 male and female Ahr-/- mice aged from 6-13 months. Forty-six percent
died or were ill by 13 months of age. Ahr-/- mice developed age-related lesions
in several organs, some of which were apparent after only 9 months of age.
Cardiovascular alterations included cardiomyopathy (100%) with hypertrophy and
focal fibrosis. Vascular hypertrophy and mild fibrosis were found in the portal
areas of the liver (81%), and vascular hypertrophy and mineralization were common
in the uterus (70%). Gastric hyperplasia that progressed with age into polyps was
evident in the pylorus of 71% of the mice over 9 months of age. Ahr-/- mice had T
cell deficiency in their spleens but not in other lymphoid organs. The immune
system deficiency described previously could be the origin for the rectal
prolapse found in 48% of the null mice, associated with Helicobacter hepaticus
infection. In the dorsal skin (53% incidence), severe, localized, interfollicular
and follicular epidermal hyperplasia, with hyperkeratosis and acanthosis, and
marked dermal fibrosis, associated with the presence of anagenic hair follicles,
were also evident. None of these lesions were found in 42 control (Ahr +/+ or +/
) mice of similar ages. These observations suggest that the AHR protein, in the
absence of an apparent exogenous (xenobiotic) ligand, plays an important role in
physiology and homeostasis in major organs in mice, and further supports an
evolutionary conserved role for this transcription factor.
PMID- 9396143
TI - S-100 immunoreactivity in melanomas of two marsupials, a bird, and a reptile.
AB - S-100 proteins are abundant in melanocytes of the skin; thus, S-100
immunoreactivity has been used as a diagnostic criterion for melanoma in humans
and other placental mammals. We tested cutaneous melanomas of two marsupials, a
bird, and a snake for S-100 immunoreactivity, using a polyclonal rabbit
antibovine S-100 antibody. The tumor from a Tasmanian Pademelon (Thylogale
billaridierii) was composed of large epithelioid cells, most of which had S-100
positive cytoplasm. In general, there were only scattered individual spindle
shaped S-100-positive cells or groups of cells in the primary mass from a Spotted
tailed Quoll (Dasyurus maculatus); S-100 staining was primarily nuclear. Cells
comprising the melanomas of the Australian Cormorant (Phalacrocorax carbo) and
the Death Adder (Acanthophis antarcticus) were S-100-negative, although
peripheral nerve bundles in both were S-100-positive.
PMID- 9396144
TI - Botryoid-type embryonal rhabdomyosarcoma of liver in a young cat.
AB - An unusual malignant mesenchymal tumor arising in the liver of a 2-year-old cat
is described. Histologically, the tumor showed considerable variation in growth
pattern, cellularity, and cell types. Phenotypical diversity was confirmed by
immunohistochemistry, showing expression of desmin, vimentin, S-100, and neuron
specific enolase in various areas of the tumor. On the basis of histopathology,
immunohistochemistry, electron microscopy, and gross morphology, the tumor was
classified as botryoid-type embryonal rhabdomyosarcoma. Differential diagnosis
included so-called undifferentiated (embryonal) sarcoma of the liver, a rare
tumor of the pediatric age group in humans. Problems of tumor heterogeneity and
differentiation in mesenchymal tumors are discussed.
PMID- 9396145
TI - Primary encephalic plasma cell tumor in a dog.
AB - A 5-year-old female spayed Spitz dog had a 5-week history of right head tilt,
seizures, and progressive quadriplegia. Analysis of cerebrospinal fluid revealed
27,600 white blood cells per microliter with 63% mononuclear phagocytes, 27%
lymphocytes, 6% neutrophils, 3% plasmacytoid cells, and 1% eosinophils, and over
2000 mg/dl protein. On contrast-enhanced magnetic resonance images, a focal 1-cm
oval lesion was identified in the right ventral brainstem. There was also marked
contrast enhancement of the meninges in the following areas: surrounding the
brainstem, outlining cerebellar folia, along the ventral floor of the brain and
extending to the falx cerebri, and partially outlining the left frontal lobe. At
necropsy, the areas of contrast enhancement corresponded to the presence of
compact cellular sheets of pleomorphic, anisocytotic, oval to polygonal
neoplastic cells with plasmacytoid differentiation. The smaller of these
plasmacytoid cells stained predominantly for cytoplasmic immunoglobulin A using
immunoperoxidase methodology. Ultrastructurally, the neoplastic cells had
morphologic features typical of plasma cells, with large amounts of predominantly
rough endoplasmic reticulum with variably prominent Golgi formation. This is the
first report of a canine primary intracranial malignant plasma cell tumor.
PMID- 9396146
TI - Two cyclohexanespiro-5'-hydantoin monohydrates.
AB - Cyclohexanespiro-5'-hydantoin monohydrate, C8H12N2O2.H2O, has a chair-shaped
cyclohexane ring with endocyclic torsion-angle magnitudes in the range 54.4 (2)
56.3 (2) degrees. All potential hydrogen-bond donors are involved in
intermolecular hydrogen bonding, with lengths in the range 2.760 (2)-2.908 (2) A.
In its indolyl adduct, 2-(3-indolyl)cyclohexanespiro-5'-hydantoin monohydrate,
C16H17N3O2.H2O, the cyclohexane moiety adopts a chair conformation with the
indolyl substituent in an equatorial position. The N-H portion of the hydantoin
ring is cis to indolyl, while the C=O of the hydantoin is trans. Endocyclic
torsion-angle magnitudes of the cyclohexane ring are in the range 54.2 (2)-56.7
(2) degrees. All potential hydrogen-bond donors are involved in intermolecular
hydrogen bonds, with lengths 2.828 (2)-3.187 (2) A.
PMID- 9396147
TI - Colocalization of microtubules and mitochondria in the yeast Schizosaccharomyces
japonicus var. versatilis.
AB - Both living and fixed cells of Schizosaccharomyces japonicus var. versatilis
showed thread-like mitochondria when studied by phase-contrast and fluorescence
microscopy. In the interphase cells, mitochondria extended from pole to pole and
converged towards the growing tips. The mitochondrial threads did not disrupt but
persisted during mitosis and, subsequently, their bundle was split between the
two daughter cells by a concentrically growing septum. Mitochondria in the
interphase cells were accompanied by cytoplasmic microtubules. These disappeared
during mitosis and, instead, spindle microtubules were formed in the nucleus. The
cytoplasmic microtubules reappeared after anaphase B, again in coaligment with
mitochondria. Protoplasting as well as the action of microtubule inhibitors
methyl-1-(butylcarbamoyl)-2-benzimidazolecarbamate (benomyl) and 2
methylbenzimidazole (MBC) resulted in rapid disintegration of microtubules and,
suprisingly, also in disruption of mitochondria into small bodies. Removal of the
inhibitors or a short regeneration of protoplasts allowed both the cytoplasmic
microtubules and the thread-like mitochondria to reaggregate into the original
pattern. Cytochalasin D treatment caused a complete disintegration of actin
filaments, while the cytoplasmic microtubules and mitochondria remained intact.
These findings of a transient close association of mitochondria and microtubules
and their relative independence of the arrangement of actin filaments suggest
that microtubules, but not actin cables, form supports for positioning or
movement of mitochondria along the cylindrical cells. The persistence of
mitochondria in the cell centre during mitosis may be accounted for by the fact
that disrupted microtubules fail to provide support for mitochondrial movement
towards the cell poles.
PMID- 9396148
TI - Influence of altered plasma membrane fatty acid composition on cesium transport
characteristics and toxicity in Saccharomyces cerevisiae.
AB - The influence of altered plasma membrane fatty acid composition on cesium uptake
and toxicity was investigated in Saccharomyces cerevisiae. Detailed kinetic
studies revealed that both the Vmax and Km values for Cs+ transport increased (by
approximately twofold in the latter case) when S. cerevisiae was grown in medium
supplemented with the polyunsaturated fatty acid linoleate. In addition, Cs+
uptake by linoleate-enriched cells was considerably less sensitive to the
competitive effects of other monovalent cations (K+, Rb+, and NH4+) than that by
unsupplemented cells. Stimulation of Cs+ uptake in the presence of certain K+ and
Rb+ concentrations was only evident in linoleate-enriched S. cerevisiae. At 100
mM CsCl, the initial rate of Cs+ uptake was greater in linoleate-supplemented
cells than in unsupplemented cells and this was reflected in a more rapid
displacement of cellular K+. However, little difference in net Cs+ accumulation
between linoleate-supplemented and unsupplemented cells was evident during
prolonged incubation in buffer or during growth. Thus, Cs+ toxicity was similar
in linoleate-supplemented and unsupplemented cells. The results were consistent
with the Cs+ (K+) transport mechanism adopting an altered conformational state in
linoleate-enriched S. cerevisiae.
PMID- 9396149
TI - Tyrosine is involved in protection from oxidative stress in Saccharomyces
cerevisiae.
AB - The phenotypic characterization of a Saccharomyces cerevisiae mutant unable to
grow under agitated conditions is presented here. When this strain was incubated
under aerobic conditions, it did not grow and the viability of the culture
decreased. The loss in viability was prevented by the addition of antioxidants or
chelating agents to the medium, indicating that this mutant was unable to
withstand the oxidative stress generated by aerobic metabolism. This strain was
complemented with plasmids from a yeast genomic library. The transformants that
were obtained carried plasmids harbouring the TYR1 gene, which codes for one of
the enzymes involved in tyrosine biosynthesis. A monogenic S. cerevisiae tyr1
mutant obtained from the Yeast Genetic Stock Center showed higher sensitivity to
hydrogen peroxide than a TYR1 strain. This sensitivity was reverted when this
strain was complemented with the TYR1 gene. Considering these results, we propose
that tyrosine plays a role in the protection against oxidative stress.
PMID- 9396150
TI - Functional analysis of sigma-70 consensus promoters in Pseudomonas aeruginosa and
Escherichia coli.
AB - A series of synthetic promoters, based upon the Escherichia coli sigma 70
consensus promoter sequence, was constructed upstream of the lacZ reporter gene
in the modified broad-host-range vector pQF52. The role of the intervening spacer
region in gene expression in Pseudomonas aeruginosa and E. coli was studied by
insertions and deletions within this region. In P. aeruginosa and E. coli the
patterns of gene expression were identical with maximum beta-galactosidase
activity being measured from promoters possessing 19 bp in their intervening
regions, presumably as a result of impeded promoter clearance with the consensus
17-bp promoter. In P. aeruginosa a second occurrence of enhanced activity, which
could not be attributed to the involvement of the alternative sigma factor RpoN
(sigma 54), was evident with the promoter having a 16-bp spacer.
PMID- 9396151
TI - Change of mechanical activity to contraction from the relaxation induced by the
intracellular Ca2+ antagonist KT-362; effects of alkylation of side chain, and
substitution of 2,3,4,5-tetrahydro-1,5-benzothiazepine derivatives.
AB - KT-362 (5-[3-[2-(3,4-Dimethoxyphenyl)ethyl]aminopropionyl]-2,3,4, 5-tetrahydro
1,5-benzothiazepine fumarate) is an intracellular Ca2+ antagonist. The compound
obtained by introducing methyl groups onto the nitrogen (R2) of the side chain of
KT-362 showed vasoconstrictive activity. Therefore we synthesized various
derivatives, and examined their activities. Substitution at position R2 of the
side chain resulted in potent contractile activity, and the optimal alkyl length
was two or three carbons. The potency was further increased by the introduction
of a chloro group at the R1 position of 2,3,4,5-tetrahydro-1,5-benzothiazepines.
One of the synthesized compounds, 8-chloro-5-?N-ethyl-N-[2-(3,4
dimethoxyphenyl)ethyl]aminopropionyl?-2,3,4, 5-tetrahydro-1,5-benzothiazepine
fumarate (9b), showed an EC50 value of 3.47 x 10(-8) M for contraction of rabbit
iliac artery. The action of compound 9b was antagonized competitively by an H1
histamine receptor antagonist, diphenhydramine, and the pA2 value was 7.82. The
maximum constriction was inhibited by a Ca2+ entry blocker, nicardipine, but not
by an alpha 1-adrenoreceptor antagonist, prazosin. In a Ca(2+)-free medium, tonic
constriction induced by 9b disappeared, and only a phasic constriction was
observed. Though this phasic constriction was inhibited by diphenhydramine, it
was not inhibited by prazosin or nicardipine.
PMID- 9396153
TI - Synthesis and antiplatelet evaluation of alpha-methylene-gamma-butyrolactone
bearing 2-methylquinoline and 8-hydroxyquinoline moieties.
AB - In a search for inhibitors of platelet aggregation, some alpha-methylene-gamma
butyrolactones bearing 2-methylquinoline and 8-hydroxyquinoline moieties were
synthesized and evaluated for antiplatelet activities against thrombin (Thr)-,
arachidonic acid (AA)-, collagen (Col)-, and platelet-activating factor (PAF)
induced aggregation in washed rabbit platelets. With the exception of 2-[[2,3,4,5
tetrahydro-4-methylene-5-oxo-2-(4-phenylphenyl)-2 -furanyl]methoxy]-8
hydroxyquinoline (8f), these alpha-methylene-gamma-butyrolactones completely
inhibited the platelet aggregation induced by AA and Col. The 2-methylquinoline
derivatives were also active against Thr- and PAF-induced aggregation, while
their 8-hydroxyquinoline counterparts were relatively inactive.
PMID- 9396152
TI - Pyrrole butyric acid derivatives as inhibitors of steroid 5 alpha-reductase.
AB - A series of pyrrole butyric acid derivatives was synthesized and evaluated for
inhibitory activity on human and rat steroid 5 alpha-reductase in vitro and ex
vivo. 3-Benzoyl-4-alkylpyrrole-1-butyric acids and 1-methyl-2-alkyl-3
benzoylpyrrole-5-butyric acid derivatives were effective inhibitors. Structure
activity relationships were evaluated among the 37 compounds synthesized.
Compound 37 (HQL-1069) shows potent inhibitory activities against both rat and
human 5 alpha-reductase.
PMID- 9396154
TI - Synthesis and antinociceptive activity of [D-Ala2]Leu-enkephalin derivatives
conjugated with the adamantane moiety.
AB - Based on the physicochemical and pharmacological properties of drugs having an
adamantane skeleton, an adamantane-based moiety was evaluated as a drug carrier
for poorly absorbed compounds, including peptides, active towards the central
nervous system (CNS). Seven [D-Ala2]Leu-enkephalin derivatives conjugated with an
adamantane-based moiety at the C-terminus or N-terminus were prepared by the
solution-phase method and their biological activities were examined. The
compounds derivatized at the C-terminus through an ester or amide linkage were
much more lipophilic than the parent peptide and exhibited moderate in vitro
opioid activity (guinea-pig ileum assay). Among them, four derivatives (1, 2, 4,
5), exhibited significant antinociceptive effects in an in vivo assay (mouse tail
pressure test) after subcutaneous administration. This result suggests that the
introduction of the lipophilic adamantane moiety into [D-Ala2]Leu-enkephalin
would improve the permeation of the poorly absorbed parent peptide through the
blood-brain-barrier (BBB) without loss of antinociceptive effect.
PMID- 9396155
TI - Amino acids and peptides. XXX. Preparation of Arg-Gly-Asp (RGD) hybrids with
poly(ethylene glycol) analogs and their antimetastatic effect.
AB - Hybrids of a fibronectin-related peptide[Arg-Gly-Asp (RGD)] with poly(ethylene
glycol) (PEG) analogs were prepared by a simple and easy procedure. Two amino-PEG
analogs were used as carriers for hybrid formation of the RGD. One was
poly(oxyethylene)dipropylamine and the other was Jeffamine ED type, which has
branched chains. RGD peptides were formed stepwise on PEG analogs by the
diisopropylcarbodiimide method. The synthetic intermediates were easily purified
by molecular-sieve gel chromatography and the final products were purified by
molecular-sieve gel chromatography, followed by HPLC. This simple and easy
preparation procedure using molecular-sieve gel chromatography for purification
of synthetic intermediates is advantageous for the preparation of peptide-polymer
hybrids. We found that PEG is stable to HF treatment at 0 degree C for 1 h. The
inhibitory effect of the RGD hybrids on experimental metastasis of B16-BL6 was
examined in mice. The Jeffamine type hybrid showed no inhibitory effect at the
dose of 1 mg/mouse, but poly(oxyethylene)dipropylamine type hybrid was inhibitory
at the same dose. The effect of the latter hybrid was about the same as that of 1
mg of RGD. One mg of the hybrid contains 0.18 mumol of RGD and 1 mg of RGD is
2.38 mumol. Thus it can be said that the inhibitory effect of RGD was potentiated
by hybrid formation with poly(oxyethylene)diisopropylamine.
PMID- 9396156
TI - Synthesis and structure-activity relationships of novel 2',2'-difluoro analogues
of docetaxel.
AB - To investigate the role of the 2'-hydroxy group at the C-13 side chain of
docetaxel in the antitumor activity, we prepared several 2',2'-difluoro
derivatives of docetaxel and evaluated their cytotoxicity against mouse leukemia
and human tumor cell lines and their microtubule disassembly-inhibitory activity.
These analogues were prepared by esterification of protected 10-deacetylbaccatin
III (21) with appropriate alpha, alpha-difluorinated carboxylic acids (Charts 1
and 2). Among these 2',2'-difluorodocetaxel derivatives, 2',2'-difluorodocetaxel
(23b) was approximately 3-10 times as active as 2'-fluorodocetaxel (29a) in terms
of cytotoxicity. In addition, the 3'-(2-furyl) (23h) and 3'-(2-pyrrolyl) (23p)
analogues showed activity comparable or superior to that of docetaxel (2).
PMID- 9396157
TI - Polyenylidene thiazolidinedione derivatives with retinoidal activities.
AB - Several polyenylidene thiazolidine or 2-thioxo-4-thiazolidinone derivatives were
synthesized and their retinoidal activities were examined in terms of the
differentiation-inducing ability towards human promyelocytic leukemia HL-60 cells
and inhibitory effect on interleukin (IL)-1 alpha-induced IL-6 production in
MC3T3-E1 cells. Compounds containing a trimethylcyclohexenyl ring induced HL-60
cell differentiation with weaker activity than retinoic acid (1a) by one or two
orders of magnitude. The thiazolidinedione derivatives (2, 5, 7) showed stronger
activity than the corresponding 2-thioxo-4-thiazolidinone derivatives (3, 6, 8).
The effects of a retinoid antagonist (LE540) and synergists (retinoid X receptor
(RXR) agonists, HX600 or HX630) on the activities of thiazolidine derivatives
indicate that these compounds elicit their activities through the nuclear
retinoic acid receptors (RARs). All the thiazolidines examined also inhibited IL
1 alpha-induced IL-6 production with IC50 values of 10 nM order. The retinoidal
activities of the thiazolidines are significant, considering that replacement of
the carboxylic acid in retinoid structures with bioisosteric functional groups is
generally ineffective, as seen in the structure-activity relationships of
retinoidal benzoic acids.
PMID- 9396158
TI - Fluorometric determination of 1,2,3,4-tetrahydro-6,7-dihydroxyisoquinoline in
biological materials by HPLC.
AB - In the belief that endogenous 1,2,3,4-tetrahydro-6,7-dihydroxyisoquinoline (DA
Fp) could be a potential marker involved in the etiology of various diseases such
as Parkinsonism, we attempted to develop a fluorescence method for DA-Fp. It was
synthesized by condensation of dopamine with formaldehyde according to an
established method. Periodate was identified by screening from various oxidation
reagents as a fluorescence reagent to DA-Fp. Optimal reaction conditions were
obtained with 0.25 mM NaIO4 in 0.1 M phosphate buffer (pH 8.0) at 37 degrees C
for 15 min. The fluorescence spectrum of the derivative showed that we had found
a new reaction specific for DA-Fp. This reaction was coupled on-line to high
performance liquid chromatography (HPLC), which enabled us to achieve a highly
sensitive method for determining DA-Fp. A working curve was linear from 2 to 800
pmol of DA-Fp per injection. To determine DA-Fp in biological materials, the
pretreatment before HPLC was optimized by hydrolysis of its conjugate and
suppression of the artifact with l-phenylephrine. Urinary excretion of DA-Fp in
men was measured by this new present method. The urinary excretion of endogenous
DA-Fp increased in a rabbit given L-DOPA. The DA-Fp concentration was determined
in rat brain. The significance of DA-Fp in these biological materials is
discussed and evaluated. We conclude that the present method will be useful for
studying tetrahydroisoquinolines involved in many diseases.
PMID- 9396159
TI - Nitroarene concentrations and direct-acting mutagenicity of diesel exhaust
particulates fractionated by silica-gel column chromatography.
AB - Diesel exhaust particulates were extracted with benzene-ethanol (3:1, v/v) and
separated into five fractions by silica-gel column chromatography. Direct-acting
mutagenic activity was assayed by the Ames test using the Salmonella typhimurium
YG1024 strain. The total activity of five fractions was about four times greater
than that of the crude extract, suggesting that the activities in the fractions
were suppressed in the crude extract. Strong activity was observed in fraction 4
which was eluted with dichloromethane (61.5% of the total activity) and fraction
5 which was eluted with ethanol (35.3%). Nitropolycyclic aromatic hydrocarbons
(NPAHs) were determined by high-performance liquid chromatography with
chemiluminescence detection. They were found mainly in fraction 4, although one
NPAH was in fraction 3 which was eluted with n-hexane-dichloromethane (3:1, v/v).
Based on these results, 53.1% of the activity in fraction 4 was attributed to
NPAHs. The contribution of 1-nitropyrene and 1,3-, 1,6- and 1,8-dinitropyrenes
was great and that of the other NPAHs was small. The mutagenic compound in
fraction 5 was not identified. Fractions 1 and 2, which were eluted with n
hexane, and fraction 3 suppressed the activity of fraction 4. Polycyclic aromatic
hydrocarbons in fractions 2 and 3 were considered as possible suppressors of
NPAHs.
PMID- 9396160
TI - Hepatoprotective principles of Swertia japonica Makino on D
galactosamine/lipopolysaccharide-induced liver injury in mice.
AB - The n-BuOH extract of Swertia japonica showed a significant hepatoprotective
effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced liver injury
in mice. The activity-guided fractionation led to the isolation of a new
tetrahydroxanthone derivative, tetrahydroswertianolin (1), as well as two known
iridoids, gentiopicroside (2) and sweroside (3). Their structures were elucidated
by spectroscopic methods and chemical reactions. Of the three compounds, 2 and 3
possessed mild hepatoprotective activity at a dose range of 25-50 mg/kg, whereas,
1 exhibited potent activity in a dose-dependent manner. The hepatoprotective
effect of tetrahydroswertianolin (1) was stronger than that of glycyrrhizin which
was used as a positive control.
PMID- 9396162
TI - Degradation of a novel tripeptide, tert-butoxycarbonyl-Tyr-Leu-Val-CH2Cl, with
inhibitory effect on human leukocyte elastase in aqueous solution and in
biological fluids.
AB - The stability of tert-butoxycarbonyl-Tyr-Leu-Val-CH2Cl (YLV) with inhibitory
effect on human leukocyte elastase was investigated in aqueous solution, alpha
chymotrypsin solution and biological media. In all cases studied here, the
degradation was observed as a pseudo-first order reaction. The half-life for the
degradation of YLV in an aqueous solution of pH 7.4 at 37 degrees C was 35.9 h.
YLV was most stable at about pH 3.8-5.8 and the effect of temperature was
explained by the Arrhenius equation. The activation energies of the degradation
in aqueous solutions at pH 2.0, 4.8, and 7.4 were 24.6, 22.1 and 23.4 kcal/mol,
respectively. The degradation products in aqueous solution were analyzed by HPLC
MS and were estimated as Boc-Tyr-Leu-Val-CH2OH at pH 7.4 and H2N-Tyr-Leu-Val
CH2Cl at pH 2.0. In a bovine pancreas alpha-chymotrypsin solution at 37 degrees
C, the half-life of YLV was 15 min at 25.6 micrograms/ml of alpha-chymotrypsin
solution. In the rat plasma, the half-life of YLV was 42.4 min (YLV 26.7
micrograms/ml plasma), and in rat liver, lung and spleen homogenates, the
degradation rate constants of YLV were 37.6, 10.3 and 23.5 times larger than that
in plasma solution, respectively (all fluids containing 5 mg protein/ml). YLV was
less stable than nafarelin acetate, secretin, adrenocorticotropic hormone (ACTH)
and gonadorelin in an aqueous solution of pH 7.4.
PMID- 9396163
TI - Nonpeptide arginine vasopressin antagonists for both V1A and V2 receptors:
synthesis and pharmacological properties of 2-phenyl-4'-[(2,3,4,5-tetrahydro-1H-1
benzazepin-1-yl)carbonyl]benzanil ide derivatives.
AB - A series of compounds structurally related to 4'-[(2,3,4,5-tetrahydro-1H-1
benzazepin-1-yl)carbonyl]benzanili de was synthesized and demonstrated to have
arginine vasopressin (AVP) antagonist activity for both V1A and V2 receptors. The
introduction of a phenyl or a 4-substituted phenyl group into the ortho position
of the benzoyl moiety resulted in an increase in both binding affinity and
antagonistic activity. The 2-(4-methylphenyl) derivative (1g) exhibited high
antagonistic activities for both V1A (8.6-fold) and V2 (38-fold) receptors and
high oral activity (8.6-fold) compared with the 2-methyl lead compound (1a).
Detail of the synthesis and the pharmacological properties of this series are
presented.
PMID- 9396164
TI - Internal structure of phonetic categories: effects of speaking rate.
AB - Many studies have shown that listeners process speech in a rate-dependent manner,
altering the location of phonetic category boundaries in accord with the acoustic
consequences of a change in rate during speech production. In a recent series of
papers that focused on a voicing contrast, we reported that the perceptual
adjustment for rate is not limited to the region of the category boundary, but
extends to well within the category, producing a change in which stimuli are
perceived to be the best category exemplars. In the current paper, we provide
evidence for the generality of this effect by showing analogous results for a /b/
/w/ contrast, specified by transition duration. The implications of these
findings for models of rate-dependent processing are discussed.
PMID- 9396165
TI - Exploring the relationship of inspiration duration to utterance duration.
AB - Previous work has indicated that there may be a positive relationship between the
duration and extent of inspiration and the length of an upcoming utterance.
However, none of that work has uniquely implied a role of planning. We attempted
to avoid some of the alternative explanations by forcing subjects to utter single
sentences ranging in length from 5 to 82 syllables (mean of 27), after inspiring
fully and then expiring down to a set level before uttering the sentence. For all
3 subjects, there was a significant positive relationship between utterance
length and inspiration duration, regardless of whether inspiration was measured
physiologically or acoustically. The 2 subjects with the higher correlations in
the articulatory measures also expended air more quickly during the shorter
sentences than longer ones, while the other subject had no correlation with
exhalation rate. Complexity of the sentence, calculated as the number of clauses
in the sentence, did not affect inspiration duration. The individual differences
need further investigation, but there is a positive correlation between the
duration of the sentence to be said and the inspiration before it when the
speaker is required to read sentences while using only one breath.
PMID- 9396166
TI - Silent mandibular oscillations in vocal babbling.
AB - Early babbling has been characterized as being fundamentally a mandibular
oscillation: the infant's repeated lowering and raising of its mandible yields a
perceived contrast between consonants produced in a closed vocal tract
configuration and vowels produced with an open tract. We wondered whether
babblers produce rhythmic mandibular oscillations without phonation and, if so,
whether there might be a relationship between such 'jaw wags' and early speech.
We report two studies: the first is a longitudinal, observational study of 14
infants, some of whom were hearing and some Deaf. Seven infants (3 hearing, 3
Deaf, and 1 hearing-impaired) produced numerous speech-like, rhythmic jaw wags
without phonation; sometimes jaw wags formed a single utterance with phonated
babbling. Most jaw wags reported here were produced when these infants were ages
8-13 months. The second study, a survey of 90 parents of 4- to 10-month-old
hearing infants, suggests that silent babbles may be a widespread phenomenon of
early speech development.
PMID- 9396167
TI - Production constraints on utterance-final consonant characteristics in babbling.
AB - In order to evaluate hypotheses regarding production constraints on final
consonants in babbling, 721 utterance-final consonants produced by 6 infants in
consonant-vowel-consonant (CVC) syllables were examined and compared with the
preceding consonant in the CVC. Consistent with earlier studies, major patterns
were observed for each of the three main consonantal properties--place and manner
of articulation and voicing. These patterns included a strong tendency for final
consonants to repeat the place of articulation of nonfinal consonants and a
tendency for relatively more fricative, nasal and voiceless consonants to occur
in final position than in nonfinal position. The high frequency with which final
consonants shared place of articulation with the preceding consonant was
considered to reflect 'frame dominance' or the tendency of a relatively constant
mandibular cycle (the frame) to determine the structure of utterances with very
little contribution from other active articulators. The manner and voicing
effects were attributed to an overall terminal energy decrease in the vocal
production system.
PMID- 9396168
TI - Active compost biofiltration of toluene.
AB - Composting of leaves and alfalfa (i.e. active compost) was used for the
biofiltration of toluene-contaminated air in a 6-L biofilter (initial bed height:
180 mm). During the thermophilic phase (45 to 55 degrees C), toluene
biodegradation rates reached 110 g toluene.m-3.h-1 at an inlet concentration of
about 5 g.m-3 and a gas residence time of 90 seconds. The highest rates were
obtained in the thermophilic phase suggesting a microbial adaptation was
occurring. Biodegradation rates decreased rapidly (50% in 48 h) in the cooling
stage. Under mesophilic conditions, the maximum biodegradation rates that could
be obtained by increasing the inlet toluene concentration were near 89 g
toluene.m-3.h-1 which is similar to that reported in the literature for mature
compost biofilters. No volatile by-product was detected by gas chromatherapy.
Mineralization of 14C-toluene and benzene showed that they were completely
degraded into CO2 and H2O under both thermophilic and mesophilic conditions.
Bacteria isolated from late mesophilic stage had the capacity to degrade all BTEX
compounds but were not able to transform chlorinated compounds. No organisms were
isolated which could use toluene as their sole source of carbon and energy at 50
degrees C. Active compost biofiltration should be an excellent process for the
treatment of gaseous BTEX by biofiltration. This is the first report of
thermophilic biofiltration of toluene.
PMID- 9396169
TI - Water stress effects on toluene biodegradation by Pseudomonas putida.
AB - We quantified the effects of matric and solute water potential on toluene
biodegradation by Pseudomonas putida mt-2, a bacterial strain originally isolated
from soil. Across the matric potential range of 0 to -1.5 MPa, growth rates were
maximal for P. putida at -0.25 MPa and further reductions in the matric potential
resulted in concomitant reductions in growth rates. Growth rates were constant
over the solute potential range 0 to -1.0 MPa and lower at -1.5 MPa. First order
toluene depletion rate coefficients were highest at 0.0 MPa as compared to other
matric water potentials down to -1.5 MPa. Solute potentials down to -1.5 MPa did
not affect first order toluene depletion rate coefficients. Total yield (protein)
and carbon utilization efficiency were not affected by water potential,
indicating that water potentials common to temperate soils were not sufficiently
stressful to change cellular energy requirements. We conclude that for P. putida:
(1) slightly negative matric potentials facilitate faster growth rates on toluene
but more negative water potentials result in slower growth, (2) toluene
utilization rate per cell mass is highest without matric water stress and is
unaffected by solute potential, (3) growth efficiency did not differ across the
range of matric water potentials 0.0 to -1.5 MPa.
PMID- 9396170
TI - Secoiridoids from Gentiana siphonantha.
AB - Repeated fractionations of the methanol extract of the subterranean parts
(rhizomes and roots) of Gentiana siphonantha afforded two new and five known
secoiridoids, in addition to the widespread plant constituents beta-sitiosterol,
daucosterol and oleanolic acid. The structures of the new acyl secoiridoid
glycosides were elucidated as 6'-gentisoyl 8-epikingiside and 2'-gentisoyl
gelidoside mainly by a combination of high field NMR techniques. The known
secoiridoids were identified as gentiolactone, gentiopicroside, sweroside,
gelidoside and trifloroside. None of these constituents was active against human
pathogenic fungi (Candida albican, Aspergillus flavus and Trichoderma viride).
The chemotaxonomic significance of the isolates is discussed briefly.
PMID- 9396171
TI - Marasmane sesquiterpenes from the basidiomycete Clitocybe hydrogramma.
AB - Investigations of solid cultures of Clitocybe hydrogramma gave rise to the
isolation of two new alpha, beta-unsaturated dialdehydes having the marasmane
skeleton. Their structures have been determined on the basis of 1H and 13C NMR
evidence.
PMID- 9396172
TI - Helicobacter pylori and gastric cancer. An endoscopic series.
AB - In a series of 92 patients with gastric cancer who had biopsies of the antrum and
fundus, we compared the 65 patients with Helicobacter pylori (71%) with the 27
negative patients. No difference was observed for age, gender or histology
(intestinal or diffuse). Significant differences concerned location (11% of H.
pylori positive patients had a cancer at the cardia or fundus vs 44%), the
presence of a normal mucosa (3% vs 30%) and atrophy in the antrum (53% vs 17%).
Seven of the ten patients with a normal mucosa had a cancer located at the cardia
(p < 0.05) and in nine of the eleven patients younger than fifty, the cancer was
of the diffuse type (p < 0.005). Thus, patients with H. pylori and gastric cancer
differ from those uninfected. Of future concern is the large increase in cancers
of the cardia, a cancer unassociated with H. pylori.
PMID- 9396173
TI - Omeprazole, nitrendipine, famotidine and stress-induced ulcers.
AB - BACKGROUND: Omeprazole inhibits gastric acid secretion by blocking the proton
pump of the gastric parietal cell. Nitrendipine is a derivative of the
dihydropyridine group of calcium channel blockers and administrated for angina
and hypertension. Famotidine is one of the newer histamine H2-receptor
antagonists and heals gastric and duodenal ulcers by reducing gastric acid
output. OBJECTIVES: The healing effects of omeprazole, nitrendipine and
famotidine on stress-induced gastric ulcers were investigated in rats. METHODS:
Forty male Wistar-albino rats were separated into five groups (n = 8), a control
(non-stress) and four experimental (stress) groups. Experimental rats were
treated with omeprazole, nitrendipine, famotidine or a placebo after the stresses
of starvation and cold-restraint. RESULT: Macroscopically, the mean area of the
affected lesional mucosa was 1/4 of the total gastric mucosa in the famotidine
treated group and 1/5 of the total gastric mucosa in the nitrendipine treated
group. A considerably decrease was observed in the omeprazole treated group in
which the mean area of the lesional mucosa was only in 1/8 of the total gastric
mucosa. On microscopic examination, congestive vessels and chronic inflammatory
cell infiltrates were significantly reduced in the omeprazole treated group.
Tissue regeneration was more prominent in the omeprazole group than the other
groups. CONCLUSION: Omeprazole was found to be superior in terms of the effect on
the healing process to nitrendipine and famotidine. Although therapeutic effects
of nitrendipine and famotidine were observed, those were less than omeprazole.
PMID- 9396174
TI - Short- and long-term efficacy of cyclosporin administration in patients with
acute severe ulcerative colitis. Belgian IBD Group.
AB - Cyclosporin (CsA) has been proposed in the management of patients with acute
ulcerative colitis (UC) in whom standard therapy failed and who were candidates
for colectomy. Seven academic hospitals contributed to this retrospective study
that included 29 patients (median age: 33 y. (15-74 y.); 12 females and 17
males). The median duration of the disease was 4 y. (0.3 to 33 y.). Before
initiating CsA, patients were unresponsive to treatment including i.v.
corticosteroids (n = 29), 5-ASA or salazopyrine (n = 19), azathioprine (n = 3),
antibiotics (n = 14). The i.v. mean dose was 4 mg/kg/day and was adapted to blood
level. Concomitant treatment included corticosteroids (n = 27). The median
duration of i.v. CsA administration was 10 days (4 to 41 days). At the end of CsA
administration, a global improvement was described in 20 patients while a surgery
had to be performed immediately in 8 patients because of exacerbation of symptoms
(n = 7) or perforation (n = 1). One other patient (74 y.) died because of
Pneumocystis carinii infection. For the responders, maintenance therapy included:
tapering dose of steroids (n = 12), azathioprine (n = 12), 5-ASA or salazopyrine
(n = 10), methotrexate (n = 1) or oral CsA (n = II). The median duration of
follow-up was 12 months (4 to 48 months). Among the 20 responders, 7 were
subsequently referred for colectomy either electively (n = 3) or because of
recurrence of the disease (n = 4). Among the 12 patients treated by azathioprine
as a maintenance therapy, only 3 had to be referred for surgery (25%). Among the
8 patients who did not receive azathioprine, 4 were subsequently referred for a
colectomy (50%) (NS). In patients with acute refractory UC who received CsA, the
short-term efficacy (avoidance of immediate colectomy) was obtained in 20 out of
29 patients (69%). However, after a median follow-up of 12 months, only 13
patients were colectomy free (45%).
PMID- 9396175
TI - Genetics and inflammatory bowel disease: from association studies to wide genome
screen.
PMID- 9396176
TI - Treatment of chronic hepatitis C: practical aspects.
AB - The initial enthusiasm about the potential of alpha-interferon therapy for
chronic hepatitis C might be weaning in view of the low virus clearance rate of
about 15%. At the same time, the potential of interferon to induce sustained
remission of the disease is rapidly growing by 3 modalities: a) prolongation of
therapy from 6 to 12 months in order to reduce relapse; b) combination of
interferon with ribavirin to reduce early non-response, breakthrough and relapse;
c) high dose induction therapy; Benefit-risks/cost ratios vary for the different
stages of chronic hepatitis C. Consensus exists on the indication of therapy for
chronic hepatitis with fibrosis, whereas benefits in very early and very late
stages of chronic hepatitis C are doubtful; patients with cirrhosis are clearly
in need of therapy but remission is less than 10% and such patients are
encouraged to participate in controlled trials assessing combination and/or newer
therapy modalities. For decompensated cirrhosis, liver transplantation is the
treatment option of choice.
PMID- 9396177
TI - Practical management of patients treated with alpha interferon.
AB - Interferon alpha is currently used in chronic hepatitis and side effects are well
known. They always must be kept in mind to start and to follow a patient under
this therapy. A large number of autoantibodies may appear during interferon
therapy, usually without clinical manifestations. The detection of dysthyroidism,
requires measurement of antithyroid antibodies and TSH before and during
interferon therapy. Exacerbation of chronic liver disease under IFN may be found
in case of seroconversion in a patient with hepatitis B cirrhosis or in patient
with a misdiagnosis of autoimmune hepatitis. Neurolopsychological disturbances
are frequently reported; most of them spontaneously disappear. However,
depression must be detected because of the risk of attempted or successful
suicide. Worsening or sudden onset of psoriasis or lichen planus have been
reported in patients treated with interferon. Appearance or aggravation of some
clinical symptoms and biochemical tests may threaten life's patient under IFN
therapy. The decision to maintain or to interrupt therapy should take into
account the response to interferon and the severity of side effect.
PMID- 9396178
TI - HCV infection and liver transplantation.
AB - Acute and chronic liver diseases related to hepatitis viruses are the main
indications for liver transplantation. The risk of viral reinfection after
transplantation is the main limitating factor in these indications. HCV
reinfection was demonstrated by demonstrating a sequence homology of the
hypervariable region of HCV RNA in 2 patients before and after liver
transplantation. HCV reinfection is almost constant, assessed by the persistence
of HCV RNA in serum in 90% of cases. Acute lobular hepatitis appeared in 75% of
patients at a median of 4 months post-transplantation with extremes between 23
days and 4 years. In our series, the 5 year actuarial rate of HCV acute hepatitis
on the graft, chronic hepatitis and cirrhosis was 75%, 60% and 8%, respectively.
HCV RNA level is dramatically increased after transplantation and seems to
correlate with the occurrence of acute hepatitis on the graft. A positive
relationship between genotype 1 b and prevalence and severity of HCV hepatitis on
the graft have been suggested in European series. There is no demonstrated way to
prevent HCV reinfection. The use of interferon for the treatment of HCV hepatitis
on the graft was disappointing due to a poor antiviral effect and the occurrence
of chronic rejection episodes in some patients. Promising results of the
combination of interferon and ribavirin have been reported and need confirmation.
The 5 year survival of patients transplanted for viral C cirrhosis in our Center
is 78%. In conclusion, patients with endstage HCV cirrhosis are candidates for
liver transplantation. Viral C reinfection is frequent, but medium term survival
is good. However, longterm graft and patient survival remains unknown, and
methods to prevent and treat HCV reinfection on the graft are needed.
PMID- 9396179
TI - Ascorbic acid metabolism and cancer in the human stomach.
AB - The high levels of ascorbic acid (vitamin C) which are maintained in the gastric
mucosa and in normal gastric juice suggest that the vitamin has a metabolic role
within the stomach. Epidemiological associations between foods containing vitamin
C and a reduced risk of gastric cancer together with the ability of ascorbate to
quench the mutagenic activity of reactive species produced in the gastric
environment, indicate a potential role in the prevention of carcinogenesis. This
short review assess the balance of the current evidence and indicates that
gastric ascorbate could provide some protection against the development of
gastric cancer. However, it is only depletion of ascorbate from the gastric lumen
that is likely to contribute significantly to increased risk of malignancy.
PMID- 9396180
TI - The role of nitric oxide in portal hypertensive systemic and portal vascular
pathology.
AB - Hypotension, low systemic vascular resistance and reduced sensitivity to
vasoconstrictor are features of hyperdynamic syndrome in portal hypertension (PH)
and are pathogenetic factors triggering most serious clinical complications of
liver cirrhosis. Nitric oxide (NO) is a powerful vasodilating agent, released
from vascular endothelium cell and effecting relaxation of vascular smooth
muscle. An increased release of NO has been proposed to play a role in the
pathogenesis of vasodilation and vascular hypocontractility associated with PH.
In agreement with this hypothesis, the whole-body production of NO has been found
to be increased in PH, and the measurement of NOS mRNA expression in different
organs suggest that the splanchnic vascular system is a major source of NO
release. Consequently, NO could play a role in the development of the splanchnic
hyperaemia, collateral circulation and portal hypertensive gastropathy.
Furthermore, increased generation of NO in central circulation likely accounts
for pulmonary vasorelaxation and cardiac dysfunction found in cirrhosis. By
contrast, PH-associated endothelial dysfunction seems to invalidate the
capability of intrahepatic and intrarenal vasculature to produce NO. A deficient
NO release in these vascular territories might contribute to enhancement of PH
and development of the hepatorenal syndrome. Overall NO hyperproduction is either
the cause (induction of iNOS) or the consequence (stimulation of ecNOS) of the
hyperdynamic syndrome. This incertitude results from the yet undefined
significance of mild and transitory activation of the endotoxin-cytokines axis
for iNOS induction and contradictory data on specific iNOS and ecNOS activities.
A contribution of each isoform of NOS to pathogenesis of the hyperdynamic
syndrome probably depends on the model of PH in animal studies and the aetiology
or severity of cirrhosis in human studies.
PMID- 9396181
TI - The role of TIPS for the treatment of portal hypertension: effects and efficacy.
AB - In patients with variceal bleedings TIPS is effective even if the portal pressure
is reduced only partially and the reduction does not reach the threshold of 12
mmHg. Since the post-TIPS pressure gradient is closely correlated to the
incidence of hepatic encephalopathy, higher gradients should be favoured in
patients with a higher risk of hepatic encephalopathy, e.g. patients > age 65
years, Child-class C patients, and active alcoholics. An 8 mm diameter-shunt is
probably the adequate size for most of these patients. Regarding patients with
ascites, the effect of TIPS is partially due to an improvement of renal blood
flow and function. The reasons for this are unknown. The systemic hemodynamic
effects of the TIPS are probably not the cause since the shunt did not result in
an improvement of the arterial filling and peripheral resistance. The
experimentally proven hepatorenal baro-reflex may be an explanation.
PMID- 9396182
TI - Cystic gastric leiomyoma--a diagnostic pitfall.
AB - A case of a 74-year-old woman with a cystic calcified leiomyoma of the stomach is
presented. The cyst was initially interpreted and treated as a pancreatic
pseudocyst with repeated punctures and cystogastrostomy. Due to failure of
elimination of the cyst, and because of infection, the patient underwent surgery.
A discussion of the differential diagnoses and treatment is presented.
PMID- 9396183
TI - Fundic gland polyps: three other case reports suggesting a possible association
with acid suppressing therapy.
AB - We describe three patients who developed fundic gland polyps after starting a
treatment with acid suppressive agents. All three patients were treated for a
long time with H2-blockers or proton pump inhibiting agents for reflux
oesophagitis. In one patient the fundic gland polyps disappeared after
discontinuation of the acid suppressing therapy. A possible causal role of these
agents is suggested. A review of the literature about fundic gland polyps and
their possible association with acid suppressive therapy and a short review about
proton pump inhibiting agents and the appearance of gastric polyps in general is
given.
PMID- 9396184
TI - Increased transaminases in psychiatry: a case report.
AB - We report the case of a patient admitted to the hospital with psychiatric
troubles. Soon after admission, he presented severe hepatitis of unknown origin.
Careful review of the charts, transvenous liver biopsy, right heart and hepatic
pressure measurements, negative toxicologic and viral screenings were highly
suggestive of hypoxic hepatitis. Indeed, the patient had previously been treated
for a decompensated cardiomyopathy and medications stopped prior to the current
admission. Without clear clinical evidence of heart failure he presented a brief
malaise two days before the increase in liver enzymes. Holter heart recording
showed afterwards bouts of ventricular tachycardia. Treatment with Dobutamine and
antiarrythmics led to a rapid decrease of transaminase levels and recovery in
liver function. Unfortunately, he died three weeks later from his cardiomyopathy.
This case illustrates the need for cardiovascular work-up in the context of
hepatitis from unknown origin.
PMID- 9396185
TI - Preparing and interpreting meta-analysis in clinical research.
AB - Meta-analysis is a procedure to systematically research and collect published and
(ideally) unpublished randomized clinical trials (RCTs) of treatments and
quantitatively summarise their results, in order to obtain an objective
assessment of efficacy. Collaboration between statisticians and clinical experts
in the field of pathology addressed by the treatment is needed for performing
reliable meta-analyses. "Typical" meta-analysis can be refined as "cumulative"
meta-analysis, where the pooled assessment of treatment effect is repeated every
time a new trial is added to a set of trials, and by meta-analysis "on individual
patient data", i.e. using information on each patient included in every trial.
Due to the emergence of Evidence-Based Medicine (EBM), the role of meta-analysis
is expanding. EBM is a way of practising medicine by integrating individual
clinical expertise with the most reliable evidence from the medical literature.
Meta-analysis is suggested as the most convenient and reliable source of data for
practising EBM. EBM is taking advantage from the Cochrane Collaboration, an
international network of experts performing, updating and disseminating meta
analyses of important treatments, according to a common model and established
procedures.
PMID- 9396186
TI - Molecular biology in uro-oncology: clinical application. Prognostic factors in
bladder cancer.
AB - In the bladder cancer the most important prognostic factors are the stage, the
grade, the presence or absence of lymph nodal metastasis, the response to therapy
with B. C. G. etc.... In any case, even in the context of the same clinical
stage, it is not possible to correctly evaluate the evolution of the disease. The
Author did a literature revision and got a personal contribution about the
effective utility of same biological prognostic factors. In a study about
superficial bladder tumor using monoclonal antibody MIB-1 (Ki-67) a correlation
between proliferation index (P.I.) and grade was noted. In particular the
presence of a P.I. above 40% correlated with greater precocity and frequency of
recurrences. A similar study showed that the expression of protein p21 correlated
with a greater precociousness and with recurrence frequency. In conclusion, we
have also carried out an evaluative study on the expression of oncosuppressor
gene p53. In superficial bladder cancer this study showed up a correlation
between the expression of protein p53 and a greater precociousness and frequency
of recurrences.
PMID- 9396188
TI - Molecular genetics of renal cell carcinoma.
AB - Significant research progress over the last few years has identified several
major genetics contributors to RCC. A new classification of RCC validated by
cytogenetic and molecular studies has been proposed including nonpapillary,
papillary, chromophobe and oncocytic tumors. The cytogenetic analysis of patients
with familial RCC, VHL disease and sporadic RCC have shown that WHL gene located
on chromosome 3P 25 is a tumor suppressor gene. Other genes may be involved in
the development of RCC, however with a less important incidence than VHL gene.
Mutations of Rb and P53 genes can be associated with metastatic disease,
mutations of the ras gene is rare whereas elevated level of myc oncogene are
frequent but of little prognostic value. Controversial the role of ploidy and
proliferation markers as independent prognostic factors.
PMID- 9396187
TI - Effects of LHRH agonists on the growth of human prostatic tumor cells: "in vitro"
and "in vivo" studies.
AB - Luteinizing Hormone Releasing Hormone (LHRH) agonists exert both "in vitro" and
"in vivo" a direct inhibitory action on the growth of both androgen-dependent
(LNCaP) and androgen-independent (DU 145) human prostatic cancer cell lines. The
present experiments have been performed to investigate the mechanisms involved in
this direct antiproliferative action of LHRH agonists. In particular, the aim was
to study whether these compounds might exert their antiproliferative effect by
interfering with the stimulatory action of epidermal growth factor (EGF) both "in
vitro" and "in vivo". To this purpose, the effects of LHRH agonist, Zoladex (LHRH
A), on the mitogenic action of EGF, on EGF-activated intracellular signaling
mechanisms (tyrosine phosphorylation of EGF receptor and c-fos proto-oncogene
expression), and on the concentration of EGF receptors have been evaluated in
both LNCaP and DU 145 cells. The results of these "in vitro" studies show that in
LNCaP cells LHRH-A counteracts the mitogenic action of EGF, abrogates the EGF
induced c-fos expression and reduces the concentration of EGF-binding sites,
without modifying the EGF induced tyrosine phosphorylation. In DU 145 cells, LHRH
A antagonizes the proliferative action of EGF, inhibits tyrosine phosphorylation
of EGF receptor induced by EGF and significantly reduces the number of EGF
binding sites, without altering the stimulation of c-fos expression induced by
EGF. For the "in vivo" experiments, male nude mice were s.c. injected in the
flank with DU 145 cells and treated for 14 days with LHRH-A (100
micrograms/days). At the end of the treatment, the concentration of EGF receptors
on membrane preparations as well as on tumor volume were found to be
significantly lower in LHRH-A treated animals than in control mice. The mitotic
index and the expression of the proliferation-associated antigen Ki67 were found
similar in control as well as in treated animals. In addition no modification of
apoptotic index (expression of p53) was observed. These data suggest that LHRH
agonists may inhibit the proliferation of the tumor cells by interfering with the
stimulatory actions of EGF.
PMID- 9396189
TI - Simple renal cysts.
AB - OBJECTIVES: To evaluate the incidence of simple renal cyst, the relationship
between both size and location of cysts, and the effect on calyces; and to
correlate symptomatology and effect on the pelvicalyceal system. METHODS:
Abdominal ultrasound examination was performed in 2010 patients for different
reasons. Simple renal cysts were demonstrated in 110 patients harbouring 198
cysts. The cysts were divided into 3 categories according to their size. The
relation between the size of the cyst to the clinical symptoms and to the effect
on the pelvicalyceal system is discussed. The clinical presentation in relation
to effect on calyces is evaluated. RESULTS: The male to female ratio was 1.4:1.
The majority of the simple renal cysts were encountered in patients above the age
of 50 years. However, the incidence of renal cysts in children in this series was
2% which is considered high as compared to other studies. Thick wall, marginal
calcification of cysts and multilocularity, each was seen in 1% of the cases.
Associated liver cysts was seen in 2% of the cases. CONCLUSIONS: We can conclude
that there is an important relationship between both size and location of cysts,
and the effect on calyces; however, no noticeable correlation between
symptomatology and effect on the pelvicalyceal system was observed.
PMID- 9396190
TI - Clinicopathologic correlation in a case of metastatic uveal tumor.
AB - A clinicopathologic correlation is reported of an ocular metastasis from an
unknown primary tumor. The tumor appeared initially confined to the choroid. The
diagnosis of metastatic adenocarcinoma was obtained by choroidal biopsy. The
metastasis was uncontrollable with teleradiotherapy. Six months later the
anterior segment also appeared infiltrated and the eye was enucleated.
PMID- 9396191
TI - Indocyanine green angiography versus fluorescein angiography in the follow-up of
choroidal melanomas treated with RU106/RH106.
AB - Indocyanine-green angiography and fluorescein angiography may complement each
other in the follow-up and evaluation of choroidal melanomas treated with
brachytherapy and may give a better understanding in the process of response of
choroidal melanomas to brachytherapie. We did a retrospective study on 18
patients treated for this pathology.
PMID- 9396192
TI - Ocular burn caused by soft brown soap.
AB - PURPOSE: To report the danger of serious chemical ocular burn caused by common
household soap. CASE HISTORY: A 20 year old male developed an extensive burn of
the right eye after the commonly used soft brown soap (also called floor soap)
fell into his face and right eye. The burn caused conjunctival ischemia and
necrosis. The cornea was oedematous and denuded of epithelium. The pH of the soap
was 11.8. The patient received treatment for alkali burn of the eye. Stem cell
transplantation was needed to heal the corneal surface defect. Scar formation and
peripheral neovascularisation have reduced the visual acuity to counting fingers
at 75 cm. CONCLUSION: This case of serious alkali burn caused by the common soft
brown soap demonstrates the potential hazard to the eyes. The manufacturer was
sought to write the pH and a warning on the exterior of the container that the
"soft brown soap" may cause serious ocular injury.
PMID- 9396194
TI - Primary acquired melanosis and melanoma of the conjunctiva.
AB - Primary acquired conjunctival melanosis presents as a unilateral conjunctival
pigmentation, mostly in middle-aged patients, with a strong tendency to progress
to malignancy. The clinical picture is specific and doesn't cause major
diagnostic problems. It is important to recognize the entity, to observe it
closely and treat it early and adequately.
PMID- 9396193
TI - Pelli-Robson contrast sensitivity test in Zaire.
AB - The purpose of this study was to establish in this first report the age standards
of the Pelli-Robson contrast sensitivity in Zaire. Contrast sensitivity using the
Pelli-Robson chart was performed in 100 normal Zairian black subjects aged from
10 to 59 years and 36 patients (22 patients with open-angle glaucoma and 14 with
optic nerve disease). Scores of normal subjects were age related (p < 0.05). The
results of Zairian young subjects were similar to those found previously in young
white subjects; scores for older subjects were lower when compared to those of
whites. Scores of patients were lower than those of normals (p < 0.001). Contrast
sensitivity using the Pelli-Robson chart can be useful in developing countries.
PMID- 9396195
TI - Sneddon's syndrome in a patient with homonymous hemianopia with macular sparing.
AB - A 48-year-old women is described with the infrequent association of generalized
livedo reticularis and cerebrovascular accident of idiopathic origin (Sneddon's
syndrome-SS). Visual field testing revealed a left homonymous hemianopia with
macular sparing. Though visual field impairments in SS have been reported, the
type could usually not be specified precisely because of the dementia and lack of
cooperation of the patients.
PMID- 9396196
TI - I-123-IDAB: a new tracer for scintigraphic visualisation of malignant melanoma.
AB - I-123-N-(2-Diethylaminoethyl) 4-lodobenzamide (I-123IDAB) has recently been
introduced as a radiopharmaceutical agent in the management of patients with
malignant melanoma. We tested the diagnostic potential of this substance in 5
patients suspected of having an ocular malignant melanoma. I-123-IDAB
scintigraphy identified 4 patients with high tracer uptake in the pathologic eye.
Three cases were confirmed histologic as a malignant melanoma, the fourth patient
was submitted to radiotherapy. The amelanotic (histologically confirmed)
irismelanoma of the fifth patient could not be detected. From these preliminary
results we conclude that I-123-IDAB scintigraphy may be a valuable tool for
establishing the diagnosis of malignant melanotic melanoma.
PMID- 9396197
TI - Indocyanine green angiographic findings in multifocal choroidopathies.
AB - With high definition videoangiography (TOPCON IMAGEnet H1024) the Authors studied
41 patients affected by multifocal choroidopathies (MC) (68 eyes with
ophthalmoscopic or indocyanine green angiographic evidences): 29 females and 12
males; age 21-51 years with a follow up of 6-29 months. In the light of the
evidence provided by FA and ICG the Authors present a classification of MC in
three stages: Stage 1 of subclinical choroidal activity (5 eyes): characterised
by the presence of hypofluorescent or hyperfluorescent spots visible only in the
late phases of ICGA; stage 2 of clinically evident choroidal activity (45 eyes):
in FA the spots are hypofluorescent in the early phases and hyperfluorescent with
a slight diffusion in the late phases, in ICGA either hypofluorescent spots or
less frequently hyperfluorescent spots and choroidal permeability alterations can
be observed; stage 3 or healed stage (18 eyes): in FA the spots are
hyperfluorescent without late leakage, in ICGA hypofluorescence can be observed
during all angiographic phases. In 5 patients in stage 1 of subclinical activity,
a systemic steroid therapy induced the regression of the hypofluorescent sports
in ICGA, in 2 cases the regression of hyperfluorescent spots in ICGA was observed
after systemic antibiotic therapy. The authors underline that ICGA could be a
particularly useful tool for an early diagnosis and clinical monitoring of MC.
PMID- 9396198
TI - Steps toward discovering causes: divergence and convergence of epidemiology and
clinical medicine.
AB - Ways in which frames of reference about causation differ across disciplines are
exemplified. The necessity for a multivariate concept of causation is emphasized.
On the epidemiological side, divergences of clinical approaches from requirements
for meeting preconditions for cause are each illustrated by several examples.
Association is discussed in terms of comparability of groups, independent
observation of associated variables, sampling and measurement. Securing time
order among variables is a matter of sequential positioning by design, and the
difficulties that inhere in the clinical situation are again illustrated by
example. On the clinical side, strengths in generating hypotheses, in discovery
of associations without conventional comparison and in potential precision in
measuring outcomes are outlined. On the epidemiological side, the discipline adds
to clinical medicine unique dimensions analogous with the basic biomedical
sciences. These are essential to capturing environmental causes and the
antecedent experience of sick individuals. Convergence between the two
perspectives is bound to yield, and has yielded, much profit.
PMID- 9396199
TI - Geriatric medicine. A new discipline for the coming century.
PMID- 9396200
TI - Cardiovascular disease in the elderly.
PMID- 9396201
TI - Isolated systolic hypertension in the elderly.
PMID- 9396202
TI - Kidney diseases in the elderly.
PMID- 9396203
TI - Infections in the elderly.
PMID- 9396204
TI - Cancer in the elderly. A special and unique entity.
PMID- 9396205
TI - Intracranial sewing needles in a 20-year-old patient.
AB - A 20-year-old patient is reported with three intracranial sewing needles, which
were located in the frontal lobes. The clinicoradiologic findings strongly
suggested that they must have been placed into the brain through the anterior
fontanelle during an unsuccessful homicide attempt in infancy.
PMID- 9396206
TI - Paraganglioma of the cauda equina: MR findings. One case.
AB - Paraganglioma of the filum terminale is a rare tumor but well described in the
neurosurgery and pathology literature. Few MRI reports are mentioned.
Paraganglioma, often misdiagnosed with ependymoma or schwannoma on MRI images,
must be kept in mind, when a highly vascular lesion with serpentine vessels is
observed.
PMID- 9396207
TI - [One hundred years of sinusoidal cells in the liver].
AB - Kupffer (1898) reported that the stellate cells were phagocytic endothelial
cells, retracting his earlier view that these cells were perivascular cells. His
new concept stimulated studies on the vital staining and the RES theory, while it
ensued several controversies in liver histology. The original stellate cells were
rediscovered in 1971, and were proved to be identical with several perisinusoidal
cells reported previously. For this cell the term hepatic stellate cell has
recently been adopted as the standardized name. The space of Disse is newly
defined as the space between the endothelial cell-stellate cell complex and the
parenchymal cells. The stellate cells display vitamin A-storage, collagen
synthesis and may contract to regulate the sinusoidal blood flow and the fluid
exchange between the sinusoidal lumen and the space of Disse. The sinusoidal
endothelial cells uptake injected lithium carmine and macromolecules by coated
vesicles. Kupffer cells clear endotoxin, bacteria and apoptotic neutrophils and
release various cytokines. The pit cells are the liver-associated NK cells and
are activated by the administration of biological response modifiers, preventing
tumor metastasis. Extrathymic pathways of T cell differentiation exist in the
hepatic sinusoid. The dendritic cells differentiate in the sinusoid and
translocate to the Glisson's sheath. Intralobular heterogeneity of sinusoidal
cells have been observed. The sinusoidal cells communicate each other with
autocrine and paracrine mechanisms to regulate various functions of the liver.
PMID- 9396208
TI - [Historical notes on anatomy of the transversalis fascia].
AB - In the early 19th century, the tissue of the peritoneum was regarded as the
duplicature of membrane. In the middle of the century, however, it was considered
to be one of serous membranes, because histology had been developed. Between the
peritoneum and the abdominal muscles, there are two fasciae, the subperitoneal
and the transversalis fascia. But, Sir Astley Cooper reported that there was only
the transversalis fascia, because he considered the subperitoneal fascia to be a
double covering of the peritoneum, that is, a part of the duplicature of the
peritoneum. In this century, Cooper's report has been interpreted through
histology. Consequently, it is the general opinion that there is no other fascia
than the transversalis fascia between the peritoneum and the abdominal muscles,
in a view which disregards the subperitoneal fascia.
PMID- 9396209
TI - [Integrins: their structures, functions and gene expressions in the central
nervous system. Acta anat].
AB - More than ten years have passed since integrin was shown to function in cellular
attachment. To date integrin research has been one of major fields in cell
biology. Integrin, which functions as an integrator of both extra- and
intracellular skeletal molecules, is regarded as one of the essential molecules
for cellular signal transduction as well. Thus, integrin appears to be essential
and indispensable for many cellular phenomena. Although every type of cell is
thought to express a few kinds of integrin molecules, their expression and
functional roles in neurons remain to be determined. Both intensive and extensive
researches should reveal one by one how integrins are involved in the neural
network formation in development, neuronal plasticity and regeneration, higher
function of CNS, and also neuronal degeneration in both inflammation and
degenerative diseases.
PMID- 9396210
TI - Differential accumulation of calcium and phosphorus in aged human arteries.
AB - To elucidate age-related changes of human arteries, relative contents (RCs) of
minerals were analyzed by inductively coupled plasma atomic emission spectrometry
on the thoracic aorta, basilar, coronary, femoral, and radial arteries from 27
subjects within the age range between 0 and 92 years old (Ys). Calcium and
phosphorus never accumulated uniformly in any of the arteries such as the
thoracic aorta, basilar, coronary, femoral, and radial arteries. The
accumulations of calcium and phosphorus occurred earlier in the order of the
femoral artery, thoracic aorta, coronary artery, and basilar or radial artery.
PMID- 9396211
TI - Right superior bronchial artery arising from the right subclavian artery and
accompanying nerve branches: an autopsy case.
AB - In one out of 8 examined cadavers a solid, right superior bronchial artery was
found to arise from the subclavian artery with its origin at the same level as
those of the right vertebral and internal thoracic arteries. This bronchial
artery was 1.5 mm in caliber and closely associated with the right sinal nerve
arising from the vagus nerve and with the right stellate cardiopulmonary nerves
arising from the right stellate ganglion. Such a close association was also
observed between other sympathetic cardiac nerves and bronchial arteries and an
extracoronary artery. On the basis of these observations it was deduced that the
general course of the bronchial arteries serves to pave the way for the extension
of the sympathetic cardiac nerves to the heart.
PMID- 9396212
TI - Trends in cancer mortality: perspectives from Italy and the United States.
AB - Cancer continues to be a major public health problem in Italy, as it is
throughout the world. We analyzed age-adjusted mortality rates for all cancers
combined and for specific cancer sites in Italy for five year periods from 1950
to 1989. We compared trends in Italian cancer mortality to those observed in the
United States during the same time period. We also considered some ancillary data
including age-specific mortality rates, as well as incidence and five year
relative survival data from the Modena Province. Age-adjusted cancer mortality
rates in Italy are increasing in males and, to a lesser extent, females. This
finding is in contrast to a recent plateau in age-adjusted cancer mortality rates
in the United States. In Italy, stomach cancer mortality has declined
substantially, counteracting marked increases in lung cancer mortality,
particularly in males, and breast and lung cancer in females. Changes in cancer
mortality in Italy, as in the US, have been driven primarily by changes in
disease incidence rather than advances in therapeutics. These data suggest a need
for realignment of cancer control resources toward prevention, particularly with
regard to lung cancer and tobacco usage.
PMID- 9396213
TI - Introduction: history of the use of asbestos.
AB - Discussion of the major milestones in the history of the modern uses of asbestos
and the first knowledge of the health effects associated with such usage.
Highlights of the studies associating exposure to asbestos with non-malignant
lung diseases, lung cancer, and mesothelioma are discussed.
PMID- 9396214
TI - Asbestos-related mortality in Italy: a geographical approach.
AB - The present contribution describes two studies of asbestos-related cancer
mortality in Italy: an analysis of the geographical distribution of mortality
from pleural neoplasms and an investigation into the relationship between pleural
and lung cancer mortality in an Italian region, Piedmont. Mortality from
malignant pleural neoplasms (ICD-IX Revision 163.0-163.9) has been studied in
Italy in the 20 regions and the over 8000 municipalities for the years 1988-92:
restriction of analysis to municipalities with at least three observed deaths and
statistically significant increases led to identification of areas where
occupational and/or environmental exposure to asbestos can have occurred. The
analysis of pleural and lung cancer mortality was carried out for the years 1980
87 in Piedmont using an empirical Bayes method for small-area disease mapping;
the results showed that the proportion of lung cancer mortality attributable to
asbestos exposure was 5.6 and 5.7 percent respectively in men and women. While
analyses of routinely collected data are no substitute for ad hoc individual
based studies, notwithstanding the limitations of geographical approaches to the
study of asbestos-related mortality, investigations carried out at the level of
small area populations appear to provide informative results, which might be of
value in terms of public health.
PMID- 9396215
TI - Pleural malignant mesothelioma and environmental asbestos exposure in Casale
Monferrato, Piedmont. Preliminary analysis of a case-control study.
AB - A case-control study on pleural malignant mesothelioma (MM) was conducted in
Casale Monferrato, where the largest Italian asbestos cement (AC) factory had
been operating from 1907 to 1985. In a previous study we observed a five to seven
fold increase in the incidence of MM among people living in that city and never
employed in the factory mentioned. The present study includes cases of MM with
histological diagnosis over the period 1.1.1987-30.6.1993 among residents in the
Local Health Unit (LHU) of Casale Monferrato. Population controls were randomly
extracted from the list of the residents in the LHU, matched to cases on sex,
date of birth, vital status and date of death. Cases and controls (or their
closest relative) were interviewed with a standardised questionnaire focusing on
asbestos exposure in the (life-long) residential and occupational histories and
in leisure time activities as well as on occupational asbestos exposure of
relatives and cohabitants, smoking and chest or occupational diseases. The
interview was blind in respect to case or control status. For the analyses the
addresses were coded on map grids with a 500 m. mesh size. Statistical analyses
were conducted with conditional logistic regression in order to keep the matching
between cases and controls. Eighty-eight cases and 244 controls were interviewed
(95.6% of cases and 80.1% of controls): 26 and 11 respectively reported an
activity in the AC industry. Seven cases and 7 controls were also exposed because
of parental occupation. The main analyses are based on the conditional regression
model including both occupational and residential exposure. The different modes
of exposure are included on an ordinal scale: each subject is classified
according to their highest level. Domestic exposure is included as an independent
factor. Odds Ratios (OR) are estimated with reference to subjects without either
occupational or residential exposure. The OR is 39.3 among subjects reporting
occupational exposure, 11.9 among those never engaged in the AC industry but
living within 1000 m. of the factory. A statistically significant risk is also
observed for persons at some time living in the other areas of Casale Monferrato.
PMID- 9396217
TI - Malignant mesothelioma of the pleura in the Trieste-Monfalcone area, with
particular regard to shipyard workers.
AB - A series of 421 malignant pleural mesotheliomas, diagnosed in the Trieste
Monfalcone area, northeastern Italy, were reviewed. A large majority of the
patients had been employed in "naval" work (shipbuilding, maritime trades, and
dock work). Latency periods (time intervals between first exposure to asbestos
and death), showed wide variations from one occupational category to another.
Such variations were attributable, but only partly, to differences in the
intensity of the exposure to asbestos. Various family cases were identified,
including people with and without blood relationships. The data, obtained in the
studies on Trieste-Monfalcone mesothelioma, suggest that interactions between
asbestos and other factors play a considerable role in the pathogenesis of
asbestos-related mesothelioma.
PMID- 9396216
TI - The experience of the Mesothelioma Registry of Tuscany in assessing health hazard
associated with asbestos exposure.
AB - All cases of pleural malignant mesothelioma occurring in Tuscany were collected,
backdated to 1980 (to 1970 for the provinces of Florence and Prato; to 1975 for
the provinces of Pisa and Siena), in order to evaluate the incidence of
occupational exposure to asbestos. The aim was to enhance primary prevention in
those workplaces still at risk nowadays. To achieve information on the possible
occupational, domestic or environmental exposure, an interview was conducted
using a semi-structured questionnaire. An exposure classification was produced to
focus preventive intervention. This surveillance system needs to be developed to
contribute to epidemiological research, especially on the effects of low level
exposures, and to primary prevention.
PMID- 9396218
TI - Mesotheliomas in some selected Italian population groups.
AB - The analysis of 335 cases of mesothelioma observed at the Ramazzini Foundation
and the Bologna Institute of Oncology has shown: 1) a high percentage of
correlation of these tumours with asbestos exposure; 2) a large number of
population categories potentially exposed to asbestos fibres and therefore at
risk of developing mesothelioma; and 3) the high risk of mesothelioma among
people exposed in various circumstances to asbestos used in railroads and sugar
refinery plants.
PMID- 9396219
TI - The riddle of risk assessment in asbestos carcinogenicity.
AB - While there appear to be some legitimate issues of scientific inquiry with regard
to asbestos carcinogenicity, there also appear to be continuing areas of
controversy which, given the state of scientific evidence, should be considered
settled. There have been real costs, both monetarily and in human suffering, with
regard to past and current uses of asbestos. With the continuing, often poorly
controlled exposure, that workers still have, more disease can be expected. The
fitting remembrance of Dr. Selikoff would be to remember the science that he
contributed and the interest he took in the lives of workers and others. It then
becomes incumbent upon those of us who continue to work in this area to carry on
in the spirit of protecting the lives and well-being of workers from this
hazardous material, as we would for other known hazards.
PMID- 9396220
TI - Conclusion: prevention of asbestos-induced disease.
PMID- 9396221
TI - DNA flow cytometry and 67Ki proliferating index as prognostic factors of early
recurrence and progression in G1-G2/Ta-T1 and G3/Ta-T1 transitional cell
carcinoma of the bladder.
AB - Using flow cytometry, gross genomic alterations, defined as DNA ploidy, and the
fraction of S-phase cells, can be calculated in bladder cancer cells. In
aneuploid superficial bladder cancer the recurrence rate has been reported to be
three times higher than in diploid forms. A correlation between the S-phase
fraction and progression has been reported for G1-G2/Ta-T1 tumours, but not for
G3/Ta-T1. The aim of our study is to evaluate whether the traditional cytometric
parameters can be used as valid predictors of early recurrences and progression
in G1-G2/Ta-T1 and G3/Ta-T1 bladder cancer patients and to compare the
proliferation indexes as defined by S-phase fraction and 67Ki monoclonal antibody
in the two groups of patients.
PMID- 9396222
TI - Sarcomas of the kidney.
AB - Sarcomas of the kidney are exceedingly uncommon. They represent between 1 and 3%
of all malignant renal tumors. Several histological types have been reported. We
have reviewed the renal tumors diagnosed in our department in the last 25 years
and found 4 cases of sarcoma out of 390 malignant renal tumors (1.02%). They were
a liposarcoma, a storiform-pleomorphic fibrous malignant histiocytoma, a
rhabdomyosarcoma and a pleomorphic leiomyosarcoma. We report the clinical data
and the outcome of the patients, together with the immunohistochemical and
ultrastructural findings in these cases.
PMID- 9396223
TI - Villous adenoma of the bladder.
AB - Villous adenomas of the bladder are rare tumors and up to now they have not been
seen to undergo malignant transformation. We report a case of villous adenoma of
the bladder with areas of adenocarcinoma in a 72-year-old man. We describe all
the morphological, histochemical and immunohistochemical features characterizing
this tumor. We recommend adequate pathological sampling and a thorough follow-up
of patients with villous adenoma. The prognosis and the behaviour of these
adenomatous papillary lesions, morphologically similar to colonic adenomas, in
the bladder is unclear. We report a case with focal area of adenocarcinoma and
review the literature.
PMID- 9396224
TI - [Acetaldehyde adducts in the cerebral cortex of ethanol-fed mice].
AB - To investigate the neurotoxicity of acetaldehyde covalent adducts,
immunohistochemical staining for acetaldehyde adducts using the antibody against
acetaldehyde adducts, was performed in the cerebral cortex of ethanol-fed
(withdrawal) mice. In the ethanol-fed mice, the degeneration in the cerebral
cortex was found, while the protein epitope related to acetaldehyde was found in
the cerebral cortex, liver and adrenal cortex. No histochemical and
immunohistochemical changes in the tissues from the control mice were found. It
is possible that acetaldehyde adducts may effect on the cerebral cortex as the
neurotoxicity which cause psychosis such as delirium and hallucination after
alcohol drinking.
PMID- 9396225
TI - [Mental and physical symptoms in alcoholics after alcohol withdrawal].
AB - Much of the recent interest in the risk factors of relapse in alcoholics has
focused on the withdrawal depressive state. Although the clinical relevance of
this syndrome is often acknowledged, definite empirical research on subjective
symptoms has not been presented in detail. Therefore, the purpose of this paper
is to explore the characteristics of mentally or physically subjective symptoms
of alcoholics and to discuss the risk factors to "slip". To evaluate the
subjective symptoms, the health questionnaire that is composed of 62 items was
applied to 73 admitted alcoholics. The principal component analysis obtained for
the questionnaire of mental symptoms extracted five factors as followed, 1)
feeling of estrangement or emptiness, 2) anxiety or impatient, 3) depressive mood
or sleeping disturbance, 4) endogenous depressive factor, 5) unstable emotion.
Additionally, five factors on physical symptoms were extracted as follows, 1)
autonomic dysregulation related to neurasthenic state, 2) autonomic dysregulation
related to hysterical neurosis, 3) loss of libido, 4) appetite loss, 5) dry mouth
or sweating. These findings emphasized that many alcoholics felt the feeling of
maladjustment and emotionally unstable under the "sobriety" state. These also
suggest the "slip" of alcoholics should depend on expectation to reduce their
tension, conflict and frustration under the influence of alcohol.
PMID- 9396226
TI - [Effect of nicotine-administration on tyrosine hydroxylase-containing neuron in
the rat forebrain; immunohistochemical study with semiquantitative morphometric
analysis].
AB - Nicotine is toxic substance that is absorbed by cigarette smoking and easily
causes dependence. It is clear that smoking is bad for health, however, the
effects of nicotine itself on the central nervous system have not been
elucidated. We studied the effects of nicotine-administration (5 mg/kg x 2/day, 7
days) on immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme
of catecholamine synthesis, in the rat forebrain including the cerebral cortex,
hippocampus, striatum and hypothalamus to investigate the influence on
catecholaminergic neurons. In the nicotine-administration group, both the number
and intensity of TH-immunoreactive fibers and terminals increased in the fronto
parietal cortex, anterior cingulate cortex and hippocampus in comparison with
those of the control group, and a significant difference was demonstrated by
computer assisted morphometric analysis. These findings suggest that nicotine
administration influences catecholaminergic neural systems in the forebrain,
especially in the cerebral cortex and hippocampus and that these effects might be
related to developing the dependence on smoking.
PMID- 9396227
TI - [The ophthalmological application of functional brain imaging].
PMID- 9396228
TI - [Physical properties of an intraocular lens coated with diamond-like carbon
film].
AB - I have invented an intraocular lens (IOL) coated with diamond-like carbon film
and have investigated its physical properties. Diamond-like carbon film is an
ultrathin film which is composed of many carbon atoms and very few hydrogen
atoms, and has properties very similar to diamond. I have measured the following
properties of the polymethylmethacrylate (PMMA) plates or IOLs coated with
diamond-like carbon film: light transmission curve, resistance against Nd:YAG
laser capsulotomy, peel-off test, and contact angle. The plates or lenses are
more ultraviolet-absorbing than uncoated PMMA plates, and PMMA plates coated with
50 nm-thick diamond-like carbon film have a light transmission curve very similar
to that of a 25-year-old human crystalline lens. The pits and cracks due to
Nd:YAG laser emission were smaller in the coated IOLs were more hydrophobic and
oleophilic than uncoated IOLs. Diamond-like carbon film coated IOLs are thought
to be very promising.
PMID- 9396230
TI - [Selective binding of fucose-recognizing lectin on the cone photoreceptor outer
segments].
AB - The distribution of fucose-containing glycoconjugates in the photoreceptor cell
layer of rat and human retinas was examined by lectin histochemistry using
Aleuria aurantia lectin (AAL), which recognizes L-fucose alpha 1, 6 residue. In
the rate retina, AAL diffusely bound to the apical outer segments and to the
basal inner segments, whereas it bound to the entire outer segments of other
photoreceptors, which were considered to be cones due to their proportion. In the
human retina, AAL bound diffusely to the basal inner segments and to the retinal
pigment epithelia, but it bound selectively to the outer segments of the cones.
The present findings revealed that the glycoconjugates, whose sugar chains
contain L-fucose alpha 1, 6 residue on their termini, are present in the cone
outer segments.
PMID- 9396229
TI - [Inhibition of experimental autoimmune uveoretinitis by transforming growth
factor-beta 1 in B10. A mice].
AB - Experimental autoimmune uveoretinitis (EAU) in mice, an organ specific autoimmune
disease, has been investigated as an animal model for human endogenous uveitis.
In this study, we report on the immunosuppressive effect of transforming growth
factor-beta 1 (TGF-beta 1) on the development of EAU in mice. Inhibition by TGF
beta 1 of proliferation of interphotoreceptor retinoid-binding protein (IRBP)
specific T cell lines in B10.A mice against IRBP antigen was dose-dependent.
However, when spleen cells used as the antigen presenting cell were first
cultured with TGF-beta 1, this anti-proliferation effect was abolished. When IRBP
immunized mice were injected intraperitoneally with TGF-beta 1, dose-dependent
suppression of EAU was obtained. The proliferation response of lymph node cells
from TGF-beta 1 injected mice with IRBP-induced EAU was suppressed compared with
phosphate buffered saline (PBS)-injected mice. These findings suggest that TGF
beta 1 may be a cytokine that plays a role in suppressing IRBP induced EAU in
mice.
PMID- 9396231
TI - [Results of vitreous surgery for proliferative vitreoretinopathy].
AB - During the past four years, we performed vitreous surgery on 73 eyes with
rhegmatogenous retinal detachments complicated with severe proliferative
vitreoretinopathy (PVR). We analyzed the surgical outcome of PVR according to the
revised classification of PVR Grade C (1991). After a mean follow-up period of 19
months, the retinas were successfully reattached in 62 of 73 eyes (85%). The
reattachment rate in the eyes with only posterior proliferation was high (96%),
regardless of the extent of posterior proliferation. However, the reattachment
rate in the eyes associated with anterior proliferation was markedly low (57%),
depending on the extent of anterior proliferation. Among 62 eyes with
successfully reattached retinas, 39 eyes (63%) had an improved postoperative
visual acuity. These results demonstrated that the eyes with anterior PVR have a
worse reattachment rate than the eyes with only posterior PVR. Using the revised
classification of PVR, we were able to analyze the surgical outcome of PVR which
could not be classified by the old classification.
PMID- 9396232
TI - [Long-term visual recovery after scleral buckling of macula-off retinal
detachments].
AB - We retrospectively investigated long-term visual recovery in 32 macular
reattached eyes which had been followed up for more than five years after
surgery. In 17 eyes (53%), the best-corrected visual acuity at 5 years after
surgery was > or = 2 lines better than best-corrected visual acuity at 3 months
postoperatively. For these 17 eyes, the mean visual acuity continued to improve
for up to 10 years after surgery. In the other 15 eyes, visual acuity changes
were within 1 line. Improvement of long-term postoperative visual acuity was
found to be statistically correlated with younger age, no or mild myopia (< -5D)
and shorter duration of macular detachment (< or = 30 days). Surgeons should be
aware that the visual function of reattached retinas may recover in the long
term, especially in eyes with these features.
PMID- 9396233
TI - [Immunohistochemical localization of MUC 1 and keratin 14 in the invasive regions
of malignant eyelid tumors].
AB - The distributional patterns of MUC 1 (the mucin whose cDNA was first cloned) and
Keratin 14 (K14) in the invasive regions of malignant eyelid tumors were
immunohistochemically examined by comparing with other histochemical markers. The
MUC 1-positive tumor cells were detected in several serial, small, invasive tumor
masses in the deep subepithelial region of the low differentiated carcinoma. They
were also continuously detected in the border region between accumulated
lymphocytes including T cells and tumor masses of the sebaceous carcinoma. On the
other hand, K14-positive tumor cells were detected in the marginal regions of
large tumor masses or those with smooth edges, some of which overlapped the
distribution of MUC 1-positive cells in the tissues of undifferentiated
carcinoma, squamous cell carcinoma, and sebaceous carcinoma. In general, MUC 1
may be expressed in the invasive tumor cells, whereas K14 may be expressed in the
marginal cells of the stable, proliferating tumor masses.
PMID- 9396234
TI - [The long-term cystic bleb appearance and safety after trabeculectomy with
mitomycin C].
AB - The clinical appearance of cystic blebs and the incidence of bleb infection were
retrospectively evaluated in 215 trabeculectomies with mitomycin C. The incidence
of cystic bleb formation in trabeculectomy was 79% (169/215). The cumulative
incidence of the cystic bleb survival when using the Kaplan-Meier method was 73%
in the 50th month after surgery. The incidence of large cystic bleb survival was
better than that of small and localized cystic blebs. There was statistically
significant difference. The incidence of cystic bleb survival without Seidel
phenomenon and bleb infection was 96% in the first year after surgery and 91% in
the third year. Bleb infections occurred in two of 169 eyes (1.2%). Bleb
infection was successfully treated and there were no cases of endophthalmitis.
The large cystic blebs had a higher incidence of bleb infection than the small
ones. In one of 25 eyes treated with antibiotic eye drops after surgery, the
Seidel test was positive and bleb infection occurred. The Seidel test was
positive in 5 of 96 eyes in which antibiotic eye drops were not used and bleb
infection occurred in one of these 5 eyes.
PMID- 9396235
TI - [Detection of cortical activities on eye movement using functional magnetic
resonance imaging].
AB - Cortical activity during eye movement was examined with functional magnetic
resonance imaging. Horizontal saccadic eye movements and smooth pursuit eye
movements were elicited in normal subjects. Activity in the frontal eye field was
found during both saccadic and smooth pursuit eye movements at the posterior
margin of the middle frontal gyrus and in parts of the precentral sulcus and
precentral gyrus bordering the middle frontal gyrus (Brodmann's areas 8, 6, and
9). In addition, activity in the parietal eye field was found in the deep, upper
margin of the angular gyrus and of the supramarginal gyrus (Brodmann's areas 39
and 40) during saccadic eye movement. Activity of V5 was found at the
intersection of the ascending limb of the inferior temporal sulcus and the
lateral occipital sulcus during smooth pursuit eye movement. Our results suggest
that functional magnetic resonance imaging is useful for detecting cortical
activity during eye movement.
PMID- 9396236
TI - [Effects of onpi-to (TJ-8117) and (-)epicatechin-3-O-gallate on the proliferating
changes in glomeruli of 5/6 nephrectomized rats].
AB - Onpi-to (TJ-8117) is a herbal medicine composed of five crude drugs (Rhei
Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti
Tuber). Our previous experiments have demonstrated that TJ-8117 suppressed the
development of glomerulosclerosis and retarded the deterioration of renal
function in 5/6 nephrectomised rats. In the present study, the effects of TJ-8117
and (-)Epicatechin-3-O-gallate (ECG), which is a component of Rhei Rhizoma, on
glomerular cell proliferation, extracellular matrix accumulation and glomerular
hypertrophy were investigated in 5/6 nephrectomized rats. Male Wistar rats (170
180 g) were subjected to 5/6 nephrectomy, and TJ-8117 (0.32%, 0.64%) or
angiotensin-converting enzyme inhibitor, captopril (CAP 0.08%) was administered
daily by mixing in normal chow and ECG (2 mg, 8 mg/100 ml) by drinking water from
the day after 5/6 nephrectomy. Following 5/6 nephrectomy, glomerular cell
poliferation was increased and reached a maximum at 1 week in the untreated
control rats, but was suppressed significantly at 1 and 2 weeks after treatment
with TJ-8117 and at only 1 week after treatment with CAP. Extracellular matrix
accumulation was detected after 1 week and increased gradually until 4 weeks in
the control rats, whereas it was significantly inhibited in both the TJ-8117- and
CAP-treated rats. In addition, immunohistochemistry revealed that TJ-8117
significantly inhibited the increase of fibronectin, and tended to reduce type I
and type IV collagen at 4 weeks. Furthermore, TJ-8117 suppressed glomerular
hypertrophy at 4 weeks. Systolic blood pressure (SBP) and urinary protein
excretion (UP) were higher in the control rats than sham-operated rats. TJ-8117
prevented this increase of SBP and UP at 1 week. ECG also suppressed glomerular
cell proliferation and the increase of SBP and UP at 1 week after 5/6
nephrectomy. These findings suggest that ECG was one of active components of TJ
8117. These results suggest that TJ-8117 suppressed proliferating changes in
glomeruli at an early stage in 5/6 nephrectomized rats, and inhibited the
development of glomerulosclerosis.
PMID- 9396237
TI - [Ouabain-containing Euro-Collins solution prevents ATN following renal cold
storage].
AB - In view of the hypothesis that suppression of energy demand may prevent ischemic
cell damage, it seemed possible that suppression of ATP utilization during
ischemia might ameliorate the severity of renal failure following kidney
preservation. To test this possibility, a short-term in situ kidney preservation
model was prepared in dogs. Euro-Collins solution containing 10(-5) M ouabain (O
EC) was used as the preservation solution. The kidney was preserved with cold O
EC for two hours and reperfused with auto blood. As the control, the kidney was
treated with Euro-Collins solution (EC) alone. Three hours after reperfusion,
recovery of creatinine clearance was 47.4 +/- 8.0% in the control and 71.6 +/-
14.0% in the O-EC group (p < 0.02). The increase in urinary excretion of N-acetyl
beta-D-glucosaminidase was significantly lower in the O-EC group. It was 21.3 +/-
4.5 nU/gr renal weight for three hours after reperfusion in the control group and
7.2 +/- 1.5 nU/gr renal weight in the O-EC group (p < 0.05). Fractional excretion
of sodium three hours after reperfusion was 1.42 +/- 0.44% and 5.51 +/- 0.63% in
the control and O-EC groups (p < 0.002), respectively. There were no significant
differences in renal blood flow, urine volume and urine osmolality between the
two groups. These results suggest that ouabain-containing EC was effective in
protecting the kidney, especially renal proximal tubular cell, against ischemic
damage.
PMID- 9396238
TI - [Influence for cultured renal cell growth ability by toxins of Escherichia coli].
AB - There have been many reports indicating that Escherichia coli from pyelonephritis
may exhibit several specific phenotypes. The purpose of the present study was to
examine the effects of various toxins from Escherichia coli on cultured renal
cell growth. alpha-hemolysin suppressed growth of Mardin Darby canine kidney
(MDCK) cells in a dose-dependent manner. A low dose of O-antigen suppressed MDCK
cell growth, while a high dose of the antigen increased the cell growth slightly.
K:1-antigen had no effect on MDCK cell growth. Mesangial cell growth was not
affected by alpha-hemolysin. A significant increase in mesangial cell growth was
recognized by the O- or K:1-antigen. From these results it can be speculated that
alpha-hemolysin from Escherichia coli may play a leading role, and O- or K
antigen may play a supporting role in the pathogenesis of pyelonephritis.
PMID- 9396239
TI - [Mechanism mediating hypertension induced by chronic inhibition of nitric oxide
synthesis].
AB - Although the inhibition of nitric oxide (NO) synthesis is known to induce
systemic hypertension, the underlying mechanisms mediating this type of
hypertension are incompletely understood. In the present study we investigated
the influence of sodium intake on the pressor effect of long-term administration
of the NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 16 mg/dl
in drinking fluid for 8 weeks), in conscious Sprague-Dawley rats. Urinary
excretion rates of catecholamine during NO synthesis inhibition were also
examined. Long-term administration of L-NAME produced a sustained elevation in
tail-cuff pressure without altering urine flow, or sodium excretion rate. L-NAME
induced hypertension was accompanied by a decreased urinary excretion of the
stable NO metabolites, NO2- and NO3-, and was aggravated when rats drank 0.9%
saline in place of tap water. Thus, inhibition of NO synthesis resulted in a
rightward shift of the pressure natriuresis relationship and a significant
decrease in the slope of this relationship. Urinary excretion of epinephrine and
norepinephrine, but not that of dopamine, in L-NAME-treated rats significantly
increased within the first week of the study when compared with those observed in
control rats. A natriuretic index of the sympathetic nervous system, the ratio of
dopamine to norepinephrine excretion, was significantly less in L-NAME-treated
rats than in control rats. After 8-week treatment with L-NAME, renal morphologic
evaluation revealed significant narrowing and obliteration of the arterioles. L
arginine (2 g/dl in drinking fluid) completely reversed the elevation of blood
pressure as well as the decrease in urinary NO2- and NO3- excretion and the
increased urinary excretion of catecholamines associated with L-NAME treatment
after 3 weeks of concomitant administration. These results suggest that the
inhibition of chronic NO synthesis produces sodium-sensitive hypertension and
that changes in sympathetic nerve activity may, at least in part, contribute to
the sodium sensitivity in this type of hypertension.
PMID- 9396240
TI - [Acquired resistance to acute renal failure in cisplatin-induced renal failure of
rats].
AB - Studies were performed to investigate whether prior cisplatin-induced acute renal
failure affords resistance to a second challenge with cisplatin in Sprague-Dawley
rats. Both the increase in serum creatinine and tubular damage following a
challenge with cisplatin (5 mg/kg, i. p.) were significantly less in rats which
had received cisplatin (3 mg/kg, i. p.) 14 days prior to the rechallenge compared
with the previously untreated animals. Attenuation of nephrotoxicity was more
obvious in the histological index than in the increase in serum creatinine, and
increase in serum creatinine concentration did not correlate with tubular
necrosis. There were fewer tubular cells that expressed proliferating cell
nuclear antigen in previously treated kidneys, suggesting that the enhanced
regeneration of tubular cells plays a minor role in the decrease of tubular
damage in kidneys recovering from prior acute renal failure. These findings
suggest that rats recovering from previous acute renal failure are resistant to a
second insult with cisplatin and that the attenuation of nephrotoxicity is more
prominent in histological damage than in functional disturbance.
PMID- 9396241
TI - [HLA-DQ region and TCR gene polymorphism associated with primary IgA nephropathy
in Japanese children].
AB - We have investigated associations between HLA-DQ beta and TCRC beta gene
polymorphisms and IgA nephropathy in Japanese children. DNA from 33 cases of IgA
nephropathy, 29 cases of nephrotic syndrome and 29 cases of healthy volunteers
were analyzed by Southern blotting using HLA-DQ beta and TCRC beta probes. A 2 kb
(Taq I) polymorphic band that hybridized to the DQ beta probe was predominant in
patients of IgA nephropathy (p < 0.05) compared to the controls. The 10 kb (Bgl
II) polymorphic band of TCRC beta was also predominantly present (but not
significantly) in the DNA of these patients. Proteinuria in IgA nephropathy
patients was found to be associated with this 10 kb TCR polymorphism. We conclude
that the HLA-DQ beta and TCR genes make major contributions to the genetic
pathogenesis of IgA nephropathy in Japanese children.
PMID- 9396242
TI - [Role of tumor necrosis factor-alpha in insulin sensitivity and effect of low
protein diet on the TNF-alpha response in patients with diabetic renal failure].
AB - In patients with diabetic renal failure, attention must be paid to the prevention
of atherosclerosis as well as the preservation of renal function. Insulin
resistance is one of the important risk-factors of atherosclerosis and the
involvement of tumor necrosis factor-alpha (TNF-alpha) has been shown in the
pathogenesis of insulin resistance in some diseases. A low-protein diet (LPD) is
recommended for patients with advanced renal disease, but a large proportion of
the total caloric intake is supplied from carbohydrates and fat in LPD.
Therefore, we designed a study to determine: (1) the effect of TNF-alpha on
insulin sensitivity, and (2) the effect of LPD on the TNF-alpha response and the
risk factors of atherosclerosis, such as insulin sensitivity and lipid
metabolism, in patients with diabetic renal failure. Insulin sensitivity was
measured by an euglycemic hyperinsulinemic clamp technique and serum TNF-alpha
level and in vitro release of TNF-alpha from peripheral blood mononuclear cells
(PBMCs) was measured in patients with diabetic renal failure. A significant
negative correlation was observed between lipopolysaccharide-stimulated TNF-alpha
release from PBMCs and insulin sensitivity (r = -0.58, p < 0.05). Secondly, risk
factors of atherosclerosis were measured before and two weeks after the
introduction of LPD in patients with diabetic renal failure. LPD did not have any
significant effect on insulin sensitivity, the production of TNF-alpha by PBMCs,
lipid metabolism and glucose metabolism. These results indicate that: (1) TNF
alpha derived from PBMCs might affect insulin sensitivity in patients with
diabetic renal failure, and (2) LPD does not have any significant effect on the
risk factors of atherosclerosis.
PMID- 9396243
TI - [Implications of obesity for target organ injuries and cardiovascular risk
factors in hypertensive subjects].
AB - The effects of obesity on target organ injuries and cardiovascular risk factors
were examined in hypertensive subjects. The subjects were 22 obese (OB-HT) and 54
nonobese (NO-HT) men with never-treated essential hypertension, and 37 obese (OB
NT) and 50 nonobese (NO-NT) normotensive men. In these 4 groups with the average
age of about 50 years, we evaluated serum lipids, glucose tolerance, and
hypertensive organ injuries in the heart, kidney, and optic fundus. Although the
fasting blood glucose levels were similar in the 4 groups, the area under the
blood glucose curve after 75 g glucose ingestion (NO-NT 15.6, OB-NT 17.5, NO-HT
15.8, OB-HT 17.6 x 10(3) mg/dl.min; p < 0.02) and the fast serum insulin level
(NO-NT 7.3, OB-NT 10.1, NO-HT 7.7, OB-HT 12.2 mU/l; p < 0.001) were increased in
obese men. In OB-HT, serum HDL-cholesterol was decreased (-11%, p < 0.05) and
triglycerides were increased (+ 58%, p < 0.01) comparing with NO-NT. The
incidence of electrocardiographic left ventricular hypertrophy was not
significantly different among the 4 groups, however, urinary albumin excretion
was increased in OB-HT (NO-NT 3.0, OB-NT 3.4, NO-HT 3.6, OB-HT 4.3 mg/g
creatinine; p < 0.05) and sclerotic lesions of the retinal arteries were observed
even in normotensive OB-NT. These data suggest that obesity unfavorably alters
lipid and glucose metabolism, and facilitates organ injuries such as
arteriosclerosis and renal dysfunction in hypertensive subjects.
PMID- 9396244
TI - [An elderly patient with purpura nephritis that appeared after extracorporeal
shock wave lithotripsy].
AB - We report a 63-year-old male patient with purpura nephritis, which appeared 7
days after extracorporeal shock wave lithotripsy (ESWL). He was referred to our
clinic because of a petechial rash on both lower extremities, pretibial edema and
massive proteinuria. Urinalysis showed proteinuria and hematuria and some hyaline
casts. A 24-hour urine sample contained 5.0 g of protein. Renal function on
admission was decreased: serum creatinine was 1.5 mg/dl and creatinine clearance,
21 ml/min. Immunoserological tests demonstrated an increase in serum IgA (424.3
mg/dl). A skin biopsy revealed leukocytoclastic vasculitis. A renal biopsy showed
endocapillary proliferation in a diffuse, but segmental fashion. However, no
crescent formation was seen. Immunofluorescence microscopy disclosed mesangial
staining for IgA and C3. Electron microscopy demonstrated severe injury to
endothelial and epithelial cells: detachment of endothelial and epithelial cells,
foot process effacement and macrophage infiltration. Electron-dense deposits were
observed in the subendothelial and paramesangial areas. Because renal function
was deteriorating rapidly, methylprednisolone pulse therapy and immunosuppressive
treatment were implemented. Treatment was effective and the patient's renal
function and proteinuria improved remarkably. The electron microscopic findings
in this case of purpura nephritis seemed to be more severe than usual, suggesting
that ESWL may aggravate glomerular damage.
PMID- 9396245
TI - [A case of systemic lupus erythematosus associated with minimal change nephrotic
syndrome].
AB - A case of systemic lupus erythematosus (SLE) associated with minimal change
nephrotic syndrome (MCNS) in a 25-year-old female is described. The patient
suddenly manifested butterfly rash and proteinuria was first pointed out on
March, 1994. On admission, her skin biopsy indicated SLE. Subsequently, she
developed nephrotic syndrome. Urinalysis showed heavy proteinuria (4.1 g/day),
with no other abnormalities in the urinary sediment. Immunological examination
revealed positive antinuclear antibody at a titer of 1:80 with a speckled
pattern. Anti-ssDNA and anti-SS-A antibodies were positive, but other antibodies
were negative. Serum complement (CH50) was within the normal range (30.5 U/ml).
The renal biopsy showed no apparent cellular proliferation or increase of
extracellular matrices in glomeruli by light microscopy. Slight deposition of
IgG, IgM, C3 and C1q was focally seen in the mesangium and capillary wall by
immunofluorescence. Electron microscopic examination revealed small and scattered
dense deposits in the mesangium, subepithelium and subendothelium, associated
with diffuse fusion of the foot processes of epithelial cells along the
glomerular basement membrane. According to the WHO classification, the
histological features were compatible with those of lupus nephritis (LN), class
Ib. The patient was treated with PREDNISOLONE, Mizorbine and Dilazep, resulting
in the disappearance of proteinuria and a normal serum level of total protein.
The association of LN and MCNS is very rare. We also investigated the
relationship between the intensity of proteinuria and histological types of 53
cases with LN examined in our laboratory. The cases with heavy proteinuria were
mostly classified as WHO-Class IV and Class V. We report here a case of LN
associated with MCNS and also review the literatures.
PMID- 9396246
TI - [A case of rapidly progressive IgA nephropathy with transient hypocomplementemia
at onset].
AB - We present a case of IgA nephropathy (IgAGN) which developed rapidly progressive
glomerulonephritis and showed marked clinical improvement with treatment. The
patient was a 7-year-old boy who initially presented with acute nephritic
syndrome with hypocomplementemia. Although the renal function improved with
normalization of the serum complement level, it deteriorated again progressively.
The first renal biopsy revealed cellular crescents in about 70 percent of 43
glomeruli. Immunofluorescent microscopy demonstrated deposits of IgA, C3 and IgG
in the mesangium; they were also deposited along the glomerular capillary walls.
He was treated with plasma exchange associated with hemodialysis and
methylprednisolone pulse therapy, followed by oral administration of
prednisolone, cyclophosphamide and warfarin. Renal function recovered to the
normal range about two months after the initiation of treatment. The second
biopsy demonstrated a marked decrease in histological activity. In this case,
transient hypocomplementemia at onset may indicate that acute glomerulonephritis
caused exacerbation of clinically silent IgAGN. Aggressive therapy may be
effective in patients with rapidly progressive IgAGN if treated at an early
stage.
PMID- 9396247
TI - [Selective transcatheter embolization for renal artery aneurysms: report of three
cases].
AB - Selective transcatheter embolization using an interlocking detachable coil (IDC)
or detachable balloon was performed in three patients with renal artery
aneurysms. All aneurysms were of the saccular type, located on segmental branches
of the renal artery. After the embolization procedures, the levels of LDH, GOT,
WBC and the body temperature were transitionally elevated in all patients.
Complete occlusion of the aneurysms were achieved in all cases. Good clinical
results were achieved in two of these patients without any renal dysfunction.
However, local infarction of ipsilateral renal parenchyma occurred in one patient
immediately after the embolization and a Tc-99m-DMSA renal scintigraphy study
suggested renal dysfunction after infarction, and the level of serum renin
activity was slightly elevated. Selective transcatheter embolization may
constitute an acceptable therapeutic approach for renal artery aneurysms because
beside avoiding surgery, it has a low risk of complications.
PMID- 9396248
TI - [Effects of a thromboxane-synthetase inhibitor in patients with chronic
persistent coughing and no airwayhyperresponsiveness].
AB - We studied the effects of the thromboxane-synthetase inhibitor ozagrel in 22
patients with chronic persistent coughing who did not have
airwayhyperresponsiveness. Treatment with ozagrel (400 mg/day for 2 weeks)
reduced coughing in 12 patients. Sputum from the patients in whom ozagrel was
effective had a higher percentage of lymphocytes and a lower percentage of
neutrophils than did sputum from those in whom ozagrel was not effective.
Furthermore, in the former group the capsaicin cough threshold increased but in
the latter it did not change consistently. These data indicate that thromboxane
A2 may contribute to coughing associated with lymphocytic airway inflammation.
PMID- 9396249
TI - [Relationship between exercise-induced hypoxemia and long-term survival in
patients with chronic obstructive pulmonary disease].
AB - In patients with chronic obstructive pulmonary disease (COPD), exercise-induced
hypoxemia (EIH) is an important limiting factor of exercise performance, but
there are very few reports of the prognostic value of EIH. We therefore examined
whether EIH is related to long-term outcome in patients with COPD. We gathered
data on survival of 77 patients with COPD who had undergone three-minute
incremental treadmill exercise tests between 1979 and 1988. A plastic catheter
was placed percutaneously into a brachial artery to measure arterial blood gases
at each stage of exercise. Expired gas was analyzed continuously during exercise
with a Respiromonitor RM-300 (Minato Medical Science). As an index of the
severity of EIH we used the delta PaO2/delta VO2 (mmHg/L/min), PaO2-slope.
Patients were assigned to two groups according to PaO2-slope, and actuarial
survival curves were plotted for the two groups. The survival data were analyzed
by generalized Wilcoxon analysis. Survival was significantly better in the group
with low PaO2-slopes (< 20 mmHg/L/min) than in the group with high PaO2-slopes (>
or = 20 mmHg/ L/min) (p = 0.0031). Also, among the patients in whom PaO2 during
exercise was less than 60 mmHg, there was a significant difference in survival
between those who received home oxygen therapy and those who did not. We conclude
that the degree of EIH can be used to predict survival in patients with COPD, and
that the degree of EIH should be considered when prescribing continuous home
oxygen therapy for these patients.
PMID- 9396250
TI - [Serum-soluble adhesion molecules in patients with idiopathic pulmonary fibrosis
and acute respiratory distress syndrome].
AB - We measured the concentrations of soluble adhesion molecules in serum obtained
from healthy volunteers and from patients with idiopathic pulmonary fibrosis
(IPF) and the acute respiratory distress syndrome (ARDS). The concentrations of
soluble intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion
molecule 1 (VCAM-1), E-selectin, and P-selectin were significantly higher in
serum from the patients than in serum from the healthy volunteers. In patients
with IPF, the concentration of soluble ICAM-1 in serum was inversely related to
the vital capacity (expressed as a percent of the predicted value). The
concentrations of L-selectin in serum from patients with ARDS were significantly
lower than those in serum from healthy volunteers and from patients with IPF.
These data suggest that serum-soluble adhesion molecules may be useful as markers
of disease activity, severity, and prognosis in ARDS and IPF.
PMID- 9396251
TI - [Effect of cessation of erythromycin therapy on diffuse panbronchiolitis].
AB - The effect of cessation of erythromycin (EM) therapy against diffuse
panbronchiolitis was studied. Nine cases were examined. After cessation of EM
therapy, the manifestations of disease were stable in five cases, but worsened in
the other four. In the former five, the period from the onset of disease until EM
therapy began was relatively short; when EM therapy was stopped the
manifestations of disease had almost completely disappeared and chest
roentgenography revealed resolution of diffuse, small, nodular opacities without
remarkable bronchiectasis. In contrast, in the latter four cases, the clinical
manifestations of disease did not disappear, and chest-roentgenographic evidence
of bronchiectasis was common before the cessation of EM therapy. In conclusion,
EM therapy for diffuse panbronchiolitis may be stopped if the clinical
manifestations of disease (especially purulent sputum) disappear, if diffuse,
nodular opacities resolve almost completely and if there is no evidence of
bronchiectasis.
PMID- 9396252
TI - [Age-related decline in forced expiratory volume in one second and forced vital
capacity based on a longitudinal observation of Japanese males].
AB - Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) of
243 healthy male Japanese workers were measured on as annual basis over seven
years, and their longitudinal decline was compared with the age coefficient of
cross-sectional prediction equations reported previously for Japanese adults. In
this study, a man, assumed to be 1.65 meter tall, was expected to have a
respective 22 ml and 11 ml decline annually in FEV1 and FVC. Age-related
differences of those indices obtained from cross-sectional prediction equations,
however, ranged from 22 ml to 31 ml a year in FEV1 and from 16 ml to 25 ml in FVC
for men of the same height. Furthermore, in those equations, age was simply
employed as a first-order explanatory variable for ages ranging from the later
teens to over sixties, although age-related acceleration of FVC decline is
suggested in this study. These results indicate that evaluations of measurements
relating to time-series pulmonary functions on cross-sectional prediction
equations might be biased. This is probably due to the influence of age-cohort.
It seems necessary to build up the reference standards for longitudinal pulmonary
function change for an appropriate evaluation of time-series data of FVC and
EFV1.
PMID- 9396253
TI - [Outcomes of noninvasive positive-pressure ventilation in patients with acute
hypercapnia complicating chronic respiratory failure].
AB - We used noninvasive positive-pressure ventilation to treat hypercapnea due to
acute exacerbations of chronic respiratory failure (21 episodes in 19 patients;
COPD, 4; pulmonary tuberculosis sequelae, 4; silicosis, 3; silicotuberculosis, 3;
bronchiectasis, 3; others, 2). All patients had acute onsets of severe
hypercapnea (PaCO2 > 45 Torr), acute decreases in pH (< 7.35), and tachypnea,
paradoxical breathing or both. During the first 2 to 4 hours of bi-level positive
airway pressure, PaCO2 decreased from 72 to 61 Torr (p < 0.0005), pH increased
from 7.26 to 7.31 (p < 0.001), and respiratory rate decreased from 30 to 25
breaths/min (p < 0.005). In three cases leakage of air through the mouth
prevented improvement in the patients' conditions, but in two of those a face
mask was then used successfully. In 17 of the 21 episodes (81%) gas exchange
improved and intubation was not necessary. In those 17, the mean duration of
noninvasive positive-pressure ventilation was 6.3 days. We conclude that
noninvasive positive-pressure ventilation can improve gas exchange in patients
with acute hypercapnea complicating chronic respiratory failure.
PMID- 9396254
TI - [Inflammatory bronchial polyps with a foreign body-like substance].
AB - A 68-year-old male complaining of hemosputum was admitted to our hospital.
Fiberoptic bronchoscopic examinations revealed bronchial polyps and a flat
foreign body-like substance in the left main bronchus. A closer inspection of a
biopsied bronchial inflammatory polyp showed inflammatory edema with
hypervascularization in the submucosal space and inflammatory cell infiltration.
Following complete removal of this foreign body-like substance, the polyps
disappeared within six weeks. It is therefore feasible to assume that the polyps
appeared as a reaction to this extrinsic substance. The origin of the foreign
matter is not obvious because the patient had no history of aspiration and
because the histological examination did not confirm that it was a foreign body.
The substance could have been formed out of the organization and calcification of
some secretes in the bronchus.
PMID- 9396255
TI - [Fulminant tracheobronchitis caused by methicillin-resistant Staphylococcus
aureus (MRSA)].
AB - A 56-year-old man was admitted to our hospital because of hemoptysis, and
dyspnea. Breathing sounds decreased and rhonchi was audible in the right lung.
Chest X-ray and Chest CT showed infiltrative shadows in the bilateral lower
lobes. He was intubated and bronchofiberscopy revealed mucosal necrosis and
hemorrhage of the lower trachea and the bilateral bronchi. MRSA was isolated from
sputum and bronchial lavage fluids. He was diagnosed as NTB caused by MRSA. On
the 7th day in hospital, he suffocated by the necrotic tissue and autopsy was
performed. NTB is a very uncommon disease in adults, especially ones who are not
under mechanical ventilation.
PMID- 9396256
TI - [Two cases of acetaminophen-induced pneumonitis].
AB - This paper deals with two patients with acetaminophen-induced pneumonitis. A 64
year-old woman suffered from mastitis while being treated by corticosteroid
therapy for phemphigoid. She was administered antibiotics and acetaminophen.
However, her fever continued and she subsequently developed dyspnea and
interstitial pneumonia. The other patient, a 70-year-old woman, was treated with
corticosteroid for lower motor neuron disease. Anti-GM1-IgM antibodies were
positive in her serum. She developed wet cough and mild fever. During treatment
with antibiotics and acetaminophen, her illness was complicated by dyspnea and
interstital pneumonia. As a result of histological findings of transbronchial
lung biopsy specimens showing interstitial infiltration of mononuclear cells, as
well as clinical courses in which cessation of acetaminophen directly lead to the
improvement of interstitial pneumonia, both patients were diagnosed to have
acetaminophen-induced pneumonitis. The peumonitis responded well to steroid
therapy. In vitro culture of peripheral lymphocytes showed stimulated
proliferation by acetaminophen in both patients. These findings suggest that
allergic mechanism was involved in the pathogenesis of the pneumonitis.
Underlying immunological disorders may have enhanced the occurrence. Although
acetaminophen is one of the most popular drugs because of a very low incidence of
side effects, this drug should be applied carefully, especially with patients who
have such immunological disorders.
PMID- 9396257
TI - [A case of Paragonimus Miyazaki with pleuritis and meningoencephalitis].
AB - A 35-year-old man was admitted to our hospital with fever and headache. Chest X
ray revealed right pleural effusion. Lab tests revealed increase of eosinophils
in his serum and pleural effusion. After admission he complained of doplopia and
neck stiffness. Lumber puncture revealed eosinophilia in the cerbrospinal fluid.
Brain CT and MRI showed characteristic images of meningoencephalitis. The patient
had eaten raw Potamon dehaani and the case was diagnosed as paragonimus miyazaki
after administration of intradermal reaction and Ouchterony's double diffusion
test. The patient was successfully treated with praziqantel. It revealed that the
pleural effusion and brain edema disappeared chest X-ray and brain MRI. This case
can be considered as a characteristic example of Paragonimus Miyazaki with
pleuritis and meningoencephalitis.
PMID- 9396258
TI - [A case of dyskeratosis congenita with acute interstitial pneumonia].
AB - This is a rare case of Dyskeratosis Congenita (DC) with acute interstitial
pneumonia. A 51-year-old man with DC was admitted to our hospital because of
cough, sputum and fever. Chest X-ray film showed ground glass opacities in all
lung fields for a while steroid's therapy proved effective, but about seven
months later the patient's condition became serious. Methylprednisolone,
cyclophosphamide and mechanical ventilation therapy were not effective. He died
and an autopsy was performed. The lung specimen showed Organizing Diffuse
Alveolar Damage, and some parts pointed to bacterial infection. But Pneumocystic
carinii pneumonia and Fungal infections were not found. It is therefore necessary
to conduct intensive examinations of lung involvement of patients with
Dyskeratosis Congenita.
PMID- 9396259
TI - [A case of chronic necrotizing pulmonary aspergillosis successfully treated with
combination therapy of antifungal drugs and ulinastatin].
AB - A 64-year-old woman with a history of old tuberculosis, had a fungus ball shadow
with meniscus sign in the upper right lung field on a chest X-ray film in 1991.
Based on the chest X-ray findings, pulmonary aspergilloma was suspected. Because
the size of the intracavitary fungus ball increased, the patient was treated with
itraconazole over one year in 1995, but there was no improvement. One month
later, she was admitted because of fever, hemoptysis and productive cough, and
chest X-ray showed an enlargement of intracavitary mass and infiltrative shadow
in the right lung. Chronic necrotizing aspergillosis was diagnosed on the basis
of her clinical and radiographic features, and positive serological test.
Although itraconazol and amphotericin B were given, cavity and intracavitary
fungus ball shadow kept growing. Combination therapy of antifungal drugs and
ulinastatin markedly improved symptoms and resulted in complete disappearance of
the fungus ball on chest CT scan.
PMID- 9396260
TI - [A case of malignant mesothelioma of the pleura and the peritoneum detected by
sudden onset of back pain and pleural effusion and ascites].
AB - A case of malignant mesothelioma of the pleura and the peritoneum is reported. In
April 1996, a 40-year-old men noticed sudden onset of back pain. Radiographic
examinations and MRI revealed pleural effusions, ascites, ringed enhanced
tumorous lesions in the right posterior diaphragm along the abdominal aorta, and
marked thickening of the right diaphragm with moderate signal intensity. On
thoracoscopic surgery, there were white small nodules on the intercostal parietal
pleura. Tumor cells of a tubulopapillary pattern had large rounded nuclei and
eosinophilic cytoplasms in a partially glandlike arrangement. Cytoplasms of tumor
cells stained for alcian blue disappeared after hyaluronidase digestion.
Immunohistochemical examinations showed positive staining for keratin but
negative for CEA. Electron micrographs showed numerous long thin microvilli,
desmosomes and intermediate tonofilaments. From these findings, malignant
mesothelioma was diagnosed. The malignant mesothelioma cells of the pleura in
this case were considered to disseminate the peritoneum directly through the
diaphragm or its lymphatic canals. MRI and thoracoscopic surgery were useful for
the demonstration of the pleural disseminations and abdominal invasions.
PMID- 9396261
TI - [A case of thymic cyst differentiated from cardiac cyst with immunostaining].
AB - This is a case of a 70-year-old woman with thymic cyst which was found by chance
on admission for treatment of acute bronchial asthma and diagnosed by
pathological examination. After remission of the asthma she was asymptomatic and
no pathological physical findings were found except of cervical thyroid tumor of
adenomatous goiter. Chest X-ray films revealed a large mediastinal mass with a
sharp margin at the right cardiophrenic angle. Chest CT and MRI revealed that it
occupied a space from upper anterior mediastinum to right cardiophrenic angle,
and that it showed low density area without enhancement, suggesting a mediastinal
cyst. A multilocular cyst, 15 cm in diameter, containing serous liquid was
excised using thoracotomy. Pathological and immunohistochemical examination of
the cyst revealed that its inner surface was lined with benign cylindrical
epithelium and that thymic tissues existed in the walls of the cyst, resulting in
a thymic cyst. The thymic cyst, of which reports have increased, should be
considered in the differential diagnosis of anterior mediastinal cysts.
PMID- 9396262
TI - [Long-term survival after multimodal therapy for lung cancer with pleural
dissemination].
AB - A 56-year-old man with peripheral T1N0M0 lung cancer underwent thoracotomy.
Pleural dissemination was recognized intraoperatively. We performed wedge
resection of the lung including the primary tumor, and applied hypotonic
cisplatin treatment. We followed this up postoperatively with chemotherapy
combined with cisplatin and irinotecan. One year later, a recurrent tumor
occurred at the resected end of the lung, so we conducted stereotactic
radiosurgery on the recurrent lung lesion, resulting in complete eradication. One
year later, no relapse of cancer was observed. We conclude that implementing
hypotonic cisplatin treatment in pleural dissemination of lung cancer followed by
stereotactic radiosurgery on any recurrent tumor in the peripheral lung was
effective for the present case.
PMID- 9396263
TI - [A case of tuberculous abscess in the chest wall close to the thickening pleural
lesion following tuberculous pleuritis].
AB - A 33-year-old woman with a history of right tuberculous pleuritis was
successfully treated in December 1992 by administration of anti-tuberculous
drugs, she demonstrated residual localized pleural thickening on chest computed
tomography (CT) and gradually developed a subcutaneous mass in the right chest
which became apparent in March 1993. In September, chest CT revealed a
periocostal abscess in the right anterior chest wall close to the localized
pleural thickening. The patient was diagnosed with tuberculous abscess in the
right chest wall on confirmation of acid-fast bacilli in a needle aspiration
material of the abscess, and was referred to our hospital. Anti-tuberculous
chemotherapy was continued but the chest abscess grew, so on January 28, 1994 she
underwent a resection of the abscess, the third costal cartilage and bone, and
the parietal pleural lesion connected to the abscess. Histopathological
examination showed that the abscess and parietal pleural lesion were compatible
with tuberculosis, i.e. both lesions consisted of caseous necrosis and epitheloid
cell granuloma, but acid-fast bacilli were not demonstrated in both lesions.
After one year of postoperative anti-tuberculous chemotherapy, she was followed
without any therapy for 3 years and there has been no recurrence to date. When a
localized thickening pleural lesion remains after tuberculous pleuritis,
complication of tuberculous abscess in the chest wall should be considered.
PMID- 9396264
TI - [A case of primary mediastinal choriocarcinoma].
AB - A 27-year-old man with primary mediastinal choriocarcinoma was reported. He was
admitted with complaint of right chest pain and dyspnea. Chest X-ray film and
computed tomography of the chest revealed a bulky mass at anterior mediastinum
and right pleural effusion. Physical examination revealed bilateral gynecomastia,
and the serum beta-HCG level was cap at 500 ng/ml. The specimens obtained by
percutaneous needle biopsy of the mediastinal mass showed cytotrophoblasts and
syncytiotrophoblasts. He received 4 cycles of anti-cancer chemotherapy, and
underwent resection for a residual mass, in which viable cancer cells remained in
histological examination. In spite of additional chemotherapy, multiple lung
metastasis developed rapidly. High dose chemotherapy, with carboplatine (200
mg/m2 x 4 days), etoposide (250 mg/m2 x 4 days) and cyclophosphamide (50 mg/kg x
2 days) was performed in combination with peripheral blood stem cell
autotransplantation. However, brain metastasis set in and he died of respiratory
failure 9 months after the onset of symptoms.
PMID- 9396265
TI - [Resection of multiple thymoma: a case report].
AB - A 74-year-old male, who had been treated for hypertension at the out-patient
clinic, was admitted to our hospital because of an abnormal shadow on a chest
radiograph. After diagnosis of thymoma by needle biopsy surgery was carried out
on July 6, 1995, when an extended thymectomy along with removal of the entire
tumor was done. During the surgery it was noticed that there was not one, but two
independent tumors located in the anterior mediastinum, the upper left portion
was growing from the level of the crania to the left brachiocephalic vein,
whereas the lower right portion was growing towards the right thoracic cavity in
front of the pericardium. Both tumors were encapsulated firmly, and connected to
each other by scantly loose connective tissues. There was no continuity or
sarring between the two tumors. Histologically both were diagnosed to be
lymphocytic thymoma. We believe that this case is a good example of multiple
thymomas and provides evidence of the potential multicentricity of thymoma. It is
possible that extended thymectomy may be seeded for a complete resection of
thymomas.
PMID- 9396266
TI - [Pulmonary sequestration associated with high levels of tumor markers in serum].
AB - A 20-year-old woman was admitted to our hospital because of an abnormal shadow on
a chest X-ray film. Laboratory tests done on admission showed high levels of
tumor markers in serum. A computed-tomographic scan of the chest showed a
multilocular cystic mass in the S10 of the right lung. Angiography revealed an
abnormal artery that branched from the abdominal aorta, and therefore pulmonary
sequestration was diagnosed. A right lower lobectomy was done. Analysis of fluid
from the cyst revealed very high levels of CA19-9, CEA, and SLX. In an
immunohistochemical study, epithelial cells of the cyst's walls were stained for
CA19-9, CEA, and SLX. After the operation the levels of these tumor markers in
serum were almost normal.
PMID- 9396268
TI - [Sexual disorder in men].
PMID- 9396267
TI - [Abnormal female reproductive function].
PMID- 9396269
TI - [The genes in the molecular cascade of the mammalian sexual development].
AB - The sex of an individual is established as a consequence of molecular events that
occur in the complex genetic cascade. During sexual development, morphological
changes are closely associated with the action of genes expression of which is
tightly regulated according to the genetic program. Recently, a number of genes
that are involved in this process have been isolated. WT-1 and SF-1 are required
for the early formation of the gonadal primordium. SRY is the switch to start the
male sexual differentiation by triggering the Sertoli cell lineage. An autosomal
gene SOX9, which can cause the sex reversal, might also be involved in the male
sex determination. SF-1 is a key factor for the male sexual differentiation,
regulating the expression of MIS and the synthesis of testosterone in the fetal
testis. DAX1 might be responsible for the female sexual development. The mutation
or abnormal expression of these regulatory genes and their downstream genes can
cause a variety types of the sex reversal and/or malformation of the gonad and
the internal and external genitalia.
PMID- 9396270
TI - [Organization and regulation of spermatogenesis].
AB - We briefly overview the process as well as hormonal and paracrine regulation of
spermatogenesis. Initiation of sperm production occurs under stimulation by FSH
and LH. Spermatogenesis can be maintained by testosterone alone at least
qualitatively. Stimulatory function of gonadotropic hormones can be modified or
modulated on the basis of the local environment present in the testis. Sertoli
cells create the blood-testis barrier modulating the entry of substances into the
seminiferous tubules. Sertoli cells play the main role in paracrine regulation of
spermatogenesis by providing factors required for the development of germ cells.
Substances regulating spermatogenesis as paracrine factors in the testis are
summarized.
PMID- 9396271
TI - [Folliculogenesis and regulating factors].
AB - Folliculogenesis and steroid production are the bases of fertility in the female
mammal. Follicle stimulating hormones (FSH) plays an essential role in this
process. It is clear that a variety of ovarian autocrine and paracrine factors
can regulate this FSH receptor signal. In the past decade, it is established that
growth factors, particularly insulin like growth factor and insulin like growth
factor binding protein can modulate FSH receptor signal directly or indirectly.
In addition to the folliculogenesis, it is possible that growth factors play a
key role in follicle selection and atresia. With increased understanding of the
intraovarian regulators in folliculogenesis, it becomes clear that several other
autocrine paracrine factors may exist in intraovarian regulation of
folliculogenesis, including steroid hormones, cytokines, inhibin, activin.
PMID- 9396272
TI - [Mechanism on onset of secondary sexual characteristics in the female].
AB - Adrenal androgens begin to increase approximately 2 years before the increase in
gonadotropin secretion. This contributes to the growth of pubic hair. The
development of the breast is primarily under the control of estrogens by the
ovary. Reactivation of hypothalamic LHRH pulse generator is the most important in
the onset of puberty. This reactivation initially occurs during sleep, followed
by sleep-associated LH release and the increase of estradiol during daytime
hours. Thereafter, the secretion of gonadotropin and estradiol increases through
puberty and the positive action of estradiol on gonadotropin release is
established in the middle to late puberty. Recently, growth hormone has been
suggested to excert direct ovarian actions and may be involved in onset of
secondary sexual characteristics.
PMID- 9396273
TI - [Endocrinological mechanism of puberty in men].
AB - Puberty is a developmental stage during which endocrinological, physical and
psycho-social changes proceed. During prepubertal period, hypothalamic-pituitary
gonadal axis is maintained in an inactive state by negative feedback regulation
or inhibitory function of central nervous system. The onset of puberty and sexual
maturation are gained by the alternation of these inhibitory system. In recent
years, highly sensitive techniques for evaluating the hormones of hypothalamic
pituitary-gonadal system have been developed. And many explorations of the
hormonal mechanisms of puberty have been achieved. In this chapter, hormonal
changes in puberty is reviewed, and mechanism of puberty in men is discussed.
PMID- 9396274
TI - [The regulation mechanism of the female menstrual cycle].
AB - The hormonal patterns during menstrual cycle, which consist of cyclic alterations
in gonadotropins, estradiol, and progesterone, are controlled by hypothalamic
pituitary-ovarian feedback mechanism. GnRH produced in hypothalamus acts on the
pituitary cells to secrete FSH and LH, which stimulate the follicular
development. The developed follicles secrete estradiol, progesterone, inhibin,
activin, and follistatin. Estradiol and progesterone, at different concentrations
and/or ratios, either positively or negatively control the feedback of
hypothalamic-pituitary axis in regulating the secretion of GnRH, FSH and LH.
Inhibin and follistatin selectively suppress, whereas activin enhances the
secretion of FSH in the pituitary. Recently, various additional factors produced
by the ovary have been identified to contribute to the follicular development by
paracrine and/or autocrine regulation as well as to feedback on hypothalamic
pituitary unit.
PMID- 9396275
TI - [Regulation of male sexual function].
AB - MECHANISM OF ERECTION: Commands transmitted from the brain to the spinal cord
during audiovisual sexual stimulation and sexual fantasy cause excitation of the
central erection-related nerves of the spinal cord, which transmit the commands
to the corpora cavernosa. As a result, the following sequence of phenomena takes
place: 1) The cavernosal and helical arterioles dilate and the volume of blood in
the lacunar spaces increases. 2) The cavernosal smooth muscle relaxes and the
vascular lacunae expand. 3) Extension of the lacunar spaces causes compression of
the veins below the albuginea corpora cavernosa of the penis. MECHANISM OF
EJACULATION: The mechanism of ejaculation can be divided broadly into two stages.
In the first stage, seminal emission to the posterior urethra and closure of the
internal urethral opening are occurred by stimulation of the hypogastric nerve.
The second stage of ejaculation, which is projectile ejaculation of the semen
from the posterior urethra, occur as the result of a spinal reflex via the
pudendal nerve. For this sequence of events to occur, simultaneous stimulation
from the hypogastric nerve is required.
PMID- 9396276
TI - [Regulation of gonadotropin secretion].
AB - Physiological gonadotropin levels are modulated by complex relationships between
sex steroids and the hypothalamic gonadotropin-releasing hormone (GnRH) pulses.
The frequency and amplitude of GnRH secretion provide signals for the
differential regulation of LH and FSH secretion. At higher GnRH pulse
frequencies, LH secretion increases more than FSH secretion, whereas, at lower
frequencies, FSH secretion is favored. Gonadotropin secretion and subunit gene
expression are regulated by sex steroids acting either directly at the pituitary
level or indirectly by alteration of GnRH pulses from the hypothalamus. And sex
steroids have positive or negative actions, depending on the model system and
physiological state. Three gonadally derived peptides, inhibin, activin, and
follistatin have been isolated and shown to have specific effects on FSH gene
expression. Although gonadotropin regulation and reproductive function have not
been fully determined, current molecular technologies will probably identify
additional targets of sex steroids and GnRH action and allow greater insight.
PMID- 9396277
TI - [Androgen--biosynthesis, receptor and action].
AB - Androgens play a key role in promoting normal sex differentiation and
development, pubertal masculinization, initiation of spermatogenesis, and
maintenance of male sexual function. In addition to these classical function,
androgens are significantly associated with cell differentiation, proliferation
as well as carcinogenesis. The function of androgens can be mediated by the
androgen receptor (AR), which transduces the steroid signal within cells. AR
belongs to the superfamily of nuclear receptors that employ complex genetic
mechanisms to control the development and physiological functions of target
tissues. AR activates or represses gene transcription through association with
specific DNA elements and/or proteins. Moreover, molecular investigations of AR
gene structure have provided new insights towards defining a genetic basis for
the relationship between the diseased conditions and androgen action. Recent data
on androgen biosynthesis, action of androgens and molecular genetic analysis of
gene structure have led to a new understanding of the pathology in affected men.
This review summarizes briefly our current view of androgen action with a special
emphasis on the alterations of AR.
PMID- 9396278
TI - [Estrogen, progesterone--biosynthesis, receptor and action].
AB - Ovarian sex steroid hormones, estrogen and progesterone, have crucial effects on
female reproductive functions such as the development and maturation of
reproductive organs and the appearance of normal menstrual cycles. The precursor
of steroid hormones is a cholesterol that is synthesized de novo from acetate or
that is taken in as LDL-cholesterol via LDL-receptor. Members of cytochrome P450
superfamily and hydroxysteroid dehydrogenase (HSD) involved in the biosynthesis
of the steroid hormones. In the corpus luteum, P450scc and 3 beta-HSD catalyze
the pathway from cholesterol to progesterone and in the granulosa cells, P450arom
(aromatase) and two HSDs catalyze the biosynthesis of estrogen from C19 steroid
synthesized in the theca cells having P450(17) alpha. In the target cell, steroid
binds to and activates its receptor located primarily in the nucleus. Binding of
ligand results in dimerization of the receptor due to its conformational change.
The steroid-receptor complex binds to specific hormone responsive element of the
target gene at the site of DNA binding region and then activates transcription of
the gene. Main action of estrogen is to stimulate the proliferation and
development of cells due to enhancement of the synthesis of specific DNAs and
proteins in the female reproductive organs. Progesterone regulates the action of
estrogen through the decrease of estrogen receptor and down regulation of its own
receptor.
PMID- 9396279
TI - [Physiology and action of prolactin].
AB - Prolactin (PRL) is a peptide hormone secreted by the lactotroph of the anterior
pituitary. Secretion of PRL is regulated negatively by hypothalamic hormone.
Dopamine is the major physiologic prolactin inhibiting factor (PIF). PRFs as TRH,
VIP and oxytosin have prolactin releasing activity. Prolactin secretion is
induced by sleep, stress, sexual intercourse and suckling stimulus. Serum level
of PRL is increased by estrogen. Therefore, PRL level is higher in women,
especially in the late follicular phase and during pregnancy. Lactation is the
major biologic function of PRL in humans and essential to reproduction. Other
function of PRL, such as regulation of ovarian function, osmoregulation and
immunoregulation is not fully established. Many action of PRL remained to be
clarified.
PMID- 9396280
TI - [Abnormal female reproductive function].
AB - Sex differentiation may be seen as a sequence of gonadal determination, gonadal
differentiation, genital differentiation. Malfunction of this causes abnormal
female reproductive function. SRY (sex-determining region Y) has been show to
induce testis which is needed to bring about development of the other male sex
organs. Absence or point or frame shift mutation in the SRY causes XY females.
Secondary sex determination depends on testosterone produced by Leydig cells.
Testicular feminization syndrome typically lack the normal androgen receptor
protein and therefore, they are distinctly female phenotype. Rokitansky syndrome
is a type of aplasia vaginae and is a malformation of the Mullerian duct. They
all present primary amenorrhea. Secondary amenorrhea is a common type of abnormal
female reproductive function and differential diagnosis depends on hormonal
analysis. One of the topics includes polycystic ovarian syndrome which is
recently treated by laparoscopic surgery.
PMID- 9396281
TI - [Definition and classification of sexual disorder--in men].
AB - Sexual disorders include the disorder of sexual differntiation and male
infertility and sexual dysfunction. Sex determination is concerned with the
control of the development of the primary and or gonadal sex, sex differentiation
encompasses the events subsequent to gonadal organogenesis. Classification of
anomalous sexual development are recognized as disorders of gonadal
differentiation, female pseudhermaphroditism, male pseudhermaphroditism and
unclassified form. Upon completion of a history and physical examination and
evaluation of semen parameters, the male infertility can usually classified into
one of nine categories: azoospermia, ejaculatory dysfunction, varicocele,
gonadotoxins, antisperm antibodies, infections, endocrinopathy, idiopathic
infertility, or miscellaneous. Erectile dysfunction (ED) is classified into two
categories: functional ED and organic ED. Vascular, neurological and
endocrinological disorders are recognized as organic causes of ED.
PMID- 9396282
TI - [Virilization syndrome and hirsutism].
AB - Severe virilization syndrome is seen in testosterone-producing ovarian or adrenal
tumor while symptom in late-onset congenital adrenal hyperplasia (CAH) are
usually mild hirsutism and amenorrhea. We determined the serum levels of 17 alpha
hydroxy pregnenolone (17P5) and 17 alpha-hydroxyprogesterone (17P4) 60 min after
the intravenous injection of 250 micrograms of ACTH in 10 normal Japanese females
with age ranging from 18 to 29 years old. In this test, 1 mg of dexamethasone had
been administered orally at 11 p.m. on the previous day to suppress the effect of
endogenous ACTH. The ratio of 17P5 to 17P4 was 10.0 +/- 3.6 (mean +/- SD). Five
females with hirsutism of no ovarian origin showed normal responses to this rapid
ACTH test, suggesting that the incidence of the late-onset CAH is not so high as
reported previously.
PMID- 9396283
TI - [Feminizing syndrome and gynecomastia in males].
AB - Gynecomastia is one of the common symptoms of feminizing syndrome in males.
Causes of feminizing syndrome are considered the increase of serum level of
estrogen, prolactin, LH and hCG and testosterone deficiency. The condition of
gynecomastia was commonly silent. Gynecomastia is classified three groups those
are physiological, pathological and ideopathic gynecomastia. Physiological
gynecomastia was reported to break out healthy males. Ideopathic gynecomastia is
the main cause in medicine. Characterization of pathological gynecomastia are
known side effect of drugs, testosterone deficiency and increased estrogen
production. Gynecomastia is making satisfactory progress by treatment of the
causes, but long term of the history merely have need resection.
PMID- 9396284
TI - [Sexual precocity].
AB - Sexual precocity results from both GnRH-dependent and GnRH-independent
mechanisms. The GnRH-dependent forms of precocious puberty can be treated
effectively with long-acting agonist analogues of GnRH. However, for some
children who have a poor growth rate during the analogue therapy, an additional
growth hormone therapy should be considered to get them near to their normal
final height. The analogue treatment could be continued until a bone age of 13 or
more. The GnRH-independent forms of precocious puberty have unique mechanisms and
unknown pathophysiology. For instance, even though it is known that
testotoxicosis and McCune Albright syndrome are caused by the molecular mechanism
disorders, further elucidation of their etiologic basis of sexual precocity is
needed. Thus being, in treating the GnRH-independent forms they should be
assessed for each particular disorder.
PMID- 9396285
TI - [Gonadal dysfunction].
AB - Function of hypothalamic-pituitary-ovarian axis is an essential factor for the
maintenance of regular cycles in mature women. The disturbance of function of
those organs causes gonadal dysfunction such as anovulation, amenorrhea and
menstrual disorders. Therefore, the correct diagnosis for the assessment of CNS
and ovarian function is clinically important to treat the patients those who have
an menstrual disorders. In this review, the mechanism of normal gonadal cycles
and the diagnostic method and the treatment of gonadal dysfunction are described.
PMID- 9396286
TI - [Male sexual insufficiency].
AB - There are patients who complaint the loss of sexual desire, loss of erection,
absence of emission, absence of orgasm, and premature ejaculation. When the
primary disturbance is in the producing or releasing process of testosterone in
the testis, it increases the gonadotropic stimulation and results in the
hypergonadotropic hypogonadism. Hypogonadotropic hypogonadism, in contrast,
suggests that the disturbance in the hypophysis or hypothalamus. Patients who
have the primary disturbance in the hypothalamus sometimes do not respond to
LHRH, but repeated pulsatile LHRH stimulation induces the response. LH
testosterone is known to be the main axis of sexual function. However, growth
hormone (GH) also has an important role. GH is necessary for adults, not only for
children. Its deficiency arises easy fatiguability, loss of sexual desire, loss
of erection, and oligo- or azoospermia. Erectile dysfunction is frequently caused
by vascular, neurological and psychosomatic disorders. A variety of drugs are
known to cause male sexual insufficiency. Many environmental factors and stress
may affect the release of LH and GH, and therefore disturb the male sexual
function.
PMID- 9396287
TI - [Galactorrhea].
AB - Galactorrhea syndromes are mainly caused by hyperprolactinemia, which has been
defined by the basal prolactin level more than 15 ng/ml. However,
normoprolactinemia can not be proved only by the basal prolactin level less than
15 ng/ml, which required the assessment of prolactin secreting capacity. Occulted
hyperprolactinemia has be well known as the same syndrome as hyperprolactinemia,
which shows basal prolactin level less than 15 ng/ml and the exceed response of
prolactin to prolactin secreting stimulation like as thyroid releasing hormone.
Women with occulted hyperprolactinemiais show temporary and intermitted
hyperprolactincmia responding to a lot of atimulous states like as stress, sleep
or elevated E2 level, which resulted in galactrrhea, menstrual disturbances or
infertility. The elevated prolactin not only suppress the pituitary ganadotropin
secretion, but also disturb follicular development and luteal function in the
ovary. Dopamine agonists, bromocriptine and teruguride an usually indicate in the
treatment of hyperptolactinemia and have brought the good results.
PMID- 9396288
TI - [Male pseudohermaphroditism].
AB - Male pseudohermaphroditism is a condition of sex differentiation disorders in
which the gonads are tests, but the genital ducts and/or external genitalia are
incompletely masculinized. This syndrome is caused by a failure of the sequential
process in embryonal development of the testis. In the presence of functioning
testis the Mullerian ducts regress, while the mesonephric ducts and urogenital
sinus differentiate into the internal and external male genitalia. Male
pseudohermaphroditism is classified to subtypes according to etiological factors:
(1) testicular unresponsiveness to hCG and LH; (2) defect in testosterone
biosynthesis; (3) end-organ resistance to androgen; (4) defects in the
intracellular metabolism of testosterone; (5) aberrations in testicular
organogenesis; (6) defects in anti-Mullerian hormone.
PMID- 9396289
TI - [Female pseudohermaphroditism].
AB - Patients with female pseudohermaphroditism have female internal genitalia and
karyotype (XX) and various degree of external genitalia virilization. External
genitalia is musculinized congenitally when female fetus is exposed to excess
androgenic environment. Congenital adrenal hyperplasia (CAH), mostly 21
hydroxylase deficiency, is the most common cause. Maternal androgen excess due to
maternal ovarian tumor or drug intake also causes female pseudohermaphroditism.
Combination of hormonal therapy and surgical correction is required for CAH. When
appropriate treatments were given, normal puberty, fertility and child bearing
are possible. HLA typing in patient's family is useful for identifying
heterozygote and homozygote, because of close linkage of 21-hydroxylase gene and
HLA gene. Prenatal diagnosis and genetic diagnosis for female
pseudohermaphroditism due to 21-hydroxylase deficiency can be performed, however
prenatal treatment is not completely established.
PMID- 9396290
TI - [Male sterility].
AB - Recently several studies have suggested a decline in the quality of semen. About
half of the infertile causes are in men, the rate is increasing in the infertile
couples. There are some therapy for the male sterility; medication, surgery or
assisted reproductive technology (ART). Medicinal effects are not expected, and
surgical cases are localized for indication. Moreover, since most of male
sterility are idiopathic insufficiency of spermatogenesis, a recent tendency in
the male sterile therapy is ART such as IVF-ET, ICSI, TESE, etc.
PMID- 9396291
TI - [Female sterility].
AB - Recent progress in female sterility of Japanese women is reported in this study.
The causes of sterility in the female side, the most popular sterile factor is a
tubal factor due to the increase of the endometriosis and pelvic inflammatory
disease. The main treatment of the tubal factor is an IVF-ET technique. The
ovulatory disturbances occupy the second position of the female sterile factor.
The precise endocrinological examinations must be done for the diagnosis of the
ovulatory disturbances. In case of the hypergonadotropic hypogonadism, the
ovulation induction is almost impossible. Generally, clomiphene citrate is used
for moderate hypothalamic anovulations, and bromocriptine or terguride is for
prolactin related diseases (hyperprolactinemia, occult hyperprolactinemia,
galactorrhea) and endocrinological PCO (LH/FSH > 1) in the beginning. If these
treatments are not effective, hMG-hCG therapy will be performed. During hMG-hCG
therapy, we must take care for the occurrence of the ovarian hyperstimulation
syndrome. For the treatment toward the cervical factor, the artificial
insemination with husband semen will be done, however, if it is not effective,
IVF-ET must be performed. For the uterine factor (such as after hysterectomy
state, adhesion of uterine cavity, etc.) surrogate mothers are hired in some
foreign countries, however, it is prohibited in Japan. If patients have anti
phospholipid antibodies, low dose aspirin and/or heparin administration will be
done for the treatment of infertility. Recently, the assisted reproductive
technology (ART) have made much progress. IVF-ET is performed widely in Japan.
Cryopreservation of the fertilized ovum and intracytoplasmic sperm injection
(ICSI) are also performed. However, the legal and ethical problems are occurring,
and much discussion must be done for the acceptance of such new technologies.
PMID- 9396292
TI - [Erectile dysfunction].
PMID- 9396293
TI - [Idiopathic delayed puberty--female].
AB - The developmental changes during puberty occur over a period of 3 to 5 years,
usually between ages 9 and 14. The age of onset of puberty is influenced by
genetic and environmental factors. Delayed puberty is a rare condition in girls,
and a genetic problem or hypothalamic-pituitary-ovarian disorder can be
suspected. In addition, anatomic abnormalities of the uterus and ovaries are rare
but important factors to consider. The history and physical examination are
useful in the diagnostic work-up. Pelvic examination and U.S. should be
completed. Also, hormonal analysis should be recommended with diagnostic plan.
Although, the possibility of rare diagnoses should always be kept in mind.
PMID- 9396294
TI - [Constitutional delay of growth and puberty in male].
AB - Constitutional delay of growth and puberty (CDGP), featuring short stature,
delayed puberty and delayed bone age, is the most common condition in pediatric
endocrine clinic and becomes an important differential diagnosis in boys with
short stature. The conventional management is to assure eventual development of
puberty and normal final stature. Treatment with androgens to induce secondary
sex characteristics is given only when the boy is under psychosocial stress.
Recent reports revealed poor final height outcomes. The results of growth hormone
treatment in idiopathic short stature, including CDGP, has not been successful.
New findings showed that adults with a history of delay puberty had significant
osteopenia and may have a risk of fracture, and that suppression of spinal growth
was closely related to pubertal delay, leading to short stature. These two facts
suggest the necessity of induction of puberty in normal timing.
PMID- 9396295
TI - [Familial male-limited precocious puberty].
AB - Familial male-limited precocious puberty (FMPP) is a gonadotropin-independent
disorder that is inherited in an autosomal dominant, male-limited pattern.
Affected males generally exhibit signs of puberty by the age of 4 years.
Testosterone production and Leydig cell hyperplasia occur autonomously in context
of prepubertal levels of luteinizing hormone (LH). The LH receptor is a member of
the family of G-protein-coupled receptors. Thus far, eleven constitutively
activating mutations of the LH receptor gene, which result in high basal cyclic
AMP levels, have been identified in pedigree with FMPP and in sporadic cases. It
has been suggested that some of the mutations have effects on the Gq coupling and
phospholipase-C activation in addition to their effects on Gs coupling and
activation of adenylate cyclase.
PMID- 9396296
TI - [Disorders of sex chromosome].
AB - Disorders of sex chromosome, X and Y, consist of abnormality of the number or
structure of the sex chromosome. Because sex chromosomes have a variety of genes
related to sexual differentiation, disorders of sex chromosome induce a variety
of disorders of sexual differentiation. At first, in this title, the process of
normal sexual differentiation is shown. Classical disorders of sex chromosome are
Klinefelter syndrome, XX male, XYY male, Turner syndrome, XXX female, and XY
female. True hermphroiditism, mixed gonadal dysgenesis, and pure gonadal
dysgenesis are also included, because most of these disorders have abnormal sex
chromosome. Molecular analysis of sex chromosome is clarifying disorders with a
minute abnormality of sex chromosome. They include male infertility, premature
ovarian failure, and fragile X syndrome. Explanations of the above disorders are
given briefly.
PMID- 9396297
TI - [Disorders of gonadal function in hypothalamic-pituitary diseases].
AB - Hypothalmic-pituitary-gonadal hormones are regulated by number of factors
including GnRH, LH and FSH, and gonadal hormones. They are regulated also by
pituitary prolactin, activin and inhibin. Hypogonadism is divided into primary
and secondary hypogonadism. Secondary hypogonadism is caused by various lesions
involving either the hypothalmus or the pituitary. In this paper, etiology,
diagnosis and treatment of the secondary hypogonadism are described. The most
frequent causes of hypothamic hypogonadism are hypothalamic tumors, such as
germinoma. As the pituitary hypogonadism, pituitary tumors, and Sheehan's
syndrome are most common disorders. Diagnosis of the secondary hypogonadism is
made based on the diagnostic criteria established by The Research Group of the
Japanese Ministry of Health and Welfare. The criteria includes signs and symptoms
in addition to laboratory examinations such as measurement of serum gonadotropin,
sex steroid and LH-RH test. First choice of the treatment of hyothalmic
hypogondism is continuous pulsatile injection of synthetic LH-RH. In the
pituitary hypogonadism, hCG, hMG, estrogen and testosterone or the combination of
these are applied depending upon the age and other factors of the patients.
PMID- 9396298
TI - [Thyroid disease and reproduction dysfunction].
AB - Thyroid disorders have been implicated in a broad spectrum of reproductive
disorders ranging from abnormal sexual development to menstrual irregularities
and infertility. Hyperthyroidism in the male is thought to cause gynecomastia. In
the female hypo and hyperthyroidism results in changes in cycles length and
amount of bleeding. The hypothyroidism in the male has less clear-cut effect on
the reproductive system. Long-standing, untreated hypothyroidism is associated
with galactorrhea. These abnormalities are reversible with adequate thyroid
supplementation or collection of hyperthyroidism. Thus during the investigation
of hirsurism, menstrual irregularity, infertility, galactorrhea, and
gynecomastia, the possibility of thyroid dysfunction must always be considered.
PMID- 9396299
TI - [Sexual and gonadal dysfunction in adrenal disorders].
AB - Among various diseases of the adrenals, major disorders that cause sexual and
gonadal disturbances are congenital adrenal hyperplasia(CAH) and Cushing's
syndrome, and the others include virilizing or feminizing adrenocortical tumors.
CAH was reviewed based on the recent advances in molecular genetics. The most
striking discovery was steroidogenic acute regulatory protein, mutations of which
produce lipoid adrenal hyperplasia that was previously attributed to P-450scc
deficiency. Reversible amenorrhea or impotence is found in patients with
Cushing's syndrome. Low plasma estrogen and testosterone levels are associated
with female and male patients, respectively. Elevated adrenal androgen accounts
for mild virilization in female patients with ACTH-dependent subtypes. The sites
of action at which hypercortisolemia suppresses the hypothalamic-pituitary
gonadal axis were discussed.
PMID- 9396300
TI - [Gender issues and eating disorders].
AB - Sexual problems are not specific for eating disorders. The etiology is complex
and no one single causal facter has been identified. However, clinical as well as
epidemiological studies have shown that eating disorders occur more commonly in
females than males. The evidence that eating disorders are more common in females
has resulted in the postulation that socio-cultural factors may be important. An
important aspect of the socio-cultural position of women which may contribute to
eating disorders is the conflict in roles. Clinical experience and research have
shown the important role of sexual problems and traumas in the development of
anorexia nervosa and bulimia. When compared to anorexics, bulimics reported
greater sexual interest and activity.
PMID- 9396301
TI - [Sexual dysfunction in diabetes mellitus].
AB - Erectile dysfunction or impotence is a very common complication in diabetic male
patients; the prevalence of which may be more than that of retinopathy. The cause
of diabetic impotence has been thought to be neuropathy or angiopathy or both of
them. The diagnosis of diabetic impotence is based on the exclusion of other
causes of impotence including psychological, iatrogenic, endocrinological
impotence. The treatment options for diabetic impotence such as vacuum device,
intracavernous self-injection or surgical procedures are available and useful at
present. In this article, other sexual dysfunction; retrograde ejaculation and
female sexual dysfunction in diabetes mellitus are also discussed.
PMID- 9396302
TI - [Sexual dysfunction in the male patients on hemodialysis].
AB - Several features of sexual dysfunction, such as infertility, decreased libido and
potency, are frequently observed in male patients with uremia, and it usually
worsens with time despite of hemodialysis(HD) therapy. Hormonal profile often
demonstrates hypergonadotropic hypogonadism, and is suggestive of primary Leydig
cell dysfunction. Hypotestosteronemia and hyperprolactinemia may partially
participate in the pathogenesis of sexual dysfunction. Uremic toxins, renal
anemia, hyperparathyroidism, zinc deficiency, vascular and neurologic
abnormalities are also reported to be the causative factors of sexual
dysfunction. Correction of anemia with recombinant human erythropoietin sometimes
results in the amelioration of sexual potency, probably due to improvement of
erectile performance by increased blood viscosity. Psychological derangement
should be kept in mind as an another factor of sexual dysfunction.
PMID- 9396303
TI - [Endocrine disturbances in liver cirrhosis--focused on sex hormones].
AB - Various endocrine disturbances are often observed in the patients with liver
cirrhosis. We focused this paper on the sex hormones. Clinical features of male
cirrhotic subjects are feminization(gynecomastia etc) and hypogonadism(testicular
atrophy, reduced fertility, loss of libido, impotence etc). Chief abnormalities
of sex hormones are a decrease in serum testosterone levels and an increase in
serum estrogen levels accompanied by an increase in ratio of estrogen to
testosterone in the patients with severe liver cirrhosis associated with the
severity of hepatic dysfunction. Hyperestrogenization may be related with
feminization of male cirrhotic subjects, whereas hypogonadism is the result of
alcohol abuse per se, rather than the indirect consequence of liver cirrhosis.
PMID- 9396304
TI - [Obesity and disturbance of sexual function].
AB - Insulin-resistance is a central character of the simple obesity, resulting from
decrease of the insulin receptor and dysfunctions of the post receptor systems.
It induces hyper-insulinemia. Excess insulin gives rise to the synthesis of
androgens by binding to the receptor of the ovary, and suppresses the SHBG and
IGFBG in the liver. As a result, in obese women, the sexual function is disturbed
by hyperandrogenic milieu. The conversion of androgens to estrone in the
lipocytes evokes overproduction of estrone, which stimulates LH release and
induces overproduction of androgens. Hyperandrogenemia is a cause of disturbance
of the sexual function in obese women.
PMID- 9396305
TI - [Polycystic ovary syndrome: PCOS].
AB - Polycystic Ovary Syndrome(PCOS) was originally reported by Stein and Leventhal in
1935, as an syndrome with bilateral polycystic ovaries, menstrual abnormality,
hirsutism and obesity etc. After this report the diagnosis of "Polycystic Ovary"
was abused for the patient only with polycystic change of ovaries, so that, the
concept or definition of PCOS has became unclear and controversial. In this
review, a classification of PCOS according to the presence of hyperandrogenemia
and/or hirsutism will be shown to reconstruct the concept or definition of PCOS.
And usefulness of this classification will be revealed by showing
endocrinological and morphological aspect of each class. Furthermore, new
therapeutic approaches for PCOS with pure FSH injection in combination with GnRH
analog against the onset of OHSS, or drillings of antral follicles with CO2 or
KTP laser will be also shown in this review.
PMID- 9396306
TI - [Cryptorchidism].
AB - Cryptorchidism represents the most common genital abnormalities in boys.
Cryptorchidism means the abnormalities that lead to the empty scrotum and
specifically refers to undescended testis. Testicular descent is multifactorial,
and abnormalities of morphogenesis and hormonal aspects are considered to be the
etiology of non-descent of the testis. Furthermore, hormonal abnormalities
associated with cryptorchidism have the potential risks of infertility and
malignancy that appear in later life. The modality of the management has
undergone major refinements with the introduction of laparoscopy. Laparoscopy has
become the most widely used and most useful diagnostic modality in the management
of the impalpable undescended testes.
PMID- 9396307
TI - [Sexual dysfunction].
AB - According to the definition of the ICD-10 or DSM-III, sexual dysfunction is not
caused by organic disorder or disease, and psychogenic. But, the patient who is
suffered from sexual dysfunction caused by organic disorder or disease, has many
psycho-social problems. So, in this article, all types of sexual dysfunction are
subjected. Especially sexual hypofunction is mentioned. And the new type of
sexual dysfunctions such as computer sex are also explained. Sex therapy of the
Masters and Johnson method and the new sex therapy of Kaplan, H. are explained.
PMID- 9396308
TI - [Sexual dysfunction following pelvic surgery].
AB - In male, sexual dysfunction was a common complication that occurred after radical
pelvic surgery: radical protectomy, radical cysto-, prostatectomy. Upon the
recent pelvic neuroanatomical findings and preservation of these nerves, it is
now possible to perform successful cancer operation on the rectum, prostate or
bladder with preservation of sexual function in the group of early cancer
patients. Depending on the location and severity of these nerve injury, this
could result in temporary or permanent erectile and ejaculation dysfunction. In
female, the total hysterectomy for cervical cancer sacrifices or injuries the
faculty of pregnancy or sexual intercourse. The oophorectomies causes a
deficiency of female hormones. But recently the numbers of patients with a small
or early stages cancer of uterine or ovary are increasing and we have become to
be able to save the functions of these organs in many patients well with minimum
local excision or partial resection of them.
PMID- 9396309
TI - [A study on sexual dysfunction in female patients with alcoholics].
AB - Few investigations have been made concerning hormonal changes and dyspareunia in
fertile aged women with alcoholics experiencing sexual dysfunction. Twenty-seven
Japanese woman with alcoholics under 40 years of age excluded with liver
cirrhosis were studied to describe alcohol drinking related to sexual
dysfunction. Among 21 sexually active women, 20(95.2%) had both symptoms of
dyspareunia and vaginal dryness, and only one had neither symptom. Most of
patients have lower estradiol levels and 92.0% of patients have the moderately
elevated prolactin levels. Eleven of them were having the second grade amenorrhea
associated with hyperprolactinemia and hypergonadotropic hypogonadism and 14 were
having the first grade amenorrhea. In this study alcoholic abuse women may have
deeply related to the hyperprolactinemia, dyspareunia, amenorrhoea, vaginal
dryness, ovarian dysfunction and fetal alcohol syndrome.
PMID- 9396310
TI - [Alcoholic effect on male sexual function].
AB - Though an adequate volume of ethanol relieves nervousness and enhances sexual
desire, acute administration of a great deal of ethanol suppresses central
nervous system and causes sensory torpor and penile erectile dysfunction. Long
term and excessive intake of ethanol causes central and/or peripheral neuropathy
and sexual dysfunction; atrophy of testicles, low serum level of testosterone,
impaired spermatogenesis and penile erectile dysfunction. It also invades various
organs in digestive tract, cardiovascular system, central and peripheral nervous
system and causes functional disorders in these organs. Successful treatment of
patients with penile erectile dysfunction should be performed with treatment of
these underlying and associated disease.
PMID- 9396311
TI - [Drug induced impotence].
AB - Medication induced impotence has been reported in the some papers. However, it is
unusual to talk about the sexual history in a general clinical interview and
there are few reports to show the possible mechanisms of induced sexual
dysfunction in Japan. Recently, the average life span of the Japanese population
has gradually increased, so now we have a chance to evaluate the sexual history
from older people. Some drugs, such as diuretics, antiarrtythmic and
antihypertensive drugs, were reported to induce impotence, however, there was not
a detailed study in Japan. We studied the effect of cardiovascular medicine to
sexual dysfunction in 1,000 patients. Almost all medication did not always reduce
sexual activities, however, sexual activities in old people might decrease
because of medications or sickness. It is important for the general physician to
ask the patients about general conditions including sexual history while on
medications.
PMID- 9396312
TI - [Hepatitis C virus as a causative agent of carcinogenesis--recent trends for
study].
AB - Hepatitis C virus (HCV) infection causes chronic hepatitis, cirrhosis and
hepatocellular carcinoma. However, the mechanism of carcinogenesis by HCV is
poorly understood. In this paper, the recent virological and molecular biological
studies of HCV published in after 1996 were summarized including the past
reported data. Major topics of the study are the biological functions of HCV
proteins and the interaction between HCV proteins and cellular proteins. HCV
replication and proliferation systems using human cultured cells were also
described. The possible role of HCV for development of hepatocellular carcinoma
is discussed.
PMID- 9396313
TI - [Demonstration on Borna disease virus in patients with chronic fatigue syndrome].
AB - Chronic fatigue syndrome (CFS), a recently named heterogeneous disorder, is an
illness of unknown etiology. The association between CFS and several viral
infection has been suggested. Here, we centered on the possible link between CFS
and Borna disease virus (BDV) infection. BDV is a neurotropic, nonsegmented
negative-strand (NNS) RNA virus. Recent epidemiological data have suggested that
BDV may be closely associated with depression and schizophrenia in humans. In
Japanese patients with CFS, the prevalence of BDV infection was 34% (30/89) and
12% (7/57) by immunoblotting and PCR analysis, respectively. Furthermore, anti
BDV antibodies and BDV RNA were detected in a family cluster with CFS. These
results suggested that this virus contributes to or initiates CFS, although the
single etiologic role of BDV is unlikely.
PMID- 9396315
TI - [Diabetes mellitus in the elderly].
PMID- 9396314
TI - [Recent advance in research of Alzheimer's disease].
PMID- 9396316
TI - [Usefulness of dipyridamole thallium scintigraphy in the diagnosis of coronary
artery disease in elderly patients].
AB - Patients suspected of having coronary artery disease (CAD) underwent dipyridamole
thallium scintigraphy, exercise electrocardiography, and coronary angiography. Of
the 500 patients studied, 163 were at least 65 years old, and 337 were less than
65 years old. Both CAD and multivessel CAD were more common in elderly than in
younger patients (81% vs 69%, p < 0.01 for CAD; and 43% vs 26% p < 0.01 for
multivessel CAD). In patients without myocardial infarction, the specificity of
exercise electrocardiography was lower among elderly patients than among younger
patients (52% vs 61%), but the sensitivity was higher (87% vs 75%). In contrast,
both the sensitivity and the specificity of dipyridamole thallium scintigraphy
were similar in the two age groups (86% vs 87% and 79% vs 74%). Among patients
with myocardial infarction and a positive exercise test, reversible defects were
equally common in the two age groups (60% vs 58%). The reversible defects were in
areas remote from the area of infarction in half of the patients in both groups.
Among patients with negative exercise-test results, reversible defects were more
common in elderly patients than in younger patients (57% vs 38%). The reversible
defects were in the infarcted area in 71% and 79% of these patients,
respectively. These results indicate that dipyridamole thallium scintigraphy is a
sensitive and specific method for detecting CAD, independent of age. It is
particularly useful in identifying myocardial viability in the infarcted area.
PMID- 9396317
TI - [Helicobacter pylori infection and endoscopic appearance of the gastric mucosa in
elderly patients with peptic ulcer].
AB - I examined the characteristics of Helicobacter pylori (H. pylori) infection in
elderly patients with peptic ulcer and its relation to the endoscopic appearance
of the gastric mucosa. 1) Infection with H. pylori was more common in middle-aged
patients (those over 40 and younger than 59 years old, 80.4%) than in younger
patients (those less than 39 years old, 63.0%). Elderly patients were less likely
than younger patients to be infected (60's: 77.7%, 70's: 70.8%, over 80 years
old: 65.8%). The percentage was higher in men than in women, in all age groups.
2) Oshima's classification was used to divide the patients into 5 groups,
according to the endoscopic appearance of blood vessels of the gastric mucosa.
Infection was found in 71.7% of the patients without atrophy, in 86.3% of those
with mild atrophy, and in 88.9% of those with moderate atrophy. In contrast,
infection was found in only 78.4% of the patients with severe atrophy. Similar
results were found in patients with peptic ulcer and in subjects with no lesion
except atrophic gastritis. 4) The percentage of patients with gastric ulcer
disease who had atrophic gastric mucosa was higher in those with ulcers above the
middle of the stomach (46.3%) than in those with ulcers in the antrum (30.2%, p <
0.05). Almost all patients with gastric ulcers in the lower part of the stomach
and in the angulus were found to be infected with H. pylori (93.3% and 94.0%,
respectively). The percentage of patients with ulcers low in the stomach who were
infected was lower (59.4%). All of the location-related differences in infection
were significant (p < 0.001).
PMID- 9396318
TI - [Evaluation by specialists of the Guidelines on Treatment of Hypertension in the
Elderly--the second questionnaire survey].
AB - The Guidelines on Treatment of Hypertension in the Elderly, 1995 was published by
the Research Group for Guidelines on Treatment of Hypertension in the Elderly
Comprehensive Research Projects on Aging and Health, the Ministry of Health and
Welfare. To assess the guidelines, and to further investigate the changes in the
therapeutic policy for hypertension in the elderly, we mailed a questionnaire to
133 Japanese hypertension specialists who had replied to the first mailed
questionnaire in 1993. We received 102 replies (77%). Overall, the guidelines
were scored 4.3/5.0. More than 95% of the specialists agreed with levels of blood
pressure (BP) indicative for treatment, as well as the goal of BP control. The
guidelines propose that the rate of increase of the drug dose should be very
slow, at least every four weeks, and that the target BP be reached after two
months. The majority of the specialists agreed with this. However, 10% of them
preferred to follow patients every two weeks. The guidelines propose long-acting
Ca antagonists and ACE inhibitors as the first choice of drug for the treatment
of uncomplicated hypertension in the elderly. Two-thirds of the specialists
agreed. However, 17% of specialists proposed adding diuretics or beta-blockers to
the first line therapy. Ten specialists (10%) expressed concerns about Ca
antagonists and three (3%) insisted on withdrowing them from the first line of
drugs. In the guidelines, alpha and beta blockers are designated as relatively
contraindicated in elderly patients with hypertension, but half the specialists
answered that these drugs can be used safely in elderly patients. These findings
indicate that the therapeutic policy of Japanese specialists in hypertension in
the elderly has not changed substantially for three years.
PMID- 9396319
TI - [Deterrent factors in rehabilitation training following cerebral vascular disease
-comparison of elderly and non-elderly patients].
AB - The purpose of the present study was to clarify the deterrent factors for
rehabilitation training (rehab) of chronic cerebral vascular disease (CVD)
patients, and also to evaluate the influence of age on these factors. Sixty-five
CVD impatients with sequelae treated at the Cerebral Vascular Center of Nanasawa
Hospital were included in the study. Patients were classified into two groups
using the Barthel index score: good effect group (n = 21) or no effect group (n =
22). The following factors were compared between the two groups in order to
investigate which factor most affects the results of rehab: age, sex, the site of
brain damage, extent of motor paralysis, character (Type A character or not),
aphasia, hemispacial neglect, depression, and positive attitude toward training.
A possible association between depression, and the site of brain damage and Type
A character was investigated. Also, the difference in mood disorders was compared
between elderly and non-elderly stroke patients. In the elderly group,
hemispacial neglect, a negative attitude toward training, and depression all
adversely affected the outcome of the rehab. In the non-elderly group, aging,
hemispacial neglect, and a negative attitude toward training influenced the
effect of the rehab, but there was no correlation with depression. Depression was
seen in 64% of the patients (38/59). Of the 38 patients in a depressed state, 24
(63%) had right hemisphere brain damage, 13 (34%) had left hemisphere brain
damage, and 1 (3%) had brain stem damage. Twenty-seven of the 38 depressed
patients (71%) were Type A character, significantly more than in the non
depressed group (92/21, 43%). In addition, 14 of the 27 Type A patients were aged
over 65 years (52%), which was more than in the non-depression group (11/38,
29%).
PMID- 9396320
TI - [Investigation of autopsy cases of patients who had endoscopic injection
sclerotherapy performed, classified by their age at the time of initial therapy].
AB - We performed endoscopic injection sclerotherapy (EIS) for esophageal varices on
approximately 214 patients between October 1981 and July 1994 at our hospital. Of
the 214 patients 114 have died, and we divided them into two groups according to
their age when EIS was first performed: (i) group 1, less than 70 years old; and
(ii) group 2, more than 70 years old. We investigated the efficacy of EIS for the
group 2 patients with esophageal varices by comparing the two groups. EIS was
considered effective in the group 2 patients because there was no difference
between the two groups in the period of observation after EIS, but the time to re
therapy in the autopsy cases of this age group was significantly less. As a
result of investigating the surgical outcome and the direct cause of death, it
was suggested that; in future, prevention of death by hepatocellular carcinoma
and hepatic failure was necessary for both groups.
PMID- 9396321
TI - [Ataxic neuropathy in the elderly--clinicopathological study of six cases].
AB - The combination of ataxia with peripheral neuropathy (ataxic neuropathy) is rare.
Six elderly patients with peripheral neuropathy who developed ataxia were
studied. Of the peripheral neuropathies, ataxic neuropathy was significantly more
frequent in patients aged more than 65 years compared with younger patients.
Ataxic neuropathy was associated with carcinoma (2 cases), Sjogren's syndrome (1
case), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, 1 case)
and chronic idiopathic ataxic neuropathy (2 cases). The two cases of
carcinomatous neuropathy initially showed ataxia, which preceded detection of the
carcinomatous lesions in the lung by approximately 1 year. The study cases had
many clinical features in common. In the nerve conduction study, sural nerve
action potential could not be measured in five of the cases; sural nerve biopsy
revealed a decreased density of myelinated fibers in all cases. In particular,
the large myelinated fibers were markedly decreased. These findings were common,
regardless of the underlying disease, except in the case of CIDP in which there
was only a slight decrease in the number of large myelinated fibers. Differential
diagnosis based on the clinicopathological features was difficult. Therefore, in
cases of ataxic neuropathy, systemic evaluation is necessary to rule out the
possibility of carcinoma or various systemic diseases, especially in elderly
patients.
PMID- 9396322
TI - [Relationship between knee pain and X-ray findings of osteoarthritis with
reference to bone mineral density measured by computed X-ray densitometry].
AB - We studied the relation between performance of activities of daily living and X
ray findings of osteoarthritis of the knee in aged persons. We made Covariance
Structure Analysis models of knee pain, X-ray findings and bone mineral density
as measured by computed X-ray densitometry. The subjects were 257 women aged from
47 to 88 years who were outpatients at an orthopedic clinic. The best-fit model
indicated that loss of bone mineral density in metacarpals was associated with X
ray findings of knee-joint degeneration, as well as with knee pain. No
relationship was found between knee-joint degeneration and knee pain. These
results suggest that bone mineral density should be taken into consideration when
interpreting X-ray findings of knee pain. This model incorporates the effects of
degeneration of the subchondral bone. In summary, we should use measurements of
bone mineral density along with X-ray findings for the diagnosis and treatment of
knee osteoarthritis. We may be able to precisely predict knee pain caused by
osteoarthritis, by analysis of a model that includes a lesion in joint cartilage.
PMID- 9396323
TI - [Relationship between cognitive deficits, behavioral disturbances and falls in
patients with dementia].
AB - Prospective study was conducted in order to investigate the relationship between
cognitive and behavioral disturbances and falls in dementia. Falls and fall
related fractures were studied in 154 ambulatory patients who were admitted to a
geriatric intermediate nursing facility with a diagnosis of Alzheimer's type
dementia (DAT) or mixed Alzheimer and vascular dementia (MIX). The Mini-Mental
State (MMS) was used for the evaluation of cognitive status, and the Dementia
Behavior Disturbance Scale (DBD) was used as a behavioral parameter. In order to
evaluate problematic behavior in walking, a derivative scale (DBD-W) was
developed from the DBD by choosing three items relevant to wandering. During the
3 months of observation, 61 patients fell more than once; 15 of them experienced
fractures. The mean MMS scores were higher in non fallers, fallers who did not
sustain fractures and those complicated with fractures, in that order, and the
difference between the non fallers and fallers with fractures was statistically
significant. When the subjects were divided into three subgroups on the basis of
the MMS scores, there was a trend toward a higher ratio of fallers or those
complicated with fractures in the subgroup with the lower MMS score. The DBD and
DBD-W scores were not associated with falls or fractures, although fallers had a
slightly higher DBD or DBD-W score than non fallers. These findings suggest that
the risk of falling or fracture becomes higher with the advance of cognitive
impairment in institutionalized ambulatory patients with DAT or MIX. The findings
also suggest that behavioral disturbances are not necessarily associated with
falls or fractures.
PMID- 9396324
TI - [A case of polymyalgia rheumatica with swelling and pitting edema of the distal
lower extremities].
AB - We report a case of an 82-year-old woman with polymyalgia rheumatica (PMR)
associated with swelling and pitting edema of the lower extremities. The patient
had been previously admitted because of PMR in 1990, but there was no history of
swollen extremities. In July 1996, at another hospital, she was again diagnosed
as having PMR on the basis of pain in the neck, shoulders and lower back.
Administration of prednisolone was followed by improvement of the symptoms. Four
months later, similar pain recurred and swelling of the lower extremities was
noted. On admission, the erythrocyte sedimentation rate was 86 mm/h, and C
reactive protein was 15.5 mg/dl. Reviewing the previous treatment, it was
ascertained that her clinical deterioration was due to premature reduction of the
steroid dosage. The cause of the swelling of the lower extremities was unlikely
to be heart, liver, kidney or endocrine disease. Prednisolone was increased from
2.5 mg to 10 mg daily with marked improvement in all the symptoms including the
swelling and pitting edema. In 1996, a study reported distal extremity swelling
with pitting edema as a manifestation of PMR, which mostly developed concurrently
with proximal symptoms or during relapses of PMR. The swelling responded poorly
to non-steroidal antiinflammatory drugs but promptly to corticosteroids. The
distal swelling was reported to be tenosynovitis and synovitis of the surrounding
structures. The present case appears similar to that report. More studies of PMR
need to be done.
PMID- 9396325
TI - [Septicemia due to methicillin-resistant Staphylococcus aureus from chronic
prurigo in an elderly woman].
AB - An 80-year-old woman being treated with anti-hypertensive drugs developed
eruption and itching of the skin. High fever and lymph node enlargement
subsequently developed in spite of discontinuing all antihypertensive drugs, and
she was admitted to our hospital. At the initial examination, multiple papules
were noted over the entire body, and the skin showed thickening and
lichenification with scratch marks. There was also generalized enlargement of the
superficial lymph nodes. From these findings, her condition was diagnosed as
chronic prurigo due to drug allergy. Laboratory tests showed inflammatory
findings, anemia and a high serum level of IgE. Analysis of the surface marker of
peripheral lymphocytes revealed no abnormalities. Bacteriologic cultures of blood
revealed methicillin-resistant Staphylococcus aureus (MRSA). Histologic
examination of the lymph nodes revealed chronic reactive lymphadenitis with a
follicular pattern. She was strongly suspected of having MRSA septicemia, and so
combination chemotherapy with vancomycin, minocycline and cefoperazone/sulbactam
was started. However, 1 month after initiation of chemotherapy, the low-grade
fever, eruption and moderate inflammatory findings persisted, and culture of the
eruptions revealed MRSA. The prurigo was therefore considered to be the source of
the septicemia, and daily application of diflucortolone ointment containing 3%
acetic acid was started. Thereafter, the clinical and laboratory findings showed
a rapid improvement. MRSA infections usually occur in compromised patients who
are receiving antibiotics during prolonged hospitalization. The present case, who
did not have any underlying disease, indicates that old-age is also an important
factor for the development of MRSA septicemia.
PMID- 9396326
TI - [Changes in serum anti-Helicobacter pylori IgG antibody, pepsinogen I, and
pepsinogen II after eradication therapy of Helicobacter pylori].
AB - To investigate the changes in serum anti-Helicobacter pylori IgG antibody (HP
Ab), pepsinogen I (PG I), pepsinogen II (PG II), and pepsinogen I/II ratio (PG
I/II) after eradication therapy of Helicobacter pylori (HP), we studied 78
patients with HP-positive peptic diseases. They received combination therapy
(proton pump inhibitor + amoxicillin: n = 17, proton pump inhibitor + amoxicillin
+ clarithromycin: n = 61). In the 68 patients in whom HP was eradicated, HP Ab,
PG I, and PG II decreased and PG I/II increased significantly after eradication.
Especially, the decrease in PG II and the increase in PG I/II were rapid and
remarkable, found 2 months after the beginning of eradication therapy, and then
continued. On the other hand, in the patients in whom HP was not eradicated, HP
Ab and PG I/II did not change significantly, while PG I and PG II temporarily
increased at the end of administration of proton pump inhibitor. In conclusion,
it seems that the measurement of PG II and PG I/II is useful for the early
detection of HP eradication.
PMID- 9396327
TI - [Percutaneous ethanol injection therapy by ethanol mixed with CO2 microbubble for
hepatocellular carcinoma].
AB - One of the shortcomings of percutaneous ethanol injection therapy (PEIT) for
hepatocellular carcinoma (HCC) is that many sessions are necessary to accomplish
the treatment. This may be caused by which the ultrasonography (US) image does
not reflect correctly to the kinetics of injected ethanol into HCC nodule. It is
considered that number of treatment sessions are able to be reduced if we just
enough injected labelled ethanol under US into HCC nodule. Therefore, we tried
PEIT by ethanol mixed with CO2 microbubble (CO2 ethanol). The injected CO2
ethanol was aquired as hyperechoic image without strong acoustic shadow to the
end of injection. Consequently we could reduce the number of treatment sessions
to almost 1 for lesions < or = 3 cm in diameter and markedly reduce total dose of
injected ethanol. The detectable rate of CO2 ethanol leaked out HCC nodule was
high. No serious complication occurred. There have been only 1 lesion of local
recurrence and no case of intrahepatic and peritoneal dissemination for 11.5
months on average of observation after PEIT by CO2 ethanol (CO2PEIT). These
findings suggest that CO2PEIT is useful method for reducing the number of
treatment sessions and total dose of injected ethanol, moreover preventing
complication by ethanol leakage.
PMID- 9396328
TI - [Histopathological study in models of chronic pancreatitis].
AB - Histopathological findings were examined in the models of chronic pancreatitis.
Using mongrel dogs, we prepared a control group (group C), a chronic ischemic
group (group I), an alcohol administration group (group A), a duct obstruction
group (group O), and an alcohol + obstruction group (group AO). Group I showed
severe inflammatory cell infiltration, fibrosis, fat replacement and loss of
acinar cells. Group A showed no change. In group O, mild periductal fibrosis was
recognized. Group AO showed moderate inter-lobular fibrosis and inflammatory cell
infiltration, resembling those of human chronic alcoholic pancreatitis.
CONCLUSION: 1) Histological findings of chronic ischemic group is severer than
that of group O and AO. 2) The model of alcohol administration with incomplete
duct obstruction is a useful model of human chronic alcoholic pancreatitis.
PMID- 9396329
TI - [A case of carbohydrate antigen 19-9 producing gastric mucinous adenocarcinoma
with the appearance of a submucosal tumor].
PMID- 9396330
TI - [A case of PTH-rP producing gastric cancer with extragastric growth].
PMID- 9396331
TI - [A case of pseudomyxoma peritonei of appendiceal origin that metastasized to the
spleen and complicated secondary systemic amyloidosis].
PMID- 9396332
TI - [A case of Crohn's disease associated with pyoderma gangrenosum].
PMID- 9396333
TI - [A case report of primary intestinal lymphangiectesia successfully treated with
low fat diet].
PMID- 9396334
TI - [A case report of ulcerative colitis complicated with protein losing enteropathy
and colon cancer in a young female].
PMID- 9396335
TI - [A case of refractory diarrhea treated with somatostatin analogue].
PMID- 9396336
TI - [A case of Meckel's diverticulum caused intestinal obstruction of loop formation
and strunglated intestine by adhesion].
PMID- 9396337
TI - [A case of drug induced hepatitis and interstitial pneumonia caused by a herbal
drug, Dai-saiko-to].
PMID- 9396338
TI - [A case of hemorrhagic retention cyst of the pancreas].
PMID- 9396339
TI - [Changes in serum lipoprotein fraction in patients with chronic hepatitis C
during interferon beta treatment].
PMID- 9396341
TI - [Etiological analysis of thrombophilia].
AB - We have established a system for etiological analysis of thrombophilia which
includes assays of antithrombin III, protein C, protein S, plasminogen,
fibrinogen, heparin cofactor II and lupus anticoagulants as well as gene
analysis. The analysis conducted on 115 patients with venous thrombosis, arterial
thrombosis and small vessel thrombosis revealed that forty-one patients(36% of
the examined patients) were accompanied with decreased activities of protein S,
protein C, antithrombin III and plasminogen. Eleven candidate causal mutations
were found by gene analysis. These studies indicate that a comprehensive
examination is instrumental in identifying and confirming the etiology in
patients with thrombophilia.
PMID- 9396343
TI - [Apoptosis in Hashimoto's thyroiditis].
AB - It has been suggested that apoptosis plays a pivotal role in the pathogenesis of
autoimmune diseases. In Hashimoto's thyroiditis which is a typical organ-specific
autoimmune disease, Fas-FasL-mediated apoptosis has been demonstrated as the
mechanism of follicular epithelial cell death in which Fas is expressed by IL-1
beta stimulation of FasL is constitutively expressed on follicular epithelial
cells. The processes involved in this finding and some questions concerning
epithelial cell death are presented. The thyroid tissue of Hashimoto's
thyroiditis was examined for DNA fragmentation of follicular epithelial cells by
the TUNEL method. DNA fragmentation was observed more frequently on thyroid
follicles in the area adjacent to lymphoid cell follicles than on those in the
central area. Electron microscopic study supported the results of TUNEL study.
Immunohistochemical study on Fas and FasL expression on follicular epithelial
cells of various thyroid diseases showed that Fas and FasL were strongly
expressed on follicular epithelial cells in Hashimoto's thyroiditis and thyroid
cancer. Epithelial cells of patients with Graves' disease and adenomatous goiter,
however, were scarcely stained. Fas and FasL expression on follicular epithelial
cells were well correlated. In vitro study on follicular epithelial cells
clarified that FasL was constitutively expressed on epithelial cells not only in
Hashimoto's thyroiditis but also in nontoxic goiter. Fas expression was induced
by IL-1 beta stimulation. IL-1 beta stimulation also brought about apoptosis of
epithelial cells and epithelial cells killed Fas-positive target cells.
Therefore, it was concluded that FasL expressed constitutively on follicular
epithelial cells interacts with Fas on epithelial cells expressed by IL-1 beta
stimulation to induce apoptosis of epithelial cells.
PMID- 9396342
TI - [Support system for diagnosing hematologic malignancies].
AB - We established a Southern blot hybridization using a DIG-labeled probe to detect
monoclonal integration of HTLV-1 proviral genome. DIG was labeled by the PCR
method and this probe was as sensitive as the 32P-labeled probe and able to
detect only 1.6% of ATL cells. The clinical diagnoses of 44 patients with
monoclonal band(s) were all ATL. In contrast, the clinical diagnoses of 39
patients without monoclonal band(s) were diseases other than ATL. We also
performed a long PCR of HTLV-1 to characterize the integrated provirus. The
method allowed us to find a defective provirus, which was frequently observed in
aggressive forms of ATL; 14 of the 18 patients with acute type(78%), 6 of the 9
patients with lymphoma type(67%), and 2 of the 12 patients with chronic type(17%)
had the defective provirus. We established a simultaneous PCR for each region of
HTLV-1 for further examination of the defective provirus. To detect the
monoclonality of IgH gene rearrangement of B-cells, we performed PCR according to
the method described. None of 13 patients with T-lymphoproliferative disorders
showed a monoclonal band. In contrast, 12 of 13 patients with CLL(92%), 22 of 25
patients with common ALL(88%), 18 of 24 patients with B-lymphoma(75%), and 3 of 3
patients with hairy cell leukemia(100%) showed a monoclonal band. We are now
expanding this kind support system for the clinical diagnosis at a molecular
biology level in the central laboratory.
PMID- 9396344
TI - [Molecular pathomechanism of HTLV-I infectious diseases].
AB - Human T-cell lymphotropic virus type I(HTLV-I) is a type C retrovirus, closely
associated with adult T-cell leukemia. In the past few years, studies have
revealed an association between the virus and disorders of organ systems
including myelopathy, polymyositis, alveolitis, and Sjogren's syndrome. In
addition, we have proposed that HTLV-I-associated proliferative changes in
nonlymphocyte synovial cells are termed HTLV-I-associated arthropathy(HAAP). To
clarify the pathologic association of HTLV-I with this arthropathy, we attempted
to detect HTLV-I proviral DNA in synovial tissue. Proviral HTLV-I DNA was
detected not only in peripheral blood mononuclear cells but also in fresh
synovial tissue cells and lymphocyte-depleted cultured synovial cells. We also
detected mRNA for HTLV-I tax/rex in cultured synovial cells by reverse
transcription polymerase chain reaction. Moreover, induction of chronic
inflammatory arthropathy in mice transgenic for HTLV-I tax gene strongly
suggested the pathogenic mechanism of HAAP. Histologic findings of affected
joints in mice showed erosions of bones and pannus-like granulomtous change with
infiltration of mononuclear cells. Thus, this novel mechanism might explain
synovial proliferation caused by HTLV-I. Tax-expressing transgenic mouse lines
also demonstrated that tax itself could serve as an oncogne in fibroblastic
cells. Tumors occurred in 100% of the mice with reproducible time periods after
wounding. We established cell lines, which expressed high levels of c-fos, c-myc,
myb, PDGF, TGF-beta, Zif, and IL-6. Antisense ablation of the p65 subunits of NF
kappa B profoundly inhibited tumor growth in vitro with no apparent affect on the
growth of normal cells. These studies were successfully extended to tax
transgenic animals. Intraperitoneal injections of NF-kappa B p65 antisense at the
40 micrograms/g weight dose led to growth arrest after 7 days, and apparent
involution after 20 days of treatment. We think activation of NF-kappa B by Tax
is important for tumor progression. This paper supports the importance of
analyzing molecular pathomechanisms.
PMID- 9396345
TI - [Determination of neutrophil function by measuring superoxide production with
whole blood flow cytometry].
AB - The function of neutrophil can be evaluated by measuring oxidative metabolism
using chemiluminescence, tetrazolium dye reduction or the others. Those results
are not always satisfactory which would be caused by subtle difference in each
preparation of the reagents and the lack of reproducibility. Recently, flow
cytometric procedures for semi-quantitating superoxide production in neutrophils
have been developed to evaluate their function. This procedure, which requires
only small amount of whole blood, can easily and rapidly yield reproducible and
reliable data. In this study, we optimized analytical conditions and then
determined reference interval to evaluate neutrophil function of patients with
various disorders. Optimal concentrations and incubation times of DCFH-DA and PMA
were 5 mumol/l for 15 minutes and 25 micrograms/ml for 20 minutes, respectively.
Production of superoxide in neutrophil was represented by relative fluorescence
intensity(RFI) with assay coefficient of variance(CV) of 4.0-11.1%. Neutrophils
had to be examined within 2 hours after venipuncture to obtain reliable data.
Reference interval was determined as 170.4 +/- 58.7(mean +/- SD) RFI. Neutrophil
function of patients with neutropenia, paroxysmal nocturnal hemoglobinuria(PNH),
renal failure, systemic lupus erythematosus(SLE), myeloperoxidase deficiency,
myelodysplastic syndrome(MDS), and diabetes mellitus were within the reference
interval as evaluated by this method. Only neutrophils of chronic granulomatous
disease, which is known to give clearly low superoxide production, showed
actually decreased value. These results indicate that this procedure would be
clinically useful for diagnosis of patient with impaired neutrophil function.
PMID- 9396346
TI - [Determination of uric acid in scalp hair for non-invasive estimation of uricemic
control in hyperuricemia].
AB - Uric acid in blood has been widely accepted as a reliable indicator of
hyperuricemia and gout, and its assay method has been established. In the present
study, we developed a simple and non-invasive rapid method for the determination
of uric acid in hair. Concentration(nmol/mg hair) of uric acid extracted from 10
20 mg of hair(95% < extractability; 0.1N KOH, 37 degrees C, 2 hr) was determined
by an enzymatic method using uricase. The concentration of uric acid(nmol/mg
hair, mean +/- SD: 0.489 +/- 0.157, n = 16) in hair from hyperuricemic patients
was significantly higher than that(0.258 +/- 0.107, n = 8) from healthy
volunteers(p < 0.01). Within-run and between-day precisions(reproducibilities,
CVs) for the assay were 9.6-10.3%(n = 10 each) and 11.6-16.3%(n = 7 each),
respectively. The concentration(y, nmol/mg hair) of uric acid in hair correlated
well with that in blood(x, g/l): y = 8.770x-0.123(r = 0.746, Syx = 0.122, n =
23). Changes in the concentration of uric acid in hair of hyperuricemic patient
treated with allopurinol paralleled to those in blood. In conclusion, it was
confirmed that the concentration of uric acid in hair reflected that in blood,
suggesting that measuring uric acid in hair can be available for the metabolic
control in hyperuricemia.
PMID- 9396347
TI - [Angiotensin I-converting enzyme gene polymorphism and renal disease].
AB - ACE inhibitor is known to have a therapeutic efficacy in renal diseases by
reducing proteinuria and maintaining renal function. However, the relationship
between ACE gene polymorphism and renal disease has not been fully elucidated. In
this study, a 287 base pair(bp) I/D polymorphism of the ACE gene was examined
with polymerase chain reaction(PCR) in 100 healthy subjects, 34 patients with
chronic glomerulonephritis(CGN), 29 with chronic renal failure(CRF) and 25 with
diabetes mellitus(DM) with(13) and without(12) nephropathy. We also measured
serum ACE activity of these patients. ACE genotype and derived allele frequencies
in each disease group did not differ significantly from those in healthy
subjects. In all disease groups, values of serum ACE activity were higher in
genotype DD than in genotype II. These findings suggest no significant
association between I/D polymorphism of the ACE gene and renal disease. Further
studies are needed to clarify these findings, considering renal function and type
of renal disease.
PMID- 9396348
TI - [Establishment of the optimal conditions for detecting anti-M2 by western
blotting in primary biliary cirrhosis].
AB - Anti-mitochondrial antibodies(AMA) are serodiagnostic markers for primary biliary
cirrhosis(PBC) but heterogenous in antigen molecules which they recognize. A
disease-specific AMA for PBC is anti-M2. The conventional examination methods are
indirect immunofluorescence and ELISA. However, there are some problems in
specificity, because the antigen preparations used are crude. Thus, analysis with
Western-blotting(W-B) is needed, because it allows the identification of a
molecule which the antibody reacts with. In this report, we established the
optimal conditions for detecting anti-M2 with W-B in PBC. As antigen, we used
mitochondrial fractions derived from beef hearts. Because a positive band at 74
kDa became negative after absorbing sera with PDH purified from porcine hearts,
this band corresponded to major antigeneity of anti-M2. Titration experiments
with SDS-PAGE showed that the optimal concentration of this antigen preparation
for loading is 0.04 mg/ml. We also performed titration experiments to determine
the optimal dilutions for second antibodies and serum samples. The results showed
that the optimal dilution for second antibodies, anti-IgG and anti-IgM, were
1:3000 and 1:1000, respectively. The optimal dilution for serum samples was shown
to be 1:10(2). Moreover, the W-B technique gave a positive result even for sera
from AMA-negative PBC patients which had tested negative with conventional
methods, if undiluted sera were examined or if anti-IgG or anti-IgM was used as a
second antibody. Thus, the W-B technique is more sensitive than conventional
methods of analysis. Based on these results, we will be able to detect anti-M2
with maximum efficiency, thus improving our ability to study the relationship
between anti-M2 and the pathological conditions in PBC.
PMID- 9396349
TI - [Western blot analysis of anti-M2 antibodies in anti-mitochondrial antibody
negative primary biliary cirrhosis].
AB - One variety of anti-mitochondrial antibody(AMA) is characteristically found in
sera from patients with primary biliary cirrhosis(PBC). The major target antigens
of this type of AMA are M2s. It is well known, however, that AMA-negative PBC
also exists. An alternative disease concept, called autoimmune cholangiopathy,
recently has been advocated. This new concept is defined by the following
criteria: 1)the failure to detect AMA and anti-M2, 2)the detection of a diffuse
type of anti-nuclear antibody and anti-smooth muscle antibody, 3)pathological
findings compatible with PBC, and 4)the effectiveness of prednisolone. However,
the difference between AMA-negative PBC and autoimmune cholangiopathy is
controversial. Therefore, we analyzed antibodies to four major M2 proteins with
Western blotting in 34 cases of immunofluorescent AMA-negative PBC. In 31(91.2%)
of these 34 AMA-negative sera, antibodies to at least one of these four major M2
proteins was detected. In serum samples from 34 control patients with AMA
positive PBC, antibodies to at least one of these four proteins were detected in
all cases. In addition, we studied the frequency of cases which satisfied the
serological criteria of autoimmune cholangiopathy. In only one(0.7%) of 141 cases
was the serological criteria met. We conclude that to clarify the serological
differences between autoimmune cholangiopathy and AMA-negative PBC, the analysis
of M2 proteins by Western blotting is essential.
PMID- 9396350
TI - [Serum levels of soluble tumor necrosis factor receptors as markers for disease
progression of human immunodeficiency virus infection].
AB - We studied whether the serum levels of soluble tumor necrosis factor
receptor(sTNFR) type I or II correlate with clinical progression of human
immunodeficiency virus type 1(HIV-1) infection. Serum levels of sTNFR type I and
II were measured by an enzyme-linked immunosorbent assay in sixty five patients
with HIV-1 infected hemophiliacs and 10 healthy controls. In a longitudinal
study, we assessed whether the decline of CD4+ lymphocyte counts were associated
with increased serum concentrations of sTNFRs. Elevated serum concentrations of
sTNFRs were found among the HIV-1 infected patients and higher in patients with
advanced clinical stage. We noticed there were two distinct patient groups in
change of CD4+ lymphocyte count when twenty-eight patients were followed
retrospectively for a median period of 65 months. 14 patients represented stable
CD4+ lymphocyte counts, but another 14 patients had more than 40% decrease of
CD4+ lymphocyte counts over the course of this study. Serum sTNFR type II levels
were 3.49 +/- 0.71 to 3.11 +/- 0.31 ng/ml in the former group, and 4.88 +/- 0.91
to 4.26 +/- 0.71 ng/ml in the latter group during the study. Significantly higher
levels of sTNFR type II were already revealed at early time in the latter group.
There was, however, no significant difference in the level of sTNFR type I
between the two. These results suggest that serum levels of sTNFR type II
provided useful information as a predictor of disease progression related to the
decline of CD4+ lymphocyte counts.
PMID- 9396351
TI - [Analysis of genome-type, serovar and antibiotic susceptibility of Pseudomonas
aeruginosa isolated in Beijing Hospital China in 1991 to 1993].
AB - We analyzed the in vitro antibiotic susceptibility pattern and serovar for 192
strains of Pseudomonas aeruginosa isolated at Beijing Hospital(China) from
October 1991 to October 1993. The frequency of resistant strains was high, more
than 15%, for ceftazidime, cefsulodin, cefoperazone, aztreonam, gentamicin,
tobramycin, tosufloxacin, ofloxacin and fosfomycin. The incidence of resistants
against piperacillin and imipenem was significantly low. Among the 192 strains,
16 were designated as being multi-drug resistant strains(i.e.; resistant to more
than 8 drugs out of 11 drugs), and all of the multi-drug resistant strains were
isolated from inpatients. Predominant serovar of 192 strains were 60(31.3%) for
G, 28(14.7%) for E, and 24(12.5%) for I. Multi-drug resistant strains have no
characteristic serovar. Restriction enzyme SpeI digestion analysis(using pulse
field electrophoresis) of P. aeruginosa-genome yielded several common patterns,
and was shown to be useful for tracing the route of nosocomial infection.
Further, isolates with closely related genome type, in which the size of one
digested band was different, showed a different minimum inhibitory concentration
of fosfomycin in one genome type or new quinolones in the other genome type.
Analysis of genome type and antibiotic susceptibility pattern may exhibit the
antibiotic resistant gene.
PMID- 9396352
TI - Differences in molar absorptivity of 4-NP with the reaction solution and
apparatus affect ALP measurement.
AB - We examined the differences in molar absorptivity of 4-NP obtained using
different kits for ALP measurement and different instruments. The apparent molar
absorptivity of 4-NP in the same reaction solution determined by six different
instruments was 15.98, 16.72, 16.06, 17.00, 16.27, 17.62 and that using four
different reaction solution kits for ALP with the same instrument was 16.90,
17.38, 17.72, 16.11. We measured ALP in three serum samples with six instruments
using the same kit and in twelve serum samples with the same instrument using
four kits. ALP activities measured using the same molar absorptivity value
differed with the instrument(p < 0.01). However, those measured using the
apparent molar absorptivity value for each instrument revealed no significant
differences(p > 0.05). In conclusion, we suggest that standard material should be
contained in each kit for enzyme measurement and the apparent epsilon for each
kit and instrument should be obtained to minimize the systematic error caused by
using the same epsilon in different laboratories.
PMID- 9396353
TI - [Cytokine-secreting cells in relapsing multiple sclerosis patients treated with
high-dose intravenous methylprednisolone].
AB - Interleukin-2 (IL-2), interleukin-2 receptor (IL-2R), interferon gamma (INF
gamma), interleukin-4 (IL-4) secreting peripheral blood cells were enumerated by
enzyme-linked immunospot (ELISPOT) assay in 9 relapsing multiple sclerosis (MS)
patients treated with high-dose intravenous methylprednisolone (MP), in 7 MS
patients with remission,and in 9 controls. IL-2, IL-2R, INF gamma, IL-4 secreting
cells were significantly higher before MP therapy in relapsing MS patients as
compared with after MP therapy in relapsing MS patients, with MS patients in
remission, and with controls. IL-2, INF gamma secreting cells before MP in
relapsing MS patients and those in remission significantly increased in response
to myelin basic protein (MBP) 4-14, 68-84 and proteolipid protein (PLP). INF
gamma secreting cells after MP therapy in relapsing MS patients significantly
increased in response to MBP 4-14, 68-84, and PLP. IL-2R secreting cells in MS
patients in remission significantly increased in response to MBP 4-14, 68-84, and
PLP and were significantly higher after MP therapy in relapsing MS patients and
in controls. This fact suggested that there was a systemic T-cell response to
myelin antigens in MS patients in remission. The use of ELISPOT to investigate
cytokine-secreting cells may play a role in the evaluation of clinical activity
during treatment with high-dose intra-venous MP in relapsing MS patients.
PMID- 9396354
TI - [A study of MRI and clinical neurology in acute cerebellar infarcts].
AB - We studied clinical manifestations of sixteen patients with cerebellar infarcts
diagnosed by MRI. In fourteen of them, the stroke developed abruptly with
vertigo, which continued for several days. At the early stage of illness, ataxia
was obscure. But after vertigo and nausea disappeared, nine cases showed truncal
ataxia, while limb ataxia was found in only five. Their vertigo was rotatory and
aggravated by head movement. Gaze-evoked nystagmus was observed in only 5 cases.
Four patients preferred to take unilateral posture since they experienced less
vertigo. The side of their lesions was the lower side of their posture. Limb
ataxia was more frequent in SCA-involving cases than in SCA-non involving cases
(3 out of 6 vs 2 out of 10, respectively). On the other hand, headache was more
frequent in PICA-involving cases than in PICA-non-involving cases (6 out of 11 vs
1 out of 5, respectively). Ataxic gait was seen more in medial branch-involving
cases than medial branch non-involving cases (5 out of 6 vs 4 out of 10,
respectively). One patient died due to obstructive hydrocephalus.
PMID- 9396355
TI - [Efficacy of TRH-T for spinocerebellar degeneration--the relation between
clinical features and effect of TRH therapy].
AB - Thyrotropin releasing hormone (TRH) therapy has been frequently attempted for the
treatment of spinocerebellar degeneration (SCD) and its efficacy has been
confirmed. However, effectiveness is considered to differ depending on disease
type, severity and the method of evaluating clinical improvement. We investigated
the efficacy of thyrotropin releasing hormone-tartrate (TRH-T) in 23 patients
with SCD consisting of cerebellar form (cortical cerebellar atrophy (CCA) and
hereditary cortical cerebellar atrophy (H-CCA)), and multiple system form
(multiple system atrophy (MSA) and hereditary olivopontocerebellar atrophy (H
OPCA)). TRH-T, 2 mg per day, was given intravenously for 20 days. The effect of
TRH therapy was evaluated by assessing changes in balance function while lying,
sitting, standing and walking, that may reflect the movement functions in active
daily life (ADL) for the patients with SCD. The speech function was also
evaluated qualitatively using acoustic analysis. The amine metabolites (HVA and 5
HIAA) in cerebrospinal fluid possibly reflecting the noradrenaline and serotonin
metabolism in the central nervous system were measured before and after
treatment. Although mild or moderate improvement of the balance function during
the course of TRH therapy was seen in 16 of the 23 patients, patients with
cerebellar forms (CCA and H-CCA) improved significantly as compared to patients
with MSA. The effect persisted for a long time (mean; 3.8 months) after TRH
therapy in nine of the 16 patients, and eight (88.9%) of the nine had the
cerebellar form of SCD. The levels of HVA and 5-HIAA in CSF also increased in
patients with CCA as compared to patients with MSA and H-OPCA. The disease
severity before the treatment in 14 (87.5%) of 16 patients who showed improvement
of balance functions by TRH therapy was mild or moderate; possible of walking
without support, or occasionally with support. Considering these results
together, TRH therapy may be effective in patients with the cerebellar form of
SCD, whose illness severity is mild, and may be recommended for support of ADL in
patients with the cerebellar form of SCD.
PMID- 9396356
TI - [Bilateral vertebral artery occlusion].
AB - We studied 9 patients with bilateral vertebral artery occlusion (BVAO). BVAO was
confirmed using angiography in order to clarify its clinical feature, mechanism,
and long term prognosis. Three patients showed bilateral intra-cranial occlusion,
3 bilateral extra-cranial occlusion, and 3 intra and extra-cranial occlusion. The
basilar artery was fed by the posterior communicating artery in 8 out of 9
patients. In one of the 8, reconstitution of the thyrocervical artery was seen.
We divided the patients into 4 groups according to MRI findings, as follows:
Group 1 with no abnormal finding on MRI (N = 2); Group 2 with deep pontine
infarcts and non-territorial small cerebellar infarcts (N = 2); Group 3 with
extended pontine infarcts (N = 3); and Group 4 with cerebellar cortical artery
infarcts, deep pontine infarcts, and non-territorial small cerebellar infarcts (N
= 2). Transient episodes were seen in all patients, 8 patients out of 9 had
vertigo/dizziness, 3 tinnitus, 2 diplopia, 2 headache, 2 numbness, and 1 hearing
disturbance. These episodes preceded a final attack or complete stroke 2 days to
5 months, and those who had a longer period of episodes in the preceding term
tended to have less severe deficits. Six of the patients had vertebro-basiler
symptoms after being in the upright position, including all the patients in
Groups 2 and 4, which had cerebellar border zone/terminal zone infarcts. These
results indicate that the hemodynamic mechanism plays an important role in BVAO.
The prognosis was not always grave. Four of the patients could walk
independently, 2 could walk with a cane, and 3 were bed ridden (2 of which died).
Long-term follow-up data (a mean of 5 years) were obtained in all patients. In
the patients who could walk, one had asymptomatic cerebellar infarcts, and one
had TIAs frequently. Patients with BVAO often also have TIAs and/or preceding
episode and show cerebellar border zone/terminal zone infarcts. This research
strongly suggests that hemodynamic mechanism might play an important role in
BVAO, and that paying attention to border zone infarction in MRI and transient
episodes can lead to earlier diagnosis and treatment.
PMID- 9396357
TI - [A pedigree of autosomal dominant limb-girdle myopathy with rimmed vacuole
formation].
AB - We describe a kindred with autosomal dominant myopathy with preferential proximal
limb muscle involvement. This disorder is characterized clinically by early adult
onset, slow progression, normal life expectancy, weakness and atrophy of proximal
limb muscles, especially in the lower limbs. Laboratory examinations showed
myopathic changes mixed with neuropathic components on needle electromyography,
slight elevation of serum creatine kinase, and absent cardiac involvement. In
biopsied muscle findings of two patients, the presence of rimmed vacuoles was the
most striking finding to explain muscle degeneration, though a few necrotic
fibers were present. The pathologic and clinical findings in the present family
are almost similar to those seen in "adult-onset autosomal dominant limb-girdle
muscular dystrophy" reported by Chutkow et al.
PMID- 9396358
TI - [Body fat loss in patients with Parkinson's disease].
AB - In order to investigate emaciation in patients with Parkinson's disease (PD), an
anthropometric study was undertaken. In 59 out-patients (29 males, 30 females)
with PD, the changes in body weight (delta BW) and in body mass index (delta BMI)
were obtained and the ratio of body fat (% Fat) was measured with a bioelectrical
impedance method. Twenty-two percent of the patients with PD had lost more than
10 Kg of BW (7% of males, 37% of females) and delta BW was -3.9 +/- 7.1 Kg, delta
BMI -1.8 +/- 3.2 Kg/m2, and %Fat 25.9 +/- 5.6%. The reductions in both the BW and
BMI of females with PD were significantly higher than for males (p < 0.003, p <
0.001, respectively). The disease duration had no correlation with delta BW or
delta BMI, but a significant negative correlation with %Fat (all: p < 0.05;
females: p < 0.03). However, no correlation was found between delta BW, delta BMI
or %Fat on the one hand, and the disease severity or the total dosage of L-dopa
with carbidopa on the other. We conclude that patients with PD, especially in
females, experience gradual body fat loss according to disease duration.
PMID- 9396359
TI - [Immunohistochemical localization of chymase; a mast cell marker and clinical
significance in diseased human skeletal muscle].
AB - In the advanced stage of dystrophinopathy, cardiac dysfunction is a serious
complication for prognosis. Recently, an angiotensin converting enzyme (ACE),
which converts angiotensin (A) 1 to A 2, has been reported to be effective for
cardiac insufficiency. The A 2 is produced more dominantly in the path via the
production of a neutral serine protease, chymase (MW 25,000), secreted from the
mast cell. We have observed localization of chymase in diseased human skeletal
muscle tissues, and evaluated its clinical significance. The frozen muscle
biopsied specimens from 91 neuromuscular disorders (muscular dystrophies,
inflammatory myopathies and neurogenic muscular disorders) were stained by using
monoclonal antibody against the chymase, and the positive cells in a whole
sectional field were counted. In the serial sections, we also performed routine
histochemistry and immunostainings of immunological markers (CD4, CD8 and others)
as well as the apoptotic proteins for comparison. RESULTS: The chymase-positive
mast cells were scattered mainly in the endomysium, partly in the perimysium and
around small vessels. Although the positivity was not disease specific, more
numerous strongly positive cells were observed in dystrophinopathy and
inflammatory myopathies, but less in myotonic dystrophy and neurogenic muscle
disorders. In the normal control muscle, however, strongly positive cells
appeared less frequently than in the above mentioned diseased muscles. The
chymase-positive cells partly corresponded to the ubiquitin-positive ones, but
perforin, granzyme A, Fas and Bcl-2 did not. In conclusion, the chymase-positive
mast cell may play a primary or secondary role in the diseased muscle, and their
more abundant appearance in dystrophinopathy and some other myopathies suggest
the effectiveness of an ACE blocker, an anti-chymase drug.
PMID- 9396360
TI - [Two cases of encephalo-myelo-radiculoneuropathy, triggered by herpes simplex
virus type-1 infection].
AB - We report two cases of encephalo-myelo-radiculoneuropathy, triggered by herpes
simplex virus type-1 (HSV-1) infection. Patient 1 (a 25-year-old man) and patient
2 (a 52-year-old man) were admitted to the hospital because of fever, headache,
abnormal behavior, and loss of consciousness. In each case, cerebrospinal fluid
(CSF) showed lymphocytic pleocytosis with protein elevation, and serum and CSF
IgG antibody titers to HSV-1 were elevated markedly. Although patient 1 was
treated with aciclovir in the early phase of encephalitis, he developed severe
quadriparesis as a sequela. Patient 2 was treated with a combination of aciclovir
and corticosteroids, and he recovered completely about 4 months after the onset
of the disease. There have been only a few reports of encephalo-myelo
radiculoneuropathy triggered by HSV-1 infection. Early corticosteroid therapy was
effective in our patients with post-HSV-1 infectious encephalo-myelo
radiculoneuropathy. These two patients were studied with flow cytometry for
peripheral blood lymphocyte subsets during the disease course. In the active
stage of the disease, the helper-inducer (CD4 + CD29+), activated T cell (CD4 +
CD25+), and cytotoxic/NK (CD8 Dull + CD11b Bright+) subsets were increased
compared with subsets in controls. An interesting finding was mismatched
responses with an increased suppressor-inducer (CD4 + Leu8+) subset and a
decreased suppressor-effecter (CD8 Bright+ CD11b Dull+) subset, indicating a
possible autoimmune character of encephalo-myelo-radiculoneuropathy triggered by
viral infection.
PMID- 9396361
TI - [A case of optic-spinal form of multiple sclerosis with lobar type large cerebral
hemorrhage].
AB - We report a 57-year-old woman with optic-spinal form of active multiple
sclerosis, who developed a large lobar type hemorrhage of the brain. She
initially suffered from left visual loss, and three month later, she was
hospitalized with paraplegia and total sensory loss up to the fourth thoracic
level accompanied by sphincteric disturbance. Diagnosis of clinically probable
multiple sclerosis was based on the relapsing-remitting clinical course and
laboratory findings. Five months after admission, she developed sudden
consciousness loss. Brain CT scan showed a massive hemorrhage in the right
frontal to parietal lobe. The patient had no risk factors for cerebral hemorrhage
including hypertension. Histopathological study of brain tissues obtained at
surgical evacuation of hematoma did not reveal any malignancy, and congo-red
staining of this specimen was negative. We analyzed coagulation, fibrinolytic,
and endothelial parameters during the follow-up period. von Willebrand factor
(vWF) as a marker for endothelial damages was elevated persistently. Moreover,
thrombin-antithrombin III complex (TAT) as a marker for activation of coagulation
was also elevated constantly throughout the clinical course. The findings suggest
that fragility of the vascular walls and permeability changes associated with
immunological mechanisms might have resulted in the cerebral hemorrhage. Although
there are few reports of cerebral hemorrhage in patients with multiple sclerosis,
it has been reported that vascular wall damage is an important aspect of the
pathology of multiple sclerosis and acute cerebral vascular damage may sometimes
occur in multiple sclerosis. We propose that coagulation studies including the
endothelial marker such as vWF would provide a useful information regarding the
risk of cerebrovascular complication in multiple sclerosis.
PMID- 9396362
TI - [Metamorphopsia and transient increase in the cerebral blood flow of the left
occipital pole on 123I-IMP SPECT: a case report].
AB - A 55-year-old right-handed man suddenly developed unformed visual hallucination
of rainbow-colored balls coming out from the lower quadrant of the right visual
field. Visual field examination revealed a right lower quadrant homonymous
hemianopia. Metamorphopsia of the hand or face appeared 6 days later when he
looked at his hands or at the face in the mirror, and persisted for about 10
minutes. 123I-IMP SPECT demonstrated a marked increase in CBF of the left
occipital pole while the patient realized the visual symptoms, and a marked
decrease in CBF after the symptoms disappeared. T1 and T2-weighted MRIs of the
brain were unremarkable, but the Gd-DTPA-enhanced T1-weighted MRI showed high
signal in the subcortical white matter of the left occipital pole. The
metamorphopsia was induced probably by the activation of the left occipital
lesion by the epileptogenic mechanism although the nature of the lesion remained
unclarified.
PMID- 9396363
TI - [A familial case of postural reflex disorder presenting high intensity area
mainly in the globus pallidus on T1-weighted cerebral MRI without clear liver
damage].
AB - A 56-year-old woman was admitted because of chronic postural reflex disorder. A
cerebral MRI revealed symmetrical high intensity area mainly in the globus
pallidus on T1-weighted image. The symptom became manifested as gait disturbance
from the age of 2 and gradually progressed. Her condition has, however, remained
stable since the age of 26. The only sign of parkinsonism was akinesia. There was
clear retropulsion but cerebellar ataxia was minimal, and dystonia was
negligible. She had no dementia. Her parents were cousins and similar symptoms
and high intensity area were found in one of her sisters. Routine liver function
tests were normal, with only ICG elevated. Serum copper and ceruloplasmin were
normal. A hereditary factor was suspected. There are no similar cases reported in
the literature, thus we thought it worth reporting.
PMID- 9396364
TI - [A case of antiphospholipid syndrome associated with myasthenia gravis].
AB - We report a 40-year-old Japanese woman with antiphospholipid antibody syndrome
(APS) associated with myasthenia gravis (MG). She had a history of miscarriage at
the age of 27 followed by pulmonary embolism 3 weeks later. At the age of 40, she
developed diplopia, bilateral ptosis and easy fatigability. Serum anti
acetylcholine receptor antibody and tensilon test were positive. She was
diagnosed as having MG. The laboratory test revealed mild thrombocytopenia,
prolonged activated partial thromboplastin time (aPTT) and positive findings for
both beta 2-glycoprotein I-dependent anticardiolipin antibody and lupus
anticoagulant. She fulfilled the diagnostic criteria of APS, but did not the
criteria proposed by American Rheumatism Association for SLE. An extended total
thymectomy was performed after administration of oral prednisolone and low-dose
aspirin. This is a patient who had APS associated with MGs: both are known to
result from autoimmune abnormality. The clinical and laboratory manifestations of
APS were ameliorated after removal of the thymus, suggesting that thymectomy
alleviates APS symptoms.
PMID- 9396365
TI - [A case of idiopathic orthostatic hypotension with selective involvement of
postganglionic noradrenergic neurons].
AB - A 44-year-old man had a 30-year history of orthostatic hypotension and diarrhea.
One month before admission, he suddenly lost consciousness by defecation, and was
hospitalized. He became alert within two days, but he could not sit up due to
severe orthostatic hypotension. At that point, he was transferred to our
hospital. On admission, talipes and microdactylia were noted. Neurological
examination revealed brisk patellar tendon reflexes. Anhidrosis or impotence was
not present. Analyses of blood and urine yielded normal results. Cardiological
examination revealed no abnormality that could be responsible for the
hypotension. MR images of the brain were also normal. However, single photon
emission tomography revealed diffuse hypoperfusion of the brain. A head-up tilt
(50 degrees) test induced a remarkable fall in systolic blood pressure from 149
(heart rate; 65/min) to 64 mmHg (83). Immersion of hand in ice-cold water failed
to increase blood pressure. Heart rate variation and cystometry results, which
represent the function of parasympathetic nerves, were normal. Warming of his
body caused normal sweating. Intravenous injection of low doses of norepinephrine
and methoxamine increased blood pressure while isoproterenol remarkably increased
heart rate, suggesting that both alpha- and beta-receptors developed
supersensitivity. Instillation of 5% cocaine and 5% tyramine into the
conjunctival sac failed to cause pupillary dilation. Clinical findings and
pharmacological challenge test results suggested that the main lesion of his
autonomic nervous system was selectively confined to the postganglionic
sympathetic nerves and noradrenergic (not cholinergic) neurons. The autonomic
failure of our patient can be classified as idiopathic orthostatic hypotension.
However, most patients with idiopathic orthostatic hypotension or pure autonomic
failure complain of anhidrosis and impotence, which were not noted in our
patient. These symptomatic differences may be the result of the highly selective
involvement of noradrenergic neurons in the postganglionic sympathetic system in
our patient.
PMID- 9396366
TI - [A case of paradoxical cerebral embolism with 'spectacular shrinking deficit'].
AB - A 66-year-old woman was admitted to our hospital because of abrupt onset of left
hemiparesis and confusional state. Ten hours prior to admission, she developed
difficulty in left hand movement, and her family noticed cloudiness of
consciousness and gait disturbance. Neurological examination revealed only a
hollow hand sign of the left hand without other neurological deficits. Cranial CT
showed a low density area in the right superior parietal region, and the follow
up CT on 6th hospital day exhibited contrast enhancement and hemorrhagic
transformation in this area. Cerebral angiography demonstrated capillary blush
and early venous filling in the right posterior parietal region. Transesophageal
color-coded Doppler echocardiography (TEE-CD) showed a shunt flow via patent
foramen ovale (PFO). Thus, we diagnosed this case as paradoxical cerebral
embolism through PFO, which is characterized by rapid recovery of clinical
manifestation, so-called spectacular shrinking deficit. Even in elderly patients
with embolic stroke of unknown origin, TEE-CD should be performed to investigate
PFO.
PMID- 9396367
TI - [A case of adult meningitis with bilateral sensorineural hearing loss at the
onset].
AB - Here we report a case of pneumococcal meningitis with bilateral sensorineural
hearing loss at the onset. The patient was a 60-year-old man who a few days
before visiting our hospital experienced common cold-like symptoms, and then he
suddenly developed bilateral hearing loss. Examination of the cerebrospinal fluid
(CSF) on the day of admission revealed pleocytosis and his CSF culture
demonstrated pneumococci. Otorhinolaryngological examinations disclosed bilateral
severe sensorineural hearing loss due to cochlear impairment. Many cases of
bacterial meningitis concomitant with hearing loss have been reported, but a case
of meningitis starting with sudden hearing loss is rare.
PMID- 9396368
TI - [Cerebrospinal fluid neuron-specific enolase as a useful indicator for the early
diagnosis of Creutzfeldt-Jakob disease].
PMID- 9396369
TI - [The future of RA treatment].
PMID- 9396370
TI - [Effects of low dose methotrexate therapy in rheumatoid arthritis: a comparison
of three different dosage regimens].
AB - The effectiveness of methotrexate (MTX) in treatment of rheumatoid arthritis (RA)
was evaluated by following the course of 232 cases. The number of cases in which
MTX treatment was assessed as effective amounted to 149 (64.2%), and among these
the number of cases in which the effect was excellent amounted to 59 (25.4%). As
for the time required to achieve the therapeutic effect, effectiveness was
evident within one month in most cases and the more prominent was the result, the
shorter was the time required to achieve the effect. In analysis of it's
effectiveness, no relationship to the patient's background such as morbidity
period, the extent of inflammation, or the period of administration of anti
rheumatic drugs was observed and this drug seems promising for treatment of
severe inflammation in cases of RA with prolonged course enabling application to
a wide range of patients. Also, therapeutic effectiveness was observed in a group
of elderly patients, who were more than 65 years old. However, in such cases, MTX
should be administered carefully because of its reported strong adverse effects.
Its effectiveness and adverse effects have been shown to be dose-dependent.
Therefore, as the optimum dosage of MTX, it is recommended to administer a dose
of 5.0 mg/week initially for an evaluation period of two months and in those
cases in which no effect is observed, the dose is then increased to 7.5 mg/week.
PMID- 9396371
TI - [Expression of matrix metalloproteinases (MMPs) and tissue inhibitor of
metalloproteinases (TIMPs) in joint tissues of rapidly destructive coxarthropathy
(RDC), analyzed by immunohistochemical study].
AB - OBJECTIVE: Rapidly destructive coxarthropathy (RDC) is characterized by rapid
destruction of hip joints, but its pathogenetic mechanism is still obscure.
Matrix metalloproteinases (MMPs) are possibly one of the candidates concerning
with this mechanism. We attempted histochemical investigation to demonstrate MMPs
and tissue inhibitor of metalloproteinases (TIMPs) in joint tissues obtained from
RDC patients to clarify their roles in the destruction mechanism. MATERIALS AND
METHODS: Joint tissues including synovia and cartilage-bone tissues were obtained
from RDC patients at total hip replacement (THR). After fixation with 4%
paraformaldehyde, cartilage-bone tissues were partly decalcified. We performed
histochemical study for paraffin sections of these tissues by using avidin-biotin
method. Antibodies used in this study were monoclonal antibodies to MMP-1, MMP-2,
MMP-7, MMP-8, MMP-9, TIMP-1, TIMP-2 and polyclonal antibody to MMP-3. RESULTS:
Histological feature of RDC was severe destruction of cartilage and bone by
invasion of non-specific granulation tissues composed of many small vessels,
macrophages and fibroblastic cells. At the same time, RDC showed apparently fewer
lymphocytic cells in these granulation tissues compare with rheumatoid arthritis.
MMP-2 and MMP-9 were expressed most demonstrably in synovia and destructive
regions of femoral heads, especially in osteoclasts, macrophages, and
fibroblastic cells, while MMP-1, MMP-3, were slightly expressed only in the
superficial layer of synovia in limited cases. MMP-8, usually contained in
neutrophils, was not present in RDC. On the other hand TIMP-1 and TIMP-2 were
presented throughout the synovia and destructive regions of femoral heads
including fibroblastic cells, macrophages, osteoblasts and osteocytes.
CONCLUSION: Immunohistochemical study revealed obvious presence of MMP-2 and MMP
9 in synovia and destructive regions of femoral heads in RDC. Those evidence
suggest that MMP-2 and MMP-9 share very important role in the destructive
mechanism of RDC, possibly under imbalance between TIMPs.
PMID- 9396372
TI - [A case of polymyalgia rheumatica with excessive increase of rheumatoid factor].
AB - A 76 year-old woman suffered from muscle pain and stiffness of acute onset in her
shoulder girdle and pelvic girdle, which were followed by mild left temporal
headache and transient arthralgia. Neither joint swelling nor sicca symptom was
observed. Laboratory data showed high ESR (128 mm/hr), positive CRP (12.9 mg/dl),
increased fibrinogen (485 mg/dl) and high titer of rheumatoid factor (RF) (RAHA x
640). Other autoantibodies examined were negative. Muscle enzymes and
electromyogram were within normal limits. Joint X ray didn't reveal the finding
suggestive of RA. After the treatment with prednisolone (PSL) 15 mg/day, clinical
symptoms and laboratory data improved dramatically. Though she had excessive
increase of RF (RAHA x 10240) during therapy, no recurrence of articular symptoms
were recognized. She continues to be well with PSL 5 mg/day after 1 year 5 months
from onset. As for polymyalgia rheumatica (PMR) followed by RA, the appearance or
exacerbation of arthritis corresponding to the elevation of RF occurred in all
previously reported 17 cases. Recurrence of arthralgia corresponding to the
elevation of RF was not recognized in this case. In addition, Hunder et al
reported that PMR with little or no observable joint swelling after several weeks
of symptoms is unlikely to develope RA. Therefore, it is speculated that this
case in unlikely to develope RA and assessment of arthritis corresponding to the
elevation of RF is important to differentiate PMR and elderly-onset RA. This case
of PMR is the 5th case with excessive increase of RF in Japan.
PMID- 9396373
TI - [Two cases with SLE and MCTD developed after a long period of chronic arthritis
that was initially diagnosed as JRA].
AB - In order to discuss the diversity of clinical features and the difficulty in
diagnosis of children with juvenile rheumatoid arthritis (JRA), we present two
cases who have documented the development of systemic lupus erythematosus (SLE)
and mixed connective tissue disease (MCTD) after a long period of disease
characterized only by arthritis that was initially diagnosed as JRA. The first
case was a girl diagnosed for her arthritic joints as polyarticular JRA at 15
years of age. At onset, she had Raynaud phenomenon but autoantibodies such as
anti-nuclear antibody (ANA), anti-DNA antibody, and rheumatoid factor were
negative. Five years after onset, she became ANA positive and 3 years later she
became pregnant. During her pregnancy, she became positive for anti-DNA antibody
without any signs of nephritis. One month after the delivery, however, she
developed butterfly rash, carditis, nephritis, and was diagnosed as SLE. No
destructive changes were observed in her joints though arthritis continued for 8
years form onset to pregnancy. The second case was a 3 years old girl who was
diagnosed as polyarticular JRA. Treatment by aspirin induced complate remission
after one year from the onset. However, 10 years after that remission, she
developed Raynaud phenomenon and arthralgia in her knees and hip joints. Her
laboratory findings showed hypergammaglobulinemia, positive ANA, positive anti
DNA antibody, positive anti-RNP antibody. She was eventually diagnosed as MCTD
when she was found to have polymyositis by EMG and serum CK. In the present
paper, two cases imply the difficulty in diagnosing JRA and diversity of
rheumatic diseases such as JRA, SLE and MCTD. Closer and longer period of
observation is essential for the JRA patients with nondestructive arthritis.
PMID- 9396374
TI - [A case of lupus myocarditis and nephritis with transient foramen jugular
syndrome].
AB - A 46-year-old man was admitted to our clinic because of acute heart failure. Six
years before admission he was pointed out cardiomegary and hematuria. One year
later, he was diagnosed as having jugular foramen syndrome. On admission, he had
a fever and dyspnea. Pansystolic blowing murmur was audible at the apex. The
chest ratio on his chest X-ray was 52.5%. An electrocardiogram showed left
ventricular hypertrophy. An echocardiogram showed marked dilatation and severe
dysfunction of left ventricle. Radionuclide scanning with technetium 99 m
pyrophosphate identified inflammatory change in the apex. Myocardial biopsy
showed fibrotic degeneration and IgG deposits in myocardium. Blood examination
showed anemia, lymphopenia. positive anti-nuclear antibody (1000 times, shaggy
pattern), positive anti ds-DNA antibody and hypocomplementemia. Furthermore,
proteinuria was pointed out. Renal biopsy showed focal segmental
glomerulonephritis with active necrotizing lesion (type III nephritis). Lupus
myocarditis and nephritis was diagnosed. After prednisolone (80 mg/day) was
administered. left ventricular function and hypocomplementemia improved. The ACE
inhibitor was also used for proteinuria. In spite of a little amount of blood
transfusion, he showed hepatic hemosiderosis. We suspect that the cause of
hemosiderosis was related chronic inflammation of active lupus. It was treated
with Erythropoietin.
PMID- 9396376
TI - [Successful treatment of interstitial pneumonia with lipo-PGE1 and pentoxifylline
in a patient with dermatomyositis].
AB - Interstitial pneumonia complicated with dermatomyositis sometimes shows a
resistance to high dose steroid therapy and a fatal course particularly in
patients without showing the elevation of creatine kinase. We experienced a 48
year old woman who developed heliotrope rash, Gottron's sign, multiple cutaneous
ulcers, and dyspnea on exertion. These symptoms were resistant to low dose
steroid therapy. Serum levels of creatine kinase were normal. Anti-nuclear
antibodies and anti-Jo-1 antibody were negative. High resolution CT scan of the
chest showed areas of multiple air space consolidation and subpleural linear
shadows. Lung biopsy performed under video-assist thoracosurgery revealed diffuse
alveolitis with scattered lymphoid folicules and mild accumulation of macrophages
in the alveolar spaces. There were no honey-combing. These features were
compatible with "non-specific interstitial penumonia" proposed by Katzenstein,
1995. The patient was treated with 10 micrograms lipo-PGE1, PGE1 incorporated in
lipid microspheres, and 300 mg pentoxifylline, which resulted in a dramatic
improvement of both interstitial pneumonia and cutaneous ulcers. The present case
suggested a novel strategy for the treatment of interstitial pneumonia.
PMID- 9396375
TI - [A case of amyopathic dermatomyositis associated with interstitial pneumonitis].
AB - A patient (47-year old female) who had erythema similar to Gottron's sign on
bilateral finger joints since two years ago, started to have polyarthralgia on
bilateral knee and shoulder on the spring of 1993. Polyarthralgia was extended to
both wrist and hand joints on Oct. of 1995. On the middle of Dec. 1995, she began
to have exertional dyspnea and was referred and admitted in our hospital on 18th,
Dec., 1995. Chest X-ray and CT scan showed the shadow for active interstitial
pneumonitis on bilateral lower lung fields. Blood gas analysis indicated hypoxia
(PaO2: 62.8 mmHg) and low % DLCO (64.7%). Skin eruption of face (heliotrope-like
erythema) and hands (Gottron's sign) and skin biopsy (right hand) findings were
compatible with that in dermatomyositis. The analysis in blood biochemistry
showed no elevation for muscle enzymes. The diagnosis for amyopathic
dermatomyositis (ADM) was made according to the criteria proposed by Euwer &
Sontheimer (1993). The steroid pulse therapy and 50 mg per day of
cyclophosphamide were immediately administered. The dyspnea and dermatitis were
improved within two weeks after therapy. She is presently in remission until Jan.
1997 with the maintenance dosis of 10 mg per day of oral prednisolone.
PMID- 9396377
TI - [The organ involvement and treatment in SLE].
PMID- 9396378
TI - [Cellular mechanisms of bone resorption in rheumatoid arthritis].
PMID- 9396379
TI - Particulate air pollution and daily mortality: can results be generalized to
Latin American countries?
AB - OBJECTIVE: Recently, a series of reports, based on ecological analyses of
routinely collected data, have shown positive associations between measures of
particle concentration and daily mortality counts in various cities of the US and
Europe. MATERIAL AND METHODS: We reviewed the process of generalization of these
results to Latin American countries addressing possible differences in air
pollution mixtures, exposure profiles, and population susceptibility. RESULTS: A
limitation to the process of generalization is the lack of a well-established
biological mechanism by which particles may act on daily mortality. Also, sources
and levels of ambient air pollution as well as population characteristics and
habits vary widely between Northern communities of Europe and the US, and Latin
American countries, which impairs the process of generalization. However, results
of studies conducted in Latin American countries suggest a similar effect to that
observed in Northern countries of Europe and the US. CONCLUSIONS: Despite
uncertainty about the mechanism, there is sufficient evidence that particles are
harmful for health. Control measures of particle emission are urgently needed in
Latin American countries. Given the potential of misclassification of exposure,
the dose-response relationship observed in Northern Europe and the US may not be
adequate for Latin American populations. There is a need for a new generation of
epidemiological studies including a specific assessment of exposure to fine
particles and of events surrounding death.
PMID- 9396380
TI - The challenge and prize for international health organizations in the Americas.
PMID- 9396381
TI - The Soteria-concept. Theoretical bases and practical 13-year-experience with a
milieu-therapeutic approach of acute schizophrenia.
PMID- 9396382
TI - [The delusion of theft in elderly with dementia--(2) Pathogenesis of the
delusion; dynamic and structural aspects].
PMID- 9396383
TI - [Clinical examination on localization-related epilepsies with elementary visual
seizures--clinical, electroencephalographic and imaging diagnostic studies].
AB - The clinical, electroencephalographic and Imaging diagnostic features of the 45
patients of Localization-related Epilepsy who had elementary visual symptoms at
seizure onset were investigated. There were 24 males and 21 females aged 19 to
78. Their ages at seizure onset ranged from 1 to 55 with a mean of 15.4. The
patients were divided into 3 groups based on the pattern of elementary visual
symptoms: Group 1; 23 patients (51%) with only elementary positive visual
symptoms, Group 2; 9 patients (20%) with only elementary negative visual
symptoms, Group 3; 13 patients (29%) with others. It came to our notice that 8
(18%) patients in Group 3 had positive + negative (P*N) visual seizures such as
scintillation scotoma. It was quite difficult to draw a distinction between the
P*N seizures and scintillation scotoma in migrainous patients in quality.
Therefore, a question arises whether similarities between them are ascribed to
the same underlying mechanism. It is possible that the mechanism of the P*N
seizures is different from that of the scintillation scotoma, but the both
produce the same condition. However, we are not competent to discuss this
hypothesis. Further work along this line is necessary. In addition to the
elementary visual symptoms, autonomic (69%), focal motor (29%), illusion (29%),
vertiginous (22%) manifestations, etc. were also observed. These manifestations
suggest that epileptic ictal discharges spread into many different brain areas.
Regarding Group 1-3, occurrence of illusional seizures was more common in Group
2. In this group, in only one patient, occipital interictal discharges were
observed. The subjects were subclassified into two groups depending on whether
the seizures were well controlled (good outcome) or poorly controlled (poor
outcome group). On these groups, comparative studies were performed. The
poportion of the patients with a family history of convulsive disorder was higher
in the latter than that in the former. To the contrary, the poportion of the
patients with a etiologic episode was higher in the former than that in the
latter. With respect to the imaging study, regardless of localizations, abnormal
findings were detected in 25% on CT scan, in 29% on MRI, and in 71% on SPECT.
Whether or not these abnormal findings completely or partially agreed with
presumed epileptogenic brain region (occipital lobes) was investigated. CT scan
was positive (correspondent) in 8%, MRI was positive in 13%, and SPECT was
positive in 54%. The incidence of SPECT abnormalities was higher in the poor
outcome group (70 %) than that in the good outcome one (43%). We may, therefore,
conclude that SPECT seems to be useful for the detection of epileptogenic region,
especially in intractable cases. But the incidence of these imaging studies'
abnormalities located in occipital lobe was not so high, therefore, there seems
to be no doubt that clinical symptoms and EEG findings are most important for
diagnosis.
PMID- 9396384
TI - Synthesis and pharmacological activity of two derivatives of the amide of
valproic acid.
AB - Valproic acid (VPA), a synthetic branched-chain fatty acid, and its pro-drug the
primary amide (VPD) are effective and widely used anti-epileptic agents. Although
the use of VPA has grown in recent years, major side effects are still associated
with this drug. We presume that it is possible, without loosing the VPD
pharmacological profile, to obtain new compounds by undertaking substitutions in
the CONH group. N,N'-bis-(2-propylpentanoyl)- 1,2-ethanediamine (3) and N,N'-bis
(2-propylpentanoyl)-1,3-propanediamine (4) were obtained from VPA (1) using a
method reported in the literature. The chemical structures of the new compounds
were demonstrated by elemental analysis, IR, and 1H NMR spectroscopy. Both
compounds are less toxic and more effective in protecting the animals from death
caused by PTZ than VPD after intraperitoneal administration to mice.
PMID- 9396385
TI - Synthesis and antitumor activity of 9-anilino, phenylhydrazino, and sulphonamido
analogs of 2- or 4-methoxy-6-nitroacridines.
AB - Synthesis of several new 9-anilino, phenylhydrazino, and sulphonamido analogs of
2- or 4-methoxy-6-nitroacridine derivatives is described. The prepared compounds
were tested for their in vitro antitumor activity against 60 human tumor cell
lines by the National Cancer Institute (NCI) and showed a potential anticancer
activity. Compounds 9-(phenylhydrazino)-2-methoxy-6-nitroacridine (8a) and 9-(4
chlorophenylhydrazino)-4-methoxy-6-nitroacridine (9b) exhibited a broad spectrum
antitumor activity with full panel (MG-MID) median growth inhibition (GI50), of
16.1 and 10.9 microM and total growth inhibition (TGI) of 66.7 and 37.9 microM,
respectively. Meanwhile, compounds 15a and 15b showed moderate selectivity toward
leukemia cell lines. As a trial to explore the mode of action of their antitumor
activity, the 6-nitroacridine analogs were evaluated for their inhibitory effect
on major cell cycle control proteins cdc2 kinase and cdc25 phosphatase as
possible molecular targets that may account for antimitotic potency. None of the
tested compounds proved to exert their activity via this antimitotic mode of
action.
PMID- 9396386
TI - Studies in sugar chemistry. VII. Glucuronides of podophyllum derivatives.
AB - The antitumor activities of several glucuronide methyl esters of podophyllum
derivatives were tested in vitro against two human tumor cell lines and their
drug resistant sublines. The most active compound studied was methyl (4'
carbobenzoxy-4'-demethyl-epipodophyllotoxin-D-glucopyranoside)uronat e 19.
Compound 19 was as potent in a colon carcinoma model and was twice as potent in a
lung carcinoma model as etoposide 6. In vivo, however, in a mouse leukemia P388
model, it had only marginal activity, with a maximum T/C% value of 125 at 37
mg/kg (iv).
PMID- 9396387
TI - Synthesis and calcium channel modulating effects of isopropyl 1,4-dihydro-2,6
dimethyl-3-nitro-4-(thienyl)-5-pyridinecarboxylates.
AB - A group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(thienyl)-5
pyridinecarboxylates++ + 7a-f were prepared using a modified Hantzsch reaction
that involved the condensation of a thienylcarboxaldehyde 4a-f with isopropyl 3
aminocrotonate 5 and nitroacetone 6. In vitro calcium channel antagonist
activities were determined using a guinea pig ileum longitudinal smooth muscle
(GPILSM) assay. Compounds 7a-f exhibited weaker calcium channel antagonist
activity (IC50 = 10(-5) to 10(-7) M range) than the reference drug nifedipine
(IC50 = 1.43 x 10(-8) M). The point of attachment of the C-4 thienyl ring system
was a determinant of antagonist activity [3-thienyl (7b) > 2-thienyl (7a)]. A 5
substituent in the 2-thienyl moiety influenced antagonist activity where the
potency order was 5-bromo-2-thienyl 7f > or = 5-methyl-2-thienyl 7c > 2-thienyl
7a. Although the 5-methyl-2-thienyl 7c and 3-methyl-2-thienyl 7d isomers are
equipotent antagonists, the 5-bromo-2-thienyl compound 7f appears to be
marginally more active than the 4-bromo-2-thienyl isomer 7e. The 2-thienyl
compound 7a, unlike the 3-thienyl isomer 7b, exhibited an agonist effect on
GPILSM in the absence of the muscarinic agonist carbachol. Effects of the 2
thienyl 7a and 3-thienyl 7b isomers on the magnitude of calcium current were
determined in guinea pig ventricular myocytes with voltage clamp techniques.
Results showed that 2-thienyl 7a inhibited calcium current (antagonist) when
voltage steps were made from a potential of -40 mV. However, when voltage steps
were made from -60 mV, 7a enhanced calcium current (agonist). The 3-thienyl
isomer 7b had little, if any, effect on calcium current.
PMID- 9396388
TI - Synthesis, uterotrophic, and antiuterotrophic activities of some estradiol
derivatives containing thiadiazole, thiazoline, and thiazolidinone moieties.
AB - The effect of structural modification on the biological activity of hormones has
been studied on five novel series of estradiol analogs bearing a variety of
substituents at the 2-position of the steroidal nucleus. The synthesized
compounds include 2-[2-(5-substituted amino-1,3,4-thiadiazol-2-yl)vinyl]estradiol
17 beta-acetate 5-9, 2-aroylmethylestradiols 10-12, 2-[2-aryl-2-(substituted
thiocarbamoylhydrazono)ethyl]estradiols 13-18 and their cyclic thiazoline 19-24,
and thiazolidinone derivatives 25-30. Among the products, the p
hydroxybenzolmethylestradiol 12 exhibited the highest antiestrogenic activity of
63%. It also elicited 34% of the uterotrophic activity of estradiol.
PMID- 9396389
TI - Microsomal catalyzed N-hydroxylation of guanfacine and reduction of N
hydroxyguanfacine.
AB - Guanfacine 1 is a well known centrally acting alpha 2-adrenoceptor agonist with
antihypertensive activity. The drug belongs to the guanidine class of compounds.
The N-oxidative biotransformation of guanfacine was investigated in vitro in the
presence of hepatic microsomal fractions from rabbits, pigs, and humans. The N
hydroxylated derivative N-hydroxyguanfacine 2 had to be synthesized as reference
for the identification of the metabolite. The corresponding in vitro
retroreduction of N-hydroxyguanfacine 2 was also investigated using the same set
of enzyme sources. A new HPLC analytical method was developed in order to isolate
and quantify the metabolites. A complete metabolic cycle involving the oxidative
metabolism of guanfacine could only be observed in the presence of microsomal
fractions from rabbitt livers, whereas enzyme sources of all species under
investigation catalyzed the N-reduction of N-hydroxyguanfacine 2.
PMID- 9396390
TI - Synthesis and evaluation of a novel series of pyrrolizine derivatives as dual
cyclooxygenase-1 and 5-lipoxygenase inhibitors.
AB - The aim of our study was to investigate structure activity relationship following
the replacement of the 6-phenyl substituent at the 6,7-diaryl-2,3
dihydropyrrolizine template by various heteroaromatic residues. In this context
we developed a new, efficient, and highly sensitive test method for the screening
of dual cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitors. We used
human platelets as a source of COX-1 and human PMNLs as a source of 5-LOX. Both
cell types were isolated from the same volume of blood. PGE2 and LTB4
respectively were determined by highly selective and sensitive ELISA kits, using
monoclonal antibodies. For a single determination at most 0.5 mL whole blood is
needed.
PMID- 9396391
TI - An improved synthesis of the anti-picornavirus flavone 3-O-methylquercetin.
PMID- 9396392
TI - Chemosensitive gliomas in adults: which ones and why?
PMID- 9396393
TI - Salvage chemotherapy with paclitaxel for recurrent oligodendrogliomas.
AB - PURPOSE: A prospective phase II study of paclitaxel was performed in adult
patients with recurrent hemispheric oligodendrogliomas. PATIENTS AND METHODS:
Twenty adult patients (14 men and six women), ages 18 to 52 years (median, 40.5),
with recurrent supratentorial hemispheric oligodendrogliomas were treated. All
patients had previously been treated with surgery, involved-field radiotherapy
(median dose, 55 Gy; range 54 to 55 Gy) and nitrosourea-based (procarbazine,
lomustine [CCNU], and vincristine [PCV-3 regimen]) chemotherapy (median number of
cycles, five; range, four to six). Fourteen patients were treated adjuvantly with
radiotherapy and nitrosourea-based chemotherapy; six were treated at recurrence
following initial gross total resection with reoperation (subtotal resection in
all), radiotherapy, and nitrosourea-based chemotherapy. Paclitaxel was
administered intravenously at a dose of 175 mg/m2 every 3 to 4 weeks with
neurologic and neuroradiographic evaluation every 8 weeks. RESULTS: A median of
three cycles of paclitaxel (range, two to 10) were administered. All patients
were assessable. Toxicity included partial alopecia (12 patients),
thrombocytopenia (six), neutropenia (three), and anemia (one). One patient
developed neutropenic fever without bacteriologic documentation and four required
transfusion of blood products (RBCs, n = 2; platelet, n = 2). No treatment
related deaths occurred. Ten patients (50%) demonstrated either a
neuroradiographic partial response (n = 3) or stable disease (n = 7), with a
median response and stable disease duration of 10 months (range, 5 to 14).
CONCLUSION: Paclitaxel demonstrated modest efficacy with minimal toxicity in this
pretreated cohort of adult patients with recurrent hemispheric
oligodendrogliomas.
PMID- 9396395
TI - Gemcitabine: a promising new agent in the treatment of advanced urothelial
cancer.
AB - PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2',2'
difluorodeoxycytidine) in previously untreated patients with advanced
transitional cell carcinoma. PATIENTS AND METHODS: Forty-one patients with
measurable advanced transitional cell carcinoma who had received no prior
chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,200
mg/m2 intravenously over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Prior
adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this
was completed greater than 1 year prior to study entry. All patients were treated
on an outpatient basis. RESULTS: There were three complete responses and six
partial responses seen in 37 assessable patients, for an overall response rate of
nine of 37 (24.3%; 95% confidence interval, 12 to 41). Four patients remain in
remission at 14, 23, 24, and 31 months. The median survival was 8 months with 17%
of patients alive at 2 years. Treatment generally was well-tolerated with three
patients having > or = grade 3 nonhematologic toxicity, five having grade 3
neutropenia, two having grade 3 thrombocytopenia, and two episodes of febrile
neutropenia. Most patients were able to receive the drug as scheduled with the
primary reason for dose reduction or dose delay being neutropenia. CONCLUSION:
Gemcitabine has promising single-agent activity against urothelial cancer with a
favorable toxicity profile. Further studies in combination with other active
agents are warranted.
PMID- 9396394
TI - NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age:
a report from the French Society of Pediatric Oncology.
AB - PURPOSE: NB87 was designed to test the efficacy of a short, non cross-resistant,
induction protocol for unselected patients over 1 year of age with stage 4
neuroblastoma. A secondary objective was to compare in a randomized study the
toxicity of two modalities of cisplatin administration. PATIENTS AND METHODS: A
total of 183 patients received two cycles of alternating sequences:
cyclophosphamide 300 mg/m2/d on days 1 to 5, vincristine 1.5 mg/m2/d on days 1
and 5, and doxorubicin 60 mg/m2/d on day 5 (CADO); and cisplatin 40 mg/m2/d and
etoposide 100 mg/m2/d on days 1 to 5 (CVP), followed by surgery of the primary
tumor (126 patients). Ninety-one were randomized to receive cisplatin either as
bolus (BO; n = 48) or continuous infusion (CI; n = 43). International
Neuroblastoma Staging System (INSS) and Response Criteria (INRC) were used with
emphasis on skeletal evaluation by meta-iodobenzylguanidine (MIBG). RESULTS:
Hematotoxicity was predominant, with a higher incidence of neutropenia (P = .01)
for CADO and of thrombocytopenia for CVP (P < .001). Severe infections, as well
as nonhematologic toxicities, occurred more often after the first sequence.
Gastrointestinal complications were predominant during both courses of CVP. The
toxic death rate, including surgery, was 3%. Complete remissions (CRs) were less
frequent on MIBG (45%) compared with marrow (66%) or other metastases (61%).
Combining all metastatic sites resulted in a 39% CR rate. After surgery, the
final CR rate was 42%. Nephrotoxicity was minimal in both arms (92% normal
clearance for CI v 82% for BO). Hearing loss greater than 40 dB at 6,000 to 8,000
Hz was reported equally in both arms (n = 6 for CI v n = 5 for BO). CONCLUSION:
Intensified chemotherapy using CADO/CVP increases CR rates despite a shorter
induction duration. However, the rate of MIBG normalization remains
unsatisfactory and could be raised through the dose-intensive use of agents such
as cyclophosphamide.
PMID- 9396396
TI - Serum tissue polypeptide antigen in bladder cancer as a tumor marker: a
prospective study.
AB - PURPOSE: Tissue polypeptide antigen (TPA) is a differentiation and proliferation
tissue marker of epithelia. Increased serum levels were found in some patients
with invasive bladder cancer. We present the results of a prospective study that
evaluated the role of serum TPA (S-TPA) in bladder carcinoma. PATIENTS AND
METHODS: The series included 167 patients treated for invasive bladder cancer
between 1989 and 1996. S-TPA concentrations were measured by radioimmunoassay
before treatment, at the end of treatment, and during follow-up evaluation. The
upper normal limit of the test was set at 80 UI/L. RESULTS: With a specificity of
100%, the diagnostic sensitivity was 46%. Pretherapeutic S-TPA levels were
significantly correlated with tumor stage (T2 v T3 and T4; P = .02), with nodal
stage (N0 v N1 and N2; P = .00001), and with metastatic stage (M0 v M1; P = 10[
6]), but not with histologic grading (grade 1 and 2 v 3). In the subset of
patients with normal pretherapeutic S-TPA levels, 95% had no residual disease at
the end of treatment, compared with 53% of patients with initial elevated S-TPA
(P = 10[-8]). Among patients who achieved a complete response, 27% experienced a
relapse, with an increase of S-TPA in 72% of cases. The mean follow-up time was
20 +/- 17 months. For patients with normal pretherapeutic S-TPA levels, 3-year
overall survival and disease-free survival rates were 76% and 67% respectively.
These were 46% (P = .001) and 25% (P = 10[-7]), respectively, for patients with
high pretherapeutic S-TPA. Multivariate analysis showed that S-TPA was an
independent prognostic factor for survival (P = .03). CONCLUSION: In invasive
bladder cancer, S-TPA level is correlated with initial tumor stage. It is a
valuable parameter for follow-up evaluation and appears to be a prognostic factor
in multivariate analysis.
PMID- 9396397
TI - Presence of circulating prostate cells in the bone marrow of patients undergoing
radical prostatectomy is predictive of disease-free survival.
AB - PURPOSE: To determine whether the presence of circulating prostate cells in the
bone marrow is associated with disease-free survival in patients undergoing
radical prostatectomy. MATERIALS AND METHODS: We evaluated the bone marrow of 86
patients with clinically localized prostate cancer treated by radical
prostatectomy for the presence of circulating prostate cells using reverse
transcriptase polymerase chain reaction (RT-PCR) amplification of prostate
specific antigen (PSA) mRNA. Follow-up duration ranged from 1 to 43 months (mean,
15.4). RESULTS: Two of 47 patients (4%) with negative RT-PCR PSA results and 10
of 39 patients (26%) with positive RT-PCR PSA results have had disease
recurrence. Patients whose RT-PCR PSA results were positive had a significantly
shorter disease-free survival period than those patients with negative RT-PCR PSA
results (P = .004). RT-PCR status correlated significantly with serum PSA level
(P = .001) and pathologic stage (P = .003). Based on Cox's proportional hazards
models, RT-PCR status was found to be a significant predictor of disease-free
survival. However, after controlling for PSA level, RT-PCR status was not
significant in predicting disease-free survival. CONCLUSION: RT-PCR PSA of bone
marrow may be a useful pretreatment prognostic test for patients undergoing
radical prostatectomy. Currently, this test should not be used to determine if
patients receive definitive local therapy.
PMID- 9396398
TI - Retinoblastoma protein and proliferating-cell nuclear antigen expression as
predictors of recurrence in well-differentiated papillary thyroid carcinoma.
AB - PURPOSE: We analyzed retinoblastoma protein (pRB) and proliferating-cell nuclear
antigen (PCNA) expression in primary tumors and recurrent lesions of well
differentiated papillary thyroid carcinoma (PTC) to clarify the relationship
between their expression and recurrent disease. PATIENTS AND METHODS: The study
included 93 patients with PTC. No recurrent disease had developed in 60 patients
within 10 years after surgery (group N). Thirty patients in whom recurrent
disease had developed after surgery were enrolled in group R. Levels of pRB and
PCNA expression were quantified using the CAS 200 system (Cell Analysis Systems,
Elmhurst, IL) following immunohistochemical staining. RESULTS: Mean pRB
expression level in the primary tumors in group R was significantly lower than
that in group N (P < .0001). pRB expression in the tumors with a diameter up to
20 mm was significantly lower than that in tumors larger than 20 mm in group R (P
< .01). There were no significant differences in the levels of expression of PCNA
in the primary tumors between group N and group R. Univariate analysis
demonstrated that the disease-free survival was significantly correlated with pN
category, pRB, and PCNA expression level. The subgroup with high-level expression
of pRB (> 25%) showed significantly long disease-free survival (P < .001).
Furthermore, the subgroup with low-level expression of PCNA (< 35%) showed
significantly longer disease-free survival (P < .05). Multivariate analysis
showed pRB expression and pN category to be independent prognostic factors for
disease-free survival in PTC. CONCLUSION: pRB expression level can be used as a
reliable predictor for recurrence of PTC.
PMID- 9396400
TI - Chronologic changes in the clinicopathologic findings and survival of gastric
cancer patients.
AB - PURPOSE: To determine the chronologic changes in the clinicopathologic features
of gastric cancer patients. PATIENTS AND METHODS: The clinicopathologic findings
of 1,795 patients with gastric cancer were examined retrospectively from hospital
records obtained between 1969 and 1995. The patients were divided into three
generations on the basis of chronologic order. The first generation included
patients treated over the period 1969 to 1977; the second generation, 1978 to
1986; and the third generation, 1987 to 1995. RESULTS: The chronologic changes in
the clinicopathologic findings for all gastric cancers included increases in the
superficial type based on macroscopic appearance (P < .005), small-sized tumor (P
< .025), superficial depth of invasion (P < .005), and earlier histologic stages
(P < .005), in addition to a decrease in lymph node metastasis (P < .005).
Overall, the postoperative survival rate has improved over time in gastric cancer
patients, with 5-year survival rates of 36.0%, 53.3%, and 68.6% in the first,
second, and third generations, respectively. In stages 1,2, and 3, the survival
rate in the third generation was the highest of the three generations, whereas in
stage 4, the survival rate did not differ between the three generations. Patients
who underwent a D2 dissection showed a higher survival rate than those with D1 or
D3 dissections, but there was no statistical difference in the survival of
patients with D1, D2, and D3 dissections when stage 4 patients were excluded.
CONCLUSION: The chronologic changes in gastric cancer patients over the past 27
years have included an increase in the incidence of earlier-staged gastric
cancers, which has had a significant impact on the improved postoperative
survival rate.
PMID- 9396399
TI - Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of
small-cell lung cancer: comparison of sequential phase II trials using different
dose-intensities.
AB - PURPOSE: In two sequential phase II studies, we evaluate the feasibility and
efficacy of adding paclitaxel to a standard platinum/etoposide regimen in the
first-line treatment of small-cell lung cancer. PATIENTS AND METHODS: One hundred
seventeen patients with small-cell lung cancer were treated between June 1993 and
July 1996. The first 38 patients received a lower-dose regimen: paclitaxel 135
mg/m2 by 1-hour infusion, carboplatin at an area under the concentration-time
curve (AUC) of 5.0, and etoposide 50 mg alternating with 100 mg orally on days 1
to 10. When only mild myelosuppression was observed, doses of paclitaxel and
carboplatin were increased in the subsequent 79 patients (paclitaxel 200 mg/m2 by
1-hour infusion and carboplatin at an AUC of 6.0). All patients received four
courses of treatment, administered at 21-day intervals. Patients with limited
stage small-cell lung cancer also received thoracic radiation therapy (1.8 Gy/d;
total dose, 45 Gy) administered concurrently with courses 3 and 4 of
chemotherapy. RESULTS: Seventy-two of 79 patients (91%) who receive the higher
dose regimen had major responses. Thirty-two of 38 (84%) with extensive-stage
disease responded (21% complete response rate); median survival was 10 months for
this group. With limited-stage disease, the overall response rate was 98%, with
71% complete responses; the median survival time has not been reached at 16
months. Median survival in extensive-stage patients was longer in patients who
received the higher-dose regimen (10 months) than in the previous group treated
with lower doses (7 months; P = .008). The higher-dose regimen was well
tolerated, with myelosuppression being the major toxicity. Compared with the
lower-dose regimen, grade 3/4 neutropenia increased from 8% to 38% of courses,
but the incidence of hospitalization for neutropenia and fever did not increase.
Other nonhematologic toxicities were uncommon, and did not increase substantially
with the higher-dose regimen. CONCLUSION: Paclitaxel can be added at full dose
(200 mg/m2) to a carboplatin/etoposide combination while maintaining a tolerable
toxicity profile. Median survival times in both extensive- and limited-stage
patients compare favorably with other reported regimens. This regimen merits
further investigation, and a randomized trial to compare this regimen with a
standard carboplatin/etoposide combination is underway.
PMID- 9396401
TI - Preoperative chemotherapy for stage IIIB extremity soft tissue sarcoma: long-term
results from a single institution.
AB - PURPOSE: To review a single institution's long-term results with doxorubicin
based preoperative chemotherapy for American Joint Committee on Cancer (AJCC)
stage IIIB extremity soft tissue sarcoma (STS). PATIENTS AND METHODS: The records
of all patients with AJCC stage IIIB extremity STS treated with preoperative
chemotherapy between 1986 and 1990 at The University of Texas M.D. Anderson
Cancer Center were reviewed to assess rates of response, local recurrence-free
survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival
(DFS), and overall survival (OS). RESULTS: Seventy-six patients with stage IIIB
disease received preoperative chemotherapy. The median sarcoma size was 10 cm.
Seventy-two patients (95%) had tumors located deep to the muscular fascia. Most
patients received a median of three preoperative cycles of doxorubicin and
dacarbazine (ADIC), cyclophosphamide and ADIC (CyADIC), or other doxorubicin
based regimens. Radiographic response rates were as follows: complete response
(CR), 9%; partial response (PR), 19%; minor response, 13%; stable disease, 30%;
and progression, 30%. The overall objective major response rate (CRs plus PRs)
was 27%. At a median follow-up time of 85 months, 5-year actuarial rates of LRFS,
DMFS, DFS, and OS with 95% confidence intervals (CIs) were 83% (CI, 73% to 94%),
52% (CI, 41% to 66%), 46% (CI, 35% to 60%), and 59% (CI, 48% to 72%),
respectively. Comparison of responding patients (CRs plus PRs) and nonresponding
patients did not show any significant differences in LRFS, DMFS, DFS, or OS.
CONCLUSION: Preoperative doxorubicin-based chemotherapy was associated with
response, DFS, and OS rates similar to those observed in randomized postoperative
chemotherapy trials. Responding patients had rates of LRFS, DMFS, DFS, and OS
comparable to those of nonresponders.
PMID- 9396402
TI - Rapid recovery of spermatogenesis after mitoxantrone, vincristine, vinblastine,
and prednisone chemotherapy for Hodgkin's disease.
AB - PURPOSE: Because the effects of mitoxantrone on human male fertility were
unknown, we determined prospectively the effects of three courses of mitoxantrone
(Novantrone), vincristine (Oncovin), vinblastine, prednisone (NOVP) chemotherapy
on the potential for fertility of men with Hodgkin's disease (HD). PATIENTS AND
METHODS: Semen analyses were performed on 58 patients with stages I-III HD
before, during, and after chemotherapy and after the sperm count recovered from
the effects of abdominal radiotherapy that was given after chemotherapy. RESULTS:
Before the initiation of treatment, 84% of the patients were normospermic. Sperm
counts declined significantly within 1 month after the start of NOVP
chemotherapy. In the month after chemotherapy, 38% of patients were azoospermic,
52% had counts < 1 million/ mL, and 10% had counts between 1 and 3 million/mL.
Between 2.6 and 4.5 months after the completion of chemotherapy, sperm counts
recovered rapidly to normospermic levels in 63% of patients. In the remaining
patients who were followed up for at least 1 year after standard upper abdominal
radiotherapy, counts also recovered to normospermic levels. CONCLUSION: NOVP
chemotherapy, like most other regimens, produced marked temporary effects or
spermatogenesis. However, sperm production recovered very rapidly, within 3 to 4
months after the end of NOVP chemotherapy. This pattern was caused by killing
differentiating spermatogenic cells, but there was little cytotoxicity or
inhibition of stem cells from mitoxantrone or the other drugs. After the
combination of NOVP plus abdominal radiotherapy, sperm counts and motility were
restored in most patients to pretreatment levels, which were compatible with
normal fertility.
PMID- 9396403
TI - Value of different modalities of granulocyte-macrophage colony-stimulating factor
applied during or after induction therapy of acute myeloid leukemia.
AB - PURPOSE: The hematopoietic growth factors (HGFs) introduced into induction
chemotherapy (CT) of acute myeloid leukemia (AML) might be of benefit to
treatment outcome by at least two mechanisms. HGFs given on days simultaneously
with CT might sensitize the leukemic cells and enhance their susceptibility to
CT. HGFs applied after CT might hasten hematopoietic recovery and reduce
morbidity or mortality. MATERIALS AND METHODS: We set out to evaluate the use of
granulocyte-macrophage colony-stimulating factor (GM-CSF; 5 microg/kg) in a
prospective randomized study of factorial design (yes or no GM-CSF during CT, and
yes or no GM-CSF after CT) in patients aged 15 to 60 years (mean, 42) with newly
diagnosed AML. GM-CSF was applied as follows: during CT only (+/-, n = 64
assessable patients), GM-CSF during and following CT (+/+, n = 66), no GM-CSF (-/
, n = 63), or GM-CSF after CT only (-/+, n = 60). RESULTS: The complete response
(CR) rate was 77%. At a median follow-up time of 42 months, probabilities of
overall survival (OS) and disease-free survival (DFS) at 3 years were 38% and 37%
in all patients. CR rates, OS, and DFS did not differ between the treatment
groups (intention-to-treat analysis). Neutrophil recovery (1.0 x 10(9)/L) and
monocyte recovery were significantly faster in patients who received GM-CSF after
CT (26 days v 30 days; neutrophils, P < .001; monocytes, P < .005). Platelet
regeneration, transfusion requirements, use of antibiotics, frequency of
infections, and duration of hospitalization did not vary as a function of any of
the therapeutic GM-CSF modalities. More frequent side effects (eg, fever and
fluid retention) were noted in GM-CSF-treated patients predominantly related to
the use of GM-CSF during CT. CONCLUSION: Priming of AML cells to the cytotoxic
effects of CT by the use of GM-CSF during CT or accelerating myeloid recovery by
the use of GM-CSF after CT does not significantly improve treatment outcome of
young and middle-aged adults with newly diagnosed AML.
PMID- 9396404
TI - Response rate accuracy in oncology trials: reasons for interobserver variability.
Groupe Francais d'Immunotherapie of the Federation Nationale des Centres de Lutte
Contre le Cancer.
AB - PURPOSE: We evaluated the impact of an evaluation committee (EC) on patients'
overall response status in a large multicenter trial in oncology. We identified
reasons for disagreements between investigators and the EC. MATERIALS AND
METHODS: The Cancer Renal Cytokine (CRECY) study was a French multicenter trial
that tested cytokine therapy in 489 patients with metastatic renal cell
carcinoma. Objective response (OR) evaluation included medical imaging and was
studied according to international guidelines. A blinded peer review of all
responders and litigious cases was performed by an EC. RESULTS: Major
disagreements occurred in 40% and minor disagreements in 10.5% of the reviewed
files. The number of significant tumor responses was reduced by 23.2% after
review by the EC. Reasons for disagreements included errors in tumor
measurements, errors in selection of measurable targets, intercurrent diseases,
and radiologic technical problems. These reasons for disagreements are analyzed
and discussed. CONCLUSION: We conclude that all therapeutic trial results should
be reviewed by peer analysis of all presumed responders by an EC. International
guidelines for response evaluation should be updated by including more reliable
methods of measurements and definition of minimal imaging procedures.
PMID- 9396405
TI - Breast cancer associated with palmar fasciitis and arthritis.
PMID- 9396406
TI - Socioeconomic status versus survival in Ontario.
PMID- 9396407
TI - Simplified regimen for the prevention of paclitaxel-associated hypersensitivity
reactions.
PMID- 9396408
TI - Does coronary endothelial dysfunction cause myocardial ischemia in the absence of
obstructive coronary artery disease?
PMID- 9396409
TI - When 'normal' cholesterol levels injure the endothelium.
PMID- 9396410
TI - Selectins: vital vasculotropic vectors involved in vascular remodeling.
PMID- 9396411
TI - Body iron stores and atherosclerosis.
PMID- 9396412
TI - Oxidative stress and cardiovascular disease.
PMID- 9396413
TI - Transient triglyceridemia decreases vascular reactivity in young, healthy men
without risk factors for coronary heart disease.
AB - BACKGROUND: Hypertriglyceridemia is now accepted as a risk factor for coronary
heart disease, although the mechanism behind the increased risk is not well
understood. The present study was undertaken to investigate the effects of
triglyceridemia on endothelial function, because impaired endothelial function is
considered a marker of atherogenesis. METHODS AND RESULTS: Flow- and
nitroglycerin-induced dilatation of the brachial artery was investigated
noninvasively by high-resolution ultrasound technique in seven young, healthy men
without risk factors for coronary heart disease. Transient triglyceridemia was
induced by infusion of a triglyceride emulsion, Intralipid, which raised free
fatty acid concentrations twofold and triglyceride levels fourfold. Flow-induced
vasodilatation decreased from 7.1+/-3.0% to 1.6+/-2.6% (P<.0002), whereas
nitroglycerin-induced vasodilatation decreased from 20.5+/-5.8% to 11.5+/-3.2%
(P<.002) before and after 1 hour of infusion of Intralipid, respectively.
CONCLUSIONS: Transient triglyceridemia decreases vascular reactivity, presumably
by both endothelium-dependent and endothelium-independent mechanisms.
PMID- 9396414
TI - Impact of respiratory maneuvers on cardiac volume within left-breast radiation
portals.
AB - BACKGROUND: Late cardiac morbidity and mortality have been reported among left
breast cancer survivors treated with radiation therapy. Radiation-induced
cardiotoxicity is affected by the volume of myocardium included in the radiation
portals. We hypothesize that simple respiratory maneuvers may alter the position
of the heart relative to the portals without altering the radiation dose
delivered to the breast. METHODS AND RESULTS: Fourteen healthy female adult
volunteers underwent cardiac MRI to determine the cardiac volume included in the
typical left-breast radiation field during respiratory maneuvers. Cardiac volume
within the radiation portals was assessed from a transverse stack of 14 1-cm
thick contiguous slices covering the entire heart, obtained during breath holding
at end-tidal volume (baseline), deep inspiration, and forced expiration. Thirteen
subjects (92%) had inclusion of a portion of the heart within the radiation
portals at end-tidal volume (median, 20.9 cm3; range, 1.3 to 88.4 cm3). In these
subjects, inspiration decreased the cardiac volume included within the radiation
portals (median change: -10.7 cm3 [-40.2%], P<.001 versus end-tidal volume),
whereas expiration increased the cardiac volume included (median change: 4.0 cm3
[21.5%]; P<.001 versus end-tidal volume). CONCLUSIONS: Inclusion of a portion of
the heart in the left-breast radiation field is common. The use of simple
inspiratory maneuvers significantly decreases cardiac volume within the radiation
portals. Such an approach during delivery of radiation therapy may allow for
preservation of radiation dosage to the breast while reducing cardiac involvement
and subsequent mortality.
PMID- 9396415
TI - Evaluation of different ventricular pacing sites in patients with severe heart
failure: results of an acute hemodynamic study.
AB - BACKGROUND: Multisite ventricular pacing has recently been proposed as an
additional treatment for patients with severe congestive heart failure. To
further assess the potential value of this technique, we compared the acute
hemodynamic changes associated with pacing the right ventricular apex (RVA) or
outflow tract (RVOT) alone, the left ventricle (LV) alone, or biventricular (BIV)
pacing of the RVA and LV together. METHODS AND RESULTS: Acute hemodynamic
findings were measured in 27 patients with severe heart failure despite optimal
therapy and either first-degree AV block and/or an intraventricular conduction
defect. In the 23 patients with a high pulmonary capillary wedge pressure (PCWP)
(>15 mm Hg), data were collected after transvenous pacing at different
ventricular sites in either the VDD mode (AV delay=100 ms) or the VVI mode in
patients with atrial fibrillation (n=6). The mean baseline cardiac index was 1.82
L x min(-1) x m(-2). Mean+/-SD baseline systolic blood pressure (SBP) (118.5+/
15.2 mm Hg), PCWP (26.4+/-6.6 mm Hg), and V-wave amplitude (39.1+/-14.6 mm Hg)
were similar before and after either RVA or RVOT pacing. In contrast, LV-based
pacing (either LV alone or BIV pacing) resulted in higher SBP (P<.03) and lower
PCWP (P<.01) and V-wave amplitude (P<.001) than either baseline or RV pacing
measurements. With LV pacing alone, SBP, PCWP, and V waves were 126.5+/-15.1,
20.7+/-5.9, and 25.5+/-8.1 mm Hg, respectively. The results with LV pacing alone
were similar to those obtained with BIV pacing. CONCLUSIONS: In patients with
severe congestive heart failure, both LV pacing alone and BIV pacing resulted in
a similar and significant acute improvement in SBP, PCWP, and V-wave amplitude
compared with baseline measurements and RV pacing alone. These results provide a
strong basis for initiating long-term studies examining the chronic effects of LV
based pacing in patients with medically refractory congestive heart failure.
PMID- 9396416
TI - Changing features of anginal pain after PTCA suggest a stenosis on a different
artery rather than restenosis.
AB - BACKGROUND: We recently found that patients who had had two myocardial
infarctions in different myocardial regions frequently reported different
locations of infarct pain, whereas patients who had had two infarcts at the same
site had a similar distribution of pain. The aim of this study was to assess
whether a different location of anginal pain may help identify patients with a
new stenosis on an artery perfusing another myocardial region as opposed to those
with restenosis after coronary angioplasty (PTCA). METHODS AND RESULTS: We
studied 38 patients (59+/-11 years old) who underwent PTCA for single-vessel
disease, with recurrence of symptoms requiring repeat coronary angiography during
a 3-year follow-up. According to our inclusion criteria, angiography showed
either a significant restenosis of the dilated lesion, with no evidence of
lesions in the other vessels (n=26), or a new stenosis in either of the other
coronary arteries, with no restenosis in the dilated vessel (n= 12). Before each
procedure, patients reported the location and radiation of anginal pain. There
was no relation between location of pain and site of the coronary stenosis.
However, none of the patients with restenosis reported a different location of
pain after angioplasty, compared with 5 patients with new stenosis (0% versus
42%, P=.002). Radiation of pain involved different areas of the body in 1 patient
with restenosis and in 6 with new stenosis (4% versus 50%, P=.002). Overall,
location or radiation of pain in a different body area had a specificity of 96%
and a sensitivity of 58% in detecting a stenosis on a new artery. CONCLUSIONS: A
different location of anginal pain may distinguish patients with a new coronary
stenosis from those with restenosis after PTCA for single-vessel disease. These
findings suggest that in individual patients, differences in the location of
cardiac pain may be indicative of the occurrence of ischemia in different
myocardial regions.
PMID- 9396417
TI - Coronary artery disease and polymorphisms in a receptor mediating shear stress
dependent platelet activation.
AB - BACKGROUND: Platelets play pivotal roles in coronary thrombosis, and antiplatelet
therapies are widely used for coronary artery disease (CAD). However, the effects
of genetic variation in platelets on CAD are poorly understood. We have assessed
the association between CAD and polymorphisms in a platelet receptor for von
Willebrand factor, the glycoprotein (GP) Ib/IX complex, which mediates shear
stress-dependent platelet activation. METHODS AND RESULTS: Genotypes of the alpha
chain of the receptor (GP Ib alpha, 145Thr/Met) were determined in 91 patients
with myocardial infarction (MI) or angina pectoris whose lesions were confirmed
by coronary angiography as well as in 105 individuals from the general population
with no history of angina or other heart diseases and normal resting ECGs. There
was no homozygote for Met/Met in either the control or patient groups. The
prevalence of the Thr/Met genotype (T/M) in all patients was not significantly
different from that in the control group. However, the frequency of T/M was
significantly higher in patients aged < or = 60 years (31.8%) than in control
subjects aged < or = 60 years (16.0%; P<.05, odds ratio=2.5). An association was
also demonstrated between CAD and the other polymorphism of GP Ib alpha, a
variable number of tandem repeats of a 13-amino acid sequence, which is known to
be linked to the 145Thr/Met polymorphism. There was an association between the
frequency of the T/M genotype and the angiographic severity of CAD: 11.1% for
Gensini score < 40 versus 50.0% for Gensini score > or = 40 (P=.0015). There was
no difference in the distribution of GP Ib alpha genotypes between patients with
MI and those with angina pectoris. CONCLUSIONS: This study suggests that the
presence of the Met allele in GP Ib alpha is a risk factor for the prevalence and
severity of CAD in individuals aged < or = 60 years. The results need to be
confirmed in a large-scale study of incident case subjects and matching control
subjects.
PMID- 9396418
TI - Endothelial dysfunction is associated with cholesterol levels in the high normal
range in humans.
AB - BACKGROUND: The purpose of this study was to test the hypothesis that cholesterol
levels in the high normal range are associated with impaired endothelium
dependent vasodilation. METHODS AND RESULTS: We studied leg blood flow (LBF)
responses to graded intrafemoral artery infusions of the endothelium-dependent
vasodilator methacholine chloride (MCh) or the endothelium-independent
vasodilator sodium nitroprusside (SNP) in normal volunteers exhibiting a wide
range of total cholesterol levels within the normal range (<75th percentile). LBF
increased in a dose-dependent fashion in response to the femoral artery infusions
of MCh and SNP (P<.001). LBF responses to MCh were significantly blunted (P<.001)
in subjects with high normal cholesterol (195+/-6 mg/dL, n=13) compared with
subjects with low normal cholesterol (146+/-5 mg/dL, n=20). Maximal endothelium
dependent vasodilation in the high normal group was decreased by nearly 50%
compared with the low normal group (146+/-13% versus 268+/-34%, P<.01). There was
a negative correlation between total cholesterol levels and maximal endothelium
dependent vasodilation (total cholesterol, r=-.41, P<.02; LDL cholesterol, r=
.42, P<.02). On the other hand, LBF responses to the endothelium-independent
vasodilator SNP did not differ between groups. CONCLUSIONS: These data suggest
that an inverse and continuous relationship exists between the prevailing
cholesterol level and endothelium-dependent vasodilation. Moreover, cholesterol
levels even in the normal range may be associated with endothelial dysfunction,
thus potentially contributing to the increased risk of macrovascular disease
conferred by cholesterol elevations.
PMID- 9396419
TI - Cardiovascular death and left ventricular remodeling two years after myocardial
infarction: baseline predictors and impact of long-term use of captopril:
information from the Survival and Ventricular Enlargement (SAVE) trial.
AB - BACKGROUND: We quantified cardiovascular death and/or left ventricular (LV)
dilatation in patients from the SAVE trial to determine whether dilatation
continued beyond 1 year, whether ACE inhibitor therapy attenuated late LV
dilatation, and whether any baseline descriptors predicted late dilatation.
METHODS AND RESULTS: Two-dimensional echocardiograms were obtained in 512
patients at 11+/-3 days and 1 and 2 years postinfarction to assess LV size,
percentage of the LV that was akinetic/dyskinetic (%AD), and LV shape index. LV
function was assessed by radionuclide ejection fraction. Two hundred sixty-three
patients (51.4%) sustained cardiovascular death and/or LV diastolic dilatation;
279 (54.5%) had cardiovascular death and/or systolic dilatation. In 373 patients
with serial echocardiograms, LV end-diastolic and end-systolic sizes increased
progressively from baseline to 2 years (both P<.01). More patients with LV
dilatation had a decrease in ejection fraction: 24.8% versus 6.8% (P<.001)
(diastole) and 25.7% versus 5.3% (P<.001) (systole). Captopril attenuated
diastolic LV dilatation at 2 years (P=.048), but this effect was carried over
from the first year of therapy because changes in LV size with captopril beyond 1
year were similar to those with placebo. Predictors of cardiovascular death
and/or dilatation were age (P=.023), prior infarction (P<.001), lower ejection
fraction (P<.001), angina (P=.007), heart failure (P=.002), LV size (P<.001), and
infarct size (%AD) (P<.001). CONCLUSIONS: Cardiovascular death and/or LV
dilatation occurred in >50% of patients by 2 years. LV dilatation is progressive,
associated with chamber distortion and deteriorating function that is unaffected
by captopril beyond 1 year.
PMID- 9396420
TI - Body iron stores and the risk of carotid atherosclerosis: prospective results
from the Bruneck study.
AB - BACKGROUND: Fe2+ released from tissue iron stores may accelerate lipid
peroxidation by virtue of its pro-oxidant properties and thus promote early
atherogenesis. METHODS AND RESULTS: The present prospective survey addresses the
potential association between serum ferritin concentrations and the 5-year
progression of carotid atherosclerosis as assessed by ultrasonographic follow-up
evaluations. The study population comprises a random sample of 826 men and women
40 to 79 years old. Serum ferritin was one of the strongest risk predictors of
overall progression of atherosclerosis. The main part of this association
appeared to act through modification of the atherogenic potential of LDL
cholesterol (OR [95% CI] for a 1-SD unit increase in ferritin at LDL levels of
2.5, 3.6, and 4.9 mmol/L: 1.55 [1.30 to 1.85], 1.77 [1.40 to 2.24], and 2.05
[1.50 to 2.80]; P=.0012 for effect modification). Changes in iron stores during
the follow-up period modified atherosclerosis risk, in that a lowering was
beneficial and further iron accumulation exerted unfavorable effects. All these
findings applied equally to incident atherosclerosis and the extension of
preexisting atherosclerotic lesions. The significance of prominent iron stores in
the development of carotid stenosis was clearly less pronounced. Finally,
ferritin and LDL cholesterol showed a synergistic association with incident
cardiovascular disease and death (n=59). CONCLUSIONS: The present study provided
strong epidemiological evidence for a role of iron stores in early atherogenesis
and suggests promotion of lipid peroxidation as the main underlying
pathomechanism. This hypothesis could in part explain the sex difference in
atherosclerotic vascular disease.
PMID- 9396421
TI - Estimating effectiveness of cardiac arrest interventions: a logistic regression
survival model.
AB - BACKGROUND: The study objective was to develop a simple, generalizable predictive
model for survival after out-of-hospital cardiac arrest due to ventricular
fibrillation. METHODS AND RESULTS: Logistic regression analysis of two
retrospective series (n=205 and n=1667, respectively) of out-of-hospital cardiac
arrests was performed on data sets from a Southwestern city (population, 415,000;
area, 406 km2) and a Northwestern county (population, 1,038,000; area, 1399 km2).
Both are served by similar two-tiered emergency response systems. All arrests
were witnessed and occurred before the arrival of emergency responders, and the
initial cardiac rhythm observed was ventricular fibrillation. The main outcome
measure was survival to hospital discharge. Patient age, initiation of CPR by
bystanders, interval from collapse to CPR, interval from collapse to
defibrillation, bystander CPR/collapse-to-CPR interval interaction, and collapse
to-CPR/collapse-to-defibrillation interval interaction were significantly
associated with survival. There was not a significant difference between observed
survival rates at the two sites after control for significant predictors. A
simplified predictive model retaining only collapse to CPR and collapse to
defibrillation intervals performed comparably to the more complicated explanatory
model. CONCLUSIONS: The effectiveness of prehospital interventions for out-of
hospital cardiac arrest may be estimated from their influence on collapse to CPR
and collapse to defibrillation intervals. A model derived from combined data from
two geographically distinct populations did not identify site as a predictor of
survival if clinically relevant predictor variables were controlled for. This
model can be generalized to other US populations and used to project the local
effectiveness of interventions to improve cardiac arrest survival.
PMID- 9396422
TI - Increased formation of the isoprostanes IPF2alpha-I and 8-epi-prostaglandin
F2alpha in acute coronary angioplasty: evidence for oxidant stress during
coronary reperfusion in humans.
AB - BACKGROUND: The role of oxidant stress in cardiac ischemia/reperfusion injury in
humans remains controversial. This is due, in part, to the limitations of
available indices of oxidant stress in vivo. Isoprostanes are stable, free
radical-catalyzed products of arachidonic acid. We assessed their formation in
patients undergoing coronary reperfusion via percutaneous transluminal coronary
angioplasty (PTCA). METHODS AND RESULTS: We developed specific, mass spectrometry
assays for two structurally distinct F2 isoprostanes, 8-epi-PGF2alpha and
IPF2alpha-I. Urine samples for isoprostane determination were collected in
patients undergoing coronary arteriography (n=11), elective PTCA (n=15), and
angiography after thrombolysis for acute myocardial infarction (MI) (n=10).
Urinary levels (pmol/mmol creatinine) of both isoprostanes were markedly
increased from baseline in the first 6 hours after PTCA for acute MI (105+/-17.8
versus 230+/-66 for 8-epi-PGF2alpha [P=.009] and 466+/-91 versus 833+/-153 for
IPF2alpha-I [P=.001]) and returned toward preprocedural values by 24 hours (122+/
18 for 8-epi-PGF2alpha and 457+/-102 for IPF2alpha-I). There was a slight
increase in urinary 8-epi-PGF2alpha levels (64.7+/-9.5 versus 84.9+/-10.6; P=.02)
after diagnostic coronary arteriography and elective PTCA (88.7+/-7.5 versus
114.3+/-16.1; P=.01). A striking correlation was observed (r=.68, P<.0001; n=33)
between urinary 8-epi-PGF2alpha and IPF2alpha-I levels in patients receiving
thrombolytic agents for acute MI. CONCLUSIONS: Urinary F2 isoprostane levels are
elevated in patients after treatments resulting in reperfusion for acute MI.
These findings provide evidence consistent with increased oxidant stress in vivo
in this setting. Measurement of urinary isoprostanes may offer a noninvasive
approach to the assessment of oxidant stress and the efficacy of antioxidant
therapies in these syndromes.
PMID- 9396423
TI - Nonuniform nighttime distribution of acute cardiac events: a possible effect of
sleep states.
AB - BACKGROUND: Although 250,000 myocardial infarctions and 38,000 sudden cardiac
deaths occur at night annually, this public health problem is underappreciated
and poorly understood. We examined whether the incidence of myocardial
infarction, sudden cardiac death, and automatic implantable cardioverter
defibrillator (AICD) discharge was nonuniform, a result that may implicate
physiological triggers such as sleep-state dependent changes in autonomic nervous
system activity. METHODS AND RESULTS: We conducted a review of the circadian
pattern of the onset of myocardial infarction (n=19), sudden cardiac death
(n=12), and AICD discharge (n=7). The nighttime period was chosen a priori as
midnight to 5:59 AM. These reports documented 11,633 nocturnal myocardial
infarctions (20% of the total myocardial infarctions), 1981 nocturnal sudden
cardiac deaths (14.6% of the total sudden cardiac deaths), and 1200 nocturnal
AICD discharges (15.0% of the total discharges). The distributions of myocardial
infarction, sudden cardiac death, and AICD discharge were each significantly
nonuniform (P<.001). The peak incidence of myocardial infarction and AICD
discharge occurred between midnight and 0:59 AM, whereas the peak incidence of
sudden cardiac death was between 1:00 and 1:59 AM. The trough in incidence
occurred between 4:00 and 4:59 AM for sudden cardiac death and between 3:00 and
3:59 AM for myocardial infarction and AICD discharge. CONCLUSIONS: Nocturnal
myocardial infarction, sudden cardiac death, and AICD discharge exhibit
nonuniform distributions. This finding is consistent with the hypothesis that
sleep-state dependent fluctuations in autonomic nervous system activity may
trigger the onset of major cardiovascular events and provides further impetus for
more directly testing this hypothesis at population, individual, and mechanistic
levels. A better understanding of nocturnal triggers may make it possible to
reduce the incidence of myocardial infarction, ventricular tachyarrhythmias, and
sudden cardiac death during the nocturnal period.
PMID- 9396424
TI - Upregulation of angiotensin-converting enzyme during the healing process after
injury at the site of percutaneous transluminal coronary angioplasty in humans.
AB - BACKGROUND: Balloon injury models in rat have shown enhanced expression of ACE in
the developing neointima. However, neointimal lesions in human coronary arteries
are complex due to atherosclerosis and different types of wall laceration. This
study was designed to investigate whether ACE is present in the neointima of
humans, including patients with restenosis after percutaneous transluminal
coronary angioplasty (PTCA). METHODS AND RESULTS: Thirty-seven sites with
angioplasty injury, obtained at autopsy, were studied using immunocytochemical
techniques. Sites with injury limited to a fibrous plaque and those with injury
extending into the media (<2 months after PTCA) showed fibrocellular repair
tissue composed mainly of smooth muscle cells that were distinctly positive for
ACE. In cellular reactions at the site of injury limited to the atheromatous
plaque (<2 months after PTCA), the expression of ACE appeared first in
accumulated macrophages; once smooth muscle cells appeared in the repair tissue,
they also expressed ACE. At a later stage (3 months after PTCA), the number of
cells with ACE expression decreased markedly; from 7 months on, ACE was no longer
expressed within the repair tissue. Basically, there were no differences with
regard to ACE expression during the healing process after PTCA between segments
with and those without angiographic evidence of restenosis. CONCLUSIONS: These
results show that PTCA injury in humans results in upregulation of ACE at sites
of active repair and, therefore, ACE could play an important role as one of the
mediators of the healing process after PTCA.
PMID- 9396425
TI - Albumin excretion rate increases during acute myocardial infarction and strongly
predicts early mortality.
AB - BACKGROUND: This study was undertaken to assess whether albumin excretion rate
(AER) increases during acute myocardial infarction (AMI) and whether it predicts
in-hospital mortality. METHODS AND RESULTS: The study was carried out in 496
subjects admitted to hospital for suspected AMI. Of these, 360 had evidence of
AMI. The other 136 were studied as control subjects. AER was assessed by
radioimmunoassay in three 24-hour urine collections performed on the first,
third, and seventh days after admission. Left ventricular ejection fraction was
measured by two-dimensional echocardiography in 254 subjects. AER adjusted for
several confounders was higher in the AMI than the non-AMI group on the first
(69.2+/-5.2 versus 27.3+/-8.5 mg/24 h, P<.0001) and third (30.3+/-2.7 versus
12.5+/-4.4 mg/24 h, P=.001) days, whereas no difference was present on the
seventh day. When the subjects with heart failure were excluded, the difference
between the two groups remained significant (first day, P<.0001; third day,
P=.001). On the basis of classification of the 26 AMI patients who died in
hospital according to whether they had normal AER, microalbuminuria, or overt
albuminuria, mortality rate progressively increased with increasing levels of AER
(P<.0001). In a Cox's proportional hazards model, AER was a better predictor of
in-hospital mortality than Killip class or echocardiographic left ventricular
ejection fraction. A cutoff value of 50 mg/24 h for first-day AER and 30 mg/24 h
for third-day AER yielded a sensitivity of 92.3% and of 88.5% and a specificity
of 72.4% and of 79.3%, respectively, for mortality. Adjusted relative risks for
the two cutoff values were 17.3 (confidence limits, 4.6 to 112.7) and 8.4
(confidence limits, 2.4 to 39.3), respectively. CONCLUSIONS: These data show that
AER increases during AMI and that it yields prognostic information additional to
that provided by clinical or echocardiographic evaluation of left ventricular
performance.
PMID- 9396426
TI - Effects of dobutamine at maximally tolerated dose on myocardial blood flow in
humans with ischemic heart disease.
AB - BACKGROUND: This study tests the hypothesis in humans with ischemic heart disease
that myocardial blood flow response to dobutamine is linearly correlated with
blood flow response to adenosine. METHODS AND RESULTS: PET with [13N]ammonia was
used to measure myocardial blood flow at rest and during adenosine and dobutamine
at the maximally tolerated dose. Myocardial segments were defined physiologically
on the basis of blood flow response to adenosine: normal, > or = 2 mL x min(-1) x
g(-1); abnormal, < 2 mL x min(-1) x g(-1); and "steal," decline versus baseline >
or = 0.15 mL x min(-1) x g(-1). The patient population consisted of 11 men and 2
women. Dobutamine increased heart rate (79+/-22 to 115+/-28 bpm) and rate
pressure product (9748+/-2862 to 15,157+/-3433 mm Hg/min) significantly (both
P<.01). Myocardial blood flow at rest in abnormal segments (0.50+/-0.23 mL x min(
1) x g(-1)) was reduced (P<.001) versus normal (0.90+/-0.45) and steal (0.92+/
0.60). Nevertheless, in abnormal segments, blood flow increased versus rest
(P<.001) with dobutamine (0.83+/-0.43) and adenosine (0.90+/-0.49). In steal
segments, myocardial blood flow declined versus baseline (P<.001) with dobutamine
(0.68+/-0.46) and adenosine (0.50+/-0.45). In normal segments, myocardial blood
flow increased (P<.001) with dobutamine (2.16+/-0.99) and adenosine (3.10+/
0.90). Over the range of flows, the correlation between adenosine and dobutamine
was good (r=.78, P<.0001). Although flow with dobutamine in normal segments
correlated with rate-pressure product (r=.81, P<.05), the slope of the line was
2.7+/-0.8 (P<.02), and normalized blood flow (3.3+/-2.5 x rest) exceeded
normalized rate-pressure product (1.9+/-0.8 x rest; P<.05). CONCLUSIONS: In
humans with ischemic heart disease, myocardial blood flow responses to dobutamine
and adenosine are linearly correlated over a wide range. The hyperemic response
to dobutamine is in excess of that predicted by rate-pressure product and
reflects the unmeasured inotropic, oxygen-wasting, and beta2-agonist effects of
the drug. Dobutamine induces coronary steal with a frequency approaching that of
adenosine.
PMID- 9396427
TI - Influence of infarct-zone viability on left ventricular remodeling after acute
myocardial infarction.
AB - BACKGROUND: The relation between residual myocardial viability after acute
myocardial infarction (AMI) and ventricular remodeling has yet to be fully
elucidated. We hypothesized that the presence of residual viability would
favorably influence left ventricular remodeling after AMI and that serial changes
in left ventricular dimensions might be related to the extent of myocardial
viability in the infarct zone. METHODS AND RESULTS: Ninety-three patients with a
first AMI successfully treated with primary coronary angioplasty underwent two
dimensional echocardiography within 24 hours of admission and low-dose dobutamine
echocardiography at a mean of 3 days after AMI. Two-dimensional echocardiography
and coronary angiography were obtained in all patients 1 and 6 months after
coronary angioplasty. On the basis of dobutamine echocardiography responses,
patients were divided in two subsets: those with (n=48; group I) and those
without (n=45; group II) infarct-zone viability. There was no difference in
minimal lesion diameter and infarct-related artery patency at 1 and 6 months
between the two groups. Group II patients had significantly greater end-diastolic
(76+/-18 versus 53+/-14 mL/m2; P<.0003) and end-systolic (42+/-17 versus 22+/-11
mL/m2; P<.0003) volumes at 6 months than did patients in group 1. The extent of
infarct-zone viability was significantly inversely correlated with percent
changes in end-diastolic volumes at 6 months (r=-.66; P<.000001) and was the most
powerful independent predictor of late left ventricular dilation. CONCLUSIONS:
After reperfused AMI, the degree of left ventricular dilation, when it occurs, is
inversely related to the extent of residual myocardial viability in the infarct
zone. Thus, the absence of residual infarct-zone viability discriminates patients
who develop progressive left ventricular dilation after reperfused AMI from those
who maintain normal left ventricular geometry.
PMID- 9396428
TI - Topographic analysis of proliferative activity in carotid endarterectomy
specimens by immunocytochemical detection of the cell cycle-related antigen Ki
67.
AB - BACKGROUND: On the basis of contradictory results found in animal experiments and
coronary atherectomy tissue, there is an ongoing debate about the significance of
cellular proliferation in human atherosclerosis. In the present prospective
study, the cell cycle-related antigen Ki-67 was detected for topographic
determination of cell turnover in distinct regions of human carotid
endarterectomy specimens harvested en bloc by surgical biopsy. METHODS AND
RESULTS: After en bloc resection, serial sections of 26 consecutive carotid
lesions were analyzed by histomorphological examination and immunohistochemistry.
Thereby, 319 high-power fields were attributed to separate plaque regions defined
as follows: distal boundary of the lesion with normal intima, plaque shoulder,
core region, and diffuse intimal thickening. Endothelial cells, smooth muscle
cells, T cells, and macrophages were identified by immunostaining of factor VIII
related protein, alpha-actin, CD68, and CD45R0. An overall proliferation index of
0.49+/-1.05% was yielded by positive anti-Ki-67 immunolabeling, predominantly in
macrophage-rich areas characterized by high cell density (>1000 cells/mm2) as
well as in reparative sites in the perimeter of atheroma, intramural thrombosis,
plaque hemorrhage, and neovascularization (P<.01). Few or no signs of
proliferation activity were found in normal intima, in areas of dense alpha-actin
positivity, or adjacent media. As shown by double immunostaining, macrophages and
unspecified mesenchymal cells represented the prevailing proliferating cell type.
CONCLUSIONS: Our results suggest that proliferation in advanced human carotid
lesions is confined to the intima and focally concentrated in central plaque
regions negative for alpha-actin. Furthermore, it apparently occurs primarily as
part of inflammatory processes and structural repair predominantly involving
macrophages, as well as unspecific mesenchymal cells.
PMID- 9396430
TI - Endothelium-dependent dilatation is impaired in young healthy subjects with a
family history of premature coronary disease.
AB - BACKGROUND: A family history of premature coronary artery disease (CAD) in a
first-degree relative is an independent risk factor for coronary disease. Both
genetic and environmental influences are likely to be responsible and may
interact, but their relative importance is unclear. METHODS AND RESULTS: We
studied endothelial function in 50 first-degree relatives (31 men, 19 women; mean
age, 25+/-8 years) of patients (men < or = 45 years, women < or = 55 years) with
proven CAD. All subjects were well, lifelong nonsmokers, not diabetic, and not
hypertensive and took no medications. Using high-resolution external vascular
ultrasound, we measured brachial artery diameter at rest and in response to
reactive hyperemia (with increased flow causing an endothelium-dependent
vasodilatation) and to sublingual glyceryltrinitrate (GTN, an endothelium
independent dilator). Vascular responses were compared with those of 50 healthy
control subjects matched for age and sex. Flow-mediated dilatation (FMD) was
impaired in the family history group (4.9+/-4.6% versus 8.3+/-3.5% in control
subjects, P<.005). In contrast, GTN caused dilatation in all subjects (family
history, 17.1+/-8.8%; control subjects, 19.0+/-6.3%; P=NS), suggesting that
reduced FMD was due to endothelial dysfunction. When the family history subjects
were subdivided, those found to have a serum cholesterol > 4.2 mmol/L (group A,
n=10) had mildly impaired FMD compared with control subjects (5.5+/-5.1% versus
8.3+/-3.5%). In others whose affected relative had coronary risk factors (group
B, n=24), FMD was also only slightly reduced (6.2+/-4.8% versus 8.3+/-3.5%). In
contrast, subjects with no risk factors and whose affected relative had a normal
cardiovascular risk factor profile (group C, n=16) had markedly impaired FMD
(2.9+/-3.7% versus 8.3+/-3.5%). Although ANOVA of the three family history
subgroups did not reach statistical significance (F=2.55, P=.09), pairwise
analysis showed that FMD in group C was significantly impaired compared with
group B (P=.026). CONCLUSIONS: Healthy young adults with a family history of
premature coronary disease may have impaired endothelium-dependent dilatation,
even in the absence of other cardiovascular risk factors. Those subjects, who
were free of risk factors and whose affected first-degree relative was free of
risk factors, had the most impaired endothelial function, suggesting a genetic
influence on early arterial physiology that may be relevant to later clinical
disease.
PMID- 9396429
TI - Prognostic value of intracoronary flow velocity and diameter stenosis in
assessing the short- and long-term outcomes of coronary balloon angioplasty: the
DEBATE Study (Doppler Endpoints Balloon Angioplasty Trial Europe).
AB - BACKGROUND: The aim of this prospective, multicenter study was the identification
of Doppler flow velocity measurements predictive of clinical outcome of patients
undergoing single-vessel balloon angioplasty with no previous Q-wave myocardial
infarction. METHODS AND RESULTS: In 297 patients, a Doppler guidewire was used to
measure basal and maximal hyperemic flow velocities proximal and distal to the
stenosis before and after angioplasty. In 225 patients with an angiographically
successful percutaneous transluminal coronary angioplasty (PTCA), postprocedural
distal coronary flow reserve (CFR) and percent diameter stenosis (DS%) were
correlated with symptoms and/or ischemia at 1 and 6 months, with the need for
target lesion revascularization, and with angiographic restenosis (defined as DS
> or = 50% at follow-up). Logistic regression and receiver operator
characteristic curve analyses were applied to determine the prognostic cutoff
value of CFR and DS separately and in combination. Optimal cutoff criteria for
predictors of these clinical events were DS, 35%; CFR, 2.5. A distal CFR after
angioplasty > 2.5 with a residual DS < or = 35% identified lesions with a low
incidence of recurrence of symptoms at 1 month (10% versus 19%, P=.149) and at 6
months (23% versus 47%, P=.005), a low need for reintervention (16% versus 34%,
P=.024), and a low restenosis rate (16% versus 41%, P=.002) compared with
patients who did not meet these criteria. CONCLUSIONS: Measurements of distal CFR
after PTCA, in combination with DS%, have a predictive value, albeit modest for
the short- and long-term outcomes after PTCA, and thus may be used to identify
patients who will or will not benefit from additional therapy such as stent
implantation.
PMID- 9396431
TI - Silent myocardial ischemia in Kawasaki disease: evaluation of percutaneous
transluminal coronary angioplasty by dobutamine stress testing.
AB - BACKGROUND: Myocardial ischemia and myocardial infarction are the most serious
complications of coronary artery lesions in children with Kawasaki disease (KD).
Therefore, early detection and treatment of myocardial ischemia in patients with
KD is essential. We studied the effectiveness of percutaneous transluminal
coronary angioplasty (PTCA) in patients with silent myocardial ischemia detected
by dobutamine stress 99mTc myocardial scintigraphy (TMS), body surface mapping
(BMS), and signal-averaged ECG late potentials (ELP). METHODS AND RESULTS: Eight
of 76 asymptomatic patients with a coronary stenosis >25% and a positive
dobutamine stress test were considered to have silent myocardial ischemia. All
eight patients had >95% stenoses demonstrated by coronary angiography (CAG) just
before PTCA. After PTCA, CAG showed that all of the coronary artery stenoses had
been reduced to <50%. Additionally, intravascular ultrasonography (IVUS)
performed in five patients before and after PTCA demonstrated adequate dilation
of the coronary stenosis after PTCA. All eight patients underwent dobutamine
stress TMS, BMS, and ELP 2 to 3 months after PTCA, which demonstrated no regions
of myocardial ischemia. Approximately 6 months later, CAG was performed in all
eight patients, and only one patient had developed restenosis. CONCLUSIONS: PTCA
effectively dilates stenotic coronary arteries in children with KD. Moreover,
dobutamine stress TMS, BMS, and ELP are useful for detecting silent myocardial
ischemia and estimating the effectiveness of PTCA. Furthermore, IVUS is useful
for evaluating the severity of coronary artery lesions before and after PTCA in
patients with KD.
PMID- 9396432
TI - Coronary endothelial dysfunction in humans is associated with myocardial
perfusion defects.
AB - BACKGROUND: Coronary endothelial dysfunction may occur in patients with minimally
obstructive coronary artery disease and angina, and potentially may cause
myocardial ischemia. METHODS AND RESULTS: Coronary endothelium-dependent
vasodilation was examined in patients with angina and <50% coronary artery
diameter (CAD) stenosis by selectively infusing acetylcholine (10(-6) mol/L to
10(-4) mol/L) into the left anterior descending coronary artery (LAD). Percent
change in CAD (%deltaCAD) was measured by quantitative coronary angiography, and
percent change in coronary blood flow (%deltaCBF) was calculated using
intracoronary flow Doppler. Coronary endothelium-independent vasodilation was
examined using intracoronary adenosine and nitroglycerin. 99mTc sestamibi was
injected intravenously just prior to the infusion of the highest dose of
acetylcholine. Patients were divided blindly into three groups: Perfusion defects
in non-LAD territory (group 1, n=6), no perfusion defects (group 2, n=7), and
perfusion defects in the LAD territory (group 3, n=7). All patients had intact
endothelium-independent vasodilation. In group 1, perfusion defects outside the
LAD territory reflected an increase in %deltaCAD and %deltaCBF by 24+/-5% and
241+/-46% in the LAD. In group 2, %deltaCAD decreased by 26+/-5%, but %deltaCBF
increased by 54+/-17%. In group 3, perfusion defects were within the LAD
territory, reflecting a decrease in %deltaCAD and %deltaCBF by 35+/-5% and 51+/
14%, respectively. CONCLUSIONS: This study demonstrates that coronary endothelial
dysfunction in humans may be temporally associated with myocardial perfusion
defects and supports a role for the coronary epicardial and microcirculation
endothelium in regulating myocardial perfusion. Myocardial ischemia may occur in
humans with impaired endothelium-dependent coronary flow reserve of the coronary
epicardial and microcirculation.
PMID- 9396433
TI - Effect of nadroparin, a low-molecular-weight heparin, on clinical and
angiographic restenosis after coronary balloon angioplasty: the FACT study.
Fraxiparine Angioplastie Coronaire Transluminale.
AB - BACKGROUND: Experimental studies suggest that the antiproliferative effect of
heparin after arterial injury is maximized by pretreatment. No previous studies
of restenosis have used a pretreatment strategy. We designed this study to
determine whether treatment with nadroparin, a low-molecular-weight heparin,
started 3 days before the procedure and continued for 3 months, affected
angiographic restenosis or clinical outcome after coronary angioplasty. METHODS
AND RESULTS: In a prospective multicenter, double-blind, randomized trial,
elective coronary angioplasty was performed on 354 patients who were treated with
daily subcutaneous nadroparin (0.6 mL of 10,250 anti-Xa IU/mL) or placebo
injections started 3 days before angioplasty and continued for 3 months.
Angiography was performed just before and immediately after angioplasty and at
follow-up. The primary study end point was angiographic restenosis, assessed by
quantitative coronary angiography 3 months after balloon angioplasty. Clinical
follow-up was continued up to 6 months. Clinical and procedural variables and the
occurrence of periprocedural complications did not differ between groups. At
angiographic follow-up, the mean minimal lumen diameter and the mean residual
stenosis in the nadroparin group (1.37+/-0.66 mm, 51.9+/-21.0%) did not differ
from the corresponding values in the control group (1.48+/-0.59 mm, 48.8+/
18.9%). Combined major cardiac-related clinical events (death, myocardial
infarction, target lesion revascularization) did not differ between groups (30.3%
versus 29.6%). CONCLUSIONS: Pretreatment with the low-molecular-weight heparin
nadroparin continued for 3 months after balloon angioplasty had no beneficial
effect on angiographic restenosis or on adverse clinical outcomes.
PMID- 9396434
TI - Aortic valve replacement in patients 80 years of age and older: survival and
cause of death based on 1100 cases: collective results from the UK Heart Valve
Registry.
AB - BACKGROUND: Aging of the population and advances in preoperative and
postoperative care are reflected in an increasing number of patients > or = 80
years of age undergoing aortic valve replacement (AVR) in the United Kingdom. The
present study presents data on postoperative 30-day mortality, actuarial
survival, and cause of death based on a large collective patient population.
METHODS AND RESULTS: Data were extracted from the UK Heart Valve Registry. From
January 1986 to December 1995, 1100 patients > or = 80 years of age underwent AVR
and were reported to the registry. Six hundred eleven patients (55.5%) were
women. The mean follow-up time was 38.9 months. The 30-day mortality was 6.6%. Of
the 73 early deaths, 42 were due to cardiac reasons. The actuarial survival was
89%, 79.3%, 68.7%, and 45.8% at 1, 3, 5, and 8 years, respectively. After the
first 30 postoperative days, 144 of the 205 deaths were due to noncardiac
reasons. Malignancy, stroke, and pneumonia were the most common causes of late
death. Bioprosthetic valves were implanted in 969 patients (88%) and mechanical
valves in 131 (12%) patients. There was no difference in early mortality and
actuarial survival between the two groups (P>.05). CONCLUSIONS: The above results
suggest that under the selection criteria for AVR currently applied in the United
Kingdom, patients > or = 80 years of age show a satisfactory early postoperative
outcome and moderate medium-term survival benefit.
PMID- 9396435
TI - Grading of mitral regurgitation by quantitative Doppler echocardiography:
calibration by left ventricular angiography in routine clinical practice.
AB - BACKGROUND: Quantitative Doppler echocardiography and proximal flow convergence
methods are validated techniques for quantifying mitral regurgitation. However,
the clinical interpretation of the values calculated is hindered by the absence
of calibration of ranges of severity in large numbers of patients. METHODS AND
RESULTS: In 180 consecutive patients (men, 62%; mean age+/-SD, 66+/-11 years),
the results of Doppler quantification of isolated mitral regurgitation were
calibrated by use of left ventricular angiographic grading performed within 3
months in routine practice and without intervening events. The thresholds of the
quantitative variables corresponding to the angiographic grades were identified
by maximizing the sum of sensitivity and specificity and minimizing their
difference. The mitral regurgitation grade by angiography was 2.7+/-1.3. The mean
value and correlation with angiographic grades for effective regurgitant orifice
were 43+/-37 mm and r=.79 (P<.0001); for regurgitant volume, 62+/-45 mL and r=.80
(P<.0001); and for regurgitant fraction, 45+/-17% and r=.78 (P<.0001). Despite
some overlap, differences between mitral regurgitation grades were all
significant (all P<.05). The thresholds for severe mitral regurgitation (grade 4)
were 60 mL, 50%, and 40 mm2 for regurgitant volume, regurgitant fraction, and
orifice, respectively. CONCLUSIONS: In routine practice in large numbers of
patients in a clinical laboratory, Doppler echocardiographic quantification of
mitral regurgitation shows highly significant correlation with qualitative
angiographic grades. Despite an expected overlap between classes, the calibration
by angiography of grading ranges for the quantitative variables provides a
framework for their interpretation and allows the definition in clinical practice
of thresholds for severe mitral regurgitation.
PMID- 9396436
TI - Increased myocardial muscarinic receptor density in idiopathic dilated
cardiomyopathy: an in vivo PET study.
AB - BACKGROUND: Congestive heart failure is associated with decreased stimulated
myocardial adenylate cyclase activity, increased Gi-binding protein, attenuated
parasympathetic tone, and increased modulation of beta-adrenergic inotropic left
ventricular stimulation by parasympathetic agonists. Despite these abnormalities,
changes in the density or affinity of ventricular muscarinic receptors have not
been demonstrated in patients. METHODS AND RESULTS: The density and affinity
constants of myocardial muscarinic receptors were evaluated noninvasively by
means of positron emission tomography with 11C-MQNB (methylquinuclidinyl
benzilate), a specific hydrophilic antagonist, in 20 patients with congestive
heart failure due to idiopathic dilated cardiomyopathy (mean left ventricular
ejection fraction, 22+/-9%) and compared with values in 12 normal subjects. The
mean receptor concentration was significantly higher in patients than in control
subjects (B'max, 34.5+/-8.9 versus 25+/-7.7 pmol/mL, P<.005), with no changes in
affinity constants. The change in heart rate after injection of 0.6 mg of cold
MQNB was lower in patients than in control subjects (34+/-20% versus 55+/-36%,
P<.05), and receptor density correlated negatively with maximal heart rate in the
patients (r=.45, P<.05). CONCLUSIONS: Congestive heart failure is associated with
an upregulation of myocardial muscarinic receptors. This may be an adaptive
mechanism to beta-agonist stimulation and should increase the number of potential
targets for pharmacological intervention.
PMID- 9396437
TI - Regional sympathetic nervous activity and oxygen consumption in obese
normotensive human subjects.
AB - BACKGROUND: Disturbed sympathetic nervous function may be of importance in
obesity; sympathetic underactivity could contribute to deficient thermogenesis,
positive energy balance, and weight gain, while in contrast, sympathetic nervous
overactivity would predispose to the development of obesity-related hypertension.
Global indices of sympathetic nervous system (SNS) function such as plasma or
urinary norepinephrine (NE) have been unable to define SNS status in obesity.
Since regional SNS activity can be altered in the absence of global changes, we
investigated SNS activity in the heart, kidneys, and hepatomesenteric bed in
healthy human subjects across a wide body mass index (BMI) range of between 19.6
and 35.5. METHODS AND RESULTS: Whole-body and regional plasma NE kinetics using
[3H]-labeled NE were assessed. Regional oxygen consumption was measured by
combining arteriovenous differences in oxygen content and regional blood flow.
Arterial plasma NE and whole-body plasma NE spillover were unrelated to BMI. With
a BMI cutoff of 27, mean cardiac NE spillover was 46% lower in the obese subjects
when compared with the lean subjects (P=.017). Renal NE spillover was
significantly correlated with BMI (r=.668, P=.001), the mean value in the obese
subjects being more than twice that in the lean subjects. Hepatomesenteric NE
spillover was comparable in lean and obese subjects. Renal and hepatomesenteric
oxygen consumption were both significantly higher in the obese subjects compared
with lean subjects. CONCLUSIONS: Regional SNS activity is heterogeneous in the
obese state. Important regional alterations, which may be clinically relevant,
occur in the absence of changes in global indices of sympathetic nervous
function. The enhanced renal NE spillover in obesity may have implications for
the development of hypertension in this group, whereas the low cardiac
sympathetic tone would be expected to be cardioprotective. Enhanced visceral
oxygen consumption evident in the kidneys and hepatomesenteric circulation in
proportion to body mass contributes to the greater resting oxygen consumption in
obesity.
PMID- 9396438
TI - Left ventricular mechanics and geometry in patients with congenital complete
atrioventricular block.
AB - BACKGROUND: Radiographic evidence of cardiomegaly is common in patients with
congenital complete atrioventricular block (CCAVB). It has been speculated that
left ventricular (LV) remodeling and increased stroke volume counteract the
bradycardia, but the effects of slow heart rate and atrioventricular asynchrony
on LV dimensions, geometry, wall stress, and function have not been examined in
detail. METHODS AND RESULTS: Thirty patients with CCAVB without associated
congenital heart disease (mean age, 8.5+/-5.3 years; range, 0.2 to 20 years) were
included in a cross-sectional two-institution study. Thirty-five echocardiograms
were performed using standard techniques. ECG and 24-hour ECG recordings were
reviewed. Seven patients did not receive a pacemaker, whereas 23 patients
underwent pacemaker implantation after the echocardiogram. Compared with normal
control subjects, LV volume (Z score=1.5+/-1.3) and LV mass (Z=1.2+/-1.5) were
significantly increased, whereas LV mass-to-volume ratio (1.1+/-0.3) and geometry
(short-axis diameter/length ratio=0.65+/-0.09) were normal. LV end-systolic
stress (ESS) (a measure of afterload) was normal (Z score=0.2+/-2.3), whereas
shortening fraction (Z=3+/-2.9) and velocity of circumferential fiber shortening
(VCF) (Z=3+/-3.1) were increased. The relationship between VCF and ESS (a preload
insensitive and afterload-adjusted index of contractility) was increased (Z=2.2+/
2) with only small increase in preload (Z=1.02+/-1.1). Regression analyses showed
no significant change over age in LV mass, volume, geometry, loading conditions,
or systolic function. Patients who ultimately met criteria for pacemaker
implantation did not differ from those who did not in terms of heart rate or LV
function but did have increased LV volume (Z score=1.8+/-1.4 versus 0.4+/-0.9,
P=.03) and LV mass (Z score=1.7+/-1.2 versus 0.2+/-1.7, P=.001) compared to the
unpaced group. CONCLUSIONS: In most patients with CCAVB, the LV was enlarged with
normal geometry and enhanced systolic function during the first two decades of
life. The degree of LV dilation and enhanced function did not significantly
change with age. In patients who ultimately underwent pacemaker implantation LV
function did not differ from those who remained unpaced, but evidence of a
slightly increased load manifested as increased end-diastolic volume and mass.
PMID- 9396439
TI - Left ventricular contractile effects of inducible nitric oxide synthase in the
human allograft.
AB - BACKGROUND: Myocardial expression of inducible (i) nitric oxide (NO) synthase
(iNOS) gene has been reported in transplant recipients and in dilated
cardiomyopathy. NO derived from NO donor or from coronary endothelium has
previously been shown in the human heart to reduce end-systolic left ventricular
(LV) pressure, especially during beta-adrenoreceptor stimulation, because of
earlier onset of LV relaxation. The present study investigated in transplant
recipients whether a similar cardiodepressant effect could be attributed to NO
derived from iNOS. METHODS AND RESULTS: In 16 transplant recipients who were free
of rejection or graft vasculopathy, microtip LV pressure recordings, LV
angiograms, and endomyocardial biopsies were obtained at annual coronary
angiography. In 8 transplant recipients, microtip LV pressure recordings were
obtained during intravenous dobutamine (5 microg x kg(-1) x min(-1)). Competitive
reverse transcription-polymerase chain reaction of iNOS mRNA was performed on the
endomyocardial biopsies, and the intensity of iNOS mRNA expression was quantified
on a scale ranging from 0 to 5+. All measures of baseline LV function were
comparable in transplant recipients with low (< or = 2+) or high myocardial iNOS
mRNA. During intravenous dobutamine infusion, there was a significant correlation
between the abbreviation of LV electromechanical systole time (LVEST is the time
from onset of QRS to dP/dt(min)) and the rise of LV dP/dt(max) (r=.79; P<.02). By
use of a multiple regression analysis, addition of the intensity of iNOS mRNA
expression as an independent variable significantly (P<.005) improved the
correlation between deltaLVEST and deltaLV dP/dt(max) (P<.001; r=.97), implying a
larger abbreviation of LV contraction for a similar rise in LV dP/dt(max), when
myocardial iNOS mRNA was higher. The larger abbreviation of LV contraction in
patients with high iNOS mRNA was associated with a decrease in LV end-systolic
pressure (-31+/-16 mm Hg). CONCLUSIONS: Myocardial iNOS gene expression in the
human allograft influences the LV contractile response to beta-adrenergic
stimulation through earlier onset of LV relaxation and reduction of LV end
systolic pressure. These effects are similar to the LV contractile effects of NO
derived from NO donor or from coronary endothelium.
PMID- 9396440
TI - Percutaneous transluminal mitral valvuloplasty normalizes baroreflex sensitivity
and sympathetic activity in patients with mitral stenosis.
AB - BACKGROUND: In patients with mitral stenosis, reduced cardiac output or altered
pulmonary hemodynamics may increase sympathetic nerve activity. However, the
magnitude of the increase in sympathetic activity in such patients and the effect
of valvuloplasty on this activity are unknown. METHODS AND RESULTS: We
microneurographically measured muscle sympathetic nerve activity before and after
mitral valvuloplasty in 10 patients (mean+/-SEM age, 48+/-2 years) with mitral
stenosis and in 10 healthy volunteers (47+/-4 years); hemodynamic variables were
also measured. Baroreflex sensitivity was assessed on the basis of the ratio of
the change in heart rate or muscle sympathetic activity to the change in mean
arterial pressure during intravenous infusion of sodium nitroprusside or
phenylephrine. At baseline, muscle sympathetic activity was significantly higher
in the patients with mitral stenosis than in the control subjects (42.1+/-3.2
versus 26.1+/-3.7 bursts/min, P<.05). However, there was no significant
difference between the groups in sympathetic activity at 1 week after
valvuloplasty. The reduction in sympathetic activity after valvuloplasty was
maintained for > or = 6 months and correlated with the increase in cardiac index
(r=.74, P<.05). Baroreflex sensitivity was significantly lower in the patients
than in the control subjects, but after valvuloplasty there was no significant
difference in baroreflex sensitivity between the groups. CONCLUSIONS: Sympathetic
activity is increased in patients with mitral stenosis. Mitral valvuloplasty in
such patients results in early and long-lasting normalization of sympathetic
nerve activity, possibly because of an improvement in arterial baroreflex
sensitivity.
PMID- 9396441
TI - Arterial baroreflex modulation of heart rate in chronic heart failure: clinical
and hemodynamic correlates and prognostic implications.
AB - BACKGROUND: In chronic heart failure (CHF), arterial baroreflex regulation of
cardiac function is impaired, leading to a reduction in the tonic restraining
influence on the sympathetic nervous system. Because baroreflex sensitivity
(BRS), as assessed by the phenylephrine technique, significantly contributes to
postinfarction risk stratification, the aim of the present study was to evaluate
whether in CHF patients a depressed BRS is associated with a worse clinical
hemodynamic status and unfavorable outcome. METHODS AND RESULTS: BRS was assessed
in 282 CHF patients in sinus rhythm receiving stable medical therapy (age, 52+/-9
years; New York Heart Association [NYHA] class, 2.4+/-0.6; left ventricular
ejection fraction [LVEF], 23+/-6%). The BRS of the entire population averaged
3.9+/-4.0 ms/mm Hg (mean+/-SD) and was significantly related to LVEF and
hemodynamic parameters (LVEF, P<.005; cardiac index and pulmonary wedge pressure,
P<.001 by regression analysis). Patients in NYHA classes III or IV and those with
severe mitral regurgitation had markedly depressed vagal reflexes. The
association of BRS with survival was described after its categorization in three
groups: below the lowest quartile (<1.3 ms/mm Hg), between the lowest quartile
and the median (1.3 to 3 ms/mm Hg), and above the median (>3 ms/mm Hg). During a
mean follow-up of 15+/-12 months, 78 primary events (cardiac death, nonfatal
cardiac arrest, and status 1 priority transplantation) occurred (27.6%). BRS was
significantly related to outcome (log rank, 9.1; P<.01), with a relative risk of
2.7 (95% confidence interval, 1.6 to 4.7) for patients with the major derangement
in BRS (<1.3 ms/mm Hg). At multivariate analysis, BRS was an independent
predictor of death after adjustment for noninvasive known risk factors but not
when hemodynamic indexes were also considered. In CHF patients with severe mitral
regurgitation, however, BRS remained a strong prognostic marker independent of
hemodynamic function. CONCLUSIONS: In moderate to severe CHF, a depressed
sensitivity of vagal reflexes parallels the deterioration of clinical and
hemodynamic status and is significantly associated with poor survival.
Particularly in patients with severe mitral regurgitation the baroreceptor
modulation of heart rate provides prognostic information of incremental value to
hemodynamic parameters.
PMID- 9396442
TI - Knowledge of perfusion and contractile reserve improves the predictive value of
recovery of regional myocardial function postrevascularization: a study using the
combination of myocardial contrast echocardiography and dobutamine
echocardiography.
AB - BACKGROUND: This study was designed to determine the value of myocardial contrast
echocardiography (MCE) and dobutamine echocardiography (DE), alone or in
combination, in predicting functional recovery in patients with resting wall
motion abnormalities due to CAD. MCE and DE have been independently shown to be
useful in detecting myocardial viability in the post-myocardial infarction
setting. METHODS AND RESULTS: Thirty-nine patients with significant coronary
artery disease and resting wall motion abnormalities underwent DE (2.5 to 20
microg x kg(-1) x min(-1)) and wall motion analysis (16-segment model). MCE was
performed with selective intracoronary injections of sonicated meglumine (2 cm3).
Myocardial viability was defined as presence of contrast effect by MCE and
contractile reserve or an ischemic response by DE. Functional recovery
(improvement in wall motion) was assessed after revascularization (percutaneous
transluminal coronary angioplasty, n=20; coronary artery bypass surgery, n=19).
When the two groups of patients were analyzed, MCE was associated with excellent
sensitivities (84%) yet poor specificities (19% to 26%); DE had lower
sensitivities (79% to 80%) but also poor specificities (30% to 36%). The
combination of both was associated with excellent sensitivities (90% to 93%) and
modest specificities (48% to 50%) for predicting functional recovery. A biphasic
response with DE was infrequent (14% to 42%) but highly specific of functional
recovery (84% to 94%). MCE had an excellent negative predictive value for
functional recovery (83%). CONCLUSIONS: The prediction of functional recovery
post-revascularization can be enhanced by combining MCE and DE.
PMID- 9396443
TI - Abundance and location of the small heat shock proteins HSP25 and alphaB
crystallin in rat and human heart.
AB - BACKGROUND: In the heart, there are high constitutive levels of the two related
small heat shock proteins, HSP25 and alphaB-crystallin. To gain insight into
their functional role, we have analyzed abundance and location of both proteins
in rat and human hearts at different stages of development and in diseased state.
METHODS AND RESULTS: Immunoblotting analysis of rat ventricular tissue at fetal,
neonatal, and adult stages reveals the level of HSP25 to decline strongly during
development, whereas the level of alphaB-crystallin remains nearly constant. In
parallel, the portion of phosphorylated isoforms of HSP25 decreases as shown by
two-dimensional polyacrylamide gel electrophoresis. HSP25 is detected in
cardiomyocytes and endothelial and vascular smooth muscle cells, whereas alphaB
crystallin is detected in cardiomyocytes only by immunofluorescence and
immunoelectron microscopy. Both proteins colocalize in the I-band and M-line
region of myofibrils in cardiomyocytes. In diseased and transplanted adult human
hearts, HSP25 and alphaB-crystallin levels are considerably elevated compared
with fetal hearts. In failing adult human hearts, phosphorylated isoforms of
HSP25 predominate, and cardiomyocytes with a partial dislocation of HSP25 and
alphaB-crystallin are observed. CONCLUSIONS: Differential accumulation and
location of HSP25 and alphaB-crystallin in heart tissue during development imply
distinct functions of both proteins, which seem to be involved in organization of
cytoskeletal structures. As judged by level, phosphorylation state, and location
of both small heat shock proteins, diseased adult human hearts share features
with fetal hearts.
PMID- 9396444
TI - Progressive anterior ablation in the coronary sinus region: evidence to support
the presence of a 'slow pathway' input in normal patients?
AB - BACKGROUND: AV node modification is an emerging approach to rate control in
patients with medically refractory atrial fibrillation. The mechanism of benefit
of this procedure is not completely understood. METHODS AND RESULTS: Twenty-two
patients (age, 65+/-11 years; 16 women) with medically refractory paroxysmal
atrial fibrillation referred for complete AV node ablation underwent serial
ablations beginning at the level of the coronary sinus os progressing in a
superior and anterior direction toward the His bundle. Serial atrial
extrastimulus testing was performed to determine the effect of the progressive
posteroseptal ablation in the region of the coronary sinus on the AV node
antegrade refractory curve. Two of 22 patients had antegrade dual AV node
pathways before ablation. Three patterns of response to serial ablation were
noted. In 10 patients (45%), loss of the terminal portion of the AV node
antegrade refractory curve occurred without evidence of fast pathway injury. In 7
patients (32%) the curve was shifted upward and to the left, consistent with
nonspecific AV node damage. In 5 patients (23%), no effect could be attained
before induction of complete AV block at superior and anterior ablation sites.
Clinical variables and site of ablation did not predict response to serial
ablations. CONCLUSIONS: These data suggest that the mechanism of benefit of AV
node modification in this population may be through elimination of "slow pathway"
tissue in half of patients and nonspecific injury in the remainder. Modification
without complete AV block may not be possible in a minority of patients, as the
response to progressive ablation appears to be "all or none" conduction.
PMID- 9396445
TI - Relationship between atrial fibrillation and typical atrial flutter in humans:
activation sequence changes during spontaneous conversion.
AB - BACKGROUND: A transitional rhythm precedes the spontaneous onset of atrial
flutter in an animal model, but few data are available in man. METHODS AND
RESULTS: In 10 patients, 16 episodes of atrial fibrillation (166+/-236 seconds)
converting into atrial flutter during electrophysiological evaluation were
analyzed. A 20-pole catheter was used for mapping the right atrial free wall.
Preceding the conversion was a characteristic sequence of events: (1) a gradual
increase in atrial fibrillation cycle length (150+/-25 ms after onset, 166+/-28
ms before conversion, P<.01); (2) an electrically silent period (267+/-45 ms);
(3) "organized atrial fibrillation" (cycle length, 184+/-24 ms) with the same
right atrial free wall activation direction as during atrial flutter; (4) another
delay on the lateral right atrium (283+/-52 ms); and (5) typical atrial flutter
(cycle length, 245+/-38 ms). The coronary sinus generally had a different rate
than the right atrial free wall until the beat that initiated flutter, when right
atrium and coronary sinus were activated in sequence. During 1313 seconds of
fibrillation, there were 171 episodes of "organized atrial fibrillation." An
additional activation delay at least 30 ms longer than the mean organized atrial
fibrillation cycle length was sensitive (100%) and specific (99%) for impending
organization into atrial flutter. During organized atrial fibrillation, right
atrial free wall activation was craniocaudal in 70% and caudocranial in 30%,
which may explain why counterclockwise flutter is a more common clinical rhythm
than clockwise flutter. Atrial flutter never degenerated into fibrillation, even
after adenosine infusion. CONCLUSIONS: Anatomic barriers, along with statistical
properties of conduction and refractoriness during atrial fibrillation, may
explain the remarkably stereotypical pattern of endocardial activation during the
initiation of atrial flutter via fibrillation and the rarity of degeneration of
flutter to fibrillation once it stabilizes.
PMID- 9396446
TI - Absence of parasympathetic control of heart rate after human orthotopic cardiac
transplantation.
AB - BACKGROUND: Partial reinnervation of cardiac sympathetic nerves has been observed
after heart transplantation; we hypothesized that parasympathetic control to the
heart after transplantation may return as well. To test this hypothesis, we
examined heart rate responses produced by two cardiovascular reflexes whose
efferent limbs are subserved by vagal fibers to the heart: (1) trigeminal reflex
(simulated diving reflex) and (2) arterial baroreflex with phenylephrine
injection. METHODS AND RESULTS: An "early" group (n=31, <24 months after
transplantation) and a "late group" (n=27, >45 months after transplantation) were
studied and compared with a control group with intact cardiac innervation (n=32)
and a renal transplant group with similar transplant immunosuppressive regimen
(n=11). For trigeminal reflex testing, responses of the donor sinus node (DSN)
(sinus node controlling heart rate) and recipient sinus node (RSN) in the
innervated remnant right atrium in cardiac transplant patients were compared with
heart rate responses in the control groups. For arterial baroreflex testing,
baroreflex gains for the DSN and RSN in the cardiac transplant groups were
compared with those of the control group. With engagement of the trigeminal
reflex, the DSN rate of both transplant groups changed minimally (early, 1.2+/
1.2 bpm; late, 1.8+/-2.5 bpm) compared with the expected decrease in control
subjects (-19.8+/-3.0 bpm) and renal transplant patients (-23.9+/-4.9 bpm)
(P<.001 versus cardiac transplants). Changes in the RSN rate of both cardiac
transplant groups (early, -13.0+/-4.0 bpm; late, -10.0+/-3.7 bpm) were similar to
the control groups. Arterial baroreflex gains for the DSN were also depressed
(early, 0.1+/-0.2 ms/mm Hg; late, 0.2+/-0.2 ms/mm Hg) compared with control
(14.9+/-1.8 ms/mm Hg) and RSN (early, 9.9+/-1.3 ms/mm Hg; late, 10.9+/-1.3 ms/mm
Hg; P<.001 versus DSN transplant). CONCLUSIONS: These data suggest that
parasympathetic influences on donor heart rate are absent in the majority of
patients up to 96 months after cardiac transplantation.
PMID- 9396447
TI - Radiofrequency catheter ablation of postinfarction ventricular tachycardia: long
term success and the significance of inducible nonclinical arrhythmias.
AB - BACKGROUND: Radiofrequency (RF) catheter ablation is effective therapy for
monomorphic ventricular tachycardia (VT) in patients without structural heart
disease. In patients with postinfarction VT; however, this procedure has been
used predominantly as adjunctive therapy, targeting only the patient's clinically
documented arrhythmia. By targeting all inducible, sustained VT morphologies, we
sought to determine the utility of RF catheter ablation as a primary cure in
patients who present with hemodynamically tolerated VT. METHODS AND RESULTS: RF
ablation was attempted in 35 patients with a previous myocardial infarction and
recurrent, hemodynamically tolerated VT. A mean of 3.9+/-2.7 VTs were induced per
patient (range, 1 to 10). The clinically documented arrhythmia was successfully
ablated in 30 of 35 patients (86%), and on follow-up electrophysiological
testing, 11 patients had no inducible VT and were discharged without other
therapy. Nineteen patients had inducible "nonclinical" arrhythmias on follow-up
testing, and the majority underwent cardiac defibrillator implantation. Freedom
from recurrent arrhythmias, including sudden death, was 91% in patients without
inducible VT and 53% in patients with persistently inducible "nonclinical"
arrhythmias (P<.05; mean follow-up, 17+/-12 and 12+/-11 months, respectively).
CONCLUSIONS: In patients with well-tolerated VT, RF catheter ablation may be
useful as a primary cure if no other ventricular arrhythmias are inducible on
follow-up testing. Ablation of all hemodynamically tolerated arrhythmias should
be attempted in patients with multiple inducible VT morphologies because of the
high rate of recurrence of unablated VTs in these patients.
PMID- 9396448
TI - Analysis of the degree of QRS fusion necessary for its visual detection:
importance for the recognition of transient entrainment.
AB - BACKGROUND: Fixed fusion is the hallmark for the demonstration of transient
entrainment. However, the degree of accuracy of its recognition on the surface
ECG is unknown. The purpose of the present study was to evaluate the ability to
detect fusion in the QRS complex. METHODS AND RESULTS: While pacing the
ventricles at a fixed rate, a model of ventricular fusion was created by
introducing late extra stimuli at a second site. In this model, the presence and
degree of fusion are known. Pacing sites were the RV apex, outflow tract, and
left ventricle in various configurations. We analyzed 433 QRS complexes with
different degrees of fusion (or no fusion) in 21 patients. Each QRS was "read" by
three investigators blinded to intracardiac recordings but having a reference QRS
with no fusion. There was a statistically significant correlation between the
degree of fusion and its recognition. Fusion was detected with a sensitivity of
75% and a specificity of 87%. Fusion was accurately detected in all
configurations only when >22% of the QRS was fused. In patients with organic left
ventricular disease, fusion was better recognized when the driving pacing site
was the left ventricle than when it was a right ventricular site. The
interobserver agreement was moderate between two pairs of observers and only fair
between the remaining pair. CONCLUSIONS: Our results suggest that an accurate
detection of ventricular fusion can only be accomplished when fusion occurs
during a significant proportion of the QRS duration. The potential lack of
recognition of minor degrees of fusion may produce underdetection of transient
entrainment.
PMID- 9396449
TI - Strength-duration relationship for human transvenous defibrillation.
AB - BACKGROUND: One of the basic characteristics of electrical defibrillation is the
strength-duration relationship, or the effect of pulse width on defibrillation
efficacy. This relationship is important for understanding the mechanism of
defibrillation and for the design of optimal waveforms. However, a detailed
evaluation of the strength-duration relationship for human transvenous
defibrillation has not been performed previously. METHODS AND RESULTS: This was a
prospective study of 29 patients undergoing initial defibrillator implantation
with a uniform dual coil, transvenous lead. In each patient defibrillation
thresholds were measured for either short (2, 3, 4, 6 ms) or long (6, 12, 18 ms)
pulse durations, with the order of testing randomized. The shock waveform was a
truncated monophasic pulse from a capacitor of 150 microF. The leading edge
voltage at defibrillation threshold was 566+/-100 V for 2-ms pulses. Voltages
declined exponentially with increasing pulse width reaching an asymptote by 6 ms
(451+/-68 V, P<.05). Defibrillation threshold voltage was insensitive to longer
pulse widths. Stored energy at defibrillation threshold showed a similar
relationship with pulse width. In contrast, mean current decreased monotonically
over the full range of pulse durations evaluated, and there was no evidence of a
rheobase. CONCLUSIONS: The shape of the strength-duration curve and the lack of
rheobase current indicate a fundamental difference between cardiac stimulation
and defibrillation. The relationship between pulse duration and defibrillation
threshold voltage or stored energy is well modeled by a parallel capacitor
resistor circuit with a time constant of 5.3 ms.
PMID- 9396450
TI - Instant power spectrum analysis of heart rate variability during orthostatic tilt
using a time-/frequency-domain method.
AB - BACKGROUND: Spectral analysis of heart rate (HR) variability (HRV) requires, as a
rule, some level of stationarity and, as a result, is inadequate to quantify
biological transients. A time-/frequency-domain method (TF) was developed to
obtain an instant spectral power (SP) of HRV during tilt. METHODS AND RESULTS: HR
was recorded by Holter monitoring in volunteers and analyzed with a TF, the
smoothed pseudo-Wigner-Ville transformation (SPWVT), with the table inclination
randomly set or continuously increased while the table rotated in head-up
position. (1) The SPWVT assesses, beat by beat, the instant center frequency
(ICF) of the SP. ICF correlates better with instant HR than the ratio of low-
(LF) to high-frequency (HF) oscillations. The transient effect of tilt is better
characterized as a shift of SP toward lower frequencies than by changes in
amplitudes. (2) The method evidences variations of HR from one second to another.
During the passage to head-up position, the vagal withdrawal and the sympathetic
activation occur nearly simultaneously, as indicated by the instant changes in
both LF and HF amplitudes and ICF. (3) The averaged results of the SPWVT give
results similar to those previously obtained with autoregressive algorithms.
CONCLUSIONS: The SPWVT is a new tool to explore HR transitions such as periods
before episodes of arrhythmias on a time scale of one beat and allows
quantification of an instant frequency index (ICF) that closely reflects the
instantaneous relationship between sympathetic and vagal modulations.
PMID- 9396451
TI - Evaluation of the specificity of morphological electrocardiographic criteria for
the differential diagnosis of wide QRS complex tachycardia in patients with
intraventricular conduction defects.
AB - BACKGROUND: Although several ECG criteria have been described for the
differential diagnosis of tachycardias with a wide QRS complex, their
applicability in patients with preexisting intraventricular conduction defects
(IVCDs) has been questioned. The specificity of previously described criteria in
this context is unknown. METHODS AND RESULTS: We analyzed prospectively the
specificity of the QRS morphological criteria previously described in ECGs during
sinus rhythm of 232 patients with IVCD. Only 5 of 12 analyzed criteria had a
specificity > or = 0.90 among our patients: (1) a triphasic configuration (Rsr'
or Rr') QRS complex in V1 in the presence of a right bundle-branch block
morphology (BBBM); (2) a QS, QR, or R QRS pattern in V6 in the presence of a
right BBBM; (3) any Q in V6 in the presence of a left BBBM; (4) a concordant
pattern in all precordial leads; and (5) the absence of an RS complex in all
precordial leads (particularly useful for left BBBM). The following criteria--QRS
duration > 140 ms; a left axis with right BBBM, right superior axis with right
BBBM, monophasic or biphasic R wave in V1 with right BBBM, and a relation R/S < 1
with right BBBM; an R > 30 ms in lead V1 or V2 with left BBBM, > 60 ms from QRS
onset to S nadir with left BBBM, a notched downstroke S wave with left BBBM, and
an R-to-S interval > 100 ms in one precordial lead--had a specificity of 0.43,
0.54, 0.87, 0.80, 0.85, 0.78, 0.66, 0.69, and 0.63 (0.84 in right BBBM),
respectively. CONCLUSIONS: Most of the previously described morphological
criteria favoring ventricular tachycardia are present in a substantial percentage
of patients with IVCD during sinus rhythm. These findings suggest a limited
applicability of these criteria in this subset of patients.
PMID- 9396452
TI - Cell-derived microparticles generated in patients during cardiopulmonary bypass
are highly procoagulant.
AB - BACKGROUND: Microparticles from platelets and other cells have been extensively
studied and characterized in vitro. Although the level of platelet-derived
microparticles is elevated in a variety of diseases, including cardiac surgery,
virtually nothing is known about their functions in vivo. The aim of the present
study was to investigate the procoagulant properties of microparticles generated
in vivo. METHODS AND RESULTS: In 6 patients at the end of cardiopulmonary bypass,
14.8 x 10(9)/L (median; range, 9.7 to 27.4 x 10(9)/L) platelet-derived
microparticles were present in pericardial blood, whereas blood obtained from the
systemic circulation contained 1.6 x 10(9)/L (median; range, 0.4 to 8.9 x
10(9)/L) of such microparticles, as determined by flow cytometry. Microparticles
stained positively for phosphatidylserine as determined with labeled annexin V.
In contrast to systemic blood, pericardial blood contained not only
microparticles of platelet origin but also microparticles that originated from
erythrocytes, monocytes, or granulocytes, and other hitherto unknown cellular
sources. Plasma prepared from pericardial blood and to a lesser extent plasma
from systemic blood obtained at the same time, stimulated formation of thrombin
in vitro. This activity of pericardial plasma was lost after removal of its
microparticles by high-speed centrifugation, whereas the corresponding
microparticle pellet was strongly procoagulant. The generation of thrombin in
vitro involved a tissue factor/factor VII-dependent and factor XII-independent
pathway. CONCLUSIONS: This study is the first to demonstrate that microparticles
generated in vivo can stimulate coagulation.
PMID- 9396453
TI - Activation of the complement system during and after cardiopulmonary bypass
surgery: postsurgery activation involves C-reactive protein and is associated
with postoperative arrhythmia.
AB - BACKGROUND: Complement activation during cardiopulmonary bypass (CPB) surgery is
considered to result from interaction of blood with the extracorporeal circuit.
We investigated whether additional mechanisms may contribute to complement
activation during and after CPB and, in particular, focused on a possible role of
the acute-phase protein C-reactive protein (CRP). METHODS AND RESULTS: In 19
patients enrolled for myocardial revascularization, perioperative and
postoperative levels of complement activation products, interleukin-6 (IL-6),
CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation
in vivo, were measured and related to clinical symptoms. A biphasic activation of
complement was observed. The ratio between the areas under the curve of
perioperative and postoperative C3b/c and C4b/c were 3:2 and 1:46, respectively.
IL-6 levels reached a maximum at 6 hours post-surgery. CRP levels peaked on the
second postoperative day. Each complement-CRP complex had peak levels on the
second or third postoperative day. By multivariate analysis, maximum levels of
CRP on the second postoperative day were mainly explained by C4b/c levels after
protamine administration, leukocyte count on the second postoperative day, and
preoperative levels of CRP. Peak levels of C4b/c after protamine administration
(P=.0073) and on the second postoperative day correlated with the occurrence of
arrhythmia on the same day (P=.0065). CONCLUSIONS: Cardiac surgery with CPB
causes a biphasic complement activation. The first phase occurs during CPB and
results from the interaction of blood with the extracorporeal circuit. The second
phase, which occurs during the first 5 days after surgery, involves CRP, is
related to baseline CRP levels, and is associated with clinical symptoms such as
arrhythmia.
PMID- 9396454
TI - Association of parvovirus B19 genome in children with myocarditis and cardiac
allograft rejection: diagnosis using the polymerase chain reaction.
AB - BACKGROUND: Inflammatory diseases of the heart, including myocarditis and cardiac
transplant rejection, are important causes of morbidity and mortality in
children. Although viral infection may be suspected in either of these clinical
conditions, the definitive etiology is often difficult to ascertain. Furthermore,
the histology is identical for both disorders. Coxsackievirus has long been
considered the most common cause of viral myocarditis; however, we previously
demonstrated by polymerase chain reaction (PCR) analysis that many different, and
sometimes unexpected, viruses may be responsible for myocarditis and cardiac
rejection. In this study, we describe the association of parvovirus genome
identified through PCR analysis of cardiac tissue in the clinical setting of
myocarditis and cardiac allograft rejection. METHODS AND RESULTS: Myocardial
tissue from endomyocardial biopsy, explant, or autopsy was analyzed for
parvovirus B19 using primers designed to amplify a 699-base pair PCR product from
the VP1 gene region. Samples tested included those obtained from patients with
suspected myocarditis (n=360) or transplant rejection (n=200) or control subjects
(n=250). Parvoviral genome was identified through PCR in 9 patients (3
myocarditis; 6 transplant) and no control patients. Of the 3 patients with
myocarditis, 1 presented with cardiac arrest leading to death, 1 developed
dilated cardiomyopathy, and the other gradually improved. Four of the 6
transplant patients had evidence of significant rejection on the basis of
endomyocardial biopsy histology. All transplant patients survived the infection.
CONCLUSIONS: Parvovirus is associated with myocarditis in a small percentage of
children and may be a potential contributor to cardiac transplant rejection. PCR
may provide a rapid and sensitive method of diagnosis.
PMID- 9396455
TI - Primate smooth muscle cell migration from aortic explants is mediated by
endogenous platelet-derived growth factor and basic fibroblast growth factor
acting through matrix metalloproteinases 2 and 9.
AB - BACKGROUND: Migration of arterial smooth muscle cells (SMCs) is regulated by
basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and
matrix metalloproteinases (MMPs) in the injured rat carotid artery. We have
recently shown that migration of SMCs from baboon aortic explants depends on the
activity of MMPs, but the identity of the stimulatory MMPs and the role of bFGF
and PDGF in this primate system are not known. METHODS AND RESULTS: These
experiments were designed to determine whether MMP2, MMP9, bFGF, or PDGF plays a
role in SMC migration from medial explants of baboon aorta. Explants were
cultured in serum-free medium with insulin, transferrin, and ovalbumin.
Neutralizing antibodies to MMP2 and antibodies that inhibit activation of proMMP9
decreased SMC migration from the aortic explants. Antibodies to bFGF and to the
alpha- and beta-subunits of the PDGF receptor also inhibited migration from the
explants. Addition of bFGF and PDGF-BB but not PDGF-AA increased migration. The
antibodies to bFGF but not the antibodies to the PDGF receptor subunits decreased
the levels of MMP9, whereas all the antibodies decreased activated MMP2.
CONCLUSIONS: These data demonstrate that SMC migration from primate aortic
explants is dependent on endogenous MMP2, MMP9, PDGF, and bFGF. The data also
suggest that PDGF-induced (PDGF-BB or possibly PDGF-AB) migration is dependent on
MMP2, whereas bFGF-induced migration depends on both MMP2 and MMP9.
PMID- 9396456
TI - In utero cardiac gene transfer via intraplacental delivery of recombinant
adenovirus.
AB - BACKGROUND: The relationship among the maternal, placental, and uniquely shunted
embryonic circulation was explored to provide access to the embryonic
cardiovascular system in utero. Manipulation of gene expression in the developing
heart would be particularly useful for studying the effects of altered gene
expression on cardiac development and in the etiology of congenital cardiac
anomalies. METHODS AND RESULTS: Dye studies demonstrated that intraplacental
injection allows direct access to the embryonic cardiac and systemic circulation.
To evaluate the efficacy of cardiac gene transfer using this approach,
replication-deficient recombinant adenoviral vectors encoding luciferase or beta
galactosidase as reporter genes were injected intraplacentally into embryonic day
(E)12.5 murine embryos, an age at which the mass of the heart was observed to be
large compared with other organs. Embryos were assayed for transgene expression
at E15.5 and at birth. Survival rates at these times were similar among vector
injected and control groups. At E15.5 and at birth, luciferase activity within
the heart was 9- and 23-fold higher, respectively, than in the remainder of the
embryo, although levels of expression were generally lower at birth than during
embryonic life. Beta-galactosidase expression was observed within all regions of
the embryonic heart and was localized to approximately 15% of atrial and
ventricular cells. CONCLUSIONS: Intraplacental delivery of adenovirus at
embryonic day 12.5 results in somatic gene transfer to the murine embryonic
heart, which persists at least until birth. The combination of intraplacental
injection to directly access the fetal coronary circulation and injection at
E12.5 when the mass of the heart is large compared with other organs results in
transgene expression in cardiac cells. Intraplacental injections early in
embryonic life may thus be useful to study the effects of temporal manipulation
of gene expression on cardiac development and disease.
PMID- 9396457
TI - Cardiovascular phenotype of a mouse strain with disruption of bradykinin B2
receptor gene.
AB - BACKGROUND: To evaluate the role of kinins in the regulation of cardiovascular
function, we studied the phenotype of a mouse strain with disruption of the
bradykinin B2-receptor gene (Bk 2r-/-). METHODS AND RESULTS: Under basal
conditions, tail-cuff blood pressure was higher in Bk2r-/- than in wild-type
Bk2r+/+ and heterozygous Bk2r+/- mice (124+/-1 versus 109+/-1 and 111+/-2 mm Hg,
respectively; P<.01 for both comparisons), a difference that was confirmed by
measurements of intra-arterial blood pressure in unanesthetized mice. Heart
weight was greater in Bk2r-/- than in Bk2r+/+ and Bk2r+/- mice (505+/-10 versus
449+/-12 and 477+/-10 mg/100 g body wt, P<.05). Chronic blockade of B2-receptors
by Icatibant (50 nmol/100 g body wt twice a day S.C.) or inhibition of nitric
oxide synthase by nitro-L-arginine-methyl ester (0.14 mmol/100 g body wt orally)
increased the blood pressure of Bk2r+/+ to the levels of Bk2r-/- mice. Compared
with the wild-type strain, both Bk2r-/- and Bk2r+/- mice showed exaggerated
vasopressor responses to angiotensin II. In addition, chronic administration of
an angiotensin AT1-receptor antagonist reduced the basal blood pressure of Bk2r-/
by 21+/-3 mmHg (P<.05) to the levels of Bk2r+/+. No difference was detected
between strains as far as plasma renin activity and the expression of renin and
AT1-receptor genes are concerned. Chronic salt loading (0.84 mmol/g chow for 15
days) increased the blood pressure of Bk2r-/- and Bk2r+/- by 34+/-3 and 14+/-6 mm
Hg, respectively, whereas it was ineffective in Bk2r+/+. CONCLUSIONS: Our results
suggest that a normally functioning B2-receptor is essential for the maintenance
of cardiovascular homeostasis in mice. Dysfunction of the kallikrein-kinin system
could contribute to increase blood pressure levels by leaving the activity of
vasoconstrictor agents unbalanced.
PMID- 9396459
TI - Intimal hyperplasia after balloon injury is attenuated by blocking selectins.
AB - BACKGROUND: Cell adhesion molecules facilitate the adherence of platelets and
leukocytes to the vascular endothelium in response to injury. Restenosis after
balloon angioplasty is thought to represent the response to vascular injury. The
role of cell adhesion in this process is unclear. METHODS AND RESULTS: This study
was performed in New Zealand White rabbits that underwent balloon angioplasty of
the iliac artery. Expression of the cell adhesion molecule E-selectin on
endothelium was determined by immunohistochemistry and increased at 6 hours with
a peak expression 24 to 48 hours after balloon injury, returning to baseline by 1
week. The expression of L-selectin on circulating leukocytes, measured by flow
cytometry, was significantly increased at 48 hours, with return to baseline by 1
week. In seven animals, the selectins were blocked with an analogue of sialyl
Lewis(x) given as an I.V. bolus of 10 mg/kg followed by 2 mg x kg(-1) x h(-1)
I.P. infusion for 7 days. After 4 weeks, compared with control animals, the study
group had a larger lumen area (57.7 versus 44.7 mm2, P<.05), smaller intima area
(9.0 versus 19.2 mm2, P<.01), smaller intima/media ratio (0.4 versus 1.0, P<.01),
and a smaller percent area stenosis (15.6% versus 34.3%, P<.01). CONCLUSIONS: The
cell adhesion molecules E-selectin and L-selectin are expressed after balloon
injury. Blockade of the selectins has a favorable effect on the response to
vascular injury.
PMID- 9396458
TI - Gap junction uncoupler heptanol prevents cell-to-cell progression of
hypercontracture and limits necrosis during myocardial reperfusion.
AB - BACKGROUND: The objective of this study was to test the hypothesis that chemical
interaction through gap junctions may result in cell-to-cell progression of
hypercontracture and that this phenomenon contributes to the final extent of
reperfused infarcts. METHODS AND RESULTS: Cell-to-cell transmission of
hypercontracture was studied in pairs of freshly isolated adult rat
cardiomyocytes. Hypercontracture induced by microinjection of a solution
containing 1 mmol/L Ca2+ and 2% lucifer yellow (LY) was transmitted to the
adjacent cell (11 of 11 pairs), and the gap junction uncoupler heptanol (2
mmol/L) prevented transmission in 6 of 8 pairs (P=.003), with a perfect
association between passage of the LY and transmission of hypercontracture. In
the isolated, perfused rat heart submitted to 30 minutes of hypoxia, addition of
heptanol to the perfusion media during the first 15 minutes of reoxygenation had
a dose-related protective effect against the oxygen paradox, as demonstrated by a
reduction of diastolic pressure and marked recovery of developed pressure
(P<.001), as well as less lactate dehydrogenase release during reoxygenation
(P<.001) and less contraction band necrosis (P<.001) than controls. In the in
situ pig heart submitted to 48 minutes of coronary occlusion, the intracoronary
infusion of heptanol during the first 15 minutes of reperfusion at a final
concentration of 1 mmol/L limited myocardial shrinkage, reflecting
hypercontracture (P<.05), reduced infarct size after 5 hours of reperfusion by
54% (P=.04), and modified infarct geometry with a characteristic fragmentation of
the area of necrosis. Heptanol at 1 mmol/L had no significant effect on
contractility of nonischemic myocardium. CONCLUSIONS: These results demonstrate
that hypercontracture may be transmitted to adjacent myocytes through gap
junctions and that heptanol may interfere with this transmission and reduce the
final extent of myocardial necrosis during reoxygenation or reperfusion. These
findings are consistent with the hypothesis tested and open a new approach to
limitation of infarct size by pharmacological control of gap junction
conductance.
PMID- 9396460
TI - Vitamins C and E inhibit O2- production in the pig coronary artery.
AB - BACKGROUND: We previously found in a pig coronary balloon injury model that
vitamins C and E as well as probucol had beneficial effects on the vessel
response to injury measured by morphometry These effects correlated with an
inhibition in the ability to oxidize LDLs ex vivo, suggesting that the
morphological response was due to the antioxidant effect of the treatments.
METHODS AND RESULTS: In the present study, the production of O2- by vessels 14
days after balloon injury was determined and correlated with circulating and
tissue levels of vitamins C and E. Twenty-five domestic pigs were divided into
four groups: control (n=7), vitamin C (500 mg/d, group C, n=6), vitamin E (1000
IU/d, group E, n=6), and vitamins C and E (500 mg/d and 1000 IU/d, group C+E,
n=6). Vitamins were administered 7 days before oversized balloon injury of the
left anterior descending coronary artery (LAD) and continued for 14 days after
injury. Vitamin C and E concentrations were determined in plasma and lymphocytes
as an index for tissue levels. Vessels were harvested after animals were killed,
and O2- production was measured by lucigenin chemiluminescence. O2- production by
the injured LAD was 2.5-fold greater than O2- production by the uninjured LAD or
right coronary artery (RCA). The increase in O2- was caused primarily by cells
present in the media and neointima. All vitamin-treated groups showed
significantly decreased O2- production in both the RCA and LAD (approximately 45%
inhibition) relative to vessels in the control, untreated group. There was a
significant correlation between LAD O2- production and lymphocyte vitamin E
levels. CONCLUSIONS: The present study is the first to show increased O2-
production in injured vessels and to demonstrate that antioxidant vitamins reduce
O2- production. These results suggest that beneficial effects of antioxidant
vitamins in coronary artery disease are related, in part, to alterations in
vessel redox state.
PMID- 9396461
TI - Differential effect of hydrogen peroxide and superoxide anion on apoptosis and
proliferation of vascular smooth muscle cells.
AB - BACKGROUND: Proliferation and apoptosis of vascular smooth muscle cells (VSMCs)
are two important components of atherosclerosis, restenosis, and hypertension.
Although reactive oxygen species have been demonstrated to participate in the
pathogenesis of these diseases, their precise involvement has not been fully
understood. We hypothesized that different reactive oxygen species exert distinct
effects on proliferation and apoptosis of VSMCs. METHODS AND RESULTS: Cultured
rat VSMCs were exposed to xanthine oxidase/xanthine (XO/X) or H2O2-Fe(II). A
single exposure to XO/X predominantly resulted in cell proliferation, whereas
frequent exposures to high levels of XO/X predominantly resulted in cell death.
Administration of superoxide dismutase and catalase revealed that O2- but not
H2O2, was mitogenic to VSMCs, whereas H2O2 was responsible for VSMC death.
Treatment with H2O2-Fe(II) alone or in the presence of different hydroxyl radical
scavengers showed that VSMC death occurred in a dose-dependent manner and was
mediated by the formation of hydroxyl radicals. Cell death caused by XO/X or H2O2
Fe(II) occurred by apoptosis as revealed by condensation of nuclei, appearance of
a "DNA ladder," increases in DNA fragmentation, and positive in situ nick-end
labeling. Northern blot analysis indicated that bcl-2 and c-fos but not p53 and c
myc may participate in mediating H2O2-Fe(II)-induced VSMC apoptosis. CONCLUSIONS:
Different reactive oxygen species exert distinct effects on VSMCs, with O2-
inducing proliferation and H2O2 causing apoptosis. Thus, reactive oxygen species
might participate in atherosclerosis, restenosis, and hypertension in a dual
manner by stimulating proliferation and triggering apoptosis of VSMCs.
PMID- 9396462
TI - Pulsatile stretch stimulates superoxide production in human aortic endothelial
cells.
AB - BACKGROUND: Free radicals such as superoxide and nitric oxide (NO) play a key
role in the pathophysiology of atherosclerosis. Mechanical forces such as
pulsatile stretch may be involved in free radical production. We studied
superoxide production by pulsatile stretch in human endothelial cells. METHODS
AND RESULTS: Human cultured aortic endothelial cells were exposed to pulsatile
stretch up to 24 hours, and superoxide production was examined. Short-term
stretch for 1 hour (10% average elongation, 50 cycles per minute) increased
superoxide production 2.2-fold. This effect was reduced by diphenyleneiodonium
chloride, an NADPH oxidase inhibitor, but not by the xanthine oxidase inhibitor
oxypurinol or the cyclooxygenase inhibitor indomethacin. Prolonged stretch up to
6 hours increased superoxide production, but it returned to near the control
level after 24 hours of stretch. However, after blockade of NO production, 24
hours of stretch did increase superoxide production 2.4-fold compared with 24
hours of stretch alone. Moreover, 24-hour stretch doubled NO synthase (NOS) (III)
protein and mRNA expression. The tetrahydrobiopterin synthesis inhibitor 2,4
diamino-6-hydroxypyrimidine had no effect on unstretched cells but doubled
superoxide production compared with 24-hour stretch alone; this increase was
halved by cotreatment with 6-methyl-5,6,7,8-tetrahydropterine, a lipid-soluble
form of tetrahydrobiopterine. CONCLUSIONS: Short-term stretch increased
superoxide production from human aortic endothelial cells via NADPH oxidase and
NOS (III), whereas prolonged stretch increased both superoxide and NO production.
The increase in NOS (III) protein with prolonged stretch acts as a scavenger
mechanism whereby NO inactivates superoxide. Tetrahydrobiopterin determines the
balance of superoxide and NO production from NOS (III) after prolonged stretch in
which NOS (III) level is upregulated.
PMID- 9396463
TI - Na+/H+ exchanger activity does not contribute to protection by ischemic
preconditioning in the isolated rat heart.
AB - BACKGROUND: Despite evidence that pharmacological inhibition of the Na+/H+
exchanger (NHE) is cardioprotective, activation of NHE has been proposed as a
protective mechanism of ischemic preconditioning (PC). METHODS AND RESULTS: In
isolated rat ventricular myocytes (n=8 to 11 per group) loaded with the
fluorescent pH indicator C-SNARF-1, we showed that HOE-642 (HOE) was a potent
inhibitor of the sarcolemmal NHE (80% inhibition at 1 micromol/L); such
inhibition was readily reversible by washout of the drug. We confirmed that 1
micromol/L HOE produces significant and reversible inhibition of NHE activity in
isolated rat hearts as well (n=4), and in this model, we tested (n=8 per group)
whether the presence of the drug during (1) the prolonged period of ischemia (40
or 60 minutes) or (2) the preceding brief periods of PC ischemia (3 minutes plus
5 minutes) modulates the protective efficacy of PC. In protocol 1, HOE was
infused for 5 minutes immediately before the prolonged ischemic period. With 40
minutes of prolonged ischemia, the postischemic recovery of left ventricular
developed pressure (LVDP) was 15+/-2% in controls and was improved to 45+/-7%
with HOE (P<.05), 55+/-5% with PC (P<.05), and 68+/-2% with PC+HOE (P<.05 versus
all groups). When the prolonged ischemic period was extended to 60 minutes, an
additive effect of PC and HOE was readily apparent and LVDP recovery with PC+HOE
(66+/-2%) was almost double that observed with HOE (37+/-4%) or PC (34+/-5%)
alone (P<.05). In protocol 2, HOE was infused for 3 minutes immediately before
each episode of PC ischemia and was subsequently washed out before a 40-minute
prolonged ischemic period (HOE+PC). LVDP recovery was 34+/-4% in controls and was
improved to 57+/-2% with PC (P<.05) and 55+/-3% with HOE+PC (P<.05). Improved
recovery of LVDP was matched by reduced creatine kinase leakage in all cases.
CONCLUSIONS: Because coadministration of HOE (at a concentration sufficient to
inhibit NHE activity) did not reduce the efficacy of PC in either protocol, we
conclude that NHE activity does not contribute to the cardioprotective actions of
PC. On the contrary, NHE inhibition during the prolonged ischemic period may
enhance the protection afforded by PC.
PMID- 9396464
TI - Physiological concentrations of estradiol attenuate endothelin 1-induced coronary
vasoconstriction in vivo.
AB - BACKGROUND: Estrogens are cardioprotective hormones and are reported to have
antianginal properties. We examined the effect of physiological concentrations of
17beta-estradiol on coronary reactivity in anesthetized female farm pigs. METHODS
AND RESULTS: Epicardial coronary cross-sectional area (CSA) was assessed by two
dimensional intravascular ultrasound, average coronary peak flow velocity (APV)
by intravascular Doppler velocimetry, and coronary blood flow (CBF) was
calculated. Dose-response curves to intracoronary endothelin-1 (ET-1, 1 pmol/L to
10 nmol/L), the selective ET(B) receptor agonist sarafotoxin (1 pmol/L to 10
nmol/L), and serotonin (0.1 nmol/L to 1 micromol/L) were assessed before and
after a 10-minute infusion of intracoronary estradiol (1 nmol/L). Before
estradiol administration, ET-1 induced significant dose-dependent decreases in
CSA, APV, and CBF. Estradiol attenuated ET-1-induced epicardial vasoconstriction
(P<.001) as well as ET-1-induced decreases in APV (P=.05) and CBF (P=.012). In an
additional five pigs, vehicle (DMSO) had no effect on ET-1-induced coronary
vasoconstriction. Before estradiol administration, sarafotoxin induced no net
change in CSA but induced increases in APV and CBF, the extent of which did not
change significantly after estradiol. Serotonin induced small decreases in CSA
but increased APV and CBF. Estradiol did not influence serotonin-induced changes
in CSA, APV, or CBF. CONCLUSIONS: We conclude that estradiol attenuates ET-1
induced vasoconstriction, possibly through effects on the ET(A) receptor, because
selective ET(B) receptor-induced stimulation with sarafotoxin remained unchanged.
Such an effect on the ET(A) receptor may relate to the antianginal properties of
estrogens.
PMID- 9396465
TI - Human protein C receptor is present primarily on endothelium of large blood
vessels: implications for the control of the protein C pathway.
AB - BACKGROUND: The protein C anticoagulant pathway is critical to the control of
hemostasis. Thrombomodulin and a newly identified receptor for protein
C/activated protein C, EPCR, are both present on endothelium. EPCR augments
activation of protein C by the thrombin-thrombomodulin complex. METHODS AND
RESULTS: To gain a better understanding of the relationship between
thrombomodulin and EPCR, we compared the cellular specificity and tissue
distributions of these two receptors by using immunohistochemistry. EPCR
expression was detected almost exclusively on endothelium in human and baboon
tissues. In most organs, EPCR was expressed relatively intensely on the
endothelium of all arteries and veins, most arterioles, and some postcapillary
venules. EPCR staining was usually negative on capillary endothelial cells. In
contrast, thrombomodulin was detected at high concentrations in both large
vessels and capillary endothelium. Both thrombomodulin and EPCR were expressed
poorly on brain capillaries. The liver sinusoids were the only capillaries in
which EPCR was expressed at moderate levels and thrombomodulin was low. EPCR and
thrombomodulin were both expressed on the endothelium of vasa recta in the renal
medulla, the lymph node subcapsular and medullary sinuses, and some capillaries
within the adrenal gland. Even in these organs the majority of capillaries were
EPCR negative or stained weakly. CONCLUSIONS: These studies suggest that EPCR may
be important in enhancing protein C activation on large vessels. The presence of
high levels of EPCR on arterial vessels may help explain why partial protein C
deficiency is a weak risk factor for arterial thrombosis.
PMID- 9396466
TI - Differential effects of endothelin receptor activation on cyclic flow variations
in rat mesenteric arteries.
AB - BACKGROUND: Cyclic flow variations (CFVs) represent repetitive cycles of platelet
adherence-aggregation and vasoconstriction, followed by dislodgment of platelet
thrombi and restoration of blood flow at the site of vascular injury. Although
activation of endothelin A (ETA) and endothelin B (ETB) receptors leads to
vasoconstriction and nitric oxide release, respectively, the roles of endogenous
endothelin-1 (ET-1) and its receptors in CFVs are unknown. METHODS AND RESULTS: A
side branch of a mesenteric artery of male Wistar rats was cannulated and a short
segment of the artery was mechanically injured to induce CFVs. After 20 minutes
of saline infusion, either saline (negative control), BQ-123 (ETA receptor
antagonist, 10 microg/min), BQ-788 (ETB receptor antagonist, 10 microg/min), or
sarafotoxin S6c (ETB receptor agonist, 10 ng/min) was infused for 20 minutes from
the side branch into the injured arterial segment. Percent (%) luminal stenosis
as well as proximal and distal vessel diameters were observed and quantitatively
measured every minute using intravital video microscopy and a micrometer
calibrated video screen. Both BQ-123 and sarafotoxin S6c significantly reduced
CFVs represented by the mean luminal stenosis (BQ-123=29+/-13% and sarafotoxin
S6c=27+/-11% reduction, respectively; P<.05 for both, compared with saline). In
contrast, BQ-788 significantly increased CFVs (33+/-6% increase, P<.05 compared
with saline). Moreover, the inhibitory effect of sarafotoxin S6c on CFVs was
completely abolished in the presence of N(omega)-nitro-L-arginine methyl ester (L
NAME) (a nitric oxide synthase inhibitor, 10(-5) mol/L) in superfusate over the
arteries (16.1+/-5% increase, P=NS compared with saline in the presence of L
NAME). In addition, BQ-123 caused a significant increase in the diameter of the
vessel distal to the injured segment (12+/-4% increase, P<.05 compared with
saline). CONCLUSIONS: Endogenous ET-1 release from sites of vascular injury
contributes to CFVs and vasomotor tone in the rat mesenteric artery CFV model.
ETA and ETB receptors have differential roles in CFVs: ETA receptor antagonism
and ETB receptor stimulation reduce CFVs, the latter at least partially through
increased nitric oxide formation.
PMID- 9396468
TI - Impaired nitric oxide-mediated renal vasodilation in rats with experimental heart
failure: role of angiotensin II.
AB - BACKGROUND: Congestive heart failure (CHF) is associated with a decrease in renal
perfusion. Because endothelium-derived NO is important in the regulation of renal
blood flow (RBF), we tested the hypothesis that an impairment in the NO system
may contribute to the decrease in RBF in rats with experimental CHF. METHODS AND
RESULTS: Studies were performed in rats with experimental high-output CHF induced
by aortocaval (AV) fistula and sham-operated controls. In controls, incremental
doses of acetylcholine (ACh, 1 to 100 microg x kg(-1) x min(-1)) increased RBF
and caused a dose-related decrease in renal vascular resistance (RVR). However,
the increase in RBF and decrease in RVR were markedly attenuated in rats with
CHF. Likewise, the effects of ACh on urinary sodium and cGMP excretion were also
diminished in CHF rats, as was the renal vasodilatory effect of the NO donor S
nitroso-N-acetylpenicillamine (SNAP). These attenuated responses to endothelium
dependent and -independent renal vasodilators in CHF rats occurred despite a
normal baseline and stimulated NO2+NO3 excretion and normal expression of renal
endothelial NO synthase (eNOS), as determined by eNOS mRNA levels and
immunoreactive protein. Infusion of the NO precursor L-arginine did not affect
baseline RBF or the response to ACh in rats with CHF. However, administration of
the nonpeptide angiotensin II receptor antagonist A81988 before ACh completely
restored the renal vasodilatory response to ACh in CHF rats. CONCLUSIONS: This
study demonstrates that despite a significant attenuation in the NO-related renal
vasodilatory responses, the integrity of the renal NO system is preserved in rats
with chronic AV fistula. This impairment in NO-mediated renal vasodilation in
experimental CHF appears to be related to increased activity of the renin
angiotensin system and may contribute further to the decrease in renal perfusion
seen in CHF.
PMID- 9396467
TI - Ca2+ release from intracellular stores is an initial step in hypoxic pulmonary
vasoconstriction of rat pulmonary artery resistance vessels.
AB - BACKGROUND: A reduction in oxygen tension in the lungs is believed to inhibit a
voltage-dependent K+ (Kv) current, which is thought to result in membrane
depolarization leading to hypoxic pulmonary vasoconstriction (HPV). However, the
direct mechanism by which hypoxia inhibits Kv current is not understood. METHODS
AND RESULTS: Experiments were performed on rat pulmonary artery resistance
vessels and single smooth muscle cells isolated from these vessels to examine the
role of Ca2+ release from intracellular stores in initiating HPV. In contractile
experiments, hypoxic challenge of endothelium-denuded rat pulmonary artery
resistance vessels caused either a sustained or transient contraction in Ca2+
containing or Ca2+-free solution, respectively (n=44 vessels from 11 animals).
When the ring segments were treated with either thapsigargin (5 micromol/L),
ryanodine (5 micromol/L), or cyclopiazonic acid (5 micromol/L) in Ca2+-containing
or Ca2+-free solution, a significant increase in pulmonary arterial tone was
observed (n=44 vessels from 11 animals). Subsequent hypoxic challenge in the
presence of each agent produced no further increase in tone (n=44 vessels from 11
animals). In isolated pulmonary resistance artery cells loaded with fura 2,
hypoxic challenge, thapsigargin, ryanodine, and cyclopiazonic acid resulted in a
significant increase in [Ca2+]i (n=18 cells from 6 animals) and depolarization of
the resting membrane potential (n=22 cells from 6 animals). However, with prior
application of thapsigargin, ryanodine, or cyclopiazonic acid, a hypoxic
challenge produced no further change in [Ca2+]i (n=18 from 6 animals) or membrane
potential (n=22 from 6 animals). Finally, application of an anti-Kv1.5 antibody
increased [Ca2+]i and caused membrane depolarization. Subsequent hypoxic
challenge resulted in a further increase in [Ca2+]i with no effect on membrane
potential (n=16 cells from 4 animals). CONCLUSIONS: In rat pulmonary artery
resistance vessels, an initial event in HPV is a release of Ca2+ from
intracellular stores. This rise in [Ca2+]i causes inhibition of voltage-dependent
K+ channels (possibly Kv1.5), membrane depolarization, and an increase in
pulmonary artery tone.
PMID- 9396469
TI - Stabilization of chronic remodeling by asynchronous cardiomyoplasty in dilated
cardiomyopathy: effects of a conditioned muscle wrap.
AB - BACKGROUND: Dynamic cardiomyoplasty is a promising new therapy for dilated
cardiomyopathy. The girdling effects of a conditioned muscle wrap alone have
recently been postulated to partly explain its mechanism. We investigated this
effect in a canine model of chronic dilated cardiomyopathy. METHODS AND RESULTS:
Twenty dogs underwent rapid ventricular pacing (RVP) for 4 weeks to create a
model of dilated cardiomyopathy. Seven dogs were then randomly selected to
undergo subsequent cardiomyoplasty, and all dogs had 6 weeks of additional RVP.
The cardiomyoplasty group also received 6 weeks of concurrent skeletal muscle
stimulation consisting of single twitches delivered asynchronously at 2 Hz to
transform the wrap without active assistance. All dogs were studied by pressure
volume analysis and echocardiography at baseline and after 4 and 10 weeks of
pacing. Systolic indices, including ejection fraction (EF), end-systolic
elastance (Ees), and preload-recruitable stroke work (PRSW) were all increased at
10 weeks in the wrap versus controls (EF, 34.0 versus 27.1, P=.008; Ees, 1.65
versus 1.26, P=.09; PRSW, 35.9 versus 25.5, P=.001). Ventricular volumes,
diastolic relaxation, and left ventricular end-diastolic pressures stabilized in
the cardiomyoplasty group but continued to deteriorate in controls. Both the end
systolic and end-diastolic pressure-volume relationships shifted farther
rightward in controls but remained stable in the cardiomyoplasty group.
CONCLUSIONS: In addition to potential benefits from active systolic assistance,
benefits from dynamic cardiomyoplasty appear to be partially accounted for by the
presence of a conditioned muscle wrap alone. This conditioned wrap stabilizes the
remodeling process of heart failure, arresting progressive deterioration of
systolic and diastolic function.
PMID- 9396470
TI - Hemodynamic evaluation of the heart with a nonfluoroscopic electromechanical
mapping technique.
AB - BACKGROUND: Clinical cardiac volumetric measurement techniques are essential for
assessing cardiac performance but produce significant inaccuracies in
extrapolation of the volume of a three-dimensional (3D) object from two
dimensional images and lack the ability to associate cardiac electrical and
mechanical activities. In this study, we tested the accuracy of cardiac
volumetric measurements using a new catheter-based system. METHODS AND RESULTS:
The system uses magnetic technology to accurately locate a special catheter at a
frequency of 125 Hz and is currently used in the field of electrophysiology, in
which activation maps are superimposed on the 3D geometry of the cardiac chamber.
The mapping procedure is based on sequentially acquiring the location of the tip
and local electrogram while in contact with the endocardium. The 3D geometry of
the chamber is reconstructed in real time, and its volume could be calculated at
every time step (8 ms). The volumetric measurements of the system were found to
be highly accurate for simple phantoms (mean+/-SEM deviation, 2.3+/-1.1%), left
ventricular casts (9.6+/-1.3%), and a dynamic test jig. In addition, left
ventricular volumes of 12 swine were measured. Intraobserver and interobserver
variabilities were found to be minimal (ejection fraction, 6.5+/-1.9% and 7.1+/
2.0%; stroke volume, 4.5+/-1.0% and 11.3+/-2.4%). Comparison with the
thermodilution method for measuring stroke volume showed an average deviation of
8.1+/-2.2%. Typical pressure-volume loops were also obtained. CONCLUSIONS: The
new mapping image provides, for the first time, simultaneous information
regarding cardiac mechanics, hemodynamics, and electrical properties.
Furthermore, all this information is achieved without the use of fluoroscopy,
contrast medium, or complicated image processing.
PMID- 9396471
TI - Etomoxir improves left ventricular performance of pressure-overloaded rat heart.
AB - BACKGROUND: Numerous studies have demonstrated diverse abnormalities in
subcellular structures of pressure-overloaded hypertrophied and failing heart.
Long-term administration of etomoxir, a carnitine palmitoyltransferase-1
inhibitor, partially normalized the proportion of myosin isozyme V1 and number of
active Ca2+ pumps in hypertrophied rat myocardium. METHODS AND RESULTS: To test
the hypothesis that long-term etomoxir treatment improves the performance of
hypertrophied ventricle, sham-operated rats and rats with ascending aorta
constriction were treated with racemic etomoxir (15 mg/kg per day) for 12 weeks.
Left ventricular geometry, dynamics of isovolumic contractions, as well as myosin
isozymes as marker of etomoxir-induced phenotype changes were assessed. Etomoxir
stimulated (P<.05) slight hypertrophic growth in right and left ventricles of
sham-operated rats as well as in right ventricles but not in overloaded left
ventricles of rats with aortic constriction. In all treated rats, etomoxir
increased (P<.05) maximal developed pressure, left ventricular pressure-volume
area, and +/- dP/dt(max). Enhanced values (P<.05) of derived indexes of
myocardial performance (normalized stress-length area, maximal rate of wall
stress rise, and decline) indicated that myocardial changes were responsible for
the improved performance. The etomoxir treatment increased selectively (P<.05)
the proportion of myosin V1 in pressure-overloaded left ventricles. CONCLUSIONS:
The long-term treatment with etomoxir improved functional capacity of pressure
overloaded left ventricle, which can be attributed to an enhanced myocardial
performance. Chronic carnitine palmitoyltransferase-1 inhibition may thus
represent a candidate approach for developing novel agents that are useful in the
prevention of undesirable consequences of pressure overload-induced cardiac
hypertrophy.
PMID- 9396472
TI - Direct measurement of three-dimensionally reconstructed flow convergence surface
area and regurgitant flow in aortic regurgitation: in vitro and chronic animal
model studies.
AB - BACKGROUND: Evaluation of flow convergence (FC) with two-dimensional (2D) imaging
systems may not be sufficiently accurate to characterize these often asymmetric,
complex phenomena. The aim of this study was to validate a three-dimensional (3D)
method for determining the severity of aortic regurgitation (AR) in an
experimental animal model. METHODS AND RESULTS: In six sheep with surgically
induced chronic AR, 20 hemodynamically different states were studied.
Instantaneous regurgitant flow rates were obtained by aortic and pulmonary
electromagnetic flow meters. Video composite data of color Doppler flow mapping
images were transferred into a TomTec computer after computer-controlled 180
degrees rotational acquisition. Direct measurement of the 3D reconstructed FC
surface areas as well as measurements of FC areas estimated with 2D methods with
hemispherical and hemielliptical assumptions were performed, and values were
multiplied by the aliasing velocity to obtain peak regurgitant flow rates. There
was better agreement between 3D and electromagnetically derived flow rates than
there was between the 2D and the reference values (r=.94, y=1.0x-0.16,
difference=0.02 L/min for the 3D method; r=.80, y=1.6x-0.3, difference=1.2 L/min
for the 2D hemispherical method; r=.75, y=0.90x+0.2, difference=-0.20 L/min for
the 2D hemielliptical method). CONCLUSIONS: Without any geometrical assumption,
the 3D method provided better delineation of the FC zones and direct measurements
of FC surface areas, permitting more accurate quantification of the severity of
AR than the 2D methods.
PMID- 9396473
TI - Vesnarinone prolongs action potential duration without reverse frequency
dependence in rabbit ventricular muscle by blocking the delayed rectifier K+
current.
AB - BACKGROUND: Methanesulfonanilide derivatives, selective inhibitors of the rapidly
activating component (I(Kr)) of the delayed rectifier potassium current (I(K)),
prolong action potential duration (APD) of cardiac muscles with reverse frequency
dependence, which limits their clinical use because of proarrhythmia.
Vesnarinone, a quinolinone derivative developed as a cardiotonic agent, has
complex pharmacological properties, but its clinical efficacy is explained in
part by I(K) reduction. Therefore, we investigated the mode of I(K) block by
vesnarinone. METHODS AND RESULTS: I(K) of the rabbit ventricular myocyte was
activated by voltage-clamp steps applied from a holding potential to various
depolarizing levels. The development of I(K) block at depolarization (+10 mV) and
its recovery process at hyperpolarization (-75 mV) were compared between
vesnarinone and E-4031. The I(K) block by vesnarinone (3 micromol/L) developed
and recovered monoexponentially, with time constants of 361 ms (n=5) and 1.87
seconds (n=4), respectively. I(K) block by E-4031 (0.3 micromol/L) developed
instantaneously, with no recovery from the block at hyperpolarization. The I(K)
block by vesnarinone, estimated by I(K) tail after a train of depolarizing pulses
(for 30 seconds at 0.2 to 2 Hz), was increased with increasing frequency (twofold
at 2 from 0.2 Hz), but that by E-4031 was unchanged. In rabbit papillary muscles,
vesnarinone (10 micromol/L) prolonged APD at stimulation frequencies >0.2 Hz,
whereas E-4031 (0.3 micromol/L) prolonged that in a reverse frequency-dependent
manner. CONCLUSIONS: Vesnarinone may prolong the repolarization of human cardiac
muscle without reverse frequency dependence, because I(Kr) is expressed in humans
as well as in the rabbit. Thus, this drug may be a model for an ideal class III
drug without the risk of proarrhythmia.
PMID- 9396474
TI - Positive chronotropic actions of parathyroid hormone and parathyroid hormone
related peptide are associated with increases in the current, I(f), and the slope
of the pacemaker potential.
AB - BACKGROUND: The classic calciotropic hormone parathyroid hormone (PTH) and its
paracrine factor parathyroid hormone-related protein (PTHrP) both increase heart
rate. METHODS AND RESULTS: We used standard electrophysiological techniques to
study the effects of PTH and PTHrP on isolated rabbit sinus node, isolated canine
Purkinje fibers, and disaggregated rabbit sinus node myocytes. Sinus node maximum
diastolic potential, activation voltage, and amplitude were unchanged by PTH or
PTHrP (P>.05). However, the slope of phase 4 and the automatic rate were
increased at PTH and PTHrP > or = 10 nmol/L (P<.05). Comparable results were seen
in canine Purkinje fibers. We then used the perforated-patch technique to study
the I(f) pacemaker current in sinus node. PTH 12.5 nmol/L and PTHrP 12.5 to 18
nmol/L increased I(f) at -65 mV by 68+/-41% (n=5) and 69+/-50% (n=5),
respectively. Actions of both agents were reversible. The increase in I(f)
appeared to result from a change in maximal conductance and not a shift in the
voltage dependence of activation. CONCLUSIONS: These observations provide, for
the first time, direct electrophysiological support for the chronotropic actions
of PTH and PTHrP. They suggest that classic hormones and paracrine factors can
have multiple functions and that in the case of PTH and PTHrP, a newly recognized
action is to alter automaticity directly.
PMID- 9396475
TI - Electrical remodeling due to atrial fibrillation in chronically instrumented
conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and
high rate of electrical activation.
AB - BACKGROUND: Recently, we developed a goat model of chronic atrial fibrillation
(AF). Due to AF, the atrial effective refractory period (AERP) shortened and its
physiological rate adaptation inversed, whereas the rate and stability of AF
increased. The goal of the present study was to evaluate the role of (1) the
autonomic nervous system, (2) ischemia, (3) stretch, (4) atrial natriuretic
factor (ANF), and (5) rapid atrial pacing in this process of electrical
remodeling. METHODS AND RESULTS: Twenty-five goats were chronically instrumented
with multiple epicardial atrial electrodes. Infusion of atropine (1.0 mg/kg; n=6)
or propranolol (0.6 mg/kg; n=6) did not abolish the AF-induced shortening of AERP
or interval (AFI). Blockade of K+(ATP) channels by glibenclamide (10 micromol/kg;
n=6) slightly increased the AFI from 95+/-4 to 101+/-5 ms, but AFI remained
considerably shorter than during acute AF (145 ms). Glibenclamide had no
significant effect on AERP after electrical cardioversion of AF (69+/-14 versus
75+/-15 ms). Volume loading by 0.5 to 1.0 L of Hemaccel (n=12) did not shorten
AERP. The median plasma level of ANF increased from 42 to 99 pg/mL after 1 to 4
weeks of AF (n=6), but ANF infusion (0.1 to 3.1 microg/min, n=4) did not shorten
AERP. Rapid atrial pacing (24 to 48 hours; n=10) progressively shortened AERP
from 134+/-10 to 105+/-6 ms and inversed its physiological rate adaptation.
CONCLUSIONS: Electrical remodeling by AF is not mediated by changes in autonomic
tone, ischemia, stretch, or ANF. The high rate of electrical activation itself
provides the stimulus for the AF-induced changes in AERP.
PMID- 9396476
TI - Mechanisms causing sustained ventricular tachycardia with multiple QRS
morphologies: results of mapping studies in the infarcted canine heart.
AB - BACKGROUND: Sustained reentrant ventricular tachycardias (VTs) with different QRS
morphologies have been observed to occur spontaneously and during programmed
stimulation in human hearts. We determined mechanisms that can cause tachycardias
with multiple morphologies in a canine model of myocardial infarction by mapping
reentrant circuits. METHODS AND RESULTS: Reentrant VT with multiple QRS
morphologies was induced in 11 canine hearts with 4-day-old infarcts. Comparison
of activation maps of the reentrant circuits in the epicardial border zone
associated with each morphology indicated two basic mechanisms. Less frequently,
VTs of different morphologies in the same heart were caused by reentrant circuits
in different regions of the infarct. Most commonly, the reentrant circuits
associated with different morphologies were in the same region. Three different
factors caused different exit routes from circuits in the same region, leading to
the multiple morphologies. (1) The reentrant wave front for each morphology
rotated around the same line of block but in different directions. (2) Reentrant
circuits associated with each morphology were similar, but there were small
changes in the extent of the central line of block. (3) Reentrant circuits with
completely different sizes and shapes caused different morphologies. CONCLUSIONS:
In this canine model, tachycardias with multiple morphologies most commonly arise
from reentrant circuits in the same region of the infarct, suggesting that most
often only one area has electrophysiological properties necessary to sustain
reentry.
PMID- 9396477
TI - Iridium oxide-coated defibrillation electrode: reduced shock polarization and
improved defibrillation efficacy.
AB - BACKGROUND: Transvenous implantable cardioverter-defibrillator (ICD) leads are
designed to deliver electric shocks to the heart for termination of ventricular
dysrhythmias. However, the efficiency of different lead materials has not been
well studied. This study compares an ICD lead coated with iridium oxide (IROX), a
material that reduces shock-induced polarization, with an otherwise identical,
uncoated lead. METHODS AND RESULTS: The defibrillation threshold (DFT) was
determined in 13 swine with both IROX-coated and uncoated ICD leads paired with
an uncoated "can" electrode. The leads were exchanged through a Teflon sheath to
reproduce the intracardiac position. The delivered energy DFT of the IROX-coated
lead was 15.9+/-5.4 J and was significantly lower than the delivered energy DFT
of the uncoated lead (19.1+/-5.1 J; P<.006). The initial lead impedance was
equivalent in both leads (IROX, 41.7+/-5.8 omega; uncoated, 41.3+/-4.7 omega;
P=NS) at DFT. However, the impedance rose by 7.3+/-2.0 omega during the first
phase and by 3.7+/-2 omega during the second phase with the uncoated lead,
whereas the corresponding impedance change was 1.0+/-0.3 omega during phase 1 and
1.6+/-0.5 omega during phase 2 (P<.01 each phase) when the IROX-coated lead was
used. CONCLUSIONS: This study shows that an IROX coating of this lead system
significantly lowers the DFT energy in the swine model. The blunting of the
impedance rise by the IROX coating that is seen is consistent with a reduction in
electrode polarization.
PMID- 9396479
TI - Myocardial contrast echocardiography: 15 years of research and development.
PMID- 9396478
TI - Significance of ventricular myocytes and nonmyocytes interaction during
cardiocyte hypertrophy: evidence for endothelin-1 as a paracrine hypertrophic
factor from cardiac nonmyocytes.
AB - BACKGROUND: In cardiac hypertrophy, both excessive enlargement of cardiac
myocytes and progressive interstitial fibrosis are well known to occur
simultaneously. In the present study, to investigate the interaction between
ventricular myocytes (MCs) and cardiac nonmyocytes (NMCs), mostly fibroblasts,
during cardiocytes hypertrophy, we examined the change in cell size and gene
expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide
(BNP) in cultured MCs as markers for hypertrophy in the neonatal rat ventricular
cardiac cell culture system. METHODS AND RESULTS: The size of cultured MCs
significantly increased in the MC-NMC coculture. Concomitantly, secretions of ANP
and BNP into culture media were significantly increased in the MC-NMC coculture
compared with in the MC culture (with the possible contamination of NMC <1% of
MC). Moreover, in the MC culture, enlargement of MC and an increase in ANP and
BNP secretions were induced by treatment with conditioned media of the NMC
culture. A considerable amount of endothelin (ET)-1 production was detected in
the NMC-conditioned media. BQ-123, an ET-A receptor antagonist, and bosentan, a
nonselective ET receptor antagonist, significantly blocked the hypertrophic
response of MCs induced by treatment with NMC-conditioned media. Angiotensin II
(Ang II) (10(-10) to 10(-6) mol/L) and transforming growth factor-beta1 (TGF
beta1) (10(-13) to 10(-9) mol/L), both of which are known to be cardiac
hypertrophic factors, did not induce hypertrophy in MC culture, but both Ang II
and TGF-beta1 increased the size of MCs and augmented ANP and BNP productions in
the MC-NMC coculture. This hypertrophic activity of Ang II and TGF-beta1 was
associated with the potentiation of ET-1 production in the MC-NMC coculture, and
the effect of Ang II or TGF-beta1 on the secretions of ANP and BNP in the
coculture was significantly suppressed by pretreatment with BQ-123. CONCLUSIONS:
These results demonstrate that NMCs regulate MC hypertrophy at least partially
via ET-1 secretion and that the interaction between MCs and NMCs plays a critical
role during the process of Ang II- or TGF-beta1-induced cardiocyte hypertrophy.
PMID- 9396480
TI - Role of the diadic cleft in myocardial contractile control.
PMID- 9396481
TI - New look to an old symptom: angina pectoris.
AB - At the turn of this century, it was proposed that ischemic cardiac pain might be
related to distension of the ventricular wall ("mechanical hypothesis"). Three
decades later, it was hypothesized that ischemic pain might be elicited by the
intramyocardial release of pain-producing substances induced by ischemia
("chemical hypothesis"). Studies carried out in the past 10 years have given
strong support to the chemical hypothesis, because they have consistently shown
that adenosine is a mediator of ischemic cardiac pain. Adenosine-induced ischemic
cardiac pain is mediated primarily by stimulation of A1 receptors located in
cardiac nerve endings and is potentiated by substance P. Conversely, the
magnitude and rate of left ventricular dilation during ischemia do not predict
the severity of angina. It is worth noting, however, that stretching of
epicardial coronary arteries appears to potentiate the severity of angina caused
by myocardial ischemia. The nervous activity generated by myocardial ischemia is
modulated in intrinsic cardiac, mediastinal, and thoracic ganglia. Then it is
further modulated in the central nervous system and projects bilaterally to the
cortex, as demonstrated in humans by positron emission tomography, where it is
decoded as a painful sensation. The causes responsible for the lack of angina
during myocardial ischemia are probably different in patients who present both
pain-free and painful myocardial ischemia, in patients with predominantly
painless ischemia, and in diabetic patients.
PMID- 9396483
TI - Images in cardiovascular medicine. False aortic aneurysm due to rupture of an
aortocoronary saphenous vein bypass graft.
PMID- 9396482
TI - Premature coronary artery disease associated with a disruptive mutation in the
estrogen receptor gene in a man.
AB - BACKGROUND: While estrogens protect against coronary artery disease in women, it
is unclear whether they influence cardiovascular function in men. The present
report describes coronary vascular abnormalities and the lipoprotein profile of a
male patient with estrogen insensitivity caused by a disruptive mutation in the
estrogen-receptor gene. METHODS AND RESULTS: Stress thallium scintigraphy,
echocardiography, and electron-beam computed tomography (CT) scanning of the
coronary arteries and detailed lipoprotein analysis were performed. Electron-beam
CT scanning of the coronary arteries showed calcium in the left anterior
descending artery. Lipoprotein analysis showed relatively low levels of total
(130 mg/dL), LDL (97 mg/dL), and HDL (34 mg/dL) cholesterol; apolipoprotein A-I
(91.7 mg/dL); and lipoprotein(a) (4.1 nmol/L), but normal levels of triglycerides
(97 mg/dL) and pre-beta-1-HDL cholesterol (61 microg/mL). CONCLUSIONS: The
absence of functional estrogen receptors may be a novel risk factor for coronary
artery disease in men.
PMID- 9396484
TI - Images in cardiovascular medicine. Left anterior descending coronary artery-to
right ventricle fistula.
PMID- 9396485
TI - Does the early hazard phenomenon exist? Do the GUSTO findings prove or disprove?
PMID- 9396486
TI - Anger and myocardial infarction.
PMID- 9396487
TI - DD genotype of the ACE gene as an atherosclerosis-independent risk factor for
myocardial infarction.
PMID- 9396488
TI - Aortic regurgitation in women.
PMID- 9396489
TI - Minimally invasive heart surgery.
PMID- 9396490
TI - Physical activity and plasma viscosity.
PMID- 9396491
TI - Coronary heart disease in India.
PMID- 9396492
TI - Preserved vasodilatory response to nitrates in saphenous vein bypass grafts.
PMID- 9396493
TI - Effects of dobutamine stimulation.
PMID- 9396494
TI - Does estrogen replacement prevent coronary heart disease?
PMID- 9396495
TI - Pathogenesis of calcification of native and bioprosthetic valves is different.
PMID- 9396496
TI - Antimineralization effect of ethanol and experimental model of accelerated
calcification study in heart valve bioprostheses.
PMID- 9396497
TI - In vitro effects of the platelet glycoprotein IIb/IIIa receptor antagonists c7E3
Fab on the activated clotting time.
PMID- 9396498
TI - Nonsustained ventricular tachycardia in severe heart failure.
PMID- 9396499
TI - Evidence for the existence of a functional cardiac renin-angiotensin system in
humans.
PMID- 9396500
TI - Plasminogen activator inhibitor-1 gene and myocardial infarction.
PMID- 9396501
TI - Effects of hypoglycemic agents on patients with diabetes.
PMID- 9396502
TI - Licensed to prescribe, but....'prior approval required'.
PMID- 9396503
TI - Concerning the units for the QT interval corrected by Bazett's formula.
PMID- 9396504
TI - Doppler features of constrictive pericarditis.
PMID- 9396505
TI - Worry and coronary heart disease.
PMID- 9396506
TI - Cholesterol-lowering therapy.
PMID- 9396507
TI - Collagen metabolism and restenosis.
PMID- 9396508
TI - Common mutation in the methylenetetrahydrofolate reductase gene offers no support
for mild hyperhomocysteinemia being a causal risk factor for cardiovascular
disease.
PMID- 9396509
TI - Oral anticoagulants in patients with mechanical cardiac valve replacement: the
role of aspirin.
PMID- 9396510
TI - Acoustic assessment of heart valves.
PMID- 9396511
TI - Acute profound thrombocytopenia after c7E3 Fab therapy.
PMID- 9396512
TI - Ischemia and glucose metabolism.
PMID- 9396513
TI - Hypocholesterolemia is associated with low levels of hemostatic risk factors.
PMID- 9396514
TI - Electrical remodeling.
PMID- 9396515
TI - Endothelin receptor antagonists.
PMID- 9396516
TI - Trials in myocardial infarction.
PMID- 9396517
TI - Partial ventriculectomy: a promising treatment for patients with end-stage
congestive heart failure.
PMID- 9396518
TI - The first Stephen L. Gans Memorial Lecture. An international strong personal
friendship in pediatric surgery.
PMID- 9396519
TI - Total colonic aganglionosis with or without small bowel involvement: a changing
profile.
AB - BACKGROUND/PURPOSE: To identify recent trends in the diagnosis and treatment of
total colonic aganglionosis with or without small bowel involvement (TCSA), the
authors analyzed the findings in 107 patients who had TCSA seen between 1988 and
1992 at 147 medical institutions throughout Japan and compared the results with
those of a previous survey conducted between 1978 and 1982. RESULTS: The
estimated incidence of total colonic aganglionosis was 1 in 58,084 live births,
the male to female ratio was 1.5:1, and the incidence of associated anomalies was
15%. These findings were all very similar to those of the previous survey. Ten
years ago, 83.6% of all patients underwent Martin's procedure. In the recent
survey, this rate had fallen to 52.1%, and a right colon patch method has also
been developed as a new procedure. A marked decrease in the overall mortality
rate from 40.9% to 21.5% was observed. However, a high mortality rate persists in
those cases with small bowel involvement (33.3%); most such cases are complicated
with enterocolitis. CONCLUSIONS: Although the general features of TCSA were
similar to those in the previous survey, a substantial improvement in the
treatment results for TCSA has occurred. However, further efforts are still
required both to prevent and more effectively to treat enterocolitis, especially
in cases involving any aganglionosis extending into small bowel.
PMID- 9396520
TI - Long-term follow-up of patients treated with ileoendorectal pull-through and
right colon onlay patch for total colonic aganglionosis.
AB - BACKGROUND/PURPOSE: This study was performed to assess the long-term follow-up of
five patients who underwent one-stage ileoendorectal pull-through with right
colon onlay patch for total colonic aganglionosis (TCA) at Kaiser Permanente
Medical Center. METHODS: A retrospective review of inpatient and outpatient
charts and telephone follow-up of all patients were conducted to obtain current
data regarding growth, development, bowel function, and postoperative and late
complications. RESULTS: Follow-up has ranged from 2 to 11 years. All patients are
at or above the 50th percentile for weight by age and are continent with 1 to 5
daily bowel movements. Only two patients required reoperation. A perirectal
abscess developed in one patient 2 months postoperatively. In the second patient
a functional obstruction was relieved by sphincterotomy. CONCLUSIONS:
Ileoendorectal pull-through with right colon onlay patch is associated with few
early and late postoperative complications; it appears to be superior to other
procedures in the early postoperative period because of the more rapid return to
acceptable stooling patterns. This method of reconstruction provides an excellent
opportunity for normal growth, development, and long-term bowel function.
PMID- 9396521
TI - Cytomegalovirus enteritis in a premature infant.
AB - BACKGROUND/PURPOSE: Up to 2.5% of newborn infants are cytomegalovirus (CMV)
positive at birth. Five percent will be symptomatic at birth, including
cytomegalic inclusion disease. Symptoms such as hearing loss and mental
retardation will ultimately develop in 15%. METHODS: The authors describe a case
of CMV enteritis in a 2.2-kg newborn that presented as necrotizing enterocolitis
(NEC) and subsequently developed a colonic stricture. RESULTS: There are four
reports of neonatal CMV enteritis in the nonEnglish-language literature.
Cytomegalovirus enteritis has become prevalent among the immunosuppressed
pediatric and adult patient population. CONCLUSIONS: We propose the addition of
CMV to the list of pathogens responsible for NEC. A review of neonatal CMV
infection is provided.
PMID- 9396522
TI - Factors influencing the outcome of liver transplantation for biliary atresia.
AB - BACKGROUND/PURPOSE: This study examined the factors present before liver
transplantation (LTx) influencing the outcome in 14 patients who had biliary
atresia (BA) who underwent LTx. RESULTS: Nine patients survived (Group A),
whereas five died primarily of infection (Group B). Rate of the attempted
multiple hepatic portoenterostomy (HPE) and existence of intestinal stoma was
significantly higher in Group B than in Group A. Pre-LTx parameters showed
significant difference between the two groups as follows: total bilirubin, 15.9
+/- 7.9 versus 29.1 +/- 14.5 mg/dL (P = .0446); gamma-glutamyl transpeptidase,
170.0 +/- 97.6 versus 65.2 +/- 38.8 IU/L (P = .0425); the body weight deviation
score, 0.17 +/- 0.88 SD versus -1.46 +/- 0.30 SD (P = .0029); total cholesterol,
129.4 +/- 33.5 versus 52.2 +/- 20.4 mg/dL (P = .0008) in Group A versus Group B.
Total cholesterol level and body weight for age remained within normal range
until the advanced stage and rapidly decreased according to deterioration of the
general condition before LTx. CONCLUSIONS: From these results, avoidance of
multiple HPE and closure of stoma before LTx may be preferable. LTx should be
performed before failure to thrive or hypocholesterolemia develops.
PMID- 9396523
TI - A new hepatic portoenterostomy with division of the ligamentum venosum for
treatment of biliary atresia: a preliminary report.
AB - BACKGROUND/PURPOSE: Kasai's operation consists of transection of the fibrous
portal cord including the bile duct remnant. However, it is difficult to transect
the fibrous cord at the level of the posterior surface of the portal vein,
because the portal vein is fixed at the porta hepatis. METHODS: The authors
described a new hepatic portoenterostomy to transect the fibrous cord under an
appropriate visual field by division of the ligamentum venosum (Arantius' canal).
Between February and December 1996, six patients who had biliary atresia
underwent this procedure. RESULTS: Jaundice resolved completely (TB < or = 1.0
mg/dL) in all six patients within 40 days. Postoperative cholangitis did not
occur and good bile drainage was obtained. CONCLUSIONS: Using this procedure, the
portal vein becomes fully mobile after dividing the ligamentum venosum, and the
porta hepatis can be widely exposed. The fibrous cord of the porta hepatis can be
easily dissected off posteriorly and laterally.
PMID- 9396524
TI - A new diagnostic approach to biliary atresia with emphasis on the
ultrasonographic triangular cord sign: comparison of ultrasonography,
hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of
infantile cholestasis.
AB - BACKGROUND/PURPOSE: The authors evaluated prospectively the utility of
ultrasonography, Tc-99m-DISIDA hepatobiliary scintigraphy, and liver needle
biopsy in differentiating biliary atresia (BA) from intrahepatic cholestasis in
73 consecutive infants who had cholestasis. METHODS: Sixty three ultrasonographic
examinations of 61 infants with 7.0-MHz transducer were carried out, focusing on
the fibrous tissue at the porta hepatis. The authors defined the triangular cord
(TC) as visualization of a triangular or tubular shaped echogenic density just
cranial to the portal vein bifurcation on a transverse or longitudinal scan.
RESULTS: Although 17 of 20 ultrasonographic examinations from infants who had BA
denoted TC, 43 ultrasonographic examinations from infants with either neonatal
hepatitis (NH) or other causes of cholestasis denoted no TC, showing a diagnostic
accuracy of 95% with 85% sensitivity and 100% specificity. Investigation with Tc
99m-DISIDA hepatobiliary scintigraphy showed that 24 of 25 infants who had BA had
no gut excretion, and 16 of 46 infants who had either NH or other causes of
cholestasis had gut excretion, showing a diagnostic accuracy of 56% with 96%
sensitivity and 35% specificity. Therefore, gut excretion of tracer excluded BA,
but no gut excretion of tracer needed further investigations as liver needle
biopsy. Forty-four liver needle biopsies were carried out in 19 infants who had
BA and 24 infants who had either NH or other causes of cholestasis. Although 18
of 20 biopsy findings in infants who had BA were correctly interpreted as having
BA, 23 of 24 biopsy results in infants who had either NH or other causes of
cholestasis were correctly diagnosed, showing a diagnostic accuracy of 93% with
90% sensitivity and 96% specificity. CONCLUSIONS: Since the introduction of
ultrasonographic TC sign in the diagnosis of BA by our institution, we have found
that it seemed to be a simple, time-saving, highly reliable, and non-invasive
tool in the diagnosis of BA from other causes of cholestasis. The authors propose
a new diagnostic strategy in the evaluation of infantile cholestasis with
emphasis on ultrasonographic TC sign as first priority of investigations. When
the TC is visualized, prompt exploratory laparotomy is mandatory without further
investigations. When the TC is not visualized, hepatobiliary scintigraphy is the
next step. Excretion of tracer into the small bowel actually rules out BA. Liver
needle biopsy is reserved only for the infants with no excretion of tracer. The
authors believe that a correct decision regarding the need for surgery can be
made in almost all cases with infantile cholestasis by this multidisciplinary
approach.
PMID- 9396525
TI - Initial experience with non-breath-hold magnetic resonance
cholangiopancreatography: a new noninvasive technique for the diagnosis of
choledochal cyst in children.
AB - BACKGROUND/PURPOSE: Magnetic resonance cholangiopancreatography (MRCP) is an
emerging tool for the noninvasive evaluation of the pancreaticobiliary tree.
METHODS: Non-breath-hold MRCP was used in three children to evaluate choledochal
cyst; a first for this new modality of diagnostic imaging. In all cases, the
intrahepatic and extrahepatic bile ducts, and the pancreatic duct were clearly
visualized. RESULTS: Two cases were found to have a fusiform choledochal cyst,
and non-breath-hold MRCP demonstrated pancreaticobiliary malunion and a long
common channel. In the remaining case, the size and location of the huge cyst
prevented visualization of any pancreaticobiliary malunion. Endoscopic retrograde
cholangiopancreatography (ERCP) in this patient failed to provide any additional
information. All patients underwent cyst excision with hepaticoenterostomy, and
made an uneventful recovery. CONCLUSIONS: Our initial experience suggests that
non-breath-hold MRCP is a reliable method for the diagnosis of choledochal cyst
in children and could replace ERCP.
PMID- 9396526
TI - Early and late results of excision of choledochal cysts.
AB - BACKGROUND/PURPOSE: Reports on the late results of choledochal cyst excision with
hepaticojejunostomy in children are relatively few. METHODS: Of the 84 patients
who had choledochal cyst who came under our care, 79 have had definitive surgery,
three are awaiting surgery, one is being observed with Caroli's disease, and the
parents of one child have refused surgery. Thirty-eight patients treated decades
ago had internal drainage procedures. Since 1972, 41 patients have had cyst
excision with hepaticojejunostomy using a 40-cm Roux loop without an antireflux
procedure. Early complications in those who underwent cyst excision with
hepaticojejunostomy included anastomotic leak in three patients who required
reoperation, cholangitis in two, and fluid collection in the gall-bladder bed
that required no intervention in one. RESULTS: During a follow-up period ranging
from 4 months to 17 years (mean, 8.5 years), anastomotic stricture, cholangitis,
and intrahepatic stone formation developed in two children after being well for 8
years and over 11 years. These children required additional surgical procedures
to overcome their problems. Asymptomatic intrahepatic stones 2 years after cyst
excision with hepaticojejunostomy developed in a third child. There was no
mortality in the entire group that underwent cyst excision and they are all
enjoying a good quality of life. CONCLUSIONS: Careful, long-term follow-up is
important in children who have choledochal cyst excision with
hepaticojejunostomy.
PMID- 9396527
TI - Two cases of torsion of the gallbladder diagnosed preoperatively.
AB - BACKGROUND: The authors experienced two cases of torsion of the gallbladder, both
of which were correctly diagnosed preoperatively. METHODS: Two boys, aged 4 and 5
years, were transferred to Yokohama City Seibu Hospital because of their acute
abdominal disorders. Diagnostic imaging demonstrated acute inflammatory changes
in the gallbladder with an abnormal arrangement of the gallbladder and common
bile duct in both cases. Laparotomy findings showed torsion of the gallbladder by
180 degrees and 360 degrees, respectively, at the cystic ducts, resulting in
gangrenous change. RESULTS: Both children recovered uneventfully after
cholecystectomy. The diagnostic imaging criteria are (1) collection of fluid
between the gallbladder and the gallbladder fossa of the liver, (2) a horizontal
rather than vertical arrangement of the long axis of the gallbladder, (3) the
presence of a well-enhanced cystic duct located on the right side of the
gallbladder, and (4) signs of inflammation including marked edema with thickening
of the wall. CONCLUSIONS: The authors report the clinical characteristics of this
uncommon condition, and discuss the significance of accurate preoperative
diagnosis of these acute surgical disorders.
PMID- 9396528
TI - Esophageal atresia in Osaka: a review of 39 years' experience.
AB - BACKGROUND: One hundred fifty-nine patients who had esophageal atresia with or
without tracheoesophageal fistula have been treated at Osaka University Medical
School and its affiliated hospitals since the initial (Japanese) experience of Dr
T. Ueda in 1957. METHODS: These cases were divided chronologically into three
groups. With earlier recognition of surgical neonates and the development of
perinatal care, the long-term survival of these patients has steadily improved
over 39 years from 28% in the first period (1957 to 1967) to 80% in the third
period (1980 to 1995). Of 141 patients treated in the second and third periods
(1968 to 1995), 92 (65.2%) had associated anomalies. Cardiovascular and
gastrointestinal malformations were the most frequently seen major anomalies.
VATER or VACTER association was seen in 12.8% (18 of 141) of these patients.
Survival of these cases according to Waterston risk factors was 100% for group A,
100% for group B, and 50% for group C, whereas the new classification proposed by
Spitz showed survival of 92% for group 1, 50% for group 2, and 0% for group 3,
showing better differentiation among the three groups. RESULTS: There was a long
gap between the proximal and distal esophageal ends in seven patients (type A),
in all of whom primary anastomosis was possible after 28 to 128 days of
elongation by bouginage. Although the survival of esophageal atresia patients
dramatically improved in recent years, there is still a high incidence of early
and long-term postoperative complications, ie, anastomotic leakage (26.5%),
recurrent fistula (7.2%), anastomotic stricture (49.1%), postoperative pneumonia
or atelectasis (57.0%), tracheomalacia (25.8%), and gastroesophageal reflux
(52.0%). CONCLUSIONS: Recently, there have been changing patterns in the
occurrence of complications, which are mainly attributed to technical
improvement, better perinatal care and early recognition of pathophysiologic
conditions such as tracheomalacia and gastroesophageal reflux.
PMID- 9396529
TI - Tracheomalacia with esophageal atresia and tracheoesophageal fistula in fetal
rats.
AB - BACKGROUND: Many patients who have esophageal atresia and tracheoesophageal
fistula (EA-TEF) have associated tracheomalacia, which is thought to be one of
the reasons for respiratory complications after surgical correction of the
abnormality. METHODS: In this study, tracheas from Adriamycin-induced EA-TEF
fetal rats were examined histologically and relevant cross-sectional parameters
of the tracheas were measured. RESULTS: The tracheal lumen in tracheomalacia was
small and irregular, losing its normal "D" shape. In most rats, the cartilaginous
ring was broken into two to four segments, making the trachea lose its rigid
support. The submucosa was thickened with prominent bulging of its membranous
part into the tracheal lumen. The ratio of the inner luminal cross-sectional area
to the outer tracheal cross-sectional area in EA-TEF rats was 15.7%, compared
with a control ratio of 47.2%. In EA-TEF rats, the length of the cartilaginous
ring was significantly shortened (P < .001), but not the length of membranous
trachea, thus resulting in a cartilaginous/membranous (C/M) ratio of 1.55:1,
markedly lower than that of normal rats (4.34:1, P < .001). The reduction of
anterior-posterior diameter of the tracheal lumen was more marked than that of
the transverse diameter. CONCLUSIONS: These observations suggest that the trachea
in EA-TEF rats has a smaller lumen and is more flaccid than normal, making it
prone to airway obstruction. The fact that tracheomalacia developed only in
fetuses who had EA-TEF indicates that the factors that result in EA-TEF also
cause tracheomalacia.
PMID- 9396530
TI - The vagus and recurrent laryngeal nerves in the rodent experimental model of
esophageal atresia.
AB - BACKGROUND: After surgical correction of their esophageal atresia and
tracheoesophageal fistula (EA-TEF), many patients exhibit evidence of esophageal
dysmotility. Controversy exists as to whether the esophageal motility disorders
result from denervation caused by surgery or from an inherent abnormal
innervation of the esophagus. METHODS: The present study used an Adriamycin
induced EA-TEF fetal rat model to trace the course and branching of both the
vagus and recurrent laryngeal nerves. Abnormalities observed in EA-TEF rat
fetuses include: (1) fewer branches from both recurrent laryngeal nerves; (2)
deviation of the left vagus from its normal course below the aorta, passing
behind the fistula to approach and join with the right vagus to form a single
nerve trunk on the right side of the esophagus; (3) relatively few branches from
the single vagal nerve trunk (composed of fibers of the left and the right vagus)
on the surface of the lower esophagus. CONCLUSIONS: Fetuses affected by EA-TEF
have inherent abnormalities in the course and branching pattern of the vagus
nerves as they descend through the thorax, culminating in a deficient extrinsic
nerve fiber plexus in the lower esophagus. These observations may account for the
esophageal motility disorders seen in patients who have EA-TEF even before
surgical intervention.
PMID- 9396531
TI - Aortic arch anomalies associated with long gap esophageal atresia and
tracheoesophageal fistula.
AB - PURPOSE: The purpose of this study was to determine whether aortic arch anomalies
are associated with long gap esophageal atresia and tracheoesophageal fistula (EA
TEF). METHODS: The authors performed a retrospective review of all infants who
had EA-TEF from 1980 to 1996 at two pediatric surgery centers. Two hundred three
infants who had EA-TEF were identified. RESULTS: Twelve infants were noted to
have both long gap EA-TEF defined as a gap length greater than 3 cm and aortic
arch anomalies. Of these 12, 7 had aberrant right subclavian arteries originating
from the descending aorta. Four of the seven infants who had aberrant right
subclavian artery (SCA) had gap lengths greater than 4 cm. All four had their
fistulae divided initially through a right thoracotomy with primary repair
performed at a later date. The remaining five infants who had long gap EA-TEF had
right-sided aortic arch with aberrant left subclavian arteries. All five
initially underwent exploration through the right chest. On discovery of the long
gap EA and concurrent vascular anomaly, the thoracotomies were closed, and the
infants underwent definitive repair of both their EA-TEF and their vascular
anomaly through a left thoracotomy. CONCLUSIONS: The authors find that aortic
arch anomalies are associated with long gap EA-TEF. Patients who have these two
anomalies tend to have a long gap. Preoperative diagnosis of these anomalies may
alter the timing and technique of surgical intervention. The embryogenesis of
these vascular lesions may account for this more severe form of esophageal
atresia.
PMID- 9396532
TI - Congenital true diverticula of the esophagus: a case report.
AB - Pseudodiverticulosis secondary to gastroesophageal reflux is a common disease in
adults, but true esophageal diverticula are rare in infants and children. A 5
year-old boy was well until the age of 1 1/2 years when he started vomiting. An
upper gastrointestinal series showed two diverticula bulging from the posterior
right side of the middle esophagus associated with slight hiatal hernia and short
esophagus. Diverticulectomy, the Collis-Nissen antireflux procedure, and
pyloroplasty were performed simultaneously through a left thoracoabdominal
incision. Histological examination of the diverticula showed that the wall of
each diverticulum consisted of a full-thickness of esophageal wall. Because there
was no tracheal remnant in the diverticula, this lesion is more likely to be a
true diverticulum than a duplication.
PMID- 9396533
TI - Selecting the surgical procedure for simple and complicated esophageal achalasia
in children.
AB - BACKGROUND/PURPOSE: Surgical experience in children who have achalasia is
limited. Surgical treatment requires esophagocardiomyotomy and an antireflux
procedure. However, when these operations fail, other procedures are needed. To
summarize the experience treating children who have this condition, the authors
reviewed retrospectively all case histories of patients treated from 1971 to 1996
at their hospital. METHODS: Three boys and a girl, ranging in age from 18 months
to 11 years, were treated. All had multiple previous dilatations. Two then
underwent operation using an abdominal approach for a Heller procedure and a
posterior fundoplasty (Guarner operation). Two children were previously treated
in another hospital. One underwent a Heller operation complicated by perforation
of the anterior mucosa. The other had undergone three previous abdominal
approaches for esophagocardiomyotomy and a Nissen fundoplication. Symptoms
persisted and imaging and endoscopy showed stenosis in both patients. In the
first patient an esophagocardioplasty with transverse closure (Wendel procedure)
and a posterior fundoplasty was performed. In the second child, the three
previous abdominal surgical approaches mandated a transthoracic approach with
transdiaphragmatic latero-lateral esophagogastric anastomosis (Heyrowsky
operation) and a modified Guarner operation using the remaining fundus and
gastric body. RESULTS: There were no intraoperative or postoperative
complications. Follow-up time ranged from 3 months to 17 years. All patients
experienced dramatic relief of symptoms and satisfactory weight gain. No
recurrence of symptomatology has occurred. CONCLUSIONS: Esophagocardiotomy
associated with an antireflux procedure may be the first option in the surgical
treatment of children who have achalasia. However, if this fails,
esophagocardioplasty and the latero-lateral esophagogastric anastomosis
associated with antireflux procedure may be successful alternatives.
PMID- 9396534
TI - Growth factor enhancement of intestinal function: dramatic response but lack of
synergism.
AB - BACKGROUND/PURPOSE: The authors have shown that gastrin and epidermal growth
factor (EGF) exert a trophic effect on intestinal epithelial cells. Because these
peptides may have different mechanisms by which they stimulate these cells, this
study was designed to determine the effect of gastrin and EGF on the intestinal
epithelial cell and to evaluate their potential synergistic effect. METHODS:
Twenty young adult male Sprague-Dawley rats underwent placement of jugular venous
catheters that were connected to subcutaneously placed osmotic minipumps. The
rats were divided into four groups based on the content of the osmotic pump:
Group 1, saline (control, n = 5); Group 2, EGF at 150 microg/kg/d (n = 5); Group
3, gastrin at 13.5 nmol/kg/d (n = 5); and Group 4, EGF at 150 microg/kg/d plus
gastrin at 13.5 nmol/kg/d (n = 5). After a 14-day intravenous infusion, [C14]
galactose and [C14] glycine absorption (pmol/cm2 intestine), mucosal DNA content
(microg/mg mucosa), and protein content (microg/mg mucosa) were measured in the
small intestine of each rat. RESULTS: The galactose absorption, glycine
absorption, DNA content, and protein content were significantly increased by EGF
(69%, 28%, 64%, and 55%, respectively) and gastrin (72%, 60%, 93%, and 48%,
respectively) when compared with control. Combining EGF and gastrin also
significantly increased these parameters (61%, 44%, 96%, and 70%, respectively)
when compared with control. However, these data demonstrate no further
enhancement than the effect of each peptide alone. CONCLUSION: EGF and gastrin
individually may be useful for patients who have inadequate intestinal function,
but when combined did not exert a synergistic benefit.
PMID- 9396535
TI - Should laparoscopic appendectomy be avoided for complicated appendicitis in
children?
AB - BACKGROUND/PURPOSE: Laparoscopic appendectomy is becoming the preferred technique
for treating acute appendicitis. However, recent literature on adults suggests
that laparoscopic appendectomy may increase the risk for postoperative infectious
complications in complicated (gangrenous or perforated) cases. This study was
undertaken to compare the results of open versus laparoscopic appendectomy for
complicated appendicitis in children. METHODS: A retrospective review from two
institutions was performed for all children treated operatively for complicated
appendicitis from January 1994 through November 1996. RESULTS: Fifty-six cases
were identified. Twenty-seven children underwent laparoscopic appendectomy,
whereas 22 underwent open appendectomy. Seven children underwent conversion from
laparoscopic to open surgery. Operating times and length of hospital stay did not
differ significantly between the laparoscopic and open groups. Postoperative
complications developed in 24 children (42.8%). Complications were more frequent
after laparoscopic appendectomy compared with open appendectomy (56% v 18%, P =
.002). A postoperative intraabdominal abscess (IAA) developed in 14 children
(25%). An IAA occurred in two children after open appendectomy compared with 11
children after laparoscopic appendectomy (9% v 41%, P = .01). CONCLUSION: The
findings suggest that laparoscopic appendectomy should be avoided in children who
have complicated appendicitis because of the increased risk for postoperative
intraabdominal abscesses. The authors propose a prospective, randomized trial to
verify this finding.
PMID- 9396536
TI - Cost-effectiveness in diagnosing infantile hypertrophic pyloric stenosis.
AB - PURPOSE: The purpose of this study was to determine which imaging study, upper
gastrointestinal series (UGI) or abdominal ultrasonography (US), is more cost
effective in diagnosing infantile hypertrophic pyloric stenosis (IHPS) using a
decision analysis model. METHODS: Probabilities were calculated from a review of
the records of all infants less than 6 months of age referred for UGI or US to
rule out IHPS over a 3-year period from January 1992 to December 1995. Cost
effectiveness was determined from hospital charges for each imaging study and its
possible outcomes. RESULTS: The positive predictive value of UGI was 1.0 and US
was 0.98 in the 246 infants evaluated for possible IHPS. In patients who had an
initially normal study finding (UGI or US), 25% of patients undergoing US first
required a second study for persistent symptoms, whereas only 6% of patients who
had a negative initial UGI finding required a second study. CONCLUSIONS: Cost
analysis found UGI to be more cost-effective than US because fewer secondary
studies were required. UGI provides information regarding other pathological
conditions as compared with US.
PMID- 9396537
TI - Long-term follow-up of childhood duodenal ulcers.
AB - PURPOSE: This study reports the long-term results in children who have duodenal
ulcers diagnosed by endoscopy who were treated with H2-receptor antagonist.
METHODS: The medical records of 32 children admitted into The Queen Mary Hospital
with endoscopically proven duodenal ulcers between 1975 and 1988 were reviewed to
evaluate the long-term outcome of childhood duodenal ulcers after initial
treatment with H2-receptor antagonist (H2RA). Follow-up details were updated and
patients who had been lost to follow-up were recalled. The age of the 22 boys and
10 girls at the time of diagnosis of the ulcers ranged from 3 to 16 years (mean,
11.8 yrs). The duration of follow-up ranged from 8.5 to 21 years (mean, 11.6
yrs). RESULTS: Their primary presentations included epigastric pain (n = 9,
28.0%); nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal
bleeding (GIB, n = 6, 18.7%); unprovoked GIB (n = 12, 37.5%); perforation (n = 4,
12.5%); and pyloric obstruction (n = 1, 3.0%). All 13 patients who had NSAID
induced ulcers (pain and bleeding) responded to H2RA therapy and required no
further treatment. All 14 patients who had unprovoked ulcers who presented with
pain or bleeding did not respond to H2RA treatment. Ulcer healing was achieved
only after eradication of Helicobacter pylori with antibiotics (n = 8) or
definitive surgery involving either truncal vagotomy and pyloroplasty (VP, n = 4)
or proximal gastric vagotomy (PGV, n = 2). The patient who had gastric outlet
obstruction had vagotomy and antrectomy. All four patients who had perforation
were initially treated with patch repair, but two had persistent ulceration
despite H2RA treatment and required PGV. Complications developed in none of the
four patients who had PGV, whereas two of the four patients with VP had problems
(diarrhea, n = 1; bezoar obstruction, n = 1). CONCLUSIONS: Unprovoked childhood
duodenal ulcer is associated with significant long-term morbidity and requires
continued follow-up. The majority of the ulcers are resistant to H2RA treatment
alone and ultimately require either eradication of H. pylori or surgery. In the
absence of obstruction, PGV may be enough to resolve the ulcer diathesis.
PMID- 9396538
TI - Pancreatoblastoma.
AB - BACKGROUND: Pancreatoblastoma is a rare pancreatic tumor with distinct acinar and
squamoid cell differentiation that generally affects infants and young children.
Just over 50 cases have been reported in the literature. METHODS: Five cases of
pathologically proven pancreatoblastoma treated at Seoul National University
Hospital from 1984 to 1994 were reviewed. There were three girls and two boys who
were 2 years to 5 years of age. All cases came to medical attention because of an
abdominal mass. RESULTS: Abdominal pain was observed in one case and anorexia,
vomiting, and weight loss in one case. There was marked elevation of serum alpha
fetoprotein (27,000 ng/mL) in one case of liver metastases. Complete excision was
performed in two cases in which the tumors were located in the tail of the
pancreas. Partial excision was performed in two patients who had unresectable
tumors of the head of the pancreas. One patient had an unresectable tumor at
diagnosis and needle aspiration biopsy was carried out under ultrasound guidance.
Electron microscopy was performed on pathological specimens of three cases and
showed zymogen granules but not neuroendocrine granules. Immunocytochemical
studies for alpha-fetoprotein, insulin, glucagon and somatostatin were performed
in one patient, and results were all negative. Of two patients who underwent
complete excision, one patient presented with liver metastases 4 months after
operation and received chemotherapy, but died of tumor 6 months after operation.
The other patient had local recurrence 1 year after operation. Reoperation and
chemotherapy were performed, and the child is now alive without evidence of
disease for 32 months. All three patients who had unresectable tumor died of
tumor despite adjuvant radiotherapy and chemotherapy. CONCLUSIONS: The authors
emphasize that the diagnosis of pancreatoblastoma in childhood should be
suspected with palpation of an abdominal mass, and the chance for cure may be
determined by complete excision of the tumor.
PMID- 9396539
TI - Is extensive surgery required for treatment of advanced neuroblastoma?
AB - BACKGROUND: Prognosis of advanced neuroblastoma is still disappointing although
recently slightly improving because of more intensive chemotherapy supported with
stem cell transfusion. Before 1985, all patients at University of Tsukuba over
the age of 1 year who had stage III and IV neuroblastoma died regardless of
extensive resection of the primary tumor. METHODS: Since the treatment protocol
of the Study Group of Japan for Advanced Neuroblastoma was introduced in 1985,
the authors treated 14 consecutive patients over the age of 1 year who had
advanced neuroblastoma with six to eight cycles of the intensive induction
chemotherapy regimens followed by resection of the primary and local lymph node
metastasis combined with intraoperative irradiation. The resection of the primary
tumor and the lymph node metastasis was much less extensive preserving adventitia
with perivascular nerves to avoid postoperative vascular occlusion, intestinal
dysmotility, and massive lymphorrhea, which interfere with postoperative
intensive chemotherapy. If the dissection of lymph nodes from major vessels was
difficult, the authors intentionally left the tumor-containing lymph nodes.
RESULTS: There were macroscopic residual tumors in 8 of 14 patients. Electron
beam irradiation, 10 to 15 Gy, was given to the tumor bed intraoperatively.
Overall survival of these 14 patients was 63% (eight patients) at 5 years with
six patients surviving without recurrence for more than 5 years. Five patients
died of tumors, two of whom died before surgery. Local tumor control failed in
only two patients. In one patient, the tumor recurred twice 47 months and 61
months after therapy. After undergoing a second resection at 69 months, this
child has survived tumor free for 12 months after the second recurrence. The
other patient who had tumor recurrence had an N-myc-amplified tumor that recurred
4 months postoperatively in the hepatoduodenal ligament locally with massive bone
metastasis. The 5-year local relapse-free probability for patients with stage III
and IV tumors who had an operation was 79% by the Kaplan-Meier method.
CONCLUSION: Systematic extensive surgery for advanced or metastatic neuroblastoma
is no longer required if supplemented with intensive pre- and postoperative
chemotherapy with intraoperative radiotherapy.
PMID- 9396540
TI - Histopathologic findings of advanced neuroblastoma after intensive induction
chemotherapy.
AB - BACKGROUND: Histopathologic findings of advanced neuroblastoma after intensive
induction chemotherapy have not been studied well. METHODS: In the present study,
all of the surgical specimens from 19 patients who had advanced abdominal
neuroblastoma and were pretreated intensively with the protocol of the Study
Group of Japan were reviewed. The authors found that dissection of the
contralateral lymph nodes is mandatory in advanced neuroblastoma when the goal is
the complete dissection of the abdominal disease. Effects of chemotherapy were
graded histologically according to the ratio of viable residual neuroblastoma
tissue to total areas of the tumor, including neuroblastoma,
ganglioneuroblastoma, ganglioneuroma, hemorrhage, necrosis and fibrosis, in five
ranks from ( ) to (-). CONCLUSIONS: The newly introduced, highly cytotoxic
regimen of the Japanese protocol, designated "A3," appears to be more effective
histologically than the conventional regimen, designated "A1" or "new A1."
Effects designated ( ) or (++) were prerequisites for survival in stage IV
disease, but some stage III patients with the (+) effect survived.
PMID- 9396541
TI - Needle localization for thoracoscopic resection of small pulmonary nodules in
children.
AB - BACKGROUND: Children who have malignant disease and pulmonary nodules frequently
need a tissue diagnosis to direct therapy. Computed tomography (CT)-guided needle
localization and methylene blue marking allow thoracoscopic resection of
nonvisible nodules. METHODS: Malignant disease was diagnosed in three patients
aged 2, 2.5, and 11 years. Pulmonary nodules seen on chest CT, representing
either metastatic disease or infection developed in each patient. All lesions
were 1 to 2 cm deep to the pleural surface, precluding thoracoscopic
visualization. A Homer mammographic needle was placed near the lesion using CT
guidance under general anesthesia. The pleura overlying the lesion was also
marked with methylene blue. Under the same anesthetic, patients went to the
operating room where the lesions were thoracoscopically resected. RESULTS: Needle
localization and methylene blue staining accurately localized the lesion in all
cases. Thoracoscopic resection provided a diagnosis of metastatic disease or
infection in all cases. There were no complications. CONCLUSION: CT-guided needle
localization of pulmonary lesions deep to the pleural surface, is a safe,
accurate method for allowing thoracoscopic resection in these children who would
otherwise need open thoracotomy for diagnosis.
PMID- 9396542
TI - Is a new biofeedback therapy effective for fecal incontinence in patients who
have anorectal malformations?
AB - PURPOSE: The authors devised computerized equipment for use in the biofeedback
therapy in the management of fecal continence after surgery for anorectal
malformations. METHODS: The therapy was used for two to eight sessions in 14
children (11 who had high-type anomalies and three who had intermediate-type
anomalies). The ages ranged 5 to 14 years. A control group of 17 children, aged 5
to 11 years, who had encopresis, was also treated with the same biofeedback
therapy. RESULTS: Clinical improvement was noted in 5 of the 14 (36%) children
who had fecal incontinence, and in 15 of the 17 children (88%) who had
encopresis. Both in patients who had fecal incontinence and in those who had
encopresis, anal resting pressures were not affected by biofeedback therapy.
Furthermore, the anal resting pressure in children who had fecal incontinence was
significantly lower than that in children who had encopresis. However, anorectal
manometry showed that the biofeedback therapy improved voluntary sphincter
function and rectal sensation in both groups. CONCLUSION: Biofeedback therapy
appears to be effective in most children who have encopresis whose sphincter
function is intact, and in some children who have fecal incontinence after
surgery for anorectal malformations.
PMID- 9396543
TI - Continent appendicostomy in the bowel management of fecally incontinent children.
AB - BACKGROUND: Fecal incontinence is common in children who have anorectal
malformations, Hirschsprung's Disease, and spina bifida and can negatively impact
their emotional and social development. Enemas have been used as an artificial
way to keep children clean and to improve their quality of life. This method is
unpleasant for many children, particularly when they reach adolescence. Malone in
1990 described an alternative method in which the appendix is used as a conduit
to administer an antegrade enema. METHODS: The authors describe their experience
with this new procedure, modified by them, and used in 20 patients. In the
original procedure, the base of the appendix is divided, inverted, and
reimplanted into the cecum with an antireflux technique. The authors simplify
this by plicating the cecum around the appendix to create a one-way valve
mechanism but leaving the appendix in its original position. The authors also
mobilize the cecum and exteriorize the appendix at the umbilicus to create an
inconspicuous stoma. If the native appendix is absent a neoappendix was created
from a flap of cecum. RESULTS: Nineteen of 20 patients (95%) are now completely
clean 24 hours a day. Stricture of the stoma occurred in two patients and
required revision. Leakage at the appendicostomy site occurred in three patients,
and two required a tighter plication. CONCLUSIONS: The technique is used to
change the route of enema administration, and is only used in patients for whom
bowel management with rectal enemas has been proven successful. The appendix must
be preserved whenever possible in patients at risk for fecal incontinence.
PMID- 9396544
TI - Prospective analysis of lung-to-head ratio predicts survival for patients with
prenatally diagnosed congenital diaphragmatic hernia.
AB - BACKGROUND: Accurate prenatal prediction of outcome for fetuses who have
congenital diaphragmatic hernia (CDH) is very difficult. The authors previously
reported a retrospective analysis of risk factors for fetal CDH and proposed a
new index of severity: the lung-to-head ratio (LHR). The authors now report a
prospective study to test whether this new index predicts neonatal outcome.
METHODS: Fifteen patients who had left-sided CDH were sonographically evaluated
at the University of California, San Francisco (UCSF) and followed prenatally and
postnatally. LHR was measured at 24 to 26 weeks' gestation. Outcome variables
included survival and the need for extracorporeal membrane oxygenation (ECMO).
RESULTS: Overall survival was 47%. LHR ranged from 0.62 to 1.86. No patient with
an LHR of less than 1.0 (n = 3) survived despite ECMO, whereas all patients with
an LHR greater than 1.4 survived (n = 4), one requiring ECMO. LHR values between
1.0 to 1.4 were associated with 38% survival (n = 8), 75% requiring ECMO.
Overall, survivors had a mean LHR of 1.4 +/- 0.33 and nonsurvivors, 1.05 +/- 0.3
(P < .05). CONCLUSION: The LHR is a useful index to help predict neonatal outcome
in patients who have left-sided CDH.
PMID- 9396545
TI - Correction of congenital diaphragmatic hernia in utero VII: a prospective trial.
AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) remains an unsolved problem.
Despite optimal postnatal care, up to 60% of CDH babies die. Experimental
evidence and clinical experience have shown that in utero repair of CDH is
feasible and can reverse pulmonary hypoplasia, but only in fetuses without liver
herniation. For this subgroup, the safety and efficacy of repair before birth has
not been compared with standard care after birth. METHODS: Four fetuses in whom
CDH without liver herniation was diagnosed underwent open fetal surgery for
repair of the CDH. Seven comparison fetuses were treated conventionally. Neonatal
mortality was the principle outcome variable. Secondary outcome variables
included death of all causes until 2 years of age, number of days of ventilatory
support, length of hospital stay, requirement for extracorporeal membrane
oxygenation (ECMO), and total hospital charges. RESULTS: There was no difference
in survival between the fetal surgery group and the postnatally treated
comparison group (75% v 86%). Fetal surgery patients were born more prematurely
than the comparison group (32 weeks v 38 weeks' gestation). Length of ventilatory
support and requirement for ECMO were equivalent in the fetal surgery group and
the postnatally treated comparison group. Length of hospital stay and hospital
charges did not differ between the groups. CONCLUSIONS: Open fetal surgery is
physiologically sound and technically feasible, but does not improve survival
over standard postnatal treatment in the subgroup of CDH fetuses without liver
herniation, primarily because overall survival in this subgroup is favorable with
or without prenatal intervention. These data suggest that fetuses who have
prenatally diagnosed CDH and without evidence of liver herniation should be
treated postnatally.
PMID- 9396546
TI - Diaphragmatic eventration in infants and children: is conservative treatment
justified?
AB - PURPOSE: The purpose of this study is to examine the justification of
diaphragmatic plication to treat diaphragmatic eventration. A retrospective
review of 50 patients who underwent diaphragmatic plication for phrenic nerve
injury (PNI) or congenital muscular deficiency (CMD) of the diaphragm was
conducted. METHODS: During the last 26 years, 50 patients, aged 4 days to 7
years, were surgically treated for diaphragmatic eventration. Twenty-five
patients had iatrogenic PNI and another 25 had CMD. Respiratory distress
developed in all patients who had PNI and 10 required mechanical ventilatory
support for 13 to 78 days (mean, 41 days) before operation. Respiratory symptoms
developed in 17 of 25 patients who had CMD, and four required ventilatory
support. In those who were asymptomatic, we justified surgical repair to optimize
future lung growth. All patients underwent diaphragmatic plication by a thoracic
approach. Reefing mattress sutures on pledgets were used for the plication.
RESULTS: In patients who had PNI, ventilatory support could be discontinued
within 0 to 6 days (mean, 3 days) after operation, with a dramatic improvement in
their respiratory status. Two patients required reoperation because the plication
was not tight enough. Seven patients died in this series, but none because of the
diaphragmatic plication. CONCLUSION: This study suggests that symptomatic
patients who have diaphragmatic eventration should be operated on immediately
with an expected dramatic resolution of their respiratory problems.
PMID- 9396547
TI - Extracorporeal life support for nonimmune hydrops fetalis.
AB - BACKGROUND/PURPOSE: Most babies born with idiopathic nonimmune hydrops fetalis
(NIHF) suffer generalized cardiopulmonary collapse and die despite maximal
medical therapy. With reported survival rates of less than 10%, many centers
consider NIHF an unsalvageable situation and the babies who have this condition,
untreatable. In this study, the authors questioned if the aggressive use of
extracorporeal life support (ECLS) could salvage this condition and improve the
chances of survival for babies born with NIHF. METHODS: The Extracorporeal Life
Support Organization's (ELSO) neonatal registry was searched for all available
information on babies treated for hydrops fetalis. The ELSO records of all
hydropic babies were then reviewed to exclude those babies who had identifiable
causes of hydrops. Survival statistics were then calculated for the remaining
core group of idiopathic NIHF babies before separating them into two groups based
on survival. A detailed analysis comparing the survivors with nonsurvivors was
then performed. RESULTS: A total of 28 hydropic babies were identified in the
ELSO registry. Four babies were excluded from analysis because of identifiable
causes of hydrops (two with congenital diaphragmatic hernia, one with Rh
incompatibility, and one with fetal anemia). Of the remaining 24 babies who had
NIHF, 54% (13 babies) survived the neonatal period and were discharged from the
hospital. Analysis comparing the survivors with the nonsurvivors in our study
showed that the groups were similar in their gestational ages, birth weights,
Apgar scores and the time to initial intubation. The most distinguishing factor
of survival in our study was that the survivors, on average, received ECLS
support 3 days sooner than nonsurvivors (mean, 17.5 +/- 1.3 hours of life for
survivors v 105 +/- 36.6 hours for nonsurvivors, P < or = .05). CONCLUSION:
Idiopathic NIHF should no longer be considered an untreatable condition but a new
indication for ECLS that, when begun early, may significantly improve the chances
of survival for these babies previously considered "unsalvageable."
PMID- 9396548
TI - Ultrasonographic study of the sternocleidomastoid muscle in the management of
congenital muscular torticollis.
AB - BACKGROUND: Congenital muscular torticollis (CMT) in infancy is caused by the
fibrotic change of the sternocleidomastoid muscle (SCMM). The etiology and
management strategies remain controversial. METHODS: One hundred ninety-seven
infants and children aged 1 month to 16 years who had CMT were examined by real
time ultrasonography of the SCMM between June 1995 and September 1996 in a
prospective and longitudinal study. A total of 362 examinations were performed.
There were 122 boys and 75 girls. RESULTS: The right side was involved in 117
patients (59.3%), the left side in 79 patients (40.1%), and both sides in one
patient. The sonographic findings were homogeneous or heterogeneous (patchy)
hyperechoic lesion within the SCMM, and all were diagnostic. The ultrasonographic
appearance of the SCMM in this study has a close resemblance to the clinical
course of CMT. The extent of fibrosis as represented by the cross section of
lesion to muscle ratio (L/M ratio) decreased from 83.6% at 2 months to 59.9% at 9
months of age and further decreased to 40% beyond 1 year of age. This consistent
decrease in fibrosis was caused by the increased normal muscle volume at the
periphery and by the regenerated muscle fibers within the lesion. In this series
of 197 patients, 32 (16.2%) eventually underwent surgery to release the SCMM
because of persistent head tilt, chin deviation and limited range of neck motion
beyond 1 year of age. The L/M ratio of the operative group was 62.7 +/- 16.0%
compared with an L/M ratio of 54.5 +/- 14.2% (P = .035) for the nonoperative
group at 1 year of age. The extent of fibrotic change in the cross section of the
muscle was a significant factor in determining prognosis. In the longitudinal
section, the fibrotic change was limited to only the lower third of the SCMM in
27 patients, and all of them recovered without operation. In 95 patients, the
fibrotic lesion was limited to the middle and lower third or middle third only,
and only six (6.3%) underwent operation. However, in 75 cases the entire length
of muscle was involved, and 26 (34.7%) required surgical release of the
contracted muscle. Whole-length muscle involvement was also important for
predicting recovery without operative intervention. CONCLUSIONS: Ultrasonographic
study of the SCMM is not only a valuable diagnostic tool but can also serve as a
useful guideline for the treatment of infants who have congenital muscular
torticollis.
PMID- 9396549
TI - A comparison of the effect of growth factors on intestinal function and structure
in short bowel syndrome.
AB - BACKGROUND/PURPOSE: Epidermal growth factor (EGF) and Insulin like growth factor
1 (IGF-1) increase substrate absorption beyond the normal adaptive response after
massive small bowel resection in the rat. However, the mechanism for this
response is unknown. This study was designed to evaluate the ultrastructural
features of the rat small intestine epithelium after exposure to EGF and IGF-1
and correlate any changes with a possible hypothesis regarding the mechanism for
the increased absorption. METHODS: Male Sprague-Dawley rats underwent an 80%
small bowel resection and jejunostomy tube placement. Seven days later an osmotic
pump placed subcutaneously and containing the test substance was connected to the
jejunostomy tube. The rats were assigned to one of three groups: group 1 received
normal saline (control, n = 5); group 2 received EGF at 150 microg/kg/d (n = 5);
and group 3 received IGF-1 at 20 mg/kg/d (n = 5). After a 14-day infusion, a
portion of mid-small bowel was resected for light and electron microscopic
evaluation from each of the animals. The following features were compared between
the groups: villous length, crypt length, villous-crypt ratio, villi per
millimeter mucosa, goblet cell distribution, eosinophilic infiltrates, number and
distribution of organelles, length of microvilli, and completeness of
microvillous surface. RESULTS: Ultrastructurally, the bowel epithelium was well
preserved in all animals. There were no objective ultrastructural differences
between the controls and growth factor-exposed animals. The mean villous-crypt
ratio, mean number of villi per millimeter of mucosa (cross section), and mean
microvillous height were not significantly different among the groups. However,
there was a subjective increase in the number of lysosomes in the enterocytes
exposed to EGF and IGF-1. CONCLUSIONS: Administration of EGF and IGF-1 after
massive small bowel resection does not appear to significantly alter the small
intestine epithelial ultrastructure when compared with the control group. The
increase in lysosomes in some of the enterocytes of the animals exposed to growth
factors may be important because this finding was not seen in any of the control
electron photomicrographs. Studies to evaluate enterocyte gene and protein
expression are necessary to determine the mechanism of EGF and IGF-1 enhancement
of substrate absorption beyond intestinal adaptation.
PMID- 9396550
TI - Excitation-contraction coupling in the day 15 embryonic chick heart with
persistent truncus arteriosus.
AB - Ca2+ transients were examined in embryonic chick hearts with an experimentally
induced cardiac neural crest-related outflow tract defect known as persistent
truncus arteriosus (PTA). In all of the animal models of neural crest-related
heart defects, prenatal mortality is too high to be attributed to structural
defects of the heart alone, suggesting that there is altered development of the
myocardium. Earlier reports indicating reduced L-type Ca2+ current in hearts with
PTA suggest that poor viability may be related to impairment of cardiac
excitation-contraction coupling. To test this hypothesis, direct measurements of
the systolic Ca2+ transient in fura-2-loaded myocytes from normal hearts and
hearts with PTA were carried out. We found that Ca2+ transients were severely
depressed in hearts with PTA and difficult to measure above background noise
unless signal averaged or treated with isoproterenol (ISO). We confirmed that the
reduced Ca2+ transients were due, at least partly, to a reduction in L-type Ca2+
current. In addition we found that although ISO could raise the L-type current in
hearts with PTA to the level found in normal hearts in the absence of ISO, it
could not fully restore the Ca2+ transient. Furthermore, caffeine-stimulated Ca2+
transients were diminished in size and the time-to-peak and the decaying phase
were significantly slowed. Interestingly, these observations were not accompanied
by a reduction in the number of Ca2+ release channels. These results indicated an
impairment of SR function in addition to the reduction in L-type Ca2+ current.
These results strongly support our hypothesis that the poor viability of embryos
with PTA is due to impaired cardiac excitation-contraction coupling.
PMID- 9396551
TI - Relative effects of cyclooxygenase and nitric oxide synthase inhibition on
vascular resistances in neonatal lamb lungs.
AB - Effective attenuation of pulmonary vasoconstriction is essential during early
postnatal development when increased pulmonary vascular resistance (PVR) may lead
to a resumption of right-to-left shunting across fetal channels. In addition,
modulation of venous resistance contributes to normal lung fluid balance. This
study was designed to identify the relative modulating effects of endothelium
derived nitric oxide (EDNO) and dilator prostaglandins (PG) on normoxic and
hypoxic pulmonary vasomotor tone in young newborns. Total and segmental PVR were
measured using inflow-outflow and double occlusion techniques in isolated lungs
of 6-h-old lambs studied under control conditions or after blocking PG and/or
EDNO synthesis with indomethacin and/or N omega-nitro-L-arginine, respectively.
During normoxia, both indomethacin and N omega-nitro-L-arginine were required to
increase total PVR, but EDNO appeared to have the greater modulating effect.
Indomethacin markedly enhanced hypoxic pulmonary vasoconstriction of large and
small arteries and small veins, whereas N omega-nitro-L-arginine caused a lesser,
but significant, increase in hypoxic pulmonary vasoconstriction of small arteries
and veins, suggesting that dilator PG played the dominant modulating role during
hypoxia. In addition, PG synthesis appeared to be enhanced after inhibition of
EDNO synthesis. In contrast, indomethacin caused a decrease in venous resistance,
suggesting that constrictor prostanoids had a greater effect than dilator PG on
this segment. EDNO had a modest modulating effect on venous resistance in these
lungs. These data suggest that dilator PG and EDNO exert complementary effects in
attenuating total and segmental PVR during normoxia and hypoxia in 6-hold lamb
lungs.
PMID- 9396552
TI - Vascular endothelial growth factor is expressed in ovine pulmonary vascular
smooth muscle cells in vitro and regulated by hypoxia and dexamethasone.
AB - Chronic lung disease in neonates results from both lung injury and inadequate
repair processes. Little is known about the growth factors involved in lung
injury and repair, but vascular endothelial growth factor (VEGF) has recently
been reported in several animal models of lung injury. VEGF is an endothelial
cell-specific mitogen, which is also known as vascular permeability factor
because of its ability to induce vascular leak in some tissues. Chronic lung
disease is complicated by increased vascular permeability, which can be improved
by avoidance of hypoxia and in some cases by dexamethasone therapy. In many
cells, hypoxia stimulates VEGF expression. Also, in some cases, dexamethasone
blocks VEGF expression. This study examined the role of hypoxia and dexamethasone
in regulating the expression of VEGF in pulmonary artery smooth muscle cells. An
ovine VEGF cDNA fragment (453 bp) was cloned and found to be highly homologous to
known human sequences for VEGF165. Sheep pulmonary artery smooth muscle cells
were cultured and exposed to room air, hypoxia, and dexamethasone, alone or in
combination for 6 h. At baseline these cells expressed VEGF mRNA at approximately
3.9 kb. The half-life of VEGF mRNA in the smooth muscle cells was 171 min, more
than 3-fold longer than previous reports for epithelial cells. Exposure to
hypoxia caused a 3-fold increase in mRNA abundance, primarily through
transcriptional up-regulation. Dexamethasone blocked the hypoxia-induced increase
in VEGF mRNA. The results demonstrate that hypoxia and dexamethasone are
regulators of VEGF expression in ovine pulmonary artery smooth muscle cells. It
is not known whether VEGF derived from these cells is involved in lung injury
and/or normal homeostatsis.
PMID- 9396553
TI - Developmental changes in the effect of acidosis on contraction, intracellular pH,
and calcium in the rabbit mesenteric small artery.
AB - The purpose of the present study was to determine developmental changes in the
effect of respiratory acidosis on vascular smooth muscle contraction. Vessel
diameter, intracellular pH (pHi), and calcium concentration ([Ca]i) were measured
in a cannulated preparation of the small mesenteric artery of newborn and adult
rabbits. In the artery precontracted by high KCl, acidosis caused a
vasorelaxation both in the newborn and the adult; the vasorelaxation was greater
in the newborn than in the adult. The fura-2 fluorescence ratio, an indicator of
[Ca]i, decreased transiently during acidosis and the decrease was similar in the
two age groups. In the artery precontracted by norepinephrine, acidosis caused a
transient vasoconstriction in the adult and a vasorelaxation in the newborn. In
these vessels, the fura-2 fluorescence ratio increased transiently during
acidosis; the increase was similar in the two groups. Upon induction of acidosis,
pHi fell rapidly in the artery precontracted by norepinephrine or high KCl, and
the depression of pHi was similar in the two groups. In the skinned smooth muscle
preparation, a tension-[Ca] relationship curve at pH 7.1 was not significantly
different from that at pH 6.8 in the adult. In the newborn, the tension-[Ca]
curve at pH 6.8 was shifted to the right, compared with that at pH 7.1. These
data suggest that the vasorelaxant effect of respiratory acidosis in the
premature vessel is greater than in the adult. The greater vasorelaxation in the
newborn cannot be explained by the age-related difference in pHi or [Ca]i during
acidosis. The greater sensitivity of myofibrils to low pHi in the newborn may, at
least in part, be responsible for the greater vasorelaxation in this age group.
PMID- 9396554
TI - Perinatal growth disturbance in the spontaneously hypertensive rat.
AB - Disproportionate fetal and placental growth are associated with the development
of hypertension in the rat and human. Here we report differences in fetal,
neonatal, and placental growth, and in metabolism and endocrinology, between the
spontaneously hypertensive rat (SHR), a genetic model for human essential
hypertension, and the control Wistar-Kyoto (WKY) strain. Gestation in SHR (23 d)
was longer than in WKY by 20 h. Body weights were lower in the SHR from fetal d
16 to 20 and on postnatal d 15. However, on fetal d 22 and postnatal d 1, there
was no significant difference in body weight between SHR and WKY. SHR placentas
were larger than those of WKY at d 20, and by term there was a difference of 30%
(p < 0.01). Other indices of disproportionate growth were hypertrophy of the
fetal heart and kidney and decreased ponderal index in the SHR neonate. Blood
glucose in SHR fetuses was lower than in WKY fetuses (p < 0.05), whereas blood
lactate was higher (p < 0.05) and fetal hematocrit was reduced (p < 0.001). These
findings suggest undernutrition and placental insufficiency may occur in SHR
fetuses. Plasma IGF-II was increased on the last day of gestation in both
strains, whereas IGF-I was unaltered. Fetal liver IGFBP-2 mRNA and plasma IGFBP-2
levels were reduced in SHR on fetal d 20 and 22 (p < 0.01). Differences in growth
and endocrine and metabolic parameters suggest abnormal perinatal physiology in
the SHR, which may influence the later development of hypertension.
PMID- 9396555
TI - Fetal atrioventricular, venous, and arterial flow velocity waveforms in the small
for gestational age fetus.
AB - Arterial, venous, and intracardiac Doppler flow velocity waveforms were studied
in 50 women with a small for gestational age (SGA) fetus according to a cross
sectional study design. No Doppler signals could be obtained in five women for
technical reasons. The remaining 45 women were compared with normal control
subjects matched for gestational age and maternal parity. The 45 SGA fetuses were
divided into birth weight below the 5th centile for gestational age (group I, n =
35) and birth weight between the 5th and 10th centile for gestational age (group
II, n = 10). A significant difference in baseline characteristics was found
between both SGA subsets and normal controls. In SGA I fetuses, the pulsatility
index in the umbilical artery and descending aorta was significantly higher, but
lower in the middle cerebral artery when compared with normal controls. At the
atrioventricular and venous level (umbilical vein, ductus venosus, and inferior
vena cava) reduced time-averaged velocities were established. PIV in the ductus
venosus and IVC showed a significant increase. Within the same SGA subset, no
relationship could be established between arterial downstream impedance and 1)
atrioventricular flow velocities and 2) pulsatility index in the ductus venosus
and inferior vena cava. Also, no relationship existed between flow velocity
waveforms and pregnancy-induced hypertension and admission to the neonatal
intensive care unit. Umbilical venous pulsations and absent/reverse flow in the
umbilical artery were associated with a high intrauterine mortality rate and low
birth weights. In SGA II fetuses, the pulsatility index in the umbilical artery
and descending aorta was significantly higher than in normal controls. It can be
concluded that fetuses with a birth weight below the 5th centile demonstrate
marked changes in arterial, atrioventricular, and venous flow velocity waveforms.
Atrioventricular and venous flow velocity waveforms change independently from
arterial downstream impedance, suggesting that other factors, such as reduced
volume flow and myocardial contraction force, may play a role in the observed
changes.
PMID- 9396557
TI - The role of recombinant platelet-activating factor acetylhydrolase in a neonatal
rat model of necrotizing enterocolitis.
AB - Previous studies have shown that the endogenous inflammatory mediator platelet
activating factor (PAF) plays an important role in the pathophysiology of
neonatal necrotizing enterocolitis (NEC). This study was designed to investigate
the role of the PAF-degrading enzyme acetylhydrolase (PAF-AH) in a neonatal rat
model of NEC. To study the absorption, localization, and activity of human
recombinant PAF-AH (rPAF-AH), newborn rats were treated with enteral rPAF-AH, and
plasma and intestines were sampled at 8 and 24 h for determination of PAF-AH
enzyme activity and rPAF-AH concentration using a specific enzyme-linked
immunoassay. To study the effect of rPAF-AH on neonatal NEC, rats were treated
with rPAF-AH via the enteral route every 3 h, and then subjected to formula
feeding and asphyxia per an established neonatal rat protocol for NEC.
Pretreatment with enteral rPAF-AH significantly reduced the incidence of NEC
compared with controls (6/26 versus 19/26, p < 0.001). We found that enteral rPAF
AH administration resulted in significant intestinal PAF-AH activity but no
circulating PAF-AH activity despite immunohistochemical localization of the
administered rPAF-AH to the intestinal epithelial cells. These findings suggest
that rPAF-AH is functional and stable in the gut of neonatal rats. We conclude
that enteral administration of rPAF-AH remains locally active and reduces the
incidence of NEC in our experimental animal model.
PMID- 9396556
TI - Correlation between the functional assay for activated protein C resistance and
factor V Leiden in the neonate.
AB - A factor V506 Arg-Gln mutation is the most common inherited cause of
thrombophilia in adults. To date, there are no data regarding the detection of
this mutation in neonatal blood or the relationship of this dysfunctional factor
V to neonatal thrombosis. This study compared a modified activated protein C
resistance functional assay with the PCR-based DNA assay for the factor V
mutation in 115 prospectively collected umbilical cord blood samples. The
incidence of activated protein C resistance in cord blood was 6%. The sensitivity
and specificity of the modified assay for the factor V Leiden mutation was 100%.
PMID- 9396558
TI - Hepatitis G virus infection in normal and prospectively followed posttransfusion
children.
AB - A recently identified RNA virus, hepatitis G virus (HGV), has been investigated
for its role in causing non-A-E hepatitis. The frequency and clinical outcome of
HGV infection in children was studied. Two hundred apparently healthy children
aged 6 mo to 12 y, and 90 children who had undergone open heart surgery in a
prospective study for posttransfusion hepatitis were included in this study. The
serum samples were tested for HGV RNA by nested reverse transcription-PCR with
primers from the 5'-untranslated region. The HGV RNA viremic rate was found to be
1% (2/200) in apparently healthy children, 30% in children after open heart
surgery. Among the 90 children, three were HGV-infected before the surgery.
Twenty-four (28%) of the remaining 87 children tested positive for HGV RNA within
6 mo after the surgery. Sixty-five percents of these viremic children eventually
became persistently infected at 1 y after surgery. No HGV RNA-positive children
exhibited elevated alanine aminotransferase levels during the follow-up period.
No coinfections of HGV with the hepatitis C virus or hepatitis B virus were
found. Patients of younger age appeared more likely to become chronic carriers.
Anti-HCV screening did not reduce the prevalence of HGV infection. In conclusion,
in children with open heart surgery, the risk of transfusion-transmitted HGV
infection and the chronicity rate have been found to be high. Young age is a risk
factor of persistent infection.
PMID- 9396559
TI - The production of macrophage inflammatory protein-1alpha in the cerebrospinal
fluid at the initial stage of meningitis in children.
AB - Neutrophils in the cerebrospinal fluid (CSF) increase during the initial stage of
meningitis. Some cytokines induce the accumulation of such neutrophils, and we
and other investigators have revealed transient increases in the levels of
granulocyte-colony stimulating factor (G-csf) and IL-8 in the CSF of patients
with meningitis. To explore the coordination of other cytokines with G-csf and IL
8 in the neutrophil accumulation in the CSF, we herein investigated macrophage
inflammatory protein-1alpha (MIP-1alpha), which can induce the infiltration of
neutrophils. The modulation of MIP-1alpha levels in the CSF in children with
bacterial (n = 10) and aseptic (n = 22) meningitis was examined using an ELISA.
MIP-1alpha levels in the CSF were detectable at the stage with symptoms of
meningitis: 289.9 +/- 270.7 ng/L in the bacterial meningitis group and 16.1 +/-
12.5 ng/L in the aseptic meningitis group. These levels decreased with the
improvement of symptoms. MIP-1alpha was not detectable (<6 ng/L) in all of the
control patients without meningitis (n = 19). The MIP-1alpha levels in the CSF
showed a significant correlation with the CSF neutrophil counts (r = 0.750, p <
0.0001; n = 80) of meningitis, and the values of MIP-1alpha (log ng/L)/neutrophil
counts (log/L) ratio were calculated (1.003 +/- 0.576). The MIP-1alpha levels in
the serum were significantly lower than those in the CSF (p = 0.0464). We found
MIP-1alpha mRNA in the CSF cells by the reverse transcriptase-PCR method, and
high levels of MIP-1alpha protein in the culture media from mononuclear cells in
the CSF in vitro. In summary, The MIP-1alpha level increases in the CSF at the
symptomatic stage of meningitis in children, and its cellular source is, in part,
mononuclear cells which have infiltrated the CSF. We propose that MIP-1alpha, in
addition to G-csf and IL-8, plays an important role in the accumulation of
neutrophils in the CSF of patients with meningitis.
PMID- 9396560
TI - Immune abnormalities in guinea pigs with asymptomatic congenital syphilis.
AB - Spleens from 1-20-wk-old guinea pigs infected in utero with Treponema pallidum
and age-matched controls, born to normal and heat-killed (56 degrees C, 2 h.) T.
pallidum-injected mothers, were examined for their in vitro lymphoproliferative
response to phytohemagglutinin, concanavalin A, and lipopolysaccharide.
Additionally, T cell surface markers (mu-chain, pan T, CD4, and CD8) were
determined in spleen, lymph node, and peripheral blood from 10-wk infected and
normal pups by single and dual parameter fluorescence-activated cell sorter
analysis. Compared with control animals, congenitally infected animals showed a
remarkable prolonged naive-type of immune response as reflected by the higher (p
< 0.01) proliferative responses to both T cell mitogens (up to 20 wk of age), and
the weaker response to the B cell mitogen, significantly different (p < 0.01) at
10 wk of age. As opposed to controls, in all organs examined the level of CD8+
(cytotoxic/suppressor) T cells was significantly diminished (p < 0.01);
consequently, the CD4/CD8 ratio was significantly elevated (p < 0.05). The role
of C4 complement component and the nature and potential role of the immature T
and B lymphocyte responses in asymptomatic congenital syphilis is discussed.
PMID- 9396561
TI - Penetration of group B streptococci through polarized Madin-Darby canine kidney
cells.
AB - Group B streptococci (GBS) are one of the major causes of invasive neonatal
infection. The pathogenesis of early onset disease is a multistep process.
Adhesion of GBS to eucaryotic cells is considered to be an important step for the
establishment of infection. Subsequent to adhesion, GBS invade cells and give
rise to septicemia and meningitis. To investigate passage of GBS across
epithelial cell linings we examined the interaction between bacteria and Madin
Darby canine kidney (MDCK) cells. When grown on permeable support, these cells
form a polarized epithelial monolayer with an apical-to-basolateral orientation,
which more reflects the in vivo situation compared with conventionally cultured
cells. Our results show that GBS are translocated in vacuoles from the apical to
the basolateral surface of MDCK cells in a temperature-dependent process. The
passage of GBS through the cells is selective with only small numbers of bacteria
penetrating in the basolateral-to-apical direction. Transcytosis of GBS starts
before decrease in transepithelial resistance of the monolayer. These data
suggest a mechanism for traversal of GBS over intact chorioamniotic membranes and
from alveoli into the circulation of the fetus.
PMID- 9396562
TI - Impact of placental restriction on the development of the sympathoadrenal system.
AB - We have investigated the impact of chronic restriction of placental function on
circulating catecholamine concentrations and responses to the indirectly acting,
sympathomimetic amine, tyramine, in the fetal sheep in late gestation. In 10
ewes, endometrial caruncles or placental placentation sites were removed before
conception (placental restriction (PR) group). Fetal sheep in the PR group were
hypoxemic throughout late gestation and growth-restricted (3.02 +/- 0.35 kg) when
compared with control fetal sheep (4.30 +/- 0.29 kg; n = 8) at 140 d of
gestation. Fetal plasma concentrations of noradrenaline and adrenaline were
higher (p < 0.05) in the PR (7.06 +/- 3.17 pmol/mL and 2.89 +/- 2.01 pmol/mL,
respectively) than in the control group (3.55 +/- 0.54 pmol/mL and 1.30 +/- 0.48
pmol/mL, respectively) throughout late gestation. Plasma noradrenaline, but not
adrenaline concentrations, increased significantly between 110 and 140 d of
gestation in both the PR and control group, and there was a significant inverse
relationship between plasma noradrenaline and arterial PO2 in the PR and control
groups (plasma noradrenaline = 12.34 - 0.40 PO2). In the PR group, plasma
noradrenaline increased (p < 0.05) after tyramine infusion from 4.51 +/- 1.28
pmol/mL to a peak of 19.40 +/- 3.56 pmol/mL. In the control group, noradrenaline
increased from 2.08 +/- 0.30 pmol/mL to a peak of 12.23 +/- 1.67 pmol/mL after
tyramine infusion. There was no difference, however, in the maximal proportional
changes in plasma noradrenaline concentrations in the PR (319 +/- 55%) and
control (449 +/- 100%) groups after tyramine. We conclude that the most likely
source of the increased plasma catecholamines in the PR group is enhanced
catecholamine synthesis and secretion from developing sympathetic neurons.
PMID- 9396563
TI - Tissue metabolism and plasma levels of thyroid hormones in critically ill very
premature infants.
AB - Thyroid status was characterized in very preterm infants (gestational age < or
=32 wk; n = 61) from birth through d 14, and in infants who died within 16 d
after delivery (n = 10), where it was also correlated with metabolism of
iodothyronines in peripheral tissues (brain, liver, kidney, skeletal muscle, and
adipose tissue). At 3 d of life, mean plasma levels of thyroxine,
triiodothyronine, and TSH started to decrease, being lower in the critically ill
compared with healthy premature neonates. Activities of the three iodothyronine
deiodinases enzymes (type I, II, and III, respectively) were detected in all
postmortem tissue samples, except for absence of the type II activity in kidney.
All activities were the highest in liver and differed in other tissues. Lack of
correlation between the type I activity in liver (and kidney), and plasma levels
of thyroid hormones suggested that the thyroid was the primary source of
circulating triiodothyronine. On the other hand, namely in brain, correlations
between activity of the deiodinases and plasma hormone levels were found which
suggested a complex control by thyroid hormones of their own metabolism. High
activity of type III in liver, adipose tissue, and skeletal muscle demonstrated a
role of these tissues in thyroid hormones degradation. Results support the view
that peripheral tissues of very preterm infants are engaged in local generation
of triiodothyronine, and inactivation of thyroid hormones, but do not represent a
major source of circulating triiodothyronine.
PMID- 9396564
TI - Assessment of the efficacious dose of arachidonic and docosahexaenoic acids in
preterm infant formulas: fatty acid composition of erythrocyte membrane lipids.
AB - The nutritional requirements of preterm infants for the long chain
polyunsaturated essential fatty acids, arachidonic acid (AA) and docosahexaenoic
acid (DHA), have not been clearly defined. The present study evaluated preterm
infants of less than 2.3 kg birth weight fed a commercial formula (Preemie SMA)
devoid of AA and DHA and compared this control group with similar infant groups
fed one of three formulas containing a range of 0.32 to 1.1% AA and 0.24 to 0.76%
DHA. An analogous group of infants fed their mothers' breast milk and a breast
milk fortifier (when indicated) was also studied. Erythrocyte membrane
phospholipids were isolated from blood samples collected at 12 d of age and after
a further 4 wk of feeding. Infants fed the formula without AA and DHA showed a
reduction in AA level in erythrocyte phosphatidylcholine, and a reduced level of
DHA in phosphatidylethanolamine in comparison with infants fed breast milk or
infant formula containing AA and DHA. Supplementing infant formula with
increasing levels of AA and DHA produced a clear dose response in the levels of
AA and DHA found in erythrocyte membrane phospholipids. From comparison of
membrane phospholipid fatty acid composition it appears that a formula level of
0.32-1.1% AA and 0.24-0.76% DHA provides sufficient levels of these fatty acids
to achieve a similar fatty acid composition to that of infants fed human milk for
most of the lipid fractions examined.
PMID- 9396565
TI - Brain docosahexaenoate accretion in fetal baboons: bioequivalence of dietary
alpha-linolenic and docosahexaenoic acids.
AB - The dietary bioequivalence during the brain growth spurt of alpha-linolenic (LNA)
and docosahexaenoic acids (DHA) as substrates for brain and retinal n-3 fatty
acid accretion is reported for the fetal baboons, whose mothers consumed a long
chain polyunsaturate-free diet with a n-6/n-3 ratio of 10:1. Pregnant baboons
received i.v. doses of U-13C-labeled fatty acids (LNA or DHA), plasma was
collected from mother and fetus, and fetal brain (occipital cortex), retina, and
liver were analyzed at various times post-dose. Fetal brain DHA plateaued 15-35 d
post-dose with 1.6% of the preformed [U-13C-]DHA dose recovered in the brain. In
contrast, LNA-derived DHA accretion also plateaued but was 20-fold lower. Liver
and retinal results were of the same order of magnitude, but showed evidence of
peaks and decline. Conversion products to n-3 long chain polyunsaturate were
observed in the maternal circulation at 1 h after administration, as was transfer
of both fatty acids to the fetus. From these measurements we estimate that a
dietary level of about 0.45% of energy as LNA is sufficient to meet the
requirements of the growing fetal brain, whereas 0.03% of energy as DHA would
suffice. These data are the first direct measurements of the bioequivalence of
DHA and LNA in developing primates and imply that n-3 fatty acid requirements for
the developing fetal brain can be met by attainable dietary LNA for diets low in
long chain polyunsaturates.
PMID- 9396566
TI - Reducing cell membrane n-6 fatty acids attenuate mucosal damage in food-sensitive
enteropathy in mice.
AB - Mucosal damage is commonly observed in food-sensitive enteropathy in infants, and
the generation of leukotrienes is involved in the pathogenesis of this
enteropathy. Because supplementing n-3 fatty acids is known to modify the
production of leukotrienes, we investigated whether a change of dietary fatty
acid composition affects leukotriene synthesis and food hypersensitivity
reactions in the intestine by using a mouse model of food-sensitive enteropathy.
The model was prepared by feeding ovalbumin to BALB/c mice after intraperitoneal
injection of cyclophosphamide. Diets were prepared from soybean oil (control),
perilla oil, lard, corn oil, and 0.125 volume of corn oil (low fat diet) and
given to mice for 4 wk. Villous heights, crypt depths, leukotriene B4 and C4
production in the intestine were measured. Crypt hyperplasia and villous atrophy
were severer in the corn oil-fed group than those of control group, whereas
mucosal damage in the perilla oil and low fat diet groups was minimal. In the
corn oil-fed group, red blood cell membrane levels of n-3 fatty acids were lower
than the control, and the synthesis of leukotrienes was highest among all groups.
In the perilla oil and low fat diet groups, n-6 fatty acids were lower than those
of control group and leukotriene production was significantly suppressed. These
results indicate that reducing cell membrane levels of n-6 fatty acids by feeding
less n-6 fatty acids or supplementing n-3 fatty acids, is important to suppress
leukotriene biosynthesis for prevention from mucosal damage in food-sensitive
enteropathy.
PMID- 9396567
TI - Mutations in the human biotinidase gene that cause profound biotinidase
deficiency in symptomatic children: molecular, biochemical, and clinical
analysis.
AB - Biotinidase deficiency is an autosomal recessively inherited disorder that
results in the inability to recycle the vitamin biotin. The disorder can cause
neurologic and cutaneous abnormalities that can be treated effectively with
pharmacologic doses of biotin. We identified 21 mutations that cause profound
biotinidase deficiency in 37 symptomatic children (30 different probands and 7
siblings), as well as provide relevant biochemical and clinical information for
each child. The two most common mutations (G98:d7i3 and R538C) were found in 31
of 60 alleles (52%), whereas the remainder of the alleles are accounted for by
the 19 other unique mutations. Serum samples were available from 18 children, of
these 11 had no detectable cross-reacting material (CRM) to antibody prepared
against normal human serum biotinidase, three had reduced quantities of CRM and
four had normal quantities of CRM in serum. All of these mutations result in
complete absence of biotinyl-transferase activity in serum. Two polymorphisms
were also identified in normal individuals. It is apparent that a child who
inherits any of these mutations, either in the homozygous state or in
combination, can develop the clinical features of the disorder if untreated.
There are, however, no clear genotype/phenotype correlations that would allow for
the prediction of the type, severity, or age of onset of symptoms.
PMID- 9396568
TI - Characterization of mutant holocarboxylase synthetase (HCS): a Km for biotin was
not elevated in a patient with HCS deficiency.
AB - Holocarboxylase synthetase (HCS) is an essential enzyme for the biotinylation of
several mammalian carboxylases. A deficiency of HCS is accountable for early
onset biotin-responsive multiple carboxylase deficiency. To address the mechanism
of biotin responsiveness, we analyzed the kinetic properties of the previously
identified mutant, L237P, and another mutant, V550M, described in this report.
The V550M mutant contains a G to A transition at position 1935, which is within
the putative biotin binding site, whereas the mutation in L237P occurs outside
the biotin binding site. Km and Vmax values for the mutant proteins were
determined by overexpressing cDNAs encoding the mutants in transformed
fibroblasts from an HCS-deficient patient. Enzyme activity assays were performed
using apo-carboxyl carrier protein as a substrate. A Km for biotin that was
larger than the value found for the wild-type cDNA was observed in fibroblasts
transfected with the V550M cDNA, but not the L237P cDNA. The Vmax for the
expressed L237P cDNA was 4.3% of that observed for the wild-type cDNA. Biotin
responsiveness in the patient with the L237P mutation was neither due to an
increased affinity for biotin nor a restoration of stability of the mutant by
biotin treatment. A new mechanism of biotin responsiveness in HCS deficiency is
presented.
PMID- 9396569
TI - Urinary galactonate in patients with galactosemia: quantitation by nuclear
magnetic resonance spectroscopy.
AB - Although numerous reports have appeared showing high levels of galactitol in the
urine of patients with galactose-1-phosphate uridylyltransferase deficiency,
little attention has been paid to measurement of urinary galactonate. Herein we
explored the use of 1H and 13C nuclear magnetic resonance, which required only
the concentration of urine without derivatization, to detect and quantitate
urinary galactonate. We report that transferase deficient infants, as well as
adults on galactose restricted diets excrete significant amounts of galactonate,
whereas none is detected in the urine of normal subjects. Galactose-toxic infants
were found to excrete large amounts of galactonate, which decreased when the
lactose-free diet was instituted. We also found that normal individuals subjected
to an oral galactose load also excrete high levels of galactonate for at least 4
h after galactose ingestion. Our data provide evidence that the first reaction in
the oxidative pathway of galactose metabolism described in rat liver in 1966 is
activated in patients with a variety of galactose-1-phosphate uridylyltransferase
gene mutations even while on a lactose-restricted diet. In both patients and
normal individuals, flux through the alternate galactonate pathway appears to be
related to the body galactose burden.
PMID- 9396570
TI - In vitro copper stimulation of plasma peptidylglycine alpha-amidating
monooxygenase in Menkes disease variant with occipital horns.
AB - We determined the concentrations of copper, the activities of ceruloplasmin and
peptidylglycine alpha-amidating monooxygenase (PAM), and the stimulation index of
PAM by the in vitro addition of copper in plasma samples obtained from three male
patients with occipital horns and a milder Menkes disease phenotype, having
severe copper deficiency due to the defect in copper transport. We found a
decreased plasma ceruloplasmin activity and an increased copper stimulation index
of plasma PAM in these patients compared with healthy control subjects. The
combination of these two determinations may provide a means for the assessment of
copper nutriture in humans using blood samples obtained in a single
microhematocrit tube. Further investigation is warranted to evaluate whether
these noninvasive measurements can be used for the diagnosis of mild copper
deficiency in humans with sufficient specificity and sensitivity.
PMID- 9396571
TI - Deficit of brain and skeletal muscle bioenergetics and low brain magnesium in
juvenile migraine: an in vivo 31P magnetic resonance spectroscopy interictal
study.
AB - We used phosphorus magnetic resonance spectroscopy (31P MRS) to investigate in
vivo the brain and skeletal muscle energy metabolism of 15 children with migraine
with aura in interictal periods. Brain 31P MRS disclosed low phosphocreatine and
high inorganic phosphate contents, and high intracellular pH in all patients.
Calculated [ADP] and the relative rate of mitochondrial oxidation were higher in
the brain of patients than in control subjects, whereas the phosphorylation
potential was lower. Brain intracellular free Mg2+ concentration was reduced by
25% in patients. Abnormal skeletal muscle mitochondrial respiration was also
disclosed in 7 of 15 patients as shown by the slow rate of phosphocreatine
postexercise recovery. The multisystem bioenergetic failure found in patients
with juvenile migraine is comparable to that found in adults with different types
of migraine.
PMID- 9396572
TI - Maturation of anoxia-induced gasping in the rat: potential role for N-methyl-D
aspartate glutamate receptors.
AB - After anoxia-induced apnea, gasping remains the last operative mechanism for
survival. In developing rats, the gasping response to anoxia exhibits triphasic
characteristics. Because anoxia is associated with enhanced release of glutamate,
we hypothesized that N-methyl-D-aspartate (NMDA) glutamate receptors may underlie
components of the gasping response. Rat pups aged 2 d (n = 50), 5 d (n = 43), 10
d (n = 42), and 15 d (n = 45) underwent anoxic challenges with 100% N2 in a whole
body plethysmograph, 30 min after intraperitoneal administration of MK801 [(+)-5
methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate;
dizocilpine] (3 mg/kg), a noncompetitive NMDA glutamate receptor channel
antagonist, or normal saline. In control pups, after primary apnea onset, a
triphasic gasping pattern was apparent at all postnatal ages and included two
distinct types of gasps (I and II). In 2- and 5-d MK801-treated animals, phase 1
and type I gasps were absent, leading to marked prolongations of the gasp latency
and phase 2, the latter displaying type II gasps only. In addition, phase 3
duration was also prolonged with increased type II gasp frequencies. In contrast,
in some 10-d-old (40%) and in all 15-d-old MK801-treated pups, although overall
gasping duration was prolonged, the triphasic gasping pattern seen in matched
controls was also present. We conclude that NMDA glutamate receptors mediate
particular phasic components of the gasping response during early postnatal life
but not at later stages of development. We speculate that developmental changes
occur in both function and expression of NMDA and other neurotransmitters within
brainstem regions underlying the neural substrate for gasp generation.
PMID- 9396573
TI - Mixed venous oxygen saturation and biochemical parameters of hypoxia during
progressive hypoxemia in 10- to 14-day-old piglets.
AB - In this study we wanted to assess the relationship between mixed venous oxygen
saturation (SVO2) and tissue oxygenation. For that, we compared the values of
SVO2 with oxygen delivery (DO2), oxygen consumption (VO2), and markers of tissue
hypoxia such as lactate and pyruvate during progressive hypoxemia. Eight 10-14-d
old piglets were anesthetized, tracheotomized, intubated, and ventilated. A
fiberoptic catheter was placed in the carotid artery to monitor arterial oxygen
saturation (SaO2). A thoracotomy was performed, and a fiberoptic catheter was
placed in the pulmonary artery to monitor SVO2. A transit time ultrasound flow
probe was positioned around the ascending aorta to measure aorta flow.
Progressive graded hypoxemia was induced by decreasing fractional inspiratory
oxygen concentration (FIO2) from 1.0 to 0.30, 0.21, 0.15, and 0.10. After each
FIO2 interval blood samples were taken for blood gases, lactate, and pyruvate.
DO2 and VO2 were calculated. SVO2 decreased similarly to SaO2. A value of SVO2 of
more than 40% excluded oxygen restricted metabolism. When DO2 decreased below a
critical range (8.4-12.8 mL/kg x min), SVO2 decreased below 15%, and lactate and
the lactate/pyruvate ratio increased. We conclude 1) that baseline SVO2 values
excluded oxygen-restricted metabolism, 2) that SVO2 values between 15 and 40%
were not a marker for oxygen-restricted metabolism, and 3) that SVO2 values below
15% were associated with oxygen-restricted metabolism. Reduced SVO2 values must
be interpreted as a change of the factors that determine the balance between DO2
and VO2 and as a warning that, with further reduction of SVO2, oxygen restricted
metabolism can develop.
PMID- 9396574
TI - Postnatal lung function after prenatal steroid treatment in sheep: effect of
gender.
AB - The effect of fetal gender on postnatal lung function and response to prenatal
steroid exposure were examined retrospectively in a group of 115 preterm lambs.
Fetuses received a single intramuscular injection of 0.5 mg/kg betamethasone
alone or in conjunction with L-thyroxine 48 h before delivery at 128-d
gestational age. Control animals received an equivalent volume of saline. After
delivery, respiratory mechanics and blood gas parameters were recorded for 40
min. Deflation pressure volume curves were constructed in excised lungs. Right
upper lobes from a randomly selected subgroup of control animals were examined
morphometrically. Control (saline-treated) females were able to be ventilated at
lower ventilatory pressures with equivalent tidal volumes and more efficient gas
exchange. There were no gender differences in compliance, conductance, or excised
lung volumes for saline-treated animals. More efficient gas exchange in females
could not be explained by thinner alveolar septa or greater alveolar surface
area. After hormone treatment, both males and females exhibited significant
improvements in respiratory mechanics, gas exchange, and an increase in alveolar
surfactant concentration. However, female exhibited a significantly greater
improvement than males for compliance, conductance, excised lung volume, and
arterial oxygen partial pressure. These data provide a comprehensive description
of gender differences in postnatal lung function and response to steroid
treatment in preterm animals, and support clinical findings of sexual dimorphism.
PMID- 9396575
TI - Repeated doses of the perfluorocarbon FC-100 improve lung function of preterm
lambs.
AB - Intratracheal administration of a single dose of the perfluorocarbon FC-100
improves lung function in surfactant-deficient animals. In this study we compared
the response to repeated doses of FC-100 (3 mL/kg 3% solution, n = 5) with that
observed after administration of Exosurf (5 mL/kg, n = 5) to mechanically
ventilated preterm lambs of 125 d of gestation. The initial dose of FC-100
rapidly increased arterial PO2, decreased arterial PCO2, and improved arterial
pH. Also dynamic lung compliance markedly improved with this agent.
Administration of an additional dose of FC-100 resulted in relatively similar
changes, albeit of lesser magnitude than those observed with the initial dose. In
contrast, Exosurf did not improve these variables even after three doses. All
lambs treated with FC-100 survived the 6-h study period, whereas one of the five
Exosurf-treated lambs survived (p < 0.05). Mean arterial blood pressure and heart
rate decreased in those lambs that received FC-100, but not in surviving lambs
that received Exosurf. Our data demonstrate that repeated intratracheal
administration of the perfluorocarbon FC-100 improves lung function and survival
of surfactant-deficient lambs better than the synthetic surfactant Exosurf. We
speculate that tensio-active agents with properties different from surfactant,
such as FC-100, might improve lung function in preterm neonates with diseases due
to surfactant deficiency.
PMID- 9396576
TI - Low birth weight and subsequent male subfertility.
AB - Male subfertility often remains unexplained. Severe intrauterine growth
retardation has previously been linked to hypergonadotropic hypogonadism. We
examined whether reduced fetal growth, as judged by low birth weight, is
associated with unexplained male subfertility later in life. Birth weight and
gestational age were obtained by questionnaire from male partners of couples
consulting for subfertility, and were transformed into birth weight SD scores.
Men with normal semen analysis (n = 128) had a median birth weight SD score of
0.0 (P25-P75 range: -0.7 to 1.0), comparable to that of men with explained
subfertility (n = 28), and higher (p = 0.012) than that of men with unexplained
subfertility (n = 32; median -0.5 SD score; P25-P75 range: -0.9 to -0.1). These
results extend the link between reduced fetal growth and male subfertility to a
range of birth weight that is well within normality. The pathophysiologic
mechanism governing this association now remains to be unraveled.
PMID- 9396577
TI - American Pediatric Society John Howland Award 1997: presentation and acceptance.
PMID- 9396578
TI - American Pediatric Society Presidential Address 1997: the ever-whirling wheel of
change.
PMID- 9396579
TI - Society for Pediatric Research Presidential Address 1997: multiculturalism in
research.
PMID- 9396580
TI - Editors and ethics.
PMID- 9396581
TI - Natural painkillers.
PMID- 9396582
TI - Effects of RU486 on HIV-1 replication.
PMID- 9396583
TI - Black market drugs are only the tip of the iceberg.
PMID- 9396584
TI - The most dangerous woman in the world?
PMID- 9396585
TI - Does Sampson see any alternative?
PMID- 9396586
TI - NIH says "yes" to acupuncture.
PMID- 9396587
TI - UNAIDS expands HIV drug access in developing countries. Joint United Nations
Programme on HIV/AIDS.
PMID- 9396588
TI - Bill may double funds for NIH bone research.
PMID- 9396589
TI - Japan to legalize the pill.
PMID- 9396590
TI - Reducing embryo implants in IVF.
PMID- 9396591
TI - Kornberg calls for scientists' association.
PMID- 9396592
TI - Medical research: the national interest.
PMID- 9396593
TI - Plasmodium falciparum malaria--sticky jams and PECAM pie.
PMID- 9396594
TI - Cystic fibrosis lung infection cleared up?
PMID- 9396595
TI - The multi-faceted personality of HIV.
PMID- 9396596
TI - Rats go with the (urine) flow.
PMID- 9396597
TI - More mayhem from molecular mimics.
PMID- 9396598
TI - Puzzling over prion partners.
PMID- 9396599
TI - Act locally, think globally.
PMID- 9396600
TI - Rotavirus vaccines at the threshold.
PMID- 9396601
TI - Prostaglandins and reproduction--what do knockouts really tell us?
PMID- 9396602
TI - Regeneration in the adult central nervous system: experimental repair strategies.
PMID- 9396603
TI - Dye efflux studies suggest that hematopoietic stem cells expressing low or
undetectable levels of CD34 antigen exist in multiple species.
AB - We previously described a method for isolating murine hematopoietic stem cells
capable of reconstituting lethally irradiated recipients, which depends solely on
dual-wavelength flow cytometric analysis of murine bone marrow cells stained with
the fluorescent DNA-binding dye Hoechst 33342. This method, which appears to rely
on the differential ability of stem cells to efflux the Hoechst dye, defines an
extremely small and homogeneous population of cells (termed SP cells). We show
here that dual-wavelength analysis of Hoechst dye-stained human, rhesus and
miniature swine bone marrow cells reveals a small, distinct population of cells
that efflux the dye in a manner identical to murine SP cells. Like the murine SP
cells, both human and rhesus SP cells are primarily CD34-negative and lineage
marker-negative. In vitro culture studies demonstrated that rhesus SP cells are
highly enriched for long-term culture-initiating cells (LTC-ICs), an indicator of
primitive hematopoietic cells, and have the capacity for differentiation into T
cells. Although rhesus SP cells do not initially possess any hematopoietic colony
forming capability, they acquire the ability to form colonies after long-term
culture on bone marrow stroma, coincident with their conversion to a CD34
positive phenotype. These studies suggest the existence of a hitherto
unrecognized population of hematopoietic stem cells that lack the CD34 surface
marker classically associated with primitive hematopoietic cells.
PMID- 9396604
TI - Murine gamma-herpesvirus 68 causes severe large-vessel arteritis in mice lacking
interferon-gamma responsiveness: a new model for virus-induced vascular disease.
AB - Fundamental issues remain unresolved regarding the possible contribution of
viruses to vascular pathology, as well as the role of the immune system in
regulating these processes. Here we demonstrate that infection of mice with gamma
herpesvirus 68 (gammaHV68) provides a novel model for addressing these issues.
Interferon-gamma receptor-deficient (IFNgammaR-/-) mice died weeks to months
after gammaHV68 infection from a severe large-vessel panarteritis. GammaHV68
infected B cell-deficient and normal weanling mice exhibited milder large-vessel
arteritis. Immunohistochemical analyses demonstrated gammaHV68 antigen in
arteritic lesions and revealed a striking tropism of gammaHV68 for smooth muscle
cells. These studies demonstrate that IFN-gamma is essential for control of
chronic vascular pathology induced by gammaHV68 and suggest gamma-herpesviruses
as candidate etiologic agents for human vasculitis.
PMID- 9396605
TI - Therapy of malignant brain tumors by intratumoral implantation of retroviral
vector-producing cells.
AB - Intratumoral implantation of murine cells modified to produce retroviral vectors
containing the herpes simplex virus-thymidine kinase (HSV-TK) gene induces
regression of experimental brain tumors in rodents after ganciclovir (GCV)
administration. We evaluated this approach in 15 patients with progressive growth
of recurrent malignant brain tumors. Antitumor activity was detected in five of
the smaller tumors (1.4 +/- 0.5 ml). In situ hybridization for HSV-TK
demonstrated survival of vector-producing cells (VPCs) at 7 days but indicated
limited gene transfer to tumors, suggesting that indirect, "bystander,"
mechanisms provide local antitumor activity in human tumors. However, the
response of only very small tumors in which a high density of vector-producing
cells had been placed suggests that techniques to improve delivery and
distribution of the therapeutic gene will need to be developed if clinical
utility is to be achieved with this approach.
PMID- 9396606
TI - Tumor regression with regional distribution of the targeted toxin TF-CRM107 in
patients with malignant brain tumors.
AB - We investigated regional therapy of recurrent malignant brain tumors with
transferrin-CRM107, a conjugate of human transferrin (Tf) and a genetic mutant of
diphtheria toxin (CRM107) that lacks native toxin binding. Physiological barriers
to delivering proteins to tumor and surrounding infiltrated brain were
circumvented with high-flow interstitial microinfusion. At least a 50% reduction
in tumor volume on magnetic resonance imaging (MRI) occurred in 9 of 15 patients
who could be evaluated (60%), including two complete responses. Peritumoral
toxicity developed 1-4 weeks after treatment in three of three patients at 1.0
microg/ml, but in zero of nine patients treated at lower concentrations. No
symptomatic systemic toxicity occurred. Regional perfusion with Tf-CRM107
produces tumor responses without systemic toxicity in patients with malignant
brain tumors refractory to conventional therapy. Direct interstitial infusion can
be used successfully to distribute a large protein in the tumor and infiltrated
brain surrounding the tumor.
PMID- 9396607
TI - Expression and function of CCR5 and CXCR4 on human Langerhans cells and
macrophages: implications for HIV primary infection.
AB - Transmission of HIV-1 is predominantly restricted to macrophage (Mphi)-tropic
strains. Langerhans cells (LCs) in mucosal epithelium, as well as macrophages
located in the submucosal tissues, may be initial targets for HIV-1. This study
was designed to determine whether restricted transmission of HIV-1 correlates
with expression and function of HIV-1 co-receptors on LCs and macrophages. Using
polyclonal rabbit IgGs specific for the HIV co-receptors cytokines CXCR4 and
CCR5, we found that freshly isolated epidermal LCs (resembling resident mucosal
LCs) expressed CCR5, but not CXCR, on their surfaces. In concordance with surface
expression, fresh LCs fused with Mphi-tropic but not with T-tropic HIV-1
envelopes. However, fresh LCs did contain intracellular CXCR4 protein that was
transported to the surface during in vitro culture. Macrophages expressed high
levels of both co-receptors on their surfaces, but only CCR5 was functional in a
fusion assay. These data provide several possible explanations for the selective
transmission of Mphi-tropic HIV variants and for the resistance to infection
conferred by the CCR5 deletion.
PMID- 9396608
TI - Complementary hydropathy identifies a cellular prion protein receptor.
AB - Prions, the etiological agents for infectious degenerative encephalopathies, act
by entering the cell and inducing conformational changes in PrPC (a normal cell
membrane sialoglycoprotein), which result in cell death. A specific cell-surface
receptor to mediate PrPC and prion endocytosis has been predicted. Complementary
hydropathy let us generate a hypothetical peptide mimicking the receptor binding
site. Antibodies raised against this peptide stain the surface of mouse neurons
and recognize a 66-kDa membrane protein that binds PrPC both in vitro and in
vivo. Furthermore, both the complementary prion peptide and antiserum against it
inhibit the toxicity of a prion-derived peptide toward neuronal cells in culture.
Such reagents might therefore have therapeutic applications.
PMID- 9396609
TI - The human 37-kDa laminin receptor precursor interacts with the prion protein in
eukaryotic cells.
AB - Prions are thought to consist of infectious proteins that cause transmissible
spongiform encephalopathies. According to overwhelming evidence, the pathogenic
prion protein PrPSc converts its host encoded isoform PrPC into insoluble
aggregates of PrPSc, concomitant with pathological modifications (for review, see
refs. 1-3). Although the physiological role of PrPC is poorly understood, studies
with PrP knockout mice demonstrated that PrPC is required for the development of
prion diseases. Using the yeast two-hybrid technology in Saccharomyces
cerevisiae, we identified the 37-kDa laminin receptor precursor (LRP) as
interacting with the cellular prion protein PrPC. Mapping analysis of the LRP-PrP
interaction site in S. cerevisiae revealed that PrP and laminin share the same
binding domain (amino acids 161 to 180) on LRP. The LRP-PrP interaction was
confirmed in vivo in insect (Sf9) and mammalian cells (COS-7). The LRP level was
increased in scrapie-infected murine N2a cells and in brain and spleen of scrapie
infected mice. In contrast, the LRP concentration was not significantly altered
in these organs from mice infected with the bovine spongiform encephalopathic
agent (BSE), which have a lower PrPSc accumulation. LRP levels, however, were
dramatically increased in brain and pancreas, slightly increased in the spleen
and not altered in the liver of crapie-infected hamsters. These data show that
enhanced LRP concentrations are correlated with PrPSc accumulation in organs from
mice and hamsters. The laminin receptor precursor, which is highly conserved
among mammals and is located on the cell surface, may act as a receptor or co
receptor for the prion protein on mammalian cells.
PMID- 9396610
TI - Passive immunization with a human monoclonal antibody protects hu-PBL-SCID mice
against challenge by primary isolates of HIV-1.
AB - How well antibodies can protect against disease due to HIV-1 infection remains a
pivotal but unresolved issue with important implications for vaccine design and
the use of prophylactic antibody to prevent infection after accidental exposure
to the virus and to interrupt transmission of virus from mother to child. Strong
doubts about the possible utility of antibodies in vivo have been raised because
of the relative resistance of primary viruses to antibody neutralization in
vitro. Primary viruses are likely to be close to the viruses transmitted during
natural infection in humans. Vaccine studies have been of little value in
assessing antibody efficacy in vivo because none of the strategies described to
date have elicited significant neutralizing antibody responses to primary
viruses. Passive immunization studies are similarly hindered by the paucity of
reagents able to neutralize primary viruses effectively and a single study has
suggested some benefit. Here we describe experiments to explore the ability of
passive antibody to protect against primary virus challenge in hu-PBL-SCID mice.
In this model, severe combined immunodeficient (SCID) mice are populated with
human peripheral blood mononuclear cells (PBMCs) and infected with HIV-1. We find
that the potent neutralizing human monoclonal antibody IgG1b12 at high dose is
able to completely protect even when given several hours after viral challenge.
The results are encouraging for antibody-based postexposure prophylaxis and
support the notion that antibody induction could contribute to an effective
vaccine.
PMID- 9396611
TI - Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased
IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA.
AB - Viruses have long been suggested to be involved in the etiology of multiple
sclerosis (MS). This suggestion is based on (1) epidemiological evidence of
childhood exposure to infectious agents and increase in disease exacerbations
with viral infection; (2) geographic association of disease susceptibility with
evidence of MS clustering; (3) evidence that migration to and from high-risk
areas influences the likelihood of developing MS; (4) abnormal immune responses
to a variety of viruses; and (5) analogy with animal models and other human
diseases in which viruses can cause diseases with long incubation periods, a
relapsing-remitting course, and demyelination. Many of these studies involve the
demonstration of increased antibody titers to a particular virus, whereas some
describe isolation of virus from MS material. However, no virus to date has been
definitively associated with this disease. Recently, human herpesvirus 6 (HHV-6),
a newly described beta-herpes virus that shares homology with cytomegalovirus
(CMV), has been reported to be present in active MS plaques. In order to extend
these observations, we have demonstrated increased IgM serum antibody responses
to HHV-6 early antigen (p41/38) in patients with relapsing-remitting MS (RRMS),
compared with patients with chronic progressive MS (CPMS), patients with other
neurologic disease (OND), patients with other autoimmune disease (OID), and
normal controls. Given the ubiquitous nature of this virus and the challenging
precedent of correlating antiviral antibodies with disease association, these
antibody studies have been supported by the detection of HHV-6 DNA from samples
of MS serum as a marker of active viral infection.
PMID- 9396612
TI - Semaphorin III can repulse and inhibit adult sensory afferents in vivo.
AB - During development, semaphorins (collapsin, fasciclin) mediate repulsive and
inhibitory guidance of neurons. Semaphorin III, a secretable member of this
family, is expressed by the ventral spinal cord at the time corresponding to
projection of sensory afferents from the dorsal root ganglion (DRG) into the
spinal cord. The inhibitory effect of E14 ventral cord is active only on nerve
growth factor (NGF)-responsive sensory afferents (small-diameter A-delta and C
fibers subserving sensations of temperature and pain). Similarly, COS cells
secreting recombinant semaphorin III are able to selectively repel DRG afferents
whose growth is stimulated by NGF and not NT-3. However, it is not known whether
these molecules can exert a functional role in the fully developed adult
peripheral nervous system. In this study, we demonstrated that gene gun
transfection and production of semaphorin III in corneal epithelial cells in
adult rabbits in vivo can cause repulsion of established A-delta and C fiber
trigeminal sensory afferents. In addition, it is shown that, following epithelial
wounding and denervation, semaphorin III is able to inhibit collateral nerve
sprouts from innervating the reepithelialized tissue. These findings are
significant in that they provide direct evidence that small-diameter adult
sensory neurons retain the ability to respond to semaphorin III. In addition, the
corneal gene gun technique may be generally used to study the in vivo effects of
neural growth modulators by quantifying the amount of sensory nerve growth.
PMID- 9396613
TI - Long-term gene therapy in the CNS: reversal of hypothalamic diabetes insipidus in
the Brattleboro rat by using an adenovirus expressing arginine vasopressin.
AB - The ability of adenovirus (Ad) to transfect most cell types efficiently has
already resulted in human gene therapy trials involving the systemic
administration of adenoviral constructs. However, because of the complexity of
brain function and the difficulty in noninvasively monitoring alterations in
neuronal gene expression, the potential of Ad gene therapy strategies for
treating disorders of the CNS has been difficult to assess. In the present study,
we have used an Ad encoding the arginine vasopressin cDNA (AdAVP) in an AVP
deficient animal model of diabetes insipidus (the Brattleboro rat), which allowed
us to monitor chronically the success of the gene therapy treatment by
noninvasive assays. Injection of AdAVP into the supraoptic nuclei (SON) of the
hypothalamus resulted in expression of AVP in magnocellular neurons. This was
accompanied by reduced daily water intake and urine volume, as well as increased
urine osmolality lasting 4 months. These data show that a single gene defect
leading to a neurological disorder can be corrected with an adenovirus-based
strategy. This study highlights the potential of using Ad gene therapy for the
long-term treatment of disorders of the CNS.
PMID- 9396615
TI - Mass spectrometry from miniaturized arrays for full comparative DNA analysis.
PMID- 9396614
TI - PECAM-1/CD31, an endothelial receptor for binding Plasmodium falciparum-infected
erythrocytes.
AB - Excessive binding of Plasmodium falciparum-infected red blood cells (pRBCs) to
the vascular endothelium (cytoadherence) and to uninfected erythrocytes
(rosetting) may lead to occlusion of the microvasculature and thereby contribute
directly to the acute pathology of severe human malaria. A number of endothelial
receptors have been identified as targets for the pRBCs, including CD36,
intercellular adhesion molecule-1 (ICAM-1) and chondroitin-4-sulfate (CSA). In
vitro, CD36 is the most frequent target of strains from patients with mild as
well as severe P. falciparum malaria, but is expressed at low levels on the
cerebral microvasculature and therefore seems unlikely to be involved in the
evolution of cerebral disease. Strains of P. falciparum that form rosettes are
associated both with the occurrence of cerebral malaria and severe anemia. Here
we report that malaria-infected RBCs adhere to platelet/endothelial cell adhesion
molecule-1 (PECAM-1/CD31) on the vascular endothelium. pRBCs bind to endothelial
cells, to PECAM-1/CD31 transfected cells, and directly to recombinant PECAM
1/CD31 absorbed onto plastic. Soluble PECAM-1/CD31 and monoclonal antibodies
specific for the amino-terminal segment of PECAM-1/CD31 (domains 1-4) blocked the
binding. Interferon-gamma (IFN-gamma)-essential for the development of cerebral
malaria in the mouse-was found to augment adhesion of human pRBCs to PECAM-1/CD31
on endothelial cell monolayers. Our results suggest that PECAM-1/CD31 is a
virulence-associated endothelial receptor of P. falciparum-infected RBCs.
PMID- 9396616
TI - Cancer vaccines.
AB - A better understanding of immune recognition of cells has led to identification
of potential new targets on tumor cells. Noticeable successes in melanoma have
been immunization with the GM2 ganglioside vaccine, and the identification of
novel antigens such as MAGE, BAGE and GAGE recognized by T cells cloned from
cancer patients with regressing disease. However, the unexpected finding that
other antigens recognized by these T cells were overexpressed normal
differentiation antigens such as tyrosinase. Pmel 17 and Melan A have led to
vaccines developed against differentiation antigens expressed in other solid
tumors. Monoclonal antibody, anti-idiotype and antigen based vaccines for
colorectal target antigens 17-1A, CEA and 791Tgp72 are all in clinical
development. Similarly HER2/neu and mucin overexpression in breast cancer
represent promising targets. Mutations in tumor oncogenes or suppressor genes
which lead to malignant transformation can also present tumor-specific antigens.
The most effective vaccines against infectious disease are live viruses. The
development of DNA vaccines which act like viruses in entering cells and show
continuous production of antigens offers great potential for the future.
PMID- 9396617
TI - Role of vindesine as neoadjuvant chemotherapy for non-small cell lung and head
and neck cancers.
AB - Although surgery is the only therapeutic intervention with potential for cure of
non-small cell lung cancer (NSCLC) and head and neck cancer, most patients
present with tumors that are too far advanced for resection. For this reason,
neoadjuvant chemotherapy is being increasingly used to down-stage primary tumor
burden before surgery. The procedure offers the possibility of enhancing
resectability and thereby improves the chances of achieving complete eradication.
In NSCLC, the most successful results have been obtained in patients with disease
that is localized to the thorax and in those achieving complete responses to
chemotherapy. A number of different combination regimens have been studied with
cisplatin as the key component. Response rates of up to 88% have been reported
together with complete sections in up to 74% of patients. The impact on survival
is still to be determined. Although there is ample data showing that combination
regimens containing vindesine have a favorable effect on survival in patients
with inoperable NSCLC, relatively few of the studies have evaluated these
regimens for use as neoadjuvant therapy. New studies should focus on increasing
the complete response rate above the 20% level that is currently attainable. The
results using neoadjuvant chemotherapy in head and neck cancer are disappointing
with no survival benefit demonstrated. However, neoadjuvant chemotherapy may help
preserve organ function and thus improve quality of life of patients.
PMID- 9396618
TI - Eriochrome Black T, structurally related to suramin, inhibits angiogenesis and
tumor growth in vivo.
AB - The polyanionic species suramin is a potential anti-cancer agent of narrow
therapeutic index. Among other pharmacological characteristics, suramin is an
inhibitor of angiogenesis. We have targeted its angiostatic properties as part of
a program to discover less toxic analogs. From screening a series of commercially
available compounds, structurally related to suramin and containing a sulfonic
acid substituted naphthylamine moiety, we discovered a new lead, Eriochrome Black
T (EBT). EBT is a novel inhibitor of angiogenesis, more potent and less toxic
than suramin in the chick chorioallantoic membrane assay. EBT was more active
than suramin in inhibiting endothelial cell proliferation in primary culture and
in inhibiting proliferation of three tumor cell lines, A431, L1210 and M5076
(IC50 10-100 microM). Cell cycle studies on the A431 line showed that both EBT
and suramin caused an accumulation of cells in the S phase, EBT being 10-fold
more potent. We suggest that this cell cycle perturbation is linked to inhibition
of topoisomerase II catalytic activity. EBT was found to be a moderate but
significant inhibitor of matrix metalloproteinases (10 microM range), more
efficient than suramin. In a s.c. M5076 sarcoma model in mice, EBT had similar
efficacy to suramin both by the i.p. or s.c. route and was moreover better
tolerated. Combined pharmacological results show that EBT compared favorably with
suramin in all assays, and that in ovo and in vivo, EBT is an analog of suramin
with diminished toxicity.
PMID- 9396619
TI - The ex vivo chemosensitivity profile of choroidal melanoma.
AB - Uveal melanoma has a high mortality rate and responds poorly to existing
chemotherapy. We have therefore examined the sensitivity of uveal melanoma to
cytotoxic agents using an ex vivo chemosensitivity assay to determine whether
some agents which have not been used for this tumor might have activity. An ATP
based tumor chemosensitivity assay (ATP-TCA) was used to determine the effect of
nine cytotoxic drugs at multiple dilutions in 28 primary uveal melanoma
specimens. Evaluable assay results from up to 16 tumors with each drug showed
variable sensitivity to alkylating agents (three of nine with mitomycin C, one of
15 with cisplatin and seven of 15 with treosulfan), cytosine arabinoside (seven
of 16), paclitaxel (one of five) and doxorubicin (two of 16). No tumors were
sensitive to temozolomide, or 5-fluorouracil, and only one of 14 to vincristine.
The combination of treosulfan with cytosine arabinoside resulted in enhanced
tumor cell inhibition in three of five tumors tested. Combinations containing
paclitaxel combined with doxorubicin or cisplatin showed some activity, but none
achieved 100% inhibition and the results were similar to those obtained with
paclitaxel alone. Uveal melanoma shows considerable heterogeneity of sensitivity
to cytotoxic drugs, with considerable resistance to most agents, matching
clinical experience. The results suggest that cytosine arabinoside or gemcitabine
plus treosulfan may be an active combination. Clinical trials will commence
shortly. The use of the ATP-TCA provides a method of testing multiple agents and
combinations in a way which would be otherwise impossible in rare tumors such as
uveal melanoma.
PMID- 9396620
TI - Schedule-dependent paclitaxel tolerance/activity: data from a 7 day infusion
phase I study with pharmacokinetics in paclitaxel refractory ovarian cancer.
AB - Our objective was to determine the maximum tolerated dose (MTD) of paclitaxel
when given as a 7 day continuous i.v. infusion, repeated every 3 weeks, and to
evaluate the toxicity and the efficacy of such a schedule of administration as a
salvage treatment in ovarian cancer patients pretreated and refractory to 3 or 24
h paclitaxel. Thirteen women were enrolled in this phase I trial. Four dose
levels ranging from 105 to 157.5 mg/m2/cycle were explored. Two of four patients
experienced dose-limiting febrile neutropenia at the dose of 157.5 mg/m2. No
objective response was observed, although three patients experienced disease
stabilization (five to six cycles), with regression of disease symptoms, two of
them having sustained 50% or greater decrease in CA 125. We conclude that the MTD
in this population was paclitaxel 140 mg/m2/7 days. Schedule-dependent mechanisms
of resistance to paclitaxel could not be demonstrated in this clinical setting of
heavily pretreated ovarian cancer patients.
PMID- 9396621
TI - Evaluation of methotrexate sensitivity in human leukemia cell lines by an
adenosine triphosphate bioluminescence assay.
AB - To verify a recently developed in vitro tumor chemosensitivity assay (TCA) based
on adenosine triphosphate (ATP) measurement for detection of methotrexate (MTX)
sensitivity or resistance in human leukemias and solid tumors in which the
antifol is indicated, we investigated the ability of the assay to discriminate
between sensitivity and resistance to this antifolate in human leukemia cell
lines sensitive (parental CCRF-CEM/S) and resistant (CCRF-CEM/E, CCRF-CEM/T and
CCRF-CEM/P sublines) to MTX by virtue of known biochemical mechanisms.
Correlation experiments with a standard cell growth inhibition assay and a
radiometric method for measurement of thymidylate (dTMP) synthesis ([5-3H]-2'
deoxyuridine tritium release assay) were performed. No significant differences
were observed in the IC50 values for the four cell lines tested as determined by
cell growth evaluation (cell number counts) and the ATP-TCA after a 72 h MTX
exposure. After short-term (4 h) high-dose MTX exposure, no significant
correlation between ATP-TCA and the classic [5-3H]-2'-deoxyuridine tritium
release assay was observed in both CCRF-CEM/S and CCRF-CEM/P cells. CCRF-CEM/T
and CCRF-CEM/E displayed, instead, complete resistance with both methods. When
using conditions proposed for clinical application (long-term exposure, i.e. 144
h) the ATP-TCA permitted the identification of cell lines highly resistant to MTX
(CCRF-CEM/F and CCRF-CEM/E), while intermediate MTX resistance due to altered
polyglutamylation was not detectable. Detection of this kind of resistance was
obtained, as expected, using a short-term exposure (4 h) to MTX followed by a
long-term efflux (72 h) in drug-free medium. On the basis of these results, ATP
TCA appears to be a suitable method for the evaluation of cytotoxicity induced by
MTX.
PMID- 9396622
TI - Potentiation of the cytotoxicity of carboquone by flavone acetic acid combined
with hyperthermia.
AB - Flavone acetic acid (FAA) has shown the effectiveness of vasoactive drugs in the
selective reduction of tumor blood flow. A FAA-mediated decrease in tumor blood
flow may produce sufficient hypoxic conditions within the tumor. Carboquone (CQ),
a naturally occurring prototype bioreductive alkylating agent like mitomycin C
(MMC), has been shown to be selectively more cytotoxic toward hypoxic tumor
cells. We have reported enhancement of the combined antitumor effects of MMC plus
FAA and hyperthermia (HT). In this study, we examined the combined effects of
FAA, CQ and HT. In vitro, although HT (43 degrees C, 60 min) reduced the
colonogenicity to 0.58 in CQ (0.01 microg/ml) alone, the combined cytotoxicity of
CQ and HT was not enhanced with exposure to FAA at a concentration of 100
microg/ml. In vivo, the tumor growth time, calculated as the time required to
reach twice the initial tumor volume, for CQ (2 mg/kg) alone, FAA (150 mg/kg)
alone, CQ+FAA, CQ+HT (43 degrees C, 15 min), FAA+HT and FAA+CQ+HT was 6.1, 5.1,
7.1, 8.0, 7.6 and 13.4 days, respectively. A significant enhancement of antitumor
effects by trimodality therapy with CQ, FAA and HT was observed, when compared to
the treatment with CQ and FAA (p < 0.05). The possible mechanisms of an increased
antitumor response achieved with the combination of CQ, FAA and HT may be
explained in the following way: the FAA-mediated decrease in tumor blood flow
produced sufficient hypoxic conditions within the tumor, and these resulted in a
significant increase of the antitumor effects of CQ and HT.
PMID- 9396623
TI - Activation of murine peritoneal macrophages after cisplatin and taxol
combination.
AB - Cisplatin and paclitaxel are potent antineoplastic agents. Their distinctly
different mechanisms of action have prompted laboratory and clinical research
into their use in combination therapies. Murine peritoneal macrophages treated
with cisplatin and paclitaxel in combination elicit an increase in their number
of lysosomes. Drug-treated macrophages, when co-incubated with sarcoma 180 cells,
establish cytoplasmic contact and transfer lysosomes into tumor cells causing
tumor cell lysis. In addition, analysis of tissue culture supernatants show
increased levels of interleukin-1alpha and tumor necrosis factor-alpha. Our study
shows that cisplatin and paclitaxel in combination enhance elements of the immune
system with greater efficacy and potency than when used alone.
PMID- 9396624
TI - 5-Fluorouracil + cisplatin + mitomycin C is a relatively most effective
combination against xenograft lines of human colorectal cancer.
AB - 5-Fluorouracil (5-FU) has been an accepted effective against colorectal cancer,
but combination regimens resulted in a lesser effect than 5-FU alone. The present
study was designed to evaluate the efficiency of various combination
chemotherapies, including 5-FU, on human colorectal cancer xenograft lines (CC-KK
and RC-TK), which had been passed by transplantation in nude mice. Eight
anticancer agents [5-FU, mitomycin C (MMC), adriamycin (ADR), 4'-epirubicin
(EPIR), carboquone (CQ), cisplatin, carboplatin and etoposide (VP-16)] and their
combinations were evaluated at 2-4 times the clinical dose. When the agents were
administered singly, 5-FU, EPIR and CQ were effective against CC-KK, and 5-FU,
MMC, EPIR, ADR, CQ and carboplatin were effective against RC-TK. Of the two-agent
combinations including 5-FU, cisplatin + 5-FU was the most effective against both
CC-KK and RC-TK. However, of the three-agent combinations, only cisplatin + 5-FU
+ MMC was more effective against both lines than cisplatin + 5-FU. These results
suggest that cisplatin + 5-FU + MMC may be the most useful regimen against
colorectal cancers in clinical application.
PMID- 9396625
TI - Cisplatin and interferon-gamma treated murine macrophages induce apoptosis in
tumor cell lines.
AB - Macrophages, treated in vitro with a combination of cisplatin and interferon
(IFN)-gamma, have been shown to develop enhanced tumoricidal activity against a
number of tumor cell types, through mechanisms which remain largely unknown. In
the present study, we have investigated the mechanism involved in the tumor cell
cytotoxicity mediated by cisplatin and lFN-gamma treated macrophages, and the
effector molecules involved therein. Peritoneal macrophages treated with
cisplatin and IFN-gamma, when co-cultured with different tumor cell types, caused
tumor cell death by induction of apoptosis. Evidence for this was provided by
percent specific DNA fragmentation assay, by specific pattern of internucleosomal
DNA fragmentation detected by agarose gel electrophoresis and by microscopic
examination of the cells, which revealed nuclear alterations, characteristic of
apoptosis. The time kinetics studies of DNA fragmentation, loss in cell viability
and apoptotic cell population showed linearity with time; most of the cells that
underwent apoptosis were found to be viable even after 24 h co-culture.
Macrophages induced apoptosis in tumor targets even in the absence of cell-to
cell contact, i.e. via diffusible effector molecules. In P815 cells, NO produced
by cisplatin and IFN-gamma treated macrophages was found to induce apoptosis as
addition of N(G)-monomethyl L-arginine (L-NMMA), a specific inhibitor of NO
synthase to the co-culture, prevented apoptosis in P815 cells. Further, direct
treatment of P815 cells with the NO donor, sodium nitroprusside (SNP), resulted
in apoptosis. In L929 cells, the effector molecule was found to be tumor necrosis
factor (TNF)-alpha as apoptosis was blocked by the addition of anti-TNF-alpha
antibodies to the co-culture but the addition of L-NMMA or SNP had no effect. The
study thus shows that cisplatin and IFN-gamma treated macrophages can kill tumor
cells by extracellular release of effector molecules which act by inducing
apoptosis in a target cell-specific manner.
PMID- 9396626
TI - Molecular characterization of a cDNA encoding a novel small GTP-binding protein
from Arabidopsis thaliana.
AB - A full-length cDNA clone encoding a novel Rab protein AtRab alpha of the
monomeric small GTP-binding protein family has been isolated from Arabidopsis
thaliana. AtRab alpha has 210 amino acids with a calculated molecular mass of
23.3 kDa. The highest homology was found to Rab1x and Rab1y from Lotus japonicus.
Southern blot analysis of genomic DNA indicated that AtRab alpha was encoded by a
single copy gene. Northern blot analysis showed that expression of the AtRab
alpha mRNA was rich in stems and roots, but poor in leaves and flowers, which is
different from the expression pattern of other Arabidopsis Rab genes.
PMID- 9396627
TI - One allele of the major histone gene cluster is enough for cell proliferation of
the DT40 chicken B cell line.
AB - Thirty-nine of the 44 chicken histone genes are located in a major histone gene
cluster of 110 kb, the others residing in four separate regions. We generated a
heterozygous chicken DT40 mutant, 1/2 delta110 kb, devoid of one allele of the
cluster, using gene targeting techniques. Analyses of the mutant revealed that
the growth rate of DT40 cells was unchanged even in the absence of one allele of
the cluster. Moreover, analyses involving a RNase protection assay, SDS-PAGE or
Triton-acid-urea-PAGE revealed not only that in the 1/2 delta110 kb mutant the
steady-state levels of total mRNAs of gene families H1, H2A, H2B, H3 and H4
remained constant, but also that the amounts of histones H1, H2A, H2B, H3 and H4
were not changed. A comparison by 2D-PAGE revealed no changes in total cellular
protein patterns of the mutant. These observations demonstrate that all the
histone gene families have the inherent ability to compensate for the disruption
of one allele of the gene cluster, with no influence on cell functions.
PMID- 9396628
TI - Expression of Tetrahymena histone H4 in yeast.
AB - Histone H4 is one of the most conserved proteins known. The very low rate of
nonsynonymous substitution in H4 suggests that it fulfills an essential function
in virtually all eukaryotes. While the majority of histone H4 sequences differ
only slightly from the general consensus H4 sequence, yeast and Tetrahymena
sequences diverge substantially from both the consensus and from each other. This
study demonstrates that despite this divergence, when Saccharomyces cerevisiae
cells are forced to use the Tetrahymena thermophila histone H4 protein, they are
viable although they have a reduced growth rate, are temperature-sensitive
relative to wild-type, have a lengthened G2 phase, and show a dramatic repression
of mating. An amino acid replacement at position 33 in the protein improves the
growth rate of these cells growing at temperatures above 28 degrees C. This
replacement changes a proline to a serine and is a further divergence from both
the Tetrahymena thermophila and Saccharomyces cerevisiae histone H4 sequences.
Thus, the replacement and expression of a non wild-type histone H4 in yeast
offers measurable effects on cell growth, identifying amino acids required for
optimal yeast functioning.
PMID- 9396629
TI - Head-to-head linkage of carp alpha- and beta-globin genes.
AB - The alpha- and beta-globin gene variants are believed to have diverged from a
single ancestral globin gene, and the divergence was primed by the duplication of
the ancestral globin gene. To understand the process of gene duplication, we
investigated the alpha- and beta-globin gene arrangement of a bony fish (carp).
From a Southern analysis of seven previously prepared lambda phage clones
(lambdaCG1-7) using radio-labelled alpha- or beta-globin gene probes, it was
found that the clones included both the alpha- and beta-globin genes, and that
they were located within a distance of 1 kb. Additionally, the linkage of two
alpha-globin genes and two beta-globin genes in the clone lambdaCG1, 5 and 7
(e.g., alpha-beta-alpha-beta in lambdaCG5) revealed an arrangement that is
different from the arrangement in higher vertebrates in which the alpha-globin
and beta-globin genes generally occur at different loci. The distances between
the detached alpha- to beta-globin genes were approximately 5 to 10 kb. DNA
sequencing of the adjacently linked alpha- and beta-globin genes in lambdaCG3
showed that they were arranged in a head-to-head orientation. PCR amplification
using primers for the internal region between the carp alpha- and beta-globin
genes gave approximately 0.9-kb products from each of the clones lambdaCG1, 3, 4,
5, 6, and 7, and from the chromosomal DNA of German mirror carp, Saku carp, Suwa
carp, and Yamato carp. This demonstrates the alternative arrangement of carp
alpha- and beta-genes in the globin gene locus (i.e., 3'alpha5'-5'beta3'
3'alpha5'-5'beta3' in lambdaCG5), and the widespread distribution of head-to-head
linked alpha- and beta-globin genes in carp. Based on the above results, we
hypothesize that the duplication of the ancestral globin gene (prior to the
divergence of the a and beta forms) occurred in a head-to-head direction.
PMID- 9396630
TI - The human zinc finger protein EGR-4 acts as autoregulatory transcriptional
repressor.
AB - The human EGR-4 (AT133) gene represents one member of a family of four related
zinc finger proteins, that are simultaneously and coordinately induced in resting
cells upon growth stimulation. In order to characterise the function of the EGR-4
zinc finger protein, we have expressed the protein in the eukaryotic baculovirus
system. The recombinant EGR-4 protein has a molecular mass of 78 kDa, as
demonstrated by SDS-PAGE and Western blotting. DNA binding studies revealed that
the EGR-4 protein binds to the EGR consensus motif GCGTGGGCG, but not to the G
rich regulatory ZIP-element of the human IL-2 gene, that is a binding site for
EGR-1. EGR-4 functions as transcriptional repressor. Overexpression of EGR-4
mediates repression of a minimal c-fos promoter through a threefold EGR consensus
site. Furthermore the EGR-4 protein displays autoregulatory activities. This
protein downregulates expression of its own gene promoter in a dose dependent
manner. A G-rich region in the EGR-4 promoter, located at position -106 to -82,
could be identified as binding site for the recombinant EGR-4 protein. A
comparison of the two related zinc finger proteins EGR-4 and EGR-1 revealed for
each protein distinct and specific DNA binding- and transcriptional regulatory
activities.
PMID- 9396631
TI - Fluorescence and NMR studies of intramolecular stacking of mRNA cap-analogues.
AB - Intramolecular stacking of a series of new synthesized dinucleotide mRNA cap
analogues has been investigated in aqueous buffers by means of fluorescence and
1H-NMR at various pH and temperatures, and compared with that for 7
methylguanosine(5')ppp(5')guanosine (m7GpppG), as well as its hypermethylated
derivative m(3)2,2,7GpppG. Thermodynamic parameters for intramolecular self
association stabilized by stacking were established by temperature-dependent
fluorescence quenching, taking into account collisional deactivation of the
excited states. Relative orientations of the stacked bases in the cap analogues
were determined with the aid of a program GEOSHIFT (Stolarski et al., Biochim.
Biophys. Acta (1996) 1293, 97), based on ring-current anisotropy. 1D-soft-TOCSY
experiments were applied to extract the exact values of vicinal coupling
constants, and hence to resolve solution conformation of the cap molecules.
Stacking interaction has been discussed in detail in terms of the cap structural
features, e.g., types of bases and length of the 5',5'-phosphate bridges, and
regarding the interactions stabilizing intramolecular stacking.
PMID- 9396632
TI - Chinese hamster ovary cells lacking GM1 and GD1a synthesize gangliosides upon
transfection with human GM2 synthase.
AB - GM3-positive Chinese hamster ovary cells (CHO-K1 cells) lack the ability to
synthesize GM2 and the complex gangliosides GM1 and GD1a from [3H]Gal added to
the culture medium. However, they acquire the ability to synthesize GM2 and to
synthesize and immunoexpress complex gangliosides upon transient transfection
with a cDNA encoding the human GM3:N-acetylgalactosaminyl transferase (GM2
synthase). The activities of endogenous GM1- and GD1a-synthases in the parental
cell line and in cells transfected with the plasmid with or without the GM2
synthase cDNA were essentially identical and comparable in terms of specific
activity with the endogenous GM3 synthase. Results indicate that
glycosyltransferases acting on GM2 to produce GM1 and GD1a are constitutively
present in CHO-K1 cells, and that the expression of their activities depend on
the supply of the acceptor GM2. In addition, these results lend support to the
notion that GM2 synthase is a key regulatory enzyme influencing the balance
between simple and complex gangliosides.
PMID- 9396633
TI - Identification of soluble type of membrane-type matrix metalloproteinase-3 formed
by alternatively spliced mRNA.
AB - Homology screening for human membrane-type MMP (MT-MMP) was carried out, and cDNA
encoding a soluble type of MT3-MMP (SM3), which is considered to be an
alternatively spliced variant of MT3-MMP, was obtained. SM3 had a novel sequence
consisting of 50 amino acids after Lys407 instead of amino acids containing the
transmembrane domain of MT3-MMP. When SM3 tagged with a FLAG epitope (SM3-flag)
was expressed in COS-7 cells, SM3-flag was present in the conditioned medium in
its activated form. The enzymatic activity of SM3 was studied using a recombinant
enzyme expressed in E. coli (SM3-e). The fluorogenic peptide substrate
hydrolyzing activity of SM3-e was inhibited by EDTA and by the tissue inhibitor
of metalloproteinase-2 (TIMP-2), whereas TIMP-1 had only relatively weak
inhibitory ability. SM3-e was able to activate proMMP-2, and this activity was
also inhibited by TIMP-2 but not by TIMP-1. SM3-e was able to cleave type III
collagen, and also digested fibronectin. In view of the homology of the primary
structures, MT3-MMP was considered to have the same catalytic activity as SM3.
The results of studies of SM3's activity on extracellular matrix (ECM) protein
suggests that MT3-MMP plays a role in ECM turnover not only by activating proMMP
2 but also by acting directly on ECM macromolecules.
PMID- 9396635
TI - Triggering and the pathophysiology of acute coronary syndromes.
AB - Insight into the pathophysiology of acute coronary syndromes can be gained by
studying the role of triggering activities, such as heavy physical exertion and
episodes of anger, in promoting plaque rupture and thrombosis, and the
determinants of plaque vulnerability to disruption, which include lipid-rich
plaque, a thin fibrous cap, and increased macrophage activity. This article
focuses on the contribution of triggering activities and the potential mechanisms
by which they may lead to acute myocardial infarction and sudden cardiac death.
PMID- 9396634
TI - Transfection of TTF-1 gene induces thyroglobulin gene expression in
undifferentiated FRT cells.
AB - The thyroglobulin gene, the substrate for thyroid hormone biosynthesis, is not
expressed in the FRT cell line, which, even though it manifests the polarised
epithelial phenotype, does not express any of the thyroid functional properties.
Two transcription factors, TTF-1 and Pax-8, have been implicated in thyroid
specific expression of the thyroglobulin gene. FRT cells contain Pax-8 but they
lack TTF-1. In this paper, we show that transfection of TTF-1 expression vectors
in FRT cells results in activation of thyroglobulin gene expression. If the
expression vector encoded for TTF-1-ER, a fusion gene coding for the entire TTF-1
protein fused to the hormone-binding domain of the steroid receptor, under the
control of the RSV promoter, thyroglobulin gene expression was controlled by
estrogen. These data provide a direct demonstration that TTF-1 activates the
chromosomal thyroglobulin promoter. Since transfection of TTF-1 expression
vectors in non-thyroid cell types did not result in thyroglobulin gene
expression, it is suggested that Pax-8, in addition, perhaps, to a specific
cellular environment, might be required for thyroid specific expression of the
thyroglobulin gene.
PMID- 9396636
TI - Antiplatelet therapy: do the new platelet inhibitors add significantly to the
clinical benefits of aspirin?
AB - The inhibitors of the platelet membrane glycoprotein IIb/IIIa show considerable
promise as antiplatelet agents. These drugs are easily titrated when administered
intravenously and are associated with less frequent and serious bleeding than
initially feared. They add significant benefit to that attributable to aspirin in
preventing the complications associated with coronary angioplasty. Pilot studies
have suggested that benefits could also be realized in acute myocardial
infarction and unstable angina. The most effective means of administering these
agents, their relative efficacy, and the consequences of long-term modulation of
the glycoprotein IIb/IIIa receptor by oral agents are challenging areas for
clinical investigation.
PMID- 9396637
TI - Successors to heparin: new antithrombotic agents.
AB - New advances in antithrombotic therapy include low-molecular weight heparins
(LMWHs), heparinoids, and direct thrombin inhibitors. LMWHs and heparinoids have
improved pharmacologic and pharmacokinetic properties compared with standard,
unfractionated heparin. LMWHs are effective in preventing venous thromboembolism
in general surgical patients, orthopedic patients, and general medical patients.
At equipotent antithrombotic doses, LMWHs produce less bleeding than does
unfractionated heparin. When given in fixed doses subcutaneously in the treatment
of venous thromboembolic disease, LMWHs have been shown to be as effective as or
more effective than and safer than standard heparin given intravenously with
regular monitoring. Recent studies have demonstrated that LMWHs are effective in
reducing the risk of death and myocardial infarction in patients with unstable
angina; they are as effective as intravenous heparin when given subcutaneously
without monitoring. Preliminary data indicate that LMWHs also may be effective in
improving outcomes in patients with ischemic stroke. The pharmacokinetic
characteristics of LMWHs permit their use in a fixed dose administered
subcutaneously without monitoring, resulting in greater clinical utility than
standard heparin. The direct thrombin inhibitors have a narrow safety window, and
in doses that do not produce excessive bleeding have not been shown to have
greater efficacy than that of unfractionated heparin.
PMID- 9396638
TI - The evolution of antithrombotic therapy in coronary stenting.
AB - A rare but important side effect associated with the use of coronary stents is
the development of subacute thrombotic occlusion within the first week after
implantation. Recent studies have indicated that the incidence of subacute
thrombosis can be reduced with a combination regimen consisting of aspirin and
ticlopidine instead of the standard regimen of aspirin and warfarin. The
evolution in our understanding of the factors causing subacute stent thrombosis,
coupled with the development of new implantation procedures, has permitted the
development of a new treatment strategy with less aggressive anticoagulation
therapy, fewer side effects, and, it is hoped, lower costs.
PMID- 9396639
TI - Rationale for low-molecular weight heparin in coronary stenting.
AB - Stents have been as revolutionary for the practice of coronary revascularization
in recent years as was the coronary angioplasty balloon 15 years ago, but they
have also been associated with a high rate of stent thrombosis. The Enoxaparin
and Ticlopidine After Elective Stenting (ENTICES) trial is designed to determine
the impact of a reduced anticoagulation regimen on clinical outcomes after stent
deployment. Patients are randomly assigned 2:1 to enoxaparin-ticlopidine-aspirin
versus the conventional warfarin regimen, and surrogate markers of platelet
activation and thrombin activity are measured after 3 days. Three factors
underpin ENTICES: (1) a desire to eliminate stent thrombosis, (2) a desire to
reduce length of stay after stent placement by avoiding the prolonged
hospitalization required with the five-drug regimen of heparin, aspirin,
dipyridamole, dextran, and warfarin, and (3) a desire to reduce the bleeding
complications associated with the intense anticoagulation typically used in
patients receiving stents. Patients are enrolled at seven sites in the United
States and include patients with recent infarctions, restenotic lesions, and
lesions as large as 30 mm in length. Other trials have also addressed issues
concerning anticoagulation in patients undergoing stenting. The Stent
Antithrombotic Regimen Study (STARS) trial compared aspirin, aspirin plus
ticlopidine, and aspirin plus warfarin in 1650 patients receiving stents. The
Aspirin/Ticlopidine vs Low-Molecular Weight Heparin/Aspirin/Ticlopidine High-Risk
Stent Trial (ATLAST) is comparing aspirin plus ticlopidine with enoxaparin,
aspirin, and ticlopidine in a group of patients at high risk undergoing stenting.
The Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial, a trial of
ticlopidine, aspirin, and 12 hours of postprocedural heparin versus phenocoumaron
on and aspirin after stenting in 517 patients, found a significantly lower
incidence of the combined end point of death, myocardial infarction, bypass
surgery, or repeated percutaneous transluminal angioplasty in the patients who
received antiplatelet therapy, but the patients enrolled were not representative
of the usual population undergoing stenting. New trials of stents and their
sequelae should include low-molecular weight heparins and should gather cost and
outcome data to satisfy capitated systems and managed care. Innovative stent
designs may also permit changes in antithrombotic regimens.
PMID- 9396640
TI - Issues of cost-effectiveness in the use of antithrombotic therapy for ischemic
heart disease.
PMID- 9396641
TI - The biology of the immune system.
AB - Intact immunity is fundamental for survival. The human immune system has evolved
with the sophisticated biologic capacity to distinguish self from nonself and for
memory through the process of clonal expansion. The ability to distinguish even
subtle differences from self, and among myriad antigens, is possible by the
rearrangement of genes that encode immunoglobulins and T-cell receptors, as well
as by the requirement for T cells to recognize antigens in the context of
presentation by HLA molecules encoded within the major histocompatibility
complex. Modulation of immune function initiated by antigenic stimulation and
cell-cell interactions is facilitated by a plethora of soluble mediators such as
cytokines. This overview of the biology of the immune system provides a framework
for understanding physiologic immune responses and how lacunar defects within the
immune system explain the pathogenesis of immunologic disorders. Through such
understanding, potential targets can be identified for therapeutic modulation of
the immune system.
PMID- 9396642
TI - The cells of the allergic response: mast cells, basophils, and eosinophils.
AB - Mast cells, basophils, and eosinophils have long been regarded as important
effector cells in allergic disorders. Indeed, it is thought that the cells'
cytoplasmic granule-associated or lipid mediators contribute to many of the signs
and symptoms that are characteristic of these diseases. Mast cells, basophils,
and eosinophils also probably contribute to protective host responses, especially
to parasites. In addition, recent evidence shows that mast cells, basophils, and
eosinophils can secrete a wide spectrum of cytokines and, in some cases, express
functions that may permit them to regulate the development or perpetuation of
allergic responses. Thus, mast cells, basophils, and eosinophils may express
immunoregulatory activities, as well as serve as effector cells.
PMID- 9396643
TI - Introduction to diagnostic laboratory immunology.
AB - Assays performed in the diagnostic immunology laboratory support the diagnosis
and management of a wide spectrum of clinical conditions. This chapter reviews
immunologic principles as they apply to diagnostic laboratory assays. Most of the
determinations are based on well-established principles of antigen-antibody
reactions. Some of the specific areas discussed include flow cytometric analyses,
critical in the care of patients with hematologic malignancies, with the acquired
immunodeficiency syndrome, or undergoing transplantation, and protein
electrophoretic assays to identify the presence of monoclonal gammopathies. We
also discuss the use of molecular techniques in the diagnosis of hematologic
malignancies and primary immunodeficiencies, characterization of the major
histocompatibility complex, and enumeration of viral burden.
PMID- 9396644
TI - Primary immunodeficiency diseases.
AB - Primary immunodeficiencies are rare, but important for 3 reasons. First, a high
index of suspicion and prompt diagnosis can lead to lifesaving treatment or
significant improvement in quality of life. Second, appreciation of the genetic
nature of a host defense defect makes possible family counseling and carrier and
prenatal diagnosis. Finally, the large and growing list of human genetic defects
in immune pathways provides an important tool for understanding human
immunoregulation. Many inherited immunodeficiency diseases have had their genetic
cause proven with the discovery of their disease genes within the past 5 years.
These diseases provide a framework into which additional diseases and disease
gene discoveries can be added as the rapid progress in molecular immunology and
genetics continues.
PMID- 9396645
TI - Rhinitis and inhalant allergens.
AB - Allergic rhinitis affects about 20% of the US population. The diagnosis is based
on patterns of symptoms, physical examination, and assessment of IgE antibodies
by skin or in vitro testing. The most common offending allergens are pollens of
grasses, trees, and weeds; fungi; animal allergens; and dust mites. In an
individual with nasal allergy, exposure leads to rapid release of mast cell
derived mediators. This immediate response is followed by a cell-dominated
response, including eosinophils and lymphocytes. Cytokines from T(H)2
lymphocytes, such as interleukin 4 and interleukin 5, orchestrate allergic
inflammation. Resulting tissue changes produce symptoms of the disease and
augment responses on subsequent exposure to allergens and irritants. Strategies
for avoiding offending agents are important in management. In intermittent
disease, antihistamines and/or decongestants are first prescribed. More
continuous symptoms may mandate intranasal steroids. Immunotherapy is often
helpful for patients who respond poorly to pharmacotherapy and avoidance.
PMID- 9396646
TI - Nasal polyps and sinusitis.
AB - Despite the prevalence and long history of nasal polyps, many questions still
exist with respect to incidence and pathogenesis. Although allergy has been
commonly thought to be a major cause, much compelling evidence argues against
this. Medical therapy consists of a short course of systemic steroids followed by
intranasal steroids. Sinusitis is the most commonly reported chronic disease in
the United States. Decrease in ostial size, retention of secretions, and decrease
in mucociliary action all contribute to the pathogenesis of sinusitis. The
clinical presentation of chronic sinusitis is generally subtle and the clinical
index of suspicion must be high. Limited coronal computed tomography is regarded
as the most definitive and cost-effective imaging technique for the diagnosis of
sinusitis. Appropriate antibiotics must be administered for a sufficient period.
In medically resistant sinusitis, functional endoscopic sinus surgery has emerged
as the procedure of choice.
PMID- 9396647
TI - Asthma.
AB - For unknown reasons, the morbidity and mortality from asthma are increasing in
many parts of the world, making it a global health concern. The heterogeneous
nature of the clinical manifestations and therapeutic responses of asthma in both
adult and pediatric patients indicate that it may be more of a syndrome rather
than a specific disease entity. Numerous factors, including viral infections,
allergen and irritant exposure, and exercise, among others, complicate both the
short- and long-term management of asthma. Therapeutic intervention has focused
on the appreciation that airway obstruction in asthma consists of bronchial
smooth muscle spasm and variable degrees of airway inflammation characterized by
edema, mucous secretion, and the influx of a variety of inflammatory cells.
Choosing appropriate medications depends on the disease severity (intermittent,
mild persistent, moderate persistent, severe persistent), patterns of disease
activity (exacerbations related to viruses, allergens, exercise, etc), and the
age at onset (infancy, childhood, adulthood).
PMID- 9396648
TI - Outcomes analysis in asthma.
AB - Physicians, patients, employers, managed care organizations, insurance companies,
and government all want to know how different approaches to management of asthma
are improving care. To this end, the field of outcomes analysis in asthma is
playing a major role. Clinical, physiologic, humanistic, and economic outcomes
are being assessed using different types of general and asthma-specific
instruments. Historically, clinical and physiologic outcomes have been of most
concern to clinicians. However, humanistic outcomes, such as health-related
quality of life and patient satisfaction, shift the focus to the patient.
Economic outcomes, especially cost-effectiveness, evaluate how to achieve the
best outcomes at the lowest cost. These outcomes have been used to evaluate
asthma intervention programs. Several large asthma outcomes research projects,
which should define the future of outcomes analysis in asthma, are under way.
PMID- 9396649
TI - Immunotherapy with allergens.
AB - Allergen immunotherapy has been shown to be efficacious in numerous studies for
the clinical indications of allergic asthma and rhinitis, as well as hymenoptera
venom hypersensitivity. How allergen immunotherapy improves clinical symptoms is
still not entirely clear. Decreases in specific IgE follow a complex cascade of
effects: a shifting of the cytokine milieu from T(H)2 to T(H)1 predominance, with
resultant decrease in interleukin 4, decreased recruitment and activation of
eosinophils, and decreased proliferation of mast cells. Allergen exposure has a
lessened ability to stimulate an inflammatory cell response, with decreased
target organ hyperreactivity. Since allergen immunotherapy is not without risk,
the decision needs to be made whether injection therapy is safe and provides
benefit not achievable by medical management. The continued clarification of
optimal allergen concentrations through careful studies of standardized extracts
will allow better control of adverse events by limiting unnecessarily potent
mixtures.
PMID- 9396650
TI - Food allergy.
AB - The evaluation of adverse reactions to foods involving abnormal immune responses
to food allergens remains an important part of the practice of allergy and
immunology. Approximately 5% of children younger than 3 years and 1.5% of the
general population experience food allergic disorders, indicating that about 4
million Americans suffer from food allergies. The evaluation of adverse reactions
to foods depends on a careful clinical history, diagnostic studies including
appropriate skin testing or in vitro testing with food extracts, and/or endoscopy
and biopsy. The mainstay of therapy remains avoidance of incriminated foods and
education to deal with inadvertent exposures. Experience over the past decade
suggests that the ready availability and early introduction of highly allergenic
foods (eg, peanuts and nuts) into the diet will only increase the number of
individuals suffering from hypersensitivity reactions to foods. Research has
focused on the identification and characterization of allergenic proteins and the
development of new therapeutic strategies, eg, plasmid DNA vaccines, to treat
these disorders.
PMID- 9396651
TI - Allergic reactions to drugs and biologic agents.
AB - Drug allergies are adverse reactions resulting from immunologic responses to
drugs or their metabolites. These reactions result in predictable patterns of
organ-specific or systemic hypersensitivity that usually recur on subsequent
exposure to the same drug. Although diagnostic testing for drug allergy is
available for only a few drugs, protocols have been developed to assist in
management of allergic reactions to many drugs and biologic agents. Other
protocols assist in the management of patients who develop drug reactions while
undergoing multiple drug therapy or those with a history of adverse drug
reactions who again require treatment for the same condition.
PMID- 9396652
TI - Allergic reactions to workplace allergens.
AB - Allergic sensitization to workplace allergens can result in occupational asthma
(OA), rhinitis, and dermatoses. Occupational asthma, accounting for 2% to 15% of
all new cases of asthma, is caused by more than 240 reactive chemicals or natural
proteins. Diisocyanates, used in urethane production and spray painting, are the
leading causes of OA. Occupational asthma must be objectively confirmed by
demonstrating significant decreases in lung function associated with exposure to
a causative agent. An early diagnosis of OA followed by elimination of exposure
to a causative agent may be curative and prevent progression to chronic asthma.
In the last decade, protein allergens in natural rubber latex gloves have emerged
as the leading cause of work-related cutaneous and respiratory allergic disorders
in health care workers. In the workplace, occupational allergic contact
dermatitis is almost always caused by chemicals, including nickel, chromates, and
epoxy resins, whereas contact urticarial reactions are most often due to protein
allergens. The primary treatment of occupational allergic disorders is strict
avoidance of exposure to the inciting agent.
PMID- 9396653
TI - Allergic and immunologic skin disorders.
AB - The skin represents a unique immunologic organ poised to protect the host from
invading organisms and environmental antigens. The skin is also an important
target for a variety of allergic and autoimmune responses. Mast cells are key to
the pathogenesis of urticaria, angioedema, and mastocytosis. Atopic dermatitis is
the consequence of an immunoregulatory abnormality resulting in a skin-directed T
helper type 2 response. Allergic contact dermatitis is an example of classic
delayed type hypersensitivity. Circulating autoantibodies against the epidermis
are a key mechanism by which bullous skin diseases occur.
PMID- 9396654
TI - Immunologic aspects of lung diseases and cystic fibrosis.
AB - Immunologic lung disorders are accompanied by an array of laboratory
abnormalities, some of which contribute to disease pathogenesis. Allergic
bronchopulmonary aspergillosis, which complicates asthma and cystic fibrosis,
causes mucous plugging of airways, eosinophilic pneumonia, and bronchiolitis
obliterans. Aspergillus fumigatus, growing saprophytically in bronchial mucus, is
responsible for most cases, and prednisone, not antifungal agents, is the drug of
choice because it controls the immunologic responses of the lung. In cystic
fibrosis, epithelial surface fluid from the lung does not kill Pseudomonas
aeruginosa, in part because antibodies to P aeruginosa are plentiful but
ineffective in opsonizing bacteria. Neutrophil-derived elastase cleaves
immunoglobulins and digests the C3b receptor on neutrophils, which limits
phagocytosis of pathogens. In helminth infections and infestations, pulmonary and
peripheral blood eosinophilia can be accompanied by increases in total and
antiparasite IgE concentrations and generate T(H)2 CD4+ T-lymphocyte responses.
Understanding the immunologic abnormalities of lung disorders may lead to more
effective therapies.
PMID- 9396655
TI - Autoimmune endocrine disease.
AB - Autoimmune endocrine diseases are serious disorders that utilize immense health
care resources and cause tremendous disability. They include type 1 diabetes
mellitus, thyroiditis, Graves disease, Addison disease, and polyglandular
syndromes. Analysis of the basis of autoimmune diseases has been aided by the
application of new knowledge in immunologic physiology. Recent investigations
using these techniques have revealed complicated disorders that have varied
pathogenesis and complex genetic predispositions. While the mainstay of treatment
for these diverse diseases remains the replacement of hormones produced by the
damaged endocrine organ, investigations into the pathogenesis of these disorders
provide hope for the development of specific therapeutic measures to block their
pathologic basis.
PMID- 9396656
TI - Immunologic aspects of renal disease.
AB - The kidney can become involved in immune-mediated diseases through 3 mechanisms.
It can be the primary target of antibody-mediated injury. Good-pasture syndrome,
with antibodies directed at the glomerular basement membrane, is an example of
this type. The kidney can be injured by immune complexes that are trapped in the
kidney and cause local inflammation. Examples include systemic lupus
erythematosus and IgA nephropathies. Finally, the kidney can be injured by immune
responses initiated in other organs. In Wegener granulomatosis, inflammation
begins in the airway but results in glomerulonephritis. Currently available
therapies lack efficacy and specificity. New therapies based on pathophysiology
are being developed in animal models.
PMID- 9396657
TI - Immunopathogenesis of gastrointestinal and hepatobiliary diseases.
AB - The largest lymphoid organ in the body is the gut and the gut-associated lymphoid
tissue. The mucosal immune system faces many challenges in protecting the body
from microbial invasion. Its chief function is to maintain a diverse population
of mature lymphocytes capable of responding to foreign antigens. This task is
accomplished with a variety of unique features that distinguish the mucosal from
the systemic immune system. In addition, the mucosal immune system plays a role
in inflammatory bowel disease, Whipple disease, autoimmune gastritis,
Helicobacter pylori infection, immunoproliferative small intestinal disease,
hepatitis A, B, C, D, E, F, and G, autoimmune hepatitis, primary biliary
cirrhosis, progressive sclerosing cholangitis, and vanishing bile duct syndrome.
PMID- 9396658
TI - Immunologic aspects of neurologic and neuromuscular diseases.
AB - Inflammatory disorders of the nervous and neuromuscular system are not uncommon
despite the fact that immune privilege exists in much of the nervous system.
Common immune-mediated neurologic diseases include multiple sclerosis, myasthenia
gravis, chronic inflammatory demyelinating polyneuropathy, and idiopathic
polymyositis. Environmental, genetic, and immunologic factors have been
postulated to be involved in the pathogenesis of these diseases, but much remains
to be elucidated about the specific identity and relative contributions of these
factors. Several new therapies have become available for these diseases in the
past few years, and many others are under investigation. Strategies that enhance
the normal tolerance mechanisms of the immune system are being developed. In
particular, strategies to block T(H)1-type responses or enhance T(H)2/3-type
responses have generated interest.
PMID- 9396659
TI - Immunologic aspects of vasculitis and cardiovascular disease.
AB - The immunologic cardiovascular diseases are a heterogeneous group of conditions.
Many of these entities are associated with serious morbidity and mortality
resulting from cardiac impairment, ischemic complications, or organ dysfunction,
particularly of the kidneys, lung, and nervous system. The systemic nature of
these conditions, coupled with vague symptoms and nonspecific initial physical
findings, makes the differential diagnosis complicated. Research has identified
specific mediators and primary origins in some conditions, with infections often
being responsible. Immunosuppressive therapy, despite the potential
complications, has improved the prognosis of some of the more serious immunologic
cardiovascular diseases. Improvement in the treatment of immunologic
cardiovascular diseases awaits identification of additional causes, improved
definition of host factors that predispose an individual to develop these
conditions, and better understanding of the immune dysregulation responsible for
the progression of disease. The potential pathophysiologic role of immunologic
mechanisms in common disorders such as congestive heart failure and
atherosclerosis is intriguing and offers the possibility of novel therapies in
these prevalent conditions.
PMID- 9396660
TI - Tumor immunology.
AB - Malignant tumors express antigens that may stimulate and serve as targets for
antitumor immunity. Virally induced tumors usually contain integrated proviral
genomes in theircellulargenomes and often express viral genome-encoded proteins
that may stimulate specific host immune responses. Antigens unique to individual
tumors that stimulate specific rejection of transplanted tumors have been
demonstrated only in experimental animals. Other tumor antigens that potentially
can stimulate immune responses are shared by different tumors. These include
products of mutated or rearranged oncogenes or tumor-suppressor genes. Tumors may
also overexpress tissue differentiation antigens or embryonic antigens, which
also have the potential to be recognized by the immune system. The recent
identification of tumor antigens recognized by cytotoxic T cells opens up new
possibilities for constructing chemically defined antigens for specific
immunotherapy. Treatment of malignant tumors in humans by immunologic approaches,
although theoretically attractive, has not yet succeeded on a large scale.
Important progress in immunotherapy of cancer is emerging with several different
treatment modalities.
PMID- 9396661
TI - Immunohematologic disorders.
AB - Immunohematology encompasses a broad array of clinical disorders in which immune
reactions are involved in the pathogenesis of hematologic diseases. Immune
reactions can involve the formed elements of the blood, producing hemolytic
anemia, thrombocytopenia, or neutropenia. Autoimmune phenomena and drug-induced
reactions are the most common mechanisms. In newborns, maternal antibodies can
cross the placenta and destroy red blood cells, platelets, or neutrophils. Immune
reactions can also occur during transfusion of blood products, leading to
hemolysis, febrile reactions, allergic reactions, and lung injury. The role of
leukocytes and cytokines released during blood component storage in mediating
febrile transfusion reactions has prompted the increased use of leukocyte-reduced
components. Immune reactions can occur to soluble clotting factors and can
produce bleeding or thrombosis. Finally, immunohematologic features of B-cell
disorders are considered.
PMID- 9396662
TI - Transplantation immunology.
AB - The practice of clinical and experimental transplantation continues to evolve at
a rapid pace. To appreciate the current transplant practices, it is first
necessary to review transplant immunology in its proper context, ie, as a
component of the complex series of events that promote the repair of damaged
tissues. These processes are generally categorized as inflammation, immunity, and
tissue repair/reinforcement. In general, there are 3 forms of graft rejection:
hyperacute, acute, and chronic rejection. All 3 forms of graft rejection
represent pathologic consequences of one or more of these repair-related
processes. The various graft rejection responses also illustrate several complex
immunologic principles that need to be considered. These include the definition
of an alloantigen, the structure and function of major histocompatibility complex
molecules, and the behavior of antigen-presenting cells and alloreactive T cells.
This review combines these concepts and principles into a discussion of the 3
forms of graft rejection, each of which is addressed at the level of
histopathology, pathobiology, incidence, and clinical strategies.
PMID- 9396663
TI - Immunization.
AB - Immunization is undergoing important changes, with improved vaccines replacing
less immunogenic or less safe vaccines, new vaccines for common diseases such as
chickenpox and hepatitis A infection, and improved immunization schedules.
Immunization is also being transformed by basic work in molecular medicine.
Vaccines made of DNA are being developed as a form of gene therapy that use the
patient's own cellular machinery to make foreign proteins that stimulate an
immune response. Currently immunization is used to protect patients prior to
exposure to an infectious agent or during the incubation phase after exposure,
but before disease has occurred. New technologies are being investigated to
induce the immune system to fight infections that have already produced chronic
disease such as acquired immunodeficiency syndrome and chronic hepatitis B virus
infection.
PMID- 9396664
TI - Immunopharmacology: immunomodulation and immunotherapy.
AB - Immunopharmacology has changed dramatically over the past 25 years. Although a
variety of traditional nonspecific immunosuppressive drug therapies are available
for the treatment of autoimmune disease and organ transplantation rejection, with
advances in cell biology and monoclonal antibody technology, a highly specific
antibody can be engineered to cell surface determinants on immune cells or tumors
or to neutralize inflammatory and immune mediators from an immune response. Many
of these modalities are still in early phases of study for the treatment of
autoimmune disease. In addition to therapies that suppress immune responses,
advances in molecular biology have led to new agents and methods to enhance
immune responses and correct immune deficits, such as growth factor replacement
and cytokine therapies. Finally, gene therapy is a method for the long-term
treatment of disorders in which a defective gene leads to disease.
PMID- 9396665
TI - Outcome analysis and cost assessment in immunologic disorders.
AB - A number of novel biologic agents are being introduced to replace, enhance, or
modulate immune responses in medical illnesses. The use of these therapies has
become crucial in treating some of these diseases, yet there is relatively little
available information about their cost-effectiveness. Two examples are presented.
Interferon gamma, used in chronic granulomatous disease, costs about $140 for a
100-microg vial; yearly costs average $21840 per patient. Study data estimated a
69% to 76% reduction in serious illness with interferon gamma treatment; a
reduced incidence of infections could cover drug costs. Intravenous
immunoglobulin is used lifelong in antibody deficiency and clearly reduces the
number of serious illnesses. Projected savings derive from fewer hospital
admissions and reduced organ damage, but infusion costs vary widely because of
the prices charged for the drug and infusion services.
PMID- 9396666
TI - Future trends in allergy and immunology.
PMID- 9396667
TI - Allergy and immunology on the Internet.
PMID- 9396668
TI - Acute sinusitis in the rabbit: a new rhinogenic model.
AB - The objective of this study was to create a rhinogenic model of sinusitis using
an implanted foreign body in the nasal cavity of the rabbit. The study design was
a prospective controlled trial of the experimental design. In this model an
obstructing foreign body was placed into the nasal cavity and then impregnated
with pathogenic bacteria. This model was studied histologically using whole-mount
techniques. Quantitative assessment of the degree of inflammation was made for
the maxillary and ethmoid sinus and for overall effect for each animal.
Bacteriologic study was performed in a limited number of animals. The results
indicated that a significant infection develops in about half of animals. This
peaks in intensity between 1 and 2 weeks after implantation and subsequently
subsides with some evidence of long-term changes present after 4 weeks. It is
concluded that this is a viable and perhaps preferable animal model to study
sinusitis. Further investigation is necessary to completely characterize this
model.
PMID- 9396669
TI - Role of middle meatus aspiration culture in the diagnosis of chronic sinusitis.
AB - Although empiric antibiotic therapy is often used for sinusitis, the emergence of
antibiotic resistance has increased the failure rate of this approach. Culture
directed therapy usually increases treatment success, but traditional antral
puncture is often accompanied by poor patient and physician acceptance.
Endoscopically directed middle meatal aspiration culture is increasingly used in
this setting, but studies have not convincingly demonstrated the validity of this
technique. Both endoscopic middle meatal and direct antral cultures were
performed during endoscopic sinus surgery. Cytologic examination was performed to
confirm the presence of inflammatory cells. When culture results were compared in
21 specimen pairs, exact correlation was found in 18 (85.7%). Based on this
study, endoscopically directed middle meatus aspiration culture appears to be a
valuable alternative to antral puncture for guiding organism-specific antibiotic
therapy in sinusitis.
PMID- 9396670
TI - Isolated sphenoid sinus disease: an analysis of 132 cases.
AB - Solitary involvement of the sphenoid sinus is a relatively uncommon entity. A
series of 132 patients with isolated sphenoid disease accumulated over a 22-year
period is reported. A retrospective chart review was performed with special
attention to the patients' presenting signs, symptoms, and radiographic findings.
There were 80 patients with inflammatory disease, 38 with neoplasms, four with
fibroosseous disorders, and 10 with traumatic and developmental lesions. The most
common presenting symptom was headache, followed by visual changes and cranial
nerve palsies. Cranial nerve abnormalities were encountered in 12% of the
inflammatory cases, 60% of the benign tumors, and 57% of the malignant tumors.
Radiographically, bone remodeling was associated with chronic inflammatory
disease, especially mucoceles. Bone erosion was found principally with neoplastic
disease, occurring rarely with mucoceles. Extension was associated with malignant
tumors.
PMID- 9396671
TI - Interaction between hypertension and diabetes mellitus in the pathogenesis of
sensorineural hearing loss.
AB - The purpose of this study is to support the hypothesis that diabetic end-organ
damage of the cochlea is augmented in the setting of hypertension. A historical
perspective reviewing the effects of diabetes and hypertension as causative
factors in the development of sensorineural hearing loss, as well as the basic
epidemiology and pathophysiology of the renal and vascular effects of diabetes
and hypertension, is presented. The results of audiologic findings in insulin
dependent diabetic patients, both normotensive and hypertensive, were analyzed
and correlated with the results of animal studies to support the hypothesis that
sensorineural hearing loss in patients and cochlear hair cell loss in animal
studies result from the effects of hypertension in conjunction with insulin
dependent diabetes mellitus.
PMID- 9396672
TI - Nucleus 22 cochlear implantation results in postmeningitic deafness.
AB - Cochlear implant surgery was performed on 13 patients with postmeningitic
deafness (seven adults, six children). Two adults and two children (30.8%) had
severe labyrinthitis ossificans requiring radical "drill-out." Five of 13 (38.5%)
had some bone growth requiring partial drill-out, and four of 13 (30.8%) had
normal insertion with no drill-out. Hearing results for patients with no bone
growth were similar to nonmeningitic patients; three of four (75%) had open-set
speech recognition. Performance of patients with total drill-out was poor;
"auditory only" performance was limited to detection and pattern perception of
speech, and no patients had open-set speech recognition. Results for patients
with partial drill-out were similar to results in patients with no bone growth.
Labyrinthitis ossificans not only presents surgical challenges to cochlear
implantation but may also adversely affect hearing outcome.
PMID- 9396673
TI - Cerebellopontine angle tumor outcomes in patients with hazardous occupations.
AB - Cerebellopontine angle (CPA) tumor surgery can produce a spectrum of sensory and
motor deficits that can alter a patient's lifestyle and occupation. An important
consideration is whether patients can return to full occupational status
especially when hazardous duties are involved. Outcome data in CPA tumor surgery
usually report that most patients are able to return to preoperative function;
however, whether these patients can return to hazardous duties is not specified.
A retrospective study of 380 consecutive, operated CPA tumor patients was
performed and 37 were identified who engaged in hazardous occupations including
active military service, working at dangerous heights, piloting jet aircraft,
aircraft navigating, and factory work with high-impact machinery. Overall,
patients were able to resume full-time work in their previous occupations and 86%
of patients reported that they were able to resume hazardous duties. CPA tumor
surgery is compatible with continued full occupational duties after surgery, even
for patients employed in hazardous situations.
PMID- 9396674
TI - Incus and stapes footplate simulator.
AB - Prosthesis placement in stapes surgery is difficult to master. Although temporal
bone dissection is an important adjunct to operative experience and anatomic
knowledge when training residents to perform this procedure, the high cost and
scarcity of temporal bones available for teaching purposes limit their
convenience as teaching tools. Therefore, to augment training of residents, the
authors developed an inexpensive, easily constructed middle ear simulator made
from a disposable drinking cup, toothpicks, and a tongue depressor. The device is
used with a microscope and ear instruments to manipulate, place, and crimp stapes
prostheses. Improved surgical skills can lead to better surgical results, and
this middle ear simulator can help to improve otologic surgical skills by giving
residents the opportunity to practice techniques necessary to master stapes
surgery.
PMID- 9396675
TI - Complications of gold weight eyelid implants for treatment of fifth and seventh
nerve paralysis.
AB - Complications occurred in six patients after gold weights were implanted into the
upper eyelid tissues for fifth and seventh nerve palsies. These complications
included implant infection without extrusion (in one patient); entropion with
trichiasis and presumed inflammatory reaction to the gold weight material (in one
patient); upper eyelid distortion and poor eyelid contour with corneal ulceration
and scarring (in one patient); significant residual lagophthalmos with exposure
keratitis (in one patient); and blepharoptosis obscuring the pupillary access (in
two patients). Resolution of the complications required 1. implant removal in
four of six patients without reinsertion of a second weight, 2. recession of the
retractors of the upper eyelids with medial and lateral canthoplasty (in four
patients), and 3. permanent tarsorrhaphy (in one patient). The authors conclude
that complications may be minimized by careful preoperative determination of the
optimum implant size, weight, and placement within the eyelid as well as
meticulous attention to the surgical technique of implantation. The use of other
eyelid protective procedures is often necessary to augment corneal protection
especially in patients with combined fifth and seventh cranial nerve palsies.
Endogenous implant infection without extrusion of the gold weight may be
distinguished from presumed inflammation due to gold allergy by clinical response
to antibiotics in the former and requirements of steroids or removal of the
implant in the latter.
PMID- 9396676
TI - Extended canine laryngeal preservation for transplantation.
AB - The goal of successfully transplanting the larynx has motivated researchers since
the 1960s. Early laryngeal transplant techniques limited the donor larynx to 45
minutes of ischemia. In this study, a method of prolonged laryngeal preservation
is employed in three canines. In vivo cold laryngeal perfusion with University of
Wisconsin Solution (UWS) was performed. The larynx was removed and placed into
cold storage in 4 degrees C UWS. After 24 hours of storage, the same canines
underwent laryngeal reimplantation. The animals were sacrificed 7 days after
reimplantation. No evidence of necrosis or vascular insufficiency was identified
histologically. The results indicate that canine larynges can be successfully
reimplanted after 24 hours of preservation. Future studies will assess the
application of this technique to laryngeal transplantation.
PMID- 9396677
TI - Deep neck infections in children: a new approach to diagnosis and treatment.
AB - Forty-seven children presented with the diagnosis of a deep neck infection-
either cellulitis or abscess--between January 1991 and July 1996. Forty-four
(94%) had contrast-enhanced computed tomography (CT) imaging consistent with this
diagnosis. Three patients with no CT scan had confirmation of an abscess at
surgical drainage. Parenteral antibiotics alone were effective in the treatment
of 24 of 47 infections (51%): seven parapharyngeal, one retropharyngeal, and 16
combined. By CT scan these infections represented cellulitis in 17 of 24 (71%),
an abscess in three of 24 (13%), and incomplete abscess in four of 24 (17%). The
average duration of hospitalization for this group was 4.8 days, with symptomatic
improvement usually seen within 24 hours. Surgical drainage was performed on 23
of 47 infections (49%): three parapharyngeal, 17 combined, and three of unknown
specific location. In 22 of these 23 children (96%), transoral drainage of the
abscess was used as the primary surgical approach. In 21 of these 22 (95%) there
was complete resolution without complications or recurrence; one abscess required
a subsequent external approach. CT scanning with contrast revealed that all deep
neck infections were located medial (usually anteromedial) to the great vessels.
Abscesses with volumes estimated to be greater than 2000 mm3 were more likely to
undergo surgery, but these differences were not statistically significant. The
use of contrast-enhanced CT scanning provides information regarding abscess size,
location, and relative position of the great vessels for safe and successful
transoral drainage. Thus we recommend CT-assisted transoral drainage for combined
retropharyngeal/parapharyngeal abscesses and selected isolated parapharyngeal
abscesses that do not respond to parenteral antibiotics.
PMID- 9396678
TI - Characterization of smoking-induced nasopharyngeal lymphoid hyperplasia.
AB - The frequency of smoking-induced nasopharyngeal lymphoid hyperplasia in heavy
smokers and its potential clinical implications are still unknown. Precise
criteria to differentiate this entity from other types of nasopharyngeal lymphoid
hyperplasia are needed. A prospective clinicopathological study of smoking
induced nasopharyngeal lymphoid hyperplasia was conducted in 17 heavy smokers.
Ten nonsmoking patients, five of them with chronic sinusitis, three with adult
onset adenoid hypertrophy, and two children with adenoidal hypertrophy served as
a control group. Both in smokers and in nonsmokers, lymphocytic infiltration of
the mucosa was characterized immunohistochemically as T cells. In smokers,
semithin (1 micron) sections revealed deformed and migrating cytotoxic
lymphocytes in the nasopharyngeal mucosa. The lymphocytes were attached to
epithelial, ciliated, and goblet cells, resulting in cell damage. Transmission
electron microscopy of biopsies from smokers revealed emperipolesis,
characterized by mucosal invasion and epithelial cell damage by an unusual
population of migrating T lymphocytes that penetrate them. These findings confirm
a direct effect of smoking on the nasopharyngeal lymphoid tissue, which forms
part of the immune system. It is concluded that the diagnostic evaluation and
therapeutic approach of heavy smokers with otological and airway symptoms should
be based on thorough endoscopic examination of the nasopharynx. When the
diagnosis is not clear-cut, selective tele-endoscopic biopsy and electron
microscopic examination are recommended. This entity should be added to the list
of known clinical manifestations of the smoking habit.
PMID- 9396679
TI - A clinical and histologic comparison of percutaneous dilational versus
conventional surgical tracheostomy.
AB - To directly compare percutaneous dilational tracheostomy (PDT) with conventional
surgical tracheostomy, a prospective study was performed in 83 patients requiring
tracheostomy for prolonged mechanical ventilation in the intensive care unit or
after surgery for a large tumor in the upper respirodigestive tract. Median
follow-up was 355 days after PDT and 338 days after conventional tracheostomy.
The overall morbidity rate was significantly lower with PDT than with
conventional tracheostomy (6.4% vs 36.1%; P < 0.001). Compared with conventional
tracheostomy, PDT was also associated with a significantly lower incidence of
postoperative bleeding (2.1% vs 13.9%; P < 0.05) and postoperative wound
infection (0% vs 22.2%; P < 0.001). There were no clinical signs of
laryngotracheal stenosis in either group. In conclusion, PDT is a simple, fast,
safe bedside procedure that is associated with significantly lower morbidity than
standard surgical tracheostomy.
PMID- 9396680
TI - Tumors of the nasal columella treated by Mohs micrographic surgery.
AB - Primary nasal columellar tumors are rare but can exhibit aggressive clinical
behavior, often leading to devastating outcomes if these tumors are not
completely removed. Eleven patients with nonmelanoma nasal columellar lesions
were evaluated. All lesions were excised by obtaining tumor-free margins with
Mohs micrographic surgery. Seven of eight cases with basal cell carcinoma have
been tumor free for more than 5 years, the eighth case remains tumor free at 4
years. The primary squamous cell carcinoma lesions treated in this study have
fared well; one patient has been tumor free for the past 4.3 years. No local
recurrence or distant metastasis has occurred to date for all cases. We conclude
that intervention with Mohs micrographic surgery for the treatment of early nasal
columellar tumors may lead to improved outcomes.
PMID- 9396681
TI - Fibrosing inflammatory pseudotumors of the central skull base.
AB - The most important step in the differential diagnosis of mass lesions of the
central skull base is to rule out malignant neoplasms. However, nonneoplastic
lesions, such as infections or nonspecific inflammatory lesions of the skull
base, can mimic malignant processes. In this study, the authors analyzed seven
cases of nonneoplastic noninfectious mass-forming lesions involving the central
skull base. In most cases, malignant processes were suspected at the initial
phase of diagnostic work-up, but subsequent histologic examinations revealed that
these lesions consisted of inflammatory cells and fibrosis without neoplastic
cells. Common manifestations were pain and other neurological symptoms related to
the involved anatomical sites. A variety of neurological dysfunctions of the
cranial nerves not including the olfactory and spinal accessory nerves were
observed. No patient developed separate lesions outside the head and neck region.
After the pathologic diagnosis, most of the patients were treated with oral
steroid therapy, with initial doses of prednisolone, 60 to 100 mg/d. It was
difficult to relate responsiveness to steroid therapy with the histologic degree
of sclerosis, fibrosis, or chronicity of the disease in these cases.
Otolaryngologists should be aware of this disease when making treatment decisions
for their patients with skull base lesions.
PMID- 9396682
TI - Analysis of the mechanical behavior of the Nijdam voice prosthesis.
AB - The valveless Nijdam prosthesis is a new voice prosthesis for laryngectomized
patients using tracheoesophageal speech. An "umbrella-like hat" covers the
esophageal side of the tracheoesophageal fistula and is deformed during speech by
air pressure. To decrease pressure loss during speech, a good understanding of
the mechanical behavior is essential. In the present study, the Finite Element
Method (FEM), used in engineering to analyze the mechanical behavior of complex
structures, was applied to analyze eight possible improvements of the Nijdam
prosthesis. This study found that, during speech, deformation of hat and soft
tissue occur. Distinct differences in the hat's deformation of the eight models
also were found. It is concluded that complex structures like the Nijdam
prosthesis can be analyzed by FEM. An optimal model was found to decrease
pressure loss while stresses in the device remain safe.
PMID- 9396684
TI - Evaluation of the bone resistance of the sphenoid and ethmoid sinuses.
AB - Functional endoscopic sinus surgery can be associated with iatrogenic
complications. Some anatomical structures have been identified this clinically as
specific danger sites. The aim of this study was to confirm and to compare these
clinical data with measurements of the bone resistance of the sphenoid and
ethmoid walls and to point out regions that have increased bony fragility.
Critical dynamometric evaluation of the resistance to breakage of these bony
structures was made on 21 anatomic specimens. This study allowed the authors to
localization of surgical complications, to demonstrate that other regions
renowned for their fragility can be relatively robust, and to point out that
robust sites can be dangerously fragile as a result of individual morphological
variations. Results from this study provide a supplement to the guidelines for
novice surgeons to use in identifying dangerous areas.
PMID- 9396683
TI - Inhibitory effect of macrolides on interleukin-8 secretion from cultured human
nasal epithelial cells.
AB - The mechanism of macrolide therapy in chronic sinusitis patients is unclear. The
authors studied the effect of macrolides on interleukin (IL)-8 secretion from
cultured human nasal epithelial cells. Epithelial cells harvested from the nasal
polyps of patients with chronic sinusitis were primary-cultured, and secreted IL
8 in culture media was measured by enzyme immunoassay. The cells secreted
considerable amounts of IL-8 constitutively and in response to
lipopolysaccharide. The secretion was significantly inhibited by 10(-5) M of
erythromycin, clarithromycin, roxithromycin, and josamycin. 10(-6) M erythromycin
still showed the inhibitory effect, whereas the same concentration of josamycin
did not. These results indicate that macrolide antibiotics may act as an
immunomodulator to reduce IL-8 in inflammatory sites and, at least partially,
account for the clinically discrepant effects between 14- and 16-membered ring
macrolides in long-term low-dose therapy for chronic sinusitis.
PMID- 9396685
TI - Needle placement with transtympanic electrocochleography.
AB - Electrocochleography (ECoG) is an objective, electrophysiologic test useful in
the clinical diagnosis of endolymphatic hydrops, or Meniere's disease. The
purpose of this study was to determine if the position of the needle, using
transtympanic methodology, gives a variable SP/AP (summating potential/action
potential) response. SP/AP ratios were obtained during routine tympanoplasty
procedures. After the tympanic membrane remnant was removed using a lateral graft
technique, precise needle placement was obtained at the medial and lateral round
window niches, as well as on the promontory. SP/AP ratios were obtained in these
three needle positions. There was no significant difference in the SP/AP ratio
responses despite the location of needle placement. The use of transtympanic
electrocochleography can give very good wave form morphology and consistent
results. Therefore, if elevated SP/AP ratios do occur, they are thought to be due
to a pathologic process of the ear and not needle placement.
PMID- 9396686
TI - Mastoid obliteration and lining using the temporoparietal fascial flap.
PMID- 9396687
TI - Correlation between preoperative computed tomography and preoperative findings in
functional endoscopy sinus surgery.
PMID- 9396689
TI - Clinical and epidemiologic features of Guillain-Barre syndrome.
AB - Guillain-Barre syndrome (GBS) is defined clinically as a peripheral neuropathy
causing limb weakness that progresses for up to 4 weeks before reaching a
plateau. The symptoms may be caused by inflammatory demyelination, axonal
degeneration, or both. GBS occurs throughout the world, with a median incidence
of 1.3 cases/100,000 population (range, 0.4-4.0). Males are more commonly
affected than females, and there are peaks in young adults and the elderly. There
is no clear seasonal association in Western countries, although this may be
because the most frequent antecedent events, respiratory and enteric infections,
have opposite seasonality. The most frequently identified cause of GBS is
Campylobacter jejuni infection, which has been identified in up to 41% of
patients and is associated with more severe disease and prolonged disability.
Summer epidemics of GBS occur among children and young adults in Northern China
and are particularly likely to be associated with C. jejuni infection.
PMID- 9396690
TI - Guillain-Barre syndrome: multifactorial mechanisms versus defined subgroups.
AB - The clinical spectrum of Guillain-Barre syndrome (GBS) is summarized in relation
to antecedent infections and anti-ganglioside antibodies. Associations exist
between a pure motor form of GBS, diarrhea, Campylobacter jejuni infection, and
anti-GM1 antibodies; between cranial nerve involvement and Miller Fisher
syndrome, C. jejuni infection, and anti-GQ1b antibodies; and between variants,
such as severe sensory involvement and cytomegalovirus infection. These three
clinical variants are suggested to form the extremes of a continuous spectrum;
they are discussed in relation to the more pathologically defined patterns of
acute motor axonal neuropathy and acute motor-sensory axonal neuropathy. In
particular, patients with a clinically pure motor variant of GBS, diarrhea, anti
GM1 antibodies, or C. jejuni infection seem to respond better to early treatment
with high-dose immunoglobulins than to plasma exchange.
PMID- 9396691
TI - Epidemiologic and clinical features of Campylobacter jejuni infections.
AB - Gram-negative bacteria of the genus Campylobacter and of related genera
frequently colonize the gastrointestinal tracts of humans, other mammals, and
birds. One organism, Campylobacter jejuni, has been recognized as an important
human pathogen, usually causing a diarrheal illness. Infection is common
throughout the world, but clinical and epidemiologic features differ in developed
and developing countries. The high incidence of C. jejuni infections and their
propensity to invade tissue and to induce inflammation are compatible with a role
in the causation of Guillain-Barre syndrome.
PMID- 9396692
TI - Microbiologic approaches for studying Campylobacter species in patients with
Guillain-Barre syndrome.
AB - Campylobacter jejuni is now considered to be the most common cause of bacterial
diarrheal disease in the United States. Sufficient evidence exists to support the
hypothesis that C. jejuni induces Guillain-Barre syndrome (GBS); however, many
questions about the biology of the organism and host factors need to be answered.
In order to study the role of C. jejuni and other Campylobacter species as a
cause of GBS, isolates from patients with different forms of GBS and appropriate
control populations must be obtained. To continue to study this association,
research teams must have laboratory support for isolating and characterizing
Campylobacter strains. This review summarizes current knowledge about the
laboratory aspects of Campylobacter infection that may be pertinent to studies on
GBS.
PMID- 9396693
TI - Structure and conserved characteristics of Campylobacter jejuni
lipopolysaccharides.
AB - The lipid A component of Campylobacter jejuni lipopolysaccharides (LPSs) contains
the same architectural principle as that found in other bacterial species;
however, unlike the case with other bacterial species, the lipid A backbone of C.
jejuni strains is composed of a phosphorylated beta(1'-6)-linked disaccharide
containing 2,3-diamino-2,3-dideoxy-D-glucose and D-glucosamine as the major
molecular species. Despite a backbone that differs structurally from that of
classic enterobacterial lipid A, C. jejuni lipid A is antigenically similar to
enterobacterial lipid A, and the respective LPSs have comparable endotoxic
activities. Structural variability is greater in the core oligosaccharide than in
lipid A of C. jejuni LPS. Nevertheless, the inner core oligosaccharides of C.
jejuni strains share a common unique tetrasaccharide and also possess a
trisaccharide that occurs in the inner core of other bacterial species.
Ganglioside mimicry in the outer core is a common feature shared by a number of
C. jejuni serotypes, but this mimicry is not conserved in all serotypes.
PMID- 9396694
TI - Nonlipopolysaccharide surface antigens of Campylobacter species.
AB - Among the protein antigens of Campylobacter species, flagellin, the subunit of
the flagellar filament, is the best characterized. The motility imparted by this
locomotory organelle is absolutely essential for Campylobacter organisms to
colonize the gastrointestinal tract and to cause diarrheal disease. Flagellin is
the immunodominant protein recognized during infection and has been suggested to
be involved in the protective immune response. Campylobacter flagellins are
glycosylated, which is an unusual posttranslational modification for prokaryotic
proteins. Although the chemical structure of the glycosylated moiety is
undetermined, the posttranslational modification includes sialic acid. The
association of glycosylated flagellin with development of Guillain-Barre syndrome
remains speculative, but the possibility of molecular mimicry between
glycosylated flagellin and eukaryotic glycoproteins exists.
PMID- 9396695
TI - Association between Campylobacter infection and Guillain-Barre syndrome.
AB - Guillain-Barre syndrome (GBS), a neurologic disease that produces ascending
paralysis, affects people all over the world. Acute infectious illnesses precede
50%-75% of the GBS cases. Although many infectious agents have been associated
with GBS, the strongest documented association is with Campylobacter infection.
The first line of evidence supporting Campylobacter infection as a trigger of GBS
is anecdotal reports. The second line of evidence is serologic surveys, which
have demonstrated that sera from GBS patients contain anti-Campylobacter jejuni
antibodies, consistent with recent infection. Finally, culture studies have
proven that a high proportion of GBS patients have C. jejuni in their stools at
the time of onset of neurologic symptoms. Neurologic symptoms are more severe and
more likely to be irreversible when GBS is preceded by C. jejuni infection. One
of every 1058 Campylobacter infections results in GBS, and 1 of 158 Campylobacter
type O:19 infections results in GBS.
PMID- 9396696
TI - Campylobacter jejuni isolates from Japanese patients with Guillain-Barre
syndrome.
AB - Serologic evidence of recent Campylobacter jejuni infection was found in 92 (45%)
of 205 Japanese patients with Guillain-Barre syndrome (GBS), and 49% of those 92
patients also had antibodies to GM1. Sixteen independent clinical isolates from
GBS patients were serotyped: 12 belonged to Penner's heat-stable (HS) O serotype
HS-19, 3 to HS-2, and 1 to HS-4. Of the patients whose C. jejuni isolates
belonged to HS-19, 80% had elevated anti-GM1 antibodies. Although the correlation
was significant between C. jejuni and GM1 antibody, anti-GM1 also was detected in
25% of patients without C. jejuni infection. Polymerase chain reaction-based
restriction fragment length polymorphism analysis of an flaA gene showed that all
HS-19 isolates, regardless of a GBS association, had an identical and
distinguishable pattern, Cj-1, suggesting that HS-19:Cj-1 isolates are
distinctive among C. jejuni isolates. Lectin typing showed that all GBS
associated HS-19 isolates contained terminal beta-N-acetylglucosamine residues on
their cell surface, but HS-19 isolates from patients with enteritis did not.
PMID- 9396697
TI - Diversity of lipopolysaccharide structures in Campylobacter jejuni.
AB - Immune blots of electrophoresed lipopolysaccharides extracted from 38
Campylobacter jejuni serostrains suggested the presence of O chains in 16 strains
and their absence in 22. Structural analysis confirmed the presence of O chains
in serostrains O:19, O:23, and O:36 and the absence of O chains in serostrains
O:1, O:2, and O:3. The O:19 strain has O repeat units of beta-D-glucuronic acid
amidated with 2-amino-2-deoxyglycerol and N-acetylglucosamine. The 0:36 O chain
has four different but closely related repeat units that each consist of N
acetylglucosamine, galactose, and a heptose that is varied in structure from one
repeat unit to the next. The O:23 O chain has three different repeat units
identical to three of O:36. Except for O:3, core oligosaccharides of strains with
or without O chains contain sialic acid (Neu5Ac) in the terminal regions that in
many cases mimic the structures of human gangliosides. Three neuropathic isolates
were found to have a core terminal trisaccharide (Neu5Ac alpha2-->8Neu5Ac alpha2-
>3Galbeta1) that was not found in nonneuropathic strains.
PMID- 9396698
TI - Guillain-Barre syndrome in South Africa associated with Campylobacter jejuni O:41
strains.
AB - Over a 20-month period, 3 adult and 6 pediatric patients were diagnosed with
Guillain-Barre syndrome (GBS) at Groote Schuur and Red Cross Hospitals in Cape
Town. All 9 GBS patients had Campylobacter jejuni biotype 2, serotype O:41 in
their stools. C. jejuni infection was confirmed by ELISA testing of patient sera.
Strains of this sero-biotype are rare: Only 12 such strains, including the GBS
associated strains, were recognized among 776 Campylobacter strains isolated and
identified at Red Cross Hospital from March 1994 to October 1995. This is the
first known association of C. jejuni biotype 2, serotype O:41 with GBS. Patients
infected with this Campylobacter strain had a particularly severe form of the
infection, requiring hospitalization and ventilation much longer than GBS
patients infected with other Campylobacter species and patients with
Campylobacter-negative stools. The O:41 Campylobacter isolates from the GBS
patients are identical by phenotypic, serologic, and molecular criteria, and they
are clonal.
PMID- 9396699
TI - Mechanisms of action of anti-GM1 and anti-GQ1b ganglioside antibodies in Guillain
Barre syndrome.
AB - Anti-GM1 and anti-GQ1b ganglioside antibodies are found in association with acute
and chronic peripheral neuropathies, including Guillain-Barre syndrome. They are
believed to arise as a result of molecular mimicry with immunogenic microbial
polysaccharides. Although anti-ganglioside antibodies are suspected to play a
causal role in neuropathy pathogenesis, the details of this have yet to be
proven. The approach in this laboratory to solving this issue has been to
generate anti-GM1 and anti-GQ1b monoclonal antibodies from peripheral blood
lymphocytes of affected patients and to study their immunolocalization in
peripheral nerve and their electrophysiologic effects in animal models in which
peripheral nerve sites are exposed to anti-ganglioside antibodies. These data
show that anti-ganglioside antibody-reactive epitopes are widely distributed in
peripheral nerve and can cause electrophysiologic abnormalities in a variety of
model systems; thus, these data support the view that anti-ganglioside antibody
reactive epitopes may directly contribute to neuropathy pathogenesis.
PMID- 9396700
TI - Molecular mimicry between gangliosides and lipopolysaccharides of Campylobacter
jejuni isolated from patients with Guillain-Barre syndrome and Miller Fisher
syndrome.
AB - Some patients developed Guillain-Barre syndrome (GBS) after being given bovine
gangliosides. Patients with GBS subsequent to Campylobacter jejuni enteritis
frequently have IgG antibody to GM1 ganglioside. Miller Fisher syndrome (MFS), a
variant of GBS, is associated with IgG antibody to GQ1b ganglioside. The
existence of molecular mimicry between GM1 and lipopolysaccharide of C. jejuni
isolated from a GBS patient and that between GQ1b and C. jejuni
lipopolysaccharides from patients with MFS are shown herein. The molecular
mimicry between infectious agents and gangliosides may function in the production
of anti-ganglioside antibodies and the development of GBS and MFS.
PMID- 9396701
TI - Acute immune polyneuropathies: correlations of serum antibodies to Campylobacter
jejuni and Helicobacter pylori with anti-GM1 antibodies and clinical patterns of
disease.
AB - Antecedent Campylobacter jejuni infection, detected by serologic tests, has been
implicated in some acute immune polyneuropathies (AIP). Antibodies to
Helicobacter pylori, C. jejuni, and GM1 ganglioside were measured in sera from 35
Chinese patients with AIP. Anti-GM1 antibodies were found in 54% of C. jejuni
seropositive, H. pylori-seronegative patients. In contrast, anti-GM1 antibodies
were rare in sera that were either seropositive for both C. jejuni and H. pylori
(P = .04) or seronegative for C. jejuni (P = .01). Motor axonal AIP was more
common in the C. jejuni-seropositive, H. pylori-seronegative patients (82%) than
in the bacterial antibody-negative group (38%). It was concluded that in AIP
patients, C. jejuni-positive sera may be polyreactive, in that it may also react
with H. pylori. In this situation, the specificity for either infection requires
further validation. In contrast, sera with specific C. jejuni seropositivity are
associated with both motor axonal AIP and selective serum IgG anti-GM1
antibodies.
PMID- 9396702
TI - Anti-tubulin autoantibodies in acquired demyelinating polyneuropathies.
AB - Selective high-titer anti-tubulin autoantibodies are associated with Guillain
Barre syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). Low
titer anti-tubulin autoantibodies are a normal component of some human sera.
Analysis of 7 human sera with monoclonal anti-tubulin autoantibodies showed that
the epitopes recognized by these antibodies are within central, conserved regions
of tubulin. Sera from 3 patients with IgM monoclonal antibodies and CIDP reacted
to an epitope spanning aa 301-314 of beta-tubulin, which has some sequence
homology to several human viruses. Natural polyclonal anti-tubulin antibodies
also bind to central regions of tubulin. In contrast, polyclonal tubulin
antibodies induced in mice react to epitopes on the amino- or carboxy-terminal.
Selective polyclonal anti-tubulin autoantibodies with low reactivity to other
neural antigens are found in about one-half of patients with CIDP.
PMID- 9396703
TI - P2-reactive T cells in inflammatory demyelination of the peripheral nerve.
AB - Lewis rats immunized with P2 protein, a 14.5-kDa protein of the peripheral nerve
myelin, develop experimental allergic neuritis, a paralytic disorder with
clinical, histologic, and electrophysiologic features similar to those of human
Guillain-Barre syndrome (GBS). T cells reactive to P2 protein or a peptide
corresponding to 53-78 residues of the protein can transfer the disease to naive
animals. The mechanisms by which these T cells induce demyelination are not well
understood; however, they may induce inflammation and demyelination in the nerves
by production of Th1 cytokines. Th2 cytokines may lead to suppression of the
inflammation and eventual recovery. There is no conclusive evidence that P2
protein plays a role in the pathogenesis of GBS, with or without association with
Campylobacter jejuni; however, studies of the immunopathogenesis of P2 protein
induced experimental allergic neuritis are important for understanding the
pathogenesis of inflammatory demyelination in the peripheral nerves, the hallmark
of GBS.
PMID- 9396704
TI - Insights into Campylobacter jejuni-induced Guillain-Barre syndrome from the Lewis
rat model of experimental allergic neuritis.
AB - Experimental allergic neuritis (EAN) is considered the in vivo model of Guillain
Barre syndrome (GBS) and has been extensively studied in the Lewis rat. Both
cellular and humoral components of the immune response are implicated in the
inflammatory demyelination of peripheral nerves that characterizes EAN. The
recognition of Campylobacter jejuni infection as a frequent antecedent event in
GBS, and in particular its association with anti-ganglioside antibodies and a
primary axonal neuropathy, has raised many questions about the specific disease
mechanisms involved. While C. jejuni can produce an acute motor neuropathy in
chickens, confirming the relationship between C. jejuni infection and acute
neuropathy, no detailed information is available from this animal model. Insights
from experimental studies relating to the effector phase of Lewis rat EAN that
may be relevant to C. jejuni-induced GBS are discussed.
PMID- 9396705
TI - Mechanisms of Schwann cell damage in inflammatory neuropathy.
AB - Inflammatory demyelination of nerve in Guillain-Barre syndrome is triggered in
most patients by prior infection with one of a series of organisms, including
Campylobacter jejuni. The resulting inflammatory cascade, involving T cells,
macrophages, complement, and cytokines, disrupts physiologic function of the
peripheral nerve in part by targeting Schwann cells, the multipotential glial
cells that synthesize multilamellar, compacted myelin and secrete growth factors.
In vitro evidence suggests that the Schwann cell may itself be able to modulate
the cascade by serving as an antigen-presenting cell and by producing cytokines
and other acute-phase reactants.
PMID- 9396706
TI - The role of cytokines in Schwann cell damage, protection, and repair.
AB - Cytokines, proteins that are secreted by many cells, including inflammatory and
glial cells, mediate interactions between cells, generally through paracrine and
autocrine networks. Their effects are highly pleiotropic, with overlap of some
activities. The pathogenesis of Guillain-Barre syndrome (GBS), especially the
classic inflammatory demyelinating polyneuropathy form, seems to involve
lymphocytes and macrophages, which are rich sources of cytokines. Macrophages
likely have a role in the pathogenesis of the primarily axonal, less inflammatory
forms of GBS. Cytokines appear to be involved in damage to Schwann cells, myelin,
and axons, although the exact roles of the different cytokines is uncertain.
There is increasing evidence that cytokines, including some proinflammatory
cytokines that ordinarily cause damage, may also protect the cells of the
peripheral nervous system and aid in its repair. The evolution of inflammatory
and demyelinating disorders, including the degree of recovery, is probably
dependent on the interactions of the different cytokines.
PMID- 9396707
TI - Differential distribution of HLA alleles in two forms of Guillain-Barre syndrome.
AB - Guillain-Barre syndrome in northern China occurs in two forms: acute inflammatory
demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN).
AMAN and AIDP have an immunologic basis, and some cases are associated with
preceding Campylobacter jejuni infection. The distribution of allelic forms of
the histocompatibility genes HLA-DPB1, DQB1, DRB1, DRB3, DRB4, and DRB5 was
examined by DNA-based technology in 34 control, 12 AIDP, and 31 AMAN cases. In
AIDP patients, the DRB1*1301 allele showed a significant increase (18% vs. 0%, P
= .055). In AMAN patients, alleles DRB1*1301-03 and DRB1*1312, taken
collectively, were increased (19% vs. 0%, P = .009), but by itself, the DRB1*1301
allele was not increased, as in AIDP patients. With a larger number of persons,
more definitive statements will be possible; however, the differential
distribution of DR13 allelic forms between AIDP and AMAN cases may suggest that
there are different immunologic mechanisms operating at the molecular level of
these diseases.
PMID- 9396708
TI - Vaccines against Campylobacter jejuni.
AB - Campylobacter jejuni is one of the most common causes of diarrhea worldwide. The
gastrointestinal manifestations of Campylobacter infection range from watery
diarrhea to severe dysentery. Campylobacter infection has also been linked to the
postinfectious sequelae of reactive arthritis and Guillain-Barre syndrome.
Evidence from epidemiologic and volunteer studies suggests that development of a
vaccine to prevent gastrointestinal disease and limit colonization is possible.
Efforts to develop live attenuated or subunit vaccines are limited by the finite
knowledge of Campylobacter pathogenesis and lack of a conserved protective
antigen, respectively. An oral killed, whole-cell vaccine has been shown to be
safe and effective in animal models and is currently being tested in phase I
volunteer studies.
PMID- 9396709
TI - Regulatory considerations for Campylobacter vaccine development.
AB - The high, worldwide incidence of Campylobacter jejuni-associated diarrheal
disease has recently prompted the development of anti-Campylobacter vaccines.
However, the association of C. jejuni infections with subsequent development of
Guillain-Barre syndrome has increased concerns from a pathogenesis standpoint and
from a vaccine development and regulation standpoint. This brief overview
describes the purpose and process of Food and Drug Administration review of
vaccine products and highlights some important considerations pertinent to
Campylobacter vaccine development.
PMID- 9396710
TI - The economic burden of Campylobacter-associated Guillain-Barre syndrome.
AB - Guillain-Barre syndrome (GBS) is an autoimmune disease characterized by acute
neuromuscular paralysis. Of an estimated annual number of 2628-9575 US cases, 526
3830 are triggered by Campylobacter infection. Research objectives were to
identify the lifetime consequences of GBS and, when possible, to quantify their
economic burden. The cost-of-illness method was used to calculate annual societal
resources spent on medical care and lost productivity due to illness or premature
death from Campylobacter-associated GBS. Estimated total costs (in US$) of
Campylobacter-associated GBS ($0.2-$1.8 billion) were added to previously
estimated costs of campylobacteriosis ($1.3-$6.2 billion) for a total annual cost
from Campylobacter of $1.5-$8.0 billion (1995 dollars). It is concluded that up
to $8.0 billion in US human illness costs are spent annually because of
Campylobacter infection. Economic evaluation of the other costs associated with
GBS, such as physical and psychological costs, would increase these estimates.
PMID- 9396711
TI - Workshop summary and recommendations regarding the development of Guillain-Barre
syndrome following Campylobacter infection.
PMID- 9396713
TI - Endothelin attenuates apoptosis in human smooth muscle cells.
AB - An imbalance between proliferation and apoptosis is an important causal factor
for disorders involving abnormal cell accumulation. Endothelin (ET)-1, a 21-amino
acid peptide with mitogenic and vasoconstricting activities, not only acts as a
mitogen, but also attenuates paclitaxel-induced apoptosis in smooth muscle cells.
In both human pericardial and prostatic smooth muscle cells, addition of ET-1
reduced paclitaxel-induced DNA fragmentation and phosphatidylserine on the cell
surface, two characteristics of apoptosis. By comparison, angiotensin II, another
vasoactive peptide, did not have a significant effect on apoptosis. The effect of
ET-1 was dose-dependent with an EC50 of 1 nM. These results suggest that ET is a
potential survival factor for smooth muscle cells, and that altered activity of
the ET system in disease states has potential to contribute to aberrant cell
growth.
PMID- 9396712
TI - Structure and physiological function of calpains.
AB - For a long time now, two ubiquitously expressed mammalian calpain isoenzymes have
been used to explore the structure and function of calpain. Although these two
calpains, mu- and m-calpains, still attract intensive interest because of their
unique characteristics, various distinct homologues to the protease domain of mu-
and m-calpains have been identified in a variety of organisms. Some of these
'novel' calpain homologues are involved in important biological functions. For
example, p94 (also called calpain 3), a mammalian calpain homologue predominantly
expressed in skeletal muscle, is genetically proved to be responsible for limb
girdle muscular dystrophy type 2A. Tra-3, a calpain homologue in nematodes, is
involved in the sex determination cascade during early development. PalB, a key
gene product involved in the alkaline adaptation of Aspergillus nidulans, is the
first example of a calpain homologue present in fungi. These findings indicate
various important functional roles for intracellular proteases belonging to the
calpain superfamily.
PMID- 9396714
TI - Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive
(ei) equilibrative nucleoside transporter from human placenta.
AB - Mammalian equilibrative nucleoside transporters are typically divided into two
classes, es and ei, based on their sensitivity or resistance respectively to
inhibition by nitrobenzylthioinosine (NBMPR). Previously, we have reported the
isolation of a cDNA clone encoding a prototypic es-type transporter, hENT1 (human
equilibrative nucleoside transporter 1), from human placenta. We now report the
molecular cloning and functional expression in Xenopus oocytes of a cDNA from the
same tissue encoding a homologous ei-type transporter, which we designate hENT2.
This 456-residue protein is 46% identical in amino acid sequence with hENT1 and
corresponds to a full-length form of the delayed-early proliferative response
gene product HNP36, a protein of unknown function previously cloned in a form
bearing a sequence deletion. In addition to placenta, hENT2 is found in brain,
heart and ovarian tissue. Like hENT1, hENT2 mediates saturable transport of the
pyrimidine nucleoside uridine (Km 0.2+/-0.03 mM) and also transports the purine
nucleoside adenosine. However, in contrast with hENT1, which is potently
inhibited by NBMPR (Ki 2 nM), hENT2 is NBMPR-insensitive (IC50<1 microM). It is
also much less sensitive to inhibition by the coronary vasoactive drugs
dipyridamole and dilazep and to the lidoflazine analogue draflazine, properties
that closely resemble those reported for classical ei-type transport in studies
with intact cells.
PMID- 9396715
TI - Nascent very-low-density lipoprotein triacylglycerol hydrolysis by lipoprotein
lipase is inhibited by apolipoprotein E in a dose-dependent manner.
AB - In the present study it was investigated whether apolipoprotein (apoE) can
inhibit the lipoprotein lipase (LPL)-mediated hydrolysis of very-low-density
lipoprotein (VLDL) triacylglycerols (TAGs). Previous studies have suggested such
an inhibitory role for apoE by using as a substrate for LPL either plasma VLDL or
artificial TAG emulsions. To mimic the in vivo situation more fully, we decided
to investigate the effect of apoE on the LPL-mediated TAG hydrolysis by using
VLDL from apoE-deficient mice that had been enriched with increasing amounts of
apoE. Furthermore, since plasma VLDL isolated from apoE-deficient mice was
relatively poor in TAGs and strongly enriched in cholesterol as compared with
VLDL from wild-type mice, we used nascent VLDL obtained by liver perfusions.
Nascent VLDL (d<1. 006) isolated from the perfusate of the apoE-deficient mouse
liver was rich in TAGs. Addition of increasing amounts of apoE to apoE-deficient
nascent VLDL effectively decreased TAG lipolysis as compared with that of apoE
deficient nascent VLDL without the addition of apoE (63.1+/-6.3 and 20.8+/-1.8%
of the control value at 2.7 microg and 29.6 microg of apoE/mg of TAG added
respectively). Since, in vivo, LPL is attached to heparan sulphate proteoglycans
(HSPG) at the endothelial matrix, we also performed lipolysis assays with LPL
bound to HSPG in order to preserve the interaction of the lipoprotein particle
with the HSPG-LPL complex. In this lipolysis system a concentration-dependent
decrease in the TAG lipolysis was also observed with increasing amounts of apoE
on nascent VLDL, although to a lesser extent than with LPL in solution (72.3+/
3.6% and 56.6+/-1.7% of control value at 2.7 microg and 29.6 microg of apoE/mg
TAGs added respectively). In conclusion, the enrichment of the VLDL particle with
apoE decreases its suitability as a substrate for LPL in a dose-dependent manner.
PMID- 9396717
TI - Nuclear localization domain of thyroid transcription factor-1 in respiratory
epithelial cells.
AB - Thyroid transcription factor-1 (TITF-1) is a homeodomain containing transcription
factor that binds to and selectively activates the expression of genes in thyroid
and pulmonary epithelial cells. TITF-1 plays a critical role in gene expression
and in organogenesis of lung and thyroid. In the present work, epitope-tagged
TITF-1 proteins were used to identify the regions of the TITF-1 polypeptide that
mediate nuclear localization and transcriptional activity in human lung
adenocarcinoma cells. A series of TITF-1-flag deletion mutants was generated and
transfected into H441 cells to determine amino acid sequences involved in
translocation to the nucleus. Transfection of the TITF-1-flag mutants
demonstrated that a nuclear localization signal (NLS) sequence, located at the N
terminus of the homeodomain, is critical for nuclear targeting. The NLS was
essential but not sufficient for translocation of TITF-1 to the nucleus, since
deletion of the homeodomain itself also blocked nuclear translocation in the
presence of NLS. Deletion of the N-terminal transactivation domain of TITF-1
completely abolished its transcriptional activation on the human surfactant
protein-B promoter, and deletion of the C-terminal domain partially reduced its
stimulatory activity. Nuclear translocation of TITF-1 depends on both an NLS and
the homeodomain of the polypeptide. Both C- and N-terminal regions of TITF-1 are
involved in transactivation of surfactant protein B gene expression in pulmonary
cells.
PMID- 9396716
TI - Separate bisphosphatase domain of chicken liver 6-phosphofructo-2-kinase/fructose
2,6-bisphosphatase: the role of the C-terminal tail in modulating enzyme
activity.
AB - The separate bisphosphatase domain (amino acid residues 243-468) of the chicken
liver bifunctional enzyme 6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase
was expressed in Escherichia coli and purified to homogeneity. The fructose-2, 6
bisphosphatase activity of the separate domain was 7-fold higher than that of the
native bifunctional enzyme, and exhibited substrate inhibition characteristic of
the native enzyme. The inhibition of the enzymes by fructose 2,6-bisphosphate
could be overcome by Pi, glycerol 3-phosphate and GTP. Deletion of 30 amino acid
residues from the C-terminus of the separate domain resulted in around a 5-fold
increase in the Vmax of the bisphosphatase. Also, the truncated form was more
accessible to chemical modification by diethyl pyrocarbonate and N
ethylmaleimide, suggesting a more open structure than the wild-type form. In
addition, the mutation of cysteine-389 to alanine increased bisphosphatase
activity by 20% and the Km value for fructose 2,6-bisphosphate by 3-fold, and
both the point mutation at cysteine-389 and the deletional mutation led to the
predominantly insoluble expression of the enzyme. The results indicated that the
C-terminal tail plays a role in modulating the enzyme activity and suggested that
the difference in the C-terminal tail sequence is responsible for the difference
in activity of the chicken and rat liver fructose-2,6-bisphosphatases. It is
postulated that an interaction between the C-terminal tail and the active site
might be present.
PMID- 9396718
TI - Effect of aging on the chaperone-like function of human alpha-crystallin assessed
by three methods.
AB - alpha-Crystallin can function as a molecular chaperone by preventing unwanted
interactions. This paper presents the effects of aging and cataract on the
chaperone-like properties of alpha-crystallin from soluble fractions from the
cortex and nucleus of human lenses by using three assays: enzyme inactivation and
two turbidity experiments. The three methods complemented each other. There was
no decrease with age of chaperone-like function of cortical alpha-low and alpha
high crystallin. Nuclear alpha-low crystallin showed a decrease, whereas alpha
high crystallin showed no age-related change but its protective effect was
diminished. Results from the nucleus of 40-year-old cataractous lenses seemed
similar to those for clear lenses of equivalent age, whereas 80-year-old
cataractous lenses showed decreased chaperone-like behaviour.
PMID- 9396719
TI - Integrin-dependent translocation of p160ROCK to cytoskeletal complex in thrombin
stimulated human platelets.
AB - p160(ROCK) is a protein serine/threonine kinase that binds to GTP-Rho and is
activated by this binding. We have recently found that the expression of
p160(ROCK) induces focal adhesions and stress fibres in HeLa cells, whereas a
dominant-negative form of this kinase suppresses Rho-induced formation of these
structures, suggesting that this kinase is a downstream target of Rho in this
process [Ishizaki, Naito, Fujisawa, Maekawa, Watanabe, Saito and Narumiya (1997)
FEBS Lett. 404, 118-124]. To find out the mode of action of p160(ROCK), we
developed immunoblotting with an anti-p160(ROCK) antibody and investigated the
subcellular localization of p160(ROCK) during platelet aggregation. In resting
human platelets, more than 90% of p160(ROCK) was present in the Triton X-100
soluble fraction. When platelets were stimulated with thrombin, approx. 10% of
p160(ROCK) was translocated to the Triton X-100-insoluble fraction. This
translocation was detected as early as 20 s after stimulation and reached a
maximum at 5 min; it was suppressed by the addition of EDTA or an Arg-Gly-Asp-Ser
peptide (RGDS), both of which inhibit integrin alphaIIbbeta3-mediated platelet
aggregation. Using [32P]Pi-loaded platelets, we found that p160(ROCK) was
phosphorylated in response to stimulation by thrombin. This phosphorylation,
however, was not affected by the addition of EDTA and RGDS. These results suggest
that p160(ROCK) translocates to cytoskeleton in a manner dependent on integrin
ligation and works in an early stage of cytoskeletal reorganization in thrombin
stimulated platelets.
PMID- 9396720
TI - Metal-ion-binding properties of synthetic conantokin-G.
AB - The secondary structure of the synthetic 17-residue peptide, conantokin-G (con
G), a gamma-carboxyglutamate-containing marine cone snail neuroactive protein, is
altered from a random conformation to one containing a very high level (>70%) of
alpha-helix on binding of multivalent cations. The proportion of alpha-helix
formed correlated well with the size of the cation and ranged from a low of
approx. 7% with large cations, such as Ba2+, to more than 70% with smaller
cations, such as Mn2+, Mg2+ and Zn2+. The valency of the multivalent cation was
not as important, since tervalent lanthanides (Eu3+, Gd3+ and Tb3+) of ionic
radius 106-109 pm induced similar levels (50-60%) of helix to those induced by
Ca2+ and Cd2+ (ionic radii 109 and 114 pm respectively). Although the correlation
was not as tight, smaller cations of the same valency allowed the helical
transition to occur at lower concentrations than the larger cations. The
spectroscopic and spectrometric properties of some of these cations permitted a
more detailed analysis of the molecular nature of the cation-con-G binding. EPR
based titrations with Mn2+ provided a binding isotherm that was deconvoluted to a
single class of 2-3 Mn2+ sites of average Kd 3.9 microM. This number of sites was
similar to that for Ca2+ [Prorok, Warder, Blandl and Castellino (1996)
Biochemistry 35, 16528-16534], but a much lower Kd was displayed with Mn2+.
Determinations by 1H NMR of the longitudinal relaxation rates of the water
protons in Mn2+/con-G solutions at different magnetic field strengths
corresponding to the proton Langmuir frequencies of 24, 300 and 500 MHz permitted
calculation of the hydration number of Mn2+ in the complex, which was found to be
1.0. This indicates that five of the six co-ordination sites of Mn2+ are occupied
by peptide atoms, probably oxygens. Titrations of the changes in Tb3+
fluorescence as a result of its binding to con-G gave an EC50 of 58 microM, a
value nearly identical with that obtained by titration of the change in helicity
of the peptide as a function of Tb3+ concentration. This shows that the
macroscopic binding of Tb3+ to con-G is directly responsible for the alteration
in secondary structure of the peptide. Finally, Cd2+ was found to be an extremely
suitable cation for an NMR-based investigation of the amino acid residues of apo
con-G that are perturbed by cation binding. In a limited example of the results
of this study, it was discovered that originally equivalent CH2(delta) protons of
Arg13 became distinctly magnetically non-equivalent in the Cd2+-bound helical
form of con-G. This indicates that Arg13 is situated in the helix in such a way
that the mobility of its side chain is highly restricted. In conclusion, the data
show that a variety of multivalent cations with measurable spectroscopic and
spectrometric properties interact similarly with con-G and generate extensive
alpha-helical conformation in this peptide.
PMID- 9396721
TI - Differential regulation of types-1 and -3 inositol trisphosphate receptors by
cytosolic Ca2+.
AB - Biphasic regulation of inositol trisphosphate (IP3)-stimulated Ca2+ mobilization
by cytosolic Ca2+ is believed to contribute to regenerative intracellular Ca2+
signals. Since cells typically express several IP3 receptor isoforms and the
effects of cytosolic Ca2+ are not mediated by a single mechanism, it is important
to resolve the properties of each receptor subtype. Full-length rat types-1 and
3 IP3 receptors were expressed in insect Sf9 cells at levels 10-40-fold higher
than the endogenous receptors. The expressed receptors were glycosylated and
assembled into tetramers, and binding of [3H]IP3 to each subtype was regulated by
cytosolic Ca2+. The effects of increased [Ca2+] on native cerebellar and type-1
receptors expressed in Sf9 cells were indistinguishable. A maximally effective
increase in [Ca2+] reversibly inhibited [3H]IP3 binding by approx. 50% by
decreasing the number of IP3-binding sites (Bmax) without affecting their
affinity for IP3. The effects of Ca2+ on type-3 receptors were more complex:
increasing [Ca2+] first stimulated [3H]IP3 binding by increasing Bmax, and then
inhibited it by causing a substantial decrease in the affinity of the receptor
for IP3. The different effects of Ca2+ on the receptor subtypes were not a
consequence of limitations in the availability of accessory proteins or of
artifactual effects of Ca2+ on membrane structure. We conclude that Ca2+ can
inhibit IP3 binding to types-1 and -3 IP3 receptors although by different
mechanisms, and that IP3 binding to type-3 receptors is stimulated at
intermediate [Ca2+]. A consequence of these differences is that, at resting
cytosolic [Ca2+], type-3 receptors are more sensitive than type-1 receptors to
IP3, but the situation reverses at higher cytosolic [Ca2+]. Such differences may
be important in generating the spatially and temporally complex changes in
cytosolic [Ca2+] evoked by receptors linked to IP3 formation.
PMID- 9396722
TI - Alternative mRNA splicing of 3'-terminal exons generates ascorbate peroxidase
isoenzymes in spinach (Spinacia oleracea) chloroplasts.
AB - We have isolated two cDNA clones encoding spinach (Spinacia oleracea) stromal and
thylakoid-bound ascorbate peroxidase isoenzymes [Ishikawa, Sakai, Yoshimura,
Takeda and Shigeoka (1996) FEBS Lett. 384, 289-293]. The gene (ApxII) encoding
both chloroplastic ascorbate peroxidase isoenzymes was isolated and the
organization of the gene was determined. Alignment between the cDNAs and the gene
for chloroplastic ascorbate peroxidase isoenzymes indicates that both enzymes
arise from a common pre-mRNA by alternative splicing of two 3'-terminal exons.
Genomic Southern-blot analysis supported this finding. The gene spanned nearly
8.5 kbp and contained 13 exons split by 12 introns. The penultimate exon 12
(residues 7376-7530) for the stromal ascorbate peroxidase mRNA consisted of one
codon for Asp365 before the TAA termination codon, and the entire 3'-untranslated
region, including a potential polyadenylation signal (AATAAA). The final exon 13
(residues 7545-7756) for the thylakoid-bound ascorbate peroxidase mRNA consisted
of the corresponding coding sequence of the hydrophobic C-terminal region, the
TGA termination codon and the entire 3'-untranslated region, including a
potential polyadenylation signal (AATATA). Both exons were interrupted by a 14 bp
non-coding sequence. Northern-blot and reverse transcription-PCR analysis showed
that the transcripts for stromal and thylakoid-bound ascorbate peroxidase are
present in spinach leaves.
PMID- 9396723
TI - Mechanism of the antimycin A-mediated enhancement of t-butylhydroperoxide-induced
single-strand breakage in DNA.
AB - Inhibitors of complex III increased the DNA strand scission induced by t
butylhydroperoxide (tB-OOH) and cumene hydroperoxide but did not affect DNA
damage induced by H2O2. The hypothesis that these effects are selectively linked
to inhibition of the electron transport from cytochrome b to cytochrome c1 is
validated by the following observations: (1) two complex III inhibitors,
antimycin A and 2-heptyl-4-hydroxyquinoline N-oxide, enhanced the tB-OOH-induced
DNA cleavage over the same concentration range as that in which inhibition of
oxygen consumption was observed; (2) the complex III inhibitor-mediated
enhancement of tB-OOH-induced DNA damage was abolished by the complex I inhibitor
rotenone or by glucose omission, and (3) the enhancing effects of antimycin A
were not observed in respiration-deficient cells. The mechanism whereby the
complex III inhibitors potentiate DNA cleavage promoted by tB-OOH was
subsequently investigated with intact as well as permeabilized cells. H2O2,
produced at the level of mitochondria via a Ca2+-dependent process, was found to
account for the enhancing effects of antimycin A.
PMID- 9396724
TI - Mammalian cells express two differently localized Bag-1 isoforms generated by
alternative translation initiation.
AB - The Bcl-2 oncoprotein is a key regulator of apoptosis and the Bag-1 protein
interacts with Bcl-2 and cooperates with Bcl-2 to suppress apoptosis. The human
Bag-1 cDNA is essentially identical with a previously described cDNA encoding
RAP46, which interacts with activated steroid hormone receptors. However, there
is considerable confusion over the structure of Bag-1/RAP46 proteins and their
relationship to endogenous Bag-1 proteins. Here we have characterized Bag-1
expression in mammalian cells. We demonstrate that, in addition to the previously
identified 32 kDa murine and 36 kDa human Bag-1 proteins, cells express a second
50 kDa Bag-1 isoform. In some murine cell lines p50 is expressed at the same
level as p32 Bag-1, and p50 and p32 Bag-1 proteins have distinct subcellular
localizations, suggesting that they are functionally distinct. The published
mouse Bag-1 cDNA is partial, and sequencing of additional murine Bag-1 RNA 5'
sequences demonstrated that human and murine Bag-1 cDNAs contain longer open
reading frames than originally suspected. We determined which open reading frames
gave rise to the Bag-1 isoforms in human cells. Surprisingly, translation of
neither protein initiated at the first in-frame methionine, and cells do not
express Bag-1/RAP46 proteins with the previously proposed structures; p50 Bag-1
initiates at an upstream CUG codon, whereas p36 Bag-1 initiates at a downstream
AUG codon. Therefore, cells express two differently localized Bag-1 isoforms
generated by alternative translation initiation, and Bag-1 proteins may play a
dual role in regulating apoptosis and steroid hormone-dependent transcription.
PMID- 9396725
TI - Reconstitution, morphology and crystallization of a fatty acid beta-oxidation
multienzyme complex from Pseudomonas fragi.
AB - The fatty acid beta-oxidation multienzyme complex from Pseudomonas fragi, HDT,
exhibits predominantly the three enzymic activities of 2-enoyl-CoA hydratase (EC
4.2.1.17), 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) and 3-oxoacyl-CoA
thiolase (EC 2.3.1.16). The HDT complex is encoded by the faoAB operon,
consisting of the faoA and faoB genes that encode two individual constituents,
the alpha-subunit and the beta-subunit. We have constructed Escherichia coli
overexpression systems for the faoAB gene product (coexpression of the alpha- and
beta-subunits), the alpha-subunit alone and the beta-subunit alone, and have
purified the three respective products. Gel-filtration analysis revealed that the
faoAB gene product forms a heterotetrameric structure, alpha2beta2, identical
with the native HDT oligomeric state from P. fragi, whereas the alpha-subunit and
beta-subunit individually form dimers. Electron microscopy demonstrated that each
protein morphologically adopts the above oligomeric structures. The HDT complex,
reconstituted in vitro from the isolated alpha- and beta-subunits, exhibits the
three original enzymic activities and yields the same crystal as those from the
native enzyme. CD measurements indicated that the alpha- and beta-dimers hardly
alter their global conformations upon the formation of the HDT complex.
Interestingly, the beta-dimer alone does not exhibit 3-oxoacyl-CoA thiolase
activity, whereas the alpha-dimer alone exhibits both the 2-enoyl-CoA hydratase
and 3-hydroxyacyl-CoA dehydrogenase activities. These results suggest that the
contact between the alpha- and beta-subunits is essential for the thiolase
activity. We have identified several structurally important proteolytic sites
within each subunit, which are protected in the intact heterotetrameric molecule.
These findings allow the possible location of the interface between the two
subunits, which should be crucial for the exhibition of thiolase activity.
PMID- 9396726
TI - Characterization of a Drosophila phosphorylation-dependent nuclear-localization
signal-binding protein.
AB - A 94 kDa nuclear-localization-signal (NLS)-binding protein was purified from
Drosophila embryos. The NLS of the simian-virus-40 T-antigen is specifically
bound by the dephosphorylated form of the protein. After phosphorylation, the
affinity of the protein for the NLS is sharply decreased. In the dephosphorylated
form, p94 (protein of 94 kDa) is the major NLS-binding protein in Drosophila
embryos. Immunoprecipitation confirmed the ATP-dependent phosphorylation of p94,
and co-precipitation of two additional phosphorylated proteins, indicated that
the NLS-binding protein is part of a larger complex in Drosophila embryos. In
agreement with the immunoprecipitation results, cross-linking experiments
demonstrated the interaction of p94 with three additional proteins. These protein
protein interactions were also phosphorylation-dependent.
PMID- 9396727
TI - Haem precursor delta-aminolaevulinic acid induces activation of the cytosolic
iron regulatory protein 1.
AB - Control of cellular iron homoeostasis is performed by iron regulatory protein 1
(IRP1) through post-transcriptional modifications. This protein is sensitive to
intracellular iron availability, being activated at low iron levels and
inactivated at high iron levels, conditions that signal the increased expression
of the transferrin receptor or of ferritin respectively. IRP1 is known to be
activated by some oxidants such as H2O2 and NO. delta-Aminolaevulinic acid (ALA),
previously found to produce reactive oxygen species and a carbon-centred radical,
to release iron from ferritin, and to increase rat liver and brain non-haem iron
and ferritin, was investigated for its effects on IRP1 activity in cultured
hamster pulmonary fibroblasts. We have found that 1-2 mM ALA produced a 2-3-fold
activation of IRP. On incubation with 1-4 mM succinylacetone methyl ester, a
potent ALA dehydratase inhibitor, a 3-4-fold activation of the protein was
observed, accompanied by a 40% increase in the intracellular ALA concentration.
When cells were incubated in the presence of ALA or succinylacetone methyl ester,
N-acetylcysteine inhibited IRP1 activation, suggesting that the observed effect
is mediated by an oxidative process. We surmise that ALA-induced IRP1 activation
might act as a co-sensor of iron homoeostasis.
PMID- 9396728
TI - Covalent complex of microperoxidase with a 21-residue synthetic peptide as a
maquette for low-molecular-mass redox proteins.
AB - Here we report the structural and functional characterization of a covalent
complex (MKP) obtained by cross-linking microperoxidase (Mp), the haem
undecapeptide obtained by the peptic digestion of cytochrome c, with a 21-residue
synthetic peptide (P21) analogous to the S-peptide of the RNase A. The covalent
complex has been prepared by introducing a disulphide bond between Cys-1 of P21
and Lys-13 of Mp, previously modified with a thiol-containing reagent. On
formation of the complex (which is a monomer), the helical content of P21
increases significantly. The results obtained indicate that His-13 of P21 co
ordinates to the sixth co-ordination position of the haem iron, thus leading to
the formation of a complex characterized by an equilibrium between an 'open' and
a 'closed' structure, as confirmed by molecular dynamics simulations. Under
acidic pH conditions, where His-13 of P21 is loosely bound to the haem iron
('open' conformation), MKP displays appreciable, quasi-reversible electrochemical
activity; in contrast, at neutral pH ('closed' conformation) electrochemical
behaviour is negligible, indicating that P21 interferes with the electron
transfer properties typical of Mp. On the whole, MKP is a suitable starting
material for building a miniature haem system, with interesting potential for
application to biosensor technology.
PMID- 9396729
TI - Dependence of the anti-chaperone activity of protein disulphide isomerase on its
chaperone activity.
AB - Protein disulphide isomerase (PDI) shows chaperone and anti-chaperone activities
in assisting refolding of denatured and reduced lysozyme in redox Hepes buffer,
but only chaperone activity in phosphate buffer and redox Hepes buffer containing
0.1 M NaCl. In non-redox Hepes buffer its anti-chaperone activity is very weak.
PDI displays its anti-chaperone activity only for those substrates showing
relatively low aggregation during refolding, and is strongly dependent on
refolding conditions, of which ionic strength appears to be an important factor.
The S-methylated PDI, fully active as a chaperone but devoid of isomerase
activity, by itself shows only anti-chaperone activity, but reinforces rather
than suppresses the chaperone activity of native PDI in the refolding of
lysozyme. A fragment of PDI with the C-terminal peptide-binding sequence removed
and devoid of chaperone activity does not show anti-chaperone activity in
lysozyme refolding. It appears that the anti-chaperone activity of PDI is
dependent on its chaperone activity.
PMID- 9396730
TI - Excess putrescine accumulation inhibits the formation of modified eukaryotic
initiation factor 5A (eIF-5A) and induces apoptosis.
AB - DH23A cells, an alpha-difluoromethylornithine-resistant variant of the parental
hepatoma tissue culture cells, express high levels of stable ornithine
decarboxylase. Aberrantly high expression of ornithine decarboxylase results in a
large accumulation of endogenous putrescine and increased apoptosis in DH23A
cells when alpha-difluoromethylornithine is removed from the culture. Treatment
of DH23A cells with exogenous putrescine in the presence of alpha
difluoromethylornithine mimics the effect of drug removal, suggesting that
putrescine is a causative agent or trigger of apoptosis. Accumulation of excess
intracellular putrescine inhibits the formation of hypusine in vivo, a reaction
that proceeds by the transfer of the butylamine moiety of spermidine to a lysine
residue in eukaryotic initiation factor 5A (eIF-5A). Treatment of DH23A cells
with diaminoheptane, a competitive inhibitor of the post-translational
modification of eIF-5A, causes both the suppression of eIF-5A modification in
vivo and induction of apoptosis. These data support the hypothesis that rapid
degradation of ornithine decarboxylase is a protective mechanism to avoid cell
toxicity from putrescine accumulation. Further, these data suggest that
suppression of modified eIF-5A formation is one mechanism by which cells may be
induced to undergo apoptosis.
PMID- 9396732
TI - Purification of feline lysosomal alpha-mannosidase, determination of its cDNA
sequence and identification of a mutation causing alpha-mannosidosis in Persian
cats.
AB - alpha-Mannosidosis is a lysosomal storage disorder that is caused by the
deficiency of lysosomal alpha-mannosidase. Feline alpha-mannosidosis is a well
characterized animal model used for studying pathological and therapeutic aspects
of lysosomal storage disorders. We here report the purification of feline liver
lysosomal alpha-mannosidase and determination of its cDNA sequence. The active
enzyme consisted of three polypeptides, with molecular masses of 72, 41 and 12
kDa, joined by non-covalent forces. The cDNA sequence of feline lysosomal alpha
mannosidase was determined from reverse transcriptase PCR products obtained from
skin fibroblast mRNA. The deduced amino acid sequence contained the N-terminal
sequences of the 72 and 41 kDa peptides. This indicated that the enzyme is
synthesized as a single-chain precursor with a putative signal peptide of 50
amino acids followed by a polypeptide chain of 957 amino acids, which is cleaved
into the three polypeptides of the mature enzyme. The deduced amino acid sequence
was 81.1 and 83.2% identical with the human and bovine lysosomal alpha
mannosidases sequences respectively. A 4 bp deletion was identified in an alpha
mannosidosis-affected Persian cat by DNA sequencing of reverse transcriptase PCR
products. The deletion resulted in a frame shift from codon 583 and premature
termination at codon 645. No lysosomal alpha-mannosidase activity could be
detected in the liver of this cat. A domestic long-haired cat expressing a milder
alpha-mannosidosis phenotype than the Persian cat had a lysosomal alpha
mannosidase activity of 2% of normal. This domestic long-haired cat did not
possess the 4 bp deletion, proving molecular heterogeneity for feline alpha
mannosidosis.
PMID- 9396731
TI - Mechanism of acylphosphatase inactivation by Woodward's reagent K.
AB - The organ common-type (CT) isoenzyme of acylphosphatase is inactivated by
Woodward's reagent K (WRK) (N-ethyl-5-phenylisoxazolium-3'-sulphonate) at pH6.0.
The inactivation reaction follows apparent pseudo first-order kinetics. The
dependence of the reciprocal of the pseudo first-order kinetic constant (kobs) on
the reciprocal WRK concentration reveals saturation kinetics, suggesting that the
WRK forms a reversible complex with the enzyme before causing inactivation.
Competitive inhibitors, such as inorganic phosphate and ATP, protect the enzyme
from WRK inactivation, suggesting that this reagent acts at or near to the enzyme
active site. The reagent-enzyme adduct, which elicits a strong absorption band
with lambdamax at 346 nm, was separated from unreacted enzyme by reverse phase
HPLC and the modified protein was cleaved with endoproteinase Glu-C to produce
fragments. The HPLC fractionation gave two reagent-labelled peptides (peak 1 and
peak 2) that were analysed by ion-spray MS and sequenced. The former is
VFFRKHTQAE (residues 20-29 of human CT acylphosphatase) and the latter
IFGKVQGVFFRKHTQAE (residues 13-29). MS demonstrated that both peptides are WRK
adducts. A fragment ion with m/z of 1171, which is present in the mass spectrum
of peak 1, has been identified as a WRK adduct of the peptide fragment 20-26. The
lambdamax at 346 nm of WRK adduct suggests that the modified residue is His-25.
Five recombinant enzymes mutated in residues included in the 20-29 polypeptide
stretch have been produced. Analysis of their reactivities with WRK demonstrates
that His-25 is the molecular target of the reagent as its modification causes the
inactivation of the enzyme. Since both His-25-->Gln and His-25-->Phe mutants
maintain high catalytic activity, we suggest that the observed enzyme
inactivation is caused by the reagent (covalently bound to His-25), which shields
the active site.
PMID- 9396733
TI - Human endothelin-converting enzyme (ECE-1): three isoforms with distinct
subcellular localizations.
AB - Endothelin-converting enzyme 1 (ECE-1) is a membrane-bound metalloprotease that
catalyses the conversion of inactive big endothelins into active endothelins. Two
different isoforms (ECE-1a and ECE-1b) have previously been identified for human
ECE-1. In the present study we have cloned a novel human ECE-1 isoform, termed
ECE-1c, and have thus shown for the first time the existence of three distinct
ECE-1 isoforms. The three isoforms differ only in their N-terminal regions and
are derived from a single gene through the use of alternative promoters.
Ribonuclease protection experiments revealed that, although the relative levels
of the three isoform mRNA species vary between human tissues, ECE-1c mRNA is
generally the predominant isoform messenger. Immunofluorescence microscopy
analysis showed distinct subcellular localizations for the three isoforms:
whereas ECE-1a and ECE-1c are localized at the cell surface, ECE-1b was found to
be intracellular and showed significant co-localization with a marker protein for
the trans-Golgi network. We determined that the three isoforms have similar
kinetic rate constants (Km, kcat and Vmax) for the processing of big endothelin 1
and that the big endothelin isoforms 1, 2 and 3 are cleaved with similar relative
velocities of 1.0:0.1:0.1 by the three isoenzymes.
PMID- 9396734
TI - Structure of the mouse leukaemia inhibitory factor receptor gene: regulated
expression of mRNA encoding a soluble receptor isoform from an alternative 5'
untranslated region.
AB - The low-affinity leukaemia inhibitory factor receptor (LIF-R) is a component of
cell-surface receptor complexes for the multifunctional cytokines leukaemia
inhibitory factor, ciliary neurotrophic factor, oncostatin M and cardiotrophin-1.
Both soluble and transmembrane forms of the protein have been described and
several LIF-R mRNAs have been reported previously. In order to determine the
coding potential of LIF-R mRNAs we have isolated and characterized the mouse LIF
R gene. mRNA encoding soluble LIF-R (sLIF-R) is formed by inclusion of an exon in
which polyadenylation signals are provided by a B2 repeat. This exon is located
centrally within the LIF-R gene but is excluded from the transmembrane LIF-R mRNA
by alternative splicing. The transmembrane receptor is encoded by 19 exons
distributed over 38 kb. Two distinct 5' non-coding exons have been identified,
indicating the existence of alternative promoters. One of these is G/C rich and
possesses a consensus initiator sequence as well as potential Sp1 binding sites.
Expression of exon 1 from this promoter occurs in a wide variety of tissues,
whereas expression of the alternative 5' untranslated region (exon 1a) is
normally restricted to liver, the principal source of sLIF-R. During pregnancy
expression of exon 1a becomes detectable also in the uterus. Expression of exon
1a increases dramatically during gestation and is accompanied by a similar
quantitative rise in expression of sLIF-R mRNA. These findings establish that
expression of LIF-R is under complex transcriptional control and indicate that
regulated expression of the soluble cytokine receptor isoform may be due
principally to an increase in the activity of a dedicated promoter.
PMID- 9396735
TI - Selective labelling of cell-surface polyamine-binding proteins on leukaemic and
solid-tumour cell types using a new polyamine photoprobe.
AB - Polyamine transport is an active process which contributes to the regulation and
maintenance of intracellular polyamine pools. Although the biochemical properties
of polyamine transport in mammalian cells have been extensively studied, attempts
to isolate and characterize the actual protein(s) have met with limited success.
As one approach, photoaffinity labelling of cell surface proteins using a
polyamine-conjugated photoprobe may lead to the identification of polyamine
binding proteins (pbps) associated with the transport apparatus and/or other
regulatory responses. In a previous study [Felschow, MacDiarmid, Bardos, Wu,
Woster and Porter (1995) J. Biol. Chem. 270, 28705-28711], we demonstrated that
the photoprobes N4-ASA-spermidine and N1-ASA-norspermine [where the ASA
(azidosalicylamidoethyl) group represents the photoreactive moiety] competed
effectively with polyamines for transport and selectively labelled two major pbps
at 118 and 50 kDa on the surface of murine and human leukaemia cells. In the
present study, a new and more potent polyamine-conjugated photoprobe, N1-ASA
spermine, has been synthesized and used to develop a method based on detergent
lysis for identifying putative cell-surface pbps on solid-tumour cell types.
Transport kinetic assays showed that the new photoprobe competed with spermidine
uptake with an apparent Ki of 1 microM, a value 20-50-fold lower than those of
earlier probes. In L1210 cells, the new probe identified pbp50 and pbp118 thus
reaffirming their identity as pbps. Two new bands were also detected. In A549
human lung adenocarcinoma cells, N1-ASA-spermine identified pbps at 39, 62, 73
and 130 kDa, the latter believed to be a size variant of pbp118. The presence of
pbp130/118 in two very different cell types suggests the generality of the
protein among mammalian cell types as well as its importance for further study.
The high affinity of the photoprobe for the polyamine-transport system strongly
suggests that at least some of the identified pbps may be associated with that
function.
PMID- 9396736
TI - Conformational changes of P-glycoprotein by nucleotide binding.
AB - P-glycoprotein (Pgp) is a membrane protein that transports chemotherapeutic
drugs, causing multidrug resistance in human cancer cells. Pgp is a member of the
ATP-binding cassette superfamily and functions as a transport ATPase. It has been
suggested that the conformation of Pgp changes in the catalytic cycle. In this
study, we tested this hypothesis by using limited proteolysis as a tool to detect
different conformational states trapped by binding of nucleotide ligands and
inhibitors. Pgp has high basal ATPase activity; that is, ATP hydrolysis by Pgp is
not rigidly associated with drug transport. This activity provides a convenient
method for studying the conformational change of Pgp induced by nucleotide
ligands, in the absence of drug substrates which may generate complications due
to their own binding. Inside-out membrane vesicles containing human Pgp were
isolated from multidrug-resistant SKOV/VLB cells and treated with trypsin in the
absence or presence of MgATP, Mg-adenosine 5'-[beta,gamma-imido]triphosphate (Mg
p[NH]ppA) and MgADP. Changes in the proteolysis profile of Pgp owing to binding
of nucleotides were used to indicate the conformational changes in Pgp. We found
that generation of tryptic fragments, including the loop linking transmembrane
(TM) regions TM8 and TM9 of Pgp, were stimulated by the binding of Mg-p[NH]ppA,
MgATP and MgADP, indicating that the Pgp conformation was changed by the binding
of these nucleotides. The effects of nucleotides on Pgp conformation are directly
associated with the binding and/or hydrolysis of these ligands. Four
conformational states of Pgp were stabilized under different conditions with
various ligands and inhibitors. We propose that cycling through these four states
couples the Pgp-mediated MgATP hydrolysis to drug transport.
PMID- 9396737
TI - Glycosylphosphatidylinositols of Plasmodium chabaudi chabaudi: a basis for the
study of malarial glycolipid toxins in a rodent model.
AB - Free and protein-bound glycosylphosphatidylinositols (GPIs) of the blood stages
of the rodent malarial parasite Plasmodium chabaudi chabaudi AS were identified
and characterized. TLC analysis of material extracted by organic solvents from
metabolically labelled parasites revealed a distinct set of glycolipids. These
glycolipids were identified as GPIs by specific chemical and enzymic treatments
and by structural analysis of their glycan and hydrophobic parts. These analyses
revealed that P.c.chabaudi AS synthesizes a set of GPI-biosynthesis intermediates
and two potential GPI-anchor precursors exhibiting the following structures:
ethanolamine-phosphate [(alpha1-2)mannose]mannose (alpha 1-2) mannose (alpha 1-6)
mannose (alpha 1-4) glucosamine - (acyl) inositol-phosphate-diacylglycerol (P.ch.
alpha) and ethanolamine-phosphate - mannose (alpha 1-2) mannose (alpha 1-6)
mannose (alpha 1-4) glucosamine-(acyl)inositol-phosphate-diacylglycerol (P.ch.
beta). One of these GPI-anchor precursors (P.ch. alpha) possesses the same
carbohydrate structure as the GPI membrane anchor of merozoite surface protein-1
from P.c.chabaudi AS.
PMID- 9396738
TI - Effects of adrenaline on triacylglycerol synthesis and turnover in ventricular
myocytes from adult rats.
AB - Ca2+-tolerant myocytes were isolated with endogenous triacylglycerol (TAG) stores
prelabelled with [3H]palmitate and subsequently incubated for a 1h chase period
with [14C]palmitate, 2% albumin and 5mM glucose. Measurements were then made of
[14C]palmitate conversion into TAG and phospholipids, of loss of [3H]TAG, of
glycerol release and of change in the total TAG content. Rates of de novo
synthesis of TAG were calculated by a balance method. With 0. 5mM palmitate
present, 5 microM adrenaline increased de novo synthesis of TAG by 81% and
incorporation of [14C]palmitate into phospholipids by 59%. Significant increases
in these processes with adrenaline were also seen with 0.08, 0.14 and 0.26 mM
palmitate. The beta-agonist isoprenaline had little effect on de novo synthesis
of TAG and had no effect on [14C]palmitate conversion into phospholipids. The
alpha1-agonist phenylephrine mimicked adrenaline in increasing [14C]palmitate
conversion into phospholipids but had no effect on de novo synthesis of TAG.
Adrenaline did not significantly alter the myocyte glycerol 3-phosphate content
but caused a persistent 40% increase in the activity of the form of
glycerolphosphate acyltransferase found predominantly in the sarcoplasmic
reticulum. With 0.5 mM palmitate present, the value [14C]TAG formed -decrease in
[3H]TAG consistently exceeded the enzymically measured change in cell TAG
content. From this it was suggested that the specific radioactivity of [3H]TAG
pool(s) mobilized during the chase period was lower than that of the overall cell
TAG. In the basal state, complete mobilization of TAG measured as glycerol
release was low, but cycling of TAG to diacylglycerol or monoacylglycerol and
back to TAG appeared to be high. With adrenaline present, glycerol release was
increased 5-6-fold but recycling of lower acylglycerols to TAG was abolished.
Glycerol release was inhibited by increasing extracellular palmitate from 0.08 to
0.5 mM. Adrenaline partially over-rode this effect.
PMID- 9396739
TI - Role of membrane-anchored heparin-binding epidermal growth factor-like growth
factor and CD9 on macrophages.
AB - Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) is a potent
mitogen for smooth-muscle cells (SMCs) belonging to the EGF family. We have
previously determined that HB-EGF is expressed in macrophages and SMCs of human
atherosclerotic lesions and that its membrane-anchored precursor, proHB-EGF, also
has a juxtacrine mitogenic activity which is markedly enhanced by CD9, a surface
marker of lymphohaemopoietic cells. Therefore, when both proHB-EGF and CD9 are
expressed on macrophages, they may strongly promote the development of
atherosclerosis. In the present study we have investigated the changes in proHB
EGF and CD9 in THP-1 cells during differentiation into macrophages and by the
addition of oxidized low-density lipoproteins (OxLDL) and assessed juxtacrine
growth activity of THP-1 macrophages for human aortic SMCs. HB-EGF and CD9 at
both the mRNA and the protein level were up-regulated after differentiation into
macrophages, and further expression of HB-EGF was induced by the addition of
OxLDL or lysophosphatidylcholine. Juxtacrine induction by formalin-fixed growth
was suppressed to control levels by an inhibitor of HB-EGF and was partially
decreased by anti-CD9 antibodies. These results suggest that co-expression of
proHB-EGF and CD9 on macrophages plays an important role in the development of
atherosclerosis by a juxtacrine mechanism.
PMID- 9396740
TI - Zeta, a novel class of glutathione transferases in a range of species from plants
to humans.
AB - Sequence alignment and phylogenetic analysis has identified a new subgroup of
glutathione S-transferase (GST)-like proteins from a range of species extending
from plants to humans. This group has been termed the Zeta class. An atomic model
of the N-terminal domain suggests that the members of the Zeta class have a
similar structure to that of other GSTs, binding glutathione in a similar
orientation in the G site. Recombinant human GSTZ1-1 has been expressed in
Escherichia coli and characterized. The protein is a dimer composed of 24.2 kDa
subunits and has minimal glutathione-conjugating activity with ethacrynic acid
and 7-chloro-4-nitrobenz-2-oxa-1, 3-diazole. Although low in comparison with
other GSTs, GSTZ1-1 has glutathione peroxidase activity with t-butyl and cumene
hydroperoxides. The members of the Zeta class have been conserved over a long
evolutionary period, suggesting that they might have a role in the metabolism of
a compound that is common in many living cells.
PMID- 9396741
TI - Temperature-sensitive mRNA degradation is an early event in hepatocyte de
differentiation.
AB - The isolation and culture of metabolically active hepatocytes by proteolytic
digestion of the extracellular matrix of the liver results in the transcriptional
silencing of liver-specific genes encoding cytochromes P-450 (CYP) and albumin
together with an induction of cellular RNase activity. The levels of albumin mRNA
are maintained in cultured hepatocytes at similar levels to that present in the
intact liver for at least 24 h, whereas the major constitutively expressed
CYP2C11 mRNA is rapidly degraded. Hepatocytes heat-shocked at 40 degrees C during
the isolation procedure (which results in an induction of heat-shock protein mRNA
species) blocks the increase in RNase activity and abrogates the loss of CYP2C11
mRNA for at least 4 h. Cycloheximide-dependent inhibition of protein synthesis
blocks the temperature-dependent induction of heat-shock proteins without
affecting the protection afforded to CYP2C11 mRNA, indicating that CYP2C11 mRNA
levels are not directly dependent on heat-shock protein induction and suggesting
that the induction of RNase activity might be responsible for the specific loss
of CYP2C11 mRNA in hepatocytes isolated at 37 degrees C. Differential rates of
degradation of CYP2C11 transcribed in vitro and of albumin mRNA are observed in
the presence of cellular extracts from cultured hepatocytes isolated at 37
degrees C (which have maximally induced levels of cellular RNase activity) but
not in comparable extracts from cultured hepatocytes isolated at 40 degrees C,
supporting the hypothesis that an RNase activity is induced in culture that
specifically degrades CYP2C11 mRNA but not albumin mRNA. These results suggest
that an early event in hepatocyte de-differentiation involves the induction of
RNase activity in addition to transcriptional silencing of liver-specific genes
and that the induced RNase activity demonstrates specificity within liver
specific gene products.
PMID- 9396742
TI - Serratia marcescens chitobiase is a retaining glycosidase utilizing substrate
acetamido group participation.
AB - The stereochemistry of the reaction catalysed by Serratia marcescens chitobiase
was determined by HPLC separation of the anomers of N-acetylglucosamine produced
during the hydrolysis of p-nitrophenyl N-acetyl-beta-d-glucosaminide (PNP
GlcNAc). In the early stages of the reaction, the beta-anomer was found to
prevail, whereas the alpha-anomer dominated at mutarotation equilibrium. This
established that chitobiase hydrolyses glycosidic bonds with overall retention of
the anomeric configuration. Chitobiase-catalysed hydrolysis of PNP-GlcNAc was
competitively inhibited by a series of chito-oligosaccharides (degree of
polymerization 2-5) that were selectively de-N-acetylated at their non-reducing
end. The results are in accord with the participation of the acetamido group at C
2 of the substrate in the catalytic mechanism of chitobiase and related enzymes.
PMID- 9396743
TI - A chromatin-associated kinesin-related protein required for normal mitotic
chromosome segregation in Drosophila.
AB - The tiovivo (tio) gene of Drosophila encodes a kinesin-related protein, KLP38B,
that colocalizes with condensed chromatin during cell division. Wild-type
function of the tio gene product KLP38B is required for normal chromosome
segregation during mitosis. Mitotic cells in tio larval brains displayed circular
mitotic figures, increased ploidy, and abnormal anaphase figures. KLP38B mRNA is
maternally provided and expressed in cells about to undergo division. We propose
that KLP38B, perhaps redundantly with other chromosome-associated microtubule
motor proteins, contributes to interactions between chromosome arms and
microtubules important for establishing bipolar attachment of chromosomes and
assembly of stable bipolar spindles.
PMID- 9396744
TI - CENP-E function at kinetochores is essential for chromosome alignment.
AB - CENP-E is a kinesin-like protein that binds to kinetochores and may provide
functions that are critical for normal chromosome motility during mitosis. To
directly test the in vivo function of CENP-E, we microinjected affinity-purified
antibodies to block the assembly of CENP-E onto kinetochores and then examined
the behavior of these chromosomes. Chromosomes lacking CENP-E at their
kinetochores consistently exhibited two types of defects that blocked their
alignment at the spindle equator. Chromosomes positioned near a pole remained
mono-oriented as they were unable to establish bipolar microtubule connections
with the opposite pole. Chromosomes within the spindle established bipolar
connections that supported oscillations and normal velocities of kinetochore
movement between the poles, but these bipolar connections were defective because
they failed to align the chromosomes into a metaphase plate. Overexpression of a
mutant that lacked the amino-terminal 803 amino acids of CENP-E was found to
saturate limiting binding sites on kinetochores and competitively blocked
endogenous CENP-E from assembling onto kinetochores. Chromosomes saturated with
the truncated CENP-E mutant were never found to be aligned but accumulated at the
poles or were strewn within the spindle as was the case when cells were
microinjected with CENP-E antibodies. As the motor domain was contained within
the portion of CENP-E that was deleted, the chromosomal defect is likely
attributed to the loss of motor function. The combined data show that CENP-E
provides kinetochore functions that are essential for monopolar chromosomes to
establish bipolar connections and for chromosomes with connections to both
spindle poles to align at the spindle equator. Both of these events rely on
activities that are provided by CENP-E's motor domain.
PMID- 9396745
TI - Probing the architecture of a simple kinetochore using DNA-protein crosslinking.
AB - In budding yeast, accurate chromosome segregation requires that one and only one
kinetochore assemble per chromosome. In this paper, we report the use of DNA
protein crosslinking and nondenaturing gel analysis to study the structure of
CBF3, a four-protein complex that binds to the essential CDEIII region of
Saccharomyces cerevisiae centromeres. We find that three subunits of CBF3 are in
direct contact with CDEIII over a region of DNA that spans 80 bp. A highly
asymmetric core complex containing p58(CTF13) p64(CEP3) and p110(NDC10) in direct
contact with DNA forms at the genetically defined center of CDEIII. This core
complex spans approximately 56 bp of CEN3. An extended complex comprising the
core complex and additional DNA-bound p110(NDC10) also forms. It spans
approximately 80 bp of DNA. CBF3 makes sequence-specific and -nonspecific
contacts with DNA. Both contribute significantly to the energy of CBF3-DNA
interaction. Moreover, important sequence-specific contacts are made with bases
that are not conserved among yeast centromeres. These findings provide a
foundation for understanding the organization of the CBF3-centromere complex, a
structure that appears to initiate the formation of microtubule attachment sites
at yeast kinetochores. These results also have implications for understanding
centromere-binding proteins in higher cells.
PMID- 9396746
TI - Export of cellubrevin from the endoplasmic reticulum is controlled by BAP31.
AB - Cellubrevin is a ubiquitously expressed membrane protein that is localized to
endosomes throughout the endocytotic pathway and functions in constitutive
exocytosis. We report that cellubrevin binds with high specificity to BAP31, a
representative of a highly conserved family of integral membrane proteins that
has recently been discovered to be binding proteins of membrane immunoglobulins.
The interaction between BAP31 and cellubrevin is sensitive to high ionic strength
and appears to require the transmembrane regions of both proteins. No other
proteins of liver membrane extracts copurified with BAP31 on immobilized
recombinant cellubrevin, demonstrating that the interaction is specific.
Synaptobrevin I bound to BAP31 with comparable affinity, whereas only weak
binding was detectable with synaptobrevin II. Furthermore, a fraction of BAP31
and cellubrevin was complexed when each of them was quantitatively
immunoprecipitated from detergent extracts of fibroblasts (BHK 21 cells). During
purification of clathrin-coated vesicles or early endosomes, BAP31 did not
cofractionate with cellubrevin. Rather, the protein was enriched in ER-containing
fractions. When BHK cells were analyzed by immunocytochemistry, BAP31 did not
overlap with cellubrevin, but rather colocalized with resident proteins of the
ER. In addition, immunoreactive vesicles were clustered in a paranuclear region
close to the microtubule organizing center, but different from the Golgi
apparatus. When microtubules were depolymerized with nocodazole, this
accumulation disappeared and BAP31 was confined to the ER. Truncation of the
cytoplasmic tail of BAP31 prevented export of cellubrevin, but not of the
transferrin receptor from the ER. We conclude that BAP31 represents a novel class
of sorting proteins that controls anterograde transport of certain membrane
proteins from the ER to the Golgi complex.
PMID- 9396747
TI - Ceramide accumulation uncovers a cycling pathway for the cis-Golgi network
marker, infectious bronchitis virus M protein.
AB - The M glycoprotein from the avian coronavirus, infectious bronchitis virus (IBV),
contains information for localization to the cis-Golgi network in its first
transmembrane domain. We hypothesize that localization to the Golgi complex may
depend in part on specific interactions between protein transmembrane domains and
membrane lipids. Because the site of sphingolipid synthesis overlaps the
localization of IBV M, we asked whether perturbation of sphingolipids affected
localization of IBV M. Short-term treatment with two inhibitors of sphingolipid
synthesis had no effect on localization of IBV M or other Golgi markers. Thus,
ongoing synthesis of these lipids was not required for proper localization.
Surprisingly, a third inhibitor, d,l-threo-1-phenyl-2-decanoylamino-3-morpholino-
1-propanol (PDMP), shifted the steady-state distribution of IBV M from the Golgi
complex to the ER. This effect was rapid and reversible and was also observed for
ERGIC-53 but not for Golgi stack proteins. At the concentration of PDMP used,
conversion of ceramide into both glucosylceramide and sphingomyelin was
inhibited. Pretreatment with upstream inhibitors partially reversed the effects
of PDMP, suggesting that ceramide accumulation mediates the PDMP-induced
alterations. Indeed, an increase in cellular ceramide was measured in PDMP
treated cells. We propose that IBV M is at least in part localized by retrieval
mechanisms. Further, ceramide accumulation reveals this cycle by upsetting the
balance of anterograde and retrograde traffic and/ or disrupting retention by
altering bilayer dynamics.
PMID- 9396748
TI - Peroxisomal targeting, import, and assembly of alcohol oxidase in Pichia
pastoris.
AB - Alcohol oxidase (AOX), the first enzyme in the yeast methanol utilization pathway
is a homooctameric peroxisomal matrix protein. In peroxisome biogenesis-defective
(pex) mutants of the yeast Pichia pastoris, AOX fails to assemble into active
octamers and instead forms inactive cytoplasmic aggregates. The apparent
inability of AOX to assemble in the cytoplasm contrasts with other peroxisomal
proteins that are able to oligomerize before import. To further investigate the
import of AOX, we first identified its peroxisomal targeting signal (PTS). We
found that sequences essential for targeting AOX are primarily located within the
four COOH-terminal amino acids of the protein leucine-alanine-arginine
phenylalanine COOH (LARF). To examine whether AOX can oligomerize before import,
we coexpressed AOX without its PTS along with wild-type AOX and determined
whether the mutant AOX could be coimported into peroxisomes. To identify the
mutant form of AOX, the COOH-terminal LARF sequence of the protein was replaced
with a hemagglutinin epitope tag (AOX-HA). Coexpression of AOX-HA with wild-type
AOX (AOX-WT) did not result in an increase in the proportion of AOX-HA present in
octameric active AOX, suggesting that newly synthesized AOX-HA cannot oligomerize
with AOX-WT in the cytoplasm. Thus, AOX cannot initiate oligomerization in the
cytoplasm, but must first be targeted to the organelle before assembly begins.
PMID- 9396750
TI - Compartmentalized IgE receptor-mediated signal transduction in living cells.
AB - Several receptor-mediated signal transduction pathways, including EGF and IgE
receptor pathways, have been proposed to be spatially restricted to plasma
membrane microdomains. However, the experimental evidence for signaling events in
these microdomains is largely based on biochemical fractionation and
immunocytochemical studies and only little is known about their spatial dynamics
in living cells. Here we constructed green fluorescent protein-tagged SH2 domains
to investigate where and when IgE receptor (FcepsilonRI)-mediated tyrosine
phosphorylation occurs in living tumor mast cells. Strikingly, within minutes
after antigen addition, tandem SH2 domains from Syk or PLC-gamma1 translocated
from a uniform cytosolic distribution to punctuate plasma membrane microdomains.
Colocalization experiments showed that the microdomains where tyrosine
phosphorylation occurred were indistinguishable from those stained by cholera
toxin B, a marker for glycosphingolipids. Competitive binding studies with
coelectroporated unlabeled Syk, PLC-gamma1, and other SH2 domains selectively
suppressed the induction of IgE receptor-mediated calcium signals as well as the
binding of the fluorescent SH2 domains. This supports the hypothesis that PLC
gamma1 and Syk SH2 domains selectively bind to Syk and IgE receptors,
respectively. Unlike the predicted prelocalization of EGF receptors to caveolae
microdomains, fluorescently labeled IgE receptors were found to be uniformly
distributed in the plasma membrane of unstimulated cells and only transiently
translocated to glycosphingolipid rich microdomains after antigen addition. Thus,
these in vivo studies support a plasma membrane signaling mechanism by which IgE
receptors transiently associate with microdomains and induce the spatially
restricted activation of Syk and PLC-gamma1.
PMID- 9396749
TI - Distinct intracellular compartments involved in invariant chain degradation and
antigenic peptide loading of major histocompatibility complex (MHC) class II
molecules.
AB - Major histocompatibility complex (MHC) class II molecules are transported to
intracellular MHC class II compartments via a transient association with the
invariant chain (Ii). After removal of the invariant chain, peptides can be
loaded onto class II molecules, a process catalyzed by human leukocyte antigen-DM
(HLA-DM) molecules. Here we show that MHC class II compartments consist of two
physically and functionally distinct organelles. Newly synthesized MHC class
II/Ii complexes were targeted to endocytic organelles lacking HLA-DM molecules,
where Ii degradation occurred. From these organelles, class II molecules were
transported to a distinct organelle containing HLA-DM, in which peptides were
loaded onto class II molecules. This latter organelle was not directly accessible
via fluid phase endocytosis, suggesting that it is not part of the endosomal
pathway. Uptake via antigen-specific membrane immunoglobulin resulted however in
small amounts of antigen in the HLA-DM positive organelles. From this peptide
loading compartment, class II-peptide complexes were transported to the plasma
membrane, in part after transit through endocytic organelles. The existence of
two separate compartments, one involved in Ii removal and the other functioning
in HLA-DM-dependent peptide loading of class II molecules, may contribute to the
efficiency of antigen presentation by the selective recruitment of peptide
receptive MHC class II molecules and HLA-DM to the same subcellular location.
PMID- 9396751
TI - Activation of a retroviral membrane fusion protein: soluble receptor-induced
liposome binding of the ALSV envelope glycoprotein.
AB - It is not known how membrane fusion proteins that function at neutral pH, for
example the human immunodeficiency virus envelope (Env) glycoprotein and
intracellular fusion machines, are activated for target bilayer binding. We have
addressed this question using a soluble oligomeric form of an avian retroviral
Env glycoprotein (API) and soluble forms of its receptor. Binding of soluble
receptor to API induces API to bind to liposomes composed of phosphatidylcholine
and cholesterol at neutral pH. Liposome binding only occurs at fusion permissive
temperatures (T > 20 degrees C), is complete between 2 to 5 min at 37 degrees C,
and is stable to high salt, carbonate, and urea. Liposome binding is mediated by
the ectodomain of the transmembrane subunit of API, and a mutant with a Val to
Glu substitution in the Env fusion peptide (located in the ectodomain of the
transmembrane subunit) shows significantly reduced liposome binding. Moreover,
under conditions of equivalent binding to API, a mutant receptor that does not
support infection (Zingler, K., and J.A.T. Young. 1996. J. Virol. 70:7510-7516)
does not induce significant liposome binding. Our results indicate that a highly
specific interaction between an avian retroviral Env and its receptor activates
the retroviral glycoprotein for target bilayer binding at neutral pH in much the
same way as low pH activates the influenza hemagglutinin. Our findings are
discussed in terms of the mechanisms of viral and cellular fusion proteins that
function at neutral pH.
PMID- 9396752
TI - Direct visualization of the translocation of the gamma-subspecies of protein
kinase C in living cells using fusion proteins with green fluorescent protein.
AB - We expressed the gamma-subspecies of protein kinase C (gamma-PKC) fused with
green fluorescent protein (GFP) in various cell lines and observed the movement
of this fusion protein in living cells under a confocal laser scanning
fluorescent microscope. gamma-PKC-GFP fusion protein had enzymological properties
very similar to that of native gamma-PKC. The fluorescence of gamma-PKC- GFP was
observed throughout the cytoplasm in transiently transfected COS-7 cells.
Stimulation by an active phorbol ester (12-O-tetradecanoylphorbol 13-acetate
[TPA]) but not by an inactive phorbol ester (4alpha-phorbol 12, 13-didecanoate)
induced a significant translocation of gamma-PKC-GFP from cytoplasm to the plasma
membrane. A23187, a Ca2+ ionophore, induced a more rapid translocation of gamma
PKC-GFP than TPA. The A23187-induced translocation was abolished by elimination
of extracellular and intracellular Ca2+. TPA- induced translocation of gamma-PKC
GFP was unidirected, while Ca2+ ionophore-induced translocation was reversible;
that is, gamma-PKC-GFP translocated to the membrane returned to the cytosol and
finally accumulated as patchy dots on the plasma membrane. To investigate the
significance of C1 and C2 domains of gamma-PKC in translocation, we expressed
mutant gamma-PKC-GFP fusion protein in which the two cysteine rich regions in the
C1 region were disrupted (designated as BS 238) or the C2 region was deleted (BS
239). BS 238 mutant was translocated by Ca2+ ionophore but not by TPA. In
contrast, BS 239 mutant was translocated by TPA but not by Ca2+ ionophore. To
examine the translocation of gamma-PKC-GFP under physiological conditions, we
expressed it in NG-108 cells, N-methyl-D-aspartate (NMDA) receptor-transfected
COS-7 cells, or CHO cells expressing metabotropic glutamate receptor 1
(CHO/mGluR1 cells). In NG-108 cells , K+ depolarization induced rapid
translocation of gamma-PKC-GFP. In NMDA receptor-transfected COS-7 cells,
application of NMDA plus glycine also translocated gamma-PKC-GFP. Furthermore,
rapid translocation and sequential retranslocation of gamma-PKC-GFP were observed
in CHO/ mGluR1 cells on stimulation with the receptor. Neither cytochalasin D nor
colchicine affected the translocation of gamma-PKC-GFP, indicating that
translocation of gamma-PKC was independent of actin and microtubule. gamma-PKC
GFP fusion protein is a useful tool for investigating the molecular mechanism of
gamma-PKC translocation and the role of gamma-PKC in the central nervous system.
PMID- 9396754
TI - The Arabidopsis KNOLLE protein is a cytokinesis-specific syntaxin.
AB - In higher plant cytokinesis, plasma membrane and cell wall originate by vesicle
fusion in the plane of cell division. The Arabidopsis KNOLLE gene, which is
required for cytokinesis, encodes a protein related to vesicle-docking syntaxins.
We have raised specific rabbit antiserum against purified recombinant KNOLLE
protein to show biochemically and by immunoelectron microscopy that KNOLLE
protein is membrane associated. Using immunofluorescence microscopy, KNOLLE
protein was found to be specifically expressed during mitosis and, unlike the
plasma membrane H+-ATPase, to localize to the plane of division during
cytokinesis. Arabidopsis dynamin-like protein ADL1 accumulates at the plane of
cell plate formation in knolle mutant cells as in wild-type cells, suggesting
that cytokinetic vesicle traffic is not affected. Furthermore, electron
microscopic analysis indicates that vesicle fusion is impaired. KNOLLE protein
was detected in mitotically dividing cells of various parts of the developing
plant, including seedling root, inflorescence meristem, floral meristems and
ovules, and the cellularizing endosperm, but not during cytokinesis after the
male second meiotic division. Thus, KNOLLE is the first syntaxin-like protein
that appears to be involved specifically in cytokinetic vesicle fusion.
PMID- 9396753
TI - Sarcomeric gene expression and contractility in myofibroblasts.
AB - Myofibroblasts are unusual cells that share morphological and functional features
of muscle and nonmuscle cells. Such cells are thought to control liver blood flow
and kidney glomerular filtration rate by having unique contractile properties. To
determine how these cells achieve their contractile properties and their
resemblance to muscle cells, we have characterized two myofibroblast cell lines.
Here, we demonstrate that myofibroblast cell lines from kidney mesangial cells
(BHK) and liver stellate cells activate extensive programs of muscle gene
expression including a wide variety of muscle structural proteins. In BHK cells,
six different striated myosin heavy chain isoforms and many thin filament
proteins, including troponin T and tropomyosin are expressed. Liver stellate
cells express a limited subset of the muscle thick filament proteins expressed in
BHK cells. Although these cells are mitotically active and do not morphologically
differentiate into myotubes, we show that MyoD and myogenin are expressed and
functional in both cell types. Finally, these cells contract in response to
endothelin-1 (ET-1); and we show that ET-1 treatment increases the expression of
sarcomeric myosin.
PMID- 9396755
TI - The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of
the septate-like paranodal junctions that assemble during myelination.
AB - We have investigated the potential role of contactin and contactin-associated
protein (Caspr) in the axonal-glial interactions of myelination. In the nervous
system, contactin is expressed by neurons, oligodendrocytes, and their
progenitors, but not by Schwann cells. Expression of Caspr, a homologue of
Neurexin IV, is restricted to neurons. Both contactin and Caspr are uniformly
expressed at high levels on the surface of unensheathed neurites and are
downregulated during myelination in vitro and in vivo. Contactin is downregulated
along the entire myelinated nerve fiber. In contrast, Caspr expression initially
remains elevated along segments of neurites associated with nascent myelin
sheaths. With further maturation, Caspr is downregulated in the internode and
becomes strikingly concentrated in the paranodal regions of the axon, suggesting
that it redistributes from the internode to these sites. Caspr expression is
similarly restricted to the paranodes of mature myelinated axons in the
peripheral and central nervous systems; it is more diffusely and persistently
expressed in gray matter and on unmyelinated axons. Immunoelectron microscopy
demonstrated that Caspr is localized to the septate-like junctions that form
between axons and the paranodal loops of myelinating cells. Caspr is poorly
extracted by nonionic detergents, suggesting that it is associated with the axon
cytoskeleton at these junctions. These results indicate that contactin and Caspr
function independently during myelination and that their expression is regulated
by glial ensheathment. They strongly implicate Caspr as a major transmembrane
component of the paranodal junctions, whose molecular composition has previously
been unknown, and suggest its role in the reciprocal signaling between axons and
glia.
PMID- 9396756
TI - Distribution and function of laminins in the neuromuscular system of developing,
adult, and mutant mice.
AB - Laminins, heterotrimers of alpha, beta, and gamma chains, are prominent
constituents of basal laminae (BLs) throughout the body. Previous studies have
shown that laminins affect both myogenesis and synaptogenesis in skeletal muscle.
Here we have studied the distribution of the 10 known laminin chains in muscle
and peripheral nerve, and assayed the ability of several heterotrimers to affect
the outgrowth of motor axons. We show that cultured muscle cells express four
different alpha chains (alpha1, alpha2, alpha4, and alpha5), and that developing
muscles incorporate all four into BLs. The portion of the muscle's BL that
occupies the synaptic cleft contains at least three alpha chains and two beta
chains, but each is regulated differently. Initially, the alpha2, alpha4, alpha5,
and beta1 chains are present both extrasynaptically and synaptically, whereas
beta2 is restricted to synaptic BL from its first appearance. As development
proceeds, alpha2 remains broadly distributed, whereas alpha4 and alpha5 are lost
from extrasynaptic BL and beta1 from synaptic BL. In adults, alpha4 is restricted
to primary synaptic clefts whereas alpha5 is present in both primary and
secondary clefts. Thus, adult extrasynaptic BL is rich in laminin 2
(alpha2beta1gamma1), and synaptic BL contains laminins 4 (alpha2beta2gamma1), 9
(alpha4beta2gamma1), and 11 (alpha5beta2gamma1). Likewise, in cultured muscle
cells, alpha2 and beta1 are broadly distributed but alpha5 and beta2 are
concentrated at acetylcholine receptor-rich "hot spots," even in the absence of
nerves. The endoneurial and perineurial BLs of peripheral nerve also contain
distinct laminin chains: alpha2, beta1, gamma1, and alpha4, alpha5, beta2,
gamma1, respectively. Mutation of the laminin alpha2 or beta2 genes in mice not
only leads to loss of the respective chains in both nerve and muscle, but also to
coordinate loss and compensatory upregulation of other chains. Notably, loss of
beta2 from synaptic BL in beta2(-/-) "knockout" mice is accompanied by loss of
alpha5, and decreased levels of alpha2 in dystrophic alpha2(dy/dy) mice are
accompanied by compensatory retention of alpha4. Finally, we show that motor
axons respond in distinct ways to different laminin heterotrimers: they grow
freely between laminin 1 (alpha1beta1gamma1) and laminin 2, fail to cross from
laminin 4 to laminin 1, and stop upon contacting laminin 11. The ability of
laminin 11 to serve as a stop signal for growing axons explains, in part, axonal
behaviors observed at developing and regenerating synapses in vivo.
PMID- 9396757
TI - Ligation of major histocompatability complex (MHC) class I molecules on human T
cells induces cell death through PI-3 kinase-induced c-Jun NH2-terminal kinase
activity: a novel apoptotic pathway distinct from Fas-induced apoptosis.
AB - Ligation of major histocompatability complex class I (MHC-I) molecules expressed
on T cells leads to both growth arrest and apoptosis. The aim of the current
study was to investigate the intracellular signal pathways that mediate these
effects. MHC-I ligation of human Jurkat T cells induced a morphologically
distinct form of apoptosis within 6 h. A specific caspase inhibitor, which
inhibited Fas-induced apoptosis, did not affect apoptosis induced by MHC-I
ligation. Furthermore, MHC-I-induced apoptosis did not involve cleavage and
activation of the poly(ADP- ribose) polymerase (PARP) endonuclease or degradation
of genomic DNA into the typical fragmentation ladder, both prominent events of
Fas-induced apoptosis. These results suggest that MHC-I ligation of Jurkat T
cells induce apoptosis through a signal pathway distinct from the Fas molecule.
In our search for other signal pathways leading to apoptosis, we found that the
regulatory 85-kD subunit of the phosphoinositide-3 kinase (PI-3) kinase was
tyrosine phosphorylated after ligation of MHC-I and the PI-3 kinase inhibitor
wortmannin selectively blocked MHC-I-, but not Fas-induced, apoptosis. As the c
Jun NH2-terminal kinase (JNK) can be activated by PI-3 kinase activity, and has
been shown to be involved in apoptosis of lymphocytes, we examined JNK activation
after MHC-I ligation. Strong JNK activity was observed after MHC-I ligation and
the activity was completely blocked by wortmannin. Inhibition of JNK activity, by
transfecting cells with a dominant-negative JNKK- MKK4 construct, led to a strong
reduction of apoptosis after MHC-I ligation. These results suggest a critical
engagement of PI-3 kinase-induced JNK activity in apoptosis induced by MHC-I
ligation.
PMID- 9396758
TI - Thyroid hormone induces apoptosis in primary cell cultures of tadpole intestine:
cell type specificity and effects of extracellular matrix.
AB - Thyroid hormone (T3 or 3,5,3'-triiodothyronine) plays a causative role during
amphibian metamorphosis. To investigate how T3 induces some cells to die and
others to proliferate and differentiate during this process, we have chosen the
model system of intestinal remodeling, which involves apoptotic degeneration of
larval epithelial cells and proliferation and differentiation of other cells,
such as the fibroblasts and adult epithelial cells, to form the adult intestine.
We have established in vitro culture conditions for intestinal epithelial cells
and fibroblasts. With this system, we show that T3 can enhance the proliferation
of both cell types. However, T3 also concurrently induces larval epithelial
apoptosis, which can be inhibited by the extracellular matrix (ECM). Our studies
with known inhibitors of mammalian cell death reveal both similarities and
differences between amphibian and mammalian cell death. These, together with gene
expression analysis, reveal that T3 appears to simultaneously induce different
pathways that lead to specific gene regulation, proliferation, and apoptotic
degeneration of the epithelial cells. Thus, our data provide an important
molecular and cellular basis for the differential responses of different cell
types to the endogenous T3 during metamorphosis and support a role of ECM during
frog metamorphosis.
PMID- 9396759
TI - Embryonic expression of the putative gamma subunit of the sodium pump is required
for acquisition of fluid transport capacity during mouse blastocyst development.
AB - The sodium/potassium pump, Na+,K+-ATPase, is generally understood to function as
a heterodimer of two subunits, a catalytic alpha subunit and a noncatalytic,
glycosylated beta subunit. Recently, a putative third subunit, the gamma subunit,
was cloned. This small protein (6.5 kD) coimmunoprecipitates with the alpha and
beta subunits and is closely associated with the ouabain binding site on the
holoenzyme, but its function is unknown. We have investigated the expression of
the gamma subunit in preimplantation mouse development, where Na+, K+-ATPase
plays a critical role as the driving force for blastocoel formation (cavitation).
Using reverse transcriptase-polymerase chain reaction, we demonstrated that the
gamma subunit mRNA accumulates continuously from the eight-cell stage onward and
that it cosediments with polyribosomes from its time of first appearance.
Confocal immunofluorescence microscopy revealed that the gamma subunit itself
accumulates and is localized at the blastomere surfaces up to the blastocyst
stage. In contrast with the alpha and beta subunits, the gamma subunit is not
concentrated in the basolateral surface of the polarized trophectoderm layer, but
is strongly expressed at the apical surface as well. When embryos were treated
with antisense oligodeoxynucleotide complementary to the gamma subunit mRNA,
ouabain-sensitive K+ transport (as indicated by 86Rb+ uptake) was reduced and
cavitation delayed. However, Na+, K+-ATPase enzymatic activity was unaffected as
determined by a direct phosphorylation assay ("back door" phosphorylation)
applied to plasma membrane preparations. These results indicate that the gamma
subunit, although not an integral component of Na+,K+-ATPase, is an important
determinant of active cation transport and that, as such, its embryonic
expression is essential for blastocoel formation in the mouse.
PMID- 9396760
TI - Key role of the Cdx2 homeobox gene in extracellular matrix-mediated intestinal
cell differentiation.
AB - To explore the role of homeobox genes in the intestine, the human colon
adenocarcinoma cell line Caco2-TC7 has been stably transfected with plasmids
synthesizing Cdx1 and Cdx2 sense and antisense RNAs. Cdx1 overexpression or
inhibition by antisense RNA does not markedly modify the cell differentiation
markers analyzed in this study. In contrast, Cdx2 overexpression stimulates two
typical markers of enterocytic differentiation: sucrase-isomaltase and lactase.
Cells in which the endogenous expression of Cdx2 is reduced by antisense RNA
attach poorly to the substratum. Conversely, Cdx2 overexpression modifies the
expression of molecules involved in cell-cell and cell-substratum interactions
and in transduction process: indeed, E-cadherin, integrin-beta4 subunit, laminin
gamma2 chain, hemidesmosomal protein, APC, and alpha-actinin are upregulated.
Interestingly, most of these molecules are preferentially expressed in vivo in
the differentiated villi enterocytes rather than in crypt cells. Cdx2
overexpression also results in the stimulation of HoxA-9 mRNA expression, an
homeobox gene selectively expressed in the colon. In contrast, Cdx2
overexpressing cells display a decline of Cdx1 mRNA, which is mostly found in
vivo in crypt cells. When implanted in nude mice, Cdx2-overexpressing cells
produce larger tumors than control cells, and form glandular and villus-like
structures. Laminin-1 is known to stimulate intestinal cell differentiation in
vitro. In the present study, we demonstrate that the differentiating effect of
laminin-1 coatings on Caco2-TC7 cells is accompanied by an upregulation of Cdx2.
To further document this observation, we analyzed a series of Caco2 clones in
which the production of laminin-alpha1 chain is differentially inhibited by
antisense RNA. We found a positive correlation between the level of Cdx2
expression, that of endogenous laminin-alpha1 chain mRNA and that of sucrase
isomaltase expression in these cell lines. Taken together, these results suggest
(a) that Cdx1 and Cdx2 homeobox genes play distinct roles in the intestinal
epithelium, (b) that Cdx2 provokes pleiotropic effects triggering cells towards
the phenotype of differentiated villus enterocytes, and (c) that Cdx2 expression
is modulated by basement membrane components. Hence, we conclude that Cdx2 plays
a key role in the extracellular matrix-mediated intestinal cell differentiation.
PMID- 9396761
TI - A single immunoglobulin-like domain of the human neural cell adhesion molecule L1
supports adhesion by multiple vascular and platelet integrins.
AB - The neural cell adhesion molecule L1 has been shown to function as a homophilic
ligand in a variety of dynamic neurological processes. Here we demonstrate that
the sixth immunoglobulin-like domain of human L1 (L1-Ig6) can function as a
heterophilic ligand for multiple members of the integrin superfamily including
alphavbeta3, alphavbeta1, alpha5beta1, and alphaIIbbeta3. The interaction between
L1-Ig6 and alphaIIbbeta3 was found to support the rapid attachment of activated
human platelets, whereas a corresponding interaction with alphavbeta3 and
alphavbeta1 supported the adhesion of umbilical vein endothelial cells. Mutation
of the single Arg-Gly-Asp (RGD) motif in human L1-Ig6 effectively abrogated
binding by the aforementioned integrins. A L1 peptide containing this RGD motif
and corresponding flanking amino acids (PSITWRGDGRDLQEL) effectively blocked L1
integrin interactions and, as an immobilized ligand, supported adhesion via
alphavbeta3, alphavbeta1, alpha5beta1, and alphaIIbbeta3. Whereas beta3 integrin
binding to L1-Ig6 was evident in the presence of either Ca2+, Mg2+, or Mn2+, a
corresponding interaction with the beta1 integrins was only observed in the
presence of Mn2+. Furthermore, such Mn2+-dependent binding by alpha5beta1 and
alphavbeta1 was significantly inhibited by exogenous Ca2+. Our findings suggest
that physiological levels of calcium will impose a hierarchy of integrin binding
to L1 such that alphavbeta3 or active alphaIIbbeta3 > alphavbeta1 > alpha5beta1.
Given that L1 can interact with multiple vascular or platelet integrins it is
significant that we also present evidence for de novo L1 expression on blood
vessels associated with certain neoplastic or inflammatory diseases. Together
these findings suggest an expanded and novel role for L1 in vascular and
thrombogenic processes.
PMID- 9396762
TI - Muscle beta1D integrin reinforces the cytoskeleton-matrix link: modulation of
integrin adhesive function by alternative splicing.
AB - Expression of muscle-specific beta1D integrin with an alternatively spliced
cytoplasmic domain in CHO and GD25, beta1 integrin-minus cells leads to their
phenotypic conversion. beta1D-transfected nonmuscle cells display rounded
morphology, lack of pseudopodial activity, retarded spreading, reduced migration,
and significantly enhanced contractility compared with their beta1A-expressing
counterparts. The transfected beta1D is targeted to focal adhesions and
efficiently displaces the endogenous beta1A and alphavbeta3 integrins from the
sites of cell-matrix contact. This displacement is observed on several types of
extracellular matrix substrata and leads to elevated stability of focal adhesions
in beta1D transfectants. Whereas a significant part of cellular beta1A integrin
is extractable in digitonin, the majority of the transfected beta1D is digitonin
insoluble and is strongly associated with the detergent-insoluble cytoskeleton.
Increased interaction of beta1D integrin with the actin cytoskeleton is
consistent with and might be mediated by its enhanced binding to talin. In
contrast, beta1A interacts more strongly with alpha-actinin, than beta1D. Inside
out driven activation of the beta1D ectodomain increases ligand binding and
fibronectin matrix assembly by beta1D transfectants. Phenotypic effects of beta1D
integrin expression in nonmuscle cells are due to its enhanced interactions with
both cytoskeletal and extracellular ligands. They parallel the transitions that
muscle cells undergo during differentiation. Modulation of beta1 integrin
adhesive function by alternative splicing serves as a physiological mechanism
reinforcing the cytoskeleton- matrix link in muscle cells. This reflects the
major role for beta1D integrin in muscle, where extremely stable association is
required for contraction.
PMID- 9396763
TI - The thrombopoietin receptor can mediate proliferation without activation of the
Jak-STAT pathway.
AB - Cytokine receptors of the hematopoietic receptor superfamily lack intrinsic
tyrosine kinase domains for the intracellular transmission of their signals.
Instead all members of this family associate with Jak family nonreceptor tyrosine
kinases. Upon ligand stimulation of the receptors, Jaks are activated to
phosphorylate target substrates. These include STAT (signal transducers and
activators of transcription) proteins, which after phosphorylation translocate to
the nucleus and modulate gene expression. The exact role of the Jak-STAT pathway
in conveying growth and differentiation signals remains unclear. Here we describe
a deletion mutant of the thrombopoietin receptor (c-mpl) that has completely lost
the capacity to activate Jaks and STATs but retains its ability to induce
proliferation. This mutant still mediates TPO-induced phosphorylation of Shc,
Vav, mitogen-activated protein kinase (MAPK) and Raf-1 as well as induction of c
fos and c-myc, although at somewhat reduced levels. Furthermore, we show that
both wild-type and mutant receptors activate phosphatidylinositol (PI) 3-kinase
upon thrombopoietin stimulation and that thrombopoietin-induced proliferation is
inhibited in the presence of the PI 3-kinase inhibitor wortmannin. These results
demonstrate that the Jak-STAT pathway is dispensable for the generation of
mitogenic signals by a cytokine receptor.
PMID- 9396764
TI - Association with FcRgamma is essential for activation signal through NKR-P1
(CD161) in natural killer (NK) cells and NK1.1+ T cells.
AB - Natural killer (NK) cells exhibit cytotoxicity against variety of tumor cells and
virus-infected cells without prior sensitization and represent unique lymphocytes
involved in primary host defense. NKR-P1 is thought to be one of NK receptors
mediating activation signals because cross-linking of NKR-P1 activates NK cells
to exhibit cytotoxicity and IFN-gamma production. However, molecular mechanism of
NK cell activation via NKR-P1 is not well elucidated. In this study, we analyzed
the cell surface complex associated with NKR-P1 on NK cells and found that NKR-P1
associates with the FcRgamma chain which is an essential component of Fc
receptors for IgG and IgE. The association between FcRgamma and NKR-P1 is
independent of Fc receptor complexes. Furthermore, NK cells from FcRgamma
deficient mice did not show cytotoxicity or IFN-gamma production upon NKR-P1
cross-linking. Similarly, NK1.1+ T cells from FcRgamma-deficient mice did not
produce IFN-gamma upon NKR-P1 crosslinking. These findings demonstrate that the
FcRgamma chain plays an important role in activation of NK cells via the NKR-P1
molecule.
PMID- 9396765
TI - Functional role for Syk tyrosine kinase in natural killer cell-mediated natural
cytotoxicity.
AB - Natural killer (NK) cells are named based on their natural cytotoxic activity
against a variety of target cells. However, the mechanisms by which sensitive
targets activate killing have been difficult to study due to the lack of a
prototypic NK cell triggering receptor. Pharmacologic evidence has implicated
protein tyrosine kinases (PTKs) in natural killing; however, Lck-deficient, Fyn
deficient, and ZAP-70-deficient mice do not exhibit defects in natural killing
despite demonstrable defects in T cell function. This discrepancy implies the
involvement of other tyrosine kinases. Here, using combined biochemical,
pharmacologic, and genetic approaches, we demonstrate a central role for the PTK
Syk in natural cytotoxicity. Biochemical analyses indicate that Syk is tyrosine
phosphorylated after stimulation with a panel of NK-sensitive target cells.
Pharmacologic exposure to piceatannol, a known Syk family kinase inhibitor,
inhibits natural cytotoxicity. In addition, gene transfer of dominant-negative
forms of Syk to NK cells inhibits natural cytotoxicity. Furthermore, sensitive
targets that are rendered NK-resistant by major histocompatibility complex (MHC)
class I transfection no longer activate Syk. These data suggest that Syk
activation is an early and requisite signaling event in the development of
natural cytotoxicity directed against a variety of cellular targets.
PMID- 9396766
TI - The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that
activates apoptosis.
AB - Nip3 (nineteen kD interacting protein-3) is an E1B 19K and Bcl-2 binding protein
of unknown function. Nip3 is detected as both a 60- and 30-kD protein in vivo and
in vitro and exhibits strong homologous interaction in a yeast two-hybrid system
indicating that it can homodimerize. Nip3 is expressed in mitochondria and a
mutant (Nip3(163)) lacking the putative transmembrane domain and COOH terminus
does not dimerize or localize to mitochondria. Transient transfection of epitope
tagged Nip3 in Rat-1 fibroblasts and MCF-7 breast carcinoma induces apoptosis
within 12 h while cells transfected with the Nip3(163) mutant have a normal
phenotype, suggesting that mitochondrial localization is necessary for induction
of cell death. Nip3 overexpression increases the sensitivity to apoptosis induced
by granzyme B and topoisomerase I and II inhibitors. After transfection, both
Nip3 and Nip3(163) protein levels decrease steadily over 48 h indicating that the
protein is rapidly degraded and this occurs in the absence of cell death. Bcl-2
overexpression initially delays the onset of apoptosis induced by Nip3 but the
resistance is completely overcome in longer periods of incubation. Nip3 protein
levels are much higher and persist longer in Bcl-2 expressing cells. In
conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can
overcome Bcl-2 suppression.
PMID- 9396767
TI - Induction of apoptosis of metastatic mammary carcinoma cells in vivo by
disruption of tumor cell surface CD44 function.
AB - To understand how the hyaluronan receptor CD44 regulates tumor metastasis, the
murine mammary carcinoma TA3/St, which constitutively expresses cell surface
CD44, was transfected with cDNAs encoding soluble isoforms of CD44 and the
transfectants (TA3sCD44) were compared with parental cells (transfected with
expression vector only) for growth in vivo and in vitro. Local release of soluble
CD44 by the transfectants inhibited the ability of endogenous cell surface CD44
to bind and internalize hyaluronan and to mediate TA3 cell invasion of hyaluronan
producing cell monolayers. Mice intravenously injected with parental TA3/St cells
developed massive pulmonary metastases within 21-28 d, whereas animals injected
with TA3sCD44 cells developed few or no tumors. Tracing of labeled parental and
transfectant tumor cells revealed that both cell types initially adhered to
pulmonary endothelium and penetrated the interstitial stroma. However, although
parental cells were dividing and forming clusters within lung tissue 48 h
following injection, >80% of TA3sCD44 cells underwent apoptosis. Although sCD44
transfectants displayed a marked reduction in their ability to internalize and
degrade hyaluronan, they elicited abundant local hyaluronan production within
invaded lung tissue, comparable to that induced by parental cells. These
observations provide direct evidence that cell surface CD44 function promotes
tumor cell survival in invaded tissue and that its suppression can induce
apoptosis of the invading tumor cells, possibly as a result of impairing their
ability to penetrate the host tissue hyaluronan barrier.
PMID- 9396768
TI - Distinct roles of lymphotoxin alpha and the type I tumor necrosis factor (TNF)
receptor in the establishment of follicular dendritic cells from non-bone marrow
derived cells.
AB - In mice deficient in either lymphotoxin alpha (LT-alpha) or type I tumor necrosis
factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC)
and germinal centers (GC) are absent from the spleen. We investigated the role of
LT-alpha and TNFR-I in the establishment of spleen FDC and GC structure by using
reciprocal bone marrow (BM) transfer. When LT-alpha-deficient mice were
reconstituted with wild-type BM, FDC organization and the ability to form GC were
restored, indicating that the LT-alpha-expressing cells required to establish
organized FDC are derived from BM. The role of LT-alpha in establishing organized
FDC structure was further investigated by the transfer of complement receptor 1
and 2 (CR1/2)-deficient BM cells into LT-alpha-deficient mice. Organized FDC were
identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM
chimeric mice, indicating that these cells were derived from the LT-alpha
deficient recipient. Thus, expression of LT-alpha in the BM-derived cells, but
not in the non-BM-derived cells, is required for the maturation of FDC from non
BM precursor cells. In contrast, when TNFR-I-deficient mice were reconstituted
with wild-type BM, they showed no detectable FDC clusters or GC formation. This
indicates that TNFR-I expression on non-BM-derived cellular components is
necessary for the establishment of these lymphoid structures. TNFR-I-deficient BM
was able to restore FDC organization and GC formation in LT-alpha-deficient mice,
indicating that formation of these structures does not require TNFR-I expression
on BM-derived cells. The data in this study demonstrate that FDC organization and
GC formation are controlled by both LT-alpha-expressing BM-derived cells and by
TNFR-I-expressing non-BM-derived cells.
PMID- 9396769
TI - Self-reactive B cells are not eliminated or inactivated by autoantigen expressed
on thyroid epithelial cells.
AB - Graves' Disease results from the production of autoantibodies against receptors
for thyroid stimulating hormone (TSH) on thyroid epithelial cells, and represents
the prototype for numerous autoimmune diseases caused by autoantibodies that bind
to organ-specific cell membrane antigens. To study how humoral tolerance is
normally maintained to organ-specific membrane antigens, transgenic mice were
generated selectively expressing membrane-bound hen egg lysozyme (mHEL) on the
thyroid epithelium. In contrast to the deletion of autoreactive B cells triggered
by systemic mHEL (Hartley, S.B., J. Crosbie, R. Brink, A.B. Kantor, A. Basten,
and C.C. Goodnow. 1991. Nature. 353:765-769), selective expression of mHEL
autoantigen on thyroid cells did not trigger elimination or inactivation of
circulating HEL-reactive B cells. These results provide evidence that tolerance
is not actively acquired to organ-specific antigens in the preimmune B cell
repertoire, underscoring the importance of maintaining tolerance to such antigens
by other mechanisms. The role of an intact endothelial barrier in sequestering
organ-specific antigens from circulating preimmune B cells is discussed.
PMID- 9396771
TI - Interferon gamma gene expression in sensory neurons: evidence for autocrine gene
regulation.
AB - We explored expression and possible function of interferon-gamma (IFN-gamma) in
cultured fetal (E15) rat dorsal root ganglion neurons combining whole cell patch
clamp electrophysiology with single cell reverse transcriptase polymerase chain
reaction and confocal laser immunocytochemistry. Morphologically, we located IFN
gamma protein in the cytoplasm of the neurons in culture as well as in situ
during peri- and postnatal development. Transcripts for classic IFN-gamma and for
its receptor were determined in probes of cytoplasm sampled from individual
cultured neurons, which had been identified by patch clamp electrophysiology. In
addition, the cultured neurons expressed both chains of the IFN-gamma receptor.
Locally produced IFN-gamma acts back on its cellular source. Phosphorylation and
nuclear translocation of the IFN-inducible transcriptional factor STAT1 as well
as IFN-gamma-dependent expression of major histocompatibility complex class I
molecules on the neuronal membrane were noted in untreated cultures. However,
both processes were substantially blocked in the presence of antibodies
neutralizing IFN-gamma. Our findings indicate a role of IFN-gamma in autocrine
regulation of sensory neurons.
PMID- 9396770
TI - Syk tyrosine kinase is required for the positive selection of immature B cells
into the recirculating B cell pool.
AB - The tyrosine kinase Syk has been implicated as a key signal transducer from the B
cell antigen receptor (BCR). We show here that mutation of the Syk gene
completely blocks the maturation of immature B cells into recirculating cells and
stops their entry into B cell follicles. Furthermore, using radiation chimeras we
demonstrate that this developmental block is due to the absence of Syk in the B
cells themselves. Syk-deficient B cells are shown to have the life span of normal
immature B cells. If this is extended by over-expression of Bcl-2, they
accumulate in the T zone and red pulp of the spleen in increased numbers, but
still fail to mature to become recirculating follicular B cells. Despite this
defect in maturation, Syk-deficient B cells were seen to give rise to switched as
well as nonswitched splenic plasma cells. Normally only a proportion of immature
B cells is recruited into the recirculating pool. Our results suggest that Syk
transduces a BCR signal that is absolutely required for the positive selection of
immature B cells into the recirculating B cell pool.
PMID- 9396772
TI - Role of CD8 in aberrant function of cytotoxic T lymphocytes.
AB - Using H-2Kd-restricted photoprobe-specific cytotoxic T lymphocyte (CTL) clones,
which permit assessment of T cell receptor (TCR)-ligand interactions by TCR
photoaffinity labeling, we observed that the efficiency of antigen recognition by
CTL was critically dependent on the half-life of TCR-ligand complexes. We show
here that antigen recognition by CTL is essentially determined by the frequency
of serial TCR engagement, except for very rapid dissociations, which resulted in
aberrant TCR signaling and antagonism. Thus agonists that were efficiently
recognized exhibited rapid TCR-ligand complex dissociation, and hence a high
frequency of serial TCR engagement, whereas the opposite was true for weak
agonists. Surprisingly, these differences were largely accounted for by the
coreceptor CD8. While it was known that CD8 substantially decreases TCR-ligand
complex dissociation, we observed in this study that this effect varied
considerably among ligand variants, indicating that epitope modifications can
alter the CD8 contribution to TCR-ligand binding, and hence the efficiency of
antigen recognition by CTL.
PMID- 9396773
TI - Determinant spreading of T helper cell 2 (Th2) responses to pancreatic islet
autoantigens.
AB - The nature (Th1 versus Th2) and dynamics of the autoimmune response during the
development of insulin-dependent diabetes mellitus (IDDM) and after immunotherapy
are unclear. Here, we show in nonobese diabetic (NOD) mice that the autoreactive
T cell response starts and spreads as a pure Th1 type autoimmunity, suggesting
that a spontaneous Th1 cascade underlies disease progression. Surprisingly,
induction of antiinflammatory Th2 responses to a single beta cell antigen
(betaCA) resulted in the spreading of Th2 cellular and humoral immunity to
unrelated betaCAs in an infectious manner and protection from IDDM. The data
suggest that both Th1 and Th2 autoimmunity evolve in amplificatory cascades by
generating site-specific, but not antigen-specific, positive feedback circuits.
Determinant spreading of Th2 responses may be a fundamental mechanism underlying
antigen-based immunotherapeutics, explaining observations of infectious tolerance
and providing a new theoretical framework for therapeutic intervention.
PMID- 9396774
TI - Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas
ligand blocks the killing.
AB - It has been believed that the Fas expressed on human peripheral blood T cells
(PBT) is nonfunctional, because these cells are insensitive to agonistic anti
Fas/Apo-1 mAbs that efficiently kill in vitro-activated T cells and many Fas
expressing cell lines. Here, we demonstrate that membrane-bound Fas ligand (FasL)
kills both fresh and in vitro-activated PBT, indicating that the Fas expressed on
fresh PBT is functional. In contrast, soluble FasL kills only the latter. Naive T
cells in umbilical cord blood do not express Fas, but can be induced to express
Fas by IFN-gamma or by a combination of IL-2 and anti-CD28 mAb, after which they
acquire sensitivity to membrane but not to soluble FasL. Soluble FasL inhibited
the killing of fresh PBT by membrane FasL. These results indicate that the
shedding of FasL from the membrane is a mechanism for downregulating at least
part of its killing activity.
PMID- 9396775
TI - Targeted deletion of the lipopolysaccharide (LPS)-binding protein gene leads to
profound suppression of LPS responses ex vivo, whereas in vivo responses remain
intact.
AB - Gram-negative bacterial lipopolysaccharide (LPS) stimulates phagocytic leukocytes
by interacting with the cell surface protein CD14. Cellular responses to LPS are
markedly potentiated by the LPS-binding protein (LBP), a lipid-transfer protein
that binds LPS aggregates and transfers LPS monomers to CD14. LBP also transfers
LPS to lipoproteins, thereby promoting the neutralization of LPS. LBP present in
normal plasma has been shown to enhance the LPS responsiveness of cells in vitro.
The role of LBP in promoting LPS responsiveness in vivo was tested in LBP
deficient mice produced by gene targeting in embryonic stem cells. Whole blood
from LBP-deficient animals was 1,000-fold less responsive to LPS as assessed by
the release of tumor necrosis factor (TNF)-alpha. Blood from gene-targeted mice
was devoid of immunoreactive LBP, essentially incapable of transferring LPS to
CD14 in vitro, and failed to support cellular responses to LPS. These activities
were restored by the addition of exogenous recombinant murine LBP to the plasma.
Despite these striking in vitro findings, no significant differences in TNF-alpha
levels were observed in plasma from wild-type and LBP-deficient mice injected
with LPS. These data suggest the presence of an LBP-independent mechanism for
responding to LPS. These LBP knockout mice may provide a tool for discovering the
nature of the presumed second mechanism for transferring LPS to responsive cells.
PMID- 9396776
TI - CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of
self-antigens and favors autoimmunity.
AB - Self-antigens expressed in extrathymic tissues such as the pancreas can be
transported to draining lymph nodes and presented in a class I-restricted manner
by bone marrow-derived antigen-presenting cells. Such cross-presentation of self
antigens leads to CD8+ T cell tolerance induction via deletion. In this report,
we investigate the influence of CD4+ T cell help on this process. Small numbers
of autoreactive OVA-specific CD8+ T cells were unable to cause diabetes when
adoptively transferred into mice expressing ovalbumin in the pancreatic beta
cells. Coinjection of OVA-specific CD4+ helper T cells, however, led to diabetes
in a large proportion of mice (68%), suggesting that provision of help favored
induction of autoimmunity. Analysis of the fate of CD8+ T cells indicated that
CD4(+) T cell help impaired their deletion. These data indicate that control of
such help is critical for the maintenance of CD8+ T cell tolerance induced by
cross-presentation.
PMID- 9396777
TI - Resistance to and recovery from lethal influenza virus infection in B lymphocyte
deficient mice.
AB - In the adaptive immune response to most viruses, both the cellular and humoral
arms of the immune system play complementary roles in eliminating virus and virus
infected cells and in promoting recovery. To evaluate the relative contribution
of CD4+ and CD8+ effector T lymphocytes in virus clearance and recovery, we have
examined the host response to lethal type A influenza virus infection in B
lymphocyte-deficient mice with a targeted disruption in the immunoglobulin mu
heavy chain. Our results indicate that naive B cell-deficient mice have a 50- 100
fold greater susceptibility to lethal type A influenza virus infection than do
wild type mice. However, after priming with sublethal doses of influenza, immune
B cell-deficient animals show an enhanced resistance to lethal virus infection.
This finding indicates that an antibody-independent immune-mediated antiviral
mechanism accounts for the increased resistance to lethal virus challenge. To
assess the contribution of influenza-specific CD4+ and CD8+ effector T cells in
this process, defined clonal populations of influenza-specific CD4+ and CD8+
effector T cells were adoptively transferred into lethally infected B cell
deficient mice. Cloned CD8+ effectors efficiently promoted recovery from lethal
infection, whereas cloned CD4+ T cells conferred only partial protection. These
results suggest that memory T lymphocytes can act independently of a humoral
immune response in order to confer resistance to influenza infection in immune
individuals. The potential implications of these results for vaccination against
human influenza infection are discussed.
PMID- 9396778
TI - Itk and Fyn make independent contributions to T cell activation.
AB - Itk is a member of the Btk/Tec/Itk family of nonreceptor protein tyrosine kinases
(PTKs), and has been implicated in T cell antigen receptor (TCR) signal
transduction. Lck and Fyn are the Src-family nonreceptor PTKs that are involved
in TCR signaling. To address the question of how these members of different
families of PTKs functionally contribute to T cell development and to T cell
activation, mice deficient for both Itk and either Lck or Fyn were generated. The
Itk/Lck doubly deficient mice exhibited a phenotype similar to that of Lck
deficient mice. The phenotype of the Itk/Fyn doubly deficient mice was similar to
that of Itk deficient mice. However the Itk/Fyn doubly deficient mice exhibited a
more severe defect in TCR-induced proliferation of thymocytes and peripheral T
cells than did mice deficient in either kinase alone. These data support the
notion that Itk and Fyn both make independent contributions to TCR-induced T cell
activation.
PMID- 9396779
TI - TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new
TNF family member predominantly expressed in T cells, is a dendritic cell
specific survival factor.
AB - TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine) is a new
member of the TNF family that is induced upon T cell receptor engagement and
activates c-Jun N-terminal kinase (JNK) after interaction with its putative
receptor (TRANCE-R). In addition, TRANCE expression is restricted to lymphoid
organs and T cells. Here, we show that high levels of TRANCE-R are detected on
mature dendritic cells (DCs) but not on freshly isolated B cells, T cells, or
macrophages. Signaling by TRANCE-R appears to be dependent on TNF receptor
associated factor 2 (TRAF2), since JNK induction is impaired in cells from
transgenic mice overexpressing a dominant negative TRAF2 protein. TRANCE inhibits
apoptosis of mouse bone marrow-derived DCs and human monocyte-derived DCs in
vitro. The resulting increase in DC survival is accompanied by a proportional
increase in DC-mediated T cell proliferation in a mixed leukocyte reaction.
TRANCE upregulates Bcl-xL expression, suggesting a potential mechanism for
enhanced DC survival. TRANCE does not induce the proliferation of or increase the
survival of T or B cells. Therefore, TRANCE is a new DC-restricted survival
factor that mediates T cell-DC communication and may provide a tool to
selectively enhance DC activity.
PMID- 9396780
TI - Agents that down-regulate or inhibit protein kinase C circumvent resistance to 1
beta-D-arabinofuranosylcytosine-induced apoptosis in human leukemia cells that
overexpress Bcl-2.
AB - The effects of the non-tumor-promoting protein kinase C (PKC) activator
bryostatin 1 and the PKC inhibitors staurosporine and UCN-01 were examined with
respect to modulation of 1-[beta-D-arabinofuranosyl]cytosine (ara-C)-induced
apoptosis in human myeloid leukemia cells (HL-60) overexpressing the
antiapoptotic protein Bcl-2. HL-60/Bcl-2 cells displayed a 5-fold increase in Bcl
2 protein compared with empty-vector counter-parts (HL-60/pCEP4) but comparable
levels of Bax, Mcl-1, and Bcl-xL. After exposure to an equimolar concentration of
ara-C (10 microM for 6 hr), HL-60/Bcl-2 cells were significantly less susceptible
to apoptosis, DNA fragmentation, and loss of clonogenicity than HL-60/pCEP4
cells. The protective effect of increased Bcl-2 expression was manifested by a
failure of ara-C to induce activation/cleavage of the Yama protease (CPP32;
caspase-3) and degradation of one of its substrates, poly(ADP-ribose)polymerase
to an 85-kDa cleavage product. When HL-60/Bcl-2 cells were preincubated with
bryostatin 1 (10 nM; 24 hr) or coincubated with either staurosporine (50 nM; 6
hr) or UCN-01 (300 nM; 6 hr) after a 1-hr preincubation, exposures that exerted
minimal effects alone, ara-C-induced apoptosis and DNA fragmentation were
restored to levels equivalent to, or greater than, those observed in empty-vector
controls. These events were accompanied by restoration of the ability of ara-C to
induce CPP32 cleavage and activation, poly(ADP-ribose) polymerase degradation,
and inhibition of colony formation. Western analysis of Bcl-2 protein obtained
from overexpressing cells treated with bryostatin 1, staurosporine, or UCN-01
revealed the appearance of a slowly migrating species and a general broadening of
the protein band, effects that were insensitive to the protein synthesis
inhibitor cycloheximide. Alterations in Bcl-2 protein mobility on sodium dodecyl
sulfate-polyacrylamide gel electrophoresis were reversed by treatment of lysates
with alkaline phosphatase or protein phosphatase 2A; actions of the latter were
blocked by the specific phosphatase inhibitor okadaic acid. In vivo labeling
studies of Bcl-2 protein demonstrated increased incorporation of
[32PO4]orthophosphate in drug-treated cells. Last, phosphorylated Bcl-2 failed to
display decreased binding to the proapoptotic protein Bax. Collectively, these
findings indicate that bryostatin 1, which down-regulates PKC, and staurosporine
and UCN-01, which directly inhibit the enzyme, circumvent resistance of Bcl-2
overexpressing leukemic cells to ara-C-induced apoptosis and activation of the
protease cascade. They also raise the possibility that modulation of Bcl-2
phosphorylation status contributes to this effect.
PMID- 9396782
TI - Ca2+ feedback on "quantal" Ca2+ release involving ryanodine receptors.
AB - The influence of luminal and cytoplasmic Ca2+ on the ability of ryanodine
sensitive stores to undergo multiple partial ("quantal") releases has been
assessed. Increased luminal Ca2+ levels do indeed modulate sarcoplasmic reticulum
Ca2+ release by lowering the threshold agonist concentration required to elicit
release, but the decrease in luminal Ca2+ that accompanies a partial release is
not sufficient by itself to terminate release. Similarly, an increase in
cytoplasmic Ca2+ lowers the threshold agonist concentration required to elicit
release; thus, the bulk cytoplasmic Ca2+ levels attained during a release would
only stimulate further release, not terminate it before it reached completion.
Very high cytoplasmic Ca2+ levels (1-3 mM) also triggered release but were unable
to terminate release before reaching completion. Thus, even the high local
cytoplasmic Ca2+ concentration that might accompany release would also not
terminate release. It is concluded that Ca2+ feedback can modulate release
through ryanodine receptors but that it does not account for the properties of
quantal release. The low affinity inhibitor tetracaine induces a decrease in the
extent of release that cannot be explained solely by heterogeneous caffeine
sensitivity of the stores. The results are interpreted in terms of a scheme that
includes (i) heterogeneous sensitivity of stores, conferred in part by
differences in luminal Ca2+ content and (ii) adaptive behavior on the part of
individual ryanodine receptors.
PMID- 9396781
TI - Distinct sites for inverse modulation of N-methyl-D-aspartate receptors by
sulfated steroids.
AB - Steroid sulfation occurs in nervous tissue and endogenous sulfated steroids can
act as positive or negative modulators of N-methyl-D-aspartate (NMDA) receptor
function. In the current study, structure-activity relationships for sulfated
steroids were examined in voltage-clamped chick spinal cord and rat hippocampal
neurons in culture and in Xenopus laevis oocytes expressing NR1(100) and NR2A
subunits. The ability of pregnenolone sulfate (a positive modulator) and
epipregnanolone sulfate (a negative modulator) to compete with each another, as
well as with other known classes of NMDA receptor modulators, was examined. The
results show that steroid positive and negative modulators act at specific,
extracellularly directed sites that are distinct from one another and from the
spermine, redox, glycine, Mg2+, MK-801, and arachidonic acid sites. Sulfated
steroids are effective as modulators of ongoing glutamate-mediated synaptic
transmission, which is consistent with their possible role as endogenous
neuromodulators in the CNS.
PMID- 9396783
TI - KvLQT1 potassium channel but not IsK is the molecular target for trans-6-cyano-4
(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl- chromane.
AB - Mutations in the KvLQT1 gene are the cause for the long QT syndrome [Circulation
94:1996-2012 (1996)]. Coexpression of KvLQT1 in association with the channel
regulator protein IsK produces a K+ current with characteristics reminiscent of
the slow component of the delayed rectifier in cardiac myocytes. We explored the
pharmacological properties of trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3
hydroxy-2,2-dime thyl- chromane (293B), a chromanol compound, on the K+ current
produced by direct intranuclear injection of KvLQT1 and IsK cDNA plasmids in COS
7 cells. Injected cells were recorded by means of the whole-cell and cell
attached patch-clamp configurations under chloride-free conditions. Cells
injected with KvLQT1 cDNA alone exhibited a fast-activating outward K+ current,
whereas cells coinjected with KvLQT1 plus IsK cDNAs exhibited a time-dependent
outward current with slower activation kinetics. The chromanol 293B blocked the
K+ current related to KvLQT1 expression in both the absence or presence of IsK.
The IC50 value for 293B to block KvLQT1-related current was not significantly
modified by the presence of IsK (9.9 microM in the absence of IsK versus 9.8
microM in its presence). The block produced by 293B was strongly voltage
dependent inasmuch as it was close to 0 at -80 mV and occurred during a
depolarizing voltage step. The time constants for the drug to block the current
were in the same order of magnitude as activation kinetics of the current.
Kinetics for drug unblock at the holding potential were much faster, in the order
of a few tenths of a msec. KvLQT1 currents recorded in the cell-attached
configuration were also blocked by externally applied 293B, suggesting that the
compound penetrated the cell to block the channel. Cromakalim, another chromanol
compound, also blocked KvLQT1 currents. Our results show that the chromanol
compound 293B is targeted to KvLQT1 channels but not to the IsK regulator.
PMID- 9396784
TI - Constitutive activity of a chimeric D2/D1 dopamine receptor.
AB - Chimeric D1/D2 receptors were constructed to identify structural determinants of
drug affinity and efficacy. We previously reported that chimeras that had D1
receptor transmembrane domain VII together with amino-terminal sequence from the
D2 receptor were nonfunctional. D2/D1 chimeras were constructed that contained D2
receptor sequence at the amino- and carboxyl-terminal ends and D1 receptor
sequence in the intervening region. Chimeric receptors with D2 sequence from
transmembrane domain 7 to the carboxyl terminus together with D2 receptor
sequence from the amino terminus through transmembrane helix 4 (D2[1-4,7]) and 5
(D2[1-5,7]) bound [3H]spiperone with high affinity, consistent with the
hypothesis that D2 receptor transmembrane domain I or II is incompatible with D1
receptor transmembrane domain VII. D2[1-4,7] and D2[1-5,7] had affinities similar
to D1 and D2 receptors for most nonselective dopamine antagonists and had
affinities for most of the selective antagonists that were intermediate between
those of the parent receptors. D2[1-4,7] and D2[1-5,7] mediated dopamine receptor
agonist-induced stimulation and inhibition, respectively, of cAMP accumulation.
The more efficient coupling of D2[1-5,7] to inhibition of cAMP accumulation,
compared with the coupling of D2[5-7] and D2[3-7], supports the view that
multiple D2 receptor cytoplasmic domains acting in concert are necessary for
receptor activation of Gi. In contrast, D2[1-4,7], which contains only one
cytoplasmic loop (the third) from the D1 receptor, is capable of activating Gs.
D2[1-4,7] exhibited several characteristics of a constitutively active receptor,
including enhanced basal (unliganded) stimulation of cAMP accumulation, high
affinity for agonists even in the presence of GTP, and blunted agonist-stimulated
cAMP accumulation. A number of dopamine receptor antagonists were inverse
agonists at D2[1-4,7], inhibiting basal cAMP accumulation. Some of these drugs
were also inverse agonists at the D1 receptor. Interestingly, several antagonists
also potentiated forskolin-stimulated cAMP accumulation via D2[1-5,7] and via the
D2 receptor, which could reflect inverse agonist inhibition of native
constitutive activity of this receptor.
PMID- 9396785
TI - Differences in agonist/antagonist binding affinity and receptor transduction
using recombinant human gamma-aminobutyric acid type A receptors.
AB - Using human gamma-aminobutyric acid type A (GABAA) receptor subunit combinations,
expressed in cell lines and Xenopus laevis oocytes, the pharmacology of a number
of ligands interacting directly with the GABA recognition site has been studied
in [3H]muscimol binding and electrophysiologically. The binding affinity of GABAA
agonist and antagonist ligands showed small but statistically significant
dependence on the subunit composition of receptors that include gamma 2 and
different alpha and beta subunits. The potency of antagonist ligands was largely
independent of receptor subunit composition, whereas the composition of receptors
expressed in oocytes strongly influenced the EC50 value of agonists. An apparent
reciprocal correlation between subunits favoring agonist binding and antagonist
binding, respectively, was observed. Whereas antagonists showed comparable
potencies in binding and functional studies, the potency of agonists in binding
studies was generally two to three orders of magnitude higher than the agonist
potencies measured electrophysiologically. 5-(4-Piperidyl)isothiazol-3-ol, which
behaves as a low efficacy partial agonist at GABAA receptors in cultured cortical
neurons, showed no efficacy in oocytes, but produced pure antagonist effects with
a binding/functional affinity ratio between those observed for the agonists and
antagonists. It is concluded that the GABAA receptor mechanisms transducing
binding into physiological response, but not the binding per se, is dependent on
the receptor subunit composition.
PMID- 9396786
TI - S-adenosylhomocysteine hydrolase inhibitors interfere with the replication of
human immunodeficiency virus type 1 through inhibition of the LTR
transactivation.
AB - Various analogues of adenosine have been described as inhibitors of S
adenosylhomocysteine (AdoHcy) hydrolase, and some of these AdoHcy hydrolase
inhibitors (e.g., 3-deazaadenosine, 3-deazaaristeromycin, and 3-deazaneplanocin
A) have also been reported to inhibit the replication of human immunodeficiency
virus type 1 (HIV-1). When evaluated against HIV-1 replication in MT-4 cells,
macrophages, or phytohemagglutinin-stimulated peripheral blood lymphocytes
infected acutely or chronically with HIV-1IIIB or HIVBaL strains, a wide range of
adenosine analogues did not inhibit HIV-1IIIB replication for 50% at subtoxic
concentrations. However, they inhibited HIV-1 replication in HeLa CD4+ LTR-LacZ
cells at concentrations well below cytotoxicity threshold. A close correlation
was found among the inhibitory effect of the compounds on AdoHcy hydrolase
activity, their inhibition of HIV-1 replication in Hela CD4+ LTR-LacZ cells, and
their inhibition of the HIV-1 Tat-dependent and -independent transactivation of
the long terminal repeat, whereas no inhibitory effect was seen on HIV-1 reverse
transcription or a Tat-independent cytomegalovirus promoter. Our results suggest
that AdoHcy hydrolase and the associated S-adenosylmethionine-dependent
methylation mechanism play a role in the process of long terminal repeat
transactivation and, hence, HIV replication.
PMID- 9396787
TI - Expression cloning and receptor pharmacology of human calcitonin receptors from
MCF-7 cells and their relationship to amylin receptors.
AB - Human breast cell carcinoma MCF-7 cells were found to bind 125I-labeled rat
amylin (rAmylin) and the peptide amylin antagonist radioligand 125I-AC512 with
high affinity. This high affinity binding possessed characteristics unique to the
already defined high affinity binding site for amylin in the rat nucleus
accumbens [Mol. Pharmacol. 44:493-497 (1993); J. Pharmacol. Exp. Ther. 270:779
787 (1994); Eur. J. Pharmacol. 262:133-141 (1994)]. To further define this
receptor, we report results of expression cloning studies from an MCF-7 cell
library. We isolated two variants of a seven-transmembrane receptor that were
identical to two previously described human calcitonin receptors (hCTR1 and
hCTR2). These receptors were characterized by expression in different surrogate
host cell systems. Transient expression of hCTR1 in COS cells yielded membranes
that bound 125I-AC512 and 125I-salmon calcitonin with high affinity, but no high
affinity binding was observed with 125I-human calcitonin (hCAL) or 125I-rAmylin.
Stable expression of hCTR1 in HEK 293 cells produced similar data. In contrast,
expression of hCTR2 in COS cells yielded membranes that bound 125I-AC512, 125I
hCAL, and 125I-rAmylin with high affinity. The agonists 125I-hCAL and 125I
rAmylin bound 65% and 1.5%, respectively, of the sites bound by the antagonist
radioligand 125I-AC512 in this expression system. This pattern of binding was
repeated in HEK 293 cells stably transfected with hCTR2 (125I-hCAL = 24.8% Bmax,
125I-rAmylin = 8% Bmax). In both expression systems, the agonists hCAL and
rAmylin were much more potent in displacing their radioligand counterparts than
was the antagonist radioligand 125I-AC512. For example, the pKi value for
displacement of 125I-AC512 by rAmylin was 7.2 in HEK 293 cells but rose to 9.1
when displacing 125I-rAmylin. Finally, hCTR2 was expressed in baculovirus
infected Ti ni cells. In this system, only specific binding to the antagonist
125I-AC512 and agonist 125I-hCAL was observed; no binding to 125I-rAmylin could
be detected. These data are discussed in terms of two working hypotheses. The
first is that amylin is a weak agonist for hCTR2 and that this receptor is
unrelated to the amylin receptor found in this cell line. The second is that
hCTR2 couples to different G proteins for calcitonin and amylin function in
different cells. At present, these data cannot be used to disprove conclusively
either hypothesis.
PMID- 9396788
TI - A multiplicity of mediators: alternative forms of transcription complexes
communicate with transcriptional regulators.
AB - The already complex process of transcription by RNA polymerase II has become even
more complicated in the last few years with the identification of auxiliary
factors in addition to the essential general initiation factors. In many cases
these factors, which have been termed mediators or co-activators, are only
required for activated or repressed transcription. In some cases the effects are
specific for certain activators and repressors. Recently some of these auxiliary
factors have been found in large complexes with either TBP, as TBP-associated
factors (TAFs) in the general factor TFIID, or with pol II and a subset of the
general factors, referred to as the 'holoenzyme'. Although the exact composition
of these huge assemblies is still a matter of some debate, it is becoming clear
that the complexes themselves come in more than one form. In particular, at least
four forms of TFIID have been described, including one that contains a tissue
specific TAF and another with a cell type-specific form of TBP. In addition, in
yeast there are at least two forms of the 'holoenzyme' distinguished by their
mediator composition and by the spectrum of transcripts whose expression they
affect. Genetic and biochemical analyses have begun to identify the interactions
between the components of these complexes and the ever increasing family of DNA
binding regulatory factors. These studies are complicated by the fact that
individual regulatory factors often appear to have redundant interactions with
multiple mediators. The existence of these different forms of transcription
complexes defines a new target for regulation of subsets of eukaryotic genes.
PMID- 9396789
TI - Template directed incorporation of nucleotide mixtures using azole-nucleobase
analogs.
AB - DNA that encodes elements for degenerate replication events by use of artificial
nucleobases offers a versatile approach to manipulating sequences for
applications in biotechnology. We have designed a family of artificial
nucleobases that are capable of assuming multiple hydrogen bonding orientations
through internal bond rotations to provide a means for degenerate molecular
recognition. Incorporation of these analogs into a single position of a PCR
primer allowed for analysis of their template effects on DNA amplification
catalyzed by Thermus aquaticus (Taq) DNA polymerase. All of the nucleobase
surrogates have similar shapes but differ by structural alterations that
influence their electronic character. These subtle distinctions were able to
influence the Taq DNA polymerase dependent incorporation of the four natural
deoxyribonucleotides and thus, significantly expand the molecular design
possibilities for biochemically functional nucleic acid analogs.
PMID- 9396790
TI - A new nomenclature for the cytoplasmic ribosomal proteins of Saccharomyces
cerevisiae.
AB - The availability of the complete sequence of the Saccharomyces cerevisiae genome
has allowed a comprehensive analysis of the genes encoding cytoplasmic ribosomal
proteins in this organism. On the basis of this complete inventory a new
nomenclature for the yeast ribosomal proteins is presented.
PMID- 9396791
TI - The CLUSTAL_X windows interface: flexible strategies for multiple sequence
alignment aided by quality analysis tools.
AB - CLUSTAL X is a new windows interface for the widely-used progressive multiple
sequence alignment program CLUSTAL W. The new system is easy to use, providing an
integrated system for performing multiple sequence and profile alignments and
analysing the results. CLUSTAL X displays the sequence alignment in a window on
the screen. A versatile sequence colouring scheme allows the user to highlight
conserved features in the alignment. Pull-down menus provide all the options
required for traditional multiple sequence and profile alignment. New features
include: the ability to cut-and-paste sequences to change the order of the
alignment, selection of a subset of the sequences to be realigned, and selection
of a sub-range of the alignment to be realigned and inserted back into the
original alignment. Alignment quality analysis can be performed and low-scoring
segments or exceptional residues can be highlighted. Quality analysis and
realignment of selected residue ranges provide the user with a powerful tool to
improve and refine difficult alignments and to trap errors in input sequences.
CLUSTAL X has been compiled on SUN Solaris, IRIX5.3 on Silicon Graphics, Digital
UNIX on DECstations, Microsoft Windows (32 bit) for PCs, Linux ELF for x86 PCs,
and Macintosh PowerMac.
PMID- 9396792
TI - Role of acceptor stem conformation in tRNAVal recognition by its cognate
synthetase.
AB - Although the anticodon is the primary element in Escherichia coli tRNAValfor
recognition by valyl-tRNA synthetase (ValRS), nucleotides in the acceptor stem
and other parts of the tRNA modulate recognition. Study of the steady state
aminoacylation kinetics of acceptor stem mutants of E.coli tRNAValdemonstrates
that replacing any base pair in the acceptor helix with another Watson-Crick base
pair has little effect on aminoacylation efficiency. The absence of essential
recognition nucleotides in the acceptor helix was confirmed by converting E.coli
tRNAAlaand yeast tRNAPhe, whose acceptor stem sequences differ significantly from
that of tRNAVal, to efficient valine acceptors. This transformation requires, in
addition to a valine anticodon, replacement of the G:U base pair in the acceptor
stem of these tRNAs. Mutational analysis of tRNAValverifies that G:U base pairs
in the acceptor helix act as negative determinants of synthetase recognition.
Insertion of G:U in place of the conserved U4:A69 in tRNAValreduces the
efficiency of aminoacylation, due largely to an increase in K m. A smaller but
significant decline in aminoacylation efficiency occurs when G:U is located at
position 3:70; lesser effects are observed for G:U at other positions in the
acceptor helix. The negative effects of G:U base pairs are strongly correlated
with changes in helix structure in the vicinity of position 4:69 as monitored
by19F NMR spectroscopy of 5-fluorouracil-substituted tRNAVal. This suggests that
maintaining regular A-type RNA helix geometry in the acceptor stem is important
for proper recognition of tRNAValby valyl-tRNA synthetase.19F NMR also shows that
formation of the tRNAVal-valyl-tRNA synthetase complex does not disrupt the first
base pair in the acceptor stem, a result different from that reported for the
tRNAGln-glutaminyl-tRNA synthetase complex.
PMID- 9396793
TI - Recognition of GC base pairs by triplex forming oligonucleotides containing
nucleosides derived from 2-aminopyridine.
AB - We have attempted to alleviate the pH dependency of triplex recognition of
guanine by using intermolecular triplexes containing 2-amino-5-(2-deoxy-d
ribofuranosyl)pyridine (AP) as an analogue of 2'-deoxycytidine (dC). We find that
for the beta-anomer of AP, the complex between (AP)6T6and the target site
G6A6*T6C6is stable, generating a clear DNase I footprint at oligonucleotide
concentrations as low as 0.25 microM at pH 5.0, in contrast to 50 microM
C6T6which has no effect on the cleavage pattern. This complex is still stable at
pH 6.5 producing a footprint with 1 microM oligonucleotide. Oligonucleotides
containing the alpha-anomer of AP are much less effective than the beta-anomer,
though in some instances they are more stable than the unmodified
oligonucleotides. The results of molecular dynamics studies on a range of AP
containing triplexes has rationalized the observed stability behaviour in terms
of hydrogen-bonding behaviour.
PMID- 9396794
TI - Mirror image alternative interaction patterns of the same tRNA with either class
I arginyl-tRNA synthetase or class II aspartyl-tRNA synthetase.
AB - Gene cloning, overproduction and an efficient purification protocol of yeast
arginyl-tRNA synthetase (ArgRS) as well as the interaction patterns of this
protein with cognate tRNAArgand non-cognate tRNAAspare described. This work was
motivated by the fact that the in vitro transcript of tRNAAspis of dual
aminoacylation specificity and is not only aspartylated but also efficiently
arginylated. The crystal structure of the complex between class II aspartyl-tRNA
synthetase (AspRS) and tRNAAsp, as well as early biochemical data, have shown
that tRNAAspis recognized by its variable region side. Here we show by
footprinting with enzymatic and chemical probes that transcribed tRNAAspis
contacted by class I ArgRS along the opposite D arm side, as is homologous
tRNAArg, but with idiosyncratic interaction patterns. Besides protection,
footprints also show enhanced accessibility of the tRNAs to the structural
probes, indicative of conformational changes in the complexed tRNAs. These
different patterns are interpreted in relation to the alternative arginine
identity sets found in the anticodon loops of tRNAArgand tRNAAsp. The mirror
image alternative interaction patterns of unmodified tRNAAspwith either class I
ArgRS or class II AspRS, accounting for the dual identity of this tRNA, are
discussed in relation to the class defining features of the synthetases. This
study indicates that complex formation between unmodified tRNAAspand either ArgRS
and AspRS is solely governed by the proteins.
PMID- 9396795
TI - Electric field directed nucleic acid hybridization on microchips.
AB - Selection and adjustment of proper physical parameters enables rapid DNA
transport, site selective concentration, and accelerated hybridization reactions
to be carried out on active microelectronic arrays. These physical parameters
include DC current, voltage, solution conductivity and buffer species. Generally,
at any given current and voltage level, the transport or mobility of DNA is
inversely proportional to electrolyte or buffer conductivity. However, only a
subset of buffer species produce both rapid transport, site specific
concentration and accelerated hybridization. These buffers include zwitterionic
and low conductivity species such as: d- and l-histidine; 1- and 3
methylhistidines; carnosine; imidazole; pyridine; and collidine. In contrast,
buffers such as glycine, beta-alanine and gamma-amino-butyric acid (GABA) produce
rapid transport and site selective concentration but do not facilitate
hybridization. Our results suggest that the ability of these buffers (histidine,
etc.) to facilitate hybridization appears linked to their ability to provide
electric field concentration of DNA; to buffer acidic conditions present at the
anode; and in this process acquire a net positive charge which then shields or
diminishes repulsion between the DNA strands, thus promoting hybridization.
PMID- 9396796
TI - CDF-1, a novel E2F-unrelated factor, interacts with cell cycle-regulated
repressor elements in multiple promoters.
AB - The cdc25C , cdc2 and cyclin A promoters are controlled by transcriptional
repression through two contiguous protein binding sites, termed the CDE and CHR.
In the present study we have identified a factor, CDF-1, which interacts with the
cdc25C CDE-CHR module. CDF-1 binds to the CDE in the major groove and to the CHR
in the minor grove in a cooperative fashion in vitro , in a manner similar to
that seen by genomic footprinting. In agreement with in vivo binding data and its
putative function as a periodic repressor, DNA binding by CDF-1 in nuclear
extracts is down-regulated during cell cycle progression. CDF-1 also binds avidly
to the CDE-CHR modules of the cdc2 and cyclin A promoters, but not to the E2F
site in the B- myb promoter. Conversely, E2F complexes do not recognize the
cdc25C CDE-CHR and CDF-1 is immunologically unrelated to all known E2F and DP
family members. This indicates that E2F- and CDF-mediated repression is
controlled by different factors acting at different stages during the cell cycle.
While E2F-mediated repression seems to be associated with genes that are up
regulated early (around mid G1), such as B- myb , CDE-CHR-controlled genes, such
as cdc25C , cdc2 and cyclin A , become derepressed later. Finally, the
fractionation of native nuclear extracts on glycerol gradients leads to
separation of CDF-1 from both E2F complexes and pocket proteins of the pRb
family. This emphasizes the conclusion that CDF-1 is not an E2F family member and
points to profound differences in the cell cycle regulation of CDF-1 and E2F.
PMID- 9396797
TI - The differential binding of E2F and CDF repressor complexes contributes to the
timing of cell cycle-regulated transcription.
AB - B- myb and cdc25C exemplify different groups of genes whose transcription is
consecutively up-regulated during the cell cycle. Both promoters are controlled
by transcriptional repression via modules consisting of an E2F binding site
(E2FBS) or the related CDE plus a contiguous CHR co-repressor element. We now
show that the B- myb repressor module, which is derepressed early (mid G1), is
preferentially recognized by E2F-DP complexes and that a mutation selectively
abolishing E2F binding impairs regulation. In contrast, the cdc25C repressor
module, which is derepressed late (S/G2), interacts selectively with CDE-CHR
binding factor-1 (CDF-1). E2F binding, but not CDF-1 binding, requires specific
nucleotides flanking the E2FBS/CDE core, while CDF-1 binding, but not E2F
binding, depends on specific nucleotides in the CHR. Swapping these nucleotides
between the two promoters profoundly changes protein binding patterns and alters
expression kinetics. Thus predominant CDF-1 binding leads to derepression in late
S, predominant E2F binding results in up-regulation in late G1, while promoters
binding both E2F and CDF-1 with high efficiency show intermediate kinetics. Our
results support a model where the differential binding of E2F and CDF-1 repressor
complexes contributes to the timing of promoter activity during the cell cycle.
PMID- 9396798
TI - CDF-1-mediated repression of cell cycle genes targets a specific subset of
transactivators.
AB - The cdc25C , cyclin A and cdc2 genes are regulated during the cell cycle through
two contiguous repressor binding sites, the CDE and CHR, located in the region of
transcription initiation and interacting with a factor termed CDF-1. The target
of this repression seems to be transcriptional activation of these promoters by
transcription factors bound upstream. The majority of these factors falls into
the class of glutamine-rich activators, suggesting that CDF-1-mediated repression
might be activation domain specific. In the present study we have used chimeric
promoter constructs to demonstrate that the cdc25C UAS, but not the core
promoter, is crucial for repression. In addition, we show that only specific
transcription factors and activation domains are responsive to CDE-CHR-mediated
cell cycle regulation. These observations clearly indicate that CDF-1 interferes
with activation of transcription by a specific subset of transactivators. The
repressible activation domains belong to the same class of glutamine-rich
activators, pointing to specific interactions of CDF-1 with components of the
transcription machinery. In agreement with this conclusion we find that a simple
inversion of the CDE-CHR module completely abrogates cell cycle-regulated
repression.
PMID- 9396799
TI - Characterization of the TATA-less core promoter of the cell cycle-regulated
cdc25C gene.
AB - The TATA- and Inr-less promoter of the human cdc25C gene is regulated during the
cell cycle through binding of a repressor to two contiguous promoter-proximal
elements, the CDE and CHR. In this study we have characterized in detail the
region of the cdc25C promoter immediately downstream of these elements. Several
lines of evidence suggest that this region of approximately 60 bp acts as the
core promoter. This sequence: (i) harbors most of the transcription initiation
sites; (ii) possesses basal promoter activity in vivo ; (iii) shows no stable
protein binding in vivo as indicated by genomic dimethyl sulfate and
phenanthroline copper footprinting; (iv) contains single-stranded regions in vivo
as shown by potassium permanganate footprinting; (v) is hypersensitive to DNase I
cleavage in permeabilized cells. Mutational analysis of the core promoter
revealed the presence of three sites which play a role in transcription. Two of
these sites were found to represent low affinity binding sites for transcription
factors of the Sp1 family. Mutation of these sites led to decreased levels of
transcription, while their alteration to canonical Sp1 sites impaired cell cycle
regulation. Thus the transient interaction of Sp1 with the core promoter appears
to be necessary for maximal transcription without perturbing cell cycle
regulation.
PMID- 9396800
TI - NUCPLOT: a program to generate schematic diagrams of protein-nucleic acid
interactions.
AB - Proteins that bind to DNA are found in all areas of genetic activity within the
cell. To help understand how these proteins perform their various functions, it
is useful to analyse which residues are involved in binding to the DNA and how
they interact with the bases and sugar-phosphate backbone of nucleic acids. Here
we describe a program called NUCPLOT which can automatically identify these
interactions from the 3D atomic coordinates of the complex from a PDB file and
generate a plot that shows all the interactions in a schematic manner. The
program produces a PostScript output file representing hydrogen, van der Waals
and covalent bonds between the protein and the DNA. The resulting diagram is both
clear and simple and allows immediate identification of important interactions
within the structure. It also facilitates comparison of binding found in
different structures. NUCPLOT is a completely automatic program, which can be
used for any protein-DNA complex and will also work for certain protein-RNA
structures.
PMID- 9396802
TI - Inhibitory properties of double-helix-forming circular oligonucleotides.
AB - Several circular oligonucleotides were synthesized and characterized by
electrospray ionization mass spectrometry. Experiments on termination of primer
extension catalysed by DNA polymerases, Klenow fragment and Tth have demonstrated
that a double helix forming circular 2'-deoxyribooligomer containing a 25mer
sequence complementary to the target single-stranded DNA along with a 34mer
random mismatching stretch appears to be a potent inhibitor of replication in
vitro. Studies on inhibition of luciferase gene expression in a cell-free
transcription-translation system have shown that a duplex forming circular 2'
deoxyribooligonucleotide containing a 25mer sequence complementary to the target
mRNA and a 14mer random mismatching stretch can serve as an effective antisense
compound as a standard linear complementary oligomer. Features of double helix
forming circular oligonucleotides composed of 2'-deoxyribonucleosides seem to be
useful for the design of new antigene and antisense agents.
PMID- 9396801
TI - A novel nucleic acid-binding protein that interacts with human rad51 recombinase.
AB - Using the yeast two-hybrid system, we isolated a cDNA encoding a novel human
protein, named Pir51, that strongly interacts with human Rad51 recombinase.
Analysis in vitro confirmed the interaction between Rad51 and Pir51. Pir51 mRNA
is expressed in a number of human organs, most notably in testis, thymus, colon
and small intestine. The Pir51 gene locus was mapped to chromosome 12p13.1-13. 2
by fluorescence in situ hybridization. The Pir51 protein was expressed in
Escherichia coli and purified to near homogeneity. Biochemical analysis shows
that the Pir51 protein binds both single- and double-stranded DNA, and is capable
of aggregating DNA. The protein also binds RNA. The Pir51 protein may represent a
new member of the multiprotein complexes postulated to carry out homologous
recombination and DNA repair in mammalian cells.
PMID- 9396803
TI - Interaction of minor groove binding ligands with long AT tracts.
AB - We have used quantitative DNase I footprinting to examine the ability of
distamycin and Hoechst 33258 to discriminate between different arrangements of AT
residues, using synthetic DNA fragments containing multiple blocks of (A/T)6or
(A/T)10in identical sequence environments. Previous studies have shown that these
ligands bind less well to (A/T)4sites containing TpA steps. We find that in
(A/T)6tracts distamycin shows little discrimination between the various sites,
binding approximately 2-fold stronger to TAATTA than (TA)3, T3A3and GAATTC. In
contrast, Hoechst 33258 binds approximately 20-fold more tightly to GAATTC and
TAATTA than T3A3and (TA)3. Hydroxyl radical footprinting reveals that both
ligands bind in similar locations at the centre of each AT tract. At (A/T)10sites
distamycin binds with similar affinity to T5A5, (TA)5and AATT, though bands in
the centre of (TA)5are protected at approximately 50-fold lower concentration
than those towards the edges. Hoechst 33258 shows a similar pattern of
preference, with strong binding to AATT, T5A5and the centre of (TA)5. Hydroxyl
radical footprinting reveals that at low concentrations both ligands bind at the
centre of (TA)5and A5T5, while at higher concentrations ligand molecules bind to
each end of the (A/T)10tracts. At T5A5two ligand molecules bind at either end of
the site, even at the lowest ligand concentration, consistent with the suggestion
that these compounds avoid the TpA step. Similar DNase I footprinting experiments
with a DNA fragment containing T n (n = 3-6) tracts reveals that both ligands
bind in the order T3< T4 << T5 = T6.
PMID- 9396804
TI - A structure-specific endonuclease from cauliflower (Brassica oleracea var.
botrytis) inflorescence.
AB - A protein with structure-specific endonuclease activity has been purified to near
homogeneity from cauliflower ( Brassica oleracea var. botrytis) inflorescence
through five successive column chromatographies. The protein is a single
polypeptide with a molecular mass of 40 kDa. Using three different branched DNA
structures (flap, pseudo-Y and stem-loop) we found that the enzyme, a cauliflower
structure-specific endonuclease, cleaved the single-stranded tail in the 5'-flap
and 5'-pseudo-Y structures, whereas it could not incise the 3'-flap and 3'-pseudo
Y structures. The incision points occur around the single strand-duplex junction
in these DNA substrates and the enzyme leaves 5'-PO4 and 3'-OH termini on DNA.
The protein also endonucleolytically cleaves on the 3'-side of the single
stranded region at the junction of unpaired and duplex DNA in the stem-loop
structure. The structure-specific endonuclease activity is stimulated by Mg2+ and
by Mn2+, but not by Ca2+. Like mammalian FEN-1, the protein has weak 5'-->3'
double-stranded DNA-specific exonuclease activity. These results indicate that
the cauliflower protein is a plant structure-specific endonuclease like mammalian
FEN-1 or may be the plant alternative.
PMID- 9396805
TI - The trypanosomatid Leptomonas collosoma 7SL RNA gene. Analysis of elements
controlling its expression.
AB - We have previously reported the co-purification of a tRNA-like molecule with the
Trypanosoma brucei SRP complex [Beja et al . (1993) Mol. Biochem. Parasitol . 57,
223-230]. To examine whether the trypanosome SRP has a unique composition
compared with that of other eukaryotes, we analyzed the 7SL RNA and the SRP
complex of the monogenetic trypanosomatid Leptomonas collosoma. The 7SL RNA from
L. collosoma was cloned, and its gene was sequenced. In contrast to T. brucei ,
two 7SL RNA transcripts were detected in L.collosoma that originate from a single
copy gene. Using stable cell lines expressing tagged 7SL RNA, we demonstrate that
the tRNAArggene located 98 bp upstream to the 7SL RNA serves as part of the 7SL
RNA extragenic promoter. The steady-state level of 7SL RNA was found to be
tightly regulated, since the presence of the gene on the multi-copy plasmid
repressed the synthesis of the chromosomal gene. Cell lines carrying truncated
7SL RNA genes were established and their expression indicated that domain I is
essential for expressing the 7SL RNA. No constructs carrying portions of the 7SL
RNA were expressed, except for a construct which lacked 23 nt from the 3'end of
the RNA. This suggests that 90% of the 7SL RNA molecule is important for its
maintenance as a stable small RNA. We propose that the repression phenomenon may
originate from a regulatory mechanism that coordinates the level of the 7SL RNA
by its binding proteins.
PMID- 9396806
TI - The effect of structure in a long target RNA on ribozyme cleavage efficiency.
AB - Inhibition of gene expression by catalytic RNA (ribozymes) requires that
ribozymes efficiently cleave specific sites within large target RNAs. However,
the cleavage of long target RNAs by ribozymes is much less efficient than
cleavage of short oligonucleotide substrates because of higher order structure in
the long target RNA. To further study the effects of long target RNA structure on
ribozyme cleavage efficiency, we determined the accessibility of seven hammerhead
ribozyme cleavage sites in a target RNA that contained human immunodeficiency
virus type 1 (HIV-1) vif - vpr . The base pairing-availability of individual
nucleotides at each cleavage site was then assessed by chemical modification
mapping. The ability of hammerhead ribozymes to cleave the long target RNA was
most strongly correlated with the availability of nucleotides near the cleavage
site for base pairing with the ribozyme. Moreover, the accessibility of the seven
hammerhead ribozyme cleavage sites in the long target RNA varied by up to 400
fold but was directly determined by the availability of cleavage sites for base
pairing with the ribozyme. It is therefore unlikely that steric interference
affected hammerhead ribozyme cleavage. Chemical modification mapping of cleavage
site structure may therefore provide a means to identify efficient hammerhead
ribozyme cleavage sites in long target RNAs.
PMID- 9396808
TI - Differential effect of H1 variant overproduction on gene expression is due to
differences in the central globular domain.
AB - The in vivo overproduction of two mouse histone H1 variants in homologous mouse
fibroblasts has opposite effects on gene expression. Overproduction of H1(0)
results in repression of transcript levels of all polymerase II genes tested. In
contrast, overproduction of H1c results in elevated levels of transcripts. We
created a series of chimeric H1 genes in which the regions encoding the three
structural domains common to this family of these proteins were systematically
switched. Overexpression of these genes in vivo resulted in the accumulation of
large amounts of the chimeric H1 in chromatin. Analysis of the effects of
overproduction of these proteins revealed that the differential effect of H1
variant overproduction on gene expression is due to differences in the central
globular domain.
PMID- 9396807
TI - Information analysis of Fis binding sites.
AB - Originally discovered in the bacteriophage Mu DNA inversion system gin, Fis
(Factor for Inversion Stimulation) regulates many genetic systems. To determine
the base frequency conservation required for Fis to locate its binding sites, we
collected a set of 60 experimentally defined wild-type Fis DNA binding sequences.
The sequence logo for Fis binding sites showed the significance and likely kinds
of base contacts, and these are consistent with available experimental data.
Scanning with an information theory based weight matrix within fis, nrd, tgt/sec
and gin revealed Fis sites not previously identified, but for which there are
published footprinting and biochemical data. DNA mobility shift experiments
showed that a site predicted to be 11 bases from the proximal Salmonella
typhimurium hin site and a site predicted to be 7 bases from the proximal P1 cin
site are bound by Fis in vitro. Two predicted sites separated by 11 bp found
within the nrd promoter region, and one in the tgt/sec promoter, were also
confirmed by gel shift analysis. A sequence in aldB previously reported to be a
Fis site, for which information theory predicts no site, did not shift. These
results demonstrate that information analysis is useful for predicting Fis DNA
binding.
PMID- 9396809
TI - A rapid in vitro method for obtaining RNA accessibility patterns for
complementary DNA probes: correlation with an intracellular pattern and known RNA
structures.
AB - A technique is described to identify the rare sequences within an RNA molecule
that are available for efficient interaction with complementary DNA probes: the
target RNA is digested by RNase H in the presence of a random pool of
complementary DNA fragments generated from the same DNA preparation that was used
for target RNA synthesis. The DNA region was amplified by PCR, partially digested
with DNase and denatured prior to RNA binding. In the presence of single-stranded
DNA fragments the RNA was digested with RNase H such that, on average, each
molecule was cut once. Cleavage sites were detected by gel electrophoresis either
directly with end-labeled RNA or by primer extension. The pattern of accessible
sites on c- raf mRNA was determined and compared with the known profile of
activity of oligonucleotides found in cells, showing the merit of the method for
predicting oligonucleotides which are efficient for in vivo antisense targeting.
New susceptible sites in the 3'-untranslated region of c- raf mRNA were
identified. Also, four RNAs were probed to ascertain to what extent structure
predicts accessibility: the P4-P6 domain of the Tetrahymena group I intron, yeast
tRNAAsp, Escherichia coli tmRNA and a part of rat 18S rRNA.
PMID- 9396810
TI - Effects of heterologous downstream sequences on the activity of the HIV-1
promoter and its response to Tat.
AB - In HIV-1 infection, Tat acts at least in part to control transcriptional
elongation by overcoming premature transcriptional termination. In some other
genes this process is governed by DNA elements called attenuators in concert with
cellular transcription factors. To understand the action of Tat more fully and
explore its role as an anti-attenuator, we examined the ability of several
natural and synthetic attenuation sequences to modulate transcription initiated
at the HIV LTR. Fragments containing these signals were inserted downstream of
the TAR element in an HIV-CAT chimera and their effects on transcription were
assessed both in vitro and in vivo. Runoff transcription assays in HeLa cell
extracts demonstrated that the attenuators give rise to premature termination of
transcripts initiated from the heterologous HIV-LTR promoter in vitro. When
transiently expressed following transfection into Cos cells, however, premature
transcript termination at the attenuation site was not observed. Nevertheless,
many of the inserted sequences exerted marked effects on CAT gene expression and
on transactivation by Tat at both the RNA and protein levels. The nature and
magnitude of the effects depended upon the identity of the attenuator and its
orientation but only one of 16 sequences tested met the criteria for a Tat
suppressible attenuator in vivo. One other sequence, in contrast, severely
reduced Tat-activated transcription without inhibiting basal transcription These
results indicate that sequences downstream of the HIV LTR can influence its
function as a promoter and its response to Tat transactivation, but lend little
support to their role as attenuators in vivo.
PMID- 9396811
TI - HUB1, a novel Kruppel type zinc finger protein, represses the human T cell
leukemia virus type I long terminal repeat-mediated expression.
AB - We have shown that human T-cell leukemia virus type I (HTLV-I) gene expression is
negatively regulated by the U5 repressive element (U5RE) of its long terminal
repeat (LTR). To isolate factors binding to U5RE, we screened a cDNA expression
library by south-western blotting with a U5RE probe. Screening 2 x10(6) clones
gave a positive clone with a 3.8 kb insert encoding a novel 671 residue
polypeptide, named HTLV-I U5RE binding protein 1 (HUB1), with five zinc finger
domains and a Kruppel-associated box like domain; HUB1 may be related to a
repressor belonging to the Kruppel type zinc finger protein. A 4.0 kb mRNA for
HUB1 is ubiquitously expressed among all human tissues tested. HUB1 recognizes
the TCCACCCC sequence as a core motif and exerts a strong repressive effect on
HTLV-I LTR-mediated expression. A new repressive domain, named HUB1 repressive
(HUR) domain, was identified, rather than the Kruppel-associated box like domain.
The N-terminal region upstream of HUR domain seemed to be also indispensable to
the repression. Thus, we propose that HUB1 is a new type repressor and plays an
important role in the HTLV-I U5-mediated repression.
PMID- 9396812
TI - Genetic interactions of conserved regions in the DEAD-box protein Prp28p.
AB - The yeast PRP28 g ene has been implicated in nuclear precursor messenger RNA (pre
mRNA) splicing, a two-step reaction involved in a multitude of RNA structural
alterations. Prp28p, the gene product of PRP28 , is a member of the
evolutionarily conserved DEAD-box proteins (DBPs). Members of DBPs are involved
in a variety of RNA-related biochemical processes, presumably by their putative
RNA helicase activities. Prp28p has been speculated to play a role in melting the
duplex between U4 and U6 small nuclear RNAs (snRNAs), leading to the formation of
an active spliceosome. To study the function of Prp28p and its interactions with
other components of the splicing machinery, we have isolated and characterized a
large number of prp28 conditional mutants. Strikingly, many of these prp28
mutations are localized in the highly conserved motifs found in all the DBPs.
Intragenic reversion analysis suggests that regions of motifs II, III and V, as
well as of motifs I and IV, in Prp28p are likely to be in close proximity to each
other. Our results thus provide the first hint of the local structural
arrangement for Prp28p, and perhaps for other DBPs as well.
PMID- 9396813
TI - Identification of DNA replication and cell cycle proteins that interact with
PCNA.
AB - The identity of DNA replication proteins and cell cycle regulatory proteins which
can be found in complexes involving PCNA were investigated by the use of PCNA
immobilized on Sepharose 4B. A column containing bovine serum albumin (BSA) bound
to Sepharose was used as a control. Fetal calf thymus extracts were
chromatographed on PCNA-Sepharose and BSA-Sepharose. The columns were washed and
then eluted with 0.5 M KCl. The salt eluates were examined for the presence of
both DNA replication proteins (Pol alpha, delta, straightepsilon, PCNA, RFC, RFA,
DNA ligase I, NDH II, Topo I and Topo II) and cell cycle proteins (Cyclins A, B1,
D1, D2, D3, E, CDK2, CDK4, CDK5 and p21) by western blotting with specific
antibodies. The DNA replication proteins which bound to PCNA-Sepharose included
DNA polymerase delta and straightepsilon, PCNA, the 37 and 40 kDa subunits of
RFC, the 70 kDa subunit of RPA, NDH II and topoisomerase I. No evidence for the
binding of DNA polymerase alpha, DNA ligase I or topoisomerase II was obtained.
Of the cell cycle proteins investigated, CDK2, CDK4 and CDK5 were bound. This
study presents strong evidence that PCNA is a component of protein complexes
containing DNA replication, repair and cell cycle regulatory proteins.
PMID- 9396814
TI - Reactivation of denatured proteins by domain V of bacterial 23S rRNA.
AB - In vitro transcripts containing domain V of the 23S rRNA of Escherichia coli and
Bacillus subtilis can reactivate denatured proteins almost as efficiently as the
total 23S rRNA. Here we show that almost the full length of domain V is required
for reactivation of denatured pig muscle lactate dehydrogenase and pig heart
cytoplasmic malate dehydrogenase: the central loop of this domain alone is not
enough for this purpose. The antibiotic chloramphenicol, which binds to domain V
of 23S rRNA, can inhibit reactivation of these proteins completely. Activity is
eliminated by EDTA at a concentration of <1 mM, even in the presence of 4 mM
MgCl2, suggesting that the three-dimensional conformation of the RNA should be
maintained for this activity.
PMID- 9396815
TI - The methylated DNA binding protein-2-H1 (MDBP-2-H1) consists of histone H1
subtypes which are truncated at the C-terminus.
AB - The methylated DNA binding protein-2-H1 (MDBP-2-H1), present in rooster liver, is
a member of the histone H1 family which inhibits transcription by binding
selectively to methylated promoters. Here we have determined the primary
structure of MDBP-2-H1. A comparison between histone H1 and MDBP-2-H1 was
achieved by analyzing reversed phase HPLC-purified and V8-digested proteins by
mass spectrometry and/or microsequencing. In rooster liver the most abundant
histone H1 subtypes are H1 01 and H1 11L. Similarly, MDBP-2-H1 contains the same
subtypes of histone H1. The histone H1 subtype H1 01 in MDBP-2-H1 has 150 amino
acids, whereas the full-size histone H1 01 is 218 amino acids. The difference in
mass between the two proteins is explained by C-terminal truncation of histone H1
01.
PMID- 9396816
TI - Functional analysis of a replication origin from Saccharomyces cerevisiae:
identification of a new replication enhancer.
AB - Yeast replication origins have a modular arrangement of essential DNA sequences
containing the ARS consensus sequence (ACS) flanked by auxiliary DNA elements
which stimulate origin function. One of the auxiliary elements identified at
several origins is a DNA replication enhancer that binds the Abf1p protein. We
have isolated an ARS sequence from Saccharomyces cerevisiae based on its ability
to bind Abf1p. Here we present a detailed molecular dissection of this ARS,
designated ARS 1501, and we demonstrate that it functions as a genomic
replication origin on chromosome XV . Mutagenesis of the Abf1p DNA-binding sites
revealed that these sequences did not contribute significantly to ARS function.
Instead, a new DNA element important for replication, designated REN1501, has
been located 5' to the T-rich strand of the ACS. We show that REN1501 functions
in either orientation and at variable distances from the ACS, defining this
element as a DNA replication enhancer. Most significantly, point mutations within
this element decreased the stability of plasmids bearing ARS 1501, suggesting
that REN1501 binds a protein important for replication initiation. Only three
elements found at origins are known to specifically bind proteins. These include
the ARS essential sequences and the Abf1p and Rap1p DNA-binding sites. We show
that the function of REN1501 at the origin cannot be replaced by a Rap1p DNA
binding site or a site that binds the transcriptional factor Gal4p and can only
be partially substituted for by an Abf1p recognition sequence. This implies that
the role of the REN1501 element at the ARS 1501 origin is specific, and suggest
that the frequency of origin firing in eukaryotic cells may be regulated by
origin-specific enhancers.
PMID- 9396817
TI - Nested genetic bit analysis (N-GBA) for mutation detection in the p53 tumor
suppressor gene.
AB - There is a growing and significant demand for reliable, simple and sensitive
methods for repeated scanning of a given gene or gene fragment for detection and
characterization of mutations. Solid-phase sequencing by single base primer
extension of nested GBATM primers on miniaturized DNA arrays can be used to
effectively scan targeted sequences for missense, insertion and deletion
mutations. This paper describes the use of N-GBA arrays designed to scan the
sequence of a 33 base region of exon 8 of the p53 gene (codons 272-282)
encompassing a hot spot for mutations associated with the development of cancer.
Synthetic DNA templates containing various missense, insertion and deletion
mutations, as well as DNA prepared from pancreatic and biliary tumor cells, were
genotyped using the exon 8 arrays.
PMID- 9396819
TI - Minor groove DNA alkylation directed by major groove triplex forming
oligodeoxyribonucleotides.
AB - We describe sequence-specific alkylation in the minor groove of double-stranded
DNA by a hybridization-triggered reactive group conjugated to a triplex forming
oligodeoxyribonucleotide (TFO) that binds in the major groove. The 24 nt TFOs
(G/A motif) were designed to form triplexes with a homopurine tract within a 65
bp target duplex. They were conjugated to an N 5-methyl-cyclopropapyrroloindole
(MCPI) residue, a structural analog of cyclopropapyrroloindole (CPI), the
reactive subunit of the potent antibiotic CC-1065. These moieties react in the
DNA minor groove, alkylating adenines at their N3 position. In order to optimize
alkylation efficiency, linkers between the TFO and the MCPI were varied both in
length and composition. Quantitative alkylation of target DNA was achieved when
the dihydropyrroloindole (DPI) subunit of CC-1065 was incorporated between an
octa(propylene phosphate) linker and MCPI. The required long linker traversed one
strand of the target duplex from the major groove-bound TFO to deliver the
reactive group to the minor groove. Alkylation was directed by relative
positioning of the TFOs. Sites in the minor groove within 4-8 nt from the end of
the TFO bearing the reactive group were selectively alkylated.
PMID- 9396818
TI - Test of the potential of a dATP surrogate for sequencing via MALDI-MS.
AB - 1-(2'-Deoxy-beta-d-ribofuranosyl)-3-nitropyrrole phosphate was incorporated into
a DNA decamer and analyzed via matrix-assisted laser desorption ionization mass
spectrometry (MALDI-MS). The extent and composition of the various fragment peaks
were compared with those in the MALDI-MS spectrum of dT4AT5. The nitropyrrole
containing oligomer proved to be more robust. Two different DNA template assays
were then used to attempt to identify DNA replicating enzymes that would
incorporate the corresponding triphosphate, i.e. 1-(2'-deoxy-beta-d
ribofuranosyl)-3-nitropyrrole triphosphate (dXTP). It was shown that dXTP was not
incorporated by some enzymes and it inhibited others. However, DNA polymerase I
Klenow fragment and avian myeloblastosis virus reverse transcriptase incorporated
dXTP in place of dATP and then replicated the template overhang in the usual way.
The potential of dXTP as a surrogate for dATP in DNA sequencing with MALDI-MS
analysis is discussed.
PMID- 9396820
TI - Use of an engineered ribozyme to produce a circular human exon.
AB - We report the use of an engineered ribozyme to produce a circular human exon in
vitro. Specifically, we have designed a derivative of a yeast self-splicing group
II intron that is able to catalyze the formation of a circular exon encoding the
first kringle domain (K1) of the human tissue plasminogen activator protein. We
show that the circular K1 exon is formed with high fidelity in vitro.
Furthermore, the system is designed such that the circular exon that is produced
consists entirely of human exon sequence. Thus, our results demonstrate that all
yeast exon sequences are dispensable for group II intron catalyzed inverse
splicing. This is the first demonstration that an engineered ribozyme can be used
to create a circular exon containing only human sequences, linked together at a
precise desired ligation point. We expect these results to be generalizable, so
that similar ribozymes can be designed to precisely create circular derivatives
of any nucleotide sequence.
PMID- 9396821
TI - Retinoblastoma protein expression facilitates chromatin remodeling at the HLA-DRA
promoter.
AB - The major histocompatibility complex (MHC) class II genes encode a series of
heterodimeric cell surface glycoproteins that bind peptide antigen. The MHC class
II/peptide complex is bound by the T-cell receptor of CD4(+) T cells, thereby
stimulating an immune response. The MHC class II genes are coordinately regulated
by conserved promoter elements and are inducible by IFN-gamma. Furthermore, IFN
gamma induction of the MHC class II genes in solid human tumor lines requires
retinoblastoma protein (Rb). In vivo footprinting analyses of the HLA-DRA gene,
which encodes the heavy chain subunit of the human MHC class II molecule, HLA-DR,
revealed that Rb facilitates occupancy of multiple HLA-DRA promoter elements.
Detecting the effect of Rb on HLA-DRA promoter occupancy in vivo required IFN
gamma treatment. However, use of a variation on the in vivo footprinting
technique, nuclei footprinting, which assays for promoter occupancy in isolated
nuclei, revealed that expression of Rb facilitates promoter occupancy even in the
absence of IFN-gamma. These results indicate that expression of Rb leads to
modification of the chromatin environment of the HLA-DRA promoter independently
of transcription.
PMID- 9396822
TI - In vivo analyses of RNA polymerase I termination in Schizosaccharomyces pombe.
AB - Recent studies on the termination of rDNA transcription by RNA polymerase I in
Saccharomyces cerevisiae and Schizosaccharomyces pombe have suggested a more
complex mechanism then previously described in higher eukaryotes. Termination
appears to occur when a DNA-bound Reb1 protein molecule induces polymerase to
pause in the context of a release element [see Reeder,R.H. and Lang,W. (1994)
Mol. Microbiol ., 12, 11-15]. Because these conclusions in yeast were based
entirely on in vitro analyses, we have examined the same termination process in
S.pombe by expressing targeted mutations in vivo . S1nuclease protection studies
indicate three tandemly arranged termination sites with most transcripts very
efficiently terminated at the first site, 267 nt after the 3' end of the mature
25S rRNA sequence. Termination at each site is mediated by conserved terminator
elements which bear limited sequence homology with that of mouse and also can be
identified in S.cerevisiae . Removal of the first terminator element transfers
dominance to the second site and construction of a new single terminator element
at +150 still results in efficient termination and rRNA processing without a need
for an additional upstream element. Genomic 'footprint' analyses and gel
retardation assays confirm a process mediated by a strongly interacting protein
factor but implicate an alternate binding site. Removal of the 5' flanking
sequence or structure also had no effect on the site or efficiency of
termination. Taken together the results in vivo suggest that the termination
process in this fission yeast more strongly resembles the single element-mediated
mechanism initially reported in mouse and is not dependent on additional upstream
sequence as first reported in S.cerevisiae and postulated to function in general.
PMID- 9396824
TI - Single substitutions of phosphorothioates in the HDV ribozyme G73 define regions
necessary for optimal self-cleaving activity.
AB - Phosphorothioate (NTPalphaS) analogues were incorporated into the HDV genomic
ribozyme by transcription with T7 polymerase. The introduction of a sulfur in
place of the pro-Rp oxygen at the phosphate 5'to positions A64, A63, A43, U27,
G62, C61, C44, C41, C22and C21appeared to inhibit self-cleavage activity of the
G73 genomic ribozyme. Except for position C22, elevated levels of Mg2+rescued the
reaction to various extents. When the sites were identified in the RNA sequence,
they were clustered in three distinct regions that, in the secondary structure
models, are predicted to be primarily single-stranded. Two of these regions have
been proposed to form extensive interactions that are thought to involve a
homopurine base pair. The third region is thought to be directly associated with
assembly of the cleavage site.
PMID- 9396825
TI - Detection of a single base exchange in PCR-amplified DNA fragments using agarose
gel electrophoresis containing bisbenzimide-PEG.
AB - Using PCR fragments of known sequences derived from isolates of two related
fungal species, simple submarine electrophoresis in agarose gels containing a
bisbenzimide-PEG conjugate (H.A.-Yellow) has been shown to be capable of
distinguishing DNA fragments 567 bp long which differ by as little as a single
base change. However, only changes affecting bisbenzimide binding sites (which
consist of at least four consecutive A/T bases) alter mobility; other changes are
ineffective. A second ligand (H.A.-Red) with high G/C specificity is suggested
which may be as effective in detecting other sequence changes.
PMID- 9396823
TI - The proofreading domain of Escherichia coli DNA polymerase I and other DNA and/or
RNA exonuclease domains.
AB - Prior sequence analysis studies have suggested that bacterial ribonuclease
(RNase) Ds comprise a complete domain that is found also in Homo sapiens
polymyositis-scleroderma overlap syndrome 100 kDa autoantigen and Werner syndrome
protein. This RNase D 3'-->5' exoribonuclease domain was predicted to have a
structure and mechanism of action similar to the 3'-->5' exodeoxyibonuclease
(proofreading) domain of DNA polymerases. Here, hidden Markov model (HMM) and
phylogenetic studies have been used to identify and characterise other sequences
that may possess this exonuclease domain. Results indicate that it is also
present in the RNase T family; Borrelia burgdorferi P93 protein, an
immunodominant antigen in Lyme disease; bacteriophage T4 dexA and Escherichia
coli exonuclease I, processive 3'-->5' exodeoxyribonucleases that degrade single
stranded DNA; Bacillus subtilis dinG, a probable helicase involved in DNA repair
and possibly replication, and peptide synthase 1; Saccharomyces cerevisiae Pab1p
dependent poly(A) nuclease PAN2 subunit, required for shortening mRNA poly(A)
tails; Caenorhabditis elegans and Mus musculus CAF1, transcription factor CCR4
associated factor 1; Xenopus laevis XPMC2, prevention of mitotic catastrophe in
fission yeast; Drosophila melanogaster egalitarian, oocyte specification and axis
determination, and exuperantia, establishment of oocyte polarity; H.sapiens
HEM45, expressed in tumour cell lines and uterus and regulated by oestrogen; and
31 open reading frames including one in Methanococcus jannaschii . Examination of
a multiple sequence alignment and two three-dimensional structures of
proofreading domains has allowed definition of the core sequence, structural and
functional elements of this exonuclease domain.
PMID- 9396826
TI - Microwave-assisted rapid deprotection of oligodeoxyribonucleotides.
AB - A novel method for the deprotection of oligodeoxyribonucleotides under microwave
irradiation has been developed. The oligodeoxynucleotides having base labile,
phenoxyacetyl (pac), protection for exocyclic amino functions were fully
deprotected in 0. 2 M sodium hydroxide (methanol:water : : 1:1, v/v) = A and 1 M
sodium hydroxide (methanol:water : : 1:1, v/v) = B using microwaves in 4 and 2
min, respectively. The deprotection of oligodeoxyribonucleotides carrying
conventional protecting groups, dAbz, dCbzand dGpac, for exocyclic amino
functions was achieved in 4 min in B without any side product formation. The
deprotected oligonucleotides were compared with the oligomers deprotected using
standard deprotection conditions (29% aq. ammonia, 16 h, 55 degrees C) with
respect to their retention time on HPLC and biological activity.
PMID- 9396827
TI - RAPD-based screening of genomic libraries for positional cloning.
AB - RAPD markers are frequently used for positional cloning. However, RAPD markers
often contain repeated sequences which prevent genomic library screening by
hybridisation. We have developed a simple RAPD analysis of genomic libraries
based on the identification of cosmid pools and clones amplifying the RAPD marker
of interest. Our method does not require the cloning or characterisation of the
RAPD marker as it relies on the analysis of cosmid pools or clones using a simple
RAPD protocol. We applied this strategy using four RAPD markers composed of
single copy or repeated sequences linked to avirulence genes of the rice blast
fungus Magnaporthe grisea . Cosmids containing these RAPD markers were easily and
rapidly identified allowing the construction of physical contigs at these loci.
PMID- 9396828
TI - Antibody-ribosome-mRNA (ARM) complexes as efficient selection particles for in
vitro display and evolution of antibody combining sites.
AB - We describe a rapid, eukaryotic, in vitro method for selection and evolution of
antibody combining sites using antibody-ribosome-mRNA (ARM) complexes as
selection particles. ARMs carrying single-chain (VH/K) binding fragments specific
for progesterone were selected using antigen-coupled magnetic beads; selection
simultaneously captured the genetic information as mRNA, making it possible to
generate and amplify cDNA by single-step RT-PCR on the ribosome-bound mRNA for
further manipulation. Using mutant libraries, antigen-binding ARMs were enriched
by a factor of 10(4)-10(5)-fold in a single cycle, with further enrichment in
repeated cycles. While demonstrated here for antibodies, the method has the
potential to be applied equally for selection of receptors or peptides from
libraries.
PMID- 9396829
TI - A 71-kDa protein from Halobacterium salinarium belongs to a ubiquitous P-loop
ATPase superfamily with head-rod-tail structure.
AB - The nucleotide sequence of a genomic fragment from Halobacterium salinarium
containing an open reading frame encoding a protein with a calculated molecular
mass of 71 kDa was determined. Database searches revealed that this protein,
Hp71, has similarities to eukaryotic cytoskeletal proteins. Heterologous
production of Hp71 in Escherichia coli allowed the isolation of anti-Hp71
antibodies. The antibodies were used (1) to verify the production of Hp71 in H.
salinarium and (2) to determine its cytoplasmic localization by immune electron
microscopy. Homologous overproduction of Hp71 in H. salinarium and heterologous
production in Haloferax volcanii resulted in modifications of cell morphology
from rods to extended rods, and from pleiomorphic cells to rods, respectively.
Structure prediction methods indicated that Hp71 has a head-rod-tail
configuration, including an N-terminal domain with a nucleotide binding motif (P
loop), and an extended discontinuous coiled-coil domain of 330 amino acids. To
identify related proteins, the complete genomes of Haemophilus influenzae,
Mycoplasma genitalium, and Methanococcus jannaschii were searched for deduced
proteins with extended coiled-coil domains. Only one or two proteins were found
for each organism, showing that Hp71 is one of only a few prokaryotic
intracellular proteins with extended coiled-coil domains. The phenotype upon
overproduction and the similarity of Hp71 to the SMC superfamily of P-loop head
rod-tail proteins (named after SMC1, which is involved in the "stability of
minichromosomes" in yeast) indicate that Hp71 might be involved in cytoskeleton
formation and/or chromosome partitioning in H. salinarium.
PMID- 9396830
TI - Growth at low temperature causes nitrogen limitation in the cyanobacterium
Synechococcus sp. PCC 7002.
AB - The coloration of cells of the cyanobacterium Synechococcus sp. PCC 7002 changed
from normal blue-green to yellow-green when cells were grown at 15 degrees C in a
medium containing nitrate as the sole nitrogen source. This change of coloration
was similar to a general response to nutrient deprivation (chlorosis). For the
chlorotic cells at 15 degrees C, the total amounts of phycobiliproteins and
chlorophyll a decreased, high levels of glycogen accumulated, and growth was
arithmetic rather than exponential. These changes in composition and growth
occurred in cells grown at low (50 microE m-2 s-1) as well as high (250 microE m
2 s-1) light intensity. After a temperature shift-up to 38 degrees C, chlorotic
cells rapidly regained their normal blue-green coloration and normal exponential
growth rate within 7 h. When cells were grown at 15 degrees C in a medium
containing urea as the reduced nitrogen source, cells grew exponentially and the
symptoms of chlorosis were not observed. The decrease in photosynthetic oxygen
evolution activity at low temperature was much smaller than the decrease in
growth rate for cells grown on nitrate as the nitrogen source. These studies
demonstrate that low-temperature-induced chlorosis of Synechococcus sp. PCC 7002
is caused by nitrogen limitation and is not the result of limited photosynthetic
activity or photodamage to the photosynthetic apparatus, and that nitrogen
assimilation is an important aspect of the low-temperature physiology of
cyanobacteria.
PMID- 9396832
TI - Purification and characterization of 9-hexadecenoic acid cis-trans isomerase from
pseudomonas sp. strain E-3
AB - A 9-hexadecenoic acid cis-trans isomerase (9-isomerase) that catalyzed the cis-to
trans isomerization of the double bond of free 9-cis-hexadecenoic acid [16:1(9c)]
was purified to homogeneity from an extract of Pseudomonas sp. strain E-3 and
characterized. Electrophoresis of the purified enzyme on both incompletely
denaturing and denaturing polyacrylamide gels yielded a single band of a protein
with a molecular mass of 80 kDa, suggesting that the isomerase is a monomeric
protein of 80 kDa. The 9-isomerase, assayed with 16:1(9c) as a substrate, had a
specific activity of 22.8 &mgr;mol h-1 (mg protein)-1 and a Km of 117.6 mM. The
optimal pH and temperature for catalysis were approximately pH 7-8 and 30 degrees
C, respectively. The 9-isomerase catalyzed the cis-to-trans conversion of a
double bond at positions 9, 10, or 11, but not that of a double bond at position
6 or 7 of cis-mono-unsaturated fatty acids with carbon chain lengths of 14, 15,
16, and 17. Octadecenoic acids with a double bond at position 9 or 11 were not
susceptible to isomerization. These results suggest that 9-isomerase has a strict
specificity for both the position of the double bond and the chain length of the
fatty acid. The enzyme catalyzed the cis-to-trans isomerization of fatty acids in
a free form, and in the presence of a membrane fraction it was also able to
isomerize 16:1(9c) esterified to phosphatidylethanolamine. The 9-isomerase was
strongly inhibited by catecholic antioxidants such as alpha-tocopherol and
nordihydroguaiaretic acid, but was not inhibited by 1, 10-phenanthroline or EDTA
or under anoxic conditions. Based on these results, the possible mechanism of
catalysis by this enzyme is discussed.
PMID- 9396831
TI - Alteration of low-temperature susceptibility of the cyanobacterium Synechococcus
sp. PCC 7002 by genetic manipulation of membrane lipid unsaturation.
AB - Cyanobacteria acclimate to low temperature by desaturating their membrane lipids.
Mutant strains of Synechococcus sp. PCC 7002 containing insertionally inactivated
desA (Delta12 acyl-lipid desaturase) and desB (omega3 acyl-lipid desaturase)
genes were produced, and their low-temperature susceptibility was characterized.
The desA mutant synthesized no linoleic acid or alpha-linolenic acid, and the
desB mutant did not produce alpha-linolenic acid. The desA mutant grew more
slowly than the wild-type at 22 degrees C and could not grow at 15 degrees C. The
desB mutant could not continuously grow at 15 degrees C, although no observable
phenotype appeared at higher temperatures. It has been shown that expression of
the desA gene occurs at 38 degrees C and is up-regulated at 22 degrees C, and
that the desB gene is only expressed at 22 degrees C. These results indicate that
the expression of the desA and desB genes occurs at higher temperatures than
those at which a significant decline in physiological activities is caused by the
absence of their products. The temperature dependency of photosynthesis was not
affected by these mutations. Since chlorosis and inability to grow at 15 degrees
C with nitrate was suppressed by the substitution of urea as a nitrogen source,
it is very likely that the chilling susceptibility of the desaturase mutants is
attributable to nutrient limitation.
PMID- 9396833
TI - Degradation of p-nitrophenol by the phototrophic bacterium Rhodobacter
capsulatus.
AB - The phototrophic bacterium Rhodobacter capsulatus detoxified p-nitrophenol and 4
nitrocatechol. The bacterium tolerated moderate concentrations of p-nitrophenol
(up to 0.5 mM) and degraded it under light at an optimal O2 pressure of 20 kPa.
The bacterium did not metabolize the xenobiotic in the dark or under strictly
anoxic conditions or high O2 pressure. Bacterial growth with acetate in the
presence of p-nitrophenol took place with the simultaneous release of
nonstoichiometric amounts of 4-nitrocatechol, which can also be degraded by the
bacterium. Crude extracts from R. capsulatus produced 4-nitrocatechol from p
nitrophenol upon the addition of NAD(P)H, although at a very low rate. A
constitutive catechol 1, 2-dioxygenase activity yielding cis,cis-muconate was
also detected in crude extracts of R. capsulatus. Further degradation of 4
nitrocatechol included both nitrite- and CO2-releasing steps since: (1) a strain
of R. capsulatus (B10) unable to assimilate nitrate and nitrite released nitrite
into the medium when grown with p-nitrophenol or 4-nitrocatechol, and the nitrite
concentration was stoichiometric with the 4-nitrocatechol degraded, and (2)
cultures of R. capsulatus growing microaerobically produced low amounts of 14CO2
from radiolabeled p-nitrophenol. The radioactivity was also incorporated into
cellular compounds from cells grown with uniformly labeled 14C-p-nitrophenol.
From these results we concluded that the xenobiotic is used as a carbon source by
R. capsulatus, but that only the strain able to assimilate nitrite (E1F1) can use
p-nitrophenol as a nitrogen source.
PMID- 9396834
TI - Skew or third moment of bacterial generation times.
AB - We studied two statistical hypotheses for the occurrence of cellular division and
compared these hypotheses to available data. The two models were tested by
observed distributions of cellular size during steady-state growth. The 30-year
old sloppy size model could be rejected, whereas the recently developed
incremental size proposal could not. The latter proposition was accepted by
default. We concluded that the time between successive divisions is not simply
derived from extant size at cellular division, but rather from interdivisional
size increment. We therefore propose that cellular division is regulated by the
need of cells at birth to accumulate a certain amount of mass or something
related to mass before division.
PMID- 9396835
TI - The Alcaligenes eutrophus hemN gene encoding the oxygen-independent
coproporphyrinogen III oxidase, is required for heme biosynthesis during
anaerobic growth.
AB - The insertion mutant HF231 of Alcaligenes eutrophus H16 failed to grow
anaerobically on nitrate and nitrite. When grown under oxygen limitation, mutant
HF231 specifically excreted coproporphyrin III, an intermediate of heme
biosynthesis. With the help of a Tn5-labeled fragment, we identified and cloned
the corresponding wild-type fragment. Sequence analysis of the mutant locus
revealed an open reading frame consisting of 1,473 bp, predicting a protein of
491 amino acids that corresponds to a size of 54.2 kDa. In the non-coding
upstream region, consensus elements that are indicative for binding sites of the
anaerobic transcriptional regulator Fnr were identified. The deduced polypeptide
showed extensive sequence similarity with various bacterial oxygen-independent
coproporphyrinogen III oxidases designated HemN. HemN catalyzes the oxidative
decarboxylation of coproporphyrinogen III to yield protoporphyrinogen IX.
Anaerobic growth on nitrate and nitrite of mutant HF231 was restored by
introducing the hemN gene of A. eutrophus or of Pseudomonas aeruginosa on a broad
host-range vector. Likewise, the A. eutrophus hemN complemented heme biosynthesis
of a Salmonella typhimurium hemF/hemN double mutant during anaerobic and aerobic
growth. Analysis of a transcriptional lacZ gene fusion showed that expression of
hemN in A. eutrophus is nitrate-independent and repressed by oxygen.
PMID- 9396836
TI - Analysis of changes in congener selectivity during PCB degradation by
Burkholderia sp. strain TSN101 with increasing concentrations of PCB and
characterization of the bphBCD genes and gene products.
AB - We isolated and characterized a gram-negative bacterium, Burkholderia sp. strain
TSN101, that can degrade polychlorinated biphenyls (PCBs) at concentrations as
high as 150 microg Kaneclor 300/ml, a PCB mixture equivalent to Aroclor 1242.
Growing cells of strain TSN101 degraded most of the tri- and tetrachlorobiphenyls
in medium containing 25 microg Kaneclor 300/ml. Using PCB concentrations of 50
150 microg of Kaneclor 300/ml, the congener selectivity pattern was different and
the pattern of chlorine substitution strongly affected degradation of some
congeners. At 25 microg Kaneclor 300/ml, strain TSN101 degraded di- and
trichlorinated congeners with chlorine substitutions at both the ortho and the
para positions. At higher concentrations of Kaneclor 300, di- and
trichlorobiphenyls with ortho substituents in both phenyl rings were not degraded
well. Trichlorobiphenyls with para and meta substitutents were degraded equally
well at all concentrations studied. The ability of strain TSN101 to degrade ortho
and para-substituted congeners was confirmed using a defined PCB mixture with
chlorine substituents at 2'- and 4'-positions. A 5-kb DNA fragment containing the
bphBCD genes was cloned and sequenced. Comparison of the deduced amino acid
sequences of these genes with related proteins indicated 99 and 98% sequence
similarity to the BphB and BphD of Comamonas testosteroni strain B-356,
respectively. The bphC gene product showed 74% sequence similarity to the BphC of
Burkholderia cepacia strain LB400 and exhibited a narrow substrate specificity
with strong affinity for 2, 3-dihydroxybiphenyl. A bphC-disrupted mutant of
Burkholderia sp. strain TSN101, constructed by gene replacement, lost the ability
to utilize biphenyl, thus supporting the role of the cloned bph gene in biphenyl
metabolism.
PMID- 9396838
TI - Amino acid degradation by the mesophilic sulfate-reducing bacterium
desulfobacterium vacuolatum
AB - Desulfobacterium vacuolatum strain IbRM was able to grow using casamino acids as
a source of carbon, energy and nitrogen. Growth was accompanied by utilization of
several amino acids and sulfide production. Proline and glutamate were used
preferentially and to the greatest extent. Glycine, serine and alanine were used
more slowly and only after proline and glutamate were used. Isoleucine, valine,
leucine and aspartate decrease was slowest and occurred in a linear fashion
throughout the growth phase. Amino acids used from casamino acids, excluding
aspartate, were also used as single carbon, energy and nitrogen sources. As a
single amino acid, aspartate could only be used as a nitrogen source. Aspartate
was not used as an electron acceptor. No growth occurred on any amino acid in the
absence of sulfate. As single substrates, isoleucine, proline and glutamate were
oxidized without formation of acetate and with molar yields of 13.1, 9.4 and 7.7
g mol-1, respectively.
PMID- 9396837
TI - Functional expression in Escherichia coli of the Haemophilus influenzae gene
coding for selenocysteine-containing selenophosphate synthetase.
AB - The selenophosphate synthetases from several organisms contain a selenocysteine
residue in their active site where the Escherichia coli enzyme contains a
cysteine. The synthesis of these enzymes, therefore, depends on their own
reaction product. To analyse how this self-dependence is correlated with the
selenium status, e.g. after recovery from severe selenium starvation, we
expressed the gene for the selenocysteine-containing selenophosphate synthetase
from Haemophilus influenzae (selDHI) in an E. coli DeltaselD strain. Gene selDHI
gave rise to a selenium-containing gene product and also supported - via its
activity - the formation of E. coli selenoproteins. The results provide evidence
either for the suppression of the UGASec codon with the insertion of an amino
acid allowing the formation of a functional product or for a bypass of the
selenophosphate requirement. We also show that the selenocysteine synthesis and
the insertion systems of the two organisms are fully compatible despite
conspicuous differences in the mRNA recognition motif.
PMID- 9396839
TI - Spontaneous mutation in a thermoacidophilic archaeon: evaluation of genetic and
physiological factors
AB - We used direct selection of pyrE and pyrF mutants to estimate the rates of
spontaneous mutation in Sulfolobus acidocaldarius as a function of genetic
background and culture conditions. Fluctuation tests were applied to several
genetically marked strains, including one isolated as a putative mutator strain,
and to cultures grown over a wide range of temperature and other physiological
conditions. The results suggested some impact of auxotrophic markers on the
apparent rate of mutation, but no obvious pattern of effect of growth conditions,
including those that gave evidence of being physiologically stressful.
PMID- 9396840
TI - Tetrahydrofolate serves as a methyl acceptor in the demethylation of
dimethylsulfoniopropionate in cell extracts of sulfate-reducing bacteria.
AB - Tetrahydrofolate was shown to function as a methyl acceptor in the anaerobic
demethylation of dimethylsulfoniopropionate to methylthiopropionate in cell
extracts of the sulfate-reducing bacterium strain WN. Dimethylsulfoniopropionate
dependent activities were 0.56 micromol methyltetrahydrofolate min-1 (mg protein)
1 and were higher than required to explain the growth rate of strain WN on
dimethylsulfoniopropionate. The reaction did not require ATP or reductive
activation by titanium(III)-nitrilotriacetic acid. Preincubation of the extract
under air significantly decreased the activity (35% loss in 3 h). Three other
dimethylsulfoniopropionate-demethylating sulfate reducers, Desulfobacterium
niacini, Desulfobacterium vacuolatum, and Desulfobacterium strain PM4, had
dimethylsulfoniopropionate:tetrahydrofolate methyltransferase activities of 0.16,
0.05, and 0.24 micromol min-1 (mg protein)-1, respectively. No methyltransferase
activity to tetrahydrofolate was found with betaine as a substrate, not even in
extracts of betaine-grown cells of these sulfate reducers.
Dimethylsulfoniopropionate demethylation in cell extracts of strain WN was
completely inhibited by 0.5 mM propyl iodide; in the light, the inhibition was
far less strong, indicating involvement of a corrinoid-dependent
methyltransferase.
PMID- 9396841
TI - Desulfovibrio inopinatus, sp. nov., A new sulfate-reducing bacterium that
degrades hydroxyhydroquinone (1,2,4-trihydroxybenzene)
PMID- 9396842
TI - Rashkind dedication.
PMID- 9396843
TI - History of pediatric interventional catheterization: pediatric therapeutic
cardiac catheterizations.
PMID- 9396844
TI - "Physicians must abandon the illusion of autonomy . . .".
AB - Radical changes are occurring in medicine which are impacting the practicing
physician. This is especially true for specialists caring for very acutely ill
patients such as those with congenital heart disease. This article explores
developments such as the reversal of fiscal and medical paradigms, risk-averse
behavior, price-based costing, and competing physician priorities. Special
emphasis is directed to issues in pediatric cardiology. Suggestions for action
are made, the primary of which is that physicians must abandon the illusion of
autonomy in order to acquire the reality of collective influence on the practice
of medicine.
PMID- 9396845
TI - Balloon pulmonary valvuloplasty.
PMID- 9396846
TI - Innovative approaches to interventional pediatric cardiology: different pokes for
different folks.
PMID- 9396847
TI - Transcatheter treatment of coarctation of the aorta: a review.
PMID- 9396848
TI - Catheterization treatment of stenosis and hypoplasia of pulmonary arteries.
AB - Stenosis of pulmonary arteries is one of the most challenging problems requiring
treatment in the care of patients with congenital and acquired cardiopulmonary
disease. Surgical approaches have been met with difficulty over the years, and
may themselves lead to further distortion of the treated arteries. Balloon
dilation first came into use in the 1980s, and has proved moderately effective.
Its use has been extended to proximal pulmonary valve stenosis in order to
improve distal flow and artery growth in some variants of tetralogy of Fallot.
More recently, the judicious application of stent implantation has improved the
outlook for pulmonary artery stenosis. The etiology, treatment (with balloon
dilation and stent placement), and prognosis of pulmonary arterial stenosis will
be discussed.
PMID- 9396849
TI - Transcatheter management of venous stenosis.
PMID- 9396850
TI - Oops-the balloon burst before the stent was deployed!
PMID- 9396852
TI - Pediatric cardiovascular embolization therapy.
AB - Transcatheter embolization of superfluous vascular structures has assumed an
important role in pediatric interventional cardiology. A variety of devices and
materials are being used to treat an increasing number of unwanted arterial,
venous, and surgically created vascular connections. In general, the occlusion
techniques are simple, the results are good, and the complication rates are low.
The current indications, devices, materials, methods, applications, and results
of pediatric cardiovascular embolization therapy are described.
PMID- 9396851
TI - Transcatheter management of patent ductus arteriosus.
PMID- 9396853
TI - Per-catheter ASD closure.
AB - Per-catheter devices for atrial septal defect (ASD) closure have been evolving
since 1974. The four major devices available for use on a limited basis in early
1997 are reviewed. These include (in alphabetical order) the Angel Wing device,
the ASDOS device, the Buttoned device, and the CardioSeal device (successor to
the Clamshell). Sufficient data have been collected to indicate that
transcatheter ASD closure is a viable alternative to surgery in selected
patients. The advantages of the concept of per-catheter closure over surgical
closure should lead to the continued development of devices and techniques for
per-catheter treatment of ASD and other septal defects in the years to come.
PMID- 9396854
TI - Electrical/ablational therapeutic cardiac catheterization.
PMID- 9396855
TI - Interventional pediatric cardiology: state of the art and future directions.
AB - Although the interventional pediatric cardiology began in the early 1950s, it was
not until the mid-1980s that a full spectrum of transcatheter interventions in
children could be undertaken including balloon atrial septostomy which has been
in usage since 1966. Enormous developments have occurred even from the mid-1980s
to date. In this review, current state-of-the-art for each broad area of
therapeutic catheterization is presented. A large variety of lesions could be
opened-up or closed, as the case may be and the results of these interventions
were either similar to or better than those reported for the alternative surgical
therapy. Indeed, therapeutic catheterization techniques have replaced the
conventional surgery for many lesions and are threatening to do so for others.
However, long-term follow-up results are scanty and are needed. Further
miniaturization of catheters/sheaths used in interventional pediatric cardiology
and development of new technology for the lesions which are not amenable to
currently available transcatheter methods are awaited. The future seems to be
bright for interventional pediatric cardiology.
PMID- 9396856
TI - Molecular analysis of skewed Tcra-V gene use in T-cell receptor beta-chain
transgenic mice.
AB - The influence of beta-chain diversity on the expressed T-cell receptor (TCR)
alpha-chain repertoire was investigated using transgenic mice which exclusively
express a single rearranged TCR beta-chain gene. Analysis of these mice using
alpha-chain-specific recombinant cDNA libraries showed that expression of the
transgene-encoded beta chain results in significant skewing in Tcra-V gene
segment usage vs nontransgenic mice. Skewing was most pronounced towards alpha
chains using TCRA-V segments. Sequence analysis of Tcra-V8-containing genes from
transgenic T cells revealed predominant use of a single Tcra-J segment (Tcra
J24), which was not detected in Tcra-V8 containing genes isolated from
nontransgenic T cells. Further analysis revealed that co-expression of Tcra-V8
with Tcra-J24 in beta-transgenic mice is exhibited almost exclusively by CD4+ T
cells, and is associated with a limited number of closely related N-regions.
Analysis of transgenic CD8+ T cells demonstrated predominant co-expression of
Tcra-V8 with another Tcra-J (Tcra-J30), together with a different, limited N
region sequence. We conclude that the composition of expressed beta chains can
profoundly influence the selection of companion alpha chains expressed in the
periphery, and that alpha-chain N and J regions play a crucial role in
discriminating between class I vs class II major histocompatibility complex (MHC)
restricted recognition. Further, these results are in agreement with recent data
concerning the crystal structure of the TCR, and most consistent with a model for
TCR structure in which the complementarity determining region (CDR)3alpha domain
participates in direct contact with the MHC.
PMID- 9396857
TI - Characterization of chimpanzee TCRV gene polymorphism: how old are human TCRV
alleles?
AB - The functional relevance of the majority of human T-cell receptor A and B
variable region gene polymorphisms is controversial. Studies of human and
nonhuman primate major histocompatibility complex (MHC) class I and II
polymorphisms show that allelic lineages predate human speciation and indicate
that selection favors the long-term maintenance of these advantageous mutations.
We investigated at the DNA level whether 15 human TCRA and B polymorphisms exist
in contemporary chimpanzee populations. Polymorphisms consisted of variable
region replacements, a recombination signal sequence base change, and silent
mutations. With one exception, none of these human TCR polymorphisms were
observed in contemporary chimpanzees. Investigation of the same polymorphisms in
a range of other nonhuman primates showed little evidence of the existence of
human polymorphism prespeciation. Chimpanzee TCRAV and BV regions were however
polymorphic for variation so far not observed in human groups. Levels of
mitochondrial and nuclear DNA sequence variation in contemporary chimpanzees
suggest that population bottlenecks have not been a feature of chimpanzee
evolution and it is therefore probable that most human TCR polymorphisms have
evolved in the estimated five million years since the speciation of human and
chimpanzees. Thus, over the evolutionary time period studied, ancient TCRA and B
polymorphisms have not been maintained by selection to the same degree as
postulated for MHC polymorphisms.
PMID- 9396858
TI - T-cell receptor variable alpha (TCRAV) polymorphisms in European, Chinese, South
American, AfroCaribbean, and Gambian populations.
AB - Interactions involving the T-cell receptor (TCR) and major histocompatibility
complex (MHC) are fundamental to the generation of a specific immune response.
The study of interpopulation differences in TCR genes may identify those genes
which are subject to selection, and also provides useful information for future
genetic studies in these populations. In this study we present analysis of five
TCRAV polymorphisms, for V5S1, V6S1, V8S1, V17S1, and V21S1 loci in five human
populations by single-strand conformational polymorphism (SSCP) analysis.
Caucasian, Chinese, Gambian, AfroCaribbean, and South American Indians (Mapuches)
showed marked interpopulation variation for both the silent (V5S1, V17S1, and
V21S1) and coding (V6S1 and V8S1) polymorphisms. In general the alleles were
conserved in the different populations, but new, additional variants were found
for V5S1 and V17S1 in Gambians and Caucasians. V6S1 overall showed the highest
nucleotide diversity, and V6S1 genotype distributions were skewed away from
expected values in Chinese and Mapuches. Analysis of allelic associations showed
a general lack of linkage disequilibrium between the loci, which was reflected by
the absence of strong population-specific haplotypes.
PMID- 9396859
TI - Characterization of 12 microsatellite loci of the human MHC in a panel of
reference cell lines.
AB - The human genome contains a large number of interspersed microsatellite repeats
which exhibit a high degree of polymorphism and are inherited in a Mendelian
fashion, making them extremely useful genetic markers. Several microsatellites
have been described in the HLA region, but allele nomenclature, a set of broadly
distributed controls, and typing methods have not been standardized, which has
resulted in discrepant microsatellite data between laboratories. In this report
we present a detailed protocol for genotyping microsatellites using a semi
automated fluorescence-based method. Twelve microsatellites within or near the
major histocompatibility complex (MHC) were typed in the 10th International
Histocompatibility Workshop homozygous typing cell lines (HTCs) and alleles were
designated based on size. All loci were sequenced in two HTCs providing some
information on the level of complexity of the repeat sequence. A comparison of
allele size obtained by genotyping versus that obtained by direct sequencing
showed minor discrepancies in some cases, but these were not unexpected given the
technical differences in the methodologies. Fluorescence-based typing of
microsatellites in the MHC described herein is highly efficient, accurate, and
reproducible, and will allow comparison of results between laboratories.
PMID- 9396860
TI - MICA, a new polymorphic HLA-related antigen, is expressed mainly by
keratinocytes, endothelial cells, and monocytes.
AB - MICA is a new polymorphic gene in the HLA region expressed in epithelial cell
lines and gastrointestinal epithelium. Little is yet known about the MICA
protein, and the pattern of its expression by freshly isolated cells has not been
established. In the present experiments, we used antibodies raised in rabbits
against alpha1 and alpha2 domain-peptides to study the expression of MICA. By
western blot and immunoprecipitation, we detected a band of 62 000 Mr in various
cell lines (THP-1, U937, HeLa, A431, Raji, MOLT-4, and HUV-EC-C) and in freshly
isolated keratinocytes, endothelial cells, and monocytes but not in CD4+ and CD8+
T cells, and CD19+ cells (B lymphocytes). It was not possible to up-regulate the
expression of MICA in different cells by stimulation with gamma-interferon, but
the expression of MICA was induced in phytohemagglutinin-stimulated T cells. We
confirmed that MICA is expressed at the cell surface by flow cytometry. Results
of immunoprecipitation studies of beta2-microglobulin (beta2m)- or MICA-depleted,
metabolically labeled HeLa cells indicated that MICA was not associated with
beta2m. Although the function of MICA is still unknown, its restricted pattern of
tissue expression, the fact that it is expressed on the cell surface, and its
polymorphic nature suggest that this new molecule, encoded close to HLA class I,
may play a role in the interaction between epithelial cells and cells of the
immune system.
PMID- 9396861
TI - Crucial role of N-terminal residue of binding peptides in recognition of the
monoclonal antibody specific for the peptide-HLA-B5, -B35 complex.
AB - The monoclonal antibody (mAb) 4D12 specific for the HLA-B5, -B35 cross-reacting
group (CREG) bound to a fraction of HLA-B*3501 and HLA-B*5101 molecules carrying
self-peptides. Analysis of the binding of mAb 4D12 to HLA-B*3501 and -B*5101
molecules pulsed with chemically synthesized peptides revealed that this mAb
recognizes a restricted number of peptides and that P1 of the bound peptides
critically influences its binding. The 4D12 mAb bound only to HLA-B*3501
molecules carrying peptides with Asn, Asp, Glu, Ser, and Val at P1. Analysis
using an HLA-B*3501 crystallographic model suggested that 4D12 may recognize the
side chain of the P1 residue that is pointing to the solvent. On the other hand,
4D12 bound only to HLA-B*5101 molecules carrying peptides with Asn or Asp at P1,
suggesting that the 4D12 epitope formed by Glu, Ser, or Val at P1 and the A
pocket was changed by the substitution of His for Tyr at residue 171 of HLA
B*3501 molecules. This was confirmed by testing the binding of mAb 4D12 to HLA
B*3501 mutant molecules at residue 171 carrying these peptides. These results
together suggest that the conformation of the A-pocket and its hydrogen bound
network with the P1 residue is also critical for the binding of mAb 4D12. The
present study shows the molecular basis of the specificity of 4D12 for the
peptide-HLA class I complex.
PMID- 9396862
TI - Four dominant loci for the vascular responses by the antitumor polysaccharide,
lentinan.
AB - Lentinan, beta-1,6;1,3-glucan, showing an antitumor effect against mouse solid
type tumors, can induce marked vascular dilation and hemorrhage (VDH) in very
localized areas such as the ears, feet, and tails of mice in the early stages
after its administration (Maeda et al. 1984). VDH has been found to be one of the
T-cell-mediated responses triggered by lentinan. We reported previously that the
responsiveness of mice to lentinan with respect to VDH induction is controlled by
a dominant gene(s), Ltn2 (formerly), and that no sex difference was observed
(Maeda et al. 1991). To determine the chromosomal location of the Ltn2 gene(s),
we typed genomic DNAs of 193 N2 segregants of crosses between a high responder
MA/MyJ and a low responder AKR/J by the polymerase chain reaction-simple sequence
length polymorphism technique using 83 chromosome-specific microsatellite
markers. We identified one major gene (Ltnr3) and three minor genes (Ltnr4,
Ltnr5, and Ltnr6) responsible for the VDH induction. Ltnr3 was closely linked to
D6Mit135 on chromosome 6 (P <0.00000) and Ltnr4, Ltnr5, and Ltnr6 to D9Mit161 on
chromosome 9 (P <0.00032), D15Mit147 on chromosome 15 (P <0.00014) and D16Mit4 on
chromosome 16 (P <0.00014), respectively.
PMID- 9396863
TI - Cytogenetic orientation of the rat major histocompatibility complex (MHC) on
chromosome 20.
PMID- 9396864
TI - Molecular cloning of major histocompatibility complex class I cDNAs from the
pufferfish Fugu rubripes.
PMID- 9396865
TI - The mouse HFE gene.
PMID- 9396866
TI - Conserved structure and tissue expression of rat eotaxin.
PMID- 9396867
TI - The future of bone density measurements.
PMID- 9396868
TI - Cardiofocal collimators for gated single-photon emission tomographic myocardial
perfusion imaging.
AB - Cardiofocal collimators (CFCs) are more sensitive than parallel-hole collimators
(PHCs) of the same resolution because the rays converge in the centre of the
field of view. After reconstruction a useful field of view with a 10 cm radius in
which both sensitivity and resolution are homogeneous is obtained. In this
article the feasibility and accuracy of gated single-photon emission tomographic
(gated SPET) myocardial perfusion imaging using a triple-head camera equipped
with CFC, is evaluated. Twenty patients with a history of myocardial infarction
were studied. SPET myocardial perfusion images, gated in eight time bins, were
acquired in a random sequence with a PHC and a CFC for each patient. Imaging was
started 60 min after the injection of 925 MBq of technetium-99m tetrofosmin at
rest. Ninety-six projections over 360 degrees were acquired, with 32 stops of 40
s for the PHC and 20 s for the CFC in order to obtain similar count densities.
The extent (EXT) and severity (SEV) of perfusion defects were quantified on polar
maps using the non-gated data. Left ventricular volumes [end-diastolic volume
(EDV), end-systolic volume (ESV)] and ejection fraction (LVEF) were calculated
from gated data using the Cedars-Sinai program. In 17 of 20 patients the complete
left ventricle was positioned within the useful field of view of the CFC. The
results in respect of perfusion, volumes and ejection fraction were almost
identical to those obtained with the PHC. The mean difference+/-SD between the
CFC and the PHC was -2.30+/-7.16 (% of LV area) for EXT, -0.48+/-2.90 for SEV
(arbitrary units), -1,50+/-5.25 (ml) for EDV and 0.53+/-4.10 (%) for LVEF. The
largest differences in EXT and LV volumes were observed in patients in whom a
part of the LV was not positioned within the useful field of view. We conclude
that, for the majority of patients, identical information with regard to both
perfusion and function can be derived from gated SPET myocardial perfusion
studies obtained with PHCs or with CFCs. Because of the greater sensitivity,
however, a much shorter acquisition time is required with CFCs.
PMID- 9396869
TI - Dual matrix ordered subsets reconstruction for accelerated 3D scatter
compensation in single-photon emission tomography.
AB - Three-dimensional (3D) iterative maximum likelihood expectation maximization (ML
EM) algorithms for single-photon emission tomography (SPET) are capable of
correcting image-degrading effects of non-uniform attenuation, distance-dependent
camera response and patient shape-dependent scatter. However, the resulting
improvements in quantitation, resolution and signal-to-noise ratio (SNR) are
obtained at the cost of a huge computational burden. This paper presents a new
acceleration method for ML-EM: dual matrix ordered subsets (DM-OS). DM-OS
combines two acceleration methods: (a) different matrices for projection and back
projection and (b) ordered subsets of projections. DM-OS was compared with ML-EM
on simulated data and on physical thorax phantom data, for both 180 degrees and
360 degrees orbits. Contrast, normalized standard deviation and mean squared
error were calculated for the digital phantom experiment. DM-OS resulted in
similar image quality to ML-EM, even for speed-up factors of 200 compared to ML
EM in the case of 120 projections. The thorax phantom data could be reconstructed
50 times faster (60 projections) using DM-OS with preservation of image quality.
ML-EM and DM-OS with scatter compensation showed significant improvement of SNR
compared to ML-EM without scatter compensation. Furthermore, inclusion of complex
image formation models in the computer code is simplified in the case of DM-OS.
It is thus shown that DM-OS is a fast and relatively simple algorithm for 3D
iterative scatter compensation, with similar results to conventional ML-EM, for
both 180 degrees and 360 degrees acquired data.
PMID- 9396870
TI - Iodine-123 labeled nor-beta-CIT as a potential tracer for serotonin transporter
imaging in the human brain with single-photon emission tomography.
AB - Iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl) (nor-beta-CIT) is an
analogue of beta-CIT, which has high affinity to the serotonin transporter.
Initial single-photon emission tomography (SPET) studies with [123I]nor-beta-CIT
were performed in five healthy volunteers. In addition, its metabolism in plasma
was investigated with gradient high performance liquid chromatography. [123I]nor
beta-CIT was prepared by a method which gave a specific radioactivity of more
than 180 GBq/micromol. Unchanged [123I]nor-beta-CIT in plasma accounted for 43%
and 19% of total radioactivity after 30 and 180 min, respectively. The dynamic
SPET studies demonstrated a high and rapid uptake of radioactivity in the brain
(6%/ID at 30 min). Highest accumulation was observed in the striatum, the mid
brain and the thalamus. The specific binding in the mid-brain was 33% higher
compared with that of [123I]beta-CIT. The high radioactivity in the mid-brain is
assumed to represent the accumulation of [123I]nor-beta-CIT in the serotonin
transporter-rich regions, which indicates that [123I]nor-beta-CIT might be a
potential tracer for visualization of serotonin transporter sites in the human
brain with SPET.
PMID- 9396871
TI - Human biodistribution and dosimetry of [123I]FP-CIT: a potent radioligand for
imaging of dopamine transporters.
AB - This study reports on the biodistribution and radiation dosimetry of iodine-123
labelled N-omega-(flu- oropropyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane
([123I]FP-CIT), a promising radioligand for the imaging of dopamine transporters.
In 12 healthy volunteers, conjugate whole-body scans were performed up to 48 h
following intravenous injection of approximately 100 MBq [123I]FP-CIT.
Attenuation correction was performed using a transmission whole-body scan
obtained prior to injection of the radioligand, employing a 123I flood source.
Blood samples were taken and urine was freely collected up to 48 h after
injection of the radiotracer. For each subject, the percentage of injected
activity measured in regions of interest over brain, striatum, lungs and liver
were fitted to a multicompartmental model to give time-activity curves. The
cumulative urine activity curve was used to model the urinary excretion rate and,
indirectly, to predict faecal excretion. Using the MIRD method, nine source
organs were considered in estimating absorbed radiation doses for organs of the
body. The images showed rapid lung uptake and hepatobiliary excretion. Diffuse
uptake and retention of activity was seen in the brain, especially in the
striatum. At 48 h following the injection of [123I]FP-CIT, mean measured urine
excretion was 60%+/-9% (SD), and mean predicted excretion in faeces was 14%+/-1%.
In general, the striatum received the highest absorbed dose (average 0.23
mGy/MBq), followed by the urinary bladder wall (average 0.054 mGy/MBq) and lungs
(average 0.043 mGy/MBq). The average effective dose equivalent of [123I]FP-CIT
was estimated to be 0.024 mSv/MBq. The amount of [123I]FP-CIT required for
adequate dopamine transporter imaging results in an acceptable effective dose
equivalent to the patient.
PMID- 9396872
TI - Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT
1 to the central dopamine transporters in rats.
AB - The purpose of this study was to investigate the influence of drugs competing for
the dopamine transporter (DAT) or changing intra- and/or extracellular dopamine
levels on the binding of a novel technetium-99m labeled tropane derivative,
technetium, [2-[[2-[[[3-(4-chloro- phenyl)-8-methyl-8-azabicyclo[3, 2, 1]oct-2
yl]methyl] (2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3)]-oxo-[1R-(exo
exo)]-, [99mTc]TRODAT-1, to DAT. This paper describes the further
characterization of [99mTc]TRODAT-1 binding sites in rats under conditions which
may exist in patients receiving various drug treatments. All experiments were
carried out using an i.v. injection of [99mTc]TRODAT-1 into male Sprague-Dawley
rats. Measurements of % dose/gram ratio of (striatum-cerebellum)/cerebellum at 1
h post injection were used as an indicator for specific DAT binding. The
biodistribution studies were performed in the presence of drugs which compete for
the binding site, such as CFT (WIN 35,428) and methylphenidate, drugs which
influence dopamine levels, such as L-DOPA, gamma-hydroxybutyrolactone, and alpha
methyl-p-tyrosine, and d-amphetamine, which both acts as a competitor for DAT
binding and increases dopamine levels. Additionally, the influence of dopamine
receptor agonists, such as apomorphine and (+)bromocriptine, on biodistribution
was tested. Binding of [99mTc]TRODAT-1 to DAT was found to be inhibited by CFT,
methylphenidate, and d-amphetamine in a dose-dependent manner. The specific
binding of [99mTc]TRODAT-1 was not altered by dopamine receptor agonists or by
drugs which cause minor changes in dopamine levels. When administered in high
doses (634 micromol/kg), L-DOPA also decreased the binding of [99mTc]TRODAT-1. It
is likely that a low dose of L-DOPA (normally needed in the treatment of
Parkinson's disease) will not affect the results on [99mTc]TRODAT-1 single-photon
emission tomographic (SPET) imaging studies. In conclusion, the results clearly
demonstrate the specificity of [99mTc]TRODAT-1 binding to DAT in vivo.
Competition for [99mTc]TRODAT-1 binding was observed only with drug treatment
that significantly increases dopamine levels or actively competes for binding at
DAT. The results suggest that prior knowledge of whether patients are receiving
various drug treatments may assist in the interpretation of DAT status as
assessed by SPET imaging studies using [99mTc]TRODAT-1.
PMID- 9396873
TI - Biodistribution and dosimetry of iodine-123-labelled Z-MIVE: an oestrogen
receptor radioligand for breast cancer imaging.
AB - This study reports on the distribution and radiation dosimetry of iodine-123
labelled cis-11beta-methoxy-17alpha-iodovinyloestradiol (Z-[123I]MIVE), a
promising radioligand for imaging of oestrogen receptors (ERs) in human breast
cancer. Whole-body scans were performed up to 24 h after intravenous injection of
138-193 MBq Z-[123I]MIVE in five healthy female volunteers, four with and one
without thyroid blockade. Blood samples were taken at various times up to 24 h
after injection. Urine was collected up to 24 h after injection in order to
calculate renal clearance and to aid in the interpretation of whole-body
clearance, including faecal excretion. Time-activity curves were generated for
the thyroid, heart, brain, breasts and liver, by fitting the organ-specific
geometric mean counts, obtained from regions of interest, to a multicompartmental
model. The MIRD formulation, using 11 source organs, was applied to calculate the
absorbed radiation doses for various organs upon administration of Z-[123I]MIVE.
The images showed rapid hepatobiliary excretion which resulted in good imaging
conditions for the thoracic region. Imaging of the abdominal region was impeded
due to extensive bowel activity. Diffuse uptake and retention of activity was
seen in breast tissue, the breast-to-non-specific uptake ratio increasing over
time. Z-[123I]MIVE was cleared by both the kidneys and the gastrointestinal
tract. At 50 h p.i. the mean excretion in urine was predicted to be 58%+/-14%
(SD) and that in faeces 31%+/-19%. If the thyroid was not blocked, it was the
most critical organ (0.33 mGy/MBq). In general, the excretory organs received the
highest absorbed doses, i.e. the lower and upper large intestinal walls (0.11 and
0.098 mGy/MBq, respectively), the urinary bladder wall (0.090 mGy/MBq), the
gallbladder wall (0.087 mGy/MBq) and the small intestine (0.043 mGy/MBq). The
average effective dose equivalent of Z-[123I]MIVE was estimated to be 0.033
mSv/MBq. The amount of Z-[123I]MIVE required for adequate breast cancer ER
imaging results in an acceptable effective dose equivalent to the patient.
PMID- 9396874
TI - Relative renal uptake and transit time measurements using functional factor
images and fuzzy regions of interest.
AB - The aim of the study was a quantitative comparison of relative renal uptake and
both the whole-kidney and the parenchymal transit time derived from factor
analysis of image sequences and provided by standard clinical procedues. In order
to extract the stable, well-interpretable factors, factor analysis was performed
locally in the problem-specific time and spatial windows and the resulting factor
images either evaluated directly as functional images or used as fuzzy regions of
interest (ROIs) for the subsequent extraction of time-activity curves from the
analysed data. The values of relative renal uptake of the left kidney measured in
the functional factor images, which demonstrate the initial accumulation of
activity in renal parenchyma (mean 51.0%), did not differ significantly from the
values obtained by a standard method (mean 51.5%, r = 0.98, P<0.001). Whole
kidney transit time calculated using fuzzy ROI curves correlated well with the
reference values (r = 0.84, P<0.001); however, both its mean value (336.5 s) and
the standard deviation (151.5 s) were substantially greater than those of the
values provided by a standard procedure (262.8+/-86.9 s). Parenchymal transit
time calculated using ROI curves correlated better with the transit time through
a wider corticomedullary region rather than through a narrow cortical region,
which is decisive in a differential diagnosis of renal disorders. In general,
values of transit times provided by factor analysis correlated well with those
provided by reference methods but with a shift towards the higher numerical
values. This may have been a consequence of a greater extent of the automatically
extracted fuzzy ROIs, or of occasionally delayed accumulation in the upper
calyces. Results of the study provide quantitative evidence that the factor
analysis of dynamic data, even without the introduction of prior physiological
information, may yield clinically relevant information. However, some basic
requirements, such as sufficiently high sampling frequency and count rate,
adaption of the method to a specific clinical task, and proper selection of time
and spatial windows for locally performed analysis, have to be fullfilled if the
method is to be successfully applied clinically.
PMID- 9396875
TI - Semi-automated renal region of interest selection method using the double
threshold technique: inter-operator variability in quantitating 99mTc-MAG3 renal
uptake.
AB - In calculating the relative and absolute renal uptake of technetium-99m
mercaptoacetyltriglycine (MAG3), inter-operator variability in the assignment of
the renal region of interest (ROI) is a critical factor. Our goal was to develop
a semi-automated method of assigning the renal ROI and then to compare the inter
operator variability in calculating the percent injected dose (%ID) in the kidney
at 1-2 min, using semi-automated versus manual ROIs. The manual ROIs were drawn
independently by three operators (A, B and C). Operator A had about 20 years,
experience in nuclear medicine, while operators B and C respectively had 3 years
and 1 year of experience. In the semi-automated renal ROI selection method using
the double-threshold technique, the operators only click around the centre of
each kidney. The same three operators processed the ROIs using this double
threshold method on 1-2 min images. The semi-automated method failed in three
kidneys with very markedly reduced function owing to superimposition by liver or
spleen. Inter-operator reproducibility in the remaining 59 kidneys was estimated
using manual and semi-automated ROIs. With manual ROIs, the %ID (mean+/-standard
error of mean) was 4.32+/-0.167 for A, 4. 14+/-0.165 for B and 3.28+/-0.139 for
C. Although there was good correlation among them, these values were
significantly different (P<0.0001). Using semi-automated ROIs, the %ID was 4.38+/
0.160 for three operators. No significant difference was observed. Complete
reproducibility was shown in 58 of 59 kidneys; the %ID difference of the
remaining kidney was only 1.2%. The lowest %ID of all the kidneys successfully
detected using the semi-automated method was 0. 77%. The semi-automated renal ROI
selection method using the double-threshold technique displays good detectability
of the renal contour. The renal uptake calculated using this method is
reproducible and acceptable in routine clinical practice.
PMID- 9396876
TI - Successful coronary revascularization improves prognosis in patients with
previous myocardial infarction and evidence of viable myocardium at thallium-201
imaging.
AB - The role of coronary revascularization of dysfunctional myocardium with preserved
thallium-201 uptake in determining the prognosis in patients after myocardial
infarction remains to be defined. This study was designed to evaluate the effects
of successful revascularization on survival and left ventricular (LV) function in
patients with previous myocardial infarction and evidence of dysfunctional but
still viable myocardium at rest-redistribution 201Tl imaging. Seventy-six
consecutive patients with LV dysfunction related to previous myocardial
infarction and evidence of viable myocardium at rest-redistribution 201Tl
tomography were followed for 17+/-8 months. LV ejection fraction (EF) was
assessed by radionuclide angiography at baseline and after 13+/-2 months. Thirty
nine patients were revascularized (group A) and 37 treated medically (group B).
During the follow-up there were nine cardiac deaths. Survival rate was 97% in
group A and 66% in group B (P<0.01). By Cox multivariate analysis, the extent of
viable myocardium was the best predictor of cardiac death (chi2=8.67, P<0.01) and
provided additional information to clinical and functional data (P<0.01). The
inclusion of revascularization as a variable improved the global chi2 of the
model from 14.1 to 21.9 (P<0.01). At follow-up, EF had improved by >/=5% in 16
patients. By multivariate logistic analysis, the extent of viable myocardium was
the best predictor of EF improvement (chi2=15.49, P<0.001) and provided
additional information to clinical and functional data (P<0.01). The inclusion of
revascularization as a variable improved the global chi2 of the model from 16.8
to 22.5 (P<0.01). These results demonstrate that the total extent of
dysfunctional myocardium with preserved 201Tl uptake is the strongest predictor
of cardiac death in patients after myocardial infarction. Successful
revascularization of dysfunctional but viable myocardium improves survival and
LVEF in such patients.
PMID- 9396877
TI - Comparison of dobutamine stress echocardiography and technetium-99m sestamibi
single-photon emission tomography for the diagnosis of coronary artery disease in
hypertensive patients with and without left ventricular hypertrophy.
AB - Stress echocardiography has been considered an accurate method for the diagnosis
of coronary artery disease in hypertensive patients and in patients with left
ventricular hypertrophy. In contrast, the specificity of myocardial perfusion
scintigraphy in these patients has been questioned. The aim of this study was to
compare the accuracy of these two imaging modalities in conjunction with
dobutamine stress test for the diagnosis of coronary artery disease in
hypertensive patients with and without left ventricular hypertrophy. Dobutamine
(up to 40 microg kg-1min-1) stress echocardiography in conjunction with sestamibi
(MIBI) single-photon emission tomography (SPET) was performed in 84 patients with
the diagnosis of systemic hypertension who had been referred for evaluation of
myocardial ischaemia. Ischaemia was defined as new or worsened wall motion
abnormalities at echocardiography and reversible perfusion defects at SPET.
Significant coronary artery disease (>/=50% luminal diameter stenosis) was
detected in 66 patients (79%). The sensitivity, specificity and accuracy of the
ischaemic pattern at echocardiography for the diagnosis of coronary artery
disease were 73% (CI 63%-82%), 83% (CI 75%-91%) and 75% (CI 66%-84%), those for
MIBI were 67% (CI 57%-77%), 83% (CI 75%-91%) and 70% (CI 60%-80%) respectively (P
= NS vs echocardiography). Significant stenosis was detected in 123 (49%) of the
252 analysed coronary arteries. The sensitivity, specificity and accuracy of
echocardiography for the regional diagnosis of coronary artery disease were 63%
(CI 56%-69%), 90% (CI 86%-94%) and 77% (CI 72%-82%). Those for MIBI were 58% (CI
51%-64%), 91% (CI 87%-94%) and 75% (CI 69%-80) respectively (P = NS vs
echocardiography). Left ventricular hypertrophy was detected in 59 patients (70%)
by echocardiography and did not influence the overall or regional specificity of
echocardiography or MIBI SPET. It is concluded that in hypertensive patients,
dobutamine stress echocardiography and MIBI SPET have a comparable accuracy for
the overall and regional diagnosis of coronary artery disease. Hypertensive
patients with or without left ventricular hypertrophy should not be considered
unsuitable candidates for stress myocardial perfusion scintigraphy.
PMID- 9396878
TI - Limited value of fluorine-18 fluorodeoxyglucose positron emission tomography for
the imaging of neuroendocrine tumours.
AB - Scintigraphy using [111In-DTPA-d-Phe1]-pentetreotide or pentavalent technetium
99m-dimercaptosuccinic acid [99mTc(V)-DMSA] has been shown to localize well
differentiated and slowly growing neuroendocrine tumours, whereas increased
fluorodeoxyglucose (FDG) uptake is associated with malignancy. The aim of this
study was to compare the value of fluorine-18 FDG positron emission tomography
(PET) with that of somatostatin receptor scintigraphy (SS-R) and dual
radionuclide scintigraphy [SS-R and 99mTc(V)-DMSA = DNS] in detecting malignant
neuroendocrine tumours. Fifteen patients with metastasizing
gastroenteropancreatic tumours (GEP tumours; n = 7), medullary thyroid carcinomas
(MTCs; n = 8) and elevated tumour markers [GEP tumours: 5-hydroxyindoleacetic
acid, insulin; MTCs: calcitonin, carcinoembryonic antigen (CEA)] were studied.
Prior to PET, all patients with GEP tumours underwent SS-R. DNS was performed in
all patients with MTC. Patients had been fasting for at least 12 h and normal
glucose plasma levels were confirmed. Sixty minutes after intravenous
administration of 18F-FDG (mean: 374 MBq) whole-body PET and regional scans were
performed. In addition, the resected tissues were prepared for
immunocytochemistry examination (cell cycle-associated Ki-67 antigen). In two
patients with less-differentiated GEP tumours associated with high proliferative
activity and increased FDG uptake, SS-R failed to detect any lesion. In
comparison, in four patients with well-differentiated GEP tumours showing low
proliferative activity, SS-R localized four primary tumours, 22 lymph node
metastases and 18 malignant liver lesions, whereas 18F-FDG PET demonstrated
normal distribution. In one patient with a metastasizing carcinoid (medium
proliferative activity) SS-R localized multiple metastases, whereas PET
demonstrated low FDG uptake in all known metastases. In patients with recurrent
MTC and rapidly increasing CEA levels DNS detected only three lesions in two
patients, whereas PET demonstrated one pulmonary, three osseous, 20 mediastinal,
ten locoregional, and four liver metastases in seven patients. Twenty-nine
malignant lesions were confirmed by follow-up and nine lymph node metastases
could be surgically removed. In conclusion, PET imaging of gastroenteropancreatic
tumours revealed increased glucose metabolism only in less-differentiated GEP
tumours with high proliferative activity and metastasizing MTC associated with
rapidly increasing CEA levels. Therefore, additional 18F-FDG PET should be
performed only if SS-R or DNS is negative.
PMID- 9396879
TI - Design, construction and six years' experience of an integrated system for
automated handling of discrete blood samples.
AB - The present paper describes the design of an integrated system to aid in the
taking and measurement of manual blood samples during nuclear medical
examinations requiring blood sampling. In contrast to previously published
systems, the present system is not used in the actual sampling of the blood, but
aims to aid in all other aspects of handling and measurement. It consists of two
main parts. One part is a distributed software system running on the scanner host
computer used to register sample times, to display information pertaining to the
ongoing examination and to collect data from a number of well crystals. The other
main part consists of an industrial robot used to perform the actual weighing,
centrifugation, pipetting and measurement of the samples. The system has been
operational for 6 years, during which time it has had an "up-time" in excess of
95% and has handled and measured the blood samples from more than 5000
examinations, each comprising an average of 15 blood samples. The throughput of
the system is 50 whole blood samples or 21 plasma samples per hour. In addition
it has to a large extent removed the "human factor" from the process, thereby
increasing the reliability of the data.
PMID- 9396880
TI - Alpha-fetoprotein, free beta-human chorionic gonadotropin, and dimeric inhibin A
produce the best results in a three-analyte, multiple-marker screening test for
fetal Down syndrome.
AB - OBJECTIVE: The purpose of this study was to determine, among six second-trimester
maternal serum analytes, the best three-analyte combination for fetal Down
syndrome detection. STUDY DESIGN: With use of commercially available assay kits,
medians for free beta-human chorionic gonadotropin, CA 125, and dimeric inhibin A
were established in stored sera from 45 to 50 euploid pregnancies at each week of
gestation from 14 to 22 weeks and from 33 Down syndrome pregnancies. Maternal
serum alpha-fetoprotein, unconjugated estriol, and intact human chorionic
gonadotropin levels measured in each sample before storage were retrieved. All 20
possible three-analyte combinations were evaluated in the multiple-marker
screening test for Down syndrome. RESULTS: The mean maternal age of the study
population was 35.6 +/- 5.3 years. The best three-analyte combination was
maternal serum alpha-fetoprotein, free beta-human chorionic gonadotropin, and
dimeric inhibin A: 97% of Down syndrome cases were detected at a false-positive
rate of 16%. At a slightly higher false-positive rate (18%) maternal serum alpha
fetoprotein, estriol, and intact human chorionic gonadotropin detected only 79%
of cases. CONCLUSIONS: Of six second-trimester maternal serum analytes, the best
three-analyte combination for fetal Down syndrome detection was maternal serum
alpha-fetoprotein, free beta-human chorionic gonadotropin, and dimeric inhibin A.
This retrospective analysis should now be confirmed prospectively.
PMID- 9396881
TI - Elevated second-trimester dimeric inhibin A levels identify Down syndrome
pregnancies.
AB - OBJECTIVE: Our purpose was to determine whether second-trimester dimeric inhibin
A levels distinguish Down syndrome pregnancies from euploid pregnancies. STUDY
DESIGN: With use of a commercially available enzyme-linked immunosorbent assay
(Serotec, Oxford) inhibin A medians were established in stored sera from 40 to 50
euploid pregnancies at each week of gestation from 14 to 20 weeks and from 33
Down syndrome pregnancies. Maternal serum alpha-fetoprotein, unconjugated
estriol, and human chorionic gonadotropin levels measured in each sample before
storage were retrieved. The performance of inhibin A in the multiple-marker
screening test was evaluated. RESULTS: The mean inhibin A multiple of the median
was significantly higher in the Down syndrome group than in the euploid group
(2.84 +/- 2.0 vs 1.22 +/- 1.0, p = 0.0001). An inhibin A level > or = 1.6
multiples of the median identified 70% of all Down syndrome pregnancies at a
false-positive rate of 22%. Replacing estriol with inhibin A in the multiple
marker screening test resulted in a higher Down syndrome detection rate at a
lower screen-positive rate. CONCLUSION: Elevated second-trimester maternal serum
inhibin A levels identify Down syndrome pregnancies; replacing estriol with
inhibin A in the multiple-marker screening test improves test performance.
PMID- 9396882
TI - Relationship between pregnancy-induced hypertension and placenta previa: a
population-based study.
AB - OBJECTIVE: Our purpose was to investigate, in a large population-based cohort,
the hypothesis that the risk of pregnancy-induced hypertension is lower among
pregnancies complicated by placenta previa compared with pregnancies occurring in
women with fundally implanted placentas. STUDY DESIGN: Data for this
retrospective cohort study were derived from the computerized Atlee perinatal
database of the Reproductive Care Program, Nova Scotia, Canada. Women who were
delivered in the province between 1980 and 1993 were included in the study.
Patients with pregnancy-induced hypertension were clinically diagnosed by the
presence of elevated blood pressure, proteinuria, or edema. The risk of pregnancy
induced hypertension was compared between women diagnosed with placenta previa
and those with a normally implanted placenta, after adjustment for potential
confounders through multivariable logistic regression models based on the method
of generalized estimating equations. RESULTS: During the 14 years (1980 to 1993),
121,082 singleton pregnancies were registered in the program, 416 (0.4%) of which
had a confirmed diagnosis of placenta previa. Women with chronic hypertension had
a relative risk of 1.2 (95% confidence interval 0.4 to 3.7) for placenta previa
compared with normotensive women. However, the risk of pregnancy-induced
hypertension was reduced by half among those with placenta previa (relative risk
0.5, 95% confidence interval 0.3 to 0.7). Adjustments for potential confounders,
including maternal age, parity, prepregnancy body weight, prior cesarean
delivery, prior spontaneous or induced abortions, and cigarette smoking, had no
influence on this association. Analyses on the basis of stratification of women
by parity (nulliparous vs multiparous), cigarette smoking (smoker vs nonsmoker),
and gestational duration (< 28, 28 to 32, 33 to 36, and > 37 completed weeks)
consistently showed reduced risks for pregnancy-induced hypertension among women
with placenta previa, indicating that the association was not a result of
shortened duration of gestation among women with placenta previa. CONCLUSIONS:
The results from this study clearly show a decreased frequency of pregnancy
induced hypertension among those pregnancies with placenta previa. We speculate
that the pathophysiologic mechanisms for this finding may be due to altered
placental perfusion seen among women diagnosed with placenta previa.
PMID- 9396883
TI - Risk factors associated with preeclampsia in healthy nulliparous women. The
Calcium for Preeclampsia Prevention (CPEP) Study Group.
AB - OBJECTIVE: Our goal was to identify risk factors for the development of
preeclampsia in nulliparous women enrolled in a multicenter trial comparing
calcium supplementation to a placebo. STUDY DESIGN: A total of 4589 women from
five centers was studied. Analysis of risk factors for preeclampsia was performed
in 4314 who carried the pregnancy to > 20 weeks. Baseline systolic and diastolic
blood pressure, demographic characteristics, and findings after randomization
were examined for the prediction of preeclampsia. Preeclampsia was defined as
hypertension (diastolic blood pressure > or = 90 mm Hg on two occasions 4 hours
to 1 week apart) and proteinuria (> or = 300 mg/24 hours, a protein/creatinine
ratio > or = 0.35, one dipstick measurement > or = 2+ or two dipstick
measurements > or = 1+ at an interval as specified for diastolic blood pressure).
RESULTS: Preeclampsia developed in 326 women (7.6%). The first analysis treated
each risk factor as a categoric variable in a univariate regression. Maternal
age, blood group and Rh factor, alcohol use, previous abortion or miscarriage,
private insurance, and calcium supplementation were not statistically
significant. Risk factors initially found to be significant were body mass index,
systolic blood pressure, diastolic blood pressure, non-white race (African
American and other), clinical center, and smoking. Adjusted odds ratios computed
with a logistic regression model revealed that body mass index (odds ratio 3.22
for > or = 35 kg/m2 vs < 19.8 kg/m2), systolic blood pressure (odds ratio 2.66
for > or = 120 vs < 101 mm Hg), diastolic blood pressure (odds ratio 1.72 for >
or = 61 mm Hg vs < 60 mm Hg), and clinical center (odds ratio 1.85 for Memphis vs
the other clinical centers) were statistically significant predictors of
preeclampsia. Results of the final model fit revealed that preeclampsia risk
increases significantly (p < 0.0001) with increased body mass index at
randomization, as well as with increased systolic and diastolic blood pressure at
randomization. Calcium supplementation had no effect on the risks posed by body
mass index and blood pressure. Among risk factors developing after randomization,
an abnormal results of a glucose screen (plasma glucose > or = 140 mg/dl 1 hour
after a 50 gm glucose challenge) was not found to be associated with a
significant risk of preeclampsia. CONCLUSION: These risk factors should be of
value in counseling women regarding preeclampsia and should aid in understanding
the pathophysiologic characteristics of this syndrome.
PMID- 9396884
TI - Better maternal outcomes are achieved with dexamethasone therapy for postpartum
HELLP (hemolysis, elevated liver enzymes, and thrombocytopenia) syndrome.
AB - OBJECTIVE: Our purpose was to determine whether the routine initiation of
dexamethasone therapy in patients with postpartum HELLP (hemolysis, elevated
liver enzymes, and thrombocytopenia) syndrome produces specific and general
therapeutic benefits. STUDY DESIGN: In this retrospective, analytic study the
puerperal courses of 43 women with postpartum HELLP syndrome who were treated
with dexamethasone were compared with those of 237 similar patients who did not
receive corticosteroids. Dexamethasone 10 mg intravenously at 12-hour intervals
was given until disease remission was noted in treated patients, at which time up
to two additional 5 mg intravenous doses were given at 12-hour intervals.
RESULTS: The two patient groups were similar in regard to mode of delivery,
gestational age, parity, and frequency of eclampsia. Compared with control
subjects, dexamethasone-treated postpartum patients were more ill with
significantly higher (p < 0.05) admission mean arterial blood pressure, higher
serum uric acid level, and severe proteinuria. Dexamethasone administration was
associated with a more rapid normalization of platelet counts and lactic
dehydrogenase values. Most impressive was a clinically significant reduction of
indicated transfusion and respiratory therapy, invasive hemodynamic monitoring,
infectious or bleeding-related morbidity, and length of postpartum hospital
course. CONCLUSIONS: Patients who received dexamethasone for postpartum-onset
HELLP syndrome experienced a shorter disease course, faster recovery, less
morbidity, and less need for other interventionist therapy compared with patients
with HELLP syndrome who did not receive dexamethasone.
PMID- 9396885
TI - A double-blind comparison of the safety and efficacy of intravaginal misoprostol
and prostaglandin E2 to induce labor.
AB - OBJECTIVE: Our purpose was to compare the safety and efficacy of intravaginally
administered misoprostol versus prostaglandin E2 for labor induction in a double
blind, randomized trial. STUDY DESIGN: One hundred three patients with
indications for labor induction (including prelabor rupture of membranes) were
randomized and received either misoprostol 50 micrograms or prostaglandin E2
(dinoprostone) 3 mg intravaginally. The dose was repeated 6, 24, and 30 hours
after the first dose until active labor was achieved. For proper blinding, the
drugs were prepared as identical-looking vaginal tablets. RESULTS: With use of a
random number-generated table 52 patients were allocated to the misoprostol group
and 51 to the prostaglandin E2 group. After exclusion of 3 patients, 50 in each
group were evaluated. Delivery within 24 hours after administration occurred more
often in the misoprostol group (70% vs 46% in the prostaglandin E2 group, p =
0.009), and fewer patients in this group needed more than two doses (12% vs 30%,
p = 0.027). No difference in cesarean section rate (12% vs 14%, p = 0.67), fetal
heart rate anomalies (33% vs 34%, p = 0.89), tachysystole (8% vs 14%, p = 0.37),
hyperstimulation syndrome (0% vs 2%, not significant), meconium passage (28% vs
18%, p = 0.22), and fetal outcome (Apgar score at 1 and 5 minutes, arterial and
venous umbilical cord blood pH, transfer to neonatal intensive care unit) was
noted between the two groups. CONCLUSION: Intravaginal misoprostol is a safe drug
for labor induction with superior effectiveness compared with intravaginal
prostaglandin E2.
PMID- 9396886
TI - International Multicentre Term Prelabor Rupture of Membranes Study: evaluation of
predictors of clinical chorioamnionitis and postpartum fever in patients with
prelabor rupture of membranes at term.
AB - OBJECTIVES: Our purpose was to determine significant predictors for the
development of clinical chorioamnionitis and postpartum fever in patients with
prelabor rupture of membranes at term. STUDY DESIGN: Logistic regression analysis
with odds ratios and 95% confidence intervals was used to determine the
significant predictors of clinical chorioamnionitis and postpartum fever in women
with prelabor rupture of membranes at term enrolled in this study. The study
recently compared in a randomized controlled trial four strategies of management:
induction with oxytocin, induction with prostaglandin, expectant management, and,
if failed, induction with oxytocin or prostaglandin. RESULTS: The following
variables were significantly associated with clinical chorioamnionitis: (1)
number of digital vaginal examinations: > 8, 7 to 8, 5 to 6, 3 to 4 (vs 0 to 2)
(odds ratio 5.07, 3.80, 2.62, 2.06); (2) duration of active labor: > or = 12, 9
to < 12, 6 to < 9 hours (vs < 3 hours) (odds ratio 4.12, 2.94, 1.97); (3)
meconium-stained amniotic fluid (odds ratio 2.28); (4) parity of 0 (odds ratio
1.80); (5) time from membrane rupture to active labor: > or = 48, 24 to < 48
hours (vs < 12 hours) (odds ratio 1.76, 1.77); and (6) group B streptococcal
colonization (odds ratio 1.71). Variables significantly associated with
postpartum fever were (1) clinical chorioamnionitis (odds ratio 5.37), (2)
duration of active labor: > or = 12, 9 to < 12, 6 to < 9, 2 to < 6 hours (vs < 3
hours) (odds ratio 4.86, 3.53, 3.46, 3.04), (3) cesarean section, operative
vaginal delivery (odds ratio 3.97, 1.86), (4) group B streptococcal colonization
(odds ratio 1.88), and (5) maternal antibiotics before delivery (odds ratio
1.94). CONCLUSIONS: Increasing numbers of digital vaginal examinations, longer
duration of active labor, and meconium staining of the amniotic fluid were the
most important risk factors for the development of clinical chorioamnionitis in
women with prelabor rupture of membranes at term. The most important risk factors
for the development of postpartum fever were clinical chorioamnionitis,
increasing duration of active labor, and cesarean section delivery.
PMID- 9396887
TI - Predictive factors for neonatal morbidity in neonates with an umbilical arterial
cord pH less than 7.00.
AB - OBJECTIVE: Fewer than 50% of neonates with an umbilical arterial pH < 7.00 have
neonatal complications. Our objective was to identify clinical predictive factors
for adverse outcomes in this group of neonates. STUDY DESIGN: In this case
control study both cases and controls had an umbilical arterial cord pH < 7.00.
Cases were defined as those neonates who had seizures, grade 3 to 4
intraventricular hemorrhage, gastrointestinal dysfunction, respiratory distress
syndrome requiring intubation, sepsis, or death. Controls had an umbilical
arterial cord pH < 7.00 and no complications. A multivariable prediction model
was created, with variables having an association with adverse outcome by
bivariate analyses, attempting to predict which neonates in this umbilical
arterial pH range are at greatest risk for adverse outcomes. RESULTS: We
identified 73 of 10,705 neonates born between July 1992 and October 1996 with an
umbilical arterial cord pH < 7.00. Thirty-five neonates met our case definition,
and the remaining 38 composed the control group. Cases had significantly lower
arterial pH values and 1- and 5-minute Apgar scores, greater arterial base
deficit values, and a higher incidence of abruptio placentae and maternal cocaine
use. More cases were delivered before 34 weeks. There were three neonatal deaths,
two cases of grade 3 or 4 intraventricular hemorrhage, five cases of
gastrointestinal dysfunction, and four cases of neonatal seizures. In our
predictive model for adverse neonatal outcome, an arterial base deficit > or = 16
mmol/L and a 5-minute Apgar score < 7 had a sensitivity and a specificity of 79%
and 80.8%, respectively. CONCLUSION: Neonatal morbidity in neonates with an
umbilical arterial cord pH < 7.00 can be predicted by a high arterial base
deficit value and low 5-minute Apgar score.
PMID- 9396888
TI - Managed care does not lower costs but may result in poorer outcomes for patients
with gestational diabetes.
AB - OBJECTIVE: Our purpose was to compare the costs of prenatal care and subsequent
maternal and neonatal outcomes in patients with gestational diabetes cared for in
an inner-city university hospital house staff clinic versus an inner-city managed
care organization. STUDY DESIGN: A retrospective cohort study was conducted. The
groups consisted of 115 patients with gestational diabetes who were cared for in
a house staff clinic and a demographically similar group of 85 patients cared for
in a neighborhood managed care organization. The groups were examined regarding
baseline demographics, intensity of prenatal care, maternal and neonatal
outcomes, and total cost of the provision of care. RESULTS: There was no
difference between groups in the total cost of maternal-infant care. A larger
percentage of patients in the house staff group saw the physician frequently. In
contrast, patients cared for in the managed care organization underwent more
tests of fetal well-being. There was a greater rate of neonatal macrosomia in the
managed care organization group compared with the house staff group. CONCLUSIONS:
Managed care does not decrease the cost of caring for patients with gestational
diabetes but does lead to a greater rate of neonatal macrosomia, which may
reflect poorer glucose control.
PMID- 9396889
TI - Fractured clavicle and Erb's palsy unrelated to birth trauma.
AB - OBJECTIVES: Our purpose was to determine the perinatal factors associated with
clavicular fracture or Erb's palsy in neonates and to document the percentage of
cases where no risk factors were involved. STUDY DESIGN: We reviewed the medical
records of all live-born singleton infants admitted to the newborn nurseries
between 1992 and 1995. Mothers and infants with clavicular fracture or Erb's
palsy were compared with those without these birth injuries. RESULTS: Of 11,636
neonates, there were 236 (2.03%) with clavicular fracture and 51 (0.44%) with
Erb's palsy. Clavicular fracture was significantly associated with shoulder
dystocia and high birth weight. Significant factors associated with Erb's palsy
were shoulder dystocia, high birth weight, prolonged second stage, instrumental
delivery, fetal distress, use of oxytocin, and epidural anesthesia. A total of
51.7% of the neonates with clavicular fracture and 29.4% of those with Erb's
palsy had none of the risk factors examined. CONCLUSIONS: Although macrosomic
fetuses and instrumental or difficult deliveries are risk factors for clavicular
fracture and Erb's palsy, > 50% and 25%, respectively, occur without the risk
factors examined.
PMID- 9396890
TI - The accuracy of the summated amniotic fluid index in evaluating amniotic fluid
volume in twin pregnancies.
AB - OBJECTIVE: Our purpose was to determine the accuracy of the summated amniotic
fluid index designed to estimate the total amniotic fluid volume in twin
pregnancies. STUDY DESIGN: The summated amniotic fluid index was measured in 62
normal diamniotic twin pregnancies by adding the deepest vertical pockets in the
four quadrants. Actual amniotic fluid volume was then determined in all 124
amniotic sacs by amniocentesis and a dye-dilution technique. For data analysis,
amniotic fluid volumes were classified by percentile with use of previously
reported norms. RESULTS: There were significant differences in the percentile
distribution of amniotic fluid volume as estimated by the summated amniotic fluid
index and the actual volume as determined by dye dilution (p < 0.001). The
summated amniotic fluid index has a sensitivity of only 13% in predicting
amniotic sac volume. CONCLUSION: The summated amniotic fluid index is a poor
predictor of intertwin differences in amniotic fluid volume and cannot identify
twin pairs at risk for oligohydramnios and hydramnios.
PMID- 9396891
TI - Monoamniotic twins: improved perinatal survival with accurate prenatal diagnosis
and antenatal fetal surveillance.
AB - OBJECTIVE: Our goal was to report our 10-year experience with monoamniotic twins
and to compare that experience with cases reported in the literature. STUDY
DESIGN: Records of all monoamniotic twin pregnancies managed at the University of
Connecticut Health Center from March 1986 to August 1996 were reviewed. A MEDLINE
search from January 1966 to August 1996 was performed, and each report was
screened for accuracy of diagnosis. Only cases with umbilical cord entanglement
of nonconjoined like-sex twins, the obstetrician's confirmation at delivery, or
pathologic confirmation of monoamniotic placentation were included. Data
collected were as follows: birth outcome, gestational age at delivery, birth
weight, gender, Apgar scores, hematocrit, cord knotting, and neonatal
complications. Cases from the literature were divided into those with prenatal
diagnosis and those without. RESULTS: Thirteen monoamniotic pregnancies resulting
in 26 infants who were born alive were managed at our center. The average
gestational age at diagnosis was 16.3 weeks. All had antenatal fetal surveillance
including serial sonograms and nonstress tests. The average gestational age and
birth weight at delivery were 32.9 weeks and 1669 gm, respectively. Cord
entanglement was noted in all cases, with knotting in 8 of 13. Two pairs of 26
newborns had evidence of twin-twin transfusion syndrome. Eight of 13 monoamniotic
pregnancies were delivered because of nonreassuring results of nonstress test,
two because of preterm labor, two electively because of lung maturity, and one
because of intrauterine growth restriction. Two of the 26 infants died in the
neonatal period, one of congenital heart disease and one of sepsis and asphyxia.
The MEDLINE search revealed 96 articles with a total of 202 sets of monoamniotic
twins. Comparison of cases (13 sets) with the historic control group without
prenatal diagnosis (77 sets) showed a 71% reduction in relative risk of perinatal
mortality. CONCLUSIONS: With accurate prenatal diagnosis, intensive fetal
surveillance, and appropriately timed delivery, perinatal survival of
monoamniotic twins is improved; it was 92% in this series.
PMID- 9396892
TI - Is size discordancy an indication for delivery of preterm twins?
AB - OBJECTIVE: Our goal was to determine the clinical significance of size
discordancy in preterm twins. STUDY DESIGN: A retrospective study was performed
to review outcomes of twins delivered between Jan. 1, 1988, and June 30, 1995.
Maternal and neonatal records were assessed for demographic data, maternal
medical history, and neonatal mortality and morbidity outcomes. Discordancy was
defined as > or = 20% difference in birth weight. The chi 2 analysis was
performed. RESULTS: There were 42 sets of discordant twins and 77 sets of
concordant twins in the final analysis. The distribution of gestational ages in
both groups was similar. We found no difference in maternal morbidity between the
groups. Discordant sets had a significantly longer hospital stay (p = 0.003) and
more cases of hyperbilirubinemia (p = 0.01), but there were no other differences
in morbid outcomes. There were no differences in outcome variables between the
two twins within discordant sets with respect to gender, size, birth order,
growth restriction, or route of delivery. There were no stillbirths among any of
the 238 infants. Of the 15 neonatal deaths, none occurred in infants delivered
after 32 weeks' gestation or in infants weighing > 2000 gm at birth. Infants who
were small for gestational age had a higher incidence of sepsis (p = 0.043) and
longer hospital stays (p = 0.005) compared with infants who were appropriate for
gestational age. CONCLUSIONS: Size discordancy alone does not appear to be an
indication for preterm delivery of twins. When results of antenatal testing are
normal and growth restriction is absent, attempts should be made to achieve a
gestational age > 32 weeks and weight > 2000 gm before delivery is considered.
PMID- 9396893
TI - Critical periods of maternal weight gain: effect on twin birth weight.
AB - OBJECTIVE: Our purpose was to evaluate the association between maternal weight
gain and twin birth weight. STUDY DESIGN: This historic cohort study was based on
646 live-born twin births of > or = 28 weeks from Baltimore, Maryland, Miami,
Florida, and Ann Arbor, Michigan. The sum of twin-pair birth weight was modeled
as a function of either net maternal weight at delivery or rates of maternal
weight gain with use of multiple regression. RESULTS: Birth weight was
significantly associated with weight gain before 20 weeks in underweight women,
before 20 weeks and after 28 weeks in overweight women, and during all three
gestational periods in normal-weight women. Weight gain before 20 weeks had the
largest effect on infants of underweight women, less of an effect on infants of
normal-weight women, and half as much effect on infants of overweight women.
Weight gain after 28 weeks significantly affected the infant birth weights of
normal-weight and overweight women, but the effect was half as great among
infants of the latter group. CONCLUSIONS: These findings suggest that weight gain
during critical periods of gestation significantly influences twin birth weight;
these critical periods vary by maternal pregravid weight status.
PMID- 9396894
TI - The relationship of infection to method of delivery in twin pregnancy.
AB - OBJECTIVE: Our purpose was to determine whether manipulation of the second twin
increases the risk of postpartum infection. STUDY DESIGN: Medical records of all
twin deliveries between January 1991 and December 1994 were reviewed. The route
of delivery (vaginal vs cesarean section) was examined. The vaginal group was
further divided into those delivered in the vertex/vertex position (i.e., no
uterine manipulation) versus those delivered vertex/breech extraction (i.e.,
manipulation). The chi 2 and Student t test were used where appropriate. RESULTS:
A total of 718 twins were identified, and maternal age, parity, gestational age
at delivery (36 weeks), and birth weight (2278 gm) were similar among groups. The
metritis rate was higher in the cesarean group (74/447 or 18%) than in the
vaginal group (17/299 or 5.7%, p < 0.001). In comparing the vaginal group
delivered without uterine manipulation with the vaginal group delivered with
manipulation (i.e., breech extraction), there was no difference in the incidence
of metritis (10/147 or 6.8% vs 7/152 or 4.6%, not significant). The length of
time between delivery of twin A and twin B did not affect the metritis rate.
Neonatal outcomes including sepsis, neonatal death, and length of hospitalization
were similar among groups (not significant). CONCLUSION: Uterine manipulation of
the second twin does not increase the risk of postpartum metritis or neonatal
sepsis. In addition, the time interval between delivery of twins A and B has no
effect on the rate of metritis. Although the rate of endometritis has been
reported to be higher with twins delivered by cesarean section compared to
singletons, the 18% rate of endometritis in twins delivered by cesarean section
in this study is slightly lower than in our general population of cesarean
deliveries (22%).
PMID- 9396895
TI - A randomized clinical trial comparing misoprostol with prostaglandin E2 gel for
preinduction cervical ripening.
AB - OBJECTIVE: Our purpose was to perform a randomized trial comparing intravaginal
misoprostol to intravaginal prostaglandin E2 gel for preinduction cervical
ripening evaluating efficacy and side effects. STUDY DESIGN: Seventy-five women
seen for induction of labor were randomized to receive 100 micrograms of
intravaginal misoprostol or 5 mg of pharmacy-prepared intravaginal prostaglandin
E2 gel for cervical ripening before oxytocin induction. Six hours after placement
of the study agent, patients were given oxytocin if they were not in labor. The
primary outcome measure was induction-to-delivery time; secondary measures were
change in Bishop score, delivery mode, and side effects. Results were analyzed by
the Student t test and Fisher's exact test, with p < 0.05 considered significant.
RESULTS: There was no difference in the incidence of primiparity or the median
initial Bishop score between the two study groups. The mean time to delivery and
the need for oxytocin was significantly less for subjects receiving misoprostol.
There was no difference in the incidence of uterine hyperstimulation syndrome or
cesarean delivery between the groups. CONCLUSIONS: This randomized clinical trial
indicates that misoprostol is efficacious for preinduction cervical ripening.
Misoprostol use resulted in a significantly shorter induction-to-delivery time
compared with prostaglandin E2 gel use. The side effects associated with
misoprostol may be dose related, and further studies to identify the optimum
dosage and interval are needed.
PMID- 9396896
TI - The association of placenta previa with history of cesarean delivery and
abortion: a metaanalysis.
AB - OBJECTIVE: Our purpose was to determine the incidence of placenta previa based on
the available epidemiologic evidence and to quantify the risk of placenta previa
based on the presence and number of cesarean deliveries and a history of
spontaneous and induced abortion. STUDY DESIGN: We reviewed studies on placenta
previa published between 1950 and 1996 on the basis of a comprehensive literature
search with use of MEDLINE and by identifying studies cited in the references of
published reports. Studies were chosen for inclusion in the metaanalysis if the
incidence of placenta previa and its cross-classification with either prior
cesarean delivery or abortions (both spontaneous and induced) or both were
available. We also extracted details about the study design (case-control or
cohort study) and place where they were conducted (United States or other
countries). Published case reports dealing with placenta previa and studies
relating to abruptio placentae were excluded from this review. We also restricted
the search to studies published in English. No attempts were made to locate any
unpublished studies. Data from studies identified during the literature search
were reviewed and abstracted by a single author. In case of discrepancies or when
the information presented in a study was unclear, abstraction by a (blinded)
second reviewer was sought to resolve the discrepancy. RESULTS: Data on the
incidence of placenta previa and its associations with previous cesarean delivery
and abortions were abstracted. Subgroup analyses were performed to identify
potential sources of heterogeneity by study design and place where they were
conducted. Statistical methods used for the metaanalysis included the fixed
effects logistic regression model, whereas potential sources of heterogeneity
among studies were evaluated by fitting random-effects models. The tabulation of
36 studies identified a total of 3.7 million pregnant women, of whom 13,992
patients were diagnosed with placenta previa. The reported incidence of placenta
previa ranged between 0.28% and 2.0%, or approximately 1 in 200 deliveries. Women
with at least one prior cesarean delivery were 2.6 (95% confidence interval 2.3
to 3.0) times at greater risk for development of placenta previa in a subsequent
pregnancy. The results varied by study design, with case-control studies showing
a stronger relative risk (relative risk 3.8, 95% confidence interval 2.3 to 6.4)
than cohort studies did (relative risk 2.4, 95% confidence interval 2.1 to 2.8).
Four studies, encompassing 170,640 pregnant women, provided data on the number of
previous cesarean deliveries. These studies showed a dose-response pattern for
the risk of previa on the basis of the number of prior cesarean deliveries.
Relative risks were 4.5 (95% confidence interval 3.6 to 5.5) for one, 7.4 (95%
confidence interval 7.1 to 7.7) for two, 6.5 (95% confidence interval 3.6 to
11.6) for three, and 44.9 (95% confidence interval 13.5 to 149.5) for four or
more prior cesarean deliveries. Women with a history of spontaneous or induced
abortion had a relative risk of placenta previa of 1.6 (95% confidence interval
1.0 to 2.6) and 1.7 (95% confidence interval 1.0 to 2.9), respectively.
Substantial heterogeneity in the results of the metaanalysis was noted among
studies. CONCLUSION: There is a strong association between having a previous
cesarean delivery, spontaneous or induced abortion, and the subsequent
development of placenta previa. The risk increases with number of prior cesarean
deliveries. Pregnant women with a history of cesarean delivery or abortion must
be regarded as high risk for placenta previa and must be monitored carefully.
This study provides yet another reason for reducing the rate of primary cesarean
delivery and for advocating vaginal birth for women with prior cesarean delivery.
PMID- 9396897
TI - Neonatal nucleated red blood cell counts in small-for-gestational age fetuses
with abnormal umbilical artery Doppler studies.
AB - OBJECTIVE: The presence of elevated nucleated red blood cell counts in neonatal
blood has been associated with fetal hypoxia. We sought to determine whether
small-for-gestational-age fetuses with abnormal umbilical artery Doppler velocity
waveforms have elevated nucleated red blood cell counts. STUDY DESIGN: Hospital
charts of neonates with the discharge diagnosis of small for gestational age
(birth weight < 10th percentile) who were delivered between October 1988 and June
1995 were reviewed for antepartum testing, delivery conditions, and neonatal
outcome. We studied fetuses who had an umbilical artery systolic/diastolic ratio
within 3 days of delivery and a complete blood cell count on the first day of
life. Multiple gestations, anomalous fetuses, and infants of diabetic mothers
were excluded. Statistical analysis included the Student t test, chi 2 analysis,
analysis of variance, and simple and stepwise regression. RESULTS: Fifty-two
infants met the inclusion criteria. Those with absent or reversed end-diastolic
velocity (n = 19) had significantly greater nucleated red blood cell counts than
did those with end-diastolic velocity present (n = 33) (nucleated red blood
cells/100 nucleated cells +/- SD: 135.5 +/- 138 vs 17.4 +/- 23.7, p < 0.0001).
These infants exhibited significantly longer time intervals for clearance of
nucleated red blood cells from their circulation (p < 0.0001). They also had
lower birth weights (p < 0.05), lower initial platelet count (p = 0.0006), lower
arterial cord blood pH (p < 0.05), higher cord blood base deficit (p < 0.05), and
an increased likelihood of cesarean section for "fetal distress" (p < 0.05).
Multivariate analysis demonstrated that absent or reversed end-diastolic velocity
(p < 0.0001) and low birth weight (p < 0.0001) contributed to the elevation of
the nucleated red blood cell count, whereas gestational age at delivery was not a
significant contributor. CONCLUSION: We observed significantly greater nucleated
red blood cell counts and lower platelet counts in small-for-gestational-age
fetuses with abnormal umbilical artery Doppler studies. This may suggest that
antenatal thrombotic events lead to an increased placental impedance. Fetal
response to this chronic condition may result in an increased nucleated red blood
cell count.
PMID- 9396898
TI - Elevated maternal serum midtrimester alpha-fetoprotein levels are associated with
fetoplacental ischemia.
AB - OBJECTIVE: Elevation of maternal serum alpha-fetoprotein in the second trimester
is associated with poor pregnancy outcome, including fetal death, preterm
delivery, and fetal growth restriction. We hypothesized that placental ischemia
may be the common underlying pathogenesis of these outcomes. Thus we tested
angiogenin, a potent inducer of neovascularization, in midtrimester amniotic
fluid of patients with elevated maternal serum alpha-fetoprotein values to
determine whether alpha-fetoprotein elevation is due to ischemia with subsequent
stimulation of angiogenesis. STUDY DESIGN: In this case-control study, patients
with elevated maternal serum alpha-fetoprotein levels (> or = 2.0 multiples of
the median, n = 9) at triple screen were matched with two controls (n = 18) on
the basis of year of amniocentesis and maternal age, race, and parity. The median
elevation of maternal serum alpha-fetoprotein in the study population was 4.01
multiples of the median (range 2.65 to 7.24 multiples of the median). Inclusion
criteria were (1) singleton gestation, (2) no evidence of fetal structural or
chromosomal anomalies, and (3) genetic amniocentesis. Amniotic fluid was
immunoassayed for angiogenin (Quantikine, R&D Systems; sensitivity 0.026 ng/ml,
interassay and intraassay coefficients of variation 4.6% and 2.9%, respectively).
Statistical analysis included one-way analysis of variance and regression with p
< 0.05 significant. Angiogenin and maternal serum alpha-fetoprotein values were
normalized with use of natural log transformation for statistical analysis.
RESULTS: Angiogenin values were significantly elevated in patients with high
maternal serum alpha-fetoprotein levels (median 31.1 [range 9.2 to 54.6] vs 17.1
[range 9.0 to 29.2] ng/ml, p = 0.02). Mean gestational age at sampling, maternal
age, and year of amniocentesis were not significantly different between the study
and control groups (each p > 0.05). As anticipated, there was a significant
increase in preterm deliveries and small-for-gestational-age neonates in the
patients with elevated maternal serum alpha-fetoprotein levels (each p < 0.01).
CONCLUSIONS: Midtrimester amniotic fluid angiogenin levels are significantly
elevated in patients with elevated midtrimester maternal serum alpha-fetoprotein
levels. Because angiogenin is a known marker of tissue ischemia, resulting in
neovascularization, we hypothesize that elevation of maternal serum alpha
fetoprotein levels at triple screen is due to placental ischemia.
PMID- 9396899
TI - Fetoplacental vascular tone during fetal circuit acidosis and acidosis with
hypoxia in the ex vivo perfused human placental cotyledon.
AB - OBJECTIVES: Our purpose was to determine the effects of acidosis and acidosis
hypoxia on fetoplacental perfusion pressure and its response to angiotensin II.
STUDY DESIGN: Perfused cotyledons from 14 placentas were studied with either an
acidotic fetal circuit perfusate (n = 7) or an acidotic-hypoxic fetal circuit
perfusate (n = 7). Each cotyledon's fetal vasculature was initially perfused
under standard conditions and bolus injected with 1 x 10(-10) moles of
angiotensin II. Fetoplacental perfusate was then replaced with either an acidotic
medium (pH 6.90 to 7.00 and Po2 516 to 613 mm Hg) or an acidotic-hypoxic medium
(pH 6.90 to 7.00 and Po2 20 to 25 mm Hg) followed by an angiotensin II injection.
The vasculature was subsequently recovered with standard perfusate and again
injected with angiotensin II. Perfusion pressures within each group were compared
by one-way analysis of variance, and results were expressed as mean pressure +/-
SEM. RESULTS: Resting fetoplacental perfusion pressure did not change when the
fetal circuit perfusate was made acidotic (28 +/- 1 mm Hg vs 25 +/- 2 mm Hg) or
acidotic-hypoxic (26 +/- 2 mm Hg vs 25 +/- 2 mm Hg). The maximal fetoplacental
perfusion pressure achieved in response to angiotensin II did not differ with an
acidotic perfusate (41 +/- 2 mm Hg vs 38 +/- 1 mm Hg) or with an acidotic-hypoxic
perfusate (39 +/- 2 mm Hg vs 36 +/- 2 mm Hg). CONCLUSIONS: In the perfused
placental cotyledon fetoplacental perfusion pressure and pressor response to
angiotensin II are not affected by fetal circuit acidosis or acidosis-hypoxia.
This suggests that neither fetal acidosis nor fetal acidosis combined with
hypoxia has a direct effect on fetoplacental vascular tone.
PMID- 9396900
TI - The fetoplacental pressor effects of low-dose acetylsalicylic acid and
angiotensin II in the ex vivo cotyledon model.
AB - OBJECTIVE: Our purpose was to investigate perfusion pressure changes ex vivo
induced by angiotensin II on fetoplacental vasculature pretreated with low-dose
acetylsalicylic acid. STUDY DESIGN: Two cotyledons from each of 12 placentas were
perfused. The intervillous space of one cotyledon was infused with
acetylsalicylic acid (5 x 10(-5) mol/L) similar to the serum concentration of
women receiving daily low-dose aspirin therapy (60 to 81 mg). The control
cotyledon was infused with an equivalent amount of normal saline solution. Two
doses of angiotensin II, 1 x 10(-11.5) and 1 x 10(-10) moles, were injected as
boluses into the chorionic arteries of each cotyledon. A 3 x 10(-7) mole dose of
angiotensin II was also injected into the intervillous space. Statistical
analysis was performed with analysis of variance, and results are expressed as
mean pressure change in millimeters of mercury +/- SEM. RESULTS: Perfusion
pressure response did not vary between cotyledons pretreated with acetylsalicylic
acid and control cotyledons when 3 x 10(-7) moles of angiotensin II was injected
into the intervillous space (8.0 +/- 1.9 mm Hg vs 9.8 +/- 1.6 mm Hg, p = 0.59).
There were no differences between cotyledons in pressure response to 1 x 10(
11.5) moles of angiotensin II injected into the fetal circuit (5.9 +/- 0.8 mm Hg
vs 6.7 +/- 0.9 mm Hg, p = 0.51). However, in the cotyledons pretreated with
acetylsalicylic acid there was a decrease in the pressor response to 1 x 10(-10)
moles of angiotensin II (14.1 +/- 1.4 mm Hg vs 21.5 +/- 3.3 mm Hg, p = 0.05).
CONCLUSIONS: Low-dose aspirin infused into the intervillous space decreases
vasoconstriction elicited by angiotensin II in the fetoplacental compartment.
This suggests that maternal low-dose aspirin therapy has effects in the
fetoplacental circulation in addition to its effects in the maternal circulation.
PMID- 9396901
TI - The association between maternal cocaine use and placenta previa.
AB - OBJECTIVE: Our aim was to determine whether maternal cocaine exposure is a risk
factor for placenta previa. STUDY DESIGN: In this case-control study, cases of
placenta previa confirmed at delivery (ascertained by International
Classification of Diseases, ninth revision, Clinical Modification, code-based
search, N = 40) were compared with a random sample of patients without placenta
previa (N = 80) in a ratio of two controls per case. Data on antecedent maternal
cocaine use, as well as other potential risk factors for placenta previa, were
obtained from a review of the prenatal chart and the hospital record.
Categorization of cocaine use was based on either patient self-report or urine
toxicologic testing, or both. Multiple logistic regression was performed to
assess the association between cocaine and placenta previa while we controlled
for other variables. RESULTS: After the effects of other variables were adjusted
for, maternal cocaine use was an independent risk factor for placenta previa
(adjusted odds ratio = 4.39, 95% confidence interval 1.17 to 16.4). Other
significant risk factors included a history of cesarean section and prior
elective abortion. CONCLUSION: These results suggest that cocaine use, as well as
prior cesarean section, prior elective abortion, and parity, are associated with
placenta previa.
PMID- 9396902
TI - New birth weight nomograms for twin gestation on the basis of accurate
gestational age.
AB - OBJECTIVE: Our purpose was to establish new nomograms for the birth weight of
twins on the basis of accurate methods to validate gestational age. STUDY DESIGN:
The medical records of 1632 consecutive twin gestations delivered between 1984
and 1996 were reviewed. Only pregnancies induced by ovulation induction
techniques or that were measured ultrasonographically for crown-rump length
during the first trimester were included. Excluded were those whose fetuses (one
or both) were stillborn, or if the mother smoked, had a significant chronic
illness, or was prescribed any regular medications. The study comprised 520 twin
pregnancies at 28 to 41 gestational weeks at delivery. RESULTS: The median and
10th and 90th percentile birth weight curves were calculated for the studied
twins and plotted against previously reported singleton nomograms. Fetuses of
twin pregnancies were found to be growth restricted in comparison with previously
reported singletons throughout the third trimester. This trend became more
evident after the thirty-fourth to thirty-sixth weeks. CONCLUSIONS: We recommend
these novel birth weight nomograms for clinical use in the management of twin
pregnancies.
PMID- 9396903
TI - Anticholinergic suppression of ovine fetal swallowing activity.
AB - OBJECTIVE: Fetal swallowing contributes importantly to amniotic fluid volume
regulation as the primary route of fluid resorption, reaching 500 to 1000 ml/day
near term. Near-term ovine fetal swallowing activity occurs predominantly during
low-voltage electrocortical activity. In view of the potential to
pharmacologically alter electrocortical activity, we hypothesized that fetal
administration of a centrally acting cholinergic antagonist may be used to
modulate fetal swallowing activity. To explore cholinergic modulation of
swallowing activity, we examined fetal swallowing and electrocortical activity in
response to central and peripheral cholinergic suppression by atropine sulfate.
STUDY DESIGN: Singleton ovine fetuses (n = 6) were chronically prepared with
vascular catheters and thyrohyoid, nuchal, and thoracic esophageal electromyogram
and biparietal electrocortical electrodes. Swallowing and electrocortical
activity were monitored for 2 hours before and after intravenous injection (1 ml
of 0.15 mol/L sodium chloride) of atropine sulfate (1 mg/kg). On a subsequent day
an identical study was performed with use off atropine methyl nitrate (3 mg/kg),
an atropine analog that does not cross the blood-brain barrier. RESULTS: Atropine
sulfate decreased low-voltage electrocortical activity (56% +/- 5% to 14% +/-
4%), increased high-voltage electrocortical activity (40% +/- 5% to 81% +/- 5%),
and did not change intermediate electrocortical activity (4% +/- 1% to 5% +/-
1%). Fetal swallowing activity decreased from 46 +/- 12 to 12 +/- 2 swallows per
hour after atropine sulfate administration. Atropine methyl nitrate had no
discernible effect on either fetal electrocortical or swallowing activity. Fetal
arterial pressure, plasma osmolality, pH, PCO2, and PO2 did not change.
CONCLUSIONS: Central cholinergic antagonism suppresses low-voltage fetal
electrocortical and swallowing activity in the ovine fetus. Studies exploring
spontaneous or induced fetal swallowing should consider the behavioral state of
the fetus when conclusions are drawn about changes in the swallowing activity.
PMID- 9396904
TI - Should the same glucose values be targeted for type 1 as for type 2 diabetics in
pregnancy?
AB - OBJECTIVE: Our purpose was to determine whether the same maternal glycemic
control is necessary to achieve similar perinatal outcomes for type 1 as for type
2 diabetics. STUDY DESIGN: The subjects were all women with pregestational
diabetes mellitus delivered of live-born singletons. Glycemic control was
achieved with diet and insulin. Self-monitoring of blood glucose was performed
before meals and at bedtime. Target glucose values were 60 to 90 mg/dl fasting
and 60 to 105 mg/dl at other times. RESULTS: Of 60,628 deliveries, 46 type 1 and
113 type 2 diabetic women met inclusion criteria. Respective differences were
found between type 1 and type 2 diabetics in average daily glucose levels (112
mg/dl vs 97 mg/dl, p < 0.001), percent of values within target ranges (35% vs
57%, p < 0.001), and mean amplitude of glycemic excursion (48.1 mg/dl vs 24.9
mg/dl, p < 0.001). At least one daily glucose value was < 50 mg/dl during 19% of
observation days for type 1 vs 2% of observation days for type 2 pregnancies (p <
0.001). There were no statistically significant differences between type 1 and
type 2 diabetic pregnancies in neonatal macrosomia (30% vs 34%), proportion of
cesarean deliveries during labor for arrest disorders (67% vs 69%), shoulder
dystocia (2% vs 6%), and neonatal hypoglycemia (18% vs 26%). CONCLUSIONS: Less
stringent maternal glycemic control may permit comparable maternal and neonatal
outcomes for type 1 compared with type 2 diabetics. Higher target values for type
1 diabetics may decrease the frequency of maternal hypoglycemic episodes.
PMID- 9396905
TI - Glucometer analysis of one-hour glucose challenge samples.
AB - OBJECTIVE: Our purpose was to explore a cost-saving measure for diabetes
screening by using glucometer testing on venous whole blood obtained after a 1
hour glucose challenge test. Glucometer results falling above an upper threshold
would predict abnormal plasma values and mandate a glucose tolerance test;
results below the lower threshold would predict normal plasma values and avoid
further testing. Results between the thresholds would require traditional plasma
analysis. STUDY DESIGN: We performed a prospective cohort study on 222
consecutive pregnant women. A standard 50 gm glucose screen was performed with
venous blood drawn at 1 hour. We immediately removed a drop of whole blood from
the venous sample and analyzed it on a portable glucometer, Accu-Chek III. The
remaining sample was submitted immediately for routine plasma analysis. All
values were obtained on the same glucometer, which was calibrated daily in our
clinic laboratory. Regression analysis was performed on 129 samples to select the
two thresholds. The selected thresholds were then applied prospectively to the
next 93 consecutive samples for validation. RESULTS: Excellent correlation (r =
0.9045) exists between the glucometer and laboratory values. Glucometer threshold
values of 110 mg/dl and 155 mg/dl were selected because they predicted plasma
values < 135 mg/dl or > 135 mg/dl with 95% certainty, respectively.
Prospectively, the thresholds were completely accurate in classifying the values.
CONCLUSION: Venous whole blood assayed by glucometer can reliably predict an
elevated or normal automated plasma glucose value. By applying thresholds, three
fourths of all patients can immediately receive reassuring information, whereas
the patients with poorest glucose tolerance are immediately identified and
diagnostic testing is scheduled. Additionally, our model reduces the number of
automated laboratory studies by 80% and reduces the cost of diabetic screening.
PMID- 9396906
TI - The effect of smoking tobacco on neonatal body composition.
AB - OBJECTIVE: Our purpose was to examine the differences in body composition in
infants of women who smoke compared with those of nonsmokers. STUDY DESIGN:
Within 24 hours of birth anthropometric measurements and total body electrical
conductivity estimates of body composition were obtained on 129 term infants (30
born to women who smoked tobacco during pregnancy and 99 born to women who did
not smoke). Anthropometric measurements included weight, skinfolds,
circumferences, and crown-heel and extremity lengths. RESULTS: There was a
significant decrease in weight in the infants of smokers (3145 +/- 414 gm vs 3354
+/- 525 gm, p = 0.05). There was a decrease in crown-heel length (49.2 +/- 2.0 cm
vs 50.1 +/- 2.2 cm, p = 0.03), the length of the lower leg (7.9 +/- 0.6 cm vs 8.4
+/- 0.6 cm, p = 0.0001), upper leg (9.1 +/- 0.7 cm vs 9.9 +/- 0.8 cm, p =
0.0001), and the lower arm (7.2 +/- 0.5 cm vs 7.5 +/- 0.4 cm, p = 0.0001). There
were no significant differences in the skinfold and limb circumference
measurements. Infants of smokers had significantly decreased fat-free mass as
estimated by total body electrical conductivity (2799 +/- 292 gm vs 2965 +/- 359
gm, p = 0.02) but no significant difference in fat mass (343 +/- 164 gm vs 387 +/
216 gm, p = 0.32). CONCLUSIONS: The decrease in birth weight in infants of women
who smoked is primarily due to a decrease in fat-free mass.
PMID- 9396907
TI - Peripartum cardiomyopathy: a longitudinal echocardiographic study.
AB - OBJECTIVE: Our purpose was to determine echocardiographic trends after initial
diagnosis of peripartum cardiomyopathy. STUDY DESIGN: Nine women diagnosed with
peripartum cardiomyopathy were prospectively recruited for a longitudinal
echocardiographic study. Severe myocardial dysfunction was defined as left
ventricular end-diastolic dimension > or = 60 mm + fractional shortening < or =
21%, and mild dysfunction was defined as left ventricular end-diastolic dimension
< 60 mm + fractional shortening 22% to 24%. Unpaired t tests were used to compare
sample means and Fisher's exact test used to compare discrete variables. RESULTS:
All women were seen initially for pulmonary edema. Echocardiography showed
decreased systolic function in all women. The mean age at diagnosis was 33.0 +/-
6.9 years. All but one woman had a diagnosis of either chronic hypertension (n =
6) or preeclampsia (n = 2). Four women were first seen ante partum and five post
partum (range 1 day to 2 months). Repeat echocardiography was performed in all
nine women (median 8 months, range 6 weeks to 5 years). There was no correlation
between antepartum or postpartum presentation and cardiovascular status on follow
up (p = 0.3). Values for initial left ventricular end-diastolic dimension, severe
versus mild dysfunction (68.3 +/- 7.2 mm vs 55.0 +/- 4.2 mm, p = 0.046), follow
up left ventricular end-diastolic dimension, severe versus mild (68.7 +/- 4.1 mm
vs 52.0 +/- 5.7 mm, p = 0.002), and follow-up fractional shortening, severe
versus mild (14.6% +/- 5.0% vs 28.5% +/- 9.2%, p = 0.02) are significant. Six of
the seven women with severe dysfunction had stable disease in follow-up and one
is awaiting heart transplant. One of the two women with mild dysfunction had
disease resolution and one had stable disease. CONCLUSION: Patients with severe
myocardial dysfunction due to peripartum cardiomyopathy are unlikely to regain
normal cardiac function on follow-up.
PMID- 9396908
TI - A randomized trial of epidural anesthesia to improve external cephalic version
success.
AB - OBJECTIVE: This study was designed to determine whether epidural anesthesia would
improve external cephalic version success in a safe and effective manner. STUDY
DESIGN: All women > 37 weeks' gestation with breech presentation scheduled for
external cephalic version at the medical center from Dec. 1, 1993, to July 31,
1996, were randomized to receive an epidural or no epidural anesthesia. Under
ultrasonographic guidance up to three version attempts were performed. RESULTS:
Sixty-nine women were randomized to receive epidural (n = 35) versus no epidural
(n = 34) anesthesia for external cephalic version. There were no statistically
significant differences in maternal age, parity, maternal weight, gestational
age, estimated fetal weight, or station of the presenting part. The success rate
was better for the epidural group (relative risk 2.12, 95% confidence interval
1.24 to 3.62). Neither anterior placentation or oligohydramnios affected the
success rate. CONCLUSION: Epidural anesthesia increases success of external
cephalic version without any apparent detrimental effect on the maternal-fetal
unit.
PMID- 9396909
TI - Impact of multiple antenatal doses of betamethasone on growth and development of
mice offspring.
AB - OBJECTIVE: Our purpose was to determine in a randomized, placebo-controlled
manner whether multiple antenatal doses of betamethasone affect long-term growth
and development of exposed mouse offspring. STUDY DESIGN: Sixty pregnant CD-1
mice received either two, four, or eight antepartum doses of 0.1 mg betamethasone
or placebo. Perinatal outcomes, growth, and development of the offspring were
compared in a blinded manner. Variables were compared by analysis of variance or
chi 2 testing. RESULTS: Betamethasone-exposed subjects gained less weight during
pregnancy and were delivered of fewer live pups, with fewer male survivors and
lower birth weights. These trends were dose related. Growth measurements were
similar after the neonatal period. No differences in functional development and
physical maturation in the offspring were noted. The reproductive capability,
perinatal outcomes, and growth and development of the second-generation offspring
were unaffected by betamethasone exposure. CONCLUSION: Multiple antenatal dosings
of betamethasone, reaching toxic levels, did not have an impact on the long-term
growth and development of the surviving mouse offspring.
PMID- 9396910
TI - Induction of labor with use of a Foley catheter and extraamniotic
corticosteroids.
AB - OBJECTIVE: Our purpose was to examine the hypothesis that corticosteroids, when
administered extraamniotically, can enhance the labor process and reduce the
induction-to-delivery interval. STUDY DESIGN: A double-blind, randomized study
was conducted on 98 women with a gestational age of 36 to 42 weeks, an
unfavorable cervix, and medical indications for delivery, who were assigned to
receive either 20 mg of dexamethasone in saline solution (study group, n = 50) or
saline solution only (control group, n = 48) administered extraamniotically
through an intracervical inflated Foley balloon catheter. The net effect of
steroids was assessed with use of multivariant logistic regression analysis.
RESULTS: The mean time intervals between induction of labor to the active phase
and between induction of labor to delivery were significantly shorter in the
study group compared with those of the control group (7.8 +/- 3.1 hours vs 9.9 +/
3.9 hours, p < 0.03, 11.9 +/- 3.0 hours vs 14.5 +/- 4.8 hours, p < 0.01,
respectively). Those not receiving steroids were at a 3.2 higher risk of having a
longer time interval of induction to delivery (95% confidence interval 1.1 to
9.5). The general success rate in achieving vaginal delivery was, however,
similar between the groups. CONCLUSIONS: Induction of labor with use of an
intracervical Foley balloon catheter and extraamniotic corticosteroids reduces
the time interval from induction of labor to delivery. This may indicate a
possible role for corticosteroids in the parturition process.
PMID- 9396911
TI - Identifying twin gestations at low risk for preterm birth with a transvaginal
ultrasonographic cervical measurement at 24 to 26 weeks' gestation.
AB - OBJECTIVE: Because twins are a high-risk group for preterm birth, many clinicians
routinely use prophylactic interventions such as home bed rest, hospital bed
rest, oral tocolytics, or home uterine activity monitoring to prevent preterm
delivery. We sought to identify twin gestations at low risk for spontaneous
preterm birth with transvaginal ultrasonography of the cervix to avoid the
unnecessary use of prophylactic interventions in these pregnancies. STUDY DESIGN:
We measured cervical length at 24 to 26 weeks' gestation by transvaginal
ultrasonography in women with twin gestations referred to our prematurity
prevention clinic. Each delivery was classified as (1) spontaneous preterm birth
< 34 weeks' gestation, (2) delivery at > or = 34 weeks' gestation with
intervention, or (3) delivery at > or = 34 weeks' gestation without intervention.
Intervention included strict bed rest at home or in the hospital, either
parenteral or oral tocolysis, or both, or home uterine activity monitoring.
Indicated preterm deliveries and patients with cerclage were excluded from this
analysis. The ability of transvaginal cervical length to predict women who would
deliver at > or = 34 weeks without intervention was evaluated. A cervical length
of 35 mm was chosen by scatter diagram as the best cutoff to discriminate between
the group delivered at term without intervention and the other two groups.
RESULTS: Of 85 women with twin gestations who underwent ultrasonographic cervical
length measurements at 24 to 26 weeks' gestation, 17 had spontaneous preterm
birth at < 34 weeks, 23 were delivered at > or = 34 weeks but required
intervention, and 45 were delivered at > or = 34 weeks without intervention. The
mean cervical length for those delivered at > or = 34 weeks' gestation without
intervention (36.4 +/- 5.8 mm) was significantly greater (p < 0.0001) than the
mean for those delivered preterm (27.4 +/- 8.5) and those delivered at > or = 34
weeks' gestation who required intervention (27.7 +/- 10.5 mm). The sensitivity,
specificity, and positive and negative predictive values of a cervical length >
35 mm for predicting delivery at > or = 34 weeks' gestation are 49%, 94%, 97%,
and 31%, respectively. CONCLUSION: A transvaginal ultrasonographic measurement of
the cervix of > 35 mm at 24 to 26 weeks in twin gestations can identify patients
who are at low risk for delivery before 34 weeks' gestation.
PMID- 9396912
TI - The challenge of complementary and alternative medicine.
AB - Complementary and alternative medicine can be defined as those medical systems,
practices, interventions, and applications that currently are not part of the
dominant or conventional medical system. There are more than 300 different topics
under the term complementary and alternative medicine that can be divided into
seven major categories on the basis of philosophy, approach to the patient, and
orientation. Most patients seeking care from complementary and alternative
medicine providers do so for the relief of signs and symptoms related to chronic
illness while they are under the care of a physician. Clinical data derived from
appropriately conducted clinical trials support the use and value of
complementary and alternative medicine for selected indications. The challenge
for both conventional medicine and complementary and alternative medicine is to
fulfill the role of patient advocate by engaging in reciprocal open
communication, facilitating the patient's informed choice, avoiding harmful or
useless practices, and implementing an integrated evidence-based care plan.
PMID- 9396913
TI - Brachial plexus palsy associated with cesarean section: an in utero injury?
AB - OBJECTIVE: Brachial plexus injury may be unrelated to manipulations performed at
the time of delivery, occurring in the absence of shoulder dystocia and in the
posterior arm of infants with anterior shoulder dystocia. To further support the
hypothesis that some of these nerve injuries appear to be of intrauterine origin,
we present a series of brachial plexus palsies associated with atraumatic
cesarean delivery among fetuses presenting in the vertex position. STUDY DESIGN:
We performed a computerized search of all deliveries from 1991 to 1995 for the
discharge diagnoses of brachial plexus injury and cesarean section. Inclusion
criteria included cephalic presentation at the time of delivery and the absence
of traumatic delivery. RESULTS: We noted six cases of Erb's palsy, with four
palsies in the anterior shoulder and two in the posterior arm. Among those five
patients undergoing cesarean section because of labor abnormalities, two had
uterine cavity abnormalities whereas one had a prolonged second stage of labor.
One brachial plexus palsy occurred in the absence of active labor. All nerve
injuries were persistent at age 1 year. CONCLUSIONS: Brachial plexus palsy can be
associated with cesarean delivery. Such palsies appear to be of intrauterine
origin and are more likely to persist.
PMID- 9396914
TI - Congenital malformations in offspring of women with hyperglycemia first detected
during pregnancy.
AB - OBJECTIVES: Our aim was to determine risk factors for congenital malformations in
offspring of women with hyperglycemia first detected during pregnancy (i.e.,
women with gestational diabetes). STUDY DESIGN: A total of 3743 pregnancies
complicated by gestational diabetes mellitus delivered at > 20 weeks of gestation
were reviewed for the presence of congenital malformations diagnosed before
hospital discharge. Anomalies were categorized as major, minor, or absent.
Pregnancies with genetic syndromes and aneuploidies were excluded. In addition to
maternal clinical and historic parameters, diagnostic glycemic parameters
(fasting and post-glucose-challenge levels from the diagnostic glucose tolerance
test, highest fasting serum glucose level, and hemoglobin A1c level before
insulin therapy) were examined by logistic regression for predictive risk of
major anomalies. RESULTS: One or more major congenital anomalies were present in
108 (2.9%) of the newborns; an additional 91 (2.4%) had only minor anomalies.
None of the maternal variables were associated with the risk of minor anomalies.
By contrast, parity, a history of gestational diabetes mellitus, and several
glycemic parameters were associated with the risk of major anomalies. The highest
fasting serum glucose level was the best independent predictor (odds ratio
1.13/10 mg/dl, 95% confidence interval 1.09 to 1.34). The fasting serum glucose
level at diagnosis, a parameter that is almost uniformly available to clinicians,
gave similar predictive information about the risk of major anomalies (odds ratio
1.13, 95% confidence interval 1.08 to 1.14). Stratification of women into
subgroups of fasting serum glucose level at diagnosis revealed the incidence of
major anomalies to be as follows: 2.1% with a fasting serum glucose level < 120
mg/dl (2973 pregnancies), 5.2% with a fasting serum glucose level of 121 to 260
mg/dl (747 pregnancies), and 30.4% with a fasting serum glucose level > 260 mg/dl
(23 pregnancies). CONCLUSION: In a large population of women without a diagnosis
of diabetes before pregnancy, the maternal fasting serum glucose concentration at
diagnosis was a useful predictor of the risk of major but not minor anomalies.
The rate of major anomalies doubled with a fasting glucose level > 120 mg/dl.
Thus a fasting glucose level below that of overt diabetes outside of pregnancy
carries an important risk of major anomalies that must be considered in the
counseling and management of these patients.
PMID- 9396915
TI - Fetal plasma iron and restoration of red blood cell mass after hemorrhage of the
ovine fetus.
AB - OBJECTIVE: Our purpose was to determine whether the restoration of fetal red
blood cell mass after acute hemorrhage of 40% of the fetal blood volume is
related to fetal plasma iron concentration. STUDY DESIGN: Ten chronically
catheterized ovine fetuses were monitored for 10 days beginning at 125 +/- 1 (SE)
days of gestation. After a 3-day control period 40% of the fetal blood was
removed over 2 hours at a rate of approximately 1 ml/min. Fetal plasma iron and
erythropoietin concentrations, hematocrit, blood volume, and red blood cell mass
were measured daily before and for 7 days after fetal hemorrhage. Statistical
analysis was by analysis of variance, correlation, and regression. RESULTS:
Although blood volume was restored within 3 days of the hemorrhage (101.0% +/-
1.4% of prehemorrhage volume), red blood cell mass was not (81.8% +/- 2.8%). Only
6 of 10 fetuses restored their red blood cell mass to prehemorrhage levels by the
end of the 7-day posthemorrhage period. On day 10 red blood cell mass correlated
positively with prehemorrhage (r = 0.74, p = 0.015) and posthemorrhage (r = 0.69,
p = 0.045) plasma iron concentration and negatively with posthemorrhage
erythropoietin concentration (r = -0.68, p = 0.047). CONCLUSION: Fetal plasma
iron concentration is an important factor in restoration of fetal red blood cell
mass after loss of blood. The negative correlation of erythropoietin
concentration with posthemorrhagic red blood cell mass suggests that iron, not
erythropoietin, may be the limiting factor in recovery from hemorrhage-induced
anemia. Thus iron supplementation of the fetus may be of benefit in the treatment
of some types of fetal anemia.
PMID- 9396916
TI - Is bleeding a predictor of endometrial hyperplasia in postmenopausal women
receiving hormone replacement therapy? Menopause Study Group (United States,
Italy, Netherlands, Switzerland, Belgium, Germany, and Finland.
AB - OBJECTIVE: We evaluated bleeding as a predictor of endometrial hyperplasia in
postmenopausal women receiving conjugated estrogens (Premarin) alone or with
medroxyprogesterone acetate. STUDY DESIGN: This study was a retrospective
assessment of bleeding and endometrial histologic data gathered during the
prospective Menopause Study Group trial. RESULTS: Approximately 20% of women (n =
57) who received unopposed conjugated estrogens for 1 year had endometrial
hyperplasia. These women (n = 56) had more bleeding days than did women who did
not have hyperplasia (p < 0.001). For users of unopposed conjugated estrogens,
the predictive value of amenorrhea to indicate a nonhyperplasia diagnosis was
95%. Irregular bleeding did not appear to be indicative of hyperplasia when
continuous or cyclic medroxyprogesterone acetate was added to conjugated
estrogens. CONCLUSION: Unanticipated prolonged bleeding in postmenopausal women
receiving unopposed estrogen is suggestive of endometrial hyperplasia. Some
irregular bleeding is anticipated in women who receive conjugated estrogens plus
medroxyprogesterone acetate as they acclimate to therapy, and this was not
associated with hyperplasia.
PMID- 9396917
TI - Bacterial vaginosis as a risk factor for upper genital tract infection.
AB - OBJECTIVE: The objective of this study was to determine whether the clinical
diagnosis of bacterial vaginosis is associated with objective evidence of acute
upper genital tract infection. STUDY DESIGN: Women who either met the Centers for
Disease Control and Prevention's minimal criteria for acute pelvic inflammatory
disease or had other "nonclassic" signs of upper genital tract infection (i.e.,
atypical pelvic pain, abnormal uterine bleeding, or cervicitis) were evaluated
with either an endometrial biopsy or a laparoscopy with endometrial and fimbrial
biopsies for objective evidence of upper genital tract infection. Bacterial
vaginosis was considered present if three of the four following criteria were
found: (1) homogeneous gray-white vaginal discharge, (2) vaginal pH > 4.5, (3)
positive "whiff" test result, and (4) the presence of > 20% of epithelial cells
classified as clue cells. Patients were considered to have upper genital tract
infection if they had histologic, microbiologic, or laparoscopic evidence of
upper tract infection. RESULTS: One hundred sixteen women were evaluated between
August 1993 and March 1997 with complete evaluations. Objective evidence of upper
tract infection was present in 56% (14/25) of women with the clinical diagnosis
of bacterial vaginosis compared with 30% of women (27/91) who did not meet the
clinical criteria (p = 0.015). Using logistic regression to control for
confounding variables, we found that the presence of bacterial vaginosis was
associated with a threefold increased risk of upper genital tract infection
(adjusted odds ratio = 3.0, 95% confidence interval 1.2 to 7.6). CONCLUSIONS:
Bacterial vaginosis is associated with an increased risk of objective evidence of
acute upper genital tract infection. Future prospective studies are needed to
determine whether treatment of bacterial vaginosis can reduce the risk of
ascending infection.
PMID- 9396918
TI - Biopsy findings in five hundred thirty-one patients with atypical glandular cells
of uncertain significance as defined by the Bethesda system.
AB - OBJECTIVES: Histologic findings in biopsy specimens obtained from patients with
atypical glandular cells of uncertain significance were studied to define the
utility and limitations of this category. STUDY DESIGN: Computerized records over
a 3-year period were retrospectively analyzed. The most significant histologic
diagnosis from all biopsy specimens submitted was compared with the subcategory
of the first Papanicolaou smear obtained showing atypical glandular cells of
uncertain significance. RESULTS: Biopsy results were available for 531 of 1117
patients with atypical glandular cells of uncertain significance (48%). Biopsy
proved preinvasive (83%) or invasive (17%) lesions were present in 191 patients
(36%). Eighty-nine percent of the preinvasive lesions were squamous, whereas 97%
of the invasive lesions were glandular. Glandular lesions were more likely to be
invasive, whereas squamous lesions were more likely to be preinvasive (p <
0.001). Twenty-eight patients had endometrial carcinoma, which represents 88% of
all invasive carcinomas detected. CONCLUSIONS: Almost three fourths of patients
with atypical glandular cells of uncertain significance and with lesions have
squamous lesions, not glandular as suggested by the name of the category. Unlike
patients with atypical squamous cells of uncertain significance, patients with
atypical glandular cells of uncertain significance have a significant risk of
malignant lesions, which are nearly all glandular and predominantly arise from
the endometrium.
PMID- 9396920
TI - Heart rate and blood pressure variabilities are increased in pregnancy-induced
hypertension.
AB - OBJECTIVE: Our purpose was to study whether cardiovascular changes in pregnancy
induced hypertension are associated with the increase in sympathetic control of
hemodynamics and change in sympathovagal balance. STUDY DESIGN: Fourteen women
with pregnancy-induced hypertension and 16 women with uncomplicated pregnancies
of similar duration were studied. Electrocardiographic signals and arterial blood
pressure (Finapres monitor, Ohmeda) were continuously measured noninvasively
throughout the study. Heart rate and blood pressure were measured while the
subject was breathing (1) with her normal tidal volume at a frequency of 15
breaths per minute and (2) as deeply as possible at a frequency of six breaths
per minute. Heart rate and systolic blood pressure variability were calculated
with use of the autoregressive model of spectral analysis. RESULTS: Heart rate
and systolic blood pressure variabilities were significantly increased in women
with pregnancy-induced hypertension compared with normotensive pregnant women.
This increase was greatest in the high frequency component of heart rate
variability (p = 0.02) while the women were breathing with a normal tidal volume.
Further, the medium frequency (p = 0.03) and high-frequency variabilities (p =
0.03) of systolic blood pressure were significantly increased in women with
preeclampsia compared with normotensive pregnant subjects. CONCLUSIONS: Neural
control of the heart rate and blood pressure are disturbed in pregnancy-induced
hypertension, as shown by increased heart rate and blood pressure variability.
Both the sympathetic and parasympathetic control of the heart rate and blood
pressure appear to be increased. The maladaptation of the cardiovascular system
in women with pregnancy-induced hypertension is manifested as a lack of the
physiologic decline in cardiovascular oscillations.
PMID- 9396919
TI - Strategies to reduce the incidence of endometrial cancer in postmenopausal women.
AB - OBJECTIVE: The purpose of this study was to develop strategies to reduce the
incidence of endometrial cancer in postmenopausal women by reviewing methods to
diagnose women at risk and providing therapies that are effective. STUDY DESIGN:
A literature search for studies between 1975 and 1995 of the association between
hormone therapy and endometrial cancer was performed with MEDLINE. There were
nine reports with a total of 66 cases of endometrial cancer developing during use
of estrogen-progestogen replacement therapy. RESULTS: The cases of endometrial
cancer diagnosed during use of estrogen-progestogen therapy because of abnormal
bleeding occurred when the dosage or duration of the progestogen was less than
that considered optimum. The minimum effective dosage of medroxyprogesterone
acetate is 10 mg and the minimum effective dosage of norethindrone acetate to 2.5
mg. The minimum effective duration of the progestogen is 12 to 14 days when it is
used sequentially. Continuous combined therapy with low dosage estrogen and
progestogen may not be fully endometrial protective. CONCLUSIONS: The progestogen
challenge test is an effective test to identify women at increased risk for
endometrial cancer. There are no adverse effects on lipids and lipoproteins from
added progestogen when adequate dosages of estrogen are given. Side effects of
progestogens can be managed with mild diuretics or by changing the type, dosage,
or route of administration. Cyclic combined therapy may be more endometrial
protective than continuous combined hormone replacement is.
PMID- 9396921
TI - Persistent cerebrovascular changes in postpartum preeclamptic women: a Doppler
evaluation.
AB - OBJECTIVE: Our goal was to evaluate the cerebral vasculature in postpartum
normotensive and preeclamptic women. STUDY DESIGN: Nineteen previously
preeclamptic women and 19 matched normotensive controls were studied at 6 weeks,
and 8 preeclamptic women and 28 normotensive controls were studied at 12 weeks
post partum. Systolic, diastolic, and mean velocities, as well as resistance and
pulsatility indexes, of the middle cerebral, ophthalmic, and central retinal
arteries were recorded. Data are presented as median and range. Statistical
significance was set at p < 0.05. RESULTS: There were no differences in maternal
age, parity, heart rate, mean arterial pressure, and proteinuria between the two
groups at 6 and 12 weeks post partum. At 6 weeks post partum the preeclamptic
group had higher ophthalmic artery diastolic velocity (9.0 cm/sec, 3.1 to 22.3,
vs 5.4 cm/sec, 3.0 to 20.1; p = 0.008), ophthalmic artery mean velocity (6.0
cm/sec, 8.8 to 34.8, vs 12.5 cm/sec, 6.8 to 35.4; p = 0.03), and central retinal
artery systolic velocity (10.0 cm/sec, 7.6 to 28.0, vs 8.4 cm/sec, 5.2 to 18.3; p
= 0.02). The ophthalmic artery resistance index (0.72, 0.43 to 0.88, vs 0.79,
0.66 to 0.90; p = 0.03) and ophthalmic artery pulsatility index (1.56, 0.94 to
2.82, vs 2.03, vs 1.13 to 3.10; p = 0.04) were lower in the preeclamptic group.
At 12 weeks post partum the preeclamptic group had elevated ophthalmic artery
mean velocity (14.5 cm/sec, 7.9 to 20.2, vs 10.9 cm/sec, 5.5 to 15.4 p = 0.01),
central retinal artery systolic velocity (11.1 cm/sec, 6.8 to 15.9, vs 8.5, 5.1
to 15.3; p = 0.02), and central retinal artery diastolic velocity (3.9 cm/sec,
1.2 to 5.2, vs 3.0, 1.4 to 5.8; p < 0.05). CONCLUSION: In the postpartum period
preeclamptic women show persistently elevated central retinal artery systolic
velocity, which suggests distal vasoconstriction.
PMID- 9396922
TI - The role of deoxyribonucleic acid image cytometric and interphase cytogenetic
analyses in the differential diagnosis, prognosis, and clinical follow-up of
hydatidiform moles. A report from the Central Molar Registration in The
Netherlands.
AB - OBJECTIVES: To assess the value of deoxyribonucleic acid ploidy in the
differential diagnosis and clinical follow-up of hydatidiform moles, the
histopathologic features, deoxyribonucleic acid ploidy, and clinical follow-up
were compared in 347 cases: 143 complete moles, 52 partial moles, and 152
abortions, of which 56 cases were hydropic abortions with histologic features of
triploidy but lacked trophoblastic hyperplasia. STUDY DESIGN: In all cases
deoxyribonucleic acid image cytometry was performed, and in 85 of these cases
interphase cytogenetics was also performed. RESULTS: With use of deoxyribonucleic
acid image cytometry and interphase cytogenetics, a bimodal polyploid
deoxyribonucleic acid pattern was present in 97% of complete moles, 27% of
partial moles, and 4% of abortions. All these cases of partial mole were
reclassified to complete mole on the basis of this deoxyribonucleic acid pattern
and the histopathologic features in spite of the presence of fetal blood cells,
amnion, or yolk sac. Deoxyribonucleic acid triploidy was found in 95% of the
remaining partial moles, in 77% of hydropic abortions with histologic features of
triploidy, and in 14% of the remaining abortions. Reliable differentiation
between deoxyribonucleic acid triploid partial moles and hydropic abortions with
histologic features of triploidy was not possible on basis of the histopathologic
features (trophoblastic hyperplasia) or 3.5c exceeding rates. Deoxyribonucleic
acid diploidy was found in 1% of complete moles, 23% of hydropic abortions with
features of triploidy, and 78% of the remaining abortions. Deoxyribonucleic acid
tetraploidy was rarely found (1% of complete moles, 2% of partial moles, 1% of
abortions). Persistent gestational trophoblastic disease developed in 33% of the
bimodal deoxyribonucleic acid polyploid cases (all complete moles), in 1% of the
diploid cases (concerning one of the two diploid complete moles), and in 1% of
the triploid cases (partial moles). CONCLUSION: Deoxyribonucleic acid analysis is
essential in the diagnosis of hydatidiform moles to decide on clinical follow-up.
PMID- 9396923
TI - Lipopolysaccharide binding protein and soluble CD14 receptor protein in amniotic
fluid and cord blood in patients at term.
AB - OBJECTIVES: Our purpose was to examine whether lipopolysaccharide binding protein
and soluble CD14 are present in amniotic fluid and to determine whether the
lipopolysaccharide binding protein and soluble CD14 concentrations are associated
with indicators of infection or labor at term. A lipopolysaccharide
lipopolysaccharide binding protein complex activates macrophages through soluble
CD14 at lipopolysaccharide concentrations up to 100 times lower than required
with lipopolysaccharide alone. Thus lipopolysaccharide binding protein and
soluble CD14 in amniotic fluid could explain the high concentrations of cytokines
found in amniotic fluid of culture-positive patients and may even explain the
presence of cytokines in some culture-negative patients. STUDY DESIGN: Healthy
women at term undergoing cesarean section had amniotic fluid, chorioamnion,
decidua, and cord blood obtained. Lipopolysaccharide binding protein was measured
by enzyme-linked immunosorbent assay. Amniotic fluid was cultured and assayed for
cytokines, and the chorioamnion and decidua were cultured and examined
histologically. RESULTS: Lipopolysaccharide binding protein and soluble CD14 were
present in all amniotic fluids and fetal cord blood. An elevated level of
lipopolysaccharide binding protein (270 ng/ml/mg of protein) was present in the
amniotic fluid of 12 (36%) of the 33 patients. An elevated level was associated
with microorganisms in the chorioamnion and decidua, cytokines (tumor necrosis
factor-alpha, interleukin-6, and interleukin-8) in amniotic fluid, histologic
chorioamnionitis, and labor. Among patients in labor, the concentration of
lipopolysaccharide binding protein appeared independent of microorganisms in the
amniotic fluid. CONCLUSIONS: Lipopolysaccharide binding protein and soluble CD14
are present in amniotic fluid, and concentrations of lipopolysaccharide binding
protein are elevated in patients in labor with and without evidence of infection.
Lipopolysaccharide binding protein and soluble CD14 may mediate intrauterine
inflammatory responses at term.
PMID- 9396924
TI - Multicenter study on the clinical value of fetal pulse oximetry. I. Methodologic
evaluation. The French Study Group on Fetal Pulse Oximetry.
AB - OBJECTIVE: Our purpose was to evaluate the feasibility of intrapartum fetal pulse
oximetry, the distribution of fetal oxygen saturation values, and the
relationship with the neonatal outcome in a population with an abnormal fetal
heart rate. STUDY DESIGN: A prospective multicenter observational study was
performed from June 1994 to November 1995. Fetal oxygen saturation was
continuously recorded with use of a Nellcor N-400 fetal pulse oximeter in case of
an abnormal fetal heart rate during labor. Simultaneous readings of fetal oxygen
saturation and fetal blood analysis were obtained at inclusion and before birth.
Feasibility, adverse effects, distribution of fetal oxygen saturation values, and
relationship with neonatal outcome were assessed. RESULTS: One hundred seventy
four patients were included. From 172 attempted sensor placements, the procedure
was impossible in three cases and fetal oxygen saturation values were obtained in
164 cases (95.3%). Physicians considered sensor placement an easier task than an
attempt at fetal blood analysis (easy in 87.5% vs 78.9% for fetal blood analysis,
p = 0.03). The mean reliable signal time (+/- SD) was 64.7% +/- 32% during the
first stage. There were no serious adverse effects in the study population. The
mean fetal oxygen saturation during the first stage of labor was 42.2% +/- 8.0%
(10th to 90th percentile range 30% to 53%). Fetal oxygen saturation was
significantly correlated with scalp pH (r = 0.29, p = 0.01) but not with neonatal
umbilical artery pH or gas values. There was a significant association between
low fetal oxygen saturation (< 30%) and poor neonatal condition. CONCLUSION: The
feasibility of fetal pulse oximetry is satisfactory in clinical practice. It is
easy to use and provides a fair rate of recorded values, even in a population
with suspicion of fetal distress. A low fetal oxygen saturation is significantly
associated with an abnormal neonatal outcome.
PMID- 9396925
TI - Circulating bioactive tumor necrosis factor-alpha, tumor necrosis factor-alpha
receptors, fibronectin, and tumor necrosis factor-alpha inducible cell adhesion
molecule VCAM-1 in uncomplicated pregnancy.
AB - OBJECTIVES: Our goal was to assess in a longitudinal study of uncomplicated
pregnancy the course of maternal plasma concentrations of the bioactive cytokine
tumor necrosis factor-alpha, the soluble tumor necrosis factor-alpha receptors
sTNFRI and sTNFRII, the soluble cell adhesion molecule sVCAM-1, and circulating
fibronectin. STUDY DESIGN: Blood was collected from 22 healthy pregnant women at
7 to 17, 18 to 22, 23 to 28, and 30 to 36 weeks' gestation and post partum.
Plasma samples were measured by bioassay for bioactive tumor necrosis factor
alpha, by immunoassay for sTNFRI, sTNFRII, and VCAM-1, and by radial
immunodiffusion for circulating fibronectin, and data were statistically
analyzed. RESULTS: Plasma concentrations of all variables were significantly
linked with gestational age. Levels of bioactive tumor necrosis factor-alpha and
sTNFRII showed a parallel rise in the second trimester and a decrease thereafter.
Values for sTNFRI and sTNFRII and for these receptors and VCAM-1 were correlated,
a weak correlation between bioactive tumor necrosis factor-alpha and sTNFRII was
observed, and no correlation between circulating fibronectin and other variables
was apparent. CONCLUSIONS: All variables studied exhibited a characteristic
pattern depending on gestational age, which supports the concept of a physiologic
role of tumor necrosis factor-alpha in pregnancy.
PMID- 9396926
TI - Coordinate expression of inducible nitric oxide synthase and cyclooxygenase-2
genes in uterine tissues of endotoxin-treated pregnant mice.
AB - OBJECTIVES: Our purpose was to investigate the relationship between expression of
cyclooxygenase-2 and inducible nitric oxide synthase genes after labor induction
with bacterial lipopolysaccharide in a murine model of preterm parturition. STUDY
DESIGN: Pregnant C57B1/6 mice were given Escherichia coli lipopolysaccharide (20
micrograms per mouse) by intraperitoneal injection on day 16 of gestation, and
the animals were followed up for signs of labor. Control mice received an
equivalent volume of 0.9% saline solution. The latency from lipopolysaccharide
injections until appearance of the first pup was recorded. Two separate groups of
mice were given either aminoguanidine or indomethacin (5 mg/kg intragastric) 24
hours before induction of preterm labor. In a separate set of experiments mice
were treated with lipopolysaccharide as described and were killed at intervals
from 0.5 to 72 hours and intrauterine tissues (uterus, placenta, and fetal
membranes) were removed and snap frozen in liquid nitrogen. Total protein and
ribonucleic acid were extracted for Western and Northern blot analysis of
cyclooxygenase-2 and inducible nitric oxide synthase protein and messenger
ribonucleic acid, respectively. RESULTS: Northern blots from uterine, placental,
and fetal membrane tissues of lipopolysaccharide- and saline solution-treated
mice revealed that cyclooxygenase-2 and inducible nitric oxide synthase messenger
ribonucleic acid transcripts were rapidly (within 0.5 to 2 hours) up-regulated
after lipopolysaccharide administration but were unchanged in mice injected with
saline solution. Immunoblot analysis with isoform-specific antibodies revealed
that both enzymes were expressed in uterus, placenta, and fetal membranes in a
coordinated fashion with peak expression seen at 6 to 8 hours. Although the
steady-state accumulation of messenger ribonucleic acid transcripts encoding
cyclooxygenase-2 and inducible nitric oxide synthase peaked at 6 hours and
declined to baseline by 16 hours after injection with lipopolysaccharide,
expression of cyclooxygenase-2 and inducible nitric oxide synthase was sustained
through the period when premature delivery was observed. Nitric oxide-dependent
cyclooxygenase-2 and inducible nitric oxide synthase expression was demonstrated
by the elimination of accumulation of both messenger ribonucleic acid transcripts
in mice pretreated with aminoguanidine before injection with lipopolysaccharide.
CONCLUSIONS: These data indicate that nitric oxide synthesis may be a
prerequisite for subsequent stimulation of cyclooxygenase-2 and inducible nitric
oxide synthase gene expression. Taken together, the data suggest that
cyclooxygenase-2 and inducible nitric oxide synthase are expressed in a
coordinated manner in the uterus of endotoxin-challenged pregnant mice and that
their enzymatic products may contribute to the signaling of uterine activity or
cervical changes culminating in expulsion of the fetus.
PMID- 9396927
TI - Role of nitric oxide in the regulation of vascular tone in pressurized and
perfused resistance myometrial arteries from term pregnant women.
AB - OBJECTIVE: Our purpose was to evaluate flow-induced responses, myogenic tone, and
norepinephrine-induced constriction in myometrial resistance arteries from normal
term pregnant women and the role that nitric oxide and prostanoids may play in
these responses. STUDY DESIGN: Arteries (approximately 200 microns, n = 14, at 40
mm Hg) were dissected from myometrial biopsy specimens from women undergoing
cesarean section and then were mounted in a pressure arteriograph. Responses to
intraluminal flow, pressure, and a constrictor agonist (norepinephrine 10(-6)
mol/L) were studied in the absence and presence of N omega-nitro-L-arginine
methyl ester (n = 7) or indomethacin (n = 5). Myogenic and norepinephrine-induced
tone were calculated after the determination of artery diameter in the absence of
extracellular calcium. RESULTS: Arteries developed myogenic tone (80 mm Hg) that
was not modulated by nitric oxide or prostanoid release, whereas norepinephrine
induced tone was significantly enhanced by the nitric oxide inhibitor. An
increase in intraluminal flow led to dilatation in physiologic salt solution and
indomethacin, but to constriction in the presence of N omega-nitro-L-arginine
methyl ester (percent increase in diameter at flow rate of 184.6 microliters/min,
24% +/- 8% in physiologic salt solution and 20% +/- 4% in the presence of
indomethacin versus -27% +/- 12% in N omega-nitro-L-arginine methyl ester alone
and -21% +/- 10% in indomethacin and N omega-nitro-L-arginine methyl ester,
respectively, analysis of variance, p < 0.05). CONCLUSIONS: Flow-induced shear
stress is a physiologic modulator of vascular tone in myometrial arteries from
pregnant women. Nitric oxide, but not prostanoids, mediates this response and
also blunts norepinephrine constriction. Nitric oxide may play a fundamental role
in the maintenance of adequate blood supply to the fetus during human pregnancy.
PMID- 9396928
TI - New technologies?
PMID- 9396929
TI - Fetal sex and cesarean section.
PMID- 9396930
TI - Public health approach to activated protein C resistance assay.
PMID- 9396931
TI - Effect of hormone replacement therapy on aortic compliance in postmenopausal
women.
PMID- 9396932
TI - Flawed study alleging prevention of diabetic embryopathy.
PMID- 9396933
TI - Intrahepatic cholestasis of pregnancy: are we really able to predict fetal
outcome?
PMID- 9396934
TI - Endometriosis and non-Hodgkin's lymphoma.
PMID- 9396935
TI - Postmenopausal female hormone use and venous thromboembolic disease in black
women.
PMID- 9396936
TI - Cost of the treatment of unruptured ectopic pregnancy: is there still a place for
laparotomy?
PMID- 9396937
TI - Umbilical cord compression, persistent pulmonary hypertension, and placental
villous hypervascularity.
PMID- 9396938
TI - What shape are we in? Gender, psychopathology, and the brain.
PMID- 9396939
TI - Linkage and association in complex genetic diseases.
PMID- 9396940
TI - Psychopathology in women and men: focus on female hormones.
AB - OBJECTIVE: The goal of this overview is to examine male/female differences in
psychopathology in light of the known effects of gonadal steroids, especially
estradiol, on neural function. METHOD: The epidemiology of specific
psychopathological syndromes is highlighted with respect to male/female
differences and discussed against the backdrop of recent neuroendocrine findings.
RESULTS: A number of differences between the sexes in rates of illness and course
of illness are documented, with Alzheimer's disease, schizophrenia, alcoholism,
and mood and anxiety disorders each illustrating slightly different hormone
mediated risks and buffers. CONCLUSIONS: Estrogens are neuroprotective with
respect to neuronal degeneration, growth, and susceptibility to toxins. The
cyclic fluctuations of estrogens and progesterone enhance the response to stress,
which confers susceptibility to depression and anxiety.
PMID- 9396941
TI - Sex differences in brain morphology in schizophrenia.
AB - OBJECTIVE: The current literature on sex differences in schizophrenia with regard
to structural brain abnormalities is inconsistent. Several studies have suggested
that male and female patients may differ in severity of brain abnormalities.
Efforts to explore this issue have been hindered by small study groups,
unbalanced groups (i.e., those with many more men than women), or both. The
relatively smaller number of female schizophrenic patients in most studies may
have made it more difficult to detect differences between patients and comparison
subjects. This study was designed to evaluate brain morphology in a carefully
selected group of patients with schizophrenia and healthy comparison subjects who
were balanced by sex. METHOD: Eighty patients (40 male and 40 female) and 80
healthy volunteers matched by sex and age were studied. Magnetic resonance
imaging scans were analyzed with the use of an automated method that yields
volumes of major brain regions. RESULTS: There was a significant sex-by-diagnosis
interaction for ventricular volume, with male patients having significantly
larger ventricles than male comparison subjects but female patients showing no
significant enlargement in comparison with healthy female subjects. Although the
overall distribution of structural brain differences was very similar in the male
and female patients, the male patients had a greater number of significant
abnormalities than the female patients. CONCLUSIONS: These findings indicate that
male and female patients with schizophrenia have the same pattern of structural
brain abnormalities, but male patients appear to manifest greater severity,
especially with regard to ventricular enlargement.
PMID- 9396942
TI - Sex-specific expression of Heschl's gyrus functional and structural abnormalities
in paranoid schizophrenia.
AB - OBJECTIVE: Evidence supports abnormal temporal lobe structure and function in
schizophrenia. Some abnormalities, particularly involving the auditory cortex,
appear to be sex specific. These findings were extended to anatomical and
physiological descriptors. METHOD: The authors quantified the volume, surface
area, and three-dimensional location of Heschl's gyri on magnetic resonance
imaging (MRI) images of 21 patients with paranoid schizophrenia and 24 healthy
comparison subjects. Neuromagnetic localizations of the 100-msec latency auditory
evoked field (M100) were compared with MRI-determined locations of Heschl's gyri,
computed as the geometric center of mass of the volume. RESULTS: Volumetric
measures revealed small Heschl's gyri only in male patients. Asymmetry was found
in the location of the Heschl's gyrus centroid (more anterior on the right)
across all groups. Male comparison subjects had M100 locations posterior to the
Heschl's gyrus centroid in the left hemisphere and close to the Heschl's gyrus
centroid on the right, while male patients had M100 sources anterior to the
Heschl's gyrus centroid on the left. All women had M100 locations posterior to
the Heschl's gyrus centroid on the left and anterior to it on the right.
CONCLUSIONS: These results demonstrate that some temporal lobe abnormalities in
schizophrenia are sex specific. They also suggest that the anomalous
lateralization of the auditory evoked field cannot be explained by a shift in the
underlying anatomy, since the anatomical substrate is lateralized in both
comparison subjects and patients of both sexes. These findings may indicate a sex
specific functional reorganization in the auditory cortex in schizophrenia.
PMID- 9396943
TI - Quantitative morphology of the cerebellum and fourth ventricle in childhood-onset
schizophrenia.
AB - OBJECTIVE: Studies have suggested that the maldeveloped neural circuitry
producing schizophrenic symptoms may include the cerebellum. The authors found
further support for this hypothesis by examining cerebellar morphology in
severely ill children and adolescents with childhood-onset schizophrenia. METHOD:
Anatomic brain scans were acquired with a 1.5-T magnetic resonance imaging
scanner for 24 patients (mean age = 14.1 years, SD = 2.2) with onset of
schizophrenia by age 12 (mean age at onset = 10.0 years, SD = 1.9) and 52 healthy
children. Volumes of the vermis, inferior posterior lobe, fourth ventricle, and
total cerebellum and the midsagittal area of the vermis were measured manually.
RESULTS: After adjustment for total cerebral volume, the volume of the vermis and
the midsagittal area and volume of the inferior posterior lobe remained
significantly smaller in the schizophrenic patients. There was no group
difference in total cerebellar or fourth ventricle volume. CONCLUSIONS: These
findings are consistent with observations of small vermal size in adult
schizophrenia and provide further support for abnormal cerebellar function in
childhood- and adult-onset schizophrenia.
PMID- 9396944
TI - Anterior cingulate gyrus dysfunction and selective attention deficits in
schizophrenia: [15O]H2O PET study during single-trial Stroop task performance.
AB - OBJECTIVE: Attentional deficits are a prominent aspect of cognitive dysfunction
in schizophrenia. The anterior cingulate gyrus is proposed to be an important
component of frontal attentional control systems. Structural and functional
abnormalities have been reported in this region in schizophrenia, but their
relationship to attentional deficits is unknown. The authors investigated the
function of the anterior cingulate gyrus and the related neural systems that are
associated with selective attention in patients with schizophrenia. METHOD: While
subjects performed multiple blocks of a single-trial Stroop task, [15O]H2O
positron emission tomography scans were obtained. Fourteen patients with
schizophrenia were compared with 15 normal subjects matched for age, gender, and
parental education. RESULTS: The patients with schizophrenia responded at the
same rate but made more errors in color naming during the color-incongruent
condition. Consistent with the authors' hypothesis, patients with schizophrenia
showed significantly less anterior cingulate gyrus activation while naming the
color of color-incongruent stimuli. CONCLUSIONS: Patients with schizophrenia fail
to activate the anterior cingulate gyrus during selective attention performance.
This finding adds to the understanding of the functional significance of the
structural and metabolic abnormalities in schizophrenia that have been previously
reported in this region of the brain.
PMID- 9396945
TI - Auditory hallucinations and the temporal cortical response to speech in
schizophrenia: a functional magnetic resonance imaging study.
AB - OBJECTIVE: The authors explored whether abnormal functional lateralization of
temporal cortical language areas in schizophrenia was associated with a
predisposition to auditory hallucinations and whether the auditory hallucinatory
state would reduce the temporal cortical response to external speech. METHOD:
Functional magnetic resonance imaging was used to measure the blood-oxygenation
level-dependent signal induced by auditory perception of speech in three groups
of male subjects: eight schizophrenic patients with a history of auditory
hallucinations (trait-positive), none of whom was currently hallucinating; seven
schizophrenic patients without such a history (trait-negative); and eight healthy
volunteers. Seven schizophrenic patients were also examined while they were
actually experiencing severe auditory verbal hallucinations and again after their
hallucinations had diminished. RESULTS: Voxel-by-voxel comparison of the median
power of subjects' responses to periodic external speech revealed that this
measure was reduced in the left superior temporal gyrus but increased in the
right middle temporal gyrus in the combined schizophrenic groups relative to the
healthy comparison group. Comparison of the trait-positive and trait-negative
patients revealed no clear difference in the power of temporal cortical
activation. Comparison of patients when experiencing severe hallucinations and
when hallucinations were mild revealed reduced responsivity of the temporal
cortex, especially the right middle temporal gyrus, to external speech during the
former state. CONCLUSIONS: These results suggest that schizophrenia is associated
with a reduced left and increased right temporal cortical response to auditory
perception of speech, with little distinction between patients who differ in
their vulnerability to hallucinations. The auditory hallucinatory state is
associated with reduced activity in temporal cortical regions that overlap with
those that normally process external speech, possibly because of competition for
common neurophysiological resources.
PMID- 9396946
TI - Synaptic elimination, neurodevelopment, and the mechanism of hallucinated
"voices" in schizophrenia.
AB - OBJECTIVE: After peaking during childhood, synaptic density in the human frontal
cortex declines by 30%-40% during adolescence because of progressive elimination
of synaptic connections. The characteristic age at onset of schizophrenia--late
adolescence and early adulthood--suggests that the disorder could arise from
irregularities involving this neurodevelopmental process. METHOD: A computer
simulation of a speech perception neural network was developed. Connections
within the working memory component of the network were eliminated on the basis
of a "Darwinian rule" in order to model loss of synapses. As a comparison,
neuronal cell death, also postulated as being linked to both neurodevelopment and
schizophrenia, was simulated. The authors determined whether these alterations at
low levels could enhance perceptual capacity and at high levels produce
spontaneous speech percepts that simulate hallucinated speech or "voices."
RESULTS: Eliminating up to 65% of working memory connections improved perceptual
ability; beyond that point, network performance declined and speech
hallucinations emerged. Simulating excitotoxic neuronal loss at low levels also
improved network performance, but in excess it did not produce hallucinations.
CONCLUSIONS: The model demonstrates perceptual advantages of selective synaptic
elimination as well as selective neuronal loss, suggesting a functional
explanation for these aspects of neurodevelopment. The model predicts that
psychosis arises from a pathological extension of one of these neurodevelopmental
trends, namely, synaptic elimination.
PMID- 9396947
TI - Posttraumatic stress disorder and functioning and quality of life outcomes in a
nationally representative sample of male Vietnam veterans.
AB - OBJECTIVE: Although posttraumatic stress disorder (PTSD) is a highly prevalent
and often chronic condition, the relationship between PTSD and functioning and
quality of life remains incompletely understood. METHOD: The authors undertook an
archival analysis of data from the National Vietnam Veterans Readjustment Study.
The study subjects consisted of the nationally representative sample of male
Vietnam veterans who participated in the National Vietnam Veterans Readjustment
Study. The authors estimated PTSD at the time of the interview with the
Mississippi Scale for Combat-Related Posttraumatic Stress Disorder. They examined
the following outcomes: diminished well-being, physical limitations, bed day in
the past 2 weeks, compromised physical health status, currently not working, and
perpetration of violence. Logistic models were used to determine the association
between PTSD and outcome; adjustment was made for demographic characteristics and
comorbid psychiatric and other medical conditions. RESULTS: The risks of poorer
outcome were significantly higher in subjects with PTSD than in subjects without
PTSD in five of the six domains. For the outcome domains of physical limitations,
not working, compromised physical health, and diminished well-being, these
significantly higher risks persisted even in the most conservative logistic
models that removed the shared effects of comorbid psychiatric and other medical
disorders. CONCLUSIONS: The suffering associated with combat related-PTSD extends
beyond the signs and symptoms of the disorder to broader areas of functional and
social morbidity. The significantly higher risk of impaired functioning and
diminished quality of life uniquely attributable to PTSD suggests that PTSD may
well be the core problem in this group of difficult to treat and multiply
afflicted patients.
PMID- 9396948
TI - One-year follow-up of survivors of a mass shooting.
AB - OBJECTIVE: This report describes a 1-year follow-up study of survivors of a mass
shooting incident. Acute-phase data from this incident were previously reported
in this journal. METHOD: The Diagnostic Interview Schedule/Disaster Supplement
was used to assess 136 survivors at 1-2 months and again a year later, with a 91%
reinterview rate. RESULTS: In the acute postdisaster period, 28% of subjects met
criteria for posttraumatic stress disorder (PTSD), and 18% of subjects qualified
for another active psychiatric diagnosis. At follow-up, 24% of subjects reported
a history of postdisaster PTSD (17% were currently symptomatic), and 12% another
current psychiatric disorder. Half (54%) of all 46 individuals identified as
having had PTSD at either interview were recovered at follow-up, and no index
predictors of recovery were identified. There were no cases of delayed-onset PTSD
(beyond 6 months). Considerable discrepancy in identified PTSD cases was apparent
between index and follow-up. Inconsistency in reporting, rather than report of
true delayed-onset, was responsible for all PTSD cases newly identified at 1
year. The majority of subjects with PTSD at index who were recovered at follow-up
reported no history of postdisaster PTSD at follow-up, suggesting considerable
influence of fading memory. CONCLUSIONS: This study's findings suggest that
disaster research that conducts single interviews at index or a year later may
overlook a significant portion of PTSD. The considerable diagnostic comorbidity
found in this study was the one robust predictor of PTSD at any time after the
disaster. Disaster survivors with a psychiatric history, especially depression,
may be most vulnerable to developing PTSD and therefore may deserve special
attention from disaster mental health workers.
PMID- 9396949
TI - Objective documentation of child abuse and dissociation in 12 murderers with
dissociative identity disorder.
AB - OBJECTIVE: The skepticism regarding the existence of dissociative identity
disorder as well as the abuse that engenders it persists for lack of objective
documentation. This is doubly so for the disorder in murderers because of issues
of suspected malingering. This article presents objective verification of both
dissociative symptoms and severe abuse during childhood in a series of adult
murderers with dissociative identity disorder. METHOD: This study consisted of a
review of the clinical records of 11 men and one woman with DSM-IV-defined
dissociative identity disorder who had committed murder. Data were gathered from
medical, psychiatric, social service, school, military, and prison records and
from records of interviews with subjects' family members and others. Handwriting
samples were also examined. Data were analyzed qualitatively. RESULTS: Signs and
symptoms of dissociative identity disorder in childhood and adulthood were
corroborated independently and from several sources in all 12 cases; objective
evidence of severe abuse was obtained in 11 cases. The subjects had amnesia for
most of the abuse and underreported it. Marked changes in writing style and/or
signatures were documented in 10 cases. CONCLUSIONS: This study establishes, once
and for all, the linkage between early severe abuse and dissociative identity
disorder. Further, the data demonstrate that the disorder can be distinguished
from malingering and from other disorders. The study shows that it is possible,
with great effort, to obtain objective evidence of both the symptoms of
dissociative identity disorder and the abuse that engenders it.
PMID- 9396950
TI - Seasonal variation in the occurrence of homicide in Finland.
AB - OBJECTIVE: Although seasonal variation in impulsive aggression related to
circannual rhythms of central serotonin neurotransmission is a topic of current
interest, there is little firm knowledge on seasonality in the occurrence of
homicide. Longitudinal studies on the seasonal rhythms of platelet imipramine
binding and L-tryptophan levels have placed the circannual peaks around January
and February and the nadirs around May and August. The aim of this study was to
test the hypothesis that the number of homicides is the lowest during winter and
the highest during spring and summer. A secondary hypothesis was that the
seasonal variations in homicides and violent suicides are correlated. METHOD: The
largest database on the monthly occurrence of homicide thus far (N = 4,553) was
used in this study, in which the monthly occurrence of all murders and
manslaughters in Finland during the years 1957-1995 was analyzed. RESULTS: During
winter the homicide rate was 6% below the expected rate. Correspondingly, during
summer there was a 6% elevation above the expected homicide rate, but no
significant peak was observed in spring. There was a significant association
between the monthly occurrence of homicides and violent suicides but not between
homicides and nonviolent suicides. CONCLUSIONS: The results suggest that a
seasonal variation in the occurrence of homicide exists. On the basis of current
literature, it could be hypothesized that this seasonal variation and the
correlation between the monthly occurrence of homicides and violent suicides are
associated with the observed circannual rhythms of serotonin transmission.
PMID- 9396951
TI - Characteristics of borderline personality disorder associated with suicidal
behavior.
AB - OBJECTIVE: This study examined the relationship between characteristics of
borderline personality disorder and suicidal behavior. The authors hypothesized
that a specific feature of borderline personality disorder, impulsivity, and
childhood trauma, a possible etiological factor in the development of
impulsivity, would be associated with suicidal behavior. METHOD: Information on
lifetime history of suicidal behavior was obtained from 214 inpatients diagnosed
with borderline personality disorder by structured clinical interview. The
authors examined the relationship between DSM-III-R criteria met and the
following measures of suicidal behavior: presence or absence of a previous
suicide attempt, number of previous attempts, and lethality and intent to die
associated with the most lethal lifetime attempt. RESULTS: Impulsivity was the
only characteristic of borderline personality disorder (excluding the self
destructive criterion) that was associated with a higher number of previous
suicide attempts after control for lifetime diagnoses of depression and substance
abuse. Global severity of pathology of borderline personality disorder was not
associated with suicidal behavior. History of childhood abuse correlated
significantly with number of lifetime suicide attempts. CONCLUSIONS: The trait of
impulsivity is associated with number of lifetime suicide attempts and may
therefore be a putative risk factor for a future suicide attempt. If so,
impulsivity is a potential target therapeutically for prevention of future
suicide attempts. The association between childhood abuse and number of lifetime
suicide attempts is consistent with the hypothesis that childhood abuse is an
etiological factor in the development of self-destructive behaviors.
PMID- 9396952
TI - HIV seroprevalence among suicide victims in New York City, 1991-1993.
AB - OBJECTIVE: The authors sought to determine the HIV seroprevalence among suicide
victims in New York City. METHOD: All suicides of city residents from 1991
through 1993 were studied. The crude proportion of all suicide victims who were
HIV positive and the proportion adjusted to the age, gender, and racial/ethnic
characteristics of the New York City population were determined. The
demographically adjusted proportion was then contrasted with HIV seroprevalence
estimates for the New York City general population. HIV-seropositive suicide
victims were assessed for pathological findings suggestive of HIV-related
illnesses. RESULTS: The crude proportion of all suicide victims who were HIV
seropositive was 0.088, and the demographically adjusted proportion was 0.049.
Over 90% of all HIV-positive suicide victims were aged 25 to 54 years, and almost
90% were men. Among black and Hispanic men aged 35 to 54 years who committed
suicide, the proportion who were HIV seropositive was 0.252--the highest
seropositive rate of any demographic group. More than two-thirds of HIV
seropositive suicide victims had no HIV-related pathology or AIDS-indicator
conditions at autopsy. CONCLUSIONS: The demographically adjusted proportion of
suicide victims who were HIV positive (approximately 0.038 to 0.059), contrasted
with the HIV seroprevalence estimates for the New York City general population
(approximately 0.014 to 0.032), the absence of HIV-related pathology among
suicide victims, and the likelihood that many HIV-positive individuals had other
risk factors for suicide, such as substance abuse, suggests that a positive HIV
serostatus is associated, at most, with a modest elevation in suicide risk.
PMID- 9396953
TI - Clinical and methodological factors related to reliability of the best-estimate
diagnostic procedure.
AB - OBJECTIVE: The reliability and accuracy of the best-estimate diagnostic procedure
were examined, and factors associated with reliability were determined. METHOD:
The subjects were 134 members of large multigenerational pedigrees densely
affected by bipolar disorders or schizophrenia. Three best-estimate diagnoses
were derived: first, by a research psychiatrist and research assistant unblind to
the relatives' diagnoses; second, by two blind independent psychiatrists; third,
by a panel of four blind psychiatrists. The subjects were characterized on
several clinical and methodological variables, which were used to compare the
agreements of two types of best-estimate diagnoses with the disagreements.
RESULTS: There was satisfactory agreement between the unblind and blind consensus
best-estimate diagnoses and between the two blind independent psychiatrists.
Latent class analyses revealed that limited sensitivity was the main source of
imperfect reliability. Confusability analyses revealed that the most problematic
diagnostic distinctions involved schizoaffective disorder, which was confused
with schizophrenia, bipolar I disorder, and schizophreniform disorder. Blindness
significantly affected diagnostic outcome in latent class analyses. Moreover, for
diagnostic disagreements, unblind diagnoses had greater continuity with the most
predominant diagnosis in the pedigree than did blind diagnoses. Diagnostic
disagreements were associated with the presence of mixed affective and psychotic
symptoms, less diagnostic certainty, and shorter duration of illness.
CONCLUSIONS: These results suggest that it is possible to identify cases that are
more likely to lead to diagnostic disagreements in family and epidemiological
studies and that blind diagnoses may help to prevent false positive diagnoses,
which may be particularly detrimental to genetic linkage analyses.
PMID- 9396954
TI - Mental disorders and disability among patients in a primary care group practice.
AB - OBJECTIVE: This article examines social and occupational disability associated
with several DSM-IV mental disorders in a group of adult primary care
outpatients. METHOD: The subjects were 1,001 primary care patients (aged 18-70
years) in a large health maintenance organization. Data on each patient's
sociodemographic characteristics and functional disability, including scores on
the Sheehan Disability Scale, were collected at the time of a medical visit. A
structured diagnostic interview for current DSM-IV disorders was then completed
by a mental health professional over the telephone within 4 days of the visit.
RESULTS: The most prevalent disorders were phobias (7.7%), major depressive
disorder (7.3%), alcohol use disorders (5.2%), generalized anxiety disorder
(3.7%), and panic disorder (3.0%). A total of 8.3% of the patients met the
criteria for more than one mental disorder. The proportion of patients with co
occurring mental disorders varied by index disorder from 50.0% (alcohol use
disorder) to 89.2% (generalized anxiety disorder). Compared with patients who had
a single mental disorder, patients with co-occurring disorders reported
significantly more disability in social and occupational functioning. After
adjustment for other mental disorders and demographic and general health factors,
compared with patients with no mental disorder, only patients with major
depressive disorder, bipolar disorder, phobias, and substance use disorders had
significantly increased disability, as measured by the Sheehan Disability Scale.
CONCLUSIONS: Primary care patients with more than one mental disorder are common
and highly disabled. Individual mental disorders have distinct patterns of
psychiatric comorbidity and disability.
PMID- 9396955
TI - Premenstrual syndrome: evidence for symptom stability across cycles.
AB - OBJECTIVE: This study assessed cycle to cycle symptom stability in women with
premenstrual syndrome (PMS). METHOD: Symptom ratings obtained prospectively over
three or more symptomatic cycles from 16 women with PMS were analyzed. Measures
of symptom severity and change were used to generate a coefficient of variation
and an intraclass correlation coefficient (ICC) for each one of 14 symptoms
across all cycles. In addition, symptoms were divided into three clusters, and
the stability of the rank order of severity of symptoms within clusters and the
correlation between symptom clusters were also calculated. RESULTS: In the 65
cycles studied, mood symptoms were the most prevalent. Mood symptoms--anxiety,
irritability, and mood lability--had the lowest coefficients of variation but
also the lowest ICCs of all symptoms. Within their respective symptom clusters,
both physical and mood symptoms showed remarkable stability across cycles of
their rank order of severity, but only the mood symptom cluster was highly
correlated with functional impairment. CONCLUSIONS: Three mood symptoms--anxiety,
irritability, and mood lability--were the most stable symptoms in this group of
women with PMS. Mood and not somatic symptoms accounted for most of the
functional impairment in this group of women. It is concluded that PMS is a
stable syndrome that may best be viewed as part of the spectrum of recurrent mood
disorders.
PMID- 9396956
TI - Evaluation of a complex case: the value of a drug washout period.
PMID- 9396957
TI - Images in psychiatry. The Payne Whitney Clinic.
PMID- 9396958
TI - Mood improvement following daily left prefrontal repetitive transcranial magnetic
stimulation in patients with depression: a placebo-controlled crossover trial.
AB - OBJECTIVE: Preliminary studies have indicated that daily left prefrontal
repetitive transcranial magnetic stimulation might have antidepressant activity.
The authors sought to confirm this finding by using a double-blind crossover
design. METHOD: Twelve depressed adults received in random order 2 weeks of
active treatment (repetitive transcranial magnetic stimulation, 20 Hz at 80%
motor threshold) and 2 weeks of sham treatment. RESULTS: Changes from the
relevant phase baseline in scores on the 21-item Hamilton depression scale showed
that repetitive transcranial magnetic stimulation significantly improved mood
over sham treatment. During the active-treatment phase, Hamilton depression scale
scores decreased 5 points, while during sham treatment the scores increased or
worsened by 3 points. No adverse effects were noted. CONCLUSIONS: These placebo
controlled results suggest that daily left prefrontal repetitive transcranial
magnetic stimulation has antidepressant activity when administered at these
parameters. Further controlled studies are indicated to explore optimal
stimulation characteristics and location, potential clinical applications, and
possible mechanisms of action.
PMID- 9396959
TI - Sexual functioning in chronically depressed patients treated with SSRI
antidepressants: a pilot study.
AB - OBJECTIVE: This prospective study assessed changes in depression and sexual
functioning in chronically depressed men and women during treatment with
selective serotonin reuptake inhibitors (SSRIs). METHOD: Twenty-five subjects (14
women, 11 men) with DSM-III-R dysthymia, chronic major depression, or double
depression were administered the Arizona Sexual Experience Scale and the Hamilton
Depression Rating Scale before and after 6 weeks of treatment with sertraline or
paroxetine. RESULTS: As measured by scores on the Arizona Sexual Experience
Scale, desire, psychological arousal, and overall sexual functioning
significantly improved in women; orgasm delay, orgasm satisfaction, and overall
sexual functioning significantly worsened in men. CONCLUSIONS: This study
suggests that after SSRI treatment, difficulties with desire and psychological
arousal in depressed women tend to remit, whereas in men orgasmic dysfunction
appears to be a side effect to medication.
PMID- 9396960
TI - Emergence of adverse events following discontinuation of treatment with extended
release venlafaxine.
AB - OBJECTIVE: The rate of adverse events following discontinuation of treatment with
extended-release venlafaxine was compared with the rate associated with
discontinuation of placebo administration. METHOD: The subjects were 20
outpatients with major depressive disorder who had participated in a multicenter,
double-blind, placebo-controlled study of the efficacy of the new extended
release formulation of venlafaxine. RESULTS: During the 3 days after
discontinuation of treatment with the study drug, seven (78%) of the nine
venlafaxine-treated subjects and two (22%) of the nine placebo-treated patients
reported the emergence of adverse events, a statistically significant difference.
CONCLUSIONS: These results suggest that clinicians discontinuing venlafaxine
treatment should consider tapering the medication dose gradually.
PMID- 9396961
TI - Plasma levels of cytokines and soluble cytokine receptors during treatment with
haloperidol.
AB - OBJECTIVE: Clozapine increases the levels of cytokines and soluble cytokine
receptors. The authors investigated whether haloperidol has similar effects.
METHOD: Rectal temperature, white blood cell counts, and plasma levels of
cytokines and soluble cytokine receptors were assessed before and during 6 weeks
of haloperidol treatment in 10 psychiatric patients. RESULTS: Haloperidol at mean
doses of 7.0 mg/day (SD = 3.4), 6.9 mg/day (SD = 3.4), and 5.0 mg/day (SD = 3.1)
at the end of the 1st, 2nd, and 6th weeks of treatment, respectively, did not
affect rectal temperature, white blood cell counts, or plasma level of
interleukin-1 receptor antagonist, interleukin-6, tumor necrosis factor-alpha
(TNF-alpha), soluble TNF receptor p55 or p75, or soluble interleukin-2 receptor.
CONCLUSIONS: Haloperidol is unlikely to confound the results of studies
investigating disease-related alterations in the levels of a broad range of
cytokines and soluble cytokine receptors in schizophrenia.
PMID- 9396962
TI - Self-reported anxiety, general medical conditions, and disability bed days.
AB - OBJECTIVE: This study examined the effect of self-reported anxiety on the number
of days persons with various general medical conditions spend in bed owing to
disability. METHOD: Self-reported medical illness and disability data from a
nationally representative household survey sample (N = 20,884) were analyzed.
RESULTS: Among respondents with general medical conditions, those with self
reported anxiety had a nearly fourfold greater length of disability (mean = 18.0
bed days) than the nonanxious respondents (mean = 4.8 bed days). After adjustment
for differences in demographic characteristics and burden of general medical
illness, anxiety was associated with an additional 3.8 bed days. CONCLUSIONS:
Self-reported anxiety in combination with general medical conditions may be
associated with extensive functional impairment.
PMID- 9396963
TI - Dispositional predictors of problem gambling in male adolescents.
AB - OBJECTIVE: This study investigated the possible relationship between impulsivity
in early adolescence and gambler status in late adolescence. METHOD: Impulsivity
measures consisting of self-reports and teacher ratings were gathered from 754
boys in early adolescence, and their gambling status in late adolescence was
assessed with a self-report measure. RESULTS: On both measures of impulsivity,
nongamblers had the lowest scores, recreational gamblers had the next higher
scores, low problem gamblers had still higher scores, and high problem gamblers
had the highest scores. CONCLUSIONS: These findings support the DSM-IV
classification of problem gambling as a deficit in impulse control.
PMID- 9396964
TI - CSF 5-HIAA and family history of antisocial personality disorder in newborns.
AB - OBJECTIVE: The relationship between genetic liability for antisocial behavior and
CSF 5-hydroxyindoleacetic acid (5-HIAA) in newborns was explored. METHOD: The
authors assayed 5-HIAA in "leftover" CSF from 193 neurologically normal newborns
and obtained family psychiatric histories of the newborns' first- and second
degree relatives. RESULTS: Levels of 5-HIAA were significantly lower in the
infants with family histories of antisocial personality disorder than in the
newborns without such family histories. CONCLUSIONS: These findings support the
possibility that serotonin mediates one component of genetic liability to
antisocial outcome, but the magnitude of that component may be less than what has
been inferred from previously published reports.
PMID- 9396965
TI - Pindolol-paroxetine combination.
PMID- 9396966
TI - Bulimia outcome.
PMID- 9396967
TI - Schizophrenia practice guideline.
PMID- 9396968
TI - Schizophrenia practice guideline.
PMID- 9396969
TI - Genetic and immunologic aspects of cystic fibrosis.
AB - LEARNING OBJECTIVES: Reading this article will enable the readers to reinforce
their knowledge of the pathophysiology of cystic fibrosis (CF), the pathogenesis
of the lung disease, the criteria for diagnosis, and CF genotype/phenotype
relationships. The focus of this review is on the genetic and immunologic aspects
of CF. DATA SOURCE: Relevant articles, current texts, data presented at the
annual North American Cystic Fibrosis Conferences and distributed to the
Directors of CF Centers by the CF Foundation were reviewed. A MEDLINE database
using subject keywords was searched from 1987 to date. Background information
derived from the author's 33 years of clinical experience at three of the CF
Foundation's CF Care, Teaching and Resource Centers was also included. STUDY
SELECTION: Since CF is an inherited disorder, the genetic aspects are emphasized.
With the cloning of the CF gene, DNA analysis has assumed an important role in
confirming the clinical diagnosis and in the improved understanding of the
pathophysiology of this disorder. Although DNA testing is highly specific, it is
not very sensitive. RESULTS: Cystic fibrosis gene structure and function are
described briefly. The pathophysiology of CF, as it relates to the CF gene
defect, and the current knowledge of the pathogenesis of the lung disease are
reviewed. The criteria for the diagnosis proposed by the Clinical Practice
Guidelines for CF are discussed. Problems of establishing the diagnosis and the
importance of correlations of laboratory and clinical findings in CF are
emphasized. CONCLUSIONS: As a multisystem disorder, CF can masquerade as other
disorders, including allergic respiratory disease. Primary care physicians often
refer patients to allergists/immunologists because of recurrent respiratory
problems. This review discusses the genetic heterogeneity of CF.
PMID- 9396970
TI - Recurrent facial angioedema with elevated antinuclear antibodies.
PMID- 9396971
TI - IgE-binding components of staphylococcal enterotoxins in patients with atopic
dermatitis.
AB - BACKGROUND: The exacerbation of atopic dermatitis may be associated with
infection of the skin with Staphylococcus aureus (S.aureus). S. aureus isolated
from the skin of patients with atopic dermatitis secretes enterotoxin A, B, and
toxic shock syndrome toxin 1. This is of interest because these patients may
develop specific IgE antibodies against components from staphylococci. OBJECTIVE:
The objective was to demonstrate IgE-sensitization to components of
Staphylococcus aureus enterotoxins A and B (purified and partially purified),
toxic shock syndrome toxin 1, and the bacterial cell component lipoteichoic acid,
in patients with atopic dermatitis. METHODS: Blood samples from 34 patients with
atopic dermatitis and 10 controls were tested by leukocyte histamine release to
the enterotoxins and lipoteichoic acid. The toxins were separated by sodium
dodecylsulfate polyacrylamide gel electrophoresis and analyzed by IgE
immunoblotting with sera from the same patients. RESULTS: The majority of
patients (96%) with clinical signs of skin infection produced specific IgE
antibodies to all three toxins. Nearly half of the patients produced IgE to
enterotoxin A and B. Only 63% of the patients with atopic dermatitis showed
cellular response judged by the release of histamine from patient basophils when
challenged in vitro with the toxins. This may indicate clinically unimportant
sensitization in a number of patients. The immunoblotting revealed that the major
allergens of the toxins were 24 and 28 kD proteins. Partially purified toxins
showed a higher frequency of leukocyte histamine release responses than purified
toxin. The only obvious difference was a difference in the content of pure toxin
of the two preparations. Lipoteichoic acid showed nonspecific activity.
CONCLUSION: These findings suggest that staphylococcal enterotoxins may act as
specific allergens and induce IgE-antibodies to enterotoxins that may exacerbate
the skin inflammation in some patients with atopic dermatitis.
PMID- 9396972
TI - Trimethoprim/sulfamethoxazole incremental dose regimen in human immunodeficiency
virus-infected persons.
AB - BACKGROUND: The mechanism of tolerance to incremental doses of trimethoprim
sulfamethoxazole given to human immunodeficiency virus-infected persons who have
had a prior intolerance to this agent has not been studied. OBJECTIVE: We
prospectively evaluated a regimen of incremental doses of oral trimethoprim
sulfamethoxazole in human immunodeficiency virus-infected persons who had a prior
trimethoprim-sulfamethoxazole-induced fever and nonexfoliative skin rash to
investigate the mechanism by which it permits tolerance. METHODS: Oral
trimethoprim (0.00004 mg)/sulfamethoxazole (0.00002 mg) was given to 22 human
immunodeficiency virus-infected persons on day 1 and gradually increased over
eight days to 1 double strength (DS) tablet/day in an outpatient setting. At
study entry, skin tests and IgG antibodies to sulfa were performed; the latter
was repeated at study week 4. RESULTS: Nineteen patients tolerated
trimethoprim/sulfamethoxazole at the completion of the 8-day protocol (86%
effective). Moderate toxicities occurred in eight persons during the
desensitization protocol; five of these were able to continue
trimethoprim/sulfamethoxazole with adjunctive prednisone. Skin tests to sulfa
antigen were negative in all persons. Eleven patients at study entry had
antibodies to sulfamethoxazole; IgG antibodies appeared at week 4 in 8 of the 11
patients who initially had no antibody detected. CONCLUSIONS: The mechanism of
tolerance to the incremental doses of trimethoprim/sulfamethoxazole given to
previously intolerant human immunodeficiency virus-infected persons is not due to
desensitization and remains undetermined.
PMID- 9396973
TI - Popsicle-induced anaphylaxis due to carmine dye allergy.
AB - BACKGROUND: IgE-mediated hypersensitivity is a suggested mechanism to explain
adverse reactions from carmine-containing products. OBJECTIVE: To describe a
patient who experienced anaphylaxis after ingestion of a popsicle colored with
carmine and to provide additional evidence that the adverse reaction was IgE
mediated. METHODS: The patient and her husband underwent skin prick tests to the
popsicle and carmine. The patient also received skin prick tests and/or open oral
challenge to each of the other components of the incriminated food. Topical
application of cosmetics with and without carmine to the patient's forearm was
also performed. To confirm carmine-specific IgE, a Prausnitz-Kustner (P-K) test
was performed using the patient's husband as recipient. Twenty control subjects
also were tested to carmine by skin prick test. RESULTS: The patient showed 4+
skin prick test responses to the popsicle and carmine. Skin prick tests and/or
open oral challenge to each of the other components of the popsicle were
negative. The patient's husband's and 20 control subjects' skin prick tests to
carmine were negative as was the patient's husband's skin prick test to the
popsicle. Skin prick test reactivity to the popsicle and carmine were
successfully transferred to the patient's husband in P-K format. Cosmetics
applied to the patient's forearm elicited no immediate response. CONCLUSION: The
positive skin prick tests to the popsicle and carmine and the successful (P-K)
transfer of skin prick test reactivity support a carmine-specific, IgE-mediated
mechanism in explaining our patient's popsicle-induced anaphylaxis.
PMID- 9396974
TI - Localized unilateral periorbital edema induced by aspirin.
AB - BACKGROUND: Aspirin intolerance manifested as bronchospasm or
urticaria/angioedema has been observed since the beginning of this century.
OBJECTIVE: To report a novel case of intolerance to aspirin ingestion. METHODS:
Case report; routine skin testing; pulmonary function testing; aspirin challenge.
RESULTS: A 30-year-old man with a history of left ocular trauma at the age of 10
noted a 3-year history of left periorbital angioedema after aspirin but not other
nonsteroidal anti-inflammatory drugs. Incremental oral aspirin challenge resulted
in this unilateral symptomatology at a dose of 673 mg. CONCLUSION: To the best of
our knowledge, this is the first reported case of unilateral periorbital edema
following aspirin ingestion.
PMID- 9396975
TI - Asthma mortality in Mauritius: 1982-1991.
AB - BACKGROUND: Bronchial asthma is a common problem in the island of Mauritius and
its prevalence seems to be increasing. OBJECTIVE: In order to appreciate the
magnitude of the problem, patterns of asthma mortality were studied during a
period of 10 years. METHOD: All death certificates issued in the island from 1982
to 1991 were reviewed and all cases of asthma deaths were selected. RESULTS: The
global asthma mortality rate was found to be 20/100,000 in 1982, and it decreased
to 12/100,000 in 1991. Similarly the asthma death rate for the 0 to 4 year age
group decreased from 20/100,000 in 1982 to 5/100,000 in 1991. For the 5 to 34
year age group, it decreased from 2.6/100,000 in 1982 to 1.02/100,000 in 1991.
There was no statistically significant difference between the various ethnic
groups. CONCLUSION: Our study showed that in a developing country such as
Mauritius asthma death rates may be high but may show decreasing trends.
Nevertheless, it is generally perceived that the prevalence of the disease is
increasing.
PMID- 9396976
TI - Skin prick reaction and nasal provocation response in diagnosis of nasal allergy
to the house dust mite.
AB - BACKGROUND: The allergen skin test is commonly used to ensure the diagnosis of
allergic rhinitis even though positive results do not necessarily indicate that
rhinitis is of allergic origin. OBJECTIVE: To determine the association between
skin prick reactions and nasal provocation responses to Dermatophagoides
pteronyssinus (Der p) allergen extract. METHODS: Twenty-six patients with
perennial rhinitis and 25 controls underwent skin prick and nasal provocation
tests to standardized Der p allergen extract. With the use of allergen extract
titration delivered by a metered dose pump, nasal stuffiness, itching, and
sneezing were noted, the amount of secretions measured, and nasal airway
resistance was recorded by active anterior rhinomanometry. RESULTS: The majority
of the patients with rhinitis (20/26), but none of the controls, exhibited strong
skin test positivity (4+) to Der p allergen extract. In addition, the majority of
the patients with 4+ skin reactions (16/20) had moderate to severe rhinitis.
Significantly increased nasal reactivity to the allergen was also observed among
those with 4+ skin test positivity. The controls exhibited nasal provocation
responses only with significantly higher end-point doses of the allergen extract
regardless of the skin test results. CONCLUSION: Only 4+ skin test positivity was
closely associated with increased nasal reactivity to Der p allergen among the
patients with perennial rhinitis. The nasal provocation technique would be a
useful adjunct testing to ensure the diagnosis of nasal allergy to the Der p
mite, particularly among those patients with rhinitis with only mild to moderate
skin test positivity.
PMID- 9396977
TI - Allergenic fungi in allergic fungal sinusitis.
AB - BACKGROUND: Patients with allergic fungal sinusitis demonstrate skin test
reactivity to many fungal extracts. Various fungi have been isolated from the
characteristic allergic mucin. OBJECTIVE: This study was designed to identify
allergens in allergic mucin and to compare them to those found in commercial
fungal extracts. METHODS: Allergic mucin was collected during functional
endoscopic sinus surgery from 11 patients meeting strict diagnostic criteria for
allergic fungal sinusitis and from three allergic rhinitis patients with chronic
sinusitis. A portion was solubilized in saline and centrifuged. To identify
allergens, proteins in allergic mucin and fungal extracts were separated by SDS
polyacrylamide gel electrophoresis, transferred to nitrocellulose and
immunostained using patient sera and enzyme-labeled anti-human IgE. RESULTS: All
patient sera recognized numerous bands ranging from 18 to 90 kD. In mucin, bands
were consistently found in the 35 to 50 kD range. Corresponding bands in fungal
extracts were found in only 1/11 patients with allergic fungal sinusitis. Sera
from 4/11 patients detected an 18-kD protein in allergic mucin, but sera from all
patients with allergic fungal sinusitis recognized an 18-kD protein in commercial
fungal extracts. Sera from selected patients with allergic fungal sinusitis
detected human epithelial proteins in the 35 to 50 kD range. CONCLUSIONS: Fungal
allergens were not detected in allergic mucin of all patients with allergic
fungal sinusitis. The 18-kD allergen appears to be shared by many fungi, and may
be a fungal panallergen. The source of the apparent allergens in the 3550-kD
range warrants further study.
PMID- 9396978
TI - Dust mite allergen avoidance in the treatment of hospitalized children with
asthma.
AB - BACKGROUND: Asthma is a leading cause of hospital admission in children. The
majority of children with asthma are sensitized and exposed to inhalant allergens
that may contribute to chronic airway inflammation. OBJECTIVE: To evaluate the
practicality and effects of dust mite (D. farinae and D. pteronyssinus) allergen
avoidance in homes of children hospitalized with acute asthma. METHODS: Children
5 to 18 years of age who were admitted with asthma to a suburban Atlanta hospital
were randomly assigned, without knowledge of allergen sensitization or exposure
in their houses, to active (n = 13) or placebo (n = 10) treatment group. Active
treatment included encasing mattress, box springs, and pillows in allergen
impermeable covers; weekly hot water wash of bed linens; replacement of bedroom
carpet with polished flooring; and 3% tannic acid spray to living room carpet.
Placebo treatment included permeable encasing for bedding, cold water wash, and
water spray for carpet. Dust samples were analyzed for dust mite, cockroach, and
cat allergens, while serum samples were analyzed for IgE antibodies to the same
allergens. Outcome measures included daily peak expiratory flow rates,
spirometry, methacholine inhalation challenge, and hospital readmission. RESULTS:
Children in both groups were similar by demographics, sensitization, and exposure
to dust mite allergen. Allergen levels fell > 3-fold in many active and placebo
homes. Children in the active group had improved PEFR at 3 and 6 months after
intervention (P < .04, P < .05, respectively). Six of seven children in the study
who were sensitized and exposed to dust mite allergen demonstrated improved PEFR
at 3 months when allergen levels fell in both bedding and bedroom floor. There
was no difference in FEV1 or methacholine challenge, although a few children in
either group could tolerate methacholine because of bronchial hyperreactivity.
Six children (four active and two placebo) were readmitted to hospital during the
study. CONCLUSION: Increases in PEFR were recorded among children in the active
treatment group and also among sensitized patients whose dust mite allergens
fell. These results support the hypothesis that avoidance can be effective even
among children admitted to hospital. The study was complicated by insufficient
numbers of mite-allergic children and poor compliance with diaries and the
protocol. Recruitment from the hospital resulted in participants with more severe
asthma than anticipated. The results also suggest that many of the patients in
this group will continue to have exacerbations triggered by upper or lower
respiratory tract infections.
PMID- 9396979
TI - Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal
allergic rhinitis.
AB - BACKGROUND: H1-receptor antagonists are effective for the treatment of seasonal
allergic rhinitis. In rare circumstances, some second-generation H1-receptor
antagonists have been associated with prolongation of the corrected QT interval
(QTc), thus increasing the risk of ventricular arrhythmias. Fexofendine HCl, the
carboxylic acid metabolite of terfenadine, is a new second-generation
antihistamine that is nonsedating and does not cause electrocardiographic
effects. OBJECTIVE: To investigate the clinical efficacy and safety of
fexofenadine HCl in the treatment of ragweed seasonal allergic rhinitis and to
characterize the dose-response relationship of fexofenadine HCl at dosages of 60,
120, and 240 mg bid. METHODS: A multicenter, 14-day, placebo-controlled, double
blind trial was conducted with patients suffering from moderate to severe ragweed
seasonal allergic rhinitis who met symptom severity criteria after a 3-day
placebo baseline period. Patients with minimal or very severe symptoms during the
baseline period were excluded. Patients were randomized to receive fexofenadine
HCl (60, 120, or 240 mg bid) or placebo at 12-hour dosing intervals (7:00 AM and
7:00 PM). The primary efficacy measure was patient-assessed 12-hour reflective
total symptom score before the evening dose (trough). RESULTS: Five hundred
seventy patients completed the trial. Fexofenadine HCl at each dosage provided
significant improvement in total symptom score (P < or = .003) and in all
individual nasal symptoms compared with placebo. The frequency of adverse events
was similar among fexofenadine HCl and placebo groups, with no dose-related
trends. No sedative effects or electrocardiographic abnormalities, including
prolongations in QTc were detected. CONCLUSIONS: Fexofenadine HCl is both
effective and safe for the treatment of ragweed seasonal allergic rhinitis.
Because there was no additional efficacy at higher dosages, 60 mg bid appears to
be the optimal therapeutic dosage for these patients.
PMID- 9396980
TI - Occupational respiratory allergic disease induced by Passiflora alata and Rhamnus
purshiana.
AB - BACKGROUND: There has been an increase in the incidence of occupational asthma
along with better understanding of its pathophysiologic mechanisms and etiologic
factors. There are no reports of patients with asthma and rhinitis to Passiflora
alata (passion flower) and Rhamnus purshiana (cascara sagrada). METHODS: We
describe two substances of plant origin as causal agents of occupational allergic
respiratory diseases in a patient who worked in a pharmacy devoted to the manual
preparation of products. RESULTS: Skin testing and Western blot confirmed the
sensitization of the patient to these plant extracts in vivo and in vitro,
respectively. Bronchial challenge confirmed the cause-effect relationship between
the allergen exposure and the diseases. CONCLUSIONS: We conclude that Passiflora
and cascara sagrada are two new etiologic agents of IgE-mediated occupational
asthma and rhinitis. The present study also serves to alert physicians to the
risks associated with work in pharmacies devoted to manual preparation of plant
extracts, emphasizing the importance of the use of protective measures in these
environments.
PMID- 9396981
TI - Sensitization to indoor allergens and the risk for asthma hospitalization in
children.
AB - BACKGROUND: Hospitalization for asthma continues to present a major health
problem despite advances in our understanding that asthma is an inflammatory
disease of the bronchi and that exposure to specific allergens can induce and
worsen this inflammation. The role of sensitization to specific indoor allergens
and hospitalization for acute asthma in children is unclear. OBJECTIVE: The
purpose of this study was to evaluate the independent contributions of
sensitization to specific indoor allergens among children with asthma to the risk
of hospitalization for asthma. METHODS: The charts of 138 consecutive children
with asthma, aged 5 to 18 years, seen at pediatric allergy clinics were reviewed
to obtain the results of skin tests to cat, dog, cockroach, and dust mite
allergens and the history of hospitalization for asthma within the year prior to
the clinic visit. Logistic regression analysis was used to examine the
association between indoor allergen sensitivity and other factors, and the risk
of hospitalization for asthma. RESULTS: In univariate analyses, hospitalization
for asthma was significantly associated with cockroach sensitivity (odds ratio
[OR] = 2.2; 95% confidence interval [CI] = 1.1, 4.3); cat sensitivity (OR = 2.9;
CI = 1.3, 6.4); black race (OR = 2.4; CI = 1.1, 5.1); public aid/self pay (OR =
2.3; CI 1.1, 4.9) and age, (OR [per year increase in age] = 0.8; CI = 0.7, 0.9).
In a stepwise multiple logistic regression analysis, only cat sensitivity (OR =
3.8; CI = 1.5, 9.2), age (OR = 0.8; CI = 0.7, 0.9) and race (OR = 3.2; CI = 1.4,
7.5) entered into the model as significant independent predictors. CONCLUSION:
Sensitivity to cat allergen may be an important determinant for asthma
hospitalization in children. Sensitization to cockroach allergen per se was not
found to be an independent risk factor. As observed in previous studies, younger
and black children were at increased risk of hospitalization for asthma.
PMID- 9396982
TI - Follow-up of pediatric patients with recurrent infection and mild serologic
immune abnormalities.
AB - BACKGROUND: Children with recurrent infections significant enough to warrant
referral to an immunologist frequently have mild abnormalities of the humoral
immune system. Parents of these children are generally reassured that their child
will outgrow the clinical problems that prompted their referral. OBJECTIVE: This
is a retrospective study with the objective being to evaluate changes in immune
measurements and clinical status of children with recurrent infections followed
in an immunology clinic. METHODS: Forty-two patients (mean age 60 months)
previously evaluated for recurrent infections were re-evaluated after at least 12
months (mean 37 months). Initial evaluation studies included quantitative
immunoglobulins in all patients and IgG subclass determinations and pre- and
postvaccination pneumococcal polysaccharide antibody titers in a subpopulation of
patients. RESULTS: Patients were assigned to one of two categories: those with
initial laboratory abnormalities (27 patients) and those with normal initial
studies (15 patients). Among the patients with initial abnormalities, partial IgA
deficiency was most commonly seen (20/27). It persisted in 15. Only 6/27 patients
had studies that were completely normal on follow-up. Among patients with no
initial abnormality, 9/15 developed a partial deficiency of at least one
immunoglobulin isotype or IgG subclass. Eighty-six percent of the patients were
clinically improved at the time of their last follow-up visit regardless of their
laboratory values. CONCLUSIONS: A high proportion of children with recurrent
infection have persistent, partial immunoglobulin deficiencies lasting in some
cases for years. Despite this finding almost all patients demonstrate clinical
improvement with time.
PMID- 9396983
TI - Comparison of ebastine with cetirizine.
PMID- 9396984
TI - Hepatitis C after intravenous immunoglobulin.
PMID- 9396985
TI - Lack of ragweed in northwestern US.
PMID- 9396986
TI - Clarification of Richard C. Ahren's editorial commenting on article by Pallares
DE et al.
PMID- 9396987
TI - Quality of life after surgery for early breast cancer.
PMID- 9396988
TI - Quality of life after breast conservation or mastectomy: a systematic review.
AB - BACKGROUND: For early breast cancer, survival after breast conservation is
similar to that after mastectomy. Some women may not have a clear preference and
wish to have further information about quality of life experienced after the
alternative treatments. This paper describes a systematic review of randomized
trials on mastectomy versus breast conservation for which there are data on
quality of life or psychosocial outcomes. METHODS: Literature was reviewed to
find all randomized controlled trials comparing breast conservation to
mastectomy, with quality of life or psychological effects as an outcome. Studies
were then critically appraised by two reviewers independently and any
disagreements about their quality and results resolved by discussion. RESULTS: A
total of six randomized trials met our inclusion criteria. In general, they are
of poor quality. Women who had breast conservation had a more favourable body
image of themselves than those who had mastectomy in all five studies in which it
was examined. The evidence was statistically inconclusive for all the other
dimensions measured, namely perceptions of psychological health, sexual health,
physical health, fear of the future and global quality of life. Radiotherapy may
be a determinant of poorer psychological health and body image. CONCLUSIONS:
Apart from body image, it is unclear whether breast conservation or mastectomy
results in better psychosocial outcomes. Moreover, the studies were done before
evidence was available to inform women about the equivalence of survival with
these alternative treatments. Therefore there is inadequate information available
to help many women decide about their choice of treatment in the future.
Preference trials should be conducted, using standardized quality-of-life
measures, in which women who are uncertain about which treatment to choose are
randomized to breast conservation or mastectomy.
PMID- 9396989
TI - Breast cancer: aetiological factors and associations (a possible protective role
of phytoestrogens).
AB - BACKGROUND: In spite of many known and suspected factors associated with the risk
of breast cancer there has until recently been no explanation for its continuing
increase in women of Western societies over recent decades or why there has not
been an equivalent increase in women of most Asian and other less Westernized
societies. It has long been suspected that a significant factor has been an
increasing change of diet in Western societies from one predominantly vegetarian
to one with a high content of meat and dairy products as well as 'refined' foods.
Although diet has long been suspected there has otherwise been no real
explanation as to the mechanism of the change in incidence of breast cancer.
METHODS: A comprehensive literature review has been made of aetiological factors
and associations concerning breast cancer to determine whether any consistent
trend can explain the rising incidence in Western societies. RESULTS: There are a
number of likely contributory factors but there is now accumulating evidence that
the single most important difference is that people having a vegetarian diet have
a high intake of legumes and other plant foods containing a variety of lignans
and isoflavonoids. These appear to have an important role as nature's sex hormone
modulators. These agents appear to be biologically active in a number of ways not
yet completely understood but they do have both a weak oestrogenic effect and an
anti-oestrogenic competitive effect, thus reducing the potential carcinogenic
action of prolonged oestrogen activity. A probable additional benefit of such
diets could be the role of dietary fibre. CONCLUSIONS: A major problem of Western
diets may not be the presence of meat or dairy products in the diet but the
absence of desirable ingredients of vegetarian diets, namely dietary fibre and
certain plant lignans and isoflavonoids. A modification of diet to include a
greater proportion of fibre and soy or other leguminous plant food should be
studied. Alternatively addition of more fibre and lignans and especially
isoflavonoids to traditional Western diets would seem worthy of serious
investigation. Such influences appear to have their greatest impact early in life
and therefore could be especially important for girls and young women in Western
societies.
PMID- 9396990
TI - Breast cancer in young women.
AB - BACKGROUND: It is believed that cancer of the breast is more difficult to
diagnose in young women and it has long been disputed whether breast cancer
occurring in women aged < or = 40 years is more aggressive than that occurring
later in life. A number of reports in the literature suggest that the disease is
of similar aggressiveness in the young patients and older age groups, while other
reports suggest that it is more aggressive and carries a higher mortality in
young women. METHODS: To address these aspects of breast cancer we have
undertaken a review of the cases treated at The Strathfield Breast Centre between
1989 and 1996 and compared the disease in the young and old groups with
particular reference to the modes of diagnosis, the pathological staging and
types of tumour and the outcomes of treatment. RESULTS: The accuracy of
ultrasound and fine needle aspiration biopsy were similar in both groups, but the
false negative rate of mammography in the young patients was 15% or 50% greater
than that which was observed in the older patients. The incidence of
histopathological type, bilaterality, size of lesion and receptor positivity were
the same in both groups. In the young group, 40% had Grade 3 tumours compared
with 27% in the older group. Nineteen per cent of young patients had 4 or more
lymph nodes involved while only 10% of the older patients had similar lymph node
involvement. Overall 5-year survival was 79% in the older patients compared with
90% in the young patients. CONCLUSIONS: The spectrum of disease is similar in
both the young and older patient and the prognosis is no worse for the young
group but mammography is less effective in the diagnosis of the young patient.
PMID- 9396991
TI - A simple index to predict prognosis independent of axillary node information in
breast cancer.
AB - BACKGROUND: Since the course of breast cancer is often unpredictable, we wished
to develop a model using characteristics of the primary tumour alone to predict
prognosis. METHODS: Several tumour features were determined, and after a median
follow-up duration of 65 months, multivariate analysis identified tumour size and
grade, oestrogen receptor concentration, axillary lymph node metastasis and
tumour cell proliferation fraction (MIB-1 count) as being independently
associated with increases in risk for both relapse and death from breast cancer.
A prognostic model was constructed using tumour size and grade, oestrogen
receptor concentration and MIB-1 count only. A score of 1 for each was given to
tumour size > 20 mm, tumour grade 2 or 3, oestrogen receptor concentration < 10
fmol/mg cytosol protein and MIB-1 count > 9%. Five groups established by
assigning a combined score of 0, 1, 2, 3 or 4 for each patient were analysed for
their associations with disease-free and overall survivals. RESULTS: This
preliminary model predicted 5-year survival rates of 97, 91, 85, 68 and 50% for
the five groups. The model was further simplified by excluding tumour grade from
the analysis. The revised model identified four risk groups with predicted 5-year
survival rates of 91, 86, 66 and 52%. This model, the Adelaide prognostic index,
was also able to identify four risk groups in both node-negative and node
positive patients. CONCLUSIONS: The Adelaide prognostic index can be used to
predict prognosis even in the absence of axillary lymph node information.
PMID- 9396993
TI - Communicating with patients: surgeons' perceptions of their skills and need for
training.
AB - BACKGROUND: This study assessed surgeons' current perceived level of competence
in a number of interactional skills, their perceptions of the need for training
and assessment in interactional skills, and their perceptions of the
appropriateness of the format and content of two existing communication skills
training packages. METHODS: Of 267 surgeons who were sent the survey, 63% (n =
143) of eligible respondents completed and returned it. RESULTS: More than three
quarters of the sample identified the following skills as being important or very
important in being a good surgeon: breaking bad news; preparing patients for
surgical procedures; educating patients about their diagnosis and treatment, and
increasing the likelihood that they will remember what they have been told;
detecting anxiety and depression in patients, encouraging patients to express
these and listening to their anxieties. More than half the sample felt at least
competent at seven of the 10 interactional skills, but almost one-third of the
sample reported being 'not or not at all competent' at increasing patients'
ability to remember what they have been told and at encouraging patients to
express anxieties about their condition, and a further 13.3% reported a lack of
competence at breaking bad news to patients about their diagnosis/prognosis. A
higher proportion reported a lack of competence in providing bereavement
counselling (59.6%), and gaining consent for organ donation (56.6%) and for
autopsy (48.9%). The majority rated different aspects of the two communication
skills training packages as either 'good' or 'excellent'. CONCLUSIONS: The survey
identified a number of communication skills which are perceived by surgeons to be
important and to require formal training and assessment.
PMID- 9396992
TI - Cosmetic outcome of breast-conserving therapy in Chinese patients with early
breast cancer.
AB - BACKGROUND: Breast-conserving surgery combined with radiotherapy has emerged as
an alternative to mastectomy for women with early breast cancer, and cosmetic
outcome has correlated closely with the psychosocial and physical well-being of
the patient. Cosmetic outcome assessment after breast-conserving therapy in
Chinese patients has so far not been conducted among the clinicians, the patients
or their spouses. METHODS: The cosmetic results from breast-conserving therapy
were evaluated in a group of 33 patients who had been selected as suitable for
undergoing local excision, axillary dissection and postoperative radiation
therapy for early stage breast cancer. The success of the procedures was assessed
by the patients, the clinicians and the patient's spouse, and their ratings were
compared with each other. RESULTS: Eighty per cent of the patients and their
spouse were satisfied with the cosmetic outcome. Using McNemar's test, when the
groups were evaluated on a case-by-case basis, there was a good level of
concordance between the patients and their spouses, and that of the patients and
the clinicians. CONCLUSIONS: Evaluation of the cosmetic and psychosocial sequelae
of breast cancer patients is essential when new approaches to treatment are
introduced; our data suggest that cosmetically successful breast conservation is
feasible in a selected group of Chinese women with early breast cancer.
PMID- 9396994
TI - Prostate cancer mortality in New Zealand: the past and projections for the
future.
AB - BACKGROUND: Ageing male populations and improved diagnosis of early stage disease
have contributed to the increasing incidence of prostate cancer observed in many
Western countries. The clinical significance of these diagnosed cancers is,
however, currently unclear. The aim of this study is to examine trends over time
in prostate cancer mortality as an indicative measure of clinically significant
disease during a 29-year period (1965-93) which preceded the extensive use of
early cancer diagnostic techniques or radical therapy protocols. METHODS: Age
specific and age-standardized rates were calculated for each year during the
study period, using routinely collected mortality and demographic data. A Poisson
regression model was used to describe trends in the age-specific rates over time
to predict numbers of prostate cancer deaths and the lifetime risk of death over
the next 20 years. RESULTS: Significant annual increases ranging from 1 to 2.6%
were found for age-specific prostate cancer mortality rates over the 29-year time
period, with the largest increases experienced in the younger age groups at risk.
Based on projected population ageing and growth alone, annual numbers of prostate
cancer deaths are predicted to increase from 487 in 1993 to 664 by the year 2006
and then to 833 by the year 2016. Continuation of the observed increases in age
specific mortality rates would result in a predicted 797 deaths by the year 2006,
while an expected 1115 deaths is calculated for the year 2016. This would
correspond with an increase in the lifetime risk of death from prostate cancer
from a present 3.7 to 4.5% in 10 years and 6.2% in 20 years. CONCLUSIONS: The
changing pattern of prostate cancer mortality described in this study is likely
to represent a significant increase in the incidence of clinically significant
disease. This will have a significant impact on the ageing New Zealand male
population, and important implications for the provision of effective treatment
and preventive strategies.
PMID- 9396995
TI - Fine needle aspiration biopsy in children.
AB - BACKGROUND: Fine needle biopsy (FNB) in children has been slow to gain acceptance
compared with the use of the technique in adults where it is regarded as standard
clinical practice in screening significant lymphadenopathy and suspicious masses.
We report our early experience with FNB in the paediatric population. METHODS:
Fifty-two biopsies were performed between June 1991 and June 1993. The age of the
children ranged from 6 months to 14 years (median 2 years, mean 5 years).
RESULTS: A definite diagnosis on cytology alone was obtained in 67%. The
pathologist was certain of malignant or nonmalignant potential in 79% (67% benign
and 12% malignant) and unsure in 21% (17% benign and 4% malignant). There were no
false positive or false negative diagnoses of malignancy. Surgical excision or
biopsy was performed in 33%. Fine needle biopsy assisted in planning surgery in
12%. Surgery was necessary for a definite diagnosis in 21% and FNB assisted 42%
of the patients to avoid surgery altogether. CONCLUSIONS: Fine needle biopsy is
simple, minimally invasive and useful in the evaluation of children with
suspicious lymph nodes and masses.
PMID- 9396996
TI - Diagnostic laparoscopy for chronic right iliac fossa pain: a pilot study.
AB - BACKGROUND: The aim of this study was to determine the value of diagnostic
laparoscopy in patients with chronic right iliac fossa pain. METHODS: A
retrospective study at Echuca Hospital involving case-note review and telephone
questionnaire of patients who had undergone diagnostic laparoscopy for chronic
right iliac fossa pain at least 12 months earlier (September 1992 to August 1995)
was carried out. RESULTS: Forty-one cases were identified and followed up 12-40
months postoperatively (median 21 months). Eleven cases had positive findings at
laparoscopy, of whom eight obtained lasting relief after treatment. Of the
remaining 30 patients 17 had a normal-looking appendix removed and 12 were cured;
these were younger patients with episodic symptoms and localized signs. Of eight
patients who had adhesions divided, four with adhesions beneath old scars
obtained relief. Altogether 32 of the 41 patients considered the laparoscopy
worthwhile even though in some cases it did not relieve their chronic pain.
CONCLUSIONS: Diagnostic laparoscopy is worthwhile for patients with chronic right
iliac fossa pain. Concurrent appendicectomy should be considered in young
patients with episodic, well-localized symptoms associated with systemic malaise
while adhesiolysis may be beneficial for viscero-parietal adhesions beneath
abdominal wall scars.
PMID- 9396997
TI - Predicting poor outcome in perforated peptic ulcer disease.
AB - BACKGROUND: Despite modern medications for peptic ulcers, patients frequently
require emergency surgery for complications of ulcer disease. Many of these
patients have coexisting medical problems which not only predispose to perforated
ulcer disease, but also influence the clinical outcome. This study reviews the
outcome of a group of patients with perforated ulcer disease and examines the
influence of a range of comorbidity factors on the outcome. METHODS: A
retrospective chart review of all cases of perforated peptic occurring over a
period of 9 years. RESULTS: One hundred and forty-nine perforated peptic ulcers
in 147 patients were diagnosed between 1987 and 1996. Coexisting malignancy, use
of immunosuppressives or corticosteroids, pre-operative shock and admission to
intensive care were all significantly associated with reperforation by univariate
analysis. However, logistic regression analysis indicated that none of these
factors independently predicted reperforation which, therefore, occurs as a
multifactorial event with all the above factors contributing. Death from
perforated ulcer disease was related to pre-operative shock, malignancy,
admission to intensive care and reperforation when examined by univariate
analysis. Furthermore, logistic regression analysis showed that coexisting
malignancy and reperforation were significant predictors of mortality.
CONCLUSIONS: Perforated peptic ulcer disease remains a frequent clinical problem
in patients with short dyspeptic histories, who may or may not have been using
ulcerogenic medications. It is a significant cause of morbidity and mortality
among an often aged and otherwise unwell group of patients. Patients with
underlying malignant disease, who may be immunosuppressed with corticosteroids or
cytotoxics, are at increased risk of dying from perforated ulcer disease.
Reperforation of an ulcer, following simple closure or conservative treatment, is
also highly predictive of increased mortality.
PMID- 9396998
TI - Previous intravenous chemotherapy does not alter response rate or survival time
of patients with hepatic metastases from colorectal cancer treated by hepatic
artery chemotherapy.
AB - BACKGROUND: The present paper addressed the issue of whether pretreatment with
intravenous (i.v.) chemotherapy affects response rate or survival in patients
receiving hepatic artery chemotherapy (HAC). METHODS: Case note reviews of 164
patients treated in a teaching hospital from June 1990 to July 1996 were carried
out. RESULTS: The response rate and carcino-embryonic antigen (CEA) fall in the
two groups was almost identical. There was a nonsignificant survival advantage in
the non-pretreatment group. CONCLUSIONS: Previous administration of i.v.
chemotherapy did not affect the CEA response of patients receiving HAC.
PMID- 9396999
TI - Benign anterior knee cyst in early childhood.
AB - BACKGROUND: Anterolateral knee cysts are not uncommon in the first 7 years of
life, but have not been described in the literature. METHODS: Four patients
presenting with an asymptomatic lump on the anterolateral joint line were
reviewed. RESULTS: The lump remains asymptomatic. CONCLUSIONS: Anterolateral knee
cysts of childhood are benign and do not require treatment. Their cause is
conjectural.
PMID- 9397000
TI - Laser photocoagulation in the treatment of malignant dysphagia.
AB - BACKGROUND: Dysphagia secondary to carcinoma of the oesophagus and gastric cardia
is the principal symptom requiring palliation in those patients who present with
late-stage disease or who are unfit for surgery. The primary aim of the present
study was to determine the safety and efficacy of laser photocoagulation in the
palliation of malignant dysphagia. Secondary aims were to look at reasons for
failure and predictors of outcome; to determine the most appropriate second line
therapy for treatment failures; and to look at the results of treatment for early
stage disease. METHODS: Sixty-seven patients treated over a 6-year period with
endoscopic Nd:YAG laser photocoagulation were evaluated and the quality of
swallowing assessed before and at intervals after treatment. RESULTS: Ninety per
cent of patients achieved successful initial palliation. This was sustained in
76% after 3 months of treatment. Within a month before death 71% of patients were
palliated but 29% required the addition of second-line treatment to achieve this.
Complications were infrequent. There were no deaths attributable to laser
treatment. Five of 10 patients treated with radiotherapy developed fibrous
stricturing that required endoscopic dilatation. No variables were independently
predictive for treatment failure. Six patients with early stage disease
experienced prolonged survival. CONCLUSIONS: We conclude that laser
photocoagulation offers safe and effective palliation of malignant dysphagia in
this group of patients and is appropriate as first-line therapy.
PMID- 9397001
TI - The management of colorectal perforation and peritonitis.
AB - BACKGROUND: Surgical outcomes in patients presenting with colonic perforation or
peritonitis tend to be poor. This study was undertaken to determine outcomes in
such patients at a time before multiple re-laparotomies were performed. METHODS:
Retrospective analysis of computer records of all patients presenting acutely to
the University Surgical Unit (Wellington School of Medicine) with colonic
perforation or peritonitis over a 15-year period. RESULTS: Seventy-three
patients, 33 males and 40 females were admitted with either perforation or
localized peritonitis of colorectal origin. Of these, 78% were managed as
emergencies, but six were admitted electively and found incidentally. Consultant
surgeons performed surgery slightly more frequently than registrars. Two patients
were managed non-operatively. Forty-one per cent received peri-operative blood
transfusion and 22% peri-operative total parenteral nutrition. The majority of
patients presented with either peritonitis or free perforation in association
with diverticular disease. The site of perforation was either ileocolic or
sigmoid colonic in the majority of patients. Hartmann's operation was the most
commonly performed resection. Respiratory, urinary and wound infections were the
most commonly observed postoperative complications. Two patients developed
anastomotic leaks (6.3%). The overall persistent intra-abdominal infection rate
was 5.5%. Seven patients died following surgery. CONCLUSIONS: Resection of the
perforated bowel is mandatory and this should be followed by anastomoses in the
case of right-sided lesions and a Hartmann's operation or resection, colostomy
and mucous fistula in distally situated lesions.
PMID- 9397002
TI - Thirty years experience with heart valve surgery: isolated mitral valve
replacement: comment.
PMID- 9397003
TI - Thirty years experience with heart valve surgery: isolated aortic valve
replacement: comment.
PMID- 9397004
TI - Gastrointestinal lavage reduces total body water: comment.
PMID- 9397005
TI - Psychiatric disturbance and acute stress responses in surgical patients: comment.
PMID- 9397006
TI - The making of a rural surgeon: comment.
PMID- 9397007
TI - Ganglioneuroma of the adrenal medulla.
PMID- 9397008
TI - Haemorrhage into bronchopulmonary sequestration following cardiac surgery.
PMID- 9397009
TI - Localized fibrous tumour of the pleura: two case reviews.
PMID- 9397010
TI - MEN type 2a presenting as an intra-abdominal emergency.
PMID- 9397011
TI - Perfusion patterns during temporal lobe seizures: relationship to surgical
outcome.
AB - We sought to determine whether patterns of ictal hyperfusion demonstrated using
[99mTC]HMPAO (hexamethylpropylene amine oxime) single photon emission computed
tomography (SPECT) predict outcome of temporal lobectomy; in particular, whether
the more extensive patterns of ictal hyperperfusion are associated with poor
outcome. We studied 63 patients who had ictal SPECT studies prior to temporal
lobectomy. Hyperperfusion on ictal SPECT scans was lateralized, and classified
into: (i) 'typical', (ii) 'typical with posterior extension', (iii) 'bilateral'
and (iv) 'atypical' patterns. Outcome (minimum of 2 years follow-up) was
classified as either seizure free, or not seizure free. Actuarial analysis was
used to test the relationship of SPECT patterns with outcome. There were 35 cases
with the typical ictal SPECT pattern, 13 posterior, nine bilateral and six
atypical cases. The atypical pattern was associated with lack of pathology in the
surgical specimen. Outcome was similar for the typical, posterior and bilateral
with 60%, 69% and 67% seizure free, respectively. In contrast, the atypical group
had a worse outcome with only 33% seizure free. Actuarial analysis showed a
significant difference in outcome between patients with the typical pattern, and
patients with the atypical pattern (P = 0.04). We conclude that extended patterns
of ictal perfusion in temporal lobe epilepsy do not predict poor outcome,
indicating that extended hyperperfusion probably represents seizure propagation
pathways rather than intrinsically epileptogenic tissue. Atypical patterns of
hyperperfusion are associated with poor outcome and may indicate diffuse or extra
temporal epileptogenicity.
PMID- 9397012
TI - Results of surgical treatment in temporal lobe epilepsy with chronic psychosis.
AB - The combination of psychosis and refractory temporal lobe epilepsy is not rare.
However, patients with chronic interictal psychosis and refractory epilepsy are
rejected from many epilepsy surgery programmes purely on psychiatric grounds. It
is often assumed that disturbed behaviour will prevent adequate preoperative
evaluation or that the patients are unable to provide informed consent for
preoperative investigations and for surgery. The observation that the psychosis
usually does not improve after operation and fears of an exacerbation of
psychosis with post-surgical seizure remission, analogous to 'forced
normalization', are further deterrents to surgery in these patients. We describe
five patients with the dual diagnoses of medically intractable temporal lobe
epilepsy and chronic psychosis who underwent temporal lobe resection. The
patients were able to provide informed consent and were easily managed during
preoperative investigation. Seizure outcome has been excellent in all. Neither
temporal lobe resection nor remission of seizures influenced the nature or
evolution of the psychosis. Subjectively the patients functioned better in
activities of daily living and freedom from seizures improved integration into
psychiatric treatment facilities. With appropriate psychiatric intervention,
patients with chronic psychosis and refractory epilepsy can participate in
presurgical investigation successfully, and can undergo surgery uneventfully.
PMID- 9397013
TI - Human hippocampal AMPA and NMDA mRNA levels in temporal lobe epilepsy patients.
AB - This study was designed to determine whether hippocampal neuronal AMPA (alpha
amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and NMDA (N-methyl-D
aspartate) mRNA levels were differentially increased in temporal lobe epilepsy
patients compared with those measured in control tissue from non-seizure
autopsies. Hippocampi from hippocampal sclerosis patients (n = 28) and temporal
mass lesion cases (n = 12) were compared with those from the autopsies (n = 4),
and studied for AMPA GluR1-3 and NMDAR1-2 mRNAs using semi-quantitative in situ
hybridization, along with fascia dentata and Ammon's horn neuron densities.
Compared with the autopsies, and without correction for neuron counts, the mass
lesion cases with neuron densities similar to autopsies showed: (i) significantly
increased NMDAR2 hybridization densities for fascia dentata granule cells; (ii)
increased AMPA GluR3 mRNA densities for Ammon's horn pyramids; and (iii) similar
or numerically increased mRNAs for all other subunits and hippocampal subfields.
Compared with the autopsies, hippocampal sclerosis cases with decreased neuron
densities showed: (i) significantly decreased AMPA GluR1-2 and NMDAR1-2
hybridization densities for Ammon's horn pyramids and (ii) similar or numerically
decreased mRNAs for all other subunits and subfields. However, correcting for
changes in neuron densities showed that hippocampal sclerosis patients had
increased AMPA and NMDA mRNA levels per neuron compared with autopsies, and in
the CA2 resistant sector GluR2 mRNA levels were numerically greater than
autopsies and mass lesion cases. Furthermore, relative to autopsies both
sclerosis and mass lesion hippocampi showed that, in the stratum granulosum, the
greatest mRNA increases were in AMPA GluR1 and NMDAR2 compared with the other
mRNAs. In chronic temporal lobe seizure patients these results indicate that mass
lesion and sclerosis cases show differential increases in hippocampal AMPA and
NMDA mRNA levels per neuron compared with autopsies, especially for AMPA GluR1
and NMDAR2 in fascia dentata granule cells. These findings support the hypothesis
that temporal lobe seizures are associated with increased ionotropic glutamate
receptor mRNA levels and alterations in receptor subunit composition that
probably contribute to neuronal hyperexcitability, synchronization and seizure
generation.
PMID- 9397015
TI - Clinical and neurophysiological features of tick paralysis.
AB - The clinical and neurophysiological findings in six Australian children with
generalized tick paralysis are described. Paralysis is usually caused by the
mature female of the species Ixodes holocyclus. It most frequently occurs in the
spring and summer months but can be seen at any time of year. Children aged 1-5
years are most commonly affected. The tick is usually found in the scalp, often
behind the ear. The typical presentation is a prodrome followed by the
development of an unsteady gait, and then ascending, symmetrical, flaccid
paralysis. Early cranial nerve involvement is a feature, particularly the
presence of both internal and external ophthalmoplegia. In contrast to the
experience with North American ticks, worsening of paralysis in the 24-48 h
following tick removal is common and the child must be carefully observed over
this period. Death from respiratory failure was relatively common in the first
half of the century and tick paralysis remains a potentially fatal condition.
Respiratory support may be required for > 1 week but full recovery occurs. This
is slow with several weeks passing before the child can walk unaided. Anti-toxin
has a role in the treatment of seriously ill children but there is a high
incidence of acute allergy and serum sickness. Neurophysiological studies reveal
low-amplitude compound muscle action potentials with normal motor conduction
velocities, normal sensory studies and normal response to repetitive stimulation.
The biochemical structure of the toxin of I. holocyclus has not been fully
characterized but there are many clinical, neurophysiological and experimental
similarities to botulinum toxin.
PMID- 9397014
TI - Cortical grey matter and benzodiazepine receptors in malformations of cortical
development. A voxel-based comparison of structural and functional imaging data.
AB - Using [11C]flumazenil-PET and statistical parametric mapping (SPM), we have shown
recently that regions of increased and decreased benzodiazepine receptor density
may be seen in patients with localization-related epilepsy due to malformations
of cortical development. These abnormalities were seen both within and beyond
lesions visually apparent on high-resolution MRI. We have also shown, using an
interactive anatomical segmentation technique and volume-of-interest
measurements, that subtle and unsuspected abnormalities of cortical grey matter
volume were found in the same group of patients on high-resolution MRI, beyond
the lesions visually apparent. In 10 patients with localization-related epilepsy
and malformations of cortical development, we have now applied the automated and
objective technique of SPM to the analysis of high-resolution structural MRI.
Each individual patient was compared with 16 normal control subjects. We have
then simultaneously compared the structural and functional data obtained for each
individual patient with normal control high-resolution MRI and [11C]flumazenil
PET image using a novel technique. This comparison allowed the detection of
functional abnormalities that were not accounted for by either visible or
unsuspected structural abnormalities, in an automated and statistically rigorous
manner. Five patients had abnormalities of cortical grey matter volume detected
using SPM; only these five patients had been found abnormal using the previous
volume-of-interest technique. Six of the 10 patients showed regions of cerebral
cortex with disproportionate flumazenil binding compared with local grey matter
volume. This included regions not found to have abnormal flumazenil binding on
analysis of the PET data alone. Furthermore, regions found to have abnormal
binding on examination of the PET data alone were, in some instances, shown to be
accounted for by abnormalities of cortical grey matter volume. We conclude that
the analysis of ligand PET data should always include a comparison with
structural MRI; such comparisons are greatly facilitated by the novel approach
described.
PMID- 9397016
TI - Miyoshi-type distal muscular dystrophy. Clinical spectrum in 24 Dutch patients.
AB - Miyoshi-type distal muscular dystrophy has now been found to be more frequent
outside Japan than was previously thought. We studied 24 Dutch patients with
Miyoshi-type distal muscular dystrophy and focused on its clinical expression and
natural history, muscle CT-scans and muscle biopsy findings. Our study shows that
Miyoshi myopathy is a heterogeneous, slowly progressive disorder. The disease
starts with weakness and atrophy of the calves and progressively involves the
proximal leg and hip muscles and, in a later stage the shoulder and upper arm
muscles. After 10 years disease duration, one-third of the patients are dependent
on wheelchairs for out-of-door transportation. Disease progression is related to
disease duration and not to early age of onset of symptoms. Onset may be at any
age and is asymmetrical in roughly half of the cases. Four cases had been
initially diagnosed as idiopathic hyper-CK-aemia.
PMID- 9397017
TI - A PET study of voluntary movement in schizophrenic patients experiencing
passivity phenomena (delusions of alien control).
AB - Schizophrenic patients experiencing passivity phenomena believe their thoughts
and actions to be those of external, or alien, entities. We wished to test the
hypothesis that voluntary motor action in such patients would be associated with
aberrant patterns of activation within the cerebral motor system. We used H2(15)O
PET to study patients while they performed paced joystick movements on two
occasions 4-6 weeks apart. During the first scan passivity symptoms were maximal,
while by the second scan these symptoms had significantly improved in five of the
seven patients. Two control groups were also scanned on two occasions: deluded
schizophrenic patients without passivity phenomena and normal subjects. In normal
subjects, performance of freely selected joystick movements with the right hand,
compared with rest, revealed relative activation of prefrontal, premotor, motor
and parietal cortical regions. Schizophrenic patients with passivity showed
hyperactivation of parietal and cingulate cortices. This hyperactivation remitted
in those subjects in whom passivity decreased over time. This reversible
hyperactivity was not a feature of schizophrenics without passivity. Given that
these hyperactive cerebral regions subserve attention to internal and external
bodily space, and the attribution of significance to sensory information, they
provide a plausible anatomical substrate for the misattribution of internally
generated acts to external entities: the cardinal feature of delusions of
passivity (alien control).
PMID- 9397019
TI - Impaired recognition of disgust in Huntington's disease gene carriers.
AB - Face processing and facial expression recognition were investigated in the
earliest stages of Huntington's disease, by studying 40 people who presented for
genetic testing. Twenty-three of these 'at risk' individuals turned out not to
carry the gene for Huntington's disease (the AR- group). Seventeen were found to
be gene carriers (the AR+ group); 15 from genetic testing, and two who showed
signs of early stages of Huntington's disease. A number of standard tasks were
used to provide background information, including recognition memory for words,
picture naming, verbal fluency, and figure copying; none revealed significant
differences between the AR+ and AR- groups. Face processing abilities were
investigated using tests of identification of familiar (famous) faces, unfamiliar
face matching, recognition memory for faces, and recognition of facial
expressions of emotion. No statistically significant differences between the AR+
and AR- groups were found for any of these tests, but the AR+ group showed a
borderline overall impairment in recognizing facial expressions of emotion (0.05
< P < 0.1). When recognition of each of the six basic emotions used was examined
separately, only disgust was found to be significantly impaired. This highly
selective deficit in the recognition of disgust was confirmed in the subgroup of
15 individuals shown by genetic testing to be Huntington's gene carriers; it was
therefore found in people who were free from clinical symptoms and did not
perform significantly more poorly than non-carriers on any of the background
tests, on any of the other face processing tasks, and even for recognition of any
other basic emotion. This points strongly to the importance of the basal ganglia
in the emotion of disgust.
PMID- 9397018
TI - Space-based and object-based visual attention: shared and specific neural
domains.
AB - Visual attention can be primarily allocated to either where an object is in space
(with little emphasis on the structure of the object itself) or to the structure
of the object (with little emphasis on where in space the object is located).
Using PET measures of regional cerebral blood flow (rCBF) to index neural
activity, we investigated the shared and specific functional anatomy underlying
both of these types of visual attention in a controlled non-cueing non-blocked
paradigm that involved identical stimuli across the conditions of interest. The
interaction of eye movements with these attentional systems was studied by
introducing fixation or free vision as an additional factor. Relative to the
control condition, object-based and space-based attention showed significant
activations of the left and right medial superior parietal cortex and the left
lateral inferior parietal cortex, the left prefrontal cortex and the cerebellar
vermis. Significant differential activations were observed during object-based
attention in the left striate and prestriate cortex. Space-based attention
activated the right prefrontal cortex and the right inferior temporal-occipital
cortex. Differential neural activity due to free vision or fixation was observed
in occipital areas only. Significant interactions of free vision/fixation on
activations due to object-based and space-based attention were observed in the
right medial superior parietal cortex and left lateral inferior parietal cortex,
respectively. The study provides direct evidence for the importance of the
parietal cortex in the control of object-based and space-based visual attention.
The results show that object-based and space-based attention share common neural
mechanisms in the parietal lobes, in addition to task specific mechanisms in
early visual processing areas of temporal and occipital cortices.
PMID- 9397020
TI - Working memory impairment in early multiple sclerosis. Evidence from an event
related potential study of patients with clinically isolated myelopathy.
AB - Auditory and visual event-related potentials were recorded during a short-term
memory task in 24 patients who had recently presented with symptomatically and
clinically isolated spinal cord syndromes suspected to be due to multiple
sclerosis, and in 24 matched control subjects. Event-related potentials (ERPs)
were recorded during two sequential components of the working memory task, first
the temporary active memorizing of sets of digits and secondly, their subsequent
manipulation, namely digit-probe recognition and matching. The patients' reaction
times were slower and showed larger increments than those of the control subjects
as the number of items to be memorized was increased. The patients' ERPs during
both memorizing and probe matching/recognition phases differed significantly from
control subjects for both auditory and visual presentations. The more marked
changes were seen in a subgroup of eight patients who had the lowest levels of
performance on a battery of general tests of memory and who also made
significantly more errors in the working memory task as the memory load
increased. In this subgroup, the abnormalities of the ERPs during recognition and
matching tests occurred in the component of the response that has been shown to
be sensitive to memory loading in healthy control subjects. This study provides
objective evidence of subclinical working memory dysfunction in patients at an
early stage of demyelinating disease, i.e. when they first present with
clinically isolated spinal cord lesions and before they have developed symptoms
of cognitive or memory dysfunction. The defect at this early stage is either
restricted to processes involved in the formation of a memory trace or, more
probably, involves both trace formation and the mechanisms that underly
recognition ('retrieval') and matching of memory traces in working memory.
PMID- 9397021
TI - Comparison of MRI criteria at first presentation to predict conversion to
clinically definite multiple sclerosis.
AB - We compared MRI criteria used to predict conversion of suspected multiple
sclerosis to clinically definite multiple sclerosis. Seventy-four patients with
clinically isolated neurological symptoms suggestive of multiple sclerosis were
studied with MRI. Logistic regression analysis was used to remove redundant
information, and a diagnostic model was built after each MRI parameter was
dichotomized according to maximum accuracy using receiver operating
characteristic analysis. Clinically definite multiple sclerosis developed in 33
patients (prevalence 45%). The optimum cut-off point (number of lesions) was one
for most MRI criteria (including gadolinium-enhancement and juxta-cortical
lesions), but three for periventricular lesions, and nine for the total number of
T2-lesions. Only gadolinium-enhancement and juxta-cortical lesions provided
independent information. A final model which, in addition, included
infratentorial and periventricular lesions, had an accuracy of 80%, and having
more abnormal criteria, predicted conversion to clinically definite multiple
sclerosis strongly. The model performed better than the criteria of Paty et al.
(Neurology 1988; 38: 180-5) and of Fazekas et al. (Neurology 1988; 38: 1822-5).
We concluded that a four-parameter dichotomized MRI model including gadolinium
enhancement, juxtacortical, infratentorial and periventricular lesions best
predicts conversion to clinically definite multiple sclerosis.
PMID- 9397022
TI - Direct observation of myelination in vivo in the mature human central nervous
system. A model for the behaviour of oligodendrocyte progenitors and their
progeny.
AB - We studied patches of CNS myelin in human retina in vivo to determine the pattern
of myelination and the local influence of axons. We analysed the position, area
and thickness of the nerve-fibre layer in 60 patches of retinal myelin in 47 eyes
(in 37 adults and two adolescents). Five patches in four eyes were studied
serially over 6-11 years. Nerve-fibre layer thickness was obtained from an atlas
of primate retina, and volumes of myelinated tissue were then estimated for each
patch. Retinal myelination occurred in three patterns: thick patches contiguous
with the optic disc (type I); thin, striated patches detached from the disc (type
II); or massive myelination of the posterior pole associated with severe
amblyopia (type III). The papillomacular bundle did not myelinate in types I and
II and was relatively spared in type III patches, suggesting that migratory
oligodendrocyte progenitors are not supported by these axons. The local nerve
fibre layer determined patch size, and quantal myelination was evident with modal
peaks of patch volume at 0.16 and 0.64 mm3. Myelination advanced at patch edges
when observed over time, consistent with the hypothesis that new oligodendrocytes
are produced in adulthood. We propose a theoretical model where patches of
retinal myelination are the clonal progeny of a few oligodendrocyte progenitors
exhibiting two different behaviours. First, a highly migratory, nonmyelinating
progenitor uses larger, phylogenetically older axons as the substrate for
movement. Secondly, a more mature progenitor generates myelinating
oligodendrocytes well into adult life, but traverses only short distances. Using
this data, we can estimate the number of oligodendrocytes in these clones and
population doubling-time. This study supports a role for axon-derived signals in
the regulation of human oligodendrocyte progenitor behaviour and myelination in
vivo.
PMID- 9397023
TI - Granulocyte-macrophage colony-stimulating factor crosses the blood--brain and
blood--spinal cord barriers.
AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF), a glycoprotein with
hormonal properties, is produced by several cell types, most of which exist
outside the CNS. GM-CSF, however, affects the CNS. If capable of crossing from
blood to CNS, GM-CSF might be an important signalling molecule between the CNS
and periphery. We used an established in vivo method in mice and rats to study
passage of radioactively labelled GM-CSF from blood to CNS. We found that GM-CSF
crossed the blood-brain barrier and blood-spinal cord barrier significantly
faster than the control substance, albumin. Labelled GM-CSF was recovered in
intact form by high performance liquid chromatography from brain after peripheral
injection, and passage was not significantly reduced by simultaneous injection of
unlabelled L-tryptophan. Both findings indicate that the observed passage of
radioactivity was intact protein. Capillary depletion experiments showed that
most of the GM-CSF was deposited in brain parenchyma rather than cerebral
capillary endothelium. Co-injection of unlabelled GM-CSF significantly reduced
the passage rate of labelled cytokine across the blood-brain and blood-spinal
cord barriers, demonstrating that passage was mediated by a saturable system. In
summary, a saturable mechanism transports GM-CSF intact from blood to CNS.
PMID- 9397024
TI - Stability of reach-to-grasp movement patterns in Parkinson's disease.
AB - The performance of patients with Parkinson's disease on two reach-to-grasp tasks
was compared with that of age-matched control subjects. The aim of the study was
to determine whether Parkinson's disease patients have problems coordinating
concurrently executed tasks within the same system of effectors in a natural
context and whether such problems would be exacerbated by increases in task
difficulty. We examined how subjects concurrently executed the transport and
grasp components of reach-to-grasp movements in the presence of two types of
change in task demands: (i) increases in demands for accurate digit pad placement
and (ii) use of two reach-to-grasp tasks, i.e. the standard unimanual task and a
bimanual task which increased the control and coordination demands relative to
the unimanual task. If Parkinson's disease patients have coordination problems
they should demonstrate increased impairment with increasing accuracy demands and
in the bimanual task; any such differences should be absent or much smaller in
the control group. The Parkinson's disease group showed substantial impairments
in all conditions, moving about 30% slower than the control group, with much
increased jerking and with signs of difficulty controlling the speed of movement.
However, there were no consistent indications that the Parkinson's disease group
were differentially impaired on the bimanual task nor that movement deficits
increased with increasing accuracy requirements. Grasp and transport components
were coordinated similarly by Parkinson's disease and control groups in both
reach-to-grasp tasks, and the Parkinson's disease group co-ordinated the two
limbs in the bimanual task effectively and in a fashion similar to that of the
control group. These results are interpreted to mean that higher levels (effector
independent levels) of motor programming are preserved in Parkinson's disease and
that execution of a motor programme need not be compromised by increasing the
number of muscle-/joint-level degrees of freedom which are used.
PMID- 9397025
TI - Hereditary demyelinating neuropathy of infancy: a genetically complex syndrome.
PMID- 9397026
TI - Transient middle cerebral artery occlusion by intraluminal suture: I. Three
dimensional autoradiographic image-analysis of local cerebral glucose metabolism
blood flow interrelationships during ischemia and early recirculation.
AB - Using autoradiographic image-averaging strategies, we studied the relationship
between local glucose utilization (LCMRglc) and blood flow (LCBF) in a highly
reproducible model of transient (2-hour) middle cerebral artery occlusion (MCAO)
produced in Sprague-Dawley rats by insertion of an intraluminal suture coated
with poly-L-lysine. Neurobehavioral examination at 60 minutes after occlusion
substantiated a high-grade deficit in all animals. In two subgroups, LCBF was
measured with 14C-iodoantipyrine at either 1.5 hours of MCAO, or at 1 hour of
recirculation after suture removal. In two other matched subgroups, LCMRglc was
measured with 14C-2-deoxyglucose at 1.5 to 2.25 hours of MCAO, and at 0.75 to 1.5
hours of recirculation after 2 hours of MCAO. Average image data sets were
generated for LCBF, LCMRglc, and the LCMRglc/LCBF ratio for each study time.
Middle cerebral artery occlusion for 2 hours induced graded LCBF decrements
affecting ipsilateral cortical and basal ganglionic regions. After 1 hour of
recirculation, LCBF in previously ischemic neocortical regions increased by 40%
to 200% above ischemic levels, but remained depressed, on average, at about 40%
of control. By contrast, frank hyperemia was noted in the previously ischemic
caudoputamen. Mean cortical LCBF values during MCAO correlated highly with their
respective LCBF values after 1 hour of recirculation (R = 0.93), suggesting that
post-ischemic LCBF recovery is related to the depth of ischemia. Despite focal
ischemia, LCMRglc during approximately 2 hours of MCAO was preserved, on average,
at near-normal levels; but following approximately 1 h of recirculation, LCMRglc
became markedly depressed (on average, 55% of control in previously densely
ischemic cortical regions). Regression analysis indicated that this depressed
glucose utilization was determined largely by the intensity of antecedent
ischemia. By pixel analysis, the ischemic core (defined as LCBF 0% to 20% of
control) comprised 33% of the ischemic hemisphere, and the penumbra (LCBF 20% to
40%) accounted for 26%. The penumbra was concentrated at the coronal poles of the
ischemic lesion and formed a thin shell around the central ischemic core. During
2 hours of MCAO, the LCMRglc/LCBF ratio within the ischemic penumbra was
increased four-fold above normal (average, 179 umol/100 mL). In marked contrast,
after approximately 1 h recirculation, this uncoupling had almost completely
subsided. The companion study (Zhao et al., 1997) further analyzes these findings
in relation to patterns of infarctive histopathology.
PMID- 9397027
TI - Transient middle cerebral artery occlusion by intraluminal suture: II.
Neurological deficits, and pixel-based correlation of histopathology with local
blood flow and glucose utilization.
AB - We conducted a pixel-based analysis of the acute hemodynamic and metabolic
determinants of infarctive histopathology in a reproducible model of temporary (2
hour) middle cerebral artery occlusion (MCAO) produced in rats by an intraluminal
suture. Three-dimensional averaged image data sets of local cerebral blood flow
(LCBF) and glucose utilization (LCMRglc) acquired in the companion study (Belayev
et al., 1997) either at the end of a 2-hour period of MCAO or after 1 hour of
recirculation were comapped (using digitized atlas-templates) with data sets
depicting the frequency of histological infarction in a matched animal group (n =
8) in which 2 hours of MCAO was followed by 3-day survival, sequential neuro
behavioral examinations, and perfusion-fixation and paraffin-embedding of brains
for light-microscopic analysis. All rats developed marked postural-reflex and
forelimb-placing deficits at 60 minutes of MCAO, signifying high-grade ischemia.
Tactile placing deficits persisted during the 72-hour observation period while
visual placing and postural-reflex abnormalities variably improved. Comapping of
LCBF and histopathology showed that in those pixels destined to undergo
infarction, LCBF measured at 2 hours of MCAO showed a sharp distributional peak
centered at 0.14 mL/g/min. In 70% of pixels destined to infarct, LCBF at 2 hours
of MCAO was 0.24 mL/g/min or below, and in 89% LCBF was below 0.47 mL/g/min (the
upper limits of the ischemic core and penumbra, respectively, as defined in the
companion study [Belayev et al., 1997]). Local cerebral glucose utilization
measured at approximately 1 hour after 2 hours of MCAO was distributed bimodally
in the previously ischemic hemisphere. The major peak, at 22 mumol/100g/min,
coincided exactly with the distribution peak of pixels destined to undergo
infarction, while in pixels with a zero probability of infarction, LCMRglc was
higher by 12 to 13 mumol/100g/min. These results indicate that local blood flow
at 2 hours of MCAO is a robust predictor of eventual infarction. Pixels with
ischemic-core levels of LCBF (0% to 20% of control) have a 96% probability of
infarction, while the fate of the penumbra is more heterogeneous: below LCBF of
0.35 mL/g/min, the probability of infarction is 92%, while approximately 20%
pixels in the upper-penumbral LCBF range (30% to 40% of control) escape
infarction. Our data strongly support the view that the likelihood of infarction
within the ischemic penumbra is highly influenced by very subtle differences in
early perfusion.
PMID- 9397028
TI - Effect of brain ischemia and reperfusion on the localization of phosphorylated
eukaryotic initiation factor 2 alpha.
AB - Postischemic brain reperfusion is associated with a substantial and long-lasting
reduction of protein synthesis in selectively vulnerable neurons. Because the
overall translation initiation rate is typically regulated by altering the
phosphorylation of serine 51 on the alpha-subunit of eukaryotic initiation factor
2 (eIF-2 alpha), we used an antibody specific to phosphorylated eIF-2 alpha [eIF
2(alpha P)] to study the regional and cellular distribution of eIF-2(alpha P) in
normal, ischemic, and reperfused rat brains. Western blots of brain
postmitochondrial supernatants revealed that approximately 1% of all eIF-2 alpha
is phosphorylated in controls, eIF-2(alpha P) is not reduced by up to 30 minutes
of ischemia, and eIF-2(alpha P) is increased approximately 20-fold after 10 and
90 minutes of reperfusion. Immunohistochemistry shows localization of eIF-2(alpha
P) to astrocytes in normal brains, a massive increase in eIF-2(alpha P) in the
cytoplasm of neurons within the first 10 minutes of reperfusion, accumulation of
eIF-2(alpha P) in the nuclei of selectively vulnerable neurons after 1 hour of
reperfusion, and morphology suggesting pyknosis or apoptosis in neuronal nuclei
that continue to display eIF-2(alpha P) after 4 hours of reperfusion. These
observations, together with the fact that eIF-2(alpha P) inhibits translation
initiation, make a compelling case that eIF-2(alpha P) is responsible for
reperfusion-induced inhibition of protein synthesis in vulnerable neurons.
PMID- 9397029
TI - Hyperglycemia and hypercapnia suppress BDNF gene expression in vulnerable regions
after transient forebrain ischemia in the rat.
AB - Preischemic hyperglycemia or superimposed hypercapnia exaggerates brain damage
caused by transient forebrain ischemia. Because high regional levels of brain
derived neurotrophic factor (BDNF) protein correlate with resistance to ischemic
damage, we studied the expression of BDNF mRNA using in situ hybridization in
rats subjected to 10 minutes of forebrain ischemia under normoglycemic,
hyperglycemic, or hypercapnic conditions. Compared with normoglycemic animals,
the increase of BDNF mRNA using in situ hybridization in rats subjected to 10
minutes of forebrain ischemia under normoglycemic, or hypercapnic conditions.
Compared with normoglycemic animals, the increase of BDNF mRNA in dentate granule
cells was attenuated and that in CA3 pyramidal neurons completely prevented in
hyperglycemic rats. No ischemia-induced increases of BDNF mRNA levels in the
hippocampal formation were detected in hypercapnic animals. Hyperglycemic and
hypercapnic rats showed transiently decreased expression of BDNF mRNA levels in
the cingulate cortex, which was not observed in normoglycemic animals. The
results suggest that suppression of the BDNF gene might contribute to the
increased vulnerability of the CA3 region and cingulate cortex in hyperglycemic
and hypercapnic animals.
PMID- 9397030
TI - Blockade of cerebral blood flow response to insulin-induced hypoglycemia by
caffeine and glibenclamide in conscious rats.
AB - The possibility that adenosine and ATP-sensitive potassium channels (KATP) might
be involved in the mechanisms of the increases in cerebral blood flow (CBF) that
occur in insulin-induced hypoglycemia was examined. Cerebral blood flow was
measured by the [14C]iodoantipyrine method in conscious rats during insulin
induced, moderate hypoglycemia (2 to 3 mmol/L glucose in arterial plasma) after
intravenous injections of 10 to 20 mg/kg of caffeine, an adenosine receptor
antagonist, or intracisternal infusion of 1 to 2 mumol/L glibenclamide, a KATP
channel inhibitor. Cerebral blood flow was also measured in corresponding
normoglycemic and drug-free control groups. Cerebral blood flow was 51% higher in
untreated hypoglycemic than in untreated normoglycemic rats (P < 0.01). Caffeine
had a small, statistically insignificant effect on CBF in normoglycemic rats, but
reduced the CBF response to hypoglycemia in a dose-dependent manner, i.e., 27%
increase with 10 mg/kg and complete elimination with 20 mg/kg. Chemical
determinations by HPLC in extracts of freeze-blown brains showed significant
increases in the levels of adenosine and its degradation products, inosine and
hypoxanthine, during hypoglycemia (P < 0.05). Intracisternal glibenclamide had
little effect on CBF in normoglycemia, but, like caffeine, produced dose
dependent reductions in the magnitude of the increases in CBF during
hypoglycemia, i.e., +66% with glibenclamide-free artificial CSF administration,
+25% with 1 mumol/L glibenclamide, and almost complete blockade (+5%) with 2
mumol/L glibenclamide. These results suggest that adenosine and KATP channels may
play a role in the increases in CBF during hypoglycemia.
PMID- 9397031
TI - Cerebral blood flow during hypoxemia and hemodilution in rabbits: different roles
for nitric oxide?
AB - Hypoxemia and anemia are associated with increased CBF, but the mechanisms that
link the changes in PaO2 or arterial O2 content (CaO2) with CBF are unclear.
These experiments were intended to examine the contribution of nitric oxide. CaO2
in pentobarbital-anesthetized rabbits was reduced to approximately 6.5 mL O2/dL
by hypoxemia (PaO2 approximately 24 to 26 mm Hg) or hemodilution with hetastarch
(hematocrit approximately 14% to 15%). Animals with normal CaO2 (approximately
17.5 to 18 mL O2/dL) served as controls. In part I, each animal was given 3, 10,
and 30 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) intravenously (total
43 mg/kg) to inhibit production of nitric oxide. Forebrain CBF was measured with
radioactive microspheres approximately 15 to 20 minutes after each dose. Baseline
CBF was greater in hypoxemic rabbits (111 +/- 31 mL x 100 g-1 x min-1, mean +/-
SD) than in hemodiluted (70 +/- 22 mL x 100 g-1 min-1) or control animals (39 +/-
12 mL x 100 g-1 min-1). L-NAME (which reduced brain tissue nitric oxide synthase
activity by approximately 65%) reduced CBF in hypoxemic animals to 80 +/- 23 mL x
100 g-1 x min-1 (P < 0.0001), but had no significant effect on CBF in either
anemic or control animals. In four additional rabbits, further hemodilution to a
CaO2 of approximately 3.5 mL O2/dL increased baseline CBF to 126 +/- 21 mL x 100
g-1 min-1, but again there was no effect of L-NAME. In part II, animals were
anesthetized as above, and a close cranial window was prepared. The cyclic GMP
(cGMP) content of the artificial CSF superfusate was measured under baseline
conditions, and then after the reduction of CaO2 to approximately 6.5 mL O2/dL by
either hypoxemia or hemodilution. Concentrations of cGMP did not change during
either control conditions or after hemodilution. However, cGMP increased
significantly with the induction of hypoxemia. The cGMP increase in hypoxemic
animals could be blocked with L-NAME. These results suggest that nitric oxide
plays some role in hypoxemic vasodilation, but not during hemodilution.
PMID- 9397032
TI - Laminar analysis of cerebral blood flow in cortex of rats by laser-Doppler
flowmetry: a pilot study.
AB - Laser-Doppler flowmetry (LDF) is a reliable method for estimation of relative
changes of CBF. The measurement depth depends on wavelength of the laser light
and the separation distance of transmitting and recording optical fibers. We
designed an LDF probe using two wavelengths of laser light (543 nm and 780 nm),
and three separation distances of optical fibers to measure CBF in four layers of
the cerebral cortex at the same time. In vitro comparison with electromagnetic
flow measurements showed linear relationship between LDF and blood flow velocity
at four depths within the range relevant to physiologic measurements. Using
artificial brain tissue slices we showed that the signal for each channel
decreased in a theoretically predictable fashion as a function of slice
thickness. Application of adenosine at various depths in neocortex of halothane
anesthetized rats showed a predominant CBF increase at the level of application.
Electrical stimulation at the surface of the cerebellar cortex demonstrated
superficial predominance of increased CBF as predicted from the distribution of
neuronal activity. In the cerebellum, hypercapnia increased CBF in a
heterogeneous fashion, the major increase being at apparent depths of
approximately 300 and 600 microns, whereas in the cerebral cortex, hypercapnia
induced a uniform increase. In contrast, the CBF response to cortical spreading
depression in the cerebral cortex was markedly heterogeneous. Thus, real-time
laminar analysis of CBF with spatial resolution of 200 to 300 microns may be
achieved by LDF. The real-time in depth resolution may give insight into the
functional organization of the cortical microcirculation and adaptive features of
CBF regulation in response to physiologic and pathophysiologic stimuli.
PMID- 9397033
TI - Vasodilator effects on canine basilar artery induced by intracisternal
interleukin-1 beta.
AB - The effect of interleukin-1 beta (IL-1 beta) on a cerebral artery was
investigated in anesthetized dogs. Intracisternal administration of IL-1 beta
(0.03 and 0.3 micrograms) dilated the canine basilar artery in a dose-dependent
manner, without affecting systemic blood pressure or heart rate. The increase in
diameter induced by 0.3 micrograms of IL-1 beta was 28.4% +/- 13.4% of control at
2 hours and was inhibited by 30 micrograms of the IL-1 beta receptor antagonist,
zinc protoporphyrin (4.5% +/- 13.5%, P < 0.05). Interleukin-1 beta did not affect
the concentration of nitric oxide metabolites in CSF. However, there was an
increase in the concentration of eicosanoids in CSF, and the elevation of 6-keto
PGF1 alpha paralleled the vasodilation. Pretreatment with 30 micrograms of the
selective inducible cyclooxygenase (COX-2) inhibitor NS-398 also inhibited the IL
1 beta-induced vasodilation significantly (5.9% +/- 9.4% at 2 hours, P < 0.01).
Western blot analysis revealed the expression of a 68-kD COX-2-like protein in
basilar artery extracts. These findings suggest that the IL-1 beta-induced
vasodilator effect is linked to the prostaglandin cascade, predominantly to
prostaglandin I2, by induction of COX-2, but not to the stimulation of nitric
oxide metabolism.
PMID- 9397034
TI - Primary prevention of skin cancer: where to now in reducing sunlight exposure?
PMID- 9397035
TI - Mammographic screening in Australia.
PMID- 9397036
TI - Surgery for severe emphysema.
PMID- 9397037
TI - "Single use only": obfuscation or the necessary attainment of zero risk?
PMID- 9397038
TI - Mammographic screening: results from the 1996 National Breast Health Survey.
AB - OBJECTIVE: To establish the extent of women's knowledge of mammographic
screening, particularly in relation to the national screening program,
BreastScreen Australia, and to estimate the proportion of women who are
participating in screening both within and outside BreastScreen Australia. DESIGN
AND SETTING: Validated prospective telephone survey of women aged 30-69 years
selected at random from across Australia. PARTICIPANTS: 2935 women with no
previous breast cancer diagnosis. RESULTS: The adjusted response rate was 64%.
Almost 90% of women had heard of the national program; only 1% correctly stated
that screening is for asymptomatic women. 60% correctly identified the current
recommended age of starting screening is about 50 years of age; 26% thought
screening should begin at about 40 years of age. Approximately 60% correctly
reported that the recommended screening interval is every two years; 27% thought
screening should be done annually. 55% reported ever having had a mammogram, and
37% reported having had at least one screening mammogram. Among women in the
target age group (50-69 years) about 70% reported ever having had a screening
mammogram, and about 50% reported having had a screening mammogram within the
national program in the last two years. Among women aged 40-49 years, 29%
reported ever having had a screening mammogram, and 22% reported having been
screened in the last two years. CONCLUSIONS: Awareness of the national screening
program is high, but some women do not know the purpose of screening, the target
age group and the recommended screening interval. Compliance with screening is
good among women in the target age group; many women in their 40s are also
participating in screening.
PMID- 9397039
TI - Self-reported morbidity of Barmah Forest virus infection on the north coast of
New South Wales.
AB - OBJECTIVE: To describe the clinical features and disability associated with
Barmah Forest virus (BFV) infection. DESIGN: Retrospective postal survey.
SETTING: North Coast Public Health Unit, Lismore, New South Wales, January to
October 1995. SUBJECTS: All 84 subjects notified by mandatory laboratory
reporting as positive for BFV IgM by enzyme-linked immunosorbent assay. OUTCOME
MEASURES: Demographic information, self-reported symptoms, disability and
treatment. RESULTS: Response rate was 77%. Peak incidence was in the 30-50 years
age group, with almost identical numbers of men and women affected. The most
common symptoms were lethargy (89%), joint pain (82%) and rash (68%). These were
also generally the first symptoms to appear. Thirty of 54 respondents (56%)
reported time off work and 27 of 53 (51%) reported illness lasting more than six
months. Those who had a rash were significantly more likely to have recovered by
the time of the survey than those who had no rash (odds ratio, 10.3; 95%
confidence interval, 1.8-76.6). No treatment led to more than slight relief of
symptoms. CONCLUSION: Symptoms of BFV infection appear similar to those of the
better-known Ross River virus infection, and clinicians should consider both in
patients with symptoms of arboviral disease. The wide distribution and long
duration of illness make BFV a potentially significant cause of morbidity in
Australia. A possible association between the presence of a rash and improved
prognosis needs further investigation.
PMID- 9397041
TI - Eye injuries caused by elasticated "octopus" straps.
AB - "Octopus" elasticated straps are a common cause of severe accidental eye
injuries, which we believe are largely preventable. In a retrospective study
(January 1990 to August 1996), we identified 42 patients with such injuries
severe enough to warrant admission to hospital. The injuries included hyphaema,
vitreous haemorrhage, retinal detachment, and choroid and globe rupture, with 28%
(12/42) of the injuries resulting in permanent visual loss. We believe octopus
straps should not be available for sale in their current form.
PMID- 9397040
TI - Lung volume reduction surgery for emphysema.
AB - OBJECTIVE: To report the results of lung volume reduction surgery (LVRS) for
severe emphysema in Australia. SETTING: A tertiary teaching hospital. DESIGN: A
prospective study of a consecutive case series. PARTICIPANTS: 20 patients (mean
age, 56 years) with severe emphysema--mean forced expiratory volume in one second
(FEV1), 0.72 L (28% of predicted) and severe gas trapping (mean residual volume,
286% of predicted). INTERVENTION: Bilateral apical LVRS was performed via a
median sternotomy with a linear stapler; bovine pericardial strips were used to
reinforce the staple line. RESULTS: There was a 95% survival, and a mean (range)
inpatient stay of 17 (8-45) days. No complications occurred in nine patients; a
further six patients had only minor complications. Five patients had major
complications (sputum retention requiring reintubation, persistent air leak
requiring reoperation, duodenal perforation, and epidural haemorrhage); one
patient died from multiorgan failure at 28 days. Intercostal drainage was left in
situ for a mean of eight days. The results of FEV1, Medical Research Council
(MRC) Dyspnoea Score and six-minute walk test improved in more than 90% of
patients. FEV1 improved an average of 0.35 L (54% over baseline) (P < 0.001).
Mean MRC Dyspnoea Score decreased from 3.4 to 2.1 (P < 0.001). Mean distance for
the six-minute walk test increased from 306 to 431 metres (P < 0.001).
CONCLUSION: Our experience confirms that LVRS produces worthwhile early outcomes
for a subgroup of patients with severe emphysema. The clinical, economic and
ethical questions raised by this new therapy will need to be assessed.
PMID- 9397042
TI - "Single use only" labelling of medical devices: always essential or sometimes
spurious?
PMID- 9397043
TI - Specific allergen immunotherapy for asthma. A position paper of the Thoracic
Society of Australia and New Zealand and the Australasian Society of Clinical
Immunology and Allergy.
PMID- 9397044
TI - MJA practice essentials. 6. Stress management and counselling in primary care.
PMID- 9397045
TI - Malnutrition and microcephaly in Australian aboriginal children.
PMID- 9397046
TI - The prevalence of hookworm infection, iron deficiency and anaemia in an
aboriginal community in north-west Australia.
PMID- 9397047
TI - Politicised Aborigine health research.
PMID- 9397048
TI - Incompletely excised basal cell carcinomas of the skin.
PMID- 9397049
TI - Incompletely excised basal cell carcinomas of the skin.
PMID- 9397050
TI - "Best practice" in surgical management of breast cancer.
PMID- 9397051
TI - Vaccination--is the evidence good enough to say there is no risk?
PMID- 9397052
TI - "On-the-spot" vaccination.
PMID- 9397053
TI - Rapid identification of Plasmodium falciparum malaria.
PMID- 9397054
TI - Kava and alcohol.
PMID- 9397055
TI - Crohn's and colitis: science progresses steadily.
PMID- 9397056
TI - Automation in cervical cytology: whose cost and whose benefit?
PMID- 9397057
TI - How can we best achieve optimal transfusion practice?
PMID- 9397058
TI - Huntington's disease: a challenge for out times.
PMID- 9397059
TI - Evaluation of the ThinPrep Pap test as an adjunct to the conventional Pap smear.
AB - OBJECTIVE: To evaluate the ThinPrep Pap test as an adjunct to the conventional
Pap smear. DESIGN AND SETTING: Prospectively collected cervical samples were
split for independent screening at a large specialised private gynaecological
pathology practice in Sydney. MAIN OUTCOME MEASURES: Detection of additional
significant abnormalities (cervical intraepithelial neoplasia 1, or more severe);
changed management recommendations from "repeat smear in 12 months" or "...six
months" to "colposcopy", a reduction in unsatisfactory reports. RESULTS: 35,560
paired (split-sample) conventional and ThinPrep slides were prepared. Significant
abnormalities were detected in 724 conventional smears (2%). Additional
significant abnormalities were found in 85 ThinPrep slides whose corresponding
conventional smear was negative or unsatisfactory even after review, representing
a 12% increase in the detection of significant abnormalities. As a result of the
addition of ThinPrep, management recommendations were changed from "repeat smear
in 12 months" or "...six months" to "colposcopy" for 89 of 1669 women whose
conventional Pap smears showed minor non-specific changes or papillomavirus.
There were 1258 conventional smears (3.5%) that were unsatisfactory compared with
235 ThinPrep slides (0.7%); for only 74 samples (0.2%) were both slides
unsatisfactory. CONCLUSIONS: The addition of the ThinPrep Pap test improves
detection and clinical management of cervical abnormalities, and reduces the
number of unsatisfactory samples which would otherwise require repeat tests.
PMID- 9397060
TI - Prevalence of hepatitis C infection in pregnant women in South Australia.
AB - OBJECTIVES: To estimate the prevalence of hepatitis C virus (HCV) seropositivity
and known risk factors for HCV infection in a group of pregnant women. DESIGN:
Cross-sectional survey. SETTING: Lyell McEwin Health Service, Elizabeth, South
Australia (a general public hospital with an annual average of about 2000
deliveries). SUBJECTS: 1537 consecutive women who delivered at the Lyell McEwin
Health Service from February 1995 to December 1995. OUTCOME MEASURES: Presence of
HCV antibodies; and associations between HCV-antibody status and known risk
factors. RESULTS: 17 women (1.1%) were HCV-seropositive. Risk factors
significantly more prevalent among HCV-seropositive patients were: a history of
injecting drug use, a past or present sexual partner who had injected drugs,
having a tattoo and having been incarcerated. The proportions who had received a
blood transfusion, had acquired a sexually transmitted disease or were positive
for hepatitis B virus surface antigen were not significantly different between
seropositive and seronegative women. Multivariate analysis showed that only
injecting drug use remained a strong independent predictor of HCV-seropositivity
(odds ratio [OR], 50.1; P < 0.001), while having a tattoo approached significance
(OR, 3.5; P = 0.07). CONCLUSION: As only 1.1% of this sample of women were HCV
seropositive, screening of all pregnant women does not seem warranted. Testing on
the basis of a history of risk factors, such as injecting drug use and having a
tattoo, would detect undiagnosed HCV infections more efficiently.
PMID- 9397061
TI - Reduction of inappropriate use of blood products by prospective monitoring of
transfusion request forms.
AB - OBJECTIVE: To determine the effect of prospective monitoring on appropriateness
of transfusions of red cells, platelets and fresh frozen plasma (FFP). DESIGN:
Prospective interventional study. SETTING: Royal Melbourne Hospital (a tertiary
teaching hospital), Melbourne, Victoria, March-May 1996. INTERVENTION: The blood
product request form was modified to incorporate indications for transfusion and
clinical and laboratory data. Requests were monitored by blood bank laboratory
staff for conformation with hospital transfusion guidelines; non-conforming
requests were discussed with the requesting medical practitioner by the
Haematology Registrar before blood products were issued. In case of disagreement,
blood products were always issued. SUBJECTS: 200 consecutive transfusion episodes
for each product (red cells, platelets and FFP). OUTCOME MEASURES:
Appropriateness of transfusion, assessed by a Consultant Haematologist according
to hospital guidelines. Rates of inappropriate transfusion episodes after
intervention were compared with rates in a previous study. RESULTS: After
intervention, rates of inappropriate transfusion episodes fell significantly (red
cells, 16% to 3% [P = 0.004]; platelets, 13% to 2.5% [P = 0.02]; and FFP, 31% to
15% [P = 0.02]). Almost all inappropriate FFP transfusion episodes post
intervention were due to failure to demonstrate prolongation of prothrombin or
activated partial thromboplastin times more than 1.5 times the control value.
CONCLUSION: Prospective monitoring of request forms can reduce rates of
inappropriate transfusions. High rates of inappropriate FFP transfusions possibly
reflect uncertainty about appropriate laboratory criteria for FFP transfusion.
While results of large prospective randomised controlled clinical trials of FFP
transfusions are awaited, currently laboratory criteria can be retained, but
should be applied with flexibility.
PMID- 9397062
TI - Leptospirosis presenting as a haemorrhagic fever in a traveller from Africa.
AB - Leptospirosis is usually a mild illness, although the severity of clinical
manifestations may vary between the serovars of leptospires. In May 1993, a 48
year-old man from Ghana presented with severe icteric leptospirosis, initially
managed as viral haemorrhagic fever. The causative serovar, bataviae, had not
been previously diagnosed in human infection in Australia.
PMID- 9397063
TI - The Australian health care system: John Hunter's long shadow.
PMID- 9397064
TI - New drugs, old drugs. Calcium antagonists.
PMID- 9397065
TI - Benzodiazepines in anxiety disorders: managing therapeutics and dependence.
PMID- 9397066
TI - Occupational lung disease.
PMID- 9397067
TI - Post-traumatic stress disorder: what's in a name?
PMID- 9397068
TI - Dantrolene and "ecstasy".
PMID- 9397069
TI - Increasing the accuracy of the Pap test.
PMID- 9397070
TI - Preventing brain damage in boxers.
PMID- 9397071
TI - Confidentiality and the AMA's new code of ethics.
PMID- 9397072
TI - An inexpensive "orthosis" for plantar fasciitis.
PMID- 9397073
TI - Dwindling supplies of anti-D.
PMID- 9397074
TI - Sexually transmitted diseases and contact tracing.
PMID- 9397075
TI - Clinical practice guidelines: to what end?
PMID- 9397076
TI - Parents' views on reduced length of stay for their asthmatic children.
PMID- 9397077
TI - Reduction in length of hospital stay for acute childhood asthma associated with
the introduction of casemix funding.
PMID- 9397078
TI - Medical treatment of caustic burns.
PMID- 9397079
TI - Peritoneal catheter fracture caused by a seatbelt.
PMID- 9397080
TI - Efficacy and tolerability of ketoprofen 200 mg controlled-release cps vs
indomethacin 50 mg cps in patients with symptomatic hip osteoarthritis. A
multicentre study.
AB - BACKGROUND: An open-label, randomised, multicentre study was carried out to
compare the efficacy and tolerability of indomethacin capsules and ketoprofen
controlled-release capsules in the symptomatic treatment of coxarthrosis.
MATERIALS AND METHODS: 113 out-patients were enrolled: 57 were assigned to
receive indomethacin 50 mg twice daily and 56 ketoprofen 200 mg once daily for 4
weeks. RESULTS: Indomethacin and ketoprofen proved equally effective in relieving
osteoarticular pain and stiffness and in improving the quality of life of
patients. There was essentially no difference as to gastrointestinal adverse
events which occurred in 25% of patients on indomethacin and in 27% of those on
ketoprofen. Indomethacin caused more non-gastrointestinal untoward effects,
especially CNS effects (headache and dizziness: 11%) which were not observed with
ketoprofen. Indomethacin was discontinued because of adverse events in a larger
proportion of patients (20%) than ketoprofen (11%).
PMID- 9397081
TI - Occult coeliac disease and iron-deficiency anaemia.
AB - Coeliac disease can cause selective malabsorption and, therefore, a poorly
specific clinical pattern. In the two cases of iron-deficiency anaemia described,
targeted diagnostic procedures enabled to find an effective therapy. The
identification of patients affected by coeliac disease in a subclinical phase may
reduce the risk of autoimmune and lymphoproliferative diseases.
PMID- 9397082
TI - Maori/non-Maori patterns of contact, expressed morbidity and resource use in
general practice: data from the Waikato Medical Care Survey 1991-2.
AB - AIMS: To compare patterns of contact, expressed morbidity and resource use in
primary care for a representative sample of patients of Maori and non-Maori
background. METHODS: The data are drawn from a survey of general practice in the
Waikato region representing a one per cent sample of all week day encounters. The
data were recorded by participating general practitioners in four collection
weeks spaced over the period of a year. In total, 12,833 patient encounter forms
were completed. RESULTS: Annual rates of general practitioner contact for Maori
are slightly lower than those for patients of non-Maori background. The case-mix
pattern of general practitioner contact is very similar between the two groups.
There is a limited correspondence between ethnic patterns of general practitioner
usage and health need (as measured by mortality levels and rates of public
hospital discharge). CONCLUSIONS: The near equivalence in ethnic rates of general
practitioner contact revealed in this study contrasts strikingly both with the
level of hospitalisation for Maori, which is nearly double that of non-Maori, and
with the difference in mortality rates (30% higher for Maori). Attention devoted
to improving access to general practitioner services among Maori may be necessary
if important areas of ill health and hospital resource use are to be addressed
effectively.
PMID- 9397083
TI - The use of behavioral methods of contraception in women seeking abortion.
AB - AIMS: To determine the extent to which behavioural methods, used alone or with
other methods of contraception, contribute to contraceptive failure in women
seeking termination of pregnancy. METHOD: A clinical audit was conducted of the
use of behavioural methods of contraception, in 1342 women attending the Parkview
Clinic for termination of pregnancy, over a four year period 1992-6. The
information was obtained through standard interview and patient records. RESULTS:
The women seen were representative of New Zealand women undergoing termination of
pregnancy. Approximately one third of women (34.9%) used one or more behavioural
methods in the month prior to conception. The two most common methods were
periodic abstinence and coitus interruptus, both used by approximately 17%. Other
methods used less frequently and not solely for contraceptive purposes, were
cleansing of the vagina and breastfeeding. Pacific Island and Asian women were
more likely to use behavioural methods than European and Maori women. Many women
(45.6%) using behavioural methods also used other methods of contraception,
especially the condom. CONCLUSIONS: Behavioural methods were found more commonly
than previously reported. Greater understanding of the use of behavioural methods
will assist in the implementation of preventive programmes to reduce the number
of terminations.
PMID- 9397084
TI - Attitudes to the use of dummies in New Zealand; a qualitative study.
AB - AIMS: To explore experiences with, and attitudes to, the use of dummies
(pacifiers). METHODS: Seven focus group discussions were held with groups of
mothers and of health professionals. RESULTS: Most mothers and health care
workers had a generally negative view of dummy use. This related particularly to
dislike of toddlers with them and practical issues such as getting lost or dirty.
All would allow their use in a very unsettled baby. No mothers had personally
experienced problems with breastfeeding due to the use of a dummy, but concern
about this possibility was expressed by some health care workers. Recommendations
varied about the length of time that dummies need to be avoided. CONCLUSIONS:
Mothers in New Zealand use dummies selectively for their infants and were
concerned with issues of weaning the baby from the dummy, keeping it clean and
not losing it. In analysing the relationships between dummy use and breastfeeding
it is important to take into consideration the context of dummy use.
PMID- 9397085
TI - Consensus viewpoint on the treatment of postmenopausal osteoporosis. The Ad Hoc
Group on Osteoporosis.
AB - Treatment for postmenopausal osteoporosis should be offered to those with a
history of fractures following minimal trauma or with a bone density
significantly below the range seen in young normal adults. Underlying diseases
contributing to the reduced bone density should be sought and treated
appropriately. Lifestyle issues such as smoking, alcohol intake and exercise
should be addressed. A calcium intake of at least 1.5 g/day should be achieved.
Hormone replacement therapy is the first line pharmacological intervention. The
bisphosphonates provide a satisfactory alternative for those unable or unwilling
to take hormone replacement therapy.
PMID- 9397086
TI - Changing to injectable polio vaccine.
PMID- 9397087
TI - Long acting bronchodilators in chronic obstructive pulmonary disease.
PMID- 9397088
TI - Fluvastatin.
PMID- 9397089
TI - Fluvastatin.
PMID- 9397090
TI - Medical evidence for aegrotats in School Certificate and Bursary examinations.
PMID- 9397091
TI - Cyclospora cayetanensis diarrhoea in a traveller.
PMID- 9397092
TI - Pregnancy outcomes in women with gestational diabetes compared with the general
obstetric population.
AB - OBJECTIVE: To compare pregnancy outcome in a homogeneous group of women with
glucose intolerance with that of women without this disorder. METHODS: This was a
retrospective cohort study of all women with singleton cephalic-presenting
pregnancies delivered at University of Texas Southwestern Medical Center during
the period January 1, 1991, through December 31, 1995. During this period, women
were screened selectively for glucose intolerance and National Diabetes Data
Group thresholds were used to diagnose gestational diabetes. Women with class A1
gestational diabetes were compared with nondiabetic women within the cohort.
Effects of confounding variables were analyzed using multiple logistic regression
and a matched-control comparison. Controls were matched according to ethnicity,
maternal age, maternal weight, and parity. RESULTS: A total of 61,209 nondiabetic
women with singleton cephalic pregnancies were delivered during the study period,
and 874 were diagnosed with class A1 gestational diabetes. Women with class A1
gestational diabetes were significantly older, heavier, of greater parity, and
more often of Hispanic ethnicity. Hypertension (17 versus 12%), cesarean delivery
(30 versus 17%), and shoulder dystocia (3 versus 1%) were significantly increased
(all P < .001) in these women compared with the general obstetric population.
Infants born to women with class A1 gestational diabetes were significantly
larger (mean birth weight 3581 +/- 616 versus 3290 +/- 546 g, P < .001), and this
accounted for the increased incidence of dystocia. The attributable risk for
large for gestational age (LGA) infants due to class A1 gestational diabetes was
12%. CONCLUSION: The main consequence of class A1 gestational diabetes is
excessive fetal size leading to increased risk of difficult labor and delivery.
We estimate that approximately one of eight women with class A1 gestational
diabetes mellitus delivers an LGA infant attributable to glucose intolerance.
PMID- 9397093
TI - Circulating cell adhesion molecule concentrations in diabetic women during
pregnancy.
AB - OBJECTIVE: To determine whether circulating concentrations of defined cell
adhesion molecules, which are thought to reflect endothelial expression, are
increased in insulin-dependent diabetic women during pregnancy. METHODS: Pregnant
diabetic women demonstrating good glycemic control and without major
complications before pregnancy were studied at 8-12 (n = 15), 18 (n = 15), 28 (n
= 16), 32 (n = 16), and 36 (n = 16) weeks' gestation. A subgroup of ten diabetic
women was sampled longitudinally through all five gestational ages. The diabetic
women were compared with healthy nondiabetic women sampled cross sectionally at
12 (n = 20), 28 (n = 19), and 36 (n = 19) weeks' gestation. Nonpregnant diabetic
(n = 22) and nonpregnant nondiabetic women (n = 28) also were studied. Plasma
concentrations of the cell adhesion molecules E-selectin, intercellular adhesion
molecule-1 (ICAM-1), and vascular endothelial cell adhesion molecule-1 (VCAM-1)
were measured by enzyme-linked immunosorbent assay. RESULTS: Significantly higher
median (range) concentrations of E-selectin (63.0 [20.2-107.0] ng/mL) and ICAM-1
(281.5 [171.6-778.4] ng/mL) but not VCAM-1 (459.7 [301.0-909.7] ng/mL) were found
in nonpregnant diabetic women compared with nonpregnant nondiabetic women (43.5
[18.1-93.2], 243.6 [174.4-329.2], and 476.0 [253.8-929.4] ng/mL, respectively).
During pregnancy these significant differences between diabetic and control
groups were lost. The median (range) concentration of E-selectin (50.0 [21.2
96.3] ng/mL) was significantly lower in pregnant compared with nonpregnant
diabetic women. The plasma concentrations of E-selectin and ICAM-1 did not change
significantly with gestation in either diabetic or nondiabetic pregnant groups.
Vascular endothelial cell adhesion molecule-1 concentration changed significantly
with gestation in the diabetic pregnant group only. CONCLUSION: Circulating
concentrations of defined vascular cell adhesion molecules are not increased
abnormally in diabetic women with good glycemic control during otherwise
uncomplicated pregnancy.
PMID- 9397094
TI - Gestational diabetes mellitus in women receiving beta-adrenergics and
corticosteroids for threatened preterm delivery.
AB - OBJECTIVE: To determine whether the incidence of gestational diabetes mellitus
(GDM) is increased in patients receiving corticosteroids with or without beta
adrenergic agents for threatened preterm delivery. METHODS: We reviewed the
laboratory records of 3396 patients undergoing screening (1-hour glucose) and
diagnostic testing (3-hour glucose tolerance test [GTT]) for GDM over 2 years.
Patients with antepartum admissions during which they received corticosteroids
with or without beta-adrenergic agents for threatened preterm delivery were
compared with a control group during the same period. Differences between the
study and control groups were analyzed using chi 2, Student t test, or Fisher
exact test where appropriate. P < .05 was considered significant. RESULTS: Fifty
patients in the study group were compared with 1985 control patients. The
remaining 1361 patients failed to meet inclusion criteria. The overall incidence
of diagnosed GDM was significantly greater in the corticosteroid-beta-adrenergic
agents study group, in which five (23.8%) of 21 patients screened had abnormal 3
hour GTT results, compared with 79 (4.0%) of 1985 controls (P = .001). One-hour
glucose screening test results were abnormal in 60% of the study group compared
with 25% of the controls (P < .001). CONCLUSION: Patients treated with beta
adrenergic agents and corticosteroids for threatened preterm delivery are at a
significantly increased risk for developing GDM. The high rate of abnormal
results in response to the 1-hour glucose screen suggests that this test is of
limited value in patients exposed to these medications.
PMID- 9397095
TI - Risk of preeclampsia in second-trimester triploid pregnancies.
AB - OBJECTIVE: To determine the magnitude of the risk and the predictive clinical
characteristics for development of preeclampsia when triploidy is diagnosed in
the second trimester. METHODS: A retrospective analysis of databases maintained
by the cytogenetics laboratories at the University of Iowa and University of
North Carolina was performed to identify all cases of triploidy. We examined the
karyotype, maternal serum screening (particularly the hCG level), ultrasound
results, and evidence of maternal hypertensive disease. RESULTS: Seventeen cases
of triploidy were identified between 1987 and 1996. Preeclampsia or hypertension
complicated six of these cases with onset between 15 and 22.5 weeks' gestation.
In these six cases, the serum hCG level was extremely high. Serum screening
results were available in seven cases in which preeclampsia did not develop, and
the hCG levels were under 0.09 multiples of the median in five of the seven
cases. In all six cases in which preeclampsia or hypertension developed, there
was sonographic evidence of placentomegaly. Sonographic findings in 16 of 17
cases revealed fetal growth restriction, oligohydramnios, fetal anomalies,
placentomegaly, or a combination of these. CONCLUSION: In our series of
pregnancies complicated by triploidy, the risk of developing preeclampsia or
hypertension in the second trimester was 35%. It appears that elevated serum hCG
levels and placentomegaly are associated with a higher risk of preeclampsia but
low hCG levels are not. This information is important in counseling patients who
are hesitant to terminate a pregnancy purely for a fetal abnormality, even if the
anomaly is lethal.
PMID- 9397096
TI - Elevated serum nicked and urinary beta-core fragment hCG in preeclamptic
pregnancies.
AB - OBJECTIVE: To determine whether different molecular forms of hCG in serum and
urine are elevated in preeclamptic pregnancies. METHODS: Forty-three pregnant
women were studied: 25 preeclamptic women and 18 normotensive women. Immediately
after blood and urine samples were collected, the protease inhibitors leupeptin
(0.35 mM) and phenanthroline (22 mM) were added. Various molecular forms of hCG
in serum (complete hCG, nonnicked hCG, complete free beta hCG) and in urine
(complete hCG, beta-core fragment hCG) were measured by matched immunoassays with
a common enzyme-labeled tracer antibody. The nicked hCG assay used a coating of
beta-subunit monoclonal antibody with the addition of scavenger antibody to
remove nonnicked hCG. Mann-Whitney U test and chi 2 test were used for
statistical analyses. RESULTS: Preeclamptic women had significantly higher median
(range) levels of serum complete and nicked hCG than did normotensive women (3620
[850-12,000] versus 2420 [310-4840] ng/mL, P = .024; and 102 [45-275] versus 71
[11-143] ng/mL, P = .010, respectively). Both median (range) urinary complete hCG
creatinine and beta-core fragment-creatinine ratios were significantly higher in
preeclamptic women than in normotensive women (37.6 [0.5-185] versus 11.3 [1.9
54], P = .013; and 11.8 [2-67] versus 5.3 [0.3-29], P = .009, respectively).
CONCLUSIONS: Various molecular forms of hCG in serum and urine were significantly
higher in preeclamptic than in normotensive pregnancies.
PMID- 9397097
TI - Random protein-creatinine ratio for the quantitation of proteinuria in pregnancy.
AB - OBJECTIVE: To compare random urine protein-creatinine ratios with 24-hour urine
protein excretion rates in patients hospitalized with hypertensive disorders in
pregnancy. METHODS: All hospitalized, hypertensive patients requiring 24-hour
urine protein excretion collections were eligible for the study. During the 24
hour urine collection a separate 2-mL aliquot was taken for a protein and
creatinine determination. RESULTS: Seventy-one samples were collected from
patients with the following diagnoses: gestational hypertension (n = 56),
preexisting hypertension and superimposed gestational hypertension (n = 11), and
syndrome of hemolysis, elevated liver enzymes and low platelets (n = 4). The
correlation coefficient between the random protein-creatinine ratio and the 24
hour urine protein excretion was 0.94. Calculated excretion rates with at least
300 mg protein in 24 hours had a sensitivity of 0.93, specificity of 0.90, and
positive and negative predictive values of 0.87 and 0.95, respectively. For those
samples with calculated excretion rates at least 5 g protein in 24 hours, the
sensitivity was 1.00, specificity was 0.99, and positive and negative predictive
values were 0.75 and 0.99, respectively. CONCLUSION: In nonambulatory
hypertensive pregnant patients, there is a strong correlation between random
voided protein-creatinine ratios and 24-hour urine protein excretions.
PMID- 9397098
TI - A comparison between two doses of intravaginal misoprostol and gemeprost for
induction of second-trimester abortion.
AB - OBJECTIVE: To compare the abortifacient efficacies of two intravaginally
administered misoprostol doses and gemeprost in termination of second-trimester
pregnancy. METHODS: Eighty-one women between 12 and 24 weeks' gestation
requesting abortion were randomized to receive intravaginally either 100
micrograms of misoprostol at 6-hour intervals (n = 27), 200 micrograms of
misoprostol at 12-hour intervals (n = 26), or 1.0 mg of gemeprost at 3-hour
intervals (n = 28). The regimen was continued until abortion, or for 36 hours,
with assessment of the rate of complete and incomplete abortions as well as side
effects within 48 hours from the start of the treatment. RESULTS: The final rates
of terminations were 74% in the 100-microgram misoprostol group, 92% in the 200
microgram misoprostol group, and 89% in the gemeprost group. Abortion was
complete in 37%, 61%, and 32% in each group, respectively (P = .03, when the 200
microgram misoprostol group was compared with the two other groups). The
induction-to-abortion interval was longer (P = .001) in the misoprostol groups
(mean 23.1 hours for the 100-microgram and 27.8 hours for the 200-microgram dose)
than in the gemeprost group (14.5 hours). There was less pain (P = .01), diarrhea
(P = .001), and vomiting (P = .01) in the misoprostol groups than in the
gemeprost group. The mean blood loss in the misoprostol groups was lower than in
the gemeprost group (P = .001). CONCLUSION: Intravaginal application of 200
micrograms of misoprostol at 12-hour intervals in induction of second-trimester
abortion is equally effective to a standard gemeprost regimen. Misoprostol causes
fewer side effects and is cheaper and more practical to use.
PMID- 9397099
TI - Opportunities for prevention of perinatal group B streptococcal disease: a
multistate surveillance analysis. The Neonatal Group B Streptococcal Disease
Study Group.
AB - OBJECTIVE: To evaluate the potential impact of ACOG and Centers for Disease
Control and Prevention (CDC) consensus strategies for the prevention of perinatal
group B streptococcal disease. METHODS: We evaluated cases of early-onset group B
streptococcal disease identified by active surveillance during 1995, in four
areas in North America with an aggregate 186,000 births per year. We reviewed the
hospital records of mothers and infants and any prenatal records available on
site. Cases were determined to be preventable based on whether group B
streptococcal screening could have been performed prenatally, sensitivity of
screening, presence of obstetric complications, and opportunity to administer
antibiotics. RESULTS: We reviewed records for 245 of 246 infants with early-onset
group B streptococcal disease in the surveillance areas. Most of the 53 case
mothers who delivered preterm and 192 who delivered full-term had had at least
one prenatal visit (83% and 99%, respectively). Few case-mothers had prenatal
group B streptococcal screening cultures, although compliance was high for other
prenatal screening tests. Fifty-four percent of case-mothers had a recognized
obstetric risk factor for group B streptococcal disease: labor or rupture of
membranes at less than 37 weeks, rupture of membranes for 18 hours on longer, or
temperature 38C or greater. The estimated preventable portion of early-onset
group B streptococcal cases was 78% for the screening-based approach (range 74%
to 82% by area), compared with 41% for the risk-based approach (range 39% to 53%
by area). CONCLUSION: Comprehensive implementation of either of the recommended
prevention strategies could potentially prevent a substantial proportion of early
onset group B streptococcal disease.
PMID- 9397101
TI - Extemporaneous preparation of misoprostol gel for cervical ripening: a randomized
trial.
AB - OBJECTIVE: To compare the safety and efficacy of intravaginal misoprostol gel
with that of tablets for ripening the cervix and inducing labor in women with
unfavorable cervices. METHODS: Four hundred sixty-seven gravidas were randomized
to receive misoprostol tablets (n = 234) or misoprostol gel (n = 233). The gel
was prepared in the antepartum unit immediately before use by dissolving the
tablet in 1 mL normal saline and mixing with 4 mL hydroxyethylcellulose gel. In
both groups, a 50-microgram dose was applied intravaginally every 8 hours for two
doses, then increased to 100-microgram for a total of six applications or 500
micrograms. RESULTS: The mean interval in hours from drug administration to start
induction or labor (13.8 versus 18.2) and delivery (22.4 versus 29.0) was
significantly less in the tablet group than in the gel group (P < .01 for both).
Oxytocin and epidural use and the mean number of misoprostol insertions (1.4
versus 1.9) were lower in the tablet group than in the gel group (P < .05 for
all). The incidences of tachysystole (13.7 versus 7.3%) and hyperstimulation
(15.8 versus 7.7%) were significantly higher in the tablet group than in the gel
group. Cesarean delivery rates and neonatal outcomes were similar between the
groups. CONCLUSION: Intravaginal misoprostol gel is associated with fewer uterine
contractile abnormalities than the tablet form of the drug but results in a
slower time to labor or delivery.
PMID- 9397100
TI - Vaginal birth after cesarean delivery: an admission scoring system.
AB - OBJECTIVE: To develop a scoring system to predict the likelihood of vaginal birth
in patients undergoing a trial of labor after previous cesarean delivery using
factors known at the time of hospital admission. METHODS: Trial of labor was
attempted in 5022 patients who were assigned randomly to score derivation and
score testing groups. Multivariate logistic regression modeling was used in the
score derivation group to develop a predictive scoring system for vaginal birth.
The scoring system was then applied to the testing group to evaluate its
predictive ability. RESULTS: Five variables significantly affected the mode of
birth and were incorporated into a weighted scoring system. Rates of successful
vaginal birth after cesarean ranged from 49% in patients scoring 0-2 to 95% in
patients scoring 8-10. Increasing score was associated linearly with increasing
probability of vaginal birth after cesarean. CONCLUSION: Increasing scores
correlate with increasing probability of vaginal birth after cesarean. The
admission vaginal birth after cesarean scoring system may be useful in counseling
patients regarding the option of vaginal birth or repeat cesarean delivery. This
information could be particularly valuable for the patient who opts for trial of
labor but has second thoughts about her mode of birth when labor begins.
PMID- 9397102
TI - The effect of pregnancy on cyclosporine levels in renal allograft patients.
AB - OBJECTIVE: To assess the effects of pregnancy on cyclosporine levels in six renal
allograft patients. METHODS: Maternal demographic, laboratory, clinical, and
perinatal outcome data were recorded in six pregnant women with previous renal
allografts receiving cyclosporine immunosuppression. The cyclosporine and serum
creatinine levels were measured before pregnancy, during each trimester, and
postpartum. RESULTS: The mean (standard deviation [SD]) maternal age was 29.1
(3.8) years. Parity ranged from 0 to 3. Mean serum creatinine levels tended to be
lower during pregnancy than before or after, as did the mean cyclosporine levels.
After adjusting for dose, five of six patients had declines in cyclosporine level
during pregnancy. The mean (SD) gestational age at delivery was 37.5 (2.8) weeks
with a mean (SD) birth weight of 2837 (538) g. CONCLUSION: Pregnancy in patients
with renal allografts can lead to a substantial decline in cyclosporine levels.
PMID- 9397103
TI - Maternal deaths due to homicide and other injuries in North Carolina: 1992-1994.
AB - OBJECTIVE: To determine the role of homicide and other injuries in maternal
deaths in North Carolina over the three-year period from 1992 through 1994.
METHODS: Maternal deaths were identified from death certificates that indicated a
maternal death and through an enhanced surveillance system that matches death
certificates with live-birth and fetal-death certificates. Deaths were classified
as direct, indirect, medically unrelated, or injury-related. Patterns of prenatal
care were ascertained from the matching live-birth or fetal-death certificates.
Maternal death rates for whites and nonwhites were calculated. RESULTS: The most
common cause of maternal death was injury, accounting for 62 of the 167 deaths
(37%). Homicide was the most common cause of injury-related death (35.5%). The
relative risk of maternal death for nonwhites compared with whites was 1.8 (95%
confidence interval [CI] 1.6, 2.1). Similarly, their relative risk for injury
related maternal death was 1.7 (95% CI 1.4, 2.2). CONCLUSION: It is essential to
include an analysis of injury-related deaths in maternal mortality reporting. As
the most common cause of maternal deaths, injury is not limited to densely
populated, metropolitan areas. Counseling regarding injury prevention, domestic
violence, and depression should be a part of both prenatal and postpartum care.
PMID- 9397104
TI - Internal and external anal sphincter anatomy as it relates to midline obstetric
lacerations.
AB - OBJECTIVE: To examine the anatomy of the internal and external anal sphincters in
the area of midline obstetric lacerations, to gain insight into sphincter damage
and repair. METHODS: The length, craniocaudal extent, and overlap of the internal
and external anal sphincters in the perineal body were measured in 17 cadavers.
Further anatomic observations were made in four sets of whole pelvis cross
sections taken in the sagittal, coronal, and transverse planes. During the repair
of 20 acute fourth-degree lacerations, observations were made to determine the
internal sphincter visibility following birth. RESULTS: The external and internal
and sphincters overlap by 17.0 mm (standard deviation [SD] 6.9), with the
internal sphincter lying between the external sphincter and the anal canal. The
internal sphincter extends an additional 12.2 mm (SD 5.9) cranial to the proximal
extent of the external sphincter, whereas the caudal margin of the internal
sphincter lies 3.7 mm (SD 7.2) cranial to the distal margin of the external
sphincter. In pregnant women who sustained a fourth-degree laceration, we found
that the internal sphincter can be identified as a rubbery white layer adjacent
to the anal submucosa lying between the external sphincter and the anal canal.
CONCLUSION: The internal anal sphincter lies between the anal mucosa and the
external anal sphincter and extends more than a centimeter above the cranial
margin of the external sphincter, a region where it is disrupted when a fourth
degree obstetric laceration has occurred.
PMID- 9397105
TI - Paracrine and intracellular signaling mechanisms of calcium waves in cultured
human uterine myocytes.
AB - OBJECTIVE: To establish mechanisms of intercellular communication in human
myometrium other than action potential propagation. METHODS: Monolayer cultured
human myometrium was used as a model system. The calcium-sensitive fluorescent
dye, calcium green-1, was used as a probe for the concentration of intracellular
free calcium. Intercellular calcium waves were initiated by mechanical
stimulation and observed with video spectrofluorimetry. This technique allowed
initiation of calcium waves from a known location at a known time while
simultaneously controlling the flow rate of the bathing solution across the
surface of the cells. Intercellular calcium waves were observed at bath flow
rates between 0 and 5.1 mL/minute through a 0.4 mL chamber. Experiments were
performed using low calcium, high potassium bathing solutions to eliminate the
possibility of action potential signaling. RESULTS: In still bathing solution,
calcium waves radiated symmetrically from the site of initiation. With the
bathing solution flowing, two mechanisms of intercellular calcium wave
propagation were observed-one dependent on and one independent of the direction
of bath flow. The calcium waves that were independent of bath flow used an
intracellular mechanism for intercellular communication, were only observed
within 100 microns of the site of wave initiation, and demonstrated mean (+/-
standard deviation [SD]) wave speeds of 14.1 +/- 2.6 microns/second. The waves
dependent on bath flow used an extracellular signaling mechanism, were observed
at distances much greater than 100 microns, and exhibited downstream biasing.
Mean (+/- SD) wave speeds of flow-dependent calcium waves were faster under flow
conditions than still bath conditions (36.0 +/- 4.7 versus 6.2 +/- 1.3
microns/second; P < .001). By exposing the cells to flurbiprofen, a water soluble
prostaglandin synthetase inhibitor, both types of calcium waves were inhibited.
CONCLUSION: Human myocytes demonstrate paracrine and intracellular signaling
mechanisms for intercellular communication that are distinctly different from
action potential propagation.
PMID- 9397106
TI - Amniotic fluid glycine-valine ratio and neonatal morbidity in fetal growth
restriction.
AB - OBJECTIVE: To test the hypothesis that an elevated amniotic fluid glycine-valine
ratio predicts neonatal morbidity in growth-restricted newborns. METHODS:
Amniotic fluid (AF) was collected from 122 third-trimester pregnancies (range 31
39 weeks), 49 of which were complicated by fetal growth restriction. Amino acid
analysis was performed by high-pressure liquid chromatography. Glycine-valine
ratios were compared between normal and growth-restricted fetuses. Neonatal
morbidity within the group of growth-restricted fetuses was characterized by
evaluation of neonatal hypoglycemia, arterial cord blood gas analysis, and birth
weight percentile. We also examined the correlation of AF glycine-valine ratio to
the umbilical artery resistance index. The median interval between AF sampling
and delivery was 1 day (range 0-8 days). Analyses were performed by Student t
test, chi 2 with Yates correction, or simple correlation when appropriate. P <
.05 was considered significant. RESULTS: Growth-restricted fetuses have a
significantly elevated AF glycine-valine ratio compared with control subjects
(3.31 +/- 1.06 versus 2.61 +/- 0.77, respectively, P < .001). There was no
association of the glycine-valine ratio with gestational age for either group. An
elevated glycine-valine ratio was not associated with neonatal hypoglycemia
within the growth-restricted group (hypoglycemia: [n = 16] 3.19 +/- 1.07; no
hypoglycemia: (n = 30) 3.44 +/- 1.09). There were no significant correlations of
glycine-valine ratio with arterial cord blood pH (r = -0.10), oxygen pressure (r
= 0.04), or base deficit (r = 0.12). There were no significant correlations of
glycine-valine ratio and birth weight percentile (r = -.24) or umbilical artery
resistance index (r = -.14). CONCLUSION: Amniotic fluid glycine-valine ratio is
elevated in growth-restricted fetuses compared with control fetuses. However, the
level of glycine-valine elevation is not associated with neonatal morbidity
related to hypoglycemia, arterial cord blood gas abnormalities, or birth weight
percentile.
PMID- 9397107
TI - Significance of a false-positive trisomy 18 multiple-marker screening test.
AB - OBJECTIVE: To determine if a false-positive trisomy 18 multiple-marker screening
test (all three analytes low: maternal serum alpha-fetoprotein [AFP] at most 0.75
multiples of the median [MoM], unconjugated estriol at most 0.60 MoM, and hCG at
most 0.55 MoM) indicates increased risk for obstetric complications or is related
to maternal weight. METHODS: We accessed our genetic database to obtain multiple
marker screening test results, fetal karyotypes, and pregnancy outcomes from all
patients with a normal multiple-marker screening test (n = 3900) and from all
patients with a positive trisomy 18 screening test (n = 103) seen in the prenatal
diagnosis clinic from 1992 to 1996. During this period, only maternal serum AFP
was adjusted for maternal weight. RESULTS: A positive trisomy 18 screen
identified five of 12 trisomy 18 fetuses. Women with a false-positive trisomy 18
screen were heavier (175.6 +/- 43.8 lb versus 159.9 +/- 37.9 lb, P < .001) and
younger (29.7 +/- 6.5 years versus 32.3 +/- 6.5 years, P < .001) than women with
a normal multiple-marker screening test, but were not at increased risk for
pregnancy complications. Weight-adjusting all three analytes reduced the false
positive trisomy 18 screen rate by 42% (from 1.9% to 1.1%) but did not change the
trisomy 18 detection rate. CONCLUSION: A false-positive trisomy 18 screening test
does not indicate increased risk to develop pregnancy complications and may be
related to inadequate correction for increased maternal weight.
PMID- 9397108
TI - Fetal nuchal translucency thickness at 10-14 weeks' gestation and congenital
diaphragmatic hernia.
AB - OBJECTIVE: To examine the possible association between increased fetal nuchal
translucency thickness at 10-14 weeks and congenital diaphragmatic hernia.
METHODS: This was a multicenter ultrasound screening study for chromosomal
defects in singleton pregnancies by a combination of maternal age and fetal
nuchal translucency at 10-14 weeks' gestation. The prevalence of diaphragmatic
hernia diagnosed prenatally or postnatally was calculated in the chromosomally
normal group and in those pregnancies resulting in live births with no dysmorphic
features suggestive of a chromosomal abnormality. We calculated the sensitivity
of nuchal translucency above the 95th centile of the normal range in the
detection of diaphragmatic hernia and the possible prognostic value of increased
nuchal translucency in the prediction of outcome. RESULTS: There were 78,639
pregnancies presumed to be normal chromosomally, including 19 with diaphragmatic
hernia. In four cases, the parents opted for termination of the pregnancy. The
other 15 pregnancies resulted in live births; nine infants survived after
successful surgical repair of the hernia, but six neonates died because of
pulmonary hypoplasia. At the 10- to 14-week scan, the fetal nuchal translucency
was above the 95th centile for crown-rump length in seven (37%) cases of
diaphragmatic hernia. The translucency was increased in five of the six cases
that resulted in neonatal death, compared with two of the nine survivors (Z =
2.32, P < .05). CONCLUSION: The prevalence of diaphragmatic hernia in
chromosomally normal fetuses is about one in 4000, and nearly 40% of affected
fetuses have increased nuchal translucency at 10-14 weeks' gestation. Increased
nuchal translucency may be a marker of intrathoracic compression-related
pulmonary hypoplasia.
PMID- 9397109
TI - Cerebral and umbilical vascular resistance response to vibroacoustic stimulation
in growth-restricted fetuses.
AB - OBJECTIVE: To test the hypothesis that after vibroacoustic stimulation the ratio
between cerebral vascular and umbilical vascular resistance in the growth
restricted fetus is different from that in the normal fetus. METHODS: The
pulsatility index (PI) of the middle cerebral artery and that of the umbilical
artery (UA) were measured by pulsed Doppler velocimetry in 30 normal and 14
growth-restricted fetuses before and after vibroacoustic stimulation. The ratios
of cerebral PI to UA PI and the changes in PI after vibroacoustic stimulation
were calculated. Comparisons were made using the Wilcoxon rank-sum test or signed
rank test. The statistical power of the study was 80%. RESULTS: Mean (+/-
standard deviation) cerebral PI values before vibroacoustic stimulation (1.50 +/-
0.29) in normals and 1.29 +/- 0.26 in the fetal growth restriction [FGR] group)
and UA PI values (1.00 +/- 0.18 in normals and 1.15 +/- 0.24 in the FGR group)
were significantly different between groups (P < .04) and significantly decreased
after vibroacoustic stimulation (P < .05). Although the cerebral to UA PI ratios
(1.50 +/- 0.38 in normals and 1.13 +/- 0.33 in the FGR group) were significantly
different between groups (P < .008), the values remained the same after
vibroacoustic stimulation (P = .39 and .80, respectively). In all fetuses the
fetal heart rate accelerated after vibroacoustic stimulation. CONCLUSION:
Cerebral vascular resistance was lower and umbilical vascular resistance higher
in the growth-restricted fetuses than in normals. The vascular resistance
response after vibroacoustic stimulation in the growth-restricted fetus was not
significantly different from the response of the normal fetus, suggesting
preservation of regulation of resistance.
PMID- 9397110
TI - Middle cerebral artery velocimetry: different clinical relevance depending on
umbilical velocimetry.
AB - OBJECTIVE: To evaluate the role of cerebral velocimetry as a predictor of
perinatal outcome in high-risk pregnancies. METHODS: Middle cerebral artery
pulsatility index was measured in 576 high-risk pregnancies undergoing umbilical
velocimetry. The results of both tests were evaluated with respect to the birth
of small for gestational age (SGA) infants and adverse perinatal outcome, defined
as perinatal death, cesarean delivery for fetal distress, or low Apgar score.
RESULTS: Once umbilical velocimetry was taken into account, cerebral velocimetry
did not improve the prediction of fetal growth restriction or adverse perinatal
outcome. Neither test was able to predict adverse perinatal outcome in normally
grown fetuses. As for SGA fetuses with adverse perinatal outcome, the
simultaneous assessment of both umbilical and cerebral velocimetry did not
improve diagnostic accuracy (kappa index 0.37 versus 0.41 for umbilical
velocimetry only). However, within the group of high-risk pregnancies with
abnormal umbilical velocimetry, the risk of being SGA and having an adverse
perinatal outcome was doubled (relative risk 2.1, 95% confidence interval 1.1,
4.3) if cerebral velocimetry also was abnormal. CONCLUSION: The routine use of
cerebral velocimetry in high-risk pregnancies adds little information beyond that
obtained from umbilical velocimetry; however, it is useful in predicting SGA
infants with adverse perinatal outcome when umbilical velocimetry is abnormal.
PMID- 9397111
TI - A prospective evaluation of fetal pericardial fluid in 506 second-trimester low
risk pregnancies.
AB - OBJECTIVE: To measure fetal pericardial fluid in low-risk second-trimester
pregnancies and to evaluate outcome for those with measurements greater than 2
mm. METHODS: Five hundred and six women were referred for sonography between 16
and 25 weeks' gestation for common obstetric indications (dating, fetal survey,
and placental location) unrelated to an increased risk of anomalies. All cases
were evaluated with two-dimensional and M-mode real-time ultrasonography with the
use of a mechanical sector transducer. The maximum distance of the fetal
hypoechoic cardiac rim was recorded. We reviewed maternal and infant charts for
those with measurements greater than 2 mm. RESULTS: Median (range) maternal age
was 25 (15-42) years. Median gravidity and parity were two (1-14) and one (0-11),
respectively. Median estimated gestational age was 20.4 (16.3-24.9) weeks. Fetal
pericardial fluid was seen in 360 of 506 (71%) fetuses. Of these 360 fetuses, the
mean distance (+/- 2 standard deviation) of the fetal hypoechoic cardiac rim was
1.20 mm +/- 0.91 mm (95% confidence interval 1.15, 1.25). Among the 506 cases,
the maximum measurement was 3 mm. Ten of the 506 (2%) cases had measurements
greater than 2 mm. None of these ten fetuses had a cardiac structural abnormality
or arrhythmia, and perinatal outcome was unremarkable. CONCLUSION: During second
trimester fetal ultrasonographic examination, visualization of pericardial fluid
up to 2 mm in the fetus with current high-resolution technology is common and
should not be regarded as pathologic.
PMID- 9397112
TI - Anti-M isoimmunization: management and outcome at the Ohio State University from
1969 to 1995.
AB - OBJECTIVE: To review the management strategies and outcome in gravidas with anti
M isoimmunization over the past 26 years at The Ohio State University. METHODS:
Data collected from 115 pregnancies found to have anti-M antibody at The Ohio
State University from September 1969 through February 1996 were reviewed
retrospectively. We analyzed indirect antiglobulin tests, amniotic fluid with
spectrophotometric examination, direct antiglobulin tests, M antigen status,
antepartum course, and perinatal outcome. RESULTS: Anti-M antibody was found in
90 women who had 115 pregnancies over 26 years. Among those with positive
indirect antiglobulin tests, 104 pregnancies had titers at or below 1:4. Only one
patient with an initial low titer experienced more than a three-fold increase to
1:64. Two women underwent a total of eight amniocenteses when titers were at or
above 1:128. Forty-two (60%) of the 70 infants tested were positive for M
antigen. Nine infants required phototherapy. Eight of these infants were
delivered preterm. There was an increase in the number of women seen with anti-M
antibody in pregnancy at our institution, with nearly 10% of all gravidas with a
positive antibody screen having anti-M alloantibodies. There were no cases of
hemolytic disease of the newborn, mild or severe. CONCLUSION: The prevalence of
anti-M isoimmunization may be increasing. The incidence of severe hemolytic
disease of the newborn due to anti-M is extremely low. We found no cases in our
review of 115 pregnancies, although there have been several cases of severe
hemolytic disease of the newborn reported. If anti-M is detected in pregnancy,
the titer is low (no more than 1:4), and there is no history of prior pregnancy
complications suggesting a hemolytic disease process, we recommend no further
testing other than an indirect antiglobulin test at 28 weeks to look for the
emergence of other alloantibodies. However, if the initial titer is elevated or
there is a concerning obstetric history, serial titers should be performed and
amniocenteses reserved for rising titers.
PMID- 9397113
TI - Variation in the incidence of uterine leiomyoma among premenopausal women by age
and race.
AB - OBJECTIVE: To quantify the incidence of uterine leiomyoma confirmed by
hysterectomy, ultrasound, or pelvic examination according to age and race among
premenopausal women. METHODS: From September 1989 through May 1993, 95,061
premenopausal nurses age 25-44 with intact uteri and no history of uterine
leiomyoma were followed to determine incidence rates of uterine leiomyoma. The
self-reported diagnosis was confirmed in 93% of the medical records obtained for
a sample of cases. Using pooled logistic regression, we estimated relative risks
(RRs) of uterine leiomyoma according to race and examined whether adjustment for
other potential risk factors could explain the variation in the race-specific
rates. RESULTS: During 327,065 woman-years, 4181 new cases of uterine leiomyoma
were reported. The incidence rates increased with age, and the age-standardized
rates of ultrasound- or hysterectomy-confirmed diagnoses per 1000 woman-years
were 8.9 among white women and 30.6 among black women. After further adjustment
for marital status, body mass index, age at first birth, years since last birth,
history of infertility, age at first oral contraceptive use, and current alcohol
consumption, the rates among black women were significantly greater for diagnoses
confirmed by ultrasound or hysterectomy (RR 3.25; 95% confidence interval [CI]
2.71, 3.88) and by hysterectomy (RR 1.82; 95% CI 1.17, 2.82) compared with rates
among white women. We observed similar RRs when the cohort was restricted to
participants who reported undergoing a screening physical examination within the
2 years before baseline. CONCLUSION: A higher prevalence of known risk factors
did not explain the excess rate of uterine leiomyoma among premenopausal black
women.
PMID- 9397114
TI - The efficacy and complications of laparoscopic presacral neurectomy in pelvic
pain.
AB - OBJECTIVE: To evaluate the efficacy and complications of laparoscopic presacral
neurectomy in pelvic pain. METHODS: We reviewed records of 655 patients receiving
laparoscopic conservative surgery and laparoscopic presacral neurectomy for
diagnoses including adenomyosis with dysmenorrhea (n = 55), moderate and severe
endometriosis with dysmenorrhea (n = 127), minimal and mild endometriosis with
dysmenorrhea (n = 208), primary dysmenorrhea (n = 99), and chronic pelvic pain
with or without pathologic disease (n = 166). Pain relief was evaluated at least
12 months postoperatively. RESULTS: Pain relief was evaluated in 527 patients.
Significant pain relief (no pain or mild pain requiring no medication) was found
in 22 (52%) of 42 women with adenomyosis, in 75 (73%) of 103 with moderate to
severe endometriosis with dysmenorrhea, in 123 (75%) of 164 with minimal to mild
endometriosis with dysmenorrhea, in 64 (77%) of 83 with primary dysmenorrhea, and
in 84 (62%) of 135 with chronic pelvic pain. There were four major complications
(0.6%) that required further surgery, including injury of the right internal
iliac artery (n = 1) and chylous ascites (n = 3). Three cases (0.5%) had
laceration of the middle sacral vein controlled during laparoscopy. In addition,
485 (74%) of the 655 patients complained of constipation after laparoscopic
presacral neurectomy, which was relieved easily by medication. CONCLUSION:
Presacral neurectomy can be performed safely and efficiently by laparoscopy and
is a valuable alternative treatment for pelvic pain.
PMID- 9397115
TI - Duration of pregnancy after carbon dioxide laser conization of the cervix:
influence of cone height.
AB - OBJECTIVE: To determine if carbon dioxide laser conization of the cervix is a
risk factor for preterm delivery in subsequent gestations and to evaluate whether
there is any relationship between cone height and duration of pregnancy. METHODS:
Patients of fertile age who had carbon dioxide laser conization were followed for
reproductive events. Cases were matched one-to-one with controls for known risk
factors for preterm delivery. Pregnancy duration, rate of preterm birth, and mode
of delivery were studied. Parametric and nonparametric tests were used for
statistical analysis. Logistic regression analysis and Cox proportional hazard
modeling were used to investigate the relationship between cone height and
subsequent preterm delivery. RESULTS: Sixty-four women with singleton pregnancies
after carbon dioxide laser conization and 64 controls were included in the study.
Overall, no difference was found in the rate of preterm delivery and duration of
pregnancy. However, women with cone height of at least 10 mm had a higher rate of
preterm delivery than either those with cone height less than 10 mm (five of 23
versus one of 41, P = .01) or the controls (five of 23 versus three of 64, P <
.05). Cone height of at least 10 mm remained significant in predicting the
occurrence of preterm delivery and the duration of pregnancy after adjusting for
known risk factors (odds ratio 11.1, P < .05). CONCLUSION: Cone height of at
least 10 mm is an independent risk factor for the duration of pregnancy and for
the occurrence of preterm delivery in the subsequent gestation.
PMID- 9397116
TI - Evaluation of parturition and other reproductive variables as risk factors for
urinary incontinence in later life.
AB - OBJECTIVE: To assess specific parturition and reproductive variables as potential
risk factors for urinary incontinence in later life. METHODS: A mail survey was
conducted with a random sample of 1922 women members of a large health
maintenance organization. Multivariate analysis was used to estimate the
independent association between parturition factors, hysterectomy, hormone use,
and incontinence. RESULTS: Completed surveys were returned by 939 women (49%),
682 of whom reported at least one episode of incontinence in the past 12 months
or ever having been treated for incontinence. On univariate analysis, women with
incontinence were more likely to be white and heavier and to have had a
hysterectomy before age 45, at least one live birth, a postdate (at least 42
weeks' gestation) birth, a labor lasting longer than 24 hours, and exposure to
oxytocin. The risk of incontinence increased significantly with the number of
exposures to oxytocin. In a multivariate model including age, there was a
significant association between incontinence and white race (odds ratio [OR] 1.8,
95% confidence interval [CI] 1.2, 2.8), body mass (OR for fourth quartile 3.0,
95% CI 1.8, 5.0), estrogen replacement (OR 1.9, 95% CI 1.3, 2.8) and oxytocin (OR
1.9, 95% CI 1.0, 3.6). Parity was also associated with incontinence (P < .05).
CONCLUSION: This study supports previous findings of a positive association
between urinary incontinence and body mass, parity, and use of estrogen. In
addition, we found a significant independent association between exposure to
oxytocin during labor and incontinence in later life.
PMID- 9397117
TI - A simplified protocol for pessary management.
AB - OBJECTIVE: To evaluate a simplified protocol for pessary management. METHODS:
Women with symptomatic pelvic organ prolapse who opted for pessaries were
enrolled in a prospective simplified protocol for pessary management. After the
initial pessary fitting, they were seen at 2 weeks for reexamination and
thereafter at 3- to 6-month intervals. RESULTS: One hundred ten women (mean age
65 years) were enrolled, and 81 (74%) of them were fitted successfully with a
pessary. Life-table analysis showed that 66% of those who used a pessary for more
than 1 month were still users after 12 months and 53% were still users after 36
months. The severity of pelvic prolapse did not predict the likelihood of pessary
failure except in cases of complete vaginal eversion. Patients complaining of
stress incontinence were less likely to have a successful pessary fitting and
more likely to opt for surgery. Current hormone use and substantial perineal
support do not predict greater likelihood of pessary fitting success. No serious
complications from using the pessary were observed in the study sample.
CONCLUSION: Stringent guidelines calling for frequent pelvic examinations during
pessary use can be relaxed safely. Pessaries can be offered as a safe long-term
option for the management of pelvic prolapse.
PMID- 9397118
TI - Effect of postmenopausal estrogen replacement on circulating androgens.
AB - OBJECTIVE: To determine the effect of estrogen replacement therapy (ERT) on serum
androgen levels in postmenopausal women. METHODS: We measured serum
dehydroepiandrosterone (DHEA), DHEA-sulfate, testosterone, estradiol (E2), LH,
FSH, and sex hormone binding globulin in 8:00 AM fasting serum samples from a
previous randomized, blinded, placebo-controlled crossover study in which 28
postmenopausal women (27 naturally menopausal) were given 2 mg/day of oral
micronized estradiol. The treatment arms were 12 weeks with a 6-week washout.
RESULTS: Estrogen replacement therapy raised mean (+/- standard error of the mean
[SEM]) serum E2 from 8.7 +/- 1.0 to 117 +/- 18.7 pg/mL (P < .001 from baseline).
Concurrently, mean (+/- SEM) DHEA-sulfate fell from 67.3 +/- 9.6 to 52.1 +/- 6.4
micrograms/dL (P < .001), and mean (+/- SEM) testosterone fell from 16.1 +/- 2.4
to 9.4 +/- 1.4 ng/dL (P = .006). Both FSH and LH declined significantly. Sex
hormone binding globulin increased by 160% with ERT (P < .001). CONCLUSION:
Menopausal ERT decreases serum androgen levels, decreasing DHEA-sulfate and
testosterone by 23% and 42%, respectively. Whereas the decline in testosterone is
likely due to decreased LH-driven ovarian stromal steroidogenesis, the declining
levels of DHEA-sulfate also may imply a direct adrenal effect of estrogen.
Bioavailable testosterone likely is reduced even more profoundly because sex
hormone binding globulin is increased 160% by estrogen. Thus, menopausal ERT may
induce relative ovarian and adrenal androgen deficiency, creating a rationale for
concurrent physiologic androgen replacement.
PMID- 9397120
TI - The 4-S modification of the Roeder knot: how to tie it.
AB - BACKGROUND: The 4-S modification of the Roeder knot may be tied laparoscopically
as a single-throw knot. TECHNIQUE: It is tied by adding a fourth wrap around the
suture loop and securing the loop in place with a square knot rather than a
single half-hitch. EXPERIENCE: We have used this knot in laparoscopic surgeries
for more than 2 years and have not observed knot slippage. CONCLUSION: This
modification results in a knot comparable in strength to the strongest
laparoscopic multiple-throw square knots.
PMID- 9397119
TI - Papanicolaou smears by the Bethesda system in endometrial malignancy: utility and
prognostic importance.
AB - OBJECTIVE: To evaluate the prognostic significance of the Bethesda system's
cytologic categories in patients with endometrial malignancy. METHODS: Patients
with biopsy or hysterectomy-proven endometrial malignancy and a Papanicolaou
smear result reported using the Bethesda system within 1 year of diagnosis were
identified through retrospective review of our computerized database. RESULTS:
After introduction of the Bethesda system in our laboratory on November 1, 1992,
until January 1, 1997, 112 eligible patients were identified (108 with carcinomas
and four with carcinosarcomas). Patients with cytologic diagnoses of malignancy
(n = 17) were significantly more likely to have International Federation of
Gynecology and Obstetrics (FIGO) grade 3 tumors and high-risk histology (serous,
clear cell, and adenosquamous carcinoma and carcinosarcoma) than those with
atypical glandular cells of uncertain significance (n = 33) or those with
cytology not suspicious for malignancy (n = 63). Patients with malignant smears
were also significantly more likely to have cervical extension, malignant
peritoneal cytology, and FIGO stage II, III, or IV than those with atypical
glandular cells of uncertain significance or those with cytology not suspicious
for malignancy. CONCLUSION: Papanicolaou smears obtained within 1 year of
histologic diagnosis of endometrial malignancy and interpreted using the Bethesda
system were suspicious for (atypical glandular cells of uncertain significance)
or diagnostic of malignancy in nearly half of all cases (29 and 15%,
respectively). Patients having malignant glandular cells were more likely to have
poor prognostic pathologic findings.
PMID- 9397121
TI - Three-dimensional method for determination of amniotic fluid volume in
intrauterine pockets.
AB - BACKGROUND: Although current ultrasound techniques provide a linear (amniotic
fluid index; AFI) or two-dimensional area index of amniotic fluid (AF), these
indices have limited correlation with actual AF volume. We sought to quantify the
three-dimensional volume of ultrasound-identified AF pockets, as assessed by the
AFI and two-dimensional area methods. The BVI 2500 (Bladder Volume Instrument
2500; Diagnostic Ultrasound Corp., Redmond, WA) has been used to quantify the
volume of residual urine in the bladder. INSTRUMENT AND METHOD: The BVI 2500
(Diagnostic Ultrasound Corp.) ultrasound uses a rotating 2-MHz transducer,
computer-defined fluid interface, and computer integration of 12 cross-sectional
images to calculate three-dimensional fluid volume. After providing written
informed consent, 14 term pregnant patients (36-42 weeks) were evaluated using
the BVI 2500 and an Ultramark 8 sector scan (Advanced Technology Laboratory,
Bothell, WA). The largest vertical fluid pocket in each quadrant of the abdomen
was identified with the sector scan, and vertical and horizontal measurements for
AFI and two-dimensional area were recorded. Simultaneous AF volume measurements
of each pocket were performed three times with the bladder volume instrument, and
maximum values were used. Three-dimensional volume, two-dimensional area, and AFI
values were compared by correlation analysis, with P < or = .05 considered
statistically significant. EXPERIENCE: Among all patients, the average (+/-
standard deviation) AFI was 7.6 +/- 4.1 (range 1.5-16.4) cm, and the average two
dimensional area was 30.9 +/- 21.1 (range 4.3-81.3) cm2. This corresponded to an
average three-dimensional volume of 215 +/- 134 (range 23-497) cm3. Three
dimensional volume correlated highly with both AFI (r = 0.9; P < .001) and two
dimensional area (r = 0.86; P < .001). One AFI centimeter was equivalent to a
volume of 30 cm3. CONCLUSION: There are highly significant linear correlations of
three-dimensional amniotic fluid volumes with AFI and two-dimensional area. The
four pockets used in AFI determination account for only 50% of total AF volume.
Three-dimensional determinations may aid in clinical assessments of AF volume.
PMID- 9397122
TI - A model clinical faculty workshop program for a multisite clerkship.
AB - Over the past 20 years, the University of Washington Department of Obstetrics and
Gynecology has conducted twice-yearly faculty development workshops at the
University for clinical faculty at community sites spread over three time zones
in Washington, Alaska, Montana, and Idaho. These workshops consist of three
separate parts: 1) a session to report on student clerkship performance and
faculty ratings, 2) a session on curriculum and/or teaching, and 3) a session to
update medical topics. Faculty found the workshops useful for improving their
clinical teaching, keeping in touch with the full-time faculty, and developing a
sense of cohesiveness. The department found the workshops useful in maintaining
the teaching of consistent content and ensuring that all sites provide students
with comparable experiences and evaluation.
PMID- 9397123
TI - Telomerase in gynecologic cancers.
AB - OBJECTIVE: To provide the obstetrician-gynecologist with the following: 1) basic
concepts of telomere shortening and telomerase activation and their relation to
cellular immortalization and cancer, 2) an overview of potential uses of
telomerase activity in cancer diagnosis, assessment of prognosis, and the
development of new anticancer therapeutic approaches, and 3) a review of the
literature on telomerase activity in gynecologic cancers. DATA SOURCES: A
computerized search for articles published in which telomerase or telomerases
were included as a subject heading or a textword was performed using the Ovid
Search Software (Ovid Technologies Inc., New York, NY). The search was conducted
of the following databases of the National Library of Medicine and the National
Cancer Institute: MEDLINE January 1966 to May 1997, HealthSTAR January 1975 to
May 1997, AIDSline January 1980 to May 1997, and CancerLit January 1980 to May
1997. Additional sources were identified through cross-referencing. METHODS OF
STUDY SELECTION: All sources identified were reviewed with particular attention
to human application, specifically in gynecologic cancers. TABULATION,
INTEGRATION, AND RESULTS: A total of 304 references was identified. Each
reference was reviewed to determine the relevant contribution to the basic
understanding of the role of telomerase in cellular immortalization and the
development of cancer, potential uses of telomerase measurement in cancer,
gynecologic applications, and potential use of telomerase inhibitors in cancer
therapy. CONCLUSION: Telomerase activity might be a valuable diagnostic and
prognostic tool in gynecologic and other types of cancer, and telomerase
inhibition might prove to be a significant therapeutic approach for some types of
cancer. Better understanding of the relation between telomerase activation, tumor
suppressor genes, and oncogenes might clarify several aspects of early
tumorigenesis and result in development of novel approaches to early cancer
detection and prevention.
PMID- 9397124
TI - Obstetrics & Gynecology in 1996: marking the progress toward evidence-based
medicine by classifying studies based on methodology.
AB - OBJECTIVE: To test the hypothesis that researchers in obstetrics and gynecology
favor an observational type of study design. DATA SOURCES: The 12 regular issues
of Obstetrics & Gynecology published during 1996 were analyzed. METHOD OF STUDY
SELECTION: All articles in the journal Obstetrics & Gynecology were reviewed for
the year 1996, except that separate issues covering case reports, case
condensations, and reviews were excluded. TABULATION, INTEGRATION, AND RESULTS:
Studies were classified as observational or experimental. Observational studies
were subclassified as either descriptive, case-control, or cohort. Experimental
studies were subclassified as either randomized controlled trial (RCT) or
uncontrolled trial. Other study designs were noted. Of the 316 studies published
during 1996, 241 (76%) were observational, 43 (14%) experimental, and 32 (10%)
other. There were 162 (51%) descriptive studies, 44 (14%) case-control studies,
35 (11%) cohort studies, 35 (11%) RCTs, and eight (3%) uncontrolled trials.
CONCLUSION: Researchers who publish in Obstetrics & Gynecology favor an
observational study design. With evidence-based medicine growing in popularity as
a new standard or paradigm, the reliance on observational studies may have
implications.
PMID- 9397125
TI - Nifedipine and ritodrine in the management of preterm labor: a randomized
multicenter trial.
PMID- 9397126
TI - Mullerian agenesis: an update.
PMID- 9397127
TI - Stress-point intervention for parents of repeatedly hospitalized children with
chronic conditions.
AB - Little is known about how to assist children with chronic conditions and their
families cope with repeated hospitalizations. A two-group, pretest-posttest study
was done to determine whether a community-based, stress-point nursing
intervention for parents could decrease distress and improve child and family
functioning. Fifty participants were randomly assigned to intervention or usual
care control groups. The intervention focused on specific, parent-verified child
and family issues. Three months after hospitalization, intervention parents had
better coping and family functioning than those in the usual care group.
Intervention parents' anxiety was initially higher and then lower. There were no
child behavior differences between the groups after hospitalization. Intervention
children had no developmental regression at 2 weeks and better developmental
gains 3 months after discharge than the usual care children. Stress-point
intervention for families and their children with chronic conditions improved
family coping and functioning, and eliminated hospitalization-induced
developmental regression.
PMID- 9397128
TI - Attention, coping, and activity in children undergoing orthopaedic surgery.
AB - The purpose of this study was to determine how children's preoperative focus of
attention on the stresses of surgery related to their preoperative coping and
return to usual activities during recovery. Children's attention was classified
according to three different foci: concrete-objective, emotion, and vague.
Children (N = 97) between the ages of 8 and 17 years who were undergoing major
orthopaedic surgery participated in the study. Data were collected the day before
surgery, and at 3, 6, and 9 months postoperatively. Children who focused on the
concrete-objective aspects of surgery had the most positive activity outcomes,
followed by the emotion-focused attention group. Children who were classified as
having vague focused attentions had the least favorable activity outcomes. When
there were significant coping by attention interaction effects, vigilant copers
who had a concrete-objective focus of attention had the most favorable activity
outcomes at each time of measurement. Children who were able to focus their
attention on concrete aspects of the experience tended to use vigilant coping and
were able to return to their usual activities sooner.
PMID- 9397129
TI - Living with fibromyalgia: sense of coherence, perception of well-being, and
stress in daily life.
AB - Fibromyalgia (FM) is a chronic pain syndrome that has a considerable impact on
the ill person's daily life. The purpose of this study was to describe levels of
sense of coherence (SOC), perceptions of well-being, and stress in daily life in
women with FM in comparison with healthy women, and to determine whether SOC is
related to perceived levels of stress and well-being. Thirty women with FM were
compared with 30 healthy women matched for Type A behavior. The results revealed
a complex picture of the women with FM. On the one hand, they reported many
symptoms but, on the other, they rated themselves as feeling quite well and
experiencing an SOC in life, despite severe problems. The FM women with a
stronger SOC perceived greater well-being than those with a weaker SOC. They felt
more hopeful, more free, more valuable, and more like others. Results suggest
that women with a weaker SOC may need extra support. More research is needed to
investigate the experience of living with FM in order to discover what it is that
makes life worthwhile despite high symptom levels.
PMID- 9397130
TI - Nicotine dependence and smoking topography among black and white women.
AB - Nicotine dependence is a complex phenomenon involving behavioral, biological, and
pharmacological components that influence smoking cessation rates. The purpose of
this study was to characterize the multidimensional aspects of nicotine
dependence and cigarette smoking topography behaviors among Black and White women
smokers. Thirty-seven women participated in a 2-hr protocol in the General
Clinical Research Center. Plasma cotinine to cigarette ratio was significantly
associated with three topography variables: total puff duration, total cigarette
time, and carbon monoxide (CO) boost. Black women scored higher on plasma
cotinine levels, cotinine per cigarette ratio, and CO increase pre- to
postcigarette than White women. Implications for clinical practice include
assessing nicotine dependence beyond self-reported cigarettes per day to develop
more appropriate smoking cessation interventions.
PMID- 9397131
TI - A causal functional explanation of maintaining a dependent elder in the
community.
AB - A causal functional structure demonstrates how a perpetual process, like
caregiving, maintains itself. The caregiver functional learning model was used to
identify factors influencing caregivers when maintaining dependent elders in the
community. These factors include seriousness of illness, power, burden, care
quality, self-assurance, an understanding of the elder's needs, and time spent in
caregiving. This five-stage theoretical model was tested using a sample of 70
caregivers. Findings supported two of the theoretical relationships: seriousness
of illness (beta = .60) with burden (R2 = 0.35), and self-assurance (beta = .36)
with time (R2 = 0.18). Three new relationships were added with the empirical
model: power (beta = .48) with burden (R2 = 0.52), seriousness of illness (beta =
.36) with self-assurance (R2 = 0.11), and burden (beta = .33) with time (R2 =
0.24). A causal functional structure can be used to explain how the phenomenon of
caregiving maintains itself.
PMID- 9397132
TI - Family involvement in the nursing home: family-oriented practices and staff
family relationships.
AB - Staff-family cooperation in caring for elders in nursing homes is recommended but
poorly understood. Family involvement and staff-family interactions in nursing
homes with differing family orientations were investigated. Friedemann's (1995)
system-based family theory guided the study. Of all 208 licensed nursing homes in
southern Michigan, 143 completed a survey about their family-oriented practices.
Family orientation was ranked accordingly. Twenty-four nursing homes were
randomly selected to conduct semistructured telephone interviews with 177 family
members. Data were analyzed by thematic interpretation. Findings showed a wide
range of involvement patterns that promoted family connectedness, maintenance of
control, growth, and learning. Families desired various types of staff
cooperation and were given such opportunities in homes with high family
orientation.
PMID- 9397134
TI - Endings, secrets, and silences: overreading in narrative inquiry.
AB - Qualitative researchers seek to understand the words of the people they interview
and may use narrative inquiry to find meaning in the stories told by research
participants. Narrative inquiry entails "overreading," a sensitivity to unspoken
or indirect statement, which is central to interpretation. Some of the tools of
the literary overreader are applied to two research interviews, particularly as
they direct readers to attend to inconsistencies, endings, repetitions, and
silence. Because overreading is also intrusive, we conclude with some
considerations about how far the overreader of the research may legitimately go.
PMID- 9397133
TI - Determination of reliability and validity in home monitoring data of pulmonary
function tests following lung transplantation.
AB - Electronic spirometry units were used to monitor lung transplantation recipients
upon their return home. The data from 77 participants were used to develop
methods to verify that the pulmonary function measurements, forced vital capacity
(FVC) and forced expiratory volume in 1 s (FEV1), were reliable and valid. The
standard deviation was calculated for the best daily effort on consecutive days
of home spirometry. An acceptable upper limit for the standard deviation, as the
measure of day-to-day reliability, was 0.20 for FVC and 0.15 for FEV1. Validity
was determined by examining the mean difference (bias) between the spirometry
done in the pulmonary function laboratory and the home monitoring results. The
clinic values were slightly higher, with an average difference of 0.15 for FVC
and 0.12 for FEV1. Therefore, the home spirometry measurements have a high degree
of reliability and validity and can now be used for early detection of serious
complications.
PMID- 9397135
TI - Excretion of epidermal growth factor in human adult polycystic kidney disease.
AB - In chronic renal failure, epidermal growth factor (EGF) excretion is decreased.
In this study, asymptomatic adult polycystic kidney disease (APKD) patients with
a relatively preserved glomerular filtration rate were examined. Excretion of EGF
was studied in 6 patients with APKD (median age 42 years; serum creatinine
[median] 95 [range-80-133] mumol/l) and compared with that of 28 healthy
controls. EGF was determined in a spot morning urine by using a specific
radioimmunoassay, and expressed in relation to creatinine excretion. Excretion of
EGF in APKD was (median) 157 (range-13-359) and in the controls (median) 546
(range-238-1199) pmol/mmol creatinine (p < 0.001). Low excretion of EGF in APKD
patients with preserved kidney function suggests a distal abnormality at an early
stage of the disease, prior to the development of renal failure.
PMID- 9397136
TI - The Israeli Diagnostic Center for Malignant Hyperthermia: 7-years' accumulated
experience.
AB - Malignant hyperthermia (MH), a rare pharmacogenetic trait, can be lethal when
susceptible individuals are exposed to triggering agents during general
anesthesia. We present our experience with the caffeine-halothane in vitro
contracture test (IVCT) for the diagnosis of malignant hyperthermia
susceptibility. Out of 75 patients that were referred for consultation to the MH
diagnostic center over a period of 7 years, we performed muscle biopsies and IVCT
in 21 patients. A total of 6 patients were found to be MH-positive. Appropriate
recommendations for future anesthetic management, and additionally, for testing
the immediate family were made following a positive diagnosis. Improved
familiarity with the syndrome of MH, and performance of IVCT when family or
clinical history suggest malignant hyperthermia susceptibility, are imperative
measures to prevent the potential fatality associated with this syndrome.
PMID- 9397137
TI - Flow parameters of the normal arterial duct in the fetus.
AB - The increasing interest in arterial duct flow patterns in the fetus warrants the
establishment of an accurate range of normal flow parameters throughout
gestation. We therefore undertook a prospective echocardiographic study of 181
normal fetuses from the 16th to the 40th week of gestation. Adequate Doppler
interrogation of the duct was obtained in 71% of the fetuses examined. Peak
gradient, mean gradient and flow velocity integral in systole and diastole were
digitized. The peak systolic gradient throughout pregnancy measured 2.7 +/- 1.4
mmHg with a slight tendency to increase with gestational age (r = 0.58). The peak
ratio, defined as peak systolic gradient divided by peak diastolic gradient (28.1
+/- 14.9), did not vary significantly with gestational age. This time-independent
index complements peak systolic flow in the assessment of normal and abnormal
ductal flow. The definition of the normal range for ductal flow parameters, based
on this relatively large fetal population, should facilitate the accurate
diagnosis of fetal duct constriction.
PMID- 9397138
TI - Alveolar macrophages fat stain in early diagnosis of fat embolism syndrome.
AB - The aim of this study was to assess the contribution of bronchoalveolar lavage
(BAL) in the diagnosis of fat embolism syndrome (FES). The presence of fat
droplets in alveolar macrophages was addressed in 13 trauma patients with bone
fractures and 10 non-trauma patients with acute respiratory distress syndrome
(ARDS). The control group was composed of 5 anesthesized patients with ischemic
heart disease, immediately prior to cardiac surgery. Two patients with suggestive
clinical and laboratory signs of FES had 40% and 24% fat-containing alveolar
cells, respectively. The trauma patients without signs of FES displayed a wide
variation in the percentage of fat-containing macrophages (from 3% to 95%). Most
of the patients with ARDS who were receiving lipid emulsion as part of their
parenteral nutrition, had a high percentage (> 85%) of fat-containing
macrophages. Patients with normal lungs had no fat-containing macrophages. Our
findings suggest that BAL Oil Red O-positive macrophages are frequently observed
in trauma patients irrespective of the presence of FES. Therefore, estimation of
the percentage of fat-containing macrophages from BAL is an unreliable marker of
FES.
PMID- 9397139
TI - Pediatric cholesterol screening: missed opportunities.
AB - The current recommendations for childhood cholesterol screening include screening
children in whom 1) a parent/grandparent has premature heart or vascular disease
or died suddenly; 2) a parent has an abnormal lipid profile; 3) the family
history is unobtainable. Over a 3-year period, 256 children referred for
hypercholesterolemia were evaluated for heritable hyperlipidemia. We reviewed
their family histories and obtained lipoprotein profiles of all of their
immediate family members. Of these families, 89 parents had unsuspected
hypercholesterolemia of whom 38, whose average age was 36 years, died of a
myocardial infarction. In addition, 83 children with no family history of
premature coronary artery disease or hypercholesterolemia, were diagnosed with
inherited hyperlipidemia (25 with hetrozygous familial hypercholesterolemia, and
58 with familial combined hyperlipidemia). Thus, many adults have no awareness of
hyperlipidemia prior to a fatal heart attack, nor of their children as having
hyperlipidemia, and a large percentage of children with inherited hyperlipidemia
would not have been diagnosed if all of their immediate family members (parents
and siblings) had not been screened for a complete lipid profile. These results
suggest that in addition to screening, all family members of hypercholesterolemic
children, pediatricians and family practitioners should urge parents who may be
unaware of their cholesterol levels or have no knowledge of their family history
to undergo cholesterol screening in order to comply with NCEP guidelines calling
for serum cholesterol measurements in all adults above the age of twenty.
PMID- 9397140
TI - Speech disorders in Israeli Arab children.
AB - The aim of this work was to study the frequency of speech disorders in Israeli
Arab children and its association with parental consanguinity. A questionnaire
was sent to the parents of 1,495 Arab children attending kindergarten and the
first two grades of the seven primary schools in the town of Taibe. Eight-six
percent (1,282 parents) responded. The answers to the questionnaire revealed that
25% of the children reportedly had a speech and language disorder. Of the
children identified by their parents as having a speech disorder, 44 were
selected randomly for examination by a speech specialist. The disorders noted in
this subgroup included errors in articulation (48.0%), poor language (18%), poor
voice quality (15.9%); stuttering (13.6%), and other problems (4.5%). Rates of
affected children of consanguineous and non-consanguineous marriages were 31% and
22.4%, respectively (p < 0.01). We conclude that speech disorders are an
important problem among Israeli Arab schoolchildren. More comprehensive programs
are needed to facilitate diagnosis and treatment.
PMID- 9397141
TI - A community hospital experience with colonoscopic polypectomies.
AB - This study analyzed 432 consecutive polypectomies performed in 279 patients in
the gastroenterology unit of a community hospital. The patients were separated
into 2 groups; group I--symptomatic patients considered suitable for colonoscopic
examination, and group II--asymptomatic high-risk patients. The mean number of
detected polyps was similar in both groups, the vast majority of the polyps in
both groups were small (< 5 mm), and were mainly of tubular histology. Polyps in
the rectosigmoid area were more common (56.6%) in the symptomatic patients than
in the asymptomatic patients (44.1%). Fourteen percent of patients in group I and
33% in group II had no polyps within 60 cm from the anal verge. Carcinoma in situ
was found in large polyps mainly in group I. Flat adenomas were not found in the
studied population. The incidence of hyperplastic polyps was similar in both
groups and did not predict the concomitant existence of adenomatous polyps. The
male:female ratio was the same in both groups. The percent of detected polyps
increased with age. A strong right shift in the location of the polyps was
evident with increasing age. Multiple polyps were a common event in this Israeli
population of symptomatic and high-risk asymptomatic patients. More than 30% of
the polyps were found outside the reach of the sigmoidoscope, with this
proportion increasing with age. These data provide further support to the claim
that colonoscopy should therefore serve as the choice diagnostic tool in these
high-risk populations.
PMID- 9397142
TI - Squamous cell carcinoma of the cervix with psoas abscess-like metastasis in an
HIV-negative patient.
AB - A psoas abscess-like metastasis of squamous cell carcinoma of uterine cervix was
diagnosed in a 50-year-old, HIV-negative woman. While there was complete
regression of the primary tumor, the psoas cystic lesion grew in size during
chemotherapy, with iliac bone destruction and invasion to the gluteus muscle. A
computed tomography-guided bone biopsy was done and histopathologic examination
revealed squamous cell carcinoma consistent with the primary lesion. Intratumoral
injection of cisplatin and radiotherapy resulted in partial relief of symptoms.
This form of aggressive, bone destruction metastasis was hitherto reported only
in association with AIDS.
PMID- 9397143
TI - Littoral cell angioma: a vascular tumor mimicking a solid tumor on a Tc-99m-red
blood cell spleen scan.
AB - A splenic space occupying lesion, in a 45-year-old woman, was negative in a Tc
99m-RBC spleen scan. A diagnostic splenectomy was performed and the lesion was
found to be a vascular tumor, lately identified as littoral cell angioma. The
histological and immunohistochemical findings are discussed in correlation with
the imaging results.
PMID- 9397144
TI - Primary biliary cirrhosis associated with antiphospholipid syndrome.
AB - A 47-year-old female was admitted for severe pain of 1 month's duration in the
third and fourth toes of the right foot, culminating in gangrene. Laboratory
findings revealed liver enzyme abnormalities, and anti-mitochondrial, anti
phospholipid and antinuclear and doubtful anti-DNA antibodies. Systemic lupus
erythematosus (SLE) was excluded on clinical grounds after a 6-year follow-up.
Therefore, a diagnosis was made of the primary antiphospholipid syndrome,
complicated by microvasculopathy, and associated with primary biliary cirrhosis.
PMID- 9397145
TI - Bilateral brachial plexopathy after E. coli sepsis.
AB - A 67-year old patient, operated for closure of ileostomy 3 days before, developed
E. coli sepsis with suspected peritonitis. Two days later, pain and weakness in
the shoulder girdle, scapula and proximal upper limb muscle appeared
simultaneously, followed by marked atrophy. Electromyography (EMG) examination
manifested bilateral active denervation of upper brachial plexus. Any trial to
isolate a pathogenic factor other than the E. coli failed. Due to the bilateral
proximal upper limb's paralysis, grooming and upper-body dressing obliged the
patient to ask for complete assistance. In other daily living activities he was
partially independent.
PMID- 9397147
TI - Gastrointestinal events related to the use of non-steroidal anti-inflammatory
drugs: some clinical and economic aspects.
PMID- 9397146
TI - Glucagon-like peptide-1 structure, function and potential use for NIDDM.
AB - Basic research on the cellular mechanisms that control the expression of the gene
encoding glucagon has led to the discovery of proglucagon. This precursor is
processed by tissue-specific proteolysis to produce glucagon in pancreatic alpha
cells and a glucagon-like peptide-1 (GLP-1) in the intestine. GLP-1 is a hormone
that is released by intestinal cells into the circulation in response to food
intake. GLP-1 and gastric inhibitory peptide (GIP) which has also been termed
glucose-dependent insulinotropic peptide appear to account for most of the
incretin effect in the augmentation of glucose-stimulated insulin secretion.
These two hormones have specific beta-cell receptors that are coupled to GTP
binding proteins to induce production of cyclic AMP and activation of cyclic AMP
dependent protein kinase. It is proposed that at least one factor contributing to
the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) is
desensitization of the GLP-1 receptor on beta-cells. At pharmacological doses,
infusion of GLP-1, but not of GLP, can improve and enhance postprandial insulin
response in NIDDM patients. Agonists of GLP-1 receptor have been proposed as new
potential therapeutic agents in NIDDM patients. The observations that GLP-1
induces both secretion and production of insulin, and that its activities are
mainly glucose-dependent, led to the suggestion that GLP-1 may present a unique
advantage over sulfonylurea drugs in the treatment of NIDDM.
PMID- 9397148
TI - Obesity epidemic puts millions at risk from related diseases.
PMID- 9397149
TI - Polio eradication effort marches on despite wars.
PMID- 9397150
TI - All-trans retinoic acid blocks the antiproliferative prodifferentiating actions
of 1,25-dihydroxyvitamin D3 in normal human keratinocytes.
AB - 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] and all-trans retinoic acid (RA), the
active metabolites of vitamins D and A respectively, regulate the proliferation
and differentiation of keratinocytes. Both the vitamin D receptor (VDR) and the
retinoic acid receptor family (RAR) bind to DNA response elements as heterodimers
with the retinoic X receptor (RXR), suggesting that there are pathways of action
that are shared by both compounds. Therefore, we examined the interactions of
1,25(OH)2D3 and RA upon the proliferation and differentiation of normal human
keratinocytes (NHK) and of a squamous cell carcinoma cell line, SCC4. Although
both 1,25(OH)2D3 and RA were each able to inhibit NHK proliferation in a dose
dependent manner, when they were administered in combination, proliferation was
stimulated, suggesting mutual antagonism. In contrast, SCC4 cells proved
insensitive in terms of proliferation to 1,25(OH)2D3 and to all but the highest
concentration (10(-6) M) of RA. 1,25(OH)2D3 exerted a biphasic effect on
transglutaminase (TGase) and involucrin (INV) mRNA levels, with maximal
stimulation at 10(-9) M. RA inhibited TGase and INV mRNA levels and antagonized
the stimulation by 1,25(OH)2D3. A similar pattern was observed for TGase protein,
but, RA, which, by itself, reduced INV, markedly enhanced the ability of
1,25(OH)2D3 to raise INV levels, possibly by inhibiting 1,25(OH)2D3-stimulated
TGase activity and cross-linking of soluble INV into the insoluble cornified
envelope (CE). Thus, in NHK cells, RA antagonizes the antiproliferative
prodifferentiating actions of 1,25(OH)2D3, but assessment of a single marker,
such as INV protein, may be misleading.
PMID- 9397151
TI - Epidermal growth factor (EGF) receptor density controls mitogenic activation of
normal rat kidney (NRK) cells by EGF.
AB - Normal rat kidney (NRK) fibroblasts are immortalized cells that are strictly
dependent on externally added growth factors for proliferation. When cultured in
the presence of epidermal growth factor (EGF) as the only growth stimulating
hormone, these cells have a normal phenotype and undergo density-dependent growth
inhibition. It has been postulated that this density-arrest results from a
decrease of EGF receptor levels below a threshold level which makes these cells
unresponsive to stimulation by EGF. In the present study, we show that NRK cells,
made quiescent by serum-deprivation at submaximum density, are mitogenically
still responsive to EGF, but show enhanced mitogenic stimulation after 8 hr pre
treatment with either transforming growth factor beta (TGF beta) or retinoic acid
(RA), while prostaglandin F2 alpha (PGF2 alpha) and bradykinin (BK) enhance the
mitogenic stimulation by EGF only slightly under these conditions. Addition of
TGF beta or RA results in an increase of both 125I-EGF-binding capacity and EGF
receptor mRNA levels. Using flow cytometric analysis, we show that pre-treatment
with TGF beta or RA increases the percentage of cells entering the cell cycle as
a function of time. Furthermore, pre-treatment of the cells with TGF beta or RA
increases the rate of mitogen-activated protein kinase (MAPK) phosphorylation by
EGF. PGF2 alpha and BK also increase EGF receptor levels, but only with delayed
kinetics. These results show that already in serum-deprived quiescent NRK cells,
EGF receptor levels limit EGF-induced mitogenic stimulation. This observation
provides further evidence for the regulating role of the EGF receptor in density
dependent growth control of NRK cells.
PMID- 9397152
TI - Analysis of the transcriptional activity of the 5'-flanking region of the rat
catalase gene in transiently transfected cells and in transgenic mice.
AB - Transiently transfected cell lines and transgenic mice were used to study the
transcriptional activity of the 5'-flanking region of the catalase gene.
Fragments of the 5'-flanking region of the rat catalase gene ranging in length
from 3,421 base pairs (bp) to 69 bp were fused to the chloramphenicol
acetyltransferase (CAT) reporter gene, and the transcriptional activity of the
reporter gene was measured following transient transfection in three cell lines:
a human hepatoma cell line (HepG2), a porcine kidney epithelial cell line
(LLCPK1), and a human glioma cell line (U-138 MG). The 3,421-bp fragment of the
5'-flanking region resulted in a high level of expression of the reporter gene in
all three cell lines. Shorter fragments of the 5'-flanking region resulted in a
decrease in the level of CAT reporter expression that varied among the three cell
lines, implying the presence of tissue-specific regulatory sites. To study the
tissue-specific regulation of the catalase promoter, transgenic mice containing
the 3,421-bp 5'-flanking sequence attached to the CAT reporter gene were
produced, and CAT expression was measured in various tissues of three independent
transgenic lines. CAT activity was consistently high in muscle tissue (heart,
skeletal muscle, and diaphragm) and low in most other tissues studied,
particularly in liver and kidney. In contrast, the endogenous expression of
catalase is low in muscle and high in liver and kidney; thus, the tissue-specific
expression of the reporter gene driven by the 3,421-bp fragment of the 5'
flanking region of the catalase gene was not similar to the expression of the
endogenous catalase gene.
PMID- 9397153
TI - Overexpression of HSP25 reduces the level of TNF alpha-induced oxidative DNA
damage biomarker, 8-hydroxy-2'-deoxyguanosine, in L929 cells.
AB - Previously we and others have demonstrated that oxidative stress involving
generation of reactive oxygen species (ROS) is responsible for the cytotoxic
action of TNF alpha. Protective effect of small heat shock proteins (HSP) against
diverse oxidative stress conditions has been suggested. Although overexpression
of small HSP was shown to provide an enhanced survival of TNF alpha-sensitive
cells when challenged with TNF alpha, neither the nature of TNF alpha-induced
cytotoxicity nor the protective mechanism of small HSP has been completely
understood. In this study, we have attempted to determine whether TNF alpha
induces oxidative DNA damage in TNF alpha-sensitive L929 cells. We chose to
measure the level of 8-hydroxy-2'-deoxyguanosine (8 ohdG), which has been
increasingly recognized as one of the most sensitive markers of oxidative DNA
damage. Our results clearly demonstrated that the level of 8 ohdG increased in
L929 cells in a TNF alpha dose-dependent manner. Subsequently, we asked whether
small HSP has a protective effect on TNF alpha-induced oxidative DNA damage. To
accomplish this goal, we have stably transfected into L929 cells, which are
devoid of endogenous small HSP, with the mouse small hsp cDNA (hsp25). We found
that TNF alpha-induced 8 ohdG was decreased in cells overexpressing exogenous
small HSP25. We also found that the cell-killing activity of TNF alpha was
decreased in these cells as measured by clonogenic survival. Taken together,
results from the current study show that a cytotoxic mechanism of TNF alpha
involves oxidative damage of DNA, and that overexpression of the small HSP25
reduces this oxidative damage. We suggest that the reduction of oxidative DNA
damage is an important protective mechanisms of small HSP against TNF alpha.
PMID- 9397155
TI - Selection of highly metastatic rat MTLn2 mammary adenocarcinoma cell variants
using in vitro growth response to transferrin.
AB - We previously found that the proliferative response to transferrin and the
expression of transferrin receptors (TfR) on the cell surface of various rat
13762NF mammary adenocarcinoma cell sublines correlated with their spontaneous
metastatic capability. To further assess the involvement of transferrin and TfR
in metastasis, transferrin-responsive cells were selected from the poorly
metastatic, low-transfferin responsive 13762NF MTLn2 subline. When maintained in
low serum (0.3%) conditions, MTLn2 cells failed to survive. However, if like
medium was supplemented with 0.5 microgram/ml rat transferrin, some colonies
emerged, presumably due to their ability to proliferate in response to the added
transferrin. The surviving cells were expanded and exposed to ten or 20 similar
cycles of transferrin growth selection to obtain the sublines MTLn2-Tf10 and
MTLn2-Tf20, respectively. The MTLn2-Tf20 cells proliferated in response to
transferrin at a rate similar to that of the high metastatic 13762NF sublines.
Using immunofluorescent staining, Scatchard analysis, and affinity isolation of
TfR, we discovered that the MTLn2-Tf20 cells had 5 to 6 times more TfR than did
the parental MTLn2 line. When injected into the mammary fat pads of rats, the
MTLn2-Tf20 line metastasized to the axillary lymph node in seven out of ten
animals and to the lungs in six out of ten (median number = 13). No metastases
were seen in the MTLn2 parental line. The MTLn2-Tf10 cells showed intermediate
properties compared with the MTLn2 and MTLn2-Tf20 cells. The results indicate
that variant cells with a high response to transferrin may be more metastatic
than the bulk cells in a poorly metastatic population. The selection of cells
with high levels of TfR and a higher proliferative response to transferrin
results in sublines with greater potentials for spontaneous metastasis.
PMID- 9397154
TI - Repression of mitogen-activated protein kinases ERK1/ERK2 activity by a protein
tyrosine phosphatase in rat fibroblasts transformed by upstream oncoproteins.
AB - The observation that mitogen-activated protein (MAP) kinases ERK1 and ERK2 are
constitutively activated in a number of oncogene-transformed cell lines has led
to the hypothesis that prolonged activation of these enzymes is required for the
transformation process. To investigate this question, we have examined the
regulation of the ERK pathway in Rat1 fibroblasts transformed with activated c
Raf-1 (Raf22W), v-Ha-Ras, and v-Src. Expression of these oncoproteins had no
effect on the enzymatic activity of ERK1 and ERK2 in either serum-starved or
exponentially growing cells. Moreover, the stimulatory effect of serum on
ERK1/ERK2 activity was substantially reduced or abrogated in these cells; this
impairment was associated with a strong attenuation of c-fos gene induction. In
contrast, expression of Raf22w, v-Ha-Ras, or v-Src resulted in the constitutive
activation of the upstream kinases MEK1 and MEK2. Treatment of the cells with
vanadate completely restored the activation of ERK1/ERK2 in oncogene-transformed
cells, suggesting the involvement of a vanadate-sensitive tyrosine phosphatase.
Northern blot analysis of VH1-like dual-specificity MAP kinase phosphatases did
not reveal any significant difference in the mRNA expression pattern of these
genes between parental and transformed Rat1 cells. Phosphoamino acid analysis
indicated that ERK1 is phosphorylated on threonine, but not on tyrosine, in
oncogene-transformed cells and that vanadate treatment restores tyrosine
phosphorylation. We conclude from these results that ERK1/ERK2 activity is
repressed by a single-specificity tyrosine phosphatase in oncogene-transformed
rat fibroblasts.
PMID- 9397156
TI - Un-cross-linked fibrin substrates inhibit keratinocyte spreading and replication:
correction with fibronectin and factor XIII cross-linking.
AB - Wound repair is characterized by the presence of a fibrin-rich matrix, but the
effect of fibrin on re-epithelialization remains unclear. In this study, we
determined the effects of different fibrin matrices on cultured human neonatal
keratinocytes. Using purified fibrinogen and fibrin gels generated by the
enzymatic action of thrombin, batroxobin (it leads to retention of fibrinopeptide
B), or Agkistrodon contortrix thrombin-like enzyme (ACTE; it leads to retention
of fibrinopeptide A), we determined the effect of each of these matrices on
keratinocyte morphology, attachment, spreading, and replication as compared to
tissue culture plastic. Morphologically, keratinocytes seeded on fibrin surfaces
were more rounded and formed three-dimensional structures. Specific cell
attachment, as measured at either 37 degrees C or 4 degrees C, was not altered on
the different fibrin substrates (P > .05) but was increased on fibrinogen and
factor XIII cross-linked fibrin (P < .01). However, keratinocytes seeded on
fibrin, regardless of the presence or absence of fibrinopeptides A or B, showed a
marked decrease (up to 71%) in cell numbers by days 5 (P = .0357) and 10 (P =
.0114). Keratinocyte spreading was decreased by 78.8% (P = .0006), 80.3% (P =
.0001), and 89.2% (P = .0001) on thrombin-, batroxobin-, and ACTE-generated
fibrin, respectively, but not on fibrinogen-coated dishes. However, either the
addition of fibronectin or cross-linking of fibrin with factor XIII allowed full
keratinocyte spreading to occur (P = .0002 and P = .0013, respectively). We
conclude that fibrin inhibits keratinocyte spreading in the absence of other
matrix or plasma proteins or cross-linking by factor XIII.
PMID- 9397157
TI - Rapid disruption of gap junctional communication and phosphorylation of
connexin43 by platelet-derived growth factor in T51B rat liver epithelial cells
expressing platelet-derived growth factor receptor.
AB - Gap junctional communication (GJC) between contacting cells has been postulated
to be involved in the regulation of cell proliferation. This suggestion stems
from numerous studies showing modulation of GJC by agents that influence cellular
proliferation. Platelet-derived growth factor (PDGF), a strong mitogen, inhibits
GJC in many cell types. To understand the molecular nature of the signal
transduction pathway responsible for the GJC blockade, T51B rat liver epithelial
cells, which lack endogenous PDGF receptor (PDGFr), were infected with a
retrovirus containing either wild-type full-length cDNA of human PDGFr beta
(Kin+) or a mutant PDGFr beta lacking receptor tyrosine kinase activity (Kin-).
PDGF caused a complete but transient interruption of cell communication in Kin+
cells within 15-20 min of addition. This interruption of GJC was not associated
with a gross destabilization of gap junction plaques but with the phosphorylation
of connexin43 (Cx43), the only known gap junction protein expressed in these
cells. These effects were exhibited in either control T51B cells or in Kin-
cells, indicating a requirement of the receptor tyrosine kinase activity. Further
examination revealed that the newly phosphorylated Cx43 then undergoes a rapid
degradation utilizing the lysosomal pathway resulting in a decreased total Cx43
protein level. The re-establishment of GJC following PDGF treatment was dependent
on protein synthesis. This report describes a suitable cell system which is
currently being utilized for the characterization of the PDGF signaling pathway
responsible for the inhibition of GJC.
PMID- 9397158
TI - Endothelial and serum factors which include apolipoprotein A1 tether elastin to
smooth muscle cells inducing serine elastase activity via tyrosine kinase
mediated transcription and translation.
AB - We previously reported that serine elastase activity is induced in cultured
porcine pulmonary artery (PA) smooth muscle cells (SMC) following serum
stimulation by a mechanism involving adhesion of elastin to an elastin binding
protein and tyrosine kinase activity. The present study demonstrates that a PA
endothelial cell factor also promotes a fourfold increase in elastin adhesion to
PA SMC and a twofold increase in serine elastase activity. The mechanism involves
tethering of the factor to SMC, since [3H]-elastin pre-incubated with serum or
endothelial cell (EC)-conditioned medium or SMC pre-treated with serum
accelerates binding of elastin and tyrosine-kinase related elastase activity. The
serum factor appears to interact with integrins as elastase induction is
partially inhibited by RGD peptides. The elastase-inducing properties of serum
could not, however, be attributed to several RGD-containing proteins. While a 120
kD fibronectin fragment partially reproduced the effect, it was not found in the
serum fraction containing elastase-inducing activity. Instead, a 27 kD serum
protein was enriched by elastin affinity chromatography, identified as
apolipoprotein (Apo) A1 by microsequence analysis, and found to have about 50% of
the elastase-inducing activity of serum. Elastase induction is inhibited by
actinomycin and cycloheximide, suggesting a requirement for mRNA transcription
and protein synthesis. Our results suggest a novel cell-extracellular matrix
interaction whereby a soluble factor, in this case a lipoprotein, binds and
tethers a matrix component to the cell surface and induces tyrosine kinase
dependent transcription of mRNA culminating in substrate proteolysis.
PMID- 9397159
TI - Increased transcription and modified growth state-dependent expression of the
plasminogen activator inhibitor type-1 gene characterize the senescent phenotype
in human diploid fibroblasts.
AB - The type-1 inhibitor of plasminogen activator (PAI-1) is a major physiologic
regulator of pericellular proteolytic activity and, as such, influences matrix
integrity, cell-to-substrate adhesion, and cellular proliferation. Excessive
accumulation of both PAI-1 mRNA and protein correlates with the progressive
acquisition of morphological and growth traits characteristic of the senescent
phenotype (Mu and Higgins, 1995, J. Cell. Physiol., 165:647-657). Compared to
early-passage IMR-90 human diploid fibroblasts, a late-passage senescence
associated 11-fold elevation in steady-state PAI-1 mRNA content reflected a 15
fold increase in constitutive PAI-1 gene transcription. Differential mRNA
stability was not a factor in age-associated PAI-1 overexpression in IMR-90
cells. Upon removal of serum, early-passage human fibroblasts enter into a state
of growth arrest with marked down-regulation of PAI-1 synthesis. Rapid induction
of both the 3.0- and 2.2-kb PAI-1 mRNA species was evident upon serum-induced
"activation" of quiescent early-passage fibroblasts; induced PAI-1 transcripts
were maximal at 2 hr post-serum stimulation and declined in late G1 prior to
entry into S phase. In contrast, late-passage (p32) fibroblasts maintained a
significant level of PAI-1 expression under serum-free culture conditions.
Although the PAI-1 gene was further responsive to serum in senescent cells,
transcript abundance remained elevated and actually increased over the 12 to 16
hr post-serum addition period (a time when early-passage fibroblasts down
regulate PAI-1 mRNA content). Development of the senescent phenotype in human
fibroblasts is associated, therefore, with significant changes in PAI-1 gene
regulation. Such reprogramming involves predominantly transcriptional events and
results in a marked increase in steady-state PAI-1 transcript abundance involving
both the 3.0- and 2.2-kb mRNA species.
PMID- 9397160
TI - Retinoic acid-induced differentiation in a human neuroblastoma cell line is
associated with an increase in nitric oxide synthesis.
AB - The human neuroblastoma cell line SK-N-BE, after incubation with 10 microM
retinoic acid (RA) or 20 nM phorbol 12-myristate 13-acetate (PMA), underwent
biochemical and morphological signs of differentiation within 10-14 days. In
parallel, SK-N-BE cells produced significantly higher amounts of nitric oxide
(NO) in comparison with controls, as assessed by the measurement of nitrite and
nitrate in the culture supernatant and of NO synthase (NOS) activity in the cell
lysates (measured as ability to convert [3H]arginine into [3H]citrulline and as
NADPH diaphorase activity). Nitrite/nitrate production was abolished by adding
the NO scavenger hemoglobin in the culture medium and was inhibited by
aminoguanidine (AG, a selective inhibitor of the inducible NOS isoform) but not
by the less selective inhibitor NG-nitro-L-arginine methylester (NAME). Western
blotting experiments with monoclonal antibodies against the ncNOS and iNOS
isoforms suggest that RA-elicited NOS activation is not attributable to an
increased expression of the protein. NAME and AG were not able to revert
inhibition of proliferation induced by RA, and the NO donor sodium nitroprusside
did not mimic the effect of RA and PMA. These data indicate that increased NO
synthesis does not mediate RA- or PMA-induced differentiation but may be an
additional marker of differentiation into sympathetic-like neuronal cells.
PMID- 9397161
TI - Induction of hepatocyte growth factor/scatter factor by interferon-gamma in human
leukemia cells.
AB - Induction of hepatocyte growth factor/scatter factor (HGF/SF) may be one of the
critical steps in organ regeneration, wound healing, and embryogenesis. We
previously reported the production of HGF/SF from various human leukemia cell
lines and a high level of the growth factor in blood and bone marrow plasma from
patients with various types of leukemia. We determined here the effects of
hematopoietic cytokines on HGF/SF production in human leukemia cell lines, KG-1,
a myeloid cell line, and RPMI-8226, a B cell line. Interferon (IFN)-gamma
remarkably stimulated HGF/SF production in both cell lines at concentrations of
more than 0.1 or 1 IU/ml. IFN-alpha and IFN-beta were as effective as IFN-gamma
in RPMI-8226 cells, but less than IFN-gamma in KG-1 cells. HGF/SF gene expression
in KG-1 cells was also up-regulated by IFN-gamma. Granulocyte colony-stimulating
factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF),
interleukin (IL)-5 and IL-6 had no effect on HGF/SF production in the 2 leukemia
cell lines. We also determined the effects of HGF/SF inducers known for human
fibroblasts on the growth factor production in leukemia cells. Out of phorbol 12
myristate 13-acetate (PMA), cholera toxin, IL-1 beta, and tumor necrosis factor
(TNF)-alpha, the former three were as effective as IFN-gamma in KG-1 cells, but
only TNF-alpha stimulated HGF/SF production in RPMI-8226 cells, whose effect was
less than those of IFN-alpha, IFN-beta, and IFN-gamma. The effect of IFN-gamma in
KG-1 cells was synergistic with that of PMA. In contrast with the effect in
leukemia cells, HGF/SF induction by IFN-gamma in human skin fibroblasts was much
less than that by PMA or cholera toxin. These results indicated that IFN-gamma is
a potent inducer of HGF/SF in human leukemia cells. This finding suggests the
presence of a homeostatic control mechanism in liver regeneration and repair:
hepatic injury, DNA synthesis inhibition, or apoptosis caused by IFN-gamma is
subsequently overcome by cytokine-induced HGF/SF, a potent promoter of liver DNA
synthesis.
PMID- 9397162
TI - Co-regulation of pituitary tumor cell adhesion and prolactin gene expression by
glucocorticoid.
AB - Rat 235-1 pituitary tumor cells are lactotrophs producing high levels of
prolactin (PRL). Dexamethasone (Dex, 100 nM) inhibits PRL gene expression in 235
1 cells by 50%, while simultaneously decreasing cell replication and cell-cell
aggregation. To determine the time course of Dex action, we used a quantitative
assay for cell-cell interaction, based on the number of single cells present
before and after re-aggregation of dispersed cells. 235-1 cells were cultured in
growth medium or medium plus 100 nM Dex for 1-4 days before assay. Control cells
had 90% re-aggregation on all days of assay. Aggregation of Dex-treated cells
decreased to 55% by day 4. Dex treatment also reduced cell numbers by 40%, but
this decrease did not contribute to reduced aggregation. To determine the
mechanism of Dex-inhibited cell-cell adhesion, we examined the expression of
cadherins and catenins. Cadherin-related mRNAs (P- and N-cadherin probes) were
detectable in 235-1 cells, but their levels were unchanged by Dex. A pancadherin
antibody was unable to detect classical cadherins in these cells. Both alpha- and
beta-catenins were detected by Western blotting and their levels were decreased
by Dex. Unlike control aggregates, aggregates of Dex-treated cells were able to
inhibit expression of PRL mRNA when added to monolayers of 235-1 cells. These
data suggest that Dex influences cadherin function by inhibiting catenin
expression and that this has the functional consequence of altering 235-1 cell
cell interactions. Overall the data show that Dex affects important aspects of
lactotroph function other than PRL gene expression. These changes may include
physical alterations in pituitary cell contacts that further support a change in
functional state.
PMID- 9397163
TI - Regulation of spermidine/spermine N1-acetyltransferase expression by cytokines
and polyamines in human hepatocarcinoma cells (HepG2).
AB - Spermidine/spermine N1-acetyltransferase (cSAT), a key enzyme in polyamine
degradation, is induced by various hepatotoxins and liver tumor promoters. In
this paper we demonstrate that physiological factors, such as cytokines, control
cSAT expression in HepG2 human hepatocarcinoma cells. Hepatocyte growth factor
(HGF) induced the cSAT mRNA precursor (3.5 kb) at 4 h. The mature form of mRNA
(1.3 kb) increased 6-8-fold between 8 and 10 h, and remained elevated until 18 h.
An increase in cSAT activity (2-fold) and high levels of N1-acetylspermidine were
observed concomitantly. Interleukin-1 beta (IL-1 beta) enhanced cSAT expression
(both mRNA and enzyme activity) similar to HGF, while tumor necrosis factor-alpha
(TNF-alpha) was less effective. This system also provides a useful means for
examining the involvement of negative and positive changes of polyamines in the
induction of cSAT and c-jun, a gene that participates in the control of cSAT
expression. alpha-Difluoromethylornithine (DFMO) pretreatment, by lowering
putrescine and spermidine in HGF- or IL-1 beta-treated cells, prevented the
induction of cSAT. This effect was reversed by exogenous putrescine or
spermidine. IL-1 beta induced c-jun mRNA more than HGF. DFMO prevented almost
completely the enhancement of c-jun mRNA expression by IL-1 beta, and this effect
was reversed by exogenous putrescine or spermidine. Therefore, we suggest that
cSAT and c-jun expression is specifically regulated by polyamine-mediated
mechanisms in IL-1 beta treated HepG2 cells. Since cSAT is inducibile by
cytokines that control tumor metabolism and growth as well as tumor-host
interaction, we hypothesize an involvement of cSAT in hepatoma growth.
PMID- 9397164
TI - Potent inhibition of cell density-dependent apoptosis and enhancement of survival
by dimethyl sulfoxide in human myeloblastic HL-60 cells.
AB - Human myeloblastic cell line HL-60 cells undergo apoptosis during in vitro
culture in a cell density-dependent manner, and this cell density-dependent
apoptosis was observed when the concentration of cultured cells exceeded 8-10 x
10(5) cells/ml. Dimethyl sulfoxide (DMSO), a differentiation inducer of HL-60
cells, did not amplify, but rather potently inhibited, this apoptosis. In a low
density culture condition, DMSO attenuated proliferation of HL-60 cells in spite
of its inhibition of apoptosis. In contrast, DMSO did support cell survival under
high cell density conditions, and DMSO-treated HL-60 cells reached an extremely
high concentration of 2-3 x 10(6) cells/ml, a condition which could never be
possible in a usual culture environment. Thus, DMSO exerted dual effects on cell
proliferation, i.e., growth inhibition and apoptosis inhibition, and the sum of
these effects resulted in an apparently distinct phenomenon according to the
culture conditions including cell density.
PMID- 9397165
TI - 3 Beta-(4-ethyl-3-iodophenyl)nortropane-2 beta-carboxylic acid methyl ester as a
high-affinity selective ligand for the serotonin transporter.
PMID- 9397167
TI - Potent and selective inhibition of neuronal nitric oxide synthase by N omega
propyl-L-arginine.
PMID- 9397166
TI - Class III antiarrhythmic activity in vivo by selective blockade of the slowly
activating cardiac delayed rectifier potassium current IKs by (R)-2-(2,4
trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)- 2, 3-dihydro-1H
benzo[e][1,4]diazepin-3-yl]acetamide.
PMID- 9397168
TI - A new approach to docking in the beta 2-adrenergic receptor that exploits the
domain structure of G-protein-coupled receptors.
AB - A novel technique for docking ligands to the beta 2-adrenergic receptor is
described which exploits the domain structure of this class of receptors. The
ligands (norepinephrine, an agonist; pindolol, a partial agonist; and
propranolol, an antagonist) were docked into the receptor using the key conserved
aspartate on helix 3 (D113) as an initial guide to the placement of the amino
group and GRID maps (Goodford, P. J. J. Med. Chem, 1985, 28, 849) to identify the
likely binding regions of the hydrophobic (and hydroxyl) moieties on the A domain
(comprising of helices 1-5). The essence of the new approach involved pulling the
B domain, which includes helices 6 and 7, away from the other domain by 5-7 A.
During the subsequent minimization and molecular dynamics, the receptor ligand
complex reformed to yield structures which were very well supported by site
directed mutagenesis data. In particular, the model predicted a number of
important interactions between the antagonist and key residues on helix 7
(notably Leu311 and Asn312) which have not been described in many previous
computer simulation studies. The justification for this new approach is discussed
in terms of (a) phase space sampling and (b) mimicking the natural domain
dynamics which may include domain swapping and dimerization to form a 5,6-domain
swapped dimer. The observed structural changes in the receptor when pindolol, the
partial agonist, was docked were midway between those observed for propranolol
and norepinephrine. These structural changes, particularly the changes in helix
helix interactions at the dimer interface, support the idea that the receptors
have a very dynamic structure and may shed some light on the activation process.
The receptor model used in these studies is well supported by experiment,
including site-directed mutagenesis (helices 1-7), zinc binding studies (helices
2, 3, 5, and 6), the substituted cysteine accessibility method (helices 3, 5, and
7), and site-directed spin-labeling studies (helices 3-6).
PMID- 9397170
TI - Syntheses and photodynamic activities of novel trisulfonated zinc phthalocyanine
derivatives.
AB - The synthesis of water-soluble, unsymmetrical, trisulfonated zinc phthalocyanines
(ZnPcS3) as single products of the ring expansion of boron tri(4
sulfo)subphthalocyanine (SubPc) is reported. The novel, water-soluble trisulfo
SubPcB(OH) was prepared via hydrolysis of the tris(4-chlorosulfonyl)SubPcB(Br)
which in turn was obtained from the condensation of 4
(chlorosulfonyl)phthalonitrile with BBr3 in 1-chlorobenzene. A number of ZnPcS3
analogues were prepared via the reaction of S3SubPcB (OH) with different
diiminoisoindoline derivatives of increasing hydrophobicity. The reaction
proceeds at relative low temperature with acceptable yields. Metalation of free
base Pc's with zinc acetate dihydrate afforded the corresponding zinc complexes.
Photodynamic activities were measured against the EMT-6 mouse mammary tumor cell
line and compared to those of the known ZnPcS3 and ZnPcS4. Added (t-Bu)benzo and
(t-Bu)naphtho groups increased the in vitro cell photoinactivation efficacy of
the ZnPcS3, whereas addition of a fourth sulfobenzo or bulky diphenylpyrazino
group decreased the activity of the parent molecule. The (t
Bu)naphthotrisulfobenzoporphyrazine induced the best in vivo photodynamic tumor
control which, combined with its good solubility and broad absorption spectrum,
renders this compound an interesting dye for photodynamic applications in
medicine.
PMID- 9397169
TI - Boron-containing polyamines as DNA targeting agents for neutron capture therapy
of brain tumors: synthesis and biological evaluation.
AB - Three series of new boron-containing spermidine/spermine (SPD/SPM) analogues have
been synthesized: N1- and N5-(4-carboranylbutyl) SPD/SPM derivatives (SPD-1, SPD
5, SPM-1, SPM-5); N1,N10-diethyl-N5-(4-carboranylbutyl)spermidine (DESPD-5),
N1,N14-diethyl-N5-(4-carboranylbutyl)spermine (DESPM-5); and N5,N10-bis(4
carboranylbutyl)spermine (SPM-5,10). In vitro studies using rat F98 glioma cells
have shown that these polyamines retain the ability to displace ethidium bromide
from calf thymus DNA and are rapidly taken up by F98 glioma cells. However, their
cytotoxicities, especially those with terminal N-substituted (SPD-1, SPM-1) boron
compounds, are greater than those of SPD/SPM. Nevertheless, the groundwork has
been created for a new class of boron-containing compounds that maybe useful for
boron neutron capture therapy of tumors.
PMID- 9397171
TI - N-hydroxyalkyl derivatives of 3 beta-phenyltropane and 1-methylspiro[1H-indoline
3,4'-piperidine]: vesamicol analogues with affinity for monoamine transporters.
AB - As part of our ongoing structure-activity studies of the vesicular acetylcholine
transporter ligand 2-(4-phenylpiperidino)cyclohexanol (vesamicol, 1), 22 N
hydroxy(phenyl)alkyl derivatives of 3 beta-phenyltropane, 6, and 1-methylspiro[1H
indoline-3,4'-piperidine], 7, were synthesized and tested for binding in vitro.
Although a few compounds displayed moderately high affinity for the vesicular
acetylcholine transporter, no compound was more potent than the prototypical
vesicular acetylcholine transporter ligand vesamicol. However, a few derivatives
of 6 displayed higher affinity for the dopamine transporter than cocaine. We
conclude that modification of the piperidyl fragment of 1 will not lead to more
potent vesicular acetylcholine transporter ligands.
PMID- 9397172
TI - Tyrosine kinase inhibitors. 13. Structure-activity relationships for soluble 7
substituted 4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidines designed as
inhibitors of the tyrosine kinase activity of the epidermal growth factor
receptor.
AB - The general class of 4-(phenylamino)quinazolines are potent (some members with
IC50 values << 1 nM) and selective inhibitors of the tyrosine kinase activity of
the epidermal growth factor receptor (EGFR), via competitive binding at the ATP
site of the enzyme, but many of the early analogues had poor aqueous solubility
(<< 1 mM). A series of 7-substituted 4-[(3-bromophenyl)-amino]pyrido[4,3
d]pyrimidines, together with selected (3-methylphenyl)amino analogues, were
prepared by reaction of the analogous 7-fluoro derivatives with appropriate amine
nucleophiles in 2-BuOH or aqueous 1-PrOH. All of the compounds were evaluated for
their ability to inhibit the tyrosine-phosphorylating action of EGF-stimulated
full-length EGFR enzyme. Selected analogues were also evaluated for their
inhibition of autophosphorylation of the EGF receptor in A431 human epidermoid
carcinoma cells in culture and against A431 tumor xenografts in mice. Analogues
bearing a wide variety of polyol, cationic, and anionic solubilizing substituents
retained activity, but the most effective in terms of both increased aqueous
solubility (> 40 mM) and retention of overall inhibitory activity (IC50's of 0.5
10 nM against isolated enzyme and 8-40 nM for inhibition of EGFR
autophosphorylation in A431 cells) were weakly basic amine derivatives. These
results are broadly consistent with a proposed model for the binding of these
compounds to EGFR, in which the 6- and 7-positions of the pyridopyrimidine ring
are in a largely hydrophobic binding region of considerable steric freedom, at
the entrance of the adenine binding cleft. The most active cationic analogues
have a weakly basic side chain where the amine moiety is three or more carbon
atoms away from the nucleus. Two of the compounds (bearing weakly basic
morpholinopropyl and strongly basic (dimethylamino)butyl solubilizing groups)
produced in vivo tumor growth delays of 13-21 days against advanced stage A431
epidermoid xenografts in nude mice, when administered i.p. twice per day on days
7-21 posttumor implant. Treated tumors did not increase in size during therapy
and resumed growth at the termination of therapy, indicating an apparent
cytostatic effect for these compounds under these treatment conditions. The data
suggest that continuous long-term therapy with these compounds may result in
substantial tumor growth inhibition.
PMID- 9397173
TI - New methodology for profiling combinatorial libraries and screening sets:
cleaning up the design process with HARPick.
AB - Combinatorial chemistry is a tool of increasing importance in the field of ligand
design, as it can yield huge increases in the number of compounds available for
screening. Unfortunately, it is often the case that the number of molecules which
could theoretically be constructed greatly exceeds potential synthesis and
screening capacity. For this new technology to be fully exploited, it will become
vital to design libraries with reference to the properties of compounds already
in existence, if the added value of each new molecular collection is truly to be
maximized. Similarly, if we are to take full advantage of the potential of
combinatorial chemistry in lead optimization, it is important that our library
design paradigms are flexible, with diversity scoring functions that can be
modified to suit particular projects. Here these challenges are addressed through
the introduction of a novel computer-aided library design tool known as HARPick
(heuristic algorithm for reagent picking). The program is accessible to the bench
chemist, and incorporates several significant advances over currently available
approaches. These include product-based diversity calculations that can be
constrained at the reagent level; diversity measures constructed from multiple
descriptors; improved pharmacophore key information and full pharmacophore
profiling of entire molecular databases. The potential of these improvements to
aid in diversity profiling is illustrated through comparison with established
methodology, and possible further enhancements are discussed.
PMID- 9397174
TI - Antirhino/enteroviral vinylacetylene benzimidazoles: a study of their activity
and oral plasma levels in mice.
AB - In an effort to find an orally bioavailable antiviral for the treatment of
rhino/enteroviral infections, a series of vinylacetylene benzimidazoles (11a-o,
12, and 18a) was made. Initial studies of this class of antivirals showed that
fluorine substitution on the left-hand phenyl ring in combination with the
vinylacetylene moiety gave the requisite mix of physical properties to achieve
good in vitro antiviral activity as well as respectable oral bioavailability in
rhesus monkeys. To ascertain the generality of this finding and to broaden the
scope of the structure-activity relationship (SAR), the present study
concentrated on fluoro substitution of this class of molecules. The initial
antiviral activity for each analogue was measured using human rhinovirus 14 (HRV
14). This served as an indicator of general antiviral activity for SAR purposes.
Subsequently, the spectrum of antirhino/enteroviral activity of the more
interesting analogues was evaluated through testing against a panel of seven
additional rhino/enteroviruses. Broad-spectrum activity was present and
consistent for all analogues tested, and it tracked closely with the antiviral
activity observed against HRV-14. A simple screening protocol for oral
bioavailability was established whereby compounds were administered orally to
mice and plasma levels were measured. This procedure facilitated the evaluation
of numerous analogues in a rapid manner. The Cmax was used as a measure of oral
bioavailability to allow relative ranking of compounds. In general, fluorine
substitution directly on the left-hand aromatic ring does give good oral blood
levels. However, fluorine incorporation at other positions in the molecule was
not as effective at maintaining either the activity or the oral plasma levels.
The constructive combination of activity and oral plasma levels was maximized in
three derivatives: 11a,e,g.
PMID- 9397175
TI - Synthesis and biological properties of new constrained CCK-B antagonists:
discrimination of two affinity states of the CCK-B receptor on transfected CHO
cells.
AB - To improve our knowledge of the bioactive conformation of CCK-B antagonists, we
have developed a new series of constrained dipeptoids whose synthesis and
biochemical properties are reported here. These compounds, of general structure N
alpha-[(2-adamantyloxy)carbonyl]-alpha-methyltryptophanyl-(4 -X)-proline, were
designed by introducing a cyclization in the structure of the previously
described CCK-B/peptoid antagonist RB 210, N-[N-[(2-adamantyloxy)carbonyl]-DL
alpha-methyltryptophanyl] -N-(2-phenylethyl)glycine (Blommaert et al. J. Med.
Chem. 1993, 36, 2868-2877), by means of a five-membered ring. Structure-affinity
relationship studies showed that an R configuration of Trp-C alpha and a cis
configuration of the pyrrolidine substituents were favorable for receptor
recognition. The most potent compounds of this new series had similar affinities
for the CCK-B receptor as RB 210 and proved to be far more efficient in
inhibiting inositol phosphate production in CHO cells stably transfected with rat
brain CCK-B receptor, with IC50 values approaching those of the commonly used
antagonists L-365,260 and PD-134,308. Moreover, binding studies performed using
transfected CHO cells showed that two affinity states of the CCK-B receptor can
be discriminated by some of these compounds which also have different biological
profiles and are therefore highly interesting tools for the biochemical and
pharmacological characterization of CCK-B receptor heterogeneity.
PMID- 9397176
TI - Cyclic enkephalin analogues with exceptional potency and selectivity for delta
opioid receptors.
AB - Superpotent and highly delta-opioid receptor selective cyclic peptides of the
general formula H-Tyr-c[D-Pen-Gly-Phe(p-X)-Pen]-Phe-OH (where X = hydrogen or
halogen) have been synthesized. In the binding assays the most selective and most
potent compound is the p-bromophenyl-alanine-4 analogue (IC50 value = 0.19 nM,
selectivity ratio = 21,000 for delta vs mu). In the GPI and MVD bioassays the
most selective and most potent analogue is the p-fluoro-substituted analogue Tyr
[D-Pen-Gly-Phe(p-F)-Pen]-Phe-OH. In the MVD assay it has an exceptionally low
IC50 value of 0.016 nM and a delta vs mu selectivity ratio of 45,000.
PMID- 9397177
TI - NAcSDKP analogues resistant to angiotensin-converting enzyme.
AB - Two series of analogues of the tetrapeptide NAcSDKP, an inhibitor of
hematopoietic stem cell proliferation, were prepared, and their enzymatic
stability toward rabbit lung angiotensin-converting enzyme (ACE) was evaluated as
well as their capacity to inhibit NAcSDKP hydrolysis by this enzyme. In the first
series, each of the peptide bonds has been successively replaced by an
aminomethylene bond. In the second one, the C-terminus of the peptide has been
modified by decarboxylation or amidation. The results reported here indicate that
all of these molecules but one have good stability toward the enzyme but none of
the compounds is able to inhibit NAcSDKP hydrolysis by ACE.
PMID- 9397178
TI - Enzymatic properties of the unnatural beta-L-enantiomers of 2',3'
dideoxyadenosine and 2',3'-didehydro-2',3'-dideoxyadenosine.
AB - The beta-L-enantiomers of 2',3'-dideoxyadenosine and 2',3'-didehydro-2',3'
dideoxyadenosine have been stereospecifically synthesized. In an attempt to
explain the previously reported antiviral activities of these compounds, their
enzymatic properties were studied with respect to adenosine kinase, deoxycytidine
kinase, adenosine deaminase, and purine nucleoside phosphorylase. Adenosine
deaminase was strictly enantioselective and favored beta-D-ddA and beta-D-d4A,
whereas adenosine kinase and purine nucleoside phosphorylase had no apparent
substrate properties for the D- or L-enantiomers of beta-ddA or beta-d4A. Human
deoxycytidine kinase showed a remarkable inversion of the expected
enantioselectivity, with beta-L-ddA and beta-L-d4A having better substrate
efficiencies than their corresponding beta-D-enantiomers. Our results demonstrate
the potential of beta-L-adenosine analogues as antiviral agents and suggest that
deoxycytidine kinase has a strategic importance in their cellular activation.
PMID- 9397179
TI - 5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1
naphthylpiperazine.
AB - A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general
formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding
experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these
derivatives are potent and selective ligands for 5-HT1B/1D subtypes with
increased binding selectivity versus the 5-HT1A receptor when compared to 1
naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP
formation mediated by the human 5-HT1B receptor demonstrate that the nature of
the arylpiperazide substituent modulates the intrinsic activity of these 1-NP
derivatives. Among them, 2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy] -1-(4
o-tolylpiperazin-1-yl)ethanone (4a) was identified as a potent neutral 5-HT1B
antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5
carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, 4a was found to
potently antagonize the hypothermia induced by a selective 5-HT1B/1D agonist in
vivo in the guinea pig following oral administration (ED50 = 0.13 mg/kg).
PMID- 9397180
TI - Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor
of HIV-1 protease.
AB - Using a combination of iterative structure-based design and an analysis of oral
pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate),
a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent
enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray
cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl
ether and phenol-amide substituents of the inhibitor interact with the S1 and S2
subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is
well absorbed orally in a variety of species and possesses favorable
pharmacokinetic properties in humans. AG1343 (Viracept) has recently been
approved for marketing for the treatment of AIDS.
PMID- 9397181
TI - Effect of stereochemistry on the clearance mechanism of 111In(III)-labeled D- or
L-benzyldiethylenetriaminepentaacetic acid.
AB - The diethylenetriaminepentaacetic acid (DTPA) derivatives L-Bn-DTPA and D-Bn-DTPA
were synthesized and radiolabeled with 111In3+. The uptake and clearance of the
compounds were determined through biodistribution and excretion studies in Wistar
rats. Both isomers readily cleared from the animal. The D isomer showed
relatively high kidney uptake and predominantly renal clearance. The L isomer
showed substantial kidney and liver uptake with equal biliary and renal
clearance. Clearance was also evaluated in TR- Wistar rats, which are defective
in the liver canalicular multispecific organic anion transporter (cMOAT) protein.
cMOAT mediates hepatobiliary clearance of many organic anions. Both compounds
were excreted through the urine in TR- Wistar rats, suggesting that cMOAT is
important in the clearance of the compounds from the liver.
PMID- 9397182
TI - Investigation of the potential impact of benchmark dose and pharmacokinetic
modeling in noncancer risk assessment.
AB - There has been relatively little attention given to incorporating knowledge of
mode of action or of dosimetry of active toxic chemical to target tissue sites in
the calculation of noncancer exposure guidelines. One exception is the focus in
the revised reference concentration (RfC) process on delivered dose adjustments
for inhaled materials. The studies reported here attempt to continue in the
spirit of the new RfC guidelines by incorporating both mechanistic and delivered
dose information using a physiologically based pharmacokinetic (PBPK) model,
along with quantitative dose-response information using the benchmark dose (BMD)
method, into the noncancer risk assessment paradigm. Two examples of the use of
PBPK and BMD techniques in noncancer risk assessment are described: methylene
chloride, and trichloroethylene. Minimal risk levels (MRLs) based on PBPK
analysis of these chemicals were generally similar to those based on the
traditional process, but individual MRLs ranged from roughly 10-fold higher to
more than 10-fold lower than existing MRLs that were not based on PBPK modeling.
Only two MRLs were based on critical studies that presented adequate data for BMD
modeling, and in these two cases the BMD models were unable to provide an
acceptable fit to the overall dose-response of the data, even using
pharmacokinetic dose metrics. A review of 10 additional chemicals indicated that
data reporting in the toxicological literature is often inadequate to support BMD
modeling. Three general observations regarding the use of PBPK and BMD modeling
in noncancer risk assessment were noted. First, a full PBPK model may not be
necessary to support a more accurate risk assessment; often only a simple
pharmacokinetic description, or an understanding of basic pharmacokinetic
principles, is needed. Second, pharmacokinetic and mode of action considerations
are a crucial factor in conducting noncancer risk assessments that involve animal
to-human extrapolation. Third, to support the application of BMD modeling in
noncancer risk assessment, reporting of toxicity results in the toxicological
literature should include both means and standard deviations for each dose group
in the case of quantitative endpoints, such as relative organ weights or testing
scores, and should report the number of animals affected in the case of
qualitative endpoints.
PMID- 9397183
TI - Comparison of the binding potential of various diisocyanates on DNA in vitro.
AB - Inhalation of diisocyanate vapors is associated with immediate-type
hypersensitivity reactions and direct toxic responses. The genotoxic effects of
diisocyanates have not been clarified. The aim of this study was to examine the
changes in DNA following in vitro exposure to three most commonly used
diisocyanates (toluene diisocyanate, TDI; methylenediphenyl-4,4'-diisocyanate,
MDI; and hexamethylene diisocyanate, HDI) and to compare their binding potential
using melting behavior of DNA and electrophoresis studies in DNA. Following
incubation of DNA with MDI (pure and mix) and HDI we found no differences in the
melting behavior compared to the control calf thymus DNA. However, DNA treated
with TDI showed differences in the shape of the native DNA curves due to changes
in hyperchromicity and exhibited 14% more DNA reconstitution after renaturation.
The small changes in the melting behavior of native DNA do not suggest the
formation of DNA intrastrand cross-links but rather conformational changes of
single- and double-stranded DNA. These conformational changes were further
explored by agarose electrophoresis of native and denatured calf thymus DNA.
Control and all diisocyanate-exposed DNA showed no differences in the size of
native DNA fragments. Conversely, electrophoresis of TDI mix-incubated DNA,
following denaturation, showed a distinct reduction in the double-stranded DNA
fragment size compared to the control, MDI-denatured (pure and mix), and HDI
denatured DNA. These findings may help to better understand the mechanisms of the
genotoxic effect of TDI.
PMID- 9397184
TI - Cadmium toxicity and distribution in metallothionein-I and -II deficient
transgenic mice.
AB - To date, numerous correlative studies have implicated metallothionein in the
detoxification of heavy metals and in the regulation of metal distribution within
an organism. In the present study cadmium-binding proteins (metallothionein
equivalents), cadmium acute toxicity, and cadmium distribution in tissues and
subcellular fractions were compared in metallothionein-I and -II deficient (MT-/
) mice and the parental strain carrying intact metallothionein genes (MT+/+) to
determine if the absence of metallothionein altered any of these parameters. In
an uninduced state, MT-/- mice expressed lower levels of cadmium-binding proteins
relative to MT+/+ mice in several tissues. Administration of zinc enhanced the
levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas,
and male sex organs, but not in cecum or brain of MT+/+ mice compared to zinc
pretreated MT-/- mice. The cadmium LD50 was similar for MT-/-, MT+/+, and zinc
pretreated MT-/- mice (15-17 mumol CdCl2/kg body weight delivered i.p.). However,
zinc-pretreated MT+/+ mice had a cadmium LD50 of 58-63 mumol CdCl2/kg body
weight. Over two-thirds of cadmium was found in liver, cecum, small intestine,
and kidney in both MT+/+ and MT-/- mice; therefore, metallothionein levels do not
appear to play a major role in the tissue distribution of cadmium. However, after
zinc pretreatment, MT+/+ mice accumulated more cadmium in the liver and less in
other tissues, whereas the amount of cadmium in the liver was not altered by zinc
pretreatment in MT-/- mice. In general, the cytosolic/particulate ratio of
cadmium was significantly higher in tissues of noninduced MT+/+ mice relative to
MT-/- mice. This difference was accentuated after zinc pretreatment. Together
these results indicate that basal levels of metallothionein do not protect from
the acute toxicity of a single i.p. cadmium challenge. Furthermore, it does not
appear that the cytosolic compartmentalization of cadmium is correlated with
reduced toxicity.
PMID- 9397185
TI - Alterations of male Wistar rat jejunum induced by Dodine (n-dodecylguanidine
acetate).
AB - The effect of Dodine on the intestine was studied after a single administration
of 1000 mg/kg, which corresponds to the LD50 in male Wistar rats. At this dose, a
significant decrease in body weight was observed, accompanied by diarrhea, which
may be associated with intestinal alterations. The chemical induced a significant
reduction of the protein content and in sucrase activity in the jejunum.
Morphological alterations included a significant decrease in crypt height and in
villus length and depth. The intestinal modifications observed in animals after
Dodine administration may explain the observed loss in body weight and diarrhea.
PMID- 9397186
TI - Gene knockout and transgenic technologies in risk assessment: the next
generation.
AB - Transgenic and knockout mice have been proposed as substitutes for one of the
standard 2-yr rodent assays. The advantages of using genetically engineered mouse
models is that fewer mice are needed, the time to develop disease is greatly
reduced, and the mice are predisposed to developing cancer by virtue of gain or
loss of functions. The models currently being used have yielded a large amount of
data and have proved to be informative for risk assessment; however, they are
still far from ideal. In fact, they inherently do not reflect the complexity of
mutation and carcinogenesis in humans. Recent advances in technology and the
creation of new knockout mice may produce more useful and more sensitive models.
This review covers two recent advances in technology--inducible and regulatable
gene expression and targeted genetic modifications in the genome--that will allow
us to make better models. I also discuss new gene deletion and transgenic mouse
models and their potential impact on risk-assessment assays. These models are
presented in the context of four basic components or events that occur in the
multistep process leading to cancer: maintenance of gene expression patterns,
genome stability and DNA repair, cell-cell communication and signaling, and cell
cycle regulation. Finally, surrogate markers and utility in risk assessment are
also discussed. This review is meant to stimulate further discussion in the field
and to generate excitement about working toward the next generation of risk
assessment models.
PMID- 9397187
TI - New directions for predicting carcinogenesis.
AB - Carcinogenicity testing today normally includes conducting 2-yr studies of rats
and mice of both sexes and following widely accepted procedures for husbandry,
selection of dose levels, pathology and toxicity observations, and statistical
interpretation of tumor data. These studies are usually preceded by tests for
genetic toxicity and subchronic toxicity studies to select dose levels for the 2
yr studies. While these data are used for quantitative risk assessment, the
mechanistic basis for effects is usually unknown, and such series of studies are
very expensive and require five or more years to conduct. Alternate approaches
are being developed that would provide more mechanistic information and perhaps
would permit decisions to be made about carcinogenic potential without the need
to conduct 2-yr studies of rats and mice of both sexes. Decisions could be based
on a profile of data rather than the result of one test. Regulatory acceptance of
new approaches for carcinogenicity testing is critical to future progress in the
field of carcinogenesis.
PMID- 9397188
TI - Potency grading in carcinogen classification.
AB - In 1992 the United Nations Conference on Environment and Development decided to
harmonize carcinogen classification systems. A proposal for a harmonized
classification system is currently being considered by the Organization for
Economic Cooperation and Development (OECD). In many countries, classification of
a chemical as carcinogenic triggers labeling requirements. Implicit in the
labeling requirements are often restrictions on the sale of consumer products and
workplace regulations. Many of the current classification systems for carcinogens
use a single concentration limit for the minimum concentration of a carcinogen in
a preparation (mixture) that requires labeling. For high-potency carcinogens, one
concentration limit may not adequately express the hazard, whereas for low
potency carcinogens, one limit may overestimate the hazard caused by the
carcinogen in the preparation (mixture). The potency grading system discussed
consists of three potency groups: high-, medium-, and low-potency carcinogens. It
is envisioned that the different classes will trigger different labeling
requirements. In the process of potency grading, a preliminary conclusion as to
whether a substance shows high, medium, or low potency is initially based on a
tumorigenic dose descriptor. The preliminary potency evaluation may then be
modified after due consideration of a number of additional elements. These may
include evaluation of the dose-response curve; site-, species-, strain-, and sex
specific activity; mechanisms including genotoxicity; mechanistic relevance to
humans; toxicokinetics; and other factors. The potency grading system discussed
is applicable to most carcinogen classification systems, including that currently
being considered by the OECD.
PMID- 9397189
TI - Differential display identified changes in mRNA levels in regenerating livers
from chloroform-treated mice.
AB - The nongenotoxic-cytotoxic carcinogen chloroform induces liver necrosis,
regenerative cell proliferation, and, eventually, liver tumors in female B6C3F1
mice when administered by gavage at doses of 238 or 477 mg/kg/d. Administration
of 1800 ppm of chloroform in the drinking water results in similar daily doses
but does not produce liver toxicity or cancer. The differential-display technique
was used to compare the expression of a subset of mRNAs in normal (control) and
regenerating liver after chloroform-induced toxicity to define the proportion of
genes whose expression changes under hepatotoxic conditions and to identify the
genes that might play a role in regeneration and perhaps cancer. RNA was purified
from the livers of female B6C3F1 mice after 4 d or 3 wk of gavage treatment with
3, 238, or 477 mg/kg/d of chloroform or treatment with 1800 ppm chloroform in
drinking water. There was a remarkably high degree of consistency of gene
expression among the animals and across dose and treatment groups as visualized
by the differential-display technique. Of the 387 bands observed, only four
(about 1%) changed expression in regenerating liver. The genes were assigned
locus names by GenBank after sequence submission. The genes with increased mRNA
levels as confirmed by northern blot analysis were MUSTIS21, a mouse primary
response gene induced by growth factors and tumor promoters; MUSMRNAH, a gene
highly homologous to a human gene isolated from a prostate carcinoma cell line;
and MUSFRA, a novel gene. The novel gene MUSFRB exhibited decreased mRNA levels.
No change in expression was seen among control mice given the nontoxic regimens
of 3 mg/kg/d chloroform or 1800 ppm chloroform in drinking water, indicating that
changes in expression were associated with toxicity and regeneration rather than
chloroform per se. These genes and others that may be identified by expanding
this approach may play a role in regeneration and perhaps in the process of
chloroform-induced carcinogenesis in rodent liver.
PMID- 9397190
TI - Susceptibility of transgenic mice carrying human prototype c-Ha-ras gene in a
short-term carcinogenicity study of vinyl carbamate and ras gene analyses of the
induced tumors.
AB - To determine if hemizygous transgenic mice carrying the human c-Ha-ras gene
(CB6F1-Tg Hras2 mice (Hras2 mice)) are susceptible to the carcinogenic potential
of known murine carcinogens, male and female Hras2 mice and their non-transgenic
CB6F1 littermates (non-Tg mice) were each given a single intraperitoneal
injection of 60 mg of vinyl carbamate (VC)/kg body weight or saline (vehicle
control) and monitored for 16 wk without further treatment. At necropsy, grossly
visible tumors were fixed for histopathologic diagnosis and, when of sufficient
size, portions were frozen for subsequent molecular analysis. Nine of 31 male and
nine of 29 female Hras2 mice treated with VC died within 16 wk as a result of
lung tumor burden. At the termination of the study, lung tumors (alveolar
bronchiolar epithelial neoplasms and hemangiosarcomas) and focal alveolar
bronchiolar hyperplasias were present in both sexes of Hras2 and non-Tg mice
treated with VC; there were significantly more proliferative lung lesions in
Hras2 than non-Tg mice. Splenic hemangiosarcomas and squamous cell tumors of the
forestomach were induced in male and female VC-treated Hras2 mice but not in VC
treated non-Tg mice. Polymerase chain reaction-single-strand conformation
polymorphism analysis and DNA sequencing of the induced lung tumors revealed
point mutations at codon 61 of the transgene in two of 29 lung tumors (one of 16
in males and one of 13 in females) from VC-treated Hras2 mice; no mutations in
murine Ki-ras were found in these tumors. Point mutations at codons 12 and 61 of
the murine Ki-ras gene were observed, however, in one of 10 and six of 10 lung
tumors respectively, from VC-treated non-Tg mice. These findings indicate that
Hras2 mice are highly sensitive to pulmonary neoplasms and splenic and lung
hemangiosarcomas after treatment with VC. The molecular analyses suggest that
point mutations of the transgene and the murine Ki-ras gene do not play a major
role in VC induction of pulmonary neoplasms in these transgenic mice.
PMID- 9397191
TI - Induction of mouse cytochrome P450 2B enzymes by amine metabolites of musk
xylene: contribution of microsomal enzyme induction to the hepatocarcinogenicity
of musk xylene.
AB - Musk xylene (MX) is a synthetic nitromusk perfume ingredient that, although
uniformly negative in genotoxicity testing, causes liver tumors in B6C3F1 mice.
MX is also capable of inducing cytochrome P450 enzymes in a manner similar to
that of phenobarbital (PB), which suggests that epigenetic mechanisms may be
involved in the carcinogenic response. At the same time, MX is metabolized in
vivo by nitroreduction, a reaction catalyzed by intestinal flora that yields
aromatic amine metabolites. These amine metabolites are also capable of
inactivating CYP2B10, the major cytochrome P450 enzyme induced by MX treatment.
In the study reported here, the monoamine metabolites of MX, o- and p-NH2-MX,
were evaluated for their potential to induce CYP2B10 and CYP1A2 mRNAs. Northern
blot analyses indicated that both amines markedly induced CYP2B10 mRNA, whereas
CYP1A2 mRNA, the enzyme implicated in the bioactivation of aromatic amines and
frequently induced by aromatic amines, was induced only slightly, a response that
was not different from that seen with PB. Induction of CYP2B10 mRNA suggested
that the amine metabolites may contribute to the enzyme induction profile seen
with MX treatment. To test this hypothesis, mice were treated with broad-spectrum
antibiotics (neomycin, tetracycline, and bacitracin) to eliminate the intestinal
flora and prevent formation of o- and p-NH2-MX. In antibiotic-treated mice
treated with MX (200 mg/kg) for 4 d, no evidence of microsomal enzyme induction
was observed, including no increases in liver weight, total cytochrome P450
content, or CYP2B protein levels. These results indicate that the amine
metabolites of MX are responsible for the enzyme induction seen after MX
administration. Thus, the biochemical and molecular effects of amine metabolites
of MX are markedly different from those of other aromatic amines but very similar
to those of PB. Therefore, it appears that MX is a non-genotoxic chemical that
may cause mouse liver tumors in a manner analogous to that of PB.
PMID- 9397192
TI - Reverse transcription-polymerase chain reaction-based methodology to quantify
differential gene expression directly from microdissected regions of frozen
tissue sections.
AB - Quantitative differences in the expression of oncogenes are a critical feature of
the cancer process. Several methods are currently available for assessing
differential gene expression, but none can be used to determine quantitative
changes in gene expression from small numbers of cells. The ability to conduct
this type of quantitative analysis would be useful in the study of definable,
early stages of carcinogenesis when very few cells are involved. We therefore
developed a highly sensitive, slide-based technique that incorporates the
benefits of in situ polymerase chain reaction (PCR) and reverse transcription-PCR
(RT-PCR) to quantify differential c-myc gene expression from liver tissue
sections having either low or high levels of proliferating hepatocytes. To
eliminate the need for isolating and quantifying mRNA, cells of interest were
microdissected from frozen histological sections and their RNA directly subjected
to RT-PCR amplification. These reactions were conducted in the presence of an
internal RNA standard that was specifically designed to normalize differential RT
and PCR efficiencies between samples. GENESCAN software analysis was used to
determine the ratios of the RT-PCR products of the target gene to the RNA
standard. These ratios were then normalized to the numbers of cells isolated, as
quantified by image analysis, and comparative gene expression values were
determined between sample groups. We conclude that this technology can be adapted
to study any gene of interest in any type of frozen tissue or isolated cells.
This methodology is particularly applicable to the molecular analysis of
histopathologically distinct preneoplastic and neoplastic lesions identified on
tissue sections.
PMID- 9397194
TI - MHC class I and II expression in prostate carcinoma and modulation by interferon
alpha and -gamma.
AB - BACKGROUND: Expression of Major Histocompatibility Complex (MHC) class I and II
antigens are critical for the cellular immune response. Loss of MHC expression
represents one mechanism by which cancer cells escape immune recognition.
PURPOSE: To define MHC class I and II expression by prostate cancer (PCa) in vivo
and in vitro and the ability to modulate MHC expression in vitro with IFN-alpha
and -gamma. METHODS: Frozen tissue sections of 25 benign prostatic hyperplasia
(BPH) and 18 PCa specimens were studied by immunohistochemistry. PCa cell lines
LNCaP, PC-3, and DU-145 were studied by FACS, ELISA, and cytospin. Class I was
detected by monoclonal antibody (mAb) W6/32, and class II by mAb 13.17. The
effects of IFN-alpha and -gamma were assessed by testing the three cell lines in
the presence or absence of varying concentrations of the cytokine for varying
incubation times. RESULTS: Class I was strongly expressed by 24/25 BPH specimens;
4/18 (22%) PCa were homogeneously class I-positive, while 5/18 (28%) were
heterogeneously positive and 9/18 (50%) were class I-negative. PC-3 and DU-145
expressed normal levels of class I, while LNCaP expressed only low levels. All
line except LNCaP demonstrated significant up-regulation of class I with either
IFN-alpha or -gamma. Class II expression was not seen in BPH epithelium nor in
17/18 PCa. Class II could be only weakly induced in the three PCa lines.
CONCLUSIONS: These findings confirm prior studies demonstrating that class I
expression is commonly lost or diminished in PCa. In addition, class II up
regulation by IFN-gamma appears very limited in relation to other normal or
neoplastic epithelium. IMPLICATIONS: The present findings, taken together with
previous studies, are most consistent with the expression of neoantigens by PCa,
which are recognized and appropriately eliminated by the cellular immune system.
This selective pressure favors outgrowth of cells which down-regulate or lose
class I and/or class II expression. Understanding PCa immunobiology will help in
the development of effective immunotherapy for this disease.
PMID- 9397193
TI - Expression and localization of aminopeptidase A, aminopeptidase N, and dipeptidyl
peptidase IV in benign and malignant human prostate tissue.
AB - BACKGROUND: Cell-surface peptidases are ectoenzymes which regulate the access of
bioactive peptides to their receptors on cell membranes. Abnormalities in their
expression and function result in altered peptide activity which contribute to
neoplastic transformation and/or progression. METHODS: Expression of
aminopeptidase A (APA), aminopeptidase N (APN, CD13), and dipeptidyl peptidase IV
(DPP IV, CD26) was immunohistochemically examined in 20 benign and 33 malignant
prostate tissues (19 primaries and 14 metastases). RESULTS: Benign prostatic
stroma exhibited no APA, APN, or DPP IV immunoreactivity. Stromal cells
surrounding prostatic carcinoma cells demonstrated increased APA expression in
24/33 (73%) of tumors. Benign prostatic epithelial cells strongly expressed APN
and DPP IV but not APA. In contrast, APN was expressed in > 80% of tumor cells in
5/33 (15%) of specimens, heterogeneously expressed (20-80% of cells positive) in
4/33 (12%) of specimens, and minimally expressed or absent in 24/33 (73%) of
tumor specimens, with a similar pattern of expression in primary and metastatic
tumors. DPP IV was expressed by > 80% of tumor cells in 18/19 (95%) of primary
prostate cancer specimens, but in only 7/14 (50%) of metastases. CONCLUSIONS:
These data show that cell-surface peptidases are differentially expressed by
normal prostatic stromal and epithelial cells, with increased expression of APA
in the stroma surrounding prostate cancer cells, absent APN expression in most
tumor cells, and a decreased frequency of DPP IV expression in metastatic tumors.
Further studies will elucidate the biological effects of the presence or loss of
cell-surface peptidases in the benign and malignant prostate.
PMID- 9397196
TI - Underutilization of health services among patients with urinary symptoms: results
of a population-based survey in Israel.
AB - BACKGROUND: Although there is firm evidence concerning the relatively-high rates
of overutilization of prostate surgery among elderly men, only minimal efforts
have been made to evaluate the existence and extent of underutilization. This
assessment, accomplished by our study, may have a significant impact on health
services planning and budgeting. METHODS: The study population comprised a
nationwide representative sample of 960 Israeli men, aged between 45 and 75
years. Data were accumulated by personal interviews conducted at the homes of the
individuals by trained staff. The questions included in the questionnaire aimed
at describing the sociodemographic and clinical status. The responses to
questions regarding male urinary symptoms were obtained by personal reports.
RESULTS: Forty-three percent of the subjects reported having experienced urinary
symptoms, but only 4.6% were severely bothered by the symptoms on a daily basis,
and 8.9% were moderately bothered. Only 55.4% of patients with bothersome urinary
symptoms visited their general practitioners, while only 39.7% were referred to a
urologist because of their complaints. CONCLUSIONS: Elderly men bothered by
urinary symptoms frequently do not seek health care. An educational program
regarding the potential benefit of medical interventions for benign prostatic
hypertrophy may significantly improve their quality of life.
PMID- 9397195
TI - Heredity and prostate cancer: a study of World War II veteran twins.
AB - BACKGROUND: Increased risk of prostate cancer among men with a family history of
the disease has been observed in several epidemiological studies, and family
studies have identified hereditary prostate cancer characterized by early onset
and autosomal dominant inheritance. METHODS: In this study, we examine prostate
cancer heritability among twins in the NAS-NRC Twin Registry, with cases
ascertained from a number of sources: recent telephone interviews, Medicare and
Department of Veterans Affairs hospitalizations, previous mail questionnaires,
and death certificates. A total of 1,009 prostate cancer cases were identified
among the cohort of 31,848 veteran twins born in the years 1917-1927. RESULTS:
Probandwise concordance for prostate cancer was substantially higher among
monozygous twin pairs, 27.1%, than among dizygous twin pairs, 7.1% (P < 0.001).
CONCLUSIONS: These data suggest that genetic influences account for approximately
57%, and environmental influences for 43%, of the variability in twin liability
for prostate cancer.
PMID- 9397197
TI - Pamidronate administration improves the secondary hyperparathyroidism due to
"Bone Hunger Syndrome" in a patient with osteoblastic metastases from prostate
cancer.
AB - BACKGROUND: The so-called Bone Hunger Syndrome is a metabolic derangement that
sometimes complicates the natural history of prostate cancer patients with
osteoblastic bone metastases. An excessive bone formation leads to calcium
entrapment in bone and the subsequent increase of parathyroid hormone (PTH)
levels, in response to calcium demand. PTH elevation stimulates the osteoclasts
in sites distant from those involving the tumor, leading to osteomalacia.
METHODS: PTH and markers of bone turnover were monitored every 3 weeks, from the
start of pamidronate treatment in a prostate cancer patient with progressive
disease, to luteinizing hormone releasing hormone analog (LHRH-A) administration,
developing hyperparathyroidism, hypophosphatemia, and albumin corrected serum
calcium close to the lower limit of normality. Serum bone alkaline phosphatase
(BALP), assessed by two different methods: electrophoretic and immunoradiometric,
and urinary levels of markers of bone collagen breakdown were also remarkably
elevated. RESULTS: As a consequence of pamidronate infusion (60 mg e.v. every 3
weeks for a total of four times), BALP and PTH decreased consistently, serum
calcium and phosphorus returned within the normal range, while markers of
collagen resorption showed a significant decrease at the 9th week, preceded by a
transient rise. CONCLUSIONS: This case report indicates that bisphosphonates
could inhibit both osteoclast activity. The anti-osteoblastic effect is mainly
responsible for the improvement of the pretreatment calcium imbalance of our
patient towards hypocalcemia and the consequent hyperparathyroidism.
PMID- 9397198
TI - Caloric restriction diminishes the age-associated loss of immunoreactive catalase
in rat prostate.
AB - BACKGROUND: Caloric restriction (CR) retards aging and diseases in mice, rats,
and other animals by unknown mechanisms. A popular hypothesis is that CR acts by
opposing age-associated increases in oxidative stress. METHODS: Because
influences of CR on antioxidant enzymes in the prostate have not been previously
investigated, immunohistologic methods (light and electron microscopy) were used
to determine the prostatic localization of catalase (CAT) in rats of diverse ages
(3-32 months) fed either normally or subjected to CR from age 16 months. RESULTS:
In 20-month-old rats fed either diet, CAT appeared as dense deposits at the
apical poles of the epithelium in the lateral lobes, and within the ductular
lumens, suggesting that CAT is secreted. Confirmation of both liver peroxisomal
and prostatic apical cytoplasmic localization of CAT was provided by electron
microscopic immunogold staining. The amount of CAT was reduced at 30 months in
normally fed rats but not in those on CR. CONCLUSIONS: CAT appears to be a
secretory product of the epithelial cells in the lateral lobes of the rat
prostate. Further, CR from late-middle age opposed the age-associated loss of
this intracellular enzyme activity.
PMID- 9397199
TI - Effects of Ca++ mobilization on expression of androgen-regulated genes:
interference with androgen receptor-mediated transactivation by AP-I proteins.
AB - BACKGROUND: The adult prostate is maintained through an equilibrium between cell
growth and death rates. Androgen deprivation induces an increase in intracellular
Ca++, AP-1 gene expression of androgen-inducible genes. METHODS: Northern blot
analysis, band-shift assays, and transient cotransfection assays were used to
study the effects of Ca++ mobilizer A23187 on gene expression in human prostate
cancer cells. RESULTS: A23187 repressed androgen-upregulated mRNAs for prostate
specific antigen (PSA) and hKLK2, and rapidly induced mRNA levels for c-fos and c
jun. AP-1 protein-DNA binding activities were elevated after A23187 treatments.
Androgen receptor (AR)-mediated induction of chloramphenicol acetyltransferase
(CAT) reporter was repressed by AP-1 proteins. CONCLUSIONS: The repression of AR
mediated induction of PSA and hKLK2 genes by Ca++ mobilizers is due to the
interference of AR transactivation activity by AP-1 proteins.
PMID- 9397200
TI - Localization of prostate cancer metastasis-suppressor activity on human
chromosome 17.
AB - BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy in American
men. Currently, it is difficult to accurately predict the clinical course of
histologically localized prostatic cancer in the individual patient.
Identification of markers for metastatic potential of prostate cancer may improve
the diagnosis and treatment of this disease. We have previously demonstrated that
human chromosome 17 (17pter-q23) suppresses the metastatic ability of AT6.1 rat
prostatic cancer cells. In this study we report on the further localization of
the metastasis suppressor activity encoded by human chromosome 17. METHODS: A
series of AT6.1-17 microcell hybrids was constructed using microcell-mediated
chromosomal transfer of human chromosome 17 into highly metastatic AT6.1 cells.
Hybrids which had spontaneously deleted regions of chromosome 17 were analyzed by
PCR for the presence of 32 sequence-tagged sites (STS) markers as well as the
prostate cancer tumor-suppressor loci reported on 17q. In addition, we examined a
number of candidate genes and markers that previously have been mapped to
chromosome 17. The in vivo metastatic potential of these AT6.1-17 deletion
hybrids was determined. RESULTS: We have localized metastasis-suppressor activity
to a approximately 70-centiMorgan (cM) portion of chromosome 17, consisting of
three distinct regions of 30 cM (D17S952-->D17S805), 6 cM (D17S930-->D17S797),
and 34 cM (D17S944-->D17S784). Three of the four markers on 17p13, including HIC1
and TP53, and 12 of the 13 markers in 17q21-23, including BRCA1 (D17S855) and
NM23 (NME1), were not retained in the conserved approximately 70-cM metastasis
suppressor region. CONCLUSIONS: These results support a role for a novel
metastasis-suppressor gene(s) or a novel metastasis-suppressor function on
chromosome 17. Complementary candidate gene and positional cloning approaches are
being used to identify the gene(s) within the approximately 70-cM conserved
region responsible for metastasis suppression.
PMID- 9397201
TI - Comparison of serum PSMA, PSA levels with results of Cytogen-356 ProstaScint
scanning in prostatic cancer patients.
AB - BACKGROUND: Stored serum from clinical trial cases undergoing ProstaScint (CYT
356) scanning were available for Prostate Specific Membrane Antigen (PSMA) assay.
Prostate Specific Antigen (PSA) levels had already been determined. This provided
an opportunity to see what correlations existed between the serum markers and the
ProstaScint scan. A group of patients had the studies preprostatectomy, whereas
another group had the studies postprostatectomy. METHODS: The scan results, serum
PSA, serum PSMA, and clinical data were separately analyzed. PSMA serum levels
were determined by Western blot. RESULTS: Preoperatively, radical prostatectomy
patients showed a correlation between serum PSA or PSMA levels and the
ProstaScint scan in the total group (n = 86), or in an untreated group (n = 38).
Preoperatively, PSMA correlated with the pathological stage, whereas PSA
correlated with the scan. Postoperatively, only PSMA serum levels correlated with
the scan in an untreated group (n = 40). CONCLUSIONS: Preoperatively or
postoperatively, Western blot PSMA serum levels predict the stage of disease or
local, regional, or distant metastases, as shown by ProstaScint scan. Both the
scan and the serum tests provide prognostic information and evaluate the extent
of disease to a more significant degree than previously possible.
PMID- 9397203
TI - Intrathoracic gastric volvulus from blunt abdominal trauma. A case report.
PMID- 9397202
TI - HHV-8 (KSHV) does not establish latency in prostate cancer cell lines.
AB - BACKGROUND: HHV-8 is a new herpesvirus found in lesions of Kaposi's sarcoma and
some lymphoproliferative diseases. More recently, a report stated that normal
prostate tissue also contains the virus. METHODS: The expression of HHV-8 was
examined by a sensitive reverse-transcriptase PCR for the viral genes ORF 72, ORF
73, ORF 74, and ORF 75. In coculture experiments we attempted to infect 3
commonly studied prostate cancer cell lines using induced and uninduced lymphoid
cell lines harboring HHV-8 (KS-1, BC-1, and BC-2). For induction of viral genes,
butyrate and phorbol esters were used. RESULTS AND CONCLUSIONS: At baseline,
prostate cancer cell lines LNCaP, DU-145, and PC-3 did not express viral gene
products. Extensive coculture experiments were also negative. In no instance
could latency for the virus be established. Our results argue against the
involvement of HHV-8 in prostate cancer and for a limited tissue tropism of HHV
8.
PMID- 9397204
TI - Polygalacturonase inhibitors in bean pods.
AB - The amount of polygalacturonase-inhibiting protein (PGIP) was 14 times higher in
bean pods than in etiolated hypocotyls. The PGIP was extracted from bean pods and
partially purified by chromatography on columns of S-Sepharose. DEAE-Sephadex A
50, and Sephadex G-75. Further purification by ion-exchange chromatography on a
Mono Q column separated two isoforms of the inhibitor. The two PGIPs were similar
in most properties but differed slightly in pI values. They also differed in one
residue of the N-terminal amino acid sequences. Both bean pod PGIPs differed in
two and possibly three residues of the deduced N-terminal amino acid sequence for
hypocotyl PGIP. Small alterations in the structure of PGIP may represent a
strategy in bean plants for resistance to a variety of pathogens.
PMID- 9397205
TI - Acyl secoiridoids and antifungal constituents from Gentiana macrophylla.
AB - LC-UV-mass spectrometry and bioassay co-directed fractionation of an aqueous
acetone extract of the roots of Gentiana macrophylla gave three new chromene
derivatives and two novel and six known secoiridoids, along with kurarinone,
kushenol I, beta-sitosterol, stigmasterol, daucosterol, beta-sitosterol-3-O
gentiobioside, alpha-amyrin, oleanolic acid, isovitexin, gentiobiose and methyl 2
hydroxy-3-(1-beta-D-glucopyranosyl)oxybenzoate. The structures of the new
products were established from spectral and chemical evidence as 2
methoxyanofinic acid and macrophyllosides A-D. The six known secoiridoids were
gentiopicroside, sweroside, 6'-O-beta-D-glucosylgentiopicroside, 6'-O-beta-D
glucosylsweroside, trifloroside and rindoside. The new acid (2-methoxyanofinic
acid), its methyl ester, kurarinone and kushenol I were shown to be active
against the plant pathogenic fungus Cladosporium cucumerinum. The methyl ester
and kurarinone inhibited also the growth of the human pathogenic yeast Candida
albicans. Structure-activity relationships were studied. Thus, addition of a
methoxyl group to the benzene nucleus of anofinic acid (2,2-dimethyl-2H-1
benzopyran-6-carboxylic acid) increased the antifungal activity remarkably
whereas glycosylation at the carboxylic moiety was found to remove the activity.
Esterification of the new acid induced its activity against C. albicans, but
decreased its growth inhibition properties against C. cucumerinum. Hydroxylation
of kurarinone at the 3 beta-position removed its activity against C. albicans and
decreased the inhibition of C. cucumerinum. In addition, the chemotaxonomic
significance of the identified constituents is discussed.
PMID- 9397206
TI - Antifungal and antibacterial naphthoquinones from Newbouldia laevis roots.
AB - From a dichloromethane extract of Newbouldia laevis roots, four new (6
hydroxydehydroiso-alpha-lapachone, 7-hydroxydehydroiso-alpha-lapachone, 5,7
dihydroxydehydroiso-alpha-lapachone and 3-hydroxy-5-methoxydehydroiso-alpha
lapachone) and six known naphthoquinones have been isolated. Their structures
were established by spectroscopic methods (UV, EI mass spectrometry, 1H and 13C
NMR) and that of 7-hydroxydehydroiso-alpha-lapachone was confirmed by X-ray
crystallography. All naphthoquinones showed antifungal activity against
Cladosporium cucumerinum and Candida albicans, and activity against the bacteria
Bacillus subtilis and Escherichia coli.
PMID- 9397207
TI - Steroid saponins from Solanum laxum.
AB - Two new steroid saponins, named laxumins A and B, were isolated from the
ethanolic extract of the aerial parts of Solanum laxum. These compounds were
characterized, using mainly NMR spectroscopy, mass spectrometry and chemical
methods, as (23S,25S)-spirost-5-en-3 beta, 15 alpha, 23-triol 3-O-{beta-D
glucopyranosyl-(1-->2)- beta-D-glucopyranosyl-(1-->4)-[alpha-L-rhamnopyranosyl-(1
->2)]-beta-D- galactopyranoside} and 3-O-{beta-D-glucopyranosyl-(1--> 4)-alpha-L
rhamnopyranosyl-(1-->2)]-beta-D-galactopyranoside}, respectively.
PMID- 9397208
TI - Steroidal saponins from fruits of Tribulus terrestris.
AB - Further studies on the constituents of the fruits of Tribulus terrestris led to
the isolation of five new steroidal saponins (terrestrosin A-E), (25R,S)-5 alpha
spirostan-3 beta-ol-3 -O-beta-D-galactopyranosyl(1-2)-beta-D- glucopyranosyl(1-4)
beta-D-galactopyranoside, (25R,S)-5 alpha-spirostan-3 beta-ol-3-O-beta-D
glucopyranosyl(1-4)-[alpha-L- rhamnopyranosyl(1-2)]-beta-D-galactopyranoside,
(25R,S)-5 alpha-spirostan-12-on-3 beta-ol-3-O-beta-D-galactopyranosyl (1-2)-beta
D-glucopyranosyl(1-4)-beta-D-galactopyranoside, hecogenin 3-O-beta-D
galactopyranosyl)1-2)-[beta-D- xylopyranosyl(1-3)]-beta-D-glucopyranosyl(1-4)
beta-D-galactopyranoside and (25R,S)-5 alpha-spirostane-2 alpha, 3 beta-diol-3- O
beta-D-galactopyranosyl(1-2)-beta-D-glucopyranosyl(1-4)-beta-D-
galactopyranoside, together with five known steroidal saponins,
desgalactotigonin, F-gitonin, desglucolanatigonin, gitonin and tigogenin 3-O-beta
D- xylopyranosyl)1-2)-[beta-D-xylopyranosyl)1-3)]-beta-D-glucopyranosyl)1-4 )-
[alpha-L-rhamnopyranosyl(1-2)]-beta-D-galactopyranoside. The structures of the
new saponins were elucidated on the basis of spectroscopic analyses, including
two-dimensional NMR techniques, and chemical reactions.
PMID- 9397209
TI - Tiagabine approved for partial seizures.
PMID- 9397210
TI - Antipsychotic choices now include quetiapine.
PMID- 9397211
TI - Growth hormone-releasing hormone product cleared for marketing.
PMID- 9397212
TI - NCQA data show wide variability in health plan performance.
PMID- 9397213
TI - HMO patients receive less costly end-of-life care.
PMID- 9397214
TI - APhA approves Guidelines for Pharmacy-Based Immunization Advocacy and
Administration.
PMID- 9397215
TI - Free vaccines, insurance status influence immunization by physicians.
PMID- 9397217
TI - Benefits of a board-certified technician.
PMID- 9397216
TI - New rules will standardize labeling for dietary supplements.
PMID- 9397218
TI - Levofloxacin and trovafloxacin: the next generation of fluoroquinolones?
AB - The pharmacology, spectrum of activity, pharmacokinetics, clinical efficacy, and
adverse effects of levofloxacin, recently approved by FDA, and trovafloxacin,
currently undergoing clinical trials, are reviewed. Compared with quinolones in
current use, levofloxacin is more potent against gram-negative bacteria and
exhibits better antipseudomonal activity as well as greater oral bioavailability.
Trovafloxacin is more potent than existing quinolones against gram-positive
bacteria. Both agents exert their antibacterial effects by inhibiting bacterial
DNA synthesis. Compared with other quinolones, levofloxacin and trovafloxacin
both demonstrate superior activity against the Bacteroides fragilis group,
Chlamydia spp., Mycoplasma pneumoniae, and Mycobacterium spp. The half-life
(t1/2) of levofloxacin is nearly eight hours. Levofloxacin can therefore be
administered once daily for mild to moderate infections and twice daily for more
serious infections. The recommended daily dose is 500 mg. Trovafloxacin has a
t1/2 of 12 hours, which allows for single daily doses, and is extensively
metabolized. Levofloxacin has demonstrated clinical efficacy in the treatment of
community-acquired respiratory-tract infections, genitourinary infections, skin
and skin-structure infections, acute bacterial sinusitis, and infections of the
head and neck. Trovafloxacin may have a role in treating skin and skin-structure
or soft-tissue infections respiratory-tract infections, sexually transmitted
diseases, and meningitis. Both agents are well tolerated, with central-nervous
system and gastrointestinal adverse effects reported most frequently. Concomitant
administration of antacids or compounds containing meal cations decreases
absorption of these quinolones. Levofloxacin and trovafloxacin have favorable
antimicrobial and pharmacokinetic profiles, offering the advantages of once-daily
doses as well as superior potency and spectrum of activity compared with
currently available quinolones.
PMID- 9397219
TI - Influence of patient information leaflets on anticonvulsant drug compliance in
prison.
AB - The effect of patient information leaflets on anticonvulsant drug compliance in a
prison system was studied. Starting in January 1996, patient information leaflets
were given to inmates in 18 prison units within the Texas Department of Criminal
Justice who were receiving anticonvulsant medications. Nine of the units had
pharmacist-operated chronic care clinics (POCs); the other nine did not. The
units were matched on the basis of demographic characteristics and patient
chronicity levels. Leaflet distribution continued until two weeks into March
1996. Certified medication aides (CMAs) watched inmates take doses and documented
administration. A report on the anticonvulsant medications prescribed, dosage
frequencies, number of patients taking each drug, and cumulative rate of
compliance for each prison unit was generated monthly. The leaflets appeared to
have a positive effect on compliance. The largest percent increases in compliance
occurred on POC units, possibly because of the reinforcement provided by
pharmacist counseling. The findings may have been affected by the integrity of
the CMAs, the possibility that some patients on POCs did not receive pharmacist
counseling, exploitation of the system by inmates for secondary gain, and other
factors. Patient information leaflets may be of some use in increasing drug
compliance in the prison population, but expectations must be tempered by the
realities of this setting.
PMID- 9397220
TI - Stability of thiotepa (lyophilized) in 0.9% sodium chloride injection.
AB - The stability of thiotepa in a new formulation of the drug was studied. Vials of
Thioplex (Immunex), a relatively new lyophilized formulation of thiotepa, were
reconstituted with sterile water and diluted with 0.9% sodium chloride injection
in polyvinyl chloride infusion bags to thiotepa concentrations of 0.5, 1, and 3
mg/mL. The solutions were stored at 8 and 25 degrees C in ambient light and
analyzed at 0, 8, 24, and in most cases 48 hours for thiotepa concentration and
chloro-adduct formation by stability-indicating high-performance liquid
chromatography. Thiotepa 1 and 3 mg/mL was stable for 48 hours at 8 degrees C and
for 24 hours at 25 degrees C. Thiotepa 0.5 mg/mL was not stable at either
temperature. Storage at 8 degrees C slowed but did not prevent chloro-adduct
formation and loss of potency. The pH tended to increase with time; turbidity
remained low. Thiotepa (lyophilized) 1 and 3 mg/mL in 0.9% sodium chloride
injection was stable for 48 hours at 8 degrees C and for 24 hours at 25 degrees
C; the drug was unstable when diluted to 0.5 mg/mL and stored under the same
conditions.
PMID- 9397221
TI - Evaluation of electronic drug information resources for answering questions
received by decentralized pharmacists.
PMID- 9397222
TI - References for health-related quality-of-life claims in prescription drug
advertisements.
PMID- 9397223
TI - Visual compatibility of warfarin sodium injection with selected medications and
solutions.
PMID- 9397224
TI - Data sources for pharmacoeconomic and health services research.
AB - Different types of databases available for health-related research, the data
contained in these databases, and potential applications for pharmacists or
researchers are discussed. Case studies that demonstrate uses for health
databases are presented. Databases can be organized by facility, by health care
provider, by disease or organ, or by sector. The types of data they contain
include financial data, utilization data, demographic data, and outcomes data.
Data can be obtained from the public sector, the private sector, or the
researcher's own health system. The costs and time associated with using existing
databases are often less than those required to collect data, but the quality and
accessibility of the data must also be considered. The researcher's choice of
database will depend on the research question. Health care databases can be used
for health management and decision-making, quality review and evaluation,
outcomes research, episode-of-illness studies, and evaluation of treatment
protocols. Researchers must comply with patient-confidentiality and other
agreements when accessing data. The format of the data needs to be matched with
the hardware and software to be used in the analysis, and the data need to be
loaded, verified, and cleaned before use. In deciding which of the many available
data sources to use, researchers must determine the appropriate balance between
external data and data available within their own health systems. The decision on
whether to use existing data sources or to collect data prospectively will depend
on the research question, the available resources, and the scope of the study.
PMID- 9397225
TI - Gastrointestinal prokinetic agents for enhancing drug response in gastroparesis.
PMID- 9397226
TI - Epoprostenol in the treatment of congestive heart failure.
PMID- 9397227
TI - Anticonvulsant cross-sensitivity.
PMID- 9397228
TI - Somatropin for treating AIDS-related wasting syndrome.
PMID- 9397230
TI - The pharmacist's perspective on newer thrombolytic therapies for acute myocardial
infarction.Introduction.
PMID- 9397229
TI - Two cases of possible cefepime-induced neutropenia.
PMID- 9397231
TI - Decision analysis in the formulary process.
AB - The use of decision analysis as a tool in making formulary decisions is
discussed. Decision analysis is best applied in formulary decisions when factors
other than acquisition costs are important in determining overall treatment costs
for two products. The decision-analysis process assigns probabilities and costs
to various treatments and outcomes. In the case of acute myocardial infarction,
the decision analyst would gather data on angioplasty and thrombolysis and assign
probabilities and costs for each treatment and subsequent endpoints on the basis
of clinical trial data. When such data do not exist, estimates may be generated
by expert panels. Applying clinical trial data to an individual hospital is not
straightforward because of differences between clinical trials and clinical
practice. Analysts and clinicians should evaluate any proposed model for its
robustness and adaptability to local conditions and practitioner variation.
Access to internal hospital data is essential in developing the model. An ideal
decision-analysis model includes all important available interventions and
defines and discloses the analyst's time frame and financial perspective. After
implementation of the formulary decision, the results can be monitored and, if
necessary, adjustments can be made in the allocation of resources. Barriers to
effective decision analysis include lack of data and differences in sources of
cost and outcome data. Despite the current limitations of decision analysis,
clinicians and policymakers may find this technique increasingly useful in the
complex formulary process.
PMID- 9397232
TI - Strategies for the management of acute myocardial infarction: selecting patients
for thrombolytic therapy.
AB - Strategies for managing acute myocardial infarction (AMI), with a focus on
thrombolytics, are reviewed. Revised guidelines published by the American College
of Cardiology and the American Heart Association strongly recommend the use of
thrombolytic therapy in carefully selected patients to promote reperfusion of
ischemic myocardium. Thrombolytics reduce in-hospital mortality, and the
mortality benefit is maintained for at least one year. Which patients are the
best candidates for thrombolytics has been debated; variables that have been
analyzed include infarct location, time after onset of symptoms, age, sex, blood
pressure, and prior AMI. Clinicians should be thoroughly familiar with the
absolute and relative contraindications to thrombolytic therapy to minimize
potential hemorrhagic complications. The diagnosis of AMI should be clearly
established. All patients should receive thrombolytic therapy if they arrive for
treatment within 12 hours of the onset of symptoms of AMI and have appropriate
ECG changes. Aspirin should be given to all patients, and beta-blockers should
also be given if there are no contraindications. Heparin may be given as
antithrombotic therapy in patients not receiving thrombolytics or as adjuvant
therapy in those receiving thrombolytics. Other adjuvant treatments, notably
angiotensin-converting-enzyme inhibitors, are used as indicated. Primary
angioplasty may have a role in selected patients. Long-term interventions are
intended to prevent recurrence of AMI. Thrombolytic therapy can substantially
improve survival and function in patients with AMI, especially when it is given
within six hours of the onset of symptoms.
PMID- 9397233
TI - A fresh look at the molecular pharmacology of plasminogen activators: from theory
to test tube to clinical outcomes.
AB - The molecular pharmacology of plasminogen activators and its implications for
thrombolytic therapy are discussed. The benefits of coronary thrombolysis were
first demonstrated with intracoronary and i.v. streptokinase. Tissue plasminogen
activator (t-PA) or recombinant t-PA (alteplase) proved to be superior to
streptokinase with respect to speed of reperfusion and reperfusion efficacy.
Since alteplase neither lessened the risk of bleeding found with streptokinase
nor generated Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow rates
above about 50%, the quest for faster-acting, safer, and more effective
thrombolytic agents has continued. The ideal agent would be highly efficient at
converting plasminogen to plasmin, have an intermediate half-life, have a low
affinity for fibrin, and be of reasonable cost. Genetic engineering of the wild
type t-PA molecule resulted in reteplase, which has a longer half-life than
alteplase and may be superior in terms of lytic activity, myocardial salvage, and
survival. Also under investigation are TNK-t-PA and n-PA, which have longer half
lives and, in animal models, seem to produce more rapid and complete
thrombolysis, at less risk of intracranial bleeding, than alteplase. The risk of
intracranial bleeding remains a problem with all thrombolytics; the risk versus
the benefit will have to be assessed in large randomized trials. An understanding
of the functions of various regions of the t-PA molecule has led to genetic
engineering of new and promising plasminogen activators.
PMID- 9397234
TI - Clinical trials in thrombolytic therapy, Part 1: Outcome markers that go beyond
mortality reduction.
AB - The use of outcome markers other than mortality reduction alone for evaluating
thrombolytic agents in patients with acute myocardial infarction (AMI) is
discussed. Mortality has been a primary endpoint in clinical trials evaluating
thrombolytic agents for treatment of AMI. However, differences in mortality rates
among thrombolytics are 1% or less and require tens of thousands of patients to
detect. Broadening the endpoints studied will allow for more extensive data
collection and more comprehensive cost-effectiveness analysis, enabling
clinicians to make better decisions. The Global Utilization of Streptokinase and
Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial
measured not only mortality but issues related to the patency of the infarct
related artery and complications. Other potentially important outcome markers
after AMI are left ventricular function; markers of reperfusion, such as early
resolution of ST-segment elevation; and resolution of chest pain. Available long
term data show that the mortality benefit from alteplase is sustained over time
and is correlated with enzymatically determined infarct size, left ventricular
function, the number of diseased vessels, and Thrombolysis in Myocardial
Infarction flow grade at the time of discharge from the hospital. Clinicians must
also consider risk factors for stroke. Outcome measures other than mortality
alone may help in determining which thrombolytic agent is most effective
clinically and in financial decision-making without requiring large, expensive
trials.
PMID- 9397235
TI - Clinical trials in thrombolytic therapy, Part 2: The open-artery hypothesis and
RAPID-1 and RAPID-2.
AB - The open-artery hypothesis as supported by thrombolytic study results is
discussed. The open-artery hypothesis states that survival after acute myocardial
infarction (AMI) is maximized by achieving early and sustained patency of the
infarct-related artery. However, two large multicenter trials did not detect any
difference in mortality between patients given alteplase and patients given
streptokinase, despite previous evidence that alteplase led to earlier
recanalization of infarct-related arteries. The Global Utilization of
Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries
(GUSTO-1) trial suggested that early and complete patency is essential for short
term survival after AMI. Subsequent observations indicated that an open infarct
related artery at the time of hospital discharge is associated with improved long
term survival. In the Reteplase Angiographic Phase II International Dose-Finding
(RAPID-1) trial, complete patency was more frequent in patients who received a
double-bolus regimen of reteplase than in patients who received standard-dose
alteplase. Similar results were obtained in the Reteplase versus Alteplase
Patency Investigation during Myocardial Infarction (RAPID-2) trial, which
compared the same double-bolus reteplase regimen with an accelerated regimen of
alteplase. In both RAPID studies, mortality was lower and other outcomes were
more favorable in reteplase recipients. Reteplase seems more likely to produce
normal blood flow soon after AMI than either standard-dose or accelerated
alteplase and may be associated with a lower mortality rate. This lends further
support to the open-artery hypothesis.
PMID- 9397236
TI - A prospective comparison of four study designs used in assessing safety and
effectiveness of drug therapy in hypertension management.
AB - The objective of the study was to compare prospectively the impact of study
design on drug therapy safety and effectiveness data obtained in hypertension
management. The main study was a randomized controlled clinical trial of four
different prospective study designs used in postmarketing assessment involving
1008 primary care practices in nine Canadian provinces. Two thousand nine hundred
sixty-four patients with mild to moderate hypertension received an angiotensin
converting enzyme (ACE) inhibitor daily for 14 weeks in one of four postmarketing
studies--a randomized double-blind clinical trial (RCT) (10 to 40 mg fosinopril
daily v 5 to 20 mg enalapril daily), two structured open label trials of 10 to 40
mg fosinopril daily (one with free drugs), or an unstructured open label trial of
10 to 40 mg fosinopril daily. Patient demographic and baseline characteristics,
systolic and diastolic blood pressures, adverse events reported, and data quality
were recorded as the outcome measures. The results showed that the RCT patients
were titrated to higher doses of ACE inhibitor than patients in the open studies,
P < .008; patients in the open studies were more likely to receive adjuvant
diuretic therapy, P < .008. The decrease in blood pressure was similar for
patients in all four studies, mean decrease in systolic BP was between 18 and 20
mm Hg, mean decrease in diastolic BP was between 11 and 13 mm Hg. Fewer patients
in the unstructured open trial reported adverse events than patients in the RCT;
a 55% relative reduction in reported adverse events (P < .008) was associated
with the unstructured trial. There were also fewer drug-related adverse events
per patient reported in the unstructured study (17 per 100 patients) than in the
other studies (27 to 41 per 100 patients), P < .008. Physician preference for
rounding off blood pressure measurements to 0 or 5 occurred most often in the
unstructured open trial (P < .008). In conclusion, despite differences in dose
titration and in the use of adjuvant therapy, antihypertensive drug therapy
effectiveness observed in an RCT may be similar to uncontrolled postmarketing
studies. Open trials with scheduled follow-up visits are as effective in
detecting severe adverse events as RCT, but postmarketing studies with
unstructured schedules of follow-up are insufficient in identifying drug-related
adverse events and have poorer quality data.
PMID- 9397237
TI - Relation between nocturnal decline in blood pressure and mortality. The Ohasama
Study.
AB - To investigate the relation between nocturnal decline in blood pressure and
mortality, we obtained ambulatory blood pressures in 1542 residents aged 40 years
or over of a rural Japanese community. Subjects were followed-up for a mean of
5.1 years and were then subdivided into four groups according to the percent
decline in nocturnal blood pressure: 1) extreme dippers: percent decline in
nocturnal blood pressure > or = 20% of the daytime blood pressure; 2) dippers:
decline of > or = 10% but < 20%; 3) nondippers: decline of > or = 0% but < 10%;
and 4) inverted dippers: no decline. The relationship between the decline in
nocturnal blood pressure and mortality was examined by the Cox proportional
hazards regression model adjusted for age, sex, smoking status, previous history
of cardiovascular disease, and the use of antihypertensive medication. The
mortality risk was highest in inverted dippers, followed by nondippers. There was
no difference in mortality between extreme dippers and dippers. This relationship
was observed for both treated and untreated subjects, was more pronounced for
cardiovascular than for noncardiovascular mortality, and did not change after the
data were adjusted for 24-h, daytime, and nighttime blood pressure levels.
PMID- 9397238
TI - Effects of N omega-nitro-L-arginine and N-acetyl-L-cysteine on the reversal of
one-kidney, one-clip hypertension.
AB - The present study evaluated whether nitric oxide (NO) synthesis blockade or
potentiation (with N omega-nitro-L-arginine or N-acetyl-L-cysteine, respectively)
modulates the systemic and renal responses to unclipping in anesthetized one
kidney, one-clip hypertensive rats (1K-1C). Cardiac output was measured by
thermodilution. In time-control rats, mean arterial pressure (MAP) decreased from
197 +/- 8 mm Hg to 139 +/- 4 mm Hg 3 h after unclipping, and cardiac index (CI)
decreased by 35%, with a transient rise in sodium and water excretion and no
changes in total peripheral resistance (TPR), glomerular filtration rate (GFR),
or renal plasma flow (RPF). Administration of N omega-nitro-L-arginine methyl
ester (NAME, 10 micrograms/kg/ min) blunted the hypotensive (from 190 +/- 6 mm Hg
to 157 +/- 3 mm Hg), diuretic and natriuretic responses and potentiated the
decrease in CI (40%) observed after unclipping, whereas TPR increased by 103%.
Also, in rats given NAME, GFR and RPF decreased by 20% and 45%, respectively, at
the end of the experiment. The effect of N-acetyl-L-cysteine (NAC, 300 mg/kg), a
sulfhydryl group donor that may protect NO from free radical destruction by
forming an S-nitrosothiol compound, was also evaluated. NAC potentiated the
depressor response to unclipping (from 180 +/- 5 mm Hg to 97 +/- 3 mm Hg), and
GFR and RPF increased by 80% and 35%, respectively. These effects of NAC appear
to be NO dependent, as they were blocked by simultaneous administration of NAME.
However, no significant differences were observed among groups in cumulative
excretion of sodium and water, demonstrating that the hemodynamic effects of NAME
and NAC after unclipping are due to mechanisms other than renal excretory
changes. The results of the present study indicate that the cardiovascular
depressor effects of unclipping are modulated by endothelium-derived nitric
oxide.
PMID- 9397239
TI - Synergistic effect of angiotensin II and a high sodium diet on the vascular
glycosaminoglycan synthesis of rats.
AB - The effect of dietary sodium supplementation on angiotensin II (ANG II)-induced
stimulation of vascular glycosaminoglycan (GAG) synthesis of rats was
investigated. Measurements were performed both ex vivo and in vivo to validate
the in vivo measurements and to estimate the relative contribution of intrinsic
and extrinsic influences to ANG II-stimulated GAG synthesis in sodium-fed rats.
Male Sprague-Dawley rats on normal (0.7% NaCl) and high sodium (4.0% NaCl) diets
were infused with 100 ng/kg/min ANG II intraperitoneally for 48 h, or sham
operated (controls). To measure tissue GAG synthesis, 35SO4 was added to the
incubation medium (ex vivo) or injected intravenously into rats (in vivo).
Systolic blood pressure of ANG II-treated rats on normal sodium diet was
unchanged, but it increased by 13 mm Hg (P < .05) in the rats on the combined
treatment of ANG II and a high sodium diet. ANG II or high sodium diet by itself
had no effect on GAG synthesis. On the combined treatment, GAG synthesis of the
aorta was increased by 17% (P < .05) when measured ex vivo, and by 38% (P < .01)
when measured in vivo. In vivo, there was also increased GAG synthesis of
mesenteric arteries (P < .01) and of vena cava (P < .02); GAG synthesis of
nonvascular tissue (diaphragm, bladder, and kidney) was unchanged. The
synergistic effect of ANG II treatment and high sodium diet on GAG synthesis
appears to be, in part, arterial pressure independent and vascular tissue
specific. The greater effect of combined treatment in vivo than ex vivo suggests
that humoral or neural stimuli may be contributing to the interaction.
PMID- 9397240
TI - Glucose metabolism and insulin receptor binding and mRNA levels in tissues of
Dahl hypertensive rats.
AB - Increased insulinemic response to an oral glucose load has been demonstrated in
Dahl salt-sensitive hypertensive rats. To determine whether this abnormality is
mediated at the level of the insulin receptor, we compared insulin receptor
binding and mRNA levels in tissues of Dahl salt-sensitive rats (DS) and in their
normotensive controls, Dahl salt-resistant rats (DR). To evaluate possible
influences of dietary sodium intake, rats were fed either low (0.07% NaCl) or
high salt (7.5% NaCl) chow until the DS became hypertensive, and then were killed
by decapitation. Fasting plasma glucose and plasma insulin levels did not differ
between DR and DS rats and were not affected by salt intake. In response to an
oral glucose load, plasma glucose had a similar increase in DR and DS rats, but
the increase in plasma insulin was significantly greater in DS rats. Scatchard
analysis of binding was obtained from in situ autoradiographic studies performed
in frozen skeletal muscle and kidney sections, and insulin receptor mRNA levels
were measured by slot-blot hybridization. Number and affinity of insulin
receptors were comparable in skeletal muscle and kidney of DR and DS rats and, in
both groups, binding parameters were not affected by dietary sodium chloride.
Hepatic and renal insulin receptor mRNA levels were also comparable in DR and DS
rats fed either low or high salt chow. Thus, increased plasma insulin response to
oral glucose load is associated with normal insulin receptor binding and gene
expression in peripheral tissues in rats with Dahl hypertension. A postreceptor
defect is likely responsible for the decreased sensitivity to insulin in this
model of genetic hypertension.
PMID- 9397241
TI - Augmented contributions of voltage-gated Ca2+ channels to contractile responses
in spontaneously hypertensive rat mesenteric arteries.
AB - The observation that organic Ca2+ channel blockers are more effective in lowering
blood pressure and peripheral resistance in hypertensive compared to normotensive
subjects suggests that there is a greater contribution from voltage-gated Ca2+
channels (CaL) to vascular force maintenance in hypertensive arteries. This study
tests this hypothesis by comparing the effects of Bay k 8644 and nisoldipine on
basal force development, contractile responses to norepinephrine and serotonin,
and Ca2+ currents (ICa) in mesenteric artery (MA) from Wistar-Kyoto rats (WKY)
and spontaneously hypertensive rats (SHR). MA rings were used to record isometric
contractions at Lmax. Single cells were isolated by collagenase plus elastase for
measurement of CaL properties by patch-clamp methods. Contractile responses to
Bay k 8644 were larger and more sensitive in SHR than WKY, and were larger in
endothelium-denuded compared to intact rings. In SHR, the addition of 10 nmol/L
Bay k 8644 increased contractile sensitivity to norepinephrine (NE) and serotonin
(5HT), and increased maximum response to 5HT. In WKY, 10 nmol/L Bay k 8644
produced a small increase in 5HT sensitivity with no effect on maximum response,
and had no effect on NE responses. In the presence of 1 mumol/L nisoldipine, the
maximum response and the sensitivity to both NE and 5HT were decreased in both
WKY and SHR with the inhibitory effects of nisoldipine being larger in SHR than
WKY. Peak ICa was larger in SHR, and current-voltage curves were shifted toward
more negative voltages compared to WKY. Bay k 8644 increased ICa in both WKY and
SHR myocytes with no apparent difference in the magnitude of its effect when
expressed as a percent of control ICa. These results suggest that CaL contribute
significantly to tonic force maintenance as well as to agonist responses in MA
from both WKY and SHR, but with a much larger contribution in SHR. Differences in
the sensitivity of CaL to Bay k 8644 were not responsible for the differences in
contractile responses to this agonist.
PMID- 9397242
TI - The role of vasopressin in essential hypertension. Plasma levels and effects of
the V1 receptor antagonist OPC-21268 during different dietary sodium intakes.
AB - To study the role of vasopressin (VP) in essential hypertension, we examined
plasma levels of VP and blood pressure (BP) response to an orally active V1
receptor antagonist, OPC-21268, in hypertensive patients on diets with different
sodium contents. Plasma VP was determined in 12 normotensive subjects and 12
patients with mild essential hypertension on a regular sodium diet, and in eight
hypertensive patients on a high sodium (250 mmol/day) and a low sodium (25
mmol/day) diet. BP response was examined for 4 h after single oral administration
of OPC-21268 (100 mg) or placebo in eight patients on the regular diet, and in
six patients on the high and low sodium diets. In four patients on the regular
diet, the effects of OPC-21268 on the baroreflex control of heart rate were also
examined with intravenous injections of methoxamine. Plasma VP did not differ
between the normotensive and hypertensive subjects. Levels of VP in the plasma
was higher in the high sodium than in the low sodium period, but the difference
was not significant. BP and heart rate did not change significantly after
administration of OPC-21268 or placebo under either condition. OPC-21268 also
failed to lower BP in salt-sensitive patients on the high sodium diet. The
baroreceptor reflex sensitivity was not modified by the administration of OPC
21268. Our results suggest that VP does not play an important role in mild
essential hypertension through its action on the V1 receptors regardless of
dietary sodium intake.
PMID- 9397243
TI - Insulin resistance is related to silent cerebral infarction in patients with
essential hypertension.
AB - Recently, hyperinsulinemia or insulin resistance has been suggested to be a risk
factor for cardiovascular diseases. We evaluated the role of insulin resistance
in the occurrence of silent cerebral infarction in 28 patients with essential
hypertension (40 to 75 years, 157 +/- 4/89 +/- 2 mm Hg). Patients with diabetes
mellitus or obesity (BMI > or = 30) were excluded. Insulin resistance was
evaluated by means of constant glucose infusion rate (M value) during euglycemic
hyperinsulinemic glucose clamp test. Infarction was defined as a focal area with
prolonged T1 and T2 relaxation times that was > 5 mm in diameter on brain
magnetic resonance imaging. The severity of periventricular hyperlucency was
evaluated by the distribution of the high intensity area. The number of silent
infarctions significantly correlated only with the M value (F = 7.58, R2 = 0.23,
P = .01) in multiple regression analysis using all variables: age, blood
pressure, smoking history, lipid profile, levels of plasma glucose and insulin on
fasting, and total amounts during 75-g OGTT. However, the severity of
periventricular hyperlucency did not show a correlation with any factors. The
occurrence of cerebral infarction was significantly correlated with thickening of
the intima-media complex (IMC) of the common carotid artery on B-mode
ultrasonography (F = 8.43, R2 = 0.25, P < .01). In conclusion, insulin resistance
and thickening of IMC show a close relationship with the occurrence of silent
cerebral infarction. Therefore, it may be important to improve insulin resistance
for prevention of cerebral infarction in essential hypertensives.
PMID- 9397244
TI - Myocardial wall thickness and left ventricular geometry in hypertensives.
Relationship with insulin.
AB - In hypertensive patients the presence of left ventricular (LV) hypertrophy has
been associated with a more severe degree of insulin resistance. Whether
myocardial wall thickness or LV geometry are associated with a different degree
of insulin resistance is still unknown in essential hypertensives. For this
reason 26 men with new diagnosed essential hypertension were enrolled. All
patients underwent echocardiographic examination and euglycemic hyperinsulinemic
glucose clamp combined with indirect calorimetry. According to LV mass and
relative wall thickness data, all patients were categorized in four groups: 1)
patients with a normal geometric LV pattern (n = 8) (PAT = 0); 2) patients with
concentric remodeling LV mass (n = 8) (PAT = 1); 3) patients with eccentric LV
hypertrophy (n = 3) (PAT = 2); and 4) patients with concentric LV hypertrophy (n
= 7) (PAT = 3). All groups were similar for anthropometric characteristics.
Patients with normal echocardiographic LV pattern (PAT = 0) had higher whole body
glucose disposal (WBGD), oxidative and nonoxidative glucose metabolism, and lower
lipid oxidation than patients with abnormal echocardiographic LV patterns (PAT =
1 to 3). Nevertheless, no significant differences among the groups with abnormal
echocardiographic patterns were found. After controlling for age, body mass index
(BMI), waist/hip ratio (WHR), and mean arterial blood pressure, only sum of the
wall thickness was significantly correlated with fasting plasma insulin (r =
0.38, P < .05), WBGD (r = - 0.50, P < .009), and NOGM (r = - 0.48, P < .02). In
multivariate analysis, a model made by age, BMI, WHR, systolic and diastolic
blood pressure, and WBGD explained 38% of the echocardiographic pattern
variability. In this model, WBGD (P < .02) was significantly and independently
associated with echocardiographic patterns explaining 19% of the
echocardiographic pattern variability. In conclusion, our data demonstrate that
in arterial hypertension hyperinsulinemia/insulin resistance mainly affects
myocardial wall thickness, whereas only a trivial association with LV geometry
occurs.
PMID- 9397245
TI - Effect of doxazosin on endothelial dysfunction in
hypercholesterolemic/antioxidant-deficient rats.
AB - Hypertension, hypercholesterolemia, atherosclerosis, and coronary heart disease
are associated with abnormal endothelium-dependent, nitric oxide-mediated
vasorelaxation. In rats, hypercholesterolemia in combination with deficiencies of
vitamin E and selenium results in increased endogenous lipid oxidation and
endothelial dysfunction. Two hydroxymetabolites of doxazosin, an alpha 1
adrenergic blocking antihypertensive agent, inhibit human lipid oxidation in
vitro in a dose-dependent fashion. The present studies were performed to
determine the effect of in vivo treatment with doxazosin on endothelial
dysfunction in hypercholesterolemic/ antioxidant-deficient rats. Dahl rats were
fed 1) a standard diet, 2) a high cholesterol (4%) diet, or 3) a high
cholesterol, vitamin E- and selenium-deficient diet. A subgroup of animals in
each group were administered doxazosin (3.5 mg/100 g/day) for 16 weeks. In the
aortas, vascular relaxations induced by acetylcholine were significantly
decreased (P < .05) in high cholesterol/antioxidant-deficient rats compared with
normal and high cholesterol animals. Doxazosin treatment prevented the impairment
in endothelium-dependent vascular relaxation in the high cholesterol/antioxidant
deficient group. Vasorelaxation in response to the exogenous nitric oxide donor
diethylamine nanoate, which was significantly impaired (P < .05) in aortas from
high cholesterol/antioxidant-deficient animals compared with normal and high
cholesterol animals, was normalized in aortas from high cholesterol/ antioxidant
deficient animals that had received doxazosin. The antioxidant effect of
doxazosin may have therapeutic implications in diseases associated with
endothelial dysfunction linked to products of lipid oxidation.
PMID- 9397246
TI - Comparison of amlodipine and long-acting diltiazem in the treatment of mild or
moderate hypertension.
AB - The comparative effects of the once a day calcium channel antagonists amlodipine
and long-acting diltiazem were assessed in a parallel design, investigator
blinded, multicenter trial in 123 patients with diastolic blood pressures ranging
from 95 to 114 mm Hg before treatment. Patients were randomized to one of the two
drugs and titrated at 2-week intervals to 5 or 10 mg of amlodipine or 180, 240,
or 360 mg of long-acting diltiazem during a 10-week treatment period. Both drugs
significantly reduced resting, sitting, standing, and 24-h ambulatory systolic
and diastolic pressures. Amlodipine caused significantly greater reductions in
sitting and standing systolic pressures, standing diastolic pressures, and 24-h
ambulatory systolic and diastolic pressures versus diltiazem. Sitting systolic
pressures were reduced from 151.9 +/- 2.0 (SE) at baseline to 137.9 +/- 1.8 mm Hg
with amlodipine treatment and from 149.0 +/- 2.1 to 145.1 +/- 2.5 mm Hg with
diltiazem. Sitting diastolic pressures were reduced from 100.2 +/- 0.6 to 87.8 +/
1.0 mm Hg with amlodipine and from 101.1 +/- 1.0 to 91.9 +/- 1.1 mm Hg with
diltiazem. Reductions in standing systolic pressures after treatment were -12.1
+/- 1.5 mm Hg amlodipine v -4.6 +/- 1.5 mm Hg diltiazem (P < .01), and reductions
in standing diastolic pressures were -11.8 +/- 0.9 mm Hg amlodipine v -8.6 +/-
0.9 mm Hg diltiazem (P < .02). Heart rates did not change significantly with
either drug during the study. Two subjects in each group dropped out because of
adverse experiences. Although both agents were well tolerated and reduced blood
pressures consistently over the 10-week test period, amlodipine was more
effective than diltiazem in reducing systolic and diastolic blood pressures to
the target pressures of < 140 mm Hg systolic and < 90 mm Hg diastolic over a
range of doses widely used in clinical practice.
PMID- 9397247
TI - Home blood pressure as a predictor of future blood pressure stability in
borderline hypertension. The Tecumseh Study.
AB - We evaluated time-related blood pressure trends in the Tecumseh study
participants, none of whom received antihypertensive treatment. At baseline the
blood pressures were measured in the field clinic and by self measurement at home
(twice daily for 7 days). After a mean of 3.2 +/- 0.42 years, the clinic and home
pressure readings were repeated. Nine hundred forty-six subjects had clinic and
home blood pressure readings at baseline. Of these 735 (380 men, 355 women;
average age, 32 years) also completed the second examination. Blood pressure,
morphometric data, and biochemical measures at the first examination were used as
predictors of future clinic blood pressures. Five hundred ninety-six subjects
were normotensive on both examinations (81%). Of 79 subjects (10.7%) with clinic
hypertension (> 140 mg Hg systolic or 90 mm Hg diastolic) at baseline, 38
remained hypertensive ("sustained hypertension") and 41 became normotensive
("transient hypertension") after 3 years. Another 60 normotensives at baseline
(10.4%) became hypertensive on second examination ("de novo hypertensives";
incidence; 8.1%). The home blood pressure readings on both examinations were
reproducible. The three hypertensive groups had elevated home blood pressure,
were overweight, had dyslipidemia, and higher insulin values. Only the home blood
pressure proved predictive of subsequent blood pressure trends. A home blood
pressure of 128 and 83 mm Hg or higher detected "sustained" hypertension with a
48% sensitivity and 93% specificity. Readings of 120 and 80 mm Hg or lower
predicted future normotension with a 45% sensitivity and a 91% specificity. We
conclude that self determination of the blood pressure at home is useful in the
management of borderline hypertension. An algorithm for the management of these
patients is proposed.
PMID- 9397248
TI - Factors that affect blood pressure variability. A community-based study in
Ohasama, Japan.
AB - Factors that affect blood pressure (BP) variability, ie, standard deviation (SD)
and variation coefficient (VC: SD/average ambulatory BP) of ambulatory BP, were
examined in a community-based sample in northeastern Japan. Screening and
ambulatory BPs were measured in 823 subjects > or = 20 years of age, and the
effects of age and BP on the SD and the VC were examined. In bivariate regression
analysis, the SD of ambulatory BP was positively correlated with age and the
ambulatory BP. The VC was also correlated with age. Both the SD and the VC were
strongly correlated with the magnitude of the nocturnal decline in BP. Ambulatory
BP was positively correlated with age and negatively correlated with heart rate
and the SD of heart rate. Multivariate analysis demonstrated that the nocturnal
decline in BP showed the strongest association with the SD and the VC of 24-h BP.
However, age and BP were still independently and positively associated with the
SD and the VC of ambulatory BP. Furthermore, pulse pressure and BMI were
independently and positively associated with the SD and the VC of ambulatory BP.
Since the SD and the VC of 24-h ambulatory BP were determined mainly by the
nocturnal decline in BP, this variable appears to be an index of the circadian
variation in BP and not an index of short-term BP variability. Pulse pressure, an
index of arterial stiffness, was a relatively strong predictor of the SD and the
VC of BP. In addition, the SD of heart rate, an index of baroreflex function,
decreased with increasing age. Findings suggest that the increase in BP
variability in hypertensive and elderly subjects may be explained, in part, by a
disturbance of baroreflex function associated with an increase in arterial
stiffness due to aging and hypertension.
PMID- 9397249
TI - Captopril test and renal duplex scanning for the primary screening of
renovascular disease.
AB - To evaluate the utility of renal duplex scanning and the captopril test in the
detection and functional assessment of renovascular disease, by comparing their
results with those of angiography and captopril isotopic renography (CIR). Sixty
hypertensive patients with aortoiliac disease and 16 with clinically suspected
renovascular hypertension (RVH) were included. All the patients underwent renal
duplex scanning prior to angiography. In addition, isotopic renograms and a
determination of peripheral plasma renin activity (PRA) at baseline and 60 min
after oral intake of 50 mg of captopril were both performed. A postcaptopril PRA
> 5.7 ng/mL/h was considered as diagnostic of a positive captopril test. On the
basis of the results of the angiography and isotopic renograms, all the patients
were classified into three groups: group I (n = 33), essential hypertension
(EHT); group II (n = 20), hypertension and angiographic RAS > 60% but negative
CIR; and group III (n = 24), RAS > 60% and positive CIR. This last condition was
considered as highly suspicious for RVH. Renal duplex scanning showed greater
accuracy than captopril PRA or CIR for detecting RAS > 60% (groups II and III)
with 87.3% versus 52.4% and 45.3% sensitivity (S), and 91.5% versus 84.4% and
92.8% specificity (Sp), respectively. The captopril test correctly identified 44
of 51 EHT patients (groups I and II) and 20 of 23 highly suspected of RVH (group
III) with 87% S, 86.5% Sp, 74.1% PPV, and 93.6% NPV. Accuracy was further
increased when a combined approach (renal duplex scanning and captopril test) was
followed (82.6% S, 93.7% Sp, 86.4 PPV, and 91.8 NPV). In our study, renal duplex
scanning was a useful screening method for detecting anatomical RAS. A
combination of both renal duplex scanning and captopril test may be an
appropriate approach to the primary screening for RVH, thereby permitting the
selection of those patients indicated for angiography.
PMID- 9397250
TI - Pressure modulates monocyte migration.
AB - Migration of monocytes into the subendothelial space of the aorta has been
considered to be an important event in the development of atherosclerosis.
Because hypertension is commonly associated with atherosclerosis, we studied the
effect of applied pressure on the migration of monocytes. Direct applied pressure
increased the migration (P < .001) of monocytes across a filter when compared
with normal atmospheric pressure. The migration of monocytes was found to be
directly related to the amount of the applied pressure. Amlodipine, a calcium
channel blocker, attenuated the migration of monocytes under normal as well as
increased pressure conditions in a dose-dependent manner. These studies provide a
basis to speculate on the role of direct pressure in the migration of monocytes
into the subendothelial space and the possibility that vasoactive agents may
modulate the migration of monocytes independent of their pressure-lowering
effect.
PMID- 9397251
TI - White-coat resistant hypertension.
AB - The aim of this study was to evaluate whether sustained hypertensives with high
clinic blood pressure, despite multiple drug treatment, show a true resistant
hypertension or a "white-coat effect," and whether the pretreatment white-coat
effect is maintained despite pharmacological therapy. The occurrence of resistant
hypertension was determined in 250 consecutive essential hypertensives who had
had an ambulatory blood pressure monitoring before treatment assignment. Twenty
seven of 250 hypertensives with persistently high clinic blood pressure despite 3
months of adequate pharmacological therapy underwent further ambulatory blood
pressure monitoring. Using our internal standards, seven patients had a true
resistant hypertension whereas 20 subjects showed a large white-coat effect
(white-coat resistant hypertension), ie, high clinic blood pressure (> 140/90)
but "normal" ambulatory daytime (< 139/90 mm Hg) and 24 h (135/85 mm Hg) blood
pressure. Using other cutoff points for ambulatory blood pressure, 134/90 and
135/85 mm Hg for daytime blood pressure, 10 and 13 patients, respectively, were
reclassified as true resistant hypertensives and 17 and 14, respectively, were
white-coat resistant hypertensives. Interestingly, in white-coat resistant
hypertensives the large differences between clinic and ambulatory daytime blood
pressure (white-coat effect), recorded before treatment assignment, were not
affected by drugs and remained constant over time. Left ventricular mass index in
white-coat resistant hypertensives was significantly lower than in truly
resistant hypertensives, suggesting that prognosis could differ between these
groups. In this study, using either our internal standards or some other cutoffs
reported in the literature, the white-coat phenomenon was an important cause of
resistant hypertension. The use of ambulatory blood pressure monitoring in these
patients may avoid misdiagnosis of resistant hypertension, unnecessary
overtreatment, and expensive procedures to look for possible secondary
hypertension.
PMID- 9397252
TI - Association study between the ANF gene and hypertension in a Gulf Arab
population.
AB - We have studied an insertion/deletion (I/D) dimorphism located in the second
intron of the human atrial natriuretic factor (ANF) gene among 232 United Arab
Emirates (UAE) nationals (112 normotensives and 120 hypertensives) from the Abu
Dhabi Emirate, with a view to evaluating the value of this marker in relation to
hypertension. Our findings show that genotype frequencies of this I/D marker
occur in Hardy-Weinberg proportions (respective genotype frequencies in the
overall sample population are: II, 51%; ID, 42%; DD, 7%). No association,
however, was evidenced between this dimorphic site and clinical diagnosis of
essential hypertension. This suggests that: 1) this I/D dimorphism is not a
useful marker to study the relationship between the ANF gene and hypertension in
the UAE; and 2) variations of the ANF gene that may be in linkage disequilibrium
with this marker do not play a major role in the determination of hypertension in
this Arab population.
PMID- 9397254
TI - Blood pressure measurement in a patient with thoracic outlet syndrome: a case
report.
PMID- 9397253
TI - Magnesium concentrations in plasma, erythrocytes, and platelets in hypertensive
and normotensive obese patients.
PMID- 9397255
TI - Do ambulatory blood pressure patterns of isolated systolic hypertension predict
atherosclerotic complications?
PMID- 9397256
TI - HpaII-polymorphism of the atrial-natriuretic-peptide gene and essential
hypertension in whites.
PMID- 9397257
TI - Subspecialization.
PMID- 9397258
TI - Presidential address of the American Orthopaedic Society for Sports Medicine. Who
are we? The past present, and future.
PMID- 9397259
TI - A prospective study of prognostic factors concerning the outcome of arthroscopic
surgery for anterior ankle impingement.
AB - Sixty-two consecutive patients with painful limited dorsiflexion of the ankle not
responding to nonoperative treatment participated in a prospective study. All 42
men and 20 women (average age, 31 years) underwent arthroscopic surgery.
Preoperative radiographs were graded according to an osteoarthritic and an
impingement classification. Standardized followup took place at 4 months and 1
and 2 years after surgery. Results showed that the degree of osteoarthritic
changes is a better prognostic factor for the outcome of arthroscopic surgery for
anterior ankle impingement than size and location of the spurs. The hypothesis is
that osteophytes without joint space narrowing are not a manifestation of
osteoarthritic changes but rather the result of local (micro)trauma. After 2
years, 73% of the patients experienced overall excellent or good results; 90% of
those without joint space narrowing had good or excellent results, and 50% of
those with joint space narrowing had good or excellent results. At the 2-year
followup, the group without joint space narrowing showed significantly better
scores in pain, swelling, ability to work, and engagement in sports. This study
also revealed that patients with less than 2 years of ankle pain before surgery
and spurs located anteromedially were more satisfied with the outcome than when
longer periods of preoperative pain were involved and when spurs were located
anterolaterally.
PMID- 9397260
TI - Salvage surgery for lateral tennis elbow.
AB - We undertook a retrospective analysis of 34 patients (35 elbows) who had prior
failed surgical intervention for lateral tennis elbow. Revision surgeries were
performed between 1979 and 1994. Each patient's non-operative and operative
history was recorded before our salvage revision surgery. At revision surgery,
findings included residual tendinosis of the extensor carpi radialis brevis
tendon in 34 of 35 elbows. In 27 elbows, the pathologic changes in the extensor
carpi radialis brevis tendon had not been previously addressed at all, and in 7
elbows the damaged tissue had not been completely excised. Salvage surgery
included excision of pathologic tissue in the extensor carpi radialis brevis
tendon origin combined with excision of excessive scar tissue and repair of the
extensor aponeurosis when necessary. Based on a 40-point functional rating scale
proposed here, 83% of the elbows (29 of 35) had good or excellent results at an
average followup of 64 months (range, 17 months to 17 years). To prevent failure
of surgical treatment for tennis elbow, the pathologic tissue usually present in
the extensor carpi radialis brevis tendon should be resected. Release operations,
which weaken the extensor aponeurosis but fail to address the pathoanatomic
changes, are not recommended.
PMID- 9397261
TI - The natural history of the anterior cruciate ligament-deficient knee. Changes in
synovial fluid cytokine and keratan sulfate concentrations.
AB - Restoring knee stability through reconstruction, while providing symptomatic
relief, has not been shown to decrease the incidence of degenerative changes
after rupture of the anterior cruciate ligament. This suggests that posttraumatic
osteoarthritis may not be purely biomechanical in origin, but also biochemical.
To test this, we measured the levels of seven cytokine modulators of cartilage
metabolism in knee joint synovial fluid after anterior cruciate ligament rupture.
We also measured keratan sulfate, a product of articular cartilage catabolism.
The sample population consisted of patients with uninjured knee joints (N = 10),
and patients with acute (N = 60), subacute (N = 18), and chronic (N = 8) anterior
cruciate ligament-deficient knees. Synovial fluid samples were analyzed by enzyme
linked immunosorbent assays. Normal synovial fluids contained high levels of the
interleukin-1 receptor antagonist but low concentrations of other cytokines.
Immediately after ligament rupture there were large increases in interleukins 6
and 8, tumor necrosis factor alpha, and keratan sulfate. Interleukin-1 levels
remained low throughout the course. As the injury became subacute and then
chronic, interleukin-6, tumor necrosis factor-alpha, and keratan sulfate levels
fell but remained considerably elevated 3 months after injury. Concentrations of
interleukin-1Ra fell dramatically. Granulocyte-macrophage colony-stimulating
factor concentrations were normal acutely and subacutely but by 3 months after
injury were elevated 10-fold. Our data reveal a persistent and evolving
disturbance in cytokine and keratan sulfate profiles within the anterior cruciate
ligament-deficient knee, suggesting an important biochemical dimension to the
development of osteoarthritis there.
PMID- 9397262
TI - The effects of hyaluronan on the meniscus and on the articular cartilage after
partial meniscectomy.
AB - The effect of hyaluronan (molecular weight = 8 x 10(5)) on the meniscus and on
the articular cartilage was assessed after partial meniscectomy in a rabbit
model. On gross examination, remodeled meniscus appeared as newly synthesized
translucent tissue, and was seen in both vehicle- and hyaluronan-treated menisci.
Histologically, safranin O staining revealed the strong presence of
glycosaminoglycans in the newly remodeled tissue, and polarized light
demonstrated the absence of mature collagen architecture. Hydration of the
hyaluronan-treated menisci was significantly less than that of the vehicle
treated menisci, and the reducible collagen cross-link dihydroxylysinonorleucine
was significantly increased in the hyaluronan-treated menisci compared with the
vehicle-treated menisci, indicative of a greater degree of collagen remodeling.
In situ hybridization of vehicle- and hyaluronan-treated menisci revealed a high
level of type I procollagen mRNA expression and minor expressions of types II and
III mRNA. Expression of the type I collagen gene appeared to be more pronounced
in the hyaluronan-treated menisci than in the vehicle-treated menisci. The tibial
plateaus revealed mild cartilage fibrillation after partial meniscectomy. A
statistically significant difference between vehicle- and hyaluronan-treated
cartilage was not demonstrated in the present study because of the slow
development (i.e., 12 weeks) of osteoarthritis after partial meniscectomy in the
rabbit model. These results suggest that in the rabbit model, hyaluronan enhances
collagen remodeling and inhibits meniscal swelling after partial meniscectomy in
the avascular region.
PMID- 9397263
TI - Distal radial growth plate injury and positive ulnar variance in nonelite
gymnasts.
AB - To assess the prevalence of stress injury to the distal radial growth plate and
of positive ulnar variance in a nonelite gymnast population, we administered a
radiographic survey and questionnaire to 44 skeletally immature nonelite gymnasts
(27 girls and 17 boys). The subjects trained an average of 11.9 hours per week.
Radiographic findings consistent with stress injury of the distal radial physis
were found in 25% (11 of 44) of participants. Ulnar variance was found to be more
positive in the gymnasts when compared with age-predicted norms. An average side
to-side difference in ulnar variance of 0.9 mm was observed. Radiographic
findings of stress injury to the growth plate and the amount of ulnar variance
were not associated with age, sex, training intensity, wrist pain, height, or
weight. There was also no significant relationship between ulnar variance and
radiographic findings. The mean ulnar variance in nonelite gymnasts was between
that measured for elite gymnasts and nongymnasts. These results indicate that
stress injury of the distal radial growth plate occurs in a significant
percentage of nonelite gymnasts. It also appears that ulnar variance is more
positive than would otherwise be predicted, suggesting growth inhibition of the
distal radius, a growth stimulation of the ulna, or a combination of both.
PMID- 9397264
TI - Reconstruction of the anterior and posterior cruciate ligaments after knee
dislocation. Use of early protected postoperative motion to decrease
arthrofibrosis.
AB - We report a critical rating of results for 11 patients with bicruciate ligament
reconstructions and immediate protected knee motion after knee dislocations
(seven acute and four chronic). Six patients had concurrent repair or
reconstruction of medial ligamentous structures, and six had reconstruction of
the lateral and posterolateral ligaments. All patients returned for followup at a
mean of 4.8 years postoperatively. Follow-up arthrometric testing at 20 degrees
of flexion showed 10 knees had less than 3 mm of increased total anterior
posterior displacement and 1 knee had 7 mm of increase. At 70 degrees of flexion,
9 knees had less than 3 mm of increased displacement and 2 knees had more than 6
mm of increase. The failure rates were as follows: 18% of posterior cruciate
ligament reconstructions (2 of 11), 9% of anterior cruciate ligament
reconstructions (1 of 11), 17% of lateral and posterolateral procedures, and 0%
of medial collateral ligament procedures. At followup, five of the seven patients
with acute injuries had no limitations with daily or sports activities. Three of
the four patients with chronic ruptures were asymptomatic with daily activities,
but only one was asymptomatic with light sports. Five patients (all acute
injuries) required treatment for knee motion limitations. Nine patients had full
range of motion at followup. We concluded that simultaneous bicruciate ligament
reconstructions, performed with associated medial or lateral procedures, are
warranted to restore function to all ligament structures. Even though immediate
motion was used, several patients required early manipulation or arthroscopic
debridement, which restored full motion and prevented permanent arthrofibrosis.
PMID- 9397265
TI - The reharvested central third of the patellar tendon. A histologic and
biomechanical analysis.
AB - We assessed the histologic, mechanical, and structural properties of the
reharvested central-third patellar tendon in greyhounds. Twelve dogs had the
central third of the patellar tendon (5 mm) removed with corresponding bone
blocks from the patella and tibia; the remaining tendon defect was loosely
closed. Six dogs were sacrificed at 6 months and six at 12 months, and the
central third of the patellar tendon was harvested from both the operative and
the contralateral control knees. Analysis of the structural changes in the
tendons revealed a significant increase in thickness for reharvested tendons at
both 6 and 12 months when compared with controls. The entire residual tendons
were narrower at 6 months and were shorter at 12 months compared with controls.
Mechanical testing showed that the average failure load, ultimate tensile
strength, strain at failure, and average modulus for the reharvested central
third of the patellar tendon were significantly less than that of controls at
both 6 and 12 months. Analysis of collagen fiber size by electron microscopy
revealed a significant increase in collagen fiber diameter at 6 months (135 +/-
41 nm versus 49 +/- 4 nm) but no difference between the operative limbs and
controls at 12 months. The reharvested bone-patellar tendon-bone complex does not
have the same properties as the primary patellar tendon graft up to 1 year after
harvest in a canine model, and its use for revision cruciate ligament
reconstruction must be carefully reexamined.
PMID- 9397266
TI - Anterior cruciate ligament reconstruction with autogenous patellar tendon graft
followed by accelerated rehabilitation. A two- to nine-year followup.
AB - We sought to determine the long-term results of 1057 consecutive patients who
underwent an anterior cruciate ligament reconstruction with an autogenous
patellar tendon graft from 1987 through 1993 and who followed an accelerated
rehabilitation program. The patients were followed prospectively and objective
physical examination data were obtained on 806 patients at a mean of 4.0 years
postoperatively. Subjective follow-up data were obtained on 948 patients at a
mean of 4.4 years postoperatively. The mean final range of motion was 5 degree/0
degrees/140 degrees. The mean manual maximum KT-1000 arthrometer score was 2.0 +/
1.5 mm. Isokinetic quadriceps muscle strength testing revealed a mean of 94%
strength after acute reconstructions and 91% strength after chronic
reconstructions. International Knee Documentation Committee evaluation after
acute reconstruction rated 42% of knees as normal, 47% as near normal, 10% as
abnormal, and 1% as severely abnormal. The same evaluation after chronic
reconstruction rated 41% of knees as normal, 44% as near normal, 14% as abnormal,
and 1% as severely abnormal. Radiographically, 94% of acute knees and 89% of
chronic knees had no joint space narrowing. Subjective modified Noyes
questionnaire results showed a mean score of 93.2 +/- 7.9 points. The mean time
for patients to return to sport-specific activities was 6.2 weeks and to athletic
competition at full capacity was 6.2 months postoperatively. In the long-term,
patients exhibited full range of motion, excellent stability, good strength, and
a return of full function in most cases.
PMID- 9397267
TI - Experimental study on external tibial rotation of the knee.
AB - Using biplanar roentgenographic photogrammetry, we investigated posterolateral
rotatory instability of the knee joint both before and after sectioning of
posterolateral structures, the posterior cruciate ligament, and the lateral
collateral ligament. Fifteen fresh-frozen cadaveric knees were used. Compared
with the intact state, sectioning of the posterior cruciate ligament alone did
not increase the amount of external tibial rotation, but the axis of external
tibial rotation shifted when the anterolateral bundle of the posterior cruciate
ligament was cut. When the posterior cruciate ligament was cut after sectioning
of the posterolateral structures and the lateral collateral ligament, external
tibial rotation increased and the axis of external rotation shifted. The results
demonstrated that sectioning of the anterolateral bundle of the posterior
cruciate ligament is associated with a change in the location of the axis of
tibial rotation. Therefore an isolated posterior cruciate ligament injury can
alter the kinematics of the knee joint by changing the axis of external tibial
rotation. The present results also demonstrate that the posterior cruciate
ligament serves as a kind of secondary restraint to posterolateral rotatory
instability in knees with injured posterolateral structures. Helical motion
analysis using biplanar roentgenographic photogrammetry is a useful method for
evaluating knee kinematics.
PMID- 9397268
TI - The combined dynamic and static contributions to subacromial impingement. A
biomechanical analysis.
AB - Ten human cadaveric shoulders were tested with a dynamic shoulder model
simulating physiologic rotator cuff, deltoid, and biceps muscle forces. The
combined effect of the muscle forces and acromial structure on subacromial
impingement was measured with minimally invasive, miniature pressure transducers.
Shoulders with large acromial spurs had significantly greater impingement
pressures at the anterolateral acromion in neutral, internal, and external
rotation compared with those with flatter acromia. Application of a biceps muscle
force reduced anterolateral acromial pressures by 10%. Failure to simulate a
supraspinatus force decreased acromial pressure 52% in shoulders with type III
acromia in neutral rotation. Without rotator cuff forces applied, the maximum
deltoid muscle force required to elevate the arm increased by 17%. Acromial
pressures were increased when no rotator cuff forces were applied, but the
increases were not significant. After an anterior acromioplasty, pressures
decreased by 99% anteriorly. However, failure to achieve a flat surface
posteriorly increased pressures in this location, especially with the shoulder in
external rotation. Modeling the rotator cuff and deltoid muscle forces
demonstrated the importance of the muscular force couple to center the humeral
head during elevation of the arm. The inferior forces of the infraspinatus, teres
minor, and subscapularis muscles were necessary to neutralize the superior shear
force produced by the deltoid and supraspinatus muscles.
PMID- 9397269
TI - Two- to five-year followup of arthroscopic Bankart reconstruction using a suture
anchor technique.
AB - This is a retrospective review of 27 patients (27 shoulders) with recurrent
anterior instability who underwent arthroscopic Bankart reconstruction with a
suture anchor technique between 1990 and 1993. Average length of followup was 40
months (range, 26 to 64). The average Bankart rating score was 88 (range, 45 to
100) with 70% good-to-excellent results and 30% fair-to-poor results. The average
University of California (Los Angeles) shoulder function score was 32 (range, 27
to 35). The average loss of external rotation in abduction was 1 degree. Eight
patients (30%) failed the procedure and had recurrent anterior shoulder
instability; seven of these had repeat traumatic events. A Pearson chi-square
analysis of multiple variables was performed to determine which variables
correlated with a successful result. A higher success rate was obtained if the
patient had five or fewer dislocations before surgical reconstruction. This
technique should be limited to patients not returning to contact sports, or in
whom the improved cosmetic results or increased postoperative external rotation
of the arthroscopic procedure are valued.
PMID- 9397270
TI - Assessment of failed arthroscopic anterior labral repairs. Findings at open
surgery.
AB - To assess capsulolabral lesions present in patients after unsuccessful
arthroscopic procedures, we reviewed the records of 20 patients who had undergone
open shoulder procedures after unsuccessful arthroscopic Bankart procedures for
chronic shoulder instability. The Bankart lesion had initially been repaired
arthroscopically by transglenoid sutures (N = 10), bioabsorbable tacks (N = 7),
suture anchors (N = 2), or arthroscopic screws (N = 1). Five of the 20 patients
(25%) had reinjuries to the shoulder after the arthroscopic procedure. The
average time from the arthroscopic to the open procedure was 17.9 months.
Overall, 12 of the 20 patients (60%) had healed Bankart lesions at the time of
open surgery. Eight of the 20 patients (40%) were found to have persistent
Bankart lesions, and 15 of the 20 patients (75%) were found to have redundant
anterior capsules. The presence of a persistent Bankart lesion significantly
correlated with postarthroscopic dislocation, and the presence of capsular laxity
significantly correlated with postarthroscopic subluxation. We concluded that
capsular laxity is difficult to quantify arthroscopically and is present in a
significant percentage of patients with chronic traumatic shoulder instability.
Failure to successfully treat either the Bankart lesion or capsular laxity at the
time of an arthroscopic Bankart procedure may lead to postoperative instability.
PMID- 9397271
TI - Posterior tibial tunnel placement to avoid anterior cruciate ligament graft
impingement by the intercondylar roof. An in vitro and in vivo study.
AB - Recent recommendations to "customize" tibial tunnel placement based on the slope
of the intercondylar roof and the amount knee hyperextension were derived from a
series of cases with graft impingement by the intercondylar roof. We believe that
this impingement is caused by anterior placement of the graft and not by
variations of notch anatomy among individual patients. In Phase 1 of this study,
we drilled tibial tunnels in the posteromedial aspect of the anterior cruciate
ligament "footprint" after the ligament was excised in cadaveric knees. We then
passed an impingement rod into the back of the knee joint. Lateral radiographs
with the knee in hyperextension were taken of each specimen, and the distance
between the superior border of the rod and intercondylar roof was measured. In
Phase 2, we prospectively obtained lateral hyperextension radiographs of 75
consecutive knees with anterior cruciate ligament reconstructions and evaluated
them for graft impingement based on recently published guidelines. In Phase 1, we
found no cases of impingement and an average roof clearance of 8.3 mm. In Phase
2, we noted no cases of severe impingement, 3 cases of moderate impingement (4%),
and 72 cases (96%) with no impingement. We conclude that posteromedial tibial
tunnel placement alone is adequate to avoid graft impingement in almost all
patients. Individualized tibial tunnel placement with specialized tibial guidance
systems is not necessary.
PMID- 9397272
TI - The strain behavior of the anterior cruciate ligament during squatting and active
flexion-extension. A comparison of an open and a closed kinetic chain exercise.
AB - The effects of weightbearing (closed kinetic chain) and nonweightbearing (open
kinetic chain) exercises on the biomechanical behavior of an injured anterior
cruciate ligament or a healing anterior cruciate ligament graft are unknown. To
understand the effects of these exercises on the healing graft, we measured the
strain behavior of the normal anterior cruciate ligament in human subjects while
they performed squatting, a closed kinetic chain exercise, and active flexion
extension of the leg, an open kinetic chain exercise. The maximum anterior
cruciate ligament strain values obtained during squatting did not differ from
those obtained during active flexion-extension. Also, anterior cruciate ligament
strain values obtained during squatting were unaffected by the application of
elastic resistance intended to increase muscle activity. These findings indicate
that squatting, which produces a substantial compressive joint force, does not
necessarily protect the anterior cruciate ligament more than active flexion
extension of the leg, which is characterized primarily by contraction of the
dominant quadriceps muscle. These findings also demonstrate that increasing
resistance during the squat exercise does not produce a significant increase in
anterior cruciate ligament strain values, unlike increased resistance during
active flexion-extension exercise.
PMID- 9397273
TI - Osteochondritis dissecans of the femoral condyles. Long-term results of excision
of the fragment.
AB - Nineteen patients with 20 osteochondritis dissecans lesions were evaluated
between 2 and 20 years after excision of a partially detached (grade III) or
loose (grade IV) fragment from the femoral condyles. Evaluation with the Hughston
rating scale for osteochondritis dissecans revealed one excellent result, four
good, four fair, six poor, and five failure results. Eleven patients had
developed osteochondritis dissecans before skeletal maturity. In contrast to what
has been stated in the literature, the results in these patients were no better
than in those who developed osteochondritis dissecans as adults. The short-term
results of excision are good, but the long-term results are extremely poor.
Consequently, we recommend bone grafting and replacement of the fragment when it
is technically possible because the long-term results are better than those after
excision.
PMID- 9397274
TI - Results of percutaneous longitudinal tenotomy for Achilles tendinopathy in middle
and long-distance runners.
AB - From August 1989 to January 1995 we performed multiple percutaneous longitudinal
tenotomies under local anesthetic on 52 middle- and long-distance runners with
unilateral Achilles tendinitis or peritendinitis that had failed conservative
treatment. Forty-eight patients were reviewed at an average of 22.1 months (SD,
6.5) after surgery. Results were rated as excellent in 25 patients, good in 12,
fair in 7, and poor in 4. Four patients developed subcutaneous hematomas. One
patient developed a superficial infection at one of the incision sites, which was
managed by oral antibiotics with full recovery. Three patients complained of over
sensitivity to the incisions; this was resolved by rubbing hand cream over the
incisions several times a day. One patient developed hypertrophic painful scars
on three of the five incisions, but corticosteroid injections yielded good
functional and cosmetic results. Isometric strength and endurance of the
gastrocsoleus complex was measured just before the procedure, and at 6 weeks and
6 months later. Both were within 10% of the normal contralateral limb by the 6th
postoperative month. Percutaneous longitudinal tenotomy is simple, can be
performed on an outpatient basis, requires minimal follow-up care, and, in our
experience, has produced no significant complications. We use this procedure as
the operative treatment of choice for cases of chronic tendinitis that have
failed conservative treatment.
PMID- 9397275
TI - Tissue shrinkage with the holmium:yttrium aluminum garnet laser. A postoperative
assessment of tissue length, stiffness, and structure.
AB - The effect of laser energy on the length, stiffness, and structure of connective
tissue was examined in a rabbit patellar tendon model. A holmium:yttrium-aluminum
garnet laser was used to deliver a calculated dose of laser energy (300 J/cm2) to
one randomly selected patellar tendon in each of 13 adult New Zealand White
rabbits. The contralateral patellar tendon was used as a control. Radiopaque
markers were placed in the patella and tibial tuberosity to allow for patellar
tendon length measurements (via standard lateral radiographs) before and after
laser application and at 4 and 8 weeks. Limbs were not immobilized during the
postoperative period. The tendons were harvested at 0 weeks (N = 7) and 8 weeks
(N = 6) and evaluated for tensile, stiffness, cross-sectional area, histologic
changes, and electron microscopic appearance. The results demonstrated
significant tendon shrinkage (6.6% +/- 1.4%) after application of the calculated
laser energy dose. However, tendon length had increased significantly beyond the
immediate postlaser length at 4 weeks and beyond its original length by 8 weeks.
At 8 weeks, the lased tendons were significantly less stiff with significantly
greater cross-sectional areas than contralateral controls. There was generalized
fibroblastic response throughout the entire lased tendon characterized by a
marked increase in cellularity. There was also a change from the normal bimodal
pattern of large- and small-diameter collagen fibers to a unimodal pattern with
predominantly small-diameter fibers in the lased tendons. The tissue alterations
seen in this study suggest that the biologic response of connective tissue to
laser energy causes a further compromise in tissue integrity, beyond that
attributed to the initial physical effects of the laser. These alterations must
be taken into consideration when determining postoperative rehabilitation of
laser-modified tissues.
PMID- 9397276
TI - Popliteomeniscal fasciculi and lateral meniscal stability.
AB - In an attempt to understand better the contribution of the anteroinferior and
posterosuperior popliteomeniscal fasciculi to lateral meniscus stability, we
objectively evaluated the stability of the lateral meniscus before and after
sequentially sectioning these fasciculi. In the biomechanical model, we attempted
to account for the inherent limitations of arthroscopic evaluation of lateral
meniscal stability. When the fasciculi were intact, the average lateral meniscal
motion with a 10-N load was 3.6 mm. When the anteroinferior fascicle was
disrupted, the average lateral meniscal motion with a 10-N load was 5.4 mm. The
mean increase in motion from the intact state was 1.8 mm or 50%, which was
significant. When both fasciculi were disrupted, the average lateral meniscal
motion with 10-N load was 6.4 mm. The mean increase in motion from the intact
state was 2.8 mm or 78% and from the single fascicle disruption state was 1.0 mm
or 18%, both differences were significant. The meniscus did not become locked
with any of these loading trials, and it spontaneously reduced to the original
position when unloaded. Both fasciculi make significant contributions to meniscal
stability. Even though the meniscus never became locked in the joint when loaded
during this study, with the variable loads seen with normal activities mechanical
symptoms might be expected when meniscal motion is almost double. An increase in
lateral meniscal motion at the time of surgery may aid in the diagnosis of
fasciculi disruption, despite normal meniscal structure on magnetic resonance
images and at arthroscopic visualization.
PMID- 9397277
TI - Adventitial cystic disease of the popliteal artery in a triathlete. A case
report.
PMID- 9397278
TI - Functional evaluation of the ligaments at the acromioclavicular joint during
anteroposterior and superoinferior translation.
AB - We examined the anatomy and measured the in situ force in ligaments at the
acromioclavicular joint using a universal force-moment sensor. The in situ force
in the coracoacromial, conoid, trapezoid, superior acromioclavicular capsular,
and inferior acromioclavicular capsular ligaments of 10 fresh-frozen cadaveric
shoulders was determined for a load of 70 N applied to the clavicle in
anteroposterior and superoinferior directions. The lengths of the conoid and
trapezoid ligaments were found to be 15.1 +/- 4.1 and 11.5 +/- 2.2 mm,
respectively; the widths of the conoid and trapezoid ligaments were 10.7 +/- 1.5
and 11.0 +/- 2.8 mm, respectively. The in situ force of the trapezoid (42.9 +/-
15.4 N) was significantly greater than that for the other ligaments during
posterior displacement. Otherwise, no statistically significant differences could
be found between any of the in situ forces in each ligament during all other
motions examined. During anterior displacement, the inferior acromioclavicular
capsular ligament appeared to be the major restraint. The trapezoid ligament was
the primary restraint during posterior displacement and provided 55.8% +/- 20.0%
of the resisting force. Our results suggest that the coracoclavicular and other
acromioclavicular joint capsular ligaments should be considered for
reconstruction to restore normal joint function, especially in the anterior,
posterior, and superior directions.
PMID- 9397279
TI - The clinical importance of the anaerobic energy system and its assessment in
human performance.
AB - The anaerobic energy system is involved in providing energy for all forms of
physical activity. The relevance of this system to human performance and physical
fitness throughout the age spectrum is underscored here and contrasted with the
aerobic energy system. The anaerobic system responds to high-intensity training
with biochemical, neural, and anatomic adaptations. Unlike the aerobic system,
this response tends to be primarily a local phenomenon with little systemic
adaptation. An important factor distinguishing anaerobic training from aerobic
training is the intensity of the exercise dose. For anaerobic training to occur,
the dose must be of high intensity and performed to near-exhaustion. The
anaerobic system can be indirectly assessed by performance tests, such as a
vertical jump or stair climb, or more directly by supramaximal bicycle tests. The
impact of recent research regarding the trainability of the anaerobic system,
particularly in the elderly population, is encouraging. The elderly respond to
anaerobic training and, as a result, their independence, quality of life, and
safety from falls can be improved. While little is known about anaerobic
rehabilitation after injury, it is known that isokinetic and performance tests
may be considered normal after rehabilitation, despite incomplete rehabilitation
of the anaerobic system. Thus, appropriate application of the anaerobic system
assessments and training principles is an important aspect of sports medicine
practice.
PMID- 9397280
TI - Athletics and osteoarthritis.
AB - Athletes, and an increasing number of middle aged and older people who want to
participate in athletics, may question whether regular vigorous physical activity
increases their risk of developing osteoarthritis. To answer this, the clinical
syndrome of osteoarthritis must be distinguished from periarticular soft tissue
pain associated with activity and from the development of osteophytes. Sports
that subject joints to repetitive high levels of impact and torsional loading
increase the risk of articular cartilage degeneration and the resulting clinical
syndrome of osteoarthritis. However, moderate habitual exercise does not increase
the risk of osteoarthritis; selected sports improve strength and mobility in
older people and people with mild and moderate osteoarthritis. People with
abnormal joint anatomy or alignment, previous significant joint injury or
surgery, joint instability, above-average body weight, disturbances of joint or
muscle innervation or inadequate muscle strength probably have increased risk of
osteoarthritis. These people and those with early osteoarthritis can benefit from
regular physical activity, but they should have a careful evaluation of their
joint structure and function before participation. They should consider measures
that decrease the intensity and frequency of impact and torsional loading of
joints, including use of sports equipment that decreases joint impact loading,
maintaining or improving muscle strength, tone, and general conditioning so that
muscle contractions help protect joints from injury and high impact, and
decreasing body weight.
PMID- 9397281
TI - A statistics primer. Tests for continuous data.
PMID- 9397283
TI - Perceived threat of illness and health protective behaviors in offspring of
adults with non-insulin-dependent diabetes mellitus.
AB - Self-reported measures of perceived threat of illness, health protective
behaviors, psychological well-being, and family modeling of health behaviors of
30 adults with a parental history of non-insulin-dependent diabetes mellitus
(NIDDM) were compared with responses from 29 adults with a parental history of
hypertension and 30 adults with no parental history of chronic illness. The NIDDM
risk group reported significantly more perceived threats of NIDDM and
hypertension and more weight-control efforts than the controls did. Reports of
the NIDDM risk respondents concerning physician screening, healthy diet, and
exercise did not differ from reports of individuals without a family history of
NIDDM. Perceived threat, psychological well-being, and family modeling did not
correlate with health-protective behaviors. The findings suggest that offspring
of adults diagnosed with NIDDM perceive themselves to be at risk of NIDDM and
engage in health behaviors, such as weight control, to protect themselves from
NIDDM onset.
PMID- 9397282
TI - The relationship between alcohol, stress, and depression in Mexican Americans and
non-Hispanic whites.
AB - The effect of alcohol use on the relationship between stress and depression in US
born Mexican American men, Mexican Americans born in Mexico, and non-Hispanic
Whites born in the United States was examined in a sample obtained from the Los
Angeles Epidemiological Catchment Area study. Chronic stress, measured by
financial strain, and acute stress, measured by negative life events, were
included in the analysis. Alcohol use was measured through a combination of
frequency, quantity, and binging behavior. Non-Hispanic Whites were found to have
a U-shaped relationship in which moderate drinkers, in the presence of stress,
had lower levels of depression than did heavy drinkers and abstainers. No such U
shaped relationship for Mexican Americans born in the United States was
indicated. Mexican Americans born in Mexico had a more J-shaped relationship,
with abstainers through moderate drinkers having lower mean depression scores
than did heavy drinkers.
PMID- 9397284
TI - A field study of stress and fatigue in long-distance bus drivers.
AB - Psychophysiological changes during long-distance driving may be associated with
driving fatigue and morbidity. Measures of stress and arousal, including heart
rate, blood pressure, catecholamines, cortisol, state anxiety, and self-ratings
of stress and arousal were collected from 10 long-distance bus drivers during 12
hour driving shifts and at matched times on nondriving rest days. Cardiovascular
and catecholamine data were elevated across the entire work day, compared with
rest days. Self-reported stress and state anxiety were elevated only at the
preshift measure, and these elevations were interpreted as the result of
anticipatory anxiety and additional work demands at the beginning of the shift.
Decelerating activation from the 9th to the 12th hours of driving were reflected
in slower heart rate and lower subjective arousal ratings. Suggested explanations
for these findings are that drivers experience a release of tension when they
anticipate the end of the shift and therefore deactivation is a signal or
precursor to the onset of fatigue in physiological adjustment mechanisms.
PMID- 9397285
TI - Maintaining attendance at a fitness center: an application of the decision
balance sheet.
AB - The effect of a decision balance sheet intervention on attendance at a university
fitness facility was examined. Facility members were randomly assigned to
control, placebo, and experimental conditions. The control condition received no
intervention, whereas the placebo and experimental conditions were called by
telephone and asked to complete either an irrelevant (smoking) or relevant
(exercising at the fitness facility) decision balance sheet. Attendance was
monitored surreptitiously for 4 weeks baseline and 8 weeks post intervention.
Statistical analyses indicated that the control and placebo conditions showed a
significant decrease in attendance from baseline to intervention, whereas those
in the experimental condition maintained attendance levels. Discussion focused on
broadening the application of the decision balance sheet, determining its
theoretical boundaries, and the necessity and appropriateness of decision
alternatives for the decision balance sheet in the exercise domain.
PMID- 9397286
TI - Self-efficacy and adjustment in cancer patients: a preliminary report.
AB - The relation between cancer self-efficacy and patient cancer adjustment,
depression, psychological distress, and behavioral dysfunction in 42 cancer
patients was studied in a preliminary investigation. Participants were male
cancer outpatients recruited from a Veterans Administration Medical Center who
completed a Cancer Self-Efficacy Scale, the Center for Epidemiological Studies
Depression Scale, the Affect Balance Scale, and the Sickness Impact Profile.
Correlational analyses indicated that self-efficacy was related to all adjustment
measures. Regression analyses revealed that when age, education, time since
initial diagnosis, and current disease status were controlled, the relationships
between patient self-efficacy expectations and cancer adjustment, psychological
distress, negative affect, positive affect, and behavioral dysfunction remained
statistically significant. Taken together, the results of the analyses suggested
that patient expectancies about control over cancer-related symptoms were related
to several important aspects of patient functioning. The results underscored the
need for further investigation of this construct in cancer patients.
PMID- 9397287
TI - Safety of calcium channel blockers: perspective on the controversy.
PMID- 9397288
TI - The endothelium in coronary artery disease.
AB - An increasing body of evidence indicates that the endothelium is crucially
involved in the regulation of coronary blood flow and cardiac function. Injury to
the endothelium precipitates atherosclerosis by leading to smooth-muscle-cell
migration and proliferation, induction of expression of growth factors and
impairment in the plasmatic coagulation and endogenous fibrinolysis system.
Strategically located between the circulating blood and the vascular smooth
muscle, endothelial cells release numerous vasoactive substances regulating the
function of vascular smooth muscle and trafficking blood cells. Important
endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and,
independent of the former, endothelium-derived hyperpolarizing factor. In
particular, nitric oxide inhibits cellular growth and migration. In concert with
prostacyclin, nitric oxide exerts potent antiatherogenic and thromboresistant
properties by preventing platelet aggregation and cell adhesion. These effects
are counterbalanced by endothelial vasoconstrictors, such as angiotensin II and
endothelin-1, both of which exert prothrombotic and growth-promoting properties.
Modern therapeutic strategies in coronary artery disease focus on preserving or
restoring endothelial integrity. Whereas nitrates partly substitute deficient
endogenous nitric oxide, calcium antagonists counteract angiotensin II and
endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and
facilitating the vasodilator effects of nitric oxide. Beyond inhibiting the renin
angiotensin system, angiotensin-converting enzyme inhibitors diminish the
inactivation of bradykinin, thus leading to an augmentation of nitric oxide
release. Furthermore, newly developed specific endothelin antagonists will
provide us with greater insight into the beneficial effects of restoring
endothelial dysfunction in cardiovascular disease. Thus, drugs can directly
affect endothelial function, prevent the action of endothelial mediators,
substitute for deficient endothelial factors or indirectly exert protective
effects by interfering with cardiovascular risk factors.
PMID- 9397289
TI - Structure and function of small arteries of essential hypertensive patients
following chronic treatment with once-a-day nifedipine.
AB - In view of the important impact of small-artery structural and functional
abnormalities on complications of hypertension and recent data suggesting that
some antihypertensive agents may correct some of these abnormalities, a study of
resistance artery structure and function in 20 well-controlled essential
hypertensive patients who had received for a prolonged period of time monotherapy
with the once-a-day extended release formulation of the calcium channel
antagonist nifedipine (nidefipine GITS) or with the beta-blocker atenolol is
reviewed. Resistance-size small arteries (standardized lumen diameter of 247 +/-
8 microns) were studied after dissection from a gluteal subcutaneous biopsy.
Small arteries were investigated on a wire myograph and as pressurized vessels.
On the myograph, the media width-to-lumen diameter ratio of arteries was 5.37 +/-
0.09% in normotensive subjects, 5.38 +/- 0.18% in patients treated with
nifedipine GITS, 6.81 +/- 0.18% in patients treated with atenolol and 7.08 +/-
0.12% in untreated hypertensives (p < 0.001, untreated or atenolol-treated
patients vs. normotensives or nifedipine-GITS-treated hypertensives), and similar
results were found in pressurized arteries. Contractility and endothelium
dependent relaxation were impaired in small arteries from untreated or atenolol
treated patients in comparison to those from normotensive subjects or nifedipine
GITS-treated patients. In conclusion, hypertensive patients with well-controlled
blood pressure under treatment for more than 1 year with nifedipine GITS exhibit
normal structure and function of small arteries, whereas similar patients whose
blood pressure is as well controlled by the beta-blocker atenolol present
abnormally thick small arteries with impaired contractility and endothelium
dependent relaxation. It will be important to determine whether small arteries of
other vascular beds are also improved by nifedipine GITS treatment of elevated
blood pressure and whether this results in reduced morbidity and mortality in
hypertensive patients.
PMID- 9397291
TI - Primary prevention of cardiovascular disease.
AB - Antihypertensive drug treatment has been shown to significantly decrease
cardiovascular morbidity and mortality rates in hypertensive subjects and to
reduce the occurrence of major hypertension-related complications, such as
stroke, coronary artery disease, congestive heart failure and renal
insufficiency. Despite these favorable effects, several issues related to
antihypertensive treatment remain to be clarified. This paper will discuss some
of these issues, with particular reference to the effects of blood pressure
lowering on renal diseases and coronary heart disease. It will also discuss the
ongoing clinical trials aimed at clarifying some unsolved issues of
antihypertensive treatment. The objective of the International Nifedipine GITS
Study Intervention as a Goal in Hypertensive Treatment was to provide information
on the effects of calcium antagonist treatment on high blood pressure values and
on hypertension-related cardiovascular complications in a high-risk hypertensive
population.
PMID- 9397290
TI - Optimal treatment of stable angina.
AB - Angina pectoris due to coronary artery disease is a common manifestation of
myocardial ischemia. Reduction of oxygen demand (beta-blockers) and relief of
coronary vasoconstriction (calcium blocker or nitrate) are additive approaches to
controlling ischemia. Risk factor reduction may improve coronary vascular
physiology, and ASA reduces the likelihood of thrombosis and myocardial
infarction. It is still unclear whether reduction of angina reduces cardiac
morbidity and/or mortality. In the Asymptomatic Cardiac Ischemia Pilot Study
(ACIP) and Total Ischemic Burden Bisoprolol Study (TIBBS) trials, data suggest
benefit from reducing myocardial ischemia. Thus control of angina pectoris is a
major goal of the treatment of coronary artery disease.
PMID- 9397292
TI - Equivalent reduction of proteinuria in hypertensives by either nifedipine GITS or
enalapril: disparate effects on neurohormones and ambulatory blood pressure and
the influence of salt.
AB - OBJECTIVE: We compared the efficacy of two classes of antihypertensive therapy on
ambulatory blood pressure control and proteinuria in patients with hypertension.
Furthermore, we determined the effects of the interaction of these therapies on
neurohormonal activation and of the patients' ambient sodium intake on the
outcomes. METHODS: Sustained-release nifedipine (nifedipine gastrointestinal
therapeutic system, GITS) 30-120 mg/day was compared in a double-blind sequential
randomized placebo-controlled trial with enalapril 5-30 mg/day regarding office
and 24-hour blood pressure control, plasma renin activity, noradrenaline and
adrenaline levels and 24-hour urinary protein and sodium in 46 elderly
nondiabetic hypertensive patients in a 16- to 18-week trial. RESULTS: Both
nifedipine GITS and enalapril controlled ambulatory blood pressure during the day
and at peak effect. Nifedipine GITS controlled ambulatory blood pressure during
the early morning surge and at night time as well. Nifedipine GITS increased
plasma renin activity and noradrenaline by 50 and 20%, respectively, compared to
the 150 and 0% change produced by enalapril. Both nifedipine GITS and enalapril
reduced proteinuria by 37%. Patients had increasing levels or proteinuria
proportional to higher ambient sodium intake (r = 0.48; p < 0.01). This effect
was accentuated during nifedipine GITS therapy as compared to enalapril.
CONCLUSION: Nifedipine GITS was superior to enalapril in controlling ambulatory
blood pressure, but they were equivalent in reducing proteinuria (37%). They had
disparate effects on neural activation and the duration of action. Raised protein
excretion appears to be associated with raised sodium intake. This was apparent
especially during nifedipine XL therapy.
PMID- 9397293
TI - Nifedipine GITS replacing nifedipine SR: ambulatory blood pressure assessment of
efficacy.
AB - The relative efficacy of two formulations of nifedipine, slow release (SR) and
gastrointestinal therapeutic system (GITS), to lower blood pressure in
hypertensive patients was evaluated in a prospective study. Nifedipine GITS 30
mg/day replaced nifedipine SR, 20 mg b.i.d. in 38 patients, 23 monitored by
routine blood pressure measurements and 15 by ambulatory monitoring. Nifedipine
GITS achieved a marked reduction in blood pressure with a smaller dose than
nifedipine SR: 30 versus 40 mg/day, respectively. It is concluded that patients
with hypertension controlled on a twice-daily dose of nifedipine prolonged action
can be converted to a lower once-daily dose of nifedipine GITS without
experiencing any increase in blood pressure. Tolerability and compliance improved
when switching to the GITS formulation.
PMID- 9397294
TI - Interaction of antihypertensive drugs with anti-inflammatory drugs.
AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce an increase in blood
pressure (BP) and may potentially reduce the efficacy of several antihypertensive
drugs. Probably the main mechanism of action is inhibition of prostaglandin (PG)
synthesis since NSAIDs have higher propensity to increase BP as the regulation of
BP (and renal function) is more PG-dependent and to interact with drugs
(diuretics, beta-blockers and ACE inhibitors) that may act through the increase
of PG formation. In contrast, NSAIDs do not interact with calcium antagonists and
central acting drugs which actions are apparently unrelated with renal/extrarenal
production of PG. It has been claimed that inhibition of natriuretic PGs could
explain the pressure effects of NSAIDs in treated hypertensive patients, but
sodium retention may be not the single explanation for such an interaction. We
found that despite indomethacin produced sodium retention after being added
either to enalapril or nifedipine-GITS, it only attenuated (by 45%) the
antihypertensive effects of enalapril. In alternative, since PG enhances
vasodilatation and attenuates vasoconstrictor influences, some NSAIDs may
counteract the PG-dependent vasodilatory tone in renal and extrarenal vascular
beds that mediate the antihypertensive action of some drugs. Thus, since calcium
antagonists are probably not affected by NSAIDs, they may be preferable to drugs
like diuretics, beta-blockers and ACE inhibitors for the treatment of high blood
pressure control in hypertensive patients who are clinically suitable for NSAIDs
therapy.
PMID- 9397295
TI - Anti-atherosclerotic properties of nifedipine. Benefit of early intervention to
prevent cardiovascular complications.
AB - Early stages of the atherosclerotic plaque are considered to be responsible for
about 2/3 of all acute coronary syndromes. Therefore, suppression of this initial
stage of plaque formation constitutes a major target to reduce the incidence of
the disease itself as well as its complications. Ca antagonists, like Nifedipine,
interfere with Ca++ ions crucially involved in atherogenesis. Consequently,
interval angiographic trials with Nifedipine in patients afflicted with coronary
artery disease assessed a significant reduction of coronary lesions. Clinical
outcome trials will establish the prognostic importance of the anti
atherosclerotic properties of Nifedipine.
PMID- 9397296
TI - Renal protection in diabetes--an emerging role for calcium antagonists.
AB - The combination of diabetes and hypertension increases the changes of progressive
renal disorder and ultimately renal failure. Roughly 40% of all diabetics,
whether insulin dependent or not, develop diabetic nephropathy. Diabetic
nephropathy is the single most important cause of end-stage renal disease in the
western world and accounts for more than a quarter of all end-stage renal
diseases. It is also a major cause of increased morbidity and mortality in
diabetic patients. Increased arterial blood pressure is an early and common
phenomenon in incipient and overt diabetic nephropathy. The relationship between
arterial blood pressure and diabetic nephropathy is a complex one, diabetic
nephropathy increasing blood pressure and blood pressure accelerating the course
of nephropathy. Calcium antagonists antagonize preglomerular vasoconstriction.
Furthermore, additional putative mechanisms include the ability to retard renal
growth and possibly to attenuate mesangial entrapment of macromolecules and to
attenuate the mitogenic effects of diverse growth factors. Calcium antagonists
(except the old short-acting dihydropyridine drugs) reduce microalbuminuria and
preserve kidney function in diabetic patients with incipient diabetic
nephropathy. Long-term trials using the new long-acting dihydropyridine calcium
antagonists for the treatment of patients with incipient nephropathy are still
lacking. A recent 1-year randomized double-blind study in hypertensive insulin
dependent diabetic patients with diabetic nephropathy showed a more beneficial
effect on the decline rate in the glomerular filtration rate of nisoldipine (long
acting dihydropyridine) than angiotensin-converting-enzyme (ACE) inhibition. The
mean arterial blood pressure during the study based on 24-hour recordings was
nearly identical, 103 (SD 9) and 101 (SD 11) mm Hg in the two groups.
Furthermore, a recent 5-year randomized open study in hypertensive noninsulin
dependent patients with diabetic nephropathy has revealed the same beneficial
effect of a calcium antagonist and ACE inhibition on the progression of
nephropathy. In a third group treated with sympatholytic drugs, more than 50% of
the subjects had a doubling of their creatinine as compared to less than 10% in
the two other groups mentioned above. However, long-term studies are needed to
consolidate these findings and expand them to insulin-dependent diabetic patients
with diabetic kidney disease.
PMID- 9397297
TI - Evaluating the association between drug use and outcome--should the information
from observational studies affect therapeutic use?
PMID- 9397298
TI - Calcium channel blockers and cancer: is there preclinical evidence for an
association?
AB - The preclinical evidence for a potential influence of calcium channel blockers
(CCB) on carcinogenesis is discussed in the light of rodent carcinogenicity
studies as well as mechanistic data. In the bioassays performed in rats and mice
on the dihydropyridine CCB nifedipine, nimodipine, nisoldipine and nitrendipine,
no evidence was found for a carcinogenic potential of these compounds. Moreover,
the mechanistic knowledge on the influence of CCB on the fundamental processes of
cell proliferation and apoptosis is not in favor of a tumor-promoting activity of
these compounds. It is, therefore, concluded that there is no preclinical
evidence that the therapeutic use of CCB of the dihydropyridine class is
associated with an increased risk of cancer.
PMID- 9397299
TI - Elevated serum cardiac markers in asymptomatic marathon runners after
competition: is the myocardium stunned?
AB - Prolonged strenuous exercise may trigger acute myocardial infarction (AMI), as
exemplified by the occurrence of sudden cardiac death during marathon running.
Serum creatine kinase MB (CK-MB) may be elevated in asymptomatic marathon runners
after competition from exertional rhabdomyolysis of skeletal muscle altered by
training, limiting its utility for evaluating acute cardiac injury in such
athletes. Myoglobin and CK-MB2 isoform levels are emerging as earlier markers of
AMI and troponin subunits as more specific than serum CK-MB mass. We tested
runners before and sequentially after the 1995 Boston Marathon for conventional
and newer markers including myoglobin, CK-MB mass and isoforms, cardiac troponin
T, and cardiac troponin I using standard laboratory methods and rapid format
assays if available. The mean serum values for myoglobin, CK-MB mass, CK
MB/myoglobin rapid panel tests, and CK-MB2 isoforms were normal or negative pre
race and elevated or positive 4 and 24 h after competition. These markers lack
specificity for acute cardiac injury in trained runners. While the mean serum
values for cardiac troponins T and I remained normal, 9 of 45 runners (20%)
showed an increase in subunits by first-generation assays. All runners remained
asymptomatic for cardiac disease and completed subsequent marathons 1 year later,
making reversible myocardial injury or stunning unlikely. Elevated values of
serum markers for AMI, including first-generation assays for both troponin
subunits should be interpreted with caution in trained runners.
PMID- 9397300
TI - Short- and long-term prognosis after coronary artery bypass grafting in relation
to smoking habits.
AB - We describe the 2- and 5-year prognoses following coronary artery bypass grafting
(CABG) in relation to smoking habits among consecutive patients being operated on
in western Sweden during a 3-year period. Among the 2,121 patients, 10.2%
admitted smoking at coronary angiography as compared with 7.5% 2 years after CABG
(NS). Among smokers, the mortality during the subsequent 2 years was 8.9% as
compared with 6.5% for exsmokers and 7.3% for never smokers (NS). During the 5
year follow-up, smokers had a mortality of 18.8% as compared with 13.6% for
exsmokers and 12.5% for never smokers (p = 0.03). When correcting for
dissimilarities in previous history, smoking was a strongly significant
independent (p < 0.0001) predictor of 5-year mortality.
PMID- 9397301
TI - Doppler echocardiographic assessment of left ventricular diastolic function in
myotonic dystrophy.
AB - We utilized Doppler echocardiography to characterize left ventricular diastolic
function in 42 patients with myotonic dystrophy (mean age 37 +/- 12 years, 64%
male) who had no symptoms of heart failure and had normal left ventricular
systolic function. Data were compared with those in 41 normal control subjects of
similar age and gender. Heart rate, systemic blood pressure, and cardiac
dimensions (wall thickness, left atrial and left ventricular cavity dimensions)
were similar and not significantly different in patients and controls. As a
group, patients showed significantly increased deceleration time and decreased
rate of decline of flow velocity in early diastole (p < 0.0001 and p < 0.01,
respectively) when compared to controls. Individual patient analysis showed that
10 (24%) of the 42 patients with myotonic dystrophy had 2 or more abnormal
Doppler indexes of diastolic function consistent with a pattern of impaired left
ventricular relaxation. The most common abnormalities were increased deceleration
time (> 224 ms; 9 patients), prolonged isovolumic relaxation time (> 103 ms; 8
patients) and reduced rate of decline of flow velocity in early diastole (< 2.1
m/s2; 5 patients). In addition, peak early diastolic flow velocity was reduced (<
43 cm/s) in 3 patients and early to atrial peak flow velocity ratio was reduced
(< 1) in 2 patients. Comparison of subgroups of patients with and without
abnormal Doppler indexes showed no significant differences with regard to age,
gender, heart rate, systemic blood pressure, severity of neuromuscular disease,
and cardiac dimensions. After study, patients were clinically followed up for a
mean period of 20 +/- 7 months (range 12-35). During observation no patients died
and none experienced symptoms of heart failure. This Doppler echocardiographic
analysis demonstrates that diastolic abnormalities may be present in patients
with myotonic dystrophy, even in the absence of symptoms of cardiac failure or
left ventricular systolic dysfunction. These diastolic abnormalities suggest an
intrinsic myocardial abnormality in patients with myotonic dystrophy; however,
whether they represent a preclinical phase of myocardial involvement or an
intrinsic feature of the primary myocardial disease process in myotonic dystrophy
remains to be elucidated.
PMID- 9397302
TI - Hyperinsulinemia in patients with spastic angina pectoris.
AB - We evaluated the association between coronary spasm and hyperinsulinemia (high
immunoreactive insulin, IRI) in patients with angina pectoris. The study cohort
comprised 30 patients with spastic angina pectoris, 30 patients with angina
pectoris showing fixed-obstructive coronary sclerosis and 30 control subjects who
were matched for body mass index, age and sex. A 75-gram oral glucose test was
performed, and blood sugar and IRI were serially measured concomitant with serum
total cholesterol, triglyceride and HDL cholesterol. The IRI level at 60 min, the
peak IRI during the test, sigma IRI and sigma IRI/sigma blood sugar were
significantly higher in the patients than in the controls. Total cholesterol and
LDL cholesterol levels were significantly increased in patients showing fixed
obstructive coronary sclerosis compared to controls.
PMID- 9397303
TI - Daily distribution of episodes of acute cardiogenic pulmonary edema.
AB - Many fatal or potentially fatal cardio-cerebrovascular diseases present a
definite circadian distribution in their onset. In order to verify if episodes of
acute cardiogenic pulmonary edema have a significant daily periodicity in their
occurrence, a retrospective analysis of 1,204 episodes has been conducted. In all
cases, the hour of the day of onset has been identified with certainty; all
episodes occurred in hospitalized patients. The rhythmometric circadian
inferential statistical analysis by means of the single cosinor method
demonstrates that the episodes of acute cardiogenic pulmonary edema present a
significant (p < 0.002) circadian distribution, with a peak at 1:00 a.m. (from
10:00 p.m. to 4:00 a.m.). No significant differences (p > 0.05) were found in the
circadian distribution regarding sex, age (less or more than 60 years), absence
or presence of arterial hypertension and coronary artery disease. Several factors
may contribute to this behavior, especially the relationships between several
endogenous circadian rhythms, sleep and disease. The knowledge that acute
pulmonary edema is a high chronorisk disease could be of interest for the better
understanding of its pathophysiology and for a better causative control and
prevention.
PMID- 9397304
TI - Cardiac involvement in Behcet's disease.
AB - To assess the prevalence and the extent of cardiac involvement in patients with
Behcet's disease and to investigate the possible causes that may predispose to
this involvement, 30 patients affected by Behcet's disease and 30 normal control
subjects were submitted to M-mode, two-dimensional, and Doppler echocardiographic
evaluation. Moreover, antinuclear and anticardiolipin autoantibodies were
determined in the sera of both patients and control subjects. Finally, HLA-B51
positivity was assessed in the patients and in a historical control group. Mitral
valve prolapse was observed in 50% and proximal aorta dilatation in 30% of the
patients. There was a significant difference in the rate of these abnormalities
in comparison with the control group. Left ventricular function parameters were
similar between the two groups. The positivity rate of antinuclear and
anticardiolipin autoantibodies was very low (7%), without differences between the
groups. HLA-B51 was detected in 82.7% of the patients versus 21.7% in the control
group (p < 0.00001). In conclusion, this study demonstrates a high rate of
cardiac abnormalities in patients with Behcet's disease.
PMID- 9397305
TI - Protein turnover in compensated chronic aortic regurgitation.
AB - We recently demonstrated dynamic alterations in protein turnover 3 days and 1
month after surgical induction of aortic regurgitation (AR). To characterize
protein synthesis and degradation during the long-term plateau phase, we
performed [3H]-leucine infusion 2.5 years after induction of AR in 10 New Zealand
White rabbits and 12 sham-operated controls. Protein fractional synthesis rates
were obtained by analyses of plasma and protein hydrolysates, growth rates from
protein concentration and heart weight measurements, and degradation rates by
subtraction of growth from synthesis rates. AR (regurgitant fraction 25 +/- 11%)
caused a 57% increase in left ventricular (LV) weight in comparison with controls
(7.4 +/- 1.7 vs. 4.7 +/- 0.6 g, p < 0.001) and no evidence of heart failure.
Although concentrations of total cardiac protein, myosin heavy chain and actin
were similar, the enlarged AR hearts had increased amounts of total cardiac
protein (1,009 +/- 312 vs. 682 +/- 120 mg/LV, p < 0.05), myosin heavy chain (148
+/- 91 vs. 81 +/- 29 mg/LV, p < 0.05), and actin (73 +/- 42 vs. 44 +/- 16 mg/LV,
p < 0.06). Individual protein fractional synthesis and degradation rates were
closely balanced. However, myosin fractional synthesis rates were 152% (p < 0.01)
greater than those of total cardiac protein in AR animals, while only 52% (p <
0.05) greater in controls (AR vs. controls, p = 0.05). Variations in actin
turnover between AR and control animals did not attain statistical significance.
Myosin and actin fractional synthesis rates correlated closely in AR rabbits (R =
0.81, p < 0.02), but not among controls (R = 0.41, NS). Thus, selective
alterations in myofibrillar protein turnover contribute to the maintenance of
increased myofibrillar protein content in the 'compensatory' LV hypertrophy of
chronic AR.
PMID- 9397306
TI - Effects of antegrade versus combined antegrade/retrograde cardioplegia on
postoperative septal wall motion in patients undergoing open heart surgery.
AB - To evaluate the influence of two techniques of myocardial protection on septal
wall motion (SWM) and left ventricular ejection fraction, 21 patients with a
normal SWM underwent surgery using either conventional antegrade cardioplegia
(group I, n = 9) or combined antegrade/retrograde cardioplegia (group II, n =
12). The patients were assessed pre- and postoperatively by radionuclide
ventriculography. A resting thallium-201 study was performed in patients (n = 6)
with a postoperatively abnormal SWM: in 2 of 9 (22%) in group I and in 4 of 12
(33%) in group II (p = NS). The left ventricular ejection fraction was similar in
both groups before surgery (57 +/- 3% in group I vs. 57 +/- 8% in group II; p =
NS) and did not change significantly after surgery. All 6 patients with an
abnormal SWM had a normal septal thallium-201 uptake. Thus, (1) an abnormal SWM
after cardiac surgery is common: (2) it is not due to perioperative ischemia or
infarction, and (3) neither the incidence of an abnormal SWM not the global left
ventricular function is influenced by the addition of retrograde cardioplegia
during open heart surgery.
PMID- 9397307
TI - Dislodgement of a Wiktor stent during intracoronary ultrasound examination.
AB - We report a case of stent dislodgement complicating adjuvant intracoronary
ultrasound (ICUS) imaging that required emergency coronary bypass grafting. This
probably very rare complication gains importance since ICUS is increasingly used
to confirm adequate stent expansion and full coverage of the lesion.
PMID- 9397308
TI - Early detection of myocardial ischemia after successful percutaneous coronary
angioplasty.
AB - We evaluated the functional significance of angiographically successful
percutaneous transluminal coronary angioplasty (PTCA) in 50 patients before and
after PTCA using an atrial pacing stress test. Before balloon angioplasty, 40/50
patients had transient ST-segment changes on the intracoronary (IC) ECG. After
PTCA 14/50 patients continued to have ischemic changes on IC-ECG. Atrial pacing
stress tests can be performed easily in the cardiac catheterization laboratory.
Despite angiographically successful dilatation, 28% of the patients have
inducible ischemia indicating functionally inadequate dilatation. Inadequate
functional dilatation may contribute to early return of symptoms in some
patients.
PMID- 9397309
TI - Clinical significance of the urinary oxygen tension in patients with ischemic
heart disease.
AB - The clinical significance of the urinary oxygen tension (PuO2) was evaluated in
60 patients with ischemic heart disease. The PuO2 had fair relations to cardiac
index and serum creatinine level (r = 0.73 and r = 0.73, respectively). Although
the PuO2 had a fair relation to serum creatinine in patients with a low cardiac
index, there was no relation to the cardiac index. In patients with increases in
PuO2 from day 1 to day 2, the cardiac index increased, and the serum creatinine
level decreased on the 2nd day, whereas a sustained decrease in cardiac index and
an increase in serum creatinine were observed in patients with a decrease in PuO2
from day 1 to day 2. Thus, PuO2 can be used as an indicator of the renal function
in patients with ischemic heart disease.
PMID- 9397310
TI - Pericardial effusion after streptokinase for acute myocardial infarction: an
echocardiographic 1-year follow-up study.
AB - Since the reported incidence of pericardial effusion following thrombolysis is
highly variable, we have evaluated 80 consecutive patients with first acute
myocardial infarction treated with streptokinase. Two-dimensional
echocardiographic studies were performed on days 1, 2, 3, and 7, at 3 and 6
weeks, and 3, 6, and 12 months following acute myocardial infarction. Throughout
the study, pericardial effusion was found in 7 of 80 (8.75%) patients, being
small in 5 patients, moderate in 1, and large in 1 patient. No clinical,
angiographic, or echocardiographic variable was associated with pericardial
effusion formation. The incidence of pericardial effusion found in our study is
almost three times lower than in other echocardiographic studies on pericardial
effusion in thrombolysed patients. Whether this differences results from the
beneficial effects of streptokinase is not clear.
PMID- 9397311
TI - Early administration of ramipril in acute myocardial infarction: neurohormonal
and hemodynamic effects and tolerability.
AB - Although several large studies indicate a beneficial effect of angiotensin
converting enzyme (ACE) inhibitors after myocardial infarction, the optimal
timing of therapy in terms of safety and the effects on neurohormones during
myocardial infarction are less well known. In order to investigate the effect of
ramipril, administered within 24 h after myocardial infarction, on hemodynamics
and neurohormones and its safety, 20 patients with a myocardial infarction were
studied. Nine patients had an anterior, 10 an inferior, and 1 a non-Q-wave
infarction. Fourteen patients received thrombolytic therapy, whereas 6 did not.
The initial dose of ramipril was 1.25 mg, but was gradually increased to 5 mg
during the next 4 days. Side effects did not occur. The mean arterial pressure
decreased 8 h after the first dose from 84 +/- 2 mm Hg (control) to 77 +/- 2 mm
Hg (p < 0.05) and remained decreased thereafter. This was accompanied by a
reduction in systemic resistance of 8% after 8 h and of 12% on day 2. Heart rate,
cardiac and stroke indexes, and pulmonary artery and wedge pressures did not
change. The ACE activity decreased within 1 h of ramipril administration with a
maximum of 71% at 4 h after the second dose and remained at this level throughout
the study. Angiotensin II decreased by 34% (day 2) and by 41% (day 5). The renin
activity gradually increased from 33 +/- 7.5 to 75.4 +/- 11.5 microM/ml on day 5,
whereas epinephrine was reduced from day 2 onwards, with a maximal reduction of
71% on day 5. Arginine vasopressin was significantly reduced 5 h after ramipril
administration until the end of the study, with a maximum of 77% on day 3.
Moreover, a late but significant decrease in norepinephrine occurred on day 5.
Thus, oral ramipril results in early ACE inhibition, followed by progressive
attenuation of the neuroendocrine activation and a reduction in afterload during
the acute phase of myocardial infarction. It is well tolerated, also in
combination with nitroglycerin and thrombolytic therapy.
PMID- 9397312
TI - Simultaneous dobutamine stress echocardiography and thallium-201 perfusion
imaging for the detection of coronary artery disease.
AB - To compare the diagnostic value of dobutamine stress echocardiography with
dobutamine thallium-201 single-photon-emission computed tomography (SPECT) in
detecting coronary artery disease, we performed both tests simultaneously on 93
patients who also underwent coronary arteriography. Dobutamine was infused at
rates of 5, 10, 20, 30 and 40 microns/kg/min in 3-min stages. The left ventricle
was divided into anteroseptal, posterolateral and inferior regions. Within each
region, wall motion or perfusion abnormalities were classified as normal,
ischemia or fixed defect. The response to stress was concordantly classified by
both tests in 67 patients (72%, kappa = 0.48). Regional agreement for
abnormalities was observed in 79% (kappa = 0.56) of the 279 regions analyzed.
Dobutamine echocardiography detected 62 (93%) and thallium SPECT 60 (90%, p = NS)
of the 67 patients with significant coronary artery disease (> or = 50% diameter
stenosis). The specificity was 77 (20 of 26) and 81% (21 of 26), respectively.
The accuracy was 88 and 87%, respectively. Combined the two tests gave a
sensitivity of 97%, a specificity of 65% and an accuracy of 88%. The accuracy for
detecting individual coronary stenosis with echocardiography was 83% for the left
anterior descending artery, 84% for the right coronary artery and 73% for the
left circumflex artery. With SPECT, it was 83, 87 and and 76%, respectively. In
conclusion, dobutamine stress echocardiography and thallium SPECT provide a
comparable accuracy for detection and localization of coronary artery disease,
and for identification of regional myocardial abnormalities. Performing the two
tests simultaneous is feasible but it adds limited value in detecting coronary
artery disease.
PMID- 9397313
TI - Influence of left ventricular diastole on left atrial appendage blood flow in
patients with nonrheumatic atrial fibrillation.
AB - The function of the left atrial appendage (LAA) reflected by the Doppler flow
velocity at the outlet of the left atrial appendage has been reported to be
correlated with spontaneous echo contrast and thrombus formation. To evaluate the
influence of left ventricular diastole on LAA flow during atrial fibrillation
(AF), 81 patients with chronic nonrheumatic AF were studied by transesophageal
echocardiography. The peak outflow velocity of LAA during ventricular diastole
was higher than that during ventricular systole (0.23 +/- 0.14 vs. 0.15 +/- 0.13
m/s, p < 0.001). The peak inflow velocity of LAA during ventricular diastole was
also higher than that during ventricular systole (0.22 +/- 0.15 vs. 0.18 +/- 0.11
m/s, p < 0.01). Patients with a good left ventricular ejection fraction have a
significantly higher peak LAA outflow velocity and a larger diastolic
augmentation of LAA outflow (defined by the difference of LAA outflow between
systolic and diastolic phases) than patients with an impaired left ventricular
function. Thus, left ventricular diastole might have an influence on LAA flow
during AF. In addition, the left ventricular function might be considered a
predictor of subsequent thromboembolism from the viewpoint of its effect on LAA
flow in patients with nonrheumatic AF.
PMID- 9397314
TI - Risk stratification prior to vascular surgery: does the location of a
dipyridamole thallium scintigram defect provide prognostic information?
AB - BACKGROUND: While the value of myocardial scintigraphy using dipyridamole
thallium is accepted for risk assessment prior to vascular surgery, it is unknown
whether the location of the thallium abnormalities provides prognostic
information. METHODS: Records from 435 consecutive patients scheduled for
vascular surgery were reviewed and patients with dipyridamole thallium
abnormalities involving the anterior distribution (ANTERIOR n = 62), or inferior
or inferolateral distribution (INFERIOR n = 105) were assessed for cardiac
complications of surgery (death, myocardial infarction, unstable angina or
ischemic congestive heart failure). RESULTS: Patients with a normal dipyridamole
thallium scintigraphy had few surgical cardiac complications: 2/86 (2%). Patients
with an ANTERIOR dipyridamole thallium defect had a 12% incidence of surgical
cardiac complications (7/57) without any cardiac deaths, while patients with an
INFERIOR dipyridamole thallium defect had a similar incidence of surgical cardiac
complications, 18% (18/100; p = 0.65 vs. ANTERIOR) including 4 cardiac deaths.
CONCLUSIONS: Significant inferior or inferolateral dipyridamole thallium
scintigraphy abnormalities are not associated with a lower risk of cardiac
complications following vascular surgery than anterior abnormalities. Rather, any
clearly abnormal dipyridamole thallium study is a marker for increased risk of
perioperative events and may warrant further evaluation and treatment.
PMID- 9397315
TI - On-line computerized vectorcardiography: influence of body position, heart rate,
radiographic contrast fluid and myocardial ischemia.
AB - On-line computerized vectorcardiography (cVCG) is increasingly being used for
continuous monitoring of myocardial ischemia, however, little is known about
factors other than ischemia causing electrocardiographic abnormalities. This
paper describes how three important cVCG parameters, STC-VM, ST-VM and QRS-VD,
are affected by different body positions, myocardial ischemia, contrast injection
and increasing heart rate in patients with and without coronary artery disease.
The main findings of the study are: contrast injection and different body
positions caused major changes in QRS-VD but affected ST-VM and STC-VM to a minor
degree. Increasing heart rate by atrial pacing produced substantial changes in
all three parameters. Ischemia during angioplasty also produced changes in all
three parameters, STC-VM being the most sensitive parameter. IN CONCLUSION: (1)
STC-VM (> or = 50 microV) is the most valuable parameter for monitoring ischemia;
(2) we propose ST-VM > or = 50 microV as criterion instead of previously used 25
microV; (3) QRS-VD cannot be used as a single marker of ischemia, and (4)
electrocardiographic changes induced by increased heart rate should be taken into
account during interpretation.
PMID- 9397316
TI - PVF velocity pattern in patients with heart failure: transesophageal
echocardiographic assessment.
AB - In order to assess the role of the pulmonary venous flow (PVF) velocity pattern
in the evaluation of patients with congestive heart failure (CHF), we studied 41
CHF patients by means of transthoracic echocardiography (TTE) and multiplane
transesophageal echocardiography (TEE). The etiology of CHF was idiopathic or
ischemic dilated cardiomyopathy in 19 patients and hypertensive heart disease in
22. Sixteen subjects without cardiovascular disease were selected as normal
controls. PVF peak systolic and peak early diastolic (D) velocities were recorded
by TEE and TTE and the systolic fraction (SF) was measured (i.e., the systolic
velocity-time integral-VTI-expressed as a fraction of the sum of systolic and
early diastolic (VTI). TEE tracings were obtained in all patients and had more
laminar-appearing spectral signals, thus were used for analysis. By TEE the
mitral flow velocity patterns were also evaluated: peak early diastolic velocity
(E), peak velocity at atrial contraction, E velocity normalized for VTI (E/VTI),
deceleration time (DT), and left ventricular isovolumic relaxation time (LVIRT).
The left ventricular ejection fraction (LVEF) was calculated by two-dimensional
echocardiographic images using the modified Simpson method. The SF was lower in
CHF patients as compared with normal controls (p < 0.0001). The E/VTI ratio was
higher, and DT and LVIRT were shorter (p < 0.0001) in CHF patients. A significant
correlation was observed between SF and LVEF in CHF patients (r = 0.76, p <
0.001). Two different PVF velocity patterns (type A:SF << 50%, D > 50 cm/s; type
B:SF approximately 50%, D > 50 cm/s) were recognized in patients with a low LVEF
(type A) and a nearly normal or normal LVEF (type B). Patients with LVEF < 40%
showed mean SF values significantly lower than patients with LVEF > 40% (33.26 +/
10.84 vs. 51.00 +/- 4.00%, p < 0.0001). Mean DT and LVIRT values were not
significantly different in patients with LVEF < 40% and > 40%. Thus in CHF
patients TEE PVF velocity patterns help in distinguishing patients with systolic
dysfunction (low LVEF and SF) from patients with predominant diastolic impairment
(normal or nearly normal LVEF, high D velocities).
PMID- 9397317
TI - Effect of controlled exercise training in coronary artery disease patients with
and without left ventricular dysfunction assessed by cardiopulmonary indices.
AB - Cardiopulmonary indices were used to evaluate the effect of controlled exercise
training prescribed on the basis of the heart rate at the ventilatory anaerobic
threshold in coronary artery disease patients with and without impaired left
ventricular function. Fifty-two patients aged 38-75 years were divided into four
groups. The first three groups included patients with a left ventricular ejection
fraction of > 45% at rest, as follows: group 1, 10 patients with single-vessel
disease; group 2, 12 patients with two-vessel disease; group 3, 10 patients with
three-vessel disease. Group 4 comprised 20 patients with left ventricular
dysfunction (ejection fraction < 35%). The left ventricular ejection fraction was
assessed by multigated acquisition radionuclear study. All patients underwent a
cardiopulmonary exercise test before and after the program which lasted 6-9
months. The variables measured were oxygen consumption (VO2), CO2 output, minute
ventilation, O2 pulse, and ventilatory anaerobic threshold. Significant
improvements in maximal VO2, maximal O2 pulse, and ventilatory anaerobic
threshold level were observed in groups 1, 2, and 4 (p < 0.1-0.0001), but not in
group 3. These findings indicate that the overall cardiac function, as evaluated
by cardiopulmonary indices, improves in patients with one- or two-vessel disease
with good left ventricular function and in patients with impaired left
ventricular function following an exercise training program. Severe coronary
disease seems to limit improvement, even in the presence of a good left
ventricular function. The results validate the heart rate at the ventilatory
anaerobic threshold as the optimal training heart rate in coronary artery disease
patients and the cardiopulmonary exercise test as a sensitive tool for evaluating
exercise training results.
PMID- 9397318
TI - Spongy myocardium.
AB - Spongy myocardium is a rare congenital anomaly. We report a 35-year-old patient
in whom diagnosis of spongy myocardium had been made by angiocardiography 20
years before. The disorder eventually resulted in progressive right and left
heart failure.
PMID- 9397319
TI - Anomalous origin of all coronary arteries from the pulmonary trunk.
AB - The origin of both coronary arteries from the pulmonary artery is a rare cardiac
malformation. We report a baby who presented with an echocardiographically
diagnosed perimembranous ventricular septal defect and normal left ventricular
(LV) function. Later on the boy developed failure to thrive and increasing
tachypnea. At the age of 5 weeks the ECG showed that LV strain and
echocardiographic LV function had worsened (FS 18%). Echocardiography and heart
catheterization showed that all coronary arteries originated from the pulmonary
trunk. Intraoperative inspection revealed a single ostium for the right and left
coronary artery in the nonfacing sinus of the pulmonary trunk. A tube was
constructed connecting the coronary artery to the ascending aorta. Coronary
perfusion was sufficient and the sinus rhythm was restored. However, in the early
postoperative period there was a sudden deterioration of cardiac output followed
by cardiac arrest. Reanimation was not successful.
PMID- 9397320
TI - Viable but denervated right ventricular myocardium: a case of Eisenmenger
reaction.
AB - We report on a 47-year-old woman who experienced an Eisenmenger reaction (mean
pulmonary artery pressure: 86 mm Hg) induced by atrial septal defect.
Radionuclide myocardial scans with 99mTc-MIBI and 123I-BMIPP showed increased
uptake to the right ventricular myocardium, whereas the 123I-MIBG scan disclosed
no uptake to the right ventricular myocardium. The scans showed no apparent
abnormality in the left ventricular myocardium. These findings suggest that the
right ventricular myocardium was viable but denervated due to severe pulmonary
hypertension. The mechanism of right ventricular failure may be closely related
to sympathetic denervation.
PMID- 9397321
TI - Primary cardiac lymphoma with infiltration of the atrioventricular node:
remission with reversal of the atrioventricular block induced by chemotherapy.
AB - We describe a rare case of primary cardiac lymphoma associated with complete
atrioventricular block, with recovery following systemic chemotherapy. A 61 year
old woman was admitted because of a massive pericardial effusion and complete
atrioventricular block. Echocardiography disclosed several polypoid masses in the
right atrium. A diagnosis of primary cardiac lymphoma was made. After three
cycles of chemotherapy, the patient achieved a complete remission, the ECG showed
first-degree atrioventricular block, and echocardiography revealed disappearance
of the right atrial masses. This is the first report of a patient recovering from
primary cardiac lymphoma and complete atrioventricular block following systemic
chemotherapy. We conclude that aggressive treatment of this malignancy can
improve cardiac function and the patient's prognosis.
PMID- 9397322
TI - Interaction between cortisol and tumour necrosis factor with concurrent
resistance and endurance training.
AB - OBJECTIVE: To determine the effect of concurrent resistance and endurance
training on tumor necrosis factor alpha (TNF alpha), urinary free cortisol,
strength [one-repetition maximum (1 RM)], and maximal oxygen consumption
(Vo2max). DESIGN: Randomized control trial of 12 weeks' duration. SETTING:
University of Alberta, Edmonton, Alberta, Canada. PARTICIPANTS: Forty-five
healthy female (n = 18) and male (n = 27) subjects who had not formally trained
for at least 6 months prior to the study but were physically active. The mean +/-
SD age, height, and body mass for all subjects were 22.3 +/- 3.3 years, 1.76 +/-
9.32 m, and 73.4 +/- 11.6 kg, respectively. INTERVENTION: The subjects were
randomly assigned to four groups: strength training only (S), n = 10; endurance
training only (E), n = 11; combined strength and endurance training (SE), n = 13;
and a control group (C), n = 10. The S and E groups performed progressively
overloaded training sessions three times per week for 12 weeks. The SE group
completed the same strength and endurance training programs on different days
(i.e., 6 days/week) for 12 weeks. MAIN OUTCOME MEASURES: Serum levels of TNF
alpha, urinary free cortisol, 1 RM, and Vo2max were measured before and after 6
and 12 weeks of training. RESULTS: Significant increases in leg press and knee
extension 1 RM occurred after training in both S and SE groups, but the relative
gains in knee extension 1 RM were greater in the S group. Similar increases in
Vo2max were observed in groups E and SE (p < 0.05). Cortisol was significantly
increased in the SE group for women and decreased in the E group for men after
training. TNF alpha was significantly elevated in the women of group E after
training. No correlation was observed between urinary free cortisol and TNF alpha
with training. CONCLUSION: These results indicate that a partial interference
effect of compromised strength gains in unilateral knee extension of the men
occurred after concurrent strength and endurance training that could not be
attributed to an interaction between cortisol and TNF alpha in response to this
type of exercise.
PMID- 9397323
TI - Injuries of young elite female basketball players over a six-year period.
AB - OBJECTIVE: To analyze injuries retrospectively among female basketball players at
the Australian Institute of Sport (AIS) from 1990 to 1995 inclusive. DESIGN: The
medical records of all the female basketball players on AIS (residential)
scholarships were examined, and all injuries were recorded. SETTING: The Sports
Medicine Department at the Australian Institute of Sport in Canberra, Australia.
PARTICIPANTS: The participants were 49 elite female basketball players, holding
full scholarships at the AIS, with an average age of 17.6 years at the time of
injury presentation. MAIN OUTCOME MEASURES: Injury presentation according to
region involved, nature of injury, and most common specific injuries (diagnoses).
RESULTS: A total of 223 injuries were recorded: 139 were acute and 84 were
chronic. The regions most frequently injured were the knee (18.8%), ankle
(16.6%), lumbar spine (11.7%), and lower legs (10.8%). The most frequent
diagnoses were ankle lateral ligament sprain (12.1%), patellar tendinitis (6.7%),
lower limb stress fractures (5.4%), finger sprains (4.9%), and mechanical low
back pain (4.5%). CONCLUSIONS: There was a high incidence of knee and ankle
injury in this group of young elite female basketball players, and stress
fractures were not uncommon. The incidence of injury in female basketball players
may be increasing. Further research in this area may help reduce the risk of
stress fractures and serious ankle and knee injuries.
PMID- 9397324
TI - Spirometry and airway reactivity in elite track and field athletes.
AB - OBJECTIVES: To characterize spirometry and to document the incidence of exercise
induced bronchospasm (EIB) during competition in elite track and field athletes.
DESIGN: Spirometry was performed in 120 men and 69 women athletes before
competition and peak expiratory flows in 50 men and 23 women athletes before and
after competition. SETTING: The 1991 (Randalls Island, NY, U.S.A.) and the 1993
(Eugene, OR, U.S.A.) National Track and Field Championships (World Championship
team-qualifying meet). PARTICIPANTS: American track and field athletes who met
World Championship qualifying standards. MEASUREMENTS: Spirometry (Cybermedic,
Inc., Boulder, CO, U.S.A.) and peak expiratory flows (Personal Best, Healthscan
Products, Cedar Grove, NJ, U.S.A.)--the best of three reproducible efforts.
RESULTS: Male sprinters had lower vital capacities than other track athletes,
whereas both male and female field (throwing) athletes had larger vital
capacities than both runners and other field athletes. Decreases of 10% peak
expiratory flows were found in 10% of men and 26% of women track athletes within
15 min after competition. The incidence was higher in longer-distance events.
Most participants did not have a history of asthma. CONCLUSIONS: A higher-than
expected prevalence of EIB was found in high-level track athletes. The results
suggest that spirometry and/or peak flows should be measured in track athletes
because small decreases in airflow may impair training or performance, a
condition that is easily treated.
PMID- 9397325
TI - Lifestyles and health risks of collegiate athletes: a multi-center study.
AB - OBJECTIVE: To determine whether college athletes are at greater risk for
maladaptive lifestyle and health-risk behaviors than their nonathletic peers and
to identify high risk taking groups by gender, sport, and other identifiers.
DESIGN: Multicenter, cross-sectional study. SETTING: Seven major geographically
represented collegiate institutions in the United States. PARTICIPANTS: A total
of 2,298 college athletes and 683 randomized nonathlete controls completed a
confidential survey questionnaire between the summer of 1993 and winter of 1994,
assessing lifestyle and health-risk behaviors over the previous 12 months. MAIN
OUTCOME MEASURES: Self-reports of lifestyle behaviors and health risks in the
following areas: motor-vehicle safety, substance abuse, sexually transmitted
diseases and contraception, mental health, cancer prevention, nutrition, exercise
and general preventive health issues. RESULTS: Athletes demonstrated
significantly higher risk-taking behaviors (p < 0.05) than their nonathlete peers
in the following areas: less likely always to use seatbelts; less likely always
to use helmets with motorcycles, mopeds, and bicycles; more often drive as a
passenger with a driver under the influence of alcohol or drugs; greater quantity
and frequency of alcoholic beverages; greater frequency of smokeless tobacco and
anabolic steroid use; less-safe sex; greater number of sexual partners; less
contraceptive use; and more involvement in physical fights. Female athletes
reported a higher prevalence of irregular menses, amenorrhea, and stress
fractures compared with female nonathletes. Male athletes had more risk-taking
behaviors than did female athletes (p < 0.05), and athletes in contact sports
demonstrated more risk-taking behaviors than did athletes in noncontact sports (p
< 0.05). Athletes with one risk-taking behavior were likely to have multiple risk
taking behaviors (p < 0.05). CONCLUSIONS: College athletes appear to be at higher
risk than their nonathletic peers for certain maladaptive lifestyle behaviors.
Athlete subgroups at highest risk include male athletes and athletes
participating in contact sports. Athletes at risk for one high-risk behavior
demonstrated an increased risk for multiple risk-taking behaviors. Preventive
health interventions deserve further study to determine strategies for risk
reduction in high-risk groups.
PMID- 9397326
TI - Management guidelines for participation in collision activities with congenital,
developmental, or postinjury lesions involving the cervical spine.
AB - OBJECTIVE: Conditions involving the cervical spine in athletes requiring a
management decision are numerous. This report presents appropriate guidelines for
return to collision activities in those with congenital, developmental, or
postinjury lesions. DATA SOURCES: Information was compiled from > 1,200 cervical
spine lesions documented by the National Football Head and Neck Injury Registry
and an extensive literature review. DATA SYNTHESIS: Available data as well as a
clinical understanding of injury mechanisms have resulted in the development of
reasonable management guidelines. Each of the congenital, developmental, and
posttraumatic conditions presented are determined to present either no
contraindication, relative contraindication, or an absolute contraindication to
sport participation on the basis of a variety of parameters. Conditions included
in the discussion are odontoid anomalies; spina bifida occulta; atlanto-occipital
fusion; Klippel-Feil anomalies; cervical canal stenosis; spear tackler's spine;
traumatic conditions of the upper, middle, and lower cervical spine, including
ligamentous injuries and fractures; intervertebral disc injuries; and
postcervical spine fusion. CONCLUSION: The proposed guidelines should be used in
the decision-making process in conjunction with other such factors as the age,
experience, ability of the individual, level of participation, and position
played, as well as the attitude and desires of the athlete and his or her parents
following an informed discussion of the problem with particular regard to
potential risk.
PMID- 9397327
TI - Collapsed ultraendurance athlete: proposed mechanisms and an approach to
management.
AB - OBJECTIVE: To review the common conditions causing collapse in ultraendurance
athletes, to propose appropriate treatment protocols for the more common medical
conditions that are encountered, and to provide practical guidelines for the
management of the medical facilities at these endurance events. DATA SOURCES:
Books published on the subject, abstracts of the American College of Sports
Medicine Annual Congress dealing with the subject over the last 5 years, and
electronic search of the Medline and Current Contents databases (last searched
May 1995). German articles were included in the search criteria. STUDY SELECTION:
Articles dealing generally with the management of medical facilities at endurance
events were chosen. Articles dealing more specifically with the common medical
conditions encountered at these events were then sourced and included in this
review. DATA EXTRACTION: Multiple reader extraction of relevant data. DATA
SYNTHESIS: A practical guideline to the management of the medical facility at an
endurance event is detailed, expanding specifically on the nature of the
conditions causing collapse during or after endurance exercise with a proposed
classification of causes of collapse for optimizing immediate management and
management protocols for specific conditions such as heatstroke, hyponatremia,
hypoglycemia, exercise-associated collapse, and muscle cramps. CONCLUSION: The
most commonly encountered medical condition at endurance athletic events is
collapse after the event. The popular view that all persons who collapse have
dehydration-induced hyperthermia has been challenged. Here we extend that
argument and provide diagnostic and management protocols and propose a triage
system that considers the most common causes of collapse in ultraendurance
athletes. These protocols can optimize the efficient and safe management of large
numbers of collapsed ultraendurance athletes. It is proposed that these protocols
can optimize the efficient and safe management of large numbers of collapsed
ultra endurance athletes.
PMID- 9397328
TI - Does repetitive physical loading inhibit radial growth in female gymnasts?
AB - OBJECTIVE: Stress-related injuries to the distal radius have been noted in female
gymnasts with potential for resultant premature closure and abnormal growth at
this site. The purpose of this study was comprehensively to review and critically
to appraise the available literature to examine the evidence related to this
question: does repetitive physical loading inhibit growth of the radius in female
gymnasts? DATA SOURCES: MEDLINE and SPORT Discuss were searched from 1975 to the
present by using "gymnast" in combination with injury, growth plate, epiphyseal,
and ulnar variance. Additional references were retrieved from the bibliographies
of the retrieved articles. STUDY SELECTION: All descriptive and analytic studies
that included data related to stress-related injuries affecting the distal radius
of competitive female gymnasts were included. Conclusions regarding the effects
of gymnastics training on radial growth of female gymnasts were limited to data
from case reports, clinical series, cross-sectional studies, and descriptive
cohort studies. Data from relevant experimental animal studies also were
included. DATA EXTRACTION AND SYNTHESIS: In reviewing the literature, particular
attention was paid to the relative strengths of the different study designs. From
these data, information associated with growth inhibition at the distal radius
was examined. MAIN RESULTS: The descriptive research reviewed included clinical,
cross-sectional, and cohort studies that establish the existence of stress
related injuries affecting one or more constituent parts of the epiphyseal
physeal-metaphyseal (EPM) complex of the distal radius, symptomatic ulna-radial
length difference (URLD), and distal radius physeal arrest among female gymnasts.
Five cross-sectional studies showed radiographic abnormalities consistent with
distal radius physeal-stress reaction in 10-85% of gymnasts studied. Two cross
sectional studies indicated "abnormal" positive URLD in 8-20% of wrists
radiographed. Four cross-sectional studies showed significant correlations
between training intensity and URLD, suggesting a dose-response relation. Three
cross-sectional studies indicate greater URLD in gymnasts compared with
nongymnasts. Radiographic evidence of distal radius physeal arrest involving
physically immature female gymnasts is presented in four studies (two clinical
series, one cross-sectional, and one descriptive cohort). In animal studies,
prolonged physical training has also been shown to inhibit or stop growth in
weight-bearing long bones. However, there were no rigorous studies (i.e.,
randomized control trials or analytic cohorts) examining the question.
CONCLUSION: The results of this critical review of the scientific literature
support the plausibility of stress-related distal radius physeal arrest with
secondary URLD. However, the strength of evidence is inadequate to be conclusive.
PMID- 9397329
TI - Pulmonary contusion secondary to blunt trauma in a collegiate football player.
PMID- 9397330
TI - Putting principles into practice: the evolution of evidence-based medicine.
PMID- 9397331
TI - Assessment of childhood phobias.
AB - Childhood phobias can be successfully treated using a variety of behavioral
strategies, provided there has been a psychometrically sound assessment. Measures
are also important for the evaluation of treatment efficacy and the testing of
hypotheses generated by new ideas and theories of children's phobias. This paper
outlines broad-based assessment procedures used in the evaluation of children's
phobias, including the behavioral or problem-focused interview, the diagnostic
interview, self-report inventories, caregiver completed instruments, behavioral
observations, self-monitoring and physiological assessment. Reflecting recent
theoretical and clinical advances in the study of childhood internalizing
disorders, we also explore laboratory-based measures and family assessment
measures. Particular attention is given to psychometric issues and developmental
sensitivity in our discussion of these assessment procedures.
PMID- 9397332
TI - Treatment approaches for pathological gamblers.
AB - Outcome literature on the treatment of pathological gambling is reviewed,
encompassing psychodynamic, behavioral, cognitive, cognitive-behavioral,
multimodal, pharmacotherapeutic, and 12-step approaches. No properly controlled
research has been conducted with psychodynamic or 12-step methods, and
pharmacotherapies require replications with larger samples to determine their
efficacy. Multimodal approaches have been tested most often in inpatient
settings, and given the range of methods combined it is difficult to infer
specific efficacy for treatment components. The largest volume of outcome
research has focused on behavioral, cognitive, and combined cognitive-behavioral
treatment methods, and findings from controlled and uncontrolled trials provide
support for efficacy of these approaches. As a whole, the literature indicates
that pathological gambling can be treated with highly successful outcomes. Needs
for further research are considered.
PMID- 9397333
TI - Meta-analysis of cognitive-behavioral treatment studies for bulimia.
AB - A meta-analysis was performed to systematically assess the effect of cognitive
behavioral treatments for bulimia. To protect against past criticisms of meta
analyses, this study focused on well-defined hypotheses with clearly articulated
conceptual foundations. Twenty-six studies of the cognitive-behavioral treatment
of bulimia were selected through computer searches. Effect sizes were calculated
for changes in behavioral outcome measures (25 independent hypothesis tests) and
cognitive-attitudinal outcome measures (17 independent hypothesis tests).
Additionally, two effect sizes were generated for within and between group
comparisons. The analysis revealed an effect size of average r = 0.69 for
behavioral outcome measures (average r = 0.64 for between group and average r =
0.74 for within group) and average r = 0.67 for cognitive-attitudinal outcome
measures (average r = 0.64 for between group and average r = 0.69 for within
group). Follow-up effect sizes were less favorable; however, the diversity of
time spans and outcome measures used to calculate follow-up effect sizes limit
their utility. Overall, results suggest that the use of a cognitive-behavioral
therapy will result in favorable treatment outcomes and implications for future
research are discussed.
PMID- 9397334
TI - A biopsychosocial model of metaphor therapy with holistic cultures.
AB - For centuries western cultures have adopted a dualistic perspective toward
people's health. The "self" has emerged as an independent entity from others as
well from the body. Human distress has been psychologized and depression and
anxiety have been attributed to intrapsychic structures and processes.
Nevertheless, many nonwestern cultures still adopt holistic perspectives. Within
these cultures, distress is manifested through physical rather than psychological
complains. Therefore, psychological approaches, based on the independence of the
self, may not be fitting for these societies. Instead, based on the assumption
that nonwestern cultures are holistic and less psychologized and their problems
are social rather than intrapsychic, a biopsychosocial approach is suggested. In
addition, nonwesterners have a different concept of reality. For instance, within
some communities fantasies and delusions are appreciated, constitute part of a
normal life, and are considered to be the "real reality." Furthermore, complains
are often described in metaphoric language. Accordingly, a biopsychosocial model
of metaphoric therapy is proposed in which therapists would incorporate their
clients' metaphoric imaginative culture. Metaphoric intervention also allow for
changes in the biological, psychological, and sociocultural reality of the
client.
PMID- 9397335
TI - "The myth of mental illness:" continuing controversies and their implications for
mental health professionals.
AB - Since the publication of "The Myth of Mental Illness" in 1960, there has been an
ongoing debate about Thomas Szasz's ideas concerning mental illness. In this
paper, Szasz's views are summarized, as are the views of Szasz's critics.
Specifically, the following areas are addressed: Szasz's definition of disease,
his notions regarding the unconscious and rationality, his beliefs regarding
culpability, his proposed differences between psychiatry and other branches of
medicine, the uses of the term "mental illness," and the possibility of
implicating physical lesions in some mental illnesses. With this discussion as a
backdrop, the importance of these issues to mental health practitioners is
addressed.
PMID- 9397336
TI - Acute stress disorder: a critical review of diagnostic issues.
AB - Acute stress disorder (ASD) is a recently developed diagnosis that describes
posttraumatic stress reactions that occur in the first month following a trauma.
Diagnostic criteria include dissociative, intrusive, avoidance, and arousal
symptoms. ASD was driven by the proposal that trauma leads to dissociative
reactions, and these are predictive of longer-term psychopathology. This paper
reviews a series of anomalies in the diagnostic criteria, highlights
discrepancies between criteria for ASD and posttraumatic stress disorder (PTSD),
and illustrates the lack of empirical evidence for some assumptions inherent in
the conceptualization of ASD. It is argued that future revisions of ASD criteria
need to be based on empirical evidence of acutely traumatized individuals.
PMID- 9397337
TI - Staff beliefs about the challenging behaviors of children and adults with mental
retardation.
AB - From both theoretical and practical perspectives, staff beliefs are likely to
have a significant impact on the process of care for children and adults with
mental retardation who engage in challenging behaviors. This paper reviews
research addressing three domains of staff beliefs: definitions of challenging
behavior, causal attributions, and beliefs about appropriate intervention. In
general, staff definitions were found to be at odds with formal definitions.
According to care staff, challenging behaviors are actions that are difficult to
manage. Staff causal attributions appear congruent with current theory, when
measured with little specificity. However, when staff are asked to suggest causes
of challenging behavior with clearly described functions they often fail to make
appropriate attributions. Beliefs about appropriate short-term interventions
suggest responses likely to develop and/or maintain challenging behavior, but
beliefs about longer-term planned intervention appear to be more closely matched
to contemporary practice. Reasons for this long-term/short-term distinction,
based on the demands of the immediate situation, are proposed. Suggestions for
future research on staff beliefs are discussed in detail. Finally, implications
for staff training, referral practice, and for analysis and intervention with
challenging behavior, are outlined.
PMID- 9397338
TI - Individual differences in the experience of emotions.
AB - The purpose of this paper is to highlight the important role of individual
difference factors in the experience of emotion. We begin by describing several
commonalties across two major approaches to the study of emotion, namely, the
neuropsychological and cognitive perspectives. Both approaches provide some
degree of support for the role of individual differences and cognitive factors in
the experience of emotion. This paper builds on these commonalities by reviewing
personality and psychopathology findings that indicate the contribution of both
positive and negative personality characteristics (e.g., extraversion, optimism
vs. neuroticism, trait anxiety) to the types of cognitive appraisals and
emotional responses exhibited by different individuals. A self-schema model of
emotion is presented as a means of integrating more fully this individual
differences perspective with a theory of emotion. In this model, self-schema
content provides the basis for individual differences in underlying core themes
and self-evaluative beliefs. The model describes how self-schema content
distinctions across individuals may have a differential impact on the initial
processing of an event, evaluation of this event with respect to the self, and
emotional and behavioral output. Several examples are then presented to
illustrate the increased predictability afforded by this individual differences
based self-schema model of emotion. The application of this model to treatment
and prevention issues in clinical and health psychology is also briefly
considered. Finally, the model is integrated with other theoretical perspectives
on emotion by describing a number of additional research and theoretical
implications. Emphasis is placed on the need for further clarification of both
cognitive and emotional components of an individual differences perspective on
the study of emotions.
PMID- 9397339
TI - Temporal reasoning and temporal data maintenance in medicine: issues and
challenges.
AB - We present a brief, nonexhaustive overview of research efforts in designing and
developing time-oriented systems in medicine. The growing volume of research on
time-oriented systems in medicine can be viewed from either an application point
of view, focusing on different generic tasks (e.g. diagnosis) and clinical areas
(e.g. cardiology), or from a methodological point of view, distinguishing between
different theoretical approaches. In this overview, we focus on highlighting
methodological and theoretical choices, and conclude with suggestions for new
research directions. Two main research directions can be noted: temporal
reasoning, which supports various temporal inference tasks (e.g. temporal
abstraction, time-oriented decision support, forecasting, data validation), and
temporal data maintenance, which deals with storage and retrieval of data that
have heterogeneous temporal dimensions. Efforts common to both research areas
include the modeling of time, of temporal entities, and of temporal queries. We
suggest that tasks such as abstraction of time-oriented data and the handling of
different temporal-granularity levels should provide common ground for
collaboration between the two research directions and fruitful areas for future
research.
PMID- 9397340
TI - Modeling medical trials in pharmacoeconomics using a temporal object model.
AB - Time is an inherent feature of many medical applications. These applications can
also benefit from the support of object database management systems which better
capture the semantics of the complex objects that arise in the medical domain. In
this paper, we present a uniform behavioral temporal object model which includes
a rich and extensible set of types and behaviors to support the various features
of a medical application. We concentrate here on the application of
pharmacoeconomic medical trials. Pharmacoeconomics is a field of medical
economics in which the costs and outcomes of alternative treatments are assessed
and compared, in order to establish which is the most appropriate treatment for a
particular illness in a particular setting. We describe in detail the histories
and timelines features of our temporal model and show how they can effectively be
used to model a pharmacoeconomic trial. We then give an instance of a
pharmacoeconomic trial as it would appear in the temporal object model and show,
using queries, how a series of different behaviors could be used to retrieve
various components of the instance. These components could then be used to assess
the alternative treatments involved in the trial and determine their cost
effectiveness.
PMID- 9397341
TI - Effective data validation of high-frequency data: time-point-, time-interval-,
and trend-based methods.
AB - Real-time systems for monitoring and therapy planning, which receive their data
from on-line monitoring equipment and computer-based patient records, require
reliable data. Data validation has to utilize and combine a set of fast methods
to detect, eliminate, and repair faulty data, which may lead to life-threatening
conclusions. The strength of data validation results from the combination of
numerical and knowledge-based methods applied to both continuously-assessed high
frequency data and discontinuously-assessed data. Dealing with high-frequency
data, examining single measurements is not sufficient. It is essential to take
into account the behavior of parameters over time. We present time-point-, time
interval-, and trend-based methods for validation and repair. These are
complemented by time-independent methods for determining an overall reliability
of measurements. The data validation benefits from the temporal data-abstraction
process, which provides automatically derived qualitative values and patterns.
The temporal abstraction is oriented on a context-sensitive and expectation
guided principle. Additional knowledge derived from domain experts forms an
essential part for all of these methods. The methods are applied in the field of
artificial ventilation of newborn infants. Examples from the real-time monitoring
and therapy-planning system VIE-VENT illustrate the usefulness and effectiveness
of the methods.
PMID- 9397342
TI - Representing and developing temporally abstracted knowledge as a means towards
facilitating time modeling in medical decision-support systems.
AB - The utilization of the appropriate level of temporal abstraction is an important
aspect of time modeling. We discuss some aspects of the relation of temporal
abstraction to important knowledge engineering parameters such as model
correctness, ease of model specification, knowledge availability, query
completeness, inference tractability, and semantic clarity. We propose that
versatile and efficient time-modeling formalisms should encompass ways to
represent and reason at more than one level of abstraction, and we discuss such a
hybrid formalism. Although many research efforts have concentrated on the
automation of specific temporal abstractions, much research needs to be done in
understanding and developing provably optimal abstractions. We provide an initial
framework for studying this problem in a manner that is independent of the
particular problem domain and knowledge representation, and suggest several
research challenges that appear worth pursuing.
PMID- 9397343
TI - Using a general theory of time and change in patient monitoring: experiment and
evaluation.
AB - In this paper, we propose to use one of the well-known general theories of time
and change, namely the Event Calculus (Kowalski and Sergot, New Generation
Computing 4, 67-95, 1986), to represent temporal aspects in intelligent medical
monitoring systems. In particular, we explore the application of CEC (Chittaro
and Montanari, Computational Intelligence 12, 359-382, 1996) (an efficient
implementation of the Event Calculus) to the management of mechanical
ventilation. First, we present the prototype we have built, which has been
extensively tested on patient's data from real clinical cases. Then, we provide a
thorough evaluation of the obtained results, pointing out both strengths and
weaknesses of the approach, and identifying a number of extensions which can be
extremely useful to scale up the medical application of the approach.
PMID- 9397344
TI - Efficient temporal probabilistic reasoning via context-sensitive model
construction.
AB - We present a language for representing context-sensitive temporal probabilistic
knowledge. Context constraints allow inference to be focused on only the relevant
portions of the probabilistic knowledge. We provide a declarative semantics for
our language. We present a sound and complete algorithm for computing posterior
probabilities of temporal queries, as well as an efficient implementation of the
algorithm. Throughout we illustrate the approach with the problem of reasoning
about the effects of medications and interventions on the state of a patient in
cardiac arrest. We empirically evaluate the efficiency of our system by comparing
its inference times on problems in this domain with those of standard Bayesian
network representations of the problems.
PMID- 9397345
TI - The prophenoloxidase activating system of the shrimp Penaeus paulensis and
associated factors.
AB - In the present study we investigated the proPO activating system of the penaeid
Penaeus paulensis, focusing on its role in the shrimp immune system. The great
majority of PO activity (more than 90%) was found in the shrimp hemocytes. The
enzyme activity was greatly enhanced by components of microorganism cell walls,
such as LPS and beta-1,3-glucans, suggesting its involvement in non-self
recognition. PO activity was also found in the shrimp serum and trypsin, and LPS
were able to increase the enzyme activity. Thus, serum can be used as an
alternative for the study of the shrimp proPO activating system, as it is much
more readily obtained than HLS. PO activity was cation-dependent, and 5 mM of
calcium and 10 mM of magnesium were the optimal concentrations for the enzyme
activity. An immune factor was found in the shrimp HLS, capable of inducing cell
adhesion and degranulation of the penaeid hemocytes.
PMID- 9397346
TI - Molecular cloning of double-stranded RNA inducible Mx genes from Atlantic salmon
(Salmo salar L.).
AB - Mx proteins are induced by type I interferons in mice and humans and inhibit the
replication of several negative-stranded RNA viruses. In this work Mx genes in
Atlantic salmon were studied using the double stranded RNA, polyinosinic:
polycytidylic acid (poly I:C), to induce interferon production. Northern blot
analysis showed Mx mRNA in liver, head kidney and gills 2 days after poly I:C
injection of fish, but not in untreated fish or fish injected with saline or LPS.
Mx transcripts of 2.4 and 1.9 kb were detected in the liver. By screening of a
cDNA library, three different full length Mx cDNA clones, ASMx1, ASMx2 and ASMx3,
were identified and sequenced. The deduced ASMx proteins all contain 623 amino
acids and show the tripartite GTP-binding motif typical of vertebrate Mx
proteins. ASMx1 and ASMx2 may represent alleles of the same gene whereas ASMx3
represents a different gene. The deduced ASMx proteins showed 96 to 98% sequence
identity with rainbow trout Mx1 and Mx3 and about 88% identity with rainbow trout
Mx2 protein.
PMID- 9397347
TI - Identification of a differential display product associated with apoptosis in
chicken thymocytes.
AB - To further elucidate the cellular mechanisms that mediate programmed cell death
in avian immune cells, differential display analysis was employed to identify
differentially expressed genes in chicken thymocytes undergoing apoptosis.
Primary cultures of thymocytes were treated with dexamethasone to activate
apoptosis and RNA was isolated for differential display analysis. A differential
display product designated A1 (479 bp) was identified. This display product was
subcloned and induced expression of the genes was confirmed by ribonuclease
protection analysis. Nucleotide sequence analysis of A1 revealed a putative 82
amino acid open reading frame that demonstrated limited homology with Bad, an
apoptotic regulatory protein. Thus, A1 may represent the avian homolog of Bad.
PMID- 9397348
TI - Phenotyping of beluga whale blood lymphocytes using monoclonal antibodies.
AB - Widespread efforts are currently made to classify morphologically
indistinguishable lymphocyte subpopulations in several species. In order to
increase the knowledge in cetacean immunology, cross-reactivity of antibodies
against bovine, human, ovine and mouse cell surface proteins was tested on beluga
whale (Delphinapterus leucas) peripheral blood lymphocytes using flow cytometry.
Anti-MHC class I and II as well as anti-CD2 reacted with virtually all peripheral
blood lymphocytes. Anti-TCR gamma delta and anti-CD4 reacted with respectively
31% and 30% of peripheral blood lymphocytes. B lymphocytes were identified by an
anti-surface IgM which was present on 6% of blood lymphocytes. Specificity of
these antibodies was demonstrated by immunoprecipitation of beluga proteins with
similar molecular weight to that of other species. These results could be useful
for further immunotoxicological evaluation of highly versus mildly contaminated
populations of belugas.
PMID- 9397349
TI - T cell progenitors in the murine small intestine.
AB - Lymphocytes in the murine small intestine epithelium are known to have a high
proportion of extrathymic T cells. To explore the possibility that small
intestine intraepithelial lymphocytes (IELs) are derived from T cell progenitors
present within the intestine, intestine-derived cells with characteristics of
early-stage T cell precursors were studied for their ability to regenerate IEL T
cell populations following transfer into irradiated recipient mice. Cells within
this population lacked markers of mature T cells but expressed heat-stable
antigen, the c-kit receptor for stem cell factor, and/or the pre-T cell alpha
gene. Upon adoptive transfer, donor cells preferentially homed to the intestine
and did not repopulate the thymus or extraintestinal peripheral lymphoid tissues.
IELs derived from the donor precursor pool included both (alpha beta and gamma
delta T subsets and consisted of phenotypically heterogeneous cell populations
defined by CD4 and CD8. These findings provide evidence that T cell progenitors
located in the intestinal mucosa are the likely source of most intestinal IELs.
PMID- 9397350
TI - Age-related changes of naive and memory CD4 rat lymphocyte subsets in mucosal and
systemic lymphoid organs.
AB - The purpose of this study was to investigate in rats, by double-label
immunofluorescence and flow cytometric analysis, the age related changes in the
CD4 subset of gut-associated lymphoid tissues and spleen. We found that the
percentage of CD4+ T cells in Peyer's patches (PP) and spleen (SP) increased
during the first 6 weeks after weaning. An age-related decrease of the CD4 subset
was observed in SP of aged rats, but not in their PP. In all lymphoid tissues
studied, an age-related decrease of the Thy-1+ subset was observed from weaning
to 2 years of age. Analysis of the naive CD4 subset (CD45RC+) showed that in SP
this subset increased during the first 9 weeks of age, and declined in aged rats.
However, in PP this subset presented a slow decrease from weaning until 2 years
of age. Together with the decrease of the naive subset, a sharp increase of the
memory/activated CD4+ cells (CD45RC- Thy-1-) was observed in PP, and to a lesser
extent in SP. When the maturation of the CD4 T cells in PP was followed during
the first week after weaning, we found that an important proportion of this
subset changes its phenotype at this time, from recent thymic emigrant (CD45RC-
Thy-1+) to naive T cell (CD45RC+ Thy-1-) and then to activated/memory cell
(CD45RC- Thy-1-). Therefore it appeared that CD4 T cells from PP mature faster
than SP CD4 T cells, and they are not subject to the deleterious effect of aging.
One surprising point was the different kinetics of the CD4 T cells observed in
mesenteric lymph nodes (MLN). No age-related changes were observed in the CD4
subset at this site. Furthermore, the percentage of the CD45RC+ cells did not
decrease in aged rats, and in the first 9 weeks of life an increase of this
subset was observed.
PMID- 9397351
TI - Is world activism a reasonable perspective?
PMID- 9397352
TI - Work while you learn or learn while you work?
PMID- 9397353
TI - An integrated, evidence-based medicine program for FP residents.
PMID- 9397354
TI - The invisible faculty.
PMID- 9397355
TI - WIN5.
PMID- 9397356
TI - The resident's perspective on community rotations.
PMID- 9397357
TI - Twenty years of consulting for excellence: the Residency Assistance Program.
AB - BACKGROUND AND OBJECTIVES: The Residency Assistance Program (RAP) in family
practice was established in 1975 to provide consultative assistance to family
practice residency program directors interested in enhancing the quality of their
training programs. Since its inception, RAP activities have been monitored and
policies approved by a project board, with representation from all the national
family medicine/practice organizations. The voluntary, confidential, nonpunitive,
collaborative problem-solving process has provided more than 800 RAP
consultations in RAP's 20 years of operation. This paper reviews the historical
development, current status, and future directions of the program.
PMID- 9397358
TI - Competency-based education in family practice.
AB - BACKGROUND AND OBJECTIVES: Since their inception, family practice residency
programs have been designed on a rotation-based format. It has been assumed that
by having residents rotate through a series of educational experiences, they
would assimilate the skills necessary to effectively serve as a family physician.
An alternative approach is based on the attainment of competency, rather than on
the completion of a set of experiences. This method of education is known as
competency-based education, mastery learning, or, more recently, outcomes-based
assessment. Within family medicine, there is a strong interest in the application
of competency-based education to family practice residency training. In response
to the growing need to discuss these and other related issues, the Society of
Teachers of Family Medicine (STFM) Board created the Task Force on Competency
based Education. Its mission is to disseminate this educational theory to STFM's
membership. This article reviews the theory of competency-based education,
describes development of a competency-based curriculum model, and discusses the
academic issues surrounding adaptation of this form of education to family
practice residency programs.
PMID- 9397359
TI - Resident partnerships: a tool for enhancing ambulatory training.
AB - BACKGROUND AND OBJECTIVES: This study examined resident partnerships and their
effect on graduates' practice patterns. METHODS: The study authors surveyed
graduates from a residency program that used resident partnerships. We also
surveyed the graduates' current practice partners, and they served as a
comparison group. RESULTS: The graduates' response rate was 86%, and their
current practice partners' response rate was 61%. Graduates from a partnership
program rated themselves better trained for outpatient medicine and more
comfortable communicating with other physicians and working within a patient care
team; they were also slightly less likely to practice inpatient medicine.
Reported benefits during residency included enhanced availability for continuity
clinics, more emotional and intellectual support, and more flexible work
schedules. CONCLUSIONS: Graduates valued partnerships during their training and
reported being better prepared to work with other physicians in ambulatory
settings.
PMID- 9397360
TI - Perceived characteristics of successful family practice residency maternity care
training programs.
AB - BACKGROUND AND OBJECTIVES: This study determined the perceived characteristics of
family practice residency training programs that produce a high percentage of
graduates who provide maternity care. METHODS: We surveyed a Delphi panel of 28
family practice maternity care experts. RESULTS: Consensus was reached after the
third survey. The characteristics of the family medicine faculty and teaching
service were rated as most important. Other essential characteristics were an
adequate obstetrical training volume; mutual respect between obstetric and family
medicine faculty and residents; support for family practice maternity care from
obstetricians, administration, and nursing staff; and family physicians being
accepted in the community as maternity care providers. CONCLUSIONS: Family
practice residency programs that produce a high percentage of graduates who
provide maternity care have a unique, family practice maternity care-friendly
environment. Residency programs wishing to increase the percentage of their
graduates who provide maternity care should ensure that their faculty support
family practice maternity care, are competent in maternity care, and model
maternity care in their own practices. They should strive to ensure an adequate
volume of obstetrical cases for resident education and work toward educating
patients and local obstetricians, nursing staff, and hospital administration
regarding family practice maternity care.
PMID- 9397361
TI - Combined residency training in family practice and other specialties.
AB - BACKGROUND AND OBJECTIVES: The University of California, Davis residencies in
family practice and psychiatry are entering the third year of a combined training
track. Graduates of the combined program will be eligible for board certification
in both specialties. The combined program has created opportunities for
collaborative training with other specialties, such as obstetrics and medical
informatics. Barriers and challenges to collaborative training include issues of
curriculum integration, establishment of an identity for residents and future
graduates, resident stress, acceptance of combined programs, counting of
generalist physicians, hospital privileges, fulfillment of unmet societal needs,
and improved collaboration at academic health centers.
PMID- 9397362
TI - A curriculum for multicultural education in family medicine.
AB - BACKGROUND AND OBJECTIVES: To deliver effective medical care to patients from all
cultural backgrounds, family physicians need to be culturally sensitive and
culturally competent. Our department implemented and evaluated a 3-year
curriculum to increase residents' knowledge, skills, and attitudes in
multicultural medicine. Our three curricular goals were to increase self
awareness about cultural influences on physicians, increase awareness about
cultural influences on patients, and improve multicultural communication in
clinical settings. Curricular objectives were arranged into five levels of
cultural competence. Content was presented in didactic sessions, clinical
settings, and community medicine projects. METHODS AND RESULTS: Residents did
self-assessments at the beginning of the second year and at the end of the third
year of the curriculum about their achievement and their level of cultural
competence. Faculty's evaluations of residents' levels of cultural competence
correlated significantly with the residents' final self-evaluations. Residents
and faculty rated the overall curriculum as 4.26 on a 5-point scale (with 5 as
the highest rating). CONCLUSIONS: Family practice residents' cultural knowledge,
cross-cultural communication skills, and level of cultural competence increased
significantly after participating in a multicultural curriculum.
PMID- 9397363
TI - A hypothetical model of the effect of medical education on specialty choice.
AB - BACKGROUND AND OBJECTIVES: Using the Theory of Reasoned Action, we propose a
model that diagrams medical school characteristics known or hypothesized to
influence the process of specialty choice. The medical school characteristics we
consider are administrative support, special programs, primary care funding,
number and quality of primary care faculty, faculty influence, primary care
residencies, committee representation, primary care environment, required time,
and student contact. This model provides explicit hypotheses to be tested in
future research on specialty choice.
PMID- 9397366
TI - Pediatric nosocomial infections: children are not little adults.
PMID- 9397365
TI - Assessing prenatal care in a family practice residency clinic.
AB - BACKGROUND AND OBJECTIVES: This study demonstrates how one family practice
residency clinic characterized obstetric clinic patients and assessed obstetric
care using birth certificate data (demographic characteristics and risk factors)
and birth outcome indicators. METHODS: We compared clinical characteristics and
birth outcomes for 901 patients who were delivered by family physicians from the
family practice residency clinic with a matched and unmatched group of patients
who were delivered by other physicians in the county during 1990-1993. RESULTS:
The study clinic patients were at higher risk and had lower use of prenatal care.
However, the outcomes of the study clinic patients were significantly better
(fewer labor and delivery complications, procedures, Cesarean deliveries,
abnormal conditions of newborn, low birth weight deliveries, and preterm birth)
or no different from the comparison group of non-clinic patients. CONCLUSIONS:
The analysis of birth certificate data provided a favorable assessment of
prenatal care provided by a family practice residency clinic. This type of
analysis permits comparisons of birth outcomes with other local or regional
providers, statewide providers, and the year 2000 national objectives established
by the National Center for Health Statistics.
PMID- 9397364
TI - Factors associated with primary care residents' satisfaction with their training.
AB - BACKGROUND AND OBJECTIVES: Satisfaction is known to impact work performance,
learning, recruitment, and retention. This study identifies the factors
associated with primary care residents' satisfaction with their training.
METHODS: We used a cross-sectional survey based on the Price-Mueller model of job
satisfaction. The model included 14 job characteristics, four personal
characteristics, and four demographic factors. Data were collected in February
and March 1996 from residents in three primary care training programs (family
practice, pediatrics, and internal medicine) at a large academic medical center.
The same standardized, self-administered questionnaires were used in all three
departments. RESULTS: Seventy-five percent (n = 119) of the residents returned
questionnaires. Five job characteristics were positively associated with resident
satisfaction: continuity of care, autonomy, collegiality, work that encourages
professional growth, and work group loyalty. Role conflict, a sixth job
characteristic, was negatively associated with satisfaction. The personal
characteristic of having an optimistic outlook on life was also positively
associated with satisfaction. The model explained 66% of the variation in self
reported satisfaction. CONCLUSIONS: The satisfaction of the residents was
significantly associated with six job characteristics and one personal factor.
Interventions based on these job characteristics may increase resident
satisfaction and may lead to better patient outcomes, better work performance,
greater patient satisfaction, and more success in recruiting top students into a
residency.
PMID- 9397367
TI - Molecular markers for differentiation of multiresistant Klebsiella pneumoniae
isolates in a pediatric hospital.
AB - OBJECTIVE: To study the spread of extended-spectrum beta-lactamase-producing, but
aminoglycoside-susceptible, Klebsiella pneumoniae strains in our hospital over an
8-month period, by using two genotypic markers. DESIGN: Ribotyping (using two
endonucleases) and randomly amplified polymorphic DNA analysis (RAPD; using two
different 10-mer primers) were applied to the epidemiological typing of clinical
K pneumoniae isolates from stools, ileal fluid, or urine of hospitalized
children. SETTING AND PATIENTS: The surgical intensive-care ward (S1: 9 patients,
17 isolates), surgical unit (S2: 2 patients, 2 isolates), and gastroenterology
ward (GE: 1 patient, 1 isolate) of the Robert Debre Hospital of Paris, France.
RESULTS: Ribotyping of the 20 clinical isolates, the type strain of the species,
and two epidemiologically unrelated isolates with EcoRI and HindIII revealed 6
and 5 different patterns, respectively. Six ribotypes were identified by using
these two enzymes. RAPD generated 6 distinct patterns, in complete agreement with
ribotyping. Our genotypic results showed that 11 patients from wards S1, S2, and
GE harbored genotypically related strains, suggesting nosocomial transmission and
cross-colonization between and within the three wards. CONCLUSIONS: Ribotyping
and RAPD appear to be reliable methods for distinguishing K pneumoniae strains.
The spread of one strain of K pneumoniae in different units of our hospital was
demonstrated by both methods. However, RAPD has the advantage of simplicity and
rapidity conferred by polymerase chain reaction.
PMID- 9397368
TI - Nosocomial pneumonia on general medical and surgical wards in a tertiary-care
hospital.
AB - OBJECTIVE: To describe the demographic, clinical, and microbiologic
characteristics of patients who develop nosocomial pneumonia on general medical
and surgical wards of a tertiary-care hospital. DESIGN: A 1-year, prospective,
descriptive study. SETTING: A 1,100-bed, tertiary-care, urban hospital.
POPULATION: Patients experiencing nosocomial pneumonia were identified through
surveillance on general medical and surgical wards, using a standard case
definition. RESULTS: 92 pneumonias in 85 patients on general wards were
identified. The mean age of patients was 63 +/- 17 years, 55 patients (65%) were
male, and 75 cases of pneumonia (81%) were acquired on surgical wards. Bacteremia
was identified in 8 (13%) of 62 episodes, and 48 (52%) grew potential pathogens
from respiratory specimens. Twenty-six patients (28%) required transfer to the
intensive-care unit (ICU), and 20 (22%) received mechanical ventilation. By
multivariate analysis, patients with a thoracic surgical procedure or with
Staphylococcus aureus isolated from respiratory secretions were more likely to
require ICU admission. The overall mortality rate was 20% (17/85), with a
directly associated mortality of 14% (12/85). Patients who died were older, more
frequently resided on a medical ward, and had a greater mean number of
comorbidities. These patients often were treated nonaggressively and were not
considered candidates for ICU admission due to advanced age and poor underlying
clinical status. CONCLUSIONS: Although the morbidity of nosocomial pneumonia in
this population was high, as evidenced by high rates of transfer to ICU, the
directly associated mortality was relatively low. Those requiring ICU admission
require further study to identify preventive measures that could decrease the
morbidity in this group. Interventions to prevent pneumonia or to improve
prognosis may not be feasible for the majority of these patients who die from
nosocomial pneumonia.
PMID- 9397369
TI - Risk factors associated with permanent access-site infections in chronic
hemodialysis patients.
AB - OBJECTIVE: To determine the epidemiological risk factors associated with
permanent access-site (PAS) infection in a population of chronic hemodialysis
patients. DESIGN: Retrospective cohort analysis. SETTING: Hemodialysis unit of a
400-bed Department of Veterans' Affairs hospital. RESULTS: A cohort of 94 males
(1,316 patient months) was studied. Fifty-one PAS infections in 31 patients were
observed. Six patients had two PAS infections, four patients had three
infections, and two patients had four infections. Twenty-nine of the 31 patients
with PAS infections were bacteremic at least once. Univariate analysis identified
seven factors significantly associated with PAS infection in this population:
location of PAS other than forearm, type of vascular access
(polytetrafluoroethylene [PTFE] versus endogenous arteriovenous [AV] fistula),
limited ambulatory status, residence in a nursing home, bacterial infection at a
distant site, number of access-site revisions, and number of hospitalizations. In
a logistic regression analysis, only graft type and number of PTFE graft
revisions were associated independently with PAS infection. The odds ratio for
PAS infection in PTFE grafts compared to endogenous AV fistula was 7.8; the odds
ratio for PAS infection with each PTFE graft revision was 1.5. CONCLUSIONS: PAS
infections were associated independently with the type of graft and the number of
PTFE graft surgical revisions.
PMID- 9397370
TI - The epidemiology of fecal carriage of vancomycin-resistant enterococci.
AB - An outbreak of vancomycin-resistant enterococci (VRE) began at the University of
Massachusetts Medical Center in May 1993. As of September 1995, we had a total of
253 patients infected or colonized with VRE, with consequent increasing demand
for private rooms. We analyzed results of surveillance cultures for VRE of 49
patients known to be colonized or infected with VRE. Of these, 34 (70%) were
classified as persistent carriers, defined as patients with at least three
consecutively positive cultures from any site taken over at least a 2-week
period. The length of carriage varied from 19 to 303 days (median, 41 days); 11
patients were converters, defined as patients with three consecutive negative
cultures from all previously colonized sites taken over a 3-week period. These
patients were free of VRE for 39 to 421 days (median, 142 days). Four were
recolonizers after they were documented to be clear of VRE for 33 to 106 days.
VRE carriage tends to be prolonged, and hospitalization of patients with VRE will
require continued isolation and contact precautions for control of transmission.
PMID- 9397371
TI - Living with methicillin-resistant Staphylococcus aureus: a 7-year experience with
endemic MRSA in a university hospital.
AB - A review of our infection control records revealed 3,159 new isolations of
methicillin-resistant Staphylococcus aureus (MRSA) from 1988 to 1994. Prior to
this period, our approach to MRSA had changed from eradication to containment
measures. We found a decline in MRSA rates from 11.4 to 5.2 first isolations per
1,000 deaths and discharges over the study period.
PMID- 9397372
TI - Prescribing pattern of vancomycin in a community teaching hospital with low
prevalence of vancomycin-resistant enterococci.
AB - A 1-month prospective survey of all inpatients given vancomycin was performed in
a community teaching hospital with a low prevalence of vancomycin-resistant
enterococci. Only 20 of the 97 vancomycin orders written from August 1 to
September 1, 1996, were consistent with Hospital Infection Control Practices
Advisory Committee (HICPAC) guidelines. Surgical prophylaxis accounted for 37 of
the 77 orders inconsistent with HICPAC guidelines.
PMID- 9397373
TI - Ribotyping and random amplification of polymorphic DNA for nosocomial
Enterobacter cloacae isolates in a pediatric intensive-care unit.
AB - Between 1987 and 1989, two sequential outbreaks of nosocomial infection caused by
Enterobacter cloacae occur-red in the pediatric intensive-care unit of a tertiary
care teaching hospital. Seventeen strains retrieved from the outbreaks and two
control strains identified in other wards were typed by ribotyping and random
amplification of polymorphic DNA (RAPD). The results indicated that the genomic
pattern of strains identified between the first and second outbreaks was
different. We conclude that both ribotyping and RAPD are highly discriminatory
and reproducible methods for typing E cloacae. RAPD seems to be more efficacious
and cost-effective.
PMID- 9397374
TI - Epidemiological study of hospital-acquired infection with vancomycin-resistant
Enterococcus faecium: possible transmission by an electronic ear-probe
thermometer.
AB - Clonal spread of vancomycin-resistant Enterococcus faecium among seven patients
on one ward of a community teaching hospital was identified by contour-clamped
homogeneous electric-field gel electrophoresis. Environmental cultures isolated
the same strain from the handle of a shared electronic ear-probe thermometer.
Cross-contamination of the clonal strain between two geographically separate
units on this ward, sharing equipment but not personnel, suggests the possibility
of an environmental source.
PMID- 9397375
TI - A cluster of serious Escherichia coli infections in a neonatal intensive-care
unit.
AB - A cluster of serious Escherichia coli infections was identified among patients in
a neonatal intensive-care unit. Infection control staff identified the outbreak
because they realized that E coli rarely caused infections in this unit. Pulsed
field gel electrophoresis confirmed that one strain of E coli was transmitted
among patients.
PMID- 9397376
TI - Cumulative yield from patient surveillance cultures for methicillin-resistant
Staphylococcus aureus during a hospital outbreak.
AB - The cumulative yield from cultures of separate sites was determined during the
investigation of a methicillin-resistant Staphylococcus aureus (MRSA) outbreak.
Surveillance cultures were submitted from clinical sites, nose, groin, and axilla
of 421 patients on two different occasions. MRSA was recovered most often from
various clinical sites, including lower respiratory tract, surgical wounds,
urinary tract, and decubitus ulcers (total, 13 patients). Four additional
patients were identified as positive from the first nasal swab, one patient from
the second nasal swab, and two others from swabs of the groin. The submission of
axillary swabs or a second groin swab did not identify additional MRSA-colonized
patients and resulted in additional costs of $4,525.
PMID- 9397377
TI - Rate of seasonal spread of respiratory syncytial virus in a pediatric hospital.
AB - The rate of nosocomial respiratory syncytial virus (RSV) infection was measured
in a large pediatric hospital using an incidence density method. The at-risk days
for nosocomial RSV were summed during a defined winter period in which there were
54 admissions with community-acquired RSV infection giving a rate of 2.9 cases
per 1,000 at-risk days (95% confidence interval, 0.3-5.4 per 1,000).
PMID- 9397378
TI - Evaluation of vancomycin use in a pediatric teaching hospital based on CDC
criteria.
AB - This study was performed to determine whether vancomycin use at our pediatric
hospital was consistent with modified Centers for Disease Control and Prevention
guidelines. Vancomycin use was inappropriate in 54% of patients. Inappropriate
use briefly decreased by 14% after educational efforts. Further education
regarding vancomycin use was deemed necessary and is continuing.
PMID- 9397379
TI - Hospital-acquired pneumonia: perspectives for the healthcare epidemiologist.
AB - Nosocomial pneumonia is defined as an infection of lung parenchyma that was
neither present nor incubating at the time of the patient's admission to the
hospital. In the United States, hospital-acquired pneumonia is the second most
common nosocomial infection and accounts for the most deaths from nosocomial
infection. We describe how infection control personnel can use targeted
surveillance to identify clusters of cases and to prevent pneumonia. We also
discuss common pathogens that cause nosocomial pneumonia; ventilator-associated
pneumonia; and strategies for prevention of hospital-acquired pneumonia.
PMID- 9397380
TI - Outbreak of highly contagious tuberculosis.
PMID- 9397381
TI - Disease transmitted through food supply.
PMID- 9397382
TI - Benefits of hormone replacement therapy--overview and update.
AB - Postmenopausal estrogen deficiency may result in a wide variety of physiologic
disorders, including vasomotor symptoms, urogenital atrophy, an increase in the
risk of coronary heart disease, osteoporotic fractures, and Alzheimer's disease.
The growing body of evidence, including much that is newly published,
demonstrating that hormone replacement therapy (HRT) can largely prevent or
mitigate these sequelae, will be reviewed in this paper. The efficacy of HRT in
alleviating vasomotor and urogenital discomfort, the most common symptoms of
postmenopausal estrogen deficiency, is well established. Evidence from over 30
epidemiologic studies indicates that estrogen reduces the risk of coronary heart
disease (CHD) by 50%. The risk of major CHD has been found to be markedly reduced
in women who receive combined estrogen/progestogen therapy compared to nonusers
(or estrogen-alone users). Estrogen is recommended as the modality of choice to
prevent bone loss: data supporting a positive effect of estrogen on the risk of
wrist and vertebral fracture are quite favorable. Similarly, outcomes of recent
investigations have demonstrated a positive impact of HRT on both psychological
function and the risk of osteoarthritis. In addition, HRT substantially reduces
the risk of colon cancer. Moreover, the potential for HRT to delay the
progression or reduce the risk for developing Alzheimer's disease is a new area
of research that shows promise. Improvements in quality-of-life assessments have
also been reported in conjunction with the relief of menopausal symptoms by HRT.
Clinicians should be aware of the large amount of new evidence that strengthens
the case for wider use of HRT. Based on these new data, physicians may conclude
that HRT would benefit the majority of their postmenopausal patients and thus
encourage HRT use in the absence of known risk factors.
PMID- 9397383
TI - Evaluation and management of the hormone replacement therapy (HRT) candidate.
AB - As knowledge about menopause and hormone replacement therapy (HRT) has increased,
it has become evident that a considerably higher percentage of postmenopausal
women than the 20% to 30% currently treated could receive HRT. It is equally
clear, however, that HRT is not appropriate for every woman and that "one size
fits all" management of menopausal women is not always suitable. This paper,
therefore, reviews published prescribing and management guidelines for
instituting and maintaining HRT and summarizes current information concerning
factors to be considered before recommending HRT. When choosing candidates,
special attention should be placed on individual patient factors. A thorough
history is required to determine the presence of contraindications and the
likelihood of potential benefits and risk factors. The hormone replacement
regimen, hormone preparations, and dosage forms that best meet the specific needs
of the individual woman should be offered. Before undertaking long-term therapy,
the candidate should be informed of the established and likely benefits and the
relative risks of hormone therapy, and that the magnitude of some risks has not
yet been definitively determined. The final decision to use therapy should be
made by the patient, guided by her physician, and based on her current symptoms
and her relative likelihood of developing coronary artery disease, osteoporotic
fractures, and cancer. The ancillary benefits, the common side effects of each
regimen, the bleeding patterns to expect, and the type and frequency of clinical
monitoring that will be necessary during therapy should also be considered.
PMID- 9397384
TI - Cross-national study of women's use of hormone replacement therapy (HRT) in
Europe.
AB - The benefits of hormone replacement therapy (HRT) to perimenopausal and
postmenopausal women are well established. Women from France, Germany, Spain, and
the United Kingdom were interviewed to determine: (1) knowledge and views of
menopause and HRT; (2) history of HRT among current and lapsed users; and (3)
reasons of non-users for never having taken HRT. In 1996, nearly 1,500 women aged
40 to 65 answered a short series of questions concerning menopause and HRT as
part of a consumer omnibus survey; others (n = 929) participated in a focused
survey of attitudes toward and use of HRT. Only one-third of perimenopausal and
13% of postmenopausal women currently were taking HRT. About 25% of
postmenopausal women reported having taken HRT at some time. The proportion of
perimenopausal women using HRT varied by country, and ranged from 18% in Spain to
55% in France. Importantly, about half (range across countries, 38% to 61%) of
the women interviewed had not discussed menopause or its symptoms with their
doctors. While levels of HRT knowledge varied by country, two-thirds of
respondents overall believed they needed more information about HRT. Decisions
about beginning HRT and choosing a formulation were viewed by most women as
matters of personal choice, to be made with advice from a physician. In summary,
despite the benefits of HRT and available choices among drug delivery options, a
fairly small proportion of European women use it, largely because most remain
poorly informed about the therapy. Increased physician-patient communication and
public education programs are needed to provide women with the information they
need to make judicious decisions concerning HRT.
PMID- 9397385
TI - Comparison of continuous and sequential transdermal progestogen with sequential
oral progestogen in postmenopausal women using continuous transdermal estrogen:
vasomotor symptoms, bleeding patterns, and serum lipids.
AB - OBJECTIVE: The efficacy, bleeding patterns, and safety of continuous transdermal
and sequential transdermal progestogen therapy were compared with those of oral
progestogen therapy in postmenopausal women receiving transdermal estrogen.
METHODS: In an open-label, 1-year (13 treatment periods, 28 days each),
randomized study, 774 postmenopausal women were assigned to receive 50
micrograms/day of continuous trans dermal estradiol with either continuous or
sequential transdermal norethisterone acetate (NETA) in daily doses of 170 or 350
micrograms in a single transdermal patch or sequential oral progestogen (1 mg
norethisterone [NET] or 20 mg dydrogesterone/day). RESULTS: The average number of
hot flushes/day decreased from prestudy by over 90% (P < .001), and this
reduction was unaffected by different progestogen regimens. With sequential
progestogen, bleeding incidence and the number of bleeding days did not change
over the course of the study but were lower in the low-dose transdermal
progestogen group. With continuous progestogen, the incidence of bleeding
decreased in both the low- and high-dose groups, from 35% and 45% in treatment
period 1 to 25% and 15%, respectively, at the end of treatment. Adverse event
incidence was similar in all groups, with 23% to 36% of subjects reporting events
possibly or probably related to HRT (excluding vaginal bleeding). Two cases of
simple hyperplasia were reported (one in each low-dose progestogen group).
Beneficial effects on coronary heart disease risk factors, such as reductions in
total cholesterol and low-density lipoprotein cholesterol and increases in high
density lipoprotein-2 cholesterol levels, were measured in all treatment groups.
Lipoprotein (a) was reduced in all but the oral progestogen group. CONCLUSIONS:
Continuous and sequential transdermal estrogen/progestogen treatments with
estradiol/NETA appear to be effective and safe alternatives to continuous
transdermal estrogen and oral sequential progestogen for the treatment of
menopausal symptoms. Continuous transdermal therapy with estradiol/NETA may be
more acceptable for a majority of patients, i.e., those who wish to avoid monthly
bleeds, whereas the sequential regimen may be preferable when the clinician
and/or patient believes monthly bleeding to be appropriate.
PMID- 9397386
TI - Transdermal sequential and continuous hormone replacement regimens with estradiol
and norethisterone acetate in postmenopausal women: effects on the endometrium.
AB - OBJECTIVE: To evaluate, in postmenopausal women, the endometrial safety and
histologic effects of two doses of transdermal norethisterone acetate (NETA)
administered in sequential and continuous treatment regimens added to continuous
transdermal estradiol, against a reference regimen consisting of sequential oral
progestogen and continuous transdermal estradiol. METHODS: A total of 774
postmenopausal women were enrolled in the open-label study of 13 treatment cycles
of 28 days each and randomly assigned evenly to regimens consisting of
transdermal estradiol, 50 micrograms/day and NETA, given sequentially (last 14
days of each treatment cycle) or continuously at two doses (170 and 350
micrograms/day). Estradiol and NETA were delivered from a transdermal system
containing both hormones. The reference group received estradiol, 50
micrograms/day transdermally and either 1 mg/day NET or 20 mg/day dydrogesterone
orally during the last 14 days of each treatment cycle. Endometrial biopsies were
taken pre-study and at the end of the treatment, if treatment had lasted at least
3 months. Safety was to be assessed in terms of the incidence of hyperplasia.
Endometrial biopsies were assigned to one of the following histological classes:
proliferative (predominant estrogen effect), suppressed proliferation (slightly,
moderately, strongly progestogenic effect), progestational atrophy (predominant
progestogenic effect), hyperplastic, cancerous, or other. RESULTS: No case of
hyperplasia was recorded in any of the treatment groups, each with > 150 subjects
enrolled, after one year of treatment. One case of serous carcinoma was found in
the LP-C group. Progestational atrophy was seen frequently in women receiving
continuous transdermal HRT (84%, high-dose NETA, 66%, low-dose NETA); it was much
rarer with the sequential regimens (i.e., between 32% and 38%). The proportion of
estrogen-dominated endometria was low, 0.9% and 2.6% with the high- and low-dose
NETA continuous regimens, respectively, 6.2% and 12.5% with the high- and low
dose NETA sequential regimens, respectively; and, 4.5% in the oral progestogen
group. CONCLUSION: Transdermal administration of either dose of NETA, whether
given sequentially or continuously, prevents the emergence of hyperplasia
expected with unopposed estradiol. Since differences in outcomes of endometrial
histology between the two NETA doses were minor for both continuous and
sequential regimens, use of the lower NETA dose is considered sufficient for a
safe transdermal combination hormone replacement therapy.
PMID- 9397387
TI - Short-term and working memory differences in language/learning disabled and
normal adults.
AB - Fifteen adults who reported a childhood history of speech-language and/or
learning disability (L/LD) were tested on two verbal memory tasks. Their
performance on sentence repetition and reading span measures was compared with
that of a matched control group who reported no childhood history of L/LD.
Results indicated statistically significant group performance differences on both
short-term and working memory tasks. This suggests that verbal memory
difficulties may be a longterm component of L/LD.
PMID- 9397388
TI - Effect of sign task on speech timing in simultaneous communication.
AB - The purpose of this investigation was to study the effect of the signing task on
temporal features of speech during simultaneous communication (SC). The effects
of three independent variables: (a) communication mode (speech only vs. SC); (b)
sign task demand (base vs. elaborated signs); and (c) type of sign movement
(kinetic vs. morphokinetic) were studied on five dependent variables: (a) word
duration; (b) sentence duration; (c) diphthong duration; (d) interword interval
before signed experimental word (IWIB); and (e) interword interval after signed
experimental word (IWIA). Audio recordings were made of 12 normal hearing,
experienced sign language users speaking experimental words that varied in sign
task demand and movement under SC and speech only (SO) conditions. Results
indicated longer sentence durations for SC than SO and longer anticipatory
durations of IWIB and diphthong before signed words, especially those using signs
with greater task demand or with movements including hand shape change. IWIA only
lengthened for SC vs. SO with no further effect of sign task demand or movement.
These results indicate finite effects of sign task demand and movement on pause
and segment durations before the sign but not as strong an effect as has been
reported for increased finger spelling task length.
PMID- 9397389
TI - Maintaining acceptably low referral rates in TEOAE-based newborn hearing
screening programs.
AB - This article describes factors that can affect the refer rate for otoacoustic
emission (OAE) based newborn hearing screening, including the population of
infants being screened, the adequacy of probe fit, software options used,
external ear conditions, screener training, and baby handling. The effect of the
infant's age on screening outcomes is also discussed using results of screening
for 1328 regular nursery newborns, ranging in age from 6 to 60 hours, who were
screened with transient evoked otoaoustic emissions (TEOAE) prior to hospital
discharge. The youngest infants (6-9 hours old) were as likely to pass (90% pass
rate) as the infants who were 24-27 hours old (94% pass rate). The results of
this study are consistent with reports from many TEOAE-based screening programs
that have demonstrated that acceptably low refer rates (mean = 6.9%) can be
obtained when appropriate screening procedures are followed.
PMID- 9397390
TI - Cost analysis of TEOAE-based universal newborn hearing screening.
AB - Although more and more hospitals are implementing universal newborn hearing
screening programs, there is still very little information available about the
costs of newborn hearing screening programs. The few articles which have been
published evaluate technologies or protocols which are no longer used, are
incomplete, or are based on hypothetical estimates of the costs and time
necessary to do screening. After briefly reviewing the extant literature, this
article describes a cost analysis of a TEOAE-based universal newborn hearing
screening program. Reasons why the cost per baby ($7.42) is lower than in
previous reports are explained, and the benefits of having accurate cost analysis
data are summarized.
PMID- 9397391
TI - Production and perception of final consonant voicing in speech during
simultaneous communication.
AB - Simultaneous communication combines both spoken and manual modes to produce each
word of an utterance. This study investigated the potential influence of
alterations in the temporal structure of speech produced during simultaneous
communication on the perception of final consonant voicing. Experienced signers
recorded words that differed only in the voicing characteristic of the final
consonant under two conditions: (a) speech alone and (b) simultaneous
communication. The words were digitally edited to remove the final consonant and
played to 20 listeners who, in a forced-choice paradigm, circled the word they
thought they heard. Results indicated that accurate perception of final consonant
voicing was not impaired by changes in the temporal structure of speech that
accompany simultaneous communication.
PMID- 9397392
TI - Objective and subjective time courses of recovery from motion sickness assessed
by repeated motion challenges.
AB - The aim of this study was to determine whether the time course of recovery of
tolerance, as assessed objectively by rechallenge with motion, paralleled the
subjective recovery from motion sickness. Subjects (n = 20) were exposed to 5
pairs of nauseogenic motion challenges in which the time interval between the end
of the first and the start of the second of each pair ranged from 15 min to 2 h.
The cross-coupled motion challenge had an incrementing profile of rotational
velocity from 4 degrees to 92 degrees.s-1 in steps of 4 degrees.s-1 every 30 s,
with 8 head movements per 30 s, of approximately 45 degrees, and was continued to
the point of moderate nausea. Objective loss of tolerance decreased from 15 min
to 60 min after the first challenge, but increased again at 2 h. By contrast,
most individuals reported subjective recovery by 15 min to 30 min. It was
concluded that there is an underlying effect of motion sickness that sensitizes
the response to subsequent motion for a period of at least 2 h. This underlying
objective effect can occur in the absence of subjective symptoms, has a slower
time course than the subjective recovery from symptoms, and appears to be non
monotonic.
PMID- 9397393
TI - Orientation illusions in spaceflight.
AB - Investigations of spontaneous illusory reactions were carried out during space
flights of various durations by ANKETA questionnaires (104 cosmonauts). From a
total of 104 cosmonauts, 24, in addition, used a dictaphone to record a verbal
description of the illusions and their sensations on tape. Analysis of data
generated by ANKETA and the tapes thus recorded have shown that during adaptation
to weightlessness, 98% of cosmonauts have noted the occurrence of various
illusions of orientation (coordinate and kinetic): illusions pertaining to their
position or illusions of self- and surround-motion. The development of spatial
orientation illusions during and after flight is not limited to certain
individuals, but is a general response of the sensory system to microgravity.
These responses differ to some extent among individuals in severity, nature, time
and duration of occurrence, and the dynamics of the process. Perceptual disorders
may occur even if the cosmonaut feels well and experiences no anomalous autonomic
reactions. The nature of spatial illusions was determined by the role and
relative contribution of various types of sensory input to spatial orientation.
After completion of the initial stage of adaptation to weightlessness, the
perceptual disorders disappear. However, spontaneous illusory reactions were
often observed after 50 days of exposure to weightlessness. The adaptation
process during long-term spaceflight had an undulating course, in which
adaptation and de-adaptation alternated. A classification of weightlessness
illusions is proposed.
PMID- 9397394
TI - The velocity storage mechanism of the optokinetic nystagmus under apparent
stimulus movements in squirrel monkeys.
AB - Experiments in two awake untrained squirrel monkeys were performed to study the
velocity storage mechanism during fast rise of OKN slow phase velocity. This was
done by testing the monkey's capability to perform OKN in response to a
stationary-appearing stroboscopically illuminated stripe pattern of a
horizontally rotating drum. Nystagmus was initially elicited during constant
illumination lasting between 0.6 and 25 s. The periodicity of the stripe pattern
was 2.37 degrees. When after the constant light the flash illumination was
switched on again, two types of behavior could occur, depending on the length of
the constant light interval (CLI): 1) when the CLI was shorter than a threshold
value of 6.2 seconds, the OKN ceased under the flash stimulation. Then a "post
OKN" occurred that increased with the length of the CLIs, indicating that the
intermittently illuminated pattern did not provoke fixation suppression of OKN
aftereffects. 2) when the CLI was above threshold, the OKN continued under the
flash light; it will be called "apparent movement OKN." The threshold CLI between
the type 1 and the type 2 response did not depend on drum velocities between 21.5
degrees/s and 71.3 degrees/s. The average gain of the apparent movement OKN was
0.83 +/- 0.04; gain and stability of slow phase eye movement velocity did not
deviate systematically from the usually elicited OKN. OKAN after apparent
movement OKN did not deviate from OKAN after constantly illuminated moving
patterns. In response to the OKN initiation by a constantly illuminated pattern
up to pattern velocities of 100 degrees/s, the OKN steady state gain was reached
within the first 2 or 3 nystagmus beats. We ascribe the increase of the post-OKN
with CLI and the existence of a threshold constant light interval to activity
accumulation in the common velocity-to-position integrator (velocity storage) of
the brain stem. Loading of the velocity storage takes place after the OKN gain
has already reached the steady-state value. Apparent movement OKN could also be
elicited in guinea pigs that lack an effective smooth pursuit system. We suggest
that apparent movement OKN is produced by mechanisms located in the brain stem.
PMID- 9397395
TI - Microgravity vestibular investigations: perception of self-orientation and self
motion.
AB - Four astronauts experienced passive whole-body rotation in a number of test
sessions during a 7-day orbital mission. Pitch (Y-axis) and roll (X-axis)
rotation required subject orientations on the rotator in which the otolith system
was at radius of 0.5 m. Thus subjects experienced a constant -0.22 Gz stimulus to
the otoliths during the 60 s constant-velocity segments of "pitch" and "roll"
ramp profiles. The Gz stimulus, a radius-dependent vector ranging from -0.22 Gz
at the otoliths to +0.36 Gz at the feet, generated sensory information that was
not interpreted as inversion in any of the 16 tests carried out in flight (12 in
pitch and 4 in roll orientation). None of the subjects was rotated with head off
center during the first 33 h of the mission. In the state of orbital adaptation
of these subjects, a -0.22 Gz otolith stimulus did not provide a vertical
reference in the presence of a gradient of +Gz stimuli to the trunk and legs.
PMID- 9397396
TI - Vestibular bibliography.
PMID- 9397397
TI - The effect of dietary docosahexaenoic acid on platelet function, platelet fatty
acid composition, and blood coagulation in humans.
AB - The effect of dietary docosahexaenoic acid (DHA) in the absence of
eicosapentaenoic acid (EPA) has been studied infrequently in humans under
controlled conditions. This 120-d study followed healthy, adult male volunteers
who lived in the metabolic research unit (MRU) of the Western Human Nutrition
Research Center for the entire study. The basal (low-DHA) diet consisted of
natural foods (30 en% fat, 15 en% protein, and 55 en% carbohydrate), containing <
50 mg/d of DHA, and met the recommended daily intake for all essential nutrients.
The high-DHA (intervention) diet was similar except that 6 g/d of DHA in the form
of a triglyceride containing 40% DHA replaced an equal amount of safflower oil in
the basal diet. The subjects (ages 20 to 39) were within -10 to +20% of ideal
body weight, nonsmoking, and not allowed alcohol in the MRU. Their exercise level
was constant, and their body weights were maintained within 2% of entry level.
They were initially fed the low-DHA diet for 30 d. On day 31, six subjects
(intervention, group A) were placed on the high-DHA diet; the other four subjects
(controls, group B) remained on the low-DHA diet. Platelet aggregation in
platelet-rich plasma was determined using ADP, collagen, and arachidonic acid. No
statistical differences could be detected between the amount of agonist required
to produce 50% aggregation of platelet-rich plasma before and after the subjects
consumed the high-DHA diet. The prothrombin time, activated partial
thromboplastin time, and the antithrombin-III levels in the subjects were
determined, and, again, there were no statistically significant differences in
these three parameters when their values were compared before and after the
subjects consumed the high-DHA diet. In addition, the in vivo bleeding times did
not show any significant difference before and after the subjects consumed the
high-DHA diet (9.4 +/- 3.1 min before and 8.0 +/- 3.4 min after). Platelets from
the volunteers exhibited more than a threefold increase in their DHA content from
1.54 +/- 0.16 to 5.48 +/- 1.21 (wt%) during the DHA feeding period. The EPA
content of the subjects' platelets increased from 0.34 +/- 0.12 to 2.67 +/- 0.91
(wt%) during the high-DHA diet despite the absence of EPA in the subjects' diets.
The results from this study on blood clotting parameters and in vitro platelet
aggregation suggest that adding 6 g/d of dietary DHA for 90 d to a typical
Western diet containing less than 50 mg/d of DHA produces no observable
physiological changes in blood coagulation, platelet function, or thrombotic
tendencies in healthy, adult males.
PMID- 9397399
TI - Pancreatic bile salt-dependent lipase activity in serum of normolipidemic
patients.
AB - Bile salt-dependent lipase (BSDL, E.C. 3.1.1.-) is a digestive enzyme secreted by
the pancreatic acinar cell. Once in the duodenum, the enzyme, upon activation by
primary bile salts, hydrolyzes dietary lipid esters such as cholesteryl esters
and lipid-soluble vitamin esters. This enzyme is partially transferred from the
duodenum or pancreas to the circulation where it has been postulated to exert a
systemic action on atheroma-generating oxidized-low density lipoprotein (LDL). In
the present study, sera from 40 healthy normolipidemic volunteers were used to
investigate the possible linkage between circulating BSDL, lipids, and
lipoproteins. We showed, firstly, that pancreatic-like BSDL activity can be
detected in these serums. Secondly, BSDL activity increased significantly with
the level of LDL-cholesterol and was also positively linked to the serum
concentration of Apo B100 and Apo A-I. Thirdly, we also established that BSDL was
associated with LDL, in part by a specific interaction with Apo B100, while no
interaction was found with Apo A-I. No linkage with other recorded parameters
(triglycerides, phospholipids, and high density lipoprotein-cholesterol) was
detected. Because an increase in LDL-cholesterol represents an important risk
factor for atheroma, the concomitant increase in BSDL, which can metabolize
atherogenic LDL, suggests for the first time that this circulating enzyme may
exert a positive effect against atherosclerosis.
PMID- 9397398
TI - The effect of dietary docosahexaenoic acid on plasma lipoproteins and tissue
fatty acid composition in humans.
AB - Normal, healthy male volunteers (n = 6) were fed diets [high docosahexaenoic acid
DHA] containing 6 g/d of DHA for 90 d. The stabilization (low-DHA) diet contained
less than 50 mg/d of DHA. A control group (n = 4) remained on the low-DHA diet
for the duration of the study (120 d). Blood samples were drawn on study days 30
(end of the stabilization period), 75 (midpoint of the intervention period), and
120 (end of the intervention period). Adipose tissue (AT) samples were taken on
days 30 and 120. The plasma cholesterol (C), low density lipoprotein (LDL)-C and
apolipoproteins (apo) [Al, B, and lipoprotein (a)] were unchanged after 90 d, but
the triglycerides (TAG) were reduced from a mean value of 76.67 +/- 24.32 to
63.83 +/- 16.99 mg/dL (n = 6, P < 0.007 using a paired t-test) and the high
density lipoprotein (HDL)-C increased from 34.83 +/- 4.38 mg/dL to 37.83 +/- 3.32
mg/dL (n = 6, P < 0.017 using a paired t-test). The control group showed no
significant reduction in plasma TAG levels. Apo-E, however, showed a marked
increase in the volunteers' plasma after 90 d on the high-DHA diet, from 7.06 +/-
4.47 mg/dL on study day 30 to 12.01 +/- 4.96 mg/dL on study day 120 (P < 0.002
using a paired t-test). The control subjects showed no significant change in the
apo-E in their plasma (8.46 +/- 2.90 on day 30 vs. 8.59 +/- 2.97 on day 120). The
weight percentage of plasma DHA rose from 1.83 +/- 0.22 to 8.12 +/- 0.76 after 90
d on the high-DHA diet. Although these volunteers were eating a diet free of
eicosapentaenoic acid (EPA), plasma EPA levels rose from 0.38 +/- 0.05 to 3.39 +/
0.52 (wt%) after consuming the high-DHA diet. The fatty acid composition of
plasma lipid fractions--cholesterol esters, TAG, and phospholipid--showed marked
similarity in the enrichment of DHA, about 10%, after the subjects consumed the
high-DHA diet. The DHA content of these plasma lipid fractions varied from less
than 1% (TAG) to 3.5% (phospholipids) at baseline, study day 30. EPA also
increased in all plasma lipid fractions after the subjects consumed the high-DHA
diet. There were no changes in the plasma DHA or EPA levels in the control group.
Consumption of DHA also caused an increase in AT levels of DHA, from 0.10 +/-
0.02 to 0.31 +/- 0.07 (wt%) (n = 6, P < 0.001 using a paired t-test), but the
amount of EPA in their AT did not change. Thus, dietary DHA will lower plasma TAG
without EPA, and DHA is retroconverted to EPA in significant amounts. Dietary DHA
appears to enhance apo-E synthesis in the liver. It appears that DHA can be a
safe and perhaps beneficial supplement to human diets.
PMID- 9397400
TI - Epicoprostanol found in adipocere from five human autopsies.
AB - Adipocere formation is well known as a later postmortem change. We collected
adipocere from five male victims which had been submerged under the sea or fresh
water for 1 mon to 4 yr. Fresh subcutaneous fat of a male victim who died from a
cerebral contusion was used as the control. The samples were homogenized, and the
lipids were extracted with chloroform and methanol followed by injection into a
gas chromatograph and a gas chromatograph-mass spectrometer. We detected hydroxy
fatty acids (10-hydroxyoctadecanoic acid and 10-hydroxyhexadecanoic acid) as well
as 10-ketooctadecanoic acid in adipocere, but not in the control. In addition, we
found for the first time a cholesterol-related peak with a molecular ion of 388
in adipocere and identified it as epicoprostanol, suggesting not only oxidation
but also reduction had occurred during the formation of adipocere. In addition,
we showed the time-course of epicoprostanol accumulation. The relationship
between the time of adipocere formation and the characteristic lipid composition
is discussed.
PMID- 9397401
TI - Prevention of ischemia-induced cardiac sudden death by n-3 polyunsaturated fatty
acids in dogs.
AB - The objective of this study was to obtain functional information associated with
the prevention by n-3 polyunsaturated fatty acids (PUFA) of ischemia-induced
fatal cardiac ventricular arrhythmias in the intact, conscious, exercising dog.
Thirteen dogs susceptible to ischemia-induced ventricular fibrillation were
prepared surgically by ligation of their anterior descending left coronary artery
and placement of an inflatable cuff around their left circumflex artery. After 4
wk of recovery, exercise-plus-ischemia tests were performed without and then with
an intravenous infusion of an emulsion of free n-3 PUFA just prior to occluding
the left circumflex artery while the animals were running on a treadmill. One
week later the exercise-plus-ischemia test was repeated but with a control
infusion replacing the emulsion of n-3 PUFA. The infusion of the free n-3 PUFA in
quantities of 1.0 to 10 g prevented ventricular fibrillation in 10 of the 13 dogs
tested (P < 0.005), apparently without esterification of the PUFA into membrane
phospholipids. The antiarrhythmic effect of the n-3 PUFA was associated with
slowing of the heart rate, shortening of the QT-interval (electrical action
potential duration), reduction of left ventricular systolic pressure, and
prolongation of the electrocardiographic atrial-ventricular conduction time (P-R
interval). These effects are comparable with those we have reported in studies
with cultured neonatal rat cardiac myocytes.
PMID- 9397402
TI - Biliary excretion of dolichols and beta-hexosaminidase--effect of ethanol and
glucagon.
AB - Alcohol has been reported to increase the urinary excretion of dolichols, and
urinary dolichols are suggested to be derived from the lysosomes of the renal
cells. In the present study we examined the effects of alcohol and glucagon on
the biliary excretion of dolichols in rats. Chronic ethanol treatment decreased
both biliary dolichol and beta-hexosaminidase excretion. The absolute amount of
dolichol excreted into the bile correlated highly significantly with the absolute
amount of biliary beta-hexosaminidase. Our results indicate that biliary
dolichols are--at least in part--derived from hepatic lysosomes. Decreased
biliary dolichol output during chronic alcohol administration suggests that
urinary and biliary dolichol excretions are regulated independently of each
other.
PMID- 9397403
TI - Effect of curcumin and capsaicin on arachidonic acid metabolism and lysosomal
enzyme secretion by rat peritoneal macrophages.
AB - The inflammatory mediators secreted by macrophages play an important role in
autoimmune diseases. Spice components, such as curcumin from turmeric and
capsaicin from red pepper, are shown to exhibit antiinflammatory properties. The
influence of these spice components on arachidonic acid metabolism and secretion
of lysosomal enzymes by macrophages was investigated. Rat peritoneal macrophages
preincubated with 10 microM curcumin or capsaicin for 1 h inhibited the
incorporation of arachidonic acid into membrane lipids by 82 and 76%:
prostaglandin E2 by 45 and 48%; leukotriene B4 by 61 and 46%, and leukotriene C4
by 34 and 48%, respectively, but did not affect the release of arachidonic acid
from macrophages stimulated by phorbol myristate acetate. However, the secretion
of 6-keto PG F1 alpha was enhanced by 40 and 29% from macrophages preincubated
with 10 microM curcumin or capsaicin, respectively, as compared to those produced
by control cells. Curcumin and capsaicin also inhibited the secretion of
collagenase, elastase, and hyaluronidase to the maximum extent of 57, 61, 66%,
and 46, 69, 67%, respectively. These results demonstrated that curcumin and
capsaicin can control the release of inflammatory mediators such as eicosanoids
and hydrolytic enzymes secreted by macrophages and thereby may exhibit
antiinflammatory properties.
PMID- 9397404
TI - Generation and remodeling of highly polyunsaturated molecular species of rat
hepatocyte phospholipids.
AB - Freshly isolated rat hepatocytes were incubated for 20 min with [U-14C]glycerol
in the presence or absence of unlabeled linoleic (18:2n-6), arachidonic (20:4n
6), or docosahexaenoic (22:6n-3) acid, added as albumin complex in 10% ethanol.
Most of the radioactivity (approximately 95%) recovered in hepatocyte lipids was
present in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and
triacylglycerol (TAG). The presence of exogenous fatty acids resulted in (i)
higher incorporation of [U-14C]glycerol, (ii) higher percentage of label in TAG,
and (iii) enhanced formation of PC and PE molecular species bearing the exogenous
fatty acid at both the sn-1 and sn-2 positions of glycerol. In each case, these
molecular species contained 60 to 70% of the label in that lipid class. Further
incubation of the cells for 40 and 80 min in the absence of labeled substrate and
exogenous fatty acids resulted in a redistribution of label among PC and PE
molecular species due to deacylation-reacylation at the sn-1 position of
glycerol.
PMID- 9397405
TI - Analysis of the seed oil of Heisteria silvanii (Olacaceae)--a rich source of a
novel C18 acetylenic fatty acid.
AB - Besides some usual fatty acids (FA), two conjugated ene-yne acetylenic FA [trans
10-heptadecen-8-ynoic acid (pyrulic acid) (7.4%), and trans-11-octadecen-9-ynoic
acid (ximenynic acid) (3.5%)], a novel ene-yne-ene acetylenic FA [cis-7, trans-11
octadecadiene-9-ynoic acid (heisteric acid) (22.6%)], and 9,10-epoxystearic acid
(0.6%) could be identified in the seed oil of Heisteria silvanii (Olacaceae). Two
further conjugated acetylenic FA [9,11-octadecadiynoic acid (0.1%) and 13
octadecene-9,11-diynoic acid (0.4%)] were identified tentatively by their mass
spectra. The FA mixture has been analyzed by gas chromatography/mass spectrometry
(GC/MS) of their methyl ester and 4,4-dimethyloxazoline derivatives. The
structure of heisteric acid was elucidated after isolation via preparative silver
ion thin-layer chromatography and by various spectroscopic methods [ultraviolet;
infrared; 1H, 13C nuclear magnetic resonance (NMR); 1H-1H and 1H-13C correlation
spectroscopy]. To determine the position of the conjugated ene-yne-ene system,
the NMR spectra were also measured after addition of the lanthanide shift reagent
Resolve-Al EuFOD. Furthermore, the triyglyceride mixture was analyzed by high
temperature GC and high-temperature GC coupled with negative chemical ionization
MS. A glass capillary column coated with a methoxy-terminated 50%-diphenyl-50%
dimethylpolysiloxane was used for the separation of the triacylglycerol (TAG)
species. No evidence of decomposition of the TAG species containing conjugated
ene-yne-ene FA was observed. Twenty-six species of the separated TAG were
identified by means of their abundant quasi molecular ion [M - H]- and their
corresponding carboxylate anions [RCOO]- of the fatty acids, respectively. The
major molecular species of the TAG were found to be 16:0/18:1/18:1,
16:0/18:1/18:3 (heisteric acid), 17:2 (pyrulic acid)/18:1/18:1, 18:1/18:1/18:3
(heisteric acid). The TAG containing acetylenic FA showed an unexpected increase
of the retention time in comparison to the TAG containing usual FA, thus making
the prediction of the elution order of lipid samples containing acetylenic FA
difficult.
PMID- 9397406
TI - Lipid specificity and location of the sterol carrier protein-2 fatty acid-binding
site: a fluorescence displacement and energy transfer study.
AB - Although it was recently recognized that sterol carrier protein-2 (SCP-2)
interacts with fatty acids, little is known regarding the specificity of SCP-2
for long-chain fatty acids or branched-chain fatty-acid-like molecules. Likewise
the location of the fatty-acid binding site within SCP-2 is unresolved. A
fluorescent cis-parinaric acid displacement assay was used to show that SCP-2
optimally interacted with 14-22 carbon chain lipidic molecules: polyunsaturated
fatty acids > monounsaturated, saturated > branched-chain isoprenoids > branched
chain phytol-derived fatty acids. In contrast, the other major fatty-acid binding
protein in liver, fatty-acid binding protein (L-FABP), displayed a much narrower
carbon chain preference in general: polyunsaturated fatty acids > branched-chain
phytol-derived fatty acids > 14- and 16-carbon saturated > branched-chain
isoprenoids. However, both SCP-2 and L-FABP displayed a very similar unsaturated
fatty-acid specificity profile. The presence and location of the SCP-2 lipid
binding site were investigated by fluorescence energy transfer. The distance
between the SCP-2 Trp50 and bound cis-parinaric acid was determined to be 40 A.
Thus, the SCP-2 fatty-acid binding site appeared to be located on the opposite
side of the SCP-2 Trp50. These findings not only contribute to our understanding
of the SCP-2 ligand binding site but also provide evidence suggesting a potential
role for SCP-2 and/or L-FABP in metabolism of branched-chain fatty acids and
isoprenoids.
PMID- 9397407
TI - Elution factors of synthetic oxotriacylglycerols as an aid in identification of
peroxidized natural triacylglycerols by reverse-phase high-performance liquid
chromatography with electrospray mass spectrometry.
AB - Selected elution factors were determined for model oxotriacylglycerols as an aid
in identification of the peroxidation products of natural triacylglycerols by
reverse-phase high-performance liquid chromatography (HPLC) with electrospray
mass spectrometry (LC/ES/MS). For this purpose synthetic triacylglycerols of
known structure were converted to hydroperoxides, hydroxides, epoxides, and core
aldehydes and their dinitrophenylhydrazones by published procedures. The
oxotriacylglycerols were resolved by normal-phase thin-layer chromatography and
reverse-phase HPLC, and the identities of the oxotriacylglycerols confirmed by
LC/ES/MS. Elution factors of oxotriacylglycerols were determined in relation to a
homologous series of saturated triacylglycerols, ranging from 24 to 54 acyl
carbons, and analyzed by reverse-phase HPLC, using a gradient of 20-80%
isopropanol in methanol as eluting solvent and an evaporative light-scattering
detector. It was shown that the elution times varied with the nature of the
functional group and its regiolocation in the triacylglycerol molecule. A total
of 31 incremental elution factors were calculated from chromatography of 33
oxygenated and nonoxygenated triacylglycerol species, ranging in carbon number
from 36 to 54 and in double-bond number from 0 to 6.
PMID- 9397409
TI - Effects of high pressure and temperature on micelle formation of sodium
deoxycholate and sodium dodecylsulfate.
PMID- 9397408
TI - Evaluating acid and base catalysts in the methylation of milk and rumen fatty
acids with special emphasis on conjugated dienes and total trans fatty acids.
AB - Milk analysis is receiving increased attention. Milk contains conjugated
octadecadienoic acids (18:2) purported to be anticarcinogenic, low levels of
essential fatty acids, and trans fatty acids that increase when essential fatty
acids are increased in dairy rations. Milk and rumen fatty acid methyl esters
(FAME) were prepared using several acid- (HCl, BF3, acetyl chloride, H2SO4) or
base-catalysts (NaOCH3, tetramethylguanidine, diazomethane), or combinations
thereof. All acid-catalyzed procedures resulted in decreased cis/trans (delta
9c,11t-18:2) and increased trans/trans (delta 9t,11t-18:2) conjugated dienes and
the production of allylic methoxy artifacts. The methoxy artifacts were
identified by gas-liquid chromatography (Gl.C)-mass spectroscopy. The base
catalyzed procedures gave no isomerization of conjugated dienes and no methoxy
artifacts, but they did not transesterify N-acyl lipids such as sphingomyelin,
and NaOCH3 did not methylate free fatty acids. In addition, reaction with
tetramethylguanidine coextracted material with hexane that interfered with the
determination of the short-chain FAME by GLC. Acid-catalyzed methylation resulted
in the loss of about 12% total conjugated dienes, 42% recovery of the delta
9c,11t-18:2 isomer, a fourfold increase in delta 9t,11t-18:2, and the formation
of methoxy artifacts, compared with the base-catalyzed reactions. Total milk FAME
showed significant infrared (IR) absorption due to conjugated dienes at 985 and
948 cm-1. The IR determination of total trans content of milk FAME was not fully
satisfactory because the 966 cm-1 trans band overlapped with the conjugated diene
bands. IR accuracy was limited by the fact that the absorptivity of methyl
elaidate, used as calibration standard, was different from those of the other
minor trans fatty acids (e.g., dienes) found in milk. In addition, acid-catalyzed
reactions produced interfering material that absorbed extensively in the trans IR
region. No single method or combination of methods could adequately prepare FAME
from all lipid classes in milk or rumen lipids, and not affect the conjugated
dienes. The best compromise for milk fatty acids was obtained with NaOCH3
followed by HCl or BF3, or diazomethane followed by NaOCH3, being aware that
sphingomyelins are ignored. For rumen samples, the best method was diazomethane
followed by NaOCH3.
PMID- 9397410
TI - Isomers in commercial samples of conjugated linoleic acid.
PMID- 9397411
TI - Determinants of protein turnover in health and disease.
AB - Protein synthesis, protein degradation, and amino acid oxidation are tightly
regulated to preserve lean body mass in healthy individuals. An adaptative
response to a reduction in dietary protein in normal adults is decreased branched
chain amino acid oxidation which increases the availability of amino acids. In
nephrosis, reduced branched-chain amino acid oxidation decreases amino acid
requirements and helps to compensate for urinary protein loss. Conversely, uremia
and other catabolic diseases are associated with muscle wasting resulting from
activation of the ubiquitin-proteasome proteolytic pathway and branched-chain
ketoacid dehydrogenase, the rate-limiting enzyme for branched-chain amino acid
catabolism. By understanding the processes responsible for muscle wasting in
catabolic states, therapeutic interventions may be designed to improve protein
balance.
PMID- 9397412
TI - Metabolic acidosis and protein catabolism: mechanisms and clinical implications.
AB - Metabolic acidosis increases protein degradation resulting in muscle wasting and
a negative nitrogen balance. The branched-chain amino acids serve as useful
markers of these changes and their catabolism is increased in acidosis,
particularly for the spontaneous acidosis associated with renal failure. As a
result, the neutral nitrogen balance is compromised and malnutrition results.
Glucocorticoids mediate these changes through the recently discovered ATP
dependent ubiquitin-proteasome pathway. Therapy necessitates correction of the
underlying acidosis either through adjustment of the alkalinity of the dialysate
for the patient on dialysis or through dietary protein restriction and sodium
bicarbonate supplements for the predialysis patient.
PMID- 9397413
TI - The impact of malnutrition on kidney function.
AB - Malnutrition is the most common cause of mortality in the world. It affects
underdeveloped as well as industrialized societies, in the latter demonstrating a
prevalence in hospitalized patients of between 30 and 50%. Although the
prevalence has decreased in recent studies, the problem is still significant
among a selected group of patients. The clinical manifestations of malnutrition
may be evident on physical examination but alterations in renal function may not
show up at the initial exam. Clinical and experimental models of protein-calorie
malnutrition have confirmed significant alterations in renal hemodynamics, renal
concentration capacity, and renal acid excretion. Children and adults with
malnutrition have been shown to have a decreased glomerular filtration rate and
renal plasma flow (RPF), as well as a lowered capacity to concentrate the urine
and excrete an acid load. Moreover, clinical and experimental models of protein
calorie malnutrition have unravelled the roles of the renin-angiotensin system,
renal prostaglandins, and urea production in the renal function changes
associated with malnutrition. We have reviewed the most pertinent and recent
studies from our and other laboratories which have improved our understanding of
renal functional alterations in malnutrition.
PMID- 9397414
TI - Growth factors: future prospects in renal failure.
AB - Chronic renal failure is associated with an abnormal growth hormone/insulin-like
growth factor-1 axis. In addition, nutritional status strongly regulates this
axis. Because these hormones are involved in growth in children and maintenance
of a normal body composition in adults, experimental and clinical studies have
tested the metabolic effects of these recombinant growth factors. Various
conditions in which these growth factors have been administered have been
reported, such as the recovery of acute renal failure, protein metabolism in
chronic renal failure, growth improvement in uremic children, the increase in
renal function in nondialyzed uremic patients, and the potential treatment of
malnutrition in adult maintenance dialysis patients.
PMID- 9397415
TI - Impact of chronic renal failure on nitrogen metabolism.
AB - Evidence indicates that both nephrotic and nonnephrotic chronic renal failure
(CRF) patients can activate normal compensatory responses when dietary protein
intake is restricted and that their protein and energy requirements are similar
to normal subjects. When properly implemented, low-protein diets are safe and the
benefits include the amelioration of uremic symptoms and some of their metabolic
complications and possibly a reduction in the rate of progression of renal
failure. To ensure dietary adequacy and compliance, patients should be monitored
when treated with low-protein diets. Recent evidence that the protein intake of
patients with progressive CRF declines when they consume unrestricted diets
should not be considered as an argument against the use of low-protein diets.
Rather, it is a persuasive argument in favor of restricting dietary protein
intake to minimize the complications of renal failure.
PMID- 9397416
TI - Derangements in protein metabolism induced by type I diabetes mellitus.
AB - In poorly controlled diabetics, the whole-body protein flux is increased by 20
30% in comparison to well-controlled type I diabetes (IDDM) and normal subjects.
Intensive insulin administration completely reverses these abnormalities. In
poorly controlled IDDM, the primary effect of insulin administration is to reduce
the increased protein catabolic rate by suppressing the accelerated rate of
protein breakdown. Studies in humans have demonstrated that the increased rate of
protein synthesis observed in these patients is the consequence of elevated
plasma amino acid levels. When IDDM subjects develop renal complications, a
protein-restricted diet may be recommended to preserve the remnant kidney
function. However, it has been demonstrated that in IDDM patients, metabolic
adaptation to protein restriction is incomplete because suppression of endogenous
proteolysis is impaired. Since this component of protein metabolism is very
sensitive to insulin action, maintaining strict metabolic control during the
protein restriction regimen has been suggested. The major studies on the effects
of amino acid and insulin on protein metabolism in patients with diabetes
mellitus are reviewed.
PMID- 9397417
TI - Protein metabolism in acute renal failure.
AB - The hallmark of metabolic alterations in acute renal failure (ARF) is accelerated
protein breakdown which, unfortunately, cannot be suppressed effectively by
provision of exogenous nutritional substrates. Causes of excessive protein
catabolism are manifold and present a combination of unspecific mechanisms
induced by the acute disease process and underlying illness or associated
complications, effects induced by the acute loss of renal function and, finally,
the type and intensity of renal replacement therapy. Specific uremic toxic
effects, insulin resistance, hormonal derangements, metabolic acidosis,
circulating proteases, inflammatory mediators, and dialysis-related losses of
nutritional substrates all contribute to the activation of protein degradation.
Metabolism in ARF is also affected by an impairment of the multiple metabolic and
endocrine functions of the kidney. Various amino acids are synthesized or
interconverted by the kidneys and may become conditionally indispensable. The
kidney is also an important organ in the degradation of peptides, such as peptide
hormones. As a consequence of these metabolic aberrations, imbalances in amino
acid pools in plasma and in the intracellular compartment occur in ARF and
elimination and utilization of infused amino acids is altered. Protein or amino
acids requirements are influenced more by the nature of the illness causing ARF,
by the extent of hypercatabolism, by associated complications, and by the type
and frequency of renal replacement therapy than by renal dysfunction per se. In
noncatabolic patients, an intake of 1 g/kg body weight per day may be sufficient,
while in critically ill hypercatabolic patients undergoing continuous renal
replacement therapy, 1.5 g amino acids/kg body weight per day should be provided
to minimize nitrogen losses. For the future, we need to identify safe methods to
control the accelerated catabolism in order to improve the efficiency of
nutritional interventions in patients with ARF.
PMID- 9397418
TI - Albumin turnover in renal disease.
AB - Hypoalbuminemia is found in patients both with the nephrotic syndrome and with
end-stage renal disease (ESRD) treated either with continuous ambulatory
peritoneal dialysis (CAPD) or hemodialysis. In nephrotic patients the primary
causes of hypoalbuminemia are urinary albumin losses, an inappropriate increase
in the fractional catabolic rate (FCR) of albumin and an insufficient increase in
the rate of albumin synthesis to replace these losses. Nevertheless, the albumin
synthetic rate is increased significantly. In patients on CAPD, albumin losses
into the urine and across the peritoneal membrane contribute significantly to
hypoalbuminemia. In contrast to nephrotic patients, albumin FCR decreases as
serum albumin falls and serum albumin levels are significantly greater than in
nephrotic patients with the same external losses of albumin. CAPD patients, like
nephrotic patients with normal renal function, can increase albumin synthesis to
replace losses. Thus ESRD does not directly suppress albumin synthesis. In
contrast, hypoalbuminemia in hemodialysis patients results from reduced albumin
synthesis. The cause of decreased albumin synthesis is a combination of response
to inflammation (acute-phase response) and, to a lesser extent, inadequate
nutrition. There is no evidence that shifts of albumin to the extravascular space
or that dilution of the plasma by volume expansion play any role in causing
hypoalbuminemia in ESRD or nephrotic patients.
PMID- 9397419
TI - Effects of a supplemented very low protein diet in predialysis patients on the
serum albumin level, proteinuria, and subsequent survival on dialysis.
AB - A very low protein diet (0.3 g/kg ideal body weight) supplemented with essential
amino acids (or ketoanalogues) is seldom employed at present in chronic renal
failure for fear of inducing protein deficiency, especially in patients who also
have the nephrotic syndrome. Nevertheless, we have used this dietary regimen in
predialysis patients for a number of years. We have shown that when these
patients reach the end stage, they rarely exhibit hypoalbuminemia, in contrast to
the reported 25-50% hypoalbuminemia at the onset of dialysis nationwide.
Furthermore, their survival for the first 2 years on dialysis is much improved,
in comparison with the national experience, adjusted for age, sex, and cause of
renal disease. When nephrotic patients are given this regimen, they exhibit some
improvement in parameters of the nephrotic state, but nevertheless progress to
dialysis, provided their initial glomerular filtration rate (GFR) is < 30 ml/min.
However, if their initial GFR is > 30 ml/min, they may show gradual but complete
remission of the nephrotic syndrome, even when the underlying disease is diabetic
nephropathy or focal segmental glomerulosclerosis. We conclude that this dietary
regimen is not only safe in patients with renal failure, with or without the
nephrotic syndrome, but may be of substantial benefit. The mechanism remains to
be explained.
PMID- 9397420
TI - Nutritional status and survival in end-stage renal disease patients.
AB - Several reports have emphasized that putative laboratory surrogates of nutrition,
such as serum albumin, creatinine, and cholesterol concentrations are
statistically more powerful independent predictors of odds risk of death for
dialysis patients than is the delivered dose of dialysis. In view of the relative
simplicity with which these blood tests can be obtained, their lack of expense,
and simplicity in interpretation, the dialysis community has greatly escalated
their importance as performance measures for the processes of patient care,
arguably without full consideration of their meaning. If malnutrition in dialysis
patients is a powerful predictor of death risk, and is amenable to corrective
interventions that result in a reduction in the odds risk of death, then the zeal
with which these laboratory tests have been embraced is appropriate. However, the
assumption that a statistical correlation between laboratory surrogates of
malnutrition, or other measures of inadequate nutrition, such as body mass index
or a subjective global assessment, indicate a direct causal relationship between
nutritional intake, nutritional status, and outcome may be incorrect. Such
apparent linkages may be a consequence of the statistical model selected alone,
i.e., another unappreciated medical condition may be the proximate cause of death
in addition to resulting in malnutrition. The mechanism(s) by which malnutrition
may adversely impact the survival of end-stage renal disease (ESRD) patients is
unclear. The impact of milder degrees of malnutrition on patient survival, their
proximate effect on survival, and the reality of their independent effect on
patient survival are also inadequately defined. Clearly, there is a statistical
link between the putative laboratory surrogates of nutrition and patient
survival. Regardless of the pathobiology of such a causal link, it is valid to
enquire if an intervention that results in a positive change in nutritional
parameters enhances patient survival. These issues surrounding nutritional status
and survival in patients with ESRD are reviewed here in detail. The conclusion of
this critique is that additional studies are needed to determine if malnutrition
is truly an independent and responsive predictor of outcome for ESRD patients.
PMID- 9397421
TI - Strategies for nutritional intervention in patients with renal failure.
AB - This review article discusses the evidence documenting the interrelationship
between nutritional status and clinical outcome of the renal patient population.
The limitations of accurately assessing the nutritional status of this patient
group with commonly used indices are detailed. An overview of the history of
nutrition supplementation as an intervention for the malnourished renal patient
reveals that the efficacy of both enteral and parenteral methods has not been
adequately explored to draw any firm conclusions. Based on available data,
recommendations for providing nutrition care for the malnourished patient are
provided. Therapeutics that are currently under investigation as future
interventions for malnutrition are identified.
PMID- 9397422
TI - Factors contributing to catabolism in end-stage renal disease patients.
AB - End-stage renal disease (ESRD) patients, whether they are treated with
hemodialysis or continuous ambulatory peritoneal dialysis, frequently suffer from
protein-energy malnutrition, which is associated with increased morbidity and
mortality. The protein requirements in dialysis patients are increased compared
to those of healthy individuals and nondialyzed patients with chronic renal
failure. The intake of protein and energy is frequently reduced because of the
underlying disease, comorbidity, psychosocial factors, and uremic anorexia
(underdialysis). There are several factors in ESRD patients that may enhance
protein catabolism and increase protein requirements, such as low energy intake,
amino acid abnormalities, metabolic acidosis, endocrine abnormalities (insulin
resistance, hyperglucagonemia, hyperparathyroidism, insensitivity to growth
hormone and insulin-like growth factor-1, cardiac failure, infection and
inflammation, anemia, and physical inactivity. The dialytic procedures per se may
enhance protein catabolism due to dialytic losses of protein and amino acids and,
in hemodialysis, an inflammatory response to blood-dialyzer interaction. The
relative importance of the various factors which cause anorexia and stimulate
protein catabolism is still not well understood.
PMID- 9397423
TI - Motivational properties of oxytocin in the conditioned place preference paradigm.
AB - We hypothesized that oxytocin might have intrinsic reinforcing properties and
studied it using a conditioned place preference. Three studies examining
motivational properties of oxytocin in nonpreferred, preferred, and balance
designs were performed utilizing two compartment apparatus. On alternate days,
compartments were paired with subcutaneously injected oxytocin (6 mg/kg) or
saline, and animal pre- and post-conditioning place preference was compared.
Whereas in animals paired with saline there was a shift to a lack of preference,
oxytocin-treated animals reversed their preference, spending more time in a
previously unpreferred, compartment. In preferred compartment design, oxytocin
treated animals further increased their preference, whereas saline-treated
animals decreased their preference toward a nonpreference for either compartment.
Our results demonstrate that oxytocin produces a reliable and robust preference
for the environment with which it is repeatedly associated, and has rewarding or
potentially anti-aversive properties. Future studies are needed to distinguish
among these possibilities.
PMID- 9397424
TI - Effects of the 5-HT3 antagonist, ondansetron, on the behavioral and physiological
effects of pentagastrin in patients with panic disorder and social phobia.
AB - Pentagastrin, a cholecystokinin (CCK) agonist, produces anxiety and panic in
patients with panic disorder and social phobia. Preclinical data suggests that
pentagastrin-induced anxiogenesis may be mediated via 5-HT3 receptors. In the
present study, 14 patients with panic disorder or social phobia underwent
pharmacological challenge in three conditions: (1) pretreatment with saline
followed by pentagastrin infusion; (2) pretreatment with ondansetron followed by
pentagastrin infusion; and (3) pretreatment with saline followed by saline
infusion. As expected, pentagastrin administration led to increased anxiety,
physical symptoms of panic attacks, pulse, plasma adrenocorticotropic hormone
(ACTH), and cortisol. Pentagastrin's behavioral effects were not blocked by
ondansetron, and in fact, tended to be exaggerated. Ondansetron pretreatment did
not alter the pentagastrin-induced cortisol increase but significantly prolonged
the pentagastrin-induced increase in ACTH. These findings suggest that
pentagastrin's behavioral effects are not mediated by 5HT3 receptors. Mechanisms
by which peripherally administered CCK agonists lead to anxiety remain to be
elucidated.
PMID- 9397425
TI - Patients with premenstrual syndrome have reduced sensitivity to midazolam
compared to control subjects.
AB - Premenstrual syndrome (PMS) depends on gonadal hormones produced by the corpus
luteum. Given the facilitory actions on GABAergic inhibitory neurotransmission
exerted by certain progesterone metabolites, further studies on the GABAA
receptor system in premenstrual syndrome are warranted. This study evaluated the
benzodiazepine sensitivity in PMS patients and control subjects, using saccadic
eye velocity (SEV) and visual analogue ratings of sedation as dependent measures.
PMS patients displayed a significantly reduced SEV responsiveness to
benzodiazepines compared to control subjects in the follicular phase, whereas
there was no difference between groups in the luteal phase. In the luteal phase,
the sedation response to benzodiazepines was significantly reduced in PMS
patients compared to control subjects. There was also an influence of PMS symptom
severity on these measures, as high-severity PMS patients displayed blunted SEV
and sedation responses to benzodiazepines compared to low-severity patients.
These results indicate that PMS patients have a reduced functional sensitivity at
the GABAA/benzodiazepine receptor complex throughout the menstrual cycle.
PMID- 9397426
TI - Effects of divalproex sodium on 5-HT1A receptor function in healthy human males:
hypothermic, hormonal, and behavioral responses to ipsapirone.
AB - Hypothermic and hormonal responses to a challenge with a selective 5-HT1A
receptor agonist ipsapirone are considered to provide an index of 5-HT1A receptor
function in humans. To examine the effects of divalproex sodium (DVP) on 5-HT1A
receptor function in humans, we measured the hypothermic, adrenocorticotropic
hormone (ACTH) cortisol, and behavioral responses to ipsapirone in 10 healthy
male volunteers. After obtaining a blood sample for baseline hormone levels and
measuring body temperature, a single dose of 0.3 mg/kg of ipsapirone was given
orally to all the subjects and further bloods and temperature reading were
obtained at regular intervals for three hours. The ipsapirone challenge tests
were repeated after the subjects had been treated with DVP (1000 mg/day) for one
week. The results showed that the hypothermia induced by ipsapirone was
significantly attenuated by the DVP treatment, whereas the ACTH/cortisol release
and the behavioral responses following ipsapirone challenges were not altered.
Our findings suggest that DVP may enhance 5-HT neurotransmission in humans via a
subsensitization of 5-HT1A autoreceptors but does not appear to affect
postsynaptic 5-HT1A receptors.
PMID- 9397427
TI - Intravenous dextroamphetamine and brain glucose metabolism.
AB - This study reports the effects of intravenous dextroamphetamine on cerebral
glucose metabolism assayed by positron emission tomography (PET) and [fluorine
18]fluorodeoxyglucose (FDG) in 13 healthy adults during the performance of a
continuous visual attention task. Two FDG PET scans were performed within a
single experimental session. The first scan was preceded by the injection of
placebo and the second scan by the injection of 0.15 mg/kg dextroamphetamine.
Global and normalized regional glucose metabolic rates (rCMRglc) were examined as
a function of pharmacological challenge and subjective experience. Subcortical,
limbic, frontal, and cerebellar rCMRglc significantly increased after
dextroamphetamine, whereas rCMRglc of the temporal cortex significantly
decreased. Physiological and self-report measures of subjective states showed the
expected alterations. These rCMRglc changes reflect both the direct
pharmacological effect of dextroamphetamine on monoaminergic neurotransmitter
systems as well as enhancement of the activation of the neural network mediating
the performance of the continuous attention task.
PMID- 9397428
TI - Decreasing striatal 6-FDOPA uptake with increasing duration of cocaine
withdrawal.
AB - It has been hypothesized that a decrease in dopaminergic presynaptic activity
during abstinence or withdrawal is related to relapse in cocaine-dependent
subjects (Dackis and Gold 1985; Markou and Koob 1991). This study measured
striatal 6-fluorodopa (6-FDOPA) uptake, an index of dopaminergic presynaptic
activity, using positron emission tomography (PET) in 11 drug-free cocaine
addicts compared to eight normal subjects. Middle abstinence cocaine addicts (n =
5, off cocaine 11-30 days) had significantly lower striatal 6-FDOPA uptake
compared to normal controls or early abstinence cocaine addicts (n = 6, off
cocaine 1-10 days). The cocaine-dependent subjects (n = 11) showed a significant
negative correlation between days off cocaine and striatal 6-FDOPA uptake. The
results suggest that during abstinence from cocaine there is a delayed decrease
in dopamine terminal activity in the striatum.
PMID- 9397429
TI - The rise and fall of HMOs.
PMID- 9397430
TI - The clinical utility of duplicate readings for musculoskeletal radiographs.
AB - It is a common practice in many hospitals to have all skeletal radiographs read
by a second physician, usually a radiologist, as well as by the treating
physician. A two-part study was performed in order to examine the cost and
clinical benefit of this practice for plain films ordered by orthopedists. In the
first part of this study, the attending orthopedic surgeons were surveyed about
the clinical usefulness and effect on patient care of 1000 radiologic reports
from plain films ordered on orthopedic patients. In the second part, the charts
of 272 patients who had 704 radiographs were reviewed with the goal of
identifying any discrepancies between the orthopedic interpretation and the
radiologic reading. Thirty-eight reports were discarded because they were not
reports of plain skeletal films. One hundred twenty-nine of the remaining 962
radiologic reports were never read by the attending orthopedist. The average time
between the taking of the film and an orthopedic attending reading the printed
report was 6.1 days. Three radiology reports contained findings that were
incorrect. Only one report contained findings that the orthopedist was unaware,
and one report may have led to an alteration in treatment. No reports resulted in
an unplanned trip to the operating room or a patient being called back to the
clinic. Of the 272 chart reviews (704 reports), 70 had no orthopedic
interpretation recorded and 94 had no radiologic report in the chart. Twelve
discrepancies were noted in the cases that had both reports. Four fracture
displacements were identified by orthopedists, but not on the written radiology
report; three of these required a return to the operating room. Four instances of
hardware displacement or breakage were noted by orthopedists, but not commented
on by the radiologists. Three incidental injuries (two fractures and an
acromioclavicular injury) were noted on printed reports of films taken for other
reasons, but not commented on by the orthopedist, and not treated. A dorsal
bunion was noted on one film by the orthopedist, but not by the radiologist. From
this study, one can conclude that the benefit of routine duplicate radiograph
interpretation by a second physician does not justify its cost.
PMID- 9397431
TI - Clinical results of the modular porous-coated anatomic (PCA) total knee
arthroplasty with cement: a 5-year prospective study.
AB - Our study examines the clinical, radiographic, and patient satisfaction outcome
of the cemented Modular Porous-Coated Anatomic (PCA) total knee arthroplasty with
a minimum 5-year follow up. All data were gathered prospectively and
consecutively. Patient satisfaction was assessed with a self-administered survey.
Statistical analysis examined the effect of 17 patient factors, 19 surgical
factors, and postoperative continuous passive motion use on range of motion (ROM)
and HSS scores at 2 years. Seventy-eight Modular PCA arthroplasties performed by
9 orthopedic surgeons on 71 patients between January 1988 and November 1989 are
reported in this study. Preoperative HSS scores averaged 51.2 and improved to an
average of 89 at 1 and 2 years, and 86 at 5 years after surgery (90% good or
excellent). ROM changed after surgery through improvement in preoperative knee
flexion contracture, but not in increased knee flexion. One patient underwent
reoperation for patellar instability, and one patient's arthroplasty was revised
at 53 months for late instability. The total reoperation rate for any reason was
7.7%. Zonal analysis for progressive radiolucency at the bone-cement interface
showed increasing frequency of narrow (< 1 mm) radiolucencies concentrated on the
anterior and medial aspect of the tibial tray. Ninety-eight percent of patients
responded to an outcome questionnaire, and 96% rated themselves improved. The
Kaplan-Meier probability of an implant surviving without loosening at 5 years was
100%. The Modular PCA TKA has a low incidence of patellofemoral problems, is
clinically successful, and results are stable at a minimum 5-year follow-up
examination.
PMID- 9397432
TI - Freeze-dried cortical allograft in posterior spinal arthrodesis: use with
segmental instrumentation for idiopathic adolescent scoliosis.
AB - Many surgeons use cancellous or corticocancellous allogeneic bone grafts to
augment spinal arthrodeses. The efficacy of onlay freeze-dried cortical
allografts for posterior spinal fusions has been questioned in the past. In this
report, freeze-dried, crushed cortical bone allograft was used as the sole fusion
material in 32 consecutive posterior spinal fusions for idiopathic adolescent
scoliosis. Absence of clinical or radiographic pseudarthrosis in all patients at
an average follow up of 34 months suggests that freeze-dried, crushed cortical
bone allograft is a suitable material for augmentation of the fusion mass during
posterior spinal fusion with segmental instrumentation.
PMID- 9397433
TI - Repair of soft tissue to bone using a biodegradable suture anchor.
AB - The medial collateral ligaments of 18 New Zealand rabbits were surgically
detached from bone. In one knee, the ligament was repaired using a biodegradable
suture anchor composed of a co-polymer of lactic and glycolic acid. The
contralateral medial collateral ligament was not repaired. Animals were
sacrificed at 4, 8, and 12 weeks after the operation, and the knee that had the
ligament repair was compared with the contralateral control knee. All knees were
tested manually tested for stability to valgus stress and then prepared for
histologic examination. Medial collateral ligaments repaired using the
biodegradable suture anchor demonstrated stability to valgus stress and anatomic
healing at the bone-tendon junction. Resorption of the implant was virtually
complete by 12 weeks. All specimens demonstrated less inflammatory reaction to
the suture anchor than to the attached Vicryl suture. This contrasts with the
control group, which was grossly unstable and demonstrated scarring in this
nonanatomic position. These results demonstrate efficacy of this particular
material of biodegradable implant and justify further investigative efforts.
PMID- 9397434
TI - Limited range of motion after total knee arthroplasty: etiology, treatment, and
prognosis.
PMID- 9397435
TI - Percutaneous pinning of proximal humerus fractures: a biomechanical study.
AB - Mechanical testing of two-part surgical neck fractures fixed with four different
pin configurations was performed. Ten fresh, frozen, unembalmed humeri stripped
of all soft tissues were used; the surgical neck was osteotomized perpendicular
to the humerus long axis. Terminally threaded 2.5-mm AO pins were used to fix the
fracture. Humeri then were tested in both torsion and bending on a custom-made
jig using Instron 1331 to assess the rigidity of pinning constructs. In torsion,
two lateral pin construct was significantly less rigid than all other pin
configurations. The addition of an anterior pin to two lateral pins did not
increase bending rigidity, but significantly increased torsional stiffness. The
addition of two bicortical tuberosity pins or two bicortical tuberosity pins and
one anterior pin to two lateral pins significantly increased rotational and
bending rigidity. Results confirm clinical data, and the authors conclude that
multiplanar pins are needed to augment torsional stiffness, and that the addition
of two bicortical tuberosity pins enhances bending rigidity.
PMID- 9397436
TI - Treatment of isolated fractures of the ulnar shaft.
PMID- 9397437
TI - Intraosseous gout: an "aggressive" solitary lesion.
PMID- 9397438
TI - Pseudoaneurysm following femoral fracture.
AB - If the physician is aware of this diagnosis and maintains an appropriate level of
suspicion and low threshold to commence duplex evaluation. The potential
morbidity of a fracture-induced traumatic pseudoaneurysm can be minimized.
PMID- 9397439
TI - Removal of a broken solid-core intramedullary femoral nail using both antegrade
and retrograde starting points.
PMID- 9397440
TI - Traumatic rupture of the transverse carpal ligament associated with compartment
syndrome of the hand.
PMID- 9397441
TI - Radiologic case study. Pes anserine bursitis.
PMID- 9397442
TI - On patient compliance with medication doses.
PMID- 9397443
TI - A pediatrician's view. A goal-oriented approach to managing children with special
healthcare needs.
PMID- 9397444
TI - Profiling the health service needs of populations: description and uses of the
NACHRI Classification of Congenital and Chronic Health Conditions.
PMID- 9397445
TI - Pediatricians partnering with states to assure that children with special health
needs are provided appropriate services: the Vermont experience with managed
Medicaid.
PMID- 9397446
TI - Managed care for children with special healthcare needs: Michigan's approach.
PMID- 9397447
TI - Paradigms of care for children with special healthcare needs.
PMID- 9397448
TI - Community resources for children with special healthcare needs.
PMID- 9397449
TI - The care of children with chronic illness in primary care practice: implications
for the pediatric generalist.
PMID- 9397450
TI - Bronchioloalveolar carcinoma: clinical, histopathologic, and radiologic findings.
AB - Bronchioloalveolar carcinoma is characterized pathologically by a pulmonary
neoplasm showing lepidic growth. More than half of all patients with
bronchioloalveolar carcinoma are asymptomatic. The most frequent symptoms and
signs are cough, sputum, shortness of breath, weight loss, hemoptysis, and fever.
Bronchorrhea is unusual and a late manifestation. Nonmucinous bronchioloalveolar
carcinoma tends to be more localized and has a lower frequency of bronchogenic
spread than mucinous bronchioloalveolar carcinoma. Bronchioloalveolar carcinoma
appears radiographically as a single nodule, segmental or lobar consolidation, or
diffuse nodules. At computed tomography (CT), the single nodular form appears as
a peripheral nodule or localized ground-glass attenuation with or without
consolidation, frequently associated with bubblelike areas of low attenuation and
open bronchus signs. The lobar consolidative form may demonstrate the CT
angiogram and open bronchus signs. The diffuse nodular form appears as multiple
nodules or areas of ground-glass attenuation or consolidation. The single nodular
form has a better prognosis than the others but may show false-negative results
for malignancy at 2-(fluorine-18) fluoro-2-deoxy-D-glucose positron emission
tomography.
PMID- 9397451
TI - Pulmonary complications after bone marrow transplantation: high-resolution CT and
pathologic findings.
AB - A wide variety of pulmonary complications occur in bone marrow transplant (BMT)
recipients and are a major cause of morbidity and death. High-resolution computed
tomography (CT) is excellent in the detection of pulmonary abnormalities, but
these findings are generally nonspecific. However, the different complications,
which reflect the immunologic status of the patients, occur in three phases. This
pattern can be used to interpret CT scans. The neutropenic phase (up to 3 weeks
after BMT) is characterized by fungal infections, notably angioinvasive
aspergillosis, alveolar hemorrhage, pulmonary edema, and drug reactions. At CT,
angioinvasive aspergillosis appears as a nodule surrounded by a halo of ground
glass attenuation; alveolar hemorrhage and drug reactions, as bilateral areas of
ground-glass attenuation or consolidation; and pulmonary edema, as prominent
pulmonary vessels, interlobar septal thickening, ground-glass attenuation, and
pleural effusions. The second phase (3 weeks to 100 days after BMT) is dominated
by cytomegalovirus pneumonia, which appears as multiple small nodules with
associated areas of consolidation or ground-glass attenuation, and Pneumocystis
carinii pneumonia, which appears predominantly as ground-glass attenuation. The
late phase (more than 100 days after BMT) is characterized by bronchiolitis
obliterans, bronchiolitis obliterans with organizing pneumonia (BOOP), and
chronic graft-versus-host disease. In bronchiolitis obliterans, CT reveals
bronchial dilatation and a mosaic pattern of attenuation; in BOOP, CT findings
usually consist of patchy consolidation or ground-glass attenuation. If CT
findings are considered in relation to the time elapsed after BMT, diagnostic
options can be narrowed sufficiently to enable accurate diagnosis.
PMID- 9397452
TI - Imaging and pathologic features of myelolipoma.
AB - Myelolipoma is a benign tumor consisting of mature fat interspersed with
hematopoietic elements resembling bone marrow. Imaging findings in a large series
of pathologically proved cases of myelolipoma were correlated with the pathologic
and histologic features of the lesions. Myelolipoma manifests in four distinct
clinicopathologic patterns: isolated adrenal myelolipoma, adrenal myelolipoma
with hemorrhage, extraadrenal myelolipoma, and myelolipoma associated with other
adrenal disease. Myelolipoma is difficult or impossible to detect at plain
radiography unless the lesion is large and predominantly fatty. At ultrasound,
myelolipoma often has heterogeneous echogenicity due to its typically nonuniform
architecture. Computed tomography (CT) frequently demonstrates large amounts of
fat with areas of interspersed higher-attenuation tissue. At magnetic resonance
imaging, predominantly fatty areas usually have increased signal intensity on T1
weighted images and moderate hyperintensity complicated by the presence of
marrowlike elements in the corresponding regions on T2-weighted images. The
imaging appearance of myelolipoma is altered by the presence of hemorrhage. In
such cases, CT is the most accurate method for evaluation. Knowledge of the
imaging characteristics of myelolipoma usually allows presumptive diagnosis,
although percutaneous needle biopsy may be needed to confirm the diagnosis in
cases of extraadrenal myelolipoma. Surgical excision is unnecessary unless the
diagnosis is unclear or the lesion is symptomatic. Asymptomatic, nonhemorrhagic
myelolipomas do not require therapy.
PMID- 9397453
TI - In vitro and in vivo MR imaging of hyaline cartilage: zonal anatomy, imaging
pitfalls, and pathologic conditions.
AB - Hyaline cartilage plays an essential role in the maintenance of normal synovial
joint function by reducing friction and distributing loads. Histologic analysis
of hyaline cartilage reveals zonal variation in cellular morphology, proteoglycan
concentration, and collagen fiber size and orientation. High-resolution magnetic
resonance (MR) imaging reveals an analogous laminar anatomy that is often visible
on clinical images obtained with proper attention to technique. In vitro and in
vivo pulse sequences show three distinct laminae: a hypointense superficial
lamina, a hyperintense intermediate lamina, and a heterogeneous deep lamina that
consists of alternating hyperintense and hypointense bands perpendicular to the
subchondral bone. Imaging pitfalls include magic angle effects, truncation
artifact, partial volume effect, regional anatomic variation, chemical shift, and
magnetic susceptibility effects. Pathologic conditions that affect articular
cartilage include chondromalacia patellae, osteoarthritis, and localized
traumatic lesions. Although detection of early cartilage disease remains elusive,
MR imaging can demonstrate intermediate and advanced lesions.
PMID- 9397454
TI - MR arthrography of the shoulder: variants and pitfalls.
AB - Use of magnetic resonance arthrography to evaluate pathologic conditions of the
shoulder is becoming widespread. However, normal anatomy or anatomic variations
can cause interpretive errors. The most common variations occur at the origins of
the glenohumeral ligaments (GHLs) and the insertion of the joint capsule. Among
the GHL variants, common origin of the superior and middle ligaments is the most
frequent followed by thinning, thickening, or absence of a ligament, most often
the middle one. Absence or thinning of one ligament is sometimes associated with
thickening of another or changes in the size and shape of the anterior capsular
recesses. Common normal variants of the labrum include foramen sublabrum
(detachment of the anterosuperior labrum from the glenoid margin) and the Buford
complex (absence of the anterosuperior labrum in association with a thick middle
GHL). Pitfalls related to the arthrographic technique include (a) visualization
of a deep sulcus between the insertion of the long head of the biceps tendon and
the superior labrum and (b) an apparent type III capsular insertion due to
overdistention of the capsule by injected contrast material.
PMID- 9397455
TI - Characterization of atherosclerotic plaques at the carotid bifurcation:
correlation of high-resolution MR imaging with histologic analysis--preliminary
study.
AB - The clinical symptoms and morbidity that result from carotid artery disease, the
primary cause of stroke, are mainly due to plaque ulceration, thrombosis,
intraplaque hemorrhage, and thinned fibrous caps. The contents of atherosclerotic
plaques of the carotid artery can be determined with in vivo high-resolution
magnetic resonance imaging with flow suppression. Eight patients scheduled to
undergo endarterectomy and four healthy volunteers were imaged with a 1.5-T
imager and custom-made carotid phased-array coils. T1-weighted spin-echo images
and cardiac-gated proton-density--weighted fast spin-echo images were acquired.
In vivo imaging findings as determined by three radiologists were correlated with
ex vivo imaging and histologic findings. Among the eight plaque specimens,
regions of hemorrhage, calcium, lipid deposits, and fibrous plaques were
identified on T1- and proton-density-weighted images. Calcium and lipid deposits
were detectable on both T1- and proton-density--weighted images. Hemorrhage and
fibrous plaques were better demonstrated on proton-density--weighted images.
PMID- 9397456
TI - MR angiography of the portal venous system: techniques, interpretation, and
clinical applications.
AB - Magnetic resonance (MR) angiography is a noninvasive means of assessing the
portal venous system that has potential advantages over currently used
modalities. Time-of-flight and phase-contrast MR angiography are useful
techniques that differ fundamentally in their means of data acquisition but are
comparable in their ability to demonstrate normal anatomy as well as
abnormalities of the portal venous system. Occasionally, artifacts caused by
respiratory motion, implanted metallic devices or surgical clips, in-plane
saturation, or areas of complex flow are seen at MR angiography of the portal
venous system. However, most artifacts can easily be identified as such and
either remedied or ignored. In addition, the suppression of signal from
surrounding soft tissues may result in poor detection of parenchymal lesions. The
utility of standard projection angiograms and source images can be increased
through the use of intravenously administered contrast material and
postprocessing techniques such as partial-volume maximum intensity projection
reconstructions and shaded surface renderings. In addition to providing
information on portal venous anatomy and portosystemic collateral vessels, MR
angiography of the portal vein has clinical application in portal venous
thrombosis and stenosis, liver transplantation, and the evaluation and planning
of surgical and transjugular intrahepatic portosystemic shunts.
PMID- 9397457
TI - CT appearances of ossicular injuries.
AB - Trauma of the ossicular chain is a frequent complication of temporal bone injury.
Skull trauma from blows to the temporal, parietal, or occipital region (with or
without fracture of the temporal bone) is the main cause of ossicular injury;
other modes of injury are rare. Ossicular injury usually occurs as a dislocation,
of which there are five types: incudostapedial joint separation, incudomalleolar
joint separation, dislocation of the incus, dislocation of the malleoincudal
complex, and stapediovestibular dislocation. Fracture of the malleus, incus, or
stapes is uncommon. High-resolution computed tomography is the method of choice
for evaluation of ossicular trauma. Joint separation and fracture of the stapes
are seen on axial images; coronal images may aid visualization. Both axial and
coronal images are needed for evaluation of a dislocated malleus or incus.
Fracture of the malleus or incus is detected with axial or coronal images;
reformatted images may also be useful.
PMID- 9397458
TI - Imaging features of radiation-induced changes in the abdomen.
AB - After external-beam radiation therapy, radiation-induced changes may be observed
in abdominal and pelvic organs at imaging. In the liver, an area of low
attenuation corresponding to the radiation port (or an area of hyperattenuation
if the underlying liver tissue shows fatty change) can be seen at computed
tomography (CT) performed within 3-6 months after therapy. Later, the liver may
be fibrotic and contracted. In the stomach, small intestine, and colon, wall
thickening and edema are early manifestations. Ulcers may also be observed. Long
term complications include strictures and fistulas. After irradiation of the
kidneys, altered attenuation of the renal parenchyma may be seen at CT. Ureteral
strictures, typically involving the distal ureter, may be observed after pelvic
irradiation. The bladder may be small and contracted with a thickened wall after
radiation exposure. Fistulas between the bladder and other pelvic organs
sometimes occur. Typical musculoskeletal changes include growth abnormalities in
skeletally immature patients, fatty replacement of bone marrow, and radiation
osteitis. Radiation-induced neoplasms are also recognized after therapy.
PMID- 9397459
TI - Hilar cholangiocarcinoma: thin-section spiral CT findings with cholangiographic
correlation.
AB - Hilar cholangiocarcinoma, a highly lethal tumor, is difficult to diagnose with
conventional computed tomography (CT) because of its small size. Spiral CT allows
more effective evaluation of these small lesions and better demonstrates the
status of the hepatic arterial or portal venous circulation. Among 27 patients
with hilar cholangiocarcinoma (infiltrative in 21, exophytic in two, polypoid in
one, diffuse in three), thin-section spiral CT allowed identification of each
tumor as an area of focal wall thickening that obliterated the lumen. Seventeen
of the infiltrative tumors (81%) showed high attenuation. Identification of the
level of biliary obstruction was possible in 63% of the patients (17 of 27). The
level of obstruction was underestimated in six patients and overestimated in
four. Spiral CT is a valuable method for diagnosis of hilar cholangiocarcinoma;
however, spiral CT is less accurate in evaluation of intraductal tumor extent
because of the limited z-axis resolution.
PMID- 9397460
TI - Use of computed radiography in the study of an historic painting.
AB - The authors demonstrate the use of radiography in the investigation of an
historic painting and describe the potential benefits of computed radiography
compared with conventional screen-film radiography. The subject for the
comparison was a 16 x 19-foot oil-on-canvas painting, Scipio Africanus Freeing
Massiva, by Giovanni Battista Tiepolo. Radiographs of the painting were obtained
by using a portable, industrial radiographic unit and both conventional screen
film and photostimulable phosphor plate cassettes. For this investigation,
computed radiography had a number of advantages over screen-film radiography,
largely due to its wider dynamic range and its capabilities for enhancing the
digital images with image processing tools such as magnification, edge
enhancement, colorization, and airbrushing. The ability to electronically combine
images from the large painting into a single composite image file was extremely
valuable, as this technique was much less cumbersome and resulted in much higher
quality composite images than could be achieved with conventional radiography. An
additional advantage of computed radiography includes the capability to easily
archive and transmit these images in a digital format for subsequent review.
PMID- 9397461
TI - Primary central nervous system lymphoma: radiologic-pathologic correlation.
AB - Once an extremely rare neoplasm, primary lymphoma of the central nervous system
(CNS) now ranks behind only meningiomas and low-grade astrocytomas in prevalence.
Understanding of primary CNS lymphoma has increased greatly in recent years as a
result of special immunohistochemical stains. Virtually all primary CNS lymphomas
are composed of B cells. Although a viral cause has been suggested in some cases,
the exact cause of the disease is still under investigation. Primary CNS lymphoma
has a distinct affinity for perivascular extension. Although granular nodules may
be seen at gross pathologic inspection, diffuse microscopic spread is always
present, which accounts for the ability of this tumor to produce distant disease
and local recurrences. The dense cellularity of the tumor and its predilection
for the periventricular region also explains its typical hyperattenuated
appearance on unenhanced computed tomographic scans and hypointensity on T2
weighted magnetic resonance images. Virtually all lesions enhance with contrast
material. Although the overall prognosis for patients with primary CNS lymphoma
remains poor, some advances have been made with radiation therapy and
chemotherapy for this once uniformly fatal disease.
PMID- 9397462
TI - The AAPM/RSNA physics tutorial for residents. X-ray generators.
AB - The x-ray generator delivers the electrical power to energize the x-ray tube and
permits the selection of x-ray energy, x-ray quantity, and exposure time. Major
internal components of the generator include transformers, diodes and rectifier
circuits, filament and stator circuits, timer switches, and kilovolt and
milliampere meters. Single-phase, three-phase, high-frequency, and constant
potential generators produce different voltage waveforms (ripple) and x-ray beam
spectra. Phototimer and automatic brightness control subsystems measure radiation
exposure incident on the image receptor to give instantaneous feedback for
optimal radiographic film densities and fluoroscopic image brightness,
respectively. At the generator control console, the operator sets the tube
voltage, tube current, exposure time, phototimer film density, spot film
acquisition, and fluoroscopic parameters. Selection of generator power and
options depends on the intended clinical use. X-ray tube focal spot size and
power loading capability should be matched to the x-ray generator and clinical
imaging requirements. Single and multiple exposure rating charts as well as anode
and housing thermal characteristic charts indicate power input and dissipation
rates specific to a generator and x-ray tube target and housing.
PMID- 9397463
TI - Value of high-frequency US for preoperative assessment of skin tumors.
AB - The purpose of this study was to evaluate the accuracy of high-frequency
ultrasound (US) in the preoperative assessment of skin tumors. A US scanner with
a 20-MHz probe was used to visualize and evaluate 70 skin lesions (38 clinically
suspected melanomas and 32 suspected basilar cell carcinomas [BCCs]) before
surgical resection. A US morphologic study and a Doppler analysis of vascularity
were performed for each tumor. Of the 70 tumors, 62 were clearly visualized,
including 19 melanomas, 12 nonmalignant nevi, and 31 BCCs. Most lesions were
hypoechoic. In 13 of 19 proved melanomas, the difference between the histologic
and US measurements was equal to or less than 0.2 mm. Vessels were visualized in
melanomas with thicknesses greater than 3 mm. All BCCs were visualized, and in
29% of cases of BCC, tumor size at US was greater than that at clinical
examination. High-frequency, high-resolution US is a simple, reliable,
noninvasive method for accurate preoperative assessment of skin tumor dimensions.
This technique allows surgical planning to be adapted and reexcision to be
avoided. However, its role is limited in the differential diagnosis of malignant
and benign skin lesions.
PMID- 9397464
TI - Improving the interactivity and functionality of Web-based radiology teaching
files with the Java programming language.
AB - Java is a programming language that runs on a "virtual machine" built into World
Wide Web (WWW)-browsing programs on multiple hardware platforms. Web pages were
developed with Java to enable Web-browsing programs to overlay transparent
graphics and text on displayed images so that the user could control the display
of labels and annotations on the images, a key feature not available with
standard Web pages. This feature was extended to include the presentation of
normal radiologic anatomy. Java programming was also used to make Web browsers
compatible with the Digital Imaging and Communications in Medicine (DICOM) file
format. By enhancing the functionality of Web pages, Java technology should
provide greater incentive for using a Web-based approach in the development of
radiology teaching material.
PMID- 9397465
TI - Content preauthoring: preparing medical imaging information for multimedia
authoring and quizzing.
AB - Recent advances in multimedia development software and related hardware have
given professionals and nonprofessionals tremendous power and flexibility to
create multimedia education and training programs. Nevertheless, content
organization remains a key and often neglected component of program development.
Content preauthoring puts findings, diagnoses, differential diagnoses, and other
standard radiologic concepts into a format that fosters logical program layout,
centralized remediation, record keeping, decreased data entry, a variety of user
levels, easy addition of cases, and linkage to a question-generating program. The
goal of content preauthoring is to organize radiologic material into a
hierarchical or spreadsheet-based structure that provides a logical basis for
software design. By separating content design from software authoring, both
processes become more manageable. This approach is applicable to visually
oriented topics that focus on identification. The highly structured, goal
oriented nature of the method makes it particularly suitable for newcomers to
multimedia authoring.
PMID- 9397466
TI - Intracranial neurenteric cysts: a differential diagnosis and review.
PMID- 9397468
TI - US case of the day. Emphysematous pyelonephritis.
PMID- 9397469
TI - Pediatric case of the day. Rubinstein-Taybi syndrome.
PMID- 9397467
TI - General case of the day. Allergic (or hypersensitivity) bronchopulmonary
aspergillosis (ABPA).
PMID- 9397470
TI - Breast imaging case of the day. Invasive papillary carcinoma.
PMID- 9397471
TI - Position, projection, method or view?
PMID- 9397472
TI - Focal film distance in chest radiography.
PMID- 9397473
TI - 3-D imaging: basic concepts for radiologic technologists.
AB - This article describes the physical principles and clinical applications of three
dimensional imaging in diagnostic radiology. It explores the history of 3-D
imaging in medicine and reviews basic 3-D concepts. In addition, it discusses the
technical aspects of medical 3-D imaging, including data sources, creation of 3-D
space and rendering techniques. The article concludes with an overview of the
clinical applications of 3-D imaging in computed tomography and magnetic
resonance imaging, as well as a commentary on the future of 3-D imaging in
radiology.
PMID- 9397474
TI - The weighted abduction Grashey shoulder method.
AB - The Grashey shoulder position is used to demonstrate damage to the glenohumeral
joint caused by osteoarthritis, sclerosis, tumors, fractures, osteophytes and
cystic changes. However, it can be difficult to assess loss of articular
cartilage using the Grashey shoulder position because little axial load is
applied to the glenohumeral joint. This article describes a method of creating a
loading force across the glenohumeral joint by adding weighted arm abduction
during the Grashey position to demonstrate loss of the articular cartilage. Case
studies and radiographs are presented to discuss the advantages of using the
Grashey position with weighted abduction.
PMID- 9397475
TI - Gonadal protection methods in neonatal chest radiography.
AB - The ideal method of gonadal shielding in the neonatal unit provides the greatest
radiation protection while minimizing the potential for cross-infection. This
study evaluated two common methods of gonadal shielding used during neonatal
chest radiography--direct shielding and shadow shielding. For direct shielding,
lead was placed over the gonadal region of a phantom. For shadow shielding, lead
was placed on top of the crib. Results showed that direct shielding provided a
greater reduction in gonadal dose than shadow shielding.
PMID- 9397476
TI - 1997 Ed. C. Jerman Memorial Lecture. Charting our own course.
PMID- 9397477
TI - A sneak preview of the sonography exam.
PMID- 9397478
TI - Reflections on what makes a good teacher.
PMID- 9397479
TI - Framed!
PMID- 9397480
TI - Radiography of shoulder dislocations.
PMID- 9397481
TI - Hydrocephalus: diagnosis and treatment.
PMID- 9397482
TI - Need to justify a project? Write a proposal.
PMID- 9397483
TI - Experts look at health care in 21st century.
PMID- 9397485
TI - [Pathogenicity of Phylloporia chrysita (Aphyllophorales: Hymenochaetaceae) on
Erythrochiton gymnanthus (Rutaceae)].
AB - The pathogenicity of Phylloporia chrysita (Berk.) Ryv. on Erythrochiton
gymnanthus K. (Rutaceae) was studied in Carara Biological Reserve, seasonal
Pacific of Costa Rica. Growth rate and distribution of basidiocarps were
determined on health and diseased plants. P. chrysita caused 52% growth reduction
on diseased plants. Fungal hyphae were observed on epidermis, parenchyma and
vascular tissue, where they caused cellular breakdown.
PMID- 9397486
TI - Intracellular calcium signalling in striated muscle cells.
AB - Calcium signalling in cells is dependent on a communication between channels/
transporters in two membrane structures: the cell membrane and the membranes of
endo- and sarcoplasmic reticula (ER/SR). In general, cytosolic Ca2+ can be raised
by influx of calcium over the cell membrane through three types of channels:
voltage-, receptor-, and store-operated channels (VOCs, ROCs and SOCs). This
small Ca2+ influx is most often amplified by a Ca2+ release from the ER/SR
through two types of channels: the IP3-receptor and the ryanodine receptor (RyR),
which are huge proteins identified and cloned in recent years. We focus on the
'synaptic' connection between VOCs (L-type calcium channels) and RyRs of the SR
in heart and skeletal muscle. Depolarization of the cell membrane (an action
potential) opens the VOC and moves it in the membrane. One VOC triggers opening
of a certain number of underlying RyRs that together release a quantum of calcium
from the SR, a calcium spark. The communication between the VOC and RyRs is
probably achieved primarily by a mechanical link in skeletal muscle (voltage
controlled calcium release), and by the small inward calcium flux through the VOC
in the heart (calcium-induced calcium release, CICR). Conditions as different as
heart failure, myasthenia gravis, malignant hyperthermia, and skeletal muscle
fatigue, may be examples of deteriorated control or function of the RyR.
PMID- 9397487
TI - Ryanodine binding sites measured in small skeletal muscle biopsies.
AB - A method allowing measurement of the concentration of [3H]ryanodine binding sites
in small skeletal muscle specimens (> 10-20 mg) was developed. A membrane
fraction containing 87% of the [3H]ryanodine binding sites of the tissue and
exhibiting one single KD of 18-27 nmol l-1 in rat and 8 nmol l-1 in human muscles
(p < 0.05) was obtained. Maximum binding to rat EDL and soleus muscles equalled
59.1 and 16.2 pmol g-1 wet wt, whereas in human gluteus muscles binding was 12.3
pmol g-1 wet wt. The [3H]ryanodine binding showed a dependency on Mg2+ and pH
similar to previously published results. As measured by Ca2+ selective mini
electrodes, the [Ca2+] causing 50% of maximum [3H]ryanodine binding (K0.5) was
200-400 nmol l-1 for different muscles. [Ca2+] higher than 1 mmol l-1 caused
strong inhibition of the [3H]ryanodine binding, and both high and low [Ca2+]
caused rapid dissociation of the complex. At ionic strength lower than 100 mmol l
1, more than 50% of the [3H]ryanodine was bound to particles with size less than
1.2 microns which were not retained by GF/C filters. Thus, we have obtained an
almost complete quantitative recovery of functional RyRs from small muscle
specimens exhibiting high affinity for Ca2+, which stimulated ligand binding.
PMID- 9397488
TI - Pamidronate and biochemical markers of bone turnover.
AB - We have examined the response of different biochemical bone turnover markers to
intravenous pamidronate administration (15 mg for 5 days) in 14 patients with
Paget's disease, on days 8, 15 and 30 after pamidronate treatment. Urinary
parameters of bone resorption, free pyridinolines (Pyr) and hydroxyproline (OHP),
as well as serum tartrate-resistant acid phosphatase (TRAP) were measured. Two
serum biochemical osteoblastic markers, alkaline phosphatase (AP) and osteocalcin
(OC), were also analysed. In addition, ionic calcium (Ca2+) was measured in
blood, and parathyroid hormone and calcitriol were measured in serum. All the
biochemical markers of bone resorption tested decreased throughout the study.
TRAP levels decreased slowly, meanwhile Pyr decreased maximally, below OHP values
on day 8. However, the latter were lowest and were lower than those of Pyr on
days 15 and 30. AP serum values also decreased during the study. Conversely, OC
serum levels increased on days 8 and 15, decreasing to baseline levels on day 30.
Ca2+ blood levels decreased while PTH plasma levels increased at all times during
the period studied. Calcitriol serum levels increased on day 15. In conclusion,
intravenous pamidronate administration was found to modify several biochemical
parameters of bone turnover, including Pyr. Moreover, the changes in these
parameters were different in intensity and "time course" during the study.
PMID- 9397489
TI - Effects of adrenergic and muscarinic agonist stimulation on IP3 and cyclic
nucleotide levels in the pressure overloaded rat heart.
AB - In this study, the dynamic interrelationships between myocardial functional state
and changes in the second messenger content in pressure-overloaded hypertrophied
hearts were investigated. Forty-three rat hearts were used after partial clamping
of the abdominal aorta. The isolated hearts were perfused with Krebs-Henseleit
buffer and allocated to perfusion for 20 s or 40 min as controls (n = 12); or
with noradrenaline (10(-6) mol l-1, n = 11); carbachol (3 x 10(-7) mol l-1, n =
9); or noradrenaline plus carbachol (10(-6) mol l-1 + 3 x 10(-7) mol l-1,
respectively, n = 11). maxdP/dt increased more than 2-fold already after 20 s on
noradrenaline stimulation, followed by a significant increase in cAMP. After 40
min, maxdP/dt was lower than the maximal value, although higher than controls.
cAMP was also decreased, but still significantly higher than controls. Perfusion
with noradrenaline plus carbachol produced the same changes in maxdP/dt as those
seen after noradrenaline stimulation alone, but failed to increase cAMP content
after both 20 s and 40 min. The inositol trisphosphate (IP3) content was
increased 40 min of control perfusion (p < 0.05). Noradrenaline and carbachol,
separately, produced an increase in IP3 content already after 20 s (p < 0.05).
The combination of noradrenaline plus carbachol also produced an increase of IP3
(p < 0.05; compared to controls), but to a lesser extent when compared either to
noradrenaline or carbachol (p < 0.05). After 40 min of perfusion, IP3 was in the
same range regardless of added agonist(s) and still slightly above control level
(p < 0.05). The early increase in maxdP/dt induced by noradrenaline or the
combination of noradrenaline plus carbachol was not paralleled by a decrease in
ATP content. This was also the case upon addition of carbachol alone. However,
after 40 min of agonistic perfusion, ATP levels were substantially decreased. In
conclusion, myocardial IP3 content in pressure-overloaded hypertrophied hearts
was not different from that of sham-operated hearts. After agonistic stimulation,
an early increase in IP3 formation was seen. Attenuation of the IP3 response by
combined stimulation with noradrenaline and carbachol was initially present in
pressure-overloaded hypertrophied hearts. After 40 min no attenuation was found
for either IP3 or for cAMP content, suggestive of induction of a desensitization.
PMID- 9397490
TI - Poor metabolic control, early age at onset, and marginal folate deficiency are
associated with increasing levels of plasma homocysteine in insulin-dependent
diabetes mellitus. A five-year follow-up study.
AB - In a previous study, we showed that diabetic patients exhibited significantly
increased concentrations of total plasma homocysteine (tHcy), but not until the
onset of nephropathy. It was suggested that the hyperhomocysteinaemia might
contribute to the accelerated atherosclerotic process in diabetic patients. In
the present study, we have analysed the main determinants of plasma homocysteine
(i.e. serum cobalamin, blood folate and serum creatinine), and also some other
parameters related to diabetes mellitus, such as medical history, metabolic and
renal quantities, on two occasions with a 5-year interval in 50 patients with
insulin-dependent diabetes mellitus, in order to further elucidate the relation
between plasma tHcy and diabetes mellitus. The result of the present study shows
that diabetic patients with the lowest age at onset and with the poorest
metabolic control are those most prone to a rapid increase in plasma tHcy
concentration. The increment in plasma tHcy concentration in this group of
patients may at least partly be explained by a marginal deficiency of blood
folate concentrations.
PMID- 9397491
TI - Detection of tumour DNA in serum of colorectal cancer patients.
AB - Circulating tumour DNA has previously been detected in serum and plasma of
patients with lung cancer and head and neck cancer. These observations could
potentially lead to new, specific and non-invasive tools for diagnosis, prognosis
and follow-up in neoplastic disease, if found to be a more general phenomenon. To
test if tumour DNA is also present in serum of patients with colorectal cancer,
we selected 14 colorectal cancer patients with advanced disease. In seven
patients, K-ras mutations were detected in the primary tumour, using mutant
specific primers for point mutations in codon 12 or 13 of the K-ras gene. All
patients were analysed for mutant DNA in serum. Tumour-specific point mutations,
corresponding to the K-ras mutations found in the primary tumour were detected in
the serum of all patients but one. No mutant K-ras could be detected in the serum
of seven patients without K-ras mutations in the primary tumour. These results
may be useful in assessing tumour burden in patients with neoplastic disease.
Moreover, consecutive testing of serum tumour DNA after surgery or chemotherapy
may be used as a tumour marker for recurrent disease.
PMID- 9397492
TI - Multicentre evaluation of the urine analyser Miditron Junior.
AB - A multicentre evaluation of the urine analyser Miditron Junior was performed at
four laboratories. The Miditron Junior analyser provides semi-quantitative
results for erythrocytes, bilirubin, urobilinogen, ketone bodies, glucose,
protein, nitrite, leukocytes, pH and relative density. Accuracy of the Miditron
Junior analyser was evaluated by comparison to quantitative analytical chemistry
methods (glucose, total protein), physical methods (pH, relative density), and
microscopic methods (erythrocytes, leukocytes). Agreement was defined as
identical or neighbouring concentration block. The level of agreement found with
chemical, physical or microscopic methods for the six analytes tested varied from
79 to 99%. The within-run precision was determined as repeatability by using 31
native urines. The results of repeated measurements (n = 10) fell in the same
concentration block, or in case of borderline concentration were spaced between
two adjacent colour blocks. Day-to-day precision covering a minimum of 20 days
using commercially available control solutions yielded results within +/- one
colour block from the mean.
PMID- 9397493
TI - An external quality assessment study on the analysis of methylmalonic acid and
total homocysteine in plasma.
AB - In spite of the increasing interest in the analysis of methylmalonic acid and
total homocysteine in plasma, data on interlaboratory variation is lacking. We
report the results of an external quality assessment study with the participation
of 15 laboratories in the Scandinavian countries performing these analyses on a
regular basis. For methylmalonic acid, using serum, heparin fluoride plasma and
an aqueous sample, CVs were found in the range of 11-17%. For total homocysteine
using EDTA plasma, heparin fluoride plasma and an aqueous sample, CVs were in the
range of 6-12%. For both analytes, a significant correlation between the
individual recoveries of added analyte and the results for the aqueous sample was
found, suggesting that the use of inconsistent calibrations in the participating
laboratories are contributing to the interlaboratory variation. An acceptable
range for results from the individual laboratory was calculated using data on the
biological within-subject and between-subject variations reported in the
literature. These ranges were violated by several laboratories when using the
consensus mean or median as target values. Even if the results of the present
study document a reasonable standard in the measurement of methylmalonic acid and
total homocysteine in plasma in the participating laboratories there is room for
improvement and a permanent scheme of external quality assessment using relevant
samples is essential. From 1997, a regular scheme has been available from our
laboratory.
PMID- 9397494
TI - 99mTc-labelled immunoglobulin scintigraphy in arthritis: an analysis of synovial
fluid activity.
AB - The distribution of 99mTc-labelled human polyclonal non-specific immunoglobulin G
(HIG) in the synovial fluid was studied in 14 patients with rheumatoid and non
rheumatoid arthritides. Analysis included the determination of the total activity
per ml synovial fluid 6 h post-injection (p.i.) of the tracer as well as of the
protein- and cell-bound fractions. At 6 h p.i., > 60% of the injected dose
remained in plasma as protein-bound radioactivity. Values in the synovial fluid
ranged between 0.001 and 0.009% of the injected dose per ml. Importantly, the
synovial fluid to plasma ratio was consistently < 1 (range: 0.09-0.43), which is
in the range of ratios observed for endogenous proteins in vivo. Similar values
were obtained in samples of synovial tissue obtained at surgery in two patients.
These data are consistent with the hypothesis that labelled HIG accumulates in
the extracellular fluid (both within the synovial tissue and fluid) by non
specific mechanisms (such as increased blood pool and capillary permeability) and
does not equilibrate with circulating plasma proteins in accordance with basic
knowledge of synovial physiology. In addition, it was found that most of the
activity remained bound to the proteins in the fluid and that cell-binding
occurred to a very low degree that cannot be considered an important mechanism of
uptake of this radiolabelled agent in vivo. These results provide the first
evidence in an in vivo human setting that radiolabelled HIG accumulates mainly by
non-specific mechanisms in inflamed joints.
PMID- 9397495
TI - Screening for EDTA-dependent deviations in platelet counts and abnormalities in
platelet distribution histograms in pseudothrombocytopenia.
AB - Screening for pseudothrombocytopenia caused by in vitro platelet clumping has
been performed in 45,000 subjects attending a general hospital. In our region,
the observed prevalence of EDTA-induced pseudothrombocytopenia in blood samples
with an initial platelet count below 150 x 10(9)/l was estimated to amount to
0.1%. EDTA-induced pseudothrombocytopenia was confirmed by detection of platelet
aggregates by means of microscopic evaluation from the blood smear. In routine
investigations, pseudothrombocytopenia could be highly suspected when the Sysmex
NE 8000 showed characteristic peculiarities in the white blood cell (WBC)
scattergram and histogram. Platelet aggregation is avoided in such cases by the
use of citrate as an anticoagulant instead of EDTA. Pseudothrombocytopenia was
detected in 46 subjects. As a screening test for pseudothrombocytopenia,
increased cut-off values derived from the WBC histogram demonstrated 90%
sensitivity and 100% specificity. Automated flagging for platelet clumps,
deviations reflecting MPV, or PDW abnormalities revealed lower scores with
respect to sensitivity.
PMID- 9397496
TI - Preconditioning the globally ischaemic, isolated rat heart: the impact of the
preconditioning model on post-ischaemic systolic and diastolic function.
AB - In studies of preconditioning, a variety of models have been used. The aim of the
present study was to find the optimal preconditioning model for preservation of
cardiac function during reperfusion of globally ischaemic, Langendorff-perfused
rat hearts. Cardiac function was assessed by the occurrence of severe reperfusion
arrhythmias (ventricular fibrillation or asystolia), heart rate (HR), left
ventricular systolic (LVSP), end diastolic (LVEDP), and developed pressures (LVDP
= LVSP - LVEDP), as well as coronary flow (CF). Series 1 (n = 17) in each group:
control perfusion for 20 min without preconditioning or 2 episodes of 2, 3, 4, or
5 min of ischaemia, each followed by 5 min reperfusion, before 25 min ischaemia
and 60 min reperfusion. Preconditioning reduced the incidence of reperfusion
arrhythmias, attenuated the reperfusion-induced increase of LVEDP, and increased
CF, but did not influence LVSP, LVDP, or rate x pressure-product (RPP = LVSP x
HR) during reperfusion. The greatest effect was found by 2 min ischaemia and 5
min reperfusion. In series 2 (n = 17 in each group) control perfusion for 7 or 28
min, or preconditioning with 1-4 episodes of 2 min ischaemia and 5 min
reperfusion before 35 min ischaemia and 60 min reperfusion were compared.
Reduction of severe reperfusion arrhythmias and LVEDP elevation, as well as
improvement of CF, LVDP, and HR in preconditioned hearts were observed in series
2. Optimal cardioprotection was achieved by only one episode of preconditioning.
In conclusion, preconditioning before global ischaemia improved cardiac function
during reperfusion of isolated rat hearts. The most marked effects were reduction
of severe reperfusion arrhythmias and attenuation of diastolic dysfunction.
Although all preconditioning models employed were cardioprotective, 1 episode of
2 min ischaemia provided optimal protection.
PMID- 9397497
TI - Use and usefulness of laboratory handbooks.
AB - The aim of this study was to investigate how reference handbooks distributed by
hospital laboratories are used by medical doctors, and to what extent this kind
of information can influence or change doctors' work habits. We also wanted to
see if books with various contents of information are valued differently by the
users, and we asked for preferences for an ideal book. A questionnaire was sent
to 2075 medical doctors served by five Norwegian hospital laboratories. The
overall response rate was 66%, of whom 76% had received a handbook. Seventy-eight
percent of respondents who stated that they had received a handbook kept it in
their consulting room and 45% used it once or more weekly. The majority (89%)
found the books beneficial in their everyday work. Many doctors (36%) claimed
that they had changed their routines as a result of the information in the book.
The way of interpreting test results was influenced most often, followed by
indications for ordering laboratory tests, sample collection and specimen
handling, and patient preparation. Nearly all respondents (97%) felt that
handbooks of this kind are beneficial to their technical and nursing staff. The
results show that handbooks distributed by medical laboratories are well
received, frequently used and highly appreciated by medical doctors.
Comprehensive books are rated higher than smaller books.
PMID- 9397498
TI - Rectal administration of N-acetylcysteine in swine: a pilot study.
AB - The purpose of this pilot study was to determine if N-acetylcysteine (NAC)
administered via the rectal route in swine is absorbed into the systemic
circulation. Fasting swine were anesthetized, intubated, monitored and i.v.
access was obtained by femoral cutdown. NAC was administered into the rectal
vault (2.0 g/kg) via a balloon-tipped Foley catheter inserted into the animals'
rectum. NAC administered via the rectal route resulted in systemic absorption as
determined by spectrophotometric methods in 5 of the 7 study animals. This study
provides important information regarding the development of a potential
alternative route for the administration of NAC.
PMID- 9397499
TI - Toxicity of waterproofing spray is influenced by the mist particle size.
AB - In a previous study, we showed that waterproofing sprays that are toxic generate
mists with smaller particles than do nontoxic products. In this study, we made 4
waterproofing sprays (A, B, C and D) with identical ingredients but with
different mist particle sizes and compared the pathological changes produced in
the lungs of mice. The mist particle diameters were 32.8 +/- 3.2, 62.0 +/- 3.8,
89.1 +/- 4.1 and 143.2 +/- 5.0 microns for sprays A, B, C and D, respectively.
Pathological lung changes were evaluated by a 6-criteria grading system
(thickening of the alveolar septum, cellular infiltrations in the alveolar
septum, alteration of the bronchial mucous membrane, hyperemia of the alveolar
wall, transudative hemorrhage, and alveolar collapse). Sprays A and B caused
significantly greater scores as compared to the control group for all the
criteria except mucosal changes, whereas the changes from sprays C and D were
slight and the differences in scores were not significant. These results suggest
that toxicity of waterproofing spray is influenced by the mist particle size
generated and may help manufacture safer waterproofing spray products.
PMID- 9397500
TI - Dietary fumonisins disrupt sphingolipid metabolism in mink and increase the free
sphinganine to sphingosine ratio in urine but not in hair.
AB - This study was conducted to investigate the effects of dietary Fusarium
moniliforme culture material (M-1325) containing known concentrations of
fumonisins B1, B2 and B3 on sphingolipids in urine and hair of mink (Mustela
vison) for use as potential, non-invasive biomarkers of exposure to fumonisins in
this species. Feeding mink diets containing 86, 22, and 7 ppm or 200, 42, and 12
ppm of fumonisins B1, B2 and B3, respectively, yielded marked increases in
urinary free sphinganine (Sa) and free sphingosine (So) concentrations, and free
Sa/free So ratios (2 to 11-fold) within 7 d, compared to controls. Free Sa and
free So concentrations and Sa/So ratios in hair samples from mink fed the control
or high dose fumonisin diets for 100 days were similar and were not apparently
altered by exposure to these mycotoxins. These results suggest that Sa/So ratios
in urine, but not in hair of mink can serve as an early indicator of exposure to
fumonisins in this species.
PMID- 9397501
TI - A modified electrometric method for measurement of erythrocyte
acetylcholinesterase activity in sheep.
AB - A modified method was compared with an original electrometric method for
measurement of erythrocyte acetylcholinesterase (EChE) activity in sheep. The
mean +/- SD (pH/30 min) of EChE activity of 8 sheep measured by the modified
procedure (0.70 +/- 0.15) was not significantly different from that of the
original method (0.64 +/- 0.12). The inherently low plasma cholinesterase
activity of the sheep as measured by the 2 methods were also not significantly
different from each other (0.09 +/- 0.04 vs 0.10 +/- 0.04). The coefficient of
variation of the modified method in measuring EChE activity was 8%. The method
was used to demonstrate in vitro inhibition of sheep EChE activity by the
organophosphorus and carbamate insecticides dichlorvos and methomyl,
respectively. The method could be well-suited for rapid measurement of EChE
activity in sheep, especially in cases of organophosphate and possibly carbamate
poisoning.
PMID- 9397502
TI - Influence of alkalinization of glutaraldehyde biocidal solutions on acute
toxicity, primary irritancy, and skin sensitization.
AB - Aqueous glutaraldehyde (GA) is used at a concentration around 2% for the cold
sterilization of endoscopy and dental instruments. Stock GA solution (pH 3.1-4.5)
is alkalinized (pH 7.8-8.0) before use to optimize biocidal activity. The
possible differential handling hazards between acidic unbuffered GA (UGA) and
alkaline buffered GA (BGA) were compared for acute toxicity, primary irritancy
and skin sensitizing potential using a 2.2% GA solution. Peroral LD5.0 values
(with 95% confidence limits) in rats (combined sexes) were 3.45 (3.13-3.80) g/kg
for UGA and 4.16 (3.13-5.52) g/kg for BGA; signs and gross pathology were
similar. A 24-h occluded cutaneous application of 16.0 g/kg in the rabbit did not
produce mortality; moderate skin irritancy was observed. No systemic effects
occurred with UGA and only a few with BGA (unsteady gait, sluggishness, rapid
breathing). Local skin irritation from a 4-h occluded contact with 0.5 ml was
relatively minor and slightly more marked with BGA than UGA. Rats exposed to a
statistically generated saturated vapor atmosphere for 6 h did not show any signs
or gross pathology, and only slight weight loss occurred (UGA females). Rabbit
eye irritation studies (0.1 ml) showed slightly more marked conjunctival
reactions with BGA, but corneal injury was marked and persistent with BGA and
only slight and transient with UGA. With 0.01 ml, no corneal injury occurred, but
conjunctival reaction was more marked with UGA. A guinea pig maximization study
showed UGA to produce a higher sensitizing index (68% at challenge, 32% at
rechallenge) than BGA (30% at challenge, 5% at rechallenge). Severity indices at
challenge was also higher for UGA [0.84 (24 h), 0.47 (48 h)] than BGA [0.45 (24
h), 0.18 (48 h)]. Both UGA and BGA have generally similar acute toxicity and skin
irritancy; BGA has greater corneal injuring potential, and UGA has a greater skin
sensitizing potential.
PMID- 9397503
TI - New treatment regimens in organophosphate (diazinon) and carbamate (methomyl)
insecticide-induced toxicosis in fowl.
AB - The objective of this work was to determine optimal treatment regimens for
organophosphate (OP) or carbamate insecticide toxicoses in fowl using the
antidotes atropine sulfate and pralidoxime chloride (2-PAM). Broiler chicks in
treatment groups, each comprising 3 replicates of 6-7 birds/replicate, were
gavaged on a body weight (BW) basis with the OP and carbamate insecticides,
diazinon and methomyl, respectively, at lethal dosages. Treatment groups were
injected with either or both of the antidotes at various dosages as soon as
clinical signs appeared. Birds appearing healthy 24 h thereafter were regarded as
having been treated successfully. At a dosage of 100 mg/kg BW, atropine was
mildly toxic and at 200 mg/kg 2-PAM was severely toxic (but not lethal), whereas
at dosages of 50 and 100 mg/kg BW, respectively, the antidotes were at their most
effective. With diazinon, atropine alone was only partially effective (12/20
survivors), whereas 2-PAM was extremely efficacious. (20/20 survivors); the
combination of the 2 antidotes at 2 dosages was slightly less effective (19/20
survivors) than 2-PAM alone. For methomyl toxicity, atropine was largely
successful (18/20 survivors), whereas 2-PAM was mostly unsuccessful (10/20
survivors); the combination at high dosage was less effective (15/20 survivors)
than atropine alone, but at a low dosage the combination was the most successful
(20/20 survivors). The results indicate that anticholinesterase insecticide
toxicoses in fowl should not be treated according to textbook recommendations,
and antidotal dosage with atropine should be up to 100 times greater than is
commonly recommended. The specific cause of the toxicoses should ideally be
determined before treatment is given, but as this is often unknown, a combination
of antidotes may be the optimal treatment protocol.
PMID- 9397504
TI - Marijuana (Cannabis sativa) toxicosis in cattle.
PMID- 9397505
TI - Flurazepam toxicosis in two dogs.
AB - Flurazepam is a benzodiazepine (BZD) derivative and a category IV controlled
substance. It is a widely prescribed hypnotic drug for use in sleep disorders.
Two dogs were maliciously poisoned with this drug and died. Flurazepam was
detected in the urine of 1 dog by thin-layer chromatography. Flumazenil, an
antagonist for BZD receptors, is currently used in humans to reverse the effects
of intoxication with BZD. It may also be of use in treating companion animals.
PMID- 9397506
TI - Neurotoxicity and secondary metabolic problems associated with low to moderate
levels of exposure to excess dietary sulphur in ruminants: a review.
AB - Problems associated with a low to moderate excess in dietary sulphur (S) intake
in ruminants are being increasingly recognized. Comparing more recent reports
with older data, there is an evident decrease in tolerance of cattle and sheep
for even moderately elevated levels of dietary S, and an apparent drastic change
in the clinical picture of chronic dietary S toxicoses. Outbreaks of
polioencephalomalacia (PEM) in ruminants in association with excess dietary S
have been reported in recent years throughout the world. Excessive levels of S
containing compounds in domestic ruminant animals' rations, and clinical problems
associated with low to moderate levels of exposure to dietary S may be more
common than previously thought. This review presents a comprehensive evaluation
of the problems associated with excessive levels of S in ruminants' rations.
Emphasis is placed on the recently increasing incidence of S-induced PEM.
Secondary metabolic disorders associated with excessive intake of S are also
discussed.
PMID- 9397507
TI - Poisonings in animals: the 1993-1994 report of the American Association of Poison
Control Centers.
AB - More than 82% of the 140,614 animal poison exposures reported in 1993 and 1994
occurred in dogs and almost 14% occurred in cats. Almost all reported were acute
exposures to a single product. Tables of detailed data are provided.
PMID- 9397508
TI - Instant methods to spot-check poisonous podophyllum root in herb samples of
clematis root.
PMID- 9397509
TI - Antihistamine-containing cough/cold medications present a low hazard in pediatric
accidental exposure incidents: analysis of Poison Control Center data.
AB - We studied accidental exposure to pediatric cough/cold medications in children
under 6-y-of-age to determine whether the presence of an antihistamine
(chlorpheniramine) in the product increased the likelihood for adverse outcomes.
General accidental exposure cases reported to the American Association of Poison
Control Centers (AAPCC) during 1988-1992 were analyzed for specific over-the
counter cough/cold pediatric products containing identical concentrations of
active ingredients except for the presence or absence of chlorpheniramine. These
case reports were evaluated for differences in medical outcome, symptom
assessment, management site and therapy, as coded by poison control centers
participating in the AAPCC Toxic Exposure Surveillance System. A total of 10,289
cases of accidental exposures were evaluated for the specific products included
in this analysis. While these cases represented a small percentage of total
exposures to these products (approximately 3% of total cases in children under 6
y-of-age reported to the AAPCC for all cough/cold medications during 1988-1992),
they provided a unique opportunity to evaluate the impact of the antihistamine
component of the formulation. This study demonstrated that the presence of
chlorpheniramine did not affect the medical outcome or the extent to which
symptoms were reported. Additionally, similar percentages of exposures for these
2 products were managed at the site of the incident, and required either no
therapy or only required fluids and observation. There were no notable
differences in the percentage of cases which involved more aggressive treatment
procedures (activated charcoal, cathartic, lavage). This analysis demonstrates
that over-the-counter cough/cold medications containing chlorpheniramine present
low potential for hazard in cases of accidental ingestions in young children and
do not show an increased likelihood for adverse outcomes of accidental exposures
compared to cough/cold medications not containing this antihistamine.
PMID- 9397510
TI - Trends in hospitalizations and mortality due to medicinal or non-medicinal
poisonings in Hong Kong.
AB - Previous epidemiologic studies of poisonings in Hong Kong are regional hospital
or poison information center-based and have focused on either adults or children.
This paper reports on the territory-wide hospitalization and mortality rates,
comparing medicinal and non-medicinal poisonings in the general population.
Between 1980 and 1995, the figures for hospitalizations and mortality due to
medicinal (ICD codes 960-977) or non-medicinal (ICD codes 980-989) poisonings
were obtained from the Annual Reports of the Department of Health, Hong Kong
Government. Rates of medicinal poisonings increased between 1980/81
(57.3/100,000) and 1987/88 (80.9/100,000), but then declined (59.1/100,000) in
1993/94. Rates of non-medicinal poisonings were rather static (49-53/100,000)
between 1980/81 and 1988/89, but then declined (22.0/100,000) in 1994/95. Between
1980/81 and 1988/89, rates of fatal medicinal poisonings (0.73-1.31/100,000) were
similar to those of fatal non-medicinal poisonings (0.98-1.70/100,000). However,
from 1989/90, there was an increase in the rates of fatal medicinal poisonings
(1.94-2.80/100,000), although rates for non-medicinal poisonings remained much
the same (0.80-1.38/100,000). Hospitalizations due to poisonings are now less
common in Hong Kong than before, due largely to a greater decline in non
medicinal poisonings.
PMID- 9397511
TI - Catnip and the alteration of human consciousness.
AB - Uncertainty exists regarding the ability of catnip (Nepeta cataria) to affect
human consciousness. We report a case of a toddler exhibiting central nervous
system depression after consuming a large quantity of catnip. His obtundation was
not attributable to another cause. We review the published literature describing
the alleged psychoactive capabilities of catnip and present our case as further
information for use in this ongoing controversy.
PMID- 9397512
TI - Photosensitization and crystal-association cholangiohepatopathy in cattle grazing
Brachiaria decumbens in Brazil.
PMID- 9397513
TI - Structural factors contributing to insecticidal and selective actions of
neonicotinoids.
AB - Nicotinoids and neonicotinoids are characterized by the presence of the 3
pyridylmethylamine moiety in their structure. In the former, the amino nitrogen
atom is ionized, while in the latter the corresponding nitrogen atom is not
ionized but bears a partial positive charge. Both types of insecticides interact
with nicotinic acetylcholine receptor (nAChR) of insect origin. The poor
interaction of neonicotinoids with vertebrate nAChR was shown by its poor binding
affinity to the nAChR from Torpedo electric organ and rat brain and poor
activation with nAChR expressed in Xenopus oocytes. The full positive charge was
essential to interact with the vertebrate nAChR, while the 3-pyridylmethylamine
moiety with a partial positive charge was enough to interact with the insect
nAChR. For penetration into the insect central nervous system, hydrophobicity
seemed to play an important role, as indicated by the binding of the injected
compounds to the housefly head nAChR. The ionization reduced hydrophobicity and
limited the penetration of nicotinoids, resulting in less insecticidal activity.
Among neonicotinoids, nitromethylene type compounds, though far higher in binding
affinity, were less hydrophobic than the corresponding nitroimine type, and the
net result was better or inferior insecticidal activity. A chlorine atom at the 6
position of the 3-pyridyl group found in commercialized neonicotinoids
contributes to increased binding affinity and more importantly hydrophobicity,
thus increasing insecticidal activity. N-Me-imidacloprid was found to be a
propesticide of imidacloprid.
PMID- 9397514
TI - CYP6D1 protects thoracic ganglia of houseflies from the neurotoxic insecticide
cypermethrin.
AB - CYP6D1 is a housefly cytochrome P450 known to metabolize neurotoxic pyrethroid
insecticides. To determine if the nervous system was capable of metabolizing
pyrethroids, we examined CYP6D1-mediated in vitro metabolism in thoracic ganglia
from pyrethroid-resistant (LPR) and -susceptible (CS) strains of housefly. SDS
PAGE/immunoblotting revealed that CYP6D1 was expressed in all tagmata and in
thoracic ganglia of both strains, but in all cases the levels of CYP6D1 were
higher in the LPR strain. Using a CYP6D1-specific antiserum, we found CYP6D1 to
be the major, and possibly the only, P450 isozyme involved in cypermethrin
metabolism in thoracic ganglia homogenates. Additionally, thoracic ganglia
homogenates from LPR houseflies metabolize more cypermethrin than preparations
from susceptible flies. This metabolism was inhibited by piperonyl butoxide and a
CYP6D1-specific antibody. Our results indicate that thoracic ganglia of LPR
houseflies are protected from the neurotoxin cypermethrin by virtue of the higher
levels of CYP6D1 compared to the susceptible houseflies. This P450-mediated
detoxification of an insecticide at the level of the target tissue helps to
explain the high levels of resistance to pyrethroids in the LPR strain.
PMID- 9397515
TI - Effects of exposure to cypermethrin on saxitoxin binding in susceptible and
pyrethroid-resistant houseflies.
AB - Saxitoxin (STX) binding was measured in susceptible (SBO) and pyrethroid
resistant (KDR) female houseflies having only target site insensitivity as a
resistance mechanism. In KDR flies, there was a quantitative decrease in STX
binding capacity (Bmax) relative to SBO flies coupled with an increase in binding
affinity (Kd). Treatment of SBO flies with sublethal doses of cypermethrin
resulted in a large decrease in the number of STX binding sites and an increase
in STX binding affinity. In KDR flies, identical treatments had the opposite
effects. Treatment of both strains with higher doses of cypermethrin resulted in
smaller decreases in Bmax values coupled with decreases in binding affinities.
The results show that physiological changes in STX binding occur upon exposure to
extremely low doses of cypermethrin. The data suggest that the kdr resistant gene
may be expressed as changes in STX binding kinetics and that measurements of STX
binding in pyrethroid-treated insects may be a useful approach for studying
pyrethroid's mode of action and resistance.
PMID- 9397516
TI - Isolation of the V-ATPase A and c subunit cDNAs from mosquito midgut and
Malpighian tubules.
AB - Using conserved amino acid sequences for the design of oligonucleotide primers,
we isolated cDNA clones for two subunits of the V-ATPase from the midgut and
Malpighian tubules of Aedes aegypti larvae. The 3.1 kb cDNA of the A subunit of
the peripheral catalytic V1 sector codes for a protein of 68.6 kDa. The protein
contains conserved motifs, including an ATP/GTP binding site, found in all other
A subunits. Southern analysis using the A subunit as a probe suggests the
presence of only a single copy of gene in the Aedes aegypti. The 0.85 kb cDNA of
the c subunit of the membrane H+ conducting V0 sector codes for a protein of kDa.
This protein has four transmembrane domains and contains a conserved glutamic
acid that serves as the binding site for dicyclohexylcarbodiimide. Southern
analysis using the c subunit as a probe suggests the presence of more than one
related gene in the genome of Aedes aegypti. Pileup analysis of various A and c
subunits shows that these subunits fall into distinct clusters, including one in
which all arthropod proteins are clustered.
PMID- 9397517
TI - Two-photon excitation of ethidium bromide labeled DNA.
AB - We examined the steady state and time-resolved emission of DNA stained with
ethidium bromide (EB) when excited with 90 fs pulses from a mode-locked titanium
sapphire laser. Over the wavelength range from 840 to 880 nm EB-DNA was found to
display two-photon excitation, with a cross-section near 7 x 10(-50) cm4s/photon.
Frequency-domain intensity decay measurements revealed similar multi-exponential
intensity decays for one- and two-photon excitation. Time-resolved anisotropy
decay measurements revealed similar correlation times, but different amplitudes
as has been observed previously for two- versus one-photon excitation. These
results indicate that two-photon excitation of EB-DNA can be accomplished with
the fundamental output of a Ti:sapphire laser without obvious heating or
perturbation of the DNA.
PMID- 9397518
TI - A study of the dielectric properties of E. coli ribosomal RNA and proteins in
solution.
AB - The permittivity of ribosomal proteins and ribosomal RNA (rRNA) in solution was
measured in the range 100 kHz to 1 GHz at four different temperatures (5, 15, 25
and 35 degrees C). The experimental dielectric relaxation was analysed by the
Cole-Cole equation and, from the best-fit parameters, the average values of the
dipole moment and molecular radius of the proteins were obtained. The activation
enthalpy was calculated from an Arrhenius plot of the relaxation time. The energy
involved in the dielectric polarization of free proteins has a magnitude of about
one hydrogen bond. The data on RNA were analysed according to the Mandel model.
This analysis allowed the calculation of the "subunit b" as defined by Mandel.
This parameter is dependent on the temperature and therefore the relaxation time
does not follow the Arrhenius law. Our data thus show that, in solution, the rRNA
structure is thermally rather unstable and highly flexible.
PMID- 9397519
TI - Interaction of DAPI with pepsin as a function of pH and ionic strength.
AB - The fluorescent probe 4',6-diamidino-2-phenylindole (DAPI), extensively used with
nucleic acids, has also recently been used with membranes and proteins (Favilla
et al., Biophys. Chem., 46 (1993) 217-226 and Mazzini et al., Biophys. Chem. 52
(1994) 145-156, respectively). The spectroscopic changes of DAPI observed, namely
a considerable enhancement of fluorescence, induced circular dichroism (CD) and
absorbance spectral shifts, have been exploited to study the binding of this dye
to both native and alkali denatured pepsin. Fluorescence and CD titrations show
that nearly two molecules of DAPI bind to either native or alkali denatured
pepsin with pH and ionic strength dependent Kd values, whereas absorbance
titrations evidentiate an interaction characterized by a lower affinity and a
larger number of binding sites. Therefore two kinds of interaction are proposed:
a specific one, involving both hydrophobic and electrostatic forces; and a non
specific one, involving surface protein negative charges only. Finally, the
behaviour of DAPI as a competitive inhibitor and the remarkable effect of
pepstatin A, a specific inhibitor of pepsin, on both the CD and fluorescence
spectra of DAPI in the presence of pepsin, show the involvement of the protein
active site in the interaction.
PMID- 9397520
TI - Alkaline denaturation and partial refolding of pepsin investigated with DAPI as
an extrinsic probe.
AB - The binding parameters of DAPI to porcine stomach pepsin have been described in
the previous article in this issue (A. Mazzini et al.). Here we exploit the
differences in the spectroscopic (fluorescence and circular dichroism) properties
of DAPI bound to either native or alkali denatured pepsin. We follow the kinetics
of pepsin denaturation around neutrality (pH range 6.8-7.4), at several phosphate
buffer ionic strengths (range 0.02-0.25). The dependence of the apparent
dissociation rate constant on pH clearly shows that the rate limiting step
follows the dissociation of about three acidic protein residues. The accelerating
effect by ionic strength we observed can be accounted for by a simple treatment
based on both transition state theory and Debye-Hueckel's limiting law.
Furthermore, when a solution of pepsin, rapidly denatured at pH 7, is reacidified
to a pH between 4.5 and 5.5, a substantial recovery of protein secondary
structure, with no enzymatic activity, is observed, judging by the far UV
circular dichroism of the protein. This process of partial refolding can easily
be followed using DAPI as an extrinsic reporter group, able to monitor the
kinetics of formation and decay of a highly fluorescent intermediate. This
process becomes faster at a lower pH, at least in the limited range investigated
(pH 4.5-5.5), in which the refolded protein does not aggregate, but, in contrast
to unfolding, is almost independent in ionic strength.
PMID- 9397521
TI - Salt and pH effects on electrochemistry of myoglobin in thick films of a bilayer
forming surfactant.
AB - Salt concentration and pH of external solutions were shown to control the
electrochemistry of the heme protein myoglobin (MbFe(III)-H2O) in stable, ordered
films of didodecyldimethylammonium bromide (DDAB). Protonation of
aquometmyoglobin (MbFe(III)-H2O) in these films precedes electron transfer from
electrodes, causing formal potentials to shift negative as pH increases from 5 to
8. At pH > 8, MbFe(III)-H2O dissociates to MbFe(III)-OH, which is reduced
directly at the electrode at higher rates than MbFe(III)-H2O. Correlations of
voltammetric data with FT-IR spectra suggested that at pH < 4.6, an unfolded form
of Mb resides in the films and is reduced directly. The concentration of salt in
solution influences electrochemical properties of Mb-DDAB films by its influence
on Mb conformation and by effects on interfacial Donnan potentials. NMR indicated
strong binding of anions to Mb within DDAB films. Bound anions may neutralize
positive charge on Mb's surface so that it can reside in a partly hydrophobic
environment, as postulated on the basis of previous ESR and linear dichroism
studies.
PMID- 9397522
TI - Effect of inhalation anaesthetics on the phase behaviour, permeability and order
of phosphatidylcholine bilayers.
AB - We have used differential scanning calorimetry and fluorescence anisotropy
measurements to investigate the effect of five inhalation anaesthetics of diverse
chemical structure (halothane, enflurane, n-pentane, chloroform and diethylether)
on the phase behaviour of liposomes prepared from dimyristoylphosphatidylcholine
(DMPC) and dipalmitoylphosphatidylcholine (DPPC), respectively. The incorporation
of these anaesthetics induced a decrease of the phase transition temperature
and/or a broadening of the phase transition peak depending on the transverse
localisation of the investigated anaesthetic. At high anaesthetic concentrations
we observed the disappearance of the pretransition peak and the appearance of a
shoulder on the main phase transition peak due to the domain formation of the
anaesthetics. An anaesthetic induced carboxyfluorescein efflux from the vesicle
lumen was completed within a few minutes after the addition of the anaesthetics,
probably resulting from a transient formation of membrane holes. All results are
discussed with regard to the physicochemical properties of the anaesthetics
applied.
PMID- 9397523
TI - Melanotropic peptides-lipid bilayer interaction. Comparison of the hormone alpha
MSH to a biologically more potent analog.
AB - The interaction of the native peptide alpha-melanocyte stimulating hormone (alpha
MSH) and the biologically more active analog [Nle4, D-Phe7]-alpha-MSH(MSH-I) with
lipid vesicles was studied by spin label electron spin resonance (ESR)
spectroscopy and circular dichroism (CD). Using spin labels located at the
membrane interface and at different depths along the acyl chain, it was shown
that the binding of both peptides to the membrane induces tighter lipid packing
at all the monitored positions. However, the effect of the analog on the spin
label ESR parameters was much more evident, and suggested that it penetrates
farthest into the lipid matrix than the native molecule. Lipid partition
coefficients were calculated based on the effect the peptides cause on the ESR
spectra of spin labels incorporated in the membrane. For the biologically more
potent peptide, the partition coefficient was found to be about 4-times greater
than that of the native hormone. For the same concentration of peptide bound to
the membrane, MSH-I was found to cause a slightly greater effect on the membrane
structure than alpha-MSH, in accord with its possible deeper penetration into the
bilayer. CD spectra in aqueous solution and in the alpha-helix inducing solvent
2,2,2-trifluoroethanol showed that the two peptides have somewhat different
structures in solution, though similar conformational changes occur in both
peptides as a result of their interaction with negatively charged vesicles or
micelles. The higher peptide-lipid association constant and the deeper
penetration of the analog into lipid bilayers could be related to its greater
activity and/or prolonged action.
PMID- 9397524
TI - Multiple nucleosome positioning with unique rotational phasing on multimers of
the light-responsive elements of pea rbcS-3A and rbcS-3.6 genes: comparison
between experimental and theoretical mapping.
AB - Nucleosome positioning along two DNA tracts, corresponding to tetramers of the
light-responsive elements of pea rbcS-3A and rbcS-3.6 genes, were studied by
experimental (exonuclease III mapping and band shift electrophoresis) as well as
theoretical methods. Multiple nucleosome positioning with unique rotational phase
was derived from both methods in satisfactorily good agreement, if nucleosome
dyad axis positions are considered. Theoretical and experimental distributions of
nucleosome frequencies appear different, probably on account of DNA sequence
dependent digestion kinetics of exonuclease III.
PMID- 9397525
TI - Delayed dissociation of in vitro moving actin filaments from heavy meromyosin
induced by low concentrations of Triton X-100.
AB - The in vitro motility of fluorescent actin filaments over heavy meromyosin (HMM)
was studied in the presence of the nonionic detergent Triton X-100. Below 0.004%
Triton X-100 concentration, motility was not affected. Above 0.007%, motility was
not observed because actin filaments were dissociated from HMM. In the Triton X
100 concentration range of 0.004-0.007%, the sliding actin filaments dissociated
from HMM with a delay. The dissociation delay time decreased with increasing
Triton X-100 concentration, increasing ATP (adenosine-5'-triphosphate)
concentration, and increasing temperature. The delayed acto-HMM dissociation was
absent when weak-binding kinetic intermediates of the myosin ATPase cycle (M.ATP
and M.ADP-Pi) were used. The presence of sliding movement was necessary to evoke
the delayed acto-HMM dissociation. The acto-HMM dissociation delay was
independent of actin filament length. For a given Triton X-100 concentration, the
dissociation delay time was found to be inversely proportional to sliding
velocity, indicating that actin filaments travel a more or less constant distance
prior to dissociation from HMM. The actin-activated HMM ATPase activity was not
inhibited by Triton X-100; rather, it was slightly enhanced. The results imply
the presence of a motility-associated conformational change in acto-HMM.
PMID- 9397526
TI - Molecular acoustic as a new tool for the study of biophysical properties of
lipoproteins.
AB - The method of measurement of velocity and absorption of ultrasound at a fixed
frequency (7.2 MHz) and measurement of density were used to study the physical
properties of high- (HDL3) and low- (LDL) density lipoproteins. We found
substantial changes in velocity number [u] and absorption number [alpha lambda]
on temperature, which reflect structural changes in the hydrophobic core of LDL
at the thermotropic-phase transition. The absorption number revealed broad
changes in temperature for both classes of lipoproteins (LP). The density of LP
also depends on temperature but in considerably less degree than the acoustic
parameters. The values of acoustic parameters were determined, showing that LDL
and HDL3 greatly differ with respect to adiabatic compressibility.
PMID- 9397527
TI - The reaction of oxygen with radicals from oxidation of tryptophan and indole-3
acetic acid.
AB - The oxidation of tryptophan and indole-3-acetic acid (IAA) by the dibromine
radical anion or peroxidase from horseradish in aqueous solution was investigated
and compared, especially with respect to the involvement of oxygen and
superoxide. Using EPR with spin-trapping, the tryptophanyl radical, generated by
either method was found to react with oxygen, although this reaction is too slow
to be observed by pulse radiolysis (k < 5 x 10(6) dm3 mol-1 s-1). No superoxide
results from this reaction, thus excluding an electron-transfer mechanism and
suggesting the formation of a tryptophan peroxyl radical, possibly in a
reversible process. These observations imply that in proteins where the
tryptophanyl radical exists as a stable species it must either have its
reactivity modified by the protein environment or be inaccessible to oxygen. The
related molecule LAA is oxidized by either peroxidase or Br2.- to a radical
cation that decarboxylates to yield a skatolyl radical. The latter reacts with
oxygen to give a peroxyl radical that does not release superoxide. However, O2.-
is formed during the peroxidase-catalyzed oxidation of indoleacetic acid. This
supports the hypothesis that the peroxidase can act in an oxidase cycle involving
ferrous enzyme and compound III, with superoxide as a product.
PMID- 9397528
TI - Surface electric properties of thylakoid membranes from Arabidopsis thaliana
mutants.
AB - Electric light scattering measurements of thylakoid membranes from wild type and
two mutant forms (JB67 and LK3) of Arabidopsis thaliana have shown that
application of external electric pulses induces electric dipole moments of
different origin. The asymmetric surface charge distribution and electric
polarizability are significantly altered by the lipid modification. Mild trypsin
treatment of Arabidopsis thylakoids leading to digestion of small polypeptides
from the light-harvesting chlorophyll a/b protein complex of photosystem II (LHCP
II) gives evidence for a lower content of LHCP II in the mutant forms. The
results demonstrate the significance of the level of thylakoid lipid unsaturation
in determining the surface charge distribution through changes either in the
pigment-protein content and membrane appression induced by the lipid modification
or in the exposure of charged polypeptides on the thylakoid membrane surface(s)
arising from alteration of the lipid geometry.
PMID- 9397529
TI - Role of phosphatidylethanolamine lipids in the stabilization of protein-lipid
contacts.
AB - We have investigated the effect of lipids with phosphatidylethanolamine (PE) head
groups on the stabilization of contacts between the tryptophan side chains of
gramicidin and the lipid head groups. We initially developed two fluorescence
methods that can be correlated to the spontaneous curvature of DOPC/DOPE and
DOPC/DOPEme. One is based on bilayer structure and measures the rotational motion
of a probe located close to the membrane surface relative to a more deeply-buried
probe. The second is based on surface hydration/polarity and measures the
emission energy of a polarity-sensitive probe located on the membrane surface. We
used these methods to estimate the pseudo-curvature (i.e., curvature obtained by
fluorescence measurements) of lipids with dimyristyl chains, and their pressure
and temperature dependence. We then investigated the stability of gramicidin
tryptophan-lipid contacts in DMPC/DMPE as a function of temperature and pressure.
Stability was assessed by tryptophan rotational motion as determined by
fluorescence anisotropy, since rotational motion is limited when the indoles are
hydrogen bonded to the lipid head groups. The results suggest that the presence
of PE lipids destabilizes these contacts due to either their smaller size
relative to PC head groups, or their tendency to self-interact. Fluorescence
quenching studies support these results.
PMID- 9397530
TI - Dynamic light scattering study of fine semiflexible fibrin networks.
AB - Fine fibrin networks have been investigated using the dynamic light scattering
(DLS) technique. At the shortest delay times, t, the dynamic structure factor
s(q,t) is found to depend on time according to an exponential function and, at
intermediate delay times (up to 1 ms), to a stretched exponential. At longer
times (t > 1 ms), a progressively increasing deviation from the stretched
exponential behaviour has been observed. These results are in agreement with the
theoretical predictions of a recently forwarded model for semiflexible polymers
in semidilute solutions [K. Kroy and E. Frey, Physical Review E 55 (1996) p.
3092.], despite the fact that fibrin networks are made up of crosslinked branched
polymers. The model, moreover, allows the calculation from the initial decay rate
gamma q(0) of the average diameter of the fibrin fibres, a. The value of a = 30
+/- 2 nm, at fibrinogen concentration c(f) = 1676 nM and ionic strength 0.5, fits
well into the data reported in electron microscopy studies. A concentration
dependence of the average diameter of the fibrin fibres has been observed which
saturates at the highest concentrations. The diameter of fibrin fibres is an
important component in determining the physical properties of the fibrin
networks, since the radial growth of fibrin fibres is limited by twisting during
protofibrils aggregation. Our results indicate the importance of taking into
account intrinsic semiflexibility in studying the physical properties of 'real'
polymers and emphasize the high sensitivity of the DLS technique to investigate
biological polymers also at the lowest concentrations where the systems are very
fragile.
PMID- 9397531
TI - The molecular biology of secreted enzyme production by fungi.
AB - Enzymes from filamentous fungi are already widely exploited, but new applications
for known enzymes and new enzymic activities continue to be found. In addition,
enzymes from less amenable non-fungal sources require heterologous production and
fungi are being used as the production hosts. In each case there is a need to
improve production and to ensure quality of product. While conventional,
mutagenesis-based, strain improvement methods will continue to be applied to
enzyme production from filamentous fungi the application of recombinant DNA
techniques is beginning to reveal important information on the molecular basis of
fungal enzyme production and this knowledge is now being applied both in the
laboratory and commercially. We review the current state of knowledge on the
molecular basis of enzyme production by filamentous fungi. We focus on
transcriptional and post-transcriptional regulation of protein production, the
transit of proteins through the secretory pathway and the structure of the
proteins produced including glycosylation.
PMID- 9397532
TI - Human gene therapy.
AB - Human gene therapy and its application for the treatment of human genetic
disorders, such as cystic fibrosis, cancer, and other diseases, are discussed.
Gene therapy is a technique in which a functioning gene is inserted into a human
cell to correct a genetic error or to introduce a new function to the cell. Many
methods, including retroviral vectors and non-viral vectors, have been developed
for both ex vivo and in vivo gene transfer into cells. Vectors need to be
developed that efficiently transfer genes to target cells, and promoter systems
are required that regulate gene expression according to physiologic needs of the
host cell. There are several safety and ethical issues related to manipulating
the human genome that need to be resolved. Current gene therapy efforts focus on
gene insertion into somatic cells only. Gene therapy has potential for the
effective treatment of genetic disorders, and gene transfer techniques are being
used for basic research, for example, in cancer, to examine the underlying
mechanism of disease. There are still many technical obstacles to be overcome
before human gene therapy can become a routine procedure. The current human
genome project provides the sequences of a vast number of human genes, leading to
the identification, characterization, and understanding of genes that are
responsible for many human diseases.
PMID- 9397533
TI - Alginate production by Azotobacter vinelandii.
AB - Although all commercial alginates are today of algal origin, there is interest in
the production of alginate-like polymers from bacteria. The species Azotobacter
vinelandii seems to be the best candidate for the industrial production of
alginate molecules characterized by a chemical composition, molecular mass and
molecular mass distribution suited to a well defined application, especially
required in the biotechnological, biomedical and pharmaceutical fields. The
production of alginate by A. vinelandii has been to date widely investigated both
in batch (mainly in the shaken flask scale) and in continuous cultures. This
article summarizes current knowledge on the structure and properties of alginates
and their applications and presents an overview of up-dated research on the
physiology, genetics and kinetics of the production of alginate by Azotobacter
vinelandii and its rheology, including the results of our recent studies.
PMID- 9397534
TI - Consequences of disrupting the gene that encodes alpha-glucosidase II in the N
linked oligosaccharide biosynthesis pathway of Dictyostelium discoideum.
AB - We have identified and disrupted the gene coding for alpha-glucosidase II in
Dictyostelium discoideum. This enzyme is responsible for removing two alpha 1,3
linked glucose residues from N-linked oligosaccharides on newly synthesized
glycoproteins. Mutagenesis by restriction enzyme-mediated integration (REMI)
generated a clone, DG1033, which grows well but forms abnormal fruiting bodies
with short, thick stalks. The strain lacks alpha-glucosidase II activity and
makes incompletely processed N-linked oligosaccharides that are abnormally large
and have fewer sulfate and phosphate esters. The morphological, enzymatic, and
oligosaccharide profile phenotypes of the disruption mutant are all recapitulated
by a targeted disruption of the normal gene. Furthermore, all of these defects
are corrected in cells transformed with a normal, full-length copy of the gene.
The phenotypic characteristics of DG1033 as well as chromosomal mapping of the
disrupted gene indicate that it is the site of the previously characterized modA
mutation. The Dictyostelium gene is highly homologous to alpha-glucosidase II
genes in the human and the pig, C. elegans, and yeast. Although various cell
lines have been reported to be defective in alpha-glucosidase II activity,
disruption of the Dictyostelium gene gives the first example of a clear
developmental phenotype associated with loss of this enzyme.
PMID- 9397535
TI - Differential expression of gap junctions in neurons and astrocytes derived from
P19 embryonal carcinoma cells.
AB - The P19 embryonal carcinoma cell line represents a pluripotential stem cell that
can differentiate along the neural or muscle cell lineage when exposed to
different environments. Exposure to retinoic acid induces P19 cells to
differentiate into neurons and astrocytes that express similar developmental
markers as their embryonic counterparts. We examined the expression of gap
junction genes during differentiation of these stem cells into neurons and
astrocytes. Untreated P19 cells express at least two gap junction proteins,
connexins 26 and 43. Connexin32 could not be detected in these cells. Treatment
for 96 hr with 0.3 mM retinoic acid induced the P19 cells to differentiate first
into neurons followed by astrocytes. Retinoic acid produced a decrease in
connexin43 mRNA, protein, and functional gap junctions. Connexin26 message was
not affected by retinoic acid treatment. The neurons that developed consisted of
small round cell bodies extending two to three neurites and expressed MAP2.
Connexin26 was detected at sites of cell-cell and cell-neurite contact within 3
days following differentiation with retinoic acid. The astrocytes were examined
for production of their intermediate filament marker, glial fibrillary acidic
protein (GFAP). GFAP was first detected at 8 days by Western blotting. In
culture, astrocytes co-expressed GFAP and connexin43 similar to primary cultures
of mouse brain astrocytes. These results suggest that differentiation of neurons
and glial cells involves specific connexin expression in each cell type. The P19
cell line will provide a valuable model with which to examine the role gap
junctions play during differentiation events of developing neurons and
astrocytes.
PMID- 9397536
TI - Characterization of a family of repetitive sequences that is eliminated late
during macronuclear development of the hypotrichous ciliate Stylonychia lemnae.
AB - A repetitive element from the hypotrichous ciliate Stylonychia lemnae was
characterized by restriction and hybridization analysis. This repetitive element
is present in about 5,000-7,000 copies per haploid genome in the micronucleus and
the macronuclear anlagen. Its DNA sequence is very conserved, but the length of
the repetitive sequence blocs is variable. In some cases, it is associated with
telomeric sequences and macronucleus-homologous sequences. Restriction analysis
of genomic micronuclear and macronuclear anlagen DNA and in situ hybridization
showed that the repetitive sequences are amplified during the formation of
polytene chromosomes. They are localized in many bands of the polytene
chromosomes and are eliminated during the degradation of the polytene
chromosomes. Possible functions of the repetitive sequences during macronuclear
differentiation are discussed.
PMID- 9397537
TI - Identification of a growth arrest specific (gas 5) gene by differential display
as a candidate gene for determining susceptibility to hyperthermia-induced
exencephaly in mice.
AB - Neural tube defects (NTDs) are among the most common congenital malformations,
affecting approximately 1 per 1,000 liveborn infants in the United States
[Nakano, 1973; Richards et al., 1972]. Maternal exposure to hyperthermia, either
through recreational sources or due to an infectious agent, is thought to account
for approximately 10% of observed NTD cases. The specific genes conferring
susceptibility or resistance to hyperthermia-induced NTDs have not been
identified. This study used differential display-polymerase chain reaction (DD
PCR) to characterize alterations in gene expression in the anterior embryonic
neural tube of two highly inbred murine strains (SWV/Fnn, LM/Bc/Fnn) known to
differ in their genetically determined susceptibility to heat-induced NTDs.
Herein, we report the neural tube-specific differential expression of the growth
arrest specific (gas 5) gene in the highly susceptible SWV/Fnn strain during
neural tube closure (NTC). Although the expression of gas 5 did not appear to be
altered by the teratogenic heat treatment, its spatial and strain-specific
pattern of expression makes it an excellent candidate gene responsible for the
observed genetic differences in NTD susceptibility between these two inbred
murine strains.
PMID- 9397538
TI - Molecular characterization of a heat shock cognate cDNA of zebrafish, hsc70, and
developmental expression of the corresponding transcripts.
AB - To elucidate the potential role of the hsp70 gene family in developmental
processes in vertebrates, we chose to study the expression of one of these genes
in zebrafish. A zebrafish gastrula cDNA library was screened with a Pleurodeles
waltl hsp70 cDNA probe. A 2.3-kb cDNA was thus isolated and sequenced. The
predicted amino acid sequence contained an open reading frame encoding for a 649
amino acid polypeptide. Sequence analysis showed strong homology with hsp70
related gene sequences in other species; in particular, the strongest homology
was found with the cognate members of this family. Tests of heat inducibility
revealed that transcripts were expressed at normal temperature, but the level of
transcript expression increased after heat shock. Moreover, experiments of the
neosynthesis of total proteins in heat shock conditions and corresponding
immunoblotting assays showed that 24-h-stage embryos are able to respond to heat
shock. The quantity of 70 kDa proteins, recognized by a specific antibody of the
HSP/C70 protein family, is expressed in control condition and increased
significantly after heat shock. Furthermore, Northern blot analysis of transcript
expression showed that the corresponding mRNAs were detected throughout embryonic
development in the absence of any heat shock. Our clone, named hsc70, thus
corresponded to a cognate member of the hsp70 gene family, expressed under normal
conditions during development, but also heat inducible. The spatio-temporal
pattern of transcripts during development was determined by in situ hybridization
on wholemount embryos at different stages. As a maternal RNA, hsc70 mRNA was
uniformly present in the embryo, up to the end of gastrulation. Later, a tissue
specific enrichment of hsc70 transcripts was detected in the central nervous
system (CNS) and in a fraction of the somites. These results suggest that the
hsc70 gene may be involved in developmental differentiation events.
PMID- 9397539
TI - Three subsets of genes whose tissue specific expression is sex and age-dependent
can be identified within the rat alpha 2u-globulin family.
AB - The rat alpha 2u-globulins are encoded by a multigene family whose 20-25 members
are subjected to multihormonal regulation that is dependent upon the sex of the
animal, the developmental stage and the tissue being examined. Using RT-PCR and
diagnostic restriction analysis of the products, we have examined the specificity
of the expression of different members of the gene family. All family members can
be classified into three subsets, depending on how the amplified cDNA responds to
digestion with ApaLI, SstI and VspI. Subset A contains the restriction sites for
both ApaLI and SstI but not VspI and typifies the genes expressed in the salivary
glands of both mature and juvenile animals of both sexes, where it is the only
subset expressed. This subset of genes also accounts for all the transcripts
observed in the kidneys and mammary glands of juvenile males. Although subset A
was represented in the transcript populations of all the other tissues examined,
its proportion relative to the total varied greatly. The two other subsets were
subset V, which contains only the restriction site for VspI, and subset N, which
lacks all three restriction sites. In all the other tissues examined, two or all
three of the subsets were expressed, usually in a manner that was unique to the
sex and age of the tissue in question. The proportion of each of the three alpha
2u-globulin subsets in the alpha 2u-globulin gene family was determined by
quantitation of the restriction products of amplified genomic DNA. Interestingly,
the most prevalent subset in the genome (N) has the most limited tissue
expression pattern, but is found in liver and preputial glands, the tissues
expressing the most substantial quantities of alpha 2u-globulin. These results
indicate the complexity of the regulation of the alpha 2u-globulins and point to
the necessity for gene specific analyses if the expression of the family is to be
understood in molecular terms.
PMID- 9397540
TI - Hyphenated liquid chromatographic method for the determination of colistin
residues in bovine tissues.
AB - A selective and sensitive high-performance liquid chromatographic (HPLC) method
has been developed for the measurement of colistin residues in milk and in four
bovine tissues (i.e., muscle, liver, kidney, and fat). The sample treatment
consists of protein precipitation using 10% (w/v) trichloroacetic acid, solid
phase purification on C18 cartridges, and precolumn derivatization of colistin
with ortho-phthalaldehyde and 2-mercaptoethanol in borate buffer (pH 10.5). This
latter step is performed automatically, and the resulting reaction mixture is
injected into a switching HPLC system including a precolumn and an analytical
column packed with end-capped LiChrospher RP18 (5 microns). Washing the precolumn
and final elution onto the analytical column are conducted using acetonitrile
0.01M phosphate buffer (pH 7.0) mixtures with respective proportions of 65:35 and
68:32 (v/v). Detection is carried out by spectrofluorometry (excitation
wavelength, 340 nm; emission wavelength, 440 nm). The retention times of the
derivatives corresponding to the two main components of colistin (i.e.,
polymyxins E2 and E1) are approximately 14 and 18 min, respectively. The
structural study of the derivatives corresponding to polymyxins E1 and E2 is
carried out by HPLC coupled with electrospray mass spectrometry; data obtained
confirms that the derivatization process occurs with the five amino groups of the
analytes. Selectivity is obtained in the HPLC system versus other coadministered
anti-infective drugs (beta-lactams, aminoglycosides, tetracyclines, and
sulphonamides) and endogenous compounds. Quantitation is performed using the sum
of the peak areas of polymyxin E1 and polymyxin E2 derivatives. Testing linearity
affords correlation coefficients greater than 0.990 for calibration curves in the
range of 10-500 microL/L for milk, 50-1000 micrograms/kg for muscle and fat, and
100-1000 micrograms/kg for kidney and liver. Relative standard deviation values
are less than 10% at a concentration of 25 micrograms/L in milk and 100
micrograms/kg in tissues (six replicates); recoveries are higher than 60%.
PMID- 9397541
TI - Determination of phloxine B and uranine in water by capillary zone
electrophoresis.
AB - Phloxine B and uranine are color additives in drugs and cosmetics as well as
potential photoactive insecticides. A capillary zone electrophoretic (CZE) method
is developed to determine phloxine B and uranine in water. A fused-silica
capillary (67 cm, 75-micron i.d.) and borate buffer are used. Migration of
phloxine B and uranine increases slightly as the pH of the running buffer
increases between the range of 8-9. Although there are only slight effects of
ionic strength on the analyte migration in the range of 0-20 mM NaCl in the
running buffer, the migration of phloxine B and uranine increases as the
percentage of methanol in the samples increases. Methanol shows little effect on
the quantitation of phloxine B and uranine. The CZE procedure is applied to
determine phloxine B and uranine fortified in tap and stream water samples. Solid
phase extraction is employed to recover the analytes spiked in the water samples.
Recoveries range from 87-112% for phloxine B spiked at 10-200 ppb in the tap and
stream water. Uranine recoveries are 86-91% at fortification levels of 10-50 ppb
in the water samples.
PMID- 9397542
TI - High-performance liquid chromatographic determination of 2-furaldehyde and 5
hydroxymethyl-2-furaldehyde in fruit juices.
AB - A method for the determination of 2-furaldehyde (F) and 5-hydroxymethyl-2
furaldehyde (HMF) in fruit juices by high-performance liquid chromatography
(HPLC) is described. The method is based on the formation of the 2,4
dinitrophenylhydrazones of carbonyl compounds and subsequent separation of these
derivatives. Derivatization is carried out by utilizing an acidic solution of 2,4
dinitrophenylhydrazine in acetonitrile. Precipitation of the derivatives of
carbonyl compounds is thus avoided, and direct injection of the sample into the
HPLC system is allowed. The procedure offers a high specificity and a detection
limit of the order of 10(-8) mol/L. Recoveries of 95-98% are obtained from apple
juice spiked at different levels with both analytes. The reproducibility (mean of
six determinations) is +/- 2% for F and +/- 3% for HMF.
PMID- 9397543
TI - Injuries due to letter bombs.
AB - In Austria in late 1993 ten letter bombs were sent to outstanding persons who
have been engaged in the care of foreigners. Four of these bombs detonated, when
they were opened by the addressee. The remaining six bombs were discovered in
time and could be deactivated by specialists. The construction of these bombs and
the lesions sustained by the four victims will be discussed. The injuries mainly
concerned the left hand, i.e., the hand used by right-handed persons to hold a
letter when opening it. The way holding the letter was of crucial influence on
the degree of injury, as with the same explosive charge (which can be assumed
deducing from the investigation of the deactivated bombs) injuries varied
considerably. They ranged from minor tissue-lesions to mutilated fingers and the
risk of exsanguination.
PMID- 9397544
TI - Extraction of single-copy nuclear DNA from forensic specimens with a variety of
postmortem histories.
AB - Specimens of human bone, teeth and dried blood spots from 3 months to 91 years
old, with a variety of postmortem histories, were used in a comparative study of
recovery of single-copy nuclear DNA sequences from forensic material. Sequences
of the amelogenin and HLA-DPB1 genes were chosen for their value in sexing and
identification. Sequences of the mitochondrial non-coding region V were also
amplified to compare the recovery of mitochondrial and single-copy nuclear DNA. A
variation of the silica method for DNA extraction was refined for application to
the forensic specimens in this sample. Single-copy nuclear DNA was amplified from
100% of recent postoperative bone specimens (n = 6), 80% of forensic teeth and
bone specimens (n = 10), 78% of recently extracted teeth (n = 18), 78% of exhumed
bone up to 91 years old (n = 37) and 69% of 15 year old bone specimens fixed in
10% formalin (n = 20). Amelogenin sexing was correct in 85% of cases (n = 74) in
which the sex of the donor had been recorded. There was no correlation between
the age of the specimen and the extent of DNA preservation.
PMID- 9397545
TI - Genetic individualization of domestic cats using feline STR loci for forensic
applications.
AB - A group of ten short tandem repeat (STR) loci suitable for PCR typing from DNA of
domestic cats is evaluated for genetic individualization using blinded samples of
eight putative feline blood specimens. The ten loci were also typed in a 70
member cat pedigree to demonstrate Mendelian inheritance and independent
assortment. A "match window" or measurement precision estimate was empirically
established by determining the maximum gel migration difference among alleles
identical by descent in different individuals of the pedigree. Hardy-Weinberg
equilibrium and abundant heterozygosity was observed for each locus in cat
population samples from Canada and the USA. The probabilities of two unrelated
individuals matching by chance (Pm) at all ten loci was estimated as 1.35 x 10(
10). We present a conservative approach to compute, for forensic consideration,
the mathematical likelihood of a chance genotypic match between DNA evidence from
a crime scene and the suspect composite STR genotypes for species or populations
when genotype frequency information is not available.
PMID- 9397546
TI - Violent behaviors associated with the antichrist delusion.
AB - Delusions involving the antichrist concept have been occasionally reported. Some
cases of the antichrist delusion have been associated with violent behavior. In
this article we describe the case of a man who suffered from a chronic antichrist
delusion and who also displayed repeated and serious violent behaviors. We also
discuss the role of the antichrist delusion as well as other psychotic symptoms
in the genesis of violence in the present case.
PMID- 9397547
TI - Sex estimation from the metatarsals.
AB - Discriminant-function analysis of osteometric data from the metatarsals of 200
individuals in the Terry Collection provides a reliable method for estimating
sex. Functions derived from individual metatarsals and from complete sets of
metatarsals are tested on the sample used to generate the functions and on two
independent samples: one comprising 25 additional individuals from the Terry
Collection and the other comprising 12 cadavers donated to the University of
Missouri, Functions based on race-specific samples (blacks and whites) and on the
pooled-race sample correctly classify 83 to 100% of each sample (including a
jackknifed study sample), with a few exceptions. These results are similar to sex
estimation methods from other regions of the appendicular skeleton.
PMID- 9397548
TI - HIV seroprevalence rates among homicide victims in New York City: 1991-1993.
AB - This study assessed HIV seroprevalence in homicide victims killed in New York
City in 1991-1993, using data from the Office of Chief Medical Examiner. Among
5852 homicide victims there were 344 (5.9%) victims who were HIV positive.
Females were just as likely as males to be HIV positive. For females, the highest
rates were in the 25-34 year (11.7%) and 35-44 year (12.6%) age categories. For
males the highest rates were in the 35-44 year (13.7%) and 45-54 year (11.5%) age
categories. Other than there being no HIV positive Asian victims, there were no
differences in HIV rates among racial/ethnic groups. The highest rates of HIV
infection for homicide victims were among those using both opiates and cocaine
(males: 23.0%; females: 27.3%). Women, not men, using cocaine alone had a high
HIV positive rate (18.4%). Victims not using these drugs had rates of HIV around
2%. The authors believe that the high risk of HIV among homicide victims, may be
due to the use of cocaine and associated risky use of needles and risky sex
practices.
PMID- 9397549
TI - Midge larvae (Diptera: Chironomidae) as indicators of postmortem submersion
interval of carcasses in a woodland stream: a preliminary report.
AB - Data on colonization of rat carcasses by aquatic insects in riffle and pool areas
of a small woodland stream were obtained to elucidate patterns potentially useful
for determining the postmortem submersion interval of corpses in flowing water
habitats. After 39 days, the carcasses had no visual signs of deterioration in
the absence of large scavenging animals. Midge larvae (Diptera: Chironomidae)
were the dominant insects colonizing the carcasses. No patterns in numbers of
larvae over time were evident, but the diversity of genera increased after 29
days in the riffle. Also, Orthocladius larvae did not begin to colonize the
carcasses until after 13 days of submersion in the riffle and after 20 days of
submersion in the pool. Although separated only by 20 m, the riffle and pool rats
had dissimilar faunal assemblages. This suggests that different indices for
determining the postmortem submersion interval of corpses based on midge larvae
colonization should be developed for these two habitats. This investigation does
not provide replicated data, but does shed light on what may happen to mammalian
carcasses placed in a stream at a particular time of the year.
PMID- 9397550
TI - The response of the Intoxilyzer 5000 to five potential interfering substances.
AB - A study was conducted of potential vapor phase interferents which could be
present on human breath and also be capable of inducing a false-positive response
for ethanol on the evidential infrared-based breath testing device, the
Intoxilyzer-5000. This involved preparation and validation of a range of vapor
standards, which were introduced to the instrument using a dynamic flow double
bubbler system. Potential interferents were chosen on the basis of both their
infrared signatures and their general availability, and included toluene, m
xylene, o-xylene, methanol and isopropanol. All compounds tested were found to be
capable of inducing false-positive readings for ethanol in a highly reproducible
manner, as a result of which it has been possible to derive precise least-squares
equations describing the ethanol readout expected for any given blood
concentration of toluene, m-xylene, o-xylene, methanol and isopropanol. The
likelihood of an interference compromising the integrity of the analysis is
related to both the toxicological significance and prevalence of a given blood
concentration of each solvent, and the point at which the instrumental
interference light is triggered in each case.
PMID- 9397551
TI - Concentration-time profiles of ethanol in arterial and venous blood and end
expired breath during and after intravenous infusion.
AB - Ethanol (0.40 g/kg) was administered to 13 healthy men by intravenous (i.v.)
infusion at a constant rate for 30 min. The concentrations of ethanol in arterial
blood (ABAC), venous blood (VBAC), and end-expired breath (BrAC) were measured at
17 exactly timed intervals. Blood-ethanol was determined by headspace gas
chromatography and breath-ethanol was measured with a quantitative infrared
analyzer (DataMaster). BrAC was multiplied by 2300 to estimate the concentrations
of alcohol in blood. During the infusion of ethanol, ABAC exceeded VBAC by about
10 mg/dL on the average and ABAC was also higher than BrAC x 2300 by about 4
mg/dL on average. When infusion of alcohol ended, ABAC, VBAC, and BrAC were 94.8
+/- 2.06 (+/- SE), 84.7 +/- 1.54, and 89.3 +/- 2.10 mg/dL, respectively. The
concentrations of alcohol in blood (ABAC and VBAC) and breath decreased abruptly
after the administration of alcohol stopped and by 5 min postinfusion, the A-V
differences in concentration of ethanol were small or negligible. The mean
apparent half-life of the distribution plunge was 7 to 8 min, being about the
same for ABAC, VBAC, and BrAC. The disappearance rate of ethanol was 15.5 +/-
0.55 mg/ dL/h (mean +/- SE) for arterial blood, 15.2 +/- 0.49 mg/dL/h for venous
blood, and 16.3 +/- 0.73 mg/230 L/h for breath; no significant differences were
noted (p > 0.05). We conclude that A-V differences in the concentration of
ethanol exist during the loading phase but are rapidly abolished when the
administration of ethanol terminates. In the post-absorptive phase of ethanol
kinetics, when alcohol has mixed with the total body water, VBAC exceeds ABAC by
about 1-2 mg/100 mL on average.
PMID- 9397552
TI - Influence of pigmentation on the codeine content of hair fibers in guinea pigs.
AB - Tortoise shell guinea pigs (n = 7) were administered codeine (1 mg/mL codeine
base) in their drinking water for 3 weeks. Black, reddish-brown and white hair
was collected separately from each animal before and after treatment. The hair
samples were analyzed by GC/MS. The experiment showed positive results for all
hair fibers with large individual variability of drug incorporation. Low drug
intake resulted in small differences of the drug content in hair fibers different
in color, whereas in cases of high drug intake a strong influence of hair
pigmentation on the analytical results was observed. The highest drug content was
always found in black hair samples, non-pigmented hair showed the lowest drug
concentrations and the drug content in reddish-brown fibers was less than in
black hair samples from the same animal. From the results it was concluded, that
eumelanins rather than phenomelanins are the decisive factor for codeine-melanin
binding in hair and the amount of drug intake was suggested to determine the
relevance of hair pigmentation on the analytical results.
PMID- 9397553
TI - Ethyl glucuronide concentration in serum of human volunteers, teetotalers, and
suspected drinking drivers.
AB - The kinetic profile of ethanol and ethyl glucuronide (EtG) in serum was
investigated in three subject groups: 1) Healthy, moderately drinking volunteers
(daily intake less than 30 g ethanol) who ingested a single dose of ethanol. In
this group the maximum of serum ethyl glucuronide concentration (SEtGC) and of
serum ethanol concentration (SEC) did not exceed 3.7 mg/L and 1.5 g/L
respectively. EtG peaked 2 to 3.5 h later than ethanol. EtG was eliminated with a
terminal half-life of 2 to 3 h. EtG decreased slower than ethanol--the metabolite
could still be determined in serum up to 8 h after complete ethanol elimination.
2) In serum samples of teetotalers neither ethanol nor EtG could be found. 3) In
37 of 50 serum samples of drivers suspected of driving under the influence of
ethanol, SEtGC was found between the limit of detection (0.1 mg/L) and 20 mg/L.
If the SEC is less than 1 g/L and the SEtGC is significantly higher than 5 mg/L,
we assume alcohol misuse.
PMID- 9397554
TI - Who does the family court refer for psychiatric services?
AB - Demographic differences between adolescents referred for psychiatric services by
the Family Court and by facility staff at a state-run juvenile justice evaluation
center are examined. Those groups are then compared to the facility's general
population. It is concluded that race, gender, age, and judicial discretion are
the factors that distinguish court-referred adolescents from their counterparts
referred by facility staff and in the general population.
PMID- 9397555
TI - Forensic analysis and psycholegal implications of parricide and attempted
parricide.
AB - In a retrospective archive study, 64 adjudicated adult cases involving the murder
or attempted murder of at least one parent, referred for forensic evaluations are
described. Biographic, demographic, diagnostic, crime scene, psycholoegal
opinion, and disposition data are presented. Results indicated a 40% rate of
insanity acquitees. Attempted parricide subjects were more likely to have
inpatient psychiatric histories, witnesses present during the criminal act,
nonresponsiveness towards their actions, competency raised, and a hospital
disposition. Gender and ethnicity were found to have a significant effect on
ultimate disposition. Fifty-four percent of the sample opined psychotic were
sentenced to prison, suggesting other factors considered by judge and jury.
Profile characteristics and typologies are presented. The findings are compared
to studies involving parricide and legal strategies involving similar cases.
PMID- 9397556
TI - A pilot study using the first cervical vertebra as an indicator of race.
AB - The articular surfaces and vertebral foramen of the first cervical vertebra can
be used to estimate race from complete and fragmentary specimens. Eight
measurements taken from 200 vertebrae from the Terry and Hamann-Todd collections
(Smithsonian Institution and Cleveland Museum of Natural History, respectively)
were used to construct 13 discriminant functions that predict race with 76-60%
accuracy.
PMID- 9397557
TI - Comparison of three DNA extraction methods on bone and blood stains up to 43
years old and amplification of three different gene sequences.
AB - Extraction of amplifiable DNA-from degraded human material in the forensic
context remains a problem, and maximization of yield and elimination of
inhibitors of the Polymerase Chain Reaction (PCR) are important issues which
rarely feature in comparative studies. The present work used PCR amplification of
three DNA sequences (HLA DPB1, amelogenin and mitochondrial) to assess the
efficiency of three methods for extracting DNA (sodium acetate, magnetic beads
and glass-milk) from 32 skeletal samples and 25 blood stains up to 43 years old.
The results, analyzed using multivariate statistics, confirmed that the
extraction method was crucial to the subsequent detection of amplification
products; the glass-milk protocol performed better than sodium acetate, which was
better than magnetic beads. Successful amplification also depended on gene
sequence, multiple copy mitochondrial sequences performing best; however, with
the singly copy sequences, the longer HLA DPB1 (327 bp) being detected just as
often as the shorter amelogenin (106/112 bp). Amplification products were
obtained more frequently from blood stains than bone, perhaps reflecting
differences inherent in the material, and from younger compared with older
specimens, though plateauing seemed to occur after 10 years. PCR inhibitors were
more frequent in sodium acetate extracts.
PMID- 9397558
TI - Austrian Caucasian population data for the quadruplex plus amelogenin: refined
mutation rate for HumvWFA31/A.
AB - Human identification of biological specimens has undergone immense change since
the development of PCR typing systems for forensic casework. In contrast to RFLP
and VNTRs, STRs are the method of choice when the investigated genomic DNA is
present in low quantity or in degraded shape. In the current study, the X-Y
homologous gene Amelogenin has been added to a widely used multiplex PCR
amplification system consisting of four tetrameric STR loci (Quadruplex-HumTH01,
HumvWFA31/A, HumFES/FPS, and HumF13A1). The modified Quadruplex was used to type
382 unrelated Caucasians from Western Austria. The population data meet Hardy
Weinberg and linkage equilibrium expectations, and do not show significant
deviations from either US, German, and Turkish Caucasian databases. In an
investigation of 382 meioses, two mutations were revealed at the HumvWFA31/A
locus. Consequently, the data in this paper provide the conditions for adding
Amelogenin to the Quadruplex, and suggest that when doing paternity testing, the
mutation rate for the HumvWFA31/A locus must be considered.
PMID- 9397559
TI - Validation studies for the genetic typing of the D1S80 locus for implementation
into forensic casework.
AB - A series of validation experiments were designed to evaluate, according to the
Technical Working Group on DNA Analysis Methods (TWGDAM) guidelines, the analysis
of the D1S80 locus for casework implementation. Approximately 400 samples from
three different populations (Minnesota Caucasian, Minnesota African Americans,
and Minnesota Native Americans) were typed to determine allele frequencies.
Simulated forensic type specimens (blood, saliva, hair and semen, or vaginal
secretions) were typed to demonstrate that deoxyribonucleic acid (DNA) extracted
from various tissues of an individual yield the same D1S80 type. Dilution studies
were performed and it was determined that a wide range of input DNA (0.5 ng to
40.0 ng) will consistently yield typeable results. The evaluation of DNA from
various animals showed that the D1S80 locus is specific to human DNA within the
limits of the parameters tested. The reproducibility of the system was tested by
duplicate analysis of approximately 200 population samples. Duplicate samples
were analyzed on both horizontal and vertical gel systems. In addition, simulated
forensic specimens were analyzed by two independent laboratories: the Minnesota
Forensic Science Laboratory (MFSL) and the Roche Biomedical Laboratories (RBL).
All analyses, including extraction, quantitation, amplification and typing, were
performed independently. All typing results for both laboratories were in
agreement. By the analysis of mixtures from various simulated casework type
mixtures, it was demonstrated that the D1S80 typing system is suitable for
analyzing mixtures. In addition to the simulated casework, evidentiary samples
from several adjudicated cases previously analyzed by restriction fragment length
polymorphism (RFLP) analysis and/or DQA1 were typed at the D1S80 locus. The D1S80
results were consistent with previous RFLP and/or DQA1 results regarding
inclusions/exclusions.
PMID- 9397560
TI - Analysis of allele distribution for six short tandem repeat loci in the French
Canadian population of Quebec.
AB - Short tandem repeat (STR) loci represent a rich source of highly polymorphic
markers in the human genome which are useful for the purposes of forensic
identification and determination of biological relatedness of individuals. Here,
as a part of an ongoing extensive study, we report the analysis of a multilocus
genotype survey of 642 to 870 chromosomes in the French Canadian Caucasian
population of Quebec at six STR loci. The loci HUMCSF1PO, HUMTPOX, HUMTH01,
HUMF13A01, HUMFESFPS, and HUMvWA were typed using two multiplex polymerase chain
reactions (PCR). Amplified DNA samples were subsequently analyzed by
polyacrylamide gel electrophoresis followed by silver staining. The heterozygote
frequencies of the loci range from 0.614 to 0.820 (0.661 to 0.818 expected) and
the number of alleles from 7 to 12 per locus. Although statistically significant
deviation from Hardy-Weinberg expectations of genotype frequencies was noted at
some loci by one or more tests, in general, the genotype frequencies are well
estimated from the product of allele frequencies at all loci. The most frequent
six-locus genotype is expected to occur in the French Canadian population with a
frequency of 3.50 by 10(-5) and together, these six loci have an average
probability of discrimination of 0.9999985. The study presented here indicates
that these six STR loci are informative genetic markers for identity testing
purposes in the French Canadian Caucasian population of Quebec.
PMID- 9397561
TI - The effects of blood transfusions on PCR DNA typing at the CSF1P0, TP0X, TH01,
D1S80, HLA-DQA1, LDLR, GYPA, HBGG, D7S8 and GC loci.
AB - Pre-transfusion and post-transfusion blood samples from eight individuals were
typed at 10 PCR amplified loci. In no case did the PCR DNA profile of the post
transfusion blood sample differ from that of the pre-transfusion profile.
PMID- 9397562
TI - Molecular detection of JC virus in embalmed, formalin-fixed, paraffin-embedded
brain tissue.
AB - Embalmed tissues are adequate for the detection of JC virus in lesions of
progressive multifocal leukoencephalopathy (PML) by immunohistologic and
molecular methods. JC virus was readily detected in embalmed brain tissue using
immunohistochemistry (IHC), in situ hybridization (ISH), and the polymerase chain
reaction (PCR). Two brains were removed from bodies that had been embalmed at
least 24 h prior to autopsy. They were subsequently post fixed in 10% buffered
formalin for 10-14 days before dissection and molecular studies were performed.
Though these techniques are not novel, their use in embalmed tissues is. Routine
embalming should not eliminate these diagnostic procedures from consideration.
PMID- 9397563
TI - GC/MS confirmation of barbiturates in blood and urine.
AB - A gas chromatography-mass spectrometric method is described for the quantitative
measurement of 6 commonly used barbiturates in blood and urine specimens. The
targeted barbiturates are butalbital, amobarbital, pentobarbital, secobarbital,
mephobarbital and phenobarbital. They are recovered along with the internal
standard, tolybarb, from blood and urine using liquid extraction then alkalated
to form the N-ethyl derivatives. The ethylated barbiturates have symmetrical
peaks which are well separated from each other on a non-polar methylsilicone
capillary column. The derivatives on a non-polar methylsilicone capillary column.
The derivatives facilitate quantitations between 50 and 10,000 ng/mL. The day-to
day CVs for all 6 barbiturates were between 4 and 9% at 200 and 5000 ng/mL. The
method has been extended for identifying other acidic drugs and drug metabolites.
They are mainly non-steroidal anti-inflammatory drugs, diuretics, and
anticonvulsants. An additional 83 compounds can be qualitatively identified.
PMID- 9397564
TI - A false report of product tampering involving a rodent and soft drink can: light
microscopy, image analysis and scanning electron microscopy/energy dispersive X
ray analysis.
AB - The "Pepsi Tamperings" of 1993 resulted in a large number of cases involving
foreign objects reportedly found inside canned soft drinks. Although the majority
of cases involved medical syringes and metallic objects, one case involved the
report of a mouse found inside a can of Caffeine-Free Diet Pepsi. Using light and
polarized light microscopy and computer-assisted image analysis, trace evidence
and tooth structure from the suspect mouse were matched to scratches and
indentions on the suspect can. Scanning electron microscopy and energy dispersive
X-ray analysis were used to compare and match particles of gnawed metal from the
lid of the suspect can to other particles recovered from the muzzle and stomach
of the suspect mouse. The forensic analyses in this case proved the mouse could
not have been canned in the soft drink product and refuted the defendant's sworn
statements.
PMID- 9397565
TI - Estimation of postmortem interval based on colony development time for
Anoplolepsis longipes (Hymenoptera: Formicidae).
AB - The postmortem interval for a set of human remains discovered inside a metal tool
box was estimated using the development time required for a stratiomyid fly
(Diptera: Stratiomyidae), Hermetia illucens, in combination with the time
required to establish a colony of the ant Anoplolepsis longipes (Hymenoptera:
Formicidae) capable of producing alate (winged) reproductives. This analysis
resulted in a postmortem interval estimate of 14 + months, with a period of 14-18
months being the most probable time interval. The victim had been missing for
approximately 18 months.
PMID- 9397566
TI - A killing of Baby Doe.
AB - An anencephalic infant died in the Neonatal Intensive Care unit six hours after
birth. Eighteen months later, in a discussion of intrusive federal "Baby Doe"
regulations with co-workers at the hospital, a registered nurse mentioned that he
had found a way to avoid these provisions, and that he had in fact done so on one
occasion by killing this particular infant. A co-worker related his story to
police, and the "wheels of justice" were set into motion. I describe the
chronology of events and the pathologic findings in this case of infanticide,
purportedly committed "with mercyaforethought."
PMID- 9397567
TI - Tissue distribution of ketamine in a mixed drug fatality.
AB - While reports of ketamine abuse are increasing, reports of ketamine deaths and
tissue concentrations associated with fatalities are rare. We report here a case
of a mixed drug fatality involving ketamine and ethanol. Ketamine analysis was
carried out by gas chromatography with a nitrogen-phosphorus detector (NPD). We
found the following tissue concentrations: blood 1.8 mg/L; urine 2.0 mg/L; brain
4.3 mg/kg; spleen 6.1 mg/kg; liver 4.9 mg/kg, and kidney 3.6 mg/kg. The blood
ethanol concentration was 170 mg/dL. Because an empty nalbuphine ampule was found
in the possession of the deceased, the blood was assayed for this opioid compound
using a gas chromatography/mass spectrometry (GC/MS) method. None was detected at
a limit of detection of 0.02 mg/L.
PMID- 9397568
TI - Two traffic fatalities related to the use of difluoroethane.
AB - The 18-year-old white male driver and 17-year-old white male passenger of an
automobile were killed when their vehicle crossed the median of a 4-lane highway
and collided with a minivan. A can of airbrush propellant was found in the
automobile of the deceased. The only drug detected during initial toxicological
analyses was 130 mg/L ethanol in the blood of the driver. When performing ethanol
analysis by headspace gas chromatography, an unidentified peak was observed in
the blood of both deceased. This peak was identified as difuoroethane (Freon
152), the propellant in the aerosol can found in the automobile. The
concentrations of difluoroethane in the blood of the driver and passenger were 78
mg/L and 35 mg/L, respectively. Based on a literature search we believe that this
is the first report of the quantitation of difluoroethane in biological samples.
PMID- 9397569
TI - Effects of 3,4-methelenedioxymethamphetamine in decomposing tissues on the
development of Parasarcophaga ruficornis (Diptera: Sarcophagidae) and detection
of the drug in postmortem blood, liver tissue, larvae and pupae.
PMID- 9397570
TI - Findings in gunshot wounds from tandem projectiles.
PMID- 9397571
TI - Barbiturates and analgesics in Calliphora vicina larvae.
PMID- 9397572
TI - An examination of the binding of aluminum to protein and mineral components of
bone and teeth.
AB - Aluminum binding by a variety of noncollagenous proteins associated with bone and
teeth (osteopontin, osteocalcin and phosphophoryn) and by hydroxyapatite are
examined. The proteins bound aluminum with a dissociation constant, KD, of the
10(-7) M or greater at pH = 7. The number of atoms of aluminum bound was found to
be related to but not equivalent to the number of phosphorylated serines in
osteopontin and phosphophoryn. Osteocalcin bound one aluminum tightly presumably
due to its gamma-carboxyl glutamate residues. Hydroxyapatite bound Al3+ tightly
releasing 1.5 equivalent Ca2+ per Al3+ bound. Addition of 3 mM Ca2+, close to the
total concentration found in animal circulating fluids, did not effect noticeably
the amount of Al3+ bound to bone which must have a KD for Al3+ < 10(-6). Silicic
acid added after equilibration with all these materials has little effect but
neither the proteins nor hydroxyapatite removed much Al3+ from pre-equilibrated
Al3+ solution with silicic acid. The results are discussed with regard to Al3+
poisoning.
PMID- 9397573
TI - Interaction of iron(II) with bile salts.
AB - Iron(II) ions react with small aggregates of cholate, glycocholate,
chenodeoxycholate, and deoxycholate to form soluble and colloidal compounds.
Taurocholate under conditions used does not react with the Fe2+ ion. Small
aggregates of dihydroxy bile salts (predominating in the premicellar region, at
concentrations of the bile salt above 1 mmol dm-3) have a larger affinity for
Fe2+ compared to those formed from cholate anions. In their interactions with
small aggregates of cholate anions, the Fe2+ ion shows an affinity comparable to
that of Cu2+ and Cd2+ and somewhat larger than that of Zn2+. Small aggregates of
cholate show a higher ability to mask Fe2+ than those of taurocholate and
glycocholate. Interaction of glycocholic acid anions with Fe2+ ions is sufficient
to prevent iron(II) precipitation.
PMID- 9397574
TI - Effects of additional iron-chelators on Fe(2+)-initiated lipid peroxidation:
evidence to support the Fe2+ ... Fe3+ complex as the initiator.
AB - The addition of chelated Fe2+ ions in a liposomal system often results in a short
lag period before peroxidation starts. The addition of a second chelator at the
end of the lag period results in an inhibition of the lipid peroxidation. The
degree of inhibition depends on the stability constants of the chelator in
ligating Fe2+ and/or Fe3+. A more striking inhibitory effect was observed for the
chelators with higher stability constant for either or both Fe(2+)- and Fe(3+)
complex, but much less inhibition was found for those with lower stability
constants for both complexes. Assuming that the "initiator" for iron-dependent
lipid peroxidation is formed through the redox process of iron ion and finally
emerged at the end of the latent period, the inhibitory effect of the second
chelator may be explained as the abstraction of either Fe2+ or Fe3+ from the
initiator by an additional free chelator, which results in the decomposition of
the initiator. This study supports the hypothesis that a Fe2+ ... Fe3+ complex is
responsible for iron-initiated lipid peroxidation.
PMID- 9397575
TI - Evidence for a novel heme adduct generated by the in vitro reaction of 2,4,6
trinitrotoluene with human hemoglobin using electrospray ionization mass
spectrometry.
AB - The bioactivation of nitroaromatic compounds to highly reactive intermediates is
responsible for the genotoxic and cytotoxic effects by reaction with DNA and
proteins. Due to its continued use as a secondary explosive and its prevalence at
contaminated sites, the mechanism of covalent binding of 2,4,6-trinitrotoluene
(TNT), or its metabolites, to critical cellular proteins has been of interest.
Herein, we report the in vitro reaction of TNT with human hemoglobin under
anaerobic and reductive (using sodium hydrosulfite) conditions, yielding a novel
adduct between a putative nitrosodinitrotoluene (MW = 211 Da) and the prosthetic
heme group (iron protoporphyrin-IX or heme b). While the covalent modification of
hemoglobin polypeptide chains by TNT has been established, to our knowledge, this
is the first example of a heme-TNT related adduct. This finding could be of
relevance in investigation of biotransformation of TNT in subjects exposed to TNT
via skin exposure or inhalation.
PMID- 9397576
TI - The berenil ligand directs the DNA binding of the cytotoxic drug Pt-berenil.
AB - To determine the affinity towards DNA sequences of novel antitumor drugs in
comparison with their parental compounds may lead to the design of new analogous
drugs with improved antitumor activity. Thus, the affinities of Pt-berenil
towards different DNA sites relative to cis-DDP and berenil drugs were analysed
using DNase I footprinting and restriction endonuclease analysis. The data show
that the Pt-berenil drug inhibits the cutting activity of Hind III enzyme to the
same extent as the berenil ligand. In contrast, inhibition by Pt-berenil of the
cutting activity of Bam HI enzyme is significantly lower than that of cis-DDP.
These results indicate that although the cis-Pt(II) centres of Pt-berenil
maintain certain affinity toward G + C regions, which are the main binding
sequences of cis-DDP, however, the berenil ligand seems to direct the Pt-berenil
molecule towards A + T regions, which are the binding sequences preferred by
berenil. In fact, 1H- and 195Pt-NMR spectra of Pt-berenil:nucleoside complexes
show that Pt-berenil not only covalently binds to N7 of guanosine but also to
N1/N7 of adenosine.
PMID- 9397577
TI - Synthesis and antitumor activity of (diamine)platinum(II) complexes of
benzylmalonate derivatives.
AB - (Diamine)platinum(II) complexes of benzylmalonate derivatives as a leaving group
designed in a wide range of lipophilicity and water-solubility were prepared and
their antitumor activities were attempted to correlate to their lipophilicity or
solubility. A good relationship was observed between their in vitro toxicity and
solubility of the title complexes with the same carrier ligand, DACH (trans-(+/-)
1,2-diaminocyclohexane): The most soluble complexes are most cytotoxic whereas
the least soluble complexes are least cytotoxic. However, no relationship could
be established between their in vivo activity and their lipophilicity or
solubility presumably due to other pharmacokinetic factors involved in vivo. The
molecular structure of (IPA)2Pt(DBM).2CH3OH (IPA = isopropylamine; DBM =
dibenzylmalonate) was determined by X-ray diffraction: space group P2(1)/n, a =
11.433 (3), b = 14.461 (4), c = 17.478 (4) A, beta = 97.25 (3) degrees, z = 4, R
= 0.0437.
PMID- 9397578
TI - Organotin complexes with pyrrole-2-carboxaldehyde monoacylhydrazones. Synthesis,
spectroscopic properties, antimicrobial activity, and genotoxicity.
AB - A series of organotin complexes with pyrrole-2-carboxaldehyde 2
hydroxybenzoylhydrazone (H3mfps) and pyrrole-2-carboxaldehyde 2
picolinoylhydrazone (H2mfpp) was investigated. The IR, 1H, and 119Sn nuclear
magnetic resonance spectroscopic characterization of all the compounds is
reported and discussed in connection with the ligand behaviour of the hydrazone
and the structure of the organotin complex. Complexes exhibit antibacterial
properties higher than those of the corresponding ligands but they turn out to be
less potent than the parent organotin compounds. Sn(H3mfps) (C6H5)2Cl2.2H2O and
Sn(Hmfpp)(n-C4H9)2Cl are the most active antibacterial compounds showing MIC
values between 3-6 micrograms/ml against Bacillus subtilis and Staphylococcus
aureus and between 6-25 micrograms/ml against Escherichia coli; the first
compound also strongly inhibits the growth of Aspergillus niger. All the ligands
and complexes are devoid of DNA-damaging activity in the Bacillus subtilis rec
assay. H2mfpp and its complexes Sn(Hmfpp)(C2H5)2Cl and Sn3(Hmfpp)(mfpp)
(C6H5)3Cl6 are shown by the Salmonella-microsome assay to be mutagenic substances
in the presence of a metabolic activation system. The obtained results are
discussed on the basis of structure-activity relationships.
PMID- 9397579
TI - The effects of muscular dystrophy on craniofacial growth in mice: a study of
heterochrony and ontogenetic allometry.
AB - Mechanical loading of muscles on bones at their sites of attachment can regulate
skeletal morphology. The present study examined the effects of muscle
degeneration on craniofacial growth, using two strains of muscular dystrophic
mice, Mus musculus, differing in pathological severity. We collected radiographic
and weight data longitudinally and digitized radiographs to obtain distances
between anatomical landmarks in different functional regions of the skull. We
then quantified heterochronic and allometric differences among genotypes and
between sexes. Because growth is nonlinear with respect to time, we first used
the Gompertz model to obtain heterochronic growth parameters, which were then
tested with ANOVA. Ontogenetic allometric analyses examined the scaling
relationships between various measurements with linear regressions. For most
measurements the severely dystrophic mice are significantly smaller in final size
than both the control and the mildly dystrophic mice, which are statistically
indistinguishable. Measures of total growth and the neurocranium exhibit more
differences among groups in heterochronic parameters of early ontogeny because
growth in these regions is controlled primarily by brain expansion that ceases
early in development. In contrast, the face and mandible exhibit more differences
in later growth parameters possibly because of the increased influence of muscles
on these regions as growth progresses. The severely dystrophic mice have flatter,
more elongate skulls and mandibles than those of the other two genotypes,
concurrent with an absence of muscular forces to stimulate growth in a superior
inferior direction.
PMID- 9397580
TI - The caudal neurosecretory system and its afferent synapses in the goldfish,
Carassius auratus: morphology, immunohistochemistry, and fine structure.
AB - Morphological features of the goldfish caudal neurosecretory system were
investigated by means of immunohistochemical localization of urotensins I and II
(UI and UII) and electron microscopic examination of the caudal neurosecretory
neurons, the urophysis, and the synaptic neuropil. The aim of the work is to
provide a detailed morphological description of the afferent synapses to the
caudal neurons and to analyze their distribution through the rostrocaudal
extension of the caudal neurosecretory system. Three morphologically different
types of neurosecretory cells have been identified according to size and shape:
large, medium, and small Dahlgren cells. The three different-sized cells share
similar patterns of immunoreactivity with the UI (or oCRF) and the UII antisera.
Electron microscopic examination of the synaptic neuropil throughout the caudal
system revealed the presence of four types of terminals: dense-cored-vesicle end
bulbs (DC), spherical-vesicle end bulbs (S), flattened-vesicle end bulbs (F), and
granular-vesicle end bulbs (G). The present study demonstrates that the small
Dahlgren cells receive different synaptic inputs from the large and the medium
neurosecretory cells. Indeed, G terminals are only found on the small Dahlgren
cells, whereas DC, S, and F terminals are distributed on the large, medium, and
small Dahlgren cell bodies and proximal processes.
PMID- 9397581
TI - Differential distribution of elastic system fibers in control and
bronchoconstricted intraparenchymatous airways in the guinea-pig lung.
AB - The elastic system fibers were studied at the light microscopic level by using
Weigert's resorcin-fuchsin method after oxidation. This study was designed to
describe the distribution of these fibers in intrapulmonary guinea-pig airways
and to characterize their conformational changes during bronchoconstriction
induced by methacholine aerosol. Airways present a palisade of elastic system
fibers just beneath the epithelial basement membrane; these fibers are also
present in the adventitial connective tissue. Thin fibers link the fibers located
in the palisade among themselves and also connect them to those fibers located in
the bronchial adventitial tissue, by traversing the airway smooth muscle. During
bronchoconstriction, the fibers located beneath the epithelial basement membrane
are divided into two components: one follows the epithelial invaginations towards
airway lumen, while the other population remains attached through airway smooth
muscle to the fibers located in the adventitial connective tissue. At the
ultrastructural level, the findings corroborated those of the light microscopy
and in addition, disclosed that typical mature elastic fibers and also elaunin
fibers attach directly to the basal lamina, a feature that has not been reported
previously in other tissues studied. This configuration is compatible with the
idea that fibers of the elastic system restrict the mucosal folding during
bronchoconstriction, and may also provide energy to restore airway configuration
to its normal status after contraction.
PMID- 9397582
TI - Sperm ultrastructure of six Australian hylid frogs from two genera (Litoria and
Cyclorana): phylogenetic implications.
AB - The spermatozoa of four fossorial (Litoria alboguttata, Cyclorana brevipes,
Cyclorana novaehollandiae and Cyclorana cryptotis) and two non-fossorial
australian hylid frogs (Litoria aurea and Litoria moorei) together with
previously examined Litoria (Hylidae: Anura) are compared. In spermatozoal
ultrastructure (in particular the structure of the sperm tail) Cyclorana includes
species which appear derived (apomorphic) relative to non-fossorial species of
Litoria while the fossorial L. alboguttata groups with Cyclorana. All hylid
species examined here are united by the bufonoid synapomorphy of a conical
subacrosomal cone consisting of separate sheaves and the eubufonoid synapomorphy
of a mitochondrial sheath or collar separated by a cytoplasmic canal from the
centriolar region and tail. Spermatozoal symplesiomorphies for the Eubufonoidea,
seen in Litoria (with the exception of L. alboguttata), are the well developed
thin undulating membrane with juxta-axonemal and axial fibre. L. alboguttata, C.
novaehollandiae and C. brevipes appear monophyletic in the apomorphic
modification of the undulating membrane as a thick, dense structure. In L.
alboguttata and C. novaehollandiae this structure retains a swelling, at the free
edge, homologized with the axial rod. C. brevipes has a further apomorphy as the
undulating membrane forms a parallel-sided dense structure with no separate
differentiation of an axial fibre. C. cryptotis, however, retains the
plesiomorphic sperm tail with a thin undulating membrane, juxta-axonemal and
axial fibre. That these differences in spermatozoal ultrastructure have
phylogenetic significance is endorsed by the similarity of the fertilization
biology of the species examined. On the basis of sperm ultrastructure three
separate lineages are discerned within Cyclorana s. lat.: 1) C. cryptotis; 2) L.
alboguttata and C. novaehollandiae; and 3) C. brevipes. The evidence of sperm
ultrastructure, supported by previously published molecular, morphological and
karyological data, clearly places Litoria alboguttata within the genus Cyclorana.
PMID- 9397583
TI - Calcific chronic lateral epicondylitis: a histological and ultrastructural study.
AB - Fragments of insertion tissue from right arm common extensor muscle have been
collected from a 25-year patient with chronic lateral epicondylitis. Specimens,
processed for light (LM) and electron (EM) microscopy, evidentiated a variety of
degenerative alterations, such as focal hyalinosis, lipoidosis, collagen fiber
redistribution, calcifications and vascular changes. Evidence of collagen normal
function maintenance and turnover have been also observed in tenocytes.
PMID- 9397584
TI - Interfollicular fibroblasts in the human thyroid gland: recognition of a CD34
positive stromal cell network communicated by gap junctions and terminated by
autonomic nerve endings.
AB - While epithelial structure and functions have been substantially investigated in
many organs, the mesenchymal elements have received less attention. Compared with
follicular epithelial cells, there are a few morphological studies on the stroma
of human thyroid gland. In order to characterize more fully and assess its
possible functions, 15 samples of surgical and autopsy human thyroid tissue were
studied by classical histology, immunohistochemistry, transmission electron
microscopy, electron microscopic immunohistochemistry, and scanning electron
microscopy. In human thyroid gland, the interfollicular connective tissue
surrounding the follicles contained collagenous matrix, fibroblasts, unmyelinated
nerve fibers with Schwann cells, small blood vessels, lymphatics, lymphocytes,
plasma cells, macrophages, and mast cells. At the ultrastructural level, gap
junctions between the cytoplasmic processes of interfollicular fibroblasts
constituted a novel observation. Immunohistochemistry using a monoclonal antibody
against Cx43 confirmed the distribution of gap junctions between stromal
fibroblastic cells, which was compatible with the ultrastructural findings. The
frequent and intimate association of fibroblastic processes with nerve terminals
was also shown. Interfollicular stromal fibroblasts also stained with CD34. The
main constituent of the human thyroid stromal tissue was a CD34 positive
reticular network involving fibroblasts, mononuclear cells and nerve terminals.
It represents a highly ordered stroma, with potential structural and functional
similarities to the stroma of bone marrow (Yamazaki and Allen, 1990).
PMID- 9397585
TI - The effect of pentoxifylline on ultrastructural picture of type II alveolar
epithelial cells and generation of reactive oxygen species during
cyclophosphamide-induced lung injury.
AB - The aim of the study was to evaluate the effect of pentoxifylline (PTXF) on the
production of reactive oxygen species in the rat lungs after intraperitoneal
(i.p.) cyclophosphamide (CP) administration (150 mg/kg b.w.) and to draw a
correlation between the morphological changes and biochemical findings.
Morphological examinations were based on ultrastructural analysis in the
transmission electron microscope. It was found that single i.p. CP administration
caused destructive changes, particularly within mitochondria and lamellar bodies
of type II alveolar epithelial cells (EP II), and within blood vessels of
interalveolar septa. The changes were accompanied by an increase in the MDA
(malondialdehyde) homogenates. The animals receiving PTXF + CP showed
normalization of MDA level and minor damage to EP II confined to alterations in
lamellar bodies of EP II. The vascular changes observed after i.p. CP
administration were manifested in endothelial swelling and accumulation of
neutrophilic granulocytes, monocytes and in the later period blood platelets
within the capillaries of interalveolar septa. The cells were tightly attached to
endothelium. The changes in the vascular system were accompanied by a significant
decrease in the activity of antioxidant enzymes (Cu,Zn-SOD and GSSG-R) in the
blood serum collected from the left ventricle of the heart. In the animals given
PTXF + CP, a higher decrease was revealed in the activity of these enzymes.
Ultrastructural examinations found morphological signs of a facilitated flow,
mainly of cellular elements, through the vessels of the interalveolar septa of
the lungs.
PMID- 9397586
TI - Cell body volume of spinal ganglion neurons: estimation by three different
methods.
AB - We estimated the mean volumes of two series of nerve cell bodies, one from rabbit
and one from rat spinal ganglia by three different methods: a procedure we
devised 25 years ago (the circle-fitting method), one of the new stereological
methods (the nucleator method) and the method of serial sectioning--the most
direct and accurate procedure presently available for estimating cell size. In
the case of the rabbit, in which most spinal ganglion neurons have a single
nucleolus, the mean volumes estimated by the first two methods are closely
similar and deviate by less than 2% from the mean obtained by serial sectioning.
In the case of the rat, in which approximately half of the spinal ganglion
neurons have more than one nucleolus, the mean volumes estimated by the first two
methods are again closely similar, but deviate by about 12% from the mean
obtained by serial sectioning. These findings show that: a) both the nucleator
method and the circle-fitting procedure are more accurate when applied to neurons
with a single nucleolus; b) if certain conditions are respected, not all the
methods previously used to estimate cell size give biased results. However, the
new stereological procedures are easier and quicker to use than the earlier
methods. These findings also show that our previous results obtained by the
circle-fitting method are to be considered valid.
PMID- 9397587
TI - Cytotoxic effect against HeLa cells of polysaccharides from the lichen Ramalina
celastri.
AB - The most active polysaccharides which show anti-tumoral activity are (1-->3)-beta
D-glucans, branched or not at O-6. Since these structures are sometimes poorly
soluble in aqueous media, alpha-D-glucans and their chemical derivatives, which
are more soluble, were also studied. The present object is to observe
morphological alterations in HeLa cells caused by two different polysaccharides
obtained from the lichen Ramalina celastri, which are (1-->3),(1-->4)-linked
alpha-D-glucan and its sulphated derivative. The cells were incubated in Eagle's
medium in the absence or presence of each polysaccharide and routinely processed
and analysed by light and electron microscopy. Even though the alpha-D-glucan
altered the cellular volume, cytoplasmic densities, and mitosis, the resulting
monolayer was similar to the control. TEM analysis showed cytoplasmic blebbing
and the presence of an amorphous electron-dense material free in the cytoplasm
and interior membranes. The enhanced injury caused by the sulphated derivative
was apparent, altering cell adhesion and causing cell aggregation. Nuclear
modifications such as fragmentation and condensation of chromatin under the
nuclear envelope, which showed to be convoluted, suggested the occurrence of cell
death by apoptosis.
PMID- 9397588
TI - Intramural coronary artery disease in swine with naturally occurring hypertrophic
cardiomyopathy.
AB - Intramural coronary artery disease (ICAD) has been reported in myocardium
affected with hypertrophic cardiomyopathy (HCM), but has never been studied in
detail with respect to the cell type or lipid infiltration involved in the wall
thickening. The lack of heart samples may be one of the rationales to hamper the
progress in investigating this disease. Recently, the discovery of naturally
occurring HCM in swine has provided an excellent opportunity for the study of
ICAD because of the high prevalence of ICAD in this animal. The present study
provides a detailed structure feature in the thickened arterial wall of ICAD by
both histologic and electron microscopic means. Morphologically, the feature of
ICAD is due primarily to the neointimal thickening. Smooth muscle cells (SMC) and
extracellular matrix (collagen and elastic fibers) are the major components
responsible for the thickened neointima. Fragmentation of the internal elastic
membrane is associated with the migration and proliferation of SMC from the media
to the intima. Therefore, pigs with HCM may be a potential animal model not only
for the study of the mechanism by which SMC migrate and proliferate into intima,
but also for the future investigation of interventions in coronary artery
occlusion.
PMID- 9397589
TI - Gender difference in noise stress-induced ultrastructural changes in rat
myocardium.
AB - Male and female rats were exposed to noise 6 h daily for 7 days running and the
effect of stress was evaluated both on myocardium ultrastructure and plasma
corticosterone level. Both sexes showed subcellular alterations of
cardiomyocytes; mitochondria, in particular, which resulted the most affected
organelles, exhibited diluted matrix and cristolysis; in some areas, the
sarcoplasmic reticulum appeared vesiculated. Quantitative analysis of altered
mitochondria revealed that atrial myocardium was more affected in males than in
females. Moreover, corticosterone plasma assay showed, in exposed animals, a
growing increase without significant gender differences. The present findings
suggest a more marked involvement of male sex when challenged with noise
stressor.
PMID- 9397590
TI - A morphometric ultrastructural study of the seminal vesicle of rats submitted to
experimental chronic alcoholism.
AB - The effects of chronic alcohol ingestion on the secretory epithelium of the
seminal vesicle were studied in rats (Rattus norvegicus). Male adult albino
Wistar rats were divided into two groups: alcoholic and control. Tips of the
seminal vesicle were removed and prepared for light and electron microscopy.
Ultrastructural observations on the epithelial cells of the seminal vesicle
showed reduced epithelial cell size, decreased apical secretory vacuoles,
irregularly shaped nuclei with deep infoldings, increased lipid droplets and
dense bodies, a small number of microvilli covering the cell surface, and signs
of degeneration. In addition to the hormonal effects, alcohol may act on the
secretory epithelium of the seminal vesicle.
PMID- 9397591
TI - Exposure to hypercholesterolemic serum modifies the expression of cytoskeletal
proteins in cultured endothelia.
AB - Arterial endothelial layer dysfunction is considered to be one of the most
important events which initiate the development of the atherosclerotic plaque and
the cell cytoskeleton plays an essential role in maintaining the integrity of the
endothelium exposed continuously to haemodynamic forces. The aim of this work was
to study the modifications of the cytoskeletal proteins in the vascular
endothelium exposed to atherogenic conditions. A hamster aortic endothelial cell
line (HAEC) grown on glass coverslips was exposed for 24 h to
hypercholesterolemic or normal homologous serum. Upon staining with Oil Red O and
examination by phase contrast and fluorescence microscopy, HAEC incubated with
hypercholesterolemic serum appeared heavily loaded with lipid droplets that
showed a yellow autofluorescence in UV light and the general aspect of a foam
cell. HAEC were incubated with: a) anti-actin serum; b) anti-vinculin monoclonal
antibody (MoAb); c) anti-alpha actinin MoAb, and d) anti-talin MoAb, followed by
appropriate secondary antibodies coupled with FITC or rhodamine. As compared to
normal HAEC, the cells exposed to hypercholesterolemic serum showed a modified
pattern for actin and vinculin localization. Actin appeared as a weakly stained
network around the nuclear zone whereas vinculin was distributed as small
granules throughout the cell cytoplasm. These experimental data suggest that in
advanced atherosclerosis, some of the endothelial cytoskeletal proteins undergo
modifications which could represent one of the important factors involved in
further development of the atheromatous plaque. In addition they indicate that
HAEC exposed to hypercholesterolemic serum could represent an in vitro working
model for studying the events occurring in the endothelium at advanced stages of
atherosclerosis.
PMID- 9397592
TI - Structural peculiarities of vascular dendritic cell tubulovesicular system in
human atherosclerotic aorta.
AB - The principal function of vascular dendritic cells has been suggested to be
antigen processing/presentation but how this might occur is not clear. To find
out whether the organisation of vascular dendritic cells might allow them to
internalise antigens, we used electron microscopy to examine their fine
cytoarchitectonics. Tubular and vesicular structures were observed to form
continuous nets through which extracellular molecules might gain access to
lysosomes. This suggests that vascular dendritic cells might be able to degrade
antigens using the same mechanisms as occur in macrophages. We also speculate
that antigen processing might be different between type I vascular dendritic
cells which possess a hypertrophied tubulovesicular system and type II vascular
dendritic cells where the tubulovesicular system is less prominent. The present
work indicates that the tubulovesicular system is functionally associated with
the extracellular space. This connection with the extracellular space through the
system of cisterns and vesicles can allow the transport of different substances
entering the cistern nets.
PMID- 9397593
TI - Submicroscopic mathematical evaluation of spermatozoa in assisted reproduction.
4. The bovine fertilization (Notulae seminologicae 10).
AB - In this paper we apply a modification of the formula of Baccetti et al. (1995) in
the evaluation of submicroscopical characteristics of bull spermatozoa used in
assisted reproduction. In the present experiment sperm quality is proposed as a
useful parameter in predicting the success of fertilization. Our results
demonstrate that the percentage of spermatozoa devoid of submicroscopic defects,
according to the particular Bayesan formula proposed by us, is clearly correlated
with the result of artificial insemination. In fact, the parameter concerning
sperm quality obtained in variously successful donors shows a large correlation
with fertility power. The synthetic parameters observed are therefore a good tool
in the prediction of sperm power in artificial fertilization. The evaluation is
mainly concerned with the quality of the acrosomal characters, the status of the
chromatin, the shape of mitochondria, the position of the postacrosomal sheath,
the perinuclear space and the axonemal pattern. All these characters are
expressed with different means in ejaculates. All these data confirm that
submicroscopic-mathematical evaluation offers a convincing and reliable diagnosis
based upon sperm structure and functions such as acrosomal reaction and cell
motility. It has been also demonstrated that sperm quality is a major factor in
the success of artificial insemination and it is clearly revealed in the
integrity of most of sperm organelles.
PMID- 9397594
TI - Microanatomy of the epididymis and vas deferens.
AB - In this review, the structural and functional characteristics of the human
epididymis, including vas efferents and ductus deferens, are revisited under the
morphological and ultrastructural point of view. New surface sperm antigens,
enabling the fertilizing power during the epididymal transit, various epididymal
microenvironments and their activities on the spermatozoa are reported. This
revision is important because the recent procedures of assisted reproduction,
aimed at overcoming the cases of obstructive azoospermia, use the spermatozoa
aspirated from the proximal segments of the epididymis and suggest a flexibility
of the epididymal function with regard to the fertilizing sperm capacity. In my
opinion these procedures must be based on an accurate investigation on the
function of the different epididymal districts. Moreover, in patients affected by
congenital absence of the vas deferens (CAV), the ultrastructural examination of
the spermatozoa aspirated from the proximal segments of the epididymis revealed
that most of them are defective: in fact the absence of the vas deferens seems to
affect the development and the functional properties of the epididymal
spermatozoa.
PMID- 9397595
TI - Chromium contamination in sediment, vegetation and fish caused by tanneries in
the state of Minas Gerais, Brazil.
AB - In order to evaluate the chromium contamination from tannery discharges into
rivers in the State of Minas Gerais, Brazil, samples of fluvial sediment,
vegetation and fish were collected and submitted to chemical analysis. The
chromium content in the samples was measured by atomic absorption
spectrophotometry. Metal inputs were related to effluent discharges into the
rivers. High concentrations of chromium were found in samples when compared with
controls. Sediment investigations indicated strong enrichment and high
geoaccumulation indices, while chromium concentrations in the analyzed vegetation
were higher than those normally found in these materials. Chromium levels in fish
exceeded 35 times the Brazilian recommendation value for human intake.
PMID- 9397596
TI - Speciation of aluminium in tea infusions studied by size exclusion chromatography
with detection by post-column reaction.
AB - Aluminium-organic species in tea infusions were studied by size exclusion
chromatography, using a Superose 12 HR column, a mobile phase of 0.12 mol l-1
tris(hydroxymethyl)aminomethane adjusted to pH 5.5 and detection by UV-visible
spectrophotometry. Aluminium was detected after post-column reaction with
pyrocatechol violet at 585 nm and the organic material was detected at 280 nm.
Teas of different origin were analyzed; the results indicate that aluminium is
bound to the same relatively narrow size-range of large organic molecules in the
tea infusions, irrespective of the origin of the tea.
PMID- 9397597
TI - Statistical evaluation of ecosystem properties influencing the uptake of As, Cd,
Co, Cu, Hg, Mn, Ni, Pb and Zn in seaweed (Eucus vesiculosus) and common mussel
(Mytilus edulis).
AB - In order to evaluate the influence of geographically varying marine ecosystem
properties on the uptake of trace elements in bioindicators, samples were taken
of seaweed (Fucus vesiculosus) and common mussel (Mytilus edulis) along the North
Sea and Baltic Sea coast. Seasonal variations of the bioindicator status were
minimized by sampling within 1 month. Ecosystem properties considered were the
geographical position, the salinity and the concentrations of the macroelements
Ca, Fe, K, Mg, Na, P and S in the bioindicators. Trace elements studied were As,
Cd, Co, Cu, Hg, Mn, Ni, Pb and Zn. Factor analysis of the concentration patterns
in the bioindicators and of salinity as a function of location confirmed the
influence of the geographically varying salinity on the biological uptake of
macroelements and trace elements. This influence of salinity was higher in the
case of seaweed than in the case of mussel. Comparison of the geographical
courses of the macroelement and trace-element concentrations by cluster analysis
revealed corresponding courses for As and Hg in both bioindicators. All other
elements showed different courses in seaweed and mussel. Subsequent cluster
analysis comparing locations with respect to the macroelement or trace-element
concentration patterns in the bioindicators, indicated a clear separation of
North and Baltic Sea locations. However, the trace-element concentration patterns
provided a regionally less distinctive ecosystem arrangement than those of the
macroelement ones. The results of the cluster analysis were verified by
discriminant analysis forming groups of locations with respect to geographical
position and salinity. Results of discriminant analysis demonstrated, both for
seaweed and for mussel as bioindicators, that the location groups formed
according to the macroelement concentration patterns corresponded well with the
geographical regions in the order of salinity. On the other hand, location groups
based on the trace-element concentration patterns again showed a modified less
distinctive ecosystem arrangement than the location groups based on macroelement
concentration patterns. This confirms modified conditions for the uptake of trace
elements in seaweed or mussel in comparison to the uptake of macroelements.
PMID- 9397598
TI - Lead levels in roadside soils and vegetation of Damascus city.
AB - This study concentrates on seasonal variations of lead levels in roadside soils,
vegetables and plants of Damascus city. Lead concentrations in soil samples
varied from 78.4 ppm to 832 ppm while mean lead levels in plants ranged from 2.6
ppm to 19.3 ppm; the highest levels were found to be in grass (44 ppm). In
addition, lead levels were lower in soil samples during the wet period (December
to April) whereas, it is higher in plants during the same period. Moreover,
traffic density, distance from traffic roads, climate and area topography (up-
and down hill) were influencing factors in lead levels in both the soil and plant
samples. The results have also shown that lead concentration in most of the
analyzed vegetable samples was high and normal washing does not decrease it to an
acceptable level.
PMID- 9397599
TI - Heavy metals: leaching from glazed surfaces of tea mugs.
AB - Heavy metals (zinc, lead, cadmium, iron, chromium, copper, manganese, nickel and
cobalt) were found to leach from the glazed surfaces of tea mugs collected from
13 different pottery units of Khurja (U.P.) and one each from Ghaziabad (U.P.)
and Calcutta (West Bengal) determined under different conditions. The leachates
used were: tea at 80 degrees C, orange juice at room temperature and 4% acetic
acid at room temperature, 40 degrees C and 60 degrees C, respectively. The volume
(capacity) of mugs ranged between 200 and 250 ml. The duration for leaching was
24 h in each case without stirring. The concentrations of metals leached in tea
at 80 degrees C were found in the range (in microgram/l): Zn, 236-730; Fe, 98
925; Cr, 62-119; Cu, 63-299; Mn, 710-2670; and Ni, 70-80 micrograms/l. The
concentrations of metals leached in orange juice at room temperature were in the
range (in microgram/l): Zn, 393-1262; Cd, 25-349; Fe, 122-342; Cr, 66-945; Cu,
135-853; Mn, 166-424; and Ni, 70-134 micrograms/l. The concentrations of heavy
metals extracted by 4% acetic acid at room temperature were found in the range
(in microgram/l): Zn, 18-192; Fe, 143-372; Cu, 51-190; and Mn, 0-48 micrograms/l;
at 40 degrees C (in microgram/l): Zn, 118-837; Fe, 124-639; Cu, 230-722; and Mn,
30-63 micrograms/l and at 60 degrees: Zn, 33-900; Fe, 83-576; Cu, 90-685; and Mn,
43-778 micrograms/l, respectively.
PMID- 9397600
TI - The impact of age, lactation and dietary habits on PCB in plasma in Swedish
women.
AB - The mean concentration of the chlorinated biphenyl 2,2',4,4',5,5'
hexachlorobiphenyl (CB-153) in plasma from 192 fishermen's wives from the Swedish
east coast was on a fresh weight basis 960 (range 80-4300) pg/g and lipid
adjusted 160 (range 20-780) ng/g lipid. The concentration of CB-153 in plasma was
significantly influenced by age, total lactation time and place of living during
childhood and adolescence (fishing village vs. other place). The residential
variable probably reflects early life consumption of fish from the Baltic Sea (at
the Swedish east coast) contaminated with persistent organochlorine compounds.
PMID- 9397601
TI - Isoprene from expired air inside a private car.
AB - The concentration of isoprene inside a small-sized parked private car with one
person was found to be of the order of 20 micrograms/m3. Isoprene was then the
major non-methane volatile hydrocarbon except in strongly traffic-polluted
parking places. On driving, with intermediate fan ventilation, the isoprene
levels were one order of magnitude lower. In the empty car, the concentrations
were still much lower, proving that isoprene originates predominantly from
expired air. Air samples were taken on triple-layer adsorbent cartridges and were
analysed for volatile hydrocarbons by gas chromatography after thermal
desorption. The analytical aluminium oxide column permitted simultaneous
determination of a range of reported traffic-emitted hydrocarbons including the
carcinogenic 1,3-butadiene and benzene.
PMID- 9397602
TI - Hepatitis A outbreak in a socially-contained religious community in rural
southern Ontario.
PMID- 9397603
TI - Outbreak of cyclosporiasis--northern Virginia-Washington, D.C.-Baltimore,
Maryland, Metropolitan area, 1997.
PMID- 9397604
TI - The risk and prevention of tuberculosis in travellers.
PMID- 9397605
TI - New era of reconstructive microsurgery.
AB - Hopfner performed the first successful experimental limb replantation in 1903,
and Malt performed the first successful clinical replantation for an above-elbow
amputation in 1962. Since then the range of applications for reconstructive
microsurgery has expanded rapidly, and it is now widely used for repair of
nerves, vessels and lymphatics. In 1972 the first successful case of free flap
transfer was performed. Many new applications followed including: (1) coverage of
extensive wound defects with exposure of bones, joints, tendons and major vessels
which can not be covered with local tissue; (2) vascularized bone transfer for
bone defects; (3) vascularized joint transfer for hand joints and the
temporomandibular joints; (4) functioning muscle transfer to replace the muscles
of the upper limbs and face; (5) toe transfer for missing fingers and thumbs; (6)
reconstruction following tumor ablation; (7) reconstruction of congenital
anomalies; (8) reconstruction of chest, pharynx and cervical esophagus; (9)
transfer of gliding tissue, fascia and sensory flaps for certain injuries. The
goals of future reconstructive microsurgery include refinement of procedures,
enhancement of functional and aesthetic results, and minimization of the
morbidity of donor sites. Improvements of instruments, sutures and computer
imaging systems will enable surgeons to perform more accurate reconstructions.
Endoscopic harvesting of flaps will be widely used. Surgery will be performed on
newborns with certain congenital anomalies. Microsurgery will be increasingly
used in conjunction with a prosthesis to improve the function of the prosthesis.
Microarthroscopy will be used in operations involving small joints. Advances in
microsurgery techniques may also change the results of vascular surgery and tumor
resection.
PMID- 9397606
TI - Modification of left ventricular isovolumic relaxation time during dobutamine
echocardiography as a diagnostic method for ischemic heart disease.
AB - BACKGROUND: The diagnostic ability of dobutamine stress two-dimensional
echocardiography is limited by the clarity of the echocardiographic image. In
this study, left ventricular isovolumic relaxation time (IVRT) was modified and
the effect of this modification on the diagnostic accuracy of dobutamine
echocardiography (DE) in detecting ischemia was assessed. METHODS: DE was
performed in 59 subjects (34 and 25 in the control and patient group,
respectively). The results were compared with coronary angiography and stress
scintigraphy. We focused on the changes of the IVRT, the corrected IVRT which was
the IVRT corrected for heart rate, and the modified IVRT which is the corrected
IVRT modified by a new-designed equation. RESULTS: These isovolumic relaxation
variables shortened with the increment of dobutamine dosage and were markedly
prolonged when ischemia developed. The sensitivity and specificity of DE were 84%
and 74%. However, using the prolongation of corrected IVRT and modified IVRT as
indicators of ischemia, the specificity increased (from 74% to 91% and to 94%,
respectively), without a significant reduction in sensitivity (from 84% to 76%
and to 84%, respectively). Patients with positive results for these variables, as
compared with negative results, had a significant result of more ischemic
segments and a tendency of more diseased vessels. CONCLUSION: The prolongation of
these isovolumic relaxation variables during myocardial ischemia improves the
diagnostic accuracy of DE and is also well correlated with the severity of
ischemia.
PMID- 9397607
TI - Malignant thymoma: a review of 44 cases.
AB - BACKGROUND: Malignant thymomas are rare neoplasms. Factors affecting prognosis
and survival of patients with this neoplasm have been intensively discussed, but
the results vary among different studies. To find possible prognostic factors, we
designed this retrospective study. METHODS: Forty-four cases of malignant
thymomas diagnosed and treated in Chang Gung Memorial Hospital, Kaohsiung, from
1986 to 1996 were reviewed. RESULTS: Of the 44 cases, 24 were male and 20 were
female (M:F = 1.2:1). Patient age ranged from 25 to 73 years (median 48 years).
Thirty-four cases (77%) belonged to type I malignant thymoma (invasive thymoma)
and 10 cases (23%) belonged to type II malignant thymomas (thymic carcinoma). The
most frequent histologic type was predominantly epithelial (43%), followed by
mixed lymphoepithelial (27%). Six patients had myasthenia gravis. Eleven (25%)
patients, including 4 cases of invasive thymoma and 7 cases of thymic carcinoma,
showed tumor metastasis to lung, bone, liver, spleen and omentum. The 5-year
survival was 73% for patients who underwent total tumor excision and 18% for
those who received partial tumor excision or biopsy only. The influence of
histologic types on prognosis is not statistically significant (P = 0.434).
CONCLUSION: Completeness of tumor excision at initial operation is the most
important prognostic factor. Predominantly epithelial and mixed lymphoepithelial
types are more aggressive forms with a higher tendency to invasion.
PMID- 9397608
TI - Influence of maternal age and weight on second-trimester serum alpha-fetoprotein,
total and free beta human chorionic gonadotropin levels.
AB - BACKGROUND: The purpose of this study was to assess the relation of maternal age
and weight on the maternal serum alpha-fetoprotein (AFP), total human chorionic
gonadotropin (hCG) and free beta-hCG levels during the second trimester. METHODS:
We collected 419 serum samples from normal singleton pregnancies to assay serum
marker levels of AFP, total hCG and free beta-hCG between 14 and 21 weeks of
gestation. Maternal age at the day of delivery and maternal weight at the time of
sampling were recorded in all cases. The relationship between maternal weight and
multiple of the median (MoM) levels of serum markers was analysed by regression
models. RESULTS: There was an inverse trend in median MoM levels of serum markers
in relation to maternal weight. No significant association between maternal age
and serum marker levels was found. CONCLUSION: Because of its impact on serum
marker levels, weight correction may be mandatory for further refinement in the
maternal serum screening for Down's syndrome.
PMID- 9397609
TI - Concurrent 5-fluorouracil, leucovorin, etoposide, cisplatin and radiotherapy for
locally advanced non-small cell lung cancer.
AB - BACKGROUND: The prognosis of Stage III unresectable non-small cell lung cancer
may be improved by concurrent chemoradiotherapy. In this study, we attempted to
evaluate the feasibility, tolerance, efficacy and toxicities of the combination
of thoracic radiation and chemotherapy with a novel regimen that included 5
fluorouracil, leucovorin, etoposide and cisplatin (the FLEP regimen) in the
treatment of this group of patients. PATIENTS AND METHODS: From July 1995 to
September 1996, 20 untreated patients with locally advanced non-small cell lung
cancer were enrolled in the study. Radiation at a dose of 44 Gy was initially
delivered in daily fractions of 2 Gy 5 days a week to the tumor and mediastinum,
followed by a boost to the tumor (20 to 26 Gy according to patients tolerance).
Concurrently with thoracic irradiation, patients were treated with chemotherapy
consisting of cisplatin at the dose of 60 mg/m2/d for 1 day, etoposide at the
dose of 60 mg/m2/d for 2 days, and 5-FU 500 mg/m2/d plus leucovorin 50 mg/d
infusion for 48 hours. Cycles of chemotherapy were repeated every 3 weeks for a
maximum of 3 cycles. RESULTS: Seventeen of 20 patients were assessable. The
overall response rate was 70.6% (95% confidence interval = 49-92%). No complete
response was achieved. The median response duration for all responding patients
is not yet estimable, with a range of 3.5 to 15.5+ months. Eleven patients remain
progression-free for 4 to 15 months. The median survival for the entire group is
not estimable. The major toxicity was esophagitis. Other grade 3 or 4 toxicities
were not frequently observed. CONCLUSION: Combined-modality therapy with FLEP
regimen and radiation is a promising treatment with a high response rate and
acceptable toxicity for locally advanced non-small cell lung cancer.
PMID- 9397610
TI - Monthly measurements of intraocular pressure in normal, ocular hypertensive, and
glaucoma male subjects of same age group.
AB - BACKGROUND: Recently it has been shown that environmental conditions have a
significant influence on intraocular pressure (IOP). Due to differences in
inherent constitution, diet and environmental conditions, there is a clear need
for well collected IOP data in different countries and ethnic groups. The
seasonal variation of IOP has never been described in Pakistani subjects.
METHODS: IOP was measured each month over the course of 12 months with the
Goldmann applanation tonometer in normal, ocular hypertensive, and glaucoma male
subjects. RESULTS: In all groups, the average intraocular pressures in the winter
months were highest, while lowest in summer months. The intraocular pressures of
spring and autumn months were nearly the same. The intraocular pressure levels in
these seasons were between the IOP levels in summer and winter seasons. The
difference between highest and lowest IOP was 1.4 +/- 0.2, 3.1 +/- 1.4, and 2.3
+/- 1.1 mmHg, in normal, ocular hypertensive, and glaucoma subjects,
respectively. The ups and downs of intraocular pressure were greater in the
ocular hypertensive subjects than in the glaucoma patients. CONCLUSIONS: This
study confirms that season influences IOP, and concludes that seasonal influence
is highest in ocular hypertensive than in normal and glaucoma subjects. As
compared to other nations, effect of seasons on IOP seems to be somewhat less
pronounced in Pakistan.
PMID- 9397611
TI - Application of cryoablation in the management of prostate cancer.
AB - BACKGROUND: Radical prostatectomy is the most common and effective therapy for
localized prostate cancer. But in addition to its surgical complications, even
highly selected series carry a positive margin rate of 35 to 50%. Radiotherapy is
another alternative for prostate cancer, but following radiotherapy there have
been high positive biopsies reported. Cryosurgery, defined as in situ freezing
and hence, devitalization of neoplastic tissues, has currently raised the
interest of urologists in the management of localized prostate cancer or failed
radiotherapy. MATERIAL: Five patients underwent transperineal cryosurgery of
prostate in Chang Gung Memorial Hospital. Among them, three cases were stage D,
one stage B and another failed radiotherapy of stage C prostate cancer. All
patients received hormone therapy too. RESULTS: PSA declined in 3 patients and
biopsies showed intraductal neoplasia. All 5 patients suffered from urine
incontinence and one persisted. No mortality has been reported. CONCLUSION:
Cryoablation of the prostate is an alternative for treatment of prostate cancer.
PMID- 9397612
TI - Prenatal diagnosis of congenital cystic adenomatoid malformation of the lung:
four cases report.
AB - Congenital cystic adenomatoid malformation of the lung (CCAML) is a rare
pulmonary lesion, characterized by excessive overgrowth of the terminal
respiratory bronchioles. Prenatal detection and serial sonographic study of
fetuses with CCAML can provide information about the natural history of these
lesions and reveal most of the nature history of pathophysiologic features which
are likely to affect the clinical outcome. This information is crucial to the
formulation of a prognosis and a management strategy. We report on four cases of
CCAML, three of which involved macrocystic lesions including two cases of type I
and one case of type II. Only one microcystic lesion, a type III CCAML, was
identified in these patients. All of the cases were diagnosed by ultrasound
between the 21 and 24 weeks of gestation. Fetal hydropic change was noted in all
four cases. All of the parents opted for termination of pregnancy before fetal
viability. Post-mortem examination confirmed the diagnosis in all four cases.
PMID- 9397613
TI - Sustained complete remission after incomplete chemoradiation complicated with
pelvic cellulitis in a patient with recurrent cervical carcinoma.
AB - We report on a 52-year-old female patient with a bulky, recurrent cervical
carcinoma involving the vagina and bladder, who developed entero-recto
vesicovaginal fistulas and sepsis with pelvic cellulitis after external radiation
of 40 Gy and 2 courses of concurrent chemotherapy. Chemoradiation was interrupted
and an ileostomy was performed. After recovery, no residual tumor was detectable.
Thirteen months after ceasation of chemoradiation, repair of vesicovaginal and
rectovaginal fistulas via posterior sagittal approach was performed. Revision of
double bowel ileostomy and ileo-T-colostomy was performed 17 months later. The
patient enjoyed the restoration of enteral and urinary function only temporarily.
She developed rectovesical fistula and underwent an ileostomy again 6 months
later. She had another episode of peritonitis and upper gastrointestinal bleeding
and expired at 4 years from initiation of salvage therapy. She had no evidence of
cancer recurrence during a series of laparotomies and biopsies. The dramatic
regression of the tumor may be attributed to its extraordinary radiosensitivity
or chemosensitivity. The acute pelvic inflammatory complications may also
contribute to the tumor cell killing. The prognosis of recurrent cervical
carcinoma is invariably poor except in small tumors confined to vagina. This case
gives support to the efficacy of chemoradiation and the potential role of
biologic therapy in treatment of this dismal disease.
PMID- 9397614
TI - Salmonella typhimurium brain abscess in a six-month-old infant: a case report and
review of the literature.
AB - We report the case of a six-month-old male infant with brain abscess caused by
Salmonella typhimurium. Upon admission, he was suffering from fever, diarrhea,
drowsiness and convulsion. Salmonella meningitis was identified by CSF
examination. Following failure of antibiotic therapy to control his fever, brain
computerized tomography (CT) was ordered 5 days later and revealed a brain
abscess. He received surgical excision of the abscess and recovered completely
after receiving ceftriaxone therapy for 8 weeks. The case of our patient,
together with 11 cases of Salmonella brain abscess from the English literature
are reviewed. There was a male preponderance among these patients (male: female =
2.67 : 1) and the majority were less than one year old. Salmonella typhimurium,
typhi, and enteritidis occurred most frequently. Fever, seizure, signs and
symptoms of increased intracranial pressure and change in mental status were the
most common clinical features. Purulent meningitis was a major predisposing
factor. Successful treatment was associated with early identification, prompt
surgical intervention, high dose, long-term antibiotic therapy, and close follow
up for possible recurrence and to determine the presence of neurological
sequelae.
PMID- 9397615
TI - Internal iliac artery aneurysmo-rectal fistula associated with multiple
aortoiliac aneurysms.
AB - Fistular communication between an internal iliac artery aneurysm and rectum
presenting as massive lower gastrointestinal tract bleeding is a rare entity in
clinical practice. Prompt diagnosis and experienced therapeutic application
determine the outcome. Herein we report the successful management of such a
complication. A 68-year-old male had multiple aneurysms over the abdominal aorta
and bilateral iliac arteries. It was the largest aneurysm arising from the right
internal iliac artery which ruptured into the rectum and resulted in massive
hematochezia. After extraanatomical bypass with right axillo-femoral and femoro
femoral crossover grafts to restore the circulation to the bilateral lower limbs,
the infrarenal abdominal aorta just immediately above the proximal aneurysm was
transected and closed as a blind stump. All the aneurysms were included in this
resection and as much of the infected aneurysm tissue was debrided as possible.
The rectum was exteriorized using Hartmann's procedure. The patient survived the
operation and was discharged in good condition.
PMID- 9397616
TI - Cyclopia in one of discordant twins: a case report.
AB - Cyclopia is an uncommon congenital anomaly resulting from arrest of the
development of the anterior end of the neural plate. It is always associated with
abnormalities of the brain. Cyclopia has never been reported in one twin only. In
this report, we describe a case of cyclopia in a female infant with normal
karyotype who was one of discordant twins. The infant died perinatally. The
parents were healthy and not sanguineously related. Prenatal imaging studies
revealed cyclopia, holoprosencephaly and hypognathia. Postmortem examinations
revealed one orbit, one eyeball and absence of the nose. The central nervous
system included rudimentary cerebral hemispheres with fusion of the two lateral
ventricles and the third ventricle forming a single large cavity. The superior
aspect of each cerebral hemisphere consisted of only a transparent membrane. The
olfactory bulb nad tract was absent. The optic nerves were not identified.
PMID- 9397617
TI - Cardiac perforation and tamponade induced by external cardiac massage: a case
report.
AB - A 76-year-old woman suffered from sudden loss of consciousness while sitting in a
chair. She was sent to a local hospital and found to be in shock. After a brief
period of external cardiac massage, she was transferred to our hospital. In our
emergency department she was lethargic with cool, clammy extremities. Her blood
pressure dropped from 113/53 mmHg on arrival to 72/42 mmHg 2 hours later.
Echocardiography showed massive pericardial effusion, fair left ventricular
contractility and no abnormal segmental motion. The echocardiographic appearance
suggested fibrin-like substance in the pericardial space, which was felt to
indicate the presence of blood. Enhanced chest computerized tomography showed
extravasation of contrast medium from the right ventricular outflow tract. At
surgery, a small perforation was found at the infundibular area of the right
ventricle, and a total of 500 mL of blood had accumulated in the pericardial
space. She was discharged 7 days postoperatively, having made an uneventful
recovery. External cardiac massage may cause cardiac disruption, and this should
be considered in patients who have secondary hemodynamic instability following
successful cardiopulmonary resuscitation.
PMID- 9397618
TI - Total knee arthroplasty in a rheumatoid arthritic knee with large geode: a case
report.
AB - Geodes (subchondral cysts) are a well-known manifestation of rheumatoid
arthritis. Solitary cysts or cysts larger than 2 cm are not generally found in
the knee joint of patients with rheumatoid arthritis (RA). We report a case of RA
involving both knees with a giant geode over the right proximal tibia. Surgical
treatment was performed including synovectomy, cyst enucleation and packing of
autogenous bone chips followed by primary total knee arthroplasty. The
postsurgical result was excellent with the knee restored to good function and
complete healing of the cystic lesion.
PMID- 9397619
TI - Fatal Haemophilus influenzae pneumonia: two cases report.
AB - Haemophilus influenzae is a common cause of acute childhood pneumonia. Most
Haemophilus pneumonia generally follow a benign course with occasional
complications of pleural effusion, pneumothorax or pneumatocele. Deaths following
invasive Haemophilus pneumonia have rarely been reported in children older than 3
years of age. We report 2 deaths in children presenting with fulminant pneumonia,
complicated by sepsis and adult respiratory distress syndrome despite vigorous
antibiotic therapy and full resuscitative measures.
PMID- 9397620
TI - Antibiotic prophylaxis and surgery.
PMID- 9397621
TI - Attic cholesteatoma and extensive tympanosclerosis.
PMID- 9397622
TI - Vocal fold scar.
PMID- 9397623
TI - Oral-facial-digital syndrome type I.
PMID- 9397624
TI - Mucocele of the pterygoid recess of the sphenoid sinus: endoscopic microdebrider
excision via a transnasal sphenoidotomy approach.
PMID- 9397625
TI - Practice guidelines and liability implications.
AB - It should be clear that the authors of this article are not enamored of practice
guidelines, thinking them of much more potential harm than good. On the other
hand, if practice guidelines are deemed essential, then they must be written with
the goal of quality patient care advocacy and with an eye toward the possible
damage they may do.
PMID- 9397626
TI - Wound infection in head and neck surgery: implications for perioperative
antibiotic treatment.
AB - Perioperative antibiotic treatment significantly reduces the risk of
postoperative wound infection and is cost-effective in clean-contaminated head
and neck operations. A clear consensus on the most suitable single agent or
combination is, however, lacking. Most surgical wound infections involve both
gram-positive and gram-negative aerobes and anaerobes; some organisms may exhibit
antibiotic resistance through beta-lactamase production. Comparative trials have
indicated that combinations with both aerobic and anaerobic activity provide
protection superior to that achieved with single agents active against only
aerobic pathogens. Recent results suggest that the beta-lactam/beta-lactamase
inhibitor combination ampicillin/sulbactam is cost-effective for perioperative
treatment of patients undergoing head and neck surgery.
PMID- 9397627
TI - Inner ear immunology and allergy: an overview of current day concepts.
PMID- 9397628
TI - p53 immunostaining of surgical margins as a predictor of local recurrence in
squamous cell carcinoma of the oral cavity and oropharynx.
AB - Local and regional recurrence is the principal reason for treatment failure in
squamous cell carcinoma (SCC) of the head and neck. The conventional method of
evaluating surgical margins for cellular atypia does not always predict risk of
local recurrence accurately. Immunostaining of surgical margins for tumor markers
may provide a more precise evaluation of risk of local recurrence. Paraffin
embedded tissue blocks of surgical margins from 24 patients with oral cavity and
oropharyngeal squamous cell carcinoma were immunostained for p53 protein. Fifty
eight percent of the patients had at least one margin stain positive for p53,
including eight of ten patients whose SCC recurred locally. The sample odds ratio
test predicted a 5.333 times higher chance of local recurrence with at least one
p53 positive surgical margin. The implications of these results for patient
management and further investigations will be discussed.
PMID- 9397629
TI - Mucocele of the sphenoid sinus due to an osteoma.
PMID- 9397630
TI - Osteoma of the base of the tongue.
AB - A 14-year-old girl developed a firm mass at the base of the tongue. Computed
tomography indicated marked density suggesting either a foreign body or bony
tissue. A thyroid scan confirmed the presence of a normally sized and positioned
gland. The mass was removed in toto and found to be an osteoma. This is the first
report of a case in which the diagnosis of this rare developmental lesion of the
tongue was achieved preoperatively based on clinical and radiologic information.
This experience should lead to greater awareness of this entity in the future.
Recognition of this entity in the pediatric age group is especially useful in
avoiding misdiagnosis of other, potentially more aggressive types of tongue mass
lesions. Our case demonstrates that it is possible to detect this entity using
computed tomography. The dense calcification is truly characteristic of the tumor
and may be relied upon to exclude alternative soft tissue mass lesions. While
other forms of osseous and cartilagenous neoplasms, such as extraskeletal
osteosarcoma and chondrosarcoma, have been reported arising in the tongue, their
malignant nature should otherwise be readily apparent. Osteoma of the tongue is
the favored diagnosis when mature bone tissue is imaged at the base of the
tongue.
PMID- 9397631
TI - Development and optimization of a purification strategy for the venom of the
scorpion Parabuthus transvaalicus.
AB - In search for the toxic components constituting the venom of the southern African
scorpion Parabuthus transvaalicus we compared and optimized several
chromatographic separation protocols resulting in an efficient venom purification
strategy. We found that the sequential combination of gelfiltration (Superdex)
together with reversed phase chromatography (C2/C18)-but not cation exchange
(Mono S)-stood surety for the best purification.
PMID- 9397632
TI - Patient satisfaction with nurse practitioner care in primary care.
PMID- 9397633
TI - Are you linking competence to outcomes?
PMID- 9397634
TI - What do you call your patients?
PMID- 9397635
TI - Four steps to creating quality indicators across sites.
AB - As multi-hospital systems develop, the demand to compare performance across sites
has become an organizational imperative. This article describes the process a six
hospital system used to create clinically reliable and valid quality assessment
indicators.
PMID- 9397636
TI - Functional teams lead to Joint Commission success.
AB - As the Joint Commission on Accreditation of Healthcare Organizations (Joint
Commission) has shifted the focus of its survey process to the organization as a
whole, new techniques are needed to prepare for surveys. Staten Island University
Hospital used teams based on the eleven important functions to achieve a
successful survey.
PMID- 9397638
TI - Does employee involvement work? Yes, sometimes.
AB - Employee involvement per se is not always effective for improving performance
and/or employee attitudes. Rather, there are several different forms of employee
involvement, some of which are effective, while others are not. This article
describes seven forms of employee involvement, giving examples, and summarizes
research findings for each form, concluding with a summary of which are the best
and which are worst. This article also describes what is necessary for effective
employee involvement, focusing on management commitment and training for both
management and employees.
PMID- 9397637
TI - Quality plan for a product line.
AB - Continuous Quality improvement (CQI) has undergone radical change as health care
facilities merge, expand, and modify their existing services. CQI has shifted
from a centralized position in health care organizations, to unit based, to
product lines. This paper describes one product line's endeavors to develop a
Quality Plan to direct CQI activities. One particular strength of our innovation
is that the Quality Plan was developed with attention to the important balance of
interdisciplinary cooperation and maintenance of appropriate discipline
boundaries.
PMID- 9397639
TI - The future of the quality professional in health care.
AB - Radical changes in health care, organizations, and the quality science have
converged, radically altering the role of many, including the quality
professional. The very existence of this role remains in question. Should it
continue, radical changes are in store for its conduct. It is critical that
quality professionals today remain aware of the issues, and strategically move
forward to chart a quality direction for both their organizations and their own
careers.
PMID- 9397640
TI - Verifying nursing home care quality using minimum data set quality indicators and
other quality measures.
AB - Researchers, providers and government agencies have devoted time and resources to
the development of a set of Quality Indicators derived from Minimum Data Set
(MDS) data. Little effort has been directed toward verifying that Quality
Indicators derived from MDS data accurately measure nursing home quality.
Researchers at the University of Missouri-Columbia have independently verified
the accuracy of QI derived from MDS data using four different methods; 1)
structured participative observation, 2) QI Observation Scoring Instrument, 3)
Independent Observable Indicators of Quality Instrument, and 4) survey citations.
Our team was able to determine that QIs derived from MDS data did differentiate
nursing homes of good quality from those of poorer quality.
PMID- 9397641
TI - Conducting unit-based research to improve quality of care.
AB - How does a tertiary care medical center without a primary academic nursing
affiliation improve quality of patient care by conducting unit-based nursing
research? The organization's strengths and opportunities include top management
support, an infrastructure for development of nurse researchers, a specific
patient care coordinator role, research supporting organizational decision
making, and success in obtaining nursing research grants. The effects of limited
consultative support, statistical avoidance, reorganization, competing staff
demands, and lack of funding must be minimized. Strategies include: continue
communication with top management, provide meaningful development opportunities
and technical research support, build on completed research, use
multidisciplinary teams, and change thinking to maximize the research
opportunities that already exist.
PMID- 9397642
TI - Anatomy of an OPTI dissected: structure, function, and the impact of budget
reconciliation legislation.
PMID- 9397643
TI - A snapshot of osteopathic medical education in 1997.
PMID- 9397644
TI - Forecast for osteopathic medical education programs in the for-profit hospital
environs.
PMID- 9397645
TI - Examining quality improvement vs cost containment.
PMID- 9397646
TI - History of osteopathic medical education accreditation.
PMID- 9397647
TI - Undergraduate osteopathic medical education.
PMID- 9397648
TI - Income and expenditures of osteopathic medical colleges.
PMID- 9397649
TI - Osteopathic graduate medical education.
PMID- 9397650
TI - Certification of osteopathic physicians.
PMID- 9397651
TI - AOA continuing medical education.
PMID- 9397652
TI - Research programs of the AOA and their role in osteopathic medical education.
PMID- 9397653
TI - The anatomy of an OPTI: Part 2. The CORE system. Ohio Osteopathic Hospital
Association. Ohio Association of Osteopathic Medical Directors. Ohio Osteopathic
Association.
AB - In July 1995, the American Osteopathic Association (AOA) Board of Trustees passed
new regulations regarding the accreditation of osteopathic graduate medical
education (GME) by establishing the Osteopathic Postdoctoral Training
Institutions (OPTI) system. This system must be phased in by July 1999. The
principal changes resulting from the OPTI system include establishing
requirements for college cosponsorship of GME programs and for the number of
residency programs, interns, and residents to be trained by the OPTI. In essence,
OPTI is an osteopathic acronym for consortium. Each OPTI must include at least
one college of osteopathic medicine (COM) and one AOA-accredited hospital. The
OPTIs will be subject to interval AOA inspections and will be required to
demonstrate a governing system, mission statement, organizational structure, and
the presence of faculty development programs. The first article in this two-part
series, published in the October JAOA, provided a general blueprint for OPTI
building and presented both positive and negative issues germane to the formation
of OPTIs. Part 2 reinforces the considerations outlined in Part 1 by describing
the formation of a large OPTI--the Ohio University College of Osteopathic
Medicine (OU-COM) Centers of Osteopathic Regional Education (CORE) system. Key
features are described, including the mission statement, organizational
structure, committee system, governance, GME programs, operations, and budget.
PMID- 9397654
TI - Pathologic and diagnostic considerations in onychomycosis.
AB - Understanding the physiology and function of the nail unit and its potential
avenues of invasion, and properly identifying invading organisms are two key
aspects of using the newer therapies available for the treatment of
onychomycosis. This article discusses the most common pathologies of
onychomycosis, as classified by the sites of entry of the invading fungi.
Susceptibility factors leading to infection are also discussed. Obtaining proper
tissue samples, using appropriate tests and culture media, and accurately
interpreting test results are all paramount to correct identification of the
invading organism and, in turn, to effective prescribing. When fungal-growth
results do not support the clinical symptoms, or if a more specific
identification of the organism is required, additional diagnostic tests are
available and are outlined here.
PMID- 9397655
TI - Impact of onychomycosis on quality of life.
AB - The author reviews the current knowledge of the impact of onychomycosis on
quality of life. Like other visible disorders of the integumentary system,
onychomycosis affects many aspects of life, including physical functioning,
interpersonal interactions, and emotional state. After examining the nature of
quality of life and the study instruments used to measure it, the author reviews
several studies that have examined the relationship between onychomycosis and
quality of life. The author concludes that onychomycosis is a significant medical
problem that has a great impact on patients' lives and should therefore be
treated as definitively as possible.
PMID- 9397656
TI - Onychomycosis. Baseline results of an observational study.
AB - The investigators present an analysis of baseline quality-of-life and patient
management approaches from an observational study of 150 patients being treated
by podiatric physicians and dermatologists for onychomycosis. The majority (73%)
made the initial office visit specifically because of their onychomycosis. Both
men and women indicated that they had substantial physical discomfort as well as
concerns related to appearance. Women reported significantly more problems than
did men as a result of their onychomycosis. Physicians reported that 54% of
patients suffered from toenail discomfort, 36% had pain while walking, 40%
reported that their condition limited wearing of shoes, and 67% were embarrassed
by the condition. The results of this study suggest that the treatment approach
of podiatric physicians is more likely to address the palliative concerns of
patients with onychomycosis, while the approach of dermatologists is more likely
to attempt a definitive cure.
PMID- 9397657
TI - Oral treatment options for onychomycosis.
AB - The author discusses the new oral antifungal agents for the treatment of
onychomycosis. The history, mechanisms of action, efficacies, dosing, safety
profiles, and costs of itraconazole, terbinafine, and fluconazole are reviewed.
The author emphasizes that use of these effective antifungals represents an
important paradigm shift for podiatric physicians away from the palliative
therapy of nail debridement to a potentially curative treatment.
PMID- 9397658
TI - Practice management and managed-care issues in onychomycosis.
AB - The author gives a general overview of recommendations for practice success in a
managed-care environment and describes a new practice paradigm for the treatment
of onychomycosis. Recommendations are provided for ensuring optimal
reimbursement, particularly in the treatment of managed-care and Medicare
patients.
PMID- 9397659
TI - ECG of the month. Questions. Ventricular tachycardia.
PMID- 9397660
TI - Comparison of conventional and deep plane facelift.
AB - Revitalization of the aging face is a complex process that must include several
components all working together in harmony to create a natural, youthful
appearance. As more details of the facial anatomy have been described, the
facelift operation has expanded tremendously to include deeper layers of the face
with a goal of achieving both a longer lasting effect from surgery and a more
complete recontouring effect of the melolabial fold. A comprehensive
understanding of the anatomy of the face and the different procedures available
is necessary in order to perform facelift surgery effectively and safely.
PMID- 9397661
TI - Radiology case of the month. Delayed onset of muscular soreness in the right hip.
Delayed onset muscle soreness (DOMS).
PMID- 9397662
TI - The journal 100 & 150 years ago. New Orleans Medical and Surgical Journal.
November 1847 & 1897.
PMID- 9397663
TI - Lafayette Community Health Care Clinic and the Lafayette Parish Medical Society
Alliance ... a working partnership.
PMID- 9397664
TI - Nicotine addiction and smoking cessation.
AB - Cigarette smoking remains the greatest threat to public health in our society and
is responsible for one of every five deaths in the United States. While the
prevalence of smoking has declined dramatically over the past 30 years, over 26%
of Americans continue to smoke. In Louisiana, one third of adult men and one
quarter of adult women smoke. The irony of this problem is that smoking is a
modifiable behavior. To better counsel their patients regarding smoking
cessation, health care practitioners should be aware of the health risks of
smoking, the benefits of smoking cessation, and therapies available to assist
their patients in breaking the habit. This article reviews the current literature
and addresses these issues.
PMID- 9397665
TI - Heritable arrhythmias, cardiomyopathies, and valvulopathies.
AB - Arrhythmias, cardiomyopathies, and valvulopathies are the most frequent forms of
heart disease that occur during the years of peak productivity. They have
interrelated pathogenetic bases and may occur in combinations. Cases in which
there is involvement of other body systems are so frequent as to suggest a need
for careful cardiological evaluation of any patient with dysmorphic features or
an inborn error of metabolism. Recent advances in embryology and molecular
genetics have increased our understanding of the heritable arrhythmias,
cardiomyopathies, and valvulopathies but clinical delineation of all of them
predated those developments. Symptomatology may be confusing or absent, so
electrocardiogram and echocardiogram are required for diagnosis. Holter
monitoring is productive if echocardiogram and electrocardiogram are not
diagnostic. For some varieties of heritable arrhythmias, cardiomyopathies, and
valvulopathies, other diagnostic modalities are required. Differentiation between
heritable and non-heritable varieties may require testing of relatives. Members
of the immediate family are most likely to be affected. For X-linked and
recessive types, more extensive genealogical investigation may be required.
Medical management, prognosis, and genetic counseling are highly dependent on
thorough elucidation.
PMID- 9397666
TI - Treatment evaluation of a patient with Hodgkin's lymphoma: a case report.
PMID- 9397667
TI - A pregnant woman with lupus Tulane Renal Biopsy Conference.
PMID- 9397668
TI - Managed care tort liability.
PMID- 9397669
TI - The art of medicine. How to get the most out of hospice care.
PMID- 9397670
TI - Making the hospice decision.
PMID- 9397671
TI - Michael H. Dawson, MD. Injury helps physician appreciate patient's pain.
PMID- 9397672
TI - But it's not the money. The real reasons why membership is so important.
PMID- 9397673
TI - Heads up--here's what's coming at you in economics and legislation.
PMID- 9397674
TI - James L. McGauley, MD. Getting it all together on patient information.
PMID- 9397675
TI - Truths and myths. Narcotic medication usage for pain management.
PMID- 9397676
TI - The spontaneous ultraweak luminescence of living systems.
AB - The results of experimental research on ultraweak photon emission carried out at
the Institute of Physics, Catania University, are presented here. A correlation
has been demonstrated to exist between photon emission and growth activity in the
germination of soya seeds and also during the exponential phase of the growth of
yeast cell cultures. In addition an experiment on the self irradiation of yeast
cells is reported that confirms the mitogenic effect hypothesized by Gurwitsch.
PMID- 9397677
TI - Oncogenous micro-organisms are confined to Mycoplasmas and Helicobacter pylori.
AB - Among the various micro-organisms isolated from man's cancerous tissues including
the blood of such patients several species were described as new to science.
Their identity is being discussed and the conclusion made that none of the
scientific names proposed as new for these micro-organisms can be utilized
taxonomically. Aberrant red cells have been commonly confounded with some
supposed blood parasites. Current research of micro-organisms suspected of
playing a role in oncogenesis is confined to two categories of true or
opportunistic pathogens: Mycoplasmas with respect to unspecified cancers and
Helicobacter pylori in regard to stomach neoplasms.
PMID- 9397678
TI - EH: a novel protein-protein interaction domain potentially involved in
intracellular sorting.
PMID- 9397679
TI - A CTD function linking transcription to splicing.
AB - Since its discovery in 1985, the function of the C-terminal domain (CTD) of RNA
polymerase II has been a puzzle. Recent studies suggest that the CTD functions as
a linear platform for assembly of complexes that splice, cleave and polyadenylate
pre-mRNA. A new set of CTD-associated SR-like proteins (CASPs) have been
implicated in pre-mRNA processing and transcription elongation as a component of
the emerging 'transcriptosome'.
PMID- 9397680
TI - A putative nucleic acid-binding domain in Bloom's and Werner's syndrome
helicases.
PMID- 9397681
TI - A eukaryotic XPB/ERCC3-like helicase in Mycobacterium leprae?
PMID- 9397682
TI - ATP synthase: an electrochemical transducer with rotatory mechanics.
AB - ATP synthase (F0F1-ATPase) uses proton- or sodium-motive force to produce ATP
form ADP and P(i). Three lines of experiment have recently demonstrated large
scale intersubunit rotation during ATP hydrolysis by F1. We discuss how ion flow
through the membrane-intrinsic portion, F0, may generate torque and how this
might be transmitted between stator and rotor to finally expel spontaneously
formed ATP from F1 into water.
PMID- 9397683
TI - The DNA polymerase alpha-primase complex couples DNA replication, cell-cycle
progression and DNA-damage response.
AB - The highly conserved DNA polymerase alpha-primase complex (pol-prism) is the only
eukaryotic DNA polymerase that can initiate DNA synthesis de novo. It is required
both for the initiation of DNA replication at chromosomal origins and for the
discontinuous synthesis of Okazaki fragments on the lagging strand of the
replication fork. The dual role of pol-prim makes it a likely target for
mechanisms that control cell-cycle S-phase entry and progression.
PMID- 9397684
TI - Inositol lipid 5-phosphatases--traffic signals and signal traffic.
AB - Several novel phosphoinositide 5-phosphatases have been identified and
characterised, revealing a growing family of regulators of inositol lipid
dependent processes. The features of these proteins, their likely partners and
their involvement in signal transduction and membrane traffic is discussed.
PMID- 9397685
TI - Dynamic mutation: possible mechanisms and significance in human disease.
AB - Increases in repeat-DNA copy number are the molecular basis of a growing list of
human genetic diseases, including fragile X syndrome, myotonic dystrophy,
Huntington disease and a form of epilepsy. Repeat-DNA sequences undergo a unique
process of dynamic mutation, the common properties of which probably reflect
common molecular events. This form of mutation is no longer restricted to
trinucleotide repeats, because repeats of different length have been found to
undergo expansion.
PMID- 9397686
TI - The Maf transcription factors: regulators of differentiation.
AB - Since the identification of the v-maf oncogene in an avian tumor virus, the Maf
protein family has grown rapidly, forming a unique subclass of basic-leucine
zipper transcription (bZIP) factors. Maf family members appear to play important
roles in the regulation of differentiation.
PMID- 9397687
TI - Linking databases and organisms: GenomeNet resources in Japan.
PMID- 9397688
TI - The protein kinase resource.
PMID- 9397689
TI - Tritium-labeled thymidine and early insights into DNA replication and chromosome
structure.
PMID- 9397690
TI - Certified occupational health nursing. Job analysis in the United States.
AB - Specialty nursing certification programs, such as that administered by the
American Board for Occupational Health Nurses, Inc. (ABOHN), must be firmly based
on current practice to maintain validity. To determine this, ABOHN performed its
most recent job analysis and role delineation study between 1992 and 1994. A
comprehensive survey tool was developed by ABOHN Board members, and administered
to all 3,805 certified occupational health nurses in practice at the time of the
study. With a final return rate of 42.7%, the results were believed to be
representative of the knowledge, skills, and abilities needed to practice
occupational health nursing in the United States at the proficient level of
practice. The results of the study formed the basis for the ABOHN test blueprints
and the creation of two credentials for occupational health nurses: the Certified
Occupational Health Nurse (COHN) and the Certified Occupational Health Nurse
Specialist (COHN-S).
PMID- 9397691
TI - Varicella vaccination. An overview for the occupational health nurse.
AB - 1. Varicella-zoster virus is highly communicable. Non-immune adults are
susceptible to infection and, if infected, have increased risk of complications.
2. Adult varicella infection poses significant economic loss for the infected
employee and potentially for exposed coworkers and the employer. Health care
employers also must be concerned about transmission of varicella infection to
clients. 3. Varicella vaccine is now available, well tolerated, and prevents
infection in approximately 94% of vaccinees. The occupational health nurse needs
to consider varicella vaccination for employees susceptible to infection.
PMID- 9397692
TI - Psychological effects of stress from restructuring and reorganization.
Assessment, intervention, and prevention strategies.
AB - 1. Demands from the economy, market competition, and the political arena have led
to restructuring, reorganization, and change in the workplace. 2. Work behaviors
indicative of stress are costly to organizations. 3. Strategies for intervention
and prevention should be directed at both managers and workers and can result in
cost savings for the organizations. 4. A collaborative approach in which
occupational health nurses work with other services inside the organization, and
with community organizations and services outside the organization, is important.
PMID- 9397693
TI - Project management for occupational health nurses.
PMID- 9397694
TI - Workers' compensation litigation review: Part I.
PMID- 9397695
TI - AAOHN and ACOEM consensus statement for confidentiality of employee health
information.
PMID- 9397696
TI - Team building. A powerful learning organization approach.
PMID- 9397697
TI - Managing staff transitions. Change is never easy.
PMID- 9397698
TI - The integrated evaluation of effectiveness and efficiency.
PMID- 9397700
TI - Impact of managed care decisions on cancer care.
PMID- 9397699
TI - Celebrating our triumphs. Moving forward with hope.
PMID- 9397701
TI - The value of a well-placed stoma.
AB - PURPOSE: The author describes the purpose, procedure, and practice of stoma-site
marking. Patient anxiety and other emotional implications of ostomy surgery are
explored, and expenses related to supplies and reimbursement issues are
discussed. OVERVIEW: Patients with specific advanced colorectal, bladder,
ovarian, or endometrial cancers sometimes require surgery that controls
malignancies but necessitates ostomy creation. Despite a well-placed and well
constructed stoma, adjustment to an ostomy is difficult and lengthy. Maladaptive
behaviors are exacerbated when an ostomy is constructed poorly and positioned
poorly on the abdominal wall. Additional expenses are incurred when this stoma
requires a customized and complex pouching system. CLINICAL IMPLICATIONS:
Malformed ostomies, leaking ostomy pouches, or skin irritations impact negatively
on the patient and family members and may result in treatment delays. The
patient's body structure, fat stores, occupation, and clothing style must be
considered when determining the appropriate stoma site. Attention also must be
paid to psychosocial support so that both emotional and physical healing occur.
PMID- 9397702
TI - Women's perception. Breast cancer treatment and sexuality.
AB - PURPOSE: The authors describe women's perceptions of how their sexuality was
affected by treatment for breast cancer. This description is part of a larger
study that tested the psychometric properties of a sexuality measure. DESCRIPTION
OF STUDY: This exploratory study analyzed 105 women's responses to one question
that asked them to describe how their sexuality had changed since their breast
cancer diagnosis. Two researchers independently used content analytic procedures
to identify themes that emerged from the data. RESULTS: Four themes emerged:
Physical Sexual Functioning, Relationship Quality, Psychological Self, and Self
as Female. Women who had reconstructive surgery indicated that the loss of
feeling in the reconstructed breast was sexually troublesome and disappointing.
Comparison of the qualitative data with quantitative data (triangulation)
provided support for the finding of no significant differences in sexual
functioning before women treated by lumpectomy versus mastectomy. CLINICAL
IMPLICATIONS: Breast cancer affects many aspects of a woman's sexuality,
including changes in physical functioning and in perception of femaleness.
Informed healthcare decisions cannot be made until patients are knowledgeable
about the sexual outcomes of cancer therapies. Healthcare professionals must
acknowledge the scope of the impact of cancer treatment on sexuality, include
such information as part of the informed consent process, and provide appropriate
education and referral.
PMID- 9397703
TI - Breast cancer detection by daughter of women with breast cancer.
PMID- 9397704
TI - Transportation as a barrier to cancer treatment.
AB - PURPOSE: Patients with cancer must overcome many psychological, social, and
economic barriers to obtain needed treatment. Because of the need for repeated
visits for cancer treatment on either an outpatient or an inpatient basis, one of
the major issues that patients with cancer must confront is that of arranging for
transportation to care. METHODS: This study compares the distance and mode of
transportation to radiotherapy and chemotherapy and perceptions of transportation
as a barrier to care among white, black, and Hispanic cancer patients receiving
treatment from a consortium of cancer treatment facilities in Texas. A mail
questionnaire was developed to assess the perceived barriers to cancer treatment
for patients who had been diagnosed clinically with breast, colon, cervical, or
prostate cancer, or lymphoma between 1989 and 1993. A total of 910 surveys were
mailed to prospective participants. Of the surveys mailed, 593 were returned,
yielding a 65.2% response rate. By race, the respondents included whites (42%),
blacks (40%), Hispanics (15%), and Asian-Pacific Islanders (3%). Two respondents
were 17 years of age; the remaining respondents were 18 years or older. RESULTS:
This study shows that some patients may forgo needed treatment because of
problems with transportation. This was perceived as an issue more for minority
patients than for white patients. Black and Hispanic patients consistently
reported that barriers such as distance, access to an automobile, and
availability of someone to drive them to the treatment center were potential
major problems. The distance to the facilities was farther for whites than for
blacks and Hispanics. Patients generally had to travel farther for chemotherapy
than for radiotherapy. CLINICAL IMPLICATIONS: Patients, particularly minorities,
may opt to forgo needed care in the absence of available and affordable means of
transportation to treatment facilities. These findings demonstrate the need for
healthcare providers to be aware of the transportation problems that patients
with cancer experience in obtaining treatment. Healthcare providers must work
with patients, their families, and volunteer agencies in the community to
facilitate transportation to cancer treatment services.
PMID- 9397705
TI - What providers should know about community cancer control.
AB - PURPOSE: The authors describe a framework for developing an effective, community
focused cancer control program. OVERVIEW: Progress in the application of cancer
control interventions has proven to be quite variable across different
populations and communities. The Kentucky Cancer Program, developed under joint
sponsorship of cancer centers at two state universities, has been using a model
that appears to provide a high degree of sensitivity to community-specific
problems and solutions. The Kentucky four-step model includes 1) using data from
a population-based cancer registry and other sources to identify problems; 2)
ensuring community involvement with providers in selecting the target population
and developing the intervention strategy; 3) implementing the intervention plan;
and 4) using cancer registry and other data to evaluate the impact of this
intervention. CLINICAL IMPLICATIONS: This framework may be useful to providers as
they try to balance the goals of their clinical practice and the goals of
community cancer control. Developing an effective, community-focused cancer
control program requires that providers gain a solid knowledge about their
community. The depth and richness of that knowledge base is enhanced by the
active participation of community members as they collaborate with the providers
on planning and implementing cancer control activities.
PMID- 9397707
TI - Cancer resources for providers in the rural community.
AB - Rural residents with cancer face many challenges--lack of specialized local care,
cost, and travel requirements--in receiving high-quality cancer care. Rural
physicians, nurses, social workers, and pharmacists have limited resources to
provide or coordinate the quality of care needed for these patients. Although
resources are sparse, creative collaboration and capitalization on community
cohesiveness may provide patients and healthcare professionals with needed
resources in rural areas. Transportation for cancer patients, for example, might
be obtained through local community organizations. Healthcare professionals may
use various national cancer and rural health organizations and Internet sites as
resources for updated oncology literature and for information on upcoming
oncology conferences and partnerships with urban cancer care providers.
PMID- 9397706
TI - An office systems approach to cancer prevention in primary care.
AB - PURPOSE: The provision of preventive services holds a central place in primary
care. Achievement of prevention standards offers a challenge. The authors address
the efficacy of an office systems approach to improving cancer prevention and
early detection services, provide a guide to assessing the appropriateness of
office systems dissemination in practices targeted for improvement, and describe
the range of dissemination strategies available. OVERVIEW: Preventive service
office systems depend on establishing practice routines, using tools such as flow
sheets, and sharing responsibilities among practice clinicians, staff, and
patients. Systems have been shown to be efficacious in a variety of settings.
Computers provide a significant enhancement to paper-based tools. Some practices
develop office systems themselves, whereas others require external support.
Before attempting to disseminate preventive services offices systems,
disseminators should ensure that adequate assistance can be provided, that
assistance follows a format that is acceptable to target practices, and that
target practices are receptive to assistance and able to cooperate. Dissemination
strategies include journal articles, continuing education programs, manuals and
tool kits, facilitation, and academic detailing. The relative expense and
efficacy of these approaches require further assessment. CLINICAL IMPLICATIONS:
Office systems hold promise in enhancing provision of cancer prevention services
in primary care. The practice should be approached as a team, and should include
practice clinicians as well as nonclinical staff members. Current research should
provide answers over the next few years about the cost-effectiveness of various
approaches and the most feasible ways to promote dissemination to practices that
need it.
PMID- 9397708
TI - Collaborative practice with children and parents. Enhancing preparation for and
management of cancer treatment.
PMID- 9397709
TI - Anastrozole. An effective, second-line hormonal treatment for advanced breast
cancer.
AB - Because advanced breast cancer is not curable, the goal of treatment is to
prolong survival yet maintain an acceptable quality of life. Anastrozole offers
another option for second-line hormonal therapy in postmenopausal women with
advanced breast cancer. This recently approved selective aromatase inhibitor is
as efficacious as other available hormonal therapies for this indication and
appears to offer an advantage with regard to adverse effects and ease of
administration.
PMID- 9397710
TI - Shareholders take stock in nursing's future.
PMID- 9397711
TI - Balancing calcium and phosphorus levels in chronic renal failure patients.
AB - Patients with chronic renal failure (CRF) can develop problems such as lethargy,
tetany, and muscle spasms, which can increase their morbidity and mortality.
Because of their non-functioning kidneys, patients with CRF require in-depth and
comprehensive monitoring of calcium (Ca) and phosphorus (P) levels. This article
presents advanced nursing actions and critical thinking strategies for use by the
critical care nurse when caring for patients with CRF.
PMID- 9397712
TI - Application of a transactional model of stress and coping with critically ill
patients.
AB - Critically ill patients are exposed to many physiologic and environmental
stressors, which can result in deleterious physiological and psychological
effects. Stress and coping within Lazarus and Folkman's transactional model is
used as a basis for describing patient responses in critical care. The authors
propose specific strategies to reduce stress and maximize coping in the
critically ill patient.
PMID- 9397713
TI - New neurointerventional therapies for stroke patients.
AB - New neurointerventional procedures affect patient outcomes following stroke.
Intraarterial thrombolysis, cerebral angioplasty, coils placed inside aneurysms,
and vessel occlusion with embolic agents serve as options for stroke patients
with conditions not as amenable to traditional surgical or medical management. By
understanding these new neurointerventional therapies, critical care nurses can
utilize a focused neurological assessment to intervene and maintain perfusion to
the brain following the procedures.
PMID- 9397714
TI - Recognizing the potential for violence in the ICU.
AB - Violence in health care institutions, specifically critical care units,
throughout the country is increasing at an alarming rate. This problem is not
confined to the urban areas but also encompasses rural regions. This article
assists the nurse in identifying the potential for violence by patients, family,
or visitors while they are in the critical care unit. The author describes
strategies that have been successful in controlling violence in the ICU and
suggests steps nurse educators and managers can take to reduce the risk of
violence in their units. The article is followed by Education STATPack material
that can be used by current subscribers for an inservice.
PMID- 9397716
TI - In the final analysis, people ... not$$$'s provide "care".
PMID- 9397717
TI - Abbreviations that cause injury, complicate communication and may kill!.
PMID- 9397715
TI - Developing a multidisciplinary brochure to teach patients and families about life
sustaining treatments.
AB - In an effort to comply with the Patient Self-Determination Act hospitals have
scurried to develop patient education emphasizing patients' rights to accept or
refuse medical treatments and to complete Advance Directives available in their
state. Despite efforts at patient and family education, nurses report family
difficulty in making end-of-life decisions because they have not fully clarified
their values with regard to life-sustaining treatments, making decisions in
crisis situations difficult. A brochure that discusses life-sustaining treatments
along with Advance Directives is needed to help families understand this
information before they reach a critical situation where anxiety makes decision
making difficult. The critical care nurse, clinical nurse specialist, or manager
can initiate a multidisciplinary task force to coordinate the development of a
brochure used to increase community awareness. The purpose of this article is to
help staff develop a brochure that can address these issues.
PMID- 9397718
TI - Heads up nurses! "Prospective payment" is coming to your Medicare skilled nursing
facility.
PMID- 9397719
TI - Teaching the snail to fly: affecting change in long-term care nursing staff.
PMID- 9397720
TI - Developing/implementing subacute programs in long-term care.
AB - Subacute care is a new and rapidly growing area. The industry is still constantly
changing. Prior experience in hospitals or long term care is not enough to ensure
success in this new arena. Success depends on giving careful consideration to the
corporate mission, staff selection and orientation, and to staff training. As the
push continues toward providing comprehensive care programs delivered at a
negotiated cost and within a set time frame, new roles for SAC facilities will
evolve. In developing their roles, SAC facilities have much to gain from the
prior experiences of their staff. However, staff members must also be willing to
adapt, and to learn new ways of doing their jobs. Success goes to those who
master the intricacies of this complex, challenging and dynamic industry.
PMID- 9397721
TI - [Responsibility matters--registration is no threat].
PMID- 9397722
TI - [Midwives' matters in the Liability Committee].
PMID- 9397723
TI - [Responsibility matters--this is a scientific council].
PMID- 9397724
TI - [Responsibility matters--pride--accountability--report].
PMID- 9397725
TI - [Responsibility matters--a liability case in Denmark].
PMID- 9397726
TI - [Alternative Birth-Center Clinic in South Hospital].
PMID- 9397727
TI - Professionalism and ministry. Can we keep our balance.
PMID- 9397728
TI - Nursing's moral standard.
PMID- 9397729
TI - The price of autonomy.
PMID- 9397730
TI - A call to servanthood.
PMID- 9397731
TI - Spiritual debridement.
PMID- 9397732
TI - Managing to care under managed care.
PMID- 9397733
TI - Sadness, survival & hope.
PMID- 9397734
TI - Not on my shift.
PMID- 9397735
TI - The towel the bath.
PMID- 9397736
TI - I'm afraid I'll cry.
PMID- 9397737
TI - Fleshing out a nursing theory. A Christian conceptual model.
PMID- 9397739
TI - Influencing our profession through continuing education.
PMID- 9397738
TI - My search for meaning & purpose.
PMID- 9397740
TI - Encouraging spiritual care.
PMID- 9397741
TI - Spiritual care. Responding to an invitation.
PMID- 9397742
TI - The gift of time.
PMID- 9397743
TI - Mentored to mentor.
PMID- 9397744
TI - Affiliated-individuation as a mediator of stress and burden in caregivers of
adults with dementia.
AB - The purpose of this study was to test a midrange model based on Modeling and Role
Modeling Theory. The self-care resource of affiliated-individuation was tested to
determine its mediational qualities between the stress and burden of caregiving
and caregiver life satisfaction. The sample of 107 family caregivers of adults
with dementia completed measures of stress, burden, affiliation, individuation,
and life satisfaction. All variables were correlated in the expected direction.
Affiliated-individuation decreased the effects of stress and burden on caregiver
life satisfaction, lending support for the theory-based model.
PMID- 9397745
TI - Potential benefits of pet ownership in health promotion.
AB - Pet ownership provides an opportunity to improve health. A pet may become a
stimulus for exercise, reduce anxiety, and provide an external focus of
attention. Pets are also a source of physical contact and comfort and may
decrease loneliness and depression while promoting an interesting lifestyle. The
benefits of pet ownership are consistent with the health promotion and disease
prevention goals outlined in Healthy People 2000. These goals include (a)
increasing physical activity and fitness and (b) improving mental health and
preventing mental disorders. Assessment of pet ownership and discussion of
potential health benefits facilitates a holistic understanding of our patients
and ourselves.
PMID- 9397746
TI - Cultural meanings of childbirth: Muslim women living in Jordan.
AB - This descriptive, ethnographic study focuses on the experience of childbirth for
Muslim women living in Jordan. Thirty-two childbearing women were interviewed in
the early postpartum weeks. The audiotaped interviews were transcribed and
translated. Themes were identified from the rich, narrative data. Motivations for
having children, as well as what constitutes the motherhood feeling, were
described. Themes also included the importance of relying on God or Allah for
support in childbearing and child rearing. A strong sense of the spiritual
dimensions of giving birth within women's traditional, religious, and cultural
context was identified. Findings from this study provide insight into the
meanings of childbirth for Muslim women living in Jordan. These meanings assist
nurses in providing culturally competent care.
PMID- 9397747
TI - Weight and weight-related distress after childbirth: relationships to stress,
social support, and depressive symptoms.
AB - The aim of this study was to explore whether women's psychosocial context was
related to weight status 1 year after childbirth. A survey sample of 149 women
provided data on life-event stress, social support, and depressive symptoms; and
three weight variables: body mass index, weight gain, and weight-related
distress. Of the women, 32 (22%) reported gains of > or = 5 kg and 50 (34%) met
the criterion for high depressive symptoms. Low social support, low income, and
high depressive symptoms were related to higher weight gain. Women with gains >
or = 5 kg reported high depressive symptoms (53% vs. 28%) more often than women
with lesser gains. Women who reported lowered self-esteem because of weight also
had higher depressive symptoms, body mass indexes, and weight gains than women
with increased or unaffected self-esteem. This study points to the importance of
incorporating women's psychosocial context into counseling about weight
management after childbirth.
PMID- 9397748
TI - Expanding self-awareness through exploration of meaningful experience.
AB - In a phenomenological investigation of nurses' meaningful experiences with
patients, the author continued investigation of caregiver/patient interaction
reported in two previous studies of confirmation and exclusion. Exploration of
meaningful experience is presented as an avenue for greater self-awareness for
the caregiver. Findings include description of study participants' lived
meaningful experiences and the essential structures of experiencing
meaningfulness. The lived meaningful experiences were characterized by intense
emotion, implicit experiencing, and relating. The essential structures of
experiencing meaningfulness were found to be a temporal process of reflecting and
articulating the discovery of self and the function of meaningful experience as a
template for both future and past experiences. Expanded self-understanding
through exploration of meaningful experience is discussed for its significance in
nursing practice and education.
PMID- 9397749
TI - The case of Baby M: nursing care in an ethical wilderness.
AB - This is a reflective case study of an infant with Down Syndrome and a potentially
fatal cardiac defect. It is a story of hope and loss, of silence and learning to
speak, and of relinquishing space and standing ground. The purpose of this
article is to explore the conflicting claims a neonatal intensive care (NICU)
nurse faces in caring for critically ill infants. The questions of "Who speaks?"
and "Who listens?" are addressed. The concepts of women's moral development and a
nursing definition of voice are included. It is proposed that the conventional
feminine voice and the embodied knowledge so integral to expert nursing actually
draw strength away from the voice that needs to be permitted into the circle of
decision makers when ethical issues are raised in the NICU.
PMID- 9397750
TI - [It is great to be a midwife].
PMID- 9397751
TI - [What is the main principle when new employees are appointed--the title and
formal qualifications or the skillful competence?].
PMID- 9397752
TI - [On titles and qualifications].
PMID- 9397753
TI - [Finnish maternity care and Chinese medicine].
PMID- 9397754
TI - [Zonal therapy courses are popular].
PMID- 9397755
TI - [Promises on the way to a better humanity].
PMID- 9397756
TI - [From the shadow to the light--the history of giving birth].
PMID- 9397757
TI - [Abortion--a subject kept in the dark].
PMID- 9397758
TI - [The rights of fetus and mother--conflict or harmony?].
PMID- 9397759
TI - [Finnish prenatal care and Chinese medicine. Acupuncture and other treatments].
PMID- 9397760
TI - [Ideal entrance of the child into the world].
PMID- 9397761
TI - [Breast feeding--secondary performance or a matter of course?].
PMID- 9397762
TI - [Confidence on every level].
PMID- 9397763
TI - [Depression after childbirth].
PMID- 9397764
TI - [Supportive measures for tired and depressed mothers in a Helsinki home for
unmarried mothers].
PMID- 9397765
TI - [HIV-infections in Finland].
PMID- 9397766
TI - [Finnish prenatal care and Chinese medicine].
PMID- 9397767
TI - [Private midwife as the muse of the woman giving birth].
PMID- 9397768
TI - [The New Zealand Model--the 10-year path from a "doctor-nurse" to a self-employed
professional].
PMID- 9397769
TI - [Breast program as the basic program for early recognition of breast cancer].
PMID- 9397771
TI - [Active birth and birth in water in Finland].
PMID- 9397770
TI - [Successful guidance?].
PMID- 9397772
TI - [Coli and children].
PMID- 9397773
TI - [Unsatisfactory sucking behavior at the breast. Detecting--preventing--treating].
PMID- 9397774
TI - [Money does not make us happy, gold does. An initiative by the coworkers in the
neonatal nursery].
PMID- 9397775
TI - [Nasal continuous positive pressure respiration as a respiratory aid in small
premature infants. From the physician's viewpoint].
PMID- 9397776
TI - [Nasal continuous positive pressure respiration as a respiratory aid in small
premature infants. From the nurse's viewpoint].
PMID- 9397777
TI - [Studying to be a nurse--report on the nursing diploma program in Osnabruck].
PMID- 9397778
TI - [Experiences with nursing education in Frankfurt/Main].
PMID- 9397779
TI - [The importance of kinesthetic infant handling in pediatric nursing].
PMID- 9397780
TI - [160 years of pediatrics in Austria].
PMID- 9397781
TI - [Development of pediatric nursing in Austria. An historical retrospective].
PMID- 9397782
TI - [The parents' work at the Glanzing Pediatric Department].
PMID- 9397783
TI - [Sudden infant death].
PMID- 9397784
TI - [Terminal care is obligatory for physicians and nurses].
PMID- 9397785
TI - [Special features in the postnatal adaptation of newborns after cesarean
section].
PMID- 9397786
TI - [Special features in the postnatal adaptation of newborns after cesarean section-
nursing aspects].
PMID- 9397787
TI - [Psychosocial care of the parents in neonatology. Report of experiences].
PMID- 9397788
TI - [In the shadow of a sick sibling].
PMID- 9397789
TI - [Caring for a newborn with meningomyelocele].
PMID- 9397790
TI - [Treatment of persistent pulmonary hypertension of the newborn by nitrogen
monoxide inhalation].
PMID- 9397791
TI - [Outpatient oncological nursing service. Description of a project].
PMID- 9397792
TI - [Interview by the Nursing Society with Elisabeth Oltrogge. Profiles in pediatric
nursing--personalities and challenges].
PMID- 9397793
TI - [10 years Charlottenburg Birthing Center. Report on 10 years of births in the 1.
European birthing center in Berlin, Klausenerplatz].
PMID- 9397794
TI - [Accident insurance legislation. Regulations for accident prevention contain
important rules of behavior].
PMID- 9397796
TI - [Kneipp year 1997].
PMID- 9397795
TI - [Management in the nursing service--workshop for nursing personnel in the
European Surgical Institute].
PMID- 9397797
TI - Sexuality and the spinal cord injured.
PMID- 9397798
TI - Sexual health: every nurse's concern.
PMID- 9397799
TI - Sexual healing.
PMID- 9397800
TI - Straight talk and humour adolescent sexual issues.
PMID- 9397801
TI - Learning about sexual health.
PMID- 9397802
TI - Respoking the wheels of health.
PMID- 9397803
TI - Sex in residential care facilities.
PMID- 9397804
TI - Save your back!
PMID- 9397805
TI - Breast cancer is the most common cause of cancer death in women.
PMID- 9397806
TI - Legal issues for nurses.
PMID- 9397807
TI - A project to obtain clearer work-related injury and illness data for the health
industry.
PMID- 9397808
TI - Lighting the Way. The Enrolled Nurse Professional Association of NSW Inc.
PMID- 9397809
TI - Sexuality is a highly complex phenomenon.
PMID- 9397810
TI - Nurse in profile. Robyn Hately. Interview by Kimberly O'Sullivan.
PMID- 9397811
TI - Ethical issues in nursing education.
PMID- 9397812
TI - Writing and evaluating computer-based training programs.
AB - Publishers are preparing for the hitech future and authors and editors need to
also. Publishers know that book sales may be down in the future, while computer
program sales are expected to increase. Most book publishers have added media
divisions to position themselves for the future. Authors and editors can also
shift from writing or editing books to developing computer-based training
programs. This author tells you how to write, edit, or evaluate the new computer
based training programs.
PMID- 9397813
TI - Book reviewing: keeping the audience in mind.
AB - Writing book reviews is an excellent way to start your publication experience and
develop a relationship with a journal editor. Most nursing journals include book
reviews, and some even select editorial board members from book reviewers who
have demonstrated their ability to write concise, honest reviews and submit them
on time. This author includes tips on writing a high-quality review by keeping
the audience in mind.
PMID- 9397814
TI - Fax etiquette for nurse authors and editors.
AB - Is the facsimile (fax) machine really as great as it seems? Yes, but there is a
potential for its misuse. Like all equipment, the fax machine is a tool that
needs to be used wisely. This article describes the Do's and Don'ts of using the
fax machine to communicate between authors and editors. Tips in this article will
help authors and editors to correspond smoothly by fax and use new fax equipment
options.
PMID- 9397815
TI - Is your co-author relationship on the rocks? How to know and what to do.
AB - Co-authorship can be successful, but there are pitfalls to avoid so that a
positive relationship does not become a disastrous one. Even experienced co
authors have to review and work on their relationship to make sure they complete
the project and retain a collegial relationship. In a past article this author
described how to develop the co-authorship relationship (Heinrich). In this
article she describes how to identify and deal with co-authorship problems when
they occur.
PMID- 9397816
TI - Checking references: tips for reviewers.
AB - When I was a new reviewer, I was uncertain if I should check some, all, or none
of the references in the manuscript. I was equally uncertain, however, if anyone
was ultimately accountable for this responsibility. Reviewers must assume
responsibility for checking references because "the most critical part of the
review process is to check the accuracy of the content." (Brooks-Brunn, 1993, p.
4). The reviewer's three main responsibilities include checking for (1) a
reference for every citation (2) accuracy of reference content (3) accuracy of
cited material (Kirchhoff, 1995).
PMID- 9397817
TI - Successful publishing in nursing: debunking some common myths.
AB - Myths can serve useful functions for a group or society. The myths related to
success in publishing, however, do not seem to serve a useful function, and may
operate as barriers or excuses that unnecessarily hinder success in publishing.
In this article, some of the common myths associated with publishing in nursing
are examined for their validity and for evidence of support for the myth in the
literature.
PMID- 9397818
TI - Submitting your manuscript on disk: a steep learning curve for authors and
editors.
AB - Many nursing journals are switching to state-of-the-art manuscript production
systems. Most of these new systems include computerized typesetting, so some
journals are requesting disk submission of manuscripts. However, computer disk
submission is not without difficulties. Editors and authors alike are
experiencing a fairly steep learning curve before developing a system where the
author's disk can work in the publisher's production system. This article
describes how authors and editors can collaborate on the disk submission system
for nursing publications.
PMID- 9397819
TI - Nurse writers internet and World Wide Web sites.
AB - Nurse writers can use the Internet to find vast amounts of current information on
topics for professional articles. The following excerpts are based on concepts in
the Second Edition of the authors' book, How to Write and Publish Articles in
Nursing, published by Springer Publishing Company. The Second Edition will is now
available.
PMID- 9397820
TI - Discovering medical products on the Web.
PMID- 9397821
TI - Myths & facts ... about aging.
PMID- 9397822
TI - Performing Allen's test.
PMID- 9397823
TI - Taking a risk for Ms. Stinson.
PMID- 9397824
TI - Managing pain during chest tube insertion.
PMID- 9397825
TI - Removing catheters. Managing freezes and fractures.
PMID- 9397826
TI - Actionstat. Acute pulmonary edema.
PMID- 9397827
TI - Looking out for adverse drug reactions.
PMID- 9397828
TI - Taking diabetes new look at an old adversary.
PMID- 9397829
TI - Ventricular tachycardia.
PMID- 9397830
TI - The art of nursing.
PMID- 9397831
TI - Pediatric patient care.
PMID- 9397832
TI - Caring for patients with benign prostatic hyperplasia.
PMID- 9397833
TI - Nurse's guide to common postoperative complications.
PMID- 9397834
TI - Closed suction wound drainage.
PMID- 9397835
TI - Looking the other way.
PMID- 9397836
TI - Breakfast in the old country.
PMID- 9397837
TI - The nurse executive: leading beyond traditional boundaries.
PMID- 9397838
TI - Profiles of leadership: a dialogue with two nursing revolutionaries.
AB - Rebels break the rules and revolutionaries rewrite them because the old rules are
no longer adequate. These revolutionary leaders examine their life journeys and
highlight issues and events that prepared them for nontraditional nursing roles;
that of consultant and CEO. Patterns of thought and behavior nested within their
stories provide a rich map for the contemporary nurse seeking to expand their
view of the health care landscape.
PMID- 9397839
TI - My labyrinth.
AB - Each of us is taking a professional journey. We use our scholarship and our
relationship building skills to learn and mentor, experience and contribute, and
lead and follow. Our creativity, flexibility, and adaptability provide us with a
"centering" that enhances our success, but our only reason to pursue the journey
with vigor is to create a better environment for professionals to practice and
for patients to receive care. Let us know ourselves so we can ground the journey
with integrity.
PMID- 9397840
TI - Nursing journalism leadership.
AB - How is leadership exemplified in the role of nurse editor? In this article, the
editor of two nursing journals describes the evolution of her editorial role with
a focus on job analysis and leadership requirements. Highlighted are catalyzing
events that shaped the author's editorial vision and leadership style. Factors
for success in the role are presented to help those who want to assume
editorships.
PMID- 9397841
TI - The private practice of nursing: the gift of entrepreneurialism.
AB - The demands of the entrepreneur extend the opportunities and creativity of the
nurse. The characteristics of independent practice are now the expectations of
the role of every nurse. Understanding the gifts of the entrepreneurial
experience helps facilitate the growth of nurses and their practice.
PMID- 9397842
TI - Leading beyond traditional boundaries: a community nursing perspective.
AB - As a nursing leader, I frame my personal and professional life from the
perspective of community. I place high value on health, relationship and the art
of nursing. As Director of Community Outreach for an integrated delivery network,
I use these values to strengthen nursing's contribution to an integrated delivery
network and managed care contracts. Most recently, my personal and professional
life has been shaped by traditional Indian medicine and my 10-year experience in
Carondelet's community-focused nursing practices.
PMID- 9397843
TI - Nurse leaders: roles driving organizational transition.
AB - Transition leaders have developed in our organizations. These roles allow nurse
leaders to combine the knowledge of the customer, the art of nursing, and the
chaos of health care in order to pioneer new strategies. These roles are
flexible, either focused or broad, and change in scope and direction. The teams
we lead are diverse in team experience, seen as disconnected from operations, and
struggle with exceedingly defined or hardly evident boundaries. Methodologies add
structure and foster active participation; they are fast, decisive, compressed,
creating results. "Change-magic" assists in making decisions and influencing the
organization to "get the job done."
PMID- 9397844
TI - Determining if shared leadership is being practiced: evaluation methodology.
AB - This article explores the use of a cognitive information-processing structure,
mental models, to assess an organizational management change to shared leadership
(SL). The purpose of this study was to describe the mental models of critical
care nurses after the implementation of an SL management model. Scenarios based
on daily clinical situations and measuring three SL concepts (empowerment,
accountability, and partnership in decision making) were posed to critical care
nurses in personal interviews. By using this evaluation methodology, nurse
administrators can determine to what extent a new management change has been
incorporated into daily nursing practice and in what areas to target further
education and resources.
PMID- 9397845
TI - Executive journey: from 1,300 FTEs to none.
AB - The story of how one woman, Mary Jane Mastorovich, traveled the journey from the
traditional role of a nurse executive, responsible for 1,300 full-time
equivalents (FTEs) and an annual budget of $166 million, to that of a major
change agent in a system-wide redesign effort. Her travels and the lessons she
learned along the way give insight into how to develop strategies and methods for
personal and professional transformation. Her story also illustrates the balance
between positional power and the power of influence as we face the roller coaster
ride that will be health care delivery in the next century.
PMID- 9397846
TI - Nurse executives in the 1990s: empowered or oppressed?
AB - Nursing executives are at the center of change. They are involved in the
reenginnering of the workplace and often implement new procedures, in addition to
downsizing staff. This article explores oppressed group behavior and its
implications for nursing executives at this time of change in the health care
system. The purpose of this exploration is to encourage a dialogue about its
relevance in order to enhance empowerment and to break the cycle of oppression.
PMID- 9397847
TI - Is nursing under new management or is it a matter of semantics?
AB - Managed care, in addition to being driven by the hegemony of market concerns, has
truly bitten into the clinical hegemony. Nursing has recognized this new order
and is attempting to manage the situation with new paradigms before other non
nursing entities do. The issue for nursing has become how to allow the patient to
drive the health care delivery system while preparing for change and not fearing
nursing's loss of preeminence as a clinical authority in its own right. At the
same time, nursing must protect a valued and needed profession.
PMID- 9397848
TI - The nurse executive in the 21st century: how do we prepare?
AB - A revolution is occurring in health care. Hospital restructuring, mergers, and
closures are occurring at an unprecedented rate. The role of the nurse executive
is being scrutinized as never before. There is considerable debate on what is the
best educational preparation for nurse executives given their increasing
management and fiscal responsibilities in organizations today. This article
reviews the evolution of graduate education in nursing administration as well as
current research on graduate education for nurse executives. Job trends for nurse
executives in industry and health care are also explored.
PMID- 9397849
TI - New RNABC president seen as a mentor for nurses.
PMID- 9397851
TI - New ways of doing things.
PMID- 9397850
TI - The VON at 100. A century of caring.
PMID- 9397852
TI - Sharing the challenge as volunteers.
PMID- 9397854
TI - Care for your community.
PMID- 9397853
TI - Partners in health.
PMID- 9397855
TI - New Code provides guidance for ethical decision-making.
PMID- 9397856
TI - Nurse clinician as learning resource. Interview by Helen Griffiths.
PMID- 9397857
TI - Continual learning. Interview by Helen Griffiths.
PMID- 9397859
TI - The disaster at Green Park.
PMID- 9397858
TI - How far is too far.
PMID- 9397860
TI - Home care of persons with AIDS.
PMID- 9397861
TI - The role of nurses in crisis intervention.
PMID- 9397862
TI - Nursing management in critical care.
PMID- 9397863
TI - New trends and old traditions in educational technology: video and beyond.
PMID- 9397864
TI - Broadening the staff development department.
PMID- 9397865
TI - The evolving age-related competency: a potential type-one trap.
PMID- 9397866
TI - Beating the mandatory blues: using the FOCUS PDCA process.
AB - By October 1995, a total of 863 nursing employees fulfilled their annual
requirements, for a compliance rate of 94.4%. Additionally, 178 employees from
various ancillary departments such as radiology, dietary and food service,
rehabilitation, and social service also attended. Therefore, we were able to use
our program beyond the nursing department and provide a hospital-wide educational
service. Overall, the poster presentations were highly successful and the
benefits to the institution included the following: 1. An increase in employee
satisfaction because the average time spent away from the patient care unit was
substantially decreased. 2. An increase in instructor availability to meet the
educational needs of the nursing staff on individually assigned units. 3. An
increase in instructor accessibility to identify and meet the learning needs of
new staff members.
PMID- 9397867
TI - Student support.
PMID- 9397868
TI - Competition in health care calls for creativity.
PMID- 9397869
TI - Innovative collaboration to prevent repeated adolescent pregnancies.
AB - Nurse educators from a university setting and staff from the county health
department collaborated to establish an innovative program to prevent repeated
pregnancy in adolescents. Called Dollar-A-Day and patterned after the original in
Denver, CO, the program was operated jointly for 5 years and today continues to
operate under the auspices of the health department. Success of the venture is
attributed to use of skills in assessment, building, managing, and evaluating, as
described by Loxley (1997). These elements were used to construct a context for
collaboration.
PMID- 9397870
TI - Why must a clinical specialist be a nurse practitioner?
PMID- 9397871
TI - Concerns of graduating baccalaureate nursing students.
AB - Senior baccalaureate nursing students (N = 397) just weeks away from graduation
were asked to complete the "Worry Clinic Form." This form invites subjective
responses from the students' perspectives about their "current" and "greatest-to
date" professional concerns. Content analysis was used to determine the
categories of these concerns. Categories of both current and greatest-to-date
professional concerns were (1) functioning as a competent registered professional
nurse and (2) the environment of work.
PMID- 9397872
TI - Academic misconduct in schools of nursing.
PMID- 9397873
TI - Cooperative learning in the clinical setting.
AB - The modern clinical practice setting presents nurses with challenges about which
they must think critically and develop increasingly autonomous problem-solving
approaches. It is essential to provide nursing students with opportunities to
practice critical thinking so that they can develop this crucial skill.
Cooperative learning strategies are interactive teaching methods that stimulate
students to think critically, communicate effectively with peers, and accept
responsibility for learning through group process activities. Group care planning
is one such cooperative strategy that also promotes a positive attitude about
care planning and sharpens time management skills. Cooperative assessment and
care planning foster the development of critical thinking and effective problem
resolution, preparing students for patient care problems they will likely
encounter in future positions.
PMID- 9397874
TI - Outcomes of occupational stressors on nurses: chronic fatigue syndrome--related
symptoms.
AB - Considering the types and number of occupational stressors involved in caring for
patients, nurses may represent a population at high risk for physical illnesses.
A sample of 3400 nurses who belong to a statewide or a national nurses
organization were randomly chosen for participation. Of this group, 202 reported
6 months or more of debilitating fatigue and completed a three-page questionnaire
assessing symptoms related to chronic fatigue syndrome (CFS) and comorbid medical
conditions. This group (N = 202) was mailed a follow-up questionnaire 1 year
later that reassessed symptoms of CFS and occupational stressors. Many sampled
nurses reported a high degree of occupationally related stress but did not report
CFS symptoms; however, perceived exposure to the threat of an accident as a nurse
and poor physical working conditions were significantly related to symptoms
reported. These findings are consistent with previous research.
PMID- 9397875
TI - Clinical process learning to improve critical thinking.
AB - A six-step process-learning strategy model serves as a framework for nursing
students to critically analyze situations encountered during their clinical
practice experience. Stephen Brookfield's four components of critical thinking
and culturalization themes relate well to how nurses learn and experience
critical thinking and serves as the model's organizing framework. This learning
strategy has implications for all nurse educators because it incorporates the
realities of nursing practice, merges nursing education with practice, involves
students in affective, cognitive, and psychomotor domains of learning, and
prepares graduates to function in dynamic and complex health care systems.
PMID- 9397876
TI - Symbols of our trade: examining our relationships with work.
PMID- 9397877
TI - Cleveland cancer advocates develop regional resource directory.
PMID- 9397878
TI - Risk assessment and risk-based programs of prevention in various settings.
AB - An assortment of screening tools exist to estimate risk for pressure ulcer
development. The Braden Scale has undergone testing in several settings which
guide users in answering the following questions: Who should assess risk? Does
cut-off score differ by setting? Does timing of assessment vary by setting? Is
formal risk assessment necessary? How does risk assessment fit into a program of
prevention? Based on these studies, RNs are able to use the Braden Scale more
reliably than Nurse Aides and LPNs. While the Braden Scale does not replace
clinical judgement, its use will help caregivers of all levels to identify at
risk patients and intervene for specific risk factors. Generally, all patients
should be assessed upon admission and 24 to 48 hours later, followed by ongoing
assessment. A formal risk-based program is effective in both reducing the
incidence of pressure ulcers and the costs associated with prevention. Protocols
can be developed to address each level of risk, with each level requiring more
aggressive preventive modalities. Some investigators have also tied interventions
to specific subscale scores. It is important that risk assessment and risk-based
protocols such as the Braden Scale become a standard of practice in all
healthcare settings.
PMID- 9397879
TI - Bandaging in the treatment of venous ulcers: a European view.
AB - The principal treatment of venous ulcers in ambulatory patients in bandaging. The
physiological rationale for this treatment is to improve the venous hemodynamic
abnormality caused by prolonged venous hypertension due to limb venous valvular
incompetency. Correct bandaging results in the reduction of limb edema and ulcer
healing. A number of different bandages and combined bandaging regimens are used
in the treatment of venous ulceration. Recently the European Tissue Repair
Society has defined different types of bandages based on their function into four
groups: (1) Extensible bandage; (2) Elastic bandage; (3) Compression bandage; and
(4) Support bandage. The ability of a bandage to produce a gradient compression
starting at 35 to 45 mmHG at the ankle and reducing as the bandage approaches the
knee is stated in the literature as a goal of bandaging. Our studies and others
have shown that routine measurements of limb circumference as an indicator of
edema reduction is another way of monitoring the efficacy of the results of
bandaging since edema reduction and control is associated with improved ulcer
healing.
PMID- 9397880
TI - The non-healing leg ulcer: peripheral vascular disease, chronic venous
insufficiency, and ischemic vasculitis.
AB - The non-healing leg ulcer is examined by discussing three disease processes:
peripheral vascular occlusive disease (PVOD), chronic venous insufficiency (CVI),
and vasculitis. For PVOD, management decisions are based on risk factors and
disease history. Comprehensive management includes the discontinuation of
smoking, exercise conditioning and regulation of diabetes, hyperlipidemia,
hypertension, and the appropriate application of anticoagulant/antiplatelet
drugs. Methods of surgical management include bypass with autogenous or synthetic
material in addition to reconstructive surgery with patch angioplasty or extra
anatomic bypass, amputation, percutaneous transluminal angioplasty/stents,
thrombolytic infusion, atherectomy, intraluminal ultrasound, and angioscopy. The
optimal healing environment for all ulcers prevents contamination, pain, and
fluid loss. In CVI, higher venous pressure in the veins of the lower limb during
exercise results in ambulatory venous hypertension and ulceration. Various
theories are associated with the disease and ulceration process; the classic
treatment of elevation, ambulation, and compression for venous disease remains
unchallenged. Diagnosis is based on history, physical examination, invasive
venography, and/or non-invasive studies. Two groups of vasculitic disorders that
share varying degrees of vascular inflammation and necrosis are arteritis (lupus,
erythematosus, periarteritis nodosa, dermatomyositis) and blood dyscrasias
(sickle cell disease, thalassemia). Leg ulcers associated with vasculitis are due
to inadequate tissue oxygenation at the local level, are typically chronic, slow
to heal, and commonly recur.
PMID- 9397881
TI - Clinical evaluation: outcomes, benchmarking, introspection, and quality
improvement.
AB - Transforming the current event-driven reimbursement system into a quality powered
marketplace will require clinical evaluation of how care is delivered. The
managed care marketplace is evolving in three stages, from an event-driven, cost
avoidance model, to which the concepts of "value" and "quality" are added, with
the final addition of a more "public health" focus. Clinical evaluation is a
scientific process of outcomes assessment, clinical guidelines, and benchmarking.
This process was applied to a hospital-based outpatient wound clinic, leading to
a determination that the overall clinic Kaplan-Meier median time to healing could
be improved. Two groups of patients were studied, 141 retrospectively from 1993
to 1994 and 57 prospectively in 1995. While there was no significant difference
in the percentage healed between the groups, a significant difference in the
median times to healing was revealed, which was linked to antibiotic use. Even
when antibiotics were used prophylactically, the median times for healing were
elevated from those without infections. Introspection led to fewer patients
receiving preventive antibiotics. The overall lower median time to healing curve
in 1995 can be explained by this change in clinical practice. This quality
improvement demonstrates the utility of the clinical evaluation process as the
healthcare marketplace evolves.
PMID- 9397882
TI - Timing issues for wound care research.
AB - While certain issues related to time, such as time to healing, are frequently
discussed in the wound care literature, other important time-related issues for
conducting and interpreting wound research are only rarely addressed. Time
presents serious philosophical and methodological challenges that can have a
significant impact on the validity, reliability or rigor of a study and are,
therefore, worthy of consideration. This article discusses four commonly
encountered time-related problems for wound research (time-congruent research
questions and designs, time specific measurement tools and protocols,
retrospective versus prospective studies, and time sampling/sequential
triangulation), presents examples to illustrate these problems, and posits some
solutions. Five questions are offered as a guide for determining whether wound
research tools and protocols adequately address time-related research issues.
PMID- 9397883
TI - The Wound Intelligence System: early issues and findings from multi-site tests.
AB - The purpose of this manuscript is to address a gap in our efforts to
incrementally improve wound care practice through evidence-based practice. The
Pressure Sore Status Tool (PSST) provides data to extend evidence-based practice
beyond clinical trials and into the clinical area itself. The computerized PSST
was evaluated over one year through over 70 beta sites. Two studies which were
part of that evaluation period are described which give a comparative analysis of
wound stage and PSST scores, and similarities and differences in wound
characteristics of four types of wounds: arterial/ischemic ulcers, neuropathic
ulcers, pressure ulcers, and venous ulcers. In the first study, a relationship
between PSST scores and staging scores for the presenting wound was present,
indicating promise for the utilization of the PSST as an alternative to staging
scores for describing changes in wound status. However, in the second study,
clear difference was not noticeable between the four wound types, suggesting that
discriminations regarding wound type may not be able to be made from PSST
assessments. The goal of these studies was to provide feedback on the use of the
computerized PSST, thereby providing feedback based on objective outcomes of the
practice of clinicians themselves.
PMID- 9397884
TI - The road to developing standards for the diagnosis and treatment of venous leg
ulcers.
AB - In early 1996 the Venous Leg Ulcer Guideline was developed for the diagnosis and
treatment of venous leg ulcers. In order to discuss the development of standards
in general, and the Venous Leg Ulcer Guideline in particular, we first need to
understand the difference between the following terms: Critical pathway,
consensus statement, guideline, and standard. There are advantages and
disadvantages to the use of guidelines. In the development of a guideline,
endorsement by a respected colleague is important. Development of the Venous Leg
Ulcer Guideline began with a consensus statement and then underwent review by a
national advisory panel and national peer review through publication. A revised
guideline has now been developed which will be tested in a pilot study for
clinical efficacy, effect on cost, and impact on quality of life. Validation will
require implementation in a prospective clinical trial. Diagnostic and Treatment
Algorithm forms for the diagnosis and treatment of venous leg ulcers were
developed as part of the preliminary testing of the guideline. Although
guidelines do not substitute for good clinical judgement, they can encourage
clinical judgement and help reduce fragmented care and the costs associated with
inappropriate treatments.
PMID- 9397885
TI - Issues in chronic wound care: where do we go from here?
AB - Understanding of the healing process and factors that may affect it, has
increased dramatically during recent years. Clinical application of this
knowledge has improved care for many patients, and helped focus attention on
information deficits. To better meet patient needs and increase awareness of the
value of prevention, wound care clinicians and researchers are encouraged to
include Quality of Life outcomes in their goals of chronic wound care. In the
absence of the results of reliability, validity and feasibility studies of
existing chronic wound care guidelines, clinicians need to be aware of their
potential usefulness and limitations. When reviewing wound care costs or
conducting studies, it is important to define cost-effectiveness as a function of
outcomes and all relevant costs. Because chronic wounds occur in every care
environment, these issues require the attention of all healthcare professionals,
educators, payors and patients. Wound care professionals are encouraged to
disseminate existing knowledge to all providers and recipients of care.
PMID- 9397887
TI - Charge nurses entitled to vote in Union elections.
PMID- 9397886
TI - Nurses have the courage to care.
PMID- 9397888
TI - Nurse's duty to guard against sexual predators on staff.
PMID- 9397889
TI - LA: improper administration of injection: nurse's failure to record "site &
mode".
PMID- 9397890
TI - PA: drug conviction triggers suspension: nurse charge board violated ADA.
PMID- 9397892
TI - A familiar tune.
PMID- 9397891
TI - Does workers' compensation cover on the job heart attack?
PMID- 9397893
TI - Ethics in action. Your cancer patient's pain.
PMID- 9397894
TI - The 1997 earnings survey. More benefits, with a price.
PMID- 9397895
TI - Analyzing the Chem 7.
PMID- 9397896
TI - Healing venous ulcers.
PMID- 9397897
TI - PA catheter numbers made easy.
PMID- 9397898
TI - Vitamins and minerals.
PMID- 9397899
TI - Subacute care: yesterday's med/surg.
PMID- 9397900
TI - When you go toe-to-toe over doctor's orders.
PMID- 9397901
TI - Breaking free from sedative addiction.
PMID- 9397902
TI - Who was I to judge?
PMID- 9397903
TI - [Challenge for professional group? Treatment of chronically ill especially
important].
PMID- 9397904
TI - [Are we really getting those new colleagues? Annual survey health care 1998].
PMID- 9397905
TI - [Needs of the people are determinant for nursing care--learning to think
globally. Interview by Willem Zandbergen and Tonny van de Pasch].
PMID- 9397906
TI - [Hospital and university work together on quality--autonomous nursing in the NDU
(Nursing Development Unit). Interview by Tonny van de Pasch].
PMID- 9397907
TI - [A week of chronic diseases. 2nd European Nursing Congress].
PMID- 9397908
TI - [Karin Spaink lives with MS for 10 years already--'When I am stable' I don't
worry about anything. Interview by Toine de Graaf].
PMID- 9397909
TI - [To be chronically ill, life style and nurse's contribution].
PMID- 9397910
TI - [Nursing care of chronically ill still not optimal--rising above the disease
image. Interview by Tonny van de Pasch].
PMID- 9397911
TI - [A special responsibility for nurses--the chronically ill in the hospital].
PMID- 9397912
TI - [2nd European Nursing Congress 5 through 8 October].
PMID- 9397913
TI - [Depression in the center--National Day for Public Mental Health].
PMID- 9397914
TI - [Nurses have trouble with inhalation therapy. 'Nurse, can you show us that
puff?'].
PMID- 9397915
TI - [Nurses can point out to parents the adverse effects for young children. Campaign
against passive smoking].
PMID- 9397916
TI - [Pilot project limited to The Netherlands. Debate on Internet about nursing
diagnosis].
PMID- 9397917
TI - [Not extending life is different from ending life. When the remedy against death
only extends the dying process].
PMID- 9397918
TI - [Searching for sense and meaning together with the patient. Giving meaning and
professional nursing practice].
PMID- 9397919
TI - [It remains different for the patient than for the nurse--the world behind the
bed bath].
PMID- 9397920
TI - [Treatment compliance is the key word in combination therapy. Current image of
AIDS (2)].
PMID- 9397921
TI - [Many requests for aid in the nurse's field. Nursing office hours for MS
patients].
PMID- 9397922
TI - [Diagnosis in nursing. Prognosis: from expectation to goal-setting].
PMID- 9397923
TI - [Nursing care and total health care costs].
PMID- 9397924
TI - [Pressure sores in ICU patients--a literature review].
AB - The purpose of this literature study is to gain an insight into the information
available on epidemiological aspects, specific factors of risk, risk assessment
instruments and preventive measures with respect to pressure sores with adult ICU
patients. There are indications that the incidence of pressure sores in the ICU
is higher than the average incidence of 3-10% in hospital populations. This
higher incidence may be accounted for by specific risk factors, such as history
before admission to the ICU, severity of the disease, the risk of prevention
measures, the use of special medicine and the nutritional state. Also structural
factors, such as the accessibility of prevention means and the unambiguous usage
of the registration of pressure sores, play a part. Risk assessment instruments
are used to quantify the risk of pressure sores in order to support or evaluate
the decision concerning preventive measures. For the ICU risk assessment
instruments have to be developed, in which the specific factors of risk are
processed. Related to preventive measures the effect of turning and re
positioning the patient on the vital functions should further be investigated. If
turning and re-positioning could be started as early as possible and in a
responsible way, the demand for expensive measures, like special beds en special
mattresses, will possibly decrease. The positive effect of these special beds on
the prevention of pressure sores seams to be irrefutable.
PMID- 9397925
TI - [The use of isolation in psychiatry--a literature study].
AB - This article reports on a literature review into the publications on the practise
of seclusion. Attention will be paid to the moral debate on seclusion. The major
part of the publications consider seclusion as a necessary intervention to manage
problem behaviour. The first part of the article will consider definitional
aspects and will result in concept clarification. The review shows differences at
definitional aspects, motives for seclusion and patient characteristics. Data on
frequencies, incidence and duration appear to be different. The experience of
patients who are secluded are mostly negative, but positive reactions are also
reported. Publications on the influence of the hospital characteristics to the
use of seclusion seem to increase during time. Finally it is concluded that
seclusion is an effective way to manage (potential) dangerous behaviour and that
seclusion is an intervention which may create therapeutic conditions.
PMID- 9397926
TI - [Ethics of nursing practice--ethics of care and ethics of rule?].
AB - Nurses' daily care for patients is imbued with moral questions. Ethics
distinguish various movements that intend to solve the problem of how to deal
with such questions. This article discusses two variants, namely ethics of rules
and ethics of care. Ethics of rules present a rational model of thinking in which
universal principles are applied to practical moral problems. According to ethics
of care, an attitude of responsibility and involvement and, accordingly, the
attention to the complex situation of a patient is considered moral. Both kinds
of ethics are attached to a case from the practice of nursing care for oncology
patients. The thinking of the nurses concerned is in line with ethics of care. It
also involves principles of ethics of rules. These principles, however, only make
sense in the complex situation of the patient. By virtue of this quality they are
taken into consideration by nurses as one of the details from the context. This
makes ethics of care function as a kind of 'breeding ground' for ethics of rules.
PMID- 9397927
TI - [Breathing-related nursing care problems--a descriptive study].
AB - Research into nursing problems related to breathing that can occur by pulmonary
patients and their relationship with literature on Nursing Diagnoses (further
referred to as diagnoses) on this subject has been done on two nursing wards.
Interviews have been held with eleven nurses working in direct patient care. From
the acquired data twelve problems with their signs and symptoms as well as the
possible etiology were found, each showing one or more similarities with
diagnoses from the North American Nursing Diagnosis Association (NANDA).
Similarities and differences between the NANDA diagnoses and the acquired data
have been analysed.
PMID- 9397928
TI - [Does the tension-filled relationship between theory and practice concern an
interactional and/or a translational process?].
PMID- 9397929
TI - Thyrotropin-releasing hormone (TRH)-related peptides.
PMID- 9397930
TI - PACAP, PACAP receptors, and intracellular signalling.
PMID- 9397931
TI - Isolation and characterization of the Xenopus laevis cDNA and genomic homologs of
neuropeptide Y.
AB - We have isolated Xenopus laevis cDNA and genomic clones encoding the neuropeptide
Y (NPY) mRNA and gene using a probe from the human NPY gene. The longest open
reading frame in the cDNA encodes a peptide 76% identical to human prepro-NPY and
73% identical to rat prepro-NPY. The putative mature Xenopus NPY (XNPY) peptide
is 94% identical to both human and rat peptides. A genomic clone containing 422
base pairs of 5'-flanking sequences and the 5'-end of the mRNA was also isolated.
Primer extension analysis was used to map the transcription initiation site of
the Xenopus NPY gene. Comparison of the 5'-flanking sequences of the Xenopus
laevis, human, and rat NPY genes resulted in areas of high conservation,
including the TATA box and the CT box previously shown to interact with Sp1-like
proteins. Distribution of the Xenopus NPY message was analyzed by Northern
analysis and RNAse protection. XNPY transcripts were not detected in whole
developing embryo RNA, but were detected in adult frog brain RNA. We have also
conducted preliminary studies of the XNPY promoter, utilizing an
XNPY/chloramphenicol acetyl-transferase fusion construct. This study has
demonstrated that Xenopus NPY shares a high degree of identity to its human and
rat counterparts and that this homology extends to the gene, which contains
similar cis-elements positioned near the transcription start site.
PMID- 9397932
TI - Immunochemical mapping of human lutropin: I. Delineation of a conformational
antigenic determinant.
AB - Lutropin (LH), follitropin (FSH), thyrotropin (TSH) and choriogonadotropin (CG)
are assembled of two non-covalently alpha (alpha) and beta (beta) subunits. We
studied the discontinuous antigenic regions recognized by a monoclonal anti-hLH
antibody designated as LH05 which binds to hLH, hCG and hTSH and does not cross
react with either the free subunits or hFSH. LH05 and an antibody designated
HT13, recognizing an epitope partly comprizing the alpha64-76 region, did not
bind simultaneously to hCG. Furthermore, LH05 was unable to combine with an anti
peptide antibody (LHP03) directed to residues 43-52 of hLHbeta. Thus, LH05
recognizes an epitope partly overlapping with those recognized by HT13 and LHP03.
Using various hybrid molecules, we showed that the human alpha-subunit plays a
critical role in the assembly of the epitope that, in contrast, contains amino
acid residues conserved in the various beta-subunit of several species. Together,
our results suggest that the amino acids Leu49-Pro50, Tyr59-Arg60 and Leu86-Ser87
in the hLHbeta and the alpha64-76 region are probably included in the epitope
recognized by LH05 which appeared to be not accessible on the CG/LH receptor.
PMID- 9397933
TI - Immunochemical mapping of human lutropin: II. Characterization of two monoclonal
antipeptide antibodies reacting with the native beta-subunit.
AB - To investigate the epitopes present on the beta-subunit of the human lutropin
(hLHbeta) and their topographical relationship at the surface of the molecule, we
produced two monoclonal antipeptide antibodies, designated LHP03 and LHP04,
capable of binding to the radiolabeled 125I-hLHbeta and directed to the 43-52 and
110-117 regions of the hLHbeta, respectively. Analysis of the accessibility of
the epitopes on hLH and on the beta-subunit of human chorionic gonadotropin
(hCGbeta), equine LH (eLHbeta) and ovine LH (oLHbeta) indicated that: (i) LHP03
binds to both the free hLHbeta subunit and dimeric hLH whereas LHP04 binds
preferentially to the free hLHbeta, (ii) LHP03 recognizes weakly the hCGbeta and
oLHbeta in comparison to hLHbeta and (iii) LHP04 binds oLHbeta as well as hLHbeta
but does not bind to hCGbeta and eLHbeta. The topographical relationship of
epitopes recognized by LHP03 and monoclonal antibodies recognizing dimer specific
epitopes on hLH allowed us to localize discontinuous antigenic sites that
overlaps or are located outside the hHLbeta(43-52) region. Together, our results
demonstrated that the hHLbeta(43-52) portion is accessible on both the free
hLHbeta subunit and hLH whereas the COOH-terminal portion, hHLbeta(110-117), is
probably buried at the alpha/beta interface of the hormone.
PMID- 9397934
TI - The Hep G2 cell line in the study of growth hormone receptor/binding protein.
AB - This study identifies specific, high affinity GH-receptors (GH-R) in human
hepatoma Hep G2 cells. The binding characteristics of GH-R in the Hep G2 cells
are similar to those of human liver membranes, such as the high specificity for
hGH, the binding affinity (Ka = 1.7 +/- 0.5 x 10[9] M[-1]) and the molecular
weight of the membrane bound GH-R (apparent 125,000 and 71,000). In addition,
lower molecular weight forms (approximately 94,000 and approximately 58,000) were
identified as GH-binding protein (GH-BP) in Hep G2 conditioned medium, or
following incubation of Hep G2 cells, in the presence of 10 mM N-ethylmaleimide
for 90 min at 30 degrees C; the latter are presumed to be shed by a proteolytic
cleavage of the GH-R. Exposure of Hep G2 cells to physiologic concentrations of
hGH resulted in a concentration-dependent increase in 3H-thymidine incorporation,
up to 48.4 +/- 7.9% above control. In summary, the demonstration of specific,
high affinity GH-R in Hep G2 cells, as well as shedding of GH-BP, suggest these
cells may provide a homologous human system to study the receptor-effector
interrelationship of hGH and to further our understanding of hepatocyte
production of soluble GH-BP.
PMID- 9397935
TI - Transcriptional and translational regulation of LH, prolactin and their
testicular receptors by hCG and bromocriptine treatments in adult and neonatal
rats.
AB - Effects of altered gonadotropin and prolactin (PRL) secretion on luteinizing
hormone (LH), PRL and their testicular receptors (R) were studied in neonatal and
adult rats. Changes in gene expression were monitored by measurements of steady
state mRNA levels. Five-day and 90-day-old male rats received a single s.c.
injection of hCG (600 IU/kg), 1 mg/kg bromocriptine (BR) twice daily, or their
combination. After 2 or 8 days, the responses of LH, PRL, their testicular R, and
testosterone (T) were assessed, including measurements of the appropriate mRNA
levels. Vehicle-treated age-matched animals served as controls. hCG suppressed
serum LH in 2 days in adult rats from 0.85 +/- 0.16 to 0.04 +/- 0.01 microg/l,
and in neonates from 0.59 +/- 0.29 to levels below 0.01 microg/l (p < 0.01 for
both). This was accompanied at both ages by a 60% decrease in pituitary content
of the LH beta-subunit mRNA (p < 0.01), but a decrease in the alpha-chain (40%, p
< 0.05) occurred only in neonates. hCG increased serum PRL in adult rats in 8
days over 2-fold (p < 0.01); this did not occur in neonates. In neonates, BR
increased the LH subunit mRNAs 2-fold in 8 days (p < 0.01) without a concomitant
effect on serum LH; no BR effects on the LH parameters were seen in adult
animals. BR decreased pituitary PRL protein and mRNA levels at both ages (p <
0.01-0.05), but serum PRL decreased only in the adults. The homologous down
regulation of testicular LHR (near 100%) was accompanied in adults by a 30%
decrease in LHR mRNA (p < 0.05). Also BR at this age decreased LHR binding (75%
in 8 days, p < 0.01), but in this case no change occurred in the cognate mRNA.
hCG and BR slightly up-regulated in adults PRLR binding, but only the 2-day
effect of BR was accompanied by a 60% increase in PRLR mRNA (p < 0.05). In
neonates, both hCG and BR increased testicular LHR and PRLR mRNA levels (p < 0.01
0.05). In adult animals, both hCG and BR suppressed testicular and serum T levels
after 8 days (40-70%, p < 0.01-0.05); only BR was inhibitory to T by 8 days in
the neonates (p < 0.05). In conclusion, the homologous and heterologous
regulatory effects of hCG and BR on LH, PRL and their testicular R levels were
only partly explained by changes in steady-state levels of the respective mRNAs.
In general, the autoregulatory effects on LHR and PRLR appeared to affect steady
state levels of cognate mRNAs, whereas heteroregulation predominately involved
changes at the protein level. The responses of the neonatal pituitary-gonadal
axis to hCG and/or BR differed greatly from those observed in the adult,
indicating that the mechanisms involved in these regulatory events in adult
animals are a result of gradual postnatal development.
PMID- 9397936
TI - Catecholestrogen modulation of steroid production by rat luteal cells: mechanism
of action.
AB - This study investigated the mechanisms underlying 2-hydroxyestradiol (2-OHE2)
effect on luteal steroidogenesis using serum-free cultures of mixed luteal cells
from day 8 pseudopregnant rats. Initially, interactions between 2-OHE2 and LH or
dibutyryl (db)cAMP on progesterone production were investigated. LH (250 ng/ml)
and 2-OHE2 (2.5 microg/ml) had comparable effects on progesterone accumulation,
while dbcAMP (5 mM) was more stimulatory. When applied together, 2-OHE2 did not
synergize with LH or dbcAMP to further enhance progesterone accumulation.
Furthermore, in time course experiments, the dose-dependent effect of 2-OHE2 was
to reduce and eventually abolish the time-dependent increase in cAMP
accumulation. In contrast LH stimulated cAMP accumulation at all times.
Experiments in which cells were co-treated with 2-OHE2, 22-OH-cholesterol and
cyanoketone, or with 2-OHE2 and 22-OH-cholesterol or pregnenolone indicated that
2-OHE2 not only had a stimulatory effect on the cholesterol side-chain cleavage
and 3beta-hydroxysteroid dehydrogenase enzymes, but it also appeared to inhibit
the 20alpha-hydroxysteroid dehydrogenase leading to a relative increase in
progesterone accumulation. Experiments with hormone antagonists suggested that
the actions of 2-OHE2 were not mediated by the estrogen, alpha- or beta
adrenergic receptors. The results of this study support the concept of a
physiological role for catecholestrogens in rat luteal steroidogenesis.
PMID- 9397937
TI - Role of specific isoforms of protein kinase C in angiotensin II and lipoxygenase
action in rat adrenal glomerulosa cells.
AB - Evidence indicates that the lipoxygenase (LO) pathway of arachidonic acid is a
key mediator of angiotensin II (AII)-induced aldosterone synthesis in adrenal
glomerulosa cells. Although protein kinase C (PKC) may play a role in AII action,
the precise PKC isoforms involved and whether LO products can activate PKC is not
clear. We therefore evaluated the effect of AII and LO products such as 12- and
15-hydroxyeicosatetraenoic acids (HETEs) on PKC activation in isolated rat
adrenal glomerulosa cells. PKC activity was measured by the phosphorylation of a
PKC specific peptide while the PKC isoforms were identified by Western
immunoblotting using antibodies that recognize the alpha, beta, gamma or epsilon
isoforms of PKC. Treatment of the cells for 15 min with AII (10[-8]M) or the LO
products 12- or 15-HETE caused a marked increase in PKC activity in membrane
fractions with reciprocal decreases in the cytosolic PKC activity. Rat
glomerulosa cells expressed only the alpha, and epsilon isoforms of PKC. AII
increased membrane bound levels of both PKC-alpha and -epsilon (1.9- and 1.5
fold, respectively), whereas the LO products predominantly activated PKC-epsilon.
Reciprocal decreases in immunoreactive cytosolic PKC levels were seen. AII
induced aldosterone synthesis was blocked by H-7 and retinal as well as by a PKC
specific pseudosubstrate inhibitor, PKC(19-36). These results suggest that AII
and LO pathway-induced actions in the adrenal glomerulosa may be mediated by
specific PKC isoforms.
PMID- 9397938
TI - Regulation of uterine collagenase gene expression: interactions between serotonin
and progesterone.
AB - This report seeks to further define the requirements for the previously
established induction of collagenase gene expression by serotonin and inhibition
by progesterone in primary cultures of rat uterine smooth muscle cells.
Detectable increases in collagenase production were observed after as little as 3
h exposure of cells to 5 microM serotonin, with maximal induction occurring after
approximately 8 h of exposure. The apparent half-life of collagenase mRNA upon
removal of serotonin was estimated to be approximately 12 h, and was not
dependent on the duration of induction. Inhibition by either cycloheximide or
progesterone showed similar half lives for collagenase mRNA, however a much
shorter half-life (6 h) was obtained in the presence of actinomycin D. These
experiments suggest that neither serotonin induction nor progesterone inhibition
of collagenase synthesis represents a primary effect on collagenase gene
transcription. Rather they appear to be secondary to changes that occur at one or
more primary intermediate genes whose induction or decay must occur prior to
changes in collagenase transcription. The progesterone receptor antagonist, RU
486, abrogates the ability of progesterone to inhibit serotonin-induced
collagenase gene expression, indicating that the effects of progestins in this
system likely are receptor-mediated. Finally, the present studies demonstrate
that pretreatment of cells for times as long as 5 days with medroxyprogesterone
in the absence of serotonin is unable to prevent subsequent serotonin-induced
collagenase mRNA increases. These data suggest the possibility of a unique
interaction between the molecular pathways of inducer and inhibitor, one in which
serotonin may help mediate the progesterone-dependent repression of the levels of
collagenase mRNA.
PMID- 9397939
TI - The 5'-untranslated region of the IGF-I receptor gene modulates reporter gene
expression by both pre- and post-transcriptional mechanisms.
AB - The insulin-like growth factor I (IGF-I) receptor gene has a large, complex 5'
untranslated region (UTR). In order to examine the role that this region plays in
regulating IGF-I receptor expression, we isolated fragments of the human IGF-I
receptor 5'-UTR and interposed them between the SV40 early promoter and the
chloramphenicol acetyl transferase reporter gene. Fragments of the IGF-I receptor
gene 5'-UTR were found to enhance reporter gene expression by increasing gene
transcription. In addition, the increased transcription and mRNA levels were in
excess of the increase in enzyme activity, providing indirect evidence that these
fragments inhibit translation, consistent with predictions.
PMID- 9397940
TI - Expression of insulin-like growth factor-I (IGF-I) receptor gene in rat brain and
liver during development and in regenerating adult rat liver.
AB - Insulin-like growth factor-I (IGF-I) is involved in the growth and development of
liver and brain during fetal life by acting through specific plasma membrane
receptors. In an attempt to determine how the changes in IGF-I receptor number
are regulated during development, we have compared [125I]IGF-I binding to
membrane fractions with the concentration of IGF-I receptor mRNA in rat liver and
brain. IGF-I binding to liver membranes was 4.5 times higher in 20-day-old
fetuses than in adult rats. After partial hepatectomy (70%) in adult rats a
transient 2-fold increase of IGF-I binding to liver membranes was observed. In
fetal and regenerating liver increases similar to those observed for IGF-I
binding were observed in IGF-I receptor mRNA concentrations. In brain microsomes
IGF-I binding was 3.5 times higher in 20-day-old fetuses than in adults. This
difference reflects a similar change in the number of IGF-I receptors without
modifications in the affinity of the receptor for the ligand. In contrast to the
liver, no significant changes in the concentration of IGF-I receptor mRNA were
observed in the developing brain when determined by hybridization solution,
Northern blot or RNase protection analysis. These findings suggest that in the
liver, the IGF-I receptor gene is regulated at pretranslational level during
development and regeneration, while in brain it is preferentially regulated at
translational or posttranslational level.
PMID- 9397941
TI - Basic fibroblast growth factor induces luteinizing hormone receptor expression in
the presence of insulin-like growth factor-I in ovarian granulosa cells.
AB - Effect of basic fibroblast growth factor (bFGF) on the expression of receptors
for luteinizing hormone (LH), a marker of differentiation, was studied using
estrogen-primed rat ovarian granulosa cells in primary culture. bFGF had no
effect by itself but dose-dependently induced expression of functional LH
receptors in the presence of insulin-like growth factor-I (IGF-I). The effect of
a combination of bFGF and IGF-I was delayed in onset and the magnitude of the
response was smaller when compared to the action of follicle-stimulating hormone
(FSH). Scatchard analysis revealed that dissociation constant (Kd) and number of
LH receptors induced by bFGF and IGF-I were 0.47 nM and 6.48 fmol/10(6) cells,
respectively. Unlike FSH, bFGF plus IGF-I did not cause an immediate increase in
cAMP release, however, considerable amount of cAMP release was observed in cells
incubated for 72 h with bFGF plus IGF-I. Indomethacin, an inhibitor of
cyclooxygenase, attenuated both LH receptor expression and cAMP release induced
by bFGF plus IGF-I but had little effect on the action of FSH. Finally, a
combination of bFGF and IGF-I increased production of prostaglandin E2 in
granulosa cells. These results indicate that bFGF is capable of inducing LH
receptor in the presence of IGF-I by a mechanism involving production of
prostaglandin E2.
PMID- 9397942
TI - Characterization of estrogen receptor cDNAs from human uterus: identification of
a novel PvuII polymorphism.
AB - Using reverse transcription and the polymerase chain reaction, we have cloned
estrogen receptor complementary DNAs from normal human uterine tissue.
Restriction endonuclease analysis identified a polymorphic PvuII recognition site
within half of the receptor cDNAs. Sequence analysis revealed a number of
differences with the sequence previously reported for the ER cDNA isolated from
MCF7 cells and confirmed that the codon for amino acid 400 was erroneously
assigned as valine (GTG) rather than glycine (GGG). Sequencing also defined the
nature of the PvuII polymorphism, with allele A coding for Glu22 and allele B
(with an additional PvuII site) coding for Gln22. We demonstrate that both
alleles of this receptor activate transcription of an estrogen-responsive gene to
the same extent. This selective cloning method should have wide application in
the investigation of naturally occurring cDNA variants from diseased tissues,
such as breast cancer cell lines and primary tumor specimens.
PMID- 9397943
TI - Recombinant murine tumor necrosis factor-alpha inhibits cholesterol side-chain
cleavage cytochrome P450 and insulin-like growth factor-I gene expression in rat
Leydig cells.
AB - The purpose of the present study was to evaluate the effects of murine
recombinant tumor necrosis factor-alpha (TNF-alpha) on rat Leydig cell function.
In primary cultures of Leydig cells, we found that in the presence of hCG (10
ng/ml), testosterone levels were markedly elevated, 69.3 +/- 3.1 ng/10(6) cells/h
(mean + SE). TNF-alpha in a concentration of 1 ng/ml markedly inhibited
testosterone biosynthesis (a 69% reduction; p < 0.01) and 100 ng/ml of TNF-alpha
almost completely inhibited testosterone formation (p < 0.001). TNF-alpha (10
ng/ml) inhibited hCG (0.1, 1 and 10 ng/ml)-induced testosterone formation by 63%,
67% and 61%, respectively. TNF-alpha (10 ng/ml) also markedly inhibited 8-bromo
cAMP-induced testosterone formation from 76 +/- 9 ng/10(6) cells/h to 4.9
ng/10(6) cells/h. This indicates that the major effect of TNF-alpha is at steps
beyond LH receptor site. To further evaluate the site(s) of action of TNF-alpha,
we evaluated its effect on the conversion of precursor steroids to testosterone.
We found that the addition of 20-hydroxy-cholesterol could not reverse inhibitory
effects of TNF-alpha on hCG-induced testosterone formation. TNF-alpha had no
effect on the conversions of pregnenolone, 17-OH-pregnenolone, DHEA and
androstenedione to testosterone. This indicates that the major effect of TNF
alpha is at the key steroidogenic enzyme, P450scc. We reported previously that
human recombinant TNF-alpha had no effect on hCG-induced testosterone formation
but did enhance the inhibitory effects of human recombinant IL-1beta. In the
present study, we demonstrated that both murine TNF-alpha and human IL-1beta were
potent inhibitors of hCG-induced testosterone formation. IL-1beta alone in
concentrations of 0.1, 1 and 10 ng/ml inhibited testosterone formation by 45%,
62% and 91%, respectively, in the presence of TNF-alpha (10 ng/ml), IL-1beta in a
concentration as low as 0.1 ng/ml completely blocked hCG-induced testosterone
formation. We next evaluated the effect of TNF-alpha on P450scc gene expression.
There was no constitutively expressed P450scc mRNA in Leydig cells after 24 h in
culture. In response to hCG, there was a 33-fold increase in the P450scc mRNA
level. Both TNF-alpha and IL-1beta inhibited hCG-induced expression of P450scc
mRNA. Finally, the effect of TNF-alpha on IGF-I gene expression was investigated
since IGF-I enhances Leydig cell androgen formation and IGF-I gene is expressed
in high levels in Leydig cells. TNF-alpha inhibited both large (7.4 kb) and small
species (0.8-1.2 kb) IGF-I mRNA levels in a dose-dependent manner. In conclusion,
murine TNF-alpha is a potent inhibitor of Leydig cell function. TNF-alpha
inhibited both P450scc and IGF-I mRNA gene expression.
PMID- 9397944
TI - Role of the exon 11 of the insulin receptor gene on insulin binding identified by
anti-peptide antibodies.
AB - The insulin receptor exists in two isoforms differing by the absence (HIR-A) or
presence (HIR-B) of 12 amino acids in the C-terminus of the alpha-subunit as a
consequence of alternative splicing of exon 11. It was shown that the two
isoforms exhibit different binding affinities for insulin, thus suggesting that
the sequence encoded by exon 11 may be important for insulin binding. To further
investigate this issue, we generated polyclonal antibodies against C-terminal
peptides of the two HIR alpha-subunit variants. Herein, we characterized two
antibodies, PA-11 and PA-12, directed against the C-terminus or the N-terminus of
the sequence encoded by exon 11, respectively, and one (PA-13) directed against a
sequence in the carboxy-terminal region of the alpha-subunit which is common to
HIR-A and HIR-B. Antibodies were characterized for their ability to
immunoprecipitate the receptor and to inhibit [125I]insulin binding to both
isoforms. We found that PA-13 immunoprecipitates both the HIR-A and the HIR-B, PA
12 immunoprecipitates exclusively the HIR-B, and PA-11 fails to precipitate both
isoforms. Interestingly, PA-12 inhibits specifically insulin to the HIR-B,
whereas other PAs fail to affect insulin binding to either isoforms. Furthermore,
PA-12 linearises the Scatchard plot of binding data, and retards the dissociation
rate of insulin, thus suggesting that antibody affects cooperative interactions
among binding sites. We conclude that the sequence encoded by exon 11 may play a
role in modulating the binding of insulin to the receptor and negative
cooperativity.
PMID- 9397945
TI - Identification of a liver-specific promoter for the ovine growth hormone
receptor.
AB - Growth hormone (GH) receptor cDNA clones from several species are characterized
by heterogeneity in the 5' untranslated region (5'UT). This has been attributed
to different promoters directing the expression of the gene from exons encoding
5'UT's which are alternatively spliced onto a common splice acceptor 11 basepairs
(bp) upstream of the initiating AUG on exon 2. The following study identifies
exon 1A of the ovine (o) GH receptor gene, corresponding to the 5'UT of a
developmentally regulated, liver-specific transcript. Exon 1A spans 206 bp at a
position 17 kilobases (kb) upstream of exon 2. Sequencing of the 669 bp region 5'
to the transcription initiation site (+1) reveals a TATA box at -31, a CCAAT box
at -88, and putative binding sites for several transcription factors involved in
liver-specific gene expression. Two repetitive sequence elements are located in
the 5' and 3' flanking regions of exon 1A. Functional analysis of the 4.5 kb
region upstream of exon 1A was performed by transfecting the human hepatoma cell
line HuH7 with luciferase reporter gene constructs. Positive and negative
regulatory regions are identified, with basal promoter activity within 473 bp of
the transcription initiation site. A 47 bp region containing putative binding
sites for the activated glucocorticoid receptor and C/EBP-like proteins, between
180 and -133, is essential for transcriptional activation.
PMID- 9397946
TI - Human colon carcinoma cells (CaCo-2) synthesize IGF-II and express IGF-I
receptors and IGF-II/M6P receptors.
AB - The IGFs have been implicated in the development of the intestinal tract. We have
studied the human colon carcinoma cell line CaCo-2 to gain more insight into the
function of the IGFs in the gut. [125I]IGF-I and -II bound specifically to CaCo-2
cells as measured in competitive binding experiments. The existence of IGF-I
receptors was further demonstrated by affinity crosslinking studies using DSS as
the crosslinking agent. Western blotting of CaCo-2 cell extracts using an anti
IGF-II/M6P receptor antiserum provided additional evidence for the expression of
the IGF-II/M6P receptor. In addition, Northern blotting experiments showed
specific IGF-I receptor and IGF-II/M6P receptor gene expression in CaCo-2 cells.
An 11 kb band was visualized with a 614 bp PstI IGF-I receptor probe on
autoradiographs. Hybridization with a 663 bp IGF-II/M6P receptor probe yielded a
9 kb RNA species. Analysis of CaCo-2 cell RNA using solution hybridization/RNase
protection assays yielded two protected fragments, approximately 379 bases in
length, with a 394 base IGF-I receptor riboprobe and a 250 base protected
fragment with a 260 base IGF-II/M6P receptor riboprobe. In a subset of
experiments a PstI 700 base fragment of the IGF-I cDNA and a 554 base SalI
fragment of the IGF-II cDNA were used for hybridization: no hybridization was
detected with the IGF-I probe. However, using the [32P]IGF-II probe bands at 6.0
and 5.0 kb were labeled in Northern blotting experiments. Analysis of CaCo-2 cell
RNA using solution hybridization/RNase protection assays yielded a 289 base
protected fragment and a faint 534 base species with a 556 base human IGF-II
riboprobe. In addition, IGF-II immunoreactivity was measured in CaCo-2 cell
conditioned medium using an IGF-binding protein blocked radioimmunoassay. CaCo-2
cell-conditioned medium contained 5-15 ng/ml IGF-II immunoreactivity. In
conclusion, (1) CaCo-2 cells express both IGF-I receptor mRNA and IGF-II/M6P
receptor mRNA and contain functional IGF-I receptor and IGF-II/M6P receptor
protein. (2) CaCo-2 cells express IGF-II mRNA and secrete IGF-II
immunoreactivity. We hypothesize that in human colon carcinoma cells IGF-II could
act as an autocrine growth factor or alternatively could serve as a regulatory
factor during differentiation.
PMID- 9397947
TI - Rat gonadotropin-releasing hormone (GnRH) receptor: tissue expression and
hormonal regulation of its mRNA.
AB - The binding of gonadotropin-releasing hormone (GnRH) to its receptor in the
anterior pituitary gland is the key molecular interaction regulating the
reproductive process of mammals. Here, we report the isolation of a cDNA
representing this receptor from rat anterior pituitary and the regulation of
expression of its mRNA. The rat GnRH receptor cDNA was composed of 2909
nucleotides and encoded a protein containing 327 amino acids having a seven
transmembrane topology. Northern blot analysis on RNA from rat pituitary, ovary
and testis showed four different transcripts (5.0, 4.5, 2.5 and 1.3 kb) of which
the 5.0 kb form was most abundant. The levels of expression of the transcripts
were found to be highest in the pituitary followed by the ovary and the testis
(about 40% and 5% compared to pituitary, respectively). Using the more sensitive
reverse transcriptase/PCR technique, we also detected GnRH receptor mRNA in the
adrenal and the hypothalamus. Measurement of pituitary GnRH receptor mRNA levels
(the 5.0 kb form) during the estrous cycle showed the lowest levels at estrus
(1.0-fold), a 2.2 +/- 0.57 (mean +/- SEM) -fold increase at diestrus I, a 3.5 +/-
0.41-fold increase at diestrus II, a 2.6 +/- 0.34-fold increase on the morning of
proestrus, and a 1.9 +/- 0.25-fold on the afternoon of proestrus. Removal of the
ovaries led to a 2.7 +/- 0.29-fold increase in GnRH receptor mRNA levels in the
pituitary gland; treatment of ovariectomized rats with estrogen resulted in a
significant decrease in GnRH receptor mRNA levels. Our studies demonstrate
ovarian regulation of GnRH receptor mRNA expression in the anterior pituitary
gland.
PMID- 9397948
TI - Phorbol 12-myristate 13-acetate and 1,25-dihydroxyvitamin D3 regulate 1,25
dihydroxyvitamin D3 receptors synergistically in rat osteosarcoma cells.
AB - In this study, we examined the effect of activation of protein kinase C (PKC)
pathways on the regulation of 1,25-dihydroxyvitamin D receptors (VDR) in rat
osteosarcoma (ROS) 17/2.8 cells. Activation of PKC with phorbol 12-myristate 13
acetate (PMA) resulted in a time- and dose-dependent increase in VDR expression
in ROS cells. Treatment of ROS cells with 4alpha-phorbol 12,13-dedeconate, a PKC
inactive phorbol ester, had no effect on VDR expression. Oleoyl acetyl glycerol
(OAG), a synthetic diacylglycerol, stimulated VDR up-regulation in ROS cells. The
PKC inhibitors (H-7, staurosporin, and sphingosine) all blocked PMA-mediated up
regulation of VDR in a dose-dependent manner. We next examined the interaction of
1,25(OH)2D3 and PKC activation by PMA on the regulation of VDR in ROS cells. We
found that PMA or 1,25(OH)2D3 treatment alone resulted in a 50 and 200% increase
in VDR, respectively. PMA treatment alone resulted in a 50% increase in VDR
protein and a marginal 20% increase in VDR mRNA. 1,25(OH)2D3 up-regulation of VDR
was associated with a 2-fold increase in VDR mRNA. In contrast, co-treatment of
ROS cells with PMA and 1,25(OH)2D3 resulted in a synergistic 10-fold induction of
VDR mRNA and the appearance of a 7.2 kb VDR transcript. VDR protein was also
synergistically up-regulated by combined PMA and 1,25(OH)2D3 treatment of ROS
cells. Scatchard analysis demonstrated that the synergistic effect of PMA and
1,25(OH)2D3 on VDR protein expression was not associated with any change in the
affinity of VDR for 1,25(OH)2D3. The synergistic effect of 1,25(OH)2D3 and PMA on
VDR expression supports a link between PKC signal pathways and the function of
VDR.
PMID- 9397949
TI - Identification of the estrogen sensitive marker in human endometrial carcinoma
RL95-2 cells.
AB - Estrogen exerts a variety of biological effects on human reproductive tissues.
However, little is understood about the estrogenic effect on human endometrial
cells in vitro. This study was designed to investigate estrogen action on c-myc
and c-fos oncogenes and lactoferrin gene expression in human endometrial
carcinoma RL95-2 cells. The results indicate that estrogen can induce c-myc
oncogene expression in 4 h. Neither c-fos nor the lactoferrin messenger was
detectable, nor could they be induced by estrogen. Transfection with human
estrogen receptor expression vector to the RL95-2 cells does not restore the
estrogen responsiveness. In addition to estrogen, epidermal growth factor (EGF)
and tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) can also induce c
myc expression with no effect on c-fos or lactoferrin expression. Our data
suggest that the c-myc oncogene in human endometrial carcinoma RL95-2 cells is
the sensitive target gene for steroid hormone and growth factor action.
PMID- 9397950
TI - A comparative study of the role of adenylate cyclase in the release of
adrenocorticotropin from the ovine and rat anterior pituitary.
AB - The interaction between corticotropin-releasing factor (CRF) and arginine
vasopressin (AVP) is important in the regulation of adrenocorticotropin (ACTH)
release from the anterior pituitary (AP). CRF exerts its effect on the AP by
activating the adenylate cyclase (AC) complex whereas AVP increases the turnover
of phosphatidylinositol. In the rat and in man, CRF is the most potent ACTH
secretagogue whereas AVP alone is only a weak agonist. Since recent studies in
the sheep indicate a reversal of this order of potency, these studies were
undertaken to test the hypothesis that a functional alteration of the AC in the
ovine corticotrope might limit the ability of CRF to release ACTH from these
cells. When rat AP cells were incubated with CRF, a dose-dependent increase in AC
activity was observed. This effect was potentiated either by AVP or PMA, although
neither agent alone altered AC activity. In contrast, CRF alone, or in
combination with AVP or PMA, did not increase AC activity in ovine AP cells. Both
cholera toxin (CT) and pertussis toxin (PT) caused a dose-dependent release of
ACTH from rat and ovine AP cells, but the amount of ACTH released from the ovine
AP cells by both agents was relatively reduced. In the ovine cells, however, AVP
acted synergistically with CT or PT to markedly increase the release of ACTH to
levels which approached those obtained when the rat AP cells were exposed to CT
or PT alone. Forskolin increased AC activity in AP cells of both species, but to
a much lower extent in ovine cells than in the rat cells. However, when the ovine
cells were exposed to AVP, the AC response to forskolin became similar to the
response observed in the rat cells when incubated with forskolin alone. Forskolin
also released significantly less ACTH from the ovine AP cells, but AVP also acted
synergistically with forskolin to greatly enhance the amount of ACTH released
from these cells. Finally, 8-bromo-cyclic AMP produced a similar release of ACTH
from both ovine and rat AP cells. We conclude that: (1) the decreased ability of
CRF to increase ACTH release from the ovine AP reflects a net decrease in AC
activity and cannot be ascribed to an ovine corticotropic resistance to cAMP; (2)
the decreased activity of the ovine corticotropic AC complex may in turn reflect
functional alterations at the level of both the G proteins and the catalytic
subunit; (3) since AVP causes protein kinase C substrate phosphorylation in the
ovine AP, AVP may increase AC activity in this tissue by phosphorylating the G
proteins and/or the catalytic subunit.
PMID- 9397951
TI - Calcitriol attenuates the basal and vasoactive intestinal peptide-stimulated cAMP
production in prolactin-secreting rat pituitary (GH4C1) cells.
AB - A clonal strain of prolactin-producing rat pituitary tumour cells (GH4C1 cells)
was used to study the effect of calcitriol on cyclic adenosine monophosphate
(cAMP) production. Calcitriol (10 nM) attenuated both the basal and vasoactive
intestinal peptide (VIP)-stimulated cAMP production after 2 days' pretreatment of
the cells. The effect was detectable at 1 nM and maximal at about 10 nM.
Calcitriol was at least 100 times more potent than calcidiol and 24
hydroxycalcidiol. Calcitriol (10 nM, 4 days) did not affect the specific binding
of 125I-VIP, but attenuated the guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS)
stimulated (100 microM) adenylyl cyclase activity by 25%. Calcitriol (10 nM, 4
days) also attenuated both the Mn2+ (1 mM) and the forskolin-stimulated (10
microM) adenylyl cyclase activity by 43 and 41%, respectively. In conclusion,
these data suggest that calcitriol attenuates the basal and VIP-stimulated cAMP
production by inhibiting the catalytic subunit of the adenylyl cyclase as well as
the amount of the G protein Gs alpha.
PMID- 9397952
TI - Pineal perfusion with calcium channel blockers inhibits differently daytime and
nighttime melatonin production in rat.
AB - In a previous study we have shown that the response of perifused pineal glands to
calcium was different according to the circadian stage at which the glands were
removed. This difference may be explained by circadian changes in calcium channel
function. Therefore in the present study we documented the effects of calcium
channel blockers in perifused rat pineal glands removed in the middle of the
light and dark spans (7 and 19 HALO (hours after light onset), in a L/D 12:12
regimen). Moreover, we have studied the effect of calcium channel blockers on
adrenergically stimulated pineal glands removed 7 HALO. Inorganic (Co2+ and Cd2+)
and organic (nifedipine and diltiazem) calcium channel blockers at 10(-4) mol/l
all significantly reduced melatonin production and this inhibition was more
effective with the glands removed 7 HALO. In a concentration of 10(-)5 mol/l,
only Cd2+ and diltiazem reduced melatonin production significantly in pineal
glands removed 7 HALO. Verapamil at 10(-4) and 10(-5) mol/l showed no significant
effect on melatonin production in glands removed both during the light and dark
spans. Mn2+ at 10(-4) mol/l (but not at 10[-5] mol/l) appeared to stimulate
melatonin production in glands removed both during the light and the dark
(significant increase only with glands removed during the dark). Cobalt showed an
immediate short inhibitory effect on both isoproterenol and norepinephrine
stimulated melatonin release, whereas nifedipine showed a significant inhibition
only on isoproterenol-stimulated melatonin release. These results strongly
suggest a circadian stage dependence of the pineal gland response to some calcium
channel blockers and the involvement of calcium in the release of melatonin from
pinealocytes.
PMID- 9397953
TI - Follicle-stimulating hormone receptor mRNA in the mouse ovary during post-natal
development in the normal mouse and in the adult hypogonadal (hpg) mouse:
structure of alternate transcripts.
AB - The structure of RNA encoding the mouse ovarian follicle-stimulating hormone
(FSH) receptor was studied during post-natal development and in the adult
hypogonadal (hpg) mouse which lacks circulating gonadotrophins. Using reverse
transcription and the polymerase chain reaction (PCR) four major transcripts of
the FSH receptor were found in the normal adult ovary. The largest transcript was
the expected size from the position of the PCR primers (on exons 1 and 10) and
sequencing confirmed that it was derived from FSH receptor mRNA. The three other
transcripts were also derived from FSH receptor mRNA but they contained deletions
corresponding to one or more complete exons. Each transcript lacked exon 2 while
exons 5 and/or 6 were lacking in the smaller species. All four transcripts were
present in ovaries of hpg mice showing that expression of receptor mRNA and
development of alternate splicing are not gonadotrophin-dependent. During
development in the mouse full-length FSH receptor transcripts were not detected
in the ovary until day 5 although shorter transcripts were present at days 1 and
3. Results confirm that the FSH receptor primary transcript undergoes alternate
splicing in the ovary and that the pattern of splicing changes as the ovary
develops, probably as a result of follicular development.
PMID- 9397954
TI - Interactions between transport of triiodothyronine and tryptophan in JAR cells.
AB - We studied the effect of a number of amino acids on uptake of L-triiodothyronine
(T3) in the human choriocarcinoma cell line, JAR. Tryptophan inhibited saturable
T3 uptake by about 57% without any significant effect on the non-saturable
uptake. Michaelis constant (Km) for T3 uptake was 1.06 +/- 0.15 microM (n = 15)
with the corresponding maximum velocity (Vmax) of 24.2 +/- 3.1 pmol/min/mg
cellular protein. For tryptophan uptake the Km was 1.31 +/- 0.26 microM (n = 7)
and Vmax was 166.4 +/- 35.7 pmol/min/mg protein. The kinetic parameters for both
uptake processes were similar to those reported in normal placenta. Uptake of T3
was inhibited by tryptophan but not phenylalanine, but tryptophan uptake was
inhibited both by T3 and phenylalanine. Inhibition of T3 uptake by tryptophan was
dose dependent, with an inhibition constant (Ki) of 2.9 +/- 0.5 mM. Similarly,
tryptophan uptake was inhibited by T3 and phenylalanine in a dose dependent way
with Ki values of 4.9 +/- 0.5 microM and 15.6 +/- 4.8 microM respectively. Km for
T3 uptake was significantly increased to 1.86 +/- 0.42 microM (n = 4) in the
presence of 3 mM unlabelled tryptophan and, similarly, Km for tryptophan uptake
was significantly increased to 9.91 +/- 2.57 microM (n = 3) in the presence of 5
microM unlabelled T3. Efflux of T3 was progressively inhibited by increasing
concentrations of both ligands, i.e. was saturable. We conclude that there is
mutual competitive inhibition between uptake systems for T3 and tryptophan in JAR
cells, but the kinetic parameters of cross-inhibition of uptake by the substrates
suggest that the carriers are distinct. T3 may be transported in JAR cells by at
least two transport systems with differing substrate specificities. We also
demonstrated the presence of a saturable membrane carrier mediating the efflux of
T3 from the cells which was subject to trans-inhibition by T3 and tryptophan.
PMID- 9397955
TI - Development of a bioassay for FSH using a recombinant human FSH receptor and a
cAMP responsive luciferase reporter gene.
AB - FSH exerts its actions primarily by increasing cAMP levels via a G protein-linked
transmembrane receptor. We report the development of a bioassay for FSH using a
cell line that stably expresses the human FSH receptor and a cAMP responsive
human glycoprotein hormone alpha subunit luciferase reporter construct. Receptor
activation by FSH was measured by changes in luciferase activity. The cell line
was shown to express 1.6 x 10(4) receptors per cell which bound FSH with high
affinity (Kd 2.76 x 10[-9] M). Human pituitary FSH caused a dose-dependent
increase in cAMP (ED50, 190 mIU/ml) and luciferase (ED50, 31.5 mIU/ml) activity.
The sensitivity of the bioassay was less than 0.6 mIU/well. Postmenopausal serum,
rat, ovine and bovine FSH elicited a dose-dependent increase in luciferase
activity. There was no significant stimulation by highly purified human LH or
recombinant human TSH. This cell line should be useful in the determination of
bioactive FSH and characterization of serum FSH inhibitors.
PMID- 9397956
TI - Progesterone initiation of the human sperm acrosome reaction: the obligatory
increase in intracellular calcium is independent of the chloride requirement.
AB - The progesterone-initiated human sperm acrosome reaction (AR) requires a rise in
intracellular Ca2+ ([Ca2+]i), extracellular Cl- and apparently increased Cl- flux
through a unique steroid receptor/Cl- channel resembling but not identical to a
GABA(A)/Cl- channel complex. The present study uses fura-2 loaded human sperm,
GABA(A)/Cl- channel blockers (picrotoxin and pregnenolone sulfate) and Cl(-)
containing and Cl(-)-deficient media to determine whether the progesterone
mediated increase in [Ca2+]i is dependent on the Cl- requirement. There was no
significant difference between the progesterone-mediated increases of [Ca2+]i
obtained in Cl(-)-containing and Cl(-)-deficient media. Picrotoxin did not
significantly inhibit the progesterone-mediated increase in [Ca2+]i, and
pregnenolone sulfate increased [Ca2+]i to the same extent as progesterone. These
results strongly suggest that the increase in [Ca2+]i essential to the AR is
independent of the AR Cl- requirement and could be explained by the existence of
two different sperm plasma membrane progesterone receptors.
PMID- 9397957
TI - Gene transfer into Xenopus hepatocytes: transcriptional regulation by members of
the nuclear receptor superfamily.
AB - A procedure to culture Xenopus laevis hepatocytes that allows the cells in
primary culture to be subjected to gene transfer experiments has been developed.
The cultured cells continue to present tissue-specific markers such as expression
of the albumin gene or estrogen-controlled vitellogenin gene expression, which
are both restricted to liver. Two efficient and reproducible gene transfer
procedures have been adapted to the Xenopus hepatocytes, namely lipofection and
calcium phosphate-mediated precipitation. The transcription of transfected
reporter genes controlled by estrogen-, glucocorticoid- or peroxisome
proliferator-response elements was stimulated by endogenous or co-transfected
receptor in a ligand-dependent manner. Furthermore, the expression of a reporter
gene under the control of the entire promoter of the vitellogenin B1 gene
mimicked the expression of the chromosomal vitellogenin gene with respect to
basal and estrogen-induced activity. Thus, this culture-transfection system will
prove very useful to study the regulation of genes expressed in the liver under
the control of various hormones or xenobiotics.
PMID- 9397958
TI - Functional analysis of an alternatively spliced estrogen receptor lacking exon 4
isolated from MCF-7 breast cancer cells and meningioma tissue.
AB - An alternatively spliced mRNA coding for a variant estrogen receptor (ER) missing
exon 4 (ERdelta4) was detected in the breast tumor cell line MCF7 and meningioma
tissue by using the reversed transcriptase PCR technique. The trans-activational
properties of this mutant ER were assessed in embryo carcinoma P19EC and human
choriocarcinoma JEG3 cells by co-transfection of the ERdelta4 expression vector
with an oxytocin promoter construct containing an estrogen-responsive element.
ERdelta4 did not trans-activate the oxytocin promoter in either a hormone
dependent or -independent manner. Co-transfection of ERdelta4 together with the
wtER did not show any interference of ERdelta4 on the stimulation of the oxytocin
promoter by the wtER. ERdelta4 was translated in vitro. Its capacity to bind
estradiol, and the binding of the variant to a synthetic estrogen-responsive
element were compared to those of the wild-type receptor. ERdelta4 did not bind
to a synthetic estrogen-responsive element, nor did it bind estradiol. Hence,
ERdelta4 appears to be a silent variant and we speculate that it is without any
role in tumor progression.
PMID- 9397959
TI - Arginine vasopressin (AVP) causes the reversible phosphorylation of the
myristoylated alanine-rich C kinase substrate (MARCKS) protein in the ovine
anterior pituitary: evidence that MARCKS phosphorylation is associated with
adrenocorticotropin (ACTH) secretion.
AB - We have recently shown that AVP causes a protein kinase C (PKC)-dependent
increase in ACTH release and biosynthesis in ovine anterior pituitary cells. In
these cells, AVP also causes the translocation of PKC from the cytosol to the
cell membrane which is maximal at 5 min, but the intracellular events distal to
protein kinase C activation that underlie ACTH secretion have not been well
characterized to date. Since the MARCKS protein has been implicated in
neurosecretion and is phosphorylated by PKC in synaptosomes, studies were carried
out to determine whether AVP might cause MARCKS phosphorylation in the ovine
anterior pituitary, and to determine whether this phenomenon might be temporally
correlated with PKC translocation and the release of ACTH. When cytosolic
fractions of rat brain, ovine anterior pituitary, and cultured ovine anterior
pituitary cells were incubated with purified PKC, several proteins were
phosphorylated including those in the region of 83-85 kDa. After precipitation of
the proteins with 40% acetic acid, the 83-85 kDa phosphoproteins were selectively
recovered in the acid soluble phase. Phosphopeptide maps of either the 83 or 85
kDa proteins were generated with Staphylococcus aureus V8 protease and revealed
13 and 9 kDa phosphopeptides, which are characteristic of the authentic MARCKS
protein. An identical phosphopeptide map was also obtained when the MARCKS
protein was selectively extracted from intact 32P-labeled anterior pituitary
cells. MARCKS phosphorylation was markedly increased when ovine anterior
pituitary cells were exposed to 1 microM phorbol 12-myristate 13-acetate (PMA).
When the cells were exposed to 1 microM AVP, MARCKS phosphorylation increased at
15 s and reached the maximal plateau value at 30 s. MARCKS phosphorylation then
started to diminish at 2 min, and baseline levels were attained by 10 min. In the
same cells, AVP stimulated ACTH release in a biphasic manner - during the first
30 s, there resulted a rapid burst of ACTH secretion that was followed by a
slower, but sustained rate of secretion. We conclude that: (1) AVP causes a
rapid, and reversible, phosphorylation of the MARCKS protein in the ovine
anterior pituitary; (2) since the AVP-induced increase in MARCKS phosphorylation
occurs much earlier in these cells than does PKC trans-location, MARCKS
phosphorylation may provide a more sensitive index of the onset of PKC activation
than the translocation assay; (3) the close temporal association between MARCKS
phosphorylation and the rapid early release of ACTH suggests that MARCKS
phosphorylation may be involved in the initial intracellular events that underly
exocytosis of the hormone.
PMID- 9397960
TI - Identification and characterization of the glucagon receptor from adipose tissue.
AB - 125I-glucagon was directly cross-linked to its receptor in isolated adipocyte
plasma membranes using a UV irradiation procedure. This investigation resulted in
identification of an adipocyte glucagon receptor complex of 62 kDa, present both
in white and brown adipose tissues. The specificity of labeling was shown by
interference of unlabeled hormone with incorporation of radioactive glucagon into
62 kDa species. Treatment of adipose plasma membranes with N-glycanase resulted
in appearance of intermediate species, indicating that the glucagon receptor is
modified with several N-linked oligosaccharide chains similarly to the hepatic
glucagon receptor. Peptide mapping of the affinity labeled adipose membranes with
Staphylococcus aureus V8 protease generated three distinct receptor fragments
identical to that of the hepatic receptor. Overall, the biochemical
characterization of the rat adipocyte glucagon receptor indicates that it closely
resembles the hepatic glucagon receptor.
PMID- 9397961
TI - Different cells and cell lines produce factors that modulate Sertoli cell
function.
AB - Peritubular myoid cells derived from immature rat testes produce factors that
modulate Sertoli cell function (P-Mod-S). The secretion of these factors is
controlled in part by androgens. Cultured prostatic stromal cells strongly
resemble peritubular myoid cells and produce mediators with similar activity.
Here we investigated whether myoid cell lines can be used as a source of P-Mod-S
like factors. Rat kidney fibroblast (NRK) and mouse fibroblast (3T3) cell lines
were used as non-myoid controls. Surprisingly, serum-free media conditioned by
all cell lines studied modulated Sertoli cell function in a similar fashion as
media conditioned by peritubular cells (PTCM) or stromal cells (STCM). Using
Sertoli cell transferrin secretion as an endpoint for P-Mod-S-like activity, the
nature of the active principles involved was further explored. The observed
activity could not be explained by residual contamination with fetal calf serum.
Moreover, the effects of the conditioned media could not be mimicked by classical
growth factors (IGF-I, bFGF, EGF, TGF-beta, NGF, PDGF-BB) added singly or in
combination with submaximally effective concentrations of PTCM. Finally, the
possibility that conditioned media might indirectly enhance Sertoli cell function
by promoting the production or deposition of extracellular matrix elements was
made unlikely by the demonstration that the observed effects were not mimicked by
Matrigel and were unaffected when Sertoli cells were seeded on Matrigel. Superdex
75 chromatography after analytical reversed-phase chromatography indicates that
the factors from different origin have a similar size (45-50 kDa). It is
concluded that mediators with P-Mod-S-like activity are produced by various cells
and cell lines both with and without smooth muscle cell characteristics. Whether
the active principles involved are really identical requires further
investigation.
PMID- 9397962
TI - Processing of proenkephalin in bovine chromaffin cells occurs in two phases.
AB - The processing of proenkephalin was studied in primary cultures of bovine adrenal
medullary chromaffin cells by pulse-chase radiolabeling, immunopurification of
proenkephalin and derivative peptides and quantitation following gel
electrophoresis and Western blotting. Proenkephalin was processed with a t1/2 of
approximately 1.1 h. Processing of proenkephalin-derived peptides of 15-25 kDa
was essentially complete by 1 h. Treatment of chromaffin cells with brefeldin A
to block the intracellular transport of proteins or with ammonium chloride to
neutralize acidic intracellular compartments had only minor effects on the
initial processing of proenkephalin. In contrast, both of these agents prevented
a second, slower phase of proenkephalin processing. These studies suggest that
proteolytic processing of proenkephalin in bovine adrenal medullary cells starts
before transport to the trans-Golgi network and packaging into the chromaffin
granules. A second phase of processing that requires an acidic environment occurs
in or distal to the trans-Golgi network.
PMID- 9397963
TI - Thyroxine control of pancreatic amylase gene expression: modulation of PTF1
binding activity.
AB - The role of pancreas specific transcription factor (PTF1) in thyroxine (T4)
modulation of amylase gene expression in suckling rats was evaluated.
Electrophoretic mobility shift assay (EMSA) was used to determine the PTF1
binding activity by the amount of a synthetic oligonucleotide containing the
amylase enhancer sequence bound by nuclear protein extracts. Nuclear protein from
rat pancreata showed a developmental increase of PTFI activity correlated with
age. To study the action of T4, pups were made hyperthyroid by T4 injection and
hypothyroid by feeding propylthiouracil (PTU) to the lactating dams. EMSA of
nuclear proteins isolated from these groups showed an increase in PTF1 binding
activity in the T4 group and a decrease in the PTU group. Concomitantly, T4
increased, while PTU decreased both amylase enzyme and mRNA concentrations. T4
replacement reversed the effect of PTU on PTF1 binding, amylase enzyme activity
and mRNA levels. To examine the age dependence of T4 effects, T4 was injected to
pups for 5 days prior to killing at the age of 15, and 25 days. T4 was effective
when given at an earlier age (15 days) but not at a later stage (25 days) in
increasing amylase activity and amylase mRNA levels. Nuclear proteins isolated
from pancreata of these groups showed an increase in PTF1 binding activity in the
T4-treated 15-day-olds but not in the 25-day-olds in comparison to their
corresponding age matched littermates. These results suggest that PTF1 is an
important intermediary in T4 modulation of amylase gene expression during
ontogeny of the rat exocrine pancreas.
PMID- 9397964
TI - Dexamethasone regulation of parathyroid hormone-related protein (PTHrP)
expression in a squamous cancer cell line.
AB - Dexamethasone regulation of PTHrP expression has been studied in an epidermal
squamous cancer cell line COLO 16, which secretes immunoreactive PTHrP into
conditioned medium. Dexamethasone was found to suppress PTHrP expression in a
time- and dose-dependent manner, which was reversible upon removal of
dexamethasone. The half-maximal effective concentration of dexamethasone was 1 nM
and an effect of dexamethasone on PTHrP mRNA was first observed after 2 h of
treatment, with maximal inhibition by 6 h. Dexamethasone action on PTHrP
expression was steroid specific since progestin, 5alpha-dihydroxytestosterone and
oestrogen did not regulate PTHrP expression in COLO 16 cells. The
gluocorticoid/progesterone receptor antagonist RU486 inhibited the dexamethasone
effect, indicating glucocorticoid receptor-mediated regulation of PTHrP
expression. The half-life of PTHrP mRNA in COLO 16 cells was approximately 120
min and was not altered by treatment of cells with dexamethasone. Nuclear run-on
assays revealed that dexamethasone reduced PTHrP gene transcription in COLO 16
cells. Transient transfection assays with a series of reporter gene constructs
encompassing 3.5 kb of the 5' end of the PTHrP gene failed to identify a region
of the gene responsible for glucocorticoid down-regulation. PCR of reverse
transcribed RNA from COLO 16 cells revealed that dexamethasone down-regulated
transcripts driven from all three promoters (i.e., the TATA promoters 5' to exons
I and IV and the GC-rich promoter 5' to exon III) of the human PTHrP gene.
PMID- 9397965
TI - Cytokine-mediated regulation of rat ovarian function: interleukin-1 inhibits
plasminogen activator activity through the induction of plasminogen activator
inhibitor-1 (PAI-1).
AB - Intraovarian IL-1 has recently been implicated as a mediator in the ovulatory
process. Since PA activation is an established component of the ovulatory
cascade, consideration was given in this report to the possibility that IL-1 may
modulate ovarian PA economy. Whole ovarian dispersates from immature rats (25-27
days-old) were cultured under serum-free conditions for 48 h in the absence or
presence of IL-1beta. Cellular PA activity was measured by plasminogen-dependent
cleavage of 14C-labeled globin. Cells grown in the absence of IL-1 exhibited
appreciable PA activity, as assessed by the cleavage of 0.074 +/- 0.026 mg [14C]
globin/5 x 10(5) cells (mean +/- SD). Exposure to IL-1 (10 ng/ml) led to a 30%
reduction in cell-associated PA activity (p < 0.001). The IL-1-mediated
inhibition occurred concurrently with a 10-fold increase in the ability of the
corresponding conditioned media to inhibit exogenous urokinase activity. At
similar cell densities of 5 x 10(5) cells/well, isolated cultures of theca and
granulosa cells exhibited comparable PA activity in the absence of IL-1. However,
only theca cells responded to IL-1 with inhibition of plasminogen activation and
enhancement of urokinase inhibitory activity. Granulosa cells in turn failed to
respond to IL-1. Both the inhibition of PA activity and the increase in urokinase
inhibitory activity proved cell-density- and IL-1 dose-dependent. The IL-1
induced inhibition of urokinase was abolished by the administration of a
polyclonal anti-rat PAI-1 IgG. Both effects of IL-1 were counteracted in a dose
dependent fashion by the soluble IL-1 receptor (which specifically complexes with
IL-1), and by a highly-specific IL-1 receptor antagonist suggesting that the IL-1
effects are receptor-mediated. The present observations indicate that ovarian PA
activity is subject to inhibition by IL-1 probably by way of PAI-1 of theca
interstitial origin. Inasmuch as IL-1 may be involved in initiating and
maintaining the preovulatory cascade, the periovulatory activation of plasminogen
must be accomplished by agents other than IL-1.
PMID- 9397966
TI - Alteration of basal release of anterior pituitary hormones by pretreatment of
primary cultured cells with trypsin.
AB - The anterior pituitary (AP) gland secretes 6 different hormones. Prolactin (PRL)
is secreted at a relatively high level without stimulation by the hypothalamus,
while secretion of the others requires the action of stimulatory factors from the
hypothalamus. In order to gain an insight into the mechanism underlying the
different spontaneous release patterns of these hormones, we investigated their
spontaneous release rate after pretreating rat anterior pituitary cells with
trypsin. Rat AP cells were cultured on Cytodex microcarrier beads for 4 days and
were then superfused with either control medium or medium containing trypsin
(0.25%) for 5 min. The subsequent release rates of the AP hormones were
monitored. The basal release of PRL was severely reduced to almost undetectable
level and began to recover 120 min after the trypsin-pretreatment. Full recovery
was attained over the next 100 min and was delayed by treatment with a protein
synthesis inhibitor, cycloheximide (7 microM). In the trypsin-pretreated cells,
basal release of PRL and growth hormone (GH) was severely reduced, while that of
thyroid stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) was
enhanced and luteinizing hormone (LH) and follicle stimulating hormone (FSH) was
not markedly affected by the treatment, suggesting that the suppression of PRL
release was not caused by nonspecific damage to the cells. Since trypsin does not
readily enter cells, the altered secretion of AP hormones seems to be the result
of restricted digestion of the external components of the cells. On the bases of
these observations, we predicted that the mechanism of spontaneous release of
hormones involves trypsin sensitive proteins (TSMP) on the plasma membranes of
the anterior pituitary cells.
PMID- 9397967
TI - Growth hormone (GH) and insulin-like growth factor-I (IGF-I) treatment of the GH
deficient dwarf rat: differential effects on IGF-I transcription start site
expression in hepatic and extrahepatic tissues and lack of effect on type I IGF
receptor mRNA expression.
AB - The rat IGF-I gene consists of six exons, with exons 3 and 4 forming a 'core'
mature IGF-I coding region to which alternate 5' and 3' regions are spliced.
Transcription occurs from four dispersed start sites (ss) approximately 382 (ss
1), approximately 343 (ss 2), approximately 245 (ss 3) and approximately 30-40
(ss 4) basepairs (bp) from the 3' end of exon 1, and from a region 50-70 bp from
the 3' end of exon 2. The expression of ss mRNAs displays tissue-specific and
ontogenic regulation. Alternate splicing of exon 5 produces E-peptide coding
domain variants (Ea and Eb mRNAs), with the Eb form found predominantly in the
liver. The regulation of IGF-I mRNA expression by GH and IGF-I in the GH
deficient dwarf (dw/dw) rat was investigated using antisense RNA probes in a
solution hybridization RNase protection assay to detect leader exon and E domain
variant mRNAs. GH treatment of dw/dw and normal Lewis rats increased the
expression of all liver leader exon ss and E domain variants coordinately (1.6
1.9-fold increase, p < 0.01), although the increase observed in Eb transcripts
was significantly higher in the dw/dw compared to the normal rat (p < 0.05). In
kidney, GH treatment significantly increased exon 1 ss 3 and ss 4 transcripts by
approximately 40% (p < 0.05). The expression of the other start sites was not
affected by GH, suggesting that transcription factors may regulate start site
usage independently. GH treatment was associated with a significant increase in
IGF-I mRNA expression in skeletal muscle (p < 0.05) but not cardiac muscle or
spleen. IGF-I treatment was associated with minor (approximately 20%) but
significant (p < 0.05) reductions in IGF-I mRNA expression in the liver and
kidney of dw/dw rats, suggesting that IGF-I can suppress IGF-I mRNA expression.
IGF-I treatment did not affect IGF-I mRNA expression in cardiac and skeletal
muscle of dw/dw rats. IGF-I receptor mRNA was detected in extrahepatic tissues
only, and was not affected by either GH or IGF-I treatment. In summary, start
site-specific regulation by GH was observed in kidney. GH increased IGF-I mRNA
expression in muscle, kidney and liver, but had no effect in heart or spleen in
the dw/dw rat. Our data suggest that systemic IGF-I can feedback on hepatic and
renal IGF-I mRNA expression in the GH-deficient state.
PMID- 9397968
TI - Transforming growth factor-beta1 regulates steady-state PTH/PTHrP receptor mRNA
levels and PTHrP binding in ROS 17/2.8 osteosarcoma cells.
AB - The effect of transforming growth factor beta1 (TGF-beta1) on the expression of
mRNA for the parathyroid hormone receptor and binding of iodinated parathyroid
hormone-related protein in ROS 17/2.8 osteosarcoma cells was evaluated. TGF-beta1
stimulated a 2-7-fold increase in steady state mRNA levels for the parathyroid
hormone receptor at a maximal dose of 5 ng/ml, with increased levels of
expression at 6 h of TGF-beta1-incubation, and peak levels at 8-24 h. Receptor
binding studies revealed a significant increase in PTHrP-specific binding with
TGF-beta1 doses as low as 0.5 ng/ml and a 55% increase in numbers of receptors
with no alteration in binding affinity with 5.0 ng/ml TGF-beta1. Time course
studies indicated that receptor binding was increased at 24 h with peak levels
reached at 48 h of treatment. PTH-stimulated cAMP levels were significantly
increased in ROS 17/2.8 cells treated with TGF-beta1 (0.5 ng/ml) for 48 h. These
data indicate that TGF-beta1 upregulates steady-state mRNA, ligand binding and
PTH/PTHrP receptor signaling in rat osteosarcoma cells. The effects of TGF-beta1
on bone may be attributed in part to regulation of the PTH/PTHrP receptor at the
molecular level.
PMID- 9397969
TI - Multiple levels of control of insulin-like growth factor gene expression.
PMID- 9397970
TI - Antisense oligonucleotide strategies in physiology.
AB - Antisense oligonucleotides can inhibit gene expression in living cells by binding
to complementary sequences of DNA, RNA or mRNA. The mechanisms include inhibition
of RNA synthesis, RNA splicing, mRNA export, binding of initiation factors,
assembly of ribosome subunits and of sliding of the ribosome along the mRNA
coding sequence. The most efficient antisense oligonucleotides also activate
RNAse H, an ubiquitous enzyme that cleaves the mRNA at sites of
mRNA/oligonucleotide duplex formation. A staggering number of oligonucleotide
modifications have been proposed to retard degradation by nucleases, enhance
cellular uptake, increase binding to the target sequence, and minimize non
specific binding to related nucleic acid sequences. Phosphorothioates are the
most popular oligonucleotides used in cell culture and in vivo, although sequence
non-specificity remains an underreported problem. Recently developed chimeras
between methylphosphonates and phosphodiester oligonucleotides appear to combine
the advantages of water solubility, nuclease resistance, enhanced cellular
uptake, activation of RNAse H, and high sequence selectivity. Antigene
oligonucleotides are also promising, because they can inhibit gene expression by
triple helix formation with DNA or by binding to one of the DNA strands. They
have so far been little used in physiological studies. Cost is still a
prohibitive factor, especially for suppressing the expression of a hormone or
hormone receptor gene in rats, for example. However, patch-clamp dialysis of
single cells or nuclear microinjections in culture, exposure of cultures to
extracellular oligonucleotides, and intra-cerebral microinjections of
oligonucleotides are feasible and highly rewarding approaches in physiology.
PMID- 9397971
TI - A constitutively active form of CREB can activate expression of the rat prolactin
promoter in non-pituitary cells.
AB - The pituitary cell-specific transcription factor Pit-1 has been show to trans
activate expression of the prolactin (PRL) promoter in non-pituitary cells.
However, the cyclic AMP response element (CRE)-binding protein CREB is known to
play a major role in cell-specific expression of hepatocyte-specific genes. Since
the PRL promoter contains an asymmetrical form of a cyclic AMP response element
(termed the CLE), we investigated whether CREB could also induce PRL promoter
activity in non-pituitary cells. Transient expression in rat glial C6 cells of a
constitutively active CREB-VP16 fusion protein strongly trans-activated
expression of a co-transfected rat PRL promoter construct, (-187)PRL-CAT.
Analysis by 5'-deletion showed that this response requires PRL promoter sequences
between positions -113/-75. CREB-VP16 did not stimulate expression in C6 cells of
any of three control promoter-CAT constructs, implying that the strong response
of the PRL promoter to activated CREB is both promoter-specific, and is not due
to non-specific transcriptional effects of the potent VP16 moiety of CREB-VP16.
Surprisingly, mutations in the CLE only slightly reduced activation by CREB-VP16
of construct (-204)PRL-CAT, implying that the major action of CREB-VP16 on the
PRL promoter does not involve a direct interaction with the CLE. CREB-VP16
stimulated PRL-CAT activity in C6 cells as strongly as, and synergistically with,
Pit-1. These results imply that CREB can strongly and specifically activate
expression of the PRL promoter in non-pituitary cells, via a mechanism different
from that employed by Pit-1.
PMID- 9397972
TI - Cytokines modulate type I iodothyronine deiodinase mRNA levels and enzyme
activity in FRTL-5 rat thyroid cells.
AB - Tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and
interferon-gamma (INF-gamma) have inhibitory effects on thyroid function both in
vivo and in vitro. We have studied the effects of these cytokines on type I 5'
deiodinase (5'-DI) mRNA expression and enzyme activity in FRTL-5 cells maintained
in standard cell culture medium containing 0 (5H) or 2 mIU/ml bovine TSH (6H).
Northern blots were hybridized with 5'-DI cDNA. 5'-DI mRNA levels were reduced to
20% of control values after treating cells with 100 ng/ml TNF-alpha in 6H for 2
days while the corresponding enzyme activity was reduced 50%. Other cytokines,
including IL-1beta and interferon-gamma, also significantly inhibited expression
of 5'-DI in FRTL-5 cells grown in 6H medium. Because the majority of circulating
T3 in the rat is secreted by the thyroid gland, the highly significant decline in
the serum T3/T4 ratio following in vivo administration of cytokines may be due to
their direct inhibitory effect on thyroidal 5'-DI expression.
PMID- 9397973
TI - Hepatitis C virus infection and type II cryoglobulinemia: an immunological
perspective.
PMID- 9397974
TI - Blunted responsiveness of the neuronal activation marker Fos in brainstem
cardiovascular nuclei of cirrhotic rats.
AB - Cardiovascular function in cirrhosis is deranged, with indirect evidence of
abnormal central cardiovascular regulation. We aimed to elucidate the role of
brainstem cardiovascular nuclei in hemodynamic regulation by examining the
protein product, Fos, of the immediate-early gene c-fos, in cirrhotic rats.
Cirrhosis was induced by chronic bile duct ligation (BDL) of 25-days duration,
while controls underwent a sham operation. To examine the effects of jaundice per
se in the absence of cirrhosis, a third group of 5-day BDL rats was also studied.
All rats were anesthetized with pentobarbital, and catheters were inserted to
measure baseline blood pressure and heart rate. Separate groups were then
subjected to volume manipulation by a hypotensive hemorrhage or isotonic saline
infusion, or no challenge. Ninety minutes after the volume manipulation, the
animals were killed and the medulla sectioned and stained for Fos by
immunohistochemisty. The nucleus tractus solitarius (NTS) of the sham-operated
unchallenged rats showed scant Fos immunoreactivity (27.8 +/- 3.3 cells), but
both hemorrhage and volume infusion significantly increased Fos staining (86.0 +/
3.7 and 95.2 +/- 8.5, respectively). In contrast, the unchallenged cirrhotic
rats showed markedly increased Fos in the NTS (154.6 +/- 27.0), but neither
hemorrhage nor volume infusion significantly changed the amount of Fos staining.
Fos staining in the ventrolateral medulla (VLM) followed a similar pattern with
low staining in the unchallenged sham rats and increased staining in the other
groups, but no differences between the unchallenged and the volume-manipulated
cirrhotic groups. The 5-day BDL jaundiced rats showed no baseline increase in Fos
staining, nor any significant increase after hemorrhage. These results showing
baseline activation of central neuronal regions responsible for blood pressure
homeostasis, but completely blunted responsiveness in cirrhotic rats, confirm a
central origin of disordered cardiovascular regulation. The presence of jaundice
may also contribute to the central cardiovascular hyporesponsiveness.
PMID- 9397975
TI - The effects of low dietary levels of polyunsaturates on alcohol-induced liver
disease in rhesus monkeys.
AB - Rhesus monkeys that were maintained on a diet containing low, yet adequate,
amounts of vitamins C and E and in which linoleate and linolenate represented
1.4% and 0.08% of the total caloric intake, respectively, developed liver
fibrosis after consuming alcohol (mean, 2.6 g kg(-1) d[-1]) over a period of 3
years. In the liver, several polyunsaturated fatty acids including 18:2n6,
20:4n6, and 22:6n3 decreased compared with dietary controls, and similar findings
were also observed in plasma lipoproteins and erythrocytes. The amount of alcohol
consumed correlated positively with plasma lipid peroxidation products, 4
hydroxynonenal (4-HNE) and 8-isoprostane F2alpha, and negatively with 20:4n6 and
22:6n3 levels. These findings imply that alcoholics who also have a marginal
intake of essential fatty acids and antioxidants in their diets may be at an
increased risk of developing liver disease.
PMID- 9397976
TI - Clinical, histological, and virological features of hepatitis C virus carriers
with persistently normal or abnormal alanine transaminase levels.
AB - This study was aimed to evaluate demographic, clinical, histological, and
virological characteristics of 46 hepatitis C virus (HCV) carriers with
persistently normal alanine transaminase (ALT) levels and to compare the results
with those obtained in a group of 52 HCV-RNA-positive patients with elevated ALT
levels. Subjects with normal ALT were more often females (P < .001), were more
likely to be asymptomatic (P < .001), and have a lower incidence of risk factors
for HCV transmission (P < .01). All patients with normal ALT had significant
histological liver damage. The mean grading and staging did not differ between
patients with normal and those with raised ALT concentrations. Moderate to severe
hepatitis was more frequently found among subjects with normal than with elevated
ALT. HCV genotype 2a was far more common in subjects with normal (43%) than with
abnormal ALT levels (6%; P < .002), genotype 1b being more frequent in these
latter (50% vs. 17%; P < .001). Patients with normal ALT levels had similar serum
HCV-RNA titers than subjects with raised ALT. Neither HCV genotype distribution
nor viral load correlated with the severity of liver damage. We conclude that
significant liver disease may occur irrespective of clinical symptoms, ALT
levels, HCV genotypes, and viral load.
PMID- 9397977
TI - Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis.
AB - Primary biliary cirrhosis (PBC) is characterized by an immune-mediated
destruction of intrahepatic small bile ducts. Apoptosis, a unique pattern of cell
death, has been suggested to be responsible for the biliary destruction in PBC.
To address this issue, we attempted to detect the apoptosis of biliary epithelial
cells by in situ nick-end labeling and by the expression of apoptosis-related
proteins using immunohistochemistry in patients with various hepatobiliary
diseases, including PBC. The data was noteworthy for several reasons. First,
apoptosis was occasionally detected on biliary cells in all liver specimens;
however, the positive rate was high in PBC and relatively low in other livers.
Strong expression of CD95 was frequently observed in the epithelial cells of the
injured bile ducts of PBC, which accompanied high intensity CD95 ligand
expressing mononuclear cells. Perforin and granzyme B immunoreactivities were
occasionally found on the bile ducts in control liver diseases as well as PBC,
but granzyme B-positive biliary cells were prominent in PBC. In contrast, Lewis Y
expression, as detected using BM-1 antibody, was consistently present in the
injured bile ducts of PBC. These data suggest that apoptosis, via the
perforin/granzyme B pathway, may be associated with the degrading fraction of
cell cycle regulation in the small-sized biliary tree under physiological and
pathological liver conditions. Moreover, enhanced apoptosis, mediated by
CD95/CD95 ligand interaction, may contribute to the bile duct injury and loss
observed in PBC.
PMID- 9397978
TI - Infection complicating percutaneous liver biopsy in liver transplant recipients.
AB - There is controversy about the frequency of and risk factors for infectious
complications of percutaneous liver biopsy in liver transplant recipients. The
aim of this study was to identify the incidence and nature of complications
associated with liver biopsy after orthotopic liver transplantation (OLT), with
particular emphasis on infection. The medical records of all patients undergoing
OLT between January 1990 and August 1994 were reviewed retrospectively to
identify complications requiring hospitalization within one week of percutaneous
liver biopsy. The nature and severity of complications were recorded and possible
risk factors for infectious complications were examined. One hundred ninety-eight
patients underwent 1,136 percutaneous liver biopsies. There were eleven
complications (0.96%), including as follows: 7 infections, 3 bleeding episodes,
and 1 vasovagal reaction. Infections after percutaneous liver biopsy included
fever and bacteremia (n = 6), and fever without bacteremia (n = 1). All
infections developed only in patients with underlying biliary tract
abnormalities; the frequency of infection was higher (9.8%) in patients with
choledochojejunostomy when compared with those with choledochocholedochostomy
(1.4%). Bacteremia was more likely caused by skin flora in patients with
choledochocholedochostomy (CDC) and by enteric bacteria in patients with
choledochojejunostomy (CDJ). All infections were treated successfully with
parenteral antibiotics. We conclude that biliary tract abnormalities are the
primary risk factors for infection after percutaneous liver biopsy, although the
risk is higher in patients with CDJ than with CDC. These data support the use of
antibiotic prophylaxis before percutaneous liver biopsy in OLT recipients with
biliary tract abnormalities.
PMID- 9397979
TI - Clinical efficacy of lactulose in cirrhotic patients with and without subclinical
hepatic encephalopathy.
AB - Seventy-five cirrhotic patients with hyperammonemia in the past or at the time of
the study were randomly divided into two groups (treated with lactulose or
nontreated) in 14 hospitals in Japan. Thirty-six cirrhotic patients were
diagnosed as having subclinical hepatic encephalopathy (SHE), and 39 were
diagnosed as non-SHE. SHE was diagnosed when the results of all three of the
quantitative psychometric tests used (number connection test, and symbol digit
and block design tests of the Wechsler adult intelligence scale [revised]) were
abnormal as compared with age-matched normal values. The mean number of abnormal
psychometric test results and the prevalence of SHE were used for a quantitative
evaluation of the efficacy of the lactulose treatment. Twenty-two of the SHE
patients were treated with lactulose (45 mL/d) for 8 weeks, and the other 14 SHE
patients did not receive lactulose. In the SHE patients administered lactulose,
the results of the quantitative psychometric evaluation were significantly
improved at 4 and 8 weeks after the beginning of the lactulose administration.
The SHE had disappeared in 10 (50%) of the 20 treated patients at week 8, but it
persisted in 11 (85%) of the untreated 13 patients. We concluded that lactulose
treatment in cirrhotic patients with SHE is effective with respect to
psychometric tests.
PMID- 9397980
TI - Large cell change (liver cell dysplasia) and hepatocellular carcinoma in
cirrhosis: matched case-control study, pathological analysis, and pathogenetic
hypothesis.
AB - Large cell change (LCC), characterized by cellular enlargement, nuclear
pleomorphism and hyperchromasia, and multinucleation of hepatocytes, is a common
lesion in cirrhotic livers, but its nature, significance, and pathogenesis remain
uncertain. Therefore, we assessed the prognostic value of LCC as a marker of
subsequent hepatocellular carcinoma (HCC) through a case-control study that
compared pretransplant liver biopsy specimens from 37 cirrhotic liver transplant
recipients with HCC to specimens from a control group of recipients without HCC,
matched for sex, age (+/-5 years), and cause of cirrhosis. LCC was identified in
16 (43%) of the study and 7 (19%) of the control group biopsy specimens. By
matched-pair analysis, LCC conveyed a moderately increased risk of later HCC with
an estimated odds ratio of 3.3 (95% CI, 1.2-15; P = .038). However, a pathology
review of 45 HCCs showed adjoining LCC in only 12 (27%) and did not suggest a
morphological transition or a histogenetic association between the two lesions.
LCC hepatocytes displayed a low proliferative rate by Ki-67 or proliferating cell
nuclear antigen immunostaining (labeling indices of 0.27 and 0.73) but showed a
greater degree of apoptosis than normal hepatocytes (labeling indices of 1.9 and
0.23; P = .03) To reconcile these findings, we propose that LCC derives from
derangements in the hepatocyte's normal process of polyploidization. Such
derangements, possibly caused by chronic inflammation-induced DNA damage, could
yield a population of enlarged liver cells with nuclear atypia and pleomorphism,
frequent binuclearity, and minimal proliferation. According to this hypothesis,
LCC would be a habitual feature of cirrhosis and a regular accompaniment of HCC
but would not represent a direct malignant precursor.
PMID- 9397981
TI - Indomethacin normalizes intracranial pressure in acute liver failure: a twenty
three-year-old woman treated with indomethacin.
AB - In patients with acute liver failure, cerebral herniation is a common cause of
death. The present study reports the effect of indomethacin on four occasions of
intracranial hypertension, in a 23-year old previously healthy woman with severe
acetaminophen poisoning. During each episode of intracranial hypertension, the
patient was treated with 25 mg of indomethacin, and each time the intracranial
pressure normalized. We recommend further controlled studies to determine the
exact effect of indomethacin on cerebral blood flow and metabolism before it is
recommended for treatment of intracranial hypertension in patients with acute
liver failure.
PMID- 9397982
TI - Quantitative liver function tests as surrogate markers for end-points in
controlled clinical trials: a retrospective feasibility study.
AB - Quantitative liver function tests such as the determination of galactose
elimination capacity (GEC) or the aminopyrine breath test (ABT) may have the
potential to serve as refined entry criteria and surrogate markers for end-points
in controlled clinical trials. The magnitude of a statistically detectable
difference in test results and the period of observation required to document
such a difference must be known to properly design such trials. Therefore, we
explored retrospectively the time course of changes in GEC and ABT and their
reproducibility from a cohort of patients with alcoholic cirrhosis followed for
12 to 42 months, with a median of 34 months. In 15 patients who stopped drinking,
GEC improved significantly by 0.64 mg/min/kg within 1 year (mean; 95% confidence
interval [CI]: 0.42; 0.86). In contrast, it deteriorated by 0.53 mg/min/kg within
1 year (95% CI: 0.32; 0.74) in another 17 patients who continued to drink (P <
.01). The residual standard deviation of the changes in GEC with respect to the
patients' initial values was 0.43 mg/min/kg (95% CI: 0.32; 0.52). In addition,
ABT improved significantly by 0.14% dose x kg/mmol CO2 (95% CI: 0.09; 0.18) in
the abstinent group, and deteriorated by 0.09% dose x kg/mmol CO2 (95% CI: 0.06;
0.13) in the nonabstinent group (P < .01). The residual standard deviation in the
above sense for ABT was 0.08% dose x kg/mmol CO2 (95% CI: 0.06; 0.10). These data
indicate that clinical trials with a sample size of n = 20 in each group must
achieve absolute differences (ADs) in GEC of 0.6 mg/min/kg and of 0.7 mg/min/kg
to reach statistical significance at the 5% and 1% level, respectively. In the
present study, a period of 11 and 12 months was necessary to observe such
differences. The corresponding results for the ABT are 0.11% dose x kg/mmol CO2
(9 months of follow-up; 5% level) and 0.13% dose x kg/mmol CO2 (11 months of
observation; 1% level), respectively. Provided that patients with liver diseases
treated with drugs are similar to the abstinent and nonabstinent patients with
alcoholic liver disease investigated in this study, such numbers could serve for
the planning of controlled clinical trials, in which the control group is likely
to deteriorate and the treated group is expected to improve. Trials based on GEC
or ABT would require only 37 or 30 patient years of observation compared with a
median of 444 patient years (range, 50-2,100 patient years) reported for various
published controlled clinical trials using survival analysis.
PMID- 9397983
TI - Coexpression of C-myc and transforming growth factor alfa in the liver promotes
early replicative senescence and diminishes regenerative capacity after partial
hepatectomy in transgenic mice.
AB - We have recently shown that overexpression of c-myc and transforming growth
factor alpha (TGF-alpha) in the liver of double-transgenic mice results in severe
DNA damage, aberrant hepatic growth, and development of tumors at a much younger
age than that observed in c-myc single-transgenic mice. We now report that double
transgenic TGF-alpha/c-myc hepatocytes rapidly lose their ability to proliferate
upon mitogenic stimulation following partial hepatectomy (PH). At 4 weeks of age,
the overall rate of bromodeoxyuridine (BrdU) incorporation following PH was
comparable in c-myc and TGF-alpha/c-myc livers and exceeded that seen in wild
type (WT) mice. However, by 10 weeks of age, c-myc single-transgenic hepatocytes
showed proliferative advantages over the WT cells, whereas TGF-alpha/c-myc double
transgenic hepatocytes had a decreased capacity to proliferate upon mitogenic
stimulation. This decreased proliferative response was accompanied by a reduction
in the total fraction of proliferating hepatocytes, as well as by a decline in
the induction of cyclin A, cyclin B, and cdc2 gene expression. These data show
that constitutive coexpression of c-myc and TGF-alpha accelerates age-related
loss in the regenerative potential following PH, and suggest that early
replicative senescence of differentiated hepatocytes may have a role in providing
a selective growth advantage to initiated cell populations in this model.
PMID- 9397984
TI - Exposure of primary rat hepatocytes in long-term DMSO culture to selected
transition metals induces hepatocyte proliferation and formation of duct-like
structures.
AB - We previously showed that primary rat hepatocytes plated on a rat-tail collagen
coated dish and fed a chemically-defined medium supplemented with 2%
dimethylsulfoxide (DMSO) can be maintained in a well-differentiated, non
replicating state for periods of several months. In this study, we show that the
addition of copper, iron, and zinc to the DMSO-containing chemically defined
medium induced DNA synthesis and cell replication during the first two months in
culture without loss of hepatic differentiation. DNA synthesis occurred
throughout the hepatocyte population without regard to cellular size. No changes
were observed in properties indicative of well-differentiated hepatocytes,
including cellular morphology, ultrastructure, albumin, or cytokeratin-8
expression. During the third month in culture, after the hepatocytes had become
confluent, pseudoduct structures became apparent. Examination of cells lining the
ducts by immunohistochemistry showed that these cells lost the ability to express
albumin and stained more intensely for cytokeratin 19 and laminin. The
ultrastructure of the cells lining the ducts was altered and became more
characteristic of bile duct cells. Immunoelectron microscopy revealed that
connexin 43, a marker of bile-duct proliferation, was expressed in the duct-like
cells. We conclude that under these specific nutritive conditions, primary rat
hepatocytes proliferate and, with time, begin to form duct-like structures with
altered gene expression and ultrastructural properties.
PMID- 9397985
TI - Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma
cells: evidence for a role of hepatocyte growth factor.
AB - The stroma of hepatocellular carcinomas (HCC) is infiltrated with myofibroblasts
(MFs). Preliminary in vivo data have suggested that liver MF express hepatocyte
growth factor (HGF), a cytokine that has been implicated in several tumor models.
Our aim was to investigate the role of MF and HGF in HCC. Cultured liver MF
expressed HGF messenger RNA (mRNA) and secreted HGF in their medium, as shown by
Western blot, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA).
Addition of MF-conditioned medium to the HepG2 HCC cell line induced cell
scattering. This was associated with a decrease in cell proliferation. MF also
increased about 100-fold the ability of HepG2 to invade Matrigel. Increased
invasiveness was also shown for HuH7 cells, but no scattering was observed and
cell proliferation was stimulated. All the effects of MF on both tumor cell types
were blocked by addition of an antibody to HGF and they all could be reproduced
by adding recombinant HGF to the tumor cells. RT-PCR and Western blot analysis
confirmed that both tumor cell lines expressed c-met, the receptor for HGF. The
effects of MF-conditioned medium were not reproduced by acidic fibroblast growth
factor, basic fibroblast growth factor, epidermal growth factor (EGF),
transforming growth factor-beta1 (TGF-beta1), or platelet-derived growth factor
(PDGF-BB). Reverse transcription-polymerase chain reaction (RT-PCR) analysis
confirmed that HGF was expressed in human HCC. Our data show that human liver MF
act on HCC cells to increase their invasiveness and suggest that MF-derived HGF
could be involved in the pathogenesis of HCC.
PMID- 9397986
TI - Modulation of liver canalicular transport processes by the tyrosine-kinase
inhibitor genistein: implications of genistein metabolism in the rat.
AB - Rat liver cells express the multispecific organic anion transporter (cmoat, cmrp,
mrp2) and P-glycoprotein (Pgp) in their canalicular membranes, proteins that are
homologous to the multidrug-resistance related protein (MRP) and multidrug
resistance (MDR) gene products in multidrug resistant tumor cells. We tested
whether genistein, a modulator of drug resistance in tumor cells, affects biliary
secretion of substrates of canalicular multispecific organic anion transporter
(cmoat) (glucuronides of bilirubin and rhodamine, glutathione conjugate of
bromsulphthalein) and of P-glycoprotein (Pgp) (rhodamine), respectively. Using
the isolated perfused rat liver of control Wistar rats (TR+) and of a mutant
strain (TR-) that expresses Pgp but not cmoat, we show that genistein effectively
inhibits the secretion of anionic substrates of cmoat in Wistar rats but
stimulates secretion of cationic rhodamine in TR- rats. Genistein is subject to
glucuronidation and sulfatation and secretion of genistein and its metabolites
stimulates bile flow in Wistar rats, but secretion is nearly absent in TR- rats.
Because genistein and its metabolites are substrates for cmoat, inhibition of
anion secretion by genistein is partially explained by competition for this
transporter. Genistein is also a substrate of uridindiphosphate (UDP)
glucuronyltransferase isoenzyme(s). Inhibition of glucuronidation reduces the
availability of bilirubin and rhodamine glucuronates for transport via cmoat, but
unconjugated cationic rhodamine becomes available for transport via Pgp at an
increased cellular concentration. Daidzein, a genistein analogue with no effect
on protein tyrosine kinase (PTK) shows Similar effects on secretion of organic
anions and cations supporting the conclusion that genistein affects transport in
liver mainly through competition with other substrates at the sites of
glucuronidation and transport via cmoat.
PMID- 9397987
TI - Presence of distinct AP-1 dimers in normal and transformed rat hepatocytes under
basal conditions and after epidermal growth factor stimulation.
AB - Activation of the transcriptional regulator AP-1, a dimeric complex formed of
various combinations of Fos and Jun proteins, is a key step in the cellular
response to mitogens. Because different dimers are believed to display different
regulatory functions, we hypothesized that transformed cells that lack normal
growth constraints might display AP-1 dimers that are different from those of
normal cells. We therefore compared in primary and transformed rat hepatocytes
(1) the composition of AP-1 dimers under basal conditions and (2) AP-1 induction
by epidermal growth factor (EGF). Under basal conditions, AP-1 contained
predominantly Jun homodimers in both cell types. However, whereas normal
hepatocytes contained only JunD, both JunD and JunB were present in the AP-1
complex of 7777 cells. EGF treatment triggered almost identical programs of fos
and jun gene activation at the messenger RNA (mRNA) level in both cell types,
with an early accumulation of c-fos, c-jun, and junB mRNAs, but no change in junD
mRNA levels. In both cell types, c-Fos and Fra-1 proteins increased after EGF
treatment, but differences in the induction of Jun proteins were noted, with an
increase of c-Jun in hepatocytes and an increase of JunB in 7777 cells. In both
cell types, activation of AP-1 DNA binding activity by EGF was accompanied by the
recruitment of Fra-1 into AP-1, detected earlier in 7777 cells than in
hepatocytes, and with the transient appearance of c-Fos in 7777 cells only.
Finally, EGF activated AP-1-dependent transcription in 7777 cells but not in
hepatocytes. These data indicate important differences in the functional activity
of AP-1 in transformed hepatocytes.
PMID- 9397988
TI - Altered expression of mitogen-activated protein kinases in a rat model of
experimental hepatocellular carcinoma.
AB - The mitogen-activated protein kinase (MAPK) cascade acts as a focal point for
signal transduction following activation of both G-protein-linked and tyrosine
kinase growth factor receptors. A common intermediate between both of these
diverse receptor subtypes includes the small guanosine triphosphate (GTP)-binding
protein, p21ras. Point mutations of p21ras have been identified in various tumor
types and lead to constitutive activation of this protein and subsequent
activation of downstream pathways including the MAPK cascade. Using an in vivo
model of hepatocellular carcinoma (HCC), we investigated the abundance and
function of individual components of the MAPK cascade and the presence of
specific p21ras mutations in this model. Expression of components of the MAPK
cascade were determined in tumor and adjacent, non-neoplastic liver specimens by
Western blot analysis and functional activity confirmed by substrate
phosphorylation assays. Mutations in p21ras were analyzed using an enzyme-linked
immunosorbent assay. In tumor, extracellular regulated kinases (ERKs) ERK1, ERK2,
and mitogen-activated ERK-regulated kinase-1 (MEK1) were elevated by three- to
fourfold as compared with adjacent nontumorigenic normal liver. In contrast, MEK2
was elevated by only 28%. Substrate phosphorylation and detection of
phosphorylated ERK1/2 proteins showed increased functional activity of these
proteins of the same magnitude as that observed for protein expression. Mutations
in p21ras were not detected in this experimental model of HCC. We conclude that
HCC is associated with marked changes in expression and function of components of
the MAPK cascade independent of common p21ras mutations.
PMID- 9397989
TI - Chromosomal aberrations in hepatocellular carcinomas: relationship with
pathological features.
AB - Fluorescence in situ hybridization performed on tissue sections can reveal
chromosomal abnormalities related to histopathological features. This technique
was performed on serial frozen sections from seven normal livers and 29
hepatocellular carcinomas (HCCs) using pericentromeric repeat-specific probes for
chromosomes 1, 4, 6, 7, 8, 16, and 17. For each HCC and each probe, the
percentage of cells showing one, two, or more than two signals was counted and
compared with the distribution in the normal liver. According to these results,
HCCs were categorized as monosomic, disomic, or polysomic (more than two signals)
for the chromosome tested. These data were compared with the main
histopathological characteristics of HCC. Chromosome gains were very common,
preferentially affecting chromosome 1 (23 of 27 cases, 85%), chromosome 16 (16 of
27 cases, 59%), chromosome 7 (16 of 29 cases, 55%), chromosome 6 (15 of 29 cases,
52%) and chromosome 8 (14 of 29 cases, 48%). Monosomy was seen more rarely,
affecting preferentially chromosome 16 (19%), chromosome 17 (14%), and chromosome
4 (10%). A significant correlation was observed between aneusomy of chromosome 4
and tumor size (P < .05) or the presence of vascular embolism (P < .05). In
conclusion, chromosomal gains are frequent genetic events in human HCC. A
significant association between a gain in chromosome 4 and large tumor size or
vascular embolism suggests that this genetic abnormality is a late event in liver
carcinogenesis.
PMID- 9397990
TI - Role of Kupffer cells in gut ischemia/reperfusion-induced hepatic microvascular
dysfunction in mice.
AB - Kupffer cells (KCs) have been implicated in the leukocyte recruitment and
microvascular dysfunction associated with liver inflammation. The overall
objective of this study was to assess the role of KCs in the leukocyte adhesion
and oxidative stress elicited in the liver by gut ischemia/reperfusion (I/R). The
accumulation of rhodamine-6G-labeled leukocytes and the number of nonperfused
sinusoids (NPS) were monitored (by intravital microscopy) in mouse liver for 1
hour after a 15-minute period of normothermic intestinal ischemia.
Autofluorescence of pyridine nucleotide [NAD(P)H] was measured as an index of
mitochondrial O2 consumption and redox status. Leukostasis, as well as increases
in NPS and NAD(P)H autofluorescence (indicating hypoxia), were observed in the
liver at 60 minutes after gut I/R. Pretreatment with gadolinium chloride (GdCl3),
which reduces KC function, attenuated the liver leukostasis and NPS elicited by
gut I/R. The platelet activating factor (PAF) antagonist, WEB2086, and a tumor
necrosis factor (TNF)-alpha-specific antibody were also effective in attenuating
the gut I/R-induced leukostasis and NAD(P)H autofluorescence. The findings of
this study suggest that KCs play an important role in mediating the leukocyte
recruitment, impaired sinusoidal perfusion, and tissue hypoxia elicited in the
liver after gut I/R. These KC-mediated responses appear to involve the
participation of both PAF and TNF-alpha.
PMID- 9397991
TI - Hepatic expression of c-Myb in chronic human liver disease.
AB - C-Myb is a sequence-specific DNA binding protein that regulates the expression of
genes involved in cell proliferation and differentiation. The present study was
designed to elucidate the role of c-Myb in the pathogenesis of chronic liver
disease by an immunohistochemical approach. In normal (control) livers, few or no
hepatic cells were positive for c-Myb. In livers from patients with chronic viral
hepatitis, positive staining for c-Myb was found not only in spindle-shaped
mesenchymal cells in expanded portal areas, but also in perisinusoidal cells
(PSCs) within liver lobules. In cirrhotic livers, a few PSCs within lobules were
positive for c-Myb, while no staining was seen in fibrous septa. Immunoelectron
microscopy revealed that c-Myb-positive PSCs displayed morphological features of
hepatic stellate cells. Other sinusoidal lining cells including Kupffer cells and
sinusoidal endothelial cells, as well as hepatocytes, were all negative for c
Myb. Dual c-Myb/alpha-smooth muscle actin (alphaSMA) staining revealed that more
than 97% of c-Myb-positive cells were alphaSMA-positive. Moreover, dual c
Myb/proliferating cell nuclear antigen (PCNA) staining showed that approximately
70% of c-Myb-positive cells also expressed PCNA. The labeling index (LI) (number
of c-Myb-positive cells/0.1 mm2) significantly correlated with serum transaminase
concentrations and increased in parallel with the disease activity. However, the
LI showed no correlation with the degree of fibrosis. These results suggest that
c-Myb may be involved in stellate cell activation and proliferation in
chronically diseased human livers, and that the level of c-Myb expression is
associated with the activity of chronic hepatitis.
PMID- 9397992
TI - Interleukin-6 protects liver against warm ischemia/reperfusion injury and
promotes hepatocyte proliferation in the rodent.
AB - Interleukin-6 (IL-6) is an acute reactant cytokine with anti-inflammatory
properties, which has been found to prevent injury in a model of acute hepatitis
in mice through downregulation of tumor necrosis factor alpha (TNF-alpha); to
correlate inversely with markers of hepatocellular injury in patients with liver
ischemia; and to initiate liver regeneration in mice. In this study, we
investigated the role of IL-6 in rodent models of hepatic warm
ischemia/reperfusion (WI/Rp) injury. IL-6-deficient mice (-/-) were subjected to
hepatic WI and compared with C57BL/6 mice, as well as IL-6 -/- mice pretreated
with recombinant IL-6 (rIL-6). The effects of rIL-6 following various periods of
ischemia were further studied in models of hepatic ischemia in rats. IL-6 -/-
mice had increased reperfusion injury as assessed by transaminase levels and a
tissue necrosis scoring system when compared with controls, an effect prevented
by pretreatment with rIL-6. Similarly, rats pretreated with rIL-6 had reduced
reperfusion injury and better survival than controls in each respective WI group.
Tissue TNF-alpha expression measured by Northern blot analysis and serum C
reactive protein (CRP) levels, a marker of inflammation, were significantly
reduced in animals pretreated with rIL-6. Administration of antibodies to TNF
alpha reproduced the beneficial effect of rIL-6. Hepatocyte proliferation, as
assessed by a scoring method for mitotic index and proliferating nuclear cell
antigen staining, was markedly increased in rIL-6-treated rats when compared with
controls. In conclusion, this study suggests that IL-6 could play an important
role in limiting hepatic warm ischemia/reperfusion (WI/Rp) injury, probably
through its anti-inflammatory properties, modulation of TNF-alpha, and/or
promotion of liver regeneration. rIL-6 might become an important cytokine in
clinical situations associated with WI/Rp injury.
PMID- 9397993
TI - Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix
metalloproteinase in fibrotic human livers.
AB - We have previously reported increased expression of matrix metalloproteinase-2
(MMP-2) using a rat model of liver fibrosis. However we did not clarify how the
precursor of MMP-2 (proMMP-2) was activated. Therefore, we used human liver
specimens with chronic hepatitis (CH) and liver cirrhosis (LC) to examine
expression of membrane-type-1-MMP (MT1-MMP), which has recently been determined
to activate proMMP-2. Northern hybridization studies showed a 5.4- and 1.4-fold
increase in MMP-2 expression in CH and LC, respectively, as compared with normal
liver. MT1-MMP gene expression simultaneously increased 4.0- and 1.4-fold in CH
and LC, respectively. In situ hybridization using 35S-cRNA probes of MMP-2 and
MT1-MMP showed prominent silver granules in elongated cells found in the lobules,
periportal areas, and fibrous septa of CH and LC samples. These elongated cells
expressed alpha-smooth muscle actin by immunohistochemistry. Immunoelectron
microscopic examination localized MMP-2 and MT1-MMP to the rough endoplasmic
reticulum of stellate cells located in the lobules and periportal areas, or to
fibroblasts in the fibrous septa, suggesting that MMP-2 and MT1-MMP were produced
by these cells. In addition, cytoplasmic and membranous immunodeposits of both
MMPs were found in endothelial cells, Kupffer cells, capillary endothelial cells,
and lymphocytes, indicating that activation of proMMP-2 occurs locally. Increased
expression of MMP-2 and MT1-MMP was detected in CH and LC, while dual over
expression was found in stellate cells and fibroblasts, possibly resulting in the
increase of active MMP-2 in and around these cells. These findings suggest that
activated MMP-2 may remodel liver parenchyma during the process of liver
fibrosis.
PMID- 9397994
TI - Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and
inflammation caused by chronic exposure to ethanol in the rat.
AB - Tumor necrosis factor (TNF)alpha, a pivotal cytokine involved in inflammation, is
produced primarily by Kupffer cells in the liver. It has been shown that
inactivation of Kupffer cells prevents alcohol-induced liver injury; therefore,
the purpose of this study was to determine if neutralizing anti-TNF-alpha
antibody is also effective. Male Wistar rats were exposed to ethanol (11 to 12 g
x kg(-1) x d[-1]) continuously for up to 4 weeks via intragastric feeding using
an enteral feeding model. Before ethanol exposure, polyclonal anti-mouse TNF
alpha rabbit serum was injected (2.0 mg/kg intravenously). There were no
significant differences in body weight, mean ethanol concentration, or cyclic
patterns of ethanol in urine when ethanol- and ethanol plus antibody-treated
groups were compared. Expression of TNF-alpha and macrophage inflammatory protein
2 (MIP-2) messenger RNA (mRNA), determined using reverse transcription-polymerase
chain reaction, was three- to four-fold higher in livers of ethanol-treated rats
than in those of rats fed an ethanol-free, high-fat control diet. In addition,
MIP-2 levels were also elevated when detected by Northern blot analysis. Anti-TNF
alpha antibody did not affect expression of mRNA for interleukin (IL) 1alpha, IL
6, transforming growth factor beta1, or TNF-alpha. However, MIP-2 mRNA
expression, which is regulated by TNF-alpha, was decreased significantly by anti
TNF-alpha antibody treatment. Serum aspartate transaminase levels were elevated
in ethanol-treated rats to 136 +/- 12 IU/L after 4 weeks but only reached 90 +/-
5 IU/L (P < .05) in rats treated with anti-TNF-alpha antibody. The hepatic
inflammation and necrosis observed in ethanol-fed rats were attenuated
significantly by antibody treatment, and steatosis was not. These results support
the hypothesis that TNF-alpha plays an important role in inflammation and
necrosis in alcohol-induced liver injury and that treatment with anti-TNF-alpha
antibody may be therapeutically useful in this disease.
PMID- 9397995
TI - Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis
factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat.
AB - We investigated the potential of dietary saturated fatty acids to decrease
endotoxemia and suppress expression of cyclooxygenase 2 (Cox-2) and tumor
necrosis factor alpha (TNF-alpha) in established alcohol-induced liver injury.
Six groups (five rats/group) of male Wistar rats were studied. Rats in group 1
were fed a fish oil-ethanol diet for 6 weeks. Rats in groups 2, 3, and 4 were fed
fish oil and ethanol for 6 weeks. Ethanol administration was stopped at this
time, and the rats were switched to isocaloric diets containing dextrose with
fish oil (group 2), palm oil (group 3), or medium-chain triglycerides (group 4)
as the source of fat for an additional 2 weeks. Rats in groups 5 and 6 were fed
fish oil-ethanol and fish oil-dextrose, respectively, for 8 weeks. Liver samples
were analyzed for histopathology, lipid peroxidation, and levels of messenger RNA
(mRNA) for Cox-2 and TNF-alpha. Concentrations of endotoxin were determined in
plasma. The most severe inflammation and fibrosis were detected in groups 1 and
5, as were the highest levels of endotoxin, lipid peroxidation, and mRNA for Cox
2 and TNF-alpha. After ethanol was discontinued, there was minimal histological
improvement in group 2 but near normalization of the histology, including
regression of fibrosis, in groups 3 and 4. Histological improvement was
associated with decreased levels of endotoxin, lipid peroxidation, and reduced
expression of Cox-2 and TNF-alpha. The data indicate that a diet enriched in
saturated fatty acids (groups 3 and 4) effectively reverses alcohol-induced liver
injury, including fibrosis. The therapeutic effects of saturated fatty acids may
be explained, at least in part, by reduced endotoxemia and lipid peroxidation,
which in turn result in decreased levels of TNF-alpha and Cox-2.
PMID- 9397996
TI - Enhanced expression of cytokine-induced neutrophil chemoattractant in rat hepatic
allografts during acute rejection.
AB - The kinetics of messenger RNA (mRNA) and protein levels of cytokine-induced
neutrophil chemoattractant (CINC) in rat hepatic allografts during acute
rejection were investigated. Infiltrating cells were identified by double
immunostaining with anti-CINC and anti-macrophage monoclonal antibodies, ED1 and
ED2. The serum CINC concentration in untreated hepatic allograft recipients
increased significantly at a constant rate over time after transplantation. No
significant increases in serum CINC concentrations were observed in hepatic
isografts or allografts treated with the immunosuppressant FK506. The number of
neutrophils in untreated hepatic allografts increased significantly at a constant
rate. Conversely, neutrophil accumulation in isografts or allografts treated with
FK506 was much less than in untreated hepaticallografts. Immunostaining revealed
that in the portal areas, mononuclear cells infiltrating untreated allograft
liver were mainly positive for CINC and that CINC+ cells represented a
subpopulation (approximately 25%) of the ED1+ cells. On the other hand, in the
sinusoidal areas CINC+ cells were scattered and mainly positive for ED2. Levels
of CINC mRNA in liver tissues taken from untreated hepatic allografts increased
after transplantation, peaked on day 5, and decreased thereafter. Hepatic
allografts treated with FK506 or isografts showed much lower levels of CINC mRNA
than untreated allografts. Allogeneic mixed lymphocyte reactions induced CINC
production. The cellular source of CINC was mononuclear cells. CINC production in
mixed lymphocyte reactions was inhibited in the presence of anti-tumor necrosis
factor alpha (TNF-alpha) antibody. These results suggest that enhanced expression
of CINC mRNA and prominent accumulation of neutrophils in the liver grafts are
characteristic features of the immune response during acute rejection.
PMID- 9397997
TI - Targeting naproxen coupled to human serum albumin to nonparenchymal cells reduces
endotoxin-induced mortality in rats with biliary cirrhosis.
AB - Endotoxin is thought to play a major role in cirrhotic liver disease. Cyclo
oxygenase inhibitors were shown to be partially protective against endotoxin but
cannot be used in cirrhotic patients because of renal side-effects. We argued
that administration of naproxen (NAP) linked to human serum albumin (HSA), which
results in specific delivery of NAP to endothelial cells (EC) and Kupffer cells
(KC) and exhibited hepatoprotective effects against lipopolysaccharide (LPS) in
vitro, could protect cirrhotic rats from LPS toxicity while preserving renal
function. The studies were performed in rats rendered cirrhotic by bile duct
ligation (BDL); animals received LPS (Escherichia coli, 800 microg/kg)
intravenously. Five groups were studied: LPS alone, rats pretreated with a
conventional dose of NAP (50 mg/kg), NAP-HSA (22 mg/kg), NAP equimolar to NAP-HSA
(1.5 mg/kg), or the HSA carrier. LPS induced significant mortality (55%); this
was not affected by equimolar NAP (57%) but accentuated by conventional NAP
(88%). In contrast, NAP-HSA provided significant protection (9%; P < .05). After
conventional NAP treatment, significant renal toxicity was observed as evidenced
by a marked reduction in sodium excretion (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 33
+/- 22 vs. 50 +/- 39 vs. 4 +/- 3 micromol/h; P < .05). Renal prostaglandin E2
(PGE2) excretion was reduced by NAP in all groups, but most markedly at the
conventional dosage (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 132 +/- 115 vs. 39 +/- 19
vs. 9 +/- 8 ng/mL; P < .05). Successful targeting was evidenced by a significant
hepatic enrichment of NAP in the NAP-HSA group compared with the equimolar
untargeted group (30.16 +/- 9.33 vs. 1.13 +/- 1.95 nmol/g liver). Thus, targeting
NAP to EC/KC results in improved survival, higher efficacy, and sparing of renal
function in cirrhotic rats.
PMID- 9397998
TI - Cytoprotection by the osmolytes betaine and taurine in ischemia-reoxygenation
injury in the perfused rat liver.
AB - Medium osmolarity sensitively regulates Kupffer cell functions like phagocytosis
and prostaglandin (PG) and cytokine production. Betaine and taurine, recently
identified as osmolytes in liver cells, interfere with these effects. Because
Kupffer cell activation is an important pathogenic mechanism in ischemia
reoxygenation injury, the influence of osmolarity and osmolytes was investigated
in a rat liver perfusion model of warm ischemia. Livers were perfused with
different medium osmolarities for 60 to 90 minutes in the absence of oxygen,
followed by another 90 minutes of reoxygenation. Lactate dehydrogenase (LDH)
leakage into the effluent perfusate during the hypoxic and the reoxygenation
period was eight- to 10-fold higher with a medium osmolarity of 385 mosmol/L than
in normo-osmolarity, and further decreased with hypo-osmolar perfusion buffer.
Betaine and taurine addition to the perfusate in near physiological
concentrations decreased hypoxia-reoxygenation-induced LDH leakage, aspartate
transaminase (AST) leakage, and perfusion pressure increase in hyperosmolar and
normo-osmolar perfusions. Stimulation of PGD2, PGE2, thromboxane B2 (TXB2), and
tumor necrosis factor alpha (TNF-alpha) release, as well as induction of carbon
uptake by the liver during reoxygenation, were suppressed by betaine and taurine,
pointing to an interference of these osmolytes with Kupffer cell function. In
contrast, endothelial cell function as assessed by hyaluronic acid (HA) uptake
was not influenced. It is concluded that warm ischemia-reoxygenation injury in
rat liver is aggravated by hyperosmolarity and attenuated by hypo-osmolarity. The
osmolytes betaine and taurine have a protective effect, presumably by inhibition
of Kupffer cell activation.
PMID- 9397999
TI - Neonatal granulocytosis is a postpartum event which is seen in the liver as well
as in the blood.
AB - In a recent series of studies, we demonstrated that stress in humans and animals,
with resultant sympathetic nerve strain, induces severe granulocytosis, because
granulocytes carry adrenergic receptors on the surface. Because activated
granulocytes produce free radicals and superoxides, they sometimes induce tissue
damage if the stress is too strong or continuous. Human neonates are also known
to show high levels of granulocytes in the peripheral blood. In this study, we
investigated whether such neonatal granulocytosis are a stress-associated
response at birth. Both human and mouse materials, before and after birth, were
used. The number of leukocytes in the blood, as well as some other factors in the
serum, were measured. Although levels of granulocytes were found to be low in
fetal humans and mice, they increased sharply after birth. In parallel with this
postpartal granulocytosis, transaminases in sera increased transiently. In
reference to results of a transient elevation in the levels of catecholamines at
birth in mice, all these phenomena resemble stress-associated responses. Indeed,
fatty liver and hematopoietic destruction in the liver were also observed in mice
and humans. At this time, the production of inducible nitric oxide synthase
(iNOS) by granulocytes in the liver was evident. These results suggest that
neonatal granulocytosis is a postpartum event which results from various stresses
(e.g., oxygen stress) at birth. This event may be responsible for such well-known
neonatal phenomena as the termination of fetal hematopoiesis in the liver and as
neonatal jaundice.
PMID- 9398000
TI - Progesterone metabolites and bile acids in serum of patients with intrahepatic
cholestasis of pregnancy: effect of ursodeoxycholic acid therapy.
AB - The concentrations in serum of sulfated metabolites of progesterone are known to
be elevated in patients with intrahepatic cholestasis of pregnancy (ICP). The
profiles of these metabolites and conjugated bile acids were analyzed in serum
from 11 patients with ICP before and during administration of ursodeoxycholic
acid (UDCA) (8 patients) or placebo (3 patients). The clinical condition of 7 of
the patients given UDCA improved markedly, and 1 patient given placebo had a
spontaneous remission of the disease. The total concentration of conjugated bile
acids in the 11 patients was 25 +/- 6 micromol/L (mean +/- SEM) and decreased to
6.3 +/- 3.5 micromol/L in the 7 patients responding to treatment with UDCA. The
level of 7alpha-hydroxy-4-cholesten-3-one was significantly lower (7.2 +/- 2.2
ng/mL) in patients with ICP than in healthy pregnancy (18 +/- 4.6 ng/mL) (P <
.05). The concentrations of 5alpha-pregnane-3alpha,20alpha-diol mono- and
disulfates decreased by 52% +/- 7.9% and 68% +/- 5.5%, respectively, in the
patients responding to treatment. Similar decreases were observed for the mono-
and disulfates of 5alpha-pregnane-3alpha,20alpha,21-triol and 5beta-pregnane
3alpha,20alpha-diol. The disulfate of 5alpha-pregnane-3beta,20alpha-diol showed a
smaller decrease, while glucuronidated steroids were not affected. The 3alpha
/3beta-hydroxysteroid ratio and di-/monosulfate ratio decreased significantly
during UDCA. The magnitudes of the changes of bile acid and steroid
concentrations during UDCA were not correlated to each other. The results suggest
that UDCA stimulates the biliary excretion of steroids with a 3alpha-sulfoxy
group and disulfates. This effect seems to be independent of the effect on bile
acid excretion, indicating the use of different transport proteins. The
possibility of an effect of UDCA on the formation of the steroid sulfates cannot
be excluded.
PMID- 9398001
TI - Modulation of circadian expression of D-site binding protein by the schedule of
parenteral nutrition in rat liver.
AB - The aim of this study was to investigate the changes in the circadian rhythm of
the expression of liver-specific genes caused by different schedules of
parenteral nutrition (PN). Rats received PN continuously throughout the day or
intermittently during the night or day for 7 days. They were examined for gene
expression of D-site binding protein (DBP), albumin, and cytochrome P450
cholesterol 7alpha-hydroxylase (CYP7) in the liver. The nocturnal PN group showed
circadian expression of DBP messenger RNA (mRNA) and protein with a peak at 10
PM, in the same manner as the control rats receiving normal chow feeding.
However, the diurnal PN group showed inverted expression of DBP mRNA and protein
with a peak at 10 AM. CYP7 mRNA levels exhibited good synchronization with the
levels of DBP mRNA in all groups, whereas albumin mRNA levels did not show such
synchronization. Gel mobility-shift assay disclosed that the binding activity of
the nuclear extracts to the CYP7 gene promoter was changed by the PN schedule in
accordance with the expression of CYP7 mRNA. The PN schedule modulates the
circadian rhythm of DBP expression and may have an effect on hepatic bile acid
formation through transcriptional regulation of the CYP7 gene.
PMID- 9398002
TI - Effect of cytochrome P450 induction on phosphorus metabolites and proton
relaxation times measured by in vivo 31P-magnetic resonance spectroscopy and 1H
magnetic resonance relaxometry in human liver.
AB - Experimental and clinical studies have led to the hypothesis that the
phosphodiester signal obtained by 31P magnetic resonance (MR) spectroscopy may be
a specific marker for the hepatic induction of oxidative metabolism (P450
induction) by phenobarbitone or ethanol. Systematic studies in humans are
lacking. Therefore, we studied 10 volunteers who received rifampin (600 mg/d) for
6 days, resulting in a documented induction of oxidative metabolism as measured
by an increase in urinary 6-beta-hydroxycortisol output in all volunteers (P =
.0004). 31P-MR spectroscopy and 1H-MR relaxometry were performed before and after
hepatic P450 induction. As shown by 31P-MR spectroscopy, the median
phosphomonoester concentration (PME) relative to nucleoside triphosphate (NTP)
increased by 21% from 0.63 (range, 0.40-0.89) before induction to 0.76 (0.49
1.67) after induction (P = .0451). The median level of phosphodiesters (PDE)
relative to NTP increased by 28% from 4.82 (3.41-6.67) before induction to 6.18
(4.63-11.63) after induction (P = .0091). An increase in the level of inorganic
phosphates (Pi) relative to NTP was observed, but changes were not significant.
As shown by 1H-MR relaxometry, a nonsignificant trend of the liver parenchyma to
shorter relaxation times was observed after P-450 induction. In conclusion, both
PME/NTP and PDE/NTP ratios (measured by in vivo 31P-MR spectroscopy) increased
significantly after hepatic induction with rifampin. Further clinical studies
with 31P-MR spectroscopy must take into account the potential effects of P450
inducing agents.
PMID- 9398003
TI - An improved digitonin-collagenase perfusion technique for the isolation of
periportal and perivenous hepatocytes from a single rat liver: physiological
implications for lobular heterogeneity.
AB - Morphological and functional heterogeneity of hepatocytes according to their
position in the liver lobule has been known for many years. The digitonin
collagenase perfusion technique is widely used to study hepatocyte heterogeneity
and has yielded reliable data. However, with this procedure, periportal (PP) or
perivenous (PV) hepatocytes are isolated from different livers, allowing only
comparison between cell populations issued from two separate animals. To overcome
this drawback, we have modified this technique by perfusing the two main rat
liver lobes of a single animal in succession. The procedure involved alternate
clamping of the median and the left lateral lobes, restricting digitonin infusion
to one lobe via the portal vein, and to the other via the caudal vena cava. Lobe
exclusion during digitonin perfusion, and zonal restriction of digitonin-induced
damage, were monitored using macroscopic and histological controls. We compared
our results with previous data on PP and PV hepatocytes issued from two different
livers using the conventional digitonin-collagenase perfusion technique. First,
we found that the cellular sensitivity to angiotensin II, a calcium-mobilizing
agonist, was 60% to 80% higher in PV than in PP hepatocytes, whereas, previously,
no difference had been recorded. Second, we found that albumin messenger RNAs
(mRNAs) were 35% more abundant in PP than in PV hepatocytes, whereas, previously,
larger differences had been reported. Our results show that PP and PV hepatocytes
may be isolated from a single liver using an improved digitonin-collagenase
perfusion technique. Furthermore, we suggest that zonal differences can be
artificially masked or amplified when comparing PP and PV cell populations from
two different livers, indicating that it is preferable to use a single liver for
accurate zonal comparisons between hepatocytes.
PMID- 9398004
TI - Hepatic growth hormone receptor, insulin-like growth factor I, and insulin-like
growth factor-binding protein messenger RNA expression in pediatric liver
disease.
AB - Major changes in serum levels of insulin-like growth factor I (IGF-I) and IGF
binding proteins (IGFBPs) occur in children with end-stage liver disease in
association with changes in body composition. We hypothesized that these changes
would be associated with changes in hepatic messenger RNA (mRNA) expression.
Eleven children with end-stage extrahepatic biliary atresia and 11 controls
(liver donors) were studied. Serum samples were obtained from the children with
biliary atresia immediately before orthotopic liver transplantation. Serum IGF-I,
IGFBP-1, and IGFBP-2 levels were measured by radioimmunoassay, and IGFBP-3 by
immunoradiometric assay. In both groups, growth hormone receptor mRNA expression
was examined by quantitative reverse transcription-polymerase chain reaction, IGF
I mRNA expression by ribonuclease protection assay, and IGFBP-1 to -4 mRNA
expression by Northern analysis. Growth hormone receptor and IGF-I mRNA levels
were reduced 1.7-fold (P = .003) and 9.6-fold (P = .0001) in biliary atresia
compared with levels in controls. Despite increased serum IGFBP-1 levels and
reduced IGFBP-3 levels in biliary atresia, there was no change in either IGFBP-1
or IGFBP-3 mRNA expression. In contrast, serum levels and mRNA expression of
IGFBP-2 were increased 1.6-fold (P = .003) and twofold (P = .0001), respectively,
compared with controls. Gene expression did not correlate with liver dysfunction
or body composition. Changes in growth hormone receptor and IGF-I mRNA expression
may account for the reduction in serum IGF-I found in pediatric liver disease. In
contrast, the marked alteration in circulating IGFBP levels was not accompanied
by changes in hepatic IGFBP gene expression, suggesting that posttranslational
mechanisms may be important.
PMID- 9398005
TI - Hepatic expression of the woodchuck hepatitis virus X-antigen during acute and
chronic infection and detection of a woodchuck hepatitis virus X-antigen antibody
response.
AB - The expression and localization of the woodchuck hepatitis virus X-antigen
(WHxAg) was examined and compared with other markers of a woodchuck hepatitis
virus (WHV) infection using rabbit antisera generated against recombinant WHxAg
produced in bacteria. Cellular fractionation studies showed that WHxAg was
localized to the soluble and cytoskeletal fractions of the cell when assayed by
immunoprecipitation of [35S]-met-cys labeled extracts derived from primary
cultures of acute WHV-infected hepatocytes. Immunohistochemical examination of
liver from chronic WHV-infected animals showed WHV core antigen (WHcAg) and WHxAg
expression in non-neoplastic tissue. The WHxAg was found localized to the
cytoplasm of infected cells, similar to WHcAg. WHxAg expression was diminished in
the foci of altered hepatocytes and in hepatocellular adenomas but was found in
only 1 of 11 hepatocellular carcinomas (HCC). Hepatic biopsies from woodchucks
experimentally inoculated with WHV were examined during the acute phase of
infection and during convalescence for WHcAg and WHxAg expression by
immunohistochemistry. Concurrent expression of WHcAg and WHxAg was observed
during the viremic phase of infection. The two antigens exhibited similar
localization to the cell cytoplasm, similar distribution within the liver lobule,
and similar patterns of clearance during convalescence. An immune response to
WHxAg was documented in some woodchucks following acute WHV infection. These
studies further define the woodchuck model of HBV infection and should allow for
the investigation of the role of hepadnaviral X-antigen expression in the
pathogenesis of chronic hepatitis and HCC.
PMID- 9398006
TI - Nucleotide sequence variations in the internal ribosome entry site of hepatitis C
virus-1b: no association with efficacy of interferon therapy or serum HCV-RNA
levels.
AB - The extreme 5'-proximal sequences of the hepatitis C virus (HCV) genome including
the 5'untranslated region (5'UTR) and the first 30 nucleotides of the core region
are highly conserved, and serve as an internal ribosome entry site (IRES) that
initiates the cap-independent translation of HCV polyprotein. Mutations in the
IRES sequence have been shown to cause changes in the efficiency of protein
translation in vitro. However, the significance of genetic variations in the IRES
is not fully known in clinical settings. Pretreatment sera of 25 patients with
HCV-1b infection who were treated with interferon were amplified by polymerase
chain reaction (PCR), and the IRES sequence was directly sequenced. Correlation
of interferon responses or other clinical features with IRES sequence variability
was studied. Eleven of 25 patients were sustained responders (SR) of interferon
treatment (negative serum HCV RNA and normal alanine transaminase levels for 6
months after the end of interferon treatment), and the other 14 patients were
nonresponders ([NR], defined as any patient with positive serum HCV RNA within 6
months after the end of interferon therapy). In each patient, one to four
nucleotide substitutions were found compared with the consensus sequence of HCV
1b genotype. There were no differences in the number of nucleotide substitutions
between either SR and NR (mean, 1.8 in SR, 2.1 in NR; P = .30), and no specific
variations associated with SR or NR were observed. Although NR had significantly
higher serum levels of pretreatment HCV RNA than SR (median, 16 vs. <0.5 Meq/mL;
P = .02), there was no correlation between the HCV-RNA level and the number of
nucleotide substitutions in the IRES (mean, 1.9 nucleotide substitutions in 12
patients with HCV RNA <0.5 Meq/ mL vs. 2.1 nucleotide substitutions in 13
patients with HCV RNA >0.5 Meq/mL; P = .61). Sequence variability of the IRES has
no influence on interferon efficacy or serum HCV-RNA concentrations in patients
with chronic HCV-1b infection.
PMID- 9398007
TI - A randomized, controlled trial of a 24-month course of interferon alfa 2b in
patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis
B e antigen in serum.
AB - Short-term interferon treatment of serum hepatitis B e antigen (HBeAg)-negative
carriers with serum hepatitis B virus (HBV) DNA and histological features of
chronic hepatitis B has been largely unsuccessful. In a pilot study of long-term
treatment, 42 such patients were randomly assigned to 6 million units of
interferon alfa 2b (IFN-alpha2b) three times per week for 24 consecutive months
(n = 21, 4 with cirrhosis) or to no therapy (n = 21, 3 with cirrhosis). Five
patients (24%) discontinued therapy because of treatment-related adverse
reactions. Serum levels of alanine transaminase (ALT) became persistently normal
and HBV DNA undetectable by dot-blot assay in 8 patients receiving interferon and
in 2 untreated controls (38% vs. 10%; P = .03). Hepatitis flare-ups disappeared
in 17 patients during therapy compared with 6 controls (81% vs. 29%; P < .001).
During a median period of 22 months after interferon was stopped, 2 treated
patients (10%) lost serum hepatitis B surface antigen (HBsAg) and seroconverted
to antibodies to hepatitis B surface antigen (anti-HBs). Serum ALT remained
persistently normal and HBV DNA undetectable by dot-blot assay in 6 initial
responders and 1 initial nonresponder, compared with none of the 21 untreated
controls (sustained response: 33% vs. 0; P < .001). Comparative analysis of pre-
and posttreatment liver biopsies showed that mean Knodell scores dropped in the
treated group (10.3 to 5.3; P = .01), but not in the untreated group (9.3 to 9.8;
not significant). In conclusion, a 24-month course of treatment with 6 MU IFN
alpha2b was well tolerated by most patients, led to sustained suppression of HBV
in one third, and attenuated hepatitis in 81% of patients.
PMID- 9398008
TI - Humoral immune response to the E2 protein of hepatitis G virus is associated with
long-term recovery from infection and reveals a high frequency of hepatitis G
virus exposure among healthy blood donors.
AB - The second envelope protein (E2) of the hepatitis G virus (HGV) was expressed in
Chinese hamster ovary (CHO) cells and showed a molecular weight of approximately
60 to 70 kd, with 15 to 25 kd of the size contributed by N-linked glycosylation.
An enzyme-linked immunosorbent assay (ELISA) using HGV-E2 was developed to test
for antibodies to this protein (anti-E2) in human sera. High sensitivity was
achieved by developing monoclonal antibodies (mAbs) to HGV-E2, which were used as
capture antibodies in the ELISA. Our studies revealed that 16% of healthy Spanish
blood donors were exposed to HGV, indicating that additional routes of viral
transmission besides parenteral exposure might exist. An even higher prevalence
of exposure to HGV (52%-73%) was found in several groups at risk of parenteral
exposure to infectious agents, i.e., intravenous drug users, transfusion history,
hemophiliacs, and hepatitis C virus (HCV)-positive patients. Most anti-E2
positive patients were HGV-RNA-negative and vice versa, indicating an inverse
correlation of these two viral markers. A panel of 16 posttransfusion patients
followed for up to 16 years revealed that patients who develop an anti-E2
response become HGV-RNA-negative, while patients who do not develop anti-E2 are
persistently infected. Immunity to HGV seems to be long-lasting, because
circulating antibody to E2 could still be detected 14 years after seroconversion.
Sequence comparisons showed that E2 is highly conserved among isolates collected
worldwide, indicating that immune escape variants are not common in HGV
infections. This reflects on a molecular level why HGV infections usually are
cleared spontaneously by the host. However, possible mechanisms of HGV
persistence, as found in some patients, remain to be elucidated.
PMID- 9398009
TI - Frequent detection of hepatitis A viral RNA in serum during the early
convalescent phase of acute hepatitis A.
AB - The diagnosis of type A hepatitis is performed mainly by immunoglobulin M (IgM)
anti-hepatitis A antibody assay, but it has not been established whether there is
a correlation between changes in viremia and the clinical course of type A
hepatitis. We examined hepatitis A virus (HAV) RNA in the sera from type A and
non-A, non-B, non-C acute hepatitis and analyzed the relation of HAV viremia with
alanine aminotransferase (ALT) and IgM-HA levels. Two hundred sera from 38
patients with type A acute hepatitis and 20 patients with non-A, non-B, non-C
acute hepatitis were examined for the presence of HAV RNA. HAV RNA was detected
by nested reverse transcription-polymerase chain reaction (RT-PCR) with primers
located at the 5' non-translated region of HAV. HAV RNA was detected in 35 of 38
(92%) type A hepatitis patients and in 60 of 156 (38%) serum samples. In
contrast, it was detected in none of 44 serum specimens from 20 non-A, non-B, non
C acute hepatitis patients. In type A hepatitis, the mean ALT level in HAV RNA
positive specimens was 1,481 +/- 2,042 (range, 20-10,370) IU/L and that in HAV
RNA negative specimens 186 +/- 330 (range, 8-1,698). The positivity of HAV RNA
was correlated with the level of transaminase at the time of sample collection.
The mean duration from the onset of symptoms to disappearance of HAV RNA was 18
+/- 14 days. The mean titer of IgM-HA in HAV RNA positive cases was 5.0 +/- 1.4,
in negative cases 5.7 +/- 1.1, with no statistical difference. Our results
indicate that HAV RNA in serum is detectable in the majority of type A hepatitis
cases in their early convalescent phase by nested RT-PCR.
PMID- 9398010
TI - Prediction of response during interferon alfa 2b therapy in chronic hepatitis C
patients using viral and biochemical characteristics: a comparison.
AB - Patients with chronic hepatitis C (n = 103) were treated for 24 weeks with
interferon alfa 2b and followed up for 24 weeks after cessation of therapy (week
48). When hepatitis C virus (HCV) RNA at week 48 was used to assess interferon
response, 15 (14.6%) were virological complete responders, and all have remained
HCV RNA negative for a mean of 3 years. At week 48, 3 of 15 virological complete
responders had elevated alanine transaminase (ALT) values. When serum ALT level
was used at week 48 to determine response to interferon, 20 (19.4%) were
biochemical complete responders. However, 8 of the 20 patients with normal ALT
levels were HCV RNA positive at week 48, and 7 of these individuals have had a
recurrence of elevated ALT levels within 3 years after cessation of treatment.
These findings indicate that measurement of HCV RNA was more accurate than ALT in
determining true responses to interferon therapy. Identification of nonresponders
early during the course of interferon treatment showed that an elevated ALT level
at week 12 was 92% predictive (odds ratio 3.7) but misidentified 33% (5 of 15) of
the patients who were virological complete responders at week 48. In contrast, a
positive HCV RNA at week 12 of treatment was 98% predictive (odds ratio 35.5) and
misidentified only 6.7% (1 of 15) of the virological complete responders. Thus,
positive HCV RNA at week 12 of therapy was more accurate in identifying eventual
virological nonresponders than measurement of ALT at this time. Termination of
interferon therapy in patients who were HCV RNA positive at week 12 would result
in a 27% reduction in the direct medical costs and keep patients from undergoing
unnecessary treatment. Therefore, testing for HCV RNA at week 12 to identify
nonresponders and then discontinuing their treatment is practical, cost-efficient
and beneficial both to patients and to third-party payers.
PMID- 9398011
TI - Histological and clinical outcome after liver transplantation for hepatitis C.
AB - Hepatitis frequently recurs after liver transplantation for hepatitis C. However,
the histological progression of disease, predictors of recurrence and disease
severity, and patient survival remain uncertain. Fifty-five patients with
cirrhosis caused by chronic hepatitis C underwent liver transplantation between
January 1990 and December 1993. Hepatitis C genotype was determined, and liver
biopsies were performed at frequent intervals posttransplantation. The median
follow-up time was 40.4 months. The cumulative rate of survival was no different
in liver transplant recipients for hepatitis C than in liver transplant
recipients for other chronic liver diseases (P = .62). Histological recurrent
hepatitis C developed in 33 of 50 patients assessable for disease recurrence; the
median recurrence-free survival time was 13.4 months. Histological activity and
stage were mild in most cases. Only 2 patients developed cirrhosis, and no
patient required a second transplantation for recurrent disease. Patients with
acute cellular rejection had a shorter recurrence-free survival (P = .0141). In
patients with recurrent hepatitis, rejection also was correlated with increased
histological grade 2 years after transplantation (P = .0061). Recurrence-free
survival was decreased in patients infected with genotype 1 (1a and 1b combined)
compared with genotypes 2 and 3 combined (P = .02), whereas there was no
difference between genotypes 1a and 1b (P > .80). Only patients infected with
genotype 1a or 1b developed bridging fibrosis or cirrhosis. In addition, patients
who had an early recurrence had a greater risk of progressing to bridging
fibrosis or cirrhosis (hazard ratio, 5.1; P = .0473). In our experience,
recurrent hepatitiS C after liver transplantation in most cases is mild and
survival is unaffected. Both acute cellular rejection and infection with genotype
1 are independent risk factors for reduced recurrence-free survival, and early
recurrence is associated with a higher risk of disease progression.
PMID- 9398012
TI - A case-control study on GB virus C/hepatitis G virus infection and hepatocellular
carcinoma. Brescia HCC Study.
AB - A new hepatitis-associated RNA virus of the Flaviviridae family has been
identified and named GB virus C/ hepatitis G virus (HGV). We carried out a case
control study to evaluate the association of HGV infection with hepatocellular
carcinoma (HCC). We recruited 170 patients hospitalized for HCC (143 male and 27
female, mean age 64 years) and 306 patients hospitalized for nonliver diseases
(controls) in Brescia, Italy. HGV RNA was detected by reverse transcription
polymerase chain reaction (RT-PCR) and antibodies against HGV E2 protein (anti
E2) by an immunoassay test. HGV RNA was found in 8 cases (4.7%) and 4 controls
(1.3%). The relative risk (RR) for HGV RNA positivity adjusted for demographic
variables and hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) RNA,
and alcohol was 7.3 (95% confidence interval, 1.7-30.6; P = .009). No HGV RNA
positive subject was also positive for anti-E2. Anti-E2 prevalence did not differ
significantly between cases (20%) and controls (15.3%), and no RR increase was
found by this marker. Among subjects with HGV exposure (HGV RNA plus anti-E2
positive), a greater proportion of cases (40%) than controls (14%) had
transfusion history. The possible role of HGV in HCC etiology seems modest
because the population-attributable risk is lower (4%) than those for HBsAg
(22%), HCV RNA (36%), and heavy alcohol intake (52%). This study supports the
hypothesis of an association between HGV infection and HCC, although at present
there are insufficient data on the causality of the association.
PMID- 9398013
TI - The prevalence of surface antigen variants of hepatitis B virus in Papua New
Guinea, South Africa, and Sardinia.
AB - Three assays, one based on monoclonal antibodies and the others on polyclonal
antibodies, were employed to detect hepatitis B surface antigen (HBsAg)-reactive
samples in both vaccinated and unvaccinated populations in areas of the world
where hepatitis B virus (HBV) is endemic. Any discordant sera were tested by
polymerase chain reaction (PCR) to confirm current infection, and sequence data
were obtained from the DNA coding for the major hydrophilic region (MHR) of HBsAg
of those samples positive for PCR. In all countries studied, samples that reacted
in one HBsAg assay but not another were found. In the most extreme case, about 5%
of viremic sera in Papua New Guinea were nonreactive in the monoclonal HBsAg
assay; 9 of the 13 PCR-positive samples had novel or once-described variants, or
a variant out of its usual genotype context. In South Africa, samples with
sequences of subtype ayw2 reacted poorly, particularly in the polyclonal assay.
Two had novel variants. In Sardinia, antibody to hepatitis B core antigen (anti
HBc) was analyzed as a marker of infection. A significant proportion of anti-HBc
positive, but monoclonal HBsAg-negative, vaccinees and unvaccinated persons were
found to be PCR positive, as were some individuals without any markers of
hepatitis B virus infection. Five more novel variants were found in these groups.
There are implications for the design of HBsAg assays, which may have to be
modified according to local sequence variability. Not all discordant samples were
explained by variants, indicating that assay sensitivity is fundamental to
diagnostic efficacy. Overall, this study defined 16 novel variants and 2 new
potential epitope clusters.
PMID- 9398015
TI - Surrogates, survival, and subversion.
PMID- 9398014
TI - Substrate specificity of sinusoidal bile acid and organic anion uptake systems in
rat and human liver.
AB - The Na+-dependent bile salt uptake systems Ntcp (rodents) and NTCP (human), and
the Na+-independent organic anion transporters oatpl (rat) and OATP (human)
mediate sinusoidal uptake of a variety of amphipathic organic compounds into
hepatocytes. Their properties indicate that an overall hepatic clearance of
albumin-bound compounds is mediated by a limited number of multispecific
transporters with partially overlapping substrate specificities.
PMID- 9398016
TI - Selective hepatic drug delivery: from basic concept to clinical practice.
PMID- 9398017
TI - A molecular basis for jaundice in intrahepatic and extrahepatic cholestasis.
PMID- 9398018
TI - Traffic jam for hemochromatosis mutant protein.
PMID- 9398019
TI - Lipoproteins: are they important components of host defense?
PMID- 9398020
TI - Immune complexes in hepatitis C.
PMID- 9398021
TI - Aplastic anemia and viral hepatitis: a second look.
PMID- 9398022
TI - Predicting the risk of tumor recurrence following transplantation for
hepatocellular carcinoma.
PMID- 9398023
TI - Hepatitis C: viral kinetics.
PMID- 9398024
TI - Prevention of variceal bleeding with band ligation.
PMID- 9398025
TI - Nitric oxide-inhibitory effect of aminoguanidine on renal function in rats.
AB - Inhibition of nitric oxide (NO) synthesis by structural analogues of L-arginine
reduces glomerular filtration, renal blood flow, sodium excretion, and urine
output. N(G)-nitro-L-arginine methyl ester (L-NAME) inhibits constitutive and
inducible isoforms of NO synthase, while aminoguanidine (AG) selectively inhibits
inducible isoforms of NO synthase. We assessed the NO-inhibitory activity of AG
on renal function. Rats were treated with aminoguanidine 50 mg/kg daily for 2
months, followed by L-NAME (25 mg/kg/day) for 1 week to inhibit all NO synthase
isoforms. After treatment with L-NAME, we performed baseline renal function
measurements, then infused L-arginine (2.5 mg/100 g BW x min) to reverse NO
inhibition and assessed whether AG exerted NO-inhibitory activity independently
of L-NAME. Prior to L-arginine infusion, AG-treated rats did not differ from
controls with respect to body weight, kidney weight, systolic blood pressure,
urine flow rate, urinary protein or albumin excretion, or urinary excretion of NO
metabolites. After L-arginine infusion, all animals showed a 10-15% decrease in
mean arterial blood pressure. L-Arginine-induced increases in urine flow, inulin
clearance, PAH clearance, sodium excretion, and NO metabolite excretion were
blunted in aminoguanidine-treated animals. To assess long-term effects of
aminoguanidine, rats were treated for 12 months. Urinary excretion of NO
metabolites was lower than controls. Inulin clearance was higher than controls.
Aminoguanidine blunts the effect of L-ariginine on renal hemodynamics
independently of the nitric oxide synthase inhibitor, L-NAME. However, the use of
aminoguanidine for 12 months in rats did not adversely affect renal function.
PMID- 9398026
TI - Glomerular basement membrane polyanionic sites and nitric oxide in genetically
salt-sensitive and resistant hypertensive rats.
AB - Cationic colloid gold, a polycationic histochemical probe, was used to analyze
the distribution of glomerular basement membrane (GBM) polyanions, including
heparan sulfate protoglycan in genetic salt-sensitive (SBH/Y) and resistant
(SBN/Y) hypertensive rats, with or without high dietary salt intake. GBM
morphology, renal function and nitric oxide, as measured by plasma and urine
nitrite (NO2) and nitrate (NO3) were also determined. In the salt-sensitive rats
the high-salt dietary intake resulted in severe hypertension, proteinuria and
decreased glomerular filtration rate. After 1 month of high-salt intake, the
average width of the GBM of salt-sensitive rats was higher by 27% than that of
salt-resistant rats. The number of GBM anionic sites (lamina rata externa and
interna) was much lower in both salt-sensitive and salt-resistant groups after 1
month of salt loading, 8.04+/-0.36 and 7.8+/-0.25 counts/cm, respectively,
compared to the respective values of non-salt-loaded animals, 20.58+/-1.08
counts/cm in the SBH/Y (p < 0.001) and 21+/-1.86 counts/cm in the SBN/Y (p <
0.001). A decreased nitric oxide production was found in the salt-sensitive rats
before and after salt loading compared with the salt-resistant group. No
correlation was found between the nitric oxide changes and the GBM modifications.
It is concluded that high-salt intake may be deleterious to the permselectivity
of the GBM. It is suggested that salt restriction in hypertension may have a
beneficial effect in preventing GBM permselectivity changes and proteinuria.
PMID- 9398027
TI - Acute effects of angiotensin II receptor antagonist on autoregulation of zonal
glomerular filtration rate in renovascular hypertensive rats.
AB - This study was designed to assess the renal capability to autoregulate total
blood flow, glomerular filtration rate (GFR) and local GFR in outer, middle and
inner cortical layers (OC, MC, IC) in the two-kidney, one-clip (2K-1C)
renovascular hypertensive rat, with or without acute infusion of the angiotensin
II receptor antagonist losartan (5 mg/kg, i.v.). Age-matched, sham-operated
Wistar rats were used as controls. The hemodynamic study in all animals was
performed 4 weeks after clipping. The clipping increased blood pressure
significantly, whereas losartan reduced the renal arterial pressure (RAP) from
165+/-8 to 125+/-6 mm Hg (p < 0.01) in 2K-1C hypertensive rats and reduced the
RAP from 107+/-2 to 101+/-1 mm Hg (p < 0.05) in normotensive animals. Renal blood
flow (RBF), total and local GFR were decreased in the nonclipped kidney of 2K-1C
hypertensive rats compared with sham-operated rats, but losartan significantly
increased the RBF and GFR. RBF was well maintained in response to reduction in
RAP in the nonclipped kidneys with and without losartan treatment. The capability
of total GFR autoregulation was impaired in untreated 2K-1C hypertensive rats and
losartan-treated sham-operated rats, whereas losartan completely abolished GFR
autoregulation in the nonclipped kidney of 2K-1C hypertensive rats. Losartan
impaired autoregulation of zonal GFR to the same extent in all three cortical
layers of sham-operated rats, whereas in the nonclipped kidney of 2K-1C
hypertensive rats losartan had a more pronounced effect on the superficial GFR
autoregulation than in middle and inner cortex, indicating that angiotensin II
plays a major role in regulating the GFR response to the acute changes of renal
arterial pressure.
PMID- 9398029
TI - Microinjection studies on the effect of furosemide on the rat nephron.
AB - The tubular site of furosemide (F) action was studied by the technique of
diuretic microinjection (MIJ) into proximal tubules of the rat nephron. F was
injected into the last proximal superficial loop of 51 proximal tubules, at the
concentration of 3 x 10(-4) mol/l in an infusate that contained 14C-inulin.
Collections were performed at the early distal tubule before and after MIJ.
Single nephron filtration rate (SNGFR) remained unchanged, while the percent of
filtered volume reabsorbed up to the site of collection was 85+/-2 before, 79+/
2% after MIJ, p < 0.005. The calculated concentration of F in the collected
distal tubular fluid during the post-MIJ measurements averaged 3 x 10(-5) mol/l.
This experiment was repeated by injecting F into the early proximal convolutions
of 43 nephrons, while the collections were performed at the last proximal
segments. In these studies of proximal volume absorption, SNGFR was 34+/-3
before, 35+/-4 nl/min after F (p > 0.6). The respective percent reabsorptions
were 70+/-3 and 73+/-3% (p +/- 0.3). In order to determine whether the technique
per se was suitable to detect changes in reabsorption, the proximal MIJ study was
repeated by using the carbonic anhydrase inhibitor dichlorphenamide 3 x 10(-5)
mol/l in the microinjectate: while SNGFR remained unchanged, percent reabsorption
fell from 63+/-5 to 45+/-7% during injection of the diuretic, p < 0.03. We
conclude that the technique is adequate to examine the effects of drugs, and that
F does not reduce proximal volume absorption at concentrations of 3 x 10(-5)
mol/l. The loop diuretic decreases distal volume absorption by abolishing the
osmotic gradient between blood and tubular fluid along the early distal
convoluted tubule.
PMID- 9398028
TI - Effect of intratubular application of angiotensin 1-7 on nephron function.
AB - Cleavage of the C-terminal tripeptide of angiotensin I (Ang I) by neutral
endopeptidase 24.11 releases angiotensin 1-7 (Ang 1-7). Because Ang I and neutral
endopeptidase 24.11 are present in proximal tubular fluid and brush border,
respectively, Ang 1-7 could be released into proximal tubular fluid to affect
nephron function. Therefore, we studied the effect of intratubular Ang 1-7 (10(
12) to 10(-8) M) on nephron function employing in vivo renal micropuncture in
inactin-anesthetized Munich-Wistar-Fromter rats. We observed that: (i)
Intratubular application of Ang 1-7 for 3, 15, or 30 min did not affect
reabsorption in the microperfused proximal convoluted tubule determined as net
fluid reabsorption. (ii) During perfusion of Henle's loop for 15 min with
artificial tubular fluid (time control), we observed a decline in fluid,
potassium and sodium reabsorption by 20, 18 and 5%, respectively. A similar
decline in reabsorption was seen with intratubular application of Ang 1-7 in a
concentration of 10(-12) or 10(-10) M. In contrast, intratubular application of
Ang 1-7 in a concentration of 10(-8) M increased fluid, potassium and sodium
reabsorption in that nephron segment by 11, 9 and 3%, respectively. The latter
response was completely abolished by AT1 angiotensin II receptor antagonist
losartan (10[-6] M). (iii) Intratubular application of Ang 1-7 did not affect net
sodium, potassium, or fluid reabsorption in the distal tubule. (iv) TGF response
assessed by measuring proximal tubular stop-flow pressure or single nephron
filtration rate during orthograde open-loop perfusion of Henle's loop was not
significantly altered by intratubular application of Ang 1-7. These findings show
that intratubular application of Ang 1-7 in concentrations which possibly cover
the physiological range does not significantly alter (i) tubular reabsorption in
proximal convoluted or distal tubule, or (ii) TGF response. Intratubular Ang 1-7
at a concentration of 10(-8) M appears to increase reabsorption in Henle's loop
by an AT1 angiotensin II receptor-mediated mechanism, the physiological relevance
of which remains to be established.
PMID- 9398030
TI - Urinary calcium excretion and renal calbindin-D28k.
AB - The present investigation examined the possible influence of urinary calcium
excretion on the concentration of renal calbindin-D28k. Thiazide diuretics
stimulate calcium transport across the epithelial cells of the distal tubule,
which express calbindin-D28k in high concentrations. Calbindin-D28k is assumed to
facilitate transcellular Ca diffusion. Reduced urine calcium excretion and
increased urine output were induced in Wistar rats by infusion of bendroflume
thiazide 1 mg/kg/day. The two control groups had infusions of either furosemide
20 mg/kg/day or vehicle, n = 8 in each group. Urinary Ca excretion was reduced to
10% in the thiazide group and increased by 50% in the furosemide group. Renal
concentrations of calbindin-D28 showed no difference between vehicle, thiazide-
and furosemide-treated rats. No differences in plasma concentrations of calcium,
magnesium, phosphorus, urea, PTH, calcitonin and 1,25-(OH)2D were found between
the groups. The present study describes that urine calcium excretion selectively
can be manipulated without accompanying changes in renal calbindin-D28k
concentrations. The data, therefore, suggest that urinary calcium excretion is
not a significant determinator of cytosolic concentrations of renal calbindin
D28k.
PMID- 9398031
TI - Alterations of the renal handling of H+ in diabetic rats.
AB - Renal acid excretion and proximal and distal nephron acidification were evaluated
20 days after induction of diabetes, in rats, by intraperitoneal injection of
streptozotocin (45 mg/kg). Titratable acidity in urine was measured by
microtitration and ammonium excretion (NH4+) by spectrophotometry. Proximal
tubular acidification was evaluated by the kinetics of reabsorption of perfused
HCO3-. Distal nephron acidification was evaluated by measuring urine - blood pCO2
differences under alkaline overload. The net acid excretion (titratable acidity +
NH4+ - HCO3-) was higher (p < 0.001) in diabetic rats (9.82+/-0.65
micromol/min/kg, n = 26) than in the control group (6.34+/-0.14, n = 24).
Proximal HCO3- reabsorption was also higher (p < 0.001) in diabetic rats (8.38+/
0.11 nmol/cm2/s, n = 12) than in the control group (2.30+/-0.10, n = 22);
however, evaluation of distal nephron H+ secretion by urine - blood pCO2
methodology was similar in both groups. We concluded that in rats with induced
diabetes mellitus there is an increased rate of proximal HCO3- reabsorption,
possibly effected by a higher density of Na+/H+ antiporter in the luminal
membrane of the proximal tubule and by an increased proton-motive force of the H+
secretory mechanism. The higher rates of H+ secretion generate lower stationary
proximal luminal pH and probably maintain the blood pH within the physiological
range.
PMID- 9398032
TI - Inhibition and restimulation by insulin of cellular autophagy in distal tubular
cells of the kidney in early diabetic rats.
AB - Cellular autophagy in the cells of distal tubular segments (DT cells) of the
kidney cortex in streptozotocin-diabetic rats was evaluated by quantitative
electron microscopy. Five days after streptozotocin administration, volume and
numerical densities of autophagic vacuoles (AVs) in DT cells were reduced by 56
and 57%, respectively. The correction of the diabetic state by insulin injection
reversed the inhibition of cellular autophagy. Volume and numerical densities of
AVs increased by 97 and 53%, respectively. Endogenous insulin replacement by
islet transplantation showed the same effect on cellular autophagy. Volume and
numerical densities of AVs increased by 82 and 34%, respectively, as compared
with sham-operated diabetic animals. The data show that, during diabetic kidney
hypertrophy, the cellular autophagy is inhibited in DT cells to the same extent
as in proximal tubular cells, suggesting that DT cells contribute in a balanced
manner to hypertrophic growth of the kidney cortex. Similarly, DT cells are
involved in the catabolic reaction, i.e., stimulation of autophagy, after
metabolic correction of the diabetic state by insulin.
PMID- 9398033
TI - Advantages of a two-chamber culture system to test drug nephrotoxicity: the
example of cephaloridine.
AB - Rabbit renal proximal tubular cells, cultured to confluency on a permeable
collagen film in a two-chamber system, were exposed for 72 h to various
concentrations of the nephrotoxic antibiotic, cephaloridine (CLD). A decrease in
cellular proteins, leakage of lactate dehydrogenase and morphological changes
appeared at CLD concentrations of 0.1, 1.0, and 0.5 mg/ml, respectively. The
permeability of the monolayer to Lucifer yellow (LY), a dye that does not cross
cell membranes, was increased by 1 or 2 mg/ml but not by lower concentrations of
CLD. The large basolateral/apical glucose concentration gradient established by
the cells was decreased by CLD. However, the fact that, at the CLD concentration
of 1 mg/ml, LY totally equilibrated by diffusion across the monolayer, whereas
the injured monolayer was still able to maintain a detectable glucose gradient,
shows that damage caused by CLD to the diffusion barrier prevails over that
affecting glucose uptake. Consistent with the data in the literature concerning
the mechanism of CLD accumulation in renal cells, our results show that CLD was
more toxic when it was added at the basolateral than at the apical side of the
cultured cells. These results illustrate the advantages of using a two-chamber
system of cell culture in nephrotoxicity studies.
PMID- 9398034
TI - Renal changes induced by envenomation with Africanized bee venom in female Wistar
rats.
AB - Human envenomation caused by bee or wasp stings has been reported to cause acute
renal failure (ARF), usually due to acute tubular necrosis (ATN), as a frequent
complication. The pathogenetic mechanisms of ATN occurring in these accidents are
still unclear. In the present study, female Wistar rats weighing 150-200 g were
injected intravenously with Africanized bee venom at a dose of 0.4 microl/100 g
body weight and used in functional and light microscopy studies. The animals were
divided into two groups: the early group was studied 3-8 h after inoculation, and
the late group was studied 24-30 h thereafter. The animals showed ARF
characterized by reduction of glomerular filtration rate with increasing levels
of plasma creatinine. They also showed increased fractional sodium and potassium
excretions, suggesting changes in the proximal portion of the nephron. The water
transport through collecting tubules was reduced, with consequent diuresis,
indicating functional changes in the distal portion of the nephron. These
functional changes were more marked in the early group, with recovery tending to
occur after 24 h. Albuminuria was also observed in this group. Light microscopy
showed ATN mainly in cortex and outer medulla, with isolated necrosis in cells or
small groups of cells and cast formation in the distal and collecting tubules.
After 24 h frequent mitotic figures were found in the tubular epithelium. The
observed ARF was due to ATN which in turn was probably caused by multiple
effects, mainly hemodynamic changes secondary to cardiotoxicity and systemic
vasodilation caused by the venom, myohemoglobinuria, and the direct action of the
venom on tubular cells.
PMID- 9398035
TI - HPV detection in children prior to sexual debut.
AB - Knowledge of the epidemiology of infection with human papillomavirus (HPV) in
childhood is important, since HPV infection early in life could represent a risk
factor for later development of anogenital cancer. A random sample of Danish
children aged 0 to 17 years was tested for the presence of HPV in the anal region
and the oral cavity by the polymerase chain reaction using a consensus HPV L1
primer. Only 4 of 249 anal beta-globin-positive samples and one of 392 oral beta
globin-positive samples were HPV-positive. All HPV-positive samples were of
unknown types. We conclude that the prevalence of anogenital HPV infection in
childhood is very low indeed and that the oral cavity does not seem to act as a
reservoir for HPV infection in childhood. This indicates that anogenital types of
HPV are not transmitted to any measureable degree by non-sexual routes and
further supports the notion that HPV infection takes place mainly later in life.
PMID- 9398036
TI - Cancer incidence in female smokers: a 26-year follow-up.
AB - A random sample of 26,000 Swedish women who were asked about their smoking habits
in the early 1960s have now been followed for 26 years with respect to cancer
incidence. Most findings regarding tobacco smoking and cancer from studies of men
were confirmed also among the women. Elevated relative risk for current smokers
compared with women who never smoked regularly were seen for cancers of the lung,
upper aerodigestive sites, pancreas, bladder, cervix and all cancers combined, as
well as a notably high relative risk for cancers of organs of the urinary tract
other than kidney and bladder. Relative risk increased with dose, measured as
grams of tobacco smoked per day, for cancers of the upper aerodigestive sites,
lung, cervix, bladder, organs of the urinary tract other than kidney and bladder
and all cancers combined. For cancers of the lung, bladder and cervix, there was
an inverse relationship with age when starting to smoke tobacco. The reported
inverse relationship between smoking and endometrial cancer could not be
corroborated, nor was there any significant relationship between smoking and
colorectal or breast cancer.
PMID- 9398037
TI - Incidence of non-melanocytic skin cancer in Geraldton, Western Australia.
AB - To measure the rate at which non-melanocytic skin cancers develop, we conducted a
population-based, longitudinal study in Geraldton, Western Australia. Subjects
were residents of Geraldton, Western Australia, who were between 40 and 64 years
of age and registered on the electoral roll in 1987. In 1987 and again in 1992,
dermatologists examined participants for skin cancers. They examined all skin
areas, apart from those covered by underwear or hair. Subjects were asked about
skin cancers that they had had treated between the 2 surveys. When all skin
cancers were counted, the incidence rates of basal cell carcinoma were 3,379 per
100,000 person-years in women and 7,067 per 100,000 in men; those of squamous
cell carcinoma were 501 per 100,000 in women and 775 per 100,000 in men. Sixteen
percent of men and 14% of women developed at least one basal cell carcinoma; 2.8%
of men and 2.2% of women had at least one squamous cell carcinoma. Most incident
skin cancers were diagnosed at the second examination. More than half of the
subjects who had a skin cancer at the first examination developed another.
Squamous cell carcinomas occurred almost exclusively on parts of the body that
are usually exposed. Basal cell carcinomas were common on the head, neck and
trunk but not on the forearms and backs of hands. A quarter of people with a skin
cancer on an exposed site also had one on the trunk. Our results show that skin
cancer is extremely common in this population and frequently undiagnosed.
Multiple skin cancers occur commonly, and skin cancers on exposed sites often are
associated with skin cancers on less exposed sites.
PMID- 9398038
TI - Dietary fat intake and risk of prostate cancer: a prospective study of 25,708
Norwegian men.
AB - The relationship between incidence of prostate cancer and intake of dietary fat
and foods rich in fat was studied in 25,708 men aged 16-56 years attending a
Norwegian health screening in 1977-1983. Linkage to the Cancer Registry of Norway
and the Central Bureau of Statistics of Norway ensured a complete follow-up until
December 31, 1992. Diet was recorded on a semi-quantitative food-frequency
questionnaire at the time of screening, and 72 cases of prostate cancer were
identified during follow-up. At the end of follow-up, mean age of the total study
sample was 56 years (range 19-68), while mean age at diagnosis of prostate cancer
was 60 years (range 47-67). No association was found between energy-adjusted
intake of total fat, saturated fat, mono-unsaturated fat or poly-unsaturated fat
and the incidence of prostate cancer. Significant positive associations were
found for body mass index (BMI) and consumption of hamburgers/meatballs, while no
association was found with consumption of frankfurters/sausages and a significant
negative association with the weekly number of main meals with meat. A
significantly increased risk of prostate cancer was associated with skim milk as
compared to whole milk. Milk preference (skim vs. whole) was associated
significantly positively with BMI. Our study of a relatively young cohort does
not confirm previous case-control and cohort studies suggesting that dietary fat,
especially from animal sources, is associated positively with risk of prostate
cancer.
PMID- 9398039
TI - p16INK4, pRB, p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in
thymoma and thymic carcinoma.
AB - There have been few reports on genetic alterations in thymomas. To investigate
the expression of p16INK4A, RB, p53 and cyclin D1 in thymomas, we first examined
36 thymomas (non-invasive type, 16 cases; invasive type, 20 cases) and 3 thymic
carcinomas, using immunohistochemistry. Abnormal expression of p16INK4A, RB, p53
and cyclin D1 was observed in 18, 8, 10 and 7 cases, respectively. Only a
subgroup of invasive thymomas and thymic carcinomas showed an inverse correlation
between p16INK4A and RB expression. Subsequently, we examined the 36 thymomas and
4 thymic carcinomas for mutations in p53 and CDKN2 genes, using PCR-SSCP and
direct-sequencing analyses. No mutation of these genes was detected in the
thymomas and thymic carcinomas examined. A polymorphism in the 3' untranslated
region of exon 3 of CDKN2 was detected in 5 cases of thymoma. We searched for
hypermethylation in the promoter region of CDKN2, observing it in 4 thymomas and
1 thymic carcinoma. Our data suggest that, unlike other more common cancers,
alteration of the p53 gene may not play a significant role in the tumorigenesis
of thymoma. However, inactivation of p16INK4A and RB may play a role in the
progression of thymoma and thymic carcinoma.
PMID- 9398040
TI - Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public
health burden. AIDS/Cancer Study Group.
AB - We describe the anatomic and histologic presentation and prognosis of non
Hodgkin's lymphoma (NHL) among people with AIDS (PWA) and determine their
contribution to the NHL burden. We linked AIDS and cancer registries in selected
areas of the United States and compared NHL sites and histologies in PWA and non
PWA, after adjusting for age, sex and ethnicity. Among 51,033 PWA, we found 2,156
cases of NHL (4.3%). Half of NHL cases occurring post-AIDS were not reported to
AIDS registries. NHL was part of an AIDS-defining condition for 3.2% of all PWA;
the relative risk of NHL with 3.5 years of another AIDS diagnosis was 165-fold
compared to non-PWA within the cancer surveillance system. Of NHLs, 39% were high
grade (vs. 12% among non-PWA), 60% were nodal (vs. 74% among non-PWA) and 15% had
brain primaries (vs. 1% among non-PWA). Excluding brain sites, extranodal sites
were still 20% more common than expected. Relative risk was elevated for all
histologic types, with the risk ranging from 652-fold for high-grade diffuse
immunoblastic tumors and 261-fold for Burkitt's lymphomas to 113 for intermediate
grade lymphoma to 14-fold for low-grade lymphoma. Survival among PWA with NHL was
poor, and tumor grade had little impact. In high-risk AIDS areas, AIDS-related
NHLs constitute a major share of the NHL burden. We conclude that NHL risk is
considerably under-estimated in AIDS registry data. The major differences between
PWA and non-PWA were the high frequency of brain lymphoma and the increase in
high-grade lymphomas in PWA. However, the grade of NHL did not influence the
prognosis among PWA with lymphoma. The increasing risk of NHL in PWA has
contributed substantially to the general increase in NHL rates in the United
States since 1981.
PMID- 9398041
TI - Analysis of E2 amino acid variants of human papillomavirus types 16 and 18 and
their associations with lesion grade and HLA DR/DQ type.
AB - Human papillomavirus (HPV) 16 and HPV 18 E2 amino acid variants and host HLA
DR/DQ haplotypes have been identified by direct nucleic acid sequencing from
cervical scrapes. HPV16 E2 variants co-segregate with a nucleotide variant at
nt350 (in E6), which previously has been associated with persistent infections.
Both HPV16 and HPV18 E2 variants occur relatively more frequently in individuals
with HLA DR/DQ haplotypes 0401/0301 and 1101/0301 but are not related to lesion
grade.
PMID- 9398042
TI - Reduced expression of the CXC chemokine hIRH/SDF-1alpha mRNA in hepatoma and
digestive tract cancer.
AB - We isolated human intercrine reduced in hepatomas (hIRH) as a mRNA whose
expression was reduced in differential displays from human hepatocellular
carcinoma. hIRH is equivalent to the alpha-chemokine SDF-1alpha/PBSF. We have
previously demonstrated on Northern blot analysis that although hIRH mRNA
expression is common in human normal tissues, it is absent from pre-malignant
colonic adenomas and from 27 human malignant cell lines. However, there are no
reports on the mRNA status of hIRH in other human cancers. The present study was
designed to investigate semi-quantitatively the expression of hIRH/SDF-1alpha
mRNA in hepatocellular carcinoma and digestive tract cancers by reverse
transcription-polymerase chain reaction (RT-PCR). The expression of hIRH/SDF
1alpha in the majority of cancer tissues analyzed was markedly reduced compared
with that in adjacent non-cancer tissue. RT-PCR was more sensitive than Northern
blots in the detection of hIRH mRNA. The average (mean +/- SE) tumor/normal (T/N)
ratio determined by RT-PCR was 0.40 +/- 0.07 in 10 pairs of hepatoma, 0.38 +/-
0.09 in 14 pairs of colon cancers, 0.43 +/- 0.07 in 10 pairs of esophageal
cancers and 0.70 +/- 0.09 in 26 pairs of gastric cancers. As a control, the mean
G3PDH T/N ratio was 1.16 +/- 0.06. The distribution of T/N ratios was
significantly different between gastric cancer and the other cancers, but there
was no correlation between hIRH/SDF-1alpha expression and clinicopathological
characteristics in gastric cancer. Our findings demonstrate that hIRH/SDF-1alpha
expression is reduced in the majority of gastrointestinal tumors.
PMID- 9398043
TI - Increased presence of CD34+ cells in the peripheral blood of head and neck cancer
patients and their differentiation into dendritic cells.
AB - Patients with head and neck squamous cell carcinoma (HNSCC) have profound immune
deficiencies. In 65% of these patients, there is an increased intra-tumoral
presence of immune-suppressive CD34+ progenitor cells. The goal of the present
study was to determine whether CD34+ cell levels were also increased in the
peripheral blood of HNSCC patients and if these immune-suppressive cells could be
differentiated into dendritic cells. Our results showed that CD34+ cell levels
are increased in the peripheral blood of HNSCC patients. To assess if these CD34+
cells could differentiate into dendritic cells, they were isolated from the blood
of HNSCC patients and cultured for 12 days with various cytokine combinations.
Culturing CD34+ cells with stem cell factor (c-kit ligand) plus granulocyte
macrophage colony-stimulating factor resulted in the appearance of a significant
proportion of cells expressing phenotypic markers characteristic of dendritic
cells. Also, including tumor necrosis factor-alpha yielded a significant
proportion of cells resembling the bipotential precursor cells for dendritic
cells and monocytes (CD14+CD1a+), in addition to the dendritic-like cells. When
the differentiation inducer 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] was added
along with the cytokine combinations, the yield of cells having characteristics
of dendritic cells was further increased. Cells that were derived from CD34+ cell
cultures containing 1,25(OH)2D3 had a more potent capacity to present the recall
antigen tetanus toxoid to autologous peripheral blood leukocytes and to stimulate
a mixed leukocyte response compared to cultures to which 1,25(OH)2D3 had not been
added. Our results show that CD34+ cells, whose frequency is increased in HNSCC
patients, can be differentiated into cells that phenotypically and functionally
resemble dendritic cells and that 1,25(OH)2D3 accentuates this differentiation.
PMID- 9398044
TI - Dietary fats and colon cancer: assessment of risk associated with specific fatty
acids.
AB - There are many biological mechanisms whereby dietary fat and specific dietary
fatty acids may alter risk of colon cancer in addition to their contribution to
total energy intake. To evaluate these potential associations, we used detailed
dietary intake data collected in a population-based study of 1,993 incident colon
cancer cases and 2,410 controls conducted in 3 areas of the United States. The
most commonly consumed fatty acid in the study population was oleic acid. One
third of dietary fats consumed came from additions to other foods at the table or
from the preparation of other foods. After adjusting for total energy intake,
physical activity and body size, neither total dietary fat nor specific fatty
acids was associated with risk of colon cancer. However, among older women, fats
from food preparation were associated with increased risk of colon cancer (OR
1.84, 95% CI 1.20-2.80), while fats from foods themselves or from additions to
other foods were not. While dietary fats were not associated with colon cancer
risk in the total population, subgroups of the population appeared to be at
slightly greater risk if they consumed a high-fat diet. Women who consumed a diet
high in mono-unsaturated fatty acids (MFAs) and poly-unsaturated fatty acids
(PFAs) and who had a family history of colorectal cancer were at greater risk of
colon cancer than those with similar intakes but without a family history of
colorectal cancer. Similar associations with family history were noted among men
diagnosed at younger ages for MFA, linolenic acid and 20-carbon PFA.
PMID- 9398045
TI - Phenotypic analysis of ovarian carcinoma: polypeptide expression in benign,
borderline and malignant tumors.
AB - Studies of multiple markers in tumors are required for adequate biological
characterization. We have characterized the expression of multiple proteins in
human ovarian tumors using the technique of 2-dimensional gel electrophoresis (2
DE/PDQUEST). Tumor cells were prepared from the tissue of 22 ovarian tumors.
Large variations were observed between tumors in the expression of various
polypeptides, indicating heterogeneity in gene expression. An increase in the
spot density of 2 cell-cycle-related proteins, PCNA and OP18/stathmin, was
observed in carcinomas. Borderline tumors expressed low levels of these proteins.
Significant increases in the levels of nm23, GST-pi, elongation factor 2 and
triose phosphate isomerase were recorded in ovarian carcinomas. Furthermore,
decreases in the levels of tropomyosin-2 and lamin C were observed in malignant
as compared with benign tumors. The pattern of expression of 9 protein markers
was examined in individual tumors. All malignant tumors showed simultaneous
alterations in the expression of 5 or more of these proteins, whereas no benign
tumor showed alterations in the expression of more than 3 polypeptides.
Borderline tumors showed alterations in 0 to 6 markers. We conclude that the
simultaneous analysis of multiple polypeptides, which can be achieved by 2-DE, is
useful for characterization of gene expression and diagnostic studies in ovarian
tumors.
PMID- 9398046
TI - Gastric cancer, gastritis and plasma vitamin C: results from an international
correlation and cross-sectional study. The Eurogast Study Group.
AB - Low intake of foods rich in vitamin C is associated with an increased risk of
gastric cancer, and geographic variation in average vitamin C intake, therefore,
could explain some of the wide international variation in gastric cancer rates.
This multicentre study investigated the relationships between plasma levels of
vitamin C, as an indicator of vitamin C intake, and gastric cancer rates, markers
of gastritis and other socio-demographic variables. Fasting plasma samples from
about 1,400 individuals from 9 centres in 7 countries worldwide were assayed for
total vitamin C using a fluorometric assay. There was no association between
average plasma vitamin C levels and either gastric cancer mortality or incidence
rates in the populations studied. Therefore, variation in fasting plasma vitamin
C levels, as an indicator of consumption of vitamin C, does not appear to explain
any of the wide geographic variation in gastric cancer rates. Furthermore, there
was no association between plasma vitamin C levels and Helicobacter pylori
infection, low serum levels of pepsinogen A (as a marker of severe chronic
atrophic gastritis) or the presence of DNA adducts in blood leukocyte DNA.
Multivariate models showed that fasting plasma vitamin C levels were associated
positively with female sex, higher levels of education, never having smoked and
increasing height and negatively with number of cigarettes smoked per day and
increasing weight. This suggests not only that gender and tobacco smoking, in
particular, are important predictors of plasma vitamin C levels but also that
their effects are consistent throughout the developed world.
PMID- 9398047
TI - Investigation of mammary epithelial cell-bone marrow stroma interactions using
primary human cell culture as a model of metastasis.
AB - A model has been established using primary human cell culture to study the cell
biology of breast cancer metastasis to bone marrow. Mammary epithelia were
obtained in single cell suspension from tumour (macroscopically involved), benign
(macroscopically uninvolved) and normal (reduction mammoplasty) breast tissue as
well as from locally involved lymph nodes. Stromal layers were generated from
long-term cultures of human bone marrow or from mammary fibroblasts derived from
normal or malignant tissue. The interaction between epithelia and stroma has been
studied in terms of adhesion of the epithelia to the stroma and their subsequent
growth in co-culture. Our results show that when assayed up to 9 hr after
plating, epithelial cells from malignant tissue (14 primary tumours and 9
metastases in lymph nodes) displayed a significant preference for adhesion to
bone marrow stroma compared with mammary fibroblasts. In contrast, epithelial
cells from 4 normal and 2 of 4 benign samples showed no significant preferential
adherence. Subsequent co-culture of mammary epithelia with each of the 3 stromal
layers revealed that under serum-free, in vitro conditions, bone marrow stromal
layers did not provide an advantageous environment for colony growth, in contrast
to their ability to provide a preferential substratum for adhesion.
PMID- 9398048
TI - Cell-transforming activity and genotoxicity of phenolphthalein in cultured Syrian
hamster embryo cells.
AB - Phenolphthalein is a cathartic agent widely used in non-prescription laxatives.
For the simultaneous assessment of in vitro carcinogenicity and mutagenicity of
phenolphthalein, the ability of this chemical to induce cell transformation and
genetic effects was examined using the Syrian hamster embryo (SHE) cell model.
Cell growth was reduced by treatment with phenolphthalein at 10-40 microM in a
dose-related manner. Treatment with phenolphthalein for 48 hr induced a dose
dependent increase in morphological transformation of SHE cells. Over the dose
range that resulted in cell transformation ( 10-40 microM), treatment of SHE
cells with phenolphthalein induced gene mutations at the hprt locus but not at
the Na+/K+ ATPase locus. A statistically significant level of chromosomal
aberrations was elicited in SHE cells treated with phenolphthalein at the highest
dose (40 microM). Meanwhile, neither numerical chromosomal changes nor DNA adduct
formation, analyzed by the nuclease P1 enhancement version of 32P-post-labeling,
were induced by treatment with phenolphthalein at any concentrations examined. We
thus report cell-transforming activity and mutagenicity of phenolphthalein
assessed with the same mammalian cells in culture. Our results provide evidence
that phenolphthalein has cell-transforming and genotoxic activity in cultured
mammalian cells. The mutagenic and clastogenic activities of phenolphthalein
could be a causal mechanism for carcinogenicity in rodents.
PMID- 9398049
TI - Modulation of p53 expression in cultured colonic adenoma cell lines by the
naturally occurring lumenal factors butyrate and deoxycholate.
AB - The high incidence of colorectal cancer in Western society is believed to be
strongly related to diet. Mutation of the p53 gene is a late event in colorectal
carcinogenesis, and thus, the majority of pre-malignant adenomas express wild
type p53. As loss of p53 protein function is an important step in colorectal
carcinogenesis, we investigated whether naturally occurring lumenal factors can
modulate the expression of p53 in non-tumorigenic human colonic adenoma cell
lines. Levels of p53 protein and mRNA were measured in adherent cells which had
been incubated with growth-inhibitory concentrations of sodium butyrate (a by
product of dietary fibre fermentation) or sodium deoxycholate (a bile acid) for
up to 48 hr. We report that both butyrate and deoxycholate can down-regulate the
expression of wild-type and mutant p53. In contrast, incubation for 48 hr with
the endogenous inhibitory growth factor TGFbeta1 did not alter p53 protein
expression. Thus, in addition to cellular mechanisms which regulate p53 function,
such as post-translational stabilisation, nuclear exclusion, negative feedback
inhibition of p53 mRNA translation or binding of p53 by cellular proteins, p53
protein levels also may be regulated by changes in the level of p53 gene
transcription. Furthermore, we show that lumenal factors are able to affect
directly the expression of p53 protein in colonic epithelial cells.
PMID- 9398050
TI - Topoisomerase-I inhibitors for human malignant glioma: differential modulation of
p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin
and beta-lapachone.
AB - Beta-lapachone and camptothecin are structurally unrelated agents thought to
inhibit topoisomerase-I activity through distinct mechanisms. We find that beta
lapachone is much more potent than camptothecin in inducing acute cytotoxic
effects on human malignant glioma cells. Acute cytotoxicity induced by both drugs
is apoptotic by electron microscopy, but not blocked by inhibitors of RNA or
protein synthesis and not associated with changes in the expression of bcl-2,
bax, p53, p21 or GADD45 proteins. In contrast, prolonged exposure of glioma cells
to both drugs for 72 hr results in growth inhibition and apoptosis, with EC50
values around 1 microM. None of 7 glioma cell lines tested were resistant to
either drug. LN-229 cells which have partial p53-wild-type activity show enhanced
expression of p53, p21 and bax protein, whereas bcl-2 levels decrease, after
exposure to camptothecin. In contrast, beta-lapachone increases bax protein
expression in the absence of p53 activation. T98G cells are mutant for p53. In
these cells, p53 levels do not change and p21 is not induced. bax accumulation in
T98G cells is induced by both drugs, with bcl-2 levels unaltered. Surprisingly,
ectopic expression of murine bcl-2 fails to abrogate the toxicity of either drug.
Camptothecin, but not beta-lapachone, sensitizes human malignant glioma cells to
apoptosis induced by the cytotoxic cytokines, tumor necrosis factor-alpha and
CD95 ligand. Thus, both drugs have potent anti-glioma activity that may be
mediated by enhanced bax expression but is not inhibited by ectopic bcl-2
expression. Camptothecin-like agents are particularly promising for
immunochemotherapy of malignant glioma using cytotoxic drugs and CD95 ligand.
PMID- 9398051
TI - Abundance of BRCA1 transcripts in human cancer and lymphoblastoid cell lines
carrying BRCA1 germ-line alterations.
AB - A competitive polymerase chain reaction has been developed for quantitation of
BRCA1 mRNA. In human cancer cell lines, the amount of BRCA1 mRNA is relatively
low, ranging from 6 to 38 copies per cell. The decay rate of these transcripts in
actinomycin-treated cells indicates that the half-life of these molecules is
about 4 hr, suggesting that the low concentration of BRCA1 messages is not due to
molecular unstability. In human lymphoblastoid cell lines derived from patients
carrying germ-line alterations of BRCA1, the amount of BRCA1 mRNA per cell is
lowered only in cell lines exhibiting alterations leading to specific loss of
transcripts from the mutated allele. These data indicate that the amount of BRCA1
available in these cells can be related directly to the number of "active"
allele.
PMID- 9398052
TI - Chemopreventive effects of diosmin and hesperidin on N-butyl-N-(4
hydroxybutyl)nitrosamine-induced urinary-bladder carcinogenesis in male ICR mice.
AB - The chemopreventive effects of 2 flavonoids (diosmin and hesperidin) on N-butyl-N
(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary-bladder carcinogenesis were
examined in male ICR mice. Animals were divided into 11 groups, and groups 1 to 7
were given OH-BBN (500 ppm) in the drinking water for 6 weeks. Groups 2 to 4 were
fed diets containing the test compounds (group 2, 1000 ppm diosmin; group 3, 1000
ppm hesperidin; group 4,900 ppm diosmin + 100 ppm hesperidin) for 8 weeks during
the initiation phase, while groups 5 to 7 were fed these diets, respectively, for
24 weeks during the post-initiation phase. Groups 8 to 11 were controls, given
only the test compounds or untreated basal diets throughout the experiment (weeks
1 to 32). The incidence of bladder lesions and cell-proliferation activity
estimated by enumeration of silver-stained nucleolar-organizer-region-associated
proteins (AgNORs) and by the 5-bromodeoxyuridine (BUdR)-labeling index was
compared among the groups. Feeding of the test compounds, singly or in
combination, during both phases caused a significant reduction in the frequency
of bladder carcinoma and preneoplasia. Dietary administration of these compounds
significantly decreased the AgNOR count and the BUdR-labeling index of various
bladder lesions. These findings suggest that the flavonoids diosmin and
hesperidin, individually and in combination, are effective in inhibiting chemical
carcinogenesis of the bladder, and that such inhibition might be partly related
to suppression of cell proliferation.
PMID- 9398053
TI - Intracellular Ca2+ release mediates ursolic acid-induced apoptosis in human
leukemic HL-60 cells.
AB - The effect of ursolic acid (UA) on tumor cell apoptosis was investigated using HL
60 human promyelocytic leukemia cells as a model cellular system. Treatment with
UA resulted in a concentration-dependent decreased cell viability assessed by MTT
assay. UA also induced genomic DNA fragmentation, a hallmark of apoptosis,
indicating that the mechanism by which UA induced cell death was through
apoptosis. The intracellular Ca2+ level was increased by treatment with UA.
Intracellular Ca2+ inhibitors, such as intracellular Ca2+-release blockers
(dantrolene, TMB-8 and ruthenium red) and an intracellular Ca2+ chelator
(BAPTA/AM), significantly blocked the UA-induced increased intracellular Ca+
concentration. These inhibitors also blocked the effects of UA on cell viability
and apoptosis. These results suggest that enhanced intracellular Ca2+ signals may
be involved in UA-induced apoptosis in HL-60 cells.
PMID- 9398054
TI - Sequence-dependent activity of the irinotecan-5FU combination in human colon
cancer model HT-29 in vitro and in vivo.
AB - Irinotecan, a DNA-topoisomerase-I inhibitor, is active against metastatic colon
carcinoma. We investigated the effects of irinotecan and 5FU combinations in
human colon-carcinoma cell line HT-29, both in vitro and in vivo. Cytotoxicity of
24-hr exposure was evaluated by SRB technique and the nature of interactions were
determined by median-effect analysis. Strong synergism between irinotecan and 5FU
was observed after sequential exposure, and only additivity after simultaneous
exposure. At 50% level of kill, the mean sums of fractional effects were 0.13 +/-
0.05 and 0.18 +/- 0.02 respectively for the 2 sequential schedules, indicating
that the combined amount of the 2 drugs necessary to kill 50% cells was only 0.18
and 0.13 times respectively, as much as would be required if they demonstrated
purely additive behavior. In nude-mice xenografts, schedule-dependent toxicity
was observed: the schedule in which irinotecan was administered i.v. 6 hours
before 5FU was the most toxic. Higher anti-tumoral activity was noted when 20
mg/kg/day of each drug was administered sequentially (a delay of 6 hr between the
2 drugs) to mice over 5 days, in comparison with simultaneous administration. In
vivo data confirmed those obtained in vitro in the same human colon-cancer model.
These results suggest that irinotecan and 5FU combinations are of clinical
interest and that the schedule of administration is a critical parameter for
chemotherapeutic efficacy.
PMID- 9398055
TI - Long-term inhibitory effects of a novel anti-estrogen on the growth of ZR-75-1
and MCF-7 human breast cancer tumors in nude mice.
AB - The effects of the novel anti-estrogen EM-343 on the growth of 2 hormone
responsive human breast cancer tumors have been examined in athymic nude mice. At
the low daily dose of 5 microg, EM-343 administered subcutaneously for 6 months
completely blocked the stimulatory effect of endogenous estrogens on the growth
of ZR-75-1 and MCF-7 tumors implanted in nude mice. In addition, uterine weight
decreased by 60% while ovarian weight increased by 37%. Estrogen receptor (ER)
levels measured by [3H]-labeled estrogen binding were markedly reduced (by 96%,
96% and 92%) in ZR-75-1 and MCF-7 tumors, and in the mouse uterus, respectively.
Accompanying the decrease in ER, progesterone receptor levels were reduced by
79%, 87% and 76%, respectively, in the above-mentioned tissues following EM-343
treatment. Our data show the pure anti-estrogenic properties of EM-343 and its
high potency as an inhibitor of growth of human ZR-75-1 and MCF-7 breast tumors
in nude mice.
PMID- 9398056
TI - Retinoic acid-enhanced invasion through reconstituted basement membrane by human
SK-N-SH neuroblastoma cells involves membrane-associated tissue-type plasminogen
activator.
AB - Al-trans retinoic acid (RA) enhanced human, S-type, SK-N-SH neuroblastoma cell
invasion of reconstituted basement membrane in vitro but did not induce terminal
differentiation of this cell line. In contrast to basal invasion, which was
urokinase (uPA)- and plasmin-dependent, RA-enhanced invasion was dependent on
tissue-type plasminogen activator (t-PA) and plasmin activity. Neither basal nor
RA-enhanced invasion involved TIMP-2 inhibitable metalloproteinases. Enhanced
invasion was associated with the induction of t-PA expression, increased
expression of the putative t-PA receptor amphoterin, increased association of t
PA with cell membranes and increased net membrane-associated PA activity.
Enhanced invasion was not associated with significant changes in the expression
of uPA or its membrane receptor UPAR; plasminogen activator inhibitors PAI-1 and
PAI-2; metalloproteinases MMP-1, MMP-2, MMP-3, MMP-9 and membrane type MMP1; or
tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. RA stimulated the
association of t-PA with the external cell membrane surface, which could be
inhibited by heparin sulphate but not by mannose sugars or chelators of divalent
cations, consistent with a role for amphoterin. Our data indicate that RA can
promote the malignant behavior of S-type neuroblastoma cells refractory to RA
mediated terminal differentiation by enhancing their basement membrane invasive
capacity. We suggest that this results from the action of a novel, RA-regulated
mechanism involving stimulation of t-PA expression and its association with the
cell membrane leading to increased PA-dependent matrix degradation.
PMID- 9398057
TI - In vivo effects of activated H-ras oncogene expressed in the liver and in
urogenital tissues.
AB - Transgenic mouse technology provides a direct genetic approach to in vivo
carcinogenesis. In order to determine the oncogenic potential of an activated ras
gene in liver, kidney and intestine, we created transgenic mice expressing the
human H-ras oncogene under control of the L-type pyruvate-kinase gene. This gene
is expressed in hepatocytes, enterocytes, proximal tubular cells of the kidney
and endocrine pancreatic cells. Depending on lines, we observed hepatocarcinoma,
polycystic kidney disease and an unexpected epididymis hyperplasia. These
transgenic mice are an interesting model of polycystic kidney disease, and
complete our study of the tissue-specificity of oncogene action.
PMID- 9398058
TI - Up-regulation of Fas (CD95) in human p53wild-type cancer cells treated with
ionizing radiation.
AB - Fas is a cell-surface protein which belongs to the tumor-necrosis-factor-receptor
family. Signals through Fas are able to induce apoptosis in sensitive cells, and
thus modalities for regulating the level of Fas expression on tumor cells are
needed. We have studied cellular responses to gamma irradiation. The level of p53
tumor-suppressor protein was found to be elevated 3 hr after irradiation of
p53wild-type MCF-7 breast-carcinoma cells. Interestingly, accumulation of p53 was
followed by up-regulation of surface Fas levels between 4 and 8 hr after
irradiation. The level of Fas up-regulation was dependent on dose and, whereas
elevation in the level of p53 was transient, enhancement of Fas expression was
stable. Fas up-regulation occurred coincidentally with induction of G1 cell-cycle
arrest, a post-irradiation phenomenon known to be dependent on wild-type-p53
activity. We studied 9 other tumor lines, 2 with wild-type p53, 5 with mutant
p53, and 2 expressing no p53. All lines expressing wild-type p53 were found to
arrest in G1 and to up-regulate Fas after irradiation. In contrast, all 7 p53null
and p53mutant lines failed not only to arrest their cell cycles in G1 phase, but
also to up-regulate Fas levels in response to treatment. These findings
demonstrate a direct correlation between wild-type-p53 activity and Fas up
regulation after treatment with ionizing radiation, strongly suggesting that post
irradiation Fas up-regulation is dependent on wild-type-p53 activity. Since low
doses of radiation were sufficient to modulate Fas expression, up-regulation of
the Fas death receptor may have clinical implications following radiotherapy.
PMID- 9398059
TI - Characterisation of novel human lung carcinoma cell lines selected for resistance
to anti-neoplastic analogues of staurosporine.
AB - The staurosporine analogues CGP 41251, UCN-01 and Ro 31-8220 are specific
inhibitors of protein kinase C (PKC). CGP 41251 and UCN-01 exert anti-neoplastic
activity against human tumours grown in rodents, and CGP 41251 reverses multidrug
resistance. The hypothesis was tested that these agents can induce drug
resistance and alter cellular levels of target kinases. Human-derived A549 lung
carcinoma cells were exposed for 6 months to CGP 41251, UCN-01 or Ro 31-8220 at
gradually increasing concentrations. Cells acquired resistance against these
agents, 4.3-fold against CGP 41251 (A549/CGP cells), 4.0-fold against UCN-01
(A549/UCN cells) and 14-fold against Ro 31-8220 (A549/Ro cells). Cells were
neither collaterally cross-resistant towards the PKC inhibitors nor resistant
against the growth-inhibitory properties of 12-O-tetradecanoylphorbol-13-acetate.
However, cross-resistance was observed in A549/CGP cells against staurosporine
(13-fold) and in A549/Ro cells against doxorubicin (26-fold). All 3 cell types
expressed multidrug resistance-associated protein, and A549/Ro cells expressed P
glycoprotein, as adjudged by Western blot analysis. Phorbol ester-stimulated PKC
activity in these cells was decreased by between 57% and 96% compared to wild
type A549 cells. Levels of the PKC isoenzymes alpha and theta in all 3 resistant
cell types and of PKC-epsilon in A549/UCN cells were concomitantly reduced. Cells
regained drug sensitivity after culture in the absence of drug for 6 (A549/Ro
cells), 5 (A549/CGP cells) and 1 (A549/UCN cells) months. Our results suggest the
following features of this type of anti-signalling drug: (i) they can induce drug
resistance, (ii) they may be potentially useful in combination because of the
lack of cross-resistance between them and (iii) they can down-regulate PKC, which
may have pharmacological or toxicological consequences.
PMID- 9398060
TI - Melanoma progression-associated glycoprotein MUC18/MCAM mediates homotypic cell
adhesion through interaction with a heterophilic ligand.
AB - MUC18/MCAM is a cell-surface glycoprotein that is strongly expressed on advanced
human melanomas. Transfection of 3 MCAM-negative melanoma cell lines with MCAM
cDNA led to cell-surface expression and to a MCAM-dependent homotypic adhesion.
This adhesion was independent of divalent cations and was inhibited at 4 degrees
C. Mixed aggregation assays with MCAM-expressing and non-expressing cells
revealed that MCAM can function as a heterophilic cell adhesion molecule
interacting with a non-MCAM ligand. Although MCAM contains a potential
glycosaminoglycan-binding site, cell-surface glycosaminoglycans do not appear to
be involved in the heterophilic adhesion observed here since these molecules were
not able to influence the adhesion. Using a functional adhesion assay, 4/4
melanoma cell lines examined were found to express an MCAM ligand. In contrast,
no evidence for an MCAM ligand was found on the 2 carcinoma or 2 hematopoietic
cell lines examined. Stable transfection of an MCAM ligand-negative colorectal
cell line resulted in MCAM surface expression but not in homotypic adhesion,
indicating that homophilic MCAM-MCAM adhesive interactions may not occur. Our
results suggest that MCAM expression by melanoma cells is associated with
increased homotypic adhesion, an event that may support tumor cell survival and
growth in vivo.
PMID- 9398061
TI - Human papillomavirus types 52 and 58 are prevalent in cervical cancer from
Chinese women.
PMID- 9398063
TI - Advances in apoptosis research.
AB - Apoptosis, also called programmed cell death, has attracted great attention in
recent years. After its discovery by Carl Vogt in 1842, apoptosis research was
dormant for more than a century. Its rediscovery in the second half of this
century, and the coining of the term apoptosis in 1972 by Kerr, Wyllie, and
Currie, ignited an unparalleled interest in this field of science. The number of
publications related to apoptosis has been growing exponentially every year ever
since. This is mainly due to three major advances, two of which have been made
recently and one that is currently seen. First, studies with the small nematode
Caenorhabditis elegans have identified a number of apoptosis regulating genes-
the first evidence that cell death is an active process under genetic control.
Many of these genes have mammalian homologs that, like their worm counterparts,
seem to regulate mammalian apoptosis. Second, elucidation of the signal
transduction pathways of apoptosis has lead especially to the identification of
specific death signaling molecules such as a new family of cysteine proteases,
the caspases. Third, it has now become clear that many diseases are characterized
by dysregulation of apoptotic programs. Many of these programs involve a family
of receptors and their ligands, the death receptor/ligand family. The hope now is
to interfere with apoptosis regulation in these systems and to develop new
therapeutic concepts.
PMID- 9398064
TI - Encoding strategies in combinatorial chemistry.
PMID- 9398065
TI - Neural codes: firing rates and beyond.
AB - Computational neuroscience has contributed significantly to our understanding of
higher brain function by combining experimental neurobiology, psychophysics,
modeling, and mathematical analysis. This article reviews recent advances in a
key area: neural coding and information processing. It is shown that synapses are
capable of supporting computations based on highly structured temporal codes.
Such codes could provide a substrate for unambiguous representations of complex
stimuli and be used to solve difficult cognitive tasks, such as the binding
problem. Unsupervised learning rules could generate the circuitry required for
precise temporal codes. Together, these results indicate that neural systems
perform a rich repertoire of computations based on action potential timing.
PMID- 9398067
TI - Gene therapy.
AB - In recent years, there have been a number of technological breakthroughs that
have allowed for clinical trials in gene therapy to be initiated. In combination
with the genome initiative, the potential for new therapeutics is limitless.
Although an enormous amount of information has been obtained in a relatively
short period of time, gene therapy is not yet ready for wide-scale practice. Some
of the successes and obstacles that remain are summarized in this report.
PMID- 9398068
TI - Motor proteins of the eukaryotic cytoskeleton.
PMID- 9398069
TI - Scanning-probe-based science and technology.
PMID- 9398070
TI - Fun with genealogy.
PMID- 9398071
TI - Life without DNA repair.
PMID- 9398072
TI - Origins of mRNA identity: capping enzymes bind to the phosphorylated C-terminal
domain of RNA polymerase II.
PMID- 9398074
TI - The orange carotenoid protein of Synechocystis PCC 6803.
AB - A water soluble protein with the carotenoid 3'-hydroxyequinenone bound to it has
been purified from the cyanobacterium Synechocystis PCC 6803. Based on partial
amino acid sequencing of the protein, oligonucleotides were synthesized and used
as primers for PCR to obtain a substantial fragment of the gene. This DNA was
sequenced and the sequence data and the size of the protein indicate that the
protein is encoded by gene slr 1963 in the Kazusa DNA sequence data bank
containing the Synechocystis 6803 genome. This protein is very similar to 3'
hydroxyechinenone proteins found in several other cyanobacteria but it shows very
little resemblance in its amino acid or gene sequence to other carotenoid binding
proteins. The protein binds 1-2 molecules of 3'-hydroxyechinenone and is slowly
cleaved by proteases in the cell extract to give a molecule of approximately half
the original mass which retains the carotenoid and which shows a striking change
in color.
PMID- 9398075
TI - Contribution to the physiological characterization of glycerol active uptake in
Saccharomyces cerevisiae.
AB - Evidence is presented here that in Saccharomyces cerevisiae IGC 3507, grown
either on glycerol, ethanol or acetate, glycerol is transported by a high
affinity uptake system of the electrogenic proton symport type, with Km of 1.7 +/
0.7 mM, Vmax 441 +/- 19 micromolh(-1) g(-1) dry weight and a stoichiometry of
1:1 proton per molecule of glycerol, at 30 degrees C and pH 5.0. No competitors
were found among other polyols and sugars. Glycerol maximum accumulation ratios
followed p.m.f. with extracellular pH. CCCP prevented glycerol accumulation, and
inhibited uptake. NaCl did not interfere with H+/glycerol kinetics and
energetics. This transport system was shown to be under glucose repression and
inactivation. Glucose-grown cells presented, instead, a lower affinity permease
for glycerol, probably a facilitated diffusion. Growth on glucose in the presence
of NaCl did not induce the high affinity carrier. The stringent control of cell
physiological condition over induction suggests for glycerol proton symport
rather a physiological role connected with growth under gluconeogenic conditions.
PMID- 9398076
TI - The pH dependences of reactions catalyzed by the complete proton-translocating
transhydrogenase from Rhodospirillum rubrum, and by the complex formed from its
recombinant nucleotide-binding domains.
AB - Transhydrogenase couples the translocation of protons across a membrane to the
transfer of reducing equivalents between NAD(H) and NADP(H). Using
transhydrogenase from Rhodospirillum rubrum we have examined the pH dependences
of the 'forward' and 'reverse' reactions, and of the 'cyclic' reaction (NADP(H)
dependent reduction of the analogue, acetyl pyridine adenine dinucleotide, by
NADH). In the case of the membrane-bound protein in chromatophores, the
imposition of a protonmotive force through the action of the light-driven
electron-transport system, stimulated forward transhydrogenation, inhibited
reverse transhydrogenation, but had no effect on the cyclic reaction. The
differential response at a range of pH values provides evidence that hydride
transfer per se is not coupled to proton translocation and supports the view that
energy transduction occurs at the level of NADP(H) binding. Chromatophore
transhydrogenase and the detergent-dispersed enzyme both have bell-shaped pH
dependences for forward and reverse transhydrogenation. The cyclic reaction,
however, is rapid at low and neutral pH, and is attenuated only at high pH. A
mixture of recombinant purified NAD(H)-binding domain I, and NADP(H)-binding
domain III, of R. rubrum transhydrogenase carry out the cyclic reaction with a
similar pH profile to that of the complete enzyme, but the forward and reverse
reactions were much less pH dependent. The rates of release of NADP+ and of NADPH
from isolated domain III were pH independent. The results are consistent with a
model for transhydrogenation, in which proton binding from one side of the
membrane is consequent upon the binding of NADP+ to the enzyme, and then proton
release on the other side of the membrane precedes NADPH release.
PMID- 9398077
TI - Exchangeability of the b subunit of the Cl(-)-translocating ATPase of
Acetabularia acetabulum with the beta subunit of E. coli F1-ATPase: construction
of the chimeric beta subunits and complementation studies.
AB - The gene encoding the b subunit of the Cl(-)-translocating ATPase (aclB) was
isolated from total RNA and poly(A)+ RNA of Acetabularia acetabulum and sequenced
(total nucleotides of 3038 bp and an open reading frame with 478 amino acids).
The deduced amino acid sequence showed high similarity to the beta subunit of the
F type ATPases, but was different in the N-terminal 120 amino acids. The role of
the N-terminal region was investigated using an F -ATPase beta-less mutant of E.
coli, JP17. The JP17 strain expressing the aclB could not grow under conditions
permitting oxidative phosphorylation, although ACLB was detected in the membrane
fraction. The beta subunit was divided into three portions: amino acid position
from 1 to 95 (portion A), 96 to 161 (portion B) and 162 to the C-terminus
(portion C). The corresponding regions of ACLB were designated as portions A'
(from 1 to 106), B' (from 107 to 172) and C' (from 173 to 478). Chimeric proteins
with combinations of A-B'-C', A-B-C' and A'-B-C restored the function as the beta
subunit in E. coli F0F1-complex, but those with combinations of A'-B'-C and A-B'
C had no function as the beta subunit. These findings suggested that portion B
plays an important role in the assembly and function of the beta subunit in the
F0F1-complex, while portion B' of ACLB exhibited inhibitory effects on assembly
and function. In addition, portion A was also important for interaction of the
beta subunit with the alpha subunit in E. coli F0F1-complex. These findings also
suggested that the b subunit of the Cl(-)-translocating ATPase of A. acetabulum
has a different function in the Cl(-)-translocating ATPase complex, although the
primary structure resembled to the beta subunit of the F1-ATPase.
PMID- 9398078
TI - Study of regulation of mitochondrial respiration in vivo. An analysis of
influence of ADP diffusion and possible role of cytoskeleton.
AB - The purpose of this work was to investigate the mechanism of regulation of
mitochondrial respiration in vivo in different muscles of normal rat and mice,
and in transgenic mice deficient in desmin. Skinned fiber technique was used to
study the mitochondrial respiration in the cells in vivo in the heart, soleus and
white gastrocnemius skeletal muscles of these animals. Also, cardiomyocytes were
isolated from the normal rat heart, permeabilized by saponin and the "ghost"
(phantom) cardiomyocytes were produced by extraction of myosin with 800 mM KCl.
Use of confocal immunofluorescent microscopy and anti-desmin antibodies showed
good preservation of mitochondria and cytoskeletal system in these phantom cells.
Kinetics of respiration regulation by ADP was also studied in these cells in
detail before and after binding of anti-desmine antibodies with intermediate
filaments. In skinned cardiac or soleus skeletal muscle fibers but not in fibers
from fast twitch skeletal muscle the kinetics of mitochondrial respiration
regulation by ADP was characterized by very high apparent Km (low affinity) equal
to 300-400 microM, exceeding that for isolated mitochondria by factor of 25. In
skinned fibers from m. soleus, partial inhibition of respiration by NaN3 did not
decrease the apparent Km for ADP significantly, this excluding the possible
explanation of low apparent affinity of mitochondria to ADP in these cells by its
rapid consumption due to high oxidative activity and by intracellular diffusion
problems. However, short treatment of fibers with trypsin decreased this constant
value to 40-70 microM, confirming the earlier proposition that mitochondrial
sensitivity to ADP in vivo is controlled by some cytoplasmic protein. Phantom
cardiomyocytes which contain mostly mitochondria and cytoskeleton and retain the
normal shape, showed also high apparent Km values for ADP. Therefore, they are
probably the most suitable system for studies of cellular factors which control
mitochondrial function in the cells in vivo. In these phantom cells anti-desmin
antibodies did not change the kinetics of respiration regulation by ADP. However,
in skinned fibers from the heart and m. soleus of transgenic desmin-deficient
mice some changes in kinetics of respiration regulation by ADP were observed: in
these fibers two populations of mitochondria were observed, one with usually high
apparent Km for ADP and the second one with very low apparent Km for ADP.
Morphological observations by electron microscopy confirmed the existence of two
distinct cellular populations in the muscle cells of desmin-deficient mice. The
results conform to the conclusion that the reason for observed high apparent Km
for ADP in regulation of oxidative phosphorylation in heart and slow twitch
skeletal muscle cells in vivo is low permeability of mitochondrial outer membrane
porins but not diffusion problems of ADP into and inside the cells. Most
probably, in these cells there is a protein associated with cytoskeleton, which
controls the permeability of the outer mitochondrial porin pores (VDAC) for ADP.
Desmin itself does not display this type of control of mitochondrial porin pores,
but its absence results in appearance of cells with disorganised structure and of
altered mitochondrial population probably lacking this unknown VDAC controlling
protein. Thus, there may be functional connection between mitochondria, cellular
structural organisation and cytoskeleton in the cells in vivo due to the
existence of still unidentified protein factor(s).
PMID- 9398079
TI - Modification of the photosystem II acceptor side function in a D1 mutant
(arginine-269-glycine) of Chlamydomonas reinhardti.
AB - Bicarbonate anions have a strong positive influence on the electron and proton
transfers in photosystem II (PS II). It has been suggested that bicarbonate binds
to the non-heme iron and the QB binding niche of the PS II reaction center. To
investigate the potential amino acid binding environment of bicarbonate, an
arginine residue (R269) of the D1 protein of PS II of Chlamydomonas reinhardtii
was mutated into a glycine; our characterization of the resultant mutant (D1
R269G) shows that both the TyrD+ and QA- Fe2+ EPR signals are substantially
reduced and assembly of the tetranuclear Mn is lost (R.S. Hutchison, J. Xiong,
R.T. Sayre, Govindjee, Biochim. Biophys. Acta 1277 (1996) 83-92). In order to
understand the molecular implications of this mutation on the electron acceptor
side of PS II, we used chlorophyll (Chl) a fluorescence as a probe of PS II
structure and function, and herbicide binding as a probe for changes in the QB
binding niche of PS II. Chl fluorescence measurements with the heterotrophically
grown D1-R269G mutant cells (or thylakoids), as compared to that of the wild
type, show that: rate of electron transfer from QA to the plastoquinone pool,
measured by flash-induced Chl a fluorescence decay kinetics, is reduced by - 17
fold; the minimum Chl a fluorescence yield when all QA- is oxidized, is elevated
by 2 fold; the level of stable charge separation as inferred from variable Chl
fluorescence is reduced by 44%; binary oscillation pattern of variable Chl a
fluorescence obtained after a series of light flashes is absent, indicative of
the loss of functioning of the two-electron gate on the PS II acceptor side; 77 K
PS II Chl a fluorescence emission bands (F685 and F695) are reduced by 20-30%
(assuming no change in the PS I emission band). Thermoluminescence data with
thylakoids show the absence of the S2QA- and S2QB- bands in the mutant. Herbicide
14C-terbutryn binding measurements, also with thylakoids, show that the QB niche
of the mutant is significantly modified, at least 7-8 fold increased terbutryn
dissociation constant is shown (220 nM in the mutant versus 29 nM in the wild
type); the PS II sensitivity to bicarbonate-reversible formate inhibition is
reduced by 5 fold in the mutant, although the formate/bicarbonate binding site
still exists in the mutant. This suggests that D1-R269 must play some role in the
binding niche of bicarbonate. On the basis of the above observations, we conclude
that the D1-R269G mutation has not only altered the structure and function of PS
II (QB niche being abnormal), but may also have a decreased net excitation energy
transfer from the PS II core to the reaction center and/or an increased number of
inactivated reaction center II. We also discuss a possible scenario for these
effects using a recently constructed three dimensional model of the PS II
reaction center.
PMID- 9398080
TI - The subcellular sites of sphingomyelin synthesis in BHK cells.
AB - The subcellular distributions of the enzymes which synthesise sphingomyelin (SM)
and glucosylceramide (GluCer) from ceramide have been assessed in BHK cells. On a
sucrose density gradient GluCer synthase (a marker of the cis/medial Golgi
apparatus) and the trans-Golgi marker galactosyltransferase showed an similar
monotonic distribution. In contrast, SM synthase showed two peaks of activity, a
minor one which migrated with the Golgi markers and a major one which had a
density close to that of plasma membrane markers (sphingomyelin, cholesterol,
PtdSer, ganglioside GM3 and alkaline phosphodiesterase). When cell homogenates
were treated with digitonin, the sedimentation characteristics of the Golgi
markers was largely unaffected whereas the plasma membrane markers and the main
peak of SM synthase activity were shifted to higher density. In contrast, when
cells were treated with brefeldin A (BFA) the Golgi markers were shifted to
higher density but not the plasma membrane markers or the main peak of SM
synthase. These results suggest that the bulk of SM synthase activity in BHK
cells is not associated with the Golgi cisternae but with a cell compartment
which is relatively rich in cholesterol (e.g., plasma membrane, endosomes or
trans-Golgi network.) Further experiments in which cells were treated with
sphingomyelinase provided evidence that SM synthase activity was in an internal
compartment and not at the plasma membrane.
PMID- 9398081
TI - Lovastatin induces apoptosis by inhibiting mitotic and post-mitotic events in
cultured mesangial cells.
AB - Lovastatin, an inhibitor of protein prenylation, was reported to inhibit DNA
synthesis and induce apoptosis in cultured cells. This report describes the
morphological consequences of lovastatin treatment. Lovastatin (50 microM)
induced mesangial cell rounding and disassembly of actin stress fibers within 24
to 48 h. After 48 to 72 h of lovastatin treatment, the cells detached from the
substratum and underwent apoptotic cell death as evidenced by condensed nuclear
chromatin, nuclear fragmentation, cell blebbing and decrease in cell size. Time
lapse cinematography revealed that lovastatin caused cell rounding by either
inhibiting cytokinesis or cell spreading following cytokinesis. Lovastatin
induced cell rounding, detachment, and apoptosis were dependent upon cell
proliferation. These effects were prevented by serum deprivation to inhibit cell
proliferation or by plating cells at densities which resulted in contact
inhibition of cell growth. Lovastatin-induced mesangial cell rounding and
apoptosis were also prevented by the inclusion of the isoprenoids all-trans
farnesol or all-trans-geranylgeraniol in the incubation medium. These results
indicate that the effects of lovastatin were mediated by inhibition of protein
isoprenylation because exogenous all-trans-geranylgeraniol can be used only in
protein prenylation. The small GTP-binding protein RhoA, which may be important
for cell spreading and cytokinesis, accumulated in the cytosol following
treatment with lovastatin, suggestive of its inactivation. This effect was also
prevented by the inclusion of either farnesol or geranylgeraniol in the
incubation medium. Thus, lovastatin-induced apoptosis in mesangial cells occurs
by interfering with prenylation dependent mitotic and post-mitotic events.
PMID- 9398082
TI - Replenishment of selenium deficient rats with selenium results in redistribution
of the selenocysteine tRNA population in a tissue specific manner.
AB - We reported previously that the selenium status of rats influences both the
steady-state levels and distributions of two selenocysteine tRNA isoacceptors and
that these isoacceptors differ by a single methyl group attached to the ribosyl
moiety at position 34. In this study, we demonstrate that repletion of selenium
deficient rats results in a gradual, tissue-dependent shift in the distribution
of these isoacceptors. Rats fed a selenium-deficient diet possess a greater
abundance of the species unmethylated on the ribosyl moiety at position 34
compared to the form methylated at this position. A redistribution of the Sec
tRNA isoacceptors occurred in tissues of selenium-supplemented rats whereby the
unmethylated form gradually shifted toward the methylated form. This was true in
each of four tissues examined, muscle, kidney, liver and heart, although the rate
of redistribution was tissue-specific. Muscle manifested a predominance of two
minor serine isoacceptors under conditions of extreme selenium-deficiency which
also appeared to respond to selenium. Ribosomal binding studies revealed that one
of the two additional isoacceptors decodes the serine codeword, AGU, and the
second decodes the serine codeword, UCU. Interestingly, muscle and heart were the
slower tissues to return to a 'selenium adequate' tRNA distribution pattern.
PMID- 9398083
TI - Pepsinogen synthesis during long-term culture of porcine chief cells.
AB - The purpose of this study was to characterize time-dependent changes in
pepsinogen (PG) synthesis of porcine gastric chief cells during long-term
monolayer culture. Porcine chief cells were isolated by pronase/collagenase
treatment of fundic mucosa and enriched by density gradient and counterflow
centrifugation. PG isoenzymes were identified in [L-35S]methionine-labelled
cultured chief cells by native polyacrylamide gel electrophoresis followed by
phosphor imager analysis, protease detection and immunoblots with specific PG A
and C antibodies. The obtained results suggest that porcine chief cell cultures,
after an initial settling period, reached an approximate steady state in total
protein content and synthesis as well as in PG content and isoenzyme pattern from
days 3 to 9 of culture. The latter was characterized by the presence of at least
two PG A and two PG C isoenzymes. During the supposed steady-state total PG
synthesis averaged out at 34 +/- 2% of total protein synthesis, as detected by [L
35S]methionine incorporation, due to the synthesis of, mainly, PG A2 and, to a
much lesser extent, PG C and A1. In line with an active secretion, PG A2
proportion was on average significantly higher in released (44 +/- 3%) than in
intracellular labelled proteins (19 +/- 2%). In addition, PG release from chief
cells cultured for 6 and 9 days could be stimulated by cholecystokinin
octapeptide. These data suggest that porcine chief cells in monolayer culture are
a model well suited for the quantitative and qualitative characterization of PG
isoenzyme synthesis and release during long-term investigations, for which an
establishment of a culture steady state appears to be a useful prerequisite.
PMID- 9398084
TI - Estrogen-stimulated transcytosis of desialylated ligands and alpha2 macroglobulin
in rat liver.
AB - Previous studies have shown that treatment of rats with 17 alpha-ethynylestradiol
(EE) causes the appearance in bile of intravenously injected, desialylated
ligands, including asialofetuin and low density lipoprotein (LDL). Here we show
that activated alpha2-macroglobulin (alpha2-M*), but not insulin, transferrin or
acetylated LDL, shows the same phenomenon. Alpha2-M* appearance in bile in EE
treated rats was inhibited by receptor associated protein, but not unlabelled
asialofetuin, strongly implicating the alpha2-macroglobulin receptor
(alpha2MR/LRP) receptor in this process. Asialofetuin, apolipoprotein B (ApoB) of
LDL and alpha2-M* appeared undegraded in the bile of EE-treated but not control
rats. When LDL was injected, not only was intact apolipoprotein B detected in
bile, but the profile of cholesterol esters appearing in bile was characteristic
of the injected human LDL rather than rat lipoproteins. After floatation of the
bile on KBr gradients, intact Apo B and cholesterol esters characteristic of
human LDL were found at the normal density of LDL suggesting that the majority of
the lipoprotein particle remains intact. Stimulation of transcytosis was specific
to estrogens, and was highest with 17alpha-ethynylestradiol. After subcutaneous
injection of 0.05 mg/kg body weight of ethynylestradiol, sufficient to give a
measurable increase in transcytosis, the plasma concentration of ethynylestradiol
rose to 2.2 nM. Thus estrogen-stimulated transcytosis of desialylated ligands and
alpha2-M* would be expected at physiological estrogen concentrations.
PMID- 9398085
TI - Activation of inducible nitric oxide synthase by human choriogonadotropin in RAW
264.7 cells.
AB - Although human choriogonadotropin (hCG) plays a crucial role in the regulation of
the menstrual cycle and maintenance of pregnancy, little is known about the other
functions. However, recently hCG receptors have been identified in nongonadal
cells. The objective of the current study was to determine the effect of hCG on
the production of nitric oxide (NO). Stimulation of RAW 264.7 cells with hCG
after treatment with recombinant interferon-gamma (rIFNgamma) resulted in
increased NO synthesis. hCG had no effect on NO synthesis itself. NO production
was inhibited by N(G)-monomethyl-L-arginine. rIFNgamma in combination with hCG
showed marked increase of the expression of the inducible nitric oxide synthase
(iNOS) gene. In addition, synergy between rIFNgamma and hCG was mainly dependent
on hCG-induced tumor necrosis factor-alpha (TNF-alpha) secretion. All the
preparations of hCG were endotoxin free. These results suggest that the capacity
of hCG to increase NO production from rIFNgamma-primed RAW 264.7 cells is the
result of hCG-induced TNF-alpha secretion.
PMID- 9398086
TI - Induction of thioredoxin in human lymphocytes with low-dose ionizing radiation.
AB - Induction of the expression of the thioredoxin (TRX) gene, producing a key
protein in regulating cellular functions through redox reaction as well as being
a radioprotector, was followed after ionizing irradiation of lymphocytes from
human donors. The TRX mRNA level increased to a peak, 5.7-fold higher than the
control at maximum, 6 h after irradiation, and then decreased. The optimum
radiation dose for enhancement of induction of the TRX mRNA was 0.25 Gy. The TRX
protein also increased to a peak, a 3-fold increase at maximum, with the same
timing as that for TRX mRNA.
PMID- 9398087
TI - Differanisole A, a novel antitumor antibiotic, enhances growth inhibition and
differentiation of human myeloid leukemia cells induced by 9-cis retinoic acid.
AB - Differanisole A, 3,5-dichloro-2-hydroxy-4-methoxy-6-n-propylbenzoic acid,
inhibited growth of human myeloid leukemia cells. The compound induced G1 arrest
and granulocytic differentiation of HL-60 cells, although the differentiation
inducing effect was modest. Differanisole A and 9-cis retinoic acid (9cisRA)
synergistically inhibited the growth and induced functional and morphologic
differentiation of HL-60 and NB4 cells, whereas the combined treatment with
differanisole A and all-trans retinoic acid or 1alpha,25-dihydroxyvitamin D3 was
less effective. Similar results were obtained in primary culture of leukemia
cells from a patient with acute promyelocytic leukemia. The synergistic effect on
growth inhibition and induction of differentiation required simultaneous
treatment with differanisole A and 9cisRA. Differanisole A and an RXR-specific
ligand (Ro47-5944) cooperatively inhibited the cell growth, while the combined
effect of differanisole A and an RAR-specific ligand Am80 was just additive.
Differanisole A in combination with 9cisRA may have implications for therapy of
acute promyelocytic leukemia patients.
PMID- 9398088
TI - Leukotriene B4 stimulates the release of arachidonate in human neutrophils via
the action of cytosolic phospholipase A2.
AB - Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation and is involved
in the receptor-mediated activation of a number of leukocyte responses including
degranulation, superoxide formation, and chemotaxis. In the present research,
stimulation of unprimed polymorphonuclear leukocytes (neutrophils) with LTB4
results in the transient release of arachidonate as measured by mass. This
release of arachidonate was maximal at an LTB4 concentration of 50-75 nM and
peaked at 45 s after stimulation with LTB4. The transient nature of this release
can be attributed, in part, to a fast (< 60 s) metabolism of the added LTB4.
Moreover, the inhibition of the reacylation of the released arachidonate with
thimerosal results in greater than 4-times as much arachidonate released. Thus, a
rapid reacylation of the released arachidonate also contributes to the transient
nature of its measured release. Multiple additions of LTB4, which would be
expected to more closely resemble the situation in vivo where the cell may come
into contact with an environment where LTB4 is in near constant supply, yielded a
more sustained release of arachidonate. No release of [3H]arachidonate was
observed when using [3H]arachidonate-labeled cells. This indicates that the
release of arachidonate as measured by mass is most probably the result of
hydrolysis of arachidonate-containing phosphatidylethanolamine within the cell
since the radiolabeled arachidonate is almost exclusively incorporated into
phosphatidylcholine and phosphatidylinositol pools under the non-equilibrium
radiolabeling conditions used. Consistent with the role of cytosolic
phospholipase A2 (cPLA2) in the release of arachidonate, potent inhibition of the
LTB4-stimulated release was observed with methylarachidonylfluorophosphonate, an
inhibitor of cPLA2 (IC50 of 1 microM). The bromoenol lactone of the calcium
independent phosphospholipase A2. failed to affect LTB4-stimulated release of
arachidonate in these cells.
PMID- 9398089
TI - Expression of calmodulin and calmodulin binding proteins in rat fibroblasts
stably transfected with protein kinase C and oncogenes.
AB - Molecular mechanisms leading to elevated calmodulin (CaM) expression in cancer
have not yet been discovered. We have quantitated the levels of transcripts
derived from all three CaM genes in a variety of the same origin rat fibroblasts
transformed with oncogenes in combination with gene for protein kinase C using
Northern blot analysis with three CaM gene specific cDNA probes. Five species of
CaM mRNA were detected in all these cells. Surprisingly many of the investigated
cell lines exhibited a decreased content of all CaM mRNAs as compared to control
cells with CaMI and CaMII transcripts showing the most pronounced alterations. In
contrast, CaM protein levels were increased in all these cell lines as determined
by a radioimmunoassay. These results suggest that oncogenic up-regulation of CaM
synthesis takes place posttranscriptionally. Several CaM binding proteins were
found at different concentrations in the studied cell lines depending on the
oncogenes used for transformation. However, CaM overexpression does not seem to
affect the overall levels of CaM binding proteins.
PMID- 9398090
TI - Baseline characteristics of patients in the coronary artery bypass graft (CABG)
Patch Trial.
AB - BACKGROUND: Patients with left ventricular dysfunction who undergo coronary
artery bypass graft (CABG) surgery frequently have late sudden cardiac death. The
CABG Patch Trial is a prospective, randomized, multicenter clinical trial that
randomized patients at high risk at the completion of CABG surgery to
implantation of an epicardial implantable cardioverter defibrillator (ICD) or to
no antiarrhythmic treatment. The trial was designed to determine whether
prophylactic implantation of an ICD at the time of CABG surgery would result in a
lower total mortality in long-term follow-up. METHODS: Patients undergoing CABG
surgery were eligible for the trial if they were younger than 80 years, had a
left ventricular ejection fraction less than 0.36, and had an abnormal signal
averaged electrocardiogram. Patients with a history of sustained ventricular
tachycardia or ventricular fibrillation were excluded from the trial. All
patients were scheduled to undergo follow-up at 3-month intervals until 42 months
after surgery. RESULTS: Randomization of patients in the trial ended in February
1996. During the recruitment period 71,855 patients were screened, 1,422 were
eligible, 1,055 were enrolled (signed consent forms), and 900 patients (76% of
eligible patients) were randomized. The mean age of the 446 patients in the ICD
group was 64 years versus 63 years for the 454 patients in the control group. A
total of 87% of the participants in the ICD group were men versus 82% in the
control group (p = NS). Most of the patients had a history of hypertension (55%),
smoking (78%), and hypercholesterolemia (54%). Half of the patients had clinical
heart failure, and the mean ejection fraction for both patient groups was 0.27 +/
0.06. No difference was seen in the history of myocardial infarction (83%),
congestive heart failure (50%), or atrial (11%) or ventricular (17%) arrhythmias
between the two groups. Major clinical characteristics (age, sex, number of
previous infarctions, incidence of heart failure, and mean left ventricular
ejection fraction) were almost identical to those found in another ICD primary
prevention trial, the Multicenter Automatic Defibrillator Implantation Trial
(MADIT). CONCLUSIONS: A high risk sample of patients was enrolled in The CABG
Patch Trial, as shown by examination of their baseline characteristics.
PMID- 9398091
TI - Differential effects of adenosine on antegrade and retrograde fast pathway
conduction in atrioventricular nodal reentry.
AB - Although adenosine depresses antegrade atrioventricular (AV) nodal conduction,
the effects of adenosine on antegrade and retrograde fast pathway conduction in
AV nodal reentry have not been determined. In 17 patients (five men, 12 women,
mean age 49 +/- 12 years) with common slow-fast AV nodal reentrant tachycardia,
the antegrade slow pathway conduction was selectively and completely ablated by
radiofrequency catheter ablation while the antegrade and retrograde fast pathway
conduction remained intact. During high right atrial pacing at a mean pacing
cycle length of 474 +/- 36 msec, adenosine was rapidly injected intravenously at
an initial dose of 0.5 mg followed by stepwise increases of 0.5 mg or 1.0 mg
given at 5-minute intervals until second-degree AV block developed. During right
ventricular apical pacing at the same pacing cycle lengths (mean 474 +/- 36 msec)
as those in the study of antegrade conduction, intravenous injection of
incremental doses of adenosine was repeated until ventriculoatrial (VA) block
occurred. The adenosine-induced prolongation of VA conduction was also determined
in the presence of verapamil (loading dose 0.15 mg/kg, maintenance dose 0.005
mg/kg/min) in seven of 17 patients. The dose of adenosine required to produce AV
block, the increase in the atrio-His interval by 50% and the maximal response
were 3.4 +/- 1.4 mg, 1.8 +/- 0.6 mg, and 58% +/- 5%, respectively. On the other
hand, the dose of adenosine required to produce VA block, the increase in the VA
interval by 50%, and the maximal response were 8.2 +/- 2.9 mg, 3.4 +/- 0.6 mg,
and 20% +/- 5%, respectively, in the control and 3.7 +/- 0.5 mg, 3.5 +/- 0.7 mg,
and 23% +/- 5%, respectively, in the presence of verapamil. In conclusion,
adenosine has a differential potency to depress AV and VA conduction in patients
with AV nodal reentry, with greater potency for slowing antegrade fast than
retrograde fast pathway conduction. Verapamil had an additive effect to adenosine
on slowing retrograde VA conduction, which further supports the evidence that the
retrograde fast pathway in part involves an AV nodal-like structure.
PMID- 9398092
TI - Sex and diagnostic evaluation of possible coronary artery disease after exercise
treadmill testing at one academic teaching center.
AB - Controversy exists as to whether a sex bias exists that affects the diagnostic
approach to suspected coronary artery disease: previous studies have used
coronary angiography, but not other noninvasive testing, as a primary end point.
This investigation examined posttest sex differences in diagnostic evaluation
after exercise treadmill testing according to a broader end point than just
coronary angiography alone. The design was a cohort analytic study with a 90-day
follow-up. The study was done at the Cleveland Clinic Foundation, an academic
group practice. Patients included consecutive adults (1023 men and 579 women)
with chest pain but no documented coronary disease who were referred for symptom
limited exercise treadmill testing without adjunctive imaging; none had undergone
prior invasive cardiac procedures. Main outcome measures included (1) performance
of any subsequent diagnostic study (invasive or noninvasive) and (2) performance
of coronary angiography as the next diagnostic study. During follow-up, 89 (8.7%)
men and 48 (8.3%) women underwent a second diagnostic study (odds ratio 0.95; 95%
confidence interval 0.66 to 1.37; p > 0.8), whereas 64 (6.3%) men and 21 (3.6%)
women went straight to coronary angiography (odds ratio 0.56; 95% confidence
interval 0.34 to 0.93; p = 0.02). In multivariable logistic regression analyses,
which considered baseline clinical characteristics, the ST-segment response, and
other prognostically important exercise responses, women tended to be less likely
than men to be referred to any second test (adjusted odds ratio 0.70; 95%
confidence interval 0.42 to 1.19; p > 0.1) but were markedly and significantly
less likely to be referred straight to coronary angiography (adjusted odds ratio
0.33; 95% confidence interval 0.17 to 0.65). After exercise treadmill testing,
women were only slightly less likely than men to be referred for subsequent
diagnostic testing; they were, however, much less likely to be referred straight
to coronary angiography as opposed to another noninvasive study.
PMID- 9398093
TI - Two-dimensional echocardiographic assessment of the progression of aortic root
size in 127 patients with chronic aortic regurgitation: role of the supraaortic
ridge and relation to the progression of the lesion.
AB - Although aortic root dilation has etiologic and prognostic significance in
patients with chronic aortic regurgitation (AR), no information is available
regarding changes over time in aortic root size in patients with the entire
spectrum of AR severity or how such changes relate to progression of the AR or to
left ventricular (LV) overload. To analyze this, a total of 127 patients with
chronic AR who had more than 6 months of follow-up by two-dimensional and Doppler
echocardiography were included in the study (69 men and 58 women; mean age 59.3
+/- 21.2 years [range 14 to 94 years]; 67 cases of mild, 45 moderate, 15 severe,
and 21 bicuspid aortic valve disease). The aortic anulus, sinuses of Valsalva,
supraaortic ridge, and ascending aorta were measured in the parasternal long-axis
view, LV volumes were calculated (biplane Simpson's approach), and the severity
of AR was quantified based on proximal jet size and graded according to an
algorithm that takes into account major color Doppler criteria. At entry to the
study, significant differences between patients with mild, moderate, and severe
AR were noted only in supraaortic ridge size (1.46 +/- 0.29 cm/m2 vs 1.63 +/-
0.33 cm/m2 [p < 0.006]; vs 1.67 +/- 0.43 cm/m2 [p < 0.03]). A significant
increase in aortic root size at all levels was observed during the follow-up
period in all three groups of severity of AR. The rate of change of the
supraaortic ridge, the upper support structure of the anulus and cusps, was
faster in patients with more severe degrees of AR (p = 0.013); this was not the
case at the other aortic levels. No differences were observed in aortic root size
or rate of progression between patients with bicuspid or tricuspid aortic valves.
Patients were considered "progressive" if they lay on the steepest positive
segment of the curve representing the rank order in the rate of aortic root
progression. Compared with "nonprogressive" patients, patients who were
progressive in supraaortic ridge size (rate >0.12 cm/yr; n = 23) had a faster
rate of progression in the degree of regurgitation as assessed by the regurgitant
jet area/LV outflow tract area ratio measured in the parasternal short-axis view
(0.48 +/- 0.45 vs 0.24 +/- 0.5/yr; p < 0.03) and a foster rate of progression of
LV end-diastolic volume (30 +/- 22.8 vs 14.4 +/- 15.6 ml/yr; p < 0.0002) and LV
mass (70.8 +/- 74.4 vs 16.8 +/- 19.2 gm/yr; p < 0.0004). In conclusion, there is
progressive dilation of the aortic root at all levels, even in patients with mild
AR. More rapid progression in aortic root size is associated with more rapid
progression of the underlying aortic insufficiency, as well as more rapid
increases in LV volume and mass.
PMID- 9398094
TI - Low dose dobutamine echocardiography is more predictive of reversible dysfunction
after acute myocardial infarction than resting single photon emission computed
tomographic thallium-201 scintigraphy.
AB - To directly compare dobutamine echocardiography and resting single photon
emission computed tomographic (SPECT) thallium-201 (Tl-201) scintigraphy for the
detection of reversible dysfunction, 64 patients underwent dobutomine
echocardiography (baseline, low dose 5 and 10 mg/kg/min, and peak dose), rest Tl
201 scintigraphy (3 mCi - 15 minute and 3- to 4-hour SPECT imaging), and coronary
angiography during the first week after acute myocardial infarction. Follow-up
echocardiography was performed 4 to 8 weeks after discharge. Wall thickening
improved at follow-up in 52% (207 of 399) of the dysfunctional segments. By
receiver operating characteristic analysis, biphasic responses and sustained
improvement during dobutamine echocardiography were more accurate (p < 0.01) than
Tl-201 uptake by SPECT scintigraphy for reversible dysfunction. The greater
accuracy of dobutamine echocardiography resulted from higher accuracy in akinetic
segments, Q wave infarction, and multivessel coronary artery disease. In
conclusion, dobutamine echocardiography was more accurate than resting SPECT Tl
201 scintigraphy for reversible dysfunction after acute myocardial infarction.
PMID- 9398095
TI - Myocardial viability in patients with chronic coronary artery disease and
previous myocardial infarction: comparison of myocardial contrast
echocardiography and myocardial perfusion scintigraphy.
AB - The aim of this study was to compare perfusion patterns on myocardial contrast
echocardiography with those on myocardial perfusion scintigraphy for the
assessment of myocardial viability in patients with previous myocardial
infarction. Accordingly, perfusion scores with the two techniques were compared
in 91 ventricular regions in 21 patients with previous (>6 weeks old) myocardial
infarction. Complete concordance between the two techniques was found in 63 (69%)
regions; 25 (27%) regions were discordant by only 1 grade, and complete
discordance (2 grades) was found in only 3 (3%) regions. A kappa statistic of
0.65 indicated good concordance between the two techniques. Although the scores
on both techniques demonstrated a relation with the wall motion score, the
correlation between the myocardial contrast echocardiography and wall motion
scores was closer (r = -0.63 vs r = -0.50, p = 0.05). It is concluded that
myocardial contrast echocardiography provides similar information regarding
myocardial viability as myocardial perfusion scintigraphy in patients with
coronary artery disease and previous myocardial infarction.
PMID- 9398096
TI - Dichloroacetate as metabolic therapy for myocardial ischemia and failure.
AB - This article critically reviews the pharmacologic effects of the investigational
drug dichloroacetate (DCA), which activates the mitochondrial pyruvate
dehydrogenase enzyme complex in cardiac tissue and thus preferentially
facilitates aerobic oxidation of carbohydrate over fatty acids. The pharmacologic
effects of DCA are compared with other interventions, such as glucose plus
insulin, inhibitors of long chain fatty acid oxidation and adenosine, that are
also thought to exert their therapeutic effects by altering myocardial energy
metabolism. Short-term clinical and laboratory experiments demonstrate that
intravenous DCA rapidly stimulates pyruvate dehydrogenase enzyme complex activity
and, therefore, aerobic glucose oxidation in myocardial cells. Typically these
effects are associated with suppression of myocardial long chain fatty acid
metabolism and increased left ventricular stroke work and cardiac output without
changes in coronary blood flow or myocardial oxygen consumption. Although long
term studies are lacking, short-term parenteral administration of DCA appears to
be safe and capable of significantly improving myocardial function in conditions
of limited oxygen availability by increasing the efficient conversion of
myocardial substrate fuels into energy.
PMID- 9398097
TI - Coronary artery bypass grafting in the elderly.
PMID- 9398098
TI - Risk factors for life-threatening cavopulmonary thrombosis in patients undergoing
bidirectional superior cavopulmonary shunt: an exploratory study.
AB - We have observed six patients with life-threatening superior vena caval or
pulmonary thrombosis after bidirectional superior cavopulmonary shunt. With the
use of a case control study we sought to identify perioperative risk factors for
this thrombotic complication. Medical records of six patients with cavopulmonary
thrombosis and those of 24 patients in a control group were reviewed to abstract
data for potential risk factors. Contingency tables and univariate logistic
regression were used to determine associations between various perioperative
parameters and occurrence of cavopulmonary thrombosis. Preoperative variables
associated with thrombosis included bilateral superior vena cavae, odds ratio:
23, p = 0.02, increased age at surgery (p = 0.05), and female sex (odds ratio: 7,
p = 0.05). The McGoon Ratio (index of relative pulmonary artery branch diameter)
was inversely related to thrombosis risk (p = 0.08). Two torr increases in mean
right atrial (p = 0.08) or ventricular end-diastolic (p = 0.05) pressures were
associated with approximately 70% increases in thrombosis risk. Intraoperative
prolongation of aortic cross-clamp time related directly to thrombosis risk (p =
0.06). Postoperative variables associated with thrombosis included increased
superior vena caval pressure within 12 hours after surgery (odds ratio > or = 10
for 5 torr increase in pressure, p = 0.02) and poor ventricular function (odds
ratio: 9, p = 0.06) We conclude that high risk variables for patients undergoing
a cavopulmonary shunt include bilateral superior vena cavae, female sex,
increasing age, decreased McGoon Ratio, and elevated right atrial and ventricular
end-diastolic pressure (before surgery), patients with prolonged aortic cross
clamp time (during surgery), and patients with elevated superior vena caval
pressure and poor ventricular function (after surgery).
PMID- 9398099
TI - Effects of amlodipine in patients with chronic heart failure.
AB - The role of calcium antagonists in patients with ischemic heart failure is
currently unclear. We examined the effects of amlodipine on exercise capacity and
central and regional hemodynamics in 32 patients with mild to moderate chronic
heart failure in a single-center, double-blind, randomized placebo-controlled
trial. All were taking at least 40 mg of furosemide daily with an angiotensin
converting enzyme inhibitor. Ischemic heart disease was the most common cause of
heart failure, but no patient had symptom-limiting angina. Mean treadmill
exercise capacity in patients taking amlodipine increased by 96 seconds (95%
confidence interval -23 to 215) and 50 seconds (-34 to 135) in the placebo group;
mean difference in change between treatments was 70 seconds (-90 to 233), p =
0.38. Active treatment with amlodipine did not affect self-paced corridor walking
times. Similarly, there were no significant effects on cardiac output, oxygen
uptake, heart rate, and mean arterial pressure at rest or during exercise. Calf
and renal blood flow were also unchanged by treatment. The lack of significant
effect demonstrated by these data suggests a limited role for amlodipine in
patients with ischemic cardiomyopathy, although it may prove beneficial in those
with nonischemic disease. More data are required before amlodipine can be
recommended for all patients with chronic heart failure.
PMID- 9398100
TI - Depressed arterial baroreflex sensitivity and not reduced heart rate variability
identifies patients with chronic heart failure and nonsustained ventricular
tachycardia: the effect of high ventricular filling pressure.
AB - In chronic heart failure (CHF) the contributing role of increased sympathetic
activity and hemodynamic dysfunction in the genesis of ventricular arrhythmias
has not been well established. To assess the relation between severe ventricular
arrhythmias, hemodynamic impairment, and autonomic nervous system derangement,
142 patients with CHF in sinus rhythm underwent 24-hour electrocardiographic
recording, right-sided heart catheterization, and evaluation of sympathovagal
balance by heart rate variability (HRV) and baroreflex sensitivity (BRS).
Patients were grouped according to the absence (without nonsustained ventricular
tachycardia [NSVT]; n = 87) or presence (with NSVT; n = 55) of NSVT. Patients
with NSVT had higher pulmonary artery and capillary pressures and more pronounced
signs of sympathetic activation and parasympathetic withdrawal compared with
those without NSVT. However, logistic regression analysis revealed that depressed
BRS but not reduced HRV was significantly associated with the presence of NSVT,
at both univariate analysis and after adjustment for clinical and hemodynamic
variables. Moreover, it was found that when depressed BRS was associated with
high pulmonary capillary pressure, the odds ratio for having NSVT rose markedly
from 3.8 to 6.5. In conclusion, this study indicates that in stable CHF the
assessment of arterial baroreflex function, but not HRV analysis, allows
identification of patients at high risk of NSVT. It is suggested that the effect
of depressed BRS is strengthened by the simultaneous presence of increased
myocardial wall stress. These data support the hypothesis of a contributory role
of autonomic nervous system dysfunction as expressed by the inability to activate
effective vagal reflexes and an indirect index of ventricular stretch in the
genesis of life-threatening arrhythmias.
PMID- 9398101
TI - Continuous home ambulatory intravenous inotropic drug therapy in severe heart
failure: safety and cost efficacy.
AB - Some patients with dilated cardiomyopathy who are inotrope dependent but remain
well by undergoing infusions can be managed by ambulatory infusions at home. We
report our results in 20 patients awaiting heart transplantation, unable to be
weaned from intravenous inotropic therapy on 2 or more occasions, but who were
well while receiving inotropes and received home ambulatory infusions. The
patients were treated with ACE inhibitors, digoxin, diuretics, vasodilators,
close electrolyte management, and low-dose amiodarone for those with more than
four-beat ventricular tachycardia. Infusions were delivered by a tunneled
subclavian catheter and syringe driver. Thirteen patients received dopamine, four
received dobutamine, and three received both. Mean duration of inotropic therapy
was 5 months with 70% of the time spent as an outpatient. Eleven patients
received transplants, two remain on the waiting list, and seven died after being
removed from the list because of general deterioration or renal dysfunction.
There were no sudden deaths. Actuarial survival was 71% at 3 months, which is not
less than that expected for an inotrope-dependent population. All patients with
idiopathic dilated cardiomyopathy survived to transplantation. In contrast, all
three with right heart failure caused by pulmonary vascular disease and four of
seven with ischemic cardiomyopathy died. Inpatient days were reduced by 70%,
leading to considerable cost savings. Home ambulatory inotropic therapy is safe,
cost-effective, best suited to those with idiopathic dilated cardiomyopathy, and
dramatically reduces inpatient hospital duration.
PMID- 9398102
TI - Heart failure between 1986 and 1994: temporal trends in drug-prescribing
practices, hospital readmissions, and survival at an academic medical center.
AB - Since 1987, publications in widely circulated medical journals have reported
improved survival and lower hospital readmission rates when patients with heart
failure and systolic dysfunction are treated with angiotensin-converting enzyme
(ACE) inhibitors. We describe changes in ACE inhibitor use among patients
hospitalized with heart failure between 1986 and 1993. Simultaneous trends in
readmissions and survival rates are reported. Subjects were 612 consecutive
patients hospitalized with a principal diagnosis of heart failure at an academic
medical center during the period of Sept. 1, 1986, to Dec. 31, 1987 (interval I)
or during the period Aug. 1, 1992, to Nov. 30, 1993 (interval II). Medical
records were reviewed for 434 patients, consisting of all patients hospitalized
with heart failure during interval II and a randomly selected 50% subset of
patients hospitalized during interval I. Among 145 patients with systolic
dysfunction whose medical records were reviewed, ACE inhibitor prescriptions
significantly increased between interval I and interval II (43% vs 71%, p < 0.01,
odds ratio 3.22, 95% confidence interval 1.62 to 6.42). Prescriptions of ACE
inhibitors combined with digoxin and a diuretic also increased (37% vs 56%, p =
0.02, odds ratio 2.22, 95% confidence interval 1.14 to 4.32). Among all 612
patients, 6-month heart failure readmission rates increased from 13% to 21% (p =
0.02, odds ratio 1.79, 95% confidence interval 1.10 to 2.82). There was no
significant change in survival rate between interval I and interval II, however,
survival rate was marginally significantly improved among patients with systolic
dysfunction. Our results suggest that drug-prescribing practices have
significantly changed between 1986 and 1993. The absence of observed improvement
in outcomes may result from changes in hospital admission criteria for heart
failure.
PMID- 9398103
TI - Digitalis increases brain natriuretic peptide in patients with severe congestive
heart failure.
AB - Ouabain can cause increased secretion of atrial natriuretic peptide (ANP) from
atrial cardiocyte culture, but the effects of digitalis in a therapeutic range on
the secretion of cardiac natriuretic peptide including ANP and brain natriuretic
peptide (BNP), mainly from the ventricle, in patients with congestive heart
failure remain to be investigated. Therefore we studied the acute effects of
intravenous infusion of a relatively low dose of digitalis or placebo on
hemodynamics and neurohumoral factors including the plasma levels of ANP and BNP
and cyclic guanosine monophosphate, a second messenger of cardiac natriuretic
peptide, in 13 patients with severe congestive heart failure. No significant
change in the hemodynamic parameters or neurohumoral factors was observed with
placebo. After 1 hour of intravenous administration of deslanoside (0.01 mg/kg),
there was a significant decrease of plasma renin activity and angiotensin II,
aldosterone, and norepinephrine levels but no significant change of plasma levels
of vasopressin and a significant decrease of the pulmonary capillary wedge
pressure but no significant change in cardiac index. In addition, plasma levels
of ANP (217 +/- 47 vs 281 +/- 70 pg/ml, p < 0.05), BNP (628 +/- 116 vs 689 +/-
132 pg/ml, p < 0.05), and cyclic guanosine monophosphate (9.7 +/- 1.1 vs 10.9 +/-
1.5 pmol/ml, p < 0.05) increased despite the decrease of pulmonary capillary
wedge pressure (19.7 +/- 2.3 vs 16.8 +/- 2.3 mm Hg, p < 0.05). These results
indicate the acute intravenous low dose of digitalis resulted in a significant
increase in plasma levels of ANP, BNP, and cyclic guanosine monophosphate
concomitant with the significant decrease of pulmonary capillary wedge pressure,
suggesting the acute direct action of digitalis on the cardiac natriuretic
peptides released from the heart in patients with severe congestive heart
failure.
PMID- 9398104
TI - Balloon angioplasty of native aortic coarctation in infants 3 months of age and
younger.
AB - The use of balloon dilation to treat native aortic coarctation is controversial,
particularly in infants. Between January 1991 and September 1996, 12 patients <
or = 3 months of age with native coarctation of the aorta (CoA) underwent balloon
angioplasty (BA). All 12 lesions were dilated successfully with a mean reduction
in peak systolic gradient from 49.3 +/- 16.5 mm Hg to 6.8 +/- 4.0 mm Hg (p <
0.001) and a mean increase in minimum CoA diameter from 2.4 +/- 0.6 mm to 5.5 +/-
1.3 mm (p < 0.001). Intimal flaps or tears were detected immediately after BA in
4 (33%) of 12 patients by angiography and in 8 (89%) of 9 patients by
intravascular ultrasonography. No deaths or major complications related to the BA
occurred. One patient had documented asymptomatic femoral artery obstruction, and
one patient with hydrops fetalis and congenital pleural effusions died with gram
negative sepsis 1 week after the procedure. Follow-up was available for 10
patients (1 was lost to follow-up) between 2 months and 4.1 years (mean 2.4 +/-
1.3 years) after BA. No patient had an aortic aneurysm. Restenosis occurred in 5
(50%) of 10 patients, requiring reintervention a mean of 2.6 +/- 2.1 months after
BA. One patient underwent surgical repair. Repeat BAs were performed in the other
four patients; three were successful, and one with partial gradient relief
required surgical repair. Five patients have not required reintervention a mean
of 2.9 +/- 1.0 years after the initial BA. Among these five patients, follow-up
intravascular ultrasound performed in three patients a mean of 2.0 +/- 1.9 years
after BA showed favorable endovascular remodeling. There was a tendency for early
reintervention in patients < 1 month of age and coexistence of a patent ductus
arteriosus at the time of BA. In conclusion, selected infants < or = 3 months of
age with discrete native CoA may be treated initially with balloon dilation. Most
patients who have restenosis respond successfully to repeat BA.
PMID- 9398105
TI - Aortic valve resistance in aortic stenosis: Doppler echocardiographic study and
surgical correlation.
AB - Four hundred seven patients with aortic stenosis who had Doppler echocardiography
before surgery were studied to determine the feasibility of Doppler-derived valve
resistance calculation and its clinical value. Patients with milder aortic
stenosis had lower mean gradient, larger valve area, and lower maximal resistance
than those with severe stenosis. Maximal resistance was related strongly to
aortic stenosis severity but did not add any information after valve area and
gradient were known and was not related to surgical mortality.
PMID- 9398106
TI - Coronary artery stenting in cardiac allograft vascular disease.
AB - Cardiac allograft vascular disease is characterized by diffuse and multifocal
heterogeneous myointimal hyperplasia with or without vascular remodeling.
Catheter-based interventions are indicated in selected patients. This study
documents our experience with percutaneous transluminal coronary angioplasty and
coronary stents (n = 48) in a group of 27 patients 5.7 +/- 2.9 years after heart
transplantation. Early and intermediate results were controlled by angiography
and intravascular ultrasound. Conventional percutaneous transluminal coronary
angioplasty resulted in a mild and mostly inadequate gain in luminal dimensions
(lumen area: 3.17 +/- 0.92 mm2 to 3.70 +/- 1.21 mm2; minimal lumen diameter: 1.84
+/- 0.23 mm to 2.04 +/- 0.36 mm). Coronary stenting led to a further improvement
of luminal gain (lumen area: 3.70 +/- 1.21 mm2 to 5.86 +/- 1.76 mm2; minimal
lumen diameter: 2.04 +/- 0.36 mm to 2.53 +/- 0.38 mm). These results were
stabilized by application of aspirin and ticlopidine only. There were no stent
thromboses or bleeding complications, and early hospital discharge of the
patients was possible. At follow-up (mean follow-up period 7.72 +/- 5.45 months
(range 0.50 to 23.13 months) all patients were clinically event free. In six of
24 stented vessels (25%) in 16 patients, significant restenosis (>50%) was found
by intravascular ultrasound (n = 20) or by angiography (n = 4) 6 months after
stent placement. We conclude that in eligible cardiac allograft vascular disease
lesions primary stenting may be the method of choice. However, further evaluation
of the modalities of stent application and different stent designs with respect
to long-term survival is necessary.
PMID- 9398107
TI - Feasibility and applicability of coronary stent implantation with the direct
brachial approach: results of a single-center study.
AB - Implantation of stents in selected patients improves outcome after coronary
angioplasty. Newer antiplatelet regimes limit access site complications
associated with stenting by the percutaneous femoral approach, but a substantial
proportion of patients will require anticoagulant therapy for concomitant disease
or will have peripheral vascular disease that prevents access from the leg. We
investigated procedural success rates and outcome in consecutive patients
undergoing elective stent implantation in our institution. In 73 patients who
were receiving anticoagulation therapy and were stented by a direct approach to
the left brachial artery, 98.6% of stents were successfully deployed, with a
major vascular access site complication rate of 1.4%. Equipment consumption,
procedural success rate, and fluoroscopy time were similar in patients stented by
the direct brachial or percutaneous femoral approach. Where the percutaneous
femoral approach is precluded or patients are anticoagulated, stent procedures
can be successfully performed by the direct brachial approach with a low rate of
access site complications, even when large-caliber guiding catheters are
required.
PMID- 9398108
TI - Effect of carteolol on silent myocardial ischemia, variability in heart rate, and
the pain-modulating system.
AB - To investigate the effects of carteolol, which is a nonselective beta-adrenergic
agent with intrinsic sympathomimetic activity, on silent myocardial ischemia,
exercise-induced myocardial ischemia, indexes of heart rate variability, and pain
modulating system, 20 patients (mean 60 +/- 9 years) with chronic stable angina
underwent exercise treadmill testing and 24-hour ambulatory electrocardiographic
monitoring during 2 weeks of carteolol administration (15 mg/day) in a double
blind, placebo-controlled design. Plasma levels of beta-endorphin and bradykinin
and electrical pain stimulation to the skin were measured at rest and peak
exercise. Indexes of heart rate variability of both time-domain and frequency
domain analysis were derived from 24-hour ambulatory electrocardiographic
monitoring. Carteolol decreased maximal heart rate responses to daily activities
during ambulatory monitoring and significantly reduced the median frequency and
duration of silent myocardial ischemic episodes (from 1.0 to 0.0 events/24 hr and
from 16 to 0 min/24 hr, respectively). Carteolol significantly decreased the rate
pressure product at rest and during exercise with improving maximal ST segment
depression, suggesting amelioration of exercise-induced myocardial ischemia.
Carteolol did not significantly affect plasma levels of beta-endorphin and
bradykinin or pain threshold. It significantly decreased some indexes (standard
deviation of all normal sinus R-R intervals in the entire 24-hour recording and
standard deviation of the mean of all 5-minute segments of normal R-R intervals
of a 24-hour recording) of heart rate variability. These results suggest that
carteolol may reduce total myocardial ischemic burden by the reduction of cardiac
oxygen demand during daily activities and exercise stress, while not affecting
plasma levels of beta-endorphin, bradykinin, and pain threshold. Because
carteolol tended to decrease indexes of heart rate variability, significant
caution might be necessary in prescribing the beta-blocking agents with intrinsic
sympathomimetic activity like carteolol to patients with potential serious
arrhythmia.
PMID- 9398109
TI - Clinical implications of cigarette smoking in acute myocardial infarction: acute
angiographic findings and long-term prognosis.
AB - This study was undertaken to assess whether reperfusion in smokers could be
achieved spontaneously or therapeutically and to assess whether favorable outcome
in smokers could be sustained for years after infarction. We studied 260 patients
with anterior myocardial infarction who underwent coronary angiography and
thrombolysis within 24 hours after the onset of chest pain. There were 158
smokers and 102 nonsmokers. Smoking was associated more with men, younger age,
and less multivessel disease. On initial angiography, the distribution of
Thrombolysis in Myocardial Infarction grade was similar between smokers and
nonsmokers. After thrombolysis, Thrombolysis in Myocardial Infarction grade 3 was
more frequent in smokers (32% vs 18%; p = 0.004). In-hospital mortality rates
were lower (8% vs 18%; p = 0.022) and long-term cardiac survival was better in
smokers (5-year survival: 82% vs 70%; p = 0.022). Our data demonstrated that the
infarct artery of smokers responded more efficiently to thrombolysis and
favorable outcome in smokers was sustained throughout 5 years.
PMID- 9398110
TI - The effects of the angiotensin-converting enzyme inhibitor imidapril on plasma
plasminogen activator inhibitor activity in patients with acute myocardial
infarction.
AB - This study sought to determine whether early treatment with angiotensin
converting enzyme (ACE) inhibitors in patients with acute myocardial infarction
(AMI) is useful for the improvement of fibrinolytic function, as well as left
ventricular function. This study was designed to examine the levels of plasma
plasminogen activator inhibitor (PAI) activity and serum ACE activity during the
course of 2 weeks in 40 patients with AMI within 12 hours after the onset of the
symptom and who randomly received early treatment with either the ACE inhibitor
imidapril or a placebo (20 patients in the imidapril group and 20 in the placebo
group). The levels of serum ACE activity in the imidapril group decreased
significantly (p < 0.01) 8 hours after the administration of imidapril, and the
levels 24 hours after administration were significantly lower than those in the
placebo group (3.6 +/- 0.6 IU/L vs 7.4 +/- 0.8 IU/L; p < 0.001). The plasma PAI
activity increased gradually to peak levels 16 hours after the administration of
imidapril and placebo. The levels in the placebo group decreased gradually but
remained high during the study period. On the other hand, the levels of PAI
activity in the imidapril group decreased rapidly and those 48 hours after
administration were significantly lower than those in the placebo group (7.9 +/-
1.9 IU/ml vs 18.4 +/- 3.5 IU/ml; p < 0.01). The levels of left ventricular
ejection fraction about 2 weeks after admission were significantly higher in the
imidapril group than in the placebo group (65.9% +/- 2.5% vs 49.1% +/- 4.4%; p <
0.01). This study showed that imidapril, an ACE inhibitor, might be useful for
the improvement of fibrinolytic function and left ventricular function in the
acute phase of myocardial infarction.
PMID- 9398111
TI - Role of nitric oxide in coronary vasomotion during handgrip exercise.
AB - BACKGROUND: Endothelium-dependent modulation of coronary vasomotion during
increased sympathetic tone remains unclear in normal and atherosclerotic human
coronory arteries. METHODS AND RESULTS: We evaluated the role of endothelium
derived nitric oxide in vasomotion during isometric exercise in normal subjects
(n = 7) and in patients with coronary artery disease (CAD) (n = 10). Coronary
blood flow and epicardial coronary artery diameter to the handgrip test were
measured before and after intracoronary administration of 100 micromol/min of
N(G)-monomethyl L-arginine (L-NMMA). Heart rate and aortic blood pressure
increased during handgrip test. Handgrip test caused a significant dilation in
the diameter of the epicardial coronary artery in normal subjects (9.9% +/- 3.9%,
mean +/- SD) and in the diameter of smooth segments of patients with CAD (5% +/-
3.7%, p < 0.05 vs normal subjects). In contrast, the diameter of irregular
segments in patients with CAD decreased during handgrip test (-9.8 +/- 3.9%).
After L-NMMA, the epicardial coronary artery significantly increased during
handgrip test compared with before L-NMMA in normal subjects. L-NMMA did not have
any effect on handgrip test induced vasodilation in the smooth segments and
vasoconstriction in the irregular segments in the patients with CAD. Handgrip
test-induced increases in coronary blood flow did not change after L-NMMA in both
groups. CONCLUSIONS: Nitric oxide does not play a major role in HNG-induced
vasodilation in epicardial and microcirculatory vessels in normal human coronary
circulation. Although the decreased release in nitric oxide may modulate the
abnormal response of the epicardial coronary artery to handgrip test, this does
not explain the paradoxic constrictive response from the depressed but still
dilatory response in the patients with CAD.
PMID- 9398112
TI - Hanshin-Awaji earthquake as a trigger for acute myocardial infarction.
AB - On Jan. 17, 1995, the Hanshin-Awaji district was struck by the most destructive
earthquake ever to occur in Japan. It is commonly believed that acute emotional
stress such as that caused by an earthquake can trigger acute myocardial
infarction (AMI). The objective of this study was to evaluate the effect of the
quake stress on the onset of AMI in our district. The number of patients with AMI
during the first 4 weeks after the quake increased by about 3.5-fold. The mean
age of patients was 72.5 +/- 2.8 years, and the proportion of women (53%) was
significantly greater than in the preceding years. The proportion of patients
without prodromal angina pectoris was 53%. The mean post-traumatic stress
disorder reaction index score (n = 14) was 40.1 +/- 4.1, which indicates a severe
stress level. The mean score in the women (45.9 +/- 4.7; n = 7) was significantly
higher than that in the men (34.3 +/- 6.4; n = 7). We concluded that after an
earthquake, severe emotional stress can trigger AMI, more often than normal in
women.
PMID- 9398113
TI - Association of hemostatic factors with peripheral vascular disease.
AB - Hemostatic risk factors have been well established in coronary artery disease but
less well studied in peripheral vascular disease. The relationship of coagulation
and fibrinolytic proteins to lower limb arterial occlusive disease and other
vascular risk factors remains poorly defined. Fibrinogen, factor VII coagulant
activity, von Willebrand factor (vWf) antigen, and plasminogen activator
inhibitor-1 (PAI-1) activity were measured in 46 adult participants in the
Arterial Disease Multiple Intervention Trial (ADMIT) and in 76 control subjects
and related to ankle-brachial systolic pressure index (ABI), a measure of lower
limb arterial stenosis. The primary inclusion criterion for the ADMIT study
population was an average of two ABIs <0.85. Fibrinogen and PAI-1 in ADMIT
subjects were significantly higher than in control subjects (331 +/- 52 mg/dl vs
273 +/- 46 mg/dl, p < 0.0001; 18.7 +/- 10 units/ml vs 13.5 +/- 8.9 units/ml, p <
0.04). There were significant correlations of fibrinogen with ABI, factor VII
coagulant activity, and systolic and diastolic blood pressures; PAI-1 with body
mass index and age; and factor VII coagulant activity with cholesterol levels.
Logistic regression analysis, considering hemostatic variables and several known
nonhemostatic risk factors of peripheral arterial disease, showed that fibrinogen
and systolic blood pressure were independently associated with ABI status in this
population. The results demonstrate a strong independent correlation between
fibrinogen levels and the presence of lower limb arterial stenosis. PAI-1 levels
were elevated in ADMIT participants, but multivariate analysis did not
demonstrate an independent relationship between PAI-1 and ABI.
PMID- 9398114
TI - Gravitational forces and bone metabolism.
PMID- 9398115
TI - Association of gender and access to cadaveric renal transplantation.
AB - Previous studies have revealed that females are less likely than males to receive
a renal transplant, the most successful form of treatment of end-stage renal
disease (ESRD). The purpose of this study was to determine whether the barrier is
to inclusion on the transplant waiting list or to transplantation after being
placed on the transplant waiting list. An existing data set was used that
included data from the Michigan Kidney Registry, supplemented with data received
from the Organ Procurement Agency of Michigan. White and black patients less than
65 years of age and starting ESRD treatment between January 1, 1984, and December
31, 1989, were included. Cox proportional hazards models were used to determine
the effect of gender on (1) time to transplantation among all ESRD patients, (2)
time from diagnosis of ESRD to inclusion on the transplant waiting list among all
ESRD patients, and (3) time from inclusion on the waiting list to transplantation
among those patients on the waiting list. Patients were censored at the time of
living-related transplantation or death, and were monitored until December 31,
1989. In all, 5,026 incident ESRD patients were included in the study (44.3%
female). Of these, 1,626 patients were included on the waiting list (40.1%
female); 823 of these received a transplant (37.7% female). Adjusting for age,
race, and diagnosis, females were 25% less likely to receive a cadaveric
transplant than males (female to male relative rate ratio [RR], 0.75; P < 0.001).
Females with ESRD aged 46 to 55 years and 56 to 65 years were 33% (RR, 0.67; P <
0.001) and 29% (RR, 0.71; P < 0.05) less likely to be included on the transplant
waiting list, respectively, than their male counterparts. There was no difference
in the rate of wait list inclusion among ESRD patients younger than 46 years.
Females with ESRD who were included on the transplant waiting list were 26% (RR,
0.74; P < 0.001) less likely to receive a transplant than males on the waiting
list. These results indicate that females are both less likely to be on the
transplant waiting list (ages over 45 years) and, once on the list, less likely
to receive a transplant (all ages) than males. Further study is necessary to
determine the factors contributing to these important barriers to transplantation
among females with ESRD.
PMID- 9398116
TI - Factors determining the rate of referral, transplantation, and survival on
dialysis in women with ESRD.
AB - The determinants of referral for transplantation in women have not been well
studied. Similarly, factors determining survival on dialysis and the rate of
transplantation in women remain controversial. Women have been reported to have
lower rates of transplantation than men, and black women have the lowest rates of
all groups. We questioned whether black women were referred at lower rates than
whites and if race and other socioeconomic factors predicted referral, rate of
renal transplantation, and patient survival on dialysis. All women in Allegheny
or Philadelphia counties in Pennsylvania initiating dialysis between January 1,
1990, and December 31, 1992, were eligible for this study. Information was
requested by questionnaire from each dialysis unit in these areas. Of the 383
eligible patients, completed questionnaires were obtained for 276 (72%). Ninety
three (54.7%) of the black patients and 57 (53.8%) of the white patients were
referred for transplantation (P = 0.8). Declining the transplant option was the
most common reason for nonreferral in both races. Patients with high school or
greater education were approximately twice as likely to be referred than those
with grade school educations (odds ratio [OR], 2.2; P = 0.04). Patients with
coexisting illness were 67% (OR, 0.33; P = 0.004) less likely to be referred
compared with patients with no other illnesses. Each additional year of age
reduced the chances of being referred by 6% (OR, 0.94; P = 0.0001). Homemakers
were 83% (P = 0.0008) and others 55% (P = 0.07) less likely to be referred
compared with employed patients. Patients in Philadelphia County were 56% less
likely to be referred compared with those in Allegheny County (P = 0.024). Race
was not significantly associated with referral. Predictors of transplantation
included age (RR, 0.96; confidence interval [CI], 0.93 to 0.99; P = 0.13), white
race (RR, 2.2; CI, 1.3 to 4.0; P = 0.0053), presence of other illnesses (RR,
0.37; CI, 0.21 to 0.65; P = 0.0006), and employment status. White homemakers were
86% (RR, 0.14; CI, 0.03 to 0.6; P = 0.0082) less likely than those with other
employment situations to receive a transplant. Factors predicting patient
survival on dialysis included race, educational status, and presence of comorbid
illnesses. White patients were approximately four times (RR, 3.7; CI, 1.7 to 8.1;
P = 0.002) more likely to die than black patients. Patients with high school or
greater education were 56% (RR, 0.44; CI, 0.2 to 0.92; P = 0.008) less likely to
die than those with grade school education alone. Patients with at least one
coexisting illness were approximately 1.7 times (RR, 1.68; CI, 1.1 to 2.4; P =
0.001) more likely to die than those without other illnesses. In summary, race
was not a factor in referral for transplantation, but was predictive of
transplantation and patient survival on dialysis. Socioeconomic factors such as
educational status, age, and employment status were highly predictive of
transplantation and long-term survival on hemodialysis. White homemakers
unexpectedly received transplants less than any other group of dialysis patients.
Further study is needed to determine why these potential transplant patients have
declined or deferred transplantation.
PMID- 9398117
TI - Minimizing racial disparity regarding receipt of a cadaver kidney transplant.
AB - This report describes the impact of race on waiting list entry and receipt of a
cadaver kidney transplant, after accounting for self-reported income, health and
functional status, and patients' attitudes about dialysis and transplantation as
treatment alternatives. Previous studies did not account for these race-related
factors and therefore produced biased estimates of the impact of race on waiting
list entry and receipt of a transplant. Data for this investigation came from a
telephone survey of a national sample of 456 end-stage renal disease patients and
from files maintained by the United Network for Organ Sharing and the Health Care
Financing Administration. Proportional hazard models were estimated with these
data. The results indicated that approximately 60% of the differences between
black and white waiting list entry rates and 52% of the black-white differences
in transplantation rates were due to race-related differences in socioeconomic
status, health and functional status, severity of illness, biological factors,
the existence of contraindications to transplantation, transplant center
characteristics, and patients' attitudes about dialysis and transplantation.
Potential ways to narrow racial differences further include better education
about treatment alternatives for black patients, more vigorous efforts to obtain
donor organs from minorities, continued research and thoughtful policy on the
access-related impacts of United Network for Organ Sharing point system
variances, and consolidation of some smaller waiting lists into larger regional
lists.
PMID- 9398118
TI - Renal transplantation in adults with autosomal recessive inheritance of hemolytic
uremic syndrome.
AB - When hemolytic uremic syndrome (HUS) is occasionally inherited in an autosomal
recessive mode, this occurs mainly in infants and children. We describe four
families in which two adult siblings were affected with HUS in each kindred. HUS
first occurred between the ages of 19 to 36 years, and the intervals between the
onset of HUS in each sibling pair ranged from 6 months to 6 years. None of the
patients had a typical prodrome of bloody diarrhea, and one had a recurrence of
HUS before transplantation. All eight patients developed renal failure requiring
dialysis and transplantation, and seven patients received kidney transplants.
Donor kidneys were from parents, siblings, and cadavers. The initial renal
transplants were performed from 6 months to 6 years after the onset of the
syndrome. HUS recurred in six of the seven patients 2 weeks to 6.5 years after
transplantation regardless of the interval between the onset of HUS and
transplantation, the origin of the allograft, or the use of cyclosporin A. The
only marker for autosomal recessive HUS is the occurrence of the syndrome in a
second sibling several months to many years after its occurrence in the proband.
In patients with the autosomal recessive form of HUS, the risk for a recurrence
in an allograft is high regardless of the source of the kidney.
PMID- 9398119
TI - Cytomegalovirus and HLA-A, B, and DR locus interactions: impact on renal
transplant graft survival.
AB - Graft failure rates for renal transplantations performed between 1989 and 1994
and recorded in the US Renal Data System database were retrospectively evaluated
for interactions between cytomegalovirus and HLA-A, B, and DR loci. Twelve
significant interactions were observed. There were significantly greater risks of
graft failure for the total effect of cytomegalovirus and donor or matched HLA
DR9, recipient or matched HLA-B-51, and matched HLA-B13. We conclude that further
study of renal transplants with these combinations of cytomegalovirus and HLA
loci is needed to determine whether the observed interactions should be taken
into consideration when matching donors with recipients.
PMID- 9398120
TI - Intradialytic hypotension: is midodrine beneficial in symptomatic hemodialysis
patients?
AB - Symptomatic hypotension during hemodialysis is a disabling complication in end
stage renal disease (ESRD) patients, especially in certain groups of patients who
are at higher risk for this problem. Autonomic dysfunction is thought to play a
significant role. We evaluated the efficacy of midodrine, an oral agent with
selective alpha-adrenergic agonist activity used in the treatment of neurogenic
orthostatic hypotension, on 10 hemodialysis patients with persistent
intradialytic hypotension. The patients were given a dose of midodrine (mean
dose, 5.5 mg; range, 5 to 10 mg) 30 minutes before each hemodialysis session. We
compared blood pressure, pulse, body weight, and laboratory values for 10
consecutive dialysis sessions off and on midodrine therapy. There was a
statistically significant improvement in lowest intradialytic systolic blood
pressure (from 96.6 to 114.7 mm Hg; P < 0.001), lowest intradialytic diastolic
blood pressure (from 53.2 to 59.0 mm Hg; P = 0.002), lowest intradialytic mean
arterial pressure (from 67.7 to 77.6 mm Hg; P < 0.001), posthemodialysis systolic
blood pressure (from 116.5 to 127.1 mm Hg; P < 0.001), posthemodialysis diastolic
blood pressure (from 66.6 to 69.7 mm Hg; P = 0.040), and posthemodialysis mean
arterial pressure (from 83.2 to 88.8 mm Hg; P = 0.001) after patients were placed
on midodrine. There also was a small but statistically significant decrease in
intradialytic pulse rate (from 86.3 to 81 beats/min; P = 0.021) and
posthemodialysis pulse rate (from 87.4 to 81.7 beats/min; P = 0.024) after
initiation of midodrine therapy. There was no significant difference in any of
the prehemodialysis blood pressure measurements or pulse rate off or on midodrine
therapy. The improvements in intradialytic and posthemodialysis blood pressure
were associated with a uniform subjective improvement in symptoms associated with
dialysis hypotension, such as cramps, fatigue, dizziness, and weakness. Other
than scalp paresthesia in one patient, no adverse effects were noted. Our results
suggest that the administration of a single dose of midodrine before hemodialysis
is an effective therapy for intradialytic hypotension. A prospective trial with
adequate patient numbers and long-term follow-up would be useful to evaluate this
drug's efficacy and safety profile in patients with ESRD.
PMID- 9398121
TI - Relationship between left ventricular hypertrophy, myocardial contractility, and
load conditions in hemodialysis patients: an echocardiographic study.
AB - Left ventricular hypertrophy (LVH) is common and is an independent cardiac risk
factor in dialysis patients. The aim of this study was to assess hemodynamic
determinants of LVH and, more particularly, the relationship between left
ventricular mass, myocardial contractility, and load conditions. Eighty dialysis
patients aged 51 +/- 15 years were prospectively studied by echocardiography. LVH
was detected in 62 patients (78%). Left ventricular mass was significantly
correlated to both end-diastolic volume (r = 0.54; P < 0.001) and end-systolic
stress/end-systolic volume, an index of contractility (r = -0.66; P < 0.001), but
not to systolic blood pressure or end-systolic stress, both indexes of afterload.
Thus, in dialysis patients, the degree of LVH is significantly correlated with
the severity of both left ventricular dilatation and contractile myocardial
failure, but not with left ventricular afterload.
PMID- 9398122
TI - Hemodialysis: an appropriate therapy in myeloma-induced renal failure.
AB - To determine whether vigorous treatment with dialysis is of benefit to patients
with myeloma-induced renal failure at presentation, we retrospectively reviewed
outcomes in a group of patients diagnosed with multiple myeloma between January
1986 and September 1993. Increased age (P = 0.003), presence of renal impairment
(P = 0.006), and failure to enter plateau phase (P < 0.001) were independently
associated with shortened survival. However, there was no difference in outcome
between patients with severe renal failure, those treated with dialysis, and
those with milder renal impairment (median survival, 22 months in both groups),
nor was reversibility of renal failure associated with any survival advantage.
The lack of correlation between severity or reversibility of the renal failure
and survival suggests that there may be characteristics of some patients or their
underlying myeloma that are responsible both for renal impairment and for adverse
prognosis. In this study, neither age, clinical stage, labeling index, nor
response to treatment was able to account for the difference in outcome between
patients with and without renal failure. The prolongation of life achieved in the
dialysis patients such that their median survival was identical with that of the
group with milder renal impairment was considered to represent a significant
benefit to these patients and to justify the offer of dialysis to all patients
requiring it.
PMID- 9398123
TI - Patient's view of dialysis care: development of a taxonomy and rating of
importance of different aspects of care. CHOICE study. Choices for Healthy
Outcomes in Caring for ESRD.
AB - Quality assessment efforts to enhance public accountability in dialysis care and
to support provider efforts to improve care have lacked patient input. To develop
brief patient evaluation or satisfaction surveys suitable for busy clinical
settings, knowing patients' priorities can be helpful in deciding which aspects
of care should be tracked. We conducted a study to identify salient attributes of
dialysis care and to rank the importance of these attributes from the perspective
of dialysis patients. We analyzed the content of patient focus group transcripts
to characterize dialysis care from the patients' perspective. We then surveyed 86
patients to determine how patients would rank the importance of each aspect to
quality of dialysis care. The 18 broad aspects of care identified in the focus
group included: (1) care provided by nephrologists, (2) care provided by other
physicians (nonnephrologists), (3) care provided by dialysis center nurses, (4)
care provided by social workers and psychologists, (5) care provided by
dieticians, (6) clergy, (7) care provided by technicians and physician
assistants/nurse practitioners, (8) care provided by dialysis center staff in
general, (9) supplies, (10) treatment choice and effectiveness, (11) patient
education and training, (12) self-care, (13) dialysis machines, (14) unit
environment and policies, (15) cost containment, (16) billing, (17) cost of care,
and (18) health outcomes. Items ranked in the top 10 by both groups of patients
included issues related to nephrologists, other doctors, nurses, and patient
education and training. Compared with hemodialysis patients, peritoneal dialysis
patients gave higher ratings to hospital doctors' and nurses' attention to
cleanliness when working with access sites, how correct the nephrologist's
instructions to patients are, whether emergency room doctors check with
nephrologists, the amount of information patients get about their diet, and how
well nurses answer patients' questions. Patients value certain aspects of
dialysis care highly, and these aspects differed in some respects for the
relatively small number of hemodialysis and peritoneal dialysis patients studied.
Construction of brief questionnaires for quality assessment and assurance
requires thoughtful consideration of what questions to include. Knowing patients'
priorities regarding the most important aspects of care that have high potential
for dissatisfaction may be helpful to continuous quality improvement of end-stage
renal disease care.
PMID- 9398124
TI - Supraclavicular approach to the subclavian/innominate vein for large-bore central
venous catheters.
AB - Infraclavicular and internal jugular catheterization are commonly used techniques
for hemodialysis access, but may at times be impeded in patients whose anatomy
makes cannulation difficult. In an effort to enlarge the spectrum of alternative
access sites, we evaluated the supraclavicular approach for large-bore catheters.
During an 18-month period we prospectively collected data on success rate and
major and minor complications of the supraclavicular access for conventional
dialysis catheters as well as Dacron-cuffed tunneled devices in 175 adult
patients admitted for various extracorporeal therapies and bone marrow
transplantation. Two hundred eight large-bore catheters (99 conventional dialysis
catheters, 63 semirigid tunneled Dacron-cuffed catheters, and 46 Hickman
catheters) were successfully placed in 164 patients (success rate, 93.8%), 58
(33.1%) of whom had been previously catheterized. Complications included
pneumothorax (one patient), arterial puncture (seven patients), and puncture of
the thoracic duct (two patients) without sequelae. Postinsertional chest
radiographs demonstrated impressive coaxial lie of most catheters. Catheter
malpositions occurred only sporadically (1%). Difficulty of introducing the
catheter via a placed sheath was rarely observed. There was no clinically
significant evidence of catheter-induced venous thrombosis or stenosis. We
conclude that the supraclavicular route is an easy and safe first approach for
large-bore catheters, as well as a useful alternative to traditional puncture
sites for precatheterized and anatomically problematic patients.
PMID- 9398125
TI - Evidence that serum phosphate is independently associated with serum PTH in
patients with chronic renal failure.
AB - There has been controversy regarding the initial pathogenic events involved with
the hyperparathyroidism of chronic renal failure (CRF). Low serum levels of 1,25
dihydroxyvitamin D in uremic patients are postulated by some as having a role in
permitting higher parathyroid hormone (PTH) secretion. However, recent animal and
in vitro studies strongly suggest that phosphate has a direct effect on
parathyroid cells to enhance PTH secretion. To evaluate the relationships among
serum phosphate, calcium, PTH, and 1,25-dihydroxyvitamin D in uremic humans, we
performed a cross-sectional analysis of 84 patients with varying levels of CRF.
Using stepwise regression analysis after adjusting for multiple comparisons, we
found that serum phosphate correlated directly with serum PTH (r = 0.62, P <
0.01) in patients with mild to moderate CRF (creatinine < or = 3.0 mg/dL),
independent of serum calcium and 1,25-dihydroxyvitamin D levels. In patients with
more severe renal failure (creatinine > 3.0 mg/dL), only the serum calcium
correlated with serum PTH (r = -0.47, P < 0.01). While serum 1 ,25
dihydroxyvitamin D showed no correlations with PTH, phosphate, or calcium at any
stage of renal failure, the mean 1,25-dihydroxyvitamin D level in patients with
mild CRF was lower than that in age-matched controls (24 +/- 3 pg/mL v 37 +/- 2
pg/mL; P < 0.01), suggesting that low 1,25-dihydroxyvitamin D was permissive for
enhanced PTH secretion. These data demonstrate an independent association of
serum phosphate with PTH in patients with CRF and suggest that phosphate may
directly enhance PTH secretion in this setting. This study supports recent animal
studies showing a direct parathyroid cell effect of phosphate on PTH secretion.
PMID- 9398126
TI - Evaluation of RBC ferritin and reticulocyte measurements in monitoring response
to intravenous iron therapy.
AB - Intravenous (IV) iron therapy can reduce erythropoietin (EPO) requirements in
dialysis patients. Monitoring this response accurately is difficult. Estimation
of red blood cell ferritin (RBCFer) and reticulocyte indices may give additional
valuable information about iron availability to the erythroblasts (erythron). We
evaluated the use of RBCFer, mean hemoglobin content of reticulocytes (CHr), and
mean hemoglobin concentration of reticulocytes (CHCMr) in a prospective,
nonblinded study of 22 hemodialysis patients (16 men and six women with a mean
age of 62 years [range, 24 to 80 years]). All patients had an initial serum
ferritin of < or = 60 microg/L. Patients with features known to produce EPO
resistance and underlying bleeding/hematologic disorders were excluded. Patients
were established on subcutaneous EPO and given IV iron therapy. The mean
hemoglobin level remained constant throughout the study (P = 0.087). Serum
ferritin and RBCFer increased significantly (P < 0.001 and 0.015, respectively)
while a reduction in transferrin saturation became significant at the end of the
study (P = 0.0047). A sharp increase in reticulocytes occurred in the first 14
days after commencement of IV iron, and there was an initial decrease in the
percentage of hypochromic RBCs. An early decline in RBCFer was apparent. CHr
increased with IV iron, indicative of increased iron supply to the developing
erythron. Measurement of RBCFer and CHr provide evidence of increased iron supply
for erythropoiesis during IV iron therapy. These measures help identify patients
with functional iron deficiency and allow more accurate monitoring of response to
IV iron therapy.
PMID- 9398127
TI - Oncotic pressure and edema formation in hypoalbuminemic HIV-infected patients
with proteinuria.
AB - Human immunodeficiency virus nephropathy (HIVN) continues to challenge
nephrologic consultative services at major urban institutions. Although noted in
the literature, the decreased incidence of peripheral edema in HIVN has been
unexplained to date. In HIV patients, total proteins frequently are found to be
elevated due to an elevated globulin fraction. The impact that plasma proteins,
specifically globulins, have on the total oncotic pressure has not been reported
in HIVN, but may play a role in the paucity of edema noted in this proteinuric
population. To evaluate the contributions of serum globulin to the total oncotic
pressure and the presence or absence of edema in HIVN, we randomly selected 27
patients with proteinuria greater than 2.5 g/24 hr and serum albumin less than
3.1 g/dL from patients presenting to the nephrology outpatient clinic at the
University of Miami/Jackson Memorial Hospital. Seventeen of the patients (63%)
had a known diagnosis of HIV infection (group 1). These patients were subdivided
into two subgroups: those presenting with clinically evident edema on physical
examination (n = 7 [41%]; group 1A) and those who had an absence of edema (n = 10
[59%]; group 1B). Conversely, group 2 comprised 10 patients without known HIV
infection, of whom six (60%) had edema (group 2A) and four (40%) did not (group
2B). Blood pressures were noted, and mean arterial pressure was calculated using
standard formulas. Serum albumin, serum total proteins, and urine total proteins
were measured using standard laboratory methods. Oncotic pressures for albumin
(alpha), globulin (beta), and total protein (c) were calculated using the
following formula: COPpl = alpha(2.8c + 0.18c2 + 0.012c3) + beta(0.9c + 0.12c2 +
0.004c3). We used Student's t-test to analyze the data. There is no significant
difference between the albumin concentrations of HIV patients without edema
(group 1B) and non-HIV patients with edema (group 2A), with mean concentrations
of 2.3 +/- 0.1 g/dL versus 2.3 +/- 0.15 g/dL, respectively (P = NS). Group 1B,
however, has a total oncotic pressure of 17.1 +/- 1.5 mm Hg, whereas both groups
with edema (groups 1A and 2A) have statistically significant lower total oncotic
pressures (12.1 +/- 2.3 mm Hg and 12.9 +/- 1.1 mm Hg, respectively; P < 0.05).
The globulin oncotic pressures may account for some of the differences in total
oncotic pressures, being significantly higher for those patients without edema in
group 1B compared with group 2A (7.1 +/- 0.9 mm Hg v 3.9 +/- 0.4 mm Hg,
respectively; P < 0.05). In patients with HIV, however, the presence or absence
of edema is mandated by albumin concentration because both groups have similar
globulin concentrations (group 1A 3.1 +/- 0.1 g/dL v group 1B 3.8 +/- 0.3 g/dL; P
= NS). Mean arterial pressure does not play a role in edema formation in this
study because the HIV patients without edema had the higher blood pressures
(group 1B 97.8 +/- 4.7 mm Hg v group 2A 84.7 +/- 5.5 mm Hg; P < 0.05). We
conclude that globulins play an important role in maintaining oncotic pressure in
low albumin states. HIVN patients with increased serum immune globulin may
benefit from higher globulin oncotic pressure, delaying the onset of clinical
edema in the setting of proteinuria.
PMID- 9398128
TI - Factors contributing to the degree of polyuria in a patient with poorly
controlled diabetes mellitus.
AB - Polyuria due to a glucose-induced osmotic diuresis is common in patients with
hyperglycemia. This diuresis usually abates when the plasma glucose level
approaches its renal threshold; the usual time course is less than 8 hours after
commencing therapy. A 69-year-old man with non-insulin-dependent diabetes
mellitus maintained hyperglycemia (540 mg/dL) and polyuria (4.7 L/24 hr) for 40
hours. Because there was no external supply of glucose, a balance study was
conducted between the third and 40th hour after commencing treatment. In this
interval, the overall concentration of glucose in the urine was less than 100
mmol/L and the urine osmolality was 378 mOsm/kg H2O. To evaluate the expected
composition of the urine during a glucose-induced osmotic diuresis, urine was
analyzed in normal rats infused with glucose plus urea and in untreated BB
diabetic rats (plasma glucose and urea similar to that in our patient) as well as
in 29 patients with hyperglycemia and polyuria. Glucose accounted for 60% of the
urinary osmoles in rats and humans. Two subgroups of patients had a much lower
urine glucose: one had an impaired concentrating ability (n = 6) and the other
had an increased rate of renal glucose reabsorption (n = 5). In conclusion, in
polyuria caused by hyperglycemia, the urine glucose should be 300 to 400 mmol/L
with normal renal function. In the case we report, both the concentration of
glucose and its excretion rate were much lower than expected with steady-state
hyperglycemia (540 mg/dL) due to the high rate of excretion of NaCl, a
concentrating defect, and excessive renal reabsorption of glucose.
PMID- 9398129
TI - Secondary collapsing glomerulopathy associated with Loa loa filariasis.
AB - This is the first case of nonprimary collapsing focal segmental
glomerulosclerosis (FSGS) associated with Loa loa filariasis. Loa loa
micofilariae were detected on a blood smear after a patient presented with
nephrotic syndrome (NS), microhematuria, and renal failure. The renal biopsy
showed a collapsing glomerulopathy variant of FSGS. Microfilariae also were
identified in renal microvasculature, including the afferent arterioles and the
glomerular and peritubular capillaries.
PMID- 9398131
TI - Xanthogranulomatous pyelonephritis in a renal allograft recipient.
AB - Xanthogranulomatous pyelonephritis rarely occurs in renal allografts. This is the
fifth reported case. Diagnosis was made by renal biopsy, which is usually
performed to evaluate an elevated serum creatinine. Associated patient
symptomology is nonspecific, and graft imaging with ultrasonography and computed
tomography was not helpful as it would be with native kidney xanthogranulomatous
pyelonephritis. Successful treatment with antibiotics may depend on the serum
creatinine at presentation. Prognosis, therefore, is guarded, with a common
outcome of irreversible renal dysfunction.
PMID- 9398130
TI - Leptospirosis: an ignored cause of acute renal failure in Taiwan.
AB - Leptospirosis, caused by a spirochete, is the most common zoonosis in domestic or
wild animals. Animals excrete infected urine in soil or water and may cause human
infections through abrased wound, mucosa, conjunctiva, or by swallowing
contaminated water. Clinical presentations of leptospirosis are mostly
subclinical. Five to ten percent of leptospirosis are fatal, causing fever,
hemorrhage, jaundice, and acute renal failure (Weil's syndrome). Leptospirosis
has been ignored as a cause of acute renal failure in Taiwan. We report two
patients with leptospirosis who presented with high fever, abdominal pain,
jaundice, and acute renal failure. Patient 1 died on day 12 of admission of
multiple organ failure associated with pancytopenia, hypogammaglobulinemia, and
reactive hemophagocytosis. Leptospirosis was recognized after death. Patient 2
was admitted with similar presentations 2 weeks later. Penicillin and doxycycline
were given early in the course, and azotemia, jaundice, respiratory failure, and
aseptic meningitis gradually improved. Renal biopsy showed interstitial
nephritis. Several tubular clearance tests showed proximal tubular defect with
severe bicarbonate wasting (FeHCO3- 20.9%) and incomplete type II renal tubular
acidosis without affecting the distal nephron. After 80 days of treatment, this
patient was discharged with recovery of conscious level and renal function. This
is the first leptospirosis patient with detailed tubular functional and
morphological studies of the kidney. Diagnosis of leptospirosis was made by
microscopic agglutination test (MAT) for antibody to leptospira and by polymerase
chain reaction (PCR) for leptospira DNA in blood and urine (interrogans serogroup
australis in case 1 and Leptospira borgpetersenii serogroup ballum in case 2).
Because active surveillance has resulted in 13 cases diagnosed as leptospirosis
islandwide thereafter, underestimation and ignorance of leptospirosis as a cause
of acute renal failure may occur in Taiwan. Therefore, an area with a low
leptospirosis incidence may actually have a very high incidence. Leptospirosis
should be suspected in febrile patients with jaundice and renal failure when
pathogens cannot be identified by traditional culture for microorganisms.
PMID- 9398132
TI - Systemic thrombolysis for acute myocardial infarction in a renal transplant
recipient.
AB - This study describes the successful management of an acute myocardial infarction
occurring in a renal transplant recipient with thrombolytic therapy. Although
primary coronary angioplasty has been addressed as an alternative therapeutic
approach, this approach raises concern for angiography-related contrast media
renal toxicity. However, pharmacological therapy with thrombolytics is effective
and relatively safe and should be considered as the first-choice treatment in
today's clinical setting.
PMID- 9398133
TI - Renal artery dissection causing renal infarction in otherwise healthy men.
AB - Arterial dissection is usually associated with pathological states such as
malignant hypertension, severe atherosclerosis, severe trauma, Marfan syndrome,
or Ehlers-Danlos syndrome. However, we report three cases in which renal artery
dissection occurred in otherwise healthy, normotensive men. In two cases, the
onset of symptoms of renal artery dissection was coincident with an unusual
degree of physical activity. In the third case, the symptoms occurred while the
patient was sitting but during a stressful business meeting. In each case, the
patient experienced severe unilateral flank pain. Urolithiasis was suspected, but
intravenous pyelography showed only ipsilateral impaired renal cortical
perfusion, and the urinalyses showed no hematuria. The diagnosis of renal artery
dissection was established by arteriography in two cases and by nephrectomy in
one case. The latter case showed fibromuscular dysplasia by arteriography
performed after the nephrectomy. The other two cases showed no evidence of
fibromuscular dysplasia. We conclude that spontaneous renal artery dissection can
occur in otherwise healthy individuals. Our experience and the reports of others
indicate that this condition occurs mainly in men, conservative (nonsurgical)
management is generally indicated, and the long-term prognosis is generally
excellent. In some patients, an unusual degree of physical exertion might be the
cause of renal artery dissection.
PMID- 9398134
TI - Influence of gender and race on therapeutic options for ESRD patients.
PMID- 9398135
TI - National Kidney Foundation report on dialyzer reuse. Task Force on Reuse of
Dialyzers, Council on Dialysis, National Kidney Foundation.
AB - The Council on Dialysis of the National Kidney Foundation convened an expert
panel to evaluate the current practice and literature related to the reuse of
hemodialyzers. The panel reviewed and evaluated literature related to reuse since
the last report of the National Kidney Foundation recommendations on reuse was
published in 1988. The group sought to develop a consensus concerning the effect
of reuse of hemodialyzers on mortality; the efficiency of delivered hemodialysis
when reused hemodialyzers are used in the clinical setting; the clinical effects
of reused dialyzers as compared with dialyzers not reused on intradialytic
symptoms; infections in patients using reused dialyzers; and the effect of reused
dialyzers on complement activation, cytokine production, and beta2-microglobulin
metabolism and clearance. In addition, the panel reviewed the literature on the
potential toxicity of germicides used in the processing of dialyzers for reuse as
well as recent changes in federally mandated regulations concerning labeling of
dialyzers for reuse, the monitoring of the reuse process, and the effectiveness
of reused dialyzers to achieve a prescribed delivered clearance as estimated by
urea kinetic modeling or by percent urea reduction. The National Kidney
Foundation takes no position for or against dialyzer reuse. The principal reason
for the practice of reuse is economical. In view of the uncertainties related to
the safety and biological impact of reuse procedures, the task force recommends
that a full discussion of the issue of reuse and its potential beneficial and
detrimental effects be undertaken with each patient. There is no conclusive
evidence to substantiate the notion that either morbidity or mortality associated
with single use or reuse is different. Microbial contamination of the water used
for dialyzer reprocessing increases patient morbidity. The chemical quality of
water used for dialyzer reprocessing should, at least, fall within the same
standards as those recommended for product water intended for hemodialysis.
Dialyzers should not be reprocessed from patients who have tested positive for
hepatitis B surface antigen. The effects of reprocessing high-flux dialyzers on
beta2-microglobulin clearance are dependent on the reprocessing technique, the
number of reuses, and the nature of the dialyzer membrane used. There are
insufficient data on the effects of reuse on beta2-microglobulin behavior to make
uniform recommendations. Untoward effects of reused dialyzers may still occur in
spite of rigorous adherence to the AAMI guidelines. For example, use of the total
cell volume method for assessing changes in small molecule clearances will not
show the loss of performance attributable to dialysate shunting. For this reason,
the measurement of Kt/V for urea as recommended by the AAMI or the determination
of the urea reduction ratio (URR) is strongly recommended at least monthly to
gauge the adequacy of the dialysis procedure. Given the significant fall in
dialyzer efficiency for urea removal that can occur after repeated uses of a
dialyzer, dialysis prescriptions in units practicing reuse should be designed to
deliver a Kt/V or URR value that exceeds the dose used for patients treated with
single-use dialyzers to make allowance for any possible reuse-induced reduction
in dialyzer efficiency. Technicians and other personnel responsible for the
reprocessing of dialyzers should receive proper training. These health care
providers should be certified in reprocessing by an examining body so that
professional competency can be assured.
PMID- 9398136
TI - Cyclophosphamide therapy of severe lupus nephritis.
PMID- 9398137
TI - Sickle cell nephropathy during the postpartum period in a patient with SLE.
PMID- 9398138
TI - Expression and function of calcineurin in the mammalian nephron: physiological
roles, receptor signaling, and ion transport.
AB - Protein phosphorylation is central to the regulation of sodium transport and
other cellular processes in the nephron. Complex interactions between protein
kinases and phosphatases catalyze the reversible phosphorylation of ion
transporting proteins on the apical and basolateral surfaces of renal epithelia.
Although the role of protein kinases in regulating sodium transport has been
extensively studied, the function of phosphatases in the nephron is less well
understood. Calcineurin is a serine-threonine phosphatase that was shown to be
the target of cyclosporin A (CsA) and FK-506 in lymphocytes. Calcineurin exists
in the cytosol as a heterotrimeric protein composed of an alpha-catalytic
subunit, beta-regulatory subunit, and calmodulin; its activity depends on calcium
and calmodulin. Three isoforms of the alpha-subunit (alpha-1, alpha-2, alpha-3)
and two isoforms of the beta-subunit (beta-1 and beta-2) of calcineurin have been
identified. In proximal tubules, alpha-1 isoforms are predominant and exceed
alpha-2 expression by fourfold. In the CCD, alpha-1 and alpha-2 expression are
approximately equal, whereas alpha-2 subunit expression is greatest in medullary
thick ascending limbs (mTAL). Alpha-3 was not detected in any nephron segment.
Calcineurin phosphatase activity in the proximal tubule is approximately 10-fold
higher than in the connecting tubules (CNT), cortical collecting ducts (CCD), or
the mTAL. Protein phosphatases 1 and 2a are also expressed in CCD, and only
protein phosphatase 1 can be detected in the proximal tubule. Calcineurin
influences basal and stimulated Na/ K-ATPase activity in the proximal and distal
nephron. In the CCD, CsA or FK-506 decrease Na/K-ATPase activity by 35% and 85%,
respectively; Na/K-ATPase activity in mTAL is decreased by 53% and 56%.
Activation of membrane receptors, including adrenergic, dopamanergic, and
angiotensin I receptors, also regulates Na/K-ATPAse activity through processes
that involve calcineurin. Lastly, steroid hormones including glucocorticoids and
mineralocorticoids appear to activate calcineurin phosphatase activity. The
mechanism is independent of transcription and appears to involve mechanisms
involving heat shock proteins associated with the steroid receptor complex.
PMID- 9398139
TI - An evidence-based approach to earlier initiation of dialysis.
AB - The objective was to review evidence addressing the optimal time to initiate
dialysis treatment. The database was derived from an evidence-based review of the
medical literature and from the Canada-United States peritoneal dialysis study.
The publications were divided into (1) those addressing the clinical impact of
early versus late referral to a dialysis program; (2) those evaluating the
association between residual renal function at initiation of dialysis and the
concurrent nutritional status; (3) those evaluating the association between
residual renal function at initiation of dialysis and subsequent clinical
outcomes, including patient survival. There were five studies evaluating early
versus late referral, three cohort design and two case-control design. Late
referrals had worse outcomes than early referrals. The former had more serious
comorbidity and many had been noncompliant with follow-up. The latter were more
likely to have hereditary renal disease. Renal function was slightly worse at
initiation among those referred late. Three studies addressed the association
between renal function at initiation of dialysis and concurrent nutritional
status. Two showed decreased protein intake with diminished glomerular filtration
rate (GFR). Poor nutritional status is associated with decreased patient survival
among both incident and prevalent dialysis patients. The third study reported
excellent patient survival among patients with late initiation of dialysis. These
patients had received a supplemented low-protein diet and were not malnourished
at initiation of dialysis. Three groups have studied the association between GFR
at initiation of dialysis and clinical outcomes. Decreased GFR at initiation of
dialysis is associated with a increased probability of hospitalization and death.
None of these studies has used the rigorous randomized clinical trial design, and
they are therefore subject to bias. Referral time bias, comorbidity, patient
compliance, and starting time bias are potential confounders. A randomized
clinical trial is required to resolve this important issue. However, there is
sufficient evidence to justify initiation of dialysis at a Ccr of 9 to 14 mL/min
if there is any clinical or laboratory evidence of malnutrition.
PMID- 9398140
TI - Achieving target hematocrit in dialysis patients: new concepts in iron
management.
AB - The management of anemia in dialysis patients involves a comprehensive
understanding of the role of erythropoietin deficiency and of the importance of
adequate available iron. It is clear that iron and recombinant human
erythropoietin (rHuEPO) in concert allow the clinician to achieve a given target
hematocrit in dialysis patients. By first repleting and then maintaining iron
stores, and with an appreciation of the concept of functional iron deficiency,
the nephrologist can achieve target hematocrits with the lowest necessary dose of
rHuEPO. Iron repletion and maintenance is difficult to achieve with oral iron,
and parenteral iron is needed in most cases. New protocols for ongoing parenteral
maintenance therapy with iron dextran or iron gluconate, a form of iron likely to
be available soon in the United States, should lead to achievement of target
hematocrits in a greater number of patients and be cost-effective in improving
patient outcomes.
PMID- 9398141
TI - Reticulocyte hemoglobin content predicts functional iron deficiency in
hemodialysis patients receiving rHuEPO.
AB - Early detection of iron sufficiency at the level of the erythropoietic cell is
necessary to optimize management of uremic anemia with recombinant human
erythropoietin (rHuEPO). "Absolute" and "functional" iron deficiency are the most
important factors causing resistance to administered rHuEPO. Transferrin
saturation and serum ferritin measurements have been noted to be insensitive and
inaccurate measures to detect functional iron deficiency. Recently, the
reticulocyte hemoglobin content (CHr) has been shown to be a sensitive and
specific indicator of functional iron deficiency in nondialysis patients treated
with rHuEPO. The purpose of this study is to compare CHr with currently used
indices of iron sufficiency in rHuEPO-treated hemodialysis (HD) patients. In
study 1, 364 stable HD patients were studied at two outpatient dialysis centers.
CHr was normally distributed, with a mean value of 28.3 pg, and was consistent
over two consecutive monthly samples in each center. CHr was weakly but
consistently correlated with transferrin saturation and serum ferritin. CHr and
reticulocyte number were inversely correlated with red blood cell (RBC) number,
suggesting that the erythropoietic stimulus of routinely administered rHuEPO may
have resulted in functional iron deficiency. Month-to-month changes in CHr
correlated weakly with changes in serum iron and percent transferrin saturation,
but not at all with changes in serum ferritin. When we analyzed those patients
with baseline CHr less than 26 pg, a level strongly suggestive of functional iron
deficiency, these correlations strengthened, and in addition, month-to-month
changes in CHr correlated strongly and directly with concomitant changes in RBC
count, hemoglobin, and hematocrit, suggesting that rising CHr was indicative of
an erythropoietic response. In study 2, 79 patients received a single-dose
infusion of 500 mg iron dextran. After intravenous iron, CHr rose within 48
hours, peaked at 96 hours, and then fell toward baseline. Patients who were iron
deficient by standard measures (serum ferritin < 100 ng/mL or transferrin
saturation less than 20%) had a greater and a sustained CHr response to
intravenous iron dextran. A CHr less than 28 pg at baseline predicted functional
iron deficiency, defined as a corrected reticulocyte increase of greater than 1%
to iron dextran, more accurately than transferrin saturation, ferritin, or their
combination. Eighty-two percent of individuals who were iron deficient at
baseline responded to intravenous iron with an increase in CHr of greater than 2
pg. Sixty percent of patients who were iron sufficient by usual iron indices also
responded to intravenous iron with a CHr rise of greater than 2 pg, suggesting
that they were, in fact, functionally iron deficient despite "normal"
conventional iron parameters. We conclude that CHr may be a more sensitive marker
of functional iron deficiency in rHuEPO-treated hemodialysis patients than
percent transferrin saturation and ferritin, particularly in those with "normal"
conventional iron parameters.
PMID- 9398142
TI - Acute phase proteins and peritoneal dialysate albumin loss are the main
determinants of serum albumin in peritoneal dialysis patients.
AB - Hypoalbuminemia predicts mortality in dialysis patients. It has been postulated
that hypoalbuminemia in the dialysis population is a consequence of poor protein
intake resulting from inadequate dialysis. To establish the cause of
hypoalbuminemia in a group of 27 patients on peritoneal dialysis (PD), we
determined the relationship between serum albumin concentration and a group of
parameters including dialysis dose delivered (Kt/V), normalized protein catabolic
rate (PCRn), transperitoneal and urinary albumin losses, and the serum
concentration of two acute-phase proteins, C-reactive protein (CRP), and serum
amyloid A (SAA). Serum albumin concentration could be predicted by a combination
of transperitoneal albumin loss and either the serum concentration of CRP or of
SAA. There was no relationship between weekly Kt/V or PCRn and serum albumin
concentration. CRP and SAA significantly correlated with one another, but neither
correlated with transperitoneal albumin losses. Hypoalbuminemia in PD patients is
a consequence of transperitoneal albumin losses and of the acute phase response.
PMID- 9398143
TI - The kidney: an unwilling accomplice in syndrome X.
AB - The ability of insulin to stimulate glucose disposal by muscle varies widely
within the population at large. Individuals with muscle insulin resistance
develop type 2 diabetes if they cannot compensate for this defect by secreting
large amounts of insulin. Although this philanthropic effort on the part of the
pancreatic B-cell may prevent gross decompensation of glucose homeostasis, it
renders such individuals at increased risk to develop a cluster of abnormalities
(syndrome X) associated with coronary heart disease. Although the kidney is not
considered to be an insulin sensitive tissue, two features of syndrome X,
hyperuricemia and hypertension, are likely to be dependent on the retention of
normal insulin action on the kidney. More specifically, there is evidence to
support the hypothesis that elevated plasma insulin concentrations may enhance
renal sodium retention and decrease urinary uric acid clearance. As such, it is
possible that a normal kidney response to the compensatory hyperinsulinemia
associated with insulin resistance in nondiabetic subjects contributes to the
development of hyperuricemia and hypertension in such individuals.
PMID- 9398144
TI - Ambulatory blood pressure monitoring in dialysis patients.
PMID- 9398145
TI - Determinants of lipid profile in renal transplant recipients.
PMID- 9398146
TI - Androgens, erythropoietin, iron stores, and lipoprotein (a) in hemodialysis
patients.
PMID- 9398147
TI - Modulation of tryptophan environment in membrane-bound melittin by negatively
charged phospholipids: implications in membrane organization and function.
AB - Melittin is a cationic hemolytic peptide isolated from the European honey bee,
Apis mellifera. Since the association of the peptide in the membrane is linked
with its physiological effects, a detailed understanding of the interaction of
melittin with membranes is crucial. We have investigated the interaction of
melittin with membranes of varying surface charge in the context of recent
studies which show that the presence of negatively charged lipids in the membrane
inhibits membrane lysis by melittin. The sole tryptophan residue in melittin has
previously been shown to be critical for its hemolytic activity. The organization
and dynamics of the tryptophan residue thus become important to understand the
peptide activity in membranes of different charge types. Wavelength-selective
fluorescence was utilized to monitor the tryptophan environment of membrane-bound
melittin. Melittin exhibits a red edge excitation shift (REES) of 5 nm when bound
to zwitterionic membranes while in negatively charged membranes, the magnitude of
REES is reduced to 2-3 nm. Further, wavelength dependence of fluorescence
polarization and near-UV circular dichroism spectra reveal characteristic
differences in the tryptophan environment for melittin bound to zwitterionic and
anionic membranes. These studies are supported by time-resolved fluorescence
measurements of membrane-bound melittin. Tryptophan penetration depths for
melittin bound to zwitterionic and anionic membranes were analyzed by the
parallax method [Chattopadhyay, A., and London, E. (1987) Biochemistry 26, 39-45]
utilizing differential fluorescence quenching obtained with phospholipids spin
labeled at two different depths. Our results provide further insight into
molecular details of membrane lysis by melittin and the modulation of lytic
activity by negatively charged lipids.
PMID- 9398148
TI - Chemical shift mapping of the RNA-binding interface of the multiple-RBD protein
sex-lethal.
AB - The Drosophila protein Sex-lethal (Sxl) contains two RNP consensus-type RNA
binding domains (RBDs) separated by a short linker sequence. Both domains are
essential for high-affinity binding to the single-stranded polypyrimidine tract
(PPT) within the regulated 3' splice site of the transformer (tra) pre-mRNA. In
this paper, the effect of RNA binding to a protein fragment containing both RBDs
from Sxl (Sxl-RBD1 + 2) has been characterized by heteronuclear NMR. Nearly
complete (85-90%) backbone resonance assignments have been obtained for unbound
and RNA-bound states of Sxl-RBD1 + 2. A comparison of amide 1H and 15N chemical
shifts between free and bound states has highlighted residues which respond to
RNA binding. The beta-sheets in both RBDs (RBD1 and RBD2) form an RNA interaction
surface, as has been observed in other RBDs. A significant number of residues
display different behavior when comparing RBD1 and RBD2. This argues for a model
in which RBD1 and RBD2 of Sxl have different or nonanalogous points of
interaction with the tra PPT. R142 (in RBD2) exhibits the largest chemical shift
change upon RNA binding. The role of R142 in RNA binding was tested by measuring
the Kd of a mutant of Sxl-RBD1 + 2 in which R142 was replaced by alanine. This
mutant lost the ability to bind RNA, showing a correlation with the chemical
shift difference data. The RNA-binding affinities of two other mutants, F146A and
T138I, were also shown to correlate with the NMR observations.
PMID- 9398150
TI - Mapping the interfacial binding surface of human secretory group IIa
phospholipase A2.
AB - Human secretory group IIa phospholipase A2 (hIIa-PLA2) contains a large number of
prominent cationic patches on its molecular surface and has exceptionally high
affinity for anionic surfaces, including anionic membranes. To identify the
cationic amino acid residues that support binding of hIIa-PLA2 to anionic
membranes, we have performed extensive site-directed mutagenesis of this protein
and measured vesicle binding and interfacial kinetic properties of the mutants
using polymerized liposomes and nonpolymerized anionic vesicles. Unlike other
secretory PLA2s, which have a few cationic residues that support binding of
enzyme to anionic membranes, interfacial binding of hIIa-PLA2 is driven in part
by electrostatic interactions involving a number of cationic residues forming
patches on the putative interfacial binding surface. Among these residues, the
amino-terminal patch composed of Arg-7, Lys-10, and Lys-16 makes the most
significant contribution to interfacial adsorption, and this is supplemented by
contributions from other patches, most notably Lys-74/Lys-87/Arg-92 and Lys
124/Arg-127. For these mutants, complete vesicle binding occurs in the presence
of high vesicle concentrations, and under these conditions the mutants display
specific activities comparable to that of wild-type enzyme. These studies
indicate that electrostatic interactions between surface lysine and arginine
residues and the interface contribute to interfacial binding of hIIa-PLA2 to
anionic vesicles and that cationic residues closest to the opening of the active
site slot make the most important interactions with the membrane. However,
because the wild type binds extremely tightly to anionic vesicles, it was not
possible to exactly determine what fraction of the total interfacial binding
energy is due to electrostatics.
PMID- 9398151
TI - Differential stabilization of the three FMN redox forms by tyrosine 94 and
tryptophan 57 in flavodoxin from Anabaena and its influence on the redox
potentials.
AB - Flavodoxins are electron transfer proteins that carry a noncovalently bound
flavin mononucleotide molecule as the redox-active center. The redox potentials
of the flavin nucleotide are profoundly altered upon interaction with the
protein. In Anabaena flavodoxin, as in many flavodoxins, the flavin is sandwiched
between two aromatic residues (Trp57 and Tyr94) thought to be implicated in the
alteration of the redox potentials. We have individually replaced these two
residues by each of the other aromatic residues, by alanine and by leucine. For
each mutant, we have determined the redox potentials and the binding energies of
the oxidized FMN--apoflavodoxin complexes. From these data, the binding energies
of the semireduced and reduced complexes have been calculated. Comparison of the
binding energies of wild-type and mutant flavodoxins at the three redox states
suggests that the interaction between Tyr94 and FMN stabilizes the apoflavodoxin-
FMN complex in all redox states. The oxidized and semireduced complexes are,
however, more strongly stabilized than the reduced complex, making the
semiquinone/hydroquinone midpoint potential more negative in flavodoxin than in
unbound FMN. Trp57 also stabilizes all redox forms of FMN, thus cooperating with
Tyr94 in strong FMN binding. On the other hand, Trp57 seems to slightly
destabilize the semireduced complex relative to the oxidized one. Finally, we
have observed that reduction of mutants lacking Trp57 is slow relative to that of
wild-type or mutants lacking Tyr94, which suggests that Trp57 could play a role
in the kinetics of flavodoxin redox reactions.
PMID- 9398152
TI - pH and temperature-induced molten globule-like denatured states of equinatoxin
II: a study by UV-melting, DSC, far- and near-UV CD spectroscopy, and ANS
fluorescence.
AB - Thermal denaturation of equinatoxin II (EqTxII) in glycine buffer solutions (pH
1.1, 2.0, 3.0, and 3.5) and in triple distilled water (pH 5.5-6.0) was examined
by differential scanning calorimetry, UV and CD spectroscopy and fluorescence
emission spectroscopy of the added hydrophobic fluorescent probe ANS. At pH 5.5
6.0 and at temperatures below 60 degrees C, the protein exists in a native state
characterized by a pronounced tertiary structure, a beta-rich secondary structure
and a low degree of ANS-binding. At higher temperatures, it undergoes a two-state
conformational transition, (delta H degree)VH = (delta H degree)DSC, into an
unfolded state, which is characterized by a complete collapse of its tertiary
structure and an incomplete denaturation of its secondary structure. At acidic
pH, the EqTxII temperature-induced conformational transition appears at lower
temperatures as non-two-state transition accompanied by the formation of an
intermediate state which shows characteristics of molten globules, i.e., absence
of defined tertiary structure, increase in alpha-rich secondary structure, and
high affinity for ANS. At pH 2.0, the low-temperature initial state of EqTxII is
already partially denatured; the tertiary structure is partially disrupted, and a
pronounced inequality (delta H degree)VH > (delta H degree)DSC is observed. At pH
value of 1.1 and below 60 degrees C, EqTxII exists in a stable acid-denatured
compact state which shows all the characteristics of a molten globule, which even
at 95 degrees C is not completely denatured. According to numerous studies on the
pore forming toxins, such acid-denatured compact states may contribute to the
protein's ability to penetrate into biological membranes.
PMID- 9398153
TI - Kinetic hole burning, hole filling, and conformational relaxation in heme
proteins: direct evidence for the functional significance of a hierarchy of
dynamical processes.
AB - Band III is a disorder and conformation-sensitive near-infrared (approximately
760 nm) charge transfer absorption band characteristic of equilibrium and
nonequilibrium five coordinate ferrous high-spin hemes. The time evolution of
this absorption band subsequent to photodissociation of six coordinate ferrous
hemoglobin or myoglobin can provide detailed information regarding conformational
relaxation, including the thermally driven fluctuations that result in the
transition from inhomogeneous to homogeneous ligand rebinding kinetic. Such time
resolved measurements over a range of temperatures are difficult due to long
sample recovery times at cryogenic temperatures. A new restoring technique that
allows for the rapid movement of a large optically accessible cryostat is used in
combination with nanosecond time-resolved near-infrared absorption spectroscopy
to generate band III as a function of time for the photoproducts of the carbon
monoxide derivative of adult human hemoglobin (COHbA) and, to a more limited
extent, horse myoglobin (COMb). The measurements are made over a wide range of
temperatures extending from well below the solvent (75% glycerol:water) glass
transition at approximately 180 K to ambient temperatures. Three temperature-
and/or viscosity-dependent phenomena are observed. At the highest temperatures,
only conformational relaxation is observed for the 75% glycerol sample. At very
high viscosity (> or = 400 cp), conformational relaxation slows dramatically, and
both kinetic hole burning followed by the filling in of the "hole" (dynamic hole
filling) are observed. As the temperature is lowered, conformational relaxation
slows and finally ceases. Kinetic hole burning and dynamic hole filling as well
as additional broadening of band III are observed down to 140 K. The observation
of kinetic hole burning (KHB) is indicative of the sample being inhomogeneous on
the time scale of the ligand rebinding giving rise to KHB. The onset of hole
filling is a direct manifestation of the thermal homogenization of the initial
inhomogeneous distribution of conformational substates responsible for KHB. The
observed dynamics are used to explain the inverse temperature effect associated
with the non-Arrhenius slow down of geminate rebinding above approximately 180 K.
The inverse temperature effect appears to arise not only from the onset of
conformational relaxation but also from the increase in the rate on thermal
averaging of the initial inhomogeneous distribution of conformational substates.
PMID- 9398154
TI - Organophosphorus hydrolase is a remarkably stable enzyme that unfolds through a
homodimeric intermediate.
AB - Organophosphorus hydrolase (OPH, EC 8.1.3.1) is a homodimeric enzyme that
catalyzes the hydrolysis of organophosphorus pesticides and nerve agents. We have
analyzed the urea- and guanidinium chloride-induced equilibrium unfolding of OPH
as monitored by far-ultraviolet circular dichroism and intrinsic tryptophan
fluorescence. These spectral methods, which monitor primarily the disruption of
protein secondary structure and tertiary structure, respectively, reveal biphasic
unfolding transitions with evidence for an intermediate form of OPH. By
investigating the protein concentration dependence of the unfolding curves, it is
clear that the second transition involves dissociation of the monomeric
polypeptide chains and that the intermediate is clearly dimeric. The dimeric
intermediate form of OPH is devoid of enzymatic activity, yet clearly behaves as
a partially folded, dimeric protein by gel filtration. Therefore, we propose an
unfolding mechanism in which the native dimer converts to an inactive, well
populated dimeric intermediate which finally dissociates and completely unfolds
to individual monomeric polypeptides. The denaturant-induced unfolding data are
described well by a three-state mechanism with delta G for the interconversion
between the native homodimer (N2) and the inactive dimeric intermediate (I2) of
4.3 kcal/mol while the overall standard state stability of the native homodimer
relative to the unfolded monomers (2U) is more than 40 kcal/mol. Thus, OPH is a
remarkably stable protein that folds through an inactive, dimeric intermediate
and will serve as a good model system for investigating the energetics of protein
association and folding in a system where we can clearly resolve these two steps.
PMID- 9398155
TI - Structure of pressure-assisted cold denatured lysozyme and comparison with
lysozyme folding intermediates.
AB - At high (> 3.5 kbar) pressures and low (< -10 degrees C) temperatures, hen egg
white lysozyme denatures readily and reversibly. Amide hydrogen exchange methods
were used to investigate the structure of the pressure-assisted cold-denatured
state of lysozyme. Protection factors were obtained for 52 backbone amide
protons. The extent of protection of many of these protons is markedly different
from that in lysozyme denatured by high temperature, high urea concentration, or
chemical modification; specifically, the protection factors are higher and are
strongly correlated with elements of secondary structure present in the native
state. Furthermore, the pattern of protection factors is similar to that observed
in lysozyme during refolding from highly denatured states, particularly during
the early stages (< 3.5 ms) of refolding [Gladwin, S. T., & Evans, P. A. (1996)
Folding Des. 1, 407]. Previous data on cold-denatured ribonuclease A were
reevaluated and compared to known folding intermediates [Houry, W. A. & Scheraga,
H. A. (1996) Biochemistry 35, 11734; Udgaonkar, J. B., & Baldwin, R. L. (1990)
Proc. Natl. Acad. Sci. U.S.A. 87, 8197] to further test the supposition that the
pressure-assisted cold-denatured states of proteins resemble the early folding
stages.
PMID- 9398156
TI - Identification and localization of slow, natural, cooperative unfolding in the
hematopoietic cell kinase SH3 domain by amide hydrogen exchange and mass
spectrometry.
AB - Protein unfolding on a fast time scale (milliseconds-minutes) has been widely
reported, but slower unfolding events (10 min-hours) have received less
attention. Amide hydrogen exchange (HX) and mass spectrometry (MS) were used to
investigate the unfolding dynamics of the hematopoietic cell kinase (Hck) SH3
domain. Analysis of mass spectra after deuterium exchange into intact Hck SH3
indicates a cooperative unfolding event involving 24-61% of the domain and
occurring with a half-life of approximately 20 min under physiological
conditions. To identify the unfolding region, SH3 was incubated in D2O and
proteolytically fragmented into peptides that were analyzed by mass spectrometry.
Correlation of HX rates and isotope patterns reveals cooperative unfolding in
several regions, including the C-terminal half of the RT-loop and a beta-sheet
flanking the binding site. Binding of a prolyl-rich segment from the HIV Nef
protein slows unfolding by a factor of 3. Further analysis yields a KD of 25
microM for the Nef peptide. These results demonstrate that an inherent
flexibility in the SH3 domain may assist interconversion of the closed,
intramolecularly ligated state and the open, active state of Src family kinases.
Furthermore, this type of previously undetectable, slow unfolding process may
provide the basis for new mechanisms in which kinetics of local unfolding
combines with thermodynamics to regulate enzymatic activity. The combination of
hydrogen exchange and mass spectrometry appears to be the only general method
capable of examining these slow unfolding processes.
PMID- 9398157
TI - VO2+(IV) complexes with pyruvate carboxylase: activation of oxaloacetate
decarboxylation and EPR properties of enzyme-VO2+ complexes.
AB - Chicken liver pyruvate carboxylase catalyzes a nonclassical ping-pong mechanism
in which the carboxylation of biotin at subsite 1 of the active site is coupled
to the biotin-dependent carboxylation of pyruvate at subsite 2. The functions of
two divalent cation cofactors and at least one monovalent cation cofactor in
catalysis are not well understood. The oxyvanadyl cation, VO2+ does not support
phosphoryl transfer at the first subsite, and uncouples the decarboxylation of
oxaloacetate at subsite 2 from the formation of ATP at subsite 1. Stimulation of
this oxaloacetate decarboxylase activity in the presence of substrates and
cofactors of the first subsite, including VO2+, VOADP-, Pi, and acetyl CoA,
suggests that these cofactors and substrates induce the movement of carboxybiotin
from the second subsite to the first subsite, where it is decarboxylated. VO2+
EPR has provided evidence for enzymic and nucleotide divalent cation binding
sites within the first subsite. The EPR properties of enzyme bound VO2+ were
altered by bicarbonate, suggesting that this substrate ligands directly to VO2+
at the enzymic metal site. Fluorescence quenching experiments suggest that a
monovalent cation may interact with bicarbonate at the first subsite as well. The
results of this study provide evidence that (i) the extrinsic metal ion cofactors
interact with the substrates at the first subsite, and that (ii) divalent cations
play a role in coupling catalysis at the two nonoverlapping subsites by inducing
the decarboxylation of carboxybiotin at the first subsite.
PMID- 9398158
TI - From ribonuclease A toward bovine seminal ribonuclease: a step by step
thermodynamic analysis.
AB - A proline, a leucine, and two cysteine residues, introduced at positions 19, 28,
31, and 32 of bovine pancreatic RNase A, i.e. the positions occupied by these
residues in the subunit of bovine seminal RNase, the only dimeric RNase of the
pancreatic-type superfamily, transform monomeric RNase A into a dimeric RNase,
endowed with the same ability of BS-RNase of swapping its N-terminal segments.
The thermodynamic consequences of the progressive introduction of these four
residues into RNase A polypeptide chain have been studied by comparing the
temperature- and urea-induced denaturation of three mutants of RNase A with that
of a stable monomeric derivative of BS-RNase. The denaturation processes proved
reversible for all proteins, and well represented by the two-state N<-->D
transition model. The progressive introduction of the four residues into RNase A
led to a gradual shift of the protein stability toward that characteristic of
monomeric BS-RNase, which, in turn, is markedly less stable than RNase A with
respect to both temperature- and urea-induced denaturation. On the other hand,
the thermal stability of a dimeric active mutant of RNase A is found to approach
that of wild-type seminal RNase.
PMID- 9398159
TI - Dissociation of bacteriophage T4 DNA polymerase and its processivity clamp after
completion of Okazaki fragment synthesis.
AB - The mechanism of bacteriophage T4 DNA polymerase (gp43) and clamp (gp45) protein
dissociation from the holoenzyme DNA complex was investigated under conditions
simulating the environment encountered upon completion of an Okazaki fragment.
Lagging strand DNA synthesis was approximated using a synthetic construct
comprised of a doubly biotinylated, streptavidin-bound 62-mer DNA template,
paired with complementary primers to generate an internal 12-base gap where the
5'-end primer contained either a 5'-OH (DNA primer) or a 5'-triphosphate (RNA
primer) group. Rapid kinetic measurements revealed that upon encountering the
blocking primer, the holoenzyme either dissociates from DNA (approximately 40%)
or strand-displaces the blocking strand (approximately 60%). The two blocking
oligonucleotides (DNA or RNA) induce a 30-50-fold increase in the rate of
holoenzyme dissociation, with both polymerase and clamp proteins dissociating
simultaneously. Inhibition of ATP hydrolysis by ATP-gamma-S did not have a
measurable effect upon holoenzyme dissociation from DNA. The presence of gp32,
the single-strand binding protein, caused a small (3-fold) increase in the rate
constant for dissociation.
PMID- 9398160
TI - Rapid deubiquitination of nucleosomal histones in human tumor cells caused by
proteasome inhibitors and stress response inducers: effects on replication,
transcription, translation, and the cellular stress response.
AB - The proteasome inhibitors, lactacystin and N-acetyl-leucyl-leucyl-norlucinal,
caused a rapid and near-complete loss of approximately 22-23-kDa ubiquitinated
nucleoproteins, which we have identified as monoubiquitinated nucleosomal
histones H2A and H2B by immunological and two-dimensional electrophoretic
techniques. In human SKBr3 breast tumor cells, depletion of monoubiquitinated
histones by the proteasome inhibitors coincided with the accumulation of high
molecular weight ubiquitinated proteins in both nucleoprotein and cytosolic
fractions and decreased unconjugated ubiquitin in the cytosol, without changes in
the nonubiquitinated core histones. Unconjugated ubiquitin was not detected in
isolated tumor cell nuclei. A similar loss in monoubiquitinated histones occurred
in cells harboring a defective, temperature-sensitive mutation of the ubiquitin
activating E1 enzyme, after these cells were elevated from 33 degrees C to the
non-permissive temperature of 39 degrees C. DNA replication and RNA transcription
were decreased by the proteasome inhibitors most strongly after 90% of the
ubiquitin had been removed from ubiquitinated histones H2A and H2B, suggesting a
relationship between the nucleosomal histone ubiquitin status and the processing
of genetic information. Interestingly, although both proteasome inhibitors caused
a generalized decrease in methionine incorporation into proteins, they strongly
induced the synthesis of the hsp72 and hsp90 stress proteins. Finally, treating
cells with heat-shock at 43 degrees C, with stress response-provoking chemicals
or with several other proteasome inhibitors caused ubiquitinated proteins to
accumulate, depleted free ubiquitin, and concomitantly decreased nucleosomal
monoubiquitinated histones. These results suggest that deubiquitination of
nucleosomal histones H2A and H2B may play a previously unrecognized role in the
cellular stress response, as well as in the processing of chromatin, and
emphasize the important role of the proteasome in cellular homeostasis.
PMID- 9398161
TI - Role of glutamine-151 of human immunodeficiency virus type-1 reverse
transcriptase in RNA-directed DNA synthesis.
AB - Glutamine-151 of HIV-1 RT has been shown to be a catalytically important residue
through the characterization of its mutant phenotype Glu151Ala (Sarafianos et
al., 1995a). To further understand the role of this residue, we have extended
this analysis to include polymerization on natural RNA template in addition to
DNA template. We find that Q151A mutant exhibited a severe reduction in the
polymerase activity without any significant effect on the affinity for dNTP
substrate. Unlike DNA-directed reactions, the rate-limiting step for RNA-directed
reactions does not appear to be either at the dNTP binding step or the chemical
step. Analysis of the products formed on natural heteromeric HIV-genomic RNA
template annealed with an 18-mer DNA primer with a sequence complementary to the
primer binding site (PBS) has shown that addition of nucleotides is nonlinear
with time since the enzyme appears to stall on the RNA template following the
incorporation of the first nucleotide. The Q151A mutant was found to be nearly
devoid of pyrophosphorolytic activity on a RNA-PBS template-primer. Similar
properties have been previously reported for a mutant of R72 (R72A) of HIV-1 RT
(Sarafianos et al., 1995b). However, R72 was implicated in stabilizing the
transition state ternary complex before and after the phosphodiester bond
formation (Kaushik et al., 1996; Sarafianos et al., 1995b). Our results with
Q151A suggest that the side chain of Q151 may help stabilize the side chain of
R72, and the loss of pyrophosphorolysis activity observed with the Q151 mutant
may be the indirect manifestation of this stabilizing effect on R72. These
observations point to the functional interdependence of residues Q151 and R72 in
the polymerase function of the enzyme. An analysis of the 3D model structure of
HIV-1 RT bound to DNA-DNA and RNA-DNA template-primer reveals that the guanidine
hydrogen of R72 seems to stabilize Q151 by hydrogen bonding with its amide
oxygen. A systematic conformational search of the side chain of Q151 also
suggests a stable orientation where its specific interaction with the base of the
RNA template may aid in stabilizing it.
PMID- 9398162
TI - Phosphorylation of the acidic ribosomal P proteins in Saccharomyces cerevisiae: a
reappraisal.
AB - Previous reports had pointed to serines 62 and 71/79 as possible phosphorylation
sites in the yeast acidic ribosomal proteins YP1 alpha and YP2 alpha,
respectively. However, it has been found that mutation of these serine residues
did not affect the phosphorylation level of the proteins. A detailed examination
of the YP2 alpha tryptic digest from the in vivo labeled protein demonstrates the
existence of a totally trypsin-insensitive site at lysine 88 that led to a
misinterpretation of previous results. The unique YP2 alpha tryptic
phosphopeptide obtained contains, in addition to serines 71 and 79, a serine at
position 96 near the carboxyl end, which automatic Edman degradation confirmed as
the phosphorylated residue. In addition, by using Staphyloccocus protease V8, it
was possible to obtain phosphopeptides containing only serine 96, whose
phosphorylation has likewise been confirmed by radioactive labeling as well as by
chemical methods. A similar analysis of the other 12 kDa acidic proteins, YP1
alpha, YP1 beta, and YP2 beta, has shown the presence of equivalent
phosphorylation sites in the four P proteins, which correspond to position 96 in
proteins YP1 alpha, YP1 beta, and YP2 alpha and position 100 in YP2 beta. This
conclusion has been confirmed by the fact that mutation of serine 96 in proteins
YP1 alpha and YP2 alpha abolishes their capacity to be phosphorylated in vivo.
The mutation of the phosphorylation site of the individual acidic proteins seems
not to alter their interaction with the ribosome. However, it has been found that
the level of phosphorylation of the stalk proteins has an effect on the response
of the cells to some specific metabolic conditions, indicating that it may
modulate the translation of specific proteins.
PMID- 9398163
TI - ATF1 and CREB trans-activate a cell cycle regulated histone H4 gene at a distal
nuclear matrix associated promoter element.
AB - Proteins of the ATF/CREB class of transcription factors stimulate gene expression
of several cell growth-related genes through protein kinase A-related cAMP
response elements. The promoter activity of cell cycle regulated histone H4 genes
is regulated by at least four principal cis-acting elements which mediate G1/S
phase control and/or enhancement of transcription during the cell cycle. Using
protein-DNA interaction assays we show that the H4 promoter contains two ATF/CREB
recognition motifs which interact with CREB, ATF1, and ATF2 but not with
ATF4/CREB2. One ATF/CRE motif is located in the distal promoter at the nuclear
matrix-associated Site IV, and the second motif is present in the proximal
promoter at Site I. Both ATF/CRE motifs overlap binding sequences for the
multifunctional YY1 transcription factor, which has previously been shown to be
nuclear matrix associated. Subnuclear fractionation reveals that there are two
ATF1 isoforms which appear to differ with respect to DNA binding activity and
partition selectively between nuclear matrix and nonmatrix compartments,
consistent with the role of the nuclear matrix in regulating gene expression.
Site-directed mutational studies demonstrate that Site I and Site IV together
support ATF1- and CREB-induced trans-activation of the H4 promoter. Thus, our
data establish that ATF/CREB factors functionally modulate histone H4 gene
transcription at distal and proximal promoter elements.
PMID- 9398164
TI - Effects of mutation of the conserved lysine-362 in cytochrome c oxidase from
Rhodobacter sphaeroides.
AB - We describe the effects of a mutation, K362M, of the conserved lysine in
cytochrome c oxidase from Rhodobacter sphaeroides, a residue located in a
putative proton channel that may convey substrate protons to the binuclear
center. Spectra of the "as prepared", ferricyanide-oxidized, and dithionite
reduced forms of the mutant protein confirm that the redox centers remain intact.
Ligand binding kinetics of the ferricyanide-oxidized enzyme and of the dithionite
reducible fraction are similar to those of the wild type, indicating that the K
channel is not the major route for CO, cyanide, formate, or peroxide entry into
the structure. Protonation of the lysine residue is not redox-linked to heme a or
CuB as judged from the essentially unaltered midpoint potentials of these centers
in the cyanide-ligated enzyme. A difficulty in electron transfer from heme a to
the binuclear center is indicated by the slow and only partial reduction of heme
a3 by dithionite or ferrocytochrome c and by the presence of some reduced heme a
in the as prepared mutant enzyme and under steady-state conditions. Further
characterization of the K362M enzyme in the steady state shows that up to one
electron, but not two, can enter the binuclear center easily. It is this
inability to form the two-electron-reduced, oxygen-reactive R state that prevents
activity. A model is proposed where the K channel serves as a dielectric well of
high dielectric strength and low proton conductivity, rather than as a pathway
for proton entry to the binuclear center. The function of this structure would be
to decrease the cost of introducing a transiently uncompensated charge into the
binuclear center prior to formation of a stable, charge-compensated R-state.
PMID- 9398165
TI - Formation of N delta-cyanoornithine from NG-hydroxy-L-arginine and hydrogen
peroxide by neuronal nitric oxide synthase: implications for mechanism.
AB - Neuronal nitric oxide synthase (nNOS) catalyzes the oxidation of NG-hydroxy-L
arginine (NHA) by hydrogen peroxide. The amino acid products were characterized
by high-performance liquid chromatography/mass spectrometry of the o
phthalaldehyde/2-mercaptoethanol derivatives and identified as citrulline and N
delta-cyanoornithine (CN-orn). The assignment of CN-orn was confirmed by
independent chemical synthesis and comparison of the properties of the enzyme
derived product with those of synthetic CN-orn. The inorganic products detected
in the enzymatic reaction were NO2- and NO3-, presumably from oxidation of NO-.
The reaction of H2O2 and NHA with nNOS was at least 10-fold slower than the
reaction of NADPH, O2, and NHA (Vmax,app = 49 +/- 2 nmol min-1 mg-1 for the
reactions with 10 microM added H4B). The reaction exhibited saturation kinetics
with respect to hydrogen peroxide [K(m,app)(H2O2) = 10 +/- 1 mM for the reactions
with 10 microM added H4B]. No H2O2-dependent reaction was observed with L
arginine as the amino acid substrate. The different products for the NADPH- and
H2O2-dependent transformations of NHA are of mechanistic significance in the NOS
reaction.
PMID- 9398166
TI - Yz. reduction kinetics in the absence of the manganese-stabilizing protein of
photosystem II.
AB - Decay of Signal IIvf of photosystem II (PSII), under repetitive flash conditions,
was examined in whole cells of wild-type Synechocystis sp. PCC6803 and in cells
of an engineered strain, delta psbO, which lacks the extrinsic 33 kDa manganese
stabilizing protein (MSP). Previous polarographic analysis had shown that O2
release during the S3-->[S4]-->S0 transition of the catalytic cycle is
significantly retarded in the delta psbO strain relative to the wild-type [Burnap
et al. (1992) Biochemistry 31, 7404-7410]. The present experiments provide
evidence that a parallel retardation in the rate of reduction of photooxidized Yz
by the H2O oxidation complex is due to the absence of MSP. The half-time of the
Signal IIvf component, corresponding to Yz. reduction during the S3-->[S4]-->S0
transition, was estimated to be 1.2 and 6.0 ms in the wild-type and delta psbO
cells, respectively.
PMID- 9398167
TI - Solution structure of the aminofluorene-intercalated conformer of the syn [AF]-C8
dG adduct opposite a--2 deletion site in the NarI hot spot sequence context.
AB - This paper addresses structural issues related to the capacity of aminofluorene
[AF] for frameshift mutations of the -2 type on C8 covalent adduct formation at
the G3 site in the d(C-G1-G2-C-G3-C-C) NarI hot spot sequence. This problem has
been approached from a combined NMR and relaxation matrix analysis computational
structural study of the [AF]dG adduct in the d(C-G-G-C-[AF]G-C-C).d(G-G-C-C-G)
sequence context at the 12/10-mer adduct level (designated [AF]dG.del(-2) 12/10
mer). The proton spectra of this system are of exceptional quality and are
consistent with the formation of an AF-intercalated conformer with the modified
guanine in a syn alignment displaced along with the 5'-flanking cytosine residue
into the major groove. The solution structure has been determined by initially
incorporating intramolecular and intermolecular proton-proton distances defined
by lower and upper bound deduced from NOESY spectra as restraints in molecular
mechanics computations in torsion angle space and subsequently refined through
restrainted molecular dynamics calculations based on a NOE distance and intensity
refinement protocol. Strikingly, the [AF]dG.del(-2) 12/10-mer duplex adopts only
one of two potential AF-intercalation alignments for the [AF]dG adduct opposite
the -2 deletion site in the NarI sequence context with the extrusion of the dC
[AF]dG step favored completely over extrusion of the [AF]dG-dC step at the lesion
site. This polarity establishes that the structural perturbation extends 5'
rather than 3' to the [AF]dG lesion site in the adduct duplex. This structure of
the [AF]dG adduct opposite a -2 deletion site shows distinct differences with
conclusions reported on the alignment of the related acetylaminofluorene [AAF]dG
adduct opposite a -2 deletion site in the identical NarI sequence context [Milhe,
C., Fuchs, R. P. P., and Lefevre, J. F. (1996) Eur. J. Biochem. 235, 120-127]. In
that study, qualitative NMR data without computational analysis were employed to
conclude that the extrusion at the lesion site occurs at the [AAF]dG-dC step for
the AAF-intercalated conformer of the adduct duplex. The structure of the [AF]dG
adduct opposite a -2 deletion site determined in our group provides molecular
insights into the architecture of extended slipped mutagenic intermediates
involving aromatic amine intercalation and base-displaced syn modified guanines
in AF and, by analogy, AAF-induced mutagenesis in the NarI hot spot sequence
context.
PMID- 9398168
TI - Solution structure of the aminofluorene-stacked conformer of the syn [AF]-C8-dG
adduct positioned at a template-primer junction.
AB - A solution structural study has been undertaken on the aminofluorene-C8-dG
([AF]dG) adduct located at a single strand-double strand d(A1-A2-C3-[AF]G4-C5-T6
A7-C8-C9-A10-T11-C12-C13).d (G14-G15-A16-T17-G18-G19-T20-A 21-G22) 13/9-mer
junction (designated [AF]dG 13/9-mer) using proton-proton distance and intensity
restraints derived from NMR data in combination with a computational protocol,
which includes intensity refinement. This single strand-double strand junction
models one arm of a replication fork composed of a 13-mer template strand, which
contains the [AF]dG modification site, and a 9-mer primer strand, which has been
elongated up to, but not including, the modified guanine. The NMR data establish
that the duplex segment retains a minimally perturbed B-DNA conformation
including Watson-Crick hydrogen-bonding at the junctional dC5.dG22 base pair. The
NMR spectra are consistent with the guanine ring of the [AF]dG4 adduct adopting a
syn glycosidic torsion angle and being displaced into the major groove with the
adjacent dC3 residue displaced into the minor groove. Such a base displacement of
the modified guanine is accompanied by stacking of one face of the fluorene ring
of [AF]dG4 with the dC5.dG22 base pair, while the other face of the flourene ring
is stacked with the purine ring of the nonadjacent dA2 residue in the intensity
refined solution structures of the [AF]dG 13/9-mer. A comparison of structural
features of the C8-[AF]dG adduct (this study) with those of the (+)-trans-anti-N2
[BP]dG adduct [Cosman et al. (1995) Biochemistry 34, 15334-15350] in the same
13/9-mer junctional sequence context has identified common features associated
with the alignment of the modified guanine adducts at the template-primer
junction. Thus, despite differences in the covalent linkage site for the C8
[AF]dG and (+)-trans-anti-N2-[BP]dG adducts, one face of the aromatic ring of the
carcinogen stacks over the junctional base pair and in so doing displaces the
modified guanine in a syn alignment into the major groove. These results lend
credence to earlier proposals that such an adduct alignment may represent a
common mutagenic conformer at a template-primer junction associated with a
replication fork.
PMID- 9398169
TI - Solution conformation of an intramolecular DNA triplex containing a nonnucleotide
linker: comparison with the DNA duplex.
AB - The solution properties of the parallel intramolecular DNA triplex d(GAGAGA-oct
TCTCTC-oct-CTCTCT) (oct = -O-(CH2)8-O-PO2-O-(CH2)8-O-PO2-) and the duplex
d(GAGAGA-oct-TCTCTC) have been examined by UV melting and high-resolution nuclear
magnetic resonance spectroscopy (NMR). All nucleotides were primarily in the S
conformation (i.e. near C2'-endo) in both the duplex and the triplex. However,
the sugars of the Hoogsteen pyrimidine strand had a lower fraction of the S state
than the Watson-Crick strands. Glycosidic torsion angles derived from nuclear
Overhauser effect (NOE) build-up curves were found in the range -103 degrees to
133 degrees, with a clear alternation in magnitude along the GAGAGA strand in the
triplex, whereas the glycosidic torsion angles were more similar in the duplex.
Internucleotide NOEs were also consistent with an overall B-like geometry, rather
than the A family. However, particularly in the Hoogsteen strand, some sequential
NOE intensities were intermediate between those of the B and A forms. Distance
and torsion constraints derived from NMR experiments were used to generate
structures and were refined by restrained molecular dynamics. Extensive chemical
shift differences between residues in the triplex and duplex were found for the
purine strand, and there were remarkable differences in the pattern of shift
differences for the A and G residues that correlated with differences in
glycosidic torsion angles. Although there are differences in structure between
the free duplex and that in the triplex, they are in important respects similar,
indicating that only small conformational adjustments are needed to make parallel
triple helices.
PMID- 9398170
TI - Thermodynamic and kinetic basis of interfacial activation: resolution of binding
and allosteric effects on pancreatic phospholipase A2 at zwitterionic interfaces.
AB - A general kinetic model for catalysis by interfacial enzymes is developed. It
couples the Michaelis-Menten catalytic turnover cycle at the interface with that
in the aqueous phase through the distribution equilibria between the interface
and the surrounding aqueous phase. Analysis under two limiting conditions fully
describes the steady-state kinetics of hydrolysis and resolves the allosteric
effects from apparent modes of interfacial activation in terms of the primary
rate and equilibrium parameters for pig pancreatic phospholipase A2 (PLA2). One
limit is observed in dispersions of anionic phospholipid vesicles, in which
intervesicle exchange of enzyme, substrate, and hydrolysis products is absent and
reaction occurs only on vesicles containing enzyme. A complete analysis at this
highly processive limit, called kinetics in the scooting mode, has been published
[Berg et al. (1991) Biochemistry 30, 7283]. Here is reported the analysis in the
other limit, PLA2-catalyzed hydrolysis of zwitterionic micelles of short-chain
phosphatidylcholines, at which substrate and products are in rapid exchange.
Hydrolysis occurs either in bulk aqueous solution with phospholipid monomers or
at the micellar interface. Above the critical micelle concentration (cmc), the
hydrolysis rate shows a hyperbolic dependence on the bulk substrate concentration
present as micelles. This dependence, characterized by the fitting parameters
KMapp and VMapp, is analyzed in terms of the primary rate and equilibrium
constants. The kinetic analysis is based on the assumption that the microscopic
steady-state condition is satisfied because substrate replenishment in the micro
environment of the enzyme is fast relative to the catalytic turnover time. Added
NaCl and anionic interface increase the hydrolysis rate in zwitterionic micelles
dramatically. The overall interfacial rate enhancement is attributed to three
factors: (a) promotion of PLA2 binding by net anionic charge of the interface,
(b) enhancement of substrate affinity of PLA2 at the interface (Ks* allostery),
and (c) stimulation of the rate-limiting chemical step (kcat* allostery).
PMID- 9398171
TI - Infrared spectroscopy of human apolipoprotein fragments in SDS/D2O: relative
lipid-binding affinities and a novel amide I assignment.
AB - Infrared absorption spectra are reported for six apolipoprotein fragments in
SDS/D2O. Five of the peptides correspond to proposed lipid-binding domains of
human apolipoproteins [apoC-I(7-24), apoC-I(35-53), apoA-II(18-30)+, apoA-I(166
185), apoE(267-289)], and the sixth is the de novo lipid associating peptide LAP
20. The amide I infrared absorption patterns are generally consistent with
predominantly helical structures (as determined previously by NMR spectroscopy
and distance geometry calculations) and further suggest that apoA-I(166-185) and
apoE(267-289) are bound to SDS relatively weakly in comparison to the other four
peptides. The latter conclusion is also supported by the temperature dependence
of the infrared spectra, as increasing temperature promotes a distinct increase
in random coil structure only for apoA-I(166-185) and apoE(267-289). In addition
to features readily ascribed to helices, the infrared spectra of all the peptides
show absorptions in the spectral region 1630-1635 cm-1 that is usually associated
with beta-structure, a motif that is clearly absent from the NMR-derived
structures. Parallel difficulties also arose in the analyses of the circular
dichroism spectra. We suggest that both the low-frequency infrared absorptions
and the ambiguities in interpreting the CD spectra may be due to unusual
structures at the peptide C-termini, involving C=O groups that form hydrogen
bonds simultaneously either with two solvent molecules or with donors from the
backbone (NH) and the solvent (OH). Analogous absorptions may be a general
feature of solvent-exposed helices, which suggests a need for caution in
assigning amide I bands below 1640 cm-1.
PMID- 9398172
TI - Dissecting the catalytic mechanism of staphylococcal lipases using carbamate
substrates: chain length selectivity, interfacial activation, and cofactor
dependence.
AB - p-Nitrophenyl N-alkylcarbamates with different alkyl chains were used as
substrates to determine separately the carbamylation and decarbamylation rates of
the lipases from Staphylococcus hyicus and S. aureus. Both enzymes are reversibly
inhibited by these compounds due to a rapid carbamylation of their active site
serines followed by a slow decarbamylation. The carbamylation reaction is
strongly pH-dependent and the pH profile suggests that an unprotonated histidine
is required for this reaction. In contrast, the decarbamylation is pH-independent
suggesting the presence of a hydrogen bond between the active site histidine and
the carbamyl moiety. S. hyicus lipase preferably reacts with medium to long chain
carbamates with an optimum for eight carbon atoms. In contrast, S. aureus lipase
is highly specific for short chain carbamates. These results are in agreement
with the respective substrate preferences of both lipases toward natural lipids.
The decarbamylation rates of both enzymes hardly depend on the alkyl chain
length, and from this it is concluded that chain length selectivity is expressed
in the first step of catalysis. Both the carbamylation and decarbamylation
reaction rates of S. hyicus lipase are enhanced in the presence of micelles, the
activation effect being most pronounced in the first step. For the S. aureus
lipase only a small influence of interfaces on both reaction steps was observed.
These results are discussed in view of a possible role of a lid covering the
active site. Kinetic experiments in the presence and absence of calcium strongly
suggest that calcium ions are important for the structural stabilization of the
unmodified as well as of the carbamylated enzymes. This structural function of
calcium was supported by urea unfolding experiments, from which it appeared that
for both enzymes the free energy for unfolding is significantly lower in the
absence of calcium. In conclusion our results show that kinetic differences
between both lipases reside in the acylation step, and that calcium is important
for the structural stabilization of the unmodified, and moreover, the acylated
enzymes.
PMID- 9398173
TI - Kinetic and structural effects of mutations of the catalytic amino-terminal
proline in 4-oxalocrotonate tautomerase.
AB - The catalytic general base, Pro-1, of the enzyme 4-oxalocrotonate tautomerase has
been mutated to Gly, Ala, Val, and Leu, residues with aliphatic side chains. The
Val mutant was partially (55%) processed by removal of the amino-terminal
methionine to yield P1V/M1P2V, while the Leu mutant was not processed and
completely retained methionine (M1P2L). The M1P2L mutant lost 2300-fold in kcat
with no change in Km, and the residual activity of the unresolvable P1V/M1P2V
mixture could be explained by the summation of two activities, one equal to that
of M1P2L and the other equal to that of the P1G mutant. The P1G and P1A mutants
showed 76- and 58-fold decreases in kcat and much smaller decreases in Km of 4-
and 2.8-fold, respectively. The dissociation constant of the substrate analog
cis,cis-muconate decreased 1.7-fold in the P1G mutant as determined by NMR
titration. 2D 1H-15N HSQC spectra and 3D 1H-15N NOESY HSQC spectra of the 15N
labeled P1G mutant showed no structural differences from the wild-type enzyme
except for small changes in backbone 15N and NH chemical shifts at the active
site. Both the P1G and P1A mutants showed no change in overall conformation by
circular dichroic spectroscopy. Both mutants and the wild-type enzyme generate
the S-enantiomer of the product [5-2H]-2-oxo-3-hexenedioate with comparable
stereoselectivities indicating a largely intact active site. The P1G and P1A
mutants showed 10- and 4-fold decreases, respectively, in catalysis of exchange
of the C3 proton of the substrate 2-oxo-1,6-hexanedioate, consistent with the
lower basicities of Gly-1 and Ala-1 compared to Pro-1. The pH dependences of
kcat/Km for the P1G and P1A mutants revealed pKa values of the general base of
5.3 and 5.9, respectively. NMR titration of the uniformly 15N-labeled P1G mutant
showed the pKa of Gly-1 to be < or = 5.6, in agreement with the kinetic data. As
with the wild-type enzyme, the active site environments on the P1G and P1A
mutants lower the pKa of the general base by at least 2.5 units. It is concluded
that the 2 order of magnitude decreases in kcat in the P1G and P1A mutants result
from both a decrease in basicity and an increase in flexibility of the general
base. The greater 10(3.4)-fold decrease in kcat found with the presence of an
additional residue at the amino-terminus is ascribed to either the complete
blockage or the drastically altered position of the general base.
PMID- 9398174
TI - Heteronuclear NMR studies of the combined Src homology domains 2 and 3 of pp60 c
Src: effects of phosphopeptide binding.
AB - The results of heteronuclear NMR studies on the combined Src homology domains 2
and 3 (SH3-SH2) of pp60 c-Src are presented. Resonance assignments were obtained
using heteronuclear triple-resonance experiments in conjunction with 15N
separated nuclear Overhauser effect spectroscopy (NOESY) data. A modified three
dimensional 13CO-15N-1H spectral correlation experiment [(HACA)CO(CA)-NH] with
improved sensitivity is presented that provided additional sequential information
and resolved several ambiguities. Chemical shifts and sequential- and medium
range NOE cross peaks indicate that the structures of both the SH3 and SH2
portions of the polypeptide are very similar to those of the isolated SH3 and SH2
domains. Binding of a high-affinity phosphopeptide, EPQpYEEIPIYL, induces large
chemical shift changes at several locations in the SH2 domain. Comparison with
known results for peptide binding to SH2 domains shows that the residues
displaying the largest effects are all involved in peptide binding or undergo
significant conformational changes upon binding. However, subtle changes of both
1H and 15N chemical shifts are observed for residues within the SH3 domain and
the connecting linker region, indicating possible cross-domain communication.
PMID- 9398175
TI - Probing the conformation of NhaA, a Na+/H+ antiporter from Escherichia coli, with
trypsin.
AB - One of the most striking features of NhaA, an Escherichia coli Na+/H+ antiporter,
is its extreme sensitivity to pH. The activity of NhaA increases 2000-fold
between pH 6.5 and 8.5. In this work, we investigated whether the activation of
NhaA by pH is accompanied by conformational changes which can be detected using
trypsin as a probe. We have found that NhaA is susceptible to proteolytic
digestion at the pH range where it is activated, suggesting that these two events
may be related; at alkaline pH, the protein becomes active and adopts an "open"
conformational state in which more domains are exposed to the enzyme. This idea
was further supported by results from two mutants of NhaA in which His-225, a
residue involved in pH sensing, has been replaced by either Arg or Asp. The
mutant H225R is activated at more acidic pH values, while H225D at more alkaline
pH. In accordance with the results described for the wild-type protein, H225R was
susceptible to digestion by trypsin at the pH at which it undergoes main
activation. NhaA has many potential tryptic cleavage sites. However, analysis of
the tryptic digestion fragments suggests that at alkaline pH, the protein is
exposed to cleavage mainly at hydrophilic loops 6, 7, and 8. Thus, upon
activation, NhaA appears to undergo a change in conformation that is reflected in
specific regions of the protein.
PMID- 9398176
TI - An early step in Pseudomonas exotoxin action is removal of the terminal lysine
residue, which allows binding to the KDEL receptor.
AB - During the intoxication process, Pseudomonas exotoxin (PE) and immunotoxins
containing PE internalize into the target cell and become processed into two
fragments, and the carboxyl fragment translocates into the cytosol where it
inactivates elongation factor 2. We have proposed that after internalization into
cells the carboxyl-terminal fragment of PE (amino acids 280-613), which ends in
REDLK, binds to the KDEL receptor (ERD2) which carries it to the endoplasmic
reticulum, from which the PE fragment translocates to the cytosol. Earlier
experiments showing that REDL but not REDLK binds to the KDEL receptor suggested
that the terminal lysine is removed sometime during the intoxication process. To
determine if and where this occurs, we exposed a peptide ending in REDLK to
malignant cells in culture and found that binding to the KDEL receptor was
restored. Restoration of receptor binding also occurred if a peptide or toxin
ending in REDLK at its carboxyl terminus was incubated with plasma, indicating
that the terminal lysine is removed prior to entry of the toxin into the cell. We
conclude that plasma carboxypeptidase(s) cleave(s) the lysine residue from the
carboxyl terminus of PE and PE-containing immunotoxins as an early and essential
step in their cellular intoxication pathway.
PMID- 9398177
TI - Proteolysis of the carboxyl-terminal GPI signal independent of GPI modification
as a mechanism for selective protein secretion.
AB - Variable amounts of soluble forms of a variety of glycosyl-phosphatidylinositol
(GPI)-anchored proteins occur extracellularly, but the molecular mechanisms
governing their release are not entirely clear. When the GPI-anchored folate
receptor (FR) type beta was expressed transiently in human 293 fibroblasts, there
was a roughly equal distribution of [3H]folic acid binding protein between the
cell surface and the medium after 24 h over a wide range of expression levels of
FR-beta. The difference in apparent molecular masses between the soluble FR-beta
and the PI-PLC-treated membrane protein indicated that the former was not
released from the membrane by the action of phospholipase. Brefeldin A inhibited
the release of soluble FR-beta from both the transfected 293 cells and stable
recombinant CHO (CHO-FR-beta) cells while pre-existing levels of cell surface FR
were unaltered suggesting the absence of a precursor-product relationship between
the membrane-associated FR-beta and the soluble protein in the medium.
[35S]Cysteine pulse-chase analysis was consistent with this finding.
Interchanging of carboxyl-terminal peptides between FR-beta and FR-alpha revealed
that the nature of the processed signal for GPI modification was responsible for
the quantitative membrane anchoring of FR-alpha and the production of soluble FR
beta. When total cell lysates were analyzed by Western blot, a diffuse band of
apparent 41 kDa and three additional sharp bands of apparent 35, 33, and 29.3 kDa
were seen. The 41 kDa band was identified as the PI-PLC sensitive cell surface
receptor. Several mutant constructs of FR-beta, in which the carboxyl-terminal
signal for GPI modification was either disrupted or deleted only gave the three
lower bands. The three sharp bands from the wild-type and the mutant forms of FR
beta were identified as nonglycosylated (29.3 kDa) or glycosylated polypeptides
in which the carboxyl-terminal peptide was at least partially proteolyzed without
GPI modification. All of the mutations in the GPI signal resulted in the recovery
of [3H]folic acid binding protein in the media which, similar to the wild-type FR
recovered from the media, were converted to the 29.3 kDa band by N-glycanase. The
results from this study indicate that a carboxyl-terminal peptide in FR-beta is
efficiently proteolyzed intracellularly by a pathway that is independent of GPI
signal recognition resulting in proper protein folding and secretion. Such
carboxyl-terminal sequences could represent a simple adaptation for proteins
whose physiologic functions reside both at the cell surface and in extracellular
fluids, allowing their selective and tissue-specific release.
PMID- 9398178
TI - Early photolysis intermediates of gecko and bovine artificial visual pigments.
AB - Nanosecond laser photolysis measurements were conducted on digitonin extracts of
artificial pigments prepared from the cone-type visual pigment, P521, of the
Tokay gecko (Gekko gekko) retina. Artificial pigments were prepared by
regeneration of bleached gecko photoreceptor membranes with 9-cis-retinal, 9-cis
14-methylretinal, or 9-cis-alpha-retinal. Absorbance difference spectra were
recorded at a sequence of time delays from 30 ns to 60 microseconds following
excitation with a pulse of 477-nm actinic light. Global analysis showed the
kinetic data for all three artificial gecko pigments to be best fit by two
exponential processes. These two-exponential decays correspond to similar decays
observed after photolysis of P521 itself, with the first process being the decay
of the equilibrated P521 Batho<-->P521 BSI mixture to P521 Lumi and the second
process being the decay of P521 Lumi to P521 Meta I. In spite of its large blue
shift relative to P521, iso-P521 displays a normal chloride depletion induced
blue shift. Iso-P521's early intermediates up to Lumi were also blue-shifted,
with the P521 Batho<-->P521 BSI equilibrated mixture being 15 nm blue-shifted and
P521 Lumi being 8 nm blue-shifted relative to the intermediates formed after P521
photolysis. The blue shift associated with the iso-pigment is reduced or
disappears entirely by P521 Meta I. Similar blue shifts were observed for the
early intermediates observed after photolysis of bovine isorhodopsin, with the
Lumi intermediate blue-shifted 5 nm compared to the Lumi intermediate formed
after photolysis of bovine rhodopsin. These shifts indicate that a difference
exists between the binding sites of 9- and 11-cis pigments which persists for
microseconds at 20 degrees C.
PMID- 9398179
TI - Role of the P6-P3' region of the serpin reactive loop in the formation and
breakdown of the inhibitory complex.
AB - Serpins have a large external peptide loop known as the reactive loop. Part of
the reactive loop functions as the primary recognition site for target proteases;
however, the complete role of the reactive loop in determining serpin specificity
is unclear. In the current study, we investigated the reactive loop region that
could potentially interact with the extended binding site of target proteases;
the P6-P3' region. We utilized a reactive loop switching strategy to determine
the extent to which the inhibitory activity of alpha-1-protease inhibitor (PI)
against human neutrophil elastase (HNE) could be transferred to alpha-1
antichymotrypsin (ACT), a serpin that does not inhibit HNE. A series of ACT-PI
chimeras were constructed in which segments of increasing length taken from the
P6-P3' region of PI replaced the corresponding residues of ACT. The effectiveness
of each chimera as an inhibitor of HNE was assessed by measuring (1) the rate of
inhibitory complex formation and (2) the rate of complex breakdown (complex
stability). Although all the ACT-PI chimeras were fully functional against
chymotrypsin-like proteases, the series of chimeras showed no consistent progress
toward the production of an inhibitor with the inhibitory properties of PI. The
most rapid complex formation and most stable complexes were observed for chimeras
with the P3-P1 residues of PI, whereas extending the replacement region to the P6
residue resulted in a considerable decrease in both inhibitory parameters. In
order to study two additional features of the PI reactive loop that may play a
role in the presentation of the P6-P3' region to HNE, we constructed variants
that contained a P4' proline and deleted the P6'-P9' residues. Changes on the
prime side appeared to have little effect on rates of inhibition or complex
stability. Overall, even the most effective chimeras demonstrated an inhibition
rate constant at least 60-fold less than that observed for PI inhibition of HNE
and the most long lived chimera-HNE complexes broke down more rapidly than PI-HNE
complexes. These results indicate that residues in the reactive loop region
predicted to contact a specific target protease cannot fully transfer inhibitory
activity from one serpin to another, suggesting that specific reactive loop
serpin body and serpin body-protease body interactions play a significant role in
determining serpin inhibitory activity against target proteases.
PMID- 9398180
TI - Hydrogen bonding at the active site of delta 5-3-ketosteroid isomerase.
AB - The solution secondary structure of the highly active Y55F/Y88F "Tyr-14-only"
mutant of delta 5-3-ketosteroid isomerase complexed with 19-nortestosterone
hemisuccinate has been shown to consist of three helices, a six-stranded mixed
beta-sheet, and five turns. The steroid binds near the general acid, Tyr-14, on
helix 1, near the general base, Asp-38, on the first strand of the beta-sheet,
and on the hydrophobic face of the beta-sheet [Zhao, Q., Abeygunawardana, C., &
Mildvan, A. S. (1997) Biochemistry 36, 3458-3472]. On this hydrophobic face, Asp
99 is the only polar residue. Free isomerase shows a deshielded exchangeable
proton resonance at 13.1 ppm assigned to the N epsilon H of neutral His-100. Its
fractionation factor (phi = 0.79) and slow exchange with solvent suggest it to be
buried or involved in an H-bond. The binding of dihydroequilenin or estradiol to
isomerase induces the appearance of two additional deshielded proton resonances,
one at 18.2 ppm assigned to the gamma-carboxyl proton of Asp-99, and the other,
at 11.6 ppm, assigned to the zeta-OH proton of Tyr-14. While mutation of Asp-99
to Ala results in the disappearance of only the resonance near 18 ppm [Wu, R. W.,
Ebrahemian, S., Zwrotny, M. E., Thornberg, L. D., Perez-Alverado, G. C.,
Brothers, P., Pollack, R. M., & Summers, M. F. (1997) Science 276, 415-418], both
of these resonances disappear in mutants lacking Tyr-14, suggesting an H-bonded
catalytic diad, Asp-99-COOH--Tyr14-OH--O-steroid enolate. The catalytic diad is
further supported by NOEs from the beta 1 and beta 2 protons of Asp-99 to the
epsilon protons of Tyr-14, and from the zeta-OH proton of Tyr-14 to the gamma
carboxyl proton of Asp-99, indicating close proximity of these two residues, and
by other data from the literature. A strong, low-barrier H-bond between Asp-99
and Tyr-14 is indicated by the 6.2 ppm deshielding, low fractionation factor (phi
= 0.34) and slow exchange of the resonance at 18.2 ppm. A normal H-bond between
Tyr-14 and the steroid is indicated by the 1.8 ppm deshielding, fractionation
factor of 0.97 and the slow exchange of the resonance at 11.6 ppm. It is
suggested that the 10(4.7)-fold contribution of Tyr-14 to catalysis is made
possible by strong H-bonding from Asp-99 in the catalytic diad which strengthens
general acid catalysis by Tyr-14. It is also noted that highly deshielded proton
resonance on enzymes between 15 and 20 ppm, assigned to low-barrier H-bonds,
generally involve carboxyl groups.
PMID- 9398181
TI - Site-directed spin-labeling study of the structure and subunit interactions along
a conserved sequence in the alpha-crystallin domain of heat-shock protein 27.
Evidence of a conserved subunit interface.
AB - Site-directed spin-labeling (SDSL) was used to investigate the secondary
structure, solvent accessibility, and tertiary and quaternary interactions along
the sequence located between residues 133 and 144 in the alpha-crystallin domain
of human heat-shock protein 27 (HSP 27). The sequence is conserved among
mammalian sHSP and shows similarity to the region of highest homology between
alpha A- and alpha B-crystallins. Eleven sequential single cysteine mutants were
prepared and reacted with a sulfhydryl-specific spin-label. The accessibilities
of attached nitroxide side chains to a paramagnetic probe in the aqueous solution
were determined. Spectral line shapes were analyzed in terms of side-chain
mobility and spatial proximity to nearby nitroxides. The sequence-specific
mobilities and accessibilities varied with a period of 2, consistent with the
presence of a beta-strand along the sequence. At even sites, the nitroxide
environment is highly ordered with virtually no accessibility to the hydrophilic
probe, indicating that one face of the strand is buried. Furthermore, spin-spin
interactions between nitroxides in the oligomeric structure strongly suggest that
equivalent strands from different subunits are in close spatial proximity. These
structural characteristics are remarkably similar to those of the equivalent
sequence in alpha A-crystallin [Berengian, A. R., Bova, M. P., and Mchaourab, H.
S. (1997) Biochemistry 36, 9951-9957]. In both proteins, a beta-strand spans the
sequence and is located at a subunit interface, indicating that one set of
interactions between subunits, and its associated symmetry, is conserved. This is
the first report of sequence-specific structural similarity between alpha A
crystallin and HSP 27 and the first identification of a conserved secondary
structural element in the alpha-crystallin domain.
PMID- 9398182
TI - Comparison of the hemolytic activity and solution structures of two snake venom
cardiotoxin analogues which only differ in their N-terminal amino acid.
AB - Cardiotoxin analogues IV (CTX IV) and II (CTX II) isolated from the venom of
Taiwan Cobra (Naja naja atra) differ in their amino acid sequence by a single
amino acid at the N-terminal end. Leucine at the N-terminal end in CTX II is
replaced by arginine in CTX IV. CTX IV is an unique snake venom cardiotoxin as it
is the only cardiotoxin isoform known so far which possesses a positively charged
residue at the N-terminal amino acid. All other cardiotoxins have a hydrophobic
amino acid (leucine or isoleucine) at their N-terminal end. The aim of the
present study is to understand the effect(s) of the presence of a cationic
residue on the structure and functional properties of cardiotoxin(s). Comparison
of the hemolytic activities of CTX IV and CTX II shows that lytic activity of the
former is at least twice as that shown by the latter. Comparison of the solution
structures of CTX IV and CTX II using two-dimensional NMR spectroscopy and
dynamical simulated annealing technique reveals that the backbone fold of both
the toxin isoforms is almost similar. The secondary structural elements in these
two cardiotoxin isoforms consist of long, triple-stranded, as well as short,
double-stranded, antiparallel beta-sheets. Thermal denaturation experiments
showed that the structure of CTX IV is more stable than that of CTX II. Critical
analysis of the three-dimensional structures of CTX IV and CTX II reveals the
presence of a "cationic" cluster comprising of positively charged residues on the
concave side of the CTX IV molecule. Similar clusters consisting of positively
charged residues are not found in CTX II. The differential erythrocyte lytic
activities of these two cardiotoxins are attributed to the difference(s) in the
distribution of the positively charged residues in their three-dimensional
structures.
PMID- 9398183
TI - Differences in active site gorge dimensions of cholinesterases revealed by
binding of inhibitors to human butyrylcholinesterase.
AB - Amino acid sequence alignments of cholinesterases revealed that 6 of 14 aromatic
amino acid residues lining the active center gorge of acetylcholinesterase are
replaced by aliphatic amino acid residues in butyrylcholinesterase. The Y337
(F330) in mammalian acetylcholinesterase, which is replaced by A328 in human
butyrylcholinesterase, is implicated in the binding of ligands such as huperzine
A, edrophonium, and acridines and one end of bisquaternary compounds such as
BW284C51 and decamethonium. Y337 may sterically hinder the binding of
phenothiazines such as ethopropazine, which contains a bulky exocyclic
substitution. Inhibition studies of (-)-huperzine A with human
butyrylcholinesterase mutants, where A328 (KI = 194.6 microM) was modified to
either F (KI = 0.6 microM, as in Torpedo acetylcholinesterase) or Y (KI = 0.032
microM, as in mammalian acetylcholinesterase), confirmed previous observations
made with acetylcholinesterase mutants that this residue is important for binding
huperzine A. Inhibition studies of ethopropazine with butyrylcholinesterase
mutants, where A328 (KI = 0.18 microM) was modified to either F (KI = 0.82
microM) or Y (KI = 0.28 microM), suggested that A328 was not solely responsible
for the selectivity of ethopropazine. Volume calculations for the active site
gorge showed that the poor inhibitory activity of ethopropazine toward
acetylcholinesterase was due to the smaller dimension of the active site gorge
which was unable to accommodate the bulky inhibitor molecule. The volume of the
butyrylcholinesterase active site gorge is approximately 200 A3 larger than that
of the acetylcholinesterase gorge, which allows the accommodation of
ethopropazine in two different orientations as demonstrated by rigid-body
refinement and molecular dynamics calculations.
PMID- 9398184
TI - A diminished role for hydrogen bonds in antifreeze protein binding to ice.
AB - The most abundant isoform (HPLC-6) of type I antifreeze protein (AFP1) in winter
flounder is a 37-amino-acid-long, alanine-rich, alpha-helical peptide, containing
four Thr spaced 11 amino acids apart. It is generally assumed that HPLC-6 binds
ice through a hydrogen-bonding match between the Thr and neighboring Asx residues
to oxygens atoms on the {2021} plane of the ice lattice. The result is a lowering
of the nonequilibrium freezing point below the melting point (thermal
hysteresis). HPLC-6, and two variants in which the central two Thr were replaced
with either Ser or Val, were synthesized. The Ser variant was virtually inactive,
while only a minor loss of activity was observed in the Val variant. CD,
ultracentrifugation, and NMR studies indicated no significant structural changes
or aggregation of the variants compared to HPLC-6. These results call into
question the role of hydrogen bonds and suggest a much more significant role for
entropic effects and van der Waals interactions in binding AFP to ice.
PMID- 9398185
TI - NMR studies of the role of hydrogen bonding in the mechanism of triosephosphate
isomerase.
AB - Triosephosphate isomerase (TIM) catalyzes the reversible interconversion of
dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP), with Glu
165 removing the pro-R proton from C1 of DHAP and neutral His-95 polarizing the
carbonyl group of the substrate. TIM and its complexes with the reactive
intermediate analogs, phosphoglycolic acid (PGA) and phosphoglycolohydroxamic
acid (PGH), were studied by 1H NMR at 600 MHz and at low temperature (-4.8
degrees C). His-95 shows an N epsilon H resonance at 13.1 ppm which shifts to
13.3 ppm in the TIM-PGA complex and to 13.5 ppm in the TIM-PGH complex. In the
TIM-PGH complex, His-95 N epsilon H shows a slow, pH-independent exchange rate
with water (kex = 80 s-1 at 30 degrees C, Eact = 19 kcal/mol), which is 44-fold
slower than that of an exposed histidine suggesting partial shielding from bulk
solvent, and a fractionation factor phi = 0.71 +/- 0.02 consistent with its
donation of a normal hydrogen bond. The formation of the TIM-PGH complex results
in the appearance of several deshielded proton resonances, including one at 14.9
ppm and one at 10.9 ppm which overlaps with another resonance. The resonance at
14.9 ppm is absent and the resonance at 10.9 ppm is much weaker in the TIM
complex of PGA, which lacks the hydroxamic acid (-NHOH) moiety. 15N-labeled PGH
was synthesized and the NH proton of free [15N]PGH shows a single 1H-15N HMQC
cross peak with delta (1H) = 10.3 ppm and delta (15N) = 168 ppm which shifts to
delta (1H) = 10.9 ppm and delta (15N) = 174 ppm in the TIM complex of [15N]PGH.
The 15N-1H coupling in the complex indicates covalent N-H bonding, and the
deshielded delta (15N) indicates a significant contribution of the imidate
resonance form of PGH. The 14.9 ppm resonance is assigned to the NOH proton of
bound PGH. This resonance shows a pH-independent exchange rate with water (kex =
3900 s-1 at 30 degrees C, Eact = 8.9 kcal/mol) which may reflect the dissociation
of the TIM-PGH complex, and meets the criteria for a low-barrier hydrogen bond on
the basis of the significant downfield shift of 6.2 ppm from the NOH proton of
the model compound acetohydroxamic acid, and a very low fractionation factor phi
= 0.38 +/- 0.06. In the X-ray structure of the TIM-PGH complex [Davenport, R. C.,
Bash, P. A., Seaton, B. A., Karplus, M., Petsko, G. A., and Ringe, D. (1991)
Biochemistry 30, 5821], the NOH proton of bound PGH is hydrogen bonded to Glu
165. A low-barrier hydrogen bond from PGH NOH to Glu-165 suggests a dual role for
Glu-165 in catalysis of proton transfer not only between the C1 and C2 carbons
but also between the O1 and O2 oxygens in the interconversion of DHAP and GAP in
wild type TIM. Such a mechanism, together with the measured exchange rate of the
His-95 N epsilon H proton with solvent protons can accommodate the classical
measurements of tritium incorporation from DHAP into GAP.
PMID- 9398186
TI - Absence of observable biotin-protein interactions in the 1.3S subunit of
transcarboxylase: an NMR study.
AB - Transcarboxylase (TC) is a biotin-containing enzyme catalyzing the transfer of a
carboxyl group from methylmalonyl-CoA to pyruvate to form propionyl-CoA and
oxalacetate. The transfer is achieved via carboxylated biotin bound to a 1.3S
subunit within the multisubunit enzyme complex. The 1.3S subunit of TC is a 123
amino acid polypeptide, to which biotin is covalently attached at Lys 89. We have
overexpressed 1.3S in Escherichia coli and characterized the biotinylated and apo
forms by 1D- and 2D-NMR spectroscopy. To search for protein-biotin interactions,
which could modulate the reactivity of the biotin ring on the 1.3S subunit, we
have compared the chemical shifts, relaxation parameters, and NH exchange rates
of the ureido ring protons of free and 1.3S-bound biotin. These properties are
similar for both forms of the biotin. Further, NOE experiments on 1.3S revealed
no detectable cross peaks between biotin and the protein. Consistent with these
findings, the 2D NMR data for holo- and apo-1.3S are essentially identical
indicating little or no changes in conformation between the two forms of the
protein. The conclusion that strong protein-biotin interactions do not exist in
1.3S contrasts with the findings for the biotin carboxylase carrier protein from
E. coli acetyl-CoA carboxylase, which reveal significant biotin-protein contacts
[Athappilly, F. K., and Hendrickson, W. A. (1995) Structure 3, 1407-1419].
Further, the biotin NH1' exchange rates determined for 1.3S show that in the
region of optimal activity for TC (pH 5.5-6.5) acid-catalyzed exchange
predominates. In this pH range the base-catalyzed rate is too small (< 1 s-1) to
account for the turnover rate of the enzyme. Thus, the means by which the N1'
atom is activated for nucleophilic attack of the carboxyl group in methylmalonyl
CoA does not appear to depend on interactions within the 1.3S subunit alone;
rather activation must occur at the interfaces of the subunits in the holoenzyme.
PMID- 9398187
TI - 13C- and 15N-labeled peptide substrates as mechanistic probes of
oligosaccharyltransferase.
AB - The carboxamide moiety that links the carbohydrate and protein moieties in N
linked glycoproteins has been unambiguously determined to arise intact from
asparagine by the use of chemically synthesized Bz-[4-13C, 15N]Asn-Leu-Thr-NH2 as
an oligosaccharyltransferase (OST) substrate. Bz-[4-13C]Asn-Leu-Thr-NH2 was also
synthesized and used to evaluate a proposed mechanism of OST catalysis similar to
that of glutamine-dependent amidotransferases using 15NH4OAc as a potential
external nucleophile. Analysis of NMR and MS spectra of the isotopically labeled
peptides and the resulting biosynthesized glycopeptides indicates that free 15NH3
is not lost from the doubly labeled substrate during catalysis nor can exogenous
15NH3 intercept any of several postulated enzyme-bound species. These results
indicate that OST-catalyzed glycosylation does not follow a mechanism involving
the transient generation of exchangeable "NH3". Thus, in contrast to several
glutamine-dependent amidotransferases, OST catalysis does not lead to transient
scission of the asparagine beta-carboxamide C-N bond. Together with previously
published results, these data argue against nucleophilic activation of the
asparagine beta-carboxamide moiety being the underlying chemical mechanism for
OST-catalyzed glycosylation of peptides.
PMID- 9398188
TI - Proton nuclear magnetic resonance investigation of the [2Fe-2S](1-)-containing
"Rieske-type" protein from Xanthobacter strain Py2.
AB - Proton NMR spectra of the Rieske-type ferredoxin from Xanthobacter strain Py2
were recorded in both H2O and D2O buffered solutions at pH 7.2. Several well
resolved hyperfine-shifted 1H NMR signals were observed in the 90 to -20 ppm
chemical shift range. Comparison of spectra recorded in H2O and D2O buffered
solutions indicated that the signals at -11.4 (L) and -15.5 (M) ppm were solvent
exchangeable and thus were assigned to the two histidine N epsilon 2H protons.
The remaining observed signals were assigned based upon chemical shift, T1
values, and one-dimensional nuclear Overhauser effect (nOe) saturation transfer
experiments to either C beta H or C alpha H protons of cluster cysteinyl or
histidine ligands. Upon oxidation of the [2Fe-2S] cluster, only two broad
resonances were observed, indicating that the two Fe(III) ions are strongly
antiferromagnetically coupled. In addition, the temperature dependence of each
observed hyperfine-shifted signal in the reduced state was determined, providing
information about the magnetic properties of the [2Fe-2S]1- cluster. Fits of the
temperature data observed for each resonance to equations describing the
hyperfine shift with their Boltzmann weighting factors provided a delta EL value
of 185 +/- 26 cm-1 which, in turn, gives -2J as 124 cm-1. These data indicate
that the two iron centers in the reduced [2Fe-2S] Rieske-type center are
moderately antiferromagnetically coupled. The combination of these data with the
available spectroscopic and crystallographic results for Rieske-type proteins has
provided new insights into the role of the Rieske-type protein from Xanthobacter
strain Py2 in alkene oxidation.
PMID- 9398189
TI - Resonance Raman characterization of reaction centers in which bacteriochlorophyll
replaces the photoactive bacteriopheophytin.
AB - Qy-excitation resonance Raman (RR) spectra are reported for two mutant reactions
centers (RCs) from Rhodobacter sphaeroides in which the photoactive
bacteriopheophytin (BPhL) is replaced by a bacteriochlorophyll (BChl) molecule,
designated by beta L. One mutation, (M)L214H, yields the pigment change via
introduction of a histidine residue at position M214. The other mutation,
(M)L214H/(L)-E104V, removes the putative hydrogen bond between beta L and the
native glutamic acid residue at position L104. The vibrational signatures of the
beta L cofactors of the mutants are compared with one another and with those of
the accessory BChls (BChlL,M) in both beta-mutant and wild-type RCs. The
spectroscopic data reveal the following: (1) The beta L cofactor is a five
coordinate BChl molecule with a histidine axial ligand. The conformation of beta
L and the strength of the Mg-histidine bond are very similar to that of BChlL,M.
(2) The beta L cofactor is oriented in the protein pocket in a manner similar to
that of BPhL of wild-type. (3) The beta L cofactor of the (M)L214H mutant forms a
hydrogen bond with glutamic acid L104 via the C9-keto group of the macrocycle.
The strength of this hydrogen bond is identical to that formed between this
protein residue and the C9-keto group of BPhL in wild-type. (4) The hydrogen
bonding interaction at the C9-keto site induces secondary cofactor-protein
interactions which involve the C2a-acetyl and Cb-alkyl substituent groups.
Collectively, the vibrational signatures of beta L indicate that its intrinsic
physicochemical properties are very similar to those of BChlL. Consequently, the
initial charge-separated intermediate in beta-type RCs is best characterized as a
thermal/quantum mechanical admixture of P+ beta L- and P+ BChlL-(P is the primary
electron donor), as originally proposed by Kirmaier et al. [(1995) J. Phys. Chem.
99, 8903-8909].
PMID- 9398190
TI - Structural coupling between the oxygen-evolving Mn cluster and a tyrosine residue
in photosystem II as revealed by Fourier transform infrared spectroscopy.
AB - The flash-induced Fourier transform infrared (FTIR) difference spectrum of the
oxygen-evolving Mn cluster upon S1-to-S2 transition (S2/S1 spectrum) was measured
using photosystem II (PS II) core complexes of Synechocystis 6803 in which
tyrosine residues were specifically labeled with 13C at the ring-4 position. The
double-difference spectrum between the unlabeled and labeled S2/S1 spectra showed
that the bands at 1254 and 1521 cm-1 downshifted by 25 and 15 cm-1, respectively,
upon ring-4-13C-Tyr labeling. This observation indicates that there is a tyrosine
residue coupled to the Mn cluster, and the vibrational modes of this tyrosine are
affected upon S2 formation. From a comparison of the above band positions and
isotopic shifts in the S2/S1 spectrum with those of the FTIR spectra of tyrosine
in aqueous solution at pH 0.6 (Tyr-OH) and pH 13.4 (Tyr-O-) and of the YD./YD
FTIR difference spectrum, the 1254 and 1521 cm-1 bands were assigned to the CO
stretching and ring CC stretching modes of tyrosine, respectively, and this
tyrosine was suggested to be protonated in PS II. The observation that the effect
of the S2 formation on the tyrosine bands appeared as a decrease in intensity
with little frequency change could not be explained by a simple electrostatic
effect by Mn oxidation, suggesting that the Mn cluster and a tyrosine are linked
via chemical and/or hydrogen bonds and the structural changes of the Mn cluster
are transmitted to the tyrosine through these bonds. On the basis of previous EPR
studies that showed close proximity of YZ to the Mn cluster, YZ was proposed as
the most probable candidate for the above tyrosine. This is the first
demonstration of the structural coupling between YZ and the Mn cluster in an
intact oxygen-evolving complex. This structural coupling may facilitate electron
transfer from the Mn cluster to YZ. Our observation also provides an experimental
support in favor of the proton or hydrogen atom abstraction model for the YZ
function.
PMID- 9398191
TI - Fourier transform infrared difference spectroscopy of photosystem II tyrosine D
using site-directed mutagenesis and specific isotope labeling.
AB - Tyrosine D (TyrD), a side path electron carrier of photosystem II (PS II), has
been studied by light-induced Fourier transform infrared (FTIR) difference
spectroscopy in PS II core complexes of Synechocystis sp. PCC 6803 using the
experimental conditions previously optimized to generate the pure TyrD./TyrD FTIR
difference spectrum in PS II-enriched membranes of spinach [Hienerwadel, R.,
Boussac, A., Breton, J., and Berthomieu, C. (1996) Biochemistry 35, 115447
115460]. IR modes of TyrD and TyrD. have been identified by specific 2H- or 13C
labeling of the tyrosine side chains. The v8a(CC) and v19(CC) IR modes of TyrD
are identified at 1615 and 1513-1510 cm-1, respectively. These frequencies show
that TyrD is protonated. Comparison of isotope-sensitive signals in situ with
those of the model compound p-methylphenol dissolved in different solvents leads
to the assignment of the v7'a(CO) and delta(COH) modes of TyrD at 1275 and 1250
cm-1, respectively. It is shown that these modes and in particular the delta(COH)
IR mode are very sensitive to the formation of hydrogen-bonded complexes with
amide C=O or with imidazole nitrogen atoms. The frequencies observed in situ show
that TyrD is hydrogen-bonded to the imidazole ring of a neutral histidine. For
the radical TyrD., isotope-sensitive IR modes are identified at 1532 and 1503 cm
1. The signal at 1503 cm-1 is assigned to the v(CO) mode of TyrD. since it is
sensitive to 13C-labeling at the ring carbon involved in the C4-O bond. The
perturbation of TyrD and TyrD. IR modes upon site-directed replacement of D2
His189 by Gln confirms that a hydrogen bond exists between both TyrD and TyrD.
and D2-His189. In the D2-His189Gln mutant, the v7'a(CO) mode of TyrD at 1267 cm-1
and the delta(COH) mode at approximately 1228 cm-1 show that a hydrogen bond is
formed between TyrD and an amide carbonyl, probably that of the D2-Gln189 side
chain. Electron nuclear double resonance (ENDOR) measurements have shown that
TyrD. is hydrogen-bonded in the wild type but not in the mutant [Tang, X.-S.,
Chrisholm, D. A., Dismukes, G. C., Brudwig, G. W., and Diner, B. A. (1993)
Biochemistry 32, 13742-13748]. The v(CO) mode of TyrD. at 1497 cm-1 is
downshifted by 6 cm-1 compared to WT PS II, indicating that hydrogen bonding
induces a frequency upshift of the v(CO) IR mode of Tyr.. IR signals from the Gln
side chain v(C=O) mode are proposed to contribute at 1659 and 1692 cm-1 in the
TyrD and TyrD. states, respectively. These frequencies are consistent with the
rupture of a hydrogen bond upon TyrD. formation in the mutant. The frequency of
the v(CO) mode of TyrD., observed at 1503 cm-1 for WT PS II, is intermediate
between that observed at 1497 cm-1 in the D2-His189Gln mutant and at 1513 cm-1
for Tyr. formed by UV irradiation in borate buffer, suggesting weaker or fewer
hydrogen bonds for TyrD. in PS II than in solution. The role of D2-His189 in
proton uptake upon TyrD. formation is also investigated.
PMID- 9398192
TI - Surface of cytochrome c: infrared spectroscopy of carboxyl groups.
AB - The carboxylate groups of organic acids give strong absorption in the infrared
between approximately 1550 and 1650 cm-1. For acetate and chloroacetate
derivatives, the infrared (IR) frequency of the carboxylate antisymmetric
stretching mode (v(a)OCO) is related to the square root of the pK of the acid,
with a shift of approximately 20 cm-1 to higher frequency for a pK drop in the
range 5-3. It follows that v(a)OCO may respond to conditions on the protein
surface. In this paper, the IR amide I' and carboxylate absorptions of cytochrome
c from horse, yeast, and tuna are compared with model compounds such as Val-Glu
and microperoxidase-11, the 11 amino acid fragment of horse cytochrome c
containing the covalently bound heme. For microperoxidase-11, the contribution
from all four carboxylates can be accounted for and the 1567 cm-1 absorption is
assigned to the heme propionates. For the proteins, the carboxylate absorption
band is inhomogeneous, i.e., there is a distribution of frequencies. Both the
amide I' and carboxylate bands are sensitive to protein conformation as shown by
their different pH, salt, and redox dependence.
PMID- 9398193
TI - A rationale for the absolute conservation of Asn70 and Pro71 in mitochondrial
cytochromes c suggested by protein engineering.
AB - The absolutely conserved residues Asn70 and Pro71 of mitochondrial cytochrome c
have been targeted for protein engineering by semisynthesis. Neither residue has
even been implicated in mechanistic schemes, and we reasoned that the
conservation of this dipeptide was to fulfill a crucial structural role.
Semisynthesis was through condensation by autocatalytic fragment religation of
natural fragment 1-65 (H) of the horse protein and synthetic 39-residue peptides
containing noncoded amino acids prepared by solid-phase methods. High yields of
the purified analogs, homoserine70 and norvaline71 cytochromes c, were obtained.
Functional tests revealed minor destabilization of the Hse70-containing
structure, with little adverse effect in in vitro assays, but [Nva71] cytochrome
c was essentially devoid of activity in these systems. This appeared to be a
consequence of a shift, more pronounced than any yet reported, in the
conformational equilibrium between the active state III conformer and the
inactive, 'alkaline' state IV. The results support our view that this dipeptide
is optimal for, and rigidifies, the right-angle bend between two alpha-helices,
thus determining the conformation of the 70s loop that terminates in the sixth
ligand Met80, and 'forcing' the coordination of iron by thioether sulfur in the
presence of the adjacent more avid amine ligands of state IV. Not only is [Nva71]
cytochrome c inactive at pH 7, but it also proves to be an extremely potent
inhibitor of electron transfer by native state III, thus providing the rationale
for the evolutionary conservation of a high pK for the ligand exchange reaction.
PMID- 9398194
TI - Kinetics of ferric cytochrome P450 reduction by NADPH-cytochrome P450 reductase:
rapid reduction in the absence of substrate and variations among cytochrome P450
systems.
AB - The reduction of ferric cytochrome P450 (P450) to ferrous is the first chemical
step in almost all P450 reactions, and many characteristics of this step have
been reported. Reduction kinetics of rabbit and human P450s were measured in a
variety of systems. As reported earlier, P450 reduction is biphasic in microsomes
and some purified P450 systems. However, this is not an inherent property of
P450s, and some low- and high-spin iron P450s were reduced with single
exponential kinetics. Contrary to a generalized view, the presence of substrate
is not necessary for rapid reduction of all P450s. Also, low-spin heme can be
reduced as rapidly as high-spin in several P450s. P450s varied considerably in
their reduction behavior, and even a single P450 showed remarkably different
reduction kinetics when placed in various environments. P450 3A4 reduction was
examined in liver microsomes, a reconstituted system, a fusion protein in which
it was linked to NADPH-P450 reductase, and baculovirus and bacterial membranes in
which P450 3A4 and NADPH-P450 reductase were coexpressed; the systems differed
considerably in terms of the need for the substrate testosterone and cytochrome
b5 (b5) for reduction and as to whether reduction was rate-limiting in the
overall catalytic cycle. When b5 was included in reconstituted systems, it
reduction kinetics were linked with those of some P450s. This behavior could be
simulated in kinetic models in which electrons flowed from the ferrous P450.CO
complex to oxidized b5. Overall, the kinetics of ferric P450 reduction cannot be
generalized among different P450s in various systems, and concepts regarding
influence of substrate, reaction sequence, and a rate-limiting step are not very
universal.
PMID- 9398195
TI - Identification of a critical phenylalanine residue in horseradish peroxidase,
Phe179, by site-directed mutagenesis and 1H-NMR: implications for complex
formation with aromatic donor molecules.
AB - The functional and structural significance of Phe179 of horseradish peroxidase
isoenzyme C (HRP C) has been investigated by site-directed mutagenesis. This
residue is located in a structurally variable insertion between helices F and G,
a motif unique to peroxidases of higher plants. Results obtained for three
recombinant enzymes, with Phe179 substituted by Ala, His, or Ser, provide the
first demonstration of the importance of this side chain for the binding of
aromatic donor molecules. Experimental parameters for direct comparison with the
wild-type enzyme were obtained by extensive solution state characterization using
both optical and 1H-NMR spectroscopy. Significant chemical shift variations for
resonances associated with the exposed heme edge, notably heme methyl C18H3 and
heme propionate C17(1)H2, were recorded in NMR spectra of both the resting and
cyanide-ligated states of the three Phe179 mutants. Furthermore, comparison of
NOE connectivities in NOESY spectra of cyanide-ligated wild-type and mutant
enzymes enabled the elusive assignment of the aromatic side chain in close
proximity to heme methyl C18H3 to be made to Phe179. Replacement of Phe179 by Ala
resulted in an 80-fold decrease in the binding affinity of the cyanide-ligated
enzyme for benzhydroxamic acid, with a Kd value similar to that determined for
cyanide-ligated HRP A2 (an acidic isoenzyme with valine at position 179). The
binding affinity of Phe179-->Ser was similarly decreased, while that of Phe179-
>His was partially restored relative to wild-type HRP C. Cyanide-ligated Phe179-
>His HRP C exhibited a unique pH-dependent spectral transition associated with a
pKa value of 6.5 +/- 0.2, assigned to the His179 side chain. Two closely related
enzyme forms exhibiting different affinities for benzhydroxamic acid were
observed at neutral pH and above, indicating that the protonation state of His179
gave rise to microheterogeneity in the aromatic donor molecule binding site.
PMID- 9398196
TI - Role of methionine-239, an amino acid residue in the mobile-loop region of the
NADH-binding domain (domain I) of proton-translocating transhydrogenase.
AB - Transhydrogenase couples the transfer of hydride equivalents between NAD(H) and
NADP(H) to proton translocation across a membrane. The one-dimensional proton NMR
spectrum of the recombinant NAD(H)-binding domain (domain I) of transhydrogenase
from Rhodospirillum rubrum reveals well-defined resonances, several of which
arise from a mobile loop at the protein surface. Four have been assigned to Met
residues (MetA-MetD). Substitution of Met239 with either Ile (dI.M239I) or Phe
(dI.M239F) resulted in loss of MetA from the NMR spectrum. Broadening and
shifting of the mobile loop resonances consequent on NAD(H) binding indicate that
the loop closes down on the protein surface. More NAD(H) had to be added to
mutant domain I than to wild type to give comparable resonance broadening. The Kd
of domain I for NADH, measured by equilibrium dialysis, was increased about three
fold by the Met239 mutations. Mutant and wild-type domain I were reconstituted
with domain I-depleted membranes from R. rubrum, and with recombinant domain III
of transhydrogenase. With membranes, the Km for acetylpyridine adenine
dinucleotide during reverse transhydrogenation was 5x and > 6x greater in
dI.M239I and dI.M239F, respectively, than in wild-type. Cyclic transhydrogenation
(in membranes and the recombinant system) was substantially more inhibited (70%
in dI.M239I, and 84% in dI.M239F) than either forward or reverse
transhydrogenation. The docking affinities of dI.M239I and dI.M239F to the
depleted membranes were similar to those of wild-type. It is concluded that
Met239 is MetA in the mobile loop of domain I, and that in proteins with amino
acid substitutions at this position, the binding affinity of NAD(H) is decreased,
and the hydride transfer step is inhibited.
PMID- 9398197
TI - A three-domain iron-sulfur flavoprotein obtained through gene fusion of
ferredoxin and ferredoxin-NADP+ reductase from spinach leaves.
AB - Ferredoxin and ferredoxin-NADP+ reductase are the two last partners of the
photosynthetic electron-transfer chain, responsible for the final reduction of
NADP+ to NADPH. Herein, we report the engineering and characterization of a novel
protein molecule in which the electron-carrier protein (ferredoxin I) and the
reductase (a flavoprotein) were covalently linked in a single polypeptide chain
by gene fusion. The gene was obtained by joining the cDNAs encoding the
respective proteins and subsequently by deleting the intervening sequence between
them by site-directed mutagenesis. No extra amino acid residues were introduced
between the C-terminus of ferredoxin I and the N-terminus of the flavoenzyme. The
chimera was purified to homogeneity and characterized. The M(r) of the chimera
apoprotein was 45,800 as determined by mass spectrometry, in agreement with the
expected value of 45,846. Both flavin and iron-sulfur cluster were in 1:1 ratio
with respect to the apoprotein. The chimera was found active as a diaphorase and,
more interestingly, highly efficient as a cytochrome c reductase, without need
for free ferredoxin addition in the assay medium. Several lines of evidence
indicate that the ferredoxin and the reductase in the chimera assume a
configuration quite similar to that in the dissociable physiological complex.
Thus, the fusion protein could be a useful tool for studying the mechanism of
protein-protein recognition and electron transfer in the ferredoxin-ferredoxin
NADP+ reductase system.
PMID- 9398198
TI - RNA secondary structure switching during DNA synthesis catalyzed by HIV-1 reverse
transcriptase.
AB - Changes in RNA secondary structure have been found to play important roles in
translational regulation, protein synthesis, and mRNA splicing. In studies
utilizing a 66 nucleotide RNA template with a stable hairpin structure, we have
examined the effects of RNA secondary structure on HIV-1 reverse transcriptase
activity. We identify several pause sites in the stem of the hairpin and show
that these pause sites are correlated with the free energy of melting the next
base pair in the stem. We also identify a pause site appearing in the loop of the
hairpin and show that this is due to the rapid formation of a new hairpin
structure occurring during the progress of DNA polymerization through the
hairpin. The rapid change in RNA secondary structure to form the new hairpin
selectively destabilizes the major hairpin and thereby accelerates the rate at
which reverse transcriptase reads through RNA secondary structure.
PMID- 9398199
TI - Decreased Stability of Transforming Growth Factor beta Type II Receptor mRNA in
RER+ Human Colon Carcinoma Cells
AB - Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell growth
and tumor progression. Previous work has shown that loss of functional TGF-beta
type II receptor (RII) due to a frameshift mutation in the 5' half of the RII
gene leads to TGF-beta resistance in a highly progressed, RER+ human colon
carcinoma cell line designated HCT116. Expression of this mutated RII gene was
highly repressed in RER+ cell lines such as HCT116 and RKO, as analyzed by RNase
protection assays. Nuclear run-on and RII promoter-reporter (CAT) assays showed
that the transcriptional levels of the RII gene in these RER+ cells were not
reduced, compared to RII-expressing cells. However, the half-lives of the RII
mRNA, as analyzed by RNase protection assays following actinomycin D treatment,
were significantly decreased. This suggested that the decreased expression of the
RII gene mutant was due to decreased mRNA stability. Furthermore, RII mRNA from
HCT116 transfected with wild-type RII had a longer half-life than the endogenous
mutated RII mRNA. A dominant negative RII mutant, which encodes a similarly
truncated RII protein as HCT116 but lacks the extensive 3' untranslated region of
RII mRNA, gave the same half-life as endogenous wild-type RII mRNA. We conclude
that the frameshift mutation which results in a premature stop codon in the 5'
half of the mRNA transcript accounts for the reduced RII mRNA levels in RER+
cells.
PMID- 9398200
TI - Specificity of an Escherichia coli RNA polymerase-associated NTPase.
AB - Standard preparations of Escherichia coli RNA polymerase harbor a 70 kDa protein
with NTPase (beta-gamma cleavage) activity that is not a recognized polymerase
subunit. The NTPase activity of this component, before and after separation from
the polymerase, is strongly dependent on the presence of DNA; single-stranded
polydeoxynucleotides are more effective than double-stranded. ATP and GTP are
cleaved, the latter much less readily. The NTPase as it occurs with the
polymerase displays cleavage preference for NTPs that are not complementary to
the DNA, a fact that has led to proposals for involvement of the NTPase in
transcriptional error prevention [Volloch, V. Z., Rits, L. & Tumerman, L. (1979)
Nucleic Acids Res. 6, 1535-1546; Libby, R. T., Nelson, J. L., Calvo, J. M., &
Gallant, J. A. (1989) EMBO J. 8, 3253-3158]. We find, however, that the lesser
cleavage in the presence of complementary DNA results from competition for the
NTP between the processes of incorporation by the polymerase and of cleavage by
the NTPase, operating on the same substrate pool. The greater cleavage with
noncomplementary DNA occurs because of the lack of incorporation by the
polymerase, which then does not compete with the NTPase for the substrate pool.
Thus, these findings indicate that the cleavage preference of the NTPase for
noncomplementary NTPs is not part of a mechanism for error prevention during
transcription.
PMID- 9398201
TI - A unique transcription factor for the A alpha fibrinogen gene is related to the
mitochondrial single-stranded DNA binding protein P16.
AB - Although stimulation of hepatic cells with interleukin-6 induces the expression
of fibrinogen, the molecular basis for this regulation remains largely
uncharacterized. A recent examination of the A alpha fibrinogen gene promoter
identified a protein, termed the A alpha-core protein, that bound constitutively
to the IL-6 response element [Liu, Z. & Fuller, G. M. (1995) J. Biol. Chem. 270,
7580-7586]. This current study provides further characterization of this
regulatory protein. The data presented show the following: (i) The A alpha-core
protein has a similar molecular weight and identical N-terminal sequence to that
of the mitochondrial single-stranded DNA binding protein P16. (ii) The A alpha
core protein and P16 have similar characteristics in terms of DNA binding
preference and antigenic properties. (iii) Overexpression of P16 gene in the
hepatoma cell lines Hep G2 and Hep 3B enhances the IL-6-induced expression of A
alpha fibrinogen. These results demonstrate that the A alpha-core protein is
closely related to P16 and involved in the IL-6-regulated transcription of A
alpha fibrinogen.
PMID- 9398202
TI - Binding of tsHMG, a mouse testis-specific HMG-domain protein, to cisplatin-DNA
adducts.
AB - The anticancer drug cisplatin is particularly effective against testicular
tumors. Although the clinical consequences of cisplatin chemotherapy are well
known, the precise mechanism of action remains elusive. Specific recognition of
cisplatin-damaged DNA by a class of proteins containing the high-mobility group
(HMG) domain DNA-binding motif could play a role in mediating the cytotoxicity of
the drug. This study presents a quantitative investigation of binding of the
murine testis-specific high-mobility group protein tsHMG to DNA modified by
cisplatin. The binding affinity and specificity of this protein to a site
specific 1,2-d(GpG) cisplatin-DNA intrastrand cross-link in a 20 bp probe were
determined. A value for the apparent dissociation constant, Kd(app), of 24 +/- 5
nM was obtained by gel mobility shift assays. Binding competition assays with the
corresponding unmodified 20 bp probe gave a ratio (rho) of nonspecific to
specific Kd(app) values of 230. A polypeptide containing tsHMG domain A (residues
1-82) was expressed and purified to homogeneity. This domain alone was sufficient
for specific recognition of cisplatin-modified DNA with a Kd(app) of 300 +/- 50
nM and a rho of 20, a comparatively high discrimination factor. DNase I
interference analysis of the adduct-containing strand revealed that tsHMG binding
extends over 14 nucleotides, centered around the platinated bases. The domain A
polypeptide protection pattern covers a slightly smaller area of 13 nucleotides.
The binding affinity and specificity of tsHMG for cisplatin-modified DNA are
exceptional compared to those of other HMG-domain proteins studied previously.
The possible relevance of these findings to the mechanism of action of cisplatin
is discussed.
PMID- 9398203
TI - Modulation of Cm/T, G/A, and G/T triplex stability by conjugate groups in the
presence and absence of KCl.
AB - Apparent equilibrium association constants were determined by gel mobility shift
analysis for triple strand formation between a duplex target containing a 21 base
long A-rich homopurine run and several end-modified C(m)/T (pyrimidine motif;
C(m) = 5-methylcytosine), G/A (purine motif), and G/T (purine-pyrimidine motif)
triplex-forming oligonucleotides (TFOs). Incubations were carried out for 24 h at
37 degrees C in 20 mM HEPES, pH 7.2, 10 mM MgCl2, and 1 mM spermine. The purine
motif triplex was the most stable (Ka = 6.2 x 10(8) M-1) even though the TFO self
associated as a linear duplex. Conjugation of a terminal hexanol or cholesterol
group to the G/A-containing TFO reduced triplex stability by 1.6- or 13-fold,
whereas an aminohexyl group or intercalating agent (acridine or psoralen)
increased triplex stability by 1.3- or 13-fold. These end groups produced similar
effects in C(m)/T and G/T triplexes, although the magnitude of the effect
sometimes differed. Addition of 140 mM KCl to mimic physiological conditions
decreased stability of the G/A triplex by 1900-fold, making it less stable than
the C(m)/T triplex. The inhibitory effect of KCl on G/A triplex formation could
be partially compensated for by conjugating the TFO to an intercalating agent (30
350-fold stabilization) or by adding the triplex selective intercalator coralyne
(1000-fold stabilization). Although the G/T triplex responded similarly to these
agents, the stability of the C(m)/T triplex was unaffected by the presence of
coralyne and was only enhanced 1.4-2.8-fold when the TFO was linked to an
intercalating agent. In physiological buffer supplemented with 40 microM
coralyne, the G/A triplex (Ka = 3.0 x 10(8) M-1) was more stable than the C(m)/T
and G/T triplexes by factors of 300 and 12, respectively.
PMID- 9398204
TI - Structural and mechanistic studies on chloroplast translational initiation factor
3 from Euglena gracilis.
AB - Chloroplast translational initiation factor 3 (IF3chl) from Euglena gracilis
contains a central region (homology domain) that is homologous to prokaryotic
IF3. The homology domain is preceded by a long NH2-terminal extension (head), and
followed by a 64 amino acid COOH-terminal extension (tail). Sequences in these
extensions reduce the activity of the homology domain. To gain insight into these
effects, a possible three-dimensional structure for the homology region of IF3chl
has been modeled using the X-ray coordinates from the N- and C-domains of
Bacillus stearothermophilus IF3. In B. stearothermophilus IF3, these two compact
domains are thought to fold independently and are separated by a helical lysine
rich linker. The modeled structure suggests that IF3chl has a similar overall
fold although some subtle differences are predicted to occur. Both the head and
tail regions of IF3chl are oriented toward the linker region in the homology
domain where they may potentially interfere with its function. Circular dichroism
spectropolarimetry (CD) indicates that the lysine-rich linker region in IF3chl is
not in a helical conformation and is probably a random coil. CD analysis
indicates that a portion of the tail region of IF3chl is helical and that the
tail has a direct interaction with the linker region in the homology domain. Site
directed mutagenesis of the linker indicates that two conserved lysine residues
are important for the function of IF3chl and play a role in the binding of IF3chl
to the 30S ribosomal subunit. Mutation of these residues affects the interaction
of the homology domain with the tail.
PMID- 9398205
TI - Triple helix formation and homologous strand exchange in pyrene-labeled
oligonucleotides.
AB - The orientations of the symmetrical third strands (G3A4G3) and (G3T4G3) within
the triplexes (C3T4C3) - (G3A4G3) x (G3A4G3) and (C3T4C3) - (G3A4G3) x (G3T4G3)
were investigated by fluorescence spectroscopy and thermal denaturation using
pyrene-labeled oligodeoxynucleotides. In the two triplex structures, both
parallel and antiparallel orientations of the third strand with respects to the
purine Watson-Crick one were identified by means of pyrene excimer formation. The
pyrene labels do not modify the melting temperature of the (C3T4C3) - (G3A4G3) x
(G3T4G3) triplex but somewhat stabilize the corresponding duplex against thermal
denaturation. The absorption melting profiles of the (C3T4C3) - (G3A4G3) x
(G3A4G3) triplex are monophasic in agreement with previous reports. In contrast,
the melting of this structure, when monitored by the pyrene excimer band, reveals
a biphasic behavior. These data, together with kinetics measurements, strongly
suggest exchange mechanisms between the homologous oligomers (G3A4G3), Hoogsteen,
and Watson-Crick strands.
PMID- 9398206
TI - Interaction of Alzheimer beta-amyloid peptide(1-40) with lipid membranes.
AB - The beta-amyloid peptide beta AP(1-40), a 40-amino acid residues peptide, is one
of the major components of Alzheimer's amyloid deposits. beta AP(1-40) exhibits
only a limited solubility in aqueous solution and undergoes a concentration
dependent, cooperative random coil reversible beta-structure transition for Cpep
> 10 microM [Terzi, E., Holzemann, G., and Seelig, J. (1995) J. Mol. Biol. 252,
633-642]. In the presence of acidic lipid, the equilibrium is shifted further
toward beta-structured aggregates. We have now characterized the lipid-peptide
interaction using circular dichroism (CD) spectroscopy, lipid monolayers, and
deuterium and phosphorus-31 solid-state nuclear magnetic resonance (NMR). CD
spectroscopy revealed a distinct interaction between beta AP(1-40) and negatively
charged unilamellar vesicles. In addition to the random coil reversible beta
structured aggregate equilibrium at low lipid-to-peptide (L/P) ratios, a beta
structure -->alpha-helix transition was observed at L/P > 55. beta AP(1-40) was
found to insert into acidic monolayers provided the lateral pressure was low (20
mN/m). The extent of incorporation increased distinctly with the content of
acidic lipid in the monolayer. However, at a lipid packing density equivalent to
that of a bilayer (lateral pressure > or = 32 mN/m), no insertion of beta AP(1
40) was observed. The lipid molecular structure in the presence of beta AP(1-40)
was studied with NMR. Phosphatidylcholine (PC) was selectively deuterated at the
choline headgroup and at the cis-double bond of the oleic acyl chain and mixed
with phosphatidylglycerol (PG). Phosphorus-31 NMR showed that the lipid phase
retained the bilayer structure at all lipid-to-protein ratios. Deuterium NMR
revealed no change in the headgroup conformation of the choline moiety or in the
flexibility and ordering of the hydrocarbon chains upon the addition of beta AP
(1-40). It can be concluded that beta AP(1-40) binds electrostatically to the
outer envelope of the polar headgroup region without penetrating between the
polar groups. The data suggest a new mechanism of helix formation induced by the
proper alignment of five positive charges of beta AP(1-40) on the negatively
charged membrane template.
PMID- 9398207
TI - Inequivalence of the two tyrosine ligands in the N-lobe of human serum
transferrin.
AB - Human serum transferrin N-lobe (hTF/2N) has four iron-binding ligands, including
one histidine, one aspartate, and two tyrosines. The present report elucidates
the inequivalence of the two tyrosine ligands (Tyr 95 and Tyr 188) on the metal
binding properties of hTF/2N by means of site-directed mutagenesis, metal release
kinetics, and absorption and electron paramagnetic resonance (EPR)
spectroscopies. When the liganding tyrosines were mutated individually to
phenylalanine, the resulting mutant Y95F showed a weak binding affinity for iron
and no affinity for copper, whereas, mutant Y188F completely lost the ability to
bind iron but formed a stable complex with copper. Since other studies have
demonstrated that mutations of the other two ligands, histidine and aspartate,
did not completely abolish iron binding, the present findings suggest that the
tyrosine ligand at position 188 is essential for binding of iron to occur.
Replacement of Tyr 188 with phenylalanine created a favorable chemical
environment for copper coordination but a fatal situation for iron binding. The
positions of the two liganding tyrosines in the metal-binding cleft suggest a
reason for the inequivalence.
PMID- 9398209
TI - Cytosine methylation enhances DNA damage produced by groove binding and
intercalating enediynes: studies with esperamicins A1 and C.
AB - Methylation of the C5 position of cytosine in CG dinucleotides represents an
important element in the control of gene expression in eukaryotic cells. This
major groove modification of DNA causes changes in DNA conformation that are
recognized by DNA-binding proteins and DNA-damaging chemicals. We have observed
that CG methylation affects the DNA damage produced by the enediyne esperamicin
A1 and its analog lacking the intercalating anthranilate, esperamicin C.
Fragments of the human phosphoglycerate kinase gene (PGK1) and the plasmid pUC19
were methylated with SssI methylase and subjected to damage by esperamicins A1
and C. Damage produced by esperamicin A1 was enhanced 1.5-2-fold near a single CG
sequence at position -101 in PGK1 and in a region containing several methylated
CG dinucleotides between positions -120 and -131. Esperamicin C-induced damage
was enhanced to a similar degree in PGK1 but only at the site that contained
multiple CG dinucleotides. There was enhancement of damage for both drugs in the
pUC19 fragment at several sites near CG sequences. Analysis of the chemistry of
esperamicin-induced DNA damage suggests that cytosine methylation does not affect
the identity of drug-abstracted hydrogen atoms. The damage chemistry was also
used to identify the DNA binding orientation of the esperamicins. The
anthranilate of esperamicin A1 is predicted to intercalate in a CT step four base
pairs in a 3'-direction to the CG sequence at -101 in PGK1 and in a CG
dinucleotide at the site containing multiple CGs (positions -120 to -131). These
observations are consistent with other studies that indicate a long range effect
of cytosine methylation on DNA conformation.
PMID- 9398208
TI - Characterization of a covalent monoadduct of neocarzinostatin chromophore at a
DNA bulge.
AB - Neocarzinostatin chromophore (NCS-Chrom) induces highly efficient site-specific
strand cleavage at the bulge of a folded single-stranded 31-mer DNA in the
presence of oxygen [Kappen, L. S., and Goldberg, I. H. (1993) Science 261, 1319
1321]. Under anaerobic conditions, the major product is a material having gel
mobility slower than that of the parent 31-mer. In order to characterize this
product, it was stabilized by reduction with borane/pyridine, labeled with 32P at
its 5' or 3' end, and subjected to chemical cleavage dependent on base
elimination or modification, and the cleavage products were analyzed on a
sequencing gel. A cleavage pattern comparable to that of the 31-mer was obtained
until the bases on either side of T22 at the bulge. Cleaved fragments inclusive
of T22 from the 5' or the 3' end had retarded and anomalous mobilities and
appeared as a smear of bands closer to the starting material, presumably due to
the presence of the covalently bound drug. Pyrimidine-specific agents such as
hydrazine and potassium permanganate, but not the DNA sugar-specific probe thiol
activated NCS-Chrom, induced strand cleavage at T22. Mass spectral analysis of
the presumed adduct isolated from anaerobic reactions containing NCS-Chrom and a
bulge duplex substrate made up of a 10-mer and an 8-mer showed that the adduct
contains one molecule of the drug and one molecule of the 10-mer. Taken together,
the results show that (i) drug adduction is at T22 on the full-length substrate;
(ii) the pyrimidine ring is accessible to base-specific chemical modifications,
hence, presumably free of the drug; (iii) it is most likely that drug adduction
is via its C6 position to the 5' carbon of T22, based on the current results and
the known chemistry of the hydrogen abstraction by the drug in the presence or
absence of oxygen; (iv) there is no involvement of the neighboring bases by way
of inter- or intrastrand cross-linking; and (v) the product is a monoadduct.
PMID- 9398210
TI - Expression, Purification, and Inhibitory Properties of Human Proteinase Inhibitor
8
AB - In a previous report, the cDNA for human proteinase inhibitor 8 (PI8) was first
identified, isolated, and subcloned into a mammalian expression vector and
expressed in baby hamster kidney cells. Initial studies indicated that PI8 was
able to inhibit the amidolytic activity of trypsin and form an SDS-stable
approximately 67-kDa complex with human thrombin [Sprecher, C. A., et al. (1995)
J. Biol Chem. 270, 29854-29861]. In the present study, we have expressed
recombinant PI8 in the methylotropic yeast Pichia pastoris, purified the
inhibitor to homogeneity, and investigated its ability to inhibit a variety of
proteinases. PI8 inhibited the amidolytic activities of porcine trypsin, human
thrombin, human coagulation factor Xa, and the Bacillus subtilis dibasic
endoproteinase subtilisin A through different mechanisms but failed to inhibit
the Staphylococcus aureus endoproteinase Glu-C. PI8 inhibited trypsin in a purely
competitive manner, with an equilibrium inhibition constant (Ki) of less than 3.8
nM. The interaction between PI8 and thrombin occurred with a second-order
association rate constant (kassoc) of 1.0 x 10(5) M-1 s-1 and a Ki of 350 pM. A
slow-binding kinetics approach was used to determine the kinetic constants for
the interactions of PI8 with factor Xa and subtilisin A. PI8 inhibited factor Xa
via a two-step mechanism with a kassoc of 7.5 x 10(4) M-1 s-1 and an overall Ki
of 272 pM. PI8 was a potent inhibitor of subtilisin A via a single-step mechanism
with a kassoc of 1.16 x 10(6) M-1 s-1 and an overall Ki of 8.4 pM. The
interaction between PI8 and subtilisin A may be of physiological significance,
since subtilisin A is an evolutionary precursor to the intracellular mammalian
dibasic processing endoproteinases.
PMID- 9398211
TI - Human alpha 2-macroglobulin is an osteogenic growth peptide-binding protein.
AB - The osteogenic growth peptide (OGP) is a 14mer mitogen of osteoblastic and
fibroblastic cells. Physiologically, OGP is present in high abundance in human
and other mammalian sera. Most of the serum OGP is complexed noncovalently to
heat sensitive, high molecular weight OGP-binding proteins (OGPBPs). Changes in
serum OGP levels that follow bone marrow ablation and the low doses of exogenous
OGP required for the stimulation of bone formation suggest a regulatory role for
the OGPBPs. In the present work, the OGP binding activity was monitored by
competitive binding to [3-125I(Tyr10)]-sOGP and the corresponding complexes were
demonstrated on nondenaturing cathodic polyacrylamide gel electrophoresis. We
show that OGP binds to both native and activated human plasma alpha 2
macroglobulin (alpha 2M). alpha 2M was also immunoidentified in reduced and
nonreduced SDS-polyacrylamide gel electrophoresis of OGP-affinity purified plasma
derived proteins. Immunoreactive OGP was detected in commercial preparations of
both forms of alpha 2M; OGP was purified to homogeneity from the commercial
preparation of activated alpha 2M. In MC3T3 E1 cells, native alpha 2M, at
concentrations < 50 ng/mL, had a substantially increased mitogenic effect in the
presence of synthetic, native-like, OGP (sOGP). Similar amounts of activated
alpha 2M inhibited the sOGP proliferative effect. These results suggest that the
native alpha 2M enhances the immediate availability of OGP to its target cells.
Activated alpha 2M may participate in the removal of OGP from the system.
PMID- 9398212
TI - Persistence of dimerization and enzymatic activity of epidermal growth factor
receptor in the absence of epidermal growth factor.
AB - Dimerized and enzymatically active epidermal growth factor receptor, in the
presence of saturating epidermal growth factor (EGF), was passed over a column
containing an immunoadsorbent for EGF. The immunoadsorbent removed both EGF free
in solution and EGF bound to EGF receptor, while EGF receptor passed through
unimpeded. Both the dimerization of EGF receptor and the activation of its
tyrosine kinase were arrested in samples containing EGF receptor that had been
mixed with saturating EGF and then immediately passed over the immunoadsorbent
for EGF. The EGF receptor in these samples, however, dimerized completely, and
its tyrosine kinase became fully active upon readdition of EGF. Samples of EGF
receptor that were fully dimerized and enzymatically active prior to being passed
over the immunoadsorbent for EGF remained dimerized and enzymatically active even
in the absence of bound EGF. The first-order rate constant for the inactivation
of the tyrosine kinase of EGF receptor depleted of EGF was estimated by
subtracting the rate constant of inactivation of the tyrosine kinase in samples
replenished with EGF from the rate constant of inactivation of the tyrosine
kinase in samples that had been depleted of EGF. The rate constant of
inactivation was found to be 0.26 +/- 0.06 h-1.
PMID- 9398213
TI - Altered ligand binding properties and enhanced stability of a constitutively
active estrogen receptor: evidence that an open pocket conformation is required
for ligand interaction.
AB - To elucidate the ligand binding properties of the estrogen receptor (ER) and how
ligand access to and release from the ligand binding pocket is affected by the
conformational state of the receptor, we have measured the rates of estradiol
association and dissociation, the equilibrium binding, and the stability of
estradiol binding to denaturants, comparing wild-type human ER and a point mutant
(Y537S ER) that shows full constitutive activity, i.e., the same full
transcriptional activity in the absence or presence of estrogen. Ligand binding
kinetics and affinity were measured with the full-length (1-595) ERs and with
truncated forms of both receptors containing domains C through F (including the
DNA binding, hinge, and ligand binding domains, amino acids 175-595) or domains E
and F (the ligand binding domain; amino acids 304-595). With all ERs, the rates
of ligand association and dissociation were considerably slower with the Y537S
mutant ER than with wild-type ER (6-fold and 3-4-fold, respectively). These
marked differences in ligand on and off rates for the wild-type and Y537S
receptors result in a predicted (k-1/k+1) and measured Kd that is 2-fold lower
for Y537S ER compared to wild-type ER. The binding of estradiol by wild-type ER
was disrupted by high concentrations of urea (above 2 M), whereas the Y537S ER
was distinctly more resistant to this disruption. These results are consistent
with a model in which wild-type ER in the absence of ligand adopts a
transcriptionally inactive collapsed pocket conformation, stabilized by specific
interactions of Y537 with nearby regions of ER. When estradiol is bound, the wild
type ER adopts a transcriptionally active, closed pocket (ligand occupied)
conformation. By contrast, the Y537S mutant ER favors the transcriptionally
active closed pocket conformation, whether occupied by ligand or not, the latter
state (closed pocket but unoccupied) accounting for its constitutive activity.
Our findings suggest that the entry or exit of ligand from the binding pocket
requires that ER adopt an open pocket conformation. The reduced rates of ligand
association and dissociation in the constitutively active form of the ER, as well
as its greater resistance to disruption of ligand binding by urea, support the
supposition that the rate at which this open pocket conformation can be accessed
from the unoccupied or ligand-occupied Y537S ER is slower than from the
unoccupied or occupied forms of wild-type ER. Thus, the binding and release of
ligand by ER require that the receptor access an open pocket state, and the ease
with which this state can be accessed is affected by mutations that alter
receptor conformation.
PMID- 9398214
TI - Structure and interaction of PA63 and EF (edema toxin) of Bacillus anthracis with
lipid membrane.
AB - The secondary structures of the two components of the Bacillus anthracis edema
toxin, protective antigen (PA63) and edema factor (EF), as well as the two EF
mutants: CYA30 (containing the N-terminal PA63-binding domain) and CYA62
(containing the C-terminal catalytic domain) were investigated as a function of
pH in the absence and in the presence of phospholipid vesicles using attenuated
total reflection Fourier transform infrared spectroscopy. Secondary structures
were independent of pH, whereas, in all cases, structural modifications were
observed upon lipid binding. The ability of PA63 and EF to undergo
hydrogen/deuterium exchange was evaluated. The binding of these proteins and the
mutants to the lipid membrane was also characterized and it was demonstrated that
the association of PA63 to the lipid bilayer was pH-dependent, while the binding
of EF to the lipid membrane took place at both neutral and acidic pH.
Interestingly, the two EF mutants are showing different lipid binding properties
in response to pH: CYA30 has a strong pH-dependence whereas CYA62, as EF, binds
to the lipid vesicles at all pHs. For the two proteins characterized by a pH
dependent lipid binding, the reversibility of binding upon neutralization was
tested and binding of PA63 to the membrane was found to be irreversible whereas
that of CYA30 was reversible.
PMID- 9398215
TI - Determination of tumor necrosis factor binding protein disulfide structure:
deviation of the fourth domain structure from the TNFR/NGFR family cysteine-rich
region signature.
AB - Tumor necrosis factor binding protein is a soluble molecule derived from the
extracellular domain of the 55 kDa human tumor necrosis factor receptor, which
can block the biological function of tumor necrosis factor by binding to the
growth factor. This cysteine-rich molecule is subdivided into four domains, each
containing six conserved cysteines that form three intrachain disulfide linkages
known as the tumor necrosis factor receptor/nerve growth factor receptor family
cysteine-rich region signature structure. In an effort to elucidate the molecular
integrity of the molecule, we performed detailed analysis and searched for
strategies to elucidate the complete disulfide structure of the E. coli-derived
tumor necrosis factor binding protein and to determine the disulfide arrangement
in the fourth domain of Chinese hamster ovary cell-derived molecule. The methods
employed included various proteolytic digestions, peptide mapping, partial
reduction, and assignment of disulfides by N-terminal sequencing and matrix
assisted laser desorption ionization mass spectrometry with post-source decay.
The first three domains of the molecule were confirmed to have disulfide
structures identical to the cysteine-rich region signature structure found in the
above-mentioned receptor superfamily. The fourth domain has a different structure
from the first three domains where the last four cysteines form two disulfide
bonds in opposite positions.
PMID- 9398216
TI - The low-affinity ATP binding site of the Escherichia coli SecA dimer is localized
at the subunit interface.
AB - The homodimeric SecA protein is the ATP-dependent force generator in the
Escherichia coli precursor protein translocation cascade. SecA contains two
essential nucleotide binding sites (NBSs), i.e., NBS1 and NBS2 that bind ATP with
high and low affinity, respectively. The photoactivatable bifunctional cross
linking agent 3'-arylazido-8-azidoadenosine 5'-triphosphate (diN3ATP) was used to
investigate the spatial arrangement of the nucleotide binding sites of SecA.
DiN3ATP is an authentic ATP analogue as it supports SecA-dependent precursor
protein translocation and translocation ATPase. UV-induced photo-cross-linking of
the diN3ATP-bound SecA results in the formation of stable dimeric species of
SecA. D209N SecA, a mutant unable to bind nucleotides at NBS1, was also photo
cross-linked by diN3ATP, whereas no cross-linking occurred with the NBS2 mutant
R509K SecA. We concluded that the low-affinity NBS2, which is located in the
carboxyl-terminal half of SecA, is the site of crosslinking and that NBS2 binds
nucleotides at or near the subunit interface of the SecA dimer.
PMID- 9398217
TI - Evidence for a glutathionyl-enzyme intermediate in the amidase activity of the
bifunctional glutathionylspermidine synthetase/amidase from Escherichia coli.
AB - Glutathionylspermidine (Gsp) is a metabolite common to Escherichia coli and
protozoal parasites of the Trypanosoma family. Though its role in E. coli is
unknown, Gsp is known to be an intermediate in the biosynthesis of N1,N8
bis(glutathionyl)spermidine (trypanothione), a metabolite unique to
trypanosomatids that may allow the parasites to overcome oxidative stresses
induced by host defense mechanisms. The bifunctional Gsp-synthetase/amidase from
E. coli catalyzes both amide bond formation and breakdown between the N1-amine of
spermidine [N-(3-aminopropyl)-1,4-diaminobutane] and the glycine carboxylate of
glutathione (gamma-Glu-Cys-Gly), with net hydrolysis of ATP [Bollinger et al.
(1995) J. Biol. Chem. 270 (23), 14031-14041]. Synthetase and amidase activities
reside in separate domains of the protein, and liberation of the amidase domain
from the synthetase domain activates the amidase activity as much as 70-fold in
kcat/K(m) for a chromogenic substrate gamma-Glu-Ala-Gly-pNA [Kwon et al., (1997)
J. Biol. Chem. 272 (4), 2429-2436]. When substrates for the Gsp-synthetase
activity are present (GSH, ATP-Mg2+), Gsp-amidase is highly activated (15-fold).
We provide kinetic and mutagenesis evidence suggesting that the amidase operates
by a nucleophilic attack mechanism involving cysteine as the catalytic
nucleophile. Stopped-flow studies on the 25 kDa Gsp-amidase fragment and the 70
kDa full-length Gsp-synthetase/amidase with gamma-Glu-Ala-Gly-ONp demonstrate
burst kinetics characteristic of a covalent acyl-enzyme intermediate. Studies
using various group-specific protease inhibitors, such as iodoacetamide, suggest
an active-site cysteine or histidine as being relevant to amidase activity, and
site-directed mutagenesis indicates that Cys-59 is essential for amidase
activity.
PMID- 9398218
TI - Adenosylcobalamin-dependent glutamate mutase: examination of substrate and
coenzyme binding in an engineered fusion protein possessing simplified subunit
structure and kinetic properties.
AB - Glutamate mutase is comprised of two weakly associating subunits; E and S, that
combine to form the coenzyme binding site. The active holoenzyme assembles in a
kinetically complex process in which both the stoichiometry and apparent Kd for
adenosylcobalamin (AdoCbl) are dependent upon the relative concentrations of the
two subunits, as is the enzyme's specific activity. To facilitate mechanistic and
structural studies on this enzyme we have genetically fused the S subunit to the
C-terminus of the E subunit through an 11 amino acid (Gly-Gln)5-Gly linker
segment. This protein, GlmES, binds AdoCbl stoichiometrically and neither the
affinity for AdoCbl nor the turnover number depends upon protein concentration.
The kcat and Km for both substrate and coenzyme, together with the deuterium
isotope effects on Vmax and Vmax/Km, have been determined for the GlmES-catalyzed
reaction proceeding in both directions. Compared with wild type, the affinity for
AdoCbl is unchanged, but for the conversion of L-glutamate to (2S,3S)-3
methylaspartate both kcat and Km for L-glutamate are decreased by about a third
and the isotope effects are reduced, suggesting product release to be more rate
limiting. To test hypotheses concerning the activation of the coenzyme, we
examined the binding of adenosylcobalamin, methylcobalamin, and cob(II)alamin to
the enzyme. Each of these is bound with essentially the same affinity (2 microM),
suggesting that, contrary to expectations, interactions between the protein and
the adenosyl moiety do not serve to weaken the cobalt-carbon bond in the ground
state.
PMID- 9398219
TI - Minimizing nonproductive substrate binding: a new look at glucoamylase subsite
affinities.
AB - A subsite model as proposed by Hiromi [Hiromi, K. (1970) Biochem. Biophys. Res.
Commun. 40, 1-6] has been applied to various hydrolases including glucoamylase
(GA). The model assumes a single enzyme complex, a hydrolytic rate constant which
is independent of substrate length, and a ratelimiting hydrolytic step. Recent
kinetic studies with GA contradict these assumptions. Here we reevaluate the
substrate binding of GA studying the pre-steady-state kinetics with glucose,
which is reported here for the first time, and maltose. The association
equilibrium constants for glucose and maltose interactions with wild-type and
Trp120-->Phe GA from Aspergillus awamori in H2O and D2O buffers were obtained.
Kinetic results indicate that a single glucose molecule binds to GA weakly by a
single-step mechanism, E + G1<-->EG1, under the conditions studied. Similar
fluorescence intensities of the GA-glucose and GA-maltose complexes, the high
tryptophan concentration around subsite 1, crystal structures of various
inhibitor complexes, pre-steady-state and steady-state modeling, feasibility of
condensation reactions, and other evidence strongly suggest that glucose binds at
subsite 1. These results conflict with the high subsite 2 and low subsite 1
affinities obtained using Hiromi's model. Using the substrate association
constants for glucose and maltose obtained by pre-steady-state kinetics, the
affinity of alpha-glucose for subsite 1 is shown to be substantially higher than
the apparent affinity of glucose for subsite 2. We propose a GA catalytic
mechanism whereby substrate binding is initiated by subsite 1 interactions with
the nonreducing end of the oligosaccharide substrate, minimizing nonproductive
substrate binding. Through conformational changes, entropic contributions, and
increased local concentration, subsite 2 subsequently has enhanced affinity for
the second covalently linked glucosyl residue.
PMID- 9398220
TI - Role of mitochondrial and cytoplasmic serine hydroxymethyltransferase isozymes in
de novo purine synthesis in Saccharomyces cerevisiae.
AB - One-carbon units are essential to a variety of anabolic processes which yield
necessary cellular components including purines, pyrimidines, amino acids, and
lipids. Serine hydroxymethyltransferase (SHMT) is the major provider of one
carbon units in the cell. The other product of this reaction is glycine. Both of
these metabolites are required in de novo purine biosynthesis. In Saccharomyces
cerevisiae, mitochondrial and cytoplasmic SHMT isozymes are encoded by distinct
nuclear genes (SHM1 and SHM2). Molecular genetic analyses have begun to define
the roles of these two isozymes in folate-mediated one-carbon metabolism [McNeil,
J. B., et al. (1996) Genetics 142, 371-381]. In our study, the SHM1 and SHM2
genes were disrupted singly and in combination to investigate the contributions
of the two SHMT isozymes to the production of glycine and one-carbon units
required in purine biosynthesis. Cell subfractionation experiments indicated that
while only 5% of total activity was localized in the mitochondria, the specific
activity in that compartment was much higher than in the cytoplasm. Growth and
13C NMR experiments indicate that the two isozymes function in different
directions, depending on the nutritional conditions of the cell. When yeast was
grown on serine as the primary one-carbon source, the cytoplasmic isozyme was the
main provider of glycine and one-carbon groups for purine synthesis. When grown
on glycine, the mitochondrial SHMT was the predominant isozyme catalyzing the
synthesis of serine from glycine and one-carbon units. However, when both serine
and glycine were present, the mitochondrial SHMT made a significant contribution
of one-carbon units, but not glycine, for purine synthesis. Finally, NMR data are
presented that suggest the existence of at least two sites of de novo purine
biosynthesis in growing yeast cells, each being fed by distinct pools of
precursors.
PMID- 9398221
TI - Catalytic mechanism of phosphorylation and dephosphorylation of CheY: kinetic
characterization of imidazole phosphates as phosphodonors and the role of acid
catalysis.
AB - Kinetic and equilibrium measurements of phosphotransfer events involving CheY
carried out over a range of pH conditions elucidated several features of the
phosphotransfer mechanism. Using tryptophan fluorescence intensity measurements
as a monitor of phosphorylation, we showed that phosphorylation using small
molecule phosphodonors occurred by fast association of CheY with the
phosphodonor, followed by rate-limiting phosphotransfer. Two previously
uncharacterized phosphodonors, monophosphoimidazole and diphosphoimdazole, were
able to phosphorylate CheY at a concentration about 6-fold lower than that of the
previously described phosphodonors acetyl phosphate and phosphoramidate. This was
shown to be due to tighter binding of the imidazole phosphates to CheY and
implied the presence of binding interactions between CheY and the imidazole
group. The ability of CheY to autophosphorylate through the pH range of 5-10
differed for various phosphodonors. Acetyl phosphate and diphosphoimidazole were
unaffected by pH over this range, whereas phosphoramidate and
monophosphoimidazole showed a steep dependence on pH with a loss of
phosphorylation ability at about pH 7.4 (midpoint) for monophosphoimidazole and
pH 7.8 (midpoint) for phosphoramidate. This behavior correlated with the loss of
the positive charge on the nitrogen atom in the nitrogen-phosphorus bond in both
monophosphoimidazole and phosphoramidate and implied that CheY was not capable of
donating a proton to the leaving group in phosphotransfer with small molecules.
The rate of phosphotransfer from [32P]CheA-phosphate to wild type CheY also
decreased markedly (> 150 times) between pH 7.5 and 10. Because the mutant CheY
proteins K109R and T87A showed the same pH dependence as the wild type, the loss
of activity in the alkaline range could not be attributed to deprotonation of
either of these active site residues. This observation, combined with the
moderate decreases in phosphotransfer rates for these mutants relative to that of
wild type CheY, indicated that it is unlikely that either Thr87 or Lys109 plays a
direct role in the catalysis of phosphotransfer. Finally, we showed that the rate
of autodephosphorylation of CheY was independent of pH over the range of 4.5-11.
Together, these studies led to a model with CheY playing a largely entropic role
in its own phosphorylation and dephosphorylation.
PMID- 9398222
TI - Mechanism of Formation of Novel Covalent Drug·DNA Interstrand Cross-Links
and Monoadducts by Enediyne Antitumor Antibiotics
AB - The potent enediyne antitumor antibiotic C1027 has been previously reported to
induce novel DNA interstrand cross-links and drug monoadducts under anaerobic
conditions [Xu et al. (1997) J. Am. Chem. Soc. 119, 1133-1134]. In the present
study, we explored the mechanism of formation of these anaerobic DNA lesions. We
found that, similar to the aerobic reaction, the diradical species of the
activated drug initiates anaerobic DNA damage by abstracting hydrogen atoms from
the C4', C1', and C5' positions of the A1, A2, and A3 nucleotides, respectively,
in the most preferred 5'GTTA1T/5'ATA2A3C binding sequence. It is proposed that
the newly generated deoxyribosyl radicals, which cannot undergo oxidation, likely
add back onto the nearby unsaturated ring system of the postactivated enediyne
core, inducing the formation of interstrand cross-links, connecting either A1 to
A2 or A1 to A3, or drug monoadducts mainly on A2 or A3. Comparative studies with
other enediynes, such as neocarzinostatin and calicheamicin gamma1I under similar
reaction conditions indicate that the anaerobic reaction process is a kinetically
competitive one, depending on the proximity of the drug unsaturated ring system
or dioxygen to the sugar radicals and their quenching by other hydrogen sources
such as solvent or thiols. It was found that C1027 mainly generates interstrand
cross-links, whereas most of the anaerobic lesions produced by neocarzinostatin
are drug monoadducts. Calicheamicin gamma1I was found to be less efficient in
producing both lesions. The anaerobic DNA lesions induced by enediyne antitumor
antibiotics may have important implications for their potent cytotoxicity in the
central regions of large tumors, where relative anaerobic conditions prevail.
PMID- 9398223
TI - Microscopic pKa values of Escherichia coli thioredoxin.
AB - Thiol:disulfide oxidoreductases have a CXXC motif within their active sites. To
initiate the reduction of a substrate disulfide bond, the thiolate form of the N
terminal cysteine residue (CXXC) of this motif performs a nucleophilic attack.
Escherichia coli thioredoxin [Trx (CGPC)] is the best characterized
thiol:disulfide oxidoreductase. Previous determinations of the active-site pKa
values of Trx have led to conflicting interpretations. Here, 13C-NMR
spectroscopy, site-specific isotopic labeling, and site-directed mutagenesis were
used to demonstrate that analysis of the titration behavior of wild-type Trx
requires the invocation of microscopic pKa values for two interacting active-site
residues: Asp26 (7.5 and 9.2) and Cys32 (CXXC; 7.5 and 9.2). By contrast, in two
Trx variants, D26N Trx and D26L Trx, Cys32 exhibits a pKa near 7.5 and has a well
defined, single-pKa titration curve. Similarly, in oxidized wild-type Trx, Asp26
has a pKa near 7.5. In CVWC and CWGC Trx, Cys32 exhibits a single pKa near 6.2.
In all five enzymes studied here, there is no evidence for a Cys35 (CXXC) pKa of
< 11. This study demonstrates that a comprehensive approach must be used to
unravel complex titration behavior of the functional groups in a protein.
PMID- 9398224
TI - Kinetics of cytochrome c folding examined by hydrogen exchange and mass
spectrometry.
AB - Pulsed hydrogen exchange/mass spectrometry, a new method for studying protein
folding, has been used to investigate folding of cytochrome c on the 5 ms to 15 s
time scale. Cytochrome c, unfolded in guanidine hydrochloride/D2O, was allowed to
refold in a high-speed quenched-flow apparatus and pulse-labeled with protium to
identify unfolded regions. Intact, labeled cytochrome c was digested into
fragments which were analyzed by HPLC electrospray ionization mass spectrometry
to determine the level of deuterium in each fragment. Bimodal distributions of
deuterium were found for most segments, indicating that regions represented by
these segments were either unfolded or completely folded in the intact
polypeptide prior to labeling. This behavior is consistent with cooperative,
localized folding which occurs in less than 10 ms in individual molecules.
Deuterium levels found in the fragments were normalized to levels found in the
same fragments derived from folded cytochrome c, pulse-labeled in the same
manner, to indicate the percentage of cytochrome c that was folded. These results
show that the N/C-terminal regions fold cooperatively on a time scale extending
from less than the mixing time of the apparatus (5 ms) to as long as 15 s, and
that the other regions also fold cooperatively. However, these regions do not
begin to fold until 30 ms after mixing. In addition to providing new information
on cytochrome c folding, these results demonstrate that pulse-hydrogen
exchange/mass spectrometry is complementary to NMR in some respects and
advantageous in others. Results of this study form the foundation required to
extend the pulsed hydrogen exchange approach to folding studies of proteins too
large to be analyzed by NMR.
PMID- 9398225
TI - Intersubunit communication in hybrid hexamers of K89L/A163G/S380A and C320S
mutants of glutamate dehydrogenase from Clostridium symbiosum.
AB - The triple mutant K89L/A163G/S380A (inactive with glutamate but active with L-Nle
and L-Met) and C320S (fully active with glutamate, entirely inactive with L-Nle
and L-Met, and also lacking reactive cysteine) mutant of glutamate dehydrogenase
(EC 1.4.1.2) of Clostridium symbiosum could be completely denatured by urea with
the loss of structure and activity. The mutants denatured by urea could be
reassociated to give stable hexamers with recovery of activity of approximately
67% by dilution in 0.1 M potassium phosphate buffer (pH 7.0) containing 2 mM
NAD+. The native, urea-denatured, and renatured states of mutant enzymes were
characterized by size exclusion chromatography on FPLC and native PAGE.
Intersubunit hybrid hexamers containing five subunits of triple mutant and one
subunit of C320S mutant were constructed by in vitro subunit hybridization
followed by affinity chromatography. Kinetic analysis showed that a 5:1 hybrid
hexamer, with only one C320S subunit able to bind NAD+ after DTNB modification,
shows classical Michaelis-Menten kinetics with regard to NAD+. This contrasts
with the apparent negative co-operativity shown by pure C320S hexamers and
suggests that the interaction in NAD+ binding among subunits is eliminated in the
hybrid. After removal of thionitrobenzoate, however, all of the subunits in the
hybrid are able to bind NAD+. In this state the hybrid enzyme showed slight
deviation from classical behavior with regard to NAD+, indicating reintroduction
of some level of allosteric interaction. The hybrid hexamer also showed much
reduced co-operativity with glutamate at pH 8.8, with a Hill coefficient of 3 for
DTNB-treated hybrid (as compared to 5.2 for the pure C320S mutant) and 2.2 for
the untreated hybrid. The fact that co-operativity in glutamate binding is not
entirely eliminated correlates with evidence that the triple mutant subunits,
though inactive toward glutamate, can nevertheless still bind this amino acid.
PMID- 9398226
TI - Fast events in protein folding: relaxation dynamics and structure of the I form
of apomyoglobin.
AB - The fast relaxation dynamics of the acid destabilized I form of apomyoglobin (pH*
3, 0.15 M NaCl; apoMb-I) following a laser-induced temperature-jump have been
probed using time-resolved infrared spectroscopy. Only a fast, single exponential
phase is observed (bleach centered at v = 1633 cm-1 and transient absorbance at
1666 cm-1) with relaxation times of 38 ns at 30 degrees C and 36 ns at 57 degrees
C; no additional slow (microsecond) phase is observed as previously found in the
native form of apomyoglobin. Folding times of approximately 66 ns are derived
from the observed rates based on a simple two-state model. The equilibrium
melting of the 1633 cm-1 component shows noncooperative linear behavior over the
temperature range studied (10-60 degrees C). The low amide I' frequency, the fast
relaxation dynamics, and the noncooperative melting behavior are characteristic
of isolated solvated helix. The analysis of the amide-I' band reveals another
major component at 1650 cm-1 assigned to native-like structure stabilized by
tertiary contacts involving the AGH core, which does not show dynamic or static
melting under our conditions. ApoMb-I has generally been taken to be a "molten
globule" species. The present results indicate a heterogeneous structure
consisting of separate regions of native-like unit(s), solvated helices, and
disordered coil, excluding a homogeneous molten globule as a model for apoMb-I.
From the current studies and other results, a detailed model of the folding of
apomyoglobin is presented.
PMID- 9398227
TI - Novel application of 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole to identify cysteine
sulfenic acid in the AhpC component of alkyl hydroperoxide reductase.
AB - The trapping of a sulfenic acid within the fully active C165S mutant of the AhpC
peroxidase protein from Salmonella typhimurium was investigated. The
electrophilic reagent employed in these studies, 7-chloro-4-nitrobenz-2-oxa-1,3
diazole (NBD-Cl), has previously been used to modify thiol, amino, and tyrosine
hydroxyl groups in proteins; at neutral pH only cysteinyl residues of AhpC
proteins are modified. The peroxide-oxidized C165S mutant of AhpC incubated with
NBD-Cl gave a product with an absorbance maximum at 347 nm, whereas the thiol-NBD
conjugate formed from the reduced protein absorbed maximally at 420 nm.
Electrospray ionization mass spectrometry of the modified proteins allowed
identification of the species absorbing at 347 nm as a Cys-S(O)-NBD derivative
containing one additional oxygen relative to the Cys-S-NBD product. The C165S
conjugates with Cys-S(O)-NBD and Cys-S-NBD had no peroxidase activity when
compared to unreacted C165S and wild-type AhpC, but were both reactivated through
removal of NBD by DTT. Oxidized C165S was also modified by dimedone, a common
sulfenic acid reagent, to give the expected inactivated conjugate of higher mass.
This reagent was not removed by DTT and blocked any further reaction of the
protein with NBD-Cl. NBD modification of Enterococcus faecalis NADH peroxidase, a
well-characterized flavoprotein with an active-site sulfenic acid (Cys-SOH), also
yielded the spectrally-distinguishable NBD conjugates following incubation of NBD
Cl with oxidized and reduced forms of the denatured peroxidase, indicating a
general utility for this reagent with other sulfenic acid-containing proteins. A
significant advantage of NBD-Cl over previously-used sulfenic acid reagents such
as dimedone is in the retention of the sulfenic acid oxygen in the modified
product; differentiation between protein-associated thiols and sulfenic acids is
therefore now possible by means of both visible absorbance properties and mass
analyses of the NBD-modified proteins.
PMID- 9398228
TI - Identification of residues essential for differential fatty acyl specificity of
Geotrichum candidum lipases I and II.
AB - The fungus Geotrichum candidum produces two lipase isoenzymes, GCL I and GCL II,
with distinct differences in substrate specificity despite their 86% identical
primary structure. GCL I prefers ester substrates with long-chain cis (delta-9)
unsaturated fatty acid moieties, whereas GCL II also accepts medium-length (C8
C14) acyl moieties in the substrate. To reveal structural elements responsible
for differences in substrate differentiating ability of these isoenzymes, we
designed, expressed, and characterized 12 recombinant lipase variants. Three
chimeric lipases containing unique portions of the N-terminal and the C-terminal
part of GCL I and GCL II, respectively, were constructed and enzymatically
characterized. Activities were measured against mixed triglyceride-poly(dimethyl
siloxane) particles. Our results indicate that residues within sequence positions
349-406 are essential for GCL I's high triolein/trioctanoin activity ratio of 20.
The substitution of that segment in the specific GCL I to the corresponding
residues in the nonspecific GCL II resulted in an enzyme with a
triolein/trioctanoin activity ratio of 1.4, identical to that of GCL II. The
reverse mutation in GCL II increased its specificity for triolein by a factor of
2, thus only in part restoring the high specificity seen with GCL I. In further
experiments, the point mutations at the active site entrance of the GCL I,
Leu358Phe and Ile357Ala/Leu358Phe, lowered the triolein/trioctanoin activity
ratio from 20 to 4 and 2.5, respectively. The substitutions Cys379Phe/Ser380Tyr
at the bottom of the active site cavity of GCL I decreased its specificity to a
value of 3.6. Measurements of lipase activity with substrate particles composed
of pure triglycerides or ethyl esters of oleic and octanoic acids resulted in
qualitatively similar results as reported above. Our data reveal for the first
time the identity of residues essential for the unusual substrate preference of
GCL I and show that the anatomy, both at the entrance and the bottom of the
active site cavity, plays a key role in substrate discrimination.
PMID- 9398229
TI - Calmodulin binds to caldesmon in an antiparallel manner.
AB - Two of the five tryptophan residues (W659 and W692) in chicken gizzard smooth
muscle caldesmon (CaD) are located within the calmodulin (CaM) binding sites in
the C-terminal region of the molecule. When these Trp residues are replaced with
Gly in either recombinant fragments or synthetic peptides of CaD, the affinity
for CaM is decreased by at least 10-fold, suggesting that both of these residues
are important for the interaction of CaD with CaM. To gain information about the
topography of the CaM-CaD complex, we have carried out fluorescence titrations of
CaM with Tb3+ as a substitute for Ca2+ in the presence of wild-type or mutated
CaD variants. By exciting Trp residues of CaD fragments or peptides while
monitoring the enhanced luminescence of CaM-bound Tb3+ ions via resonance energy
transfer, we were able to estimate the relative proximity between the bound metal
ions in the two domains of CaM and the Trp residues of CaD. Our results suggest
that in the CaM-CaD complex the metal-binding sites III and IV in the C-terminal
domain of CaM are very close to W659 of CaD; the N-terminal domain of CaM appears
associated with the region of CaD in the vicinity of W692, although sites I and
II are relatively far away from this Trp residue. These findings are consistent
with a model in which CaM binds to CaD in an antiparallel manner. Such a binding
mode, however, may be flexible enough to accommodate alternative spatial
arrangements when the preferred binding sites are either altered or rendered
unavailable.
PMID- 9398230
TI - Reconstruction of quaternary structures of class II tRNA synthetases by rational
mutagenensis of a conserved domain.
AB - Class II tRNA synthetases have long been known to have quaternary structures of
alpha, alpha2, alpha2beta2, and alpha4, depending on the amino acid specificity
and the organism from which the synthetase was isolated. Even the quaternary
structures of enzymes for the same amino acid show variations in evolution. The
basis for these variations has not been understood. We report here that sequence
manipulations of a structural motif (motif 1) characteristic of all class II tRNA
synthetases can generate most of the evolutionary diversity of quaternary forms
of class II synthetases. Thus, the principles elucidated here for quaternary
structure assembly may be general.
PMID- 9398231
TI - Remarkable ability of horse spleen apoferritin to demetallate hemin and to
metallate protoporphyrin IX as a function of pH.
AB - In previous studies it has been shown that reaction of crystalline horse spleen
apoferritin with hemin leads to a protoporphyrin IX-apoferritin complex
[Precigoux et al. (1994) Acta Crystallogr. D50, 739-743]. We show here the
following. (i) Hemin binds to two classes of sites in horse spleen apoferritin at
pH 8, each with a binding stoichiometry of 0.5 hemin/subunit; protoporphyrin IX
also binds to horse spleen apoferritin with an apparent binding stoichiometry of
1 molecule of protoporphyrin IX/subunit. (ii) When Fe(III)-protoporphyrin IX
binds to apoferritin, there is a pH-dependent loss of the metal ion, extremely
slow at alkaline pH values (half-time of weeks) and much more rapid at acidic pH
values (half-time of seconds below pH 5.0); maximum rates of demetallation are
found at pH 4.0, and at lower pH values they decrease. (iii) Chemical
modification of 11 carboxyl groups/subunit in horse spleen apoferritin does not
affect hemin binding at alkaline pH values; however, it prevents hemin
demetallation at acidic pH values. (iv) Hemin that has been demetallated at
acidic pH values can be remetallated by increasing the pH; the rate of
remetallation is greater at more alkaline pH values. (v) When around 20 atoms of
iron/molecule are incorporated into horse spleen apoferritin and protoporphyrin
IX is then bound, iron can subsequently be transferred to the porphyrin at pH
8.0. A mechanism is proposed to explain demetallation of heme, involving attack
on the tetrapyrrole nitrogens of the protoporphyrin IX-Fe by protons derived from
protein carboxylic acid groups and subsequent complexation of the iron by the
corresponding carboxylates and binding of protoporphyrin IX to a preformed pocket
in the inner surface of the apoferritin protein shell. The cluster of
carboxylates involved is situated at the entrance to the pocket in which the
protoporphyrin IX molecule is bound and has been previously identified as the
site of iron incorporation into L-chain apoferritins. This appears to be the
first example of iron removal and incorporation into porphyrins under relatively
mild physiological conditions.
PMID- 9398232
TI - Site-directed spin-labeling of transmembrane domain VII and the 4B1 antibody
epitope in the lactose permease of Escherichia coli.
AB - Functional lactose permease mutants containing single Cys residues at positions
233-255 and a biotin acceptor domain at the C terminus were solubilized in
dodecyl beta-d-maltopyranoside and purified by avidin affinity chromatography.
Each mutant protein was derivatized with a thiol-selective nitroxide reagent and
examined by conventional and power saturation electron paramagnetic resonance
spectroscopy (EPR). The EPR spectral line shapes and the influence of nonpolar O2
or polar potassium chromium oxalate relaxation agents on the saturation behavior
of the spin-labeled proteins were measured in order to obtain information on the
mobility of the spin-labeled side chains and their accessibility to the
relaxation agents, respectively. The results provide evidence that residues
Ser233-Asn246 are within the hydrophobic core of the membrane and that Phe247 is
at the lipid headgroup-solvent interface. Along with Phe247, Phe250 and Gly254
are also surface-exposed, as indicated by studies on the epitope for monoclonal
antibody 4B1 [Sun, J., Wu, J., Carasco, N., and Kaback, H. R. (1996) Biochemistry
35, 990-998]. Furthermore, the nitroxide-labeled intramembrane Cys replacements
exhibit variations in mobility and accessibility that are consistent with the
conclusion that TM VII is an alpha-helix in contact with surrounding helices in
the tertiary structure of the permease.
PMID- 9398233
TI - Three-dimensional structure of leucocin A in trifluoroethanol and
dodecylphosphocholine micelles: spatial location of residues critical for
biological activity in type IIa bacteriocins from lactic acid bacteria.
AB - The first three-dimensional structure of a type IIa bacteriocin from lactic acid
bacteria is reported. Complete 1H resonance assignments of leucocin A, a 37 amino
acid antimicrobial peptide isolated from the lactic acid bacterium Leuconostoc
gelidum UAL187, were determined in 90% trifluoroethanol (TFE)-water and in
aqueous dodecylphosphocholine (DPC) micelles (1:40 ratio of leucocin A:DPC) using
two-dimensional NMR techniques (e.g., DQF-COSY, TOCSY, NOESY). Circular dichroism
spectra, NMR chemical shift indices, amide hydrogen exchange rates, and long
range nuclear Overhauser effects indicate that leucocin A adopts a reasonably
well defined structure in both TFE and DPC micelle environments but exists as a
random coil in water or aqueous DMSO. Distance geometry and simulated annealing
calculations were employed to generate structures for leucocin A in both
lipophilic media. While some differences were noted between the structures
calculated for the two different solvent systems, in both, the region
encompassing residues 17-31 assumes an essentially identical amphiphilic alpha
helix conformation. A three-strand antiparallel beta-sheet domain (residues 2
16), anchored by the disulfide bridge, is also observed in both media. In TFE,
these two regions have a more defined relationship relative to each other, while,
in DPC micelles, the C-terminus is folded back onto the alpha-helix. The
implications of these structural features with regard to the antimicrobial
mechanism of action and target recognition are discussed.
PMID- 9398234
TI - X-ray crystallographic studies of unique cross-linked lattices between four
isomeric biantennary oligosaccharides and soybean agglutinin.
AB - Soybean agglutinin (SBA) (Glycine max) is a tetrameric GalNAc/Gal-specific lectin
which forms unique cross-linked complexes with a series of naturally occurring
and synthetic multiantennary carbohydrates with terminal GalNAc or Gal residues
[Gupta et al. (1994) Biochemistry 33, 7495-7504]. We recently reported the X-ray
crystal structure of SBA cross-linked with a biantennary analog of the blood
group I carbohydrate antigen [Dessen et al. (1995) Biochemistry 34, 4933-4942].
In order to determine the molecular basis of different carbohydrate-lectin cross
linked lattices, a comparison has been made of the X-ray crystallographic
structures of SBA cross-linked with four isomeric analogs of the biantennary
blood group I carbohydrate antigen. The four pentasaccharides possess the common
structure of (beta-LacNAc)2Gal-beta-R, where R is -O(CH2)5COOCH3. The beta-LacNAc
moieties in the four carbohydrates are linked to the 2,3-, 2,4-, 3,6-, and 2,6
positions of the core Gal residue(s), respectively. The structures of all four
complexes have been refined to approximately 2.4-2.8 A. Noncovalent lattice
formation in all four complexes is promoted uniquely by the bridging action of
the two arms of each bivalent carbohydrate. Association between SBA tetramers
involves binding of the terminal Gal residues of the pentasaccharides at
identical sites in each monomer, with the sugar(s) cross-linking to a symmetry
related neighbor molecule. While the 2,4-, 3,6-, and 2,6-pentasaccharide
complexes possess a common P6422 space group, their unit cell dimensions differ.
The 2, 3-pentasaccharide cross-linked complex, on the other hand, possesses the
space group I4122. Thus, all four complexes are crystallographically distinct.
The four cross-linking carbohydrates are in similar conformations, possessing a
pseudo-2-fold axis of symmetry which lies on a crystallographic 2-fold axis of
symmetry in each lattice. In the case of the 3,6- and 2,6-pentasaccharides, the
symmetry of their cross-linked lattices requires different rotamer orientations
about their beta(1,6) glycosidic bonds. The results demonstrate that crystal
packing interactions are the molecular basis for the formation of distinct cross
linked lattices between SBA and four isomeric pentasaccharides. The present
findings are discussed in terms of lectins forming unique cross-linked complexes
with glycoconjugate receptors in biological systems.
PMID- 9398235
TI - Three-dimensional structure of Escherichia coli dihydrodipicolinate reductase in
complex with NADH and the inhibitor 2,6-pyridinedicarboxylate.
AB - Dihydrodipicolinate reductase catalyzes the NAD(P)H-dependent reduction of the
alpha,beta-unsaturated cyclic imine dihydrodipicolinate to form the cyclic imine
tetrahydrodipicolinate. The enzyme is a component of the biosynthetic pathway
that leads to diaminopimelate and lysine in bacteria and higher plants. Because
these pathways are unique to microorganisms and plants, they may represent
attractive targets for new antimicrobial or herbicidal compounds. The three
dimensional structure of the ternary complex of Escherichia coli
dihydrodipicolinate reductase with NADH and the inhibitor 2,6
pyridinedicarboxylate has been solved using a combination of molecular
replacement and noncrystallographic symmetry averaging procedures and refined
against 2.6 A resolution data to a crystallographic R-factor of 21.4% (Rfree is
29.7%). The native enzyme is a 120 000 molecular weight tetramer of identical
subunits. The refined crystallographic model contains a tetramer, three molecules
of NADH, three molecules of inhibitor, one phosphate ion, and 186 water molecules
per asymmetric unit. Each subunit consists of two domains connected by two
flexible hinge regions. While three of the four subunits of the tetramer have a
closed conformation, in which the nicotinamide ring of the cofactor bound to the
N-terminal domain and the reducible carbon of the substrate bound to the
substrate binding domain are about 3.5 A away, the fourth subunit is unliganded
and shows an open conformation, suggesting that the enzyme undergoes a major
conformational change upon binding of both substrates. The residues involved in
binding of the inhibitor and the residues involved in catalysis have been
identified on the basis of the three-dimensional structure. Site-directed mutants
have been used to further characterize the role of these residues in binding and
catalysis. A chemical mechanism for the enzyme, based on these and previously
reported data, is proposed.
PMID- 9398236
TI - Structure of the carboxy-terminal fragment of the apo-biotin carboxyl carrier
subunit of Escherichia coli acetyl-CoA carboxylase.
AB - The biotin carboxyl carrier protein (BCCP) is a subunit of acetyl-CoA
carboxylase, a biotin-dependent enzyme that catalyzes the first committed step of
fatty acid biosynthesis. In its functional cycle the biotin carboxyl carrier
protein engages in heterologous protein-protein interactions with three distinct
partners, depending on its state of posttranslational modification. Apo-BCCP
interacts specifically with the biotin holoenzyme synthetase, BirA, which results
in the posttranslational attachment of biotin to an essential lysine residue on
BCCP. Holo-BCCP then interacts with the biotin carboxylase subunit, which leads
to the addition of the carboxylate group of bicarbonate to biotin. Finally, the
carboxybiotinylated form of BCCP interacts with transcarboxylase in the
conversion of acetyl-CoA to malonyl-CoA. The determinants of protein-protein
interaction specificity in this system are unknown. One hypothesis is that
posttranslational modification of BCCP may result in conformational changes that
regulate specific protein-protein interactions. To test this hypothesis, we have
determined the NMR solution structure of the unbiotinylated form of an 87 residue
C-terminal domain fragment of BCCP (apoBCCP87) from Escherichia coli acetyl-CoA
carboxylase and compared this structure with the high-resolution structure of the
biotinylated form that was recently solved by X-ray crystallographic techniques.
Although the overall folding of the two proteins is highly similar, small
structural differences are apparent for residues of the biotin-binding loop that
may be important for mediating specific protein-protein interactions.
PMID- 9398237
TI - Identification and structural and functional characterization of human enamelysin
(MMP-20).
AB - A cDNA encoding a new human matrix metalloproteinase (MMP) has been cloned from
RNA prepared from odontoblastic cells. The open reading frame of the cloned cDNA
codes for a polypeptide of 483 amino acids and is extensively similar to the
sequence of recently described porcine enamelysin, suggesting that the isolated
cDNA codes for the human homologue of this enzyme. Human enamelysin (MMP-20) has
a domain organization similar to other MMPs, including a signal peptide, a
prodomain with the conserved motif PRCGVPD involved in maintaining enzyme
latency, a catalytic domain with a Zn-binding site, and a COOH-terminal fragment
similar to the sequence of hemopexin. The calculated molecular mass of human
enamelysin is about 54 kDa, which is similar to that of collagenases or
stromelysins. However, this human MMP lacks a series of structural features
distinctive of these subfamilies of MMPs. The full-length human enamelysin cDNA
has been expressed in Escherichia coli, and the purified and refolded recombinant
protein is able to degrade synthetic peptides used as substrates of MMPs,
confirming that human enamelysin belongs to this family of proteases.
Furthermore, the recombinant human enamelysin is able to degrade amelogenin, the
major protein component of the enamel matrix. On the basis of its degrading
activity on amelogenin, and its highly restricted expression to dental tissues,
we suggest that human enamelysin plays a central role in the process of tooth
enamel formation. Finally, we have found that the human enamelysin gene (MMP-20)
maps to chromosome 11q22, clustered to at least seven other members of the MMP
gene family.
PMID- 9398238
TI - Iron-sulfur cluster cysteine-to-serine mutants of Anabaena -2Fe-2S- ferredoxin
exhibit unexpected redox properties and are competent in electron transfer to
ferredoxin:NADP+ reductase.
AB - The reduction potentials and the rate constants for electron transfer (et) to
ferredoxin:NADP+ reductase (FNR) are reported for site-directed mutants of the
[2Fe-2S] vegetative cell ferredoxin (Fd) from Anabaena PCC 7120, each of which
has a cluster ligating cysteine residue mutated to serine (C41S, C46S, and C49S).
The X-ray crystal structure of the C49S mutant has also been determined. The UV
visible optical and CD spectra of the mutants differ from each other and from
wild-type (wt) Fd. This is a consequence of oxygen replacing one of the ligating
cysteine sulfur atoms, thus altering the ligand --> Fe charge transfer transition
energies and the chiro-optical properties of the chromophore. Each mutant is able
to rapidly accept an electron from deazariboflavin semiquinone (dRfH.) and to
transfer an electron from its reduced form to oxidized FNR although all are
somewhat less reactive (30-50%) toward FNR and are appreciably less stable in
solution than is wt Fd. Whereas the reduction potential of C46S (-381 mV) is not
significantly altered from that of wt Fd (-384 mV), the potential of the C49S
mutant (-329 mV) is shifted positively by 55 mV, demonstrating that the cluster
potential is sensitive to mutations made at the ferric iron in reduced [2Fe-2S]
Fds with localized valences. Despite the decrease in thermodynamic driving force
for et from C49S to FNR, the et rate constant is similar to that measured for
C46S. Thus, the et reactivity of the mutants does not correlate with altered
reduction potentials. The et rate constants of the mutants also do not correlate
with the apparent binding constants of the intermediate (Fdred:FNRox) complexes
or with the ability of the prosthetic group to be reduced by dRfH.. Furthermore,
the X-ray crystal structure of the C49S mutant is virtually identical to that of
wt Fd. We conclude from these data that cysteine sulfur d-orbitals are not
essential for et into or out of the iron atoms of the cluster and that the
decreased et reactivity of these Fd mutants toward FNR may be due to small
changes in the mutual orientation of the proteins within the intermediate complex
and/or alterations in the electronic structure of the [2Fe-2S] cluster.
PMID- 9398239
TI - Substitution of the urease active site carbamate by dithiocarbamate and vanadate.
AB - Urease possesses a dinuclear nickel active site with the metals bridged by a
carbamylated lysine residue. In vitro activation of apoprotein (Apo) is achieved
by incubation with Ni(II) and bicarbonate as a source of CO2. Analogues of CO2
and bicarbonate were examined for their effects on the Apo activation process.
While SO2 had little effect, CS2 was shown to inhibit Apo activation via its
ability to substitute for CO2 to yield an inactive dithiocarbamate-containing
protein. Sulfur-to-Ni charge-transfer transitions arising from this species
yielded an electronic absorption band at 324 nm with a shoulder at 382 nm.
Borate, sulfate, phosphate, and molybdate had essentially no effect on Apo
activation and did not substitute for bicarbonate, while treatment of Apo with
Ni(II) plus vanadate led to the production of active urease containing two Ni and
one V per active site. Vanadate-dependent activation of Apo resembled the normal
activation process in terms of concentration of anion required, optimal pH, and
incubation time needed. Furthermore, the UV-visible spectrum, maximal specific
activity [386 +/- 26 U.(mg of protein)-1], Km (1.83 +/- 0.20 mM urea), and pH
dependence for the vanadate-containing urease were essentially identical to
properties observed for bicarbonate-activated enzyme. Vanadate-activated Apo is
proposed to possess a vanadylated lysine that bridges the two Ni ions comprising
its metallocenter.
PMID- 9398240
TI - Characterization of alanine-rich peptides, Ac-(AAKAA)n-GY-NH2 (n = 1-4), using
vibrational circular dichroism and Fourier transform infrared. Conformational
determination and thermal unfolding.
AB - Vibrational circular dichroism (VCD) and Fourier transform IR (FTIR) were
measured for a series of short alanine-based peptides having the general formula
Ac-(AAKAA)n-GY-NH2 (n = 1-4) from 5 to 50 degrees C in D2O and at room
temperature in both TFE and H2O. In both of these latter solvents, the dominant
structural form at the lowest temperature for the longest oligomers is alpha
helical. The same is true for the n = 4 peptide in D2O, but under these more
dilute aqueous conditions, the shorter (n = 3) peptides have mixed helix-coil
structures and the n = 1 and 2 peptides are random coils. The VCD data do not
support the 310-helix as a dominant contributor to the conformation of these
oligomers in any of these solvents. These vibrational spectral data are
consistent with lower-concentration electronic CD results and additionally
indicate increased helical stability at higher concentrations. VCD amide I data
for the 22mer (n = 4) in D2O indicate that the peptide undergoes a transition
from a highly helical conformation at 5 degrees C to a dominant random coil
structure at approximately 45 degrees C with a Tm of approximately 25 degrees C
(effective midpoint). Factor analysis of the thermal data showed that three
principal components were required to describe both the VCD and FTIR data for the
n = 4 peptide in D2O. The transition is characterized by a gradual loss of
contribution from a spectral component representing the alpha-helical fraction.
The third component is evidence of an optically detected intermediate
conformation best viewed as a mixed coil-helix structure resulting from end
fraying of the helical peptide as the temperature is increased. The nature of the
junction between the interior helix and frayed ends is not determined by these
data and could involve local (phi and psi) angles mimicking a 310-helix that
would provide consistency with ESR and NMR results from Millhauser and co
workers.
PMID- 9398241
TI - Effect of prolyl isomerase on the folding reactions of staphylococcal nuclease.
AB - The low-temperature fluorescence-detected refolding of staphylococcal nuclease
(SNase) can be described by three slow kinetic phases. The slowest phase is
absent in the P117G mutant of SNase. Peptidyl prolyl cis-trans isomerase
(cyclophilin), which has been shown to catalyze the slow folding reactions of
some proteins, was employed to determine which of the refolding reactions of
SNase and P117G SNase involve proline isomerization. We report here that all
three folding phases of the wild type and the slower phase of P117G SNase are
catalyzed by prolyl isomerase, indicating that proline isomerization is involved
in these fluorescence-detected phases in the refolding of SNase. Since the rates
of these phases are denaturant-dependent, we conclude that the slow folding steps
involve isomerization of non-native cis proline peptide bonds and are tightly
coupled to denaturant-sensitive structural changes.
PMID- 9398242
TI - The conformation of the alpha-helical coiled coil domain of macrophage scavenger
receptor is pH dependent.
AB - Macrophage scavenger receptor is a trimerized membrane protein that binds ligands
and undergoes internalization by endocytosis. The receptor releases the ligands
in the endosome, and then is recycled. The mechanisms of the ligand release and
the recycling of the receptor have not been clearly determined. We analyzed the
structure of the alpha-helical coiled coil domain considered to be responsible
for acid-mediated ligand dissociation, by chemical cross-linking, sedimentation
equilibrium, Western blot, and circular dichroism analyses. This domain has 22
heptad repeats, which are characteristic of the sequence of an alpha-helical
coiled coil structure, with a discontinuity in the middle. We prepared three
peptides, corresponding to the entire alpha-helical coiled coil domain (alpha),
its N-terminal half (alpha-N), and its C-terminal half (alpha-C), by expression
of each gene in Escherichia coli. The alpha and alpha-N peptides show triple
stranded alpha-helical coiled coil structures, but in contrast, the alpha-C
peptide shows a random structure. When connected to the N-terminus by a chemical
ligation method, the alpha-C peptide also shows an alpha-helical coiled coil
structure, but only at an acidic pH. These results suggest that the N-terminus of
the alpha-helical coiled coil domain is responsible for the formation of a stable
trimer and the C-terminus exhibits the pH-dependent conformational change that
might be involved in the ligand release by the macrophage scavenger receptor.
PMID- 9398243
TI - Characterization of the reaction mechanism for Trypanosoma brucei ornithine
decarboxylase by multiwavelength stopped-flow spectroscopy.
AB - Ornithine decarboxylase (ODC), a pyridoxal 5'-phosphate (PLP)-dependent enzyme,
catalyzes the first committed step in the biosynthesis of polyamines. The UV
visible spectra of PLP (300-500 nm) was used to monitor the formation and
breakdown of ODC reaction intermediates by multiwavelength stopped-flow
spectroscopy to determine the reaction mechanism. Global kinetic analysis of the
spectral data acquired after mixing ODC with saturating substrate (S) or product
(P) (10 mM ornithine or 10 mM putrescine at 4 degrees C) suggests that ODC
catalyzed decarboxylation proceeds by the following reaction mechanism: ODC + S
if A --> B --> C --> D --> E/F if ODC + P, where A-F are intermediates along the
reaction path. Species B, which has absorbance maxima of 350 and 450 nm, is
spectrally distinct from the other intermediates. On the basis of the calculated
spectral characteristics, species B is likely to represent a quinoid intermediate
which would be formed directly upon decarboxylation of ornithine. Thus, the data
suggest that the reaction proceeds via formation of a Schiff base intermediate
(species A) during the dead time of the stopped-flow instrument, followed by
formation of a quinoid intermediate with a rate constant of 21 s-1. The quinoid
intermediate decays in two steps (with rates of 145 and 1.0 s-1, respectively) to
a Schiff base with putrescine (species D). Protonation of the Calpha carbon is
required for the formation of species D, suggesting that the first of these
events represents this step. The decay of species D to free enzyme and product
occurs via a minimum of two intermediates and at an overall rate constant of 1-3
s-1. By comparison to the steady-state turnover number (kcat = 0.5 s-1 at 4
degrees C), these data identify product release as a rate-determining step in the
overall reaction.
PMID- 9398244
TI - A biophysical study of integral membrane protein folding.
AB - In order to characterize the thermodynamic constraints on the process of integral
membrane protein folding and assembly, we have conducted a biophysical dissection
of the structure of bacteriorhodopsin (BR), a prototypical alpha-helical integral
membrane protein. Seven polypeptides were synthesized, corresponding to each of
the seven transmembrane alpha-helices in BR, and the structure of each individual
polypeptide was characterized in reconstituted phospholipid vesicles. Five of the
seven polypeptides form stable transmembrane alpha-helices in isolation from the
remainder of the tertiary structure of BR. However, using our reconstitution
protocols, the polypeptide corresponding to the F helix in BR does not form any
stable secondary structure in reconstituted vesicles, and the polypeptide
corresponding to the G helix forms a hyperstable beta-sheet structure with its
strands oriented perpendicular to the plane of the membrane. [The polypeptide
corresponding to the C helix spontaneously equilibrates in a pH-dependent manner
between a transmembrane alpha-helical conformation, a peripherally bound
nonhelical conformation, and a fully water soluble conformation; the
conformational properties of this polypeptide are the subject of the accompanying
paper: Hunt et al. (1997) Biochemistry 36, 15177-15192.] Our observations suggest
that the folding of alpha-helical integral membrane proteins may proceed
spontaneously. However, the preference for a non-native conformation exhibited by
two of the polypeptides suggests that the formation of some transmembrane
substructures could require external constraints such as the links between the
helices, interactions with the rest of the protein, or the involvement of
cellular chaperones or translocases. Our results also suggest a strategy for
improving the thermodynamic stability of alpha-helical integral membrane
proteins, a goal that could facilitate attempts to overexpress and/or refold
them.
PMID- 9398245
TI - Spontaneous, pH-dependent membrane insertion of a transbilayer alpha-helix.
AB - A question of fundamental importance concerning the biosynthesis of integral
membrane proteins is whether transmembrane secondary structure can insert
spontaneously into a lipid bilayer. It has proven to be difficult to address this
issue experimentally because of the poor solubility in aqueous solution of
peptides and proteins containing these extremely hydrophobic sequences. We have
identified a system in which the kinetics and thermodynamics of alpha-helix
insertion into lipid bilayers can be studied systematically and quantitatively
using simple spectroscopic assays. Specifically, we have discovered that a 36
residue polypeptide containing the sequence of the C-helix of the integral
membrane protein bacteriorhodopsin exhibits significant solubility in aqueous
buffers free of both detergents and denaturants. This helix contains two aspartic
acid residues in the membrane-spanning region. At neutral pH, the peptide
associates with lipid bilayers in a nonhelical and presumably peripheral
conformation. With a pKa of 6.0, the peptide inserts into the bilayer as a
transbilayer alpha-helix. The insertion reaction proceeds rapidly at room
temperature and is fully reversible.
PMID- 9398246
TI - Interruption of G protein-coupling in CXCR2 does not alter ligand binding, but
eliminates ligand-activation of GTPgamma35S binding, calcium mobilization, and
chemotaxis.
AB - CXCR2 is a seven-transmembrane receptor that transduces intracellular signals in
response to the chemokines IL-8, MGSA/GRO, and other ELR motif-containing CXC
chemokines by coupling to heterotrimeric GTP-binding proteins. In this study, we
have mutated two putative G protein-coupling regions of CXCR2 and characterized
the effects of these mutations on ligand-activated signal transductions: aspartic
acid 89 in the second transmembrane domain and the HRAMR sequence (BBXXB motif,
found in the third intracellular loop where B indicates a basic amino acid and X
represents any amino acid). The Asp89 was replaced by either asparagine (D89N) or
glutamic acid (D89E). For the BBXXB motif, the first two basic amino acids were
mutated to two neutral isoleucines (HR-II), or alternatively, two isoleucines
were inserted between alanine and methionine (II-insert). When expressed in human
embryonic kidney 293 cells, the D89E mutant was localized intracellularly with no
detectable cell surface expression. In contrast, D89N, HR-II, and II-insert
mutants displayed cell surface expression, with Kd values and expression levels
similar to that of the wild-type transfectant. The ability of the mutants to
transduce signal was assessed by ligand-stimulated GTPgamma35S binding,
mobilization of intracellular free Ca2+, and chemotaxis assays. Both D89N and HR
II mutants signaled similarly to a wild-type receptor in all three assays.
However, the II-insert mutant exhibited a loss of ligand-stimulated GTPgamma35S
binding, calcium mobilization, and chemotaxis. Unexpectedly, this receptor
underwent ligand-induced sequestration comparable to wild-type CXCR2. These data
indicate that Asp89 and the basic amino acids in the third intracellular domain
do not play essential roles in ligand-induced signal transduction through CXCR2.
However, proper secondary structure and orientation of the third intracellular
loop of CXCR2 are essential for ligand-mediated signal transduction but not for
receptor sequestration.
PMID- 9398247
TI - Oligomerization of a 45 kilodalton fragment of diphtheria toxin at pH 5.0 to a
molecule of 20-24 subunits.
AB - Diphtheria toxin (DT) is a 58 kDa protein, secreted by lysogenic strains of
Corynebacterium diphtheriae, that causes the disease diphtheria in humans. The
catalytic (C) domain of DT kills host cells by gaining entry into the cytoplasm
and inhibiting protein synthesis. The translocation of the C domain across the
endosomal membrane and into the cytoplasm of a host cell is mediated by the
translocation (T) domain of DT. This process is triggered by acidification from
pH approximately 7 to pH approximately 5 within the endosome. Here we show that
crm45 (cross-reacting material of 45 kDa), a 45 kDa deletion mutant of DT which
contains the C and T domains but lacks the C-terminal receptor-binding (R)
domain, undergoes a transition from a monomer to a large oligomer upon
acidification from pH 7.0 to pH 5.0. Dynamic light scattering analysis of crm45
at pH 5.0 results in a polydispersity value of only 8-17%, suggesting that the
oligomer is uniformly sized. Using analytical ultracentrifugation, measurements
of the sedimentation rate and diffusion coefficient of crm45 at pH 5.0 result in
a molecular mass determination of 890 +/- 40 kDa (20 +/- 1 subunits) for the
oligomer. Equilibrium sedimentation data on crm45 at pH 5.0 are best fit by a
single species with a mass of 1000 +/- 50 kDa (24 +/- 1 subunits). These results
reveal the pH-dependent formation of a uniformly sized, 20-24 subunit oligomer of
the C and T domains of DT, in solution. Because the oligomer of crm45 forms at
the pH of the acidified endosome, it could be relevant to the translocation of
the C domain of DT across the endosomal membrane and into the cytoplasm of host
cells. The possible relevance of this oligomer of crm45 to the membrane
translocation of the C domain of DT correlates with earlier kinetic studies of DT
intoxication of Vero cells, which inferred the transfer of approximately 20 C
domains of DT to the cytoplasm of host cells, in a single event.
PMID- 9398248
TI - Binding of steroid modulators to recombinant cytosolic domain from mouse P
glycoprotein in close proximity to the ATP site.
AB - We recently found that recombinant NBD1 cytosolic domain corresponding to segment
395-581 of mouse mdr1 P-glycoprotein bound fluorescent 2'(3')-N
methylanthraniloyl-ATP (MANT-ATP) with high affinity [Dayan, G., Baubichon
Cortay, H., Jault, J.-M., Cortay, J. -C., Deleage, G., & Di Pietro, A. (1996) J.
Biol. Chem. 271, 11652-11658]. The present work shows that a longer 371-705
domain (extended-NBD1), including tryptophan-696 as an intrinsic probe, which
bound MANT-ATP with identical affinity, also interacted with steroids known to
modulate anticancer drug efflux from P-glycoprotein-positive multidrug-resistant
cells. Progesterone, which is not transported, its hydrophobic derivatives
medroxyprogesterone acetate and megestrol acetate, and Delta6-progesterone
produced nearly a 50% saturating quenching of the domain intrinsic fluorescence,
with dissociation constants ranging from 53 to 18 microM. The even more
hydrophobic antiprogestin RU 486 produced a complete quenching of tryptophan-696
fluorescence, in contrast to more hydrophilic derivatives of progesterone
containing hydroxyl groups at positions 11, 16, 17, and 21 and known to be
transported, which produced very little quenching. A similar differential
interaction was observed with full-length purified P-glycoprotein. The steroid
binding region within extended-NBD1 appeared distinct from the nucleotide-binding
site as the RU 486-induced quenching was neither prevented nor reversed by high
ATP concentrations. In contrast, MANT-ATP binding was efficiently prevented or
displaced by RU 486, suggesting that the hydrophobic MANT group of the bound
nucleotide analogue overlaps, at least partially, the adjacent steroid-binding
region revealed by RU 486.
PMID- 9398249
TI - Nitric oxide inhibition of lipid peroxidation: kinetics of reaction with lipid
peroxyl radicals and comparison with alpha-tocopherol.
AB - The reaction between nitric oxide (*NO) and lipid peroxyl radicals (LOO*) has
been proposed to account for the potent inhibitory properties of *NO toward lipid
peroxidation processes; however, the mechanisms of this reaction, including
kinetic parameters and nature of termination products, have not been defined.
Here, the reaction between linoleate peroxyl radicals and *NO was examined using
2, 2'-azobis(2-amidinopropane) hydrochloride-dependent oxidation of linoleate.
Addition of *NO (0.5-20 microM) to peroxidizing lipid led to cessation of oxygen
uptake, which resumed at original rates when all *NO had been consumed. At high
*NO concentrations (>3 microM), the time of inhibition (Tinh) of chain
propagation became increasingly dependent on oxygen concentration, due to the
competing reaction of oxygen with *NO. Kinetic analysis revealed that a simple
radical-radical termination reaction (*NO:ROO* = 1:1) does not account for the
inhibition of lipid oxidation by *NO, and at least two molecules of *NO are
consumed per termination reaction. A mechanism is proposed whereby *NO first
reacts with LOO* (k = 2 x 10(9) M-1 s-1) to form LOONO. Following decomposition
of LOONO to LO* and *NO2, a second *NO is consumed via reaction with LO*, with
the composite rate constant for this reaction being k = 7 x 10(4) M-1 s-1. At
equal concentrations, greater inhibition of oxidation was observed with *NO than
with alpha-tocopherol. Since *NO reacts with LOO* at an almost diffusion-limited
rate, steady state concentrations of 30 nM *NO would effectively compete with
endogenous alpha-tocopherol concentrations (about 20 microM) as a scavenger of
LOO* in the lipid phase. This indicates that biological *NO concentrations (up to
2 microM) will significantly influence peroxidation reactions in vivo.
PMID- 9398250
TI - Conformational changes in aerolysin during the transition from the water-soluble
protoxin to the membrane channel.
AB - Proteolytic activation, oligomerization, and membrane insertion are three steps
that precede channel formation by the bacterial toxin aerolysin. Using attenuated
total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and hydrogen
deuterium exchange, the structural changes associated with each step were
analyzed. Our results show that activation induces a significant change in
secondary structure, characterized by a decrease in random structure and an
increase in beta-sheet content. We show that release of the propeptide is
essential for this conformational change to occur and that changes are not
restricted to the vicinity of the cleavage site but appear to propagate along the
molecule. In contrast, subsequent oligomerization of the mature toxin does not
involve any change in overall secondary structure but does involve a modification
of the tertiary interactions. Finally, insertion of the heptameric complex into
dimyristoylphosphatidylcholine vesicles also occurs without major modification of
the secondary structure. Studies on the orientations of the secondary structures
of the heptamer in the lipid bilayer have also been performed.
PMID- 9398251
TI - Effects of clusterin overexpression on TNFalpha- and TGFbeta-mediated death of
L929 cells.
AB - Clusterin is a widely distributed and highly conserved protein for which many
functions have been proposed. We used transfected L929 cells to study the effect
of clusterin expression on the regulation of cell death signals. We showed that
high levels of clusterin expression, about 0.2 pg clusterin secreted per cell per
48 h period, specifically protected L929 cells from TNFalpha-mediated
cytotoxicity, while low expression (about 4 fg/cell/48 h) had no effect. However,
clusterin expression did not provide transfected L929 cells with protection
against death mediated by colchicine, staurosporine or azide. High level
expression of clusterin in transfected L929 cells also potentiated the
cytotoxicity of TGFbeta. It had previously been shown that exposure of L929 cells
to TGFbeta provides protection against TNFalpha. We showed that this protective
effect is not additive to that of clusterin expression. One interpretation of
this data is that it suggests that clusterin and TGFbeta may act via a common
mechanism to provide protection against the cytotoxicity of TNFalpha. Our results
indicate that an intracellular action of clusterin protein is responsible for
protection against TNFalpha cytotoxicity. Exposure to TNFalpha induces an
increase in the level of cell-associated clusterin and specifically in the level
of a novel clusterin molecule, which when analyzed under reducing conditions by
SDS/PAGE and immunoblotting appears as two closely spaced bands at about 36 and
38.5 kDa. When analyzed under the same conditions, the normal form of
intracellular clusterin, which is present with or without exposure to TNFalpha,
appears as two poorly resolved bands at about 43-45 kDa. Since the novel form of
clusterin is also expressed in cells exposed to TGFbeta, colchicine,
staurosporine, and azide, it may result from toxin-induced disruption of
processes of normal cellular protein production.
PMID- 9398252
TI - Photoassembly of the photosystem II (Mn)4 cluster in site-directed mutants
impaired in the binding of the manganese-stabilizing protein.
AB - Photoactivation is the light-dependent ligation of Mn2+ into the H2O oxidation
complex of photosystem II (PSII) and culminates in the formation of an
enzymatically active complex containing Ca2+ and four Mn>/=3+. Previous kinetic
analysis demonstrated that the genetic removal of the extrinsic manganese
stabilizing protein (MSP) increases the quantum yield of photoactivation 4-fold
relative to that of the wild type, consistent with the hypothesis that MSP
hinders access of Mn2+ to a site of photoligation [Burnap, R. L., et al. (1996)
Biochemistry35, 874-882]. In this report, several Synechocystis sp. PCC6803
mutants with defined amino acid substitutions in the N-terminal region of MSP or
the e-loop of intrinsic PSII protein CP47 [Putnam-Evans, C., et al. (1996)
Biochemistry 35, 4046-4053] were characterized in terms of the binding of MSP to
the intrinsic portion of the PSII complex and in terms of photoactivation
kinetics. The charge-pair switch mutation, Arg384Arg385 --> Glu384Glu385 in the
lumenal e-loop of CP47 (CP47 RR384385EE), exhibited the most severe impairment of
MSP binding, whereas the Arg384Arg385 --> Gly384Gly385 (CP47 RR384385GG) mutation
caused a more moderate impairment in binding. Single-substitution mutations at
the highly conserved Asp9 or Asp10 positions in the amino-terminal region of MSP
also resulted in a reduced binding affinity, but not as severe as that in CP47
RR384385EE. The relative quantum yield of photoactivation of hydroxylamine
extracted mutant PSII was generally found to correlate with the degree of MSP
binding impairment, with the CP47 RR384385 mutants exhibiting the highest quantum
yields. A two-locus, double-mutant construct involving deletion of MSP in the
CP47 RR384385EE background was found to be only slightly more impaired in H2O
oxidation activity than either of the corresponding single-locus mutant
derivatives, indicating that mutations at these genetically separate loci encode
physically interacting products affecting the same reaction parameter during H2O
oxidation. Taken together, the results reinforce the concept that MSP interacts
with the e-loop of CP47 at Arg384Arg385 and that disruption of this interaction
causes significant alterations of the site of H2O oxidation in terms of assembly
and enzymatic activity of the Mn cluster.
PMID- 9398253
TI - Design of fluorescent substrates and potent inhibitors of CYP73As, P450s that
catalyze 4-hydroxylation of cinnamic acid in higher plants.
AB - CYP73As are the major functional cytochromes P450 in higher plants. Several of
them have been shown to catalyze the 4-hydroxylation of cinnamic acid, the first
oxidative step in the synthesis of lignin, flavonoids, coumarins, and other
phenylpropanoids. The coding sequence for CYP73A1, the enzyme from Helianthus
tuberosus, has been isolated and expressed in yeast. Previous studies indicate
that the yeast-expressed enzyme is capable of metabolizing cinnamic acid and
several small, planar molecules but with low efficiency. Using this we further
examined how CYP73A1 could bind and metabolize a set of possible alternate
substrates. We show here that naphthalenes, quinolines, and indoles substituted
with an aldehyde, a carboxylic, or a sulfonic acid group make good ligands and
substrates for CYP73A1. The best ligands are hydroxynaphthoic acids, which show
higher affinity than cinnamate. Naphthalene, 2-naphthol, and molecules with two
carbon side chains, such as natural and synthetic auxins, are not substrates of
this enzyme. Methyl-2-naphthoate and 2-hydroxy-1-naphthoic acid are strong
ligands of CYP73A1 but are not metabolized. Uncoupling and low spin conversion
induced by these compounds suggest that their positioning in the heme pocket is
inadequate for catalysis. These compounds can act as potent inhibitors of the
second step of the phenylpropanoid pathway, the first described so far. The
molecule which most closely mimics cinnamic acid, 2-naphthoic acid, is
metabolized with a catalytic turnover and efficiency similar to those measured
with the physiological substrate. Using this compound we designed a fluorometric
assay to measure the catalytic activity of CYP73As. This assay was then used to
monitor the CYP73As activity in microsomes from transgenic yeast and several
plant species.
PMID- 9398254
TI - Energy transfer in LHCII monomers at 77K studied by sub-picosecond transient
absorption spectroscopy.
AB - Energy transfer from chlorophyll b (Chl b) to chlorophyll a (Chl a) in monomeric
preparations of light-harvesting complex II (LHCII) from spinach was studied at
77 K using pump-probe experiments. Sub-picosecond excitation pulses centered at
650 nm were used to excite preferentially Chl b and difference absorption spectra
were detected from 630 to 700 nm. Two distinct Chl b to Chl a transfer times,
approximately 200 fs and 3 ps, were found. A clearly distinguishable energy
transfer process between Chl a molecules occurred with a time constant of 18 ps.
The LHCII monomer data are compared to previously obtained LHCII trimer data, and
both data sets are fitted simultaneously using a global analysis fitting routine.
Both sets could be described with the following time constants: 140 fs, 600 fs, 8
ps, 20 ps, and 2.9 ns. In both monomers and trimers 50% of the Chl b to Chl a
transfer is ultrafast (<200 fs). However, for monomers this transfer occurs to
Chl a molecules that absorb significantly more toward shorter wavelengths than
for trimers. Part of the transfer from Chl b to Chl a that occurs with a time
constant of 600 fs in trimers is slowed down to several picoseconds in monomers.
However, it is argued that observed differences between monomers and trimers
should be ascribed to the loss of some Chl a upon monomerization or a shift of
the absorption maximum of one or several Chl a molecules. It is concluded that
Chl b to Chl a transfer occurs only within monomeric subunits of the trimers and
not between different subunits.
PMID- 9398255
TI - Conformation-activated protonation in reaction centers of the photosynthetic
bacterium Rhodobacter sphaeroides.
AB - Kinetics and stoichiometry of proton binding/unbinding induced by intense (1 W cm
2) and continuous illumination were measured in the isolated reaction center (RC)
protein from photosynthetic purple bacterium Rhodobacter sphaeroides in the
absence of an external electron donor. At high ionic strength (100 mM), large
proton release (approximately 6 H+ per RC) was observed at pH 6 and
substoichiometric H+-ion binding (approximately 0.3 H+ per RC) at pH 8. These
observations together with optical spectroscopy on the oxidized dimer indicate
that, at room temperature, two distinct conformations of the RC can be obtained
depending on the pH, Eh, and illumination. Acidic pH, a large redox gap between
the actual Eh of the solution and the midpoint potential of the acceptor quinone,
and strong illumination favor the conversion of the RC from the dark-adapted
state to the light-adapted state. These conformations differ greatly in the rates
of primary photochemistry, the reoxidation of semiquinone and the rereduction of
the oxidized dimer, and the protonation states of the amino acids of the protein.
Whereas substoichiometric proton unbinding is observed in the P+Q redox state of
the protein in the dark-adapted conformation, much larger H+-ion release is
detected in the light-adapted conformation. From the pH dependence of the key
processes in the conformational change and reoxidation of semiquinone, we
concluded that they are controlled by protonatable groups available in the
protein. A simple phenomenological model is presented that relates the rates and
equilibrium constants of the electron transfer reactions and the conformational
change of the RC.
PMID- 9398256
TI - Involvement of the reductase domain of neuronal nitric oxide synthase in
superoxide anion production.
AB - Neuronal nitric oxide synthase (nNOS) is a modular enzyme which consists of a
flavin-containing reductase domain and a heme-containing oxygenase domain, linked
by a stretch of amino acids which contains a calmodulin (CaM) binding site. CaM
binding to nNOS facilitates the transfer of NADPH-derived electrons from the
reductase domain to the oxygenase domain, resulting in the conversion of L
arginine to L-citrulline with the concomitant formation of a guanylate cyclase
activating factor, putatively nitric oxide. Numerous studies have established
that peroxynitrite-derived nitrogen oxides are present following nNOS turnover.
Since peroxynitrite is formed by the diffusion-limited reaction between the two
radical species, nitric oxide and O2.-, we employed the adrenochrome assay to
examine whether nNOS was capable of producing O2.- during catalytic turnover in
the presence of L-arginine. To differentiate between the role played by the
reductase domain and that of the oxygenase domain in O2.- production, we compared
its production by nNOS against that of a nNOS mutant (CYS-331), which was unable
to transfer NADPH-derived electrons efficiently to the heme iron under special
conditions, and against that of a flavoprotein module construct of nNOS. We
report that O2.- production by nNOS and the CYS-331 mutant is CaM-dependent and
that O2.- production can be modulated by substrates and inhibitors of nNOS. O2.-
was also produced by the reductase domain of nNOS; however, it did not display
the same CaM dependency. We conclude that both the reductase and oxygenase
domains of nNOS produce O2.-, but that the reductase domain is both necessary and
sufficient for O2.- production.
PMID- 9398257
TI - Cross-linking and N-(1-pyrenyl)maleimide labeling of cysteine mutants of proton
pumping pyridine nucleotide transhydrogenase of Escherichia coli.
AB - The pyridine nucleotide transhydrogenase of Escherichiacoli is a proton pump
composed of two subunits (alpha and beta) organized as an alpha2beta2 tetramer.
The enzyme contains seven cysteine residues, five in the alpha-subunit and two in
the beta-subunit. The reaction of these residues with the cross-linking agent
cupric 1, 10-phenanthrolinate and with the fluorescent thiol reagent N-(1
pyrenyl)maleimide was investigated in mutants in which one or more of these
cysteine residues had been mutated to serine or threonine residues. Mutation of
alphaCys395 and alphaCys397 prevented disulfide bond formation to give the cross
linked alpha2 dimer. We concluded that the two alpha-subunits of the holoenzyme
interface in the region of these two cysteine residues. Pyrenylmaleimide reacted
with detergent-washed cytoplasmic membrane vesicles containing high levels of
transhydrogenase protein to show characteristic fluorescence emission bands at
378-379, 397-398, and 419-420 nm. At higher ratios of
pyrenylmaleimide:transhydrogenase (>5:1) and longer times of reaction, an eximer
band at 470 nm was formed. This was attributed to interaction between
noncovalently bound molecules of pyrenylmaleimide. The cysteine residues of the
beta-subunit (betaCys147 and betaCys260) were covalently modified by
pyrenylmaleimide. betaCys147 reacted more strongly than betaCys260 with the
fluorophore, and the pyrene derivative of betaCys147 was more accessible to
quenching by 5-doxylstearate, suggesting a proximity to the surface of the
membrane. Covalent modification of betaCys260 resulted in inhibition of enzyme
activity. The inhibition was attributed to the introduction of the bulky pyrene
group into the enzyme.
PMID- 9398258
TI - Charge recombination and proton transfer in manganese-depleted photosystem II.
AB - The proton transfer reactions induced by the oxidation and reduction of the
secondary donor, tyrosine YZ, have been studied in photosystem II after
inactivation (Mn-depletion) of the oxygen-evolving complex. The rate of the
recombination reaction of YZox with the reduced primary acceptor QA- appears
modulated by a protonatable group with pK approximately 6 in the presence of
YZox. The finding of monophasic recombination kinetics requires that the proton
equilibration of this group is faster than the recombination rate. The same group
modulates the extent of proton release, from 0 below pH 5 to 1 per center above
pH 7. The kinetics of proton appearance and disappearance in the bulk medium are
markedly dependent on the material used. In PSII core particles, the release is
observed in the 100 micros range and the uptake accompanies the recombination
reaction. In PSII membranes, both of these reactions are markedly delayed, so
that the uptake considerably lags behind the completion of the recombination
reaction. An electrochromic shift of a chlorophyll is present during the whole
lifetime of YZox, suggesting a charged character of this species. A fast
decreasing phase of this signal was observed in particles in the same time range
as proton release. These results are discussed in the framework of a model where
the proton originating from the formation of the neutral oxidized tyrosine
radical (YZ.) remains locally trapped. In turn, this proton shifts the pK of a
nearby group from a value >/=9 to a value of 6.
PMID- 9398259
TI - A Pneumocystis carinii group I intron ribozyme that does not require 2' OH groups
on its 5' exon mimic for binding to the catalytic core.
AB - The recent increase in the population of immunocompromised patients has led to an
insurgence of opportunistic human fungal infections. The lack of effective
treatments against some of these pathogens makes it important to develop new
therapeutic strategies. One such strategy is to target key RNAs with antisense
compounds. We report the development of a model system for studying the potential
for antisense targeting of group I self-splicing introns in fungal pathogens. The
group I intron from the large ribosomal subunit RNA of mouse-derived Pneumocystis
carinii has been isolated and characterized. This intron self-splices in vitro. A
catalytically active ribozyme, P-8/4x, has been constructed from this intron to
allow measurement of dissociation constants for potential antisense agents. At 37
degrees C, in 50 mM Hepes (25 mM Na+), 15 mM MgCl2, and 135 mM KCl at pH 7.5, the
exogenous 5' exon mimic r(AUGACU) binds about 60 000 times more tightly to this
ribozyme than to r(GGUCAU), a mimic of its complementary binding site on the
ribozyme. This enhanced binding is due to tertiary interactions. This tertiary
stabilization is increased by single deoxynucleotide substitutions in the exon
mimic at every position except for the internal A, which is essentially
unchanged. Thus 2' OH groups of the 5' exon mimic do not form stabilizing
tertiary interactions with the P-8/4x ribozyme, in contrast to the Tetrahymena L
21 ScaI ribozyme. Furthermore, at 37 degrees C, the exogenous 5' exon mimic
d(ATGACT) binds nearly 32 000 times more tightly to the P-8/4x ribozyme than to
r(GGUCAU). Therefore, oligonucleotides without 2' OH groups can exploit tertiary
stabilization to bind dramatically more tightly and with more specificity than
possible from base pairing. These results suggest a new paradigm for antisense
targeting: targeting the tertiary interactions of structural RNAs with short
antisense oligonucleotides.
PMID- 9398260
TI - A new type of DNA minor-groove complex: carbazole dication-DNA interactions.
AB - The effect of opportunistic infections (OI) on immune-compromised populations has
been known for decades, but the recent AIDS epidemic has sparked renewed interest
in the development of new anti-OI agents. The mechanism of action of a series of
cationic unfused-aromatic anti-OI drugs is believed to involve binding of the
drug to AT sequences in the minor groove of DNA. Some new anti-OI drug candidates
have been synthesized with fused aromatic ring systems (e.g. carbazoles) that do
not resemble the classical paradigm for minor-groove interactions at AT sequences
in DNA. To characterize the DNA interactions of these compounds, we have used UV
vis absorbance, fluorescence, kinetic measurements, and circular dichroism in
conjunction with NMR spectroscopy to evaluate the structure of the complexes
formed between the carbazoles and DNA. Application of these methods to carbazoles
substituted at either the 3,6 or 2,7 positions with cationic imidazoline groups
gave conclusive, but very surprising, evidence that both compounds bind strongly
in the minor groove at AT DNA sequences. NMR and molecular modeling of the
complexes formed between the 3,6- and 2,7-carbazoles and the self-complementary
oligomer d(GCGAATTCGC) have been used to establish structural details for the
minor-groove complex. These results have been used as constraints for molecular
modeling calculations to construct models of the minor-groove-carbazole complexes
and to draw conclusions regarding the molecular basis for the effects of
substituent position on carbazole-DNA affinities. The surprising result is that
the 2,7 carbazole binds in AT sequences with hydrogen bonds involving one
imidazoline group and the carbazole NH. The 3,6-carbazole compound binds in a
more "classical" model that uses both imidazoline groups for H-bonding while the
carbazole NH points out of the minor groove. The carbazoles thus form a new type
of DNA minor groove complex and their excellent biological activities indicate
that a variety of fused-ring minor-groove binding agents should be investigated.
PMID- 9398261
TI - The relative stabilities of base pair stacking interactions and single mismatches
in long RNA measured by temperature gradient gel electrophoresis.
AB - The thermal stability of RNA duplexes differing by a single base pair (bp)
substitution or mismatch were investigated by temperature gradient gel
electrophoresis (TGGE). All base pair substitutions and mismatches were examined
at six sites, and limited changes were investigated at three other sites. DNA
templates for in vitro transcription were generated by the polymerase chain
reaction (PCR). Transcribed forward and reverse single stranded RNAs were
annealed to form 345 bp dupex RNA. Solution melting curves of selected RNAs were
in good agreement with the predicted three step transitions. Parallel TGGE was
used to determine the relative stabilities of the RNAs, and perpendicular TGGE
was employed to obtain mobility transitions and midpoint transition temperatures
(Tmu) of the RNAs' first melting domain. The gel solvent included formamide and
urea. The Tmu values of the first melting domain were influenced by the identity
of the base pair substitution or mismatch as well as by the site's neighboring
base pairs. The difference in the transition temperatures (deltaTmu) between
pairs of RNA ranged from 0 to 5 degrees C. deltaTmu values were used to determine
free energy differences (deltaDeltaG). For RNA pairs distinguished by a base pair
substitution, the deltaDeltaG values were closely correlated with free energy
differences calculated from stacking free energies determined from melting
studies in 1 M Na+ [Serra, M. J., and Turner, D. H. (1995) Methods Enzymol. 259,
242-261.] An algorithm was developed using the free energies of terminal
mismatches [Serra, M. J., and Turner, D. H. (1995) Methods Enzymol. 259, 242-261]
that provided very good agreement with experimental free energies for the single
internal mismatches.
PMID- 9398262
TI - Kinetics of DNA polymerase I (Klenow fragment exo-) activity on damaged DNA
templates: effect of proximal and distal template damage on DNA synthesis.
AB - Mutagenic DNA adducts have been analyzed with respect to the rate of nucleotide
insertion opposite the modified base, extension from that "mispair", and
nucleotide insertion preference. To complement and extend these studies we have
investigated the long-range effects of DNA adducts on DNA polymerase activity. To
address this question, primer extension reactions were performed using DNA
polymerase I, Klenow fragment exo-. Templates containing 7,8-dihydro-8
oxoguanine, dG-C8-aminofluorene, dG-C8-(acetylamino)fluorene, and the model
abasic site, tetrahydrofuran, were used for these studies, and the steady-state
kinetics of correct nucleotide insertion were determined at positions (-2), (-1),
(+1), (+2), (+3), and (+5) with respect to the template lesion. The kinetics of
primer extension by Klenow fragment exo- at template positions 3' to the lesion
showed only a small inhibitory effect, <3-fold, even for the strongly blocking
lesion, dG-C8-(acetylamino)fluorene, indicating that Klenow fragment exo-
activity is not greatly affected by lesions in the single-stranded portion of the
template-primer. In contrast, a dramatic decrease in the frequency of primer
extension was observed at template sites 5' to the site of adduction. Inhibition
of polymerase activity decreased as the distance from the lesion increased;
however, a relatively large effect was seen at the (+2) and (+3) positions for dG
C8-(acetylamino)fluorene and tetrahydrofuran. For these blocking lesions, the
effect on extension 5 bases from the lesion was greatly reduced. We conclude from
these studies that DNA damage at positions remote from the site of the lesion
affects DNA polymerase function.
PMID- 9398263
TI - The cyanobacterial repressor SmtB is predominantly a dimer and binds two Zn2+
ions per subunit.
AB - The Synechococcus PCC7942 metallothionein repressor gene smtB has been cloned
into a high expression vector and the protein purified to near homogeneity
(>/=98%). Analytical ultracentrifugation studies demonstrate that the protein is
predominantly dimeric in 0.1 M NaCl, pH 7.4, and 22 degrees C, exhibiting a
monomer-dimer-tetramer equilibrium. The monomer-dimer (Ka(1,2)) and the dimer
tetramer (Ka(2,4)) association constants are 3.24 x 10(5) and 9.90 x 10(2) M-1,
respectively. The repressor binds two Zn2+ ions per subunit with an overall Kd of
3.49 x 10(-6) M. In the presence of Zn2+, Ka(1, 2) increases by 2 orders of
magnitude to 1.25 x 10(7) M-1 and the apparent weight-averaged sedimentation
coefficient increases from 2. 00 to 2.22 S. The fact that the increase in
sedimentation coefficient is greater than that predicted by increased
dimerization is interpreted as caused by compaction of the structure in the
presence of metal ions. At pH 6.0, 0.1 M NaCl, and 22 degrees C, the protein
exhibits only a monomer-dimer equilibrium, with Ka(1,2) = 1.52 x 10(7) M-1 which
is almost identical to that seen upon binding Zn2+ at pH 7.4. The compaction and
conformational change in SmtB caused by Zn2+ is consistent with a role for this
altered quaternary state in derepression of smtA in Synechococcus challenged with
heavy metal ions.
PMID- 9398264
TI - Mechanism of DNA binding enhancement by hepatitis B virus protein pX.
AB - At least three hundred million people worldwide are infected with the hepatitis B
virus (HBV), and epidemiological studies show a clear correlation between chronic
HBV infection and the development of hepatocellular carcinoma. HBV encodes a
protein, pX, which abducts the cellular transcriptional machinery in several ways
including direct interactions with bZIP transcription factors. These interactions
increase the DNA affinities of target bZIP proteins in a DNA sequence-dependent
manner. Here we use a series of bZIP peptide models to explore the mechanism by
which pX interacts with bZIP proteins. Our results suggest that pX increases
bZIP.DNA stability by increasing the stability of the bZIP dimer as well as the
affinity of the dimer for DNA. Additional experiments provide evidence for a
mechanism in which pX recognizes the composite structure of the peptide.DNA
complex, not simply the primary peptide sequence. These experiments provide a
framework for understanding how pX alters the patterns of transcription within
the nucleus. The similarities between the mechanism proposed for pX and the
mechanism previously proposed for the human T-cell leukemia virus protein Tax are
discussed.
PMID- 9398265
TI - Biochemical and mutational investigations of the enzymatic activity of macrophage
migration inhibitory factor.
AB - The protein mediator MIF has been identified as being released from immune cells
by glucocorticoid stimulation and to counter-regulate glucocorticoid action. MIF
also has been described recently to exhibit dopachrome tautomerase activity and
to be structurally homologous to the bacterial enzymes 4-oxalocrotonate
tautomerase (4-OT) and 5-carboxymethyl-2-hydroxymuconate isomerase (CHMI). We
performed site-directed mutagenesis and biochemical analyses of mouse MIF in
order to identify amino acid residues and protein domains that are essential for
enzymatic reactivity. Mutant proteins which lacked a free N-terminal proline
residue were enzymatically inactive, as was a preparation of native MIF modified
covalently at its N terminus by 3-bromopyruvate, suggesting that this proline has
a catalytic function. Substitutions of the internal histidine residues 42 and 63
did not affect enzymatic activity, indicating that these basic residues are not
involved in dopachrome tautomerization. Carboxy-truncated forms of MIF (residues
1-110 and 1-104) also were inactive, affirming the role of the carboxy terminus
in stable trimer formation and the importance of the trimer for enzymatic
activity. Additional evidence for the homotrimeric structure of MIF under native
solution conditions was obtained by SDS-PAGE analysis of MIF after chemical cross
linking at low protein concentrations. The enzymatic activity of MIF was found to
be reversibly inhibited by micromolar concentrations of fatty acids with chain
lengths of at least 16 carbon atoms. Of note, molecular modeling of the substrate
L-dopachrome methyl ester into the active site of MIF suggests an acid-catalyzed
enzymatic mechanism that is different from that deduced from studies of the
enzymes 4-OT and CHMI. Finally, in vitro analysis of an enzymatically inactive
MIF species (P2 --> S) indicates that the glucocorticoid counter-regulatory
activity of MIF can be functionally dissociated from its tautomerization
activity.
PMID- 9398266
TI - Activation of the 43 kDa inositol polyphosphate 5-phosphatase by 14-3-3zeta.
AB - The 43 kDa inositol polyphosphate 5-phosphatase (5-phosphatase) hydrolyzes and
thereby inactivates the second messenger molecules inositol 1,4,5-trisphosphate
Ins(1,4,5)P3- and inositol 1,3,4,5-tetrakisphosphate in a signal terminating
reaction. Recent studies have shown that the platelet protein pleckstrin forms a
complex with the 43 kDa 5-phosphatase and activates Ins(1,4,5)P3 hydrolysis 2
fold [Auethavekiat, V., Abrams, C. S., & Majerus, P. W. (1997) J. Biol. Chem.
272, 1786-1790]. We now show that another platelet protein, 14-3-3zeta, forms a
complex with the 43 kDa 5-phosphatase and thereby activates the hydrolysis of
Ins(1,4,5)P3. Both pleckstrin and 14-3-3zeta contain one or more pleckstrin
homology domains, both are present in platelet cytosol, and both dimerize and
form complexes with other signalling proteins. Purified platelet pleckstrin and
14-3-3zeta enhanced the rate of the hydrolysis of Ins(1,4,5)P3 by the 43 kDa 5
phosphatase 1.9- and 3.8-fold, respectively, but did not activate the 75 kDa 5
phosphatase. We have demonstrated that the mechanism of 5-phosphatase activation
by 14-3-3zeta results from specific complex formation between the 43 kDa 5
phosphatase and 14-3-3zeta. Recombinant 43 kDa 5-phosphatase bound to recombinant
glutathione S-transferase (GST)/14-3-3zeta fusion protein, but not GST alone,
immobilized on glutathione-Sepharose. A potential 14-3-3 binding motif was
located in the 43 kDa, but not the 75 kDa, 5-phosphatase. The motif "363RSESEE"
is present in close proximity to the proposed catalytic domain of the 43 kDa 5
phosphatase. A synthetic peptide corresponding to the putative 14-3-3 binding
motif demonstrated specific, saturable binding to purified 125I-14-3-3, with a Kd
of 92 nM. In addition, platelet cytosolic 5-phosphatase bound to recombinant 14-3
3zeta immobilized on glutathione-Sepharose. Thus, 14-3-3zeta serves in human
platelets to activate the 43 kDa 5-phosphatase and may thereby function to
prevent generation of Ins(1,4,5)P3 -mediated calcium release in unstimulated
platelets.
PMID- 9398267
TI - Cloning and characterization of cDNAs encoding chicken mitogen-activated protein
kinase kinase type 2, MEK2: downregulation of MEK2 in response to inhibition of
mitochondrial DNA expression.
AB - The present work was initiated with the aim of identifying nuclear genes whose
expression is sensitive to the mitochondrial DNA (mtDNA) status of transformed
chicken DU24 cells. We cloned and sequenced cDNAs for the mitogen-activated
protein kinase kinase type 2, MEK2, a protein involved in the mitogenic growth
factor signal transduction pathway in vertebrates. Sequence comparisons between
the chicken protein and its mammalian counterparts indicated that MEK2 proteins
are highly conserved among vertebrates. Southern blot analysis of endonuclease
digested genomic DNA from primary chick embryo fibroblasts (CEF) suggested that
MEK2 is a single-copy gene in this vertebrate species. The steady-state level of
MEK2 transcripts is decreased in DUS3 mtDNA-less (rho0) cells developed by long
term exposure of DU24 rho+ cells to ethidium bromide (EtdBr). Run-on in vitro
transcription assays and mRNA stability studies indicated that the decrease in
MEK2 mRNA content is associated with post-transcriptional regulation. In parental
DU24 cells, MEK2 mRNA content decreased after inhibition of mtDNA transcription
by EtdBr and inhibition of translation on mitoribosomes by chloramphenicol (CAM).
Cytoplasmic hybrids (cybrids) constructed by fusion of chicken rho0 cells with
enucleated parental cells and CEF recovered a basal level of MEK2 expression. The
MEK2 protein content is decreased in DUS3 rho0 cells and in parental DU24 rho+
cells treated with EtdBr and CAM for 6 days, while that of MEK1, a closely
related kinase, remained unchanged. On the basis of these observations, we
propose that mitochondria participate in the mitogenic signal transduction
pathway in chicken cells through regulation of MEK2 expression.
PMID- 9398268
TI - Demonstration of an extracellular ATP-binding site in NCAM: functional
implications of nucleotide binding.
AB - A minor fraction of the total ecto-type (E-type) ATPase activity of rat
synaptosomes has been detected in immunoprecipitates of the neural cell adhesion
molecule, NCAM, indicating that this either is an intrinsic enzymatic activity of
NCAM or of an ATPase tightly associated to NCAM [Dzhandzhugazyan & Bock (1993)
FEBS Lett. 336, 279-283]. We here demonstrate ATPase activity in preparations of
the lipid-anchored as well as the transmembrane NCAM isoforms immunoisolated from
transfected L-cells. A fraction of the E-type ATPase activity is spontaneously
released from synaptosomes. Released material was fractionated by various
chromatographic procedures and an extracellular fragment of NCAM was shown to co
elute with the major part of the enzymatic activity. Furthermore, it was shown
that agarose-coupled NCAM-antibodies retained 85% of the ATPase activity released
from synaptosomes after treatment with phosphatidylinositol-specific
phospholipase C. These findings restricted the association or expression of the
enzymatic activity to the extracellular part of NCAM. An affinity reagent, 5'-p
fluorosulfonylbenzoyl adenosine, FSBA, was shown to inhibit ATPase activity of
immunoisolated NCAM, and incorporation of FSBA was detected in all three major
NCAM isoforms (A, B, and C). An excess of ATP prevented both inactivation of the
enzyme and affinity labeling of NCAM. Thus, NCAM contains an ATP-binding site,
and this site is localized extracellularly and probably has the catalytic
function. Binding of the substrate or FSBA protected a proteolytic cleavage site
in NCAM localized close to the membrane presumably by induction of a local
conformational change in NCAM, indicating a mechanism by which ATP may regulate
NCAM adhesion and adhesion-triggered processes. A possible role of this mechanism
in synaptic plasticity and memory consolidation is proposed.
PMID- 9398269
TI - Mutations in the transmembrane domain of APP altering gamma-secretase
specificity.
AB - Alzheimer's disease (AD) beta-amyloid peptide (Abeta and betaA4) is derived from
the amyloid precursor protein (APP) by the subsequent action of the so-far
unidentified beta- and gamma-secretases. gamma-secretase, which generates the C
terminus of Abeta, cleaves within the transmembrane domain of APP, preferentially
after Abeta-residue 40 (Abeta 40) but also after residue 42 (Abeta 42). This
Abeta 42 represents the major subunit of the plaques in AD. Since the position of
gamma-secretase cleavage is crucial for understanding the pathogenic pathway, we
investigated the effect of different point mutations at Thr43 on gamma-secretase
specificity in SPA4CT (SPC99)-expressing COS7 cells. These constructs only
require gamma-cleavage for Abeta release. We observed that all Thr43 mutations
altered the specificity of gamma-secretase. Small hydrophobic residues favored
the generation of Abeta 42, leading to an increase in the 42/40 ratio of Abeta
(1.6-2.8-fold). The increase was even stronger (5.6-5.8-fold) when combined with
the familial mutation Val46Phe. Thus, these constructs might be highly valuable
for the generation of animal models for AD. Processing of full-length APP or
SPA4CT yielded the same 42/40 ratio of Abeta (4. 7%). Both constructs, bearing
the familial AD mutation Val46Phe, led to a similar increase in the 42/40 ratio
(3.3- versus 3.6-fold). The p3 fragment, produced by alpha- and gamma-secretase,
showed 42/40 ratios similar to Abeta when derived from wild-type and mutant
proteins. These results suggest that the different Abeta- and p3-species are
generated by gamma-cleavage activities with a similar enzymatic mechanism.
PMID- 9398270
TI - An all-D amino acid peptide model of alpha1(IV)531-543 from type IV collagen
binds the alpha3beta1 integrin and mediates tumor cell adhesion, spreading, and
motility.
AB - Type IV collagen promotes integrin-mediated cell adhesion, spreading, and
motility. Several regions within the triple-helical domain of type IV collagen
have been identified as tumor cellular recognition sites. Among these regions,
the alpha1(IV)531-543 sequence, designated L-Hep-III, promotes integrin-mediated
tumor cell adhesion and directly binds to the alpha3beta1 integrin [Miles, A. J.,
et al. (1994) J. Biol. Chem. 269, 30939-30945; Miles, A. J., et al. (1995) J.
Biol. Chem. 270, 29047-29050]. We have presently compared the activities of the
all-d enantiomeric peptide model of alpha1(IV)531-543, designated D-Hep-III, with
L-Hep-III, for promoting the adhesion, spreading, and motility of metastatic
melanoma and breast carcinoma cells. D-Hep-III was found to support melanoma and
breast carcinoma cell adhesion, spreading, and motility in a dose-dependent
fashion similar to that of L-Hep-III. The adhesions of melanoma and breast
carcinoma cells to both type IV collagen and fibronectin were effectively
inhibited by L-Hep-III and D-Hep-III. Melanoma cell invasion of the basement
membrane was also inhibited by D-Hep-III. Characterization of the cell surface
receptor for D-Hep-III was acheived via cell adhesion assays and affinity
chromatography using monoclonal antibodies against integrin subunits.
Immunoprecipitation analysis following EDTA elution from a D-Hep-III affinity
column indicated that D-Hep-III binds to the alpha3beta1 integrin but not to the
alpha2 or alpha6 integrin subunits. In summary, these studies demonstrate that an
all-D model of the alpha1(IV)531-543 sequence mimics the biological activities of
the all-L peptide. D-Hep-III is the first all-D peptide that has been shown to
promote tumor cell adhesion, spreading, and migration, inhibit tumor cell
adhesion and migration on type IV collagen and invasion of the basement membrane,
and bind directly to an integrin. Due to the resistance to proteolysis, all-D
receptor-binding peptides such as D-Hep-III have great potential for in vivo
studies and as therapeutic agents.
PMID- 9398271
TI - Evidence for a common active site for cleavage of an AP site and the benzene
derived exocyclic adduct, 3,N4-benzetheno-dC, in the major human AP endonuclease.
AB - We have previously reported that the 3,N4-benzetheno-dC (p-BQ-dC) endonuclease
activity found in HeLa cells is a novel function of the major human AP
endonuclease (HAP1) [Hang et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 13737
13741]. In this study, we compare the enzymatic and biochemical properties of the
enzyme toward p-BQ-dC and an AP site in a defined oligonucleotide. A comparative
analysis of the specificity constants (Kcat./Km) for p-BQ-dC and an AP site
indicates that the AP site is the preferred substrate. The enzyme does not cleave
other structurally related exocyclic adducts and modified nucleosides such as
1,N6-etheno-dA, 3,N4-etheno-dC, 1, N2-etheno-dG, 1,N2-propano-dG, 8-oxo-dG, and
thymine glycol. The p-BQ-dC activity requires a double-stranded DNA substrate and
is affected by the base in the opposite strand, with maximal activity for a p-BQ
dC.G pair and minimal activity for a p-BQ-dC.C pair. The p-BQ-dC activity also
requires Mg2+, Mn2+, or Zn2+ with optimal concentration spectra similar to those
for the AP function. The optimal pH ranges for these two functions are also
similar to each other (5.5-6.5). Six mutant HAP1 proteins containing single amino
acid substitutions were assayed in parallel for comparison of their activities
toward p-BQ-dC and the AP site. These mutants either concomitantly lost (N212A,
D210N) or had reduced (D219A, E96A, and N212Q) or unchanged (H116N) p-BQ-dC and
AP activities. This parallelism strongly supports the hypothesis that cleavage of
p-BQ-dC requires the same catalytic active site as that proposed for the AP
function. This dual activity toward two structurally unrelated substrates, an AP
site and a bulky exocyclic adduct, has implications for substrate recognition.
The AP site and p-BQ-dC cause different changes in the local conformation around
the lesion as it is visualized by molecular modeling.
PMID- 9398272
TI - Time-resolved fluorescence of O-acetylserine sulfhydrylase catalytic
intermediates.
AB - The reaction of the substrate O-acetyl-L-serine (OAS) with the pyridoxal 5'
phosphate (PLP)-dependent enzyme O-acetylserine sulfhydrylase-A (OASS-A) proceeds
via the transient formation of an external aldimine absorbing at 420 nm and a
stable alpha-aminoacrylate intermediate absorbing at 330 and 465 nm. Stable
external aldimine species are obtained by reaction of the enzyme with either the
reaction product L-cysteine or the product analog L-serine. Static and time
resolved fluorescence emission properties of the coenzyme in the above catalytic
intermediates have been used to directly probe the active site conformation at
different stages of the catalytic pathway. Upon excitation at either 420 or 330
nm, the external aldimines with L-cysteine and L-serine exhibit a structured
emission centered at 490 nm with a shoulder at 530 nm. Fluorescence decays upon
excitation at 420 nm are best fitted using two components with lifetimes of 1.1
and 3.8 ns, with the fractional intensity of the slow component being 0.92 with L
cysteine and 0.75 with L-serine, respectively. The fast component, emitting at
530 nm, is attributed to a dipolar species formed in the excited state by proton
dissociation, and the slow component, emitting at 490 nm, is attributed to a
ketoenamine tautomer of the external aldimine. The slow component for external
aldimine fluorescence decay is characterized by the same lifetime value as that
of the internal aldimine with an increased fractional intensity, indicating that
the distribution between the ketoenamine and the dipolar species is shifted
toward the ketoenamine tautomer in the external aldimine, compared to the
internal aldimine. Differences in equilibrium distribution of ketoenamine and
enolimine tautomers can also account for differences in the emission properties
of the external aldimines of L-cysteine and L-serine. The alpha-aminoacrylate
species is characterized by a relatively weak emission. Upon excitation at 330
nm, the emission exhibits two bands centered at 420 and 540 nm, whereas upon
excitation at 420 nm the emission bands are centered at 500 and 540 nm, and upon
excitation at 465 nm, the main absorbance peak of the alpha-aminoacrylate
species, the emission spectrum shows a band at 540 nm. The fluorescence decays,
upon excitation at 330 nm, are best fitted using three components with lifetime
values similar to those found for the internal aldimine, with the slow component
predominating. Species-associated spectra, collected between 400 and 520 nm upon
excitation at 350 nm, indicate the presence of a fast component overlapping the
slow component on the blue side of the emission spectrum, as detected for the
internal aldimine. When the excitation wavelength is 420 nm, there are only two
components with the fast one predominating. A further increase in the fractional
intensity of the fast component is observed upon excitation at 465 nm. The weak
emission and the short lifetime of the emission excited at 465 nm indicate that
this alpha-aminoacrylate tautomer interacts significantly with neighboring groups
of the protein matrix and may be endowed with a higher mobility than the external
aldimine.
PMID- 9398273
TI - Allosteric interactions between DNA strands and monovalent cations in DNA
quadruplex assembly: thermodynamic evidence for three linked association
pathways.
AB - The series of cooperative transitions that lead to [d(TG4)4.(K+)m] quadruplex
assembly upon rapid addition of KCl to d(TG4) strands were studied. Quadruplex
samples were dialyzed against KCl then Li-EDTA and found to retain between three
and five strongly bound potassiums with affinities >10(6) M-2. Absorbance thermal
denaturation (melt) and circular dichroism (CD) equilibrium binding data were
obtained. The latter were analyzed using two classes of binding models to
simulate the effects of the assumed intermolecular interactions on the binding
curves (isotherms). The melt experiments yielded equilibrium dissociation
constants (Kd) ranging from 10(-11) to 10(-12) M3 at the melting temperatures.
Extrapolating these values to 23 degrees C predicts Kd values in the 10(-28) M3
range if the heat capacity (Cp) is not strongly dependent upon temperature
changes over this range. Assuming Ka is equal to 1/Kd (from melting analyses),
very large association free energies stabilize the quadruplex at 23 degrees C in
100 mM KCl (DeltaGa = -43 kcal mol-1). Plots of the differential melt curve peak
half-widths, a measure of cooperativity, versus d(TG4) concentration showed that
quadruplex dissociation is much more cooperative at 400 mM KCl than at 100 mM
KCl. Forty-eight hour quadruplex assembly time courses were monitored by CD at
264 nm. Equilibrium quadruplex accumulation generally required over 10 h, and net
reaction extents were in the 10-85% range. Hill plots of the data show that
initial steps in the multistep pathway are positively cooperative, presumably due
to strong strand-cation and strand-strand binding interactions in duplex and
triplex assembly reactions, then negatively cooperative in quadruplex formation.
Models were developed to rationalize the experimental observations in terms of
consecutive cooperative allosteric transitions from cation-deficient relaxed (R)
strand-aggregates to cation-containing tense (T) structures, driven by the
allosteric effector K+. Quantitative mappings of positive and then negative
cooperativity were obtained by fitting the results as a function of strand number
incorporated during quadruplex assembly. Surprisingly, models for reactions
involving incorporation of five and six strands fit the data better than models
involving only four strands. The 5-step "induced fit" model fits the data as well
as or better than 3- and 4-step models and better than all of the strand
aggregation models that were devised and investigated. Net association free
energies (summation operatori=1,n) ranged from -20 to -26 kcal mol-1,
approximately half the magnitude of the apparent stabilities measured by
absorbance melts. Likely explanations for this discrepancy involve hysteresis and
errors due to inadequate equilibration in the melt experiments. Hysteresis is
thought to be produced by irreversibility due to different predominant mechanisms
in absorbance (dissociation) and CD (association) experiments. The kinetic block
to quadruplex assembly can be unambiguously attributed to quadruplex formation
and not intermediate steps in the assembly mechanism. On the basis of these
results we propose that, in addition to the more conventional assembly mechanisms
involving duplex dimerization and stepwise strand addition, quadruplex formation
can also proceed by triplex-triplex disproportionation. Interaction statistics
arguments that support the energetic feasibility of the disproportionation
pathway are presented. The allosteric quadruplex assembly model provides a
mechanism which could be used by the cell to simultaneously modulate DNA
structure and activity within telomeres, transcriptional promoters, recombination
prone chromatin, and other G-rich DNAs. As a result of this allosterism, cation
and strand availability and strand-pairing capabilities could profoundly
influence the functional capacity of a particular strand over a relatively narrow
range of effector concentration changes. (ABSTRACT TRUNCATED)
PMID- 9398274
TI - A leucine zipper motif in the ectodomain of Sendai virus fusion protein assembles
in solution and in membranes and specifically binds biologically-active peptides
and the virus.
AB - We have detected a leucine zipper-like motif in the ectodomain of the Sendai
virus fusion protein (aa 269-307) which is extremely conserved in the family of
Sendai viruses. To find a possible role for this motif, we synthesized SV-269, a
39 amino acid peptide corresponding to this domain, and a mutant peptide, MuSV
269, with an amino acid pair interchanged their positions. The peptides were
labeled with fluorescent probes at their N-terminal amino acid and functionally
and structurally characterized. The data show that SV-269, but not MuSV-269,
specifically binds Sendai virus. Expectedly, SV-269 is more active than the
mutant MuSV-269 in inhibiting Sendai virus-mediated hemolysis. Fluorescence
studies reveal that SV-269 assembles in aqueous solution, binds to zwitterionic
PC and negatively-charged PS/PC vesicles, and assembles therein. Although MuSV
269 similarly binds to both types of vesicles, it only slightly assembles in
solution and not at all in membranes. Moreover, SV-269, but not MuSV-269,
coassembles with the biologically-active heptad repeats SV-150 and SV-473
(Rapaport et al. , 1995) in solution as revealed by fluorescence and circular
dichroism (CD) spectroscopy, and with SV-150 within negatively-charged PS/PC and
zwitterionic PC vesicles. Despite these differences, both SV-269 and MuSV-269
adopt similar secondary structures in 40% TFE and 1% SDS as revealed by CD
spectroscopy, and disrupt the packing of the lipid bilayers to the same extent,
as shown by the dissipation of diffusion potential. The role of this leucine
zipper motif is discussed in terms of the assembly of the Sendai virus fusion
protein in solution and within membranes. Since most of the heptadic leucines are
also conserved in the corresponding domains of other paramyxoviruses such as
rinderpest, measles, SV5, and parainfluenza, it may indicate a similar role of
this domain in these viruses as well.
PMID- 9398275
TI - FTIR spectroscopic studies of oligonucleotides that model a triple-helical domain
in self-splicing group I introns.
AB - Fourier Transform infrared (FTIR) spectroscopy was used to characterize the Mg2+
dependent association of a 23-mer mixed ribo-deoxyribonucleotide (23-mer RNA) and
a 7-mer oligoribonucleotide (7-mer RNA) that models the triple-helical domain of
a self-splicing group I intron [Sarkar et al. (1996) Biochemistry 35, 4678-4688].
To elucidate the effect of deoxyribose substitution in the entire backbone, as
well as at specific positions, in the assembly of the triple-helical domain,
parallel studies were carried out on the association of pure deoxyribonucleotides
having base sequences corresponding to the oligoribonucleotides and also between
23-mer RNA and two 7-mer RNA variants. In the variants, either the ribose
attached to G451 or the ribose attached to U453 was changed to deoxyribose. FTIR
monitored thermal denaturation of the two 23-mer hairpins shows two distinct
melting regions in 1 M NaCl, in case of the RNA hairpin but not for the 23-mer
DNA. Triple-helix association between the two strands (7-mer and 23-mer) studied
by FTIR show that only when both strands are RNA, association takes place with
the formation of the P6 helix. Our results also show that the interactions
between the two RNA strands involve some participation of the riboses, which
could also involve the 2'-OH groups of the RNA backbone. The assembly of the
triple-helical domain is not possible with a deoxyribose backbone and is
completely perturbed even when only one ribose at either G451 or U453 position is
substituted by deoxyribose.
PMID- 9398276
TI - Detection and identification of transient enzyme intermediates using rapid
mixing, pulsed-flow electrospray mass spectrometry.
AB - Rapid chemical quench methods coupled with off-line detection have proven to be
very useful in identifying enzyme reaction intermediates. However, a limitation
to this approach involves enzyme intermediates which are too labile under the
chemical quenching conditions to allow detection and characterization. In this
report, we describe the development of a novel approach for the detection and
characterization of enzyme intermediates on the subsecond time scale using a
"pulsed flow" method which employs a direct interface between a rapid-mixing
device and electrospray ionization mass spectrometry. The application of this
technique with the enzyme 5-enolpyruvoyl-shikimate-3-phosphate (EPSP) synthase is
demonstrated. This enzyme converts shikimate-3-phosphate (S3P) and phosphoenol
pyruvate (PEP) to EPSP and inorganic phosphate. Previous rapid chemical quench
studies have shown that this reaction proceeds through a tetrahedral intermediate
[Anderson, K. S., et al. (1988) J. Am.Chem. Soc. 110, 6577-6579] formed
transiently at the enzyme active site. We have shown that this tetrahedral
intermediate can be directly detected on a subsecond time scale without chemical
quenching by interfacing a rapid mixing apparatus directly with an on-line
electrospray ionization ion trap mass spectrometer. Negative ion mass spectra
collected by electrospray ionization indicate peaks for S3P (m/z 253), PEP (m/z
167), EPSP (m/z323), and the tetrahedral intermediate (m/z 421). Further
confirmation was provided by performing the same experiment with [13C-1]-labeled
PEP. These spectra confirmed the anticipated shift of 1 atomic mass unit for PEP
(m/z 168), EPSP (m/z 324), and the tetrahedral intermediate (m/z 422) with no
change in S3P (m/z 253). The collision-induced dissociation of the unlabeled
tetrahedral intermediate peak (m/z421) produced a daughter ion at m/z 323, which
is most likely EPSP resulting from the loss of phosphate and is consistent with
previous studies which have examined the chemical breakdown of the tetrahedral
intermediate in solution [Anderson, K. S., et al. (1990) J. Biol. Chem. 265, 5567
6672]. This technique is under development and should be a useful method to study
the transient formation of enzyme intermediates.
PMID- 9398277
TI - Kinetic and spectroscopic investigations of wild-type and mutant forms of apple 1
aminocyclopropane-1-carboxylate synthase.
AB - Two catalytically inactive mutant forms of 1-aminocyclopropane-1-carboxylate
(ACC) synthase, Y85A and K273A, were mixed in low concentrations of guanidine
hydrochloride (GdnHCl). About 15% of the wild-type activity was recovered
(theoretical 25% for a binomial distribution), proving that the functional unit
of the enzyme is a dimer, or theoretically, a higher order oligomer. The enzyme
catalyzes the conversion of S-adenosyl-L-methionine (SAM) to ACC. The value of
kcat/KM is 1.2 x 10(6) M-1 s-1 at pH 8.3. Viscosity variation experiments with
glycerol and sucrose as viscosogenic reagents showed that this reaction is nearly
100% diffusion controlled. The sensitivity to viscosity for the corresponding
reaction of the less reactive Y233F mutant is much reduced, thus the latter
reaction serves as a control for that of the wild-type enzyme. The kcat/KM vs pH
profile for wild-type enzyme exhibits pKa values of 7.5 and 8.9. The former is
assigned to the pKa of the alpha-amino group of SAM, while the latter corresponds
to the independently determined spectrophotometric pKa of the internal aldimine.
The kcat vs pH profile exhibits similar pKas, which means that the above pKa
values are not perturbed in the Michaelis complex. The phenolic hydroxyl group of
Tyr233 forms a hydrogen bond to the 3'-O- of PLP. The spectral and kinetic pKa
(kcat/KM) values of the Y233F mutant are not identical (spectral 10.2, kinetic
8.7). A model that accounts quantitatively for these data posits two parallel
pathways to the external aldimine for this mutant, the minor one has the alpha
amino group free base form of SAM reacting with the protonated imine form of the
enzyme with kcat/KM approximately 6.0 x 10(3) M-1 s-1, while the major pathway
involves reaction of the aldehyde form of PLP with SAM with kcat/KM approximately
7.0 x 10(5) M-1 s-1. The spectral pKa is defined only by the less reactive
species.
PMID- 9398278
TI - Evidence that galactanase A from Pseudomonas fluorescens subspecies cellulosa is
a retaining family 53 glycosyl hydrolase in which E161 and E270 are the catalytic
residues.
AB - A genomic library of Pseudomonas fluorescens subsp. cellulosa DNA was screened
for galactanase-positive recombinants. The nine galactanase positive phage
isolated contained the same galactanase gene designated galA. The deduced primary
structure of the enzyme (galactanase A; GalA) encoded by galA had a Mr of 42 130
and exhibited significant sequence identity with a galactanase from Aspergillus
aculeatus, placing GalA in glycosyl hydrolase family 53. The enzyme displayed
properties typical of an endo-beta1, 4-galactanase and exhibited no activity
against the other plant structural polysaccharides evaluated. Analysis of the
stereochemical course of 2,4-dinitrophenyl-beta-galactobioside (2,4-DNPG2)
hydrolysis by GalA indicated that the galactanase catalyzes the hydrolysis of
glycosidic bonds by a double displacement general acid-base mechanism.
Hydrophobic cluster analysis (HCA) suggested that family 53 enzymes are related
to the GH-A clan of glycosyl hydrolases, which have an (alpha/beta)8 barrel
structure. HCA also predicted that E161 and E270 were the acid-base and
nucleophilic residues, respectively. Mutants of GalA in which E161 and E270 had
been replaced with alanine residues were essentially inactive against galactan.
Against 2,4-DNPG2, E161A exhibited a much lower Km and kcat than native GalA,
while E270A was inactive against the substrate. Analysis of the pre-steady-state
kinetics of 2,4-DNPG2 hydrolysis by E161A showed that there was an initial rapid
release of 2,4-dinitrophenol (2,4-DNP), which then decayed to a slow steady-state
rate of product formation. No pre-steady-state burst of 2,4-DNP release was
observed with the wild-type enzyme. These data are consistent with the HCA
prediction that E161 and E270 are the acid-base and nucleophilic catalytic
residues of GalA, respectively.
PMID- 9398279
TI - Evidence for interaction between transmembrane segments in assembly of Kv1.3.
AB - Previously, we showed that the N-terminal recognition domain (T1) of Kv1.3 was
not required for assembly of functional channels [Tu et al. (1996) J. Biol. Chem.
271, 18904-18911]. Moreover, specific Kv1.3 peptide fragments including regions
of the central core are able to inhibit expression of current produced from a
channel lacking the T1 domain, Kv1.3(T1-). To elucidate the mechanism whereby
Kv1.3 peptide fragments suppress Kv1.3(T1-) current, we have studied the ability
of peptide fragments containing the transmembrane segments S1, S1-S2, or S1-S2-S3
to physically associate with the Kv1.3(T1-) polypeptide subunit in vitro in
microsomal membranes. Using c-myc (9E10) epitope-labeled peptide fragments and
anti-myc antibody as well as antisera to the Kv1.3 C-terminus, we now demonstrate
specific association of these peptide fragments with Kv1.3(T1-). Association of
peptide fragments with Kv1.3(T1-) was correlated with integration of both
proteins into the membrane. Furthermore, the relative strength and kinetics of
this association directly correlated with the ability of fragments to suppress
Kv1.3(T1-) current. The rate-limiting step in the sequential synthesis,
integration, and formation of a complex was the association of integrated
polypeptides within the plane of the lipid bilayer. These results strongly
suggest that the physical association of transmembrane segments provides the
basis for suppression of K+ channel function by K+ channel peptide fragments in
vivo. Moreover, the S1-S2-S3 peptide fragment potently suppressed full-length
Kv1.3, thus implicating a role for the S1-S2-S3 region of Kv1.3 in the assembly
of the Kv1.3 channel. We refer to these putative association sites as IMA
(intramembrane association) sites.
PMID- 9398280
TI - Affinity cleavage at the metal-binding site of phosphoenolpyruvate carboxykinase.
AB - Chicken liver phosphoenolpyruvate carboxykinase (PEPCK) was rapidly inactivated
by micromolar concentrations of ferrous sulfate in the presence of ascorbate at
pH 7.4. Omitting ascorbate or replacing the Fe2+ with Mn2+ or Mg2+ gives no
inactivation. Mn2+, Mg2+, or Co2+ at 100-fold molar excess over Fe2+ offered
complete protection from Fe2+/ascorbate-induced inactivation. The substrates PEP
and GTP, but not OAA, GDP, or CO2, offered full protection from inactivation. The
addition of 5 mM EDTA stopped further inactivation of the enzyme. Thermodynamic
studies indicate that the inactive enzyme no longer binds Mn2+ but still had high
affinity for GTP indicating that the inactivation process was specific for the
metal site. A decrease in cysteine content was observed over time following PEPCK
treatment with Fe2+ and ascorbate. The apparent first-order rate constant for
free sulfhydryl loss (0.085 +/- 0.005 min-1) is similar to the apparent first
order rate constant for inactivation (0.067 +/- 0.005 min-1). Amino acid
composition analysis revealed that cysteic acid was generated upon Fe2+/ascorbate
addition to PEPCK. Native chicken liver PEPCK has an Mr of 67 kDa. SDS-PAGE of
the inactivated enzyme showed the presence of two new bands at 31.7 and 35.3 kDa
indicating that PEPCK was specifically cleaved at a single site. The rate of
cleavage was slower than the rate of inactivation and fully inactivated enzyme
was only 50% cleaved. The Fe2+/ascorbate-catalyzed inactivation was not solely
due to protein cleavage. The protein fragments generated by cleavage were
separated by C4 reverse phase HPLC. The cleavage exposed a new N-terminus which
was identified to be the 35.3 kDa C-terminal half of PEPCK. Sequencing of the
fragments indicated that the site of cleavage was between Asp296 and Ile297.
These results indicate that Asp296 is involved in metal chelation. This agrees
with previous studies [Hlavaty, J. J., & Nowak, T. (1997) Biochemistry 36, 3389
3403] that suggested that Asp295 and Asp296 are involved in metal binding.
PMID- 9398281
TI - One- and two-dimensional ESEEM spectroscopy of flavoproteins.
AB - One- and two-dimensional (1D and 2D) electron spin echo envelope modulation
(ESEEM) spectroscopy was applied to study the flavin cofactors in the neutral
semiquinone states of flavodoxin and ferredoxin-NADP+ reductase (FNR) from the
cyanobacterium Anabaena PCC 7119, and the anionic semiquinone state of
cholesterol oxidase from Brevibacterium sterolicum. High-resolution crystal
structures are available for all these proteins. Three- and 4-pulse ESEEM and
hyperfine sublevel correlation spectroscopy (HYSCORE) techniques at X-band were
used. HYSCORE spectra showed correlations between transitions caused by
interaction of the isoalloxazine unpaired electronic spin present in the
semiquinone state with several nitrogen and hydrogen nuclei. Measurements of
isotopic labeled samples ([15N]FMN flavodoxin and [2H]flavodoxin) allowed the
assignment of all the detected transitions to nuclei belonging to the FMN
cofactor group. Interactions of nitrogens in positions 1 and 3 of the
isoalloxazine ring were determined to have isotropic hyperfine coupling constants
in the 1-2 and 0.5-1 MHz ranges for all the different flavoprotein semiquinones
studied. Information about the quadrupolar term of these nuclei was also
obtained. An intense correlation in the negative quadrant was detected. It has
been associated to the strongly interacting N(10) nucleus. The complete hyperfine
term parameters (including the sign) were obtained from detailed analysis of this
signal, being the quadrupolar parameter, K, also estimated. Another correlation
in the HYSCORE spectra, corresponding to hydrogen bound to the N(5) position in
neutral flavin semiquinones, was detected. Its interaction parameters were also
determined. This study demonstrates that ESEEM spectroscopy, and in particular
the HYSCORE technique, are of particular utility for detecting and assigning
nuclear transition frequencies in flavoprotein semiquinones. Moreover, the
results reported here are complementary to ENDOR studies, and both techniques
together provide an important tool for obtaining information about spin
distribution in the flavin ring of flavoproteins in the semiquinone state.
PMID- 9398282
TI - Special folding pathway to tetramer only through the micelle state of the
corticotropin-releasing factor.
AB - The ovine corticotropin-releasing factor (CRF), a peptide hormone of 41 residues
stimulating the secretion of adrenocorticotropic hormone, was thermodynamically
investigated. By means of size exclusion chromatography and/or ultrafiltration,
the CRF solution could be separated into random coil monomers and highly alpha
helical tetramers, which seem to have amphipathic helix bundle structure.
Circular dichroism measurements along with diluting or concentrating the CRF
solution revealed that there exists the micelle state above the concentration of
0.1 mM, which would be the critical micelle concentration (cmc). The micelle
state was also proved by binding ability for 8-anilino-1-naphthalenesulfonate and
endothermic change by dilution across the cmc. The tetramer showed the
cooperative thermal transition at about 55 degrees C in the buffer solution (pH
7.5), so that it would have native-protein-like folding. On the other hand, the
micelle undergoes gradual change to dissociated state by heating, regardless of
the similar alpha-helicity to the tetramer. Above the cmc the equilibrium between
the tetramer and the micelle takes place as well as that between the monomer and
the micelle. Whereas, the direct conversion between the tetramer and the monomer
scarcely occurred below the cmc. The titration experiment with 2,2,2
trifluoroethanol (TFE) revealed that the cmc decreases with increasing the
concentration of TFE. This tendency is the same as that of general surfactants.
Most of experimental results can be well explained by this three-phase model
involving the monomer, the tetramer, and the micelle. The lack of the equilibrium
between the monomer and the tetramer indicates that the folding pathway of the
tetramer is the transformation only through the micelle state and not from the
monomer. This pathway resembles the collapse model among the phenomenological
models for thermodynamic protein folding. By the mathematical consideration for
the dissociation of micelle, we have demonstrated that the expected content of
undegradable k-mer is 2/(k + 1), which agreed well with the observed tetramer
content of CRF (40%).
PMID- 9398283
TI - Bacillus thuringiensis cytolytic toxin associates specifically with its synthetic
helices A and C in the membrane bound state. Implications for the assembly of
oligomeric transmembrane pores.
AB - The CytA toxin exerts its activity by the formation of pores within target cell
membranes. However, the exact mechanism of pore formation and the structural
elements that are involved in the toxic activity are yet to be determined.
Recently, the structure of the highly similar CytB toxin was solved (Li et al.,
1996), and a beta-barrel was suggested as a possible structure of the pores. Due
to the similarity between the toxins, the existence and positioning of alpha
helices and beta-sheets in CytA were predicted from the alignment of the
sequences. Here peptides corresponding to beta5, beta6, and beta7 strands, to a
conserved nonhelical region of the CytA toxin (P149-170), to helices B and D, and
to an analogue of helix A were synthesized, fluorescently labeled, and
characterized. We found that, unlike helices A and C (Gazit and Shai, 1993),
neither the beta-strand peptides nor helix B could interact with lipid membranes,
whereas P149-170 and helix D bind the membrane weakly. Membrane permeation
experiments suggested that CytA toxin exerts its activity by aggregation of
several monomers. To learn about the structural elements that may mediate CytA
oligomerization, the ability of the synthetic peptides to interact with membrane
bound CytA was studied. Helices A and C, but not the beta-strands, helix D, or a
control peptide, caused a large increase in the fluorescence of membrane-bound
fluorescein-labeled CytA, whereas helix B had only a slight effect. Moreover, the
addition of rearranged helix A, a peptide with the same composition as helix A,
but with only two pairs of amino acids rearranged, did not affect the
fluorescence. The addition of unlabeled CytA also caused an increase in the
fluorescence intensity, further demonstrating the interaction between CytA
monomers within the membrane. Taken together, our results provide further support
for the suggestion that the CytA toxin self-assembles within membrane and that
helices A and C are major structural elements involved in the membrane
interaction and intermolecular assembly of the toxin.
PMID- 9398284
TI - Purealin blocks the sliding movement of sea urchin flagellar axonemes by
selective inhibition of half the ATPase activity of axonemal dyneins.
AB - Ciliary and flagellar movements are explained by active sliding between the outer
doublet microtubules of an axoneme via their inner and outer dynein arms.
Purealin, a novel bioactive principle of a sea sponge Psammaplysilla purea,
blocked the motility of Triton-demembranated sea urchin sperm flagella within 5
min at concentrations above 20 microM. In a similar concentration range, purealin
blocked the sliding movement of the flagellar axonemes in vitro within a few
minutes judging from the turbidity measurements. The ATPase activity of axonemes
was partially inhibited by purealin in a concentration-dependent manner. The
maximum inhibition reached approximately 50% at concentrations above 20 microM,
indicating that half the axonemal ATPase activity is sensitive to purealin.
Similar results were observed on the ATPase activity of outer-arm-depleted
axonemes and that of a mixture of 21S dynein and salt-extracted axonemes. On the
other hand, ATPase activity of isolated 21S dynein was not inhibited by purealin.
The inhibitory action of purealin on the axonemal ATPases was reversed by
dilution of purealin. The effect of purealin on the double-reciprocal plot of the
ATPase activity as a function of ATP concentrations showed that the inhibition
was not a competitive type. In accord with this finding, purealin did not affect
the vanadate-mediated UV photocleavage of axonemal dyneins. These results suggest
that purealin binds reversibly to a site other than the catalytic ATP-binding
site and inhibits half the ATPase activity of axonemes. Taken together, our
results suggest that purealin-sensitive ATPase activity of the dynein arms plays
an essential role in generating the sliding movement of flagellar axonemes.
PMID- 9398285
TI - Participation of the N-terminal region of Cepsilon3 in the binding of human IgE
to its high-affinity receptor FcepsilonRI.
AB - The binding of immunoglobulin E (IgE) to its high-affinity receptor (FcepsilonRI)
expressed on mast cells and basophils is central to the development of an
allergic reaction. Previous studies have implicated the third constant domain of
IgE-Fc (Cepsilon3) as the site of the interaction with FcepsilonRI. We have
prepared a series of site-directed mutants of human IgE-Fc, particularly focusing
on the N-terminal "linker" region and AB loop of Cepsilon3. The kinetics of
binding IgE and its Fc fragments to the immobilized receptor were determined by
surface plasmon resonance (SPR), and two phases of binding were observed. We
identified one mutation in the N-terminal linker region, R334S, that has a
dramatic effect on binding. R334S lowers the affinity of IgE-Fc for FcepsilonRI
by 120-fold, principally through an increase in the dissociation rate of the
slower phase of the interaction. This mutation has a similar effect in Fcepsilon3
4, a truncated form of IgE-Fc which lacks the Cepsilon2 domain pair, and thus it
does not exert its effect through altering the quaternary structure of IgE-Fc,
firmly implicating Arg334 as a contact residue in the complex. However R334S has
no effect on the binding of FcepsilonRII (CD23), the low-affinity receptor for
IgE, demonstrating the structural integrity of the mutated IgE-Fc. Circular
dichroism spectroscopy and thermal stability studies further indicate that the
R334S mutation does not disorder or destabilize the structure of IgE-Fc or
Fcepsilon3-4. These results demonstrate the importance of the N-terminal linker
region of Cepsilon3 in the interaction of IgE with FcepsilonRI.
PMID- 9398286
TI - Identification of contact residues in the IgE binding site of human
FcepsilonRIalpha.
AB - The high-affinity receptor for immunoglobulin E (IgE), FcepsilonRI, is an
alphabetagamma2 tetramer found on mast cells, basophils, and several other types
of immune effector cells. The interaction of IgE with the alpha-subunit of
FcepsilonRI is central to the pathogenesis of allergy. Detailed knowledge of the
mode of interaction of FcepsilonRI with IgE may facilitate the development of
inhibitors for general use in the treatment of allergic disease. To this end we
have performed site-directed mutagenesis on a soluble form of the FcepsilonRI
alpha-chain (sFcepsilonRIalpha). The effects of four mutations in the second
immunoglobulin-like domain of sFcepsilonRIalpha upon the kinetics of binding to
IgE and fragments of IgE have been analyzed using surface plasmon resonance. As
described in the preceding paper of this issue [Henry, A. J., et al. (1997)
Biochemistry 36, 15568-15578], biphasic binding kinetics was observed. Two of the
mutations had significant effects on binding: K117D reduced the affinity of
sFcepsilonRIalpha for IgE by a factor of 30, while D159K increased the affinity
for IgE by a factor of 7, both principally through changes in the rates of
dissociation of the slower phase of the interaction. Circular dichroism spectra
of sFcepsilonRIalpha incorporating either of these mutations were
indistinguishable from those of wild-type sFcepsilonRIalpha, demonstrating that
the native conformation had not been disrupted. Our results, together with those
from site-directed mutagenesis on fragments of IgE presented in the accompanying
paper, define the contact surfaces in the IgE:sFcepsilonRIalpha complex.
PMID- 9398287
TI - Ionic properties of membrane association by vitamin K-dependent proteins: the
case for univalency.
AB - Ionic properties of membrane interaction by prothrombin, protein Z, and other
vitamin K-dependent proteins were studied to determine the relevance of a
monovalent membrane contact mechanism between one phospholipid headgroup and a
calcium-lined pore in the protein [McDonald, J. F., Shah, A. M., Schwalbe, R. A.,
Kisiel, W., Dahlback, B., and Nelsestuen, G. L. (1997) Biochemistry 36, 5120
5127]. For comparison, multivalent ionic interaction was illustrated by peptides
of +3 to +5 net charge and by blood clotting factor V. As expected, the peptides
were easily dissociated by salt and gave nominal charge-charge interactions (zazb
values) of -13 to -17. Factor V showed much higher binding affinity despite
nominal zazb values of about 9. Membrane-bound prothrombin and protein Z showed
very low sensitivity to salt as long as calcium was at saturating levels (zazb
values of approximately -1.3 to -1.4), appropriate for univalent ionic
attraction. Prothrombin contains +3 charge groups (Lys-2, Lys-11, Arg-10) that
are absent from the GLA domain (residues 1-35) of protein Z, while protein Z
contains -4 charge groups (Gla-11, Asp-34, Asp-35) that are absent in
prothrombin. Thus, similar zazb relationships indicated little role for these
surface charges in direct membrane contact. Calcium-saturated protein Z bound to
phosphatidylcholine (PC) in a manner which indicated the addition of one calcium
ion, bringing the total calcium stoichiometry in the protein-membrane complex to
at least 8. Protein Z bound to phosphatidic acid (PA) in a manner suggesting the
need for a fully ionized phosphate headgroup, a property expected by ion pairing
in an isolated environment. Electrostatic calculations showed that the proposed
protein site for phosphate interaction was electropositive. The cluster of
hydrophobic amino acids (Phe-5, Leu-6, and Val-9) on the surface of prothrombin
was electronegative, suggesting a role in the electrostatic architecture of the
GLA domain. Overall, membrane binding by vitamin K-dependent proteins appeared
consistent with the formation of an ion pair in an isolated environment.
PMID- 9398288
TI - pH dependence of antibody/lysozyme complexation.
AB - Association between proteins often depends on the pH and ionic strength
conditions of the medium in which it takes place. This is especially true in
complexation involving titratable residues at the complex interface. Continuum
electrostatics methods were used to calculate the pH-dependent energetics of
association of hen egg lysozyme with two closely related monoclonal antibodies
raised against it and the association of these antibodies against an avian
species variant. A detailed analysis of the energetic contributions reveals that
even though the hallmark of association in the two complexes is the presence of
conserved charged-residue interactions, the environment of these interactions
significantly influences the titration behavior and concomitantly the energetics.
The contributing factors include minor structural rearrangements, buried
interfacial area, dielectric environment of the key titratable residues, and
geometry of the residue dispositions. Modeled structures of several mutant
complexes were also studied so as to further delineate the contribution of
individual factors to the titration behavior.
PMID- 9398289
TI - Regulation of protein kinase C betaII by its C2 domain.
AB - The C2 domain serves as a membrane-targeting module in a diverse group of
proteins that includes the conventional protein kinase Cs. This work examines the
mechanism by which the C2 domain targets protein kinase C to membranes. Molecular
modeling identified two highly-charged surfaces on the C2 domain of protein
kinase C betaIotaIota: the Ca2+ binding site which contains five aspartates and a
basic face positioned behind the Ca2+ site that contains seven lysine residues.
Both surfaces were mutated to assess their role in Ca2+-dependent membrane
binding. Surprisingly, removal of four positive charges on the basic face had no
effect on protein kinase C's lipid or Ca2+ sensitivity, revealing that the basic
face does not provide determinants involved in lipid binding, nor is it
positioned close enough to the membrane to enhance nonspecific recruitment by its
electropositive face. In contrast, replacement of two negative charges with two
positive charges in the Ca2+ binding site decreased protein kinase C's affinity
both for Ca2+ and for anionic lipids by several orders of magnitude. The dramatic
reduction in electronegative potential resulting from this mutation did not
increase protein kinase C's affinity for acidic membranes in the absence of Ca2+,
revealing that simple charge neutralization does not account for how Ca2+
increases protein kinase C's affinity for anionic membranes. Our data suggest
that (1) the membrane interaction surface of the C2 domain is localized to the
Ca2+-binding site, with the positive face positioned away from the membrane, and
(2) the Ca2+ site does not serve as a simple electrostatic switch.
PMID- 9398290
TI - Mapping the suramin-binding sites of human neutrophil elastase: investigation by
fluorescence resonance energy transfer and molecular modeling.
AB - Neutrophil elastase (NE), a mediator of inflammation, binds with high affinity
numerous anionic molecules including suramin, a polysulfated naphthylurea, which
inhibits it with a Ki of 0.2 microM and a 4:1 suramin:NE stoichiometry and thus
constitutes a potential therapeutic agent. In an attempt to locate the suramin
molecules on NE, we investigated the NE-suramin interaction using steady-state
and time-resolved fluorescence spectroscopy. The time-resolved intensity decay of
NE, a protein with three Trp residues, in positions 27, 141, and 237
(chymotrypsin numbering system) was best described by a three-exponential
function with lifetimes ranging from 0.22 to 2.28 ns. Comparison of the
accessibility of the three lifetime classes to the fluorescence quenchers
acrylamide and iodide with the computed solvent accessibility of the three Trp
residues in the crystal structure of NE indicates that the main, if not the sole,
contribution to the 2.28 ns lifetime class is brought about by the fully buried
Trp 141 residue. The addition of suramin to NE induces a sharp decrease in NE
fluorescence and a corresponding increase in suramin fluorescence due to an
efficient fluorescence resonance energy transfer (FRET) between the Trp residues
of NE, acting as donors, and the naphthalene rings of suramin, behaving as
acceptors. From the fate of the longest lifetime class in the presence of
variable suramin concentrations, we deduce that two suramins are bound at less
than 17 A from Trp 141, whereas the two others are located at least 29 A from Trp
141. Moreover, neither the binding of suramin to NE nor the FRET process was
modified when NE was complexed with a peptide chloromethylketone inhibitor,
suggesting that suramin does not directly interfere with the substrate binding
site of NE. These data were used as constraints to model the NE-suramin complex.
PMID- 9398291
TI - Ligand-induced conformational changes in lactose repressor: a fluorescence study
of single tryptophan mutants.
AB - A key element in the ability of lac repressor protein to control transcription
reversibly is the capacity to assume different conformations in response to
ligand binding. To investigate regions of the protein involved in these
conformational changes, mutant repressor proteins containing single tryptophans
were created by mutating each of the two native tryptophan residues to tyrosine
and changing the residue of interest to tryptophan. Tryptophans substituted in
the following locations were highly accessible to quenchers with no changes in
fluorescence or quenching properties in the presence of ligands: in the N
terminal helix-turn-helix for Y7, at the junction between the N-terminus and N
subdomain for L62, in the N-subdomain of the monomer-monomer interface for
residue E100 or Q117, or at the C-terminal region for K325. Tryptophan at
position F226 in the C-subdomain subunit interface was only moderately exposed to
quenchers and unresponsive to ligands. In contrast, the fluorescence and
quenching properties of single tryptophans placed in the central region of the
protein were affected by ligands. Inducer binding altered the accessibility to
quencher for tryptophan at H74 or F293, but no changes were detected upon binding
operator. Exposure of tryptophan at the position occupied by Y273 was affected by
both inducer and operator, indicating alterations in this region by both ligands.
These results suggest that, in the areas of the lac repressor probed by these
substitutions, the inducer-bound form differs from the conformation of the
unliganded form.
PMID- 9398292
TI - Identification of catalytically important residues in yeast transketolase.
AB - The possible roles of four histidine residues in the active site of yeast
transketolase were examined by site-directed mutagenesis. Replacement of the
invariant His69 with alanine yielded a mutant enzyme with 1.5% of the specific
activity of the wild-type enzyme and with an increased KM for the donor. This
residue is located at the bottom of the substrate cleft close to the C1 hydroxyl
group of the donor substrate, and the side chain of His69 might be required for
recognition of this hydroxyl group and possibly for maintenance of the proper
orientation of the reaction intermediate, (alpha, beta-dihydroxyethyl)thiamin
diphosphate. Amino acid replacements of His481 by alanine, serine, and glutamine
resulted in mutant enzymes with significantly increased KM values for the donor
substrate and specific activities of 4.4%, 1.9%, and 5.5% of the wild-type
enzyme. The kinetic data suggest that this residue, although close to the C2
carbonyl oxygen of the substrate, is not absolutely required for stabilization of
the negative charge that develops at this oxygen in the transition state. This
points toward the 4'-NH2 group of the pyrimidine ring of thiamin diphosphate as
the major source of charge stabilization. Mutations at positions His30 and His263
result in mutant enzymes severely impaired in catalytic activity (1.5% and less
of the activity of wild-type transketolase). The KM value for the donor substrate
was increased for the His30Ala mutant but remained unchanged in the His263Ala
enzyme. The side chains of both residues interact with the C3 hydroxyl group of
the donor substrate, and the results indicate that the two residues act in
concert during proton abstraction of the C3 hydroxyl proton during catalysis.
PMID- 9398293
TI - Acyl-adenylate motif of the acyl-adenylate/thioester-forming enzyme superfamily:
a site-directed mutagenesis study with the Pseudomonas sp. strain CBS3 4
chlorobenzoate:coenzyme A ligase.
AB - 4-Chlorobenzoate:coenzyme A (4-CBA:CoA) ligase catalyzes 4-chlorobenzoyl-coenzyme
A formation in a two-step reaction consisting of the adenylation of 4
chlorobenzoate with adenosine 5'-triphosphate followed by acyl transfer from the
4-chlorobenzoyl adenosine 5'-monophosphate diester intermediate to coenzyme A. In
this study, two core motifs present in the Pseudomonas sp. strain CBS3 4-CBA:CoA
ligase (motif I, 161T-S-G-T-T-G-L-P-K-G170, and motif II, 302Y-G-T-T-E306) and
conserved among the sequences representing the acyl-adenylate/thioester-forming
enzyme family (to which the ligase belongs) were tested for their possible role
in substrate binding and/or catalysis. The site-directed mutants G163I, G166I,
P168A, K169M, and E306Q were prepared and then subjected to steady-state and
transient kinetic studies. The results, which indicate reduced catalysis of the
adenylation of 4-chlorobenzoate in the mutant enzymes, are interpreted within the
context of the three-dimensional structure of the acyl-adenylate/thioester
forming enzyme family member, firefly luciferase.
PMID- 9398294
TI - Structural and biochemical characterization of the GTPgammaS-, GDP.Pi-, and GDP
bound forms of a GTPase-deficient Gly42 --> Val mutant of Gialpha1.
AB - The Gly42 --> Val mutant of Gialpha1 was characterized structurally and
biochemically to elucidate two important features of Gialpha1-catalyzed GTP
hydrolysis. The crystal structure of the GTPgammaS-bound G42VGialpha1 protein
demonstrates that the steric bulk of Val42 pushes the Gln204 residue into a
catalytically incompetent conformation, providing a rationale for the diminished
GTPase activity of this mutant. The same phenomenon may also account for the
diminished GTPase activity of the homologous transforming Gly42 --> Val mutation
in p21(ras). Similarly, the steric bulk of the unique Ser42 residue in Gzalpha
may account for the comparatively slower rate of GTP hydrolysis by this Galpha
subunit. The G42VGialpha1 subunit was also characterized structurally in its
GDP.Pi- and GDP-bound states, providing a unique opportunity to view three
"snapshots" of GTP hydrolysis. Hydrolysis of GTP to a transient GDP.Pi-bound
intermediate is associated with substantial conformational changes in the switch
II segment of the protein. Eventual release of Pi results in further removal of
switch I from the active site and a highly mobile switch II segment. Despite
their disparate biochemical properties, the structural similarity of G42VGialpha1
to the G203AGialpha1 mutant in the GDP.Pi-bound form suggests that both mutations
stabilize a conformation of the GDP. Pi-bound protein that occurs only
transiently in the wild-type protein. The structures of the GDP-bound forms of
the wild-type and mutant proteins are similar.
PMID- 9398295
TI - Role of the extracellular loops of the thyrotropin-releasing hormone receptor:
evidence for an initial interaction with thyrotropin-releasing hormone.
AB - Thyrotropin-releasing hormone (TRH), like most small ligands, appears to bind
within the seven transmembrane-spanning helices (TMs) of its G protein-coupled
receptor (TRH-R). A role for the extracellular loops (ECLs) of TRH-R has not been
established. We substituted residues in the ECLs of TRH-R and show that Tyr-181
is important for high-affinity binding because its substitution leads to a 3700
fold lowering of the estimated affinity compared to wild-type TRH-R. Using TRH
analogues, we provide evidence that there is a specific interaction between Tyr
181 in ECL-2 and the pyroGlu moiety of TRH. It was previously suggested that the
pyroGlu of TRH may interact with Asn-110 in TM-3 and with Asn-289 in ECL-3; N110A
and N289A TRH-Rs exhibit similar apparent affinities that are only 20-30-fold
lower than wild-type TRH-R. To better understand these findings, we analyzed a
computer-generated model which predicts that the ECLs form an entry channel into
the TRH-R TM bundle, that Tyr-181 projects into this channel and that the pyroGlu
of TRH cannot simultaneously interact with residues in the TMs and ECLs. Kinetic
analysis showed that the association rate of [Ntau-methyl-His]TRH with N289A TRH
R is slower than with wild-type TRH-R and largely accounts for the lower apparent
affinity; the association rate with N110A TRH-R is similar to that of wild-type
TRH-R. These data are consistent with the idea that there are initial
interactions between TRH and the residues of a putative entry channel of TRH-R.
We suggest that a role of the ECLs in all G protein-coupled receptors for small
ligands may be to initially contact the ligand and allow entry into a TM binding
pocket.
PMID- 9398296
TI - Role of gamma-carboxyglutamic acid in the calcium-induced structural transition
of conantokin G, a conotoxin from the marine snail Conus geographus.
AB - Conantokin G is a gamma-carboxyglutamic acid- (Gla-) containing conotoxin
isolated from the venom of the marine cone snail Conus geographus. This 17
residue polypeptide, which contains five gamma-carboxyglutamic acid residues, is
a N-methyl-d-aspartate- (NMDA-) type glutamate receptor antagonist. To
investigate the role of gamma-carboxyglutamic acid in the calcium-induced
structural transition of conantokin G, we determined the three-dimensional
structure of the conantokin G/Ca2+ complex by two-dimensional 1H NMR spectroscopy
and compared it to the high-resolution structure of conantokin G in the absence
of metal ions [Rigby et al. (1997) Biochemistry 36, 6906]. Complete resonance
assignments were made by two dimensional 1H NMR spectroscopy at pH 5.6 in the
presence of saturating amounts of Ca2+. Distance geometry and simulated annealing
methods were used to derive 23 convergent structures from a set of 302
interproton distance restraints and two torsion angle measurements. A high
resolution structure, with the backbone root mean square deviation to the
geometric average of the 23 structures of 0.6 +/- 0.1 A, contains a linear alpha
helix from Gla 3 to Lys 15. Gla residues 3, 7, 10, and 14 are aligned in a linear
array on one face of the helix. A genetic algorithm was applied to determine the
calcium positions in conantokin G, and the conantokin G/Ca2+ complex refined by
molecular simulation. Upon binding of Ca2+ to gamma-carboxyglutamic acid,
conantokin G undergoes a conformational transition from a distorted curvilinear
310 helix to a linear alpha-helix. Occupancy of the metal binding sites, defined
by gamma-carboxyglutamic acids, results in formation of a calcium-carboxylate
network that linearizes the helix and exposes the hydrophobic amino acids on the
opposite face of the helix.
PMID- 9398297
TI - Folding dynamics of the src SH3 domain.
AB - The thermodynamics and kinetics of folding of the chicken src SH3 domain were
characterized using equilibrium and stopped-flow fluorescence, circular dichroism
(CD), and nuclear magnetic resonance (NMR) hydrogen exchange experiments. As
found for other SH3 domains, guanidinium chloride (GdmCl) denaturation melts
followed by both fluorescence and circular dichroism were nearly superimposable,
indicating the concerted formation of secondary and tertiary structure. Kinetic
studies confirmed the two-state character of the folding reaction. Except for a
very slow refolding phase due to proline isomerization, both folding and
unfolding traces fit well to single exponentials over a wide range of GdmCl
concentrations, and no burst phase in amplitude was observed during the dead time
of the stopped-flow instrument. The entropy, enthalpy, and heat capacity changes
upon unfolding were determined by global fitting of temperature melts at varying
GdmCl concentrations (0.4-3.7 M). Estimates of the free energy of unfolding,
DeltaGUH2O, from guanidine denaturation, thermal denaturation, and kinetic
experiments were in good agreement. To complement these data on the global
characteristics of src SH3 folding, individual hydrogen-deuterium (HD) exchange
rates were measured for approximately half of the backbone amides in 0 and 0.7 M
GdmCl. The calculated free energies of the opening reaction leading to exchange
(DeltaGHD) indicated that unfolding is highly cooperative--slowly exchanging
protons were distributed throughout the core of the protein. The slowly
exchanging protons exhibited DeltaGHD values higher than the global DeltaGUH2O by
approximately 1 kcal/mol, suggesting that the denatured state might be somewhat
compact under native conditions. Comparison of the src SH3 with homologous SH3
domains as well as with other small well-characterized beta-sheet proteins
provides insights into the determinants of folding kinetics and protein
stability.
PMID- 9398298
TI - Three-dimensional solution structure of alpha-conotoxin MII, an alpha3beta2
neuronal nicotinic acetylcholine receptor-targeted ligand.
AB - alpha-Conotoxin MII, isolated from Conus magus, is a potent peptidic toxin which
specifically targets the mammalian neuronal nicotinic acetylcholine receptor,
alpha3beta2 subtype. The three-dimensional structure of alpha-conotoxin MII in
aqueous solution has been determined by two-dimensional 1H NMR spectroscopy. NOE
derived distances, refined by an iterative relaxation matrix approach, as well as
dihedral and chirality restraints were used in high-temperature biphasic
simulated annealing calculations. Fourteen minimum energy structures out of 50
subjected to the SA simulations were chosen for evaluation; these 14 structures
have a final RMS deviation of 0.76 +/- 0.31 and 1.35 +/- 0.34 A for the backbone
and heavy atoms, respectively. The overall structure is unusually well-defined
due to a large helical component around the two disulfide bridges. The principal
backbone folding motif may be common to a subclass of alpha-conotoxins. There are
two distinct surfaces on the molecule almost at right angles to one another. One
entirely consists of the hydrophobic residues Gly1, Cys2, Cys3, Leu15, and Cys16.
The second comprises the hydrophilic residues Glu11, His12, Ser13, and Asn14.
These surfaces on the ligand could be essential for the subtype-specific
recognition of the receptor.
PMID- 9398299
TI - Tyrosine and tryptophan structure markers in hemoglobin ultraviolet resonance
Raman spectra: mode assignments via subunit-specific isotope labeling of
recombinant protein.
AB - Phenyl-deuterated tyrosine (Tyr-d4) and indole-deuterated tryptophan (Trp-d5)
have been selectively incorporated into hemoglobin (Hb) by expressing the gene in
auxotrophic strains of Escherichia coli. Ultraviolet resonance Raman (UVRR)
spectra, using 229-nm excitation, show that difference features characteristic of
the Hb quaternary R --> T transition are not perturbed by the incorporation of
the isotopes. All the UVRR bands between 800 and 1700 cm-1 are assigned to either
Tyr or Trp except for the 1511 cm-1 band, which had been thought to arise from
the Trp 2 x W18 overtone. This band does not shift upon Trp or Tyr labeling but
does shift 5 cm-1 in D2O, suggesting assignment to a histidine (His) residue. Its
intensification in the T-state is consistent with His protonation. The alpha- and
beta-subunits were selectively labeled, by reconstitution of labeled subunits
with unlabeled subunits, to make isotope hybrids. Selective Tyr labeling
identified the alpha subunits as the locus of the Y8a upshift observed in Hb,
supporting the previous inference that this shift is associated with the T-state
H-bond involving the interfacial Tyr alpha42 [Rodgers, Su, Subramaniam, & Spiro
(1992) J. Am. Chem. Soc. 114, 3697]. Selective Trp labeling showed the Trp
alpha14 contributions to the T - R difference spectrum to be negligible and
confirmed Trp beta37 as the locus of the W3 difference signal, and probably of
the remaining Trp signals as well. The observed downshift of W17 and upshift of
Wd5 in the T-state are consistent with a stronger T-state H-bond between Trp
beta37 and Asp alpha94; the resulting excitation profile red shift accounts for
the dominance of the Trp beta37 contribution to the T - R difference UVRR
spectrum.
PMID- 9398300
TI - Flavin conformational changes in the catalytic cycle of p-hydroxybenzoate
hydroxylase substituted with 6-azido- and 6-aminoflavin adenine dinucleotide.
AB - Crystallographic studies have demonstrated two flavin conformations for p
hydroxybenzoate hydroxylase (PHBH) [Gatti, D. L., Palfey, B. A. , Lah, M. S.,
Entsch, B., Massey, V., Ballou, D. P., & Ludwig, M. L. (1994) Science 266, 110
114. Schreuder, H. A., Mattevi, A., Obmolova, G., Kalk, K. H., Hol, W. G. J., van
der Bolt, F. J. T., & van Berkel, W. J. H. (1994) Biochemistry 33, 10161-10170].
The isoalloxazine ring system of one conformation (the "out" conformation) is
significantly more exposed to solvent and is not in position for necessary
catalytic reactions, but when the natural substrate is bound to the enzyme, the
isoalloxazine is in the correct position (the "in" conformation) for its chemical
function. In this study, several aspects of the function of the conformational
change in catalysis were explored using the wild-type and Tyr222Phe forms of PHBH
substituted with 6-azido FAD. This flavin served as both a spectral probe and a
photolabel. The enzyme containing 6-azido FAD was a relatively effective catalyst
for the hydroxylation of p-hydroxybenzoate. However, the intermediate reduced 6
azido enzyme was chemically unstable, and a small fraction converted to 6-amino
PHBH by the elimination of N2 during each catalytic cycle. The reduction of 6
azido FAD PHBH by NADPH was almost as fast as the reduction of the natural
enzyme. The characteristic spectral change caused by NADPH binding prior to
hydride transfer strongly suggests that flavin movement from the "in" to the
"out" conformation precedes flavin reduction. Irradiation of 6-azido PHBH with
visible light covalently labeled proline 293, an active site residue, under
conditions in which the flavin adopted the "in" conformation, while no protein
labeling occurred under conditions in which the flavin was "out". The labeled
protein exchanged substrate and was reduced by NADPH much more slowly than before
photolysis. It is therefore concluded that isoalloxazine movement is required for
pyridine nucleotide to gain access to the active site and for the exchange of
aromatic ligands.
PMID- 9398301
TI - Inactivation of 4-oxalocrotonate tautomerase by 2-oxo-3-pentynoate.
AB - The compound, 2-oxo-3-pentynoate, has been synthesized and tested as an inhibitor
of the enzyme 4-oxalocrotonate tautomerase. The enzyme is rapidly and
irreversibly inactivated by the acetylenic product analogue in a time-dependent
fashion. The enzyme displays saturation kinetics and is protected from
inactivation by the presence of substrate. These observations are consistent with
inactivation taking place at the active site. Partial reactivation (
approximately 18%) occurs by incubating the inactivated enzyme with 10 mM
hydroxylamine (pH 7.3). The partition ratio, determined to be approximately 0.4,
suggests that the inactivation of 4-OT by 2-oxo-3-pentynoate shows half-of-the
sites stoichiometry. The same phenomenon is observed in the inactivation of 4-OT
by 3-bromopyruvate and can be explained by examination of the crystal structure.
Mass spectral analysis shows that a single residue is modified on the enzyme
which has been localized to the nine residue amino-terminal fragment Pro-1 to Glu
9. It can be reasonably concluded that Pro-1 is the site of covalent attachment.
Inactivation of 4-OT can occur by either a Michael addition of 4-OT to C-4 of 2
oxo-3-pentynoate or by the enzyme-catalyzed rearrangement of 2-oxo-3-pentynoate
to an allene derivative which alkylates Pro-1. These results provide the
foundation for the use of 2-oxo-3-pentynoate in future mechanistic studies and as
a ligand in an inactivated 4-OT complex that can be studied by X-ray
crystallography. Finally, 2-oxo-3-pentynoate is an acetylene analogue of a
variety of 2-oxo acids and as such may have general utility as an inhibitor of
reactions that bind and process these compounds.
PMID- 9398302
TI - Participation of ADP dissociation in the rate-determining step in cAMP-dependent
protein kinase.
AB - Pre-steady-state kinetic analyses of the catalytic subunit of cAMP-dependent
protein kinase showed that the rate constant for phosphoryl transfer is fast and
either the release of one or both of the products or a conformational change
controls turnover [Grant, B., & Adams, J. A. (1996) Biochemistry 35, 2022-2029].
To determine which step or steps control turnover in the wild-type enzyme, we
used a catalytic trapping technique to measure directly the dissociation rate
constant for ADP. The phosphorylation of two peptide substrates, LRRASLG and
GRTGRRNSI, was monitored using a rapid quench flow technique under conditions
where saturating concentrations of ADP were preequilibrated with the enzyme
before excess ATP and one of the substrates were added to trap the free enzyme
and to start the phosphorylation reaction. Under ADP preequilibration conditions,
no 'burst' phase was observed, and although the rate of linear, steady-state
turnover was unaffected, the net production of phosphopeptide lagged behind the
non-preequilibrated control. This phenomenon occurs due to the slow release of
the product, and kinetic modeling suggests that this effect can be explained if
the dissociation rate constant for ADP is 24 s-1 and solely limits turnover (kcat
= 23 s-1) for the phosphorylation of LRRASLG. Using GRTGRRNSI, the dissociation
rate constant for ADP is 35 s-1 and limits turnover (kcat = 29 s-1) if the
reaction is initiated by the addition of enzyme. Under preequilibration
conditions with either ATP or GRTGRRNSI, turnover is approximately 50% lower,
suggesting that ADP release may partially control this parameter. This
preequilibration effect can be explained by slowly interconverting enzyme forms
with specific peptide-induced turnover properties. These studies indicate that
ADP release is an essential rate-limiting component for turnover but also
suggests that other factors contribute subtly when the structure of the substrate
is altered.
PMID- 9398303
TI - Changes in protonation associated with substrate binding and Cob(I)alamin
formation in cobalamin-dependent methionine synthase.
AB - Methionine synthase catalyzes the transfer of a methyl group from methylcobalamin
enzyme to homocysteine, generating methionine and cob(I)alamin enzyme, and then
from methyltetrahydrofolate to cob(I)alamin enzyme, generating tetrahydrofolate
and regenerating the methylcobalamin enzyme. The reactions catalyzed by
methionine synthase require deprotonation of the substrate, homocysteine, and
protonation of the product tetrahydrofolate, with no net change in proton
stoichiometry for a complete turnover cycle. In addition, formation of the
intermediate cob(I)alamin enzyme requires a change in the cobalt ligand geometry
from 6-coordinate to 4-coordinate, and this rearrangement may require the
transient protonation of protein residues to stabilize the cob(I)alamin enzyme.
In the E. coli enzyme, the lower face of the methylcobalamin cofactor is
coordinated by histidine 759, which is hydrogen bonded to aspartate 757 and then
to serine 810, forming a "ligand triad". It has previously been shown that
reduction of cob(II)alamin enzyme to cob(I)alamin is associated with the uptake
of a proton from solution, and it has been postulated that this proton resides
within the His759-Asp757 pair. Cob(I)alamin can also be generated by
demethylation of methylcobalamin enzyme by homocysteine; it was not known whether
this mode of cob(I)alamin formation was associated with proton uptake. In this
paper, we use equilibrium titrations and kinetic analyses in the presence of the
pH indicator dye phenol red, along with studies of the pH dependence of
oxidation/reduction equilibria, to identify and characterize mechanistic steps
associated with proton uptake and release in both the turnover and reactivation
of the enzyme. We confirm that cob(I)alamin formation by reduction of
cob(II)alamin enzyme is associated with proton uptake and show that mutation of
Asp757 to Glu abolishes the pH dependence of this reduction. Demethylation of
methylcobalamin enzyme also leads to cob(I)alamin formation and is also shown to
be associated with proton uptake. By observing pre-steady-state reactions with
homocysteine and methyltetrahydrofolate in the presence of phenol red, we show
that this proton uptake occurs at a rate that is equal to the rate of formation
of the cob(I)alamin enzyme. In addition, we show that binding of homocysteine to
the enzyme results in the rapid release of a proton, presumably the homocysteine
thiol proton. In contrast, binding methyltetrahydrofolate to the enzyme does not
result in proton uptake, suggesting that the proton destined for the product
tetrahydrofolate is already present on the free methylcobalamin enzyme.
PMID- 9398304
TI - Cobalamin-dependent methionine synthase from Escherichia coli: involvement of
zinc in homocysteine activation.
AB - Methionine synthase (MetH) is a modular protein with at least four distinct
regions; amino acids 2-353 comprise a region responsible for binding and
activation of homocysteine, amino acids 345-649 are thought to be involved in the
binding and activation of methyltetrahydrofolate, amino acids 650-896 are
responsible for binding of the prosthetic group methylcobalamin, and amino acids
897-1227 are involved in binding adensylmethionine and are required for reductive
activation of enzyme in the cob(II)alamin form. Previous studies have shown that
mutations of Cys310 or Cys311 to either alanine or serine result in loss of all
detectable catalytic activity. These mutant proteins retain the ability to
catalyze methyl transfer from methyltetrahydrofolate to exogenous cob(I)alamin,
but have lost the ability to transfer methyl groups from exogenous
methylcobalamin to homocysteine [Goulding, C. W., Postigo, D., and Matthews, R.
G. (1997) Biochemistry 36, 8082-8091]. We now demonstrate that both MetH
holoenzyme and a truncated MetH(2-649) protein, which lacks a cobalamin
prosthetic group, contain 0.9 equiv of zinc, while the Cys310Ser and Cys311Ser
mutant proteins contain less than 0.05 equiv of zinc. Addition of l-homocysteine
to MetH(2-649) is accompanied by release of 1 equiv of protons/mol of protein,
while addition of l-homocysteine to the Cys310Ser and Cys311Ser mutant truncated
proteins does not result in proton release. The Cys310Ala and Cys311Ala mutant
methylcobalamin holoenzymes have completely lost the ability to transfer the
methyl group from methylcobalamin to homocysteine, suggesting that zinc is
required for this reaction. Further evidence that zinc is required for catalytic
activity comes from experiments in which the zinc is removed from MetH(2-1227).
Removal of zinc from methylated wild-type holoenzyme by treatment with methyl
methanethiolsulfonate and then with dithiothreitol and EDTA results in loss of
the ability of the protein to catalyze methyl transfer from
methyltetrahydrofolate to homocysteine. Reconstitution of the zinc-depleted
holoenzyme results in incorporation of 0.4 equiv of zinc/mol of protein and
partial restoration of the ability of the protein to catalyze homocysteine
methylation.
PMID- 9398305
TI - Glutamate and aspartate as proton shuttles in mutants of carbonic anhydrase.
AB - Maximal turnover rates for the hydration of CO2 and the depletion of 18O from CO2
catalyzed by carbonic anhydrase III (CA III) and carbonic anhydrase V (CA V) are
limited by proton transfer involving zinc-bound water or hydroxide in the active
site. We have investigated the capacity of glutamic and aspartic acids at
position 64 in human CA III and murine CA V to act as proton shuttles in this
pathway. The distance from the Calpha of position 64 to the zinc is near 9.5 A in
the crystal structures of both CA III and CA V. Rates of intramolecular proton
transfer between these proton shuttle groups and the zinc-bound water molecule
were estimated as the predominant rate-contributing step in the catalytic
turnover kcat in the hydration of CO2 measured by stopped flow and in the 18O
exchange between CO2 and water measured by mass spectrometry. We found that both
glutamate and aspartate residues at position 64 are efficient proton shuttles in
HCA III. The rate constant for intramolecular proton transfer from either residue
to zinc-bound hydroxide is 4 x 10(4) s-1, about 20-fold greater than that of the
wild type which has lysine at position 64. When the active site residue Phe 198
in human CA III was replaced with Leu, measurement of catalysis showed that Glu
64 retained but Asp 64 lost its capacity to act as a proton shuttle. These
observations were supported in studies of catalysis by murine CA V which contains
Leu 198; here again, Glu 64 acted as a proton shuttle, but Asp 64 did not. Phe
198 in HCA III is thus a significant factor in the capacity of the active site to
sustain proton transfer, possibly through its stabilization of hydrogen-bonded
water bridges that enhance proton translocation from both Glu and Asp at position
64 to the zinc-bound hydroxide.
PMID- 9398306
TI - Feed-back inhibition of oxidative stress by oxidized lipid/amino acid reaction
products.
AB - Three oxidized lipid/amino acid reaction products (OLAARPs): 1-methyl-4-pentyl
1,4-dihydropyridine-3,5-dicarbaldehyde, 1-(5-amino-1-carboxypentyl)pyrrole, and N
(carbobenzyloxy)-1(3)-[1-(formylmethyl)hexyl]-l-histidine dihydrate, were
prepared and tested for antioxidative activity in a microsomal system in order to
investigate the effect that OLAARP formation may be playing in the oxidative
stress process. The microsomal system consisted of freshly prepared trout muscle
microsomes, which were oxidized in the presence of 5 microM Cu2+, 1 mM Fe3+/5 mM
ascorbate, or 1 mM Cu2+/10 mM H2O2, and the compound to be tested as antioxidant
added at 50 microM. At different periods of time, samples were tested for lipid
peroxidation, assessed by the formation of thiobarbituric acid reactive
substances (TBARS), and protein damage, which was evaluated by the formation of
protein carbonyls and amino acid analysis. The three OLAARPs and butylated
hydroxytoluene significantly (p < 0.05) protected against lipid peroxidation and
protein damage for the three systems assayed. On the contrary, neither the amino
acids used in the preparation of OLAARPs nor alpha-tocopherol, mannitol,
aminoguanidine, or 4, 5-dihydroxy-1,3-benzenedisulfonic acid exhibited this
constant protection. Because OLAARPs were produced at inhibitory levels during
microsomal lipid peroxidation, these results suggest that OLAARP formation may be
an antioxidative defense mechanism by which oxidative stress is feed-back
inhibited, delaying the damage caused by reactive oxygen species.
PMID- 9398307
TI - Molecular mechanism of regulation of the pyruvate dehydrogenase complex from E.
coli.
AB - The pyruvate dehydrogenase multienzyme complex from E. coli shows a sigmoidal
dependency of the reaction rate on the substrate concentration when product
formation is followed in the presence of physiological concentrations of the
cofactor thiamin diphosphate. To elucidate the molecular mechanism of this
regulation, the influence of the substrate pyruvate on the coenzyme-protein
interaction has been investigated using several coenzyme analogues. The observed
binding constants of all coenzymatically active analogues are increased in the
presence of the substrate pyruvate, whereas those of all coenzymatically inactive
analogues are not altered in the presence of pyruvate. This points to an
increased binding affinity of a reaction-intermediate-coenzyme complex to the
protein. Since cofactor binding and dissociation at physiological concentrations
of thiamin diphosphate are slow compared to the catalytic reaction, a slow
transition to the active state of the enzyme occurs. After lowering the pyruvate
concentration, the opposite effect, a dissociation of the thiamin diphosphate
from the enzyme is observed. This slow substrate dependent enhancement of
cofactor binding enables efficient regulation of the pyruvate dehydrogenase
complex by its substrate pyruvate.
PMID- 9398308
TI - Histidine --> carboxamide ligand substitutions in the zinc binding site of
carbonic anhydrase II alter metal coordination geometry but retain catalytic
activity.
AB - The catalytic zinc ion of human carbonic anhydrase II (CAII) is coordinated by
three histidine ligands (H94, H96, and H119) and a hydroxide ion with tetrahedral
geometry. Structural and functional analysis of variants in which the zinc
ligands H94 and H119 are substituted with asparagine and glutamine, and
comparison with results obtained with aspartate and glutamate substitutions
indicate that the neutral ligand field provided by the protein optimizes the
electrostatic environment for the catalytic function of the metal ion, including
stabilization of bound anions. This is demonstrated by catalytic activity
measurements for ester hydrolysis and CO2 hydration, as well as sulfonamide
inhibitor affinity assays. High-resolution X-ray crystal structure determinations
of H94N, H119N, and H119Q CAIIs reveal that the engineered carboxamide side
chains coordinate to zinc with optimal stereochemistry. However, zinc
coordination geometry remains tetrahedral only in H119Q CAII. Metal geometry
changes to trigonal bipyramidal in H119N CAII due to the addition of a second
water molecule to the zinc coordination polyhedron and also in H94N CAII due to
the displacement of zinc-bound hydroxide by the bidentate coordination of a Tris
molecule. Possibly, the bulky histidine imidazole ligands of the native enzyme
play a role in disfavoring trigonal bipyramidal coordination geometry for zinc.
Protein-metal affinity is significantly compromised by all histidine -->
carboxamide ligand substitutions. Diminished affinity may result from significant
movements (up to 1 A) of the metal ion from its position in the wild-type enzyme,
as well as the associated, minor conformational changes of metal ligands and
their neighboring residues.
PMID- 9398309
TI - Evidence for a functional role of the dynamics of glycine-121 of Escherichia coli
dihydrofolate reductase obtained from kinetic analysis of a site-directed mutant.
AB - Two-dimensional heteronuclear (1H-15N) nuclear magnetic relaxation studies of
dihydrofolate reductase (DHFR) from Escherichia coli have demonstrated that
glycine-121 which is 19 A from the catalytic center of the enzyme has large
amplitude backbone motions on the nanosecond time scale [Epstein, D. M.,
Benkovic, S. J., and Wright, P. E. (1995) Biochemistry 34, 11037-11048]. In order
to probe the dynamic-function relationships of this residue, we constructed a
mutant enzyme in which this glycine was changed to valine. Equilibrium binding
studies indicated that the Val-121 mutant retained wild-type binding properties
with respect to dihydrofolate and tetrahydrofolate; however, binding to NADPH and
NADP+ was decreased by 40-fold and 2-fold, respectively, relative to wild-type
DHFR. Single-turnover experiments indicated that hydride transfer was reduced by
200-fold to a rate of 1.3 s-1 and was the rate-limiting step in the steady state.
Interestingly, pre-steady-state kinetic analysis of the Val-121 mutant revealed a
conformational change which preceded chemistry that occurred at a rate of 3.5 s
1. If this step exists in the kinetic mechanism of the wild-type enzyme, then it
would be predicted to occur at a rate of approximately 2000 s-1. Glycine-121 was
also changed to alanine, serine, leucine, and proline. While the Ala-121 and Ser
121 mutants behaved similar to wild-type DHFR, the Leu-121 and Pro-121 mutants
behaved like Val-121 DHFR in that hydride transfer was the rate-limiting step in
the steady state and a conformational change preceding chemistry was observed.
Finally, insertion of a glycine or valine between amino acids 121 and 122
produced mutant enzymes with properties similar to wild-type or Val-121 DHFRs,
respectively. Taken together, these results provide compelling evidence for
dynamic coupling of a remote residue to kinetic events at the active site of
DHFR.
PMID- 9398310
TI - Modification of aldose reductase by S-nitrosoglutathione.
AB - Kinetic and structural changes in recombinant human aldose reductase (AR) due to
modification by S-nitrosoglutathione (GSNO) were investigated. Incubation of the
enzyme with 10-50 microM GSNO led to a time- and concentration-dependent
inactivation of the enzyme, with a second-order rate constant of 0.087 +/- 0.009
M-1 min-1. However, upon exhaustive modification, 30-40% of the enzyme activity
was retained. The non-inactivated enzyme displayed a 2-3-fold change in Km for
NADPH and Km fordl-glyceraldehyde, whereas the Km for the lipid peroxidation
product, 4-hydroxy-2-trans nonenal (HNE), was comparable to that of the untreated
enzyme. The residual activity of the enzyme after GSNO treatment was less
sensitive to inhibition by the active site inhibitor sorbinil or to activation by
sulfate. Significantly higher catalytic activity was retained when the enzyme was
modified in the presence of NADPH, suggesting relatively low reactivity of the E
NADPH complex with GSNO. The modification site was identified using site-directed
mutants in which each of the solvent-exposed cysteines of the enzyme was replaced
individually by serine. The mutant C298S was insensitive to GSNO, whereas the
sensitivity of the mutants C303S and C80S was comparable to that of the wild-type
enzyme. Electrospray ionization mass spectroscopy of the GSNO-modified enzyme
revealed a major modified species (70% of the protein) with a molecular mass that
was 306 Da higher than that of the untreated enzyme, which is consistent with the
addition of a single glutathione molecule to the enzyme. The remaining 30% of the
protein displayed a molecular mass that was not significantly different from that
of the native enzyme. No nitrosated forms of the enzyme were observed. These
results suggest that inactivation of AR by GSNO is due to the selective formation
of a single mixed disulfide between glutathione and Cys-298 located at the
NADP(H)-binding site of the enzyme.
PMID- 9398311
TI - General acid/base catalysis in the active site of Escherichia coli thioredoxin.
AB - Enzymic catalysts of thiol:disulfide oxidoreduction contain two cysteine residues
in their active sites. Another common residue is an aspartate (or glutamate), the
role of which has been unclear. Escherichia coli thioredoxin (Trx) is the best
characterized thiol:disulfide oxidoreductase, and in Trx these three active-site
residues are Cys32, Cys35, and Asp26. Structural analyses had indicated that the
carboxylate of Asp26 is positioned properly for the deprotonation of the thiol of
Cys35, which would facilitate its attack on Cys32 in enzyme-substrate mixed
disulfides. Here, Asp26 of Trx was replaced with isologous asparagine and leucine
residues. D26N Trx and D26L Trx are reduced and oxidized more slowly than is wild
type Trx during catalysis by E.coli thioredoxin reductase. Stopped-flow
spectroscopy demonstrated that the cleavage of the mixed disulfide between Trx
and a substrate is slower in the D26N and D26L enzymes. Buffers increase the rate
of mixed disulfide cleavage in these variants but not in wild-type Trx. These
results indicate that Asp26 serves as an acid/base in the oxidation/reduction
reactions catalyzed by Trx. Specifically, Asp26 protonates (during substrate
oxidation) or deprotonates (during substrate reduction) the thiol of Cys35. A
similar role is likely filled by the analogous aspartate (or glutamate) residue
in protein disulfide isomerase, DsbA, and other thiol:disulfide oxidoreductases.
Moreover, these results provide the first evidence for general acid/base
catalysis in a thiol:disulfide interchange reaction.
PMID- 9398312
TI - Steady-state kinetics and inhibitor binding of 3-deoxy-D-arabino-heptulosonate-7
phosphate synthase (tryptophan sensitive) from Escherichia coli.
AB - The tryptophan-inhibited 3-deoxy-d-arabino-heptulosonate-7-phosphate synthase
[DAHPS(Trp)] of Escherichia coli was analyzed with respect to steady-state
kinetics and tryptophan binding. DAHPS(Trp) is one of three differentially
regulated isoforms that catalyze the first step of aromatic biosynthesis, the
condensation of phosphoenolpyruvate and erythrose-4-phosphate to form 3-deoxy-D
arabino-heptulosonate-7-phosphate. The DAHP synthase isozymes are
metalloproteins, being activated in vitro by a variety of divalent metals. Both
catalytic activity and substrate affinity are dependent on the species of
activating metal ion. We report here kinetic and binding studies of metal
homogeneous (Mn2+-activated) DAHPS(Trp). The homodimeric enzyme had an apparent
kcat of 21 s-1 and displayed sigmoidal kinetics with respect to both substrates.
The S0.5 was 35 microM for erythrose-4-phosphate and 5.3 microM for
phosphoenolpyruvate. Equilibrium binding studies with radiolabeled tryptophan
demonstrated two independent inhibitor binding sites per enzyme dimer, with KdTrp
of 1 microM. L-Tryptophan binding decreased kcat, increased affinity for both
substrates, decreased positive homotropic cooperativity for both substrates and
activated the enzyme at low concentrations of erythrose-4-phosphate. The results
suggest an inhibition mechanism analogous to system C5 hyperbolic mixed-type
inhibition with respect to erythrose-4-phosphate and partial noncompetitive
inhibition with respect to phosphoenolpyruvate.
PMID- 9398313
TI - Use of thiouredopyrenetrisulfonate photochemistry for driving electron transfer
reactions in aqueous solutions.
AB - Photoexcitation of 1-thiouredopyrene-3,6,8-trisulfonic adducts (TUPS) of amino
acids by the third harmonic frequency of a Nd:YAG laser (355 nm) generates the
triplet state of the dye with high quantum efficiency. Relaxation of the triplet
proceeds in anaerobiosis with a half decay time of 0.5 ms. The relaxation rate
increases 100-fold in the presence of dioxygen. A radiative transition between
the triplet and the ground state of the dye results in phosphorescent emission
centered at 658 nm. The excited state of TUPS, being a strong reductant, can
donate its electron to a variety of acceptors. Transient absorption spectroscopy
was used to directly measure the photoinduced electron transfer from the excited
dye to rhodamine B (RB) and cytochrome c. The reaction with RB was followed by
monitoring the oxidation of the triplet state of TUPS at 487 nm (epsilon = 25 000
+/- 5 000 M-1 cm-1) or the reduction of RB at 553 nm. The second order rate
constant for the reaction was found to be (2.5 +/- 0.2) x 10(9) M-1 s-1, a value
compatible with that for diffusion controlled reactions. When directed to
cytochrome c the photoinduced perturbation causes rapid reduction of the
protein's heme group, seen as a monophasic increase of absorbance at 550 nm. The
combination of appropriate redox properties with the capability of covalent
protein modification makes the dye useful for initiation and analysis of electron
transfer reactions in chemical and biological systems.
PMID- 9398314
TI - Photoinduced electron transfer in singly labeled thiouredopyrenetrisulfonate
cytochrome c derivatives.
AB - A novel method for initiation of intramolecular electron transfer reactions in
cytochrome c is reported. The method is based on photoexcitation of covalently
attached thiouredopyrenetrisulfonate (TUPS) by the third harmonic frequency of a
Nd:YAG laser (355 nm), the reaction that generates the low-potential triplet
state of the dye with high quantum efficiency. TUPS derivatives of horse heart
cytochrome c singly labeled at specific lysine residues were prepared and
purified to homogeneity by ion-exchange high-pressure liquid chromatography.
Eight derivatives were characterized by determination of the location of the
modification, reduction potentials, and measurement of enzymatic activity with
cytochrome oxidase. Transient absorption spectroscopy was used to directly
measure the rate constants for the electron transfer reaction from the
photoexcited triplet state of TUPS to the oxidized heme group and the back
reaction from the ferrous heme to the oxidized dye. For all singly labeled
derivatives, the rate constants for heme reduction were 1 or 2 orders of
magnitude larger than for its reoxidation, consistent with the greater
thermodynamic driving force for the oxidation reaction. Analysis of the variation
of electron-transfer rates with the distance separating the dye and the heme
reveals a value of coupling decay constant (beta) of 0.46 A-1. Rapid and
effective photoreduction of cytochrome c makes it a useful tool for fast
initiation of electron transfer in the reductive direction within complexes of
cytochrome c with other redox proteins.
PMID- 9398315
TI - Cooperativity and regulation of scallop myosin and myosin fragments.
AB - Scallop heavy meromyosin (HMM) preparation obtained by a new improved method
showed a Mg-ATPase activity that was activated 15-fold by calcium. The ATPase
activity depended on ionic strength and reached maximum at 0.1 M without altering
calcium sensitivity. The highly regulated HMM and myosin preparations showed
cooperative properties not seen with unregulated subfragment 1 (S1). ATPase
activity of myosin and HMM increased steeply with calcium concentration, yielding
Hill coefficients about 3 and 4, respectively. Calcium binding by HMM and myosin
became cooperative in the presence of ADP, AMP-PNP, or ADP.Vi yielding Hill
coefficients of 1.8 and 2.8, respectively. Binding of calcium by HMM in the
presence of ATP was also cooperative at physiological ionic strength, whereas at
low ionic strength the data fit best to a simple binding curve. In contrast,
calcium binding by unregulated S1 followed a normal binding curve and was not
affected by the presence of nucleotide analogues. Calcium decreased the affinity
of ADP and ADP-PNP to myosin and HMM, but had no effect on the nucleotide binding
to S1. The results indicate that communication between the nucleotide and calcium
binding sites requires the presence of two heads and exists only in the "off"
state. We propose that in the presence of calcium, interaction between the two
heads is disrupted and they act independently.
PMID- 9398316
TI - Alignment of fibrillin molecules in elastic microfibrils is defined by
transglutaminase-derived cross-links.
AB - Microfibrils were extracted from human amnion in the form of a beaded filament
and analyzed for the presence of transglutaminase-derived cross-links using
acrylonitrile derivatization. The cross-link structure was isolated from protease
hydrolysates of beaded filaments and identified as a phenylthiocarbamyl amino
acid derivative by comparison to a standard. Acid hydrolysis of the isolated
cross-link gave the expected lysine and glutamic acid in a 1:1 ratio. The beaded
filaments were also treated with trypsin to produce a fraction that contained the
bead structure and a fraction containing fragments of the interbead filaments.
Cross-links were detected in the interbead filaments but not in the beads. A
large tryptic peptide that contained a cross-link was isolated and sequenced. The
two amino acid sequences obtained identified both of the cross-linked molecules
as fibrillin-1 and enabled the approximate localization of the cross-link sites
within the molecule. The locations of cross-link sites on two adjacent molecules
fixed the relative positions of fibrillin monomers within the microfibrils,
providing insight into the spatial organization of fibrillin within the elastic
microfibrils.
PMID- 9398317
TI - Probing the effects of calcium on gelsolin.
AB - Gelsolin is a calcium-regulated actin severing and capping protein that binds two
calcium ions and has three sites for actin; two recognize monomeric actin and one
attaches to the sides of filaments. It contains six repeating sequence segments
(G1-6). Here, we have analyzed the effects of calcium ions on (i) limited
proteolysis of bacterially expressed human gelsolin by plasmin and (ii) dynamic
light scattering and circular dichroism of gelsolin and various of its
subdomains. Following cleavage of gelsolin in the absence of calcium between
Lys150 and His151 (the junction between G1 and G2), the molecule does not fall
apart, nor does it bind actin without added calcium. This same molecule can be
reconstituted by mixing an excess of G1 with G2-6 in EGTA. The noncovalently
linked form of gelsolin shows three actin binding sites in calcium and requires 3
microM calcium for 50% activation of actin binding. Measurements of light
scattering and circular dichroism revealed structural changes in response to
calcium for intact gelsolin and a number of its actin-binding subdomains. Many of
these changes occurred at calcium concentrations below 100 nM. These results are
discussed in relation to the calcium control of gelsolin function and its three
dimensional structure (Burtnick et al.(1997) Cell 90, 661-670). Nanomolar
concentrations of calcium initiate the unlatching of structural constraints that
maintain the inaccessibility of the actin binding sites, but actin binding occurs
only after additional micromolar calcium sites in both the N-terminal and C
terminal halves of the molecule are occupied.
PMID- 9398318
TI - Identification of acetylcholine receptor channel-lining residues in the M1
segment of the beta-subunit.
AB - The substituted cysteine accessibility method (SCAM) was applied to the first
membrane-spanning segment (M1) of the mouse-muscle acetylcholine (ACh) receptor
beta subunit. One at a time, each residue from betaR219 to betaP247, except
betaC233, was mutated to Cys, and the mutant beta subunits were expressed
together with wild-type alpha, gamma, and delta in Xenopus oocytes. All 28
mutants yielded functional receptors. The accessibility of the substituted Cys to
the methanethiosulfonate (MTS) derivatives, MTS ethylammonium (MTSEA), MTS
ethyltrimethylammonium (MTSET), and MTS ethylsulfonate (MTSES), added
extracellularly in the absence or the presence of ACh, was inferred from their
irreversible effects on ACh-induced current. Three consecutive residues close to
the extracellular end of M1, betaF224C, betaY225C, and betaL226C, reacted both in
the absence and presence of ACh, and one deeper residue, betaV229C reacted only
in the presence of ACh. betaV229C also reacted with 2-aminoethyl-2
aminoethanethiosulfonate (AEAETS) and with 2-hydroxyethyl MTS (MTSEH). The rate
constants for the reactions of betaV229C with MTSEA, which permeates the open
channel, and with MTSEH, which is uncharged, were independent of membrane
potential. The rate constant for the reaction of the doubly positively charged
AEAETS, however, was dependent on membrane potential, consistent with the
exposure of betaV229C in the open channel. The N-terminal third of betaM1, like
that of alphaM1, contributes to the lining of the channel and undergoes
structural changes during gating.
PMID- 9398319
TI - Orientation in lipid bilayers of a synthetic peptide representing the C-terminus
of the A1 domain of shiga toxin. A polarized ATR-FTIR study.
AB - The interaction of a synthetic peptide representing the C-terminal 27 amino acids
of the A1 domain of Shiga toxin (residues 220-246) with acidic phospholipid model
membranes was characterized by FTIR spectroscopy. This peptide resembles a signal
sequence and may mediate the translocation of the catalytic A1 chain of Shiga
toxin to the cytoplasm following its retrograde transport to the lumenal
compartment of the endoplasmic reticulum (ER). At pH 7 and 5, the peptide
underwent a conformational change from random coil to alpha-helix upon addition
of negatively charged phospholipids. Examination of the amide II band in the
spectrum of the complex at pH 7 and pH 5 showed that in both cases, the N-H
groups in the peptide backbone are largely protected from H/D exchange. Using
polarized attenuated total reflectance Fourier transform infrared spectroscopy
(ATR-FTIR) measurements, the orientation of the alpha-helical portion of the
peptide was found to be almost perpendicular with respect to the membrane plane
at pH 7. However, at pH 5.0-5.4, the alpha-helix axis was preferentially oriented
parallel to the membrane plane. The results suggest that at the neutral pH of the
ER lumen, the peptide may insert into the membrane, while at the lower pH levels
present in earlier endocytic compartments, the peptide would be less likely to
traverse the bilayer. In summary, this putative signal peptide may not be able to
cause a significant translocation of the A1 domain of Shiga toxin to the cytosol
until it reaches the neutral pH of the ER compartment.
PMID- 9398320
TI - MAP4 is the in vivo substrate for CDC2 kinase in HeLa cells: identification of an
M-phase specific and a cell cycle-independent phosphorylation site in MAP4.
AB - We reported previously that cdc2 kinase decreased the microtubule-stabilizing
ability of a major HeLa cell microtubule-associated protein, MAP4, by
phosphorylation in vitro [Ookata, K., et al. (1995) J. Cell Biol. 128, 849-862].
An important question raised by this study is whether MAP4 is indeed
phosphorylated by cdc2 kinase at mitosis in vivo. We present here evidence that
cdc2 kinase is the major M-phase MAP4 kinase, and, further, we identify two
phosphorylation sites within the proline-rich domain of MAP4. Metabolic 32P
labeling showed the increased phosphorylation of MAP4 at mitosis. A specific
inhibitor of cdc2 kinase, butyrolactone I, inhibited phosphorylation of MAP4 both
in mitotic HeLa cells and in the mitotic HeLa cell extract. The phosphopeptide
map analysis revealed the high similarity of in vivo labeled mitotic MAP4 to that
phosphorylated by cdc2 kinase in vitro. Ser-696 and Ser-787, both of which lie
within SPXK consensus sequences for cdc2 kinase, were identified as
phosphorylation sites in the proline-rich region of MAP4 in vivo and in vitro.
Immunoblotting with antibodies that recognize the phosphorylation state of Ser
696 or Ser-787 showed that Ser-787 in the SPSK sequence was specifically
phosphorylated at mitosis while Ser-696 in the SPEK sequence was phosphorylated
both at mitosis and in interphase. These results suggest that cdc2 kinase
directly regulates microtubule dynamics at mitosis through phosphorylation of
MAP4 at a number of sites, including Ser-787.
PMID- 9398321
TI - Covalent attachment of ethidium to DNA results in enhanced topoisomerase II
mediated DNA cleavage.
AB - The classic DNA intercalator, ethidium, was used to probe the effects of (i)
intercalation and (ii) covalent modification of the DNA on the catalytic activity
of topoisomerase II. Ethidium bromide, which binds reversibly to DNA via
intercalation, does not stimulate topoisomerase II-mediated DNA cleavage at
concentrations up to 100 microM, indicating that the intercalative binding of
this molecule to DNA is not sufficient to alter the activity of the enzyme. In
contrast, covalent attachment of the photoreactive ethidium analog to DNA
resulted in marked enhancement of topoisomerase II-mediated single- and double
stranded DNA cleavage. This increase in DNA cleavage was observed at very low
drug binding densities (<1 drug per 10-80 base pairs) which correspond to
nanomolar concentrations, as compared with other topoisomerase II poisons such as
etoposide or m-AMSA which require micromolar concentrations to elicit comparable
DNA cleavage levels. Over the past decade, topoisomerase II has been an important
target for a variety of clinically relevant anticancer agents due to the
abilities of these agents to convert this enzyme to a cellular toxin resulting in
an increase in the levels of enzyme-mediated DNA breaks. Modification of DNA by
covalently attaching a DNA-targeting intercalating agent (i.e., ethidium bromide)
resulted in a marked shift of the cleavage/religation equilibrium of the enzyme
toward the cleaved state "poison" topoisomerase II as observed by the enhancement
in single- and double-stranded cleavage; thus, key insight was gained into the
mechanism(s) through which DNA binding agents may influence the catalytic
properties of topoisomerase II. These data demonstrate that conversion of a
reversible ethidium-DNA complex to an irreversible adduct results in the
transformation of an ineffective intercalating drug into a potent topoisomerase
II-targeted agent. Finally, they provide support for the recently proposed
"positional poisoning model" for the actions of DNA lesions and anticancer drugs
on the type II enzyme.
PMID- 9398322
TI - Elongation properties of vaccinia virus RNA polymerase: pausing, slippage, 3' end
addition, and termination site choice.
AB - We have analyzed the elongation properties of vaccinia virus RNA polymerase
during a single round of transcription in vitro. RNA-labeled ternary complexes
were halted at a unique template position located upstream of a T-run (TTTTTTTTT)
in the nontemplate strand; this element encodes an RNA signal for factor
dependent transcription termination at distal sites on the template. The halted
ternary complexes were purified and allowed to resume elongation under a variety
of conditions. We found that the T-run constituted a strong elongation block,
even at high nucleotide concentrations. The principal sites of pausing were at a
C position situated two nucleotides upstream of the first T in the T-run and at
the first three to four T positions within the T-run. There was relatively little
pausing at the five downstream Ts. Intrinsic pausing was exacerbated at
suboptimal nucleotide concentrations. Ternary complexes arrested by the T-run at
10 microM NTPs rapidly traversed the T-run when the NTP pool was increased to 1
mM. Limiting GTP (1 microM) resulted in polymerase stuttering at the 3' margin of
the T-run, immediately prior to a templated G position; this generated a ladder
of slippage synthesis products. We found that vaccinia ternary complexes remained
intact after elongating to the very end of a linear DNA template and that such
complexes catalyzed the addition of extra nucleotides to the 3' end of the RNA
chain. The 3' end addition required much higher concentrations of NTPs than did
templated chain elongation. Finally, we report that factor-dependent
transcription termination by vaccinia RNA polymerase downstream of the T-run was
affected by nucleotide concentration. Limiting UTP caused the polymerase to
terminate at sites closer to the UUUUUNU termination signal. This is consistent
with the kinetic coupling model for factor-dependent termination.
PMID- 9398323
TI - DNA-Binding properties of the replication telomere protein.
AB - The replication Telomere Protein, rTP, is a nuclear protein from the ciliate
Euplotes crassus that appears to be a novel telomere replication factor. rTP
shares extensive amino acid sequence identity with the two proteins that bind and
protect the macronuclear telomeres from the ciliates Oxytricha and Euplotes.
Since the most extended regions of conservation fall within the DNA-binding
domains of the telomere-binding proteins, when rTP was first identified it was
predicted to be another structural telomere-binding protein. However, subsequent
research demonstrated that rTP transcripts accumulate only during DNA replication
and the rTP protein localizes to the sites of DNA replication within Euplotes
macronuclei. We have now expressed rTP in a heterologous expression system and
have examined the DNA-binding properties of the recombinant protein. We show that
rTP binds specifically to the G-strand of Euplotes telomeric DNA and hence has
some of the same DNA-binding characteristics as the Euplotes and Oxytricha
telomere-binding proteins. However, other aspects of rTP binding are unique. In
particular, the protein exhibits a very high off-rate and can bind double
stranded DNA as well as internal tracts of telomeric sequence. We conclude that
rTP and the telomere-binding proteins are members of a class of proteins that
have a conserved DNA-binding motif tailored to bind the G-strand of telomeric
DNA. However, the unique DNA-binding characteristics of rTP indicate that the
protein has evolved to fulfil a specialized role during telomere replication.
PMID- 9398324
TI - A novel dCMP methylase by engineering thymidylate synthase.
AB - X-ray crystal structures of binary complexes of dUMP or dCMP with the
Lactobacillus caseiTS mutant N229D, a dCMP methylase, revealed that there is a
steric clash between the 4-NH2 of dCMP and His 199, a residue which normally H
bonds to the 4-O of dUMP but is not essential for activity. As a result, the
cytosine moiety of dCMP is displaced from the active site and the catalytic thiol
is moved from the C6 of the substrate about 0.5 A further than in the wild-type
TS-dUMP complex. We reasoned that combining the N229D mutation with mutations at
residue 199 which did not impinge on the 4-NH2 of dCMP should correct the
displacements and further favor methylation of dCMP. We therefore prepared
several TS N229D mutants and characterized their steady state kinetic parameters.
TS H199A/N229D showed a 10(11) change in specificity for methylation of dCMP
versus dUMP. The structures of TS H199A/N229D in complex with dCMP and dUMP
confirmed that the position and orientation of bound dCMP closely approaches that
of dUMP in wild-type TS, whereas dUMP was displaced from the optimal catalytic
binding site.
PMID- 9398325
TI - Human histone acetyltransferase GCN5 exists in a stable macromolecular complex
lacking the adapter ADA2.
AB - Acetylation of core histones is an important regulatory step in transcriptional
activation from chromatin templates. The yeast transcriptional coactivator
protein GCN5 was recently shown to be a nuclear histone acetyltransferase (HAT).
Genetic and biochemical studies in yeast suggest that GCN5 functions with the
adapter proteins ADA1, ADA2, ADA3, and ADA5 in a heteromeric complex. We have
established conditions for chromatographic fractionation of HATs and ADA2 from
human K562 erythroleukemia cells. Gel-filtration chromatography revealed two
populations of GCN5 with Stokes' radii of 67 and 33 A, consistent with a large
macromolecular complex and a monomer, respectively. The GCN5-related HAT, PCAF,
was resolved as a stable complex with a Stokes' radius of 74 A. The HAT complexes
were resistant to 0.3 M NaCl and DNase I. ADA2 was characterized by a Stokes'
radius of 35 A, consistent with a monomer. Thus, in contrast to the stable GCN5
adapter complex in yeast, human GCN5 and ADA2 are not stably associated with each
other. The implications of this result are discussed vis-a-vis the mechanism of
recruitment of GCN5 to regulatory regions of genes.
PMID- 9398326
TI - Short-chain phosphatidylinositol conformation and its relevance to
phosphatidylinositol-specific phospholipase C.
AB - The solution conformation of chiral diheptanoylphosphatidylinositol (D- and L
inositol isomers) has been characterized by NMR spectroscopy. A positive NOE
between the inositol C2 proton and an sn-3 glycerol CH2 proton has been observed
in the D- but not in the L-inositol isomer of diheptanoylphosphatidylinositol
(PI). Computer modeling using QUANTA constrained by this NOE and ring coupling
constants suggests that the inositol ring is nearly parallel to the chain packing
direction, leaving the phosphate ester accessible to attack by
phosphatidylinositol-specific phospholipase C enzymes. In this model, the
hydroxyl groups in the 2- and 6-positions of inositol form hydrogen bonds with
the pro-R and ester oxygens, respectively. Chemical shifts and 13C spin-lattice
relaxation times were also used to assess conformation and lipid dynamics in
monomer and micelle states. The 13C T1's of inositol C2 and C6 in monomeric
phosphatidylinositol were markedly less than for other inositol ring carbons.
These results are consistent with the hydrogen bonds to the phosphate
constraining the motions of C2 and C6. Diheptanoylphosphatidyl-2-O-methylinositol
is a good inhibitor of PI-specific phospholipase C because it blocks the initial
phosphotransferase step in PI hydrolysis. Introduction of the methyl group on the
C-2 hydroxyl group lowers the CMC of the derivative compared to
diheptanoylphosphatidylinositol. However, an NOE between an sn-3 glycerol proton
and the inositol C2 proton constrains the orientation of the inositol ring with
respect to the glycerol backbone in a conformation similar to
diheptanoylphosphatidylinositol. Modeling of the 2-O-methylinositol derivative
suggests that the methyl group blocks one side of the phosphate, consistent with
the observation that nonspecific phospholipase C enzymes which are able to
hydrolyze PI, albeit poorly, are unable to hydrolyze diheptanoylphosphatidyl-2-O
methylinositol.
PMID- 9398327
TI - Functional consequence of mutating conserved residues of the yeast farnesyl
protein transferase beta-subunit Ram1(Dpr1).
AB - Ras proteins, fungal mating pheromones, and other proteins terminating in the
sequence CaaX (where C is Cys, a is any aliphatic amino acid, and X is the C
terminal residue) are posttranslationally prenylated. Farnesyl-protein
transferase (FPTase) transfers the farnesyl moiety of farnesyl pyrophosphate
(FPP) to the thiol of the CaaX box cysteine in a reaction that requires Zn2+ and
Mg2+. We have created mutations in conserved amino acids of the yeast Ram1
protein to identify residues important for Zn2+-dependent FPTase activity. Wild
type and mutant Ram1 proteins were expressed as operon fusions in bacteria, and
FPTase activity was measured. Mutations in conserved residues Glu256, His258,
Asp307, Cys309, Asp360, and His363 reduce FPTase activity. Asp307, Cys309, and
His363 correspond to the residues that have been shown to coordinate Zn2+ in
mammalian FPTase. The H258N mutant enzyme exhibited an increased sensitivity to
the Zn2+ chelator 1,10-phenanthroline, required higher concentrations of Zn2+ to
restore activity to the apoenzyme, and had a 10-fold reduction in catalytic
efficiency. The decreases in FPTase activity observed do not appear to be caused
by major structural perturbations because the mutants were stably expressed and
retained the ability to interact with Ram2p during purification. The FPTase
activity of the mutants measured in vitro correlated well with their ability to
complement the mating and growth defects of a ram1Delta strain in vivo.
PMID- 9398328
TI - Structural studies of detergent-solubilized and vesicle-reconstituted low-density
lipoprotein (LDL) receptor.
AB - The low-density lipoprotein (LDL) receptor plays a key role in maintaining
circulating and cellular cholesterol homeostasis. The LDL receptor is a
transmembrane glycoprotein whose biochemical and genetic properties have been
extensively studied notably by Brown, Goldstein and colleagues [Brown, M. S., &
Goldstein, J. L., (1986) Science 232, 34-47]. However, few if any structural
studies of the LDL receptor have been reported, and details of its secondary and
tertiary structure are lacking. In an attempt to determine the low-resolution
structure of the LDL receptor, we have purified the receptor from bovine adrenal
cortices using modifications of the method of Schneider et al. [Schneider, W. J.,
Goldstein, J. L., & Brown, M. S. (1985) Methods in Enzymol.109, 405-417]. Using
circular dichroism, the secondary structure of the detergent-solubilized bovine
LDL receptor at 25 degrees C was shown to be 19% alpha-helix, 42% beta-sheet, and
39% random coil. Interestingly, the detergent-solubilized receptor appeared to be
quite resistant to changes in secondary structure over the temperature range 10
90 degrees C, with only minor but reversible changes being observed. In contrast,
a more pronounced unfolding of the detergent-solubilized receptor was observed in
the presence of guanidinium hydrochloride. Using the complete sequence of the
human LDL receptor, sequence analysis by the Chou-Fasman prediction algorithm
showed quite good agreement with the experimentally determined secondary
structure of the bovine LDL receptor at 25 degrees C. Finally, the purified,
bovine LDL receptor was reconstituted into large unilamellar vesicles of egg yolk
phosphatidylcholine using a procedure exploiting preformed vesicles and detergent
dialysis. We showed previously using negative stain electron microscopy that
reconstituted vesicles bind LDL. Now, using cryoelectron microscopy of frozen
hydrated reconstituted vesicles evidence of an extended, stick-like morphology
(length approximately 120 A) for the extracellular domain of the LDL receptor has
been obtained. Successful purification of the receptor, its incorporation into
single bilayer vesicles, and its direct visualization by cryoelectron microscopy
pave the way for more detailed structural studies of the LDL receptor and the
receptor-LDL complex.
PMID- 9398329
TI - Suppression of phospholipase C beta, gamma, and delta families alters cell growth
and phosphatidylinositol 4,5-bisphosphate levels.
AB - Phosphatidylinositol-specific phospholipase C (PLC) activity reflects a summation
of the activities of three families, beta, gamma, and delta, each of which is
regulated differently. In order to understand the contribution of each family to
cell proliferation signaling, expression of each family was suppressed by use of
an inducible expression vector for antisense PLC sequences in a single cell line,
FTO-2B rat hepatocytes. Activation of second messengers of PLC [diacylglycerol
(DAG) and inositol 1,4,5-tris(phosphate) (IP3)] was dramatically reduced,
providing a strategy for probing the consequences of PLC deficiency on cell
function. Importantly, while one PLC family was suppressed, the other PLCs
actively responded to specific stimuli, suggesting parallel and independent
signaling pathways for each PLC family in FTO-2B cells. Selective suppression of
each PLC family altered cell growth markedly and differentially. The rank order
for suppression of cell growth by loss of a PLC family was gamma > delta > beta.
Exploration of down-stream growth regulators revealed that loss of beta and
gamma, but not delta, families was associated with markedly reduced basal ras and
protein kinase C activity. Moreover, suppression of each of the three PLC
families caused remarkably reduced basal and stimulated MAP kinase activities.
Interestingly, cellular levels of PIP2 were increased and dramatically correlated
with growth inhibition rate in the clones with suppressed PLC activity,
suggesting that PIP2 itself can serve as a second messenger of cell growth
regulation.
PMID- 9398330
TI - Localization of the heme binding region in soluble guanylate cyclase.
AB - Soluble guanylate cyclase (sGC) is a heterodimeric hemoprotein composed of alpha1
and beta1 subunits. sGC is activated by nitric oxide (NO) and therefore plays a
central role in NO signal transduction. Activation of sGC by NO is believed to be
mediated by the interaction between NO and the heme of sGC. Spectroscopic and
kinetic studies have shown that the heme of sGC is in a unique environment.
Characterization of the heme environment is critical to the understanding of the
mechanism of NO activation. To approach this goal, the beta1 N-terminal fragment
consisting of residues 1-385 [beta1(1-385)] of sGC was expressed in E. coli.
beta1(1-385) was then purified to homogeneity in two steps by DEAE ion exchange
and gel filtration chromatography. Purified beta1(1-385) was found to contain a
stoichiometric amount of heme. The UV-visible spectrum of beta1(1-385) is almost
identical to that of the native heterodimeric sGC purified from bovine lung.
beta1(1-385) binds both NO and CO, leading to a shift in the Soret maximum from
431 nm to 398 and 423 nm, respectively. These spectral shifts are identical to
those observed with heterodimeric sGC purified from bovine lung. These results
suggest that the heme in the beta1(1-385) is similar to that in the heterodimeric
sGC. Therefore, for the first time, the heme binding region of sGC has been
unambiguously localized to the N-terminal region of the beta1 subunit. Our data
also suggest that the N-terminal region of the beta1 subunit of sGC is itself
sufficient for heme binding.
PMID- 9398331
TI - A targeted library of small-molecule, tyrosine, and dual-specificity phosphatase
inhibitors derived from a rational core design and random side chain variation.
AB - Tyrosine phosphatases (PTPases) dephosphorylate phosphotyrosines while dual
specificity phosphatases (DSPases) dephosphorylate contiguous and semicontiguous
phosphothreonine and phosphotyrosine on cyclin dependent kinases and mitogen
activated protein kinases. Consequently, PTPases and DSPases have a central role
controlling signal transduction and cell cycle progression. Currently, there are
few readily available potent inhibitors of PTPases or DSPases other than
vanadate. Using a pharmacophore modeled on natural product inhibitors of
phosphothreonine phosphatases, we generated a refined library of novel, phosphate
free, small-molecule compounds synthesized by a parallel, solid-phase
combinatorial-based approach. Among the initial 18 members of this targeted
diversity library, we identified several inhibitors of DSPases: Cdc25A, -B, and
C and the PTPase PTP1B. These compounds at 100 microM did not significantly
inhibit the protein serine/threonine phosphatases PP1 and PP2A. Kinetic studies
with two members of this library indicated competitive inhibition for Cdc25
DSPases and noncompetitive inhibition for PTP1B. Compound AC-alphaalpha69 had a
Ki of approximately 10 microM for recombinant human Cdc25A, -B, and -C, and a Ki
of 0.85 microM for the PTP1B. The marked differences in Cdc25 inhibition as
compared to PTP1B inhibition seen with relatively modest chemical modifications
in the modular side chains demonstrate the structurally demanding nature of the
DSPase catalytic site distinct from the PTPase catalytic site. These results
represent the first fundamental advance toward a readily modifiable pharmacophore
for synthetic PTPase and DSPase inhibitors and illustrate the significant
potential of a combinatorial-based strategy that supplements the rational design
of a core structure by a randomized variation of peripheral substituents.
PMID- 9398332
TI - Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a clathrin-associated
protein is negatively regulated by tyrosine phosphorylation.
AB - CTLA-4 (CD152), high-avidity receptor for CD80 and CD86, is a powerful regulator
of T cell activation. While CTLA-4 functions at the cell surface, it is primarily
localized in intracellular vesicles and cycles to the cell surface. The CTLA-4
cytoplasmic domain contains sequences that direct its intracellular localization
and regulate its signaling. Here we demonstrate that effector molecules involved
in receptor trafficking and signaling interact with distinct, but overlapping,
sequences in the CTLA-4 cytoplasmic domain. Using the yeast two-hybrid method, we
demonstrate association of the mu2 subunit of AP-2, the clathrin-associated
complex found in plasma membrane-associated coated pits, with the cytoplasmic
tail of CTLA-4, but not CD28. The mu1 subunit of AP-1, found in Golgi-associated
coated pits, associated with neither CTLA-4 nor CD28. Sequences required for
interaction of mu2 and CTLA-4 were localized to residues, 161TTGVY in CTLA-4;
this sequence is N-terminal to, but overlaps with, a previously identified SH2
binding motif, 165YVKM, involved in CTLA-4 signaling. Mu2 interacted
preferentially with CTLA-4 when residue 165Y was nonphosphorylated, whereas a PI3
kinase SH2 domain interacted preferentially when 165Y was phosphorylated. In co
transfection experiments, both tyrosine residues in the cytoplasmic tail of CTLA
4 (165Y and 182Y) were phosphorylated by the T lymphocyte-associated tyrosine
kinase, p56lck. Thus, phosphorylation of CTLA-4 residue 165Y may reciprocally
regulate signaling and trafficking of CTLA-4 by determining which effector
molecules bind to its cytoplasmic tail.
PMID- 9398333
TI - Site-directed mutagenesis of rubredoxin reveals the molecular basis of its
electron transfer properties.
AB - Rubredoxins contain a single non-heme iron atom coordinated by four cysteines.
This iron is redox active and confers a role to these proteins in electron
transfer chains. The structural features responsible for setting the values of
the reduction potential and of the electron self-exchange rate constant have been
probed by site-directed mutagenesis. Replacements of the highly conserved
residues in positions 8, 10, and 11 (valine, glycine, and tyrosine, respectively)
all lead to shifts of the reduction potential, up to 75 mV. These cannot be
explained by simple considerations about the physicochemical properties of the
substituting side chains but rather indicate that the value of the reduction
potential is finely tuned by a variety of interactions. In contrast, the electron
self exchange rate constant measured by nuclear magnetic resonance does not vary
much, except when a charged residue is included in position 8 or 10, at the
surface of the protein closest to the iron atom. Analysis of the data with a
model for electrostatic interactions, including both monopolar and dipolar terms,
indicates that the presence of a charge in this region not only increases the
repulsion between molecules but also affects the electron transfer efficiency of
the bimolecular complexes formed. The studies presented constitute a first step
toward probing the structural elements modulating the reactivity of the FeS4 unit
in a protein and defining the electron transfer active site(s) of rubredoxin.
PMID- 9398334
TI - Role of beta87 Thr in the beta6 Val acceptor site during deoxy Hb S
polymerization.
AB - Three new Hb S variants containing beta87 Leu, Trp, or Asp instead of Thr were
expressed in yeast in order to further define the role of the beta87 position in
stability and polymerization of deoxy Hb S. Previous studies showed that
hydrophobicity at beta85 Phe and beta88 Leu is critical for stabilization of
hemoglobin. Results with the three Hb S beta87 variants, however, showed minimal
differences in stability, suggesting that beta87 amino acid hydrophobicity is not
critical for stabilization of hemoglobin. Polymerization properties of the
variants in the deoxy form, however, were affected by the beta87 amino acid.
Polymerization of Hb S beta87 Thr --> Leu and Hb S beta87 Thr --> Trp was
preceded by a delay time like Hb S, while Hb S beta87 Thr --> Asp did not show a
delay time. In addition, changes in time required for half polymer formation
(T1/2) as a function of hemoglobin concentration for Hb S beta87 Thr --> Asp were
similar to that for beta87 Thr --> Gln. Hb S beta87 Thr --> Leu polymerized at a
lower hemoglobin concentration than Hb S while beta87 Thr --> Trp and Hb S beta87
Thr --> Asp required much higher hemoglobin concentrations for polymer formation.
Critical concentration required for deoxy Hb S beta87 Thr --> Asp polymerization
was 6- and 2.3-fold greater than that for Hb S beta85 Phe --> Glu and Hb S beta88
Leu --> Glu, respectively. These results suggest that even though beta87 Thr is
not a direct interaction site for beta6 Val in deoxy Hb S polymers, it does play
a critical role in formation of the hydrophobic acceptor pocket which then
promotes protein-protein interactions facilitating formation of stable nuclei and
polymers of deoxy Hb S.
PMID- 9398335
TI - Metal-catalyzed oxidation and mutagenesis studies on the iron(II) binding site of
1-aminocyclopropane-1-carboxylate oxidase.
AB - The final step in the biosynthesis of the plant signaling molecule ethylene is
catalyzed by 1-aminocyclopropane-1-carboxylate (ACC) oxidase, a member of the non
heme iron(II) dependent family of oxygenases and oxidases, which has a
requirement for ascorbate as a co-substrate and carbon dioxide as an activator.
ACC oxidase (tomato) has a particularly short half-life under catalytic
conditions undergoing metal-catalyzed oxidative (MCO) fragmentation. Sequence
comparisons of ACC oxidases with isopenicillin N synthase (IPNS) and members of
the 2-oxoglutarate Fe(II) dependent dioxygenases show an aspartate and two of six
ACC oxidase conserved histidine residues are completely conserved throughout this
subfamily of Fe(II) dependent oxygenases/oxidases. Previous mutagenesis,
spectroscopic, and crystallographic studies on IPNS indicate that the two
completely conserved histidine and aspartate residues act as Fe(II) ligands. To
investigate the role of the conserved aspartate and histidine residues in ACC
oxidase (tomato fruit), they were substituted via site-directed mutagenesis.
Modified ACC oxidases produced were H39Q, H56Q, H94Q, H177Q, H177D, H177E, D179E,
D179N, H177D&D179E, H211Q, H234Q, H234D, and H234E. Among those histidine mutants
replaced by glutamine, H39Q, H56Q, H94Q, and H211Q were catalytically active,
indicating these histidines are not essential for catalysis. Mutant enzymes
H177D, H177Q, D179N, H177D&D179E, H234Q, H234D, and H234E were catalytically
inactive consistent with the assignment of H177, D179, and H234 as iron ligands.
Replacement of H177 with glutamate or D179 with glutamate resulted in modified
ACC oxidases which still effected the conversion of ACC to ethylene, albeit at a
very low level of activity, which was stimulated by bicarbonate. The H177D
(inactive), H177E (low activity), D179E (low activity), and H234Q (inactive)
modified ACC oxidases all underwent MCO fragmentation, indicating that they can
bind iron, dioxygen, ACC, and ascorbate. The results suggest that MCO cleavage
results from active site-mediated reactions and imply that, while H177, D179, and
H234 are all involved in metal ligation during catalysis, ligation to H234 is not
required for fragmentation. It is possible that MCO fragmentation results from
reaction of incorrectly folded or "primed" ACC oxidase.
PMID- 9398336
TI - Mutagenesis of some positive and negative residues occurring in repeat triad
residues in the ADP/ATP carrier from yeast.
AB - In AAC2 from Saccharomyces cerevisiae, nine additional charged residues (six
positive, three negative) were neutralized by mutagenesis following the previous
mutation of six arginines. Oxidative phosphorylation (OxPhos) in cells and
mitochondria, the expression level of AAC protein, and the various transport
modes of AAC in the reconstituted system were measured. Mutations are: within the
first helix at K38A which is exclusive for AAC; K48A, and R152A, part of a
positive triad occurring in the matrix portion of each repeat; two matrix
lysines, K179M and K182I, and the negative triad helix-terminating residues,
E45G, D149S, D249S. Cellular ATP synthesis (OxPhos) is nearly completely
inhibited in K48A, R152A, D149S, and D249S, but still amounts to 10% in K38A and
between 30% and 90% in the gly+ mutants K179M, K179I + K182I, and E45G.
Comparison of the AAC content measured by ELISA and the binding of [3H]CAT and
[3H]BKA reveals discrepancies in K48A, D149S, and D249S mitochondria, which
provide evidence that these mutations largely abolish inhibitor binding. Also
these mitochondria have undetectable OxPhos. Differently in K38A, CAT and BKA
binding are retained at high AAC levels but OxPhos is very low. This reveals a
special functional role of K38, different from the more structural role of R152,
K48, D149, and D249. Transport activity was measured with reconstituted AAC. The
electroneutral ADP/ADP exchange of gly- mutants is largely or fully suppressed in
K48A, D149S, and D249S. K38A and R152A are still active at 18% and 30% of wt. The
other three exchange modes, ATP/ADP, ADP/ATP, and ATP/ATP, are nearly suppressed
in all gly- mutants but remain high in gly+ mutants. ATP-linked modes are higher
than the ADP/ADP mode in gly+ but lower in gly- mutants, resulting in an exchange
mode inversion (EMI). In the competition for AAC2 transport capacity, the weak
ATP exporting modes are suppressed by the much stronger unproductive ADP/ADP mode
causing inhibition of OxPhos. Together with previous results all members of three
charge triads are now mutagenized, revealing drastic functional rotatory
asymmetries within the three repeat domains. In the intrahelical arginine triad
the third (R294A), in the positive matrix triad the second (R152A), and in the
helix-terminating negative triad the first (E45G) still show high activity.
PMID- 9398337
TI - Site-directed mutagenesis of the active site glutamate in human matrilysin:
investigation of its role in catalysis.
AB - Glu-198 of human matrilysin is a conserved residue in the matrix
metalloproteinases and is considered to play an important role in catalysis by
acting as a general base catalyst toward the zinc-bound water molecule, on the
basis of mechanistic proposals for other zinc proteases. In the present study,
Glu-198 is mutated into Asp, Cys, Gln, and Ala, and the zinc binding properties,
kinetic parameters, and pH dependence of each mutant are determined in order to
examine the role of Glu-198 in catalysis. The mutations chosen either modify (C
and D) or eliminate (A and Q) the general base properties of residue-198. All the
mutants bind 2 mol of zinc per mol of enzyme, indicating that Glu-198 is not
crucial to the binding of the catalytic zinc to the enzyme. The value of kcat/Km
for the E198D mutant is only 4-fold lower than that of wild-type enzyme at the pH
optimum of 7.5, while that for the E198C mutant is decreased by 160-fold. The
E198Q and E198A enzymes containing the mutations that have eliminated the
nucleophilic and acid/base properties of the residue are still active, having
lower kcat/Km values of 590- and 1900-fold, respectively. The decrease in
activity of all the mutants is essentially due to a decrease in kcat. The kcat/Km
values of the mutants as a function of pH display broad bell-shaped curves that
are similar to the wild-type enzyme. The acidic pKa value is not greatly affected
by the change in the chemical properties of residue-198. The similarity in the pH
profiles for the mutant and wild-type enzymes indicates that the ionization of
Glu-198 is not responsible for the acidic pKa. Ionization of the zinc-bound water
may be responsible for this pKa since the three His ligands and the scaffolding
of the matrilysin catalytic zinc site are different from that observed in
carboxypeptidase A and would predict a lower pKa for the metal-bound water. If
the zinc-bound water is the nucleophile in the reaction, the role of Glu-198 in
catalysis may be to stabilize the transition state or act as a general acid
catalyst after the rate-determining step.
PMID- 9398338
TI - In vivo footprinting using N-ethyl,N-nitrosourea: improved resolution of the DNA
protein interactions in the human gamma-globin gene promoter region.
AB - N-Ethyl, N-nitrosourea (ENU) was used as a probing agent in conjunction with a
modified ligation-mediated polymerase chain reaction in a new in vivo
footprinting procedure. In the present work, we examined the promoter region of
the human gamma-globin gene under both uninduced and hemin-induced conditions in
K562 cells. In the course of comparing this method with the standard dimethyl
sulfate (DMS) in vivo method and previously reported results, we were able to
verify our new method. However, discrepancies between these methods were observed
at the stage selector element, -50 region, of gamma-globin promoter. Our in vivo
footprinting result showed DNA-protein interaction at this region under the hemin
induced condition which was not revealed by the conventional DMS in vivo
footprinting method. This approach, using ENU-modified in vivo footprinting, is
now being applied to clarify the mechanism of cytotoxic drug-induced fetal
hemoglobin augmentation.
PMID- 9398339
TI - Determination of the dissociation constant of phosvitin-anti-phosphoserine
interaction by affinity capillary electrophoresis.
AB - We used affinity capillary electrophoresis (ACE) to study the interaction of a
monoclonal anti-phosphoserine antibody (mAb) to a homopolyvalent antigen (hpAg),
phosvitin. A model system, which allows the measurement of the true dissociation
constant (Kd) in Ag excess based on measurement of migration shifts of mAb-hpAg
complexes at different Ag concentrations in solution, is presented for the study
of the interactions between a mAb and an Ag that has identical determinants. The
experimental value of Kd (22.4 x 10(-6) M) obtained by ACE is shown to be in
close agreement with the value (17.8 x 10(-6) M) obtained by the conventional
immunoassay based on indirect competition enzyme-linked immunosorbent assay
(ELISA). Moreover, the Kds of mAb-hpAg complexes were measured and shown to be
independent of the applied electrical field strength. Thus, under conditions
where the total Ag concentration is in large excess over the total Ab
concentration and when certain requirements are fulfilled, this method offers the
advantage of dealing with the determination of Kd for unlabeled mAb and
homopolymeric Ag molecules in free solution rather than at the liquid-solid
interface.
PMID- 9398340
TI - A colorimetric assay for phosphate to measure amplicon accumulation in polymerase
chain reaction.
AB - We describe a rapid colorimetric method for the detection of PCR products. Color
generation is complete within 5 min of mixing reagents with a PCR. The method is
simple and does not require affinity capture steps or special labeling to be
carried out. The color development can be monitored by eye or a simple
spectrophotometer can be used to read sample absorbance. We demonstrate the
method by its use in the amplification refractory mutation system (ARMS) analysis
[C. R. Newton, A. Graham, L. E. Heptinstall, S. J. Powell, C. Summers, N.
Kalsheker, et al. (1989) Nucleic Acids Res. 17, 2503-2515] of cystic fibrosis [J.
R. Riordan, J. M. Rommens, B. Kerem, N. Alon, R. Rozmahel, Z. Grzelczak, et al.
(1989) Science 245, 1066-1073] and factor V [R. M. Bertina, B. P. C. Koeleman, T.
Koster, F. R. Rosendaal, R. J. Dirven, H. de Ronde, P. A. van der Velden, and P.
H. Reitsma (1994) Nature 369, 64-67] allelic variants.
PMID- 9398341
TI - A large-scale in situ hybridization system using an equalized cDNA library.
AB - We have developed a large-scale in situ hybridization system in which all the
procedures are carried out on a 96-well format: digoxigenin-labeled probes were
synthesized from PCR-amplified templates, sections were mounted on 96-well
plates, and hybridization and immunohistochemistry protocols were carried out in
each well of the plates. This system in combination with equalized (normalized)
cDNA library as the source for the probes enables us to identify the cellular
distribution of many mRNAs in various tissues rapidly and efficiently. Thus, this
system may be a novel cloning method of identify genes differentially expressed
in many tissues. In addition, this system has a potential to be automated.
PMID- 9398343
TI - A set of constructed type spectra for the practical estimation of peptide
secondary structure from circular dichroism.
AB - While reliable methods have been developed for the estimation of globular protein
secondary structure content from their far UV circular dichroism spectra, these
are not suitable for the analysis of simple peptides. Model peptides have been
measured in purely alpha-helical, beta-sheet, and coil form, and are often used
for fitting the CD spectra of peptides, but these are mainly derived from
homopolymers and exhibit side-chain-dependent characteristics that do not
accurately represent the situation in natural sequences. We have attempted to
reduce the side-chain bias inherent in these spectra by constructing a series of
frequency-weighted "average" spectra from all available data on model peptides.
These have proved quite satisfactory in estimating the secondary structure of a
number of peptides. A computer program incorporating these spectra has been
developed for practical use.
PMID- 9398342
TI - Detection and analyses of ascorbyl radical in cerebrospinal fluid and serum of
acute lymphoblastic leukemia.
AB - We have detected and analyzed a free radical in human cerebrospinal fluid (CSF)
of acute lymphoblastic leukemia (ALL) for the first time using electron
paramagnetic resonance (EPR) at ambient temperature. We have also introduced an
alternative capillary method to measure the radical. EPR spectra of the radical
show a characteristic doublet with hyperfine coupling value of 1.8 G and g =
2.005. Based on EPR measurements, computer simulation, and literature values, we
have determined that the species is ascorbyl radical (AsR). The radical has been
investigated in CSF samples from ALL patients having no therapy, undergoing
chemotherapy, and following therapy. Determination of the ascorbyl radical
concentrations in CSF and serum was attempted using known concentrations of a
nitroxyl radical. In addition, comparison in CSF and serum for ALL has been made
along with statistical analyses of the data obtained. We found that AsR in CSF
and serum has a strong correlation in patients undergoing chemotherapy (n = 57, r
= 0.57, P < 0.0001). Ascorbate in CSF and serum show good correlation in patients
having therapy but not for patients after therapy.
PMID- 9398344
TI - Fluorometric assay of binding specificity of plant lectins to yeast cells by
biotin-avidin system and its application to the classification of yeast cells.
AB - A fluorometric assay of lectin binding to yeast cells is reported. The relative
amount of biotinylated lectins bound to the yeast cells was estimated by enzyme
activity using 4-methylumbelliferyl-beta-D-galactoside as a substrate for the
lectin-bound beta-galactosidase through biotin-avidin interaction. Binding
properties of 4 mannose-specific and 3 glucose/mannose-specific lectins to 22
different species of yeast cells were studied. The binding reaction of
biotinylated lectins to the yeast cells was rapid and became constant within 10
min. Each lectin showed its characteristic binding specificity to each yeast
species. The relative fluorescent intensities observed for 4-methylumbelliferone
released by the action of bound beta-galactosidase were good indicators for the
classification of yeast cells in quantitative base. We found that the yeast cells
of the Saccharomyces genus can be classified into three groups, and those of
Pichia were grouped into two groups. The present method can examine many samples
simultaneously and be completed within 3 h.
PMID- 9398345
TI - Reassessment of stereochemical configuration of natural phosphatidylglycerols by
chiral-phase high-performance liquid chromatography and electrospray mass
spectrometry.
AB - Using chiral-phase high-performance liquid chromatography (HPLC) and electrospray
ionization-mass spectrometry (ESI/MS), we have redetermined the stereochemical
configuration of some natural and synthetic phosphatidylglycerols (PG). For this
purpose, the synthetic and natural PG were converted to their bis-3,5
dinitrophenylurethanes (DNPU), which were separated by HPLC using two columns
having chiral phases of opposite configuration, (R)-(+)- and (S)-(-)-1-(1
naphthyl)ethylamine polymers. The molecular species were identified by on-line
negative-ion ESI/MS. Absolute configurations of the resolved peaks were assigned
by comparison with the elution order of the corresponding 1(3)-monoacyl-sn
glycerol enantiomers as bis-DNPU derivatives on the same column. The results
clearly showed that the PG from cabbage leaf lipids and soybean phospholipids
consisted of single R,S isomers (1,2-diacyl-sn-glycero-3-phospho-1'-sn
glycerols), despite the presence of nonstereospecific phospholipase D in the
tissues. On the other hand, the PG derived from egg yolk phosphatidylcholine and
glycerol by transphosphatidylation with cabbage phospholipase D was a mixture of
45% R,S isomers (1, 2-diacyl-sn-glycero-3-phospho-1'-sn-glycerols) and 55% R,R
isomers (1,2-diacyl-sn-glycero-3-phospho-3'-sn-glycerols). The PG from
Escherichia coli lipids was a mixture of 89% R,S and 11% R,R isomers. The present
study demonstrates that chiral-phase HPLC and negative-ion ESI/MS provide direct
and unambiguous information about the configuration, identity, and quantity of
molecular species in natural and synthetic PG.
PMID- 9398346
TI - A colorimetric assay method for 3beta-hydroxy-delta5-steroid dehydrogenase.
AB - 3beta-Hydroxy-Delta5-steroid dehydrogenase is an important enzyme of steroid
hormone biosynthesis present in steroidogenic tissues like adrenal, testis, and
ovary of vertebrates. The enzyme is assayed mainly by radiochemical substrates.
Spectrophotometric assay is not adequately sensitive to detect the enzyme
activity since it is often present in low levels. We have developed a simple
colorimetric assay based on formazan formation due to the reduction of the
tetrazolium salt. The reaction mixture containing the substrate, pregnenolone or
dehydroepiandrosterone, NAD and iodonitrotetrazolium in 0.1 M Tris-HCl buffer (pH
7.8), and the enzyme extract is incubated for 1 h at 37 degrees C. Absorbance at
490 nm is read in a spectrophotometer. The enzyme activity was linear with time
and protein concentration. The assay works well with adrenal tissue extract,
whereas in the case of testis, Leydig cell preparation may be required. We have
assayed the enzyme activity in the adrenal of rat, mouse, and gerbil. The method
is two- to threefold more sensitive than the spectrophotometric assay.
PMID- 9398347
TI - Interaction of immobilized avidin with an aequorin-biotin conjugate: an aequorin
linked assay for biotin.
AB - Biotinylated recombinant aequorin was used in the development of a heterogeneous
bioluminescence binding assay for biotin. This assay is based on a competition
between a biotinylated aequorin conjugate and biotin for the binding sites of
avidin immobilized on solid particles. Dose-response curves were obtained that
relate solid-phase aequorin activity to the concentration of biotin. Under
certain experimental conditions these curves were biphasic; i.e., as the biotin
concentration increased, the solid-phase aequorin activity first increased
reaching a maximum and then decreased at higher biotin concentrations. This
"hook" effect was observed with four different types of immobilization supports.
The effect was more pronounced when low concentrations of aequorin-biotin
conjugate were used, and diminished at a high conjugate concentration. This
behavior indicates a possible positive cooperativity in the interaction between
the immobilized avidin and biotin. Scatchard plot analysis was also consistent
with a positive cooperativity mechanism. By using the ascending portion of the
dose-response curve, the detection limit of the assay for biotin was 1 x 10(-15)
M (100 zmol of biotin in the sample).
PMID- 9398348
TI - Transfection of myoblasts in primary culture with isomeric cationic cholesterol
derivatives.
AB - Transfection of satellite cells from dog muscle (myoblasts) in primary culture
has been optimized with respect to the position of the cholesteryl moiety along
the polyamine chain of spermidine or spermine. Spermidine or spermine were
derivatized with cholesterylchloroformate giving rise to three isomers in the
case of spermidine and two isomers for spermine that were separated by reversed
phase high-performance liquid chromatography (rp-HPLC). The position of the
cholesteryl moiety was assigned by 13C-NMR and coelution with synthetic isomers
of defined structure. The isomeric cationic lipids were evaluated for their
transfection activity in myoblasts from dog muscle and a human lung epithelial
cell line (A549) using plasmid DNA expressing the luciferase reporter gene. The
results showed that the position of the cholesteryl moiety is of critical
importance for efficient transfection of myoblasts in primary culture with
isomers having a derivatized secondary amine being significantly more effective
than those with a derivatized primary amine. On the contrary, differences in the
A549 cell line were less pronounced and did not follow the same pattern. The
results show that slight structural differences between cationic lipids lead to
significantly different transfection efficiencies for myoblasts in primary
culture. This may also represent an advantage in view of cell or organ targeting.
PMID- 9398349
TI - Quantitation of the Escherichia coli methionine repressor-operator interaction by
surface plasmon resonance is not affected by the presence of a dextran matrix.
AB - The effect of a dextran matrix on the apparent rate constants measured for the
interaction of the Escherichia coli methionine repressor, MetJ, with its
immobilized consensus operator has been studied using surface plasmon resonance
(SPR) in a commercial biosensor, BIACORE (Biacore AB). Based on the results of
computer simulations, it has been proposed that such data can deviate from the
expected simple kinetic behavior due to effects generated by the dextran matrix,
used at the biosensor surface to anchor one of the interacting molecules. We have
tested this possibility experimentally by measuring the apparent rate constants
for the interaction of MetJ with its operator DNA on sensor chip surfaces with no
dextran matrix or having matrices 30 or 100 nm thick. The data show that for the
MetJ-operator interaction, the dextran matrix has no significant effect on the
apparent rate constants measured and that comparative measurements using this
technique are informative.
PMID- 9398351
TI - Measurement of biochemical affinities with a Gill titration calorimeter.
AB - A Gill titration calorimeter is evaluated as an instrument to determine in one
experiment the equilibrium constant and the enthalpy change of a biochemical
reaction. The dimensionless parameter kc (the product of the association
equilibrium constant and the concentration of the reagent to be titrated; Wiseman
et al., Anal. Biochem. 179, 131-137, 1989) is used to analyze the instrument
performance. The analysis of simulated titration data corresponding to a simple
model case shows that association equilibrium constants in the 10(2)-10(7) M-1
range may be determined when the kc parameter is between 1 and 1000. In addition
we use a Monte Carlo approach to estimate the precision in the thermodynamic
parameters of the reaction under study. The relative precision in the calculated
constants ranges from 3 to 80% depending on the macromolecule concentration and
kc value in the experiment. These results were checked with the study of the
reactions of beta-trypsin with its inhibitor and ribonuclease A with cytidine 2'
monophosphate and cytidine 3'-monophosphate.
PMID- 9398350
TI - Site-specific fluorescence labeling of the beta2 adrenergic receptor amino
terminus.
AB - A modified human beta2 receptor, designated 0K-beta2, was developed for site
specific labeling at the amino terminus with amine reactive fluorescent probes.
0K-beta2 has the following modifications: (1) all 16 lysines in the wild-type
beta2 receptor were mutated to arginines, (2) a FLAG epitope preceded by a
cleaved hemagglutinin signal sequence was fused to the amino terminus, and (3) a
hexahistidine tail was added to the carboxyl terminus. The FLAG epitope and
hexahistidine tail were added to facilitate purification while lysine to arginine
mutations eliminate potential labeling sites for amine-reactive fluorescent
probes. The remaining primary amines in the 0K-beta2 receptor, the amino terminal
amine and the epsilon-amine of Lys3, both reside in the amino-terminal FLAG
epitope. The 0K-beta2 receptor expressed in Sf9 insect cells exhibited ligand
binding and G-protein coupling characteristics similar to the wild-type beta2
receptor. The modified receptor was labeled with fluorescamine, an amine-reactive
fluorescent probe. Proteolysis with factor Xa showed that labeling was confined
to the amino terminus of the 0K-beta2 receptor. Our results demonstrate site
specific fluorescamine labeling at the amino terminus of the 0K-beta2 receptor, a
lysine-depleted beta2 receptor that retains functional characteristics of the
wild-type receptor.
PMID- 9398352
TI - Radiolabeling of the lipids of chinese hamster ovary cells with the probe [3
(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine].
AB - [125I]TID [3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine] is a commercially
available, hydrophobic, photoactivatable, gamma-emitting reagent mostly used to
label protein hydrophobic domains. It has also been used to radiolabel the
phospholipids of lung surfactant (Gilliard et al., Anal. Biochem. 193, 310-315,
1991). Since a nonspecific, highly sensitive, lipid-labeling probe would be a
very useful tool to investigate lipid-protein interactions in biological
membranes, we characterized further the [125I]TID-labeling products of lipids
from cultured Chinese hamster ovary cells (IR-CHO). After labeling of whole
cells, TLC analysis followed by autoradiography enabled detection of
sphingomyelin, phosphatidylcholine, phosphatidylinositol, phosphatidylserine,
phosphatidylethanolamine, cardiolipin, diglycerides, cholesterol and its esters,
and triglycerides. Analysis of the radioactivity associated with the
saponification products of different lipids showed that [125I]TID was mostly
(80%) extracted with the fatty acid moiety of the lipids whereas 20% remained
associated with the hydrosoluble moiety. Similar radioactivity profiles were
observed after labeling of whole cells or extracted and liposome-reconstituted
lipids; the [125I]TID probe was able to diffuse in all intracellular organelles.
Labeling was not equivalent between the different lipid classes, and it appeared
that the amount of associated radioactivity correlated well with the degree of
lipid unsaturation. This was confirmed by studying [125I]TID incorporation in
phosphatidylcholines of different chain length and unsaturation. Taken together,
our data demonstrate that [125I]TID can be used as a radiolabel for lipids in
cultured cells. It is rapidly incorporated in the hydrophobic part of membranes,
diffuses into all cellular compartments, and labels all lipid classes, including
phospholipids, cholesterol, and glycerides, with a sensitivity in the nanomolar
range.
PMID- 9398353
TI - Optimized alcoholytic deacetylation of N-acetyl-blocked polypeptides for
subsequent Edman degradation.
AB - N-terminal protein acetylation is a common posttranslational modification,
blocking Edman degradation during sequencer analysis. Use of mass spectrometry
allows the analysis also of acetyl-blocked polypeptides; however, for large
proteins mass spectrometry is not always informative, and deacetylation by
chemical pretreatments is desirable for making direct sequencer analysis
possible. For this purpose, alcoholytic deacetylation is attractive. In the
present work, we have studied the optimal conditions for specific removal of the
acetyl group without extensive cleavage of peptide bonds in general. We find that
incubation with trifluoroacetic acid in methanol (1:1, by volume) at an elevated
temperature ( approximately 47 degrees C) for 2-3 days results in efficient
deacetylation allowing direct application to sequencer analysis with initial
yields up to approximately 50% of the amount applied for deblocking.
Deacetylation compared to internal peptide bond cleavage is often high, as
evaluated by recoveries of residues from the deblocked sequence over those from
the background, and this applies to both peptides (up to the order of 10:1 for
the specific residue versus the background) and proteins (>2:1). Although yields
may still vary and some sequences be only partly susceptible to the chemistry,
this deblocking can in many cases allow unambiguous interpretation of N
terminally acetyl-blocked sequences.
PMID- 9398354
TI - Fluorescence detection of calcium-binding proteins with quinoline Ca-indicator
quin2.
AB - We have established a fluorescence method to detect calcium-binding proteins by
making use of the quinoline Ca indicator quin2. Authentic calcium-binding
proteins were subjected to sodium dodecyl sulfate-polyacrylamide gel
electrophoresis and then electrophoretically transferred onto polyvinylidene
difluoride membranes. Transfers were incubated with nonradioactive calcium ions,
then with quin2 to detect the calcium-binding proteins as fluorescent bands by
illumination with UV light. Calmodulin and parvalbumin of EF hand conformation
calcium-binding type were clearly identified. Quin2 distinguished smooth muscle
alpha-actinin from skeletal muscle alpha-actinin; the former was faintly
fluorescent, having a low affinity for calcium ions. In whole myofibril
preparations from skeletal muscles, troponin-C, connectin (titin), and nebulin
were intensely fluorescent, being shown to have calcium-binding ability. The
fluorescence method is an accurate, safe, and simple procedure to detect the
binding of calcium ions to proteins following electrophoresis. The overlay
technique described can be completed within 15 h and detects as little as 38
ng/well of troponin-C in the starting sample.
PMID- 9398355
TI - Macroscopic orientation of natural and model membranes for structural studies.
AB - One approach for obtaining high-resolution structural and functional information
for biomembranes and their proteins is by static solid-state NMR of oriented
systems. Here, a general procedure to align fully functional biological membranes
containing large membrane proteins (Mr >30,000) is described. The method, based
on the isopotential spin-dry ultracentrifugation technique, relies on the
centrifugation of membrane fragments onto a support with simultaneous, or
subsequent, partial evaporation of the solvent which aids alignment. The quality
of orientation, as shown by the mosaic spread of the samples, was monitored by
static solid-state 31P NMR for the phospholipids and by 2H NMR for a deuterated
retinal in bovine rhodopsin. The generality of this method is demonstrated with
three different membranes containing bovine rhodopsin in reconstituted bilayers,
natural membranes with the red cell anion exchange transport protein in
erythrocytes, band 3, and the nicotinic acetylcholine receptor.
PMID- 9398356
TI - A packaging system for SV40 vectors without viral coding sequences.
AB - SV40 vectors have been used as expression vectors for mammalian cells since the
early 1980s. More recently, they have been used as gene transfer vectors in mice
and in human peripheral blood cells. Here we described a system for packaging
SV40 vectors without viral coding sequences. Recombinant adenovirus-expressing
SV40 capsids can effectively package plasmids that contain the SV40 replication
origin. The final yield of infectious SV40 vector is about 3 x 10(5), with a SV40
to adenoviral vector ratio of about 1000:1. Helper adenoviruses can be
effectively heat-inactivated with no effect on the infectivity of SV40 vectors.
PMID- 9398357
TI - Continuous assay of proteases using a microtiter plate fluorescence reader.
PMID- 9398358
TI - A modified pGEX vector with a C-terminal histidine tag: recombinant double-tagged
protein obtained in greater yield and purity.
PMID- 9398359
TI - A set of pBR322-compatible plasmids allowing the testing of chaperone-assisted
folding of proteins overexpressed in Escherichia coli.
PMID- 9398360
TI - Assay of protein phosphatase activities with phosphopeptide-magnetic particle
conjugates.
PMID- 9398361
TI - Feeding chases and food allocation in Adelie penguins, Pygoscelis adeliae
AB - Among penguins, well-developed feeding chases where chicks run after adults and
beg for food are found only in the genera PygoscelisAptenodytesFeeding chases
involving adult Adelie penguins, with two chicks, compared to feeding chases
involving those with one chick, were longer, occurred further from the breeding
group and included more runs between each feed. Feeding chases were more likely
when chicks were close together, and which chick was fed was more likely to
switch after a feeding chase. These results suggest that feeding chases serve to
minimize harassment from other chicks during feeding and to reduce the effects of
sibling competition.Copyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398362
TI - A field test of threat sensitivity in a marine gastropod
AB - In the Mingan Islands, the whelk Buccinum undatum displays defensive manoeuvres
to both contact and water-borne chemical cues from the predatory asteroid
Leptasterias polarisIn spite of this, whelks occasionally aggregate in great
numbers near L. polaris while it is ingesting a prey; they then attempt to steal
food from their predator and also wait for leftovers. In this study, the response
of whelks in different types of encounters with L. polaris was examined to test
the hypothesis that whelks are sensitive to the magnitude of the threat their
predator represents. In a field experiment, whelks consistently fled both non
feeding and feeding L. polaris (asteroids used were consuming small prey items
that were unlikely to provide food for whelks). When current flow was stable,
whelks fled more directly down current and more frequently displayed violent
defensive behaviours, in response to non-feeding L. polariswhich presented a
higher risk, than in response to feeding asteroids (lower risk; 47% versus 2%).
Consequently, whelks tested with non-feeding asteroids more rapidly distanced
themselves from the predators than did whelks tested with feeding asteroids. In a
field survey, there were more active whelks in the vicinity of cruising (higher
risk) than stationary (lower risk) L. polaris (53% versus 14%). Among those
whelks that were active, defensive behaviour patterns such as shell rocking and
leaping escape movements were frequently shown by whelks near cruising predators
(69%), but never by whelks near stationary predators (0%). The discriminative
capabilities apparent in these results are likely to be adaptive, because they
enable whelks to limit the cost of escape responses while still keeping predation
risk low, and also because they facilitate a close association with L. polaris
from which the whelks receive feeding benefits.Copyright 1997 The Association for
the Study of Animal Behaviour1997The Association for the Study of Animal
Behaviour
PMID- 9398363
TI - Does brood reduction provide nestling survivors with a food bonus?
AB - Siblicide is common in many asynchronously hatching birds, including brown
pelicans, Pelecanus occidentalisMost adaptive models of siblicide, and of brood
reduction in general, tacitly assume that parental deliveries of food remain
fixed, and therefore that supplies to seniors remain unchanged or increase after
a junior's death. If parents match deliveries to brood size, however, then
seniors may get less food following brood reduction. To test the assumption that
parental deliveries remain constant, and to determine how brood reduction
affected seniors, food deliveries to control (three-chick) and experimentally
reduced (two-chick) broods of brown pelicans were compared. Parents brought less
food to reduced than to control broods. Similarly, a literature review revealed
that avian parents generally delivered less food to smaller than to larger broods
of experimentally altered sizes. In brown pelicans, when food deliveries
decreased following brood reduction, second-hatched ('B') chicks received less
food, but first-hatched ('A') chicks' supplies remained unchanged. B-chicks may
have gained more in control broods by appropriating the extra food that last
hatched ('C') chicks otherwise would have gained. If brood reduction decreases
fighting, nestlings may gain more net energy even if they receive less food.
Fighting did not decrease significantly in reduced broods, perhaps because
fledging averaged one chick/brood, so A and B-chicks still competed intensely.
Alternatively, small sample sizes may have prevented detection of differences in
fighting. Seniors did not concentrate their attacks on C-chicks, perhaps because
seniors may benefit by delaying the decreases in parental food deliveries that
follow brood reduction.Copyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398364
TI - Responses to conspecific and heterospecific olfactory cues in the swordtail
Xiphophorus cortezi
AB - Female Xiphophorus cortezi responded to olfactory cues from both conspecific
males and heterospecific X. nigrensisX. montezumae males when given a choice
between the stimulus and water. When given a choice between the conspecific and
heterospecific cues, however, females demonstrated a strong preference for the
conspecific stimulus. Of the two heterospecific species, females responded more
strongly to their close relative X. nigrensis than they did to the more distantly
related X. montezumaeMate recognition in northern swordtails is evidently not a
simple process based upon a response to one variable, but the outcome of complex
responses to information from at least both visual and olfactory cues.Copyright
1997 The Association for the Study of Animal Behaviour1997The Association for the
Study of Animal Behaviour
PMID- 9398365
TI - Social mating system affects the frequency of extra-pair paternity in house wrens
AB - We tested two hypotheses regarding the effect of the social mating system on
extra-pair paternity in an Illinois population of house wrens, Troglodytes
aedonAccording to the genetic-quality hypothesis, polygynous males are of higher
quality than monogamists, and monogamously paired females, in an attempt to
obtain high-quality genes, should have a greater proportion of extra-pair
nestlings in their nests than polygynously paired females. According to the trade
off hypothesis, polygynists, with temporally overlapping nests, will have a
greater proportion of extra-pair nestlings in their nests than monogamists,
because polygynists have difficulty guarding one or both of their social mates.
DNA fingerprinting revealed that extra-pair paternity was most frequent in
secondary nests of polygynists. The proportion of secondary broods with extra
pair nestlings increased with the temporal overlap of polygynists' nests,
although this trend was not significant. Both results are consistent with the
trade-off hypothesis but not with the genetic-quality hypothesis. We did not
address the effects of genetic quality on male success at siring nestlings in the
nests of other males. Although the trade-off hypothesis focuses on male mate
guarding, female behaviours may also affect frequencies of extra-pair paternity.
Secondary females may compensate for reduced male defence by engaging in extra
pair copulations with neighbours to reduce the likelihood that neighbours destroy
their nests. Thus, in house wrens, female participation in extra-pair copulations
in combination with male mate-guarding constraints may generate higher levels of
extra-pair paternity in secondary broods than in primary polygynous or monogamous
broods.Copyright 1997 The Association for the Study of Animal Behaviour1997The
Association for the Study of Animal Behaviour
PMID- 9398366
TI - Parent-offspring recognition in tree swallows, Tachycineta bicolor
AB - Parent-offspring recognition appears to be highly developed in species in which
the risk of misdirecting care is high (e.g. colonial species). Some of the best
evidence for this relationship comes from comparative work on swallows of the
family Hirundinidae. Using methods followed in earlier studies, we determined
whether parent-offspring recognition occurs in the tree swallow, Tachycineta
bicolora non-colonial species closely related to the highly colonial bank
swallow, Riparia ripariaand the solitary rough-winged swallow, Stelgidopteryx
ruficollisParents did not discriminate between playbacks of the calls of their
own versus non-related nestlings. However, older nestlings called more in
response to playback of parental calls than non-parental calls, suggesting that
they recognized their own parents. Despite significant individual variation in
parental and nestling calls, variation in tree swallow nestling calls was lower
than analogous calls in the bank swallow. Our results provide further support for
a positive relationship between recognition, individual variation in call
structure and coloniality.Copyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398367
TI - Hormonal dynamics during mate choice in the northern pintail: a test of the
'challenge' hypothesis
AB - In previous mate choice experiments, we found no relationship between dominance
rank and pairing success in male northern pintails, Anas acutaOnce chosen by a
female, however, males became aggressive, initiated fights with higher-ranked
males and quickly established dominance. In the present study, we tested a
variation of the 'challenge' hypothesis, that the behavioural stimuli associated
with acquiring and defending a mate induce an increase in testosterone level,
which in turn facilitates aggressive behaviours required for males to establish
dominance. We measured plasma hormone levels (testosterone, dihydrotestosterone,
luteinizing hormone and corticosterone) before and after mate choice in two
experiments in which males competed for a single female (experiments 1 and 2) and
in a control experiment in which no female was introduced (experiment 3). We used
groups of either three adult males (experiment 1) or one adult and two yearling
males (experiments 2 and 3). Contrary to expectation, in experiment 1, plasma
levels of corticosterone increased significantly and testosterone levels
decreased in chosen males following mate choice. The magnitude of change in
corticosterone was positively correlated with the rate of aggression by males.
Chosen adult males in experiment 2 showed similar patterns of hormone change
(corticosterone increase and testosterone decrease), although not all changes
were significant. Hormone levels of unchosen yearlings in experiment 2 and
control adults and yearlings in experiment 3 showed no changes. The results are
consistent with the hypothesis that behavioural stimuli associated with
successful pair formation induce a transitory increase in circulating levels of
corticosterone, which in turn mediates the behavioural response of increased
aggression leading to the establishment of dominance following mate choice. A
short-term increase in corticosterone may be adaptive in this situation because
it would mobilize energy stores needed by the male to defend the new pair bond
and establish dominance.Copyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398368
TI - Signalling displays during predator-prey interactions in a Puerto Rican anole,
Anolis cristatellus
AB - We examined conspicuous signalling displays in the context of predator-prey
interactions. To determine in which context Puerto Rican crested anoles, Anolis
cristatellusperform conspicuous signals, we exposed wild lizards to a model of a
natural snake predator. The lizards gave six behavioural responses to the model:
immobility, predator inspection, flight, lateral face-off, dewlapping and push
ups. They displayed significantly more push-ups and push-up bouts in the presence
of the snake model. Alternative theories regarding the function of conspicuous
signals in A. cristatellusthe flash concealment and predator deterrent
hypotheses, were also tested. The flash concealment hypothesis proposes that the
sudden display exhibition of signalling behaviour followed by the flight of the
animal may confuse the predator about the position of the prey, thus causing the
predator to abort the attack. The pursuit deterrent hypothesis contends that
because the chances of the predator successfully attacking its prey decrease when
the prey is aware of the incoming predator, prey have evolved signalling
behaviours that communicate to the predator that it has been detected, therefore
discouraging the attack. Results supported the use of push-ups, dewlapping,
lateral face-off and predator inspection as predator deterrent signals. During
the recognition phase of a predatory encounter, A. cristatellus may rely more on
behavioural signals than on flight to avoid predation. Because the predator
deterrent signals are the same as the signals used in social interactions, it is
suggested that predation pressure may have reinforced the effects of sexual
selection in the evolution of Anolis signalling displays.Copyright 1997 The
Association for the Study of Animal Behaviour1997The Association for the Study of
Animal Behaviour
PMID- 9398369
TI - Scent-marking by coyotes, Canis latrans: the influence of social and ecological
factors
AB - We observed 49 coyotes, Canis latransfrom five resident packs for 2456 h and five
transient coyotes for 51 h from January 1991 to June 1993 in the Lamar River
Valley, Yellowstone National Park, Wyoming, U.S.A. During these observations we
recorded 3042 urinations, 451 defecations, 446 ground scratches and 743 double
marks. The rate of scent-marking (via urination) was influenced by the social
organization (resident versus transient) to which the coyote belonged, the social
class (alpha, beta or pup) of the animal and the time of the year. Transient
coyotes scent-marked at a lower rate than did members of a resident pack. Within
the resident packs, alpha coyotes scent-marked at a higher rate than beta coyotes
(adults and yearlings subordinant to alphas, but dominant over pups) and pups.
Alpha coyotes increased their rate of marking during the breeding season; beta
and pup coyotes performed scent-marks at a relatively constant rate throughout
the year. There was no influence of social class or time of year on the rate of
defecation. The rate of double-marking was highest among alpha coyotes with a
peak during the breeding season. Alpha coyotes ground-scratched at a higher rate
than did beta and pup coyotes. Alpha and beta coyotes scent-marked more than
expected along the periphery of the territory compared to the interior; pups
marked in the interior and edge in proportion to expected frequencies. Double
marking and ground-scratching were higher than expected along the periphery of
the territory. The distribution of defecations was not different from expected
along the edge versus the interior of the territory. Pack size did not influence
the rate of scent-marking performed by individuals in the pack or by the alpha
pair. We concluded that alpha coyotes were the primary members of the resident
pack involved in scent-marking. The large coyote packs and the high rate of
marking by the alpha pairs were parallel to the scent-marking behaviour displayed
by wolves, C. lupusto a greater extent than previously reported. Scent-marks
appear to provide internal information to the members of the resident pack
(internal map of territory, breeding condition, reproductive synchrony) and
enhance demarcation of territorial boundaries.Copyright 1997 The Association for
the Study of Animal Behaviour1997The Association for the Study of Animal
Behaviour
PMID- 9398370
TI - Species-specific footdrumming in kangaroo rats: Dipodomys ingens, D. deserti, D.
spectabilis
AB - Footdrumming was compared in three allopatric species of kangaroo rat,
Dipodomysfrom three habitats. Analysis of footdrumming recordings revealed
species-specific patterns of drumming ranging from single thumps to individual
footdrumming signatures. The desert kangaroo rat, D. desertidrums single thumps
spaced 0.25-0.30 s apart that are sometimes introduced with a short footroll. The
giant kangaroo rat, D. ingensdrums long footrolls that can average over 100 drums
at 18 drums/s. The banner-tailed kangaroo rat, D. spectabilisdrums three to 38
footdrums in a footroll combined into sequences of two to 12 footrolls at a rate
of 17 drums/s. In playback tests, all three species stood in alert postures and
entered the burrow in response to footdrumming of their own and the other
species. The rats also responded in species-specific ways. Dipodomys
spectabilisdrummed to its own species' footdrumming, but not to playbacks of the
single drums of D. desertiInstead of footdrumming to playbacks of its own
species, D. deserti approached the speaker more frequently than did either of the
other two species. Dipodomys ingens footdrummed equally to all footdrumming
playbacks. The species' differences reflect differences in social tolerance and
spacing. Dipodomys deserti rarely engages in footdrumming exchanges and chases
visitors from the burrow. Dipodomys spectabilis engages in frequent footdrumming
exchanges and some chases, and D. ingens seems to tolerate close neighbours and
footdrums periodically.Copyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398371
TI - Testosterone implants increase song but not aggression in male Lapland longspurs
AB - Lapland longspurs, Calcarius lapponicusare tundra-nesting arctic birds with an
extremely short breeding season. Males show a pronounced brief peak of plasma
testosterone early in the season. We studied the effect of exogenous testosterone
on song and aggression in free-living male Lapland longspurs. We gave high
testosterone implants to 16 birds, low-testosterone implants to seven birds, and
empty or no implants to 33 birds. The implants resulted in significantly
different plasma testosterone levels during incubation (high-testosterone
mean=20.79±3.4 ng/ml, low-testosterone mean=2.54±0.5 ng/ml, control
mean=0.53±0.1 ng/ml). High-testosterone birds had larger cloacal
protuberances than controls, but low-testosterone birds did not. We measured
aggression and song with simulated territorial intrusions during incubation, a
mean of 12.03±1.45 days after the insertion of implants. High-testosterone
birds and low-testosterone birds were no more aggressive than controls. However,
high-testosterone birds, but not low-testosterone birds, were significantly more
likely than controls to sing. These results suggest that the high, brief
testosterone peak of Lapland longspurs may be related more to song than to
territorial aggression. Alternatively, both aggression and song may be
testosterone-influenced, but aggression may be more readily suppressed during
incubation. The hormone-behaviour patterns demonstrated in this study may be
adaptations for breeding in the short arctic summer.Copyright 1997 The
Association for the Study of Animal Behaviour1997The Association for the Study of
Animal Behaviour
PMID- 9398372
TI - Non-nutritional maternal support in the brown long-eared bat
AB - Adult female brown long-eared bats, Plecotus aurituswere taken into captivity
over a 3-year period and housed in two free-flight enclosures. They were
maintained in small groups, each roosting in a single, heated roost box while
monitored by an infra-red sensitive video camera. The predicted percentage of
records spent by lactating females in direct contact with the young on day 1 of
lactation did not differ significantly from 100%. This declined to 13% on day 50
of lactation. Over time, the mothers groomed the young less. Lactating females
visited the roost more times per night, but spent less time self grooming than
non-reproductive females. The total amount of grooming behaviour (estimated as
the percentage of records spent in self grooming plus those allocated to grooming
of the young) for lactating females was 50% of the value for non-reproductive
females. In general, care-giving behaviours declined with the progress of
lactation. The temporal expression of these behaviours was opposite in direction
to that of the expected energetic demands of milk production.Copyright 1997 The
Association for the Study of Animal Behaviour1997The Association for the Study of
Animal Behaviour
PMID- 9398373
TI - The role of bright plumage in male-male interactions in the ring-necked pheasant
AB - The brightness and colour of birds' plumages have been considered sexually
selected traits, indicating health, condition or parasite resistance. However,
recent studies with pheasants, Phasianus colchicussuggest they are not signals
used by females in mate choice. Instead, males might rely on plumage when
assessing the quality of competitors. In this study, bright and experimentally
dulled males were presented to a group of captive male pheasants to determine the
response to differences in plumage brightness of the intruder. Males in the group
directed more aggression to the experimentally dulled males than they did to any
other males. This may be partly because they considered the dull males as novel
males. When the bright and the dull males were both unknown, both still received
more aggression than the average for any individual in the group, but dull males
were attacked by more males. Bright males were attacked more by the dominants and
dull males by the subordinates. The results show that plumage brightness may
affect individual recognition, but also that it is used by males to assess the
quality of competitors. Male-male interactions, therefore, may have played a role
in the evolution of plumage brightness, either in the context of competition for
mates or for resources when males gather into unisexual groups.Copyright 1997 The
Association for the Study of Animal Behaviour1997The Association for the Study of
Animal Behaviour
PMID- 9398374
TI - Capuchin monkeys, Cebus apella fail to understand a cooperative task
AB - We investigated whether capuchin monkeys cooperate to solve a task and to what
extent they take into account the behaviour of another individual when
cooperating. Two groups of capuchin monkeys (N=5 and 6) were tested in a task
whose solution required simultaneous pulling of two handles which were too far
from one another to be pulled by one monkey. Before carrying out the cooperation
study, individual monkeys were trained to pull one handle (training phase 1) and
to pull two handles simultaneously (training phase 2) for a food reward. Nine
subjects were successful in training phase 1, and five in training phase 2. In
the cooperation study seven subjects were successful, that is, pulled one handle
while a companion pulled the other. Further analyses revealed that capuchins did
not increase their pulling actions when a partner was close to or at the other
handle, that is, when cooperation might occur. These data suggest that capuchin
monkeys acted together at the task and got the reward without understanding the
role of the partner and without taking its behaviour into consideration. Social
tolerance, as well as their tendency to explore and their manual dexterity, were
the major factors accounting for the capuchins' success.Copyright 1997 The
Association for the Study of Animal Behaviour1997The Association for the Study of
Animal Behaviour
PMID- 9398375
TI - Great spotted cuckoos improve their reproductive success by damaging magpie host
eggs
AB - Adult great spotted cuckoos, Clamator glandariusdamage the eggs of their magpie,
Pica picahost without removing or eating them. The number of damaged magpie eggs
was recorded in 360 parasitized nests of which 62.2% contained between one and
eight damaged magpie eggs. Egg-destroying behaviour may be adaptive if it reduces
nestling competition and/or enhances the hatching success of the cuckoo. To
clarify the role of egg destruction for the reproductive success of great spotted
cuckoos, unparasitized magpie nests were experimentally parasitized (without egg
damage) by introducing cuckoo eggs or chicks. Egg damage was common in
parasitized nests but the eggs were not damaged by the hosts. Egg damage
increased the breeding success of the cuckoos, by both reducing the number of
competing host chicks in the nest and increasing the likelihood that late-laid
cuckoo eggs would hatch.Copyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398376
TI - Cohort size and the allocation of social effort by female mountain baboons
AB - Dunbar (1992,Behav. Ecol. Sociobiol.33, 35-49) argued that constraints on social
time limited the size to which savannah baboon, Papio cynocephalustroops in any
given population could grow before fissioning. Since this should be reflected in
population structure, we have elsewhere (Henzi et al. 1997a, Anim. Behav. 53, 525
535) constructed a model, based on a rising probability of fission, that fits the
observed distribution of troop sizes of mountain baboons, P. c. ursinusin the
Drakensberg mountains of South Africa and which predicts that the probability of
fission will rapidly increase once a troop has more than 23 members (or 8.7
females). We test this prediction in this paper. Since Dunbar argued that females
will drive fission once they cannot engage in the grooming necessary to sustain
alliances, we compared the grooming interactions of adult females from four
troops in the Drakensberg mountains. The mean female grooming clique size reached
an asymptote at 7.4 females, so that females in cohorts of eight or more no
longer attempted to groom all other females, and mean grooming bout length
declined as the cohort grew to 7.9 females and then increased again. These values
are coincident with the female cohort size predicted by our model of troop growth
and fission. We argue that females attempt to groom all other females as well as
sustain closer relationships with a few females through longer bouts of
reciprocated grooming. When the demands of grooming all other females reduce bout
length to a point when no reciprocated bouts are possible, female clique size is
capped. As a troop continues to grow, the mechanical difficulties involved in
gaining access to grooming partners leads to a reduction in the diversity of
grooming relationships. This weakening of the total female network, as cliques
become more differentiated, is likely to facilitate fission. We conclude that our
data provide the first within-population validation of Dunbar's hypothesis
concerning the mechanism underpinning fission. In the Drakensberg, where there is
no advantage to female coalitions, we propose, as an amendment, that females will
leave a troop not to escape local competition, but to follow a male with whom
they have a close friendship.Copyright 1997 The Association for the Study of
Animal Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398377
TI - Motivational aspects of individual variation in response to nestboxes by laying
hens
AB - Laying hens, Gallus gallus domesticusshow individual variation in pre-laying
behaviour including their ultimate choice of nest site. In housing systems with
nestboxes, the majority of hens make a small number of long visits to nestboxes
and lay their eggs therein, but some hens make many short visits and occasionally
lay outside the nestbox. We investigated the motivational basis of this
individual variation using six consistent hens which always laid in nestboxes and
six inconsistent hens which sometimes laid outside nestboxes. Each hen was housed
in a pen (containing either no nestbox, a semi-enclosed nestbox or an enclosed
nestbox) with access to a ring-shaped tunnel which increased the opportunity to
perform locomotor activity. Access to the tunnel could be restricted by narrowing
the doorway to 140, 125, 110 or 95 mm (compared with a mean hen width of 114 mm).
In trials with no nestbox, there was no difference in the pre-laying behaviour of
consistent and inconsistent hens. Narrowing the doorway reduced the number of
visits to the tunnel, but all hens persisted in visiting the tunnel and doorwidth
had no effect on time spent therein. With both designs of nestbox, however,
inconsistent hens visited the tunnel more often than consistent hens prior to
oviposition, and continued to pass the narrowest doors to enter the tunnel,
whilst consistent hens would not pass doors of 110 or 95 mm. After oviposition,
there was no difference in the two groups' behaviour in any treatment and no hens
would pass doors of either 110 or 95 mm to visit the tunnel. Individual variation
in nest-site choice, therefore, appeared to result from different perception of
nestboxes rather than lower nesting motivation. Inconsistent hens worked as hard
as consistent hens to perform pre-laying locomotion, but appeared to be less
responsive to the cues provided by nestboxes than consistent hens, because they
persisted with pre-laying locomotion when provided with either design of
nestbox.Copyright 1997 The Association for the Study of Animal Behaviour1997The
Association for the Study of Animal Behaviour
PMID- 9398378
TI - Mole-rat harderian gland secretions inhibit aggression
AB - The harderian gland secretions of mole-rats, Spalax ehrenbergiusually released by
self-grooming, include odorous substances which are sex dependent. Male
secretions were the most attractive to both sexes, while female secretions were
attractive to males but not to other females. The rate of attacks by females
towards intact males was higher than towards males whose harderian gland had been
removed. However, grooming by intact male mole-rats decreased the rate of attacks
by their opponents, while grooming by males without harderian glands did not;
thus the male harderian secretions appear to have appeasement qualities. Grooming
by females with and without harderian glands failed to reduce aggression. Unlike
intact males, those without harderian glands had almost no volatiles on their
fur, and thus are probably not considered to be a threat to conspecifics. Gas
chromatography spectra showed that substances of harderian origin were added to
the fur during grooming. Some of these substances remained on the fur long after
the animal ceased grooming, and appear to give the animal its specific odour, but
some volatile substances peaked briefly after grooming, and were probably
responsible for the decline of aggression that occurred after grooming. Although
grooming has long been considered to be a displacement activity, we suggest that
in the mole-rat its performance is too risky to be merely this, and it has
acquired the meaning of appeasement through the release of chemical
cues.Copyright 1997 The Association for the Study of Animal Behaviour1997The
Association for the Study of Animal Behaviour
PMID- 9398379
TI - Territorial intrusions and copulation behaviour in the great skua, Catharacta
skua
AB - Birds of many species intrude on to territories in order to obtain extra-pair
copulations, and frequent within-pair copulations are thought to be a response to
cuckoldry where mate guarding is not possible. Great skuas are colonial birds in
which females are left alone in the breeding territory while males forage for the
pair. Opportunities for cuckoldry are therefore numerous, and it could be
predicted that sperm competition should be intense in this species. We tested
several hypotheses that attempt to explain territorial intrusions by female great
skuas. Few intrusions coincided with the main fertile period and extra-pair
copulations were almost never solicited, and therefore the sperm competition
hypothesis was rejected. Only 0.9% of the copulations observed (N=339) were extra
pair. Thus opportunity for cuckoldry is a very poor predictor of the intensity of
sperm competition, in spite of the relevance given to this factor in the
literature. Of three extra-pair copulations observed, two involved unpaired
territorial males. This suggests that genetic benefits were not the aim of
unfaithful females. All three were preceded by courtship feeding, while only 26%
of within-pair copulations followed successful food begging. This statistically
significant difference constitutes evidence for a trade of copulations for food
in a monogamous bird. Evidence is presented supporting hypotheses that females
intrude on to territories in order to induce males to give away some food, and to
become familiarized with potential partners for future breeding seasons.Copyright
1997 The Association for the Study of Animal Behaviour1997The Association for the
Study of Animal Behaviour
PMID- 9398380
TI - Laterality in detour behaviour: interspecific variation in poeciliid fish
AB - We measured whether males of five species of poeciliid fish made detours to the
right or left of a vertical-bar obstacle in order to approach a group of females.
Three of these species, Gambusia holbrookiGambusia nicaraguensis and Poecilia
reticulata showed a significant bias to the left, whereas Brachyrhaphis roseni
and Girardinus falcatus showed a significant bias to the right. When tested for
direction of turning in front of an opaque barrier, or when a dummy predator was
used as a target in a detour test, G. holbrooki and G. falcatus showed similar
biases to the right (opaque barrier) and left (predator), thus suggesting that
the difference observed when females were used as a target could arise from
species differences in the degree of sexual motivation in a novel environment.
The two species that showed bias to the right with the females were less likely
to exhibit sexual behaviour when placed in a novel environment. Moreover,
manipulation of the factors affecting the relative strength of sexual motivation
and of fear of a novel environment, such as how long fish were maintained in
captivity or in the test apparatus before being tested, caused shifts in the
direction of the lateral asymmetries. These results suggest that the presence of
functional asymmetries in behaviour could be widespread among vertebrates and
that the direction of such asymmetries tends to be strikingly similar in closely
related species, thus supporting the hypothesis of an early evolution of
laterality in brain and behaviour.Copyright 1997 The Association for the Study of
Animal Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398381
TI - Behavioural responses of Eurasian treecreepers, Certhia familiaris, to
competition with ants
AB - Competition for a specific resource that is essential for the survival of both
the competitors may be intense even between very dissimilar taxa. However, the
importance of the effects caused by such interspecific competition has seldom
been emphasized. These effects can appear as differences in individual foraging
behaviour during the breeding season, which can result in critical variation in
fitness. In this study we examined the effects of wood ants (Formica rufa group)
on the abundance of other invertebrates on tree trunks and on the foraging site
selection of breeding Eurasian treecreepers, which use the same habitat as wood
ants. Arthropods were scarcer on the trunks with ants present; the treecreepers
avoided these trunks and foraged for a shorter time on trunks with ants than on
trunks without ants. We also tested experimentally the existence of competition
between ants and treecreepers by comparing the foraging behaviour of breeding
treecreepers on spruce trunks with ants, without ants and with experimentally
reduced numbers of ants. On average arthropods were scarcest on trunks with ants
present. Male treecreepers also foraged for a shorter time on spruce trunks with
ants. The reduction in ant numbers allowed food resources on trunks to recover
over a week and led to longer foraging times of the treecreepers on these trunks
than on trunks with ants present. The longest treecreeper visits were on trunks
without ants. Our results suggest that competition between two very different
taxa may be effective in determining the behaviour of foraging
individuals.Copyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398382
TI - Male aerial display and reversed sexual size dimorphism in the dunlin
AB - Reversed sexual size dimorphism, with males smaller than females, is common in
waders. The aerial display hypothesis suggests that sexual selection in males
favours aerial agility, and hence small size, in species with male display
flights. We tested this hypothesis in the dunlin, Calidris alpinaDisplay flights
were uncommon in the early breeding season but increased markedly when females
began laying. Male display areas were largely overlapping, and display flight
seemed to be mainly an advertising signal to potential mates. Display rate, as
well as proportion of time spent in aerial display, increased with decreasing
male size. During aerial display, small males also performed costly hovering
flights more often and for relatively longer than large males. These results
support the aerial display hypothesis.Copyright 1997 The Association for the
Study of Animal Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398383
TI - Size and pairing success in Gammarus duebeni: can females be too big?
AB - The crustacean Gammarus duebeni exhibits precopula mate guarding and size
assortative pairing, in which larger males tend to pair with larger females. Size
assortative pairing may result from sexual selection or natural selection
(mechanical or loading constraints limiting the size of female that can be
carried by the male). If loading constraints are important, large females should
have lower pairing success than females of intermediate size as they will be less
likely to encounter sufficiently large males capable of carrying them in
precopula. We tested this hypothesis in a laboratory study. Female pairing
success was dependent on size; however, the relationship was curvilinear: pairing
success increased with size up to a point, but larger females suffered decreased
pairing success. This supports the hypothesis that loading constraints play a
part in structuring size-assortative pairing in this species. We found no
evidence for size-related female resistance in structuring the pattern of
pairing. We considered size-related pairing success with regard to environmental
sex determination and parasitic sex-ratio distortion in G. duebeni1997 The
Association for the Study of Animal BehaviourCopyright 1997 The Association for
the Study of Animal Behaviour1997The Association for the Study of Animal
Behaviour
PMID- 9398384
TI - Cooperative signalling between opponents in fish fights
AB - Cichlids of the species Nannacara anomala employ several colour displays during
fights which do not seem to signal either fighting ability or motivation. How
should these colour displays be interpreted when winning is reliably predicted by
weight asymmetries? Medial Line colour displays were associated with, and
predicted, tail-beating, while Vertical Bar colour displays were associated with
mouth-wrestling. I suggest that these colour displays are used to facilitate the
transmission of assessment information within a fight, and that they are an
example of cooperative signalling between opponents. The results support the idea
that the structure of fights contains strong cooperative aspects.Copyright 1997
The Association for the Study of Animal Behaviour1997The Association for the
Study of Animal Behaviour
PMID- 9398385
TI - Foraging costs in social carnivores
AB - No abstractCopyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398386
TI - Cooperative hunting and group size: assumptions and currencies
AB - No abstractCopyright 1997 The Association for the Study of Animal
Behaviour1997The Association for the Study of Animal Behaviour
PMID- 9398387
TI - A perspective on the neurobiology of language.
AB - This paper provides a perspective on current issues and challenges in the
investigation of the neurobiology of language. It is proposed that the
speech/language deficits of aphasic patients reflect impairments in the
processing components involved in accessing language. More specifically, it is
hypothesized that many of these deficits result from changes in the activation
level of word candidates in the lexicon. Because word recognition and lexical
access processes are crucially involved in virtually all aspects of language
processing, such an impairment has repercussions throughout the components of the
linguistic grammar. It is suggested that the intersection of such language
behaviors with the identification of underlying neural systems will define future
research directions. Methodological and technological issues are discussed as
they impact on current and future research.
PMID- 9398388
TI - Phonological, semantic, and mediated priming in aphasia.
AB - An auditory lexical decision task was conducted to examine rhyme, semantic, and
mediated priming in nonfluent and fluent aphasic patients and normal controls.
Overall, monosyllabic word targets were responded to faster when preceded by
rhyming word and nonword primes than unrelated primes. Similarly, semantically
related primes facilitated lexical decisions to word targets. No evidence of
mediated priming emerged. Results for individual subjects suggest differences in
patterns across the subject groups. Implications of the findings for the
integrity of lexical access in aphasic patients are considered.
PMID- 9398389
TI - Levels of morphological deficit: indications from inflectional regularity.
AB - A language impairment that affects the production of inflected and/or derived
words may result from a deficit that specifically affects morphological
processing mechanisms, but it might also arise from whole-word processing
failures as well (Badecker & Caramazza, 1987; Funnell, 1987). However, to
motivate a true morphological impairment, the deficit must be understood in terms
of one or more different levels of morphological structure. Minimally, we can
distinguish a word's morphosyntactic representation from its morphophonological
representation. In the single-case study reported here a deficit affecting the
representation or processing of morphosyntactic representations is motivated. A
critical part of the argument is that the deficit affects both regular and
irregular inflection, and that no whole-word processing deficit can account for
the particular pattern observed in this patient.
PMID- 9398390
TI - Primary progressive aphasia: a review of 112 cases.
AB - Primary progressive aphasia (PPA) was first recognized by Mesulam in 1982.
Although dozens of cases have since been described, it has been difficult to
place these cases into a coherent framework due to the wide variation in measures
which have been reported. We review 170 contacts with 112 patients to provide a
clinical, neuroanatomical, and neuropsychological profile of patients with the
disorder. The progression of the disease is analyzed over a 10-year reporting
period starting from symptom onset to show how progression affects five general
linguistic skills: oral and written naming, reading, repetition, and general
comprehension. The pattern of functional and neurological deficits in PPA is
heterogeneous. Differences in the distribution of neurological anomalies between
patients with bilateral and unilateral changes suggest that there may be two
separate disease processes involved.
PMID- 9398391
TI - Category-specific naming deficit for medical terms after dominant
thalamic/capsular hemorrhage.
AB - Postmortem, retrograde degeneration, and electrical stimulation studies have
implicated the anterior pulvinar in language processing. We examined a patient
who, after a hemorrhage affecting the dominant pulvinar and internal capsule,
exhibited a circumscribed anomia for medical items and conditions. No other
language disturbance was noted. Five category-specific word lists, matched for
word frequency, were administered in a naming-to-definition format. Results
indicated that the patient exhibited a significant category-specific naming
deficit for medical items and conditions compared to matched control subjects.
Although medical item lists were found to differ from nonmedical item lists in
imageability and abstractness, B.C.'s category-specific deficit did not seem to
be caused by word frequency, concept familiarity, imageability, or abstractness.
Nor could the patient's performance be explained on the basis of deficits in
broader semantic classifications (i.e., animate vs inanimate or man-made vs
natural). The patient was unable to retrieve medical items even when given
phonemic cues for those he could not name. Findings indicate that subtotal damage
in the dominant pulvinar may create category-specific deficits.
PMID- 9398392
TI - Lexical acquisition in probable Alzheimer's disease.
AB - Patients with probable Alzheimer's disease (pAD) were exposed to a new verb in a
naturalistic fashion. We probed their knowledge of the word's semantic and
grammatical characteristics for several minutes following this exposure, and
compared this with their performance on parallel measures assessing known words.
Significant differences were seen between pAD patients and controls in the
acquisition of the new verb's semantic meaning and its argument structure, but
pAD patients did not differ from controls in the acquisition of the new word's
grammatical form class. Individual patient analyses demonstrated parallel
deficits restricted to the semantic meaning and argument structure of the new
word and known words in several pAD patients, suggesting that a selective
language impairment contributed to their word learning deficit. This pattern is
consistent with an intimate relationship between semantic meaning and argument
structure in semantic memory. Other pAD patients had difficulty learning about
all aspects of the new word, despite good performance with known words,
suggesting that compromised memory may have limited their lexical acquisition.
PMID- 9398393
TI - Cerebral asymmetries in processing strategies for letter and symbol trigrams.
AB - Several studies have shown that laterally presented consonant-vowel-consonant
(CVC) strings produce both superior performance, and a more wholistic processing
strategy in the right visual field/left hemisphere (RVF/LHEM), and a more
sequential strategy in the inferior left visual field (LVF). To determine whether
these strategies are applied to other types of trigrams subjects (n = 30) were
asked to identify consonant and symbol trigrams briefly projected unilaterally to
the LVF or RVF, or bilaterally (the same trigram in both fields--BVF). A second
group of subjects (n = 30) first practiced pronouncing consonant trigrams and
then viewed them tachistoscopically. Both tasks yield RVF advantages. Symbols are
processed more wholistically in the LVF, more sequentially in the RVF and in an
intermediate pattern when presented bilaterally. In contrast, subjects seem to
chunk letters as bigrams, and do so equally well in all fields, and visual field
differences in strategies emerge for consonants only when they are pronounced.
Pronounceability of consonant trigrams, assessed with ratings and vocal reaction
times, was predicted by orthographic regularity. Since the RHEM has limited
phonetic skills, but it, like the LHEM, is privy to information on orthographic
regularity, the error pattern on consonant strings indicates non-phonetic
processing, whereas the RVF wholistic strategy for consonant-vowel-consonant
strings appears to reflect phonetic processing.
PMID- 9398394
TI - Image and language in human reasoning: a syllogistic illustration.
AB - Existing accounts of syllogistic reasoning oppose rule-based and model-based
methods. Stenning and Oberlander (1995) show that the latter are isomorphic to
well-known graphical methods, when these are correctly interpreted. We here
extend these results by showing that equivalent sentential implementations exist,
thus revealing that all these theories are members of a family of abstract
individual identification algorithms variously implemented in diagrams or
sentences. This abstract logical analysis suggests a novel individual
identification task for observing syllogistic reasoning processes. Comparison of
the results of this task with the Standard Task confirms that the tasks are
psychologically closely related, throwing light on sources of error, on subjects'
sensitivity to metalogical properties, and on term-ordering phenomena. Since it
avoids posing the subtask of formulating a quantified conclusion, the new task
allows comparison of explanations of problem difficulty in terms of the number of
models (e.g., Johnson-Laird & Bara, 1984) with alternatives in terms of the
difficulty of choosing a quantifier for the conclusion. Logical concepts of
source and conditional premisses provide a comprehensive account of term order
data, including figural effects, at a level abstract with regard to imagistic or
sentential representations. These results argue that much richer empirical
evidence will be required to discriminate phenomenologically distinct reasoning
processes than has hitherto been supposed.
PMID- 9398396
TI - What Does Nonword Repetition Measure? A Reply to Gathercole and Baddeley
PMID- 9398395
TI - Symmetry and asymmetry of human spatial memory.
AB - Six experiments investigated the limiting conditions on and the causes of
asymmetries in estimates of euclidean distance. Participants estimated distances
between locations on recently learned maps or between buildings on their college
campus. Estimates between landmarks and neighboring nonlandmarks were often
asymmetric, but estimates between other pairs of locations were typically
symmetric. These and other results were inconsistent with the predictions of
models that attribute asymmetries to stimulus or to retrieval bias. A contextual
scaling model of asymmetry is proposed. According to this model, asymmetries in
proximity judgments are caused by general principles of human memory and
judgment: (a) Stimuli differ in the contexts they establish in working memory and
(b) magnitude estimates are scaled by the context in which they are made.
PMID- 9398397
TI - A new concept of immune specificity emerges from a consideration of the self
nonself discrimination.
AB - The necessity to make a Self(S)-NonSelf(NS) discrimination is the evolutionary
selection pressure for specificity of the immune response. A new definition of
paratopic specificity, which is heuristic and generalizable, can be derived from
an understanding of this selection pressure. Specificity of the paratope is
defined by a Specificity Constant, K, which is the probability that a functional
change in recognition will be anti-Self. In an antigen-unselected population, K
is the proportion of cells that are anti-Self. This definition is unique in that
it is derived from the function upon which evolution selects, namely the effector
output. This paper describes how the concept of a Specificity Constant was
derived, how it is estimated, what it can be used to explain, and how it impacts
on repertoire and effectiveness of response.
PMID- 9398398
TI - Circulating levels of IL-10 are critically related to growth and rejection
patterns of murine mastocytoma cells.
AB - Previously tumorigenic P815 tumor cells are rejected by histocompatible mice
after transfection with a mutated retroviral gene, and the host is made resistant
to subsequent challenge with tumorigenic (control) cells transfected with the
nonmutated sequence. To functionally characterize the class I-restricted response
to the tumor cell vaccine, we have assessed the in vitro (by CD8+ cells) and in
vivo production of type 1 or type 2 cytokines in mice injected with either type
of transfected P815 derivative. IL-12 and IL-10 were selectively or
preferentially expressed by the regressor mice, and this correlated with the
detection of functional type 1 reactivity in vivo (i.e., delayed-type
hypersensitivity). Other cytokines were produced by the regressor mice only in
vitro (IFN-gamma) or were not detected at all with either type of tumor recipient
(IL-4). By means of monoclonal antibody-mediated neutralization or enhancement of
endogenous cytokine levels, IL-10 was found to serve an important role in the
growth and rejection patterns of the transfected P815 derivatives. In addition to
previous evidence for an IL-12 requirement in promoting anti-P815 reactivity,
these data establish IL-10 as an important cytokine in permitting optimal
expression of this reactivity, which apparently develops in the absence of a
strong bias toward a type 1 or type 2 cytokine response.
PMID- 9398399
TI - Cross-linking of protein S bound to lymphocytes promotes aggregation and inhibits
proliferation.
AB - Recently, we reported that expression of the anticoagulant protein S is IL-4
inducible in primary T cells, and that protein S inhibits lymphoid cell
procoagulant activity. Here, using a flow cytometric assay, we demonstrate that
protein S binds to the surface of B and T lymphocytes. In addition, we show that
cross-linking of protein S bound to lymphocytes induces aggregation and inhibits
growth in cultures of primary B and T lymphocytes. Thus, our studies suggest that
protein S is an IL-4-inducible T cell product that can affect B and T cell growth
and aggregation via a lymphocyte protein S receptor. Interestingly, protein S
joins thrombin and factor Xa as coagulation factors that modulate lymphocyte
activation, suggesting that the clotting pathway may regulate wound-related
inflammatory responses.
PMID- 9398400
TI - Prolonged allogeneic and xenogeneic microchimerism in unmatched primates without
immunosuppression by intrathymic implantation of CD34+ donor marrow cells.
AB - Engraftment of stem cell-enriched donor marrow implanted in the thymus of a
foreign host might facilitate acceptance of donor-specific organ or tissue
grafts. To test this hypothesis, allogeneic and xenogeneic CD34+ marrow cells
from unrelated adult male baboons and humans were injected intrathymically in
eight infant female baboons, both with and without standard cyclosporine-based
immunosuppression. In allogeneic experiments, male (donor) cells, of both T- and
B-cell lineages, were detected by PCR in the peripheral blood of all six
recipients and persisted for at least 15 months in 2/4 recipients studied
longtutudinally. Donor-derived skin grafts survived twice as long as third party
grafts in unimmunosuppressed recipients. In xenogeneic protocols, human male
(donor) cells were demonstrable for 7 and 15 months, respectively, in two baboon
recipients with evidence that implanted human CD34+ cells had produced lymphoid
progeny. Survival of donor-specific skin xenografts was prolonged in one of two
recipients. These experiments demonstrate that the intrathymic injection of CD34+
marrow cells can result in long-lasting lymphohematopoietic microchimerism in
unrelated primates even without immunosuppression and can alter donor-specific
skin graft survival.
PMID- 9398401
TI - Ligation of CD40 potentiates Fas-mediated activation of the cysteine protease
CPP32, cleavage of its death substrate PARP, and apoptosis in Ramos-Burkitt
lymphoma B cells.
AB - The proliferation and survival of a B cell population is necessarily tightly
controlled to prevent the arisal of malignancy or autoimmunity. The expansion or
elimination of a B cell clone is determined through a complex interaction of the
tumour necrosis factor receptor/nerve growth factor receptor family members CD40
and Fas, which are expressed on the B cell surface, with their respective
physiological ligands (CD40L and FasL) expressed on the surface of CD4+ T cells.
The regulation of B cell growth by signals transduced through CD40 and Fas
contributes to the maintenance of peripheral tolerance and likely takes place and
in the germinal centres (GC) of secondary lymphoid tissues. In this study, we
investigate the relationship between the expression of Fas and B cell survival
following engagement of CD40 and Fas in the Epstein-Barr virus-genome-negative
Ramos-Burkitt lymphoma (Ramos-BL) B cell line model of GC B lymphocyte selection
during maturation of the humoral immune response. We now present evidence that
Ramos-BL B cells constitutively express both Fas and FasL on their surface and
that expression of Fas, but not FasL, is enhanced following ligation of CD40.
Coligation of CD40 and Fas, triggers for growth inhibition, activation of the
interleukin-1 beta-converting enzyme, now caspase, family member CPP32 (caspase
3) but not Ich-1L (caspase-2), cleavage of its death substrate poly(ADP-ribose)
polymerase, and apoptosis from the G1 phase of cell cycle; engagement of Fas
alone fails to trigger for growth inhibition and apoptosis but enhances AgR
mediated cellular death. This CD40-potentiated Fas-triggered growth inhibition
and apoptosis occurs in the presence of CD40-induced expression of the anti
apoptotic proteins Bcl-xL and Bcl-2. Taken together, these data indicate that
ligation of CD40 facilitates efficient coupling of Fas to the caspase-mediated
pathway of apoptosis.
PMID- 9398402
TI - Influence of retinoic acid on the differentiation pathway of T cells in the
thymus.
AB - This study investigated the ability of retinoic acid (RA) to influence T cell
differentiation. All-trans-RA had marked effects on T cell differentiation in
murine fetal thymic organ cultures (FTOCs). The time course of the effect of all
trans-RA in FTOC of day 14 C57BL/6 embryos revealed a twofold increase in the
frequency of CD4 single-positive (SP) cells and a high level of CD3-bearing cells
(CD3high cells) at a later stage of T cell development. At an earlier stage, all
trans-RA induced a twofold increase in the frequency of CD4 SP cells, but
significantly suppressed the upregulation of CD3 and TCR. Reverse transcription
PCR using RA receptor (RAR) subtype-specific primers showed that RAR alpha but
not beta and gamma is expressed during T cell development in the thymus and that
its expression was associated with the generation of CD4/CD8 double-positive (DP)
cells. In FTOC of day 16 BALB/c embryos, the level of V beta 3high cells was
greatly reduced (1.4% of the CD3high cells) in response to the mouse mammary
tumor virus-6-encoded superantigen, but V beta 3-bearing cells were rescued from
the deletion in the presence of all-trans-RA (5.6% of the CD3high cells).
Further, the inhibitory effect of all-trans-RA on thymocyte deletion was observed
when the deletion was induced by a low concentration of staphylococcal
enterotoxin B in FTOC. Taken together, these data suggest that RA increases the
frequency of mature and self-reactive T cells in the thymus, possibly by
inhibiting the process of negative selection at the DP stage of T cell
differentiation.
PMID- 9398403
TI - Selective antigen presenting activity of cortical thymic epithelial cells against
CD4+ T cells associated with both lack of costimulatory molecules and inefficient
presentation of MHC-peptide ligands.
AB - Selective activation among several effector functions of a T cell clone, DB14,
specific for pigeon cytochrome c 43-58 (p43-58) and restricted to I-Ab/d was
induced by antigen (Ag) presentation with nonprofessional Ag-presenting cells
(APC), cortical thymic epithelial cells (c-TEC) (B7-1- CD40-), whereas full
activation of the DB14 was induced with another nonprofessional APC, I-Ab L cell
(B7-1+ CD40+). In the present study, to elucidate the mechanism underlying the
selective activation of DB14 cells by c-TEC, we established c-TEC transfected
with human CD40 alone (huCD40-c-TEC) or both human CD40 and murine B7-1
(huCD40/mB7-1-c-TEC), and compared the APC functions with those of the original c
TEC and I-Ab L cell. IFN-gamma production but not the proliferative response of
DB14 was elevated by Ag presentation with huCD40-c-TEC as compared with
unmanipulated c-TEC. On the other hand, upon stimulation with Ag plus huCD40/mB7
1-c-TEC both a significant proliferative response and IFN-gamma production were
induced in DB14. However, the level of these responses did not reach that induced
in the presence of I-Ab L cell. A similar pattern of APC functions was
demonstrated with the other B7-independent T cell clone, PAB3, or T cell
hybridomas (DBhy22 and BD7-5) which are basically independent of costimulation
for the activation. The present finding along with our previous report that
several structural differences of I-Ab molecules are present between c-TEC and I
Ab L cell suggests that the distinct APC activity of c-TEC is attributable not
only to a lack of B7-1 and CD40 but also to inefficient presentation of MHC
peptide complex on the c-TEC.
PMID- 9398404
TI - IL-2 and IL-7 induce heterodimerization of STAT5 isoforms in human peripheral
blood T lymphoblasts.
AB - Despite differences in T cell responses induced by interleukin (IL)-2 and IL-7,
both cytokines modulate T cell functions by activation of signal transducers and
activators of transcription (STAT) proteins. We examined the contribution of the
two isoforms of STAT5, STAT5A and STAT5B, to IL-2- and IL-7-induced activation of
human peripheral blood T lymphoblasts. Both cytokines induced assembly of STAT5A
and STAT5B containing complexes capable of binding to the interferon-gamma
activation sequence (GAS), and these complexes rapidly translocated (within 1
min) into the nucleus of IL-2- or IL-7-treated cells. The kinetics of this
translocation were delayed in IL-7-treated as compared to IL-2-treated cells. IL
2 and IL-7 were equivalent in their ability to induce tyrosine phosphorylation of
STAT5A and STAT5B and to facilitate binding of these STATs to an immobilized GAS
element. Both IL-2 and IL-7 induced substantial amounts of STAT5A/STAT5B
heterodimerization. Moreover, we observed constitutive association of STAT3 with
each STAT5 isomer. These data suggest that IL-2 and IL-7 induce assembly of STAT
heterodimers in a similar manner and that subsequent cellular responses may be
driven by induction of similar sets of genes.
PMID- 9398405
TI - Suppression of human B cell responsiveness by CD4+ T cells does not involve CD95
CD95 ligand interactions.
AB - Although human CD4+ T cells have been shown to regulate humoral immune responses
by directly inhibiting B cells, the precise sequelae for the mechanism of
suppression have not yet been delineated. The present study was therefore
designed to explore the nature of T cell-B cell collaboration to suppress B cell
responses. Special attention was directed to the roles of Fas (CD95)-Fas ligand
(FasL) interactions. The suppressive activity was assessed by the effects of
mitomycin C-untreated CD4+ T cells activated by immobilized anti-CD3 for 72 h
(CD4+ suppressors) on the production of IgM and IgG of B cells stimulated for 72
h with immobilized anti-CD3-activated mitomycin C-treated CD4+ T cells. In this
model system, B cells stimulated with anti-CD3-activated mitomycin C-treated CD4+
T cells expressed functional Fas receptors. Accordingly, addition of anti-Fas mAb
CH-11 inhibited the cluster formation and differentiation of activated B cells as
a result of apoptotic cell death in a manner that was completely reversed by a
neutralizing anti-Fas mAb ZB4. However, neither ZB4 nor anti-FasL mAb reversed
the suppression of B cell responses by anti-CD3-induced CD4+ suppressors. Of
interest, ZB4 significantly enhanced the production of IgM and IgG induced by
anti-CD3-activated mitomycin C-treated CD4+ T cells in the absence of CD4+
suppressors. Consistently, mitomycin C-treated CD4+ T cells as well as mitomycin
C-untreated CD4+ T cells expressed comparable levels of FasL upon activation with
immobilized anti-CD3, although their intensities were very modest. These results
indicate that B cells activated with anti-CD3-stimulated CD4+ T cells express
functional Fas receptors and are sensitive to Fas-mediated apoptosis. However,
the data also suggest that interactions other than Fas-FasL may play a critical
role in direct cellular collaboration between activated B cells and anti-CD3
induced CD4+ suppressors to inhibit B cell responses.
PMID- 9398406
TI - Surface Coverage and Its Determination: Role of Acid-Base Interactions in the
Surface Treatment of Mineral Fillers
AB - The role of acid-base interactions in the nonreactive surface treatment of
mineral fillers was studied by a dissolution method. The effect of treatment on
the surface properties of CaCO3 covered with stearic acid was determined by ESCA
measurements and by the calculation of the basicity of the treated fillers. The
dissolution measurements were carried out in twelve different solvents. The
maximum amount of surfactant adsorbed on the filler surface (cmax) proved to be
independent of the acid-base character of the solvent, while the amount bonded
proportionally (c100) depended strongly on it. The results showed that
competitive processes determine the surface coverage of the filler: the
adsorption of the surfactant and the solvent on the filler surface competes with
the solution of the treating material in the solvent. Sedimentation experiments
gave valuable information about the strength of solvent/filler interaction. The
surface characteristics of the filler changed with surface coverage; the
surfactant concentration at which basicity attains its minimum agrees well with
the monolayer coverage determined by ESCA and with the c100 value obtained in
apolar solvents. The results have practical relevance as well, similar
competitive solution/adsorption processes may take place also in composites
containing surface treated fillers. Copyright 1997 Academic Press. Copyright
1997Academic Press
PMID- 9398407
TI - Studies on Interaction of Dodecyltrimethylammonium Bromide with Na- and Al
Montmorillonite
AB - The adsorption isotherms and adsorption enthalpies of dodecyltrimethylammonium
bromide (DDTMAB) on Na- and Al-montmorillonite were determined in the pH range 2
12. The basal spacings of the clays were also studied by X-ray diffraction.
Interactions of DDTMAB with the two montmorillonites predominate mostly through
cation exchange in the pH range studied. In the case of Na-montmorillonite, the
amount of adsorption increases with pH, but adsorption enthalpy decreases with
pH. For Al-montmorillonite, adsorption enthalpy exhibits nonmonotonic variation
with pH, although the amount of adsorption increases with pH monotonously. The
adsorption enthalpies of DDTMAB on the clays are negative. The adsorbed DDTMAB
molecules in clay interlayers present a bilayer arrangement at saturation.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398408
TI - Determination of the Surface Tension of Microporous Membranes Using Contact Angle
Measurements
AB - In this paper, a new method of determining the surface tension of the solid
material that a microporous membrane is made from is introduced. The method is
based on the well known determination of the so-called contact angle that is
formed on the solid/liquid/gaseous three phase line. A nonideal state of the
solid phase leads to a deviation of the contact angle that can be observed
experimentally from the equilibrium angle that arises from the thermodynamically
state of lowest energy, as it must be used to calculate the solid surface tension
via the Young equation. The deviation caused from the porous structure of the
solid material will be taken into account in this work. Doing so, we derived an
equation that connects the surface porosity, the measured contact angle, and the
equilibrium contact angle. Using this equation, the measured and therefore
deviated contact angles can be corrected for the porosity of the solid material,
yielding the contact angle observable on a surface made from the same but
nonporous material. The equation derived was tested on different microporous
membranes made from expanded poly(tetrafluoroethylene). The surface porosity
needed was determined using scanning electron microscopy followed by computerized
image analysis. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398409
TI - Static Drops on an Inclined Plane: Equilibrium Modeling and Numerical Analysis
AB - The continuum description of the equilibrium of small liquid drops located on a
sloping plane is still discussed. The effect of drop holdup on the contact
surface is modeled by describing the counteraction of a possible rolling liquid
flow. This paper studies numerically the effect of the contact angle hysteresis,
the critical slope angle at which the drop flows out. Copyright 1997 Academic
Press. Copyright 1997Academic Press
PMID- 9398410
TI - Nonideal Mixing in Adsorbed Film and Micelle of Ionic-Nonionic Surfactant
Mixtures
AB - The surface tension of aqueous solutions of dodecylammonium chloride-octyl methyl
sulfoxide (OMS) and dodecyltrimethylammonium bromide-OMS mixtures was measured as
a function of the total molality of surfactants and the composition of OMS. The
results were analyzed according to our thermodynamic procedure; the phase
diagrams of adsorption and micelle formation and the diagram illustrating the
composition relation between the micelle and the adsorbed film at the critical
micelle concentration were drawn. The activity coefficient and excess Gibbs
energy in the adsorbed film and the micelle were defined and then evaluated from
the phase diagrams. They were found to give useful information on the deviation
from ideal mixing and intermolecular interaction in the adsorbed film and
micelle. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398411
TI - Small-Angle X-Ray Scattering Study of the Formation of Colloidal Silica Particles
from Alkoxides: Primary Particles or Not?
AB - The formation of colloidal silica particles and the dynamics of the nanostructure
of the particles are investigated by small-angle X-ray scattering (SAXS)
technique. Solute concentrations of 0.5 M tetraethylorthosilicate (TEOS), 1.1 or
2.2 M water (H2O), and 0.04 or 0.1 M ammonia base (NH3) in ethanol were used to
obtain reaction conditions as close to those of the Stober method as possible and
to have reaction kinetics that were slow enough to probe the changes in the
nanostructure of the growing particles and to obtain good statistics from the
SAXS measurements. We measured the changes in the radius of gyration and the
fractal dimension as a function of time during growth. Remarkably, we find that,
after an induction period, the first particles to appear in the solution have a
radius of gyration of approximately 10 nm and are mass fractals characterized by
their polymeric, open structure. This stage is followed by an intraparticle
densification process and smoothing of the interface, leading to the usual
compact nonfractal, stable structures. The growth models proposed so far cannot
account for the observed continuous changes of stages during the formation and
growth of the particles. Copyright 1997 Academic Press. Copyright 1997Academic
Press
PMID- 9398412
TI - Spectroscopic Studies of Dextrin Adsorption onto Colloidal ZnS
AB - The interaction of dextrin with colloidal ZnS has been investigated through
adsorption studies and FT-IR spectroscopy in the 4000-400 cm-1 range. The
adsorption capacity is estimated to be around 1 mg/m2. Maximum adsorption is
found to be constant below pH approximately 7 and to increase with pH at least up
to pH 11. Eighty percent of maximum adsorption is achieved within 3 min after
addition of the dextrin. Based upon FT-IR studies and titration data, an
adsorption mechanism is proposed. Copyright 1997 Academic Press. Copyright
1997Academic Press
PMID- 9398413
TI - Structural and Dynamic Properties of Lecithin-Alcohol Based w/o Microemulsions: A
Luminescence Quenching Study
AB - Water-in-oil microemulsions have been made with lecithin in the presence of some
alcohols. The structure of the microemulsions has been studied by steady-state
and time-resolved analysis of the luminescence quenching of Ru(bipy)32+ by
Fe(CN)63-. We found that well-defined microemulsions can be made only in the
presence of short-chain alcohols such as propanol-1 and butanol-1. There exists a
threshold for water content in order to obtain typical reverse micelles. Thus in
the case of propanol-1, water/surfactant ratio wo should be above 20. By varying
water content in the range 20 < wo = 40, the microemulsion droplets suffer
dramatic structural changes and the system passes through a percolation
threshold. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398414
TI - Preparation and Characterization of Surface-Covered Nanometer-Sized Catalyst by
Carboxylate Phase Transfer
AB - Surface-covered nanometer-sized CuO/Al2O3, CuO-ZnO/Al2O3, and CuO/ZnO catalysts
were prepared by phase transfer with carboxylate. The surface-covered structure
was studied using XPS, XRD, TEM, and high-resolution electron microscope. The
results indicated that amorphous CuO and ZnO were dispersed on the surface of
nanometer-sized Al2O3 particles in catalysts CuO-ZnO/Al2O3 and CuO/Al2O3,
respectively. The thickness of its surface layer is about several angstroms. No
spinel structure was found in the catalyst. The particle size of the surface
covered CuO/Al2O3 catalyst was about 2-3 nm. Al2O3 in the catalyst was amorphous.
Surface-covered material CuO in the catalyst with low CuO content was also
armophous. A large amount of copper carboxylate resulted in crystalline CuO and
Cu2O. The protective ability of carboxylate to sol particles differs from the
metal element of carboxylate. Copyright 1997 Academic Press. Copyright
1997Academic Press
PMID- 9398415
TI - Chemical Interactions of Ultraviolet Light with Wool Fiber Surfaces
AB - The surface compositions, chemistry, and wettability of wool fiber fabrics in
both native and UV-exposed states have been investigated. X-ray photoelectron
spectroscopy shows surface oxygen levels of 10-12 at.% for native wool, which
increase to as much as 27.5 at.% on UV exposure. Investigation of C1s and S2p
photoelectron line energies shows this increase to be due largely to oxidative
cleavage of native disulfide bonds to form sulfonic acid groups together with
some formation of COOH/COOR on the wool fiber surfaces. A quantitative
relationship is demonstrated between surface chemical states and water
wettability. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398416
TI - Determination of the Surface Isoelectric Point of Oxide Films on Metals by
Contact Angle Titration
AB - The surface isoelectric point for the native air-formed oxide films on aluminum,
chromium, and tantalum has been determined by measurement of contact angles at
the hexadecane/aqueous solution interface as a function of pH of the aqueous
phase. Application of Young's equation, the Gibbs equation, and surface
equilibria conditions for hydroxylated oxide films leads to a mathematical
expression which shows that the contact angle goes though a maximum at the
isoelectric point of the oxide. The experimentally determined isoelectric point
of oxide-covered chromium is 5.2 to 5.3, of oxide-covered aluminum is 9.5, and of
oxide-covered tantalum is approximately -0.7. These values for the oxide films
are within one to three pH units of the reported isoelectric points for the
corresponding bulk oxide powders. The oxide-covered metal surfaces were cleaned
by argon plasma treatment prior to measurement of contact angles, in that XPS
measurements showed this treatment to be effective in reducing the thickness of
the carbon contamination layer. In addition, interfacial tensions were measured
at the hexadecane/aqueous solution interface and were observed to have only a
slight dependence on the pH of the aqueous phase. Copyright 1997 Academic Press.
Copyright 1997Academic Press
PMID- 9398417
TI - Interaction between Cetyl Pyridinium Chloride and Water-Soluble Polymers in
Aqueous Solutions
AB - The interaction between cetyl pyridinium chloride and different-molecular-weight
poly(vinylpyrrolidone) (PVP) and poly(ethylene glycol) (PEG) polymers has been
investigated by means of electrical conductivity and fluorescence probing. No
interaction between the low-molecular-weight PVP polymers and the surfactant was
detected, whereas a significant interaction was observed between high-molecular
weight PVP polymers or PEG polymers and cetyl pyridinium chloride. The results
indicate that polymer-surfactant aggregates start to form at a surfactant
concentration higher than the critical micelle concentration of micelles without
polymers. In contrast, the degree of ionization and the interface polarity
decrease as compared with values of micelles without polymers. The Gibbs free
energy associated with the interaction was also calculated. The values show that
the addition of polymers stabilizes polymer-surfactant aggregates. Copyright 1997
Academic Press. Copyright 1997Academic Press
PMID- 9398418
TI - Evaluation of Surface Plasmon Resonance (SPR) for Heparin Assay
AB - The concentration of heparin, an anticoagulant in blood, is usually inferred from
clotting type assay, which determines a parameter related to the heparin
activity. Because of the heterogeneity of heparin, however, it is desirable to
monitor the absolute concentration of heparin directly in the clinical range of 0
2 U/ml. Surface plasmon resonance (SPR) provides a optical direct method of
monitoring binding events. Gold films, as required for SPR, were modified with
protamine; the immoblized protamine interacts electrostatically with heparin so
that the heparin adsorption is dependent on the absolute concentration. The
"thickness" of the immobilized protamine layer determined the linear range of the
sensor's response and the sensitivity. Less densely packed layers of protamine
showed a lower detection limit for heparin, suggesting a mixing of the heparin
into the incomplete protamine layer. On the other hand, thicker, denser protamine
layers did not show a low concentration sensitivity to heparin although their
maximum heparin binding capacity was increased. It was shown that the linear
response range of the protamine modified SPR device to heparin could be modulated
by altering both the protamine loading and its method of immobilization.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398419
TI - Evaluation of Surface Plasmon Resonance (SPR) for Heparin Assay
AB - Heparin adsorption onto polyethylene imine (PEI) films was investigated. The
adsorption was followed with time-dependent surface plasmon resonance (SPR) for
PEI cast on gold films, and the thickness of the adsorbed heparin was determined
by fitting the angular reflection curves to Fresnel's equations. The average
thickness of the PEI determined the heparin adsorption range and it was found
that both heparin binding capacity and sensitivity increased with PEI thickness.
At an appropriate thickness of 10 ± 2 nm, adsorption of heparin in the
clinically applicable range of 0-2 U/ml caused a linear concentration dependent
change in the SPR reflectivity at a fixed angle, with excellent sensitivity (0.05
U/ml). The results are compared to heparin adsorption on immobilized protamine
and the surface coverage and probable heparin distribution discussed. Copyright
1997 Academic Press. Copyright 1997Academic Press
PMID- 9398420
TI - Adsorption Isotherms at a Silica/Water Interface of the Oligomers of
Polydispersed Nonionic Surfactants of the Alkylpolyoxyethylated Series
AB - Adsorption isotherms of the oligomers of three commercial alkylethoxylated
nonionic surfactants at a silica/water interface have been determined using a
HPLC method. The surfactants investigated are of the type used in detergency. The
compounds, here noted A, B, and C, were mixtures of surfactants. A and B were of
the general formulas C13E7 + C15E7 and C13E10 + C15E10, respectively. Compound C
was a mixture of oligomers ranging from C12E7 to C16E7 in various proportions.
About 10 isotherms are presented for the most important oligomers for each of
these detergents. Compound C could be more thoroughly discussed than compounds A
and B because adsorption data for the pure surfactant of the same surfactant
series with even numbers of carbon atoms in the alkyl chain were made available.
Thus, the behavior of representative oligomers of C could be compared with that
of the same pure surfactants at the silica/water interface. It is shown that at
low surface coverage, polydispersity effects of either alkyl chains or ethoxy
groups on global surfactant adsorption are negligible and the oligomers behave
essentially as pure, single surfactants. At higher surface coverage, the
simultaneous presence of oligomers with long chain lengths or with small numbers
of ethoxy groups does not favor the formation of large structures, disks, or
patched bilayers at the silica surface as do single pure surfactants. However, it
is demonstrated that the opposing effects of oligomers with small and large alkyl
chain lengths cancel out in the global isotherms. So it may be concluded that
polydispersity in the case of commercial nonionic surfactants of the type used in
the present investigation does not affect to any great extent the behavior of
such compounds at a silica/water interface. The consequences of these findings
can be extended to other nonionic surfactant series. Copyright 1997 Academic
Press. Copyright 1997Academic Press
PMID- 9398421
TI - Determining Surface Areas from Linear Adsorption Isotherms at Supercritical
Conditions
AB - Here we demonstrate that there is a wide range of pressures at supercritical
temperatures where there is essentially monolayer coverage (i.e., there is nearly
a complete layer of molecules adsorbed adjacent to the surface, but very little
excess density in the second and subsequent layers). In this regime, the
dependence of the Gibbs adsorption on the density is linear, and coefficients of
this linear function depend on the monolayer capacity and surface area. It is
shown that measurements of the Gibbs adsorption in this regime can be used to
determine surface area without knowledge of the area per molecule or a model for
the adsorption isotherm. This new method has the potential to provide reliable
values of specific surface area for macroporous, mesoporous, and microporous
systems without the limitations of previous methods. Lattice-theory calculations
suggest that the best conditions for surface area measurements are in the
supercritical region with temperatures about twice the critical temperature and
pressures well above the critical pressure. These conditions allow nearly
complete monolayer coverage but there is not multilayer adsorption because the
temperature is sufficiently above the critical temperature of the adsorbate.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398422
TI - Surface Chemical Analysis and Electrokinetic Properties of Spherical Hematite
Particles Coated with Yttrium Compounds
AB - We describe in this work the chemical and electrokinetic surface characterization
of core-shell particles consisting of a practically spherical hematite nucleus
coated by a layer of yttrium basic carbonate or yttrium oxide (obtained after
calcination of the carbonate-coated particles, following the method of E.
Matijevic and B. Aiken (J. Colloid Interface Sci. 126, 645 (1988))). The
morphological and surface characteristics of the particles were controlled by
modifying the initial yttrium nitrate concentration and the growing time. A total
of 14 samples of hematite-yttrium basic carbonate composites were obtained, and
three of them (obtained by keeping at 90degreesC solutions containing 6.5 x 10(
4) M alpha-Fe2O3, 1.8 M urea, and 1.1, 3, and 4.9 mM Y(NO3)3, respectively) were
then converted into hematite-Y2O3 particles. Transmission electron microscopy was
used to ascertain the shape and size of the particles. The spherical geometry of
the core hematite is found, as a rule, on the core-shell particles; in general,
carbonate samples obtained with intermediate initial concentration of Y(NO3)3
have the maximum coating thickness, whereas increasing that concentration does
not lead to thicker coatings. Hence, formation of individual yttrium basic
carbonate, together with coated hematite, cannot be completely ruled out under
such conditions. Two techniques were employed for the elucidation of the surface
composition of the particles, namely EDX and XPS (or ESCA). In particular, XPS
data show that the coating of hematite by yttrium carbonate is almost complete in
the case of particles obtained with 3 mM Y(NO3)3 concentration and 9-h heating
time. The oxide samples obtained after calcination show high contents of yttrium
and low iron surface concentration for initial [Y(NO3)3] = 1.1 mM (sample OB9)
and 3 mM. According to XPS analysis, both types of particles have a quite similar
surface composition and structure. For all types of particles but the carbonate
coated ones obtained at the shortest reaction times, the pHiep was found to be
above that of pure hematite, approaching that of yttrium basic carbonate or
oxide. In particular, among the oxide-coated particles, it is sample OB9 the one
that most closely approaches its pHiep to that of Y2O3, in good agreement with
the surface chemical analysis performed with XPS. Copyright 1997 Academic Press.
Copyright 1997Academic Press
PMID- 9398423
TI - Determination of the Main Forces Driving DNA Oligonucleotide Adsorption onto
Aminated Silica Wafers
AB - The adsorption of a 20-base long 5'-amino-linked oligodeoxyribonucleotide (ODN)
onto aminopropylsilane-modified silica wafers has been investigated. At first,
silanized surfaces were characterized by contact angle measurements, X-ray
photoelectron spectroscopy (XPS), ellipsometry, and atomic force microscopy
(AFM). Adsorbed amount of oligonucleotides was estimated by radioactive counting
or colorimetric hybridization reaction. The first technique was useful for direct
counting, while colorimetric detection, implying an hybridization reaction
between adsorbed ODN and its complementary sequence, provided information about
its accessibility on the wafer. With the purpose of determining the driving
forces of the ODN adsorption onto these surfaces, conditions such as initial ODN
concentration, pH, and ionic strength have been examined. The adsorption process
could be described as a Langmuir reversible adsorption type. Surface charge
contribution has been investigated by raising pH values from 4 to 10.8.
Electrostatic interactions between the negatively charged ODN and the aminated
groups on the silica wafers were found to play a major role in the adsorption
process. Moreover, a drastic influence of the ionic strength on the ODN adsorbed
amount was evidenced. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398424
TI - Surface Energetics of the Adsorption Process of a Cationic Dye on Leacril Fabrics
AB - In this paper are presented data on the zeta potential, adsorption processes, and
energy of interaction between Leacril and a cationic dye, crystal violet (CV) in
the process of dyeing of Leacril. The method for obtaining the values of zeta
potential of the system is the streaming potential technique. Previous models of
bundles of capillaries have been tested by comparison with precise values of the
zeta potential of the system. The model that presents a higher confidence level
is the Goring and Mason model. The zeta potential results reveal that the uptake
of crystal violet on Leacril fibers takes place by means of electrostatic
attraction between the cation of the dye and both the sulfonate and the sulfate
end-groups of the Leacril. Given the hydrophobic character of the Leacril and the
amphiphilic nature of the dye molecules, hydrophobic attractions between the
fiber and the hydrophobic part of the crystal violet might account for the
adsorption of the cationic dye onto the fibers even when hindered by
electrostatic repulsion. The data for the adsorption of the dye on the fibers
indicate that the adsorption is favored by increasing the temperature of the
process. This could be due to increased ionization of the sulfonate and sulfate
end-groups of the Leacril, with increasing temperature of adsorption. The
behavior of the components of the interaction energy, between the Leacril and the
dye, is analyzed in the present paper in light of van Oss's theory. Using both
the thin layer wicking and contact angle techniques, we have determined the
values of the components of the surface-free energy of Leacril fabrics and of the
crystal violet, respectively. The total interaction energy between the Leacril
and the cationic dye has been obtained by means of sum of three components, the
electrical, DeltaGEL, acid-base, DeltaGAB, and Lifshitz-van der Waals, DeltaGLW,
respectively. Estimation of the electrical component makes use of the zeta
potential of the system Leacril/cationic dye obtained by means of the streaming
potential technique. Two approaches were followed in order to estimate the
interfacial (excluding electrostatic) free energy of interaction DeltaGIF between
Leacril fibers and CV: (i) the determination of the interactions between the
fiber and dye solutions of different concentrations and (ii) estimations of
DeltaGIF between fiber and dye molecules in the presence of water. These combined
methods are in agreement with the experimental results obtained in this work.
These methods explain qualitatively the adsorption of the cationic dye on Leacril
in the entire range of concentrations of dye used in the present work. Based on
the study of the interfacial interactions carried out in the present work the
adsorption of crystal violet onto Leacril is favorable from a thermodynamic point
of view. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398425
TI - Thiolation of Maghemite Nanoparticles by Dimercaptosuccinic Acid
AB - Magnetic particle-effector conjugates are widely used in vitro for cell sorting
in various pathologies. The coupling between the particles and the effectors
being realized through S-S bridges, the particles must first be thiolated before
the coupling. In this work, the synthesis, in aqueous medium, of nanoparticles of
maghemite thiolated by dimercaptosuccinic acid is described. The superficial
complexation by a thiol-containing ligand induces a reductive dissolution of the
oxide and leads to the adsorption of polydisulfide species coming from the
oxidation of the ligand. Adsorption and redox reactions being strongly correlated
to the composition of the medium, the amount of adsorbed ligand and the quantity
of iron(II) released into the medium have been simultaneously determined, at
various pH, for different concentrations of ligand added. The charge of the
particles is drastically modified in the presence of a chelating agent; as a
consequence, the colloidal stability is greatly affected and so the flocculation
ranges of the complexed particles have been established for different pH. When
the quantity of ligand added is sufficient (0.05 mol/mol of iron), the ferrofluid
based on thiolated maghemite particles is stable between pH 3 and 11 and can be
used for biomedical applications. Copyright 1997 Academic Press. Copyright
1997Academic Press
PMID- 9398426
TI - Water Adsorption on Pyrogenic Silica Followed by 1H MAS NMR
AB - On the surface of two commercial pyrogenic silicas (Degussa and Cabot), five
resonances were identified on the basis of the chemical shift, homonuclear
coupling (T2), and spin-lattice relaxation behavior (T1). In accordance with
previous studies we observed three different types of silanol groups: (i) weakly
coupled (long T2), water inaccessible, isolated "internal" silanols at 1.8 ppm;
(ii) weakly coupled, external "free" silanols revealed upon dehydration at 2.5
ppm; and (iii) strongly coupled external hydrogen bound silanols with an
unresolved broad resonance between 3 and 7 ppm. The resonance of water, whose
position between 2.6 and 4.6 ppm depended on water content, corresponded to two
unresolved species of slightly different T1. By equating this resonance to the
weighted average of two distinct populations of water, we were able to
distinguish the first layer of strongly hydrogen bound water at 2.7 ppm from
liquid-like water at 5 ppm. The first layer is complete for water relative
humidity as low as 3.6% and corresponds to a surface coverage of 4.75 H2O/nm2. If
we assumed a cristobalite-based surface structure, this meant a 1:1 ratio between
surface hydroxyls and the first layer of physisorbed water. This ratio was the
same for the two silicas regardless of surface area. Copyright 1997 Academic
Press. Copyright 1997Academic Press
PMID- 9398427
TI - Characterization of the Sorption of Europium(III) on Calcite by Site-Selective
and Time-Resolved Luminescence Spectroscopy
AB - Sorption of europium(III) on calcite from aqueous solution was investigated by
kinetics and sorption isotherms at 323 K and by site-selective and time-resolved
luminescence spectroscopy at 15 K. Three sorption sites (A, B, C) were
characterized by this last technique. B constitutes a major family which appears
in all samples with sorbed Eu and is characterized by an environment involving
water or hydroxyl ions. The C family is observed only for the highest Eu
concentrations. In these sites, the environment is more hydrated than in sites B.
Site A constitutes a minority but appears in all samples. It corresponds to the
centrosymmetric structural Ca site of calcite in position 2b, thus demonstrating
that sorbed Eu(III) can substitute for Ca in calcite. Copyright 1997 Academic
Press. Copyright 1997Academic Press
PMID- 9398428
TI - Two-Surface Virial Analysis of Alkane Adsorption on Carbopack C with and without
Hydrogen Treatment
AB - Second gas-solid virial coefficients for propane, butane, pentane, and hexane
were found for Carbopack C and Carbopack C-HT (Supelco Inc.) within the
temperature range of 323 to 471 K using gas-solid chromatography in the Henry's
law region of adsorption. Carbopack C and Carbopack C-HT are both graphitized
carbon black powders. Treatment of Carbopack C with hydrogen at 1273 K converts
it to Carbopack C-HT and is believed to remove certain high energy sites or "hot
spots" from the carbon surface. These two surfaces provide appropriate model
systems to test a two-surface virial analysis. Surface areas for both powders
were calculated using a uniform single-surface model and a two-surface model.
Only the two-surface virial model which is based on gas-solid interaction
parameters determined by an iterative process and numerical integration gave
reasonable areas for the two surfaces: 13.2 and 13.9 m2/g for Carbopack C and
Carbopack C-HT, respectively. The percentage of high energy sites on the
Carbopack C was found to be 2.6% and for Carbopack C-HT was found to be 1.5%. The
gas-solid interaction energy for the high energy sites was found to be 1.80 times
greater than the corresponding value for the low energy portion of the surface.
In addition, the gas-solid adsorption energies for the four alkane adsorbates
were found to have a linear correlation with their boiling points and with the
ratio of their critical temperatures divided by the square root of their critical
pressures. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398429
TI - Adsorption Energy Evaluation from Luminescence Spectra of Uranyl Ions (UO22+)
Adsorbed on Disperse Silica Surfaces
AB - Luminescent measurements are utilized to evaluate the adsorption energy for
hydrated uranyl groups on the disperse silica surface. The position of the UO22+
0-0 electronic transition and the frequencies of intramolecular vibrations
appearing in luminescence spectra were used in that evaluation. The method is
based on the dependence of the adsorption bond force constants corresponding to
each type of surface sites on the respective perturbation energy of uranyl ions.
To calculate the corresponding force constants of adsorption bonds, a vibrational
problem is solved. The molecular adsorbate on the silica surface is modeled by
means of hypothetical diatomic and triatomic molecules with Cinfinityv and C2v
symmetry, in which the UO22+ ion is predominantly fixed on the silica surface
through one and two water molecules, respectively. The perturbations of
stretching and deformational vibrations of hypothetical molecules by the presence
of the substrate are considered. It has been shown that due to a large value of
uranium mass the proposed models can be used for the analysis of vibrational
spectra of hydrated uranyl groups adsorbed on the silica surface. A comparison of
experimental data with theoretical calculations shows one to suggest that
hydrated uranyl groups are attached to the surface by means of two water
molecules. The adsorption energy for hydrated uranyl groups physically and
chemically adsorbed on the silica surface were evaluated. Copyright 1997 Academic
Press. Copyright 1997Academic Press
PMID- 9398430
TI - Growth and Structure of Zirconium Hydrous Polymers in Aqueous Solutions
AB - Zirconium oxychloride solutions prepared at different pH were heated at elevated
temperatures for various aging periods to gain an understanding of the growth
mechanism and structure of zirconium hydrous polymers. Small angle X-ray
scattering (SAXS) measurements were made on these solutions. It was observed that
shape of clusters at the earlier stages of growth is close to a rod rather than a
sheet as suggested earlier. The scattering data indicate that a rod-shaped
primary particle is formed at pH 1.2, and on an increase in the pH, the primary
particles become more branched. On aging more than 1250 min at 92°C, these
primary particles form large aggregates while retaining the primary particle
structure. These aggregates, which are mass fractal in nature, restructure while
growing in size and eventually transform into dense particles. Scattering data in
this study were not enough to determine a specific kinetic growth model of the
aggregates because the scattering intensity at low q constantly changes with time
during the restructuring process. Copyright 1997 Academic Press. Copyright
1997Academic Press
PMID- 9398431
TI - Surface Reactivity of Iron Oxide Pigmentary Powders toward Atmospheric
Components: XPS, FESEM, and Gravimetry of CO and CO2 Adsorption
AB - The adsorption of carbon monoxide and carbon dioxide (CO and CO2) on a number of
specially prepared alpha-Fe2O3 samples was measured gravimetrically at 25°C.
The samples were prepared from a steel-pickling waste (97 wt% FeSO4·7H2O)
by roasting the original material at 700°C for 5 h in air, oxygen, and
nitrogen. Estimated surface coverages by the adsorbed CO and CO2 were made on the
basis of nitrogen-adsorption-based surface areas, while the nature of the sample
surfaces was investigated by both X-ray photoelectron spectroscopy (XPS) and
field emission SEM (FESEM) techniques. In addition a depth profiling study
utilizing a sputtering argon beam and XPS was undertaken. Morphological studies
using FESEM showed that neither CO nor CO2 caused any significant structural
changes. The nature of the resultant alpha-Fe2O3 sample surfaces differed, with
the degree of oxygenation decreasing in the order of preparatory gases: oxygen,
(wet) air, nitrogen [IP(O), IP(A), and IP(N)]. The amounts of both CO and CO2
adsorbed decreased in the sample order IP(A) > IP(O) > IP(N), though in the case
of CO adsorption, the amounts adsorbed on IP(A) and IP(O) were not greatly
different. In all cases the amounts adsorbed represented only fractional
coverage. Adsorption of the more acidic CO2 is thought to be favored more by
basic Ox-2 than by O2- sites on both IP(O) and IP(A), but with surface hydroxyl
groups also playing a role (particularly on IP(A)). The CO2 adsorption should
result in the formation of mono-, di-, and polydentate carbonate and bicarbonate
species, with increasing degassing temperatures favoring the polydentate species
and the decomposition of the bicarbonate and carbonate to form undissociated CO2.
The adsorption of CO (a weak base) is postulated to take place on strong Lewis
acid, highly coordinated, metal sites to form metal carbonyl species, on strong
base sites (O2-) to form carbonite, oxalate, and ketenic species, and, to a
lesser degree, on surface hydroxyl groups to form formyl and formate species.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398432
TI - Mixed cultures of avian blastoderm cells and the quail mesoderm cell line QCE-6
provide evidence for the pluripotentiality of early mesoderm.
AB - During the early stages of embryogenesis, the mesoderm gives rise to cells of the
cardiovascular system which include cardiac myocytes and vascular endothelial and
red blood cells. We have investigated the development of these cell phenotypes
using aggregate cultures of avian blastoderm cells, which replicated mesodermal
cell diversification. The cell phenotypes expressed by the blastoderm cells were
dependent upon the age of the blastoderm cells, with Hamburger-Hamilton stage 3
or 4 cells giving rise to endothelial and red blood cells and stage 5 cells
producing endothelial and myocardial cells. To begin to understand the stage
dependency of the cellular diversification of these aggregate cultures, we
treated the cultures with various signaling factors that have been shown to be
present in the early avian embryo. These experiments showed that stem cell factor
and TGF alpha altered cell phenotypes by stimulating red blood cell and
myocardial differentiation, respectively. The ability of these growth factors to
shift the differentiation profile of aggregate cultures demonstrated the
plasticity of early embryonic cells. To explore the diversification of individual
mesodermal cells, labeled QCE-6 cells were incorporated within these blastoderm
aggregate cultures. Previous studies have shown that this quail mesodermal cell
line possesses characteristics of early nondifferentiated mesodermal cells and
can be induced to express either myocardial or endothelial cell phenotypes (C. A.
Eisenberg and D. M. Bader, 1996, Circ. Res. 78, 205-216). In the present study,
we show that when these cells were cultured as a component of blastoderm cell
aggregates, they differentiated into fully contractile cardiomyocytes or
endothelial or red blood cells. Moreover, QCE-6 cell differentiation was in
accordance with that displayed by the blastoderm cells. Specifically, QCE-6 cells
differentiated into red blood cells when cultured within stage 3 or stage 4, but
not stage 5, blastoderm cell aggregates. Accordingly, the differentiation of QCE
6 cells into beating cardiomyocytes only occurred when these cells were
incorporated into stage 5 blastoderm cell aggregates. The identical sorting and
differentiation patterns that were exhibited by QCE-6 and blastoderm cells
suggest that expression of differentiated cell types within the early mesoderm is
directed by the surrounding environment without immediate cellular commitment. In
addition, these results provide further evidence that QCE-6 cells are
representative of a multipotential mesodermal stem cell and that they possess the
potential to exhibit fully differentiated cell phenotypes.
PMID- 9398433
TI - MAP and cdc2 kinase activities at germinal vesicle breakdown in Chaetopterus.
AB - In frog oocytes, activation of mitogen-activated protein kinase (MAPK, ERK) leads
to activation of cdc2 and germinal vesicle breakdown (GVBD). By contrast, in
starfish, MAPK is activated after GVBD. Here we have examined the relative
involvements of MAPK and cdc2 in GVBD of Chaetopterus oocytes. MAPK was rapidly
tyrosine-phosphorylated and activated (within 1-2 min) in response to exposure of
the oocytes either to natural seawater (the normal trigger of GVBD in this
organism) or to the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol 13
acetate (TPA), which can also elicit GVBD. This response preceded the tyrosine
dephosphorylation and activation of cdc2 by several minutes. MAPK phosphorylation
and activation were transient, lasting only until GVBD occurred and the spindle
migrated to the cortex. The enzyme was not phosphorylated again as a result of
egg activation. These results are consistent with the hypothesis that the
activation of MAPK has a role in GVBD. However, PD 98059, a potent and selective
inhibitor of MEK, the protein kinase that phosphorylates and activates MAPK,
blocked the phosphorylation of MAPK but did not block GVBD, the dephosphorylation
and activation of cdc2, or spindle formation and migration. Oocytes that
underwent GVBD in PD 98059 could be fertilized and cleaved normally. Ionophore
A23187, although it caused germinal vesicles to disappear and caused transient
phosphorylation of MAPK, did not cause dephosphorylation of cdc2, and therefore
this disappearance is artifactual. These results suggest that MAPK activation is
neither obligatory nor sufficient for either GVBD or meiotic metaphase arrest in
Chaetopterus and that activation of MAPK and cdc2 occur on independent, parallel
pathways.
PMID- 9398434
TI - A critical period of ear development controlled by distinct populations of
ciliated cells in the zebrafish.
AB - The zebrafish (Danio rerio) is a useful model system for analyzing development of
the inner ear. A number of mutations affecting the inner ear have been
identified. Here we investigate the initial stages of otolith morphogenesis in
wild-type embryos as well as in monolith (mnl) mutant embryos, which fail to form
anterior otoliths but otherwise appear normal. Otolith growth is initiated at 18
18.5 h by localized accretion of free-moving precursor particles. This process,
referred to as otolith seeding, is regulated by two classes of cilia: First,
kinocilia of precociously forming hair cells (tether cells) bind seeding
particles, thereby localizing otolith formation. Tether cells usually occur in
pairs at the anterior and posterior ends of the ear. Despite the presence of
functional kinocilia, tether cells initially appear immature and do not acquire
the characteristics of mature hair cells until approximately 21.5 h. Second,
beating cilia distributed throughout the ear agitate seeding particles, thereby
inhibiting premature agglutination. Constraining particles with laser tweezers
caused them to fuse into large untethered masses. Bringing such masses into
contact with tethered otoliths caused them to fuse, greatly enhancing otolith
growth. Selectively enhancing one otolith greatly inhibited growth of the second,
creating an imbalance that persisted for many days. Seeding particles and beating
cilia disappear soon after 24 h, and the rate of otolith growth decreases by
nearly 90%. In mnl mutant embryos, tethers and beating cilia are distributed
normally, but anterior otoliths fail to form in 80-85% of mutant ears. The
binding properties of seeding particles appear normal, as shown by their ability
to fuse when entrapped by laser tweezers and their binding to posterior tethers.
We infer that anterior tethers have a weakened ability to bind seeding particles
in mnl embryos. Immobilizing mnl embryos with the anterior end of the ear
oriented downward effectively concentrated the dense seeding particles near the
anterior tethers and permitted all to form anterior otoliths. However,
immobilizing mnl embryos after 24 h when seeding particles were depleted did not
facilitate anterior otolith formation. Together, these data demonstrate that the
ability to initiate otolith formation is limited to a critical period, from 18.5
to 24 h, and that interfering with the functions of tether cell kinocilia or
beating cilia impairs otolith seeding and subsequent otolith morphogenesis.
PMID- 9398435
TI - Mesoderm is required for the formation of a segmented endodermal cell layer in
the leech Helobdella.
AB - The homeobox gene Lox3 is expressed in a segmentally iterated pattern within the
endoderm of the leech Helobdella. We use that expression here to study endoderm
differentiation following experimental ablations of mesoderm. Lox3 RNA was first
detected by in situ hybridization at the stage when a definitive cellular
endoderm is formed from its syncytial precursor and was never observed in
derivatives of other germ layers. Expression is initially distributed throughout
the endoderm, but rapidly disappears from specific regions of the nascent gut
wall so as to produce a pattern of segmental stripes. The stripe pattern differs
markedly between midgut organs, with thin stripes of Lox3 expression in the
intercaecal constrictions of the crop and wide stripes of Lox3 expression marking
the caecal bulges of the intestine. Lox3 expression in the rectum is not
obviously segmental. Ablation of segmental mesoderm in the early Helobdella
embryo prevents the formation of definitive endoderm and the expression of Lox3
RNA and leads to abnormalities in the morphogenesis of the gut tube. These
endodermal deficits are precisely coextensive with the zone of mesodermal
deficiency, suggesting that the mesoderm normally acts to promote the formation
of the endodermal cell layer via local cell interactions. The segmental pattern
of Lox3 expression is largely unaffected in portions of the endoderm surrounding
such deficits, suggesting that endodermal segmentation is not established by
lateral interactions within that tissue layer. Rather, we propose that the
segmental organization of the endoderm is imprinted by vertical interactions with
the segmental mesoderm.
PMID- 9398436
TI - The expression domain of two related homeobox genes defines a compartment in the
chicken inner ear that may be involved in semicircular canal formation.
AB - Homeobox-containing genes encode a class of proteins that control patterning in
developing systems, in some cases by acting as selector genes that define
compartment identity. In an effort to demonstrate a similar role for such genes
during ear development in the chicken, we present a detailed expression study of
two related homeobox-containing genes, SOHo-1 and GH6, using in situ
hybridization. At otocyst stages the two genes define a broad lateral domain of
expression, which may represent a developmental compartment. Three-dimensional
computer reconstructions of SOHo-1 expression at these and later stages revealed
that the lateral domain becomes progressively restricted to the three
semicircular canals. Thus, SOHo-1 and GH6 are among a small group of markers for
a specific structural component of the inner ear. The gene expression domain
initially includes the sensory regions of the semicircular canals, known as the
cristae ampullaris, but none of the other four sensory organs which were
recognizable by BMP4 expression during early morphogenesis (stages 19-24).
Significantly, two of the sensory organs (the superior and posterior cristae)
were found at the limits, or boundaries, of the SOHo-1/GH6 expression domain,
suggesting that compartment boundaries may be involved in specifying sensory
organ location as well as identity. Maintained expression at the boundaries may
aid in specifying the location of canal outgrowth. These concepts are presented
as a formal model which emphasizes that patterning information could be provided
at the boundaries of gene expression domains in the inner ear.
PMID- 9398437
TI - Altered forebrain and hindbrain development in mice mutant for the Gsh-2 homeobox
gene.
AB - The patterning of the mammalian brain is orchestrated by a large battery of
regulatory genes. Here we examine the developmental function of the Gsh-2
nonclustered homeobox gene. Whole-mount and serial section in situ hybridizations
have been used to better define Gsh-2 expression domains within the developing
forebrain, midbrain, and hindbrain. Gsh-2 transcripts are shown to be
particularly abundant in the hindbrain and within the developing ganglionic
eminences of the forebrain. In addition, mice carrying a targeted mutation of Gsh
2 have been generated and characterized. Homozygous mutants uniformly failed to
survive more than 1 day following birth. At the physiologic level the mutants
experienced apnea and reduced levels of hemoglobin oxygenation. Histologically,
the mutant brains had striking alterations of discrete components. In the
forebrain the lateral ganglionic eminence was reduced in size. In the hindbrain,
the area postrema, an important cardiorespiratory chemosensory center, was
absent. The contiguous nucleus tractus solitarius, involved in integrating
sensory input to maintain homeostasis, was also severely malformed in mutants.
Immunohistochemistry was used to examine the mutant brains for alterations in the
distribution of markers specific for serotonergic and cholinergic neurons. In
addition, in situ hybridizations were used to define expression patterns of the
Dlx 2 and Nkx 2.1 homeobox genes in Gsh-2 mutant mice. The mutant lateral
ganglionic eminences showed an abnormal absence of Dlx 2 expression. These
results better define the genetic program of development of the mammalian brain,
support neuromeric models of brain development, and further suggest similar
patterning function for homeobox genes in phylogenetically diverse organisms.
PMID- 9398438
TI - Cellular mechanism underlying neural convergent extension in Xenopus laevis
embryos.
AB - Convergent extension, the simultaneous narrowing and lengthening of a tissue,
plays a major role in shaping and patterning the neural ectoderm in vertebrate
embryos. In this paper, we characterize the cellular mechanism underlying
convergent extension of the neural ectoderm in the Xenopus laevis late gastrula
and neurula embryo. Neural ectoderm in X. laevis consists of two components, a
superficial layer of epithelial cells overlying deep mesenchymal cells. To
investigate the force contribution of the deep cells to convergent extension, we
explanted single layers of neural deep cells from late gastrula stage embryos.
These "neural deep cell explants" undergo active convergent extension
autonomously, implying that these cells contribute force for neural convergent
extension in vivo. Using time-lapse videorecording of these explants, we observed
the neural deep cell behaviors (previously hidden behind an opaque epithelium)
underlying convergent extension. We show that neural deep cells mediolaterally
intercalate to form a longer, narrower tissue and that cell shape change and cell
division contribute little to their convergent extension. Moreover, we
characterize the neural deep cell motility driving mediolateral intercalation,
also using time-lapse videorecordings. Analyses of these videos revealed that, on
average, neural deep cells exhibit mediolaterally biased protrusive activity
which is expressed in an episodic fashion. We propose that neural deep cells
accomplish mediolateral intercalation by applying their protrusions upon one
another, exerting traction, and pulling themselves between one another. This
mechanism is similar to that previously described for convergent extension of the
mesodermal cells. However, because the neural deep cells do not mediolaterally
elongate during their convergent extension as the mesodermal cells do, we predict
that a given intercalation will result in more extension for neural deep cells
than for the mesodermal cells. Intercalation of neural cells also likely occurs
in a more episodic manner than that of the mesodermal cells because the neural
cells' mediolateral protrusive activity is episodic, whereas the protrusive
activity of mesodermal cells is more continuous. These differences in protrusive
activity and cell shape changes between the neural and mesodermal regions may
reflect specializations of the same basic mechanism of mediolateral
intercalation, tailored to accommodate other aspects of patterning and
development of each tissue. These descriptions of the active cell motility
underlying neural convergent extension in X. laevis are the first high-resolution
video documentation of protrusive activity during neural convergent extension in
any system. Our findings provide an important step in the investigation of neural
convergent extension in X. laevis and further our understanding of convergent
extension in general.
PMID- 9398439
TI - Heterogeneous expression of multiple putative patterning genes by single cells
from the chick hindbrain.
AB - The metameric organization of the vertebrate hindbrain into rhombomeres appears
to result from the patterned expression of several transcription factors and
putative signaling molecules. We have applied a refined single-cell reverse
transcription-polymerase chain reaction strategy to examine the molecular logic
proposed to pattern the hindbrain at the single-cell level. This technique allows
analysis of the concurrent expression of several genes within an individual cell
at higher sensitivity than by in situ hybridization. Our results demonstrate that
cells in rhombomere (r) 4 and r5 are heterogeneous in their expression of Hoxa-3,
Hoxb-2, Sek-1, and Krox-20, suggesting that single cells are dynamically
regulating their rhombomere-specific gene-expression profiles. Furthermore, the
strong correlation between Sek-1 and Krox-20 expression at stage 12 was greatly
diminished by stage 16, suggesting that the proposed interdependence of these two
genes is present only at early stages of hindbrain development.
PMID- 9398440
TI - Single-cell analysis of regulatory gene expression in quiescent and activated
mouse skeletal muscle satellite cells.
AB - Repair and regeneration of adult skeletal muscle are mediated by satellite cells.
In healthy muscle these rare mononucleate muscle precursor cells are mitotically
quiescent. Upon muscle injury or degeneration, members of this self-renewing pool
are activated to proliferate and then differentiate. Here we analyzed in single
satellite cells the expression of a set of regulatory genes that are candidates
for causal roles in satellite cell activation, maturation, and differentiation.
Individual cells were identified as satellite cells and selected for analysis
based on their physical association with single explanted myofibers or their
position beneath the basal lamina in unperturbed muscle tissue. Using a multiplex
single-cell RT-PCR assay we simultaneously monitored expression of all four MyoD
family regulators of muscle determination and differentiation (MRFs) together
with two candidate markers of satellite cell identity, c-met and m-cadherin. By
making these measurements on large numbers of individual cells during the time
course of satellite cell activation, we were able to define which expression
states (possible combinations of the six genes) were represented and to specify
how the representation of each state changed with time. Activated satellite cells
began to express either MyoD or myf5 first among the MRFs; most cells then
expressed both myf-5 and MyoD simultaneously; myogenin came on later in cells
expressing both MyoD and myf5; and many cells ultimately expressed all four MRFs
simultaneously. The results for fiber-associated satellite cells from either
predominantly fast or slow muscles were indistinguishable from each other. The c
met receptor tyrosine kinase was also monitored because it is a candidate for
mediating activation of quiescent satellite cells (Allen et al., 1995) and
because it might also be a candidate molecular marker for satellite cells. A
significant difficulty in studying mouse satellite cells has been the absence of
molecular markers that could identify them in the quiescent state before
expression of MRFs or desmin and distinguish them from fibroblasts. We show here
that c-met receptor is present beneath the basal lamina on presumptive satellite
cells in intact muscle and that c-met mRNA and protein are expressed by all
myofiber-associated satellite cells from the time of explant through the course
of activation, proliferation, and differentiation. c-met was not detected in
muscle-derived fibroblasts or in other mononucleate cells from healthy muscle
explants. When compared directly with m-cadherin, which has previously been
suggested as a marker for quiescent satellite cells, m-cadherin mRNA was detected
only in a small subset of satellite cells at early times after myofiber explant.
However, at late times following activation (by 96 hr in this fiber culture
system), c-met and m-cadherin were uniformly coexpressed. From the individual
satellite cell expression types observed, a model of the satellite cell
population at rest and during the time course of activation was generated.
PMID- 9398441
TI - A Drosophila kinesin-like protein, Klp38B, functions during meiosis, mitosis, and
segmentation.
AB - We show that klp38B, isolated as a mutation that dominantly prolongs blastoderm
mitotic cycles in Drosophila, encodes a Drosophila kinesin-like protein. Further
genetic analyses show that Klp38B not only functions during mitosis, but is also
required for meiosis and abdominal segmentation. Sequence comparisons suggest
that Klp38B encodes an amino-terminal microtubule motor domain, a central alpha
helical coiled-coil domain, and a C-terminal globular domain. Evidence that
Klp38B is required during meiosis is that flies transheterozygous for mutations
in both klp38B and nod have a high frequency of 4th chromosome meiotic
nondisjunction. Nod is a chromokinesin, a chromosome binding kinesin, that is
believed to provide astral-exclusion forces during the metaphase stage of
meiosis. Evidence that Klp38B is required during mitosis is that embryos from
female germline clones of klp38B mutations have holes in the cuticle similar to a
zygotic string (dCDC25) phenotype. Also, anti-Klp38B antibody injection into
precellularization blastoderm embryos causes developmental arrest and the
formation of circular mitotic figures. We speculate, based on these phenotypes,
that Klp38B is a chromokinesin that provides astral-exclusion forces on the
chromosomes during meiosis and mitosis. Consistent with this hypothesis, we have
identified an HMG-1 homologous region on Klp38B that could potentially bind AT
rich DNA sequences. Finally, we show that klp38B mutations have defects in
abdominal segmentation, suggesting that Klp38B, like Xenopus chromokinesin Xklp1,
might be involved in polar granule formation.
PMID- 9398442
TI - ARNT-deficient mice and placental differentiation.
AB - We used homologous recombination in embryonic stem cells to generate mice
heterozygous for an aryl hydrocarbon nuclear translocator (ARNT) null mutation.
These mice were intercrossed, but no live homozygous Arnt-/- knockout mice were
produced among 64 newborns. Homozygotes die in utero between 9.5 and 10.5 days of
gestation. Abnormalities included neural tube closure defects, forebrain
hypoplasia, delayed rotation of the embryo, placental hemorrhaging, and visceral
arch abnormalities. However, the primary cause of lethality appears to be failure
of the embryonic component of the placenta to vascularize and form the
labyrinthine spongiotrophoblast. This may be related to ARNT's known role in
hypoxic induction of angiogenesis. We found no defects in yolk sac circulation.
PMID- 9398443
TI - NGF-mediated survival depends on p21ras in chick sympathetic neurons from the
superior cervical but not from lumbosacral ganglia.
AB - In rat embryonic sympathetic neurons from the superior cervical ganglia (SCG) NGF
mediated survival depends on the activation of the trkA receptor tyrosine kinase
and on the activity of the intracellular plasmamembrane-anchored small G-protein
p21ras. In contrast, chick sympathetic neurons derived from the more caudally
located lumbosacral chain ganglia (LSCG) do not respond to activated p21ras (G12V
Ha-ras mutant). In these neurons endogenous p21ras and its downstream effector
MAP kinase are activated but are not essential for NGF-dependent survival. Here
we show that also in chick sympathetic neurons of the SCG permanently activated
p21ras protein does promote neuron survival. Consistently, their NGF-mediated
survival is sensitive to Fab fragments blocking endogenous p21ras activity. These
results suggest that sympathetic neurons derived from sympathoenteric (SCG) and
sympathoadrenal (LSCG) lineages differ in their requirement for p21ras in the NGF
mediated survival pathways.
PMID- 9398444
TI - Glial changes in the phrenic nucleus following superimposed cervical spinal cord
hemisection and peripheral chronic phrenicotomy injuries in adult rats.
AB - The objective of the present study was to characterize the microglial and
astroglial reaction in the phrenic nucleus following either an ipsilateral C2
spinal cord hemisection, a peripheral phrenicotomy, or a combination of the two
injuries in the same adult rat. The present study used three different
fluorescent markers and a confocal laser image analysis system to study glial
cells and phrenic motoneurons at the light microscopic level. Young adult female
rats were divided into one combined injury group (left phrenicotomy and left C2
spinal hemisection with periods of 1 to 4 weeks between injuries, N = 12) and
three other groups consisting of noninjured animals (N = 3), animals that
received C2 hemisection only (N = 3), and animals with phrenicotomy only
(survival periods of 2 (N = 3) and 4 (N = 3) weeks after phrenicotomy).
Fluorogold was injected into the diaphragm to label phrenic motoneurons in all
animals. Microglia and astrocytes were labeled with Texas red and fluorescein,
respectively, and were visualized simultaneously along with phrenic motoneurons.
The results suggest that the microglial and astrocytic response in the
superimposed injury model are similar to the glial reactions characteristically
seen in a peripheral axotomy alone model. These reactions include proliferation
and migration of microglial cells along the perineuronal surface (peaking at 2
weeks) and the hypertrophy of astrocytes (peaking at 4 weeks). In addition, the
increase in astrocytic tissue, which is characteristically seen in response to
axotomy alone, is significantly enhanced in the superimposed injury model. Also,
there is a large and rapid increase in GFAP-positive astrocytes within 24 hours
after hemisection alone. The information gained from the present study will aid
in determining, predicting, and eventually manipulating central nervous system
responses to multiple injuries with the objective of reestablishing function in
the damaged CNS.
PMID- 9398445
TI - Presenilin 1 immunostaining using well-characterized antibodies in human tissues.
AB - Using well-characterized monoclonal antibodies which recognize the N-terminus of
presenilin 1 (PS1), we examined by immunohistochemistry brain tissues from
patients with nonneurological conditions, Alzheimer's disease (AD) and cerebral
infarction, as well as normal human liver tissues. The antibodies to PS1 did not
reveal any positive staining in nonneurological conditions. In AD, the antibody
showed positive staining of intraneuronal neurofibrillary tangles and neuropil
threads. In cerebral infarcts, some macrophages were positively stained. In
contrast to the C-terminal fragment of PS1, which has been claimed to be present
in senile plaques, the N-terminal fragment binds to intracellular and
intradendritic pathological structures and may play a role in tau phosphorylation
in AD.
PMID- 9398446
TI - Axotomized rubrospinal neurons rescued by fetal spinal cord transplants maintain
axon collaterals to rostral CNS targets.
AB - Neurons that maintain extensive axon collaterals proximal to the site of axotomy
may be better able to survive injury. Early lesions of the rubrospinal tract lead
to retrograde cell death of the majority of axotomized immature neurons.
Transplants of fetal spinal cord tissue rescue axotomized rubrospinal neurons and
promote their axonal regeneration. Rubrospinal neurons develop many of their axon
collaterals postnatally. The present study tests the hypothesis that the
axotomized rubrospinal neurons that are rescued by transplants and regenerate
their axons are those neurons that have established axon collaterals to targets
rostral to the lesion. Neonatal rats received a transplant of fetal spinal cord
tissue placed into a midthoracic spinal cord hemisection. One month after
transplantation, the retrogradely transported fluorescent tracers fast blue (FB)
and diamidino yellow (DY) were used to identify rubrospinal neurons with
collaterals to particular targets. FB was injected either into the interpositus
nucleus of the cerebellum or into the gray matter of the cervical enlargement to
identify collaterals to these targets, and DY was injected into the spinal cord
approximately 5 mm caudal to the transplant and lesion site to label retrogradely
the neurons that regenerated their axons. Double labeling was observed in the
axotomized neurons of the red nucleus after tracer injections into the cervical
spinal cord but not after injections into the cerebellum. This labeling pattern
indicates that axotomized rubrospinal neurons that are rescued and regenerate
axons caudal to the transplant maintain axon collaterals at cervical spinal cord
levels. Cerebellar collaterals do not appear to play a role in the survival and
regrowth of axotomized rubrospinal neurons.
PMID- 9398447
TI - Neurotoxicity of endogenous cysteinylcatechols.
AB - Progression of Parkinson's disease has been associated with several biochemical
changes in the substantia nigra including increased oxidative challenge, catechol
oxidation, and inhibition of mitochondrial complex I activity.
Cysteinylcatechols, formed by nucleophilic addition of cysteine to oxidized
catechols, have been identified as markers of catechol oxidation in brain tissue.
We have examined the neurotoxicity of a series of cysteinylcatechols. Of the
compounds examined, only 5-S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac) was
specifically cytotoxic to differentiated P19 neuroglial cultures. Cysdopac also
was neurotoxic to pyramidal neurons in organotypic cultures of hippocampus, and
this effect was ablated by selective N-methyl-D-aspartate (NMDA) receptor
antagonists. In vitro, cysdopac was a potent inhibitor of mitochondrial complex I
activity. However, electrophysiologic experiments failed to demonstrate NMDA
receptor agonist activity for cysdopac, nor did cysdopac inhibit glutamate
uptake. These results showed that cysdopac was the most potent neurotoxin of this
series of cysteinylcatechols and suggest that cysdopac may function as an
indirect excitotoxin, potentially via inhibition of mitochondrial respiration.
PMID- 9398448
TI - Immunolocalization of nitric oxide synthases at the postsynaptic domain of human
and rat neuromuscular junctions--light and electron microscopic studies.
AB - Neuronal (n) and inducible (i) nitric oxide synthase (NOS) were immunolocalized
at the postsynaptic domain of human and rat neuromuscular junctions (NMJs) by
light and electron microscopy. We applied polyclonal and monoclonal antibodies
for colocalization with three other synaptic proteins, utilizing double and
triple fluorescence labeling, and gold and peroxidase for immunoelectron
microscopy. By light microscopy, nNOS and iNOS colocalized with desmin and
dystrophin, known postsynaptic components, but not with neurofilament protein, a
presynaptic component. By electronmicroscopy, nNOS, but not iNOS, colocalized
postsynaptically on the same structures as desmin; iNOS was also postsynaptic,
but did not colocalize with desmin immunoreactivity. At the NMJs of Duchenne
muscular dystrophy patients, both nNOS and iNOS were strongly immunoreactive. At
the NMJs of a patient with myasthenia gravis, nNOS was weaker than in controls.
Total denervation of rat sciatic nerve did not cause any decrease of nNOS or iNOS
immunoreactivity 7 days thereafter. At 15 days after denervation, there was a
gradual decrease of immunoreactivity, and immunoreactivity disappeared 30 days
after denervation, corresponding to the ultrastructurally detectable
disorganization of the postsynaptic region. This seems to be the first combined
light and electron microscopic description of the postsynaptic localization of
nNOS and iNOS at human and rat NMJs.
PMID- 9398449
TI - Effects of isradipine, an L-type calcium channel blocker on permanent and
transient focal cerebral ischemia in spontaneously hypertensive rats.
AB - Permanent or transient focal cerebral ischemia was induced in spontaneously
hypertensive rats (SHR) using the intraluminal filament method. Successful
occlusion of the middle cerebral artery (MCA) was achieved using 4/O filaments
(terminal diameter 0.20-0.25 mm) coated with poly-L-lysine. The L-type calcium
channel blocker isradipine (2.5 mg/kg) administered subcutaneously 30 min
following permanent MCA occlusion significantly reduced the volume of ischemic
brain damage in the cerebral hemisphere (25%; P = 0.0001), cerebral cortex (18%;
P = 0.0034), and caudate nucleus (33%; P = 0.0002) when assessed at 24 h post-MCA
occlusion. Isradipine did not affect the functional deficit (measured using a
subjective neurological scoring system) induced by MCA occlusion. In SHR
undergoing transient (2 h) MCA occlusion isradipine administered 30 min post-MCA
occlusion produced a significant reduction (47%; P = 0.001) in hemispheric
infarct volume, whereas isradipine administered at the onset of reperfusion did
not confer any significant neuroprotection. No change in functional deficit was
seen with isradipine with either dosing paradigm at 24 h post-MCA occlusion.
These results demonstrate that the intraluminal filament method of MCA occlusion
can be used in the SHR strain and also substantiates the neuroprotective efficacy
of isradipine in SHR models of permanent and transient focal cerebral ischemia.
PMID- 9398450
TI - Regenerating and sprouting axons differ in their requirements for growth after
injury.
AB - After spinal cord injury at birth, axotomized brainstem-spinal and corticospinal
neurons are capable of permanent regenerative axonal growth into and through a
fetal spinal cord transplant placed into the site of either a spinal cord
hemisection or transection. In contrast, if fetal tissue which is not a normal
target of the axotomized neurons (embryonic hippocampus or cortex) is placed into
a neonatal spinal cord hemisection, brainstem-spinal serotonergic axons
transiently innervate the transplant, but subsequently withdraw. The first set of
experiments was designed to test the hypothesis that after spinal cord
transection, serotonergic axons would cross the nontarget transplant, reach
normal spinal cord targets caudal to the transection, and gain access to
requisite target-derived cues, permitting permanent maintenance. Surprisingly,
after a complete spinal cord transection, brainstem-spinal axons failed to grow
into an inappropriate target even transiently. These observations suggest that
the transient axonal ingrowth into nontarget transplants may represent lesion
induced axonal sprouting by contralateral uninjured axons. We have used double
labeling with fluorescent dyes, to test directly whether axonal sprouting of
neurons which maintain collaterals to uninjured spinal cord targets (1) provide
the transient ingrowth of brainstem-spinal axons into a nontarget transplant and
(2) contribute to permanent ingrowth into target-specific transplants. Uninjured
red nucleus, raphe nucleus, and locus coeruleus neurons extend axons into the
nontarget transplant while maintaining collaterals to the host spinal cord caudal
to the transplant. The lesion-induced sprouting by uninjured axons was also
observed with a target-specific transplant. Taken together, these studies suggest
that sprouting and regenerating axons may differ in their requirements for growth
after injury.
PMID- 9398451
TI - Increased expression of microtubule-associated protein 1B in the hippocampus,
subiculum, and perforant path of rats treated with a high dose of
pentylenetetrazole.
AB - A single administration of the convulsant pentylenetetrazole (PTZ) initiates a
complex pattern of long-term changes in microtubule-associated protein 1B (MAP1B)
expression across the hippocampal formation. Using Northern blot and in situ
hybridization we show that the first increases in MAP1B mRNA were detected at 15
h following PTZ administration in the granule cells of the dentate gyrus and CA3
region of the hippocampus and reached a maximum at 44 h. The levels of MAP1B mRNA
in the subiculum peaked at later times (5 days). At 72 h MAP1B immunoreactivity
was mainly localized in the granule-cell bodies and dentate inner and
midmolecular layer as well as in neuronal cell bodies and the stratum lucidum,
including the mossy fiber pathway of the CA3 region. By 5-10 days the levels of
MAP1B in the pyramidal cells in the CA3 region decreased to very low levels;
rather, heavy staining of interneuron-like cells and "strings-of-bead" structures
all over the hippocampus and at the stratum oriens/alveus border were seen. The
levels of MAP1B in the hippocampus returned to control levels by 20 days after
PTZ administration. MAP1B immunoreactivity in the alvear path was also evident at
5 days postinjection at the CA1/alveus border. The intensity of MAP1B staining
increased gradually in the perforant path starting at 72 h and persisted at high
levels until day 35. Our studies show that (i) MAP1B is a temporal and regional
marker for rapid and acute epileptic seizures and (ii) long-term increases in
MAP1B in the perforant path might play a role in PTZ-induced seizures.
PMID- 9398452
TI - Expression of brain-derived neurotrophic factor and TrkB neurotrophin receptors
after striatal injury in the mouse.
AB - Brain-derived neurotrophic factor (BDNF) promotes the survival and
differentiation of nigral dopaminergic neurons and supports the activity of
dopaminergic cells grafted into the striatum. However, little attention has been
given to the physiological role of endogenous BDNF and its receptor TrkB within
the nigrostriatal dopamine system. We know that striatal injury is followed by
long-term stimulation of dopaminergic activity in the striatum, could BDNF play a
role in this phenomenon? One week after physical injury to the striatum of
C57/Black mice, just before dopaminergic activation becomes obvious, in situ
hybridization on coronal sections through mouse striatum reveals that BDNF mRNA
expression increases significantly before returning to basal levels within 1
month. Expression of mRNA for TrkB follows a very different pattern. No change of
expression of the full-length and catalytically competent TrkBTK+ receptor is
seen. However, expression of the truncated form of the receptor TrkTK-, which
lacks the catalytic tyrosine kinase domain, does increase and stays elevated for
at least 2 months after injury. When combined with observations of dopaminergic
activation after striatal injury and the neuroprotective effects of BDNF
introduced into the striatum, our findings suggest that BDNF and TrkBTK- do
indeed play a role in dopaminergic regeneration and repair.
PMID- 9398453
TI - Signals that regulate astroglial gene expression: induction of GFAP mRNA
following seizures or injury is blocked by protein synthesis inhibitors.
AB - Previous studies have revealed that a single electroconvulsive seizure (ECS)
strongly induces glial fibrillary acidic protein (GFAP) expression in astrocytes
in the hippocampal dentate gyrus. The signals that trigger this induction are not
known, but circumstantial evidence suggests the hypothesis that GFAP expression
may be induced as a result of the induction of growth factor expression by
dentate granule cells that also occurs as a result of the ECS and other types of
seizures. The present study tests one prediction of this hypothesis by evaluating
whether increases in GFAP mRNA levels after ECS are blocked by inhibiting protein
synthesis at various times after the ECS. We report that the upregulation of GFAP
expression following ECS is blocked by protein synthesis inhibitors given 5 min
before or up to 12 h after a single ECS. This temporal gradient suggests an
intermediate step involving the increased expression of a protein growth factor.
PMID- 9398454
TI - The attenuation of kainate-induced neurotoxicity by chlormethiazole and its
enhancement by dizocilpine, muscimol, and adenosine receptor agonists.
AB - Systemically administered kainate (10 mg.kg-1) caused neuronal loss in both the
hippocampus and the entorhinal regions of the rat brain. This resulted in a loss
of 68.3 +/- 13.8 and 53.3 +/- 12.8% of pyramidal neurones in the hippocampal CA1
and CA3a regions, respectively. Chlormethiazole attenuated the loss of neurones
in the hippocampal cell layers CA1 (cell loss 10 +/- 3.2%) and CA3a (cell loss 10
+/- 7.7%). The neuroprotective activity of chlormethiazole was apparent in the
presence or absence of a low dose of clonazepam (200 micrograms.kg-1 i.p.). The
kainate-induced damage could also be measured by the increase in binding of the
peripheral benzodiazepine ligand ([3H]PK11195) in the hippocampus. In kainate
treated rats there was a 350-500% increase in binding indicative of reactive
gliosis. Chlormethiazole prevented this elevation in a dose- and time-dependent
manner, with an ED50 of 10.64 mg.kg-1 and an effective therapeutic window from 1
to 4 h posttreatment. Dizocilpine also attenuated damage significantly. The GABAA
agonist muscimol was also able to attenuate the increase in [3H]PK11195 binding
in a dose-dependent manner, with an ED50 of approximately 0.1 mg.kg-1. If
muscimol, dizocilpine, or the adenosine A1 receptor agonist R-N6-phenylisopropyl
adenosine were administered together with chlormethiazole at their respective
ED25 doses, a potentiation was apparent in the degree of neuroprotection. It is
concluded that the combination of neuroprotective agents with different
mechanisms of action can lead to a synergistic protection against excitotoxicity.
PMID- 9398455
TI - Triazolam impairs delayed recall but not acquisition of various everyday memory
tasks in humans.
AB - A double-blind test battery was administered to 24 human subjects (8 control, 16
drug) to assess the effects of 0.125 mg triazolam (oral) on memory encoding and
retention across delay intervals ranging from seconds to 1 week after
presentation. Although the drug reduced immediate psychomotor performance, it did
not impair recall of previously learned information, nor did it significantly
impair encoding of new information. The drug enhanced immediate recall of the
location and identity of playing cards, without affecting 4-h delayed recall. The
drug treatment impaired correct recall of object names after a delay of 20 min.
At 4 h delay, the drug impaired olfactory recognition and free-recall of object
names. At both 1 day and 1 week delay, the drug impaired recall of biographical
information and correct identification of picture-photographer pair associations.
The drug also impaired the daily improvement of the drug group as compared with
the control group in a geometric puzzle solving task. The time course of these
memory impairments compares well with the known effects of triazolam on long-term
potentiation (LTP), a candidate biological mechanism underlying telencephalic
memory formation and expression.
PMID- 9398457
TI - In vitro cell density-dependent clonal growth of EGF-responsive murine neural
progenitor cells under serum-free conditions.
AB - Neural progenitor cell populations responsive to epidermal growth factor (EGF)
have been shown to have proliferative potential and give rise to neurons,
astrocytes, and oligodendrocytes. We have characterized EGF-responsive neural
progenitor cells that give rise to bilineage neuronal/glial colonies (colony
forming unit neuron-glia; CFU-NeGl) and unilineage neuronal colonies (CFU-Ne).
Clonality was confirmed utilizing mixtures of brain cells from Balb/c and ROSA26
(transgenic for beta-galactosidase) mice. With a few exceptions, colonies showed
either all blue cells or all clear cells after staining with X-Gal. Clonal growth
was analyzed after 10-11 days in relation to cell density by determining colony
size and plating efficiency. Growth was density dependent (no growth below 10,000
cell/ml) and thus single cell cloning was not accomplished. An average plating
efficiency of 4% was found for EGF-responsive neural cells derived from day 15-18
murine embryos when cultured at 12,500 to 200,000 cells/ml. Similar results were
obtained with 1-day-old postnatal neural cells. When colonies were categorized by
size, the relative number of colonies over 50 cells appeared to be maximum at
50,000 plated cells/ml. After 11 days in culture, 94, 96, and 78% of the colonies
contained cells that expressed nestin, neurofilament, and GFAP, respectively.
Double-label experiments revealed that > 62% of the colonies contained both GFAP
and neurofilament expressing cells. These studies establish the existence of at
least two populations of clonal neural progenitors: CFU-Ne and CFU-NeGl in fetal
and postnatal murine brain.
PMID- 9398456
TI - Long-term survival of human central nervous system progenitor cells transplanted
into a rat model of Parkinson's disease.
AB - Progenitor cells were isolated from the developing human central nervous system
(CNS), induced to divide using a combination of epidermal growth factor and
fibroblast growth factor-2, and then transplanted into the striatum of adult rats
with unilateral dopaminergic lesions. Large grafts were found at 2 weeks survival
which contained many undifferentiated cells, some of which were migrating into
the host striatum. However, by 20 weeks survival, only a thin strip of cells
remained at the graft core while a large number of migrating astrocytes labeled
with a human-specific antibody could be seen throughout the striatum. Fully
differentiated graft-derived neurons, also labeled with a human-specific
antibody, were seen close to the transplant site in some animals. A number of
these neurons expressed tyrosine hydroxylase and were sufficient to partially
ameliorate lesion-induced behavioral deficits in two animals. These results show
that expanded populations of human CNS progenitor cells maintained in a
proliferative state in culture can migrate and differentiate into both neurons
and astrocytes following intracerebral grafting. As such these cells may have
potential for development as an alternative source of tissue for neural
transplantation in degenerative diseases.
PMID- 9398459
TI - Adenovirus vector-mediated gene transfer into human epileptogenic brain slices:
prospects for gene therapy in epilepsy.
AB - As a first step in the development of a gene therapy approach to epilepsy, we
evaluated the ability of adenovirus vectors to direct the transfer into and
expression of a marker gene in human brain slices obtained from patients
undergoing surgery for medically intractable epilepsy. Following injection of
adenovirus vectors containing the Escherichia coli lacZ gene into hippocampal and
cortical brain slices, lacZ mRNA, beta-galactosidase protein, and enzymatic
activity were detected, confirming successful gene transfer, transcription, and
translation into a functional protein. Transfected cells were predominantly
glial, with some neurons expressing beta-galactosidase as well. These results
support the potential of adenovirus vectors to transfer genetic information into
human epileptogenic brain, resulting in expression of the gene into a functional
protein. These findings also have implications for the development of gene
therapy approaches to certain seizure disorders. A number of potential
therapeutic approaches are discussed, including the elevation of inhibitory
neurotransmitter or neuropeptide levels, expression or modulation of postsynaptic
receptors, and manipulation of signal transduction systems.
PMID- 9398458
TI - Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of
rat cerebellar granule cells.
AB - We have studied in a well-characterized in vitro neuronal system, cultures of
cerebellar granule cells, the toxicity of polyamines endogenously present in the
brain: spermine, spermidine, and putrescine. Twenty-four-hour exposure of mature
(8 days in vitro) cultures to 1-500 microM spermine resulted in a dose-dependent
death of granule cells, with the half-maximal effect being reached below 50
microM concentration. Putrescine was moderately toxic but only at 500 microM
concentration. Spermidine was tested at 50 and 100 microM concentration and its
toxicity was evaluated to be about 50% that of spermine. Neuronal death caused by
spermine occurred, at least in part, by apoptosis. Spermine toxicity was
completely prevented by competitive (CGP 39551) and noncompetitive (MK-801)
antagonists of the NMDA receptor, but was unaffected by a non-NMDA antagonist
(NBQX) or by antagonists of the polyamine site present on the NMDA receptor
complex, such as ifenprodil. A partial protection from spermine toxicity was
obtained through the simultaneous presence of free radical scavengers or through
inhibition of the free radical-generating enzyme nitric oxide synthase, known to
be partially effective against direct glutamate toxicity. The link between
spermine toxicity and glutamate was further strengthened by the fact that, under
culture conditions in which glutamate toxicity was ineffective or much reduced,
spermine toxicity was absent or very much decreased. Exposure to spermine was
accompanied by a progressive accumulation of glutamate in the medium of granule
cell cultures. This was attributed to glutamate leaking out from dying or dead
cells and was substantially prevented by the simultaneous presence of MK-801 or
CGP 39551. The present results demonstrate that polyamines are toxic to granule
cells in culture and that this toxicity is mediated through the NMDA receptor by
interaction of exogenously added polyamines with endogenous glutamate released by
neurons in the medium. The involvement of brain polyamines, in particular
spermine and spermidine, in excitotoxic neuronal death is strongly supported by
our present results.
PMID- 9398460
TI - Spinal Cord Transection-No Loss of Distal Ventral Horn Neurons
AB - Anterograde transneuronal degeneration is caused by the loss of afferent input to
the nerve cells and may occur in a number of neuronal systems. Transection of the
adult spinal cord, causing anterograde transneuronal degeneration in ventral horn
neurons, distal to the lesion, has been reported by some authors, while others
contend that no such changes take place. The present study was undertaken in
order to investigate whether transection of adult mouse thoracic spinal cord
induces neuronal death in the ventral horns distal to the lesion. By means of
modern stereological techniques such as the optical disector, the total number of
cells in the lumbar ventral horns was estimated 7 weeks after transection. The
mean numbers of neurons and glial and endothelial cells were 82,000 versus
89,000, 259,000 versus 301,000, and 129,000 versus 144,000 in the transected (n =
6) and sham-operated animals (n = 5), respectively. These differences were not
statistically significant. Furthermore, neuronal soma volume was estimated by
another stereological method, the vertical rotator. Mean neuronal soma volume was
not significantly different between transected (2762 &mgr;m3) and sham-operated
(2617 &mgr;m3) mice. Although no reduction in cell number or neuronal soma volume
was observed, the mean volume of the ventral horns in the lumbar segments was
significantly less in transected than in sham-operated animals, 2.49 mm3 versus
3.05 mm3 (P < 0.05). In conclusion, the transection of adult mouse thoracic
spinal cord does not induce neuronal degeneration in the lumbar ventral horns.
Copyright 1997 Academic Press. Copyright 1997 Academic Press
PMID- 9398461
TI - Generation and transplantation of EGF-responsive neural stem cells derived from
GFAP-hNGF transgenic mice.
AB - EGF-responsive neural stem cells isolated from murine striatum have the capacity
to differentiate into both neurons and glia in vitro. Genetic modification of
these cells is hindered by a number of problems such as gene stability and
transfection efficiency. To circumvent these problems we generated transgenic
mice in which the human GFAP promoter directs the expression of human NGF. Neural
stem cells isolated from the forebrain of these transgenic animals proliferate
and form clusters, which appear identical to stem cells generated from control
animals. Upon differentiation in vitro, the transgenic stem cell-derived
astrocytes express and secrete bioactive hNGF. Undifferentiated GFAP-hNGF or
control stem cells were transplanted into the striatum of adult rats. One and 3
weeks after transplantation, hNGF was detected immunocytochemically in an halo
around the transplant sites. In GFAP-hNGF-grafted animals, intrinsic striatal
neurons proximal to the graft appear to have taken up hNGF secreted by the
grafted cells. Ipsilateral to implants of GFAP-hNGF-secreting cells, choline
acetyltransferase-immunoreactive neurons within the striatum were hypertrophied
relative to the contralateral side or control-grafted animals. Further, GFAP-hNGF
grafted rats displayed a robust sprouting of p75 neurotrophin receptor-positive
fibers emanating from the underlying basal forebrain. These studies indicate that
EGF-responsive stem cells which secrete hNGF under the direction of the GFAP
promoter display in vitro and in vivo properties similar to that seen following
other methods of NGF delivery and this source of cells may provide an excellent
avenue for delivery of neurotrophins such as NGF to the central nervous system.
PMID- 9398462
TI - Serotonin promotes the survival of cortical glutamatergic neurons in vitro.
AB - The appearance of 5-hydroxytryptamine (serotonin; 5-HT) in the cerebral cortex
coincides with developmental events such as cell proliferation, survival, and
differentiation. We tested the hypothesis that 5-HT plays a role in these events
by examining rat cortical progenitor cells in vitro. Using bromodeoxyuridine
incorporation we found that 5-HT did not affect the proliferation of these cells,
but a cell survival assay indicated that it promoted their survival. The observed
survival effect was mimicked by the 5-HT2a/2c receptor agonist alpha-methyl-5-HT
and blocked by the 5-HT2a receptor antagonist cinanserin. Consistent with
increased survival was the finding, using the terminal transferase nick end
labeling method, of reduced cell death in cultures exposed to 5-HT.
Immunohistochemical analysis with cell-specific markers revealed that the effect
of 5-HT was directed specifically to the glutamate-containing neuronal population
and not to any other cortical cell types. These results indicate that 5-HT does
not exert its effects on dividing neuroepithelial cells in the developing cortex,
but rather on postmitotic neurons.
PMID- 9398463
TI - Hydrocephalus in the Otx2+/- mutant mouse.
AB - Mice with the Otx2+/- mutation often die during the postneonatal period. Before
death these animals, generated from TT2 ES cells and crossed with CBA mice,
develop a dome-shaped head, weakness of the limbs, kyphosis, lethargy,
drowsiness, and emaciation. Autopsy of these mice revealed eminent dilatation of
lateral ventricles and a ballooned cerebrum. Histological analysis shows
edematous change of the periventricular white matter. These results suggest that
Otx2 functions as a head organizer, and a mutation of this gene is a likely cause
of hydrocephalus in mammals. Additionally, craniobasal skeletal anomaly in half
of the heterozygotes and dwarfism in some of the female heterozygotes are
described.
PMID- 9398464
TI - Regulation of D-aspartate release and uptake in adult brain stem auditory nuclei
after unilateral middle ear ossicle removal and cochlear ablation.
AB - In young adult guinea pigs, the effects of unilateral ossicle removal and
cochlear ablation were determined on transmitter release from glutamatergic
presynaptic endings and glutamate inactivation via uptake. (i) D-[3H]Aspartate
release and uptake were measured in subdivisions of the cochlear nucleus (CN) and
in nuclei of the superior olive (SOC) and auditory midbrain (MB) up to 145 days
after placing the lesions. Activities were compared to those from age-matched
unlesioned controls. Fiber degeneration was visualized histologically. (ii) In
the ipsilateral CN, changes in release and uptake were governed by the type of
lesion. Ossicle removal produced sparse pruning of fibers only after 112 days and
decreased release and uptake at 145 days, consistent with regulatory weakening of
excitatory glutamatergic transmission. Cochlear ablation deafferented the CN,
producing deficient release and uptake at 2 days and abundant fiber degeneration
at 7 days. Subsequently, the residual release and uptake increased in magnitude,
consistent with strengthening of excitatory glutamatergic transmission. (iii) In
the contralateral CN, after either lesion, changes in release and uptake usually
matched those in the ipsilateral CN. Thus, the auditory pathway associated with
the lesioned ear probably provided cues for the regulation of synaptic strength
in the contralateral CN. (iv) Both lesions increased release in the SOC and MB,
and uptake in the SOC, consistent with strengthening of excitatory glutamatergic
transmission. Sparse fiber degeneration, suggesting axonal pruning, appeared in
the SOC and MB after cochlear ablation. (v) The strengthening of excitatory
glutamatergic transmission may facilitate and maintain symptoms such as loudness
recruitment and tinnitus which often accompany hearing loss.
PMID- 9398465
TI - Sciatic nerve regeneration through venous or nervous grafts in the rat.
AB - This study analyses the interest of isologous venous grafts filled with saline or
with Schwann cells versus nerve grafts as guides for regeneration of the sciatic
nerve in 35 Wistar rats. Electrophysiological parameters (conduction velocities
and distal latencies of motor responses) and the functional index of De
Medinacelli were measured several times from 1 month to 1 year after surgery. An
histological analysis was performed on 2 control rats and on 3 rats killed 6 or
12 months after surgery: the total number of fibers was counted on a montage
photoprint of the whole nerve, and the diameters of axons and the thickness of
the myelin sheath were measured on digitized images. With a portion of nerve as
guide, the regeneration is faster than with a vein. However, regeneration after 6
months is at least as good with a venous graft filled with Schwann cells, as
assessed by electrophysiological, functional, and histological analysis. The
addition of Schwann cells in grafted veins allows the nerve to regenerate through
longer gaps than previously described (25 vs 15 mm). In order to assess the
quality of nerve regeneration, functional, electrophysiological, and histological
analysis are complementary.
PMID- 9398466
TI - Genetic transfer of the wobbler gene to a C57BL/6J x NZB hybrid stock: natural
history of the motor neuron disease and response to CNTF and BDNF cotreatment.
AB - Preclinical diagnosis of motor neuron disease (MND) in the wobbler mouse (wr/wr)
has been impossible until recently. However, with the development of a new
hybrid, the C57BL/6J x New Zealand Black (B6NZB) wr/wr mouse, the polymerase
chain reaction (PCR) can be used to establish the preclinical diagnosis. We
compared the clinical and histological features of MND and the effects of
neurotrophic factor cotreatment between the hybrid B6NZB-wr/wr and the congenic
C57BL/6J-wr/wr mice. Clinical assessments of body weight, grip strength, running
speed, paw position, and walking pattern were made weekly from age 2 weeks
through 8 weeks (n = 10, B6NZB-wr/wr; n = 15, C57BL/6J-wr/wr). Survival was
analyzed (n = 7, each strain) as was C5 and C6 spinal cord motoneuron morphology
and ventral root histometry (n = 7, each strain). For cotreatment, 8 B6NZB-wr/wr
and 7 C57BL/6J-wr/wr mice received subcutaneous ciliary neurotrophic factor (1
mg/kg) and brain-derived neurotrophic factor (5 mg/kg) on alternate days, 6
days/week for 4 weeks. B6NZB-wr/wr mice could be distinguished from C57BL/6J
wr/wr mice at age 3 weeks by a more abnormal paw position (P < 0.01) and walking
pattern (P < 0.05) and lower grip strength (P < 0.001) and running speed (P <
0.001). After 3 weeks, the changes continued to be greater in B6NZB-wr/wr mice.
Although B6NZB-wr/wr mice were more severely affected early in the disease, their
survival was comparable to C57BL/6J-wr/wr mice. Anterior horn cell vacuolar
degeneration and myelinated fiber histometry were similar in both strains. The
clinical response to CNTF/BDNF cotreatment was marked in both groups although it
was weaker in B6NZB-wr/wr mice. Thus, the hybrid B6NZB-wr/wr mice have a more
severe clinical phenotype and offer a unique opportunity to study the mechanisms
of presymptomatic motor neuron degeneration and the effects of therapeutic agents
for human MND.
PMID- 9398467
TI - Magnetic resonance imaging and behavioral analysis of immature rats with kaolin
induced hydrocephalus: pre- and postshunting observations.
AB - The motor and cognitive dysfunction associated with hydrocephalus remains a
clinical problem in children. We hypothesized that young rats with hydrocephalus
should exhibit similar dysfunction and that the dysfunction should be reversible
by shunting. Hydrocephalus was induced in 3-week-old rats by injection of kaolin
into the cisterna magna. Rats were assessed by T2-weighted images obtained with a
7-T magnetic resonance device and by repeated behavioral testing including
ability to traverse a narrow beam and ability to find a hidden platform in a
water pool. Some of the rats underwent a shunting procedure 1 or 4 weeks after
kaolin injection. Magnetic resonance images were used to measure ventricle size.
They clearly demonstrated increased signal in periventricular white matter, which
corresponded to increased brain water content. A flow-void phenomenon was
observed in the cerebral aqueduct. Ability to traverse the beam did not correlate
with the degree of ventriculomegaly. Ability to swim to the hidden platform
demonstrated a progressive impairment of learning function which may have been
accentuated by motor disability. When rats were shunted after 1 week, the
behavioral dysfunction was prevented. Late shunting after 4 weeks was associated
with gradual recovery of the behavioral disability which was not complete after 4
weeks. We conclude that early shunting is superior to late shunting with regard
to behavioral dysfunction. High-resolution MR imaging shows features in
hydrocephalic rats similar to those found in hydrocephalic humans.
PMID- 9398469
TI - Effect of embryonic donor age and dissection on the DARPP-32 content of cell
suspensions used for intrastriatal transplantation.
AB - The aim of this study was to determine in vitro the DARPP-32 content of donor
cells used for striatal transplantation in vivo. The effect of selective
embryonic dissection of the lateral ganglionic eminence (LGE) was compared with
the standard dissection of the whole ganglionic eminence (WGE) at each of three
embryonic ages (14, 15, and 16 days of gestation) in the rat. The resultant cell
suspensions were cultured for up to 7 days and incubated with antibodies against
DARPP-32, a marker of striatal medium spiny neurons; beta-tubulin III, a neuronal
marker; GFAP, a marker of reactive astrocytes; and Gal-C, a marker of
oligodendrocytes. LGE dissection gave rise to more DARPP-32 neurons compared to
WGE; but this relationship was only observed in the younger embryos. When older
(16 days gestation) embryos are used there is no difference in the yield of DARPP
32 cells obtained from LGE and WGE. LGE dissections were also observed to contain
fewer glial cells. There was no beneficial effect of LGE over WGE on survival of
striatal neurons in vitro. These results have important implications for the
selection and dissection of fetal donor material used in clinical trials of
intrastriatal transplantation as a potential treatment for Huntington's disease.
PMID- 9398470
TI - Densitometric quantification of neuronal viability by computerized image
analysis.
AB - A new method is presented for the quantification of cell viability based on
densitometry with computerized image analysis. Neuronal cells were stained with
crystal violet and densitometric analysis was performed with an IBAS 2.0 image
analyzer (Kontron/ Zeiss), using specially implemented dedicated software which
integrates the optical density of the culture in each well with the area covered
by the stained cells. To test the reliability of the densitometric method
cortical cells were plated at different concentrations (5 x 10(4)-10(6)/ml); the
standard curve obtained by analysis of crystal violet staining showed a linear
proportion between cell number and optical density signal. The validation and
accuracy of the method were assessed and compared with other methods using rat
cortical cells cultured in vitro for 10 days and exposed to kainic acid (250
microM) for 24 h. Neuronal viability was reduced by 40-50% and comparison with
direct cell counting, MTT assay, and spectrophotometric analysis confirmed that
the method is simple, quick, and reliable.
PMID- 9398468
TI - The cannabinoid receptor agonist WIN 55,212-2 reduces D2, but not D1, dopamine
receptor-mediated alleviation of akinesia in the reserpine-treated rat model of
Parkinson's disease.
AB - The effects of the synthetic cannabinoid receptor agonist WIN 55,212-2 on
dopamine receptor-mediated alleviation of akinesia were evaluated in the
reserpine-treated rat model of parkinsonism. The dopamine D2 receptor agonist
quinpirole (0.1 mg/kg, ip) caused a significant alleviation of the akinesia. This
effect was significantly reduced by coinjection with the cannabinoid receptor
agonist WIN 55,212-2 (0.1 and 0.3 mg/kg). The simultaneous administration of the
cannabinoid receptor antagonist SR 141716A (3 mg/kg, ip) with quinpirole and WIN
55,212-2 blocked the effect of WIN 55,212-2 on quinpirole-induced alleviation of
akinesia. The selective dopamine D1 receptor agonist chloro-APB (SKF82958, 0.1
mg/kg) alleviated akinesia in a significant manner. WIN 55,212-2 (0.1-1 mg/kg,
ip) did not affect the antiakinetic effect of chloro-APB. Combined injection of
both D1 and D2 dopamine receptor agonists (both at either 0.1 or 0.02 mg/kg)
resulted in a marked synergism of the antiakinetic effect. WIN 55,212-2 (0.1-1
mg/kg) significantly reduced the antiakinetic effect of combined injections of
quinpirole and chloro-APB at both 0.1 and 0.02 mg/kg. The effect of 0.3 mg/kg WIN
55,212-2 on combined D1 and D2 agonist-induced locomotion (0.02 mg/kg) was
blocked by SR 141761A (3 mg/kg). Neither WIN 55,212-2 alone (0.1 and 0.3 mg/kg)
nor SR 141716A (3 and 30 mg/kg) alone had an antiparkinsonian effect. These
results suggest that cannabinoids may modulate neurotransmission in the pathway
linking the striatum indirectly to basal ganglia outputs via the lateral globus
pallidus and the subthalamic nucleus.
PMID- 9398471
TI - Effects of different schedules of MPTP administration on dopaminergic
neurodegeneration in mice.
AB - Although a valuable 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal
model of human Parkinson's disease has been developed, our knowledge of the
course of nigral degeneration remains fragmentary. Experimental factors which
could possibly influence the destructive process must be taken into account. To
evaluate the impact of experimental design, we compared the effects of different
schedules of injection of the same cumulative dose of MPTP, in mice, by measuring
tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta.
Massive injection of the total dose over 1 day (4 injections of 20 mg/kg)
destroyed more dopaminergic neurons than did the long-term daily injections of a
lower dose of MPTP (20 injections of 4 mg/kg). This suggests that different
schedules of administration of MPTP might induce different mechanisms of neuronal
death. These mechanisms need to be better understood if chronic models of
intoxication that replicate the evolution of human Parkinson's disease more
precisely are to be developed.
PMID- 9398472
TI - Chronic hypoxia does not induce synaptic plasticity in the phrenic nucleus.
AB - Interruption of the main descending respiratory drive to phrenic motoneurons by
cold block or spinal cord hemisection results in morphological modifications of
the ipsilateral phrenic nucleus in the rat. The modifications consist of an
increase in the number of multiple synapses and dendrodendritic appositions and
elongation of the asymmetric and symmetric synaptic active zones. Hemisection and
hemispinalization by cold block cause not only "functional deafferentation" of
the ipsilateral phrenic neurons (i.e., a loss of ipsilateral descending
respiratory drive), but also an increase in the remaining contralateral
descending respiratory drive. The contralateral respiratory pathways connect with
phrenic motoneurons ipsilateral to cold block or hemisection by decussating
collateral axons which cross the spinal cord midline below the hemisection/cold
block site. Thus, the phrenic nucleus synaptic plasticity could possibly be
induced by functional deafferentation or by an increase of the descending
respiratory drive. To differentiate between these two possible inducers of the
plasticity, we assessed the synaptic morphology of the phrenic nucleus of
nonoperated rats exposed to 48 h of hypoxia in an atmosphere chamber. The hypoxia
exposure produces an increased descending respiratory drive without functional
deafferentation. The quantitative data extracted from electron micrographs of the
phrenic nucleus from four experimental rats were compared with the data from four
normal breathing animals. Phrenic nucleus morphometric analysis showed that there
was no significant difference in the mean number of single synapses between the
samples from control animals (141 +/- 12.12) and the experimental animals (156 +/
26.73). Similarly, no significant difference was detected in the total number of
synaptic active zones of control animals (178.25 +/- 11.13) and experimental
animals (195.05 +/- 5.35). Furthermore, the length of synaptic active zones of
asymmetrical synapses (0.21 +/- 0.024 micron) or symmetrical synapses (0.22 +/-
0.022 micron) did not change significantly compared to the synaptic active zone
length in control animals (0.21 +/- 0.018 micron for asymmetrical and 0.21 +/-
0.010 micron for symmetrical). We conclude that no synaptic plasticity occurs in
the phrenic nucleus without functional deafferentation in spite of an increase in
descending respiratory drive. Therefore functional deafferentation may be the
primary inducer of phrenic nucleus synaptic plasticity occurring after
hemisection or cold block.
PMID- 9398473
TI - Delayed maturation of regenerating myelinated axons in mice lacking
neurofilaments.
AB - Using the technique of homologous recombination in embryonic stem cells, we
generated mice bearing a targeted disruption of the gene encoding the
neurofilament light (NF-L) protein. The absence of NF-L protein in mice resulted
in dramatic declines of approximately 20-fold in the levels of neurofilament
medium and heavy proteins in the brain and sciatic nerve while increases were
detected for other cytoskeletal proteins such as tubulin and GAP-43. Despite a
lack of neurofilaments and hypotrophy of axons, the NF-L knockout mice develop
normally and do not exhibit overt phenotypes. However, in both NF-L -/- and NF-L
+/- mice, the regeneration of myelinated axons following crush injury of
peripheral nerves was found to be abnormal. In the second week after axotomy, the
number of newly regenerated myelinated axons in the sciatic nerve and facial
nerve of NF-L -/- mice corresponded to only approximately 25 and approximately 5%
of the number of myelinated axons found in normal mice, respectively. At this
early postaxotomy stage, electron microscopy of nerve segments distal to the
crush site in NF-L -/- mice revealed abundant clusters of axonal sprouts that
were indicative of retarded maturation of regenerating fibers. The analysis of
the distal sciatic nerve at 2 months after crush indicated that neurofilament
deficient axons have the capacity to regrow for a long distance and to
remyelinate, albeit at a slower rate. These results provide the first direct
evidence for a role of neurofilaments in the maturation of regenerating
myelinated axons.
PMID- 9398474
TI - Effects of prenatal protein malnutrition on hippocampal long-term potentiation in
freely moving rats.
AB - It has been demonstrated that prenatal protein malnutrition significantly affects
hippocampal plasticity, as measured by long-term potentiation, throughout
development. This paper focuses on the hippocampal dentate granule cell
population response to two separate paradigms of tetanization of the medial
perforant pathway in prenatally protein-malnourished and normally nourished adult
male rats. The 100-pulse paradigm consisted of the application of ten 25-ms
duration bursts of 400 Hz stimulation with an interburst interval of 10 s. The
1000-pulse paradigm consisted of the application of five 500-ms bursts of 400 Hz
stimulation with an interburst interval of 5 s. No between-group differences were
obtained for input/output response measures prior to tetanization. No between
group, nor between-paradigm, differences were obtained in the degree of
population EPSP slope enhancement. However, in response to both paradigms,
prenatally malnourished animals showed significantly less enhancement of the
population spike amplitude (PSA) measure than normally nourished animals.
Normally nourished animals showed a significantly greater level of PSA
enhancement in response to the 100-pulse paradigm than the 1000-pulse paradigm.
Prenatally malnourished animals showed no significant differences in the degree
of PSA enhancement between the two paradigms. Results indicate that short
duration bursts (< or = 25 ms) are more effective in inducing maximal PSA
enhancement in normally nourished rats than longer duration stimulus bursts. The
apparent inability of prenatally malnourished rats to transfer enhanced cellular
activation (population EPSP slope enhancement) into enhanced cellular discharge
(PSA enhancement) suggests that a preferential enhancement of GABAergic
inhibitory modulation of granule cell excitability may result from the prenatal
dietary insult. Such potentiation of inhibitory activity would significantly
lower the probability of granule cell population discharge, resulting in the
significantly lower level of PSA enhancement obtained from these animals.
PMID- 9398475
TI - Tirilazad mesylate increases dopaminergic neuronal survival in the in Oculo
grafting model.
AB - Grafting of fetal ventral mesencephalon in Parkinson's disease has been
extensively studied. A crucial draw back of this technique is the low survival
rate of the dopaminergic neurons. It has been documented that only 5-20% of the
grafted neurons survive, and to enhance graft efficacy to a satisfying level,
increased cell survival is of utmost desire. In this study we have used the
antioxidant tiriliazad mesylate (U-74006F) to study the effect on the survival of
dopaminergic neurons after grafting. The in oculo grafting model was used and
ventral mesencephalon was dissected from E14-E15 rat fetuses in Hanks' balanced
salt solution (HBSS), in Dulbecco's modified Eagle medium (DMEM), or in 0.3, 3.0,
or 30 microM U-74006F diluted in DMEM. The tissue was then inserted into the
anterior chamber of the eye. Some of the transplants were further treated with
intraocular injections of 3 or 30 microM U-74006F (5 microliters) weekly for 2
weeks. Quantification of tyrosine hydroxylase (TH)-immunoreactive profiles
revealed that in transplants treated with U-74006F at dissection only, no change
in the number of TH-positive neurons was found. Pretreatment of 0.3 microM U
74006F during dissection combined with intraocular injections of U-74006F after
grafting, on the other hand, resulted in a dose-dependent enhancement of survival
of TH-positive neurons. Dissection in, and intraocular treatment with, 3 microM U
74006F resulted in a significantly enhanced survival of TH-positive neurons
whereas using U-74006F at a concentration of 30 microM did not change the cell
survival compared to solely DMEM-treated grafts. Thus, 30 microM was interpreted
to be an overdose. Comparing cell survival when dissected in DMEM with that
dissected in HBSS showed that DMEM was clearly superior. Nerve fiber formation
was most pronounced in grafts treated with 3 microM U-74006F. In conclusion,
survival of TH-positive neurons is enhanced by U-74006F, which is readily
available for clinical use and thus could be employed to enhance graft survival
when transplanting patients suffering from Parkinson's disease.
PMID- 9398476
TI - Rat intrastriatal neural allografts challenged with skin allografts at different
time points.
AB - The present study was designed to address two questions. First, can an
intrastriatal neural allograft exhibit long-term survival (18 weeks) if the host
is immunized by an orthotopic skin graft 6 weeks after neural transplantation
(the 6w-Long group)? Second, can an intrastriatal neural allograft survive when
the host is challenged by an orthotopic skin allograft either simultaneously
(Sim) with the intracerebral graft surgery or 2 (2w) weeks later? Dissociated
embryonic ventral mesencephalic tissue from Lewis rats was stereotaxically
injected into the striatum of Sprague-Dawley rats with unilateral 6
hydroxydopamine lesions. Six weeks after neural grafting, no reduction in
amphetamine-induced motor asymmetry was observed in the Sim and 2w groups. At 6
weeks after skin grafting, the mean motor asymmetry scores had returned to the
initial pretransplantation levels in the 6w-Long group. All the neural allografts
in the Sim group were completely rejected, and the mean number of tyrosine
hydroxylase immunoreactivity neurons in the grafts was significantly reduced in
the 2w and the 6w-Long group, when compared to the no-skin control group. There
were very high levels of expression of MHC class I and II antigens, marked
cellular infiltrates containing macrophages and T-lymphocytes, and several
activated microglia and astrocytes in and around the surviving intracerebral
transplants in the 2w and the 6w-Long groups. The results suggest that
intrastriatal neural allografts are more likely to be rejected rapidly if the
host is efficiently immunized with the same alloantigens simultaneously or soon
after the neural transplantation than at a later time point. When established
neural allografts are subjected to a strong immunological challenge, they undergo
protracted rejection.
PMID- 9398477
TI - Regulation of astroglial-derived dopaminergic neurotrophic factors by interleukin
1 beta in the striatum of young and middle-aged mice.
AB - Interleukin-1 beta (IL-1 beta) can induce dopaminergic axonal sprouting in the
denervated striatum of parkinsonian animals. In order to determine whether IL-1
beta effects on dopaminergic axonal sprouting are mediated by the induction of
astroglial-derived dopaminergic neurotrophic factors, effects of IL-1 beta
treatment on acidic and basic fibroblast growth factor (aFGF and bFGF) and glial
cell line-derived growth factor (GDNF) gene expression were examined in primary
striatal astrocyte cultures and after in vivo administration. We found a
selective induction of bFGF mRNA synthesis but not aFGF or GDNF mRNA after IL-1
beta treatment both in vitro and in vivo. This suggests that bFGF may be the
putative endogenous dopaminergic neurotrophic factor mediating lesion-induced
plasticity of dopamine neurons. In addition, to determine why recovery from
injury becomes reduced with age, we examined whether there was an aging
associated decline in the ability of IL-1 beta to induce the synthesis of
neurotrophic factors in middle-aged animals compared to young mice.
Interestingly, IL-1 beta stimulated a greater induction in bFGF mRNA levels in
the middle-aged mice compared to young mice. These results suggest that the
regulation of bFGF and possibly its receptor signaling efficacy may vary as the
brain ages.
PMID- 9398478
TI - The effects of variable periods of functional deprivation on olfactory bulb
development in rats.
AB - Dramatic alterations occur in the developing olfactory bulb when air flow is
reduced through one-half of the nasal cavity. Naris closure on the day after the
day of birth (P1) in rats, for example, results in reduced cell survival in the
ipsilateral bulb by P20 and a substantial (25%) decrease in bulb size by P30.
Almost immediate changes in protein synthesis and cell metabolism are also
observed, and one prevalent theory suggests that these changes may be important
in specifying which cells are subsequently eliminated. In the present study we
used a reversible technique for unilateral naris closure to examine the sensitive
period for the effects of olfactory deprivation on bulb size and cell survival.
This technique involves the insertion of removable plugs into a rat pup's
external naris. We occluded the naris for increasing periods of time (P1-P10, P1
P15, or P1-P20), reared all animals to P30, and measured volumes of bulb laminae.
In addition, we examined the duration of naris closure needed to affect cell
survival by injecting animals with the thymidine analogue bromodeoxyuridine to
label cells born soon after the onset of olfactory deprivation. Results indicate
that relatively long periods of naris occlusion (P1-P15 or longer) are required
to produce a substantial reduction in experimental bulb size. Cell survival was
decreased following olfactory deprivation from P1 to P10, but not after
deprivation from P1 to P3. These data support the hypothesis that changes that
occur within 48 h of naris closure are not sufficient to affect cell survival.
PMID- 9398479
TI - c-Jun expression in adult rat dorsal root ganglion neurons: differential response
after central or peripheral axotomy.
AB - The response of the mature central nervous system (CNS) to injury differs
significantly from the response of the peripheral nervous system (PNS).
Axotomized PNS neurons generally regenerate following injury, while CNS neurons
do not. The mechanisms that are responsible for these differences are not
completely known, but both intrinsic neuronal and extrinsic environmental
influences are likely to contribute to regenerative success or failure. One
intrinsic factor that may contribute to successful axonal regeneration is the
induction of specific genes in the injured neurons. In the present study, we have
evaluated the hypothesis that expression of the immediate early gene c-jun is
involved in a successful regenerative response. We have compared c-Jun expression
in dorsal root ganglion (DRG) neurons following central or peripheral axotomy. We
prepared animals that received either a sciatic nerve (peripheral) lesion or a
dorsal rhizotomy in combination with spinal cord hemisection (central lesion). In
a third group of animals, several dorsal roots were placed into the hemisection
site along with a fetal spinal cord transplant. This intervention has been
demonstrated to promote regrowth of severed axons and provides a model to examine
DRG neurons during regenerative growth after central lesion. Our results
indicated that c-Jun was upregulated substantially in DRG neurons following a
peripheral axotomy, but following a central axotomy, only 18% of the neurons
expressed c-Jun. Following dorsal rhizotomy and transplantation, however, c-Jun
expression was upregulated dramatically; under those experimental conditions, 63%
of the DRG neurons were c-Jun-positive. These data indicate that c-Jun expression
may be related to successful regenerative growth following both PNS and CNS
lesions.
PMID- 9398480
TI - Predegenerated nerve allografts versus fresh nerve allografts in nerve repair.
AB - This study reevaluated the possibility of using predegenerated nerves as donor
nerve allografts for nerve repair and compared the results of functional recovery
to those obtained after standard, fresh nerve allograft repair. Twenty donor rats
underwent a ligature/ section of the left sciatic nerve 4 weeks before nerve
graft harvesting. Forty recipient rats underwent severing of the left sciatic
nerve leaving a 15-mm gap between the nerve stumps. Graft repair was undertaken
using either the predegenerated left sciatic nerve of the 20 donor rats
(predegenerated group, 20 recipient rats) or the normal right sciatic nerve of
the 20 donor rats (fresh group, 20 recipient rats). Recovery of function was
assessed by gait analysis, electrophysiologic testing and histologic studies.
Walking tracks measurements at 2 and 3 months, electromyography parameters at 2
and 3 months, peroperative nerve conduction velocity and nerve action potential
amplitude measurements at 3 months, as well as assessments of myelinated nerve
fiber density and surface of myelination showed that fresh and predegenerated
nerve grafts induced a comparable return of function although there was some
trend in higher electrophysiologic values in the predegenerated group. The only
slight but significant difference was a larger mean nerve fiber diameter in the
nerve segment distal to a predegenerated nerve graft compared to a fresh nerve
graft. Although our study does not show a dramatic long-term advantage for
predegenerated nerve grafts compared to fresh nerve grafts, their use as
prosthetic material is encouraging.
PMID- 9398481
TI - Intracerebral transplantation of testis-derived sertoli cells promotes functional
recovery in female rats with 6-hydroxydopamine-induced hemiparkinsonism.
AB - Recently, we demonstrated amelioration of behavioral deficits associated with 6
hydroxydopamine-induced hemiparkinsonism by transplanting rat testis-derived
Sertoli cells into adult male rat brains. In the present study, we used adult
female hemiparkinsonian rats to investigate whether the beneficial effects of
transplantation of Sertoli cells may be differentially affected by gender of the
animal transplant recipient. At 1 month posttransplantation, animals transplanted
with Sertoli cells showed functional recovery as revealed by significant
reductions in apomorphine-induced rotational behavior and asymmetrical elevated
body swing behavior. Control animals that received medium alone did not display
any visible behavioral recovery. These results suggest that transplantation of
Sertoli cells is not male hormone-dependent and further support the use of these
cells as a graft source for Parkinson's disease and other neurological disorders.
PMID- 9398482
TI - LETTER TO THE EDITOR
PMID- 9398483
TI - Genetic polymorphisms in human drug metabolic enzymes.
AB - Results obtained from both epidemiologic studies and experimental animal model
systems have shown a wide range of phenotypic variation in the ability of
individuals to metabolize drugs and environmental chemicals. Several studies have
noted correlations between specific metabolic phenotypes and the incidence of
disease, suggesting that certain allelic forms of drug metabolic enzymes can
render the individual either more sensitive or resistant to the toxic or
therapeutic effects of exogenous drugs and chemicals. While some of this
variation can be attributed to different environmental exposures, it has become
clear that genetic factors also play an important role in determining the
response of the individual organism to exogenous agents. Recent advances in
molecular biological techniques have begun to allow scientists to correlate
observed phenotypic differences with the actual differences in genetic sequence
at the gene level. This has allowed a correlation between gene structure and
function, thus providing a mechanistic basis to explain the interaction between
genetic background and individual response to environmental exposures. Results
presented at this symposium discussed how genetic polymorphisms for both Phase I
and Phase II metabolic enzymes in the human population modulate the response to
environmental toxicants.
PMID- 9398484
TI - Subchronic nasal toxicity of hexamethylphosphoramide administered to rats orally
for 90 days.
AB - Rats were administered hexamethylphosphoramide (HMPA) at dosages of 10, 100, 300,
and 1000 ppm in drinking water or at 15, 40, or 120 mg/kg/day by gavage for
approximately 90 days. Another group of rats was implanted subcutaneously with
HMPA-filled osmotic minipumps, designed to deliver a dosage of 40 mg/kg/day to
prevent the possibility of direct contact of HMPA with the nasal epithelium.
After 90 days at 10 ppm in the drinking water, some rats had tracheas lined with
regenerated epithelium, but no HMPA-related lesions were present in any other
organs and tissues. At 100 ppm, nasal lesions (epithelial denudation,
regeneration, and squamous metaplasia) were mostly in the maxilloturbinates, tips
of nasoturbinates, and the adjacent septum in the anterior nasal cavity (level
I), but the lesions were confined to the ventral region of the mid-anterior nasal
cavity (level II) and to recesses of the posterior nasal cavity (levels III and
IV). At 300 ppm, nasal turbinates in level I were partially adhered to the nasal
septum by fibrous tissue. In level II the lesions were mainly confined to the
ventral medial meatus, but were scattered diffusely in levels III and IV. Denuded
turbinates showed minimal bone proliferation. At 1000 ppm, the anterior nasal
cavity was partially occluded by extensive adhesion of the turbinates to the
nasal septum by granulation tissue and proliferating turbinate bone. The general
architecture of the posterior nasal cavity was obliterated by the marked
proliferation of turbinate bone and fibrous tissue in the interturbinate spaces.
Tracheas showed regenerated epithelium and bronchi had focal epithelial
denudation at 100, 300, and 1000 ppm. Foamy alveolar macrophages (histiocytosis)
were increased in the lungs at 300 and 1000 ppm. Testicular atrophy occurred at
1000 ppm. No other tissues were affected by HMPA treatment. Nasal lesions in rats
given HMPA by gavage were identical in nature to, but sometimes slightly more
severe than, the lesions in rats given HMPA in the drinking water. Rats given 40
mg/kg/day HMPA via an osmotic minipump had slightly less severe nasal lesions
than did the rats given the same dosage of HMPA by gavage. Testicular atrophy was
present in the rats given 120 mg/kg/day by gavage. The results of this study show
that, with the exception of bone proliferation, systemic delivery of HMPA or its
metabolites to the nasal tissue following oral administration causes tissue
damage similar to that caused by direct exposure of the nasal tissue via
inhalation. Oral administration of HMPA is a less potent route for producing
nasal lesions than is inhalation.
PMID- 9398485
TI - Effect of dosing vehicle on the developmental toxicity of bromodichloromethane
and carbon tetrachloride in rats.
AB - Several halocarbons have been shown to cause full-litter resorption (FLR) in
Fischer-344 rats when administered orally in corn oil. Since halocarbons often
occur as contaminants of drinking water, we sought to determine the influence of
the vehicle, aqueous versus lipid, on the developmental toxicity of two of these
agents. In separate assays, bromodichloromethane (BDCM) and carbon tetrachloride
(CCl4) were administered by gavage to Fischer-344 rats on gestation days (GD) 6
15 at 0, 25, 50, or 75 mg/kg/day in either corn oil or an aqueous vehicle
containing 10% Emulphor EL-620. Dams were allowed to deliver and the litters were
examined postnatally. Uteri of females that did not deliver were stained with 10%
ammonium sulfide to detect FLR. Effects of both agents on maternal weight gain
were slightly more pronounced in the aqueous vehicle at lower doses, but at the
highest dose, CCl4 was more maternally toxic in corn oil. Developmentally, both
agents caused FLR at 50 and 75 mg/kg in both vehicles. At 75 mg/kg, dams
receiving corn oil had significantly higher rates of FLR (83% for BDCM, 67% for
CCl4) compared to their aqueous-vehicle counterparts (21% for BDCM, 8% for CCl4).
Blood concentrations of BDCM following GD-6 gavage revealed a shorter elimination
half-life in the aqueous dosing vehicle (2.7 h) compared to the oil vehicle (3.6
h). Benchmark doses of CCl4 were similar for the oil (18.9 mg/kg) and aqueous
(14.0 mg/kg) vehicles. For BDCM, the corn oil vehicle yielded a less conservative
(i.e., higher) value (39.3 mg/kg) than the aqueous vehicle (11.3 mg/kg),
reflecting different confidence intervals around the estimated 5%-effect dose
levels.
PMID- 9398486
TI - Evaluation of effect profiles: Functional Observational Battery outcomes.
AB - The Functional Observational Battery (FOB) is a neurotoxicity screening assay
composed of 25-30 descriptive, scalar, binary, and continuous endpoints. These
outcomes have been grouped into six biologically logical domains as a means to
interpret the neuroactive properties of tested chemicals (V. C. Moser, 1992, J.
Am. Coll. Toxicol. 10(6), 661-669). However, no data-based exploration of these
functional domains has been done. We investigated the degree to which
experimental data correspond to the domain groupings by examining severity scores
from 10 chemicals tested using a standardized protocol for acute exposure (V. C.
Moser et al., 1995, J. Toxicol. Environ. Health 45, 173-210) and identifying
endpoint groupings (factors) that best describe the interrelationships in the
data, allowing a statistical assessment of whether the FOB endpoints break into
domains. We also used a standard measure of bivariate association to confirm the
results of the factor analysis. Our results show that while there are clear
relationships among variables that compose some domains, there is often
substantial correlation among endpoints in different domains. In addition, we
investigated a related issue concerning the relative power of the chosen endpoint
groupings for identifying significant domain effects. Results from a
randomization analysis of the 10 chemicals suggest that the neurophysiologic
domain structuring may provide some degree of statistical efficiency for
identifying effects.
PMID- 9398487
TI - Cardiovascular effects after inhalation of large doses of albuterol dry powder in
rats, monkeys, and dogs: a species comparison.
AB - Albuterol is a quickly acting beta-2 adrenergic agonist bronchodilator widely
used by asthmatics. Because recent case-control studies have suggested a
relationship between the increase in mortality of asthmatics over the past decade
and the use of beta 2-adrenergic agonists in the control of asthma, concern has
developed regarding the potential cardiotoxicity of beta 2-specific adrenergic
agonists, including albuterol. The aim of this investigation was to assess the
potential for cardiotoxicity of inhaled albuterol dry powder in rats, monkeys,
and dogs. All species were exposed to an aerosol of albuterol 1 h per day, 7 days
per week, for at least 2 weeks. Control groups were exposed to filtered
conditioned air and handled in the same manner as the albuterol-exposed animals.
Plasma concentrations of albuterol confirmed systemic exposure. The daily inhaled
dose received by the animals was calculated based on measured respiratory minute
volumes, published respiratory tract deposition data, as well as HPLC-determined
particle size distribution data and aerosolized albuterol concentrations.
Multiples of the maximum daily clinical dose (presentation of 15 micrograms/kg in
a 70-kg human) were approximately 0.25- to 2500-fold in the rat, 9- to 100-fold
in the monkey, and 0.5- to 90-fold in the dog. No findings attributed to
albuterol were observed in the monkey. Tachycardia and transient hypokalemia
occurred in rats at multiples of 1.5 times or greater of the maximum clinical
dose. Absolute and relative heart weights increased in rats receiving multiples
of 47 times or greater of the maximum human dose. In the absence of
histopathologic findings, the increases in rat heart weights were considered a
physiologic hypertrophic response to tachycardia. In dogs tachycardia and
transient hypokalemia occurred at all doses tested. Slight to mild fibrosis in
the papillary muscles of the left ventricle of the heart occurred in dogs at
multiples > or = 19 times the clinical dose. The cardiovascular effects observed
were consistent with the known pharmacologic action of beta 2-adrenergic
agonists. Due to the lack of toxicologically relevant findings in rats and
monkeys and the wide safety margin in dogs, the findings in this study do not
suggest a cardiotoxicity risk in the human population after repeated exposures to
clinical doses of albuterol currently used in the treatment of asthma.
PMID- 9398488
TI - Repeated independent exposures to domoic acid do not enhance symptomatic toxicity
in outbred or seizure-sensitive inbred mice.
AB - Domoic acid (DA) is an environmental neurotoxin to humans. This work examines
whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of
domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred
strains of laboratory mice. A multiple independent exposure paradigm was designed
in which doses were administered intraperitoneally every other day for 7 days to
achieve four separate exposures to domoic acid. We first examined the effect of
repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did
not differ following a single or repeated exposure. We next examined the effect
of repeated exposure on symptomatic toxicity. The mean toxicity scores did not
show a significant difference between single and repeated exposures of either
subsymptomatic (0.5 mg/kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic
acid. We then examined the effects of repeated domoic acid exposure on a second
strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid
induced seizures; however, the ICR mice were more sensitive to low-dose domoic
acid toxicity, particularly in terms of onset and duration of stereotypic
scratching behavior. Our results indicate that both strains of mice have
comparable concentration-dependent toxic responses to domoic acid; however,
differences exist in the magnitude of the response and in specific symptoms. The
mean toxicity scores did not show a significant difference when a single exposure
(1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were
compared in the DBA mice. This study provides no evidence that short-term
repeated exposure to domoic acid in laboratory mice alters domoic acid clearance
from the serum, or leads to a more sensitive or a greater neurotoxic response.
PMID- 9398489
TI - Effects of acute and repeated exposures to Aroclor 1254 in adult rats: motor
activity and flavor aversion conditioning.
AB - While considerable research has focused on the neurotoxicity of developmental
exposures to polychlorinated biphenyls, including Aroclor 1254, relatively little
is known about exposures in adult animals. This study investigated the behavioral
effects of acute and repeated Aroclor 1254 exposures to adult rats on motor
activity and flavor aversion conditioning. Male Long-Evans rats (60 days old)
were tested for motor activity in a photocell device after acute (0, 100, 300, or
1000 mg/kg, p.o.) or repeated (0, 1, 3, 10, 30 or 100 mg/kg/day, po, 5 days/week
for 4 to 6 weeks exposure to Aroclor 1254. Motor activity was decreased dose
dependently at doses of 300 mg/kg or more after acute exposure. Severe body
weight loss and deaths occurred at 1000 mg/kg. Recovery of activity occurred over
9 weeks but was incomplete. After repeated exposure, motor activity was decreased
dose-dependently at doses of 30 mg/kg or more, and severe weight loss and deaths
occurred at 100 mg/kg. In contrast to acute exposure, complete recovery of
activity occurred 3 weeks after exposure. Additional rats were water deprived (30
min/day) and received acute po administration of Aroclor 1254 (0, 10, 15, 25, 30,
100, or 300 mg/kg) shortly after consuming a saccharin solution. Three days later
they were given the choice between consuming saccharin or water, and saccharin
preferences were recorded. Saccharin preference was decreased at doses of 25
mg/kg or more. Additional experiments determined the effect of repeated saccharin
Aroclor 1254 pairings (0, 3.75, 7.5, or 15 mg/kg/day, 14 days) followed by a
choice test 1 day after the last dose. Repeated exposure to 15 mg/kg produced
robust flavor aversion conditioning. Repeated exposure to 7.5 mg/kg produced
flavor aversion conditioning in four of 12 rats. These results demonstrate that
Aroclor 1254 causes hypoactivity and flavor aversions in adult rats; the no
observable effect level (NOEL) for motor activity was 100 mg/kg for acute
exposure and 10 mg/kg for repeated exposure for a period of up to 6 weeks. The
acute NOEL for flavor aversion conditioning was 15 mg/kg while the repeated NOEL
was 7.5 mg/kg.
PMID- 9398490
TI - Trimethylphosphate: a 30-month chronic toxicity/carcinogenicity study in Wistar
rats with administration in drinking water.
AB - Trimethylphosphate (TMPO) was administered to 50 male and 50 female Wistar rats
through their drinking water at doses of 0, 1, 10, or 100 mg/kg body weight up to
30 months. The dosage of 100 mg/kg was reduced to 50 mg/kg in week 54 for reasons
of tolerance, and the animals were euthanized in week 100. Additional 10 animals
per dose and sex were treated for 12 months and then euthanized for interim
analysis. Weakness of the hind limbs, increased incidences of sunken flanks,
distended abdomen, and poor general condition were observed in both sexes of the
100/50 mg/kg group beginning with week 46. Food intake was reduced in high dose
males. At 10 mg/kg body weights were up to 10% (males) and at 100/50 mg/kg up to
20% (males) or 15% (females) lower than in controls. Mortality was not affected
in animals receiving up to 10 mg/kg. At 100/50 mg/kg it was markedly increased,
reaching about 70% at week 100. Relatively slight hematologic changes (reduced
hemoglobin, hematocrit, erythrocyte counts, increased reticulocyte numbers, and
thrombocyte counts as well as a shift in the differential blood count) at 100/50
mg/kg are interpreted as changes most probably secondary to the other toxic
effects. Increased cholesterol concentrations in plasma, shifts in the serum
protein electrophoresis (males), increased organ weights (females), and an
increased incidence of necroses and lymphocytic infiltrations point to a
treatment-related effect on the liver at 100/50 mg/kg. Slightly increased protein
excretion, increased relative kidney weights, and an increased incidence of
chronic progressive nephropathy are considered treatment-related but rather
secondary effects at 100/50 mg/kg. At 100/50 mg/kg an increased incidence and
severity of bilateral tubular atrophy in the testes was diagnosed. The most
important toxic effect was neurotoxicity, consisting of degeneration and loss of
nerve fibers in the peripheral nerves and the spinal cord, associated with
myopathic changes, and occurring at 100/50 mg/kg. The no-observed-adverse-effect
level, based on the suppression of body weight gain, is 1 mg/kg in males and 10
mg/kg in females. The incidence, time of occurrence, spectrum of types, and
localizations of tumors provided no indication of a tumorigenic/carcinogenic
effect of the test substance. TMPO is therefore considered not to be carcinogenic
in Wistar rats.
PMID- 9398491
TI - Two-generation reproductive toxicity study of dietary tributyl phosphate in CD
rats.
AB - Tributyl phosphate (TBP) was tested for reproductive toxicity in rats. Thirty
weanlings/sex (F0) were exposed to TBP in the diet ad libitum at 0, 200, 700, or
3000 ppm for 10 weeks and then randomly mated within groups for 3 weeks with
continued exposure. F0 parents and 10 F1 weanlings/sex/dose were necropsied, and
adult reproductive organs, urinary bladders (both sexes), kidneys (males), and
livers (females) were evaluated histologically. Thirty F1 weanlings/sex/dose
continued exposure for 11 weeks and were bred as described above. F1 parents and
F2 weanlings, 10/sex/dose, were then necropsied as described above. Adult
toxicity was observed in both sexes and generations at 700 and 3000 ppm;
observations included reduced body weights, weight gain and feed consumption,
urinary bladder epithelial hyperplasia (both sexes), renal pelvis epithelial
hyperplasia only at 3000 ppm (male kidneys), and centrilobular hypertrophy
(female livers). At 200 ppm, transient reductions in body weight were observed in
F0 and F1 females, with urinary bladder epithelial hyperplasia in F0 males and
females and in F1 males. There was no evidence of reproductive toxicity, of
reproductive organ pathology, or of effects on gestation or lactation at any dose
tested. Postnatal toxicity was evidenced by consistent reductions in F1 and F2
pup body weights at 3000 ppm and by occasional weight reductions in F2 litters at
700 ppm, and was associated with maternal toxicity observed at these doses and
times. Under the conditions of this study, a NOAEL was not determined for adult
toxicity; the NOAEL for reproductive toxicity was at least 3000 ppm and the NOAEL
for postnatal toxicity was approximately 200 ppm.
PMID- 9398492
TI - Trihalomethane comparative toxicity: acute renal and hepatic toxicity of
chloroform and bromodichloromethane following aqueous gavage.
AB - Bromodichloromethane (BDCM) and chloroform (CHCl3) are by-products of drinking
water chlorination and are the two most prevalent trihalomethanes (THMs) in
finished drinking water. To date, no comprehensive comparison of the acute renal
and hepatic effects of BDCM and CHCl3 following oral gavage in an aqueous dosing
vehicle has been conducted. To characterize BDCM- and CHCl3-induced nephro- and
hepatotoxicity following aqueous gavage and compare directly the responses
between these THMs, 95-day-old male F-344 rats were given single oral doses of
0.0, 0.75, 1.0, 1.5, 2.0, or 3.0 mmol BDCM or CHCl3/kg body wt in an aqueous 10%
Emulphor solution. Compound-related hepatic and renal damage was evaluated by
quantitating clinical toxicity markers in the serum and urine, respectively. Both
THMs appear to be equally hepatotoxic after 24 h, but BDCM caused significantly
greater elevations in serum hepatotoxicity markers than CHCl3 at 48 h following
exposure to 2.0 and 3.0 mmol/kg. In addition to causing more persistent liver
toxicity than CHCl3, BDCM also appears to be slightly more toxic to the kidney at
lower doses. Potency differences between the two THMs may be due to
pharmacokinetic dissimilarities such as greater metabolism of BDCM to reactive
metabolites or more extensive partitioning of BDCM into kidneys and fat depots,
resulting in prolonged target tissue exposure.
PMID- 9398493
TI - Single-dose and chronic dietary neurotoxicity screening studies on 2,4
dichlorophenoxyacetic acid in rats.
AB - Forms of 2,4-dichlorophenoxyacetic acid (collectively known as 2,4-D) are
herbicides used to control a wide variety of broadleaf and woody plants. Single
dose acute and 1-year chronic neurotoxicity screening studies in male and female
Fischer 344 rats (10/sex/dose) were conducted on 2,4-D according to the U.S. EPA
1991 guidelines. The studies emphasized a Functional Observational Battery (which
included grip performance and hindlimb splay tests), automated motor activity
testing, and comprehensive neurohistopathology of perfused tissues. Dosages were
up to 250 mg/kg by gavage for the single-dose study, and up to 150 mg/kg/day in
the diet for 52 weeks in the repeated-dose study. In the acute study, gavage with
250 mg/kg test material caused slight transient gait and coordination changes and
clearly decreased motor activity at the time of maximal effect on the day of
treatment (day 1). Mild locomotor effects occurred in one mid-dose rat (75
mg/kg), on Day 1 only. No gait, coordination, or motor activity effects were
noted by day 8. In the chronic study, the only finding of neurotoxicologic
significance was retinal degeneration in females in the high-dose group (150
mg/kg/day). Body weights of both sexes were slightly less than controls in the
mid-dose group, and 10% less than controls in the high-dose group. In summary,
the findings of these studies indicated a mild, transient locomotor effect from
high-level acute exposure, and retinal degeneration in female rats from high
level chronic exposure. Based on the results from these two studies, the no
observed-adverse-effect level for acute neurotoxicity was 15 mg/kg/day and for
chronic neurotoxicity was 75 mg/kg/day.
PMID- 9398494
TI - Lack of embryotoxicity of fumonisin B1 in New Zealand white rabbits.
AB - Fumonisin B1 (FB1) is one of a number of mycotoxins produced by fungi, especially
Fusarium sp. As a contaminant of many maize-derived products, this toxin is
associated with a variety of animal diseases, including esophageal cancer and
possibly neural tube defects in humans. We have investigated the embryotoxic
potential of this compound in New Zealand White rabbits. Animals were dosed by
gavage daily on GD 3-19 with purified FB1 at 0.10, 0.50, or 1.00 mg/kg/day.
Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined
on GD 29, there were no differences in maternal body weight, maternal weight
gain, maternal organ weights, number of nonlive implantations, and number of
malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%,
respectively); this was true for male and female pups. Fetal liver and kidney
weights were also decreased at these doses. Analysis of embryonic sphinganine to
sphingosine ratios demonstrated no differences between control and treated
embryos on GD 20, although these ratios were increased in maternal urine, serum,
and kidney when compared to control animals. These data suggest that FB1 did not
cross the placenta and that the observed decreased fetal weight was probably the
result of maternal toxicity, rather than any developmental toxicity produced by
FB1.
PMID- 9398495
TI - Expression of the immediate-early genes, c-fos, c-jun, and c-myc: a comparison in
rats of nongenotoxic hepatocarcinogens with noncarcinogenic liver mitogens.
AB - The involvement of the immediate-early (IE) genes c-fos, c-jun, and c-myc in
regenerative liver hyperplasia is accepted, but their involvement in direct
hyperplasia is uncertain. We have examined the hypothesis that the ability to
induce IE genes may reflect the hepatocarcinogenic potential of a chemical. The
ability of 1,4-dichlorobenzene (DCB) (300 mg/kg) (a noncarcinogenic rat liver
mitogen), diethylhexyl phthalate (DEHP) (950 mg/kg), and chlorendic acid (120
mg/kg) (both nongenotoxic hepatocarcinogens) to induce c-fos, c-jun, and c-myc
expression in rat liver was determined by Northern blot analysis and by in situ
hybridization. Results were correlated to hepatic labeling index (LI) as
determined by incorporation of BrdU in each of three lobes for each of three male
F344 rats per group. Carbon tetrachloride (CCl4) (2 ml/kg) was used as a positive
control. Increased LI was preceded by elevated expression of all three IE genes
after CCl4, but also after DCB and DEHP, although induction by these was less
marked. In all cases, there was considerable interanimal variation within groups,
but little interlobe variation. Interestingly, there was a good correlation (r2 >
or = 0.85) between c-myc expression and LI, but not between LI and c-fos or c
jun. Despite the disparate carcinogenic potential of DEHP and DCB, both chemicals
induced similar patterns of IE gene expression, suggesting that this cannot
distinguish hepatocarcinogenic liver mitogens from noncarcinogenic liver
mitogens. These data assist in the evaluation of IE gene expression both as a
marker of direct versus regenerative hyperplasia and as an indicator of the
hepatocarcinogenic potential of liver mitogens.
PMID- 9398497
TI - Evaluation of the pre-, peri-, and postnatal toxicity of monoethanolamine in rats
following repeated oral administration during organogenesis.
AB - Pregnant Wistar rats (40/group) were administered monoethanolamine (MEA) as an
aqueous solution by gavage at dose levels of 0, 40, 120, and 450 mg/kg/day on
days 6 through 15 of gestation. On day 20 of gestation, 25 dams/group were
euthanized and the fetuses were delivered by cesarean section, weighted, sexed,
and examined for external, visceral, and skeletal alterations. The remaining dams
(15/group) were allowed to litter and rear their pups to day 21 postpartum. The
dams and pups were then euthanized and examined for gross pathologic changes.
Gavage administration of 450 mg MEA/kg/day to pregnant rats resulted in maternal
toxicity as evidenced by statistically significant (alpha = 0.05) decreases in
feed consumption on gestation days 6-8 and 17-20 and on postpartum days 0-4.
Additionally, statistically significant decreases in mean maternal body weights
were observed on gestation days 15, 17, and 20 and on lactation days 0, 4, 7, and
21. Body weight gains of the 450 mg/kg/day dams were also significantly decreased
(13% relative to controls) on gestation days 15-20. There was no evidence of
maternal toxicity at 40 or 120 mg/kg/day of MEA. Despite the maternal effects
observed at 450 mg/kg/day, no significant fetal effects were observed at this or
any dose level tested, nor were there any indications of a treatment-related
effect on postnatal growth or on the viability of offspring. Thus, it was
concluded that MEA was not developmentally toxic to Wistar rats following
repeated oral administration, even at maternally toxic dose levels as high as 450
mg/kg/day.
PMID- 9398496
TI - The effects of perinatal/juvenile methoxychlor exposure on adult rat nervous,
immune, and reproductive system function.
AB - In order to address data gaps identified by the NAS report Pesticides in the
Diets of Infants and Children, a study was performed using methoxychlor (MXC).
Female rats were gavaged with MXC at 0, 5, 50, or 150 mg/kg/day for the week
before and the week after birth, whereupon the pups were directly dosed with MXC
from postnatal day (pnd) 7. Some dams were killed pnd7 and milk and plasma were
assayed for MXC and metabolites. For one cohort of juveniles, treatment stopped
at pnd21; a modified functional observational battery was used to assess
neurobehavioral changes. Other cohorts of juveniles were dosed until pnd42 and
evaluated for changes to the immune system and for reproductive toxicity. Dose
dependent amounts of MXC and metabolites were present in milk and plasma of dams
and pups. The high dose of MXC reduced litter size by approximately 17%. Ano
genital distance was unchanged, although vaginal opening was accelerated in all
treated groups, and male prepuce separation was delayed at the middle and high
doses by 8 and 34 days, respectively. In the neurobehavioral evaluation, high
dose males were more excitable, but other changes were inconsistent and
insubstantial. A decrease in the antibody plaque-forming cell response was seen
in males only. Adult estrous cyclicity was disrupted at 50 and 150 MXC, doses
which also showed reduced rates of pregnancy and delivery. Uterine weights
(corrected for pregnancy) were reduced in all treated pregnant females. High-dose
males impregnated fewer untreated females; epididymal sperm count and testis
weight were reduced at the high, or top two, doses, respectively. All groups of
treated females showed uterine dysplasias and less mammary alveolar development;
estrous levels of follicle stimulating hormone were lower in all treated groups,
and estrus progesterone levels were lower at 50 and 150 MXC, attributed to fewer
corpora lutea secondary to ovulation defects. These data collectively show that
the primary adult effects of early exposure to MXC are reproductive, show that 5
mg/kg/day is not a NO(A)EL in rats with this exposure paradigm (based on changes
in day of vaginal opening, pubertal ovary weights, adult uterine and seminal
vesicle weights, and female hormone data) and imply that the sites of action are
both central and peripheral.
PMID- 9398498
TI - Co-response Coefficients, Monovalent Units, and Combinatorial Rules: Unification
of Concepts in Metabolic Control Analysis
AB - The Jacobian H of a linear metabolic pathway without feedback loops is
tridiagonal. Its inverse, H-1, which is needed for calculating control
coefficients or elasticities, can be decomposed into two regions of mutually
dependent rows and columns. For each of these regions of H-1, all sub
determinants of order two are zero. The existence of the two regions is shown to
cause certain invariance properties of the ratios of control coefficients that
can be expressed as co-response coefficients. Also the concept of monovalent
functional units seems to be related to the existence of the regions. Moreover,
the combinatorial rules for selecting the right modulations originate from the
fact that certain sub-determinants of H-1 are zero when located within the
regions. The regions of zero sub-determinants of order two of H-1 are thus a
central element for the analysis of the linear pathway. The unifying potential of
H-1 is not restricted to the linear chain but is also expected to be valid for
complex metabolic systems.Copyright 1997 Academic Press Limited Copyright 1997
Academic Press Limited
PMID- 9398499
TI - Self-organized huddles of rat pups modeled by simple rules of individual
behavior.
AB - Starting at infancy and continuing throughout adult life, huddling is a major
component of the behavioral repertoire of Norway rats (Rattus norvegicus).
Huddling behavior maintains the cohesion of litters throughout early life, and in
adulthood, it remains a consistent feature of social behavior of R. norvegicus.
During infancy, rats have severely limited sensorimotor capabilities, and yet
they are capable of aggregating and display a form of group regulatory behavior
that conserves metabolic effort and augments body temperature regulation. The
functions of huddling are generally understood as group adaptations, which are
beyond the capabilities of the individual infant rat. We show, however, that
huddling as aggregative or cohesive behavior can emerge as a self-organizing
process from autonomous individuals following simple sensorimotor rules. In our
model, two sets of sensorimotor parameters characterize the topotaxic responses
and the dynamics of contact in 7-day-old rats. The first set of parameters are
conditional probabilities of activity and inactivity given prior activity or
inactivity and the second set are preferences for objects in the infant rat's
environment. We found that the behavior of the model and of actual rat pups
compare very favorably, demonstrating that the aggregative feature of huddling
can emerge from the local sensorimotor interactions of individuals, and that
complex group regulatory behaviors in infant rats may also emerge from self
organizing processes. We discuss the model and the underlying approach as a
paradigm for investigating the dynamics of social interactions, group behavior,
and developmental change.
PMID- 9398500
TI - A discussion about the DiFrancesco-Noble model.
AB - An obvious defect in the DiFrancesco-Noble (DN) model was found, so methods to
overcome this inadequacy are put forward. Based on these methods, different kinds
of modified DN model can be obtained, and numerical results show that most of the
dynamics of the DN model can be essentially preserved by these modified systems.
PMID- 9398501
TI - A conservation principle and its effect on the formulation of Na-Ca exchanger
current in cardiac cells.
AB - In this paper we show the presence of a latent conservation principle in the
formulation of ionic currents in cardiac cells and examine its effect on a
formulation of the sodium-calcium exchange current appearing in the Noble model
of the sinoatrial node cell in the mammalian heart [see Noble et al. (1989) or
Winslow et al. (1991)]. Our objective is to show that this formulation, if not
corrected, will result in a serious instability in this cardiac cell model. In
particular, under certain initial conditions, the solutions of the model
equations will blow-up in finite time. We also propose a correction to the model
equation for the sodium-calcium exchange current, and we show that the modified
model agrees favorably with the original model. These phenomena also occur in the
other cardiac cell models, such as those modeling the Purkinje fiber, the atrial
cell and the ventricular cell. The changes proposed in this paper can be applied
directly to these models as well.
PMID- 9398502
TI - A Model for Cell Movement During Dictyostelium Mound Formation
AB - Dictyostelium development is based on cell-cell communication by propagating cAMP
signals and cell movement in response to these signals. In this paper we present
a model describing wave propagation and cell movement during the early stages of
Dictyostelium development, i.e. aggregation and mound formation. We model cells
as distinct units whose cAMP relay system is described by the Martiel-Goldbeter
model. To describe cell movement we single out three components: chemotactic
motion, random motion and motion due to pressure between cells. This pressure
result in cells crawling on top of each other and therefore to the extension of
the aggregate into the third dimension. Using this model we are able to describe
aggregation up to the mound stage. The cells in the mound move in a rotational
fashion and their movement is directed by the counter-rotating spiral of the
chemo-attractant cAMP. Furthermore, we show that the presence of two
subpopulations with different inherent chemotactic velocities can lead to cell
sorting in the mound. The fast moving cells collect into the centre while the
slow cells occupy the rest of the mound. This model allows the direct comparison
of the properties of the cAMP waves properties and movement behavior of
individual cells with experimental data. Thereby it allows a critical test of our
understanding of the basic cellular principles involved in the morphogenesis of a
simple eukaryote.Copyright 1997 Academic Press Limited Copyright 1997 Academic
Press Limited
PMID- 9398503
TI - Sex, the Prisoner's Dilemma Game, and the evolutionary inevitability of
cooperation.
AB - It will be a universal feature of sexual populations that individuals prefer
mates with typical rather than rare characteristics--essentially because most
mutations reduce fitness. This is termed koinophilia. Koinophilia will also apply
to behaviour. In particular, individuals will prefer mates that behave in social
interactions that follow whatever rules are common in that population. Suppose
that individuals interact in situations which can be represented by the Iterated
Prisoner's Dilemma Game (IPD). If koinophilia is ignored, previous authors have
shown that it is hard to find an evolutionarily stable strategy, and that
strategies cycle indefinitely. However, if koinophilia is included, it has the
effect of increasing the fitness of whatever happens to be the common strategy.
This, in turn, has the effect of stabilizing almost any strategy (that has, for
whatever reason, become the local norm) in the IPD. Different, partially isolated
groups will thus become evolutionarily trapped in different behaviours, which are
defended against alternative strategies originating through mutation or
immigration. Groups that happen, by chance, to reach a cooperative strategy will
be fitter, as groups, than those that reach defection (even though, in one-to-one
encounters, it is the selfish individual who always wins). The ultimate result
will be the replacement of selfish groups by cooperative groups.
PMID- 9398504
TI - Pattern formation and spatiotemporal irregularity in a model for macrophage
tumour interactions.
AB - Solid tumours do not develop as a homogeneous mass of mutant cells, rather, they
grow in tandem with normal tissue cells initially present, and may also recruit
other cell types including lymphatic and endothelial cells. Many solid tumours
contain a high proportion of macrophages, a type of white blood cell which can
have a variety of effects upon the tumour, leading to a delicate balance between
growth promotion and inhibition. In this paper we present a brief review of the
main properties and interactions of such tumour-associated macrophages, leading
to a description of a mathematical model for the spatial interactions of
macrophages, tumour cells and normal tissue cells, focusing on the ability of
macrophages to kill mutant cells. Analysis of the homogeneous steady states shows
that, for this model, normal tissue is unstable to the introduction of mutant
cells despite such an immune response, but that the composition of the resulting
tumour can be significantly altered. Including random cell movement and chemical
diffusion, we demonstrate the existence of travelling wave solutions connecting
the normal tissue and tumour steady states, corresponding to a growing tumour,
and of the development of a spatial instability behind the wave front. Numerical
solutions are illustrated in one and two dimensions. We go on to estimate
macrophage motility parameters using data from Boyden chamber experiments. We
then extend our model to include macrophage chemotaxis, that is, their directed
movement in response to gradients of chemicals secreted by tumours. Solutions in
one dimension indicate the possibility of spatiotemporal irregularities within
the growing tumour, which are deduced to be the result of a series of
bifurcations as the effective domain length increases, leading to a permanently
transient solution. These results suggest that tumour heterogeneity may arise, in
part, as a natural consequence of the macrophage infiltration. Recent experiments
suggest that macrophages may indeed be involved in spatiotemporal variations
within some human tumours.
PMID- 9398505
TI - Radiation damage accumulation over large time intervals: a descriptive model.
AB - A simple model of DNA damage (mutation load) accumulation is considered. For time
intervals exceeding average life duration, the kinetics of mutation load is
determined. The major process determining these kinetics is shown to be natural
selection (or any equivalent process of removal of the most affected lines). The
characteristic time of this process (which is around three generations) is the
approximate time of integration of the dose rate for determination of radiation
damage. The conclusion is made that the maximum permissible dose should be
established for this characteristic time, as it determines the remote effects of
prolonged exposure to radiation. After this, the accumulated genetic damage
presents "dose rate-effect" rather than "dose-effect" dependence. Dependence of
mutation load on dose rate and parameters of selection processes is examined for
different types of mutations. The cases of stable and exponentially decreasing
dose rate are considered. The applicability of the model to human population is
discussed.
PMID- 9398506
TI - Single-beat estimation of the ventricular pumping mechanics in terms of the
systolic elastance and resistance.
AB - An elastance-resistance model has long been used to assess the systolic
mechanical behavior of the ventricular pump under an in situ, open-chest
experiment. However, there is difficulty in the clinical application of such a
model because of the required isovolumetric signal that is obtained by occluding
the ascending aorta in diastole. In this study, we determine the characteristics
of an elastance-resistance model in the absence of isovolumeric measurement to
quantify the physical properties of the left ventricle. A high-fidelity
multisensor catheter was used to record the left ventricular pressure and
ascending aortic flow in nine anesthetized, closed-chest dogs. The isovolumetric
pressure was estimated from the instantaneous pressure of an ejecting contraction
by a curve-fitting technique. Thus, the parameters in the characterization of
systolic pumping mechanics could be inferred by the use of fitting this elastance
resistance model. The results showed that the maximal systolic elastance was 7.3
+/- 2.8 mmHg and theoretical maximum flow was 494 +/- 194 ml s-1. These data were
compatible with other reports in the literature. Moreover, in every dog studied
the maximal systolic elastance was smaller than the end-systolic elastance which
was determined by using the end-systolic pressure-volume relation. We suggested
that an elastance-resistance model with the estimated isovolumetric pressure has
the potential to measure the intrinsic systolic mechanics of the left ventricle
in a closed-chest cardiovascular system.
PMID- 9398507
TI - The adaptational system as a dynamical feedback system.
AB - The characteristics of biological systems of adaptation are developed from the
principle that the manifestations of life are modified by and must conform with
their environment in order to enable organismic persistence. The two roles of the
environment, termed "modifying" and "adaptive", give rise to the distinction of
three elementary and sequentially coupled subsystems characterizing the
adaptational system: the modifying system, comparator system, and state
regulation system. The third system determines which state alterations are
required for adaptation of manifestations (responses) to the demands of the
adaptive environment. Adaptational valuation is introduced as a measure of
adaptedness of response to adaptive environment. The dynamical aspect of
adaptation is shown to be completely described by the timing of feedback.
Discrete and continuous forms of adaptation can thus be treated on the same
conceptional basis. All steps of the generic system formulation are illustrated
with the help of a simple model with additive effects and linear state
regulation. The system representation is used to demonstrate how basic intuitive
conceptions, such as adaptational lag or adaptational capacity, can be made
amenable to precise analysis. Another demonstration concerns recognition of
adaptational clues resulting from the distinction between the two environmental
classes, modifying and adaptive. Among these clues are challenges of low
correlation between the two classes to adaptational systems and the specification
of questions of the evolution of phenotypic plasticity.
PMID- 9398508
TI - Modelling Bacterial Degradation of Organic Compounds with Genetic Networks
AB - The bacterial degradation of organic compounds plays a crucial role in the
biogeochemical cycles of the earth and in the clean-up of contaminated soils. The
processes are carried out by bacterial consortia, rather than isolated strains,
which are usually modelled by phenomenological kinetic equations which describe a
fictitious, homogeneous bacterial species which mimics the behaviour of the
consortium. An alternative modelling framework is presented here, where the
bacterial consortia are considered as networks of genes interacting with other
genes as well as with chemicals, which may be either introduced from outside or
produced by bacterial metabolism. The model is based on an extension of the
random Boolean network model of genetic networks, which makes use of continuous
dynamical variables. Three different models are introduced, which differ in the
way how they account for the existence of different species: (i) a single
supercell model, where all the genes can interact strongly with each other; (ii)
a graded interaction model, where genes interact strongly within a species, and
weakly among different species; and (iii) a separate subsets model, where genes
interact only within species. It is shown how this modelling framework is sound,
as it is able to reproduce some of the generic behaviours of bacterial consortia,
describing experimentally observed phenomena like population changes induced by
contamination, and prey-predator dynamics.Copyright 1997 Academic Press Limited
Copyright 1997 Academic Press Limited
PMID- 9398509
TI - Activation of P2 late transcription by P2 Ogr protein requires a discrete contact
site on the C terminus of the alpha subunit of Escherichia coli RNA polymerase.
AB - Bacteriophage P2 late transcription requires the product of the P2 ogr gene. Ogr
dependent transcription from P2 late promoters is blocked by certain point
mutations affecting the alpha subunits of the host RNA polymerase. An alanine
scan spanning the putative activation target in the alpha C-terminal domain
(alphaCTD) was carried out to identify individual residues essential for Ogr
dependent transcription from P2 late promoters. In addition, the effects of
alanine substitutions in the regions of the alphaCTD previously reported to
affect CAP-dependent activation of the lac promoter and UP-element DNA binding
were examined. Residues E286, V287, L289 and L290 in helix 3, and residue L300 at
the beginning of helix 4, define a surface-exposed patch on the alphaCTD
important for Ogr-dependent activation. These residues, adjacent to the recently
identified DNA-binding determinants, constitute a newly identified activation
surface for protein:protein contact. Alanine substitutions at some of the
residues that affect UP-element DNA binding also impaired activation. This
suggests that upstream DNA-alpha contacts, in addition to alpha-Ogr contacts, may
be important in P2 late transcription. Other residues implicated in the
interaction of alpha with CAP are not required for activation by Ogr, consistent
with previous genetic evidence suggesting that these activators contact different
sites on the alphaCTD.
PMID- 9398510
TI - Pactamycin resistance mutations in functional sites of 16 S rRNA.
AB - Mutants of an archaeon Halobacterium halobium, resistant to the universal
inhibitor of translation, pactamycin, were isolated. Pactamycin resistance
correlated with the presence of mutations in the 16 S rRNA gene of H. halobium
single rRNA operon. Three types of mutations were found in pactamycin resistant
cells, A694G, C795U and C796U (Escherichia coli 16 S rRNA numeration) located
distantly in rRNA primary structure but probably neighboring each other in the
three-dimensional structure. Pactamycin resistance mutations either overlapped
(C795U) or were located in the immediate vicinity of nucleotides protected by the
drug in E. coli and H. halobium 16 S rRNA indicating that corresponding rRNA
sites might be directly involved in pactamycin binding. Ribosomal functions were
not affected significantly either by mutation of C795 (one of the positions
protected by the P-site-bound tRNA), or by mutations of A694 and C796 (which
neighbor nucleotides protected by tRNA) suggesting that tRNA-dependent
protections of C795 and G693 are explained by a conformational change in the
ribosome induced by the P-site-bound tRNA. A novel mode of pactamycin action is
proposed suggesting that pactamycin restricts structural transitions in 16 S rRNA
preventing the ribosome from adopting a functional conformation induced by tRNA
binding.
PMID- 9398511
TI - Crystal structure of annexin V with its ligand K-201 as a calcium channel
activity inhibitor.
AB - The crystal structure of recombinant human annexin V complexed with K-201, an
inhibitor of the calcium ion channel activity of annexin V, was solved at 3.0 A
by molecular replacement including the apo and high-calcium forms. K-201 was
bound at the hinge region cavity formed by the N-terminal strand and domains II,
III and IV, at the side opposite the calcium and membrane-binding surface, in an
L-shaped conformation. Based on the complex and other annexin structures, K-201
is proposed to restrain the hinge movement of annexin V in an allosteric manner,
resulting in the inhibition of calcium movement across the annexin V molecule.
PMID- 9398512
TI - Structural characterization of the myoglobin active site using infrared
crystallography.
AB - We use polarized IR absorption on single crystals to determine the orientation of
carbon monoxide bound at the active site of myoglobin, and conclude that the C-O
bond lies approximately 7 degrees from the normal to the mean plane of the heme.
This result disagrees with much larger angular displacements reported in
structural models derived from X-ray and neutron diffraction measurements. The
insensitivity of the IR-derived orientation to changes in pH or crystal packing
contrasts with the wide variations in CO orientation among diffraction-based
models and suggests that the latter are in error. The small energies required to
displace the C-O bond 7 degrees from its energetically preferred upright geometry
suggest that distortion of the surrounding protein, rather than the relatively
undeformable Fe-C-O unit, is the main steric mechanism inhibiting CO binding to
myoglobin.
PMID- 9398513
TI - The central region of RepE initiator protein of mini-F plasmid plays a crucial
role in dimerization required for negative replication control.
AB - The RepE protein (251 residues, 29 kDa) of mini-F plasmid, mostly found as
dimers, plays a key role in mini-F replication. Whereas monomers bind to the
origin to initiate replication, dimers bind to the repE operator to repress its
own transcription. Among the host factors required for mini-F replication, a set
of molecular chaperones (DnaK, DnaJ and GrpE) is thought to facilitate
monomerization of RepE dimers. To further understand the structural basis of
functional differentiation between the two forms of RepE, we examined the
region(s) critical for dimerization by isolation and characterization of RepE
mutants that were defective in autogenous repressor function. Such mutations were
isolated from two separate regions of RepE, the central region (residues 111 to
161) and the C-terminal region (residues 195 to 208). The central region
overlapped the region where the chaperone-independent copy-up mutations were
previously isolated (residues 93 to 135). Likewise the mini-F mutant plasmids,
carrying the mutations in the central region, could replicate in a dnaK null
mutant host. One of them, S111P (111th serine changed to proline), showed a very
high origin-binding activity vis-a-vis a severely reduced operator-binding
activity, much like the RepE54 (R118P) mutant previously shown to form only
monomers. Gel filtration and chemical crosslinking studies with purified RepE
revealed that S111P primarily formed monomers, whereas other mutant proteins
formed mostly dimers. On the other hand, analysis of deletion mutants revealed
that the N-terminal 42 and the C-terminal 57 residues were dispensable for
dimerization. Thus, the region spanning residues 93 to 161 of RepE (including
Ser111 and Arg118) appeared to be primarily involved in dimerization,
contributing to the negative regulation of plasmid replication.
PMID- 9398514
TI - Structure-function correlations in the XerD site-specific recombinase revealed by
pentapeptide scanning mutagenesis.
AB - Xer-mediated site-specific recombination contributes to the stability of circular
chromosomes in bacteria by resolving plasmid multimers and chromosome dimers to
monomers prior to cell division. Two related site-specific recombinases, XerC and
XerD, each catalyse one pair of strand exchange during Xer recombination. In
order to relate the recently determined structure of XerD to its function, the
XerD protein was subjected to pentapeptide scanning mutagenesis, which leads to a
variable five amino acid cassette being introduced randomly into the target
protein. This has allowed identification of regions of XerD involved in specific
DNA binding, in communicating with the partner recombinase, XerC, and in
catalysis and its control. The C-terminal domain of XerD, comprising two-thirds
of the protein, contains the catalytic active site and comprises ten alpha
helices (alphaE to alphaN) and a beta hairpin. A flexible linker connects this
domain to the N-terminal domain that comprises four alpha helices (alphaA to
alphaD). Pentapeptide insertions into alphaB, alphaD, alphaG, or alphaJ
interfered with DNA binding. Helices alphaG and alphaJ comprise a pseudo helix
turn-helix DNA binding motif that may provide specificity of recombinase binding.
An insertion in alphaL, adjacent to an active site arginine residue, led to loss
of cooperative interactions between XerC and XerD and abolished recombination
activity. Other insertions close to active site residues also abolished
recombination activity. Proteins with an insertion in the beta hairpin turn bound
DNA, interacted cooperatively with XerC and had a phenotype that is consistent
with the protein being defective in XerD catalysis. This beta hairpin appears to
be highly conserved in related proteins. Insertions at a number of dispersed
locations did not impair XerD catalytic activity or DNA binding, but failed to
allow XerC catalysis in vivo, indicating that several sites of interaction
between XerD and XerC may be important for activation of XerC catalysis by XerD.
PMID- 9398515
TI - Rules governing the orientation of the 2'-hydroxyl group in RNA.
AB - Molecular dynamics simulations reveal that, in C3'-endo sugar puckers, only three
orientations are accessible to the 2'-hydroxyl groups distinctive of RNA
molecules: towards (i) the O3', (ii) the O4' of the same sugar, and (iii) the
shallow groove base atoms. In the rarer C2'-endo sugar puckers, orientations
towards the O3' atom of the same sugar are strongly favoured. Surprisingly, in
helical regions, the frequently suggested intra-strand O2'-H(n)...O4'(n+1)
interaction is not found. This observation led to the detection of an axial C
H...O interaction between the C2'-H2'(n) group and the O4'(n+1) atom contributing
to the stabilization of RNA helical regions. Subsequent analysis of
crystallographic structures of both RNA and A-DNA helices fully supports this
finding. Specific hydration patterns are also thought to play a significant role
in the stabilization of RNA structures. In the shallow groove of RNA, known as a
favourable RNA or protein-binding region, three well-defined hydration sites are
located around the O2' atom. These hydration sites, occupied by water molecules
exchanging with the bulk, constitute, after dehydration, anchor points for
specific interactions between RNA and nucleic acids, proteins or drugs.
Therefore, the fact that the 2'-hydroxyl group is not monopolised by axial
stabilization, together with its water-like behaviour, facilitates complex
formation involving RNA helical regions.
PMID- 9398516
TI - X-ray fibre diffraction study of an elevated temperature structure of
poly(dA).poly(dT).
AB - A reversible conformational transition between two discrete double helical forms
of poly(dA).poly(dT) has been put into evidence by X-ray fibre diffraction. We
observed that the transition between the well known B' conformation and a new
helical structure (B*) occurs at a relative humidity near 80%, when the
temperature is raised above 30 degrees C. It appears that the B* conformation is
not just a distorted B' form of poly(dA).poly(dT) but rather a stable (up to a
least 70 degrees C) distinct double helical structure of that polynucleotide.
Analysis of X-ray patterns allowed us to present the geometrical parameters of a
molecular model of this new double helix. It consists of 11.4 nucleotide pairs
per turn in a pitch length of about 36.7 A. The proposed high-temperature right
handed helical structure of poly(dA).poly(dT) is a member of the B-DNA family
since the duplex has C1'-exo furanoses in both antiparallel but geometrically
identical sugar-phosphate strands. The present finding may shed light on
interpretations of results obtained from premelting or nucleosome formation
processes involving (dA.dT) tracts in synthetic or natural DNA polymers.
PMID- 9398517
TI - Structure and dynamics of the iron responsive element RNA: implications for
binding of the RNA by iron regulatory binding proteins.
AB - The iron responsive element (IRE) is a approximately 30 nucleotide RNA hairpin
that is located in the 5' untranslated region of all ferritin mRNAs and in the 3'
untranslated region of all transferrin receptor mRNAs. The IREs are bound by two
related IRE-binding proteins (IRPs) which help control intracellular levels of
iron by regulating the expression of both ferritin and transferrin receptor
genes. Multi-dimensional NMR and computational approaches were used to study the
structure and dynamics of the IRE RNA in solution. The NMR data are consistent
with formation of A-form helical stem regions, a one-base internal bulge and a
Watson-Crick C.G base-pair between the first and fifth nucleotides in the loop. A
superposition of refined structures indicates that the conserved C in the
internal bulge, and three residues in the six-nucleotide hairpin loop are quite
dynamic in this RNA. The structural roles of the stems, the loop and the bulge in
the function of the IRE RNA and in possible interactions with the iron regulatory
protein are discussed.
PMID- 9398518
TI - The structures of human glutathione transferase P1-1 in complex with glutathione
and various inhibitors at high resolution.
AB - The human pi-class glutathione S-transferase (hGST P1-1) is a target for
structure-based inhibitor design with the aim of developing drugs that could be
used as adjuvants in chemotherapeutic treatment. Here we present seven crystal
structures of the enzyme in complex with substrate (glutathione) and two
inhibitors (S-hexyl glutathione and gamma-glutamyl- (S-benzyl)cysteinyl-D
phenylglycine). The binding of the modified glutathione inhibitor, gamma-glutamyl
(S-benzyl)cysteinyl-D-phenylglycine, has been characterized with the phenyl group
stacking against the benzyl moiety of the inhibitor and making interactions with
the active-site residues Phe8 and Trp38. The structure provides an explanation as
to why this compound inhibits the pi-class GST much better than the other GST
classes. The structure of the enzyme in complex with glutathione has been
determined to high resolution (1.9 to 2.2 A) in three different crystal forms and
at two different temperatures (100 and 288 K). In one crystal form, the direct
hydrogen-bonding interaction between the hydroxyl group of Tyr7, a residue
involved in catalysis, and the thiol group of the substrate, glutathione, is
broken and replaced by a water molecule that mediates the interaction. The
hydrogen-bonding partner of the hydroxyl group of Tyr108, another residue
implicated in the catalysis, is space-group dependent. A high-resolution (2.0 A)
structure of the enzyme in complex with S-hexyl glutathione in a new crystal form
is presented. The enzyme-inhibitor complexes show that the binding of ligand into
the electrophilic binding site does not lead to any conformational changes of the
protein.
PMID- 9398519
TI - The RNA binding domain of ribosomal protein L11: three-dimensional structure of
the RNA-bound form of the protein and its interaction with 23 S rRNA.
AB - The three-dimensional solution structure has been determined by NMR spectroscopy
of the 75 residue C-terminal domain of ribosomal protein L11 (L11-C76) in its RNA
bound state. L11-C76 recognizes and binds tightly to a highly conserved 58
nucleotide domain of 23 S ribosomal RNA, whose secondary structure consists of
three helical stems and a central junction loop. The NMR data reveal that the
conserved structural core of the protein, which consists of a bundle of three
alpha-helices and a two-stranded parallel beta-sheet four residues in length, is
nearly the same as the solution structure determined for the non-liganded form of
the protein. There are however, substantial chemical shift perturbations which
accompany RNA binding, the largest of which map onto an extended loop which
bridges the C-terminal end of alpha-helix 1 and the first strand of parallel beta
sheet. Substantial shift perturbations are also observed in the N-terminal end of
alpha-helix 1, the intervening loop that bridges helices 2 and 3, and alpha-helix
3. The four contact regions identified by the shift perturbation data also
displayed protein-RNA NOEs, as identified by isotope-filtered three-dimensional
NOE spectroscopy. The shift perturbation and NOE data not only implicate helix 3
as playing an important role in RNA binding, but also indicate that regions
flanking helix 3 are involved as well. Loop 1 is of particular interest as it was
found to be flexible and disordered for L11-C76 free in solution, but not in the
RNA-bound form of the protein, where it appears rigid and adopts a specific
conformation as a result of its direct contact to RNA.
PMID- 9398520
TI - Ligand-induced conformational changes in ras p21: a normal mode and energy
minimization analysis.
AB - A normal mode and energy minimization of ras p21 is used to determine the
flexibility of the protein and the origin of the conformational differences
between GTP and GDP-bound forms. To preserve the integrity of the structures, a
hydration shell of water molecules was included as part of the system. Certain
low-frequency modes were found to have high involvement coefficients with the
conformational transition between the GTP and GDP-bound structures; the
involvement coefficients of some of the modes increase when the gamma-phosphate
group is removed. Two unstable modes that appear in the GTP-bound structure upon
deletion of the gamma-phosphate group were determined and shown to have dominant
contributions in the regions of switch I and switch II; there was also a
significant displacement of loop 1. The initial motion in these regions is
predicted by the modes to be approximately perpendicular to the direction of the
transition from the GTP-bound state to the GDP-bound state. The overall
conformational change in the switch I and II regions involves rearrangements of
the protein backbone within these regions, rather than rigid body motion.
Differences in the low-frequency modes of the GTP and GDP-bound forms appear to
play a role in ligand binding. A coupling between the helix alpha3 position and
the deletion of the gamma-phosphate group may be involved in the interaction with
GAP. The oncogenic mutation G12D leads to a global increase in the rigidity of
the protein. Thus, the mutant is likely to have a higher barrier for the
conformational change to the inactive form; this would slow the transition and
could be related to its oncogenic properties.
PMID- 9398521
TI - Contribution of water molecules in the interior of a protein to the
conformational stability.
AB - Water molecules frequently occur in the interior of globular proteins. To
elucidate the contribution of buried water molecules to the conformational
stability of a protein, we examined the crystal structures and the thermodynamic
parameters of denaturation of six Ile to Ala/Gly mutant human lysozymes, in which
a cavity is created at each mutation site by the substitution of a smaller side
chain for a larger one. One or two ordered water molecules were found in the
cavities created in some mutants (I106A, I59A and I59G). The cavity volumes for
these three mutants were bigger than those that remained empty in the other
mutants. The stability of the mutant proteins with the newly introduced water
molecules was about 8 kJ/mol higher than that expected from the change in
hydrophobic surface area (DeltaDeltaASAHP) exposed upon denaturation. It was
concluded that a water molecule in a cavity created in the interior of a protein
contributes favorably to the stability.
PMID- 9398522
TI - Clarification of the dimerization domain and its functional significance for the
Escherichia coli nucleoid protein H-NS.
AB - The Escherichia coli nucleoid protein, H-NS, functions as a global regulator for
expression of a wide variety of genes. We recently analyzed the structure
function relationship of H-NS with special reference to the domains responsible
for transcriptional repression and DNA-binding, respectively. However,
identification of the presumed dimerization domain of H-NS and its functional
significance was elusive. To address this particular issue, we first examined a
set of N-terminally or C-terminally truncated forms of H-NS, in terms of their so
called dominant-negative effect on the in vivo function of the wild-type H-NS.
The results showed that certain truncated forms exhibit such a dominant-negative
effect, but others did not. As judged by the results of the dominant-negative
effect, it was assumed that a relatively central portion of H-NS extending from
residues 21 to 63 is involved in dimerization. This was confirmed by an in vitro
chemical cross-linking analysis and a gel filtration analysis with these
truncated forms of H-NS. Furthermore, the use of the dominant-negative phenotype,
caused by a truncated form of H-NS (named N91), allowed us to isolate a missense
mutant, which was expected to be specifically defective in dimerization. This
mutant had an amino acid substitution at position 30 (Leu30 to Pro) in N91
consisting of the N-terminal 91 amino acids of H-NS. This mutant was indeed
defective in the in vitro ability to form a heterodimer with the wild-type H-NS.
When this particular single amino acid substitution was introduced into the full
length H-NS, the resultant H-NS mutant had lost the ability to form dimers in
vitro and to function as a transcriptional repressor. These findings collectively
provided us with evidence that the ability of H-NS to form a dimer is crucial for
H-NS to function as a transcriptional repressor.
PMID- 9398523
TI - NMR analysis of main-chain conformational preferences in an unfolded fibronectin
binding protein.
AB - A 130-residue fragment of the Staphylococcus aureus fibronectin-binding protein
has been found to exist in a highly unfolded conformation at neutral pH.
Measurement of experimental NMR 3JHNalpha coupling constants provides evidence
for individual residues having distinct main-chain conformational preferences
that are dependent both on the amino acid concerned and on neighbouring residues
in the sequence. Analysis shows that these variations in the populations of
individual residues can be explained in detail in terms of statistical
distributions of conformational states derived from the protein data base. In
particular, when the preceding residue has a beta-branched or aromatic side
chain, a significant increase occurs in the population of the less sterically
restricted b region of phi,psi space. The results indicate that the local
structure of the fibronectin binding protein in solution, under conditions where
it displays full activity, approximates very closely to a statistical random coil
structure. This may be an important feature in the biological role of this and
other polypeptides involved in protein-protein interactions.
PMID- 9398524
TI - Assembly of the N-dependent antitermination complex of phage lambda: NusA and RNA
bind independently to different unfolded domains of the N protein.
AB - The N protein of bacteriophage lambda activates expression of the delayed early
genes of this phage by modifying RNA polymerase (RNAP) into a form that is
resistant to termination signals. N binds to the boxB hairpin that forms in the
nascent RNA transcript upon transcription of the nut regulatory element, and then
interacts with RNAP by RNA looping. The binding of the N-boxB subassembly to the
transcription complex is further stabilized by interaction with the Escherichia
coli NusA protein. N, free in solution, exists as an unfolded protein that
becomes partially structured upon binding specifically to boxB RNA. Because NusA
does not assist in antitermination unless N is specifically bound to boxB, we
have asked whether the structural change induced by binding to boxB affects the
interaction of N with NusA. Using fluorescence spectroscopy, we have measured the
affinity of N for NusA in the presence and absence of boxB RNA. We find that NusA
binds to the unfolded N protein with a dissociation constant (Kd) of
approximately 70 nM, and although N undergoes a significant structural change
upon binding to boxB, the binding affinity of NusA for a N protein complexed with
boxB is not altered. We have also shown that the boxA element of nut does not
affect NusA binding to N-boxB. These results demonstrate that the interaction of
N with NusA is independent of RNA binding, arguing that NusA must interact with
an unfolded region of the polypeptide that remains unstructured even when N binds
to boxB RNA. To further establish this point we isolated a truncated peptide
containing the amino-terminal 36 residues of the N protein. Binding of boxB RNA
to this peptide showed that all of the structural change in N that occurs upon
binding to boxB RNA is localized within the amino-terminal 36 residues of N,
therefore the C terminus of N, including the regions necessary for NusA binding
and RNAP activation, remains unfolded when the full length N binds to boxB RNA.
Thus it appears that N can be described as an unfolded multi-domain protein that
becomes ordered in a modular fashion as it encounters its various binding
partners within the N-dependent antitermination complex.
PMID- 9398525
TI - SelD homolog from Drosophila lacking selenide-dependent monoselenophosphate
synthetase activity.
AB - The isolation and molecular characterization of an invertebrate gene that encodes
a homolog of the human selenophosphate synthetase 1 is described. This Drosophila
gene, termed selD-like, is located in the cytogenetic interval 50 D/E on the
right arm of chromosome 2. It is expressed ubiquitously throughout embryogenesis
and found to be highly enriched in the developing gut and in the nervous system
of the embryo. The SelD-like from Drosophila was purified after expression in
Escherichia coli. The purified protein does not catalyze the selenide-dependent
ATP hydrolysis reaction and its gene does not complement a selD lesion in E.
coli. These results and the fact that selD-like possesses an arginine residue at
the position of the essential Cys17 (E. coli nomenclature) indicate that the
Drosophila gene exerts a function different from that of the classical
selenophosphate synthetases. Two classes of SelD proteins can therefore be
differentiated. The class I proteins contain a cysteine or selenocysteine residue
in the active site and display selenide-dependent selenophosphate synthetase
activity. Class II proteins, including Drosophila selD-like and human
selenophosphate synthetase 1 are devoid of this activity and they possess other
amino acids in position 17.
PMID- 9398526
TI - Stress-induced duplex DNA destabilization in scaffold/matrix attachment regions.
AB - S/MARs are DNA elements 300 to several thousand base-pairs long, which are
operationally defined by their affinity for the nuclear scaffold or matrix.
S/MARs occur exclusively in eukaryotic genomes, where they mediate several
functions. Because S/MARs do not have a clearcut consensus sequence, the
characteristics that define their activity are thought to be structural.
Ubiquitous S/MAR binding proteins have been identified, but to date no unique
binding sequence or structural motif has been found. Here we show by
computational analysis that S/MARs conform to a specific design whose essential
attribute is the presence of stress-induced base-unpairing regions (BURs). Stress
induced destabilization (SIDD) profiles are calculated using a previously
developed statistical mechanical procedure in which the superhelical deformation
is partitioned between strand separation, twisting within denatured regions, and
residual superhelicity. The results of these calculations show that BURs exhibit
a succession of evenly spaced destabilized sites that would render part or all of
the S/MAR sequence single stranded at sufficient superhelicity. These analyses
are performed for a range of sequenced S/MAR elements from the borders of
eukaryotic gene domains, from centromeres, and from positions where S/MARs are
known to support the action of an enhancer. The results reported here are in
excellent agreement with earlier in vitro chemical reactivity studies. This
approach demonstrates the potential for computational analysis to predict the
points of division of the eukaryotic genome into functional units (domains), and
also to locate certain cis-regulatory sequences.
PMID- 9398527
TI - Inter-domain cross-linking and molecular modelling of the hairpin ribozyme.
AB - The hairpin ribozyme is a small catalytic RNA composed of two helical domains
containing a small and a large internal loop and, thus, constitutes a valuable
paradigm for the study of RNA structure and catalysis. We have carried out
molecular modelling of the hairpin ribozyme to learn how the two domains (A and
B) might fold and approach each other. To help distinguish alternative inter
domain orientations, we have chemically synthesized hairpin ribozymes containing
2'-2' disulphide linkages of known spacing (12 or 16 A) between defined ribose
residues in the internal loop regions of each domain. The abilities of cross
linked ribozymes to carry out RNA cleavage under single turnover conditions were
compared to the corresponding disulphide-reduced, untethered ribozymes. Ribozymes
were classed in three categories according to whether their cleavage rates were
marginally, moderately, or strongly affected by cross-linking. This rank order of
activity guided the docking of the two domains in the molecular modelling
process. The proposed three-dimensional model of the hairpin ribozyme
incorporates three different crystallographically determined structural motifs:
in domain A, the 5'-GAR-3'-motif of the hammerhead ribozyme, in domain B, the
J4/5 motif of group I ribozymes, and connecting the two domains, a "ribose
zipper", another group I ribozyme feature, formed between the hydroxyl groups of
residues A10, G11 of domain A and C25, A24 of domain B. This latter feature might
be key to the selection and precise orientation of the inter-domain docking
necessary for the specific phosphodiester cleavage. The model provides an
important basis for further studies of hairpin ribozyme structure and function.
PMID- 9398528
TI - An interaction between a specified surface of the C-terminal domain of RecA
protein and double-stranded DNA for homologous pairing.
AB - RecA protein and its homologs catalyze homologous pairing of dsDNA and ssDNA, a
critical reaction in homologous genetic recombination in various organisms from a
virus, microbes to higher eukaryotes. In this reaction, RecA protein forms a
nucleoprotein filament on ssDNA, which in turn binds to naked dsDNA for homology
search. We suggested that the C-terminal domain of RecA protein plays a role in
capturing the dsDNA. Here, we isolated the C-terminal domain as a soluble form
and determined the solution structure by NMR spectroscopy. The overall folding of
the NMR structure agrees with that of the corresponding part of the reported
crystal structure, but a remarkable difference was found in a solvent-exposed
region due to intermolecular contacts in the crystal. Then, we studied the
interaction between the C-terminal domain and DNA, and found that significant
chemical shift changes were induced in a specific region by titration with dsDNA.
SsDNA induced a much smaller chemical shift perturbation. The difference of DNA
concentrations to give the half-saturation of the chemical shift change showed a
higher affinity of the C-terminal region toward dsDNA. Combined with our previous
results, these provide direct evidence that the defined region in the C-terminal
domain furnishes a binding surface for DNA.
PMID- 9398529
TI - Three-dimensional structure of diferric bovine lactoferrin at 2.8 A resolution.
AB - The three-dimensional structure of diferric bovine lactoferrin (bLf) has been
determined by X-ray crystallography in order to investigate the factors that
influence iron binding and release by transferrins. The structure was solved by
molecular replacement, using the coordinates of diferric human lactoferrin (hLf)
as a search model, and was refined with data to 2.8 A resolution by simulated
annealing (X-PLOR) and restrained least squares (TNT). The final model comprises
5310 protein atoms (residues 5 to 689), 124 carbohydrate atoms (from ten
monosaccharide units, in three glycan chains), 2 Fe3+, 2 CO32- and 50 water
molecules. This model gives an R-factor of 0.232 for 21440 reflections in the
resolution range 30.0 to 2.8 A. The folding of the bLf molecule is essentially
the same as that of hLf, but bLf differs in the extent of closure of the two
domains of each lobe, and in the relative orientations of the two lobes.
Differences in domain closure are attributed to amino acid changes in the
interface, and differences in lobe orientations to slightly altered packing of
two hydrophobic patches between the lobes. Changed interdomain interactions may
explain the lesser iron affinity of bLf, compared with hLf, and two lysine
residues behind the N-lobe iron site of bLf offer new insights into the "dilysine
trigger" mechanism proposed for iron release by transferrins. The bLf structure
is also notable for several well-defined oligosaccharide units which demonstrate
the structural factors that stabilise carbohydrate structure. One glycan chain,
attached to Asn545, appears to contribute to interdomain interactions and may
modulate iron release from the C-lobe.
PMID- 9398530
TI - The native and the heat-induced denatured states of alpha-chymotrypsinogen A:
thermodynamic and spectroscopic studies.
AB - We report the first protein phase-diagram characterized by a combination of
volumetric, calorimetric, and spectroscopic techniques. More specifically, we use
ultrasonic velocimetry, densimetry, and differential scanning calorimetry, in
conjunction with UV absorbance and CD spectroscopy to detect and to characterize
the conformational transitions of alpha-chymotrypsinogen A as a function of both
pH and temperature. As judged by the CD spectra, we find that, at room
temperature, the protein remains in the native state over the entire pH range
investigated (pH 1 to 10). The melting profiles of the native state reveal three
distinct pH domains in which protein denaturation produces different final
states. Below pH 3.1, we find the heat-induced denatured state of the protein to
be molten globule (MG), lacking the native-like tertiary structure, while
exhibiting significant secondary structural elements. At neutral and alkaline pH,
we find the heat-induced denatured state to be unfolded (U), lacking both
tertiary and secondary structures, while being structurally similar to the urea
unfolded state. At intermediate pH values (between pH 3.1 and 7), we find the
heat-induced denatured state to exhibit properties characteristic of both the MG
and U states. Although at room temperature the protein remains native within the
whole pH range studied (pH 1 to 10), our volumetric data reveal that the native
state slightly "softens" at low pH, probably, due to pH-induced alterations in
electrostatic forces causing the packing of the protein interior at low pH and
room temperature to become less "tight". This softening of the protein at low pH
is reflected in an 8% increase in the intrinsic compressibility, kM, of the
protein "native" state. Our volumetric data also allow us to conclude that the
heat-induced MG state retains a liquid-like, water-inaccessible core, with a
volume that corresponds to about 40% of the solvent-inaccessible core of the
native state. By contrast, our volumetric data are consistent with the U state of
the protein being essentially unfolded, with the majority of its constituent
atomic groups being solvent exposed and, therefore, strongly hydrated.
PMID- 9398532
TI - Folding of barnase in the presence of the molecular chaperone SecB.
AB - SecB is a molecular chaperone dedicated to interact exclusively with proteins
destined for translocation across membranes. We find that SecB interacts with
barnase during its folding in a similar manner to its interaction with GroEL. On
mixing acid-denatured barnase with SecB in a stopped-flow spectrofluorimeter
under conditions that favour refolding, we observe a series of fluorescence
changes, corresponding to the binding of the denatured protein and the subsequent
refolding of multiply and singly bound forms. The different phases were assigned
using a combination of kinetics and mutant proteins. The refolding of barnase
when bound to SecB is strongly retarded but never blocked. Multiply bound barnase
is less tightly bound and refolds with a higher rate constant than singly bound
barnase. Up to 4 mol of denatured barnase bind to 1 mol of tetrameric SecB.
PMID- 9398531
TI - Electrostatic and non-electrostatic contributions to the binding free energies of
anthracycline antibiotics to DNA.
AB - The knowledge about molecular factors driving simple ligand-DNA interactions is
still limited. The aim of the present study was to investigate the electrostatic
and non-electrostatic contributions to the binding free energies of anthracycline
compounds with DNA. Theoretical calculations based on continuum methods (Poisson
Boltzmann and solvent accessible surface area) were performed to estimate the
binding free energies of five selected anthracycline ligands (daunomycin,
adriamycin, 9-deoxyadriamycin, hydroxyrubicin, and adriamycinone) to DNA. The
free energy calculations also took into account the conformational change that
DNA undergoes upon ligand binding. This conformational change appeared to be very
important for estimating absolute free energies of binding. Our studies revealed
that the absolute values of all computed contributions to the binding free energy
were quite large compared to the total free energy of binding. However, the sum
of these large positive and negative values produced a small negative value of
the free energy around -10 kcal/mol. This value is in good agreement with
experimental data. Experimental values for relative binding free energies were
also reproduced for charged ligands by our calculations. Together, it was found
that the driving force for ligand-DNA complex formation is the non-polar
interaction between the ligand and DNA even if the ligand is positively charged.
PMID- 9398533
TI - C-capping and helix stability: the Pro C-capping motif.
AB - Here we have performed a statistical analysis of the protein database to find new
putative local C-terminal motifs in alpha-helices. Our analysis shows that
certain combinations of X-Pro pairs (Asn, Cys, His, Phe, Tyr, Trp, Ile, Val and
Leu), in which residue X is the C-cap and the Pro is at position C', are more
abundant than expected. In those pairs, except for the aliphatic residues, the
presence of the Pro residue at C' tends to restrict the phi and psi dihedral
angles of the residue at position C-cap, around -130 degrees , 70 degrees ,
respectively. For the aromatic residues as well as for His, the chi1 angle is
around -60 degrees and the edge of the His and aromatic rings are close to the
carbonyl group of the residue i - 4. In all the pairs having the above dihedral
angles for residue C-cap, the main-chain amino group of Pro at C' is close to the
last three main-chain carbonyls of the alpha-helix. The above structural
arrangements suggests the existence of a stabilising electrostatic interaction of
the residues at positions C-cap and C' with the helix macrodipole. We have
denominated this putative local motif, the Pro-capping motif. To asses its
importance in helix stability we have analysed by nuclear magnetic resonance
(NMR) and far-UV circular dichroism (CD) a set of polyalanine-based peptides
containing two of the above pairs: His-Pro and Phe-Pro, as well as the
corresponding controls. In the case of the His-Pro pair we have found NMR
evidence for the formation of the Pro-capping motif in aqueous solution. CD
analysis shows that the presence of a Pro residue alters the C-cap properties of
the preceding amino acids in the case of His and Phe makes them more favourable.
The Pro-capping motif with the appropriate sequence, determines the location of
the C terminus of alpha-helices and stabilises the helical conformation having
Pro as the C' residue.
PMID- 9398534
TI - Hydroxylamine treatment increases glutathione-protein and protein-protein binding
in human erythrocytes.
AB - Hydroxylamine is a direct-acting hematotoxic agent leading to hemolytic anemia in
animals and man. The effect of hydroxylamine on the morphology, sulfhydryl status
and membrane skeletal proteins of human erythrocytes were studied. Loss of
reduced glutathione (GSH) from the red blood cells was directly proportional to
the hydroxylamine concentration used. This loss of GSH was larger than the sum of
the increase in the amounts of extracellular glutathione and intracellular
oxidized glutathione (GSSG). The extracellular glutathione is mainly present as
GSSG, which is in agreement with the fact that only GSSG is exported from the
erythrocytes by membrane bound ATPases. Lack of GSSG export was not limited by
decreased ATP levels in the erythrocytes and we concluded that the GSH that
disappeared did not become available as intracellular GSSG. After reduction of
the erythrocyte incubates the lost GSH was almost completely recovered indicating
that the lost GSH is present in the cell as protein-glutathione mixed disulfides.
Glutathione thus stored within the cell can be quickly recovered by combined
thioltransferase and glutathione reductase activity when conditions become more
favorable again. SDS-polyacrylamide gel electrophoresis of membrane ghosts from
human red cells revealed changes in skeletal proteins with a smearing of bands 1,
2 and 3 to the higher molecular weight end of the gel and the appearance of new
monomeric and dimeric hemoglobin bands at about 16 and 30 kD. The observed
alterations are probably a consequence of disulfide bridge formation between
cellular proteins (mainly hemoglobin) and skeletal proteins as well as between
hemoglobin monomers. Exposure of hydroxylamine to erythrocytes caused severe
Heinz body formation but the outside morphology of the cells was only marginally
altered. The described changes in sulfhydryl status of the red blood cells are
likely to play a major role in the premature splenic sequestration of
hydroxylamine-damaged erythrocytes.
PMID- 9398535
TI - A novel interferon-inducible gene expressed during myeloid differentiation.
AB - The acute promyelocytic leukemia cell line, NB4, can be induced to differentiate
to mature granulocytes by retinoic acid treatment. A novel retinoic acid
inducible cDNA clone, designated RI58, was isolated from a cDNA library
constructed from retinoic acid-treated NB4 cells by differential hybridization.
RI58 cDNA encodes a protein of 58kDa which has a similarity in its amino acids
sequence to interferon (IFN)-inducible proteins. In addition, RI58 was induced by
recombinant human IFN-alpha (rhIFN-alpha) in NB4 cells. RI58 was detectable
within 4 hours post-stimulation with rhIFN-alpha, while it took as long as 1day
after retinoic acid stimulation. Culture supernatant from retinoic acid-treated
NB4 cells also induced RI58 expression similarly as rhIFN-alpha. This activity in
culture supernatant was inhibited by anti-leukocyte IFN antiserum which showed
specific reactivity to rhIFN-alpha. These results indicate that RI58 is induced
by retinoic acid stimulation through autocrinally secreted IFN-alpha from NB4
cells. In the retinoic acid-treated NB4 cells, the expression of RI58 was
increased along the process of differentiation. On the other hand, it was
expressed constitutively in untreated non-hematopoietic cell lines and mature
hematopoietic cell lines.
PMID- 9398536
TI - Structural and functional analysis of the Pig-a protein that is mutated in
paroxysmal nocturnal hemoglobinuria.
AB - There is now convincing evidence that the Pig-a gene is mutated in patients with
paroxysmal nocturnal hemoglobinuria (PNH), a disease in which one or more clones
of hematopoietic cells have incomplete assembly of glycosylphosphatidylinositol
(GPI) anchors and absence of GPI-linked protein expression on the cell surface.
Little is known, however, about the Pig-a protein product that is necessary for
GPI anchor bioassembly. Relatively few substitution (missense) Pig-a gene
mutations have been identified, but we noted two apparent clusters at codons 128
129 and 151-156 and hypothesized that these might represent critical regions of
the Pig-a protein. We therefore used site-directed mutagenesis to create
conservative mutations in the Pig-a protein, then performed structural and
functional analysis. Each Pig-a mutation generated a Pig-a protein of normal size
and stability, but certain mutations had substantial deleterious effects on
protein function. Conservative mutation of codons histidine 128 (H128), serine
129 (S129), and serine 155 (S155) had greatly diminished function, while
mutations of flanking residues had no effect on function. Our results represent
the first structure/function analysis of the Pig-a protein, and suggest that
codons H128, S129, and S155 represent critical regions of the Pig-a protein. Our
results also suggest a means by which transgenic mice with a "partial knock-out"
of Pig-a function could be generated, which would allow investigation of PNH in
an animal model.
PMID- 9398538
TI - An exonic polymorphism in the human glucose phosphate isomerase (GPI) gene.
AB - A polymorphic site has been found in the human glucose phosphate isomerase (GPI)
gene. This site is produced by a A-->G substitution at nt 489 of GPI cDNA,
resulting in a silent mutation. To our knowledge, it is the first defined
polymorphism in the gene. It is present with similar gene frequencies in Asian,
American White, African American, and Jewish populations.
PMID- 9398537
TI - Expression of alpha IIb beta 3 integrin (GPIIb-IIIa) in myeloid cell lines and
normal CD34+/CD33+ bone marrow cells.
AB - Regulation of myeloid cell proliferation and differentiation in the bone marrow
is mediated, in part, by the interaction of integrins on early myeloid cells with
the extracellular matrix proteins secreted by stromal cells. To further define
adhesive protein receptors of early myeloid cells, we examined the expression of
the integrin GPIIb-IIIa (alphaIIbbeta3) in leukemic cell lines KG-1a, KG-1, and
HL-60, that represent early stages of myeloid differentiation. All three cell
lines expressed surface GPIIb-IIIa as measured by flow cytometry and by binding
of 125I-anti-GPIIb-IIIa monoclonal antibody. Preincubation of cells with human AB
serum or platelet releasate increased GPIIb-IIIa surface expression. GPIIb
transcripts were identified in all three cell lines by Northern blot analysis.
Furthermore, we readily detected GPIIb transcripts in fluorescence activated cell
sorted (FACS) myeloid cells from normal human bone marrow by RT-PCR. Cloning and
sequencing of the PCR products established the identity of GPIIb transcripts in
the leukemic cell lines and CD34+/CD33+ normal bone marrow cells. Since the
normal myeloid cells also demonstrated markers corresponding to the maturational
stage of KG-1a/KG-1 cells, we propose that GPIIb-IIIa may serve as a myeloid
differentiation antigen and as a key integrin of myeloid precursors.
PMID- 9398539
TI - Air-Broadening and Shift Coefficients of O3 Lines in the nu2 Band and Their
Temperature Dependence
AB - Room temperature measurements of self- and air-broadening coefficients are
reported for over 370 transitions covering a range of 0 = J" = 45 and 1 =
Ka" = 12 for the nu2 ozone band in the 630 to 800 cm-1 spectral region. In
addition, the temperature dependence of air-broadened halfwidth and air-induced
pressure shift coefficients have been determined for over 350 spectral lines. A
total of 29 O3 absorption spectra (0.005-cm-1 resolution) recorded at various
temperatures (29 to -63°C) with a Fourier transform spectrometer were used in
the analysis. The spectral line parameters were deduced by analyzing all of the
29 spectra simultaneously using a nonlinear least-squares fitting technique. The
results are compared with similar measurements obtained in the ozone nu1 band.
Copyright 1997Academic Press
PMID- 9398540
TI - Temperature Dependence of Air-Broadening and Shift Coefficients of O3 Lines in
the nu1 Band
AB - High-resolution Fourier transform absorption spectra of ozone broadened by dry
air have been recorded at a number of temperatures from -63°C to 29°C.
Using a multispectrum nonlinear least-squares procedure, we fit 29 of these
spectra simultaneously to determine the air-broadening and shift coefficients and
their temperature dependences for 450 lines in the 9-&mgr;m region; most of these
belong to the nu1 band. Partial air-broadening results were obtained for 104
additional lines, and room-temperature self-broadening coefficients were also
determined for most of the 554 lines measured. These results cover a wide range
of rotational quantum numbers, particularly in the R branch, with J" = 55 and
Ka" = 12. The variation of the retrieved broadening and shift parameters with
the rotational quantum numbers has been examined; particularly interesting
behavior of the broadening coefficients is noted as the value of Ka" approaches
that of J". The broadening and shift coefficients compare well with previous room
temperature measurements in the nu1 and other bands. The temperature-dependence
results are also consistent (within the stated uncertainties) with the few
previous measurements of the temperature dependence of air- and N2-broadening
coefficients in other O3 bands, but disagree with the mean value given in the
HITRAN compilation. Copyright 1997Academic Press
PMID- 9398541
TI - Dipole Polarizabilities of Li, C, and O and Long-Range Coefficients for Various
Molecular States of Li2, CO, and O2
AB - Dynamic polarizabilities with imaginary frequencies are calculated for Li(2s 2S),
Li(3s 2S), Li(2p 2P), C(2p2 3P), and O(2p4 3P) atoms with a time-dependent gauge
invariant method. Coulombic long-range interactions are deduced for various
states of Li2, CO, and O2 and compared to previous calculated and experimental
results. Copyright 1997Academic Press
PMID- 9398542
TI - High-Resolution Laser Spectroscopy of the A3Pi1u <-- X1Sigmag+ System of I2 with
a Titanium:Sapphire Ring Laser
AB - The Doppler-limited absorption spectrum of the vibrotational lines in the A3Pi1u
<-- X1Sigmag+ system of I2 was measured in the region from 11,200 to 12,450 cm-1
using a Ti:sapphire ring laser. The Q-branch lines of J = 10 to 100 belonging to
the v' <-- v" = (26' approximately 45') <-- 0", (19' approximately 45') <-- 1",
(16' approximately 45') <-- 2", (16' approximately 42') <-- 3", and (22'
approximately 31') <-- 4" progressions were assigned. The hyperfine splittings
were observed at the vibrational states around the near-dissociation limit. The
unperturbed line positions were obtained by first order approximation for the
high-J rotational state. The values of nuQ0, Bvf' - Bv", Dvf' - Dv", and Hv' -
Hv" were determined using a least-squares fitting procedure. The spectroscopic
constants of Tv', Bvf', Dvf', and Hvf' of v' = 16 approximately 45 were
calculated with the aid of the Dunham expansion parameters of the X state and
were compared with those reported by D. R. T. Appadoo et al. (J. Chem. Phys.
104(3), 903 (1996)). Copyright 1997Academic Press
PMID- 9398543
TI - Ab Initio Study of the Electronic Spectrum of B2H2
AB - The present paper represents the first part of an extensive theoretical study on
the electronic spectrum of B2H2. The results of ab initio calculations of the
vertical spectrum and the trans- and cis-bending potential curves for the low
lying triplet and singlet electronic states are reported. Special attention is
paid to the study of the interaction between valence- and Rydberg-type electronic
species. Copyright 1997Academic Press
PMID- 9398544
TI - Ab Initio Study of the Electronic Spectrum of B2H2
AB - The results of ab initio calculations of the potential curves for the torsional
motion, symmetric H-B stretching, and B-B stretching in low-lying valence- and
Rydberg-character triplet and singlet electronic states of B2H2 are reported.
Particularly, the dissociation process B2H2 --> BH + BH out of various electronic
states of B2H2 is studied. The nature of binding in B2H2 is discussed in terms of
the composition of the electronic wavefunctions. Copyright 1997Academic Press
PMID- 9398545
TI - Laser Spectroscopy of Vibration-Rotation Lines in the 3 <-- 0, 5 <-- 0, and 6 <--
0 Overtones of HBr
AB - The Doppler-limited vibration-rotation absorption spectrum of HBr in the near
infrared wavelength region was measured using a GaAs semiconductor laser and a
ring-type titanium sapphire laser. About 100 lines in the v = 3 <-- 0, 5 <-- 0,
and 6 <-- 0 bands were assigned and 16 Dunham coefficients Y10-Y50, Y01-Y41, Y02
Y22, Y03-Y13, and Y04 for H79Br and H81Br species were determined by a global
least-squares fit using the v = 0, v = 1 --> 0, and v = 2 --> 1 lines by V. Braun
and P. F. Bernath (J. Mol. Spectrosc. 167, 282-287, 1994), the v = 7 <-- 0 lines
by P. Bernage and P. Niay (C. R. Acad. Sci. Paris Ser. B 282, 243-245, 1976), and
the v = 3 <-- 0, v = 5 <-- 0, and v = 6 <-- 0 lines by this work. Copyright
1997Academic Press
PMID- 9398546
TI - High Resolution Study of the 3nu2, nu1 + nu2, and nu2 + nu3 Bands of H2Te
AB - High-resolution Fourier transform spectra of a natural sample of hydrogen
telluride and of monoisotopic H2130Te have been recorded in the 3.2-4-0 MUm
spectral region where the 3nu2, nu1 + nu2, and nu2 + nu3 bands of this molecule
absorb. The (030) rotational levels were least-squares fitted using a Watson-type
Hamiltonian whereas it proved necessary to consider the strong Coriolis
interaction coupling the (110) and the (011) rotational levels. In this way all
the experimental levels were calculated to within their experimental uncertainty
and precise sets of vibrational energies and rotational and coupling constants
were obtained for the (030), (110), and (011) vibrational states of H2130Te,
H2128Te, H2126Te, H2125Te, H2124Te, H2123Te, and H2122Te. The band centers for
the most abundant isotopic species, namely H2130Te, are:nuo(3nu2) = 2565.4428,
nuo(nu1 + nu2) = 2911.4098, nuo(nu2 + nu3) = 2915.9599 cm-1 Copyright
1997Academic Press
PMID- 9398547
TI - Analysis of the 2nu1 + nu2 + 2nu3 Band of Ozone
AB - The 2nu1 + nu2 + 2nu3 band of ozone, occurring in the 4780 cm-1 region, has been
observed for the first time, using a Fourier transform spectrometer, at 0.008 cm
1 resolution and using a large path length pressure product. Assignments of
vibration-rotational transitions have been made up to J = 48 and Ka = 9. As a few
levels with Ka = 1 or 2 are perturbed, it has been necessary to take into account
the Coriolis resonance between the (212) and (141) vibrational states. With the
effective Hamiltonian explicitly accounting for the interaction between these two
states, the fit on 165 energy levels leads to the rms deviation of 1.9 x 10(-3)
cm-1, which is near the experimental accuracy. Line intensities of the 2nu1 + nu2
+ 2nu3 band have been measured and calculated. The set of spectroscopic
parameters for interacting bands, as well as transition moment constants, is
given. A complete list of line positions and intensities, with a cutoff of 1 x
10(-26) cm-1/molecule.cm-2 at 296 K up to J = 65 and Ka = 15, has been generated,
which leads to the integrated band intensity Sv (2nu1 + nu2 + 2nu3) = (5.1 +/-
2.0) x 10(-23) cm-1/molecule.cm-2. Copyright 1997Academic Press
PMID- 9398548
TI - The High-Resolution FTIR Spectrum of Jet-Cooled CH3CF2Cl
AB - The infrared spectrum of HCFC-142b, CH3CF2Cl, has been recorded at high and low
resolution using a supersonic jet-FTIR spectrometer system. Molecular parameters
for a number of vibrational states have been obtained from rovibrational analyses
of the C-type bands nu14 (1192 cm-1) and nu15 (967 cm-1), the A-type band nu7
(905 cm-1), and the B-type bands nu5 (1234 cm-1) and nu7 + nu11 (1215 cm-1). A
rotational temperature of ca. 50 K in the jet expansion has been estimated from a
comparison of the experimental spectrum with band simulations calculated using
the resultant molecular constants. Copyright 1997Academic Press
PMID- 9398549
TI - Direct Measurements of Line-Mixing Coefficients in the nu1 + nu2 Q Branch of CO2
AB - High-resolution measurements of the (nu1 + nu2) Q branch of pure CO2 were made
using a difference frequency spectrometer with resolution of 5 x 10(-5) cm-1 and
a signal-to-noise ratio of 2000:1. Lines Q(2) through Q(32) were measured with up
to 14 lines in a single spectrum. The analysis of the branch has been performed
on data taken at 301 K and pressures less than 11 kPa. The spectra were analyzed
on a line-by-line basis within the Rosenkranz approximation of weak overlap [P.
W. Rosenkranz, IEEE Trans. Antennas Propagation AP-23, 498 (1975)]. The lineshape
profile included Doppler broadening and Dicke narrowing [R. H. Dicke, Phys. Rev.
89, 472 (1953)] using a modified hard collision model [S. G. Rautian and I. I.
Sobel'man, Sov. Phys. Uspekh. 9, 701 (1967)] with line mixing. For each line the
broadening, Dicke narrowing, and line-mixing coefficients were determined. The
broadening coefficients are in good agreement with measurements of lines
belonging to different CO2 bands. Our measured line-mixing parameters are
compared to those predicted by a relaxation matrix which was calculated from an
exponential power gap (EPG) law [L. L. Strow, D. C. Tobin, and S. E. Hannon, J.
Quant. Spectrosc. Radiat. Transfer 52, 281 (1994)]. The vibrational band
intensity and the linear pressure shift of the branch were also measured.
Copyright 1997Academic Press
PMID- 9398550
TI - Ab initio Calculated Rotation-Vibration Linestrengths for HeH2+
AB - Together with the recently determined potential energy surface for the ground
electronic state of HeH2+ [V. Spirko and W. P. Kraemer, J. Mol. Spectrosc. 172,
265-274 (1995)], the electric dipole moment components were calculated directly
as expectation values with the corresponding length operators at the center of
mass of the ion and using the variationally optimized configuration interaction
wavefunctions. From the fitted potential energy and dipole moment functions all
bound rotation-vibration energy levels and the line strengths of all dipole
allowed bound-bound transitions were evaluated variationally within the framework
of the Sutcliffe-Tennyson Hamiltonian. Strong transitions, especially for the
(He...H2)+ stretching motion, were obtained in the 500-800 cm-1 infrared
frequency range. The present calculations demonstrate that the conditions for
detecting the still unobserved rotation-vibration spectrum of HeH2+ are rather
promising. Copyright 1997Academic Press
PMID- 9398551
TI - High-Resolution Infrared Spectrum of Vinyl Fluoride at 500 cm-1
AB - The infrared spectrum of vinyl fluoride (CH2=CHF) has been investigated in the
region 390-590 cm-1 at room temperature and at a resolution of 0.0016 cm-1 using
a Fourier transform spectrometer. The rovibrational analysis of the spectral
features allowed us to assign about 11 000 lines (J = 60) of the nu9 ab-type
band centered at 483.0666 cm-1 and more than 700 lines (J = 40) of the 2nu9 -
nu9 ab-type hot band, the bandcenter of which is located at 485.6687 cm-1. The
experimental data provided the rotational and centrifugal distortion constants
for the vibrational excited states v9 = 1 and 2 employing Watson's A-reduction
Hamiltonian in the Ir representation. Moreover, band origins, harmonic frequency,
and anharmonicity factor have been obtained from the vibrational analysis of the
fundamental and the associated hot band. Copyright 1997Academic Press
PMID- 9398552
TI - The Fluorescence Excitation Spectrum of HCO &Btilde;2A'-&Xtilde;2A', 000 Band
AB - The rotationally resolved laser-induced fluorescence spectrum of the HCO
&Btilde;2A'-&Xtilde;2A' transition in the 000 band is observed under thermalized
conditions. The formyl radical is produced from acetaldehyde photolyzed at
wavelengths 310 or 308 nm. Some spin-splittings of the spectra are resolved.
About 988 transitions to Ka' = 3 and N' = 24, approximately 94% of the
observed lines, are assigned in this work including weak DeltaKa = ±2
transitions that become allowed because of the effects of axis-switching.
Copyright 1997Academic Press
PMID- 9398553
TI - Simultaneous Analysis of the 2nu2, nu1, and nu3 Bands of Hydrogen Telluride
AB - Spectra of a natural sample of hydrogen telluride as well as a spectrum of
monoisotopic H2 130Te have been recorded by means of Fourier transform
spectrometry with a resolution of 0.003 cm-1 in the spectral domain 7.5-4.3 MUm
where it is easy to observe the main absorbing bands nu1 and nu3. We have located
and assigned for the first time the 2nu2 band which appears in the lower
wavenumber range of the recorded spectral domain near 1700 cm-1. It proved
necessary to treat simultaneously the three states (020), (100), and (001). nu1
and nu3 are indeed Coriolis-coupled vibration-rotation bands and it was observed
that a few rotational levels of (001) could not be fitted to within their
experimental accuracy without considering the second-order Coriolis interaction
between the rotational levels of (020) and (001). In this way all the
experimental levels were calculated to within the experimental uncertainty, and
precise sets of vibrational energies and rotational and coupling constants were
obtained for the seven most abundant H2Te isotopic species, namely H2 130Te, H2
128Te, H2 126Te, H2 125Te, H2 124Te, H2 123Te, and H2 122Te. For the most
abundant isotopic species H2 130Te the bands centers arenu0 (2nu2) = 1715.9568,
nu0 (nu1) = 2065.2709, nu0 (nu3) = 2072.1101 cm-1. Copyright 1997Academic Press
PMID- 9398554
TI - Methyl Isocyanide Hot Bands in the Region 1300-1560 cm-1
AB - The hot bands accompanying the fundamentals nu6 and nu3 of CH3NC in the region
1300-1560 cm-1 observed in high-resolution Fourier transform recordings
complemented by diode laser spectra have been analyzed. The observed transitions
comprise 16 subbands of the pair of perpendicular E-E bands nu6± +
nu8± - nu8± and nu7-/+ + 2nu80 - nu8± whose upper states
form a Fermi dyad, 18 subbands of the A1,2-E perpendicular bands nu6-/+ +
nu8± - nu8±/nu7± + 2nu8±2 - nu8± with upper
states forming another Fermi dyad, and 8 subbands of the bi-parallel E-E band nu3
+ nu8± - nu8±. The anharmonic, Coriolis, and l-type interactions
which couple these upper states with each other and with the states nu7-/+ +
2nu8±2, nu4 + 3nu8±1, and nu4 + 3nu8±3 have been included in
an 18 x 18 Hamiltonian matrix whose eigenvalues model the upper levels of the
observed transitions. The values of 46 upper state spectroscopic constants and
interaction constants have been adjusted by least squares to 950 observed lines.
The results provide a reliable quantitative picture of the interacting states and
yield accurate values for the spectroscopic constants of the various states and
for the anharmonic constants x68, x68 (g68), and x38. Copyright 1997Academic
Press
PMID- 9398555
TI - Fourier Transform Far-Infrared Spectroscopy of the NH2, NHD, and ND2 Radicals
AB - The gas-phase far-infrared absorption spectra of the NH2, NHD, and ND2 radicals
have been observed in the 51-366 cm-1 region with a high-resolution Fourier
transform spectrometer. The NH2 radical was generated in a multiple-traversal
absorption cell by a dc discharge in an NH3 and Ar mixture. A discharge in an
NH3, D2, and Ar mixture was used for production of NHD and ND2. The observed
spectra with a resolved fine structure were analyzed by Watson's A-reduced
Hamiltonian including a spin-rotation interaction term. The rotational and spin
rotation constants were determined to higher order. In the same experiment of
NH2, the rotational spectrum of the NH radical was also observed. From the
rotational constants, inertia defect Delta and r0 structure were determined, as
follows, with one standard deviation in parentheses:NH2ND2r0
(A)1.0245(37)1.0239(19)theta0 (degree)103.34(51)103.33(27)Deltaobs
(amuA2)0.049561(4)0.06770(4);Dgr;calc (amuA2)0.0476530.066566 Copyright
1997Academic Press
PMID- 9398556
TI - Analysis of the 0-0 and 1-0 Bands of the A1Pi-X1Sigma+ System of the 13CD+
Radical
PMID- 9398557
TI - The Water Vapor Linestrengths between 11 600 and 12 750 cm-1
AB - The water vapor linestrengths in the region of the 3nu + delta resonance polyad
of interacting vibrational states (the corresponding upper states are (310),
(211), (112), (013), (131), (230), (032), and (051)) have been analyzed leading
to accurate dipole moment transition parameters. The effective rotational
Hamiltonian constants used to calculate the vibration-rotation wavefunctions (J.
M. Flaud, C. Camy-Peyret, A. Bykov, O. Naumenko, T. Petrova, A. Scherbakov, L.
Sinitsa, 1994. J. Mol. Spectrosc. 183, 300-309) take into account both strong
centrifugal distortion effects and dark states presence. These effects are known
to be important for the highly excited vibrational states of water-like
molecules. The input data set included the line intensities measured by Toth (R.
Toth, 1994. J. Mol. Spectrosc. 166, 176-183) and the line intensities of the weak
bands 2nu1 + 3nu2, 3nu2 + 2nu3, and 3nu1 + nu2 derived from peak absorptions of a
spectrum recorded at a pressure of 17.0 Torr and a path length of 434 m. The
parameters of the effective dipole moment operator determined by least square
fitting give a very satisfactory agreement with experimental values since the
mean error for the 876 experimental linestrengths is only 3.9%. It is worth
noticing that such an agreement could be reached only because high-order
resonance couplings with dark states were explicitly taken into account.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398558
TI - Self and Polar Foreign Gas Line Broadening and Frequency Shifting of CH3F: Effect
of the Speed Dependence Observed by Millimeter-Wave Coherent Transients
AB - The shape of the (J, K: 2, 1 <-- 1, 1) millimeter line of CH3F in collision with
polar buffer molecules has been investigated in the temperature range 140-300 K.
The experiments exploit a Stark switching coherent transient technique, namely
the optical free precession phenomenon, the Fourier transform of which is the
usual steady state absorption lineshape. Using various buffer gases (CH3Br, CH3F,
and NH3), the observed time domain signals provide the first experimental
evidence in the millimeter range that line broadenings as well as frequency
shiftings depend on the relative speed of collision partners; that is, lineshapes
can become narrowed and asymmetric according to the molecular mass ratio and the
type of collisional interaction involved. The experimental signals are analyzed
with a time domain speed-dependent Voigt profile: for the polar buffer molecules
considered, it is shown that a simultaneous interpretation of the broadening and
narrowing parameters as well as of their temperature dependence can be
satisfactorily obtained only with a realistic collision theory; in contrast with
atomic buffer gases, velocity changing collisions play a negligible role.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398559
TI - On the Spectroscopically Determined Potential Energy Surfaces for the Electronic
Ground States of NO2 and H2O
AB - Previous spectroscopically determined potentials for both H216O and NO2 are
discussed. It is shown that a recent H216O potential energy surface due to D. Xie
and G. Yan (1996. Chem. Phys. Lett. 248, 409), which was determined by fits to
vibrational term values alone and was claimed to be more accurate than other
published spectroscopically determined potentials for this system, actually gives
unacceptably poor results for rotationally excited water. Reasons for this
failure are discussed and the dangers of relying on vibrational term values alone
are emphasized. Previous spectroscopic potentials for ground state NO2 are all
found to have problems with unphysical minima ("holes"). Starting from the
potential energy surface for the ground (&Xtilde;2A1) electronic state of NO2
constructed by S. A. Tashkun and P. Jensen (1994. J. Mol. Spectrosc. 165, 173)
using the approximate MORBID approach a suitable starting point for fits using an
exact kinetic energy operator approach was constructed. Least-squares fits to 17
potential parameters gives a potential which reproduces 173 vibrational term
values with a standard deviation of only 2.8 cm-1 in the low-energy region (<10
000 cm-1). For many even levels below, and all levels above, approximately 10 000
cm-1 the first excited electronic state (Ã2B2) perturbs the vibrational
energy levels of the ground state. We were unable to fit these levels. Tests show
that the resulting effective potential surface has no problems with unphysical
holes and gives a reasonable representation of the rotational structure of the
low-lying vibrational states of NO2. Copyright 1997 Academic Press. Copyright
1997Academic Press
PMID- 9398560
TI - Absolute Wavenumbers and Self-Induced Pressure Lineshift Coefficients for the 3-0
Vibration-Rotation Band of 12C16O
AB - The absolute wavenumbers for 36 lines of the 3-0 band of 12C16O are measured from
P(17) at 6271 cm-1 to R(19) at 6405 cm-1, with an uncertainty of about +/-3 x 10(
5) cm-1 (about +/-1 MHz). The experimental positions are compared with the best
predicted positions from recent Dunham coefficients. Self-induced pressure
lineshifts are determined and reach, at most, about -8 x 10(-3) cm-1 atm-1.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398561
TI - Electronic States of Scandium Monoiodide
AB - The many electronic transitions observed in high-resolution spectra of the
fluorescence of scandium monoiodide following excitation by Ar+ and Kr+ laser
lines have been extensively analyzed. Equilibrium vibrational and rotational
constants are obtained for the six lowest electronic states. Spin-orbit constants
in a3Delta and b3Pi are also determined. The laser-excited levels are regrouped
into two electronic states, of 1Pi and 3Pi symmetries, for which molecular
constants are derived. Copyright 1997 Academic Press. Copyright 1997Academic
Press
PMID- 9398562
TI - Effective Reduction of Wavenumbers of Rotational and Vibration-Rotational
Transitions of LiH X1Sigma+
AB - A deformationally self-consistent procedure is applied to reduce the wavenumbers
of 594 pure rotational and vibration-rotational transitions of 7Li1H, 6Li1H,
7Li2H, and 6Li2H to 15 unconstrained and 2 constrained parameters with sigma; =
1.098, sigma = 0.000554 cm-1, and F = 7.704 x 10(14). The quality of the Born
Oppenheimer approximation and the extent of its breakdown in LiH are reexamined.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398563
TI - On the Speed-Dependent Hard Collision Lineshape Models: Application to C2H2
Perturbed by Xe
AB - Three infrared absorption lines of the nu5 band of C2H2 diluted by Xe at
pressures ranging from 40 to 300 mbar have been recorded at high resolution near
750 cm-1, using a tunable diode-laser spectrometer. Their lineshapes have been
first analyzed by means of models using either the Dicke narrowing effect or the
absorber speed-dependent collisional broadening and shifting. None of these
models have given satisfactory results over the full pressure range of the
perturber. It is shown that a correct treatment must include both line narrowing
effects. We have investigated two possibilities of doing so: a convolution
between two profiles corresponding to each effect and a noncorrelated and speed
dependent Rautian profile that we have developed here. The latter lineshape model
appears to be the most appropriate. Copyright 1997 Academic Press. Copyright
1997Academic Press
PMID- 9398564
TI - Coriolis Interactions in the nu2, nu4a, nu4b, and nu3a States of Phosphine-d1
AB - Spectra of the nu4a (HPH bend) and nu4b (HPD bend) bands of the PH2D molecule
have been recorded and analyzed. The Coriolis interactions between the two states
as well as the various Coriolis interactions of the nu4a and nu4b states with the
nu2 state have been included in the analysis. Several new assignments of
transitions which occur with enhanced intensity in the nu2 band also have been
made. The parameters of the nu4a and nu4b states, improved parameters of the nu2
state, and the interaction parameters have been determined. The data on the nu3a
band of PH2D have been reanalyzed by taking into account the b-axis Coriolis
interaction of the nu3a state with the 2nu2 state. Copyright 1997 Academic Press.
Copyright 1997Academic Press
PMID- 9398565
TI - A Potential Energy Surface for the Electronic Ground State of H2Te Derived from
Experiment
AB - We report here the determination of a new potential energy surface for the
electronic ground state of the H2Te molecule by fitting to an extensive set of
very recent experimental spectroscopic data (see J.-M. Flaud, P. Arcas, H.
Burger, O. Polanz, and L. Halonen, J. Mol. Spectrosc. 183, 310-335 (1997), and
references therein) by means of the MORBID (Morse Oscillator Rigid Bender
Internal Dynamics) computer program. The fitting to all 1111 input data
(involving rotation-vibrational states with J = 10) had a standard deviation of
0.18 cm-1 and was obtained by varying 14 parameters. With the new potential
energy function, the rotation-vibration energies of H2130Te have been calculated
with the MORBID program. In particular, we have calculated the rotational energy
manifolds for J = 40 in the lowest vibrational states. Compared to previous
potential energy functions for H2Te, the new function has substantially improved
the reproduction of the rotational spacings in the excited vibrational states. An
important aim of the present work is the further characterization of the
anomalous "fourfold cluster effect" (i.e., the formation of four-member groups of
nearly degenerate rotation-vibration energies at high rotational excitation)
exhibited by the energy levels of H2Te. Comparison of our theoretical results
with the experimental results of J.-M. Flaud, M. Betrencourt, P. Arcas, H.
Burger, O. Polanz, and W. J. Lafferty (1997, J. Mol. Spectrosc. 182, 396-420)
provides conclusive evidence for the existence of so-called Type II clusters
(clusters formed by coalescence of two energy doublets belonging to two different
vibrational states) in the nu1/nu3 vibrational states of H2130Te. Copyright 1997
Academic Press. Copyright 1997Academic Press
PMID- 9398566
TI - Far-Infrared Rotational Spectra of ZnH and ZnD in the X2Sigma+ (v = 0) State
AB - Several rotational transitions of zinc hydride and deuteride within the v = 0
level of the X2Sigma+ state have been measured in both electron spin components
over the ranges N" = 2 to 10 for ZnH and N" = 9 to 21 for ZnD. A least-squares
fit to these data in combination with low-N microwave data measured by other
workers has resulted in improved values of the rotational, fine, and hyperfine
structure constants. The values of the proton hyperfine constants are discussed
in the context of a molecular orbital analysis of zinc hydride. Copyright 1997
Academic Press. Copyright 1997Academic Press
PMID- 9398567
TI - High-Resolution FTIR and Photoacoustic Overtone Spectrum of HCCI
AB - The first and second C-H overtone vibration-rotation absorption spectra of
monoiodoacetylene (HCCI) have been recorded using an FTIR spectrometer with an
instrument resolution of about 0.005 cm-1 (0.9/MOPD). The third overtone spectrum
has been obtained using a titanium:sapphire ring laser spectrometer with a
spectral resolution of about 0.02 cm-1. Due to anharmonic resonances like Fermi
and Darling-Dennison resonances, accompanying bands can be observed close to the
main overtone band. All the observed bands have been rotationally analyzed.
Published vibrational data together with present results are used in a model
which includes anharmonic resonances. Vibrational assignments of the observed
bands are based on this calculation. The agreement between calculated and
observed energy levels is good considering the amount of data available.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398568
TI - High-Resolution Study of the A2A' --> X2A" Transition of HO2: Analysis of the 000
000 Band
AB - The near-infrared emission spectrum of the A2A' --> X2A" transition of the
hydroperoxyl radical, HO2, has been studied by Fourier transform spectrometry.
The 000 --> 000 band has been recorded at high spectral resolution. DeltaKa = +/
1 subbands up to Ka' = 9 --> Ka" = 8 and Ka' = 8 --> Ka" = 9 comprising lines
from rotational levels up to N' = 32 have been observed. With about a factor of
10 lower intensity, DeltaKa = 0 subbands 0-0 to 6-6 were found which are shown to
be due to magnetic dipole transitions. In addition, in the 2-2 sub-band
"forbidden" electric dipole lines were observed. These likely are induced by
Renner-Teller interaction. Local perturbations extending over 3-10 N' values are
found in the Ka' = 0-7 levels of the A2A' state. One series of perturbations is
attributed to DeltaKa = 0, DeltaJ = 0 interactions with the 112 level of the X2A"
ground state. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398569
TI - Investigation of C-O Stretching Band of CD3OH: Assignments of Far-Infrared Laser
Lines
AB - We have investigated the high-resolution Fourier transform spectrum of the C-O
stretching fundamental band of CD3OH in order to assign far-infrared (FIR) laser
transitions. The absorption spectrum was analyzed by means of the "Ritz" program,
which calculates the energy level values directly from the Rydberg-Ritz
combination principle. We have also used the "LaseRitz" program to facilitate the
assignment of the FIR laser lines. As a consequence we could determine 12 new
assignments, confirming 4 previously proposed ones and predicting new FIR laser
emissions. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398570
TI - Near-Infrared Diode Laser Spectroscopy of the Nitrogen Molecule in Rydberg State:
Analysis of the c1Piu - a"1Sigmag+, v = 1-0 Band
AB - A new singlet-singlet absorption band between Rydberg states of the nitrogen
molecule was studied by near-infrared diode laser spectroscopy in the 1.3 &mgr;m
region. An analysis was made for the band to establish line assignments and
determine molecular parameters for both the lower and the upper vibronic states.
As a result of the analysis, this band was assigned to the c1Piu-a"1Sigmag+, v =
1-0 band. The anomaly of the Lambda-type doubling structure in the c1Piu (v = 1)
state was discussed in connection with the interaction with the b'1Sigmau+ (v =
4) state. The predissociation in the c1Piu (v = 1) state was also discussed
relating with the line broadening observed. Copyright 1997 Academic Press.
Copyright 1997Academic Press
PMID- 9398571
TI - The 3nu1 + nu2 Combination Band of HOCl: Assignments, Perturbations, and Line
Intensities
AB - The high-resolution spectra (0.012 cm-1) of the 3nu1 + nu2 combination band of
hypochlorous acid HO35(37)Cl in the near infrared ( approximately 11 478 cm-1)
have been measured using a titanium:sapphire intracavity laser absorption (ICLA)
spectrometer. Line assignments, absolute intensities, and the total band
intensity for both isotopomers are reported. In the course of the band analysis
two Ka branches (Ka = 2,3) were found to be perturbed via low-order Fermi-type
(anharmonic) resonances by a dark perturber which has been identified to be the
2nu1 + 2nu2 + 3nu3 state. The data are compared with intensity predictions from
simple empirical models and discussed with regard to detection limits for this
molecule in the near infrared spectral region of the atmosphere. Copyright 1997
Academic Press. Copyright 1997Academic Press
PMID- 9398572
TI - Lambda-Splittings and Line Intensities in the First Overtone of Nitric Oxide
AB - Using Fourier transform spectra, absolute line parameters (positions, Lambda
splittings, and intensities) have been measured in the two allowed subbands
2Pi1/2-2Pi1/2 and 2Pi3/2-2Pi3/2 of the 2 <-- 0 vibrational band of the 14N16O
molecule. These line parameters have been compared with previous experimental
results and with the values available in the current HITRAN database. The
measured line intensities led to the determination of the transition dipole
moment as well as the Herman-Wallis coefficients. Improved spectroscopic
constants were also obtained for the v = 2 vibrational state. Copyright 1997
Academic Press. Copyright 1997Academic Press
PMID- 9398573
TI - Intensity Measurements of Deltal > 1 Transitions of Several Isotopomers of HCN
AB - The intensities of the forbidden Q-branch transitions 02(2f)0-00(0)0, 12(2f)0
00(0)0, and 02(2f)1-00(0)0 for HCN have been measured. The intensities of the
02(2f)0-00(0)0 transitions of DCN, D13C15N, and H12C15N were also measured, as
well as the 02(2f)1-00(0)0 transitions of H12C15N and H13C15N. These Q-branch
transitions are forbidden even when the effects of l-type resonance are
considered so they must get their intensity from some other Coriolis
interactions. The much stronger P- and R-branch lines for the e levels of these
same vibrational transitions were also measured and they are shown to get most of
their intensity from l-type resonance. However, the same Coriolis resonance that
gives intensity to the Q-branch transitions seems to affect the DeltaJ =
±1 transitions as shown by the difference in the intensities of the DeltaJ
= +1 and DeltaJ = -1 transitions. Measurements of the intensity of the 03(3e)0
00(0)0 and 03(3f)0-00(0)0 transitions shows that they derive most, but perhaps
not all, of their intensity from l-type resonance. An unsuccessful search for
forbidden DeltaJ = 0, e-e transitions for the strong 10(0)0-00(0)0 band shows
that there is no detectable mixing of the e and f levels. Copyright 1997 Academic
Press. Copyright 1997Academic Press
PMID- 9398574
TI - Nitrogen Broadening of Absorption Lines in the nu1, nu2, and nu3 Bands of H2S
Determined by Applying an IR Diode Laser Spectrometer
AB - With an infrared diode laser spectrometer in pulse mode we studied the N2
broadening of H2S absorption lines in the nu1, nu2, and nu3 bands. Altogether 22
lines were investigated: 16 lines from the R branch of the nu1 band (3 = J" =
17, 0 = Ka" = 6), 5 lines from the R branch of the nu3 band (3 = J" = 7,
1 = Ka" = 7), and one line from the R branch of the nu2 band (J" = 4, Ka" =
3). The nitrogen broadening coefficients varies strongly between 0.028 cm-1/atm
= gammaH2S-N2 = 0.109 cm-1/atm. We observed a pronounced J" dependence in the
studied quantum number range; i.e., with increasing J" there is a decrease of the
broadening coefficient gammaH2S-N2. In contrast the Ka" dependence shows only a
weak tendency. For gammaH2S-N2 of the nu1, nu2, and nu3 bands there is no
significant difference between lines with comparable rotational quantum numbers.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398575
TI - Millimeter-Wave Absorption Free Jet Spectrum, Barriers to Internal Rotation, and
Torsional Relaxation in p-Anisaldehyde
AB - The rotational spectrum of p-anisaldehyde in a supersonic expansion has been
investigated in the frequency range 60-78 GHz. Transitions up to J = 57 measured
for the anti and syn conformers have been used to determine complete sets of
fourth-order centrifugal distortion constants. Methyl group internal rotation
splittings have also been observed for some of the lines and have yielded the
respective barriers for both conformers. A vibrational satellite observed for
each of the two conformers has been assigned to the respective first excited
methoxy torsional state. The jet conditions, in particular the stagnation
pressure of the carrier gas, can be adjusted to control the degree of cooling
achieved in the expansion. This possibility has been exploited in the present
work to enhance the intensities of the observed vibrational satellites. Applying
a two-dimensional flexible model to the methoxyl and aldehydic groups torsions,
the potential energy and structural deformation parameters transferred from
anisole and benzaldehyde have been found to be suitable to describe these motions
in p-anisaldehyde. Mixing of anti and syn conformations has been found to be
insignificant within the first 82 calculated torsional eigenstates and therefore
less likely to explain the intermediate bands observed in the low-resolution
microwave spectrum than the internal vibrational relaxation suggested by R. K.
Bohn, M. S. Farag, C. M. Ott, J. Radhakrishnan, S. A. Sorenson, and N. S. True
(1992, J. Mol. Struct. 268, 107-121). A qualitative discussion of relaxation
among the torsional states and its effect on the rotational spectrum is given.
Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398576
TI - High-Resolution Infrared Spectrum of D3Si79Br in the nu1/nu4 Region: The
Structure of Silyl Bromide
AB - FTIR spectra of monoisotopic D3Si79Br covering the bands nu1 (a1, 1580.637 cm-1)
and nu4 (e, 1615.085 cm-1) have been recorded with a resolution of 3 x 10(-3) cm
1. The rovibrational analysis revealed severe perturbations of the -5 = KDeltaK
= 4 series of nu4 while nu1 and the high-K subbands of nu4 are almost
unperturbed and served to determine the parameters of the v1 = 1 and v4 = 1
states, with sigma(Fit) ca. 5 x 10(-4) cm-1. Equilibrium rotational constants of
H3Si79Br and D3Si79Br were deduced with the help of the vibrational corrections
alphai. The r0, rs, rmrho, and re structures of silyl bromide have been
determined. The experimental values of the HSiH angle and of the Si-H distance
are found in excellent agreement with their ab initio predictions. The re
structure is re(Si-H) = 1.470(2) A, re(Si-Br) = 2.207(1) A, and alphae(HSiH) =
110.5(2)degrees. Copyright 1997 Academic Press. Copyright 1997Academic Press
PMID- 9398577
TI - Can Isotopic Substitution Change a Bright State into a Dark State? The Case of
the v3 = 1 State of FClO3
AB - High-resolution infrared spectra of monoisotopic samples of F35Cl18O3 and
F37Cl18O3 have been recorded with the purpose of analyzing the nu3 fundamental at
535 cm-1. However, this band could not be observed whereas it had been seen and
studied earlier in F35Cl16O3. To determine the parameters of the v3 = 1 state,
indirect methods were used. Hot bands nun + nu3 - nu3 (n = 1 or 2) were first
analyzed and their LSCD (Lower State Combination Differences) yielded rotational
parameters of nu3. Then, with the help of nu1 + nu3, all rovibrational parameters
of nu3 were obtained. Similar methods were applied to spectra of F35Cl16O3 and
F37Cl16O3 to prove that the parameters of nu3 obtained in this fashion are
identical to those determined directly for these isotopomers and are even more
comprehensive. It is shown that the different character of nu3 in the two 18O and
in the two 16O isotopomers is due to the fact that the former are much closer to
a spherical top molecule ((A0 - B0)/A0 = 0.015). This is not only reflected in
intensities different by two orders of magnitude but also in the very different
values of alpha3B in these two pairs. Copyright 1997 Academic Press. Copyright
1997Academic Press
PMID- 9398578
TI - Prediction of 11B Quadrupole Coupling Constants in Molecules
AB - The B3LYP/6-31G(df, p) model is shown to be a viable alternative to the
computationally demanding MP2/6-311G(3df, 3pd) model for the prediction of 11B
nuclear quadrupole coupling constants in molecules. Using eQ/h as a best fit
parameter, coupling constants calculated with the B3LYP model show a root mean
square (rms) deviation of 0.059 MHz from the experimental values for 11
molecules; those calculated with the MP2 model, 0.049 MHz. Comparison of coupling
constants predicted by the two models for a sample size increased to 25 molecules
yields a rms difference between models of 0.036 MHz. Copyright 1997 Academic
Press. Copyright 1997Academic Press
PMID- 9398579
TI - Infrared Spectrum of Ozone in the 4600 and 5300 cm-1 Regions: High Order
Accidental Resonances through the Analysis of nu1 + 2nu2 + 3nu3 - nu2, nu1 + 2nu2
+ 3nu3, and 4nu1 + nu3 Bands
AB - The very weak bands nu1 + 2nu2 + 3nu3 and 4nu1 + nu3 of 16O3 have been observed
for the first time, using the Fourier transform spectrometer (FTS) of Reims and
the usual experimental setup providing a large product p x l of approximately 38
Torr x 36 m. The upper levels of these A-type bands which are rather close in
energy (they appear respectively at 5291.722 and 5307.790 cm-1) belong to two
different sets of interacting polyads. To correctly reproduce the rotation
vibration energy levels and account for the observed perturbations, both bands
are treated in a dyad approximation: the (123) state in the Coriolis resonance
with the (330) state, and the (401) state in the Coriolis resonance with the
(024) state. The assignments of the rotation-vibration levels of the (123) state
are confirmed by measurements of line positions of the hot band nu1 + 2nu2 + 3nu3
- nu2 which has also been observed for the first time. The fits are very
satisfactory: the r.m.s. deviation for 249 energy levels of the (123) state is
2.4 x 10(-3) cm-1 and is 2.0 x 10(-3) cm-1 for 266 levels of the (401) state.
These r.m.s. are near experimental accuracy. Transition moments for the three
observed bands are determined from measured line intensities. Copyright 1997
Academic Press. Copyright 1997Academic Press
PMID- 9398580
TI - Dunham Series Coefficients up to 20th Order
PMID- 9398581
TI - The AuH AO+ --> X1 summation operator+ System
PMID- 9398583
TI - LETTER TO THE EDITOR
PMID- 9398582
TI - LETTER TO THE EDITOR
PMID- 9398584
TI - Reliability, distribution, and validity of age-related cognitive deficits in the
Morris water maze.
AB - In the present study, F-344 rats throughout 1.5 to 26 months of age were tested
in the reference memory version, a moving-platform repeated acquisition version,
and in a cued platform version of the Morris water maze. The results suggest
that: (1) performance in the water maze declines continuously, beginning at the
earliest age, and very closely fits a linear function; (2) there are robust,
reliable differences between individuals in terms of their performance in the
Morris water maze, but chronological age accounts for only a fraction of the
variance between individuals; (3) there is no evidence of a bimodal distribution
among aged rats--there is no distinct subgroup of individuals that performs so
poorly that they are qualitatively different from the majority of the population,
and distinctions between "impaired" and "unimpaired" subjects must be based on
arbitrary criteria that may not be consistent from one study to the next; (4) age
related deficits in the Morris water maze may not be restricted to learning and
memory, but may also include deficits in attention, the ability to process
spatial information, and/or the ability to develop efficient spatial search
strategies; and (5) swim distance is the most appropriate measure of cognitive
function in the Morris water maze, but the relationship between this measure and
other measures of noncognitive function make it clear that swim distance may not
be a pure measure of cognitive function. Although the Morris water maze remains a
valuable preclinical test with better validity and specificity than many other
behavioral tests, measures of performance in the Morris water maze should not be
considered synonymous with cognitive function.
PMID- 9398585
TI - Epinephrine effects on memory are not dependent on hepatic glucose release.
AB - Epinephrine released or administered soon after a given training task modulates
memory processes. Since epinephrine does not readily cross the blood-brain
barrier, studies have suggested that some of the central effects of epinephrine
might be mediated by peripheral release of glucose. These experiments examined
the involvement of blood glucose levels in the posttraining effects of
peripherally administered epinephrine. The effects of the administration of
epinephrine (25 and 625 microg/kg) [corrected] on memory of an inhibitory
avoidance task were evaluated in fed and fasted rats (depleted glycogen stores in
liver). Blood glucose levels after the task in each group were also measured.
Female Wistar rats were divided in two groups. Fed and 48-h-fasted animals were
submitted to the inhibitory avoidance task and received i.p. epinephrine or
saline immediately after training. The test session was carried out 48 h after
training. Epinephrine (25 or 625 microg/kg) [corrected] caused an increased
glycemia in fed rats, but no effect was observed in fasted animals.
Administration of epinephrine 25 microg/kg [corrected] induced a facilitation of
memory, while epinephrine 625 microg/kg [corrected] impaired retention (either in
fasted or in fed animals). There was no relation between increased glycemia
induced by epinephrine and its effects on memory, since this drug presented its
classical effects independently of the previous state of the animal (fed or
fasted). The results of the present study suggest that the effects of systemic
released or administered epinephrine on memory processes are not dependent on
hepatic glucose release.
PMID- 9398586
TI - Effects of dark rearing and light exposure on memory for a passive avoidance task
in day-old chicks.
AB - Light exposure during embryogenesis is necessary for functional and morphological
maturation in the domestic chick. In the present study, dark incubation was
demonstrated to induce a weak amnestic effect on retention for a passive
avoidance task and a diminution in discriminative memory ability in day-old
chicks. Putative explanations based on possible motor, attentional, or visual
impairment were excluded. Light exposure of dark-reared eggs, specifically during
embryonic days E19 to E20, alleviated the retention and discrimination deficits.
The processes which might mediate between prehatch light stimulation and
posthatch behavioral effects are discussed.
PMID- 9398587
TI - Rotation of water in the Morris water maze interferes with path integration
mechanisms of place navigation.
AB - The idea that place navigation in the Morris water maze is implemented by path
integration between locations determined by landmark sighting was investigated in
a 200-cm-diameter pool in which circular (7.2 degrees/s) motion of water could be
induced by tangentially arranged water jets. The rats were trained at 8 trials
per day to navigate to an erectable platform which was raised after the rat had
spent a criterion time in the target annulus (30 cm in diameter) in the midpoint
of the NW quadrant. Asymptotic escape latency of 7 s was reached after 9 days in
moving water (n = 8) and after 6 days in stationary water (n = 8). The group
overtrained for 13 days in stable water performed well even after it was
transferred to moving water. Changing the sense of rotation of water from
counterclockwise to clockwise did not affect the asymptotic performance. The
above findings show that overtrained rats rely on landmark sighting rather than
on path integration. The influence of water movement reappeared when place
navigation to a new target (SW) was examined in alternating 2-s periods of light
(L) and darkness (D). On the first day, the latencies were 15.2 +/- 1.2 and 22.8
+/- 1.9 s in stable and moving water, respectively, but dropped to 10 s on the
following day. The tracks generated in the L period were more tortuous than those
generated in the D period and this difference was more pronounced in moving than
in stable water. It is concluded that path integration mechanisms supporting
navigation during intervals of darkness are impaired in moving water but that
this impairment disappears in overtrained animals.
PMID- 9398588
TI - Intracerebroventricular infusion of the NMDA receptor-associated glycine site
antagonist 7-chlorokynurenate impairs water maze performance but fails to block
hippocampal long-term potentiation in vivo.
AB - Most previous studies investigating the relationship between N-methyl-D-aspartate
receptor-dependent synaptic plasticity and learning have employed drugs that
either compete with glutamate for access to the primary agonist binding site
(e.g., D-2-amino-5-phosphopentanoic acid) or block the associated ion channel
(e.g., dizocilpine). This study targeted the glycine receptor site located on the
NMDA receptor complex. Chronic intracerebroventricular infusion of the glycine
site antagonist 7-chlorokynurenate (7CK; 75 mM, 0.5 microliter/h, icv, for up to
14 days) impaired performance of male Lister hooded rats during acquisition of a
spatial reference memory task in the water maze. In addition, however, these
animals showed sensorimotor deficits, including a prolonged righting reflex,
ataxia, and difficulty in staying on the escape platform. On completion of
behavioral testing, the rats were anesthetized with urethane and an attempt was
made to induce LTP in the hippocampus ipsilateral to the infusion cannula. Both
control and 7CK-infused animals displayed equivalent long-term potentiation (LTP)
60 min posttetanus. A novel analytical technique for assaying drug tissue levels
involving high-performance liquid chromotography with fluorescence detection
revealed that tissue levels of 7CK in hippocampus were extremely low and unlikely
to be sufficient to affect LTP, as observed. These findings neither support nor
compromise the LTP/learning hypothesis, but they illustrate some of the problems
of using drugs to elucidate the neurobiological mechanisms of learning and memory
and the importance of a within-subjects design incorporating behavioral,
physiological, and biochemical measures.
PMID- 9398589
TI - Synelfin regulation during the critical period for song learning in normal and
isolated juvenile zebra finches.
AB - Male zebra finches (Taeniopygia guttata) learn to sing during a critical period
in adolescence. We previously described a presynaptic protein, synelfin, whose
mRNA is increased early in this critical period in a brain nucleus specifically
implicated in song learning, lateral MAN (lMAN). In the current study, in situ
hybridization was used to map this change in gene expression to the subregion of
lMAN that projects to the robust nucleus of the archistriatum (RA), the principal
motor output of the telencephalic circuit that controls song production. Using
confocal immunofluorescence microscopy, we detected numerous puncta of synelfin
immunoreactivity that apparently represent presynaptic terminals from lMAN in the
RA of young males. Synelfin immunoreactivity in RA declined abruptly between 40
and 45 days of age, a time of major synaptic reorganization in RA. This change
did not occur until about 10 days after the decline in synelfin mRNA in cell
bodies within lMAN, indicating a relatively slow turnover of the protein in
presynaptic terminals and suggesting that some of the functional changes that
occur during the critical period may arise from regulatory decisions that were
initiated a week or more earlier. Depriving birds of tutoring did not halt or
delay the decline of synelfin mRNA in lMAN. This change in gene expression must
not be a consequence of early song learning, but may reflect an innate or
programmed step in song circuit development.
PMID- 9398590
TI - Memory formation: the sequence of biochemical events in the hippocampus and its
connection to activity in other brain structures.
AB - Recent data have demonstrated a biochemical sequence of events in the rat
hippocampus that is necessary for memory formation of inhibitory avoidance
behavior. The sequence initially involves the activation of three different types
of glutamate receptors followed by changes in second messengers and biochemical
cascades led by enhanced activity of protein kinases A, C, and G and calcium
calmodulin protein kinase II, followed by changes in glutamate receptor subunits
and binding properties and increased expression of constitutive and inducible
transcription factors. The biochemical events are regulated early after training
by hormonal and neurohumoral mechanisms related to alertness, anxiety, and
stress, and 3-6 h after training by pathways related to mood and affect. The
early modulation is mediated locally by GABAergic, cholinergic, and noradrenergic
synapses and by putative retrograde synaptic messengers, and extrinsically by the
amygdala and possibly the medial septum, which handle emotional components of
memories and are direct or indirect sites of action for several hormones and
neurotransmitters. The late modulation relies on dopamine D1, beta-noradrenergic,
and 5HT1A receptors in the hippocampus and dopaminergic, noradrenergic, and
serotoninergic pathways. Evidence indicates that hippocampal activity mediated by
glutamate AMPA receptors must persist during at least 3 h after training in order
for memories to be consolidated. Probably, this activity is transmitted to other
areas, including the source of the dopaminergic, noradrenergic, and
serotoninergic pathways, and the entorhinal and posterior parietal cortex. The
entorhinal and posterior parietal cortex participate in memory consolidation
minutes after the hippocampal chain of events starts, in both cases through
glutamate NMDA receptor-mediated processes, and their intervention is necessary
in order to complete memory consolidation. The hippocampus, amygdala, entorhinal
cortex, and parietal cortex are involved in retrieval in the first few days after
training; at 30 days from training only the entorhinal and parietal cortex are
involved, and at 60 days only the parietal cortex is necessary for retrieval.
Based on observations on other forms of hippocampal plasticity and on memory
formation in the chick brain, it is suggested that the hippocampal chain of
events that underlies memory formation is linked to long-term storage elsewhere
through activity-dependent changes in cell connectivity.
PMID- 9398591
TI - 2-Deoxy-D-galactose effects on passive avoidance memorization in the rat.
AB - 2-Deoxy-D-galactose (do-gal) hinders glycoprotein fucosylation. This compound was
intracerebroventricularly administered to male adult Wistar rats in order to
assess whether it could exert amnesic effects on a passive avoidance response
(PAR) to be learned in the light-dark box apparatus. Three experiments were
performed. In the first, do-gal was administered immediately after the
acquisition trials at three dosages (2, 4, and 8 mumol). It was found that only
the 4-mumol dosage was followed by PAR disruption. In the second, do-gal was
administered at the adequate dosage (4 mumol) either 30 min before the
acquisition trial or 30 min before retrieval testing. It was found that only the
preretrieval administration was followed by PAR impairment. In the third, do-gal
(4 mumol) was administered in postacquisition, at increasing postacquisition
delays (0.25, 1.5, 4, and 6 h). It was found that there was PAR disruption only
after do-gal administration at the shortest (0.25 h) delay. The results confirm
that in the rat, glycoprotein fucosylation is involved in some of the phases of
memory trace processing, and they are discussed in relation to other findings in
the rat and the chick.
PMID- 9398592
TI - A brain of her own: a neural correlate of song assessment in a female songbird.
AB - The song control region in the avian forebrain is a series of discrete,
interconnected nuclei mediating song learning and production. It has been studied
in males or in species where both sexes sing. Little is known about the neural
correlates of song perception in nonsinging females, often the intended
recipients of song. We studied cowbirds (Molothrus ater), a species in which only
males sing but in which females discriminate between males on the basis of song.
We focused on nucleus lMAN because it has been implicated in early song
acquisition, a stage relevant to both sexes to choose among competing acoustic
models. We found that volume of lMAN was monomorphic in cowbirds. Moreover, the
volume and neuronal number of female lMAN were positively correlated with
selectivity of copulatory responding. The results provide strong evidence of
nonsinging female's use of "song" control nuclei for song perception without the
possibility of song production.
PMID- 9398593
TI - Arecoline via miniosmotic pump improves AF64A-impaired radial maze performance in
rats: a possible model of Alzheimer's disease.
AB - Male Sprague-Dawley rats, preoperatively trained in a 1-h delay non-match-to
position radial maze task, received bilateral stereotaxic injections of a
selective cholinotoxin, ethylcholine aziridinium ion (AF64A: 3 nmol/3
microliters/lateral ventricle). Animals treated with AF64A made significantly
more total postdelay errors than vehicle controls. Sustained delivery, via
miniosmotic pumps, of arecoline (0.1, 0.3, 1, 3, 10, or 30 mg/kg/day sc for 14
days) attenuated the AF64A-induced cognitive impairment in a dose-dependent
manner, producing an inverted U-shaped dose-response function which was optimal
at 1.0 mg/kg/day. Following these studies, choline acetyltransferase activity was
significantly reduced in hippocampi extracted from the AF64A-treated rats,
indicating successful cholinotoxicity. This paradigm may be useful as a possible
screen for potential Alzheimer's disease therapeutic agents. This conclusion is
supported by published reports of beneficial arecoline effects observed following
2-week intravenous infusions in patients with Alzheimer's disease (Soncrant,
Raffaele, Asthana, Berardi, Morris, & Haxby, 1993).
PMID- 9398594
TI - Long-term enhancement but not short-term in Hermissenda is dependent upon mRNA
synthesis.
AB - The reversible transcription inhibitor 5,6-dichloro-1-beta-D-ribobenzimidazole
(DRB) was used to examine the contribution of mRNA synthesis to long-term
enhancement (LTE) following one-trial conditioning of Hermissenda. Inhibition of
mRNA synthesis by DRB or inhibition of protein synthesis by anisomycin did not
significantly affect the induction and maintenance of short-term enhancement
(STE) examined 1 h after one-trial conditioning. In contrast to the absence of an
effect of the inhibitors on STE, LTE was blocked by DRB or anisomycin applied
shortly before and during the presentation of the conditioning trial. Consistent
with previous reports, animals that received an unpaired CS and US did not
exhibit LTE. In addition, a control group that received a concentration of DRB
(10(-7) M) that does not significantly affect mRNA synthesis exhibited typical
LTE when tested 24 h postconditioning. These results demonstrate that the
induction of LTE produced by one-trial conditioning is dependent upon
transcription and the regulation of gene expression.
PMID- 9398595
TI - Biochemical and Genetic Tests for Inhibitors of Leishmania Pteridine Pathways
AB - The study of antifolate-resistant mutants of the protozoan parasite Leishmania
has provided useful information about genetic processes such as gene
amplification and mutation and knowledge of the unique features of the pteridine
metabolic pathway in this primitive eukaryote. The novel bifunctional
dihydrofolate reductase-thymidylate synthase (DHFR-TS) is an essential enzyme,
yet most DHFR-TS inhibitors show little promise as potential drugs. Leishmania
possess a novel alternative pteridine reductase (PTR1) which is relatively
insensitive to methotrexate. We have proposed that the ability of PTR1 to serve
as a metabolic bypass and thus modulate drug inhibition of DHFR-TS activity may
be responsible for the poor efficacy of many antifolates. In this work, we have
sought inhibitors of L. major PTR1 from a collection of 74 compounds. The most
potent inhibitors were also tested against L. major DHFR-TS and human DHFR and
several compounds showing good activity for PTR1 alone, or for all three
reductases, were identified. The activity of these compounds was tested against
wild-type promastigotes, and those which were potent inhibitors of both PTR1 and
DHFR-TS (but not those active against only PTR1) showed good potencies. Growth
inhibition tests of L. major mutants, lacking PTR1 or DHFR-TS (ptr1(-) and dhfr
ts- knockouts) or overexpressing PTR1, were used as a "genetic screen" to assess
whether these two pteridine reductases were targets in vivo. Remarkably, only one
compound showed a methotrexate-like pattern of inhibition. Six compounds showed
good inhibition of Leishmania growth regardless of PTR1 or DHFR-TS levels. These
findings suggest that Leishmania cells contain multiple targets for a diverse set
of antifolates, with one or more significant targets in addition to DHFR-TS and
PTR1. This emphasizes the necessity of combined biochemical and genetic screens
in efforts to rationally design chemotherapeutic strategies in Leishmania.
Copyright 1997 Academic Press. Copyright 1997 Academic Press
PMID- 9398596
TI - Tyrosine kinase signaling at fertilization.
AB - The unfertilized egg is a highly differentiated cell that retains unlimited
developmental potential. The execution of that potential requires signal
transduction pathways that release the egg from its quiescent metabolic state,
direct the union of the maternal and paternal genome, and initiate a
developmental program that will guide embryogenesis. The egg is equipped with an
array of cytosolic as well as cell surface receptor protein tyrosine kinases as
part of a preassembled signal transduction mechanism. These protein tyrosine
kinases have been found to act at several points during this egg activation
process, beginning as early as the initial sperm-egg interaction. While many of
these kinase functions are common to all cells, several functions unique to
fertilization demonstrate the versatility of this class of protein kinases.
PMID- 9398598
TI - Expression, purification, and characterization of a murine CD4 fragment
containing the first two N-terminal domains.
AB - CD4 is a membrane glycoprotein on T lymphocytes that binds to the same
peptide:major histocompatibility complex (MHC) class II molecules recognized by
the antigen-specific T cell receptor (TcR). Recent evidence supports the
importance of coaggregation of CD4 and TcR for effective T cell activation. Here,
we report that a transfected Chinese hamster ovary (CHO) cell line expressing a
murine CD4 fragment containing the first two N-terminal domains secretes both
monomeric molecules and disulfide-linked multimers. Elimination of the predicted
N-linked glycosylation site at residue 161 that is next to the fourth cysteine
does not affect the formation of interchain disulfide bonds. N-Terminal amino
acid sequencing of the purified CD4 fragment demonstrates that the leader signal
sequence is properly cleaved off the expressed protein. Circular dichroism
studies suggest that both monomeric and disulfide-linked proteins are folded as
primarily beta-sheet.
PMID- 9398597
TI - Transcriptional analysis of the threonine dehydrogenase gene of Xanthomonas
campestris.
AB - The nucleotide sequence has previously been determined for the Xanthomonas
campestris pv. campestris gene coding for threonine dehydrogenase (tdh). Flanking
this gene are the upstream region possessing promoter activity and the downstream
perfect inverted repeat having potential to form a stem-loop structure which
resembles a transcription terminator. In addition, Northern blot analysis
suggested the transcript of this gene to be monocistronic. In the present study,
the essential region for promoter activity was narrowed down to a stretch of 57
bp which still retained 84% of the promoter activity. The first nucleotide to be
transcribed is the guanosine at 30 nt upstream from the proposed tdh start codon.
The putative terminator exhibited transcriptional termination activity
bidirectionally in both Escherichia coli and X. campestris. These observations
indicate that the transcriptional structure of X. campestris tdh is different
from that of E. coli where tdh and kbl are organized into the tdh operon.
Furthermore, the expression of tdh in X. campestris is repressed by leucine, a
situation different from that in E. coli where leucine induces the expression of
tdh operon.
PMID- 9398599
TI - Recombinant Mycobacterium aurum expressing Escherichia coli beta-galactosidase in
high throughput screening of antituberculosis drugs.
AB - Mycobacterium aurum is considered a surrogate of M. tuberculosis and recently has
been proposed as test organism in high throughput screening of antituberculosis
drugs (3). In this investigation, we suggest use of a recombinant M. aurum
expressing E. coli lacZ gene, in which beta-galactosidase production is the
reporter system as recently reported by us (6). The assay is based on production
of beta-galactosidase in presence of drugs during growth. Enzyme production was
inhibited within 4 h by frontline antimycobacterial drugs like streptomycin,
rifampicin, isoniazid, ethambutol, ofloxacin, and sparfloxacin at their MICs. The
assay could be performed conveniently in 96-well microtiter plate format.
PMID- 9398600
TI - A cryptic protease activity from Trypanosoma cruzi revealed by preincubation with
kininogen at low temperatures.
AB - Cysteine proteases have been identified in parasitic protozoa including the
causative agent of Chagas' disease Trypanosoma cruzi. T. cruzi lysates subjected
to substrate-containing SDS-polyacrylamide gel electrophoresis exhibit major
bands of proteolytic activity in the 45-55 kDa molecular mass range (cruzipain
activity). Paradoxically, addition of kininogen (a cystatin-like protease
inhibitor) to the lysates before electrophoresis results in the appearance of
additional bands of proteolytic activity in the 160-190 kDa molecular mass range.
This inhibitor-activated protease activity depends upon the reaction conditions
and exhibits novel properties. For example, a 24-48 hour preincubation at low
temperature (-20 degrees C optimum) greatly enhances the proteolytic activity.
The results suggest that a metastable complex forms between kininogen and a
cryptic 30 kDa cysteine protease from T. cruzi and that this complex participates
in the activation of proteolytic activity.
PMID- 9398601
TI - Universal skew of T cell receptor (TCR) V beta usage for Crohn's disease (CrD).
AB - It would be of clear interest and importance to identify T cell populations which
correlate with the initiation of some T cell-mediated diseases; however, it is
difficult to observe the initial response of T cells in these diseases because of
modification due to immunosuppressive treatment. We investigated T cell receptor
(TCR) V beta usage in both affected and unaffected mucosa from 16 patients with
active Crohn's disease (CrD), undergoing nutritional therapy without any
immunomodulatory medications. Semiquantitative reverse transcriptase-polymerase
chain reaction showed increased expression of V beta 12 and 13 in the entire
mucosa of CrD but not in the controls. This was confirmed by introducing a random
cloning method. Such skewing was observed primarily in CD4+ lamina propria
lymphocytes. DNA sequence analysis demonstrated a striking clonal expansion of V
beta 12 T cells, but the dominant clones were not identical in the patients.
These findings suggest the importance of superantigen as well as specific T cell
response in the pathogenesis of CrD.
PMID- 9398602
TI - Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic loop helix/PAS domain
transcription factors involved in adaptative responses to hypoxic stresses.
AB - Expression of many mammalian genes is regulated by oxygen tension. HIF-1 alpha
and HLF/EPAS are two basic helix-loop-helix/PAS domain transcription factors that
bind to hypoxia sensitive elements in the promoters /enhancers of hypoxia
sensitive genes such as vascular endothelial growth factor (VEGF). This paper
describes the structure of rat HIF-1 alpha and analyses expressions HIF-1 alpha
and of HLF/EPAS mRNAs in lung and cardiac tissues from the rat. HLF/EPAS mRNAs
appear at birth in the two tissues and are maintained at high levels throughout
adult life. HIF-1 alpha mRNAs are expressed at a constant level during lung
development. Their abundance increase transiently at birth in cardiac tissues.
Cultured cardiomyocytes from new born rats only express HIF-1 alpha mRNAs. HIF-1
alpha mRNA expression is increased by phorbol myristate acetate but not by anoxia
or cobalt. The results indicate (i) that HIF-1 alpha and HLF/EPAS are expressed
in a cell specific manner and (ii) that the hypoxic induction of VEGF mRNA
expression by isolated cardiomyocytes is independent of HLF/EPAS. Finally, they
suggest that protein kinase C may prime hypoxia induced gene regulation by
inducing expression of HIF-1 alpha mRNAs.
PMID- 9398603
TI - New DNA minor-groove binding molecules with high sequence-selectivities and
binding affinities.
AB - New DNA minor-groove binding molecules with high binding affinities and sequence
selectivities are described. The effects of structural changes in ligands with a
three-ring backbone on their DNA-binding properties have been studied. Of a pool
of eight potential ligands, two showed binding affinities and sequence
selectivities rivaling distamycin. The two best ligands share a common structural
motif that involves a para-di-substituted benzene ring flanked by two meta-di
substituted benzene rings.
PMID- 9398605
TI - Structural characterization of mouse monoclonal antibody 13-1 against a porphyrin
derivative: identification of a disulfide bond in CDR-H3 of Mab 13-1.
AB - The amino acid sequence of a mouse monoclonal antibody Mab13-1, a catalytic
antibody against TCPP (meso-tetrakis(4-carboxyphenyl)porphyrin), was confirmed by
mass spectrometric (MS) peptide mapping. The amino-terminal sequence of the heavy
chain was established by MS/MS analysis of the isolated N-terminal peptide. The
presence of a unique disulfide bond between Cys93H and Cys102H was identified by
MS peptide mapping and sequence analysis of an S-S containing peptide. Positions
of other disulfide bonds were identified to be conserved. The non-conserved
disulfide bridge was found to be resistant as other intra-chain disulfide bonds
against reduction under non-denaturing condition, and to be buried inside the
molecule. This extra disulfide bond is expected to support antigen-binding by
restricting the flexibility of CDR-H3 loop, and it might be favorable for the
recognition of a plane antigen, a porphyrin derivative.
PMID- 9398604
TI - Helicobacter pylori induces interleukin-8 expression in endothelial cells and the
signal pathway is protein tyrosine kinase dependent.
AB - Helicobacter pylori (HP) infection has been shown to increase gastric mucosal
interleukin 8 (IL-8) expression, and whether HP or its toxin induces endothelial
cell IL-8 expression is unknown. We aimed to compare the IL-8 expression in
endothelial cells after stimulation with HP toxin, tumor necrosis factor alpha
(TNF-alpha), and lipopolysaccharide (LPS) and to study their signal pathways. HP
or its toxin induced significant IL-8 expression in endothelial cells. HP toxin,
TNF-alpha, and LPS also showed a time- and dose-dependent increase in IL-8
expression over the control. Both protein kinase C (PKC) and protein kinase A
(PKA) inhibitors had no effect on IL-8 response to these stimuli. Protein
tyrosine kinase (PTK) inhibitor genistein at concentrations of 150, 300, and 450
microM dose-dependently reduced LPS- and TNF-alpha-induced IL-8 expression by
29.43, 43.8, and 47.3% and 20.5, 49.9, and 61.8% respectively, whereas HP toxin
induced IL-8 secretion could only be reduced at 450 microM by 35.7%.
Geldanamycin, a more potent PTK inhibitor, at doses of 0.5, 1, and 2 microM dose
dependently reduced HP toxin induced endothelial cell IL-8 expression by 24.8,
26, and 44.3% respectively. It is concluded that HP and its toxin can increase IL
8 expression in endothelial cells, and the expression of IL-8 elicited by HP
toxin, TNF-alpha, and LPS is partially dependent on PTK but not PKA or PKC
activation.
PMID- 9398606
TI - Heterogeneity of binding sites and bioeffects of raloxifene on the human leukemic
cell line FLG 29.1.
AB - The benzothiophene divarative raloxifene is known to mimic estrogen in human bone
remodeling. To investigate the "in vitro" properties of raloxifene on osteoclast
precursors, the human leukemic cell line FLG 29.1, which differentiates toward
the osteoclastic phenotype, was examined for raloxifene binding and for evidence
of its bioeffects. Scatchard and Hill analysis of binding data with the tritiated
raloxifene demonstrated the presence of two classes of binding sites in both
nuclear and cytosol fractions with Kd values of approximately 1 nM and
approximately 5 nM, respectively. In addition, analysis of binding data using
tritiated 17 beta E2 as ligand at high concentrations (10-40 nM) and either
unlabeled 17 beta E2 or raloxifene as competitors gave similar results
demonstrating the presence of type II EBS in these cells. Picomolar
concentrations of raloxifene significantly (p < 0.05) inhibited cell
proliferation. Moreover, the compound at nanomolar concentrations induced a
significant dose- and time-dependent increase of progesterone receptor, and
activated apoptotic cell death. These findings clearly demonstrate that
raloxifene acts as an estrogen agonist in FLG 29.1 cells, acting through the
estrogen receptor and, possibly, via multiple cooperative binding component(s).
PMID- 9398607
TI - The rat S-adenosylhomocysteine hydrolase promoter.
AB - The 1.2-kb DNA sequence flanking the transcription start of the AdoHcy hydrolase
gene was cloned into the luciferase reporter plasmid pGL3-basic, and promoter
activity was measured in transiently transfected CHO cells. Deletion analysis
showed that most promoter activity was located within a 153 bp fragment
immediately upstream from the predominant transcription start. The 153 bp
fragment includes sites for AP-2, glucocorticoid-responsive element, SP-1, and a
TATA-like sequence TATTTAAA. Mutational analysis demonstrated that the SP-1 site
nearest the start of transcription contributed significantly to promoter
activity, whereas, the other elements, including the appropriately positioned
TATTTAAA sequence, had little affect on promoter activity.
PMID- 9398608
TI - Expression and purification of His-tagged beta-1,4-galactosyltransferase in yeast
and in COS cells.
AB - His6-tag technology has been introduced for easy purification of recombinant
proteins expressed in Escherichia coli. Aiming at extending this technology to
purification of glycoproteins expressed in Saccharomyces cerevisiae or in animal
cells, respectively, we adapted this protocol to recombinant soluble beta-1,4
galactosyltransferase (rgal-T). A His6-tag was introduced to the N-terminus of
the protein (hisGal-T). The Histagged enzyme expressed in yeast S. cerevisiae was
enzymically active but could not be purified from the cell extract by virtue of
the His6-tag. Binding efficiency of hisGal-T was found to be impaired by a bulky
N-glycan close to the His-tag. Removal of the unique site of N-glycosylation
using site-directed mutagenesis restored binding of hisGal-T to the Ni-NTA resin.
In comparison N-glycosylated hisGal-T transiently expressed in COS cells was
secreted as a soluble active enzyme and could be purified in one single step by
virtue of the His6-tag.
PMID- 9398609
TI - In vitro lipolytic effect of leptin on mouse adipocytes: evidence for a possible
autocrine/paracrine role of leptin.
AB - The present study has examined the effects of the adipocyte-derived hormone,
leptin, on lipolysis in fat cells of different types of mice. Exposure to leptin
(1.25.10(-6) M to 1.25.10(-12) M) increased (P < 0.01) the lipolytic activity of
fat cells obtained from lean mice. A greater stimulation was observed when
adipocytes from ob/ob mice were examined. Throughout the concentrations tested,
the leptin-induced lipolysis observed in fat cells of lean animals was smaller
than that obtained in ob/ob mice. The maximal lipolytic effect in obese animals
was observed with 10(-8) M of OB protein. The lipolytic activity following the
addition of 1.25.10(-10) M to 1.25.10(-6) M was significantly increased (P <
0.01) in ob/ob mice compared to lean animals. Adipocytes from ob/ob mice
responded in a dose-dependent manner to the OB protein, while the leptin-induced
lipolysis observed in lean animals was dose-independent. In contrast to lean and
ob/ob mice, leptin did not stimulate lipolysis in adipocytes from db/db mice,
which have a mutation in the leptin receptor gene. These in vitro studies suggest
an autocrine/paracrine action of leptin on white fat cells and envisages the
involvement of the OB protein, not only in centrally mediated pathways, but also
in physiological functions which take place peripherally.
PMID- 9398610
TI - Glycated proteins modulate tissue-plasminogen activator-catalyzed plasminogen
activation.
AB - Plasminogen activation by tissue-plasminogen activator (t-PA) is accelerated by
the presence of a macromolecular surface, which acts as a template that brings
enzyme and substrate in close proximity. Modification of lysine residues, which
are important for this template function, occurs in diabetic patients as a
consequence of glycation of proteins. In this study, we investigated the effects
of glycation of fibrin and other proteins in t-PA-catalyzed plasmin formation.
Plasminogen activation on glycated fibrin(ogen) was increased compared to non
glycated fibrin(ogen), which could fully be attributed to an increased affinity
of t-PA for glycated fibrin(ogen). Binding of plasminogen to glycated fibrin was
increased, but did not contribute to increased plasminogen activation. Both
plasminogen activator inhibitor-1 (PAI-1) binding and activity were increased on
glycated fibrin. Induction of template function in plasminogen activation was
also observed on immobilized glycated bovine serum albumin (BSA) and human gamma
globulins (IgG). Increased plasmin generation at sites of deposition of glycated
proteins may lead to increased extracellular matrix breakdown and thereby affect
the integrity of the endothelial monolayer. Moreover, soluble glycated BSA and
glycated IgG can inhibit t-PA binding to immobilized glycated fibrin and
interfere with fibrinolysis in diabetic patients.
PMID- 9398611
TI - Phosphorylation of osteopontin by Golgi apparatus casein kinase.
AB - Osteopontin (OPN) is a ubiquitous multiphosphorylated secretory glycoprotein.
Twenty-seven phosphorylated serines have been identified in bovine milk OPN (E.
S. Sorensen et al. (1995) Protein Sci. 4, 2040-2049). Nineteen of these
phosphoacceptor sites are fully conserved in rat OPN, all displaying the
consensus for the Golgi apparatus casein kinase, G-CK (S-x-E/Sp). Here we show
that rat OPN is indeed phosphorylated more readily than casein itself by G-CK
from either rat mammary gland or liver. OPN is also phosphorylated by casein
kinases-1 and -2 (CK1, CK2), though less readily than casein. If OPN kinase
activities are normalized in terms of casein phosphorylation, OPN phosphorylation
rate by G-CK is 78-fold and 19-fold higher than those measured with CK2 and CK1,
respectively. These data, in conjunction with the specific location of G-CK to
the Golgi apparatus, where CK2 and CK1 are hardly detectable, support the view
that G-CK is the main if not the only physiological agent committed to the
phosphorylation of OPN.
PMID- 9398612
TI - Human canalicular multispecific organic anion transporter (cMOAT) is expressed in
human lung, gastric, and colorectal cancer cells.
AB - Human canalicular multispecific organic anion transporter (cMOAT), a glutathione
conjugate membrane transporter, has been isolated from cisplatin-resistant cancer
cells and is distributed mainly in normal liver. We analyzed the expression of
human cMOAT in 14 lung, 11 gastric, and 9 colorectal non-drug-selected human
cancer cells, two multidrug-resistant cells, and one cisplatin-resistant cells,
using quantitative RT-PCR and newly developed anti-human cMOAT antibody. All cell
lines analyzed here expressed human cMOAT at the level of mRNA and protein, and
some of them expressed higher levels of human cMOAT than the cisplatin-resistant
cells. The two multidrug-resistant cell lines co-expressed human cMOAT gene and
both or either of MRP and MDR1 genes. Immunostaining showed that human cMOAT was
predominantly localized to the cytoplasm of these single cells. Our results
indicate that human cMOAT is expressed in various human cancer cells including
drug-resistant cells.
PMID- 9398613
TI - Dihydropyridine receptor and ryanodine receptor gene expression in long-term
denervated rat muscles.
AB - Following disruption of the nerve supply, extensor digitorum longus (EDL) and
soleus (SOL) muscles in rats are known to exhibit alterations in excitation
contraction coupling. After total RNA isolation from the denervated and the
contralateral control muscles performed at 25 and 50 days following denervation,
RNase protection assays were carried out with four cDNA probes specific for the
skeletal and cardiac isoforms of both the DHPR alpha 1-subunit and the RyR.
Longterm denervation increased the expression of the mRNA for skeletal DHPR and
skeletal RyR in SOL muscle, but it also significantly increased the expression of
the mRNA for the cardiac isoform of the DHPR alpha 1 subunit in EDL muscle.
PMID- 9398614
TI - Molecular assembly of the extracellular domain of P2X2, an ATP-gated ion channel.
AB - We have produced the putative extracellular domain (ECD) of the ATP-gated ion
channel, P2X2, in a bacterial expression system. The hexahistidine-tagged protein
was purified by immobilized metal affinity chromatography and refolded by
sulfitolysis and dialysis. We demonstrate that P2X2-ECD forms a stable tetramer
in solution by gel filtration chromatography, dynamic light scattering and
analytical sedimentation centrifugation. [alpha-32P]ATP has been covalently cross
linked by UV irradiation to the P2X2-ECD and this binding is specific and
competable by antagonists suramin and cibacron blue. These results indicate that
the binding affinity among P2X2-ECD subunits is appreciably stronger than 3.4
microM (0.1 mg/ml), implying that the extracellular domain of P2X2 is primarly
responsible for tetramerization of whole P2X2 and thus probably plays a role in
determining homo- and heteromerization specificity of P2X channel subunits.
PMID- 9398615
TI - Mutations and deletions within the S8-S9 interdomain region abolish
complementation of N- and C-terminal domains of Ca(2+)-activated K+ (BK)
channels.
AB - A full length alpha-subunit of the Ca(2+)-activated K+ (BK) channel with an
inactivating mutation in the C-terminus can complement a functional C-terminal
fragment. We analyzed deletions and amino acid changes within the S8-S9
interdomain region for their ability to allow complementation. Cys612 and His616
that are located in a region that contains two overlapping signature sequences, a
immunoglobulin signature sequence and a heme binding domain, are essential for a
functional channel. These two amino acid residues are also essential for
complementation. The deletion of the PEST sequence does not affect the function
of the BK channel; however, without the PEST sequence, complementation by a
functional C-terminal fragments is no longer possible. The ability to complement
a functional channel is restricted to the C-terminal fragment and requires that
the complete alpha-subunit or the larger N-terminal fragment contains both, the
immunoglobulin signature sequence the PEST sequence.
PMID- 9398616
TI - Bacterial lipopolysaccharide induces early and late activation of protein kinase
C in inflammatory macrophages by selective activation of PKC-epsilon.
AB - Experiments from our and other laboratories have shown that specific inhibitors
of protein kinase C (PKC) inhibited the secretion of nitric oxide, TNF alpha, and
IL-1 beta from lipopolysaccharide (LPS)-stimulated macrophages, suggesting an
important role for PKC in the inflammatory response. The present study was
designed to investigate the mechanism whereby LPS stimulates PKC activity in
inflammatory macrophages. Mouse macrophages were stimulated with 0-1 microgram/ml
LPS for 0-18 hours, and PKC activity was detected in cell lysates. PKC isoform
specificity was determined by blocking PKC activity with isoform-specific
antibodies. Treatment of macrophages with 1 microgram/ml LPS induced a two-fold
increase in PKC activity within 15 minutes and an additional more significant
peak of PKC activity appeared 3 hours post-LPS stimulation. A lower dose of LPS
(10 ng/ml) induced the later peak only. The enhancement in PKC activity induced
by LPS occurred in both the cytosol and membrane fractions, but the enhancement
in the membrane fraction was significantly greater than in the cytosol. The
increase in PKC activity in both peaks was abolished only by the addition of anti
PKC-epsilon antibody. The present experiments suggest that PKC activation is an
important pathway in the LPS-induced secretory response of macrophages and that
PKC-epsilon is the major isoform involved.
PMID- 9398617
TI - Interactions of FLT-1 and KDR with phospholipase C gamma: identification of the
phosphotyrosine binding sites.
AB - Vascular endothelial cell growth factor interacts with the receptor tyrosine
kinases Flt-1 and KDR/Flk-1. We report that both receptors bind to PLC gamma and
display specificity for the N-SH2 over the C-SH2 domain. Extensive site-directed
mutagenesis of Flt-1 reveals that the juxta-membrane Y794, and the carboxyl
terminal Y1169, are two major sites of interaction. Amino acids in the +1, +2 and
+3 positions following these tyrosines are LSI and IPI, respectively. Peptide
maps generated from wild type and mutant Flt-1 confirms that these residues are
autophosphorylated. As predicted, mutagenesis of the analogous amino acids in
KDR, positions Y801F and Y1175F, which lie in contexts YLSI and YIVL,
respectively, reduced interactions of PLC gamma with this receptor. We conclude
that both Flt-1 and KDR have the potential to signal through PLC gamma via
phosphotyrosine residues located in juxta-membrane and carboxyl tail regions.
PMID- 9398618
TI - Cell-cycle regulation of DNA damage-induced expression of the suppressor gene
PML.
AB - The promyelocytic leukemia (PML) gene, which encodes a growth- and transformation
suppressor, has been identified at the non-random chromosomal translocation break
point t(15; 17)(q22; q12) of acute promyelocytic leukemia. To elucidate if PML
may play a role in cellular response to DNA damage, PML expression was analyzed
by immunofluorescence staining in HeLa cells treated with ionizing radiation (IR)
and cisplatin. Our studies demonstrated IR at 20Gy, and cisplatin at 6
micrograms/ml caused more than 5-10 fold increases in PML protein expression in
the PML Oncogenic Domain (POD) by immunofluorescent staining. Northern blotting
showed that there was no gross increase in mRNA levels indicating that the
induction is a post-transcriptional event. Flow cytometry showed that HeLa cells
treated with IR were progressively arrested in G1, which correlates with the
optimal expression of PML in the cell cycle. To determine if PML expression was
under the control of the tumor suppressor p53, which is known to arrest cells in
G1, HeLa cells were transfected with the wild-type p53 gene. PML expression in
p53 transduced cells were 5-10 fold higher than the control, indicating that the
enhanced expression of PML is apparently dependent on the p53 pathway. These data
also indicate that PML may play an important role in cellular response to DNA
damage such as DNA repair or apoptosis during G1 arrest.
PMID- 9398619
TI - Channel formation and [Ca2+]i accumulation induced by perforin N-terminus
peptides: comparison with purified perforin and whole lytic granules.
AB - Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells express the pore
forming protein perforin, which contributes to lymphocytotoxicity. The hallmark
of perforin action is opening high-conductance transmembrane channels that enable
massive influx of Ca2+ ions (deleterious to many cell types), as well as
granzymes, which may trigger the apoptotic pathway. To explore the functional
domains in the perforin molecule, we investigated in PN71 lymphocytes, the
ability of perforin N-terminus synthetic peptides (compared to purified perforin
and perforin-containing lytic granules), to cause intracellular Ca2+ ([Ca2+]i)
accumulation and open transmembrane channels. To this end, we used the whole cell
recording technique and Indo 1 fluorescence to measure membrane currents and
[Ca2+]i, respectively. We have demonstrated that the N-terminus peptide Hu-34
(amino acids 1-34) closely resembled perforin action, reflected by [Ca2+]i
accumulation and channel activity, while shorter peptides (e.g., Hu-16) generated
mostly short-lived channels but no [Ca2+]i elevation. Hence, the first 34 amino
acids of the perforin N-terminus sequence are sufficient for the perforin action.
PMID- 9398620
TI - TTX resistivity of Na+ channel in newt retinal neuron.
AB - We examined voltage-dependent, TTX-resistant Na+ channels of newt retina (nRNaCh)
electrophysiologically. IC50-TTX value of nRNaCh is more than 20 microM. We
determined partial cDNA sequences of nRNaCh restricted to TTX binding sites (SS2
regions of all four repeats). While the amino acid sequences of SS2 regions of
repeats II, III and IV of nRNaCh are identical to those of TTX-sensitive Na+
channels, only one amino acid in SS2 of repeat I of nRNaCh is different. nRNaCh
have nonaromatic amino acid (Ala) in this site instead of the aromatic amino acid
in a case of TTX-sensitive Na+ channels. Many studies suggested that the
differences of TTX sensitivity of Na+ channels are decided by whether amino acid
in this site is aromatic or not. Therefore nRNaCh acquire their TTX resistivity
with the same mechanism as TTX-resistant cardiac Na+ channels do.
PMID- 9398621
TI - Presence of antibacterial peptides on the laid egg chorion of the medfly
Ceratitis capitata.
AB - Female reproductive accessory glands of the medfly Ceratitis capitata produce a
secretion with antibacterial activity mainly ascribed to ceratotoxin peptides. To
study whether the secretion from the accessory glands of the female protects the
eggs and early larva from microbes, we examined whether ceratotoxins and other
accessory gland components could be found on the egg surface. This was found to
be the case; a water-soluble material with the same protein and antibacterial
pattern as that of the accessory gland secretion was recovered from the laid egg
surface and was observed as electrondense, clustered droplets over the outer
exochorion. Such material showed the same electrophoretic pattern in both mated
and virgin females. These findings indicate that the accessory gland secretion is
spread, at oviposition, onto the eggs producing an antibacterial coating,
irrespective of fertilization. This is the first report of antimicrobial
components recovered from a material layered on insect laid eggs.
PMID- 9398622
TI - Nitric oxide is not involved in lipopolysaccharide and cytokine mixture-induced
cellular injuries in primary cultured hepatocytes.
AB - Nitric oxide (NO) from artificial NO donors induces cell death through complete
inhibition of mitochondrial respiration of hepatocytes. Treatment of hepatocytes
with lipopolysaccharide (LPS) and cytokine mixture (interferon gamma and tumor
necrosis factor alpha) not only results in NO production but also causes cellular
respiration suppression and cell death in hepatocytes. NG-monomethyl-L-arginine,
a specific inhibitor of nitric oxide synthase, inhibits hepatocyte NO synthesis
but cannot prevent hepatocytes from LPS and cytokine mixture-induced cellular
injuries. Similarly, some metabolic intermediates capable of inhibiting
hepatocyte NO synthesis cannot block LPS and cytokine mixture-mediated cellular
injuries in hepatocytes. These results imply that lipopolysaccharide and cytokine
mixture-induced cellular injuries and NO syntheses are parallel events, NO is not
involved in LPS and cytokine mixture-induced cell damage.
PMID- 9398623
TI - Evidence that exposure of particulate air pollutants to human and rat alveolar
macrophages leads to differential oxidative response.
AB - Macrophages and inflammatory cells generate active oxygen species in the process
of killing and degrading microorganisms. Air pollutant particles may be ingested
by macrophages and stimulate the same mechanisms to produce a long term oxidative
burden to the lung if particles are not degraded. In the present study human and
rat alveolar macrophages (AM) were compared in their response to inhaled
particles using luminol dependent chemiluminescence (CL) and peroxide dependent
CL assays. Cytotoxicity was measured by the release of lactate dehydrogenase
(LDH) activity in the supernatant. Human AM produced more oxidants than rat AM
whether, unstimulated, after addition of particles or addition of particles then
peroxidase. Human AM also had a different spectrum of response to the same
particles. Our results suggest that human macrophages produce more reactive
oxygen species in respond to particles than rat AM.
PMID- 9398624
TI - Binding specificity of avian heat shock protein 108.
AB - Chicken heat shock protein 108 (HSP108), the avian homolog of GRP94, was
originally isolated from hen oviduct and binds Fe-ovotransferrin (Fe-OTf). The
liver is also a rich source, and liver membranes bind Fe-OTf with a KD of 1.7 x
10(-7) M, a value similar to oviduct membranes. A competition assay, based on the
binding of 125I-Fe-OTf to liver membranes, was utilized to examine the binding
specificity of HSP108. Ovalbumin and avidin competed effectively, with KD's of
1.8 x 10(-7) M and 1.4 x 10(-7) M, respectively. Iron-free OTf bound with a 10
fold higher KD. Egg white lysozyme, chicken IgG, human transferrin, rabbit muscle
actin, and porcine insulin do not bind. Neither do denatured ovalbumin or
ovalbumin tryptic peptides. Thus, the binding activity of HSP108 is not
restricted to Fe-OTf, nor is it universal.
PMID- 9398625
TI - Differences in hypervariable region 1 quasispecies between immune complexed and
non-immune complexed hepatitis C virus particles.
AB - Antibody to the hypervariable region 1 of hepatitis C virus (HCV) is thought to
have neutralizing activity. The complexity of hypervariable region 1 quasispecies
was compared between immune complexed and non-immune complexed HCV particles.
Immune complexes and non-immune complexes, including intact HCV virions, were
separated by differential flotation centrifugation and immunoprecipitation, and
immune complexes were observed in 9 of 11 patients with chronic hepatitis C.
Considerable differences in both hypervariable region 1 quasispecies and
predominant clones were demonstrated between immune complexes and non-immune
complexes in 4 patients and not in 5 patients. These results suggest that the
specificity of antibody to hypervariable region 1 is related to the formation of
immune complexes and that escape mutants with highly different quasispecies are
resistant to neutralization by antibody to hypervariable region 1.
PMID- 9398626
TI - Downregulation of MAP kinase activity signalled by HIV-1-gp120 coat protein in
granular neurons and glial cells from rat cerebellum.
AB - We have studied the effect of gp120 coat protein from HIV-1 on tyrosine
phosphorylation processes in primary cultures of granular neurons or glial cells
from the cerebellum of neonatal rats. The extracellular application of
recombinant gp120 (200 pM) was able to reduce the phosphotyrosine content and the
immunoreactivity for active form-specific antibodies of MAP kinase. Whereas in
neurons MAP kinase appeared to be the only protein whose phosphotyrosine content
was decreased, in glial cultures the inhibitory effect of gp120 on tyrosine
phosphorylation processes appeared to be more widespread. In neuronal cultures,
the effect of the viral protein was prevented by the concomitant treatment with
depolarizing agents.
PMID- 9398627
TI - Aberrant tau phosphorylation and neurite retraction during NGF deprivation in
PC12 cells.
AB - Recently apoptotic markers have been found in Alzheimer's Disease (AD) brain. To
investigate the relation between tau phosphorylation and apoptosis,
immunocytochemistry of AT8 (indicating the degree of phosphorylation at the tau
Ser202/Thr205 site) was quantitatively determined the degree of tau
phosphorylation at the Ser202 site was monitored during neuronal apoptosis in
differentiated PC12 cells after nerve growth factor (NGF) deprivation. During
this programmed cell death a prominent retraction of neurites took place that was
associated with a clear increase in the level of AT8 signalaberrant
phosphorylated tau at the Ser202 site. The broad spectrum kinase inhibitor
staurosporine attenuated both this increase in tau phosphorylation, neurite
retraction, and apoptosis. We suggest that at some point during programmed cell
death, kinases with tau as substrate become activated and that the resulting loss
of cytoskeletal integrity leads to neurite instability.
PMID- 9398628
TI - Wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase, enhances LPS
induced NO production from murine peritoneal macrophages.
AB - To elucidate the role of phosphatidylinositol-3-kinase (PI3K) during macrophage
activation, we examined the effects of wortmannin, a specific inhibitor of PI3K,
on the induction of nitric oxide (NO) synthesis and tumor necrosis factor-alpha
(TNF-alpha) secretion from lipopolysaccharide (LPS)-stimulated macrophages.
Wortmannin had no effects on NO synthesis and TNF-alpha secretion by itself.
Wortmannin markedly potentiated the LPS-induced NO production in a dose-dependent
manner. Western blot analysis demonstrated that significantly increased levels of
iNOS protein were expressed in LPS-stimulated macrophages treated with
wortmannin, compared to those without LPS. Furthermore, enhancement of TNF-alpha
secretion was observed in the initiation stage for activation of LPS-stimulated
macrophages treated with wortmannin. These results suggest that PI3K plays an
important role in transducing the signal that is involved in LPS-induced
macrophage activation.
PMID- 9398629
TI - Nuclear accumulation of G-actin in isolated rat hepatocytes by adenine
nucleotides.
AB - Extracellular ATP induces bleb formation in isolated rat hepatocytes. We examined
the effect of extracellular ATP on the actin cytoskeleton of these hepatocytes.
Exposure to 100 microM ATP caused pronounced nuclear accumulation of G-actin.
ADP, AMP, adenosine, and dibutyryl-cAMP induced the same effect. Adenosine
deaminase could inhibit both ATP- and adenosine-induced nuclear accumulation. The
P2-receptor agonists, UTP and 2' & 3'-O-(4-benzoylbenzoyl)-adenosine 5'
triphosphate, did not induce this redistribution of G-actin. Phalloidin, which
prevents depolymerisation of F-actin filaments to G-actin monomers, inhibited
adenosine-induced nuclear accumulation of G-actin. These observations suggest
that nuclear accumulation of G-actin is mediated by adenosine receptors.
PMID- 9398630
TI - A conserved region in the first intron of the insulin receptor gene binds nuclear
proteins during adipocyte differentiation.
AB - The insulin receptor gene is induced 8 to 10-fold during adipocyte
differentiation. Plasmids containing the promoter, exon 1 and a portion of the
first intron from either the mouse or human gene are able to modulate the
expression of an insulin receptor/CAT gene 3 to 7-fold during differentiation. We
have shown that several nuclear proteins from both preadipocyte and adipocyte
nuclear extracts bind to two discrete sites within a 278-bp region in the 5' end
of the first intron. Sequence comparison between the first intron of the human
gene and the mouse gene shows two regions of sequence identity which correspond
to the protein binding regions detected by DNase footprinting. One of these sites
binds proteins that are enriched in adipocyte nuclear extracts and can be
competed by adipose regulatory element, ARE6.
PMID- 9398631
TI - Insulin-like growth factor binding proteins-3 and -5 form sodium dodecyl sulfate
stable multimers.
AB - Insulin-like growth factor binding proteins (IGFBPs) are important modulators of
IGF actions. IGFBP-3 and IGFBP-5 can bind to the extracellular matrix of a number
of cell types. We now describe a new posttranslational structural modification of
IGFBP-3 and IGFBP-5, which could play a role in determining their localization.
We incubated radioiodinated forms of all six IGFBPs in the presence of a redox
buffer consisting of 10 mM reduced glutathione and 0.2 mM oxidized glutathione.
Under these conditions IGFBP-3 and IGFBP-5, but not the other IGFBPs, formed high
molecular weight disulfide-linked multimers. Heparin and a peptide encompassing
the high-affinity heparin-binding site in the C-terminal portion of IGFBP-3 were
capable of blocking the multimerization of IGFBP-3. IGFBP-3, but not IGFBP-1, was
shown to be able to self-associate non-covalently, which could be a requisite
first step in the formation of covalent multimers. The self-association of IGFBP
3 required the high-affinity heparin-binding site in the C-terminal portion of
the molecule.
PMID- 9398632
TI - Detection of apolipoprotein E/dimeric soluble amyloid beta complexes in
Alzheimer's disease brain supernatants.
AB - The inheritance of the apolipoprotein (apo) E4 allele is an important risk factor
for late-onset Alzheimer's disease (AD). A major component of the Alzheimer's
disease neuritic plaques is amyloid beta (A beta). We previously identified
apoE/A beta complexes within neuritic plaques (1). It was not known if this
interaction takes place before or after A beta peptides become incorporated into
neuritic plaques. To address this question we sought evidence of apoE complexes
with brain soluble A beta peptides in AD and control patients. In addition,
numerous proteins have been shown to bind A beta peptides in vitro. It is not
know if any of these bind brain sA beta in vivo. We found evidence for the
presence of apoE/dimeric sA beta complexes in the AD brain and could not detect
complexes with other A beta peptide binding proteins. The binding of sA beta to
apoE may be one factor influencing its clearance from the brain and/or its
conformational state.
PMID- 9398633
TI - Oligomerization is an intrinsic property of calsequestrin in normal and
transformed skeletal muscle.
AB - In skeletal muscle fibers, the high-capacity medium-affinity Ca(2+)-binding
protein calsequestrin functions as the major Ca(2+)-reservoir of the sarcoplasmic
reticulum. To determine the oligomeric status of calsequestrin, immunoblotting of
microsomal proteins following chemical crosslinking was performed. Diagonal non
reducing/reducing two-dimensional gel electrophoresis was employed to
unequivocally differentiate between cross-linked species of 63 kDa calsequestrin
and calsequestrin-like proteins of higher relative molecular mass. Since chronic
low-frequency stimulation has a profound effect on the expression of many muscle
specific protein isoforms, we investigated normal and conditioned muscle fibers.
Calsequestrin was found to exist in a wide range of high-molecular-mass clusters
in normal and chronically stimulated skeletal muscle fibers. Hence,
oligomerization is an intrinsic property of this important Ca(2+)-binding protein
and does not appear to be influenced by the fast-to-slow transformation process.
Although fiber-type specific differences exist in the physiology of the skeletal
muscle Ca(2+)-regulatory system, oligomerization of calsequestrin seems to be
essential for proper functioning.
PMID- 9398634
TI - Determination of a cleavage site of presenilin 2 protein in stably transfected SH
SY5Y human neuroblastoma cell lines.
AB - Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes are associated
with early-onset autosomal dominant familial Alzheimer's disease, and the gene
products are endoproteolytically processed to yield N-terminal fragments (NTF)
and C-terminal fragments (CTF). We have studied the cleavage site of the PS2
protein in stably transfected human neuroblastoma cells. The 23 kD PS2-CTF was
isolated by a combination of anion exchange chromatography and affinity
chromatography and directly sequenced. The N-terminus of the PS2-CTF started at
residue 307, which indicated that the cleavage occurs between Lys306 and Leu307
in the proximal portion of the large hydrophilic loop. This site is close to the
cleavage positions observed in the PS1 protein.
PMID- 9398635
TI - Ursodeoxycholic acid enhances glucocorticoid-induced tyrosine aminotransferase
gene expression in cultured rat hepatocytes.
AB - Ursodeoxycholic acid (UDCA) is an effective treatment for immune-mediated liver
diseases, suggesting that UDCA is functionally similar to glucocorticoids (GCs).
We investigated the effects of UDCA on the enzyme activity and the mRNA levels of
tyrosine aminotransferase (TAT), a hepatocyte-specific marker of GC action, in
primary cultured rat hepatocytes. Addition of UDCA resulted in a significant
increase in TAT activity in the presence of dexamethasone (DEX), compared with
DEX alone, and this increase was completely suppressed by sphingosine, a protein
kinase C (PKC) inhibitor, or actinomycin D, a transcriptional inhibitor. UDCA
could not induce TAT activity in the absence of DEX. UDCA increased the TAT mRNA
levels in the presence of DEX. In conclusion, UDCA enhances the GC-induced TAT
gene expression in hepatocytes, and UDCA-activated PKC may play a role in this
upregulation.
PMID- 9398636
TI - Cloning of cDNAs encoding G protein-coupled receptor expressed in human
endothelial cells exposed to fluid shear stress.
AB - A cDNA library of human umbilical vein endothelial cells exposed to fluid shear
stress was constructed to search for functional endothelial genes expressed under
flow conditions, and cDNAs encoding members of the G protein-coupled receptor
(GPCR) family were cloned by a polymerase chain reaction (PCR) method using
degenerate oligonucleotide primers. One of the two GPCR clones obtained was edg
1, and the other clone is a novel gene named FEG-1 that encodes a 375-amino acid
protein similar to the receptors for both angiotensin II and chemokines. Reverse
transcriptase-PCR showed that the FEG-1 and edg-1 mRNA levels in endothelial
cells increased markedly in response to fluid flow. This suggests that FEG-1 and
edg-1 may be receptor genes that play important roles in the regulation of
endothelial function under physiological blood flow conditions.
PMID- 9398637
TI - Leptin is present in human milk and is related to maternal plasma leptin
concentration and adiposity.
AB - Leptin is elevated during pregnancy and may be involved in the regulation of milk
production in women. Immunoreactive leptin was quantified in human milk by
modified radioimmunoassay. Leptin concentration was higher in whole vs. skim milk
fractions; however, leptin concentration was not correlated with percentage milk
fat. Leptin concentrations in whole and skim milk were correlated with maternal
plasma leptin concentrations, maternal body weight, body mass index, and tricep
skinfold thickness, but not with plasma insulin concentration. These data provide
the first evidence for the presence of leptin in human milk in the range of
concentrations found in human plasma and indicate that the concentration of
leptin in milk reflects maternal adiposity. Determining the biological role(s) of
milk-borne leptin could add to our understanding of neonatal metabolism and the
mechanisms underlying the development of body fat and obesity in humans.
PMID- 9398639
TI - Hydroxy juvenile hormones: new putative juvenile hormones biosynthesized by
locust corpora allata in vitro.
AB - The in vitro production of sesquiterpenoids was investigated by using corpora
allata (CA) of the African locust Locusta migratoria migratorioides. Labeled
products from unstimulated biosynthesis were extracted, purified by normal phase
HPLC, and derivatized to determine the functional groups present. An extra
hydroxyl group was detected in each of two juvenile hormone (JH) biosynthetic
products. One compound, NP-8, was found to co-migrate with a chemically
synthesized (Z)-hydroxymethyl isomer, 12'-OH JH-III, but not with the (E)
hydroxymethyl isomer, 12-OH JH III. Mass spectral analyses further supported the
identity of the synthetic material with that biosynthesized by the corpora
allata. A second compound was identified as the 8'-OH JH-III based on
spectroscopic analyses. 12'-OH JH-III exhibited morphogenetic activity when
tested on the heterospecific Tenebrio test. These data suggest that 12'-OH JH-III
and 8'-OH JH-III are additional biosynthetically-produced and biologically-active
juvenile hormones, and constitute the first known members of the class of hydroxy
juvenile hormones (HJHs).
PMID- 9398640
TI - APP gene promoter constructs are preferentially expressed in the CNS and testis
of transgenic mice.
AB - Transgenic animals were used to examine the spatial and temporal regulation of
the human beta amyloid precursor protein (APP) gene promoter region in vivo. A
2.9 kb DNA fragment encompassing the APP gene promoter was fused to the
chloramphenical acetyltransferase (CAT) reporter gene (pAMY-CAT) or a partial
cDNA encoding the potentially amyloidogenic C-terminal 100 amino acid region of
APP (pAMY-C100). Expression of these transgenes occurred primarily, but not
exclusively, in the central nervous system (CNS) and testis in multiple
independent lineages of transgenic mice. Temporal expression of the CAT reporter
gene during development paralleled that reported for the endogenous APP gene.
These studies suggest that a CNS-responsive cis-acting element(s) may exist in
the promoter/5'-flanking region of the APP gene.
PMID- 9398641
TI - Receptor-mediated calcium entry is required for maximal effects of platelet
activating factor primed responses in human neutrophils.
AB - The effect of receptor mediated calcium entry (RMCE) on platelet activating
factor (PAF) stimulated human neutrophils (PMNs) was investigated using SKF
96365, a selective inhibitor of RMCE. Changes in cytosolic calcium concentration
were determined by the fluorometric dye indo-1, AM, superoxide generation by
cytochrome c reduction, and CD11b surface expression by flow cytometry. SKF 96365
pre-treatment diminished the cytosolic calcium rise in PAF primed PMNs. SKF 96365
treatment significantly (p < 0.05) decreased superoxide generation in PAF primed
PMNs, but did not affect activation of the PMN oxidase by fMLP or PMA. Chelation
of extracellular calcium by EGTA, intracellular calcium by BAPTA, AM, and RMCE
blockade by SKF 96365 all statistically inhibited the PAF induced increase in
surface expression of CD11b (p < 0.05); moreover, SKF 96365 inhibited to a
greater extent than EGTA or BAPTA, AM treatment. These results suggest that RMCE
is required for maximal effects of PAF on PMN function.
PMID- 9398642
TI - A novel brain gene, norbin, induced by treatment of tetraethylammonium in rat
hippocampal slice and accompanied with neurite-outgrowth in neuro 2a cells.
AB - Tetraethylammonium (TEA) induces long-term potentiation (LTP)-like synaptic
enhancement in rat hippocampal slices. To find the genes related to this
phenomenon, subtraction screening was performed between the mRNA of TEA-treated
slices and that of untreated whole brain. One of the clones induced by the TEA
treatment, named as norbin, was expressed only in neural tissues. The predicted
protein sequence of norbin consisted of 729 amino acids, and no homologies in the
sequence were found with known genes or proteins. Overexpression of norbin in
cultured Neuro 2a cells by cDNA transfection induced neurite-outgrowth. Since in
the course of neural plasticity the formation of new synapses should occur, the
neurite-outgrowth-related protein, norbin, might play an important role in neural
plasticity.
PMID- 9398643
TI - Potentiation of depolarization-induced calcium release from skeletal muscle
triads by cyclic ADP-ribose and inositol 1,4,5-trisphosphate.
AB - Two second messengers, cyclic ADP-ribose (cADPR) and inositol 1,4,5-trisphosphate
(IP3), potentiated the Ca2+ release from sarcoplasmic reticulum induced by
transverse tubular membrane depolarization monitored in a triadic vesicle
prepared from skeletal muscle. However, without depolarization they could not
trigger the Ca2+ release. On the contrary, only cADPR potentiated caffeine
induced Ca2+ release. Because Ca2+ releases potentiated by cADPR and IP3 were
inhibited by 1 microM ruthenium red and 100 microM ryanodine, probably these
second messengers potentiated the Ca2+ release through ryanodine receptor Ca2+
channels. These results suggest that in skeletal excitation-contraction coupling,
cADPR and IP3 play a role as a potentiator or a modifier in vivo, but both
modification pathways are different from each other.
PMID- 9398644
TI - Spermine conjugated peptide nucleic acids (spPNA): UV and fluorescence studies of
PNA-DNA hybrids with improved stability.
AB - Peptide Nucleic Acids (PNAs), the achiral DNA mimics with amide backbone, are
emerging as attractive leads for drug development by antisense approach. Two
major limitations of PNAs from an application perspective are their limited
solubility in aqueous systems and pronounced self-organization. In this paper, it
is shown that covalent conjugation of spermine at C-terminus of PNA (spPNA)
improves its solubility and binds to complementary DNA 20 times stronger than the
corresponding binding of PNA. Fluorescence kinetics shows a 2 fold acceleration
of the bimolecular association process in spPNA:DNA hybrids, due to electrostatic
interaction cationic spermine tagged to PNA with anionic DNA. This modification
is easy to incorporate into PNA synthetic protocols to make them more effective
in biological applications and may improve the poor cell uptake of PNA.
PMID- 9398645
TI - Single transduction in the transcriptional activator CooA containing a heme-based
CO sensor: isolation of a dominant positive mutant which is active as the
transcriptional activator even in the absence of CO.
AB - We constructed an in vivo reporter system to measure the activity of CooA as the
transcriptional activator and showed that the recombinant CooA was active as the
transcriptional activator in the presence of CO even in E. coli cells. A dominant
positive mutant of CooA, in which Met131 was replaced by Leu, was isolated by a
random mutagenesis with this reporter system. The electronic absorption spectra
of M131L mutant were identical to those of wild type CooA in oxidized (Fe3+),
reduced (Fe2+), and CO-bound (CO-Fe2+) state, indicating that the coordination
structure and environment of the heme were not changed by this mutation.
Methionine at position 131 was the carboxyl-terminal end of the heme-binding
domain of CooA, which would be adjacent to the hinge region connecting the heme
binding domain and the DNA-binding domain.
PMID- 9398646
TI - A pluripotent polyphenol oxidase from the melanogenic marine Alteromonas sp
shares catalytic capabilities of tyrosinases and laccases.
AB - The recently characterized marine melanogenic bacterium MMB-1 contains a
pluripotent polyphenol oxidase (PPO) which catalyzes the oxidation of a very wide
range of substrates considered specific for tyrosinase or laccase. This range
includes monophenols such as L-tyrosine, o-diphenols such as L-dopa, p-diphenols
such as hydroquinone, o-aminophenols such as 3-hydroxyanthranilic acid, activated
monophenols such as 2,6-dimethoxyphenol and syringaldazine, and chromophores such
as ABTS. This is the first report of an enzyme that is able to catalyze the
oxidation of compounds so far considered specific for tyrosinases (L-tyrosine) or
laccase (syringaldazine), showing cresolase, catechol oxidase and laccase
activities. Such PPO could be a very useful model to study the structural
requirements, catalytic mechanisms and involvement of the copper sites existing
in non-blue and blue copper-oxidases.
PMID- 9398647
TI - Positively charged liposome functions as an efficient immunoadjuvant in inducing
immune responses to soluble proteins.
AB - To design an optimum liposome immunoadjuvant for soluble protein antigens, we
investigated the relationship between liposomal surface charge and adjuvant
action. Positively charged multilamellar vesicles (MLV) were taken up efficiently
by macrophages, while negatively charged and neutral MLVs were hardly picked up.
Consistent with this, positively charged MLVs containing soluble chicken egg
albumin (OVA) functioned as a more potent inducer of antigen-specific cytotoxic T
lymphocyte (CTL) responses and antibody production than negatively charged and
neutral MLVs containing the same concentrations of antigens. These results
indicate that the positive charge on the surface of liposomes represents an
important factor for enhancing their immunoadjuvancy in the induction of antigen
specific immune responses.
PMID- 9398648
TI - The placenta is not the main source of leptin production in pregnant rat:
gestational profile of leptin in plasma and adipose tissues.
AB - The gestational profiles of leptin in plasma, adipose tissue and placenta were
investigated in rats. Leptin in plasma and the adipose tissue of the maternal
compartment increased as pregnancy advanced and remained high during the latter
half of pregnancy (approximately 2-fold compared with the non-pregnant state),
followed by a rapid decrease just before parturition. Leptin in fetal plasma and
amniotic fluid was first detectable on day 19 and then increased to levels
comparable to those in maternal plasma of non-pregnant and day 21 pregnant rats.
The total amount of mRNA in maternal adipose tissues significantly increased as
pregnancy advanced and reached about 2.5-fold of those of non-pregnant rats on
day 19 of pregnancy, followed by a marked decrease on day 3 of lactation.
Placentae and decidual tissues did not show any expression of leptin mRNA on day
12 and 19 of pregnancy. These results indicate that the placenta is not a major
source of leptin production in rats and also suggest the physiological
significance of leptin in rat pregnancy.
PMID- 9398649
TI - Interaction of mutagenic tryptophan pyrolysate with d(CGATCG)2: intercalation
model based on NMR experiments.
AB - The solution structure of the complex of 3-amino-1,4-dimethyl-5H-pyrido[4,3
b]indole (Trp-P-1), a potent mutacarcinogen isolated from tryptophan pyrolysate,
with the hexamer duplex d(CGATCG)2, was analysed by 1H-NMR spectroscopy and
molecular dynamic calculation. Trp-P-1 was intercalated between the CpG base
pairings in a suitable manner to form the guanosine-Trp-P-1 adduct which
corresponds to the major reactant of Trp-P-1 with DNA.
PMID- 9398650
TI - Intronic sequences are involved in neural targeting of human dopamine transporter
gene expression.
AB - Dopamine transporter (DAT) plays a key role in terminating synaptic dopaminergic
transmission. DAT acts exclusively on the plasma membrane of presynaptic
dopaminergic neurons and DAT gene is an appropriate model for the study of
dopaminergic neuron-specific regulation of gene activity. DAT represents an
important target for widely used neuroleptic drugs and psychostimulants and for
catecholamine-selective neurotoxins. Functional abnormalities of DAT have been
implicated in diverse neurologic and psychiatric disorders. Understanding the
mechanisms regulating human DAT gene activity is an important step towards
elucidation of the molecular bases of a number of disorders and psychostimulant
drug abuse and dependence. In this study we have cloned and characterised a 7-kb
segment of the human DAT gene which includes at least 4 kb of its 5'-flanking
region, localised its essential, or core-promoter, and identified the region
involved in regulation of DAT neurospecific expression.
PMID- 9398651
TI - CD36 forms covalently associated dimers and multimers in platelets and
transfected COS-7 cells.
AB - CD36 is a transmembrane glycoprotein expressed on the surface of a number of cell
types. The analysis of CD36 from platelets using immunoblotting, gel filtration,
and native PAGE indicated the presence of high molecular complexes exceeding the
Mr of monomeric CD36. Experiments using transfected COS-7 cells revealed these
complexes were homodimers and -multimers of CD36. The multimers could be
dissociated by treatment with a reducing agent, indicating they were formed by
intermolecular cysteine-bridging. Mutagenesis of the cDNA for CD36 implicated the
cysteines in the extracellular domain of the molecule. The potential
physiological roles of CD36 multimerisation are discussed.
PMID- 9398652
TI - The lipoic acid analogue 1,2-diselenolane-3-pentanoic acid protects human low
density lipoprotein against oxidative modification mediated by copper ion.
AB - 1,2-Diselenolane-3-pentanoic acid, in which the sulfur atoms of alpha-lipoic acid
are replaced with selenium, displayed markedly different antioxidant properties
when compared to alpha-lipoic acid. 1,2-Diselenolane-3-pentanoic acid was unable
to inhibit protein oxidative modification of human low density lipoprotein (LDL)
and bovine serum albumin induced by copper ion or hydroxyl radical, whereas alpha
lipoic acid showed significant protection. However, 1,2-diselenolane-3-pentanoic
acid was able to inhibit the formation of lipid peroxidation products in LDL
after oxidation by copper, while alpha-lipoic acid did not. Hence the diselenium
compound exerts its effects in a lipophilic environment whilst lipoic acid exerts
its effects in a hydrophilic environment. These differences in antioxidant
activities of the two compounds may be explained, at least in part, by their
differing partition coefficients.
PMID- 9398653
TI - Modulation of translation initiation in rat skeletal muscle and liver in response
to food intake.
AB - Protein synthesis is altered in both skeletal muscle and liver in response to
nutritional status with food deprivation being associated with an inhibition of
mRNA translation. In the present study, the effect of food-intake on the
initiation of mRNA translation was examined in rats fasted for 18-h and then
refed a complete diet. Fasting and refeeding caused alterations in translation
initiation in both skeletal muscle and liver that were not associated with any
detectable changes in the activity of eIF2B or in the phosphorylation state of
eIF2 alpha. Instead, alterations in initiation were associated with changes in
the phosphorylation state of eIF4E and/or the association of eIF4E with eIF4G as
well as the eIF4E binding protein, 4E-BP1. In muscle from fasted rats, the amount
of eIF4E present in an inactive complex with 4E-BP1 was increased 5-fold compared
to freely fed control animals. One hour after refeeding a complete diet, the
amount of 4E-BP1 bound to eIF4E was reduced to freely fed control values. Reduced
association of the two proteins was the result of increased phosphorylation of 4E
BP1. Refeeding a complete diet also stimulated the binding of eIF4E to eIF4G to
form the active eIF4F complex. In liver, the amount of eIF4E associated with
eIF4G, but not the amount of eIF4E associated with 4E-BP1, was altered by fasting
and refeeding. Furthermore, in liver, but not in skeletal muscle, fasting and
refeeding resulted in modulation of the phosphorylation state of eIF4E. Overall,
the results suggest that protein synthesis may be differentially regulated in
muscle and liver in response to fasting and refeeding. In muscle, protein
synthesis is regulated through modulation of the binding of eIF4E to eIF4G and in
liver through modulation of both phosphorylation of eIF4E as well as binding of
eIF4E to eIF4G.
PMID- 9398654
TI - Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid
cancer cell lines and suppresses expression of functional symporter in
nontransformed FRTL-5 rat thyroid cells.
AB - Decreased iodide uptake in de-differentiated thyroid carcinomas impedes
radioiodide therapy. RTPCR analysis revealed reduced expression of Na+/I-
symporter (NIS) mRNA in human thyroid carcinomas as compared to normal thyroid.
However, in follicular thyroid carcinoma cell lines FTC-133 and FTC-238,
treatment with 1 microM all-trans retinoic acid (RA) markedly increased NIS mRNA
levels. Anaplastic thyroid carcinoma cell lines HTh74 and C643 showed basal
expression of NIS mRNA, but no RA-stimulation. All four cell lines contained the
approximately 80 kD NIS protein as judged by Western blot, although they did not
accumulate iodide. In contrast, in nontransformed rat FRTL-5 cells, 1 microM RA
downregulated NIS mRNA levels, inhibited the TSH- or forskolin-triggered
induction of NIS message after TSH-depletion, and reduced iodide uptake to 38%
after 5 d. This divergent RA-responsivity of NIS may provide the means to target
radioiodide to thyroid carcinomas by upregulating iodide transport into tumor
tissue while simultaneously inhibiting iodide accumulation in normal thyrocytes
and may thus re-establish the potential for radioiodide therapy.
PMID- 9398655
TI - Stability of protease Q against autolysis and in sodium dodecyl sulfate and urea
solutions.
AB - Protease Q, a recently discovered subtilisin-like protease, exhibited unusual
stability in 10% sodium dodecyl sulfate (SDS) and 8 M urea solutions. In 2% SDS
it exhibited higher activity than the control, and in 10% SDS it retained 50% of
its original activity when azocoll was used as substrate. Kinetic studies showed
that the decrease in the activity of protease Q in SDS solutions followed a first
order kinetics with a half-life of 446, 278, 78, and 24 h in 1%, 2%, 5%, and 10%
SDS, respectively, at 25 degrees C. Protease Q was also stable against autolysis.
In 20 mM Tris-HCl buffer (pH 8.3) containing 1.0 mM CaCl2, protease Q had a half
life of 2822 h and 725 h at room temperature and at 37 degrees C, respectively.
The enzyme was able to completely hydrolyze beta-lactoglobulin, beta-casein, and
keratin in 8-10 M urea.
PMID- 9398656
TI - Functional characterization of RNase H1 from Drosophila melanogaster.
AB - We have cloned and functionally characterized the RNase H1 gene from D.
melanogaster. The longest open reading frame consists of 5 exons that encode a
333 amino acid protein with a molecular mass of 37.1 kDa. This is the first
demonstration of specific nuclease activity of a cloned RNase gene from a
multicellular higher eukaryote. No additional proteins or cofactors are required
for this nuclease activity. Comparison of Drosophila RNase H1 amino acid sequence
to that of other cellular eukaryotic homologs reveals the presence of three
evolutionarily distinct domains. The N- and C-terminal conserved domains are
connected by a highly variable domain. The C-terminal domain has high amino acid
similarity to bacterial RNase HI and the RNase H domain of retroviral reverse
transcriptase, while the N-terminus, of unknown function, is similar to the P6
translational activator of caulimoviruses.
PMID- 9398657
TI - Potent inactivator of alpha-chymotrypsin: 2,2-dimethyl-3-(N-4-cyanobenzoyl)amino
5-phenyl pentanoic anhydride.
AB - We synthesized a novel potent alpha-chymotrypsin inactivator, 2,2-dimethyl-3-(N-4
cyanobenzoyl) amino-5-phenyl pentanoic anhydride, which fulfilled the criteria of
a mechanism-based inactivator: first-order kinetics, irreversibility, saturation
kinetics and substrate protection. The inactivation rate constant (kinact) and
the enzyme-inhibitor dissociation constant (KI) were calculated to be 0.017s-1
and 0.071 microM, respectively (kinact/KI = 242,000 M-1s-1). These kinetic
parameters indicate that this compound is one of the most powerful alpha
chymotrypsin inactivators ever reported. The average number of alpha-chymotrypsin
turnovers per inactivation (partition ratio) was calculated to be 1, which
indicates that it is a stoichiometrically ideal inactivator of alpha
chymotrypsin. We compared the IC50 values of this compound with those of several
chymotrypsin-like serine proteinases (bovine alpha-chymotrypsin, recombinant
human chymase and human neutrophil cathepsin G) and a metallo proteinase, rabbit
angiotensin converting enzyme (ACE). Our compound, 2,2-dimethyl-3-(N-4
cyanobenzoyl) amino-5-phenyl pentanoic anhydride, inhibited bovine alpha
chymotrypsin potently (IC50 = 1.0 (+/- 0.2) x 10(-9) M) as well as other
chymotrypsin-like serine proteinase; recombinant human chymase (IC50 = 7.0 (+/-
1.0) x 10(-8) M) and human neutrophil cathepsin G (IC50 = 1.8 (+/- 0.2) x 10(-7)
M). However, rabbit ACE was not inhibited by this compound (IC50 > 1 x 10(-4) M).
PMID- 9398658
TI - Lysophosphatidic acid inhibits epidermal-growth-factor-induced Stat1 signaling in
human epidermoid carcinoma A431 cells.
AB - Lysophosphatidic acid (LPA) is a lipid mediator which acts on its putative G
protein-coupled receptor (GPCR). Recently, activation of signal transducers and
activators of transcription (STATs) mediated by GPCR has been reported. In this
study, we examined the effect of LPA on STAT activation using the electrophoretic
mobility shift assays and the heterologous promoter analysis in human epidermoid
carcinoma A431 cells. We found that LPA inhibited epidermal growth factor (EGF)
induced Stat1 activation in a concentration-dependent manner. Other phospholipase
C (PLC)-coupled GPCR agonists, bradykinin and ATP, also inhibited Stat1
activation. This inhibitory effect of LPA was completely mimicked by an activator
of protein kinase C (PKC), a PLC-downstream effector. These findings suggest that
the inhibitory effect on EGF-induced Stat1 activation may be a general
characteristic of PLC-coupled GPCRs and PKC pathway may be mainly associated with
this inhibitory effect. This is the first evidence showing that GPCR agonists
inhibit the Janus kinase-independent Stat1 activation induced by receptor
tyrosine kinase.
PMID- 9398659
TI - Interferon induces up-regulation of Spi-1/PU.1 in human leukemia K562 cells.
AB - The human K562 cell line is derived from a chronic myelogenous leukemia in
blastic crisis. Treatment of K562 cells with interferons alpha, beta or gamma
resulted in inhibition of cell proliferation. Spi-1/PU.1 is a transcription
factor of the Ets family which is required for normal hematopoyesis. We have
found that spi-1 mRNA and protein as well as Spi-1-DNA binding activity increase
after exposure of K562 cells to interferons. The increase in spi-1 expression
ranged from 4- to 8-fold with the different interferons. K562 cells can be
differentiated in vitro towards erythroid cells or monocyte-macrophage cells.
Interestingly, the regulation of spi-1 by interferon-alpha depended on the
differentiated phenotype of K562 cells: interferon-alpha failed to induce spi-1
in erythroid differentiated cells, whereas it induced spi-1 in monocyte
macrophage differentiated cells. The results suggest a role for Spi-1 in the
cytostatic response to interferons.
PMID- 9398660
TI - Distance between the basic group of the amino acid residue's side chain in
position P1 of trypsin inhibitor CMTI-III and Asp189 in the substrate pocket of
trypsin has an essential influence on the inhibitory activity.
AB - Three new analogues of trypsin inhibitor CMTI-III were synthesized by the solid
phase method: [Lys5]-CMTI-III, [Orn5]CMTI-III and [Dab5]CMTI-III. Only one
analogue with L-lysine residue in position P1 showed inhibitory activity of the
same order of magnitude as did wild CMTI-III. Two remaining analogues were
completely inactive. A conclusion was drawn that the distance between the basic
group of the amino acid residue's side chain in position P1 of the trypsin
inhibitor CMTI-III and Asp189 in the substrate pocket of trypsin plays an
essential role for the trypsin-inhibitor interaction.
PMID- 9398661
TI - Organization of G proteins and adenylyl cyclase at the plasma membrane.
AB - There is mounting evidence for the organization and compartmentation of signaling
molecules at the plasma membrane. We find that hormone-sensitive adenylyl cyclase
activity is enriched in a subset of regulatory G protein-containing fractions of
the plasma membrane. These subfractions resemble, in low buoyant density,
structures of the plasma membrane termed caveolae. Immunofluorescence experiments
revealed a punctate pattern of G protein alpha and beta subunits, consistent with
concentration of these proteins at distinct sites on the plasma membrane. Partial
coincidence of localization of G protein alpha subunits with caveolin (a marker
for caveolae) was observed by double immunofluorescence. Results of immunogold
electron microscopy suggest that some G protein is associated with invaginated
caveolae, but most of the protein resides in irregular structures of the plasma
membrane that could not be identified morphologically. Because regulated adenylyl
cyclase activity is present in low-density subfractions of plasma membrane from a
cell type (S49 lymphoma) that does not express caveolin, this protein is not
required for organization of the adenylyl cyclase system. The data suggest that
hormone-sensitive adenylyl cyclase systems are localized in a specialized
subdomain of the plasma membrane that may optimize the efficiency and fidelity of
signal transduction.
PMID- 9398662
TI - RanGTP targets p97 to RanBP2, a filamentous protein localized at the cytoplasmic
periphery of the nuclear pore complex.
AB - RanBP2, a protein containing FG repeat motifs and four binding sites for the
guanosine triphosphatase Ran, is localized at the cytoplasmic periphery of the
nuclear pore complex (NPC) and is believed to play a critical role in nuclear
protein import. We purified RanBP2 from rat liver nuclear envelopes and examined
its structural and biochemical properties. Electron microscopy showed that RanBP2
forms a flexible filamentous molecule with a length of approximately 36 nm,
suggesting that it comprises a major portion of the cytoplasmic fibrils
implicated in initial binding of import substrates to the NPC. Using in vitro
assays, we characterized the ability of RanBP2 to bind p97, a cytosolic factor
implicated in the association of the nuclear localization signal receptor with
the NPC. We found that RanGTP promotes the binding of p97 to RanBP2, whereas it
inhibits the binding of p97 to other FG repeat nucleoporins. These data suggest
that RanGTP acts to specifically target p97 to RanBP2, where p97 may support the
binding of an nuclear localization signal receptor/substrate complex to RanBP2 in
an early step of nuclear import.
PMID- 9398663
TI - Gradual phenotypic conversion associated with immortalization of cultured human
mammary epithelial cells.
AB - Examination of the process of immortal transformation in early passages of two
human mammary epithelial cell (HMEC) lines suggests the involvement of an
epigenetic step. These lines, 184A1 and 184B5, arose after in vitro exposure of
finite lifespan 184 HMEC to a chemical carcinogen, and both are clonally derived.
Although early-passage mass cultures of 184A1 and 184B5 maintained continuous
slow growth, most individual cells lost proliferative ability. Uniform good
growth did not occur until 20-30 passages after the lines first appeared. Early
passage cultures expressed little or no telomerase activity and telomeres
continued to shorten with increasing passage. Telomerase activity was first
detected when the telomeres became critically short, and activity levels
gradually increased thereafter. Early-passage cultures had little or no ability
to maintain growth in transforming growth factor-beta (TGFbeta); however, both
mass cultures and clonal isolates showed a very gradual increase in the number of
cells displaying progressively increased ability to maintain growth in TGFbeta. A
strong correlation between capacity to maintain growth in the presence of TGFbeta
and expression of telomerase activity was observed. We have used the term
"conversion" to describe this process of gradual acquisition of increased growth
capacity in the absence or presence of TGFbeta and reactivation of telomerase. We
speculate that the development of extremely short telomeres may result in
gradual, epigenetic-based changes in gene expression. Understanding the
underlying mechanisms of HMEC conversion in vitro may provide new insight into
the process of carcinogenic progression in vivo and offer novel modes for
therapeutic intervention.
PMID- 9398664
TI - Dissociation of Oct-1 from the nuclear peripheral structure induces the cellular
aging-associated collagenase gene expression.
AB - The cellular aging-associated transcriptional repressor that we previously named
as Orpheus was identical to Oct-1, a member of the POU domain family. Oct-1
represses the collagenase gene, one of the cellular aging-associated genes, by
interacting with an AT-rich cis-element in the upstream of the gene in
preimmortalized cells at earlier population-doubling levels and in immortalized
cells. In these stages of cells, considerable fractions of the Oct-1 protein were
prominently localized in the nuclear periphery and colocalized with lamin B.
During the cellular aging process, however, this subspecies of Oct-1 disappeared
from the nuclear periphery. The cells lacking the nuclear peripheral Oct-1
protein exhibited strong collagenase expression and carried typical senescent
morphologies. Concomitantly, the binding activity and the amount of nuclear Oct-1
protein were reduced in the aging process and resumed after immortalization.
However, the whole cellular amounts of Oct-1 protein were not significantly
changed during either process. Thus, the cellular aging-associated genes
including the collagenase gene seemed to be derepressed by the dissociation of
Oct-1 protein from the nuclear peripheral structure. Oct-1 may form a
transcriptional repressive apparatus by anchoring nuclear matrix attachment
regions onto the nuclear lamina in the nuclear periphery.
PMID- 9398665
TI - SET1, a yeast member of the trithorax family, functions in transcriptional
silencing and diverse cellular processes.
AB - The trithorax gene family contains members implicated in the control of
transcription, development, chromosome structure, and human leukemia. A feature
shared by some family members, and by other proteins that function in chromatin
mediated transcriptional regulation, is the presence of a 130- to 140-amino acid
motif dubbed the SET or Tromo domain. Here we present analysis of SET1, a yeast
member of the trithorax gene family that was identified by sequence inspection to
encode a 1080-amino acid protein with a C-terminal SET domain. In addition to its
SET domain, which is 40-50% identical to those previously characterized, SET1
also shares dispersed but significant similarity to Drosophila and human
trithorax homologues. To understand SET1 function(s), we created a null mutant.
Mutant strains, although viable, are defective in transcriptional silencing of
the silent mating-type loci and telomeres. The telomeric silencing defect is
rescued not only by full-length episomal SET1 but also by the conserved SET
domain of SET1. set1 mutant strains display other phenotypes including
morphological abnormalities, stationary phase defects, and growth and sporulation
defects. Candidate genes that may interact with SET1 include those with functions
in transcription, growth, and cell cycle control. These data suggest that yeast
SET1, like its SET domain counterparts in other organisms, functions in diverse
biological processes including transcription and chromatin structure.
PMID- 9398667
TI - alphavbeta3 integrin mediates the cell-adhesive capacity and biological activity
of basic fibroblast growth factor (FGF-2) in cultured endothelial cells.
AB - Fibroblast growth factor-2 (FGF-2) immobilized on non-tissue culture plastic
promotes adhesion and spreading of bovine and human endothelial cells that are
inhibited by anti-FGF-2 antibody. Heat-inactivated FGF-2 retains its cell
adhesive activity despite its incapacity to bind to tyrosine-kinase FGF receptors
or to cell-surface heparan sulfate proteoglycans. Recombinant glutathione-S
transferase-FGF-2 chimeras and synthetic FGF-2 fragments identify two cell
adhesive domains in FGF-2 corresponding to amino acid sequences 38-61 and 82-101.
Both regions are distinct from the FGF-receptor-binding domain of FGF-2 and
contain a DGR sequence that is the inverse of the RGD cell-recognition sequence.
Calcium deprivation, RGD-containing eptapeptides, soluble vitronectin (VN), but
not fibronectin (FN), inhibit cell adhesion to FGF-2. Conversely, soluble FGF-2
prevents cell adhesion to VN but not FN, thus implicating VN receptor in the cell
adhesive activity of FGF-2. Accordingly, monoclonal and polyclonal anti
alphavbeta3 antibodies prevent cell adhesion to FGF-2. Also, purified human
alphavbeta3 binds to immobilized FGF-2 in a cation-dependent manner, and this
interaction is competed by soluble VN but not by soluble FN. Finally, anti
alphavbeta3 monoclonal and polyclonal antibodies specifically inhibit mitogenesis
and urokinase-type plasminogen activator (uPA) up-regulation induced by free FGF
2 in endothelial cells adherent to tissue culture plastic. These data demonstrate
that FGF-2 interacts with alphavbeta3 integrin and that this interaction mediates
the capacity of the angiogenic growth factor to induce cell adhesion,
mitogenesis, and uPA up-regulation in endothelial cells.
PMID- 9398666
TI - Inhibition of RhoA translocation and calcium sensitization by in vivo ADP
ribosylation with the chimeric toxin DC3B.
AB - Pretreatment of intact rabbit portal vein smooth muscle with the chimeric toxin
DC3B (10(-6) M, 48 h; ; ) ADP-ribosylated endogenous RhoA, including cytosolic
RhoA complexed with rhoGDI, and inhibited the tonic phase of phenylephrine
induced contraction and the Ca2+-sensitization of force by phenylephrine,
endothelin and guanosine triphosphate (GTP)gammaS, but did not inhibit Ca2+
sensitization by phorbol dibutyrate. DC3B also inhibited GTPgammaS-induced
translocation of cytosolic RhoA () to the membrane fraction. In DC3B-treated
muscles the small fraction of membrane-associated RhoA could be
immunoprecipitated, even after exposure to GTPgammaS, which prevents
immunoprecipitation of non-ADP-ribosylated RhoA. Dissociation of cytosolic RhoA
rhoGDI complexes with SDS restored the immunoprecipitability and ADP
ribosylatability of RhoA, indicating that both the ADP-ribosylation site (Asn 41)
and RhoA insert loop (Wei et al., 1997) are masked by rhoGDI and that the long
axes of the two proteins are in parallel in the heterodimer. We conclude that
RhoA plays a significant role in G-protein-, but not protein kinase C-mediated,
Ca2+ sensitization and that ADP ribosylation inhibits in vivo the Ca2+
sensitizing effect of RhoA by interfering with its binding to a membrane
associated effector.
PMID- 9398668
TI - Interaction of class I human leukocyte antigen (HLA-I) molecules with insulin
receptors and its effect on the insulin-signaling cascade.
AB - Insulin receptor (IR) and class I major histocompatibility complex molecules
associate with one another in cell membranes, but the functional consequences of
this association are not defined. We found that IR and human class I molecules
(HLA-I) associate in liposome membranes and that the affinity of IR for insulin
and its tyrosine kinase activity increase as the HLA:IR ratio increases over the
range 1:1 to 20:1. The same relationship between HLA:IR and IR function was found
in a series of B-LCL cell lines. The association of HLA-I and IR depends upon the
presence of free HLA heavy chains. All of the effects noted were reduced or
abrogated if liposomes or cells were incubated with excess HLA-I light chain,
beta2-microglobulin. Increasing HLA:IR also enhanced phosphorylation of insulin
receptor substrate-1 and the activation of phosphoinositide 3-kinase. HLA-I
molecules themselves were phosphorylated on tyrosine and associated with
phosphoinositide 3-kinase when B-LCL were stimulated with insulin.
PMID- 9398669
TI - A WD repeat protein controls the cell cycle and differentiation by negatively
regulating Cdc2/B-type cyclin complexes.
AB - In the fission yeast Schizosaccharomyces pombe, p34(cdc2) plays a central role
controlling the cell cycle. We recently isolated a new gene named srw1(+),
capable of encoding a WD repeat protein, as a multicopy suppressor of
hyperactivated p34(cdc2). Cells lacking srw1(+) are sterile and defective in cell
cycle controls. When starved for nitrogen source, they fail to effectively arrest
in G1 and die of accelerated mitotic catastrophe if regulation of p34(cdc2)/Cdc13
by inhibitory tyrosine phosphorylation is compromised by partial inactivation of
Wee1 kinase. Fertility is restored to the disruptant by deletion of Cig2 B-type
cyclin or slight inactivation of p34(cdc2). srw1(+) shares functional similarity
with rum1(+), having abilities to induce endoreplication and restore fertility to
rum1 disruptants. In the srw1 disruptant, Cdc13 fails to be degraded when cells
are starved for nitrogen. We conclude that Srw1 controls differentiation and cell
cycling at least by negatively regulating Cig2- and Cdc13-associated p34(cdc2)
and that one of its roles is to down-regulate the level of the mitotic cyclin
particularly in nitrogen-poor environments.
PMID- 9398670
TI - Yeast cycloheximide-resistant crl mutants are proteasome mutants defective in
protein degradation.
AB - In 1988 McCusker and Haber generated a series of mutants which are resistant to
the minimum inhibitory concentration of the protein synthesis inhibitor
cycloheximide. These cycloheximide-resistant, temperature-sensitive (crl)
mutants, in addition, exhibited other pleiotropic phenotypes, e.g., incorrect
response to starvation, hypersensitivity against amino acid analogues, and other
protein synthesis inhibitors. Temperature sensitivity of one of these mutants,
crl3-2, had been found to be suppressed by a mutation, SCL1-1, which resided in
an alpha-type subunit of the 20S proteasome. We cloned the CRL3 gene by
complementation and found CRL3 to be identical to the SUG1/CIM3 gene coding for a
subunit of the 19S cap complex of the 26S proteasome. Another mutation, crl21,
revealed to be allelic with the 20S proteasomal gene PRE3. crl3-2 and crl21
mutant cells show significant defects in proteasome-dependent proteolysis,
whereas the SCL1-1 suppressor mutation causes partial restoration of crl3-2
induced proteolytic defects. Notably, cycloheximide resistance was also detected
for other proteolytically deficient proteasome mutants (pre1-1, pre2-1, pre3-1,
pre4-1). Moreover, proteasomal genes were found within genomic sequences of 9 of
13 chromosomal loci to which crl mutations had been mapped. We therefore assume
that most if not all crl mutations reside in the proteasome and that phenotypes
found are a result of defective protein degradation.
PMID- 9398672
TI - Gene conversion of major histocompatibility complex genes in the mouse
spermatogenesis is a premeiotic event.
AB - The molecular genetic mechanism of gene conversion in higher eukaryotes remains
unknown. We find it of considerable interest to determine when during
spermatogenesis gene conversion occurs. We have therefore purified pachytene
spermatocytes and haploid spermatocytes from adult mice and analyzed these
fractions for the presence of gene conversion products resulting from the
transfer between the major histocompatibility complex class II genes Ebd and Abk
in a polymerase chain reaction assay. We have further isolated spermatogenic
cells from prepubescent mice and analyzed them for the presence of the same gene
conversion products. We can detect gene conversion products in testis cells as
early as in 8-d-old mice where the only existing spermatogenic cells are
spermatogonia. The frequency of gene conversion products remains the same as the
cells reach meiosis in 18-d-old mice, and is unchanged after meiosis is completed
in haploid spermatocytes. Gene conversion of this specific fragment therefore
appears to be a premeiotic event and, consequently, relies on genetic mechanisms
other than normal meiotic recombination.
PMID- 9398671
TI - Differential in vivo regulation of steroid hormone receptor activation by Cdc37p.
AB - The CDC37 gene is essential for the activity of p60(v-src) when expressed in
yeast cells. Since the activation pathway for p60(v-src) and steroid hormone
receptors is similar, the present study analyzed the hormone-dependent
transactivation by androgen receptors and glucocorticoid receptors in yeast cells
expressing a mutant version of the CDC37 gene. In this mutant, hormone-dependent
transactivation by androgen receptors was defective at both permissive and
restrictive temperatures, although transactivation by glucocorticoid receptors
was mildly defective only at the restrictive temperature. Cdc37p appears to
function via the androgen receptor ligand-binding domain, although it does not
influence receptor hormone-binding affinity. Models for Cdc37p regulation of
steroid hormone receptors are discussed.
PMID- 9398673
TI - Characterization of Saccharomyces cerevisiae dna2 mutants suggests a role for the
helicase late in S phase.
AB - The TOR proteins, originally identified as targets of the immunosuppressant
rapamycin, contain an ATM-like "lipid kinase" domain and are required for early
G1 progression in eukaryotes. Using a screen to identify Saccharomyces cerevisiae
mutants requiring overexpression of Tor1p for viability, we have isolated
mutations in a gene we call ROT1 (requires overexpression of Tor1p). This gene is
identical to DNA2, encoding a helicase required for DNA replication. As with its
role in cell cycle progression, both the N-terminal and C-terminal regions, as
well as the kinase domain of Tor1p, are required for rescue of dna2 mutants. Dna2
mutants are also rescued by Tor2p and show synthetic lethality with tor1 deletion
mutants under specific conditions. Temperature-sensitive (Ts) dna2 mutants arrest
irreversibly at G2/M in a RAD9- and MEC1-dependent manner, suggesting that Dna2p
has a role in S phase. Frequencies of mitotic recombination and chromosome loss
are elevated in dna2 mutants, also supporting a role for the protein in DNA
synthesis. Temperature-shift experiments indicate that Dna2p functions during
late S phase, although dna2 mutants are not deficient in bulk DNA synthesis.
These data suggest that Dna2p is not required for replication fork progression
but may be needed for a later event such as Okazaki fragment maturation.
PMID- 9398675
TI - Ubiquitously expressed dynamin-II has a higher intrinsic GTPase activity and a
greater propensity for self-assembly than neuronal dynamin-I.
AB - To begin to understand mechanistic differences in endocytosis in neurons and
nonneuronal cells, we have compared the biochemical properties of the
ubiquitously expressed dynamin-II isoform with those of neuron-specific dynamin
I. Like dynamin-I, dynamin-II is specifically localized to and highly
concentrated in coated pits on the plasma membrane and can assemble in vitro into
rings and helical arrays. As expected, the two closely related isoforms share a
similar mechanism for GTP hydrolysis: both are stimulated in vitro by self
assembly and by interaction with microtubules or the SH3 domain-containing
protein, grb2. Deletion of the C-terminal proline/arginine-rich domain from
either isoform abrogates self-assembly and assembly-dependent increases in GTP
hydrolysis. However, dynamin-II exhibits a approximately threefold higher rate of
intrinsic GTP hydrolysis and higher affinity for GTP than dynamin-I. Strikingly,
the stimulated GTPase activity of dynamin-II can be >40-fold higher than dynamin
I, due principally to its greater propensity for self-assembly and the increased
resistance of assembled dynamin-II to GTP-triggered disassembly. These results
are consistent with the hypothesis that self-assembly is a major regulator of
dynamin GTPase activity and that the intrinsic rate of GTP hydrolysis reflects a
dynamic, GTP-dependent equilibrium of assembly and disassembly.
PMID- 9398676
TI - Modulatory roles for integrin activation and the synergy site of fibronectin
during matrix assembly.
AB - Initiation of fibronectin (FN) matrix assembly is dependent on specific
interactions between FN and cell surface integrin receptors. Here, we show that
de novo FN matrix assembly exhibits a slow phase during initiation of
fibrillogenesis followed by a more rapid growth phase. Mn2+, which acts by
enhancing integrin function, increased the rate of FN fibril growth, but only
after the initial lag phase. The RGD cell-binding sequence in type III repeat 10
is an absolute requirement for initiation by alpha5beta1 integrin. To investigate
the role of the cell-binding synergy site in the adjacent repeat III9, a full
length recombinant FN containing a synergy mutation, FN(syn-), was tested for its
ability to form fibrils. Mutation of this site drastically reduced FN assembly by
CHOalpha5 cells. Only sparse short fibrils were formed even after prolonged
incubation, indicating that FN(syn-) is defective in progression of the assembly
process. These results show that the synergy site is essential for alpha5beta1
mediated accumulation of a FN matrix. However, the incorporation of FN(syn-) into
fibrils and the deoxycholate-insoluble matrix could be stimulated by Mn2+.
Therefore, exogenous activation of integrin receptors can overcome the
requirement for FN's synergy site as well as modulate the rate of FN matrix
formation.
PMID- 9398674
TI - Derepressed hyphal growth and reduced virulence in a VH1 family-related protein
phosphatase mutant of the human pathogen Candida albicans.
AB - Mitogen-activated protein (MAP) kinases are pivotal components of eukaryotic
signaling cascades. Phosphorylation of tyrosine and threonine residues activates
MAP kinases, but either dual-specificity or monospecificity phosphatases can
inactivate them. The Candida albicans CPP1 gene, a structural member of the VH1
family of dual- specificity phosphatases, was previously cloned by its ability to
block the pheromone response MAP kinase cascade in Saccharomyces cerevisiae.
Cpp1p inactivated mammalian MAP kinases in vitro and acted as a tyrosine-specific
enzyme. In C. albicans a MAP kinase cascade can trigger the transition from the
budding yeast form to a more invasive filamentous form. Disruption of the CPP1
gene in C. albicans derepressed the yeast to hyphal transition at ambient
temperatures, on solid surfaces. A hyphal growth rate defect under physiological
conditions in vitro was also observed and could explain a reduction in virulence
associated with reduced fungal burden in the kidneys seen in a systemic mouse
model. A hyper-hyphal pathway may thus have some detrimental effects on C.
albicans cells. Disruption of the MAP kinase homologue CEK1 suppressed the
morphological effects of the CPP1 disruption in C. albicans. The results
presented here demonstrate the biological importance of a tyrosine phosphatase in
cell-fate decisions and virulence in C. albicans.
PMID- 9398677
TI - A mutational analysis identifies three functional regions of the spindle pole
component Spc110p in Saccharomyces cerevisiae.
AB - The central coiled coil of the essential spindle pole component Spc110p spans the
distance between the central and inner plaques of the Saccharomyces cerevisiae
spindle pole body (SPB). The carboxy terminus of Spc110p, which binds calmodulin,
resides at the central plaque, and the amino terminus resides at the inner plaque
from which nuclear microtubules originate. To dissect the functions of Spc110p,
we created temperature-sensitive mutations in the amino and carboxy termini.
Analysis of the temperature-sensitive spc110 mutations and intragenic
complementation analysis of the spc110 alleles defined three functional regions
of Spc110p. Region I is located at the amino terminus. Region II is located at
the carboxy-terminal end of the coiled coil, and region III is the previously
defined calmodulin-binding site. Overexpression of SPC98 suppresses the
temperature sensitivity conferred by mutations in region I but not the phenotypes
conferred by mutations in the other two regions, suggesting that the amino
terminus of Spc110p is involved in an interaction with the gamma-tubulin complex
composed of Spc97p, Spc98p, and Tub4p. Mutations in region II lead to loss of SPB
integrity during mitosis, suggesting that this region is required for the stable
attachment of Spc110p to the central plaque. Our results strongly argue that
Spc110p links the gamma-tubulin complex to the central plaque of the SPB.
PMID- 9398678
TI - A T42A Ran mutation: differential interactions with effectors and regulators, and
defect in nuclear protein import.
AB - Ran, the small, predominantly nuclear GTPase, has been implicated in the
regulation of a variety of cellular processes including cell cycle progression,
nuclear-cytoplasmic trafficking of RNA and protein, nuclear structure, and DNA
synthesis. It is not known whether Ran functions directly in each process or
whether many of its roles may be secondary to a direct role in only one, for
example, nuclear protein import. To identify biochemical links between Ran and
its functional target(s), we have generated and examined the properties of a
putative Ran effector mutation, T42A-Ran. T42A-Ran binds guanine nucleotides as
well as wild-type Ran and responds as well as wild-type Ran to GTP or GDP
exchange stimulated by the Ran-specific guanine nucleotide exchange factor, RCC1.
T42A-Ran.GDP also retains the ability to bind p10/NTF2, a component of the
nuclear import pathway. In contrast to wild-type Ran, T42A-Ran.GTP binds very
weakly or not detectably to three proposed Ran effectors, Ran-binding protein 1
(RanBP1), Ran-binding protein 2 (RanBP2, a nucleoporin), and karyopherin beta (a
component of the nuclear protein import pathway), and is not stimulated to
hydrolyze bound GTP by Ran GTPase-activating protein, RanGAP1. Also in contrast
to wild-type Ran, T42A-Ran does not stimulate nuclear protein import in a
digitonin permeabilized cell assay and also inhibits wild-type Ran function in
this system. However, the T42A mutation does not block the docking of karyophilic
substrates at the nuclear pore. These properties of T42A-Ran are consistent with
its classification as an effector mutant and define the exposed region of Ran
containing the mutation as a probable effector loop.
PMID- 9398679
TI - Myosin heavy chain phosphorylation sites regulate myosin localization during
cytokinesis in live cells.
AB - Conventional myosin II plays a fundamental role in the process of cytokinesis
where, in the form of bipolar thick filaments, it is thought to be the molecular
motor that generates the force necessary to divide the cell. In Dictyostelium,
the formation of thick filaments is regulated by the phosphorylation of three
threonine residues in the tail region of the myosin heavy chain. We report here
on the effects of this regulation on the localization of myosin in live cells
undergoing cytokinesis. We imaged fusion proteins of the green-fluorescent
protein with wild-type myosin and with myosins where the three critical
threonines had been changed to either alanine or aspartic acid. We provide
evidence that thick filament formation is required for the accumulation of myosin
in the cleavage furrow and that if thick filaments are overproduced, this
accumulation is markedly enhanced. This suggests that myosin localization in
dividing cells is regulated by myosin heavy chain phosphorylation.
PMID- 9398680
TI - On the role of myosin-II in cytokinesis: division of Dictyostelium cells under
adhesive and nonadhesive conditions.
AB - We have investigated the role of myosin in cytokinesis in Dictyostelium cells by
examining cells under both adhesive and nonadhesive conditions. On an adhesive
surface, both wild-type and myosin-null cells undergo the normal processes of
mitotic rounding, cell elongation, polar ruffling, furrow ingression, and
separation of daughter cells. When cells are denied adhesion through culturing in
suspension or on a hydrophobic surface, wild-type cells undergo these same
processes. However, cells lacking myosin round up and polar ruffle, but fail to
elongate, furrow, or divide. These differences show that cell division can be
driven by two mechanisms that we term Cytokinesis A, which requires myosin, and
Cytokinesis B, which is cell adhesion dependent. We have used these approaches to
examine cells expressing a myosin whose two light chain-binding sites were
deleted (DeltaBLCBS-myosin). Although this myosin is a slower motor than wild
type myosin and has constitutively high activity due to the abolition of
regulation by light-chain phosphorylation, cells expressing DeltaBLCBS-myosin
were previously shown to divide in suspension (Uyeda et al., 1996). However, we
suspected their behavior during cytokinesis to be different from wild-type cells
given the large alteration in their myosin. Surprisingly, DeltaBLCBS-myosin
undergoes relatively normal spatial and temporal changes in localization during
mitosis. Furthermore, the rate of furrow progression in cells expressing a
DeltaBLCBS-myosin is similar to that in wild-type cells.
PMID- 9398681
TI - Accumulation of major histocompatibility complex class II molecules in mast cell
secretory granules and their release upon degranulation.
AB - To investigate the relationship between major histocompatibility complex (MHC)
class II compartments, secretory granules, and secretory lysosomes, we analyzed
the localization and fate of MHC class II molecules in mast cells. In bone marrow
derived mast cells, the bulk of MHC class II molecules is contained in two
distinct compartments, with features of both lysosomal compartments and secretory
granules defined by their protein content and their accessibility to endocytic
tracers. Type I granules display internal membrane vesicles and are accessed by
exogenous molecules after a time lag of 20 min; type II granules are reached by
the endocytic tracer later and possess a serotonin-rich electron-dense core
surrounded by a multivesicular domain. In these type I and type II granules, MHC
class II molecules, mannose-6-phosphate receptors and lysosomal membrane proteins
(lamp1 and lamp2) localize to small intralumenal vesicles. These 60-80-nm
vesicles are released along with inflammatory mediators during mast cell
degranulation triggered by IgE-antigen complexes. These observations emphasize
the intimate connection between the endocytic and secretory pathways in cells of
the hematopoietic lineage which allows regulated secretion of the contents of
secretory lysosomes, including membrane proteins associated with small vesicles.
PMID- 9398682
TI - Defining extracellular integrin alpha-chain sites that affect cell adhesion and
adhesion strengthening without altering soluble ligand binding.
AB - It was previously shown that mutations of integrin alpha4 chain sites, within
putative EF-hand-type divalent cation-binding domains, each caused a marked
reduction in alpha4beta1-dependent cell adhesion. Some reports have suggested
that alpha-chain "EF-hand" sites may interact directly with ligands. However, we
show here that mutations of three different alpha4 "EF-hand" sites each had no
effect on binding of soluble monovalent or bivalent vascular cell adhesion
molecule 1 whether measured indirectly or directly. Furthermore, these mutations
had minimal effect on alpha4beta1-dependent cell tethering to vascular cell
adhesion molecule 1 under shear. However, EF-hand mutants did show severe
impairments in cellular resistance to detachment under shear flow. Thus, mutation
of integrin alpha4 "EF-hand-like" sites may impair 1) static cell adhesion and 2)
adhesion strengthening under shear flow by a mechanism that does not involve
alterations of initial ligand binding.
PMID- 9398683
TI - Characterization of a novel yeast SNARE protein implicated in Golgi retrograde
traffic.
AB - The protein trafficking machinery of eukaryotic cells is employed for protein
secretion and for the localization of resident proteins of the exocytic and
endocytic pathways. Protein transit between organelles is mediated by transport
vesicles that bear integral membrane proteins (v-SNAREs) which selectively
interact with similar proteins on the target membrane (t-SNAREs), resulting in a
docked vesicle. A novel Saccharomyces cerevisiae SNARE protein, which has been
termed Vti1p, was identified by its sequence similarity to known SNAREs. Vti1p is
a predominantly Golgi-localized 25-kDa type II integral membrane protein that is
essential for yeast viability. Vti1p can bind Sec17p (yeast SNAP) and enter into
a Sec18p (NSF)-sensitive complex with the cis-Golgi t-SNARE Sed5p. This
Sed5p/Vti1p complex is distinct from the previously described Sed5p/Sec22p
anterograde vesicle docking complex. Depletion of Vti1p in vivo causes a defect
in the transport of the vacuolar protein carboxypeptidase Y through the Golgi.
Temperature-sensitive mutants of Vti1p show a similar carboxypeptidase Y
trafficking defect, but the secretion of invertase and gp400/hsp150 is not
significantly affected. The temperature-sensitive vti1 growth defect can be
rescued by the overexpression of the v-SNARE, Ykt6p, which physically interacts
with Vti1p. We propose that Vti1p, along with Ykt6p and perhaps Sft1p, acts as a
retrograde v-SNARE capable of interacting with the cis-Golgi t-SNARE Sed5p.
PMID- 9398684
TI - BIM1 encodes a microtubule-binding protein in yeast.
AB - A previously uncharacterized yeast gene (YER016w) that we have named BIM1
(binding to microtubules) was obtained from a two-hybrid screen of a yeast cDNA
library using as bait the entire coding sequence of TUB1 (encoding alpha
tubulin). Deletion of BIM1 results in a strong bilateral karyogamy defect,
hypersensitivity to benomyl, and aberrant spindle behavior, all phenotypes
associated with mutations affecting microtubules in yeast, and inviability at
extreme temperatures (i.e., >/=37 degrees C or =14 degrees C). Overexpression
of BIM1 in wild-type cells is lethal. A fusion of Bim1p with green fluorescent
protein that complements the bim1Delta phenotypes allows visualization in vivo of
both intranuclear spindles and extranuclear microtubules in otherwise wild-type
cells. A bim1 deletion displays synthetic lethality with deletion alleles of
bik1, num1, and bub3 as well as a limited subset of tub1 conditional-lethal
alleles. A systematic study of 51 tub1 alleles suggests a correlation between
specific failure to interact with Bim1p in the two-hybrid assay and synthetic
lethality with the bim1Delta allele. The sequence of BIM1 shows substantial
similarity to sequences from organisms across the evolutionary spectrum. One of
the human homologues, EB1, has been reported previously as binding APC, itself a
microtubule-binding protein and the product of a gene implicated in the etiology
of human colon cancer.
PMID- 9398685
TI - Identification of a second myosin-II in Schizosaccharomyces pombe: Myp2p is
conditionally required for cytokinesis.
AB - As in many eukaryotic cells, fission yeast cytokinesis depends on the assembly of
an actin ring. We cloned myp2(+), a myosin-II in Schizosaccharomyces pombe,
conditionally required for cytokinesis. myp2(+), the second myosin-II identified
in S. pombe, does not completely overlap in function with myo2(+). The catalytic
domain of Myp2p is highly homologous to known myosin-IIs, and phylogenetic
analysis places Myp2p in the myosin-II family. The Myp2p sequence contains well
conserved ATP- and actin-binding motifs, as well as two IQ motifs. However, the
tail sequence is unusual, since it is predicted to form two long coiled-coils
separated by a stretch of sequence containing 19 prolines. Disruption of myp2(+)
is not lethal but under nutrient limiting conditions cells lacking myp2(+)
function are multiseptated, elongated, and branched, indicative of a defect in
cytokinesis. The presence of salt enhances these morphological defects.
Additionally, Deltamyp2 cells are cold sensitive in high salt, failing to form
colonies at 17 degrees C. Thus, myp2(+) is required under conditions of stress,
possibly linking extracellular growth conditions to efficient cytokinesis and
cell growth. GFP-Myp2p localizes to a ring in the middle of late mitotic cells,
consistent with a role in cytokinesis. Additionally, we constructed double
mutants of Deltamyp2 with temperature-sensitive mutant strains defective in
cytokinesis. We observed synthetic lethal interactions between Deltamyp2 and
three alleles of cdc11ts, as well as more modest synthetic interactions with
cdc14ts and cdc16ts, implicating myp2(+) function for efficient cytokinesis under
normal conditions.
PMID- 9398686
TI - Clinical review 91: Female sex hormones and cardiovascular disease in women.
AB - Cardiovascular disease is the leading cause of mortality in women, a fact that is
underappreciated by women and physicians. Clinical and experimental data
underscore the cardioprotective effects of female sex hormones, particularly
estrogen. Indeed, the loss of female sex hormones after menopause contributes to
the striking increase in the incidence of cardiovascular morbidity and mortality
after menopause. Estrogen replacement therapy improved lipoprotein profiles in
the postmenopausal women, but this accounts for less than half of the
cardioprotective effects of estrogen replacement therapy. Addition of progestins
to estrogen therapy in women appears not to significantly attenuate the
cardioprotective effects of estrogen replacement therapy despite experimental
data suggesting otherwise. This review addresses potential mechanisms, other than
influences on lipoproteins, by which estrogen and progesterone exert their
cardiovascular protective effects. Particular emphasis is directed to genomic and
nongenomic effects of estrogen and progesterone that are exerted directly on
cardiovascular tissue.
PMID- 9398687
TI - Growth hormone/insulin-like growth factor-I axis in aging: a summary of a
National Institutes of Aging-Sponsored Symposium.
PMID- 9398688
TI - Steroid therapy for adrenal disorders--getting the dose right.
PMID- 9398689
TI - The effects of glucocorticoid replacement therapy on growth, bone mineral
density, and bone turnover markers in children with congenital adrenal
hyperplasia.
AB - Even with current so called physiologic doses of glucocorticoid replacement
therapy, children with congenital adrenal hyperplasia (CAH) often show relative
short stature and delayed bone maturation, an observation that suggests possible
long-term effects on bone metabolism of daily transient post-absorptive
hypercortisolemia. In 28 patients with 21-hydroxylase or 17 alpha-hydroxylase
deficiency (16 females and 12 males, ages 4.9-22 yr) who had received oral
cortisol 10-15 mg/M2/day for 4.7-22 yr, we studied cortisol bioavailability,
growth, bone maturation, vertebral bone mineral density, and various markers of
bone formation and resorption. Patients were grouped according to mean on-therapy
serum 170H-progesterone or progesterone levels as tight control (170HP < 10
nmol/L), fair control (170HP 10-40 nmol/L or progesterone 1.0-1.5 nmol/L), or
poor control (170HP > 40 nmol/L). There was no difference in peak post-absorptive
serum cortisol or area under the concentration-time curve, and only three
patients had a peak serum cortisol of more than 700 nmol/L. There was no
difference in present height Z-score (-0.96; -0.24; -0.6), height Z-score at age
2 yr (-1.5; +0.4; -1.3), or current growth velocity Z-score (-0.1; +1.2; -2.2)
between the groups, but bone maturation Z-score was significantly delayed (-1.63)
in the tight control group and advanced (+0.8) in the poor control group. Present
height was highly correlated (r = 0.8) with height at age 2 yr. Serum calcium,
phosphorus, alkaline phosphatase, parathormone, and 25OH-vitamin D levels were
all normal. There was no difference between the groups in age-corrected vertebral
bone mineral density, and no difference in serum osteocalcin, procollagen
peptide, or collagen C-terminal telopeptide, nor in urinary amino-terminal
telopeptide. The data suggest that current methods of cortisol replacement do not
significantly influence bone formation, resorption or density during childhood
and therefore should not contribute to adult osteoporosis. The possibility
remains that hypercortisolemia during infancy produces the short stature and
delayed bone maturation that are present by the age 2 yr.
PMID- 9398690
TI - Resistance to TSH in patients with normal TSH receptors--where do we turn when
"Sutton's law" proves false?
PMID- 9398691
TI - Resistance to thyrotropin (TSH) in three families is not associated with
mutations in the TSH receptor or TSH.
AB - Resistance to TSH (RTSH) is a recently described syndrome of reduced sensitivity
to TSH that manifests as euthyroid hyperthyrotropinemia. It is usually identified
at birth during routine neonatal screening for congenital hypothyroidism. In less
than 2 yr, 13 subjects with RTSH belonging to 8 families have been reported, and
all were shown to harbor mutations in the TSH receptor (TSHR) gene. We now report
the occurrence of RTSH in 3 unrelated families. Contrary to previous reports, the
inheritance of RTSH in 2 of the families was dominant rather than recessive and
was not associated with abnormalities in the TSHR gene. Abnormalities in the TSHR
gene were excluded by sequencing all coding sequences, exon/intron junctions, and
the promoter region of the gene. Furthermore, the involvement of the TSHR in the
manifestation of the RTSH phenotype was excluded in 2 families by linkage
analysis using intragenic polymorphic markers. We excluded defects in the TSH
beta-subunit by sequencing its gene and by showing that the circulating TSH in
affected subjects from all families had normal bioactivity. Also, no
abnormalities were found in the Gs alpha gene of one family analyzed by GC
clamped denaturing gradient gel electrophoresis. This study shows that RTSH may
be a manifestation of several different genetic defects that requires the
exploration of other candidate genes involved in the TSH-TSHR-Gs alpha cascade
and genes participating in its regulation.
PMID- 9398692
TI - The binding protein's binding protein--clinical applications of acid-labile
subunit (ALS) measurement.
PMID- 9398693
TI - Acid-labile subunit of human insulin-like growth factor-binding protein complex:
measurement, molecular, and clinical evaluation.
AB - Although the acid-labile subunit (ALS) of the approximately 150-kDa insulin-like
growth factor (IGF)-binding protein (IGFBP) complex was described over a decade
ago, details of ALS physiology have remained largely uncertain. We evaluated
antibodies to synthetic human ALS and constructed a noncompetitive ALS enzyme
linked immunosorbent assay. Whereas uncomplexed ALS is directly measured,
determination of total levels required sample pretreatment with SDS, which was
found to optimally dissociate complexed ALS and significantly enhance ALS
immunoreactivity. ALS in random adult sera was approximately 50% uncomplexed, and
samples devoid of complexed ALS by immunoaffinity separation contained about 54%
of the total levels. Serum ALS fractionated by gel filtration high performance
liquid chromatography eluted in a single peak at approximately 150 kDa with IGF-I
and IGFBP-3, but appeared at about 400-500 kDa after sample acidification and
fractionation under acidic condition. The unexpected shift in ALS
immunoreactivity remained unchanged when acid-neutralized or SDS-treated samples
were fractionated under neutral pH and was reproducible when the 150-kDa complex
was isolated, treated with acid or SDS, and rechromatographed. ALS in adult sera
more tightly correlated with IGFBP-3 than IGF-I or IGF-II. The total levels (mean
+/- SD) were 16.7 +/- 3.7 mg/L in 22 normal subjects, 28.3 +/- 8.1 mg/L in 20
acromegalic patients, and 9.5 +/- 3.8 in 32 GH-deficient adults. Little or no ALS
was detectable in amniotic fluid, cerebrospinal fluid, seminal plasma, or milk,
whereas high levels were present in synovial fluid. The development of ALS enzyme
linked immunosorbent assay should greatly facilitate further investigations of
this unique glycoprotein.
PMID- 9398694
TI - Multiple beneficial effects of estrogen on lipoprotein metabolism.
PMID- 9398695
TI - Effect of estrogen on very low density lipoprotein and low density lipoprotein
subclass metabolism in postmenopausal women.
AB - Estrogen decreases low density lipoprotein (LDL) particle size, and smaller LDL
particles are associated with coronary atherosclerosis. To understand the
metabolic basis for this change, we studied the effect of oral 17 beta-estradiol
(2 mg/day) on apolipoprotein B-100 (apoB) metabolism, in eight healthy
postmenopausal women. The study was a randomized, double blinded, placebo
controlled, cross-over trial with intervention sequences of 6 weeks each. ApoB in
very low density lipoprotein, intermediate density lipoprotein, and LDL
subclasses was endogenously labeled with [D3]L-leucine, and metabolic rates were
calculated by computer modeling. The overall effect of oral estrogen therapy on
apoB metabolism was to accelerate the fractional catabolic rates of all particles
studied and production rates of all except IDL. For light LDL (density = 1.019
1.036 g/mL), estrogen increased the mean fractional catabolic rate by 63% from
0.59 to 0.96 pools/day (P = 0.02), whereas the production rate increased by a
lesser amount (42%) from 575 to 817 mg/day (P = 0.10). These metabolic changes
reduced light LDL cholesterol and apoB concentrations by 26% (P = 0.005) and 19%
(P = 0.03), respectively. In contrast, dense LDL (density = 1.036-1.063 g/mL)
cholesterol and apoB concentrations were unchanged by the intervention, as both
the apoB fractional catabolic rate and production rate were significantly
increased by similar amounts, 39% (from 0.41 to 0.57 pools/day, P = 0.01) and 38%
(from 434 to 601 mg/day; P = 0.003), respectively. Estrogen decreased the
predominant LDL peak particle size from 273 to 268 A (P = 0.04). Thus, estrogen
therapy increases the clearance of both light and dense LDL, counteracting
increases in production rates. The reduced plasma residence times of light and
dense LDL both may be antiatherogenic, even though, for dense LDL, the
concentration did not change.
PMID- 9398696
TI - Mutations and disorders involving the thyroid iodide transporter--the next wave
in thyroid diseases.
PMID- 9398697
TI - A homozygous missense mutation of the sodium/iodide symporter gene causing iodide
transport defect.
AB - Iodide transport defect is a disorder characterized by an inability of the
thyroid to maintain an iodide concentration difference between the plasma and the
thyroid. The recent cloning of the sodium/iodide symporter (NIS) gene enabled us
to characterize the NIS gene in this disorder. We identified a homozygous
missense mutation of A-->C at nucleotide +1060 in NIS complementary DNA in a male
patient who was born from consanguineous marriage, had a huge goiter, and lacked
the ability to accumulate iodide but was essentially euthyroid. The mutation
results in an amino acid replacement of Thr354-->Pro in the middle of the ninth
transmembrane domain. COS-7 cells transfected with the mutant NIS complementary
DNA showed markedly decreased iodide uptake, confirming that this mutation was
the direct cause of the disorder in the patient. Northern analysis of thyroid
ribonucleic acid revealed that NIS messenger ribonucleic acid level was markedly
increased (> 100-fold) compared with that in the normal thyroid, suggesting
possible compensation by overexpression.
PMID- 9398698
TI - A 37-year-old female with a shoulder mass and hypertensive crisis.
PMID- 9398699
TI - Serum inhibin B in healthy pubertal and adolescent boys: relation to age, stage
of puberty, and follicle-stimulating hormone, luteinizing hormone, testosterone,
and estradiol levels.
AB - Inhibin B levels were measured in serum from 400 healthy Danish prepubertal,
pubertal, and adolescent males, aged 6-20 yr, in a cross-sectional study using a
recently developed immunoassay that is specific for inhibin B, the
physiologically important inhibin form in men. In addition, serum levels of FSH,
LH, testosterone, and estradiol levels were measured. Serum levels of inhibin B,
FSH, LH, testosterone, and estradiol all increased significantly between stages I
and II of puberty. From stage II of puberty the inhibin B level was relatively
constant, whereas the FSH level continued to increase between stages II and III.
From stage III of puberty the FSH level was also relatively constant, although
there was a nonsignificant trend of slightly decreased FSH levels at pubertal
stage V compared to stage IV. The levels of serum LH, testosterone, and estradiol
increased progressively throughout puberty. In prepubertal boys younger than 9
yr, there were no correlation between inhibin B and the other three hormones. In
prepubertal boys older than 9 yr, a significant positive correlation was observed
between inhibin B and FSH, LH, and testosterone. However, at this pubertal stage,
each hormone correlated strongly with age, and when the effect of age was taken
into account, only the partial correlation between inhibin B and LH/testosterone
remained statistically significant. At stage II of puberty, the positive partial
correlation between inhibin B and LH/testosterone was still present. At stage III
of puberty, an negative partial correlation between inhibin B and FSH, LH, and
estradiol was present, whereas no correlation between inhibin B and testosterone
could be observed from stage III onward. The negative correlation between inhibin
B and FSH persisted from stage III of puberty onward, whereas the correlation
between inhibin B and LH and between inhibin B and estradiol was nonsignificant
at stages IV and V of puberty. In conclusion, in boys, serum inhibin B levels
increase early in puberty; by pubertal stage II the adult level of inhibin B has
been reached. The correlation of inhibin B to FSH, LH, and testosterone changes
during pubertal development. Early puberty is characterized by a positive
correlation between inhibin B and LH/testosterone, but no correlation to FSH.
Late puberty (from stage III) is characterized by a negative correlation between
inhibin B and FSH (which is maintained in adult men), a diminishing negative
correlation between inhibin B and LH, and no correlation between inhibin B and
testosterone, suggesting that developmental and maturational processes in the
hypothalamic-pituitary-gonadal axis take place, leading to the establishment of
the closed loop feedback regulation system operating in adult men. The positive
correlation between inhibin B and LH/ testosterone at the time when serum inhibin
B levels rise early in puberty suggests that Leydig cell factors may play an
important role in the maturation and stimulation of Sertoli cells in the
beginning of pubertal development.
PMID- 9398700
TI - Use of insulin-like growth factor I (IGF-I) and IGF-binding protein measurements
to monitor feeding of premature infants.
AB - To determine whether peptides of the insulin-like growth factor (IGF) system
might be useful indicators of nutritional adequacy in premature infants, we
studied 50 premature (25-34 weeks gestation) infants prospectively to define the
relationship between nutrient intake and serum concentrations of IGF-I, IGF
binding protein-2 (IGFBP-2), and IGFBP-3. Each infant was monitored for at least
2 weeks. Nutrient intake was quantified from daily logs; weight was determined
daily, and measurements of IGF-I, IGFBP-2, and IGFBP-3 in serum were made twice
weekly. Serum IGF-I correlated strongly with length of gestation, increasing 4.03
+/- 0.95 ng/mL for each additional week of gestation (P < 0.0001) and 0.36 +/-
0.07 ng/mL day each day since birth (P < 0.0001). A higher intake of calories
increased IGF-I by 0.07 +/- 0.01 ng/mL for each calorie per kg ingested over the
previous 3 days (P < 0.0001). IGF-I increased quadratically as protein intake
increased. For each change of 1% in calories as protein squared, IGF-I increased
0.36 +/- 0.11 ng/mL (P < 0.0001). Serum IGFBP-3 concentrations also correlated
with length of gestation, increasing 25.06 +/- 11.83 micrograms/L.wk (P = 0.035)
and 4.14 +/- 1.33 micrograms/.day since birth (P = 0.003). Unlike IGF-I,
variation in the amount of protein supplied did not change IGFBP-3. As calorie
intake increased, IGFBP-3 increased by 0.54 +/- 0.17 microgram/L for each calorie
per kg consumed over the previous 3 days (P = 0.0015). In contrast to IGF-I and
IGFBP-3, IGFBP-2 declined as the length of gestation increased (56.12 +/- 16.92
ng/mL.week; P = 0.001) and with each additional day of life (7.57 +/- 2.44
ng/mL.day; P = 0.003). Dietary protein, the predominant regulator of IGFBP-2,
caused a decrease of 33.22 +/- 9.00 ng/mL with each percent increase in dietary
calories as protein (P < 0.0003). Calorie intake had less effect on IGFBP-2 than
protein intake. These results indicate that each of the three peptides studied is
regulated in premature infants by nutritional intake, and that their regulatory
patterns are qualitatively similar to those observed in older individuals.
Measurements of these peptides in premature infants may be useful indicators of
nutritional status and adequacy of nutrient intake.
PMID- 9398701
TI - Effects of luteinizing hormone-releasing hormone analog-induced pubertal delay in
growth hormone (GH)-deficient children treated with GH: preliminary results.
AB - To study the effect of delaying epiphyseal fusion on the growth of GH-deficient
children, we studied 14 pubertal, treatment naive, GH-deficient patients (6 girls
and 8 boys) in a prospective, randomized, placebo-controlled trial. Chronological
age was 14.5 +/- 0.5 yr, and bone age was 11.6 +/- 0.3 yr (mean +/- SEM) at the
beginning of the study. Patients were assigned randomly to receive GH and LH
releasing hormone (LHRH) analog (n = 8) or GH and placebo (n = 6) during 3 yr,
with planned continuation of GH treatment until epiphyseal fusion. Patients were
measured with a stadiometer and had serum LHRH tests, serum testosterone (boys),
serum estradiol (girls), and bone age performed every 6 months. Patients treated
with GH and LHRH analog showed a clear suppression of their pituitary-gonadal
axis and a marked delay in bone age progression. We observed a greater gain in
height prediction in these patients than in the patients treated with GH and
placebo after 3 yr of treatment (mean +/- SEM, 14.0 +/- 1.6 vs. 8.0 +/- 2.4 cm; P
< 0.05). These preliminary findings suggest that delaying epiphyseal fusion with
LHRH analog in pubertal GH-deficient children treated with GH increases height
prediction and may increase final height compared to treatment with GH alone.
PMID- 9398702
TI - Diabetes during pregnancy does not alter whole body bone mineral content in
infants.
AB - A previous study using single photon absorptiometry has reported low bone mineral
density of the radius in infants of diabetic mothers. The aim of this study was
to assess by dual x-ray absorptiometry the whole body bone mineral content
(WbBMC) and the body composition of 40 infants of diabetic mothers at birth (mean
gestational age +/- SD, 37.5 +/- 1.3 weeks; mean birth weight +/- SD, 3815 +/-
641 g). WbBMC was not correlated with gestational age, but was well correlated
with birth weight (r = 0.73; P = 0.0001) and also with fat mass (r = 0.87; P =
0.0001) and lean mass (r = 0.42; P = 0.008). The z-scores +/- SD adjusted for
weight for WbBMC and fat mass were significantly increased (1.3 +/- 0.9 and 2.6
+/- 1.3, respectively (P < 0.0001), but were not significantly influenced either
by in utero growth or by the type of the diabetes mellitus of the mother. Bone
mineralization and fat mass studied by whole body dual x-ray absorptiometry are
increased at birth in these infants compared with reference curves.
PMID- 9398703
TI - Characterization of monoclonal thyroid-stimulating and thyrotropin binding
inhibiting autoantibodies from a Hashimoto's patient whose children had
intrauterine and neonatal thyroid disease.
AB - A multiplicity of TSH receptor autoantibodies (TSHRAbs) have been characterized
after subcloning heterohybridomas produced from the lymphocytes of a patient who
has Hashimoto's thyroiditis and had three children with intrauterine or neonatal
hyperthyroidism. Twelve clones produced stimulating TSHRAbs that increased cAMP
levels and iodide uptake in rat FRTL-5 thyroid cells and increased cAMP levels in
Chinese hamster ovary (CHO) cells transfected with the human TSHR; like 95% of
Graves' stimulating TSHRAbs, all 12 have their functional epitope on the N
terminus of the TSHR extracellular domain, requiring residues 90-165 for
activity. All 12 bind to human thyroid membranes in the absence, but not the
presence, of TSH, but are only weak inhibitors of TSH binding in assays measuring
TSH binding-inhibiting Igs (TBIIs). In contrast, 8 different clones produced
TSHRAbs that did not increase cAMP levels, but, instead, exhibited significant
TBII activity. Four inhibited the ability of TSH or a stimulating TSHRAb to
increase cAMP levels and had their functional epitope on the C-terminal portion
of the TSHR external domain, residues 261-370, mimicking the properties of
blocking TSHRAbs that cause hypothyroidism in patients with idiopathic myxedema.
The 4 other TBIIs inhibited the ability of TSH, but not that of a stimulating
TSHRAb, to increase cAMP levels, like TBIIs in Graves' patients. The functional
epitope for 3 of these Graves'-like TBIIs was residues 90-165; the functional
epitope for the fourth was residues 24-89. The fourth also increased arachidonic
acid release and inositol phosphate levels in FRTL-5 thyroid cells and exhibited
conversion activity, i.e. the ability to increase cAMP levels in the presence of
an anti-human IgG. Thus, this TBII exhibited signal transduction activity, unlike
the other 3 Graves'-like TBIIs. The patient, therefore, has stimulating TSHRAbs
and 3 different types of TBIIs, each with different functional properties and
different epitopes on the TSHR.
PMID- 9398704
TI - Acute effects of estradiol infusion and naloxone on luteinizing hormone secretion
in pubertal boys.
AB - We have shown previously in pubertal boys that testosterone (T) suppresses the
nocturnal augmentation of luteinizing hormone (LH) secretion principally by
decreasing LH pulse frequency. As T can be aromatised to estradiol (E2), and E2
effects on LH secretory dynamics may be separate from those of T, we examined the
effects of acute E2 infusion on LH secretion in pubertal boys. Opioid receptor
blockade has been reported to increase LH secretion after estradiol suppression
in adult men, so we also examined whether naloxone might augment LH secretion
during E2 treatment in pubertal boys. Starting at 1000 h, eight pubertal boys
were given a 33 h saline infusion, followed 1 week later by an E2 infusion at 4.6
nmol/m2/h. During both infusions, four iv boluses of saline were given hourly
beginning at 1200 h on the first day, and four naloxone iv boluses, 0.1 mg/kg
each, were given hourly beginning at 1200 h on the second day. Blood was obtained
every 15 min for LH, and every 60 min for T and E2, from 1200 h until the end of
the infusion. Pituitary responsiveness to gonadotropin-releasing hormone (GnRH)
was assessed after both infusions by iv administration of 250 ng/kg synthetic
GnRH. Estradiol infusion increased the mean plasma E2 concentration from 23 +/- 4
to 46 +/- 6 pmol/L (P < 0.01) and suppressed mean plasma T from 4.9 +/- 1.4 to
3.0 +/- 3.5 nmol/L (saline vs. E2 infusion, P < 0.05). The overall mean LH was
suppressed by E2 infusion from 3.7 +/- 0.5 to 2.2 +/- 0.4 IU/L (saline vs. E2
infusion, P < 0.01). LH pulse frequency was suppressed by 50%, whereas mean LH
pulse amplitude was not different between saline and E2 infusions. Administration
of naloxone did not alter the mean LH, LH pulse frequency, or amplitude during
either saline or E2 infusions. Pituitary responsiveness to exogenous GnRH was
similar during both infusions. These studies indicate that E2 produces its
negative feedback in pubertal boys principally by suppression of LH pulse
frequency, and naloxone does not reverse these suppressive effects. Thus E2
suppression of LH secretion is mediated by a decrease of hypothalamic GnRH
secretion that is independent of endogenous opioid pathways.
PMID- 9398705
TI - Seasonal variation in glucocorticoid activity in healthy men.
AB - Many endocrine systems are subject to seasonal variation. However, studies of the
hypothalamic-pituitary-adrenal axis in man have been limited to patients with
psychiatric illness with conflicting results. We studied 105 healthy men, age 24
33 yr, during a 15-month period that included two winters. We measured cortisol
and its metabolites by gas chromatography/mass spectrometry in plasma and urine
and the intensity of dermal blanching after overnight topical application of
beclomethasone dipropionate. There were no differences between subjects studied
during the two winter periods, but marked differences between subjects studied in
winter and summer. In winter, 0900-h plasma cortisol concentrations were higher
(73 +/- 10 ng/mL, n = 41 vs. 35 +/- 4, n = 25 in summer; P < 0.01), total
cortisol metabolite excretion was lower (678 +/- 67 micrograms/mmol creatinine
vs. 900 +/- 98; P < 0.05), the ratio of metabolites of cortisol to those of
cortisone was higher (3.0 +/- 0.2 vs. 2.1 +/- 0.1; P < 0.01), and dermal
glucocorticoid sensitivity was higher (7.2 +/- 0.4 arbitrary units vs. 5.6 +/-
0.5; P < 0.02). Although blood pressure and fasting insulin/glucose relationships
were not measurably different between seasons, these correlated with dermal
vasoconstriction and cortisol metabolite excretion rate. We conclude that plasma
cortisol and tissue sensitivity to glucocorticoids are higher in winter, but
cortisol production rate is reduced. This could be explained by a reduction in
cortisol clearance rate: urinary free cortisol/cortisone ratios were not
different but A-ring-reduced metabolites of cortisol were higher in winter,
suggesting that conversion of cortisone to cortisol by hepatic 11 beta
hydroxysteroid dehydrogenase 1 is enhanced. It is an intriguing possibility that
increased glucocorticoid activity contributes to the increased prevalence of
disease during the winter.
PMID- 9398706
TI - Thyroid nodules in the follow-up of irradiated individuals: comparison of thyroid
ultrasound with scanning and palpation.
AB - In 1974 we began a prospective study of a cohort of 4296 individuals exposed to
therapeutic head and neck irradiation during childhood for benign conditions. To
define the role of thyroid ultrasonography in following irradiated individuals,
we studied a subgroup of 54 individuals. They all had been screened between 1974
1976 and had normal thyroid scans and no palpable nodules at that time. Thyroid
ultrasonography, thyroid scanning, physical examination, and serum thyroglobulin
measurements were performed. One or more discrete ultrasound-detected nodules
were present in 47 of 54 (87%) subjects. There were a total of 157 nodules, 40 of
which were 1.0 cm or larger in largest dimension. These 40 nodules occurred in 28
(52%) of the subjects. Thirty (75%) of these 1.0-cm or larger nodules matched
discrete areas of diminished uptake on corresponding thyroid scans. The 10 that
did not match (false negative scans for > or = 1.0-cm nodules) were the only
nodules of this size in 7 subjects. Of 11 nodules 1.5 cm or larger, only 5 were
palpable. Serum thyroglobulin correlated to the number (P = 0.04; r2 = 0.10), but
not the volume of the thyroid nodules (P = 0.07; r2 = 0.08). We conclude that
thyroid nodules are continuing to occur and are exceedingly common in this
irradiated cohort of individuals. The results confirm that thyroid
ultrasonography is more sensitive than physical examination and scanning.
However, thyroid ultrasound is so sensitive and nodules so prevalent that great
caution is needed in interpreting the results.
PMID- 9398707
TI - Fetal plasma hypoxanthine level in growth-retarded fetuses before labor.
AB - Hypoxanthine is one of the purine nucleotides and is presumed to accumulate
during hypoxia and acidemia. It remains uncertain, however, whether plasma
hypoxanthine concentration is a useful indicator of fetal asphyxia; and its
relationship to other markers of fetal physiologic state is not clearly defined.
The aim of this study was to evaluate whether the level of fetal plasma
hypoxanthine is correlated with fetal hypoxia and acidosis in growth-retarded
fetuses before the onset of labor. Cordocentesis was performed in 34 growth
retarded fetuses at 31-35 weeks' gestation for the measurement of umbilical
venous plasma concentrations of hypoxanthine, hemoglobin and lactate
concentrations, blood gases, and base deficit. Umbilical venous plasma
hypoxanthine concentration was found to be increased significantly, in parallel
with the degree of acidosis (r = -0.74, P < 0.05) and base deficit (r = -0.41, P
< 0.05), but not to bear a significant relationship to the degree of hypoxemia or
other measured variables. We conclude that increases in the plasma concentration
of hypoxanthine may reflect an impaired physiological state in growth-retarded
fetuses before labor.
PMID- 9398708
TI - Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients
with nonthyroidal illness.
AB - Changes in hypothalamus-pituitary-thyroid function occur in patients with a
variety of illnesses and are referred to as the euthyroid sick syndrome or
nonthyroidal illness (NTI). In NTI, serum concentrations of T3 decrease to low,
or even undetectable, levels without giving rise to elevated concentrations of
TSH. We hypothesized that decreased activity of TRH-producing cells in the
paraventricular nucleus (PVN) contributes to the persistence of low TSH levels.
To test this hypothesis, we collected a series of formalin-fixed, paraffin
embedded hypothalami of patients whose plasma concentrations of T3, T4, and TSH
had been measured in a blood sample taken less than 24 h before death.
Quantitative TRH messenger RNA in situ hybridization (intraassay coefficient of
variation: 13%) was performed in the PVN. Total TRH messenger RNA in the PVN
showed a positive correlation with serum T3 (r = 0.66; P < 0.05) and with logTSH
(r = 0.64; P < 0.05), but not with T4 (r = -0.02; P = 0.95). This is the first
study to correlate premortem serum concentrations of thyroid hormones with
postmortem gene expression of identified neurons in the human hypothalamus. The
results suggest an important role for TRH cells in the pathogenesis of NTI.
PMID- 9398709
TI - Effect of obesity on the response to insulin therapy in noninsulin-dependent
diabetes mellitus.
AB - An initial improvement in glycemic control is often followed by gradual
deterioration of glycemia during insulin treatment of patients with noninsulin
dependent diabetes mellitus (NIDDM). We examined the causes of such worsening in
a 12-month follow-up analysis of 100 insulin-treated NIDDM patients in the
Finnish Multicenter Insulin Therapy Study who were treated with either
combination therapy with insulin or insulin alone. In the entire study group,
glycemic control averaged 9.7 +/- 0.2% at 0 months and 8.0 +/- 0.1%, 8.0 +/-
0.1%, 8.2 +/- 0.1%, and 8.5 +/- 0.2% at 3, 6, 9, and 12 months (P < 0.001 for
each time point vs. 0 months). Glycemic control at 12 months was significantly
worse than that at 3 (P < 0.001), 6 (P < 0.001), and 9 months (P < 0.02).
Baseline body mass index was the most significant predictor of deterioration in
glycemic control. During 1 yr, hemoglobin A1c decreased almost 3-fold more (by
1.7 +/- 0.2%; P < 0.001 vs. 0 months) in patients whose baseline weight was below
the mean baseline body mass index of 28.1 kg/m2 (nonobese patients) than in those
whose weight exceeded 28.1 kg/m2 (obese patients; 0.5 +/- 0.2%; P = NS vs. 0
months; P < 0.01 vs. obese patients). Glycemic control improved similarly over 1
yr in the nonobese subjects and deteriorated similarly in the obese patients
regardless of their treatment regimen. Insulin doses, per body weight, were
similar in the nonobese and obese patients. The nonobese patients consistently
gained less weight during 12 months of combination therapy with insulin (3.5 +/-
0.6 kg at 12 months) than during insulin therapy alone (5.1 +/- 0.6 kg; P <
0.05). The treatment regimen did not influence weight gain in the obese group,
who gained 4.4 +/- 1.0 kg during combination therapy with insulin and 4.5 +/- 1.1
kg during insulin therapy alone. We reached the following conclusions: 1) after
an initial good response, glycemic control deteriorates more in obese than in
nonobese patients with NIDDM; 2) in obese patients, weight gain per se cannot
explain the poor glycemic response to combination or insulin therapy, but it may
induce a disproportionately large increase in insulin requirements because of
greater insulin resistance in the obese than in the nonobese; 3) in nonobese
patients, glycemic control improves equally during 1 yr with combination therapy
with insulin and insulin alone, but combination therapy with insulin is
associated with less weight gain than treatment with insulin alone; 4) weight
gain appears harmful, as it is associated with increases in blood pressure and
low density lipoprotein cholesterol.
PMID- 9398710
TI - A novel cyclic adenosine monophosphate analog induces hypercalcemia via
production of 1,25-dihydroxyvitamin D in patients with solid tumors.
AB - The treatment of cancer patients with conventional chemotherapy is sometimes
associated with severe systemic toxicity and only a minimal survival benefit.
Because of this, new less toxic and more efficacious treatments have been sought.
8-Chloro-cAMP (8-Cl-cAMP) is one of a new generation of anticancer drugs that act
at the level of signal transduction. In preclinical models, 8-Cl-cAMP modulates
protein kinase A (PKA) leading to growth inhibition and increased differentiation
of cancer cells. 8-Cl-cAMP was given to 16 patients with advanced cancer as an
infusion via an indwelling subclavian venous catheter. We showed that 8-Cl-cAMP
had a parathyroid hormone-like effect leading to increased synthesis of renal
1,25-dihydroxyvitamin D [up to 14 times the baseline value, median 3.6 times; P =
0.00001 (Student's paired t test)]. This produced the dose-limiting toxicity of
reversible hypercalcemia that could not be controlled by the administration of
either pamidronate or dexamethasone. The treatment was otherwise well tolerated,
and other cAMP-dependent pathways (cortisol and TSH) were not affected,
emphasizing the marked differences between organs in their sensitivity to this
cAMP analog. Our results have shown that 8-Cl-cAMP is biologically active, and it
is feasible that if the hypercalcemia can be controlled, then this drug may have
a role as a single agent, or as a short infusion between cycles of chemotherapy.
PMID- 9398711
TI - Randomized, double blind, placebo-controlled trial of low dose iodide in endemic
goiter.
AB - Iodine (I) is essential for normal thyroid function, and the majority of subjects
tolerate a wide range of dietary levels. However, a subset of individuals upon
exposure to normal or elevated levels of I develop thyroid dysfunction and
autoimmunity. In this double blind trial, we evaluated efficacy and tolerability
of low dose I in adults with euthyroid, diffuse, endemic goiter. Sixty-two
subjects were randomly assigned I (0.2 mg/day) or placebo for 12 months. After
termination of therapy, both groups were followed for a further 6 months. Thyroid
sonography and determinations of thyroid-related hormones, urinary I excretion
per 24 h, and thyroid antibodies were carried out at baseline and at 3, 6, 9, 12,
15, and 18 months. Markedly elevated urinary I values were found during therapy
in subjects receiving I (32 at baseline vs. 213 micrograms/24 h at 12 months; P =
0.0001) compared to placebo (34 and 33 micrograms/24 h, respectively; P < 0.0001
vs. I). I substantially reduced thyroid volume (29 vs. 18 mL at 12 months; -38%;
P = 0.0001), and at 18 months, the therapeutic effect was sustained. In the
placebo group, no significant changes were observed. High microsomal and
thyroglobulin autoantibody titers were present in 3 of 31 (9.7%) subjects
receiving I, and I-induced hypo- and hyperthyroidism developed in 2 and 1,
respectively. Fine needle biopsy revealed marked lymphocytic infiltration in all
3 cases. After withdrawal of I, thyroid dysfunctions spontaneously remitted, and
antibody titers as well as lymphocytic infiltration decreased markedly. Follow-up
of these 3 subjects for an additional 2 yr showed normalization of antibody
titers in 2. Thus, among subjects with endemic goiter, low dose I successfully
normalized thyroid volume and body I supplementation; nevertheless, reversible I
induced thyroid dysfunctions and autoimmunity were observed in nearly 10% of the
subjects.
PMID- 9398712
TI - A new compound heterozygous mutation in the 11 beta-hydroxysteroid dehydrogenase
type 2 gene in a case of apparent mineralocorticoid excess.
AB - Apparent mineralocorticoid excess (AME) characterized by early-onset hypertension
and hypokalemia is due to congenital deficiency of 11 beta-hydroxysteroid
dehydrogenase (11 beta HSD). Two isoforms of human 11 beta HSD are known, and the
type 2 isoform (11 beta HSD2) has been recently shown to be responsible for AME.
In this study we have analyzed the 11 beta HSD2 gene of a Japanese patient with
AME. PCR amplification and subsequent nucleotide sequencing of the 11 beta HSD2
gene from the patient and his family members revealed that the patient has a
compound heterozygous mutation of this gene. In 1 allele, an undescribed single
nucleotide transition in codon 208 in exon 3 resulted in a substitution of
arginine to histidine (CGC to CAC: R208H). In the other allele, a deletion of 3
nucleotides in codons 337-338 in exon 5 resulted in a substitution of arginine to
histidine and a deletion of tyrosine residue (CGCTAT to CAT: R337H, delta Y338),
which has been previously shown to abolish 11 beta HSD2 enzyme activity. A
chloramphenicol acetyltransferase assay-based expression study involving the
mineralocorticoid receptor indicated that the novel R208H mutation eliminates the
enzymatic activity of 11 beta HSD2. From the genetic analysis of 50 healthy
subjects, the novel R208H mutation was unlikely to be due to polymorphism.
Together, these results indicate that this patient is a compound heterozygote for
the mutation in the 11 beta HSD2 gene (R208H and R337H, delta Y338) and that
these mutations inactivate the 11 beta HSD2 function and give rise to clinically
manifest AME.
PMID- 9398713
TI - Inhibin B as a serum marker of spermatogenesis: correlation to differences in
sperm concentration and follicle-stimulating hormone levels. A study of 349
Danish men.
AB - Recent studies have focused on reproductive health of men in the general
population. However, semen samples are difficult to obtain within sampling frames
that allow comparisons. Blood samples are easier to obtain than ejaculates.
Therefore, serum biomarkers of spermatogenesis are of major interest for
population studies. FSH has previously been used as a marker of spermatogenesis,
although it is also influenced by the hypothalamus. Serum inhibin B was recently
suggested as a possible, more direct serum marker of spermatogenesis in men with
testicular disorders. In a Danish nationwide collaborative study, we found an
unexpected difference in semen concentration between two groups of men recruited
from two different centres. We, therefore, analyzed reproductive hormones in
blood, including inhibin B, to test whether the observed difference in semen
concentration was reflected in the reproductive hormones. From 1992 to 1995, a
total of 430 men, 20-35 yr old, who lived with a partner and who had not
previously attempted to achieve a pregnancy, were recruited. The couples were
enrolled into the study in one of two centres (centre A, n = 231; and centre B, n
= 199) when they discontinued birth control. At enrollment, they provided a semen
sample (n = 419), and a blood sample was drawn (n = 349). The semen analysis was
performed in accordance with the WHO 1992 guidelines, and interlaboratory
differences were tested. Inhibin B was measured in an enzyme immunometric assay,
which has previously been described. All blood samples were analyzed in the same
laboratory. Median sperm concentration and the percentage of morphologically
normal spermatozoa were significantly higher among men from centre A (56.0
mill/mL and 42.5%), compared with men from centre B (44.8 mill/mL and 39%). Men
from centre B had a significantly higher median FSH (3.42 IU/L) and a lower
inhibin B (186 pg/mL) than men from centre A (3.21 IU/L and 209 pg/mL). The
differences persisted after control for potentially confounding variables. A
significant correlation was found between the cubic root-transformed serum FSH
and inhibin B levels (r = -0.61, P < 0.001), between the cubic root-transformed
serum FSH and sperm concentration (r = -0.40, P < 0.001), and between the cubic
root-transformed inhibin B and sperm concentration (r = 0.38, P < 0.001). The
predictive power of detecting sperm counts below 20 mill/mL among men who's
inhibin B and FSH both were below 80 pg/mL and above 10 IU/L, respectively, was
100%. The unexpected significant difference in semen concentration between two
groups of normal Danish men was probably caused by differences in sampling
procedures in the two centres where the men were recruited, rather than
geographical differences. However, similar differences in serum levels of inhibin
B and FSH between centres were found. These findings suggest that a real
difference in spermatogenic potential between the two groups of men existed. We
suggest that serum inhibin B, in future population studies on male reproductive
health, may serve as a new marker of spermatogenesis, in addition to sperm
concentration and serum FSH.
PMID- 9398714
TI - Metabolism of progesterone by human lymphocytes: production of neuroactive
steroids.
AB - Although it has long been recognized that lymphocytes have the capacity to reduce
cortisol at the C3, C5, and C20 positions, the specificity and the physiological
variation of these reactions have received little attention. We have shown that
such reactions also occur with progesterone. Lymphocytes were isolated from whole
blood using Percoll density gradient centrifugation. The cells were incubated for
20 h with tritiated progesterone as radioactive tracer. After extractions into
ethyl acetate, the residue was subjected to high performance liquid
chromatography, and the radioactivities of the separated compounds were
determined. Without cells, 95-97% of the tracer added was recovered in the
progesterone peak, while in the presence of 4 x 10(6) lymphocytes, this was
reduced to 45-90%. The metabolites obtained included at least 10 different
compounds, including those corresponding in their retention times to the
neuroactive 5 alpha and 5 beta dihydroprogesterones and their 3 alpha- and 3 beta
tetrahydroprogesterone derivatives. The conversion decreased with the addition
of other steroids such as testosterone, cortisol, and corticosterone, suggesting
that these steroids are metabolized by the same enzymes. When the cells from two
pregnant patients were combined and incubated with tracer, and with and without
nonradioactive progesterone, no peaks were detected by two progesterone
radioimmunoassays in the absence of added nonradioactive progesterone, while in
its presence three peaks corresponding to 5 alpha-dihydroprogesterone, 3 alpha
hydroxy-5 alpha-pregnane-20-dione and 3 beta-hydroxy-5 alpha-pregnane-20-dione
eluted before the P peak. Their identities were confirmed using the two different
progesterone radioassays that cross-reacted with these metabolites. The highest
mean conversion (44.7% +/- 3.2 SE) was found with the lymphocytes of pregnant
women and with that of one lactating woman (50%). Conversions by lymphocytes of
women in the follicular phase (29.3% +/- 1.3 SE) were significantly lower than
those in pregnancy (P = 0.014) but did not differ significantly (P > or = 0.05)
from those of women in the luteal phase (22.2% +/- 3.4 SE), those of
postmenopausal women (23.5% +/- 4.9 SE), or of men (22.5% +/- 2.4 SE).
Lymphocytes appear to provide a hitherto unrecognized but possibly important
source of neuroactive steroids.
PMID- 9398715
TI - Studies of genetic variability of the uncoupling protein 1 gene in Caucasian
subjects with juvenile-onset obesity.
AB - Our objective was to investigate whether genetic variants of the uncoupling
protein 1 (UCP1) gene are associated with juvenile-onset obesity or alterations
in weight gain and insulin sensitivity in young healthy Caucasians. Single-strand
conformation polymorphism and heteroduplex analysis of the coding region of the
UCP1 gene was performed in 56 subjects randomly selected at the draft board
examination from a cohort of 156 males with juvenile-onset obesity. Association
studies of amino acid variants were undertaken in the cohort of males with
juvenile-onset obesity, a cohort of 205 randomly selected control males, and a
subgroup of this cohort comprising 76 lean subjects. Genetic variants of the
coding region as well as a previously described a-->g nucleotide polymorphism of
the 5'-flanking region of the UCP1 gene were examined for associations with
accelerated weight gain or reduced sensitivity to insulin in a cohort of 380
young healthy Caucasians. The mutational analysis revealed five nucleotide
substitutions that changed the sequence of UCP1, Arg/Trp40, Ala/Thr64,
Val/Met137, Met/Leu229, and Lys/Asn257 and two nucleotide substitutions in the
nontranslated region of exon 1. Among subjects with juvenile-onset obesity, the
allelic frequencies of Ala/Thr64 and Met/Leu229 were both 8.2% (95% confidence
interval: 5.1-11.3%) vs. 8.8% (6.0-11.6%) and 8.1% (5.3-10.9%), respectively, in
the cohort of randomly selected control subjects. Among lean control subjects,
the allelic frequencies of the polymorphisms were 8.2% (3.7-12.7%) and 5.6% (1.9
9.3%), respectively. In the cohort of young healthy subjects, measurements of
obesity and insulin sensitivity did not differ between carriers of the Ala/Thr64
and Met/Leu229 variants and wild-type carriers. The Val/Met137 and Lys/Asn257
mutations were each found in one subject with juvenile-onset obesity, and the
Arg/Trp40 mutation was found in two obese subjects and in one control subject.
The allelic frequency of the nucleotide polymorphism of the 5'-flanking region of
the UCP1 gene was 25.3% (22.2-28.4%) in the cohort of 380 young Danes. There were
no differences in body mass index, fat mass, waist-to-hip ratio, or weight gain
during childhood or adolescence between carriers and noncarriers of this
nucleotide variant. Although we cannot exclude an effect of the rare mutations in
the UCP1 gene on susceptibility to juvenile-onset obesity, genetic variation of
the coding region of the UCP1 gene is not a common factor contributing to obesity
in Caucasian subjects of Danish ancestry.
PMID- 9398716
TI - Lean women with polycystic ovary syndrome respond to insulin reduction with
decreases in ovarian P450c17 alpha activity and serum androgens.
AB - It is unknown whether hyperinsulinemia plays a role in the pathogenesis of
polycystic ovary syndrome (PCOS) in normal weight or thin women. Evidence
indicates that these women are insulin resistant and hyperinsulinemic, and this
study was conducted to test the hypothesis that hyperinsulinemia stimulates
ovarian cytochrome P450c17 alpha activity in nonobese women with PCOS, thereby
increasing serum androgen concentrations. We assessed ovarian P450c17 alpha
activity (by measuring the response of 17 alpha-hydroxyprogesterone to a GnRH
agonist), fasting serum steroids, and oral glucose tolerance before and after
oral administration of either metformin (500 mg) or placebo three times daily for
4-6 weeks in 31 nonobese women with PCOS. In the 19 women given metformin, the
mean (+/- SE) area under the serum insulin curve after oral glucose
administration decreased from 44 +/- 5 to 24 +/- 3 nmol/L.min (P = 0.003). Basal
serum 17 alpha-hydroxyprogesterone decreased from 3.4 +/- 0.3 to 2.5 +/- 0.4
nmol/L (P = 0.05), and GnRH-stimulated peak serum 17 alpha-hydroxyprogesterone
decreased from 12.2 +/- 1.6 to 7.5 +/- 0.7 nmol/L (P = 0.005). Serum 17 alpha
hydroxyprogesterone values did not change in the placebo group. In the metformin
group, serum free testosterone decreased by 70% from 18.2 +/- 3.1 to 5.5 +/- 0.7
pmol/L (P < 0.001), and serum sex hormone-binding globulin increased from 84 +/-
6 to 134 +/- 15 nmol/L (P = 0.002). None of these values changed in the placebo
group. These findings suggest that hyperinsulinemia stimulates ovarian P450c17
alpha activity in nonobese women with PCOS. They also indicate that decreasing
serum insulin with metformin reduces ovarian cytochrome P450c17 alpha activity
and ameliorates the hyperandrogenism of these women.
PMID- 9398717
TI - Tumor necrosis factor increases serum leptin levels in humans.
AB - Leptin is a pleiotropic hormone believed to regulate body weight. Its function in
wasting during inflammatory disease in humans is unknown. We studied the effect
of repeated tumor necrosis factor (TNF) infusion on serum leptin levels in six
patients with solid tumors. TNF infusion on day 1 resulted in an increase in
serum leptin levels from 3.1 (SEM +/- 0.28) ng/mL to 5.2 (SEM +/- 0.6) ng/mL
after 12 h (P < 0.001). The serum levels returned to baseline within 24 h.
Similar results were obtained when TNF was infused on subsequent days. The study
shows that leptin serum levels are under control of TNF.
PMID- 9398718
TI - Insulin does not stimulate protein synthesis acutely in prepubertal children with
insulin-dependent diabetes mellitus.
AB - Insulin treatment in adult type I diabetic patients decreases protein loss
primarily by inhibiting protein breakdown without stimulating protein synthesis.
In young growing rodents, insulin treatment has been reported to stimulate
protein synthesis. We examined whether insulin stimulates protein synthesis in
normally growing prepubertal children with insulin-dependent diabetes mellitus.
Five prepubertal children with insulin-dependent diabetes mellitus (aged 8.6
11.25 yr) were studied in the postabsorptive state on two occasions: once during
insulin deprivation (I-; blood glucose, 325 +/- 67.8 mg/dL; mean +/- SD) and once
during insulin administration for 4 h (I+; blood glucose, 96 +/- 23.6 mg/dL).
Leucine kinetics were measured using a 4-h primed continuous infusion of L-[1
13C]leucine. Serum insulin concentrations were lower (I- vs. I+, 0.6 +/- 0.3 vs.
7.5 +/- 4.3 microU/mL; mean +/- SD; P = 0.02), whereas serum beta-hydroxy
butyrate (I- vs. I+, 3.4 +/- 0.5 vs. 0.9 +/- 0.5 mg/dL; P < 0.001) and free fatty
acid concentrations (I- vs. I+, 2.9 +/- 0.4 vs. 0.9 +/- 0.4 mEq/L; P < 0.001)
were higher in the insulin-deprived state than during insulin administration.
Leucine Ra, an index of protein breakdown (I- vs. I+, 200.5 +/- 23.4 vs. 167 +/-
17 mumol/kg.h; P = 0.008), and leucine oxidation (I- vs. I+, 56.5 +/- 20.7 vs.
29.6 +/- 9.3 mumol/kg.h; P = 0.03) were reduced by insulin treatment.
Nonoxidative leucine disposal, an index of protein synthesis, was not affected by
insulin treatment (I- vs. I+, 144 +/- 20.8 vs. 137.5 +/- 13.5 mumol/kg.h; P =
0.4). We conclude that the acute decline in net protein loss during insulin
treatment in growing prepubertal children, like that in adults, is due primarily
to an inhibition of protein breakdown without stimulation of protein synthesis.
PMID- 9398719
TI - Increased disorderliness of basal insulin release, attenuated insulin secretory
burst mass, and reduced ultradian rhythmicity of insulin secretion in older
individuals.
AB - Insulin is secreted in a pulsatile fashion. Rapid pulses are considered to be
important for inhibiting hepatic glucose output, and ultradian pulses for
stimulating peripheral glucose disposal. Aging is characterized by a progressive
impairment in carbohydrate tolerance. We undertook the current studies to
determine whether alterations in pulsatile insulin release accompany the age
related changes in carbohydrate metabolism. Healthy young (n = 8; body mass
index, 21 +/- 1 kg/m2; age, 24 +/- 1 yr) and old (n = 9; body mass index, 24 +/-
1 kg/m2; age, 77 +/- 2 yr) volunteers underwent two studies. In the first study,
insulin was sampled every 1 min for 150 min, and pulse analysis was conducted
using a recently validated multiparameter deconvolution technique. In the second
study, insulin was sampled every 10 min for 600 min, and insulin release was
evaluated by Cluster analysis. In the 150-min studies, insulin secretory burst
mass (P < 0.05) and amplitude (P < 0.01) were reduced in the elderly. In
addition, approximate entropy, a measure of irregularity or disorderliness of
insulin release, was increased in the aged (P < 0.01). In the 600-min studies,
interpulse interval was greater in the aged (P < 0.05), and burst number was less
(P < 0.05). We conclude that normal aging is characterized by more disorderly
insulin release, a reduction in the amplitude and mass of rapid insulin pulses,
and a decreased frequency of ultradian pulses. Whether these alterations in
insulin pulsatility contribute directly to the age-related changes in
carbohydrate metabolism will require further study.
PMID- 9398720
TI - Cytokine production by a new undifferentiated human thyroid carcinoma cell line,
FB-1.
AB - A human anaplastic thyroid cancer cell line FB-1, derived from a 68-yr-old woman
who underwent surgery for anaplastic thyroid cancer, has been established. The
spindlelike cells have been proliferating stably for more than 2 yr. Karyotype
analysis shows many abnormalities and many marker chromosomes have been observed.
Heterotransplant of FB-1 cells into severe combined immunodeficient mice has
resulted in rapidly growing tumors classified as anaplastic carcinomas, although
50% have shown areas with a trabecular pattern. FB-1 cells failed to express
messenger RNA for thyroglobulin; TSH-receptor; thyroperoxidase, and placental
angiogenic growth factor. Conversely, PAX8 and thyroid transcription factor 1,
whose expression is thyroid specific, was kept in an FB-1 cell line at a level
comparable with that observed in normal thyroid tissue. In addition, the present
cell line expressed high levels of messenger RNA for high-mobility group proteins
(Y) and -C. The in vitro study revealed that FB-1 cells are able to produce high
levels of interleukin (IL)-8 and medium amount of IL-6, whereas no release of IL
1-alpha, IL-1-beta, and IL-4 was observed. No modulation of cell proliferation
and DNA synthesis in FB-1 cells has been observed after the addition of exogenous
IL-6.
PMID- 9398721
TI - Sporadic pheochromocytomas are rarely associated with germline mutations in the
vhl tumor suppressor gene or the ret protooncogene.
AB - Pheochromocytoma is a tumor that may occur sporadically or may be a manifestation
of a hereditary disease, such as von Hippel-Lindau disease (VHL) and multiple
endocrine neoplasia (MEN) type 2. As patients with VHL or MEN type 2 are at risk
to develop multiple tumors, they must be distinguished from sporadic cases. We
determined the incidence of VHL and MEN type 2 among 62 German patients diagnosed
with pheochromocytoma without a history of a hereditary disease. Germline
analyses of the vhl gene and exons 10, 11, and 13 of the ret protooncogene were
performed by PCR, single strand conformation polymorphism, enzyme digestion, or
sequencing. Two patients (3%) showed vhl mutations (95% confidence interval, 1
11%). One patient showed loss of the MspI restriction site at nucleotides
712/713. Another patient had a C/T change at an intronic site that was also
detected in 2 of his offspring. No mutations were detected in the ret
protooncogene (97.5% confidence interval, 0-6%). In Germany, most sporadic
pheochromocytomas are not due to VHL or MEN type 2. Therefore, clinical work-up
in patients with pheochromocytoma without signs of hereditary disease is not
recommended. However, because the costs of genetic screening are relatively low,
and each index case allows optimal care for family members, molecular testing
might be cost-effective.
PMID- 9398722
TI - Functional differentiation of placental syncytiotrophoblasts during baboon
pregnancy: developmental expression of chorionic somatomammotropin messenger
ribonucleic acid and protein levels.
AB - The objective of the present study was to determine whether, in addition to the
onset of chorionic somatomammotropin (CS) production previously shown to result
from the morphological differentiation of cytotrophoblasts into
syncytiotrophoblasts, there is a further developmental increase in the capacity
of syncytiotrophoblasts to produce CS with advancing stages of baboon pregnancy.
Placentas were obtained from baboons in early (days 48-62), mid (days 97-110),
and late (days 161-175) gestation (term = 184 days), and CS messenger ribonucleic
acid (mRNA) and protein levels were determined in a syncytiotrophoblast-rich cell
fraction isolated by Percoll gradient centrifugation. CS mRNA levels in
syncytiotrophoblasts, expressed as a ratio of beta-actin, exhibited a progressive
increase from early (0.04 +/- 0.04 relative arbitrary units) to mid (2.37 +/-
0.33; P < 0.001) to late (3.66 +/- 0.39; P < 0.05) gestation. Levels of the 22
kDa CS protein were very low on days 48-55 (0.83 +/- 0.09 arbitrary units),
increased 10-fold (P < 0.001) on days 57-60 (8.11 +/- 0.68), and increased (P <
0.001) to a maximum of 14.58 +/- 0.58 near term. CS mRNA levels in whole
placental villous tissue increased (P < 0.05) between early (0.89 +/- 0.48) and
mid (2.97 +/- 0.47) gestation, then remained constant. CS protein exhibited a
similar increase (P < 0.001) in villous tissue between early (2.32 +/- 0.40) and
mid (6.07 +/- 0.24) gestation, then remained constant. The increase in mRNA and
protein levels of CS in the placenta was accompanied by a progressive (P < 0.001)
rise in serum CS. We conclude that in addition to the morphological
differentiation of cytotrophoblasts into syncytiotrophoblasts that has been well
established to result in the onset of CS biosynthesis, villous
syncytiotrophoblasts undergo functional/biochemical differentiation thereafter,
manifested as an increase in the capacity for the synthesis of CS.
PMID- 9398723
TI - Calcium absorptive effects of vitamin D and its major metabolites.
AB - The absorptive response to graded doses of vitamin D3, 25(OH)D, and 1,25(OH)2D
was measured in healthy adult men after treatment periods of eight, four, and two
weeks, respectively. While no relationship was found between baseline absorption
and serum vitamin D metabolite levels, all three vitamin D compounds
significantly elevated 45Ca absorption from a 300 mg calcium load given as part
of a standard test meal. 1,25(OH)2D was active even at the lowest dose (0.5
microgram/day), and the slope was such that doubling of absorption would occur at
an oral dose of approximately 3 micrograms/day. 25(OH)D was also active in
elevating absorption and did so without raising total 1,25(OH)2D levels. On the
basis of the dose response curves for 1,25(OH)2D and 25(OH)D, the two compounds
exhibited a molar ratio for physiological potency of approximately 100:1. The
absorptive effect of vitamin D3 was seen only at the highest dose level (1250
micrograms, or 50,000 IU/day) and was apparently mediated by conversion to
25(OH)D. Analysis of the pooled 25(OH)D data from both the 25(OH)D- and vitamin
D3-treated groups suggests that approximately one eighth of circulating vitamin D
like absorptive activity under untreated conditions in winter may reside in
25(OH)D. This is a substantially larger share than has been predicted from
studies of in vitro receptor binding.
PMID- 9398724
TI - Persistent elevation and metabolic dependence of circulating E-selectin after
delivery in women with gestational diabetes mellitus.
AB - The increased risk of premature atherosclerosis in noninsulin-dependent diabetes
mellitus (NIDDM) might be related in part to augmented expression of endothelial
adhesion molecules (AMs). So far it is, however, unknown whether increased
circulating (c) AMs in NIDDM are only a consequence of this disease or also
involved in its sequelae. To determine the presence of cAMs in a population at
increased risk for subsequent development of NIDDM, we analyzed fasting and
postprandial [oral glucose tolerance test (OGTT): 100 g] serum concentrations of
circulating E-selectin, vascular cell adhesion molecule-1 (cVCAM-1), and
intercellular adhesion molecule-1 (cICAM-1) in pregnant women with either
gestational diabetes (GDM) or normal glucose tolerance (NT) before and after
delivery vs. nonpregnant healthy women (C). During pregnancy cE-selectin and
cVCAM-1 were elevated in both GDM and NT vs. nonpregnant females (P < 0.01 vs.
C). Following delivery, all GDM females regained normal glucose tolerance
according to OGTT criteria, but showed slightly higher postprandial [area under
the curve (AUC)180 min] glycemia and HbA1c values than nonpregnant healthy women
(P < 0.05), indicating persisting subtle abnormalities in carbohydrate
metabolism. cE-selectin and cVCAM-1 remained increased in GDM (P < 0.01 vs.C)
after delivery, but fell to normal in NT (P < 0.05 before vs. after delivery).
Furthermore, a correlation was seen in GDM females between cE-selectin and HbA1c
(P < 0.005), fasting glucose (P < 0.01), and insulin (P < 0.05) as well as
postprandial (AUC180 min) glucose and insulin concentrations (P < 0.05) during
OGTTs, both before and after delivery. ICAM-1, however, did not differ
significantly between groups. In summary, GDM is characterized by persistently
raised levels of cE-selectin and cVCAM-1 12 weeks after delivery. Whether these
persistent elevations of cE-selectin and cVCAM-1 reflect early vascular injury or
represent a risk factor for atherosclerosis in women at increased risk for NIDDM
remains to be determined.
PMID- 9398726
TI - Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's
thyroiditis and Addison's disease.
AB - Endocrine autoimmune disorders share susceptibility and resistance factors of the
human leukocyte antigen system on the short arm of chromosome 6, but other gene
loci also contribute to predisposition and protection. Because the cytotoxic T
lymphocyte antigen 4 (CTLA4) alanine-17 encoded by the CTLA4 gene on chromosome
2q33 confers susceptibility to Graves' disease, as well as to type 1 (insulin
dependent) diabetes mellitus, we investigated this dimorphism in the other
endocrine autoimmune disorders: Hashimoto's thyroiditis and Addison's disease. We
analyzed the CTLA4 exon 1 polymorphism (49 A/G) in 73 patients with Hashimoto's
thyroiditis, 76 with Addison's disease, and 466 healthy controls. This dimorphism
corresponds to an aminoacid exchange (Thr/Ala) in the leader peptide of the
expressed protein. CTLA4 alleles were defined by PCR, single-strand
conformational polymorphism analysis, and restriction fragment length
polymorphism analysis using BbvI. Patients with Hashimoto's thyroiditis had
significantly more Ala alleles than controls, both as homozygotes (22% vs. 15%)
and heterozygotes (53% vs. 46%), and less Thr than controls as homozygotes (25%
vs. 39%), P < 0.04. The phenotypic frequency for Ala was significantly higher in
patients (75%), compared with controls (61%), P < 0.03. Patients with Addison's
disease did not differ significantly from controls, but those carrying the
suceptibility marker, human leukocyte antigen DQA1*0501, were significantly more
CTLA4 Ala17 positive than controls with the same DQA1 allele (P < 0.05). In
conclusion, an alanine at codon 17 of CTLA4 confers genetic susceptibility to
Hashimoto's thyroiditis, whereas this applies only to the subgroup of DQA1*0501+
patients with Addison's disease.
PMID- 9398725
TI - Identification, characterization, and biological activity of endothelin receptors
in human ovary.
AB - We previously reported the expression of endothelin-1 (ET-1) in granulosa cells
(GCs) of the human ovary and the presence of ET-1-like immunoreactivity in human
follicular fluid obtained from women in an in vitro fertilization program. In
follicular fluid, but not in plasma, the levels of ET-1-like immunoreactivity
were higher in gonadotropin-stimulated vs. spontaneous cycles, suggesting
hormonal regulation of follicular ET-1. To identify and characterize ET receptors
in human ovary, we performed autoradiography, radioligand binding, and functional
studies. Mathematical analysis of families of self- and cross-competition curves
among [125I]ET-1, [125I]ET-3, and selective analogs indicates that human ovary
expresses both subtypes of ET receptors, i.e. ETA and ETB receptors. However, the
concentration of the ETB site was 100-fold lower than that of the ETA one. By
using [125I]ET-1, we demonstrated that the density of binding sites in human
ovary is not affected by the hormonal milieu (similar concentrations in normal
cycling, postmenopausal, and combined oral contraceptive-treated women). In situ
binding studies indicate that the majority of ETA and ETB receptors are expressed
in the blood vessels of the ovary. In particular, ETA receptors are abundant in
the ovulatory follicles and localized in the theca interna, in close proximity to
the granulosa layer. Few GCs of the ovulatory follicle were specifically labeled.
Conversely, in the rat ovary, used as a control, ETB receptors were predominantly
expressed and localized in GCs. Accordingly, ETB receptors negatively regulated
estrogen accumulation in rat GCs. In human granulosa-luteal cells, neither ET-1
(unselective ligand) nor ET-3 or sarafotoxin 6c (ETB ligands) affected estrogen
or progesterone secretion. ET-1 was 2.5-fold more potent than noradrenaline in
eliciting contraction of ovarian artery, acting through the ETA receptor. Our
results indicate that in human ovary, at variance with rat ovary, the endothelin
system is primarily involved in the regulation of ovarian blood flow and not
steroidogenesis.
PMID- 9398727
TI - Contractile properties and fiber type distribution of quadriceps muscles in
adults with childhood-onset growth hormone deficiency.
AB - Adults with GH deficiency (GHD) report weakness and fatigability. The origin of
such symptoms is still debated. This work aimed to clarify whether weakness and
fatigability depend on impairment of skeletal muscle contractile capacity. Five
males with childhood-onset GHD (age +/- SE, 29.6 +/- 1.9) and 13 age- and sex
matched controls were enrolled in the study. Quadriceps muscle cross-sectional
area (CSA), strength, twitch characteristics, and fatigue index of voluntary and
electrically evoked contractions were determined in vivo in all subjects. Fiber
type distribution and CSA of identified types of skeletal fibers were determined
on needle biopsy samples of the vastus lateralis muscle of all subjects. Fiber
type distribution was assessed on the basis of myosin heavy chain (MHC) isoform
composition determined by electrophoresis on polyacrylamide gels. Fiber CSA was
determined on cross-cryosections of fiber bundles immunostained by monoclonal
antibodies against MHC isoforms. Absolute values of strength and fiber CSA of
quadriceps were significantly lower in patients affected by GHD than in controls.
However, once strength and fiber CSA were normalized for quadriceps CSA and
subject height, respectively, differences disappeared. No difference was found
between GHD patients and controls for quadriceps muscle twitch characteristics,
fatigue index, and fiber type distribution. The results reported here suggest
that weakness and fatigability in childhood-onset GHD do not have a skeletal
muscle origin.
PMID- 9398728
TI - Isoproterenol and somatostatin decrease plasma leptin in humans: a novel
mechanism regulating leptin secretion.
AB - In cultured adipocytes, leptin is increased by insulin and decreased by cAMP. In
animal models, insulin and agents that increase intracellular cAMP have been
shown to similarly affect plasma leptin in vivo. This study was undertaken to
test the hypothesis that in humans increased cAMP induced by isoproterenol would
decrease leptin. Five groups of normal weight subjects were studied; 1) subjects
infused with isoproterenol at a rate of 24 ng/kg/min (ISO24); 2) subjects infused
with isoproterenol at a rate of 8 ng/kg/min (ISO8); 3) subjects infused with
somatostatin/insulin/GH followed by coinfusion with 8 ng/kg/min isoproterenol
(ISO8 + SRIH); 4) subjects infused with somatostatin/insulin/GH alone (SRIH); and
5) control subjects infused with saline (NS). ISO24 infusion resulted in a 27%
decrease in plasma leptin over 120 min. ISO24 also increased plasma insulin over
the infusion. ISO8 resulted in a 16% decrease in leptin. Saline did not change
leptin. SRIH alone decreased leptin 19% over the first 120 min, however no
additional fall was seen over the next 120 min the SRIH group. Nonetheless, the
addition of 8 ng/kg/min ISO during the second 120 min (ISO8 + SRIH) caused a 15%
further decline in plasma leptin. Therefore both isoproterenol and somatostatin
reduce plasma leptin in humans. The effect of isoproterenol is likely mediated by
beta-adrenergic receptors, whereas the effect of somatostatin suggests a novel
mechanism for the regulation of leptin.
PMID- 9398729
TI - Expression of functional leptin receptors in the human ovary.
AB - The size of body fat stores is known to influence fertility, indicating a link
between adipose tissue and the reproductive system. Studies in mice have
identified the adipocyte-derived hormone, leptin (Ob protein), as a possible
mediator of this effect. The aim of this study was to investigate the possibility
that leptin may have direct effects on the human ovary. To probe this hypothesis
we first analyzed the expression of leptin receptors in the human ovary.
Transcripts encoding both the long and short isoforms of the leptin receptor were
present in human granulosa cells and thecal cells; however, the short isoforms
were expressed at much higher levels. Immunoreactive leptin was present in
follicular fluid at levels similar to those found in serum. ob gene expression,
however, was undetectable in the ovary, as determined by reverse transcription
PCR, whereas it was easily detected in adipose tissue. To determine whether
leptin could induce a biological response in ovarian cells, we examined the
effect of leptin on estradiol production in cultured granulosa cells. Leptin (100
ng/mL) inhibited LH (0.1 ng/mL)-stimulated estradiol production. In contrast,
leptin had no effect on estradiol production in the absence of LH. In conclusion,
this study has demonstrated that the leptin receptor is expressed in the human
ovary, that leptin is present in follicular fluid, and that leptin can induce a
biological response in ovarian cells. These results suggest that leptin may have
a direct effect on the human ovary.
PMID- 9398730
TI - Serum leptin and energy expenditure in children.
AB - Leptin has been hypothesized to play an important role in energy balance by
affecting both energy intake and energy expenditure. The purpose of our study was
to determine the relationship between fasting serum leptin concentrations and
measures of energy expenditure in prepubertal children. We measured total energy
expenditure (TEE; by the doubly labeled water technique), resting energy
expenditure (REE; after an overnight fast), activity energy expenditure (AEE; TEE
REE), body composition (by dual energy x-ray absorptiometry), and fasting serum
leptin concentration (by RIA) in 76 children. Simple correlations showed that all
measures of energy expenditure (TEE, REE, and AEE) were positively related to the
serum leptin concentration (r = 0.50, P < 0.001; r = 0.45, P < 0.001; and r =
0.30, P < 0.01, respectively). However, after adjusting for body composition (fat
free mass and fat mass), gender, and ethnicity, serum leptin concentrations were
not related to any measure of energy expenditure (TEE, P = 0.61; REE, P = 0.97;
AEE, P = 0.65). These latter findings were further confirmed using structural
equation models with leptin and energy expenditure as dependent variables, and
fat-free mass and fat mass as independent variables. Results from these models
showed no direct effect of leptin and no indirect effect of fat mass (through
leptin) on any measure of energy expenditure, when a path between fat mass and
energy expenditure was present in the model. Thus, our data do not support the
hypothesis that the serum leptin concentration (independent of fat mass) is
related to measures of energy expenditure in children.
PMID- 9398731
TI - Evidence for production and functional activity of nitric oxide in seminiferous
tubules and blood vessels of the human testis.
AB - Previous studies have demonstrated that nitric oxide (NO) influences Leydig cell
function. Here we provide evidence for NO production and activity in seminiferous
tubules and blood vessels of the human testis. By immunohistochemistry, the
soluble guanylyl cyclase (sGC), the intracellular NO receptor, and the second
messenger, cyclic guanosine monophosphate (cGMP), were detected in myofibroblasts
of the peritubular lamina propria in Sertoli cells, as well as in endothelial and
smooth muscle cells of testicular blood vessels. Performed with isolated tubules
and blood vessels, the biological activity of sGC could be proved by cGMP
generation in response to treatments with the NO donor, sodium nitroprusside. The
endothelial and neuronal subtypes of NO synthase (NOS) were localized
immunohistochemically to the same cell types that express sGC and cGMP. In
isolated tubules and vessels, the presence of endothelial NOS and neuronal NOS
was confirmed by immunoblotting, and NOS activity was demonstrated by decreased
cGMP production upon incubation with the NOS inhibitor L-nitro arginine
methylester. These findings show that peritubular cells, Sertoli cells, and
testicular blood vessels may be sites of NO production and activity, possibly
involved in relaxation of seminiferous tubules and blood vessels to modulate
sperm transport and testicular blood flow, respectively.
PMID- 9398732
TI - Comparison of hormone-sensitive lipase activity in visceral and subcutaneous
human adipose tissue.
AB - The possible role of hormone-sensitive lipase (HSL) in determining regional
differences in lipolysis activation in humans was studied in vitro. Small adipose
tissue biopsies were obtained from the abdominal sc and omental regions during
surgery in 21 subjects spanning a wide range of body mass index (22-50 kg/m2). In
lipolysis experiments, isolated fat cells were incubated with lipolytic agents
acting at different levels in the lipolytic cascade. The activity and messenger
ribonucleic acid expression of HSL were determined. The maximum lipolytic
capacity was higher in sc than in omental fat cells as were HSL activity and
messenger ribonucleic acid expression. The maximum lipolysis rate was
significantly correlated to HSL activity. This is in accordance with the role of
HSL as the rate-limiting step of lipolysis. However, adipocytes were 24% larger
in the sc than in the omental region, and the lipolysis rate was significantly
correlated to fat cell size regardless of either the region of origin or gender.
This indicates that the regulation of HSL activity in healthy subjects, which
appears to occur at a transcriptional level, is to a large extent dependent on
fat cell size.
PMID- 9398733
TI - Dose-dependent effects of recombinant human interleukin-6 on glucose regulation.
AB - Inflammatory cytokines have metabolic actions that probably contribute to the
general adaptation of the organism during infectious or inflammatory stress. To
examine the effects of interleukin 6 (IL-6), the main circulating cytokine, on
glucose metabolism in man, we performed dose-response studies of recombinant
human IL-6 in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0,
3.0, and 10.0 mg/Kg BW) were injected sc in 15 healthy male volunteers (3 in each
dose) after a 12-h fast. All IL-6 doses were tolerated well and produced no
significant adverse effects. We measured the circulating levels of glucose,
insulin, C-peptide, and glucagon at baseline and half-hourly over 4 h after the
IL-6 injection. Mean peak plasma levels of IL-6 were achieved between 120 and 240
min and were 8, 22, 65, 290, and 4050 pg/mL, respectively, for the 5 doses. After
administration of the 2 smaller IL-6 doses, we observed no significant changes in
plasma glucose levels, which, because of continued fasting, decreased slightly
over time. By 60 min after the 3 higher IL-6 doses, however, the decline in
fasting blood glucose was arrested, and glucose levels increased in a dose
dependent fashion. The concurrent levels of plasma insulin and C-peptide were not
affected by any IL-6 dose. In contrast, IL-6 caused significant increases in
plasma glucagon levels, which peaked between 120 and 150 min after the IL-6
injection. In conclusion, sc IL-6 administration induced dose-dependent increases
in fasting blood glucose, probably by stimulating glucagon release and other
counteregulatory hormones and/or by inducing peripheral resistance to insulin
action.
PMID- 9398734
TI - Nitric oxide inhibits corticotropin-releasing hormone exocytosis but not
synthesis by cultured human trophoblasts.
AB - Nitric oxide (NO) plays an important role in many cell-cell signaling systems,
but its mechanism of action is variable. We have previously reported that NO
reduces secretion of the peptide hormone, CRH, from cultured placental cells and
the perfused placenta. Because placental CRH production seems linked to human
parturition, we wished to explore the mechanism of action of NO in this setting
in more detail. We report here that in the placenta, NO specifically inhibited
CRH exocytosis, not synthesis, and that endogenous NO affects this process.
Cytotrophoblasts were prepared from term human placentas and cultured as
monolayers. CRH immunoreactivity in the cell supernatants and cell extracts were
measured by RIA. CRH messenger RNA was determined by Northern blot analysis.
Sodium nitroprusside (SNP; 1-100 mumol/L) and S-nitroso-N-acetyl-penicillamine
(SNAP; 1-100 mumol/L), NO donors, significantly reduced basal CRH concentration
in the media, while increasing the concentration of CRH in the cells (P < 0.01),
suggesting that exocytosis of CRH was inhibited. These effects could be
attenuated by the NO scavenger hemoglobin (20 micrograms/mL). KCl (45 mmol/L),
which causes exocytosis by depolarizing the cell membrane, increased CRH release
by 2- to 3-fold, and this was inhibited by SNP. Basal release of CRH was
augmented by the NO synthase competitive inhibitor N omega-L-arginine methyl
ester (1 mmol/L; P < 0.01) and the guanylate cyclase inhibitor, LY83583 (1
mumol/L; P < 0.01). The inhibitory effect of SNP was also blocked by LY83583. CRH
messenger RNA content did not change when the placental cells were incubated with
SNP, N omega-L-arginine methyl ester, and LY83583 for 6 and 24 h, and this was
consistent with studies showing that total CRH immunoreactivity (cells plus
media) did not change in the presence of SNP. These studies indicate that
exogenous NO inhibits CRH exocytosis, rather than biosynthesis, by human
trophoblasts and that endogenous NO has tonic inhibitory effects on CRH release
by these cells. The inhibitory effect of NO on basal and stimulated CRH release
by placental trophoblasts seems to be a guanylate cyclase-mediated inhibition of
exocytosis.
PMID- 9398735
TI - A novel point mutation in the intracellular domain of the ret protooncogene in a
family with medullary thyroid carcinoma.
AB - Specific mutations in the ret protooncogene have been found associated with
multiple endocrine neoplasia type 2A (MEN 2A) and type 2B (MEN 2B) and familial
medullary thyroid carcinoma (FMTC). Mutations in one of five cysteine residues in
the extracellular domain have been found in over 95% of families with MEN 2A and
88% of families with FMTC. In MEN 2B patients, a specific mutation at codon 918,
substituting a threonine for a methionine, has been found in 95% of cases. In
FMTC, in addition to the mutations of the extracellular cysteines, three
intracellular base pair changes have been reported at codons 768 and 804. Here we
describe a novel intracellular mutation in exon 15 of the ret gene that leads to
the substitution of an alanine for a serine at codon 891 in a family with
medullary thyroid carcinoma. This amino acid change may be important in
determining substrate specificity or, alternatively, may play a role in ATP
binding.
PMID- 9398736
TI - Resistance of gonadotropin releasing hormone drive to sex steroid-induced
suppression in hyperandrogenic anovulation.
AB - Women with hyperandrogenic anovulation (HAA) exhibit increased GnRH drive, as
evidenced by a faster LH pulse frequency that slows in response to progestin
induced opioidergic tone. To determine whether increased GnRH-LH drive in HAA
reflects altered sex steroid exposure caused by chronic anovulation or is an
intrinsic hypothalamic attribute, we compared the pulsatile LH response to oral
contraceptive (OC)-induced suppression in seven women with HAA, with that of
seven eumenorrheic women (EW). LH levels were determined at 10-min intervals for
12 h after 19-21 days of OC use and 5-7 days after cessation. Testosterone,
androstenedione, estradiol, FSH, and LH levels were determined at weekly
intervals before, during, and after OC use. LH pulse number/12 h was higher (P <
0.001) in HAA during and after OCs, when compared with that of EW. Mean LH was
increased in HAA before, during, and after OCs. Testosterone, androstenedione,
and estradiol levels were higher in HAA before OCs, but they decreased to similar
levels during OC use in both groups. FSH concentrations were similar before and
during OCs but rose more after cessation of OCs in EW. These findings indicate
that GnRH drive in HAA is resistant to OC-induced suppression and, therefore,
could be an intrinsic hypothalamic attribute.
PMID- 9398737
TI - Pituitary adenomas: screening for G alpha q mutations.
AB - Mutant, guanosine triphosphatase-deficient, alpha-subunits of the G protein, Gs,
gsp ocogene have been discovered in 40% of GH-secreting pituitary adenomas.
Therefore, we hypothesized that a novel G protein class, G alpha q, involved in
pituitary signal transduction, might be involved in pituitary tumorigenesis.
Recombinant mutations of G alpha q result in constitutive activation of
phospholipase C and have transforming activity. Therefore, we screened tumor
samples from 37 pituitary adenomas for the presence of activating mutations of
the G alpha q gene. Importantly, our sample contains 8 FSH and LH adenomas. In
the pituitary gland, FSH and LH are linked to the GnRH-G alpha q signaling
cascade, making these tumors a logical choice for screening for G alpha q
mutations. Complementary DNA (cDNA) was synthesized by RT-PCR with G alpha q
specific primers to exclude pseudogene transcripts. Fragments of G alpha q cDNA
encompassing residues (Arg183, Gln209) were screened by single-strand
conformation polymorphism and then sequenced in both directions. No mutations
were detected. We conclude that mutations in these regions of the G alpha q cDNA
occur infrequently, if at all, in human pituitary adenomas. Alternative
mechanisms underlying pituitary tumorigenesis should be explored.
PMID- 9398738
TI - Endometrial alpha-2 macroglobulin; localization by in situ hybridization and
effect on mouse embryo development in vitro.
AB - alpha-2 macroglobulin (A2M) is a 718,000-kDA broad spectrum plasma protease
inhibitor whose production by the human endometrium was recently reported. The
multifunctional A2M receptor, also known as low-density lipoprotein receptor
related protein, was also recently immunolocalized to the endometrial stroma. The
objective of this study was to further characterize the endometrial site of
expression of A2M, and to study its effects on mouse embryo development in vitro,
to gain some insight into the functional significance of its endometrial
production. Formalin-fixed, paraffin-embedded human endometrium from hysterectomy
and endometrial biopsy specimen was used for in situ hybridization analysis, with
35S-labeled riboprobes representing subcloned A2M complementary DNA (cDNA)
fragments. Duplicate sections of human endometrium were hybridized with sense and
antisense probe and coated with photographic emulsion. Resultant autoradiograms
were analyzed qualitatively by light- and darkfield microscopy and quantitatively
by a computerized analysis of the signal intensity. Immunohistochemistry and
immunoblotting for endometrial tissues were performed using an affinity-purified
polyclonal antibody to human A2M. The effect of A2M on mouse embryo development
was studied by exposure of one cell mouse embryo in culture to physiological
concentrations of biologically active and inactive A2M. Expression signals for
A2M were more numerous and intense in the secretory endometrium, compared with
proliferative endometrium. Endothelial cells lining the endometrial blood vessels
seemed to be the main source of A2M expression. The A2M expression signals in
secretory endothelium were 2- to 3-fold stronger than the proliferative
endothelium, suggesting transcriptional activation of A2M expression in the
secretory endothelium. Glandular expression was observed in secretory endometrium
from two patients with endometriosis. Ectopic endometrial tissues also produced
A2M. A2M at concentrations of 400-500 mumol/L significantly inhibited blastocyst
development of mouse embryos in vitro. A2M is expressed predominantly by the
endometrial endothelial cells and may be involved in endometrial physiology.
Physiological concentrations of A2M inhibit mouse embryo development in vitro,
suggesting that endometrial production of A2M may play a role in regulating
preimplantation embryo development.
PMID- 9398739
TI - Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor
alpha, in vivo.
AB - We measured arterio-venous differences in concentrations of tumor necrosis factor
alpha (TNF alpha) and interleukin-6 (IL-6) across a sc adipose tissue bed in the
postabsorptive state in 39 subjects [22 women and 17 men; median age, 36 yr
(interquartile range, 26-48 yr); body mass index, 31.8 kg/m2 (range, 22.3- 38.7
kg/m2); percent body fat, 28.7% (range, 17.6-50.7%)]. A subgroup of 8 subjects
had arteriovenous differences measured across forearm muscle. Thirty subjects
were studied from late morning to early evening; 19 ate a high carbohydrate meal
around 1300 h, and 11 continued to fast. We found a greater than 2-fold increase
in IL-6 concentrations across the adipose tissue bed [arterial, 2.27 pg/mL
(range, 1.42-3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36-9.62 pg/mL); P <
0.001], but not across forearm muscle. Arterial plasma concentrations of IL-6
correlated significantly with body mass index (Spearman's r = 0.48; P < 0.01) and
percent body fat (Spearman's r = 0.49; P < 0.01). Subcutaneous adipose tissue IL
6 production increased by the early evening (1800-1900 h) in both subjects who
had extended their fasting and those who had eaten. Neither deep forearm nor sc
adipose tissue consistently released TNF alpha [across adipose tissue: arterial,
1.83 pg/mL (range, 1.36-2.34 pg/mL); venous, 1.85 pg/mL (range, 1.44-2.53 pg/mL);
P = NS: across forearm muscle: arterial, 1.22 pg/mL (range, 0.74-2.76 pg/mL);
venous, 0.99 pg/mL (range, 0.69-1.70 pg/mL); P = NS]. Although both IL-6 and TNF
alpha are expressed by adipose tissue, our results show that there are important
differences in their systemic release. TNF alpha is not released by this sc
depot. In contrast, IL-6 is released from the depot and is thereby able to signal
systemically.
PMID- 9398740
TI - Expression of variant forms of insulin receptor substrate-1 identified in
patients with noninsulin-dependent diabetes mellitus.
AB - Several polymorphisms have been identified in the amino acid sequence of human
insulin receptor substrate-1 (IRS-1). Some of the variant sequences have been
reported to be increased in prevalence among patients with noninsulin-dependent
diabetes mellitus (NIDDM). This observation led to the hypothesis that these
amino acid substitutions may impair the function of IRS-1, thereby causing the
insulin resistance seen in patients with NIDDM. To address this question, we have
designed studies to evaluate the effects of three variant sequences identified in
our laboratory: Gly819-->Arg, Gly972-->Arg, and Arg1221-->Cys. We constructed
four IRS-1 expression vectors for transfection in COS-7 cells: wild-type, single
mutant (Gly819-->Arg), double mutant (Gly819-->Arg; Gly972-->Arg), and triple
mutant (Gly819-->Arg; Gly972-->Arg; Arg1221-->Cys) IRS-1. The mutations did not
alter the level of expression or the extent of insulin receptor-mediated tyrosine
phosphorylation of recombinant IRS-1. Moreover, the mutations did not lead to a
detectable impairment in the association of recombinant IRS-1 with important
downstream effectors, including the p85 subunit of phosphatidylinositol 3-kinase
and growth factor receptor-binding protein-2. We conclude that these amino acid
substitutions do not appear to cause a major defect in the function of IRS-1, as
judged by our assays. However, this type of assay probably lacks the sensitivity
to detect subtle functional defects. In light of the suggestive associations
observed in epidemiological studies, it is premature to totally discard the
hypothesis that variant sequences of IRS-1 may contribute to the pathogenesis of
NIDDM. Nevertheless, our studies cannot be interpreted as lending support to that
hypothesis.
PMID- 9398741
TI - Stimulation of mitochondrial fatty acid oxidation by growth hormone in human
fibroblasts.
AB - In vivo administration of GH induces lipolysis and lipid oxidation. However, it
is not clear whether the stimulation of lipid oxidation is a direct effect of GH
or is driven by increased substrate supply secondary to lipolysis. An in vitro
bioassay has been established for assessing beta-oxidation of fatty acids in
mitochondria, based on the measurement of conversion of tritiated palmitic acid
to 5H2O by fibroblasts in culture. We have modified this assay to investigate
whether GH stimulates fatty acid oxidation. GH stimulated oxidation of palmitic
acid maximally by 26.7 +/- 2.5% (mean +/- SEM; P < 0.0001). The stimulation was
biphasic, with the oxidation rate increasing with increasing GH concentration to
a peak response at 1.5 nmol/L and declining to a level not significantly
different from control thereafter. Insulin-like growth factor-I at concentrations
of up to 250 nmol/L had no significant effect on fatty acid oxidation. GH-binding
protein attenuated the effect of GH. An anti-GH receptor (GHR) antibody (MAb263),
which dimerizes the receptor and induces GH-like biological actions,
significantly stimulated fatty acid oxidation. Another anti-GHR antibody (MAb5),
which prevents receptor dimerization, suppressed GH action. In summary, GH
directly stimulated fatty acid oxidation, an action not mediated by insulin-like
growth factor-I. Dimerization of GHRs was necessary for this effect. This
bioassay is a practical tool for studying the regulatory effects of GH on lipid
oxidation.
PMID- 9398742
TI - Telomerase activity in human thyroid carcinomas originating from the follicular
cells.
AB - Telomerase activity is known to be absent from most normal and well
differentiated tissues, although being detectable in the vast majority of
malignant tumors. An increasing number of reports demonstrate that telomerase may
be activated in benign tumors, such as adenomas. We have investigated a series of
normal and neoplastic thyroid tissues for the presence of telomerase activity. As
expected, all normal thyroid tissues (n = 20) had no display of telomerase
activity. Amongst cancers, the incidence of telomerase activity varied with the
histological subtypes. Telomerase activity was present in only 3/15 cases (20%)
of papillary carcinomas. Telomerase activity was more frequently detected in
follicular (4/6) and in undifferentiated (2/3) carcinomas. Unexpectedly, one case
(1/12) of adenoma contained high levels of telomerase activity. Taken together,
these results indicate that telomerase may play some role in the pathogenesis of
thyroid tumors, in particular in follicular and undifferentiated carcinomas that
are known to have the most aggressive behavior.
PMID- 9398743
TI - Thyroid hormone autoantibodies elicited by diagnostic fine needle biopsy.
AB - Based on the knowledge that diagnostic fine needle biopsy of the thyroid (FNAB)
results in a prompt increase in circulating thyroglobulin (Tg); we evaluated
whether Tg is indeed the postulated antigen for circulating antibodies against
thyroid hormones (THAb). Preliminarily, we verified that FNAB causes the release
into the bloodstream of iodinated, heterologous, and thus potentially
immunogenic, molecules of Tg. Of the initially enrolled 400 patients, 214 had a
number of blood drawings sufficient to evaluate over time (before FNAB and 1-3 h,
3 days, 15 days, 30 days, 3 months, 6 months, and 12 months after FNAB) the
following parameters: THAb of both IgM and IgG classes, Tg antibodies (TgAb; by a
sensitive immunoradiometric assay), and Tg (in the 156 patients who were TgAb
negative). We found the following. 1) Serum Tg most often peaks 1-3 h after FNAB
(61 +/- 45% of the baseline level; mean +/- SD). 2) Only 7% of the initially TgAb
negative patients converted to positive, and only 12% of those initially positive
had an increase in the levels of TgAb. 3) THAb were detected in 0 of 400 patients
before FNAB, but were found in 9 of 214 (4.2%) after FNAB. This proportion is 2
orders of magnitude higher than that (149 of 369,000 or 0.04%) found in
consecutive patients attending European thyroid clinics. Of the 9 cases, 6 had
Hashimoto's thyroiditis (HT), 2 had euthyroid colloid goiter, and 1 had Hurthle
cell carcinoma. In the 5 of 9 cases who were TgAb negative, the post-FNAB
increment in Tg was 21-99%, i.e. lower than that of the majority of patients (101
12,500%). 4) THAb were of the IgM class in all 9 (6 against T3 and 3 against T4),
and were accompanied and/or followed up to 3 months after FNAB by IgG-THAb of the
same specificity (2 against T3 and 1 against T4) in 3 cases. In a fourth case,
IgM-T3 were followed by a long-lasting synthesis of IgG-T3 (i.e. up to 1 yr post
FNAB). All 4 cases with IgG-THAb had HT and remained TgAb positive. 5) In the 2
HT and the 3 non-HT patients with undetectable TgAb, THAb were of the IgM class
only. 6) In the HT group, 2 risk factors for the development of post-FNAB THAb
appeared to be pre-FNAB TgAb levels below 400 U/mL that did not increase after
FNAB and Tg released from a colloid nodule. We conclude that Tg release from the
thyroid is sufficient to elicit THAb synthesis. In patients with autoimmune
thyroid disease (HT), this synthesis occurs with a frequency 10-fold higher than
that in patients with nonautoimmune thyroid diseases (21% vs. 2%). However, in
only a fraction of patients with autoimmune disease, who need to be TgAb positive
by a sensitive assay, the primary immune response (IgM) is followed by a
secondary one (IgG). As, once present, this secondary response is long lasting in
only a minority of our patients, we think that this could contribute to the
rarity of naturally occurring THAb.
PMID- 9398744
TI - A novel transcript for the thyrotropin-releasing hormone receptor in human
pituitary and pituitary tumors.
AB - We measured the amounts of TRH receptor (TRHR) messenger ribonucleic acid (mRNA)
in human normal pituitary and pituitary tumors and found a novel transcript of
the TRHR gene. Competitive PCR revealed expression of the TRHR mRNA in all
pituitary adenomas examined, and its level was variable and similar to that in
the normal pituitary. When the C-terminal region was amplified by PCR, an
additional short product was observed. Cloning and sequence analysis of this
short fragment revealed that the deleted sequence corresponded exactly to the 5'
sequence of exon 3, indicating alternative splicing of the TRHR mRNA. This
alternative splicing resulted in a frame shift, yielding a C-terminal truncated
protein (HTRHR2) on translation. Expression analysis of HTRHR2 in Chinese hamster
ovary cells showed no significant binding to [3HIMeTRH or response of
intracellular calcium to TRH administration. However, the mRNA ratio of HTRHR2
vs. the wild type (HTRHR1) was significantly different among pituitary tumors.
The highest ratio was observed in prolactinomas (30%), and almost no detectable
expression was found in GH-producing tumors. These findings indicate that this
novel transcript of the human TRH receptor gene is produced in a tumor-specific
manner and may be a useful parameter for evaluation of individual pituitary
tumors.
PMID- 9398745
TI - Identification of constitutively activating somatic thyrotropin receptor
mutations in a subset of toxic multinodular goiters.
AB - Constitutively activating mutations in the TSH receptor (TSHR) gene and in the Gs
alpha gene are frequent molecular causes for solitary toxic nodules of the
thyroid. However, the etiology of toxic multinodular goiter is still largely
unknown. Therefore, DNA from nodular and quiescent surrounding tissue of six
patients with toxic multinodular goiters was screened for mutations in exons 9
and 10 of the TSHR gene and exons 7-10 of the Gs alpha gene by direct automated
sequencing. In one patient, two different somatic TSHR mutations were identified
in two different toxic nodules (L632I and F631L). In another patient, two
different toxic nodules harbored the same TSHR mutation (I630L), whereas only one
TSHR mutation (F631L) was identified in one of the two toxic nodules of an
additional patient. In the other three patients, no mutations could be found in
exons 9 and 10 of the TSHR gene or in exons 7-10 of the Gs alpha gene. Our
results demonstrate that not only solitary toxic adenomas but also toxic
multinodular goiters can be caused by constitutively activating mutations of the
TSHR. In addition to mutations in the TSHR and possibly in Gs alpha, there are
probably other still unknown mechanisms that cause hot nodules in toxic
multinodular goiters.
PMID- 9398746
TI - Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a
family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism.
AB - Constitutively activating germline mutations in the TSH receptor (TSHR) gene have
been identified as a cause of autosomal dominant nonautoimmune hyperthyroidism
and sporadic congenital hyperthyroidism. We report a 10-yr-old boy and his 31-yr
old mother, both presenting with a history of recurring toxic thyroid hyperplasia
and no evidence for autoimmune thyroid disease. In the boy, onset of
hyperthyroidism and goiter was neonatal. In the mother, onset of thyroid disease
dates back to early childhood. There was no history of thyroid disease in the
rest of the family. Screening for germline mutations in exon 10 of the TSHR was
performed by direct sequencing of genomic DNA extracted from peripheral blood
leukocytes of both patients. In the boy and his mother, an identical heterozygous
TSHR mutation was identified, exchanging leucine for phenylalanine at residue 629
of the TSHR (TTG-->TTT). Transient expression of the mutated TSHR construct in
COS-7 cells confirmed the constitutive activity of the new TSHR germline
mutation. This is the second family displaying congenital manifestation of
hyperthyroidism in familial nonautoimmune hyperthyroidism.
PMID- 9398747
TI - Prenatal diagnosis and treatment of dyshormonogenetic fetal goiter due to
defective thyroglobulin synthesis.
PMID- 9398748
TI - Localization of the steroidogenic acute regulatory protein in human tissues.
AB - The rate-limiting step in steroid hormone production in the adrenal cortex and
gonads, the translocation of cholesterol from the outer to the inner
mitochondrial membranes, is mediated by the steroidogenic acute regulatory
protein (StAR). Heretofore, the localization of StAR in human adult and fetal
tissues has not been defined. To this end, expression of StAR was detected in
formalin-fixed, paraffin-embedded specimens using a polyclonal antiserum raised
against recombinant human StAR. Primordial follicles of adult ovaries did not
contain StAR, whereas antral follicles stained intensely in the thecal layer,
with occasional staining of granulosa cells. Corpora lutea were intensely
stained, but with a patchy distribution. Corpora albicantia did not stain. A
luteoma of pregnancy stained with patches of moderate intensity. Ovaries with
hyperthecosis contained areas of intense thecal staining. An ovarian Leydig cell
tumor stained intensely, whereas granulosa cell tumors were negative. Ovarian
adenocarcinomas, borderline tumors, teratomas, cystadenomas, and a Brenner tumor
displayed no specific StAR immunostaining. Testicular Leydig cells stained
moderately to intensely, as did a testicular Leydig cell tumor. Sertoli cells
stained weakly in some specimens. Seminomas and testicular germ cell tumors were
negative. There was minimal to moderate staining in the adrenal glomerulosa and
faciculata and minimal staining in the reticularis, while the medulla was
negative. Adrenal cortical adenomas, hyperplasias, and carcinomas all contained
areas of StAR staining. The renal distal tubules stained with moderate to marked
intensity. Renal carcinomas had occasional modest staining. No immunostaining was
found in the placenta. Fetal ovaries contained sporadic stromal cells displaying
intense StAR staining, particularly in the hilar region. Oocytes from a 32-week
fetal ovary showed moderate to intense staining. Fetal testes displayed intense
Leydig cell staining. The neocortex of the fetal adrenal glands displayed only
minimal StAR staining, whereas moderate to intense staining was found in the
fetal zone. The fetal kidneys had moderate StAR staining of the distal convoluted
tubules. We conclude that StAR is localized to normal and neoplastic cells in the
gonads and adrenal cortex, which produce large amounts of pregnenolone. StAR
protein was not detected in the placenta, documenting that placental progestin
synthesis occurs through StAR-independent mechanisms. The presence of StAR in
cells that do not express cholesterol side-chain cleavage enzyme cytochrome P450,
including renal distal tubules, Sertoli cells, and fetal oocytes, suggests that
StAR has roles in metabolic processes in addition to stimulating pregnenolone
synthesis.
PMID- 9398749
TI - 11 beta-Hydroxysteroid dehydrogenase type II in the human endometrium:
localization and activity during the menstrual cycle.
AB - The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) is a
potent inactivator of glucocorticoids and is present in high amounts in the
placental syncytiotrophoblast and sodium-transporting epithelia. Placental 11
beta HSD2 is thought to protect the fetus from high circulating levels of
maternal glucocorticoids, whereas the renal enzyme is important in conferring
aldosterone specificity on the mineralocorticoid receptor. An isoform of 11 beta
HSD (11 beta HSD1) is also present in a wide range of tissues, but usually acts
as an oxoreductase, converting the biologically inactive cortisone to cortisol.
In the present study we have used an immunopurified antibody to the carboxy
terminus of human 11 beta HSD2 (HUH23) to demonstrate localization of the enzyme
in luminal and glandular epithelia of human endometrium. In some specimens
staining was uniformly distributed, but in others there was clear evidence of
heterogeneity both between and within epithelia. Although 11 beta HSD2 was found
mainly in the cytoplasm, some cells showed evidence of nuclear staining only.
Western blot analysis showed a band at 41 kDa in endometrium and myometrium,
confirming the presence of 11 beta HSD2. Measurement of activity throughout the
menstrual cycle showed that mean levels (+/- SEM) of activity were 156 +/- 17 and
6.1 +/- 1.1 pmol product/min.g homogenate protein for 11 beta HSD2 and 11 beta
HSD1, respectively. Patients taking combined estrogen/progesterone contraceptives
had significantly lower activities of both enzymes (76 +/- 19 and 1.9 +/- 0.4;
both P < 0.01) compared with the control group. 11 beta HSD2 activity was
significantly higher in the secretory than in the proliferative phase of the
cycle in controls (193 +/- 22 vs. 120 +/- 23; P < 0.05). All groups contained
outliers with elevated enzyme activities, with some patients displaying 11 beta
HSD2 levels comparable to those observed in human kidney (> 1000 pmol/min.g).
Further analysis showed that there was a statistically significant correlation (r
= 0.43; P < 0.001) between the levels of 11 beta HSD1 and 11 beta HSD2. There was
no detectable mineralocorticoid receptor binding in endometrial cytosols prepared
from patients with a range of 11 beta HSD2 activities. It remains to be
determined whether elevated or suppressed levels of either isoform are associated
with fertility or endometrial pathology.
PMID- 9398750
TI - Human estrogen receptor beta-gene structure, chromosomal localization, and
expression pattern.
AB - The estrogen receptor (ER) is a ligand-activated transcription factor that
mediates the effects of the steroid hormone 17 beta-estradiol, in both males and
females. Since the isolation and cloning of ER, the consensus has been that only
one such receptor exists. The finding of a second subtype of ER (ER beta) has
caused considerable excitement amongst endocrinologists. In this article, we
present data regarding the genomic structure and chromosomal localization of the
human ER beta gene, demonstrating that two independent ER genes do exist in the
human. Furthermore, we present data regarding the tissue distribution of human ER
beta, showing that this receptor is expressed in multiple tissues. For instance,
ER beta is found in developing spermatids of the testis, a finding of potential
relevance for the ongoing debate on the effects of environmental estrogens on
sperm counts. In addition, we find ER beta in ovarian granulosa cells, indicating
that estrogens also participate in the regulation of follicular growth in the
human.
PMID- 9398751
TI - Genetic control of anti-thyrotropin receptor antibody generation in H-2K mice
immunized with thyrotropin receptor-transfected fibroblasts.
PMID- 9398752
TI - Presence of leptin in colostrum and/or breast milk from lactating mothers: a
potential role in the regulation of neonatal food intake.
AB - In neonates both nutrients and regulatory factors are transferred from the mother
to the suckling infant via milk. In the present work, it has been shown that
human milk contains immunoreactive leptin which is identical to intact human
leptin by criteria of charge, size, immunorecognition and SDS-PAGE mobility. In
experimental animals it was demonstrated that leptin is transferred from the
circulation to mothers' milk, then to the infant's stomach and afterwards to
infant blood. Maternal leptin in milk may play a regulatory role in the suckling
infant.
PMID- 9398753
TI - Familial nonmedullary thyroid carcinomas: a heterogeneous syndrome with different
natural history and variable long-term prognosis.
PMID- 9398754
TI - 21-Hydroxylase heterozygotism and immune regulation.
PMID- 9398755
TI - Potassium and aldosterone secretion in glucocorticoid-remediable aldosteronism.
PMID- 9398757
TI - Commentary on article by Rudavsky and Freeman.
PMID- 9398759
TI - Leptin levels are elevated despite low thyroid hormone levels in the "euthyroid
sick" syndrome.
PMID- 9398760
TI - Health care reform and the emergency physician: a personal strategy.
AB - Annals' 25th anniversary is a cause for celebration, but the future imposes a new
set of ethical questions and moral dilemmas for emergency physicians. Each
physician will need to make personal choices consistent with the courage,
judgment, integrity, and dedication of past leaders when dealing with the moral
dilemmas of the future.
PMID- 9398761
TI - The troubled road to universal health care.
AB - In our country the increasing commercialization of medicine is taking control of
our medical school faculties, hospitals, and education. There is an overemphasis
on health care efficiency, with a dramatic decrease in the commitment to
research, an increase in the cost of medical education and resultant staggering
student debt, an increasing number of medically uninsured, and an ever-widening
gap between the best that American medicine can offer and that which the indigent
receive.
PMID- 9398762
TI - Thoughts on the clinician's response to health care reform: a cautionary note.
AB - In the course of contemporary health care discussion, we frequently refer to
"health care reform" and its effect on health care delivery. The context within
which we use the expression somehow manages to convey the idea that there is some
kind of discreet "fait accompli" to which we can point. This basic premise is
incorrect and ascribing to it renders much of the discussion about it in error.
PMID- 9398763
TI - Health care reform is dead--long live health care reform.
AB - The 1993 Clinton health care reform effort was not the end of reform but the
inauspicious start of a fiercely contested round of reform that may take another
decade or two to complete. The 1993 Clinton plan was just the latest stage of a
battle for national action on health care than began with Teddy Roosevelt's
promise of compulsory health insurance in the 1912 presidential campaign.
PMID- 9398764
TI - Medicine at the millennium.
AB - What will the future bring? Will biomedical advances move rapidly and affordably
into clinical practice, stimulated by the demands of the educated consumer? Or
will changes in the way health care is financed and physician inability to stay
abreast of clinical changes widen the gap between high-quality and mediocre
medical care? Is there a limit to what we can afford to provide, regardless of
availability?
PMID- 9398765
TI - The future of emergency medicine.
AB - When considering the future of emergency medicine, we need to study the multiple
environments that affect the specialty. This review considers three broad
environments: federal government, state jurisdictions, and the private system.
PMID- 9398766
TI - The future of the private practice of emergency medicine.
AB - No specialty better personifies the changes occurring throughout the health care
delivery system than emergency medicine. It was just a short 25 years ago that
the specialty of emergency medicine, as it is known today, emerged. The full-time
staffing of EDs arose out of a need by patients who were presenting in ever
increasing numbers to hospital EDs that were staffed by a nurse or part-time
physician. The specialty has continued to be responsive to the changing health
care system throughout the past 25 years with innovations such as fast track
units, observation units, and chest pain treatment center. To develop a vision
for the future of the specialty, it is important to first evaluate the current
trends in health care and their influences on the specialty. Three significant
areas stand out in the current health care landscape: consolidation of hospital
systems, emergence of publicly traded physician practice management companies,
and the increasing penetration of managed care.
PMID- 9398767
TI - Emergency medicine: a plan for the twenty-first century.
AB - Emergency physicians, especially those currently charged with fiscal
responsibility within their group, know very well the complicated issues of
today's health care environment. We must remain open-minded about all the
possible relationships that might ensure optimum patient care and our specialty's
future.
PMID- 9398768
TI - Economic credentialing.
AB - In the 1990s, hospital management and trustees introduced the concept of
evaluating physicians for appointment, reappointment, and privilege delineation
with the addition of financial criteria. Although emergency physicians are
advocates for cost-effective care, they must make certain that credentials are
determined by the provision of quality medical care, and that if economic
criteria are used, the criteria chosen truly reflect quality of care.
PMID- 9398769
TI - Key issues in emergency medicine workforce planning.
AB - The goal of workforce planning should be to match the supply of providers with
the nation's demand. Whatever workforce planning process evolves, it will be
necessary for the specialty to portray accurately our workforce needs. Because
this portrait requires a clear understanding of the development of and funding
mechanisms for graduate medical education and specific data describing both the
supply and demand for emergency physicians, we address these issues.
PMID- 9398770
TI - Emergency medicine and the academic health center.
AB - The last 3 to 5 years have witnessed a tremendous change in direction for the
academic health center. The major trends in this regard are increased importance
of managed care, cost consciousness, development of a clinical system, pressure
to downsize graduate medical education, and increased competition.
PMID- 9398771
TI - The future of the certification system in emergency medicine.
AB - The heart of the specialty of emergency medicine, like all specialties and
subspecialties, is training. The excellence in medical care that has accrued to
the American public has proceeded from the belief that a well-defined and
accredited program of education will produce the highest probability that a
physician providing care will be competent. There is now a joint opportunity in
emergency medicine to build a certification and recertification system that meets
the criteria to provide the highest quality care for the public and to offer an
efficient and effective system for the members of the specialty.
PMID- 9398772
TI - Access, quality, and cost control in emergency medicine: can we have all three? A
resident's perspective on the future of emergency medicine.
AB - The triad of access, quality, and cost provides a useful framework for the
discussion of health care reform. A quote from a recent review of the Oregon
Health Plan illustrates the conflict between these three factors very well. "The
administrators of the plan are realistic people; they once placed a sign on the
wall: 'Cost, access, quality--pick any two."
PMID- 9398773
TI - Scientific publication in emergency medicine: imprint on the future.
AB - Intensified research efforts in emergency medicine have resulted in a unique body
of knowledge based on investigations involving emergency patients and conducted
by emergency medicine researchers. The success and effectiveness of emergency
medicine publications in the future rely on adherence to rigorous standards for
peer review and editorial evaluation, introduction of value-added innovations,
creative applications for electronic publication of scientific materials, and an
unyielding commitment to quality and integrity.
PMID- 9398774
TI - Quantifying the scanty science of prehospital emergency care.
AB - Research can produce false-positive results just as can diagnostic tests.
Uncontrolled studies have a specificity of only 11%, versus 88% for randomized
controlled trials (RCTs), which have been designed to minimize the bias of
investigators toward a positive outcome. A search of all the scientific studies
in Medicine since 1985 revealed 5,842 publications on prehospital EMS, but only
54 were RCTs (and therefore unlikely to produce false-positive results). By way
of comparison, during the same time hundreds of RCTs have been conducted on major
medical emergency conditions, and RCTs on even minor topics such as urticaria and
constipation exceed the scientific database on all of EMS. Of the 54 EMS RCTs, 4
(7%) reported harm from the new therapy, and 74% reported no effect of the new
therapy at all. Only 7 (13%) RCTs showing a positive outcome of the intervention
were uncontradicted; of these only 1 examined a major outcome such as survival,
and only 1 compared the intervention with a placebo and could therefore evaluate
the efficacy of EMS itself. Because there is such a paucity of scientific support
for EMS interventions and because monitoring of outcomes and adverse effects is
so poor, a serious reexamination of EMS practice is indicated.
PMID- 9398775
TI - Developing a foundation for the evaluation of expanded-scope EMS: a window of
opportunity that cannot be ignored.
AB - EMS systems are about to undergo a major transformation. Not only will the scope
of EMS change, but many experts believe that it will dramatically expand. Some
see the "expanded scope" as entailing relatively limited changes, whereas others
consider them to be more broad. Although no agreement is evident about the
definition for expanded-scope EMS, it is hoped that all EMS professionals can
agree that it must be implemented in a manner that can be carefully evaluated to
determine its effects on patients and EMS systems. We present a framework for
evaluating the effect of expanded-scope EMS in the various types of systems that
currently exist. Special consideration must be given to the indirect effects that
system changes may have on survival from out-of-hospital cardiac arrest. Numerous
issues will affect our ability to properly assess expanded-scope EMS. The basic
research models necessary to assess the impact of system change are lacking. Few
EMS systems consistently produce significant volumes of good systems research ...
that is, there are few "EMS laboratories." Cost-effectiveness and issues
surrounding the "societal value" of EMS remain essentially unstudied. Reliable
scoring methods, severity scales, and outcome measures are lacking: and, it is
ethically and logistically difficult to justify withholding the "standard of
care" in an effort to understand the impact of EMS interventions. Despite all of
these barriers, it is time to pay the price of doing methodologically sound
evaluations that ensure the most optimal societal impact by the EMS systems of
the future.
PMID- 9398776
TI - Multiple options and unique pathways: a new direction for EMS?
AB - The same forces transforming the health care delivery system also are reshaping
EMS. The changing economic and organizational structures of the health services
delivery system may predict how EMS systems will redesign themselves. We discuss
one template for future EMS systems.
PMID- 9398777
TI - Emergency medicine in population-based systems of care.
AB - EDs and emergency physicians play a critical role in health care delivery-
providing care to those with life-threatening conditions, as well as serving as
provider of last resort to those without options for primary care. This diversity
of functions provides unique opportunities for identifying important unmet
community needs and developing solutions to address these needs. Future
challenges for emergency medicine include assessing and improving the quality of
care provided within the ED and identifying the role of the ED in systems of
care. Health services research can help define the optimal functions of emergency
medicine in enhancing population health.
PMID- 9398778
TI - The "new VA": delivering health care value through integrated service networks.
AB - In an effort to meet powerful societal and industry-wide forces of change, the
Veterans Health Administration has initiated a fundamental reengineering of
itself, and is currently undergoing an innovative transformation that is among
the most profound of any organization in American history.
PMID- 9398779
TI - Fifty years of defibrillation.
PMID- 9398780
TI - Guidelines for evaluation of international emergency medicine assistance and
development projects.
AB - Interest in the development of the specialty of emergency medicine and of
emergency health care systems has greatly increased worldwide in the last few
years. The guidelines in this article were developed in an effort to assist
others in design and evaluation of all types of emergency medicine projects.
PMID- 9398781
TI - Partners in progress: joining together against impaired driving.
PMID- 9398782
TI - Current research in alcohol.
PMID- 9398783
TI - Commentary: missing in action--emergency medicine and the problem drinker.
PMID- 9398784
TI - Incarceration of a gravid fibroid uterus.
AB - The case of an incarcerated gravid fibroid uterus in a 32-year-old woman is
presented. This rare complication of pregnancy is readily identified by specific
symptoms, physical examination, and ultrasound findings. If the condition is
undiagnosed and untreated, spontaneous abortion and preterm labor often occur.
PMID- 9398785
TI - Successful use of propofol in refractory delirium tremens.
AB - Alcohol withdrawal is a common problem encountered by emergency physicians, with
delirium tremens (DT) as the extreme manifestation. DT is a true medical
emergency. Although benzodiazepines are the mainstay of therapy, some patients
require massive amounts to control their symptoms. We report the successful use
of propofol for DT refractory to benzodiazepines in a 42-year-old alcoholic man.
We briefly discuss alcohol withdrawal, as well as the pharmacokinetics and
adverse affects of propofol. The use of propofol in treating DT refractory to
benzodiazepines has previously not been reported.
PMID- 9398786
TI - Treatment of methanol poisoning with intravenous 4-methylpyrazole.
AB - Treatment of human methanol poisoning with the alcohol dehydrogenase inhibitor, 4
methylpyrazole (fomepizole), has not been previously described. We report the
clinical and toxicokinetic data of a patient with methanol poisoning who was
treated with fomepizole. Formic acid levels remained undetectable during
fomepizole treatment, the toxic effects of methanol were prevented, and the
patient made a full recovery.
PMID- 9398787
TI - "I'm sorry doctor! I'll just take the pain!".
PMID- 9398788
TI - Frontline footage.
PMID- 9398789
TI - Alarming defibrillator headlines.
PMID- 9398790
TI - Treatment of panic disorder in the ED.
PMID- 9398791
TI - Panic disorders, hyperventilation, and the dreaded brown paper bag.
PMID- 9398792
TI - Acute toluene ingestion toxicity.
PMID- 9398793
TI - Evaluation of gastric emptying function in clinical practice.
AB - In this retrospective analysis, we compared different methods to evaluate gastric
emptying function, aiming to improve the sensitivity and the clinical
availability of our diagnostic testing. In the first study, we compared, in 72
patients clinically suspected of gastroparesis, the emptying of a meal containing
two solid nutrients with different disintegration rates: 111In-labeled scrambled
eggs and 99Tc-labeled liver cubes. Gastric emptying of 111In-labeled egg was
delayed in 12 of our patients and the evacuation of the 99Tc-labeled liver was
prolonged in 19 patients. The choice of the nutrient was not important for the
identification of diabetic gastroparesis (43% vs 57%; NS), but it was determinant
in the case of patients suspected of idiopathic gastroparesis (12% were positive
with the egg and 25% with the liver; P < 0.05). In the second study, we compared
two different diagnostic methods in 46 patients: a simple radiological detection
of the gastric emptying of radiopaque pellets, and the scintigraphic emptying of
a solid meal containing 99Tc-labeled liver cubes. Both tests correlated perfectly
in 78% of our patients. In 15% of the population (six of these seven patients
were diabetics suspected of gastroparesis) the scintigraphic method was normal,
while the evacuation of radiopaque pellets was delayed. For clinical purposes, we
therefore propose: (1) the scintigraphic method should use liver rather than egg
as a radiolabeled tracer in order to improve the sensitivity of the test for
detection of gastroparesis; and (2) the radiological detection of radiopaque
markers is a reliable and convenient method for the detection of gastroparesis in
clinical practice. It is possibly more sensitive than scintigraphy.
PMID- 9398795
TI - Effects of biofeedback therapy on anorectal function in obstructive defecation.
AB - Biofeedback therapy improves symptoms in patients with constipation and
obstructive defecation. Whether it also improves anorectal function is unclear.
Our purpose was to investigate prospectively the effects of biofeedback therapy
on subjective and objective parameters of anorectal function in 25 consecutive
patients with obstructive defecation. Biofeedback therapy consisted of pelvic
floor relaxation exercises (phase I) and neuromuscular conditioning of rectal
sensation and rectoanal coordination, with a solid state manometry system and
simulated defecation maneuvers (phase II). The number of sessions was customized
for each patient. Clinical improvement was assessed from the changes in anorectal
manometry, balloon (50 cc) expulsion test, and the symptom and stool diaries. The
number of therapy sessions varied [mean (range) = 6 (2-10)]. After therapy, when
straining as if to defecate, the percentage anal relaxation, intrarectal
pressure, and defecation index increased (P < 0.001). The balloon expulsion time,
laxative consumption, and straining effort decreased (P < 0.001). Before therapy,
16/25 (64%) patients had impaired rectal sensation, and after therapy this
improved (P < 0.001). After therapy, 15/25 (60%) patients reported > or = 75%
satisfaction with bowel habit and 8/25 (32%) reported > or = 50% satisfaction (P
< 0.001); 15/16 (94%) patients discontinued digital disimpaction. Biofeedback
therapy not only improves subjective but also objective parameters of anorectal
function in at least 76% of patients by rectifying the underlying
pathophysiologic disturbance(s). Sensory conditioning and customizing the number
of sessions may offer additional benefits.
PMID- 9398794
TI - Differential responsiveness to contractile agents of isolated smooth muscle cells
from human colons as a function of age and inflammation.
AB - To study the involvement of age and inflammation in motor colonic activity in
man, contractile responses to CCK, carbachol, and KCl of isolated colonic smooth
muscle cells (SMC) from normal and inflamed human colons were evaluated; the
incidence of sex and smoking on contraction was also analyzed. Contractile
responses to the three agonists were significantly lower in tissues with a low
degree of inflammation than in tissues with high level of inflammation or normal
tissues. This reduction in cell responsiveness appears to be nonspecific and
nonreceptor mediated. A positive correlation of the contractile responses to the
three stimulants with the age of patients was observed. In contrast, no
association was found between sex, smoking, and cell contraction. In conclusion,
contractions of SMC due to CCK, carbachol, and KCl were significantly modified
during life; inflammation of the colon led to a loss of SMC responsiveness.
PMID- 9398796
TI - Hyperglycemia-induced attenuation of rectal perception depends upon pattern of
rectal balloon inflation.
AB - This study investigated the effects of acute hyperglycemia on conscious rectal
perception in response to two different rectal distension paradigms. Eleven
healthy males were studied in random order on two separate days during euglycemia
and hyperglycemia with blood glucose concentrations clamped to 3.8 +/- 0.6 and
14.8 +/- 0.86 mmol/liter, respectively. In order to evoke sensory responses,
rapid phasic and ramplike distensions were applied to an intrarectal balloon.
Rectal sensation thresholds for initial sensation, sensation of stool and
discomfort, and sensory intensities were recorded. Additionally, anorectal motor
responses were investigated during phasic distension. Acute hyperglycemia did not
modify rectal sensory pressure thresholds and perception scores in response to
phasic distension. Neither did hyperglycemia alter the resting anal sphincter
pressure, the pressure threshold for eliciting the rectoanal inhibitory reflex,
or the maximal anal squeeze pressure. In contrast, hyperglycemia attenuated
rectal perception in response to ramplike distension. The pressure thresholds,
10.0 +/- 1.8 and 17.0 +/- 3.6 mm Hg for initial sensation and discomfort,
respectively, during hyperglycemia were significantly higher than the
corresponding thresholds of 4.4 +/- 1.4 and 11.4 +/- 1.9 mm Hg observed during
euglycemia (P < 0.01). Higher rectal pressures were observed at all intensities
of sensation of stool and discomfort during hyperglycemia than those obtained
during euglycemia (P < 0.01). Hyperglycemia did not alter the compliance of the
rectum. The results of this study demonstrate that acute hyperglycemia attenuates
rectal perception, and this attenuation depends upon the type of distension
employed. Our findings also demonstrate that anal sphincter motor function is not
appreciably modified by hyperglycemia.
PMID- 9398797
TI - Adrenergic denervation hypersensitivity in ileal circular smooth muscle after
small bowel transplantation in rats.
AB - Effects of small bowel transplantation (SBT) on ileal motility are unknown. The
aim of the present study was to investigate changes in spontaneous contractile
activity and sensitivity to cholinergic and adrenergic agents in the ileal
circular muscle after SBT in rats. Orthotopic SBT was performed in syngeneic rats
to avoid immune phenomena. Distal ileal circular muscle strips from rats one week
(N = 10) and eight weeks (N = 10) after SBT were stretched to optimal length
(Lo), and basal spontaneous activity at Lo was measured. Dose-response
experiments to the cholinergic agonist bethanechol (Be, 10(-8)-10(-4) M) were
performed in the presence of tetrodotoxin (TTX, 10(-6) M) and to the adrenergic
agonist norepinephrine (NE, 10(-8)-10(-4) M) with or without TTX. ED50 (negative
log of drug-concentration that induced 50% effect) was calculated. We also
studied rats with selective jejunoileal ischemia/ reperfusion, intestinal
transection/reanastomosis, naive controls, and sham operated controls (N > or =
8/group). Spontaneous basal activity did not differ among groups. Sensitivity to
Be was not different in rats after SBT or in other groups compared to control
tissue. After SBT, hypersensitivity to NE was shown by a significant increase of
ED50 at one and eight weeks after SBT (5.1 +/- 0.3 vs 6.2 +/- 0.4 and 6.2 +/-
0.2, respectively; P < 0.05) regardless of the presence of TTX. No
hypersensitivity was observed after ischemia-reperfusion intestinal transection
reanastomosis, or sham operation. It is concluded that ileal hypersensitivity to
NE was related to the extrinsic denervation obligated by the transplantation
procedure, possibly mediated through an increase in number of receptors on smooth
muscle, not on the enteric nerves.
PMID- 9398798
TI - Dual-channel ambulatory esophageal pH monitoring. A useful diagnostic tool?
AB - Ambulatory pH monitoring of the distal esophagus is the most accurate diagnostic
study for patients with suspected gastroesophageal reflux disease (GERD). The
measurement of proximal esophageal acid exposure time may be useful in patients
with atypical reflux symptoms. The aim of this study is to evaluate if proximal
esophageal pH monitoring provides useful information beyond that learned with
distal esophageal pH monitoring. We routinely performed dual-channel pH
monitoring with pH electrodes positioned at 20 and 5 cm above the manometric
lower esophageal sphincter from January 1992 to August 1995. All patients scored
their esophageal symptoms from zero (none) to four (severe). We compared proximal
esophageal reflux (PR) in patients with typical symptoms (i.e., heartburn,
regurgitation) and in patients with atypical symptoms (i.e., chest pain, cough,
hoarseness, and asthma). We compared symptom profiles between patients with and
without PR. We reviewed our experience in patients with abnormal PR, but with a
normal amount of distal esophageal reflux (DR). We studied 441 consecutive
patients. There were no significant differences in PR between patients with
typical and atypical symptoms. There were no differences in symptom profiles
between patients with normal and abnormal PR. There were no differences of PR
between the different atypical symptoms. PR did not correlate with the severity
of the patient's symptoms. PR correlated well only with DR. Twenty-four patients
had isolated abnormal PR, but only six patients improved with antireflux therapy.
We conclude that routine ambulatory esophageal pH monitoring of the proximal
esophagus appears to be of little value. The decision to offer patients an
empiric trial of antireflux therapy for suspected GERD should not be based on the
presence or absence of PR.
PMID- 9398799
TI - Receiver operator characteristic analysis of endoscopy as a test for gastritis.
AB - Endoscopic evaluation of the presence or absence of gastritis is often performed
in lieu of biopsy and histologic diagnosis. The purpose of our study was to
assess the value of endoscopic examination as a diagnostic test for gastritis.
Two endoscopists prospectively assessed the antrum of 73 patients undergoing
upper gastrointestinal endoscopy and graded, on a scale of 0-4 (0 = completely
absent, 4 = definitely present), the likelihood of gastritis. The following
features were also assessed at the time of endoscopy: erythema, nodularity,
erosion, edema, and friability. Two concomitant antral biopsies (3 cm from the
pylorus on the greater curvature of the stomach) were performed regardless of the
endoscopic impression. The histologic findings were graded independently on a
scale of 0-3 by two pathologists who were not aware of the endoscopic findings.
The following histologic features were graded: acute inflammation, chronic
inflammation, lymphoid aggregates, intestinal metaplasia, and quantity of
Helicobacter pylori organisms. Receiver operator characteristic analysis, a
method derived from signal detection theory, assesses the trade-off of
sensitivity and specificity over all cutoff points of a test and is considered
the best method by which to compare tests and determine the diagnostic utility of
a given test. Receiver operator characteristic analysis gave an area of 0.65 +/-
0.01 SE for endoscopy as a test for gastritis (0.5 = chance, 1 = perfect) as
defined by the histologic presence of inflammation. Additionally, endoscopy as a
test for the presence of histologically proven Helicobacter pylori gave an area
of 0.55 +/- 0.01 SE. All endoscopically graded features treated as separate tests
for gastritis and/or H. pylori gave areas of approximately 0.44-0.61, indicative
of a poor test. While H. pylori was always associated with at least some degree
of inflammation, linear regression analysis revealed no correlation among any of
the histologic features or of any histologic feature with any endoscopic feature.
We conclude that a tissue diagnosis is essential for the proper diagnosis of
gastritis.
PMID- 9398800
TI - Differential effects of deoxycholic acid on proliferation of neoplastic and
differentiated colonocytes in vitro.
AB - The secondary bile acid deoxycholic acid is believed to be a promoter of large
bowel cancer, in part by inducing colonic epithelial proliferation. The effects
of deoxycholic acid on [3H]thymidine incorporation by the human colon cancer cell
line HT29 and two differentiated subclones were measured and compared. The
subclone HT29-C1 has features of mature absorptive cells and HT29-N2 cells
secrete mucus under cholinergic control. The three cell lines were treated with
deoxycholic acid (DCA) at concentrations of 0, 5, 10, 50, 100, 150, and 300
microM for 3, 6, 9, 15, 24, and 48 hr. A significant increase in proliferation
was noted in HT29 cells only at 6 hr with 5 and 10 microM deoxycholic acid.
Neither the subclone HT29-C1, nor HT29-N2 cells exhibited significant change in
[3H]thymidine incorporation with DCA at these concentrations or time points.
Higher doses of deoxycholic acid above 50 microM and duration of exposure greater
than 24 hr were cytotoxic to all three cell lines. The proliferative effects of
DCA in HT29 cells were not paralleled by changes in protein kinase C activity or
protein kinase C isoform expression. Quantitative and qualitative differences in
PKC isoform expression were not noted in the three cell lines used in this study.
The proliferative effects of DCA on HT29 cells appear to be independent of the
PKC signal transduction pathway.
PMID- 9398801
TI - Primary hepatic high-grade non-Hodgkin's lymphoma and chronic hepatitis C
infection.
AB - Little is known about the coincidence of hepatitis C virus infection (HCV) and
non-Hodgkin's lymphoma, although there is an increased incidence of chronic HCV
infection with cryoglobulinemia type II and, interestingly, low-grade non
Hodgkin's lymphoma (NHL) in a few patients. We therefore report on a 74-year-old
white male with known chronic hepatitis C virus infection who was admitted to the
clinic due to weight loss and pain in the right upper quadrant. Ultrasound
examination was performed for suspected hepatocellular carcinoma since a lesion
in the left lobe of the liver was seen. X-ray of the lungs showed a few scattered
lesions, suggestive of metastases. The ultrasound-guided fine-needle puncture
revealed a high-grade malignant B-cell NHL While alpha-fetoprotein was normal,
both cryoglobulin type II and the polymerase chain reaction (PCR) for HCV were
positive. After six cycles of chemotherapy consisting of CHOP, the patient showed
complete remission over three years. Ultimately, he died due to a sudden myeloic
blast crisis. In summary, we discuss the possible etiopathologic role of the
hepatitis viruses in the occurrence of non-Hodgkin's lymphoma. As we and others
showed that HCV infects peripheral mononuclear blood cells (PBML), the infected
PBML not only may be a source for reinfection after orthotopic liver
transplantation, but also could be the cause for transformation and monoclonal
propagation of lymphomatous tissue.
PMID- 9398802
TI - Serologic assay for secretory component distinguishes mechanical from
hepatocellular cholestasis in humans.
AB - In rats, serum secretory component (SC) is elevated in mechanical but not
hepatocellular cholestasis. To determine if serum SC might distinguish
cholestatic syndromes in humans, serum samples were obtained from control
subjects and patients with mechanical and hepatocellular cholestasis. Equal
volumes of serum were assayed for SC by immunoblotting with an antibody specific
for human SC. Quantitative densitometry of these immunoblots showed that in
mechanically obstructed patients serum SC was reversibly elevated to a level
approximately 10-fold higher than that of patients with hepatocellular
cholestasis (P < 0.001). When comparing the two cholestatic groups, levels of
serum alkaline phosphatase, but not bilirubin and alanine aminotransferase, were
significantly higher in the group with mechanical cholestasis (P < 0.01). When
comparing individual patients, serum SC was more reliable than alkaline
phosphatase in distinguishing the two cholestatic syndromes (P < 0.05). Thus,
serum SC may distinguish mechanical from hepatocellular cholestasis in humans.
PMID- 9398803
TI - Effects of somatostatin (SMS) on pancreatic microcirculation.
AB - The effect of bolus infusion of increasing somatostatin (SMS) concentrations (1,
10, 100, 200 micrograms/100 g body wt) on pancreatic microcirculation and
pancreatic tissue PO2 were investigated by using in vivo epifluorescence
microscopy and a polarographic PO2 measurement technique. Additionally, the
microperfusion of the pancreas, liver, spleen, stomach, and duodenum was measured
by a laser Doppler device. Bolus infusion of SMS caused a significant, transient,
and dose-dependent decrease in pancreatic capillary RBC velocities (to 50% of
baseline) and acinar capillary overall perfusion (to 20% of baseline), which was
not caused by a macrocirculatory depression. This pronounced decrease in
microperfusion was not paralleled by a decline in tissue PO2. Laser Doppler
measurements revealed that pancreatic and gastric microperfusion were reduced
only at maximal SMS concentrations, considering that microperfusion of the liver,
spleen, and duodenum was not altered. Therefore, we found further evidence that
circulatory adjustment might occur during SMS inhibited secretory activity of the
exocrine pancreas.
PMID- 9398804
TI - Frequent detection of hepatitis B virus X-gene DNA in hepatocellular carcinoma
and adjacent liver tissue in hepatitis B surface antigen-negative patients.
AB - Hepatitis B virus is associated with human hepatocellular carcinoma. We performed
polymerase chain reaction for the X, C, S, and preS2/S regions of the viral
genome in 23 hepatitis B surface antigen-negative hepatocellular carcinomas and
adjacent liver. Hepatitis B viral genomes were detected in 17 of 23 tumors and
adjacent tissues (73.9%). Among recognized transactivators, the X gene was
present in 16 (69.6%) cases of hepatocellular carcinoma, but preS2/S was detected
in only 7 (30.4%). Hepatitis B virus C and S regions were detected in 3 (13.0%)
and 9 (39.1%) hepatocellular carcinomas, respectively. Serologic study revealed
antibodies to hepatitis B surface antigen, hepatitis B core antigen, and
hepatitis B e antigen in 14 patients; among these, X-gene DNA was detected in 12
of 14 tumors (85.7%). The X gene was also detected in 4 of 9 tumors of
seronegative patients. The X gene, present in many hepatocellular carcinomas, may
promote hepatocellular carcinoma in hepatitis B surface antigen-negative
patients.
PMID- 9398805
TI - Prediction of effect of interferon on chronic hepatitis C.
AB - Clinical, pathological, and virological analysis including hypervariable region-1
of hepatitis C virus (HCV) was performed to predict the effect of interferon
(IFN) on 41 patients with chronic hepatitis type C. The low virus load, low
frequency of the mutation in the hypervariable region-1 as the change of amino
acid and high level of serum aminotransferase make one estimate the good effect
of IFN on patients with HCV. Mutation in the hypervariable region-1 of HCV
measured by fast assay fluorescence single-stranded conformational polymorphism
was more frequent in nonresponders to IFN than responders. The most frequently
mutated position was amino acid number 406. This indicates that the specific
mutation site might affect the response of IFN.
PMID- 9398806
TI - Increased levels of soluble adhesion molecules in the serum of patients with
hepatitis C. Correlation with cytokine concentrations and liver inflammation and
fibrosis.
AB - Lymphocyte adhesion to endothelium, extravasation, and adhesion to hepatocytes
are mediated by adhesion molecules and constitute important steps in the liver
inflammation due to chronic hepatitis C (HCV-CH). We measured soluble
intercellular adhesion molecule (sICAM-1, sCD54), vascular cell adhesion molecule
(sVCAM-1, sCD106), E-selectin (sCD62E), as well as interleukin (IL)-1 beta, IL-8,
and tumor necrosis factor-alpha (TNF-alpha) concentrations in the serum of 22
patients with HCV-CH in comparison to 20 seronegative healthy volunteers. sICAM
1, sVCAM-1, sCD62E, TNF-alpha, and IL-8 but not IL-1 beta concentrations were
significantly elevated in patients. sICAM-1 and sCD62E correlated with TNF-alpha
and aspartate amino transferases levels. sICAM-1 correlated with liver lobular
inflammation whereas sVCAM-1, sCD62E, and IL-8 correlated with liver fibrosis.
Measurement of soluble adhesion molecules may be an easy way to follow liver
inflammation and fibrosis during HCV-CH.
PMID- 9398807
TI - Hepatitis C serotypes in nonalcoholic and alcoholic patients.
AB - Genotyping of the hepatitis C virus (HCV) RNA can be performed by a variety of
methods following polymerase chain reaction amplification of a stable RNA portion
of the genome. The gold standard is amplification of the RNA from the NS5 region,
followed by direct sequencing and homology comparison. This method is extremely
labor intensive. In this study, we compared an immunoblot serotyping technique
(HCV SIA) to a reverse-hybridization line-probe assay (LiPA) for genotype
classification among non-alcoholic HCV infected patients. We then compared and
contrasted the response in this cohort to a population of alcoholic patients with
HCV infection. To validate the serotype assay, sera from 110 patients with
chronic HCV infection was utilized. Serotyping (Chiron SIA) and genotyping by the
LiPA (Line Probe Assay, Innogenetics) reverse-hybridization technique was
performed. Additionally, both methods were compared to sequence-derived
genotyping in 26 patients based on PCR amplification of the NS5 region. After the
validation phase, sera from 105 alcoholic patients was genotypically classified
by the serologic method. The nonalcoholic and alcoholic groups were then compared
with regard to serotype, demographics, and frequency of untypable test results.
Among typable pairs, the overall concordance rate between serotyping and LiPA
based genotyping was 93.75%. Patients with genotype 1 by reverse hybridization
demonstrated a 95.8% concordance with serotype. Untypable samples were present
for both techniques, but since they occurred in different patients, the
techniques were complementary. Alcoholic patients were significantly more likely
to be infected with untypable serotypes than those without a pattern of alcohol
abuse. These patients were also more likely to be HCV RNA negative than sera from
typable patients. Serotype 1 was associated with high HCV RNA titer and poor
interferon treatment response among both nonalcoholic and alcoholic patients. An
immunoblot method for the evaluation of genotype classification was rapid and
easily performed compared to sequence-based genotyping. There was a high degree
of concordance compared to reverse-hybridization and sequence-based genotype
characterization methods. Failure to detect HCV RNA in the serum is associated
with a higher likelihood of classification failure. This problem was particularly
prevalent in the alcoholic population. HCV RNA titers and treatment outcomes were
strongly associated with serotype classification results, demonstrating clinical
utility of this assay technique.
PMID- 9398808
TI - Hepatic denervation ameliorates sodium and water retention in experimental
cirrhosis in rats.
AB - Increased activity in the hepatic sympathetic nervous system may exacerbate salt
and water retention in patients with liver cirrhosis. The aim of this study was
to evaluate sodium and water homeostasis in rats with cirrhosis induced by
diethylnitrosamine and to investigate the influence of hepatic denervation in
this model. Animals were randomized into three groups: diethylnitrosamine-treated
rats with (N = 13) and without (N = 8) hepatic denervation and control rats (N =
8). Rats were fed a normal salt diet (0.23% sodium ad libitum). The 24-hr
measurements for sodium balance, water balance, and creatinine clearance were
performed every two weeks for 12 weeks after surgery. Diethylnitrosamine-induced
cirrhosis was confirmed histologically. The cumulative change in sodium balance
in the innervated diethylnitrosamine-treated rat increased progressively and was
significantly higher than the control during the last four weeks of the study.
Meanwhile, rats with hepatic denervation showed significantly smaller changes in
cumulative sodium balance at week 12 than those in the innervated group. The
cumulative changes in water balance in the innervated group were significantly
greater at weeks 10 and 12 than those of the denervated and control group, which
remained unchanged throughout the study. Creatinine clearance in the innervated
group decreased at weeks 10 and 12 by approximately 70% from baseline (P < 0.05);
in contrast, it did not change significantly in the denervated group and control
group throughout the study. These results demonstrated that hepatic denervation
ameliorates sodium and water retention as well as glomerular function in
cirrhosis model in rats.
PMID- 9398809
TI - Touch cytology. A reliable and cost-effective method for diagnosis of
Helicobacter pylori infection.
AB - A variety of reliable methods are available for detecting Helicobacter pylori
(Hp) during upper gastrointestinal endoscopy. We evaluated the clinical utility
and cost-effectiveness of rapid urease test (RUT), touch cytology (TC), and
histology (H). Two hundred thirty-eight consecutive patients (178 without
previous medical treatment and 60 formerly treated with anti-Hp therapy) were
tested for Hp infection by RUT, TC, and H (H&E stain). The infection status for
each patient was established by a concordance of two test results. The time to
carry out the three tests and their cost were also calculated. Sensitivity of TC
(100%) was significantly higher than that of RUT (86.8%; P < 0.001), but not than
that of H (94.9%). RUT was significantly more specific than H (100% vs 95.6%; P <
0.05), but not than TC (96.4%). Hp infection was more frequent in the patients
with chronic active gastritis than in those with chronic nonactive gastritis (P <
0.001). No Hp infection was detected in absence of chronic antral inflammation.
RUT resulted the cheapest method and H the most expensive; TC is faster and
cheaper than H. When additional information about the severity of mucosal damage
or the presence of cell atypias is not necessary, histologic examination can be
omitted, and a cost-effective strategy for assessing Hp status might consist in
taking two antral biopsies, the former for performing RUT and the latter for
preparing a slide by TC, which should be stained and examined only when the RUT
result is negative.
PMID- 9398810
TI - Effect of omeprazole 40 mg once daily on intraduodenal and intragastric pH in H.
pylori-negative healthy subjects.
AB - There is a lack of information about the effect of omeprazole or other
antisecretory drugs on intraduodenal pH. Aim of the study was to document the
variation over time of intraduodenal pH during a 24-hr period and to
simultaneously study the effect of omeprazole 40 mg once daily on intragastric
and intraduodenal pH in healthy H. pylori-negative subjects. In a randomized,
placebo-controlled study, eight subjects (five women, three men, mean age 22.7
years) received oral 40 mg omeprazole or placebo once daily for eight days. On
day 7, intragastric and intraduodenal pH was measured continuously for 24 hr,
using two miniature glass-membrane electrodes placed in the stomach (fundus) and
in the distal third of the duodenum. The 24-hr median intraduodenal pH was 5.95
with placebo and 5.85 with omeprazole. Median intragastric pH was 1.68 without
and 4.93 with omeprazole. During omeprazole therapy, intragastric pH fell below
4.0 in five of eight subjects. In the 2- and 3-hr postprandial periods, the
percentage of time with pH < 5 was significantly reduced with omeprazole. In
healthy subjects, 24-hr median and postprandial pH in the distal part of the
duodenum was lower than previously thought. Omeprazole significantly reduced the
percentage of time with pH < 5 postprandially. At night, intragastric pH fell
below 4.0 with omeprazole 40 mg once daily. Omeprazole does not change 24-hr
median intraduodenal pH significantly.
PMID- 9398811
TI - Is electrogastrography a substitute for manometric studies in children with
functional gastrointestinal disorders?
AB - We performed simultaneous fasting and fed antroduodenal manometry and EGG in 25
children with functional bowel disorders. Three patients (12%) had an
uninterpretable EGG. The manometric studies showed severe neuropathy in six
patients; milder neuropathic changes in five patients; postprandial hypomotility
in one patient; myopathy in four patients, and normal motility in the remaining
six patients. The percentage of tachygastria time (frequency > 3.5 cycles/min)
was higher in the patiens with mild (44.1 +/- 15.8%) and severe (48 +/- 19.1%)
neuropathy than in the patients with myopathy (20 +/- 16.2%, P < 0.05) or with
normal motility (23 +/- 13.3%, P < 0.05). There was a considerable overlap in the
percentage of tachygastria and total arrhythmia time among the different study
groups. The ratio of post- to preprandial power was significantly higher (2.5 +/-
0.07) in children with normal motility than in the other patients groups. Every
child with total arrhythmia time < 35% and a ratio of post- to preprandial power
> 2.4 had normal manometry. In summary, EGG differentiated groups of children
with normal manometry from others with neuropathic or myopathic changes, but in a
minority of patients the study was not interpretable and there was overlap in EGG
results between children with normal and abnormal manometry.
PMID- 9398812
TI - Impedance planimetric characterization of esophagus in systemic sclerosis
patients with severe involvement of esophagus.
AB - This study was designed to evaluate the distensibility and secondary peristalsis
of the esophagus in patients suffering from systemic sclerosis with severe
esophageal involvement. Balloon distension with impedance planimetric measurement
of luminal cross-sectional area was done 7 and 15 cm above the lower esophageal
sphincter in 13 patients and nine healthy controls. The controls were studied
both with and without receiving the anticholinergic drug butylscopolamine. The
cross-sectional area--pressure relations were nonlinear with the largest cross
sectional area in patients at both measuring sites when compared to controls (P <
0.001). The anticholinergic drug butylscopolamine increased the cross-sectional
area in controls (P < 0.001). The cross-sectional area distensibility, defined as
CSA0(-1) delta CSA delta P-1 did not differ between patients and controls.
Balloon distensions elicited contractions proximal to the distension site. The
amplitude and frequency of contractions at the distal distension site were
significantly reduced in the patients when compared to the controls (P < 0.05).
In conclusion, the distal esophagus is most severely affected in patients with
systemic sclerosis with increased cross-sectional area and impaired peristalsis.
PMID- 9398813
TI - Dyspepsia due to eosinophilic gastroenteritis.
AB - Classical eosinophilic gastroenteritis is a rare disease but may be misdiagnosed
in clinical practice. We report eosinophilic gastroenteritis that was diagnosed
in six patients (four males and two females; mean age 31.5 years) using standard
criteria (presence of gastrointestinal symptoms, a predominant eosinophilic
infiltrate on biopsy, and exclusion of other causes of eosinophilia). All had
gastric mucosal disease and presented with dyspepsia. The median duration of
symptoms prior to diagnosis was three months (range five weeks to 13 years).
Epigastric pain or discomfort was the most common symptom (100%) followed by
anorexia, nausea, and vomiting (67%, 67% and 33%, respectively). None had
diarrhea. Half the patients had a history of allergy, while 67% had peripheral
eosinophilia. All responded to oral steroids within two months; one third needed
to continue on a small dose of maintenance steroids to remain in remission. A
high degree of suspicion and biopsy at upper endoscopy is necessary for diagnosis
of this rare disease.
PMID- 9398814
TI - The place of upper gastrointestinal tract endoscopy before and after vertical
banded gastroplasty for morbid obesity.
AB - In industrialized countries, surgical gastroplasty is performed more and more
frequently in patients with morbid obesity. The aims of this prospective study
were to determine the incidence of upper gastrointestinal lesions in obese
patients and to assess the place of digestive endoscopy in symptomatic patients
after gastroplasty. A consecutive group of 159 obese patients were studied before
and after vertical banded gastroplasty. In the preoperative evaluation, reflux
esophagitis and gastroduodenal lesions were endoscopically observed in 31% and
37% of the patients, respectively. Interestingly, the majority of the obese
patients with upper gastrointestinal lesions were asymptomatic. In the
postoperative follow-up period, 55 of the 159 patients complained of upper
gastrointestinal symptoms such as vomiting (72%), esophageal reflux (17%), and
epigastric pain (3%). Stenosis of the outlet of the gastric pouch was described
in 40 of the 55 symptomatic patients. Esophagitis was observed in 60% of these
patients. Endoscopic dilation using Savary bougies or TTS balloon was
successfully performed in all the patients with symptomatic stenosis of the
gastric outlet. Food impaction was endoscopically removed in four patients. Thus,
we recommend performing an upper gastrointestinal endoscopy in obese patients who
are candidates for surgical gastroplasty because of the high incidence of upper
gastrointestinal peptic lesions. Endoscopy is also helpful in patients with
digestive disorders occurring after gastroplasty in order to define and to treat
the lesions.
PMID- 9398815
TI - Peripheral blood lymphocyte beta 2 integrin and ICAM expression in inflammatory
bowel disease.
AB - The beta 2 integrin intercellular adhesion molecule (ICAM) adhesion pathway is
likely pivotal in the immunopathogenesis of inflammatory bowel disease (IBD). We
have undertaken a comprehensive study of peripheral blood lymphocyte (PBL)
expression of all beta 2 integrins and ICAMs in patients with IBD using flow
cytometry and assessed our data on the basis of IBD diagnosis, disease state of
activity, and use of corticosteroids. Blood was collected from patients with
Crohn's disease (N = 49), ulcerative colitis (N = 43), and normal control
volunteers (N = 15). Mononuclear cells were separated using a Ficoll-Hypaque
gradient and prepared for flow cytometry. The data were analyzed for percentage
expression, mean fluorescent intensity (MFI) as well as for histogram patterns.
The analysis was stratified for disease diagnosis, disease activity level, and
for use of prednisone among patients with active disease. There was decreased
percentage expression of CD11a, CD18, and ICAM-3 in Crohn's disease and
ulcerative colitis compared with normal, but an increased MFI for these molecules
among patients with Crohn's disease. Active Crohn's disease showed a greater
change in this pattern compared with both inactive disease and active ulcerative
colitis. CD11a and CD18 histograms typically had two peaks of expression. The
predominance of one peak over the other varied with disease diagnosis and
activity. CD11b and alpha d expression patterns were not different in IBD
compared with normal. CD11c was not expressed by PBLs and, ICAM-2, typically an
endothelial ligand, was expressed on PBLs. There were changes in the expression
of beta 2 integrins in IBD, which were more evident in Crohn's disease than
ulcerative colitis. We hypothesize that the decreased percentage expression and
increased MFI of CD11a, CD18, and ICAM-3 may suggest that cells up-regulate these
ligands following activation and are egressing into tissue.
PMID- 9398816
TI - Immunoglobulin G subclass distribution of anti-endothelial cell antibodies (AECA)
in patients with ulcerative colitis or Crohn's disease.
AB - Anti-endothelial cell antibodies have been described in sera from patients with
inflammatory bowel disease. The aim of this study was to determine, by ELISA, the
IgG subclass distribution of anti-endothelial cell antibodies, in patients with
ulcerative colitis (N = 28) or Crohn's disease (N = 82) as compared with blood
donors (N = 95). Thirty-six percent of ulcerative colitis and 23% of Crohn's
disease patients were positive for at least one of the IgG anti-endothelial cell
subclasses. Interestingly, the pattern of IgG anti-endothelial cell subclass
observed in the two inflammatory bowel diseases differs. In Crohn's disease, the
IgG1 anti-endothelial cell antibody level was significantly increased (P < 0.05)
while IgG2 and IgG4 anti-endothelial cell antibody levels were decreased (P <
0.0001 and P < 0.01, respectively) as compared to ulcerative colitis patients.
The immunoglobulin G3 anti-endothelial cell antibody level was decreased in both
ulcerative colitis and Crohn's disease patients as compared to healthy blood
donors. No relationship was detected between disease activity of ulcerative
colitis or Crohn's disease patients and anti-endothelial cell IgG subclasses.
Finally, the disparity of IgG anti-endothelial cell subclass distribution in
these two inflammatory bowel diseases suggests that the ability to activate
effector mechanisms is not identical, and hence, deals with the concept of
distinctive pathogenetic mechanisms in these two diseases.
PMID- 9398818
TI - Intractable Crohn's colitis and perianal disease responding to cyclophosphamide
and epirubicin.
AB - A case is reported where intractable Crohn's disease responded to chemotherapy
for breast carcinoma. The drug most likely responsible was cyclophosphamide.
Cyclophosphamide may have a role in the management of inflammatory bowel disease,
but this needs to be confirmed before it can be recommended as a treatment
option.
PMID- 9398817
TI - Activation of plasma contact and coagulation systems and neutrophils in the
active phase of ulcerative colitis.
AB - We have shown that the contact (kallikrein-kinin) system is involved in the
pathogenesis of experimental enterocolitis. We now investigate activation of the
contact and coagulation pathways, platelets, and neutrophils in active and
inactive ulcerative colitis patients as compared to normal controls. In active
ulcerative colitis patients, a significant decrease of plasma prekallikrein, high
molecular weight kininogen, and C1 inhibitor levels was observed as compared with
controls, as well as prekallikrein activation on western blots. Significant
elevation of prothrombin fragment (F1 + 2), which indicates thrombin generation,
and elastase-alpha 1-antitrypsin complexes, reflecting neutrophil activation,
were found in patients with active disease. Plasma beta-thromboglobulin, a marker
of platelet activation, was elevated in both active and inactive disease and
appears to be a feature of ulcerative colitis. Activation of contact and
coagulation pathways, as well as neutrophils, may mediate inflammation in the
active phase of ulcerative colitis.
PMID- 9398819
TI - Modification of colonic fermentation by bifidobacteria and pH in vitro. Impact on
lactose metabolism, short-chain fatty acid, and lactate production.
AB - Colonic fermentation plays an important role in the prevention of lactose
intolerance and intestinal disorders. The objectives of this study were to
evaluate whether supplementation with bifidobacteria modify colonic fermentation
of lactose and short-chain fatty acid production and to assess influence of the
pH in an in vitro continuous culture system. There was a significantly greater
reduction in lactose concentrations at pH 6.7 than that at either pH 6.2 or pH
5.7, accompanied by the highest beta-galactosidase activity and D-lactate
production. Bifidus supplementation reduced lactose and D-lactate concentrations
and increased acetate production at pH 6.7. The study demonstrates that lactose
is rapidly metabolized by colonic bacteria and lactose fermentation in vitro is
pH dependent with a maximum rate at pH 6.7. Bifidobacteria supplementation may
have the potential to improve lactose fermentation and to manipulate SCFA and
lactate production.
PMID- 9398821
TI - Morphological characteristics, epithelial cell proliferation, and crypt fission
in cecum and colon of growing pigs.
AB - Morphological characteristics and cellular proliferation were investigated in the
hindgut tissue of 25 pigs ranging from 5 to 261 days of age; the three youngest
pigs were unweaned. Tissue samples were taken from the cecum and from the
proximal, middle, and distal part of the colon. In the young pigs a high
incidence of branched crypts was observed. During the first three to four months
there was an increase in crypt height and proliferative activity, as determined
by the mitotic count, as well as an increase in the mucin secretion, especially
the sulfomucins. Distinct regional differences were observed between the four
intestinal sites. In general, the crypts were deeper and more closely spaced and
the turnover time was higher in the distal part of the colon as compared to the
cecum and the proximal colon. Furthermore, a greater proportion of the mucins in
the middle and distal part of the colon are acidic or sulfated as compared to the
cecum, where the mucins are more of the neutral type. These regional and age
related differences in morphological characteristics of the hindgut in pigs may
have significance for the etiology of intestinal infections.
PMID- 9398820
TI - Submandibular gland peptide-T (SGP-T) inhibits intestinal anaphylaxis.
AB - A novel peptide, submandibular gland peptide-T (SGP-T), which reduces allergen
induced hypotension, was examined for effects on intestinal anaphylaxis. Hooded
Lister rats were sensitized to egg albumin and prepared for the measurement of in
vivo myoelectric activity of the jejunum. The disruption of migrating myoelectric
complexes (MMCs) that occurs upon intraluminal, duodenal challenge with antigen
of sensitized rats was inhibited by 75% upon intravenous treatment with 100
micrograms/kg of SGP-T. In addition, SGP-T reduced the number of rats
experiencing anaphylactic diarrhea and disrupted MMCs, but the peptide did not
alter antigen-provoked release of rat mast cell protease II. The mechanism of
action of SGP-T remains to be determined, but it apparently does not act directly
on mast cells to exert its antianaphylactic action. These results emphasize that
modulation of immediate hypersensitivity reactions is only one of several
gastrointestinal activities that are affected by growth factors and peptides
released from salivary glands.
PMID- 9398822
TI - St. John's wort.
PMID- 9398823
TI - Olopatadine for allergic conjunctivitis.
PMID- 9398824
TI - Pramipexole and ropinirole for Parkinson's disease.
PMID- 9398825
TI - Genetic(al) correctness.
PMID- 9398826
TI - The genetics of air pollution.
PMID- 9398827
TI - Sugar and spice and all things splice?
PMID- 9398828
TI - Parsing age, mutations and time.
PMID- 9398829
TI - Sounding out a novel sulphate transporter.
PMID- 9398830
TI - Expanding on population studies.
PMID- 9398831
TI - Haemochromatosis, HFE and genetic complexity.
PMID- 9398832
TI - Cytosine methylation targetted to pre-determined sequences.
PMID- 9398833
TI - Normal meiotic recombination in p53-deficient mice.
PMID- 9398834
TI - Mouse loci for malaria-induced mortality and the control of parasitaemia.
PMID- 9398835
TI - Genetic control of blood parasitaemia in mouse malaria maps to chromosome 8.
PMID- 9398836
TI - Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY.
PMID- 9398837
TI - A CAG/CTG expansion in the normal population.
PMID- 9398838
TI - A twin-pronged attack on complex traits.
AB - Before one starts the hunt for quantitative trait loci (QTLs) for a complex
trait, it is necessary to show that the trait is genetically influenced. This
evidence is most likely to come from the classical twin study--the demonstration
that monozygotic twins are more similar for the trait than dizygotic twins. The
strengths and weaknesses of twin studies are discussed, and it is suggested that,
far from becoming irrelevant with advances in molecular biology, they can improve
the efficiency of QTL detection and play an important role in unravelling
developmental genetic mechanisms.
PMID- 9398839
TI - Positional cloning of the APECED gene.
AB - Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an
autosomal-recessive disorder that maps to human chromosome 21q22.3 between
markers D21S49 and D21S171 by linkage studies. We have isolated a novel gene from
this region, AIRE (autoimmune regulator), which encodes a protein containing
motifs suggestive of a transcription factor including two zinc-finger (PHD
finger) motifs, a proline-rich region and three LXXLL motifs. Two mutations, a C-
>T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A-->G
substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in
this novel gene in Swiss and Finnish APECED patients. The Arg257stop (R257X) is
the predominant mutation in Finnish APECED patients, accounting for 10/12 alleles
studied. These results indicate that this gene is responsible for the
pathogenesis of APECED. The identification of the gene defective in APECED should
facilitate the genetic diagnosis and potential treatment of the disease and
further enhance our general understanding of the mechanisms underlying autoimmune
diseases.
PMID- 9398840
TI - An autoimmune disease, APECED, caused by mutations in a novel gene featuring two
PHD-type zinc-finger domains.
AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the
only described systemic autoimmune disease with established monogenic background,
and the first autoimmune disorder localized outside the major histocompatibility
complex (MHC) region. The primary biochemical defect in APECED is unknown. We
have isolated a novel gene, AIRE, encoding for a putative nuclear protein
featuring two PHD-type zinc-finger motifs, suggesting its involvement in
transcriptional regulation. Five mutations in AIRE are reported in individuals
with this disorder. This is the first report of a single-gene defect causing a
systemic human autoimmune disease, providing a tool for exploring the molecular
basis of autoimmunity.
PMID- 9398841
TI - Huntingtin is required for neurogenesis and is not impaired by the Huntington's
disease CAG expansion.
AB - Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder
caused by a CAG repeat expansion that lengthens a glutamine segment in the novel
huntingtin protein. To elucidate the molecular basis of HD, we extended the
polyglutamine tract of the mouse homologue, Hdh, by targetted introduction of an
expanded human HD CAG repeat, creating mutant HdhneoQ50 and HdhQ50 alleles that
express reduced and wild-type levels of altered huntingtin, respectively. Mice
homozygous for reduced levels displayed characteristic aberrant brain development
and perinatal lethality, indicating a critical function for Hdh in neurogenesis.
However, mice with normal levels of mutant huntingtin did not display these
abnormalities, indicating that the expanded CAG repeat does not eliminate or
detectably impair huntingtin's neurogenic function. Thus, the HD defect in man
does not mimic complete or partial Hdh inactivation and appears to cause
neurodegenerative disease by a gain-of-function mechanism.
PMID- 9398842
TI - Pendred syndrome is caused by mutations in a putative sulphate transporter gene
(PDS).
AB - Pendred syndrome is a recessively inherited disorder with the hallmark features
of congenital deafness and thyroid goitre. By some estimates, the disorder may
account for upwards of 10% of hereditary deafness. Previous genetic linkage
studies localized the gene to a broad interval on human chromosome 7q22-31.1.
Using a positional cloning strategy, we have identified the gene (PDS) mutated in
Pendred syndrome and found three apparently deleterious mutations, each
segregating with the disease in the respective families in which they occur. PDS
produces a transcript of approximately 5 kb that was found to be expressed at
significant levels only in the thyroid. The predicted protein, pendrin, is
closely related to a number of known sulphate transporters. These studies provide
compelling evidence that defects in pendrin cause Pendred syndrome thereby
launching a new area of investigation into thyroid physiology, the pathogenesis
of congenital deafness and the role of altered sulphate transport in human
disease.
PMID- 9398843
TI - Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation.
AB - Germline mutation of the BRCA2 gene carries a high risk of developing breast
cancer. To study the function of this gene, we generated a mutation in Brca2 in
mice. Unlike other mutations in the Brca2 gene, which are lethal early in
embryogenesis when homozygous, some of our homozygous mutant mice survive to
adulthood. These animals have a wide range of defects, including small size,
improper differentiation of tissues, absence of germ cells and the development of
lethal thymic lymphomas. Fibroblasts cultured from BrcaZ-/-embryos have a defect
in proliferation that may be mediated by over-expression of p53 and p21Waf1/CIP1.
We show that Brca2 is required for efficient DNA repair, and our results suggest
that loss of the p53 checkpoint may be essential for tumour progression triggered
by mutations in BRCA2.
PMID- 9398844
TI - Rapid accumulation of genome rearrangements in liver but not in brain of old
mice.
AB - Somatic mutations have long been considered a possible cause of ageing. To
directly study mutational events in organs and tissues of ageing mammals, a
transgenic mouse model has been generated that harbours lacZ reporter genes as
part of chromosomally integrated plasmids. Using this model, we determined
spontaneous mutant frequencies and spectra in mouse liver and brain as a function
of age. In the liver, mutant frequencies increased with age from birth to 34
months; in the brain, an increase was observed only between birth and 4-6 months.
Molecular characterization of the mutations showed that a substantial portion
involved genome rearrangement events, with one breakpoint in a reporter gene and
the other in the mouse flanking sequence. In the liver, these genome
rearrangements did not increase with age until after 27 months, when they
increased rapidly. In brain, the frequency of genome rearrangements was lower
than in liver and did not increase with age.
PMID- 9398845
TI - Demographic history and linkage disequilibrium in human populations.
AB - In the human genome, linkage disequilibrium (LD)--the non-random association of
alleles at chromosomal loci--has been studied mainly in regions surrounding
disease genes on affected chromosomes. Consequently, little information is
available on the distribution of LD across anonymous genomic regions in the
general population. However, demographic history is expected to influence the
extent of overall LD across the genome, so a population that has been of constant
size will display higher levels of LD than a population that has expanded. In
support of this, the extent of LD between anonymous loci on chromosome 4 in
chimpanzees (as a model of a population of constant size) has been compared to
that in Finns (as a model of an expanded population; refs 8,9) and found to
exhibit more LD than in the latter population. In Europe, studies of
mitochondrial (mt) DNA sequences have suggested that most populations have
experienced expansion, whereas the Saami in northern Fenno-Scandinavia have been
of constant size (Table 1). Thus, in northern Europe, populations with radically
different demographic histories live in close geographic proximity to each other.
We studied the allelic associations between anonymous microsatellite loci on the
X chromosome in the Saami and neighbouring populations and found dramatically
higher levels of LD in the Saami than in other populations in the region. This
indicates that whereas recently expanded populations, such as the Finns, are well
suited to map single disease genes affected by recent mutations, populations that
have been of constant size, such as the Saami, may be much better suited to map
genes for complex traits that are caused by older mutations.
PMID- 9398846
TI - Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm
formation.
AB - The molecular mechanisms predisposing to atherosclerotic aneurysm formation
remain undefined. Nevertheless, rupture of aortic aneurysms is a major cause of
death in Western societies, with few available treatments and poor long-term
prognosis. Indirect evidence suggests that matrix metalloproteinases (MMPs) and
plasminogen activators (PAs) are involved in its pathogenesis. MMPs are secreted
as inactive zymogens (pro-MMPs), requiring activation in the extracellular
compartment. Plasmin, generated from the zymogen plasminogen by tissue-type
plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA; refs
14,15), has been proposed as a possible activator in vitro, but evidence for such
a role in vivo is lacking. Analysis of atherosclerotic aorta in mice with a
deficiency of apoliprotein E (Apoe-/-; ref. 18), singly or combined with a
deficiency of t-PA (Apoe-/-:Plat-/-) or of u-PA (Apoe-/-:Plau-/-; ref. 19),
indicated that deficiency of u-PA protected against media destruction and
aneurysm formation, probably by means of reduced plasmin-dependent activation of
pro-MMPs. This genetic evidence suggests that plasmin is a pathophysiologically
significant activator of pro-MMPs in vivo and may have implications for the
design of therapeutic strategies to prevent aortic-wall destruction by
controlling Plau gene function.
PMID- 9398847
TI - Mutations in PEX1 are the most common cause of peroxisome biogenesis disorders.
AB - The peroxisome biogenesis disorders (PBDs) are a group of lethal autosomal
recessive diseases caused by defects in peroxisomal matrix protein import, with
the concomitant loss of multiple peroxisomal enzyme activities. Ten
complementation groups (CGs) have been identified for the PBDs, with CG1
accounting for 51% of all PBD patients. We identified the human orthologue of
yeast PEX1, a gene required for peroxisomal matrix protein import. Expression of
human PEX1 restored peroxisomal protein import in fibroblasts from 30 CG1
patients, and PEX1 mutations were detected in multiple CG1 probands. A common
PEX1 allele, G843D, is present in approximately half of CG1 patients and has a
deleterious effect on PEX1 activity. Phenotypic analysis of PEX1-deficient cells
revealed severe defects in peroxisomal matrix protein import and destabilization
of PEX5, the receptor for the type-1 peroxisomal targetting signal, even though
peroxisomes were present in these cells and capable of importing peroxisomal
membrane proteins. These data demonstrate an important role for PEX1 in
peroxisome biogenesis and suggest that mutations in this gene are the most common
cause of the PBDs.
PMID- 9398848
TI - Human PEX1 is mutated in complementation group 1 of the peroxisome biogenesis
disorders.
AB - Human peroxisome biogenesis disorders (PBDs) are a group of genetically
heterogeneous autosomal-recessive disease caused by mutations in PEX genes that
encode peroxins, proteins required for peroxisome biogenesis. These lethal
diseases include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD)
and infantile Refsum's disease (IRD), three phenotypes now thought to represent a
continuum of clinical features that are most severe in ZS, milder in NALD and
least severe in IRD2. At least eleven PBD complementation groups have been
identified by somatic-cell hybridization analysis compared to the eighteen PEX
complementation groups that have been found in yeast. We have cloned the human
PEX1 gene encoding a 147-kD member of the AAA protein family (ATPases associated
with diverse cellular activities), which is the putative orthologue of
Saccharomyces cerevisiae Pex1p (ScPex1p). Human PEX1 has been identified by
computer-based 'homology probing' using the ScPex1p sequence to screen databases
of expressed sequence tags (dbEST) for human cDNA clones. Expression of PEX1
rescued the cells from the biogenesis defect in human fibroblasts of
complementation group 1 (CG1), the largest PBD complementation group. We show
that PEX1 is mutated in CG1 patients.
PMID- 9398849
TI - Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and
apoptotic pathways.
AB - Atm is part of a pathway that responds to DNA damage from ionizing radiation
(IR). This pathway involves p53, as Atm-deficient cell lines and mice are
defective in p53 induction after IR. p53 is a multi-functional protein that
simultaneously regulates distinct downstream pathways controlling cell-cycle
progression and apoptosis. However, the mechanisms by which p53 differentially
activates downstream pathways are unknown. To determine the relationship between
Atm and p53, we examined cell-cycle and apoptotic responses in Atm-, p53-(ref. 8)
and p21-deficient mice after IR in the whole animal. As expected, p53 protein
levels were not induced by IR in thymus of Atm-deficient mice. IR-induced cell
cycle checkpoint function was also defective, and induction of p21 was attenuated
in thymus from Atm-deficient mice. However, IR-induced apoptosis and Bax
induction were completely normal; both of which are mediated by p53. IR-induced
thymic apoptosis was suppressed in Atm/p53 double-mutant mice but not in Atm/p21
double mutants, demonstrating p53 dependence and Atm independence. Thus, Atm
deficiency results in lack of p53 induction by IR, but only selective disruption
of p53-dependent functions. Our results support a model in which upstream
effectors such as Atm selectively activate p53 to regulate specific downstream
pathways, providing a mechanism for controlling distinct cell-cycle and apoptotic
responses.
PMID- 9398850
TI - ATM and RPA in meiotic chromosome synapsis and recombination.
AB - ATM is a member of the phosphatidylinositol 3-kinase (PIK)-like kinases, some of
which are active in regulating DNA damage-induced mitotic cell-cycle checkpoints.
ATM also plays a role in meiosis. Spermatogenesis in Atm-/- male mice is
disrupted, with chromosome fragmentation leading to meiotic arrest; in human
patients with ataxia-telangiectasia (A-T), gonadal atrophy is common. Immuno
localization studies indicate that ATM is associated with sites along the
synaptonemal complex (SC), the specialized structure along which meiotic
recombination occurs. Recombination, preceded by pairing of homologous
chromosomes, is thought to require heteroduplex formation between homologous DNA,
followed by strand exchange. These early meiotic steps (entailing the formation
and processing of meiotic recombination intermediates with DNA-strand
interruptions) require ssDNA-binding proteins such as replication protein A (RPA;
refs 5-7). In somatic cells, DNA damage induces ATM-dependent phosphorylation of
RPA. We demonstrate here that ATM and RPA co-localize along synapsed meiotic
chromosomes and at sites where interactions between ectopic homologous chromosome
regions appear to initiate. In Atm-/- meiotic prophase spermatocytes, immuno
localization shows that RPA is present along synapsing chromosomes and at sites
of fragmentation of the SC. These results suggest that RPA and ATM co-localize at
sites where interhomologous-DNA interactions occur during meiotic prophase and
where breaks associated with meiotic recombination take place after synapsis,
implying a possible functional interaction between these two proteins.
PMID- 9398851
TI - Partial rescue of the prophase I defects of Atm-deficient mice by p53 and p21
null alleles.
AB - Patients with the human disorder ataxia-telangiectasia (A-T; refs 1,2) and Atm
deficient mice have a pleiotropic phenotype that includes infertility. Here we
demonstrate that male gametogenesis is severely disrupted in Atm-deficient mice
in the earliest stages of meiotic prophase I, resulting in apoptotic
degeneration. Atm is required for proper assembly of Rad51 onto the chromosomal
axial elements during meiosis. In addition, p53, p21 and Bax are elevated in
testes from Atm-deficient mice. To determine whether these elevated protein
levels are important factors in the meiotic disruption of Atm-deficient mice, we
analysed the meiotic phenotype of Atm/p53 or Atm/p21 double mutants. In these
double mutants, meiosis progressed to later stages but was only partly rescued.
Assembly of Rad51 foci on axial elements remained defective, and gametogenesis
proceeded only to pachytene of prophase I. Previous results demonstrated that
mice homozygous for a null mutation in Rad51 (ref. 6) display an early embryonic
lethal phenotype that can be partly rescued by removing p53 and/or p21. Because
Atm-deficient mice are viable but completely infertile, our studies suggest that
the Rad51 assembly defects and elevated levels of p53, p21 and Bax represent
tissue-specific responses to the absence of Atm.
PMID- 9398852
TI - Donor splice-site mutations in WT1 are responsible for Frasier syndrome.
AB - Frasier syndrome (FS) is a rare disease defined by male pseudo-hermaphroditism
and progressive glomerulopathy. Patients present with normal female external
genitalia, streak gonads and XY karyotype and frequently develop gonadoblastoma.
Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome,
characterized by unspecific focal and segmental glomerular sclerosis, progressing
to end-stage renal failure in adolescence or early adulthood. No case of Wilms'
tumour has been reported, even in patients with extended follow-up. In contrast
with FS patients, most individuals with Denys-Drash syndrome (DDS; refs 6,7) have
ambiguous genitalia or a female phenotype, an XY karyotype and dysgenetic gonads.
Renal symptoms are characterized by diffuse mesangial sclerosis, usually before
the age of one year, and patients frequently develop Wilms' tumour. Mutations of
the Wilms'-tumour gene, WT1, cause different pathologies of the urogenital
system, including DDS. WT1 is composed of ten exons and encodes a protein with
four zinc-finger motifs and transcriptional and tumour-suppressor activities.
Alternative splicing generates four isoforms: the fifth exon may or may not be
present, and an alternative splice site in intron 9 allows the addition of three
amino acids (KTS) between the third and fourth zinc fingers of WT1 (ref. 17).
Here we demonstrate that FS is caused by mutations in the donor splice site in
intron 9 of WT1, with the predicted loss of the +KTS isoform. Examination of WT1
transcripts indeed showed a diminution of the +KTS/-KTS isoform ratio in patients
with FS.
PMID- 9398853
TI - Genetic analysis of ozone-induced acute lung injury in sensitive and resistant
strains of mice.
AB - Epidemiological studies have found air pollution to be associated with excessive
mortality, particularly death from respiratory and cardiovascular causes.
Interpretation of these findings is controversial, however, because toxicological
mechanisms controlling mortality are uncertain. Susceptibility to many air
pollutants entails an oxidative stress response. Accordingly, the best
characterized oxidant air pollutant is ozone, which causes direct oxidative
damage of lung biomolecules. An underlying characteristic derived from clinical
and epidemiological studies of healthy and asthmatic individuals of all ages is
marked variability in the respiratory effects of ozone. This susceptibility
difference among humans suggests that genetic determinants may control
predisposition to the harmful effects of ozone. Mice also vary considerably in
their response to ozone. Moreover, ozone-induced differences in strain responses
indicate that susceptibility in mice can be genetically determined. Therefore, we
used inbred mice to investigate the genetic determinants of acute lung injury.
Recombinant inbred (RI) strains derived from A/J (A) mice (sensitive) and
C57BL/6J (B) mice (resistant) showed a continuous phenotypic pattern, suggesting
a multigenic trait. Quantitative trait locus and RI analyses suggested three
major loci linked to ozone susceptibility. Differences in phenotype ratios among
the reciprocal back-crosses were consistent with parental imprinting. These
findings implicate various genetic and epigenetic factors in individual
susceptibility to air pollution.
PMID- 9398855
TI - Genetic interaction between PARP and DNA-PK in V(D)J recombination and
tumorigenesis.
AB - Poly(ADP-ribose) polymerase (PARP) and DNA-dependent protein kinase (DNA-PK) are
DNA break-activated molecules, Although mice that lack PARP display no gross
phenotype and normal DNA excision repair, they exhibit high levels of sister
chromatid exchange, indicative of elevated recombination rates. Mutation of the
gene for DNA-PK catalytic subunit (Prkdc) cases defective antigen receptor V(D)J
recombination and arrests B- and T-lymphocyte development in severe combined
immune-deficiency (SCID) mice. SCID V(D)J recombination can be partly rescued in
T-lymphocytes by either DNA-damaging agents (gamma-irradiation and bieomycin) or
a null mutation of the p53 gene, possibly because of transiently elevated DNA
repair activity in response to DNA damage or to delayed apoptosis in the absence
of p53. To determine whether the increased chromosomal recombination observed in
PARP-deficient cells affects SCID V(D)J recombination, we generated mice lacking
both PARP and DNA-PK. Here, we show that thymocytes of SCID mice express both CD4
and CD8 co-receptors, bypassing the SCID block. Double-mutant T-cells in the
periphery express TCR beta, which is attributable to productive TCR beta joints.
Double-mutant mice develop a high frequency of T-cell lymphoma. These results
demonstrate that increased recombination activity after the loss of PARP anti
recombinogenic function can rescue V(D)J recombination in SCID mice and indicate
that PARP and DNA-PK cooperate to minimize genomic damage caused by DNA strand
breaks.
PMID- 9398854
TI - Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred
mice.
AB - Exposures to the common air pollutant ozone (O3) cause decrements in pulmonary
function and induce airway inflammation that is characterized by infiltration of
polymorphonuclear neutrophils (PMNs; refs 1-4). Because of the impact that O3 may
have on public health, it is critical to identify susceptibility factors. Highly
reproducible, significant inter-individual variations in human pulmonary function
responses to O3 support the hypothesis that genetic background is an important
determinant. Initial analysis of PMN responses to O3 exposure in segregant
populations derived from inflammation-prone (susceptible) C57BL/6J (B6) and
inflammation-resistant C3H/HeJ (C3) inbred mice indicated that susceptibility was
controlled by a locus we termed Inf2 (ref. 7). Subsequent analyses with
recombinant inbred strains suggested that a more complex interaction of genes is
involved. In this report, we identify a quantitative trait locus (QTL) for O3
susceptibility on chromosome 17. Candidate genes for the locus include Tnf, the
gene encoding the pro-inflammatory cytokine tumour necrosis factor-alpha (Tnf).
Antibody neutralization of the protein product of this putative candidate gene
significantly protected against O3 injury in susceptible mice. These results
strongly support linkage of O3 susceptibility to a QTL on chromosome 17 and Tnf
as a candidate gene.
PMID- 9398856
TI - DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus.
AB - Severe combined immunodeficiency (SCID) mice are defective in their ability to
rearrange their variable (V), diversity (D) and joining (J) genetic elements to
generate functional immunoglobulin (Ig) and T-cell receptor (TCR) molecules; as a
result, they lack mature B and T cells. These mice are highly sensitive to
ionizing radiation, suggesting that the product of the scid gene plays a critical
role in both V(D)J recombination and DNA double-strand break repair. Recent
studies suggest that the SCID defect lies in the gene encoding the catalytic
subunit of DNA-dependent protein kinase (DNA-PK; refs 6-8), a nuclear protein
made up of the Ku 70 and Ku 86 subunits as well as the large catalytic subunit,
DNA-PKcs. Other reports have implied that the SCID phenotype correlates with
nonsense mutations at the extreme 3' end of Prkdc, the DNA-PKcs gene. The
identity of the gene remains in doubt, however, because the consequences of
genetic inactivation of Prkdc have not been determined. This study shows that
complete inactivation of Prkdc in a novel insertional mouse mutant recapitulates
the SCID phenotype and that Prkdc and scid are alleic. Significantly, DNA-PKcs
null mice demonstrate complete penetrance of thymic lymphoblastic lymphomas,
strongly suggesting that Prkdc functions in mice as a T-cell tumour suppressor
and, by virtue of its association with DNA repair and recombination, belongs to
the 'caretaker' class of tumour-suppressor genes that includes ATM, BRCA1 and
BRCA2 (ref. 15).
PMID- 9398857
TI - The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex.
AB - Fanconi anaemia (FA) is an autosomal-recessive disorder characterized by genomic
instability, developmental defects, DNA crosslinking agent hypersensitivity and
cancer susceptibility. Somatic-cell hybrid studies have revealed five FA
complementation groups (A-E; refs 4-6) displaying similar phenotypes, suggesting
that FA genes are functionally related. The two cloned FA genes, FAA and FAC,
encode proteins that are unrelated to each other or to other proteins in GenBank.
In the current study, we demonstrate the FAA and FAC bind each other and form a
complex. Protein binding correlates with the functional activity of FAA and FAC,
as patient-derived mutant FAC (L554P) fails to bind FAA. Although unbound FAA and
FAC localize predominantly to the cytoplasm, the FAA-FAC complex is found in
similar abundance in both cytoplasm and nucleus. Our results confirm the
interrelatedness of the FA genes in a pathway, suggesting the cooperation of FAA
and FAC in a nuclear function.
PMID- 9398858
TI - Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies
fish-odour syndrome.
AB - Individuals with primary trimethylaminuria exhibit a body odour reminiscent of
rotting fish, due to excessive excretion of trimethylamine (TMA; refs 1-3). The
disorder, colloquially known as fish-odour syndrome, is inherited recessively as
a defect in hepatic N-oxidation of dietary-derived TMA and cannot be considered
benign, as sufferers may display a variety of psychosocial reactions, ranging
from social isolation of clinical depression and attempted suicide. TMA oxidation
is catalyzed by flavin-containing mono-oxygenase (FMO; refs 7,8), and tissue
localization and functional studies have established FMO3 as the form most likely
to be defective in fish-odour syndrome. Direct sequencing of the coding exons of
FMO3 amplified from a patient with fish-odour syndrome identified two missense
mutations. Although one of these represented a common polymorphism, the other, a
C-->T transition in exon 4, was found only in an affected pedigree, in which it
segregated with the disorder. The latter mutation predicts a proline-->leucine
substitution at residue 153 and abolishes FMO3 catalytic activity. Our results
indicate that defects in FMO3 underlie fish-odour syndrome and that the Pro 153-
>Leu 153 mutation described here is a cause of this distressing condition.
PMID- 9398860
TI - Reconstitution of human telomerase with the template RNA component hTR and the
catalytic protein subunit hTRT.
AB - The maintenance of chromosome termini, or telomeres, requires the action of the
enzyme telomerase, as conventional DNA polymerases cannot fully replicate the
ends of linear molecules. Telomerase is expressed and telomere length is
maintained in human germ cells and the great majority of primary human tumours.
However, telomerase is not detectable in most normal somatic cells; this
corresponds to the gradual telomere loss observed with each cell division. It has
been proposed that telomere erosion eventually signals entry into senescence or
cell crisis and that activation of telomerase is usually required for immortal
cell proliferation. In addition to the human telomerase RNA component (hTR; ref.
11), TR1/TLP1 (refs 12, 13), a protein that is homologous to the p80 protein
associated with the Tetrahymena enzyme, has been identified in humans. More
recently, the human telomerase reverse transcriptase (hTRT; refs 15, 16), which
is homologous to the reverse transcriptase (RT)-like proteins associated with the
Euplotes aediculatus (Ea_p123), Saccharomyces cerevisiae (Est2p) and
Schizosaccharomyces pombe (5pTrt1) telomerases, has been reported to be a
telomerase protein subunit. A catalytic function has been demonstrated for Est2p
in the RT-like class but not for p80 or its homologues. We now report that in
vitro transcription and translation of hTRT when co-synthesized or mixed with hTR
reconstitutes telomerase activity that exhibits enzymatic properties like those
of the native enzyme. Single amino-acid changes in conserved telomerase-specific
and RT motifs reduce or abolish activity, providing direct evidence that hTRT is
the catalytic protein component of telomerase. Normal human diploid cells
transiently expressing hTRT possessed telomerase activity, demonstrating that
hTRT is the limiting component necessary for restoration of telomerase activity
in these cells. The ability to reconstitute telomerase permits further analysis
of its biochemical and biological roles in cell aging and carcinogenesis.
PMID- 9398861
TI - A case of acute lymphoblastic leukemia, near-triploidy, and poor outcome:
characterization by fluorescence in situ hybridization using chromosome-specific
libraries from all human chromosomes.
AB - We have applied fluorescence in situ hybridization (FISH) using chromosome
specific libraries from all 24 chromosomes on metaphase spreads from bone marrow
cells, in order to resolve the chromosomal changes in leukemic cells from a 10
year-old boy with acute lymphoblastic leukemia (ALL), near-triploidy, and a
subsequent poor outcome. The FISH analysis revealed a pattern of chromosome gains
and losses that differed from all cases previously described. Most of the
affected chromosomes were present in three copies (trisomy for chromosomes 1, 2,
5, 6, 7, 11, 12, 13, 14, 16, 17, 18, 19, 20, and 22), but the patient had four
copies of chromosomes 8 and 21, two copies of chromosomes 3, 4, 9, 10, 15, and X,
and one Y chromosome. No structural abnormalities could be detected. Thus, the
karyotype of the malignant clone was 66,XXY-3,-4,+8,-9,-10,-15,+21.
PMID- 9398859
TI - EWS/FLI1-induced manic fringe renders NIH 3T3 cells tumorigenic.
AB - EWS/FLI1, a fusion gene found in Ewing's sarcoma, encodes a transcriptional
regulator and promotes cellular transformation by modulating the transcription of
specific target genes. We have found that EWS/FLI1 and structurally related
fusion proteins upregulate manic fringe (MFNG), a recently described member of
the Fringe gene family instrumental in somatic development. MFNG is also
expressed in human tumour-derived cell lines expressing EWS/FLI1. Overexpression
of MFNG in NIH 3T3 cells renders them tumorigenic in mice with severe combined
immunodeficiency disease (SCID). These data demonstrate that part of the
oncogenic effect of EWS/FLI1 is to transcriptionally deregulate a member of a
family of morphogenic genes.
PMID- 9398862
TI - Translocations between the long arms of chromosomes 1 and 5 in hematologic
malignancies are strongly associated with neoplasms of the myeloid lineages.
AB - The clinical, morphologic, and cytogenetic features of two hematologic
malignancies--one acute myeloid leukemia with minimal differentiation (AML-MO)
and one therapy-related myelodysplastic syndrome (MDS)--with unbalanced
translocations between 1q and 5q are reported. The translocations resulted in
loss of 5q material in both cases and gain of 1q in the MDS. A compilation of
previously published hematologic malignancies with translocations involving the
long arms of chromosomes 1 and 5 revealed a total of 23 cases--11 with unbalanced
and 12 with balanced t(1;5)--with the following morphologies: 11 AML, three MDS,
two Philadelphia-positive chronic myeloid leukemias, three chronic
myeloproliferative disorders, three acute lymphoblastic leukemias, and one
chronic lymphocytic leukemia. Four patients had received chemotherapy including
alkylating agents for a previous malignancy and one had been exposed to
thorotrast. Among the 14 patients for whom survival data exist, all except three
have died. The t(1;5) was found as the sole abnormality in six cases, whereas it
was apparently secondary--occurring in a subclone or together with the well-known
primary abnormalities t(8;21), t(9;22), and t(15;17)--in nine cases. The
breakpoints in 1q varied from 1q11 to 1q43, with a clustering to 1q21-23, and the
5q breaks occurred in 5q11 to 5q35, mainly in the distal 5q3 region. The
unbalanced 1;5 translocations resulted in gain of 1q material in eight of the 11
cases, 1q21-1qter being duplicated in four of them, and in loss of 5q, most often
the 5q3 region, in 10 of the neoplasms. We conclude that translocations between
1q and 5q, although cytogenetically heterogeneous, are associated with
hematologic malignancies of the myeloid lineages and with previous mutagenic
exposure, and that t(1;5) seems to confer a poor prognosis.
PMID- 9398864
TI - Specific cytogenetic aberrations in two novel human prostatic cell lines
immortalized by human papillomavirus type 18 DNA.
AB - Using chromosome banding and fluorescence in situ hybridization (FISH) with
painting probes, sequential cytogenetic analysis was performed of two novel
prostate cell lines, PZ-HPV-7 and CA-HPV-10, established by human papillomavirus
(HPV) 18 DNA transformation. PZ-HPV-7 originates from a normal diploid prostate
epithelial cell strain. PZ-HPV-7 progressed from an initial diploid to a
hypertetraploid chromosome number with a relative gain of chromosomes 5 and 20 (7
to 8 copies each). Structural changes were limited; 3p- (2 copies), 3q- (1 copy),
and possibly a der(16p;12q). CA-HPV-10 originates from an epithelial cell strain
derived from a high-grade human prostate cancer specimen, which showed several
karyotypic abnormalities including an extra Y chromosome and double minutes
(dmin). In early passage the karyotype of CA-HPV-10 appeared unstable with a
decreasing number of cells exhibiting dmin. In late passage the dmin were
replaced by a large homogeneously staining region (hsr) on 9p+ marker. The hsr
was shown by FISH to be of chromosome 1 origin. The modal number was mainly
hypertriploid (72, range 69 to 75). Loss of Y was remarkable (0 to 1 copy).
Consistent markers included two copies each of del(1)(q12q31) and
der(9)t(1;9)(?;p22), and one der(11)t(4;11) (?;q21). HPV type 18 genomic
integration sites were identified on 1p for PZ-HPV-7 and on the 9p+ marker for CA
HPV-10. In conclusion, both PZ-HPV-7 and CA-HPV-10 showed clonal cytogenetic
changes. These two cell lines constitute a novel in vitro model to study the
mechanisms involved in human prostate carcino-genesis.
PMID- 9398863
TI - Interphase detection of BCL6/IgH fusion gene in non-Hodgkin lymphoma by
fluorescence in situ hybridization.
AB - We characterized a t(3;14)(q27;q32) translocation in nine patients with B-cell,
non-Hodgkin lymphoma (B-NHL) by fluorescence in situ hybridization (FISH).
Fluorescence in situ hybridization with immunoglobulin heavy chain (IgH) and BCL6
gene probes detected t(3;14) rapidly and accurately, including complex t(3;14) in
three patients; one with t(3;12;8;14)(q27;p13;q24.1;q32) and two with
t(3;?;14)(q27;?;q32). Among these nine patients, seven escaped from cytogenetic
detection by our G-banding analysis. Double-color FISH with IgH (Y6) and BCL6
(cosB5-1) showed fusion of BCL6 and IgH genes on der(3)t(3;14) in all nine
patients, suggesting that der(3) may play a critical role in the development of
lymphoma carrying complex as well as standard t(3;14) translocations. BCL6/IgH
fusion gene was also demonstrated in interphase nuclei at a frequency of 23% to
91.5% over the cut-off value in control studies (9.0 +/- 2.76%). The breakpoints
assessed by FISH with two cosmid clones containing BCL6 probes, cosB5-1 and cosB5
2, were within the cluster region in seven patients including one with complex
type, but were not evaluated in two patients with t(3;?;14), because of the loss
of partner chromosome. Using double-color FISH with these two BCL6-specific
probes, none of an additional 32 patients in whom mitotic spreads were available
showed 3q27 translocations. Fluorescence in situ hybridization with IgH and BCL6
gene probes is a rapid and sensitive method to detect t(3;14) in routine
cytogenetic studies.
PMID- 9398865
TI - Highly complex chromosomal aberrations in bone marrow of a patient with
metastatic prostate neoplasm.
AB - Prostate cancer is the single most common malignancy among men in North America.
Nevertheless, cytogenetic evaluation of bone marrow in patients with metastatic
prostate neoplasm has been rare and, to date, only five such patients have been
reported. We report an additional case where chromosomal abnormalities of a
bizarre nature were found in the bone marrow. Though cytogenetic findings in
prostate cancer are heterogeneously complex, the chromosome regions involved
include 1p, 1q, 7q, 8p, 10q, 12p, and 17q and are considered hot spots. What is
the significance of these so-called hot spots in metastasis of prostatic cancer
to the bone marrow? At present, no meaningful conclusion can be drawn, as data
are limited, but accumulation of such cases may provide valuable information
concerning the role of chromosomal abnormalities in patients--specifically with
metastatic stage--and may help urologists during therapeutic decision making,
particularly if a genetic marker for aggressiveness can be determined.
PMID- 9398866
TI - Cytogenetic findings in malignant mixed mesodermal tumors of the uterus.
AB - Cytogenetic analyses of four malignant mixed mesodermal tumors (MMMT) of the
uterus are reported, of which one was of the homologous type and three of the
heterologous. Karyotypic analyses were obtained in two cases from original tumors
and in two cases from tumors xenotransplanted into nude mice. The karyotype of
the homologous MMMT was normal in three different passages of a nude mice
xenograft line established from the primary tumor. The heterologous tumors showed
normal karyotype in one case and hyperdiploid and near triploid range with
extensive numerical and structural rearrangements in two cases. Deletion of
chromosome 1 at p32, and deletion of chromosome 11 at q13 were common markers in
anomalous cases. The chromosomes most often involved in structural rearrangements
were chromosomes 1, 9, 11, 12, 17, and 19. Double minutes, homogeneously staining
regions, and telomeric association were also seen.
PMID- 9398867
TI - Increased levels of mutagen-induced chromosome breakage in Down syndrome children
with malignancy.
AB - Even though an association between Down syndrome (DS) and malignancies has been
established, the mechanism behind this is still unclear. We therefore
investigated constitutional chromosomal abnormalities and bleomycin-induced
chromosome sensitivity in 12 DS children, 8 DS children with malignancies, and 10
normal controls to explore whether these factors play any role in cancer
predisposition. Trisomy 21 was the only constitutional cytogenetic abnormality
observed in all the DS children. But there was significant variation between the
patients and controls with regard to bleomycin sensitivity. Compared to the
normal controls, all the DS patients expressed significantly higher chromosomal
breaks per cell (b/c) values indicating sensitivity to bleomycin. Furthermore, DS
children with malignancies demonstrated significantly higher b/c values than DS
children with malignancies. These results permit us to assume that DS children
showing mutagen hypersensitivity may be having defective DNA repair competence
and hence may be predisposed to malignancies.
PMID- 9398868
TI - Monosomy 22 in a fibrothecoma.
AB - We found a 45,XX, -22 karyotype as the sole chromosome change in a fibrothecoma
of a 67-year-old woman. These cytogenetic findings are discussed in the light of
relevant cytogenetic and pathology literature data on ovarian sex cord tumors.
PMID- 9398869
TI - Chromosome analysis in angiomyolipoma.
AB - Cytogenetic data on angiomyolipomas are scarce. We report a series of 10 cases
from nine patients without clinical history of tuberous sclerosis. We found
chromosome abnormalities in two, and in both cases the chromosomal changes were
only numerical ones, i.e., trisomy 7 and trisomy 8.
PMID- 9398870
TI - Immunohistochemical detection of Helicobacter pylori in the surface mucous gel
layer and its clinicopathological significance.
AB - BACKGROUND: Attempts have been made to develop an accurate method for detecting
Helicobacter pylori in histological sections. MATERIALS AND METHODS: Biopsy
specimens were obtained from the stomachs of 167 patients with gastric ulcer
(33), duodenal ulcer (52), gastroduodenal ulcer (15), chronic gastritis (45), and
normal mucosa (22) before antimicrobial treatment and from 108 of these patients
after treatment. Biopsy specimens were (1) cultured, (2) fixed in 10% buffered
formalin, or (3) fixed in Carnoy's solution. The latter method was employed to
preserve the surface mucous gel layer (SMGL) covering gastric surface mucous
cells. Histological sections were stained with hematoxylin and eosin (H&E), with
immunostaining using a commercially available polyclonal anti-H. pylori antibody.
RESULTS: Cultures were positive for H. pylori in 61% of the cases before
treatment and in 16% after treatment; by H&E staining using formalin-fixed
materials: 70% and 9%; by immunostaining using formalin-fixed materials: 78% and
21%; and by immunostaining using Carnoy-fixed materials: 85% and 41% of biopsy
specimens, respectively. The difference in detection rates between materials
fixed in formalin and those in Carnoy's solution was due to the detection of H.
pylori in the SMGL by the latter, especially after antimicrobial treatment.
CONCLUSIONS: Immunostaining for H. pylori using materials fixed in Carnoy's
solution revealed H. pylori in the SMGL as well as on the surface mucous cells
and in the gastric pits and permitted the optimal detection of H. pylori in
tissue sections.
PMID- 9398872
TI - Serum and gastric luminal epidermal growth factor in Helicobacter pylori
associated gastritis and peptic ulcer disease.
AB - BACKGROUND: Helicobacter pylori is the cause of chronic (type B) gastritis,
duodenal ulceration (DU), and gastric ulceration (GU). Smoking is associated with
delayed ulcer healing. Epidermal growth factor (EGF) is produced in the salivary
and Brunner's glands of the upper gastrointestinal tract, inhibits gastric acid
secretion, and is a powerful mitogen. MATERIALS AND METHODS: We sought to
determine gastric luminal EGF (GL-EGF) in smokers and patients with Hp-associated
DU and the effects of Hp eradication. Our aim was to determine GL-EGF in patients
with GU and the effect of ulcer healing and to measure serum EGF in patients with
Hp gastritis with or without DU disease. RESULTS: GL-EGF was reduced in smokers
compared to controls (p = .008). Subjects with HP gastritis had reduced GL-EGF
compared to controls (p = .0002). There was no difference in GL-EGF between Hp
positive subjects who had DU and those with chronic gastritis alone. Eradication
of Hp from those patients with DU had no effect on the low levels of GL-EGF.
There was no difference between GL-EGF in Hp gastritis alone and in Hp-associated
active GU. GL-EGF fell after ulcer healing (p = .04), a difference confirmed by
analysis of paired samples from patients before and after ulcer healing (p =
.03). There was no difference in serum EGF between controls and subjects with Hp
infection. There was no difference in serum EGF in subjects with DU associated
and non-ulcer-associated gastritis. CONCLUSIONS: Subjects with Hp gastritis, or
those who smoke, had low concentrations of GL-EGF regardless of whether DU was
present. Eradication of Hp did not return the concentrations of GL-EGF to normal
in DU subjects. Individuals and Hp gastritis and inactive GU had low levels of GL
EGF compared to non-ulcer Hp infection. The relative increase in GL-EGF that
occurred with ulceration of the gastric mucosa may have resulted from the
development of an ulcer-associated cell lineage. Serum EGF did not play a role in
the pathogenesis of Hp gastritis or of associated DU ulcer disease.
PMID- 9398871
TI - Helicobacter pylori and the surface mucous gel layer of the human stomach.
AB - BACKGROUND: The colonization of Helicobacter pylori in the surface mucous gel
layer (SMGL) was investigated. MATERIALS AND METHODS: Surgically removed stomachs
were obtained from patients and included gastric ulcer (4 cases), duodenal ulcer
(2), and gastric cancer (24). Five of these cases were examined at 8, 19, 28,
143, and 171 days after the end of eradication therapy. For the preservation of
the SMGL, these specimens were fixed in cold Carnoy's solution, cleared in
xylene, and embedded in paraffin. Serial sections were obtained and were stained
by dual staining with the galactose oxidase-cold thionin Schiff reaction followed
by paradoxical Concanavalin A staining and immunostaining for H. pylori. RESULTS:
H. pylori characteristically attached to surface mucous cells and colonized in
the SMGL H. pylori in the SMGL was more abundant than that attached to the
surface mucous cells. The degree of H. pylori infection both on the surface of
surface mucous cells and in the SMGL correlated well with the severity of
gastritis. In the SMGL, this organism obviously preferred to colonize in the
layer of surface mucous cell-type mucins, and the multilaminated structure of the
SMGL deteriorated markedly. Eradication of H. pylori restored the structure of
the SMGL, and the inflammatory reaction decreased gradually. CONCLUSION: The SMGL
is an indispensable site of H. pylori colonization, and this organism damaged the
gastric mucosa partially by causing deterioration of the SMGL. Removal of the
organism from the SMGL should be considered for eradication of this organism.
PMID- 9398873
TI - The correlation in dyspeptic patients of Helicobacter pylori infection with
changes in interdigestive gastroduodenal motility patterns but not in gastric
emptying.
AB - BACKGROUND: Available data conflict regarding the possible relation between
chronic gastritis, Helicobacter pylori (Hp), and gastric motor disorders in
nonulcer dyspepsia. The aim of this study, therefore, was (1) to evaluate both
gastroduodenal fasting motility and gastric emptying in subjects with functional
dyspepsia, with and without gastritis, and (2) to correlate the motility pattern
to Hp infection. MATERIALS AND METHODS: Thirty-eight patients were studied, 20
positive for Hp infection (15 with gastritis) and 18 Hp-negative (8 with
gastritis). All the subjects underwent 240-minute manometric recording of the
interdigestive migrating motor complex, with evaluation of gastric and duodenal
motility pattern and scintigraphic study of gastric emptying. RESULTS: Whereas
gastric emptying half-time did not differ in the subgroups of dyspeptic patients,
a significant reduction of gastric phase IIIs of the migrating motor complex was
detected between Hp-positive and Hp-negative subjects, both in overall patients
(p < .01) and in patients with gastritis (p < .05). CONCLUSION: Hp infection
seems to be related to a reduction of interdigestive gastric activity fronts,
though it does not affect gastric emptying. The conflicting data regarding
gastric emptying and interdigestive motility in Hp infection could be explained
as probably investigating two different functional aspects.
PMID- 9398874
TI - Triple therapy with lansoprazole, clarithromycin, and amoxicillin for the cure of
Helicobacter pylori infection: a short report.
AB - BACKGROUND: Given the therapeutic potential of proton pump inhibitor-based triple
therapy for successful cure of Helicobacter pylori infection, we evaluated the
efficacy and safety of lansoprazole with clarithromycin and amoxicillin in an
open-label, single-center study. MATERIALS AND METHODS: H. pylori-positive
patients self-administered lansoprazole, 30 mg; clarithromycin, 500 mg; and
amoxicillin, 1 gm bid for 14 days. Patients were assessed pretreatment, at which
time the presence of H. pylori was documented by rapid urease test, culture, or
histology, following study drug administration (week 2) for a brief evaluation
only, and at least 4 weeks posttreatment (week 6), which included endoscopy with
collection of biopsy specimens for culture and histology testing. RESULTS:
Primary clarithromycin and metronidazole resistance were observed in 6% (2 of 30)
and 43% (13 of 30) of study patients, respectively. One month after the end of
therapy, H. pylori infection was cured in 23 of 25 patients (92%; 95% confidence
interval, 74%-99%). The triple-therapy regimen was well-tolerated; 17% of
patients (5 of 30) reported mild to moderate adverse effects during the treatment
period. CONCLUSION: A 2-week, triple-drug combination of lansoprazole,
clarithoromycin, and amoxicillin is highly effective for cure of H. pylori
infection. Additionally, the triple-drug combination was well-tolerated by
patients infected with H. pylori.
PMID- 9398876
TI - Seven-day triple therapy with lansoprazole, clarithromycin, and metronidazole for
the cure of Helicobacter pylori infection: a short report.
AB - BACKGROUND: To refine our understanding of anti-Helicobacter pylori treatment
regimens further, we evaluated the efficacy and safety of lansoprazole given in
combination with clarithromycin and metronidazole for 7 days in an open-label,
multicenter study. MATERIALS AND METHODS: H. pylori-positive patients self
administered lansoprazole, 30 mg; clarithromycin, 500 mg; and metronidazole, 500
mg bid for 7 days. Patients were assessed at pretreatment, at which time the
presence of H. pylori was documented by rapid urease test or histology and
culture, following study drug administration (week 1) for a brief evaluation
only, and at least 4 weeks posttreatment (week 5), including endoscopy with
collection of biopsy specimens for culture and histology testing. RESULTS: Of the
60 patients enrolled in the study, 59 had confirmed H. pylori infection, and 51
were included in an intent-to-treat analysis of efficacy. Primary metronidazole
and clarithromycin resistance were observed in 84% and 8% of study patients,
respectively. One month after the end of therapy, H. pylori infection was cured
in 40 of 51 patients (78%); 95% confidence interval, (65%-89%). The triple
therapy regimen was well-tolerated, with only 2 patients (4%) requiring premature
withdrawal from the study due to treatment-related adverse events. Taste
perversion (15.0%) and diarrhea (11.7%) were the most frequently reported adverse
events possibly or probably related to study medication during the treatment
period. CONCLUSION: Despite a high prevalence of metronidazole resistance, a 1
week, triple-drug combination of lansoprazole, clarithromycin, and metronidazole
is effective treatment for and well-tolerated by patients with H. pylori
infection.
PMID- 9398875
TI - Double-blind, multicenter evaluation of lansoprazole and amoxicillin dual therapy
for the cure of Helicobacter pylori infection.
AB - BACKGROUND: Treatment with amoxicillin plus omeprazole results in disappointing
cure rates of Helicobacter pylori infection. The minimal inhibitory concentration
of lansoprazole for H. pylori in vitro is lower than that for omeprazole,
prompting interest in treatment with amoxicillin plus lansoprazole. MATERIALS AND
METHODS: H. pylori-infected patients with endoscopically documented duodenal
ulcer either currently or within the past year were randomized to 14 days of (1)
lansoprazole, 30 mg bid, plus amoxicillin, 1 gm tid; (2) lansoprazole, 30 mg tid,
plus amoxicillin, 1 gm tid; (3) lansoprazole, 30 mg tid alone; or (4)
amoxicillin, 1 gm tid alone. Endoscopy was done at enrollment and at 4 to 6 weeks
after completion of treatment or for recurrent symptoms. H. pylori status was
assessed by culture and histology. Ulcer prevalence was evaluated at follow-up
endoscopy. RESULTS: Two hundred sixty-two patients met enrollment criteria and
were treated. By per-protocol analysis, H. pylori infection was cured in 57% of
those treated with lansoprazole twice daily plus amoxicillin and in 67% of those
treated with lansoprazole three times daily plus amoxicillin, compared with 0%
treated with lansoprazole alone or amoxicillin alone (p < .001 for dual therapy
versus either monotherapy). Amoxicillin resistance was not observed. At follow-up
endoscopy, ulcer prevalence was 17% in patients treated with lansoprazole twice
daily plus amoxicillin, 23% in those treated with lansoprazole three times daily
plus amoxicillin, 33% in those treated with lansoprazole alone, and 35% in those
treated with amoxicillin alone (p = .024; lansoprazole twice daily plus
amoxicillin versus amoxicillin alone). CONCLUSIONS: Treatment with amoxicillin
plus lansoprazole, 30 mg tid, led to cure of H. pylori infection in 67% of
patients with active or recently healed duodenal ulcer.
PMID- 9398877
TI - The best gastric site for obtaining a positive rapid ureas test.
AB - BACKGROUND: Rapid ureas tests (RUTs) provide a simple, sensitive method of
detecting Helicobacter pylori infection. OBJECTIVES: Our aim, therefore, was to
determine whether the yield of detecting H. pylori infection by RUT varied
depending on the site of gastric biopsy. MATERIALS AND METHODS: Gastric biopsies
were obtained from 50 patients for RUT by use of hpfast (GI Supply, Camp Hill,
PA). Biopsies were taken from the prepyloric greater curve antrum, from the
gastric angle, and from the greater curve in mid-corpus. One biopsy specimen was
placed in the RUT gel, and the biopsy from the adjacent mucosa was placed in
formalin for subsequent histological evaluation by using the Genta stain. RUTs
were examined and scored at intervals of 5, 10, 15, 30, and 45 minutes and after
1, 2, 4, and 24 hours. RESULTS: Fifty patients were entered in the rest (150
RUTs), 32 having H. pylori infection. There were no false-positive RUTs
(specificity, 100%). The gastric angle site was positive in 100%. The prepyloric
site was positive in 87%, and the corpus site was positive in 84.4% (p < .052 for
angle or prepyloric antrum versus corpus). The most common pattern was for all to
be positive (74%). The median time to positivity was similar with angle and
prepyloric sites (37.5 and 60 minutes, respectively, p = not significant) and
shorter than the corpus biopsy (180 minutes); (p < .05 for angle or prepyloric
antrum versus corpus). CONCLUSION: The maximum probability for detecting H.
pylori infection using a RUT is to obtain a biopsy from the gastric angle. To
prevent missing a positive result when intestinal metaplasia is present, we
recommend that (at a minimum) biopsies be taken from both the angle and the
corpus.
PMID- 9398878
TI - Duodenal ulcer healing after 7-day treatment: a pilot study with lansoprazole,
amoxicillin, and clarithromycin.
PMID- 9398879
TI - How to manage the dyspeptic patient.
PMID- 9398880
TI - Comparison of one or two weeks of lansoprazole, amoxicillin, and clarithromycin
in the treatment of Helicobacter pylori.
AB - BACKGROUND: The simplest, most effective, and least expensive Helicobacter pylori
therapy remains to be determined. Two weeks of 30 mg lansoprazole bid, 1 gm
amoxicillin bid, and 500 mg clarithromycin bid (LAC2) had been shown to be an
effective therapy for H. pylori. The aim of this study was to assess whether 1
week of this regimen (LAC1) would have a similar efficacy. MATERIALS AND METHODS:
H. pylori-positive patients assessed histologically, by rapid urease test,
microbiologically, and by a 13C-urea breath test (13C-UBT) were randomized to
receive either LAC1 or LAC2 in a single-center open study. Patients were
interviewed 1 to 3 days after completion of therapy to evaluate adverse events
and compliance. Efficacy was determined by 13C-UBT at least 4 weeks after
antibiotic therapy. RESULTS: Seventy evaluable patients were randomized to
receive LAC1 (n = 33) LAC2 (n = 37). Of the 33 LAC1 patients, 30 (91%) were
treated successfully (95% confidence interval (CI) = 76-98%), compared with 32 of
37 (86%) in the LAC2 group (95% CI = 71-96%). There was no difference in efficacy
between the two groups (Fisher's exact test p = 1.0; 95% CI = -10.3%-19.2%).
Patients taking LAC1 experienced significantly fewer severe adverse events than
those taking LAC2 (Mann-Whitney U test). One of 64 patients had primary
resistance to clarithromycin, and treatment was unsuccessful in this case. Six of
the 7 remaining treatment failures developed secondary resistance to
clarithromycin. CONCLUSIONS: LAC1 is as effective as LAC2 and is associated with
less toxicity. Posttreatment clarithromycin resistance is common in patients who
do not experience success with therapy.
PMID- 9398881
TI - Epidemiology of gastric non-Hodgkin's lymphoma patients: parallels with
Helicobacter pylori.
AB - BACKGROUND: The incidence of gastric non-Hodgkin's lymphoma (NHL) is increasing
in the United States. However, little is known about the etiology of the disease.
Some studies have shown an association between gastric NHL and Helicobacter
pylori. No study has specifically delineated demographic features that
distinguish gastric NHL patients from nongastric NHL patients. MATERIALS AND
METHODS: To obtain information about the differences between gastric and
nongastric NHL patients, we conducted a hospital chart review study. We examined
charts of all 25 cases of primary gastric NHL, as well as charts of 75 randomly
selected nongastric NHL patients as controls. All patients were seen in the
Division of Oncology at Stanford University Medical Center from 1972 to 1991.
Demographic information was tabulated, and differences between the cases and
controls were noted. The identified risk factors were determined by both
univariate and logistic regression analyses. RESULTS: There was no difference
between gastric NHL cases and nongastric controls with respect to age, gender,
race, and family history of any cancer. However, in logistical regression,
persons with gastric NHL were more likely than those with other forms of NHL to
be born outside the United States (odds ratio = 12.8; 95% confidence interval =
2.9-56.0) and also to have a family history of stomach cancer (odds ratio = 18.4;
95% confidence interval 2.1-160.1). CONCLUSIONS: Gastric NHL is more likely than
NHL at other sites to occur in persons with a family history of gastric cancer or
in those born in developing countries. This epidemiological pattern supports the
identified role of H. pylori in the development of gastric lymphoma.
PMID- 9398882
TI - Is Helicobacter pylori transmitted from cats to humans?
AB - BACKGROUND: Subsequent to the isolation of Helicobacter pylori from domestic
cats, it has been suggested that the organism might be transmitted from cats to
humans. This hypothesis has already gained considerable media attention.
MATERIALS AND METHODS: In a previous study of risk factors for H. pylori
infection, 447 factory workers from Stoke on Trent in the UK had provided blood
samples for H. pylori serological workup. They had also completed a detailed
questionnaire concerning their living conditions, including the possession of any
household pets, in childhood. Logistic regression was used to assess the
association between cat ownership in childhood and H. pylori seropositivity.
RESULTS: After adjustment for potential confounders, it was found that subjects
who had owned a pet as a child were slightly more likely to be H. pylori
seropositive than subjects who had not. There was, however, no difference between
subjects who had owned a cat and those with other pets. CONCLUSIONS: These data
do not support the hypothesis that H. pylori infection might be transmitted from
cats to humans.
PMID- 9398883
TI - Helicobacter pylori and socioeconomic factors in Russia.
AB - BACKGROUND: The factors influencing the acquisition and prevalence of
Helicobacter pylori infection remain incompletely understood. In Russia, the
demographic and socioeconomic factors are relatively similar, allowing
investigation of risk factors that might not be identifiable in a more diverse
population. MATERIALS AND METHODS: Sero-prevalence of H. pylori infection was
studied in 520 asymptomatic individuals between the ages of 1 and 75 years,
residing in St. Petersburg, Russia. Forty-four children lived in orphanages or
communal apartments. Demographic information and socioeconomic factors were
evaluated, including educational level, income, and living conditions.
Helicobacter pylori status was evaluated by using an enzyme-linked immunosorbent
assay for anti-H. pylori IgG. RESULTS: The prevalence of H. pylori infection was
44% in children and 88% in adults (P < .001). In adults, H. pylori prevalence was
independent of socioeconomic factors. The crude and the age-adjusted odds ratios
(ORs) in children showed an inverse correlation between the mother's educational
level and H. pylori seropositivity [e.g., OR, 1.8; (95% confidence interval (CI)
= 1-3.2] for children whose mothers completed only 8 to 10 years of school
compared to children whose mothers completed university. Overcrowding in
childhood also was associated with increased H. pylori prevalence. Children from
orphanages and communal apartments had the highest crowding index and also were
at the greatest risk for H. pylori acquisition (age-adjusted OR, 2.1; 95% CI =
1.2-2.5). CONCLUSIONS: The prevalence of H. pylori infection in Russia correlated
with socioeconomic factors, suggesting there are differences sufficient to affect
H. pylori transmission. The prevalence of H. pylori infection during childhood
forms the basis for the variances in prevalence among populations.
PMID- 9398884
TI - Is antrum or corpus the best site for culture of Helicobacter pylori?
AB - BACKGROUND: Isolating Helicobacter pylori on culture media and performing
antibiotic susceptibility testing is potentially the most useful tool for guiding
antibiotic therapy, especially when antimicrobial resistance is suspected. The
aim of this study was to determine whether the yield of H. pylori culture was
related to the site from which the gastric specimen was obtained either before or
after therapy. METHODS: Gastric mucosal biopsies from the antrum and the corpus
of the stomach were cultured. H. pylori status was determined by histological
assessment using the Genta stain. RESULTS: Fifty-two patients with documented H.
pylori infection were studied: Twenty-three were tested before antibiotic therapy
and 29 after therapy had failed. In 47 patients (90%), both antral and corpus
culture specimens were positive. In 5 patients (10%), only one site was positive,
with three false-negative antral and two false negative corpus cultures. The
overall sensitivity of culture in detecting H. pylori infection was 95% (95%
confidence interval = 89-98%) and was not significantly different for the antrum
or corpus, either before or after therapy. CONCLUSION: Culture of gastric
biopsies from either the antrum or the corpus has an excellent diagnostic yield
even in patients who failed antimicrobial therapy.
PMID- 9398885
TI - Different expression of Helicobacter pylori gastritis in children: evidence for a
specific pediatric disease?
AB - BACKGROUND: Infection with Helicobacter pylori causes active chronic gastritis.
Once the infection is acquired, gastritis will persist for almost the rest of
one's life. To date, very few data are available on H. pylori gastritis in
relation to age. Therefore, we attempted to investigate whether H. pylori
gastritis in children exhibits features different from H. pylori gastritis in
adults of two different age groups. MATERIALS AND METHODS: Fifty consecutive
children with a median age of 11 years (range, 3-18 years) were compared with two
groups of 50 adult patients, one group with a median age of 43 (range, 19-56
years) and another group with a median age of 70 years (range, 59-86 years). All
patients had H. pylori gastritis unrelated to active peptic ulcer disease. Two
biopsy specimens were taken from the antrum and two from the corpus, and the
following gastritis parameters were evaluated: degree and activity of gastritis,
H, pylori colonization, replacement of foveolar epithelium by regenerative
epithelium, mucous depletion, presence of atrophic gastritis with intestinal
metaplasia, and presence of lymphoid follicles. RESULTS: Degree and activity of
gastritis, extent of H. pylori colonization, degree of replacement by
regenerative epithelium, extent of mucous depletion, degree of atrophic gastritis
with intestinal metaplasia, and the presence of lymphoid follicles in the antrum,
as well as the presence of lymphoid follicles in the corpus differed
significantly (chi-square test: p < .05). All these differences--except the once
frequent occurrence of atrophic gastritis with intestinal metaplasia in adults-
were attributable to a higher expression of these gastritis parameters in
children. CONCLUSIONS: We conclude that H. pylori gastritis, particularly in the
antrum, is more severely expressed in childhood. One reason for this might be a
child-specific immune response to an infection with H. pylori. Alternatively,
infection may represent a pediatric disease characterized by a nonatrophic,
highly expressed form of gastritis, which changes its appearance once the host
becomes adapted over time.
PMID- 9398886
TI - Mixed infection with cagA-positive and cagA-negative strains of Helicobacter
pylori.
AB - BACKGROUND: Helicobacter pylori infection has been implicated strongly in the
pathogenesis of gastritis, peptic ulcer disease, gastric adenocarcinoma, and
gastric lymphoma, but the reasons for these widely different clinical outcomes
are unknown. The aim of this study was to determine whether these differences
could be due in part to mixed infection in the same individual, with bacteria
having differences in pathogenic factors associated with ulcers. MATERIALS AND
METHODS: The cagA gene of H. pylori was used to test for mixed infection because
it is present in only some strains, and its presence has been associated with
ulcers. Polymerase chain reaction (PCR) assays for the cagA gene were applied to
H. pylori culture isolates and endoscopic gastric aspirates. Individual bacterial
clones were tested for genetic similarity by random primer amplification and
restriction endonuclease digestion of urease gene PCR products. RESULTS: The
majority of H. pylori-positive patients had strongly cagA-positive culture
isolates and endoscopic samples (62.5% and 69.6%, respectively). However, many of
these patients had evidence of mixed infection with cagA negative and cagA
positive strains in cultures isolates and endoscopic samples (25% and 17.4%,
respectively). Mixed infection was found to be due to genetically unrelated
strains in two patients in whom genetic analysis was performed. CONCLUSION: Mixed
infection with differences in substrain pathogenic factors might occur in H.
pylori infection and might contribute to differences in clinical outcome.
PMID- 9398887
TI - Presence of the cagA gene in the majority of Helicobacter pylori strains is
independent of whether the individual has duodenal ulcer or asymptomatic
gastritis.
AB - BACKGROUND: Helicobacter pylori infection presents as many different diseases,
including asymptomatic gastritis, peptic ulcer disease, and gastric cancer.
Although the virulence factor(s) responsible for different H. pylori-related
diseases have not been identified, several candidate genes are being investigated
for such an association. The polymerase chain reaction (PCR) frequently is used
to assess the presence of genetic factors associated with pathogenesis of
disease; the cagA gene and its product have been postulated to have a disease
specific relationship to peptic ulcer and gastric cancer because of differential
expression in these diseases compared to histological gastritis alone. MATERIALS
AND METHODS: Genomic DNA was amplified by PCR, using synthetic oligonucleotide
primers to the cagA gene to determine the prevalence of the cagA gene in 60 H.
pylori isolates obtained from well-documented duodenal ulcer or asymptomatic
gastritis patients (30 each). Results were confirmed by hybridization with a 1.4
Kb cagA probe. RESULTS: The expected PCR product was obtained in 90% of isolates
from duodenal ulcer patients, compared to 70% of isolates from individuals with
asymptomatic gastritis. The PCR products were polymorphic in size, suggesting
cagA gene sequence differences among isolates. Evaluation for the presence of the
cagA gene by hybridization with a 1.4-Kb cagA probe showed a homologous product
in 29 of 30 strains [96.7%; 95% confidence interval (CI) = 83-100%] from duodenal
ulcer patients versus 25 of 30 strains (83.3%; 95% CI = 65-94%) obtained from
individuals with asymptomatic gastritis (p = 0.19). CONCLUSIONS: The high
prevalence of the cagA gene in asymptomatic gastritis suggests that it will not
prove to be a useful marker to distinguish more virulent or disease-specific H.
pylori strains. The genetic heterogeneity among H. pylori strains makes PCR an
unwise choice as the single method to determine prevalence of a putative
virulence factor. In evaluation of the prevalence of a gene or genetic factor in
a population of H. pylori, hybridization with extended probes might be important
to ensure that the results are representative of the organism's genotype.
PMID- 9398888
TI - Conservation and diversity of the Helicobacter pylori copper-transporting ATPase
gene (copA) sequence among Helicobacter species and Campylobacter species
detected by PCR and RFLP.
AB - BACKGROUND: Helicobacter pylori is a causative pathogen of such human stomach
diseases as chronic type B gastritis, ulcer, and possibly gastric carcinoma. As a
cofactor in various redox enzymes and an essential trace metal required for the
synthesis of metalloproteins, copper might play a role in the pathogenesis of H.
pylori. A gene, copA, associated with copper transport, has been isolated from H.
pylori UA802. In this study, conservation and diversity of this gene were
analyzed among some Helicobacter and Campylobacter species. MATERIALS AND
METHODS: Twenty-one clinical isolates and strains of helicobacters and
campylobacters were used in this study. Methods including polymerase chain
reaction (PCR) amplification, restriction fragment-length polymorphisms (RFLPs),
and hybridization were employed to carry out this work. RESULTS: The copA gene
was highly conserved in all the H. pylori isolates tested (Helicobacter
nemestrinae and Helicobacter felis but not in Helicobacter mustelae and the
Campylobacter species), whereas the sequence downstream of the copA appears to
diverge among H. pylori isolates. In addition, two restriction patterns of the
PCR-amplified copA fragments from seven H. pylori isolates and H. nemestrinae
were identified, and the RFLP of H. nemestrinae was identical to that of one of
the H. pylori isolate group. CONCLUSIONS: The adenosine triposphatase-derived
copper-transporting mechanism is employed by various H. pylori strains, H.
nemestrinae, H. felis, and perhaps by other Helicobacter species. The nucleotide
mutations have risen in the copA gene. It appears that there is a genetic
relatedness of the copA gene to H. pylori and H. nemestrinae.
PMID- 9398889
TI - Treatment of Helicobacter pylori infection: summary of a meeting at the Fourth
United European Gastroenterology Week, September 20, 1995.
PMID- 9398890
TI - A standardized system of abbreviation for describing treatment regimens for
Helicobacter pylori.
PMID- 9398891
TI - Quadruple therapy: the golden bullet or a drug too far?
PMID- 9398892
TI - Transformation of H. pylori by plasmid.
PMID- 9398893
TI - Double-blind, multicenter, placebo-controlled evaluation of clarithromycin and
omeprazole for Helicobacter pylori-associated duodenal ulcer.
AB - BACKGROUND: Eradication of Helicobacter pylori leads to faster ulcer healing and
a significant decrease in ulcer recurrence. Clarithromycin is the most effective
monotherapy for eradicating H. pylori from the gastric mucosa, and omeprazole
frequently is used for the treatment of duodenal ulcer disease, prompting the
interest to investigate rigorously the combination of clarithromycin and
omeprazole for eradicating H. pylori. MATERIALS AND METHODS: The aim of this
double-blind, randomized, multicenter (n = 30), multinational (n = 10) study was
to compare clarithromycin and omeprazole with omeprazole monotherapy for the
eradication of H. pylori from the gastric mucosa, endoscopic healing, and
reduction of symptoms and ulcer recurrence in patients with active duodenal
ulcer. Patients with active duodenal ulcer associated with H. pylori infection
were randomized to receive omeprazole, 40 mg every morning for 14 days, with
either clarithromycin, 500 mg, or placebo three times daily, which was followed
by omeprazole, 20 mg every morning for 14 days. Patients underwent endoscopy
before enrolling in the study, immediately after finishing treatment, and at 4-
to 6-week and 6-month follow-up evaluations or at the recurrence of symptoms.
RESULTS: Two hundred and eight patients with active duodenal ulcer associated
with confirmed H. pylori infection were randomized to treatment with either
clarithromycin and omeprazole (n = 102) or omeprazole and placebo (n = 106). Four
to six weeks after treatment was completed, H. pylori was eradicated in 74% (95%
confidence interval, 63.0%-82.4%) of patients receiving clarithromycin and
omeprazole, compared with 1% (0.0%-6.2%) of patients receiving omeprazole
monotherapy (p < .001). Clarithromycin resistance developed in eight patients
treated with clarithromycin and omeprazole and in none given omeprazole and
placebo. Ulcers, which were healed following treatment in more than 95% of study
patients, recurred by the 6-month follow-up visit in 10% (5%-19%) of dual therapy
recipients, compared with 50% (39%-61%) of those who took omeprazole alone (p <
.001). CONCLUSION: Clarithromycin and omeprazole dual therapy is simple and well
tolerated and leads to consistently high eradication rates for patients with
duodenal ulcer associated with H. pylori infection.
PMID- 9398894
TI - Eradication of Helicobacter pylori using one-week triple therapies combining
omeprazole with two antimicrobials: the MACH I Study.
AB - BACKGROUND: Eradication of Helicobacter pylori provides potential cure in the
majority of patients with peptic ulcer disease, and eradication rates of more
than 90% have been reported, using omeprazole in combination with two
antimicrobials. The choice of antimicrobials, dose regimen and duration of
treatment have varied between studies, however, and an optimal treatment still
has to be established. MATERIALS AND METHODS: We conducted an international,
randomized, double-blind, placebo-controlled study involving more than 100
patients in each of six treatment groups in 43 hospital gastrointestinal units in
Canada, Germany, Ireland, Sweden, and the United Kingdom. Patients (n = 787) with
proved duodenal ulcer disease were randomized to treatment twice daily for 1 week
with omeprazole, 20 mg (O), plus either placebo (P) or combinations of two of the
following antimicrobials: amoxicillin, 1 gm (A), clarithromycin, 250 or 500 mg
(C250, C500), or metronidazole, 400 mg (M). Eradication of H. pylori was
evaluated by 13C-UBT, performed before and 4 weeks after treatment cessation.
RESULTS: The eradication rates for the all-patients-treated analysis were 96%,
OAC500; 95%, OMC250; 90%, OMC500; 84%, OAC250; 79%, OAM; and 1%, OP. OAC500 and
OMC250 achieved eradication rates with lower 95% confidence interval limits
exceeding 90%. All regimens were well-tolerated, 96% of patients complied with
their dose regimen, and 2.3% of the patients discontinued treatment owing to
adverse events. CONCLUSIONS: Omeprazole triple therapies given twice daily for 1
week produce high eradication rates, are well-tolerated, and are associated with
high patient compliance. The two most effective therapies were those combining
omeprazole, 20 mg, with either amoxicillin, 1 gm, plus clarithromycin, 500 mg, or
metronidazole, 400 mg, plus clarithromycin, 250 mg, all given twice daily.
PMID- 9398895
TI - Effectiveness of quadruple therapy using lansoprazole, instead of omeprazole, in
curing Helicobacter pylori infection.
AB - BACKGROUND: Omeprazole enhances the efficacy of bismuth-based triple therapy. It
is unknown whether the same is true for other proton pump inhibitors.
Lansoprazole has superior anti-Helicobacter activity in vitro and possibly also
in vivo; therefore we investigated quadruple therapy with lansoprazole. MATERIALS
AND METHODS: In two studies performed in separate hospitals, a total of 67
Helicobacter pylori-positive patients were treated with 7-day quadruple therapy
(lansoprazole, colloidal bismuth subcitrate, tetracycline, and metronidazole)
after 3 days of lansoprazole pretreatment. Testing for cure was done by endoscopy
in study 1 and by breath test in study 2. RESULTS: Cure rates per protocol were
31 of 31 (100%) in study 1 and 30 of 32 (94%) in study 2. Intention-to-treat cure
rates were 31 of 35 (89%) in study 1 and 30 of 32 (94%) in study 2. Cured overall
were 32 of 34 with a metronidazole sensitive strain and 3 of 3 with a
metronidazole-resistant strain. Data on side effects were collected from 51
patients. Twelve (21%) had no side effects, 27 (53%) had mild side effects, 10
(20%) had moderate side effects, but only 2 (4%) had severe side effects. Side
effects, never were the reason that a patient stopped taking the medication.
CONCLUSIONS: The results with lansoprazole-quadruple therapy are comparable to
the historic control group treated with omeprazole-quadruple therapy. The cure
rare is very high, and although mild to moderate side effects occurred in many
patients, everybody finished the treatment regime.
PMID- 9398896
TI - Helicobacter pylori-positive duodenal ulcer: a long-term double-blind randomized
study in patients healed with H2-receptor antagonists.
AB - BACKGROUND: The NIH Consensus Conference in 1994 (1) concluded that all patients
with peptic ulcer disease should be tested and treated for Helicobacter pylori
and that further evaluation was needed for patients in remission. MATERIALS AND
METHODS: We evaluated in a double blind randomization 30 patients whose duodenal
ulcers had been healed with H2-receptor antagonists and who remained in remission
on maintenance therapy. After ulcer healing and the presence of H. pylori had
been confirmed, these patients were randomized to receive eradication therapy or
placebo and were followed for a mean period of 23 months. RESULTS: Almost all
patients receiving placebo had ulcer recurrence, whereas the patients treated
with antibiotics demonstrate a low recurrence rate. CONCLUSION: These data
suggest, for the first time to our knowledge, the importance of treating with
antibiotics duodenal ulcer patients whose disease is in remission.
PMID- 9398897
TI - Effect of omeprazole therapy on the survival of Helicobacter pylori, urease
activity, and antral gastric histology in patients with duodenal ulcer.
AB - BACKGROUND: Helicobacter pylori is associated with chronic active gastritis and
peptic ulceration (PU). Omeprazole is a proton pump inhibitor that is effective
in healing PU and reducing gastritis. Previously it has been found that
omeprazole has some bacteriostatic activity against H. pylori both in vitro and
in vivo and in inhibiting urease activity in vitro. Our aim was to evaluate the
effect of omeprazole on H. pylori colonization of the gastric mucosa, urease
activity in vivo, and the presence of associated gastritis in patients with
duodenal ulcer (DU). MATERIALS AND METHODS: We studied 12 patients (7 men and 5
women, ages 22-68 yr) with Du larger than 5 mm in diameter with a positive
CLOtest (Delta West Ltd., Australia). Omeprazole, 20 mg bid, was given for 8
weeks to each patient, patients were endoscoped at the end of this period to
check for healing of DU, and repeat biopsies were obtained from the gastric
antrum for histological analysis, CLOtest, and culture. RESULTS: DU healed
completely in all patients. Likewise in all patients there was significant
reduction in the urease activity, from 22.1 +/- 4.17 to 1.58 +/- 0.92 units/ml (p
< .001; 95% confidence interval of the difference between means, 32.7-14.1), and
reduced H. pylori density, from 1,403.46 +/- 128.23 to 422.5 +/- 172.39 colony
forming units (CFU) per milligram of tissue biopsy (p < .001; 95% confidence
interval of the difference between means, 1,486.1-590.5). The numbers of H.
pylori were reduced on the gastric mucosa after omeprazole therapy and
disappeared in six patients, a result that correlated with a negative CLOtest
reading after 24 hours. CONCLUSION: Omeprazole, 20 mg bid, is capable of reducing
H. pylori numbers and urease activity in vivo. There was no significant reduction
in the severity of antral gastritis in DU patients studied.
PMID- 9398898
TI - Gastric juice polymerase chain reaction: an alternative to histology in the
diagnosis of Helicobacter pylori infection.
AB - BACKGROUND: Infection from Helicobacter pylori plays a role in several
gastroduodenal diseases. The recent availability of molecular techniques,
particularly the polymerase chain reaction (PCR), allows us to detect small
amounts of this bacterium. The aims of this study were to compare PCR and
histological findings and to ascertain the clinical usefulness of H. pylori PCR
identification in different biological samples. MATERIALS AND METHODS: We studied
94 consecutive patients. Saliva, gastric juice, and four antral and four body
biopsies were obtained from each patient. H. pylori was evaluated histologically
in two antral and two body biopsies (Giemsa or Warthin-Starry stain). After
extraction, DNA was submitted for PCR amplification using the two primers HPU1
and HPU2, which amplified a 411-bp product from the urease gene A. RESULTS: Forty
nine patients were H. pylori-positive at histological workup. The sensitivity of
PCR was 92% for gastric juice, 73% for antral biopsies, 61% for body biopsies,
and 13% for saliva. Of the 45 H. pylori-negative patients at histological
assessment, 7 (16%) had positive findings on PCR, mainly when gastric juice was
examined. CONCLUSIONS: These results indicate that PCR is as sensitive as
histological assessment. We suggest that PCR H. pylori detection in gastric juice
is a sensitive method for diagnosing this infection.
PMID- 9398899
TI - Twenty-minute fasting version of the US 13C-urea breath test for the diagnosis of
H. pylori infection.
AB - BACKGROUND: In large-scale multi-center clinical trials, the US 13C-urea breath
test (UBT) has proven to have a sensitivity and specificity of approximately 95%.
Ingestion of a meal to delay gastric emptying has advantages of increasing the
level of signal as well as prolonging the duration of significantly increased 13C
excretion, at the expense of requiring 40 to 60 minutes to complete the test. Our
aim was to explore the utility of the 13C-UBT with a total duration of 30 minutes
or less. METHODS: After a baseline breath sample was obtained, 125 mg of 13C-urea
was given in 100 ml of water, and additional breath samples were taken after 20
and 30 minutes. The results of the UBT were compared to histological assessment,
culture, and the rapid urease test. 13C-UBTs were carried out on normal
volunteers who underwent gastroscopy during which six mucosal biopsies were
taken. Three biopsies were for histological evaluation (Genta stain), two for
culture, and one was for agar gel rapid urease testing. The UBT was conducted 2
to 3 days either before or after the endoscopic procedure. RESULTS: The cutoff
value for a positive UBT was enrichment of 2.4 delta/1000 (delta over baseline).
Of the 66 tests, 51/1000 were Helicobacter pylori-positive. There were no false
positive UBTs and only two false negative UBTs at 20 minutes (sensitivity, 96%;
specificity, 100%). At 30 minutes, one other UBT was false negative (gray zone of
2.36/1000) (sensitivity, 94%; specificity, 100%). CONCLUSION: These results
suggest that omission of the meal and shortening the duration of the US 13C-UBT
to 20 minutes still may maintain excellent specificity and sensitivity of the
test.
PMID- 9398900
TI - Helicobacter pylori infection in congestive gastropathy.
AB - BACKGROUND: This study determines the prevalence and significance of Helicobacter
pylori infection in portal hypertensive patients. MATERIALS AND METHODS: Patients
numbered 118 and consisted of 90 patients with portal hypertension (66 men; 24
women; mean age, 49.1 +/- 2.1 years) and 28 noncirrhotic patients with nonulcer
dyspepsia, (12 men; 16 women; mean age, 47.6 +/- 2.8 years), who made up the
control group. In all patients, diagnostic upper endoscopy was performed, and
gastric biopsies were taken for histological examination and diagnosis of H.
pylori. RESULTS: Of the portal hypertensive patients, 42 (47%) had congestive
gastropathy, 11 (26%) of whom were positive for H. pylori, and 48 (53%) did not
have gastropathy, 12 (25%) of whom were positive for H. pylori. In the control
group, 15 of 28 (54%) were positive for H. pylori. H. Pylori was found less
frequently in congestive gastropathy patients than in the control group. We found
also that the presence and severity of congestive gastropathy is independent of
H. pylori status. CONCLUSIONS: We conclude that the role of H. pylori in the
pathogenesis of congestive gastropathy is unlikely, and we suggest that there is
no need for its routine eradication in cirrhotic patients.
PMID- 9398901
TI - Helicobacter pylori infection, gastritis, and the temperature of choice for hot
drinks.
AB - BACKGROUND: The role of the temperature of the diet as a potential etiological
factor for gastritis or peptic ulcer disease has been postulated since the
beginning of the century. Animal studies have demonstrated damage to gastric
mucosa caused by hot water at 60 to 80 degrees C. In the pre-Helicobacter pylori
era it was reported that the majority of ulcer patients preferred hot drinks. It
also was reported that the temperature of choice for drinks increased with
severity of histological grade of gastritis. We evaluated the association between
the preferred temperature of hot drinks and the presence of H. pylori infection.
METHODS: We tested the temperature of choice for hot drinking liquids among 12 H.
pylori-negative and 43 H. pylori-positive volunteers. We also compared the effect
of H. pylori therapy on hot drink temperature preference and, in 32 individuals,
whether there was a relation between temperature and the degree of gastric
atrophy. RESULTS: There was no difference in the preferred temperature for hot
drinks between those volunteers with and without H. pylori infection (63.4
degrees +/- 6 degrees C compared to 61.3 degrees +/- 7 degrees C, respectively)
(mean +/- 1 SD, p = .3). There was no change in preferred temperature after
successful therapy of the H. pylori infection compared to unsuccessful H. pylori
therapy, nor was there a correlation between the preferred temperature and the
presence, absence, or degree of gastric atrophy (r2 < 0.001). CONCLUSION: The
temperature of preference for hot drinks was not influenced by H. pylori
infection or by the presence of atrophic gastritis.
PMID- 9398902
TI - Reservoirs of Helicobacter pylori and modes of transmission.
PMID- 9398903
TI - Egg passage of rodshaped and coccoid forms of Helicobacter pylori: preliminary
studies.
AB - BACKGROUND: We used egg passage of bacteria stored in water to evaluate the
culturability of the coccoid form of Helicobacter pylori, as a complement to the
results obtained from various animal models. Egg passage was performed, as it is
a simple, rapid, and well-characterized old method by which to culture and
evaluate culturability of bacteria compared to experiments in animal models. Egg
passage has been used in such experiments since 1938 for isolation and growth of,
for example, Rickettsiae sp. and Chlamydia sp. MATERIALS AND METHODS: The rod
shaped form of H. pylori was produced by plate cultures for 4 and 7 days. The
coccoid form of H. pylori was produced by culture on agar plates for 10 days,
followed by storage in water. These preparations then were inoculated into the
yolk sac of differently aged fertilized eggs. RESULTS: Positive culture was
obtained from 14 of 17 eggs (82%) inoculated with rod-shaped H. pylori compared
to 0 of 22 eggs (0%) inoculated with the coccoid form. CONCLUSION: Culturability
of H. pylori is reduced when it converts into the coccoid form produced by
starvation and age followed by storage in water for several weeks at room
temperature. Egg passage did not raise the culturability of the coccoid form of
H. pylori. Our study demonstrates some clear differences between fresh rods and
stored cocci forms of H. pylori in terms of culturability when passed through
eggs.
PMID- 9398904
TI - Hypothesis: Helicobacter toxins and liver.
PMID- 9398906
TI - Helicobacter: a new scientific journal.
PMID- 9398905
TI - Helicobacter pylori expresses Lewis X.
PMID- 9398907
TI - Reflections on the first description of the presence of Helicobacter species in
the stomach of mammals.
PMID- 9398908
TI - Treatment of Helicobacter pylori infection: a review of the world literature.
AB - BACKGROUND: None of the currently used anti-Helicobacter pylori drug regimens
cures the infection 100%, and cure results still vary considerably. The present
article reviews the effectiveness of currently used antimicrobial regimens, aimed
to cure H. pylori infection. METHODS: Data collection started from the beginning
of the anti-H. pylori-therapy era until May 1995. No attempt at formal
metanalysis has been made, because many studies have been published only in
abstract form. Attempts were made to exclude duplicates of studies by comparison
to previously reported ones; the authors of suspected duplicates were contacted.
After amalgamation of the number of included patients and the number of
successfully treated patients, the mean values of eradication rates and the 95%
confidence intervals were calculated. RESULTS: A total of 237 treatment arms were
analyzed. Bismuth triple therapy continues to reach high eradication rates
worldwide (78-89%). Side effects leading to diminished patient compliance and the
marked decline of eradication efficacy in cases of metronidazole resistance are
considered to be the major drawbacks of this therapy. Proton pump inhibitor (PPI)
dual therapy is better tolerated with fewer side effects than is bismuth triple
therapy. The mean eradication rates vary from 55 to 75%, and the extremes lie
between 24 and 93%. PPI triple therapies have been shown to be very effective
against H. pylori (eradication rates, 80-89%). Quadruple therapy leads to a mean
eradication rate of 96%. CONCLUSION: Based on efficacy, PPI triple or bismuth
triple therapy are recommended as first-line treatment for H. pylori infection.
Quadruple therapy could serve as second-line treatment for eradication of initial
failures and in case of metronidazole resistance.
PMID- 9398909
TI - Immune evasion by Helicobacter pylori: gastric spiral bacteria lack surface
immunoglobulin deposition and reactivity with homologous antibodies.
AB - BACKGROUND: Helicobacter pylori infection persists in the presence of potent
serum and gastric mucosal antibody responses against bacterial antigens. The aim
of this article is to report on a study determine whether there is antibody
deposition on H. pylori in vivo in the stomach of infected patients and whether
gastric and cultured forms of H. pylori differ in their antibody reactivity.
MATERIALS AND METHODS: Serum, gastric biopsies, and antral brushings were
obtained from 10 patients having endoscopy. H. pylori was cultured from gastric
biopsies. Bacterial samples were stained directly for immunoglobulin deposition
and indirectly using rabbit antiurease serum or patient serum. Samples were
examined by immunofluorescence microscopy and flow cytometry. RESULTS: Although
spiral bacteria could be identified easily by acridine orange staining and
antiurease staining of gastric brushings from H. pylori infected patients,
gastric bacteria did not have detectable IgG or IgA present, and only one of five
samples could be stained for IgG and IgA indirectly using patient serum. In
contrast, cultured bacteria could be stained readily with homologous serum for
IgG and IgA in the majority of cases. Low pH inhibited immunoglobulin reactivity
with cultured H. pylori. CONCLUSIONS: Gastric H. pylori may evade humoral defense
owing to poor deposition of immunoglobulin in the gastric environment or failure
to express surface antigens that are present on cultured forms of H. pylori.
PMID- 9398911
TI - Natural and experimental Helicobacter mustelae reinfection following successful
antimicrobial eradication in ferrets.
AB - BACKGROUND: Recrudescence or reinfection may occur after eradication of
Helicobacter pylori in humans. MATERIALS AND METHODS: We used the ferret
Helicobacter mustelae model to investigate the effect of prior infection and
eradication on reinfection by experimental and natural routes. Two groups of
ferrets with naturally acquired H. mustelae infection were treated with an
eradication protocol using amoxicillin, metronidazole, and bismuth subsalicylate.
The ferrets were monitored for recrudescence by repeated cultures of endoscopic
gastric mucosal biopsies. The ferrets were challenged at 17 months (group I) and
6 months (group II) after eradication with a strain of H. mustelae having a
distinctive restriction endonuclease analysis pattern. The eradication protocol
was repeated to eliminate the infection produced by experimental challenge. The
ferrets were then cohoused intermittently with naturally infected ferrets.
RESULTS: The original H. mustelae infection was successfully eliminated by the
eradication protocol. No recrudescence was observed in group I for 12 months nor
for 3 months in group II after eradication. All ferrets became persistently
reinfected with the challenge strain. The infection from the challenge strain was
eradicated successfully. No ferrets in group I and all ferrets in group II became
infected through cohousing. CONCLUSIONS: These results suggest that though prior
infection with H. mustelae may confer some protection against reinfection, such
protection is not universal in all circumstances; that susceptibility to
reinfection by contact with infected animals varies between individuals; and that
age may be a factor in this individual variability. These results are applicable
to studies of reinfection after eradication of H. pylori in humans.
PMID- 9398910
TI - Susceptibility of Helicobacter pylori to the bactericidal activity of human
serum.
AB - BACKGROUND: Human serum represents an important barrier to the entry of most
mucosal organisms into tissues and to the systemic circulation. If at all
present, Helicobacter pylori within gastric tissue is rare, and bacteremia for
this organism has been described only once. METHODS: To assess the susceptibility
of H. pylori to the bactericidal activity present in normal human serum (NHS), we
examined 13 H. pylori isolates. To assess the contributions of the classical and
alternative complement pathways to killing, we added either C2-deficient or
factor B-deficient serum, respectively, to heat-inactivated NHS. Also we assessed
the ability of the strains to bind 125I-C3. RESULTS: After incubation for 60
minutes at 37 degrees C, all 13 H. pylori strains were killed by NHS; heating to
56 degrees C for 30 minutes ablated killing, indicating complement dependence for
this phenomenon. In the absence of an antibody source, there was no killing when
either an alternative or classical complement pathway source was used. Adding B
deficient serum to heat-inactivated normal human serum did not restore killing,
but adding C2-deficient serum permitted partial killing. All of the 13 strains
bound 125I-C3. Although the kinetics varied from strain to strain, C3 bound was
significantly correlated (r = 0.61, p = 0.03) with serum susceptibility.
CONCLUSIONS: H. pylori are susceptible to complement, alternative pathway
activation appears critical, and C3 binding is a major locus of variability.
PMID- 9398912
TI - Characterization and therapy for experimental infection by Helicobacter mustelae
in ferrets.
AB - BACKGROUND: Numerous clinical trials evaluating the efficacy of various
antimicrobial compounds against Helicobacter pylori infection have been performed
in humans. A convenient animal model for Helicobacter infection would facilitate
the evaluation of novel therapies. These experiments were performed to evaluate
the use of ferrets as a model of Helicobacter infection. MATERIALS AND METHODS:
Ferrets were infected experimentally with Helicobacter mustelae and subsequently
treated with bismuth subsalicylate (BSS) triple therapy (BSS, metronidazole, and
amoxicillin), or left untreated. The status of infection and serology was
assessed during treatment and for 8 weeks posttreatment. Seven ferrets
successfully treated with triple therapy were challenged with H. mustelae and
monitored for infection for an additional 5 weeks. RESULTS: Infection of ferrets
by H. mustelae was accompanied by gastritis and a specific antibody response.
Treatment of H. mustelae-infected ferrets with BSS suppressed bacterial growth in
four of nine animals but did not eradicate infection. Triple therapy eradicated
infection in all nine ferrets with a reduction in gastric inflammation. No
relapse of infection occurred up to 8 weeks posttherapy. Challenge with H.
mustelae of ferrets successfully treated with triple therapy resulted in a 100%
rate of reinfection. CONCLUSIONS: H. mustelae infection can be eliminated by
triple therapy, but this does not result in protective immunity against
reinfection by H. mustelae. This model, using a strain of Helicobacter indigenous
to the host, may be useful for assessing therapeutic efficacy of novel therapies
for the treatment of human infection by H. pylori.
PMID- 9398913
TI - Atrophic changes of gastric mucosa are caused by Helicobacter pylori infection
rather than aging: studies in asymptomatic Japanese adults.
AB - BACKGROUND: The current study was designed to evaluate the effect of aging and
Helicobacter pylori infection on the gastric mucosa in asymptomatic Japanese
adults. MATERIALS AND METHODS: Eighty-five asymptomatic healthy adults were
recruited from a health-screening center in Sapporo. All subjects underwent
endoscopy and gastric biopsy, and serum was obtained for IgG antibodies to H.
pylori, serum gastrin, and pepsinogen levels. RESULTS: The prevalence of atrophic
change of the gastric mucosa assessed by pathological findings increased with age
(49% in the 30- to 39-year-old group compared to 89% in those 60 years and older,
p < .001). The frequency of intestinal metaplasia also increased with age (38% in
the 30- to 39-year-old group compared to 82% in those 60 years and older, p <
.001). In contrast, the frequency of atrophic gastritis and intestinal metaplasia
was extremely low in the H. pylori seronegative group regardless of age. Mean
serum gastrin level in H. pylori-positive adults was significantly greater than
in those who were H. pylori-negative (114.3 +/- 11.2 compared to 65.8 +/- 6.5
pg/ml, p < .03). The serum pepsinogen I-II ratio was significantly lower in those
with H. pylori infection than in those without (3.1 compared to 6.6, p < .0001).
CONCLUSIONS: These results suggest that the chronological changes in the gastric
mucosa in Japanese individuals are either entirely related to H. pylori infection
or the process is greatly accelerated by H. pylori infection.
PMID- 9398914
TI - An increase in Helicobacter pylori strains resistant to metronidazole: a five
year study.
AB - BACKGROUND: Metronidazole is one of the most commonly used antimicrobial agents
for the treatment of Helicobacter pylori infection. Resistance to metronidazole
has been reported worldwide but with a wide range of prevalence. We started using
the classical triple therapy (bismuth, tetracycline, and metronidazole) for H.
pylori infection in 1991 but recently have experienced a decline in its efficacy
in curing the infection. Thus our aim was to investigate in a single center the
prevalence of metronidazole-resistant H. pylori over a period of 5 years.
MATERIALS AND METHODS: A total of 1,015 different H. pylori strains collected
over a period of 5 years were tested for sensitivity against metronidazole,
ampicillin, tetracycline, and imipenem. Antibiotic sensitivity was tested by the
disk diffusion and agar dilution methods. To elucidate further the possible
relationship between these metronidazole-resistant strains, genomic DNA digestion
by the Hae III endonuclease and ribotyping were undertaken in a selected group of
isolates. RESULTS: In 1991, 29 of 132 (22.0%) tested strains of H. pylori were
found to be resistant to metronidazole. Since our initiation at that time of a
triple therapy of bismuth, metronidazole, and tetracycline, the prevalence of
metronidazole-resistant strains rose rapidly to 73.2% in 1995. All H. pylori
isolates were sensitive to ampicillin, tetracycline, and imipenem. A high degree
of genomic heterogeneity was found among these isolates. Thus it is unlikely that
the resistant strains of H. pylori were originated from a single clone.
CONCLUSIONS: This study shows a rapid increase in metronidazole-resistant H.
pylori with the use of an anti-Helicobacter regimen that contains metronidazole.
We anticipate that the efficacy of metronidazole-containing anti-Helicobacter
regimens will decline with the rapid rise in resistant strains of H. pylori.
PMID- 9398915
TI - Culture of Helicobacter pylori: effect of preimmersion of biopsy forceps in
formalin.
AB - BACKGROUND: Treatment of antibiotic-resistant Helicobacter pylori should be based
on bacterial sensitivity testing that requires the ability to isolate the
bacterium from gastric mucosal biopsies. The aim of this study was to determine
whether the yield for detecting H. pylori infection by culture is reduced by
immersion of biopsy forceps in formalin prior to obtaining the specimen.
MATERIALS AND METHODS: Gastric antral mucosal biopsies (100 specimens) from 50
patients were obtained for culture of H. pylori. An antral biopsy was taken for
culture, and with the same forceps a biopsy was taken for histological
examination. The biopsy specimen was removed by shaking, whereas the forceps was
immersed in 10% buffered formalin for the histological investigation. The forceps
was then used without rinsing to obtain a second specimen for culture from an
area adjacent to the first site. H. pylori status was determined by histological
assessment with the Genta stain and a rapid urease test. RESULTS: Fifty patients
with H. pylori infection documented by histological inquiry and positive rapid
urease testing entered the study; 29 had duodenal ulcers, 5 had gastric ulcers, 1
had mucosal associated lymphoid tissue (MALT) lymphoma, and 15 were without ulcer
disease. The results of culture both before and after immersion in formalin were
identical. One patient had both cultures negative; the sensitivity of culture for
detection of H. pylori infection was 98% (95% confidence interval = 93%-100%).
CONCLUSION: Preimmersion of biopsy forceps in formalin does not adversely affect
the ability to culture H. pylori.
PMID- 9398916
TI - The influence of Helicobacter pylori status on circulating levels of the
coagulation factors fibrinogen, von Willebrand factor, factor VII, and factor
VIII.
AB - BACKGROUND: Helicobacter pylori (H. pylori) infection has been associated with an
increased risk of developing ischemic heart disease (IHD). It has been suggested
that a persisting low-grade acute phase response results from the chronic
inflammation caused by H. pylori infection, which may give rise to increased
circulating levels of certain coagulation factors. MATERIALS AND METHODS: One
hundred three (53 male) nonconsecutive, randomly selected white subjects with
symptoms of dyspepsia were recruited for study from an outpatient endoscopy
clinic at Leeds General Infirmary. The presence of H. pylori was determined by
histological and microbiological investigation, a rapid urease test, and a
13carbon urea breath test (13C-UBT). Fibrinogen was measured by the Clauss
method, factor VIII:C (FVIII:C) and factor VII:C (FVII:C) were measured by
clotting rate assays, and the von Willebrand factor (vWF) was determined by an
enzyme-linked immunosorbent assay. RESULTS: No difference was found in levels of
coagulation factors according to H. pylori status. Multiple regression models
were used to account for the effect of covariates and H. pylori status on levels
of FVII:C, FVIII:C, vWF, and fibrinogen, and again H. pylori status was not a
significant determinant of levels of any of these coagulation factors. No
difference occurred in full blood count, platelet count, white cell count, or
plasma viscosity in individuals who were H. pylori-positive compared with those
who were negative. CONCLUSIONS: H. pylori infection is not associated with
increased circulating levels of fibrinogen, FVII:C, vWF.Ag, or FVIII:C or
hemorrheology in this patient group.
PMID- 9398918
TI - Sodium cromoglycate ophthalmic solution as a Pharmacy Medicine for the management
of mild-to-moderate, non-infectious inflammation of the conjunctiva in adults.
PMID- 9398917
TI - Assessment of vision behind cataracts.
PMID- 9398919
TI - Gonioscopy: evaluation of the anterior chamber angle. Part I.
PMID- 9398920
TI - The clinical features and classification of diabetic retinopathy.
PMID- 9398922
TI - Has head and neck surgery a real future?
PMID- 9398921
TI - Fibroblasts obtained from human nasal, laryngeal and tracheal mucosa produce the
chemokine RANTES.
AB - RANTES is a chemokine that was already found in tissues obtained from nasal
polyps of patients suffering from chronic polypous sinusitis and in lung biopsies
of patients suffering from bronchial asthma. Nasal fibroblasts could be shown to
be a cellular origin of RANTES. The aim of this study was to investigate whether
human nasal, laryngeal and tracheal mucosa fibroblasts are differentiated in
production of RANTES. Fibroblasts obtained from healthy human nasal, laryngeal
and tracheal mucosa, were cultured. Secretion of RANTES-protein in supernatants
was investigated after stimulation with 50 ng/ml tumor necrosis factor-alpha (TNF
alpha), interleukin-1-beta (IL-1-beta), lipopolysaccharide (LPS), phorbolmyrisate
acetate (PMA), interferon-gamma (IFN-gamma) and serum-free medium (SFM) for 24
hours. Cultivated nasal, laryngeal and tracheal fibroblasts secreted RANTES
protein upon TNF-alpha, IL-1-beta and IFN-gamma stimulation. The amounts of
RANTES-protein production ranged from 10 ng/ml (PMA) to 198 ng/ml (TNF-alpha).
Secretion of significant amounts of RANTES-protein were detected in the
supernatants from either nasal, laryngeal or tracheal fibroblasts. There was no
significant difference between the differential fibroblasts. We conclude that
nasal, laryngeal and tracheal fibroblasts could be a cellular source of RANTES in
nasal and bronchial mucosa or in secrets of patients suffering from diseases
where eosinophilic tissue infiltration represents a characteristic
histopathological feature. Results suggest that additional local factors are
needed to develop asthma bronchiale and chronic polypous sinusitis.
PMID- 9398923
TI - Assessment of genetic susceptibility as a risk factor for head and neck squamous
cell carcinoma.
PMID- 9398924
TI - Minimal invasive ear, nose and throat surgery--advances through modern
technologies.
AB - Three fundamentals have to be fulfilled to optimize minimally invasive surgery:
three-dimensional imaging, free maneuverability of the instruments, sensorial
feedback. Projection of two pictures from a stereoendoscope and subsequent
separation with a LCD shutter allows three-dimensional videoendoscopy to be
performed. A high frequency shutter technique (100/120 Hz) presents pictures from
the two video cameras to the right and left eye, respectively, so that the
surgeon has spatial vision of the operative field. Steerable instruments have
four components: a control unit, rigid shaft, steerable multijoint, distal
effector. The steerable multijoints give two additional degrees of freedom
compared to conventional rigid instruments in endoscopic surgery. For intuitive
movements, however, an electronic control system is necessary that is comparable
to the "master slave" priniciple in remote technology. A remote manipulator
system with six degrees of freedom is now available. Additionally, a
multifunctional distal tip permits different surgical steps to be performed
without changing the instrument. For better control of the instrument and the
operative procedure tactile feedback can be achieved with appropriate microsensor
system. Recent projects suggest that an artificial sensor system can be
established within the foreseeable future.
PMID- 9398925
TI - The link between substance abuse and posttraumatic stress disorder in women. A
research review.
AB - Research has documented a high incidence of comorbid post-traumatic stress
disorder (PTSD) and substance abuse. Women substance abusers, in particular, show
high rates of this dual diagnosis (30% to 59%), most commonly deriving from a
history of repetitive childhood physical and/or sexual assault. Rates for men are
two to three times lower and typically stem from combat or crime trauma. Patients
with both disorders are characterized by high severity on a multitude of
psychological and treatment variables and use of the most severe drugs (cocaine
and opioids). Treatment research on women is limited but suggests the possibility
of retaining patients and achieving positive outcomes.
PMID- 9398926
TI - Course and severity of substance abuse among patients with comorbid major
depression.
AB - The authors assessed the course and severity of substance-related disorder (SRD)
among patients with comorbid major depressive disorder (MDD) by means of both
retrospective and concurrent data. A total of 642 patients were assessed. Data on
course included lifetime use, age at first use, years of use, use in the last
year; periods of abstinence, and current diagnosis. Data on severity included two
measures of SRD-associated problems, substance abuse vs. dependence, self-help
activities, and number of substances being abused. SRD-MDD patients tended to
manifest lower levels of cannabis, opiate, and cocaine use, and more SRD-only
patients were abusing three or more substances. Men with SRD-MDD demonstrated
longer mean durations of abstinence compared with men with SRD-only, whereas SRD
MDD women demonstrated shorter mean durations of abstinence, compared with women
with SRD-only. MDD-SRD patients showed slightly less substance abuse, but SRD
severity was comparable with SRD-only patients.
PMID- 9398927
TI - Retention in substance abuse treatment. Role of psychiatric symptom severity.
AB - The authors investigated the association between psychiatric symptom severity and
subsequent treatment retention among substance abusers. The Symptom Check List-90
R was administered, after admission to an addiction treatment facility, to 308
male and 106 female clients with moderate-to-severe substance abuse problems.
Mean scores on nine symptom and three summary scales were computed. Controlling
for other sociodemographic and treatment variables, somatization was
significantly associated with dropout from specialized outpatient and inpatient
treatment programs. This study, however, suggests that psychopathologic symptom
severity at admission has only limited utility in predicting subsequent treatment
retention among substance abusers with overall moderate levels of psychological
distress.
PMID- 9398928
TI - Suicide and alcoholism. Distinguishing alcoholic patients with and without
comorbid drug abuse.
AB - Psychological autopsy data were used to test the hypothesis that alcoholic
patients with comorbid drug use disorders who committed suicide (A + D; n = 26)
are distinguishable from alcoholic suicide victims without a comorbid drug use
disorder (A; n = 35). Dependent variables included demographics, suicidal
behavior; psychiatric symptoms, and medical illness burden. The A group were
older, white, and tended to be living alone. Analyses that controlled for age and
sex indicated that As were more likely to have had a comorbid major depression
and less likely to tell someone they were contemplating suicide. Scores on a
measure of illness burden increased with age among the A group but not the A + D
group, though the latter were more likely to be under a physician's care with
increasing age. These differences should be considered when designing preventive
measures.
PMID- 9398929
TI - Differences between men and women in dual-diagnosis treatment.
AB - The authors reviewed the charts of all women and a randomly selected sample of
men over a 6-month period on two addiction treatment units at Bellevue Hospital
Center in New York. The men were more likely to be admitted with schizophrenia
and to have used substances of abuse other than alcohol, and the women were more
likely to be admitted with affective disorders. Also, the women on the dual
diagnosis ward were more likely to be domiciled (i.e., not homeless), and the
women on both units were significantly more likely to report having been crime
victims. These findings suggest that dually diagnosed women need a substantially
different treatment paradigm from men.
PMID- 9398930
TI - Associations between ADHD and psychoactive substance use disorders. Findings from
a longitudinal study of high-risk siblings of ADHD children.
AB - This article investigates the relationship between attention
deficit/hyperactivity disorder (ADHD) and psychoactive substance use disorders
(PSUD) in siblings of ADHD and normal-control probands and addresses issues of
psychiatric comorbidity and gender. Using DSM-III-R structured diagnostic
interviews and blind raters, the authors conducted a 4-year follow-up of
siblings. ADHD and male gender predicted higher rates and an earlier onset of
PSUD after adjusting for high-risk status, other psychiatric disorders, and age.
Risk was particularly high if the siblings had ADHD plus conduct disorder. This
study's findings confirms the authors' prior report high-lighting the importance
of drug and alcohol prevention and cessation programs aimed at ADHD youth and
their siblings, particularly those with comorbid conduct disorder.
PMID- 9398931
TI - Managing disability benefits as part of treatment for persons with severe mental
illness and comorbid drug/alcohol disorders. A comparative study of payee and non
payee participants.
AB - The objective of this pilot study is to describe the use of a Social Security
representative payee program as a clinical intervention integrated into long
term, dual-disorder treatment of severely mentally ill outpatients with comorbid
drug/alcohol disorders. Compared with non-payees, patients selected to be payee
participants were more likely to be male, have a diagnosis of schizophrenia, have
a history of high inpatient utilization, and have higher current ratings of
psychiatric symptoms, substance use, and functional disability. Despite these
higher severity ratings, which usually predict poor outpatient compliance and
higher rate of adverse outcomes, the payee participants attended about twice the
number of outpatient service sessions as non-payees and were no more likely to be
currently homeless, hospitalized, or incarcerated. The payee intervention is
described, and ethical and research issues are discussed.
PMID- 9398932
TI - Methadone vs. L-alpha-acetylmethadol (LAAM) in the treatment of opiate addiction.
A meta-analysis of the randomized, controlled trials.
AB - The authors conducted a meta-analysis of the reported randomized, controlled
trials comparing methadone to L-alpha-acetylmethadol (LAAM) to assess the
efficacy of LAAM relative to methadone in the treatment of opiate addiction. All
studies were conducted in standard outpatient opiate addiction treatment clinics.
Most patients were men from lower socioeconomic strata. A statistically
significant risk difference favoring methadone was detected for retention-in
treatment and discontinuation of treatment because of side effects. The risk
difference for illicit drug use favored LAAM, but was not significant. A small
treatment difference in favor of methadone was noted. LAAM does appear to be a
relatively effective alternative in the treatment of opiate addiction, more so in
certain select situations.
PMID- 9398934
TI - Addressing epistemologic and practical issues in multimethod research: a
procedure for conceptual triangulation.
AB - Although a combination of quantitative and qualitative methods are being used
increasingly in nursing research, little practical advice exists about the
conduct of such studies. Conceptual triangulation offers one approach to
multimethod research, addressing epistemologic and practical issues that have
long plagued investigators. Conducting quantitative and qualitative research as
parallel studies and using method-specific criteria for rigor provide an
alternative to blending methodologic assumptions. Systematic examination of the
support for findings guides judgments about model development, and the provision
for multiple conceptual models resolves issues about the interpretation of
findings.
PMID- 9398935
TI - Constructivism: a naturalistic methodology for nursing inquiry.
AB - This article will explore the philosophical underpinnings of the constructivist
research paradigm. Despite its increasing popularity in evaluative health
research studies there is limited recognition of constructivism in popular
research texts. Lincoln and Guba's original approach to constructivist
methodology is outlined and a detailed framework for nursing research is offered.
Fundamental issues and concerns surrounding this methodology are debated and
differences between method and methodology are highlighted.
PMID- 9398936
TI - Expanding the praxis debate: contributions to clinical inquiry.
AB - Nursing science continues to debate the adequacy of various philosophic paradigms
for their ability to forward the discipline. Nursing must embrace multiple
paradigms, methodologies, and their philosophic assumptions to adequately address
the complex and multifaceted human phenomena that is the focus of clinical
inquiry in nursing. This article examines the differences in interpretive and
critical approaches to clinical inquiry relative to praxis, expanding how praxis
can be used to inform nursing practice. Differences in the nature of knowledge,
goals of inquiry, and claims to praxis between the interpretive and critical
traditions are discussed. Praxis, realized through clinical inquiry in both the
interpretive and the critical paradigms, may contribute important pieces of the
puzzle to improve the human condition. Expanding the praxis debate challenges
nurses to consider the emancipatory possibilities of clinical inquiry within both
interpretive and clinical paradigms.
PMID- 9398937
TI - Advocacy oral history: a research methodology for social activism in nursing.
AB - The reinstatement of social activism as a central feature of nursing practice has
been advocated by nursing scholars and is consistent with contemporary
conceptualizations of primary health care and health promotion that are rooted in
critical social theory's concept of empowerment. Advocacy oral history from a
feminist postmodern perspective offers a method of research that has the
potential and purpose to empower participants to transform their political and
social realities and may, therefore, be considered social activism. A recent
study of public health nurses who had experienced significant distress through
the reduction and redirection of their practice is provided as an exemplar of
advocacy oral history. Philosophies underpinning the research method and
characteristics of feminist postmodern research are reviewed and implications for
the use of this methodology for social activism in nursing are drawn.
PMID- 9398938
TI - The facilitator in participatory action research: les raisons d'etre.
AB - Participatory action research (PAR) is a form of qualitative inquiry that posits
a collaborative, self-reflective process among its participants to develop
knowledge. The researcher, along with the participants in this critical research
process, identify and illustrate their individual concerns, beliefs, and values.
The role of the researcher, as facilitator, is an extremely important social and
political position within the participant group, within nursing, and within
society. However, how the nurse as facilitator initially "guides" the discussions
within the participatory group is a contentious issue for researchers involved in
PAR.
PMID- 9398939
TI - Summary oral reflective analysis: a method for interview data analysis in
feminist qualitative research.
AB - This article explores an innovative approach to qualitative data analysis called
Summary Oral Reflective Analysis (SORA). The method preserves the richness and
contextuality of in-depth interview data within a broader feminist philosophical
perspective. This multidisciplinary approach was developed in two individual
research programs within a cooperative, collaborative arrangement. It represents
a creative response to perceived deficiencies in the pragmatics of qualitative
data analysis where the maintenance of data contextuality is critical.
PMID- 9398940
TI - Secondary analysis of qualitative data.
AB - Secondary analysis of qualitative data is a valid mode of clinical inquiry.
However, there is limited information available on its use in nursing. This
article describes the use of secondary analysis for a study of family caregivers
of relatives with dementia. The advantages, limitations, and application of
secondary analysis are outlined; data management, analysis, and rigor are also
discussed. The article concludes that this method is cost-effective, decreases
respondent burden, and is a useful research method for students. However, the
secondary analyst must be aware of the limitations of using secondary analysis of
qualitative data.
PMID- 9398941
TI - The responsive use of self in community health nursing practice.
AB - This interpretive study examined the expertise that is often unrecognized in the
everyday practice of community health nurses. Twenty-five nurses participated in
the study and were asked to describe meaningful clinical situations during group
and individual interviews. Field notes of observations of clinical situations and
transcribed interviews were analyzed as a text. A major finding of the study
involved the nurse's responsive use of self. Responsiveness to the other enabled
the nurse to gain a situated understanding of clients' lives and to cultivate
clients' strengths and connections to a responsive community.
PMID- 9398943
TI - The mechanism for the effect of selenium supplementation on immunity.
AB - Lipid peroxide (LPO) in lymphocytes from mice was evaluated by measuring
substances reactive to thiobarbituric acid (TBA). The product resulting from the
reaction of TBA with lymphocytes was extracted with n-butyl and fluorescence
intensity was determined. The degree of lipid peroxidation, expressed as
fluorescence intensity f547, was assessed for stimulation of lymphocytes with
concanavalin A (Con A), and was related to lymphocyte proliferation in response
to Con A if Se was administered. The lymphocyte proliferation was determined by
[3H]thymidine incorporation, expressed as cpm. The effect of superoxide dismutase
(SOD), added to cell culture on lymphocyte proliferation was also evaluated. It
was found that LPO in lymphocytes before Con A stimulation was significantly less
than that after stimulation (p < 0.001), and that SOD promoted lymphocyte
proliferation dose dependently. The addition of Na2Seo3 to lymphocyte culture or
supplementation in drinking water to mice decreased the produced LPO in
lymphocyte in response to Con A. In the presence of Se, there is an inverse
correlation between the levels of LPO in lymphocyte and the stimulated
proliferation (r = -0.8902, r = -0.9439). In conclusion, active oxygen species
scavenging was proposed as one of the mechanisms for Se to promote immunity.
PMID- 9398942
TI - Activities of liver microsomal fatty acid desaturases in zinc-deficient rats
force-fed diets with a coconut oil/safflower oil mixture of linseed oil.
AB - The present study was conducted to investigate the effect of zinc deficiency on
fatty acid desaturation in rats fed two different types of dietary fat, a mixture
of coconut oil and safflower oil (7:1, w/w, "coconut oil diet") or linseed oil
("linseed oil diet"). In order to ensure an adequate food intake, all rats were
force-fed by gastric tube. Zinc deficiency caused statistical significant
reduction of delta 9-desaturase activity in liver microsomes of rats fed coconut
oil diet and tendencial reduction (p < 0.15) in rats fed linseed oil diet
compared with control rats fed diets with the same type of fat. In agreement with
this effect, zinc deficiency in the rats fed both types of dietary fat increased
the ratio between total saturated and total monounsaturated fatty in liver
phospholipids and liver microsomes. Zinc deficient rats on the coconut oil diet
had unchanged delta 6-desaturase activity with linoleic acid as substrate and
lowered activity with alpha-linolenic acid as substrate. In contrast, zinc
deficient rats on the linseed oil diet had increased delta 6-desaturase activity
with linoleic acid as substrate and unchanged activity with alpha-linolenic acid.
Because linoleic acid is the main substrate for delta 6-desaturase in the rats
fed coconut oil diet, and alpha-linolenic acid is the main substrate in the rats
fed linseed oil diet, it is concluded that in vivo delta 6-desaturation was not
changed by zinc deficiency in the rats fed both types of dietary fat. Activity of
delta 5-desaturase was also not changed by zinc deficiency in the rats fed both
dietary fats. Levels of fatty acids in liver phospholipids and microsomes derived
by delta 4-, delta 5-, and delta 6-desaturation were not consistently changed by
zinc deficiency in the rats fed both types of dietary fat. Thus, the enzyme
studies and also fatty acid composition data of liver phospholipids and
microsomes indicate that zinc deficiency does not considerably disturb
desaturation of linoleic and alpha-linolenic acid. Therefore, it is suggested
that similarities between deficiencies of zinc and essential fatty acids
described in literature are not due to disturbed desaturation of linoleic acid in
zinc deficiency. The present study also indicates that zinc deficiency enhances
incorporation of eicosapentaenoic acid into phosphatidylcholine of rats fed diets
with large amounts of n-3 polyunsaturated fatty acids.
PMID- 9398944
TI - Effect of selenium in recovery of immunity damaged by H2O2 and 60Co radiation.
AB - Con A stimulated lymphocytes proliferation was measured as [3H]thymidine
incorporation and IgG was quantified by single radial immunodiffusion to study
recovering or protecting effect of selenium (Se) on immunity attacked by
exogenous active oxygen species, H2O2 and 60Co-radiation, respectively. Lipid
peroxidation was also determined to observe the relation between antioxidation
ability and protecting ability of Se. It was found that H2O2 injured lymphocytes
immunocompetence deeply and 60Co-radiation decreased immune response capacity
greatly, but that administration of Se counteracts this damage. The antioxidative
ability of Se was correlated with its protecting ability.
PMID- 9398945
TI - Chemical speciation of arsenic in urine of patients with blackfoot disease.
AB - Blackfoot disease is a peripheral vascular disease resulting in gangrene of the
lower extremities. Although extensive epidemiological study has implicated high
arsenic content in artesian well water of the endemic area bears some important
connection with the disease, the etiology of the disease is still not clarified.
In this study, attention is paid to chemical speciation of arsenic in order to
find out whether the concentrations of arsenic species in urine of Blackfoot
disease patients are different from those of controls. Experimental results
indicate that the total arsenic, inorganic arsenic, monomethylarsonic acid, and
other forms of arsenic in the urine of patients are significantly higher than
those of the controls. The possible connection of those arsenic species with the
etiology of the disease is discussed.
PMID- 9398946
TI - Trace element concentration and arsenic speciation in the well water of a Taiwan
area with endemic blackfoot disease.
AB - Blackfoot disease is a peripheral vascular disease resulting in gangrene of the
lower extremities. Although extensive epidemiological study has implicated high
arsenic content in artesian well water in the endemic area, there is more to
learn about the etiology of the disease. In this study, effort is paid on
multielement determination and arsenic speciation in order to find out whether
the trace element concentration pattern in well water in the Blackfoot disease
endemic area is different from those of two control areas. Experimental results
indicate that the concentrations of Fe, P, Na, and Ba in well water in the
Blackfoot disease endemic area are found to be significantly higher than those of
the controls, but they are still below the drinking water standard. The total
arsenic in well water in the endemic area (671 +/- 149 ppb) is much higher than
that of one normal control area of Hsin-Chu (< 0.7 ppb), but is a similar level
as that of other control areas of I-Lan (653 +/- 71 ppb) where no Blackfoot
disease has ever been found. It was also found that the insoluble arsenic in the
endemic area (21.9 ppb) is much higher than that in two control areas (< or = 1.8
ppb), and the concentration ratio between As(III) and As(V) species in the
endemic area (2.6) is much lower than that in one of the control areas, where the
total arsenic is also high (14.7). The possible connection of Blackfoot disease
with trace elements, arsenic species, and possibly other as yet undefined
environmental factors in the artesian well water, is discussed.
PMID- 9398947
TI - Time course effects of vanadium supplement on cytosolic reduced glutathione level
and glutathione S-transferase activity.
AB - The influence of vanadium, an important dietary micronutrient, was evaluated on
the cytosolic reduced glutathione (GSH) content and glutathione S-transferase
(GST) activity in several rat target tissues. Supplementation of drinking water
with vanadium at the level of 0.2 or 0.5 ppm for 4, 8, or 12 wk was found to
increase the GSH level with a concomitant elevation in GST activity in the liver
followed by small intestine mucosa, large intestine mucosa, and kidney. The
results were almost dose-dependent and mostly pronounced with 0.5 ppm vanadium
after 12 wk of its continuous supplementation. Neither the GSH level nor GST
activity was significantly altered in forestomach and lung following vanadium
supplementation throughout the study. The levels of vanadium that were found to
increase the content of GSH and activity of GST in the liver, intestine, and
kidney did not exert any toxic manifestation as evidenced from water and food
consumption as well as the growth responses of the experimental animals.
Moreover, these doses of vanadium did not impair either hepatic or renal
functions as they did not alter the serum activities of glutamic oxaloacetic
transaminase (GOT), glutamic pyruvic transaminase (GPT), sorbitol dehydrogenase
(SDH), as well as serum urea and creatinine level. All these results clearly
indicate that vanadium under the doses employed in our study has a significant
inducing role on GSH content with a concurrent elevation in GST activity in the
liver and specific extrahepatic tissues without any apparent sign of
cytotoxicity. This attribute of vanadium may have a greater importance in terms
of biotransformation and detoxification of xenobiotics, including carcinogens. In
addition, since the ability to afford an increment in the endogenous GSH-GST pool
by anticarcinogenic natural substances has been found to correlate with their
activity to inhibit neoplastic transformation, the trace element vanadium may be
considered as a novel anticancer agent.
PMID- 9398949
TI - Neuromuscular relaxants--1997.
PMID- 9398948
TI - Effects of nickel oxide on the production of tumor necrosis factor by alveolar
macrophages of rats.
AB - To evaluate the effect of green nickel oxide (NiO) on the production of tumor
necrosis factor (TNF) by alveolar macrophages, alveolar macrophages were exposed
to NiO in vitro and in vivo. For the in vitro study, rats alveolar macrophages
were incubated with NiO on a microplate for 24 h. TNF activity in the culture
supernatant was determined by the L929 bioassay. Rats alveolar macrophages
cultured with 100 and 200 micrograms/mL of NiO in vitro induced the production of
TNF, however, it was not statistically significant compared with the control that
was free from NiO exposure. For exposure in vivo, rats were divided into two
groups. Five were exposed to a daily concentration of 11.7 +/- 2.0 mg/m3 of NiO
for an 8-hr/d, 5 d/wk, for 4 wk, and five rats (control) were kept in a cage and
not exposed to NiO. Bronchoalveolar lavage was performed and the recovered
alveolar macrophages were incubated on a microplate for 24 h. TNF production by
exposed alveolar macrophages was significantly higher than that of controls.
PMID- 9398950
TI - Comparison of vecuronium with ORG 9487 and their interaction.
AB - PURPOSE: To compare the pharmacodynamic behaviour of vecuronium with that of ORG
9487, we measured the time-course of action of equipotent doses of ORG 9487 and
vecuronium and investigated their mutual interaction when given in succession.
METHODS: Sixty ASA I-II patients were anaesthetized with thiopentone, fentanyl,
halothane and nitrous oxide and assigned randomly to four groups. Each patient
received an initial dose (ID) of either vecuronium (V) or ORG 9487 (O) followed
by maintenance doses (MDn) of either V or O (ID/MD: O/O, V/O, O/V, and V/V). The
time course of action was measured mechanomyographically, determining the
duration until 25% recovery of the single twitch (DUR25). RESULTS: The onset time
of an ID of ORG 9487 was shorter than that of an ID of vecuronium (96 vs 203 sec,
P < 0.001). The DUR25 of the ID of ORG 9487 was less than half that of vecuronium
(10.7 +/- 2.8 vs 28.8 +/- 6.1 min, P < 0.001). The DUR25 of MD1 and MD2 of ORG
9487 were shorter than those of vecuronium (O/O: 7.3 +/- 2.8 and 8.5 +/- 2.4 min;
V/O: 12.7 +/- 3.3 and 11.5 +/- 3.5 min, vs O/V: 16.4 +/- 4.5 and 20.6 +/- 4.7
min; V/V: 18.8 +/- 3.0 and 20.1 +/- 3.8 min, respectively, P < 0.05). AN ID of
vecuronium prolonged the DUR25 of MD1 and MD2 of ORG 9487 (P < 0.05). CONCLUSION:
ORG 9487 is a muscle relaxant with a shorter duration of action than vecuronium.
Maintenance doses of ORG 9487 are also shorter acting than roughly equipotent
maintenance doses of vecuronium, irrespective of which relaxant is given
initially.
PMID- 9398951
TI - Comparison of rocuronium and d-tubocurarine for prevention of succinylcholine
induced fasciculations and myalgia.
AB - PURPOSE: We compared d-tubocurarine and rocuronium for the prevention of
succinylcholine-induced fasciculations and postoperative myalgia (POM) and
evaluated the influence of both drugs on the speed of onset and recovery of
succinylcholine. METHODS: Seventy-five women undergoing surgery of short duration
were studied. They were randomized to one of three groups: group SAL received
normal saline followed three minutes later by 1.0 mg.kg-1 succinylcholine; group
ROC received 0.05 mg.kg-1 rocuronium + 1.5 mg.kg-1 succinylcholine; group DTC
received 0.05 mg.kg-1 d-tubocurarine + 1.5 mg.kg-1 succinylcholine. Single-twitch
stimulation was applied to the ulnar nerve every 10 sec and the EMG response of
the adductor pollicis was recorded. Fasciculations were assessed by a blinded
observer on a scale of 0-3. Patients were asked 24 and 48 hr later to rate POM
using a scale of 0-10. RESULTS: The interval needed for twitch height to decrease
to 10% of initial value after succinylcholine was longer in group ROC (58 +/- 20
sec) (mean +/- SD) compared with group SAL (44 +/- 13 sec) (P < 0.05). Recovery
to 20% occurred faster in group ROC (324 +/- 83 sec) than in groups SAL (456 +/-
103 sec) and DTC (450 +/-132 sec) (P < 0.05). Fasciculations were more intense in
groups SAL than in groups ROC and DTC (P < 0.001). Patients rated POM as less
intense 24hr postoperatively only in group ROC (1.2 +/- 2.4) compared with group
SAL (3.3 +/- 3.5) (P < 0.05). CONCLUSION: Rocuronium prevents succinylcholine
induced fasciculations and POM. Rocuronium also delays the onset of
succinylcholine and shortens its duration compared with d-tubocurarine.
PMID- 9398952
TI - Physostigmine increases the dose of propofol required to induce anaesthesia.
AB - PURPOSE: This prospective, randomized, double-blind study was performed to
determine the effect of administration of physostigmine on the dose of propofol
required to produce loss of consciousness. METHODS: Forty female unpremedicated
patients were assigned in a random blind design to receive either 2 mg
physostigmine or equal volume of normal saline i.v. five minutes before induction
of anaesthesia with propofol. All patients received general anaesthesia for
breast surgery. Propofol was infused at a constant rate of 200 ml.hr-1 while
patients were breathing oxygen 100% via a face mask. In each patient the dose of
propofol required to produce loss of the ability to grasp a 20 ml syringe was
recorded as the end-point of loss of consciousness. At this point the protocol
was terminated and, after intubation of the trachea, anaesthesia was maintained
with a nitrous oxide-isoflurane or sevoflurane mixture in oxygen, increments of
an opioid and a muscle relaxant. Doses of anaesthetic drugs and duration of
anaesthesia varied and depended on the type of breast surgery, determined by
frozen section. RESULTS: The mean +/- SD dose of propofol required to produce
loss of consciousness was 2.4 +/- 0.6 mg.kg-1 and 2.0 +/- 0.4 mg.kg-1 in the
physostigmine and in the normal saline groups respectively (P = 0.014).
CONCLUSION: Physostigmine pretreatment increases the dose of propofol required to
produce loss of consciousness.
PMID- 9398953
TI - Pharmacoeconomics of intravenous regional anaesthesia vs general anaesthesia for
outpatient hand surgery.
AB - PURPOSE: To compare the cost and effectiveness of intravenous regional
anaesthesia (IVRA) with general anaesthesia (GA) for outpatient hand surgery.
METHOD: A retrospective record analysis of 121 patients who received IVRA were
compared with 64 patients who received GA in our Daycare centre. The costs of
anaesthesia and recovery were calculated from an institutional perspective using
1995 Canadian Dollar values. Effectiveness was measured in terms of time for
anaesthesia, recovery and discharge, % with unsatisfactory anaesthesia and
complications. RESULTS: Both groups were well matched in terms of weight, sex and
ASA class. Patients in the IVRA group were older (45 +/- 16 vs 38 +/- 13 yr) and
had a lower frequency of two types of operation. The median total cost for the
IVRA group of $24.60 (15.76-55.29) was less than that for the GA group of
+f448.66 (35.59-73.11), (P < 0.00001). Anaesthesia was unsatisfactory in 11% of
the IVRA group, but in none having GA,(P < 0.01). Recovery was faster in the IVRA
group with a median time to discharge of 70 (35-180) min compared with 118 (45
320) min in the GA group, (P < 0.00001). Vomiting requiring treatment occurred in
5% of the GA group, but in none having IVRA, (P < 0.05). Dizziness which delayed
discharged also occurred in 5% of the GA group, but in none having IVRA, (P <
0.05). CONCLUSION: The cost of anaesthesia and recovery using IVRA for outpatient
hand surgery was half that of GA. intravenous regional anaesthesia was less
effective than GA in achieving satisfactory anaesthesia, equally effective in
time to administer anaesthesia, and more effective in speeding recovery and
minimising postoperative complications.
PMID- 9398954
TI - Platelet aggregation is impaired during anaesthesia with sevoflurane but not with
isoflurane.
AB - PURPOSE: Halothane suppresses platelet aggregation in vitro and ex vivo, and
prolongs bleeding time. In a previous in vitro study we demonstrated that
sevoflurane had a more suppressive effect on platelet aggregation than did
halothane. The present study investigated whether the clinical use of sevoflurane
affected platelet aggregation ex vivo. METHODS: Thirty-eight patients undergoing
minor elective surgery were divided randomly into sevoflurane and isoflurane
groups. Anaesthesia was induced with thiopentone i.v., and was maintained with
sevoflurane or isoflurane with nitrous oxide. Blood was collected to measure
platelet aggregation induced by adenosine diphosphate (ADP) and epinephrine. The
first (control) blood collection was performed in the operating room before
induction of anaesthesia, and the second 5-10 min after tracheal intubation but
before the start of surgery, when the end-expiratory sevoflurane or isoflurane
concentrations had stabilised at 1-1.5 times the minimum alveolar concentration
(MAC) and mean arterial pressures were between 80-120% of preanaesthetic values.
RESULTS: In all samples obtained during sevoflurane anaesthesia (n = 15), ADP and
epinephrine could not induce secondary aggregation, although they did induce
primary aggregation. In contrast, in the isoflurane group, both primary and
secondary aggregation were observed in 14 out of 15 patients, and secondary
aggregation was abolished in only one of the samples obtained during anaesthesia.
CONCLUSIONS: Sevoflurane, but not isoflurane, alters platelet aggregation in the
clinical situation, possibly by suppression of thromboxane A2 formation.
PMID- 9398955
TI - Arterial oxygenation during one lung ventilation.
AB - PURPOSE: To compare the effects of isoflurane and sevoflurane on arterial
oxygenation and middle cerebral artery blood flow velocity during one lung
ventilation. METHODS: This was a randomized, crossover study in 20 patients
undergoing thoracotomy for oesophageal cancer and scheduled for long term one
lung ventilation (OLV). They were randomized to one of two groups: group A,
firstly isoflurane was administered followed by sevoflurane, and then isoflurane
was resumed; group B, the order of the administration was reversed. Arterial
blood gas samples were drawn at the start of OLV, 30 and 60 min after the
initiation of OLV and the end of OLV (the change of volatile anesthetics was done
30 and 60 min after the start of OLV). Middle cerebral artery (MCA) was monitored
continuously with the probe positioned over the temporal bone window. This probe
transmitted 2 MHZ wave Doppler signals. Time-averaged MCA blood flow velocity was
calculated from the signals. RESULTS: The PaO2 values decreased 30 min after the
start of OLV (364.4 +/- 33.4 mmHg vs 179.0 +/- 19.5, and 338.7 +/- 24.8 mmHg vs
139.7-19.9 in groups A and B respectively), but there was no difference between
the groups. Blood flow velocity of MCA did not change after the start of OLV
(53.1 +/- 3.2, 55.9 +/- 3.0, 56.4 +/- 2.4, and 54.1 +/- 1.9 vs 50.8 +/- 2.1, 50.7
+/- 2.4, 53.7 +/- 1.5, 50.8 +/- 2.2 cm.sec-1 in groups A and B respectively):
there was no difference between the groups. (P < 0.05). CONCLUSION: In clinical
practice, the selection of either isoflurane and sevoflurane for OLV was of no
difference in terms of the arterial blood oxygenation. With both agents MCA blood
flow velocity was maintained during OLV.
PMID- 9398956
TI - Prophylactic oral dolasetron mesylate reduces nausea and vomiting after abdominal
hysterectomy. The Canadian Dolasetron Study Group.
AB - PURPOSE: The incidence of postoperative nausea and vomiting (PONV) varies from
50% to 75% after gynaecological surgery under general anaesthesia. This study
evaluates the dose-response relationships, safety, and efficacy of the new 5-HT3
antagonist, dolasetron mesylate, in the prevention of PONV in women undergoing
total abdominal hysterectomy (TAH). METHODS: Three hundred and seventy four women
scheduled for TAH under general anaesthesia were studied at 13 Canadian centres.
Patients received in a randomized, double-blind manner 25, 50, 100, or 200 mg
dolasetron or placebo po one to two hours before induction of anaesthesia. The
anesthetic protocol was standardized. Efficacy was evaluated for 24 hr after
surgery by comparing the number of emetic episodes, administration of rescue
medication, severity of nausea, and patient satisfaction. RESULTS: Analysis of
complete response (no emetic episodes and no rescue for 24 hr) revealed a linear
dose-response relationship across dolasetron groups (P < 0.002). Dolasetron 100
mg (P < 0.003) and 200 mg (P < 0.01) were superior to placebo. The percentage of
patients with no emetic episodes increased from 29.3% (placebo) to 54.1 % (100
mg). Subgroup analysis revealed ASA status (I > II), previous history of PONV,
previous history of motion sickness, and total morphine dose (> 55 mg associated
with less PONV than < 55 mg) influenced the incidence of emetic symptoms, but did
not alter the results of the primary analysis. CONCLUSION: Prophylactic
dolasetron (100 mg and 200 mg) reduces the incidence of PONV in patients having
total abdominal hysterectomy.
PMID- 9398957
TI - Peripartum management of a patient with Isaacs' syndrome.
AB - PURPOSE: To describe the peripartum management of a patient with Isaacs' syndrome
with specific reference to the anaesthetic implications of the disease process.
Associated medical problems included obesity, pregnancy induced hypertension and
a difficult airway. CLINICAL FEATURES: This 30-yr-old gravida V para 0 woman
presented to the anaesthesia consultation clinic at 37-wk gestation to discuss
pain relief options for labour and delivery. She had a history of Isaacs'
syndrome (a peripheral motor neuron disorder), congenital heart disease (ASD and
VSD), treated Hashimotos thyroiditis, obesity and a family history of
haemachromatosis. On the day of consultation, she was hypertensive and peripheral
oedema was noted. Her urine showed trace protein. Four days later, she presented
to the labour suite and her cervix was 9 cm dilated. An epidural anaesthetic was
given without difficulty and she had an uneventful labour and delivery course.
There were no subsequent neurological complications. CONCLUSION: Isaacs' syndrome
is an extremely rare peripheral motor neuron disorder. This patient was
successfully managed with epidural analgesia for labour and delivered a healthy
child with no congenital anomalies.
PMID- 9398958
TI - Spinal artery syndrome masked by postoperative epidural analgesia.
AB - PURPOSE: We report a case of a patient who developed a postoperative anterior
spinal artery syndrome that was masked by the use of epidural analgesia. We wish
to alert other anaesthetists that the use of epidural anaesthesia in this setting
may mask the symptoms and delay the diagnosis of this rare complication. CLINICAL
FEATURES: The patient was a 22-yr-old obese man with metastatic testicular
carcinoma who underwent a left-sided thoracoabdominal retroperitoneal tumour
resection. A lumbar epidural catheter was placed preoperatively for pain
management. Postoperatively, the patient developed bilateral lower extremity
weakness, which was at first attributed to epidural administration of local
anaesthetics. Despite discontinuation of the local anaesthetics, the symptoms
persisted. Further work-up led to the diagnosis of anterior spinal artery
syndrome. The patient was sent to a rehabilitation hospital and had a partial
recovery. CONCLUSION: Anterior spinal artery syndrome can occur following
retroperitoneal surgery. It is important to recognize the potential for this
complication when postoperative epidural analgesia is contemplated, especially
following a left-sided surgical dissection. The use of epidural local
anaesthetics immediately after surgery delays the diagnosis of a postoperative
neurological deficit. Moreover, when the deficit is recognized the epidural
itself may be falsely blamed for postoperative paraplegia. If epidural analgesia
is used, opioids may be preferred over local anaesthetics in the immediate
postoperative period to prevent masking of an anterior spinal artery syndrome.
PMID- 9398960
TI - Venous air embolism during orthotopic liver transplantation in a child.
AB - PURPOSE: A first case of massive venous air embolism is reported as a
complication of orthotopic liver transplantation in a 17-month-old child during
the dissection phase. CLINICAL FEATURES: During the hepatic dissection phase,
perforation of suprahepatic veins was responsible for an air embolism with a
decrease of P(ET)CO2 (27 to 6 mmHg), hypoxaemia (SpO2 decreased from 100 to 88%),
and haemodynamic instability (systolic blood pressure decreased from 85 to 50
mmHg, central venous pressure increased from 6 to 10 mmHg). Central venous
aspiration of air was unsuccessful but immediate resolution occurred and
neurological outcome was normal. CONCLUSION: Venous air embolism during the
dissection phase of liver transplantation in children is a risk that should be
considered
PMID- 9398959
TI - Continuous haemodiafiltration during and after cardiopulmonary bypass in renal
failure patients.
AB - PURPOSE: Continuous haemodiafiltration (CHDF) is a technique enhancing the
efficiency of solute clearance of haemofiltration by infusing dialysis fluid
through the haemofilter. It has been reported to control water and electrolyte
balance continuously without haemodynamic instability in critically ill patients
with renal failure, Therefore, we used CHDF during and after cardiopulmonary
bypass (CPB) in two renal failure patients, and discuss its efficacy. CLINICAL
FEATURES: The first patient undergoing aortic valve replacement had dialysis
dependent renal failure. Chronic renal failure in the second patient undergoing
mitral valve replacement and coronary revascularization was controlled
preoperatively with diuretics. In both cases, CHDF was performed not only during
CPB but also in the post-CPB period. Serum concentrations of potassium, urea and
creatinine were well-controlled in spite of large amount of blood transfused in
the post-CPB period (1000 ml fresh blood and 400 ml fresh frozen plasma in the
fist patient, and 1400 ml fresh blood in the second patient). There was no
difficulty in haemostasis during the use of nafamostat mesilate as an
anticoagulant to keep activated clotting time at about 150 sec for CHDF in the
post-CPB period. CONCLUSION: Our initial experiences of CHDF during and after CPB
suggest that the technique provides excellent electrolyte, metabolite and fluid
management for the cardiac patients with chronic renal failure. Combined with
nafamostat mesilate for anticoagulation, CHDF was simple and safe and did not
increase the risk of bleeding.
PMID- 9398961
TI - The cost for construction and operation of a simulation centre.
AB - PURPOSE: Lack of financial information results in planning difficulties and may
delay the introduction of simulator based education. We collected data from an
existing simulation centre and describe a construction and operating budget to
facilitate planning and construction for interested institutions. METHODS: After
obtaining approval from the managing board, the plans and financial statements of
the Canadian Simulation Centre, Sunnybrook Health Science Centre, University of
Toronto were reviewed from the period from July 1994 through June 1996. Costs
were calculated from the financial reports and separated into construction and
operation phases. A list of the ongoing educational and research activities was
compiled. RESULTS: All dollar figures are expressed in 1996 Canadian Dollars. The
planning and construction took place from July 1994 through June 1995.
Construction costs for the simulation centre totalled $665,000, of which 85% was
related to capital equipment purchases and 15% for salary support. The net costs
of ongoing education and research activities (3.35 days/week) were $167,250 from
July 1995 through June 1996. About 65% of this consisted of salary support and
was absorbed by the existing educational resources of the University of Toronto
Department of Anaesthesia. CONCLUSION: Substantial resources are required for the
construction of a simulation centre ($665,000) primarily use of capital equipment
purchases. However, there is also a considerable operating cost per year
($167,250) which consists mostly of salary support.
PMID- 9398963
TI - Assessment of a new ultrafiltration blood processing system.
AB - PURPOSE: To report our clinical experience with a new blood processing device
which uses ultrafiltration. We assessed safety and efficacy by evaluating: 1 )
the quality and the quantity of intraoperative shed blood processed and reinfused
to the patient 2) homologous blood requirements 3) clinical status of the patient
post-transfusion. METHODS: With Ethics Committee approval, the ultrafiltration
device was used in six consenting patients undergoing major elective spinal
surgery. Blood samples for haematology and biochemistry tests were collected from
patients post-induction of anaesthesia (baseline), 1 hr and 24 hr post
autotransfusion. Volumes of blood collected and processed, and all autologous and
homologous transfusions were recorded. Patients were assessed post-operatively
for any adverse effects. RESULTS: Five patients had donated blood preoperatively.
One patient required homologous blood products in addition to autologous blood.
In two patients, the filtration cartridge became blocked and required changing
midprocessing. No patient sustained device-related complications. One patient had
postoperative haematuria which resolved spontaneously within two hours.
CONCLUSION: The ultrafiltration device was safe and effective in reducing
homologous blood requirements in six patients undergoing elective spinal surgery.
Further evaluation of the ultrafiltration device will be necessary, especially in
view of the blockage of the filtration cartridge.
PMID- 9398962
TI - Halothane inhibition of acetylcholine-induced relaxation in rat mesenteric artery
and aorta.
AB - PURPOSE: The effect of halothane was compared on acetylcholine (ACh)-induced
relaxation of the mesenteric artery and the aorta in rats. METHODS: The responses
of isolated rat aortic and mesenteric arterial ring segments precontracted with
phenylephrine to ACh (10(-8)-10(-5) M), in the presence of halothane 0-3%, were
compared using isometric force tension recordings. Effects of NG-nitro-l-arginine
(L-NOARG, 3 x 10(-5), methylene blue (MB, 5 x 10(-6) M), oxyhaemoglobin in
(OxyHB, 10(-7) M), and various potassium channel inhibitors; tetraethylammonium
(TEA, 10(-5) M, 10(-3) M), apamin (AP, 10(-7) M), charybdotoxin (ChTx, 10(-7) M)
and glibenclamide (GC, 10(-5) M) on ACh-induced relaxation in mesenteric artery
were tested. Using radioimmunoassay, ACh (10(-6) M)-induced guanosine 3':5'
cyclic monophosphate (cGMP) accumulation of mesenteric arterial rings pretreated
with L-NAORG were also measured. RESULTS: L-NOARG partially inhibited ACh-induced
relaxation in mesenteric arterial rings (P < 0.05, maximum relaxation reduced by
approximately 50%), whereas it abolished them in aortic rings. The remaining
relaxation resistant to L-NOARG in mesenteric arterial rings was insensitive to
additional MB or OxyHB, and was not accompanied by increases in cGMP contents of
rings. Halothane inhibited endothelium-dependent relaxation in aorta and
mesenteric arterial rings. This inhibitory effect was larger in aorta. Halothane
also inhibited NO independent EDHF-dependent relaxation in the mesenteric
arterial rings, CONCLUSION: Despite a similar inhibitory effect on the EDHF
relaxing pathway, halothane has a larger effect on endothelium-dependent
relaxation in the aorta (NO dependent mainly) than in the mesenteric rings (NO
and EDHF dependent).
PMID- 9398964
TI - Onset of vecuronium neuromuscular blockade at the hand with an arterio-venous
shunt.
AB - PURPOSE: To evaluate the onset of vecuronium neuromuscular blockade in the hand
with an arterio-venous shunt for haemodialysis. METHODS: In 15 adult patients
receiving haemodialysis for renal failure the onset of vecuronium-induced
neuromuscular blockade after 0.08 mg-kg-1 vecuronium i.v. was measured. Using
train-of-four mechanomyographic monitoring, the force of contraction of the
adductor pollicis of both hands with and without arterio-venous shunt was
measured simultaneously. RESULTS: The times from the injection to the first
depression of twitch response (latent onset) and 95% twitch depression (onset) in
the hand with and without arterio-venous shunt were 114.7 +/- 33.4 and 218.7 +/-
59.9 and 117.3 +/- 34.3 and 208.7 +/- 60.9 sec respectively. No difference in the
onset of vecuronium neuromuscular blockade in the hand an arterio-venous shunt
was demonstrated. CONCLUSION: The presence of an arteriovenous fistula does not
modify the onset on neuromuscular blockade. Either arm can be used to monitor
onset of neuromuscular blockade in chronic renal failure patients with an arterio
venous shunt in the hand for haemodialysis.
PMID- 9398965
TI - Prostaglandin E1, lidocaine, and prostaglandin E1-lidocaine combination for
attenuating cardiovascular responses to extubation.
AB - PURPOSE: Tracheal extubation produces haemodynamic changes that may cause
myocardial ischaemia in patients with coronary arterial disease. Intravenous
infusion of prostaglandin E1 (PGE1) attenuated the hypertensive response to
tracheal extubation but failed to blunt the tachycardia, which was attenuated by
intravenous lidocaine. Thus, we investigated whether a combination of PGE1 and
lidocaine can overcome the drawbacks of treatment with PGE1 alone. METHODS: One
hundred adult patients (ASA 1) undergoing elective minor surgery were randomly
assigned to receive one of four treatments: saline (as a control), 1 mg-kg-1
lidocaine, infusion of 0.1 microgram-1.kg-1.min-1 PGE1, or infusion of 0.1
microgram-1.kg-1.min-1 PGE1 plus injection of 1 mg-1.kg-1 lidocaine. Lidocaine
was injected two minutes before tracheal extubation. The PGE1 was infused from
completion of surgery until five minutes after tracheal extubation. Anaesthesia
was maintained with sevoflurane 1.0%-2.5% and nitrous oxide 60%. Heart rate (HR)
and blood pressure (BP) were measured before and after tracheal extubation.
RESULTS: Lidocaine alone and PGE1-lidocaine combination attenuated the increases
in BP and HR observed in the control group: PGE1 alone was effective in
attenuating hypertensive response but ineffective for tachycardia. The
suppressive effect of the PGE1-lidocaine combination on BP increase was superior
to that of each drug alone, and the combined effect on HR increase was similar to
that of lidocaine alone. CONCLUSION: The combination of PGE1 infusion and
lidocaine is a more effective method of attenuating hypertension and tachycardia
associated with tracheal extubation than either drug alone.
PMID- 9398966
TI - Canadian Anaesthetists' Society Gold Medal.
PMID- 9398967
TI - Inhalation induction with sevoflurane.
PMID- 9398968
TI - Cricoid pressure.
PMID- 9398969
TI - Stethoscopy.
PMID- 9398970
TI - Anaesthesia and congenital tracheal stenosis.
PMID- 9398971
TI - Bias in uncontrolled brain tumor trials.
PMID- 9398972
TI - The crisis of biomedical research funding in Canada.
PMID- 9398973
TI - Neurotrophin regulation of gene expression.
AB - The neurotrophins comprise a family of secreted proteins that elicit profound
responses in cells of the developing and mature vertebrate nervous system
including the regulation of neuronal survival and differentiation. The molecular
mechanisms by which the neurotrophins exert their effects have been the subject
of intense investigation. The neurotrophins elicit responses in neurons via
members of the Trk family of receptors and the p75 neurotrophin receptor. Once
activated, neurotrophin receptors trigger a large number of biochemical events
that propagate the neurotrophin signal from the plasma membrane to the interior
of the cell. An important target of the neurotrophin-induced signaling pathways
is the nucleus, where neurotrophin-induced signals are coupled to alterations in
gene expression. These neurotrophin-induced changes in gene expression are
critical for many of the phenotypic effects of neurotrophins including the
regulation of neuronal survival and differentiation.
PMID- 9398974
TI - Role of the ipsilateral motor cortex in voluntary movement.
AB - The ipsilateral primary motor cortex (M1) plays a role in voluntary movement. In
our studies, we used repetitive transcranial magnetic stimulation (rTMS) to study
the effects of transient disruption of the ipsilateral M1 on the performance of
finger sequences in right-handed normal subjects. Stimulation of the M1
ipsilateral to the movement induced timing errors in both simple and complex
sequences performed with either hand, but with complex sequences, the effects
were more pronounced with the left-sided stimulation. Recent studies in both
animals and humans have confirmed the traditional view that ipsilateral
projections from M1 to the upper limb are mainly directed to truncal and proximal
muscles, with little evidence for direct connections to distal muscles. The
ipsilateral motor pathway appears to be an important mechanism for functional
recovery after focal brain injury during infancy, but its role in functional
recovery for older children and adults has not yet been clearly demonstrated.
There is increasing evidence from studies using different methodologies such as
rTMS, functional imaging and movement-related cortical potentials, that M1 is
involved in ipsilateral hand movements, with greater involvement in more complex
tasks and the left hemisphere playing a greater role than the right.
PMID- 9398975
TI - Neural transplantation in Parkinson's disease.
AB - Parkinson's disease is a neurodegenerative disorder that affects about 1% of
Canadians between the ages of fifty and seventy. The medical management for these
patients consists of drug therapy that is initially effective but has limited
long term benefits and does not alter the progressive course of the disease. The
recalcitrance of longstanding Parkinson's disease to medical management has
prompted the use of alternative surgical therapies. Many neurosurgical procedures
have been utilized in order to improve the disabling symptoms these patients
harbour. Although most of the current procedures involve making destructive
lesions within various basal ganglia nuclei, neural transplantation attempts to
reconstitute the normal nigrostriatal pathway and restore striatal dopamine. The
initial success of neural transplantation in the rodent and primate parkinsonian
models has led to its clinical application in the treatment of parkinsonian
patients. Currently, well over one hundred patients throughout the world have
been grafted with fetal tissue in an effort to ameliorate their parkinsonian
symptoms. Although the results of neural transplantation in clinical trials are
promising, a number of issues need to be resolved before this technology can
become a standard treatment option. This review focuses on the current status of
neural transplantation in Parkinson's disease within the context of other
surgical therapies in current use.
PMID- 9398976
TI - Hormones, radiosurgery and virtual reality: new aspects of meningioma management.
AB - The understanding and management of meningiomas is changing significantly today.
One of the most striking features of their pathophysiology is their predominance
in women. In a series of 517 patients with meningiomas seen by the Brain Tumor
Group at Brigham and Women's Hospital, the female:male ratio was 24:1. The
progesterone receptor appears to be the major candidate to explain this
difference. Although meningioma cells variably express receptors for estrogen,
androgen, platelet-derived growth factor, epidermal growth factor, and
somatostatin, these molecules do not explain the differences because they are not
differentially expressed or are not activated. Progesterone receptor can be shown
to be expressed in 81% of women and 40% of men with meningiomas; it can also be
shown to be activated by transfecting a construct with the progesterone
responsive element and a reporter in it and using the cell's own receptors to
activate this construct. Surgery remains the mainstay of meningioma management.
At the Brigham and Women's Hospital three-dimensional reconstruction techniques
have markedly improved the ability to visualize the tumor as well as its relation
to vascular structures. With MRI reconstruction, it is possible to know the
tumor's relation to the sagittal and other sinuses, to identify feeders and
proximity to major arteries, and to establish its location and relation to cortex
by frameless stereotaxis. These techniques can be used in a virtual reality
format are some of the most powerful in neurosurgery both for teaching and for
the surgical procedure itself. External beam radiation has been shown by others
to be an effective adjunctive treatment to prevent meningioma recurrence.
Recently, linear accelerator radiosurgery and stereotactic radiotherapy have
changed the pattern of radiation at our institution. In a series of 56 skull base
meningiomas, for example, 95% were controlled (i.e., showed no growth) over a
four year period. Fractionated focal radiation potentially offers the same
control rate with fewer complications. With increasing understanding and
treatment possibilities, meningiomas remain one of the most intriguing and
challenging tumors in the nervous system.
PMID- 9398977
TI - Measuring bias in uncontrolled brain tumor trials--to randomize or not to
randomize?
AB - PURPOSE: To help investigators decide if new therapies for glioma warrant
definitive evaluation in randomized studies we have been developing a method for
assessing the degree to which patient selection may have enhanced the results of
uncontrolled treatment trials. In this study, we analyzed the impact of case
selection on the survival of patients with malignant glioma receiving adjuvant
stereotactic radiosurgery, a promising therapy reserved for those with small
tumors and good performance status. METHODS: Following published eligibility
criteria we simulated the patient selection process for stereotactic radiosurgery
given as a boost at the conclusion of conventional radiotherapy. Eligible
patients were culled from a pre-existing clinical/imaging database of 101
consecutive conventionally-treated patients with biopsy-proven malignant glioma
and known survival times. Median durations of survival and 2- and 3-year survival
rates were determined for those judged eligible or ineligible for stereotactic
radiosurgery. RESULTS: Twenty-seven percent of patients were deemed eligible for
stereotactic radiosurgery, eligible patients had more favorable prognostic
factors and significantly longer median survival than ineligible patients (23.4
vs. 8.6 months; 2-year rate, 48% vs. 15%; 3-year rate, 30% vs. 7%); eligible
patients also had a longer median survival than the entire group of unselected
patients (23.4 vs. 11.4 months). Radiosurgery-eligible, conventionally-treated
patients with glioblastoma multiforme and a group of radiosurgery-treated
patients at a special referral center had similar median survival times (16.4 vs.
19.7 months). CONCLUSION: We provide additional evidence for selection bias in
uncontrolled trials of stereotactic radiosurgery and by simulating the selection
process accurately have detected a larger bias effect than noted previously.
Judging from experience with interstitial radiation and intraarterial
chemotherapy where substantial selection bias also occurred and randomized
controlled trials proved disappointing, we conclude that a phase III study of
stereotactic radiosurgery for malignant glioma is unlikely to yield a positive
result and may not be necessary.
PMID- 9398978
TI - Prognostic factors in oligodendroglioma.
AB - BACKGROUND: A reliable marker for tumor oligodendroglial cells is not yet
available, so that the histological recognition of the tumor still encounters
uncertainties. There is no general agreement also on prognostic factors in
oligodendroglioma. The inconsistency concerns mainly the histopathological
factors. The aim of the study was recognition of prognostic factors in
oligodendroglioma. METHODS: In a series of ninety-eight oligodendrogliomas,
including twenty mixed oligoastrocytomas, clinical [sex, age at surgery, tumor
location, symptoms at presentation], therapeutic [extent of resection, year of
surgery, post-operative Karnofsky score, post-operative radiotherapy, post
operative chemotherapy], histological [cell density, nuclear pleomorphism,
vascular endothelial proliferation, necrosis, microcysts, mitoses, mitotic index
(MI), apoptosis, apoptotic index (AI)] and immunohistochemical parameters [MIB-1
and PCNA Labeling Indexes (LIs), staining for GFAP, positivity for p53] were
correlated with survival in uni- and multivariate analysis in order to identify
their prognostic significance. RESULTS: Age at surgery, extent of surgical
resection, year of surgery, post-operative Karnofsky score and MIB-1 LI were
associated with survival in both uni- and multivariate analysis. Location,
symptoms at presentation, mitoses, MI, AI, and PCNA LI showed a significant
correlation with survival in uni- but not in multivariate analysis. The twenty
cases of oligoastrocytomas did not show any difference in survival from pure
oligodendrogliomas. CONCLUSIONS: Some clinical and therapeutic factors together
with MIB-1 LI play a prognostic role. MIB-1 LI is prognostic with a cutoff of 8%.
Histology gives a limited contribution to the prognosis. Oligoastrocytomas had
the same outcome and prognostic factors as pure oligodendrogliomas.
PMID- 9398979
TI - An electroencephalographic classification for coma.
AB - BACKGROUND: The assessment of thalamocortical function in comatose patients in
the intensive care unit (ICU) can be difficult to determine. Since the
electroencephalogram (EEG) affords such assessment, we have developed an EEG
classification for comatose patients in our general ICU. METHODS: One hundred
EEGs were classified in a blinded fashion by two EEGers, using our method and
that of Synek. Interobserver agreement was assessed using kappa score
determination. RESULTS: Kappa scores were 0.90 for our system and 0.75 for the
Synek system. (The Kappa score represents the inter-rater agreement that is
beyond chance; 0.90 is almost perfect agreement, while 0.75 is substantial
agreement). CONCLUSION: Our system for classifying EEGs in comatose patients has
a higher interobserver reliability than one that was previously published. This
EEG classification scheme should be useful in clinical electrophysiological
research involving ICU patients, allowing for internal consistency and
comparisons among centres.
PMID- 9398980
TI - Familial intracranial aneurysms: recurrence risk and accidental aggregation
study.
AB - BACKGROUND: The Saguenay-Lac-Saint-Jean (SLSJ) region is a geographically
isolated area (population 285,955) located in the Northeastern part of the
Province of Quebec, Canada. Using a population-based register, the genealogical
reconstruction of 502 individuals with ruptured intracranial aneurysm (RIA)
showed a familial aggregation (the presence of aneurysm in two or more first- to
third-degree relatives) for 144 (28.7%) of them; this proportion is much higher
than reported elsewhere. OBJECTIVE: In order to assess the genetic predisposition
to RIA in the SLSJ population, the objective of the present study is to compare
familial and non-familial cases and to provide an estimate of the recurrence risk
ratio for siblings. RESULTS: The age at the time of rupture, the number of
intracranial aneurysms for each patient and the location of RIAs were not
statistically different in the familial versus the non-familial group. Of the
3449 siblings, 20 (0.58%) had suffered a RIA. The recurrence risk ratio
calculated for siblings (defined as the risk of disease among siblings divided by
the estimated population prevalence) is 1.6 (CI 95% 1.0-2.4). In other respects,
we observed very large kinships in the SLSJ population, with an average number of
siblings of 7.2 (SD +/- 3.4), ranging from 0 to 17 individuals. With such large
families and on the basis of chance alone, we expected 31.3% of the patients to
have at least one first- to third-degree relative with RIA. CONCLUSION: These
data show that siblings of patients with RIA in the SLSJ population have a
greater risk of RIA than the general population. Nevertheless, the largest part
of the familial occurrence observed in the SLSJ region can be explained by
accidental aggregation, due to large kinships. We propose that, in this
population, an underlying genetic predisposition must be suspected only when
three or more cases of RIA are identified among first- to third-degree relatives.
PMID- 9398981
TI - Motor evoked potentials and disability in secondary progressive multiple
sclerosis.
AB - BACKGROUND: To investigate the mechanisms underlying disability in multiple
sclerosis (MS), 40 patients with the relapsing-remitting form of the disease and
13 patients with secondary progressive MS underwent multimodal evoked potential
(EP), motor evoked potential (MEP), and spinal motor conduction time evaluation.
Clinical disability was evaluated by the expanded disability status scale (EDSS)
and functional system scales. In secondary progressive MS patients, magnetic
resonance imaging (MRI) was used to obtain a semiquantitATive estimate of the
total lesion load of the brain. RESULTS: Spinal motor conduction time was
significantly longer in secondary progressive MS patients than controls (p <
0.001) and relapsing-remitting MS patients (p < 0.05), but did not differ between
relapsing-remitting patients and controls. Spinal motor conduction times also
correlated directly with EDSS scores (p < 0.001) and pyramidal functional system
scores (p < 0.001). Brain lesion load (4960.3 +/- 3719.0 mm2) and the total
number of lesions (67.7 +/- 37.0) in secondary progressive MS did not correlate
with disability scores. For the following EPs, the frequencies of abnormalities
were significantly higher in secondary progressive MS patients than relapsing
remitting patients: visual evoked potentials (p < 0.05), somatosensory evoked
potentials and upper limb motor evoked potentials (p < 0.01), and brainstem
auditory evoked potentials, lower limb somatosensory evoked potentials and lower
limb motor evoked potentials (p < 0.001). CONCLUSIONS: These findings suggest
that disability in secondary progressive MS patients is mainly due to progressive
involvement of corticospinal tract in the spinal cord.
PMID- 9398982
TI - Symptoms experienced by patients with carpal tunnel syndrome.
AB - BACKGROUND: Patients with carpal tunnel syndrome (CTS) sometimes report sensory
symptoms outside the median nerve distribution. This study was designed to
provide a more detailed assessment of these symptoms. METHODS: Patients with
clinical suspicion of upper limb neuromuscular lesions were divided into those
with electrodiagnostic (EDX) evidence of CTS, and those without. CTS patients
with superimposed nerve abnormalities were excluded. Motor and sensory symptoms
were assessed in the exclusive CTS patients. RESULTS: Over 50% of patients with
exclusive CTS reported tingling or numbness over the whole hand, ulnar or radial
nerve distributions. Some patients reported symptoms proximal to the wrist.
Sensory signs did not extend beyond the median nerve distribution. Numbness and
nocturnal pain were predictive of positive EDX evidence of CTS. CONCLUSIONS:
Sensory symptoms outside the distribution of the median nerve are common in CTS.
For enhanced sensitivity in diagnosis it is useful to be aware of these
"atypical" symptoms. Reports of numbness and nocturnal pain are strong indicators
of CTS.
PMID- 9398983
TI - Reversal of syphilitic hydrocephalus with intravenous penicillin.
AB - BACKGROUND: CSF shunting procedures are generally considered the fundamental
therapy of syphilitic hydrocephalus. METHODS: We followed up with CSF analysis
and MR imaging a patient with progressive mental and gait disturbances and
tetraventricular hydrocephalus due to tertiary syphilis who was treated for 14
days with high dose intravenous penicillin alone. RESULTS: Clinical and CSF
abnormalities resolved within a few months, whereas the hydrocephalus disappeared
only 30 months after therapy. CONCLUSIONS: Before consideration of a CSF shunting
procedure, a trial of high dose intravenous penicillin is warranted for patients
with syphilitic hydrocephalus.
PMID- 9398984
TI - Epilepsy and driving: a survey of Canadian neurologists.
AB - BACKGROUND: A seizure is the most common cause of loss of driving privileges for
medical reasons but there is variability in how physicians and the authorities
who regulate driving approach this issue. METHODS: A questionnaire regarding
epilepsy and driving was sent to all adult neurologists in Canada (n = 494).
RESULTS: Of 289 (59%) neurologists responding, 50% usually report patients with
seizures to the department of motor vehicles compared to only 4% for stroke/TIA,
26% for dementia and 8% for other neurologic disorders (p < 0.0001). In the five
provinces with mandatory reporting laws, seizures were reported most of the time
by 84% compared to only 19% in the five provinces with discretionary reporting (p
< 0.0001). Nationwide, 44% agreed with mandatory reporting but this also differed
in provinces with and without mandatory reporting legislation (63% vs. 37%, p <
0.0001). Only 49% agreed with the current recommendation of at least one year
seizure free interval before resuming driving. CONCLUSIONS: Seizures are
disproportionately reported compared to other neurological conditions. Many
neurologists disagree with the recommended Canadian standards for duration of
driving restriction after seizures. Variability in the attitude and practice of
neurologists in regard to reporting of seizures is confirmed.
PMID- 9398985
TI - What effect does an untreated aneurysm have on life expectancy.
PMID- 9398986
TI - Early seizures after closed head injury.
PMID- 9398987
TI - Musical hallucinosis with brain lesions.
PMID- 9398988
TI - Comparative study of invasive squamous cell carcinoma and verrucous carcinoma of
the oral cavity: expression of bcl-2, p53, and Her-2/neu, and indexes of cell
turnover.
AB - Significant clinical and biological differences are found between invasive
squamous cell carcinoma (SCCA) and verrucous carcinoma (VC) of the oral cavity.
The correct diagnosis of these tumors has important therapeutic implications.
Immunoperoxidase stains for bcl-2, p53, and Her-2/neu, and in situ end-labeling
of DNA to identify apoptosis were performed in eight VC and eight SCCA matched
for age, sex, and stage. Marked differences were identified in the pattern of
expression of oncogenes and the indexes of cell turnover in these two types of
tumors. VC displayed minimal apoptosis in rare keratinizing cells (0 to 3%); p53
positive cells (4/8) and Ki-67 (8/8) were confined to the nuclei of the basal
proliferating layers; and bcl-2 (4/8) was expressed only in the cytoplasm of rare
tumor cells. In contrast, SCCA displayed higher apoptosis rates (5 to 10%),
whereas p53- (5/8) and Ki-67- (8/8) positive nuclei were distributed randomly
throughout the tumor. Very well differentiated areas in one SCCA case had a
pattern of staining for p53 and Ki-67 similar to the one seen in VC. In SCCA bcl
2 showed patchy cytoplasmic staining (4/8) or strong cytoplasmic and nuclear
positivity (2/8) in the less differentiated tumors. Her-2/neu was negative in all
VC and SCCA cases. The different levels and patterns of gene expression and cell
turnover between SCCA and VC undoubtedly correlate with the different biology and
prognosis of these tumors.
PMID- 9398989
TI - Rapid diagnostic imaging of cancer using radiolabeled liposomes.
AB - A novel tumor diagnostic imaging method was developed that allows tumor
localization soon after administration of radiolabeled liposomes. Although
previous studies showed that radiolabeled liposomes can reach various tumors in a
short time, their blood clearance is slow, and the high blood background hinders
early imaging. Therefore, we attempted to remove actively the liposomes from the
circulation using the strong affinity between avidin and biotin. Liposomes that
had biotin bound to their surface and were labeled with 111In, 67Ga, or 99mTc
were administered to mice bearing sarcoma 180, followed by administration of
avidin 2 or 4 h later. Avidin initiated liposomal aggregation, resulting in their
rapid removal by the reticuloendothelial system. Consequently, their blood level
was markedly reduced without any changes in tumor levels. The tumor-to-blood
ratio reached about 13 at only 2.5 h after administration of 99mTc-labeled
liposomes, versus 1.0 or less without postadministration of avidin. Increased
liver accumulation was also observed, but it decreased gradually with time.
PMID- 9398990
TI - Smoking history and cancer patient survival: a hospital cancer registry study.
AB - While tobacco use is clearly the most preventable cause of cancer, little is
known about whether smoking adversely influences cancer patients' survival. The
goal of this study was to examine the effect of smoking history on survival among
cancer patients. Data from Memorial Sloan-Kettering Cancer Center's tumor
registry was used to identify 25,436 cases of cancer (12,447 male patients and
12,989 female patients). Information regarding smoking and alcohol consumption,
histologic grade, tumor stage, and survival time was available. Proportional
hazard analysis was used to examine the effect of smoking on the death from all
causes among patients. Patients who had a history of smoking were found to have a
lower rate of survival than nonsmokers. After controlling for age, race, alcohol
use, and histologic grade, the risk ratios were 1.55 for males and 1.43 for
females. A dose-response relationship was found between ever-smoking and cancer
patient survival. The predictive effect of smoking on survival was significant
for patients with oral, pancreatic, breast, and prostate cancers, but not for
esophageal, stomach, colon, rectum, laryngeal, lung, cervix uteri, urinary
bladder, and kidney cancers. Black patients with oral or breast cancer had a
poorer prognosis associated with smoking compared with white and other nonwhite
patients. The strongest effect of smoking on survival was found mainly among
patients with breast cancer with a distant tumor stage or with prostate cancer
with a regional tumor stage. Alcohol use alone was associated with a higher risk
of death for nonsmokers with oral and pancreatic cancers than for similar cancer
patients without a history of alcohol use. Smoking history plays a critical role
in influencing cancer patient survival, especially for patients diagnosed with
oral, pancreatic, breast, or prostatic cancers. In addition, alcohol consumption
is independently related to survival in patients with oral and pancreatic
cancers. Our study suggests that a potential means of improving cancer patient
survival, especially from oral, pancreatic, breast, and prostatic cancers, may be
achieved through smoking cessation.
PMID- 9398991
TI - Factors associated with breast and cervical cancer screening practices among
Vietnamese American women.
AB - PURPOSE: To investigate predictors of breast and cervical cancer screening tests
among Vietnamese women in California in preparation for developing and testing
interventions to promote such screening. METHODS: Cross-sectional telephone
survey of 933 randomly selected Vietnamese women in four California counties.
RESULTS: Overall, 70% of the respondents had had at least one prior clinical
breast examination, but only 30% had had a mammogram and 53% a Pap test. Among
women who had been screened, more than two-thirds were up-to-date and among those
who had not been screened, more than two-thirds were planning future tests.
Factors positively associated with receipt of one or more of the tests included
age (among women < 40 years old), number of years in the United States, having
ever married, and having health insurance. Factors negatively associated with
test receipt included having a Vietnamese doctor, being unemployed, and being of
Chinese-Vietnamese background. CONCLUSION: The multiple factors associated with
utilization suggest intervention targets for promoting breast and cervical
screening among new immigrant women. Increasing screening test receipt to
recommended levels will require a two-pronged approach directed at both
Vietnamese consumers and Vietnamese physicians.
PMID- 9398992
TI - Tamoxifen and ocular toxicity.
AB - Tamoxifen, widely used in the management of breast cancer, has been associated
with a reduction of mortality and recurrence as well as occurrence of
controlateral tumors. It is generally well tolerated, apart from certain well
documented adverse effects concerning mainly the reproductive organs, the most
worrying being its carcinogenicity for the endometrium. Ocular toxicity has also
been reported as one possible complication of the drug, with lesions described in
the retina, the cornea, or the optic nerve, especially in women treated with high
daily or cumulated doses of tamoxifen, although some cases have also been
reported with standard doses. The incidence of such ocular complications is
rather low considering the large number of patients receiving tamoxifen. The
possible reversibility of these lesions, if discovered in time, emphasizes the
need for clinicians to be aware of these ocular reactions and raises the question
of periodic ophthalmological screening examinations among patients receiving
tamoxifen.
PMID- 9398993
TI - Immunohistochemical assessment of proliferation markers and altered gene
expression in archival specimens of ovarian epithelial tumors.
AB - Recently reported morphologic and molecular genetic evidence suggests that some
ovarian carcinomas arise from their benign and low malignant potential (LMP)
counterparts. In order to help reach a better understanding of ovarian
tumorigenesis, we studied a wide range of gene products involved in cellular
growth regulation in archival material obtained from three groups of tumors with
graduated malignant potential. Immunohistochemical staining was performed for Ki
67, proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor
(EGFR), HER-2/neu-encoded receptor protein, p53 gene product, and multidrug
resistance gene product (P-glycoprotein). The expression of EGFR, HER-2/neu
encoded receptor protein, and mutant p53 product was significantly lower in LMP
tumors than in carcinomas (p < 0.05). HER-2/neu immunopositivity was more
prevalent in adenocarcinomas than in LMP tumors, and the proportion of HER-2/neu
positive adenocarcinomas increased with the progression of the disease. The
staining differences between LMP tumors and adenocarcinomas with antibodies
against Ki-67, PCNA, and P-glycoprotein were not statistically significant.
Immunohistochemical detection of EGFR, HER-2/neu, and p53 in ovarian epithelial
tumor is relevant to ovarian tumorigenesis. It could serve as a powerful tool for
the pursuit of retrospective studies focused on these important biologic markers.
PMID- 9398994
TI - Deficient DNA repair in chronic ulcerative colitis.
AB - Carcinoma of the colon is a serious complication of chronic ulcerative colitis
(CUC), a disease of unknown etiology. Peripheral blood lymphocytes from nine
patients with CUC showed deficient repair of radiation-induced DNA damage
compared with a group of healthy controls. DNA repair was measured indirectly by
quantifying chromatid breaks after irradiation of cells with X-rays or
ultraviolet during G2 phase of the cell cycle. Such breaks represent unrepaired
DNA strand breaks that may arise directly from the damaging agent or indirectly
during repair processes. Two types of deficiency were revealed. One was an
abnormally high frequency of chromatid breaks after G2-phase X-irradiation. These
may reflect deficient strand-break repair. The second deficiency was manifest as
a low frequency of breaks not increased by addition of the DNA repair inhibitor
araC. This low frequency apparently results from negligible incision activity.
Deficient DNA repair in CUC may thus be a requisite predisposing factor for
genomic instability and the potential development of colon carcinoma.
PMID- 9398995
TI - Pancreatic cancer cell regulation by lipids and by basic fibroblast growth factor
expression.
AB - High fat intake is a risk factor for pancreatic cancer. Lipids may act either
directly or in cooperation with growth-promoting polypeptides. In this study, the
role of serum lipids, and mainly the often expressed intracellular basic
fibroblast growth factor (bFGF) isoforms in cancer cells, was analyzed in
pancreatic tumor cell proliferation. Serum lipids alone induced a 1.9-fold
increase of human pancreatic cancer cell growth (p < 0.001). Treatment with bFGF
had a weak mitogenic effect (1.2- to 1.3-fold increase) compared with those of
insulin and transferrin (1.7- to 1.6-fold increase, respectively). The bFGF
expression by a rat pancreatic cancer cell line that was transfected with bFGF
cDNAs modified cell lipid contents and induced a higher proliferation rate than
that found with the exogenous bFGF. Combined extra- and intracellular bFGFs
increased cell growth by two to three times (p < 0.001), regardless the presence
of extracellular lipids. The results obtained reflect the direct mitogenic effect
of serum lipids and suggest that the endogenous bFGF of high molecular weight may
be implicated in pancreatic cancer cell growth. By modifying cell lipids, bFGFs
may interfere with other cell functions, like signal transduction.
PMID- 9398996
TI - Effects of catechols on free radical formation by chemotherapeutic agents
(adriamycin, farmorubicin, and mitomycin).
AB - The aim of the present study was to investigate the effects of biologically
important catechols on the cytotoxicity of adriamycin, farmorubicin, and
mitomycin C with respect to hydroxyl radical production. Catecholamines
(adrenalin, noradrenaline, dopamine) and DOPA enhance the generation of hydroxyl
radicals by chemotherapeutic antibiotics. Measures were done using a deoxyribose
assay, in presence of the Co(II) + H2O2 system. Catalase and hydroxyl radical
scavengers (mannitol, thiourea, cysteine, glutathione, L-lactic dehydrogenase)
inhibited the deoxyribose damage caused by the drugs.
PMID- 9398997
TI - Visual disturbances in migraine.
PMID- 9398998
TI - The rise and fall of estrogen levels.
PMID- 9398999
TI - A negative clinical study in the search for a migraine treatment.
PMID- 9399000
TI - Role of the suprachiasmatic nucleus in the pathogenesis of migraine attacks.
AB - Neuroanatomic, morphometric, immunocytochemical, neurobiochemical and clinical
data support the hypothesis that the suprachiasmatic nucleus of the hypothalamus
might be the initial site of migraine attacks. The prodromal phase of a migraine
attack could be considered a syndrome of functional suprachiasmatic nucleus
insufficiency, and other phases a reactive denervation hypersensitivity with the
affection of the visual, nociceptive, antinociceptive and cranial vasomotor
system.
PMID- 9399001
TI - Olfaction in migraine.
AB - Olfactory thresholds for acetone and vanillin and the unpleasantness rating of
concentrated acetone were measured in 20 migraine sufferers and 21 controls. The
olfactory threshold for vanillin was lower in migraine sufferers than in
controls. In addition, patients who reported that odours frequently seemed
stronger during attacks of migraine were able to detect acetone at a lower
concentration than most other patients. No differences were found between
migraine sufferers and controls for ratings of the unpleasantness of concentrated
acetone. These findings suggest that hyperacuity to odours persists between
episodes of migraine. Sensitivity to odours could contribute to the migraine
predisposition.
PMID- 9399002
TI - Light-induced discomfort and pain in migraine.
AB - Quantitative thresholds for discomfort and pain with monocular and binocular
light stimuli were measured in 67 controls and 67 migraine patients (37 migraine
with aura and 30 migraine without aura). Patients were more photophobic during
attack than outside attack (p < 0.03), and they were more sensitive to light than
controls even between attacks (p < or = 0.0001). We found no differences in light
sensitivity between migraine with aura and migraine without aura (p > or = 0.93).
Unilateral pain affected light sensitivity on both sides. When asked with a
questionnaire, 74% of patients answered that they were sensitive to light outside
attack and 100% were sensitive during attack. Pain thresholds were generally
lower among sensitive than non-sensitive patients (p = 0.004), indicating some
agreement between subjective opinion and objective measurements of photophobia.
Photophobia seems to be an intrinsic property of migraineurs. It is increased by
migraine pain, but seems to be unrelated to migraine characteristics such as
nausea, severity of attacks, pain character and pain laterality.
PMID- 9399003
TI - Simultaneous recording of pattern reversal electroretinograms and visual evoked
potentials in migraine.
AB - We recorded full-field pattern reversal electroretinograms (PERGs) and visual
evoked potentials (PVEPs) simultaneously in 15 migraine with aura, 14 migraine
without aura patients during the interictal period, and in 23 sex- and age
matched normal subjects. All subjects had normal visual fields. The visual aura
in all patients was hemianopsia or fortification spectra. Neither migraine group
showed significant differences from normal in latency and amplitude of PERGs. In
migraine with aura, the amplitudes of PVEPs in classic migraine at the mid
occipital electrode were significantly (p < 0.01) higher than normal. PVEP
amplitudes were significantly (p < 0.01) higher on the contralateral side of the
aura than the ipsilateral side in both visual aura and normal subjects, but there
was no significant difference in latency. This high amplitude and asymmetry of
PVEPs may contribute to defective inhibition between interhemispheric visual
occipital areas or striate and peristriate areas.
PMID- 9399004
TI - The reproducibility of cephalic pain pressure thresholds in control subjects and
headache patients.
AB - Pain pressure thresholds (PPT) were measured at 13 cephalic points bilaterally in
30 headache patients (10 with tension-type headache, 10 with migraine and 10 with
cervicogenic headache) and 10 control subjects on three different days. During
the sessions, the subjects reported their pain intensity on the right and left
sides of the head on a visual analogue scale (VAS). The variability between days
was estimated as a coefficient of repeatability (CR = 2 standard deviations of
intraindividual differences). The mean CR across all 13 locations was larger in
headache patients (2.0 kg/cm2) than in controls (1.68 kg/cm2). Variability (CR)
was larger in headache patients as compared to control subjects for 11 of the 13
points (p = 0.02). Reliability was better in controls (intraclass correlation
coefficients (ICC) ranging from 0.55 to 0.85) than in headache patients (ICC
ranging from 0.43 to 0.78). A moderate negative association between PPT and pain
intensity was demonstrated. The intraindividual PPT difference (PPT on the most
painful occasions-PPT on the least painful occasions) was negative at 12 of 13
cephalic points (p = 0.003, across-location mean difference: -0.20 kg/cm2). The
PPT differed significantly from one day to the next. A part of this variation was
presumably related to the circumstances around the procedure; thresholds were
lower when the subjects came directly to algometry without any preceding medical
examination at all 13 points (p = 0.0002). These results have implications for
the planning of future algometer studies. The sample size that is required in
studies of headache patients is greater than that in studies of healthy subjects,
especially when patients suffer from pain during the PPT session. Particular
attention should be paid to circumstances (e.g. preceding medical investigations)
around the algometry procedure in order to reduce variability.
PMID- 9399005
TI - Power spectral analysis of heart rate and diastolic blood pressure variability in
migraine with and without aura.
AB - Autonomic function in migraineurs during headache-free periods was studied by
means of cardiovascular reflexes and power spectral analysis of heart rate and
diastolic blood pressure variability. We examined 56 patients: 37 suffering from
migraine without aura and 19 from migraine with aura. Cardiovascular responses to
the tilt test and Valsalva manoeuvre showed a normal function of the overall
baroreceptor reflex arc. Normal heart rate responses to Valsalva manoeuvre and
deep breathing suggested an intact parasympathetic function. Power spectral
analysis of both heart rate and diastolic blood pressure variability in basal
conditions and during orthostatic test showed similar sympathovagal interactions
modulating cardiovascular control in migraine patients and in controls.
PMID- 9399006
TI - Platelet sulphotransferase activity, plasma sulphate levels and sulphation
capacity in patients with migraine and tension headache.
AB - Activity of both the M- and P-forms of sulphotransferase (ST) was measured in
platelets from patients with migraine, tension headache and controls. Mean PST
values were 0.065 +/- 0.023 and 0.057 +/- 0.052 nmol/mg protein/min for migraine
patients with and without aura. The corresponding values for tension headache and
controls were 0.122 +/- 0.059 and 0.127 +/- 0.093 nmol/mg protein/min
respectively (p < 0.05). Mean MST values were not different for any of the
groups, and MST and PST activities measured in two patients during a migraine
attack were not significantly altered from baseline levels. Mean plasma inorganic
sulphate concentrations and paracetamol metabolites were not significantly
different in any of the groups studied. The results suggest that PST activity may
be a factor in the aetiology of migraine.
PMID- 9399007
TI - Headache during pregnancy.
AB - A questionnaire was submitted to 430 women 3 days after delivery, asking mainly
about features of headache before and during pregnancy, and their possible
modification or recurrence; moreover, delivery modalities and the condition of
the newborn were evaluated. One-hundred-and-twenty-six (29.3%) were found to be
primary headache sufferers (IHS criteria, 1988), 81 of whom had migraine without
aura (MO), 12 migraine with aura (MA), and 33 tension-type headache (TH). In all
three groups, about 80% showed complete remission or a higher than 50% decrease
in the number of attacks. The improvement was more evident after the end of the
first trimester; this trend was common to the three primary headaches considered.
In our series of primary headaches, there was only one case (MO) which began
during pregnancy. In a subgroup of pluripara, headache maintained the improvement
presented in the first pregnancy also during the following gravidic periods in
about 50% of cases, whereas in the remaining 50% a worsening in parallel with
successive pregnancies was found. Primary headaches "per se" do not seem to
increase the pregnancy or delivery risks, nor the vitality of the newborn. During
pregnancy, drug use was very much reduced and was restricted to a limited number
of compounds.
PMID- 9399008
TI - Epidemiology of migraine headache in Santiago, Chile: a prevalence study.
AB - OBJECTIVE: To describe the importance of migraine in Santiago, Chile, by
analyzing its prevalence, clinical features and impact by age, gender and
socioeconomic status. METHODS: In 1993, a representative sample of 1,540 adults
of the province of Santiago were interviewed using a standard questionnaire. A
total of 1,385 (89.9%) subjects responded to the survey. Initially, a designated
member of each household responded to the questionnaire. Subsequently, each
household member with headaches was asked to respond to questions about severity,
frequency, location, duration, associated symptoms and impact in work and social
activities of their most frequent headaches. Migraine diagnoses were determined
in accordance with the International Headache Society (IHS) criteria of 1988.
RESULTS: Recurrent headaches in the past year were found in 516 (36.82%)
respondents, 145 (28.1%) males and 371 (71.9%) females. Total prevalence of
migraine was found to be 7.3% (95% CI 5.9-8.6); 11.9% (95% CI 9.6-14.2) in
females and 2.0% (95% CI 0.9-3.0) in males. Overall, migraine constituted 19.6%
(101/516) of all headaches reported in this sample. The prevalence did not vary
significantly by age groups or socioeconomic status (SES). Migraine with aura had
an overall prevalence of 3.5% (CI 0.8-7.1), and was significantly more frequent
in females. In 60-70% of cases the attacks lasted 2-6 h and the frequency was 3.3
and 3.4 per month in females and males respectively. Both males and females
reported significantly high percentages of attacks during work. CONCLUSIONS:
Migraine prevalence in a sample of adults of Santiago is similar to that reported
in previous studies using IHS criteria. Women of all socioeconomic levels are at
an increased risk.
PMID- 9399009
TI - Post-lumbar puncture headache: clinical features and suggestions for diagnostic
criteria.
AB - The aim of the present prospective study was to describe clinical features of
post-lumbar puncture headache (PPH), and to test the validity of the diagnostic
criteria of the International Headache Society (IHS). Eighty-eight of the 239
included patients (36.8%) experienced PPH. Females were affected more frequently
than males (45.2% vs 21.4%; p < 0.001). First onset of PPH occurred within the
first day in 40 patients (53%), within 2 days in 89%, and never after the fourth
day. When PPH occurred for the first time on the day the lumbar puncture was
performed, it was usually experienced much later in the day (median 14.00 h) than
it first occurred on the second day (median 09.30 h) or later. The median
duration of PPH was 6 days (range 1-29 days). Patients with headache performed a
"Rising Manoeuvre" twice daily as long as the headache period lasted, and
recorded pain and time variables. The severity of PPH was negatively correlated
to the time till the headache started or worsened upon rising (T1) and the time
from the headache started to increase till it reached its maximum (T2), but was
not significantly correlated to the time to restitution upon lying down (T3). The
results are in good accordance with the leakage theory. T1 varied from immediate
onset to 265 min (median 20 sec). T2 (median 30 sec, range 0-60 min) and T3
(median 20 sec, range 0-15 min) varied considerably as well. During the course of
PPH, 45% of the patients occasionally reported non-postural headache or no
headache when the Rising Manoeuvre was performed. It is suggested that PPH should
be diagnosed in any patient who experiences postural headache at least once
within 4 days of lumbar puncture.
PMID- 9399010
TI - Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study.
AB - Lanepitant is a high-affinity, selective neurokinin-1 receptor (NK-1) and is
effective in the dural inflammation model of acute migraine. Lanepitant 30, 80,
and 240 mg given orally was evaluated in a double-blind, placebo-controlled
crossover study to determine its effect in reducing migraine pain and severity of
associated symptoms. Outpatients treated four migraine headaches of moderate or
severe pain intensity with study drug according to a randomization schedule. They
recorded their pain intensity and severity of migraine-associated symptoms at 30,
60, 90, and 120 min. Although 53 patients were randomly allocated to a treatment
sequence, only 40 patients completed all treatments. There was no statistically
significant difference in improvement in migraine pain at any time for any of the
treatments. Additionally, there was no change in severity of migraine-associated
symptoms associated with lanepitant therapy. No adverse events could be
attributed to lanepitant. Lanepitant was ineffective orally in treating acute
migraine in this trial. This may be due to poor bioavailability during a migraine
attack. Alternatively, the neurogenic inflammation hypothesis may not apply to
migraine.
PMID- 9399011
TI - Zolmitriptan. Introduction.
PMID- 9399012
TI - Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally
and peripherally acting 5HT1B/1D agonist for migraine.
AB - Zolmitriptan (Zomig; formerly 311C90) is a novel 5-hydroxytryptamine (5HT)1B/1D
receptor agonist with proven efficacy in the acute treatment of migraine with or
without preceding aura. The drug differs from presently available members of this
drug class in that it combines 5HT1B/1D receptor partial agonist activity with
robust oral pharmacokinetics and an ability to inhibit trigeminovascular
activation centrally as well as peripherally in preclinical studies. Consistent
with its selectivity for 5HT1B/1D receptors, zolmitriptan produces constriction
of various isolated blood vessels, most notably cranial arteries. In
anaesthetized animals, these vascular effects manifest as a selective
constriction of cranial arterio-venous anastomoses resulting in a redistribution
of carotid arterial blood flow. This effect is produced without significant
effects on heart rate, blood pressure or blood flow to the brain, heart or lungs.
Zolmitriptan also inhibits trigeminal-evoked increases in cerebral blood flow in
anaesthetized cats and blocks trigeminal-evoked plasma protein extravasation in
the dura of guinea-pigs. These actions are consistent with a pre-junctional
inhibition of neuropeptide release from perivascular afferents of the trigeminal
nerve, as confirmed by independent studies showing that zolmitriptan blocks
elevations of calcitonin-gene-related peptide in jugular venous blood during
electrical stimulation of the trigeminal ganglion. In all of these effects,
zolmitriptan is three to four times more potent than sumatriptan, but produces
the same maximum response. Zolmitriptan crosses the intact blood-brain barrier to
inhibit trigeminovascular activation in the brainstem. This was shown initially
by the ability of the drug to block a brainstem reflex provoking vasoactive
intestinal peptide release from the VIIth cranial (facial) nerve during
trigeminal stimulation. Subsequent ex vivo autoradiography confirmed that
intravenously injected [3H]zolmitriptan labels a discrete population of cells in
the trigeminal nucleus caudalis (TNC) and nucleus tractus solitarius. Direct
evidence for a central neuromodulatory effect of zolmitriptan was provided by
electrophysiological experiments which clearly demonstrated that the drug
inhibits the excitability of cells in the TNC after systemic administration. This
novel pre-clinical profile not only distinguishes zolmitriptan from sumatriptan,
but raises intriguing questions about the clinical relevance of a dual action.
Studies to date show that zolmitriptan indeed modulates cranial sensory
processing in humans, yet central side-effects are no different from sumatriptan.
This property may account for the remarkable consistency in clinical efficacy
observed in clinical trials.
PMID- 9399013
TI - The clinical pharmacokinetics of zolmitriptan.
AB - Zolmitriptan (Zomig, formerly 311C90) is a novel, oral, acute treatment for
migraine. In healthy volunteers it is rapidly and extensively absorbed and has
favorable oral bioavailability (approximately 40%) which is not affected by
concomitant food intake. On average, 75% of its eventual Cmax is achieved within
1 h of dosing. Plasma concentrations are sustained for 4 to 6 h after dosing with
single or multiple peaks in the plasma concentration-time profile, reflecting
continued absorption down the gastrointestinal tract. The pharmacokinetics of
zolmitriptan indicate dose proportionality over the dose range of 2.5 to 50 mg
and there are no significant changes on multiple dosing. Zolmitriptan is cleared
by metabolism followed by urinary excretion of the metabolites. There are three
major metabolites, one of which, the N-desmethyl metabolite, is active as a 5HT1D
agonist and has mean plasma concentrations approximately two thirds those of the
parent compound. The other two metabolites, the N-oxide and indoleacetic acid,
are inactive. The elimination half lives of zolmitriptan and its metabolites are
similar, approximately 3 h. Zolmitriptan and its active metabolite are minimally
protein bound in the plasma (approximately 25%). In migraine patients, plasma
concentrations of zolmitriptan and its metabolites are lower during a migraine
attack than outside an attack. In summary, the pharmacokinetics of zolmitriptan
are simple, predictable and appropriate to an acute oral treatment for migraine.
PMID- 9399014
TI - Potential drug interactions with the novel antimigraine compound zolmitriptan
(Zomig, 311C90).
AB - Seven randomized studies in healthy volunteers have investigated interactions
between zolmitriptan (Zomig, formerly 311C90), a 5HT1B/1D agonist for acute
migraine therapy, and selected drugs with which there was a possibility of
interaction or a likelihood of concurrent use. Co-administration of oral
dihydroergotamine, ergotamine, pizotifen, fluoxetine, paracetamol
(acetaminophen)/metoclopramide or selegiline had no clinically significant
effects on the pharmacokinetics of zolmitriptan or its metabolites, although
small changes were observed in some cases. Co-administration of propranolol
resulted in a 56% increase in the area under the plasma concentration-time curve
(AUC) of zolmitriptan and a 11% decrease in the AUC of the active metabolite
183C91. However, these pharmacokinetic changes are unlikely to be relevant at
lower clinical doses. Moclobemide, a monoamine oxidase A (MAO-A) inhibitor,
decreased the clearance of zolmitriptan and, in particular, 183C91. This suggests
that MAO-A is involved in the metabolism of 183C91 and it may be prudent to limit
the daily zolmitriptan dose in migraine patients maintained on a MAO-A inhibitor.
The clinically insignificant blood pressure increases produced by zolmitriptan,
and the tolerability profile of this agent, were unaffected by any of the
concomitant medications. Clinically significant interactions between zolmitriptan
and commonly co-prescribed antimigraine therapies are unlikely.
PMID- 9399015
TI - Zolmitriptan (Zomig, 311C90), a novel dual central and peripheral 5HT1B/1D
agonist: an overview of efficacy.
AB - The efficacy of zolmitriptan (Zomig, 311C90), a 5-hydroxytryptamine (5HT)1B/1D
receptor agonist, in the acute oral treatment of migraine was evaluated in an
extensive clinical trial program. Four randomized, placebo-controlled studies
(total 2480 patients) were performed; data from two of these trials established
that a 2.5 mg dose was on the shoulder of the dose-response curve (2-h headache
response rate 64%), showing similar efficacy to the 5 mg dose (67%). In this
program, the efficacy of zolmitriptan was not influenced by the pretreatment
headache duration; the presence of aura preceding the headache, migraine
associated with menses or migraine upon awakening; or by concomitant use of oral
contraceptives or antidepressants. In addition, zolmitriptan 5 mg proved
consistently effective in the treatment of multiple migraine attacks for up to 1
year. Zolmitriptan reduced the incidence of nausea, photophobia and phonophobia,
reduced impairment of normal activity and demonstrated positive effects on
patients' quality of life. Thus, zolmitriptan is a highly effective acute oral
antimigraine therapy, with 2.5 mg providing the optimal balance between efficacy
and tolerability.
PMID- 9399016
TI - Tolerability profile of zolmitriptan (Zomig; 311C90), a novel dual central and
peripherally acting 5HT1B/1D agonist. International clinical experience based on
> 3000 subjects treated with zolmitriptan.
AB - Zolmitriptan (Zomig, formerly 311C90) at doses of 0.5-50 mg was administered to
316 unique volunteers in clinical pharmacology studies and 2,750 unique patients
in eight clinical studies of acute migraine treatment. Overall, subjects received
almost 50,000 doses; 97% of exposures were at doses > or = 2.5 mg. In the
clinical pharmacology studies, the overall incidence of subject exposures
experiencing at least one adverse event was 52% with zolmitriptan 2.5 mg (28%
with placebo). In placebo-controlled studies, the overall incidence of patients
with at least one adverse event was dose-dependent for zolmitriptan over the 1-15
mg dose range, e.g. 42% and 46% with 1 and 2.5 mg, respectively and 58% with 5 mg
(29% with placebo). Only four serious adverse events attributable to zolmitriptan
were reported. In a long-term study, during which 2,058 outpatients treated a
total of 31,579 migraine attacks with either one or two zolmitriptan 5 mg doses
over a period of up to 1 year, the number of attacks associated with at least one
adverse event was similar after one (26%) and two (24%) doses. The majority (59%)
of the adverse events reported in this study (59%) occurred within 2 h of dosing,
were predominantly mild (59%) or moderate (35%) in intensity, of < or = 4 h
duration (58%), required no further action (94%). In placebo-controlled studies,
the percentage of patients who reported severe adverse events was similar with
zolmitriptan 2.5 mg (4%) and placebo (5%). The most frequently reported adverse
events with zolmitriptan in the placebo-controlled clinical studies were
asthenia, heaviness (other than chest or neck), dry mouth, nausea, dizziness,
somnolence, paresthesia and warm sensations. The type and severity of the adverse
events was not influenced by gender (although the frequency of reported adverse
events was higher in females, as was the case in the placebo group), age,
presence of aura prior to the attack, association of migraine with menstruation,
concurrent medication, or by the addition of a second zolmitriptan dose.
Zolmitriptan showed a similar tolerability profile in the long-term study, in
which a low withdrawal rate due to adverse events of 8% was observed.
Zolmitriptan was not associated with an increased frequency of central nervous
system-related adverse events in a comparative study of sumatriptan, despite pre
clinical and neurophysiological evidence of a dual peripheral and central action
of zolmitriptan. Moreover, zolmitriptan doses of 5-20 mg produced no
statistically significant effects on objective assessments of psychometric
function. Zolmitriptan had no clinically significant effects on blood pressure
(even in patients with controlled mild to moderate hypertension or impaired renal
function), ECGs (e.g. there was no evidence of ischemic events) or clinical
chemistry, hematological or urinalysis measurements. In summary, zolmitriptan is
well tolerated, particularly at the recommended dose of 2.5 mg. Zolmitriptan has
a well-defined dose-response with 2.5 mg proving highly effective and optimizing
the benefit/risk ratio of treatment. Thus, zolmitriptan is well suited as an
acute oral treatment for migraine in the outpatient setting.
PMID- 9399017
TI - Clinical applications of zolmitriptan (Zomig, 311C90).
AB - Zolmitriptan (Zomig, formerly 311C90) is a novel, oral antimigraine drug that is
consistently effective and well tolerated in the acute treatment of migraine
headache and its associated symptoms. The purpose of this article is to review
data available from pharmacological and clinical trials with zolmitriptan and to
summarize the clinically relevant features that distinguish this agent. We will
review the attributes desirable in a migraine drug and use this as a template for
assessing zolmitriptan. Zolmitriptan provides a new oral treatment option for
physicians which should help improve patient outcomes.
PMID- 9399018
TI - Diabetes-induced alterations in platelet metabolism.
AB - OBJECTIVES: This review summarizes the recent findings on some aspects of
platelet metabolism that appear to be affected as a consequence of diabetes
mellitus. The metabolites include glutathione, L-Arginine/nitric oxide, as well
as the ATP-dependent exchange of Na+/K+ and Ca2+. CONCLUSIONS: Several aspects of
platelet metabolism are altered in diabetics. These metabolic events give rise to
a platelet that has less antioxidants, and higher levels of peroxides. The direct
consequence of this is the overproduction platelet agonists. In addition, there
is evidence for altered Ca2+ and Na+ transport across the plasma membrane. Recent
evidence indicates that plasma ATPases in diabetic platelets are not damaged
instead their activities are likely to be modulated by oxidized LDL. Finally,
platelet inhibitory mechanisms regulated by NO appear to be perturbed in the
diabetes disease-state. The combined production of NO and superoxide by NOS
isoforms in the platelet could be a major contributory factor to platelet
pathogenesis in diabetes mellitus.
PMID- 9399019
TI - Reverse cholesterol transport--a review of the process and its clinical
implications.
AB - OBJECTIVES: This review article will summarize the current knowledge surrounding
the reverse cholesterol transport system; the process, the effect of mutations in
genes coding for proteins which function in the system, and the possible clinical
implications of these alterations. RESULTS: High-density lipoprotein-cholesterol
(HDL-C) concentration is a marker for the reverse cholesterol transport (RCT)
system, whereby cholesterol is returned from peripheral cells to the liver for
reuse or excretion in the bile. Increased HDL-C concentrations are generally
accepted to be protective against the future development of atherosclerosis and
coronary artery disease (CAD), but recent evidence has indicated that the
underlying cause of the increased HDL-C may affect whether it is protective or
detrimental. The major steps in the RCT pathway are the efflux of free
cholesterol from cells and binding by pre-beta HDL, esterification of HDL-bound
cholesterol by lecithin cholesterol acyl transferase (LCAT), cholesteryl ester
transfer protein (CETP) mediated exchange of cholesteryl ester and triglycerides
between HDL and apo B-containing particles, and hepatic lipase (HL) mediated
uptake of cholesterol and triglycerides by the liver. Mutations in proteins
active in the RCT pathway can shed light on the functions and control of the
various steps in the system. LCAT deficiency, leading to greatly reduced HDL and
fish eye disease, is not usually associated with increased risk of CAD. Several
new mutations in LCAT have recently been reported, however, which do result in
CAD. Mutations leading to reduced CETP activity result in less CE being directed
into apo-B containing particles and more remaining in the HDL. This has been
associated with increased HDL-C concentrations. The generally accepted hypothesis
that reduced CETP activity leads to reduced CAD risk has been challenged by a
number of recent publications, and has become an area of active investigation.
Mutations leading to reduced HL activity are rare occurrences. To date, all have
been associated with increased HDL-C concentrations and CAD. CONCLUSION: The
development of techniques to identify and characterize the functional
significance of mutations in proteins involved in RCT will aid in the
understanding of the mechanisms and control of this pathway.
PMID- 9399020
TI - Effect of repeated freeze-thaw cycles on maternal serum biological markers for
the detection of fetal trisomies.
AB - OBJECTIVES: We studied the stability of maternal blood markers for screening for
Down syndrome (alpha-fetoprotein, unconjugated estriol, intact human chorionic
gonadotropin (hCG) and free beta-human chorionic gonadotropin) upon repeated
freeze-thaw cycles. DESIGN AND METHODS: Forty-three samples collected from second
trimester normal pregnancies were submitted to five freeze-thaw cycles. After
each cycle, the markers were measured using kits and instruments from Wallac
Canada (AutoDelfia). Results were compared by repeated measures analysis of
variance and by analysis of linear trend (after mathematical transformation of
the results in order to decrease between-sample variation) as a function of the
number of freeze-thaw cycles. RESULTS: No significant differences were observed
by ANOVA (p > 0.1) for any marker. Intact hCG showed a statistically significant
linear downward trend (slope = -0.0063, p = 0.009) while free beta-hCG increased
(slope = 0.011, p = 0.004). After five freeze-thaw cycles, a mean decrease of
3.2% is predicted for intact hCG while free beta-hCG would increase by 5.5% on
average. CONCLUSION: We conclude that the studied markers do not show clinically
significant changes under the evaluated conditions. The observed changes of
intact hCG and free beta-hCG would have a limited impact on the screening
performance.
PMID- 9399021
TI - LDL receptor activity in human leukocyte subtypes: regulation by insulin.
AB - OBJECTIVES: LDL receptors of leukocytes play a key role in lipoprotein uptake,
immunoregulation and the pathogenesis of atherosclerosis. Numerous studies with
different methods of low reliability yielded conflicting results of its
regulation in leukocyte subtypes. DESIGN AND METHODS: LDL receptors of human
leukocytes were measured with use of the monoclonal antibody C-7. Specific C-7
binding was detected by FACS analysis using phycoerythrin-anti-mouse-IgG.
Parallel incubations with FITC-labelled anti-LEU 4 (CD 3), anti-LEU 12 (CD 19)
and anti-MY 4 (CD 14) antibodies were used to distinguish C-7 binding of specific
cell types (T-, B-lymphocytes and monocytes). RESULTS: In contrast to monocytes,
T and B-lymphocytes freshly isolated from healthy blood donors had no detectable
binding capacity for C-7. After 24 and 48 h incubation of cells in a lipid-free
medium, lymphocytes acquired some C-7 binding, albeit still much less than
monocytes. Incubation with insulin for 24 h in a concentration of 0.5
microgram/mL led to an increase in C-7 binding for monocytes (up to 180%).
Saturation experiments with the ligand suggests an increase in the number of
receptors. In contrast the same insulin concentration inhibited C-7 binding of B-
and T-lymphocytes by 35%. CONCLUSIONS: FACS analysis using monoclonal antibodies
seems to be a feasible method for the investigation of lipid metabolism in
leukocytes. The LDL receptor expression and its regulation by insulin differs in
circulating monocytes and lymphocytes.
PMID- 9399022
TI - Radioreceptor assay for sirolimus in patients with decreased platelet counts.
AB - OBJECTIVE: Sirolimus (RAPA) is a new immunosuppressive drug currently in Phase
III clinical trials in combination with cyclosporine A (CsA). The toxicity
profiles for CsA and RAPA are only partially overlapping, with RAPA toxicity
consisting primarily of hyperlipidemia and myelodepression but without the
nephrotoxicity, neurotoxicity, and hepatotoxicity, which are seen with CsA.
Patients in the clinical trial are being monitored using HPLC or LC/MS/MS assays;
there is no immunoassay for RAPA reported to date. We have previously reported a
radioreceptor assay (RRA) for RAPA, which has an excellent correlation with the
HPLC assay (r = 0.997). The RRA has several advantages including excellent
precision, sensitivity, rapid turnaround time, and a one-step extraction
procedure. We report the evaluation of blood samples from patients who were
exhibiting RAPA toxicity and comparison of the RRA results with the HPLC results.
METHODS: EDTA whole blood specimens (n = 42) were obtained from six renal
transplant recipients taking RAPA and CsA and exhibiting decreased platelet
counts. Thirty-two samples from patients without decreased platelet counts were
also received. The samples were analyzed with the RRA and the results were
compared to those obtained with the HPLC assay. RESULTS: By HPLC, the results
ranged from 3.2-72.6 micrograms/L RAPA with 43% of the results > or = 30
micrograms/L. With the RRA, the range was 7.7-83.0 micrograms/L RAPA equivalents,
with 60% of the results > or = 30 micrograms/L. The RRA results are distinctly
higher than the HPLC results all along the range. The correlation between the two
assays was 0.861, with a slope of 0.966 and a Y-intercept of 11.1. CONCLUSION:
Since the RRA is consistently higher than HPLC concentration in patients with
decreased platelet counts, but correlates well in patients with no signs of
toxicity, the RRA may be useful for monitoring patients for toxicity, by giving a
better indication of increasing degree of immunosuppression than the HPLC assay.
PMID- 9399023
TI - Intestinal alkaline phosphatase isoforms in rabbit tissues differ in
glycosylation patterns.
AB - OBJECTIVES: In patients with advanced liver cirrhosis or chronic nephritis, an
intestinal alkaline phosphatase (IAP)-like enzyme is ectopically expressed in the
liver or kidney. In this study, we used rabbit organs as a human pathological
model, because the rabbit liver or kidney expresses an IAP-like enzyme as the
predominant isozyme, unlike humans. METHODS: IAP and the IAP-like enzyme were
purified from rabbit intestine and kidney, respectively, by immunoaffinity
chromatography using a monoclonal antihuman IAP antibody. Some properties of the
IAP and IAP-like enzyme expressed in rabbit organs are compared. RESULTS: Some of
their catalytic and physicochemical properties differed. In particular, the net
charge, molecular mass, and hydrophobicity of IAP from rabbit intestine was
slightly different from the IAP-like enzyme from rabbit kidney. There was a
difference in the sugar chain structure between the two enzymes according to the
results of lectin affinity chromatography, and part of the peptide maps differed
slightly. However, there was no difference in the peptide maps after treatment
with endo-N-acetylglucosaminidase F. CONCLUSIONS: The primary structures of IAP
and the IAP-like enzyme are basically similar, except for the glycosylation
process of the respective AP isozymes.
PMID- 9399025
TI - Plasma diamine oxidase activities in renal dialysis patients, a human with
spontaneous copper deficiency and marginally copper deficient rats.
AB - OBJECTIVES: Intestine and kidney are generally the most concentrated sources of
the copper metalloenzyme diamine oxidase (DAO). Clinically, plasma DAO activities
are used to diagnose disruptions in intestinal integrity. This study determined
whether DAO activities were also affected by kidney injury or copper nutritional
status. DESIGN AND METHODS: Plasma DAO activities were measured in renal dialysis
patients without diagnosed intestinal disease (n = 75), controls (n = 23), an
adult with spontaneous copper deficiency before and after copper repletions, and
in rats fed either adequate or marginal copper diets (8 or 2 mg copper/kg diet)
for 7 months. RESULTS: This study found high DAO activities in renal dialysis
patients and low activities during spontaneous copper deficiency. Low activities
were also seen for marginally copper deficient rats. CONCLUSIONS: Tissue injury
induced elevation of DAO activities is not limited to intestinal injury, and low
DAO values may be useful for assessing copper nutritional status.
PMID- 9399024
TI - Plasma total antioxidant capacity in an adult Hong Kong Chinese population.
AB - OBJECTIVES: To examine plasma total antioxidant capacity (TAOC) in a Chinese
population with a lower incidence of cardiovascular disease compared with
Caucasian populations, in relation to dietary intake, age, sex, and the presence
of cardiovascular diseases. DESIGN AND METHODS: As part of a randomized territory
wide survey stratified by sex and 10-year age groups; 728 subjects (367 men, 361
women) were recruited. Dietary intake assessment was by a food frequency
questionnaire; plasma TAOC was estimated by the ABTS method. RESULTS: The TAOC
values were normally distributed, the mean +/- SD being 1.78 +/- 0.18 mmol/L. The
mean value was higher in men compared with women, inspite of a lower dietary
intake of vitamins A and C per 1000 kcal in the former. Subjects who consumed
water spinach twice or more a week had higher mean levels. No difference in mean
levels was observed between those with and without hypertension or cardiovascular
disease. CONCLUSION: Measurement of plasma TAOC as a risk factor in
epidemiological studies of cardiovascular diseases may have limited use, since
TAOC include substances associated with a protective effect as well as increased
risk.
PMID- 9399026
TI - Analysis of sertraline and desmethylsertraline in human plasma and red blood
cells.
PMID- 9399027
TI - Serum Mn-superoxide dismutase in acute myocardial infarction.
PMID- 9399028
TI - Hereditary kidney diseases. Introduction.
PMID- 9399029
TI - Pathogenesis of autosomal dominant polycystic kidney disease: recent
developments.
PMID- 9399030
TI - Autosomal recessive polycystic kidney disease.
PMID- 9399031
TI - Prevalence of hypertension according to phenotype and gender in autosomal
dominant polycystic kidney disease.
PMID- 9399032
TI - Role of renin-angiotensin-aldosterone system and of sympathetic activity in
arterial hypertension associated with autosomal dominant polycystic kidney
disease.
PMID- 9399033
TI - Hypertension in polycystic kidney disease type 1 and 2 and its effect on the age
of onset of end-stage renal disease.
PMID- 9399034
TI - Sodium-lithium countertransport in autosomal polycystic kidney disease.
PMID- 9399035
TI - Inflammatory cytokine profile in autosomal dominant polycystic kidney disease.
PMID- 9399036
TI - Extracellular matrix abnormality may be responsible for cyst development.
PMID- 9399037
TI - Mutations and intragenic polymorphisms in the diagnosis of autosomal dominant
polycystic kidney disease type 1.
PMID- 9399038
TI - Expression of protein fragments from the human PKD1 gene and production of rabbit
polyclonal antibodies to the recombinant proteins.
PMID- 9399039
TI - Molecular genetic investigations in autosomal dominant polycystic kidney disease.
Gene Mutation detection, linkage analysis, and preliminary ACE gene I/D
polymorphism association studies: an update.
PMID- 9399040
TI - Oral-facial-digital syndrome type 1 coexisting with polycystic kidney disease.
PMID- 9399041
TI - Nephronophthisis-medullary cystic kidney disease complex: a report on 24 patients
from 5 families with Italian ancestry.
PMID- 9399042
TI - Renal manifestations of tuberous sclerosis complex.
PMID- 9399043
TI - The TSC2/PKD1 contiguous gene syndrome.
PMID- 9399044
TI - A case of Pringle-Bourneville tuberous sclerosis with renal angiomyolipomas:
clinical and radiological aspects.
PMID- 9399045
TI - Tuberous sclerosis and nephrocalcinosis.
PMID- 9399046
TI - A tuberous sclerosis patient with a large TSC2 and PKD1 gene deletion shows
extrarenal signs of autosomal dominant polycystic kidney disease.
PMID- 9399047
TI - Tuberous sclerosis complex and early-onset autosomal dominant polycystic kidney
disease as a 'contiguous gene' syndrome: report of a case.
PMID- 9399048
TI - Pulmonary lymphangioleiomyomatosis and tuberous sclerosis complex.
PMID- 9399049
TI - The kidney and von Hippel-Lindau disease: impact of molecular genetic analysis of
the VHL gene for clinical management.
PMID- 9399050
TI - Von Hippel-Lindau (VHL) gene analysis in Italian families with VHL disease.
PMID- 9399051
TI - Planning kidney surgery in von Hippel-Lindau disease.
PMID- 9399052
TI - Alport syndrome: clinical and genetic correlation in a type-IV collagen disease.
PMID- 9399053
TI - Clinical and molecular diagnosis in inherited kidney diseases: three examples.
PMID- 9399054
TI - Expression of alpha (IV) chains in Alport's syndrome and its correlation with
ultrastructural and genetic data.
PMID- 9399055
TI - Molecular diagnosis of Alport syndrome: the experience in Siena.
PMID- 9399056
TI - X-linked Alport syndrome with normal distribution of collagen IV alpha chains in
epidermal basement membrane.
PMID- 9399057
TI - Kidney transplantation in Alport's syndrome.
PMID- 9399058
TI - Primary hyperoxaluria.
PMID- 9399059
TI - Renal pathology in hyperoxaluria.
PMID- 9399060
TI - Clinical aspects of cystinuria.
PMID- 9399061
TI - Cystinuria: recent advances in pathophysiology and genetics.
PMID- 9399062
TI - Kidney involvement in Anderson-Fabry disease.
PMID- 9399063
TI - Anderson-Fabry disease. Three families detected in 2 years: unusual occurrence or
good interdisciplinary collaboration?
PMID- 9399064
TI - Genetic approach to the study of cellular ion transport anomalies in idiopathic
calcium nephrolithiasis.
PMID- 9399066
TI - Familial hemolytic uremic syndrome: simulation linkage analysis.
PMID- 9399065
TI - Constitutive nitric oxide synthase gene expression in Bartter's and Gitelman's
syndrome and its relationship to their vascular hyporesponsiveness.
PMID- 9399067
TI - Abnormal blood glucose and insulin response during oral glucose tolerance test in
familial renal glycosuria.
PMID- 9399068
TI - Renal transplantation in patients with hereditary kidney disease: our experience.
PMID- 9399069
TI - An information center for rare diseases: a tool for epidemiologic and clinical
studies in rare diseases.
PMID- 9399070
TI - Transcriptional regulation of vertebrate Hox genes during embryogenesis.
AB - The identification in transgenic mice of Hox gene DNA regulatory elements that
can recapitulate certain aspects of the endogenous gene's expression pattern has
proceeded with great success. However, perfect reproduction of the correct
expression pattern is uncommon, even when large genomic fragments spanning
neighboring genes are analyzed, suggesting that important regulatory regions may
be located at large distances from the genes they control or that their specific
context may be important. Currently, four groups of transcriptional regulators
have been identified that have been shown to directly regulate Hox gene
expression in the vertebrate embryo: retinoic acid receptors, Krox20, members of
the Pbx/exd family, and the Hox genes themselves.
PMID- 9399071
TI - Histone H1 and chromatin higher-order structure.
AB - The linker histone H1, or its variants such as H5, have long thought to be
involved in promoting the organization of chromatin into a higher-order
structure, the 30 nm filament. However, the location of H1 in the filament, its
role in filament formation and the structure of the 30 nm filament itself have
all been controversial. This article reviews recent results that address these
questions.
PMID- 9399072
TI - Application of atomic force microscopy to visualization of DNA, chromatin, and
chromosomes.
AB - The scanning force microscope (SFM, also called the atomic force microscope, AFM)
provides a new and powerful method for visualization and manipulation of
biological samples. Its high precision and sensitivity allow the investigator to
interrogate samples at very high spatial resolution and simultaneously accumulate
a variety of data types, including topography, viscoelasticity, chemical
properties, and local friction. We provide here a brief review of the literature
describing the current state of the art in the application of SFM to the study of
DNA, chromatin and chromosomes, and some examples from this laboratory.
Suggestions for future directions of this technology are also presented.
PMID- 9399073
TI - The regulation of clotting factors.
AB - Blood clotting involves a multitude of proteins that act in concert in response
to vascular injury to produce the procoagulant enzyme alpha-thrombin, which in
turn is responsible for the generation of the fibrin plug. However, while
generation of the fibrin plug is required for the arrest of excessive bleeding,
unregulated clotting will result in the occlusion of the blood vessels and
thrombosis. Thus, the regulation of the delicate balance between the procoagulant
and anticoagulant mechanisms is of extreme importance for survival. While the
majority of proteins involved in blood coagulation circulate as inactive zymogens
that require proteolytic activation in order to function, approximately 1% of the
circulating factor VII molecules are active. Factor VIIa, possess a serine
protease active site, has poor catalytic activity, and is not inhibited by the
circulating stoichiometric protease inhibitors. Following injury to the
vasculature and subsequent exposure of the integral membrane glycoprotein, tissue
factor (TF), the circulating factor VIIa molecules can bind to the exposed TF
forming the extrinsic tenase complex (TF/factor VIIa) and initiate the blood
coagulation process. Formation of the TF/factor VIIa complex increases the
catalytic efficiency of the enzyme by four orders of magnitude when compared with
factor VIIa alone. This cell-associated enzymatic complex initiates a series of
enzymatic reactions, leading to the generation of alpha-thrombin and ultimately
to the formation of the fibrin plug. The procoagulant enzymatic complexes (i.e.,
prothrombinase, intrinsic tenase, and extrinsic tenase) are similar in structure
and composed of an enzyme, a cofactor, and the substrate associated on a cell
surface in the presence of divalent metal ions. While the activity of the
extrinsic tenase complex is limited by the availability (exposure) of its cell
associated cofactor (TF) it is remarkable that the activities of both the
prothrombinase complex (factor Va/factor Xa) as well as the intrinsic tenase
complex (factor VIIIa/factor IXa) are limited by the presence of the two soluble,
nonenzymatic cofactors, factor Va and factor VIIIa. Factor Va and factor VIIIa,
which are very similar in structure and function, are required for prothrombinase
and intrinsic tenase activities, respectively, because both cofactors express a
dual function in their respective complexes, acting as an enzyme receptor and
catalytic effector on the cell surface. The cofactors derive from inactive plasma
precursors by regulatory proteolytic events that involve alpha-thrombin. In
general, bleeding tendencies are usually associated with defects in the
activation of one of the zymogens or the cofactors of the procoagulant complexes.
However, the activity of all of the complexes is also limited by the availability
of an adequate membrane surface provided by endothelial cells, platelets, and
monocytes. The cell surface provides a site for the recruitment of the
appropriate proteins and allows for fast and efficient clot formation. In the
absence of an appropriate membrane surface, the procoagulant complexes have
limited catalytic efficiency. Thus, timely exposure of the adequate membrane
surface is an additional step in the regulation of alpha-thrombin formation.
alpha-Thrombin participates in its own down-regulation by binding to the
endothelial cell receptor thrombomodulin, initiating the protein C pathway, which
in turn leads to the formation of activated protein C (APC). APC is required for
efficient neutralization of factor Va cofactor activity, which results in the
inactivation of the prothrombin-activating complex. This inactivation can only
occur in the presence of the appropriate membrane surface. Thus, while following
alpha-thrombin activation, factor VIIIa is rapidly and spontaneously inactivated
by dissociation of the A2 domain from the rest of the cofactor, APC is required
for down-regulation of alpha-thrombin formation by prothrombinase. (ABSTRACT
PMID- 9399074
TI - Vasculitis in children: a diagnostic challenge.
PMID- 9399075
TI - Paternal effects in Drosophila: implications for mechanisms of early development.
AB - The study of paternal effects on development provides a means to identify sperm
supplied products required for fertilization and the initiation of embryogenesis.
This review describes paternal effects on animal development and discusses their
implications for the role of the sperm in egg activation, centrosome activity,
and biparental inheritance in different animal species. Paternal effects observed
in Caenorhabditis elegans and in mammals are briefly reviewed. Emphasis is placed
on paternal effects in Drosophila melanogaster. Genetic and cytologic evidence
for paternal imprinting on chromosome behavior and gene expression in Drosophila
are summarized. These effects are compared to chromosome imprinting that leads to
paternal chromosome loss in sciarid and coccid insects and mammalian gametic
imprinting that results in differential expression of paternal and maternal loci.
The phenotypes caused by several early-acting maternal effect mutations identify
specific maternal factors that affect the behavior of paternal components during
fertilization and the early embryonic mitotic divisions. In addition, maternal
effect defects suggest that two types of regulatory mechanisms coordinate
parental components and synchronize their progression through mitosis. Some
activities are coordinated by independent responses of parental components to
shared regulatory factors, while others require communication between paternal
and maternal components. Analyses of the paternal effects mutations sneaky, K81,
paternal loss, and Horka have identified paternal products that play a role in
mediating the initial response of the sperm to the egg cytoplasm, participation
of the male pronucleus in the first mitosis, and stable inheritance of the
paternal chromosomes in the early embryo.
PMID- 9399076
TI - Drosophila myogenesis and insights into the role of nautilus.
AB - Several aspects of muscle development appear to be conserved between Drosophila
and vertebrate organisms. Among these is the conservation of genes that are
critical to the myogenic process, including transcription factors such as
nautilus. From a simplistic point of view, Drosophila therefore seems to be a
useful organism for the identification of molecules that are essential for
myogenesis in both Drosophila and in other species. nautilus, the focal point of
this review, appears to be involved in the specification and/or differentiation
of a specific subset of muscle founder cells. As with several of its vertebrate
and invertebrate counterparts, it is capable of inducing a myogenic program of
differentiation reminiscent of that of somatic muscle precursors when expressed
in other cell types. We therefore favor the model that nautilus implements the
specific differentiation program of these founder cells, rather than their
specification. Further analyses are necessary to establish the validity of this
working hypothesis. Studies have revealed a critical role for Pax-3 in specifying
a particular subset of myogenic cells, the progenitors of the limb muscles. These
myogenic cells migrate from the somite into the periphery of the organism, where
they differentiate. These myoblasts do not express MyoD or myf5 until they have
arrived at their destination and begin the morphologic process of myogenesis
(Bober et al., 1994; Goulding et al., 1994; Williams and Ordahl, 1994). They then
begin to express these genes, possibly to put the myogenic plan into action.
Thus, as with nautilus, MyoD and myf5 may be necessary for the manifestation of a
muscle-specific commitment that has already occurred. By comparison with
vertebrates, it was anticipated that the single Drosophila gene would serve the
purpose of all four vertebrate genes. However, its restricted pattern of
expression and apparent loss-of-function phenotype are inconsistent with this
expectation. It remains to be determined whether nautilus functions in a manner
similar to just one of the vertebrate genes. Since the myf5- and MyoD-expressing
myoblasts are proliferative, the loss of one cell type appears to be compensated
by proliferation of the remaining cell type. This apparent plasticity may obscure
differences in mutant phenotype resulting from the loss of particular cells that
express each of these genes. In Drosophila, by comparison, nautilus-expressing
cells committed to the myogenic program undergo few, if any, additional cell
divisions, and thus no other cells are available to compensate for the loss of
nautilus. Therefore, the apparent differences between the Drosophila nautilus
gene and its vertebrate counterparts may reflect, at least in part, differences
in the developmental systems rather than differences in the function of the genes
themselves.
PMID- 9399077
TI - Hydrozoa metamorphosis and pattern formation.
PMID- 9399078
TI - Primate embryonic stem cells.
AB - Primate embryonic stem (ES) cells are derived from preimplantation embryos, have
a normal karyotype, and are capable of indefinite, undifferentiated
proliferation. Even after culture for more than a year, primate ES cells maintain
the potential to differentiate to trophoblast and derivatives of embryonic
endoderm, mesoderm, and ectoderm. In this review, we compare the characteristics
of ES cell lines from two primate species, the rhesus monkey (Macaca mulatta) and
the common marmoset (Callithrix jacchus), with the characteristics of mouse ES
cells and human embryonal carcinoma cells. We also discuss the implications of
using primate ES cells to understand early human development and discuss the
practical and ethical implications for the understanding and treatment of human
disease.
PMID- 9399079
TI - Sex determination in plants.
AB - The majority of flowering plants produce flowers that are "perfect." These
flowers are both staminate (with stamens) and pistillate (with one or more
carpels). In a small number of species, there is spatial separation of the sexual
organs either as monoecy, where the male and female organs are carried on
separate flowers on the same plant, or dioecy, where male and female flowers are
carried on separate male (staminate) or female (pistillate) individuals. Sex
determination systems in plants, leading to unisexuality as monoecy or dioecy,
have evolved independently many times. In dioecious plant species, the point of
divergence from the hermaphrodite pattern shows wide variation between species,
implying that the genetic bases are very different. This review considers
monoecious and dioecious flowering plants and focuses on the underlying genetic
and molecular mechanisms. We propose that dioecy arises either from monoecy as an
environmentally unstable system controlled by plant growth substances or from
hermaphroditism where the underlying mechanisms are highly stable and control
does not involve plant growth substances.
PMID- 9399080
TI - Somitogenesis.
AB - We are still far from understanding "somitogenesis" as a whole, but there is an
emerging picture of the tissue interactions and molecular mechanisms that
underlie and govern various aspects of this essential multistep patterning
process in vertebrates. The ability to form segmental units appears to be a
property specific to the paraxial mesoderm (as opposed to lateral or limb
mesoderm), and this ability is probably acquired during early development, when
paraxial mesoderm is specified and emerges from the primitive streak. Signaling
molecules expressed in the primitive streak and tail bud are prime candidates
involved in specifying paraxial (as well as other mesodermal) fates. Increasing
levels of signaling molecules may be required in posterior regions of the embryo,
and combinatorial signals may be essential to specify the paraxial mesoderm along
the entire anterior-posterior axis. However, most of the pivotal signals, and the
ways in which they are integrated and interact, remain enigmatic. Once the
paraxial mesoderm is formed, segmentation proceeds largely without the
requirement for continuous interactions with surrounding tissues. Somitomeres
represent a morphologic pattern in the mesenchymal presomitic mesoderm, but their
significance for somite formation is unclear. Molecular patterns are established
in the presomitic mesoderm and probably are of functional significance. Cell
interactions within the paraxial mesoderm appear to be involved in forming
segment borders and ensuring their maintenance during subsequent differentiation
of somites. These interactions are, at least in part, mediated by components of
the conserved Notch signaling pathway, which may have multiple functions during
somitogenesis. Epithelial somites are clearly a result of segmentation, but
epithelialization is not the mechanism to form segments, supporting the idea that
the basic mechanisms that govern segmentation in the mesoderm of vertebrates are
very similar in different species despite divergent types of resulting segments
(i.e., epithelial somites versus rotated myotomes). Concomitantly with
segmentation, segment polarity and positional specification are established. How
these processes are linked to, and depend on, each other is unknown, as is how
they are regulated and how segmentation is coordinated on both sides of the
neural tube. In contrast to early patterning in the presomitic mesoderm,
patterning of the mature somites during their subsequent differentiation is the
result of extensive tissue interactions. Virtually all tissues in close proximity
to somites provide signals that are involved in induction or inhibition of
particular differentiation pathways, but how these pathways are initiated is less
clear. Some of the molecules mediating inductive signals and tissue interactions
are known, and a growing number of candidate genes are potentially involved in
regulating various steps of somitogenesis. The roles of these genes have yet to
be analyzed. In addition, the molecular genetic analysis of mutations affecting
somitogenesis, which were collected in the mouse and more recently in the
zebrafish (Driever et al., 1996; Haffter et al., 1996; van Eeden et al., 1996),
promises to add important new insights into this process. Much remains to be
done, but the tools are at hand to provide further understanding of the molecular
mechanisms underlying somitogenesis.
PMID- 9399081
TI - Improving control of patient status in critical care.
PMID- 9399082
TI - A clinical description of the IMPROVE Data Library.
PMID- 9399083
TI - Building the IMPROVE Data Library.
PMID- 9399084
TI - Collecting EEG signals in the IMPROVE Data Library.
PMID- 9399085
TI - Using artificial neural networks for classifying ICU patient states.
PMID- 9399086
TI - Data fusion of electrophysiological and haemodynamic signals for ventricular
rhythm tracking.
PMID- 9399087
TI - Signal processing in prolonged EEG recordings during intensive care.
PMID- 9399088
TI - Monitoring the autonomic nervous system in the ICU through cardiovascular
variability signals.
PMID- 9399089
TI - Evaluating time-varying heart-rate variability power spectral density.
PMID- 9399090
TI - A portable monitor for fetal heart rate and uterine contraction.
PMID- 9399091
TI - Locomotion and steering aspects in automation of colonoscopy. Part one.A
literature review.
PMID- 9399093
TI - Bowel-sound signal enhancement using adaptive filtering.
PMID- 9399092
TI - Relative and intermittent cardiorespiratory coordination.
PMID- 9399094
TI - Patenting biotechnology: ethical and philosophical issues.
PMID- 9399095
TI - Whitaker Foundation funds genome-related research.
PMID- 9399096
TI - Identification of localized anti-host responses in the graft mesenteric lymph
node and Peyer's patches after rat small bowel transplantation.
AB - This study determined the activation status of recipient and donor lymphocyte
populations in the graft mesenteric lymph node (MLN) and Peyer's patches (PP)
after allogeneic, heterotopic rat small bowel transplantation without
immunosuppression. Untransplanted and isografted animals served as controls. The
activation status of lymphocyte subsets was determined by flow cytometric
evaluation of lymphoblastoid transformation (forward light scatter; FSc). The
proportion of activated lymphocytes in the MLN and PP of allografted animals
progressively increased. There was also an early transient activation of MLN
lymphocytes in isografted animals which probably resulted from surgery-related
inflammation. Activated alpha/beta TCR+ and CD4+ cells were detected in the MLN
as early as day 3, whereas there was little activation of CD8+ cells.
Interestingly, donor lymphocytes became more activated than recipient
lymphocytes. Allografting also led to activation of graft-derived PP alpha/beta
TCR+ and CD8+ cells, yet there was no detectable activation of recipient-derived
lymphocytes. In summary, this study has identified activated donor lymphocytes in
the graft MLN and PP after allogeneic small bowel transplantation. Although
rejection predominates without immunosuppression, the presence of an underlying
anti-recipient response within the small bowel allograft may contribute to graft
damage via the localized release of cytokines and inflammatory mediators.
PMID- 9399097
TI - Identification of core B cell epitope in the synthetic peptide inducing cross
inhibiting antibodies to a surface protein antigen of Streptococcus mutans.
AB - A surface protein antigen (PAc) of Streptococcus mutans, in particular, A-region
of the molecule, has been considered as a possible target for the development of
an effective anticaries vaccine. This region might be implicated in the induction
of dental caries via interaction with salivary components. We have recently
specified a unique peptide, TYEAALKQYEADL, as one of the minimum peptides that
completely corresponds to the amino acid sequence of a part of the A-region. The
unique peptide contains both T and B cell epitopes for the induction of cross
reacting antibodies to the PAc. In this study, we synthesized valine or glycine
substituted peptide analogs of this peptide and examined core B cell epitopes of
this unique peptide by using ELISA inhibition assay. As a result, the core amino
acid residues of -Y------Y---- for B cell recognition were found to likely be not
only important amino acids stabilizing the structure, but also might be essential
for induction of the cross-inhibiting antibodies against PAc. These results will
hopefully provide us with useful information for the design of an effective
anticaries peptide vaccine.
PMID- 9399098
TI - Comparison of different immunoenzymatic methods for the determination of the fine
specificity and affinity constants of polyclonal antibodies against pseudopeptide
haptens.
AB - We evaluated two phosphinopeptides and one phosphonopeptide, which are transition
state analogs of a proteolytic reaction, for their ability to generate murine
polyclonal antibodies. The specificity of these antisera was determined by
indirect and competitive ELISA. Cross-reactivity analysis by these ELISA showed
that the antisera recognized selectively haptens containing a phosphate group.
The pseudopeptides recognized by the antisera in the indirect ELISA were not the
same, however, as those recognized in the competitive ELISA. The differences
between these results are probably due to the presentation forms of the hapten,
i.e., passively adsorbed in the former ELISA format and soluble in the latter.
The affinity of the antibodies was then determined by using two methods based on
competitive ELISA, one described by Friguet et al. and the other by Seligman. The
dissociation constant (Kd) values calculated by the two methods, for an antiserum
and its homologous hapten, are similar. However, only the middle portion of the
inhibition scale in Seligman's method gave access to reliable values.
Nevertheless, the Seligman representation allowed us to underscore the large
range of affinity constants of the polyclonal antibodies.
PMID- 9399099
TI - In vitro suppression of the normal mitogenic T lymphocyte response by steady
state sickle cell disease sera.
AB - This study is part of a long term evaluation of sickle cell disease (SCD) as a
paradigm for immunosuppression. Serum was obtained from 43 SCD patients during
the steady (healthy) state. Peripheral blood mononuclear cells (PBMC), separated
by density gradient were obtained from 8 normal healthy donors. PBMC were
utilized in assays directly or as a source for obtaining, total T (CD3) and
helper T (CD4) cell populations separated by specific T cell columns. Standard in
vitro phytohemagglutinin (PHA) stimulation of lymphocyte cultures was done with
culture media containing 10% SCD serum, as compared to normal pooled O, Rh+ (O+)
serum. Mitogenic responses were expressed as mean counts per minute (cpm) and
stimulation index of triplicate cultures. Results revealed PHA responses were
positive in all experiments when a standard stimulation index of 10 or greater
was used as a test parameter for comparison. Positive results were demonstrated
in 43/43 (100%) of triplicate cultures regardless of serum type in all
experiments. Conversely, by using mean cpm as the test criterion, suppression of
PHA response was shown in SCD serum supplemented cells as follow; 36/43 (84%) of
PBMC, 35/43 (81%) of CD3 and 37/43 (86%) of CD4 cultures. The degree of
suppression ranged from > 10% to 98% in individual experiments, as compared to O+
serum. Inhibitors of normal T lymphocyte in vitro PHA response appear to be
present in a significant percentage of SCD sera even during the healthy state of
disease. Type 2 cytokines which suppress cell mediated immunity would seem to be
the most likely inhibitory agents.
PMID- 9399100
TI - Immunoglobulins for intravenous use inhibit TNF alpha cytotoxicity in vitro.
AB - Intravenous immunoglobulins (IVIg) have been used as an immunomodulatory therapy
in a variety of diseases. Several mechanisms of action have been proposed, one of
which is interference with the cytokine network. We have investigated the effect
of IVIg on the cytotoxicity of human TNF alpha. IVIg was capable of protecting
L929 fibroblasts from TNF alpha induced cell death. This effect was not species
specific and was mediated by both the Fc and the Fab portion of immunoglobulins.
Since the effect was also seen when IVIg was added after the removal of TNF alpha
from the culture medium, it seems to be independent of the interaction of TNF
alpha with its receptor. We conclude that IVIg either act on some point of the
TNF alpha signalling pathway or influence the cell cycle unspecifically. The
cytoprotective effect of IVIg potentially could contribute to the beneficial
effect described for various diseases.
PMID- 9399101
TI - Amaranthus leucocarpus lectin recognizes human naive T cell subpopulations.
AB - Amaranthus leucocarpus lectin (ALL) is specific for GalNAc residue found in the
inner core of Gal beta 1,3GalNAc alpha 1,O-Ser/Thr disaccharide (T-antigen) or
GalNAc alpha 1,O-Ser/Thr (Tn-antigen). Flow cytometric analysis using fluorescein
labeled lectin and monoclonal antibodies against human cell surface markers
indicated that 5.7% of mononuclear cells from human healthy donors are recognized
by ALL. These cells have the phenotype CD2+CD4+CD19- and most of the lymphocytes
recognized are also CD27+, CD45RA+ and CD43+. ALL possesses mitogenic activity on
lymphocytes after neuraminidase treatment. Our results indicate that the
receptors recognized by ALL could be considered surface markers for naive human T
lymphocyte subsets.
PMID- 9399102
TI - Early recipient-donor switch of the complement type after liver
xenotransplantation.
AB - Liver transplantation is an immunological peculiarity with respect to the
resistance of the graft to humoral rejection. We undertook a kinetic analysis of
molecules involved in humoral rejection for a period of one week following
xenografting in the hamster to rat model system. A complement-dependent
lymphocytotoxicity test (CDC) was used to detect anti-donor antibodies in the
recipient rats. Complement was studied by two methods. Function of the classical
complement pathway was evaluated with a hemolytic assay, and C3 was measured by
radial immunodiffusion. Conversion of the major plasma proteins from recipient to
donor profile was studied by zone electrophoresis on agarose. CDC showed antibody
titers rose during the first week post-transplantation, and they were of
complement-activating isotypes. Zone electrophoresis showed almost complete
replacement of rat C3 by hamster C3 within 72 hours. Hemolytic assay of
complement on day 6 post-transplant showed serum of the xenograft recipients
could lyse erythrocytes sensitized with rat antibody with 80% of efficiency of
normal rat serum. Our data show the effector molecules for humoral rejection, rat
antibodies with anti-hamster specificity and a functional complement cascade,
were present within the first week following transplantation. Rapid conversion of
serum complement to hamster proteins maintains compatibility with the species
specific membrane inhibitors of complement activation expressed by the
xenografted hepatocytes, and could limit complement-mediated damage.
PMID- 9399103
TI - Regulatory role of CD8 in major histocompatibility complex-unrestricted
tumoricidal activity of mouse T cells activated with anti-CD3 monoclonal
antibody.
AB - Antigen-nonspecific CD8+ cytotoxic T cells induced with anti-CD3 monoclonal
antibody (mAb) are able to kill tumor cells in a major histocompatibility complex
(MHC)-unrestricted fashion. However, the role of CD8 in the MHC-independent
tumoricidal activity of anti-CD3-activated killer T (AK-T) cells has not been
investigated. Here we show that anti-CD8 alpha mAb inhibits, in a dose-dependent
fashion, lysis of P815 and YAC-1 tumor cells by mouse AK-T cells. The inhibition
of MHC-unrestricted cytotoxicity by anti-CD8 alpha mAb cannot be attributed to
interference with an adhesion-like function of CD8 towards class I MHC molecules
on the target cells because anti-CD8 alpha mAb (i) had equal inhibitory effects
on the cytolysis of tumor target cells regardless of their relative level of
class I MHC molecule expression and (ii) did not interfere with the formation of
conjugates between AK-T cells and class I MHC-bearing P815 tumor cells. However,
anti-CD8 alpha mAb abrogated AK-T cell granule exocytosis in the presence of P815
tumor cells, indicating a regulatory role for CD8 in the signal transduction
events which result in lysis of the tumor target cells. Immunoblot analysis of
the post-nuclear fraction of lysates from AK-T cells exposed to P815 tumor cells
in the presence of anti-CD8 alpha mAb revealed reduced phosphorylation of
tyrosine residues on a protein with an Mr of approximately 62 kDa. Taken
together, these data suggest that CD8 is able to affect the tumoricidal activity
of MHC-unrestricted AK-T cells independent of class I MHC molecules on the target
cell.
PMID- 9399104
TI - Mechanisms involved in activation of human eosinophil exocytosis by substance P:
an in vitro model of sensory neuroimmunomodulation.
AB - Substance P (SP), a tachykinin with a wide range of biological activities
including a priming effect on human eosinophil chemotaxis, was investigated for
its influence on eosinophil cytotoxic function measured as degranulation of
eosinophil-derived neurotoxin (EDN). Peripheral blood was obtained from healthy
volunteers and the degranulation assays were performed using radioimmunoassay
(RIA). SP and its C-terminal elicited EDN release in a time-dependent mode at a
narrow range of doses with optimal activity of 10(-6) M. FK888 (NK-1 receptor
antagonist) inhibited EDN release stimulated by SP in dose dependency, also a
complete inhibition was observed when eosinophils were preincubated with 1000
ng/ml pertussis toxin (PTX). Pre-exposure of eosinophils to staurosporine
resulted in blockage of SP-induced EDN release in a dose-dependent mode. On the
other hand, SP at 10(-7) M and 10(-8) M primed eosinophils to suboptimal dose
(10(-8) M) of Platelet activating factor (PAF) resulting into significant
enhancement of EDN release. SP(4-11) fragment showed a similar activity while
SP(1-4) fragment was not active. SP priming of eosinophils was not affected by
Ca2+ depletion, however, it caused a change in the pattern of the intracellular
calcium influx against the suboptimal dose of PAF. These results suggest that SP
i) may induced human eosinophil matrix protein degranulation through a receptor
mediated mechanism coupled to PTX sensitive G protein(s) with the probability of
linkage to phospholipase C activation, and, ii) primes human eosinophils for an
exalted inflammatory response through a Ca2+ independent pathway.
PMID- 9399105
TI - CD5+ B cell-dependent regulation of the murine T-cell independent immune response
against the human blood group A antigen.
AB - The CD5+B lymphocyte (B1a) population is known to be involved in most immune
responses to microorganism TI antigens. Moreover, xid mice deficient for immune
responses against TI-2 antigens are known to lack the B1a population, suggesting
a role for B1a cells in TI-2 immune responses. We previously established that the
oligosaccharide human blood group A antigen stimulated murine TI-2 immune
responses. In this work, we show that the frequency of anti-A-secreting
hybridomas was higher in mice with larger splenic B1a populations and that in
vivo anti-CD5 treatment reduced anti-A immune response without affecting the
response against TD RBC antigens. A similar effect was observed by in vitro anti
CD5 treatment of splenocytes. The in vivo anti-CD5 treatment also interfered with
the immunization-dependent increase in splenocyte numbers. These results are in
agreement with an important role for the B-cell CD5 receptor in the regulation of
TI-2 immune responses possibly mediated by its interaction with the CD72 ligand.
PMID- 9399106
TI - Interleukin-1 and interleukin-1 receptor antagonist in systemic lupus
erythematosus.
AB - Interleukin-1 (IL-1) is thought to play an important role in the immunopathology
of systemic lupus erythematosus (SLE). IL-1 receptor antagonist (IL-1ra) exhibits
a dose-responsive inhibition of IL-1 effects, and Fcr receptors play a key role
in IL-1ra production. To clarify the relationship between IL-1, IL-1 receptor
antagonist (IL-1ra) production, and Fcr receptors in SLE, fifteen untreated lupus
patients (9 females and 6 males) were evaluated. IL-1 and IL-1ra production from
both monocytes and neutrophils was determined by both a murine thymocyte
proliferation assay and ELISA. The expression of Fcr receptors on both monocytes
and polymorphonuclear cells was measured by flow cytometry. There was no
significant difference between IL-1 beta and IL-1ra production from ex vivo
monocytes between lupus patients and normals. However, serum IL-1ra was
significantly higher in lupus patients than in normals. The expression of FcrRII
(CD32) on monocytes was lower in lupus patients than in normals. There was no
correlation between the expression of FcrRII and the serum immune complexes; the
production of IL-1ra and the expression of CD32, serum immune complex levels, and
serum IgG. Both serum IL-ra and the production of IL-1ra had no correlation to
SLEDAI, C3, C4, C1q, or ESR. These observations suggest that although IL-1 and IL
1ra may not play a major role in the initiation of pathogenesis of lupus, the low
FcrRII expression in lupus may reflect low immune complex clearance and
contribute to disease pathogenesis.
PMID- 9399107
TI - Immunoassay of human Neisseria meningitidis serogroup A antibody.
AB - An enzyme immunoassay is described which quantitates antibodies to Neisseria
meningitidis serogroup A capsular polysaccharide in human sera. Modifications of
a previously developed two-day assay by Carlone et al. were made to permit
analysis in one day and to be compatible with automation. The allowable
variations in assay conditions and the areas in which stringent control must be
maintained for consistent assay performance are described. Antigen-coating
parameters, the kinetics of primary and secondary antibody incubation steps, the
buffer compositions, including detergents, serum requirements, and the need for
blocking steps were examined. Our modified one-day assay showed excellent
agreement with the standardized method of Carlone, with a correlation coefficient
between the two methods of 0.989. This assay is adaptable within a permissible
range of parameters thus facilitating the implementation of the standardized
assay. This will maximize the consistency of results from serum analysis for
conjugate vaccine trials related to serotype A Neisseria meningitidis.
PMID- 9399108
TI - Gender, race, class, and aging: advances and opportunities.
AB - Key debates in social science and health research have centered on how to
increase the inclusiveness of such research and hence its relevance for
understanding the intersections of race, class, gender, and aging. This article
uses gerontology as a case in point, examining the challenges of inclusivity and
interlocking oppressions/intersectionality for better apprehending how broad
structural factors shape and determine the experience of aging and growing old.
The authors discuss alternative hypotheses being used to explore inequalities in
the aging experience and the limitations of current concepts and methods.
Promising new developments in sociology, epidemiology, and other fields are
described in terms of their relevance for better understanding the dynamic
interplay of race, class, gender, and aging.
PMID- 9399109
TI - The potential role of unemployment benefits in shaping the mental health impact
of unemployment.
AB - This study looks at the association between formal systems of support
(unemployment compensation or welfare) and mental health outcomes during periods
of unemployment. It assesses whether unemployed persons not receiving
unemployment benefits are at greater risk of reporting depression and suffering
ill-health than those receiving some kind of unemployment compensation,
independent of total household income. The authors performed a secondary analysis
of data collected in the National Survey of Families and Households, 1987-1988.
Outcome measures included an index of depression and perception of health status.
Multiple regression analyses were used. The unemployed receiving unemployment
compensation or benefits from other entitlement programs did not report
significantly higher depression relative to the employed. Rather, the study found
a significantly higher index of depression among unemployed persons receiving
welfare benefits or no benefits, even after controlling for total household
income and previous employment/unemployment history. Thus unemployment
compensation may play an important role in ameliorating the impact of
unemployment on depression. By contrast, means-tested benefits may not be
sufficient to reduce the risk for reporting depression and suffering ill-health
in comparison with the full-time employed. The implications of the findings are
discussed in terms of social policy development.
PMID- 9399110
TI - Karoshi--death from overwork: occupational health consequences of Japanese
production management.
AB - There is considerable international interest in Japanese production management
(JPM), known in the West as "lean production." Advocates of this new form of
management argue that it improves both economic productivity and health. In
Japan, however, the relationship between JPM and sudden death due to
cardiovascular and cerebrovascular disease has been an important topic of debate
since the 1970s. Japanese have named these types of deaths karoshi, which means
"death from overwork." In North America and Western Europe a number of studies
have demonstrated a significant relationship between high job strain (high
production demands and low levels of control and social support) and
cardiovascular disease. This article reviews the elements of JPM and examines
their potential health consequences. The authors present an overview of karoshi,
discuss its possible connections to specific ideological and organizational
characteristics of JPM, and suggest the job strain mechanism as a possible
pathway between karoshi and JPM. They conclude by discussing the need for
comparative research that examines the health effects of work organization and
management methods cross-culturally.
PMID- 9399111
TI - The growth of corporate private hospitals in Malaysia: policy contradictions in
health system pluralism.
AB - The rapid growth of corporate investment in the Malaysian private hospital sector
has had a considerable impact on the health care system. Sustained economic
growth, the development of new urban areas, an enlarged middle class, and the
inclusion of hospital insurance in salary packages have all contributed to a
financially lucrative investment environment for hospital entrepreneurs. Many of
Malaysia's most technologically advanced hospitals employing leading specialists
are owned and operated as corporate business ventures. Corporate hospital
investment has been actively encouraged by the government, which regards an
expanded private sector as a vital complement to the public hospital system. Yet
this rapid growth of corporately owned private hospitals has posed serious
contradictions for health care policy in terms of issues such as equity, cost and
quality, the effect on the wider health system, and the very role of the state in
health care provision. This article describes the growth of corporate investment
in Malaysia's private hospital sector and explores some of the attendant policy
contradictions.
PMID- 9399112
TI - Caught in the "traps of managed competition"? Examples of Russian health care
reforms from St. Petersburg and the Leningrad region.
AB - Elements of a "managed market" for health services have been introduced into the
Russian health care system, which under the Soviet regime was run as a
comprehensive state-managed system. The authors examine the recent development of
health service reforms in a case study of the city of St. Petersburg and the
surrounding Leningrad region. Evidence from key informants and a local survey of
service users shows how alternative models of the managed market are being
introduced in different parts of the study area. A critical review of the market
oriented strategies for reform emerging in the case study suggests that such
reforms carry risks associated with the "traps of managed competition." Future
policy for health service systems in Russia must take these risks more fully into
account.
PMID- 9399113
TI - The future of primary care in a managed care era.
AB - Health care reform in the United States and elsewhere raises many questions about
equity and effectiveness of health services. Although the impetus has been cost
containment, the reforms have often been justified on the grounds that they will
enhance primary care. In this article, health care reform efforts are divided
into two types: market-driven, demand-based systems versus systems predicated on
meeting population health needs. The two "scenarios" are contrasted with regard
to their likely impact on the attainment of primary care characteristics: first
contact care, longitudinality, comprehensive services, and coordination. Since
the ultimate outcome of these reforms cannot be predicted, there is compelling
need for evaluating them as they proceed.
PMID- 9399114
TI - Local government decision-making and access to primary physician services in
Norway.
AB - Public responsibility for health care can be justified by ambitious egalitarian
objectives, as it is commonly believed that the private sector generates greater
disparities than the public sector. Government institutions can be designed to
achieve equality in provision of health services. The article addresses the
geographical distribution of primary care physicians in Norway, where primary
physician services are the responsibility of local governments, primarily
financed by general taxation. The authors analyze the allocation of physicians
using a local government demand model, a synthesis of consumers' demand and local
government resource allocation. Analyses were performed on a panel data set of
all Norwegian municipalities covering the period 1986-1992. The results are
encouraging. A decentralized system of primary physician services does seem to be
fairly effective in securing equity in access to these services for the municipal
population. In particular, local governments seem to respond well to the health
care needs of their populations. Distribution of physicians is only to a very
small extent dependent on the wealth of the municipality.
PMID- 9399116
TI - Special interests or citizens' rights? "Senior power," Social Security, and
Medicare.
AB - Conventional political analysts and mainstream media accounts attribute
substantial political power to the elderly in the United States. This attribution
of "senior power" is usually made in the context of the politics of Social
Security and Medicare. This article contrasts the conventional construction of
elderly political actors as a special interest with a more critical perspective
that views Social Security and Medicare as citizens' rights. Critical examination
of the welfare state's role in creating age as a potential political cleavage and
the politics of Social Security and Medicare reveals that there is no
undifferentiated politics of aging in the United States. Rather, age interacts
with a variety of other statuses such as race/ethnicity, gender, and class to
condition citizens' political mobilization. Welfare state policies--social
insurance programs like Social Security and Medicare, means--tested programs like
Medicaid and Supplemental Security Income, and targeted tax expenditures for
private pensions and health insurance--differentially empower particular
subgroups of elderly citizens and routinely disadvantage the most vulnerable
elderly, including minority elders, women, and the oldest old.
PMID- 9399115
TI - The challenge of moving from welfare to work.
AB - Despite overall low unemployment rates in 1996, various subgroups of the
population had rates much higher than the average. This brief article considers
the labor market profile of welfare recipients and examines the unemployment and
underemployment rates of groups with similar demographic characteristics. In some
cases, such rates are three and four times the overall national average.
PMID- 9399117
TI - Austria's new attendance allowance: a consumer-choice model of care for the frail
and disabled.
AB - Austria's new social welfare provision, an attendance allowance, adopted in 1993,
is a prototype for a consumer-directed care model for persons who are frail or
disabled. This article describes the background to and provisions of the new
legislation, including the unique political interests from the left and the right
that converged to facilitate its passage. The author discusses eligibility
criteria, the consumer autonomy principles underlying the model, and the impacts
and implications anticipated. Such a model has been mentioned as an option for
states considering creative expansion of long-term care provisions in the United
States.
PMID- 9399118
TI - The use of mass campaigns in the expanded program on immunization: a review of
reported advantages and disadvantages.
AB - The use of mass immunization campaigns (MICs) has been and remains controversial.
To evaluate these campaigns, the authors review the literature relating to their
effectiveness, sustainability, and cost-effectiveness in controlling diseases and
raising immunization coverage levels, and their impact on the subsequent
development of routine immunization services. Well-conducted campaigns have
increased vaccine coverage levels and decreased disease morbidity and mortality.
Their use in the Americas has been associated with the apparent elimination of
poliomyelitis. However, unless health care infrastructure is improved, or
campaigns are repeated, gains in coverage levels may not be sustained. Studies
suggest that MICs are often not as cost-effective for raising coverage as the
delivery of vaccines through routine services, but the use of coverage as the
only outcome measure is questionable. Mass immunization campaigns can increase
awareness of vaccination and may be appropriate in situations where new programs
are to be initiated, in refugee situations where people congregate into areas
with little infrastructure, and in disease eradication efforts when specific time
goals are set. Little information is available on whether MICs strengthen or
interfere with the development of routine services. To be successful, MICs
require a well-coordinated and planned effort on the part of national authorities
with the identification of specific goals, intensive social promotion, and strong
management. In addition, research is needed to clarify how MICs should be
evaluated.
PMID- 9399119
TI - Economy, politics, and health status in Cuba.
AB - An economic contraction occurred in Cuba at the beginning of the 1990s, of a
magnitude greater than in any developed country in the last half century. This
resulted primarily from the disappearance of the European socialist bloc and
simultaneous tightening of the U.S. government's blockade at a time when Cuba was
engaged in correcting its main economic problems. The economic crisis affected a
number of areas of Cuban society. The state adopted a series of measures to cope
with the socioeconomic situation, which have yielded positive results in the
social and economic fields, as well as some undesirable results. In the health
sector, the economic crisis has mainly reduced the availability of resources and
has adversely affected some health determinants and some aspects of the
population's health status. Despite the prevailing economic difficulties, the
government is determined to preserve the country's achievements in health, and to
develop them still further. The solution is not privatization or the introduction
of health insurance systems or similar measures. Rather, Cuba will seek greater
rationality and economic efficiency in the health sector. It has ratified the
principles that the state should continue to finance the health system and
maintain universal coverage and accessibility through free services.
PMID- 9399120
TI - The analysis of EDTA in dried bloodstains by electrospray LC-MS-MS and ion
chromatography.
AB - Analytical methods were developed to determine the presence of
ethylenediaminetetraacetic acid (EDTA) in dried bloodstains to provide probative
information when allegations of evidence tampering have been made in criminal
cases. A simple screening method using ion chromatography to analyze stains was
found to be quantitative to the 5 ppm level. The presence of EDTA was then
confirmed using negative and positive ion mode liquid chromatography-tandem mass
spectrometry (LC-MS-MS) methods. A blind trial of these methods on 42 samples
correctly determined the bloodstains that did and did not contain the
preservative EDTA. One interesting observation in these results was the
adsorption and postanalysis release of EDTA in the chromatographic system. In
order to avoid cross contamination of samples resulting from this phenomena, it
was found to be necessary to use EDTA-free blood extracts as blanks in the LC-MS
analysis of bloodstains.
PMID- 9399121
TI - Identification of tramadol and its metabolites in blood from drug-related deaths
and drug-impaired drivers.
AB - Tramadol is a centrally acting, binary analgesic that is neither an opiate
derived nor a nonsteroidal anti-inflammatory drug and that was approved for use
in the United States in 1995. It is used to control moderate pain in chronic pain
settings such as osteoarthritis and postoperative cases. Used in therapy as a
racemic mixture, the (+)-enantiomer weakly binds to the mu-opioid receptor, and
both enantiomers inhibit serotonin and norepinephrine reuptake. Tramadol's major
active metabolite, O-desmethyltramadol (ODT), shows higher affinity for the mu
opioid receptor and has twice the analgesic potency of the parent drug. The
synergism of these effects contributes to tramadol's analgesic properties with
the (+)-enantiomer exhibiting 10-fold higher analgesic activity than the (-)
enantiomer. Although tramadol was initially thought to exhibit low abuse
potential, Ortho-McNeil, the drug's manufacturer, recently reported a large
number of adverse events attributed to tramadol including abuse by opioid
dependent patients, allergic reactions, and seizures. The high number of adverse
reactions has prompted the company to update the prescribing information for the
drug. An analytical method using gas chromatography-mass spectrometry (GC-MS)
without derivatization for the determination of tramadol and its metabolites is
reported. An n-butyl chloride extraction is followed by GC-MS analysis using a 5%
phenylmethylsilicone column (30 m x 0.32-micron i.d.). Analysis of 12 blood
samples from tramadol-related deaths and four nonfatal intoxications involving
tramadol revealed concentrations ranging from 0.03 to 22.59 mg/L for tramadol,
from 0.02 to 1.84 mg/L for ODT, and from 0.01 to 2.08 mg/L for N
desmethyltramadol. Three deaths were clearly attributable to acute morphine
toxicity, one was a doxepin overdose, and six were multiple drug overdoses. The
role of tramadol in each death is explored.
PMID- 9399122
TI - GC-MS-MS confirmation of unusually high delta 9-tetrahydrocannabinol levels in
two postmortem blood samples.
AB - Unusually high levels of delta 9-tetrahydrocannabinol (delta 9-THC) were detected
in two postmortem blood samples. Because of sample decomposition, the major
metabolite, 11-nor-9-carboxy-tetrahydrocannabinol (delta 9-THCCOOH), could not be
determined using the routine EI-MS technique, which cast some doubt on the delta
9-THC result. Analysis of the sample extracts by GC-MS-MS confirmed the presence
of delta 9-THC, although no delta 9-THCCOOH was detected.
PMID- 9399123
TI - Multicomponent spectroscopic assay for hemoglobin and ferrihemoglobin species in
methemoglobin treatment of cyanide poisoning.
AB - Monitoring the concentrations of various hemoglobin and ferrihemoglobin species
and their cyanide complexes is important in the study of the efficacy of
methemoglobin-forming agents for the treatment of cyanide toxicity. In this
study, the visible absorption spectra of three hemoglobin intermediates were
experimentally determined and compared with computer-generated spectra. The data
supported the assumption that the molar absorptivities of the intermediates are
equivalent to the combined absorptivities of the component subunits. A
multicomponent Fourier transform (FT)-aided full spectrum quantitation system
(FSQ) to simultaneously measure hemoglobin (Hb), hemimethemoglobin (hemiMetHb),
and the cyanide complex dicyanohemimethemoglobin (dicyhemiMetHb) was also
evaluated. It was found that FSQ had satisfactory accuracy and precision to
quantitate hemiMetHb and dicyhemiMetHb at concentrations from 2 to 20% of the
total Hb, a range commonly encountered in the treatment of cyanide poisoning
using methemoglobin-forming agents. The simplicity and rapid throughput of the
method make it suitable for clinical evaluation studies and form the basis for
the design of a portable instrument for field analysis of these species.
PMID- 9399124
TI - Reversed-phase HPLC determination of eight anticoagulant rodenticides in animal
liver.
AB - A reversed-phase high-performance liquid chromatographic method was developed for
the analysis of eight anticoagulant rodenticides in animal liver. Coumarinic
anticoagulant rodenticides (brodifacoum, bromadiolone, coumachlor, coumatetralyl,
difenacoum, and warfarin) were detected by using a gradient elution and a
fluorimetric detection. Indanedione anticoagulant rodenticides (chlorophacinone
and diphacinone) were detected by using an isocratic elution and an UV detection.
Anticoagulants were extracted from liver with mixtures of acetone/diethylether
and acetone/chloroform. Extracts were applied to solid-phase extraction
cartridges. Linearity was checked over the concentration range 0.1-0.6
microgram/g. Relative standard deviations of within-run and between-run
variability were all between 5.7 and 10.3%. Recoveries from spiked liver samples
were between 51.7 (difenacoum) and 78.2% (warfarin). Limits of detection were
between 0.01 (difenacoum and warfarin) and 0.11 microgram/g (chlorophacinone).
PMID- 9399125
TI - The online screening technique for urinary benzodiazepines: comparison with EMIT,
FPIA, and GC-MS.
AB - Three commercial immunoassay systems (EMIT, EPIA, Online) for the screening of
benzodiazepines in urine were evaluated using authentic patient samples with gas
chromatography-mass spectrometry (GC-MS) as the reference method. The Online
system (kinetic interaction of microparticles in solution) gained in performance
by applying a 100-ng/mL cutoff limit and by incorporating beta-glucuronidase
treatment, which could be automated on the Cobas Mira Plus instrument. When using
enzymatic hydrolysis, all three immunoassay systems had high levels of
sensitivity, including samples containing only flunitrazepam and nitrazepam
metabolites. A high degree of concordance was observed between the Online and
FPIA (fluorescence polarization immunoassay) systems when analyzing 138 randomly
selected patient samples. The EMIT II and EMIT d.a.u. (enzyme multiplied immuno
technique) systems gave a higher number of positive results, but the presence of
benzodiazepines could not be verified by GC-MS in a substantial number of these
cases. The rate of unconfirmed positive results was increased when enzyme
hydrolysis was incorporated in the EMIT II assay. Although differences in the
performances of the investigated assay systems were observed, they all seem
appropriate for clinical use in detecting benzodiazepine intake in drug abusers
when enzymatic hydrolysis is included.
PMID- 9399126
TI - Standardization of a method for the routine analysis of polychlorinated biphenyl
congeners and selected pesticides in human serum and milk.
AB - A methodology is presented for the routine determination of specific
polychlorinated biphenyl (PCB) congeners in serum and milk samples. The
procedures include standardized extraction, cleanup and quantitation by high
resolution gas chromatography (GC) and comprehensive quality assurance program to
minimize systematic and erratic errors. The analyses of 68 PCB congeners and
three pesticides, p,p1-dichloro diphenyl dichloro ethylene (DDE),
hexachlorobenzene (HCB), and Mirex, at part-per-billion levels include the
addition of surrogate congener standards (IUPAC isomers #46 and #142), extraction
with hexane after protein precipitation, cleanup with Florisil, and analysis by
GC with capillary column and electron capture detection. Quantitation is based on
calibration standards and response factors using isomers #30 and #204 as internal
standards. The quality control activities consist of analyses of samples in
batches of 6 to 10 simultaneously with quality control (QC) samples. The quality
assurance program checks that the procedures are under control by the use of
control charts and set the criteria for data acceptability. The detection limits
for the congeners and pesticides associated with the analyses of 500 serum
samples and of 100 milk samples are reported. In addition, typical profiles of
congener distribution in both matrices are illustrated.
PMID- 9399127
TI - A fatality involving zolpidem.
AB - An elderly woman residing in an independent-living retirement community was found
dead in the bathtub. She had a history of depression and was prescribed Ambien
(generic name zolpidem) for the treatment of insomnia. Two empty prescription
bottles of Ambien were found; both were for 10-mg tablets with a total quantity
of 60. A postmortem examination was conducted, and blood, urine, and gastric
contents were submitted for toxicology screening. The cause of death was
drowning. The only remarkable toxicology finding was zolpidem. Quantitative
analysis by gas chromatography-mass spectrometry determined the following
concentrations of zolpidem: blood, 7.9 micrograms/mL and urine, 4.1
micrograms/mL. A total of 7 mg unabsorbed zolpidem was found in the gastric
contents. Our findings report the highest blood concentration of zolpidem
reported to date and corroborate other studies that imply that death due solely
to overdosage of zolpidem is an unlikely occurrence.
PMID- 9399128
TI - Excretion of MBDB and BDB in urine, saliva, and sweat following single oral
administration.
AB - A procedure based on gas chromatography-mass spectrometry (GC-MS) for the
simultaneous identification of N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine
(MBDB) and its desmethylated metabolite 3,4-(methylenedioxyphenyl)-2-butanamine
(BDB) in urine, saliva, and sweat specimens is presented. For urine and saliva,
the method involved the alkaline extraction of a 1-mL specimen (MDEA-d5 internal
standard) into ethyl acetate followed by derivatization with heptafluorobutyric
anhydride. Sweat specimens, which were collected by a sweat patch, were tested
after methanolic elution. The procedure was used to study the excretion of MBDB
and BDB in urine, saliva, and sweat after single oral administration of 100 mg of
MBDB to one subject. Urine tested positive for 36 h with a peak concentration at
4 h. Immunoassays were positive for 24 and 4 h using FPIA and EMIT, respectively.
Peak saliva concentration was observed at 2 h. MBDB and BDB were detected in
saliva during the first 17 h. Finally, both compounds were excreted into sweat
with a constant increase in concentration during the first 36 h followed by a
decrease for the remaining time. In all the biological specimens that were
tested, MBDB was present in higher concentrations than its metabolite.
PMID- 9399129
TI - Diltiazem and pentoxifylline determination in postmortem specimens.
AB - A 78-year-old woman was found dead in her basement. Qualitative screening of
available postmortem specimens detected the presence of diltiazem and
pentoxifylline. Quantitations were carried out by gas chromatography using
nitrogen-phosphorus detection and confirmed by gas chromatography-mass
spectrometry with the following results: blood, 0.59 mg/dL diltiazem and 0.63
mg/dL pentoxifylline; urine, 1.17 mg/dL diltiazem and 0.08 mg/dL pentoxifylline;
bile, 0.40 mg/dL diltiazem and 0.22 mg/dL pentoxifylline; gastric contents, 0.28
mg/dL diltiazem and 0.02 mg/dL pentoxifylline. Both drugs were found
qualitatively in formaline-fixed tissues.
PMID- 9399130
TI - Analytical findings in a fatal poisoning with silver compound.
AB - A 69-year-old male radio technician drank an unknown amount of a liquid and died
within 5 h at a hospital. Mainly silver, potassium, and calcium, among other
substances, were found in the residue of the liquid from the empty bottle by
means of the spectrographic method (30.7% silver and 25.5% potassium using atomic
absorption spectometry [AAS] method). The toxicological analysis of the
postmortem material for silver performed by the flame AAS method (stomach, 2.43
micrograms/g; intestines, 1.12 micrograms/g; liver, 6.29 micrograms/g; kidney,
4.85 micrograms/g; spleen, 30.1 micrograms/g; heart, 10.8 micrograms/g; lung,
14.8 micrograms/g; and brain, 0.61 microgram/g) confirmed fatal silver compound
poisoning. The results were verified by the standard additions technique and
recovery examination. However, no increase in the potassium concentrations was
observed in the postmortem material. There have been no data in available
literature on the distribution of silver in tissues in people after oral
administration of silver salts.
PMID- 9399132
TI - Appreciable blood-ethanol concentration after washing abraised and lacerated skin
with surgical spirit.
PMID- 9399131
TI - A case of homicidal poisoning involving several drugs.
AB - Accidental or suicidal poisonings due to benzodiazepines have been previously
reported. A case of fatal, homicidal poisoning with benzodiazepines, antipyretic
analgesics (anti-inflammatory drugs), and beer is described here. In this
homicidal poisoning, the drugs and beer were given to the decedent by his wife.
Autopsy findings showed no clinically significant macroscopic findings except for
slight postmortem change. Capillary gas chromatography coupled to mass
spectrometry was employed to quantitate the drugs in biological fluids and
stomach contents. Six drugs (brotizolam, triazolam, ibuprofen, dihydrocodeine,
phenylpropanolamine, and chlorpheniramine) were identified and quantitated in
blood, urine, and stomach contents. Although each drug was present in a very
small quantity, the cause of death was determined to be the combination of these
drugs and alcohol poisoning.
PMID- 9399133
TI - Immunoassay responses of MBDB.
PMID- 9399134
TI - Ecstasy and related substances--serum levels in impaired drivers.
PMID- 9399135
TI - Face facts: a history of physiognomy from ancient Mesopotamia to the end of the
19th century.
AB - Inscribed on the face is a code, the translation of which has entertained and
eluded humankind for many centuries. The practice of reading the face dates back
as early as the paleobabylonian period in Mesopotamia. It wasn't until much
later, however, that this ancient tradition was named.
PMID- 9399136
TI - Bringing it into focus: visual cues and their role in directing attention.
AB - Visual cues are powerful tools for directing the user's eyes to relevant
information. When incorporated into the design of a medical/scientific
illustration, important details are more quickly conveyed. This article discusses
the use of line, color, contrast, light and shadow, spatial relationships, image
size and location, rhythm, and graphic devices as attention-directing cues
utilized in focusing the user's eyes to pertinent information.
PMID- 9399138
TI - The use of biomaterials in the repair of abdominal wall defects: a comparative
study between polypropylene meshes (Marlex) and a new polytetrafluoroethylene
prosthesis (Dual Mesh).
AB - In this study we compared the behaviour of the non-porous on one side ePTFE Dual
Mesh prosthesis and the macroporous polypropylene mesh Marlex in the repair of
abdominal wall defects in rabbits. We evaluated the degree of integration with
recipient tissue, biological tolerance, adhesion formation with viscera and the
biomechanical resistance of the repair zone. Our results showed good biological
tolerance of both prostheses and a high degree of adhesion formation in Marlex
implants. In animals with Dual Mesh implants, only loose adhesions were seen.
Marlex implants induced the presence of disorganized scar tissue, while the Dual
Mesh prostheses were encapsulated by organized tissue. The macrophage response
was similar in both decreasing with time. The resistance to traction was higher
when the reparation was done with polypropylene. We concluded that the structure
of the prosthesis determines its degree of integration and the resistance to
traction of the repaired zone.
PMID- 9399137
TI - Chemical and physical characterization of a novel poly(carbonate urea) urethane
surface with protein crosslinker sites.
AB - A major complication which occurs with implantable polyurethane biomaterials is
bioincompatibility between blood and the biomaterial surface. Development of a
novel biodurable polyurethane surface to which biological agents, such as growth
factors or anticoagulants could be covalently bound, would be beneficial. The
purpose of this study was to synthesize a novel poly(carbonate urea) urethane
polymer with carboxylic acid groups which would serve as "anchor" sites for
protein attachment. Physical characteristics such as tensile strength, initial
modulus, ultimate elongation, tear strength, water/alcohol uptake and water vapor
permeation were then evaluated and compared to other biomedical-grade
polyurethanes. Covalent linkage of the blood protein albumin to this novel
surface was then examined. A biodurable polycarbonate-based polyurethane
containing carboxylic acid groups (cPU) was synthesized using a two step
procedure incorporating the chain extender 2,2-bis(hydroxymethyl)-propionic acid
(DHMPA). Tensile strength of this cPU film was 2.7 and 2.6 fold greater than both
a polycarbonate-based polyurethane synthesized with a 1,4-butanediol chain
extender (bdPU) and Mitrathane (Mit) controls, respectively. The cPU polymer also
possessed 7.8 and 31 fold greater structural rigidity upon evaluation of initial
modulus as compared to the bdPU and Mit, respectively. Ultimate elongation for
the bdPU films was slightly higher than the cPU and Mit films, which had
comparable elongation properties. The force required to tear the bdPU film was
1.9 and 32 fold greater than the cPU and Mit films, respectively. Alcohol
solution uptake by all of the polyurethane segments increased with increasing
alcohol concentrations, with the cPU having the greatest uptake. Water uptake was
minimal for all the polyurethanes examined and was not affected by altering pH.
Water vapor permeation was lowest for the cPU films as compared to both bdPU and
Mit. Swelling the cPU in 50% ethanol prior to evaluation slightly increased water
vapor permeation through the films. Covalent linkage of the radiolabelled blood
protein albumin (125I-BSA) to the cPU segments incubated with the
heterobifunctional crosslinker 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride (EDC) was greatest in the higher percent of ethanol as compared to
controls. These results serve as foundation for developing a novel poly(carbonate
urea) urethane with physical characteristics comparable to other medical-grade
polyurethanes while having protein binding capabilities.
PMID- 9399139
TI - Assessment of encrustation behaviour on urinary tract biomaterials.
AB - The effective clinical use of biomaterials within the urinary tract is often
hindered by the associated problems of bacterial biofilm formation and
encrustation which may cause obstruction or blockage of urethral catheters and
ureteral stents. Methods for assessing encrustation formation on these devices
are reviewed and novel urinary tract biomaterials which may be more effective at
resisting encrustation are discussed.
PMID- 9399140
TI - Blood compatible phospholipid-containing polyurethanes: synthesis
characterization and blood compatibility evaluation.
AB - A new diol, bis[2-(2-hydroxyethyldimethylammonio)ethyl] butylenediphosphate, that
contains two phosphatidylcholine analogous moieties in one diol molecule, was
synthesized and characterized. The diol together with 1,4-butanediol as chain
extender was further incorporated into the propolymer of poly(ethylene oxide) (Mn
= 1000, 2000, 6000) and 4,4'-methylenediphenyl diisocyanate. The resulting
phospholipid poly(ether urethane)s show viscosity behavior of common
polyelectrolytes. The bulk and surface characteristics of the new phospholipid
poly(ether urethane)s were investigated by IR, GPC, ATR-FTIR, ESCA and contact
angle measurements. The new polymers possessed relatively hydrophilic surface
revealed by contact angle measurements. The blood compatibilities of the
polyurethanes were evaluated by platelet rich plasma contacting studies and
scanning electron microscopy observation using medical grade PVC as the
reference. No platelet adhesion was observed for all new phospholipid
polyurethane casting films. This new type of phospholipid polyurethane is
expected to have potential biomedical applications.
PMID- 9399141
TI - Synthesis, characterization, biodegradation, and drug delivery application of
biodegradable lactic/glycolic acid oligomers: I. Synthesis and characterization.
AB - A series of oligomers or low molecular weight polymers of lactic and/or glycolic
acid has been synthesized with different molar ratios of lactic to glycolic acid.
These oligomers have been characterized with respect to oligomer composition,
molecular weight, intrinsic viscosity, crystallinity, melting temperature, and
glass transition temperature. The polymerization conditions for the
lactic/glycolic acid oligomer syntheses were as follows: 180-220 degrees C, 5 mm
Hg, 5 h, and 0.1 wt% of catalyst (antimony oxide) concentration. The polymeric
compositions correlated to the feed ratios of lactic to glycolic acid. The
molecular weight of the oligomers ranged from 895.8 +/- 48.7 to 1368.0 +/- 0 D
with the intrinsic viscosity ranging from 0.0513 to 0.0814 dl g-1. The
lactic/glycolic acid oligomers were found to be amorphous. The glass transition
temperatures of the lactic/glycolic acid oligomers were lower than physiological
temperature.
PMID- 9399142
TI - New treatments using alginate in order to reduce the calcification of bovine
bioprosthetic heart valve tissue.
AB - Calcification limits the functional lifetime of cardiac valve substitutes
fabricated from glutaraldehyde preserved bovine pericardium. Host factors, mainly
younger age, and implant factors, mainly glutaraldehyde cross-linking, are
implicated in the calcification process. Glutaraldehyde cross-linking is believed
to activate the potential sites in the tissues for biocalcification. In the
present work, we investigated the possibility of using alginate azide (AA)
instead of glutaraldehyde for the preservation of pericardial tissues in order to
enhance the durability of bioprosthetic heart valves. Grafting with poly(GMA-BA)
copolymer to the alginate azide cross-linked pericardial (AACPC) tissue was
carried out to obtain better stability, strength, and anticalcification
properties. The strength property and thermal stability of the AA cross-linked
tissues were studied. Calcification studies in rat subdermal models reveal that
AA cross-linking reduces the calcification to negligible levels. After 30 days
implantation, the calcium content was found to be 10.4 +/- 1.2 and 6.1 +/- 0.3
micrograms mg-1 for untreated AACPC and polymer grafted AACPC, respectively,
compared to a value of 100 +/- 1.2 micrograms mg-1 calcium recorded for control
glutaraldehyde cross-linked pericardial (GCPC) tissues.
PMID- 9399143
TI - Design of macromolecular biological response modifier by immobilizing of D
glucose analogue of muramyl dipeptide on carboxymethyl-dextran having mannose
branches.
AB - It is well known that muramyl dipeptide is a minimum required structure of
bacterial peptidoglycan responsible for immunoadjuvant activity. Since mannose
receptors exist on the surface of macrophages, polymers with branched mannose
residues are expected to target moieties to macrophages. To achieve an efficient
delivery of D-glucose analogue of muramyl dipeptide (GADP) via receptor-mediated
endocytosis by mannose receptors on the surface of macrophages,
GADP/carboxymethyl-dextran (CM-Dex)/Man conjugate was synthesized. Moreover, to
study the effect of the introduction of mannose residues, we also synthesized
GADP/CM-glucomannan (CM-GM) and GADP/CM-Dex conjugates. The immunological
enhancement activities of their conjugates were evaluated by measurements of
glucose consumption and beta-D-glucuronidase activity from macrophage-like cells.
The GADP/CM-Dex/Man and GADP/CM-GM conjugates showed higher immunological
enhancement activity than the GADP/CM-Dex conjugate. The immunological
enhancement activity of GADP/CM-Dex/Man and GADP/CM-GM conjugates was decreased
to the same level of immunological enhancement activity of GADP/CM-Dex conjugate
under the presence of excess mannose. These results suggested that the
introduction of mannose residues into GADP/CM-Dex conjugate could increase the
affinity against macrophage and the immunological enhancement activity of GADP/CM
Dex conjugate itself.
PMID- 9399144
TI - Rifampicin carrying polyhydroxybutyrate microspheres as a potential
chemoembolization agent.
AB - In this study, we attempted to prepare microspheres from a microbial
biodegradable polyester, i.e. polyhydroxybutyrate (PHB) as a potential
chemoembolization agent. The drug loaded PHB microspheres were prepared by a
solvent evaporation technique, in which methylene chloride, distilled water, and
polyvinyl alcohol were utilized as the solvent, dispersion medium, and
emulsifier, respectively. Microspheres were obtained within a size range of 5-100
microns by changing the initial polymer/solvent ratio, emulsifier concentration,
stirring rate, and initial drug concentration. It was possible to obtain PHB with
very narrow size distributions by applying gravity field-flow fractionation
technique. Very high drug loadings of up to 407.6 mg rifampicin/g PHB were
achieved. Drug release rates were very rapid. Almost 90% of the drug loaded was
released in about 24 h. Both the size and drug content of PHB microspheres were
found to be effective in controlling the drug release from these microspheres.
PMID- 9399145
TI - Immobilization of functionalized alkyl-poly(ethylene oxide) surfactants on
poly(ethylene) surfaces by means of an argon plasma treatment.
AB - Alkyl-poly(ethylene oxide) (PEO) surfactants containing a terminal hydroxyl,
sulfate, or carboxylate group were grafted at the surface of poly(ethylene) (PE)
samples to improve their blood compatibility. Grafting was achieved by
immobilizing PEO surfactants on PE using an argon plasma treatment. The sulfate
group containing PEO surfactant was synthesized by sulfating
polyoxyethylene(20)stearylether (Brij78; B) with chlorosulfonic acid. A
carboxylate-terminated surfactant was synthesized by a substitution reaction of
the sodium alkoxide form of B with sodium iodoacetate. XPS analysis of the
modified PE samples showed that at short plasma treatment times of up to 5 s the
structure of the immobilized surfactants is largely retained. When plasma
treatment times longer than 30 s were applied, the PEO chains of the surfactants
were degraded. The wettability of the modified PE samples was improved compared
to the unmodified PE samples. The wettability of the modified samples did not
change when they were stored in air at room temperature for at least 12 weeks.
PMID- 9399146
TI - Use of chemically modified nucleotides to determine a 62-nucleotide RNA crystal
structure: a survey of phosphorothioates, Br, Pt and Hg.
AB - Two important challenges confronting RNA crystallographers are producing crystals
and finding isomorphous heavy-atom derivatives. Non-isomorphism can be addressed
by determining the phases using the multiwavelength anomalous dispersion (MAD)
method. These phases can be greatly improved by combining phases from MAD
experiments done on different heavy-atom derivatives. Heavy-atom derivatives can
be created by chemically modifying the RNA through covalent attachment of bromine
or mercury to C5 of pyrimidines or [Pt(NH3)3]2+ to N7 of guanine. While
phosphorothioates can provide mercury binding sites, disorder can reduce their
value for phase determination. The location of these chemical modifications is
critical since crystallization of these derivatized RNAs is sensitive to heavy
atom induced conformational alterations and crystal packing.
PMID- 9399147
TI - Correlation of hydrophobicity and packing in A-DNA oligonucleotides.
AB - A-DNA oligomers pack in a slanted fashion with the terminal base pairs abutting
into the minor groove of neighboring molecules unlike the other forms of DNA
which pack by vertically stacking one over the other into helical columns. To
explain the differences in packing we have advanced a hypothesis that the
orientation of the sugar-phosphate backbone is different in A-DNA from that in
the other forms of DNA, mainly due to the differences in the sugar puckering.
PMID- 9399148
TI - The SRY cantilever motif discriminates between sequence- and structure-specific
DNA recognition: alanine mutagenesis of an HMG box.
AB - The high-mobility-group (HMG) box defines a DNA-bending motif conserved among
architectural transcription factors. A "hydrophobic wedge" at the protein surface
provides a mechanism of DNA bending: disruption of base stacking by insertion of
a sidechain "cantilever." First described in the mammalian testis-determining
factor SRY, the cantilever motif consists of adjacent aromatic and nonpolar
sidechains at the crux of the HMG box (residues 12 and 13). Here, the role of
these side chains in DNA recognition is investigated by alanine mutagenesis. F12A
and I13A substitutions in the SRY HMG box each permit native folding and thermal
stability (as monitored by circular dichroism and 1H-NMR) but eliminate sequence
specific DNA-binding activity (as detected by gel-mobility shift). On binding to
the sharp angles of a four-way DNA junction (4WJ), however, the substitutions
each promote formation of a high-molecular-weight aggregate, presumably by DNA
dependent oligomerization. The substitutions have opposite effects on initial
binding to the 4WJ: whereas such binding is attenuated ten-fold by F12A, it is
enhanced by I13A. A foreshortened "alanine cantilever", not observed among
specific HMG boxes, occurs in a non-specific domain (HMG-1A) and may enhance
architecture-selective DNA recognition.
PMID- 9399150
TI - Variability analysis of HIV-1 gp120 V3 region: I. Point estimators for the amino
acid distribution characteristics.
AB - Enumerating procedure for symbol sequences is proposed. Relationship between
Hamming distance for symbol sequences and Euclidean distance for corresponding
enumerations is established, and more universal Hamming-transformed Euclidean
measure is constructed. A distribution function of amino acid substitutions and
some of its point estimators (consensus, subconsensus, sample mean, sample
central moments and asymmetry coefficient) are introduced. Hamming-transformed
Euclidean measures between consensus, subconsensus and sample means for ten HIV-1
taxons of gp120 V3 regions are calculated. It is demonstrated that these taxons
have a complicated pattern which is significant for their classification.
PMID- 9399149
TI - Structure of an anti-HIV-1 hammerhead ribozyme complex with a 17-mer DNA
substrate analog of HIV-1 gag RNA and a mechanism for the cleavage reaction: 750
MHz NMR and computer experiments.
AB - The structure of an anti-HIV-1 ribozyme-DNA abortive substrate complex was
investigated by 750 MHz NMR and computer modeling experiments. The ribozyme was a
chimeric molecule with 30 residues-18 DNA nucleotides, and 12 RNA residues in the
conserved core. The DNA substrate analog had 17 residues. The chimeric ribozyme
and the DNA substrate formed a shortened ribozyme-abortive substrate complex of
47 nucleotides with two DNA stems (stems I and III) and a loop consisting of the
conserved core residues. Circular dichroism spectra showed that the DNA stems
assume A-family conformation at the NMR concentration and a temperature of 15
degrees C, contrary to the conventional wisdom that DNA duplexes in aqueous
solution populate entirely in the B-form. It is proposed that the A-family RNA
residues at the core expand the A-family initiated at the core into the DNA stems
because of the large free energy requirement for the formation of A/B junctions.
Assignments of the base H8/H6 protons and H1' of the 47 residues were made by a
NOESY walk. In addition to the methyl groups of all T's, the imino resonances of
stems I and III and AH2's were assigned from appropriate NOESY walks. The
extracted NMR data along with available crystallographic data, were used to
derive a structural model of the complex. Stems I and III of the final model
displayed a remarkable similarity to the A form of DNA; in stem III, a GC base
pair was found to be moving into the floor of the minor groove defined by
flanking AT pairs; data suggest the formation of a buckled rhombic structure with
the adjacent pair; in addition, the base pair at the interface of stem III and
the loop region displayed deformed geometry. The loop with the catalytic core,
and the immediate region of the stems displayed conformational multiplicity
within the NMR time scale. A catalytic mechanism for ribozyme action based on the
derived structure, and consistent with biochemical data in the literature, is
proposed. The complex between the anti HIV-1 gag ribozyme and its abortive DNA
substrate manifests in the detection of a continuous track of A.T base pairs;
this suggests that the interaction between the ribozyme and its DNA substrate is
stronger than the one observed in the case of the free ribozyme where the bases
in stem I and stem III regions interact strongly with the ribozyme core region
(Sarma, R. H., et al. FEBS Letters 375, 317-23, 1995). The complex formation
provides certain guidelines in the design of suitable therapeutic ribozymes. If
the residues in the ribozyme stem regions interact with the conserved core, it
may either prevent or interfere with the formation of a catalytically active
tertiary structure.
PMID- 9399151
TI - Variability analysis of HIV-1 gp120 V3 region: II. Hierarchy of taxons.
AB - In the previous work (M. Yu. Shchelkanov, A. N. Yudin, A. V. Antonov, N. S.
Starikov, A. A. Vedenov, E. V. Karamov, J. Biomol. Struct. Dyn. 15, 217-229
(1997)) we have introduced the amino acid distribution function within HIV-1
taxons and Hamming-transformed Euclidean measures between their characteristics:
consensus, subconsensus and sample mean. In this work the referred
characteristics are used for hierarchical classification of amino acid sequences
of gp120 V3 region belonging to different HIV-1 taxons. A comparative analysis of
the results produced by various classification methods is carried out.
Multidimensional scaling of distance matrix for the specified characteristics is
used to visualize the pattern of HIV-1 variability.
PMID- 9399152
TI - Single-strand-preferring RNases degrade double-stranded RNAs by destabilizing its
secondary structure.
AB - To establish the mechanism of dsRNA degradation by mammalian single-stranded
preferring ribonucleases, and, in particular, the influence of their positively
charged non-catalytic amino acid residues, we have studied the kinetic parameters
of the depolimerization of single- and double-stranded polyribonucleotides such
as poly(U), poly(U).poly(A), poly(C) and poly(C).poly(I) by the action of human
seminal RNase, bovine seminal RNase and ox pancreas RNase A. While the activities
of these RNases on poly(I).poly(C) were definitely lower than those on poly(C),
the activities of human seminal and bovine seminal RNases on poly(U).poly(A) and
poly(U) were of the same order of magnitude under physiological salt conditions.
The ratio of the RNase A degrading activities towards poly(U) and poly(U).poly(A)
at I = 0.16 M is ten times higher than the corresponding ratios determined with
bovine seminal and human seminal ribonucleases. The high activities of these two
RNases towards poly(U).poly(A) are discussed on the basis of their efficient
estabilishing action on this double-helical nucleic acid due to their high
affinity for poly(A). The destabilizing action of human seminal RNase and bovine
seminal RNase on the poly (U).poly(A) duplex is higher than that measurable with
bovine RNase A because of the higher number of positive charges present on those
enzyme molecules. This may therefore explain why human seminal and bovine seminal
ribonucleases are more efficient than RNase A in the depolymerization of
poly(U).poly(A) at physiological ionic strength.
PMID- 9399153
TI - Thermodynamic cycle between DNA and RNA constituents for conformation of the
sugar ring from nuclear magnetic resonance study.
AB - The effect of a structural change of ribose to deoxyribose, by replacement of 2'
OH by 2'-H, on the conformational equilibrium of the sugar ring is described in
terms of one thermodynamic cycle. The method is based on the observation that
conformational correlations of the sugar ring--side chain ensemble in DNA and RNA
components show one general pattern, reflecting an intrinsic physical property of
this ensemble. The pattern determines a choice of model systems to study. The
systems consist of pairs of DNA and RNA components, nucleosides and nucleotides
in aqueous solution, where all conformational factors are fully controlled. This
approach allowed us to describe the thermodynamic cycle and measure its
fundamental parameters, equilibrium constants and free energy differences, delta
delta G, from a nuclear magnetic resonance study. The delta delta G values as
determined for pairs of ribo- and deoxyribo-nucleosides in classes of syn
constrained and anti-preferred models, are comparable and lie in a narrow range,
delta delta G = 1.7 +/- 0.1 [kJ/mol]. For pairs of ribo- and deoxyribo
nucleotides, the delta delta G values also lie in narrow ranges, delta delta G =
1.7 +/- 0.1 [kJ/mol] for 5'-phosphate nucleotides and delta delta G = 1.9 +/- 0.1
[kJ/mol] for 3'-phosphate nucleotides, i.e. similar to those observed for
nucleosides. The measured quantity, delta delta G, is generally observed in a
relatively narrow range, delta delta G = 1.75 +/- 0.15 [kJ/mol], irrespective of
the class of the model system. This quantity represents a "pure" constant
contribution, pe one sugar moiety, as a "driving force" for the N-->S shift in
the sugar ring conformational equilibrium, when one compares RNA and DNA. This
important thermodynamic quantity, delta delta G, has not hitherto been determined
for nucleic acids. Ultimately the delta delta G quantity is revealed in the
tendency to adopt S(C2'endo) sugar puckering domain by the majority of DNA
structures, whereas RNA generally adopt an N(C3'endo) puckering domain. A
possible biological significance of the delta delta G quantity may include
evolutionary aspects of nucleic acids.
PMID- 9399154
TI - Curvature and sequence analysis of eukaryotic promoters.
AB - We have calculated the curvature of 504 eukaryotic promoters predicted by the
bent A-tract model of Bolshoy et al. (Proc. Natl. Acad. Sci. USA, 88(6), pp. 2312
16) and the bent non-A-tract models of Calladine et al. (J. Mol. Biol., 201, pp.
127-37) and Satchwell et al. (J. Mol. Biol., 191, pp. 659-75) and found in each
case a correlation between TBP binding sites and DNA curvature. Characterizing
the TBP binding sites revealed that in addition to the classical TATA box
(TATAAA) five more elements occur significantly often in the promoters, nearly
all of them being one point mutations of the classical TATA box element. Separate
curvature calculations for promoters with canonical and non-canonical TATA boxes
have shown that in both cases the strong curvature of the helix axes in the
domain of the binding sites is maintained (classical TBP binding sites: + 64
135%, non-classical TBP binding sites: + 27-49%). These results support the
proposition that beside DNA flexibility and DNA-protein interactions intrinsic
curvature of DNA is one further important criterion for the recognition of
different DNA elements by TBP.
PMID- 9399155
TI - An improved method for the rapid assessment of DNA bending by small molecules.
AB - Assessing the effects of non-covalently bound chemicals on DNA structure is
particularly challenging. Traditional methods require the use of cumbersome
electrophoretic techniques or that the compounds bind DNA with an extremely high
affinity. Here we demonstrate that, by extending the use of the exonuclease Bal
31, we can rely on a standard cyclization assay technique and one dimensional gel
electrophoresis to identify and quantitate chemical induced DNA bending. An
important application of this method is to the study of small molecules that bind
to DNA non-covalently and we illustrate the method with the antitumor antibiotic
calicheamicin. Our results suggest that the distribution of circles resulting
from the polymerization of a 21 bp DNA construct reflects the kinetics of the
competing cyclization and dimerization reactions and provides a method for
rapidly screening compounds for DNA bending.
PMID- 9399156
TI - Structure of poly d(AI).poly d(CT) in two different packing arrangements.
AB - X-ray diffraction analysis of poly d(AI).poly d(CT) in oriented and
polycrystalline fibers has revealed the DNA structure to be a 10-fold, right
handed, antiparallel, Watson-Crick base paired double helix in two distinct
packing arrangements corresponding to one and two helices, respectively, in the
unit cell. The helix pitch is 32.1 A and 32.4 A in the two cases, almost 1.5 A
shorter than in classical B-DNA. The resulting B'-DNA geometry, described in
terms of a tetranucleotide repeat which is conformationally similar to B-DNA, has
its minor groove closely shut and major groove correspondingly widened, thus
striking a sharp morphological contrast to B-DNA. According to difference
electron density maps, a spine of hydration along the minor groove connects both
strands and provides structural stability; ordered sodium ions and water
molecules are actively involved in bridging the phosphate groups of neighboring
helices. The crystallographic R-values for these two allomorphs are 0.26 and
0.20, respectively, for data up to 3.0 A resolution.
PMID- 9399158
TI - Dynamic bis-intercalation of a homodimeric thiazole orange dye in DNA: evidence
of intercalator creeping.
AB - We have used one and two dimensional exchange 1H NMR spectroscopy to characterize
the dynamics of the binding of a homodimeric thiazole orange dye, 1,1'-(4,4,8,8
tetramethyl-4,8-diaza-undecamethylene)-bis- 4-(3-methyl-2,3-dihydro-(benzo-1,3
thiazole)-2-methylidene)-quinol inium tetraiodide (TOTO), to double stranded DNA
(dsDNA). The double stranded oligonucleotides used were d-(CGCTAGCG)2 (1) and
d(CGCTAGCTAGCG)2 (2). TOTO binds preferentially to the (5'-CTAG-3')2 sites and
forms mixtures of 1:1 and 1:2 dsDNA-TOTO complexes with 2 in ratios dependent on
the relative amount of TOTO and the oligonucleotide in the sample. The dynamic
exchange between preferential binding sites in the case of a 2:1 1-TOTO mixture
is an intermolecular exchange process between two binding sites on different
oligonucleotides. In the case of the 1:1 2-TOTO complex an intramolecular
exchange process occur between two different binding sites on the same strand.
Both processes were studied. The results demonstrate the ability of TOTO to
migrate along a dsDNA strand in an intramolecular exchange process. The migration
process ("creeping") along the DNA strand is 6 times faster than the rate of
intermolecular exchange between sites in two different oligonucleotides.
PMID- 9399157
TI - Structural studies by high-field NMR spectroscopy of a binary-addressed
complementary oligonucleotide system juxtaposing pyrene and perfluoro-azide
units.
AB - Recently, a new approach has been proposed to improve the site-specificity and
efficiency of the modification of nucleic acid target sequences, the binary
system of complementary-addressing nucleic acid sequences. The binary system
comprises two oligonucleotides, one modified with a photosensitizing group and
the other with a photoreactive group. The sites of chemical modification are
arranged to bring the two chemical functions close enough together in space to
allow efficient energy transfer from the photo-excited photosensitizer to an
arylazide moiety which expels N2 to form a nitrene which subsequently covalently
labels the target nucleic acid. Structural analysis performed by high-resolution
2D NMR spectroscopy (400 MHz and 600 MHz) are reported for the model binary
system 1:2:3, where 1 is the target 12-mer pdGTATCAGTTTCT, 2 is a
photoactivatable fluoroazide derivative dAGAAACp-L-Az and 3 is the
photosensitizer derivative Pyr-pdTGATAC (here: Az is the p-azidotetrafluorobenzyl
group, Pyr the pyrenyl-1-methylamino group, L a linker group). The assignment of
oligonucleotide and modifying group protons was performed using 1H COSY, TOCSY
and NOESY experiments. Comprehensive analysis of 1H NOESY spectra of 1:2:3 showed
that terminal fragments of the complex [5'p-1T-2G-3A-4T-], [-21A-22T-23A-24C], [
8T-9T-10T-11C-12T] and [13A-14G-15A-15A-17A-18C-] gave a continuous set of intra-
and inter-nucleotide interactions, typical of regular double-stranded B-DNA. In
contrast, the central region of the complex composed of 5C, 6A, 7G, 19T and 20G
nucleotide residues, nearest the Pyr and Az groups, was found to be distorted.
Thus some signals from aromatic and/or sugar-ring protons of the above nucleotide
residues were extremely broadened or almost absent. Moreover, some intra- and/or
inter-nucleotide interactions, typical of the regular DNA duplex, were not
detected for the [-5C-6A-7G-] and [-19T-20G-] regions of the tandem system.
Instead of that, some cross-peaks of low-intensity between the H2 proton of the
Pyr group and 7G(H1'), 7G(H2'/H2"), 7G(H3'), 4T(H2"), 4T(H4') and 4T(H5'/H5")
were observed. Additional 1H -1H NOE-interactions between methylene protons of
the linker group L and some sugar ring protons of 18C nucleotide residue were
detected. A preliminary structural model, constructed using proton-proton
distances between Pyr and the DNA and Az-L and DNA obtained from a 1H NOESY
experiment at 300 ms mixing time as constraints for the refinement of the
structure, displayed significant distortion from B-DNA of the double-stranded
helix in the middle of the complex, (-5C-6A-7G, -18C-19T-20G-). The Pyr group was
located in what remains of the minor groove near 4T, 5C, 6A and 7G and the
centroid of the azide ring less than 9A degrees from the centroid of the ring
system of Pyr group.
PMID- 9399159
TI - Sequence-independent recombination triple helices: a molecular dynamics study.
AB - Recent experimental studies have shown that the Rec-A mediated homologous
recombination reaction involves a triple helical intermediate, in which the third
strand base forms hydrogen bonds with both the bases in the major groove of the
Watson-Crick duplex. Such 'mixed' hydrogen bonds allow formation of sequence
independent triplexes. DNA triple helices involving 'mixed' hydrogen bonds have
been studied, using model building, molecular mechanics (MM) and molecular
dynamics (MD). Models were built for a triplex comprising all four possible
triplets viz., G.C*C, C.G*G, A.T*T and T.A*A. To check the stability of all the
'mixed' hydrogen bonds in such triplexes and the conformational preferences of
such triplex structures, MD studies were carried out starting from two structures
with 30 degrees and 36 degrees twist between the basepairs. It was observed that
though the two triplexes converged towards a similar structure, the various
hydrogen bonds between the WC duplex and the third strand showed differential
stabilities. An MD simulation with restrained hydrogen bonds showed that the
resulting structure was stable and remained close to the starting structure.
These studies help us in defining stable hydrogen bond geometries involving the
third strand and the WC duplex. It was observed that in the C.G*G triplets the N7
atom of the second strand is always involved in hydrogen bonding. In the G.C*C
triplets, either N3 or O2 in the third strand cytosine can interchangeably act as
a hydrogen bond acceptor.
PMID- 9399161
TI - Search for rigid sub domains in DNA from molecular dynamics simulations.
AB - A strategy is presented for searching which atoms can be regrouped within rigid
sub-units during the time course of Molecular Dynamics simulations of
biopolymers. The root mean square fluctuations of the interatomic distances are
used as a criterion. The number of rigid sub-units which are found depends on the
tolerance rc for the definition of a rigid body, i.e. until which value the
fluctuations can be neglected. The method is applied to two self-complementary
oligonucleotides belonging to the B-form family which give identical results.
With rc = 0.027 nm each nucleotide may be described as 3 rigid sub-units: the
sugar ring, the base and the backbone (PO4 + C5' atoms). With rc = 0.01 nm, the
same sub-units are obtained except that C5' can no more be regrouped with the PO4
atoms. It is shown that the variation of the coulombic potential owing to the
deformation of the sub-units during the time course of the simulation is on the
same order of magnitude as the inaccuracy due to the choice of the force field
parameters.
PMID- 9399160
TI - Protein-nucleic acid recognition: simulation of base and "model" amino acids
complexes in DMSO by the Monte Carlo method.
AB - A computer simulation of guanine (G), cytosine (C), the G-C base pair, protonated
C (CH+), acetic acid in neutral (AcOH) and deprotonated (AcO-) forms, G-AcO-, C
AcOH, and CH(+)-AcO- complexes, solvated in DMSO was carried out by the Monte
Carlo method. It is shown that the G-C base pair formation in DMSO is
energetically favorable. The G-AcO- complex formation is comparable with the
formation of G-C base pair in energetically favorability. In this case the
acetate anion can replace C in the G-C base pair. The formation of the C-AcOH
complex is much less favorable than the formation of the G-C pair. However proton
transfer from AcOH to C leads to the formation of the CH(+)-AcO- complex, which
is the most favorable of all complexes studied. Here the acetic acid can replace
G in a G-C base pair. The formation of G-AcO- and CH(+)-AcO- specific complexes
detected in DMSO with the help of experiment and theory is a competitive process
with respect to the formation of G-C base pairs, and can be considered the
primary step in the real mechanism of protein-nucleic acid recognition.
PMID- 9399162
TI - Cooperative interactions of the oligodeoxyribonucleotides on the complementary
template. The influence of chemical groups and mismatched nucleotides at the 5'-
and 3'-ends of oligonucleotides on the parameters of cooperativity.
AB - Parameters of cooperative interactions of two or three oligodeoxyribonucleotides
or their derivatives bound with the adjacent sites of the complementary template
were measured using method of "complementary addressed modification titration"
(CAMT). Complementary template (target) were modified with the reactive
oligonucleotide derivatives (reagents) bearing covalently attached alkylating 4
[N-(2-chloroethyl)-N-methylamino]benzylamino- group (C1RCH2NH)- at 5'-terminal
phosphate. The targets had only one binding site for the reagent and either no
(T10), or one (T'22 and T22) or two sites (T26) for the oligonucleotides
(effectors) cooperatively bound with the adjacent sites on the template. Both
unmodified oligonucleotides E1, E2 and their derivatives E1Phn, E2Phn bearing N
(2-hydroxyethyl)-phenazinium residues Phn- both at 5'- and 3'-ends covalently
linked via ethylenediamine linker were used as effectors. Effectors E1 and E2
(E1Phn and E2Phn) bind, respectively, upstream or downstream from the reagent.
Hexameric (X6) or octameric (X8 or X8m) reagents were used for the target
modification. The reagent X8m formed one TT-mismatch with the target at the end
opposite to location of the reactive moiety. The cooperativity parameter values
characterizing the mutual interactions between the reagents X6, X8, X8m and
effectors E1, E2, E1Phn, E2Phn have been found as the ratio of the association
constants of the reagents in the presence of effectors. The association constants
were calculated from the dependencies of the target modification extent on
initial concentrations of the reagents. The use of T26 existing both in linear
and hairpin conformations permitted us to estimate additionally the role of
indirect cooperativity originating from the induction of the target
conformational change by the effectors. The following conclusions were done from
the quantitative results. The efficiency of direct cooperativity is independent
on the length of oligonucleotide for the same nature of the contact. The
cooperativity parameter increases by factor about 3 in the presence of Phn-group
covalently attached to oligonucleotides and located at the junctions. The
presence of either alkylating group C1RCH2NH- or TT-mismatch at the junctions
eliminates cooperative interaction between the bases. In the same time
sufficiently effective cooperative interaction takes place in the case of
simultaneous presence of both Phn- and either C1RCH2NH- group or TT-mismatch at
the junction.
PMID- 9399163
TI - Dielectric relaxation, molecular motion and interprotein interactions in
myoglobin solution.
AB - The results of the investigation of protein molecule dynamic in solution by Time
Domain Dielectric Spectroscopy are presented. The horse myoglobin solutions in
wide range of concentration from 0.6% to 54% at 20 degrees C have been
investigated. The result of analysis produced in the term of dipole correlation
function has shown that the obtained correlation function of macromolecule motion
may be presented as sum of three components corresponding to three kinds of
protein motions: anisotropic intramolecular motion, anisotropic Brownian tumbling
and isotropic slow motion. We suppose that the cause of protein tumbling
anisotropy and the possibility to keep slow motion is the interprotein
electrostatic interactions. The characteristic time of slow motion depends on the
concentration of protein and perhaps is controlled by translational diffusion.
The dipole moment of myoglobin calculated by the Onsager-Oncley equation is 200D
for solutions less than 10% protein concentration. It is in a good agreement with
the theoretical value.
PMID- 9399164
TI - Modeling of in vivo proteolytic degradation of hemoglobin.
AB - Based on the amino acid sequences of endogenous peptides and X-ray spatial
structure, mechanism of the in vivo proteolly degradation of bovine hemoglobin
was analysed. The degradation was shown to be a multi-stage process. Its first
stage is determined by the spatial organization of the native protein substrate,
and the next stages-by the distribution of the electrostatic field potential of
the protein fragments formed at the earlier stage.
PMID- 9399165
TI - Aromatic-aromatic ring interaction revisited with model compounds of Wilcox.
AB - Aromatic-aromatic nonbonded interactions have been reexamined using model
compounds of Wilcox and collaborators (J. Am. Chem. Soc. 1994, 116, 4497). It was
found that at low temperatures down to 210 degrees K, the population of the
folded conformers (A) is higher than that of the unfolded conformers (B),
suggesting that edge-to-face aromatic-aromatic ring interactions are in effect.
However, the free energy difference between the two types of conformers did not
vary linearly with temperature, which is against what we expected from the
thermodynamic relationship of delta G = delta H-T delta S. This suggests that in
the presence of solvent molecules a free energy cancellation effect operates
between the two conformers. Although A has a free energy gain of only
approximately 0.5 kcal/mol over B in organic solvents, as obtained by subtracting
the solvent-induced unfolding effect, it could still be a significant energy with
respect to conformational preference.
PMID- 9399166
TI - Current status of computed radiography in emergency departments.
AB - This study reports the findings of a computed radiography (CR) imaging experience
questionnaire sent to 35 emergency departments (ED) in North America. A total of
25 responses to the questionnaire were received corresponding to a return rate of
71%. The median daily workload was 71 patient examinations and the average number
of films per patient examination for the 21 facilities was 3.0 +/- 0.8. A total
of 91% of respondents printed to film all ED trauma images obtained with CR with
only one ED claiming to be filmless. CR in the ED was easy to use and had
significant benefits of reducing examination repeat rates, permitting a prompt
availability of radiographic images, improving image quality, providing improved
operational efficiency, and eliminating lost films. Major limitations of CR were
deemed to be limited viewing stations, CR costs, and inefficient patient ID
entry. Radiology departments were very happy with the introduction of CR into the
ED setting with approximately half being highly satisfied and half somewhat
satisfied. The degree of satisfaction by ED personnel was similar with about half
being highly satisfied, 40% somewhat satisfied, and the remainder neutral. The
fact that not a single respondent was in any way dissatisfied shows that CR can
play a useful role in the ED setting.
PMID- 9399167
TI - Eye-tracking device comparisons of three methods of magnetic resonance image
series displays.
AB - This study evaluated the effectiveness of three kinds of display methods for
magnetic resonance (MR) image interpretation using an eye-tracking device. Seven
radiologists interpreted head MR studies by using a single monitor (17-inch,
1,024 X 1,280 bit) in the 4 images/screen display format. Three paging modes were
compared: (A) rapid paging only, (B) multiple image series display at the same
slice position with consecutive rapid paging, and (C) simultaneous display of
multiple series with each image series being browsed independently. Using an eye
mark camera, the radiologist's point of fixation and the duration of fixation
were recorded during actual image interpretation. In mode A, the duration of
fixation was short, and the points of fixation were distributed randomly over the
visual field. In mode B, the points of fixation were clustered chiefly on a
specific image series. In mode C, the points of fixation were not clustered on a
specified series, but the duration of viewing the T2 series was relatively long.
The total tracing area in mode B and C was smaller than that in mode A. Multiple
series display, in which selected key series of slices could be viewed
effectively, was found to be suitable for MR image interpretation.
PMID- 9399168
TI - Receiver operating characteristic study of image preprocessing for teleradiology
and digital workstations.
AB - The purpose of this study was to evaluate whether digitized analog images
displayed on a digital workstation can be improved by using a preprocessing
algorithm, and if so, whether the quality of the resulting images can reach that
of the original films. The material contained 120 difficult cases (about 50% with
selected pathology). Four radiologists each evaluated half of the randomly
ordered cases with the digital workstation and half of the cases with the
original radiographs. The data were compared with a previous similar study, where
the workstation had no option for preprocessed images. Preprocessed digital
images were clearly superior to digital images without preprocessing, although
for those of the highest diagnostic difficulty they were inferior to the original
films. The preprocessing algorithm has improved the diagnostic quality of the
digital workstation. There is room yet for improvement compared to plain films,
although the current setup may be sufficient in some settings.
PMID- 9399169
TI - A brief review of human perception factors in digital displays for picture
archiving and communications systems.
AB - The purpose of this review is to further inform radiologists, physicists,
technologists, and engineers working with digital image display devices of issues
related to human perception. This article will briefly review the effects of
several factors in human perception that are specifically relevant to a digital
display environment. These factors include the following: the spatial and
contrast resolution of the display device; background luminance level and
luminance range of the display system; brightness uniformity; extraneous light in
the reading room; displayed field size; viewing distance; image motion and
monitor flickering; signal to noise ratio of the displayed image; magnification
functions; and the user interface. After reviewing the perception study results,
a checklist of desirable features and quality assurance issues for a digital
display workstation are presented as an appendix.
PMID- 9399170
TI - The effect of lossy discrete cosine transform compression on subtle bone
fractures.
AB - Extensive research efforts have been devoted to the feasibility of picture
archiving and communication systems (PACS) in recent years. The advantages of
PACS are numerous but mainly include reduced cost and improvement in the
operational efficiency of a PACS-based radiology department. In digital
radiography, images are viewed either in hard-copy or soft-copy format. Usually,
these images are subsequently compressed and archived for future evaluation.
There are various methods used in image compression. In this study, computed
radiography images showing subtle pediatric bone fractures were compressed with
the lossy method of image compression after they had been initially evaluated on
workstation monitors. These studies were subsequently evaluated by observers, who
were unaware of the interpretations of these images before compression, to
determine if they could detect similar abnormalities. Our conclusion is that
there is no difference in the interpretation of soft-copy computed radiographic
images before or after lossy 10:1 compression in studies of subtle pediatric bone
fractures. This is a US government work. There are no restrictions on its use.
PMID- 9399172
TI - The Society for Computer Applications in Radiology.
PMID- 9399171
TI - The effect of intensity windowing on the detection of simulated masses embedded
in dense portions of digitized mammograms in a laboratory setting.
AB - The purpose of this study was to determine whether intensity windowing (IW)
improves detection of simulated masses in dense mammograms. Simulated masses were
embedded in dense mammograms digitized at 50 microns/pixel, 12 bits deep. Images
were printed with no windowing applied and with nine window width and level
combinations applied. A simulated mass was embedded in a realistic background of
dense breast tissue, with the position of the mass (against the background)
varied. The key variables involved in each trial included the position of the
mass, the contrast levels and the IW setting applied to the image. Combining the
10 image processing conditions, 4 contrast levels, and 4 quadrant positions gave
160 combinations. The trials were constructed by pairing 160 combinations of key
variables with 160 backgrounds. The entire experiment consisted of 800 trials.
Twenty observers were asked to detect the quadrant of the image into which the
mass was located. There was a statistically significant improvement in detection
performance for masses when the window width was set at 1024 with a level of
3328. IW should be tested in the clinic to determine whether mass detection
performance in real mammograms is improved.
PMID- 9399173
TI - And thus, the hand revealed its beauty. Moving toward aesthetics.
PMID- 9399174
TI - The architects of the future.
PMID- 9399175
TI - Fractures of the distal radius: what are the expectations of therapy? A two-year
retrospective study.
AB - This retrospective study addressed two basic questions important to hand
therapists: what are the expectations of therapy vis-a-vis range of motion and
strength among patients with distal radius fractures, and do patients treated by
different therapists within a center experience substantially similar or
dissimilar outcomes? Differences between patient groups were tested using ANOVA,
and changes in performance were tested using the Student's t-test; significant
differences between patient groups treated by different therapists were lacking
and patients demonstrated significant changes in active motion and strength. Data
were used to derive regression equations that yielded good estimates of active
motion at discharge from therapy. Patients were treated an average of ten times;
at discharge, they demonstrated active wrist and forearm motion compatible with
the performance of activities of daily living.
PMID- 9399176
TI - Pillar pain as a postoperative complication of carpal tunnel release: a review of
the literature.
AB - Carpal Tunnel Syndrome (CTS) has been referred to as the most common peripheral
entrapment neuropathy. As Mirza and colleagues note, its incidence continues to
increase. Einhorn and Leddy cite Palmer's estimated incidence of 1% in the
general population and 5% or more of workers in certain industries which require
repetitive use of the hands and wrists. Conservative treatment of CTS includes
splinting and modification of activities. However, surgical release of the
transverse carpal ligament or the flexor retinaculum is an extremely common
procedure. The open surgical technique has been used since 1924 and is still
considered by many to be the gold standard. In 1989 Oksuto introduced the
endoscopic carpal tunnel release (ECTR) with the rationale of potentially
decreasing the prevalence of complications. In the ensuing years, endoscopic
results have generated a tremendous amount of study and controversy. Berger
reported that many "passionate arguments both for and against the use of ECTR"
exist. This paper briefly reviews the literature generated by this debate,
focusing on one potential postoperative complication: pillar pain. Various
definitions of pillar pain are noted, and suggested etiologies are grouped into
four categories. This is followed by a brief discussion of the treatment
approaches and issues.
PMID- 9399177
TI - The effect of use of a wrist orthosis during functional activities on surface
electromyography of the wrist extensors in normal subjects.
AB - Wrist orthoses are advocated for patients with lateral epicondylitis on the
assumption that use of the orthosis decreases muscle activity of the wrist
extensors during activities. The purpose of this study was to compare the amount
of electrical activity, root mean square (RMS) calculated from surface EMG
recorded over the wrist extensors, during activities when applying four
conditions of wrist orthoses: dorsal; volar; semicircular; and no orthosis.
Thirteen normal subjects (mean age 27.7 years) performed three lifting and two
gripping tasks, repeated on three consecutive days under four orthotic
conditions. Measured were RMS and maximum voluntary grip strength. Repeated
measures ANOVA's indicated a significant decrease of RMS using the semicircular
design during lifting (p < .0005). Grip strength decreased significantly using
all three orthotic designs, but RMS recorded during gripping did not. It was
concluded that application of a wrist orthosis reduces electrical activity of the
wrist extensors less than anticipated and only during lifting.
PMID- 9399178
TI - Reliability of isometric wrist extension torque using the LIDO WorkSET for late
follow-up of postoperative wrist patients.
AB - The objectives of this study were to determine interobserver, intraobserver, and
overall reliability of isometric wrist extension torque using the LIDO WorkSET
and then to estimate the minimal level of detectable change using the standard
error of measurement. A generalizability study was conducted on 18 postoperative
patients. Primary outcome was mean torque of three trials. Variance components
were used to calculate generalizability coefficients for intraobserver (G =
0.96), interobserver (G = 0.94), and overall reliability (G = 0.92). When the
same therapist is evaluating a patient on different days, a change of more than
16 inch-lb is needed to be 90% confident that true change has occurred. A greater
value for change (23 inch-lb) is required when different therapists evaluate a
patient on different days. The LIDO WorkSET measures wrist torque in a
reproducible manner in an applied setting. The testing protocol is sensitive to
differences in wrist torque between individuals and tolerated in the late
postoperative period.
PMID- 9399179
TI - The force/time relationship of clinically used sensory testing instruments.
AB - The stimuli of commonly used sensibility measurement instruments tested in this
study demonstrate unequivocally that "hand-held instruments" produce variations
in application force from one stimulation to another, one instrument to another,
and from one examiner to another. These application force variations cannot be
compensated for by care in technique and need to be controlled for measurement
reliability. Only the Semmes-Weinstein monofilaments provide some control of
force during application and can be considered force controlled if calibrated and
applied correctly. The monofilaments, too, become less controllable if applied
too quickly and bounced against the skin. Two-point discrimination instruments,
in particular, lack control of application force, with the force of one point
significantly different from two points. A difference in applied force makes it
possible for a patient to solve the two-point discrimination test by discerning
the difference between heavier and lighter forces, rather than one or two-point
recognition. Tuning fork instruments for vibration testing have even larger
variations in application force amplitude rendering their stimulus highly
uncontrolled and masking the actual vibration of the tuning fork. Spectral
analysis of the force frequency signal produced by hand held sensibility
measurement instruments shows they all produce both high and low frequency
signals sufficient in strength to stimulate both slowly adapting and quickly
adapting end organs, and are not capable of stimulating one particular group.
These dynamic properties of testing stimuli explain why our tests are not as
repeatable and sensitive as desired. The understanding of these dynamic
properties in sensibility measurement is a key for improved instruments and more
repeatable findings in clinical testing.
PMID- 9399180
TI - The clamshell digit splint with Otoform lining.
PMID- 9399181
TI - A static progressive splint for Dupuytren's release.
PMID- 9399182
TI - Defining handedness: a critical variable.
PMID- 9399183
TI - A review of esthetic alternatives for the restoration of anterior teeth.
AB - PURPOSE: This article describes different options for the esthetic treatment of
anterior teeth, starting with minimally invasive procedures, such as facial
surface bleaching and bonding with composites. METHODS: The importance of metal
ceramic restorations, porcelain shoulder techniques, and metal free ceramics are
also emphasized. The options are carefully demonstrated to identify advantages
and limitations of each technique.
PMID- 9399184
TI - Temperature rise in pulpal chamber during fabrication of provisional resinous
crowns.
AB - STATEMENT OF PROBLEM: The heat generated during the exothermic polymerization
reaction of autopolymerizing resinous materials and the heat generated by
ultraviolet lamps during irradiation of photopolymerizing resinous materials
could cause pulpal damage when a direct technique is used to fabricate
provisional restorations. This could occur if temperature elevations overcome the
physiological heat dissipating mechanisms of the dental-periodontal system.
PURPOSE: This in vitro study compared the rise in temperatures in the pulpal
chamber during fabrication of provisional complete veneer crowns by direct method
with different autopolymerizing and photopolymerizing resins. The effect of
curing resinous crowns in different matrices, such as a polyvinyl siloxane
impression and a vaccuum-formed polypropylene sheet, was also evaluated. RESULTS:
The results demonstrated that the amount of heat generated during resin
polymerization and transmitted to the pulpal chamber could be damaging to pulpal
tissues including odontoblasts. When curing of provisional resinous crowns was
performed in the polyvinyl siloxane impression, significantly lower temperatures
were recorded compared with curing in the vacuum-formed polypropylene sheet.
CONCLUSIONS: To prevent pulpal damage, effective cooling procedures are strongly
recommended when directly fabricating resinous provisional crowns.
PMID- 9399186
TI - Effect of different surface textures on retentive strength of tapered posts.
AB - STATEMENT OF PROBLEM: Tapered posts allow for the preservation of tooth substance
in the fragile apical area and are advantageous in clinical situations where they
conform to the root and canal configuration of endodontically treated teeth.
However, their lower retention compared with passive parallel-sided or active
threaded posts is a disadvantage. PURPOSE: This study determined the retentive
strength of tapered titanium posts with different surface textures and examined
the effect of roughening dentinal walls of the prepared post space. MATERIAL AND
METHODS: Posts with four surface configurations (smooth, with and without
grooves, and sandblasted, with and without grooves) were examined when cemented
in extracted anterior teeth. RESULTS: The smooth post showed the lowest retentive
strength. Sandblasting the smooth post more than doubled its retentive strength.
The retentive strength of both smooth and sandblasted posts could be further
increased by the addition of circumferential grooves. Roughening the dentinal
walls of the prepared post space increased the retentive strength of sandblasted
posts with and without grooves even more. CONCLUSIONS: These findings indicated
that, when a tapered post is used, roughening the dentin canal wall, as well as
sandblasting and grooving the post, can provide statistically significant
additional resistance to dislodgment.
PMID- 9399185
TI - Fracture strengths of provisional restorations reinforced with plasma-treated
woven polyethylene fiber.
AB - STATEMENT OF PROBLEM: Fracture strength of interim fixed partial prosthesis is of
great concern, especially in long-span restorations or areas of heavy occlusal
stress. PURPOSE: Effects of a plasma-treated woven polyethylene fiber (Ribbond)
on the fracture strength of polymethyl methacrylate (Coldpac) and a resin-based
two-phase curing provisional restorative material (Provipont DC) were evaluated.
MATERIAL AND METHODS: A polyvinyl siloxane template was used to fabricate three
unit posterior provisional prostheses on a stainless steel die with two abutments
22 mm apart. The reinforced groups were fabricated by affixing 3 mm wide pieces
of fiber treated with methyl methacrylate monomer or polyisocyanate (activator
part of Provipont DC) on the occlusal surfaces of abutments. The interim
materials were mixed, according to the manufacturers' specifications, and placed
in the template. The template was pressed on the die and held secure until
complete setting of the material occurred by light curing (Provipont DC) or
autopolymerization (PMMA). The specimens were divided into 4 groups of 10 each
(A, reinforced Provipont DC; B, unreinforced Provipont DC; C, reinforced PMMA;
and D, unreinforced PMMA). A central compressive load force was exerted on the
specimen to determine the fracture load of the restorations. RESULTS: The data
revealed mean fracture loads of A, 65.59 +/- 11.27 kg; B, 46.59 +/- 14.84 kg; C,
53.46 +/- 7.76 kg; and D, 49.86 +/- 14.44 kg. CONCLUSION: Plasma-treated
polyethylene reinforced PMMA restorations showed no significant increase in
fracture loads when compared with unreinforced restorations (p > 0.10), whereas
reinforced resin-based restorations revealed significantly higher fracture loads
(p < 0.01) than the unreinforced resin-based and PMMA provisional restorations.
PMID- 9399187
TI - Cyclic fatigue testing of five endodontic post designs supported by four core
materials.
AB - PURPOSE: This pilot study examined the cyclic fatigue of five endodontic post
systems (AccessPost, Flexi-Flange, Flexi-Post, ParaPost, and Vlock) with four
core materials (Tytin silver amalgam, Ti-Core, Ketac-Silver and G-C Miracle Mix).
MATERIAL AND METHODS: In vitro cyclic fatigue was performed with a machine
designed to simulate masticatory fatigue forces. An instantaneous force of 22.2 N
(5 pounds) was applied to each post and core combination for a test configuration
of 4,000,000 repetitions, or until failure occurred. The type of failure and
number of repetitions at failure was recorded for each sample tested. Two-way
analysis of variance (ANOVA) was used to compare groups. RESULTS: All posts/core
samples with Ti-Core composite and Tytin silver amalgam completed the test with
no failures. All posts/core samples with Ketac-Silver material failed before the
4,000,000 test cycle configuration and all failures were core failures. All
posts/core samples with G-C Miracle Mix material failed in a similar manner.
Newman-Keuls multiple comparison test illustrated that, with this simulated
fatigue test, Ti-Core material and Tytin silver amalgam were superior to both G-C
Miracle Mix and Ketac-Silver materials.
PMID- 9399188
TI - Clinical performance of resin-bonded fixed partial dentures and extracoronal
attachments for removable prostheses.
AB - STATEMENT OF PROBLEM: It is important to evaluate the long-term clinical
performance of resin-bonded fixed partial dentures and extracoronal attachments
for removable prostheses. PURPOSE: A prospective, long-term clinical study was
conducted to evaluate the success of resin-bonded fixed partial dentures since
1985 and of resin-bonded extracoronal attachments from 1987. METHODS: Until 1993,
a total of 130 resin-bonded fixed partial dentures had been seated in 101
patients, as well as 12 removable partial dentures (RPDs) with 24 extracoronal
retainers in 10 patients. The clinical treatment protocol and the laboratory
procedures were standardized. By the end of 1993, it was possible to reexamine 98
patients with a total of 127 resin-bonded fixed partial dentures and all 10
patients with removable partial dentures. The average time in function for the
resin-bonded fixed partial dentures at the time of examination was 3.4 years and
2.3 years for the removable restorations. RESULTS: During the period of
observation, one retainer failed on six of the resin-bonded fixed partial
dentures, which represents a failure rate of 4.7%. Debonding of extracoronal
attachments was recorded for 8.3% of the total number of retainers. CONCLUSION:
The resin-bonded fixed partial denture technique can be considered to be a
clinically reliable method of treatment, and permits the expansion of indications
beyond a classical three-unit resin-bonded fixed partial denture. Long-term
clinical success of removable partial dentures with resin-bonded extracoronal
retainers warrants additional clinical studies.
PMID- 9399189
TI - "Prosthetic condition" and patients' judgment of complete dentures.
AB - PURPOSE: This study introduces the concept "prosthetic condition", which combines
the quality of complete dentures and residual alveolar ridges. MATERIAL AND
METHODS: A pilot study was performed to select quality criteria with an
acceptable interobserver agreement. With these criteria, a clinical examination
was performed to assess the quality of the existing complete dentures and the
residual alveolar ridges of 397 complete denture wearers. During clinical
examination, the interobserver agreement of the selected criteria was retested.
The "prosthetic condition" was assessed by combining the scores for denture
quality and quality of the residual alveolar ridges. Subsequently, participants'
satisfaction with and complaints about their dentures were scored according to
their answers to specific questions. RESULTS: Logistic regression analysis
demonstrated that no variable of the "prosthetic condition" proved to explain the
denture satisfaction. Some variables of the "prosthetic condition" had a
significant but not relevant correlation with some denture complaints.
CONCLUSIONS: More research is necessary to substantiate the concept "prosthetic
condition" as an acceptable measure of professionally quality assessment of
dentures and denture-bearing surfaces. However, in determining the treatment need
of community-dwelling groups, this concept seems a more realistic measure than
denture quality only.
PMID- 9399191
TI - AllCeram crowns for single replacement implant abutments.
AB - Clinicians who are comfortable with traditional porcelain fused to metal
restorations may find the thickness of veneering porcelain addition to the
CeraOne single tooth ceramic cap disconcerting. When using a premanufactured
ceramic cap to fit the space of the final restoration, substantial amounts of
"unsupported" veneer porcelain may be required to achieve tooth contact to
adjacent or opposing dentition. A potential problem of weak, unsupported veneer
porcelain has been addressed by a modification of an existing manufacturing
process. By using CAD/CAM technology, a custom-designed Procera AllCeram coping
can be created for the implant abutment that eliminates any concerns regarding
the resultant design of the underlying ceramic cap substructure.
PMID- 9399190
TI - The effect of diet on the bearing mucosa during adjustment to new complete
dentures: a pilot study.
AB - PURPOSE: This pilot study investigated the reliability of the conventional
prosthodontic wisdom that a modified diet ameliorates soreness during the
adjustment to new complete dentures. Tissue ulceration of the bearing mucosa
served as the indicator of patient soreness as a function of diet. MATERIAL AND
METHODS: Fourteen men were randomly assigned to two equal treatment groups. One
group consumed a consistency-gradated diet and the other (control) ate as they
wished. New complete dentures were fabricated for both groups by the same
provider, technician, materials, and method; the study was double-blinded. Tissue
ulceration was assessed and totaled for the 10 days after denture placement,
constituting a soreness score. RESULTS: Data analysis identified a significant
difference in soreness scores between dietary groups (p < 0.05). Wearing time had
a significant inverse relation to soreness (p < 0.05) in this study. A host of
potential explanatory variables of clinical interest failed to relate
significantly to the outcome of soreness. CONCLUSIONS: The results of this study
indicated that a consistency-gradated diet had a significant effect in
diminishing tissue ulceration during the immediate postplacement period for this
group of men. Potentially, these findings could contribute to enhanced quality of
care and to the more efficient allocation of provider-based resources.
PMID- 9399192
TI - A longitudinal clinical assessment of spark erosion technology in implant
retained overdenture prostheses: a preliminary report.
AB - STATEMENT OF PROBLEM: As adapted for the dental profession, spark erosion
technology permits precise machining of retentive metal overdenture frameworks
for use in implant prosthetics. PURPOSE: The resultant prostheses are retentive
and provide a number of benefits offered by both conventional overdenture and
fixed prosthetic designs. MATERIAL AND METHODS: Preliminary data collected from
an ongoing 5-year clinical trial were reviewed to qualitatively assess the
clinical results obtained from 25 spark eroded implant-retained overdenture
prostheses placed in 24 subjects. RESULTS: Throughout an evaluation period of
13.33 months (range 4 to 19 months), subject responses measured by questionnaire
were uniformly good. Few complications were encountered and were limited to resin
denture base/tooth fractures or retentive component failures that were easily
repaired. CONCLUSION: Overdenture prostheses retained by spark eroded milled
frameworks offer an acceptable treatment alternative for patients undergoing
dental implant therapy.
PMID- 9399193
TI - Effects of implant anchorage on midface prostheses.
AB - STATEMENT OF PROBLEM: Acquired midface defects may produce functional and
psychologic impairments that adversely effects a patient's quality of life.
Conventional prostheses may lack adequate retention and stability, diminishing
the patient's confidence that the prosthesis will remain in place during routine
activities. PURPOSE: The experience with and patient response to endosseous
implants in prosthetic restoration of midface defects is presented in this study.
MATERIAL AND METHODS: Five patients in age from 36 to 88 years were treated with
19 titanium endosseous root-form implants to provide retention and stability for
prostheses. Patients responded to a questionnaire rating overall use,
effectiveness, and satisfaction of their prosthesis, before and after the use of
implants. RESULTS: All 19 implants were judged to be osseointegrated at abutment
connection. Of the 17 implants used prosthetically, 14 (82%) remained
osseointegrated and 3 (18%) failed. Analysis of the questionnaire tends to
indicate an improvement of the quality of life for the patients with an implant
retained prosthesis.
PMID- 9399194
TI - Dynamic mechanical thermal analysis of maxillofacial elastomers.
AB - STATEMENT OF PROBLEM: Maxillofacial prosthetic materials should simulate the oral
tissues as much as possible and therefore have a similar flexibility and
resilience. In light of the oral tissues constantly moving, the dynamic
deformation properties of maxillofacial materials would seem the most relevant.
PURPOSE: In this study, dynamic mechanical thermal analysis was used to evaluate
the deformation properties of five silicone rubber materials used to construct
facial prostheses. The technique involves the application of a sinusoidally
oscillating stress to a material and analyzes how the material elastically or
viscoelastically responds to the stress. The dynamic mechanical thermal analysis
can operate at a fixed frequency or range of frequencies over a specific
temperature range and also isothermally as a function of time. RESULTS: Cosmesil
and A-2186 materials were the most resilient materials and Silbione had the
greater energy absorption capacity, which was particularly noticeable at the
higher frequencies. Silbione also had a lower shear modulus (G'), which indicated
it was more flexible than the other materials. CONCLUSION: The dynamic mechanical
thermal analysis proved to be a rapid, reliable, and convenient method for the
determination of viscoelastic properties of maxillofacial materials.
PMID- 9399195
TI - Clinical effect of full coverage occlusal splint therapy for specific
temporomandibular disorder conditions and symptoms.
AB - PURPOSE: The purpose of this retrospective study was to evaluate the effect of
maxillary full-coverage occlusal splint (stabilization splint) therapy for
specific temporomandibular disorders and their symptoms/signs. MATERIAL AND
METHODS: This study assessed the outcome of 232 patients who were suffering from
chronic pain on movements, joint noise except reciprocal clicking, and difficulty
of mouth opening. All were treated with the stabilization splint alone. RESULTS:
The total remission rate was 41% and, including those reporting some improvement,
the rate was 84%. The presence of displaced disk significantly decreased the
success rate. However, the presence or absence of radiographic changes in the
temporomandibular joint did not influence the treatment outcome. CONCLUSION: From
this study, it is suggested that the stabilization splint therapy may be a useful
treatment modality in treatment of temporomandibular disorders, especially for
the patients without clinical evidence of displaced disk.
PMID- 9399196
TI - Shear bond strength to feldspathic porcelain of two luting cements in combination
with three surface treatments.
AB - STATEMENT OF PROBLEM: Although selection of clinically reliable bonding system is
essential, limited information concerning the combination of durable ceramic
bonding and luting agents is available. PURPOSE: This in vitro study was
conducted for the purpose of evaluating bond strengths of ceramic bonding
materials in conjunction with their initiation and silane-activation modes.
MATERIAL AND METHODS: Disk-shaped fired porcelain specimens were air-abraded with
alumina, then bonded with six combinations of three silane priming and two luting
agents; specimens were also bonded with two luting cements without priming. Shear
bond strengths were determined both before and after thermocycling. RESULTS: For
the two unprimed control groups, as well as two of the groups bonded with Panavia
21 cement (Clearfil Porcelain Bond and Panavia 21; Panavia Ceramic Primer and
Panavia 21) the reduction in bond strengths after thermocycling was remarkable as
compared with the corresponding prethermocycling groups (p < 0.05). A dual-cured
luting cement (Clapearl DC) used with each of three silane priming materials
(Clapearl Bonding Agent, Clearfil Porcelain Bond, and Panavia Ceramic Primer)
exhibited consistent shear bond strength greater than 30 MPa after 20,000
thermocycles. CONCLUSION: The above three systems appeared to be useful for the
long-term clinical success of feldspathic porcelain restorations.
PMID- 9399197
TI - Quantitative study of bacterial colonization of dental casts.
AB - STATEMENT OF PROBLEM: Contamination of dental casts can occur if the record bases
are improperly disinfected or inadvertently not disinfected during fabrication of
a prosthesis. It is essential to develop an effective means of disinfecting
dental casts from professional, medical, and legal points of view. PURPOSE: This
study determined whether: (1) saliva contamination on the surface of the dental
cast contributed to bacterial growth over time and (2) cleaning or disinfecting
of dental casts can minimize bacterial growth. MATERIAL AND METHODS: Five dental
casts were contaminated with saliva. Each cast was divided into six areas and
swabbed at 15, 30, 60, 120, 180, and 240 minutes. Sheep blood agar plates were
inoculated and incubated at 37 degrees C for 72 hours. Standardized dental stone
cylinders were contaminated with 25 microliters of saliva and treated by rinsing
in tap water, scrubbing with soap and tap water, soaking in 2% glutaraldehyde, or
as controls with and without saliva contamination (n = 12). The treated dental
stone cylinders were placed in individual test tubes containing 2.5 ml of sterile
phosphate-buffered solution and a final dilution of 10(-4) was achieved. Sheep
blood agar plates were inoculated and incubated at 37 degrees C for 24 hours.
RESULTS: Contamination of dental casts did not decrease, even when allowed to sit
4 hours before handling. Results also demonstrated that rinsing saliva-treated
stone cylinders for 20 seconds significantly diminished bacterial contamination.
Scrubbing with soap and tap water or soaking in 2% glutaraldehyde significantly
reduced the bacterial contamination of saliva-treated stone cylinders when
compared with rinsing with tap water. CONCLUSION: Bacterial contamination of
dental casts can occur and requires an effective method of disinfecting.
PMID- 9399198
TI - The effect of environmental pressure changes during diving on the retentive
strength of different luting agents for full cast crowns.
AB - STATEMENT OF PROBLEM: The effect of pressure cycling on the bond strength of
cement luting agents is largely unknown. PURPOSE: This study investigated the
effect of pressure cycling on the retention of full cast crowns to extracted
teeth. MATERIAL AND METHODS: Sixty extracted single-rooted premolar teeth had
full cast crowns cemented, 20 with a zinc phosphate cement, 20 with a glass
ionomer, and 20 with a resin cement. After 7 days of storage, each of the teeth
in the experimental groups was pressure cycled 15 times from 0 to 3 atmospheres
(304 KPa), after which the force required to dislodge the crowns was tested in an
Instron testing machine. RESULTS: A significant difference was found (Students t
test; p > 0.01) between the force required to remove the crowns in the zinc
phosphate control (142.10 +/- 36.42 N) and experimental (15.93 +/- 11.13 N)
groups and the glass ionomer cemented control (186.33 +/- 24.33 N) and
experimental (91.50 +/- 33.07 N) groups; no difference was found between the
resin cemented control (291.15 +/- 78.48 N) and experimental (281.32 +/- 85.43 N)
groups. CONCLUSION: This study showed that the retention of full cast crowns to
extracted teeth is reduced after pressure cycling if the crowns are cemented with
either zinc phosphate cement or glass ionomer cement. Dentists should consider
using a resin cement when cementing crowns and fixed partial dentures for
patients, such as divers, who are likely to be exposed to pressure cycling.
PMID- 9399199
TI - Fabrication of long-span provisional restorations with multiple pontics: a
modified method by using a vacuum-formed matrix.
PMID- 9399200
TI - A simple antirotational device for implant abutment screws.
PMID- 9399201
TI - Customized absorbent wafers for saliva control in implant patients.
PMID- 9399202
TI - A simple procedure for boxing elastomeric impressions.
PMID- 9399203
TI - Making an impression of a maxillary edentulous patient with gag reflex by
pressing caves.
PMID- 9399205
TI - Parkinson's disease is not a long-latency illness.
PMID- 9399204
TI - Essential tremor: the beginning of a new era.
PMID- 9399206
TI - The role of the immune system in neurodegenerative disorders.
PMID- 9399207
TI - A gene (ETM) for essential tremor maps to chromosome 2p22-p25.
AB - We report the results of linkage analysis in a large American family of Czech
descent with dominantly inherited "pure" essential tremor (ET) and genetic
anticipation. Genetic loci on chromosome 2p22-p25 establish linkage to this
region with a maximum LOD score (Zmax) = 5.92 for the locus, D2S272. Obligate
recombinant events place the ETM gene in a 15-cM candidate interval between the
genetic loci D2S168 and D2S224. Repeat expansion detection analysis suggests that
expanded CAG trinucleotide sequences are associated with ET. These findings will
facilitate the search for an ETM gene and may further our understanding of the
human motor system.
PMID- 9399208
TI - Globus pallidus internus pallidotomy for generalized dystonia.
AB - The authors present a young boy with severe generalized dystonia treated with
bilateral simultaneous pallidotomy. Microelectrode recordings with the patient
under propofol anesthesia showed that the mean discharge rate of globus pallidus
internus (GPi) neurons was between 21 and 31 Hz. This contrasts sharply with the
mean GPi neuronal firing rates of approximately 80 Hz that are characteristic of
Parkinson's disease. The patient had no immediate benefit from surgery, but a
progressive improvement in both axial and limb dystonia began within 3 days. The
Burke-Fahn-Marsden scores were 75 (maximum possible = 120) at baseline, 52 at 5
days, and 16 at 3 months after surgery. The mechanism of action of pallidotomy
for dystonia and the reasons for the delayed and progressive improvement are
unknown. Nevertheless, the magnitude of the improvement and the safety of the
procedure in this one patient warrant a careful evaluation of pallidotomy for
dystonia.
PMID- 9399209
TI - Symptoms and duration of the prodromal phase in Parkinson's disease.
AB - To investigate the duration of a prodromal phase before the onset of the classic
symptoms of idiopathic Parkinson's disease, the authors conducted a retrospective
case-control study of 60 patients with Parkinson's disease and 58 age- and sex
matched control subjects, covering the decade preceding the onset of classic
Parkinson's disease. The symptoms were derived from files of the patients'
general practitioners. Compared with control subjects, patients pre-Parkinson's
disease had more central nervous system, psychologic, musculoskeletal, and
cardiovascular (i.e., autonomic) symptoms. Patients pre-Parkinson's disease also
made more visits to general practitioners and medical specialists. The results
indicate that the onset of classic parkinsonism is frequently preceded by a
prodromal phase lasting from 4-6 years.
PMID- 9399210
TI - Postprandial hypotension and parkinsonian state in Parkinson's disease.
AB - Abnormal postprandial cardiovascular responses such as postprandial hypotension
(PPH) occur in primary autonomic failure and contribute significantly to
morbidity. The extent and frequency of PPH and its relationship to the
parkinsonian state in idiopathic Parkinson's disease (IPD) is unknown. By
studying 20 patients with IPD (without autonomic failure) and 16 age-matched
controls after both groups ingested a standard isocaloric balanced liquid meal,
we have shown that supine PPH complicates IPD and is related to marked worsening
of the parkinsonian state as measured by a cumulative score of tremor, rigidity,
bradykinesia, posture, and gait. Furthermore, significant postural hypotension is
unmasked that results in postural intolerance due to presyncopal symptoms. Our
study indicates that, in patients with IPD, ingestion of a meal may lead to
abnormal postprandial cardiovascular responses and aggravation of the
parkinsonian stage. The underlying mechanisms are unclear, although vasodilatory
gut peptides released in response to food ingestion may be contributory.
PMID- 9399211
TI - Differential modification of dopamine transporter and tyrosine hydroxylase mRNAs
in midbrain of subjects with Parkinson's, Alzheimer's with parkinsonism, and
Alzheimer's disease.
AB - The molecular characteristics of midbrain dopamine (DA) neurons have been
extensively studied in Parkinson's disease (PD). No such studies of the
characteristics of midbrain DA neurons in Alzheimer's disease (AD) or Alzheimer's
disease with parkinsonism (AD/Park) have been published. We examined the levels
of tyrosine hydroxylase (TH) protein, and the expression of TH and dopamine
transporter (DAT) mRNAs, in midbrain neurons of PD, AD, and AD/Park cases. In PD,
the loss of TH protein in the ventral tier of the substantia nigra pars compacta
(SNpc) of the PD group in accompanied by severe losses in the number of neurons
that express TH mRNA and DAT mRNA (74% loss). Remaining neurons show a shift to
higher concentrations of TH mRNA but a shift to lower concentrations of DAT mRNA
per cell. Hence, there is evidence that compensation in the remaining neurons can
elevate concentrations of TH mRNA and lower DAT mRNA. Alternatively, there may be
a predilection for a loss of neurons with high levels of DAT mRNA and low TH mRNA
levels within the SNpc of PD cases. There was no change in TH protein but an
elevation of TH mRNA concentrations per neuron without any change in
concentrations of DAT mRNA in the AD group. The AD/Park group did not exhibit
changes in the level of TH protein, but showed a small loss (26%) of neurons in
the SNpc and a greater loss in other regions of the midbrain (43-53%). Remaining
DA neurons showed a marked shift to lower concentrations of DAT mRNA per neuron
and a nonsignificant shift in cellular concentration of TH mRNA to higher levels.
This is consistent with our previous work showing that with AD/Park there is a
significant reduction in the number of DAT sites located on DA terminals in the
striatum, but the midbrain neurons have not died. Our results indicate that the
differential regulation of mRNAs encoding TH and DAT is similar in the
parkinsonian disorders (PD and AD/Park) even though the degree of cell death is
very different. This might suggest that compensatory events occur in these DA
neurons in AD/Park that are similar to those in PD and that result in
differential effects on mRNAs encoding TH and DAT proteins.
PMID- 9399212
TI - [123]IBZM binding predicts dopaminergic responsiveness in patients with
parkinsonism and previous dopaminomimetic therapy.
AB - We investigated the cases of 55 patients with parkinsonism and prior
dopaminomimetic therapy in whom the response to this treatment was questionable
or reported to be negative. None of these patients had shown motor fluctuations
prior to this study. We compared the results of imaging of dopamine-D2 receptors
by using [123I]iodobenzamide-single-photon-emission computed tomography (IBZM
SPECT) with the improvement in motor signs following a subcutaneous injection of
apomorphine and a subsequent increase in oral dopaminomimetic therapy. IBZM-SPECT
accurately predicted a positive or negative response to apomorphine in 37 (84%)
of 44 patients. The sensitivity/specificity was calculated as 96.3%/ 64.7%. The
sensitivity/specificity of IBZM-SPECT for the response to oral treatment with
levodopa (L-dopa) was calculated as 100%/75%. After a follow-up period of 2-4
years, 25 patients developed motor fluctuations. All of these patients had normal
IBZM binding. Nine developed clinical signs indicating a basal ganglia disorder
other than Parkinson's disease. Eight of these nine patients had reduced, and one
patient had normal, IBZM binding. We conclude that normal IBZM binding is a
useful predictor of a good response to dopaminergic drugs in patients with
parkinsonism and a questionable response to previous dopaminomimetic therapy.
Reduced IBZM binding seems to exclude a diagnosis of Parkinson's disease, because
none of the latter patients clearly benefited from L-dopa and 66.7% developed
clinical signs indicating another disorder of the basal ganglia.
PMID- 9399213
TI - Proton magnetic resonance spectroscopy in Parkinson's disease and atypical
parkinsonian disorders.
AB - Proton magnetic resonance spectroscopy (1H-MRS), localized to the lentiform
nucleus, was carried out in 12 patients with idiopathic Parkinson's disease
(IPD), seven patients with multiple-system atrophy (MSA), seven patients with
progressive supranuclear palsy (PSP), and 10 healthy age-matched controls. The
study assessed the level of N-acetylaspartate (NAA), creatine-phosphocreatine
(Cr), and choline (Cho) in the putamen and globus pallidus of these patients.
NAA/Cho and NAA/Cr ratios were significantly reduced in MSA and PSP patients. No
significant difference was found between IPD patients and controls. These results
suggest an NAA deficit, due to neuronal loss, in the lentiform nucleus of MSA and
PSP patients. 1H-MRS is a noninvasive technique that can provide useful
information regarding striatal neuronal loss in basal ganglia of patients with
atypical parkinsonian disorders and represents a potential tool for diagnosing
these disorders.
PMID- 9399214
TI - Dependency in Parkinson's disease: a population-based survey in nondemented
elderly subjects.
AB - Little epidemiological data are available on the dependency status of elderly
patients with Parkinson's disease (PD) living in the community. This study
assessed the activities of daily living (ADL), the instrumental activities of
daily living (IADL), and mobility in a representative sample of elderly
nondemented PD subjects (n = 20), compared to a control population (n = 2,697).
We found a significantly higher level of dependency in the PD sample based on
ADL, IADL, and mobility scales. Half of the PD subjects were dependent for ADL
(versus 13.2% for controls), 80% were dependent for IADL (versus 28% for
controls), and 20% had their mobility restricted to their home (versus 1.5% for
controls). The proportion of PD patients tended to be higher in those more
depressed or with more severe motor symptoms. PD patients were not found to be
more isolated socially or from family than was the control group and, in any
case, dependency seemed not to be associated with isolation. When adjusting for
age, sex, depressive symptoms, Mini Mental Status examination score, and dyspnea,
PD remained significantly associated with dependency. PD thus constitutes a
significant factor of dependency in elderly subjects living at home.
Institutionalization occurred over four times more frequently in the PD group
than in the general population, but no specific factor of institutionalization
was noted.
PMID- 9399215
TI - Health-related quality of life in Parkinson's disease: a study of outpatient
clinic attenders.
AB - OBJECTIVE: To assess the validity and responsiveness of a questionnaire to assess
health-related quality of life in Parkinson's disease (PD)--the 39-item
Parkinson's Disease Questionnaire (PDQ-39)--and to report problems experienced by
patients by means of the questionnaire. METHODS: Patients completed the PDQ-39
and the SF-36 at baseline and 4 months later. At the same assessments,
neurologists rated patients with Hoehn and Yahr and Columbia Scales. RESULTS:
Evidence for validity of the new questionnaire was observed by agreement of
scores with clinical scales at both assessments. Evidence for responsiveness of
scales assessing physical function, particularly mobility and activities of daily
living, was observed from significant paired t tests for differences between
scores at baseline and follow-up, and correlations with patients' retrospective
judgments and changes in the SF-36 summary scores. However, there were no
significant associations with changes in neurologists' clinical scores. Patients
most frequently reported problems of physical function in the PDQ-39. Scores for
several dimensions of the PDQ-39 were significantly more favorable than those
reported by nonclinic samples of patients with PD. CONCLUSIONS: The PDQ-39 has
validity for use among patients attending neurological clinics for treatment of
PD. There is also some evidence of responsiveness. The questionnaire identifies
problems that are important to patients and that appear to be more commonly
experienced by nonclinic attenders.
PMID- 9399216
TI - Sexuality in women with Parkinson's disease.
AB - There is a renewed interest in sexuality in chronic disease states. Whereas there
is some literature on male sexuality in Parkinson's disease (PD), no study has
been devoted exclusively to women. We compared 27 women who had PD with community
controls matched for age and marital status by using the Brief Index of Sexual
Functioning in Women. Approximately 50% of both samples were sexually active. The
women with PD were more likely to be dissatisfied with the quality of the sexual
experiences. There were significant differences in the two groups with respect to
anxiety or inhibition, vaginal tightness, and involuntary urination.
Preoccupation with health problems interfering with sex and dissatisfaction with
body appearance were also more prevalent in parkinsonian women, but not
statistically different from controls. The PD patients were less satisfied with
their sexual relationships and with their partners, and were more depressed as a
group when compared with controls (Beck Depression Inventory of 11.8 vs 6.3). In
both groups, age was associated with significant changes in satisfaction and
activity. In summary, qualitative differences exist in the sexual experiences of
women with PD compared with controls.
PMID- 9399217
TI - Tolcapone added to levodopa in stable parkinsonian patients: a double-blind
placebo-controlled study. Tolcapone in Parkinson's Disease Study Group II (TIPS
II).
AB - The primary objective of this study was to assess the effect of tolcapone on
levodopa dosage in parkinsonian patients whose "wearing-off" phenomenon has been
controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97
patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg
three times daily (t.i.d.). Levodopa dosage was reduced by -35% on day 1 of study
and subsequently retitrated as required. After 6 weeks, the tolcapone groups
crossed over to receive the other dose for a further 3 weeks for exploratory
purposes. Both tolcapone groups had greater reductions in levodopa dosage than
the placebo group at week 6 (not statistically different). The 200-mg t.i.d.
group showed greatest improvement in estimated mean scores for all efficacy
parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease
Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events
were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d.
The most frequently reported dopaminergic adverse events were nausea, cramps,
dyskinesia, and dystonia. The most frequently reported unanticipated adverse
event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to
patients with moderately advanced Parkinson's disease with treated "wearing-off"
phenomenon.
PMID- 9399218
TI - Entacapone enhances levodopa-induced reversal of motor disability in MPTP-treated
common marmosets.
AB - Oral administration of levodopa (L-dopa) (2.5-25.0 mg/kg) plus carbidopa (12.5
mg/kg p.o.) to MPTP-treated common marmosets produced a dose-related increase in
locomotor activity and a corresponding decrease in motor disability. Pretreatment
with the peripheral COMT inhibitor entacapone (12.5 mg/kg p.o.) enhanced the
intensity and duration of the increase in locomotor activity and the reversal of
motor disability produced by a threshold dose of L-dopa (2.5 mg/kg p.o.) plus
carbidopa. By contrast, entacapone pretreatment did not potentiate the increased
locomotor activity or reversal of motor disability produced by a near-maximal
dose of L-dopa (12.5 mg/kg p.o.) plus carbidopa. The effects of entacapone (5.0
25.0 mg/kg p.o.) were dose related, with doses of > 12.5 mg/kg tending to produce
less potentiation of L-dopa's effects compared to lower doses. Pretreatment with
entacapone (12.5 mg/kg p.o.) without carbidopa caused a short-lasting enhancement
of L-dopa's (12.5 mg/kg p.o.) action, whereas pretreatment with carbidopa (12.5
mg/kg p.o.) alone had a more dramatic effect. However, pretreatment with both
carbidopa and entacapone produced the greatest overall motor response. In
conclusion, entacapone enhances the motor response produced by a low-threshold
dose of L-dopa plus carbidopa. However, optimization of both the dose of L-dopa
and entacapone appears necessary to obtain the maximal therapeutic response.
PMID- 9399219
TI - Constipation in Parkinson's disease: objective assessment and response to
psyllium.
AB - We evaluated the reliability of patient history and the effect of psyllium on
symptoms and colorectal function in 12 patients with Parkinson's disease (PD) and
constipation. In all but two, constipation anteceded the development of
parkinsonian symptoms. A comparison with prospectively obtained stool diaries
confirmed the patients' reported constipation in 7 of the 12 patients. Those
patients with confirmed constipation had lower stool weights and reported more
straining at stool. Measures of colonic and anorectal function were similar in
those who were truly constipated and those who were not. Among those PD subjects
with confirmed constipation, psyllium increased stool frequency and weight but
did not alter colonic transit or anorectal function. We conclude that
prospectively obtained stool diaries should be employed to confirm constipation
in PD and that psyllium produces both subjective and objective improvements in
constipation related to PD.
PMID- 9399220
TI - Effect of chronic oral domperidone therapy on gastrointestinal symptoms and
gastric emptying in patients with Parkinson's disease.
AB - This study investigated whether domperidone could improve gastrointestinal
symptoms in patients with Parkinson's disease who were receiving levodopa
therapy. A total of 11 patients were studied. Following a baseline gastric
emptying test, patients were treated with a starting dose of domperidone 20 mg
p.o. q.i.d. A follow-up gastric emptying test was repeated at least 4 months
after starting domperidone therapy. At the beginning and at each 3-month follow
up visit, symptoms of nausea, vomiting, anorexia, abdominal bloating, heartburn,
regurgitation, dysphagia, and constipation were evaluated and scored on a scale
of 0-3. The overall mean follow-up period was 3 years. Compared with their
baseline evaluation, patients experienced a significant improvement in all
symptoms (p < 0.05) except dysphagia and constipation. Gastric emptying of an
isotope-labeled solid meal was significantly faster, with a baseline result of
60.2 +/- 6.4% retention of isotope 2 h after the meal compared with 37.0 +/- 2.2%
retention during domperidone therapy (p < 0.05). Patients' global assessment of
Parkinson's disease remained stable or improved. Serum prolactin was elevated in
all patients after domperidone therapy (p < 0.05). Domperidone therapy
significantly reduces upper gastrointestinal symptoms and accelerates gastric
emptying of a solid meal, but does not interfere with response to
antiparkinsonism treatment.
PMID- 9399221
TI - Interlimb coordination deficits in patients with Parkinson's disease during the
production of two-joint oscillations in the sagittal plane.
AB - Two-limb coordination patterns involving cyclical flexion-extension movements,
performed in the same or in different directions, were studied in patients with
Parkinson's disease and a group of elderly subjects. The three patterns referred
to the homologous (both arms or legs), homolateral (right or left arm and leg),
and heterolateral (right arm and left leg or vice versa) limb segment
combinations that were performed in the sagittal plane from a seated position.
Findings revealed that interlimb coordination deficits were evident in patients
with Parkinson's disease. Moreover, mean cycle duration and its variability were
increased, particularly during the production of nonhomologous limb movements in
different directions. These temporal findings suggest that movement slowness was
not a primary consequence of an intrinsic inability to move the limb segments at
the required speed but rather reflected an intentional strategy to cope with the
complexity of the coordination pattern. Finally, movement amplitude was
substantially smaller and more variable in patients with Parkinson's disease,
suggestive of hypometria during the production of these cyclical tasks.
PMID- 9399222
TI - Clinical expression of essential tremor: effects of gender and age.
AB - Essential tremor (ET) is considered to be a monosymptomatic disorder consisting
primarily of postural hand tremor. Nevertheless, clinical expression can vary
based on the body region affected by tremor and the coexistence of other
neurologic signs, such as tandem gait disturbance. We conducted a two-part study
to test the hypothesis that variability in ET clinical expression is influenced
by gender and age. In part 1, we examined a large ET clinical database (n = 450),
comparing ratings of postural hand and head/voice tremor based on gender.
Head/voice tremor was significantly more frequent and more severe among female ET
patients; men had more severe postural hand tremor. In part 2, ET patients (n =
40) had significantly more missteps when tandem walking in comparison to age
matched controls. Poor tandem walk in ET cases was associated with more advanced
age, but not gender, disease duration, or ratings of postural hand or head/voice
tremor. We conclude that gender influences the body region most affected by ET
possibly through the effects of the sex chromosomes or hormones. Ataxia (tandem
gait difficulty) is common in ET and may be an accentuation of cerebellar
dysfunction due to aging.
PMID- 9399223
TI - Agreement among movement disorder specialists on the clinical diagnosis of
essential tremor.
AB - Even though essential tremor (ET) is the most prevalent movement disorder, there
has been little agreement in the neurologic literature regarding diagnostic
criteria for ET. The authors attempted to determine the extent and source of
agreement and disagreement among neurologists regarding diagnostic criteria for
clinically definite ET. The authors designed and mailed a semistructured
questionnaire to 160 neurologists who specialize in movement disorders in 24
countries. The questionnaire included three sections: a list of inclusion
criteria, a list of exclusion criteria, and a list of potential clinical
scenarios (for example, isolated site-specific tremor and primary orthostatic
tremor). The questionnaire was completed by 98 (61%) of 160 targeted
neurologists. There was greater consensus regarding features considered
unnecessary inclusion criteria for clinically definite ET (extent of disability,
disease duration, and positive family history) than for those considered
necessary inclusion criteria (postural versus action tremor). With regard to
exclusion criteria, there was some consensus in terms of the presence of
Parkinson's disease, dystonia, history of hyperthyroidism or concurrent use of
tremor-inducing medications, and cerebellar signs. The majority of neurologists
would diagnose ET in the setting of isolated head or voice tremor. There are
areas of both consensus and divergence among neurologists with regard to
diagnostic criteria for ET. The choice of diagnostic criteria may vary depending
on the intended use of the criteria (that is, clinical versus genetic studies).
Hopefully, this study will foster further discussion to achieve a more general
consensus.
PMID- 9399224
TI - Cerebellar axial postural tremor.
AB - Three cases are presented with a predominantly axial postural tremor, without
visible palatal tremor. Tremor varied in frequency between 3 and 10 Hz, often
jumping from one frequency to another in this band. All three patients had
evidence of cerebellar pathology. Cases 1 and 2 developed tremor in the setting
of a late-onset cerebellar degeneration and after excision of a right cerebellar
haemangioblastoma, respectively. Etiology was unclear in Case 3. Nevertheless,
this patient had a cerebellar dysarthria. The tremor was similar to that
sometimes seen in conjunction with palatal tremor, and EMG studies in Case 3
demonstrated a subclinical modulation of palatal muscle activity simultaneous
with the truncal tremor. It is suggested that an axial postural tremor may be due
to pathology of the cerebellum and its outflow pathways, despite the absence of
clinically apparent palatal tremor.
PMID- 9399225
TI - Validity of long-term electromyography in the quantification of tremor.
AB - We previously developed a method of tremor quantification using long-term
electromyography registration of antagonistic forearm muscles that is reliable,
sensitive, and specific for pathologic tremors. The present study demonstrates
that tremor occurrence as measured by this method correlates well with clinical
parameters of tremor in idiopathic Parkinson's disease (PD) and essential tremor
(ET) (subscores of the Unified Parkinson's Disease Rating Scale for PD, tremor
rating according to Bain et al. for ET). We conclude that the method is a valid
and objective means of tremor quantification in PD and ET.
PMID- 9399227
TI - Frequency of familial inheritance among 488 index patients with idiopathic focal
dystonia and clinical variability in a large family.
AB - Idiopathic torsion dystonia is characterized by involuntary twisting movements
and postures. One molecularly defined form with generalized dystonia has been
shown to be autosomal dominantly inherited with reduced penetrance in chromosome
9q34.1, especially in Ashkenazi Jewish families, while other generalized families
from Europe and families with other subtypes of dystonia have been excluded from
linkage to this locus. Genealogical studies suggest that the much more frequent
focal dystonia follows an autosomal dominant inheritance with reduced penetrance
as well. For our study, 488 patients with focal dystonia, without a tendency for
generalization, were interviewed for their family history. Evidence for
hereditary disposition was found in 88 individuals. In a second step, all
available family members of 17 of the 488 index patients (chosen for cooperation)
were clinically examined. Objective diagnosis of affected relative was
established in 13 families, whereas only 4 of the 17 index patients had
previously admitted a positive family history. Furthermore, a large three
generation family with focal dystonia linked to chromosome 18p (linkage data
described elsewhere) was identified. The familial pattern of all reported
families is compatible with autosomal dominant inheritance with reduced
penetrance. Assessment only on patients' report leads to underestimation of the
frequency of familial idiopathic focal dystonia.
PMID- 9399226
TI - Analysis of action tremor and impaired control of movement velocity in multiple
sclerosis during visually guided wrist-tracking tasks.
AB - We investigated the relationship between action tremor (AT) and impaired control
of movement velocity (MV) in visually guided tracking tasks, in normal subjects
and in patients with multiple sclerosis (MS) with or without motor deficits. The
effects of withdrawing visual feedback of either the target or the cursor were
then investigated. Visually cued simple reaction times (SRTs) were also measured.
The effects of thalamotomy on motor performance in these tasks were evaluated in
seven patients. In the MS patients with tremor, there was no correlation between
AT and impairment in control of MV, but the latter was highly correlated with an
increased delay in SRT. Withdrawal of visually guiding cues increased the error
significantly in MV, but reduced AT by approximately 30% in magnitude. Frequency
analysis indicated that the AT had two components: (a) non-visual-dependent,
oscillatory movements, mainly at 4 Hz; and (2) visual-dependent, repetitive
movements, with significant power at 1-2 Hz. Thalamotomy significantly reduced AT
but hardly improved accuracy in MV. These results suggest that visual feedback of
a spatial mismatch signal may provoke a visually dependent repetitive movement
contributing to AT. Conduction delays along either the cortico-cerebello-cortical
or the proprioceptive pathways and impaired working memory caused by MS may be
responsible for the movement disorders in these patients.
PMID- 9399228
TI - Paroxysmal exercise-induced dystonia: eight new sporadic cases and a review of
the literature.
AB - We report eight new sporadic cases of paroxysmal dystonia induced by prolonged or
sustained exercise and review an additional seven previously reported cases. The
attacks in our patients lasted from a few minutes to up to 2 h, and patient age
at onset ranged from 2 to 30 years. Four of the eight patients had hemidystonic
attacks, both legs were involved in two other cases, and the remaining two
patients had involvement of the right foot only. We propose that such cases
should be classified as paroxysmal exercise-induced dystonia.
PMID- 9399229
TI - DYSBOT: a single-blind, randomized parallel study to determine whether any
differences can be detected in the efficacy and tolerability of two formulations
of botulinum toxin type A--Dysport and Botox--assuming a ratio of 4:1.
AB - BACKGROUND: Elston and Russell discovered a difference in the biological potency
of the English formulation of botulinum toxin type A or BTX-A (Dysport) and the
American formulation (Botox). Potency of both is expressed in LD50 mouse units,
but because of assay differences, these units are not equivalent. Since the first
warning by Quinn and Hallet on the clinical importance of this issue, it has been
impossible to reach a consensus on the conversion factor for the potency of these
formulations. OBJECTIVE: To test the hypothesis that the conversion factor for
the clinical potency of Dysport to Botox is approximately 4:1. DYSBOT is an
acronym that results from adding "DYS" from Dysport with "BOT" from Botox.
PATIENTS AND METHODS: DESIGN: A single-blind, randomized, parallel comparison. A
total of 91 patients with blepharospasm or hemifacial spasm were randomized to
treatment with Dysport or Botox using a fixed potency ratio of 4:1. Clinical
evaluations: The patients were evaluated at baseline (day of the treatment). 1
month after treatment, and whenever the effect was judged to be fading. Objective
and functional rating scales were used as quantitative measures of the change in
clinical status. Adverse reactions were collected using a systematic
questionnaire. RESULTS: Using this ratio between products, both Dysport and Botox
groups produced similar clinical efficacy and tolerability. For patients showing
a positive response without the need of a booster, the duration of effect was
13.3 +/- 5.9 weeks for the Dysport group and 11.2 +/- 5.8 weeks for the Botox
group. Of 48 patients, 11 (23%) needed booster treatment in the Dysport group
compared with five (12%) of 43 in Botox group. Adverse events were noted in 24
(50%) of 48 patients in the Dysport group and 20 (47%) of 43 of the Botox-treated
group. CONCLUSIONS: Using a 4:1 conversion ratio for Dysport and Botox, similar
results were obtained for the two treatments in an appropriately powered study,
suggesting that this conversion factor is a good estimate of their comparative
clinical potencies.
PMID- 9399230
TI - Kinematic analysis of articulatory movements in central motor disorders.
AB - The various components of the central motor system are expected to play a similar
role in speech production and in upper limb control. Slowed articulatory
performance, therefore, must be expected in disorders of the corticobulbar
tracts, cerebellum, and basal ganglia. Using an optoelectronic device, the
present study recorded lower lip trajectories during production of sentence
utterances in patients with Parkinson's disease (PD), Huntington's disease (HD),
cerebellar atrophy (CA), and pseudobulbar palsy (PB). The various subject groups
showed a similar range of overall motor disability. Patients with CA and PB
exhibited slowed movement execution in terms of a reduced ratio of peak velocity
to maximum amplitude ("stiffness"). In contrast to upper limb motor control, the
lip excursions showed an uncompromised shape of velocity profiles. Two different
patterns emerged in HD. A single patient suffering from the akinetic-rigid
Westphal variant of this disease had articulatory hypometria, whereas the
remaining subjects showed significant bradykinesia under increased temporal
demands, concomitant with normal movement amplitudes. The PD patients had
unimpaired velocity-displacement relationships. Presumably, biomechanical
constraints such as the rather small excursions of articulatory lower lip
gestures or the scarce spindle supply of facial muscles account for the observed
discrepancies between upper limb and speech motor control in PD.
PMID- 9399231
TI - Analysis of blink rate patterns in normal subjects.
AB - The present study measured the normal blink rate (BR) variations in relation to
behavioral tasks in 150 healthy volunteers (70 males and 80 females; aged 35.9 +/
17.9 years, range 5-87 years). The subjects were videotaped in a standard
setting while performing three different tasks: resting quietly, reading a short
passage, talking freely. The mean BR was computed during each task; the data were
compared by means of analysis of variance and Student's t tests. Mean BR at rest
was 17 blinks/min, during conversation it increased to 26, and it was as low as
4.5 while reading. As compared with rest, BR decreased by -55.08% while reading
(p < 1 x 10(-15)) and increased by 99.70% during conversation (p < 1 x 10(-9)).
As compared with reading, BR increased during conversation by 577.8% (p < 1 x 10(
17). The distribution curves were highly reproducible in each task. The best
curve fit was represented by a log-normal distribution, with the upper tail of
each curve having a normal distribution. Eye color and eyeglass wearing did not
influence BR. Women had higher BR than men just while reading. No age-related
differences were found. The most common BR pattern was conversation > rest >
reading, which occurred in 101 subjects (67.3%); 34 subjects (22.7%) had the
pattern rest > conversation > reading; 12 (8.0%) had the pattern conversation >
reading > rest. This study identified three normal behavioral BR patterns and
showed that BR is more influenced by cognitive processes than by age, eye color,
or local factors. The present findings provide a normal reference for the
analysis of BR in movement disorders such as dystonia or tics.
PMID- 9399232
TI - Parkinsonism associated with acute intracranial hematomas: an [18F]dopa positron
emission tomography study.
AB - We present the case of a 36-year-old woman with a right temporal hematoma and an
overlying subdural hematoma following rupture of a right middle cerebral artery
aneurysm. Three weeks after recovering consciousness, she developed a levodopa
responsive parkinsonian syndrome involving the right limbs. A year after the
vascular event, she reported subjective improvement in her parkinsonism, which
has remained stable since. 18F-dopa positron-emission tomography showed a marked
reduction of uptake in the left putamen, raising the possibility that the
intracranial hemorrhage unmasked latent Parkinson's disease. To the best of our
knowledge, this is the first case of parkinsonism associated with spontaneous
acute intracerebral and subdural hematomas.
PMID- 9399233
TI - Efficacy of a patient-training videotape on motor fluctuations for on-off diaries
in Parkinson's disease.
AB - Patient on-off diaries are used in clinical trials, but a method to assure
agreement between patient and examiner has never been developed. We tested
whether a patient-teaching tape increased the rate of agreement between patient
diary ratings and simultaneous neurologic assessment by a trained professional. A
total of 32 consecutive patients who had Parkinson's disease with motor
fluctuations independently completed a 4-h on-off diary (nine ratings) at the
same time as an examiner. Those with < 80% agreement with the examiner (n = 20)
were randomized to view either a training tape that showed motor fluctuations
(experimental group) or-another videotape of general patient educational material
(control group). All patients then underwent the same 4-h assessment of motor
fluctuations. To test for long-term retention, they returned 1 month later and,
without reviewing the videotape, underwent a final 4-h correlation assessment.
After the training tape, the experimental group showed significant improvement,
whereas the control group showed no improvement. Furthermore, another month
later, the improvement in the experimental group was retained. Based on these
findings, we suggest that future clinical trials assessing motor fluctuations
incorporate this tape into their basic methodology.
PMID- 9399234
TI - Spinal myoclonus induced by an intrathecal catheter.
AB - We report a case of spinal myoclonus induced by the tip of an intrathecal
catheter in a 35-year-old patient with severe, adult-onset, generalized dystonia
of unknown cause, treated for 2 years using intrathecal baclofen. One month after
a falling episode, the patient developed focal myoclonus of the right proximal
leg whenever she stood up from a seated position. The electrophysiologic
recordings were compatible with spinal segmental myoclonus, originating at a
focus corresponding to the L2-S2 segments. At this site, the tip of the
intrathecal catheter was demonstrated by myelography to be in close proximity to
the nerve roots and conus medullaris. The myoclonus resolved promptly once the
catheter tip was withdrawn. We review the literature on spinal myoclonus and
discuss the possible mechanisms of spinal myoclonus pertaining to the present
case. This report represents an unusual complication of intrathecal catheter
systems that, if recognized, can lead to prompt therapeutic intervention.
PMID- 9399236
TI - Adult-onset tics associated with peripheral injury.
AB - We report the cases of two patients with adult-onset, simple, nonvarying tic
disorder that commenced after a peripheral (non-CNS) injury. The first patient is
a 38-year-old man who suffered a right facial injury when his car fell off its
jack while he was working underneath. Bilateral facial twitching began hours
after the trauma and was characterized as a sniffinglike gesture. The movements
waxed and waned, were suppressible, and were associated with a premonitory
sensation. The tics remitted after 9 months but still recur occasionally under
stressful situations. The second patient is a 34-year-old man with a 3-year
history of abrupt, rapid head-turning movements that began 12 months after a
motor vehicle accident in which he injured his neck. The tics continue to wax and
wane, are suppressible, and are associated with an urge. Neither patient suffered
a head injury or had a family history of Tourette syndrome. Based on the clinical
and historical features of these patients, the temporal relationship between the
trauma and onset of tics, and the occurrence of tics only in the traumatized
region, a causal relationship is possible. These may represent the first reported
cases of tic disorder in association with peripheral injury. The mechanism by
which the tic disorder resulted from the peripheral injury is unclear, but these
patients might have been susceptible individuals and the trauma acted as a
trigger.
PMID- 9399237
TI - Spinal rigidity following acute myelitis.
AB - A patient with a 2(1/2)-year history of painful spasms and rigidity of both lower
limbs is described. Symptoms began after an episode of acute myelitis. The spasms
-which were spontaneous and stimulus sensitive and occurred on voluntary action-
involved the repetitive grouped discharge of motor units. Continuous motor unit
activity was present at rest in the muscles of both legs, and cutaneomuscular
reflexes were abnormal. This patient is similar to those recently reported as
having stiffness and spasms of the legs due to a possible chronic spinal
interneuronitis and provides further evidence that this kind of movement disorder
may be caused by spinal cord pathology.
PMID- 9399235
TI - Cortical Myoclonus in Huntington's disease associated with an enlarged
somatosensory evoked potential.
AB - We report the electrophysiologic findings of myoclonus in a patient with
Huntington's disease (HD). This patient was studied postoperatively after a
bilateral fetal cell transplant in his striatum. Incomplete transient improvement
was seen in the myoclonus, followed by gradual deterioration. The myoclonus
itself had a cortical correlate and was associated with an enlarged somatosensory
evoked potential (SEP), consistent with the presence of cortical reflex
myoclonus. An enlarged SEP has not been previously reported in myoclonus
associated with HD. The postulated mechanisms for myoclonus, when it occurs in
HD, have differed in the literature. The reason for the transient improvement of
the myoclonus following transplantation is unclear, but this case raises the
possibility that basal ganglia circuits may modulate cortical myoclonic activity.
PMID- 9399238
TI - Botulinum toxin A improves muscle spasms and rigidity in stiff-person syndrome.
AB - We studied the effect of botulinum toxin A (BTA) on painful muscular spasms and
rigidity in two bedridden patients with clinical, electrophysiologic, and
immunologic evidence of stiff-person syndrome. We injected BTA or saline solution
into several limb muscles with both the rater and patient blinded to the order of
the injections. A physician, unaware of the treatment order, used an objective
rating scale for rigidity and spasm frequency scale and independently assessed
the treatment results. BTA administration significantly reduced rigidity and
stopped the spasms in all limbs. Following BTA injection on one side, the spasm
frequency decreased bilaterally possibly because of the spread of hematogenous
toxin.
PMID- 9399240
TI - The shaking palsy, the first forty-five years: a journey through the British
literature.
AB - The authors examined the British medical literature published in the 45-year
period following Parkinson's treatise on the shaking palsy to determine the
number and type of references to the shaking palsy or paralysis agitans during
this particular period. Several sources suggest that Parkinson's 1817 treatise on
the shaking palsy received little immediate attention in his native country,
England, and that not until 1861, in France, did Charcot began to elucidate the
clinical features of this entity, separating it from other neurologic disorders
(for example, multiple sclerosis). A review of the British medical literature
from the 45-year-period 1817-1861 revealed a number of references to paralysis
agitans, including those by Cooke (1820), Good (1824 and 1829), Elliotson (1827,
1829, 1830, 1831, and 1833), Gowry (1831), anonymous (1832), Todd (1833), Watson
(1836), Gibson (1839), Hall (1838 and 1841), Thompson (1842), Graves (1843),
Birkett (1853), Paget (1855), and Reynolds (1855). Many of these did not report
new or personally observed cases, did not separate Parkinson's disease from other
disease entities characterized by both "shaking" and "palsy" (for example, tonic
clonic seizures), or misattributed motor signs to dysfunction of the pyramidal
system rather than an extrapyramidal system (that is, attributing bradykinesia or
rigidity to weakness). Although there were several references to "shaking palsy"
in the early- to mid-19th-century British medical literature, there were few
original case reports of Parkinson's disease. This may have contributed to the
fact that during this period little was added to the original observations made
by Parkinson in 1817. In particular, the separation of bradykinesia and weakness
did not become apparent until later work by the French.
PMID- 9399239
TI - Idiosyncratic adverse reactions to intramuscular botulinum toxin type A
injection.
AB - Three cases of adverse reactions to repeated intramuscular botulinum toxin A
(BTA) injections are described: a persistent rash on the face at the site of
injection, a localized anaphylactic reaction following BTA injection into one
leg, and bilateral ptosis repeatedly following BTA injection into neck muscles.
The mechanisms for these idiosyncratic adverse responses are not known.
PMID- 9399241
TI - A historical case of probable corticobasal degeneration?
AB - In 1925, Jean Lhermitte and colleagues published a work on spatial representation
in apraxic patients, based on two illustrative cases. One of these displayed a
clinical picture that would nowadays be clinically classified as probable
corticobasal degeneration.
PMID- 9399242
TI - Progressive cognitive decline with truncal/limb ataxia and ballistic movements.
PMID- 9399243
TI - Botulinum toxin injections to one leg alleviate freezing of gait in a patient
with Parkinson's disease.
PMID- 9399244
TI - Unilateral parkinsonism following a large infarct in the territory of the
lenticulostriate arteries.
PMID- 9399245
TI - Remitting parkinsonism as a symptom of multiple sclerosis and the associated
magnetic resonance imaging findings.
PMID- 9399246
TI - Left arm monoballism as a relapse in multiple sclerosis.
PMID- 9399247
TI - Spasmodic torticollis associated with multiple sclerosis: report of two cases.
PMID- 9399248
TI - Painful tonic spasms and pure motor hemiparesis due to lacunar pontine infarct.
PMID- 9399249
TI - Unilateral postural and action tremor resulting from thalamic toxoplasmosis in a
patient with acquired immunodeficiency syndrome.
PMID- 9399250
TI - Delayed onset postural tremor caused by parietal lesion.
PMID- 9399251
TI - Sustained effect of high-dose intrathecal baclofen in primary generalized
dystonia: a 2-year follow-up study.
PMID- 9399252
TI - Successful treatment of fluoxetine-induced dystonia with low-dose mianserin.
PMID- 9399253
TI - Apraxia of eyelid closure accompanied by denial of eye opening.
PMID- 9399254
TI - Tardive dyskinesia in a neuroleptic-naive patient with bipolar-I disorder:
persistent exacerbation after lithium intoxication.
PMID- 9399255
TI - Italian buckwheat (Fagopyrum esculentum) starch: physico-chemical and functional
characterization and in vitro digestibility.
AB - A study on the physico-chemical properties and structure together with the
evaluation of starch digestibility was carried out on starch isolated from
buckwheat (Fagopyrum esculentum) cultivated in different Italian areas. Results
showed that buckwheat samples analysed were different among them and from wheat
starch used as reference. Buckwheat granules were polygonal in shape and had a
smaller diameter than the wheat starch granule. The starch obtained from
buckwheat had a higher swelling power than the wheat one, probably as a
consequence of the wheaker but more extensive bonding forces in the granule.
During cooling, buckwheat samples showed a good paste stability.
PMID- 9399256
TI - Available iron and zinc in major lean meat cuts and their contribution to the
recommended trace element supply in Switzerland.
AB - The objective of the present study was to analyze iron and zinc in major lean
meat cuts in order to estimate the contribution of the average lean meat
consumption in Switzerland (1995) for these trace elements. Iron, heme iron and
zinc contents were analyzed in following muscles: pork (longissimus dorsi muscle
and shoulder), beef (longissimus dorsi muscle and shoulder), veal (longissimus
dorsi muscle) and chicken (breast and thigh). Beef and pork shoulder were the
best sources of iron, heme iron and zinc. Pork and veal longissimus dorsi muscle
and chicken were relatively poor in these trace elements. With an average daily
lean meat consumption of 105 g, iron and zinc intake were about 1.1 mg/d and 3.8
mg/d, respectively. Recommendations for daily iron intake were met to 11% (men)
and 7% (women) and for zinc to 25% (men) and 32% (women). Applying a modified
Monsen model, the requirements for absorbed iron were met in the range of 10-30%
and 7-20% for men and women, respectively. Taking into account a zinc absorption
rate from meat of about 20-36%, the daily requirements for absorbed zinc were
covered to 32-56%. In conclusion, the average amount of lean meat as consumed in
Switzerland was high enough to be an important source of available iron and zinc,
particularly for people with low iron and zinc status.
PMID- 9399257
TI - Production of iron-fortified bread employing some selected natural iron sources.
AB - Iron fortification of wheat breads is the optimal approach for reducing the high
prevalence of iron deficiency in wheat-eating developing countries as in Egypt.
The effectiveness of some natural iron-fortificants for potential use in Egyptian
bread was tested. Defatted soybean flour, soybean flour, soybean hull flour,
molasses and fenugreek flour at different levels besides FeSO4.7H2O as standard
were separately incorporated in the wheat flour dough. Dough characteristics were
studied using a Brabender Farinograph, where addition of such fortificants
improves significantly (p < 0.05) the water absorption, development time, dough
stability and dough weakening. Good breads with high nutritive value, excellent
crust color, crumb grain and high overall acceptability were produced by adding
either 10% defatted soybean flour, 5% soybean hull flour, 2% molasses or 4%
fenugreek flour. Rat feeding trials have shown a good haematological response,
i.e. higher haemoglobin (Hb) and haematocrit (Hct) values gained. Additional work
is needed to identify other fortification options and to develop targeted
fortification programes that will supply iron to all segments of a population in
greatest need.
PMID- 9399258
TI - Influence of vegetarian and mixed nutrition on selected haematological and
biochemical parameters in children.
AB - To evaluate the health and nutritional status of children with two different
nutritional habits, the authors examined 26 vegetarians (lacto- and lacto-ovo; an
average period of vegetarianism 2.8 years) and 32 individuals on mixed diet
(omnivores) in the age range 11-14 years. Vegetarian children had significantly
lower erythrocyte number as well as reduced levels of haemoglobin and iron
compared to omnivores. The average level of iron did not reach the lower limit of
the physiological range and hyposiderinemia was found in 58% of vegetarians vs 9%
of omnivores. Reduced iron levels were observed in spite of increased intake of
vegetable iron sources and vitamin C (which facilitates the conversion to ferro
form). This reduction can be attributed to the absence of animal iron sources
with high utilizability and to lower iron utilization in the presence of phytic
acid (higher intake of grains compared to omnivores). The incidence of
hypoalbuminemia and hypoproteinemia in vegetarian children was 38 and 12%,
respectively, compared to 0% in omnivores. The protein mixture from milk, eggs
and vegetable sources is complete, but vegetarian children had significantly
reduced intake of milk and dairy products. Favourable lipid and antioxidant
parameters in vegetarian children reflect the optimal nutrition composition with
respect to the prevention of free radical diseases. Such a nutrition results in
significantly lower levels of cholesterol and LDL-cholesterol compared to
omnivores and significantly higher and over threshold values of essential
antioxidants--vitamin C, vitamin E/cholesterol (more effective protection against
LDL oxidation), beta-carotene, vitamin A.
PMID- 9399259
TI - More questions than answers.
PMID- 9399260
TI - Article on breast cancer risk and induced abortion concerns readers.
PMID- 9399261
TI - Multispecialty clinics enhance consultation and care.
PMID- 9399262
TI - Critical pathway improves outcomes for patients with sickle-cell disease.
PMID- 9399263
TI - Laying the foundation: leadership council operationalizes values and goals.
PMID- 9399264
TI - Ambulatory nurses establish group practices to improve efficiency and
satisfaction.
PMID- 9399265
TI - Primary nursing improves access to and quality of care in screening clinics.
PMID- 9399266
TI - Linkage key to rural outreach program success.
PMID- 9399267
TI - Go light your world.
PMID- 9399268
TI - The nurse as coach: a conceptual framework for clinical practice.
AB - PURPOSE/OBJECTIVES: To operationalize a professional educational counseling model
for nurses that derives from the client's frame of reference and adds to the
client's behavioral management of the impact of cancer, including self-care
skills and cognitive control. DATA SOURCES: Published literature and four years
of clinical experience with 84 couples in which coaching behavior was applied in
home-based intervention sessions. DATA SYNTHESIS: Nurse coaching behavior
includes six dimensions. Attending to the Story, Encircling the Experience,
inviting the Work, Exploring Solutions, Anchoring the Skill, and Setting Up
Success. CONCLUSIONS: Nurse coaching behavior is designed to facilitate the
cognitive emotional processing of the cancer experience and to add to the patient
and family member's repertoire of behavioral self-care and self-management
skills. Future research is needed to evaluate the processes and outcomes of nurse
coaching behavior when working with patients and family members experiencing
cancer. IMPLICATIONS FOR NURSING PRACTICE: Nurse coaching provides a practice
framework that complements patient teaching and supportive therapy as a method
for enhancing self-care and self-management behavior for people with cancer and
their family members.
PMID- 9399269
TI - Addressing issues for early detection and screening in ethnic populations.
AB - PURPOSE/OBJECTIVES: To describe how multicultural knowledge and skills are
applied in culturally competent practice to develop and deliver available,
accessible, acceptable, and appropriate programs in early cancer detection and
screening programs in ethnic communities. DATA SOURCES: Literature and clinical
community practice reports. DATA SYNTHESIS: Successful community screening
programs can be conducted within ethnic minority populations. Practitioners must
tailor care based on salient cultural differences of the population of focus.
Culturally based practice results in the (a) increased ability to think
critically in community and individual assessments, (b) development of more
accurate program plans and designs, and (c) increased likelihood that appropriate
outcomes will be used in the evaluation of care. CONCLUSIONS: Greater cultural
competence increases the accuracy of care and thereby its effectiveness,
efficiency, and success in providing acceptable and optimal programs.
IMPLICATIONS FOR NURSING PRACTICE: The first step in a cultural assessment is to
know one's own beliefs and attitudes. The second step, conducted in parallel,
requires knowledge about the groups that make up the patient and staff
populations within the practice setting and then integrating those perspectives
into practice. Practitioners then can begin the third step of negotiation of all
stages of the project with members of the various communities on an equal basis
that recognizes the expertise and integrity of all parties.
PMID- 9399270
TI - Determinants of exercise during colorectal cancer treatment: an application of
the theory of planned behavior.
AB - PURPOSE/OBJECTIVES: To examine determinants of exercise during colorectal cancer
treatment using the theory of planned behavior. DESIGN: A retrospective survey.
SETTING: Cancer Registry of Alberta, Canada. SAMPLE: Randomly selected survivors
of colorectal cancer (N = 110) diagnosed between 1992 and 1995 who had undergone
adjuvant therapy. Participants' ages ranged from 26 to 77 years (mean = 61 years;
SD = 11), 63% were male, and 85% were disease stage II or III. METHODS: Initial
open-ended elicitation questionnaire to determine salient beliefs, a mailed main
questionnaire, a postcard reminder one week later, and a second questionnaire
three weeks later. Exercise was assessed by the Godin Leisure Time Exercise
Questionnaire. MAIN RESEARCH VARIABLES: Exercise during cancer treatment,
intention, perceived behavioral control, attitude, subjective norm, and salient
beliefs. FINDINGS: Exercise during cancer treatment was determined by intention
and perceived behavioral control. Intention was determined solely by attitude.
Salient beliefs about exercise were different for patients with cancer as
compared to a healthy population. CONCLUSIONS: The theory of planned behavior may
be a viable framework on which to base interventions to promote exercise in
patients with colorectal cancer. IMPLICATIONS FOR NURSING PRACTICE: Oncology
nurses need to have an understanding of motivational factors related to exercise
during cancer treatment to be able to assist patients with cancer to initiate and
maintain exercise.
PMID- 9399271
TI - Oncology nurses' practices of assisted suicide and patient-requested euthanasia.
AB - PURPOSE/OBJECTIVES: To provide reliable and valid empirical data related to New
England Oncology Nursing Society (ONS) members' self-reported practices of
assisted suicide and patient-requested euthanasia. Analysis focused on the
nurses' practices, a comparison of their practices to a similar sample of
oncology physicians, and their use of the healthcare team. DESIGN: Quantitative
survey. SETTING: New England region of the United States. SAMPLE: 600 ONS members
surveyed by mail, 441 of whom responded (74% return rate). Only nurses who worked
at least 20 hours per week, were ONS members for at least one year, and worked
with adult patients with cancer were included. METHODS: Replication and extension
of a survey of oncology physicians. MAIN RESEARCH VARIABLES: Frequency of
requests for and responses to patient requests for assisted suicide and
euthanasia and the use of the healthcare team in response to these requests.
FINDINGS: More physicians than nurses assisted their patients' suicides (11%
versus 1%). However, nurses were more likely than physicians to have performed
patient-requested euthanasia (4% versus 1%). Nurses frequently consulted with
others--particularly physicians--about patient requests for assistance with death
but rarely with one another including nursing supervisors. CONCLUSIONS: The
relative number of healthcare professionals (physicians or nurses) who admit to
hastening a patient's death is small. Nurses in this study received fewer
requests to perform euthanasia than physicians, but they performed patient
requested euthanasia four times more frequently than physicians. Professional
affiliation appears to be one factor in determining whether or not a patient's
request for assistance with death will be granted. IMPLICATIONS FOR NURSING
PRACTICES: The policy debate about professional roles in actions that end the
lives of patients must be extended beyond physicians to include nurses. Nurses
must take an active role in the discussion and definition of acceptable practice
at the end of life.
PMID- 9399273
TI - Primary caregiver perceptions of intake cessation in patients who are terminally
Ill.
AB - PURPOSE/OBJECTIVES: To explore the meaning of nutrition cessation in adult in
home hospice patients with cancer as described by women primary caregivers during
the first year of bereavement. SETTING: In-home hospice in the northeastern
region of the United States. SAMPLE: Twelve English-speaking adult women who had
cared for patients who were terminally III with cancer who ceased oral intake.
DESIGN: Qualitative phenomenologic inquiry. METHOD: Verbatim written transcripts
of semistructured interviews were studied line by line to identify themes. Shared
themes emerged through ongoing comparison across cases. FINDINGS: Within the
framework of transition, seven essential themes emerged: The Meaning of Food,
Caregiver as Sustainer, Concurrent Losses, Personal Responses, Ceasing to Be-
"Starved to Death," Being Bereaved--The Meaning Now, and Paradox. Patient changes
in intake patterns and caregiver actions to encourage intake were described.
Decreasing intake led to ongoing and spiraling losses. Caregiver intake patterns
also changed. CONCLUSIONS: Caregivers believed that patient-nutrition cessation
was naturally occurring and not physically painful. IMPLICATIONS FOR NURSING
PRACTICE: Sensitized nurses can look for the presence of the phenomenon in cancer
caregiving families and open dialogue. Anticipatory guidance can serve to
normalize the situation and ease the transition. Future research should focus on
what nurses know and what they share with families regarding intake cessation.
Research with caregivers could address values clarification, decision making,
knowledge needed for caregiving, the perceptions of caregiving men, and
caregivers of diverse cultures. More research conducted with patients ceasing
intake is needed to determine whether and to what degree patients suffer.
PMID- 9399272
TI - Health promotion and early detection of cancer in older adults: assessing
knowledge about cancer.
AB - PURPOSE/OBJECTIVES: To identify the knowledge level concerning cancer in older
Canadian adults. DESIGN: Descriptive. SETTING: Urban community in Canada. SAMPLE:
Convenience sample of 513 adults over the age of 55 (72% female; 68% born in
countries other than Canada). METHODS: A self-report questionnaire, the Cancer
Knowledge Survey for Elders, was administered to participants in their native
language (eight different language groups). Distribution was through community
workers and public healthy nurses who worked with older adults. MAIN RESEARCH
VARIABLES: Knowledge about cancer, language group, length of time living in the
country. FINDINGS: The highest number of correct responses (87%) was for the item
"Can some cancers be cured if they are discovered early?" The highest number of
wrong answers (67%) was for the item "Can a bump or bruise to the body cause
cancer?" Sixty-six percent did not consider age as a risk factor. For all but
three items, the proportion of English language to non-English language
individuals with correct answers was significantly different individuals whose
native language was not English were less knowledgeable about cancer.
IMPLICATIONS FOR NURSING PRACTICE: This study offers a basis for a large
multicultural survey. Should the observations be confirmed in a larger sample,
implications exist for public education about the risk factors and signs and
symptoms of cancer, especially with individuals for whom English is not a native
language. CONCLUSIONS: In this sample, specific areas were identified in which
knowledge about cancer was lacking. In particular, the increased risk of cancer
with advancing age was not recognized by a significant portion of study
participants.
PMID- 9399275
TI - Patients' knowledge of and attitudes toward the management of cancer pain.
AB - PURPOSE/OBJECTIVES: To examine patients' knowledge of and attitudes toward the
management of cancer pain and to identify, from the patients' perspectives,
factors contributing to effective and ineffective pain relief. DESIGN:
Descriptive, correlational. SETTING: Ambulatory care oncology facility in Canada.
SAMPLE: Convenience sample of 42 patients receiving oral pain medication for
chronic cancer-related pain. METHODS: Participants completed a modified version
of the Patient Pain Questionnaire and a demographic questionnaire and responded
to two open-ended questions. MAIN RESEARCH VARIABLES: Patients' knowledge of and
attitudes toward cancer pain management and their perceptions of factors
contributing to effective and ineffective pain relief. FINDINGS: Many patients
locked knowledge of the principles involved in effective cancer pain management
and had unrealistic concerns about taking pain medications. Significant negative
relationships were found between pain intensity ratings and factors such as
patients' knowledge of pain management, their level of satisfaction with pain
relief, and their perception of the goal of pain management. Patients identified
a number of impediments to effective pain relief, including concerns about
addiction and various side effects to pain medications. CONCLUSIONS: Many
patients have inadequate knowledge about the management of cancers pain and have
unrealistic concerns about taking pain medications, both of which have been
identified in the literature as barriers to effective cancer pain management.
IMPLICATIONS FOR NURSING PRACTICE: A need exists for patient education that
addresses patients' misconceptions and concerns about using pain medications and
the principles involved in effective cancer pain management.
PMID- 9399274
TI - The effectiveness of the breast self-examination facilitation shield.
AB - PURPOSE/OBJECTIVES: To evaluate the degree to which the recently developed breast
self-examination facilitation shield (i.e., breast shield) is effective in
helping women detect breast lumps during breast self-examination (BSE). DESIGN:
Women were randomly assigned to examine silicone lump breast models while using
the breast shield and while not using the breast shield. SETTING: A university
medical center school of nursing in a mid-Atlantic state. SAMPLE: 52 English
speaking women, predominantly healthcare professionals, ages 18 through 67, who
had no physical limitations that might impede lump detection using their fingers.
MAIN RESEARCH VARIABLES: Lumps correctly detected, lumps falsely detected, and
time needed to complete the examination while using or not using the breast
shield during examination. FINDINGS: Women correctly identified more than half of
the lamps in models, regardless of whether or not the breast shield was used.
False lump detection was not increased while using the breast shield. Time taken
to perform breast examination increased, often significantly (p < or = 0.05),
while using the breast shield. CONCLUSIONS: Lump detection using the breast
shield was similar to that of not using the breast shield. Use of the breast
shield did not increase false positive reports and was associated with increased
examination time. IMPLICATIONS FOR NURSING PRACTICE: The breast shield provides
or useful complement to teaching BSE. While guiding a woman's fingers over her
breast following the exam pattern, the nurse can indicate and teach about
underlying breast structures and can provide an individualized, graphic guide to
monthly BSE.
PMID- 9399276
TI - The effects of infusion rate on platelet outcomes and patient responses in
children with cancer: an in vitro and in vivo study.
AB - PURPOSE/OBJECTIVES: To determine the influence of infusion rate on quality of
transfused platelets and patients' physical and subjective responses. DESIGN:
Linked in vitro and in vivo studies with repeated measures and crossover designs,
respectively. SETTING: A 52-bed pediatric cancer center in the midsouthern United
States. SAMPLE: In vitro: 12 randomly selected platelet units. in vivo:
convenience sample of 26 children, ages 3-20 years, with cancer and
thrombocytopenia requiring platelet transfusion. METHODS: Four infusion rates
studied in vitro: two infusion rates studied in vivo. MAIN RESEARCH VARIABLES:
Platelet count, morphology score, corrected count increment, and patients'
physical and subjective responses. FINDINGS: No clinically significant
differences were found in outcomes across the four rates in vitro. Similarly, no
statistically significant differences were found between the two in vivo rates on
objective or subjective outcomes. CONCLUSIONS: In this setting, the more rapid
infusion rate is clinically preferable because it does not negatively affect
platelet recovery or patient outcomes and it decreases the infusion time by half.
IMPLICATIONS FOR NURSING PRACTICE: Findings provided a basis for altering
platelet infusion rates at the study setting. Benefits of the faster infusion
rate include more rapid correction of thrombocytopenia, decreased time that
outpatients must remain in the clinic for transfusion. Increased time available
for other parenteral infusions in the impatient setting, and substantial savings
in nursing time and associated costs.
PMID- 9399277
TI - A patient-education tool for patient-controlled analgesia.
AB - PURPOSE/OBJECTIVES: To develop a pamphlet for educating patients about patient
controlled analgesia (PCA). DATA SOURCES: Journal articles and pump
manufacturers' materials. DATA SYNTHESIS: This pamphlet defines PCA and describes
PCA pump operation, pain assessment, medication side effects, and safety
considerations. A numerical pain-assessment tool also is included. CONCLUSIONS:
This pamphlet has been helpful in assisting patients to use PCA pumps
effectively. IMPLICATIONS FOR NURSING PRACTICE: Nurses can use this tool to
educate patients requiring PCA therapy for pain management.
PMID- 9399278
TI - Repetitive practice of a single joint movement for enhancing elbow function in
hemiparetic patients.
AB - The primary goal of this study was to assess whether repetitive practice of
flexion-extension movements of the affected elbow in hemiparetic patients
enhances performance and to compare the effects of this practice mode to the
effects of the physical therapy variable exercise program which is routinely
applied during sessions. Subjects were 27 poststroke hemiparetic patients,
residents of a rehabilitation institute, divided into an experimental (n = 15)
and a control group (n = 12). The former were treated with 800 repeated elbow
movements in a maximal predetermined amplitude of 80 degrees, provided in 8 equal
sessions every other day. The latter received 10 min. of conventional physical
therapy for the paretic upper extremity at similar time intervals. Pre- and
posttreatment assessments included the bilateral measurements of kinematic
variables and activation latencies of the biceps and triceps brachi muscles as
well as motor and functional tests. For all criterion variables, the findings
pointed to comparable improvement in both groups. It was concluded that
repetitive elbow movements had no unique training effect on the kinematics of
movement and on activation latencies of the primary muscles controlling elbow
function in hemiparetic patients. Further, transfer of the effects of training to
execution of movements towards and from the mouth was also comparable in both
groups, pointing again to there being no particular advantage in using repetitive
movements as a training mode for enhancement of elbow function in hemiparetic
patients.
PMID- 9399279
TI - Brain hemisphere dominance and personality.
PMID- 9399280
TI - A facilitator in self-reported perception of physical symptoms: the role of
contingency between physical symptom and aversive event.
AB - Perceptions of physical symptoms are influenced not only by the passive process
of physiological stimuli but also by psychological factors such as the
contingency between a physical symptom and an aversive event which we examined
here in two experiments. 18 subjects in Exp. 1 and 14 subjects in Exp. 2
performed motor tasks. In the Physical condition, an aversive event was
contingent on the physical symptom of 'racing heart' in Exp. 1, and on the
symptom of 'overstraining shoulder muscles' in Exp. 2. In the Motor condition, an
aversive event was contingent on the response of the 'disordered pace of motor
tasks' in both experiments. Self-reported scores on attention to and perception
of the physical symptoms under the Physical condition were higher than those
under the Motor condition. However, there were no differences in the actual
physical responses between the two conditions. These results suggest that a
contingency between a physical symptom and an aversive event facilitates
attention to and perception of the physical symptom.
PMID- 9399281
TI - Loneliness and health-related variables in young adults.
AB - In classrooms, 69 young adults responded to the Revised UCLA Loneliness Scale,
the Symptom Pattern Scale, and the General Health Rating Index, a measure of
perceived health status. A statistically significant positive correlation of .21
was found between scores for loneliness and ratings for symptom patterns. A
statistically inverse correlation of -.35 was found between scores for loneliness
and ratings for perceived health status. These findings replicated those found
earlier with adolescents.
PMID- 9399282
TI - The Multidimensional Dream Inventory: preliminary evidence for validity and
reliability.
AB - The present study focused on the development of the Multidimensional Dream
Inventory, an individual difference measure of dimensions of dreams. Items were
administered to 151 college students. Consistent with expectations, results of an
exploratory factor analysis of intercorrelations among items indicated a four
factor solution was appropriate. As a result, four dream-relevant scales were
constructed, viz, Dream Importance, Dream Vividness, Dream Usefulness, and Dream
Recall. In addition, these scales showed good internal consistency for research.
Implications and uses for the Multidimensional Dream Inventory were discussed.
PMID- 9399283
TI - Speech and language characteristics of children with strokes due to sickle cell
disease.
AB - The receptive and expressive language skills of 10 children with strokes due to
sickle cell disease were significantly poorer than those of their matched
controls. The children with strokes had greatest difficulty in following oral
directions and formulating sentences.
PMID- 9399284
TI - Correlations for social support with depression in the chronic postsroke period.
AB - This study examined correlations of social support with rated mood states,
including depression, for 47 patients with cerebrovascular disease during the
chronic poststroke period. After the Structured Clinical Interview for DSM-III-R,
four psychological measures, the Zung Self-depression Scale, the Hamilton
Depression Scale, Profile of Mood States, and Social Support Scale, were
administered. The patients with cerebrovascular disease exhibited significantly
more psychiatric disorders, including depression, and had poorer social support
than healthy controls. The severity of depression was significantly related to
poor social support and particularly to the presence of social support rather
than just the perception of poor social support. Depressed patients may also rate
their support as poor because they are depressed. For some patients with
cerebrovascular disease during the chronic poststroke period, depression may be
related to low social support.
PMID- 9399285
TI - Effects of instruction and practice on the length-reproduction task using the
Muller-Lyer figure.
AB - Two experiments were conducted to investigate the effects of instruction and
practice on the length-reproduction task using the Muller-Lyer figure. The task
consisted of reproducing visually presented lines by positioning the arm. In Exp.
1, 20 subjects were asked to move a stylus exactly the same length as the line
presented in the illusory figure. Instructed subjects were told to ignore the
visual illusion, while uninstructed subjects were told nothing. No differences in
groups' constant errors were observed; however, subjects in both groups
reproduced longer or shorter lines in accordance with the visual illusion. In
Exp. 2, we investigated the effect of visual illusion in relation to learned
movement. After practicing a length reproduction task 200 times, subjects
performed a test session in which illusory figures were among the presented
lines. Subjects were instructed to ignore any visual illusions, but this again
had no effect on the reproduced length, that is, longer or shorter lines were
reproduced in accord with the illusion. The findings show that visual illusion
still had an effect after subjects were instructed to ignore it or had practiced
the task extensively.
PMID- 9399286
TI - Students' tactics of resistance and teachers' stress.
AB - In a study of 134 college teachers, teachers' self-reported stress scores were
significantly and positively related with their perceptions of students' use of
reluctant compliance and deception tactics in resistance to on-task learning.
PMID- 9399287
TI - Worth Index.
AB - A measure of the perception of the source of one's worth was developed. The Worth
Index focussed on whether people think that the value or worth of their lives is
something which they must earn or is something that is innate and therefore
cannot be earned. Estimates of validity and reliability are reported.
PMID- 9399288
TI - Effects of virtual reality-enhanced exercise equipment on adherence and exercise
induced feeling states.
AB - A field study was conducted to test the effectiveness of virtual reality-enhanced
cardiovascular exercise equipment for increasing adherence and attendance in a
mixed-sex adult sample. Attendance was significantly higher in the virtual
reality-enhanced condition than in the conditions without virtual reality over
the 14-wk. period. Adherence was also highest (83.33%) in the virtual-reality
bicycle group. Postexercise feelings of positive engagement, revitalization,
tranquility, and physical exhaustion, as measured by the Exercise-induced Feeling
Inventory, did not differ among groups. Contrary to previous findings, Self
motivation Inventory scores were not associated with either attendance or
adherence. While findings suggest that virtual-reality features may promote
exercise adherence or attendance, it is not yet known what psychological
variables they affect. Implications were drawn regarding the practical
possibilities for exercise promotion.
PMID- 9399289
TI - Human ethology: age and sex differences in mall walking.
AB - Well-controlled experimental research has examined the biomechanical aspects of
walking in homo sapiens on a track. The research reported here also examined
cadence, velocity, and stride length for estimated ages ranging from 15 to over
55 years but in a shopping mall. Women at all ages walked faster than men in the
mall setting which was opposite to what was found in the track research.
Apparently context may influence how fast people walk. Hunter-gatherer
differences could explain these results.
PMID- 9399290
TI - Percept-genesis of the mother-child separation theme among panic and asthma
patients.
AB - A stimulus portraying a mother figure who is leaving a baby alone on the floor
(Separation Theme) was presented tachistoscopically at increasing exposure times,
according to the method of the Defense Mechanism Test, to three sex-matched
groups of 31 normal subjects, 31 patients with bronchial asthma, and 31 patients
with Panic Disorder and Agoraphobia. The frequency of several codings was
significantly higher in both clinical groups compared with normal controls.
Asthma patients were characterized by reports of the child seen as a statue and
of contact or fusion between mother and child. Agoraphobic patients employed
different strategies, centered on the mother rather than on the child and mainly
represented by the denial of mother's action, e.g., she is not leaving, she is
entering. The findings support the hypothesis of a difference in defensive
organization between neurotic and psychosomatic patients.
PMID- 9399291
TI - Criteria used to judge obese persons in the workplace.
AB - Researchers have speculated that employers are less likely to hire obese persons
for more publicly visible jobs, although this hypothesis remains untested. In the
present study, 54 undergraduate students rated 40 jobs on several items,
including the likelihood they would hire an obese person for each job.
Multidimensional scaling showed a one-dimensional solution, labeled as physical
activity, with participants less likely to hire obese persons for more active
jobs. For hiring likelihood ratings for jobs at either end of the dimension
appear to be most similar for men and individuals with more positive attitudes
toward obese persons versus women and individuals with more negative attitudes
toward obese persons. Implications for both theory and practice are discussed.
PMID- 9399292
TI - Maintenance of exercise behavior for individuals at risk for cardiovascular
disease.
AB - The purpose of the study was to examine psychological factors associated with
maintenance of exercise behavior in a population of middle-aged individuals with
elevated risk factors for cardiovascular disease. 191 males and 17 females took
part in a one-year diet and/or exercise intervention during 1990-1991. Four years
later questionnaires were sent out to the 200 former participants who were still
available for contact. 67.9% of those who answered (n = 140) were categorized as
exercisers, and 30.7% were categorized as nonexercisers. The majority of the
exercisers had exercised at least one and a half years. A chi-squared analysis
showed that whether the individuals were exercising or not at present was
independent of whether they had exercised or not during the intervention study.
Discriminant analyses were used to determine how well physical self-perceptions
at different times would categorize exercisers and nonexercisers. Current
physical self-perceptions categorized the Active Exercisers (86.9%) and the
Nonexercisers (63.3%) the best (in total 79.1% correct classifications). Neither
change in physical self-perceptions during the intervention not change in
physical self-perceptions from the end of the intervention until four years
later, classified the exercise behavior as well. Three social cognitive models,
The Self-perception model, The Health Belief model, and The Self-efficacy model,
were investigated as discriminators between Active Exercisers and Nonexercisers.
Active Exercisers were classified better than Nonexercisers, and current physical
self-perceptions showed the highest percentage of total correct classifications.
The proposed models were also analyzed as predictors of the variance in self
rated Motivation for Exercise. Outcome Expectations, Compliance Self-efficacy,
Perceived Fitness, and Exercise Mastery explained 45% of the variance in self
rated Motivation for Exercise.
PMID- 9399293
TI - Creative synthesis of visual images is not associated with individual
differences.
AB - 50 undergraduates were tested on a mental synthesis task aimed at producing
creative visual patterns and were administered three questionnaires measuring
imagery vividness and control. Analysis did not support a relationship between
scores on visual synthesis and imagery and showed that neither kind of score was
influenced by sex and studies attended.
PMID- 9399294
TI - Of time and preference: temporal stability of environmental preferences.
AB - Time is a central issue in discussions about art and in Berlyne's aesthetic
theory. This article reports on the temporal stabilities of preferences for a
novel and controversial building at three times after construction (2 years, 18
years, 23 years), and public preferences for 20 ordinary and noncontroversial
buildings at three times over nine years. In all there were 5543 respondents.
Analyses suggested that the initial response to the novel building was stable
over the next 23 years, and the public responses for the 20 nonnovel buildings
were stable over nine years. Implications for research are discussed.
PMID- 9399295
TI - Fantasy and reality distinction of congenitally blind children.
AB - 40 congenitally blind and 40 sighted children were tested for fantasy-reality
distinctions of real and imagined objects and the development of concepts of
darkness, hidden objects, space, dreams, emotions, facial expressions, size, and
height. Analysis indicated that the blind children distinguished between contents
of fantasy and reality, although they were less sure about the reality status of
the objects. The sighted group gave more reality responses than the blind group
for the concepts of dreams and hidden objects, but the remaining concepts were
somewhat the same. Cognitive development explained in terms of theory formation
may not explain the development of young blind children completely. Their
knowledge that contents of fantasy are not real may be obtained through
interpersonal experiences that are publicly shared.
PMID- 9399296
TI - Development of a short test for accident proneness.
AB - In developing the Accident Proneness Prediction Test to measure motor control
skills related to safety aptitudes subjects were instructed to draw on a sheet of
paper as many circles as possible within a limited amount of time. The responses
were scored in terms of the speed and quality (irregularities) of the produced
circles. Although 103 accident-prone drivers produced more circles than the 178
good drivers, the quality of performance of the accident-prone drivers was poorer
than that of the good drivers. Based on this validity study, we proposed these
predictive criteria for further testing of accident proneness.
PMID- 9399297
TI - The Fitness Facility Membership Questionnaire: a measure of reasons for joining.
AB - This study describes the development of the Fitness Facility Membership
Questionnaire of 43 items, designed to identify reasons for joining a fitness
facility. Items were generated from responses to an open-ended questionnaire. A
50-item version of the questionnaire was completed by 152 members of five
community-based fitness facilities. Principal components analysis with varimax
rotation yielded 8 factors, accounting for 63.8% of the variance. The factors
were labeled Socialization, Aquatic-related Facilities, Extrinsic Motivation,
Recreational Facilities, Intrinsic Motivation, Resistance Equipment, Aerobic
Equipment, and Amenities. The internal consistency of the eight factors was
acceptable with Cronbach coefficients alpha ranging from .72 to .89. Discriminant
analysis of responses is also presented.
PMID- 9399298
TI - Reproductive status of mothers affects sex-biased parental investment in humans.
AB - An analysis of the sexual differences in birth weights of 381 children showed
that boys are heavier than girls for multiparous mothers but not for primiparous
ones. The results support the current hypotheses that predict sex biases in
parental investment, with higher costs of producing male offspring in some
mammals.
PMID- 9399299
TI - Graphologists' assessment of extraversion compared with assessment by means of a
psychological test.
AB - The study investigated whether graphologists can infer extraversion from
handwriting correctly. On the basis of three personality questionnaires, three
persons (targets) were classified as extraverted and three as introverted. Ten
graphologists independently analysed the handwriting of the targets and
classified them as extraverted or introverted. Of the 60 (10 graphologists for 6
targets) classifications 58 were correct, which shows the graphologists assessed
the classification of extraversion from handwriting. Graphologists agreed
substantially on which characteristics of the handwriting were indicative for
classification as extraversion or introversion. In each handwriting sample,
however, both extraverted and introverted characteristics were present. Eventual
classification may be based on the relative frequency of the two kinds of
characteristics. Comparative studies like this one indicate that in research one
should consider whether graphologists and psychologists share the same notion of
extraversion.
PMID- 9399300
TI - Assessing lumbar stabilization from point-light and normal video displays of
manual lifting.
AB - Routinely, physical therapists use visual observation to assess qualitatively a
patient's performance. The literature, however, indicates that assessments of
gait and lumbar stabilization from visual observation are at best only moderately
reliable. Point-light video displays have been used to study the visual
perception of human motion. The present purpose was to examine the reliability of
assessments made by a physical therapist when viewing point light and normal
video displays of subjects performing a lifting task. Three physical therapists
assessed lumbar stabilization by viewing normal and point-light displays of 25
subjects who lifted an 8-lb. milkcrate from floor to waist height. Greater
agreement of the therapists' ratings of lumbar stabilization was achieved on
assessments made from point-light displays than on those made from normal
displays. This finding suggests that the use of point-light displays may improve
the reliability of qualitative assessments of performance on motor tasks.
PMID- 9399301
TI - Paranormal beliefs and personality scores of high school students.
PMID- 9399302
TI - Alexithymic characteristics in responses to the Synthetic House-Tree-Person (HTP)
Drawing Test.
AB - This study examined the association of certain complex personality traits
assessed by the Synthetic House-Tree-Person Drawing Test and alexithymic
characteristics assessed by the 20-item Toronto Alexithymia Scale for a sample of
589 Japanese college students. Alexithymic students who scored over 61 points on
the Toronto Alexithymia Scale-20 exhibited two characteristics relative to the
test: poor relationships between figures and additional written explanations.
These two characteristics projected on the Synthetic House-Tree-Person Drawing
Test may be related to alexithymic characteristics and related factors.
PMID- 9399303
TI - Perception of well-being among older persons in nonmetropolitan America.
AB - This study examined the relationships of some selected sociodemographic variables
to perception of well-being by elderly individuals living in nonmetropolitan
areas in the United States. Data used were from the National Opinion Research
Center's (NORC) General Social Surveys for the ten years between 1982-1991. Seven
sociodemographic variables and six attitudinal variables were considered
independent variables, and perception of well-being was treated as the dependent
variable. Analysis of variance and multiple regression analysis indicated marital
status, education, financial status, and religious attendance were significantly
related to perception of well-being and five attitudinal variables increased the
total variance accounted for in perceived well-being.
PMID- 9399304
TI - Spatial representation in face drawing and block design by nine groups from
hunter-gatherers to literates.
AB - A rank-order correlation was performed for nine cultural groups ranging from
preliterate hunter-gatherers to literate medium-city dwellers. Two spatial tests
of intrapattern spatial relations were used, the Draw-A-Person-With-Fade-In-Front
test and the Kohs Block Design, a test of constructive praxia. In contrast to
traditional "Western" evaluations, credit was given for the preservation of the
essential intrapattern shapes even when exact spatial relations among these
shapes was incorrect. Such "errors" were labelled "neolithic face" patterns and
"nonrandom errors," respectively. Analysis suggested that the neglected
intrapattern (in contrast to interobject) spatial relational skills emerge with
literacy but is not yet actualized in preliterates whose survival requires quick
fight or flight response upon prompt, albeit gross, assessment of salient shapes
of prey or predators (human or animals). The positive Spearman rank-order
correlation of absent or low literacy skills with the percent of "neolithic face"
drawings was .95 and with the "nonrandom" block designs .67. Suggestions were
developed for assessing certain unusual "ecological" present situations or
certain brain dysfunctions.
PMID- 9399305
TI - Aesthetic preferences for combinations of color and music.
AB - 135 university undergraduates heard 12 preludes from J. S. Bach's Well-tempered
Clavier (Vol. 1) while viewing alternating red, yellow, green, and blue colored
lights. Their task was to rank-order the lights according to how well they
"matched" the music. Preferences for combinations of color and music differed
depending on whether the music was in a major or a minor key. The present
findings along with those of some earlier studies suggest that aesthetic
experience may be heightened when colors are seen that match the mental images
music evokes.
PMID- 9399306
TI - Comparisons of teaching presentation and development of content: implications for
effectiveness of teaching.
AB - The purpose of this study was to describe the choices of content development and
task presentations of four teachers with varying experience and the subsequent
achievement in skills test of their 125 junior high school students over the
course of an 11-day volleyball unit. The results supported the importance of
teachers presenting clear, detailed, and game-oriented progressions of content
and tasks to improve students' learning.
PMID- 9399307
TI - A modified step test based on a function of subjects' stature.
AB - A number of submaximal step tests have been developed to predict maximal aerobic
capacity. Because step height may influence biomechanical efficiency and heart
rate, step tests based on subjects' stature may more accurately predict maximal
aerobic capacity. Eighteen women performed the Queens College step test and a
modified Queens College step test. The modified step test was performed with the
height of the bench set even with the height of the foot at a knee angle of 90
degrees. Analysis of the data indicated a lower recovery heart rate following
this test (p < .05). Further, correlations between maximal aerobic capacity and
recovery heart rate for both tests were moderate (r = -.80 and -.75,
respectively). Our results suggest that step tests based on subjects' stature do
not more accurately predict aerobic capacity than those using a standardized
bench height.
PMID- 9399308
TI - The Health Student Academic Locus of Control Scale.
AB - The Health Student Academic Locus of Control Scale is a 20-item context-specific
scale, developed to measure Internal and External control beliefs of students in
courses allied to medicine. Psychometric properties are acceptable (N = 164) so
the scale can be used to measure control beliefs in a longitudinal study.
PMID- 9399309
TI - Computer-aided cognitive rehabilitation: possible application to the attentional
deficit of schizophrenia, a report of negative results.
AB - The cognitive deficits associated with schizophrenia commonly include impairment
in attention, which may contribute to difficulties with learning, memory, and
executive function. This study evaluated the effectiveness of computer-aided
training of attentional skills in schizophrenia. Two groups of schizophrenic
subjects (9 men and 1 woman) were matched for age, estimated premorbid IQ, and
positive and negative symptom scores. Both groups were assessed using a battery
of attentional tests. Subjects then received either six 1-hr. computer-aided
cognitive rehabilitation sessions (experimental condition) or six sessions of
graphics-based computer games (control condition). Both groups were reassessed
with attentional measures. There was significant improvement on only one test, a
letter-cancellation task. This improvement was evident in both groups suggesting
that this was a practise effect. Apart from the letter-cancellation test,
subjects undertaking the computer-aided rehabilitation treatment did not show
significant improvement on any attentional tasks.
PMID- 9399310
TI - Morphed images of basic emotional expressions: ratings on Russell's bipolar
field.
AB - An object may be gradually changed into another object by a technique called
"morphing" as in the current study. Although in some studies, such as by Coren
and Russell, subjects were asked to rate psychologically synthesized facial
images seen in a stereoscope, there do not seem to be any studies in which facial
images were physically synthesized as morphed images. Our question then was how
subjects would rate them. Multidimensional scaling indicated that ratings of
facial images, physically synthesized by morphing, showed essentially the same
configuration as those of psychologically synthesized faces and that our results
conformed to the well-known dimensions of emotional space. In contrast, ratings
of fear might not conform to the dimensional emotional space, suggesting cultural
differences in emotion between Japan and the United States.
PMID- 9399311
TI - Speed and accuracy in the learning of a complex motor skill.
AB - The effect of emphasizing speed or accuracy on the learning of a high speed-high
accuracy skill, the fastpitch softball pitch was investigated. 26 10- and 11-yr.
old girls were randomly assigned to two groups receiving feedback on speed of
throwing or accuracy of throwing during a 6-wk. training. Measurements of speed
and accuracy were made and recorded on all participants at each practice session
and a videotape of their pitching technique was also made at each session. Data
were subjected to 2 x 3 (2 groups by 3 testing times) repeated-measures analyses
of variance. The speed group threw faster and with better technique during the
study and was able to maintain speed and accuracy in the reversed test condition.
PMID- 9399312
TI - Confirmatory factor analysis of the French translation of the 20-item Toronto
Alexithymia Scale.
PMID- 9399313
TI - Influence of physical exercise on simple reaction time: effect of physical
fitness.
AB - The influence of physical fitness and energy expenditure on a simple reaction
time task performed during exercise was investigated. Two groups of 10 subjects
were used, one was composed of trained middle-distance runners and one of
students who had no regular physical training. The subjects performed a simple
reaction time task while pedalling on a cycloergometer at different relative
power output corresponding to 20, 40, 60, and 80% of their own maximal aerobic
power and immediately after exercise. During exercise, the results showed a
decrease in cognitive performance for both groups whereas no significant effect
was found after exercise. A significant effect of physical fitness on simple
reaction time was noted during exercise. The data are interpreted in terms of
optimization of performance focusing particularly on the relations between energy
cost of the physical task and attentional demand.
PMID- 9399314
TI - Spatial visualization: running visualization for empty squares.
AB - A technique is reported in which an oral description of empty squares had to be
visualized. A tone signaled completion, and a response was made whether the last
square had touched a previous square. The chain lengths varied from 10 to 19
squares at closure. Local closure sizes consisted of 4 to 10 squares. Closures up
to 6 squares produced the least errors. There were biases in response as a
function of response type and chain length. The technique could be useful for
monitoring continuous spatial visualization.
PMID- 9399315
TI - The aetiology and long-term effects of injuries due to bicycle accidents in
persons aged fifty years and older.
AB - This retrospective study concerns the aetiology and psychological long-term
effects of injuries due to bicycle accidents in 329 patients 50 years and older
who attended the Emergency Unit of the University Hospital at Groningen during
the period 1990 through 1992. Long-term effects were assessed three years after
hospital discharge. The one-sided bicycle accident (with no other traffic
involved) was the major (63.2%) cause, mostly due to loss of balance or to a foot
slipping from the pedal. The main category of the second major cause was
collision with other traffic. Of the bicycle accidents 66% occurred within 15
minutes after departure; 80% of the accidents happened in good weather conditions
and daylight, and 7.6% of the patients had taken tranquilizers before biking. The
majority of the injuries were observed at the upper extremities (28.8%) and head
or face (25.8%). The percentage of clinically treated patients increased across
ages from 25% in the 50- to 54-yr.-old category to 45% in the category 75-yr. and
older. Three years after the incident, long-term psychological effects were still
observed in 29% of the patients.
PMID- 9399316
TI - Order effect for two measures of hypnotizability.
PMID- 9399317
TI - Depth perception in simple line drawings.
AB - Three-dimensional interpretation of simple line drawings, composed of two
triangles with a common side, was studied through the quantitative measurement of
perceived orientation of the surface indicated by a stimulus figure. In a single
triangle, depth perception is ambiguous and is not stable even if perceived. In
two triangles with a common side, however, depth is stably perceived. Depth
effect, defined as the magnitude of the angle formed by the two perceived
surfaces, increased linearly as the magnitude of an angle at a vertex facing the
common side became larger. The depth effect did not vary significantly for the
change of a triangular from when the magnitude of the angle at the vertex facing
the common side was constant. These results suggest that the depth effect changes
systematically with variation in the triangle's form.
PMID- 9399318
TI - Spring peak in suicides.
PMID- 9399319
TI - Magnitude estimation scaling of the loudness of a wide range of auditory stimuli.
AB - The study of the perception of loudness lends itself well to the psychophysical
scaling technique of magnitude estimation. This study was designed to extend the
range of auditory stimuli used to study the magnitude estimation scaling of
loudness. The five stimuli chosen were a 1000-Hz pure tone, narrow band noise
(700-1300 Hz band width), broad band noise (100-10,000 Hz band width), rock
music, and babble speech, i.e., speech in which meaning is not discernible
because several individuals are talking at once. Subjects were 30 normal young
women (M = 19 yr.). During the auditory magnitude-estimation task for each of the
five stimuli, a subject was instructed to assign numbers to stimulus presented in
a randomly ordered series of nine sensation levels (10, 20, 30, 40, 50, 60, 70,
80, and 90 dB SL). Multivariate analysis of variance for repeated measures
indicated there were no significant differences in the numerical responses of the
subjects for the five stimuli. A possible explanation for these results is the
presence of an underlying stabilizing factor (internal scaling mechanism) that
allows adults to scale loudness consistently irrespective of the type of auditory
stimulus.
PMID- 9399320
TI - Speech delay in seven siblings with unusual sound preferences.
AB - By the age of 8 years, children who are developing normally show almost adult
speech skills. Children with serious phonological disorders, however, may exhibit
significant differences in development well beyond the age of 8 years with little
or no improvement in speech if therapy is not provided. This is a descriptive
study of seven siblings, ranging in age from 6 to 14 years of age who had never
attended school or received speech therapy until these ages. All of the children
exhibited moderate to severe speech disorder with no evidence of predisposing
genetic factors, hearing loss, physical abuse, or prenatal drug exposure. These
cases, which would obviously be impossible to duplicate in a controlled study,
provide strong support for the efficacy of speech therapy. Children with serious
speech delays will not improve appreciably without direct intervention.
PMID- 9399321
TI - Relationship between body image and percent body fat among male and female
college students enrolled in an introductory 14-week weight-training course.
AB - Students (39 men and 27 women) from a southern university, who were enrolled in a
14-wk. introductory weight-training course, were administered a 20-item body
image questionnaire and subsequently underwent skinfold measurements to assess
percent body fat. Mean scores were correlated with percent body fat. For men,
women, and both sexes combined correlations were significant and inverse (rs =
.68, -.41, -.66, respectively). Body image as measured was inversely related to
percent body fat among these college students. Researchers should examine how
dietary and exercise-induced changes in adiposity (pre-post design) influence
scores on body image.
PMID- 9399322
TI - Cognitive correlates of complexity of children's drawings.
AB - 240 children (60 each at ages 4, 6, 8, and 10 years) were administered Dennis'
(1987) Five Drawing Tasks and five additional developmental tasks. Three
hypotheses were tested: that object recognition and working memory would be
related to increasing complexity, that both would load on separate factors, and
that higher-order analyses would indicate an underlying second-order spatial
factor. Analysis included very strong zero-order correlations with age. When age
was partialed out, three first-order factors were obtained. Higher-order analyses
yielded one second-order factor which appeared related to a general factor of
spatial intelligence.
PMID- 9399323
TI - The birthday blues.
PMID- 9399324
TI - Possible interaction between vibration thresholds by sex and motor dominance in
the index finger and big toe.
AB - Two studies suggest a possible interaction among sex, motor dominance, and
vibrotactile threshold for the great toe and index finger. In study 1 a forced
choice procedure with the Vibratron II (Physitemp Instruments, Inc.) was used; a
significant interaction between sex and foot dominance for vibratory threshold
was noted with no main effects for the great toe. The greatest difference between
men and women was on the nondominant side on the foot. Study 2 replicated Study 1
using the index finger as well as the great toe and used the Semmes. Weinstein
monofilament test for a cross-modal comparison. A method of limits procedure was
used to increase the generalizability of the data. A similar interaction was
found between sex and motor dominance for the index finger but not the great toe.
This was attributed to skewing of data for the toe. No effects were found for the
Semmes-Weinstein test. Possible usefulness in detecting neuropathies is
considered. Larger normative studies including variables such as age, height, and
weight are required for generalizable conclusions.
PMID- 9399325
TI - Affect identification bias demonstrated with individual chimeric faces.
AB - The current study extends previous findings of a left visual-field bias in
chimeric face tasks, by using a new procedure which incorporates chimeric stimuli
depicting both positive and negative target affects and requires the
identification of affect in individually presented faces. This new procedure is
more representative of the types of judgements made in daily social interaction.
Results with this new procedure are consistent with previous findings, indicating
a significant left visual-field bias for both positive and negative affects in
the majority of subjects. Handedness was significantly related to lateralization
scores, with dextrals showing greater left visual-field biases than sinistrals.
Among sinistrals, a left visual-field bias was noted only for happy chimera.
PMID- 9399326
TI - A parental survey of speech, language, and physical development of infants and
toddlers with sickle cell disease.
AB - 16 parents of infants and toddlers (9 girls, 7 boys) with sickle cell disease
reported normal speech and language development in their children but perceived
slow physical development. Such perceptions may be related to the smaller
physical size of children with this disease.
PMID- 9399327
TI - Language of sport fans: sportugese revisited.
AB - In 1959, Tannenbaum and Noah reported that sports writers and readers possessed a
better understanding of sport terminology than nonreaders. The current
investigation extended Tannenbaum and Noah's research using current sport terms.
A positive relationship between understanding sport terminology, extent of team
identification, strength of sport fandom, and self-proclaimed sport knowledge was
hypothesized. Scores of 57 participants confirmed the predicted pattern.
Discussion concerned research examining sport terminology.
PMID- 9399328
TI - Aiming accuracy of the line of gaze and redesign of the gaze-pointing system.
AB - The current experiment tested the aiming accuracy of the eye for targets at nine
different positions and of two different sizes. The left eye was tracked to
record the line of gaze with an infrared eye-monitoring device. For each subject,
horizontal shift, vertical shift, standard deviations of the X and Y coordinates,
and 95th percentile of the horizontal and vertical shifts from the nine target
centers were calculated to indicate the precision, accuracy, and possible design
limits of the gaze points. Analysis showed that the target's position had a
strong effect on the vertical shift, standard deviations of the Y coordinate, and
95th percentile of the vertical shift. The effect of target size was not
significant on any of the dependent measures. The research findings have
important implications for the redesign of the gaze-pointing device. Visual
targets appearing below the horizontal line of sight should be larger than those
above. Based on the 95th percentile of the horizontal and vertical shifts,
targets should be approximately 2.0 degrees wide and 2.4 degrees long above or
coinciding with the horizontal line of gaze and 2.6 degrees wide and 3.9 degrees
(cm) long below the horizontal line of gaze.
PMID- 9399329
TI - Landmark enhancement and strategic processing: an evaluation of strategies for
spatial navigation training.
AB - Viewing a filmed route offers an alternative to more expensive and rigid methods
of learning navigation skills. One advantage of film is the ability to enhance
important landmarks or focus on particularly relevant information. The current
research used a videotape of a spatial route to assess the usefulness of
participants' interaction with landmarks and enhancement of landmarks for
training spatial navigation. 48 participants were exposed to one of four
videotaped route conditions: Landmark-enhanced, Question-based Interaction,
Landmark-enhanced Plus Question-based Interaction, or Control (Nonenhanced
without Question-based Interaction). Following the spatial navigation training
with videotape, participants were asked to traverse the route in the actual
building. Analyses of variance indicated that the Question-based Interaction
group made significantly fewer wrong turns during traversal of the route than did
the Control group. Also, enhancement of the landmarks did not significantly
reduce wrong turns; in fact, it may have hindered the benefit of question-based
interaction in reducing wrong turns.
PMID- 9399330
TI - Perceptual defense and vigilance to perinatal stimuli.
AB - The presentation times (milliseconds on a computer screen followed by a masking
grid) required for the correct identification of tachistoscopically presented
perinatal stimuli were compared for 30 pregnant women and 25 perimenopausal
women. Analysis indicated a differential facilitation or inhibition of perception
in logical relation to subjects' closeness to pregnancy or menopause: pregnant
women are quicker to identify stimuli related to pregnancy or babies but slower
to recognize pictures of a pregnant woman with her father or mother. This
supports the validity of measurements based on the theory of perceptual defense
or vigilance.
PMID- 9399331
TI - The NMDA receptor competitive antagonist CPP modulates benzodiazepine tolerance
and discontinuation.
AB - Benzodiazepine discontinuation is characterized by a syndrome of increased
activity and reduced seizure threshold that is similar to effects mediated by the
glutamatergic system. To elucidate the involvement of the glutamatergic system in
benzodiazepine tolerance and discontinuation, we administered lorazepam, the NMDA
antagonist CPP, and the combination of these compounds either concomitantly or
consecutively to mice via osmotic pumps and evaluated pentylenetetrazole-induced
seizure threshold, open-field activity, and benzodiazepine receptor binding
during and after chronic administration. Animals receiving lorazepam alone
developed partial tolerance at 7 days and complete tolerance at 14 days to the
anticonvulsant effects of lorazepam. This effect was partly attenuated by CPP
coadministration with lorazepam. This combination produced only partial
tolerance. A reduction in seizure threshold was observed 4 days after
discontinuation of lorazepam alone. This effect was abolished by coadministration
of CPP with lorazepam and by CPP administration during the withdrawal period.
Benzodiazepine binding in most structures examined was significantly reduced at
14 days during chronic lorazepam administration (versus 1 day), and
coadministration of CPP did not alter this decrement. After lorazepam
discontinuation, binding was increased at 4 and 7 days versus chronically treated
animals and versus vehicle within the cerebral cortex. This effect was abolished
by coadministration of CPP as well as by CPP administration during the lorazepam
withdrawal period. These data support the involvement of the glutamatergic system
in benzodiazepine tolerance and discontinuation.
PMID- 9399332
TI - Effects of phenytoin on the amygdala neurons in vitro.
AB - The present study was aimed at elucidating the possible mechanisms underlying the
anticonvulsant efficacy of phenytoin using intracellular recording techniques in
the in vitro amygdalar slice preparation. Synaptic response mediated by the N
methyl-D-aspartate (NMDA) receptor (EPSPNMDA) was isolated pharmacologically by
application of a solution containing non-NMDA receptor antagonist 6-cyano-7
nitroquinoxaline-2,3-dione (10 mumol/l) and gamma-aminobutyric acidA receptor
antagonist bicuculline (20 mumol/l). Phenytoin inhibits the amplitude of EPSPNMDA
without affecting the postsynaptic depolarization induced by exogenous
application of NMDA. In addition, phenytoin increases the magnitude of paired
pulse facilitation which is consistent with a presynaptic mode of action. These
results suggest that inhibition of transmitter release due to presynaptic
blockade of Na+ and/or Ca2+ channels may account largely for the anticonvulsant
efficacy of phenytoin.
PMID- 9399333
TI - Metabolism of the tricyclic antidepressant amitriptyline by cDNA-expressed human
cytochrome P450 enzymes.
AB - The metabolism of amitriptyline was studied in vitro using cDNA-expressed human
cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6 and 2E1. CYP 2C19 was the
most important enzyme with regard to the demethylation of amitriptyline, the
quantitatively most important metabolic pathway. CYP 1A2, 3A4, 2C9 and CYP 2D6
also participated in the demethylation of amitriptyline. CYP 2D6 was the sole
enzyme mediating the hydroxylation of amitriptyline, and (E)-10-OH-amitriptyline
was exclusively produced. CYP 2E1 did not metabolize amitriptyline. Concerning
the quantitative relations, CYP 2C19 and 2D6 exhibited high affinities with Km
values in the range of 5-13 mumol/l, whereas the affinities of 1A2, 3A4 and 2C9
were somewhat lower with Km values ranging from 74 to 92 mumol/l. CYP 2C19
displayed the highest reaction capacity per mole with Vmax equal to 475 mol h-1
(mol CYP)-1. The other enzymes had Vmax values in the range of 90-145 mol h-1
(mol CYP)-1. Allowing for the typical relative distribution of amounts of CYP
enzymes in the liver, a simulation study suggested that, at therapeutic doses, on
average about 60% of the metabolism depended on CYP 2C19. At toxic doses, CYP
2C19 is expected to be saturated, and CYP 3A4 may now play a dominant role in the
metabolism.
PMID- 9399334
TI - Inhibition of sympathetic outflow by the angiotensin II receptor antagonist,
eprosartan, but not by losartan, valsartan or irbesartan: relationship to
differences in prejunctional angiotensin II receptor blockade.
AB - It is well established that angiotensin II can enhance sympathetic nervous system
function by activating prejunctional angiotensin II type I (AT1) receptors
located on sympathetic nerve terminals. Stimulation of these receptors enhances
stimulus-evoked norepinephrine release, leading to increased activation of
vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In
the present study, the effects of several chemically distinct nonpeptide
angiotensin II receptor antagonists were evaluated on pressor responses evoked by
activation of sympathetic outflow through spinal cord stimulation in the pithed
rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced
frequency-dependent pressor responses. Infusion of sub-pressor doses of
angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for
increases in blood pressure, indicating augmented sympathetic outflow.
Furthermore, pressor responses resulting in spinal cord stimulation were
inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8
[angiotensin II] (10 micrograms/kg/min). These results confirm the existence of
prejunctional angiotensin II receptors at the vascular neuroeffector junction
that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor
antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced
by spinal cord stimulation in a manner similar to that observed with the peptide
antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg
i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan,
valsartan, and irbesartan, had no effect on spinal cord stimulation of
sympathetic outflow in the pithed rat. Although the mechanism by which
eprosartan, but not the other nonpeptide angiotensin II receptor antagonists,
inhibits sympathetic outflow in the pithed rat is unknown, one possibility is
that eprosartan is a more effective antagonist of prejunctional angiotensin II
receptors that augment neurotransmitter release. Because eprosartan is more
effective in inhibiting sympathetic nervous system activity compared to other
chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan
may be more effective in lowering systolic blood pressure and in treating
isolated systolic hypertension.
PMID- 9399335
TI - Effect of trilinolein on superoxide dismutase activity and left ventricular
pressure in isolated rat hearts subjected to hypoxia and normoxic perfusion.
AB - Oxygen-derived free radicals have been implicated in the development of
myocardial injury during hypoxia/reperfusion. Antioxidants can effectively
inhibit the formation of free radicals and ameliorate the myocardial damage which
may occur during hypoxia/reperfusion. Trilinolein is a triacylglycerol recently
purified from the traditional Chinese medicinal plant Panax pseudo-ginseng. It
has linoleic-acid residues as the only type of fatty acid residue in all three
esterified positions of the triacyglycerol. It has been proposed that decreased
endogenous superoxide dismutase (SOD) activity may contribute to free radical
mediated reperfusion injury of the ischemic myocardium. In the present study,
when isolated rat hearts were subjected to hypoxia for 10, 30, 60 and 90 min
without normoxic perfusion, a significant decrease in Mn-SOD activity was shown
throughout the period of hypoxia, whereas the Cu.Zn-SOD activity was increased at
10 and 30 min but was not different from the baseline at 60 and 90 min of
hypoxia. In rat hearts pretreated with 10(-7) mol/l trilinolein and subjected to
60 min of hypoxia without normoxic perfusion, Cu.Zn-SOD was augmented compared
with baseline and compared with hearts subjected to 60 min of hypoxia without
trilinolein, whereas Mn-SOD activity was still reduced compared with baseline,
although less so than after 60 min of hypoxia without trilinolein. Pretreatment
with trilinolein was associated with better preservation of left ventricular
function during hypoxia and more rapid return to recovery during normoxic
perfusion. This myocardial protective effect may be related to an antioxidant
effect through potentiation of SOD, particularly Cu.Zn-SOD during hypoxia.
PMID- 9399336
TI - Lidocaine attenuates mechanical and metabolic derangements induced by palmitoyl-L
carnitine in the isolated perfused rat heart.
AB - The effect of lidocaine on the palmitoyl-L-carnitine (PALCAR)-induced mechanical
and metabolic derangements was studied in Langendorff rat hearts, perfused
aerobically at a constant flow rate and paced electrically. PALCAR (5 mumol/l)
increased the left ventricular end-diastolic pressure, decreased the left
ventricular developed pressure (i.e., mechanical dysfunction), and decreased the
tissue levels of adenosine triphosphate and creatine phosphate (i.e., metabolic
change). These mechanical and metabolic alterations induced by PALCAR were
concentration-dependently attenuated by lidocaine (20, 50 or 100 mumol/l).
Nevertheless, lidocaine (20, 50 or 100 mumol/l) did not affect the mechanical
function and energy metabolism of the normal (PALCAR-untreated) heart. These
results indicate that lidocaine has a cardioprotective action against the PALCAR
induced mechanical and metabolic derangements.
PMID- 9399337
TI - Circadian rhythm and drug delivery design.
PMID- 9399338
TI - New 5-aminoacyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-ones with
antiarrhythmic activity.
AB - A series of new 5-substituted tricyclic 5,10-dihydro-11H-dibenzo[b,e][1,4]
diazepin-11-ones was identified as potential antiarrhythmic agents against
bradyarrhythmias [1, 2]. The in vitro and in vivo interactions of the compounds
with muscarinic receptors and the antiarrhythmic activity were examined. In
receptor binding studies some derivatives showed a high affinity to the cardiac
M2 receptor (Ki 10 nmol/l), an equal or smaller affinity to cortical M1 receptor
and a lower affinity to the glandular M3 binding site. Functional experiments
showed the derivatives as competitive antagonists with high affinity to the
cardiac and smaller affinity to the intestinal muscarinic receptor. In vivo
experiments correspond with the M2 selectivity. First the vagal or agonist
induced bradycardia was inhibited in rats and guinea pigs while the McNA-343
induced increase of blood pressure, methacholine-induced bronchi and bladder
constriction as well as the salivation were inhibited only at higher doses. In
conscious cats the tachycardia was examined in comparison with pupillomotoricity.
The effect duration and the therapeutical range were determined in comparison to
the M2 selective blocking agent AF-DX116. The antiarrhythmic activity was
examined compared to quinidine sulfate in CaCl2-arrhythmia of rats, in atrial
fibrillation and atrial flutter in dogs according to Scherf [2] and in electric
induced atrial fibrillation under vagal stimulation in cats. In the atrial
arrhythmias the derivatives are clearly longer effective than quinidine sulfate.
The antiischemic activity was examined in the two-stages coronary ligature in
dogs according to Harris. The long-running regularization of ectopies (about 2 h
after i.v. injection) occurred without decrease of the heart rate, an effect
particularly convenient to therapy of bradycardic dysrhythmias.
PMID- 9399339
TI - Enzymatic degradation of the triterpenoid saponin helianthoside 2.
AB - Helianthoside 2 (1), the main bisdesmosidic saponin of Helianthus annuus L. was
converted to the products 2, 3 and 4 by several, optimized enzymatic hydrolysis
methods. Monosaccharide units of the acylglycosidic at C-28 of the sapogenin
bonded, linear chain oligosaccharide were cleaved, but the branched trisaccharide
at C-3 of the aglycone are stable under the conditions used. Compounds 2 and 3
are new triterpenoid glycosides, which were characterized as 28-O-alpha-L
rhamnopyranosyl-(1-->2)-alpha-L-arabinopyranoside (2) and 28-O-alpha-L
arabinopyranoside (3) of 3-O-[alpha-L-rhamnopyranosyl-(1-->3)][beta-D
xylopyranosyl-(1-->4)] beta-D-glucopyranoside of 3 beta,16 alpha-dihydroxy-olean
12-en-28-oic acid.
PMID- 9399340
TI - Synthesis, structures and biological activity of some 4-amino-3-cinnoline
carboxylic acid derivatives. Part 3: 1,3-Oxazino[5,4-c]cinnolines and
pyrimido[5,4-c]cinnolines.
AB - 6,7,8-Substituted 4-amino-3-cinnolinecarboxylic acids 1 were condensed with acid
anhydrides to corresponding 1,3-oxazino[5,4-c]cinnolines 2. The reactions of 1,3
oxazino[5,4-c]cinnolines 2 with amines, hydrazine, hydroxylamine, alanine ethyl
ester provided pyrimido[5,4-c]cinnolines 3, 4. Selected 3-substituted 2
methylpyrimido[5,4-c]cinnolin-4(3 H)-ones have been screened for CNS activity.
PMID- 9399341
TI - Synthesis and antimicrobial testing of 4H-1,2,4-triazole, 1,2,4-triazolo[3,4
b][1,3,4]thiadiazole and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives of
1H-benzimidazole.
AB - Three novel series of benzimidazole derivatives namely 6-substituted 3-[1-(2
alkyl-1 H-benzimidazolyl)methyl]-1,2,4-triazolo[3,4-b][1,3,4] thiadiazoles 5a-h,
6-substituted 3-[1-(2-alkyl-1H-benzimidazolyl)methyl]-7H-1,2,4 -triazolo[3,4-b]
[1,3,4]thiadiazines 6a-j and 6-thioxo-3-[1-(2-alkyl-1H-benzimidazolyl)methyl]-5,6
dihydro-1,2,4 -triazolo[3,4-b][1,3,4]-thiadiazoles 7a, b have been prepared by
cyclization of the key intermediate 1-[(4-amino-5-mercapto-4 H-1,2,4-triazol-3
yl)methyl]-2-alkyl-1 H-benzimidazoles 3a, b. Furthermore, 1-[(4-arylideneamino-5
mercapto- 4H-1,2,4-triazol-3-yl)-methyl]-2-alkyl- 1 H-benzimidazoles 4a-h have
been prepared and some of them were cyclized to 6-substituted 3-[1-(2-alkyl-1H
benzimidazolyl)methyl]-1,2,4-triazolo [3,4-b][1,3,4]thiadiazoles 5d, h using
thionyl chloride. The prepared compounds were tested for antimicrobial activity
in vitro; they showed moderate activity.
PMID- 9399342
TI - Determination of fluoxetine in human plasma using reserved phase HPLC.
AB - A rapid, simple, accurate method for the determination of fluoxetine in human
plasma is presented. Liquid-liquid extraction of fluoxetine was carried out using
diethyl ether. Chlorprothixene was applied as an internal standard. The samples
were chromatographed on a LiChrosorb RP-18 (10 microns) column and the mobile
phase was acetonitrile/phosphate buffer pH 2.70 (9:1). The detection was carried
at 254 nm. A linear quantitative response curve was generated over a
concentration range of 100-600 ng/ml. Overall extraction efficiency of the
extraction procedure was found to be 86 to 91% with a correlation coefficient of
0.992.
PMID- 9399343
TI - Phenytoin transfer across the in situ perfused rat term placenta.
AB - Transfer of phenytoin (PHT) across the rat term placenta perfused in situ was
investigated and compared with that of antipyrine (AP) as a marker of passive
diffusion. PHT was shown to cross the placenta with similar kinetics as AP did.
Both the first order transfer constant (ktr = 0.070 min-1) and the first order
equilibration constant (keq = 0.027 min-1) of PHT were comparable to those of AP
(ktr = 0.046 min-1, keq = 0.022 min-1). Similarly, there were significant
differences between PHT and AP in the foeto-maternal concentration ratio at
equilibrium (FMCReq = 1.01 and 1.09, respectively). The present data indicate
that the transfer of PHT through the rat placenta is governed by the same
principles as that of AP, i.e. by the mechanism of passive diffusion.
Surprisingly, maternal plasma protein binding of PHT (60.5%) did not seem to
influence either its rate of transfer or its eventual foeto-maternal
concentration ratio.
PMID- 9399344
TI - Heat and ionic limitations do not change the inhibition pattern of ribosomal
peptidyltransferase by aminohexosyl-cytosine nucleoside antibiotics.
AB - In a cell-free system derived from Escherichia coli, we investigated the
inhibition of peptide bond formation by blasticidin S at 100 mM NH4+ and 5
degrees C or at 50 mM NH4+ and 25 degrees C. At both conditions, a transient
phase of competitive inhibition is observed, followed by a mixed noncompetitive
phase. The two phases of inhibition are compatible with a model in which a slow
isomerization of the ribosome-drug complex occurs, as a result of ribosomal
conformational changes. After this step, the mutually exclusive binding between
acceptor substrate and antibiotic is converted to simultaneous binding. In
comparison with a previous study carried out at 100 mM NH4+ and 25 degrees C, the
present results demonstrate that the ribosomal conformational changes induced by
blasticidin S can occur irrespectively of the reaction temperature and the ionic
conditions.
PMID- 9399345
TI - The hydrolysis of an alkylammonium salt series by rat liver microsomal esterase.
PMID- 9399346
TI - Chemical composition and antimicrobial activity of Tanacetum parthenium essential
oil.
PMID- 9399347
TI - Prenatal sonographic findings in 187 fetuses with Down syndrome.
AB - We determined the type and frequency of abnormal sonographic findings in 187 Down
syndrome fetuses. Examinations were performed transvaginally or transabdominally
between 9 and 28 weeks' gestation. Consecutive scans performed prior to knowledge
of the fetal karyotype (n = 144) were analysed separately for one of the
participating centres. In 93 fetuses (49.7 per cent), a total of 138
abnormalities were observed. The most commonly detected anomalies were cystic
hygroma and increased nuchal fold thickness (30.5 per cent), hydrops (9.6 per
cent), cardiac defects (7.5 per cent), pyelectasis or hydronephrosis (5.9 per
cent), echogenic bowel (4.8 per cent), and a large variety of internal organ
abnormalities (16.0 per cent) which are not typically associated with Down
syndrome. Two anomalies or three anomalies in the same fetus were observed in 21
and 5 fetuses, respectively. No patterns of concurrent malformations were
apparent among these fetuses. Sensitivity for Down syndrome detection by
ultrasound scans performed without knowledge of the fetal karyotype was 24.1 and
42.6 per cent before 13 weeks and between 14 and 23 weeks, respectively. We
conclude that structural abnormalities are frequently observed in Down syndrome
fetuses, but many sonographic findings are not typically associated with this
syndrome.
PMID- 9399348
TI - Women's opinions and the implications of first- versus second-trimester screening
for fetal Down's syndrome.
AB - Two groups of pregnant women were questioned regarding their opinions on serum
screening for Down's syndrome in the first trimester of pregnancy. One group
comprised 83 women attending our antenatal clinic who were questioned at the time
of the existing second-trimester screening test. Seventy-six per cent of those
who participated in the second-trimester screening programme would have preferred
the test to have been in the first trimester, mainly because of the easier
termination of pregnancy and/or the earlier reassurance provided. The remaining
24 per cent could see no advantage in the earlier time frame. Of the 49 women who
had declined second-trimester screening, only two would have participated in
screening had it been in the first trimester. The other group comprised those
women attending our antenatal diagnosis clinic who were considering chorionic
villus sampling (CVS). Forty-four per cent of these women would have allowed
serum screening in the first trimester to influence their decision as to whether
to undergo definitive prenatal diagnostic testing. In general, those women who
made use of second-trimester serum screening would also do so in the first
trimester. Those who declined the existing screening programme would also decline
first-trimester screening. Many women currently deciding to undergo CVS would
allow a first-trimester screening test to influence their decision.
PMID- 9399350
TI - Elevated hCG as an isolated finding during the second trimester biochemical
screen: genetic, ultrasonic, and perinatal significance.
AB - This study was undertaken in an attempt to determine the significance of elevated
maternal serum human chorionic gonadotropin (MShCG), in the presence of an
otherwise normal screen with respect to fetal malformations, chromosomal
aberrations, and pregnancy outcome. Targeted ultrasound findings and perinatal
outcome of 298 women in whom serum hCG was > or = 2.5 MOM and who were screen
negative for Down syndrome (the study group) were compared with a control group
of 229 women in whom serum hCG as well as the other parameters were within the
normal range. Genetic amniocentesis was performed in 125 women from the study
group. Ultrasonically detected malformations were significantly more frequent
among the study group (12 vs. 1, P = 0.01). Pregnancy complications were similar
in the two groups, with the exception of pre-eclampsia-toxaemia, which was
significantly more frequent in the study group (5 vs. 0, P = 0.02). There was one
case of an abnormal karyotype (47,XXY). Although genetic amniocentesis does not
appear warranted, isolated elevated MShCG levels during the second trimester
screening was associated with an increased risk of fetal anomalies detected by
ultrasound and of toxaemia of pregnancy.
PMID- 9399349
TI - Minimally-invasive early prenatal diagnosis using fluorescence in situ
hybridization on samples from uterine lavage.
AB - A two-phase study was undertaken to examine the efficiency of using transcervical
cells (TCCs) collected by uterine lavage and fluorescence in situ hybridization
(FISH) for early prenatal diagnosis of fetal chromosome aneuploidy. Uterine
lavage was performed in 50 women scheduled for elective termination of pregnancy
(TOP, n = 35) or chorionic villus sampling (CVS, n = 15) between 6 and 11 weeks
of gestation. TCCS were dissociated by trypsin and collagenase, and interphase
FISH was carried out for chromosomes X, Y, 13/21, and 18. The phase I study
comprised 36 women. The FISH results were compared with the cytogenetic analysis
from long-term culture of villus samples collected at TOP or CVS. Among the 36
samples, 15 had a normal male karyotype and 21 had a normal female karyotype.
FISH on TCCs correctly identified 13 out of the 15 pregnancies with a male fetus.
In phase II, uterine lavage was performed on 14 women. The samples were first
tested for the presence of trophoblasts with an anti-trophoblast antibody, GB25,
by immunohistochemical staining. Among 12 GB25-positive samples, the FISH results
corresponded to the fetal karyotype. One of the GB25-positive samples had five
signals for the chromosome 13/21 probe. The cytogenetic analysis confirmed that
the fetus had a karyotype of 47, XX, +21. In the GB25-negative samples, FISH
failed to identify one male pregnancy. Follow-up was carried out on 13 ongoing
pregnancies and no maternal or fetal complications were discovered. This study
demonstrates that fetal chromosome numeration can be carried out using FISH on
uterine lavage samples in early pregnancy. However, a specific fetal cell marker,
such as specific anti-trophoblast antibody, is necessary to avoid a false
negative result.
PMID- 9399351
TI - Prenatal diagnosis of 22q11 microdeletion.
AB - Microdeletion of 22q11 is responsible for DiGeorge syndrome, velocardiofacial
syndrome, congenital conotruncal heart defects, and related disorders. Familial
transmission accounts for about 10-20 per cent of cases and most of the parents
with deletions are nearly asymptomatic. This phenotypic variability makes it
difficult to give appropriate genetic counselling. We report our experience on
prenatal diagnosis of 22q11 deletion. We proposed prenatal detection of 22q11
microdeletion in 33 pregnancies. In two instances the parents refused prenatal
diagnosis and one pregnancy ended spontaneously before the time of sampling.
Fluorescent in situ hybridization (FISH) analysis on cultured amniotic cells with
probes mapping in the commonly deleted region was used in the remaining 30 cases.
Indications were classified into two groups. The first group included four
couples with an abnormal family history of a deleted child and/or a deleted
parent. No deletion was found in this group. The second one concerned pregnancies
with a prenatally detected heart defect. Among these pregnancies with abnormal
ultrasound findings, three deletions were found in the 26 samples tested.
PMID- 9399352
TI - Maternal serum alpha-fetoprotein and human chorionic gonadotropin in pregnant
women with acute parvovirus B19 infection with and without fetal complications.
AB - Maternal serum alpha-fetoprotein (MS-AFP) and human gonadotropin (MS-hCG) were
retrospectively determined in 137 sera from 65 pregnant women with an acute
parvovirus B19 infection. In 35 of the pregnant women, fetal complications
occurred (group 1); in the remaining 30 women, there were no fetal complications
(group 2). In group I, significant elevations of MS-AFP were detected in 13 of
the 35 women (37 per cent) and of MS-hCG in 25 of the 35 women (71 per cent). In
nine of those women, sera were obtained before occurrence of fetal complications
and MS-AFP was elevated in one case and MS-hCG in four cases. In one woman, both
MS-AFP and MS-hCG were elevated. In group 2, significant elevations of MS-AFP
were found in two of the 30 women (6-7 per cent) and of MS-hCG in five of the 30
women (16.7 per cent). Neither MS-AFP nor MS-hCG appears to be a regular early
marker for poor pregnancy outcome in parvovirus B19-infected pregnancies,
although they were frequently elevated at the time of complications.
PMID- 9399354
TI - Ultrasound imaging of fetal neck anomalies: implications for the risk of
aneuploidy and structural anomalies.
AB - This study summarizes 24,000 transvaginal ultrasound examinations which were
performed in a predominantly low-risk population at 14-16 weeks' gestation. 1254
(5.2 per cent) fetuses had a nuchal fold or a non-septated cystic hygroma. Of
these fetuses, 140 (11.1 per cent) had additional structural anomalies.
Cardiovascular anomalies were the most commonly detected structural
malformations. Forty-three (3.4 per cent) fetuses were aneuploid. Trisomy 21 was
the most common chromosomal anomaly (n = 27). Aneuploidy was significantly more
common in fetuses who had a nuchal finding and an associated structural anomaly.
The prevalence of nuchal fold and non-septated cystic hygroma, as well as the
incidence of their associated structural anomalies, was similar. Based on these
data, it is concluded that a complete ultrasonic survey of the fetus and
karyotyping are advocated in fetuses with a nuchal abnormality, irrespective of
maternal age or triple serum screening results.
PMID- 9399353
TI - Prenatal diagnosis of congenital toxoplasmosis in 261 pregnancies.
AB - Two hundred and sixty-one pregnant women underwent prenatal screening by
cordocentesis and/or amniocentesis between 1987 and 1994. The following tests
were used: (i) detection of anti-Toxoplasma gondii IgM, IgA, and IgE antibodies
by immunocapture and the comparative immunological profile method based on enzyme
linked immunofiltration assay of fetal blood and (ii) direct detection of the
parasite in cell culture and by mouse inoculation with fetal blood (FB) and/or
amniotic fluid (AF). Of the 31 cases of congenital toxoplasmosis, 24 (77 per
cent) were detected prenatally. Overall, the FB and AF inoculation methods were
the most effective (50 per cent sensitivity with FB inoculation to mice and/or
cell culture and 74 per cent with AF). However, antibody detection in FB was the
only positive test in three cases. Of 18 surviving children diagnosed prenatally,
only one developed chorioretinitis (9 months of age). Seven newborns (23 per
cent) with negative prenatal tests were diagnosed by postnatal laboratory
monitoring, but none of these children developed clinical toxoplasmosis. There
may have been more false negatives, as only 48 per cent of unaffected children
were followed up for at least 12 months. All the tests had a specificity of 100
per cent. Fetal blood sampling has considerable value but also carries some risks
and is currently being abandoned in favour of amniocentesis alone with gene
amplification and mouse inoculation.
PMID- 9399355
TI - A magnetic colloid system for isolation of rare cells from blood for fish
analysis.
AB - To improve cell recovery of trophoblast and nucleated red blood cells from
maternal blood for diagnosis of chromosomal abnormalities, we have investigated
the use of a magnetic sorting system that utilizes a ferrofluid. The main
advantage of this system is that the beads used are small enough to allow
visualization of chromosome-specific sequences by fluorescence in situ
hybridization (FISH). The ferrofluid was validated using MAb340, a trophoblast
specific antibody, and anti-CD71, used to sort for nucleated red blood cells.
Antigen-positive cells could be efficiently sorted from a 1000-fold excess of
antigen-negative cells and easily stained by FISH. We are currently evaluating
its use on maternal blood samples.
PMID- 9399356
TI - Expect the worse or hope for the best? Prenatal diagnosis of geleophysic
dysplasia.
AB - Geleophysic dysplasia is a rare, autosomal recessive disorder which causes
disproportionate short stature associated with severe physical handicaps, but is
compatible with survival into adulthood. We present a case, a first-born child,
where genetic counselling difficulties arose following ultrasound recognition of
short-limbed dwarfism in association with polyhydramnios and an initial incorrect
prenatal diagnosis of lethal chondrodysplasia. After birth of the surviving
affected infant, the parents had great difficulty accepting that there had been a
prenatal misdiagnosis and they were greatly disappointed by our inability to
predict the postnatal survival of an infant to whom no hope of life had
previously been given. The correct diagnosis was not made until the proband was
nearly 1 year old, and the true prognosis then became clearer. This experience
underlines the relative ease of prenatal recognition of skeletal growth
abnormalities compared with the considerable difficulties experienced in reaching
a precise diagnosis. Thus, following prenatal diagnosis of unspecified
chondrodysplasia when parents seek definite information about the prognosis, the
temptation to be either overpessimistic or overoptimistic should be avoided.
PMID- 9399357
TI - Prenatal diagnosis of a fetal head and neck neoplasm: differential diagnosis,
management, and histology.
AB - A fetal head and neck malignancy was prenatally diagnosed. The parents allowed
the fetus to die during labour, due to the poor prognosis. We discuss the
corresponding pathology findings, differential diagnosis, and management of this
rare entity. Prenatal diagnosis of fetal neoplasms theoretically improves
outcome, although this was not true in our case.
PMID- 9399358
TI - Glycosaminoglycan analysis in amniotic fluid and in cultured fibroblasts from
normal and holoprosencephalic human embryonic organs.
AB - Glycosaminoglycans are polysaccharides involved in epithelial-mesenchymal
interaction and cell differentiation and provide a meshwork which is essential to
maintain a proper intercellular milieu. The development of embryonic organs can
be accompanied by alterations in the glycosaminoglycan pattern. In pregnancies
with malformed fetuses, there are alterations in total glycosaminoglycans and
their components (chondroitin 4-6 sulphate, dermatan sulphate, and hyaluronic
acid) in amniotic fluid. We examined total glycosaminoglycans and the percentage
variations of the single classes in both amniotic fluid and culture medium of
fibroblasts from heart, lung, and skin obtained from five normal human fetuses
and one with holoprosencephaly. In the amniotic fluid total glycosaminoglycans
and their sulphate classes were increased, whereas hyaluronic acid was decreased,
compared with controls. The extracellular glycosaminoglycans showed hyaluronic
acid reduction in skin, while chondroitin 4-6 sulphate plus dermatan sulphate and
heparan sulphate were higher in skin and heart. Our data demonstrate that
variations in the glycosaminoglycan pattern are associated with alterations of
the cellular environment, which can prevent normal organogenesis.
PMID- 9399359
TI - Prenatal ultrasonographic and molecular diagnosis of Apert syndrome.
AB - Apert syndrome is a rare craniosynostosis syndrome with significant bilateral
syndactyly of the hands and feet. Usually it is detected by ultrasonography
during the third trimester unless there is a family history. We present an
interesting sporadic case with features consistent with Apert syndrome detected
as early as the first trimester. A first-trimester ultrasound evaluation prior to
chorionic villus sampling (CVS) for maternal age 41 was within normal limits
except for the suggestion of a 'mitten-like' hand and proximally placed thumb.
Mid-trimester ultrasound was not diagnostic; however, following the development
of polyhydramnios in the third trimester, the evaluation of the digits and facial
features were strongly suggestive of Apert syndrome. Amniocentesis was performed
and a molecular diagnosis of Apert syndrome was made and confirmed on cord blood.
PMID- 9399360
TI - Maternal serum alpha-fetoprotein and human chorionic gonadotrophin in a pregnancy
complicated by fetal sacrococcygeal teratoma.
PMID- 9399361
TI - A 46,XX,der(13;14)(q10;q10),+21 child born after a 45,XX,der(13;14)(q10;q10)
chromosomal finding in CVS.
PMID- 9399363
TI - Current awareness in prenatal diagnosis.
PMID- 9399362
TI - Maternal serum alpha-fetoprotein levels in congenital nephrosis.
PMID- 9399364
TI - Benzodiazepine self-administration in humans and laboratory animals--implications
for problems of long-term use and abuse.
AB - Drug reinforcement may represent the primary behavioral-pharmacological mechanism
underlying two types of problematic use of benzodiazepines--recreational abuse by
polydrug abusers and inappropriate chronic use by patients. High dose polydrug
abuse for the purpose of getting high is readily recognized as a significant
social problem. Inappropriate chronic benzodiazepine use is more subtle but
relatively common: for anxiolytics, 36% of past-year users (3% of the adult
population in the US) report using these drugs for 4 consecutive months or
longer. The risks of such long-term use are much better documented than the
benefits. This paper provides a current review of various problems that have been
identified with the long-term use and the recreational abuse of benzodiazepines,
including memory impairment, risk of accidents, falls and hip fractures in the
elderly, a withdrawal syndrome, brain damage, overuse in the elderly, overuse by
chronic pain patients, overuse by alcoholics and recreational abuse among
alcoholics and polydrug abusers. A comprehensive review of the literature on
benzodiazepine reinforcing effects in humans and laboratory animals is also
provided. Drug self-administration studies in humans and laboratory animals
provide models of both types of problematic benzodiazepine use. Recreational
abuse of benzodiazepines has been modeled in human research with polydrug abusers
and in laboratory animal studies, which show that the reinforcing effect of
benzodiazepines is intermediate relative to other sedative compounds and is
increased in subjects with histories of previous sedative drug self
administration. The problem of inappropriate long-term use of benzodiazepines by
people without histories of drug abuse has been partially modeled in human
studies showing that benzodiazepines function as reinforcers in subjects with
anxiety, insomnia, and histories of moderate alcohol consumption, and in
preclinical studies showing stable, low-rate benzodiazepine self-injection with
concurrent physical dependence under conditions of continuous availability. Both
human and animal research suggests that the drug history and current behavioral
context may be important in the establishment of benzodiazepines as reinforcers.
Limited human and animal research provides little support for the common belief
that physical dependence enhances benzodiazepine reinforcement.
PMID- 9399365
TI - Effects of cocaine and quinpirole on perceptual and motor functions in baboons.
AB - The effects of cocaine and quinpirole were studied in baboons to determine
whether quinpirole, a relatively selective D2/D3 dopamine agonist, produced
effects similar to those of cocaine on perceptual and motor processes. To measure
perceptual and motor function, three baboons were trained to discriminate
differences between a standard vowel and four other synthetic vowels: response
accuracy as well as response latencies, or "reaction times", were measured
following drug administrations. Cocaine reduced reaction times in two baboons,
and did not affect reaction times in a third; on the other hand, quinpirole
lengthened reaction times in a dose-dependent manner in all baboons. Cocaine and
quinpirole also differed in the time course to produce the maximal reaction time
effect following drug administration. Cocaine and quinpirole did not differ
consistently in their perceptual effects, as indicated by similar changes in d',
a signal-detection index of discriminability. These distinct profiles of effects
for cocaine and quinpirole suggest differing neurochemical actions for these two
drugs.
PMID- 9399366
TI - Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3
0593.
AB - Endogeneously occurring neuroactive steroids, metabolites of progesterone and
deoxycorticosterone, have been shown previously to interact with the GABAA
receptor with great specificity in vitro and to have anticonvulsant, anxiolytic
and sedative activity in vivo. However, these endogenously occurring steroids are
not useful as therapeutic agents due to their potential metabolism to hormonally
active steroids and their poor oral bioavailability. In an attempt to develop
therapeutic agents which would maintain the pharmacological profiles of
endogeneous neuroactive steroids but with increased oral bioavailability and
reduced metabolic liability, we explored simple substitutions at the 3 beta
position of the endogenous neuroactive steroid, 3 alpha-hydroxy-5 alpha-pregnan
20-one (3 alpha, 5 alpha-P). This report describes part of the in vitro and in
vivo pharmacological profile of a 3 beta-substituted analog, 3 beta-ethenyl-3
alpha-hydroxy-5 alpha-pregnan-20-one (Co 3-0593). The compound exhibited
anticonvulsant activity against pentylenetrazol-induced seizures in mice and rats
(ED50 = 5.6 and 11.5 mg/kg, i.p., respectively). Co 3-0593 showed robust
anxiolytic effects, comparable to benzodiazepines in the Geller-Seifter test
after both SC and oral administration. Furthermore, the anxiolytic activity was
maintained after chronic administration suggesting an absence of tolerance. The
compound did not affect the acquisition of a learned response at both
anticonvulsant and anxiolytic doses. However, at higher doses the compound showed
rotorod deficit which was further enhanced by ethanol. In summary, 3 beta-ethenyl
substituted 3 alpha, 5 alpha-P appeared to maintain the pharmacological
activities of the endogenous neuroactive steroid with apparent oral activity.
PMID- 9399367
TI - Blockade of pre- and post-synaptic 5-HT1A receptors does not modify the effect of
fluoxetine or 5-hydroxytryptophan on ethanol and food intake in rats.
AB - Selective serotonin reuptake inhibitors (SSRIs) or serotonin precursors inhibit
ethanol and food intake by increasing the synaptic availability of 5-HT in the
central nervous system. However, these agents can also increase 5-HT levels at
somatodendritic 5-HT1A autoreceptors, with negative effects on serotonergic
transmission. (+)WAY100135 [N-ter-butyl 3-4-(2-methoxy-phenyl) piperazin-1-yl-2
phenylpropanamide dihydrochloride] is a selective antagonist both at pre- and
post-synaptic 5-HT1A receptors. The present study investigated the effect on
ethanol and food intake of (+)WAY100135, given alone or coadministered with the
SSRI fluoxetine or the 5-HT precursor 5-hydroxytryptophan (5-HTP) in genetically
selected alcohol-preferring rats. Blockade of presynaptic 5-HT1A receptors after
injection of (+)WAY100135, 0.1 or 1 microgram/rat, into the dorsal raphe did not
significantly modify ethanol, food or total fluid intake. The same doses of
(+)WAY100135 did not modify the inhibition of ethanol and food intake induced by
intraperitoneal (i.p.) injection of fluoxetine, 5 mg/kg. Subcutaneous (s.c.)
administration of (+)WAY100135 (1 or 10 mg/kg) did not affect the 3-h, or the
overnight intake of ethanol, food or total fluids. Given together with i.p.
fluoxetine (5 mg/kg) or s.c. 5-HTP (100 mg/kg plus carbidopa. 12.5 mg/kg), the
same s.c. doses of (+)WAY100135 did not modify their inhibitory effect on ethanol
and food consumption. Present findings suggest that blockade either of pre- or of
pre- and postsynaptic 5-HT1A receptors does not potentiate the inhibitory effect
of fluoxetine or 5-HTP on ethanol and food intake.
PMID- 9399368
TI - Differential effects of ondansetron and alpha-flupenthixol on responding for
conditioned reward.
AB - Previous experiments have suggested that 5-HT3 antagonists such as ondansetron
may alter reward-related behaviour that is dependent in part upon raised
mesolimbic dopamine activity. However, the evidence for this is far from
conclusive. One major behavioural role of dopamine is in the control of behaviour
elicited by conditioned rewarding stimuli. To date, the effects of 5-HT3
antagonists on this function of mesolimbic dopamine have not been examined. Two
experimental procedures were employed to examine the effects of ondansetron (10
and 100 micrograms/kg) on the acquisition of responding for conditioned reward,
and on the response potentiating effect of intra-accumbens d-amphetamine (10
micrograms). These effects were compared to those elicited by the dopamine
antagonist alpha-flupenthixol (0.1 mg/kg). In the first procedure, rats were
trained to associate food pellet delivery with a conditioned stimulus (CS). Rats
subsequently allowed to respond on a lever delivering this CS, and on an inactive
lever, showed a greater preference for the lever delivering the CS, indicating
that this CS functioned as a conditioned reward (CR). Ondansetron administered
during the conditioning phase did not alter subsequent responding for the CR, but
alpha-flupenthixol induced a small but significant reduction in responding on the
CR lever. These results suggest that blockade of dopamine receptors, but not 5
HT3 receptors interfere with the learning of stimulus reward relationships. In
the second procedure, d-amphetamine injected into the nucleus accumbens markedly
potentiated responding for CR. Ondansetron at 10 micrograms/kg induced a small
attenuation of this effect, without altering responding in its own right.
However, at a higher dose (100 micrograms/kg) ondansetron plus amphetamine
treatment significantly enhanced responding on the inactive lever. At both doses,
the net effect of ondansetron was to produce a subtle impairment in the
allocation of responses such that the differential responding on the CR versus
NCR lever was diminished. In contrast to these effects alpha-flupenthixol
significantly attenuated d-amphetamine's selective enhancement of responding for
conditioned reward, as well as impairing the ability of the conditioned reward to
elicit and maintain behaviour. These results confirm the role of dopamine in
responding for conditioned reward, and suggest a possible modulators role for 5
HT3 receptors in this process. However, the effects of ondansetron on the
acquisition of, and responding for, conditioned reward are clearly different from
those induced by blockade of dopamine receptors.
PMID- 9399369
TI - A behavioural analysis of the delayed non-matching to position task: the effects
of scopolamine, lesions of the fornix and of the prelimbic region on mediating
behaviours by rats.
AB - The delayed non-matching to position task (DNMP) is a widely used automated test
of spatial memory, yet its validity has been challenged by suggestions that
animals use motor mediating behaviours which facilitate correct responding. This
possibility was systematically studied by analysing video recordings of rats
displaying delay-dependent and delay-independent deficits following lesions or
drug manipulations. Rats were first trained to perform the DNMP task and whilst
untreated, a number of potential mediating behaviours were identified from the
video recorded behaviour. Two independent raters recorded any apparent motor
strategies and attempted to predict the response the animals made during the
choice phase of the task by viewing only behaviour during the delay periods.
Subsequently, the behaviour of the same animals was examined following
scopolamine treatment and following lesions of the prelimbic cortex or of the
fornix. The experiment confirmed previous reports of delay-dependent and delay
independent deficits under the varying conditions (drug, lesions), but also
revealed that rats use clearly identifiable mediating behaviours that appear to
facilitate correct responding in the DNMP task. Consequently, apparent "memory"
impairments in the DNMP task, may reflect a disruption of behavioural strategies
used by the animal to assist in performing the task.
PMID- 9399370
TI - Ethanol attenuation of morphine dependence: comparison to dizocilpine.
AB - Recent studies indicate that morphine dependence, assessed as the severity of
naloxone-precipitated opiate withdrawal in rats, is attenuated by dizocipline, a
non-competitive, excitatory amino acid antagonist. Because ethanol is a putative
excitatory amino acid antagonist, the present study compared the effects of co
administration of ethanol to that of dizocilpine on morphine dependence. Rats
were administered morphine (10 mg/kg) twice daily for 9 days. One group received
ethanol (1 g/kg) co-administration, another received dizocilpine (0.05 mg/kg) co
administration, and a third served as vehicle controls. On day 10, all rats
received naloxone (4 mg/kg) injections and ratings of several classic signs of
opiate withdrawal were made. Both ethanol- and dizocilpine-treated rats showed
significantly less severe precipitated opiate withdrawal overall, with the
ethanol group showing reduced ratings of some specific signs. These results
demonstrate that ethanol, like dizocilpine, attenuates the development of
morphine dependence. The results are consistent with the action of ethanol at
glutamate receptors.
PMID- 9399371
TI - The effects of food deprivation and incentive motivation on blood glucose levels
and cognitive function.
AB - The current study investigated the relationships between blood glucose levels,
mild food deprivation, sympathetic arousal, and cognitive processing efficiency.
Subjects (n = 82) were randomly assigned to four experimental conditions,
comprising combined manipulations of food deprivation and incentive motivation.
Baseline and mid-session measurements of blood glucose, blood pressure and pulse
rate were taken. Subjects completed a number of measures of cognitive processing
efficiency and self report measures of affective and somatic state. Although
glucose levels were lowered following food deprivation, there was no significant
detrimental effect of food deprivation on task performance. However, improved
recognition memory processing times were associated with deprivation. Incentive
motivation was associated with faster simple reaction times and higher diastolic
blood pressure. There were no significant relationships between glucose levels
and task performance, further supporting the hypothesis that the brain is
relatively invulnerable to short food deprivation.
PMID- 9399373
TI - The mechanism of action of alpha 2 adrenoceptor blockers as revealed by effects
on open field locomotion and escape reactions in the shuttle-box.
AB - The precise mechanism of action of alpha 2 adrenoceptor blockers in not known,
although in principle they have two main effects: (i) they stimulate the
norepinephrinergic system by inhibiting the negative feed back of norepinephrine
release (presynaptic effect) and (ii) they inhibit the effects of norepinephrine
on postsynaptic alpha 2 adrenoceptors. We postulate that if the presynaptic
actions of the antagonists prevail, the enhanced norepinephrine release leads to
an activation of postsynaptic alpha 1 or beta adrenoceptors. In this case the
effects of alpha 2 adrenoceptor blockers can be reversed by antagonists acting on
the latter two adrenoceptors, since postsynaptic alpha 2 adrenoceptors are also
blocked. If the postsynaptic blockade of alpha 2 adrenoceptors is the main cause
of effects, than the blockade of alpha 1 or beta adrenoceptors should not reverse
the action of alpha 2 blockers. The alpha 2 blocker idazoxan (dose 0.5-5 mg/kg)
increased locomotor activity in an open field, an effect that was abolished by
both alpha 1 and beta receptor blockers (prazosin and propranolol, respectively).
Escape responses in a shuttle box were strongly suppressed by idazoxan (0.5-2
mg/kg). However, this effect was not changed by concomitant alpha 1 or beta
receptor blockade. These results suggest that the mechanism of action of alpha 2
adrenoceptor blockers depends on which effects are studied. Exploration seems to
be affected by a presynaptic mechanism as neurons bearing postsynaptic alpha 1 or
beta adrenoceptors are involved in the control of this behavior, while escape
reactions appear to be affected by the postsynaptic blockade of alpha 2
adrenoceptors (i.e. neurons bearing postsynaptic alpha 2 adrenoceptors are
involved in its control). Thus, there is no generalized mechanism of action for
alpha 2 adrenoceptor blockers; their precise mode of action should be
investigated in each particular case.
PMID- 9399372
TI - Effects of scopolamine on delayed-matching-to-sample and paired associates tests
of visual memory and learning in human subjects: comparison with diazepam and
implications for dementia.
AB - Two experiments examined dose-related effects of 200, 400 and 600 micrograms
scopolamine (n = 24, s.c.) and 5 and 10 mg diazepam (n = 6, PO) on parallel tests
of visual memory and learning taken from the CANTAB battery. Scopolamine
significantly impaired accuracy of performance on a delayed matching to sample
test of visual recognition memory in a dose- and delay-dependent manner, but had
only marginal decremental effects on a test of visuospatial paired associates
learning. Scopolamine significantly lengthened decision times in a visual search
matching to sample task at the 400 and 600 micrograms doses, without
significantly affecting accuracy. The drug also impaired performance on tests of
spatial (on accuracy and response time measures) and pattern (on response time
only) memory. Most of the deleterious effects on scopolamine were removed by
covariance analyses with indices of subjective sedation, but the effects of
delayed matching accuracy and latency remained. By contrast, diazepam
significantly impaired paired associates learning but affected delayed matching
to sample in a delay-independent manner. These results suggest that scopolamine
can produce selective deficits in tests of short-term visual recognition memory
which do not depend on overall impairments in arousal and which contrast with
deficits in visual associative learning produced by diazepam. They have
implications for the pharmacological modelling of dementia and memory disorders
in man and for the neurochemical substrates of the short-term recognition memory
and associative learning for visual stimuli.
PMID- 9399374
TI - Psychotropic drug intake in residents newly admitted to nursing homes.
AB - While several surveys have shown that psychotropic drugs are frequently used by
nursing home residents, no studies have been performed to investigate whether the
rates of drug use increase during the stay in nursing homes or whether residents
have taken these drugs already before admission. Therefore, we investigated 262
residents admitted to rural and urban nursing homes in Austria for prevalence of
psychotropic drug intake before admission, shortly after admission, and 6 months
later. Two weeks after admission, 72.1% of the residents were being treated with
psychotropics, while 6 months later 79.0% were receiving these drugs. The
significantly higher rates of psychotropic drug use among the psychiatrically ill
and in those suffering from sleeping problems suggest that these drugs were
prescribed aptly, but residents without appropriate criteria for drug intake were
often also treated with psychotropics. During 3 months before admission to
nursing homes, 45.5% of the sample reported having taken psychotropics. In more
than half of residents without drug intake before admission, psychotropic
treatment was initiated within the first 2 weeks after admission, while during
the first 6 months after admission the rate of drug use increased only slightly.
This suggests that a large percentage of psychotropic intake is due to nursing
home orders.
PMID- 9399375
TI - Behavioural and biochemical adaptations to nicotine in rats: influence of MK801,
an NMDA receptor antagonist.
AB - Chronic exposure of rats to nicotine can result in sensitization to the stimulant
effects of nicotine on locomotor activity. At a biochemical level, chronic
exposure to nicotine increases the number of CNS nicotinic binding sites, and
this has been suggested as the basis for sensitization to nicotine. The present
experiment was conducted to examine the effects of MK801, an NMDA receptor
antagonist, on sensitization to nicotine. In addition, the hypothesis that MK801
may block behavioural sensitization by preventing the up-regulation of nicotinic
receptors was tested by measuring receptor numbers in the same individuals using
quantitative autoradiography with [3H]-cytisine and [3H]-MK801. Male Sprague
Dawley rats were chronically treated with nicotine (0.4 mg/kg s.c.) or saline
daily for 7 days. Over the next 2 days, in a counterbalanced order, rats were
challenged with nicotine (0.4 mg/kg s.c.) or saline and locomotor activity was
monitored. In saline-pretreated rats, nicotine produced a small increase in
activity. Nicotine-pretreated rats exhibited higher levels of activity following
a nicotine challenge. This sensitized response was attenuated in rats
administered MK801 (0.3 mg/kg i.p.) 30 min before each daily nicotine injection.
Rats pretreated with MK801 alone showed activity scores no different from saline
pretreated control groups. Biochemical studies revealed increased [3H]-cytisine
binding following chronic nicotine treatment; however, receptor increases were
significantly attenuated by MK801 pretreatment. Binding of [3H]-MK801 remained
unchanged across the four groups. The results suggest that MK801 prevents
behavioural sensitization to nicotine via the prevention of receptor up
regulation. Although the findings support the notion that receptor up-regulation
may be the basis for the increased responsiveness to nicotine, other
interpretations are possible.
PMID- 9399376
TI - Genetics, haloperidol-induced catalepsy and haloperidol-induced changes in
acoustic startle and prepulse inhibition.
AB - The acoustic startle response (ASR), prepulse inhibition (PPI) of the ASR and the
effects of haloperidol on the ASR and PPI were examined in C57BL/6J (B6) and
DBA/2 (D2) inbred mouse strains and their F1 and F2 progeny. The startle stimulus
was a 60-ms, 110-dB, 10-kHz tone; the prepulse stimuli were 20-ms, white noise
bursts at 56, 68 and 80 dB against a 50-dB background presented 100-ms before the
startle pulse. The B6 strain showed modest PPI (25-40%); in contrast, the D2
strain showed on average no PPI and numerous individuals showed prepulse
augmentation (PPA). The F2 progeny showed an intermediate PPI; however, the
extreme values ranged from 200% PPA to essentially 100% PPI. Haloperidol in dose
dependent fashion, increased PPI in both the B6 and D2 strains; the threshold
dose was in the range of 0.1-0.2 mg/kg. Raclopride (0.3 mg/kg), clozapine (2
mg/kg) and risperidone (0.4 mg/kg) also increased PPI in both strains. The
effects of haloperidol (0.4 mg/kg) on PPI in 140 F2 progeny were examined. For
all prepulse intensities, there were highly significant (r > 0.80) and negative
correlations between baseline PPI and the haloperidol-induced change in PPI.
Thus, those animals that showed the greatest PPA showed the greatest haloperidol
induced increase in PPI. There was, however, significant variance in the
haloperidol response; plots of the regression residuals showed the most and least
responsive animals differed by almost 100% in effect on PPI. The F2 progeny were
subsequently phenotyped for haloperidol-induced catalepsy. There was no
association between the variation in effects on catalepsy and PPI. However, it
was observed that those individuals with the poorest baseline PPI were catalepsy
non-responsive.
PMID- 9399377
TI - Sexual segregation in infant mice: behavioural and neuroendocrine responses to d
amphetamine administration.
AB - Individual differences arise from both genetic and epigenetic factors. The aim of
this study was to test whether pups raised in distinct socio-sexual conditions
would show different behavioural and neuroendocrine responses to d-amphetamine
(AMPH) administration upon placement in a novel environment. This issue was
addressed by testing infant CD-1 mouse pups of both sexes at three different
developmental ages [3, 8, or 18 postnatal (PND) days]. These pups were raised
from birth in all-male, all-female, or mixed-sex litters. AMPH effects were
assessed as a function of the hypothalamic-pituitary-adrenal (HPA) axis
activational state using litters that were either maternally deprived for 24 h
(DEP) or normally kept with the dam (NDEP). A concomitant maternal behaviour
score carried out on selected postpartum days showed that mothers taking care of
all-male litters were more often involved in Active nursing than those rearing
the mixed-sex ones, whereas the latter were found more often Laying still out of
the nest. Basal and stress-induced corticosterone (CORT) secretion was increased
in unisexually reared pups following maternal deprivation, an effect limited to
PND 3. In general, neuroendocrine and behavioural responses to AMPH were found to
be dissociated and were affected by sexual segregation only in conjunction with
maternal deprivation. On PND 3, AMPH injection (1 or 3 mg/kg, i.p.) decreased
CORT secretion in deprived unisexually reared subjects without affecting their
behaviour. As a whole, behavioural changes due to unisexual rearing were limited
to female subjects. On PND 8, unisexually reared females showed, upon maternal
deprivation, a generalized shift to the left in the dose-response curve to AMPH
for Crossing behaviour, while on PND 18 AMPH-induced stereotypies were
considerably reduced in sexually segregated females, especially following
maternal deprivation. Thus, maternal deprivation appeared to "sensitize" the
monoaminergic system to an AMPH challenge. The individual behavioural and
neuroendocrine profiles shown in response to a stressful challenge suggest that
changes in social stimulation early during development might produce subtle
shifts in the function of selected central monoaminergic systems.
PMID- 9399378
TI - Treatment of neuroleptic-induced akathisia with nicotine patches.
AB - We administered 14 mg nicotine patches to 16 patients, all non-smokers, who
displayed akathisia from antipsychotic drugs. On single-blind ratings, akathisia
appeared significantly reduced on days when patients were wearing the patches as
compared to the baseline day. These findings, if confirmed, may help to explain
the high rates of tobacco use among psychotic patients, and may suggest avenues
for the treatment of akathisia.
PMID- 9399379
TI - A time-activity baseline to measure pharmacological and non-pharmacological
manipulations of PCP-induced activity in mice.
AB - At critical doses of PCP (10 mg/kg i.p. in the present studies), locomotor
stimulation in mice is initially suppressed by short-lasting ataxia, albeit at
higher levels of activity than controls. This provides a time-activity baseline
of PCP-stimulated locomotion potentially sensitive to i) pharmacological
antagonism indicated by a change in the time-activity relationship to that seen
at lower PCP doses, ii) interaction with the ataxic phase resulting in further
decreases in activity similar to that seen at higher PCP doses and iii)
reductions in activity without a change in the time-activity relationship. This
baseline was explored using three manipulations employed in the clinical
management of PCP toxicity: treatment with a neuroleptic (haloperidol), a
benzodiazepine (chlordiazepoxide) and modification in environmental stimulation
(changing of lighting conditions). Both haloperidol (0.125-0.5 mg/ kg, i.p.) and
chlordiazepoxide (5-20 mg/kg i.p.) further reduced activity during the ataxic
phase of the PCP time-activity relationship qualitatively similar to the effects
of pentobarbital (20-40 mg/kg i.p.). Changing of lighting conditions from red to
white light resulted in significant reductions in levels of activity of PCP
treated animals but no change in the time-activity relationship. No manipulation
resulted in true reversal of the PCP induced time-activity relationship. The
results parallel the clinical findings that neuroleptic and benzodiazepine
administration have no specific effects upon PCP-intoxication and that
environmental manipulation may modify the degree of PCP stimulation. The time
activity baseline described may prove useful in the evaluation of the effects of
pharmacological and non-pharmacological manipulations of PCP-induced activity in
rodents.
PMID- 9399380
TI - Effects of hot tea, coffee and water ingestion on physiological responses and
mood: the role of caffeine, water and beverage type.
AB - Psychopharmacological studies using caffeinated beverages or caffeine have rarely
considered temporal effects on psychological and physiological function or the
specific contribution of caffeine, hot water, or beverage type to the observed
effects. The effect of 400 ml hot tea, coffee, and water consumption on systolic
and diastolic blood pressure (SBP and DBP), heart rate, skin conductance (a
measure of sympathetic nervous system activation), skin temperature, salivary
cortisol, and mood were monitored in 16 healthy caffeine-withdrawn (14 h)
subjects in a complete crossover design. Beverages were ingested with/without 100
mg caffeine and milk (tea/coffee only). Hot beverage ingestion rapidly increased
skin conductance and temperature (+1.7 degrees C) with peak effects observed only
10-30 min post-consumption. Caffeine in the beverage rapidly augmented skin
conductance responses but, in contrast to the effect of hot water, reduced the
skin temperature response and increased SBP (+2.8 mmHg) and DBP (+2.1 mmHg) 30-60
min post-consumption. Both caffeine and milk addition to beverages independently
improved mood and reduced anxiety 30 and 60 min post-consumption. Milk addition
had no other effects apart from attenuating the transient increase in
physiological responses associated with the drinking phase. There were no effects
of beverage consumption on salivary cortisol or of beverage vehicle on salivary
caffeine levels, the latter indicating that caffeine pharmacokinetics was similar
in both tea and coffee, and not different from caffeinated water. In keeping with
this, the responses to tea and coffee ingestion were similar and largely
accounted for by the effects of hot water and caffeine. However, tea potentiated
the increase in skin temperature compared to coffee and water indicative of a
greater vasodilatory response plausibly related to the presence of flavonoids in
tea. We conclude that ingestion of hot caffeinated beverages stimulates
physiological processes faster than hitherto described, primarily via the effects
of hot water and caffeine, but with beverage type and milk playing important
modulatory roles.
PMID- 9399381
TI - Corticotropin-releasing factor binding sites in cortex of depressed suicides.
AB - Corticotropin-releasing factor (CRF) receptors were measured by saturation
binding in frontal and motor cortex of suicides with a firm retrospective
diagnosis of depression, and matched controls. The suicides were divided into
those who were free of antidepressant drugs, and those in whom prescription of
antidepressant drugs was clearly documented. There were no differences in the
number or affinity of CRF receptors between antidepressant-free or antidepressant
treated suicides and matched controls in either brain region. When suicides were
divided according to violence of death, again there were no differences between
violent or non-violent suicides and controls.
PMID- 9399382
TI - Effect of central 5-hydroxytryptamine depletion on performance in the "time-left"
procedure: further evidence for a role of the 5-hydroxytryptaminergic pathways in
behavioural "switching".
AB - This experiment examined the effect of destruction of the ascending 5
hydroxytryptaminergic (5HTergic) pathways on performance in a free-operant timing
schedule: the "time-left" procedure. Rats received either injections of 5,7
dihydroxytryptamine into the dorsal and median raphe nuclei or sham lesions. They
were trained in a discrete trials schedule in which reinforcers were provided for
responding on either of two levers, A and B. At a random time point, t s after
the start of each trial, a response on A resulted in the delivery of one food
pellet after dA s, whereas a response on B resulted in the delivery of two
pellets after 60-t s. The value of dA was varied between 1 and 8 s in different
phases of the experiment. Both groups showed decreasing response rates on lever A
and increasing response rates on lever B as a function of time within the trial.
An index of timing (T75: the time within the trial at which relative response
rate on B attained a value of 75%) was systematically related to the value of dA,
but did not differ significantly between lesioned and control rats. However, the
lesioned group showed significantly higher rates of switching between response
alternatives than the sham-lesioned group at all values of dA. The levels of 5HT
and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats,
but the levels of noradrenaline and dopamine were not significantly altered. The
results provide further evidence that the ascending 5HTergic pathways may
contribute to the inhibitory regulation of switching between behavioural states.
PMID- 9399383
TI - Nicotine-induced decreases in VTA electrical self-stimulation thresholds:
blockade by haloperidol and mecamylamine but not scopolamine or ondansetron.
AB - The effects of repeated daily injections of (-)-nicotine (+) hydrogen tartrate
(mg kg-1 s.c.) on electrical self-stimulation of the ventral tegmental area were
investigated. Nicotine reduced the frequency required to maintain half-maximal
response rates with animals responding in rate-frequency threshold tests. Under
these conditions, nicotine induced an increase in the total number of self
stimulation responses per session, but had no statistically significant effects
on the maximal response rate. These effects of nicotine were observed by the
second day of administration of this drug. Acute injections of the D2-like
dopamine receptor antagonist haloperidol (0.03 mg kg-1 s.c.) and of the nicotinic
acetylcholine receptor antagonist mecamylamine (1 mg kg-1 s.c.) attenuated the
effects of nicotine, indicating that the observed effects involve stimulation of
D2-like dopamine receptors as a result of nicotinic receptor activation. The
muscarinic acetylcholine receptor antagonist scopolamine (3 mg kg-1 s.c.) and the
serotonin 5-HT3 receptor antagonist ondansetron (0.01 and 0.1 mg kg-1 s.c.) did
not alter the effects of nicotine. The results of this study indicate that
repeated daily administration of (-)-nicotine increases the rewarding effects of
electrical self-stimulation of the ventral tegmental area. These data are
consistent with the proposal that repeated daily injections of nicotine
positively effect a mesolimbic dopaminergic substrate of reward.
PMID- 9399384
TI - Locomotor sensitization to quinpirole: environment-modulated increase in efficacy
and context-dependent increase in potency.
AB - This study examines whether behavioural sensitization to the dopamine agonist,
quinpirole, reflects an increase in the drug's potency and/or efficacy to induce
locomotion, and how these parameters are influenced by environmental context.
Three experiments were conducted in which animals received either chronic
quinpirole (10 x 0.5 mg/kg, twice weekly) or saline injections in either the home
cage environment, an alternate environment or the testing environment (activity
monitors), followed by a dose-response test for the expression of sensitization
in the activity monitors. Compared to the acute dose-response relationship,
chronic quinpirole increased the maximum response. This increase in efficacy was
significantly higher in animals treated with quinpirole in a non-home cage
environment compared to those that received chronic treatment in the home cage. A
leftward shift in the dose-effect function was observed only in animals with
prior drug experience in the testing environment. Results indicate that locomotor
sensitization to quinpirole reflects an environment-modulated increase in the
drug's efficacy, and an environment-dependent increase in drug potency. Efficacy
and potency may be subject to sensitization by non-associational and
associational mechanisms, respectively.
PMID- 9399385
TI - Dopaminergic mediation of the discriminative stimulus effects of bupropion in
rats.
AB - Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological
action of monoamine uptake inhibition. The drug resembles a psychostimulant in
terms of its neurochemical and behavioural profiles in vivo, but it does not
reliably produce stimulant-like effects in humans at clinically prescribed doses.
Bupropion binds with modest selectivity to the dopamine transporter, but its
behavioural effects have often been attributed to its inhibition of
norepinephrine uptake. This experiment examines monoaminergic involvement in the
discriminative stimulus effects of bupropion. Rats were trained to press one
lever when injected i.p. with bupropion (17.0 mg/kg), and another lever when
injected with saline. In substitution tests, dose-response curves were obtained
for several monoamine uptake inhibitors. Nine of ten dopamine uptake blockers
fully substituted for bupropion; the exception, indatraline (LU 19-005),
partially substituted (71% bupropion-appropriate responding). Serotonin and
norepinephrine uptake blockers (zimelidine and nisoxetine, respectively) produced
negligible or limited substitution, and the anti-muscarinic dopamine uptake
blocker benztropine produced limited partial substitution. A series of dopamine
D1-like and D2-like receptor agonists were also tested: only the D2-like agonist
RU 24213 fully substituted; three other D2-like agonists and four D1-like
agonists partially substituted (50% < drug responding < 80%). Antagonism of the
discriminative effects of bupropion was obtained with a D1- and a D2-like
dopamine antagonist. The results demonstrate strong similarities with those
obtained using other dopamine uptake inhibitors as training drugs, and support
the view that the behavioural effects of bupropion are primarily mediated by
dopaminergic mechanisms.
PMID- 9399386
TI - The significance and potential molecular mechanisms of gastrointestinal barrier
homeostasis.
PMID- 9399387
TI - Quality of life in patients with different types of functional constipation.
AB - BACKGROUND: Little information is available about the health-related quality of
life (QoL) in patients with different types of chronic constipation. METHODS: We
used two self-administered questionnaires, the Psychological General Well-Being
(PGWB) index and the Gastrointestinal Symptom Rating Scale (GSRS) to assess QoL
and gastrointestinal symptoms in 102 consecutive patients with chronic
constipation. The type of constipation was determined from transit time,
electrophysiologic investigation of sphincter function, anorectal manometry, and
defecography. RESULTS: Overall, our patients with constipation reported low
scores for general well-being (mean score, 85.5, compared with 102.9 in a healthy
population). Patients with normal-transit constipation (n = 49) reported
considerably lower scores in the PGWB than those with slow-transit constipation
(n = 35). The symptoms increased frequency of defecation, loose stools, and
urgent need for defecation were commoner in normal-transit constipation, which
indicates that this group may have a relation to the irritable bowel syndrome.
The overall PGWB index was strongly correlated with the total GSRS (P < 0.001).
CONCLUSIONS: The general well-being of patients with chronic constipation is
lower than that of a comparable normal population. Symptom severity correlates
negatively with perceived quality of life.
PMID- 9399388
TI - Osteoporosis after total gastrectomy. Results of a prospective, clinical study.
AB - BACKGROUND: Osteopenia and enhanced risk of fractures have been reported after
partial gastrectomy, but the significance of total gastrectomy is still unknown.
METHODS: Twenty-six patients were followed up for at least 3 years after total
gastrectomy. The intake and S-levels of vitamin D, phosphate, magnesium, and
calcium were prospectively studied, and a whole-body dual-energy X-ray
absorptiometry scan was performed at a mean of 5 years after gastrectomy.
RESULTS: At this time point we found normal blood levels of vitamin D, calcium,
and phosphate. Food intakes of phosphate, calcium, magnesium, and vitamin D
reached the recommended daily allowances. Bone mineral density was similar to
that of a control population, and increasing values were seen concomitant with an
increase in body weight with the time after gastrectomy. CONCLUSIONS: Calcium
homeostasis and bone mineral densities seem not to be affected by total
gastrectomy, at least when studied over a period of 5 years, an observation that
hypothetically can be explained by weight recovery with time after the operation.
PMID- 9399389
TI - Use of commonly prescribed antibiotics is not associated with prevalence of
Helicobacter pylori infection in adults.
AB - BACKGROUND: The aim of the study was to investigate the association of the use of
commonly prescribed antibiotics with prevalence of Helicobacter pylori infection
in a population of adult outpatients. METHODS: All patients aged 15-79 years who
visited the practice of a general practitioner (GP) between June and September
1996 in a suburban community near Ulm, a city in southern Germany, were asked to
participate in the study. Infection status was determined with a 13C-urea breath
test. In addition, the patients were asked to fill out a self-administered
questionnaire. RESULTS: Overall, 475 outpatients were included in the study
(response, 94.1%). A total of 266 patients (56.0%) reported a history of
antibiotic treatment within the past 5 years, whereas 147 patients (30.9%) did
not (62 patients (13.1%) did not know). Prevalence of infection in patients with
a history of antibiotic medication during the past 5 years was 23.3%, whereas the
prevalence of infection was 20.4% in subjects without antibiotic treatment (P =
0.283 after stratification for age). Control for other potential confounders by
multivariable analysis did not materially alter the results. CONCLUSION:
Coincidental antibiotic treatment is not associated with H. pylori prevalence in
adults.
PMID- 9399390
TI - The effect of cisapride in maintaining symptomatic remission in patients with
gastro-oesophageal reflux disease.
AB - BACKGROUND: Successful treatment of gastro-oesophageal reflux disease (GORD) has
traditionally been assessed as healing of reflux oesophagitis, which may not be
relevant in patients with moderate disease. In these patients symptom relief and
patient satisfaction with therapy are of fundamental importance. Cisapride has
well-documented prokinetic effects and may be well suited for long-term therapy
of GORD, but its effectiveness in purely symptomatic treatment is unknown. We
therefore compared two dosage regimens of cisapride with placebo over a period of
6 months in patients with evidence of gastrooesophageal reflux, initially treated
with antisecretory medication, with regard to maintaining symptom relief and
satisfaction with treatment. METHODS: Five hundred and thirty-five patients with
reflux oesophagitis grade 1 (n = 293) or 2 (n = 124) or with no reflux
oesophagitis but pathologic 24-h pH-metry (n = 118) achieved satisfactory symptom
relief with an H2-receptor antagonist or proton pump inhibitor within 4-8 weeks.
In a double-blind randomized, parallel-group study, they were then treated with
cisapride, 20 mg at night or 20 mg twice daily, or placebo and followed up for a
maximum period of 6 months. Relapse was defined as dissatisfaction with therapy
or an average consumption of more than two antacid tablets a day. RESULTS: Median
time to relapse was 63 days for cisapride, 20 mg twice daily; 59 days for
cisapride, 20 mg at night; and 49 days for placebo. Time to relapse was not
significantly different (P = 0.09). Presence and grade of oesophagitis at base
line, type of therapy before randomization, and pattern of non-reflux symptoms at
base line did not influence these findings significantly. CONCLUSION: The study
indicates that cisapride is of limited value in maintenance therapy of GORD in
patients in whom symptom relief has been accomplished with potent antisecretory
medication. This 'step-down' approach to therapy seems disadvantageous in the
long-term therapy of GORD.
PMID- 9399391
TI - Gastrointestinal motility disorders in patients with inactive Crohn's disease.
AB - BACKGROUND: Although some symptoms of Crohn's disease may be related to
gastrointestinal motility disorders, studies on gastrointestinal motility in
inactive Crohn's disease are lacking. METHODS: Fasting and postprandial motor
activity (1 h) was recorded in the gastric antrum and upper small intestine of 35
patients with inactive Crohn's disease and 18 controls, using conventional
manometry. RESULTS: Motor disorders were observed in 26 of 35 patients. The
number of phase-II contractions was reduced (1.3 +/- 0.7/min versus 1.8 +/-
0.6/min in controls; P < 0.02) (mean +/- standard deviation), whereas the
incidence of propagated single (2.2 +/- 3.2/h versus 0.5 +/- 0.6/h; P < 0.03) and
clustered contractions (3.8 +/- 7/h versus 1.1 +/- 1.4, P < 0.04) was markedly
increased. Motor abnormalities were more frequent and severe in patients with
Crohn's ileitis than in controls, and in patients with gastrointestinal symptoms
than in asymptomatic patients. CONCLUSION: Most patients with inactive,
uncomplicated Crohn's disease show marked gastrointestinal motor disorders,
characterized either by reduced incidence of small-bowel contractions and
increased incidence of single or clustered propagated contractions.
PMID- 9399392
TI - Effects of insulin-like growth factor-I administration on radiation enteritis in
rats.
AB - BACKGROUND: Acute radiation-induced damage to the small bowel occurs frequently
during abdominal radiotherapy. Since the small intestine is selectively
responsive to the growth-promoting effects of insulin-like growth factor-I (IGF
I), we investigated the effects of IGF-I administration on mucosal recovery from
radiation enteritis in the rat. METHODS: Rats received a single 10-Gy dose of
total abdominal irradiation followed by implantation of mini-pumps infusing
either IGF-I or vehicle for 4 days. After the rats had been killed, gut organs
were weighed before light microscopic and biochemical examination. RESULTS:
Irradiated rats receiving IGF-I lost less body weight than vehicle-treated rats,
whereas the wet weights of the stomach, small intestine, and colon were increased
by 10%, 19%, and 21%, respectively, and crypt depth was increased in the
duodenum, jejunum, and ileum. CONCLUSIONS: IGF-I administration after abdominal
irradiation increased small-intestinal mass and improved indicators of mucosal
integrity, suggesting acceleration of small-intestinal mucosal recovery from
radiation injury.
PMID- 9399393
TI - Intestinal obstruction after appendectomy.
AB - BACKGROUND: The frequency of intestinal obstruction varies in the literature (0.2
10.7%) and requires evaluation in a proper design. METHODS: From 1978 to 1985,
1951 patients underwent appendectomy; 58 patients were excluded because of
appendectomy per occasionem, 156 because of previous laparotomy, and 190 because
of simultaneous major surgery. Three foreigners were lost to follow-up. The
cohort was linked to the Danish National Inpatient Register for identification of
cases, defined by intestinal obstruction requiring surgical intervention.
RESULTS: The follow-up period was long (median, 3563 days; range, 2-5113). Twenty
one patients developed intestinal obstruction. The cumulated incidence was 0.33%
after 30 days, 0.79% after 1 year, and 1.51% after 14 years. Female sex as
compared with male sex (RR = 3.91; 95% confidence limits (CL), 1.25-12.0) and
removal of a removal of a normal appendix as compared with an inflamed appendix
(RR = 4.0; 95% CL, 1.28-12.5) carried a significantly higher risk of intestinal
obstruction. CONCLUSION: Intestinal obstruction after open appendectomy is rare.
PMID- 9399394
TI - High incidence and prevalence of adult coeliac disease. Augmented diagnostic
approach.
AB - BACKGROUND: The diagnosis of coeliac disease is easily overlooked as patients can
present with mild or atypical symptoms, or the condition can even be clinically
silent. Our aim was to detect coeliac disease patients with such atypical or no
symptoms as well as those with typical features. METHODS: The incidence of adult
coeliac disease in Tampere was calculated from 1975 to 1994 and the prevalence as
of 31 December 1994. Open-access endoscopy was available for general
practitioners, and small-bowel biopsy was done routinely. Serologic screening was
applied to patients with an increased risk of coeliac disease. RESULTS: The
incidence of coeliac disease increased tenfold, and the prevalence was 270 per
100,000 inhabitants in 1994. Twenty per cent were found by serologic screening
and 10% as a result of routine biopsy; 24% had dermatitis herpetiformis.
CONCLUSIONS: Our diagnostic approach gave a coeliac prevalence similar to that
found in population screening studies. One-third had silent coeliac disease.
PMID- 9399395
TI - Inflammatory bowel diseases: health care and costs in Sweden in 1994.
AB - BACKGROUND: Inflammatory bowel disease (IBD) has highly variable course and
severity. Since comprehensive data on its impact are scarce, we analyzed all IBD
care and costs in Sweden (population, 8.8 million). METHODS: A cross-sectional
observational study, using national registers and surveys on ambulatory care,
hospital admissions, medication, sickness leave, and early retirement for IBD in
1994, was carried out. We calculated direct health care costs and indirect 1-year
costs caused by morbidity. RESULTS: Ambulatory care was concentrated to
specialists in internal medicine at hospitals. One-fourth of the patients
accounted for 48% of 1994 hospital admissions. Medication was predominantly
aminosalicylates and steroids. Sickness leave episodes were long--on average, 6
weeks. Although uncommon, early retirements lasted 14 years on average. With
regard to the underlying prevalence, the use of health care and compensations by
Crohn's disease patients was two to four times that of patients with ulcerative
colitis. Morbidity took 68% of total costs. Among direct costs, admissions
accounted for 58%. Neither complications nor surveillance added much. CONCLUSION:
Ulcerative colitis is twice as common as Crohn's disease. In health care use,
these roles are reversed. Since morbidity causes two-thirds of the costs,
comprehensive analyses, including indirect costs, are necessary when evaluating
new diagnostics and therapies.
PMID- 9399396
TI - Prevalence of Helicobacter pylori infection and related upper gastrointestinal
lesions in patients with inflammatory bowel diseases. A cross-sectional study
with matching.
AB - BACKGROUND: Although a reduced prevalence of Helicobacter pylori infection has
been observed in inflammatory bowel disease (IBD) patients, the clinical
significance of H. pylori infection in this setting remains unknown. The aim of
this study was, therefore, to evaluate the prevalence of H. pylori infection in a
large series of IBD patients and the frequency of gastroduodenal lesions in those
who agreed to undergo upper GI endoscopy. METHODS: Two hundred and sixteen
consecutive IBD patients (123 with Crohn's disease (CD) and 93 with ulcerative
colitis (UC)) had their anti-H. pylori IgG titres measured. Two hundred and
sixteen blood donors matched for age, sex, place of birth in Italy, and
socioeconomic status served as controls. All patients were offered the
possibility of undergoing endoscopy with antral and corpus biopsies regardless of
their H. pylori status. RESULTS: The overall seroprevalence of H. pylori
infection was 48% in IBD patients versus 59% in the control group (P < 0.05),
with a significantly lower frequency in CD versus UC patients (41% versus 56%).
After adjustment for age, education, and socioeconomic status CD remained
associated with a significantly lower risk of H. pylori infection. Previous
therapy with sulphasalazine but not with 5-aminosalicylic acid or with
steroids/immunosuppressants was associated with a reduced risk of H. pylori
infection both in CD and UC patients. One hundred and eighty-nine patients (110
with CD and 79 with UC) underwent endoscopy; the prevalence of peptic ulcer was
similar in both groups (5.5% in CD and 5.1% in UC patients); however, 11 more CD
patients had gastroduodenal ulcers that were interpreted as CD-related; 7 of
these patients had never had foregut symptoms. Two CD patients had granulomatous
gastritis at histology, and another 16 patients with CD had H. pylori-negative
gastritis. CONCLUSIONS: IBD patients have a reduced prevalence of H. pylori
infection as compared with matched healthy controls; this appears mostly
attributable to a reduced frequency of H. pylori colonization in CD patients.
Previous use of sulphasalazine is associated with a reduced risk of infection
both in CD and UC patients. Of CD patients 10% have a gastroduodenal localization
of their disease, which is often asymptomatic. Of CD patients 15% also have H.
pylori-negative gastritis at histology.
PMID- 9399397
TI - Detection of p53 autoantibodies in sera of gastric cancer patients and their
prognostic relevance.
AB - BACKGROUND: Changes in the p53 gene product can be immunogenic and enable the
formation of p53 serum antibodies (p53ab), detectable in patients with different
cancer types. So far, there have been no reports describing the detectability of
p53ab in gastric cancer patients. METHODS: We investigated the presence of p53ab
and their clinical relevance in a cohort of 74 gastric cancer patients, using an
enzyme-linked immunosorbent assay system. RESULTS: In our investigation 20.3% of
all patients (15 of 74) and 46.9% of the patients with immunohistochemically
(IHC) p53-positive tumors (15 of 32) showed detectable p53ab in serum. All p53ab
positive patients had IHC p53-positive tumors. We have found a significant
correlation of p53ab with a higher tumor stage (P = 0.002) and also with a poor
prognosis of survival (P = 0.04). CONCLUSION: We have shown that in gastric
cancer patients p53ab are also detectable and that p53ab positivity is a
predictor of an unfavorable prognosis.
PMID- 9399398
TI - The anti-proliferative effect of plasma from rats with acute fulminant hepatic
failure.
AB - BACKGROUND: During fulminant hepatic failure (FHF) metabolites normally cleared
by the liver accumulate in the circulation and cause hepatic coma. It is believed
that the plasma of FHF patients has an inhibitory effect on liver regeneration.
Plasma exchange was used to study the effect of plasma collected from donor FHF
rats on liver regeneration in two-thirds partially hepatectomized syngeneic
animals. METHODS: FHF and hepatic coma were induced in donors by administration
of galactosamine at a dose of 1.85 g/kg. Plasma from donors in either grade-II or
-IV coma was transfused by plasma exchange into partially hepatectomized animals
2h after resection. RESULTS: The livers from donor animals showed evidence of
oval cell activation 1-2 days after galactosamine, but differentiation of oval
cells to hepatocytes did not occur before the development of coma. The plasma
collected from animals in grade-IV coma totally abolished regeneration in the
partially hepatectomized recipients. CONCLUSION: These results support the
hypothesis that metabolites present in the plasma during FHF inhibit liver
regeneration.
PMID- 9399399
TI - Frequent occurrence of non-specific gliadin antibodies in chronic liver disease.
Endomysial but not gliadin antibodies predict coeliac disease in patients with
chronic liver disease.
AB - BACKGROUND: The frequency of gliadin antibody (GA) positivity has been found to
be increased among patients with chronic liver disease, as has that of coeliac
disease (CD). CD has also been found to be increased among patients with primary
biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). METHODS: To
investigate these relationships further, a micro-enzyme-linked immunosorbent
assay and immunofluorescence tests for GAs and endomysial antibodies (EMAs) were
performed in large subgroups of patients representing various chronic liver
diseases and in healthy blood donors. RESULTS: As compared with blood donors
(among whom it was 5%) the frequency of IgA GA positivity was higher in all
patient subgroups: alcoholic liver disease, 20% (22 of 110, P < 0.001); PBC, 16%
(16 of 101, P < 0.001); PSC, 24% (19 of 80, P < 0.001); chronic hepatitis, 19%
(13 of 70, P < 0.001); and hepatitis C virus infection, 11% (11 of 104, P <
0.01). Two patients with autoimmune chronic hepatitis were EMA-positive, and in
both cases the presence of CD was verified by small-bowel biopsy. CONCLUSIONS:
IgA GA positivity generally occurs at increased frequency among patients with
chronic liver disease and may represent non-specific immune activation. In liver
disease GA testing is not useful in screening for CD, whereas the EMA test seems
to be highly specific. CD is more prevalent than expected among patients with
autoimmune chronic hepatitis but not among those with PBC or PSC.
PMID- 9399400
TI - Percutaneous ethanol injection in the treatment of hepatocellular carcinoma. A
multicenter survey of evaluation practices and complication rates.
AB - BACKGROUND: Percutaneous ethanol injection (PEI) has become a widely used
procedure in the treatment of hepatocellular carcinoma (HCC). However, the
criteria for selecting patients are not standardized, and little information is
available about the complications of the procedure. METHODS: A questionnaire was
sent to 11 experienced Italian centers. It investigated: the size and the number
of HCC nodules suitable for treatment and the Child-Pugh risk class of the
associated cirrhosis; the performance of the procedure; the number and
characteristics of the patients treated; and, finally, any complications.
RESULTS: Most of the centers performed PEI in single HCC nodules less than 5 cm
in diameter or in multiple nodules if fewer than three, the larger being less
than 3 cm. Patients in Child-Pugh's classes A, B, and C with single nodules were
generally considered for PEI. A prothrombin time of less than 40% and a platelet
count of less than 40,000/mm3 contraindicated PEI in most of the centers. PEI was
generally performed on outpatients, using Chiba or spinal needles. One thousand
and sixty-six patients (8118 sessions) were enrolled; 74% had a single HCC nodule
and 26% multiple nodules. All except four had cirrhosis; 53% were in Child class
A, 38% in class B, and 9% in class C. The mean number of sessions needed to
destroy an HCC nodule was 6.7 (range, 2-14), with a mean alcohol injection volume
of 5.0 ml per session (range, 2-20 ml). One death (0.09%) and 34 complications
(3.2%) were reported. Among the complications we call attention to the
hemorrhagic ones (eight cases) and tumoral seeding (seven cases). Severe pain
experienced during the maneuver led to discontinuation of the procedure in 3.7%
of the patients; 13.5% of the patients required analgesics and 24% had fever
after PEI. CONCLUSIONS: Some procedural aspects of PEI treatment differ among the
various centers a standardization is advisable. In the present survey PEI is a
low-risk technique.
PMID- 9399402
TI - Salmonellosis: an unusual complication of hepatocellular carcinoma.
AB - Salmonella abscess of a tumor is extremely rare, only three occurrences having
been described to date. An unusual case is presented in which Salmonella infantis
septicemia was the presenting symptom of multicentric hepatocellular carcinoma in
a previously healthy 67-year-old man.
PMID- 9399401
TI - Female sex and the risk of liver cirrhosis. Collaborative Groups for the Study of
Liver Diseases in Italy.
AB - BACKGROUND: Evidence on gender-related differences in susceptibility to alcohol
induced liver diseases is questionable with regard to both methodologic and
clinical aspects. With the aim to assess the role of gender in the risk of liver
cirrhosis, independently and in combination with known risk factors, data from
three case-control studies performed in various Italian areas were analysed.
METHODS: The cases were 462 cirrhotic patients (300 men and 162 women) admitted
for the first time to hospital for liver decompensation. Controls were 651
patients (355 men and 296 women) admitted to the same hospitals during the same
period as the cases, for acute diseases unrelated to alcohol. Alcohol consumption
was expressed as lifetime daily alcohol intake. RESULTS: A significant and
independent associations between alcohol intake, chronic hepatitis B and C virus
infections, and the risk of liver cirrhosis was observed. The effect of alcohol
intake was multiplicatively increased in women. The odds ratio (OR) increased
from 1.0 (reference category: men, lifetime abstainers) to 31.4 (95% confidence
interval (CI), 10.3-95.8) in men drinking more than 100 g/day of alcohol, and
from 2.2 (95% CI, 1.0-7.1) in abstaining women to 44.8 (95% CI, 8.2-224.0) in
women drinking more than 100 g/day of alcohol. An increased risk of liver
cirrhosis associated with female gender independently of alcohol consumption and
virus infection was also observed. CONCLUSIONS: A higher susceptibility to
alcohol-induced liver diseases was confirmed for women, and an independent effect
of female sex on the risk of cirrhosis was observed. Besides alcohol and viruses,
some unknown gender-related factor might then be involved in the occurrence of
the disease.
PMID- 9399403
TI - Helicobacter pylori and non-ulcer dyspepsia.
PMID- 9399404
TI - Biochemistry and pharmacology of low molecular weight heparin.
PMID- 9399405
TI - Low molecular weight heparins: prophylaxis of venous thromboembolism in surgical
patients.
PMID- 9399406
TI - Comparison of the relative efficacy and safety of low molecular weight heparin
and unfractionated heparin for the treatment of deep venous thrombosis.
PMID- 9399407
TI - Treatment of arterial thrombosis with low molecular weight heparins.
PMID- 9399408
TI - Low molecular weight heparins: practical considerations.
PMID- 9399409
TI - Low molecular weight heparins and antithrombotic therapy: results of an audience
interactive symposium.
PMID- 9399410
TI - Assembly of the dorsal horn somatotopic map.
AB - We hypothesize: (a) peripheral innervation densities determine map scales in
dorsal horn, (b) dorsal horn cell (DHC) receptive field (RF) geometries are
determined by map scales, and (c) morphologies of primary afferents (PAs) and
DHCs reflect their developmental history. We suggest the following sequence: (A)
PAs project in a somatotopic mediolateral sequence. (B) DHCs assemble prototype
RFs by sampling presynaptic neuropil with their dendrites. (C) PAs then project
to all levels where their RFs are contained within prototype RFs of DHCs. (D) A
competitive mechanism produces the adult form of DHC RFs. (E) Adult distributions
of PA terminals and DHC dendrites reflect this developmental history. (F)
Mediolateral somatotopic gradients are determined by RF densities of axons
entering at the same levels. (G) Map scales at different rostrocaudal levels are
determined by somatotopic gradients. (H) Geometries of DHC RFs are determined by
constant convergence and divergence of monosynaptic connections. (I) Secondary
processes further modify geometries of DHC RFs. (J) Residual self-organizing
capacity supports maintenance and plastic mechanisms. We adduce the following
evidence: (1) agreement between monosynaptically coupled inputs and cells'
excitatory low threshold mechanoreceptive fields; (2) the temporal sequence of
events during penetration of the gray matter by PAs; (3)variation of PA terminal
and DHC dendritic domains as a function of map scale; (4) somatotopic gradients
and geometries of DHC RFs in adult dorsal horn; (5) calculations of peripheral
innervation densities and dorsal horn map scales; and (6) constant divergence and
convergence between PAs and DHCs.
PMID- 9399411
TI - Spatial summation of perceived pressure, sharpness and mechanically evoked
cutaneous pain.
AB - Psychophysically, spatial summation can be demonstrated as a decrease in
threshold accompanying an increased field of stimulation. The present study
examined to what extent different mechanically evoked percepts (pressure,
sharpness, and pain) show spatial summation. Various probes were used to apply
prescribed forces to the dorsal surface of the digits of 19 healthy subjects. The
threshold for three perceptual qualities showed differing degrees of spatial
summation: sharpness showed no statistically significant spatial summation; pain
demonstrated some significant summation (46% on average); pressure showed the
greatest degree of spatial summation (76% on average). The lack of significant
spatial summation for sharpness threshold is consistent with the theory that
perceived sharpness can be evoked by near threshold activity of a single
nociceptor. The modest amount of spatial summation for pain implies that
distinctly suprathreshold activation of nociceptors is required for mechanically
evoked pain perception, and such input summates centrally, but not completely.
The greater spatial summation observed for pressure vs. pain thresholds implies a
greater degree of central summation for slowly adapting mechanoreceptors vs.
nociceptors.
PMID- 9399412
TI - Comparative psychophysical characteristics of cutaneous CO2 laser and contact
heat stimulation.
AB - Psychophysical visual analog scaling can be used to reveal critical determinants
of the neural processing underlying non-painful and painful heat sensations
produced by radiant and contact heat stimulation. This study determined the
stimulus-response (S-R) functions of cutaneous non-painful and painful heat
stimuli delivered by an infra-red CO2 laser or by a contact thermode in a series
of experiments in healthy volunteers. In experiments 1 (n = 12), with the rating
scale anchored at pain threshold, the S-R curve for brief (60 ms) laser pulse
stimulation with a beam diameter of 10 mm was a negatively accelerating function.
Transformation of laser stimulus intensity (W) into temperatures (degree C) did
not change the form of the S-R curve. In experiment 2 (n = 9), using the same
laser stimulus parameters as in experiment 1, but without an anchored rating
scale, the form of the S-R relationship did not change. In experiment 3 (n = 9),
increases of the laser pulse duration up to 5 s and the beam diameter up to 18 mm
produced linear S-R curves. In contrast, in experiment 4 (n = 21), the S-R curve
for cutaneous contact heat stimuli applied for 5 s with an 18 mm diameter probe
was best described by a positively accelerating power function with an exponent
greater than 2.0. These experiments have (1) characterized the S-R functions for
different parameters of infra-red laser stimulation of the skin, and (2) have
shown that the form of the S-R function for innocuous and noxious heat sensation
is influenced strongly by the physical conditions of heat stimulus application,
including mechanical contact with the skin.
PMID- 9399413
TI - Spatial summation of heat induced pain within and between dermatomes.
AB - The aim was to study spatial summation within and between ipsi- and contralateral
dermatomes at different painful temperatures. For heat stimulation we used a
computer controlled thermofoil based thermode. The thermode area could be varied
in five discrete steps from 3.14 to 15.70 cm2. When we applied the stimuli within
a dermatome, the mean heat pain threshold decreased significantly from 45.6 to
43.5 degrees C as the area was increased from minimum (3.14 cm2) to maximum
(15.70 cm2). When the areas were increased involving different dermatomes (both
ipsi- or contralateral), we found similar decreases in pain threshold. Spatial
summation was also found within and between dermatomes at supra-threshold
temperatures (46, 48, 50 degrees C). The study shows that spatial summation of
pain is most likely a mechanism acting across segments and is existing from pain
threshold to tolerance.
PMID- 9399414
TI - Mastication-related neurons in the orofacial first somatosensory cortex of awake
cats.
AB - In the orofacial area of the first somatosensory cortex (SI), we recorded single
unit activity from 699 neurons in 11 awake cats. Fifty-two percent (362/699) were
mastication-related neurons (MRNs) showing activity related to some aspects of
masticatory movements. MRNs were divided into three types by their activity
patterns: (1) the rhythmical type, showing rhythmical bursts in pace with the
masticatory rhythm; (2) the sustained type, showing a sustained firing during the
period of taking food and (3) the transient (biting) type, showing intense
discharges in coincidence with biting hard food. MRNs had mechanoreceptive fields
in the perioral, tongue, periodontal and mandibular regions. The activities of
perioral rhythmical-MRNs, mandibular transient-MRNs, tongue rhythmical-MRNs and
periodontal transient-MRNs were correlated with food texture, while perioral
rhythmical-MRNs, perioral sustained-MRNs and tongue sustained-MRMs were not. Both
facial and intraoral MRNs were scattered throughout the facial and intraoral
projection areas in SI. These findings provide evidence that the orofacial SI
monitors masticatory movements for food ingestion.
PMID- 9399415
TI - Activation of a wide-spread network of inhibitory neurons in barrel cortex.
AB - The one-to-one correspondence of whiskers to barrels in layer IV of rodent
somatosensory cortex can be demonstrated by a precise match between columns of
heavy 2-deoxyglucose (2DG) label in layer IV barrels and other layers which
correspond to stimulated whiskers. While there is specificity of peripheral-to
central mapping, the extent to which integration and/or modulation are generated
by circuitry within or interactions between the barrel-defined whisker columns is
not clear. Following stimulation of selected whiskers, large cells at the layer
IV-V boundary throughout the barrel field are heavily labeled by 2-deoxyglucose
(2DG) at high resolution. Many of these cells are outside the barrel columns of
the stimulated whiskers. Further, the number of cells labeled is not directly
related to the number of activated barrel columns. These neurons are not labeled
in animals anesthetized before 2DG injection and are not as heavily labeled in
barrel fields of somnolent animals. Most of the heavily labeled neurons
immunolabel for glutamate decarboxylase (GAD) and are presumed to be inhibitory,
while a smaller number of labeled neurons, presumed to be excitatory, immunolabel
for glutamate (Glu). Similar populations of large, heavily 2DG-labeled neurons
are found in other cortical areas. These relatively few neurons are exceptionally
active and may modulate integrative functions of cerebral cortex.
PMID- 9399416
TI - Benzene--a review of the literature from a health effects perspective.
AB - A literature review of the impact on human health of exposure to benzene was
conducted. Special emphasis in this report is given to the health effects
reported in excess of national norms by participants in the Benzene Subregistry
of the National Exposure Registry--people having documented exposure to benzene
through the use of benzene-contaminated water for domestic purposes. The health
effects reported in excess (p < or = .01) by some or all of the sex and age
groups studied were diabetes, kidney disease, respiratory allergies, skin rashes,
and urinary tract disorders; anemia was also increased for females, but not
significantly so.
PMID- 9399417
TI - Reproductive and neurobehavioral effects of chlorpropham administered to mice in
the diet.
AB - Chlorpropham was given in the diet to provide levels of 0(control), 0.15, 0.30,
and 0.60%, from 5 weeks of age of the F0 generation to 9 weeks of age of the F1
generation in mice, and selected reproductive and neurobehavioral parameters were
measured. There were no adverse effects of chlorpropham on either litter size or
litter weight and sex ratio at birth. The average body weight of offspring was
significantly affected in the low-dose group of each sex and in the high-dose
group of females, and was increased in the middle-dose group of males during the
lactation period. In neurobehavioral parameters, surface righting at postnatal
day (PND) 7 was significantly affected in male offspring in a dose-related
manner. Swimming head angle at PND 4 was significantly restrained in male
offspring in a dose-related manner, and olfactory orientation at PND 14 was
significantly depressed in female offspring in a dose-related manner. The dose
levels of chlorpropham in the present study produced some adverse effects in
reproductive and neurobehavioral parameters in mice.
PMID- 9399418
TI - The effects of carcinogenic methylcholanthrene on carbohydrate residues of NK
cells.
AB - The present study examines the effect of methylcholanthrene (MCA), a a
carcinogenic polycyclic hydrocarbon, on the carbohydrate receptor determinants
(RD) on natural killer (NK) cell surface using the bead-coupled lectin assay.
Murine NK cells exhibited different degrees of preferential binding to the
specific lectins tested. Of the ten lectins tested, five exhibited a positive
binding affinity while the remaining five exhibited no or insignificant binding.
NK cells bind to beads derivatized with mannose specific lectins: Concanavalin A
(Con A), Lens culinaris, and Pisum sativum. NK cells also bind to other lectin
beads such as Triticum vulgaris (GalNac) and Vicia villosa (D-GlcNAc). All these
lectin beads exhibited greater than 90% adhesion. The underivatized control beads
exhibited no NK binding. The NK cells that were exposed to MCA for 2 h
demonstrated a significant decrease in lectin bead-cell coupling in a dose
dependent manner. MCA (10 micrograms/mL) caused a 17.8%, 40% and 4.7% decrease in
binding affinity when introduced to the mannose specific lectins; Con A, L.
culinaris and P. sativum beads, respectively. The binding of T. vulgaris and V.
villosa to NK cells was inhibited (23.4% and 28%) by MCA treatment. An increase
in the dose to 20 micrograms/mL resulted in a greater inhibition in binding
affinity towards lectin beads. Con A, 35.3%, L. culinaris, 62.6%, P. sativum,
30.9%, T. vulgaris, 44.2% and V. villosa, 46.2%. The effect of MCA activation and
cytotoxic response. Hydrolysis of PI metabolites (PIP and PIP2) cause generation
of secondary messenger: inositol-1,4,5-triphosphate and diacylglycerol, both of
which elicit an immune response through their products (Ca2+ and PKC)
respectively. Identification of the relationship between receptor level,
induction of second messenger and cytotoxic activity may resolve the molecular
basis of suppression of NK cytotoxicity by MCA and other PAH compounds.
PMID- 9399419
TI - Reactive airway disease in patients with prolonged exposure to industrial
solvents.
AB - This study examines the effects of volatile organic compounds (VOCs) at the
workplace on pulmonary function tests. Forty-two patients with a history of
industrial exposure to organic solvents and pulmonary symptomatology were
studied. Lung function tests were determined utilizing screening spirometry lung
volumes, diffusion capacity and methacholine stimulation test. While only 10-15%
of the symptomatic patients had abnormal screening spirometry, 42% of the
patients had significantly abnormal methacholine stimulation tests. These data
show that exposure to volatile organic solvents is associated with bronchial
hyperreactivity not commonly detected by screening spirometry and requires
methacholine stimulation testing in individuals with unexplained symptomatology
and history of exposure to industrial solvents. These findings indicate that the
incidence of bronchial hyperreactivity is underestimated in patients with (1)
verifiable exposure history to volatile organic compounds known to be pulmonary
irritants, (2) pulmonary symptomatology with normal screening spirometry.
PMID- 9399420
TI - Determination of the distribution of malathion in rats following various routes
of administration by whole-body electronic autoradiography.
AB - The distribution of [14C]-malathion, an organophosphorus pesticide, in rats after
intravenous, oral and dermal administration was carried out using electronic
autoradiography of whole body sections of treated animals. The study indicated
that a major difference in the disposition of [14C]-malathion occurred following
various routes of administration to rats. Following intravenous administration,
the liver and kidney accumulated extremely high levels of the chemical. After
oral administration, [14C]-malathion absorption from the stomach was slow and its
excretion followed mostly the fecal route. Dermal application of [14C]-malathion
may represent a high risk for exposure to the organophosphorus pesticide where
the entire skin, not only the site of application, may act as reservoir for the
compound.
PMID- 9399421
TI - Dioxin and dioxin-like compounds in soil, Part I: ATSDR interim policy guideline.
Agency for Toxic Substances and Disease Registry.
PMID- 9399423
TI - Development of birth weight in Austria from 1970-1995.
AB - We analysed the development of birth weight of all Austrian live births in the
period 1970-1995. The relationship between birth weight and the variables
maternal age, length and sex of the newborn and year of birth is described by
means of a linear regression model. Over the 26 years an increase of up to 60 g
was observed in the mean birth weight. This positive trend may partly be due to
the extensive use of the maternity care program ("mother-and-child Passport")
introduced in 1974. Maternity payment was made to the mother it she underwent at
least five examinations within the antenatal care program. This payment was
reduced from 15,000 AS in 1996 to 2000 AS as from January 1st 1997, a measure
which may lead to a reduction in the use of this maternity care program, with
consequent negative implications for the morbidity of both mother and child and
for the positive trend of birth weight development over the past decades.
PMID- 9399422
TI - Dioxin and dioxin-like compounds in soil, Part II: Technical support document for
ATSDR interim policy guideline.
PMID- 9399424
TI - Lipaemia and liver composition in pregnant rats consuming olive oil and olive oil
used for frying.
AB - The effect of the consumption of unused olive oil (polar content, 2%; oleic acid,
78.9 mg/100 mg oil, and linoleic acid 7 mg/100 mg oil) and olive oil used
discontinuously for frying potatoes 15 times (polar content, 9%; oleic acid, 75.8
mg/100 mg oil and linoleic acid 6.2 mg/100 mg oil) was studied in pregnant rats
with the aim of better understanding the relationship between the consumption of
fat used in frying and lipid metabolism during periods of intense anabolism.
Trials were performed in pregnant Wistar rats, divided into 2 groups and fed
isocaloric diets in which the fat content (15% wt/wt) consisted of unused olive
oil (P1) or oil previously used for frying (P2), and the results were compared
with those of nonpregnant rats fed unused olive oil (NP1) and olive oil used for
frying (NP2). Pregnancy increased (p < 0.01) food intake, body weight, weight
gain, and food efficiency ratio (P2 vs NP2 and P1 vs NP1, respectively), but the
treatment of oil included in the diets did not alter these parameters. Gestation
significantly increased the serum triglyceride (TG) (p < 0.01) and total
cholesterol (TC) (p < 0.05) concentrations and diminished that of phospholipids
(PH) (p < 0.01). A significant effect of the type of oil consumed and a pregnancy
x oil interaction on Tg and PH levels was observed. The weight of the liver and
its fat content increased significantly (p < 0.05) as a result of pregnancy.
Liver TC, TG, and PH increased (approximately 3 times the original values) during
gestation, but no significant differences due to the intake of used or unused oil
(P2 vs P1) were observed. The results indicate that the consumption of moderately
altered olive oil, as the sole source of fat, does not alter the effect of
pregnancy on the mothers' weight gain, lipaemia, and hepatic fat composition to
any important degree.
PMID- 9399425
TI - Obesity as a major determinant of underreporting in a self-administered food
frequency questionnaire: results from the EPIC-Potsdam Study.
AB - The phenomenon of underreporting of dietary intake has been observed previously
in many epidemiologic studies. In this study it was investigated whether
dependencies exist between energy intake obtained by a semi-quantitative, self
administered food frequency questionnaire and lifestyle or anthropometric
factors, particularly obesity. The study population consisted of 2,531 subjects,
men aged 40 to 64 years and women aged 35 to 64 years from the general population
of Potsdam and the surrounding areas. First, subjects were allocated into
quintiles of the ratio 'reported energy intake (EI)' to 'calculated basal
metabolic rate (BMR)' as a measure of age and weight adjusted energy intake. No
apparent dependencies between socio-economic variables and the ratio EI/BMR were
observed. Among anthropometric variables, BMI and related measures of obesity
were inversely related to the ratio EI/BMR in men and women. While dietary intake
was directly related to the ratio EI/BMR in absolute quantities, energy adjusted
intake of fat, protein, carbohydrate, and alcohol was found to be independent of
this ratio. Energy adjusted food group consumption was also found to be
independent of the ratio EI/BMR, showing only slightly increasing trends across
quintiles of EI/BMR for cereals and fats, and a slightly decreasing trend for
sweet foods in women. When subjects were classified into three categories of BMI,
reported energy intake decreased across categories. Estimated energy expenditure
based on BMR was increasing with BMI categories. A close direct relationship was
observed between BMI categories and the difference between reported energy intake
and estimated energy expenditure. It is concluded that obesity is a major
determinant of under-reporting. Energy adjusted dietary variables were found to
be largely independent of such methodological influences.
PMID- 9399426
TI - Exercise-induced sweat nitrogen excretion: evaluation of a regional collection
method using gauze pads.
AB - The exercise-induced sweat nitrogen excretion was investigated during a 45-minute
run at moderate intensity on a treadmill. Sweat was collected with a regional
collection technique using gauze pads and compared with the whole-body wash-down
(WBW) method. In the regional collection, sweat was sampled from the upper back
(UB), lower back (LB), abdomen (AB), and thigh (TH). Additionally, the relation
of sweat urea, ammonia, and amino acids was investigated with the regional
collection method during a second 45-minute run. Independent of the sweat
collection method, a significant and positive correlation was found between sweat
rate and the excretion rate of the largest nitrogen fraction urea, suggesting
that the sweating response to exercise might be one of the most important factors
determining absolute sweat nitrogen losses. The urea nitrogen excretion was
nearly 140 mg.h-1 in the second run, representing the largest nitrogen fraction.
Ammonia nitrogen and amino acid-derived nitrogen rate were approximately 30 mg.h
1 and 10 mg.h-1, respectively. The comparison of the sampling methods during the
first run revealed that the urea nitrogen rate was significantly higher, but the
ammonia nitrogen rate significantly lower in the WBW. After summing urea and
ammonia nitrogen, no significant difference between the methods was observed
anymore, except for UB. It is concluded that the regional collection method using
gauze pads is a valuable approach to measure exercise-induced sweat nitrogen
losses during moderate running exercise.
PMID- 9399427
TI - [Osteoid osteoma of the hand].
PMID- 9399428
TI - A study on biliary ductal system and bile fistula in the American alligator,
Alligator mississippiensis.
AB - The anomalous arrangement of bile ducts in the Crocodylia has not been fully
appreciated. A clear understanding of biliary anatomy is necessary in order to
create complete bile drainage in these reptiles. The object of this study was to
clarify the anatomy of the bile ductal system and to establish total bile
fistulas in the American alligator, Alligator mississippiensis. Bile duct anatomy
was studied in 104 juvenile alligators, and bile fistulas were constructed in
seven alligators. In 93 out of 104 (89%) of the juveniles dissected there was an
interconnection between the right and left hepatic duct before the right hepatic
duct emptied into the gallbladder. The left hepatic duct then entered the
duodenum independently of the cystic duct which drained the gallbladder directly
into the duodenum. In 8% of the animals, the left hepatic duct did not enter the
duodenum but joined with the right duct, forming a common hepatic duct that
emptied into the gallbladder. In 3% of the cases, the right hepatic duct emptied
into the gallbladder, while the left duct had no communication with the right
hepatic duct and drained separately into the duodenum. This arrangement of bile
ducts is similar to that seen in birds and reflects the common ancestry of
crocodiles and birds. In other reptiles, the biliary system shows much more
variability and is different from the alligator. In five of seven alligators in
which total biliary diversion was attempted, the biliary catheter remained in
place and stayed patent from 2-7 weeks. Bile flow was extremely low (1.5-2.5
ml/24 h) when compared to that of mammals (80-100 ml/24 h). This study
demonstrates the variable nature of the biliary ductal system in Alligator
mississippiensis and suggest a method for constructing an effective total bile
fistula in these animals.
PMID- 9399429
TI - Abnormal limb regeneration in the short-toes mutant of the axolotl, Ambystoma
mexicanum: studies of age, level of amputation, and extracellular matrix.
AB - Limb regeneration in the short-toes axolotl is impaired. Our goal was to
characterize the regeneration process in this mutant by histological and
immunocytochemical methods. Previous research indicates that age and a defective
basement membrane may be instrumental factors in short-toes axolotl regeneration
(Del Rio-Tsonis et al. [1992] Proc. Natl. Acad. Sci. U.S.A., 89:5502-5506). The
present results show that limb regeneration can occur even in older (1-2-year
old) short-toes axolotls. The process was always significantly delayed, but the
time required for complete regeneration varied. Even so, the basement membrane of
short-toes regenerates showed no differences in thickness or shape compared with
wild-type regenerates. Distally amputated short-toes limbs gave rise to more
digits in the regenerate, indicating that regeneration may be somewhat dependent
on the level of amputation. Since extracellular matrix (ECM) remodeling occurs
extensively during regeneration, we compared the ECM of the short-toes and wild
type regenerates using monoclonal antibodies (mAbs) MT2 and ST1 (Tassava et al.
[1996] Wound Rep. Reg., 4:75-81). The short-toes regenerates showed decreased
reactivity to mAb MT2, which identifies type XII collagen, an ECM protein that is
normally unregulated during regeneration, and increased reactivity to mAb ST1,
which identifies a limb ECM component that typically undergoes breakdown in the
distal stump. Thus, impaired regeneration in the short-toes axolotl is correlated
with impaired ECM remodeling in the distal limb stump. This supports the view
that ECM remodeling plays an important role in regeneration.
PMID- 9399430
TI - Hormonal induction of thumb pads and the evolution of secondary sexual
characteristics of the Southeast Asian fanged frog, Rana blythii.
AB - The fanged frogs of Southeast Asia do not express most of the hormone-dependent
secondary sexual characteristics such as thumb pads that are common to other
ranid frogs. At the same point in the evolutionary history of the group that
these androgen-mediated characteristics are lost, male parental care first
evolves. This behavior is often correlated with low androgen levels. Prior work
indicates that in one of the fanged frogs, Rana blythii, adult males have low
androgen levels compared to North Temperate species of Rana. This leads to the
question of whether these low androgen levels are related to the unusual male
parental care and the lack of expression of the thumb pad and other hormone
dependent secondary sexual characteristics in this species. We tested that
hypothesis by examining the effects of exogenous dihydrotestosterone supplements
on the expression of thumb pads in Rana blythii. Dihydrotestosterone injections
appear to stimulate the expression of the thumb pad in R. blythii. These results
support the hypothesis that low androgen levels are involved in the loss of the
thumb pad in R. blythii. This work provides an example of how mapping characters
on phylogenies can be a powerful approach for gaining insights into proximate
physiological mechanisms of selection at the evolutionary level.
PMID- 9399431
TI - Characterization of vitellogenin and vitellin from land crab Potamon potamios:
identification of a precursor polypeptide in the molecule.
AB - A female-specific protein, vitellogenin (Vg), and its corresponding egg vitellin
(Vn) were identified in the land crab Potamon potamios. Electrophoretic analysis
of the hemolymph protein during the annual reproduction cycle revealed that the
processing of vitellogenesis did not occur in males or in females of a
previtellogenic stage. The analysis of ovarian and egg extracts revealed the
presence of Vn, which was identical to Vg. Both Vg and Vn were present in three
different aggregational states that represented monomeric, dimeric, and trimeric
species of the proteins. In both proteins, the predominant form was the dimeric,
which had a molecular mass of 551 kDa for Vg and 510 kDa for Vn. Under denaturing
conditions, each of the individual Vg and Vn aggregates released three
polypeptides with molecular masses of 115, 105, and 85 kDa. In spite of the
difference in terms of native molecular mass, the Vg and Vn were similar in their
lipid, carotenoid, and carbohydrate composition. However, Vg of some animals
contained a fourth polypeptide with a molecular mass of 181 kDa. This polypeptide
and the three other Vg and Vn polypeptides were immunoreactive against anti-Vg
prepared from the 85 kDa Vg polypeptide. Furthermore, proteolytic cleavage
experiments confirmed that the 115 and 105 kDa Vg polypeptides were derived from
the 181 kDa polypeptide. We conclude that the presence of the 181 kDa polypeptide
in the Vg molecule resulted in the higher molecular mass of Vg.
PMID- 9399432
TI - Duration of the luteotrophic memory of the stud male odors formed in the female
mouse.
AB - Presence of the stud male prevents the novel male-induced block to early
pregnancy in mice, while reexposure to the stud male after the pregnancy block
induces pseudopregnancy in the females. These two phenomena involve luteotrophy
in the female, and a (luteotrophic) memory of the stud male characteristics
formed in her is necessary for such a luteotrophic response. Two experiments were
conducted to evaluate the effective duration of the "luteotrophic memory" of the
stud male odors formed in the female mouse. The first experiment investigated
whether exposure to excreta of the stud male at different intervals will induce
pseudopregnancy in pregnancy-blocked females; some females mated with a second
male and experienced a second consecutive pregnancy failure before the exposure
to the excreta of the first stud male. The females, mated once or twice, failed
to exhibit pseudopregnancy when exposure to the excreta of the first stud male
was begun 8 or 9 days after the first mating. In the second experiment, each
pregnancy-blocked female was mated with the (alien) male that induced failure of
the first pregnancy and then housed with simultaneous access to the excreta of
another alien male and that of the first stud male. Excreta of the first stud
male did not prevent failure of the second pregnancy. The results indicate that
the (luteotrophic) memory of the stud male-originating olfactory cues formed in
the female or its effectiveness in reactivating the luteotrophic system (when the
female is reexposed to the odors of the first stud male) lasts only up to about
day 7 postcoitum. The present results also show that exposure to only the excreta
of the stud male can prevent the pheromonal block to pregnancy or induce
pseudopregnancy after pregnancy block in the female mouse.
PMID- 9399433
TI - Regulation of levels of proline as an osmolyte in plants under water stress.
AB - Compatible osmolytes are potent osmoprotectants that play a role in counteracting
the effects of osmotic stress. Proline (Pro) is one of the most common compatible
osmolytes in water-stressed plants. The accumulation of Pro in dehydrated plants
is caused both by activation of the biosynthesis of Pro and by inactivation of
the degradation of Pro. In plants, L-Pro is synthesized from L-glutamic acid (L
Glu) via delta(1)-pyrroline-5-carboxylate (P5C) by two enzymes, P5C synthetase
(P5CS) and P5C reductase (P5CR). L-Pro is metabolized to L-Glu via P5C by two
enzymes, proline dehydrogenase (oxidase) (ProDH; EC 1.5.99.8) and P5C
dehydrogenase (P5CDH; EC 1.5.1.12). Such metabolism of Pro is inhibited when Pro
accumulates during dehydration and it is activated when rehydration occurs. Under
dehydration conditions, when expression of the gene for P5CS is strongly induced,
expression of the gene for ProDH is inhibited. By contrast, under rehydration
conditions, when the expression of the gene for ProDH is strongly induced, the
expression of the gene for P5CS is inhibited. Thus, P5CS, which acts during the
biosynthesis of Pro, and ProDH, which acts during the metabolism of Pro, appear
to be the rate-limiting factors under water stress. Therefore, it is suggested
that levels of Pro are regulated at the level of transcriptional the genes of
these two enzymes during dehydration and rehydration. Moreover, it has been
demonstrated that Pro acts as an osmoprotectant and that overproduction of Pro
results in increased tolerance to osmotic stress of transgenic tobacco plants.
Genetically engineered crop plants that overproduce Pro might, thus, acquire
osmotolerance, namely, the ability to tolerate environmental stresses such as
drought and high salinity.
PMID- 9399434
TI - Expression and internal feedback regulation of ACC synthase and ACC oxidase genes
in ripening tomato fruit.
AB - We have examined whether or not a positive feedback regulation of gene expression
for 1-aminocyclopropane-1-carboxylate (ACC) synthase and ACC oxidase also
operates in ripening tomato (Lycopersicon esculentum) fruit during the burst of
ethylene production. Two cDNA fragments for ACC synthase and one for ACC oxidase
were cloned with high homology to already known genes involved in ethylene
biosynthesis in ripening tomato fruit. Accumulation of mRNAs which hybridize to
these cDNA probes were induced in mature green fruit within two days by treatment
with propylene. In the fruit ripened from the turning stage, red color
development, ethylene production, ACC content, and activities of ACC synthase and
ACC oxidase increased as maturity progressed. The abundance of two ACC synthase
and one ACC oxidase mRNAs in the fruit increased from the turning to pink stage
and were followed by a slight decline towards the red stage. These increases in
mRNAs abundance with ripening were prevented to a large extent by treatment with
the ethylene action inhibitor, 1-methylcyclopropene (MCP). This was most
pronounced in the fruit treated with MCP at the turning stage, in which the
accumulation of ACC synthase and ACC oxidase transcripts was almost completely
eliminated in the first two d, precisely the same stage at which the control
fruit had the greatest level of each mRNA accumulation. The inhibition of
transcript accumulation recovered to the control level within two to four d. MCP
also decreased ethylene biosynthetic activity, although this decrease did not
reflect the reduction in the mRNAs accumulation. These results suggest that a
strong positive feedback regulation is involved in ethylene biosynthesis at the
gene transcriptional level in tomato fruit, even at the stage with a burst of
ethylene production.
PMID- 9399435
TI - Generation of superoxide anion and localization of CuZn-superoxide dismutase in
the vascular tissue of spinach hypocotyls: their association with lignification.
AB - The sites of generations of superoxide anions and hydrogen peroxide in cross
sections of hypocotyls from spinach seedlings were located by staining with
nitroblue tetrazolium (NBT) and with starch-iodide, respectively. Formazan,
produced upon the reduction of NBT by superoxide, was observed mainly in the
vascular tissue only in the presence of inhibitors of CuZn-superoxide dismutase
(CuZn-SOD), and its formation was suppressed under anaerobic conditions. Thus,
NBT was reduced to formazan specifically by the superoxide anions generated in
vascular tissue. The reduction of NBT was suppressed by inhibitors of NAD(P)H
oxidase, but neither by cyanide nor azide, indicating the involvement of NAD(P)H
oxidase in the generation of superoxide anions in the vascular tissue. Starch-I2
complex also was formed in the vascular tissue, but not in the presence of either
the CuZn-SOD inhibitor or the NAD(P)H oxidase inhibitor, indicating that the
hydrogen peroxide is produced via the catalytic disproportionation with CuZn-SOD
of the superoxide generated by NAD(P)H oxidase. Generations of superoxide anions
and hydrogen peroxide in the vascular tissue were particularly apparent in the
xylem and associated with the sites of distribution of CuZn-SOD as determined by
an immunohistochemical method, and also with the location of lignin as determined
by the phloroglucin-HCl reaction.
PMID- 9399436
TI - Morphological responses and molecular modifications in tomato plants after
mechanical stimulation.
AB - Study of the growth responses of Lycopersicon esculentum (Mill. cv. VFN8) to
mechanical stimulation applied to a single young internode showed a rapid and
sharp decrease in stem elongation and an inhibition of elongation of several
internodes, indicative of information transmission in the plant. A new tomato
cDNA partial clone encoding calmodulin was isolated and used to study the time
course of the gene induction in response to the rubbing treatment. Northern blot
analysis showed a maximum accumulation of calmodulin mRNA 2 h after mechanical
stimulation, not only in the rubbed internode, but also in upper and lower
internodes and in young leaves. Treatment of the plant with calcium and EGTA
showed the involvement of calcium and, in particular, intracellular calcium in
calmodulin gene expression and cellular response.
PMID- 9399437
TI - Gibberellin A3 causes a decrease in the accumulation of mRNA for ACC oxidase and
in the activity of the enzyme in azuki bean (Vigna angularis) epicotyls.
AB - Differential screening, aimed at the isolation of cDNA clones of mRNAs whose
accumulation is influenced by GA3, resulted in the isolation of a cDNA clone of
an mRNA whose level was decreased by GA3 in segments of epicotyls of Vigna
angularis. The putative protein encoded by this cDNA resembled the 1
aminocyclopropane-1-carboxylate oxidases (ACC oxidases) identified in other plant
species (about 80% homology at the amino acid level). Thus, the corresponding
gene was designated AB-ACO1 (azuki bean ACC oxidase). GA3 also decreased the
activity of ACC oxidase in azuki bean epicotyls, but it did not decrease the rate
of ethylene evolution. In fact, GA3 increased the rate of ethylene evolution and
the level of ACC. Thus, GA3 seemed to increase the production of ethylene by
promoting the synthesis of ACC.
PMID- 9399438
TI - The requirements for Ca2+, protein phosphorylation, and dephosphorylation for
ethylene signal transduction in Pisum sativum L.
AB - The role of Ca2+ and protein phosphorylation in the transduction of the ethylene
signal resulting in induction of 1-aminocyclopropane-1-carboxylic acid (ACC)
oxidase has been studied in peas (Pisum sativum L.) by a pharmacological
approach. 2,5-Norbornadiene (NBD) and aminoethoxyvinylglycine (AVG) reduced the
basal level of ACC oxidase transcript and its enzyme activity. Only NBD was shown
to inhibit the ethylene response, the accumulation of ACC oxidase transcript and
the stimulation of its enzyme activity. Ethylene influenced 45Ca2+ influx into
the segment tissues from pea epicotyls, and ethylene glycol-bis(beta-aminoethyl
ether)N,N,N'N'-tetraacetic acid (EGTA) a Ca2+ chelator, inhibited the ethylene
response. Ca2+ depletion by pretreatment with EGTA also blocked the ethylene
response, which almost completely recovered when Ca2+ was added exogenously after
Ca2+ depletion. Ca2+ channel blockers, verapamil, and LaCl3, used to certify the
role of extracellular Ca2+, all inhibited the ethylene response. A protein kinase
inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), and protein
phosphatase inhibitors, vanadate and okadaic acid, also inhibited the ethylene
response. The results of the present study suggest that Ca2+ influx from the
extracellular space, protein phosphorylation, and dephosphorylation are required
for the induction of ACC oxidase by ethylene.
PMID- 9399439
TI - Purification and characterization of arginine decarboxylase from soybean (Glycine
max) hypocotyls.
AB - Arginine decarboxylase (EC 4.1.1.19) was purified from soybean, Glycine max,
hypocotyls by a procedure which includes ammonium sulfate fractionation, acetone
precipitation, gel filtration chromatography, and affinity chromatography. Using
this procedure, ADC was purified to one band in non-denaturing PAGE. The purified
ADC has an M(r) of 240 kDa based on gel filtration chromatography and is a trimer
of identical subunits which has an estimated M(r) of 74 kDa based on SDS-PAGE.
ADC is active between 30 and 50 degrees C and has a Km value of 46.1 microM. ADC
is very sensitive to agmatine or putrescine but not to spermidine or spermine. In
the presence of 0.5 mM agmatine (or putrescine), the enzyme activity was
inhibited by 70%. However, at the same concentration of spermidine (or spermine),
the enzyme activity was inhibited by only 10-20%.
PMID- 9399440
TI - Differential expression of ADC mRNA during development and upon acid stress in
soybean (Glycine max) hypocotyls.
AB - Arginine decarboxylase (ADC) is one of the key enzymes in the biosynthesis of
putrescine in plants. The regulation of its activity depends on the physiological
condition, developmental stage, and type of tissue. We have cloned ADC cDNA from
soybean (Glycine max) hypocotyls to understand the regulation mechanisms of this
enzyme activity. Using the cDNA clone, we examined the relationship between
changes in the ADC activity and the level of ADC mRNA during development, in
different tissues, and upon acid stress. The ADC activity began to increase 2 d
after initiation of germination, reached a peak at the 5th d, and then declined.
This change in the enzyme activity was preceded by similar changes in the level
of the mRNA. The ADC activity was expressed tissue-specifically; this expression
was well corelated with the mRNA content of the respective tissues. Incubation of
the 5-d-old hypocotyls in pH 3 potassium phosphate solution caused a rapid
increase in ADC activity. Within 2 h of acid treatment, the ADC activity
increased more than threefold. This increase was also preceded by a corresponding
increase in the mRNA content and was also regulated tissue-specifically. These
results suggest that the change in the content of ADC mRNA has an important role
in the regulation of the enzyme activity during early development, in different
tissues, and upon acid stress.
PMID- 9399441
TI - Cloning of maize ferredoxin III gene: presence of a unique repetitive nucleotide
sequence within an intron found in the 5'-untranslated region.
AB - A genomic clone encoding the precursor of a non-photosynthetic ferredoxin (Fd
III) from maize has been isolated and characterized. In comparison with the
corresponding cDNA, the gene (fedIII) was found to be interrupted in the 5'
untranslated region by an intron consisting of 3,037 bp. About 80% of the total
region of this intron is organized into four classes of tandemly repeated
sequences with monomeric lengths of about 200 bp, 320 bp, 130 bp, and 90 bp. This
unique intron organization is present in the fedIII gene of three related maize
cultivars examined.
PMID- 9399442
TI - Cervical Spine Research Society Presidential Address: a 25-year correlation with
history.
PMID- 9399443
TI - Murine nucleus pulposus-derived cells secrete interleukins-1-beta, -6, and -10
and granulocyte-macrophage colony-stimulating factor in cell culture.
AB - STUDY DESIGN: Cultures established from murine disc-derived cells were stimulated
by lipopolysaccharide. The cells' capacity to secrete proinflammatory cytokines
and interleukin-10 with and without lipopolysaccharide stimulation was determined
using enzyme-linked immunosorbent assays. OBJECTIVES: To determine the capacity
of disc-derived cells to secrete proinflammatory cytokines, and the effect of
lipopolysaccharide stimulation on such secretion. SUMMARY OF BACKGROUND DATA: The
pathophysiology of compressive radiculopathy is unclear. Inflammation is a
possible explanation. Proinflammatory cytokine secretion was demonstrated in
herniated nucleus pulposus. It is unknown whether these cytokines are secreted
from disc-derived cells or from infiltrating inflammatory cells in the herniated
nucleus pulposus. METHODS: Discs were microsurgically harvested from inbred mice
and cut to allow the nucleus pulposus to establish cell culture. A study group
was exposed to lipopolysaccharide stimulation. Media were harvested from the
study and control groups 24 hours later. Secretion of interleukins-1-, -6, and
10, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor
alpha were determined using enzyme-linked immunosorbent assays. RESULTS: Basal
secretion of interleukins-6 and -10, but no basal secretion of interleukin-1-,
granulocyte-macrophage colony-stimulating factor, or tumor necrosis factor-alpha
was detected. Secretion of interleukin-1- rose from zero to 27.69 pg/10(5) cells,
and granulocyte-macrophage colony-stimulating factor secretion rose from zero to
9.77 pg/10(5) cells after lipopolysaccharide stimulation. A 75-fold increase in
interleukin-6 secretion and a 150-fold increase in interleukin-10 secretion were
detected after stimulation with lipopolysaccharide. No tumor necrosis factor
alpha secretion was detectable. All result had high statistical significance (all
P < 0.001). CONCLUSIONS: Cultured murine disc-derived cells have the capacity to
secrete proinflammatory cytokines and interleukin-10 in the absence of
inflammatory cells. This finding supports the hypothesis that disc-derived cells
are capable of initiating or amplifying an inflammatory process.
PMID- 9399444
TI - Clinical course of conservatively managed rheumatoid arthritis patients with
myelopathy.
AB - STUDY DESIGN: The clinical course of rheumatoid arthritis patients with
myelopathy who do not undergo surgery was studied. OBJECTIVES: To establish a
more accurate prognosis for rheumatoid arthritis patients who do not undergo
surgery. SUMMARY OF BACKGROUND DATA: Cervical myelopathy has been reported in two
thirds of rheumatoid arthritis patients with atlantoaxial dislocation.
Atlantoaxial fusion, or occipitocervical fusion, is widely performed on these
patients. However, several researchers reported serious complications from the
surgery, including nonunion, worsening myelopathy, and high mortality. The
natural course of disease in rheumatoid arthritis patients with myelopathy should
be known before definitive treatments can be outlined. MATERIALS AND METHODS:
Twenty-one rheumatoid arthritis patients with myelopathy resulting from
atlantoaxial dislocation were studied. Fourteen of the 21 cases were associated
with upward migration of the odontoid process. All of these patients were
recommended for surgery, but they refused. Patients were reviewed by direct
examination yearly. Radiographic changes and clinical course, including the
survival rate, were observed. RESULTS: Atlantodental interval and Redlund-Johnell
measurements deteriorated. The patients showed no neural improvement, and
deterioration was found in 16 (76%) cases during follow-up. All patients became
bedridden within 3 years of the onset of myelopathy. Seven of the 21 patients
died suddenly for unknown reasons, 3 died of pneumonia, and 1 died of multiple
organ failure. The three sudden-death cases showed progressive upward migration
of the odontoid process. The cumulative probability of survival was 0% in the
first 7 years after the onset of myelopathy. CONCLUSIONS: The clinical results
for rheumatoid arthritis patients with myelopathy treated without surgery are
extremely poor. Surgical treatment is recommended for rheumatoid arthritis
patients with myelopathy.
PMID- 9399445
TI - Neurologic outcome of early versus late surgery for cervical spinal cord injury.
AB - STUDY DESIGN: A prospective analysis evaluating neurologic outcome after early
versus late surgery for cervical spinal cord trauma. OBJECTIVES: The study was
conducted to determine whether neurologic and functional outcome is improved in
traumatic cervical spinal cord-injured patients (C3-T1, American Spinal Injury
Association grades A-D) who had early surgery (<72 hours after spinal cord
injury) compared with those patients who had late surgery (>5 days after spinal
cord injury). SUMMARY OF BACKGROUND DATA: There is considerable controversy as to
the appropriate timing of surgical decompression and stabilization for cervical
spinal cord trauma. There have been numerous retrospective studies, but no
prospective studies, to determine whether neurologic outcome is best after early
versus late surgical treatment for cervical spinal cord injury. METHODS: Patients
meeting appropriate inclusion criteria were randomized to an early (<72 hours
after spinal cord injury) or late (>5 days after spinal cord injury) surgical
treatment protocol. The neurologic and functional outcomes were recorded from the
acute hospital admission to the most recent follow-up. RESULTS: Comparison of the
two groups showed no significant difference in length of acute postoperative
intensive care stay, length of inpatient rehabilitation, or improvement in
American Spinal Injury Association grade or motor score between early (mean, 1.8
days) versus late (mean, 16.8 days) surgery. CONCLUSIONS: The results of this
study reveal no significant neurologic benefit when cervical spinal cord
decompression after trauma is performed less than 72 hours after injury (mean,
1.8 days) as opposed to waiting longer than 5 days (mean, 16.8 days).
PMID- 9399446
TI - The management of unilateral lateral mass/facet fractures of the subaxial
cervical spine: the use of magnetic resonance imaging to predict instability.
AB - STUDY DESIGN: Retrospective review of the clinical course and cervical spine
plain radiographs, computed tomography, and magnetic resonance imaging of 24
consecutive patients for a 2-year period with a unilateral lateral mass/facet
fracture. OBJECTIVE: To propose a treatment algorithm for the management of
unilateral lateral mass/facet fractures of the subaxial cervical spine based on
ligamentous injury detected by magnetic resonance imaging. SUMMARY OF BACKGROUND
DATA: There have been no previous reports of the use of magnetic resonance
imaging to predict clinical instability. METHODS: A retrospective review of the
clinical course of all unilateral mass/facet fractures identified over a 2-year
period was conducted. All cervical spine plain radiographs, computed tomography
scans, and magnetic resonance images were reviewed by a neuroradiologist blinded
to the clinical course of the patient. Magnetic resonance T1-weighted and
inversion recovery images were used to evaluate the integrity of the facet
region, interspinous ligament, anterior longitudinal ligament, and posterior
longitudinal ligament. RESULTS: Twenty-four unilateral lateral mass/facet
fractures were identified. Only six initial cervical spine series demonstrated a
bony abnormality at the level of the fracture. The fractures were identified by
computed tomography and were almost all nondisplaced or minimally displaced. Less
than half of the fractures extended ventrally to involve the transverse process
or foramen transversarium or dorsally to involve the lamina. Twelve fractures
were nonoperatively treated and 12 were treated surgically for stabilization. Ten
patients in the operative group presented with or developed a subluxation. Nine
of these patients had injury to at least three of the four ligaments evaluated by
magnetic resonance imaging. In the nonoperative group, only three patients had
extensive ligamentous injury at the level of the fracture. All three of these
patients were lost to follow-up. CONCLUSIONS: Plain radiographs of the cervical
spine lack sensitivity to detect the presence of lateral mass/ facet fractures.
The appearance of the fracture on computed tomography does not indicate
instability. The degree of ligamentous injury at the level of the fracture
demonstrated on magnetic resonance imaging correlates with instability in this
series. Operative stabilization may be indicated for unilateral lateral mass
fractures that present with a subluxation or that have injury to at least three
of the following ligaments: the facet region, the interspinous ligament, the
anterior longitudinal ligament, and the posterior longitudinal ligament. However,
before a definitive management plan can be formulated, results from this small
series require further validation.
PMID- 9399447
TI - Three-level anterior cervical discectomy and fusion: radiographic and clinical
results.
AB - STUDY DESIGN: A retrospective study of 16 patients who underwent the modified
Robinson anterior cervical discectomy and fusion at three operative levels.
OBJECTIVES: To provide long-term follow-up data on the surgical success and
patient outcome of three-level anterior cervical discectomies and fusions.
SUMMARY OF BACKGROUND DATA: The success of arthrodesis for anterior cervical
fusion depends on several factors, including the number of surgical levels. To
the authors' knowledge, there are no long-term follow-up reports to describe the
arthrodesis rate and outcome for patients having specifically three-level
discectomy and fusion procedures. METHODS: Sixteen patients, with an average age
of 59 years, were followed for an average of 37 months. All had an anterior
discectomy, burring of the endplates, and placement of an autogenous tricortical
iliac crest graft at three levels. All patients had follow-up office visits with
examinations and radiographs. Radiographic union, postoperative pain relief, and
neurologic recovery were evaluated. RESULTS: Only 9 (56%) of the 16 patients went
on to achieve solid arthrodesis at all three levels. Of the seven patients with
pseudarthrosis, two had severe pain and required revision; two had moderate pain
and three no pain. Of the nine with the solid fusion, three had mild pain and six
no pain, a statistically significant difference in comparing the two outcomes (P
< 0.01). All patients with preoperative motor deficit recovered, but two patients
in whom a pseudarthrosis had developed had limited improvement in function until
the nonunion was surgically repaired. CONCLUSIONS: A three-level modified
Robinson cervical discectomy and fusion results in an unacceptably high rate of
pseudarthrosis. Although not all pseudarthroses are painful, these data suggest
that those with a successful fusion have a better outcome. It is recommended that
these patients undergo additional or alternative measures to achieve arthrodesis
consistently.
PMID- 9399448
TI - Characterization of the scoliosis that develops after pinealectomy in the chicken
and comparison with adolescent idiopathic scoliosis in humans.
AB - STUDY DESIGN: The characteristics of the scoliosis that develops after
pinealectomy in young chickens were determined from weekly posteroanterior
radiographs. These data were compared with similar data collected from human
patients with adolescent idiopathic scoliosis. OBJECTIVES: To characterize the
scoliosis produced in young chickens after pinealectomy and to compare these
characteristics with those seen in human patients with adolescent idiopathic
scoliosis. SUMMARY OF BACKGROUND DATA: Although it has been recognized that
pinealectomy produces scoliosis in chickens, the characteristics of these curves
have never been well described other than by simple visual descriptions. METHODS:
The characteristics of the scoliosis produced in chickens after pinealectomy done
3 days after hatching were measured from radiographs taken at weekly intervals.
These characteristics were compared with similar data collected from human
patients with adolescent idiopathic scoliosis. RESULTS: Similarities included
development of single and double curves, degree of curvature, stability of the
curve, numbers of vertebrae involved, direction of rotation, and progression
characteristics. Differences included wedged vertebrae in the chickens, in
conjunction with curve development and increased variability in vertebrae
involved. CONCLUSIONS: There are many similarities in the development of
scoliosis in young chickens after pinealectomy and in children with adolescent
idiopathic scoliosis. The few differences might be related to the different
biomechanical properties associated with the spine in the two species.
PMID- 9399449
TI - Lumbar spinal canal stenosis examined electrophysiologically in a rat model of
chronic cauda equina compression.
AB - STUDY DESIGN: A model of chronic cauda equina compression with conductive stress
was studied electrophysiologically. OBJECTIVE: To analyze the pathophysiology
arising from chronic compression electrophysiologically. SUMMARY OF BACKGROUND
DATA: This rat model of cauda equina compression that is chronic, not acute, has
been reported elsewhere. METHODS: A stainless steel wire and plate were fastened
to the spine at L5 of 8 rats 3 weeks old. One year later, the ascending and
descending nerve action potentials were recorded and the conduction velocities
(CVs) were measured. Electrophysiologic changes after high-frequency stimulation
(HFS) were observed. RESULTS: The waveform of the ascending cauda equina action
potential at the cauda equina had three peaks, and that at the conus medullaris
had a peak followed by a broad wave. The waveform of the descending nerve action
potential had two peaks. The mean ascending and descending CVs of the treated
rats were slower (P < 0.001) than those of the control rats. In the control rats,
the mean CV and mean amplitude after HFS decreased slightly and returned to
normal within 30 seconds, and the waveform was unchanged. In treated rats, the
mean CV decreased after HFS but returned to normal within 10 minutes. The mean
amplitude decreased after HFS and did not return to normal within 10 minutes. The
waveform was unchanged. CONCLUSIONS: Because the differences between treated and
control rats in amplitude (and CVs) were greater before HFS than after HFS, we
concluded that treated rats had disturbance of the blood flow in vessels around
the nerves of the cauda equina with histologic damage. In human patients, such
disturbance may be one cause of intermittent claudication.
PMID- 9399450
TI - Pathogenesis of tears of the anulus investigated by multiple-level transaxial
analysis of the T12-L1 disc.
AB - STUDY DESIGN: Three transaxial slices, dividing each disc into four layers of
equal thickness, were made in each of 19 T12-L1 discs. Naked-eye and stereoscopic
examination was used to record abnormalities of the T12 (superior) surface of the
upper slice, opposing surfaces of the central slice, and the L1 (inferior)
surface of the lower slice. OBJECTIVES: To characterize and quantify structural
abnormalities to determine their incidence and three-dimensional arrangement, and
to test the hypotheses 1) that the frequency and location of tears of the anulus
are related to age and nucleus condition; and 2) that rim lesions initiate the
development of concentric tears. SUMMARY OF BACKGROUND DATA: Most previous
studies of disc disease have been based on the examination of single sagittal
slices, some on single transaxial slices, and a few have used both. This single
slice approach underrecords abnormalities that have not involved the disc center,
and may inhibit the interpretation of magnetic resonance imaging and computed
tomography images. METHODS: Spines from 19 human cadavers (mean age, 47.4 years;
range, 20-79 years) were used. An initial transaxial slice through the center of
the T12-L1 disc was followed by cranial and caudal transaxial slices midway
between the center and endplate. Soft tissues were then removed to allow
examination of the endplate. Abnormalities recorded at each stage were summated
for all disc levels. The incidence of the abnormalities in each disc sector was
analyzed using the Spearman-Rank correlation coefficient and the Bonferroni
correction. RESULTS: With the exception of radiating tears, which most commonly
affected the posterior disc, the right anterior quadrant tended to show
abnormalities more frequently than the other quadrants. Although concentric tears
(in 74%), rim lesions (in 47%), and radiating tears (in 47%) were frequent, no
correlations were found between these three types of anulus tear. Concentric
tears were present after approximately 10% of the anulus had undergone some
delamination. Rim lesions correlated with focal thickening of anulus lamellae.
One fifth of radiating tears extended to involve the outer anulus zone.
CONCLUSIONS: Neither hypothesis was substantiated. Because lesions of the nucleus
and anulus lack uniform shape and are three-dimensionally complex, it is
inappropriate to interpret cadaver disc disease on single, mid-disc slices. The
three different types of anulus tears appear to evolve independent of age and
each other.
PMID- 9399451
TI - The effect of fatigue on multijoint kinematics and load sharing during a
repetitive lifting test.
AB - STUDY DESIGN: A repetitive lifting test in the sagittal plane was performed with
a submaximal load at a maximal lifting rate to understand the effects of fatigue
on kinematic and kinetic measures of performance. OBJECTIVES: To quantify the
effect of fatigue during a highly repetitive lifting task, in terms of lifting
force transmitted to the load, joint motion patterns, and internal joint load
sharing. SUMMARY OF BACKGROUND DATA: Industrial surveillance and epidemiologic
data suggest that repetitive lifting is a risk factor for low back pain. Previous
studies examining the effect of fatigue have either been constrained to isolated
trunk movement, or have not explored the internal load distribution and potential
alteration in the loading patterns. METHODS: Sixteen healthy male subjects
performed repetitive lifting in the sagittal plane with a load equal to 25% of
their maximal lifting capacity, at a maximal lifting rate. Changes in lifting
performance were determined from the power transferred to the box, joint
kinematics, and joint kinetics. Data from three cycles at the start and end of
the exercise were tested for the effect of fatigue using repeated-measures
analysis of variance. RESULTS: Fatigue was documented by a reduction in average
lifting force and hip and spine torque generation, whereas internal joint load
sharing was relatively unchanged. The fatigue was associated with decreased knee
and hip motion, and increased lumbar flexion. Decreased postural stability also
was evident. CONCLUSIONS: The significant decrease in postural stability and
force generation capability because of the repetitive lifting task indicated a
higher risk of injury in the presence of unexpected perturbation. Multijoint
coordinated lifting tasks provide a more realistic protocol to study
neuromuscular fatigue.
PMID- 9399452
TI - The effect of spinal destabilization and instrumentation on lumbar intradiscal
pressure: an in vitro biomechanical analysis.
AB - STUDY DESIGN: In vitro biomechanical testing was performed in human cadaveric
lumbar spines, using pressure needle transducers to analyze the effects of spinal
destabilization and instrumentation on lumbar intradiscal pressures. OBJECTIVES:
To quantify changes in lumbar intradiscal pressures at three adjacent disc levels
under conditions of spinal reconstruction, and to evaluate the possibility of
pressure-induced disc pathology secondary to spinal instrumentation. SUMMARY OF
BACKGROUND DATA: Lumbar intradiscal pressures under in vivo and in vitro
conditions and the use and development of spinal instrumentation have been
investigated comprehensively. However, the effects of spinal destabilization and
instrumentation on lumbar intradiscal pressure have not been delineated clearly.
METHODS: In 11 human cadaveric lumbosacral specimens, specially designed pressure
needle transducers quantified intradiscal pressure changes at three adjacent disc
levels (L2-L3, proximal; L3-L4, operative; and L4-L5, distal) under four
conditions of spinal stability: intact, destabilized, laminar hook and pedicle
screw reconstructions. Biomechanical testing was performed under axial
compression (0-600 N), anterior flexion (+12.5 degrees) and extension (-12.5
degrees), after which the level of degeneration and disc area (cm2) were
quantified. RESULTS: In response to destabilization and instrumentation, proximal
disc pressures increased as much as 45%, and operative pressure levels decreased
41-55% (P < 0.05), depending on the instrumentation technique. Linear regression
and correlation analyses comparing intradiscal pressure to the grade of disc
degeneration were not significant (r = 0.24). CONCLUSIONS: Changes in segmental
intradiscal pressure levels occur in response to spinal destabilization and
instrumentation (P < 0.05). Intradiscal cyclic pressure differentials drive the
metabolic production and exchange of disc substances. Conditions of high or low
disc pressure secondary to spinal instrumentation may serve as the impetus for
altered metabolic exchange and predispose operative and adjacent levels to disc
pathology.
PMID- 9399453
TI - Vulnerability of the recurrent laryngeal nerve in the anterior approach to the
lower cervical spine.
AB - STUDY DESIGN: To perform anatomic dissections and measurements of the recurrent
laryngeal nerve between the inferior thyroid artery and superior border of the
clavicle (mid-portion) on both sides. OBJECTIVES: To determine quantitatively the
differences in course and location between the recurrent laryngeal nerves on both
sides and to relate this to the vulnerability of the recurrent laryngeal nerve
during an anterior approach to the lower cervical spine. SUMMARY OF BACKGROUND
DATA: The midportion of the recurrent laryngeal nerve is usually encountered in
the anterior approach to the lower cervical spine, especially on the right side.
No quantitative regional anatomy describing the course and location of the mid
portion of the recurrent laryngeal nerve is available in the literature. METHODS:
Fifteen adult cadavers were used for dissections of the recurrent laryngeal
nerve. The length of the recurrent laryngeal nerve between the superior border of
the clavicle and the inferior thyroid artery, and the angle of the recurrent
laryngeal nerve with respect to sagittal plane, were measured bilaterally. In
addition, six cross-sections at C7 were obtained to determine the linear
distances between esophagotracheal groove and the recurrent laryngeal nerve.
RESULTS: The recurrent laryngeal nerve on the right runs in a superior and medial
direction, with an angle of 25.0 degrees +/- 4.7 degrees relative to sagittal
plane, compared with 4.7 degrees +/- 3.7 degrees on the left. The length of the
recurrent laryngeal nerve between the superior border of the clavicle and the
inferior thyroid artery is 23.0 +/- 4.4 mm on the left, and 22.8 +/- 4.3 mm on
the right. The recurrent laryngeal nerve lies deep within the esophagotracheal
groove on the left, but 6.5 +/- 1.2 mm anterior and 7.3 +/- 0.8 mm lateral to the
esophagotracheal groove on the right. CONCLUSIONS: The recurrent laryngeal nerve
on the right side is highly vulnerable to injury if ligature of the inferior
thyroid vessels is not performed as laterally as possible or if retraction of the
midline structures along with the recurrent laryngeal nerve is not performed
intermittently. Avoiding injury to the recurrent laryngeal nerve, especially on
the right side, is a major consideration during an anterior approach to lower
cervical spine.
PMID- 9399454
TI - Accuracy of using computed tomography to identify pedicle screw placement in
cadaveric human lumbar spine.
AB - STUDY DESIGN: Utility of using computed tomography to predict pedicle screw
misplacement. OBJECTIVE: This study defines the sensitivity and specificity of
predicting pedicle screw placement by experienced clinicians using a CT scan
image. SUMMARY OF BACKGROUND DATA: In clinical and research settings, the method
most commonly used to evaluate pedicle screws placement has been computed
tomography. However, no current literature describes the accuracy of this method
of evaluating screw placement. METHOD: Cobalt-chrome and titanium alloy pedicle
screws of identical size were placed in six cadaveric human lumbar spine. Wide
laminectomy was performed to allow complete visualization of the pedicles. Three
consecutive lumbar levels were instrumented in each spine, giving 36 pedicle
screw placements to identify. The instrumented spines were imaged, and four
orthopaedic spine surgeons and a musculoskeletal radiologist were asked to read
the images to identify the accuracy of screw placement within the pedicles.
RESULTS: The sensitivity rate of identifying a misplaced screw was 67 +/- 6% for
cobalt-chrome screws compared with 86 +/- 5% for titanium screws (P < 0.005). The
specificity rates of radiographic diagnosis of misplaced pedicle screws were 66
+/- 10% for cobalt-chrome screws and 88 +/- 8% for titanium screws (P < 0.005).
Similarly, a statistically significant difference was found in the sensitivity
rates of identifying screws placed correctly in the pedicle: 70 +/- 10% for
cobalt-chrome screws versus 89 +/- 8% for titanium screws (P < 0.005). Overall
accuracy rates were 68 +/- 7% for cobalt chrome screws versus 87 +/- 3% for
titanium screws (P < 0.002). CONCLUSION: Reliance on the computed tomography scan
data alone in determining accuracy of pedicle screws can lead to inaccuracies in
both clinical and research conditions.
PMID- 9399455
TI - Differentiation of submaximal from maximal trunk extension effort: an isokinetic
study using a new testing protocol.
AB - STUDY DESIGN: An evaluation of the relations between concentric and eccentric
contractions of the trunk extensors and extension effort performed at maximal and
submaximal levels. OBJECTIVE: To define quantitative parameter(s) derivable from
isokinetic dynamometry that may differentiate submaximal from maximal trunk
extension moment. SUMMARY OF BACKGROUND DATA: Using various consistency-related
parameters, researchers in previous studies have not been able confirm the
potential of isokinetic dynamometry for identifying submaximal effort during
trunk extension. METHODS: Twenty healthy subjects, 8 women and 12 men without low
back pain history, aged 21 to 30 years, took part in this study. Testing
consisted of three experimental conditions using four intermittent concentric and
eccentric contractions at 20 degrees and 60 degrees/second. The first condition,
in which subjects were asked to exert maximal concentric and eccentric effort,
served as the baseline. In the second condition, subjects were asked to exert 50%
of the force measured in the first condition. In the third condition, subjects
repeated the second condition but were asked to exert the best reproducible level
of force. RESULTS: The highest differentiating power among the experimental
conditions was attributed to the intervelocity difference between the concentric
and eccentric contractions (P < 0.0001). CONCLUSIONS: This protocol effectively
differentiates submaximal from maximal trunk extension effort in normal subjects.
PMID- 9399456
TI - Elective cervical discectomy in California: postoperative in-hospital
complications and their risk factors.
AB - STUDY DESIGN: A retrospective cohort study of short-term outcomes after elective
cervical discectomy in California hospitals. OBJECTIVES: To compare the frequency
of elective cervical discectomy across population strata, to determine the
frequency of adverse outcomes in the early postoperative period, and to identify
risk factors for such outcomes. SUMMARY OF BACKGROUND DATA: Previous cervical
discectomy series have been too small to analyze risk factors for early
complications, and have originated from centers that may not adequately represent
the population. METHODS: Computerized hospital discharge abstracts were obtained
from the California Office of Statewide Health Planning and Development.
Inclusion and exclusion criteria were applied to identify 10,416 routine
discectomies at 257 hospitals in 1990-1991. Several categories of postoperative
complications were identified, along with inpatient deaths, early reoperations,
and nursing home transfers. Logistic regression was used to estimate the
independent effects of patient characteristics on short-term outcomes. RESULTS:
After adjustment for age and gender, blacks were 51% and Hispanics were 24% as
likely as whites to undergo elective cervical discectomy. Overall, 6.7% of
patients had one or more reported postoperative complications: 1.8% had
noninfectious surgical complications, 1.8% had infectious complications, 4.0% had
other medical complications, and 0.35% had unplanned reoperations before
discharge. Fourteen inpatient deaths were reported (0.13%). Congestive heart
failure, alcohol/drug abuse, chronic lung disease, previous spine surgery,
psychological disorders, and chronic musculoskeletal disorders were independently
associated with postoperative complications. Even after adjustment, risk was
higher with advancing age, higher among women than among men, and higher after
posterior fusion than after discectomy without fusion. CONCLUSIONS: The ethnic
disparity in cervical discectomy rates suggests overuse among whites or underuse
among minority populations. The complication rates reported here are similar to
those synthesized from previous literature, except that the lower incidence of
neurologic complications reflects our inability to distinguish preoperative from
postoperative deficits. Important comorbidities should be identified and treated,
if appropriate, before cervical spine surgery.
PMID- 9399457
TI - Lower urinary tract symptoms in lumbar root compression syndromes: a prospective
survey.
AB - STUDY DESIGN: A prospective, observational survey. OBJECTIVES: To describe lower
urinary tract symptoms in uncomplicated lumbar root compression syndromes with
special reference to prevalence, nature, and severity, and to analyze whether the
occurrence of lower urinary tract symptoms correlates with age, pain, analgesic
intake, or the type and level of compression. SUMMARY OF BACKGROUND DATA: Lower
urinary tract symptoms with lumbar root compression are well known in the classic
but rather rare cauda equina syndrome. However, micturition difficulties seem to
be far more frequent in lumbar root compression syndromes. METHODS: One hundred
eight male patients admitted for surgery for lumbar disc herniation or spinal
stenosis were investigated with an extensive questionnaire about their
micturition. RESULTS: Fifty-five percent had significant lower urinary tract
symptoms. Eighty percent of the patients with spinal stenosis had symptoms.
Thirty-three patients had irritative symptoms, 36 had obstructive symptoms, and
23 had retention symptoms. Twenty-four had severe symptoms. Median compression
resulted in more symptoms than paramedian compression. There was no correlation
between age, level of compression, drug intake, or pain score and lower urinary
tract symptoms. CONCLUSIONS: Lower urinary tract symptoms of mixed type occur
with a high prevalence in male patients with lumbar root compression syndromes
referred for neurosurgical evaluation and treatment.
PMID- 9399458
TI - Pediatric chance fracture associated with pedicle screw use: a case report.
AB - STUDY DESIGN: A previously undescribed clinic entity is presented, along with
suggestions to prevent its reoccurrence. OBJECTIVE: To identify a potential
pitfall in the use of pedicle screw instrumentation in trauma cases. Also, to
emphasize the need to identify and treat noncontiguous spinal fractures. SUMMARY
OF BACKGROUND DATA: No previous cases have yet been described with this
particular complication, which would be remedied easily with established methods.
Pedicle screw instrumentation previously has been associated primarily with
complications due to aberrant screw insertion and injury to adjoining tissues, or
due to fracture of the construct itself in the absence of fusion formation.
METHODS: A 15-year-old girl suffered a traumatic T12-L1 fracture dislocation and
paraplegia. After pedicle screw instrumentation, her apparently benign L3
fracture progressed to a severely displaced Chance fracture. This was repaired
with caudal laminar hook compression instrumentation. RESULTS: Postoperatively,
at a 1-year follow-up, the patient's spinal deformity was completely alleviated,
though she remains paraplegic. CONCLUSIONS: Unstable traumatic spinal injuries
treated with pedicular instrumentation should have additional laminar hook
compression configuration reinforcement at the ends of the constructs to prevent
further stress-induced injury from the screws alone. Instrumentation constructs
should not end at even minimally fractured levels.
PMID- 9399459
TI - Current status of percutaneous mechanical thrombectomy. Part I. General
principles.
PMID- 9399461
TI - Distal embolization during thrombectomy with use of the hydrolyser (hydrodynamic
thrombectomy catheter): in vitro testing.
AB - PURPOSE: To evaluate distal embolization while using the Hydrolyser (hydrodynamic
thrombectomy catheter) with special attention to the severity of the stenosis and
temporary distal or proximal flow obstruction. MATERIALS AND METHODS: The
Hydrolyser procedure was assessed in plastic tubes (5-8 mm) with a 70% or 90%
diameter stenosis with or without temporary distal flow obstruction and a 72-hour
old clot proximal to the stenosis. The weight of the embolized particles was
established after passage through filters of 1,000, 500, 100, and 10 microm. To
evaluate the influence of the absolute inner diameter of the stenosis 1.0-, 2.1-,
and 3.0-mm stenoses were compared in 10-mm tubes. RESULTS: Thrombus removal was
greater than 99.9% in all but one of the cases in the 5-8-mm tubes. Embolization
with a weight of more than 1 mg was only found in tubes with a relative stenosis
of 70% and a stenosis inner diameter of greater than 1.5 mm. There was a positive
relationship between inner diameter of the stenosis and the amount of distal
embolization. In the presence of a proximal or distal temporary flow obstruction
during thrombectomy, no distal embolization greater than 1 mg was found.
CONCLUSION: In this in vitro study, the Hydrolyser thrombectomy device
demonstrated minimal distal embolization. The amount of distal embolization that
did occur was related to the absolute stenosis diameter and could be prevented by
a severe distal stenosis and/or a temporary proximal or distal flow obstruction.
PMID- 9399460
TI - Mechanical thrombectomy in acute and subacute thrombosis with use of the Amplatz
device: arterial and venous applications.
AB - PURPOSE: To perform a feasibility study of the Amplatz Thrombectomy Device (ATD)
in a variety of vascular territories with acute or subacute thrombosis. MATERIALS
AND METHODS: Thirteen patients (mean age, 44.6 years) with multiple risk factors
who had acute/subacute thrombosis of the inferior vena cava (IVC) and iliac veins
(n = 3), superior vena cava (SVC) and/or subclavian veins (n = 3), lower
extremity polytetrafluoroethylene (PTFE) graft (n = 2), iliac artery (n = 2),
portal vein and transjugular intrahepatic portosystemic shunt (TIPS) (n = 2), and
an IVC to pulmonary artery Fontan conduit (n = 1), were treated by means of
mechanical thrombectomy with use of the ATD. Thrombolysis failed to recanalize
the vessels when used before thrombectomy for 12-34 hours in three patients, and
was contraindicated in three other patients. Thrombolysis was used as a
complement to the ATD procedure in five patients. RESULTS: Technical success was
achieved in 11 patients, and procedure success was achieved in 10 patients.
Failure was observed in the remaining three patients. One patient with a PTFE
graft was successfully declotted but thrombosis occurred 2 weeks later, requiring
surgery. The other patient with a PTFE graft did not improve and needed surgery
to declot and treat the distal anastomosis and distal circulation. The two
patients with an occluded iliac artery underwent successful declotting but
rethrombosis occurred in one shortly after the procedure requiring thrombolytic
therapy. One patient with TIPS thrombosis improved and another patient with a
thrombosed portal vein did not improve after thrombectomy. CONCLUSION: The ATD is
useful for recanalization of acute/subacute clotted native vessels and grafts.
The application of the device is broad, and although declotting can be achieved
in most cases, long-term success may be limited by anatomical and technical
problems of the grafts and multifactorial clinical problems of severely sick
patients, as was the case in the series. The use of additional thrombolytic
therapy may be necessary in a number of patients.
PMID- 9399462
TI - Rheolytic thrombectomy with use of the AngioJet-F105 catheter: preclinical
evaluation of safety.
AB - PURPOSE: A preclinical evaluation of the safety of the AngioJet-F105 rheolytic
thrombectomy catheter. MATERIALS AND METHODS: The AngioJet-F105 catheter uses
multiple retrograde high-speed fluid jets impinging on a primary aspiration lumen
to create a hydrodynamic recirculation vortex that traps and fragments adjacent
thrombus, with simultaneous evacuation of the resulting debris through the
aspiration lumen. The effect of the AngioJet on treated vessels was evaluated in
10 canines. Vascular integrity on histopathologic examination and endothelial
coverage on scanning electron microscopic study were examined in 15 vessel
segments treated with the AngioJet-F105 catheter, compared with four vessel
segments subjected to the Fogarty balloon maneuver, and 10 untreated vessel
segments. The size distribution of particulate debris, upstream and downstream,
after thrombectomy was determined in a flow-circuit model simulating the
superficial femoral artery. Aliquots from the downstream effluent were then
injected into the renal arteries of two healthy canines. RESULTS: The device
caused only minimal focal endothelial denudation and no significant deep injury.
No significant difference in endothelial coverage occurred in AngioJet-treated
vessel segments compared to untreated control vessels (mean +/- standard
deviation: 88.0% +/- 7.9% vs 89.7% +/- 11.6%, P = .77). Vessels treated with the
Fogarty balloon pullback maneuver had significantly less residual endothelial
coverage (58.0% +/- 8.0%, P < .03). Particulate microemboli in the effluent of
the flow model accounted for 12% of the initial thrombus volume (0% > 100 microm,
99.83% < or = 10 microm). Histopathologic evaluation of the four renal beds
injected with the resulting debris demonstrated no signs of necrosis. A moderate
transient increase in plasma-free hemoglobin occurred, with a mild corresponding
decrease in hematocrit. CONCLUSIONS: The AngioJet-F105 catheter resulted in only
mild and focal injury to the treated vessels. The vast majority of resulting
particulate debris consist of microscopic particles, without significant ischemic
effect.
PMID- 9399463
TI - Acute and delayed outcomes of mechanical thrombectomy with use of the steerable
Amplatz thrombectomy device in a model of subacute inferior vena cava thrombosis.
AB - PURPOSE: To study the efficacy and delayed outcome of mechanical thrombectomy
with the Amplatz thrombectomy device (ATD) in an experimental model of subacute
inferior vena cava (IVC) thrombosis. MATERIALS AND METHODS: Mechanical
thrombectomy was performed in 23 dogs with subacute infrarenal IVC thrombosis (6
15 days old). Heparin was administered during thrombectomy in all procedures
(activated clotting time > or = 300 sec). Thirteen animals were killed
immediately after thrombectomy, and the remaining 10 were allowed to survive for
up to 1 month with no anticoagulation therapy. RESULTS: Venographic patency of
the IVC was restored in all animals, although residual mural thrombus remained in
nine dogs (< 20% narrowing in seven, 20%-30% narrowing in two). No
histopathologic evidence of mechanical wall disruption attributed to mechanical
thrombectomy was seen. However, foci of organizing residual thrombus with
associated transmural phlebitic changes with round-cellular infiltration were
present in all acute specimens, including those appearing clear at venography.
Venography at 1 week or 1 month after thrombectomy showed IVC rethrombosis in
eight dogs (80%) who were not receiving anticoagulants. During mechanical
thrombectomy, a small increase in mean pulmonary artery pressure occurred, with a
corresponding decrease in systemic arterial oxygen saturation. No acute emboli
were noted on the post-thrombectomy pulmonary angiograms. However,
histopathologic examination of acutely explanted lungs in 11 animals showed
arteriolar microemboli (100-500 microm) in four. CONCLUSION: Mechanical
thrombectomy with use of the ATD can effectively clear subacute IVC thrombus.
However, rethrombosis is common and may be due to the high prevalence of
phlebitis and residual thrombus. Anticoagulation may need to be continued after
successful thrombectomy to prevent progression of residual thrombus and allow
mural phlebitic changes to subside.
PMID- 9399464
TI - Guide wire directed manipulation of malfunctioning peritoneal dialysis catheters:
a critical analysis.
AB - PURPOSE: To evaluate patency rates after guide wire directed manipulation of
malfunctioning continuous ambulatory peritoneal dialysis (CAPD) catheters.
MATERIALS AND METHODS: During a 58-month period, 23 patients underwent 34
outpatient guide wire directed manipulations of their CAPD catheter to improve
function (n = 30) or reduce pain and improve function (n = 4) during dialysis.
Catheter patency rates were subsequently determined by review of departmental,
hospital, and dialysis center charts; procedural reports; and patient telephone
interviews. RESULTS: Among 12 patients who underwent a single guide wire directed
manipulation, long-term (> 30 days) catheter patency was achieved in seven (58%).
With use of the Kaplan-Meier survival method, the 3-, 6-, and 12-month
probability of patency after a single guide wire manipulation was 0.61, 0.54, and
0.11, respectively. The mean duration of patency achieved in this group was 131
days (range, 2-421 days). In those patients (n = 8) who underwent multiple
catheter manipulations (n = 19), 11 (58%) procedures resulted in long-term
patency, with each patient (100%) achieving at least one such period. The Kaplan
Meier survival method determined the probability of patency in this group at 3,
6, and 12 months to be 0.75, 0.69, and 0.54, respectively. The mean secondary
catheter patency was 235 days (range, 2-646 days). Overall, 75% of patients
followed up achieved at least one period of long-term catheter patency during the
time of this study. One (3%) episode of postprocedure peritonitis occurred.
CONCLUSION: Guide wire directed CAPD catheter manipulation is a relatively simple
outpatient procedure that restores long-term catheter function for most patients
with minimal risk for a major complication. Patients with nonfunctioning CAPD
catheters who do not have peritonitis or sepsis will most likely benefit from at
least one attempt at radiologic manipulation of their catheter.
PMID- 9399465
TI - Prospective randomized trial of a metallic intravascular stent in hemodialysis
graft maintenance.
AB - PURPOSE: To evaluate percutaneous transluminal angioplasty (PTA) alone versus PTA
and flexible self-expanding stent placement for the management of hemodialysis
access graft stenoses. MATERIALS AND METHODS: Thirty-seven grafts in 34 patients
were evaluated for abnormal intradialytic parameters (n = 27) or occlusion (n =
10). Angiography identified stenoses (mean, 69%; range, 50%-95%) at or within 3
cm of the vein-graft junction (70%) or in the peripheral outflow vein (30%) that
had recurred within a 6-month period after previous PTA. They were randomized to
PTA alone (n = 20) or PTA with Wallstent (n = 17). Additional lesions were
treated by PTA alone, and a mean of 1.4 (range, 1-3) lesions were treated per
patient. Significant differences existed in the mean number of previous accesses
(1.8 and 0.8 in the PTA and stent groups, respectively) and in the mean number of
previous interventions in the current access (1.8 and 2.9, respectively). End
points were subsequent radiologic or surgical intervention, transplantation, and
death. RESULTS: Technical success was 100% (mean residual stenosis, 12%; range,
0%-30%). The primary patency of 128 days and secondary patency of 431 days were
similar for both groups. Secondary patency required a mean of 1.8 and 1.6
additional interventions for the PTA and stent groups, respectively. The
adjunctive stent placement increased the cost of the procedure by 90%.
CONCLUSION: Despite significant added costs, there was no advantage to stent
placement for recurrent peripheral hemodialysis graft stenoses that were already
adequately dilated with balloon angioplasty.
PMID- 9399466
TI - Wallstents and Craggstents in hemodialysis grafts and fistulas: results for
selective indications.
AB - PURPOSE: To report the value of selective placement of self-expandable stents
(Wallstent and Craggstent) for the treatment of limitations and, occasionally, of
complications of dilation in hemodialysis access, and especially for delaying
restenosis. MATERIALS AND METHODS: This is a retrospective study of a 7-year
period, during which 41 Wallstents and 11 Craggstents were placed in 26
polytetrafluoroethylene (PTFE) grafts, 15 native fistulas, and nine central veins
of 47 patients. The indications were stenosis recoil (n = 13), recurrent
restenosis within 6 months (n = 33), restenosis after 6 months (n = 3), and acute
angioplasty-induced rupture (n = 1). Restenosis after stent placement
necessitated redilation and percutaneous declotting and 10 additional stent
placements. RESULTS: Two initial misplacements were corrected immediately.
Primary patency rates for PTFE grafts were 58% +/- 10% at 6 months and 23% +/-
10% at 1 year, respectively. Secondary patency rates were 100% at 6 months and
88% +/- 8% at 1 year, respectively. For native fistulas, primary patency rates
were 47% +/- 12% at 6 months and 20% +/- 18% at 1 year. Secondary patency rates
were 95% +/- 6% at 6 months and 79% +/- 14% at 1 year. It was necessary to
reintervene after stent placement to maintain or to restore patency every 9
months for PTFE grafts and every 7.3 months for native fistulas. When stents were
placed for treatment of early recurring restenosis, the mean interval between
radiologic interventions (redilations or declottings) performed to maintain or to
restore patency before stent placement was multiplied by 2.1 after stent
placement for both grafts (3.2 months increased to 6.9, P < .01) and native
fistulas (2.9 months increased to 6.2, P < .02). CONCLUSIONS: Wallstents and
Craggstents are valuable for the treatment of failure of regular dilation and
they double the intervals between reinterventions for early (< 6 months)
recurring stenoses in PTFE grafts and native fistulas.
PMID- 9399467
TI - Experience with 100 consecutive central venous access arm ports placed by
interventional radiologists.
AB - PURPOSE: This study reports the authors' experience with long-term follow-up of
100 consecutive peripherally inserted, subcutaneous arm ports for central venous
access. MATERIALS AND METHODS: One hundred patients with subcutaneous arm ports
inserted by interventional radiologists were retrospectively studied. Data were
collected from the patients' medical records and from telephone canvassing. Using
each insertion period as an observation, the complication rates per 100 catheter
days were determined with 95% confidence intervals (CIs). RESULTS: One hundred
subcutaneously implanted ports were placed in 98 patients; three devices (three
patients) were lost to follow-up, leaving 97 devices in 95 patients. Total
exposure time was 23,842 days (mean, 246 days; range, 2-865 days). Seven
infectious and two noninfectious complications occurred with seven (7.2%) devices
in six patients (6.3%), yielding 0.038 complications per 100 catheter days at
risk (95% CI; 0.011-0.069) and 0.029 infections per 100 catheter days at risk
(95% CI; 0.008-0.058). A successful clinical outcome was defined as a functional
port at removal, time of death, or at study closure (minimum of 6 months of
follow-up), which was not removed because of a complication. This successful
outcome was achieved in 91 ports (93.8%). Procedural-related complications,
defined as those occurring up to 30 days after insertion, occurred in only one
port (thrombophlebitis and catheter tip infection-day 9). All other patients
received several months of service from their port. Fifteen devices were placed
in 13 patients with HIV for 3,486 days, with a total complication rate of 0.11
per 100 catheter days (95% CI; 0.0-0.28), all of which were infections. Devices
in HIV-positive patients were associated with higher total complication (20% vs
4.9%) and infection rates (20% vs 3.7%) than devices in patients without HIV
infection. This gives a relative risk 8.17 x (P = .04) greater for infectious
complications for devices placed in HIV-infected individuals. CONCLUSIONS:
Subcutaneous arm ports placed by interventional radiologists are effective for
central venous access with excellent functionality (93.8% achieved a successful
long-term outcome) and a very low procedural complication rate. Although
infections were more frequent in HIV-infected individuals, these devices are
associated with a very low incidence of both immediate and long-term
complications, including infection, for all patients.
PMID- 9399468
TI - Outcome of 350 implanted chest ports placed by interventional radiologists.
AB - PURPOSE: To determine the outcome of implanted chest ports placed by
interventional radiologists. MATERIALS AND METHODS: Between June 1993 and July
1996, a single institution placed 350 implanted chest ports in 346 patients by
means of the subclavian vein approach. The medical records of these patients were
reviewed to determine the outcome of the ports. Ports were implanted for
chemotherapy (n = 341), blood transfusion (n = 7), or antibiotics (n = 2).
RESULTS: Immediate complications were seven (2%) pneumothoraces and one (0.3%)
hematoma. Four (1.1%) of the pneumothoraces necessitated hospital admission and
treatment with a chest tube. The remaining three were managed on an outpatient
basis. One was successfully treated in the interventional suite by catheter
suction. Two pneumothoraces were observed and resolved spontaneously. Mean time
of patient follow-up was 260 days (range, 22-929 days). Total time of follow-up
was 91,000 catheter days. Delayed complications were 10 cases of thrombosis (2.9%
or 0.11 per 1,000 catheter days) of the subclavian vein, four infections (1.1% or
0.04 per 1,000 catheter days), four catheter coiling or tip malpositions (1.1% or
0.04 per 1,000 catheter days), three catheter occlusions (0.9% or 0.03 per 1,000
catheter days), and one catheter leak (0.3% or 0.01 per 1,000 catheter days). Six
(1.7%) ports had to be removed as a result of a delayed complication. CONCLUSION:
Chest port implantation by interventional radiologists within the radiology
department is a successful and safe procedure with complication rates equivalent
to, or lower than, those reported in surgical placement series.
PMID- 9399469
TI - Mural delivery of iloprost with use of hydrogel-coated balloon catheters
suppresses local platelet aggregation.
AB - PURPOSE: To develop reproducible and quantifiable methods for mural delivery of
iloprost, a potent agent against platelet aggregation, with use of hydrogel
coated angioplasty balloons, and to determine the in vivo effect of direct
iloprost delivery on platelet aggregation at the angioplasty site. MATERIALS AND
METHODS: Drug loading of tritiated iloprost from an immersion solution onto
hydrogel-coated balloons was evaluated as a function of balloon size (3 mm x 2
cm, 6 mm x 2 cm, 8 mm x 3 cm; n = 4 each), drug concentration (0.0715 mg/mL,
0.1072 mg/mL, 0.1430 mg/mL; n = 3 each), and duration of immersion (40 seconds,
60 seconds, 120 seconds; n = 3 each). In another set of experiments, optimal
drying methods were tested to minimize drug loss within a protective delivery
sheath (n = 3 each). Ex vivo angioplasty was performed on excised swine arteries
to estimate how much of the drug present on the balloon could be delivered to the
wall (n = 3 iliac segments). Finally, in vivo angioplasty was performed in three
Yorkshire pigs (n = 6 iloprost-treated and 6 control arteries) and indium-111
labeled platelet aggregation was measured at these sites, which were harvested 1
hour after the procedure. RESULTS: In the initial set of experiments, the authors
found that the volume of drug loaded is determined by the wet-volume of the
hydrogel coating, that the majority of volume loading occurs within the first 2
minutes, and that the volume uptake is independent of the drug concentration. The
optimal drying method resulting in the least loss of iloprost within the sheath
(only 4%) was prolonged drying (5 hours) under ambient conditions. Ex vivo
angioplasty experiments showed that approximately 33% of the drug present on the
balloon can be delivered to the wall. Finally, in vivo experiments showed that
platelet aggregation is significantly suppressed at treated sites (by
approximately 33% compared to control sites; P = .03) by minuscule mural doses of
iloprost (roughly estimated at under 1 microg). CONCLUSION: Quantifiable and
reproducible methods for loading iloprost onto hydrogel-coated angioplasty
balloons were developed. The best of these methods was able to deliver enough
iloprost into the wall to significantly reduce local platelet aggregation.
PMID- 9399470
TI - Transcatheter venous thrombolysis--pitfalls and pratfalls: a case discussion of
indications, technique, and alternatives.
PMID- 9399471
TI - Detection of implanted metallic devices by airport security.
AB - PURPOSE: Permanent metallic implants are commonly placed by interventional
radiologists. The authors evaluate the ability of these and various orthopedic
devices to be detected by airport security metal detectors. MATERIALS AND
METHODS: A variety of commonly placed radiologic and orthopedic implants were
evaluated by three types of metal detectors at Toronto International Airport.
RESULTS: No radiologic devices were detected by walk-through detectors. Metal
containing ports were the only device to set off the hand-held scanners.
CONCLUSION: Radiology patients can be reassured that their devices will not set
off walk-through airport security metal detectors, however, some metallic ports
may be detected by hand-held scanning devices.
PMID- 9399472
TI - Digital subtraction versus film-screen angiography for detecting acute pulmonary
emboli: evaluation in a porcine model.
AB - PURPOSE: To compare the diagnostic performance of digital subtraction angiography
(DSA) to that of film-screen angiography (FSA) for detecting acute pulmonary
embolism (PE) in a porcine model. MATERIALS AND METHODS: DSA and FSA were
performed in 13 pigs before and after central venous administration of autologous
emboli. Results were compared to findings at necropsy with use of ex vivo
pulmonary angiography to guide pathologic sectioning. The sensitivity and
predictive value of a positive case for detecting each embolus were computed for
each pulmonary artery branch order and compared with use of 95% confidence
intervals. Interobserver variability among three readers for individual PE
detection was calculated. RESULTS: Pathologic examination of the lungs revealed
100 total PEs (location by vessel order: 1st = 1, 2nd = 0, 3rd = 15, 4th = 32, >
5th = 52). On average, FSA review identified 72 (72%) emboli and DSA review, 65
(65%). There was no significant difference in sensitivity or predictive value of
a positive case between DSA and FSA for detecting emboli (P > .05). There was
similar agreement among readers for individual PE detection with DSA (mean, 84%)
and FSA (mean, 80%). CONCLUSION: The diagnostic performance of DSA is equivalent
to that of FSA for detecting emboli in porcine PA branches. Interobserver
agreement for individual PE detection is similar for both imaging techniques.
PMID- 9399473
TI - Life-threatening gastrointestinal hemorrhage secondary to nonmesenteric sources.
PMID- 9399474
TI - IVC filter tilt and asymmetry: comparison of the over-the-wire stainless-steel
and titanium Greenfield IVC filters.
AB - PURPOSE: A comparison of tilting, caval coverage, asymmetry, and insertion
problems with the over-the-wire stainless-steel and titanium versions of the
Greenfield filter. MATERIALS AND METHODS: The study compared 104 stainless-steel
and 141 titanium Greenfield inferior vena cava (IVC) filter insertions. The angle
the sheath and deployed filter made relative to the cava, as well as filter strut
distribution, were determined from spot films. The proportionate caval coverage
was computed from the cavogram (anteroposterior projection). Mean filter tilts,
subgrouped by insertion site, and caval coverage were compared with the Student t
test, whereas strut patterns were analyzed with a contingency table. RESULTS: The
filter caval and sheath caval angles correlated. The filter caval angles varied
with insertion site, but were lowest with a right jugular approach. Caval
coverage was identical with both designs. The stainless-steel version resulted in
a more uniform distribution of struts in comparison with the titanium version.
The incidence of insertion problems was not significantly different between the
filter types. CONCLUSIONS: While IVC filter tilting was not improved with the
newer design, the pattern of struts was more uniformly symmetric with the
stainless-steel device. The right jugular insertion site was associated with the
lowest filter caval angles and the most symmetric pattern of struts.
PMID- 9399475
TI - Distal embolization from an unsuspected external iliac artery pseudoaneurysm:
diagnosis during urokinase infusion.
PMID- 9399476
TI - Treatment of hemoptysis in Behcet syndrome with pulmonary and bronchial
embolization.
PMID- 9399477
TI - Treatment of chronic iliac artery occlusions with guide wire recanalization and
primary stent placement.
AB - PURPOSE: To evaluate the results of primary stent placement without initial
thrombolysis in the treatment of iliac occlusions. MATERIALS AND METHODS: During
a 3-year period, 61 iliac artery occlusions were treated in 59 patients. The mean
length of the occluded segment was 10 cm (range, 4-25 cm). The occluded arteries
were treated with primary placement of self-expandable metallic stents. RESULTS:
Successful recanalization with primary stent placement was possible in 56 of 61
occlusions (92% technical success rate). Mean Doppler ankle/brachial index
increased from 0.51 to 0.90 immediately after treatment and was 0.91 on the last
follow-up (P < .05). Primary patency rate at 24 months was 73%, and secondary
patency rate was 88%. Procedural complications included distal embolization (n =
4) and an episode of massive intra-abdominal bleeding. Three patients developed a
hematoma at the puncture site that did not require additional therapy. Late
complications included stent occlusion (n = 9) and significant stenosis related
to intimal hyperplasia (n = 1). Mean follow-up period was 29 months (range, 7-55
months). CONCLUSION: Primary stent placement is an effective therapeutic option
for iliac artery occlusions.
PMID- 9399478
TI - Endovascular stents covered with pre-expanded polytetrafluoroethylene for
treatment of iliac artery aneurysms and fistulas.
AB - PURPOSE: This report describes the early clinical experience with use of a
transluminally placed endovascular graft (TPEG) covered with pre-expanded
polytetrafluoroethylene (PTFE) to treat iliac artery aneurysms and fistulas.
MATERIALS AND METHODS: Eight patients with iliac artery aneurysms (n = 7) and
common iliac artery to common iliac vein fistula (n = 1) were treated with TPEGs.
The iliac artery aneurysms were either common iliac (n = 6) or hypogastric (n =
1). All of the patients had significant comorbid diseases. The TPEG devices were
made with pre-expanded PTFE sutured to Palmaz stents and delivered through 10- or
12-F sheaths. RESULTS: The aneurysms were successfully excluded in six of seven
patients and the one iliac artery-to-vein fistula was successfully occluded.
There were no immediate procedural complications related to the TPEG devices.
Follow-up was limited (mean, 12 months), but no stenoses or occlusions of the
TPEG devices were detected. The one failure was probably due to the marked
tortuousity of the iliac artery, which prevented an adequate seal. CONCLUSION: In
the authors' early clinical experience, the use of TPEG devices with pre-expanded
PTFE successfully treated iliac artery aneurysms and an iliac artery-to-vein
fistula. Although the results are encouraging, longer follow-up is necessary to
better evaluate this type of treatment.
PMID- 9399479
TI - Treatment of traumatic carotid pseudoaneurysm with endovascular stent placement.
PMID- 9399480
TI - Use of a Palmaz stent deployed in the superior mesenteric artery for chronic
mesenteric ischemia.
PMID- 9399481
TI - Use of CT-guided marking of the portal vein in creation of 150 transjugular
intrahepatic portosystemic shunts.
PMID- 9399482
TI - Percutaneous treatment of an iliac artery pseudoaneurysm associated with a stent
graft.
PMID- 9399483
TI - Vascular or interventional procedures in patients with diabetes.
PMID- 9399484
TI - Dislodgment of a stainless-steel Greenfield filter during exchange of a central
venous catheter.
PMID- 9399485
TI - Venous injection to assess for thoracic aortic trauma.
PMID- 9399486
TI - IS6110 fingerprinting of drug-resistant Mycobacterium tuberculosis strains
isolated in Germany during 1995.
AB - The epidemiological relatedness of drug-resistant Mycobacterium tuberculosis
strains isolated in Germany in 1995 was evaluated by the standardized IS6110
fingerprinting method. Altogether, 196 M. tuberculosis isolates from 167 patients
were analyzed. A large degree of IS6110 polymorphism was found, ranging from 1 to
20 copies. Multiple isolates from one patient generally remained stable over a
period of up to 1 year. However, one strain showed an additional fragment 7
months after the first isolate was obtained. Isolates from 55 patients (33%)
showed identical fingerprint patterns or fingerprint patterns that differed only
in one band, and thus they were clustered in 22 fingerprint groups. Specific
transmission links could be established between members of four groups, e.g.,
transmission by family contacts. In one case, transmission of a multidrug
resistant strain to a patient initially infected with a drug-susceptible strain
could be shown. Besides these fingerprint groups, 30 of the 167 isolates
(approximately 18%) could be grouped in two fingerprint clusters with a
similarity of at least 78%. Approximately 60% of the patients of these two
clusters were known to be immigrants from the former Soviet Union, and one
patient is still living in Belarus. In conclusion, our results indicate that (i)
transmission of drug-resistant strains contributes substantially to the emergence
of drug-resistant tuberculosis in Germany and (ii) drug-resistant M. tuberculosis
strains were presumably carried over from the former Soviet Union to Germany by
immigrants.
PMID- 9399487
TI - Differentiation of Helicobacter pylori strains directly from gastric biopsy
specimens by PCR-based restriction fragment length polymorphism analysis without
culture.
AB - Recent studies have shown the usefulness of PCR-based restriction fragment length
polymorphism (RFLP) analysis for differentiating Helicobacter pylori strains
isolated by culture. For this study, a PCR-based RFLP assay was developed for
directly typing H. pylori strains from gastric biopsy specimens. Nineteen gastric
biopsy specimens obtained from patients undergoing endoscopy for gastrointestinal
complaints were cultured for isolation of H. pylori. Genomic DNA preparations
from these gastric biopsy specimens and the corresponding H. pylori isolates were
tested by our PCR-based RFLP assay. The 1,179-bp H. pylori DNA fragments
amplified by the PCR assay were digested with the restriction enzymes HhaI, MboI,
and AluI and analyzed by agarose gel electrophoresis. HhaI, MboI, and AluI
digestion produced 11, 10, and 6 distinguishable digestion patterns,
respectively, from the 19 H. pylori isolates tested and generated 13, 11, and 6
different patterns, respectively, from the 19 gastric biopsy specimens. The
patterns from 13 of the 19 gastric biopsy specimens matched those of the H.
pylori isolates from the corresponding patients. The patterns from the remaining
six biopsy specimens appeared to represent infection by two strains of H. pylori;
the pattern of one strain was identical to that of the isolate from the
corresponding patient. By combining all the restriction enzyme digestion patterns
obtained by using HhaI, MboI, and AluI, we observed 19 distinct RFLP patterns
from the 19 specimens. The results suggest that the PCR-based RFLP analysis
method may be useful as a primary technique to identify and distinguish H. pylori
strains directly from gastric biopsy specimens without culture of the organisms.
PMID- 9399488
TI - Fecal carriage of vancomycin-resistant enterococci in hospitalized patients and
those living in the community in The Netherlands.
AB - In order to determine the prevalence of vancomycin-resistant enterococci (VRE) in
The Netherlands, 624 hospitalized patients from intensive care units or hemato
oncology wards in nine hospitals and 200 patients living in the community were
screened for VRE colonization. Enterococci were found in 49% of the hospitalized
patients and in 80% of the patients living in the community. Of these strains, 43
and 32%, respectively, were Enterococcus faecium. VRE were isolated from 12 of
624 (2%) and 4 of 200 (2%) hospitalized patients and patients living in the
community, respectively. PCR analysis of these 16 strains and 11 additional
clinical VRE isolates from one of the participating hospitals revealed 24 vanA
gene-containing, 1 vanB gene-containing, and 2 vanC1 gene-containing strains. All
strains were cross-resistant to avoparcin but were sensitive to the novel
glycopeptide antibiotic LY333328. Genotyping of the strains by arbitrarily primed
PCR and pulsed-field gel electrophoresis revealed a high degree of genetic
heterogeneity. This underscores a lack of hospital-driven endemicity of VRE
clones. It is suggested that the VRE in hospitalized patients have originated
from unknown sources in the community.
PMID- 9399489
TI - Molecular tracking of Candida albicans in a neonatal intensive care unit: long
term colonizations versus catheter-related infections.
AB - Nosocomial neonatal candidiasis is a major problem in infants requiring intensive
therapy. The subjects of this retrospective study were nine preterm infants
admitted to the neonatal intensive care unit of the Hospital Central de Asturias
between March 1993 and August 1994. The infants were infected with or colonized
by Candida albicans. Five patients developed C. albicans bloodstream infections.
A total of 36 isolates (including isolates from catheters and parenteral
nutrition) were examined for molecular relatedness by PCR fingerprinting and
restriction fragment length polymorphism (RFLP) analysis. The core sequence of
phage M13 was used as a single primer in the PCR-based fingerprinting procedure,
and RFLP analysis was performed with C. albicans-specific DNA probe 27A. Both
techniques were evaluated with a panel of eight C. albicans reference strains,
and each technique showed eight different patterns. With the 36 isolates from
neonates, each technique enabled us to identify by PCR and RFLP analysis seven
and six different patterns, respectively. The combination of these two methods
(composite DNA type) identified eight different profiles. A strain with one of
these profiles was present in three patients and in their respective catheters.
Patients infected with or colonized by this isolate profile were clustered in
time. Among the other patients, each patient was infected over time and at
multiple anatomic sites with a C. albicans strain with a distinct DNA type. We
conclude that C. albicans was most commonly producing long-term colonizations,
although horizontal transmission probably due to catheters also occurred.
PMID- 9399490
TI - Racial tropism of a highly toxic clone of Actinobacillus actinomycetemcomitans
associated with juvenile periodontitis.
AB - Actinobacillus actinomycetemcomitans strains with enhanced levels of production
of leukotoxin are characterized by a 530-bp deletion from the promoter region of
the leukotoxin gene operon. Previous isolates with this deletion constituted a
single clone belonging to serotype b, although they displayed minor differences
among each other. We have analyzed the geographic dissemination of this clone by
examining 326 A. actinomycetemcomitans isolates from healthy and periodontally
diseased individuals as well as from patients with different types of extraoral
infections originating from countries worldwide. A total of 38 isolates, all
belonging to the same clone, showed the 530-bp deletion. Comparison of a 440-bp
sequence from the promoter region of the leukotoxin gene operon from 10 of these
strains revealed complete identity, which indicates that the deletion originates
from a single mutational event. This particular clone was exclusively associated
with localized juvenile periodontitis (LJP). In at least 12 of 28 families from
which the clone was isolated, more than one family member had LJP. Notably, all
the subjects carrying this clone had a genetic affiliation with the African
population. These observations suggest that juvenile periodontitis in some
adolescents with an African origin is associated with a disseminating clone of A.
actinomycetemcomitans.
PMID- 9399491
TI - Immunoblot analysis of Leishmania panamensis antigens in sera of patients with
American cutaneous leishmaniasis.
AB - Sera from 86 Colombian patients with parasitologically confirmed cutaneous
leishmaniasis were studied by immunoblot analysis in order to identify a specific
pattern for Leishmania infection. A soluble extract of Leishmania panamensis was
used as the antigen. Sera from patients with Chagas' disease and sera from
patients with no record of infection with trypanosomatids were also studied. The
sera from patients with cutaneous leishmaniasis specifically recognized fractions
of 120 kDa (76.7%), 123 and 129 kDa (69.7%), 138 kDa (61.6%), 141 kDa (53.4%),
and 78 kDa (44.1%). No band common to all patients infected with Leishmania
parasites was found at the time of diagnosis. Likewise, the pattern of immunoblot
change after the patients were treated and apparently cured with meglumine
antimoniate (Glucantime) was studied by evaluating sera pretreatment and 1 year
posttreatment. Only minor changes in the color intensity at the same serum
dilution between pre- and posttreatment sera were found, although the antibody
titers by indirect immunofluorescence were negative for the posttreatment sample.
This study shows that Western blot analysis is a more sensitive test for the
detection of anti-Leishmania antibodies. However, the importance of whether the
presence of antibodies correlates with the presence of Leishmania antigens could
not be resolved by the data obtained from this study.
PMID- 9399492
TI - Distinctive IS200 insertion between gyrA and rcsC genes in Salmonella typhi.
AB - While probing the vicinity of ompC, a copy of the IS200 insertion element was
found between the gyrA and rcsC genes of Salmonella typhi, the causal agent of
typhoid fever. This distinctive feature was conserved throughout 63 S. typhi
isolates of different geographical origins and was absent from 46 other
Salmonella serotypes, including those most associated with human infections, as
well as from 19 other enteric bacteria. Furthermore, the location of this IS200
copy corresponds to a constant band, present throughout the 14 PstI S. typhi
IS200 fingerprints, encompassing several Vi phage types. Interestingly, an
apparently unrelated serotype not frequently associated with human disease,
Salmonella weltevreden, contained an IS200 copy at the same position, although it
was accompanied by an additional segment of cryptic DNA. On the basis of these
findings, PCR assays were designed for molecular typing of S. typhi, and these
are potentially useful in studying the epidemiology of typhoid fever.
PMID- 9399493
TI - Identification of Legionella species by lipopolysaccharide antigen pattern.
AB - Electrophoretic analysis of lipopolysaccharide (LPS) extracts from 430 previously
serotyped Legionella isolates and 28 American Type Culture Collection (ATCC) non
Legionella pneumophila Legionella reference strains representing different
Legionella species and serogroups has been performed. LPS was prepared from
Legionella suspensions by sonication and proteinase K digestion. Following sodium
dodecyl sulfate-polyacrylamide gel electrophoresis, LPS bands were either stained
with silver nitrate or transferred onto a nitrocellulose membrane and detected
with rabbit antibodies raised against L. pneumophila serogroup 5, which was known
to cross-react with L. pneumophila serogroups 1 to 14. Silver staining revealed
that each of the 28 ATCC non-L. pneumophila Legionella strains possessed an
individual and characteristic LPS banding pattern. The LPS profile was defined by
the molecular weight of the visualized bands and/or the individual ladder-like
LPS pattern. It was demonstrated by immunoblotting that non-L. pneumophila
Legionella strains did not react with the serogroup 5 antiserum, thus allowing
for the differentiation between L. pneumophila and non-L. pneumophila species.
PMID- 9399494
TI - Use of serum-specific immunoglobulins A and G for detection of Helicobacter
pylori infection in patients with chronic gastritis by immunoblot analysis.
AB - Multiple invasive and noninvasive tests for detecting Helicobacter pylori
infection are available. The current "gold standard" for the diagnosis of H.
pylori infection requires histology and the rapid urease test. Our aim was to
test the performance of immunoglobulin A (IgA) and IgG immunoblot assays in
comparison with that of the gold standard tests for the diagnosis of H. pylori
infection. Ninety patients who underwent gastroscopy were analyzed in a
prospective study. Fifty-nine of them were defined to be H. pylori positive by
the gold standard tests. The IgA and IgG immunoblot assays correctly identified
H. pylori infection in 17 and 58 of these patients, respectively, indicating that
determination of IgA antibodies seems to be of low diagnostic value for H. pylori
infection. In contrast, the sensitivity and specificity of the IgG immunoblot
assay were 98 and 71%, respectively, with positive and negative predictive values
of 87 and 96%, respectively. Therefore, the IgG immunoblot assay proved to be a
sensitive and useful, noninvasive test for the diagnosis of H. pylori infection.
PMID- 9399495
TI - Antigenic variation of core, NS3, and NS5 proteins among genotypes of hepatitis C
virus.
AB - Assays that detect antibody to hepatitis C virus (HCV) are used to screen blood
donors and patients with hepatitis. Current enzyme-linked immunosorbent assay
(ELISA)-based methods are invariably based upon antigens from expressed
recombinant proteins or oligopeptides from HCV type 1. Some HCV antigens used in
screening assays are coded by regions of the HCV genome that show extensive
variability; therefore, HCV type 1-based assays may be less effective for the
detection of antibody elicited by infection with other genotypes. In this study,
we have measured antibody reactivity of sera from 110 hepatitis C patients
infected with type 1b, 3a, or 4a to genotype-specific and cross-reactive epitopes
present in recombinant proteins from HCV genotypes 1b (core, NS3, and NS5), 3a
(NS3, NS5), and 4a (core, NS3), corresponding to those used in current third
generation screening ELISAs. By comparing the serological reactivities of sera to
type-homologous and type-heterologous antigens, we detected a significant type
specific component to the reactivity to NS3 (61 to 77% of the total reactivity)
and NS5 (60% of the total reactivity). Furthermore, despite the similarities in
the amino acid sequences of the core antigens of type 1b and type 4a, we also
found significantly greater reactivity to type-homologous antigens, with
approximately 25% of reactivity being type specific. These findings are
consistent with previous findings of fivefold weaker reactivity of sera from HCV
type 2- and HCV type 3-infected blood donors in the currently used third
generation ELISAs and suggest that these assays are suboptimal for screening
populations in which the predominant genotype is not type 1.
PMID- 9399496
TI - Multicenter study using standardized protocols and reagents for evaluation of
reproducibility of PCR-based fingerprinting of Acinetobacter spp.
AB - Seven laboratories in six European countries examined 40 isolates belonging to
the Acinetobacter calcoaceticus-Acinetobacter baumannii complex to investigate
whether standardized protocols and quality-controlled reagents could produce
reliable, discriminatory, and reproducible PCR-based fingerprinting results. Four
PCR protocols with different primers (primers DAF4, ERIC-2, M13, and REP1 + REP2)
were used. The epidemiological conclusions reached by the participating
laboratories were substantially correct, with 96.4% of the total isolate grouping
allocations agreeing with the consensus view. All laboratories identified the
main epidemiological clusters, and each laboratory also identified two non
outbreak-related isolates. There were no significant differences between the
isolate grouping results obtained by the different protocols and with the
different primers. Visual comparison indicated that the standardized protocols
and reagents yielded reproducible fingerprint patterns, but with some variations
in particular band intensities. Minor variations in fingerprint profiles were
detected, but computer-assisted analysis of PCR fingerprints obtained on agarose
gels demonstrated that 88.3 to 91.6% (depending on the source of DNA) of the
patterns clustered correctly, while 96.4 to 98.9% of the patterns clustered
correctly following automated high-resolution laser fluorescence analysis.
Correlation of the patterns for isogenic isolates ranged from 83.3 to 86.6% but
was slightly better (mean correlation, 87.1%) for centrally prepared DNA extracts
than for DNA extracts prepared by individual laboratories (mean correlation,
84.7%). It was concluded that independently produced PCR fingerprint patterns can
be obtained reproducibly for Acinetobacter spp. at the practical level if (i)
quality-controlled reagents, (ii) standardized extraction of DNA, and (iii)
standardized amplification conditions are used.
PMID- 9399497
TI - Influence of endocervical specimen adequacy on PCR and direct fluorescent
antibody staining for detection of Chlamydia trachomatis infections.
AB - The cellular quality of the endocervical swab specimen used for the detection of
Chlamydia trachomatis may dramatically impact the sensitivity of the diagnostic
assay used. An evaluation of the adequacy of 319 endocervical swab specimens from
women attending two inner-city sexually transmitted disease and family planning
clinics, as well as five high school-based family planning clinics, was
performed, and the resulting data were compared with the diagnostic results
obtained by both Amplicor PCR and Microtrak direct fluorescent-antibody (DFA)
staining. The swab from each patient was rolled across the open circular area of
a DFA slide and then used to inoculate a transport tube for PCR (Roche), after
which the swab was discarded. The slides were stained and examined by
epifluorescence microscopy for the presence of C. trachomatis elementary bodies
and for the presence and number of cell types to determine specimen adequacy.
Cellular adequacy for a cervical swab specimen was defined as the presence of one
or more columnar epithelial or metaplastic epithelial cells or the presence of
more than 100 erythrocytes per high-power microscopic field. Of the 319 specimens
read by DFA, 204 (63.9%) were determined to be adequate. There were 34 (10.7%)
positive specimens by DFA and/or PCR. Twenty-nine (9.1%) specimens were positive
by PCR, 20 (6.3%) specimens were DFA positive, and 15 (4.7%) were concordantly
positive by both tests. The prevalence of chlamydia among adequate specimens was
14.2% (29/204), compared to 4.3% (5/115) for inadequate specimens (P < 0.0001).
Variations in specimen quality and the sensitivity of the diagnostic assay used
have a significant impact on determining the prevalence of C. trachomatis in a
population.
PMID- 9399499
TI - Typing of Pneumocystis carinii f. sp. hominis by single-strand conformation
polymorphism of four genomic regions.
AB - To better investigate Pneumocystis carinii f. sp. hominis epidemiology, we have
developed a molecular typing method. Because of the limited genetic variability
of the P. carinii hominis genome, a multitarget approach was used. Four variable
regions of the genome were amplified by PCR, polymorphism in each region was
assessed by the single-strand conformation polymorphism (SSCP) technique, and the
results for the four regions of each patient were combined. Bronchoalveolar
lavage specimens collected from 11 patients were examined. Four patients were
probably infected by a single strain, since their specimens yielded simple SSCP
patterns (two bands corresponding to one allele). The combinations of these
patterns were unique, suggesting that the strains which infected these patients
were different. For the other seven patients, complex patterns were found (three
or four bands corresponding to two alleles). The presence of more than one allele
of a region in a patient is likely to be due to coinfection. Polymorphism was
also assessed by sequencing, which revealed variations at nucleotide positions
previously reported to vary. About half of the observed alleles had already been
reported by laboratories in different countries. Multitarget typing of P. carinii
hominis by PCR-SSCP should allow investigation of strain diversity and thus be
useful for future epidemiological studies.
PMID- 9399498
TI - Diagnostic value of the strand displacement amplification method compared to
those of Roche Amplicor PCR and culture for detecting mycobacteria in sputum
samples.
AB - We compared the ability of the semiautomated BDProbeTec-SDA system, which uses
the strand displacement amplification (SDA) method, with that of the Roche
Amplicor-PCR system and the Septi-Chek AFB culture system to directly detect
Mycobacterium tuberculosis complex (MTB) and other mycobacteria in sputum
samples. A total of 530 sputum samples from 299 patients were examined in this
study. Of the 530 samples, 129 were culture positive for acid-fast bacilli with
the Septi-Chek AFB system; 95 for MTB, 29 for M. avium-M. intracellulare complex
(MAC), and 5 for other mycobacteria. The BDProbeTec-SDA system detected 90 of the
95 samples culture positive for MTB (sensitivity, 94.7%), and the Amplicor-PCR
system detected 85 of the 95 samples culture positive for MTB (sensitivity,
89.5%). The specificity of each system, based on the clinical diagnosis, was
99.8% for SDA and 100% for PCR, respectively. Among the 29 samples culture
positive for MAC, the BDProbeTec-SDA system detected MAC in 24 samples
(sensitivity, 82.8%), whereas the Amplicor-PCR system detected MAC in 23 samples
(sensitivity, 79.3%). The specificities of the systems were 98.3 and 100%,
respectively. The high degrees of sensitivity and specificity of the BDProbeTec
SDA system suggest that it should be very useful in clinical laboratories for the
rapid detection of mycobacteria in sputum samples.
PMID- 9399500
TI - Analysis of an outbreak of non-phage-typeable methicillin-resistant
Staphylococcus aureus by using a randomly amplified polymorphic DNA assay.
AB - A cluster of methicillin-resistant Staphylococcus aureus (MRSA) infections among
patients on an intensive care unit (ICU) was detected by routine infection
control surveillance. In the period from 5 January to 22 June 1995, 10 patients
on the ICU and a further 6 patients (5 on one ward that had received colonized
patients transferred from the ICU) were affected by MRSA strains with the same
antibiotic susceptibility patterns. Seven (44%) of these 16 colonized patients
developed MRSA bacteremia. MRSA isolates with the same characteristics were also
found on the hands of one member of the ICU staff. The isolates were untypeable
by phage typing, but 15 of 17 outbreak strains analyzed genetically had identical
randomly amplified polymorphic DNA (RAPD) and pulsed-field gel electrophoresis
(PFGE) profiles. A single strain of MRSA that was nontypeable by phage typing and
that was isolated on the ICU on 1 January and six nontypeable and
epidemiologically unrelated MRSA isolates all had RAPD profiles distinct from
that of the outbreak strain. Implementation of strict infection control measures
stopped the further spread of MRSA on the ICU, the affected general ward, and
seven other wards that received MRSA carriers from the ICU. Although nontypeable
by phage typing and not previously recognized as an epidemic strain, this strain
of MRSA was readily transmissible and highly virulent. RAPD typing was found to
be a simple, rapid, and effective method for the epidemiological investigation of
this outbreak, and performance of typing by this method was simpler and less time
consuming than that of typing by PFGE. RAPD typing may have more general
application for the study of S. aureus infections in hospitals.
PMID- 9399501
TI - Human papillomavirus and host variables as predictors of clinical course in
patients with juvenile-onset recurrent respiratory papillomatosis.
AB - This study provides the first systematic evaluation of papillomavirus type and
viral mutation occurring during the course of juvenile-onset recurrent
respiratory papillomatosis. One hundred ninety-nine consecutive papillomas
excised from 47 children between 1981 and 1996 at The New Children's Hospital in
Sydney, Australia, were tested for human papillomavirus (HPV) DNA by PCR. PCR
products from the viral upstream regulatory region (URR) enhancer were sequenced,
and variation was related to clinical variables. Forty-four of the 47 children
had HPV-induced papillomas, with type 11 accounting for 24 (55%) and type 6
accounting for 19 (43%); one (2%) was positive for either type 6 or 11. Overall,
183 (98%) of the 186 samples with amplifiable DNA were HPV positive. There was no
change in HPV type over time and no statistically significant association between
HPV type and disease aggressiveness. One novel, large-scale URR duplication was
identified in an HPV type 11 isolate in the last of a series of six papillomas
examined and the first from the bronchus. However, the duplication was not found
in HPV type 11 isolates from the associated pulmonary carcinoma and its
metastases in other organs. Three of 14 URR point mutations coincided with
transcription factor binding sites, but there were no obvious associations with
clinical course. Chi-square and multiple linear regression analyses of
clinicopathological variables revealed early age at diagnosis (less than 4 years)
as an independent predictor of aggressive disease (P < 0.001). A bimodal
distribution of the age at diagnosis was noted, with peaks at 2 and 11 years of
age.
PMID- 9399502
TI - Comparison of enzyme immunoassay, PCR, and type-specific cDNA probe techniques
for identification of group A rotavirus gene 4 types (P types).
AB - This study was designed to evaluate three techniques most commonly used to
identify the VP4 (P) types of human group A fecal rotaviruses. The techniques
included PCR with nested primers and hybridization with PCR-generated probes (to
determine the P genotypes). The results obtained by these genetic techniques were
evaluated against those obtained by an enzyme immunoassay (EIA) incorporating
neutralizing monoclonal antibodies (N-MAbs) reacting with three major human P
serotypes (serotypes P1A, P1B, and P2A). The P types of the rotaviruses present
in 102 fecal specimens were determined under code by each of the three assays.
The specificity of each assay was evaluated against a "gold standard" putative P
type (P serotype and genotype) deduced from knowledge of the VP7 (G) type and the
origin of the fecal specimen. Overall comparison of the results showed respective
sensitivities and specificities of 92 and 92% for reverse transcription-PCR, 80
and 99% for hybridization, and 73 and 91% for EIA with N-MAbs. The hybridization
assay retained high sensitivity with specimens stored for > or = 10 years.
Hybridization assays with nonradioactive probes are relatively inexpensive and
are suited for use in developing countries. In summary, both genetic assays
showed high sensitivities and specificities in assigning a P type to human fecal
rotavirus strains. Further evaluation of the EIA with N-MAbs is required,
together with incorporation of new N-MAbs for the detection of the additional P
types detected in developing countries.
PMID- 9399503
TI - Clinical utility of broth cultures of cerebrospinal fluid from patients at risk
for shunt infections.
AB - For patients with cerebrospinal fluid (CSF) shunts, culture of the CSF remains
the most valuable tool in the evaluation of suspected shunt infections. To detect
anaerobic Propionibacterium sp., a well-described cause of these infections, many
clinical microbiology laboratories routinely employ a broth medium as an adjunct
to solid media. The use of broth, however, creates a diagnostic dilemma since
many contaminants also are isolated from broth cultures. Therefore, we
retrospectively reviewed the records of 59 patients with CSF shunts in whom an
organism was isolated from only broth cultures to assess their utility for the
diagnosis of shunt infection. We found that no single clinical or laboratory
parameter, including fever, leukocytosis, pleocytosis, or CSF protein and
glucose, could reliably predict or exclude a shunt infection. Isolation of
coagulase-negative staphylococci only in broth, in the absence of growth on solid
media in concurrent or immediately preceding cultures, virtually always
represented contamination. The isolation of Propionibacterium sp. from broth only
usually represented contamination; however, infection could not be excluded
without a repeated CSF culture, even in the absence of pleocytosis. We recommend
that specific comments be appended to laboratory reports for isolates from CSF in
broth only as an aid to the physician in interpreting the clinical importance of
such isolates.
PMID- 9399504
TI - Evaluation of six commercial kits for detection of human immunoglobulin M
antibodies to Toxoplasma gondii. The FDA Toxoplasmosis Ad Hoc Working Group.
AB - As a result of reports received by the Food and Drug Administration (FDA) of
false-positive results obtained with FDA-cleared in vitro diagnostic kits for the
detection of Toxoplasma-specific human immunoglobulin M (IgM) antibodies, an FDA
sponsored evaluation of six kits was performed. A battery of 258 serum specimens,
including 30 specimens drawn 1 to 5 months after initial Toxoplasma infection and
228 specimens from Toxoplasma IgG-positive individuals, Toxoplasma IgG-negative
individuals, rheumatoid factor-positive persons, and persons determined to be
Toxoplasma IgM positive by commercially available assays, was assembled, randomly
assorted, and coded. The battery was tested at the FDA with six commercially
available kits, at the Palo Alto Medical Foundation (PAMF) by the PAMF double
sandwich IgM enzyme-linked immunosorbent assay (PAMF IgM ELISA), and at the
Centers for Disease Control and Prevention (CDC) by the CDC EIA IgM. The results
of the PAMF IgM ELISA that were obtained with the battery were considered to be
the "gold standard" for this study; specificity rates were computed by
considering the PAMF results to be 100% specific. Sensitivity and specificity
rates were found to be as follows: CDC EIA IgM, 100 and 99.1%, respectively;
Abbott IMx Toxo IgM, version 1, 100 and 77.5%, respectively; Abbott IMx Toxo IgM,
version 2, 93.3 and 97.3%, respectively; Abbott Toxo-M EIA, 100 and 84.2%,
respectively; BioMerieux Vitek VIDAS Toxo IgM, 100 and 98.6%, respectively;
BioWhittaker Toxocap-M, 100 and 95.9%, respectively; Gull Toxo IgM, 97 and 85.6%,
respectively; and Sanofi Diagnostics Pasteur Platelia Toxo IgM, 100 and 96.8%,
respectively. Although the extent of false-positive reactions with these kits
cannot be calculated because the study was retrospective and sample choices were
biased, the results may be useful as an indicator of the relative specificities
of these kits.
PMID- 9399506
TI - Multicenter evaluation of the updated and extended API (RAPID) Coryne database
2.0.
AB - In a multicenter study, 407 strains of coryneform bacteria were tested with the
updated and extended API (RAPID) Coryne system with database 2.0 (bioMerieux, La
Balme-les-Grottes, France) in order to evaluate the system's capability of
identifying these bacteria. The design of the system was exactly the same as for
the previous API (RAPID) Coryne strip with database 1.0, i.e., the 20 biochemical
reactions covered were identical, but database 2.0 included both more taxa and
additional differential tests. Three hundred ninety strains tested belonged to
the 49 taxa covered by database 2.0, and 17 strains belonged to taxa not covered.
Overall, the system correctly identified 90.5% of the strains belonging to taxa
included, with additional tests needed for correct identification for 55.1% of
all strains tested. Only 5.6% of all strains were not identified, and 3.8% were
misidentified. Identification problems were observed in particular for
Corynebacterium coyleae, Propionibacterium acnes, and Aureobacterium spp. The
numerical profiles and corresponding identification results for the taxa not
covered by the new database 2.0 were also given. In comparison to the results
from published previous evaluations of the API (RAPID) Coryne database 1.0, more
additional tests had to be performed with version 2.0 in order to completely
identify the strains. This was the result of current changes in taxonomy and to
provide for organisms described since the appearance of version 1.0. We conclude
that the new API (RAPID) Coryne system 2.0 is a useful tool for identifying the
diverse group of coryneform bacteria encountered in the routine clinical
laboratory.
PMID- 9399505
TI - Identification of Staphylococcus species and subspecies by the chaperonin 60 gene
identification method and reverse checkerboard hybridization.
AB - A previous study (S. H. Goh et al., J. Clin. Microbiol. 34:818-823, 1996)
demonstrated that a 600-bp region of the chaperonin 60 (Cpn60) genes from various
bacterial isolates could be amplified by PCR with a pair of degenerate primers
and that the products could be used as species-specific probes for Staphylococcus
aureus, S. epidermidis, S. haemolyticus, S. lugdunensis, S. saprophyticus, and S.
schleiferi. To further validate the utility of bacterial Cpn60 genes as universal
targets for bacterial identification (ID), reverse checkerboard chemiluminescent
hybridization experiments were performed with DNA probes from 34 different
Staphylococcus species and subspecies. With the exception of probes from the
Cpn60 genes of S. intermedius and S. delphini, which cross hybridized, all were
species specific. Two subspecies of both S. capitis and S. cohnii were
differentiated from one another, while DNAs from the two S. schleiferi subspecies
cross hybridized. When 40 known Staphylococcus isolates were tested in a blind
experiment by the Cpn60 gene method, 36 strains, representing six species and one
subspecies (S. sciuri, S. caseolyticus, S. hominis, S. warneri, S. hyicus, S.
haemolyticus, and S. capitis subsp. ureolyticus), were correctly identified. DNA
from the four remaining isolates, known to be S. hyicus bovine strains, failed to
hybridize to DNA from the S. hyicus target strain or any other Staphylococcus
species. However, DNAs from these S. hyicus isolates did cross hybridize with
each other. New DNA sequence data and evidence from previous studies suggest some
genetic divergence between the two groups of S. hyicus isolates. Our results
demonstrate that this Cpn60 gene-based ID method has the potential to be a basic
method for bacterial ID. Studies are in progress to further validate the utility
of this Cpn60 gene system for ID of Staphylococcus and other genera, including
those of slow-growing microorganisms.
PMID- 9399507
TI - Evaluation of the MB/BacT system and comparison to the BACTEC 460 system and
solid media for isolation of mycobacteria from clinical specimens.
AB - The MB/BacT automated system is designed for the isolation of mycobacteria from
clinical specimens. It utilizes a colorimetric sensor and reflected light to
continuously monitor the CO2 concentration in the culture medium. We compared its
performance to that of the BACTEC 12B media for the radiometric BACTEC 460
instrument and that of solid culture media. Respiratory specimens and urine
samples were decontaminated with 4% NaOH. The vials of the two instruments were
inoculated with 500 microl of sample and two solid egg-based media at 200 microl
each. All vials were incubated at 37 degrees C for 6 weeks. A total of 1,078
specimens (633 respiratory specimens, 78 cerebrospinal fluid specimens, 177 other
body fluid specimens, 87 urine specimens, and 103 other types of specimens) were
cultured in parallel. Mycobacteria could be identified from 73 (6.8%) specimens:
67 M. tuberculosis, 3 M. kansasii, 1 M. xenopi, 1 M. terrae, and 1 mixed M. avium
with M. scrofulaceum. Of these, 63 (86.3%) specimens were positive with the
MB/BacT system, 67 (91.8%) were positive with the BACTEC 460 instrument, and 58
(79.5%) were positive with the two egg-based media. MB/BacT cultures were
positive on average after 17.5 (+/-6.4) days, BACTEC cultures with a growth index
of >20 (mean, 200) were positive after 14.3 (+/-8.2) days, and egg-based media
were positive after 24.2 (+/-7.5) days. Microorganisms other than mycobacteria
contaminated 46 (4.3%) MB/BacT cultures and 31 (2.9%) BACTEC cultures, which had
to be discarded. The MB/BacT system is a well-automated system for the detection
of M. tuberculosis in clinical specimens without using radioactive reagents.
Further trials are required to determine whether it is suitable for the culture
of nontuberculous mycobacteria.
PMID- 9399508
TI - Randomly amplified polymorphic DNA PCR for comparison of Mycobacterium abscessus
strains from nosocomial outbreaks.
AB - Mycobacterium abscessus is an important cause of water-related nosocomial
outbreaks or pseudo-outbreaks. Strain comparison has relied on pulsed-field gel
electrophoresis (PFGE). Unfortunately, almost 50% of strains cannot be assessed
by this method. We studied 118 strains of M. abscessus previously studied by PFGE
by randomly amplified polymorphic DNA (RAPD) PCR, including isolates from eight
nosocomial outbreaks. Ten random primers were evaluated by using DNA prepared by
boiling or phenol-chloroform extraction. Both DNA preparations gave the same
grouping of isolates for three outbreaks compared to the groupings obtained by
PFGE. Five outbreaks due to M. abscessus which gave broken DNA by PFGE gave
evaluable patterns when studied by RAPD-PCR, with isolate clustering being
consistent with that from other laboratory and epidemiologic data. The patterns
were highly method dependent, strain comparison required the use of multiple
primers, and the method worked best with purified DNA and by using strains for
comparison on the same gel. We propose categories of indistinguishable,
different, and inconclusive when comparing strains by RAPD-PCR. This study
demonstrates that RAPD-PCR can be used for genetic comparison of M. abscessus
strains, including strains which cannot be compared by PFGE, but the potential
for misinterpretation is greater than that by PFGE.
PMID- 9399509
TI - Identification of pathogenic Leptospira genospecies by continuous monitoring of
fluorogenic hybridization probes during rapid-cycle PCR.
AB - Partial sequences of 23S rRNA gene PCR products from 23 strains of 6 pathogenic
Leptospira genospecies and from 8 strains of the saprophytic Leptospira biflexa
were determined. Sequence analyses enabled Leptospira genus-specific
amplification primers and pathogen-specific fluorogenic adjacent hybridization
probes to be designed and synthesized. A PCR protocol was developed in which
changes in fluorescence emission resulting from specific annealing of fluorogenic
adjacent hybridization probes to the target DNA were continuously monitored. Nine
strains of the pathogenic Leptospira genospecies could be differentiated from
Leptonema illini, Escherichia coli, and eight strains of Leptospira biflexa. The
PCR method was rapid, requiring 18 min for the completion of 45 cycles. It was
also simple and flexible, as DNA templates prepared by four different methods,
including the simple boiling method, could be used without adverse effects. Two
hundred copies of target, equivalent to 100 cells, could be detected.
PMID- 9399510
TI - Reversed passive latex agglutination assay for detection of toxigenic
Corynebacterium diphtheriae.
AB - A reversed passive latex agglutination (RPLA) assay for determining the
toxigenicity of Corynebacterium diphtheriae is presented. Rabbit antitoxin
antiserum was raised by using commercially available diphtheria toxoid. This
antiserum reacted with the diphtheria toxin when the culture supernatant was
assayed by Western blotting, and it did not cross-react with other extracellular
antigens. Affinity-purified antibodies for latex sensitization were obtained by
using a Hi Trap N-hydroxysuccinimide-activated column. Demonstration of toxin in
five of seven clinical isolates was in accordance with the PCR assay and the Vero
cell cytotoxicity test. Culture of the bacteria for 6 h was sufficient for toxin
production, and an additional 6 h was needed to observe latex agglutination.
Therefore, diphtheria toxin can be detected in 12 h by this method. The lowest
concentration of diphtheria toxin detectable by the RPLA assay was about 5 ng/ml.
The RPLA assay can provide a convenient and reliable method for laboratories
involved in the identification of toxinogenic corynebacteria.
PMID- 9399511
TI - Emergence of a unique O3:K6 clone of Vibrio parahaemolyticus in Calcutta, India,
and isolation of strains from the same clonal group from Southeast Asian
travelers arriving in Japan.
AB - Active surveillance of Vibrio parahaemolyticus infection among hospitalized
patients in Calcutta, India, was initiated in January 1994. The incidence of
cases of V. parahaemolyticus infection suddenly increased in February 1996 and
has remained high since then. One hundred thirty-four strains of V.
parahaemolyticus isolated from January 1994 to August 1996 were examined for
serovar, the presence of the thermostable direct hemolysin gene (tdh) and tdh
related hemolysin genes (trh1 and trh2), production of urease, and antibiogram.
Strains of the O3:K6 serovar appeared for the first time in February 1996. The
O3:K6 serovar strains accounted for 50 to 80% of the strains isolated during the
high-incidence period (February to August 1996). All of the serovar O3:K6 strains
carried the tdh gene but not the trh genes and did not produce urease. All of the
isolates except two were sensitive to all of the antibiotics tested. These and
the results of analysis by an arbitrarily primed PCR method indicated that the
O3:K6 serovar strains belong to a unique clone. When the O3:K6 serovar strains,
isolated from travelers arriving in Japan from Southeast Asian countries, were
compared by the arbitrarily primed PCR method, the strains isolated between 1982
and 1993 were distinct from Calcutta O3:K6 while the strains isolated in 1995 and
1996 were indistinguishable from the Calcutta O3:K6 strains. The results suggest
that this unique O3:K6 clone may have become prevalent not only in Calcutta but
also in Southeast Asian countries very recently. Not only the O3:K6 strains but
also the non-O3:K6, tdh-bearing strains isolated in 1996 produced thermostable
direct hemolysin at high levels, and thus the level of hemolysin produced does
not appear to have influenced the high incidence of serovar O3:K6 strains.
PMID- 9399512
TI - Determination of hepatitis C virus genotypes in the United States by cleavase
fragment length polymorphism analysis.
AB - We describe the application of a new DNA-scanning method, which has been termed
Cleavase Fragment Length Polymorphism (CFLP; Third Wave Technologies, Inc.,
Madison, Wis.), for the determination of the genotype of hepatitis C virus (HCV).
CFLP analysis results in the generation of structural fingerprints that allow
discrimination of different DNA sequences. We analyzed 251-bp cDNA products
generated by reverse transcription-PCR of the well-conserved 5'-noncoding region
of HCV. We determined the genotypes of 87 samples by DNA sequencing and found
isolates representing 98% of the types typically encountered in the United
States, i.e., types 1a, 1b, 2a/c, 2b, 3a, and 4. Blinded CFLP analysis of these
samples was 100% concordant with DNA sequencing results, such that closely
related genotypes yielded patterns with strong familial resemblance whereas more
divergent sequences yielded patterns with pronounced dissimilarities. In each
case, the aggregate pattern was indicative of genotypic grouping, while finer
changes suggested subgenotypic differences. We also assessed the reproducibility
of CFLP analysis in HCV genotyping by analyzing three distinct isolates belonging
to a single subtype. These three isolates yielded indistinguishable CFLP
patterns, as did replicate analysis of a single isolate. This study demonstrates
the suitability of this technology for HCV genotyping and suggests that it may
provide a low-cost, high-throughput alternative to DNA sequencing or other, more
costly or cumbersome genotyping approaches.
PMID- 9399513
TI - Outbreak of Shigella sonnei in a clinical microbiology laboratory.
AB - Laboratory technologists (22%) developed infections with Shigella sonnei. The
isolates had the same antibiogram and pulse-field gel electrophoresis pattern as
an unknown isolate handled by a laboratory student. Covering faucet handles with
paper towels during hand washing in the laboratory was protective. No further
cases occurred after the laboratory was cleaned with a phenolic agent and a
handle-free faucet was installed.
PMID- 9399514
TI - Clinical and epidemiological significance of enterococci intrinsically resistant
to vancomycin (possessing the vanC genotype)
AB - Constitutive low-level vancomycin resistance is found intrinsically in certain
enterococcal species and is encoded by vanC ligase genes. These intrinsically
vancomycin-resistant enterococci (VRE) will be referred to as VANC VRE. A
prospective study to determine the clinical and epidemiologic significance of
VANC VRE was conducted. VANC VRE were recovered from the stools of 34 of 601
(5.7%) patients, a rate similar to that obtained for the stools of 100
outpatients in the community (5%). VANC VRE were also isolated from the nonstool
specimens of 9 of 538 patients (1.7%), including two patients with bacteremia. No
VRE of the vanA or vanB genotypes were detected in nonstool specimens. Eighty-two
hospital contacts of the first 23 patients found to be colonized or infected with
VANC VRE were screened, and 6 contacts were found to be gastrointestinal carriers
of VANC VRE. However, typing of isolates from these 6 contacts by pulsed-field
gel electrophoresis with SmaI showed the isolates to be unique and different from
those recovered from the index patients. In fact, all VANC VRE isolates from
different patients in this study were unique. A case-control study with patients
who were negative when screened for VANC VRE as controls failed to identify any
risk factor associated with colonization or infection with this organism. VANC
VRE were infrequently recovered from clinical specimens but were occasionally
found as part of the normal stool flora. Since no transmission between patients
was documented, additional isolation procedures may not be necessary for patients
colonized or infected with VANC VRE.
PMID- 9399515
TI - Comparison of use of phenotypic and genotypic characteristics for identification
of species of the anamorph genus Candida and related teleomorph yeast species.
AB - A total of 49 type and neotype isolates and 32 clinical isolates of the anamorph
genus Candida and related teleomorph genera were obtained from different culture
collections and clinical laboratories. Isolates were subjected to two phenotypic
methods of identification, Vitek yeast biochemical card (YBC) and API ID 32C,
both based on carbohydrate assimilation, and one genotypic method, PCR
fingerprinting, based on the detection of DNA polymorphisms between minisatellite
specific sequences with the primer M13 (5' GAGGGTGGCGGTTCT 3'). The correct
identification of a strain at the Centraalbureau voor Schimmelcultures was used
as the gold standard for the identification of an isolate. When the study was
restricted to species included in the respective biochemical databases, the Vitek
YBC and API ID 32C systems performed adequately with positive identification
rates of 87.3 and 76.8%, respectively. When uncommon species were added to the
study, several of which are not included in the databases, the identification
efficiencies were 76.5 and 77.5%, respectively. By comparison, all isolates were
correctly identified by PCR fingerprinting, with 63 reference species profiles in
the databank. Sufficient polymorphisms among the total set of banding patterns
were observed, with adequate similarity in the major patterns obtained from a
given species, to allow each isolate to be assigned unambiguously to a particular
species. In addition, variations in minor bands allowed for differentiation to
the strain level. PCR fingerprinting was found to be rapid, reproducible, and
more cost-effective than either biochemical approach. Our results provide
reference laboratories with an improved identification method for yeasts based on
genotypic rather than phenotypic markers.
PMID- 9399516
TI - Fecal microflora in a patient with short-bowel syndrome and identification of
dominant lactobacilli.
AB - Fecal microflora and lactate concentrations in blood and feces obtained from a
patient (a 5 year-old boy) with short-bowel syndrome (SBS) were compared during
acidosis to results for the normal condition (no SBS symptoms). The taxonomical
position of the lactobacilli found predominantly in the feces sample obtained 2
days before the fifth attack was also studied. The D-lactate level in serum
obtained 1 day after the fourth attack was 10-fold higher than that for the
normal condition, although there was not a great difference in L-lactate levels.
D-Lactate (3.91 mM) and L-lactate (2.86 mM) were also detected in the feces
samples collected 2 days before the fifth attack, while no lactate was detected
in the feces sample for the normal condition. The counts of total fecal bacteria,
especially anaerobic bacteria such as members of the family Bacteroidaceae, were
found to be low. The counts of lactobacilli and the total population of
lactobacilli relative to total fecal bacteria in the feces 2 days before the
fifth attack (40.4%) were extremely high. In this case, a majority of the
lactobacilli were D-lactate producers as determined by homolactic fermentation.
These lactobacilli were identified as Lactobacillus delbrueckii subsp. lactis.
The percentages of bifidobacteria relative to total fecal bacteria in feces
samples obtained both 2 days before the fifth attack (50.9%) and for normal
condition (61.9%) were also high, although these bacteria were L-lactate
producers. In the feces samples for the normal condition, the D-lactate producers
decreased to less than 10(9) per g, while the counts of L- or DL-lactate
producers were 100-fold higher than the numbers in feces samples obtained 2 days
before the fifth attack. These results suggested that an increase in the level of
D-lactate producers, such as L. delbrueckii subsp. lactis, in the colon may be
associated with the clinical expression of metabolic acidosis.
PMID- 9399517
TI - Evaluation of the BBL Crystal Anaerobe identification system.
AB - The BBL Crystal Anaerobe (ANR) identification system was evaluated, and the
results were compared with those from conventional anaerobic methods. We tested
322 clinically significant anaerobic bacteria according to the manufacturer's
instructions. The system identified correctly 286 of 322 (88.8%) of the anaerobic
bacteria tested. Of these, 263 of 322 (81.7%) were identified correctly on
initial testing and 49 were identified correctly only to the genus level; on
repeat testing, 23 of 49 (46.9%) were identified correctly to both the genus and
the species levels. A total of 26 (8.5%) were misidentified at the species level,
and 10 (3.1%) were not identified. Performance characteristics for individual
strains varied. The system correctly identified all tested strains of
Campylobacter, Desulfomonas, Desulfovibrio, Leptotrichia, Mobiluncus,
Peptostreptococcus, Porphyromonas, Provetella, Propionibacterium, Tisierella, and
Veillonella and 36 of 37 (97.3%) Actinomyces strains, 42 of 46 (91.3%) B.
fragilis group strains, 79 of 103 (76.7%) Clostridium strains, (however, the
system failed to identify any of the 7 C. innocuum and 9 C. tetani strains
tested), and 8 of 15 (53.3%) Bacteroides strains. This system was easy to use,
did not involve the addition of reagents, and was faster than conventional
anaerobic procedures. It would be a useful addition to the anaerobe laboratory of
most hospitals.
PMID- 9399518
TI - Highly sensitive single-step PCR protocol for diagnosis and monitoring of human
cytomegalovirus infection in renal transplant recipients.
AB - A multiplex, single-step PCR protocol for the detection of human cytomegalovirus
(HCMV) DNA is described. The protocol amplifies regions of the viral LA and IE
genes and employs elevated temperatures for both reagent mixing and primer
annealing together with product detection by silver staining on polyacrylamide
gels. This assay detects one to five HCMV genomes in clinical samples containing
up to 100 ng of human DNA, a level of sensitivity equivalent to that of more
complex assays involving either nested PCR or postamplification hybridization. As
well as being of importance in clinical situations where high-sensitivity
qualitative diagnosis is required, this assay is also applicable to the
monitoring of HCMV infection in renal transplant recipients. Due to its multiplex
format the assay provides quantitative information, in that samples from which a
single target is amplified contain on average sevenfold fewer viral genomes per
10(6) leukocytes than those from which both targets are amplified. When weekly
blood leukocyte DNA preparations from renal transplant patients were assayed,
findings of three consecutive tests in which both HCMV targets were amplified
were highly indicative of patients who had developed very high loads of HCMV
(100% sensitivity, 88% specificity). We thus show that the same simple PCR assay
which permits highly sensitive HCMV diagnosis can also be used for the efficient
identification of transplant recipients at risk of clinically significant
infection.
PMID- 9399519
TI - Disk diffusion test interpretive criteria and quality control recommendations for
testing linezolid (U-100766) and eperezolid (U-100592) with commercially prepared
reagents.
AB - Two new oxazolidinones were tested to determine interpretive susceptibility
testing criteria for MIC and disk diffusion methods. Commercial lots of linezolid
(formerly U-100766) and eperezolid (formerly U-100592) disks containing 30 microg
of drug were tested against 728 isolates of bacteria with defined mechanisms of
resistance. Results from linezolid were highlighted because of its choice for
clinical development. By using preliminary pharmacokinetic data, a tentative
susceptibility breakpoint of < or = 4 microg/ml was selected. Corresponding
breakpoint zone diameters for linezolid were > or = 21 mm (< or = 4 microg/ml)
for susceptibility and < or = 17 mm (> or = 16 microg/ml) for resistance.
Regression statistics demonstrated a high correlation coefficient (r > or =
0.98), and absolute categorical agreement between methods was obtained, when
staphylococci and enterococci were tested with the cited criteria. When
Streptococcus spp. (including S. pneumoniae) were tested, only the susceptibility
breakpoint was suggested. Quality control (QC) guidelines for linezolid disk
diffusion tests were established by a multilaboratory trial as follows: 27 to 31
mm for Staphylococcus aureus ATCC 25923 and 28 to 34 mm for S. pneumoniae ATCC
49619. More than 95% of all QC results were within these proposed ranges.
Although not advanced to clinical trials, eperezolid demonstrated potency
comparable to that of linezolid and had identical interpretive testing criteria.
These preliminary interpretive criteria and QC limits (accepted by the National
Committee for Clinical Laboratory Standards) should be applied to linezolid tests
during the clinical-trial phases of oxazolidinone drug development in order to
ensure test accuracy and reproducibility.
PMID- 9399520
TI - A new agent of mycobacterial lymphadenitis in children: Mycobacterium
heidelbergense sp. nov.
AB - Nontuberculous mycobacterial lymphadenitis presents an increasing clinical
problem in immunocompetent young children. A slowly growing, nonphotochromogenic
mycobacterium was recovered twice (isolates 2553/91 and 2554/91) from the
lymphatic tissue of a child with recurrent cervical lymphadenitis. It could be
differentiated biochemically from described Mycobacterium species, although it
most closely resembled Mycobacterium malmoense by thin-layer chromatography and
high-performance liquid chromatography of mycolic acids. A striking
characteristic of the isolate was its high degree of susceptibility to
antituberculous drugs in vitro, including isoniazid. Direct determination of the
16S rRNA gene sequence revealed a unique sequence and positioned the strain
phylogenetically on a branch separate from M. malmoense within a group of slowly
growing mycobacteria that show a high degree of similarity to M. simiae at the
16S rRNA gene level. Despite 99.6% sequence identity with M. simiae at the 16S
rRNA gene level, DNA-DNA hybridization studies (hydroxyapatite method)
demonstrated DNA relatedness of less than 40%. We conclude that this organism is
a new species for which we propose the name M. heidelbergense. A culture of the
type strain, strain 2554/91, has been deposited in the American Type Culture
Collection as strain ATCC 51253.
PMID- 9399521
TI - Laboratory methods for detection of Chlamydia trachomatis: survey of laboratories
in Washington State.
AB - The last decade has witnessed the development of a wide variety of diagnostic
tests for Chlamydia trachomatis. In order to determine what laboratory methods
are being used to detect C. trachomatis infections in Washington State and to
identify factors influencing test selection, between April 1995 and October 1995
we conducted a mailed questionnaire survey of all 112 laboratories certified to
do chlamydia testing. Of these, 20 had discontinued testing for C. trachomatis,
and responses were obtained from 89 (97%) of the remaining 92 laboratories.
Surprisingly, 38 (43%) of the 89 laboratories used rapid tests such as Clearview
and Surecell, making such tests the most commonly used laboratory tests.
Laboratories which used rapid tests had lower test volumes, less experience
performing tests for C. trachomatis, less frequent attendance at professional
meetings, and greater reliance on manufacturers for information compared with
laboratories which used other methods. Confirmation of non-culture-positive
results was provided by 28 (34%) of the 82 laboratories doing non-culture-based
tests. Forty-one (47%) of 88 laboratories reported having compared their method
with another method. Test volume was the strongest predictor of laboratories
which confirmed positive non-culture-based test results and which had performed a
laboratory comparison of methods. We conclude that rapid tests for C. trachomatis
are often being used inappropriately and that efforts are needed to improve
effective implementation and quality assurance of laboratory testing for C.
trachomatis.
PMID- 9399522
TI - Confirmation of suspicious cases of meningococcal meningitis by PCR and enzyme
linked immunosorbent assay.
AB - A significant problem in efficacy trials of meningococcal vaccines has been
accurate identification of all cases of meningococcal disease that occur in study
populations. The accuracy of case determination would be improved by utilizing
methods which confirm or disprove suspicious cases of meningococcal disease that
are culture negative. A collection of serum and cerebrospinal fluid (CSF) samples
from a meningococcal vaccine field trial performed in Iquique, Chile, were
utilized to assess the status of patients for whom cultures, Gram stains, and
clinical evaluations for meningococcal disease were available. Nested PCRs
(nPCRs) for amplification of Neisseria meningitidis DNA in CSF samples and enzyme
linked immunosorbent assays (ELISAs) for quantification of serum immunoglobulin G
antibodies specific for N. meningitidis were used in combination to confirm or
eliminate cases classified by physicians as suspicious for meningococcal disease.
Samples from 12 of 79 patients suspected of having meningococcal meningitis
tested positive by both methods; specimens from 61 of the 79 were negative by
both methods; and samples from 6 patients yielded ambiguous results, and these
cases remained unconfirmed. Direct sequence analysis of amplified DNA from
patients suspected of having meningococcal disease confirmed that 2 of the 12
newly confirmed cases were not attributable to the typical epidemic strain
(B:15:P1.[7],3) while the others were due to the epidemic strain. A combination
of nPCR and ELISA reduced the number of suspicious cases in this study from 79 to
6, thereby improving the potential for assessment of vaccine efficacy. Molecular
identification by nPCR in conjunction with immunological assessment of patient
response could be considered diagnostic of disease in future testing of
meningococcal vaccines to improve efficacy analyses.
PMID- 9399523
TI - Characterization of group A Streptococcus strains recovered from Mexican children
with pharyngitis by automated DNA sequencing of virulence-related genes:
unexpectedly large variation in the gene (sic) encoding a complement-inhibiting
protein.
AB - Sequence variation was studied in several target genes in 54 strains of group A
Streptococcus (GAS) cultured from children with pharyngitis in Mexico City.
Although 16 distinct emm alleles were identified, only 4 had not been previously
described. Virtually all bacteria (31 of 33 [94%] with the streptococcal
pyrogenic exotoxin gene (speA) had emm1-related, emm3, or emm6 alleles. The gene
(sic) encoding an extracellular GAS protein that inhibits complement function was
unusually variable among isolates with the emm1 family of alleles, with a total
of seven variants identified. The data suggest that many GAS strains infecting
Mexican children are genetically similar to organisms commonly encountered in the
United States and western Europe. Sequence variation in the sic gene is useful
for rapid differentiation among GAS isolates with the emm1 family of alleles.
PMID- 9399524
TI - Specific identification of Mycobacterium tuberculosis with the luciferase
reporter mycobacteriophage: use of p-nitro-alpha-acetylamino-beta-hydroxy
propiophenone.
AB - We have previously described a luciferase reporter mycobacteriophage (LRP) assay
that can detect Mycobacterium tuberculosis and characterize mycobacterial drug
susceptibility patterns within 24 to 48 h in positive cultures. One drawback of
this LRP protocol is the ability of the recombinant mycobacteriophage phAE40 to
infect a variety of Mycobacterium species, thus limiting its specificity for the
detection of M. tuberculosis. In this study, we have (i) explored the host range
of phAE40, (ii) developed a modified LRP assay that exploits the selective
inhibitory effect of the compound p-nitro-alpha-acetylamino-beta-hydroxy
propiophenone (NAP) against members of the M. tuberculosis complex to
differentiate between the tubercle bacillus and other mycobacterial species, and
(iii) tested over 300 samples, including primary clinical isolates and drug
resistant strains of M. tuberculosis, demonstrating the ability of the NAP
modified LRP assay to identify M. tuberculosis complex organisms with high
degrees of sensitivity and specificity.
PMID- 9399525
TI - Conditionally replicating luciferase reporter phages: improved sensitivity for
rapid detection and assessment of drug susceptibility of Mycobacterium
tuberculosis.
AB - TM4 is a lytic mycobacteriophage which infects mycobacteria of clinical
importance. A luciferase reporter phage, phAE40, has been constructed from TM4
and was previously shown to be useful for the rapid detection and drug
susceptibility testing of Mycobacterium tuberculosis. However, the lytic nature
of the phage results in a loss of detectable light output and limits the
sensitivity of detection. We describe several strategies aimed at improving the
luciferase activity generated by TM4 luciferase phages, including (i) varying the
position of the luciferase gene in the phage genome, (ii) isolating host-range
mutants of the phage, and (iii) introducing temperature-sensitive mutations in
the phage such that it will not replicate at the infecting temperature. Several
new phages generated by these methods show increased intensity of luciferase
production compared to the first-generation reporter phage phAE40, and one phage,
phAE88, also demonstrates an enhanced duration of luciferase activity. This has
allowed the detection of as few as 120 BCG cells and the determination of drug
susceptibilities of M. tuberculosis in as little as 1 day.
PMID- 9399526
TI - Use of the BioMerieux ID 32C yeast identification system for identification of
aerobic actinomycetes of medical importance.
AB - The BioMerieux ID 32C Yeast Identification System was examined to determine its
usefulness as a rapid method for the identification of medically important
aerobic actinomycetes. More than 290 strains were tested by this method and the
results were compared to those obtained by conventional methods. It was found
that aerobic actinomycetes could be differentiated to species level in 7 days by
the ID 32C system.
PMID- 9399527
TI - Human granulocytic ehrlichiosis in southern Germany: increased seroprevalence in
high-risk groups.
AB - To date, human granulocytic ehrlichiosis (HGE), the causative agent of which is
likely transmitted by ticks in the Ixodes ricinus-Ixodes persulcatus complex, has
not been diagnosed with certainty in patients outside the United States. The
presence of a closely related vector tick, I. ricinus, as well as the occurrence
of similar Ehrlichia spp. of veterinary importance, suggests that this disease is
likely to be present in Europe. The aim of the present study was to compare the
prevalence of antibodies against the HGE agent in sera collected from patients in
groups at high risk for exposure to I. ricinus with that of a control population.
Risk groups consisted of 150 forestry workers and 105 patients with an
established diagnosis of Lyme disease. The control group was 103 healthy blood
donors without a history of tick bites. We used a patient isolate of the HGE
agent from Minnesota (J. L. Goodman, C. Nelson, B. Vitale, J. E. Madigan, J. S.
Dumler, T. J. Kurtti, and U. G. Munderloh, N. Engl. J. Med. 334:209-215, 1996)
propagated in HL60 cells as the source of antigen for a specific
immunofluorescence assay (IFA). Elevated IFA titers (> or = 1:80) were present in
21 of 150 (14%) serum samples from forestry workers and in 12 of 105 (11.4%)
serum samples from Lyme disease patients, but in only 2 of 103 (1.9%) serum
samples from blood donors (P < or = 0.01 for either of the at-risk groups versus
blood donors). The results of this study suggest that the HGE agent or a closely
related organism exists in southern Germany and that seroconversion to it is
common among groups exposed to Ixodes ticks. Final proof that HGE occurs in
Germany will require the isolation of the causative agent from patients. HGE
should be considered in the differential diagnosis of febrile illnesses in
individuals exposed to Ixodes ticks in Europe as well as in North America.
PMID- 9399528
TI - Direct detection of Mycobacterium tuberculosis complex in clinical samples from
patients in Norway by ligase chain reaction.
AB - Our aim was to investigate the use of DNA amplification with the ligase chain
reaction (LCR) for detection of the Mycobacterium tuberculosis complex directly
in human clinical specimens. The LCR assay employed was the Abbott LCx MTB Assay,
which uses the gene encoding protein antigen b as the target template. Four
hundred eighty-two samples from 457 patients in one clinical microbiology
laboratory in Norway were processed by routine culture analysis (BACTEC culture),
direct microscopy (Ziehl-Neelsen staining) and LCR. Of the 118 specimens
containing cultivable M. tuberculosis, 106 (90.6%) were detected by LCR. Among
the 364 culture-negative specimens, 356 samples were negative also by LCR and 8
(1.6%) were positive by LCR. In five of the eight LCR-positive and culture
negative samples, another sample from the same patient was M. tuberculosis
culture positive and/or the patient had symptoms of tuberculosis. In comparison
with culture, the sensitivity of LCR was 96.7% for smear-positive samples and
72.0% for smear-negative samples, respectively. For all samples combined, the
sensitivity, specificity, and positive and negative predictive values were 90.2,
99.2, 97.4, and 96.7%, respectively. Challenging the M. tuberculosis LCR test
with DNAs and cultures from strains of Mycobacterium ulcerans and Mycobacterium
marinum, which are the mycobacterial species most closely related to the M.
tuberculosis complex, resulted in all-negative test results. The sensitivity,
specificity, and positive and negative predictive values of BACTEC culture in
comparison with the LCR test and clinical criteria were 95.9, 100, 100, and
98.6%, respectively. A certain prioritization of samples subjected to the LCR
assay should be based on clinical indications and risks with regard to infection
transmission and patient isolation policy. More automation and lower expenses are
generally desired for nucleic acid amplification kits. However, this M.
tuberculosis LCR assay represents a valuable tool in routine mycobacterial
diagnostics.
PMID- 9399529
TI - Comparison of PCR, culture, and histopathology for diagnosis of tuberculous
pericarditis.
AB - Nucleic acid amplification techniques for the diagnosis of tuberculosis (TB) are
rapidly being developed. Scant work, however, has focused on pericardial TB.
Using cryopreserved specimens from a prior study of pericarditis, we compared PCR
to culture and histopathology for the diagnosis of tuberculous pericarditis in 36
specimens of pericardial fluid and 19 specimens of pericardial tissue from 20
patients. Fluid and tissue were cultured on Lowenstein-Jensen and Middlebrook
solid media and in BACTEC radiometric broth. Tissue specimens were stained with
hematoxylin-eosin, Ziehl-Neelsen, auramine O, and Kinyoun stains and were
examined for granuloma formation and acid-fast bacilli. PCR was performed with
both fluid and tissue with IS6110-based primers specific for the Mycobacterium
tuberculosis complex by published methods. Sixteen of the 20 patients had
tuberculous pericarditis and 4 patients had other diagnoses. TB was correctly
diagnosed by culture in 15 (93%) patients, by PCR in 13 (81%) patients, and by
histology in 13 of 15 (87%) patients. PCR gave one false-positive result for a
patient with Staphylococcus aureus pericarditis. Considering the individual
specimens as the unit of analysis, M. tuberculosis was identified by culture in
30 of 43 specimens (70%) from patients with tuberculous pericarditis and by PCR
in 14 of 28 specimens (50%) from patients with tuberculous pericarditis (P >
0.15). The sensitivity of PCR was higher with tissue specimens (12 of 15; 80%)
than with fluid specimens (2 of 13; 15%; P = 0.002). In conclusion, the overall
accuracy of PCR approached the results of conventional methods, although PCR was
much faster. Therefore, PCR merits further development in this regard. The
sensitivity of PCR with pericardial fluid was poor, and false-positive results
with PCR remain a concern.
PMID- 9399530
TI - Comparison of agar dilution, broth microdilution, E-test, disk diffusion, and
automated Vitek methods for testing susceptibilities of Enterococcus spp. to
vancomycin.
AB - An evaluation was undertaken to determine the optimal method for testing the
susceptibilities of 100 clinical isolates and two reference strains of
Enterococcus spp. to vancomycin in vitro. Six testing methods were studied by
using the following media and incubation times: agar screen with the Synergy Quad
Plate (Remel, Lenexa, Kans.), an in-house-prepared brain heart infusion (BHI)
agar plate, and an in-house-prepared Mueller-Hinton (MH) agar plate, all
incubated for 24 or 48 h; broth microdilution (Sensititre Just One Strip; AccuMed
International, Inc., West Lake, Ohio) with BHI or cation-adjusted MH broth
incubated for 24 or 48 h; agar dilution with BHI or MH agar incubated for 24 or
48 h; epsilometer test (E test; AB BioDisk, Solna, Sweden) with BHI or MH agar
incubated for 24 or 48 h; disk diffusion with BHI or MH agar incubated for 24 or
48 h; and the automated Vitek method with the gram-positive susceptibility
Staphylococcus aureus card and R02.03 software (bioMerieux, Inc., Hazelwood,
Mo.). Growth failures occurred with MH media (n = 6) but not with BHI media. One
growth failure occurred with the Vitek method. Results for each testing method
for each Enterococcus strain were interpreted as susceptible, intermediate, or
resistant according to current National Committee for Clinical Laboratory
Standards (NCCLS) criteria and compared to the vancomycin resistance genotype
(i.e., vanA, vanB, vanC-1, or vanC-2/3). For all methods, extension of the
incubation time from 24 h to 48 h either produced no difference in the results or
gave poorer results. The following methods produced no very major or major
interpretive errors: broth microdilution with BHI media incubated for 24 h, agar
dilution with BHI media incubated for 24 or 48 h, and E test with BHI media
incubated for 24 or 48 h. Unacceptable frequencies of very major errors (> 1%)
occurred with all methods for which MH media were used. Minor interpretive errors
were frequent with all methods. These minor interpretive errors also occurred
most frequently with Enterococcus strains with vanC genes, which encoded low
level vancomycin resistance (MIC < or = 8 microg/ml), as opposed to Enterococcus
strains which possessed vanA or vanB genes, which encoded higher-level vancomycin
resistance (MIC > or = 64 microg/ml). Modification of NCCLS breakpoints,
especially for motile Enterococcus spp. (E. casseliflavus, E. flavescens, and E.
gallinarum), may resolve this problem; however, in the current study, one E.
faecalis strain and one E. faecium strain carried only the vanC gene. The agar
screen method may also require reformulation. The current agar screen plate
contains 6 microg of vancomycin per ml, which may not detect all low-level
resistance associated with vanC genotypes. Nevertheless, the clinical
significance of this low-level vancomycin resistance remains unknown.
PMID- 9399532
TI - Evaluation of Vitek GNI+ and Becton Dickinson Microbiology Systems Crystal E/NF
identification systems for identification of members of the family
Enterobacteriaceae and other gram-negative, glucose-fermenting and non-glucose
fermenting bacilli.
AB - We evaluated the Vitek GNI+ and Becton Dickinson Crystal E/NF identification
systems for their ability to accurately identify 619 and 626 strains,
respectively, of members of the family Enterobacteriaceae and other glucose
fermenting and non-glucose-fermenting gram-negative rods. All strains tested were
taken from a stock collection and passed three times on 5% sheep blood agar prior
to testing. These strains represented a more rigorous challenge to both systems
than one resulting from the testing of consecutive clinical isolates. Testing
with both systems was done according to the manufacturers' instructions, and
tests were repeated in duplicate when errors occurred. Vitek version 5.01 and
Crystal version 3.0 softwares were used for identifications. The identification
results from each system were compared with identifications previously determined
with reference biochemicals. At the completion of the appropriate incubation
period, the GNI+ and Crystal systems correctly identified 80.1 and 71.1% of the
total isolates, respectively. After additional tests suggested by the software
programs were completed, the GNI+ had an accuracy of 87.6% and the Crystal
system's accuracy had improved to 87.9%. The error rates for the GNI+ and Crystal
systems were 6.5 and 5.3%, respectively. A report of "no identification" was
given for 6.0 and 6.9% of the isolates, respectively, and was associated with no
particular organism group. One isolate each of Acinetobacter lwoffii and Vibrio
alginolyticus would not grow in the Vitek card. The average times to detection
for correct enteric identifications in the GNI+ system were 4.1 and 6.8 h for
nonenteric identifications, while the Crystal results were routinely read at 18
h. We conclude that there was no significant difference (P > 0.05) between the
results of the GNI+ card and those of the Crystal E/NF system after additional
testing was performed with the group of organisms tested, but the overall
accuracy for both systems in this study was below 90%.
PMID- 9399531
TI - Evaluation of serological methods for diagnosis of Puumala hantavirus infection
(nephropathia epidemica).
AB - Nephropathia epidemica (NE), Puumala (PUU) virus infection, is a febrile disease
which is commonly associated with acute renal impairment. To differentiate NE
from other acute febrile illnesses, a rapid and reliable serological diagnosis is
important, and a number of different protocols have recently been introduced. In
the present report we describe a comparative evaluation of six PUU virus
immunoglobulin M (IgM) and seven IgG enzyme-linked immunosorbent assay (ELISA)
protocols based on native, Escherichia coli-expressed, or baculovirus-expressed
nucleocapsid protein (N). Neutralization and immunofluorescence assays were
included for comparison. Equally high sensitivities and specificities were
obtained with three mu-capture-based IgM ELISAs using native, baculovirus
expressed, and E. coli-expressed N antigens, respectively, and by an ELISA based
on purified E. coli-expressed full-length N adsorbed to solid phase. The assays
based on truncated amino-terminal N proteins, including a commercially available
PUU virus IgM ELISA, all showed lower sensitivities. For detection of PUU virus
specific IgG, ELISAs based on monoclonal antibody-captured native or baculovirus
expressed N antigens showed optimal sensitivities and specificities, while the
assays based on E. coli-expressed N did not detect all PUU virus IgG-positive
serum samples. A commercially available PUU virus IgG ELISA based on E. coli
expressed amino-terminal N showed a significantly lower sensitivity than those of
all other IgG assays.
PMID- 9399533
TI - Incidence and risk factors for hepatitis C among injection drug users in
Baltimore, Maryland.
AB - Between 1988 and 1996, the incidence of and risk factors for hepatitis C virus
(HCV) infection were studied in a cohort of injection drug users in Baltimore,
Maryland. By second-generation antibody testing of stored serum samples, 142
participants were found to be susceptible to HCV at the time they entered the
study. After a median follow-up of 6.5 years, 43 participants (30.3%) developed
antibodies to HCV (anti-HCV). The overall incidence was 6.4 cases per 100 person
years, but a substantial decline in the annual incidence rate was observed after
the first 2 years (1988 to 1990, 13.4/100 person-years; 1991 to 1996, 2.3/100
person-years [P = 0.0001 for trend]). Participants who acknowledged active drug
use, especially those who acknowledged frequent use and sharing of drug
paraphernalia, were at increased risk of HCV infection. However, high-risk sexual
practices were not associated with HCV seroconversion. Efforts to reduce HCV
infection must be focused on curbing drug use and especially on the sharing of
needles and drug paraphernalia.
PMID- 9399534
TI - Use of monoclonal antibodies in diagnosis of paracoccidioidomycosis: new
strategies for detection of circulating antigens.
AB - The precise diagnosis of paracoccidioidomycosis, in most cases, is established by
direct methods and indirect immunological tests. The latter method is reliant on
the identification of the host's humoral responses, which are usually impaired or
absent in patients with severe juvenile forms of the disease and in
immunocompromised patients. Determining disease activity or assessing treatment
responses by measuring antibody levels is difficult, since antibody titer may
remain elevated or persist at stationary levels, even in the presence of clinical
improvement. Consequently, there is a need for alternative tests aimed at the
identification of circulating antigens. A modification of the standard hybridoma
production method was used to raise a panel of murine monoclonal antibodies
(MAbs) against the yeast form of Paracoccidioides brasiliensis. Of these, MAb
PIB, directed against an 87-kDa determinant, was used to develop an inhibition
ELISA (inh-ELISA) capable of detecting as little as 5.8 ng of circulating antigen
per ml of serum. Sera from 46 patients with paracoccidioidomycosis or other
mycoses and sera from healthy individuals were evaluated by the inh-ELISA;
overall sensitivity was 80.4% (37 of 46 paracoccidioidomycosis patients tested
positive), and specificity compared with that of normal controls from areas of
endemicity was 81.4%. The inh-ELISA detected circulating antigen in 100% of
patients with the acute form of paracoccidioidomycosis and in 83.3 and 60% of
patients with the chronic multifocal and unifocal forms of paracoccidioidomycosis
according to the patients' clinical presentation. These results indicate that the
inh-ELISA with MAb PIB is effective in the detection of circulating antigen and
that this test may be useful for monitoring responses to treatment and
establishing disease prognoses.
PMID- 9399535
TI - Detection of antibodies to Candida albicans germ tubes for diagnosis and
therapeutic monitoring of invasive candidiasis in patients with hematologic
malignancies.
AB - We prospectively investigated the ability of detection of antibodies to Candida
albicans germ tubes (CAGT) to diagnose invasive candidiasis in 95 consecutive
admissions of 73 patients with hematologic disorders undergoing intensive
chemotherapy. The episodes were divided into three groups according to clinical
and microbiological diagnosis. Group 1 comprised eight admissions of eight
patients with invasive candidiasis. Group 2 comprised 42 admissions of 34
patients without evidence of invasive candidiasis. Group 3 comprised the
remaining 45 admissions of 37 patients with febrile episodes which were not
diagnosed by microbiological culture. Antibodies to CAGT were detected in 87.5%
of group 1 patients. Detection of antibodies to CAGT in patients with Candida
fungemia was delayed somewhat relative to the time the blood culture was
positive, but antibodies to CAGT were detected earlier than a diagnosis was made
in patients with deep-tissue candidiasis. Sera from 2 admissions in group 2 and
12 admissions in group 3 revealed antibodies to CAGT. At a titer of > or = 1:20,
detection of antibodies to CAGT had a sensitivity of 87.5%, specificity of 95.2%,
positive predictive value of 77.8%, and negative predictive value of 97.6%.
Antibodies to CAGT were usually detected before beginning of empiric antifungal
therapy. Titers of antibodies to CAGT were maintained in most patients who died
but declined and eventually disappeared in the patients who survived. Since
antibodies to CAGT were detected in all patients with tissue-proven invasive
candidiasis but negative by blood culture, detection of antibodies to CAGT
complemented blood cultures for diagnosis and therapeutic monitoring of patients
with hematologic malignancies and invasive candidiasis.
PMID- 9399536
TI - Comparison of the Amplicor HIV-1 monitor test and the nucleic acid sequence-based
amplification assay for quantitation of human immunodeficiency virus RNA in
plasma, serum, and plasma subjected to freeze-thaw cycles.
AB - The Amplicor HIV-1 Monitor test was compared to the nucleic acid sequence-based
amplification (Nasba) assay system for the quantitation of human immunodeficiency
virus (HIV) RNA in three different types of clinical samples: plasma, serum, and
plasma subjected to freeze-and-thaw cycles. Each assay detected HIV RNA in the
same 73 (90%) of 81 samples tested, and the quantitative results obtained with
the two assays were significantly correlated. Both assays detected higher RNA
levels in patients with CD4+ cell counts lower than 200 cells/mm3 than in
patients with CD4+ cell counts higher than 200 cells/mm3. In addition, RNA levels
in plasma higher than 5 logs predicted higher numbers of clinical events than did
RNA levels in plasma lower than 5 logs. Quantitation of HIV RNA in paired plasma
and serum samples showed lower HIV RNA content in serum than in the paired plasma
sample, with mean differences between HIV RNA contents of plasma and serum of
0.54 and 0.28 log RNA copy/ml by the Nasba assay and the Amplicor HIV-1 Monitor
assay, respectively. No significant loss of HIV RNA was detected with either
assay in plasma samples subjected to multiple freeze-and-thaw cycles. These
studies demonstrate that the Nasba and Amplicor assays perform similarly with
plasma and serum samples. Further, the results indicate that freeze-and-thaw
cycles do not result in significant loss of detectable HIV RNA.
PMID- 9399537
TI - Quantitative urine cultures do not reliably detect renal candidiasis in rabbits.
AB - The significance of quantitative urine cultures in patients at risk for
hematogenous disseminated candidiasis is controversial. While various
concentrations of Candida spp. in urine have been suggested as critical cutoff
points in the diagnosis of renal candidiasis, other investigators consider
quantitative cultures less critical in diagnosing upper tract infections. To
determine the significance of quantitative urine cultures in renal candidiasis,
we studied serial quantitative urinary cultures of Candida albicans in a rabbit
model of hematogenous infection. Of 197 urine samples from 34 infected animals,
144 were culture positive, with a sensitivity of 73.1% for urine cultures and a
lower limit of detection of 10 CFU/ml. The yield of urine cultures varied
according to severity and duration of infection. The mean renal and urinary
concentrations of C. albicans from rabbits with subacute candidiasis differed
significantly from those from rabbits with acute candidiasis (P = 0.013 and P <
or = 0.001, respectively). During the first 4 days of subacute renal candidiasis,
more than one-half of all urine cultures were negative for C. albicans. Only 12
(8.1%) of 148 urine cultures in animals with subacute renal candidiasis had
concentrations of > 10(3) CFU/ml, 2.7% had concentrations of > 10(4) CFU/ml, and
none were > or = 10(5) CFU/ml. By comparison, all urine cultures from the animals
with lethal acute renal candidiasis had higher concentrations of C. albicans and
were positive throughout the course of infection. Urinary concentrations of C.
albicans were not predictive of the amount of Candida in the kidney (r < or =
0.49) and did not correlate with survival (r = 0.0232). However, the renal
concentration of C. albicans (in CFU/gram) inversely correlated with the duration
of survival (in days) of rabbits with renal candidiasis (r = 0.76; P < 0.001).
These findings indicate that a negative urine culture in rabbits does not
preclude the presence of renal candidiasis. The interpretation of a urine culture
positive at any concentration, on the other hand, must involve an analysis of the
risk factors for renal candidiasis, for any urinary concentration of C. albicans
may reflect kidney infection.
PMID- 9399538
TI - GEMHEP multicenter quality control study of PCR detection of GB virus C/hepatitis
G virus RNA in serum.
AB - PCR is, to date, the only available tool for the detection of GB virus C (GBV-C)
and hepatitis G virus (HGV) RNAs. Twenty-two French laboratories participated in
a quality control study to assess the sensitivity and specificity of their
procedures. The panel included 13 positive controls and 7 negative controls. The
laboratories used either in-house PCR techniques adapted from the literature or
partly standardized commercial tests. Three laboratories performed faultlessly
with the entire panel. Most laboratories had excellent specificity (100% in 20 of
22 laboratories). Sensitivity was acceptable (85 to 100%) in 15 centers and
insufficient (38 to 77%) in 7. As with nonstandardized in-house PCR, the
commercial assays gave discrepant performances in different laboratories. These
results suggest that laboratories willing to use PCR for detection of GBV-C/HGV
RNA for research or diagnostic purposes should participate in multicenter quality
control trials.
PMID- 9399540
TI - Surveillance of cytomegalovirus after solid-organ transplantation: comparison of
pp65 antigenemia assay with a quantitative DNA hybridization assay.
AB - In a multicenter study, 113 blood samples from 19 organ transplant patients were
analyzed for cytomegalovirus by the pp65 antigenemia assay and a quantitative DNA
hybridization assay. Overall, there was 84% agreement among the results obtained
by the two tests. Fifteen of 16 episodes of active infection were detected by
both assays. One episode was missed by the pp65 assay, and one patient showed
significant DNA-emia but only low-level antigenemia.
PMID- 9399539
TI - Reproducibility of AMPLICOR enterovirus PCR test results.
AB - The reproducibility of AMPLICOR enterovirus PCR test results was determined with
clinical samples of cerebrospinal fluid, serum, urine, and throat and rectal
swabs. Among 608 samples from which duplicate aliquots were run simultaneously,
only seven pairs gave discordant results. Among 104 samples from which duplicate
aliquots were run in separate assays, no discordance was seen. Overall, the
reproducibility of test kit results was 99% (705 of 712).
PMID- 9399541
TI - Algaemia due to Prototheca wickerhamii in a patient with myasthenia gravis.
AB - Prototheca wickerhamii is a rare cause of systemic infection in humans. While
some cases occur in previously healthy individuals, others are associated with a
variety of preexisting diseases. Here we present, for the first time, a case of
P. wickerhamii algaemia in a patient with myasthenia gravis. The patient was
successfully treated with amphotericin B.
PMID- 9399542
TI - Comparison of the InPouch TV culture system and Diamond's modified medium for
detection of Trichomonas vaginalis.
AB - This study compared the use of Diamond's modified medium to InPouch for the
culture of Trichomonas vaginalis from pooled vaginal secretions. The sensitivity
for InPouch was 82.4% (61/74) versus 87.8% (65/74) for Diamond's modified medium.
There were no significant differences in the sensitivity and negative predictive
value of InPouch compared to Diamond's modified medium.
PMID- 9399543
TI - Comparison of different methods for extraction of DNA of fungal pathogens from
cultures and blood.
AB - Five commercially available extraction kits and an in-house DNA extraction method
for the release of DNA from Candida albicans and Aspergillus niger cells were
assessed for sensitivity, purity, duration, and cost. All commercially available
kits helped to shorten the duration of DNA extraction. However, the sensitivity
varied from 1 to 1,000 fungal cells/ml and costs varied from $0.10 to 2.30. The
QIAmp Tissue kit was the commercially available assay that yielded the same
sensitivity and purity of fungal DNA release as the in-house protocol but was the
most expensive method. In comparing these two extraction protocols, a 99%
concordance of PCR results for 125 blood samples analyzed could be demonstrated.
PMID- 9399544
TI - Detection of immunoglobulin G (IgG) and IgM antibodies to Toxoplasma gondii:
evaluation of four commercial immunoassay systems.
AB - A comparative evaluation of the following commercial immunoassays for the
determination of antibodies to Toxoplasma gondii was performed: Behring
Diagnostics OPUS Toxo G and Toxo M, Abbott Diagnostics IMX Toxo-IgG 2.0 and Toxo
IgM, Sanofi Diagnostics Pasteur Platelia Toxo IgG and Toxo IgM, and bioMerieux
Vitek VIDAS Toxo IgG and IgM. Of 676 specimens that were tested for Toxoplasma
specific immunoglobulin G (IgG) antibodies, 26% were reactive by all methods
while 8% displayed some discrepancy. Of 718 specimens that were tested for
Toxoplasma-specific IgM antibodies, 3% were reactive by all methods while 10%
displayed some discrepancy. Analysis of discrepant specimens revealed performance
shortcomings with all IgM-specific assays. The impact of such shortcomings is
magnified in a population with a low prevalence of toxoplasmosis.
PMID- 9399545
TI - Serodiagnosis of American trypanosomosis by using nonpathogenic trypanosomatid
antigen.
AB - Crithidia luciliae, a nonpathogenic trypanosomatid, could provide a good
alternative source of antigen for serodiagnosis of Chagas' disease. An enzyme
linked immunosorbent assay showed 100% sensitivity and 83% specificity when 91
human serum samples from Chagas' disease patients and 127 human serum samples
from people suffering from toxoplasmosis (21 samples), leishmaniasis (32
samples), systemic rheumatic diseases (33 samples), and heart diseases (41
samples) were tested simultaneously with Trypanosoma cruzi and C. luciliae crude
extracts. By Western blotting, an immunodominant band (30 kDa) was recognized by
chagasic sera on the C. luciliae crude extract; specificity reached 97% with
respect to this protein band. The carbohydrate moieties were not antigenic.
PMID- 9399546
TI - Increased levels of macrophage colony-stimulating factor, gamma interferon, and
tumor necrosis factor alpha in sera of patients with Orientia tsutsugamushi
infection.
AB - Levels of macrophage colony-stimulating factor (nine of nine patients) and gamma
interferon (six of nine patients) in serum were elevated above the range of
normal in the acute phase of tsutsugamushi disease. Significant increases in
levels of tumor necrosis factor alpha were observed during the convalescent phase
in five patients, and they exceeded the levels observed during the acute phase.
Hypercytokinemia appeared to be responsible for the emergence of the symptoms of
tsutsugamushi disease.
PMID- 9399547
TI - Susceptibilities of Chryseobacterium indologenes and Chryseobacterium
meningosepticum to cefepime and cefpirome.
AB - In vitro activities of cefepime and cefpirome against 96 isolates of
Chryseobacterium indologenes and 21 of C. meningosepticum were determined by the
agar dilution method. Overall, cefepime was more active than cefpirome against C.
indologenes (MIC at which 50% of the isolates were inhibited [MIC50] and MIC90, 4
and 16 microg/ml, respectively, for cefepime and 8 and 128 microg/ml,
respectively, for cefpirome). Both agents had poor potency against C.
meningosepticum (MIC50 and MIC90, 64 and >256 microg/ml, respectively, for
cefepime and 128 and >256 microg/ml, respectively, for cefpirome).
PMID- 9399549
TI - Identification by spoligotyping of a caprine genotype in Mycobacterium bovis
strains causing human tuberculosis.
AB - We have used spoligotyping to characterize 18 Mycobacterium bovis strains
isolated from cattle and 23 M. bovis strains isolated from goats. The
spoligotypes revealed that caprine strains form a separate and well
differentiated group that we refer to hereafter in this abstract as the caprine
genotype. To evaluate the importance of this genotype as a cause of tuberculosis
in other animal species, including humans, we applied the spoligotyping method to
112 strains, including to all isolates identified as M. bovis by a Mycobacterial
National Reference Laboratory (Majadahonda, Madrid) from 1994 to 1996. Eighty
three of these strains were identified in human isolates. In addition to being
identified in three goat isolates and two sheep isolates, the caprine genotype
was also found in three isolates causing human tuberculosis. Evidence to support
the argument that there is a zoonotic risk of caprine tuberculosis was presented
by the identification of the caprine genotype in an isolate from a veterinary
worker with a recent history of contact with tuberculous goats.
PMID- 9399550
TI - Rapid discrimination of Mycobacterium tuberculosis complex strains by ligation
mediated PCR fingerprint analysis.
AB - A ligation-mediated PCR (LMPCR) method for the amplification of sequences
flanking the IS6110 of the Mycobacterium tuberculosis complex has been developed.
The method uses one primer specific for IS6110 and a second specific for a linker
ligated to SalI-restricted genomic DNA. LMPCR is a rapid screening method,
valuable for the fingerprinting of M. tuberculosis complex strains.
PMID- 9399548
TI - Reliability of mycobacteria growth indicator tube for testing susceptibility of
Mycobacterium tuberculosis to ethambutol and streptomycin.
AB - The reliability of mycobacterial growth indicator tubes (MGIT) for testing
susceptibility of Mycobacterium tuberculosis to ethambutol and streptomycin was
evaluated by comparing MGIT results to those obtained by the radiometric BACTEC
TB system and the method of proportion. The method of proportion was considered
the reference method. To resolve discrepancies, all three testing methods were
repeated. For the 74 isolates evaluated, initial ethambutol results agreed by all
three methods for 64 (86.5%) of them; 58 were susceptible and 6 were resistant.
MGIT and method-of-proportion results agreed for 67 isolates, and BACTEC results
agreed with method-of-proportion results for 71 (P = 0.096). Initial streptomycin
results obtained by all three methods agreed for 69 (93.2%) isolates: 55 were
susceptible and 14 were resistant. MGIT and method-of-proportion results were
concordant for 69 isolates, and BACTEC and method-of-proportion results agreed
for 73 (P = 0.049). The mean times to MGIT results were 5.58 +/- 0.10 days
(range, 3 to 9 days) for ethambutol and 5.47 +/- 0.11 days (range, 3 to 9 days)
for streptomycin, compared to a mean of 7.41 +/- 0.20 days (range, 4 to 12 days)
for both drugs with the BACTEC system (P < 0.001).
PMID- 9399552
TI - Peritonitis associated with a CDC group EO-3 organism.
AB - A 63-year-old female with chronic renal failure on continuous ambulatory
peritoneal dialysis developed chronic peritonitis. A CDC group EO-3 organism was
isolated from the peritoneal dialysis fluid on five occasions over a period of 4
months. This is the first reported isolation of this organism in which it is
associated with a patient on continuous ambulatory peritoneal dialysis.
PMID- 9399551
TI - Necrotizing pneumonia caused by Penicillium chrysogenum.
AB - We report a case of necrotizing pneumonia due to Penicillium chrysogenum in a 57
year-old woman operated on for lung cancer. The residual right lower pulmonary
lobe was infiltrated by Penicillium chrysogenum. The patient underwent a second
pulmonary right lobectomy and was successfully treated with oral itraconazole. To
our knowledge, this is the first case of pneumonia due to P. chrysogenum.
PMID- 9399553
TI - Isolation of Cryptococcus neoformans var. gattii from Eucalyptus camaldulensis in
India.
AB - Cryptococcus neoformans var. gattii has an ecological association with five
Eucalyptus species: E. blakelyi, E. camaldulensis, E. gomphocephala, E. rudis,
and E. tereticornis. After human infections due to C. neoformans var. gattii were
diagnosed in the states of Punjab, Himachal Pradesh, and Karnataka, India, a
study was undertaken to investigate the association of C. neoformans var. gattii
with Indian eucalypts, especially in the state of Punjab. A total of 696
specimens collected from E. camaldulensis, E. citriodora and E. tereticornis
(hybrid) trees were examined for the presence of C. neoformans var. gattii.
Flowers from two trees of E. camaldulensis in the Chak Sarkar forest and one from
the village of Periana near the Ferozepur area yielded five isolates of C.
neoformans var. gattii. The origin of the trees could be traced to Australia,
thus providing evidence that the distribution of E. camaldulensis correlated with
the distribution of human cryptococcosis cases caused by C. neoformans var.
gattii in northern India.
PMID- 9399554
TI - Cutaneous hyalohyphomycosis caused by Fusarium solani in a loggerhead sea turtle
(Caretta caretta L.).
AB - Fusarium solani was reported as the agent of a cutaneous infection in an injured
sea turtle collected in the Mediterranean Sea. The turtle was treated with both a
topical 10% solution of iodine in alcohol and ketoconazole. The source of the
causal agent was traced to the sand in the tank in which the turtle was
maintained. The strain was only sensitive in vitro to amphotericin B and was
resistant to 5-fluorocytosine, fluconazole, itraconazole, and ketoconazole.
PMID- 9399555
TI - Yersinia enterocolitica serotype O:8 septicemia in an otherwise healthy adult:
analysis of chromosome DNA pattern by pulsed-field gel electrophoresis.
AB - We report the first case of blood culture-positive Yersinia enterocolitica
serotype O:8 septicemia in Japan. Y. enterocolitica serotype O:8 infection is
very rare, but chromosomal DNA analysis suggested that this bacterium may persist
latently in healthy carriers throughout Japan.
PMID- 9399556
TI - Unique organization of the CTX genetic element in Vibrio cholerae O139 strains
which reemerged in Calcutta, India, in September 1996.
AB - We studied the restriction fragment length polymorphism of the rRNA gene and CTX
genetic element in Vibrio cholerae O139 Bengal, which resurged in Calcutta in
September 1996 after a gap of 32 months. While the strains from this resurgence
were indistinguishable from the earlier strains by ribotyping, the structure of
the CTX genetic element present in the current O139 strains was found to be
unconventional.
PMID- 9399557
TI - Healthy puppies and kittens as carriers of Campylobacter spp., with special
reference to Campylobacter upsaliensis.
AB - Living in a household with a dog or cat has previously been identified as a
significant risk factor for acquiring campylobacteriosis, in particular, with
reference to Campylobacter upsaliensis infection. In a cross-sectional study
carried out in Denmark between August and December 1996, 72 healthy puppies and
42 healthy kittens, aged between 11 and 17 weeks, were sampled for fecal
campylobacter shedding by culture of rectal swab specimens on blood-free agar
base with cefoperazone at 32 mg/liter and amphotericin at 10 mg/liter and on
blood-free agar base with cefoperazone at 8 mg/liter, teicoplanin at 4 mg/liter,
and amphotericin at 10 mg/liter. Additionally, with respect to the C. upsaliensis
transmission potential of poultry, a chicken cloacal swab sample from each of 100
different broiler flocks was included in the study for comparison. We found 21
(29%) of the puppies positive for Campylobacter spp., with a species distribution
of 76% C. jejuni, 5% C. coli, and 19% C. upsaliensis. Of the kittens examined,
two (5%) excreted campylobacters; both strains were C. upsaliensis. None of the
chicken samples examined were found to be positive for C. upsaliensis. We
concluded that young puppies and kittens are potential transmitters of human
pathogenic Campylobacter spp., including C. upsaliensis, while poultry seems
negligible in C. upsaliensis epidemiology.
PMID- 9399558
TI - Citrobacter farmeri bacteremia in a child with short-bowel syndrome.
AB - A case of sepsis in a pediatric patient due to the newly described Citrobacter
species C. farmeri is described. Factors predisposing this child to infection
included short-bowel syndrome requiring total parenteral nutrition.
PMID- 9399559
TI - Detection of Chlamydia trachomatis in urine samples by nucleic acid tests:
comparison with culture and enzyme immunoassay of genital swab specimens.
AB - Two commercially available nucleic acid-based tests, ligase chain reaction (LCR;
Abbott Laboratories) and PCR (Roche Diagnostics), for the detection of Chlamydia
trachomatis in male and female urine samples were compared with culture and
enzyme immunoassay (EIA) (Microtrak; Syva) for C. trachomatis detection in
genital samples. The samples were collected from 1,005 patients who attended a
sexually transmitted disease clinic. In this study population, the prevalence of
the infection was 4%. Specimens which were reactive in any of the tests were
retested with a different PCR test using primers directed against the major outer
membrane protein gene. With a "gold standard" of a positive culture, or any other
positive test result if it was confirmed by an independent test, the Roche PCR
(95% sensitive, 99.9% specific) was more sensitive than the LCR (75% sensitive,
100% specific) (chi2, P < 0.0001) while both tests were more sensitive than
culture (58% sensitive, 100% specific) or EIA (45% sensitive, 100% specific)
(chi2, P < 0.001). The Roche PCR and Abbott LCR tests of urine identified 65% and
30% more positive patients, respectively, than did testing by culture of urethral
or cervical specimens. Nucleic acid testing of urine specimens for C. trachomatis
is a more sensitive and convenient method for the detection of genital infection.
PMID- 9399560
TI - Salivary immunoglobulin G assay to diagnose Helicobacter pylori infection in
children.
AB - An in-house enzyme-linked immunosorbent assay (ELISA) for measurement of
Helicobacter pylori-specific immunoglobulin G (IgG) and IgA in saliva was
evaluated by comparison with histopathologic (Giemsa staining) and biochemical
(urease quick test) examination of gastric biopsy specimens obtained from 112
children referred for diagnostic gastroscopy. Serum H. pylori IgG was also
measured in a subgroup of 50 children by the same ELISA. Salivary H. pylori IgG
levels were significantly higher in H. pylori-positive (n = 57) than in H. pylori
negative (n = 55) children (P < 0.001). The sensitivity and specificity of the
salivary IgG test were 93 and 82%, respectively; the positive and negative
predictive values were 84 and 92%, respectively; and the accuracy was 87.5%.
Salivary H. pylori IgA did not distinguish H. pylori-positive from H. pylori
negative children. The performance of serum H. pylori IgG was slightly (3 to 6%)
better than that of salivary H. pylori IgG. The salivary IgG test can be
considered a useful tool for the screening of H. pylori infection in children.
PMID- 9399561
TI - Reproducibility and performance of the AMPLICOR Chlamydia trachomatis test.
PMID- 9399562
TI - Shewanella putrefaciens abscess of the lower extremity.
PMID- 9399563
TI - PCR-based detection of Vibrio cholerae O139 Bengal with sequences encoding
glycosyltransferases.
PMID- 9399565
TI - Inhibitory properties of a swab transport device.
PMID- 9399564
TI - Coexistence of Ehrlichia phagocytophila and Borrelia burgdorferi sensu lato in
Ixodes ricinus ticks from Italy as determined by 16S rRNA gene sequencing.
PMID- 9399566
TI - Mistyping of two Slovenian hepatitis C virus subtype 2c isolates as subtype 2b by
two 5' noncoding region genotyping methods.
PMID- 9399567
TI - Crystallization and preliminary X-ray analysis of a truncated family A alkaline
endoglucanase isolated from Bacillus sp. KSM-635.
AB - The catalytic domain of an alkaline endo-1,4-beta-glucanase (family A) isolated
from Bacillus sp. KSM-635 (Mr = 40.2 kDa) was crystallized using the hanging drop
vapor diffusion method. Two different crystal forms were obtained. Form 2
crystals (trigonal space group R3 with cell dimensions of a = b = 111.9 and c =
207.1 angstroms in a hexagonal lattice) were found to be more stable than form 1
ones upon X-ray irradiation. A full data set for form 2 crystals has been
collected up to 3.3 angstroms resolution.
PMID- 9399568
TI - Construction of transforming growth factor alpha (TGF-alpha) phage library and
identification of high binders of epidermal growth factor receptor (EGFR) by
phage display.
AB - TGF-alpha, a 50 amino acid growth factor containing 3 disulfide bonds, was fused
to the N-terminal domain of the pIII protein of fusN, a derivative of phagemid fd
tet, to form a TGF-alpha phage. The fusion phage showed binding activity to
epidermal growth factor receptor (EGFR). A library of approximately 4 x 10(7)
variants of TGF-alpha was generated with substitutions of total of 10 amino acids
located in the C-loop region. This C-loop subdomain of TGF-alpha consists of a
small antiparallel double hairpin structure involving interactions between intra
polypeptide segments. Mutants isolated from the phage library with greatly
increased binding affinity were selected through panning with A431 cells (a cell
line expressing an elevated number of EGFRs). Following two rounds of stringent
selection, variant phages with higher binding affinity than wild type TGF-alpha
were identified and the phage DNAs were sequenced for the alignment analysis.
Absolute selection at position 42 as Arg, preferential selection at position 38
and 45 as Tyr or Phe with aromatic side chain and selection at position 41 with
acidic residues, were obtained. Although an amino acid residue with smaller side
chain at position 35 and one with larger side chain at position 36 were
preferred, the steric hindering of the structure in side chains was minimized
between these adjacent amino acids.
PMID- 9399569
TI - Expression of the human UDP-galactose transporter in the Golgi membranes of
murine Had-1 cells that lack the endogenous transporter.
AB - In our previous study, we demonstrated that UDP-galactose transporter cDNAs
(hUGT1 and hUGT2) were able to complement the genetic defect of murine Had-1
cells that were deficient in the UDP-galactose transporter, and that the
microsomal vesicles isolated from Had-1-transformants, which were obtained
through transfection with these cDNAs, had recovered the ability to uptake UDP
galactose [Ishida, N. et al. (1996) J. Biochem. 120, 1074-1078]. In this report,
we describe the preparation of peptide antibodies that recognize the hUGT
isozymes, and the detection of hUGT proteins expressed in the transformants. The
occurrence of the endogenous hUGT1 protein in HeLa cells was also detected. Using
the hUGT1-specific antibodies, the subcellular localization of hUGT1 in the Golgi
membrane was demonstrated by immunofluorescence microscopy and subcellular
fractionation. These studies led us to develop a simple procedure, based on
Percoll density gradient centrifugation, for preparing functional Golgi vesicles
from the hUGT1-transformed Had-1 cells, that will facilitate future biochemical
analyses of the UDP-galactose transporter for the elucidation of its structure
function relationship.
PMID- 9399570
TI - Structure and function in Escherichia coli of plasmids containing
pyrimidine/purine-biased stretch originated from the 5'-flanking region of the
basidiomycete ras gene.
AB - The Basidiomycete ras gene possesses a pyrimidine-rich stretch (CT-motif) with a
short (7 bases) mirror repeat in which its major transcription start point is
contained. To analyze the tertiary structure induced by the CT/AG-biased sequence
and its effect on gene expression in supercoiled plasmids in Escherichia coli,
the DNA fragment containing the ras CT/AG sequence was inserted into the EcoRI
site on pBR322 in both orientations and the resulting pBR322 derivatives, named
pBR-CT[ras] and pBR-invCT[ras] were introduced into E. coli strains DM800
(deltatopA gyrB225) and JM109 (topA+ gyrA96). In pBR-CT [ras] the pyrimidine-rich
sequence is on the pBR322 tetracycline-resistance gene (tet)coding strand and in
pBR-invCT[ras] the complementary purine-rich sequence is on this strand. DNAs of
pBR-CT[ras] and pBR-invCT[ras] isolated from DM800 were frequently cleaved with
single-strand-specific S1 nuclease within the CT/AG sequence, showing the
formation of extended open structure. Compared with those carrying pBR322, DM800
and JM109 carrying pBR-CT [ras] showed much higher levels of tetracycline
resistance (Tcr), while both strains carrying pBR-invCT[ras] showed clearly lower
levels of Tcr. pBR-CT [ras] and pBR-invCT [ras], however, conferred reduced
activity of beta-lactamase on DM800 and JM109. pBR-CT [ras] derivatives lacking
the counterpart of the mirror repeat did not form the S1-cleavable open structure
within the CT/AG sequence and conferred pBR322-like Tcr and beta-lactamase
activity. The tertiary structure formed in the CT/AG sequence via the mirror
repeat was suggested to affect the expressions of pBR322-tet and -bla genes.
PMID- 9399571
TI - CBP/p300 functions as a possible transcriptional coactivator of Ah receptor
nuclear translocator (Arnt).
AB - A heterodimer of AhR (aryl hydrocarbon receptor) and Arnt (AhR nuclear
translocator) conveys a transactivation signal of aromatic hydrocarbons such as
2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene to the genes for a
group of drug-metabolizing enzymes. This inducible expression of the genes is
inhibited by adenovirus E1A, suggesting that CBP/p300 is somehow involved in the
transactivation of the genes by the AhR and Arnt heterodimer. Yeast and mammalian
two hybrid systems revealed that CBP/p300 interacted with the transactivation
domain of Arnt, but not with that of AhR, via the CREB-binding domain. The pull
down assay using GST-Arnt hybrid protein confirmed the interaction between Arnt
and CBP/p300. Considering these results and that Arnt or Arnt2 functions as a
common partner in the formation of transcriptional regulators with other bHLH/PAS
proteins such as AhR, HLF, and HIF-1alpha, the possibility arises that CBP/p300
is extensively involved as a coactivator in the transactivation process by
bHLH/PAS (a conserved sequence motif among Per, Arnt, and Sim) heterodimer
transcription factors through interaction with Arnt or Arnt2.
PMID- 9399572
TI - Dimerization and DNA binding facilitate alpha-helix formation of Max in solution.
AB - Max is a basic region/helix-loop-helix/leucine zipper (b/HLH/Z) protein that
forms a hetero-complex with the Myc family proteins Myc, Mad, and Mxi1, and a
homo-complex with itself. These complexes specifically bind to double-stranded
DNA containing CACGTG sequences. Here, we report on the structural properties in
aqueous solution of a 109-amino-acid protein, Max110, corresponding to the N
terminal domain of Max containing the b/HLH/Z motif (residues 2-110), as
characterized by combined use of circular dichroism (CD) and sedimentation
equilibrium experiments. The results showed that the alpha-helical content of
Max110 increases with increasing protein concentration. The sedimentation
equilibrium data indicated that Max110 exists as a monomer at low protein
concentration, and forms a dimer at high protein concentration. Further increases
in the alpha-helical content of Max110 occur upon addition of DNA with the CACGTG
recognition sequence. Thus, dimerization and binding to DNA of Max both favor an
increase of the alpha-helical content.
PMID- 9399573
TI - Antisense oligodeoxynucleotides of IGF-II selectively inhibit growth of human
hepatoma cells overproducing IGF-II.
AB - Insulin-like growth factor II (IGF-II) is expressed in many developing embryonic
tissues and is involved in mammalian growth and development. After birth, serum
IGF-II is mainly produced by liver cells. Many reports have indicated that IGF-II
is overexpressed in some hepatocellular carcinoma (HCC) tissue. These findings
imply the possible importance of this growth factor in carcinogenesis. We
screened four human HCC cell lines and three rat HCC cell lines and found that
HuH-7 and HepG2 cells produced fivefold more intracellular IGF-II than the other
cell lines. Experimental data indicate that IGF-II functions through the
intracrine mode for HuH-7 cells. To study whether the overexpression of IGF-II is
significant for the growth of HCC or only a consequence of HCC development, we
used antisense oligodeoxynucleotides (ATON) to arrest the translation of IGF-II
mRNA, and then measured the effects on cell growth. We found that the production
of IGF-II was suppressed by ATON, and the decrease of IGF-II resulted in growth
inhibition of HuH-7 and HepG2. ATON had no effect on the other tested cell lines,
which produced lower levels of IGF-II. The growth inhibition was mainly
attributed to a decrease of cell proliferative activity. The results indicate
that the IGF-II-overproducing cell lines do depend on IGF-II for growth, and ATON
of IGF-II can selectively inhibit the growth of these cells. ATON may be a
potential therapeutic agent for this type of HCC in vivo.
PMID- 9399574
TI - Relationships of subunits of type-1 serine/threonine protein phosphatase to
morphology and aggregation of B cells.
AB - To elucidate the roles of serine/threonine protein phosphatases PP1 and PP2A in
the morphological changes of B-lymphocytes during development and in immune
responses, we investigated alterations of protein levels of catalytic subunits of
PP1 and PP2A and regulatory subunits of PP1 including M130/M133, inhibitor-1 (I
1) and inhibitor-2 (I-2) in B-cell lines at different maturational stages and
during their aggregation induced by phorbol myristate acetate (PMA). The protein
levels of PP1delta and/or M130/M133 were significantly lower in B-cell lines
without pseudopods, WEHI-231, BAL-17, Daudi, and CESS, than in those with
pseudopods, Bcl.1, A20, M12, and SKW6.4, whereas the amounts of PP1alpha and PP2A
were similar among them. During aggregation of A20 and CESS cells induced by PMA,
an activator of PKC, the amount of PP1delta was progressively decreased, and this
decrease was blocked by H7, an inhibitor of PKC. The amount of PP1alpha was
constant under these conditions. Okadaic acid, an inhibitor of PP1 and PP2A, also
induced aggregation of A20 cells at concentrations sufficient to inhibit PP1, but
not at lower concentrations that inhibit PP2A alone. These results suggest that
myosin light chain phosphatase composed of PP1delta and M130/M133 is involved in
the maintenance and regulation of cytoskeletal structures in B-lymphocytes.
PMID- 9399575
TI - Alterations in type-1 serine/threonine protein phosphatase PP1alpha in response
to B-cell receptor stimulation.
AB - In response to stimulation of B-cells through cell surface IgM, the activity of
the serine/threonine protein phosphatase PP1, but not PP2A, was transiently
decreased and reached a minimum 10-20 min after the stimulation. The decrease was
more profound in the immature B-cell line WEHI-231, than in the mature B-cell
line BAL-17. Under these conditions, PP1alpha, an isoform of PP1, showed unique
alterations in the patterns of several spots with distinct isoelectic points in
the Western blot after two-dimensional electrophoresis, whereas another isoform,
PP1delta, did not show any alteration. PP1gamma1 and PP1gamma2 were not detected
in B-cells. Similar alterations in these spots were observed in B-cells
stimulated by PMA. When partially purified PP1 consisting of PP1alpha and
PP1delta was incubated with [gamma-32P]ATP and PKC, radioactive spots of PP1alpha
could be detected, but no spot of PP1delta was detected. Because differences in
sequence among PP1 isoforms are mostly restricted to their C-terminals,
phosphorylation rates of the C-terminal peptides containing the PKC
phosphorylation motif were compared. The C-terminal peptide of PP1alpha is a
better substrate for PKC than those of PP1gamma1 and PP1gamma2, and is
phosphorylated at the serine residue corresponding to Ser-325 of PP1alpha. The
corresponding C-terminal region of PP1delta does not contain the phosphorylation
site. On the other hand, there was a large difference in subcellular distribution
of PP1delta, but not PP1alpha, between immature and mature B-cells. From these
results, it was strongly suggested that PP1alpha is involved, via phosphorylation
by PKC, in the regulation of signal transduction in response to the stimulation
of B-cells through cell surface IgM.
PMID- 9399576
TI - Inhibition of phosphoinositide hydrolysis and cell growth of Swiss 3T3 cells by
myristoylated phospholipase C inhibitor peptides.
AB - It has been demonstrated that the phospholipase C-gamma (PLC-gamma) molecule
contains within it a phospholipase C inhibitor (PCI) region and that synthetic
peptides based on the sequence of this region (PCI peptides) suppress the
enzymatic activity of PLC isoforms [Y. Homma and T. Takenawa (1992) J. Biol.
Chem. 267, 21884-21889]. In order to improve the permeability of the plasma
membrane to PCI peptides, we synthesized myristoylated PCI peptides, myr
GLYRKAMRLRYPV [myr-PCI(Y)] and myr-GLFRKAMRLRFPV [myr-PCI(F)], which are
identical except for the replacement of the two tyrosine residues in myr-PCI(Y)
by phenylalanines in myr-PCI(F), and examined their inhibitory activity on PLC
enzymes in vitro and in vivo. This fatty acid modification potentiated the
inhibitory activity of the original PCI peptides and both myr-PCI(Y) and myr
PCI(F) suppressed the PIP2-hydrolyzing activity of purified PLC isoforms in
vitro. The Ki values of myr-PCI(Y) and myr-PCI(F) for purified PLC-gamma1 were
3.5 and 55 microM, respectively. Myr-PCI(Y) at concentrations in the sub
micromolar range significantly suppressed IP3 formation induced by EGF, PDGF,
bombesin, or serum in Swiss 3T3 cells. Furthermore, myr-PCI(Y) also strongly
inhibited cell proliferation induced by these stimuli. The inhibitory effect on
IP3 formation and proliferation of myr-PCI(F) was much less potent than that of
myr-PCI(Y). These results suggest that myristoylated PCI peptides could be
applied to living cells as specific inhibitors of PLC signaling pathways and that
PLC pathways are at least in part required for growth in Swiss 3T3 cells.
PMID- 9399577
TI - Downregulation of calpastatin in rat heart after brief ischemia and reperfusion.
AB - The activities of calpain and its endogenous inhibitor, calpastatin, were
measured in the soluble fraction of perfused rat heart after ischemia for 5-20
min and reperfusion for up to 30 min. The method for m-calpain measurement was
modified: washing of the DEAE-cellulose column with 0.18 M NaCl instead of 0.15 M
NaCl increased the m-calpain activity 12.5-fold. Ischemia for 20 min followed by
reperfusion for 30 min did not affect the m-calpain activity but decreased the
calpastatin activity. m-Calpain was enriched in the nucleus-myofibril fraction
but was not further translocated on ischemia-reperfusion. Mu-calpain was below
the limit of detection on immunoblotting or casein zymography, but its mRNA was
substantially expressed, as detected on Northern blotting. Casein zymography also
revealed a novel Ca2+-dependent protease without the typical characteristics of
mu- or m-calpain. The immunoblotting of myocardial fractions showed that
calpastatin was proteolyzed on ischemia-reperfusion. The calpastatin proteolysis
was suppressed by a calpain inhibitor, Ac-Leu-Leu-norleucinal. Calpastatin may
sequester calpain from its substrates in the normal myocardium, but may be
proteolyzed by calpain in the presence of an unidentified activator in the early
phase of calpain activation during ischemia-reperfusion, resulting in the
proteolysis of calpastatin and then other calpain substrates.
PMID- 9399578
TI - Cleavage activity of hepatitis C virus serine proteinase.
AB - To study the character of the hepatitis C virus (HCV) encoding serine proteinase
and to search for inhibitors, a practical in vitro assay system using the
purified enzyme and synthetic peptide substrates was established. The enzyme used
was expressed in Escherichia coli as a fusion form with protein tags and purified
to apparent homogeneity by single-step affinity chromatography. The purified
enzyme exhibited proteolytic activity with pH optima of around eight, and the
addition of NS4A fragments increased the activity as well as the thermal
stability of the enzyme. The activity was inhibited by EDTA and some divalent
ions, i.e., copper and zinc, though calcium, magnesium, and manganese were
stimulative both in the presence and absence of the NS4A fragment. None of the
common protease inhibitors, including serine protease inhibitors, effectively
inhibited the activity. Based on the kinetic parameters of the cleavage reaction
of the synthetic 20 mer peptides corresponding to the three cleavage sites,
NS4A/4B, NS4B/5A, and NS5A/5B, the peptide with the NS5A/5B junction was found to
be the most efficient substrate. Analysis of the minimal peptide substrate of
NS5A/5B indicated that 5 to 7 amino acids on both sides of the junction were
required for efficient cleavage. These findings are expected to contribute to the
search for a proteinase inhibitor.
PMID- 9399579
TI - Identification and characterization of a major lysosomal membrane glycoprotein,
LGP85/LIMP II in mouse liver.
AB - We previously have purified and characterized a major lysosomal membrane
glycoprotein termed LGP85 (LIMP II) in rat liver lysosomes. In this study, LGP85
in mouse liver lysosomes was identified and characterized by biochemical and
molecular biological methods. Lysosomal membranes were isolated from murine liver
by differential centrifugation. LGP85 was present in the lysosomal membrane
fraction from mouse liver in a comparable amount to another lysosomal membrane
glycoprotein, lamp-2. Mouse LGP85 (M-LGP85) from liver lysosomal membranes
exhibited an Mr of 80,000 on SDS-PAGE, which is smaller by 5,000 than that of rat
LGP85 (R-LGP85). M-LGP85 was immunochemically detected in the extracts of brain,
heart, lung, liver, and kidney. A cDNA encoding M-LGP85 was cloned from mouse
liver cDNA library. The primary protein structure deduced from a nucleotide
sequence of M-LGP85 cDNA indicated that M-LGP85 consists of 478 amino acids with
Mr of 54,069. M-LGP85 showed 93.3 and 86.0% sequence similarities to its rat and
human counterparts in amino acids, respectively. M-LGP85 contains 11 potential N
glycosylation sites which are heavily glycosylated, resulting in the increased Mr
of M-LGP85 present in the mouse liver lysosomes. It is likely that M-LGP85
traverses the lysosomal membrane twice, with an NH2-terminal transmembrane
domain, and another hydrophobic domain near the COOH-terminus. M-LGP85 has a
protruding COOH-terminal cytoplasmic tail consisting of amino acid residues
including the leucine-isoleucine sequence shown to be the lysosomal targeting
signal of R-LGP85 and human LGP85 (H-LGP85). The high level of expression of M
LGP85 in the lysosomal membrane, the high structural similarities among M-, R-,
and H-LGP85, and the occurrence of M-LGP85 in all the mouse tissues examined
suggest the essential and constitutive function of LGP85 in lysosomes.
PMID- 9399580
TI - A novel cytochrome b(o/a)3-type oxidase from Bacillus stearothermophilus
catalyzes cytochrome c-551 oxidation.
AB - Gram-positive thermophilic Bacillus species contain cytochrome caa3-type
cytochrome c oxidase as their main terminal oxidase in the respiratory chain. To
identify alternative oxidases, we isolated several mutants from B.
stearothermophilus defective in the caa3-type oxidase activity [Sakamoto, J. et
al (1996) FEMS Microbiol. Lett. 143, 151-158]. A novel oxidase was isolated from
membrane preparations of one of the mutants, K17. The oxidase was composed of two
subunits with molecular masses of 56 and 19 kDa, and contained protoheme IX, heme
O, heme A, and Cu in a ratio of 1:0.7:0.2:3. CO difference spectra indicate that
the high-spin heme is mainly heme O. These results suggest that the enzyme
belongs to the heme-copper oxidase family and is a cytochrome b(o/a)3-type
oxidase, whose high-spin heme is mainly heme O and partly heme A. The enzyme
oxidized cytochrome c-551, which is a membrane-bound lipoprotein of thermophilic
Bacillus. The turnover rate of the activity (Vmax = 190 s[-1]) and its affinity
for cytochrome c-551 (Km = 0.15 microM) were much higher than those for yeast and
equine heart cytochromes c. The oxidase activity was enhanced by the presence of
salts and inhibited by sodium cyanide with a Ki value of 19 microM. The enzyme
kinetics suggests that cytochrome c-551 is the natural substrate to this oxidase.
Furthermore, the oxidase had similarity to cytochrome ba3-type oxidase from
Thermus thermophilus in the subunit composition, partial amino acid sequence, and
prosthetic groups, and therefore is suggested to belong to a unique subgroup of
the heme-copper oxidase family together with the Thermus enzyme and archaeal
oxidases such as Sulfolobus SoxABCD.
PMID- 9399581
TI - Purification, staphylolytic activity, and cleavage sites of alpha-lytic protease
from Achromobacter lyticus.
AB - Alpha-lytic protease (alp) was purified from a bacteriolytic agent,
Achromopeptidase from Achromobacter lyticus M497-1, and has been shown to possess
staphylolytic activity. Cleavage sites of this enzyme on the peptidoglycan of
Staphylococcus aureus were determined by N-terminal amino acid sequence and amino
acid composition analyses. Alp cleaved the N-acetylmuramoyl-L-alanine amide bond,
the junction between the polysaccharide and peptide moieties, in addition to the
D-Ala-Gly and Gly-Gly peptide bonds, implying that this enzyme recognizes the
amino acid of D-configuration at the P1 site and possesses N-acetylmuramoyl-L
alanine amidase activity. However, alp could not cleave the D-Ala-Gly peptide
bond in a synthetic peptide, suggesting that this hydrolytic activity of alp is
peptidoglycan-specific. The results obtained from different consecutive actions
of alp and glycosidase on S. aureus peptidoglycan indicate that the presence of
polysaccharide in the peptidoglycan is necessary for the bacteriolytic activity
of alp.
PMID- 9399582
TI - Alanyl aminopeptidase from human seminal plasma: purification, characterization,
and immunohistochemical localization in the male genital tract.
AB - Alanyl aminopeptidase (AAP) was purified to homogeneity from human seminal
plasma. The calculated molecular weight of the purified enzyme was approximately
137,000+/-5,000 from light scattering, 140,000 (main) and 137,000 (minor) from
non-denatured PAGE and 153,000 from SDS-PAGE in the absence or presence of 2
mercaptoethanol (2-ME). These findings suggest that the enzyme is monomeric in
form in human seminal plasma. The enzyme hydrolyzed several amino acid 4-methyl
coumaryl-7-amide (MCA) substrates. The order of Kcat/Km values of AAP at optimal
pH (pH 7.5) was Ala- > Lys-Ala- > or = Met- > Leu- > Phe- > Arg- > or = Arg-Arg-
> Lys- > Gly-MCAs. AAP was potently inhibited by bestatin, leuhistin, actinonin,
amastatin, and 1,10-phenanthroline. These findings suggest that AAP is an
aminopeptidase. We determined that the amino acid sequence of the first 22
residues of the enzyme was Ser1-Thr-Thr-Pro-Ser5-Ala-Ser-Ala-Thr-Thr10-Asn-Pro-Al
a-Ser-Ala15-Thr-Thr-Leu-Asp-Gln20-Ser-Lys-. This sequence was completely
coincident with that downstream of the transmembrane site of human intestinal
alanyl aminopeptidase N (CD13). We also isolated cDNA encoding AAP from human
prostate cDNA library, sequenced its structure, and confirmed human seminal
plasma AAP to be identical with alanyl aminopeptidase N. We postulated that
native human seminal plasma alanyl aminopeptidase is released into the seminal
plasma after the specific site is cleaved by elastase or an elastase-like enzyme.
The enzyme level in human seminal plasma determined by single radial
immunodiffusion was 5.2+/-3.2 mg/100 ml (mean+/-SD, n=20) in individuals 20-47
years of age. AAP was immunohistochemically stained in the luminal site-cell
membrane of epithelial cells in the prostatic gland and ductuli efferentes of the
testis.
PMID- 9399583
TI - Resynthesis of reactive site peptide bond and temporary inhibition of
Streptomyces metalloproteinase inhibitor.
AB - Streptomyces metalloproteinase inhibitor (SMPI) is a small proteinaceous
inhibitor which inhibits metalloproteinases such as thermolysin (Ki =1.14 x 10(
10) M). When incubated with the enzyme, it is gradually hydrolyzed at the Cys64
Val65 peptide bond, which was identified as the reactive site by mutational
analysis. To achieve a further understanding of the inhibition mechanism, we
attempted to resynthesize the cleaved reactive site by using the enzyme catalytic
action. The native inhibitor was resynthesized from the modified inhibitor (Ki
=2.18 x 10(-8) M) by incubation with a catalytic amount of thermolysin under the
same conditions as used for hydrolysis (pH 7.5, 25 degrees C), suggesting that
SMPI follows the standard mechanism of inhibition of serine proteinase
inhibitors. Temporary inhibition was observed when the native inhibitor and
thermolysin were incubated at a 1:100 (mol/mol) enzyme-inhibitor ratio at 37
degrees C. SMPI showed temporary inhibition towards all the enzymes it inhibited.
The inhibitory spectrum of SMPI was analyzed with various metalloproteinases
based on the Ki values and limited proteolysis patterns. Pseudomonas elastase and
Streptomyces griseus metalloproteinase II formed more stable complexes and showed
much lower Ki values (approximately 2 pM) than thermolysin. In the limited
proteolysis experiments weak inhibitors were degraded by the enzymes. SMPI did
not inhibit almelysin, Streptomyces caespitosus neutral proteinase or matrix
metalloproteinases. SMPI specifically inhibits metalloproteinases which are
sensitive to phosphoramidon.
PMID- 9399584
TI - Genomic organization of the rat nuclear factor I-A gene.
AB - The nuclear factor 1 (NF1) protein family functions as a cellular transcription
factor as well as an adenovirus DNA replication factor. This family consists of
four subtypes, NFI-A, NFI-B, NFI-C, and NFI-X, each encoded by a different gene.
Each subtype possesses different isoforms generated by alternative splicing. To
date, only a porcine NFI-C gene has been cloned, and the gene structures of the
other NF1 proteins have not yet been identified. We recently isolated four kinds
of NFI-A cDNA clones from the rat liver. To gain additional insight into the
structure of NFI-A, we isolated the rat NFI-A gene. This gene is composed of 11
exons spanning over 70 kb. All of the exon/intron boundaries are consistent with
the GT/AG rule, and consensus sequences surrounding the splice boundaries are
also found. The 5'-flanking region lacks a canonical TATA box, but contains
several GC-box and AP2 binding sites. A 5'-rapid amplification of cDNA end
analysis indicated that the transcription of the NFI-A gene is initiated at
multiple sites. We also found conservation in the genomic structure between the
rat NFI-A and the porcine NFI-C, suggesting that duplication of an ancestral gene
occurred rather recently to produce the NFI-A and NFI-C genes.
PMID- 9399585
TI - Involvement of Glu-264 and Arg-235 in the essential interaction between the
catalytic imidazole and substrate for the D-lactate dehydrogenase catalysis.
AB - For Lactobacillus pentosus D-lactate dehydrogenase, the binding of 2-ketoacids is
markedly stabilized through interactions between the protonated imidazole of His
296, an acid/base catalyst of the enzyme, and the carbonyl oxygen of 2-ketoacids.
The replacement of Arg-235 with Gln destabilized the inhibitory binding of
oxamate much more than that of formate, acetate, or propionate, and the Arg to
Lys substitution specifically diminished only oxamate binding. On the other hand,
replacement of a conserved Glu, Glu-264, with Gln severely impaired the enzyme
activity and markedly reduced affinity to 2-keto acids. The pH dependence of the
oxamate inhibition revealed that the substitutions of Arg-235 and Glu-264 induced
a great loss of the imidazole-carbonyl interaction. However, replacement of Glu
264 with Asp, another acidic amino acid, affected the enzyme function less than
the Glu to Gln substitution. In addition, both the Arg-235 and Glu-264
substitutions induced marked increases in the primary isotope effect on the
catalysis, suggesting that these amino acids stimulate the hydrogen transfer step
in the catalysis. We concluded, therefore, that the guanidino and carboxyl groups
of Arg-235 and Glu-264, respectively, cooperatively promote the essential
imidazole-substrate interaction, enhancing the substrate binding and catalysis.
PMID- 9399586
TI - Functional expression of human mannan-binding proteins (MBPs) in human hepatoma
cell lines infected by recombinant vaccinia virus: post-translational
modification, molecular assembly, and differentiation of serum and liver MBP.
AB - Human mannan-binding proteins (MBPs) occur in two forms, serum MBP (S-MBP) and
liver MBP (L-MBP), both of which are synthesized in the liver from a single form
of human MBP mRNA. To investigate further the mechanisms of post-translational
modification, molecular assembly and differentiation of S-MBP and L-MBP in vitro,
we expressed a full-length human MBP cDNA in three human hepatoma cell lines,
using the vaccinia virus expression system. The expression of human MBP cDNA
reproduced the native MBP differentiation of S-MBP and L-MBP in human hepatoma
cells. The recombinant S-MBP was secreted into the medium, and the recombinant L
MBP retained in the cells. The former had the ability to activate the complement
through the classical or lectin pathway but the latter did not. Furthermore, one
notable difference between the two MBPs was the degree of oligomerization through
interchain disulfide bonds between subunits. In addition, we showed that both S
MBP and L-MBP undergo hydroxylation of lysine and proline residues in collagen
like sequences, and that the hydroxylysine is glycosylated to form
glucosylgalactosylhydroxylysine (GluGalHyl) and galactosylhydroxylysine (GalHyl).
Hydroxylation was required for S-MBP to be assembled into large complexes, the
apparent molecular sizes of which were estimated to be 200-1,300 kDa by SDS-PAGE
under non-reducing conditions and gel filtration under non-denaturing conditions.
The hydroxylation and subsequent glycosylation and oligomerization were inhibited
by alpha,alpha'-dipyridyl, an inhibitor of collagen lysyl and prolyl
hydroxylases. These results suggested that newly synthesized lectins undergo post
translational modifications unique to the two forms of MBP, S-MBP, and L-MBP, in
human hepatocytes and hepatoma cells, and that the collagen-like domains of the
MBPs play an important role in promoting molecular assembly.
PMID- 9399587
TI - Cloning, expression and isoform classification of a minor oleosin in sesame oil
bodies.
AB - The oil bodies of plant seeds contain a triacylglycerol matrix surrounded by a
monolayer of phospholipids embedded with alkaline proteins termed oleosins. Two
distinct oleosins are present in the oil bodies of diverse angiosperms, and
classified as high and low Mr isoforms according to their relative molecular
masses in each species. In sesame oil bodies, besides the two ubiquitous oleosin
isoforms (17 and 15 kDa), an additional minor oleosin (15.5 kDa) was revealed on
Tricine SDS-PAGE. A full-length cDNA fragment was cloned, sequenced and deduced
to be a putative oleosin of 15,446 Da. The gene was constructed in a fusion or
non-fusion vector and then over-expressed with different efficiency in
Escherichia coli. All three oleosins purified from sesame oil bodies were
subjected to immunoassaying using antibodies raised against the over-expressed
oleosin. The results confirmed that this gene encodes the sesame 15.5 kDa
oleosin. Sequence comparisons with other known oleosins revealed that sesame 15.5
kDa oleosin does not represent a new oleosin isoform class but may have been
derived through gene duplication and truncation of sesame 17 kDa oleosin, and
possesses the minimal structure of the high Mr oleosin isoform. A conserved
amphipathic alpha-helix is predicted in sesame 15.5 kDa oleosin, which may imply
a potential biological function associated with this isoform.
PMID- 9399588
TI - Structural and mechanistic studies on D-amino acid oxidase x substrate complex:
implications of the crystal structure of enzyme x substrate analog complex.
AB - As an extension of our recent X-ray crystallographic determination of the
tertiary structure of D-amino acid oxidase (DAO) [Mizutani, H. et al. (1996) J.
Biochem. 120, 14-17], we solved the crystal structure of the complex of DAO with
a substrate analog, o-aminobenzoate (OAB). The alignment between flavin and OAB
in the crystal structure of the complex is consistent with charge-transfer
interaction through the overlap between the highest occupied molecular orbital of
OAB and the lowest unoccupied molecular orbital of flavin. Starting with the
atomic coordinates of this complex as the initial model, we carried out molecular
mechanics simulation for the DAO-D-leucine complex and thus obtained a model for
the enzyme-substrate complex. According to the enzyme-substrate complex model,
the alpha-proton is pointed toward N(5) of flavin while the lone-pair of the
substrate amino group can approach C(4a) of flavin within an interacting
distance. This model as well as DAO-OAB complex enables the evaluation of the
substrate-flavin interaction prior to electron transfer from the substrate to
flavin and provides two possible mechanisms for the reductive-half reaction of
DAO, i.e., the electron-proton-electron transfer mechanism and the ionic
mechanism.
PMID- 9399589
TI - Functions of characteristic Cys-Gly-His-Cys (CGHC) and Gln-Glu-Asp-Leu (QEDL)
motifs of microsomal ER-60 protease.
AB - The human ER-60 protease cDNA was expressed in Escherichia coli BL21 (DE3) cells
using the pET-20b(+) T7 promoter. The recombinant ER-60 protease was obtained in
a water-soluble form and purified through four sequential chromatographies. The
ER-60 protease contains two CGHC motifs. When an alanine residue was substituted
for the N-terminal cysteine residue in both motifs, the protease activity was not
lost. However, when the C-terminal cysteine residue in both motifs was replaced
by a serine residue, the cysteine protease activity, which was inhibited by p
chloromercuribenzoic acid (pCMB) but not by diisopropyl fluorophosphate (DFP),
changed to serine protease activity, which was inhibited by DFP but not by pCMB.
These results indicate that the C-terminal cysteine residue(s) of the CGHC motifs
may constitute the active site(s) of ER-60 protease. The ER-60 protease has a C
terminal QEDL sequence, which was proved to serve as an ER-retention signal by
deletion of the QEDL sequence. However, because QEDL could not serve as the ER
retention signal for protein disulfide isomerase or ERp72, it is suggested that
amino acid residue(s) of ER-60 protease, other than the QEDL sequence itself, is
complimentarily responsible for the ER retention of this protein.
PMID- 9399590
TI - Methionine aminopeptidase from the hyperthermophilic Archaeon Pyrococcus
furiosus: molecular cloning and overexpression in Escherichia coli of the gene,
and characteristics of the enzyme.
AB - A gene for a methionine aminopeptidase (MAP; EC 3.4.11.18), which catalyzes the
removal of amino-terminal methionine from the growing peptide chain on the
ribosome, has been cloned from the hyperthermophilic Archaeon, Pyrococcus
furiosus, by a novel method effectively using its cosmid protein library,
sequenced and expressed in Escherichia coli. The DNA sequence encodes a protein
containing 295 amino acid residues with methionine at the N-terminus. From
protein analyses of the recombinant protein expressed in E. coli, by using both
amino acid sequence analysis from the N-terminus by automated Edman degradation
and analyses of molecular masses of the peptides generated by two enzymatic
cleavages performed independently, digestions with lysylendopeptidase and
Endoproteinase Asp-N, with ionspray mass spectrometry, the primary structure of
the protein has been elucidated to be completely identical with that deduced from
its DNA sequence. Comparison of the amino acid sequence of P. furiosus MAP (P.f.
MAP) with those of other MAPs from Eukarya and Bacteria showed that the protein
has a high degree of sequence homology in the stretches surrounding the five
cobalt-binding residues fully preserved in all of MAPs determined so far, but
P.f. MAP belongs to Type II because it has an extra long insertion of about 60
amino acid residues between the fourth and fifth cobalt-binding ligands, similar
to MAPs from human and rat, and to Met-AP2 from Saccharomyces cerevisiae, in
comparison to Type I MAPs from Bacteria. Therefore, P.f. MAP seems to be rather
close to those from Eukarya, although it is distinct in lacking the N-terminal
extension of about 90-150 residues universally found in MAPs from Eukarya. These
findings suggest that P.f. MAP is evolutionally located at the Eukarya-Bacteria
boundary. The enzyme expressed in E. coli exhibits a considerable
thermostability, with a half-life of approximately 4.5 h at 90 degrees C and an
optimum temperature of around 90 degrees C.
PMID- 9399591
TI - Modification of proteoglycan synthesis by corneal stromal cells on co-culture
with either epithelial or endothelial cells.
AB - Corneal stromal cells, prepared from 2-day-old chicks and embedded in collagen
gel on an insert dish, were co-cultured with corneal epithelial cells or
endothelial cells on a fibronectin-coated companion plate. Cell growth and
proteoglycan synthesis, as determined as the incorporation of [35S] sulfate and
[3H] glucosamine, were examined for each cell type in both combinations. In
comparison with single cultures, growth was affected little, while proteoglycan
synthesis was appreciably altered in both combinations. Stromal and epithelial
cells stimulated proteoglycan synthesis by each other, while endothelial cells
stimulated the synthesis by stromal cells, but stromal cells reduced that by
endothelial cells to some extent. Endothelial cells alone synthesized
proteoglycans much more actively than did epithelial or stromal cells. Analysis
of the radiolabeled proteoglycans revealed that endothelial and epithelial cells
had different effects on proteoglycan synthesis by stromal cells: the former
tended to increase keratan sulfate synthesis by stromal cells, while the latter
tended to increase chondroitin sulfate/dermatan sulfate synthesis. Proteoglycan
synthesis in the corneal stroma in vivo might thus be controlled by the balance
between the antipodal actions of the epithelial and endothelial cell layers.
PMID- 9399592
TI - Lipid peroxide overcomes the inability of platelet secretory phospholipase A2 to
hydrolyze membrane phospholipids in rabbit platelets.
AB - The present study investigated the effect of lipid peroxide on the ability of
group IIA secretory phospholipase A2 (IIAsPLA2) to hydrolyze platelet membrane
phospholipids. The treatment of rabbit platelets with tert-butyl hydroperoxide
(BHP) and FeSO4 generated malondialdehyde, an index of lipid peroxidation, and
slightly induced arachidonic acid liberation and lysophosphatidylcholine
formation. Further addition of IIAsPLA2 purified from rabbit platelets
synergistically enhanced the liberation and the formation induced by the
oxidizing reagents, although the enzyme alone did not. When the IIAsPLA2 was
pretreated with heparin, the enhancement was not observed. The combination of
IIAsPLA2 with linoleic acid hydroperoxide and FeSO4 also caused synergistic
arachidonic acid liberation. Furthermore, IIAsPLA2 enhanced thromboxane B2
generation and platelet aggregation induced by BHP and FeSO4. The synergistic
aggregation was sensitive to indomethacin. With a membrane fraction as a
substrate, IIAsPLA2 caused arachidonic acid liberation, which was enhanced in the
presence of BHP and FeSO4. These results suggest that modification of membrane
phospholipids by oxidizing reagents increases the accessibility of the membrane
to platelet IIAsPLA2, and sequential enhancement of arachidonic acid liberation
may contribute to the propagation of oxidative stress-induced cellular injury.
PMID- 9399593
TI - Identification of endogenous substrates for Drosophila calpain from a salt
extracted fraction of Drosophila ovaries.
AB - Drosophila calpain (Dm-calpain) produced in Escherichia coli has a distinct Ca2+
dependent activity. By using a recombinant Dm-calpain, we searched for its
substrates occurring in Drosophila ovaries, where Dm-calpain is expressed. Among
a number of major proteins, several proteins in a salt-extracted fraction were
selectively degraded by Dm-calpain in a Ca2+-dependent manner. The major
substrates were identified by microsequencing the lysylendopeptidase-digested
proteins. Three ribosomal proteins, the L5, L7, and L8 subunits of the 60S
ribosome, were found to be potential Dm-calpain substrates. In addition, the
alpha subunit of elongation factor-1 (EF-1alpha), a multi-functional protein
involved in both protein synthesis and cytoskeletal regulation, was shown to be
cleaved by Dm-calpain into several distinct fragments when expressed as a GST
fusion protein. Endogenous EF-1alpha in ovary extracts was also shown by western
blot analysis to be similarly degraded. These observations suggest that Dm
calpain may regulate protein synthesis and cytoskeletal structure through its
degradative or processing activity.
PMID- 9399594
TI - Isolation of a novel human gene from the Down syndrome critical region of
chromosome 21q22.2.
AB - Down syndrome is the most common birth defect, and is caused by trisomy 21. We
identified a novel gene in the so-called Down syndrome critical region by means
of computer-aided exon prediction and subsequent cDNA cloning. The gene,
designated as DCRA (Down syndrome Critical Region gene A), consists of eight
exons of 3,252 bp in total and encodes a large open reading frame of 297 amino
acid residues. The open reading frame shows significant homology to Hbeta58, a
mouse gene essential for embryogenesis, PEP8, a yeast homologue of Hbeta58, and
an expressed sequence tag of Arabidopsis thariana, suggesting that DCRA has some
important function that has been conserved during the course of evolution. DCRA
is expressed in most tissues examined, including fetal and adult brain, heart,
lung, liver, and kidney. The cDNA of the DCRA mouse homologue, Dcra, was also
cloned. It is 2,157 bp long and has an open reading frame of 297 amino acid
residues, which shows 92% identity to human DCRA. Dcra is expressed in all the
embryo and adult tissues examined.
PMID- 9399595
TI - Identification of the nucleotides in the A-rich bulge of the Tetrahymena ribozyme
responsible for an efficient self-splicing reaction.
AB - P5abc is a large extension of the P5 element characteristic of subclasses IC1 and
IC2 of group I introns. It has a conserved region termed the A-rich bulge, that
is responsible for activation of the Tetrahymena self-splicing intron. By
employing a modified color-colony assay system, we identified four adenosines in
the bulge that are responsible for an efficient splicing reaction. On comparison
with the X-ray crystal structure of the P4-5-6 domains of the Tetrahymena intron,
three adenosines at positions 183, 184, and 186 were found to be identical to
those significantly contributing to the formation of its tertiary structure.
However, our results show that an adenosine at 187 is involved in the formation
of a Watson-Crick base pair with U135, although it forms a Hoogsteen base pair in
the crystal structure.
PMID- 9399596
TI - Analysis of the substrate binding site and carboxyl terminal region of vacuolar
H+-pyrophosphatase of mung bean with peptide antibodies.
AB - Vacuolar H+-translocating inorganic pyrophosphatase is a single-protein enzyme
and uses a simple substance as an energy donor. Functional domains of the enzyme
were investigated by using antibodies specific to peptides corresponding to the
putative substrate-binding site (DVGADLVGKVE) in the hydrophilic loop and the
carboxyl terminal part. The antibody to the former peptide clearly reacted with
the pyrophosphatases of different plant species, and strongly inhibited the
hydrolytic activity of the purified enzymes and the proton pumping activity of
membrane vesicles. These results indicate that the sequence functions as an
actual substrate-binding site and is a common motif. The antibody to the carboxyl
terminal part reacted only to the mung bean enzyme, suppressing its hydrolytic
and proton pumping activities. The results suggest that the carboxyl terminus is
exposed to the cytosol and is close to the catalytic site. H+-Pyrophosphatase
hydrolyzed triphosphate and tetraphosphate at low rates. Phytic acid, myo
inositol hexaphosphate, inhibited the enzyme even in the presence of Mg2+. The
concentration for 50% inhibition was 0.15 mM. The inhibition of H+-PPase by
dicyclohexyldiimide was partly reversed by Mg2+. The catalytic site and the
membrane topology of the enzyme are discussed.
PMID- 9399597
TI - Is the cannabinoid CB1 receptor a 2-arachidonoylglycerol receptor? Structural
requirements for triggering a Ca2+ transient in NG108-15 cells.
AB - The effects of delta9-tetrahydrocannabinol and 2-arachidonoylglycerol on the
intracellular free Ca2+ concentration ([Ca2+]i) in NG108-15 cells were examined
in detail. We found that delta9-tetrahydrocannabinol induces a rapid, modest
increase in [Ca2+]i. The response was detectable with 3 nM delta9
tetrahydrocannabinol. We also found that very low concentrations of 2
arachidonoylglycerol elicit a rapid, more prominent increase in [Ca2+]i. Such a
response was observed not only in NG108-15 cells but also in N18TG2 cells. The
response induced by 2-arachidonoylglycerol in either NG108-15 cells or N18TG2
cells was abolished by pretreatment of the cells with a cannabinoid CB1 receptor
specific antagonist, SR141716A, suggesting that 2-arachidonoylglycerol interacts
with the CB1 receptor to induce the response. The results of an experiment
involving a phospholipase C inhibitor suggested that phospholipase C is involved
in the rapid increase in [Ca2+]i induced by 2-arachidonoylglycerol. We also found
that 1(3)-arachidonoylglycerol exhibits similar activity to that of 2
arachidonoylglycerol, although its activity at low concentrations was somewhat
weak compared with that of 2-arachidonoylglycerol. We further confirmed that
several structural analogues of 2-arachidonoylglycerol were less active compared
with 2-arachidonoylglycerol. These results suggest that the structure of 2
arachidonoylglycerol is strictly recognized by the CB1 receptor, which raises the
possibility that the CB1 receptor is originally a 2-arachidonoylglycerol
receptor.
PMID- 9399598
TI - Sparfloxacin: potential clinical and economic impact in the treatment of
respiratory infections.
AB - Sparfloxacin is a new oral fluoroquinolone antimicrobial that is highly active
against common respiratory pathogens, including multiresistant strains. It is
well absorbed and has excellent penetration into upper and lower respiratory
tissues. Sparfloxacin is administered once a day and does not interfere with the
metabolism of other drugs. The agent is highly effective and safe in the
treatment of acute sinusitis, exacerbations of chronic bronchitis, and community
acquired pneumonia. Due to its activity against multidrug-resistant respiratory
pathogens, it has the potential to prevent hospitalization as well as decrease
parenteral antibiotic therapy. Consequently, it may generate significant
pharmacoeconomic benefits to patients and payers of medical care.
PMID- 9399599
TI - Sirolimus, a new, potent immunosuppressive agent.
AB - Sirolimus (SRL), a potent immunosuppressant, is currently being investigated in
phase III trials for prophylaxis of renal transplant rejection. The mechanism of
action of SRL is a blockade of the response of T and B cells to cytokines,
thereby preventing cell cycle progression in G1 and consequently cell
proliferation. There seems to be a good correlation between SRL concentrations,
estimated as exposure by the area under the concentration versus time curve, and
trough whole blood concentration, so that therapeutic monitoring may be done by
trough levels only. Because of the low frequency of allograft rejection, there
has been no documented correlation between trough concentrations and efficacy.
Trough SRL concentrations of 15 ng/ml or higher seem to be associated with an
increased frequency of adverse effects. Drug-associated toxicities include
thrombocytopenia, leukopenia, and increases in cholesterol and triglyceride
levels. The drug has synergy with cyclosporine (CsA) in vitro as well as in
animal and clinical studies. In phase II trials the combination of SRL-CsA
therapy reduced the frequency of acute rejection episodes, permit withdrawal of
concomitant corticosteroid therapy, and allowed reduction of CsA dosages in
nonblack patients.
PMID- 9399600
TI - Atorvastatin calcium: an addition to HMG-CoA reductase inhibitors.
AB - Atorvastatin calcium is an HMG-coenzyme A (CoA) reductase inhibitor that was
approved by the Food and Drug Administration on December 17, 1996. Like other
such agents, it inhibits the action of HMG-CoA reductase and thereby decreases
endogenous cholesterol synthesis, leading to a decrease in circulating low
density lipoprotein cholesterol. In addition to its effect on lipoprotein
profile, atorvastatin reduces triglycerides to a greater extent than other HMG
CoA reductase inhibitors. These actions occur in a dose-dependent fashion. The
adverse effect profile is similar to that of other agents in this class.
Indications for atorvastatin include primary hypercholesterolemia as well as
other lipid disorders.
PMID- 9399601
TI - Mycophenolate mofetil.
AB - Mycophenolate mofetil is the morpholinoethylester prodrug of mycophenolic acid,
an agent that inhibits the proliferation of B and T lymphocytes through
noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, a
key enzyme in the de novo synthetic pathway of guanine nucleotides. Currently,
mycophenolate mofetil is approved for the prevention of acute renal allograft
rejection when given in combination with cyclosporine and steroids. Several
studies also demonstrated that the agent is effective in the treatment of
refractory rejection in renal, heart, and liver transplant recipients, and may
have efficacy in the treatment of chronic rejection as well.
PMID- 9399602
TI - New drug interactions with zidovudine.
AB - Polypharmacy is commonly encountered in human immunodeficiency virus (HIV)
positive patients, and the risk and frequency of drug-drug interactions are
significant in this patient population. Most HIV-positive patients receive the
antiretroviral drug zidovudine (3'-azido-3'-deoxythymidine, ZDV), the first drug
to be approved for the treatment of HIV. Many drug interactions with ZDV have
already been reported. As HIV pharmacotherapy becomes more complex, the potential
for drug-drug interactions is likely to increase significantly.
PMID- 9399603
TI - A systematic review and meta-analysis of the incidence of cancer in randomized,
controlled trials of verapamil.
AB - We conducted a systematic review of all published randomized, controlled trials
to assess the risk of cancer or death in patients receiving verapamil for
hypertension, angina pectoris, or cardiac arrhythmias. Meta-analysis comparing
the risk of new cancers, cancer deaths, and all deaths was performed. Thirty-nine
trials comprising 11,201 patients were eligible. Study durations ranged from 8
days-6 years (mean 29.5 wks). Nine trials (6507 patients) were 24 weeks in
duration or longer. For cancer and cancer death, OR was 1.20 (95% CI = 0.60-2.42)
for verapamil versus active controls and 0.73 (95% CI = 0.39-1.39) for verapamil
versus placebo. For all deaths, OR was 1.13 (95% CI = 0.70-1.82) for verapamil
versus active controls and 0.85 (95% CI = 0.71-1.00) for verapamil versus
placebo. Sensitivity analysis for the 9 trials 24 weeks' duration or longer gave
similar results. There is no statistically significant increased risk of cancer
or deaths with verapamil compared with active controls or placebo.
PMID- 9399604
TI - Drug-induced neuromuscular blockade and myasthenia gravis.
AB - Myasthenia gravis is an uncommon disorder of the neuromuscular junction resulting
in weakness of all striated voluntary muscles. Therapeutic advances have
increased patients' age and survival. Older patients with myasthenia gravis may
have additional medication needs. Numerous drugs have experimental and clinical
evidence of neuromuscular blockade. A MEDLINE search of the English literature
from 1966 to the present pertinent to drug-induced myasthenia gravis was
performed. Additional literature was obtained from reference citations of
relevant articles. Drugs with several reports of neuromuscular blockade were
assessed for causality by a recognized probability scale. Prednisone was most
commonly implicated as aggravating myasthenia gravis, and D-penicillamine was
most commonly associated with myasthenic syndrome. The greatest frequency of drug
induced neuromuscular blockade was seen with aminoglycoside-induced postoperative
respiratory depression. However, drugs most likely to impact myasthenic patients
negatively are those used in the treatment of the disease. These include overuse
of anticholinesterase drugs, high-dose prednisone, and anesthesia and
neuromuscular blockers for thymectomy.
PMID- 9399605
TI - Is oral sotalol effective in converting atrial fibrillation to sinus rhythm?
AB - d,l-Sotalol is a noncardioselective beta-blocker that has class III
antiarrhythmic activity. It is often used to convert atrial fibrillation (AF) to
normal sinus rhythm. Since class III agents increase action potential duration
and refractoriness in atrial tissue without affecting conduction, they are
theoretically considered ideal agents for the treatment of reentrant arrhythmias
such as AF. We reviewed the literature evaluating the efficacy of sotalol for
restoring sinus rhythm in patients with acute or chronic AF. Articles indexed on
MEDLINE (1966-1996) and referenced articles not identified by MEDLINE that
compared sotalol with placebo or another antiarrhythmic agent were included.
Sotalol was significantly inferior to quinidine in converting AF of recent onset
(< 48 hrs) to sinus rhythm. In patients with duration of AF of more than 48
hours, sotalol was significantly less effective than quinidine and comparable
with placebo. Conversion rates for sotalol in all studies combined ranged from 8
49%. Published studies do not support the drug for conversion of AF to sinus
rhythm. Larger well-designed studies are required to evaluate its efficacy and
optimum dosage for this indication. Until further data are available,
pharmacologic cardioversion with traditional class I antiarrhythmic agents may be
preferable as they are effective particularly for recent-onset AF.
PMID- 9399606
TI - Comparison of intravenous diltiazem and verapamil for the acute treatment of
atrial fibrillation and atrial flutter.
AB - STUDY OBJECTIVES: To compare the efficacy and safety of intravenous diltiazem and
verapamil in controlling ventricular rate in patients with atrial fibrillation or
flutter, and to evaluate the effects of these agents on left ventricular systolic
function. DESIGN: Prospective, randomized, double-blind, crossover study.
SETTING: University-affiliated hospital and Veterans Administration hospital.
PATIENTS: Seventeen men with atrial fibrillation or flutter with a ventricular
rate of 120 beats/minute or higher and a systolic blood pressure of 100 mm Hg or
greater. INTERVENTIONS: Patients received up to two intravenous boluses of either
diltiazem or verapamil, followed by an 8-hour continuous infusion if a
therapeutic response was achieved (phase I). After a washout period, patients who
responded were crossed over to receive the other drug in a similar fashion (phase
II). MEASUREMENTS AND MAIN RESULTS: At the end of each infusion, the patient's
ejection fraction was assessed by gated angiography. Of the 17 men initially
randomized, 8 successfully completed both phases I and II. In these patients,
baseline mean (+/- SD) ventricular rates before treatment with intravenous
diltiazem and verapamil were 138 +/- 15 and 132 +/- 9 beats/minute, respectively
(NS). At 2 minutes after the initial bolus dose, the mean ventricular rate
decreased to 100 +/- 13 beats/minute in the diltiazem group compared with 114 +/-
17 beats/minute in those receiving verapamil (p < 0.05). Mean ventricular rates
of 96 +/- 11 and 97 +/- 9 beats/minute were maintained during the 8-hour
continuous infusion of diltiazem and verapamil, respectively (NS). On completion
of the bolus dose(s) and during continuous infusions, there were no significant
differences in blood pressures between the groups. Mean ejection fractions were
35.6 +/- 13.6% and 35.5 +/- 15.4% in the diltiazem and verapamil groups,
respectively (NS). For the 17 patients, the mean maximum percentage decreases in
blood pressure were not significantly different between groups. However, three
patients developed symptomatic hypotension, all of whom were randomized to
receive verapamil initially. CONCLUSION: Intravenous diltiazem and verapamil are
comparable in terms of efficacy and effect on systolic function in patients with
rapid atrial fibrillation and flutter. However, hypotension may limit therapy
with verapamil in some patients.
PMID- 9399607
TI - Cisplatin nephrotoxicity: a multivariate analysis of potential predisposing
factors.
AB - STUDY OBJECTIVE: To evaluate the usefulness of biologic and pharmacologic
parameters for early identification of cisplatin-induced renal dysfunction.
DESIGN: Prospective evaluation of 62 consecutively admitted patients with cancer.
SETTING: Cancer center. PATIENTS: Sixty-two consecutive patients with cancer (52
men, 10 women; mean age 61.9 yrs). INTERVENTIONS: Patients received cisplatin as
a single short intravenous infusion every 3 weeks. One hundred twenty-one cycles
were analyzed. The dosage in the first cycle ranged between 61 and 105 mg/m2
(mean 84 mg/m2). All patients received a standard hydration protocol.
MEASUREMENTS AND MAIN RESULTS: Renal function was evaluated for each cycle before
treatment (day 0) and before next cycle (day 21) based on the estimated
creatinine clearance (Clcr). For each cycle, the weighted relative decrease (WD)
of Clcr was calculated (WDClcr = 100 x [Clcr (day 0) - Clcr (day 21)]/[Clcr (day
0)](2). Total and ultrafilterable (UF) platinum were measured as a single-sample
assay taken 16 hours after the end of cisplatin administration. The mean WDClcr
was 0.07 min/100 ml (range -1.0 to +1.7 min/100 ml). The intensity of renal
dysfunction evaluated by WDClcr was independent of cisplatin dosage, age, sex,
body surface area, initial Clcr, and cycle number. Of interest, total and UF
platinum concentrations were significantly correlated to WDClcr: the higher the
platinum concentration, the greater the intensity of renal dysfunction. In
stepwise regression analysis, UF platinum concentration was the only selected
factor. The best prediction of UF platinum was obtained by stepwise regression
including cisplatin dosage, initial Clcr, and cycle number (r=0.58, p<0.0001).
CONCLUSION: We consider our results to be a first step toward a clinical strategy
to identify patients at risk for renal dysfunction after cisplatin treatment.
PMID- 9399609
TI - Evidence for negative feedback of extracellular methotrexate on blasts of acute
lymphoblastic leukemia in vitro.
AB - STUDY OBJECTIVE: To explore the value of high-dose methotrexate (MTX). SUBJECTS:
Blast cells from 15 patients with acute lymphoblastic leukemia. INTERVENTIONS: We
compared uptake and polyglutamation of [3H]-MTX by freshly isolated leukemic
blasts in vitro after 24-hour exposure to 1, 10, and 50 microM [3H]-MTX.
MEASUREMENTS AND MAIN RESULTS: Mean MTX uptake (pmol/10(6) cells) was 0.78 +/-
0.19, 2.3 +/- 0.54, and 5.9 +/- 1.9, respectively, and mean polyglutamation was
82%, 66%, and 46%. Consequently, mean MTX polyglutamates were 0.68 +/- 0.18, 1.5
+/- 0.47, and 2.2 +/- 0.67 pmol/10(6) cells. Three of 15 patient samples had no
detectable polyglutamation of MTX at 50 microM but MTX polyglutamates were
detectable at 1 microM. Two of these three had a decrease in MTX polyglutamates
at 10 versus 1 microM. In eight precursor B cell samples there was a significant
difference in median MTX polyglutamates at 1 versus 10 microM but not 10 versus
50 microM. CONCLUSION: Increasing extracellular MTX concentrations may be
counterproductive for some patients with acute lymphoblastic leukemia. If MTX
polyglutamates are important for efficacy, optimal delivery of MTX may have to be
determined by individual metabolism rather than by targeting a specific drug
concentration.
PMID- 9399608
TI - Long-acting diltiazem CD is safe and effective in a hypertensive Mexican-American
population.
AB - STUDY OBJECTIVE: To evaluate the safety and effectiveness of diltiazem CD for
reducing blood pressure in Mexican-American patients with mild to moderate
hypertension. DESIGN: Randomized, double-blind, placebo-controlled trial.
SETTING: Twelve clinical sites in the United States. PATIENTS: Patients with
baseline diastolic blood pressures between 95 and 115 mm Hg. INTERVENTIONS:
Patients were treated with an average daily dose of diltiazem CD 246 mg (60
patients) or placebo (58 patients) to achieve a trough diastolic blood pressure
below 90 mm Hg. MEASUREMENTS AND MAIN RESULTS: Diltiazem CD significantly reduced
mean diastolic blood pressure compared with placebo, -8.2 versus -4.1 mm Hg,
respectively (p=0.0025). Diastolic blood pressure below 90 mm Hg or a reduction
of 10 mm Hg or more was achieved by 57% of diltiazem CD versus 28% of placebo
recipients. Systolic blood pressure and heart rate were also reduced with
diltiazem CD. Adverse events were mild, with similar frequency for diltiazem CD
(15%) and placebo (19%). CONCLUSION: Diltiazem CD is safe and effective in
hypertensive Mexican-Americans, and diastolic blood pressure reductions compare
with those in non-Hispanic white patients.
PMID- 9399610
TI - Lidocaine does not affect myocardial electrical heterogeneity: implications for
low proarrhythmic actions.
AB - An area of unidirectional conduction block is one requirement for reentrant
arrhythmias to occur. Functional block caused by dispersion of repolarization and
refractoriness is the most probable mechanism of drug-induced unidirectional
conduction block. We assessed the effects of lidocaine on spatial dispersion of
myocardial repolarization and refractoriness in the intact porcine heart.
Monophasic action potential duration at 90% repolarization, effective refractory
period (ERP), and ventricular fibrillation cycle length (VFCL) were measured at
two endocardial and one epicardial sites at baseline and during a treatment phase
with D5W (n=11) or lidocaine 10 mg/kg/hour (n=12). Dispersion was calculated as
the difference between the maximum and minimum values of the three recording
sites. Lidocaine produced significant changes in ERP, VFCL, paced QRS duration,
and intraventricular conduction time. It did not change basal levels of
dispersion in repolarization and refractoriness. Lidocaine produced changes in
myocardial electrophysiology that are uniform across the myocardium and thus did
not change myocardial electrical heterogeneity. This may be a mechanism of the
agent's lower proarrhythmic effects compared with other sodium channel blockers
that increase myocardial electrical heterogeneity.
PMID- 9399611
TI - Evaluation of hypertensive patients after care provided by community pharmacists
in a rural setting.
AB - We evaluated blood pressure control, quality of life, quality of care, and
satisfaction of patients who were monitored by specially trained community
pharmacists in a group medical practice. After participating in an intensive
skill development program, pharmacists performed in an interdisciplinary team in
a rural clinic. The primary objective was assessed by evaluating outcome
variables at 6 months compared with baseline in 25 patients randomly assigned to
a study group. A control group of 26 patients was also evaluated to determine if
outcome variables remained constant from baseline to 6 months. Systolic blood
pressure was reduced in the study group (151 mm Hg baseline, 140 mm Hg at 6 mo,
p<0.001) and diastolic blood pressure was significantly lower at 2, 4, and 5
months compared with baseline. Ratings from a blinded peer review panel indicated
significant improvement in the appropriateness of the blood pressure regimen,
going from 8.7 +/- 4.7 to 10.9 +/- 4.5 in the study group (p<0.01), but they did
not change in the control group. Several quality of life scores improved
significantly in the study group after 6 months (p<0.05). These included physical
functioning (61.6 vs 70.7), physical role limitations (56.8 vs 72.8), and bodily
pain (60.0 vs 71.7) at baseline and 6 months, respectively. There were no
significant changes in the control group. Patient satisfaction scores were
consistently higher in the study group at the end of the study. Our results
indicate that when community pharmacists in a clinic setting are trained and
included as members of the primary care team, significant improvements in blood
pressure control, quality of life, and patient satisfaction can be achieved.
PMID- 9399612
TI - Cost analysis of the American College of Chest Physicians guidelines for deep
vein thrombosis prophylaxis in patients undergoing orthopedic arthroplastic
surgery.
AB - Guidelines for prophylaxis of deep vein thrombosis secondary to orthopedic
surgery have been developed. In selecting a specific drug for formulary
inclusion, it is ideal for an individual institution to determine the cost of
therapy, as well as the frequency of adverse events and the cost of treating them
for each agent undergoing consideration. Cost-effectiveness analysis using
incremental cost-effectiveness ratios and sensitivity analyses are useful for
determining which drug may be most cost effective.
PMID- 9399613
TI - Effect of infusing fat emulsion into extracorporeal membrane oxygenation
circuits.
AB - Our objectives were to identify problems associated with the administration of
fat emulsion by extracorporeal membrane oxygenation (ECMO) circuits, and gather
information from other institutions on standards of practice and the
complications associated with infusion of fat emulsion by ECMO to infants and
children. In vitro analysis was performed using six circuits. Fat emulsion was
infused into a prereservoir port at 3 ml/hour. Circuits and blood samples
collected distal to the oxygenator were inspected visually for layering
(separation of fat emulsion from blood), agglutination, and phase separation
(formation of an oil layer) at 0.5, 1, 2, 4, 6, 12, and 24 hours. At 24 hours,
samples were reevaluated and circuits dissected. All circuits showed layering and
agglutination. Blood clots were present in five circuits during the simulation.
There was no evidence of phase separation in the samples. Adhesion of emulsion to
the equipment was present in all circuits. Five of the membrane oxygenators
contained clots. One contained long strands of fat; separation of its mesh
revealed an oily residue indicating disruption of the stability of the emulsion.
Survey responses from 54 centers found that 78% used fat emulsion routinely in
neonatal or pediatric patients receiving ECMO. Most used both ECMO and separate
venous access for the infusion, depending on availability. Twenty-two (52%) of
the 42 centers using fat emulsion had a policy in place regarding site selection.
Of those, 73% preferred central venous access, another 18% used a prereservoir
port of the ECMO circuit. The most frequently reported problems with
administration through the circuit were cracking of stopcocks, clogging and
malfunction of the membrane oxygenator, agglutination of the emulsion, and
increase in blood clot formation. Our results suggest that fat emulsion should be
infused through a separate intravenous site whenever possible. Based on these
results and current practices of most ECMO centers, a clinical trial is currently
being conducted to provide additional information.
PMID- 9399614
TI - Experience with crystalline niacin as the preferred drug for dyslipidemia in a
specialty clinic.
AB - To determine the tolerability and efficacy of crystalline niacin in reaching
target lipid goals, we conducted a retrospective review of medical records of 62
patients treated with the agent over 2 years in a lipid clinic at a nonacademic
veterans hospital. Most patients received niacin for hypercholesterolemia. Thirty
one patients (50%) stopped therapy due to adverse events, principally,
intolerable cutaneous reactions. Twenty-nine withdrew from therapy during the
first 6 weeks of treatment. Of those who tolerated niacin, 23 did not achieve
target lipid serum concentrations at the maximum tolerated dosage; 8 did achieve
target concentrations. Thus crystalline niacin was largely ineffective in
treating patients with dyslipidemia.
PMID- 9399615
TI - N-desmethylclozapine, an insensitive marker of clozapine-induced agranulocytosis
and granulocytopenia.
AB - We reviewed the charts of 58 patients with treatment-refractory schizophrenia who
were receiving clozapine, to determine if the drug's active metabolite, N
desmethylclozapine, is a biologic marker for impending clozapine-induced
granulocytopenia and agranulocytosis. No significant correlation between
granulocyte counts and patient demographic variables of clozapine and N
desmethylclozapine steady-state plasma concentrations, clozapine:N
desmethylclozapine ratio, age, gender, clozapine dosage, smoking status, and race
were found. We believe N-desmethylclozapine is not a clinically useful marker for
monitoring the effect of clozapine on granulocyte integrity. On the contrary, its
plasma concentrations correlated positively with granulocyte counts.
PMID- 9399616
TI - Impact of CYP2D6 poor metabolizer phenotype on propranolol pharmacokinetics and
response.
AB - We conducted an open-label study to determine the impact of cytochrome P-4502D6
(CYP2D6) on propranolol pharmacokinetics and response in 12 healthy men with
CYP2D6 extensive metabolizer (EM) phenotype and 3 healthy men with CYP2D6 poor
metabolizer (PM) phenotype. Subjects received R,S-propranolol hydrochloride 80 mg
every 8 hours for 16 doses. After the sixteenth dose, blood and urine samples
were collected for 24 hours, and serum propranolol and urine metabolite
concentrations were determined by chiral high-performance liquid chromatography.
Heart rate response to treadmill exercise was measured serially over 24 hours.
Apparent oral clearance of propranolol and partial metabolic clearance values of
propranolol to 4-hydroxypropranolol (HOP), propranolol glucuronide, and
naphloxylactic acid (NLA) were estimated. Apparent oral clearance and elimination
half-life of propranolol were not different between EMs and PMs. Partial
metabolic clearance of propranolol to HOP was significantly higher and to NLA was
significantly lower in EMs than in PMs. No differences in percentage reductions
in exercise heart rate were observed between EMs and PMs. The CYP2D6 PM phenotype
has no effect on propranolol blood concentrations and does not alter response to
propranolol. Our data also suggest that CYP2D6 mediates approximately 65% and 70%
of S- and R-propranolol's 4-hydroxylation, respectively.
PMID- 9399617
TI - Paradoxic excitation with diphenhydramine in an adult.
AB - Although paradoxic excitation may rarely occur in children and adults with
conventional dosages of antihistamines, few case reports have appeared in the
literature. We cared for a 46-year-old patient who became extremely agitated
after receiving a dose of intravenous diphenhydramine.
PMID- 9399618
TI - Elevation of the erythrocyte sedimentation rate precedes exacerbation of
bleomycin-induced pulmonary toxicity: report of two cases and review of
literature.
AB - Bleomycin is included in a number of potentially curative chemotherapy regimens.
It is associated with distinct forms of pulmonary toxicity, with interstitial
pneumonitis the most common. Early detection of pulmonary toxicity is not always
predictable by monitoring serial chest radiographs and pulmonary function tests.
Even newer serum markers are not useful indicators of bleomycin-induced pulmonary
damage. Two patients developed bleomycin pulmonary toxicity, in both of whom
increases in erythrocyte sedimentation rate (ESR) preceded clinical deterioration
and radiographic changes. The ESR may have potential significance as a monitoring
test in patients receiving bleomycin.
PMID- 9399619
TI - Cross-resistance to both atracurium- and vecuronium-induced neuromuscular
blockade in a critically ill patient.
AB - A previously healthy 33-year-old woman received neuromuscular blocking agents
during treatment of severe adult respiratory distress syndrome secondary to
pneumococcal pneumonia and septic shock. Atracurium infusion rates were
progressively increased, preceded by repeated loading doses up to a maximum of
3.57 mg/kg/hour, but produced inadequate neuromuscular blockade as assessed by
clinical and ventilatory parameters as well as train-of-four (TOF) monitoring.
Atracurium was discontinued and vecuronium infusions of 2.3 mg/kg/hour finally
produced adequate paralysis for 7 days. Increasing vecuronium requirements then
prompted discontinuation of neuromuscular blockade. Atracurium was reinstituted 2
days later because of worsening pulmonary function. Infusion rates of 3.04
mg/kg/hour were again required, together with high-dose midazolam and fentanyl,
to achieve adequate oxygenation with acceptable airway pressures; however, TOF
monitoring showed an unacceptable level of paralysis. Cross-resistance among
chemically dissimilar neuromuscular blocking agents poses a difficult patient
management problem and supports a pharmacodynamic basis of resistance to these
agents.
PMID- 9399620
TI - Bradycardia associated with intravenous administration of tacrolimus in a liver
transplant recipient.
AB - Cardiotoxicity due to tacrolimus is documented infrequently in the medical
literature. Sinus bradycardia associated with intravenous tacrolimus occurred in
a 15-year-old orthotopic liver transplant recipient. The mechanism of this
adverse effect is unknown; however, it does not appear to be concentration
dependent, and in this patient it resolved on changing to oral therapy.
Practitioners should be aware that intravenous administration of tacrolimus may
be associated with adverse cardiac events including sinus bradycardia.
PMID- 9399621
TI - Warfarin resistance associated with intravenous lipid administration: discussion
of propofol and review of the literature.
AB - Intravenous lipids are often required for parenteral nutritional (PN) support in
critically ill patients and are administered with continuous sedation if patients
are receiving propofol, which contains soybean oil 10% as an emulsified
preparation. High-dose propofol infusion was associated with reversal of enteral
and intravenous warfarin anticoagulation in a 39-year-old woman with severe
Crohn's disease. Despite increasing the daily dose of warfarin to 30 mg,
anticoagulation was not achieved until propofol was discontinued. Reversal of
anticoagulation recurred when PN support was supplemented with Liposyn II 20%.
Lipid emulsions may interfere pharmacodynamically with warfarin activity by
enhancing the production of clotting factors, facilitating platelet aggregation,
or supplying vitamin K. They also may facilitate warfarin binding to albumin.
Until further information regarding the mechanism of interference is elucidated,
heparin therapy should be considered for initial anticoagulation in patients with
intestinal absorptive deficiencies who receive high-dose lipid emulsions and
require reliable anticoagulation. If warfarin is given, the international
normalized ratio should be monitored daily to ensure adequate anticoagulation.
PMID- 9399622
TI - Prolonged hypoglycemic crisis associated with glyburide.
AB - An elderly patient taking glyburide 5 mg/day for noninsulin-dependent diabetes
mellitus was hospitalized because of severe hypoglycemia. Laboratory results
indicated both renal and hepatic abnormalities were present at the time of
admission. Despite infusion of 10% dextrose and supplemental boluses of 50%
dextrose, the hypoglycemic crisis persisted for 3 days. After it resolved, the
patient's diabetes was controlled by diet alone. The patient's age and the
presence of hepatic and/or renal impairment must be taken in account in
prescribing glyburide. Recognizing patients who may require dosage changes, and
educating them on the signs and symptoms of hypoglycemia, may help prevent
hospitalizations resulting from this complication associated with glyburide.
PMID- 9399623
TI - Delayed hypersensitivity reaction to vancomycin.
AB - The use of vancomycin has increased dramatically in recent years with the
emergence of methicillin-resistant Staphylococcus aureus and coagulase-negative
staphylococci as important hospital pathogens. A patient receiving vancomycin
1.75 g intravenously as a single daily dose developed a syndrome characterized by
high fever, erythema multiforme, eosinophilia, and presumed interstitial
nephritis. This delayed hypersensitivity reaction resolved with discontinuation
of the drug and treatment with methylprednisolone.
PMID- 9399625
TI - A simpler approach to pharmacokinetic dosage adjustments.
PMID- 9399624
TI - Diltiazem-associated thrombocytopenia.
AB - Nine days after starting diltiazem therapy for new-onset atrial fibrillation, a
patient's platelet count had diminished to 61 x 10(3)/mm3, and 2 weeks later the
nadir was reached at 23 x 10(3)/mm3. No hypersensitivity reaction otherwise was
noted, and other hematologic values were unaffected. The patient's platelet
counts were not affected by platelet transfusions. Bone marrow examination showed
normal to increased numbers of megakaryocytes, suggesting peripheral destruction.
After discontinuing diltiazem and administering high-dose immunoglobulin
infusions, the platelet count returned to normal. This case suggests an immune
mediated cause for thrombocytopenia after exposure to diltiazem.
PMID- 9399626
TI - The role of academia in community-based pharmaceutical care.
AB - Developing models of pharmaceutical care (PC) for educating students and
practitioners represents a fundamental role for schools of pharmacy. Virginia
Commonwealth University has sought to facilitate the implementation of PC in the
community by hiring faculty to practice in this setting. The mission of the
faculty is to implement PC in a community pharmacy practice, to develop clerkship
sites for Pharm.D. students, and to evaluate the impact of PC services in the
community. Examples of an independent pharmacy model, a grocery chain model, and
a retail chain model of care may serve a dual purpose for faculty members, that
is, define responsibilities for the academic institution and for the community
practice environment.
PMID- 9399627
TI - CCK biosynthesis and processing: recent progress and future challenges.
AB - The peptide cholecystokinin (CCK), like other peptides which pass through the
regulated secretory pathway, undergoes a number of post-translational
modifications during its biosynthesis including tyrosine sulfation,
endoproteolytic cleavage, and trimming by carboxypeptidases. This minireview
summarizes what is known about this process in endocrine cells and in the
Cpe(fat)/Cpe(fat) mouse and points out what challenges remain for future
research.
PMID- 9399628
TI - Effect of high salt intake on plasma and tissue concentration of endogenous
ouabain-like substance in the rat.
AB - The effect of high salt intake on serum concentration and tissue distribution of
ouabain-like substance (OLS) was examined in rats. Sprague-Dawley rats (n=8) were
placed on a high salt diet by the inclusion of 1.8% sodium chloride in drinking
water for 7 days and a 'control' group (n=8) was maintained on normal drinking
water during the study period. Serum and tissue OLS was measured by
radioimmunoassay after solid phase extraction. High salt intake significantly
increased serum OLS concentration (1.43 +/- 0.06 vs 1.14 +/- 0.05 nmol/L; mean +/
SEM, P=0.002). In both groups, the adrenal showed significantly (p < 0.001)
higher OLS content compared to liver, kidney, heart and brain. HPLC of rat serum
extract resolved a major peak with a retention time identical to that of standard
ouabain, further confirming the nature of OLS. We conclude that high salt intake
increases endogenous production of OLS, which appears to originate from the
adrenal gland in the rat.
PMID- 9399629
TI - NADPH-diaphorase containing cells and fibers in the central nervous system of
squid, Loligo bleekeri keferstein.
AB - Distribution of NADPH-diaphorase in the central nervous system of squid was
determined using histochemical technique. We found NADPH-diaphorase positive cell
bodies and fibers both in the optic and the posterior anterior lobe and fibers in
the peduncle lobe. These results clarify the biochemical similarity between two
structurally similar organs of invertebrate and vertebrate, the peduncle lobe and
the anterior basal lobe, and the cerebellum. NADPH-diaphorase positive fibers
innervated the inner granule layer and the outer plexiform layer of the outer
cortex of the optic lobe. This is in good agreement with avian centrifugal
projection from isthmo-optic nucleus to retina where nitric oxide synthase is
known to be contained. There may be at least two distinct neural systems, the
motor control system and the visual information processing system, which use
nitric oxide as a transmitter or modulator in the squid central nervous system.
PMID- 9399630
TI - Metabolism of haloperidol to pyridinium species in patients receiving high doses
intravenously: is HPTP an intermediate?
AB - The metabolism of haloperidol (HP) to the potentially neurotoxic pyridinium
species, HPP+ and RHPP+, has been demonstrated in humans. In vitro studies in
microsomes harvested from various animal species indicate that the
tetrahydropyridines, HPTP and RHPTP, could be intermediates in this pathway.
However, this has not yet been demonstrated in vivo in humans. In this study,
plasma and urine collected from eight critically ill patients treated with high
doses of intravenous HP were analyzed for HPTP and RHPTP using HPLC with
electrochemical detection. However, neither HPTP nor RHPTP were detected despite
plasma concentrations of HP and RHP higher than any previously reported. HPP+ and
RHPP+ were both present in the urine in high concentrations and accounted for 1.1
+/- 0.5% and 5.3 +/- 3.6%, respectively, of the administered dose of HP. The
apparent elimination half-lives of HPP+ and RHPP+ were 67.3 +/- 11.0 hr and 63.3
+/- 11.6 hr, respectively. The absence of HPTP and RHPTP in plasma and urine
suggests that in humans these tetrahydropyridines either are insignificant
intermediates in the metabolism of HP in vivo or are present only transiently at
their site of formation and are not released into the circulation.
PMID- 9399631
TI - Hormonal regulation of intestinal 11beta-hydroxysteroid dehydrogenase.
AB - We have previously demonstrated the developmental increase of the activity of
11beta-hydroxysteroid dehydrogenase (11betaHSD) in the rat ileum which correlated
with the developmental surge of plasma concentrations of corticosteroids, thyroid
hormones and insulin. To ascertain whether these hormones directly stimulate
11betaHSD activity we used explant cultures of ileum and distal colon. The
intestinal segments of young, 7-day-old rats, were cultured 48 hours in the
presence of aldosterone (10[-7] M), dexamethasone (10[-7] M), triiodothyronine
(10[-7] M) or insulin (10[-7] M) and 11betaHSD activity was evaluated by
measuring the conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone.
The activity of 11betaHSD was significantly increased following 48 h treatment
with dexamethasone and aldosterone, whereas insulin and triiodothyronine were
without any effect. Corticosterone oxidation was inhibited by carbenoxolone and
progesterone. It is being concluded, that both glucocorticoids and
mineralocorticoids but not insulin or triiodothyronine induce intestinal
11betaHSD activity.
PMID- 9399632
TI - TGF-beta2 prevents the impaired chondrocyte proliferation induced by unloading in
growth plates of young rats.
AB - Growth plate width and cartilage organization are altered during skeletal
unloading in growing rats. Immunohistochemical studies have identified TGF-beta
in calcified cartilage, and TGF-beta is known to induce mitogenic effects on
chondrocytes in vitro. On the other hand, IGF-1 was shown to be expressed in the
proximal tibial growth plate and to mediate GH-induced longitudinal bone growth
in rats. We therefore investigated the effect of recombinant human (rh) IGF-1 and
rhTGF-beta2 infusion on the changes induced by unloading in the cellular
organization of the growth plate in growing rats. Hindlimb unloading for 14 days
induced a 13% reduction in growth cartilage height in the proximal tibia. This
effect was mostly related to a 17% and 14% decrease in the proliferative zone
height and chondrocyte number, respectively. In unloaded rats treated with a
systemic infusion of rhTGF-beta2 (2microg/kg/day) the number of chondrocytes in
the proliferative zone was not different from those of normal loaded animals. In
contrast, rhIGF-1 treatment at a 2mg/kg/day dose was not effective in
counteracting the effects of unloading on growth plate height and chondrocyte
number. These results show that systemic administration of rhTGF-beta2 prevents
in large part the reduced growth of chondrocytes in the proliferative zone and
the reduced epiphyseal growth plate growth induced by unloading in rats.
PMID- 9399633
TI - Reduced kidney branched chain aminotransferase expression in puromycin
aminonucleoside-induced nephrotic syndrome.
AB - Injection of puromycin aminonucleoside to rats induces nephrotic syndrome
characterized by hypoalbuminemia, proteinuria and hypercholesterolemia. In these
rats, a low protein diet (6% casein diet) increased serum albumin by 26.3%,
decreased proteinuria by 39% and reduced total cholesterol by 32%. Branched chain
aminotransferase activity in kidney mitochondria of nephrotic rats fed 20 or 6%
casein diet decreased by 30 and 24% with respect to their pair-fed groups and it
was not modified by the protein content of the diet. Mitochondrial branched chain
aminotransferase mRNA expression decreased by 67.3 and 72.5% in nephrotic rats
fed 20 and 6% casein diet in comparison to their pair-fed groups. Total serum
branched chain amino acids concentration (leucine, isoleucine, valine) in
nephrotic rats was 30% higher than their pair-fed groups and it was associated
with a decrease in the branched chain aminotransferase activity and mRNA
expression suggesting that the catabolism of branched chain amino acid is reduced
to conserve body nitrogen.
PMID- 9399634
TI - The transcription of the XRCC1 gene in spleen following ionizing irradiation in
radiosensitive and radioresistant mice.
AB - The XRCC1 gene was described to play a role for the sensitivity of mammalian cell
lines towards ionizing irradiation. Cells with a mutation of this gene present
with decreased single strand break repair, reduced recombination repair, show
increased double strand breaks and sister chromatid exchange is increased up to
tenfold. The goal of our study was to investigate the transcription of this gene
in the spleen following ionizing irradiation in the mouse. Furthermore, we
intended to examine whether radiation sensitive (RS) mice would show a
transcriptional pattern different from radiation resistant (RR) mice. Radiation
sensitive BALB/c/J Him mice and radiation resistant C3H He/Him mice were
untreated or whole body irradiated with X-ray at 4 and 6 Gy and sacrificed 5, 15
and 30 min after irradiation. mRNA was isolated from the spleen and hybridized
with probes for XRCC1 and beta-actin as a house keeping gene control.
Transcription of XRCC1 was not different in unirradiated or 4 Gy-irradiated mouse
RR or RS mouse strains. When irradiated at 6 Gy, RR mice showed an approximately
threefold increase of mRNA XRCC1/mRNA beta actin as early as 15 min after
irradiation. We conclude that radiation resistant mice show a higher
transcription level for the XRCC1 gene in the spleen early after high dose X-ray
whole body irradiation. This finding is the first in vivo study on XRCC1 of this
kind and may in part explain the differences in the radiation sensitivity between
the two strains studied.
PMID- 9399635
TI - Isoflurane anesthesia blunts cerebral responses to noxious and innocuous stimuli:
a fMRI study.
AB - We used functional magnetic resonance imaging to determine how isoflurane
affected cerebral neuronal activation resulting from noxious and innocuous
stimuli. Five male volunteers were subjected to mild electrical shock and tactile
stimuli applied to the hand. During low (0.7%) and moderate (1.3%) isoflurane
anesthesia the stimuli were repeated and a supramaximal electrical shock was also
applied. Tactile stimulation activated bilateral SI and SII, but resulted in no
significant activation at low or moderate anesthesia. Electrical shock activated
contralateral SI and bilateral SII; low anesthesia completely abolished this
response. The supramaximal stimulus activated the caudate nucleus and bilateral
thalamus at low anesthesia; these responses were diminished at moderate
anesthesia. Isoflurane anesthesia blunts cerebral responses to somatosensory
stimuli, and the absence of cortical activation during supramaximal stimulation
suggests that noxious-induced movement is generated in lower CNS structures.
PMID- 9399636
TI - Chronic steroid sulfatase inhibition by (p-O-sulfamoyl)-N-tetradecanoyl tyramine
increases dehydroepiandrosterone sulfate in whole brain.
AB - Dehydroepiandrosterone sulfate (DHEAS) is a neurosteroid which functions as a
negative allosteric modulator of the GABA(A) receptor-gated chloride channel.
Steroid sulfatase inhibitors including (p-O-sulfamoyl)-N-tetradecanoyl tyramine
(DU-14), can potentiate the blockade of the amnestic effects of scopolamine by
exogenously administered DHEAS. Moreover, when administered over a 15 day period,
DU-14 can block scopolamine amnesia without the concurrent administration of
DHEAS. Since the enzyme, steroid sulfatase, facilitates the hydrolysis of the
sulfate moiety from DHEAS, the intent of this study was to determine whether
chronic administration of DU-14 could increase whole brain concentrations of
endogenous DHEAS. Rats were administered DU-14 or corn oil vehicle for 15 days.
Following the last day the animals were sacrificed and the brains were removed
and analyzed for DHEAS content. DU-14 increased the whole brain concentration of
DHEAS 77.6%, from 0.65 +/- 0.06 to 1.15 +/- 0.12 microg/g (mean +/- SEM). This
result suggests that steroid sulfatase inhibitors may enhance cognitive function
following chronic treatment by increasing the concentration of excitatory
neurosteroids such as DHEAS in the brain. Steroid sulfatase inhibitors,
therefore, may provide a novel mechanism for facilitating central nervous system
function.
PMID- 9399637
TI - Effect of dopamine on immune cell proliferation in mice.
AB - Dopamine is known as a precursor of catecholamine and one of the
neurotransmitters in brain and peripheral tissues. Recent studies suggest an
important role of dopamine in immune responses. In the present study,
intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) which lowered endogenous dopamine suppressed splenocyte proliferation in
response to mitogens such as lipopolysaccharide (LPS) and concanavalin A (Con A).
Moreover, intravenous injection of the specific agonists of dopamine DA-1
receptor (SKF38393) or DA-2 receptor (LY171555) into mice enhanced the splenocyte
proliferation stimulated by LPS or Con A. In the in vitro cultures, dopamine,
SKF38393 and LY171555 directly promoted cell proliferation to LPS or Con A. These
results indicate that dopamine has an ability to regulate B- and T-cell
proliferation both in vivo and in vitro.
PMID- 9399638
TI - Aspalatone, a new antiplatelet agent, attenuates the neurotoxicity induced by
kainic acid in the rat.
AB - The antioxidant efficacy of aspalatone (APT; acetyl salicylic acid maltol ester),
a new antiplatelet agent, has been characterized in vivo as well as in vitro, and
several observations indicated that the antioxidant could prevent the
neuroexcitation caused by oxidative stress. In this report, the effect of APT was
evaluated on kainic acid (KA)-induced neurotoxicity, since the neurotoxicity
induced by KA is, at least in part, mediated via the formation of free radicals.
The results showed that pretreatments with APT or maltol (MAL) significantly
attenuated seizure activity, oxidative stress (lipid peroxidation and protein
oxidation) and the loss of hippocampal neurons induced by KA. On the other hand,
the pretreatments with aspirin (ASP), ASP together with MAL or vitamin E failed
to protect against the toxicity produced by KA suggesting that the mechanism of
action for APT on the KA-induced neurotoxicity is different from that of ASP.
These finding raise the possibility that salicylmaltol, a metabolite of APT,
plays a role in preventing the neurotoxicity evoked by KA. Therefore, our results
suggest that an APT-related antioxidant mechanism, which is linked to the MAL
moiety, is involved in the neuroprotective effect against KA.
PMID- 9399639
TI - Cbl-b, a member of the Sli-1/c-Cbl protein family, inhibits Vav-mediated c-Jun N
terminal kinase activation.
AB - We have used the yeast two-hybrid system to identify proteins that interact with
Vav, a GDP/GTP exchange factor for the Rac-1 GTPase that plays an important role
in cell signaling and oncogenic transformation. This experimental approach
resulted in the isolation of Cbl-b, a signal transduction molecule highly related
to the mammalian c-cbl proto-oncogene product and to the C. elegans Sli-1
protein, a negative regulator of the EGF-receptor-like Let23 protein. The
interaction between Vav and Cbl-b requires the entire SH3-SH2-SH3 carboxy
terminal domain of Vav and a long stretch of proline-rich sequences present in
the central region of Cbl-b. Stimulation of quiescent rodent fibroblasts with
either epidermal or platelet-derived growth factors induces an increased affinity
of Vav for Cbl-b and results in the subsequent formation of a Vav-dependent
trimeric complex with the ligand-stimulated tyrosine kinase receptors. During
this process, Vav, but not Cbl-b, becomes highly phosphorylated on tyrosine
residues. Overexpression of Cbl-b inhibits the signal transduction pathway of Vav
that leads to the stimulation of c-Jun N-terminal kinase. By contrast, expression
of truncated Cbl-b proteins and of missense mutants analogous to those found in
inactive Sli-1 proteins have no detectable effect on Vav activity. These results
indicate that Vav and Cbl-b act coordinately in the first steps of tyrosine
protein kinase receptor-mediated signaling and suggest that members of the Sli
1/Cbl family are also negative regulators of signal transduction in mammalian
cells.
PMID- 9399640
TI - Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast
differentiation.
AB - Expression of oncogenic H-Ras in 23A2 myoblasts (A2:H-Ras cells) is sufficient to
induce both a transformed phenotype and a differentiation-defective phenotype.
Because oncogenic Ras is known to induce the secretion of several different
growth factors involved in maintaining the transformed phenotype of both
fibroblast and epithelial cells, we explored the possibility that expression of
oncogenic Ras in 23A2 myoblasts might lead to the secretion of a factor which
inhibits differentiation. The differentiation of 23A2 myoblasts was inhibited (i)
by coculture with an equal number of A2:H-Ras cells, (ii) by culture with an
equal number of A2:H-Ras cells in the same tissue culture medium on an insert
which allowed equilibration of molecules smaller than 1 micron, and (iii) by
culture in media previously conditioned by A2:H-Ras cells. Similar results were
obtained when 23A2 myoblasts expressing oncogenic N-Ras were substituted for A2:H
Ras cells in each assay. No inhibition of differentiation was observed, however,
when differentiation-defective E1A-expressing 23A2 cells or C3H10T1/2 fibroblasts
were substituted for A2:H-Ras cells. The differentiation inhibitor(s) in media
conditioned by A2:H-Ras cells is heat stable, larger than 3 kD, and sensitive to
the non-specific growth factor antagonist, suramin. Western analyses failed to
detect either FGF-2 or TGFbeta (the known inhibitors of myoblast differentiation)
in media conditioned by A2:H-Ras cells. Furthermore, while FGF-2 is a potent
activator of MAP kinase and TGFbeta is a potent inhibitor of mink lung epithelial
cell (CCL64) growth, conditioned media from A2:H-Ras cells does not activate MAP
kinase and does not inhibit the growth of CCL64 cells. These results indicate
that expression of oncogenic Ras induces the secretion of a novel inhibitor of
skeletal myoblast differentiation. Furthermore, these results are the first to
implicate an autocrine/paracrine mechanism in the inhibition of differentiation
by oncogenic Ras.
PMID- 9399641
TI - Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal
transduction.
AB - The binding of insulin to its receptor initiates multiple signal transduction
pathways regulating such diverse processes as proliferation, differentiation,
glucose transport, and glycogen metabolism. The STAT-family of transcription
factors has been demonstrated to play a critical role in gene induction by a
variety of hemopoietic cytokines and hormones. Furthermore, constitutive
activation of STATs is observed in transformed cells. Here we describe activation
of a transcriptional complex binding to a consensus STAT-transcriptional element
in response to insulin challenge. This complex is induced rapidly after tyrosine
autophosphorylation of the insulin receptor, and is sustained for several hours.
Supershift analysis of the insulin-induced complex reveals that it specifically
contains the transcription factor Stat3. DAN binding of this complex is inhibited
by pre-incubation with tyrosine, but not serine/threonine protein kinase
inhibitors, whereas transcriptional activation is inhibited by both. Utilising a
dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3
DNA-binding and also transactivation do not require p21ras. Furthermore, although
previous studies have suggested a role for MAP kinases (ERKs) and PI-3K in STAT
activation, utilising the specific MEK inhibitor PD098059 and the PI-3K inhibitor
wortmannin, we demonstrate that activation of ERKs or PI-3K are not required for
insulin induced Stat3 phosphorylation or transactivation.
PMID- 9399642
TI - Biological activity of p27kip1 and its amino- and carboxy-terminal domains in
G2/M transition of Xenopus oocytes.
AB - p27kip1 is a general inhibitor of Cdks that preferentially accumulates and
functions during G1 phase, before the restriction point of the mammalian cell
cycle. We observed that injection of purified p27kip1 into Xenopus oocytes
potently inhibits the G2/M transition and activation/dephosphorylation of the
maturation promoting factor (MPF, p34cdc2/cyclin B complex) kinase associated
with germinal vesicle breakdown (GVBD) induced by progesterone or insulin.
Addition of exogenous p27kip1 in vitro to lysates of hormonally matured oocytes
blocked the enzymatic activity of the activated MPF kinase present in those
extracts. Interestingly, the isolated amino-terminal region of p27kip1 (p27N),
encompassing only the Cdk binding site, exhibited a similar inhibitory behavior
in vitro and a weaker inhibitory effect in vivo than the complete p27kip1
protein. Surprisingly, the remaining carboxy-terminal region of p27kip1 (p27C)
actually induced GVBD when injected alone into the oocytes, and also accelerated
the kinetics of insulin- or progesterone-induced GVBD. Consistent with the in
vivo observations, p27C formed a complex with, and activated, the MPF kinase in
lysates of immature oocytes, although this activation was blocked by simultaneous
addition of p27N or complete p27kip1. Active MPF was able to phosphorylate p27C
only in the absence of p27N or whole p27kip1, suggesting that the inhibitory
activity associated with the amino terminus is dominant over the activation
produced by p27C. These results demonstrate the functional interaction of p27kip1
with cyclin B/p34cdc2 complexes during G2/M progression in oocytes, and suggest
that the amino and carboxy terminal portions of this protein may play opposite
regulatory roles, reminiscent of the corresponding N- and C-terminal portions of
p21waf. We speculate that accumulation of a truncated, C-terminal p27 fragment
may play a physiological regulatory role in progression through G2 and later
stages of the cell cycle.
PMID- 9399643
TI - SCH 51344-induced reversal of RAS-transformation is accompanied by the specific
inhibition of the RAS and RAC-dependent cell morphology pathway.
AB - RAS interacts with multiple targets in the cell and controls at least two
signaling pathways, one regulating extracellular signal-regulated kinase (ERK)
activation and the other controlling membrane ruffling formation. These two
pathways appear to act synergistically to cause transformation. SCH 51344 is a
pyrazolo-quinoline derivative identified based on its ability to derepress
transformation sensitive alpha-actin promoter in RAS-transformed cells. Previous
studies have shown that SCH 51344 is a potent inhibitor of RAS-transformation.
However, SCH 51344 had very little effect on the activities of proteins in the
ERK pathway, suggesting that it inhibits RAS-transformation by a novel mechanism.
In this study, we show that SCH 51344 specifically blocks membrane ruffling
induced by activated forms of H-RAS, K-RAS, N-RAS and RAC. Treatment of
fibroblast cells with this compound had very little effect on RAS-mediated
activation of ERK and JUN kinase activities. SCH 51344 was effective in
inhibiting the anchorage-independent growth of Rat-2 fibroblast cells transformed
by the three forms of oncogenic RAS and RAC V12. These results indicate that SCH
51344 inhibits a critical component of the membrane ruffling pathway downstream
from RAC and suggest that targeting this pathway may be an effective approach to
inhibit transformation by RAS and other oncogenes.
PMID- 9399644
TI - Cdk2-dependent phosphorylation of p27 facilitates its Myc-induced release from
cyclin E/cdk2 complexes.
AB - Activation of Myc triggers a rapid induction of cyclin E/cdk2 kinase activity and
degradation of p27. Overt degradation of p27 is preceded by a specific
dissociation of p27 from cyclin E/cdk2, but not from cyclin D/cdk4 complexes. We
now show that cyclin E/cdk2 phosphorylates p27 at a carboxy-terminal threonine
residue (T187) in vitro; mutation of this residue to valine stabilises cyclin
E/cdk2 complexes. This reaction is not significantly inhibited by high
concentrations of p27, suggesting that cdk2 bound to p27 is catalytically active.
In vivo, p27 bound to cyclins E and A, but not to D-type cyclins is
phosphorylated. Myc-induced release of p27 from cdk2 requires cdk2 kinase
activity and is delayed in a T187V mutant of p27. After induction of Myc, p27
phosphorylated at threonine 187 transiently accumulates in a non cdk2 bound form.
Our data suggest a mechanism in which p27 is released from cyclin E/cdk2 upon
phosphorylation; in Myc-transformed cells, release is efficient as phosphorylated
p27 is transiently bound in a non-cdk2 containing complex and subsequently
degraded.
PMID- 9399645
TI - Characterization of human N8 protein.
AB - We have shown before that the N8 mRNA is expressed at higher levels in lung tumor
and lung tumor-derived cell lines than normal lung cells. In this paper, we have
characterized the N8 protein, and studied its properties. The N8 gene encodes a
major 24 kDa protein and its expression correlates well with the N8 mRNA
expression pattern observed in different cell lines. N8 protein is capable of
forming a homodimer or multimeter in vitro. It is a phosphorylated cytoplasmic
protein and phosphorylation occurs mainly at serine residues. N8 protein is
expressed at higher levels in epithelial cells than in mesenchymal cells. N8
protein expression is induced in a fibroblast cell line expressing adenoviral Ela
protein, which acquired epithelial-like characteristics. Furthermore, ectopic
expression of N8 protein in NIH3T3 cells converts them into a spheroid form.
These spheroids also have some of the characteristic features of epithelial
cells. Taken together, these results suggest that the N8 protein may be
associated with the development or maintenance of epithelial cell phenotype.
PMID- 9399646
TI - Reexpression of the retinoblastoma protein in tumor cells induces senescence and
telomerase inhibition.
AB - Normal human diploid cells senesce in vitro and in vivo after a limited number of
cell divisions. This process known as cellular senescence is an underlying cause
of aging and a critical barrier for development of human cancers. We demonstrate
here that reexpression of functional pRB alone in RB/p53-defective tumor cells
via a modified tetracycline-regulated gene expression system resulted in a stable
growth arrest at the G0/G1 phase of the cell cycle, preventing tumor cells from
entering S phase in response to a variety of mitogenic stimuli. These cells
displayed multiple morphological changes consistent with cellular senescence and
expressed a senescence-associated beta-galactosidase biomarker. Further studies
indicated that telomerase activity, which was assumably essential for an extended
proliferative life-span of neoplastic cells, was abrogated or repressed in the
tumor cell lines after induction of pRB (but not p53) expression. Strikingly,
when returned to an non-permissive medium for pRB expression, the pRB-induced
senescent tumor cells resumed DNA synthesis, attempted to divide but most died in
the process, a phenomenon similar to postsenescent crisis of SV40 T-antigen
transformed human diploid fibroblasts in late passage. These observations provide
direct evidence that overexpression of pRB alone in RB/p53-defective tumor cells
is sufficient to reverse their immortality and cause a phenotype that is, by all
generally accepted criteria, indistinguishable from replicative senescence. The
results suggest that pRB may play a causal role in the intrinsic cellular
senescence program.
PMID- 9399647
TI - Role of wild type p53 in the G2 phase: regulation of the gamma-irradiation
induced delay and DNA repair.
AB - Upregulation of the p53 protein was shown to induce cell cycle arrest at the G1/S
border and in some cases at the G2/M border. Furthermore, it was suggested that
p53 is associated with the induction of the various DNA repair pathways.
Previously, we demonstrated that cells co-expressing endogenous wild type p53
protein, together with dominant negative mutant p53, exhibit deregulation of
apoptosis, G1 arrest and delay in G2 following gamma-irradiation. In the present
study, we investigated the role of p53 protein in the DNA damage response at the
G2 phase. Using p53-null, wild type p53 and mutant p53-producer cell lines, we
found that the two C-terminally spliced p53 forms could prevent gamma-irradiation
induced mutagenesis prior to mitosis, at the G2/M checkpoint. We found that at
the G2 phase, p53 may facilitate repair of DNA breaks giving rise to micronuclei,
and regulate the exit from the G2 checkpoint. At the G1 phase, only the regularly
spliced form of p53 caused growth arrest. In contrast, both the regularly and the
alternatively spliced p53 forms directed postmitotic micronucleated cells towards
apoptosis. These results provide a functional explanation for the cell cycle
independent expression of p53 in normal cycling cells, as well as in cells where
p53 is up-regulated, following DNA damage.
PMID- 9399648
TI - Methylation of the multi tumor suppressor gene-2 (MTS2, CDKN1, p15INK4B) in
childhood acute lymphoblastic leukemia.
AB - The multi tumor suppressor genes MTS1 (CDKN2 p16INK4A) and MTS2 (CDKN1, p15INK4B)
located at 9p21-22 are inactivated in some human cancers via several mechanisms
including deletion and hypermethylation. We have investigated the deletion and
methylation status of MTS1 and MTS2 in childhood acute lymphoblastic leukemia
(ALL) of both T-cell (17 cases) and B-cell phenotypes (29 cases), and p16INK4A
and p15INK4B mRNA expression in 36 of these cases. Biallelic or monoallelic loss
of both MTS1 and MTS2 was observed in 12 cases of B-ALL and nine cases of T-ALL.
Two cases of T-ALL showed deletion of MTS1 but not MTS2. The 5' CpG region of
MTS2 was hypermethylated in 12 cases of precursor B-ALL and eight cases of T-ALL
but no hypermethylation was found in the 5' CpG region of MTS1. All cases with
homozygous deletion of MTS1 or MTS2 had no or low levels of mRNA expression and
similar low levels of expression were found in cases in which MTS2 was present
but fully methylated. Thus hypermethylation of MTS2, in contrast to MTS1, is
frequent in childhood ALL. Furthermore our data show that although inactivation
of MTS1 by deletion is common, inactivation of MTS2 by a combination of deletion
and hypermethylation is more frequent in both B-ALL (20/29, 69%) and T-ALL
(17/17, 100%). This suggests that both MTS1 and MTS2 are important targets of the
9p21-22 deletion.
PMID- 9399649
TI - Malignant transformation by cyclin E and Ha-Ras correlates with lower sensitivity
towards induction of cell death but requires functional Myc and CDK4.
AB - We demonstrate in this paper that the G1 phase specific cell cycle regulator
cyclin E is able to provoke focus formation when cotransfected with activated Ha
ras into primary rat embryo fibroblasts (REFs). Cyclin E/Ha-ras transformed cells
are highly tumorigenic in synergeneic rats, are able to form colonies in soft
agar and show protection towards apoptosis upon serum starvation or DNA damage
compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large
T-antigen and Ha-ras. Lines that were established after cyclin E/Ha-ras or cyclin
D1/Ha-ras transformation contain a large percentage of polyploid cells. This was
not observed in cells transformed with other oncoproteins and Ha-ras pointing to
an involvement of D- and E type cyclins in genomic instability. The cyclin
dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus
formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin
E still requires functional G1 specific cyclin/CDK complexes. Moreover,
inhibition of Myc function also blocks the oncogenic activity of cyclin E
indicating a requirement of Myc for cyclin E function. The findings presented
here demonstrate that cyclin E can act as an oncoprotein with a potential
involvement in genomic instability and the prevention of cell death. Our data
also present more evidence for a strict functional interdependency between G1
cyclin/CDK complexes and c-Myc.
PMID- 9399650
TI - Suppression of morphological transformation by radicicol is accompanied by
enhanced gelsolin expression.
AB - Radicicol, an inhibitor of Src-family protein-tyrosine kinases, causes
morphological reversion of v-src- and v-Ha-ras-transformed fibroblasts and arrest
of the cell cycle at both the G1 and the G2 phases. Radicicol was found to
inhibit the growth of several other oncogene-transformed cell lines and human
carcinoma cell lines and to revert their cell morphology to be flat. In the
radicicol-treated flat cells, actin stress fiber bundles were reorganized. Since
this effect of radicicol on these cell lines was inhibited by cycloheximide, de
novo protein synthesis is required for the morphological reversion. Screening of
cellular proteins enhanced in response to radicicol by two-dimensional gel
electrophoresis suggested that the amount of gelsolin, an actin regulatory
protein, was distinctly increased upon radicicol treatment. Western blot and
Northern blot analyses showed that radicicol enhanced transcription of the
gelsolin gene in human carcinoma cell lines, as a result of which the amount of
gelsolin was increased several folds. Injection with an anti-gelsolin antibody
into cells and successive treatment with radicicol resulted in approximately 80%
reduction of the number of flat cells with stress fibers in comparison with
controls treated with an irrelevant antibody. These results show that elevated
expression of gelsolin is associated, at least in part, with the suppression of
transformation and the restoration of actin stress fibers in human carcinoma
cells by radicicol.
PMID- 9399652
TI - Epstein-Barr-virus-associated gastric cancer in Russia.
AB - The present investigation was carried out to estimate the prevalence of EBV
associated cases among gastric carcinoma (GC) patients of Russia and the
Republics of the former Soviet Union (FSU). With this aim, formalin-fixed
paraffin-embedded blocks from 206 gastric carcinomas obtained from patients of
the Cancer Research Center, Moscow, were investigated by EBV-encoded RNA-1 (EBER
1) in situ hybridization applied to paraffin sections. As a result, 18 GC cases
(8.7%) revealed uniform EBER-1 expression restricted to the carcinoma cells.
Hybridized signals not detected in non-neoplastic gastric epithelium. EBV
involvement was significantly more frequent among males, especially in tumors of
less differentiated types (moderately differentiated tubular adenocarcinomas and
poorly differentiated solid adenocarcinomas) and located in the upper stomach
(cardia and middle). Most EBV-positive GCs were characterized by strong lymphoid
compartment involvement. Our findings concerning the distribution of EBV-positive
GCs by sex, site and hystological type are similar to those in Japan, however,
EBV-positive rate of GC cases in Russia is higher than in Japan and lower than in
USA.
PMID- 9399651
TI - A sero-epidemiological study of the relationship between sexually transmitted
agents and cervical cancer in Honduras.
AB - To investigate a possible cause-and-effect relationship between sexually
transmitted diseases and cervical cancer, we performed a sero-epidemiological
study on the presence of antibodies against a number of sexually transmitted
agents (STAs) in patients with cervical cancer and their matched controls. In
this study, we used serological techniques to investigate the presence of
antibodies to cytomegalovirus, herpes simplex virus type 2, human
immunodeficiency virus, Chlamydia trachomatis, Treponema pallidum and human
papillomavirus (HPV) early protein E7 in sera from patients with cervical cancer,
cervical intra-epithelial neoplasia and individually matched, healthy controls.
The presence of antibodies to infectious agents other than HPV appeared not to be
associated with risk of cervical neoplasia in either univariate or multivariate
analysis. After adjustment for cytology, schooling and presence of HPV DNA in
cervical scrapes, there was a significantly higher prevalence of antibodies to
HPV-16 E7 protein in sera from patients with cervical cancer (OR = 3.6, 95% CI
1.0-12.9) than in healthy controls. The highest antibody prevalence was found
among HPV-16 DNA-positive cervical cancer patients (33%). Our results indicate
that in these study groups past infections with the STA considered seems to be of
no apparent relevance for cervical carcinogenesis and that the HPV-16 anti-E7
response appears to be associated with cervical cancer.
PMID- 9399653
TI - Induction of a T- and B-cell response against a unique amino acid sequence of the
mouse IgG2A hinge region in a MAb-treated patient.
AB - A patient with malignant glioblastoma was treated with intratumoral infusions of
the murine MAb425 (IgG2A) directed against the epidermal growth factor receptor.
At the 10th infusion, the patient developed somnolence, fever and headache. The
symptoms increased during the subsequent 48 hr but then gradually disappeared
within a week. The cerebrospinal fluid (CSF) contained increased concentrations
of interleukin-2. The main CSF cell subset was CD4 T-cells. A marked blood
lymphocyte proliferative response against mouse IgG2A was noted. The reactive T
cell epitope(s) could be localized to a 14 amino acid (RGPTIKPCPPCKCP) long
peptide of the hinge region. A B-cell response (IgG antibodies) against this
peptide was also induced.
PMID- 9399654
TI - A novel gastric-cancer-associated mucin antigen defined by a monoclonal antibody
A3D4.
AB - De-glycosylation of mucins may expose new tumor-associated core protein epitopes.
In this study, to attempt to develop useful markers for gastric cancers, we have
purified and de-glycosylated gastric mucin and tried to establish monoclonal
antibodies (MAbs). A MAb designated A3D4 among established MAbs was shown to
react with gastric cancer with high frequency, but not with normal gastric
epithelium. Among normal digestive organs, only the colon and gall bladder were
positive for MAb A3D4. The incidence of positivity in gastric cancer was 75% for
intestinal-type adenocarcinoma (n = 28), 40% for solid-type adenocarcinoma (n =
5) and 33% for signet/scirrhous-type adenocarcinoma (n = 15). Interestingly,
adenoma and intestinal metaplasia (IM) with chronic gastritis or peptic ulcer
were negative for MAb A3D4, whereas 8 out of 13 cases (62%) of IM with gastric
cancer was positive. Western-blot analysis using the lysate from normal colon
tissues revealed a high-molecular-weight (> 300-kDa) smear-like band.
Immunohistochemical analysis indicated that the reactivity of MAb A3D4 was
clearly increased when tissue sections were pre-treated with periodic acid or O
glycanase, while it was decreased by pre-treatment with trypsin or protease V8.
There was no reactivity with the synthetic peptide encompassing the tandem-repeat
sequence of MUC2 or MUC3. These data suggest that MAb A3D4 detects a novel
gastric-cancer-associated mucin antigen whose epitope may be peptide in nature.
PMID- 9399655
TI - p53 mutations in childhood thyroid tumours from Belarus and in thyroid tumours
without radiation history.
AB - Mutations in the p53 tumour-suppressor gene (exons 5-8) were investigated in 31
Belarussian childhood thyroid tumours (24 cases of papillary thyroid carcinoma, 3
benign tumours and 2 cases each of thyroiditis and goiter); 33 thyroid tumours
from juveniles and adults without radiation exposures (25 carcinomas of various
histological types, including 11 papillary carcinomas and 8 adenomas) and 6
tumours from adults (4 papillary carcinomas, 1 adenoma, 1 goiter) served as
controls. The mutational spectrum of p53 differed greatly between the childhood
thyroid carcinomas from Belarus and the control groups. In the control groups of
29 malignant thyroid tumours, 7 different mutations were detected on exons 5-8,
none of which occurred among the 15 papillary carcinomas in this group. Five
mutations were found in tissue samples of the 24 childhood papillary carcinomas,
and they were all the same p53 point mutation (CGA --> CGG) on codon 213 of exon
6. To determine whether this mutation is simply a polymorphism or whether it is
specific to the tumour cells, laser-assisted microdissection was applied to
collect various areas of tumorous and non-tumorous cells (10-20 cells per sample)
from each paraffin-embedded tissue section of 8 of the papillary thyroid
carcinomas. Using PCR-SSCP and sequence analysis on these cells, the very same
p53 mutation on codon 213 was detected in various microdissected tumour samples
of 2 cases, but it was not found in any microdissected non-tumorous sample. The
exclusive occurrence of this p53 mutation in selective microdissected samples of
tumour cells, even as homozygous mutation in 1 case, reflects a distinct tumour
heterogeneity within papillary childhood thyroid carcinomas.
PMID- 9399656
TI - Incidence of prostatic intra-epithelial neoplasia in Osaka, Japan.
AB - High-grade prostatic intra-epithelial neoplasia (HGPIN) is the most likely
precancerous lesion for prostatic carcinoma. A high incidence of its association
with cancer has been reported in Western countries. On the other hand,
information regarding its incidence is limited in Japan, where the mortality due
to prostate cancer is much lower. We reviewed 53 clinical stage T2 or T3
prostatic cancers of Japanese patients living in Osaka, Japan (mean age, 67.2
years). These cases were subdivided into a pre-operatively non-castrated group
(34 cases) and a medically or surgically castrated group (19 cases). HGPIN was
found in 27 cases. The incidence of HGPIN was significantly lower in the
castrated group (21.0%) compared with the non-castrated group (67.6%). In the non
castrated group, patient age, pathological stage, Gleason score, tumor size and
serum prostate-specific antigen showed no significant correlation with HGPIN.
Advanced pathological stage and tumor size tended to decrease the incidence of
HGPIN, although this was not statistically significant. When the study group was
limited to stage T2 tumors of the non-castrated group, the incidence of HGPIN was
81.0%. HGPIN in Japan may also be clinically and etiologically significant as a
precursor of clinical cancer.
PMID- 9399657
TI - Calcitonin receptors, bone sialoprotein and osteopontin are expressed in primary
breast cancers.
AB - Several human breast cancer cell lines express the calcitonin receptor (CTR), but
this has not been demonstrated previously in clinical breast cancers. We examined
18 primary breast cancers by reverse transcription-PCR, for expression of CTR and
of the bone proteins osteopontin (OPN) and bone sialoprotein (BSP). OPN and CTR
were expressed by each of the tumours, and 7 (39%) additionally expressed an
alternate form of CTR, whilst BSP was expressed by 13 tumours (72%). In situ
hybridisation confirmed that expression of OPN and CTR was confined to the tumour
cells. Expression of CTR, BSP and OPN may prove to be a useful marker for breast
cancers, and their role in the homing of breast cancer cells to bone remains to
be investigated.
PMID- 9399658
TI - Heterogeneous p53 mutations in a Burkitt lymphoma from an AIDS patient with
monoclonal c-myc and VDJ rearrangements.
AB - This study investigates the timing of p53 mutations detected in the malignant
cells of a Burkitt's lymphoma cell line (BRG-P) with respect to other maturation
or transforming events. The BRG-P cell line, derived from an AIDS patient, was of
special value since it displayed subclones that had undergone an isotype switch
from IgM to IgA1 (BRG-M and BRG-A cells). BRG-M and BRG-A cells were
characterized by the same monoclonal c-myc and VDJ rearrangements and by the
expression of Ig receptors with specificity for a 45 kDa protein of human breast
cells. Analysis of p53 mutations in the different BRG subclones showed that 1)
BRG-M cells displayed 2 different p53 mutations in trans; since the original BL
cells also showed the same mutations, this finding indicated that both occurred
in vivo; 2) one of the p53 alleles of BRG-A cells was lost, while the other
showed a mutation different from those seen in BRG-M cells; and 3) all 3
mutations observed in BRG-M or BRG-A cells resulted in the functional
inactivation of the transcriptional activation function of p53. Together, our
data demonstrate that p53 mutations were relatively late events during
lymphomagenesis. Moreover, in view of the role of p53 in cell apoptosis, it is
conceivable that BRG cells were subjected to a strong selective pressure that
favored p53 inactivation. Such inactivation was possibly required to
counterbalance other potentially apoptotic events, including the presence of a
deregulated c-myc oncogene and signals delivered by the host environment in situ.
PMID- 9399659
TI - Cancer risk in first-degree relatives of children with malignant tumours
(Province of Trieste, Italy).
AB - We conducted a population-based cohort study in the province of Trieste, Italy,
to assess whether the first-degree relatives of children with malignancies had an
increased risk of cancer compared with the general population. We examined
cancers occurring in all first-degree relatives of children who experienced
malignancies under the age of 15 years between 1971 and 1993 (probands). A cohort
of the 394 relatives of the 125 probands contributed 7,939 person-years of
observation. Among the relatives as a whole, we found a statistically significant
increased risk of developing all malignancies except non-melanoma skin carcinoma
(21 observed relatives with cancer and 12.46 expected, for a standardized
incidence ratio [SIR] of 1.69), of developing breast cancer (SIR = 3.09) and of
developing haemolymphatic system neoplasms (SIR = 4.03). This was mainly due to
the excess cancer risk in the relatives of probands with intracranial tumours,
who showed a significant 3.1-fold risk for developing all cancers but non
melanoma skin tumours. Our findings and the previously reported steep rise in the
incidence of childhood brain tumours in our area may imply that not only genetic
factors but also shared environmental agents might be involved in the observed
aggregation of cancer in the families of probands with intracranial tumours.
PMID- 9399660
TI - Occupational exposure to polyvinyl chloride as a risk factor for testicular
cancer evaluated in a case-control study.
AB - Occupational exposures were assessed in a case-control study on testicular cancer
using self-administered questionnaires. In total, answers were obtained for 148
(91%) cases and 315 (87%) controls. Of the cases, 101 had seminoma and 47 had
embryonal testicular cancer. An increased odds ratio (OR) was found for exposure
to polyvinyl chloride (PVC) yielding an OR of 6.6 (95% confidence interval, 1.4
32). The risk increased further if cases with self-reported cryptorchidism or
orchitis were excluded. Six of the 7 exposed cases had seminoma. Exposure to
other types of plastics did not significantly increase the risk of testicular
cancer.
PMID- 9399663
TI - Risk of second cancers in classical Kaposi's sarcoma.
AB - An association between Kaposi's sarcoma (KS) and malignant lymphoma has been
suspected for many years. Both cancers belong to the group of malignancies
associated with immune suppression and have been known to occur in the same
individual. Accordingly, a common etiology has been suspected. Through linkage
within the Nordic cancer registries, we studied the occurrence of cancers in a
population-based cohort of 741 patients with classical KS. The relative risk of
subsequent malignancies was expressed as the ratio of the observed numbers of
cancer to the numbers expected based on age-, sex-, period- and country-specific
incidence rates, i.e., the standardized incidence ratio (SIR). A total of 104
cancers was observed during 5,802 person-years of follow-up, which was close to
the expected 98.8 cases (SIR, 1.05). During the first year of follow-up, 3
lymphomas were observed, which is in significant excess of the 0.2 lymphomas
expected (SIR, 13.0). In contrast, no lymphomas occurred in the period beyond the
first year of follow-up vs. 2.3 expected. Cancers of the buccal cavity and
pharynx (SIR, 10.6; n = 4) and of the colon (SIR, 2.7; n = 7) occurred in excess
among women but not among men. Accordingly, our results indicate that patients
with classical KS are not at increased risk of cancer in general. In particular,
the overall risk of lymphomas was not significantly increased. The high relative
risk of malignant lymphoma immediately after KS was based on a limited number of
cases, and this observation is unlikely to indicate a common etiology.
PMID- 9399661
TI - Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families.
AB - Hereditary non-polyposis colon cancer (HNPCC) is a common hereditary disease
characterized by a predisposition to an early onset of colorectal cancer. The
majority of the HNPCC families carry germline mutations of either hMSH2 or hMLH1
genes, whereas germline mutations of hPMS1 and hPMS2 genes have rarely been
observed. Almost all of the germline mutations reported so far concern typical
HNPCC families. However, there are families that display aggregations of colon
cancer even though they do not fulfil all HNPCC criteria (incomplete HNPCC
families) as well as sporadic cases of early onset colon cancers that could be
related to germline mutations of these genes. Therefore, we screened germline
mutations of hMSH2 and hMLH1 genes in 3 groups of patients from France and
Turkey: typical HNPCC (n = 3), incomplete HNPCC (n = 9) and young patients
without apparent familial history (n = 7). By in vitro synthesis of protein
assay, heteroduplex analysis and direct genomic sequencing, we identified 1
family with hMSH2 mutation and 5 families with hMLH1 mutations. Two of the 3
HNPCC families (66%) displayed hMLH1 germline mutations. Interestingly, 4 of 9
families with incomplete HNPCC (44%) also displayed mutations of hMSH2 or hMLH1
genes. In contrast, no germline mutation of these genes was found in 7 young
patients. Our results show that germline mutations of hMSH2 and hMLH1 genes
contribute to a significant fraction of familial predisposition to colon cancer
cases that do not fulfil all diagnostic criteria of HNPCC.
PMID- 9399662
TI - Histological diagnosis of Helicobacter pylori gastritis is predictive of a high
risk of gastric carcinoma.
AB - Chronic Helicobacter pylori infection has been identified as a major risk factor
for the subsequent development of gastric carcinoma On the basis of
seroepidemiological studies the relative risk for infected persons was estimated
to range between 3 and 6. Our study attempted to determine the relative risk of
gastric carcinoma in H. pylori-infected individuals based on the histological
evaluation of gastritis in gastric carcinoma patients in the light of a declining
prevalence of H. pylori infection in Western countries. We histologically
determined the H. pylori infection rate in 215 patients with early gastric
carcinoma (tumor stage pT1), and compared it with that of 215 asymptomatic
persons matched by age and sex who were tested by the 13C urea breath test. On
the basis of these data an odds ratio of 16.7 (CI 9.6-29.1) was calculated for
the relative risk of developing gastric carcinoma in H. pylori-infected people.
The histological diagnosis of gastritis permits a separate risk assessment for
patients with autoimmune gastritis, and by excluding these patients from the
analysis we calculated an odds ratio for H. pylori-infected persons of 150 (CI
36.4-622.9). The endoscopic-histological diagnosis of H. pylori infection is
associated with an increased risk of the subsequent development of gastric
carcinoma of approximately 150-fold compared with H. pylori-negative patients who
do not have chronic atrophic corpus gastritis of the autoimmune type (type A
gastritis).
PMID- 9399664
TI - Genetic immunotherapy by intrapleural, intraperitoneal and subcutaneous injection
of IL-2 gene-modified Lewis lung carcinoma cells.
AB - The induction and augmentation of tumor non-specific immunity and of tumor
specific immunity by intrapleural, intraperitoneal and subcutaneous injection of
interleukin-2 (IL-2) gene-modified Lewis lung carcinoma (LLC) cells (LLC-IL2) was
tested in C57BL/6 mice. Intrapleural injection of LLC cells induced lung tumors
with a malignant effusion, intraperitoneal injection induced peritoneal tumors
with ascites and subcutaneous injection induced subcutaneous tumors. Intrapleural
injection of irradiated LLC-IL2 cured pre-existing lung LLC tumors and extended
the survival of the mice but did not affect survival of mice with pre-existing
peritoneal tumors nor did it affect the growth of s.c. tumors. Intraperitoneal
injection of irradiated LLC-IL2 cured pre-existing LLC peritoneal tumors and
extended the survival of the mice but did not affect survival of mice bearing
lung tumors nor did it affect the growth of s.c. tumors. Subcutaneous injection
of irradiated LLC-IL2 did not affect the growth of preexisting s.c. tumors and
also did not improve survival of mice bearing the lung or peritoneal tumors.
Injection with irradiated LLC-IL2 by all routes, i.e., intrapleural,
intraperitoneal and s.c., protected against subsequent re-challenge with LLC.
Eight days after the initial immunization (early stage of immunization), non
adherent mononuclear cells in the peritoneal cavity of the mice treated with
intraperitoneal injection of irradiated LLC-IL2 displayed enhanced cytotoxicity
against LLC, B16-F10 and P815 cells, while the cytotoxic activity of spleen cells
in the same mice did not change. The efficiency of induction of tumor-specific
immunity was the strongest after intraperitoneal immunization and weakest after
s.c. immunization. In vitro analysis using the spleen cells of mice immunized
with irradiated LLC-IL2 suggested that CD8+ T cells play a key role in tumor
specific immunity.
PMID- 9399665
TI - Remodeling of glycoconjugates on CD44 enhances cell adhesion to hyaluronate,
tumor growth and metastasis in B16 melanoma cells expressing beta1,4-N
acetylglucosaminyltransferase III.
AB - Beta1-4 N-acetylglucosaminyltransferase III (GnT-III) synthesizes bisecting N
acetylglucosamine structures on asparagine-linked oligosaccharides. Using B16-hm
mouse melanoma cells stably expressing GnT-III activity as positive
transfectants, the effect of bisecting N-acetylglucosamine on the function of
CD44 was analyzed in association with adhesion to hyaluronate and tumor spread in
mice. Transfection of GnT-III caused increased affinity of immunoprecipitated
CD44 to erythro-agglutinating phytohemagglutinin, that preferentially recognizes
bisecting N-acetylglucosamine, without affecting the surface CD44 amount,
indicating an increase in bisecting N-acetylglucosamine residues on CD44 in
positive transfectants. CD44-mediated adhesion to immobilized hyaluronate and the
binding of fluorescence-labeled hyaluronate to the cell surface were increased in
positive transfectants. The enhanced adhesion in positive transfectants was
suppressed by the treatment with beta-N-acetylhexosaminidase, indicating that N
acetylglucosamine residues were responsible for the enhanced adhesion. Positive
transfectants showed promoted CD44-mediated tumor growth and metastatic
development in the spleen after subcutaneous inoculation into mice. These results
indicate that glycosylation of CD44 due to GnT-III causes enhanced adhesion to
hyaluronate, local tumor growth and metastatic growth in spleen, suggesting that
the CD44-mediated adhesion and tumor spread can be modified through introduction
of a glycosyltransferase gene.
PMID- 9399666
TI - Folate-maytansinoids: target-selective drugs of low molecular weight.
AB - Folate receptor is over-expressed in a variety of carcinomas. To design a
cytotoxic drug that would selectively target these carcinomas, we synthesized
folate-maytansinoids. These drugs showed high affinity toward folate receptor,
appeared to enter cells exclusively via the folate receptor-mediated caveolar
pathway and displayed high cytotoxic potency (in the range of 10[-11] to 10[-10]
M) and remarkable selectivity for folate receptor-expressing carcinoma cell
lines. Folate-maytansinoids represent a new class of tumor-specific agents in
which the targeting and the cytotoxic function can be altered independently.
PMID- 9399668
TI - Neutral metoclopramide sensitizes cytotoxicity induced by ionizing radiation in
SCID mice xenografted with a human brain astrocytoma.
AB - A formulation of metoclopramide (MCA) conformationally altered by neutralization
of pH (nMCA, Neu-Sensamide) has been shown to have the same efficacy of enhancing
the cytotoxicity of a single dose of 1 Gy radiation as acidic formulations (e.g.,
Primperan, Sensamide) in a human lung adenocarcinoma (H2981) xenografted into
SCID mice. In the present study, 2 x 1 Gy radiation was combined with 2 x 2 mg
nMCA/kg body weight injected 2 hr before radiation treatment for evaluation of
radiosensitization in SCID mice xenografted with a human brain astrocytoma (T24).
Given in this treatment schedule, nMCA alone at 2 mg/kg showed no cytotoxic
effect on tumor growth in vivo. When combined with 2 x 1 Gy of radiation,
however, the cytotoxicity was significantly increased as measured by tumor growth
delay over the radiation-only-treated group. Furthermore, nMCA was absorbed into
brains of mice and rats as efficiently as acidic MCA (aMCA) when analyzed 45 min
after i.m. injection by high-performance liquid chromatography.
PMID- 9399667
TI - Targeting the tumor vasculature: inhibition of tumor growth by a vascular
endothelial growth factor-toxin conjugate.
AB - Tumor-derived vascular endothelial growth factor (VEGF)/ vascular permeability
factor (VPF) plays an important role in neovascularization and the development of
tumor stroma. Furthermore, VEGF receptors are over-expressed in the endothelial
cells of tumor vasculature and almost non-detectable in the vascular endothelium
of adjoining normal tissues. The differential expression of receptor offers a
selective advantage for targeting cytotoxic toxin polypeptides. We have prepared
a vascular targeting reagent by chemically linking recombinant VEGF to a
truncated form of diphtheria toxin. The VEGF-toxin conjugate was selectively
toxic to endothelial cell lines and inhibited experimental neovascularization of
the chick chorioallantoic membrane. In the present study, we examined the effects
of VEGF-toxin conjugate on solid tumor growth. Athymic nude mice with established
subcutaneous tumors were treated with daily intraperitoneal injections of the
VEGF-toxin conjugate or free toxin. When compared with control animals treated
with the toxin polypeptide alone, the conjugate-treated animals displayed a
significant inhibition of tumor growth. Histological analysis of tumors from
conjugate-treated animals revealed hemorrhagic necrosis consistent with a
vascular-mediated injury. In contrast, highly vascularized normal tissues from
conjugate-treated animals demonstrated no evidence of hemorrhage or tissue
injury. The conjugate was well tolerated without apparent toxicities. Our results
illustrate the anti-tumor activity of a VEGF-toxin conjugate selectively
targeting the tumor neovasculature.
PMID- 9399669
TI - Soluble HER-2/neu neutralizes biologic effects of anti-HER-2/neu antibody on
breast cancer cells in vitro.
AB - Amplification and over-expression of the HER-2/neu proto-oncogene are associated
with poor prognosis in women with both node-positive and node-negative breast
cancer. Therefore, the encoded surface glycoprotein represents an attractive
target for cancer immunotherapies. Furthermore, the extracellular domain of HER
2/neu is released from the cell surface by proteolytic cleavage. In the present
experiments, we investigated the potential biologic effects of soluble HER-2/neu
with particular emphasis on its interaction with anti-HER-2/neu antibodies. A
monoclonal antibody specific for the extracellular domain of HER-2/neu dose
dependently inhibited the proliferation of highly HER-2/neu-expressing SK-BR-3
and BT-474 breast cancer cells but had no effect on the proliferation of weakly
to moderately HER-2/neu-expressing MCF-7, HBL-100 and ZR-75-1 breast cells.
Addition of SK-BR-3 or BT-474 cell supernatants with high concentrations of
soluble HER-2/neu led to a neutralization of anti-HER-2/neu antibody-mediated
inhibition of proliferation due to a binding of soluble HER-2/neu by the
antibody, which could be demonstrated by immunoprecipitation. Furthermore, the
ability of anti-HER-2/neu antibodies to mediate antibody-dependent cellular
cytotoxicity (ADCC) by lymphokine-activated killer cells was assessed. Cytolysis
of SK-BR-3 tumor cells was increased significantly in the presence of anti-HER
2/neu antibodies. Similar to the proliferation inhibition, ADCC was neutralized
by addition of soluble HER-2/neu-containing supernatants. Our data suggest that
tumors rich in HER-2/neu might thus escape certain steps of immunologic control
by neutralizing biologic activities of anti HER-2/neu antibodies due to the
presence of soluble HER-2/neu.
PMID- 9399670
TI - Effect of aspirin on cell proliferation and differentiation of colon
adenocarcinoma Caco-2 cells.
AB - Several lines of evidence suggest that long-term treatment with non-steroidal
anti-inflammatory drugs may reduce the risk of colon cancer and the size and
number of colonic polyps in patients with familial adenomatous polyposis. Aspirin
has also been shown to inhibit cell proliferation in human tumor cell lines and
to induce apoptosis in colonic mucosa of familial polyposis patients. To
elucidate the molecular mechanisms of the antiproliferative action of aspirin, we
studied the effects of aspirin on cell growth and differentiation of the human
colon carcinoma Caco-2 cell line. These cells represent a useful tool for
studying the mechanisms involved in the regulation of cell growth and
differentiation of intestinal epithelial cells since they spontaneously
differentiate into polarized cells, expressing brush border enzymes. We show in
this study that aspirin (0.1-10 mM) induces a profound inhibition of cell
replication as assessed either by cell counts or thymidine incorporation.
Moreover, aspirin concentrations of 5 and 10 mM induce apoptosis, whereas
concentrations of 1 and 2 mM do not. The inhibition of growth is associated with
a dose-dependent reduction in insulin-like growth factor II mRNA expression and
with an increase in sucrase activity (a brush border enzyme) and apolipoprotein A
I mRNA expression, 2 specific markers of the differentiative status of this cell
line. Our data thus show that aspirin-dependent inhibition of cell growth is
associated with the enterocyte-like differentiation of Caco-2 cells.
PMID- 9399671
TI - Paracrine interactions between mesothelial and colon-carcinoma cells in a rat
model.
AB - This study used a co-culture system with Transwell tissue-culture inserts to
investigate the role of primary cultures of rat peritoneal mesothelial cells on
the proliferation of rat colon-carcinoma cells (CC531 cells). Mesothelial cells
significantly inhibited the growth of CC531 cells, while, conversely, CC531 cells
stimulated the growth of mesothelial cells. Receptor-binding studies demonstrated
the presence of high-affinity IGF-I receptors on the mesothelial and CC531 cells.
Both cell types also produced IGF-I, as measured by radioimmunoassay. IGF-I
stimulated DNA synthesis in mesothelial cells, but had no effect on the growth of
CC531 cells. In co-culture, it was found that IGF-I potentiated the inhibitory
effect of mesothelial cells on CC531 cells. The effect of IGF-I on mesothelial
cell proliferation was additive to the stimulatory effect of CC531 cells. TGF
beta had no effect on the growth of the CC531 cells, suggesting that this growth
(-inhibitory) factor is not involved in the inhibitory effect of mesothelial
cells on CC531 cell growth. The study provides evidence for the existence of a
paracrine loop between mesothelial and colon-carcinoma cells, giving more insight
into the basic cellular mechanisms that may modulate the growth of
intraperitoneal colon carcinoma. Inhibition of CC531-cell proliferation by rat
mesothelial cells might explain the earlier finding that tumour cells grow poorly
in a surgically uncompromised abdomen.
PMID- 9399672
TI - Anti-tumor activity of CPT-11 in experimental human ovarian cancer and human soft
tissue sarcoma.
AB - CPT-11, a semi-synthetic derivative of camptothecin, was investigated for its
activity in panels of 15 human ovarian-cancer lines and 10 human soft-tissue
sarcoma lines grown s.c. in nude mice. Various factors were analyzed that may be
of influence on the extent of tumor-growth inhibition induced by CPT-11. At
equitoxic doses, CPT-11 was more effective in the daily x5 schedule than the
weekly x2 schedule, although a 2-fold higher dose was administered in the weekly
x2 schedule. Since i.p. and i.v. injections were similarly effective, the
selected treatment schedule was 20 mg/kg i.p. daily x5, starting when tumors
measured approximately 150 mm3. Growth inhibition of > or = 75% was obtained in
8/15 human ovarian-cancer lines and in 6/10 human soft-tissue sarcoma lines. A
weak correlation was found between topoisomerase-I mRNA in xenograft tissues and
sensitivity to CPT-11. Relative topoisomerase-I expression was highest in MRI-H
207 and WLS-160 xenografts, in which CPT-11 was able to induce cures of all
tumors. The high efficacy in the 2 panels of human tumor lines suggests over
prediction of its potential clinical activity in these tumor types. The
difference in efficacy of CPT-11 between species may be related to the metabolism
of the drug, since CPT-11 is converted more efficiently into SN-38 in mice. In
addition, mice may be less sensitive to SN-38-induced side-effects. On the basis
of the preclinical data, frequent administration of lower doses of CPT-11 should
be considered in order to increase response rates in the clinic.
PMID- 9399673
TI - Induction of glutathione S-transferase pi as a bioassay for the evaluation of
potency of inhibitors of benzo(a)pyrene-induced cancer in a murine model.
AB - There is a growing need for short-term and cost-effective bioassay to assess the
efficacy of potential chemo-preventive agents. We report that the induction of
glutathione (GSH) S-transferase pi (mGSTP1-1) by a chemo-preventive agent can be
used as a reliable marker to assess its efficacy in retarding chemical
carcinogenesis induced by benzo(a)pyrene (BP), which is a widespread
environmental pollutant and believed to be a risk factor in human chemical
carcinogenesis. This conclusion is based on 1) the relative contribution of
mGSTP1-1 of the liver and forestomach of female A/J mice in the detoxification of
the ultimate carcinogenic metabolite of BP, (+)-anti-7,8-dihydroxy-9, 10-oxy
7,8,9, 10-tetrahydrobenzo(a)pyrene [(+)-anti-BPDE]; and 2) a positive correlation
between the induction of hepatic and forestomach mGSTP1-1 by 5 naturally
occurring organosulfides (OSCs) from garlic (diallyl sulfide, diallyl disulfide,
diallyl trisulfide, dipropyl sulfide and dipropyl disulfide) and their
effectiveness in preventing BP-induced forestomach neoplasia in mice. In the
liver, the combined contribution of other GSTs in the detoxification of (+)-anti
BPDE was far less than the contribution of mGSTP1-1 alone. Likewise, in the
forestomach, the contribution of mGSTP1-1 far exceeded the combined contribution
of other GSTs. Studies on the effects of OSCs against BP-induced forestomach
neoplasia revealed a good correlation between their chemo-preventive efficacy and
their ability to induce mGSTP1-1 expression in the liver (r = -0.89; p < 0.05) as
well as in the forestomach (r = -0.97; p < 0.05). Our results suggest that the
induction of mGSTP1-1 may be a reliable marker for evaluating the efficacy of
potential inhibitors of BP-induced cancer in a murine model.
PMID- 9399674
TI - Le(y) glycolipid acts as a co-factor for tumor procoagulant activity.
AB - We have generated a monoclonal antibody (MAb), FS01, which inhibits the
procoagulant activity (CCA-1) produced by a human squamous cell carcinoma cell
line, LK52. Expression of the antigen recognized by FS01 MAb in various cancer
cell lines correlated well with the procoagulant activities of the expressing
cell lines. Our objective was to characterize the molecule reacting with FS01 MAb
and to analyze its involvement in the CCA-1 procoagulant activity. The molecule
was identified as a glycolipid and found to be involved in the procoagulant
activity because both procoagulant activity and reactivity to FS01 MAb were lost
after endoglycoceramidase treatment of CCA-1. Furthermore, FS01 MAb recognized
the Lewis Y (Le[y]) antigen. To confirm the involvement of a glycolipid
incorporating the Le(y) antigen in the procoagulant activity, we attempted to
purify CCA-1 from LK52 culture supernatant. In one of the purification steps, a
fraction containing low procoagulant activity (CCA-1p) separated from the Le(y)
positive fraction (CCA-1c). Although CCA-1c alone did not show procoagulant
activity, the procoagulant activity of CCA-1p was augmented by CCA-1c and this
augmentation was inhibited by FS01 MAb. Furthermore, CCA-1c enhanced the
procoagulant activity of 33 cell lines tested as well as CCA-1p. In addition,
purified Le(y) glycolipid from canine intestine augmented the procoagulant
activity of CCA-1p, and this augmentation also could be inhibited by FS01 MAb. We
conclude that Le(y) glycolipid is a co-factor for the procoagulant activity
derived from cancer cells.
PMID- 9399675
TI - Androgens are not a direct requirement for the proliferation of human prostatic
epithelium in vitro.
AB - The androgen receptor pathway is known to be a key regulator of growth in the
normal and pathological prostate. However, the precise mechanisms of this
signaling pathway with respect to the different cellular compartments of the
prostate remain largely unknown. We have used a primary culture system to grow
human prostatic epithelial cells of normal, benign, tumor and metastatic origin,
as well as immortalized human prostatic epithelial cell lines, to demonstrate the
absence of a direct or indirect effect of androgens on cellular proliferation in
vitro. In parallel to this observed androgen independence for growth, all cell
systems lost significant expression of androgen receptor, prostate-specific
antigen and prostatic acid phosphatase. Since the androgen receptor is expressed
in the epithelium in situ, our results suggest that the androgen effect on
epithelial cells may be one of prostatic differentiation rather than
proliferation, and that the androgen receptor/growth factor pathway acts through
mesenchymal-epithelial interactions.
PMID- 9399676
TI - Role of heparin-binding EGF-related peptides in proliferation and apoptosis of
activated ras-stimulated intestinal epithelial cells.
AB - The ras mutation is a common and critical step in carcinogenesis. Autocrine
growth factors are also known to play an important role in cancer cell growth and
transformation. However, the contribution of autocrine growth factors in
regulation of proliferation and apoptosis of activated ras-stimulated intestinal
epithelium is not fully understood. Therefore, we constructed activated ras
transfected intestinal epithelial cell clones (IEC-ras) to examine the role of
epidermal growth factor (EGF)-related peptides in the behavior of IEC-ras.
Overexpression of EGF family growth factors (transforming growth factor alpha,
heparin-binding EGF-like growth factor, amphiregulin and betacellulin) and
stronger phosphorylation of the EGF receptor was observed in IEC-ras compared
with control cells. IEC-ras proliferated more rapidly than control cells, and a
specific EGF receptor kinase inhibitor, AG 1478, abolished the increased
proliferation of IEC-ras. Heparitinase and chlorate also prevented increased
proliferation of IEC-ras. Additionally, IEC-ras expressed more bcl-2 and was more
resistant to apoptosis induction by UV radiation and mitomycin C. AG 1478
suppressed bcl-2 expression and inhibited resistance to apoptosis of IEC-ras.
Heparitinase and chlorate had effects similar to those of AG 1478. Our data
indicate that heparin-binding EGF family growth factors play an important role in
both increased proliferation and resistance to apoptosis of ras-stimulated
intestinal epithelial cells.
PMID- 9399677
TI - 5-Fluorouracil-resistant colonic tumors are highly responsive to sodium
butyrate/interleukin-2 bitherapy in rats.
AB - Advanced colorectal cancer is generally refractory to 5-fluorouracil (5-FU)
chemotherapy. This is linked to the emergence of resistant cell populations,
probably due to a selection process. The identification of molecular markers and
the improvement of alternative therapies thus remain important. We have used as
an experimental model a rat colon cancer cell line (PROb), which exhibits
features similar to those of the human situation. 5-FU treatment of rats bearing
PROb tumors enhanced their survival but did not lead to cure. A PROb 5-FU
resistant subline (PRObR1) was obtained by continuous in vitro exposure to 5-FU.
Resistance to 5-FU was accompanied by a 2-fold increase in thymidylate synthase
activity and a substantially higher incorporation of thymidine in the presence of
5-FU, compared with parental PROb cells. Unexpectedly, in syngeneic rats, PRObR1
tumors exhibited delayed growth when compared with parental PROb tumors. This was
ascribed to an increased sensitivity of PRObR1 cells to host immune response
since no growth delay was observed in immunocompromised nude mice and since there
was no detectable difference in proliferation rates between PROb and PRObR1
cells. 5-FU treatment was inefficient in prolonging the survival of rats bearing
PRObR1 tumors. In contrast, an immunotherapeutic protocol combining sodium
butyrate and recombinant interleukin-2 (NaBut/rIL-2) cured 80% of the rats
bearing established PRObR1 tumors. Our results suggest that NaBut/rIL-2 treatment
is efficient against 5-FU-chemoresistant rat colon cancer.
PMID- 9399679
TI - Focusing in on the medial temporal lobe.
PMID- 9399680
TI - Puzzles of psychiatric genetics--new candidate gene approaches.
PMID- 9399681
TI - Depressing transmission in GABAergic hippocampal neurons.
PMID- 9399682
TI - The search for infectious agents in neuropsychiatric disorders: lessons from
multiple sclerosis.
PMID- 9399683
TI - Mood disorders across the continents.
PMID- 9399684
TI - Computational functions of the hippocampus: does it encode all episodic memories?
PMID- 9399685
TI - Serotonin transporter mRNA in schizophrenia.
PMID- 9399686
TI - Interactions among genes for transcription factors in hypothalamic neurons:
implications for reproductive behaviors.
AB - Gene products for nuclear hormone receptors, which are transcription factors,
interact in the cell nuclei of neurons in a manner important for the hypothalamic
control of instinctive behaviors. In doing so, the combinatorial logic of their
competition or synergy may serve to integrate environmental and physiological
constraints upon those behaviors.
PMID- 9399687
TI - Changes in brain gene expression in psychiatric illness: mRNA differential
display provides some clues.
AB - The 20th century has witnessed a progressive increase in our understanding of
brain structure, organisation and function and now includes knowledge at the
macromolecular and ionic levels. Investigations of such diverse functions as
cognition, memory and mood, performed mainly in whole animal studies, are now
advancing rapidly with the application of modern molecular biological techniques.
In this article we consider the contribution of mRNA differential display to the
analysis of altered gene expression in vitro and in vivo. The role that this
technique may play in the identification of genes involved in the aetiology of
psychiatric disorders and their treatment is discussed.
PMID- 9399688
TI - Serotonin transporter gene polymorphisms: ethnic difference and possible
association with bipolar affective disorder.
AB - There is some evidence suggesting that a polymorphism of variable number of
tandem repeats (VNTR) in the second intron of the serotonin transporter (5-HTT)
gene and another variation which lies 1.2 kb upstream of the promoter of the gene
(5-HTTLPR) are associated with affective disorders. However, conflicting results
have also been reported. We examined an allelic association of these two
polymorphisms in a Japanese sample of 191 patients with affective disorders (142
bipolar and 49 unipolar) and 212 controls. Substantial differences in the number
and frequency of alleles between Caucasians and Japanese were observed for both
polymorphisms. A significant association between the VNTR polymorphism and
bipolar disorder (genotypic association: odds ratio 2.2, 95% CI 1.2-4.0; allelic
association: odds ratio 1.7, 95% CI 1.0-3.0) was found, but not between the 5
HTTLPR polymorphism and bipolar disorder. No significant association with
unipolar depression was detected using either genetic marker, although this may
be attributable to the relatively small number of subjects with unipolar
depression. Our results suggest that the VNTR itself or another unknown
functional polymorphism which would be in linkage disequilibrium to the VNTR has
an effect on susceptibility to bipolar disorder.
PMID- 9399690
TI - Additional evidence for an association between the dopamine D4 receptor (D4DR)
exon III repeat polymorphism and the human personality trait of Novelty Seeking.
AB - The long alleles (> or =6 repeats) of the dopamine D4 dopamine receptor exon III
polymorphism have been linked in some, but not all, studies to Novelty Seeking
(NS), one of four personality traits defined by Cloninger's tridimensional
personality questionnarie (TPQ). In order to further examine the robustness of
our original observation we have recruited an additional cohort similar in
demographic structure to the original cohort. Although no significant difference
in mean NS scores was observed when the new subjects (n=94) were grouped by
presence (NS=17.83 +/- 1.16) or absence (NS=16.45 +/- 0.65) of the 7 repeat
allele, a significant difference in range of NS scores was observed (non
parametric Moses range test, P = 0.01). The effect of the seven allele was also
significant in those individuals scoring highest on NS (>1 standard deviation
from the mean; t-test, t=5.13, P=0.002). In the expanded cohort (n=218) a
significant effect of the seven allele on NS is demonstrated by both parametric
(t=2.26, P=0.01) and non-parametric (range test, P=0.004) statistical tests. The
effect is also observed in both principal ethnic groups (Ashkenazi and non
Ashkenazi Jews). In the expanded cohort the effect is significant in female
(t=2.2, P=0.03, n=98) but not in male subjects (t=1.12, P>0.1, n=116). We discuss
both direct and indirect evidence that in our opinion continues to support a
modest role for the long alleles of the dopamine D4 receptor repeat polymorphism
in the determination of NS behavior at least in some population groups.
PMID- 9399689
TI - Cerebral benzodiazepine receptor binding and distribution in generalized anxiety
disorder: a fractal analysis.
AB - Data obtained from animal and human brain imaging studies indicate that frontal
cortex and medial temporal lobe are involved in experiencing and controlling fear
and anxiety. We tested the hypothesis that benzodiazepine receptor binding is
decreased in the left temporal pole and increased in the right prefrontal area
among patients suffering from anxiety. We studied 10 drug-naive female patients
with generalized anxiety disorder (GAD) and 10 age- and gender-matched healthy
controls with MRI and with SPET by using a new (123)I-labelled specific
benzodiazepine receptor radioligand, NNC 13-8241. Blindly analyzed results showed
that the benzodiazepine receptor binding of [(123)I]NNC 13-8241 was significantly
decreased in the left temporal pole among patients with GAD when compared with
age- and sex-matched healthy controls. This hemispheric asymmetry was studied
further with a fractal analysis of the SPET images. The fractal dimension of the
left hemispheric benzodiazepine receptor binding in patients with GAD was
significantly higher than that of controls (1.28 +/- 0.09 and 1.17 +/- 0.07,
respectively), whereas the intercept was decreased by 43 +/- 23% reflecting more
homogeneous cerebral benzodiazepine receptor density distribution in patients
with GAD. The finding is analogous to the decreased heterogeneity of myocardial
blood flow observed in patients with ischemic heart disease. The results are
consistent with the general hypothesis that high regional heterogeneity of
perfusion, metabolism and receptor density is necessary to maintain adaptation
ability in the living organism.
PMID- 9399692
TI - Lack of linkage between the corticotropin-releasing hormone (CRH) gene and
bipolar affective disorder.
AB - Corticotropin-releasing hormone (CRH) plays a key role in the regulation of the
stress response. Abnormalities in CRH secretion have been documented in both the
depression and manic phases of bipolar disorder (BPD). In the present study, we
investigated genetic linkage between the CRH gene and BPD in 22 pedigrees. A
highly informative, short tandem repeat (STR) polymorphism adjacent to the CRH
gene on human chromosomal region 8q13 was used to examine linkage. Affected
sibling pair (ASP) and the likelihood-based disequilibrium tests revealed
nonsignificant values. We conclude that the CRH gene is not linked to BPD; if
genes involved in the regulation of stress response are indeed linked to BPD, the
search should be directed towards those that regulate CRH secretion or its
effects on target tissues.
PMID- 9399691
TI - No evidence for expanded polyglutamine sequences in bipolar disorder and
schizophrenia.
AB - Several recent studies have suggested that expanded CAG repeats may contribute to
the genetic transmission of bipolar disorder and schizophrenia. In all known
disorders associated with expanded CAG repeats, the repeat sequence is translated
into glutamine. Therefore the simplest hypothesis is that one or more proteins
with expanded polyglutamine sequences are involved in the pathogenesis of bipolar
disorder and schizophrenia. In order to examine this hypothesis, we have used an
antibody against expanded polyglutamine sequences to examine Western blots
prepared from lymphoblastoid cell lines of patients with schizophrenia and
bipolar disorder. We also examined Western blots prepared from left frontal
cortex tissue samples obtained from 11 schizophrenics post mortem. With the
exception of the TATA-binding protein (TBP), we did not detect any proteins
containing expanded polyglutamine sequences. Our data therefore suggest either
that the expanded repeats which are associated with these disorders do not encode
polyglutamine, or that they are within genes that are not expressed within the
tissues investigated here.
PMID- 9399693
TI - Genotypic selection provides experimental confirmation for an alcohol consumption
quantitative trait locus in mouse.
AB - Quantitative genetic research has produced a wealth of basic information
concerning genetic influence on alcohol-related processes. Recent developments in
quantitative trait locus (QTL) methodology were promptly applied to the task of
individuating polygenes affecting alcohol-related attributes in animal models and
a body of reliable data is gradually coming into focus as a result of replication
and convergence of evidence from a variety of methods. A key issue in QTL
research is the need to distinguish true positive results from the false positive
results that are inherent in analytical procedures requiring large numbers of
significance tests. One school of thought holds that stringent significance
levels should be imposed; another suggests more modest criteria for QTL
nomination, with subsequent confirmation trials with independent samples.
Recombinant inbred strains and various types of intercrosses have been used in
correlational designs, both for nomination and confirmation studies. Alternative
experimental procedures include knockout preparations and short-term phenotypic
selective breeding. We present here results from a third experimental method-that
of marker-based genotypic selection--in evaluation of two nominated QTLs for
alcohol acceptance in mice.
PMID- 9399694
TI - Mu opioid receptor gene variants: lack of association with alcohol dependence.
AB - The mu opioid receptor is implicated in the reward, tolerance and withdrawal
effects of alcohol and other drugs of abuse. This hypothesis is supported by the
effects of alcohol on beta-endorphin release, of mu opioid receptor agonists and
antagonists on alcohol consumption, and by the activation of the dopaminergic
reward system by both alcohol and opiates. In addition, the murine mu opioid
receptor locus, Oprm, is implicated as the major quantitative trait locus (QTL)
affecting the different levels of morphine consumption between two inbred mouse
strains that also exhibit differences in alcohol and cocaine consumption.
Detection of genetic variation affecting OPRM1 expression or mu opioid receptor
function would be an important step towards understanding the origins of inter
individual variation in response to mu opioid receptor ligands and in diseases of
substance dependence. We directly sequenced the human mu opioid receptor locus,
OPRM1, to detect natural variation that might affect function and/or be
associated with psychiatric phenotypes related to opioid function. Four DNA
sequence variants were found: three non-synonymous substitutions (Ala6Val [rare],
Asn40Asp, [0.10-0.16], Ser147Cys [rare]) and one intronic variant (IVS2+691G/C
[0.55-0.63]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically
characterized population samples (US Caucasian [USC, n=100], Finnish Caucasian
[FC, n=324] and Southwestern American Indian [SAI, n=367]), were used to perform
association and sib-pair linkage analyses with alcohol and drug dependence
diagnoses. No significant association of OPRM1 genetic variation to phenotype was
observed. This analysis has 80% power to detect a small to moderate effect of
OPRM1 variation on alcohol dependence and 100% power to detect effects of the
magnitude of the ALDH2*2 variant. While these data do not support a role of the
mu opioid receptor in susceptibility to alcohol dependence, the potential
relationship between OPRM1 genetic variation and response to endogenous opioids
and exogenous opiates can now be investigated.
PMID- 9399695
TI - Prodynorphin mRNA expression is increased in the patch vs matrix compartment of
the caudate nucleus in suicide subjects.
AB - Experimental and clinical studies suggest an involvement of the opioid
neuropeptide system in psychiatric disorders. Notably, opioid peptide
immunoreactivity is altered in the cerebrospinal fluid of chronic schizophrenics
and manic-depressive subjects. Despite these clinical findings, few postmortem
investigations have examined the association of endogenous opioid neuropeptides
with schizophrenia and suicide. Anatomically, a tight interaction exists within
the neostriatum between the opioid peptide (dynorphin and enkephalin) system and
classical neurotransmitters such as dopamine which has been implicated in both
the psychotic symptoms and the cognitive deficits that characterize schizophrenia
(see review). The neostriatum is differentially organized into patch and matrix
neurochemical mosaic compartments anatomically connected to limbic- and
sensorimotor-related brain regions, respectively. Moreover, the human neostriatum
is characterized by a heterogenous expression of the prodynorphin opioid gene:
high in the patch, but low in the matrix compartment. The present results show
for the first time a differential alteration of prodynorphin within distinct
striatal compartments in postmortem tissue from nonschizophrenic suicide
subjects. The prodynorphin patch/matrix mRNA expression was elevated in the
caudate nucleus of suicide subjects as compared to normal controls and
schizophrenics in which no alterations in opioid peptides or D1 and D2 mRNA
expression were apparent. Altogether the findings suggest that discrete
dysfunction of the endogenous opioid dynorphin system might contribute to
depression and the risk of suicide in nonschizophrenic subjects.
PMID- 9399696
TI - An integrated physical map of 18p11.2: a susceptibility region for bipolar
disorder.
AB - The reported linkage between bipolar disorder and a large pericentric portion of
chromosome 18 has been replicated in an independent study. Further examination of
this region showed that 18p11.2 had the greatest allele sharing in our pedigrees
and increased sharing in other independently ascertained pedigree series
permitting refinement of the region of significance. To facilitate positional
cloning of a susceptibility gene, we used a combination of mapping reagents,
including a subchromosomal somatic cell hybrid panel, a contig of clones in yeast
artificial chromosomes (YAC), and a radiation hybrid (RH) panel, to construct a
high resolution physical map of the region including sequence tag sites (STSs)
and expressed sequence tags (ESTs). This approach generated the interlocus
distance and order of 15 STSs and 16 ESTs including four novel transcripts, with
an average of approximately 200 kb between loci, over a approximately 6-Mb
region. This high resolution integrated map will be an important tool in
providing loci for contig construction, and positional candidates for mutation
screening.
PMID- 9399697
TI - Cerebral changes and cerebrospinal fluid beta-amyloid in Alzheimer's disease: a
study with quantitative magnetic resonance imaging.
AB - Pathological and biochemical studies indicate that beta-amyloid (betaA4)
deposition is a hallmark in the pathogenesis of Alzheimer's disease (AD).
Neuroimaging studies demonstrate that the respective cerebral changes primarily
strike the temporal lobe and the amygdala-hippocampus complex and may be reliably
assessed using quantitative magnetic resonance imaging (MRI). Therefore one may
expect that reduced betaA4-levels are significantly correlated with measures of
the temporal lobe rather than global cerebral atrophy in AD patients. To test
this hypothesis in a clinical study, cerebrospinal fluid concentrations of total
betaA4 and its major C-terminal variations betaA4 1-40 and betaA4 1-42 were
compared with cerebral changes as assessed by quantitative magnetic resonance
imaging (MRI). Significantly (P< 0.05) reduced betaA4 1-40 and betaA4 1-42 levels
were found in the AD patients (17 female; six male; AD/NINCDS-ADRDA-criteria) in
comparison to the patients with major depression (seven female; two male; DSM-III
R). Within the AD group, betaA4 and betaA4 1-42 levels were significantly
correlated with the volume of the temporal lobes (r= 0.46 and r= 0.48,
respectively) but none of the other volumetric measures. These findings indicate
that changes in cerebral betaA4 levels contribute to temporal lobe atrophy in AD
and support the possibility that betaA4 is central to the etiology of AD.
PMID- 9399698
TI - Transcriptional regulation of the human IL5 gene by ionizing radiation in Jurkat
T cells: evidence for repression by an NF-AT-like element.
AB - Eosinophilia is often observed in patients with parasitic infections and atopic
diseases like allergic asthma and atopic dermatitis. Additionally, it is a
typical feature of the inflammatory reaction after therapeutic and accidental
exposure to ionizing radiation. This uniquely specific phenomenon regulated by
the cytokine interleukin 5 (IL-5) suggests specific control for IL5 gene
expression. In this study, we generated promoter-CAT constructs containing
different human IL-5 promoter regions spanning from positions -507 to +43.
Transfection experiments in Jurkat T cells revealed that the promoter sequence
from -57 to +43 was required for constitutive and inducible IL-5 promoter
activity. Low baseline CAT activity could be enhanced by treatment with
phenylmercuric acetate (PMA) or the combination of PMA and calcium ionophore. The
promoter region between positions -97 and +43 showed responsiveness to low-dose X
rays. Electrophoretic mobility shift assays demonstrated that the region from
117 to -97 was responsive to irradiation. Transcription factors specifically
bound to this sequence showed a dose-dependent response to single doses of X rays
between 1 and 8 Gy. Competition analysis indicated that the protein-DNA complexes
at this region were related to the nuclear factor of activated T cells (NF-AT).
Further confirmation was obtained by the addition of specific antibodies into
protein-DNA reactions. For the first time, we have demonstrated that specific DNA
binding of NF-ATp at the promoter region from -117 to -97 is involved in
transcriptional regulation of the human IL5 gene in response to ionizing
radiation.
PMID- 9399699
TI - Enhanced neoplastic transformation in an inhomogeneous radiation field: an effect
of the presence of heavily damaged cells.
AB - In the inhomogeneous radiation field surrounding small beta-particle sources,
nonlethally and heavily damaged cells are in proximity, permitting interaction
via extracellular signals. This situation is typical of hot particles such as
those released during the accident at Chernobyl. Beta-particle-emitting yttrium
90 wires (average energy 934 keV) were employed to investigate radiation-induced
neoplastic transformation under these conditions. Integrated 24-h doses ranging
from 0 to 750 Gy across the exposure field were applied. At equal levels of
toxicity a 10-fold enhancement of neoplastic transformation frequency in C3H
10T1/2 cells was observed in the presence of heavily damaged cells. Homogeneous
fields of low-dose-rate beta-particle radiation produced neoplastic
transformation frequencies typical for comparable photon exposures reported in
the literature.
PMID- 9399700
TI - Comparisons of the frequencies and molecular spectra of HPRT mutants when human
cancer cells were X-irradiated during G1 or S phase.
AB - In an attempt to elucidate mechanisms underlying the variation in
radiosensitivity during the cell cycle, mutations in the HPRT gene were selected
with 6-thioguanine, quantified and characterized in synchronous human bladder
carcinoma cells (EJ30-15) that were irradiated in G1 or S phase with 3 or 6 Gy.
Synchronous cells were obtained by mitotic selection, with approximately 98% of
the cells in G1 phase when they were irradiated after 3 h of incubation, and 75%
in S phase when they were irradiated after 14 h of incubation. The mutant
frequencies were approximately 4-fold higher (P < 0.01) when cells were
irradiated in G1 phase compared with S phase, and the lowest frequency (1.5 x 10(
5) for 3 Gy during S phase) was approximately 10-fold higher than the spontaneous
frequency. Exon analysis by multiplex polymerase chain reaction was performed on
DNA isolated from each independent mutant. The different types of mutants were
categorized as class 1, which consisted of base-pair changes or small deletions
less than 20 bp; class 2, which consisted of deletions greater than 20 bp but
with one or more HPRT exons present; and class 3, which consisted of deletions
encompassing the entire HPRT gene and usually genomic markers located 350-750 kbp
from the 5' end of the gene and/or 300-1400 kbp from the 3' end. A "hotspot" for
class 2 deletions was observed between exons 6 and 9 (P < 0.01). For cells
irradiated during G1 phase, the percentages for the different classes (total of
78 mutants) were similar for 3 and 6 Gy, with a selective induction of class 3
mutants (34-38%) compared with spontaneous mutants (3%, total 20). When S-phase
cells were irradiated with 3 Gy, there were fewer class 1 mutants (21%, total 37)
than when cells were irradiated in G1 phase with 3 Gy (45%, total 42) (P < 0.01).
The greatest change was observed when the dose was increased in S phase from 3 Gy
to 6 Gy (total of 43 mutants), with the frequency of class 2 mutants decreasing
dramatically from 30% to 1% (P < 0.005). A similar decrease in class 2 mutants
with an increase in dose has been observed by others in asynchronous cultures of
normal human fibroblasts. We hypothesize that these differences occur because:
(a) there is more error-free repair of double-strand breaks (DSBs) during S than
G1 phase; (b) a single DSB within the HPRT gene causes a class 2 mutation or a
certain percentage of class 1 mutations, while two DSBs, with one in each
approximately 1-Mbp region 5' and 3' of the gene, cause a class 3 mutation; and
(c) a repair process that is induced when the dose during S phase is increased
from 3 to 6 Gy results in a preferential decrease in class 2 mutations.
PMID- 9399701
TI - Higher-order chromatin structure-dependent repair of DNA double-strand breaks:
modeling the elution of DNA from nucleoids.
AB - A possible relationship between the repair of DNA double-strand breaks (DSBs) and
their distribution within higher-order chromatin (Johnston and Bryant, Int. J.
Radiat. Biol. 66, 531-536, 1994) has recently been demonstrated. Radiosensitive
cells deficient for components of the DNA-dependent protein kinase DSB repair
pathway exhibited a particular failure in the rejoining of DSBs occurring as
multiples within looped DNA structures. Here, a Poisson-based model of induction
of DSBs and elution of DNA from residual nuclear structures is presented. By
applying this model to cells of a panel of human and rodent cell lines, a mean of
1.6 Mbp for the size of the relevant looped structures was obtained. Such large
chromatin structures are of the same magnitude as those observed by functional
mapping of interphase and mitotic chromosome structure, nucleoid sedimentation
and the "replicon clusters" apparent during DNA replication. This work supports
the hypotheses that (1) such structures are critical targets for induction of
DSBs and (2) the distribution of damage within these domains may be a factor in
the response and sensitivity of mammalian cells to ionizing radiation.
PMID- 9399702
TI - Temperature dependence of radiation-induced DNA-protein crosslinks formed under
hypoxic conditions.
AB - Recently, we demonstrated that the oxygen dependence of the formation of DNA
protein crosslinks (DPCs) in irradiated mammalian cells measured by the alkaline
elution technique is the mirror image of the oxygen dependence of radiation
induced cell killing. Consequently, these radiation-induced DPCs could be used to
detect hypoxic cells or estimate the hypoxic fraction of cells in solid tumors.
Although several techniques, including alkaline elution, gas chromatography/mass
spectrometry (GC/MS) and nitrocellulose filter binding, have been used to measure
radiation-induced DPCs, the published reports suggest that the characteristics of
these DPCs may depend on both the type of sample irradiated (cellular compared to
model systems, oxygenated compared to hypoxic, etc.) and the technique used to
measure these radiation-induced DPCs. In the present study, the radiation-induced
DPCs measured by our alkaline elution technique with and without proteinase K in
the lysis solution were characterized by studying the dependence of their
formation on temperature in hypoxic rat 9L brain tumor cells. Exponentially
growing 9L rat brain tumor cells were rendered hypoxic at 4 degrees C or at 37
degrees C and then irradiated with either 7.5 Gy or 15 Gy. The cells were
trypsinized at 4 degrees C, either immediately after the irradiation or after one
half-time of strand break repair at 37 degrees C. The results demonstrated that
the radiation-induced DPCs produced in 9L cells under hypoxic conditions,
measured by our alkaline elution technique after low to moderate radiation doses,
required metabolism for their formation, unlike the radiation-induced DPCs
reported by others using the GC/MS or nitrocellulose filter binding technique.
PMID- 9399703
TI - The involvement of topoisomerase I in the induction of DNA-protein crosslinks and
DNA single-strand breaks in cells of ultraviolet-irradiated human and frog cell
lines.
AB - Exposure of GM 4390 human skin fibroblasts and ICR 2A frog cells to 10 kJ m(-2)
of ultraviolet B (UVB) radiation resulted in the formation of DNA-protein
crosslinks (DPCs) and DNA single-strand breaks (SSBs). However, upon incubation,
there were rapid increases in the yields of both DPCs and SSBs. An enhancement in
these DNA alterations was detected within 12 min after irradiation and their
levels continued to rise by 5-8-fold within 15 h after exposure to UV radiation.
Using an antibody-based assay that measures covalent complex formation between
topoisomerase (topo) I and genomic DNA, it was found that topo I is one of the
proteins involved in these DPCs induced by UV radiation. The levels and rate of
increase of topo I-DNA covalent complexes were similar to the UV-radiation
dependent formation of DPCs and SSBs. A UV-radiation-sensitive mutant frog cell
line, DRP 153, was also examined and was found to be deficient in this induction
of DPCs and SSBs by UV radiation. When these cells were transfected with the
human SUVCC3 gene, the resulting transformant displayed kinetics for the
induction of DPCs and SSBs similar to the human and parental frog cells. However,
human topo I was not defected in the transformed frog cells, indicating that
SUVCC3 does not encode topo I. It is likely that SUVCC3 encodes an associated
enzymatic activity which permits normal stimulation of topo I-DNA covalent
complexes in UV-irradiated cells.
PMID- 9399704
TI - Coumarin-3-carboxylic acid as a detector for hydroxyl radicals generated
chemically and by gamma radiation.
AB - Coumarin-3-carboxylic acid (3-CCA) was used as a detector for hydroxyl radicals
(.OH) in aqueous solution. The .OH was generated by gamma irradiation or
chemically by the Cu2+-mediated oxidation of ascorbic acid (ASC). The excitation
and emission spectra of 3-CCA, hydroxylated either chemically or by gamma
irradiation, were nearly identical to those of an authentic 7-hydroxycoumarin-3
carboxylic acid (7-OHCCA). The pH-titration curves for the fluorescence at 450 nm
(excitation at 395 nm) of 3-CCA, hydroxylated either chemically or by gamma
radiation, were also identical to those of authentic 7-OHCCA (pK = 7.4). Time
resolved measurements of the fluorescence decays of radiation- or chemically
hydroxylated 3-CCA, as well as those of 7-OHCCA, indicate a monoexponential fit.
The fluorescence lifetime for the product of 3-CCA hydroxylation was identical to
that of 7-OHCCA (approximately 4 ns). These data, together with analysis of end
products by high-performance liquid chromatography, show that the major
fluorescent product formed by radiation-induced or chemical hydroxylation of 3
CCA is 7-OHCCA. Fluorescence detection of 3-CCA hydroxylation allows real-time
measurement of the kinetics of .OH generation. The kinetics of 3-CCA
hydroxylation by gamma radiation is linear, although the kinetics of 3-CCA
hydroxylation by the Cu2+-ASC reaction shows a sigmoid shape. The initial (slow)
step of 3-CCA hydroxylation is sensitive to Cu2+, but the steeper (fast) step is
sensitive to ASC. Analysis of the kinetics of 3-CCA hydroxylation shows a
diffusion-controlled reaction with a rate constant 5.0 +/- 1.0 x 10(9) M(-1) s(
1). The scavenging of .OH by 3-CCA was approximately 14% for chemical generation
with Cu2+-ASC and approximately 50% for gamma-radiation-produced .OH. The yield
of 7-OHCCA under the same radiation conditions was approximately 4.4% and
increased linearly with radiation dose. The 3-CCA method of detection of .OH is
quantitative, sensitive, specific and therefore accurate. It has an excellent
potential for use in biological systems.
PMID- 9399705
TI - A semi-empirical approach to the evaluation of the relative biological
effectiveness of therapeutic proton beams: the methodological framework.
AB - We address the problem of the evaluation of the relative biological effectiveness
(RBE) of therapeutic proton beams for cell inactivation. We consider a general
approach to the evaluation of the lethal effect of protons which is applicable to
different situations, including those in which an extended Bragg peak is obtained
via a modulated beam. Our approach combines two kinds of information: (1) the
experimental results available in the literature for the response of Chinese
hamster V79 cells to monoenergetic beams and (2) the energy spectrum of the beam
in the target volume, computed through a Monte Carlo algorithm. We have applied
this method to a simple Bragg peak produced by a broad-field proton beam of about
70 MeV initial energy, such as those that, after attenuation, are typically used
for treatment of ocular tumors. We have found that the RBE increases with depth,
even beyond the Bragg peak, up to a value close to 2, when evaluated at the same
surviving fraction as that resulting after exposure to 2 Gy of X rays.
PMID- 9399706
TI - Microdosimetry of astatine-211 using histological images: application to bone
marrow.
AB - A method is presented for calculating the small-scale dosimetry of 211At in red
bone marrow using chord-length distributions obtained from digitized histological
images. This study used histological samples of bone marrow from beagle dogs to
convey morphological information about cell conglomerations within bone marrow.
Two 211At activity distributions were considered within the extracellular fluid
and the surface of red bone marrow cells. Results confirmed the influence of cell
conglomeration and activity distribution in determining the microdosimetry of red
bone marrow. Average S* values of 1.6 x 10(-9) and 1.90 x 10(-9) Gy g Bq(-1) s(
1) were calculated for activity distributions located within the extracellular
fluid and the surface of red bone marrow cells, respectively. The cumulated
activity required to reduce survival probability to 0.37 also was calculated as a
function of cell sensitivity for both activity distributions. The activity
distribution on the cell surface resulted in a higher cell-killing efficiency,
requiring a lower activity concentration of approximately 25% when compared with
activity located in the extracellular fluid. Of relevance to potential clinical
studies with 211At, the probability for zero hits for red bone marrow cells was >
10% for cumulated activities of less than 5.5 x 10(8) Bq s g(-1) in bone marrow.
PMID- 9399708
TI - Measurement of DNA damage after exposure to electromagnetic radiation in the
cellular phone communication frequency band (835.62 and 847.74 MHz).
AB - Mouse C3H 10T1/2 fibroblasts and human glioblastoma U87MG cells were exposed to
cellular phone communication frequency radiations to investigate whether such
exposure produces DNA damage in in vitro cultures. Two types of frequency
modulations were studied: frequency-modulated continuous-wave (FMCW), with a
carrier frequency of 835.62 MHz, and code-division multiple-access (CDMA)
centered on 847.74 MHz. Exponentially growing (U87MG and C3H 10T1/2 cells) and
plateau-phase (C3H 10T1/2 cells) cultures were exposed to either FMCW or CDMA
radiation for varying periods up to 24 h in specially designed radial
transmission lines (RTLs) that provided relatively uniform exposure with a
specific absorption rate (SAR) of 0.6 W/kg. Temperatures in the RTLs were
monitored continuously and maintained at 37 +/- 0.3 degrees C. Sham exposure of
cultures in an RTL (negative control) and 137Cs gamma-irradiated samples
(positive control) were included with every experiment. The alkaline comet assay
as described by Olive et al. (Exp. Cell Res. 198, 259-269, 1992) was used to
measure DNA damage. No significant differences were observed between the test
group exposed to FMCW or CDMA radiation and the sham-treated negative controls.
Our results indicate that exposure of cultured mammalian cells to cellular phone
communication frequencies under these conditions at an SAR of 0.6 W/kg does not
cause DNA damage as measured by the alkaline comet assay.
PMID- 9399707
TI - Measurement of DNA damage after exposure to 2450 MHz electromagnetic radiation.
AB - Recent reports suggest that exposure to 2450 MHz electromagnetic radiation causes
DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) in cells of rat
brain irradiated in vivo (Lai and Singh, Bioelectromagnetics 16, 207-210, 1995;
Int. J. Radiat. Biol. 69, 513-521, 1996). Therefore, we endeavored to determine
if exposure of cultured mammalian cells in vitro to 2450 MHz radiation causes DNA
damage. The alkaline comet assay (single-cell gel electrophoresis), which is
reportedly the most sensitive method to assay DNA damage in individual cells, was
used to measure DNA damage after in vitro 2450 MHz irradiation. Exponentially
growing U87MG and C3H 10T1/2 cells were exposed to 2450 MHz continuous-wave (CW)
radiation in specially designed radial transmission lines (RTLs) that provided
relatively uniform microwave exposure. Specific absorption rates (SARs) were
calculated to be 0.7 and 1.9 W/kg. Temperatures in the RTLs were measured in real
time and were maintained at 37 +/- 0.3 degrees C. Every experiment included sham
exposure(s) in an RTL. Cells were irradiated for 2 h, 2 h followed by a 4-h
incubation at 37 degrees C in an incubator, 4 h and 24 h. After these treatments
samples were subjected to the alkaline comet assay as described by Olive et al.
(Exp. Cell Res. 198, 259-267, 1992). Images of comets were digitized and analyzed
using a PC-based image analysis system, and the "normalized comet moment" and
"comet length" were determined. No significant differences were observed between
the test group and the controls after exposure to 2450 MHz CW irradiation. Thus
2450 MHz irradiation does not appear to cause DNA damage in cultured mammalian
cells under these exposure conditions as measured by this assay.
PMID- 9399709
TI - Merril Eisenbud (1915-1997).
PMID- 9399710
TI - Prognostic significance of myocardial ischemia detected by ambulatory
electrocardiography, exercise treadmill testing, and electrocardiogram at rest to
predict cardiac events by one year (the Asymptomatic Cardiac Ischemia Pilot
[ACIP] study)
AB - Myocardial ischemia identified by ambulatory electrocardiography (AECG),
exercising treadmill testing, (ETT), or 12-lead electrocardiogram at rest is
associated with an adverse prognosis, but the effect of improving these ischemic
manifestations by treatment on outcome is unknown. The Asymptomatic Cardiac
Ischemia Pilot (ACIP) study was a National Heart, Lung, and Blood Institute
funded study to determine the feasibility of conducting a large-scale prognosis
study and to assess the effect of 3 treatment strategies (angina-guided strategy,
AECG ischemia-guided strategy, and revascularization strategy) in reducing the
manifestations of ischemia as indicated by AECG and ETT. The study cohort for
this database study consisted of 496 randomized patients who performed the AECG,
ETT, and 12-lead electrocardiogram at rest at both the qualifying and week 12
visits. The effect of modifying ischemia by treatment on the incidence of cardiac
events (death, myocardial infarction, coronary revascularization procedure, or
hospitalization for an ischemic event) at 1 year was examined. In the 2 medical
treatment groups (n = 328) there was an association between the number of
ambulatory electrocardiographic ischemic episodes at the qualifying visit and
combined cardiac events at 1 year (p = 0.003). In the AECG ischemia-guided
patients there was a trend associating greater reduction in the number of
ambulatory electrocardiographic ischemia episodes with a reduced incidence of
combined cardiac events (r = -0.15, p = 0.06). In the revascularization strategy
patients this association was absent. In the medical treatment patients the
exercise duration on the baseline ETT was inversely associated with an adverse
prognosis (p = 0.02). The medical treatment strategies only slightly improved the
exercise time and the exercise duration remained of prognostic significance. In
the revascularization group strategy patients this association was absent. Thus,
myocardial ischemia detected by AECG and an abnormal ETT are each independently
associated with an adverse cardiac outcome in patients subsequently treated
medically.
PMID- 9399711
TI - Improved specificity of transesophageal dobutamine stress echocardiography
compared to standard tests for evaluation of coronary artery disease in women
presenting with chest pain.
AB - The detection of coronary artery disease (CAD) by noninvasive methods has been
hindered in women by the high rate of false-positive results. To determine the
feasibility and accuracy of transesophageal dobutamine stress echocardiography
for identification of CAD in women, we studied 84 patients (age 51 +/- 11 years)
who underwent symptom-limited exercise treadmill testing, exercise thallium-201
scintigraphy, and coronary angiography for evaluation of anginal chest pain. Of
the 84 patients, 62 had normal coronary arteries or nonsignificant coronary
lesions, and 22 had significant stenosis of > or = 1 major coronary artery.
During treadmill exercise, repolarization changes were observed in 16 of 21
patients with CAD and in 19 of 60 patients with normal coronary arteries. With
thallium scintigraphy, a reversible defect was observed in 19 of 22 patients with
CAD and in 12 of 60 patients with normal coronary arteries. Regional wall motion
abnormalities during dobutamine infusion developed in 18 of 22 patients with CAD
and in none of the 62 patients with normal coronary arteries. All 3 tests had
similar sensitivity for detection of CAD (76% for exercise treadmill test, 86%
for thallium scintigraphy, and 82% for transesophageal dobutamine stress
echocardiography). However, transesophageal dobutamine stress echocardiography
had significantly higher specificity than the other 2 tests (100% vs 68% for
exercise treadmill test and 80% for thallium scintigraphy; p = 0.0001). Thus,
transesophageal dobutamine stress echocardiography is accurate for evaluation of
CAD among women presenting with chest pain; its use should be considered when
more conventional tests are equivocal or technically suboptimal.
PMID- 9399712
TI - Variations of remodeling in response to left main atherosclerosis assessed with
intravascular ultrasound in vivo.
AB - Histopathologic studies have demonstrated that vessels enlarge to compensate for
an increase in plaque burden; this has been confirmed in vivo using intravascular
ultrasound (IVUS). The initial studies suggested a biphasic course of lesion
formation with (1) preservation of lumen dimensions up to a plaque burden of
approximately 40%, and (2) luminal narrowing as plaque burden further increases.
In this study, we used IVUS and angiography to assess the extent of left main
(LM) atherosclerosis in 107 patients undergoing catheter-based procedures of the
left anterior descending or left circumflex coronary arteries. Using IVUS,
atherosclerotic plaques were found in all LM arteries, but only 26 (24%) had
varying degrees of luminal narrowing on the angiogram. Nevertheless, there was an
inverse relation (r = -0.62, p <0.0001) between the minimal lumen area and the
plaque burden (i.e., plaque + media divided by total vessel area) that was not
restricted to plaque burden values >40% (or >30%), but persisted at plaque burden
values of 20% to 40%. In addition, LM arteries with a plaque burden <40% had a
similar total vessel area as did LM arteries with a plaque burden > or =40% (22.9
+/- 6.1 vs 21.8 +/- 4.8 mm2, p = 0.30). These data suggest that lumen dimensions
may not be preserved even if plaque occupies no more than 20% to 40% of the total
vessel area. Thus, there is more variation in remodeling response during earlier
stages of plaque accumulation within the LM artery than is commonly suggested.
PMID- 9399713
TI - Gender differences in the accuracy of dobutamine stress echocardiography for the
diagnosis of coronary artery disease.
AB - The accuracy of dobutamine stress echocardiography (DSE) for the diagnosis of
coronary artery disease (CAD) has not been yet evaluated in women. We studied the
effect of gender on the accuracy of DSE for the diagnosis of CAD in 306
consecutive patients (210 men and 96 women) with limited exercise capacity and
suspected myocardial ischemia who underwent coronary angiography within 3 months
of DSE. There were no serious complications during DSE. Men had a higher
prevalence of nonsustained ventricular tachycardia (7% vs 0.03%, p <0.05) and
supraventricular tachycardia (9% vs 0.03%, p <0.05) during the test compared with
women. Peak stress rate-pressure product was not different in men and women
(18,140 +/- 4,187 vs 18,543 +/- 4,223). Significant CAD (> or =50% luminal
diameter stenosis) was present in 171 men (81%) and in 62 women (65%, p <0.005).
The sensitivity, specificity, and accuracy of ischemic pattern at DSE for the
diagnosis of significant CAD were 76% (confidence interval [CI] 67 to 84), 94%
(CI 89 to 99), and 82% (CI 75 to 90) in women and 73% (CI 67 to 79), 77% (CI 71
to 83), and 74% (CI 68 to 80) in men, respectively. Overall specificity was
higher in women than in men (p <0.05). Regional accuracy of DSE was significantly
higher in women than in men in the 3 arterial regions (84% [CI 79 to 88] vs 75%
[CI 72 to 79], p <0.005). It is concluded that DSE is a safe and feasible method
for the diagnosis of CAD in women. The overall specificity and the regional
accuracy of DSE are higher in women than in men. Further studies are required to
evaluate the functional significance of these findings and their reproducibility
in different patient populations.
PMID- 9399714
TI - Recanalization of total coronary occlusions using a laser guidewire (the European
TOTAL Surveillance Study).
AB - The success rates of coronary angioplasty for the treatment of chronic total
occlusions are less favorable than for coronary stenosis. Therefore, a new laser
guidewire (LW) was designed to facilitate the crossing of chronic total
occlusions. We report on the results of a European multicenter surveillance
study, evaluating the laser guidewire performance. Between May 1994 and July
1996, 345 patients (age 59 +/- 10 years, 291 men) with chronic total occlusions
were enrolled in 28 European centers. The median age of occlusion was 29 weeks
(range 2 to 884), the occlusion length 19 +/- 10 mm. LW recanalization was
successful in 205 patients (59%/). LW perforation occurred in 73 patients (21%),
with hemodynamic consequences in 4 (1%). There were no deaths, emergency coronary
artery bypass graft surgery, or Q-wave myocardial infarctions. In a multivariate
regression analysis an occlusion age of <40 weeks (p = 0.001, RR = 1.34) and an
occlusion length <30 mm (p = 0.01, RR = 1.59) were independent predictors of
success. Results indicate that the LW is an effective and safe tool in the
treatment of chronic total occlusion refractory to conventional guidewires.
PMID- 9399715
TI - Treatment of in-stent coronary restenosis by excimer laser angioplasty.
AB - We evaluated the efficacy and safety of excimer laser angioplasty (ELCA) with
adjunctive balloon angioplasty in patients with restenotic or occluded coronary
stents. ELCA was performed in 70 patients (60 +/- 9 years), who had previously
been treated with Micro Stents (n = 65), Palmaz-Schatz (n = 38), Wiktor, NIR,
Freedom, and Multi-Link stents (n = 1 each). Restenosis (> or =50% diameter
stenosis) was documented in 90 stents, another 17 stents were occluded. Laser
energy was delivered to the lesions with catheters 1.4, 1.7 (eccentric), and 2.0
mm in diameter. Procedural success was controlled by intravascular ultrasound in
a subgroup. Laser catheters crossed all restenotic or occluded stents and
decreased diameter stenosis from 80 +/- 13% to 44 +/- 11% (p <0.001). Adjunctive
balloon angioplasty further reduced diameter stenosis to 13 +/- 13% (p <0.001).
In 13 patients with 21 stents, serial intravascular ultrasound imaging revealed a
reduction of plaque area within the stent by 34 +/- 22% (from 4.2 +/- 1.8 mm2 to
2.7 +/- 1.1 mm2) after ELCA and a reduction by 65 +/- 16% (to 1.5 +/- 0.7 mm2)
after balloon angioplasty (p <0.01). There were 4 patients with an increase of
creatine kinase levels, 8 patients with major dissections (in 7 patients they
were related to adjunctive balloon angioplasty), 1 patient with distal
embolization, 2 with minor perforations, and 1 patient with stent dislocation.
Reintervention during hospitalization was necessary in 3 patients. ELCA is an
efficient and safe technique to debulk tissue in restenotic lesions and total
occlusions within stents. The incidence of procedure related complications was
low.
PMID- 9399716
TI - Relation of coronary artery disease to atherosclerotic disease in the aorta,
carotid, and femoral arteries evaluated by ultrasound.
AB - This prospective study was conducted to correlate the presence of
angiographically significant coronary artery disease (CAD) and atherosclerotic
disease in the aorta, carotid, and femoral arteries as measured by ultrasound.
One hundred two consecutive patients admitted for coronary angiography for
suspected CAD participated in the study. All patients underwent transesophageal
echocardiography for the evaluation of thoracic aortic atherosclerosis and B-mode
ultrasound for evaluation of carotid and femoral atherosclerosis. Intimal-medial
thickness > 1 mm in the thoracic aorta or peripheral vessels was considered as
evidence of atherosclerosis. Patients with CAD (n = 64) had a significantly
higher incidence of atherosclerotic plaques in the thoracic aorta, carotid, and
femoral arteries than subjects with normal coronary arteries: 91%, 72%, 77% vs
31%, 47% and 42%, respectively. Extracoronary plaque was a stronger predictor of
CAD than conventional risk factors. Evidence of plaque in patients younger than
median age (64 years) had a higher specificity than in patients above median age
(77% vs 40%, respectively, p <0.0001). Plaque score of the extracardiac vessels
was significantly higher in patients with multivessel CAD than in patients with 1
vessel CAD disease and in subjects with normal coronary arteries (p <0.001).
Thus, atherosclerotic plaques in the aortic and femoral arteries and, to a lesser
extent, in the carotid arteries are strong predictors of CAD.
PMID- 9399717
TI - Influence of physical activity on 24-hour measurements of heart rate variability
in patients with coronary artery disease.
AB - This study assessed the influence of physical activity on time domain variables
of heart rate variability (HRV) during 24-hour electrocardiographic
registrations. Changes in time domain variables of HRV (in particular SDNN)
obtained from Holter recordings were proven as strong predictors of cardiac
events in patients with coronary artery disease. Although 24-hour measurements of
HRV recordings are a standard technique, little is known about the effects of the
environment during the registration period. This applies especially to the type
and nature of physical activity. In a prospective study, 106 patients with
angiographically proven coronary artery disease were randomized into 2 groups.
Group 1 consisted of 54 patients with recordings under normal daily physical
activities. Group 2 consisted of 52 patients who were immobilized during the
recording. Both groups were comparable concerning clinical parameters. The
results of 24-hour measurements of HRV with analysis of time domain variables
(SDNN, SDANN, SDNN index, rMSSD, and pNN50) were compared among the 2 patients
groups, and with a healthy control group. Comparison of immobilized patients with
healthy controls showed statistically significant differences of all HRV
parameters (p <0.01). However, when comparing the activity group with healthy
controls, none of the parameters showed any significant differences. Comparison
of the subgroups revealed statistically significant differences of the parameters
SDNN, SDANN (p <0.01), and borderline results for rMSSD and pNN50 (p = 0.05). Our
results indicate that time domain variables of HRV calculated from 24-hour
recordings are significantly influenced by the level of physical activity and the
upright posture during registration. This methodologic aspect has to be
considered, especially if HRV measurements are used as prognostic markers in
patients with coronary heart disease.
PMID- 9399718
TI - Radiofrequency catheter ablation for paroxysmal supraventricular tachycardia in
children and adolescents without structural heart disease. Pediatric EP Society,
Radiofrequency Catheter Ablation Registry.
AB - Since 1990, management options available for children with paroxysmal
supraventricular tachycardia (PSVT) have included radiofrequency catheter
ablation (RCA). To determine the efficacy and safety of the procedure and to
maintain a database for long-term follow-up, the Pediatric Electrophysiology
Society began a Pediatric RCA Registry on January 1, 1991, to which 46 centers
have submitted data from 4,135 total children and adolescents (patient age 0.1 to
20.9 years) who underwent 4,651 RCAs (through September 15, 1996). Of the 88%
with a structurally normal heart, PSVT mechanisms (n = 4,030) included 3,110
accessory pathways and 920 atrioventricular node reentry tachycardia (AVNRT)
during 3,653 procedures for 3,277 patients. During the 7 years of the Registry,
analysis of indications for the procedure has shown a gradual shift. During the
first year of the Registry for this PSVT group, "medically refractory
tachycardia" was listed as the indication for 44% and "patient choice" was listed
as 33%, compared with 29% and 58%, respectively, for the years 1995 to 1996 (p
<0.005). Registry results were: 90% immediate success for accessory pathways (95%
for left lateral; 87% for septal; 86% for right free wall) and 96% for AVNRT;
mean fluoroscopy time 47.6 +/- 40 SD minutes; procedure time 257 +/- 157 SD
minutes; major complication rate at the time of the procedure 3.2%. Procedure
related deaths included 1 immediate and 3 at 2, 12 and 68 weeks after the
procedure (2 were infants). Follow-up revealed 77% and 71% freedom from
recurrence at 3 years for accessory pathways AVNRT, respectively, and rare (<1%)
detection of additional complications. RCA has evolved into a standard management
option for PSVT in children with a structurally normal heart. RCA for children
and adolescents should be recommended after consideration of the procedural
risk/benefit compared with that of other management options, the natural history,
and individual tolerance/symptoms related to PSVT.
PMID- 9399719
TI - Comparison of power- and temperature-guided radiofrequency modification of the
atrioventricular node. Polaris Investigator Group.
AB - The purpose of this study was to compare the performance and clinical outcome of
radiofrequency ablation of the substrate of atrioventricular (AV) nodal reentrant
tachycardia (AVNRT) when guided by power output or temperature monitoring. Two
sequential multicenter studies of power-controlled and open-loop, temperature
controlled radiofrequency ablation were analyzed in 171 patients undergoing AV
node modification for the treatment of AVNRT. After successful ablation of AVNRT,
complete elimination of slow AV node pathway function was accomplished more often
with than without temperature monitoring (92% vs 69%, p = 0.005). Greater power
was delivered to each patient with than without temperature monitoring (median 47
W, range 10 to 57, vs median 35 W, range 5 to 68, p = 0.001). Acute elimination
of tachycardia (100% vs 96%), 3-month recurrence (6% vs 8%), procedural times
(162 vs 170 minutes), fluoroscopy times (24.6 vs 29.5 minutes), complications (6%
vs 3%), and catheter removals to check for coagulum (8% vs 6%) did not differ
between patients treated with and without temperature monitoring, respectively.
Power- and temperature-controlled radiofrequency techniques are highly successful
with low complication rates for slow pathway ablation. Temperature monitoring may
allow the safe delivery of more power, and the more complete elimination of slow
AV node pathway function.
PMID- 9399720
TI - Effect of reproducibility of baseline arrhythmia induction on drug efficacy
predictions and outcome in the Electrophysiologic Study Versus
Electrocardiographic Monitoring (ESVEM) trial.
AB - Spontaneous variability over time in the ease of induction of ventricular
arrhythmias may mimic a drug effect and affect the predictive value of drug
therapy guided by programmed stimulation. We assessed the effect of baseline
reproducibility of arrhythmia induction on the incidence and accuracy of drug
efficacy predictions in the Electrophysiologic Study Versus Electrocardiographic
Monitoring (ESVEM) trial. Patients with sustained ventricular tachyarrhythmias
induced twice during baseline electrophysiologic testing with the same
stimulation technique, i.e., induced at the same pacing site with the same drive
cycle length and number of extrastimuli, were identified from the ESVEM database.
These patients with highly reproducible arrhythmia induction were compared to
those with less reproducible arrhythmias. Of 473 randomized patients with
reproducibility data, 313 (66%) had highly reproducible arrhythmias. In patients
randomized to electrophysiologic testing, baseline arrhythmia reproducibility did
not affect the incidence of drug efficacy predictions (70 of 157 [45%], drug
efficacy predictions in patients with highly reproducible arrhythmias vs 34 of 79
[43%] with less reproducible arrhythmias, p = 0.890). Drug efficacy predictions
obtained by electrophysiologic testing in patients with highly reproducible
arrhythmias were not associated with decreases in arrhythmia recurrence (p =
0.202), all-cause mortality (p = 0.301), cardiac death (p = 0.358), or arrhythmic
death (p = 0.307) compared to those with less reproducible arrhythmias. Analysis
of patients with highly reproducible sustained monomorphic ventricular
tachycardia led to similar results. In the ESVEM trial, most patients had highly
reproducible arrhythmia induction during baseline electrophysiologic testing.
Reproducibility of arrhythmia induction in the baseline state had no effect on
the incidence or accuracy of drug efficacy predictions.
PMID- 9399721
TI - Effect of calcium antagonists on plasma norepinephrine levels, heart rate, and
blood pressure.
AB - To evaluate the effects of calcium antagonists on sympathetic activity in
hypertensive patients, a MEDLINE search for English language articles published
between 1975 and May 1996 using the terms calcium antagonists, sympathetic
nervous system, and catecholamines was conducted. Clinical studies only reporting
the effects of calcium antagonists on blood pressure, heart rate, and plasma
norepinephrine (NE) levels in patients with hypertension were included. Data were
combined and analyzed according to class of calcium antagonist (dihydropyridine
vs nondihydropyridine), their duration of action (short-acting [SA] vs long
acting [LA]), and treatment duration. We identified 63 studies involving 1,252
patients. Acutely after single dosing, SA calcium antagonists decreased mean
arterial pressure by 13.7 +/- 1.1% and increased heart rate by 13.7 +/- 1.4% and
NE levels by 28.6 +/- 2.5%. Change in NE levels correlated with change in heart
rate (r = 0.59, p <0.01) and inversely with change in arterial pressure (r =
0.46, p <0.05) in patients taking dihydropyridine calcium antagonists acutely.
With sustained therapy, both classes of SA calcium antagonists increased NE
levels. Whereas NE levels remained slightly elevated and heart rate unchanged
with LA dihydropyridine calcium antagonists, both heart rate and NE levels
decreased with LA nondihydropyridine calcium antagonists. SA calcium antagonists
stimulate sympathetic activity when given acutely and over the long term,
irrespective of their molecular structure. Sympathetic activation is less
pronounced with LA dihydropyridine calcium antagonists and decreases with LA
nondihydropyridine calcium antagonists. These data offer a possible
pathophysiologic explanation for the increase in morbidity and mortality observed
in some studies using SA calcium antagonists.
PMID- 9399722
TI - Usefulness of low doses of atropine to quantify the vagal stimulus-response
relation in patients with congestive heart failure.
AB - The response of low doses of atropine is reported to be attenuated in patients
with congestive heart failure (CHF). Judging from the main site of action of low
doses of atropine, we may be able to assess the functional state of the vagal
center in the central nervous system. This study examines the clinical
significance of heart rate (HR) response to a low dose of atropine in patients
with CHF. Low and high doses of atropine were administered intravenously in 72
patients with CHF. HR after a low (parasympathomimetic) dose injection was
assessed by the ratio Rm (minimal HR/basal HR), and after a high
(parasympatholytic) dose by the ratio R1 (augmented HR/basal HR). Rm and R1 were
related to indexes of CHF. Rm increased with progression of CHF (0.92 +/- 0.03 in
New York Heart Association functional class I, 0.98 +/- 0.05 in class II, and
1.00 +/- 0.04 in class III). It also correlated with ejection fraction (r =
0.48, p <0.01) and more importantly, with peak oxygen uptake (r = -0.59, p
<0.01). R1 exhibited weak correlation with basal HR (r = -0.33, p <0.05) and
ejection fraction (r = 0.31, p <0.05), but had no correlation with other indexes.
The vagal center may be already blunted in New York Heart Association class II
with respect to increased Rm, which may be related to depressed exercise
capacity. A low dose of atropine injection offers a simple and safe method for
providing important information on the functional state of the vagal center in
the central nervous system in patients with CHF.
PMID- 9399723
TI - Time-related trends in the preoperative evaluation of patients with valvular
stenosis.
AB - To investigate time-related trends in the use of preoperative invasive
hemodynamics in patients with pure valvular stenosis, the preoperative
evaluations and preoperative echocardiograms of consecutive patients who
underwent aortic or mitral valve surgery from 1986 to 1994 at the Cleveland
Clinic Foundation were reviewed. The study group consisted of 1,985 patients,
1,476 with aortic stenosis and 509 with mitral stenosis. Preoperative cardiac
catheterization was performed in 1,456 patients with aortic stenosis (99%) and
488 with mitral stenosis (96%). Measurement of invasive hemodynamics (including
transvalvular gradients and estimated valve areas) during catheterization
decreased over time both in patients with aortic (from 64% in 1986 to 30% in
1994, test for trend p <0.0001) and mitral stenosis (from 63% in 1986 to 18% in
1994, test for trend p <0.0001). After adjusting for age, gender, and other
characteristics, the only predictors of performance of invasive hemodynamics in
patients with aortic stenosis were more recent surgery (inverse relation, p =
0.0001) and New York Heart Association class (p = 0.01); in patients with mitral
stenosis the only predictor was also more recent surgery (inverse relation, p =
0.0001). Thus, use of preoperative invasive hemodynamics in patients with
valvular stenosis has markedly decreased over the last decade. This is an example
of how a noninvasive modality can supercede an invasive one, even when
surrounding a procedure as fundamentally invasive as valvular heart surgery.
PMID- 9399725
TI - Treatment and outcome in silent myocardial ischemia: more pieces of the puzzle.
PMID- 9399724
TI - Cardiovascular function before, during, and after the first and subsequent
pregnancies.
AB - This study was designed to test the hypothesis that the vascular remodeling of
pregnancy begins early, persists for at least 1 year after delivery, and is
accentuated by a second pregnancy. Serial estimates of heart rate, arterial
pressure, left ventricular volumes, cardiac output, and calculated peripheral
resistance were obtained before pregnancy, every 8 weeks during pregnancy, and
12, 24, and 52 weeks postpartum in 15 nulliparous and 15 parous women using
electrocardiography, automated manometry, and M-mode ultrasound. During
pregnancy, body weight increased 14.5 +/- 1.8 kg and returned to prepregnancy
values 1 year postpartum. Heart rate peaked at term 15 +/- 1 beat/min above
prepregnancy levels (57 +/- 1 beat/min). Mean arterial pressure reached its nadir
(-6 +/- 1 mm Hg) at 16 weeks, returning to baseline at term. The increases in
left ventricular volumes and cardiac output (2.2 +/- 0.2 L/min) peaked at 24
weeks as did the 500 +/- 29 dynes x cm x s(-5) decrease in peripheral resistance,
and their magnitude was significantly greater in the parous women. Postpartum
they gradually returned toward baseline but remained significantly different from
prepregnancy values in both groups at 1 year. We conclude that cardiovascular
adaptations to the initial pregnancy begin early, persist postpartum, and appear
to be enhanced by a subsequent pregnancy. We speculate that persistence of these
changes may lower cardiovascular risk in later life.
PMID- 9399726
TI - Coronary angioplasty induces a systemic inflammatory response.
AB - C-reactive protein (CRP) levels increased more than sixfold above baseline when
measured 48 hours after elective percutaneous transluminal coronary angioplasty
(PTCA) in patients without underlying inflammatory conditions and did not change
significantly in controls undergoing coronary angiography. Only 3 of the 42 PTCA
patients had clinical restenosis and underwent target vessel revascularization
during the 6-month follow-up, but 2 of the 3 had very high CRP levels 48 hours
after the procedure.
PMID- 9399727
TI - Relation between arteriosclerosis in the coronary and renal arteries.
AB - This study analyzes the severity of coronary artery disease in terms of the
severity of renal artery disease in 609 patients undergoing coronary and renal
angiography. The presence of renal artery disease of any severity is strongly
suggestive of advanced coronary artery disease.
PMID- 9399728
TI - Predictive accuracy of echocardiographic response of mildly dyssynergic
myocardial segments to low-dose dobutamine.
AB - Low-dose dobutamine echocardiography has a high sensitivity for predicting
functional recovery after revascularization. In segments with mild wall motion
abnormalities, the specificity of the technique is rather low, suggesting
overestimation of functional recovery in these segments.
PMID- 9399729
TI - Insulin resistance in patients with familial combined hyperlipidemia and coronary
artery disease.
AB - The minimum model modified by the administration of insulin provides an objective
and relatively easily measured index of peripheral sensitivity to insulin which
was significantly lower (p <0.02) in familial combined hyperlipidemia (FCH) with
ischemic heart disease (IHD) than in FCH without IHD and in control subjects (1.2
+/- 0.6, 1.9 +/- 1.0, 2.9 +/- 1.2 x 10(-4) mU/L/ min, respectively). In patients
with FCH, insulin resistance explains, at least in part, their metabolic
alterations (hypertension, abnormal glucose tolerance, hyperinsulinemia) and
elevated IHD.
PMID- 9399730
TI - Antitachycardia pacing in patients with implantable cardioverter-defibrillators:
inverse circadian variation of therapy success and acceleration.
AB - We analyzed spontaneous ventricular tachycardias treated by antitachycardia
pacing during long-term follow-up in 138 recipients of an implantable
cardioverter-defibrillator. An inverse circadian variation of the antitachycardia
pacing termination and acceleration rates with the worst antitachycardia pacing
success during the time period with the highest episode frequency (morning hours)
was demonstrated.
PMID- 9399731
TI - Tolerability of internal low-energy shock strengths currently needed for
endocardial atrial cardioversion.
AB - There seems to be no relation between shock strength and patient's tolerability
using energy levels currently needed for low-energy internal atrial
cardioversion. Every patient felt that the second delivered shock, independent of
the amount of energy, was more uncomfortable than the first one, which indicates
that psychological conditioning may also play an important role in determining
discomfort.
PMID- 9399732
TI - Symptomatic conduction system disease in cardiac amyloidosis.
AB - Symptomatic conduction system disease in cardiac amyloidosis and its management
has been reported infrequently. We report our experience of patients with
amyloidosis having symptomatic conduction system disease requiring permanent
pacemaker implantation.
PMID- 9399733
TI - Immediate reproducibility of tilt-table test results in elderly patients referred
for evaluation of syncope or presyncope.
AB - We studied the immediate reproducibility of the results of the head-up tilt-table
test in elderly patients (age > or =60 years). Twenty-seven consecutive men
underwent 51 tests. The overall reproducibility was 98%, including 92% of a
positive test and 100% of a negative test. The finding of this study validates
the use of intravenous pharmacologic intervention in the elderly population.
PMID- 9399734
TI - Value of the electrocardiogram in determining cardiac events and mortality in
myotonic dystrophy.
AB - Electrocardiograms were recorded at baseline and regular intervals in 53 patients
with myotonic dystrophy who were followed for a mean of 6.3 +/- 4.0 years.
Patients with cardiac events had a significantly prolonged PR interval (p
<0.001), a later age of onset of neuromuscular symptoms (p <0.05), and were older
(p <0.005).
PMID- 9399735
TI - Effectiveness of five-loop coils to occlude patent ductus arteriosus.
AB - Coil occlusion of patent ductus arteriosus with 5-loop coils was undertaken in 10
patients without coil embolizations, and with 90% immediate occlusion and 100%
occlusion at follow-up. We conclude that 5-loop coil occlusion of patent ductus
arteriosus is safe and effective.
PMID- 9399736
TI - Effectiveness of an umbilical artery "snare assisted" approach for critical
pulmonary valve stenosis or atresia in the neonate.
AB - Thirteen neonates with critical pulmonary valve stenosis/atresia underwent
successful transcatheter balloon valvuloplasty using an umbilical artery "snare
assisted" approach. This technique simplifies the procedure and avoids femoral
artery injury by using the umbilical artery, reduces fluoroscopy exposure, and
eliminates the need for a gradational approach which reduces costs.
PMID- 9399737
TI - Effects of hormone therapy on inflammatory cell adhesion molecules in
postmenopausal healthy women.
AB - To investigate the effect of estrogen with antioxidant potential on soluble
markers of chronic vascular inflammation, we administered either transdermal
17beta-estradiol 0.1 mg/day (9 women) or 17beta-estradiol 0.1 mg and
medroxyprogesterone acetate 2.5 mg/day (11 women) for 1-month treatment in a
randomized design, with measurement of cell adhesion molecules. Hormone therapy
significantly lowered intercellular adhesion molecules-1 levels by 8% (p = 0.009)
and tended to lower E-selectin levels (by 6%, p = 0.096), and VCAM-1 levels (by
4%, p = 0.084).
PMID- 9399738
TI - Coronary vasospasm induced during isoproterenol head-up tilt test.
PMID- 9399739
TI - Use of telemetered permanent pacemaker intracardiac electrograms to diagnose
ventricular tachycardia.
PMID- 9399740
TI - Transcoronary alcohol ablation of infundibular hypertrophy in patients with
idiopathic infundibular pulmonic stenosis.
PMID- 9399741
TI - Unresolved issues in gastroesophageal reflux-related ear, nose, and throat
problems.
PMID- 9399742
TI - Molecular screening: why haven't we started yet?
PMID- 9399743
TI - The role of the oral cavity in Helicobacter pylori infection.
PMID- 9399744
TI - New trends in liver transplantation for viral hepatitis.
PMID- 9399745
TI - Empiric trial of high-dose omeprazole in patients with posterior laryngitis: a
prospective study.
AB - The optimal management of patients suspected with gastroesophageal reflux-related
posterior laryngitis is unclear. History, physical examination, and ambulatory pH
monitoring all have significant limitations in identifying patients who will
respond to antireflux therapy. OBJECTIVE: To evaluate the merit of empiric
omeprazole therapy in patients with posterior laryngitis. METHODS: Twenty-two
patients (11 men/11 women, median age 58 yr) with newly diagnosed posterior
laryngitis were enrolled. All had persistent laryngeal symptoms for at least 1
month. An empiric trial of omeprazole at 40 mg q.h.s. was given for 8 wk. Four
laryngeal symptoms (hoarseness, throat burning/pain, throat clearing, and cough)
and four esophageal symptoms (heartburn, regurgitation, dysphagia, and
odynophagia) were scored from 0 to 3. Symptom scores were obtained before, 4 wk
after, and 8 wk after the start of omeprazole. Patients were classified as
responders if they were symptom free or satisfied with results. Omeprazole was
stopped in the responders to look for relapse. Ambulatory pH monitoring was
performed in patients who did not respond. RESULTS: One patient discontinued
omeprazole and withdrew from the study. In the remaining 21 patients, the total
laryngeal and esophageal symptom scores significantly improved after empiric
omeprazole. Fourteen patients (67%) were classified as responders. Eight patients
(38%) had a relapse when omeprazole was stopped. Six patients (29%),
interestingly, did not relapse and did not require long-term antireflux therapy.
Seven patients (33%) were classified as nonresponders. Ambulatory pH monitoring
was abnormal in four of the five patients who agreed to have this test.
Increasing the dose of omeprazole to 40 mg b.i.d. provided no additional benefit
in the nonresponders. CONCLUSIONS: Empiric omeprazole therapy is a reasonable,
initial approach to patients with suspected gastroesophageal reflux-related
posterior laryngitis. A significant number of patients do well with a short
course of antireflux therapy. Additionally, a third of the patients may not
completely respond to intensive medical therapy despite the fact that reflux is
documented.
PMID- 9399746
TI - Detection of Ki-ras mutations by PCR and differential hybridization and of p53
mutations by SSCP analysis in endoscopically obtained lavage solution from
patients with long-standing ulcerative colitis.
AB - OBJECTIVES: The goal of this study was the early detection of malignant
transformation in patients with long-standing ulcerative colitis; therefore,
mutations of the Ki-ras and p53 gene were analyzed in lavage solution and
biopsies obtained at surveillance colonoscopy. METHODS: DNA was isolated from 14
patients (nine female, five male) with a history of pancolitis for more than 10
yr. Exon 1 of the Ki-ras gene and exons 5-8 of the p53 gene were amplified via
polymerase chain reaction. Mutations of the p53 gene were detected via single
strand conformation polymorphism analysis; point mutations of the Ki-ras gene
were hybridized on dot blots with oligonucleotides marked with digoxigenin.
RESULTS: Wild-type Ki-ras and wild-type p53 were detected in all cases of
ulcerative colitis and in four of seven control patients. In two ulcerative
colitis patients, a mutation was found in the Ki-ras gene (Gly --> Asp 12 and Gly
--> Val 12), and in one patient, a mutation in exon 5 of the p53 gene. Mutations
were found only in the lavage fluid, whereas random biopsies were negative.
CONCLUSIONS: From colonic lavage fluid, it is possible to extract DNA of
sufficient quantity and quality for polymerase chain reaction-based amplification
and subsequent analysis via single-strand conformation polymorphism or
hybridization. Mutations were found in three of 14 patients with long-standing
ulcerative colitis but were not found in controls. The method may be useful for
the screening of such patients.
PMID- 9399747
TI - Patient preferences and quality of life associated with colorectal cancer
screening.
AB - OBJECTIVES: The goal of this study was to describe the attitudes of patients
toward colorectal cancer screening, colon cancer, and colostomy. METHODS: Using
the time trade-off technique, we interviewed four groups of patients at a
veterans' hospital: 1) 46 patients with colorectal cancer, 2) 24 patients
undergoing screening sigmoidoscopy, 3) 114 subjects participating in a screening
colonoscopy study, and 4) 62 patients who have never undergone endoscopic
screening for colorectal cancer. Using this technique, we measured quality of
life for six scenarios pertaining to screening for colorectal cancer, the
patient's current health, colorectal cancer, and colostomy. RESULTS: Unscreened
patients were willing to give up significantly more time to avoid screening
sigmoidoscopy and colonoscopy (median 91 days and 183 days, respectively) than
were patients undergoing screening sigmoidoscopy (median 0 days and 7 days,
respectively), screening colonoscopy (median 0 days and 0 days, respectively), or
patients with colorectal cancer (median 0 days and 0 days, respectively). Cancer
patients rated their current health state lower than volunteers for screening.
Colon cancer and colostomy were rated similarly by all four groups. Substantial
variation in patient attitudes was present in all groups. CONCLUSIONS: Patients
are generally very accepting of endoscopic screening for colorectal cancer.
However, decisions regarding recommendations for colorectal cancer screening must
take into account the variability in patient preferences. Effective alternative
strategies should be available for those whose preferences do not comply with
standard recommendations. The effect of patient education and physician
recommendations on subjects' attitudes toward screening warrants further
investigation.
PMID- 9399748
TI - Proton pump inhibitors or histamine-2 receptor antagonists for the prevention of
recurrences of erosive reflux esophagitis: a cost-effectiveness analysis.
AB - OBJECTIVES: Erosive esophagitis is a recurring condition for which many patients
require preventive therapy. If maintenance therapy must be provided, the most
cost-effective treatment strategy should be established. We evaluated the costs
and benefits associated with three treatment strategies: 1) maintenance therapy
with a proton pump inhibitor (PPI) strategy, 2) maintenance therapy with a high
dose histamine-2 receptor antagonist (H2RA) strategy, and 3) maintenance therapy
with a standard-dose H2RA. If patients experience a symptomatic recurrence on the
H2RA strategies, they then receive PPI maintenance. METHODS: We used a cost
effectiveness model with a 1-yr time frame; data were obtained from randomized
trials of lansoprazole and ranitidine, from case series, and expert opinion.
RESULTS: In most situations, the high-dose H2RA strategy is the most costly, yet
it is less effective than the PPI strategy. Among the remaining two options, the
PPI strategy is more costly and more effective than the standard-dose H2RA
strategy, requiring an additional $52-688 per recurrence prevented, depending on
drug acquisition costs. The greater the degree to which esophagitis decreases
quality of life, the more cost effective is the PPI strategy. For example, with a
$50,000 per quality-adjusted life year cost-effectiveness threshold and a market
weighted average of drug costs, the PPI strategy appears cost effective for those
patients who report that symptoms of esophagitis cause greater than a 9%
decrement in quality of life. CONCLUSIONS: The high-dose H2RA strategy is not
preferred in terms of either costs or benefits. The PPI strategy appears cost
effective relative to the standard-dose H2RA strategy in the following
situations: when patients are significantly bothered by esophagitis and in
institutional settings where the difference in drug costs between PPIs and H2RAs
is small.
PMID- 9399749
TI - Coated expandable esophageal stents in the treatment of digestive-respiratory
fistulas.
AB - BACKGROUND: Malignant digestive-respiratory fistula (DRF) is associated with
significant morbidity and mortality. In addition to the other recognized
advantages of expandable stents, coated expandable stents can seal off DRF.
METHODS: Eight men and five women, mean age 52 yr, with endoscopically and
radiographically proven DRF were treated with the coated Wallstent (Schneider).
Eleven had dysphagia, 11 postprandial cough, and two required mechanical
ventilation. The DRF was proximal in four, mid-esophageal in seven, and distal in
two. Two had a normal esophagus and 11 had stricture. RESULTS: Stent placement
and DRF obliteration were successful in all. During a median follow-up of 157
days (range 30-423), no recurrent DRF were noted. The median dysphagia score
improved from 3.4 to 1.3. Respiratory symptoms were corrected in all. A
gastrostomy tube was required in three. The only complications were transient
chest pain and foreign body sensation in three patients and constant sensation of
belching in one. There was no procedure-related mortality. CONCLUSION: In this
small group of patients, the coated Wallstent demonstrated excellent palliation
of DRF with minimal morbidity and no mortality.
PMID- 9399750
TI - Does chemoradiation therapy increase the incidence of complications with self
expanding coated stents in the management of malignant esophageal strictures?
AB - BACKGROUND: Expandable stents offer excellent palliation of malignant dysphagia
and digestive-respiratory fistula. There are insufficient data regarding factors
that may affect the complication rate of expandable stents, but an association
between previous treatment with chemotherapy and/or radiation therapy and stent
related life-threatening complications has been suggested. METHODS: We
retrospectively analyzed our data on 60 patients; in all of them, a coated
Wallstent had been successfully placed for malignant dysphagia and/or digestive
respiratory fistula. Our objective in this study was to determine the overall
complication rate as well as whether previous or ongoing chemoradiation therapy
increased the rate of life-threatening complications. RESULTS: Among 21 patients
with no previous chemotherapy or radiation therapy, two (9.5%) had life
threatening complications (both had bleeding tumors; blood transfusions were
required in two and endoscopic hemostasis in one). Among 39 patients who had had
either radiation therapy, chemotherapy, or both, life-threatening complications
occurred in three (8%). Two of the three had gastrointestinal bleeding (two
received blood transfusions, and one had external radiation therapy), and in the
third, an esophageal tear was treated with the stent. There was no procedure- or
stent-related mortality in either group. CONCLUSIONS: Palliation of malignant
dysphagia or digestive-respiratory fistulas with the coated Wallstent in patients
with previous chemotherapy and/or radiation therapy is not associated with an
increased risk of life-threatening complications.
PMID- 9399751
TI - Genetic distinctions between types 1 and 2 autoimmune hepatitis.
AB - OBJECTIVES: Our aim was to determine whether alleles affecting susceptibility to
type 1 autoimmune hepatitis in the United States occur as commonly in German
patients with type 2 disease. METHODS: DNA specimens from 12 German patients with
type 2 autoimmune hepatitis were tested for class II alleles of the major
histocompatibility complex by polymerase chain reaction using sequence specific
primers. Eighty-six American patients with type 1 disease and 102 Caucasoid
normal subjects from the United States were tested in a similar manner. RESULTS:
American patients with type 1 autoimmune hepatitis had DRB1*03 alleles more
commonly than the German patients with type 2 disease (51% vs 17%, p = 0.03) and
DRB1*0301 occurred more frequently in the type 1 patients (51% vs 17%, p = 0.03).
The frequency of DRB1*04 alleles was also higher in the type 1 patients after
exclusion of the DR1*03 alleles (64% vs 20%, p = 0.01). In contrast, patients
with type 2 disease more commonly had DRB1*07 (p = 0.003), DRB1*15 (p = 0.004),
and DQB1*06 (p = 0.0004). DRB1*07 (p = 0.005), DRB4*01 (p = 0.03), and DQB1*06 (p
= 0.03) also occurred more frequently in the type 2 patients from Germany than in
the normal subjects from the United States, although none of these frequencies
were statistically significant by an adjusted p value. CONCLUSIONS: German
patients with type 2 autoimmune hepatitis do not have the same susceptibility
alleles as American patients with type 1 disease. Regional differences in
prevalence may reflect the genetic profiles of the populations at risk.
PMID- 9399752
TI - Safety of topical 5-aminosalicylic acid in pregnancy.
AB - OBJECTIVE: To assess the safety and efficacy of topical 5-aminosalicylic acid
preparations for therapy of distal colitis during pregnancy. METHODS: Nineteen
pregnancies in sixteen consecutive patients with proven distal colitis were
identified prospectively at a tertiary care center. All patients were given
trials of weaning off medication and all failed. All subjects were on maintenance
topical 5-aminosalicylic acid therapy at the time of conception. They were
followed throughout their pregnancy and thereafter. Their children were also
closely examined and followed by a pediatrician. RESULTS: The mean age at
delivery was 25.8 yr, and the mean duration of illness was 4.6 yr. After taking
topical therapy, there were no relapses during the pregnancy. There were 19
successful full-term pregnancies with no fetal abnormalities. The mothers and
children were followed for more than 6 months. CONCLUSION: In this series,
topical 5-aminosalicylic acid appears safe, effective, and well tolerated in the
management of pregnant patients with distal colitis.
PMID- 9399753
TI - Methotrexate in chronic active Crohn's disease: a double-blind, randomized,
Israeli multicenter trial.
AB - BACKGROUND: At present only one large controlled study has indicated that
parenteral methotrexate may be effective in chronic active Crohn's disease (CD).
AIM: To evaluate the effectiveness of oral methotrexate in chronic steroid
dependent CD. PATIENTS: Patients with active CD, who have received steroids
and/or immunosuppressives for at least 4 months during the preceding 12 months
and with a current Harvey-Bradshaw index of > or = 7 were studied. METHODS:
Methotrexate (12.5 mg weekly) or 6-mercaptopurine (50 mg daily), or placebo were
given during the 9 months of the trial in addition to steroids and 5
aminosalicylic acid as clinically indicated. RESULTS: Eighty-four patients were
included (methotrexate, 26 patients; 6-mercaptopurine, 32 patients; placebo, 26
patients). The proportion of patients entering first remission as well as the
proportions of patients relapsing after first remission were not significantly
different between the groups. The mean Harvey-Bradshaw index and the mean monthly
steroid dose were also similar. However, when each patient was evaluated as his
or her own control, the reduction in steroid dose, the general well being, and
the reduction in abdominal pain were significantly better in the methotrexate
treated patients. CONCLUSIONS: Methotrexate at a weekly oral dose of 12.5 mg was
found to be moderately better than 6-mercaptopurine and placebo in patients with
chronic active CD.
PMID- 9399754
TI - High prevalence of celiac disease among patients with insulin-dependent (type I)
diabetes mellitus.
AB - OBJECTIVES: Diagnosis of unrecognized celiac disease is potentially important.
The prevalence of celiac disease in patients with insulin-dependent diabetes
mellitus is uncertain. We report the prevalence of celiac disease in a stratified
random sample (n = 101) of adult insulin-dependent diabetic patients (age, 18-59
yr) attending our clinic, and in an age- and sex-matched control group (n = 51).
METHODS: Screening was by anti-endomysial antibody, measured by indirect
immunofluorescence using sections of human umbilical cord. RESULTS: Celiac
disease had not been suspected in any patient at the time of screening. Eight
patients tested positive for anti-endomysial antibody, all of whom had a distal
duodenal biopsy performed. Five patients had histologic evidence of celiac
disease. One patient with negative histology was receiving immunosuppressive
therapy for a renal-pancreas transplant. Of the five patients with abnormal
histology, two improved on gluten restriction, one was unable to comply, one
refused treatment, and one was lost to follow-up. No control subject tested
positive for endomysial antibody. CONCLUSIONS: Patients with insulin-dependent
diabetes have an increased prevalence of celiac disease. Because most cases are
clinically unrecognized, consideration should be given to screening all insulin
dependent diabetes mellitus patients with endomysial antibodies.
PMID- 9399755
TI - Randomized comparison of ranitidine bismuth citrate-based triple therapies for
Helicobacter pylori.
AB - OBJECTIVES: In an attempt to increase the efficacy and simplicity of FDA-approved
regimens for Helicobacter pylori, we studied (1) addition of an inexpensive
antibiotic (amoxicillin) to twice-daily ranitidine bismuth citrate (RBC)
clarithromycin dual therapy, and (2) substitution of RBC for bismuth
subsalicylate + H2-receptor antagonist in bismuth-based triple therapy. METHODS:
Subjects with previously untreated Helicobacter pylori infection documented by
13C-urea breath test plus either endoscopic biopsy or serology were randomly
assigned to a 2-wk course of (1) RBC 400 mg b.i.d., amoxicillin 1 g b.i.d., and
clarithromycin 500 mg b.i.d. (RAC), or (2) RBC 400 mg b.i.d., metronidazole 250
mg t.i.d., and tetracycline 500 mg t.i.d. (RMT). Repeat breath test was performed
4 wk after the completion of therapy. RESULTS: Intent-to-treat and per-protocol
cure rates for RAC were 46 of 50 patients (92%) and 45 of 47 patients (96%); for
RMT they were 40 of 50 patients (80%) and 37 of 42 patients (88%). Study drugs
were stopped due to side effects in three patients (6%) taking RAC and six
patients (12%) taking RMT. CONCLUSIONS: Twice-daily RBC-based triple therapy with
clarithromycin and amoxicillin produces Helicobacter pylori eradication rates
over 90%, which is comparable to rates seen with proton pump inhibitor-based
triple therapies. RBC also may be substituted for bismuth subsalicylate and an +
H2-receptor antagonist in standard bismuth-based triple therapy.
PMID- 9399756
TI - Is duodenal gastric metaplasia a consequence of Helicobacter pylori infection in
children?
AB - BACKGROUND: Duodenal gastric metaplasia (DGM) is commonly found in association
with Helicobacter pylori (Hp)-associated gastritis in adults. DGM is also
considered a risk factor for duodenal ulcer development. The prevalence of DGM in
children and its association with gastritis, duodenitis, or the presence of Hp
organisms is not clear. We investigated the prevalence of DGM in children and
explore its association with several possible risk factors, including age,
gender, gastritis, duodenitis, or Hp presence in the gastric antrum. METHODS: A
retrospective analysis of 173 upper endoscopy procedures performed between 1993
and 1995 at Cabell Huntington Hospital, Huntington, WV, was done. Gastric and
duodenal biopsies were stained with Giemsa for Hp detection, periodic acid-Schiff
for DGM, and hematoxylin and eosin for histologic assessment. Gastric mucosal
inflammation was graded according to Sydney criteria. RESULTS: Duodenal gastric
metaplasia was identified in 23 of 173 (13%) patients. Duodenitis but not age,
gender, gastritis, or the presence of Hp in the gastric antrum was associated
with DGM development. In 4 of 23 DGM foci, Hp was identified. CONCLUSIONS: In
children, DGM is not the consequence of Hp infection.
PMID- 9399757
TI - Prevalence and pattern of Helicobacter pylori gastritis in the gastric cardia.
AB - OBJECTIVES: Helicobacter pylori has a predilection for antral colonization. Local
acid production is the major determinant of colonization. Because production is
low in the antrum and cardia, H. pylori should also colonize the cardia. We
therefore investigated the histologic pattern of gastritis and the prevalence of
H. pylori in the cardia compared with the antrum and corpus. METHODS: From 135 H.
pylori-infected patients with gastritis, ulcer disease, or reflux esophagitis,
biopsies were obtained from the antrum, corpus, and cardia. The prevalence,
topography, and histologic parameters of gastritis were examined. RESULTS: All
135 patients had active antral H. pylori gastritis: in the cardia, 132 of these
patients (97.7%) showed active gastritis, and 124 patients (91.9%) had H. pylori
visible on staining. Gastritis of the cardia in most patients resembled antral
gastritis, but the density of bacteria and the inflammatory responses were less
marked. The most striking finding in the cardia of patients with gastroesophageal
reflux was a lower density of bacteria compared with antrum and corpus.
Intestinal metaplasia was found in 32 patients in antral mucosa (23.7%) versus 28
patients in the cardia (20.7%), versus 11 patients in the corpus (8.1%), and was
multifocal in 17 patients (12.6%). CONCLUSIONS: H. pylori gastritis commonly
involves the cardia. The histologic density of the bacteria and inflammatory
responses are lower than in the antrum. Intestinal metaplasia in the cardia is a
common finding in H. pylori gastritis. The cause of the lower bacterial density
in the cardia of patients with reflux esophagitis needs further investigation.
PMID- 9399758
TI - Usefulness of anti-Helicobacter pylori and anti-CagA antibodies in the selection
of patients for gastroscopy.
AB - OBJECTIVES: Screening of dyspeptic patients with serological tests for
Helicobacter pylori before open-access gastroscopy has been suggested to be
worthwhile. CagA-positive H. pylori strains may be associated with major
pathology more often than CagA-negative strains. The usefulness of anti-H. pylori
and anti-CagA antibodies in screening for gastroscopy was evaluated in unselected
dyspeptic patients. METHODS: Four hundred consecutive, unselected dyspeptic
patients (mean age, 56.8 yr) in primary care were investigated with gastroscopy,
ultrasonography of the upper abdomen, laboratory tests (including serological
tests for H. pylori and CagA), and other examinations if needed. The patients
were followed for 1 yr. RESULTS: Results of serological tests were positive for
H. pylori in 56.2% of patients, of whom 64.4% also had results positive for CagA.
Use of H. pylori and CagA serology-based screening combined with a history of
nonsteroidal anti-inflammatory drug use would have detected only 80 and 70% of
the major pathologies (peptic ulcer, moderate or severe esophagitis, celiac
disease, or malignancy), respectively, in these patients. Gastroscopy would have
been avoided in 30 and 41%, respectively, if only patients who had positive
results on serological tests or who were nonsteroidal anti-inflammatory drug
users would have been referred. In patients younger than 45 yr of age (n = 87),
60-74% of gastroscopies would have been avoided, but 50-60% of major pathologies
would have been missed, by using the screening strategy studied. One of the nine
malignancies (all in patients >45 yr of age) was H. pylori-negative, and two were
CagA-negative. CONCLUSIONS: Anti-CagA antibodies do not offer advantages compared
with anti-H. pylori antibodies in screening patients for gastroscopy. A
remarkable share of major pathologies are missed by both of these screening
methods. Therefore, the results of these screening tests are not recommended as
selective criteria for gastroscopy.
PMID- 9399759
TI - Storage temperature of the unbuffered rapid urease test.
AB - OBJECTIVES: The unbuffered rapid urease test (RUT) is an accurate, rapid, and
inexpensive method for detecting Helicobacter pylori. However, it is generally
recommended that the reagent be prepared daily. This prospective study was
undertaken to evaluate the shelf life of our unbuffered RUT when stored at 4 and
20 degrees C. METHODS: Ninety-five patients were studied. Three sets of antral
(X2) and body (X1) biopsy samples were taken from each patient. The samples were
subjected to histological examination, with the RUTs stored at 4 and -20 degrees
C. The RUT tubes were examined at 1 and 15 min. RESULTS: Fifty-six patients (59%)
were infected with H. pylori as defined by histological examination. The reagent
was classified according to storage time (group I, < or = 5 days; group II, > 5
days). The mean (SD) storage time of group I (n = 59) and group II (n = 36) was
3.2 (1.4) and 9.9 (5.0) days, respectively. At 15 min, the sensitivity of our RUT
stored at 4 degrees C was significantly higher in group I than in group II (92 vs
47%). On the other hand, the sensitivity of our RUT stored at -20 degrees C
remained consistently high in both groups (15 min: group I, 92%; group II, 100%).
Our RUTs stored at 4 and -20 degrees C were highly specific in both groups.
CONCLUSIONS: Our RUT remains highly sensitive and specific when it is stored at 4
degrees C for up to 5 days. When the RUT is expected to be stored for a longer
period of time, the bottles should be frozen at -20 degrees C.
PMID- 9399760
TI - Determination of hepatitis delta virus (HDV)-RNA in asymptomatic cases of HDV
infection.
AB - OBJECTIVES: To assess the frequency of hepatitis delta virus (HDV) viremia in
asymptomatic cases of HDV infection and the clinical significance of the HDV
viremia, we conducted a cross-sectional, community-based study. METHODS: Of 2207
examinees, 210 (9.5%) were found to be positive for hepatitis B surface antigen
(HBsAg). Antibody to HDV was detected in 47 (22.4%) of the 210 examinees, and 43
of the 47 were further evaluated for serum HDV-RNA by polymerase chain reaction.
RESULTS: Twenty-one (48.8%) of the 43 had detectable levels of HDV-RNA in serum,
and 22 (51.2%) were negative for serum HDV-RNA. The majority (61.9%) of the HDV
RNA-positive HBsAg carriers had high levels of serum ALT. In contrast, the
frequency of an abnormally high level of serum ALT was only 9.1% in the HBsAg
carriers positive for HDV antibody but negative for HDV-RNA, and the frequency
did not differ from that seen in the HBsAg-negative individuals. The
semiquantified HDV-RNA levels did not correlate with the serum ALT levels.
CONCLUSION: Seropositivity of HDV-RNA was strongly associated with liver cell
damage, even in asymptomatic cases. The absence of a detectable level of serum
HDV-RNA might be related to previous HDV infection.
PMID- 9399761
TI - Idiopathic colonic inflammation in AIDS: an open trial of prednisone.
AB - OBJECTIVES: Idiopathic colonic inflammation and ulceration have been described in
HIV infection, but only as isolated case reports. We have been treating this
condition with a uniform corticosteroid protocol and now report our results.
METHODS: We describe the cases of eight patients with HIV infection who had
diarrhea for more than 4 wk and inflammation and/or ulceration in the colon at
endoscopy, confirmed by biopsy, without any invasive pathogens despite extensive
evaluation. Each patient was treated with prednisone, starting at 40 mg/day, then
tapered according to a standardized protocol. RESULTS: The diarrhea completely
resolved in three patients and partially improved in five. One patient had some
improvement but was unable to tolerate the prednisone because of a severe
exacerbation of anal warts. He responded to subtotal colectomy. After a minimum
follow-up of 8 months (mean, 17 months), only one patient (complete response to
prednisone) was found to have an enteric pathogen. In this patient,
cytomegalovirus colitis was diagnosed 15 months after prednisone was started.
CONCLUSION: Idiopathic colonic inflammation or ulceration in HIV infection (1)
may respond to corticosteroid therapy without life-threatening side effects and
(2) is only rarely followed by the detection of a recognized pathogen. These
observations suggest that enteric pathogens are not missed by standard
techniques.
PMID- 9399762
TI - Differences in risk of Crohn's disease in offspring of mothers and fathers with
inflammatory bowel disease.
AB - OBJECTIVE: To determine whether there are any unusual patterns of transmission of
susceptibility to inflammatory bowel disease (IBD) within multiplex families.
METHODS: Individuals with IBD were recruited for genome-wide screening of
susceptibility genes. The extent of familial aggregation and blood relationships
in multiplex families were determined by questionnaires given to participants
followed up by confirmation of disease diagnosis by participants' physicians.
RESULTS: Of 135 families identified in which both a parent and a child had IBD,
93 involved transmission of susceptibility to disease from mother to child versus
42 examples of transmission from father to child (p = 0.00001, exact two-tailed
binomial test). This distortion in transmission on the basis of the sex of the
parent was observed only among non-Jewish pairs with Crohn's disease (CD), in
which, of 33 parent-child pairs with CD, disease susceptibility was transmitted
from the mother 28 times (p = 0.00007). CONCLUSION: Susceptibility to CD in a
subset of patients may involve a gene that is imprinted.
PMID- 9399763
TI - Increased portal tract infiltration of mast cells and eosinophils in primary
biliary cirrhosis.
AB - OBJECTIVES: Although recent reports demonstrate that eosinophilia is a
distinctive feature of early stage primary biliary cirrhosis (PBC), the
pathogenesis of this eosinophilia remains unknown. Clinical and experimental data
suggest potential mast cell activation in cholestatic liver diseases. Because
mast cell-derived mediators could induce eosinophil chemotaxis and activation, we
hypothesized that mast cell activation may play a role in the pathogenesis of
eosinophilia in PBC. Thus, as the first step in examining a possible link between
mast cell activation and eosinophilia in PBC, we quantified the infiltration of
mast cells and eosinophils in the livers of patients with PBC. METHODS: The study
population consisted of 11 patients with stage I or stage II PBC and 11 patients
with chronic viral hepatitis. Mast cells and eosinophils were identified by
immunohistochemistry using monoclonal antibodies against mast cell tryptase (AA1)
and eosinophilic cationic protein (EG2), respectively. Cell infiltration in the
portal tract was quantitated morphometrically. RESULTS: When compared with
patients with chronic viral hepatitis, patients with PBC showed significantly
increased portal infiltration with mast cells (140 +/- 25 vs 72 +/- 10 cells/mm2
[mean +/- SEM, p < 0.05]) and eosinophils (76 +/- 19 vs 32 +/- 9 cells/mm2 [p <
0.05]). Numbers of portal mast cells correlated with numbers of eosinophils in
patients with PBC (r = 0.60, p < 0.05) but not in patients with chronic hepatitis
(r = 0.34, p = 0.47). CONCLUSION: Concomitant increases in mast cell and
eosinophil infiltration in the portal tract suggest a role for mast cell
activation in the pathogenesis of eosinophilia in PBC.
PMID- 9399764
TI - Octreotide inhibition of flushing and colonic motor dysfunction in carcinoid
syndrome.
AB - OBJECTIVES: Previous studies showed increased plasma motilin and substance P
concentrations and accelerated motor function in the small bowel and colon in
patients with carcinoid diarrhea. Octreotide is beneficial in patients with
carcinoid syndrome. Our hypothesis was that octreotide inhibits accelerated
motility and gut neuropeptides in carcinoid syndrome. METHODS: In 12 patients
with metastatic carcinoid syndrome, we investigated the effect of octreotide 50
microg s.c. t.i.d (n = 6) or placebo (n = 6) on postprandial symptoms, GI
transit, colonic motility, and circulating levels of selected circulating
peptides and amines. RESULTS: Octreotide reduced postprandial flushing (p = 0.03)
but not pain. Octreotide significantly retarded overall colonic transit and
proximal colonic emptying (p < 0.05); it tended to prolong small bowel transit
time (p = 0.13) and to reduce postprandial colonic tone (p = 0.08) compared with
placebo. Octreotide also reduced circulating levels of peptide YY, neurotensin,
vasoactive intestinal polypeptide, and substance P but had no effect on plasma
motilin, neuropeptide Y, calcitonin gene-related peptide, or histamine after meal
ingestion. CONCLUSION: Octreotide ameliorates gut motor dysfunctions that
characterize carcinoid diarrhea; the potential role of specific antagonism of
serotonin, substance P, and vasoactive intestinal polypeptide alone or in
combination with agents that inhibit their release in carcinoid diarrhea deserves
further study.
PMID- 9399765
TI - Clinical and microbiological features of liver abscess after transarterial
embolization for hepatocellular carcinoma.
AB - OBJECTIVES: To present the clinical and microbiological features of liver abscess
after transarterial embolization (TAE) for hepatocellular carcinoma (HCC).
METHODS: We retrospectively reviewed records of 452 TAE procedures in 289
patients with HCC over a 2-yr period. RESULTS: Four men and one woman with a mean
age of 68.4 yr were diagnosed with liver abscess 1-8 wk (mean 4.6 wk) after the
embolization. The incidence was 1.1% (5/452). Common symptoms included fever,
chills, and right upper quadrant pain. Serum aminotransferase, alkaline
phosphatase, and gamma-glutamyltransferase levels and leukocyte count were
frequently elevated. All the abscesses appeared as areas of hypodensity on CT
scan and hypoechogenicity on ultrasonogram. The areas contained gas in the
embolized tumor, which led to the suspicion and finally the diagnosis of abscess.
In contrast to predominance of gram-negative aerobes in sporadic pyogenic liver
abscesses, the causative microorganism was predominantly gram positive (60%). All
patients were treated with parenteral antibiotics plus percutaneous aspiration,
drainage, or operation, but one patient died from the abscess. CONCLUSIONS: For
patients receiving TAE for HCC, few specific clinical or radiological features
could readily differentiate patients complicated with liver abscess from those
without. This may delay a timely diagnosis and lead to significant morbidity.
Hence, in patients with risk factors, including old age, previous biliary tract
disease, large tumor size (>5 cm), and gas forming in the embolized tumor,
aspiration of the suspected focal hepatic lesion should be performed as soon as
possible.
PMID- 9399766
TI - Zinc, copper, and superoxide dismutase in hepatocellular carcinoma.
AB - Superoxide dismutase (Cu/Zn), a metalloenzyme, activity was found to be
significantly lower in the human hepatocellular carcinoma (hepatoma tissue) (0.78
+/- 0.33 U/microg protein) compared with that seen in the surrounding "normal" or
cirrhotic tissue (1.40 +/- 0.48 U/microg; 1.27 +/- 0.64 U/microg). The SOD
activity of "normal" appearing liver cells adjacent to the tumor or cirrhotic
tissue is still lower than that level observed in the normal liver from the
subjects without known liver disease (1.40 +/- 0.48 U/microg vs 2.94 +/- 1.53
U/microg). We have also observed that the trace elements of zinc and copper,
which are essential in expressing the enzyme activity are also significantly
lower in the hepatoma (22.54 +/- 6.73 microg and 2.83 +/- 1.16 microg per gram of
tissue) compared with those in the surrounding "normal" hepatic tissue (Zn2+,
64.36 +/- 9.17 microg/g; Cu2+, 11.43 +/- 4.74 microg/g). The difference in the
zinc content between the "normal" and the cirrhotic tissue is also significant
(64.36 +/- 9.17 microg/g vs 42.37 +/- 10.97 microg/g). However, the copper
content in the cirrhotic tissue is higher but not statistically different from
that level in the "normal" tissue (15.53 +/- 5.90 microg/g vs 11.43 +/- 4.74
microg/g). Furthermore, the plasma zinc level is significantly lower among the
patients who have suffered from hepatoma compared with those subjects without
known liver disease (631.73 +/- 52.43 microg/L vs 845.53 +/- 68.13 microg/L). Our
data suggest that the superoxide dismutase activity is impaired in the hepatoma
tissue. The lower concentration of trace elements (Zn2+ and Cu2+) found in the
hepatoma tissue may contribute to cause the difference in the observed enzymic
activities.
PMID- 9399767
TI - Pancreatic-biliary ascariasis: experience of 300 cases.
AB - BACKGROUND: Infestation with Ascaris lumbricoides is seen worldwide. Recently,
there has been much interest in the pancreatic-biliary complications of Ascaris
infection. In this study, we present our experience of 300 patients seen in a
tertiary referral center. MATERIALS AND METHODS: Case charts of patients seen in
the Department of Gastroenterology, University of Damascus, Syria, were analyzed,
retrospectively, over a 5-yr period (September of 1988 to August of 1993). During
this period, 1666 endoscopic retrograde cholangiopancreatographic studies were
performed and pancreatic-biliary ascariasis was diagnosed in 300 patients (18%).
RESULTS: The most common presenting symptom was abdominal pain, seen in 98% of
patients (294 patients). Complications observed were ascending cholangitis (48
patients; 16%), acute pancreatitis (13 patients; 4.3%), and obstructive jaundice
(4 patients; 1.3%). History of worm emesis was present in 25% of patients (76
patients). Most patients (240 patients; 80%) had previously undergone a
cholecystectomy or an endoscopic sphincterotomy (232 patients; 77%). Worms were
successfully extracted endoscopically in all except two patients, and there were
no procedure-related complications. CONCLUSIONS: In endemic countries, ascariasis
should be suspected in patients with pancreatic-biliary disease, especially if a
cholecystectomy or sphincterotomy has been performed in the past. Endoscopic
management results in rapid resolution of symptoms and prevents development of
complications.
PMID- 9399768
TI - Monoethylglycinexylidide formation measurement as a hepatic function test to
assess severity of chronic liver disease.
AB - OBJECTIVES: Monoethylglycinexylidide (MEGX) is the main lidocaine metabolite and
its formation depends on liver microsomal activity. MEGX formation was studied in
comparison with the histological score of chronic hepatitis and with the clinical
score (Child-Pugh) of cirrhosis. Furthermore, we evaluated its ability to
distinguish between the two liver diseases. METHODS: We studied 284 patients: 130
with chronic hepatitis (on the basis of the histological activity index, 45 had
mild chronic hepatitis, 54 had moderate chronic hepatitis, and 31 had chronic
hepatitis with cirrhosis) and 154 with cirrhosis (49 Child-Pugh's class A, 78
class B, and 27 class C). MEGX formation was evaluated 15, 30, and 60 min after
lidocaine administration. RESULTS: MEGX formation showed a stepwise decline
corresponding to worsened liver disease. MEGX values were related both to the
histological score in chronic hepatitis and to the clinical score in cirrhosis.
Significantly lower values were found in females < 50 yr of age than in males of
the same age. The MEGX test showed great efficacy in discriminating between
chronic hepatitis and cirrhosis compared with standard liver tests. CONCLUSIONS:
Measurement of MEGX formation proved to be a safe test, allowing us to show that
functional subgroups can be identified both in chronic hepatitis and in
cirrhosis. Thus, this test could integrate both the histological grading of
chronic hepatitis and the clinical staging of cirrhosis.
PMID- 9399769
TI - Gallbladder motility and cholecystokinin secretion during continuous enteral
nutrition.
AB - OBJECTIVES: During total parenteral nutrition, gallbladder motility is impaired,
resulting in sludge and stone formation. Little is known about gallbladder
motility during prolonged enteral nutrition. METHODS: We studied gallbladder
motility during continuous enteral nutrition (CEN) in nine hospitalized patients
with active inflammatory bowel disease. The patients received a polymeric diet
(2000 kcal/24 h) by CEN through a nasogastric tube for a prolonged period.
Gallbladder volumes were obtained daily by ultrasonography, starting from day 0
(before CEN) and on 7 consecutive days during CEN. At days 0, 1, 4, and 7, the
gallbladder response to i.v. cholecystokinin (CCK-33; 0.5 Ivy Dog unit/kg/h) was
studied. Plasma CCK levels were determined at regular intervals by
radioimmunoassay. RESULTS: No significant differences were observed on day 0
between patients and a group of nine healthy control subjects in fasting
gallbladder volumes (19.4 +/- 2.3 and 19.6 +/- 2.4 cm3, respectively) and
gallbladder contraction during CCK infusion (56 +/- 14% and 69 +/- 7%,
respectively). During CEN, from day 1 to day 7, mean gallbladder volume remained
significantly (p < 0.05) reduced compared with fasting gallbladder volume, and
mean plasma CCK levels remained significantly (p < 0.05) increased compared with
fasting levels. Although gallbladder volume was significantly reduced during CEN,
the gallbladder contractile response to CCK was not affected; at days 1, 4, and
7, gallbladder contraction was 36-57%. CONCLUSIONS: During CEN, 1) gallbladder
volume is significantly reduced and plasma CCK levels are significantly
increased, 2) these effects are sustained over time (7 days), and 3) the
gallbladder remains responsive to exogenous CCK. These results indicate that
gallbladder contractility and gallbladder responsiveness to CCK are preserved
during prolonged CEN in patients with inflammatory bowel disease.
PMID- 9399770
TI - Acid steatocrit: a simple, rapid gravimetric method to determine steatorrhea.
AB - OBJECTIVES: The detection and evaluation of steatorrhea in a rapid, quantitative
fashion are clinically needed in patients with suspected steatorrhea. Our aim was
to evaluate the acid steatocrit method, on random spot stools in adults with and
without steatorrhea, relative to the qualitative (microscopic) and quantitative
assessments for fecal fat. METHODS: Stool samples were collected 72 h after a
diet of 100 g of fat per day and randomly from 15 healthy controls, 14 patients
with chronic pancreatitis, and seven patients with small bowel disease. All
stools had quantitative, qualitative, and acid steatocrit analyses performed for
fecal fat. RESULTS: The sensitivity and specificity for the detection of
steatorrhea by the spot stool qualitative fecal fat were 78 and 70%,
respectively. The spot stool acid steatocrit correlated linearly with the 72-h
stool quantitative fecal fat (g/24 h), r = 0.761 and p < 0.001. The acid
steatocrit on random spot stools, compared with the 72-h stool quantitative fecal
fat, revealed a sensitivity of 100%, a specificity of 95%, and a positive
predictive value of 90% for the detection of steatorrhea. It also estimated the
quantitative fecal fat. CONCLUSIONS: The acid steatocrit can be performed
accurately on random spot stools and can be used to detect the presence of
steatorrhea and estimate the quantitative fecal fat. This assay can be done with
readily available equipment for rapid evaluation. Use of a spot stool sample
simplifies the acid steatocrit, further improving on the practicality of this
test. This study also confirms the clinical usefulness of this simplified method
to detect steatorrhea.
PMID- 9399771
TI - Inflammatory bowel disease and immune thrombocytopenic purpura: is there a
correlation?
AB - Different hematologic abnormalities are often encountered in patients with
inflammatory bowel disease. Among them anemia, leukocytosis, and thrombocytosis
are commonly seen. Leukopenia and thrombocytopenia are observed mostly as a side
effect of therapy, particularly with use of immunosuppressive drugs. Immune
thrombocytopenic purpura is rarely reported in association with inflammatory
bowel disease. We present two cases with combination of these entities along with
a literature review and treatment options. Immune thrombocytopenic purpura in
these patients presented as an extraintestinal manifestation of inflammatory
bowel disease mediated by a disturbance of the immune system.
PMID- 9399772
TI - Dietl's crisis: a syndrome of episodic abdominal pain of urologic origin that may
present to a gastroenterologist.
AB - A 53-yr-old woman presented with a 2-yr history of recurrent episodes of severe
abdominal pain and nausea. Multiple investigations by a general surgeon, a
urologist, and a gastroenterologist failed to identify the cause. She was
referred to our Biliary Service for ERCP and sphincter of Oddi manometry.
However, a detailed history was inconsistent with biliary pain, and the patient,
having discussed the risks and benefits, elected not to proceed with ERCP. The
patient was asked to come to the hospital during an acute attack of her pain for
assessment. When this was done, transabdominal ultrasound revealed right
hydronephrosis; intravenous urography showed obstruction at the level of the
ureteropelvic junction, consistent with the presence of an aberrant artery. The
syndrome of episodic abdominal pain and hydronephrosis caused by extrinsic
pressure from such an artery is known as Dietl's crisis. In our patient, the
diagnosis was confirmed at surgery, when the ureteric obstruction was dealt with
by pyeloplasty. She made an uneventful recovery and remains asymptomatic 12
months later. The keys to diagnosing Dietl's crisis are awareness of the entity,
taking a detailed pain history, and timely cross-sectional abdominal imaging
during an attack.
PMID- 9399773
TI - Gastric antral vascular ectasia with portal hypertension: treatment with TIPSS.
AB - Gastric antral vascular ectasia, or "watermelon stomach," is a distinct clinical
entity within the spectrum of upper gastrointestinal mucosal vascular
abnormalities. The pathobiology of the disease is unclear. We here describe a
case that emphasizes the importance of the "watermelon stomach" as differential
diagnosis of occult gastrointestinal blood loss and report on its successful
treatment through installation of a transjugular intrahepatic portosystemic stent
shunt (TIPSS).
PMID- 9399774
TI - Management of ingested foreign bodies within the appendix: a case report with
review of the literature.
AB - A case is reported of an elective appendectomy in a patient with known ingestion
of a sharp foreign body. The metal drill bit was ingested unintentionally 3
months before presentation at our institution. Plain abdominal films demonstrated
the foreign body in the right lower abdominal quadrant. Because the gold dental
drill bit was sharp and thought to be lodged in the terminal ileum or cecum, an
attempt was made to remove the object during colonoscopy. This attempt was
unsuccessful because no drill bit could be detected in the colon or terminal
ileum. A laparoscopic exploration was performed, and the foreign body was found
to lie in the appendix, after bowel manipulation under fluoroscopic guidance and
with direct laparoscopic visualization. A laparoscopic assisted appendectomy was
performed. On pathologic examination the drill bit was embedded in the tip of the
appendix with signs of intramucosal acute inflammation. Management and indication
for surgery of foreign bodies in the appendix are discussed, and we review the
related literature. This is the second reported case of a dental drill bit in the
appendix causing appendicitis.
PMID- 9399775
TI - Malignant lymphoma of the transverse colon associated with macroglobulinemia.
AB - We present an unusual case of a malignant lymphoma of the transverse colon
associated with macroglobulinemia. A 73-yr-old man was incidentally discovered to
have high serum gamma-globulin on a regular check-up. Serum immunoquantitation
revealed an IgM level of 3490 mg/dl. Kappa-type Bence-Jones protein was positive
in the urine. Immunoelectrophoresis identified the abnormal protein as IgM-kappa.
After hospitalization an abdominal tumor was detected with barium and CT,
identified as a tumor of the transverse colon. Partial resection of the
transverse colon was carried out. Histopathologically the tumor were confirmed as
small lymphocytic non-Hodgkin lymphoma of B-cell origin, based on the Working
Formulation. According to flowcytometric analysis, the tumor cells were positive
for IgM-kappa. The lymphoma cells produced monoclonal IgM, giving rise to
macroglobulinemia.
PMID- 9399776
TI - Acute pancreatitis after long-term 5-aminosalicylic acid therapy.
AB - Acute pancreatitis is a known, although rare, complication of mesalamine
treatment. This complication typically appears within the first days or weeks
after initiation of therapy. We describe two cases of acute pancreatitis that
occurred after long term mesalamine therapy for ulcerative colitis. A
rechallenge, performed in both patients, confirmed the diagnosis of mesalamine
induced pancreatitis. These case reports provide evidence that 5-aminosalicylic
acid may induce acute pancreatitis after long term treatment.
PMID- 9399777
TI - Synchronous adenomas in a colonic interposition graft and the native colon.
PMID- 9399778
TI - Use of transjugular intrahepatic portosystemic shunt as a bridge to
transplantation in fulminant hepatic failure due to Budd-Chiari syndrome.
AB - We report a case of fulminant hepatic failure in a 55-yr-old man due to Budd
Chiari syndrome in the setting of polycythemia rubra vera. The patient presented
with acute hepatic failure, which rapidly progressed to grade IV hepatic
encephalopathy. Placement of a transjugular intrahepatic portosystemic shunt
resulted in marked improvement of the encephalopathy and stabilized the liver
failure. Subsequently, he underwent successful nonemergent orthotopic liver
transplantation. Transjugular intrahepatic portosystemic shunt placement is a
safe, effective, therapeutic option to bridge patients with fulminant Budd-Chiari
to liver transplantation.
PMID- 9399780
TI - Ulcerative colitis, hyperamylasemia, and asymptomatic pancreatic calcifications:
making the case for pancreatitis as an extra luminal manifestation.
PMID- 9399779
TI - Pneumomediastinum during relapse of ulcerative colitis.
AB - Pneumomediastinum can be caused by gas dissecting along fascial tissue planes
into the mediastinum from remote locations, including the retroperitoneum. One
potential source of retroperitoneal gas is the colon. We present the third
reported case of pneumomediastinum (plus pneumothorax and subcutaneous emphysema)
without free intraperitoneal gas developing during an attack of ulcerative
colitis. Because there was no colonic perforation noted at colectomy, the
extracolonic gas was presumed to originate from a microscopic or partial
thickness perforation of the colon. GI perforation must be considered not only in
patients who have free intraperitoneal gas but also in those who present with
symptoms, signs, or studies consistent with retroperitoneal gas, such as
subcutaneous emphysema, pneumomediastinum, or pneumothorax.
PMID- 9399782
TI - Factor V Leiden mutation presenting as repeated massive GI hemorrhages secondary
to venous thrombosis.
PMID- 9399781
TI - Mirizzi's syndrome with a high CA19-9 level mimicking cholangiocarcinoma.
PMID- 9399783
TI - Thalidomide for AIDS diarrhea?
PMID- 9399784
TI - Cure of Helicobacter pylori: a hidden curse?
PMID- 9399785
TI - Why do we need a newer generation of recombinant vaccines against hepatitis B?
PMID- 9399786
TI - Acid control and regression of Barrett's esophagus: is the glass half full or
half empty?
PMID- 9399787
TI - Oxandrolone use in Crohn's disease.
PMID- 9399788
TI - Placement of a percutaneous gastrostomy tube in patients with an existing
esophageal prosthesis.
PMID- 9399789
TI - Enhanced expression of CA19-9 in mucinous gastric carcinoma.
PMID- 9399790
TI - GenBank.
AB - The GenBank(R) sequence database (http://www.ncbi.nlm.nih.gov/) incorporates DNA
sequences from all available public sources, primarily through the direct
submission of sequence data from individual laboratories and from large-scale
sequencing projects. Most submitters use the BankIt (WWW) or Sequin programs to
send their sequence data. Data exchange with the EMBL Data Library and the DNA
Data Bank of Japan helps ensure comprehensive worldwide coverage. GenBank data is
accessible through NCBI's integrated retrieval system, Entrez , which integrates
data from the major DNA and protein sequence databases along with taxonomy,
genome and protein structure information. MEDLINE(R) abstracts from published
articles describing the sequences are also included as an additional source of
biological annotation. Sequence similarity searching is offered through the BLAST
series of database search programs. In addition to FTP, e-mail and server/client
versions of Entrez and BLAST, NCBI offers a wide range of World Wide Web
retrieval and analysis services of interest to biologists.
PMID- 9399791
TI - The EMBL nucleotide sequence database.
AB - The EMBL Nucleotide Sequence Database (http://www.ebi.ac.uk/embl. html )
constitutes Europe's primary nucleotide sequence resource. DNA and RNA sequences
are directly submitted from researchers and genome sequencing groups and
collected from the scientific literature and patent applications (Fig. 1). In
collaboration with DDBJ and GenBank the database is produced, maintained and
distributed at the European Bioinformatics Institute. Database releases are
produced quarterly and are distributed on CD-ROM. EBI's network services allow
access to the most up-to-date data collection via Internet and World Wide Web
interface, providing database searching and sequence similarity facilities plus
access to a large number of additional databases.
PMID- 9399792
TI - DNA Data Bank of Japan at work on genome sequence data.
AB - We at the DNA Data Bank of Japan (DDBJ) (http://www.ddbj.nig.ac.jp) have recently
begun receiving, processing and releasing EST and genome sequence data submitted
by various Japanese genome projects. The data include those for human,
Arabidopsis thaliana, rice, nematode, Synechocystis sp. and Escherichia coli.
Since the quantity of data is very large, we organized teams to conduct
preliminary discussions with project teams about data submission and handling for
release to the public. We also developed a mass submission tool to cope with a
large quantity of data. In addition, to provide genome data on WWW, we developed
a genome information system using Java. This system
(http://mol.genes.nig.ac.jp/ecoli/) can in theory be used for any genome sequence
data. These activities will facilitate processing of large quantities of EST and
genome data.
PMID- 9399793
TI - The Genome Sequence DataBase (GSDB): improving data quality and data access.
AB - In 1997 the primary focus of the Genome Sequence DataBase (GSDB; www.
ncgr.org/gsdb ) located at the National Center for Genome Resources was to
improve data quality and accessibility. Efforts to increase the quality of data
within the database included two major projects; one to identify and remove all
vector contamination from sequences in the database and one to create premier
sequence sets (including both alignments and discontiguous sequences). Data
accessibility was improved during the course of the last year in several ways.
First, a graphical database sequence viewer was made available to researchers.
Second, an update process was implemented for the web-based query tool, Maestro.
Third, a web-based tool, Excerpt, was developed to retrieve selected regions of
any sequence in the database. And lastly, a GSDB flatfile that contains
annotation unique to GSDB (e.g., sequence analysis and alignment data) was
developed. Additionally, the GSDB web site provides a tool for the detection of
matrix attachment regions (MARs), which can be used to identify regions of high
coding potential. The ultimate goal of this work is to make GSDB a more useful
resource for genomic comparison studies and gene level studies by improving data
quality and by providing data access capabilities that are consistent with the
needs of both types of studies.
PMID- 9399794
TI - The PIR-International Protein Sequence Database.
AB - From its origin the Protein Information Resource (http://www-nbrf.
georgetown.edu/pir/) has supported research on evolution and computational
biology by designing and compiling a comprehensive, quality controlled, and well
organized protein sequence database. The database has been produced and updated
on a regular schedule since 1984. Since 1988 it has been maintained
collaboratively by the PIR-International, an association of data collection
centers engaged in international cooperation for the development of this research
resource during a period of explosive acquisition of new data. As of June 1997,
essentially all sequence entries have been classified into families, allowing the
efficient application of methods to propagate and standardize annotation among
related sequences. The databases are available through the Internet by the World
Wide Web and FTP, or on CD-ROM and magnetic media.
PMID- 9399795
TI - MIPS: a database for protein sequences and complete genomes.
AB - The MIPS group [Munich Information Center for Protein Sequences of the German
National Center for Environment and Health (GSF)] at the Max-Planck-Institute for
Biochemistry, Martinsried near Munich, Germany, is involved in a number of data
collection activities, including a comprehensive database of the yeast genome, a
database reflecting the progress in sequencing the Arabidopsis thaliana genome,
the systematic analysis of other small genomes and the collection of protein
sequence data within the framework of the PIR-International Protein Sequence
Database (described elsewhere in this volume). Through its WWW server
(http://www.mips.biochem.mpg.de ) MIPS provides access to a variety of generic
databases, including a database of protein families as well as automatically
generated data by the systematic application of sequence analysis algorithms. The
yeast genome sequence and its related information was also compiled on CD-ROM to
provide dynamic interactive access to the 16 chromosomes of the first eukaryotic
genome unraveled.
PMID- 9399796
TI - The SWISS-PROT protein sequence data bank and its supplement TrEMBL in 1998.
AB - SWISS-PROT (http://www.expasy.ch/) is a curated protein sequence database which
strives to provide a high level of annotations (such as the description of the
function of a protein, its domains structure, post-translational modifications,
variants, etc.), a minimal level of redundancy and high level of integration with
other databases. Recent developments of the database include: an increase in the
number and scope of model organisms; cross-references to two additional
databases; a variety of new documentation files and improvements to TrEMBL, a
computer annotated supplement to SWISS-PROT. TrEMBL consists of entries in SWISS
PROT-like format derived from the translation of all coding sequences (CDS) in
the EMBL nucleotide sequence database, except the CDS already included in SWISS
PROT.
PMID- 9399797
TI - Compilation of DNA sequences of Escherichia coli K12: description of the
interactive databases ECD and ECDC.
AB - We have compiled the DNA sequence data for Escherichia coli K12 available from
the GenBank and EMBL data libraries and independently from the literature. We
provide the most definitive version of the ECD Escherichia coli database now
exclusively via the World Wide Web System (http://susi.bio.uni
giessen.de/ecdc.html ). Our database encloses the completed genome sequence
recently published by two competing groups and an assembled set of all elder
sequences. The organisation of the database allows precise physical location of
each individual gene or regulatory region, even taking into consideration
discrepancies in nomenclature. The WWW program allows to the user to branch into
the original EMBL and SWISS-PROT datafiles. A number of links to other WWW
servers dealing with E. coli is provided. A FASTA and BLAST search may be
performed online. Besides the WWW format a flat file version may be obtained via
ftp. A number of discrepancies between the two systematic sequence determinations
and/or the literature have not yet been resolved. However, our database may serve
as a reference source for resolution and/or the assignment of strain difference.
PMID- 9399798
TI - EcoCyc: Encyclopedia of Escherichia coli genes and metabolism.
AB - The encyclopedia of Escherichia coli genes and metabolism (EcoCyc) is a database
that combines information about the genome and the intermediary metabolism of
E.coli. The database describes 3030 genes of E.coli , 695 enzymes encoded by a
subset of these genes, 595 metabolic reactions that occur in E.coli, and the
organization of these reactions into 123 metabolic pathways. The EcoCyc graphical
user interface allows scientists to query and explore the EcoCyc database using
visualization tools such as genomic-map browsers and automatic layouts of
metabolic pathways. EcoCyc can be thought of as an electronic review article
because of its copious references to the primary literature, and as a
(qualitative) computational model of E.coli metabolism. EcoCyc is available at
URL http://ecocyc.PangeaSystems.com/ecocyc/
PMID- 9399799
TI - Genes and proteins of Escherichia coli K-12.
AB - GenProtEC is a database of Escherichia coli genes and their gene products,
classified by type of function and physiological role and with citations to the
literature for each. Also present are data on sequence similarities among E.coli
proteins, representing groups of paralogous genes, with PAM values, percent
identity of amino acids, length of alignment and percent aligned. GenProtEC can
be accessed at the URL http://www.mbl.edu/html/ecoli.html
PMID- 9399800
TI - RegulonDB: a database on transcriptional regulation in Escherichia coli.
AB - RegulonDB is a DataBase that integrates biological knowledge of the mechanisms
that regulate the transcription initiation in Escherichia coli , as well as
knowledge on the organization of the genes and regulatory signals into operons in
the chromosome. The operon is the basic structure used in RegulonDB to describe
the elements and properties of transcriptional regulation. The current version
contains information around some 500 regulation mechanisms, essentially for sigma
70 promoters.
PMID- 9399801
TI - The non-redundant Bacillus subtilis (NRSub) database: update 1998.
AB - The non-redundant Bacillus subtilis database (NRSub) has been developed in the
context of the sequencing project devoted to this bacterium. As this project has
reached completion, the whole genome is now available as a single contig. Thanks
to the ACNUC database management system and its associated retrieval system
Query_win, each functional region of the genome can be accessed individually.
Extra annotations have been added such as accession numbers for the genes,
locations on the genetic map, codon adaptation index values, as well as cross
references with other collections. NRSub is distributed through anonymous FTP as
a text file in EMBL format and as an ACNUC database. It is also possible to
access NRSub through two dedicated World Wide Web servers located in France
(http://acnuc. univ-lyon1.fr/nrsub/nrsub.html ) and in Japan
(http://ddbjs4h.genes. nig.ac.jp/ ).
PMID- 9399802
TI - CyanoBase, a www database containing the complete nucleotide sequence of the
genome of Synechocystis sp. strain PCC6803.
AB - CyanoBase (http://www.kazusa.or.jp/cyano/) is a database containing genomic
information on the cyanobacterium Synechocystis sp. strain PCC6803. It furnishes
an annotation to each of the 3168 protein genes deduced from the entire
nucleotide sequence of this genome. Information on the genome can be directly
accessed through three different menus: a clickable physical map of the genome, a
gene classification list, and a keyword search menu, all of which are accessible
from the main page of the database. The entry page for a gene annotation contains
the following information: the location of the gene on the genome, the nucleotide
and deduced amino acid sequence of the gene, the result of a similarity search,
and the classification of the deduced gene product according to its function.
This page has reverse-links to the local physical map and gene classification
list so that relevant genes can be searched in terms of their location on the
genome and their function. In addition, the main page of CyanoBase provides
engines for similarity searches between a query sequence and the entire genome
sequence and for keyword searches, in addition to numerous links to pages
containing related information.
PMID- 9399803
TI - The Yeast Protein Database (YPD): a curated proteome database for Saccharomyces
cerevisiae.
AB - The Yeast Protein Database (YPD) is a curated database for the proteome of
Saccharomyces cerevisiae . It consists of approximately 6000 Yeast Protein
Reports, one for each of the known or predicted yeast proteins. Each Yeast
Protein Report is a one-page presentation of protein properties, annotation lines
that summarize findings from the literature, and references. In the past year,
the number of annotation lines has grown from 25 000 to approximately 35 000, and
the number of articles curated has grown from approximately 3500 to >5000.
Recently, new data types have been included in YPD: protein-protein interactions,
genetic interactions, and regulators of gene expression. Finally, a new layer of
information, the YPD Protein Minireviews, has recently been introduced. The Yeast
Protein Database can be found on the Web at http://www.proteome.com/YPDhome. html
PMID- 9399805
TI - AtDB, the Arabidopsis thaliana database, and graphical-web-display of progress by
the Arabidopsis Genome Initiative.
AB - AtDB, the Arabidopsis thaliana Database, has a primary role to provide public
access to the collected genomic information for A. thaliana via the World Wide
Web (URL: http://genome-www.stanford. edu/ ). AtDB presents interactive physical
and genetics maps that are hyperlinked with detailed information about the clones
and markers placed on these maps. A large literature collection on Arabidopsis ,
contact information on researchers worldwide, laboratory method manuals and other
information useful to plant molecular biologists are also provided. This paper
discusses the database-driven clickable displays that provide easy navigation
within a variety of genomic maps, including those summarizing progress of the
international Arabidopsis genomic sequencing effort, AGI (the Arabidopsis Genome
Initiative). The interface uses client-side hyperlinked GIF-images that direct
the user to detailed database-information. A new BLAST service is also described.
This gives users access to the thousands of Arabidopsis BAC clone end-sequences
and includes hyperlinked images summarizing the search results. The linking of
genetic and physically mapped regions and their sequence into information for
loci within that region is an ongoing goal for this project.
PMID- 9399804
TI - SGD: Saccharomyces Genome Database.
AB - The Saccharomyces Genome Database (SGD) provides Internet access to the complete
Saccharomyces cerevisiae genomic sequence, its genes and their products, the
phenotypes of its mutants, and the literature supporting these data. The amount
of information and the number of features provided by SGD have increased greatly
following the release of the S.cerevisiae genomic sequence, which is currently
the only complete sequence of a eukaryotic genome. SGD aids researchers by
providing not only basic information, but also tools such as sequence similarity
searching that lead to detailed information about features of the genome and
relationships between genes. SGD presents information using a variety of user
friendly, dynamically created graphical displays illustrating physical, genetic
and sequence feature maps. SGD can be accessed via the World Wide Web at
http://genome-www.stanford.edu/Saccharomyces/
PMID- 9399806
TI - FlyBase: a Drosophila database.
AB - FlyBase (http://flybase.bio.indiana.edu/) is a comprehensive database of genetic
and molecular data concerning Drosophila . FlyBase is maintained as a relational
database (in Sybase) and is made available as html documents and flat files. The
scope of FlyBase includes: genes, alleles (with phenotypes), aberrations,
transposons, pointers to sequence data, gene products, maps, clones, stock lists,
Drosophila workers and bibliographic references.
PMID- 9399807
TI - FlyNets and GIF-DB, two internet databases for molecular interactions in
Drosophila melanogaster.
AB - GIF-DB and FlyNets are two WWW databases describing molecular (protein-DNA,
protein-RNA and protein-protein) interactions occuring in the fly Drosophila
melanogaster (http://gifts.univ-mrs.fr/GIFTS_home_page.html ). GIF-DB is a
specialised database which focuses on molecular interactions involved in the
process of embryonic pattern formation, whereas FlyNets is a new and more general
database, the long-term goal of which is to report on any published molecular
interaction occuring in the fly. The information content of both databases is
distributed in specific lines arranged into an EMBL- (or GenBank-) like format.
These databases achieve a high level of integration with other databases such as
FlyBase, EMBL, GenBank and SWISS-PROT through numerous hyperlinks. In addition,
we also describe SOS-DGDB, a new collection of annotated Drosophila gene
sequences, in which binding sites for regulatory proteins are directly visible on
the DNA primary sequence and hyperlinked both to GIF-DB and TRANSFAC database
entries.
PMID- 9399809
TI - Virgil: a database of rich links between GDB and GenBank.
AB - Database interconnection requires the development of links between related
objects from different databases. We built a database of links, called Virgil, to
manage and distribute rich (documented) links between GDB genes and GenBank human
sequences. Virgil contains 18 667 unique links. In addition to a simple Web form
for ad-hoc queries, we propose a generic Web interface and a prototype CORBA
server for link distribution. Materials described in this paper are available
from http://www.infobiogen.fr/services/virgil/home. html
PMID- 9399808
TI - GDB: the Human Genome Database.
AB - The Genome Database (GDB, http://www.gdb.org ) is a public repository of data on
human genes, clones, STSs, polymorphisms and maps. GDB entries are highly cross
linked to each other, to literature citations and to entries in other databases,
including the sequence databases, OMIM, and the Mouse Genome Database. Mapping
data from large genome centers and smaller mapping efforts are added to GDB on an
ongoing basis. The database can be searched by a variety of methods, ranging from
keyword searches to complex queries. Major functionality extensions in the last
year include the ongoing computation of integrated human genome maps, called
Comprehensive Maps, and the use of those maps to support positional queries and
graphic displays. The capabilities of the GDB map viewer (Mapview) have been
extended to include map printing and the graphical display of ad hoc query
results. The HUGO Nomenclature Committee continues to curate the proposed and
official gene symbols and related data in collaboration with GDB. As genome
research shifts its emphasis from mapping to sequencing and functional analysis,
the scope of the GDB schema is being extended. We are in the process of adding
representations of gene function and expression, and improving our representation
of human polymorphism and mutation.
PMID- 9399810
TI - The Radiation Hybrid Database.
AB - Since July 1995, the European Bioinformatics Institute (EBI) has maintained RHdb
(http://www.ebi.ac.uk/RHdb/RHdb.html ), a public database for radiation hybrid
data. Radiation hybrid mapping is an important technique for determining high
resolution maps. Recently, CORBA access has been added to Rhdb. The EBI is an
Outstation of the European Molecular Biology Laboratory (EMBL).
PMID- 9399811
TI - HuGeMap: a distributed and integrated Human Genome Map database.
AB - The HuGeMap database stores the major genetic and physical maps of the human
genome. It is also interconnected with the gene radiation hybrid mapping database
RHdb. HuGeMap is accessible through a Web server for interactive browsing at URL
http://www.infobiogen. fr/services/Hugemap , as well as through a CORBA server
for effective programming. HuGeMap is intended as an attempt to build open,
interconnected databases, that is databases that distribute their objects
worldwide in compliance with a recognized standard of distribution. Maps can be
displayed and compared with a java applet
(http://babbage.infobiogen.fr:15000/Mappet/Show. html ) that queries the HuGeMap
ORB server as well as the RHdb ORB server at the EBI.
PMID- 9399812
TI - IXDB, an X chromosome integrated database.
AB - The integrated X chromosome database (IXDB) is a repository for physical mapping
data of the human X chromosome. Its current content is the result of a strict
integration of data stemming from many different sources. The main features of
IXDB include a flexible and extendible schema, a comfortable and fully cross
referenced WWW interface (http://ixdb.mpimg-berlin-dahlem.mpg.de ) and a
graphical map viewer implemented in JAVA. The database stores objects used in
physical mapping as well as the maps resulting from this work, but a strong
emphasis is placed on recording experiments that connect objects together. This
should greatly contribute to fulfilling one of the major goals of the database:
to support the construction of an integrated physical, genetic, transcript and
sequence map of the human X chromosome.
PMID- 9399813
TI - MITOMAP: a human mitochondrial genome database--1998 update.
AB - We have continued to develop MITOMAP (http://www.gen.emory. edu/MITOMAP ), a
comprehensive database for the human mitochondrial DNA (mtDNA). MITOMAP uses the
mtDNA sequence as the unifying element for bringing together information on
mitochondrial genome structure and function, pathogenic mutations and their
clinical characteristics, population associated variation, and gene-gene
interactions. Over the past year we have increased the degree of interlinking of
MITOMAP information available on the web page, by using our generalized
information management system, GENOME. As increasingly larger regions of the
human genome are sequenced and characterized, the need for integrating such
information is growing. Consequently, MITOMAP and GENOME provide a valuable
reference for the mitochondrial biologist, in addition to being a model for the
development of comprehensive, information storage and retrieval systems for other
components of the human genome. This paper documents the changes to MITOMAP which
have been implemented over the past year.
PMID- 9399814
TI - The mitBASE human dataset structure.
AB - MitBASE is a comprehensive and integrated mitochondrial genome database funded
within the EU BIOTECH PROGRAM. It is a project for the development and
implementation of an integrated and comprehensive database of mitochondrial data
which will collect all available information from different organisms and from
intraspecies variants and mutants. The present paper describes the structure of
the Human dataset in mitBASE where human molecular data are distinguished from
clinical and pathological data. MitBASE home page address is:
http://www.ebi.ac.uk/htbin/Mitbase/mitb ase.pl
PMID- 9399815
TI - Update of MmtDB: a Metazoa mitochondrial DNA variants database.
AB - The present paper describes the improvements in MmtDB, a specialised database
designed to collect Metazoa mitochondrial DNA variants. Priority in the data
collection has been given to Metazoa for which a large amount of variants is
available, e.g., for humans. Starting from the sequences available in the
Nucleotide Sequence Databases, the redundant sequences have been removed and new
sequences from other sources have been added. Value-added information is
associated to each variant sequence, e.g., analysed region, experimental method,
tissue and cell lines, population data, sex, age, family code and information
about the variation events (nucleotide position, involved gene, restriction site
gain or loss). Cross-references are introduced to the EMBL Data Library, as well
as an internal cross-referencing among MmtDB entries according to tissual,
heteroplasmic, familiar and aplotypical correlation. Furthermore MmtDB has a new
section, AMmtDB: Aligned Metazoan mitochondrial biosequences. MmtDB can be
accessed through the World Wide Web at URL http://WWW.ba.cnr.it/[symbol: see
text]areamt08/MmtDBWWW.htm
PMID- 9399817
TI - The Mouse Genome Database (MGD): a community resource. Status and enhancements.
The Mouse Genome Informatics Group.
AB - The Mouse Genome Database (MGD) is a comprehensive community database that
integrates genetic, genomic and phenotypic information about the laboratory
mouse. MGD provides detailed information about genes and genetic markers,
elemental data from mapping experiments, descriptions of molecular segments
including ESTs, probes, and cDNA clones, homology information between mouse and
many other mammalian genomes, and phenotypic descriptions of gene mutations, gene
function and mouse strains. All data are supported by citations. Interactive
graphical displays of cytogenetic, genetic and physical maps are available. User
support is provided through dedicated staff, bulletin boards, and user
documentation. MGD can be accessed at http://www.informatics.jax.org
PMID- 9399816
TI - Compilation of human mtDNA control region sequences.
AB - This paper describes the organisation of a database for human mitochondrial
control-region sequences. The data are divided into three ASCII files that
contain aligned sequences from the hypervariable region I (HVRI), from the
hypervariable region II (HVRII), and the available information about the
individuals, from whom the sequences stem. The current collection comprises 4079
HVRI and 969 HVRII sequences. From 728 individuals sequences of both HVRI and
HVRII are available. For easy access, the collection is made available to the
scientific community via World Wide Web at URL http://www.zi.biologie.uni
muenchen.de/[symbol: see text]meyers/mtdna.html
PMID- 9399818
TI - The Organelle Genome Database Project (GOBASE).
AB - The taxonomically broad organelle genome database (GOBASE) organizes and
integrates diverse data related to organelles (mitochondria and chloroplasts).
The current version of GOBASE focuses on the mitochondrial subset of data and
contains molecular sequences, RNA secondary structures and genetic maps, as well
as taxonomic information for all eukaryotic species represented. The database has
been designed so that complex biological queries, especially ones posed in a
comparative genomics context, are supported. GOBASE has been implemented as a
relational database with a web-based user interface
(http://megasun.bch.umontreal.ca/gobase/gobas e.html ). Custom software tools
have been written in house to assist in the population of the database, data
validation, nomenclature standardization and front-end design. The database is
fully operational and publicly accessible via the World Wide Web, allowing
interactive browsing, sophisticated searching and easy downloading of data.
PMID- 9399819
TI - Molecular Probe Data Base (MPDB).
AB - In this paper, the current status of the Molecular Probe Data Base
(http://www.biotech.ist.unige.it/interlab/ mpdb.html ) is briefly presented
together with a short analysis of its activity during 1997. This has been
performed by statistically evaluating the 'logs' of the Internet servers that are
used for its distribution with reference to the geographical origin of the
requests, the words that were utilized to carry out of the searches and the
oligonucleotides that were retrieved. Planned enhancements of this database are
also described. They include a revision of its data structure and, even more
relevant, of its data management procedures.
PMID- 9399820
TI - Compilation of tRNA sequences and sequences of tRNA genes.
AB - Sequences of 3279 sequences of tRNA genes and tRNAs published up to December 1996
are included in the compilation. Alignment of the sequences, which is most
compatible with the tRNA phylogeny and known three-dimensional structures of
tRNA, is used. Sequences and references are available under http://www.uni
bayreuth. de/departments/biochemie/trna/
PMID- 9399821
TI - A FastA based compilation of higher plant mitochondrial tRNA genes.
AB - A new version of the compilation of higher plant mitochondrial tRNA genes
(http://www.ebi.ac.uk/service ) has been obtained by means of the FastA program
for similarity searching in nucleotide sequence Databases. This approach improves
the previous collection, which was based on literature data analysis. The current
compilation contains 158 sequences with an increase of 43 units. In this paper,
some interesting features of the new entries are briefly presented.
PMID- 9399822
TI - 5S rRNA Data Bank.
AB - In this paper we present the updated version of the compilation of 5S rRNA and 5S
rDNA nucleotide sequences. It contains 1622 primary structures of 5S rRNAs and 5S
rRNA genes from 888 species. These include 58 archaeal, 427 eubacterial, 34
plastid, nine mitochondrial and 1094 eukaryotic DNA or RNA nucleotide sequences.
The sequence entries are divided according to the taxonomic position of the
organisms. All individual sequences deposited in the 5S rRNA Database can be
retrieved using the WWW-based, taxonomic browser at
http://rose.man.poznan.pl/5SData/5SRNA.html++ + or http://www.chemie. fu
berlin.de/fb_chemie/agerdmann/5S_rRNA.html . The files with complete sets of data
as well as sequence alignments are available via anonymous ftp.
PMID- 9399823
TI - Small RNA database.
AB - The small RNA database is a compilation of all the small size RNA sequences
available to date, including nuclear, nucleolar, cytoplasmic and mitochondria
small RNAs from eukaryotic organisms and small RNAs from prokaryotic cells as
well as viruses. Currently, approximately 600 small RNA sequences are in our
database. It also gives the sources of individual RNAs and their GenBank
accession numbers. The small RNA database can be accessed through the WWW (World
Wide Web). Our WWW URL address is: http://mbcr.bcm.tmc.
edu/smallRNA/smallrna.html . The new small RNA sequences published since our last
compilation are listed in this paper (Table 1).
PMID- 9399825
TI - The tmRNA database (tmRDB).
AB - This first release of the tmRNA database (tmRDB) contains 19 tmRNA sequences, a
tmRNA sequence alignment with emphasis of base pairs that are supported by
comparative sequence analysis, and a tabulation of tmRNA-encoded tag peptides.
The tmRNADB also offers an RNA secondary structure diagram of the Escherichia
coli tmRNA, as well as PDB-formatted coordinates for three-dimensional modeling.
The data are available on the World Wide Web at http://www.uthct.
edu/tmRDB/tmRDB.html
PMID- 9399824
TI - The tmRNA Website.
AB - tmRNA (also known as 10Sa RNA) is so-named for its dual tRNA-like and mRNA-like
nature. It is employed in a remarkable trans -translation process to add a C
terminal peptide tag to the incomplete protein product of a broken mRNA; the tag
targets the abnormal protein for proteolysis. tmRNA sequences have been
identified in genomes of diverse bacterial phyla, including the most deeply
branching. They have also been identified in plastids of the 'red' lineage. The
tmRNA Website (http://www.wi.mit. edu/bartel/tmRNA/home ) contains a database
currently including sequences from 37 species, with provisional alignments, as
well as the tentatively predicted proteolysis tag sequences. A brief review and
guide to the literature is also provided.
PMID- 9399826
TI - The guide RNA database.
AB - Guide RNAs (gRNAs) are small, metabolically stable RNA molecules which perform a
pivotal, template-like function during the RNA editing process in kinetoplastid
protozoa. The gRNA database currently contains 250 guide RNA sequences as well as
secondary and tertiary structure models and other relevant information. The
database is made available as a hypertext document accessible via the World Wide
Web (WWW) at the URL: http://www.biochem.mpg.de/ goeringe/
PMID- 9399827
TI - U-insertion/deletion Edited Sequence Database.
AB - Uridine insertion/deletion RNA editing is a post-transcriptional RNA modification
occurring in the mitochondria of kinetoplastid protozoa. The U-insertion/deletion
Edited Sequence Database is a compilation of mitochondrial genes and edited mRNAs
from five kinetoplastid species. It contains separate files with the DNA, mRNA
(both unedited and edited) and predicted protein sequences, as well as alignments
of the Leishmania tarentolae and Trypanosoma brucei protein sequences from edited
and unedited genes. The sequence files are in GCG format. A 'map' sequence file
showing the location of U-deletions, U-insertions and the translated amino acid
sequences is also provided for each gene. Genomic maps for each species are also
provided with clickable genes, including maxicircle-encoded gRNAs. Sets of
aligned nuclear rRNA sequences from kinetoplastid protozoa are also provided,
which were used for phylogenetic reconstructions in an analysis of the origin of
RNA editing. The database is available through the World Wide Web as an HTML
document at the URLhttp://www.lifesci.ucla.edu/RNA/trypanosome/ database.html
PMID- 9399828
TI - The Signal Recognition Particle Database (SRPDB).
AB - This release of the SRPDB (signal recognition particle database,
http://pegasus.uthct.edu/SRPDB/SRPDB . html ) adds four SRP RNA sequences (a
total of 99 SRP RNA sequences), 23 SRP protein sequences (a total of 63 protein
sequences from SRP9, SRP14, SRP19, SRP21, SRP54, SRP68 or SRP72), and, for the
first time, sequences of the alpha subunit of the eukaryotic SRP receptor and its
homologous bacterial proteins (a total of 21 sequences). Sequences are offered
phylogenetically ordered, annotated with links to the primary databases, and in
aligned form. Also downloadable are sample SRP RNA secondary structure diagrams,
three-dimensional models of representative SRP RNAs, and search motifs.
PMID- 9399829
TI - Database on the structure of small ribosomal subunit RNA.
AB - About 8600 complete or nearly complete sequences are now available from the
Antwerp database on small ribosomal subunit RNA. All these sequences are aligned
with one another on the basis of the adopted secondary structure model, which is
corroborated by the observation of compensating substitutions in the alignment.
Literature references, accession numbers and detailed taxonomic information are
also compiled. The database can be consulted via the World Wide Web at URL
http://rrna.uia.ac.be/ssu/
PMID- 9399830
TI - Database on the structure of large ribosomal subunit RNA.
AB - The rRNA WWW Server at URL http://rrna.uia.ac.be/ now provides a database of 496
large subunit ribosomal RNA sequences. All these sequences are aligned,
incorporate secondary structure information, and can be obtained in a number of
formats. Other information about the sequences, such as literature references,
accession numbers and taxonomic information is also available and searchable. If
necessary, the data on the server can also be obtained by anonymous ftp.
PMID- 9399831
TI - The Database of Ribosomal Cross links (DRC).
AB - The Database of Ribosomal Cross-links (DRC) provides a complete collection of all
the published data produced by cross-linking studies on the Escherichia coli
ribosome, as well as on its components and functional ligands. The DRC currently
includes data on 986 cross-links from >100 research papers, yielded by >40
different reagents. For each cross-link, information is given concerning its
location in the ribosome, the chemical or photochemical reagent applied, a brief
description of the method(s) used to locate the cross-link, and the literature
reference. The DRC is freely available via the World Wide Web at:
http://Ribosome.Genebee.MSU.SU/DRC/ or at http://WWW:MPIMG-Berlin
Dahlem.MPG.DE/[symbol: see text]baranov/DRC/
PMID- 9399832
TI - The viroid and viroid-like RNA database.
AB - The viroid and viroid-like RNA database is a compilation of all natural sequences
published in journals or available from the GenBank and EMBL nucleotide sequence
libraries. Several information regarding these RNA species such as the position
of their self-catalytic domains and the open reading frame of the human
hepatitits delta virus are provided. The database also includes a determination
of the likely ancestral sequence of most species and a prediction of the most
stable secondary structures of these sequences. This online database is available
on the World Wide Web (http://www.callisto.si.usherb.ca/[symbol: see text]jpperra
). It should provide an excellent reference point for further phylogenetic and
structure-function studies of these RNA species.
PMID- 9399833
TI - UTRdb: a specialized database of 5'- and 3'-untranslated regions of eukaryotic
mRNAs.
AB - The important role the untranslated regions of eukaryotic mRNAs may play in gene
regulation and expression is now widely acknowledged. For this reason we
developed UTRdb, a specialized database of 5'- and 3'-untranslated sequences of
eukaryotic mRNAs cleaned from redundancy. UTRdb entries are enriched with
specialized information not present in the primary databases, including the
presence of functional patterns already demonstrated by experimental analysis to
have some functional role. A collection of such patterns is being collected in
UTRsite database (http://bio-www.ba.cnr.it:8000/srs5/) which can also be used
with appropriate computational tools to detect known functional patterns
contained in mRNA untranslated regions.
PMID- 9399834
TI - The RNA modification database--1998.
AB - The RNA modification database provides a comprehensive listing of
posttranscriptionally modified nucleosides from RNA, and is maintained as an
updated version of the initial printed report [Limbach,P.A., Crain,P.F. and
McCloskey,J.A. (1994) Nucleic Acids Res. , 22, 2183-2196]. Information provided
for each nucleoside includes: the type of RNA in which it occurs and phylogenetic
distribution; common chemical name and symbol; Chemical Abstracts registry number
and index name; chemical structure; initial literature citations for structural
characterization or occurrence, and for chemical synthesis. The data are
available through the World Wide Web at: http://www
medlib.med.utah/RNAmods/RNAmods .html
PMID- 9399835
TI - Databases and software for the analysis of mutations in the human p53 gene, human
hprt gene and both the lacI and lacZ gene in transgenic rodents.
AB - We have created databases and software applications for the analysis of DNA
mutations at the human p53 gene, the human hprt gene and both the rodent
transgenic lacI and lacZ loci. The databases themselves are stand-alone dBASE
files and the software for analysis of the databases runs on IBM-compatible
computers with Microsoft Windows. Each database has a separate software analysis
program. The software created for these databases permit the filtering, ordering,
report generation and display of information in the database. In addition, a
significant number of routines have been developed for the analysis of single
base substitutions. One method of obtaining the databases and software is via the
World Wide Web. Open the following home page with a Web Browser:
http://sunsite.unc.edu/dnam/mainpage. html . Alternatively, the databases and
programs are available via public FTP from: anonymous@sunsite.unc.edu. There is
no password required to enter the system. The databases and software are found
beneath the subdirectory: pub/academic/biology/dna-mutations. Two other programs
are available at the site, a program for comparison of mutational spectra and a
program for entry of mutational data into a relational database.
PMID- 9399836
TI - p53 gene mutation: software and database.
AB - A large number of different mutations in the p53 tumor suppressor gene have been
identified in all types of cancer. As of October, 1997, this database (http://
perso.curie.fr/tsoussi ) contained >7500 mutations. Such a substantial increase
since our previous reports should enable epidemiological analyses which were not
previously possible. In order to analyse these new data, the UMD software has
been improved. A new Web version of the UMD software enables online analysis of
the database. The present report describes various improvements since the last
release of the database.
PMID- 9399837
TI - IARC Database of p53 gene mutations in human tumors and cell lines: updated
compilation, revised formats and new visualisation tools.
AB - Since 1989, about 570 different p53 mutations have been identified in more than
8000 human cancers. A database of these mutations was initiated by M. Hollstein
and C. C. Harris in 1990. This database originally consisted of a list of somatic
point mutations in the p 53 gene of human tumors and cell lines, compiled from
the published literature and made available in a standard electronic form. The
database is maintained at the International Agency for Research on Cancer (IARC)
and updated versions are released twice a year (January and July). The current
version (July 1997) contains records on 6800 published mutations and will surpass
the 8000 mark in the January 1998 release. The database now contains information
on somatic and germline mutations in a new format to facilitate data retrieval.
In addition, new tools are constructed to improve data analysis, such as a
Mutation Viewer Java applet developed at the European Bioinformatics Institute
(EBI) to visualise the location and impact of mutations on p53 protein structure.
The database is available in different electronic formats at IARC
(http://www.iarc. fr/p53/homepage.htm ) or from the EBI server
(http://www.ebi.ac.uk ). The IARC p53 website also provides reports on database
analysis and links with other p53 sites as well as with related databases. In
this report, we describe the criteria for inclusion of data, the revised format
and the new visualisation tools. We also briefly discuss the relevance of p 53
mutations to clinical and biological questions.
PMID- 9399838
TI - A database of germline p53 mutations in cancer-prone families.
AB - We created a comprehensive database covering all published cases of germline p53
mutations. The current version lists 580 tumours in 448 individuals belonging to
122 independent pedigrees. The database describes each p53 mutation (type of the
mutation, exon and codon affected by the mutation, nucleotide and amino acid
change), each family (family history of cancer, diagnosis of Li-Fraumeni
syndrome), each affected individual (sex, generation, p53 status, from which
parent the mutation was inherited) and each tumour (type, age of onset, p53
status-loss of heterozygosity, immunostaining). Each entry contains the original
reference(s). The database is freely available and can be obtained from
http://www.lf2.cuni.cz
PMID- 9399839
TI - The factor VIII Structure and Mutation Resource Site: HAMSTeRS version 4.
AB - Since 1996 the HAMSTeRS (Haemophilia A Mutation, Search, Test and Resource Site)
WWW site has provided an online resource for access to data on the molecular
pathology of haemophilia A, replacing previous text editions of the Haemophilia A
Database published in Nucleic Acids Research . This report describes the
continued development of the site (version 4), and in particular the expansion of
factor VIII (FVIII) structure-related features. Access to the mutation database
itself, both for searching the listings and for submission of new mutations, is
via custom-designed forms: more powerful Boolean searches of the point mutations
in the database are also available. During 1997 a total of 22 novel missense
mutations were reported, increasing the total number of unique variants now
described to 252 (238 in exonic sequences and 14 at intronic splice junctions).
Currently, a total of 586 individual reports with associated phenotypic data are
available for searching by any category including phenotype. The FVIII structure
section now includes a download of a FVIII A domain homology model in Protein
Data Bank format and a multiple alignment of the FVIII amino-acid sequencies from
four species (human, murine, porcine and canine) in addition to the virtual
reality simulations, secondary structural data and FVIII animation already
available. Finally, to aid navigation across this site, a clickable roadmap of
the main features provides easy access to the page desired. Our intention is that
continued development and updating of the site shall provide workers in the
fields of molecular and structural biology with a one-stop resource site to
facilitate FVIII research and education. The HAMSTeRS URL is
http://europium.mrc.rpms.ac.uk
PMID- 9399840
TI - PAH Mutation Analysis Consortium Database: 1997. Prototype for relational locus
specific mutation databases.
AB - PAHdb (http://www.mcgill.ca/pahdb ) is a curated relational database (Fig. 1) of
nucleotide variation in the human PAH cDNA (GenBank U49897). Among 328 different
mutations by state (Fig. 2) the majority are rare mutations causing
hyperphenylalaninemia (HPA) (OMIM 261600), the remainder are polymorphic variants
without apparent effect on phenotype. PAHdb modules contain mutations,
polymorphic haplotypes, genotype-phenotype correlations, expression analysis,
sources of information and the reference sequence; the database also contains
pages of clinical information and data on three ENU mouse orthologues of human
HPA. Only six different mutations account for 60% of human HPA chromosomes
worldwide, mutations stratify by population and geographic region, and the
Oriental and Caucasian mutation sets are different (Fig. 3). PAHdb provides
curated electronic publication and one third of its incoming reports are direct
submissions. Each different mutation receives a systematic (nucleotide) name and
a unique identifier (UID). Data are accessed both by a Newsletter and a search
engine on the website; integrity of the database is ensured by keeping the
curated template offline. There have been >6500 online interrogations of the
website.
PMID- 9399841
TI - aCHEdb: the database system for ESTHER, the alpha/beta fold family of proteins
and the Cholinesterase gene server.
AB - Acetylcholinesterase belongs to a family of proteins, the alpha/beta hydrolase
fold family, whose constituents evolutionarily diverged from a common ancestor
and share a similar structure of a central beta sheet surrounded by alpha
helices. These proteins fulfil a wide range of physiological functions
(hydrolases, adhesion molecules, hormone precursors) [Krejci,E., Duval,N.,
Chatonnet,A., Vincens,P. and Massoulie,J. (1991) Proc. Natl. Acad. Sci. USA , 88,
6647-6651]. ESTHER (for esterases, alpha/beta hydrolase enzymes and relatives) is
a database aimed at collecting in one information system, sequence data together
with biological annotations and experimental biochemical results related to the
structure-function analysis of the enzymes of the family. The major upgrade of
the database comes from the use of a new database management system: aCHEdb which
uses the ACeDB program designed by Richard Durbin and Jean Thierry-Mieg. It can
be found at http://www.ensam.inra.fr/cholinesterase
PMID- 9399842
TI - Marfan Database (third edition): new mutations and new routines for the software.
AB - The Marfan database is a software that contains routines for the analysis of
mutations identified in the FBN1 gene that encodes fibrillin-1. Mutations in this
gene are associated not only with Marfan syndrome but also with a spectrum of
overlapping disorders. The third version of the Marfan database contains 137
entries. The software has been modified to accommodate four new routines and is
now accessible on the World Wide Web at http://www.umd.necker.fr
PMID- 9399843
TI - The Androgen Receptor Gene Mutations Database.
AB - The current version of the androgen receptor (AR) gene mutations database is
described. The total number of reported mutations has risen from 272 to 309 in
the past year. We have expanded the database: (i) by giving each entry an
accession number; (ii) by adding information on the length of polymorphic
polyglutamine (polyGln) and polyglycine (polyGly) tracts in exon 1; (iii) by
adding information on large gene deletions; (iv) by providing a direct link with
a completely searchable database (courtesy EMBL-European Bioinformatics
Institute). The addition of the exon 1 polymorphisms is discussed in light of
their possible relevance as markers for predisposition to prostate or breast
cancer. The database is also available on the internet (http://www.mcgill.
ca/androgendb/ ), from EMBL-European Bioinformatics Institute (ftp.
ebi.ac.uk/pub/databases/androgen ), or as a Macintosh FilemakerPro or Word file
(MC33@musica.mcgill.ca).
PMID- 9399844
TI - BTKbase, mutation database for X-linked agammaglobulinemia (XLA).
AB - X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in
the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database
(BTKbase) of BTK mutations has been compiled and the recent update lists 463
mutation entries from 406 unrelated families showing 303 unique molecular events.
In addition to mutations, the database also lists variants or polymorphisms. Each
patient is given a unique patient identity number (PIN). Information is included
regarding the phenotype including symptoms. Mutations in all the five domains of
BTK have been noticed to cause the disease, the most common event being missense
mutations. The mutations appear almost uniformly throughout the molecule and
frequently affect CpG sites that code for arginine residues. The putative
structural implications of all the missense mutations are given in the database.
The improved version of the registry having a number of new features is available
at http://www. helsinki.fi/science/signal/btkbase.html
PMID- 9399845
TI - LDLR Database (second edition): new additions to the database and the software,
and results of the first molecular analysis.
AB - Mutations in the LDL receptor gene (LDLR) cause familial hypercholesterolemia
(FH), a common autosomal dominant disorder. The LDLR database is a computerized
tool that has been developed to provide tools to analyse the numerous mutations
that have been identified in the LDLR gene. The second version of the LDLR
database contains 140 new entries and the software has been modified to
accommodate four new routines. The analysis of the updated data (350 mutations)
gives the following informations: (i) 63% of the mutations are missense, and only
20% occur in CpG dinucleotides; (ii) although the mutations are widely
distributed throughout the gene, there is an excess of mutations in exons 4 and
9, and a deficit in exons 13 and 15; (iii) the analysis of the distribution of
mutations located within the ligand-binding domain shows that 74% of the
mutations in this domain affect a conserved amino-acid, and that they are mostly
confined in the C-terminal region of the repeats. Conversely, the same analysis
in the EGF-like domain shows that 64% of the mutations in this domain affect a
non-conserved amino-acid, and, that they are mostly confined in the N-terminal
half of the repeats. The database is now accessible on the World Wide Web at
http://www.umd.necker.fr
PMID- 9399846
TI - The Human Collagen Mutation Database 1998.
AB - The collagens are a large and diverse family of proteins which are found in the
extracellular matrix. In common with one another, the 19 known collagen types
have triple-helical domains of variable length but they differ with respect to
their overall size and the nature and location of their globular domains.
Collagen mutations lead to heritable defects of connective tissues and mutation
data for collagen types I and III are presented here. The mutation data are
accessible on the world wide web at http://www.le.ac.uk/genetics/collagen/
PMID- 9399847
TI - Software and database for the analysis of mutations in the VHL gene.
AB - VHL is a tumor suppressor gene localized on chromosome 3p25-26. Mutations of the
VHL gene were described at first in the heritable von Hippel-Lindau disease and
in the sporadic Renal Cell Carcinoma (RCC). More recently, VHL has also been
shown to harbor mutations in mesothelioma and small cell lung carcinoma. To date
more than 500 mutations have been identified. These mutations are mainly private
with only one hot spot at codon 167 associated with pheochromocytoma. The
germline mutations are essentially missense while somatic mutations include
deletions, insertions and nonsense. To standardize the collection of these
informations, facilitate the mutational analysis of the VHL gene and promote the
genotype-phenotype analysis, a software package along with a computerized
database have been created. The current database and the analysis software are
accessible via the internet and world wide web interface at the
URL:http://www.umd.necker.fr
PMID- 9399848
TI - The Human PAX6 Mutation Database.
AB - The Human PAX6 Mutation Database contains details of 94 mutations of the PAX6
gene. A Microsoft Access program is used by the Curator to store, update and
search the database entries. Mutations can be entered directly by the Curator, or
imported from submissions made via the World Wide Web. The PAX6 Mutation Database
web page at URL http://www.hgu.mrc.ac.uk/Softdata/PAX6/ provides information
about PAX6, as well as a fill-in form through which new mutations can be
submitted to the Curator. A search facility allows remote users to query the
database. A plain text format file of the data can be downloaded via the World
Wide Web. The Curation program contains prior knowledge of the genetic code and
of the PAX6 gene including cDNA sequence, location of intron/exon boundaries, and
protein domains, so that the minimum of information need be provided by the
submitter or Curator.
PMID- 9399849
TI - Haemophilia B: database of point mutations and short additions and deletions-
eighth edition.
AB - The eighth edition of the haemophilia B database (http://www.umds.ac.
uk/molgen/haemBdatabase.htm ) lists in an easily accessible form all known factor
IX mutations due to small changes (base substitutions and short additions and/or
deletions of <30 bp) identified in haemophilia B patients. The 1713 patient
entries are ordered by the nucleotide number of their mutation. Where known,
details are given on: factor IX activity, factor IX antigen in circulation,
presence of inhibitor and origin of mutation. References to published mutations
are given and the laboratories generating the data are indicated.
PMID- 9399850
TI - APC gene: database of germline and somatic mutations in human tumors and cell
lines.
AB - A database (http://perso.curie.fr/tsoussi ) is described, in which over 1000
mutations in the human APC gene of tumors (colon cancer predominantly) are
compiled from the literature. It includes both molecular information about the
mutations and clinical data about the patients. Software has been designed to
analyse all this information in the database.
PMID- 9399851
TI - Software and database for the analysis of mutations in the human WT1 gene.
AB - The WT1 gene, located at 11p13, encodes a zinc finger transcription factor
involved in renal and gonadal development and in Wilms' tumor. Constitutional
mutations of this gene have been described in most patients with Denys Drash
syndrome (mesangial sclerosis associated with male pseudohermaphrodism and/or
Wilms' tumor), but also in patients with genitourinary abnormalities and Wilms'
tumor (WT) or presenting with only unilateral or bilateral WT. Moreover,
approximately 10% of Wilms' tumors carry WT1 mutations at the somatic level. To
facilitate the genotype-phenotype correlation analyses, we have created a
software package along with a computerized database of germline (70 entries) and
somatic (28 entries) mutations reported in the literature.
PMID- 9399852
TI - GPCRDB: an information system for G protein-coupled receptors.
AB - The GPCRDB is a G protein-coupled receptor (GPCR) database system aimed at the
collection and dissemination of GPCR related data. It holds sequences, mutant
data and ligand binding constants as primary (experimental) data. Computationally
derived data such as multiple sequence alignments, three dimensional models,
phylogenetic trees and two dimensional visualization tools are added to enhance
the database's usefulness. The GPCRDB is an EU sponsored project aimed at
building a generic molecular class specific database capable of dealing with
highly heterogeneous data. GPCRs were chosen as test molecules because of their
enormous importance for medical sciences and due to the availability of so much
highly heterogeneous data. The GPCRDB is available via the WWW at
http://www.gpcr.org/7tm
PMID- 9399853
TI - Expanded versions of the 16S and 23S ribosomal RNA mutation databases (16SMDBexp
and 23SMDBexp)
AB - Expanded versions of the Ribosomal RNA Mutation Databases provide lists of
mutated positions in 16S and 16S-like ribosomal RNA (16SMDBexp) and 23S and 23S
like ribosomal RNA (23SMDBexp) and the identity of each alteration. Alterations
from organisms other than Escherichia coli are reported at positions according to
the E.coli numbering system. Information provided for each mutation includes: (i)
a brief description of the phenotype(s) associated with each mutation, (ii)
whether a mutant phenotype has been detected by in vivo or in vitro methods, and
(iii) relevant literature citations. The databases are available via ftp and on
the World Wide Web at the following URL: http:
//www.fandm.edu/Departments/Biology/Databases/RNA.h tml
PMID- 9399854
TI - The human gene mutation database.
AB - The Human Gene Mutation Database (HGMD) represents a comprehensive core
collection of data on published germline mutations in nuclear genes underlying
human inherited disease. By September 1997, the database contained nearly 12 000
different lesions in a total of 636 different genes, with new entries currently
accumulating at a rate of over 2000 per annum. Although originally established
for the scientific study of mutational mechanisms in human genes, HGMD has
acquired a much broader utility to researchers, physicians and genetic
counsellors so that it was made publicly available at
http://uwcm.ac.uk/uwcm/mg/hgmd0.html in April 1996. Mutation data in HGMD are
accessible on the basis of every gene being allocated one web page per mutation
type, if data of that type are present. Meaningful integration with phenotypic,
structural and mapping information has been accomplished through bi-directional
links between HGMD and both the Genome Database (GDB) and Online Mendelian
Inheritance in Man (OMIM), Baltimore, USA. Hypertext links have also been
established to Medline abstracts through Entrez , and to a collection of 458
reference cDNA sequences also used for data checking. Being both comprehensive
and fully integrated into the existing bioinformatics structures relevant to
human genetics, HGMD has established itself as the central core database of
inherited human gene mutations.
PMID- 9399855
TI - EpoDB: a database of genes expressed during vertebrate erythropoiesis.
AB - EpoDB is a database designed for the study of gene regulation during
differentiation and development of vertebrate red blood cells. In building EpoDB,
we have taken the in advance approach to the data integration problem: we have
extracted data relevant to red blood cells from GenBank, SWISS-PROT, TRRD
(transcriptional regulation data) and GERD (expression levels data) to create a
single integrated, highly curated view. Tools have been developed to automate
data extraction from online resources, cleanse data of errors, enter information
manually from the primary literature, generate a uniform, canonical
representation of information and maintain data currency. The database is
organized around biological features, e.g., genes, rather than sequences, which
are supported by a controlled and consistent vocabulary for gene names and gene
family names. Beyond the standard database queries, the functionality of EpoDB
includes the ability to extract features and subsequences, display sequences and
features graphically using bioWidget viewers and integrated analysis tools. EpoDB
may be accessed at: http://cbil.humgen.upenn.edu/epodb/
PMID- 9399856
TI - A mutation spectra database for bacterial and mammalian genes: 1998.
AB - This database consists of over 24 000 mutations in 18 viral, bacterial, yeast or
mammalian genes. The data are grouped as sets of DNA base sequence changes or
spectra caused by a particular mutagen under defined conditions. The spectra are
available on the World Wide Web at http://info.med.yale.edu/mutbase/ in two
formats; in text format that can be browsed on-line or downloaded for use with a
text editor and in dBASEIII format for use, after downloading, by relational
database programs or by spreadsheets. Researchers are encouraged to submit DNA
sequence changes to a suitable mutation database such as ours. A data entry
program, MUTSIN, can be retrieved from this site. MUTSIN diagrams each mutation
on the computer screen and alerts the user to any discrepancies.
PMID- 9399857
TI - Database of mutations within the adenovirus 5 E1A oncogene.
AB - The Ad5 E1A database is a listing of mutations affecting the early region 1A
(E1A) proteins of human adenovirus type 5. The database contains the name of the
mutation, the nucleic acid sequence changes, the resulting alterations in amino
acid sequence and reference. Additional notes and references are provided on the
effect of each mutation on E1A function. The database is contained within the
Adenovirus 5 E1A page on the World Wide Web at:
http://www.geocities.com/CapeCanaveral/Hangar /2541/
PMID- 9399858
TI - SV40 large tumor antigen (T antigen): database of mutants.
AB - The SV40 T antigen database (http://www.pitt.edu/pipaslab/) lists viruses and
plasmids expressing mutant forms of large T antigen. Each entry contains
information regarding the mutant designation, mutant type, virus strain,
nucleotide change, amino acid change and pertinent references. The database is
now available as an internet searchable index.
PMID- 9399859
TI - IMGT, the International ImMunoGeneTics database.
AB - IMGT, the international ImMunoGeneTics database, is an integrated database
specialising in Immunoglobulins (Ig), T cell Receptors (TcR) and Major
Histocompatibility Complex (MHC) of all vertebrate species, created by Marie
Paule Lefranc, CNRS, Montpellier II University, Montpellier, France
(lefranc@ligm.crbm.cnrs-mop.fr). IMGT includes three databases: LIGM-DB (for Ig
and TcR), MHC/HLA-DB and PRIMER-DB (the last two in development). IMGT comprises
expertly annotated sequences and alignment tables. LIGM-DB contains more than 23
000 Immunoglobulin and T cell Receptor sequences from 78 species. MHC/HLA-DB
contains Class I and Class II Human Leucocyte Antigen alignment tables. An IMGT
tool, DNAPLOT, developed for Ig, TcR and MHC sequence alignments, is also
available. IMGT works in close collaboration with the EMBL database. IMGT goals
are to establish a common data access to all immunogenetics data, including
nucleotide and protein sequences, oligonucleotide primers, gene maps and other
genetic data of Ig, TcR and MHC molecules, and to provide a graphical user
friendly data access. IMGT has important implications in medical research
(repertoire in autoimmune diseases, AIDS, leukemias, lymphomas), therapeutical
approaches (antibody engineering), genome diversity and genome evolution studies.
IMGT is freely available at http://imgt.cnusc.fr:8104
PMID- 9399860
TI - The PRINTS protein fingerprint database in its fifth year.
AB - PRINTS is a database of protein family 'fingerprints' offering a diagnostic
resource for newly-determined sequences. By contrast with PROSITE, which uses
single consensus expressions to characterise particular families, PRINTS exploits
groups of motifs to build characteristic signatures. These signatures offer
improved diagnostic reliability by virtue of the mutual context provided by motif
neighbours. To date, 800 fingerprints have been constructed and stored in PRINTS.
The current version, 17.0, encodes approximately 4500 motifs, covering a range of
globular and membrane proteins, modular polypeptides, and so on. The database is
accessible via the UCL Bioinformatics World Wide Web (WWW) Server at http://www.
biochem.ucl.ac.uk/bsm/dbbrowser/ . We have recently enhanced the usefulness of
PRINTS by making available new, intuitive search software. This allows both
individual query sequence and bulk data submission, permitting easy analysis of
single sequences or complete genomes. Preliminary results indicate that use of
the PRINTS system is able to assign additional functions not found by other
methods, and hence offers a useful adjunct to current genome analysis protocols.
PMID- 9399861
TI - Superior performance in protein homology detection with the Blocks Database
servers.
AB - The Blocks Database World Wide Web (http://www.blocks.fhcrc.org ) and Email
(blocks@blocks.fhcrc.org) servers provide tools for the detection and analysis of
protein homology based on alignment blocks representing conserved regions of
proteins. During the past year, searching has been augmented by supplementation
of the Blocks Database with blocks from the Prints Database, for a total of 4754
blocks from 1163 families. Blocks from both the Blocks and Prints Databases and
blocks that are constructed from sequences submitted to Block Maker can be used
for blocks-versus-blocks searching of these databases with LAMA, and for viewing
logos and bootstrap trees. Sensitive searches of up-to-date protein sequence
databanks are carried out via direct links to the MAST server using position
specific scoring matrices and to the BLAST and PSI-BLAST servers using consensus
embedded sequence queries. Utilizing the trypsin family to evaluate performance,
we illustrate the superiority of blocks-based tools over expert pairwise
searching or Hidden Markov Models.
PMID- 9399862
TI - The HSSP database of protein structure-sequence alignments and family profiles.
AB - HSSP (http: //www.sander.embl-ebi.ac.uk/hssp/) is a derived database merging
structure (3-D) and sequence (1-D) information. For each protein of known 3D
structure from the Protein Data Bank (PDB), we provide a multiple sequence
alignment of putative homologues and a sequence profile characteristic of the
protein family, centered on the known structure. The list of homologues is the
result of an iterative database search in SWISS-PROT using a position-weighted
dynamic programming method for sequence profile alignment (MaxHom). The database
is updated frequently. The listed putative homologues are very likely to have the
same 3D structure as the PDB protein to which they have been aligned. As a
result, the database not only provides aligned sequence families, but also
implies secondary and tertiary structures covering 33% of all sequences in SWISS
PROT.
PMID- 9399863
TI - Touring protein fold space with Dali/FSSP.
AB - The FSSP database and its new supplement, the Dali Domain Dictionary, present a
continuously updated classification of all known 3D protein structures. The
classification is derived using an automatic structure alignment program (Dali)
for the all-against-all comparison of structures in the Protein Data Bank. From
the resulting enumeration of structural neighbours (which form a surprisingly
continuous distribution in fold space) we derive a discrete fold classification
in three steps: (i) sequence-related families are covered by a representative set
of protein chains; (ii) protein chains are decomposed into structural domains
based on the recurrence of structural motifs; (iii) folds are defined as tight
clusters of domains in fold space. The fold classification, domain definitions
and test sets for sequence-structure alignment (threading) are accessible on the
web at www.embl-ebi.ac.uk/dali . The web interface provides a rich network of
links between neighbours in fold space, between domains and proteins, and between
structures and sequences leading, for example, to a database of explicit multiple
alignments of protein families in the twilight zone of sequence similarity. The
Dali/FSSP organization of protein structures provides a map of the currently
known regions of the protein universe that is useful for the analysis of folding
principles, for the evolutionary unification of protein families and for
maximizing the information return from experimental structure determination.
PMID- 9399864
TI - Pfam: multiple sequence alignments and HMM-profiles of protein domains.
AB - Pfam contains multiple alignments and hidden Markov model based profiles (HMM
profiles) of complete protein domains. The definition of domain boundaries,
family members and alignment is done semi-automatically based on expert
knowledge, sequence similarity, other protein family databases and the ability of
HMM-profiles to correctly identify and align the members. Release 2.0 of Pfam
contains 527 manually verified families which are available for browsing and on
line searching via the World Wide Web in the UK at http://www.sanger.ac.uk/Pfam/
and in the US at http://genome.wustl. edu/Pfam/ Pfam 2.0 matches one or more
domains in 50% of Swissprot-34 sequences, and 25% of a large sample of predicted
proteins from the Caenorhabditis elegans genome.
PMID- 9399865
TI - The ProDom database of protein domain families.
AB - The ProDom database contains protein domain families generated from the SWISS
PROT database by automated sequence comparisons. It can be searched on the World
Wide Web (http://protein.toulouse.inra. fr/prodom.html ) or by E-mail
(prodom@toulouse.inra.fr) to study domain arrangements within known families or
new proteins. Strong emphasis has been put on the graphical user interface which
allows for interactive analysis of protein homology relationships. Recent
improvements to the server include: ProDom search by keyword; links to PROSITE
and PDB entries; more sensitive ProDom similarity search with BLAST or WU-BLAST;
alignments of query sequences with homologous ProDom domain families; and links
to the SWISS-MODEL server (http: //www.expasy.ch/swissmod/SWISS-MODEL.html ) for
homology based 3-D domain modelling where possible.
PMID- 9399866
TI - An Integrated Sequence-Structure Database incorporating matching mRNA sequence,
amino acid sequence and protein three-dimensional structure data.
AB - We have constructed a non-homologous database, termed the Integrated Sequence
Structure Database (ISSD) which comprises the coding sequences of genes, amino
acid sequences of the corresponding proteins, their secondary structure and
straight phi,psi angles assignments, and polypeptide backbone coordinates. Each
protein entry in the database holds the alignment of nucleotide sequence, amino
acid sequence and the PDB three-dimensional structure data. The nucleotide and
amino acid sequences for each entry are selected on the basis of exact matches of
the source organism and cell environment. The current version 1.0 of ISSD is
available on the WWW at http://www.protein.bio.msu.su/issd/ and includes 107 non
homologous mammalian proteins, of which 80 are human proteins. The database has
been used by us for the analysis of synonymous codon usage patterns in mRNA
sequences showing their correlation with the three-dimensional structure features
in the encoded proteins. Possible ISSD applications include optimisation of
protein expression, improvement of the protein structure prediction accuracy, and
analysis of evolutionary aspects of the nucleotide sequence-protein structure
relationship.
PMID- 9399867
TI - Current status of the SWISS-2DPAGE database.
AB - The SWISS-2DPAGE database (http: //www.expasy.ch/ch2d/ch2d-top.html ) consists of
two-dimensional polyacrylamide gel electrophoresis images, as well as textual
descriptions of the proteins that have been identified on them. The current
release contains 15 reference maps from human biological samples, as well as from
Saccharomyces cerevisiae , Escherichia coli and Dictyostelium discoideum origin.
These reference maps have 2088 identified spots, corresponding to 410 separate
protein entries in the database, in addition to virtual entries for each SWISS
PROT sequence.
PMID- 9399868
TI - Codon usage tabulated from the international DNA sequence databases.
AB - CUTG (codon usage tabulated from GenBank) is a comprehensive database for codon
usage. The codon usage for each full-length protein gene has been calculated
using the nucleotide sequence obtained from GenBank sequence database. The sum of
the codon use of each organism has been also calculated. The data files can be
obtained from anonymous ftp sites of DDBJ, DISC and EBI. The list of codonusage
of genes in organisms was made searchableby name of organism through a web site
http://www.dna.affrc.go.jp/ approximately nakamura/CUTG.html The compilation is
synchronized with major release of GenBank.
PMID- 9399869
TI - The translational signal database, TransTerm, is now a relational database.
AB - TransTerm-97 contains more than 97 500 non-redundant coding-sequence initiation
and termination contexts compiled from GenBank, release 101 (15-June-1997). In
addition, several coding sequence parameters are available: coding sequence
length, Nc, GC3, and, when it is computable, codon adaptation index (CAI). Codon
usage tables and summaries of start and stop codon contexts are also included.
The information covers more than 325 species and organelles, including seven
complete bacterial genomes and one complete eukaryotic genome. To promote
research in translational control of protein synthesis, TransTerm has been
converted into a relational database to ease the process of making queries. The
relational database manager, Postgresql, gives access to the database using SQL
(Structured Query Language). A World Wide Web interface using forms is being
completed to allow the casual user access to the database. Extensions are planned
to include the full 5'-UTR, full coding sequence and 3'-UTR. TransTerm-97 is
available on the World Wide Web at:http://biochem.
otago.ac.nz:800/Transterm/homepage.html
PMID- 9399870
TI - REBASE - restriction enzymes and methylases.
AB - REBASE is a comprehensive database of information about restriction enzymes and
their associated methylases, including their recognition and cleavage sites and
their commercial availability. Also included is a listing of homing
endonucleases. Information from REBASE is available via monthly electronic
mailings as well as via anonymous ftp and through the World Wide Web. The REBASE
web site, http://www. neb.com/rebase , is where we maintain a web page for every
enzyme, reference and supplier. Additionally, there is a search facility, help
and NEWS pages, and a complete description of our various services. Specialized
files are available that can be used directly by many software packages.
PMID- 9399871
TI - The ribonuclease P database.
AB - Ribonuclease P is responsible for the 5'-maturation of tRNA precursors.
Ribonuclease P is a ribonucleoprotein, and in bacteria the RNA subunit alone is
catalytically active in vitro , i.e., it is a ribozyme. The Ribonuclease P
Database is a compilation of ribonuclease P sequences, sequence alignments,
secondary structures, three-dimensional models, and accessory information,
available via the World Wide Web (http: //www.mbio.ncsu.edu/RNaseP/home.html ).
PMID- 9399872
TI - The Eukaryotic Promoter Database EPD.
AB - The Eukaryotic Promoter Database (EPD) is an annotated non-redundant collection
of experimentally characterised eukaryotic POL II promoters. The underlying
definition of a promoter is that of a transcription initiation site. All
information presented in EPD results from an independent evaluation of primary
experimental data shown in the biological literature. Sequences flanking
transcription initiation sites are indirectly given by pointers to EMBL
sequences. The annotation part of a promoter entry includes description of the
promoter-defining evidence, cross-references to other databases, and
bibliographic references. Being designed as a resource for comparative sequence
analysis, EPD is structured in a way that facilitates dynamic extraction of
biologically meaningful promoter subsets. The database is available through the
World Wide Web at URL http://cmpteam4.unil.ch
PMID- 9399873
TI - PLACE: a database of plant cis-acting regulatory DNA elements.
AB - PLACE (http://www.dna.affrc.go.jp/htdocs/PLACE/) is a database of motifs found in
plant cis -acting regulatory DNA elements, all from previously published reports.
It covers vascular plants only. In addition to the motifs originally reported,
their variations in other genes or in other plant species reported later are also
compiled. The PLACE database also contains a brief description of each motif and
relevant literature with PubMed ID numbers. This report summarizes the present
status of this database and available tools.
PMID- 9399874
TI - OOTFD (Object-Oriented Transcription Factors Database): an object-oriented
successor to TFD.
AB - ooTFD (object-oriented Transcription Factors Database) is a successor to TFD
(Transcription Factors Database). ooTFD contains information represented in TFD
but also allows the representation of containment, composite, and interaction
relationships between transcription factor polypeptides. ooTFD is designed to
represent information about all transcription factors, both eukaryotic and
prokaryotic, basal as well as regulatory factors, and multiprotein complexes as
well as monomers. ooTFD and associated tools and services can be accessed at
http://www.isbi.net/
PMID- 9399875
TI - Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL.
AB - TRANSFAC, TRRD (Transcription Regulatory Region Database) and COMPEL are
databases which store information about transcriptional regulation in eukaryotic
cells. The three databases provide distinct views on the components involved in
transcription: transcription factors and their binding sites and binding profiles
(TRANSFAC), the regulatory hierarchy of whole genes (TRRD), and the structural
and functional properties of composite elements (COMPEL). The quantitative and
qualitative changes of all three databases and connected programs are described.
The databases are accessible via WWW:http://transfac.gbf.de/TRANSFAC
orhttp://www.bionet.nsc.ru/TRRD
PMID- 9399876
TI - MHCPEP, a database of MHC-binding peptides: update 1997.
AB - MHCPEP (http://wehih.wehi.edu.au/mhcpep/) is a curated database comprising over
13 000 peptide sequences known to bind MHC molecules. Entries are compiled from
published reports as well as from direct submissions of experimental data. Each
entry contains the peptide sequence, its MHC specificity and where available,
experimental method, observed activity, binding affinity, source protein and
anchor positions, as well as publication references. The present format of the
database allows text string matching searches but can easily be converted for use
in conjunction with sequence analysis packages. The database can be accessed via
Internet using WWW or FTP.
PMID- 9399877
TI - Histone Sequence Database: new histone fold family members.
AB - Searches of the major public protein databases with core and linker chicken and
human histone sequences have resulted in the compilation of an annotated set of
histone protein sequences. In addition, new database searches with two distinct
motif search algorithms have identified several members of the histone fold
family, including human DRAP1 and yeast CSE4. Database resources include
information on conflicts between similar sequence entries in different source
databases, multiple sequence alignments, links to the Entrez integrated
information retrieval system, structures for histone and histone fold proteins,
and the ability to visualize structural data through Cn3D. The database currently
contains >1000 protein sequences, which are searchable by protein type, accession
number, organism name, or any other free text appearing in the definition line of
the entry. All sequences and alignments in this database are available through
the World Wide Web at http://www.nhgri.nih. gov/DIR/GTB/HISTONES or
http://www.ncbi.nlm.nih. gov/Baxevani/HISTONES
PMID- 9399878
TI - PROMISE: a database of information on prosthetic centres and metal ions in
protein active sites.
AB - The PROMISE (Prosthetic centres andmetalions in protein activesites) database
aims to gather together comprehensive sequence, structural, functional and
bibliographic information on proteins which possess prosthetic centres, with an
emphasis on active site structure and function. The database is available on the
World Wide Web at http://bioinf.leeds.ac.uk/promise/
PMID- 9399879
TI - PhosphoBase: a database of phosphorylation sites.
AB - PhosphoBase is a database of experimentally verified phosphorylation sites.
Version 1.0 contains 156 entries and 398 experimentally determined
phosphorylation sites. Entries are compiled and revised from the literature and
from major protein sequence databases such as SwissProt and PIR. The entries
provide information about the phosphoprotein and the exact position of its
phosphorylation sites. Furthermore, part of the entries contain information about
kinetic data obtained from enzyme assays on specific peptides. To illustrate the
use of data extracted from PhosphoBase we present a sequence logo displaying the
overall conservation of positions around serines phosphorylated by protein kinase
A (PKA). PhosphoBase is available on the WWW at
http://www.cbs.dtu.dk/databases/PhosphoBase/
PMID- 9399880
TI - O-GLYCBASE Version 3.0: a revised database of O-glycosylated proteins.
AB - O-GLYCBASE is a revised database of information on glycoproteins and their O
linked glycosylation sites. Entries are compiled and revised from the literature,
and from the sequence databases. Entries include information about species,
sequence, glycosylation sites and glycan type and is fully cross-referenced.
Compared to version 2.0 the number of entries has increased by 20%. Sequence
logos displaying the acceptor specificity patterns for the GalNAc, mannose and
GlcNAc transferases are shown. The O-GLYCBASE database is available through the
WWW at http://www.cbs.dtu. dk/databases/OGLYCBASE/
PMID- 9399881
TI - Use of a quantitative trait to map a locus associated with severity of positive
symptoms in familial schizophrenia to chromosome 6p.
AB - A number of recent linkage studies have suggested the presence of a schizophrenia
susceptibility locus on chromosome 6p. We evaluated 28 genetic markers, spanning
chromosome 6, for linkage to schizophrenia in 10 moderately large Canadian
families of Celtic ancestry. Parametric analyses of these families under
autosomal dominant and recessive models, using broad and narrow definitions of
schizophrenia, produced no significant evidence for linkage. A sib-pair analysis
using categorical disease definitions also failed to produce significant evidence
for linkage. We then conducted a separate sibpair analysis using scores on
positive-symptom (psychotic), negative-symptom (deficit), and general
psychopathology-symptom scales as quantitative traits. With the positive symptom
scale scores, the marker D6S1960 produced P = 1.2 x 10(-5) under two-point and P
= 5.4 x 10(-6) under multipoint analyses. Using simulation studies, we determined
that these nominal P values correspond to empirical P values of .034 and .0085,
respectively. These results suggest that a schizophrenia susceptibility locus on
chromosome 6p may be related to the severity of psychotic symptoms. Assessment of
behavioral quantitative traits may provide increased power over categorical
phenotype assignment for detection of linkage in complex psychiatric disorders.
PMID- 9399882
TI - Inherited interstitial duplications of proximal 15q: genotype-phenotype
correlations.
AB - We present the cytogenetic, molecular cytogenetic, and molecular genetic results
on 20 unrelated patients with an interstitial duplication of the proximal long
arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman
critical region (PWACR) was included in the duplication in 4/20 patients, each
ascertained with developmental delay. The duplication was also found in two
affected but not in three unaffected sibs of one of these patients. All four
probands had inherited their duplication from their mothers, three of whom were
also affected. Two of the affected mothers also carried a maternally inherited
duplication, whereas the duplication in the unaffected mother and in an
unaffected grandmother was paternal in origin, raising the possibility of a
parental-origin effect. The PWACR was not duplicated in the remaining 16
patients, of whom 4 were referred with developmental delay. In the 14 families
for which parental samples were available, the duplication was inherited with
equal frequency from a phenotypically normal parent, mother or father.
Comparative genomic hybridization undertaken on two patients suggested that
proximal 15q outside the PWACR was the origin of the duplicated material. The use
of PWACR probes discriminates between a large group of duplications of no
apparent clinical significance and a smaller group, in which a maternally derived
PWACR duplication is consistently associated with developmental delay and speech
difficulties but not with overt features of either Prader-Willi syndrome or
Angelman syndrome.
PMID- 9399885
TI - Genetic segregation analysis of early-onset recurrent unipolar depression.
AB - Major depression is a relatively common psychiatric disorder that can be quite
debilitating. Family, twin, and adoption studies indicate that unipolar
depression has both genetic and environmental components. Early age at onset and
recurrent episodes in the proband each increase the familiarity of the illness.
To investigate the potential genetic underpinnings of the disease, we have
performed a complex segregation analysis on 832 individuals from 50
multigenerational families ascertained through a proband with early-onset
recurrent unipolar major depression. The analysis was conducted by use of
regressive models, to test a variety of hypotheses to explain the familial
aggregation of recurrent unipolar depression. Analyses were conducted under two
alternative definitions of affection status for the relatives of probands: (1)
"narrow," in which relatives were assumed to be affected only if they were
diagnosed with recurrent unipolar depression; and (2) "broad," in which relatives
were assumed to be affected if diagnosed with any major affective illness. Under
the narrow-definition assumption, the model that best explains these family data
is a transmitted (although non-Mendelian) recessive major effect with significant
residual parental effects on affection status. Under the broad-definition
assumption, the best-fitting model is a Mendelian codominant major locus with
significant residual parental and spousal effects.
PMID- 9399886
TI - Cloning of the human carnitine-acylcarnitine carrier cDNA and identification of
the molecular defect in a patient.
AB - The carnitine-acylcarnitine carrier (CAC) catalyzes the translocation of long
chain fatty acids across the inner mitochondrial membrane. We cloned and
sequenced the human CAC cDNA, which has an open reading frame of 903 nucleotides.
Northern blot studies revealed different expression levels of CAC in various
human tissues. Furthermore, mutation analysis was performed for a CAC-deficient
infant. Direct sequencing of the patient's cDNA revealed a homozygous cytosine
nucleotide insertion. This insertion provokes a frameshift and an extension of
the open reading frame with 23 novel codons. This is the first report documenting
a mutation, in the CAC cDNA, responsible for mitochondrial beta-oxidation
impairment.
PMID- 9399887
TI - Diversity and age of the four major mtDNA haplogroups, and their implications for
the peopling of the New World.
AB - Despite considerable investigation, two main questions on the origin of Native
Americans remain the topic of intense debate-namely, the number and time of the
migration(s) into the Americas. Using the 720 available Amerindian mtDNA control
region sequences, we reanalyzed the nucleotide diversity found within each of the
four major mtDNA haplogroups (A-D) thought to have been present in the
colonization of the New World. We first verified whether the within-haplogroup
sequence diversity could be used as a measure of the haplogroup's age. The
pattern of shared polymorphism, the mismatch distribution, the phylogenetic
trees, the value of Tajima's D, and the computer simulations all suggested that
the four haplogroups underwent a bottleneck followed by a large population
expansion. The four haplogroup diversities were very similar to each other,
offering a strong support for their single origin. They suggested that the
beginning of the Native Americans' ancestral-population differentiation occurred
approximately 30,000-40,000 years before the present (ybp), with a 95%-confidence
interval lower bound of approximately 25,000 ybp. These values are in good
agreement with the New World-settlement model that we have presented elsewhere,
extending the results initially found for haplogroup A to the three other major
groups of mtDNA sequences found in the Americas. These results put the peopling
of the Americas clearly in an early, pre-Clovis time frame.
PMID- 9399888
TI - Linkage of bipolar affective disorder to chromosome 18 markers in a new pedigree
series.
AB - Several groups have reported evidence suggesting linkage of bipolar affective
disorder (BPAD) to chromosome 18. We have reported data from 28 pedigrees that
showed linkage to marker loci on 18p and to loci 40 cM distant on 18q. Most of
the linkage evidence derived from families with affected phenotypes in only the
paternal lineage and from marker alleles transmitted on the paternal chromosome.
We now report results from a series of 30 new pedigrees (259 individuals)
genotyped for 13 polymorphic markers spanning chromosome 18. Subjects were
interviewed by a psychiatrist and were diagnosed by highly reliable methods.
Genotypes were generated with automated technology and were scored blind to
phenotype. Affected sib pairs showed excess allele sharing at the 18q markers
D18S541 and D18S38. A parent-of-origin effect was observed, but it was not
consistently paternal. No robust evidence of linkage was detected for markers
elsewhere on chromosome 18. Multipoint nonparametric linkage analysis in the new
sample combined with the original sample of families supports linkage on
chromosome 18q, but the susceptibility gene is not well localized.
PMID- 9399889
TI - Meiotic microdeletion breakpoints in the BRCA1 gene are significantly associated
with symmetric DNA-sequence elements.
PMID- 9399890
TI - Mutations of the Fanconi anemia group A gene (FAA) in Italian patients.
AB - Fanconi anemia (FA) is an autosomal recessive disease characterized by
progressive pancytopenia, congenital malformations, and predisposition to acute
myeloid leukemia. At least five complementation groups (FA-A-FA-E) have been
identified. The relative prevalence of FA-A has been estimated at an average of
approximately 65% but may widely vary according to ethnic background. In Italy,
11 of 12 patients analyzed by cell-fusion studies were assigned to group FA-A,
suggesting an unusually high relative prevalence of this FA subtype in patients
of Italian ancestry. We have screened the 43 exons of the FAA gene and their
flanking intronic sequences in 38 Italian FA patients, using RNA-SSCP. Ten
different mutations were detected: three nonsense and one missense substitutions,
four putative splice mutations, an insertion, and a duplication. Most of the
mutations are expected to cause a premature termination of the FAA protein at
various sites throughout the molecule. Four protein variants were also found,
three of which were polymorphisms. The missense mutation D1359Y, not found in
chromosomes from healthy unrelated individuals, was responsible for a local
alteration of hydrophobicity in the FAA protein, and it was likely to be
pathogenic. Thus, the mutations so far encountered in the FAA gene are
essentially all different. Since screening based on the analysis of single exons
by genomic DNA amplification apparently detects only a minority of the mutations,
methods designed to detect alterations in the genomic structure of the gene or in
the FAA polypeptide may be helpful in the identification of FAA mutations.
PMID- 9399892
TI - Identification of an interstitial deletion in an adult female with schizophrenia,
mental retardation, and dysmorphic features: further support for a putative
schizophrenia-susceptibility locus at 5q21-23.1.
PMID- 9399891
TI - Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis.
AB - Patients with multiple schwannomas without vestibular schwannomas have been
postulated to compose a distinct subclass of neurofibromatosis (NF), termed
"schwannomatosis." To compare the molecular-genetic basis of schwannomatosis with
NF2, we examined the NF2 locus in 20 unrelated schwannomatosis patients and their
affected relatives. Tumors from these patients frequently harbored typical
truncating mutations of the NF2 gene and loss of heterozygosity of the
surrounding region of chromosome 22. Surprisingly, unlike patients with NF2, no
heterozygous NF2-gene changes were seen in normal tissues. Examination of
multiple tumors from the same patient revealed that some schwannomatosis patients
are somatic mosaics for NF2-gene changes. By contrast, other individuals,
particularly those with a positive family history, appear to have an inherited
predisposition to formation of tumors that carry somatic alterations of the NF2
gene. Further work is needed to define the pathogenetics of this unusual disease
mechanism.
PMID- 9399893
TI - Comparison of nonparametric statistics for detection of linkage in nuclear
families: single-marker evaluation.
AB - We have evaluated 23 different statistics, from a total of 10 popular software
packages for model-free linkage analysis of nuclear-family data, by applying them
to single-marker data simulated under several two-locus disease models. The
statistics that we examined fall into two broad categories: (1) those that test
directly for increased identity-by-state or identity-by-descent sharing (by use
of the programs APM, Genetic Analysis System [GAS] SIBSTATE and SIBDES, SAGE
SIBPAL, ERPA, SimIBD, and Genehunter NPL) and (2) those that are based on
likelihood-ratio tests and that report LOD scores (by use of the programs Splink,
SIBPAIR, Mapmaker/Sibs, ASPEX, and GAS SIBMLS). For each of eight two-locus
disease models, we analyzed six data sets; the first three data sets consisted of
two-child families with both sibs affected and zero, one, or both parents typed,
whereas the other three data sets consisted of four-child families with at least
two affected sibs and zero, one, or both parents typed. We report false-positive
rates, overall rank by power, and the power for each statistic. We give rough
recommendations regarding which programs provide the most powerful tests for
linkage, as well as the programs to be avoided under certain conditions. For the
likelihood-ratio-based statistics, we examined the effects of various treatments
of sibships with multiple affected individuals. Finally, we explored the use of
some simple two-of-three composite statistics and found that such tests are of
only marginal benefit over the most powerful single statistic.
PMID- 9399894
TI - Variable levels of a heteroplasmic point mutation in individual hair roots.
AB - During direct sequencing of the first hypervariable segment of the human
mitochondrial control region, we identified one individual with a heteroplasmic
point mutation at nt 16,256. We used primer extension to analyze the proportions
of each mitochondrial haplotype in peripheral blood, buccal cells, and single
hair roots from this individual and from eight members of his maternal lineage.
Significant levels of heteroplasmy were found in only three individuals, and, in
these cases, the proportions of each haplotype were similar in both blood and
buccal cells. From the changes in mitochondrial haplotypes within mother
offspring pairs, we calculated that the most likely size of a mitochondrial
bottleneck during development was 1-27 segregating units. However, highly
variable levels of heteroplasmy were found in single hair roots, even among roots
from the same individual. We analyzed a large number of hair roots from one
individual and found that the proportion of one haplotype was within a range of
9% to > 99% in different roots. Roots originating from within a small patch of
skin had haplotype proportions as variable as those from different areas of skin.
PMID- 9399895
TI - Genomewide scan of multiple sclerosis in Finnish multiplex families.
AB - Multiple sclerosis (MS) is a neurological, demyelinating disorder with a putative
autoimmune etiology. It is thought to be a multifactorial disease with a complex
mode of inheritance. Here we report the results of a two-stage genomewide scan
for loci predisposing to MS. The first stage of the screen, with a low-resolution
map, was performed in a selection of 16 pedigrees collected from an isolated
Finnish population. Multipoint, non-parametric linkage analysis of the 328
markers did not reveal statistically significant results. However, 10 slightly
interesting regions (P = .1-.15) emerged, including our previous findings of the
HLA complex on 6p21 and a putative locus on 5p14-p12. Eight of these novel
regions were further analyzed by use of denser marker maps, in the second stage
of the scan. For the chromosomal regions 4cen, 11tel, and 17q, the statistical
significance increased, but not conclusively; for 2q32 and 10q21, the statistical
significance did not change. Accordingly, genotyping of the high-density markers
in these regions was performed, and the data were analyzed by use of two-point,
parametric linkage analysis using the complete pedigree information of the 21
Finnish multiplex families. We detected suggestive evidence for a predisposing
locus on chromosomal region 17q22-q24. Several markers on 17q22-q24 yielded
positive LOD scores, with the maximum LOD score (Zmax) occurring with D17S807
(Zmax = 2.8, theta = .04; dominant model). Interestingly, a suggestive linkage
between MS and the markers on 17q22-q24 was also revealed by a recent genomewide
scan in MS families from the United Kingdom.
PMID- 9399896
TI - Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a
metanalysis of genotype-phenotype correlations.
AB - We analyzed correlations between mutant genotypes at the human phenylalanine
hydroxylase locus (gene symbol PAH) and the corresponding hyperphenylalaninemia
(HPA) phenotypes (notably, phenylketonuria [OMIM 261600]). We used reports, both
published and in the PAH Mutation Analysis Consortium Database, on 365 patients
harboring 73 different PAH mutations in 161 different genotypes. HPA phenotypes
were classified as phenylketonuria (PKU), variant PKU, and non-PKU HPA. By
analysis both of homoallelic mutant genotypes and of "functionally hemizygous"
heteroallelic genotypes, we characterized the phenotypic effect of 48 of the 73
different, largely missense mutations. Among those with consistent in vivo
expression, 24 caused PKU, 3 caused variant PKU, and 10 caused non-PKU HPA.
However, 11 mutations were inconsistent in their effect: 9 appeared in two
different phenotype classes, and 2 (I65T and Y414C) appeared in all three
classes. Seven mutations were inconsistent in phenotypic effect when in vitro
(unit-protein) expression was compared with the corresponding in vivo phenotype
(an emergent property). We conclude that the majority of PAH mutations confer a
consistent phenotype and that this is concordant with their effects, when known,
predicted from in vitro expression analysis. However, significant
inconsistencies, both between in vitro and in vivo phenotypes and between
different individuals with similar PAH genotypes, reveal that the HPA-phenotype
is more complex than that predicted by Mendelian inheritance of alleles at the
PAH locus.
PMID- 9399898
TI - The frequency of the methylenetetrahydrofolate reductase-gene mutation varies
with age in the normal population.
PMID- 9399897
TI - Inherited mutations in PTEN that are associated with breast cancer, cowden
disease, and juvenile polyposis.
AB - PTEN, a protein tyrosine phosphatase with homology to tensin, is a tumor
suppressor gene on chromosome 10q23. Somatic mutations in PTEN occur in multiple
tumors, most markedly glioblastomas. Germ-line mutations in PTEN are responsible
for Cowden disease (CD), a rare autosomal dominant multiple-hamartoma syndrome.
PTEN was sequenced from constitutional DNA from 25 families. Germ-line PTEN
mutations were detected in all of five families with both breast cancer and CD,
in one family with juvenile polyposis syndrome, and in one of four families with
breast and thyroid tumors. In this last case, signs of CD were subtle and were
diagnosed only in the context of mutation analysis. PTEN mutations were not
detected in 13 families at high risk of breast and/or ovarian cancer. No PTEN
coding-sequence polymorphisms were detected in 70 independent chromosomes. Seven
PTEN germ-line mutations occurred, five nonsense and two missense mutations, in
six of nine PTEN exons. The wild-type PTEN allele was lost from renal, uterine,
breast, and thyroid tumors from a single patient. Loss of PTEN expression was an
early event, reflected in loss of the wild-type allele in DNA from normal tissue
adjacent to the breast and thyroid tumors. In RNA from normal tissues from three
families, mutant transcripts appeared unstable. Germ-line PTEN mutations
predispose to breast cancer in association with CD, although the signs of CD may
be subtle.
PMID- 9399899
TI - Splicing defects in the COL3A1 gene: marked preference for 5' (donor) spice-site
mutations in patients with exon-skipping mutations and Ehlers-Danlos syndrome
type IV.
AB - Ehlers-Danlos syndrome (EDS) type IV results from mutations in the COL3A1 gene,
which encodes the constituent chains of type III procollagen. We have identified,
in 33 unrelated individuals or families with EDS type IV, mutations that affect
splicing, of which 30 are point mutations at splice junctions and 3 are small
deletions that remove splice-junction sequences and partial exon sequences.
Except for one point mutation at a donor site, which leads to partial intron
inclusion, and a single base-pair substitution at an acceptor site, which gives
rise to inclusion of the complete upstream intron into the mature mRNA, all
mutations result in deletion of a single exon as the only splice alteration. Of
the exon-skipping mutations that are due to single base substitutions, which we
have identified in 28 separate individuals, only two affect the splice-acceptor
site. The underrepresentation of splice acceptor-site mutations suggests that the
favored consequence of 3' mutations is the use of an alternative acceptor site
that creates a null allele with a premature-termination codon. The phenotypes of
those mutations may differ, with respect to either their severity or their
symptomatic range, from the usual presentation of EDS type IV and thus have been
excluded from analysis.
PMID- 9399900
TI - Localization of the gene for thiamine-responsive megaloblastic anemia syndrome,
on the long arm of chromosome 1, by homozygosity mapping.
AB - Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers
syndrome," is an early-onset autosomal recessive disorder defined by the
occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural
deafness, responding in varying degrees to thiamine treatment. On the basis of a
linkage analysis of affected families of Alaskan and of Italian origin, we found,
using homozygosity mapping, that the TRMA-syndrome gene maps to a region on
chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of
additional consanguineous kindreds of Israeli-Arab origin, the putative disease
gene interval also has been confirmed and narrowed, suggesting genetic
homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1
at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and
recombination events narrowed the TRMA locus to a 16-cM region between markers
D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness,
or megaloblastic anemia, which raised the possibility that mutations at this
locus predispose carriers in general to these manifestations. Characterization of
the metabolic defect of TRMA may shed light on the role of thiamine deficiency in
such common diseases.
PMID- 9399901
TI - Autosomal dominant postaxial polydactyly, nail dystrophy, and dental
abnormalities map to chromosome 4p16, in the region containing the Ellis-van
Creveld syndrome locus.
AB - We have studied a four-generation family with features of Weyers acrofacial
dysostosis, in which the proband has a more severe phenotype, resembling Ellis
van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant
condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild
short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal
recessive inheritance and the additional features of disproportionate dwarfism,
thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis
determined that the disease locus in this pedigree resides on chromosome 4p16,
distal to the genetic marker D4S3007 and within a 17-cM region flanking the
genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus,
which previously was reported to map within a 3-cM region between genetic markers
D4S2957 and D4S827. Either the genes for the condition in our family and for
Ellis-van Creveld syndrome are near one another or these two conditions are
allelic with mutations in the same gene. These data also raise the possibility
that Weyers acrofacial dysostosis is the heterozygous expression of a mutation
that, in homozygous form, causes the autosomal recessive disorder Ellis-van
Creveld syndrome.
PMID- 9399902
TI - Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and
identification of a potential second locus, on 19q13.4.
AB - Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease with variable
expression and incomplete penetrance, characterized by mucocutaneous pigmentation
and hamartomatous polyposis. Patients with PJS have increased frequency of
gastrointestinal and extraintestinal malignancies (ovaries, testes, and breast).
In order to map the locus (or loci) associated with PJS, we performed a
genomewide linkage analysis, using DNA polymorphisms in six families (two from
Spain, two from India, one from the United States, and one from Portugal)
comprising a total of 93 individuals, including 39 affected and 48 unaffected
individuals and 6 individuals with unknown status. During this study,
localization of a PJS gene to 19p13.3 (around marker D19S886) had been reported
elsewhere. For our families, marker D19S886 yielded a maximum LOD score of 4.74
at a recombination fraction (theta) of .045; multipoint linkage analysis resulted
in a LOD score of 7.51 for the interval between D19S886 and 19 pter. However,
markers on 19q13.4 also showed significant evidence for linkage. For example,
D19S880 resulted in a maximum LOD score of 3.8 at theta = .13. Most of this
positive linkage was contributed by a single family, PJS07. These results confirm
the mapping of a common PJS locus on 19p13.3 but also suggest the existence, in a
minority of families, of a potential second PJS locus, on 19q13.4. Positional
cloning and characterization of the PJS mutations will clarify the genetics of
the syndrome and the implication of the gene(s) in the predisposition to
neoplasias.
PMID- 9399904
TI - Spectrum of mutations in the RPGR gene that are identified in 20% of families
with X-linked retinitis pigmentosa.
AB - The RPGR (retinitis pigmentosa GTPase regulator) gene for RP3, the most frequent
genetic subtype of X-linked retinitis pigmentosa (XLRP), has been shown to be
mutated in 10%-15% of European XLRP patients. We have examined the RPGR gene for
mutations in a cohort of 80 affected males from apparently unrelated XLRP
families, by direct sequencing of the PCR-amplified products from the genomic
DNA. Fifteen different putative disease-causing mutations were identified in 17
of the 80 families; these include four nonsense mutations, one missense mutation,
six microdeletions, and four intronic-sequence substitutions resulting in splice
defects. Most of the mutations were detected in the conserved N-terminal region
of the RPGR protein, containing tandem repeats homologous to those present in the
RCC-1 protein (a guanine nucleotide-exchange factor for Ran-GTPase). Our results
indicate that mutations either in as yet uncharacterized sequences of the RPGR
gene or in another gene located in its vicinity may be a more frequent cause of
XLRP. The reported studies will be beneficial in establishing genotype-phenotype
correlations and should lead to further investigations seeking to understand the
mechanism of disease pathogenesis.
PMID- 9399903
TI - Novel alleles of the chemokine-receptor gene CCR5.
AB - The CCR5 gene encodes a cell-surface chemokine-receptor molecule that serves as a
coreceptor for macrophage-tropic strains of HIV-1. Mutations in this gene may
alter expression or function of the protein product, thereby altering chemokine
binding/signaling or HIV-1 infection of cells that normally express CCR5 protein.
Indeed, homozygotes for a 32-bp deletion allele of CCR5 (CCR5-delta 32), which
causes a frameshift at amino acid 185, are relatively resistant to HIV-1
infection. Here we report the identification of 16 additional mutations in the
coding region of the CCR5 gene, all but 3 of which are codon altering or
"nonsynonymous." Most mutations were rare (found only once or twice in the
sample); five were detected exclusively among African Americans, whereas eight
were observed only in Caucasians. The mutations included 11 codon-altering
nonsynonymous variants, one trinucleotide deletion, one chain-termination mutant,
and three synonymous mutations. The high predominance of codon-altering alleles
among CCR5 mutants (14/17 [81%], including CCR5-delta 32) is consistent with an
adaptive accumulation of function-altering alleles for this gene, perhaps as a
consequence of historic selective pressures.
PMID- 9399905
TI - Fragile X premutations are not a major cause of early menopause.
AB - Fragile X syndrome is an X-linked mental retardation condition that usually is
due to a trinucleotide-repeat expansion in the FMR1 gene. Whereas full-mutation
alleles (> 230 repeats) lead to fragile X syndrome, premutation alleles
(approximately 60-200 repeats) are apparently non-penetrant. However, previous
studies have suggested that female premutation carriers may have an increased
incidence of premature menopause. To test this possible association, we screened
for premutation alleles among 216 women with early menopause (at age < 47 years),
33 of whom had premature menopause (at age < 40 years), as well as among 107
control women, all of whom were ascertained solely on the basis of age at
menopause. No full-mutation alleles were found; and only one premutation allele
was found, but, it was in a member of the control group. These results are
consistent with what would be expected on the basis of chance only. Our sample
size was sufficient to rule out a > or = 3-fold increased risk of early menopause
and a > or = 9-fold increased risk of premature menopause due to an FMR1
premutation, under a model considering the risk of both sporadic and familial
early menopause. Likewise, our results rule out a > or = 4-fold increased risk of
familial early menopause and a > or = 26-fold increased risk of familial
premature menopause, under a less probable model in which only familial early
menopause is considered. These results indicate that the fragile X premutation is
not a major risk factor for early menopause and suggest that the risk of
premature menopause to fragile X-premutation carriers may not be as great as that
reported elsewhere.
PMID- 9399906
TI - Genomewide transmission/disequilibrium testing--consideration of the genotypic
relative risks at disease loci.
AB - Genomewide association studies are set to become the tool of the future for
detection of small-effect genes in complex diseases. It will therefore be
necessary to calculate sufficient sample sizes with which to perform them. In
this paper I illustrate how to calculate the required number of families for
general genotypic relative risks (GRRs). I show the superior sensitivity of the
genomewide association study over the standard genomewide affected-sib-pair
linkage analysis, for a range of different underlying GRR patterns. I also
illustrate the extent of change in the sample sizes that is necessary for a
genomewide association analysis depending on the pattern of the GRRs at the
disease locus. In many cases, the comparative numbers of families required under
different genetic mechanisms vary by several orders of magnitude. These sometimes
dramatic differences have important implications for the determination of the
size of the collection of samples prior to analysis and for the types of effects
that are likely--and unlikely--to be detected by such an analysis.
PMID- 9399907
TI - Homogeneity of kerato-epithelin codon 124 mutations in Japanese patients with
either of two types of corneal stromal dystrophy.
PMID- 9399908
TI - Isolation and chromosomal localization of a cornea-specific human keratin 12 gene
and detection of four mutations in Meesmann corneal epithelial dystrophy.
AB - Keratin 12 (K12) is an intermediate-filament protein expressed specifically in
corneal epithelium. Recently, we isolated K12 cDNA from a human corneal
epithelial cDNA library and determined its full sequence. Herein, we present the
exon-intron boundary structure and chromosomal localization of human K12. In
addition, we report four K12 mutations in Meesmann corneal epithelial dystrophy
(MCD), an autosomal dominant disorder characterized by intraepithelial microcysts
and corneal epithelial fragility in which mutations in keratin 3 (K3) and K12
have recently been implicated. In the human K12 gene, we identified seven
introns, defining eight individual exons that cover the coding sequence. Together
the exons and introns span approximately 6 kb of genomic DNA. Using FISH, we
found that the K12 gene mapped to 17q12, where a type I keratin cluster exists.
In this study, four new K12 mutations (Arg135Gly, Arg135Ile, Tyr429Asp, and
Leu140Arg) were identified in three unrelated MCD pedigrees and in one individual
with MCD. All mutations were either in the highly conserved alpha-helix
initiation motif of rod domain 1A or in the alpha-helix-termination motif of rod
domain 2B. These sites are essential for keratin filament assembly, suggesting
that the mutations described above may be causative for MCD. Of particular
interest, one of these mutations (Tyr429Asp), detected in both affected
individuals in one of our pedigrees, is the first mutation to be identified
within the alpha-helix-termination motif in type I keratin.
PMID- 9399909
TI - Skewed X-chromosome inactivation is common in fetuses or newborns associated with
confined placental mosaicism.
AB - The inactivation of one X chromosome in females is normally random with regard to
which X is inactivated. However, exclusive or almost-exclusive inactivation of
one X may be observed in association with some X-autosomal rearrangements,
mutations of the XIST gene, certain X-linked diseases, and MZ twinning. In the
present study, a methylation difference near a polymorphism in the X-linked
androgen-receptor gene was used to investigate the possibility that nonrandom X
inactivation is increases in fetuses and newborns that are associated with
confined placental mosaicism (CPM) involving an autosomal trisomy. Extreme
skewing was observed in 7 (58%) of 12 cases with a meiotic origin of the trisomy,
but in none of 10 cases examined with a somatic origin of the trisomy, and in
only 1 (4%) of 27 control adult females. In addition, an extremely skewed X
inactivation pattern was observed in 3 of 10 informative cases of female
uniparental disomy (UPD) of chromosome 15. This may reflect the fact that a
proportion of UPD cases arise by "rescue" of a chromosomally abnormal conceptus
and are therefore associated with CPM. A skewed pattern of X inactivation in CPM
cases is hypothesized to result from a reduction in the size of the early
embryonic cell pool, because of either poor early growth or subsequent selection
against the trisomic cells. Since approximately 2% of pregnancies detected by
chorionic villus sampling are associated with CPM, this is likely a significant
contributor to both skewed X inactivation observed in the newborn population and
the expression of recessive X-linked diseases in females.
PMID- 9399910
TI - Goosecoid-like sequences and the smallest region of deletion overlap in DiGeorge
and velocardiofacial syndromes.
PMID- 9399912
TI - Instability of the (CTG)n repeat in congenital myotonic dystrophy.
PMID- 9399911
TI - Mutations in PDX1, the human lipoyl-containing component X of the pyruvate
dehydrogenase-complex gene on chromosome 11p1, in congenital lactic acidosis.
AB - We have identified and sequenced a cDNA that encodes an apparent human orthologue
of a yeast protein-X component (ScPDX1) of pyruvate dehydrogenase multienzyme
complexes. The new human cDNA that has been referred to as "HsPDX1" cDNA was
cloned by use of the "database cloning" strategy and had a 1,506-bp open reading
frame. The amino acid sequence of the protein encoded by the cDNA was 20%
identical with that encoded by the yeast PDX1 gene and 40% identical with that
encoded by the lipoate acetyltransferase component of the pyruvate dehydrogenase
and included a lipoyl-bearing domain that is conserved in some dehydrogenase
enzyme complexes. Northern blot analysis demonstrated that the major HsPDX1 mRNA
was 2.5 kb in length and was expressed mainly in human skeletal and cardiac
muscles but was also present, at low levels, in other tissues. FISH analysis
performed with a P1-derived artificial chromosome (PAC)-containing HsPDX1 gene
sublocalized the gene to 11p1.3. Molecular investigation of PDX1 deficiency in
four patients with neonatal lactic acidemias revealed mutations 78del85 and
965del59 in a homozygous state, and one other patient had no PDX1 mRNA
expression.
PMID- 9399913
TI - Genomic imprinting: a chromatin connection.
PMID- 9399915
TI - Centromere DNA dynamics: latent centromeres and neocentromere formation.
PMID- 9399916
TI - Dynamic interrelationships between DNA replication, methylation, and repair.
PMID- 9399935
TI - Clinically relevant findings.
PMID- 9399917
TI - PTEN: sometimes taking it off can be better than putting it on.
PMID- 9399936
TI - An emerging paradigm shift on the role of leukocyte adhesion molecules.
PMID- 9399937
TI - The Epstein-Barr virus and systemic lupus erythematosus.
PMID- 9399938
TI - Pathways and mechanisms for cytokine signaling of the central nervous system.
PMID- 9399939
TI - Cytokines in the brain during viral infection: clues to HIV-associated dementia.
PMID- 9399940
TI - Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast
cancer.
AB - Expression of nuclear factor-kappaB (NF-kappaB)/Rel transcription factors has
recently been found to promote cell survival, inhibiting the induction of
apoptosis. In most cells other than B lymphocytes, NF-kappaB/Rel is inactive,
sequestered in the cytoplasm. For example, nuclear extracts from two human
untransformed breast epithelial cell lines expressed only very low levels of NF
kappaB. Unexpectedly, nuclear extracts from two human breast tumor cell lines
displayed significant levels of NF-kappaB/Rel. Direct inhibition of this NF
kappaB/ Rel activity in breast cancer cells induced apoptosis. High levels of NF
kappaB/Rel binding were also observed in carcinogen-induced primary rat mammary
tumors, whereas only expectedly low levels were seen in normal rat mammary
glands. Furthermore, multiple human breast cancer specimens contained significant
levels of nuclear NF-kappaB/Rel subunits. Thus, aberrant nuclear expression of NF
kappaB/Rel is associated with breast cancer. Given the role of NF-kappaB/Rel
factors in cell survival, this aberrant activity may play a role in tumor
progression, and represents a possible therapeutic target in the treatment of
these tumors.
PMID- 9399941
TI - Constitutive nuclear factor-kappaB-RelA activation is required for proliferation
and survival of Hodgkin's disease tumor cells.
AB - The pathogenesis and etiology of Hodgkin's disease, a common human malignant
lymphoma, is still unresolved. As a unique characteristic, we have identified
constitutive activation of the transcription factor nuclear factor (NF)-kappaB
p50-RelA in Hodgkin/Reed-Sternberg (H/RS) cells, which discriminates these
neoplastic cells from most cell types studied to date. In contrast to other
lymphoid and nonlymphoid cell lines tested, proliferation of H/RS cells depended
on activated NF-kappaB. Furthermore, constitutive NF-kappaB p50-RelA prevented
Hodgkin's lymphoma cells from undergoing apoptosis under stress conditions.
Consistent with this dual function, Hodgkin's lymphoma cells depleted of
constitutive nuclear NF-kappaB revealed strongly impaired tumor growth in severe
combined immunodeficient mice. Our findings identify NF-kappaB as an important
component for understanding the pathogenesis of Hodgkin's disease and for
developing new therapeutic strategies against it.
PMID- 9399942
TI - Preferential localization of systemically administered radiolabeled interleukin
1alpha in experimental inflammation in mice by binding to the type II receptor.
AB - Previously, we have shown that systemically administered radiolabeled interleukin
1alpha (IL-1alpha) accumulates preferentially in inflammatory foci in mice. Since
inflammation is characterized by influx of leukocytes, which represent IL-1
receptor (IL-1R) positive cells, radiolabeled IL-1 may specifically localize in
inflammation by binding to its receptors on infiltrated leukocytes. This
hypothesis was tested in a series of studies in mice with acute focal
inflammations. Evidence for specific IL-1-IL-1R interaction in induced
inflammation was found: microscopic autoradiography revealed that 125I-IL-1alpha
localized at the site of inflammatory cells with time; 125I-myoglobin, a similar
sized protein with no known interactions in vivo, was not retained in the
inflammation. Furthermore, the uptake 125I-IL-1alpha in inflammatory tissue was
significantly lower in neutropenic mice than in immunocompetent mice (0.05+/
0.004 vs. 0.65+/-0.06% ID/g at 48 h after injection, P < 0.0007). Moreover, the
uptake of 125I-IL-1alpha at the inflammatory site could be blocked with the anti
IL-1R type II antibody 4E2. At 48 h after injection, the uptake with and without
blocking the type II IL-1R was 0.13+/-0.01 and 0. 65+/-0.05% ID/g, respectively
(P < 0.0001). These in vivo studies provide evidence that systemically
administered radiolabeled IL-1alpha localizes in inflammatory tissue by specific
receptor binding, predominantly by binding to the type II IL-1R.
PMID- 9399943
TI - The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in
rats with renal insufficiency. Control of parathyroid cell growth via a calcium
receptor.
AB - Parathyroid (PT) cell hyperplasia is a common consequence of chronic renal
insufficiency (CRI). NPS R-568 is a phenylalkylamine compound that acts as an
agonist (calcimimetic) at the cell surface calcium receptor (CaR). To test the
hypothesis that the CaR plays a role in PT hyperplasia in CRI, we tested the
effect of NPS R-568 on PT cell proliferation in rats with renal insufficiency.
Rats were subjected to 5/6 nephrectomy and then infused intraperitoneally with 5
bromodeoxyuridine (BrdU) to label S-phase cells. Two groups of nephrectomized
rats received NPS R-568 by gavage twice daily for 4 d (1.5 and 15 mg/kg body wt).
On day 5, the number of BrdU-positive PT cells of vehicle-treated nephrectomized
rats was 2.6-fold greater than that of the sham-operated control. Low and high
doses of NPS R-568 reduced the number of BrdU-positive PT cells by 20 and 50%,
respectively. No changes in staining, however, were observed in ileal epithelial
cells (CaR-negative) or in thyroidal C-cells (CaR-positive). Furthermore, the
effect of NPS R-568 could not be explained by changes in serum 1,25(OH)2D3 or
phosphorus. These results indicate that NPS R-568 suppresses PT cell
proliferation in rats with renal insufficiency, and lend support to the linkage
between the CaR and PT hyperplasia in CRI.
PMID- 9399944
TI - Role of nitric oxide in experimental obliterative bronchiolitis (chronic
rejection) in the rat.
AB - The role of nitric oxide in obliterative bronchiolitis development, i.e., chronic
rejection, was investigated in the heterotopic rat tracheal allograft model. An
increase in the intragraft inducible nitric oxide synthase (iNOS) mRNA and
mononuclear inflammatory cell iNOS immunoreactivity was demonstrated during
progressive loss of respiratory epithelium and airway occlusion in nontreated
allografts compared to syngeneic grafts. In nontreated allografts, however,
intragraft nitric oxide production was decreased, most likely because of loss of
iNOS epithelial expression. Treatment with aminoguanidine, a preferential
inhibitor of inducible nitric oxide synthase, was associated with enhanced
proliferation of alpha-smooth muscle actin immunoreactive cells and the intensity
of obliterative bronchiolitis early after transplantation. Aminoguanidine
treatment did not affect iNOS mRNA synthesis or intragraft nitric oxide
production, but decreased iNOS immunoreactivity in smooth muscle cells. Treatment
with L-arginine, a precursor of nitric oxide, significantly reduced obliterative
changes. L-arginine supplementation enhanced intragraft iNOS mRNA synthesis and
iNOS immunoreactivity in capillary endothelial and smooth muscle cells as well as
intragraft nitric oxide production. Immunohistochemical analysis of allografts
showed that neither iNOS inhibition nor supplementation of the nitric oxide
pathway affected the number of graft-infiltrating CD4+ and CD8+ T cells, ED1+ and
ED3+ macrophages, immune activation with expression of IL-2R or MHC class II, or
production of macrophage or Th1 cytokines. In contrast, L-arginine treatment was
associated with increased staining for Th2 cytokines IL-4 and IL-10. In
conclusion, this study demonstrates that nitric oxide has a protective role in
obliterative bronchiolitis development in this model, and suggests that nitric
oxide either directly or indirectly inhibits smooth muscle cell proliferation and
modulates immune response towards Th2 cytokines.
PMID- 9399945
TI - Immunohistochemical colocalization of glycoxidation products and lipid
peroxidation products in diabetic renal glomerular lesions. Implication for
glycoxidative stress in the pathogenesis of diabetic nephropathy.
AB - Advanced glycation end products (AGEs) include a variety of protein adducts whose
accumulation alters the structure and function of tissue proteins and stimulates
cellular responses. They have been implicated in tissue damage associated with
diabetic complications. To assess the possible link between AGE accumulation and
the development of diabetic nephropathy (DN), we have examined the
immunohistochemical localization of various AGE structures postulated to date,
i.e., pentosidine, Nepsilon-(carboxymethyl)lysine (CML), and pyrraline, in
diabetic and control kidneys. CML and pentosidine accumulate in the expanded
mesangial matrix and thickened glomerular capillary walls of early DN and in
nodular lesions and arterial walls of advanced DN, but were absent in control
kidneys. By contrast, pyrraline was not found within diabetic glomeruli but was
detected in the interstitial connective tissue of both normal and diabetic
kidneys. Although the distribution of pyrraline was topographically identical to
type III collagen, distribution of pentosidine and CML was not specific for
collagen type, suggesting that difference in matrix protein composition per se
could not explain heterogeneous AGE localization. Since oxidation is linked
closely to the formation of pentosidine and CML, we also immunostained
malondialdehyde (MDA), a lipid peroxidation product whose formation is
accelerated by oxidative stress, assuming that local oxidative stress may serve
as a mechanism of pentosidine and CML accumulation. Consistent with our
assumption, diabetic nodular lesions were stained positive for MDA. These
findings show that AGE localization in DN varies according to AGE structure, and
suggest that the colocalization of markers of glycoxidation (pentosidine and CML)
with a marker of lipid peroxidation reflects a local oxidative stress in
association with the pathogenesis of diabetic glomerular lesions. Thus,
glycoxidation markers may serve as useful biomarkers of oxidative damage in DN.
PMID- 9399946
TI - Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and
associate with altered adipocyte beta-2 adrenoceptor function.
AB - Catecholamines play a central role in the regulation of energy expenditure, in
part by stimulating lipid mobilization through lipolysis in fat cells. The beta-2
adrenoceptor (BAR-2) is a major lipolytic receptor in human fat cells. To
determine whether known polymorphisms in codons 16, 27, and 164 of this receptor
play a role in obesity and subcutaneous adipocyte BAR-2 lipolytic function, we
investigated a group of 140 women with a large variation in body fat mass. Only
the polymorphisms in codons 16 and 27 were common in the study population. The
Gln27Glu polymorphism was markedly associated with obesity with a relative risk
for obesity of approximately 7 and an odds ratio of approximately 10. Homozygotes
for Glu27 had an average fat mass excess of 20 kg and approximately 50% larger
fat cells than controls. However, no significant association with changes in BAR
2 function was observed. The Arg16Gly polymorphism was associated with altered
BAR-2 function with Gly16 carriers showing a fivefold increased agonist
sensitivity and without any change in BAR-2 expression. However, it was not
significantly linked with obesity. These findings suggest that genetic
variability in the human BAR-2 gene could be of major importance for obesity,
energy expenditure, and lipolytic BAR-2 function in adipose tissue, at least in
women.
PMID- 9399947
TI - Immunization against the agent of human granulocytic ehrlichiosis in a murine
model.
AB - The agent of human granulocytic ehrlichiosis (HGE) is a newly recognized tick
borne pathogen that resides within polymorphonuclear leukocytes. C3H/HeN mice can
become infected with the agent of HGE (designated aoHGE) by syringe inoculation
or tick-borne infection and develop transient neutropenia. They thereby partially
mimic human disease and provide a model in which to study immunity to this
microorganism. Mice vaccinated with lysates of purified aoHGE, or administered
aoHGE antisera, were partially protected from both syringe- and tick-transmitted
challenge with aoHGE. These data suggest that antibodies are sufficient to
provide substantial, but not complete, immunity against aoHGE.
PMID- 9399948
TI - An increased prevalence of Epstein-Barr virus infection in young patients
suggests a possible etiology for systemic lupus erythematosus.
AB - An unknown environmental agent has been suspected to induce systemic lupus
erythematosus (lupus) in man. Prompted by our recent immunochemical findings, we
sought evidence for an association between Epstein-Barr virus infection and
lupus. Because the vast majority of adults have been infected with Epstein-Barr
virus, we chose to study children and young adults. Virtually all (116 of 117, or
99%) of these young patients had seroconverted against Epstein-Barr virus, as
compared with only 70% (107 of 153) of their controls (odds ratio 49.9, 95%
confidence interval 9.3-1025, P < 0. 00000000001). The difference in the rate of
Epstein-Barr virus seroconversion could not be explained by serum IgG level or by
cross-reacting anti-Sm/nRNP autoantibodies. No similar difference was found in
the seroconversion rates against four other herpes viruses. An assay for Epstein
Barr viral DNA in peripheral blood lymphocytes established Epstein-Barr virus
infection in the peripheral blood of all 32 of the lupus patients tested, while
only 23 of the 32 matched controls were infected (odds ratio > 10, 95% confidence
interval 2.53-infinity, P < 0.002). When considered with other evidence
supporting a relationship between Epstein-Barr virus and lupus, these data are
consistent with, but do not in themselves establish, Epstein-Barr virus infection
as an etiologic factor in lupus.
PMID- 9399950
TI - An interleukin-2 receptor gamma chain mutation with normal thymus morphology.
AB - One of the most common human immunodeficiencies is an X-linked condition arising
from mutations of the gamma subunit of the interleukin-2 receptor (IL-2Rgamma).
The IL-2Rgamma protein is one chain of the heterotrimeric (alpha, beta, gamma) IL
2 receptor, but also participates in the formation of the IL-4, 7, 9, and 15
receptor complexes. The diagnosis of X-linked SCID is usually relatively simple
due to the distinctive immunological presentation; IL-2Rgamma-deficient patients
typically lacking mature T lymphocytes (T-B+). However, it is becoming clear that
this merely represents one extreme of a potential range of clinical
presentations. We describe here a novel mutation of the human IL-2Rgamma chain
(R222C) resulting in an unusual immunological phenotype. Although clinically
immunodeficient, this patient has normal numbers of peripheral T and B cells,
responds normally to mitogenic stimuli, and unusually, has a normal thymus gland.
This IL-2Rgamma mutation is distinctive in that the protein is sufficiently
stable to be expressed at the cell surface. While the T cell receptor repertoire
appears complete, suggesting normal T cell differentiation occurs, patient T
cells demonstrate a reduced ability to bind IL-2 and this appears sufficient to
cause a deficiency in their ability to participate in antigenic responses. Early
clinical recognition of this phenotype is critical as a delay in diagnosis may
result in a fatal infection.
PMID- 9399949
TI - Prevention of experimental myasthenia gravis by nasal administration of synthetic
acetylcholine receptor T epitope sequences.
AB - T cell tolerization prevents and improves T cell-mediated experimental autoimmune
diseases. We investigated here whether similar approaches could be used for
antibody (Ab)-mediated autoimmune diseases. Myasthenia gravis, caused by IgG Ab
against muscle acetylcholine receptor (AChR), is perhaps the best characterized
of them. We used an animal model, experimental myasthenia gravis induced in
C57Bl/6 mice by immunization with Torpedo acetylcholine receptor (TAChR), to
demonstrate that nasal administration of synthetic sequences of the TAChR alpha
subunit- forming epitopes recognized by anti-TAChR CD4+ T helper cells (residues
alpha150-169, alpha181-200, and alpha360-378), given before and during
immunization with TAChR, causes decreased CD4+ responsiveness to those epitopes
and to TAChR, reduced synthesis of anti-TAChR Ab, and prevented experimental
myasthenia gravis. These effects were not induced by nasal administration of
synthetic epitopes of diphtheria toxin. Secretion of IL-2, IL-4, and IL-10 by
spleen T cells from TAChR immunized mice, in response to challenge with TAChR in
vitro, indicated that in sham-tolerized mice only Th1 cells responded to TAChR,
while peptide-treated mice had also an AChR-specific Th2 response. The TAChR
peptide treatment induced also in vitro anergy to the TAChR of the spleen T
cells, which was reversed by IL-2.
PMID- 9399951
TI - Overexpression of Rab3D enhances regulated amylase secretion from pancreatic
acini of transgenic mice.
AB - Rab3D, a member of the ras-related GTP-binding protein Rab family, is localized
to secretory granules of various exocrine tissues such as acinar cells of the
pancreas, chief cells of the stomach, and parotid and lacrimal secretory cells.
To elucidate the function of Rab3D in exocytosis, we have generated transgenic
mice that over-express Rab3D specifically in pancreatic acinar cells.
Hemagglutinin-tagged Rab3D was localized to zymogen granules by
immunohistochemistry, and was shown to be present on zymogen granule membranes by
Western blotting; both results are similar to previous studies of endogenous
Rab3D. Secretion measurements in isolated acinar preparations showed that
overexpression of Rab3D enhanced amylase release. Amylase secretion from intact
acini of transgenic mice 5 min after 10 pM cholecystokinin octapeptide (CCK)
stimulation was enhanced by 160% of control. In streptolysin-O-permeabilized
acini of transgenic mice, amylase secretion induced by 100 microM GTP-gamma-S was
enhanced by 150%, and 10 microM Ca2+-stimulated amylase secretion was augmented
by 206% of that of the control. To further elucidate Rab3D involvement in
stimulus-secretion coupling, we examined the effect of CCK on the rate of GTP
binding to Rab3D. Stimulation of permeabilized acini with 10 pM CCK increased the
incorporation of radiolabeled GTP into HA-tagged Rab3D. These results indicate
that overexpression of Rab3D enhances secretagogue-stimulated amylase secretion
through both calcium and GTP pathways. We conclude that Rab3D protein on zymogen
granules plays a stimulatory role in regulated amylase secretion from pancreatic
acini.
PMID- 9399952
TI - Myocardial ischemia induces differential regulation of KATP channel gene
expression in rat hearts.
AB - The cardiac ATP-sensitive potassium (KATP) channel is thought to be a complex
composed of an inward rectifier potassium channel (Kir6.1 and/or Kir6.2) subunit
and the sulfonylurea receptor (SUR2). This channel is activated during myocardial
ischemia and protects the heart from ischemic injury. We examined the
transcriptional expression of these genes in rats with myocardial ischemia. 60
min of myocardial regional ischemia followed by 24-72 h, but not 3-6 h, of
reperfusion specifically upregulated Kir6.1 mRNA not only in the ischemic
(approximately 2.7-3.1-fold) but also in the nonischemic (approximately 2.0-2.6
fold) region of the left ventricle. 24 h of continuous ischemia without
reperfusion also induced an increase in Kir6.1 mRNA in both regions, whereas 15
30 min of ischemia followed by 24 h of reperfusion did not induce such
expression. In contrast, mRNAs for Kir6.2 and SUR2 remained unchanged under these
ischemic procedures. Western blotting demonstrated similar increases in the
Kir6.1 protein level both in the ischemic (2.4-fold) and the nonischemic (2.2
fold) region of rat hearts subjected to 60 min of ischemia followed by 24 h of
reperfusion. Thus, prolonged myocardial ischemia rather than reperfusion induces
delayed and differential regulation of cardiac KATP channel gene expression.
PMID- 9399953
TI - Lung disease in mice with cystic fibrosis.
AB - The leading cause of mortality and morbidity in humans with cystic fibrosis is
lung disease. Advances in our understanding of the pathogenesis of the lung
disease of cystic fibrosis, as well as development of innovative therapeutic
interventions, have been compromised by the lack of a natural animal model. The
utility of the CFTR-knockout mouse in studying the pathogenesis of cystic
fibrosis has been limited because of their failure, despite the presence of
severe intestinal disease, to develop lung disease. Herein, we describe the
phenotype of an inbred congenic strain of CFTR-knockout mouse that develops
spontaneous and progressive lung disease of early onset. The major features of
the lung disease include failure of effective mucociliary transport,
postbronchiolar over inflation of alveoli and parenchymal interstitial
thickening, with evidence of fibrosis and inflammatory cell recruitment. We
speculate that the basis for development of lung disease in the congenic CFTR
knockout mice is their observed lack of a non-CFTR chloride channel normally
found in CFTR-knockout mice of mixed genetic background.
PMID- 9399954
TI - Microtubule-associated protein 1 light chain 3 is a fibronectin mRNA-binding
protein linked to mRNA translation in lamb vascular smooth muscle cells.
AB - Intimal cushions form in the fetal ductus arteriosus by fibronectin-dependent
smooth muscle cell migration which is associated with greater efficiency of
fibronectin mRNA translation. We investigated whether the AU-rich element (ARE),
UUAUUUAU, in the 3'-untranslated region (3'UTR) of fibronectin mRNA is involved
in this mechanism by transfecting smooth muscle cells with plasmids containing
the chloramphenicol acetyltransferase coding region with its 3'UTR replaced by
fibronectin 3'UTR bearing intact or mutated ARE. More efficient translation of
fusion mRNA with intact versus mutated ARE was observed. This effect was
amplified in ductus (10.9-fold) compared with nonmigratory, lower fibronectin
producing aorta cells (6.5-fold). Ductus cells transfected with wild-type but not
ARE-mutated plasmid reverted to the stellate phenotype of aorta cells associated
with reduced fibronectin production. This suggested that plasmid ARE sequesters
RNA-binding factors, thereby reducing endogenous fibronectin mRNA translation. We
next purified a 15-kD fibronectin ARE-dependent RNA-binding protein and
identified it as microtubule-associated protein 1 light chain 3 (LC3). LC3 is
present in greater amounts in ductus compared with aorta cells, and
overexpression of LC3 in aortic cells by transfection enhances fibronectin mRNA
translation to levels observed in ductus cells.
PMID- 9399955
TI - Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating
leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model
of asthma.
AB - Immunized mice after inhalation of specific antigen have the following
characteristic features of human asthma: airway eosinophilia, mucus and Th2
cytokine release, and hyperresponsiveness to methacholine. A model of late-phase
allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address
the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and
hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal
administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL
5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade
on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented
the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary
leukocyte distinct from the eosinophil is the key effector cell of allergen
induced pulmonary inflammation and hyperresponsiveness.
PMID- 9399956
TI - Characterization of the AD7C-NTP cDNA expression in Alzheimer's disease and
measurement of a 41-kD protein in cerebrospinal fluid.
AB - We have isolated a novel Alu sequence-containing cDNA, designated AD7c-NTP, that
is expressed in neurons, and overexpressed in brains with Alzheimer's disease
(AD). The 1,442-nucleotide AD7c-NTP cDNA encodes an approximately 41-kD protein.
Expression of AD7c-NTP was confirmed by nucleic acid sequencing of reverse
transcriptase PCR products isolated from brain. AD7c-NTP cDNA probes hybridized
with 1. 4 kB mRNA transcripts by Northern blot analysis, and monoclonal
antibodies generated with the recombinant protein were immunoreactive with
approximately 41-45-kD and approximately 18-21-kD molecules by Western blot
analysis. In situ hybridization and immunostaining studies localized AD7c-NTP
gene expression in neurons. Using a quantitative enzyme-linked sandwich
immunoassay (Ghanbari, K., I. Beheshti, and H. Ghanbari, manuscript submitted for
publication) constructed with antibodies to the recombinant protein, AD7c-NTP
levels were measured under code in 323 clinical and postmortem cerebrospinal
fluid (CSF) samples from AD, age-matched control, Parkinson's disease, and
neurological disease control patients. The molecular mass of the AD7c-NTP
detected in CSF was approximately 41 kD. In postmortem CSF, the mean
concentration of AD7c-NTP in cases of definite AD (9.2+/-8.2 ng/ml) was higher
than in the aged control group (1.6+/-0.9; P < 0.0001). In CSF samples from
individuals with early possible or probable AD, the mean concentration of AD7c
NTP (4.6+/-3.4) was also elevated relative to the levels in CSF from age-matched
(1.2+/-0.7) and neurological disease (1.0+/-0.9) controls, and ambulatory
patients with Parkinson's disease (1.8+/-1.1) (all P < 0.001). CSF levels of AD7c
NTP were correlated with Blessed dementia scale scores (r = 0. 66; P = 0.0001)
rather than age (r = -0.06; P > 0.1). In vitro studies demonstrated that
overexpression of AD7c-NTP in transfected neuronal cells promotes neuritic
sprouting and cell death, the two principal neuroanatomical lesions correlated
with dementia in AD. The results suggest that abnormal AD7c-NTP expression is
associated with AD neurodegeneration, and during the early stages of disease, CSF
levels correlate with the severity of dementia.
PMID- 9399957
TI - Leptin selectively decreases visceral adiposity and enhances insulin action.
AB - Intraabdominal adiposity and insulin resistance are risk factors for diabetes
mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived
protein encoded by the ob gene, has been postulated to be a sensor of energy
storage in adipose tissue capable of mediating a feedback signal to sites
involved in the regulation of energy homeostasis. Here, we provide evidence for
specific effects of leptin on fat distribution and in vivo insulin action. Leptin
(LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed
adult rats. During the 8 d of the study, body weight and total fat mass decreased
similarly in LEP and in CON. However, while moderate calorie restriction (CON)
resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat,
leptin administration led to a specific and marked decrease (by 62%) in visceral
adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly
enhanced insulin action on both inhibition of hepatic glucose production and
stimulation of glucose uptake. Finally, leptin exerted complex effects on the
hepatic gene expression of key metabolic enzymes and on the intrahepatic
partitioning of metabolic fluxes, which are likely to represent a defense against
excessive storage of energy in adipose depots. These studies demonstrate novel
actions of circulating leptin in the regulation of fat distribution, insulin
action, and hepatic gene expression and suggest that it may play a role in the
pathophysiology of abdominal obesity and insulin resistance.
PMID- 9399958
TI - The antifungal antibiotic, clotrimazole, inhibits chloride secretion by human
intestinal T84 cells via blockade of distinct basolateral K+ conductances.
Demonstration of efficacy in intact rabbit colon and in an in vivo mouse model of
cholera.
AB - The antifungal antibiotic clotrimazole (CLT) blocks directly and with high
potency the Ca2+-activated K+ channels of human erythrocytes, erythroleukemia
cells, and ferret vascular smooth muscle cells. We recently reported that CLT
inhibits Cl- secretion in human intestinal T84 cells, likely by affecting K+
transport (Rufo, P.A., L. Jiang, S.J. Moe, C. Brugnara, S.L. Alper, and W.I.
Lencer. 1996. J. Clin. Invest. 98:2066-2075). To determine if CLT had direct
effects on K+ conductances in T84 cells, we selectively permeabilized apical
membranes of confluent T84 cell monolayers using the ionophore amphotericin B.
This technique permits direct measurement of basolateral K+ transport. We found
that CLT and a stable des-imidazolyl derivative inhibited directly two
pharmacologically distinct basolateral membrane K+conductances, but had no effect
on apical membrane Cl- conductances. The effects of CLT on Cl- secretion were
also examined in intact tissue. CLT inhibited forskolin-induced Cl- secretion in
rabbit colonic mucosal sheets mounted in Ussing chambers by 91%. CLT also
inhibited cholera toxin-induced intestinal Cl- secretion in intact mice by 94%.
These data provide direct evidence that CLT blocks Cl- secretion in intestinal
T84 cells by inhibition of basolateral K+ conductances, and show that CLT
inhibits salt and water secretion from intact tissue in vitro and in vivo. The
results further support the suggestion that CLT and its metabolites may show
clinical efficacy in the treatment of secretory diarrheas of diverse etiologies.
PMID- 9399959
TI - Indirect effect of insulin to suppress endogenous glucose production is dominant,
even with hyperglucagonemia.
AB - Suppression of endogenous glucose production (EGP) is one of insulin's primary
metabolic effects and failure of this action is a major contributor to fasting
hyperglycemia of type 2 diabetes mellitus. Classically, insulin was thought to
suppress the liver directly, via hyperinsulinemia in the portal vein. Recently,
however, we and others have demonstrated that at least part, and possibly most of
insulin's action to suppress EGP is normally mediated via an extrahepatic (i.e.,
indirect) mechanism. We have suggested that this mechanism involves insulin
suppression of adipocyte lipolysis, leading to lowered FFA and reduced EGP
("Single Gateway Hypothesis"). Previous studies of the indirect insulin effect
from this laboratory were done under conditions of lowered portal glucagon.
Because of the possibility that the direct (i.e., portal) effect of insulin may
have been underestimated with hypoglucagonemia, these studies examined the
relative importance of portal insulin, versus peripheral insulin (administered at
one-half the dose to equalize peripheral insulin levels) at four rates of portal
glucagon infusion: 0, 0.65 (under-), 1.5 (basal-), and 3.0 ng/kg per min (over
replacement). Portal versus peripheral insulin suppressed steady-state EGP to the
same extent (52%), confirming that the primary effect of insulin to suppress EGP
is via the peripheral mechanism. This conclusion was maintained regardless of
portal glucagonemia, although there was some evidence for an increase in the
direct insulin effect at hyperglucagonemia. The indirect effect of insulin is the
primary mechanism of steady-state EGP suppression under normal conditions. The
direct effect increases with hyperglucagonemia; however, the indirect effect
remains predominant even under those conditions.
PMID- 9399961
TI - B lymphocytes from patients with chronic lymphocytic leukemia contain signal
transducer and activator of transcription (STAT) 1 and STAT3 constitutively
phosphorylated on serine residues.
AB - To explore the pathogenesis of chronic lymphocytic leukemia (CLL), we examined
whether phosphorylation of one or more signal transducer and activator of
transcription (STAT) factors was abnormal in cells from CLL patients. No
constitutive tyrosine phosphorylation was detected on any STAT in CLL cells. To
assess the phosphorylation of serine residues of STAT1 and STAT3 in CLL cells, we
raised antibodies that specifically recognize the form of STAT1 phosphorylated on
ser-727 and the form of STAT3 phosphorylated on ser-727. We found that in 100% of
patients with CLL (n = 32), STAT1 and STAT3 were constitutively phosphorylated on
serine. This was in contrast to normal peripheral blood B lymphocytes or CD5+) B
cells isolated from tonsils, in which this phosphorylation was absent. Serine
phosphorylation of STAT1 and STAT3 was seen occasionally in other leukemias, but
it was a universal finding only in CLL. The serine phosphorylation of these STATs
was a continuous process, as incubation of CLL cells with the kinase inhibitor H7
led to the dephosphorylation of these serine residues. The STAT serine kinase in
CLL cells has not been identified, and appears to be neither mitogen-activated
protein kinase nor pp70(s6k). In summary, the constitutive serine phosphorylation
of STAT1 and STAT3 is present in all CLL samples tested to date, although the
physiologic significance of this modification remains to be determined.
PMID- 9399960
TI - Nitric oxide production contributes to the angiogenic properties of vascular
endothelial growth factor in human endothelial cells.
AB - Vascular endothelial growth factor (VEGF) is a regulator of vasculogenesis and
angiogenesis. To investigate the role of nitric oxide (NO) in VEGF-induced
proliferation and in vitro angiogenesis, human umbilical vein endothelial cells
(HUVEC) were used. VEGF stimulated the growth of HUVEC in an NO-dependent manner.
In addition, VEGF promoted the NO-dependent formation of network-like structures
in HUVEC cultured in three dimensional (3D) collagen gels. Exposure of cells to
VEGF led to a concentration-dependent increase in cGMP levels, an indicator of NO
production, that was inhibited by nitro-L-arginine methyl ester. VEGF-stimulated
NO production required activation of tyrosine kinases and increases in
intracellular calcium, since tyrosine kinase inhibitors and calcium chelators
attenuated VEGF-induced NO release. Moreover, two chemically distinct
phosphoinositide 3 kinase (PI-3K) inhibitors attenuated NO release after VEGF
stimulation. In addition, HUVEC incubated with VEGF for 24 h showed an increase
in the amount of endothelial NO synthase (eNOS) protein and the release of NO. In
summary, both short- and long-term exposure of human EC to VEGF stimulates the
release of biologically active NO. While long-term exposure increases eNOS
protein levels, short-term stimulation with VEGF promotes NO release through
mechanisms involving tyrosine and PI-3K kinases, suggesting that NO mediates
aspects of VEGF signaling required for EC proliferation and organization in
vitro.
PMID- 9399962
TI - Activators of peroxisome proliferator-activated receptor gamma have depot
specific effects on human preadipocyte differentiation.
AB - Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear
receptor highly expressed in adipocytes, induces the differentiation of murine
preadipocyte cell lines. Recently, thiazolidinediones (TZDs), a novel class of
insulin-sensitizing compounds effective in the treatment of non-insulin-dependent
diabetes mellitus (NIDDM) have been shown to bind to PPARgamma with high
affinity. We have examined the effects of these compounds on the differentiation
of human preadipocytes derived from subcutaneous (SC) and omental (Om) fat.
Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, and
mRNA levels, subcultured preadipocytes isolated from either SC or Om depots did
not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or
troglitazone) or 15-deoxyDelta12,14prostaglandin J2 (a natural PPARgamma ligand)
enhanced markedly the differentiation of preadipocytes from SC sites, assessed by
all three criteria. The rank order of potency of these agents in inducing
differentiation matched their ability to activate transcription via human
PPARgamma. In contrast, preadipocytes from Om sites in the same individuals were
refractory to TZDs, although PPARgamma was expressed at similar levels in both
depots. The mechanism of this depot-specific TZD response is unknown. However,
given the association between Om adiposity and NIDDM, the site-specific
responsiveness of human preadipocytes to TZDs may be involved in the beneficial
effects of these compounds on in vivo insulin sensitivity.
PMID- 9399963
TI - Interferon-gamma and tumor necrosis factor-alpha specifically induce formation of
cytomegalovirus-permissive monocyte-derived macrophages that are refractory to
the antiviral activity of these cytokines.
AB - Monocytes/macrophages are key cells in the pathogenesis of human cytomegalovirus
(HCMV). Although HCMV infection in monocytes is restricted to early events of
gene expression, productive infection has been demonstrated in differentiated
macrophages in vitro. We examined the cellular and cytokine components that are
essential for HCMV replication in Concanavalin A-stimulated monocyte-derived
macrophages (MDM). By negative selection, depletion of CD8+ T lymphocytes, but
not CD4+ T lymphocytes, CD19+ B cells, or CD56+ NK cells, resulted in a 60-70%
reduction in the number of HCMV-infected MDM, and a 4 log decrease in virus
production. Neutralization of IFN-gamma and TNF-alpha, but not IL-1, IL-2, or TGF
beta, decreased production of virus by 4 logs and 2 logs, respectively.
Subsequently, addition of recombinant IFN-gamma or TNF-alpha to purified monocyte
cultures was sufficient to produce HCMV-permissive MDM. While IFN-gamma and TNF
alpha possess antiviral properties, addition of these cytokines to permissive MDM
cultures did not affect production of HCMV. Thus, rather than inhibiting
replication of HCMV, IFN-gamma and TNF-alpha specifically induce differentiation
of monocytes into HCMV-permissive MDM, which are resistant to the antiviral
effects of these cytokines.
PMID- 9399964
TI - Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2)
and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese
diabetic (ob/ob) mouse.
AB - Intracellular insulin signaling involves a series of alternative and
complementary pathways created by the multiple substrates of the insulin receptor
(IRS) and the various isoforms of SH2 domain signaling molecules that can
interact with these substrates. In this study, we have evaluated the roles of IRS
1 and IRS-2 in signaling to the phosphatidylinositol (PI) 3-kinase pathway in the
ob/ob mouse, a model of the insulin resistance of obesity and non-insulin
dependent diabetes mellitus. We find that the levels of expression of both IRS-1
and IRS-2 are decreased approximately 50% in muscle, whereas in liver the
decrease is significantly greater for IRS-2 (72%) than for IRS-1 (29%). This
results in differential decreases in IRS-1 and IRS-2 phosphorylation, docking of
the p85alpha regulatory subunit of PI 3-kinase, and activation of this enzyme in
these two insulin target tissues. In ob/ob liver there is also a change in
expression of the alternatively spliced isoforms of the regulatory subunits for
PI 3-kinase that was detected at the protein and mRNA level. This resulted in a
45% decrease in the p85alpha form of PI 3-kinase, a ninefold increase in the
AS53/p55alpha, and a twofold increase in p50alpha isoforms. Thus, there are
multiple alterations in the early steps of insulin signaling in the ob/ob mouse,
with differential regulation of IRS-1 and IRS-2, various PI 3-kinase regulatory
isoforms, and a lack of compensation for the decrease in insulin signaling by any
of the known alternative pathways at these levels.
PMID- 9399965
TI - Following the fate of individual T cells throughout activation and clonal
expansion. Signals from T cell receptor and CD28 differentially regulate the
induction and duration of a proliferative response.
AB - A detailed understanding of the effects of costimulatory signals on primary T
cell expansion has been limited by experimental approaches that measure the bulk
response of a cell population, without distinguishing responses of individual
cells. Here, we have labeled live T cells in vitro with a stable, fluorescent dye
that segregates equally between daughter cells upon cell division, allowing the
proliferative history of any T cell present or generated during a response to be
monitored over time. This system permits simultaneous evaluation of T cell
surface markers, allowing concomitant assessment of cellular activation and
quantitative determination of T cell receptor (TCR) occupancy on individual
cells. Through this approach, we find that TCR engagement primarily regulates the
frequency of T cells that enter the proliferative pool, but has relatively little
effect on the number of times these cells will ultimately divide. In contrast,
CD28-costimulation regulates both the frequency of responding cells (particularly
at sub-maximal levels of TCR engagement), and more prominently, the number of
mitotic events that responding cells undergo. When CD28-stimulation is blocked,
provision of IL-2 restores the frequency of responding cells and the normal
pattern of mitotic progression, indicating that the other CD28-induced genes are
not required for this effect. An unexpected finding was that even at maximal
levels of TCR engagement and CD28-mediated costimulation, only 50-60% of the
original T cells in culture can be induced to divide. The nondividing cells are
heterogeneous for naive versus memory markers, suggesting a more complex
relationship between expression of memory markers and the ability to be recruited
into the dividing pool. From these studies, we conclude that a stringent
checkpoint regulates the participation of activated T cells in clonal expansion,
with TCR and CD28 signals having both overlapping and differential effects on the
induction and maintenance of T cell responses.
PMID- 9399966
TI - Association between genetic polymorphisms of the beta2-adrenoceptor and response
to albuterol in children with and without a history of wheezing.
AB - The beta2-adrenergic receptor (beta2AR) agonists are the most widely used agents
in the treatment of asthma, but the genetic determinants of responsiveness to
these agents are unknown. Two polymorphic loci within the coding region of the
beta2AR have been recently described at amino acids 16 and 27. It has been
reported that glycine at codon 16 (Gly-16) is associated with increased agonist
promoted downregulation of the beta2AR as compared with arginine-16 (Arg-16). The
form of the receptor with glutamic acid at codon 27 (Glu-27), on the other hand,
has been shown to be resistant to downregulation when compared with glutamine-27
(Gln-27), but only when coexpressed with Arg-16. To assess if different genotypes
of these two polymorphisms would show differential responses to inhaled beta2AR
agonists, we genotyped 269 children who were participants in a longitudinal study
of asthma. Spirometry was performed before and after administration of 180 microg
of albuterol, and a positive response was considered an increase of >15.3%
predicted FEV1. There was marked linkage disequilibrium between the two
polymorphisms, with 97.8% of all chromosomes that carried Arg-16 also carrying
Gln-27. When compared to homozygotes for Gly-16, homozygotes for Arg-16 were 5.3
times (95% confidence interval 1.6-17.7) and heterozygotes for beta2AR-16 were
2.3 times (1.3-4.2) more likely to respond to albuterol, respectively. Similar
trends were observed for asthmatic and nonasthmatic children, and results were
independent of baseline lung function, ethnic origin, and previous use of
antiasthma medication. No association was found between the beta2AR-27
polymorphism and response to albuterol. These results may explain some of the
variability in response to therapeutic doses of albuterol in children.
PMID- 9399967
TI - Anabaseine is a potent agonist on muscle and neuronal alpha-bungarotoxin
sensitive nicotinic receptors.
AB - We assessed the pharmacological activity of anabaseine, a toxin found in certain
animal venoms, relative to nicotine and anabasine on a variety of vertebrate
nicotinic receptors, using cultured cells, the Xenopus oocyte expression system,
contractility assays with skeletal and smooth muscle strips containing nicotinic
receptors and in vivo rat prostration assay involving direct injection into the
lateral ventricle of the brain. Anabaseine stimulated every subtype of nicotinic
receptor that was tested. It was the most potent frog skeletal muscle nicotinic
receptor agonist. At higher concentrations it also blocked the BC3H1 (adult
mouse) muscle type receptor ion channel. The affinities of the three nicotinoid
compounds for rat brain membrane alpha-bungarotoxin binding sites and their
potencies for stimulating Xenopus oocyte homomeric alpha7 receptors, expressed in
terms of their active monocation concentrations, displayed the same rank order,
anabaseine>anabasine> nicotine. Although the maximum currents generated by
anabaseine and anabasine at alpha7 receptors were equivalent to that of
acetylcholine, the maximum response to nicotine was only about 65% of the
acetylcholine response. At alpha4-beta2 receptors the affinities and apparent
efficacies of anabaseine and anabasine were much less than that of nicotine.
Anabaseine, nicotine and anabasine were nearly equipotent on sympathetic (PC12)
receptors, although parasympathetic (myenteric plexus) receptors were much more
sensitive to anabaseine and nicotine but less sensitive to anabasine. These
differences suggest that there may be different subunit combinations in these two
autonomic nicotinic receptors. The preferential interactions of anabaseine,
anabasine and nicotine with different receptor subtypes provides molecular clues
that should be helpful in the design of selective nicotinic agonists.
PMID- 9399968
TI - Nifedipine, an L-type calcium channel blocker, restores the hypnotic response in
rats made tolerant to the alpha-2 adrenergic agonist dexmedetomidine.
AB - Rats were made tolerant to the hypnotic effects of the alpha-2 adrenergic agonist
dexmedetomidine by a 7- or 14-day continuous systemic administration of the same,
and the ability of nifedipine to reverse dexmedetomidine tolerance was assessed.
Acute administration of nifedipine (10 mg/kg i.p.) restored the hypnotic response
to dexmedetomidine in the alpha-2 tolerant rats. Concurrent administration of
nifedipine during induction of tolerance, either partially (continuous
administration 10 mg/kg/day delivered by minipumps) or completely (twice daily
injections, 20 mg/kg s.c.) restored hypnotic responsiveness to control levels.
Induction of tolerance reduced the affinity of [3H]PN200-110 for the L-type
calcium channel. Chronically administered nifedipine treatment (20 mg/kg s.c.
twice daily), at doses that partially restored the behavioral response to normal,
did not change ligand binding affinity of [3H]PN200-110. An increase in Bmax for
[3H]PN200-110 was noted in the dexmedetomidine tolerant state which did not
change with chronic nifedipine. In naive rats, the phosphodiesterase inhibitor
rolipram (275 microg/kg i.p.), mimicked the state of tolerance, as it resulted in
a decreased hypnotic response to dexmedetomidine. Nifedipine (10 mg/kg i.p.) also
reversed the rolipram-induced attenuation of the hypnotic response to
dexmedetomidine. These data implicate a role for the L-type calcium channel in
the mechanism of the hypnotic response in alpha-2 tolerant rats and suggest the
involvement of the cAMP pathway.
PMID- 9399969
TI - Comparison of effect of mosapride citrate and existing 5-HT4 receptor agonists on
gastrointestinal motility in vivo and in vitro.
AB - Mosapride citrate is a new gastroprokinetic agent that enhances the upper GI
motility by stimulating 5-hydroxytryptamine4 (5-HT4) receptors. The purpose of
this study was to compare the effects of mosapride and the existing 5-HT4
receptor agonists on GI motility in conscious dogs and on various 5-HT4 receptor
mediated responses in vitro. In conscious dogs with force transducers implanted,
mosapride (0.3-3 mg/kg i.v.) stimulated the antral motility without affecting the
colonic motility. However, cisapride, zacopride and BIMU 8 (0. 1-1 mg/kg i.v.)
stimulated both antral and colonic motility. The enhanced GI motility induced by
mosapride or cisapride was antagonized by pretreatment with GR113808 (1 mg/kg
bolus i.v., thereafter 1 mg/kg/hr infusion), a selective 5-HT4 receptor
antagonist. In the receptor binding studies, mosapride inhibited [3H]-GR113808
binding to 5-HT4 receptor sites of guinea pig striatum with an IC50 value of 113
nM. In addition, mosapride caused relaxation of the carbachol-precontracted rat
esophagus, enhanced the electrically evoked contractions of guinea pig ileum and
evoked the contractions of guinea pig distal colon with EC50 values of 208, 73,
and 3029 nM, respectively; this indicates that mosapride has a low affinity for
colon than for the rest of the GI tract. In contrast, cisapride, zacopride or
BIMU 8 had similar potencies in all preparations examined. In conclusion, these
studies indicate that mosapride selectively stimulates upper GI motility in vivo
and in vitro. These results also suggest heterogeneity of 5-HT4 receptors in the
GI tract.
PMID- 9399970
TI - Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine:
cross-substitution by mu and delta opioid agonists.
AB - The purpose of this investigation was to evaluate the discriminative stimulus
effects of the mixed-opioid agonist/antagonist dezocine. In pigeons trained to
discriminate 1.7 mg/kg dezocine from saline, a series of opioids with activity at
the mu opioid receptor substituted completely for the dezocine stimulus with a
rank order of potency similar to that obtained in other assays sensitive to the
effects of mu agonists (i.e., fentanyl >[-]-cyclazocine >buprenorphine =
butorphanol >l-methadone >nalbuphine >[-]-metazocine >morphine). (-)-N
allylnormetazocine and (+)-propoxyphene substituted partially for the dezocine
stimulus, an effect obtained even when tested up to doses that suppressed
responding. Naloxone (0.1 - 10 mg/kg) antagonized the stimulus effects of
dezocine, (+)-propoxyphene and fentanyl in a dose-related manner, whereas doses
of naloxone that antagonized fentanyl's rate-decreasing effects failed to
antagonize the rate-decreasing effects of dezocine and (+)-propoxyphene. A 10
mg/kg dose of the mu-selective, noncompetitive antagonist beta-funaltrexamine was
more effective against the stimulus effects of dezocine and nalbuphine than
against morphine and fentanyl. As was observed with naloxone, beta-funaltrexamine
failed to antagonize dezocine's rate-decreasing effects. The delta agonists
BW373U86 and SNC80 substituted partially for the dezocine stimulus, and these
effects were reversed by doses of the delta-selective antagonist naltrindole (0.1
and 1.0 mg/kg) that had no effect on the dezocine stimulus. Naltrindole also
antagonized the rate-decreasing effects produced by BW373U86 and SNC80, but not
those of dezocine. The kappa agonists bremazocine, spiradoline, U50,488 and
U69,593 failed to substitute for the dezocine stimulus. The kappa-selective
antagonist norbinaltorphimine (1.0 mg/kg) failed to antagonize dezocine's
stimulus or rate-decreasing effects. The present findings indicate that dezocine
shares similar stimulus effects with both mu and delta agonists, its stimulus
effects are reversed by mu-selective antagonists, and its rate-decreasing effects
are not mediated by activity at mu, kappa or delta opioid receptors.
PMID- 9399971
TI - Selective brain to blood efflux transport of para-aminohippuric acid across the
blood-brain barrier: in vivo evidence by use of the brain efflux index method.
AB - Efflux transport of para-aminohippuric acid (PAH) across the blood-brain barrier
(BBB) has been demonstrated by use of the brain efflux index (BEI) method. PAH
was eliminated from the ipsilateral cerebrum extensively with an apparent efflux
rate constant of 0.0587 (min-1) after microinjection into a cerebral cortex
region termed Par2. This efflux transport showed a saturation with the Michaelis
constant of approximately 400 microM. No more than 3% dose of PAH and carboxyl
inulin, used as a reference compound showing limited permeability at the BBB,
were found in the contralateral cerebrum, cerebellum or cerebrospinal fluid up to
20 min after administration. Under saturated conditions for carrier-mediated
efflux of PAH via the blood-cerebrospinal fluid barrier, the BEI value of PAH did
not change significantly, which suggested that blood-cerebrospinal fluid barrier
was not responsible for the elimination of PAH from the brain after
microinjection. No significant metabolism of PAH was demonstrated in the brain
for at least 20 min after microinjection, and most of the radioactivity in the
ipsilateral and contralateral carotid veins was as the intact form. With the
distribution volume of PAH, 0.800 ml/g brain, obtained from the brain slice
uptake experiment, the apparent efflux clearance was calculated as 46.9
microl/min/g brain. In addition, the influx clearance of PAH across the BBB
determined by the in vivo brain uptake index method was much smaller than the
efflux clearance, which demonstrates that BBB transports PAH selectively from the
brain to the circulating blood.
PMID- 9399972
TI - Effects of tachykinins on rapidly adapting pulmonary stretch receptors and total
lung resistance in anesthetized, artificially ventilated rabbits.
AB - In anesthetized, artificially ventilated rabbits not treated with thiorphan (2
mg/kg), a neutral endopeptidase (NEP) inhibitor, substance P (SP) and neurokinin
A (NKA) in doses from 0.2 to 2.7 microg/kg produced dose-related increases in
rapidly adapting pulmonary stretch receptor (RAR) activity without any
significant changes in total lung resistance (RL), whereas neurokinin B (NKB) at
the same concentrations did not significantly alter either RAR activity or RL. In
comparison with the excitatory responses of RAR activity to SP and NKA, the
magnitudes of increased receptor activity evoked SP were significantly larger
than those after NKA administration. The rank order of tachykinins for RAR
stimulus potency was SP > NKA > KB. Pretreatment with thiorphan potentiated the
increases of RAR activity and RL induced by SP but had no effect on the RAR and
RL responses to NKA and NKB. Subsequent administration of L 659, 877 (a selective
NK2 receptor antagonist, 2. 3 and 7.6 microg/kg) that dose-dependently inhibited
NKA-induced RAR stimulation did not significantly influence augmentation of the
RAR and RL responses to SP. Administration of atropine (2 mg/kg, n = 6) in
thiorphan-treated rabbits, which had no effect on NKA- and NKB-induced RAR
stimuli, significantly attenuated the increases of RAR activity and RL induced by
SP. These results suggest that tachykinin-induced RAR stimulation is mediated by
the activation of NK2 receptors, probably involving participation of NK1
receptors. Furthermore, potentiation of the increases of RAR activity and RL
produced by SP administration in the presence of thiorphan is partly mediated by
facilitation of cholinergic neurotransmission.
PMID- 9399973
TI - Heparinase III exerts endothelial and cardioprotective effects in feline
myocardial ischemia-reperfusion injury.
AB - The initial phase of neutrophil (PMN) adherence in the pathophysiology of
myocardial ischemia-reperfusion (MI/R) injury depends on the selectins,
particularly P- and L-selectin. Several ligands for these selectins have been
identified, one of which may be a heparan sulfate proteoglycan (HSPG). Cats
subjected to 90 min of MI and 270 min of R were given either heparinase III
(0.033, 0.33 or 3.33 IU/kg/min) or its vehicle beginning 10 min before R and
continuing throughout the 270-min R period. Heparinase III at 3.33 IU/kg/min
provided a marked cardioprotective effect compared with cats receiving only
vehicle as evidenced by a significant attenuation in myocardial necrosis (P <
.01). In addition, endothelium-dependent vasorelaxation to acetylcholine in
coronary artery rings isolated from MI/R cats treated with heparinase III was
significantly preserved (P < .01). Adherence of PMNs to the coronary vascular
endothelium after 270 min of R was also significantly attenuated in heparinase
III-treated cats compared with vehicle (P < .01). At 0.33 IU/kg/min, heparinase
III exerted modest, significant cardioprotective effects, whereas at 0.033
IU/kg/min, no significant beneficial effects were observed. Our results indicate
that heparinase III is cardioprotective in a dose-dependent manner, preserves
endothelial function and attenuates PMN adherence to the coronary vascular
endothelium.
PMID- 9399974
TI - Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion
transporter, OAT-K1.
AB - We recently cloned and characterized the rat kidney-specific organic anion
transporter, OAT-K1, which was suggested to mediate renal tubular transport of
methotrexate. In this study, we investigated the interactions of nonsteroidal
anti-inflammatory drugs (NSAIDs) with OAT-K1 by evaluating the effects of these
drugs on renal distribution of methotrexate in vivo, and on methotrexate
accumulation in the stably transfected LLC-PK1 cells expressing OAT-K1 (LLC-OAT
K1). NSAIDs such as indomethacin and ketoprofen had significant inhibitory
effects on renal accumulation of methotrexate in rats after coadministration.
Indomethacin and ketoprofen inhibited methotrexate accumulation by LLC-OAT-K1
cells in a competitive manner with the apparent inhibition constant values of 1.
0 mM and 1.9 mM, respectively. Other NSAIDs including ibuprofen, flufenamate and
phenylbutazone also showed potent inhibitory effects on methotrexate
accumulation. However, indomethacin was not transported via OAT-K1. These results
indicate that NSAIDs have potent inhibitory effects against the OAT-K1-mediated
methotrexate transport, which suggests that the OAT-K1 may be one of interaction
sites for methotrexate and NSAIDs in the kidney.
PMID- 9399975
TI - Positive modulation of pepsinogen secretion by gastric acidity after vagal
cholinergic stimulation.
AB - Parallel increments of gastric acid and pepsinogen secretion generally occur
after the application of cholinergic stimuli. However, it still remains to be
established whether the changes in acid output associated with cholinergic
stimulation play a role in regulation of the concomitant peptic secretory
activity. In the present study, an anesthetized rat model was used for the
evaluation of pepsinogen secretion in order to pursue a dual purpose: 1) to
assess the relative functional relevance of direct and acid-dependent control
exerted by cholinergic pathways on pepsinogen output; 2) to characterize the
mechanisms through which changes in acidity within the stomach lumen may affect
the peptic secretory activity of gastric mucosa. Bethanechol, 2-deoxy-D-glucose
or electrical vagal stimulation caused parallel and atropine-sensitive increments
of peptic and acid secretions. Omeprazole, a selective inhibitor of gastric H+:K+
adenosintriphosphatase, blocked the increase in acid but not pepsinogen secretion
induced by bethanechol. However, 2-deoxy-D-glucose or electrical vagal
stimulation failed to increase either pepsinogen or acid secretion in omeprazole
pretreated rats. When tested in animals pretreated with both omeprazole and
physostigmine (a drug able to prevent the enzymatic breakdown of vagally released
ACh through the blockade of acetylcholinesterase), 2-deoxy-D-glucose or
electrical vagal stimulation significantly increased pepsinogen secretion without
affecting acid secretion. In omeprazole-pretreated rats, perfusion of the gastric
lumen with acid solutions caused a pH-dependent and atropine-sensitive increase
in peptic output only when applied in combination with electrical vagal
stimulation. Functional ablation of capsaicin-sensitive sensory neurons did not
modify the gastric secretory responses induced by bethanechol or electrical vagal
stimulation. However, after topical application of lidocaine to the gastric
mucosal surface, bethanechol stimulated both peptic and acid outputs, whereas
electrical vagal stimulation only evoked acid secretion without affecting basal
peptic output. The present results indicate that the activation of muscarinic
receptors by vagally released ACh is not sufficient by itself to stimulate
pepsinogen secretion and that a facilitatory action mediated by acid secretion is
necessary to allow an increment of peptic output in response to vagal cholinergic
stimuli. It is suggested that such facilitatory input is driven to chief cells by
local intramural reflexes that involve capsaicin-insensitive intrinsic nerves.
PMID- 9399976
TI - Pharmacokinetic-pharmacodynamic characterization of the cardiovascular, hypnotic,
EEG and ventilatory responses to dexmedetomidine in the rat.
AB - This study characterizes the pharmacokinetic-pharmacodynamic (PK-PD)
relationships of the cardiovascular, EEG, hypnotic and ventilatory effects of the
alpha-2 adrenergic agonist dexmedetomidine in rats. Dexmedetomidine was
administered by a single rapid infusion (n = 6) and by an infusion regimen of
gradually increasing rate (n = 8). HR, mean arterial pressure (MAP) and EEG
signals were recorded continuously, as was the time at which the rats woke up
spontaneously from drug-induced sleep, a measure of hypnosis. Arterial
concentrations of dexmedetomidine and blood gases were determined regularly. A
sigmoidal Emax model was used to describe the HR, MAP and EEG concentration
effect relationships, with the EEG effect (activity in 0.5-3.5-Hz frequency band)
linked to an effect-site model. The PK of dexmedetomidine could be described by a
two-compartment model, with similar PK parameters for both infusion regimens.
Plasma protein binding was 84.1[0.7]%. Because of complex cardiovascular
homeostatic reflex mechanisms, HR and MAP could only be analyzed during gradually
increasing infusions. The maximal decrease in HR was 35(2)%, and the maximal
increase in MAP was 37(2)%. For both infusion regimens, similar PD parameters
were found for the EEG and the hypnotic measure. These data suggest the absence
of active metabolites or tolerance of the EEG and hypnotic effects. Judging on
the basis of concentrations of dexmedetomidine (mean (S.E. M.)), HR decrease was
the most sensitive response [EC50 of 0.65(0. 09) ng/ml], followed by increase in
MAP [EC50 of 2.01(0.14) ng/ml], change in EEG activity [EC50 of 2.24(0.16) ng/ml]
and the hypnotic measure [Cwake-up of 2.64(0.10) ng/ml]. Ventilatory effects were
minor.
PMID- 9399977
TI - SB 202026: a novel muscarinic partial agonist with functional selectivity for M1
receptors.
AB - The finding that ascending cholinergic systems are severely degenerated in
Alzheimer's disease has driven the search for a cholinomimetic therapy. Adverse
effects observed with cholinesterase inhibitors and high-efficacy muscarinic
agonists led us to design compounds with an improved profile. SB 202026 (R-(Z)
(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced
[3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity
(IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13
nM), but exhibited low affinity for cholinergic nicotinic receptors and other
neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026
possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate
from all muscarinic receptor subtypes. In functional models in vitro, SB 202026
caused maximal depolarization of the rat superior cervical ganglion at low
concentrations (300 nM) (M1-mediated effect), while producing a lower maximal
effect than the high-efficacy agonists oxotremorine-M and carbachol on M2
mediated release of ACh and M3-mediated smooth muscle contraction (guinea pig
ileum), respectively. The functional selectivity and partial agonist profile seen
in vitro were reflected in vivo through potent cognition-related activity (M1
induced increase in hippocampal EEG power) combined with low efficacy, compared
with arecoline or oxotremorine, on induction of bradycardia (M2-mediated
response), hypotension (via M3-mediated vasorelaxation) and tremor (thought to be
mediated by M3 receptors). The foregoing profile of SB 202026 predicted that
cognition-enhancing activity would be achieved at doses below those that initiate
undesirable side effects, and this has subsequently been demonstrated in rodents,
marmosets and humans.
PMID- 9399978
TI - Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and
prostaglandin E2 production.
AB - PGs derived from cyclooxygenase-2 (COX-2), in particular PGE2, play important
roles in the initiation of inflammation and pain. In the present study, we
evaluated the role of COX-2-derived PGE2 in an animal model of established
hyperalgesia. Inflammation and hyperalgesia were first induced by injection of
carrageenan into rat footpads. Then we investigated the effects of subsequent
therapeutic treatment with a selective COX inhibitor, with a nonsteroidal anti
inflammatory drug and with anti-PGE2 antibody. Test compounds were administered 1
to 3 hr after carrageenan challenge, and inhibition of pain (hyperalgesia,
measured by withdrawal from a thermal stimulus), and changes in paw edema and PG
levels were evaluated. The i.v. administration of a nonselective COX inhibitor,
ketorolac, caused a rapid reduction in hyperalgesia in the inflamed footpad,
returning it to near-normal values within 1 hr. Normal (control) paw response
times were not affected. Therapeutic administration of ketorolac prevented most
further swelling caused by carrageenan but did not reverse edema already present
at the time of dosing. Administered p.o., a selective COX-2 inhibitor (SC-58635)
was as efficacious as ketorolac in reducing inflammatory hyperalgesia. Footpad PG
levels returned to base line or below within 5 min of dosing with ketorolac,
which suggests rapid turnover of PG in the inflamed tissue. Therapeutic treatment
with a monoclonal anti-PGE2 antibody also fully reversed the hyperalgesia
response. These studies suggest that continuous production of PGE2 by the COX-2
enzyme is a critical element in sustaining the hyperalgesic response at sites of
tissue inflammation.
PMID- 9399979
TI - Active immunization alters the plasma nicotine concentration in rats.
AB - The ability of active immunization to alter nicotine distribution was studied in
rats. Animals were immunized with 6-(carboxymethylureido)-(+/-)-nicotine (CMUNic)
linked to keyhole limpet hemocyanin (KLH). Antibody titers determined by ELISA,
using CMUNic coupled to albumin as the coating antigen, were greater than
1:10,000. Antibody binding was inhibited by neither of the nicotine metabolites
cotinine and nicotine-N-oxide but was inhibited to a greater extent by CMUNic
than by nicotine; this suggests the presence of antibodies to the linker
structure as well as antibodies to nicotine. Antibody affinity for nicotine
measured by soluble radioimmunoassay was 2.4 +/- 1.6 x 10(7) M-1, and binding
capacity was 1.3 +/- 0.7 x 10(-6) M, which corresponds to 0.1 +/- 0.05 mg/ml of
nicotine-specific IgG per milliliter of serum. One week after their second boost,
groups of eight anesthetized rats immunized with either CMUNic-KLH or KLH alone
received nicotine 0.03 mg/kg (equivalent to two cigarettes in a human) via the
jugular vein over 10 sec. This dosing regimen was shown to mimic the arterio
venous nicotine concentration gradient typical of nicotine delivered by cigarette
smoking in humans. Plasma nicotine concentrations at 10 to 40 min were 4 to 6
fold higher in the CMUNic-KLH rats than in controls (P < .001). Nicotine binding
in plasma determined by equilibrium dialysis was markedly increased in the CMUNic
KLH group (83.4 +/- 6.8% vs. 16.4 +/- 14.2%), but brain nicotine concentrations
at 40 min did not differ (37.9 +/- 4.5 vs. 44.0 +/- 8. 4 ng/g, CMUNic-KLH vs.
KLH, P = .1). The amount of nicotine bound to antibody in plasma, estimated from
the in vivo data, was 9% of the administered dose. These data demonstrate that
active immunization can bind a significant fraction of a clinically relevant
nicotine dose in plasma. Observing this effect with antibodies of modest affinity
and titer is encouraging, but better immunogens may be needed to alter nicotine
distribution to brain and modify nicotine's behavioral effects.
PMID- 9399981
TI - Alcohol dehydrogenase-2*3 allele protects against alcohol-related birth defects
among African Americans.
AB - Considerable variation in offspring outcome is observed after intrauterine
alcohol exposure. The underlying mechanism may include genetic diversity in the
enzymes responsible for alcohol metabolism. Of the known genetic polymorphisms,
differences at the alcohol dehydrogenase-2 locus (ADH2) are likely most critical
because the resulting enzymes are >30-fold different in their kinetic constants.
To test whether differences in maternal or offspring ADH2 genotype are
determinants of risk for alcohol-related birth defects, maternal-infant pairs (n
= 243) were enrolled on the basis of maternal alcohol intake during pregnancy and
maternal ADH2 genotype. Infant outcome was measured using the Bayley Scales of
Infant Development Mental Index (MDI) at 12 months of age. Drinking during
pregnancy was associated with lower MDI scores but only in the offspring of
mothers without an ADH2*3 allele (P < .01, analysis of variance, post hoc). The
offspring of drinking women with at least one ADH2*3 allele had MDI scores
similar to those of nondrinking women of either ADH2 genotype. Lower MDI scores
were associated with the three-way interaction among increasing alcohol intake
and maternal and offspring absence of the ADH2*3 allele (P < .01, multiple linear
regression). We suggest that the protection afforded by this allele is secondary
to its encoding of the high-Km/high-Vmax ADH beta3 isoenzyme, which would provide
more efficient alcohol metabolism at high blood alcohol concentrations. These
observations are supportive of alcohol, rather than acetaldehyde, being the more
important proximate teratogen and are the first observations of a specific
genetic explanation for susceptibility differences to alcohol-related birth
defects.
PMID- 9399980
TI - Angiotensin-converting enzyme inhibition and angiotensin II subtype-1 receptor
blockade during the progression of left ventricular dysfunction: differential
effects on myocyte contractile processes.
AB - Inhibition of the angiotensin-converting enzyme (ACE) in the setting of chronic
left ventricular (LV) dysfunction has been demonstrated to have beneficial
effects on survival and symptoms. However, whether ACE inhibition has direct
effects on myocyte contractile processes and if these effects are mediated
primarily through the AT1 angiotensin-II receptor subtype remains unclear. The
present project examined the relationship between changes in LV and myocyte
function and beta adrenergic receptor transduction in four groups of six dogs
each: (1) Rapid Pace: LV failure induced by chronic rapid pacing (4 weeks; 216 +/
2 bpm); (2) Rapid Pace/ACEI: concomitant ACE inhibition (ACEI: fosinopril 30
mg/kg b.i.d.) with chronic pacing; (3) Rapid Pace/AT1 Block: concomitant AT1 Ang
II receptor blockade [Irbesartan: SR 47436(BMS-186295) 30 mg/kg b.i.d.] with
chronic pacing; and (4) CONTROL: sham controls. With Rapid Pace, the LV end
diastolic volume increased by 62% and the ejection fraction decreased by 53% from
control. With Rapid Pace/ACEI, the LV end-diastolic volume was reduced by 24% and
the ejection fraction increased by 26% from Rapid Pace only values. Rapid
Pace/AT1 Block did not improve LV geometry or function from Rapid Pace values.
Myocyte contractile function decreased by 40% with Rapid Pace and increased from
this value by 32% with Rapid Pace/ACEI. Rapid Pace/AT1 Block had no effect on
myocyte function when compared with Rapid Pace values. With Rapid Pace/ACEI, beta
receptor density and cyclic AMP production were normalized and associated with an
improvement in myocyte beta adrenergic response compared with Rapid Pace only.
Although Rapid Pace/AT1 also normalized beta receptor density, cyclic AMP
production was unchanged and myocyte beta adrenergic response was reduced by 15%
compared with Rapid Pace only. ACE inhibition with chronic rapid pacing improved
LV and myocyte geometry and function, and normalized beta receptor density and
cyclic AMP production. However, AT1 Ang-II receptor blockade with chronic rapid
pacing failed to provide similar protective effects on LV and myocyte geometry
and function. These unique findings suggest that the effects of ACE inhibition on
LV geometry and myocyte contractile processes in the setting of developing LV
failure are not primarily caused by modulation of AT1 Ang-II receptor activation.
PMID- 9399982
TI - Absence of tachykinin involvement in leukotriene D4 and antigen-induced
contraction of guinea pig isolated bronchus.
AB - In guinea pig airways, contractions induced by leukotriene D4 or antigen are
thought to be mediated primarily by an action of the agonist or of released mast
cell-derived mediators directly on the airway smooth muscle cell. An indirect
contractile action mediated by endogenous tachykinins also has been described for
both of these stimuli. The present study evaluated the contribution of endogenous
tachykinins to ovalbumin- and leukotriene D4-induced contractions in the guinea
pig bronchus by modulating the concentrations of tachykinins within the tissues
and by using neurokinin receptor antagonists. Acute depletion of tachykinins with
capsaicin had no effect on responses elicited by either stimulus. Similarly,
tetrodotoxin treatment failed to influence leukotriene D4-induced contractions.
Inhibitors of neutral endopeptidase (thiorphan) and angiotensin-converting enzyme
(lisinopril) enhanced neurally mediated tachykininergic responses and potentiated
leukotriene D4. The latter effect persisted in the presence of tetrodotoxin or
the neurokinin antagonists CP99994 and SR48968 and in tissues treated acutely
with capsaicin. The potentiation was absent, however, from bronchi incubated with
L-cysteine. Ovalbumin-induced contractions were unaltered by inhibition of
neutral endopeptidase and angiotensin-converting enzyme. These observations
suggest that tachykinins are not involved in mediation of leukotriene D4- or
antigen-induced contractions of the guinea pig bronchus. The ability of protease
inhibitors to potentiate leukotriene D4 but not antigen-induced responses is
therefore ascribed to inhibition of bioinactivation of leukotriene D4 to
leukotriene E4.
PMID- 9399983
TI - Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and
effects on experimental cerebral vasospasm.
AB - Endothelin (ET) receptor antagonists are of great potential clinical interest for
the treatment pathological conditions associated with vasospasm, such as
subarachnoid hemorrhage (SAH). We developed for parenteral use a compound of a
class of trifunctionalized heteroarylsulfonamide pyrimidines specially designed
for high water solubility. Ro 61-1790 [5-methyl-pyridine-2-sulfonic acid 6-(2
hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)
pyrimidin-4-ylamide] is a competitive ET antagonist with an affinity to ETA
receptor in the subnanomolar range. It has a approximately 1000-fold selectivity
for the ETA vs. the ETB receptor as assessed on functional assays (e.g., ET-1
induced inositol-1,4, 5-triphosphate release or ET-1-induced intracellular
calcium mobilization). Ro 61-1790 also had a high functional potency for
inhibiting contraction induced by ET-1 on isolated rat aorta (ETA receptors; pA2
= 9.5) or by sarafotoxin S6c on rat trachea (ETB receptors; pA2 = 6.4). In vivo,
Ro 61-1790 inhibited the pressor effect of big ET-1 in pithed rats with an ID50
value of 0.05 mg/kg. Intravenous bolus of Ro 61-1790 induced a long-lasting
antihypertensive effect in deoxycorticosterone acetate salt rats instrumented
with telemetry. In a double-hemorrhage canine model of SAH, Ro 61-1790 both
prevented and reversed cerebral vasospasm in a dose-dependent manner. In an
established cerebral vasospasm, 3 mg/kg Ro 61-1790 i.v. was half as efficacious
as intrabasilar papaverine. Ro 61-1790 (20 mg/kg/day) totally prevented the
occurrence of vasospasm. In summary, these data demonstrate that Ro 61-1790 is a
potent and selective ETA receptor antagonist suitable for parenteral use and
potentially useful for preventing delayed ischemic deficit in patients with SAH.
PMID- 9399984
TI - Pharmacokinetic-pharmacodynamic modeling of stimulatory and sedative effects of
alprazolam: timing performance deficits.
AB - Alprazolam decreased the reinforcement rate and increased the shorter-response
rate of contingency-controlled timing behavior under a differential reinforcement
of low-rate schedule (DRL 45-s) in rats. An integrated pharmacokinetic
pharmacodynamic (PK-PD) model was developed to describe and characterize the
effects of i.v. and s. c. administration of alprazolam. The onset, peak and
disappearance of alprazolam effects were evaluated during a 3-hr session. After
s. c. alprazolam administration, two peak increases in shorter-response rate
occurred at moderate alprazolam serum levels, first in the ascending and then in
the descending limb of the concentration-time profile. We used a stimulation
sedation PD model incorporating two opposing effect-link sigmoidal Emax functions
to model the two peaks after s.c. alprazolam administration. The model suggested
that alprazolam possesses both stimulatory and sedative effects in a continuous
but sequential fashion, which corresponded to low- and high-concentration effects
as indicated by the EC50 values of 0.09 and 0.18 microg/ml, respectively. Owing
to the rapid onset of i.v. administration, the first peak (a transition phase
before the onset of the sedative effect) was absent, with the presence of the
second peak again coinciding with the offset of the sedative effect. The
reinforcement rate (IC50 = 0.02 microg/ml) characterized by the indirect response
model to account for the initial hysteresis is an index for evaluating the
deficit in timing performance. Although the effects of alprazolam can be
described in behavioral terms, simultaneous PK-PD optimization numerically
defines the performance and hypothesizes the coexistence of stimulation and
sedation components for alprazolam. The stimulation-sedation model may help in
delineating the possible mechanisms for adverse rebound side effects and of
tolerance in humans.
PMID- 9399985
TI - Nonpeptide endothelin receptor antagonists. X. Inhibition of endothelin-1- and
hypoxia-induced pulmonary pressor responses in the guinea pig by the endothelin
receptor antagonist, SB 217242.
AB - This study investigated the effects of the nonpeptide endothelin (ET) receptor
antagonist, SB 217242, against ET-1-induced pulmonary pressor responses and in a
model of hypoxia-induced pulmonary hypertension in the guinea pig. In guinea pig
isolated pulmonary artery rings, SB 217242 (3-300 nM) produced a concentration
dependent inhibition of ET-1-induced contractions, with a pA2 of 8.1. SB 217242
(1 or 3 mg/kg i.v.) elicited a dose-related inhibition of ET-1-induced increases
in pulmonary artery and airway insufflation pressure responses in anesthetized
guinea pigs. Chronic exposure to hypoxia (9% O2 for 0-14 days) produced a time
dependent increase in mean pulmonary artery pressure. After a 10-day exposure to
hypoxia there was about a 100% elevation in pulmonary artery pressure, and right
ventricular mass and plasma irET levels increased 3-fold compared with normoxic
animals. SB 217242, administered by continuous intraperitoneal infusion via mini
osmotic pump (0.36, 3.6 or 10.8 mg/day), significantly reduced (by about 50%)
hypoxia-induced pulmonary artery pressure increases at all three doses used. The
hypoxia-induced right ventricular hypertrophy was significantly attenuated by the
3.6 and 10.8 mg/day doses. Based on hematocrit, hemoglobin and red blood cell
counts, SB 217242 did not affect the normal physiological erythropoietic response
to hypoxia. There were no appreciable differences in the maximum contractile
effects of ET-1 or the potency of SB 217242 (pKB values, 8.3 and 8.0,
respectively) versus ET-1-induced responses in isolated pulmonary arteries from
hypoxic versus normoxic guinea pigs. However, there was a marked reduction in
endothelium-dependent relaxation of precontracted pulmonary artery isolated from
hypoxic compared with normoxic animals. The results of the present study provide
further preclinical evidence for a pathophysiological role of ET-1 and the
potential therapeutic utility of ET receptor antagonists, such as SB 217242, in
pulmonary hypertension.
PMID- 9399987
TI - Elevated environmental temperatures can induce hyperthermia during d-fenfluramine
exposure and enhance 5-hydroxytryptamine (5-HT) depletion in the brain.
AB - d-Fenfluramine (d-Fen) has been demonstrated to alter body temperature (BT),
decrease 5-hydroxytryptamine (5-HT) and decrease 5-HT plasma membrane
transporters (PMT) in rats. Therefore, experiments were designed to test whether
a correlation existed between elevated BT and brain 5-HT depletions. It was
hypothesized that d-Fen would induce hyperthermia if the environmental
temperature was elevated. Experiments were conducted to determine 1) the dose
response of d-Fen on BT in a 28 degrees C environment, 2) the acute effect of d
Fen on long-term depletion of 5-HT and 5-HT PMT in a 4 degrees C, 22 degrees C or
28 degrees C environment and 3) the effect of a 22 degrees C environment vs. a 28
degrees C environment on the plasma levels of d-Fen and d-norfenfluramine. d-Fen
produced a dose-dependent elevation of BT in the 28 degrees C environment,
decreased BT in the 4 degrees C environment and had no effect on BT in the 22
degrees C environment. Exposure to d-Fen in the 4 degrees C or 22 degrees C
environment reduced 5-HT and 5-HT PMT concentrations compared with control.
However, greater reductions of 5-HT and 5-HT PMT concentrations occurred in the
28 degrees C environment. Conversely, the plasma levels of d-Fen and d
norfenfluramine were not altered. Thus these experiments demonstrate that
increased BT during d-Fen exposure occurs at elevated environmental temperatures
without altering the plasma concentrations of the drug and results in an enhanced
long-term depletion of brain 5-HT and 5-HT PMT.
PMID- 9399986
TI - The effect of the enzyme inhibitor phenylmethylsulfonyl fluoride on the
pharmacological effect of anandamide in the mouse model of cannabimimetic
activity.
AB - Anandamide is an putative endogenous cannabinoid ligand that produces
pharmacological effects similar to those of Delta9-tetrahydrocannabinol, the
principle psychoactive constituent in marijuana. There is considerable evidence
that the enzyme inhibitor phenylmethylsulfonyl fluoride (PMSF) is capable of
altering the actions of anandamide in vitro by blocking its metabolism.
Therefore, studies were conducted in mice to determine whether PMSF could produce
cannabinoid effects by altering endogenous levels of anandamide as well as
determining whether PMSF could potentiate the effects of exogenously administered
anandamide. Mice receiving i.p. injections of PMSF exhibited cannabinoid effects
that included antinociception, hypothermia and immobility with ED50 values of 86,
224 and 206 mg/kg, respectively. Spontaneous activity was reduced at doses
greater than 100 mg/kg. However, none of these effects was blocked by the
cannabinoid antagonist SR 141716A. On the other hand, pretreatment with an
inactive dose of PMSF (30 mg/kg) potentiated the effects of anandamide on tail
flick response (antinociception), spontaneous activity and mobility by 5-, 10-
and 8-fold, respectively. PMSF did not alter anandamide's hypothermic effects.
Overall, these findings with PMSF underscore the importance of metabolism in the
actions of anandamide. It still must be established whether metabolites of
anandamide contribute to its pharmacological activity.
PMID- 9399988
TI - Blood-brain disposition and antinociceptive effects of -D-penicillamine2,5
enkephalin in the mouse.
AB - Although intravenous administration of [D-penicillamine2, 5]-enkephalin (DPDPE)
produces significant antinociception in rodents, the duration of antinociception
is short ( approximately 15 min). The present study was conducted to test the
hypothesis that duration of antinociception for DPDPE is determined by both
systemic and regional disposition (i.e., blood-brain translocation), and that the
magnitude of antinociception is related more closely to concentrations in brain
tissue than in blood. Systemic disposition was examined after i.v. administration
of DPDPE (10-100 mg/kg) to male CD-1 mice. The relationship between
antinociception and concentration in blood and brain tissue was assessed by
determining antinociception 10 min after administration of DPDPE (10-100 mg/kg);
effect versus brain tissue concentration data were fit with pharmacodynamic
models to recover EC50 estimates. In addition, the time course of
antinociception, as well as blood and brain tissue concentrations, were examined
after an i.v. bolus dose (40 mg/kg) of DPDPE. The systemic disposition of DPDPE
was nonlinear; both clearance and volume of distribution were dose-dependent.
Antinociception increased proportionately with increasing concentrations of DPDPE
in blood or brain tissue, with an EC50 of 1.42 +/- 0.06 microg/g expressed as
brain tissue concentration. However, the brain-to-blood concentration ratio also
increased with increasing dose, suggestive of saturable translocation of DPDPE
across the blood-brain barrier. Antinociception appeared rapidly (within 5 min)
and dissipated within approximately 15 min after a 40 mg/kg i.v. dose. These
results suggest that rapid elimination from blood and active efflux from brain
limit the duration of action of DPDPE.
PMID- 9399989
TI - Synergistic effects of cocaine with lateral hypothalamic brain stimulation
reward: lack of tolerance or sensitization.
AB - The curve-shift (rate-frequency) paradigm was used to quantify the interaction of
cocaine administration with the rewarding effects of lateral hypothalamic
electrical stimulation. First, eight animals were tested at 48-h intervals with
increasing doses of cocaine (0.5, 1, 2, 4, 8, 16 or 32 mg/kg i.p.); tests with
saline were given on intervening days. Cocaine produced dose-orderly leftward
shifts of the functions relating response rate to stimulation frequency, which
reduced, for each animal, the amount of stimulation required to sustain
responding; the two highest doses of the drug shifted the mean rate-frequency
curve by 0.47 log units, more than doubling the rewarding potency of the brain
stimulation. Baseline thresholds did not change between tests. Next, evidence for
sensitization or tolerance was sought from five additional groups of animals, one
group given 4 mg/kg and two groups given 16 mg/kg of cocaine at 48-h intervals,
and another two groups maintained for 7 days with thrice-daily injections of 10
mg/kg of cocaine or saline. Consistent with results seen in other brain
stimulation reward paradigms, there was no evidence of tolerance or sensitization
to cocaine's reward-potentiating effects as quantified in the rate-frequency
paradigm.
PMID- 9399990
TI - The In vitro hepatic metabolism of quinine in mice, rats and dogs: comparison
with human liver microsomes.
AB - The major metabolic pathway of quinine in the human has been shown to be 3
hydroxylation mediated mainly by human cytochrome P450 (CYP) 3A4. In this
extended in vitro study, quinine 3-hydroxylation was further investigated using
microsomes from mouse, rat, dog and human livers and was compared among them in
terms of the in vitro enzyme-kinetic parameters and quinine-drug interaction
screenings. In all species, 3-hydroxyquinine was the principal metabolite of
quinine. There was intra- and interspecies variability among all the kinetic
parameters, and dogs exhibited a closer resemblance to humans in terms of the
mean kinetic data. Ketoconazole and troleandomycin inhibited the 3-hydroxylation
of quinine in all species. Both alpha-naphthoflavone and diazepam showed an
interspecies difference in quinine 3-hydroxylation: a trend toward an activation
in dog and human, and a significant inhibition in mouse and rat, liver
microsomes. Antisera raised against rat CYP3A2 strongly inhibited quinine 3
hydroxylation by about 96, 84 and 92% with mouse, rat and dog liver microsomes,
respectively, but neither anti-rat 2C11 and 2E1 antisera did so with rat liver
microsomes. Primaquine, doxycycline and tetracycline substantially inhibited the
formation of 3-hydroxyquinine in rat, dog and human species, but proguanil had no
such effect in any species. Chloroquine inhibited quinine 3-hydroxylation with
rat and dog liver microsomes but not with human liver microsomes. There was a
significant correlation (r = 0.986, P < .001) between the CYP3A contents and the
formation rates of 3-hydroxyquinine in eight human liver microsomal samples. It
is concluded that 3-hydroxyquinine is a main metabolite of quinine and that
CYP3A/Cyp3a is a principal isoform involved in this metabolic pathway in the
respective (rat, dog and human/mouse) species tested. The dog and possibly the
rat may be qualitatively and quantitatively suitable animal models for exploring
the quinine 3-hydroxylase activity and for screening quinine-drug interactions in
vitro, at certain inconsistency with the human liver microsomal data.
PMID- 9399991
TI - Calpains mediate calcium and chloride influx during the late phase of cell
injury.
AB - The role of Ca++ in cell death is controversial. Extracellular Ca++ influx and
calpain activation occurred during the late phase of renal proximal tubule cell
injury produced by the mitochondrial inhibitor antimycin A. Chelation of
intracellular Ca++, extracellular Ca++, the calcium channel blocker nifedipine,
calpain inhibitor 1 and the dissimilar calpain inhibitor PD150606 blocked
antimycin A-induced influx of extracellular Ca++ and cell death. The calcium
channel blocker verapamil was ineffective. Calpain inhibitor 1 and PD150606 were
cytoprotective also against tetrafluoroethyl-L-cysteine-, bromohydroquinone-,
oxidant (t-butylhydroperoxide)- and calcium ionophore (ionomycin)-induced cell
death. Extracellular Ca++ influx was associated with the translocation of calpain
activity from the cytosol to the membrane and was prevented by calpain inhibitor
1, PD150606 and nifedipine. Finally, nifedipine, calpain inhibitor 1, PD150606
and the Cl- channel inhibitors [5-nitro-2-(3-phenylpropylamino)-benzoate,
niflumic acid, diphenylamine-2-carboxylate, and indanyloxyacetic acid] blocked
the increase in Cl- influx that occurs during the late phase of cell injury and
triggers terminal cell swelling and death. These data suggest that Ca++ and
calpains play a common and critical role in renal proximal tubule cell death
produced by diverse agents. In addition, calpain activation appears to play a
dual role during the late phase of cell injury. Initial calpain activation
elicits extracellular Ca++ influx through a nifedipine-sensitive pathway,
resulting in calpain translocation to the membrane and in turn Cl- influx.
PMID- 9399992
TI - Modulation of nociception by microinjection of delta-1 and delta-2 opioid
receptor ligands in the ventromedial medulla of the rat.
AB - In this study, we characterized the role of delta-1 and delta-2 opioid receptors
in the ventromedial medulla (VMM) in the modulation of thermal nociception. Male
Sprague-Dawley rats were prepared with an intracerebral guide cannula aimed at
the nucleus raphe magnus or nucleus reticularis gigantocellularis pars alpha.
Microinjection of the delta-1 opioid receptor agonist [D-Pen2,D-Pen5]enkephalin
(DPDPE) or the delta-2 opioid receptor agonist [D-Ala2, Glu4]deltorphin (DELT) in
the VMM increased response latency in the radiant heat tail-flick test with
respective ED50 values (95% CL) of 0.66 (0.07-1.5) nmol and 0.1 (0.03-0.21) nmol.
In the 55 degrees C hot-plate test, DELT produced a modest, transient increase in
response latency and DPDPE was ineffective. The antinociception produced by DPDPE
was antagonized by microinjection at the same site of 1.5 pmol of the delta-1
opioid receptor antagonist 7-benzylidenenaltrexone (BNTX) but not by 0.15 nmol of
the delta-2 opioid receptor antagonist naltriben (NTB). Conversely, the
antinociception produced by DELT was antagonized by microinjection at the same
site of 0.15 nmol of NTB but not by 1.5 pmol of BNTX. These doses of BNTX or NTB
alone did not alter either tail-flick or hot-plate latency when microinjected in
the VMM. However, at 10-fold higher doses, BNTX lost its selectivity for the
delta-1 opioid receptor, and NTB by itself increased tail-flick and hot-plate
latencies. These results collectively implicate both delta-1 and delta-2 opioid
receptors in the VMM in the modulation of nociception. They also indicate that
the antinociceptive effects of DPDPE and DELT can be distinguished by BNTX and
NTB, providing additional support for the existence of delta-1 and delta-2 opioid
receptor subtypes at supraspinal loci. Finally, the failure of effective doses of
either BNTX or NTB to alter nociceptive threshold suggests that neurons in the
VMM do not receive a tonic, inhibitory enkephalinergic input mediated by delta-1
or delta-2 receptors.
PMID- 9399993
TI - Inhibition of guinea pig detrusor contraction by NS-1619 is associated with
activation of BKCa and inhibition of calcium currents.
AB - The effects of NS-1619 on bladder contractile function and on transmembrane
currents were evaluated in vitro on isolated guinea pig detrusor strips and
isolated detrusor myocytes, respectively. In the isolated bladder strip, NS-1619
inhibited KCl-induced contractions in a concentration-dependent manner (IC50 =
12.2 +/- 3. 2 microM). Isolated detrusor myocytes were quiescent and had resting
membrane potentials that averaged -45.3 +/- 2.7 mV. With patch-clamp techniques
we demonstrated that exposure to 10 to 100 microM NS-1619 increased an
iberiotoxin-sensitive current consistent with the activation of the large
conductance calcium-dependent potassium channel (BKCa). Single-channel analysis
confirmed that NS-1619 increased the open probability of BKCa channels. NS-1619
also appeared to decrease inward calcium current (ICa). After exposure to 30
microM NS-1619, peak current amplitude significantly decreased by approximately
50%. Analysis of the current voltage relationship revealed a significant decrease
in maximal conductance from 10.5 +/- 4 to 6.2 +/- 3 nS. The voltage dependence of
calcium current activation and inactivation was well fit by a Boltzmann
relationship. Besides the decrease in conductance, there was a small, but
significant shift in the half-inactivation voltage, which suggests that NS-1619
preferentially blocks the open state of the channel. Steady-state (window)
calcium current was also decreased. Analysis of the theoretical window current
revealed a 71% decrease in this noninactivating current. These data indicate that
NS-1619 inhibits detrusor smooth muscle contraction in a concentration-dependent
manner and that the underlying mechanism of action for this effect involves
inhibition of calcium current, and may also include activation of the BKCa
channel. Compounds with this profile may be useful in the treatment of bladder
instability.
PMID- 9399994
TI - Inhibition of neutrophil elastase in CF sputum by L-658,758.
AB - Elastases in cystic fibrosis (CF) pulmonary fluids damage lung tissue and
perpetuate cycles of infection, inflammation and injury. Elastases from three
different sources may be present in CF airways: neutrophils, macrophages and
Pseudomonas. We measured how well the cephalosporin-based antielastase L-658,758
blocks the activity of human neutrophil elastase (NE), human proteinase-3, human
macrophage metalloelastase, mouse macrophage metalloelastase and Pseudomonas
aeruginosa elastase. We also examined the ability of L-658,758 to block elastases
in CF sputum in vitro. Sputum samples from adult CF patients were fractionated to
obtain the aqueous sol phase. These were then studied individually or pooled.
Elastinolytic activity, which ranged from 3.2 microg elastin degraded/ml sol/min
to 26.3 microg elastin degraded/ml sol/min, was measurable in every individual
sol sample and in the pooled sol. L-658,758 effectively inhibited elastinolysis
by NE, proteinase-3 and the pooled sol but did not inhibit the activity of the
metalloelastases, human and mouse macrophage metalloelastase and Pseudomonas
elastase. Secretory leukoprotease inhibitor, which inhibited NE but did not
inhibit proteinase-3, blocked 90% of sol elastinolytic activity; this suggests
that the majority of this activity in the pooled sol derived from NE. L-658,758
was an effective inhibitor of sol elastase, blocking more than 97% of
elastinolytic activity in the individual sol samples. We conclude that L-658,758
is an effective inhibitor of NE, proteinase-3 and CF sputum sol elastase.
PMID- 9399995
TI - Pharmacological characterization of novel cyanoguanidines as vascular KATP
channel blockers.
AB - KATP blockers derived from cyanoguanidine KATP opener (P1075) chemistry were
characterized in isolated rabbit mesenteric artery and evaluated functionally by
their ability to antagonize maximal relaxation induced by pinacidil (1 microM) of
norepinephrine (5 microM) contraction. PNU-89692, PNU-97025E and PNU-99963 were
identified as KATP blockers with IC50 values of 860, 83 and 18 nM, respectively.
Studies with selected chiral compounds demonstrated that the (R)-enantiomers were
more potent as KATP blockers than the (S)-enantiomers. Further studies
demonstrated that PNU-99963 (1) inhibited relaxations by other KATP openers, such
as cromakalim (0.5 microM) and minoxidil sulfate (5 microM); (2) was more potent
than the other known vascular KATP blockers (glyburide and PNU-37883A); and (3)
acted as a KATP blocker in isolated rat aorta as well as dog coronary artery. PNU
99963 actions were selective because PNU-99963 (100 nM) was without any
inhibitory effect on relaxations induced by forskolin (0.5 microM), nitroglycerin
(1 microM), D600 (25 or 500 nM) or 15 mM K+-induced relaxations of NE
contractions in K+-free PSS. The discovery of KATP blockers and openers from the
same chemical series is a first for the K+ channel field. The close structural
similarity between P1075 (KATP opener) and PNU-99963 (KATP blocker),
stereospecificity of action and potency and selectivity all suggest that these
molecules may prove to be valuable tools in understanding the structure and
function of the KATP channel complex in vascular smooth muscle.
PMID- 9399996
TI - Chronic ethanol exposure leads to a selective enhancement of N-methyl-D-aspartate
receptor function in cultured hippocampal neurons.
AB - Effects of chronic ethanol exposure on N-methyl-D-aspartate (NMDA) receptor
function were examined in hippocampal neurons. Rat hippocampal neurons grown in
culture were chronically exposed to 100 mM ethanol to examine mechanisms that
could underlie ethanol-induced changes in receptor function and excitotoxicity.
NMDA-stimulated, but not kainic acid-stimulated, increases in intracellular
calcium were enhanced after 1-, 2- and 7-day exposures to 100 mM ethanol. Chronic
exposure to ethanol for 7 days duration increased the magnitude of cell death
mediated by NMDA application, but not that mediated by alpha-amino-3-hydroxy-5
methylisoxazole-4-propionate or kainic acid exposure. In addition, NMDA-induced
excitotoxicity after chronic ethanol exposure (CEE) was not altered in the
presence of nifedipine. The enhancement of NMDA-induced neuronal cell death was
evident after 2 days of CEE, but not significantly different after a 1-day
exposure to 100 mM ethanol. The enhancement of NMDA-induced calcium responses and
excitotoxicity could be mimicked by a chronic 7-day exposure to
aminophosphonovaleric acid. However, a concomitant chronic exposure of
ethanol/aminophosphonovaleric acid did not enhance NMDA-induced calcium responses
or excitotoxicity. Chronic exposure paradigms did not consistently alter basal
intracellular calcium levels nor total cell number in the absence of exposure to
glutamate receptor agonist. These findings support the hypothesis that NMDA
receptor function is enhanced after CEE, and this predisposes hippocampal neurons
to excitotoxicity.
PMID- 9399997
TI - Interaction of Alkyl/Arylphosphonates, phosphonocarboxylates and diphosphonates
with different anion transport systems in the proximal renal tubule.
AB - Luminal and contraluminal stop-flow microperfusion was applied, and the apparent
Ki values (mmol/l) against the luminal phosphate and the contraluminal p
aminohippurate (PAH), sulfate and dicarboxylate transport systems were evaluated.
Luminal phosphate transporter: Among the 20 compounds tested only
phosphonoformate (foscarnet), etidronate, and clodronate have a good affinity
(app.Ki < 1 mmol/l), whereas the 2-naphthylphosphonates, phosphonoacetate,
pamidronate, alendronate and aminomethanediphosphonates have a moderate affinity
(app.Ki, 1.6-6.0 mmol/l). The other compounds tested had a low (app. Ki > 6
mmol/l) or no affinity. Contraluminal PAH transporter: The hydrophobic phenyl-,
benzyl- or 2-naphthylphosphonates have good to moderate affinity, whereas the
less hydrophobic alkylphosphonates, the phosphonocarboxylates (except 4
phosphonobutyrate) and all tested diphosphonates show no interaction. Sulfate
transporter: 2-Naphthylmethylphosphonate and 2-naphthylmethyldifluorophosphonate
have a good affinity (app.Ki = 0.5 mmol/l), whereas Cl-F-methylphosphonate, 2OH
5NO2-benzyl-phosphonate, 2-naphthylhydroxymethylphosphonate, phosphonoacetate
etidonate and clodronate have only a moderate affinity (app.Ki approximately 3
mmol/l). The other tested compounds have a low or no affinity. Dicarboxylate
transporter: Among the tested compounds only 3-phosphonopropionate (app.Ki, 4.2
mmol/l) and 4 phosphonobutyrate (app.Ki, 7.0 mmol/l) interact with this
transporter. Thus, we might conclude that in the submillimolar range only
phosphonoformate (foscarnet), etidronate and clodronate inhibit luminal phosphate
transport. As predictable from previous structure-activity studies for the
contraluminal PAH, sulfate and dicarboxylate transporters the
alkyl/arylphosphonates and the phosphonocarboxylates interact with these
transporters according to their hydrophobicity and charge distribution. Among the
seven diphosphonates tested, only etidronate and clodronate have a moderate
affinity to the sulfate transporter, whereas the aminodiphosphonates have no (or
low) affinity to any of the contraluminal anion transporters.
PMID- 9399998
TI - Regulation of adenosine concentration and cytoprotective effects of novel
reversible adenosine deaminase inhibitors.
AB - The physiological role of adenosine (Ado) is well known. Although a number of
pharmacological attempts have been made to manipulate Ado concentrations in
ischemic conditions in different tissues, none have been clinically accepted up
to now, mostly due to insufficient elevation of Ado concentrations or
unacceptable toxicity. In this study, we evaluated the biochemical and
pharmacological actions of several novel erythro-9-(2-hydroxy-3-nonyl)adenine
(EHNA) analogs to identify new reversible adenosine deaminase (ADA) inhibitors
with potential clinical utility. In cell culture experiments, these compounds
elevate cellular Ado concentrations under conditions of simulated ischemic stress
but very little, if any, under normoxic conditions. Two compounds were selected
for study: 9'-chloro-EHNA (CPC-405) and 9'-phthalimido-EHNA (CPC-406), which
specifically inhibit ADA in cell-free preparations as well as in intact cells.
CPC-405 and CPC-406 do not affect adenosine kinase activity, and they do not
affect adenosine transport (influx). CPC-405 and CPC-406 are also more potent
than EHNA in elevating adenosine release from human astrocytoma cells and bovine
heart microvascular endothelial cells in 2-deoxyglucose-simulated ischemia or
under anaerobic conditions. Inhibition of adenosine deaminase by CPC-405 or CPC
406, as well as the 2'-deoxyadenosine toxicity expressed in the presence of these
ADA inhibitors, is reversed when the inhibitors are removed by washing the cells.
In the isolated rat heart model of ischemia, these novel ADA inhibitors showed
enhanced recovery of left ventricular end-diastolic pressure, left ventricular
developed pressure, +dP/dtmax and -dP/dtmax. In the rat hippocampal slice model
of hypoxia, these compounds also showed neuroprotective effects on CA1 hypoxic
injury. In conclusion, these novel ADA inhibitors may represent clinically useful
Ado elevating compounds that show cardioprotective, as well as neuroprotective,
effects. Also, their potential for immunotoxicity, if any, appears to be
transient in nature, representing an important clinical advantage compared with
tight-binding ADA inhibitors such as deoxycoformycin.
PMID- 9399999
TI - Effectiveness of vigabatrin against focally evoked pilocarpine-induced seizures
and concomitant changes in extracellular hippocampal and cerebellar glutamate,
gamma-aminobutyric acid and dopamine levels, a microdialysis-electrocorticography
study in freely moving rats.
AB - Limbic seizures were evoked in freely moving rats by intrahippocampal
administration of the muscarinic agonist pilocarpine via the microdialysis probe
(10 mM for 40 min at 2 microl/min). This study monitored changes in extracellular
hippocampal gamma-aminobutyric acid (GABA), glutamate and dopamine levels after
systemic (30 mg/kg/day) or local (intrahippocampal or intranigral, 5 mM or 600
microM for 180 min at 2 microl/min) vigabatrin administration, and evaluated the
effectiveness of this antiepileptic drug against pilocarpine-induced seizure
activity. Extracellular GABA and glutamate overflow in the ipsilateral cerebellum
was studied simultaneously. Microdialysis was used as an in vivo sampling
technique and as a drug-delivery tool. Electrophysiological evidence for the
presence or absence of seizures was recorded with electrocorticography. The
observed alterations in extracellular hippocampal amino acid levels support the
hypothesis that muscarinic receptor stimulation by the intrahippocampal
administration of 10 mM pilocarpine is responsible for the seizure onset, and
that the amino acids maintain the sustained seizure activity. The focally evoked
pilocarpine-induced seizures were completely prevented by intraperitoneal
vigabatrin premedication for 7 days or by a single intraperitoneal injection.
Effective protection was reflected in a lack of sustained elevations of
hippocampal glutamate levels. Rats receiving vigabatrin intrahippocampally or
intranigrally still developed seizures, although there appeared to be a partial
protective effect. During the intrahippocampal perfusion with 5 mM vigabatrin,
extracellular hippocampal GABA levels increased, whereas the extracellular
glutamate and dopamine overflow decreased. The lack of a complete neuroprotection
after local vigabatrin treatment is discussed.
PMID- 9400000
TI - The competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor
antagonist LY293558 attenuates and reverses analgesic tolerance to morphine but
not to delta or kappa opioids.
AB - Antagonists of the NMDA type of excitatory amino acid (EAA) receptor attenuate or
reverse the development of tolerance to the analgesic effects of the mu opioid
agonist morphine, the delta-1 opioid agonist DPDPE but not the kappa-1 agonist
U50,488H or the kappa-3 agonist naloxone benzoylhydrazone. The role of the AMPA
subtype of EAA receptor in analgesic tolerance was examined using LY293558, a
selective competitive antagonist that is active after systemic administration.
Administration of morphine, DPDPE, or U50,488H three times daily for 3 days
according to an escalating dosing schedule resulted in analgesic tolerance as
indicated by an increase in analgesic ED50 values using the tail-flick test in
mice. Analgesic tolerance was attenuated when mice received a continuous
subcutaneous infusion of LY293558 at doses of 30, 45 or 60 mg/kg/24 hr via an
osmotic pump concurrent with the morphine treatment. Continuous subcutaneous
infusion of LY293558 (45 mg/kg/24 hr) also reversed established morphine
tolerance. In contrast, continuous subcutaneous infusion of the highest dose of
LY293558 (60 mg/kg/24 hr) was ineffective in preventing the development of
analgesic tolerance to DPDPE or U50,488H. Continuous subcutaneous infusion of
LY293558 (60 mg/kg/24 hr) for 3 days protected mice from generalized convulsions
produced by the selective AMPA agonist ATPA, indicating that the dosage of
LY293558 that attenuated morphine tolerance was effective as an antagonist at
AMPA receptors. These results demonstrate that AMPA receptors may play a role in
the development and maintenance of morphine, but not DPDPE or U50,488H, analgesic
tolerance.
PMID- 9400001
TI - L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit
a neuroleptic-like profile in rodent behavioral tests.
AB - This study examined the high-affinity, selective dopamine D4 receptor antagonist,
L-745,870 (3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2, 3
b]pyridine) in rodent behavioral models used to predict antipsychotic potential
and side-effect liabilities in humans. In contrast to the classical neuroleptic,
haloperidol, and the atypical neuroleptic, clozapine, L-745,870 failed to
antagonize amphetamine-induced hyperactivity in mice or impair conditioned
avoidance responding in the rat at doses selectively blocking D4 receptors.
Furthermore, L-745,870 failed to reverse the deficit in prepulse inhibition of
acoustic startle responding induced by the nonselective dopamine D2/3/4 receptor
agonist apomorphine, an effect which was abolished in rats pretreated with the
D2/3 receptor antagonist, raclopride (0.2 mg/kg s.c.). L-745,870 had no effect on
apomorphine-induced stereotypy in the rat but did induce catalepsy in the mouse,
albeit at a high dose of 100 mg/kg, which is likely to occupy dopamine D2
receptors in vivo. High doses also impaired motor performance; in rats L-745,870
significantly reduced spontaneous locomotor activity (minimum effective dose = 30
mg/kg) and in mice, L-745,870 reduced the time spent on a rotarod revolving at 15
rpm (minimum effective dose = 100 mg/kg). Altogether these results suggest that
dopamine D4 receptor antagonism is not responsible for the ability of clozapine
to attenuate amphetamine-induced hyperactivity and conditioned avoidance
responding in rodents. Furthermore, the lack of effect of L-745,870 in these
behavioral tests is consistent with the inability of the compound to alleviate
psychotic symptoms in humans.
PMID- 9400002
TI - Novel systemically active antagonists of the glycine site of the N-methyl-D
aspartate receptor: electrophysiological, biochemical and behavioral
characterization.
AB - A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for
antagonistic effects at the strychnine-insensitive modulatory site of the N
methyl-D-aspartate (NMDA) receptor (glycineB). All compounds displaced [3H]MDL
105,519 binding to rat cortical membranes with IC50 values of between 90 nM and
3.6 microM. In patch-clamp experiments, steady-state inward current responses of
cultured hippocampal neurons to NMDA (200 microM, glycine 1 microM) were
antagonized by these same compounds with IC50 values of 0.14 to 13.8 microM. The
antagonism observed was typical for glycineB antagonists, i.e., they induced
desensitization and their effects were not use or voltage dependent. Moreover,
increasing concentrations of glycine were able to decrease their apparent
potency. Much higher concentrations (>100 microM) were required to antagonize
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced currents. They
were potent, systemically active NMDA receptor antagonists in vivo against
responses of single neurons in the rat spinal cord to microelectrophoretic
application of NMDA with ID50 values in the low milligram per kilogram i.v.
range. They also inhibited pentylenetetrazol-, NMDA- and maximal electroshock
induced convulsions in mice with ED50 values ranging from 8 to 100 mg/kg i.p. The
duration of anticonvulsive action was rather short but was prolonged by the
organic acid transport inhibitor probenecid (200 mg/kg). The agents tested
represent a novel class of systemically active glycineB antagonists with greatly
improved bioavailability.
PMID- 9400003
TI - Delta opioid modulation of the binding of guanosine-5'-O-(3
[35S]thio)triphosphate to NG108-15 cell membranes: characterization of agonist
and inverse agonist effects.
AB - The ability of the delta opioid agonist DPDPE ([D-Pen2, D-Pen4]enkephalin) to
stimulate binding of the GTP analog guanosine-5'-O-(3-[35S]thio)triphosphate
([35S]GTPgammaS) to pertussis toxin-sensitive G proteins has been characterized
in membranes from NG108-15 mouse neuroblastoma X rat glioma cells. The presence
of GDP, or its hydrolysis-resistant analog GDPbetaS, and Mg++ ions was essential
to observe agonist-mediated stimulation of [35S]GTPgammaS binding, although the
guanine dinucleotides alone had complex inhibitory and stimulatory effects on
[35S]GTPgammaS binding. The relative ability of the delta antagonists
benzylidenenaltrexone and naltriben to inhibit DPDPE-stimulated [35S]GTPgammaS
binding suggested the opioid receptor involved was of the delta-2 subtype. Ligand
binding assays demonstrated biphasic binding of these antagonists to this single
receptor type. [35S]GTPgammaS binding was also stimulated by [D
Ser2,Leu5,Thr6]enkephalin > deltorphin II = DPDPE = etorphine > levallorphan =
diprenorphine = nalorphine = naltrindole. The delta antagonists
benzylidenenaltrexone, TIPP (Tyr-Tic-Phe-Phe) and naltriben had no effect, but
ICI 174864 (N, N-diallyl-Tyr-Aib-Phe-Leu-OH) acted as an inverse agonist and
inhibited [35S]GTPgammaS binding. Pertussis toxin pretreatment blocked agonist
stimulation of [35S]GTPgammaS binding and also reduced basal binding, thus
confirming the presence of constitutively active delta receptors. Replacement of
Na+ in the assay buffer with K+ afforded an increased level of basal
[35S]GTPgammaS binding and an apparent increase in both the inverse agonist
activity of ICI 174864 and the agonist activity of the partial agonist
diprenorphine relative to the full agonist [D-Ser2, Leu5,Thr6]enkephalin. The
stimulation of [35S]GTPgammaS binding to NG108-15 cell membranes allows a
functional measure of delta opioid activity that can provide systems of differing
relative efficacy.
PMID- 9400004
TI - Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate
receptors containing the NR2B subunit. Characterization in vitro.
AB - The interaction of Ro 25-6981 with N-methyl-D-aspartate (NMDA) receptors was
characterized by a variety of different tests in vitro. Ro 25-6981 inhibited 3H
MK-801 binding to rat forebrain membranes in a biphasic manner with IC50 values
of 0.003 microM and 149 microM for high- (about 60%) and low-affinity sites,
respectively. NMDA receptor subtypes expressed in Xenopus oocytes were blocked
with IC50 values of 0.009 microM and 52 microM for the subunit combinations NR1C
& NR2B and NR1C & NR2A, respectively, which indicated a >5000-fold selectivity.
Like ifenprodil, Ro 25-6981 blocked NMDA receptor subtypes in an activity
dependent manner. Ro 25-6981 protected cultured cortical neurons against
glutamate toxicity (16 h exposure to 300 microM glutamate) and combined oxygen
and glucose deprivation (60 min followed by 20 h recovery) with IC50 values of
0.4 microM and 0.04 microM, respectively. Ro 25-6981 was more potent than
ifenprodil in all of these tests. It showed no protection against kainate
toxicity (exposure to 500 microM for 20 h) and only weak activity in blocking Na+
and Ca++ channels, activated by exposure of cortical neurons to veratridine (10
microM) and potassium (50 mM), respectively. These findings demonstrate that Ro
25-6981 is a highly selective, activity-dependent blocker of NMDA receptors that
contain the NR2B subunit.
PMID- 9400005
TI - Acute experimental esophagitis activates a second signal transduction pathway in
cat smooth muscle from the lower esophageal sphincter.
AB - In single cells, isolated by enzymatic digestion from the circular muscle layer
of the lower esophageal sphincter (LES), acute experimental esophagitis (AE)
alters signal transduction in response to a maximally effective dose of
acetylcholine. In normal LES contraction was inhibited by M3 >> M1 or M2
antagonists. In AE inhibition by M2 antagonists increased significantly so that
contraction was inhibited by M3 > M2 > M1 antagonists. In normal cells
permeabilized by saponin, contraction was antagonized by antibodies against
Gq/11, by the phosphatidylinositol-specific phospholipase C (PI-PLC) antagonist U
73122, but not by the phosphatidylcholine-specific phospholipase C (PC-PLC)
inhibitor D609, or by the phospholipase D pathway inhibitor propranolol. In AE
contraction was reduced by Gq/11 and Gi3 antibodies and by U73122, propranolol
and D609. After thapsigargin treatment of normal cells to reduce intracellular
Ca++ stores, contraction was inhibited by M2 and M3 antagonists, by antibodies
against Gq/11 and Gi3, by U73122, D609 and propranolol, suggesting that depletion
of Ca++ stores reproduces the changes induced by AE. We conclude that in normal
LES smooth muscle cells acetylcholine-induced contraction is mediated by M3
receptors linked to Gq/11 and PI-PLC, whereas in AE, contraction through this
pathway is reduced, perhaps because of reduction in Ca++ stores, and a second
pathway is activated by M2 receptors linked to Gi3, PC-PLC and phospholipase D.
PMID- 9400006
TI - Neurotransmitter receptor and transporter binding profile of antidepressants and
their metabolites.
AB - Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine
transporters (NET) have been introduced into clinical practice the past several
years. This report focuses on the further pharmacologic characterization of
nefazodone and its metabolites within the serotonergic and noradrenergic systems,
in comparison with other antidepressants. By use of radioligand binding assays,
we measured the affinity (Ki) of 13 antidepressants and 6 metabolites for the rat
and human SERT and NET. The Ki values for eight of the antidepressants and three
metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic
cholinergic receptors, the guinea pig histamine1 receptor and the human alpha-1
and alpha-2 receptors. These data are useful for predicting side effect profiles
and the potential for pharmacodynamic drug-drug interactions of antidepressants.
Of particular interest were the findings that paroxetine, generally thought of as
a selective SERT antagonist, possesses moderately high affinity for the NET and
that venlafaxine, which has been described as a "dual uptake inhibitor",
possesses weak affinity for the NET. We observed significant correlations in SERT
(r = 0.965) or NET (r = 0.983) affinity between rat and human transporters.
Significant correlations were also observed between muscarinic cholinergic and
NET affinity. There are several significant correlations between affinities for
the 5-HT1A, 5-HT2A, histamine1, alpha-1 and alpha-2 receptors. These novel
findings, not widely described previously, suggest that many of the individual
drugs studied in these experiments possess some structural characteristic that
determines affinity for several G protein-coupled, but not muscarinic, receptors.
PMID- 9400007
TI - The selective sigma2-ligand Lu 28-179 has potent anxiolytic-like effects in
rodents.
AB - The anxiolytic potential of the selective sigma2 ligand 1-[4-[1-(4-Fluorophenyl)
1H-indol-3-yl]-1-butyl]spiro[isobenzofuran-1(3H),4-piperidine] [corrected] (Lu 28
179) was assessed in various animal models of anxiety in rodents. Lu 28-179
facilitated the exploratory behavior of mice and rats in the black and white two
compartment box over a large dose range. In the rat, the minimal effective dose
(MED) was 0.18 nmol/kg (0.1 microg/kg), and in the mouse, the MED was 0.00018
nmol/kg (0.1 ng/kg). The anxiolytic-like effect was maintained after treatment
with 1 microg/kg/day for up to 14 days, and no anxiogenic-like effects were seen
upon withdrawal from repeated treatment. Lu 28-179 increased the time that pairs
of rats spent in active social interaction (unfamiliar high-light conditions),
MED = 0.1 ng/kg. Daily treatment with Lu 28-179 (1.8 nmol/kg = 1 microg/kg/day)
for up to 4 weeks increased the social interaction time significantly compared
with controls, and no anxiogenic-like effects were seen upon withdrawal.
Furthermore, Lu 28-179 reversed shock-induced suppression of drinking in the rat
(MED = 18,000 nmol/kg = 10 mg/kg). Lu 28-179 did not inhibit footshock-induced
ultrasonic vocalization in the rat or isolation-induced aggressive behavior in
the mouse. Lu 28-179 was over 100 times more potent than diazepam in the rat and
mouse black and white test box and the rat social interaction test, whereas the
potency of Lu 28-179 was comparable to that of lorazepam in reversal of shock
induced suppression of drinking. Lu 28-179 neither induced sedation nor impaired
motor coordination, even at high doses (70,000 nmol/kg = 40 mg/kg). In
conclusion, Lu 28-179 exerts potent and long-lasting anxiolytic-like effects in
rodents without inducing sedation and withdrawal anxiogenesis.
PMID- 9400008
TI - Neonatal administration of the selective serotonin reuptake inhibitor Lu 10-134-C
increases forced swimming-induced immobility in adult rats: a putative animal
model of depression?
AB - Chronic administration of the tricyclic antidepressant clomipramine to neonatal
rats from postnatal days 8 to 21 is reported to induce several behavioral changes
in adult life, and it may serve as an animal model of human depressive disorder.
Findings include increased immobility time in the forced swim test and locomotor
hyperactivity in the open field test. Clomipramine is a serotonergic reuptake
inhibitor, which suggests that altered development of the serotonergic system
could account for the observed behavioral changes in the adult rat. The present
study was carried out with a selective serotonin reuptake inhibitor (SSRI) to
investigate whether the serotonin system, in particular, is involved in the
neonatal animal model. The substance, Lu 10-134-C (LU), was characterized in
monoamine reuptake and receptor binding assays and found to be an SSRI. Rats
received LU during postnatal days 8 to 21 (2.5-15 mg/kg b. i.d.), and they were
assessed in open field, forced swim and social interaction tests at the age of 4
months. Behavior of LU-treated rats and saline controls did not differ in the
open field and social interaction tests. However, in the forced swim tests LU
treated neonates showed prolonged immobility time compared with saline controls.
In conclusion, chronic LU treatment during neonatal life produces long-term
changes in the forced swim test, but not in the open field and social interaction
tests. The behavioral changes in the forced swim test suggest that the central
serotonergic system may be involved in the putative neonatal animal model of
depression.
PMID- 9400009
TI - GR89,696 is a kappa-2 opioid receptor agonist and a kappa-1 opioid receptor
antagonist in the guinea pig hippocampus.
AB - Receptor binding studies and electrophysiological studies demonstrated the
existence of at least two kappa opioid receptors, which have been designated
kappa-1 and kappa-2. Several agonists and antagonists are selective for the kappa
1 receptor whereas no known ligands are selective for the kappa-2 receptor. In
this study, the kappa opioid GR89,696 was tested in the guinea pig hippocampal
slice preparation for kappa-1 versus kappa-2 activity. The perforant path-evoked
population spike in the dentate was use to evaluate activity at the kappa-1
receptor, and the Schaffer collateral-evoked N-methyl-D-aspartate (NMDA) receptor
mediated synaptic current in CA3 pyramidal cells was used to measure kappa-2
receptor activation. GR89,696 had no effect on the perforant path-evoked dentate
population spike; however, it did reverse the effects of the selective kappa-1
agonist U69,593 when co-perfused over the slices. In the CA3, GR89,696 inhibited
the NMDA receptor-mediated synaptic current. The inhibition was antagonized by
naloxone. The EC50 for GR89,696 on the NMDA current was 41.7 nM (95% CL, 7.0-248
nM). These findings indicate that GR89,696 is an agonist for kappa-2 opioid
receptors and an antagonist at kappa-1 receptors in the guinea pig hippocampus.
PMID- 9400010
TI - Role of endogenous dopamine in the neurochemical deficits induced by
methcathinone.
AB - Multiple administrations of methcathinone caused persistent deficits in
monoaminergic systems, as reflected by decreases in dopamine and 5
hydroxytryptamine uptake capacity, tissue content and associated rate-limiting
synthetic enzyme activities. Because dopamine has been implicated in mediating
such effects after administration of related amphetamine analogs, its role in
effecting methcathinone-induced monoaminergic neuronal impairment was assessed. A
single high-dose administration of methcathinone increased striatal dopamine
release, as measured by microdialysis in conscious rats and reflected by
increases in striatal neurotensin-like immunoreactivity. Dopaminergic deficits
observed 18 hr after a multiple-dose treatment with methcathinone were prevented
by pretreatment with the selective D1 antagonist SCH23390 and D2 receptor
antagonist eticlopride, but 5-hydroxytryptaminergic deficits were not altered. 5
Hydroxytryptaminergic changes did not occur in animals depleted of striatal
dopamine by 6-hydroxydopamine lesions. These results indicate that dopaminergic
systems are profoundly affected by methcathinone administration and that dopamine
likely contributes to the monoaminergic effects of this stimulant.
PMID- 9400011
TI - In vivo effects of remoxipride and aromatic ring metabolites in the rat.
AB - The in vivo effects of remoxipride, in relation to some of its identified
metabolites, were investigated in adult male Sprague-Dawley rats. The methods
used included: (1) estimation of the in vivo rate of brain monoamine synthesis by
measuring the accumulation of dihydroxyphenylalanine and 5-hydroxytryptophan
after decarboxylase inhibition; (2) observations of spontaneous locomotor
activity in a photocell-equipped open-field arena ( approximately 0. 5 m2); (3)
treadmill locomotion ( approximately 4 m min-1); (4) inclined grid (60 degrees )
catalepsy test; (5) d-amphetamine-induced (1.0 mg kg-1) hyperlocomotion;(6)
quinpirole-induced (0.4 mg kg-1) hypothermia. By use of one or more of these
tests, the findings with remoxipride were as follows: First, remoxipride had a
late onset of action (up to 3 h). Second, potency and efficacy depended on
exposure to hepatic metabolism. Thus, intraperitoneal administration was more
effective than the subcutaneous route, whereas virtually all biological effects
were lost on intracerebroventricular administration. The ED50 values (micromol kg
1, neostriatal dihydroxyphenylalanine accumulation) for remoxipride and a range
of its phenolic aromatic ring metabolites were: remoxipride (approximately 20),
NCQ-344 (approximately 0.01), FLA-797 (approximately 0.1), FLA-908 (approximately
2.2), NCQ-436 (approximately 25) and NCQ-469 (approximately 30). Considering
remoxipride as a nonclozapine atypical antipsychotic drug, together with the fact
that remoxipride behaves as a prodrug in the laboratory studies above, further
characterization of the pharmacodynamic profile of its metabolites remains a
challenge.
PMID- 9400012
TI - Involvement of alpha-2 adrenoceptors in the effects of moxonidine on intestinal
motility and fluid transport.
AB - The aims of this study were to examine how the imidazoline (I)1/alpha-2 receptor
agonist moxonidine and the putative endogenous imidazoline receptor agonist
agmatine might affect intestinal motility and fluid transport. The effects of
moxonidine were compared with those of UK 14,304, a highly selective alpha-2
adrenoceptor agonist with very low affinity for I1 receptors. Moxonidine and UK
14,304 inhibited the peristaltic reflex in the isolated rat ileum. The inhibitory
effects were antagonized by the selective alpha-2 adrenoceptor antagonist
yohimbine and the I1/alpha-2 antagonist efaroxan and almost completely blocked by
the irreversible alpha-2 adrenoceptor antagonist EEDQ (N-ethoxycarbonyl-2-ethoxy
1,2-dihydroquinoline), which has a low affinity for imidazoline receptors.
Yohimbine (3 microM) and efaroxan (0.01 and 1 microM) caused parallel rightward
shifts to the concentration-response curves of moxonidine and UK 14,304, yielding
pKB values corresponding to those at alpha-2 binding sites. Moxonidine induced
dose-dependent proabsorptive effects in the jejunum and ileum and also reversed
the secretory phase of the vasoactive intestinal peptide-induced responses. The
degree of antagonism by yohimbine and efaroxan was similar against moxonidine and
UK 14,304 on the proabsorptive and antisecretory effects. We conclude that the
effects of moxonidine in mediating inhibition of intestinal motility and
enhancing fluid transport are attributed predominantly to interaction with alpha
2 adrenoceptors. Agmatine had no effect on peristalsis but significantly
decreased the rate of fluid absorption from the jejunum and ileum, an effect in
contrast to moxonidine. A physiological role for agmatine in the regulation of
intestinal transport remains to be clarified.
PMID- 9400013
TI - Neutrophil cytotoxicity of the chemically reactive metabolite(s) of clozapine:
possible role in agranulocytosis.
AB - Clozapine is associated with a 0.8% incidence of agranulocytosis. Bioactivation
to an unstable protein-reactive metabolite, identified as a nitrenium
intermediate, has been implicated in the toxicity. In this study, we investigated
whether the reactive metabolite is cytotoxic toward polymorphonuclear leukocytes
and mononuclear leukocytes using horseradish peroxidase and H2O2 to generate the
metabolite in situ. In the absence of a full metabolizing system (i. e., lack of
horseradish peroxidase and/or H2O2), clozapine (0-100 microM) and its stable
metabolites were not cytotoxic. With a full metabolizing system, both clozapine
(30 microM) and demethylclozapine exhibited cytotoxicity toward polymorphonuclear
leukocytes (50.7 +/- 7.7% and 17.6 +/- 1.2% cell death, respectively) and
mononuclear leukocytes (36.6 +/- 2.1% and 24.6 +/- 4.1%, respectively), whereas
clozapine N-oxide was not cytotoxic. Exogenous glutathione (GSH), N
acetylcysteine and ascorbic acid all protected the cells. Bioactivation of
clozapine and demethylclozapine, but not the N-oxide, was accompanied by
depletion of intracellular GSH. [14C]Clozapine was metabolized to the previously
identified C6 and C9 glutathionyl conjugates; GSH conjugates were also detected
when demethylclozapine and clozapine N-oxide were bioactivated by horseradish
peroxidase and H2O2. In conclusion, using a novel in vitro assay, we have shown
that clozapine and its stable metabolites are not cytotoxic per se but are
bioactivated to cytotoxic metabolites. The cytotoxic metabolite of clozapine is
identical to the protein-reactive metabolite that has been characterized
previously. These cytotoxic metabolites may play an important role in the
pathogenesis of clozapine agranulocytosis; the mechanism by which this occurs is
currently being investigated.
PMID- 9400014
TI - Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice.
AB - The mechanisms underlying the circadian rhythm of the toxicity induced by
irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(1-piperidino)-1
piperidino]carbonyloxycamptothecin) were investigated from the viewpoint of the
sensitivity of living organisms and the pharmacokinetics of the drug. ICR male
mice were housed under standardized light-dark cycle conditions (lights on at
0700, off at 1900) with food and water ad libitum. The loss of body weight after
an intraperitoneal injection of CPT-11 (100 mg/kg) was more serious in the late
dark and the early light and milder in the late light and the early dark. The CPT
11-induced leukopenia was more serious in the late dark and milder in the late
light. The lower toxicity of CPT-11 was observed when DNA synthesis and type I
DNA topoisomerase activity in bone marrow cells decreased and the higher toxicity
was observed when these activities began to increase. There were circadian stage
dependent changes in the concentrations of CPT-11 and its major metabolite (SN
38; 7-ethyl-10-hydroxycamptothecin) in plasma. The higher concentrations of CPT
11 and SN-38 in plasma were observed when the level of CPT-11-induced toxicity
increased. The present study suggests that the toxicity of CPT-11 is influenced
by circadian rhythm-dependent processes.
PMID- 9400015
TI - Abnormality in plasma catecholamines and myocardial adrenoceptors in
cardiomyopathic BIO 53.58 Syrian hamsters and improvement by metoprolol
treatment.
AB - The catecholaminergic neuronal activity and the densities of alpha-1 and beta
adrenoceptors and angiotensin II receptors were simultaneously determined in BIO
53.58, a model of idiopathic dilated cardiomyopathy, and F1B control hamsters.
Further, we examined the effect of repeated p.o. administration of metoprolol on
these biochemical parameters. Compared with F1B control hamsters, there was a
significant decrease in Bmax of specific binding of both (-)
[125I]iodocyanopindolol and [3H]prazosin with a marked elevation of plasma
catecholamine (mainly norepinephrine and epinephrine) concentrations, in BIO
53.58 hamsters at 11 and 18 weeks of age (severe cardiomyopathic stage), but not
at 5 weeks of age. On the other hand, the Bmax value of myocardial
[125I]angiotensin II binding in BIO 53.58 hamsters was almost identical to that
in F1B hamsters. These results suggest a development of down-regulation of
myocardial beta and alpha-1 adrenoceptors because of an increased
catecholaminergic neuronal activity with aging in BIO 53.58 hamsters. Repeated
p.o. administration of a relatively low dose (1 mg/kg/day) of metoprolol for 7
weeks in 11-week-old BIO 53.58 hamsters caused a significant increase of
myocardial (-)-[125I]iodocyanopindolol binding sites with a marked reduction in
plasma catecholamine levels; this indicated a significant recovery to the F1B
levels. The improvement of these biochemical parameters by metoprolol treatment
was also accompanied by a significant decrease in the fibrosis in the heart in
BIO 53.58 hamsters. These data suggest that catecholaminergic neurons and
adrenoceptors play a part in the development of heart failure in idiopathic
dilated cardiomyopathy. Consequently, the present study may provide a further
pharmacological basis for the use of beta-1 adrenoceptor antagonists in patients
with idiopathic dilated cardiomyopathy.
PMID- 9400016
TI - Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric
acid release from CA1 neurons of rat hippocampal slices.
AB - In the present study we investigated electrophysiologically the nicotinic
responses of pyramidal neurons and interneurons visualized by infrared-assisted
videomicroscopy and fluorescence in the CA1 field of hippocampal slices obtained
from 8- to 24-day-old rats. Application of nicotinic agonists to CA1 neurons
evoked at least four types of nicotinic responses. Of major interest was the
ability of these agonists to induce the release of gamma-aminobutyric acid (GABA)
from interneurons. Slowly decaying ACh whole-cell currents and GABA-mediated
postsynaptic currents could be recorded from pyramidal neurons and interneurons,
whereas fast-decaying nicotinic currents and fast current transients were
recorded only from interneurons. Nicotinic responses were sensitive to blockade
by d-tubocurarine (10 microM), which indicated that they were mediated by
nicotinic acetylcholine receptors (nAChRs). The slowly decaying currents, the
postsynaptic currents and the fast current transients were insensitive to
blockade by the alpha-7 nAChR-specific antagonist methyllycaconitine (up to 1
microM) or alpha-bungarotoxin (100 nM). On the other hand, the slowly decaying
nicotinic currents recorded from the interneurons were blocked by the alpha4beta2
nAChR-specific antagonist dihydro-beta-erythroidine, and the fast-desensitizing
nicotinic currents were evoked by the alpha-7 nAChR-specific agonist choline. In
experimental conditions similar to those used to record nicotinic responses from
neurons in slice (i. e., in the absence of tetrodotoxin), we observed that
nicotinic agonists can also induce the release of GABA from hippocampal neurons
in culture. In summary, these results provide direct evidence for more than one
subtype of functional nAChR in CA1 neurons and suggest that activation of nAChRs
present in GABAergic interneurons can evoke inhibitory activity in CA1 pyramidal
neurons, thereby modulating processing of information in the hippocampus.
PMID- 9400017
TI - -(S)-Alpha-phenyl-2-pyridine-ethanamine Dihydrochloride-, a low affinity
uncompetitive N-methyl-D-aspartic acid antagonist, is effective in rodent models
of global and focal ischemia.
AB - [(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low
affinity uncompetitive N-methyl-D-aspartic acid receptor antagonist that was
tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL
15896AR extended survival time during exposure to hypoxia. With the rat four
vessel occlusion model of global ischemia (20 min), oral dosing commencing at
reflow, resulted in significant protection of the CA1 hippocampal neurons. ARL
15896AR was, however, ineffective in the rat two-vessel occlusion model and in
the gerbil models of forebrain ischemia, the latter due to an inability to attain
suitable plasma levels. In the spontaneously hypertensive rat model of middle
cerebral artery occlusion (MCAO) (2 hr plus 22 hr reflow), acute dosing with ARL
15896AR (i.p.) beginning from 30 min before or up to 1 hr post-MCAO significantly
reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct
size, as well as functional correlates was examined in SHR after 90 min of MCAO.
T2 weighted magnetic resonance images taken at 2 and 6 days post-MCAO revealed
significantly smaller lesion sizes in the group receiving injections with ARL
15896AR beginning 30 min after occlusion. Spontaneously hypertensive rats were
subsequently tested (30-42 days post-MCAO) and found to be deficient in skilled
use of the forepaws (staircase test). The contralateral forepaw was most severely
impaired, however, ARL 15896AR treatment prevented motor impairment in only the
ipsilateral forepaw. Histopathological examination of cortical infarct size was
unremarkable between treated and control rats. The findings indicate that ARL
15896AR exhibits neuroprotection in global and focal models of ischemia
PMID- 9400018
TI - Isolation, heterologous expression and functional characterization of a novel
cytochrome P450 3A enzyme from a canine liver cDNA library.
AB - A cDNA encoding a new member of the cytochrome P450 3A subfamily, P450 3A26, has
been isolated from phenobarbital-induced canine liver. The sequence encodes a
protein of 503 amino acids with 33 nucleotide differences conferring 22 amino
acid substitutions when compared with the previously identified canine CYP3A12
enzyme. Nine of the amino acid differences are within the substrate recognition
sites (SRSs) identified for P450 family 2, with five residue substitutions
clustered within SRS-6. To facilitate heterologous expression in Escherichia
coli, the N-terminus of 3A26 was modified. The expressed protein comigrated with
a 3A-immunoreactive protein in dog liver microsomes with a slightly greater
electrophoretic mobility on sodium dodecyl sulfate-polyacrylamide gel
electrophoresis than 3A12, which suggests that 3A26 corresponds to a previously
noted but never characterized 3A enzyme in dogs. Functional characterization of
3A26 was undertaken with use of progesterone, testosterone and androstenedione as
substrates. Assays of expressed 3A26 and 3A12 demonstrated that 3A26 displays low
steroid hydroxylase activity. Identification of an additional canine 3A enzyme
should increase our understanding of xenobiotic metabolism in this important
animal model. These findings also suggest that 3A26 and 3A12 may be an
interesting model system for the investigation of structure-function
relationships involved in steroid metabolism catalyzed by members of the
cytochrome P450 3A subfamily.
PMID- 9400019
TI - In vitro pharmacological characterization of PD 166285, a new nanomolar potent
and broadly active protein tyrosine kinase inhibitor.
AB - PD 166285, a novel protein tyrosine kinase inhibitor of a new structural class,
the 6-aryl-pyrido[2,3-d]pyrimidines, was synthesized as the most potent and
soluble analog of a series of small molecules originally identified by screening
a compound library with assays that measured protein tyrosine kinase activity. PD
166285 was found to inhibit Src nonreceptor tyrosine kinase, fibroblast growth
factor receptor-1, epidermal growth factor receptor and platelet-derived growth
factor receptor beta subunit (PDGFR-beta), tyrosine kinases with half-maximal
inhibitory potencies (IC50 values) of 8.4 +/- 2.3 nM (n = 6), 39.3 +/- 2.8 nM (n
= 16), 87.5 +/- 13.7 nM (n = 6) and 98.3 +/- 7.9 nM (n = 16), respectively. PD
166285 also demonstrated inhibitory activity against mitogen-activated protein
kinase (IC50 = 5 microM) and protein kinase C (IC50 = 22.7 microM). PD 166285 was
further characterized as an ATP competitive inhibitor of Src nonreceptor tyrosine
kinase, PDGFR-beta, fibroblast growth factor receptor-1 and epidermal growth
factor receptor tyrosine kinases. In addition, PD 166285 inhibited PDGF- and EGF
stimulated receptor autophosphorylation in vascular smooth muscle cells (VSMCs)
and A431 cells, respectively, and basic fibroblast growth factor-mediated
tyrosine phosphorylation in Sf9 cells, with IC50 values of 6.5 nM, 1.6 microM and
97.3 nM, respectively, further establishing a tyrosine kinase mechanism of
inhibition. The inhibition of PDGF receptor autophosphorylation in VSMCs by PD
166285 was long lasting and persisted for 4 days after a single 1-hr exposure
followed by extensive washing. The PDGF-induced tyrosine phosphorylation of the
44- and 42-kDa mitogen-activated protein kinase isoforms was also blocked as a
result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD
166285 in VSMCs. The effects of PD 166285 were also demonstrated in functional
assays of cell attachment, migration and proliferation, in which vascular cell
adhesion to vitronectin, PDGF-directed chemotaxis and serum-stimulated cell
growth were all potently inhibited with IC50 values of 80 yo 120 nM. Finally, PD
166285 uniquely demonstrated potent inhibition of phorbol ester-induced
production of 92-kDa gelatinase A (MMP-9) in VSMC without affecting 72-kDa
gelatinase B (MMP-2) as measured by gelatin zymography. These results highlight
the biological characteristics of PD 166285 as a broadly active protein tyrosine
kinase capable of potently inhibiting a number of kinase mediated cellular
functions, including cell attachment, movement and replication. The potential
therapeutic utility of this broadly acting inhibitor as an antiproliferative and
antimigratory agent could extend to such diseases as cancer, atherosclerosis and
restenosis, in which redundancies in protein kinase signaling pathways are known
to exist.
PMID- 9400020
TI - Enhanced dopamine release and phosphorylation of synapsin I and neuromodulin in
striatal synaptosomes after repeated amphetamine.
AB - Repeated, intermittent treatment of rats with amphetamine followed by a
withdrawal period leads to an enhancement in amphetamine-induced dopamine
release. We previously reported an increased stoichiometry of site 3-phospho
synapsin I and increased levels of phospho-Ser41-neuromodulin in striatum after
repeated amphetamine. In this study, we examined whether the enhanced amphetamine
induced dopamine release and increased levels of these phosphoproteins would be
detected in synaptosomes from rats pretreated and withdrawn from repeated
amphetamine. Enhanced amphetamine-induced dopamine release was detected in
striatal synaptosomes from rats treated with repeated amphetamine compared with
controls. The enhanced dopamine release was Ca++ dependent. State-specific
antibodies were used to measure the levels of site 3-phospho-synapsin I,
phosphorylated by CaM kinase II, and phospho-Ser41-neuromodulin, phosphorylated
by protein kinase C, in incubated striatal S1 fractions and synaptosomes. The
levels of site 3-phospho-synapsin I and phospho-Ser41-neuromodulin were increased
by 40% and 30%, respectively, in amphetamine-pretreated rats compared with
controls. Total neuromodulin and synapsin I was not altered. There was a
significant 26% increase in CaM kinase II activity in the synaptosomes from
amphetamine-pretreated rats but no change in content. No change in protein kinase
C activity or content of the alpha-isozyme was detected after repeated
amphetamine. Our results demonstrate that the enhanced amphetamine-induced
dopamine release and occurring after repeated amphetamine can be detected in
synaptosome preparations. Repeated amphetamine leads to alterations in
phosphorylation/dephosphorylation activities that can be detected in the
incubated synaptosomes. Because the enhanced amphetamine-induced dopamine release
after repeated amphetamine appears to be Ca++ sensitive, it is possible that the
altered phosphorylation systems, and perhaps site 3-phospho-synapsin I and
phospho-Ser41-neuromodulin, play a role in the enhanced dopamine release.
PMID- 9400021
TI - Attenuation by phosphodiesterase inhibitors of lipopolysaccharide-induced
thromboxane release and bronchoconstriction in rat lungs.
AB - Exposure of perfused rat lungs to lipopolysaccharides (LPS) causes induction of
cyclooxygenase-2 followed by thromboxane (TX)-mediated bronchoconstriction (BC).
Recently, phosphodiesterase (PDE) inhibitors have received much interest because
they not only are bronchodilators but also can suppress release of
proinflammatory mediators. In the present study, we investigated the effect of
three different PDE inhibitors on TX release and BC in LPS-exposed perfused rat
lungs. The PDE inhibitors used were motapizone (PDE III specific), rolipram (PDE
IV specific), and zardaverine (mixed PDE III and IV specific). At 5 microM, a
concentration at which all three compounds selectively block their respective PDE
isoenzyme, rolipram (IC50 = 0.04 microM) and zardaverine (IC50 = 1.8 microM)
largely attenuated the LPS-induced BC, whereas motapizone was almost ineffective
(IC50 = 40 microM). In contrast to LPS, BC induced by the TX-mimetic U46619 was
prevented with comparable strength by motapizone and rolipram. In LPS-treated
lungs, the TX release was reduced to 50% of controls by rolipram and zardaverine
but was unaltered in the presence of 5 microM motapizone. Increasing
intracellular cAMP through perfusion of db-cAMP or forskolin (activates adenylate
cyclase) also reduced TX release and BC. We conclude that PDE inhibitors act via
elevation of intracellular cAMP. Although both PDE III and PDE IV inhibitors can
relax airway smooth muscle, in the model of LPS-induced BC, PDE IV inhibitors are
more effective because (in contrast to PDE III inhibitors) they also attenuate TX
release.
PMID- 9400022
TI - Ochratoxin A-induced stimulation of extracellular signal-regulated kinases 1/2 is
associated with Madin-Darby canine kidney-C7 cell dedifferentiation.
AB - The kidneys represent one of the main targets of ochratoxin A (OTA), a secondary
fungal metabolite that is produced by certain species of Aspergillus and
Penicillium. OTA has the ability to disturb Madin-Darby canine kidney (MDCK) cell
pH homeostasis, leading to intracellular alkalinization and morphological
alterations resembling those that occur when MDCK cells are exposed to transient
alkaline stress. Because alkali-induced epithelial dedifferentiation of MDCK-C7
cells is associated with an increase in the activity of extracellular signal
regulated kinases (ERK), we performed experiments that investigated a possible
role for ERK1 and ERK2 as intracellular signaling molecules mediating some of the
mycotoxin's effects on renal epithelia. We studied the effects of OTA on ERK1/2
phosphorylation and activation, as well as on cell morphology by using cloned
MDCK-C7 and MDCK-C11 cells. In MDCK-C7 cells, but not in MDCK-C11 cells, OTA led
to a time-dependent and concentration-dependent increase in ERK1/2
phosphorylation. OTA-induced ERK1/2 phosphorylation in MDCK-C7 cells occurred at
concentrations of 500 nM, started after 2 hr and was maximal after 8 hr.
Furthermore, after 8 hr of incubation, 500 nM and 1 microM OTA significantly
increased ERK1/2 activity in MDCK-C7 but not in MDCK-C11 cells. This OTA
stimulated ERK1/2 phosphorylation and ERK1/2 activation in MDCK-C7 cells was
partially inhibited by the synthetic mitogen-activated protein kinase kinase (MKK
or MEK) inhibitor PD098059. Transepithelial resistance and lactate dehydrogenase
release remained unaltered after incubation in the presence of 1 microM OTA for 8
hr or of 100 nM OTA for 24 hr, so it is unlikely that these OTA effects on ERK1/2
are due to secondary toxic effects of the mycotoxin. Interestingly, OTA-induced
long-term activation of ERK1/2 in MDCK-C7 cells was associated with epithelial
dedifferentiation, as assessed by analysis of vectorial solute and water
transport as well as cell morphology. In contrast, MDCK-C11 cells, which do not
show significant increases in ERK1/2 phosphorylation and ERK1/2 activity in
response to OTA, retained their epithelial phenotype under identical experimental
conditions. Taken together, our data demonstrate an epithelial dedifferentiation
of MDCK-C7 cells, but not of MDCK-C11 cells, after long-term incubation in the
presence of OTA, a result associated with the ability of this mycotoxin to
stimulate ERK1/2 in MDCK-C7 cells but not in MDCK-C11 cells. We conclude that OTA
induced activation of ERK1/2 could be an important intracellular signaling
pathway that mediates some of the mycotoxin's effects on renal epithelia.
PMID- 9400023
TI - Influence of streptozotocin diabetes on the alpha-1 adrenoceptor and associated G
proteins in rat arteries.
AB - Previous studies from this laboratory have demonstrated an enhancement in both
the contractile and signaling response to stimulation of either alpha-1
adrenoceptors or guanine nucleotide binding proteins (G proteins) in arteries
from male Wistar rats with 12 to 14 weeks of streptozotocin-induced diabetes. The
purpose of the present investigation was to determine whether changes in arterial
alpha-1 adrenoceptors or the G proteins coupled to them are associated with the
enhanced responsiveness of the diabetic arteries. No difference in affinity was
detected between control and diabetic aorta or caudal artery membranes in
saturation binding of [3H]prazosin to alpha-1 adrenoceptors. However, the alpha-1
adrenoceptor number was significantly decreased in caudal artery but not aorta
from diabetic rats. In competition binding experiments, a low-affinity and a high
affinity binding site for norepinephrine were detected in the absence of guanine
nucleotides and NaCl in control arteries, whereas only the low-affinity site was
detected in diabetic arteries, suggesting that coupling of the alpha-1
adrenoceptor to G proteins is impaired in diabetic aorta and caudal artery. The
levels of immunoreactive Gi2,3alpha and Gq/11alpha were not different between
control and diabetic aorta or caudal artery. Thus, not only do changes in the
number and coupling of the alpha-1 adrenoceptor or level of G proteins not
explain the enhanced contractile responses of diabetic arteries to
norepinephrine, but also the changes in alpha-1 adrenoceptor binding would
counteract the enhancement. Instead, an increase in the activity of the G
proteins or phospholipase C-beta coupled to the alpha-1 adrenoceptor may be
mediating the enhanced responsiveness elicited by alpha-1 adrenoceptor
stimulation in diabetic arteries.
PMID- 9400024
TI - Irreversible inhibition of cytochrome P450 by nitric oxide.
AB - Nitric oxide (NO) modulates various metabolisms through interaction with thiol
proteins and hemoproteins. Although NO interacts reversibly with iron moieties of
heme proteins, including cytochrome P450 (P450), dynamic aspects of the
formation, catalytic functions and fates of NO-P450 adducts remain to be
elucidated. When incubated with NOC7, which spontaneously and stoichiometrically
releases NO within 5 min, microsomal P450 rapidly formed nitrosyl-heme adducts as
determined by the electron spin resonance method. The signal intensity for the
complex increased with time, peaking at 30 min and decreasing to below detectable
levels by 60 min of incubation. In contrast, the microsomal levels of low-spin
ferric forms of P450 (g = 2.26) rapidly decreased during the initial 30 min but
recovered time-dependently thereafter. Analysis by differential spectra (reduced
form/CO-reduced form) revealed that on incubation with NOC7, the form of
microsomal P450 also changed in a biphasic manner. To elucidate the mechanism for
the decrease in the levels of P450, microsomal levels of P450 isozymes (CYPs)
were determined by Western blot analysis using specific antibodies against CYP3A2
and CYP2C11, major isoforms found in male rat liver. Kinetic analysis revealed
that no appreciable degradation of P450 proteins occurred during the incubation
of microsomes with NOC7. The effect of NO on the catalytic activity of the
enzymes was determined by using testosterone as substrate because hydroxylation
of steroid hormones is one of the major functions of P450. When exposed to NO,
the hydroxylation activity in microsomes rapidly decreased during the initial 10
min and then disappeared slowly. These results suggested that NO formed
dissociable complexes with P450 isozymes and the catalytic functions of these
isozymes were irreversibly inactivated after dissociation from their heme moiety.
PMID- 9400025
TI - Hormonal regulation of microsomal cytochrome P450 2C11 in rat liver and kidney.
AB - The current study was conducted to investigate hormonal regulation of cytochrome
P450 2C11 (CYP2C11) in rat liver and kidney of adult male rats. In two
experiments, hypophysectomy (Hx) resulted in decreased (P < .05) hepatic CYP2C11
apoprotein and mRNA levels. Growth hormone (GH) replacement of Hx rats prevented
the decline in hepatic CYP2C11 apoprotein and mRNA levels, whereas, subcutaneous
injection of testosterone had no effect. Rat pituitary extract is equally
effective in intact or castrated Hx rats in preventing the decline in hepatic
CYP2C11 apoprotein and mRNA levels. Specific neutralization of rat GH by sheep
anti-rat GH serum reduced (P < . 05) serum IGF-I concentrations, hepatic CYP2C11
apoprotein and mRNA levels. Hx of male rat resulted in decreased (P < .05) renal
CYP2C11 apoprotein and mRNA levels, and treatment with GH failed to prevent these
effects; however, supplementation of Hx rats with testosterone or rat pituitary
extract prevented the Hx-induced decrease of renal CYP2C11 apoprotein and mRNA
levels, and the effects of rat pituitary extract occurred only in intact rats.
Neutralization of rat GH by anti-rGH significantly reduced (P < .05) CYP2C11 mRNA
levels and serum T concentrations but not serum LH concentrations. These results
indicate that although hepatic CYP2C11 is regulated by GH, rat renal CYP2C11 is
regulated primarily by gonadal steroids.
PMID- 9400026
TI - Possible involvement of 5-HT2 receptor activation in aggravation of diet-induced
acute pancreatitis in mice.
AB - Acute pancreatitis was induced in mice by feeding with a choline-deficient
ethionine-supplemented diet. All the mice developed acute pancreatitis, and
approximately 80% of them died within 4 days. Stereomicroscopic and light
microscopic examinations revealed that pancreatic necrosis and circulatory
disturbance that were not apparent on day 1 were increased markedly on days 2 and
3. Serum levels of pancreatic enzymes were normal or reduced on day 1 but then
increased to peak on day 3. Plasma 5-hydroxyindoleacetic acid levels, which may
indicate serotonin release, were significantly increased on days 1 through 3.
Pretreatment with D, L-p-chlorophenylalanine methylester hydrochloride (200-400
mg/kg) significantly attenuated the mortality of the mice with pancreatitis. Dose
dependent attenuation was also obtained with ketaserin (0. 01-10 mg/kg),
cyproheptadine (0.01-10 mg/kg), pindolol (0.1-100 mg/kg) and NAN-190 (0.1-100
mg/kg), but not with 0.01 to 10 mg/kg of ICS205-930 or M-840, and the activities
were significantly correlated with the binding affinities for serotonin2 receptor
on the rat cerebral cortex. In addition, ketanserin or cyproheptadine attenuated
the morphologic changes in the choline-deficient ethionine-supplemented diet mice
at a dose (3.2 mg/kg) that hardly affected the serum enzyme levels. We propose
that serotonin2 receptor activation plays an important role in the aggravation of
diet-induced acute pancreatitis.
PMID- 9400027
TI - Chronic administration of a glycine partial agonist alters the expression of N
methyl-D-aspartate receptor subunit mRNAs.
AB - Both acute and chronic treatments with the glycine partial agonist 1
aminocyclopropanecarboxylic acid (ACPC) are neuroprotective in animal models of
focal, global and spinal ischemia. After a chronic regimen of ACPC, brain and
plasma levels were undetectable at the time of ischemic insult, which suggests
that the neuroprotective effects of acute and chronic ACPC are mediated by
different mechanisms. To investigate the possibility that chronic administration
of ACPC alters N-methyl-D-aspartate (NMDA) receptor composition, the levels of
mRNAs encoding zeta and epsilon subunits were quantified by in situ hybridization
histochemistry with 35S-labeled riboprobes. Chronic ACPC administered to mice
(200 mg/kg for 14 days) increased the level of epsilon-1 mRNA in the hippocampus
(particularly CA1 and CA2 regions) and cerebral cortex (frontal, parietal and
occipital regions), without altering levels in cerebellum. In contrast, this
regimen decreased epsilon-3 subunit mRNA levels in the hippocampus (especially
CA1 and dentate gyrus) and frontal and occipital cortices. Decreases in epsilon-2
subunit mRNA levels in cerebral cortex (especially frontal and parietal cortices)
were also observed without accompanying alterations in the cerebellum,
hippocampus or dentate gyrus. The levels of zeta subunit mRNA (determined with a
probe that detects all splice variants) were not altered in any brain areas
examined. Based on studies in recombinant receptors, these region-specific
changes in mRNAs produced by a chronic regimen of ACPC could result in NMDA
receptors with reduced affinities for glycine and glutamate. It is hypothesized
that such alterations in NMDA receptor subunit composition may explain the
neuroprotective effects produced by chronic ACPC.
PMID- 9400028
TI - Discovery of less nephrotoxic FK506 analogs and determining immunophilin
dependence of immunosuppressant nephrotoxicity with a novel single-dose rat
cisplatin potentiation assay.
AB - Comparing nephrotoxicity of numerous drug analogs is impractical with chronic in
vivo models. We devised a new cisplatin potentiation assay (CISPA) that
sensitively detects renal injury as a serum creatinine increase when only one
dose of test compound is followed by cisplatin. Reference nephrotoxins known to
act on various sites in kidney tubules, glomeruli or renal papilla were all
detected by the CISPA at single doses that without cisplatin gave little change,
which showed that this simple, sensitive assay has broad potential utility for
mechanistic studies of nephrotoxicity. We used the CISPA both to probe the
nephrotoxic mode of action of immunosuppressants and to search for safer
compounds. Although several non-nephrotoxic immunosuppressants were inactive,
cyclosporine, FK506, ascomycin (C21-ethyl-FK506) and rapamycin were nephrotoxic
in the CISPA at single doses equal to the daily amounts required to reduce
creatinine clearance with 14 days of treatment. Similar therapeutic indices were
derived comparing toxicity by either method to prevention of rat ear-heart
allograft rejection. C18-OH-ascomycin, an FK506-binding protein (FKBP)
antagonist, reversed in vivo immunosuppression by FK506 and ascomycin in the rat,
and pretreatment in the CISPA blocked FK506 and ascomycin nephrotoxicity, which
showed a common immunophilin dependence. Rapamycin nephrotoxicity was unaffected
(as with cyclosporine), which indicated that binding to FKBP was not required.
Rapamycin nephrotoxicity thus appears mechanistically unrelated to its
immunosuppressive mode of action. Screening with the CISPA enabled discovery of A
119435, a less nephrotoxic ascomycin analog having a 10-fold higher therapeutic
index.
PMID- 9400029
TI - The protective effect of metallothionein against lipid peroxidation caused by
retinoic acid in human breast cancer cells.
AB - The treatment of breast cancer by retinoic acid (RA) may be mediated by lipid
peroxidation. Expression of metallothionein (MT) in cancer cells, however, can
protect against lipid peroxidation by scavenging hydroxyl radicals. In this
study, a two-by-six factorial design was used to investigate the interactive
effects of all-trans-RA and zinc (Zn)-induced MT on the growth of two human
breast cancer cell lines differing in basal expression of MT and estrogen
receptors; MCF7 cells express estrogen receptor, BT-20 cells do not. Cells were
treated with Zn to induce MT and then treated with six RA concentrations. Cell
proliferation, lipid peroxidation, MT protein, MT mRNA and glutathione
concentrations were measured. BT-20 cells expressed higher constitutive MT
concentrations than MCF7 cells. MT was significantly increased by Zn treatment in
BT-20 cells but not in MCF7 cells. Low RA concentrations stimulated growth
proliferation but higher concentrations inhibited cell proliferation. Elevated RA
concentrations increased lipid peroxidation as measured by thiobarbituric acid
reactive substances. There was a significant negative correlation between lipid
peroxidation and cell proliferation. Growth inhibition and lipid peroxidation
were reduced by Zn pretreatment in BT-20 cells but not in MCF7 cells. RA
increased MT levels in both cell lines, which suggests that RA may generate free
radicals which will induce MT mRNA expression. Glutathione did not appear to be a
significant factor. Therefore, induction of MT by Zn may modulate the growth
inhibitory effects of RA in human breast cancer cells. One mechanism of growth
inhibition may be through increased lipid peroxidation. Induction of MT by RA may
be one explanation for acquired RA resistance in cancer.
PMID- 9400030
TI - Enhanced renal toxicity by inorganic mercury in metallothionein-null mice.
AB - To elucidate a protective role of metallothionein (MT) in the manifestation of
inorganic mercury toxicity, we studied the susceptibility of MT-null mice to the
renal toxicity of mercuric chloride. Because the MT-null (J) mice are a genetic
background of 129/Sv strain, the 129/Sv mice were used as wild-type controls.
Nine-week-old male MT-null (J) and 129/Sv mice were given subcutaneous injections
of mercuric chloride at doses of 10 to 40 micromol/kg. The basal MT level in the
kidney of MT-null (J) mice was undetectable (<0.2 microg/g of tissue) and
approximately 2.5 microg/g of tissue in 129/Sv mice. The sensitivity to the renal
toxicity of mercuric chloride was markedly enhanced in the MT-null (J) mice
compared with the 129/Sv mice. The renal mercury level was similar for the MT
null (J) and 129/Sv mice at 4 hr after the injection of mercuric chloride (20
micromol/kg) but became significantly lower in MT-null (J) mice than in 129/Sv
mice at 24 and 72 hr. Based on the present results, we conclude that MT is an
important protective factor against the renal toxicity caused by inorganic
mercury and that it may play a major role in the retention of mercury in the
kidney.
PMID- 9400031
TI - Novel qualitative structure-activity relationships for the antinociceptive
actions of H2 antagonists, H3 antagonists and derivatives.
AB - Recent studies have shown that cimetidine, burimamide and improgan (also known as
SKF92374, a cimetidine congener lacking H2 antagonist activity) induce
antinociception after intracerebroventricular administration in rodents. Because
these substances closely resemble the structure of histamine (a known mediator of
some endogenous analgesic responses), yet no role for known histamine receptors
has been found in the analgesic actions of these agents, the structure-activity
relationships for the antinociceptive effects of 21 compounds chemically related
to H2 and H3 antagonists were investigated in this study. Antinociceptive
activity was assessed on the hot-plate and tail-flick tests after
intracerebroventricular administration in rats. Eleven compounds induced time
dependent (10-min peak) and dose-dependent antinociceptive activity with no
observable behavioral impairment. ED50 values, estimated by nonlinear regression,
were highly correlated across nociceptive assays (r2 = 0.98, n = 11).
Antinociceptive potencies varied more than 6-fold (80-464 nmol), but were not
correlated with activity on H1, H2 or H3 receptors. Although highly potent H3
antagonists such as thioperamide lacked antinociceptive activity, homologs of
burimamide and thioperamide containing N-aromatic substituents retained H3
antagonist activity and also showed potent, effective analgesia. A literature
review of the pharmacology of these agents did not find a basis for their
antinociceptive effects. Taken with previous findings, the present results
suggest: 1) these compounds act on the brain to activate powerful analgesic
responses that are independent of known histamine receptors, 2) the structure
activity profile of these agents is novel and 3) brain-penetrating derivatives of
these compounds could be clinically useful analgesics.
PMID- 9400032
TI - Nephrotoxicity of the glutathione and cysteine S-conjugates of the sevoflurane
degradation product 2-(fluoromethoxy)-1,1,3,3, 3-pentafluoro-1-propene (Compound
A) in male Fischer 344 rats.
AB - 2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (Compound A) is a halogenated
alkene that is nephrotoxic in rats when administered by inhalation or
intraperitoneally. Compound A undergoes glutathione-dependent metabolism:
Compound A-derived glutathione S-conjugates and mercapturates are excreted in the
bile and urine, respectively, of rats given Compound A. The present experiments
were designed to study the nephrotoxicity of the Compound A-derived glutathione
and cysteine S-conjugates, S-[2-(fluoromethoxy)-1,1,3,3, 3
pentafluoropropyl]glutathione , S-[2-(fluoromethoxy)-1,3,3, 3-tetrafluoro-1
propenyl]glutathione , S-[2-(fluoromethoxy)-1,1,3,3, 3-pentafluoropropyl]-L
cysteine and S-[2-(fluoromethoxy)-1,3,3, 3-tetrafluoro-1-propenyl]-L-cysteine .
Conjugates , and given intraperitoneally produced dose-dependent nephrotoxicity
that was characterized by diuresis, increased excretion of glucose and protein,
elevated blood urea nitrogen concentrations and severe morphological changes in
the kidneys, particularly in the proximal tubules. Glutathione S-conjugate , at a
dose of 500 micromol/kg, was hepatotoxic. Cysteine S-conjugate was not
nephrotoxic, apparently because of its facile cyclization to the thiazoline 2-[1
(fluoromethoxy)-2,2,2-trifluoroethyl]-4,5-dihydro-1, 3-thiazole-4-carboxylic
acid, which is not a beta-lyase substrate. Also, the alpha-methyl analog of
cysteine S-conjugate S-[2-(fluoromethoxy)-1,1,3,3, 3-pentafluoropropyl]-DL-alpha
methylcysteine, which cannot undergo beta-lyase-dependent bioactivation, was not
nephrotoxic. These in vivo data show that Compound A-derived S-conjugates are
nephrotoxic and that the toxicity is associated with beta-lyase-dependent
bioactivation.
PMID- 9400033
TI - Characterization of interintestinal and intraintestinal variations in human CYP3A
dependent metabolism.
AB - Cytochrome P450 3A (CYP3A) metabolizes a diverse array of clinically important
drugs. For some of these (e.g., cyclosporine, verapamil, midazolam), CYP3A in the
intestinal mucosa contributes to their extensive and variable first-pass
extraction. To further characterize this phenomenon, we measured CYP3A content
and catalytic activity toward the probe substrate midazolam in mucosa isolated
from duodenal, jejunal and ileal sections of 20 human donor intestines. For
comparison, the same measurements were performed for 20 human donor livers, eight
of which were obtained from the same donors as eight of the intestines. Excellent
correlations existed between homogenate and microsomal CYP3A content for the
three intestinal regions. Median microsomal CYP3A content was greatest in the
duodenum and lowest in the ileum (31 vs. 17 pmol/mg of protein). With respect to
midazolam 1'-hydroxylation kinetics, the median Km for each intestinal region was
similar to the median hepatic Km, approximately 4 microM. In contrast, the median
Vmax decreased from liver to duodenum to jejunum to ileum (850 vs. 644 vs. 426
vs. 68 pmol/min/mg). Intrinsic clearance (Vmax/Km) followed a similar trend for
the intestinal regions; median duodenal intrinsic clearance was comparable to
hepatic intrinsic clearance (157 and 200 microl/min/mg, respectively). Vmax
correlated with CYP3A content for all tissues except the ileum. Duodenal and
jejunal Vmax and CYP3A content varied by >30-fold among donors. Microsomes
prepared from every other 1-foot section of six intestines were also analyzed for
CYP3A as well as for two coenzymes. In general, CYP3A activity, CYP3A content and
CYP reductase activity rose slightly from duodenum to middle jejunum and then
declined to distal jejunum and ileum. Cytochrome b5 content and cytochrome b5
reductase activity varied little throughout the intestinal tract. Regional
intrinsic midazolam 1'-hydroxylation clearance was greatest for the jejunum,
followed by the duodenum and ileum (144, 50 and 19 ml/min, respectively).
Collectively, these results demonstrate that the upper small intestine serves as
the major site for intestinal CYP3A-mediated first-pass metabolism and provides a
rationale for interindividual differences in oral bioavailability for some CYP3A
substrates.
PMID- 9400034
TI - Preoperative amiodarone as prophylaxis against atrial fibrillation after heart
surgery.
AB - BACKGROUND: Atrial fibrillation occurs commonly after open-heart surgery and may
delay hospital discharge. The purpose of this study was to assess the use of
preoperative amiodarone as prophylaxis against atrial fibrillation after cardiac
surgery. METHODS: In this double-blind, randomized study, 124 patients were given
either oral amiodarone (64 patients) or placebo (60 patients) for a minimum of
seven days before elective cardiac surgery. Therapy consisted of 600 mg of
amiodarone per day for seven days, then 200 mg per day until the day of discharge
from the hospital. The mean (+/-SD) preoperative total dose of amiodarone was
4.8+/-0.96 g over a period of 13+/-7 days. RESULTS: Postoperative atrial
fibrillation occurred in 16 of the 64 patients in the amiodarone group (25
percent) and 32 of the 60 patients in the placebo group (53 percent) (P=0.003).
Patients in the amiodarone group were hospitalized for significantly fewer days
than were patients in the placebo group (6.5+/-2.6 vs. 7.9+/-4.3 days, P=0.04).
Nonfatal postoperative complications occurred in eight amiodarone-treated
patients (12 percent) and in six patients receiving placebo (10 percent, P=0.78).
Fatal postoperative complications occurred in three patients who received
amiodarone (5 percent) and in two who received placebo (3 percent, P= 1.00).
Total hospitalization costs were significantly less for the amiodarone group than
for the placebo group ($18,375+/-$13,863 vs. $26,491+/-$23,837, P=0.03).
CONCLUSIONS: Preoperative oral amiodarone in patients undergoing complex cardiac
surgery is well tolerated and significantly reduces the incidence of
postoperative atrial fibrillation and the duration and cost of hospitalization.
PMID- 9400035
TI - Transvaginal ultrasonography compared with endometrial biopsy for the detection
of endometrial disease. Postmenopausal Estrogen/Progestin Interventions Trial.
AB - BACKGROUND: Transvaginal ultrasonography is a noninvasive procedure that may be
used to detect endometrial disease. However, its usefulness in screening for
asymptomatic disease in postmenopausal women before or during treatment with
estrogen or estrogen-progesterone replacement is not known. METHODS: We compared
the sensitivity and specificity of transvaginal ultrasonography and endometrial
biopsy for the detection of endometrial disease in 448 postmenopausal women who
received estrogen alone, cyclic or continuous estrogen-progesterone, or placebo
for three years. RESULTS: Concurrent ultrasonographic and biopsy results were
available for 577 examinations in the 448 women, 99 percent of whom were
undergoing routine annual follow-up. Endometrial thickness was less than 5 mm in
45 percent of the examinations, 5 to 10 mm in 41 percent, more than 10 mm in 12
percent, and not measured in 2 percent, and it was higher in the women receiving
estrogen alone than in the other groups. Biopsy detected 11 cases of serious
disease: 1 case of adenocarcinoma, 2 cases of atypical simple hyperplasia, and 8
cases of complex hyperplasia. Biopsy also detected simple hyperplasia in 20
cases. At a threshold value of 5 mm for endometrial thickness, transvaginal
ultrasonography had a positive predictive value of 9 percent for detecting any
abnormality, with 90 percent sensitivity, 48 percent specificity, and a negative
predictive value of 99 percent. With this threshold, a biopsy would be indicated
in more than half the women, only 4 percent of whom had serious disease.
CONCLUSIONS: Transvaginal ultrasonography has a poor positive predictive value
but a high negative predictive value for detecting serious endometrial disease in
asymptomatic postmenopausal women.
PMID- 9400036
TI - Cellular adaptations in the diaphragm in chronic obstructive pulmonary disease.
AB - BACKGROUND: In patients with severe chronic obstructive pulmonary disease, the
diaphragm undergoes physiologic adaptations characterized by an increase in
energy expenditure and relative resistance to fatigue. We hypothesized that these
physiologic characteristics would be associated with structural adaptations
consisting of an increased proportion of less-fatigable slow-twitch muscle fibers
and slow isoforms of myofibrillar proteins. METHODS: We obtained biopsy specimens
of the diaphragm from 6 patients with severe chronic obstructive pulmonary
disease (mean [+/-SE] forced expiratory volume in one second, 33+/-4 percent of
the predicted value; residual volume, 259+/-25 percent of the predicted value)
and 10 control subjects. The proportions of the various isoforms of myosin heavy
chains, myosin light chains, troponin, and tropomyosin were determined by sodium
dodecyl sulfate-polyacrylamide-gel electrophoresis. We also used
immunocytochemical techniques to determine the proportions of the various types
of muscle fibers. RESULTS: The diaphragm-biopsy specimens from the patients had
higher percentages of slow myosin heavy chain I (64+/-3 vs. 45+/-2 percent,
P<0.001), and lower percentages of fast myosin heavy chains IIa (29+/-3 vs. 39+/
2 percent, P=0.01) and IIb (8+/-1 vs. 17+/-1 percent, P<0.001) than the
diaphragms of the controls. Similar differences were noted when
immunohistochemical techniques were used to compare the percentages of these
fiber types in the two groups. In addition, the patients had higher percentages
of the slow isoforms of myosin light chains, troponins, and tropomyosin, whereas
the controls had higher percentages of the fast isoforms of these proteins.
CONCLUSIONS: Severe chronic obstructive pulmonary disease increases the slow
twitch characteristics of the muscle fibers in the diaphragm, an adaptation that
increases resistance to fatigue.
PMID- 9400037
TI - Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome.
Lamictal Lennox-Gastaut Study Group.
AB - BACKGROUND: The Lennox-Gastaut syndrome, a severe form of epilepsy that usually
begins in early childhood, is difficult to treat. Dose-related drug toxicity is
common. METHODS: We conducted a double-blind, placebo-controlled trial of the
antiepileptic drug lamotrigine in patients with the Lennox-Gastaut syndrome.
Eligible patients had more than one type of predominantly generalized seizure,
including tonic-clonic, atonic, tonic, and major myoclonic, and had seizures on
average at least every other day. After a 4-week base-line period in which all
participants received placebo, we randomly assigned 169 patients (age range, 3 to
25 years) to 16 weeks of lamotrigine (n= 79) or placebo (n=90) in addition to
their other antiepileptic drugs. RESULTS: The median frequency of all major
seizures changed from base-line levels of 16.4 and 13.5 per week in the
lamotrigine and placebo groups, respectively, to 9.9 and 14.2 per week after 16
weeks of treatment (P=0.002). Thirty-three percent of the patients in the
lamotrigine group and 16 percent of those in the placebo group had a reduction of
at least 50 percent in the frequency of seizures (P= 0.01). There were no
significant differences between groups in the incidence of adverse events, except
for colds or viral illnesses, which was more common in the lamotrigine group
(P=0.05). CONCLUSIONS: Lamotrigine was an effective and well-tolerated treatment
for seizures associated with the Lennox-Gastaut syndrome.
PMID- 9400038
TI - Images in clinical medicine. Amiodarone-induced skin discoloration.
PMID- 9400039
TI - Images in clinical medicine. Amiodarone-induced pulmonary toxicity.
PMID- 9400040
TI - House calls to the elderly--a vanishing practice among physicians.
AB - BACKGROUND: Despite the growth in other home health care services, the number of
house calls by physicians has declined dramatically during this century. We
determined the frequency of house calls made by physicians to elderly U.S.
patients in 1993 and analyzed the characteristics of the physicians and patients
involved. METHODS: We analyzed a 5 percent random sample of the 1993 Medicare
Part B claims data for beneficiaries over the age of 65 who were not enrolled in
health maintenance organizations (HMOs). With supplemental information from the
Area Resource File and the American Medical Association's Physician Masterfile,
we determined how many house calls were made, their cost, and a number of
specific characteristics of the physicians and the patients. RESULTS: In our 1993
sample, 36,350 house calls were made to 11,917 of the 1,357,262 patients. When
extrapolated to all Medicare beneficiaries over age 65 and not enrolled in HMOs,
these figures correspond to 727,000 house calls to 238,340 patients nationwide.
We estimated the cost of these house calls to be $63 million. The patients who
received house calls from physicians were older than those who did not, were more
likely to die within the calendar year, had higher rates of hospitalization, and
were more likely to receive care from other home health providers, hospice
programs, and skilled-nursing facilities. Patients residing in rural areas and
those in areas with high physician-to-population ratios had an increased
likelihood of receiving a house call. The physicians who made house calls were
more likely than others to be generalists, osteopaths, older, male, board
certified, practicing in the Northeast, and in solo practice. CONCLUSIONS: A very
small percentage (0.88 percent) of elderly Medicare patients, mainly those who
are very sick and near the end of life, receive house calls from physicians.
PMID- 9400041
TI - Transmissible spongiform encephalopathies.
PMID- 9400043
TI - Optimizing the accuracy of transvaginal ultrasonography of the endometrium.
PMID- 9400044
TI - Can house calls survive?
PMID- 9400045
TI - Inappropriate drug-donation practices in Bosnia and Herzegovina, 1992 to 1996.
PMID- 9400046
TI - An unusual congenital anomaly: ectopic sigmoid kidney combined with
hermaphroditism in a newly born calf.
AB - A rare case of hermaphroditism accompanied with ectopic sigmoid kidney in cross
bred calf is reported. Findings revealed fused kidneys located near urinary
bladder, and presence of uterus, vagina, penis and testicles. Both urinary and
genital defects seemed to occur in combination and to be interrelated.
PMID- 9400047
TI - Observations on the fine structure of the liver in the camel (Camelus
dromedarius).
AB - The structure of macroscopically inconspicuous livers in 23 adult camels (Camelus
dromedarius) was studied by light and transmission electron microscopy. A well
developed connective tissue characterizes the camel liver. Thick trabeculae
divide the liver parenchyma into lobules. Portal tracts and central veins are
surrounded by a variable amount of fibrous tissue. In the perisinusoidal space
(DISSE), collagen fibres form a dense three-dimensional network around the
sinusoids. A mild to moderate fatty infiltration is present in hepatocytes of all
animals. In the epithelial cells of the bile ducts, small to medium sized lipid
inclusions are a common feature. The ultrastructure of hepatocytes in the camel
liver corresponds to that of other domestic mammalian species. The endothelial
cells lining the sinusoids show a multiple fenestration and are surrounded by a
discontinuous basal lamina. Fat-storing cells are numerous and contain lipid
droplets varying in size, number and electron density from one cell to another.
PMID- 9400048
TI - Elastic fibre system of the female canine urethra. Histochemical identification
of elastic, elaunin and oxytalan fibres.
AB - The elastic system fibres of the female urethra were investigated in seven dogs
of different breeds. The fibres were stained and differentiated with orcein,
Verhoeff's iron hematoxylin, and pararosanilin-based aldehyde fuchsin, with and
without previous oxidation. Orcein and aldehyde fuchsin revealed some
subepithelial longitudinally orientated delicate fibres (elaunin fibres) and
numerous coarse longitudinal fibres (elastic fibres) in the deeper subepithelial
connective tissue containing the vascular plexus, as well as a network of fibres
of different calibers in the periurethral connective tissue. Elastic system
fibres were also found in association with the sinusoids of the vascular plexus
and the urethral smooth musculature. Verhoeff's iron hematoxylin only reacted
distinctly with coarse (elastic) fibres. When applied following oxidation,
aldehyde fuchsin disclosed an extensive meshwork of additional delicate fibres
(oxytalan fibres) in the subepithelial connective tissue adjacent to the basement
membrane. Oxytalan fibres were also discernible in the sinusoidal adventitia of
the vascular plexus, as well as between smooth and striated muscle fibres. Due to
the predominantly longitudinal orientation of the elastic system fibres and the
low urethral resistance to manual expression of urine from the bladder post
mortally, when the elasticity of the urethra is still intact and the activity of
other continence factors can be excluded, the elastic tissue is not judged to be
a major contributory factor to urinary continence.
PMID- 9400049
TI - Histochemical demonstration of lipase activity in the gastric mucosa of the cat.
AB - The aim of the present study was to determine, histochemically, the onset and
location of production of preduodenal lipase in fetal, suckling, weaned and adult
cats. Strong enzymatic activity was localized in the surface mucous cells of the
gastric mucosa in animals at postpartal day 1 after ingestion of milk. Activity
of gastric lipase persisted as long as animals were nursed. No gastric lipase
could be demonstrated in weaned and adult cats. Lingual lipase was not found at
any developmental stage examined. Thus, in the newborn cat, lipase of the gastric
mucosa is responsible for milk fat lipolysis.
PMID- 9400050
TI - A stereological study of the different cell populations in chicken testes treated
with follicle-stimulating hormone during embryonic development.
AB - Quantitative morphological methods were used to analyse the histomorphometric
changes and variations in the number and size of cells from diverse cellular
populations in testes of newly hatched chicks treated with follicle stimulating
hormone (FSH) during embryonic development. The tissue was fixed and embedded in
Epon and sections were morphometrically measured under light microscopy, using
point counting for volume densities and the Floderus equation to determine
numerical density. The average volume of the individual cell was determined by
dividing the volume density by the numerical density. Results indicate that FSH
administration causes an increase in the number of Sertoli cells and
spermatogonia, as well as enlargement of the individual Sertoli cells leading
consequently to an increase in the diameter and volume density of the testicular
seminiferous tubules. Results also reveal an increase in the volume density of
the interstitial cords of the Leydig cells, this expansion is due to the
enlargement of the individual Leydig cells and not to an increase in their
number, which remains constant. We conclude that testes of chick embryos are able
to respond to FSH treatment, as revealed by the changes in the number and size of
the cells conforming the diverse cellular populations of the testis. FSH
treatment during embryonic development induces histomorphometric changes in both
the interstitial tissue and seminiferous tubules, accelerating their growth and
differentiation.
PMID- 9400051
TI - Ultrastructural study on the stomach of Tilapia spp (Teleostei).
AB - An ultrastructural study has been made of gastric mucosa of a teleostean fish,
Tilapia spp. The cytological features of the surface mucous cells, mucous neck
cells, glandular cells and endocrine cells are described. The surface mucous
cells, identified by their superficial localization, are characterized by apical
granules. The mucous neck cells are distinguished by the appearance of their
mucous granules and their localization between surface mucous cells and glandular
cells. The gastric glands contain only one form of cell whose fine structure is
similar to cells that secrete hydrochloric acid. Physiological implications of
some ultrastructural features are also discussed.
PMID- 9400052
TI - The annual testicular cycle of the domestic quail (Coturnix coturnix japonica).
AB - A morphometric study was conducted on the testis of the domestic quail Coturnix
coturnix japonica to determine testicular kinetics. We investigated the
variability along the year of testicular parameters such as seminiferous tubule
diameter, germinal epithelium height and amount of meiotic figures of maturing
spermatids in the seminiferous epithelium and of sperm in the tubular lumen. The
results of morphometric analysis showed the occurrence of an annual testicular
cycle defined by four distinct phases: a resting phase (at the end of summer), a
recrudescence phase (in the fall), a proliferative phase (at the end of winter
and beginning of spring), and a regression phase (spring and summer). We also
observed that the testes of adult quails present elevated and maximal
spermatogenic activity in fall-winter (short-day period) and at the beginning of
spring, respectively, and lower values in spring and summer (long-day periods),
with minimum values at the end of summer.
PMID- 9400054
TI - Torsion of accessory spleen in an adult patient: imaging findings at CT, MRI and
angiography.
AB - A 40-year-old woman presented with acute left upper quadrant pain due to torsion
of an accessory spleen around its long vascular pedicle, causing infarction.
Torsion of an accessory spleen is extremely rare. As far as we known only 14
cases have previously been reported in the literature, and more than half
patients were children. MRI can be helpful in the differential diagnosis of
infarction by suggesting haemorrhagic necrosis on the T2-weighted images.
PMID- 9400053
TI - Safety and efficacy of contrast-enhanced MRI in the brain, head and neck:
gadodiamide injection versus gadopentate dimeglumine.
AB - The objective of the present study was to evaluate the safety and efficacy of
gadodiamide injection, a non ionic MRI contrast medium in comparison with the
ionic agent gadopentate dimeglumine. Two groups of 50 patients with known or
suspected lesions of the brain or head and neck were enrolled in a double -blind,
randomised trial. In the gadopentate dimeglumine group three patients reported
four adverse events, and in the gadodiamide injection group, four patients
reported four side effects. All events were minor. Two radiologists analyzed pre
and post-contrast MR images. The parameters evaluated were the number of lesions,
delineation of the lesion, gain of diagnostic information, and final diagnosis.
Both contrast media gave identical diagnostic information.
PMID- 9400055
TI - Shock bowel following massive pulmonary embolism.
AB - Wide-spread abnormalities of the small bowel on CT scan after massive pulmonary
embolism and acute hemodynamic collapse are described. These small bowel
abnormalities are secondary to hypotension with prolonged hypoperfusion. They
consist of diffuse thickening of the small-bowel wall, fluid-filled, dilated
loops and increased contrast enhancement of the small-bowel wall (shock bowel).
These abnormalities are reversible and should be distinguished from acute
vascular occlusion.
PMID- 9400056
TI - Pseudomyxoma peritonei in association with primary malignant tumor of the ovary
and colon.
AB - Pseudomyxoma peritonei (PMP) is a rare entity that is characterised by abundant
intraperitoneal mucinous and gelatinous material associated with an
intraperitoneal adenocarcinoma. We report the case of a patient who presented
with PMP associated with a ruptured well-differentiated mucinous adenocarcinoma
of the ovary and an infiltrating moderately-differentiated mucinous
adenocarcinoma of the sigmoid. Diagnosis was made by ultrasonography and CT. Due
to the presence of 2 mucinous tumors with different histological grade the most
likely pathogenesis was that of multifocal metaplasia. The ovarian and colonic
mucinous tumors were independent primary neoplasms and PMP probably was the
result of rupture of one of these tumors with peritoneal seeding of viable mucus
secreting tumor cells. Aggressive surgical debulking in addition to left
hemicolectomy and radical hysterectomy were performed.
PMID- 9400057
TI - Pericystic emphysema in pulmonary hydatid disease.
AB - The case of a 12-year-old Caucasian boy, living in a non-endemic area, with two
intrapulmonary masses is presented. Conventional X-rays and computed tomography
images were highly suggestive of pulmonary Echinococcus disease because of the
presence of pericystic emphysema in one of both masses, a finding known as the
"crescent" or "meniscus" sign. This radiological feature and other highly
suggestive imaging findings of pulmonary hydatid disease are presented and
discussed.
PMID- 9400058
TI - Giant cell tumor of the tendon sheath in the knee.
AB - The clinical, imaging and pathologic findings in a 28-year-old patient with a
giant cell tumor of the tendon sheath in the knee are reported.
PMID- 9400060
TI - Benefits of a new direct digital x-ray imaging system.
PMID- 9400059
TI - MR imaging of bone infarction and epiphyseal osteonecrosis.
AB - No single musculoskeletal disorder has generated more passionate discussion than
bone osteonecrosis. Surprisingly, its physiopathogenesis remains largely unknown
despite in-depth studies. Its treatment is still debated, and its wide range of
clinical manifestations which vary from totally asymptomatic to the catastrophic
event of irreversible epiphyseal collapse remains a fascinating question for the
clinicians (1-4). Magnetic Resonance (MR) imaging has given a large tribute to
the discussion during the last decade by allowing detection of marrow infarcts at
a presymptomatic period of the disease, thus providing data on its natural
history. Unfortunately, MR imaging has also contributed to increase the confusion
among various epiphyseal disorders. The aim of the current paper is to provide an
overview of the current knowledge of imaging features by stressing accepted data
and delineating blind areas.
PMID- 9400061
TI - Three-dimensional strain analysis of the human left ventricle.
PMID- 9400062
TI - Fast volumetric data acquisition in abdominal computed tomography and magnetic
resonance imaging.
PMID- 9400063
TI - Some preliminary studies on the ability of Africanized honey bees (Apis mellifera
L.) to tolerate cold temperatures when placed inside a refrigerator.
AB - Cold is often suggested as an ecological mechanism to prevent the migration of
Africanized honey bees. The ability of Africanized honey bees to tolerate cold
temperatures was investigated. In one study an observation hive was placed inside
a refrigerator at 25 degrees C. The study was conceptualized as a choice
experiment in which the colony could remain in a cold environment or leave for a
warm environment. Analysis indicated that the bees remained at 9 +/- 1 degrees C
for 14 days before leaving. In a second series of studies, testing the tolerance
to 0 degree C, 280 bees were placed individually in small metal tubes. The data
gathered included survival rate, time to regain consciousness, and ability to
feed. Analysis indicated that Africanized bees can survive for up to 3 hr. at 0
degree C with few ill effects. At 4 hr., however, the survival rate is low.
Limitations of the study, the use of cold as a possible deterrent to honey bee
mites, and suggestions for additional research are discussed.
PMID- 9400064
TI - Racial attitudes of preschoolers: age, race of examiner, and child-care setting.
AB - Racial attitudes of 60 preschool children (28 boys, 32 girls) from either a
monoracial Euro-American child-care program (n = 16), a monoracial African
American program (n = 12), or a multiracial program (25 Euro-Americans, 7 African
Americans) were assessed using the Preschool Racial Attitudes Measure II. Despite
the over-all neutral attitudes reflected by these children, evidence of a Euro
American bias among older children was found. If replicated with a large randomly
selected sample recognizing and understanding early racial attitudes may be a key
factor in fostering positive racial identity and preventing the formation of
prejudice.
PMID- 9400065
TI - A prospective study of hope, optimism, and health.
AB - The present investigation sought to distinguish hope from optimism in the context
of a 10-wk. prospective study involving reports of health outcomes. Gottschalk's
(1985) Hope Scale and Scheier and Carver's (1987) Life Orientation Test which
assesses optimism were given to subjects, along with a health questionnaire. Ten
weeks later subjects were given a second health questionnaire. To rule out
potential confounds we included measures of neuroticism, depression,
extroversion, and social desirability. After controlling for the effects of
correlated confounds, we found that lower hope scores (but not optimism) were
correlated with several dimensions of reported health, including frequency and
severity of illness.
PMID- 9400066
TI - Patients' task-orientation and perceived benefit of amplification in hearing
impaired elderly persons.
AB - This study investigated the reported handicap of 50 elderly hearing-impaired
patients who were classified as high or low in task-orientation. Measures of
perceived handicap were taken when subjects were fitted with hearing aids and
three months later. Analysis indicated that subjects classified as both high and
low on task-orientation reported significant increases in their hearing
impairment at 3 mo., but subjects classified as high on task-orientation reported
significantly less handicap than subjects classified as low.
PMID- 9400067
TI - Note on an MMPI-2 scale of early sexual abuse.
AB - The mean of 191 female psychiatric inpatients on the Griffith, Myers, and
Tankersley (1996) MMPI-2 scale of childhood sexual abuse was compared with means
of 2 community samples (58 sexually abused women and 57 nonabused women). The
mean of the patients was substantially larger than that of the nonabused women
but slightly larger than that of the abused women. The scale may measure general
maladjustment or psychopathology instead of, or in addition to, specific sequelae
of sexual abuse. Further investigation is necessary to cross-validate the scale
in community samples and to examine whether scores differentiate abused and non
abused women in clinical samples. This note illustrates use of an archival data
set with results of recent research.
PMID- 9400068
TI - Dyskinesias subside off all medication in a boy with autistic disorder and severe
mental retardation.
AB - A boy with autistic disorder and severe mental retardation developed severe
dyskinesias, including objective akathisia (probable) and tics, a month after
discontinuation of at least two years of treatment with drugs block dopamine
receptors. These dyskinesias greatly subsided during a 17-wk. open-label nonblind
clinical trial of clomipramine, and returned transiently when the parents
abruptly discontinued clomipramine. However, the dyskinesias gradually subsided
during two and a half years of follow-up with the boy being off all medication. A
few stereotypies remain. We believe this suggests the hypothesis that movement
disorders, such as withdrawal and tardive akathisia and tics, occurring in boys
with autistic disorder treated with dopamine receptor-blocking drugs may subside
months or years after discontinuation of the agents and that clomipramine may
facilitate this process. We also hypothesize that some boys with autistic
disorder and mental retardation exhibit fewer movement disorders, fewer
psychiatric symptoms, and better over-all functioning after they have received no
dopamine receptor-blocking drugs for several months, and this improvement
continues years after the medication has ceased.
PMID- 9400069
TI - Achromatic visual backward masking of colored stimuli in type I diabetes.
AB - On a visual backward masking task using color stimuli with an achromatic
patterned mask, we compared the masking performances of 3 Type I diabetics with
those of 9 participants in a control group. Analysis indicated that the diabetics
show a marked decrement in performance with blue stimuli and a lesser decrement
with red stimuli. Suggestions for further theoretical and parametric studies are
discussed.
PMID- 9400070
TI - Locus of control of smokers, nonsmokers, and nonpracticing smokers.
AB - In this survey, score analyses of 123 male and female respondents, ages 21 to 33
years, yielded no significant differences between either sex and smokers versus
nonsmokers on Rotter's locus of control scale. Of particular interest was that
nonpracticing smokers (quitters) scored more internal than either smokers or
nonsmokers.
PMID- 9400071
TI - Fear of AIDS and Homophobia Scales: additional estimates of reliability and
validity.
AB - Psychometric properties of the Fear of AIDS Scale and the Homophobia Scale from
85 heterosexual undergraduates (and 44 gay, lesbian, and bisexual undergraduates)
were estimated. Responses on the Homophobia Scale were internally consistent
(alpha = .88), had 4% standard error of measurement, and scores differed by
subjects' sexual orientation. Responses to Fear of AIDS Scale were moderately
internally consistent (alpha = .75), had 12% standard error, and were
significantly different for the two groups. Scores on the tests were correlated
.66. Researchers must assess the relationship between scores on these measures.
PMID- 9400072
TI - Comparison of scores on the MMPI-A and MMPI-2 for young adults.
AB - Male college students' profiles look more pathological on the adult version of
the MMPI than on the adolescent version. In the present study, men showed
elevated scores on the F, Pa, and Sc scales on the MMPI-2. In contrast, women's
profiles were more normal on the adult version. When designing the MMPI-A, the
authors attempted to maintain correspondence with the original MMPI and the MMPI
2 so the scales could be interpreted similarly. This study compared scores on the
MMPI-A and MMPI-2 by administering both tests to the same subjects (N = 43; 19
men and 24 women). Validity and standard scale scores were compared using Pearson
product-moment correlations (r), T-score means and standard deviations, and
average profiles. Codetype comparisons were also made. In general, MMPI-A and
MMPI-2 codetype analyses did not agree. The codetype approach is not recommended
for interpretation of the MMPI-A. The finding that young college men show
elevated scores on MMPI-2 scales is consistent with previous research and
suggests that the MMPI-A may be a useful tool for 18-yr.-old men.
PMID- 9400073
TI - Loneliness and sexual risk behavior in gay men.
AB - This study examined loneliness in a sample of gay men and its association with
unprotected anal intercourse, social support, instability of self-esteem,
intimacy, and coping. A sample of 470 urban gay men completed a self-administered
questionnaire. Participants scored high on Loneliness in comparison to other
samples. Measures of Intimacy, Social Support, Instability of Self-esteem,
monogamous relationship status, and use of Avoidance Coping predicted 58.5% of
the variance in Loneliness scores. Both social and psychological variables appear
to be important for understanding loneliness in this population. Men who had
unprotected anal intercourse with nonprimary partners during the previous six
months scored higher on Loneliness than other participants, but those who did so
with primary partners scored the lowest. Episodes of unprotected anal intercourse
with nonprimary partners might have been Avoidance strategies to help
participants cope with loneliness or or other negative affect.
PMID- 9400074
TI - Personality correlates of religiosity among adults in the Republic of Ireland.
AB - This study examined the relationship between measures of personal religiosity
(religious attitude, frequency of personal prayer), a measure of public
religiosity (church attendance), and the Abbreviated form of the Revised Eysenck
Personality Questionnaire among 216 adults in the Republic of Ireland. A
significant negative correlation was found between scores on psychoticism and on
the three measures of religiosity among men (religious attitude, -.36; frequency
of personal prayer, -.40; and frequency of church attendance, -.30) and among
women (religious attitude, -.40; frequency of personal prayer, -.47; and
frequency of church attendance, -.31). No significant relationship was found
between any of the religiosity measures and the other measures contained within
the Eysenck scores. A further analysis of the data suggests that the relationship
for measures of public religiosity with low psychoticism is only a facet of the
relationship between public and personal religiosity. These findings add to a
growing body of research which locates religiosity within the psychoticism
dimension of Eysenck's model of personality and adds to prior suggestions that
this approach is applicable only to personal aspects of religiosity.
PMID- 9400075
TI - Duty-related stressors and PTSD symptoms in suburban police officers.
AB - This study examined the effects of duty-related stress on police officers. Using
a sample of 100 suburban police officers, an anonymous questionnaire requested
demographic information and included a measure of duty-related stressors, SCL-90
R, the Posttraumatic Stress Disorder scale of the Impact of Events Scale-Revised,
and a locus of control scale. Also assessed was whether Critical Incident Stress
Debriefing was experienced. The results showed significant correlations between
scores on duty-related stress, somatization, and symptoms of PTSD. 13% of the
sample met the DSM-IV (1994) diagnostic criteria for PTSD. Results of the
regression analysis showed the best predictors for the diagnosis of PTSD were
associated with the factor of Exposure to Death and Life Threat, which
corresponds to the DSM-IV AI criteria. Finally, 63% of the respondents stated
that a critical incident debriefing would be beneficial following an extremely
stressful event related to duty.
PMID- 9400076
TI - Is sex of fetus associated with duration of labor in nulliparas?
AB - In a post facto study to examine whether sex of fetus was related to duration of
nulliparas' labor 30 nulliparous (had not given birth previously) women who
delivered boys and 30 others who delivered girls were matched according to the
criteria that they were nulliparous, received an epidural for analgesia during
labor, and their labors were either induced or augmented. All delivered
vaginally. Duration of labor was not statistically significantly related to sex
of the fetus.
PMID- 9400077
TI - Definition and measurement of affective variables: theoretical and methodological
considerations.
AB - Research in the affective domain is handicapped by the absence of a theory to
guide empirical work. Without a theoretical framework to guide the selection of
variables, to design appropriate measures, and to interpret results, research
consists of a set of discrete studies that have no collective impact.
PMID- 9400078
TI - Parental divorce and narcissism among college students.
AB - 342 women and 225 men, undergraduate students, participated in a study to assess
whether experiencing the divorce of one's parents affected narcissistic
development. In a larger study on the long-term effects of divorce, these
students completed the Narcissistic Personality Inventory. The analyses indicated
that the scores for children from divorced families did not differ from the
scores of children from intact families on any of the seven subscales.
PMID- 9400079
TI - Testing the McBeath hypothesis: relation of sexual orientation and belief in the
paranormal.
AB - According to McBeath, the incidence of homosexuality among experiments of
paranormal phenomena exceeds that which would be expected by chance. Therefore,
50 homosexual men and 50 heterosexual men were administered the forced-choice
version of the 18-item Australian Sheep-Goat Scale as a measure of belief in and
alleged experience of the paranormal. As no differences were found in scores on
belief/experience, there was no evidence for McBeath's hypothesis.
PMID- 9400080
TI - Effects of reading motivation on the belief in and consumption of newspapers
among youth.
AB - A motivational model of newspaper consumption was elaborated. In this model,
reading motives are supposed to generate certain beliefs in newspapers. The
belief in the satisfying properties of a newspaper is based on an evaluation of
how well the attributes of a newspaper are expected to match the motives of
individuals. Once a match between the motives and the belief is established, then
motivation is triggered, and newspaper consumption should occur. We tested the
model with the hypotheses that reading motives explain belief in newspapers to a
greater extent than the consumption of them and that beliefs explain consumption
to a greater extent than reading motives. Reading motives, beliefs and
consumption of general broadsheet, business and tabloid newspapers were measured
in 1343 young people between the ages of 15 and 25. The results supported the
hypotheses. The results indicate that the profiling and development of the
newspapers toward more loyal and new readers should be based on the readers'
beliefs in newspapers and the motives explaining them.
PMID- 9400081
TI - Anxiety and confidence in using a library by college freshmen and seniors.
AB - The first study using a measure of library anxiety showed that 180 college
freshmen have significantly higher scores than college seniors. A second study
found that among freshmen students, those with high scores on Library Anxiety
reported less confidence in using the library than those with low scores, even
though the students were equal on several indices of academic ability and
performance.
PMID- 9400082
TI - Environmental factors and clients' self-disclosure in counseling.
AB - Self-disclosure by clients is regarded as a fundamental component of counseling,
with increased self-disclosure being related to positive outcome of treatment;
however, scant attention has focused on environmental characteristics that may
facilitate self-disclosure among clients. An evaluation of prior research in this
area leads to suggestions for studies on environmental factors and self
disclosure.
PMID- 9400083
TI - Psychology of computer use: XLVIII: Relation between playfulness and computer
anxiety.
AB - Correlations between scores for computer anxiety and for playfulness were
investigated (N = 265). Scores on computer anxiety correlated negatively with
overall scores on the playfulness scale and the factors, Fun and Creative. Only
the correlation with scores on Creative remained significant when control for
computer experience was imposed. The results imply that playfulness relates to
computer anxiety indirectly through its relation with computer experience. The
implications of the results for the validity of the Adult Playfulness Scale are
briefly discussed.
PMID- 9400084
TI - A validity study of the MMPI-TRI Acting-out Scale.
AB - 49 college men and 45 women were administered the 1995 MMPI-TRI by Swanson,
Templer, Thomas-Dobson, Cannon, Streiner, Reynolds, and Miller and a short form
of the MMPI with scales for Subjective Distress, Acting-out, and Psychosis. To
test the validity of the Acting-out scale respondents also took measures of
sexual and aggressive acting out as well as a measure of alcohol use. They were
asked about their use of drugs. Women had significant correlations between scores
on the Acting-out Scale and scores on measures of Sexual Sensation Seeking .57,
Sexual Compulsion .54, Anger Control -.40, Anger-out .50, Anger-in .32, and Drug
Use .40. Men had significant correlations for scores on measures of Sexual
Compulsion .51, Anger Control -.39, Anger-in .37, and Alcohol Use .35 but not
Anger-out. Results suggest the Acting-out scale is more valid for college women
than for men.
PMID- 9400085
TI - An informational versus monetary incentive in increasing physicians' response
rates.
AB - This study examined return rates for a cancer prevention survey by pediatricians
in relation to an informational booklet versus a monetary incentive in the first
of a three-wave mailing. Of the 300 surveys sent which included an informational
booklet incentive, 189 (64%) were returned. Of the 300 surveys sent which
included a $1.00 incentive 227 (79%) were returned, indicating the $1.00
incentive was more effective than the informational incentive in increasing
return rates in this sample of physicians.
PMID- 9400086
TI - Religiosity and psychological disturbance.
PMID- 9400088
TI - Social anxiety and performance in an interpersonal perception task.
AB - The Interpersonal Perception Task-15 videotape served as a criterion measure to
test hypotheses about individual differences in interpersonal perception. 160
undergraduates completed the Personal Report of Communication Apprehension Scale,
the Shyness and Sociability Scale, and the Interpersonal Perception Task-15.
Scores on the Communication Apprehension Scale were negatively correlated with
Interpersonal Perception Task-15 scores, as predicted. Scores on the Shyness
scale were negatively correlated with scores on the Interpersonal Perception Task
15, while Sociability scale scores were positively correlated. These results
underscore the association between social anxiety and interpersonal perception.
PMID- 9400087
TI - An MMPI-2 scale to identify history of sexual abuse.
AB - This study attempted to extract an MMPI-2 scale identifying adult male and female
victims of severely traumatogenic childhood sexual abuse. Such a scale might aid
in the early detection and diagnosis of trauma sustained from abuse and lead to
prevention of childhood sexual abuse in subsequent generations since victims are
more likely to expose their offspring to similar abuse. Victims of severe
childhood sexual abuse almost inevitably suffer from trauma. Taking the severity
of abuse into consideration, a higher identification rate than the one obtained
in previous attempts was expected. The sample (N = 201), recruited from a low-fee
outpatient clinic and a community mental health center, was divided into a severe
childhood sexual abuse-reporting group and a control group, based on Russell's
(1983) definitions. To cross validate, the data were analyzed three ways. A
stepwise discriminant function analysis based on Wilks Lambda yielded 95% correct
classification (using 52 MMPI-2 items), a discriminant function analysis based on
chi-squared yielded 77% classification (using 63 items), and a stepwise logit
analysis yielded 71% classification (using 15 items). There was little agreement
among the items identified by the three solutions.
PMID- 9400089
TI - Threats and anti-semitic blaming.
AB - A strategy for efficiently and effectively reducing anti-Semitic stereo-typing
was presented, supported by the results of a questionnaire responded to by 15
randomly selected students between the ages of 18 and 32 years, at L.I.F.E. Bible
College (associated with the Pentacostal Four-Square Church) in San Dimas, CA in
1993. Relationships predicted among stereotypic blaming and related threats were
supported by the data--principally, that very negative combinations of common
blamings called compound blamings, e.g., "Jews are rich because Jews are more
dishonest," correlated significantly with a large group of far less negative anti
Semitic blamings and related threats. It was argued that a single compound
blaming when deconditioned in a classroom, would be more effective in reducing
over-all anti-Semitic blaming than deconditioning any other blaming or by using
the more traditional group discussion or lecture methods for reducing prejudicial
attitudes.
PMID- 9400090
TI - APA, science, and the Defense of Marriage Act.
AB - This paper uses the APA position on the Defense of Marriage Act to demonstrate
that APA's advocacy policy regarding homosexual marriage is not based on science.
It shows that the politics of advocacy have led a purportedly scientific
organization to misinterpret, overgeneralize, and distort the results of research
and to ignore the original purpose of the organization.
PMID- 9400091
TI - Inducing positive mood without demand characteristics.
AB - The possibility that a state of private self-awareness induced by a small mirror
can facilitate the effect of procedures which induce a positive mood was
investigated. Participants were 171 female and 60 male undergraduates who were
randomly assigned to one of six conditions in a 2 (Mirror vs No-mirror) x 3
(Control vs Velten manipulation vs Music manipulation) design. As predicted,
participants who experienced the Velten and Music manipulations in the presence
of the mirror reported elevated mood relative to control participants. The mood
of participants who experienced the Velten and Music manipulations without the
mirror did not differ from the mood of control participants. The potential
benefits of using a small mirror as a substitute for explicit instructions about
the expected effect of mood-induction procedures are discussed.
PMID- 9400093
TI - The prevalence of lung lesions in pigs at slaughter in Switzerland.
AB - A survey of the prevalence of lung lesions in randomly selected slaughtered swine
representative of the Swiss fattening pig population was carried out from May to
September 1992 in six large abattoirs. In total 8921 lungs out of 561 herds were
examined. Histological investigations were completed in every herd. No gross
lesions could be found in 56% of the pigs. The most frequent lesions in
individuals were bronchopneumonia (21%) and diffuse pleuritis (21%). Linear scars
(9%), focal pleural fibrosis without any pneumonic lesion (2%), pleuropneumonia
(1%) and abscesses (1%) were less prevalent. The prevalence of lesions at the
herd level was completely different. The lungs of only 14% of the herds were free
of any lesions. The main finding at the herd level was a diffuse pleuritis (75%),
followed by bronchopneumonia (64%), linear scars (60%), focal pleural fibrosis
(20%), abscesses (14%) and pleuropneumonia (9%). In 94% of the herd samples with
macroscopically diagnosed bronchopneumonia, the histological lesions were
consistent with enzootic pneumonia of pigs.
PMID- 9400092
TI - The effect of fenarimol on marker enzymes in rat liver in two-stages model of
hepatocarcinogenesis.
AB - The two-stage model for the development of early markers of hepatocarcinogenesis
was applied to assess the potential of fungicide fenarimol (alpha-(2
chlorophenyl)-alpha-(4-chlorophenyl)-5-pirimidinemethanol++ +) as a possible
promoter in this process. In this experiment the rats were subjected to partial
hepatectomy (to induce proliferation), followed by the single (50 mg/kg bw) dose
of diethylnitrosamine (DEN) (initiator) and then, followed by the 26 weeks
exposure to fenarimol administered in the olive oil suspension (250 mg/kg daily).
The activities of gamma-glutamyltransferase (GGTase), glucose-6-phosphatase (G-6
Pase) and alkaline phosphatase (APase) regarded as markers of early stages of
hepatocarcinogenesis were measured biochemically and histochemically in the
livers of exposed rats as well as in the respective positive and negative
controls. Rats exposed to 2-acetylaminofluorene (2-AAF), instead of fenarimol,
served as positive controls. It was found that in the full initiation/promotion
regimen both 2-AAF and fenarimol induced the increase of GGTase activity in the
liver and formation of GGTase-positive hepatocytes. However the exposure to
fenarimol alone also increased GGTase activity, although this response was not
observed in rats exposed to 2-AAF alone. The possible mechanisms and explanation
for such types of responses were discussed, and conclusion has been drawn that
fenarimol did not affect the rat hepatocarcinogenesis induced by PH and DEN.
PMID- 9400094
TI - ANA hails passage of Medicare reimbursement.
PMID- 9400095
TI - Health and safety on the job: nurse, protect thyself.
PMID- 9400097
TI - Colorado case blurs line between board of nursing admin. law and criminal action.
PMID- 9400096
TI - Long-awaited Providence ruling upholds right of charge nurses to bargain.
PMID- 9400098
TI - Nursing ethical code reflects changing times.
PMID- 9400099
TI - SNAS key in securing Medicare reimbursement for NPs, CNSs.
PMID- 9400100
TI - Arkansas, Louisiana partner to address membership issues.
PMID- 9400101
TI - ONA intensifies campaign against hazardous powdered latex gloves.
PMID- 9400102
TI - ANA quality indicators applied to unit research.
PMID- 9400103
TI - Nurses lead response to flooding in North Dakota and Minnesota.
PMID- 9400104
TI - Western approaches--Part 2.
PMID- 9400105
TI - The child in theatre: should parents be involved?
AB - In this article the author will discuss the parental role in relation to children
undergoing surgery. The gap between theory and practice in relation to this issue
is recognised, and an inter-relationship which must occur has been described
(McCaugherty 1991). The principles of theory are valuable, but it is only through
application to practice that problems can be properly identified. Equally, the
ability to deal with such problems as they arise can only occur when the
underpinning knowledge of theory enables foresight. The author will examine
theories and research into parental involvement in their child's care whilst the
child is in the operating department and discuss problems which have arisen
during application to practice.
PMID- 9400106
TI - The perioperative nurse--carer or technician?
PMID- 9400107
TI - NATN/3M Award Winner. Benchmarks.
PMID- 9400108
TI - Universal precautions and infection control in the perioperative setting.
PMID- 9400109
TI - Homeostasis--the key concept to physiological control.
AB - The maintenance of body water content is a classic example of homeostasis at
work. Water is continuously lost and added to the systems. The regulation of a
balance between the factors involved demonstrates the dynamic nature of
homeostatic processes. Surgery places additional demands on such processes,
partly because there are additional factors in the balance equation and partly
because of the hormonal responses to trauma which also affect water balance.
Promoting the return to a balance state and maintaining it, during and after
surgery, is important to patient well-being and may even facilitate recovery. The
risks associated with a disturbance in water balance are of potentially greater
consequence if there is water overload, particularly if the patient has
underlying cardiovascular or respiratory problems. Slight dehydration is probably
a better target to aim for in order to reduce such risk but there are no easy
ways to achieve this state as individuals will vary in their responses to
surgery. The hydration, and electrolyte, needs, will vary between patients so
fluid therapies should be individualised. Whilst a patient's fluid balance chart
provides a means of assessing water balance, the interpretation is complicated
after surgery. An awareness of other signs is therefore essential.
PMID- 9400110
TI - Alison Bell Memorial Writers Award. Creutzfeldt-Jakob disease--an emerging risk.
PMID- 9400111
TI - The shortage of theatre personnel--a crisis!
PMID- 9400112
TI - Pet therapy ... a howling success.
PMID- 9400113
TI - New guidelines for cardiac rehab.
PMID- 9400114
TI - An update on prescriptive authority.
PMID- 9400115
TI - Professional boundaries in nursing.
PMID- 9400116
TI - Consumer Knowledge: the key to managed care success.
PMID- 9400117
TI - Nursing education is key to reducing organ and tissue shortage.
PMID- 9400119
TI - Nursing certification ... a student's perspective.
PMID- 9400118
TI - A job no one else can do.
PMID- 9400120
TI - The memories of a mentor.
PMID- 9400121
TI - Health needs impact academics.
PMID- 9400122
TI - The nurse as witness: depositions.
PMID- 9400123
TI - Workplace issues.
PMID- 9400124
TI - Healthcare outcome studies: eliminating the "yes but" factor.
PMID- 9400125
TI - Nurses caring for nurses.
PMID- 9400126
TI - You can't have a better employee than a recovering nurse.
PMID- 9400127
TI - Supervision of and delegation to UAPs.
PMID- 9400128
TI - Perceptions of parent and nurse relationships and attitudes of parental
participation in caring for infants in the NICU.
PMID- 9400130
TI - Nursing pins: passe or proof.
PMID- 9400129
TI - Report of survey results: the 1995 Kentucky Nurses Association Workplace Survey.
PMID- 9400131
TI - Moving forward: advanced practice psychiatric/mental health nursing.
PMID- 9400132
TI - Show me the way to go home.
PMID- 9400133
TI - Kentucky Board of Nursing. Advisory opinion statement. Roles of nurses in the
supervision and delegation of nursing acts to unlicensed personnel.
PMID- 9400134
TI - Are you a negligent delegator?
PMID- 9400136
TI - KNA takes patient safety to Frankfort.
PMID- 9400135
TI - The Kentucky Board of Nursing and the Kentucky Nurses Association: what's the
difference? A comparison of the organizations.
PMID- 9400137
TI - What's it like to have an angioplasty?
PMID- 9400138
TI - Nurses need collective bargaining collective bargaining is professional.
PMID- 9400139
TI - Follow-up of intracoronary stent patients.
PMID- 9400140
TI - Perkins Center offers comprehensive vocational rehabilitation.
PMID- 9400141
TI - Workplace woes.
PMID- 9400142
TI - Collaboration and nurse anesthesia.
PMID- 9400143
TI - Defining collaboration.
PMID- 9400145
TI - [Starting in Cologne: the initiative: chronic wounds. Guideline: decubitus
ulcer].
PMID- 9400144
TI - Policymaking and politics: through the eyes of nursing students.
PMID- 9400146
TI - [Thr initiative "chronic wounds"--reasons and aims].
PMID- 9400147
TI - [The economic situation of chronic wounds].
PMID- 9400148
TI - [Renaissance of infectious diseases. Which infections are of importance today?].
PMID- 9400150
TI - [Health care expenses--an international comparison].
PMID- 9400151
TI - [Early diagnosis of onychomycosis. The less severe, the better are the chances
for a cure].
PMID- 9400149
TI - [Patients with vascular diseases--their care in theory and practice. Living with
the disease--everyday experiences at the department].
PMID- 9400152
TI - [Training of auxiliary personnel--an important contribution to the relief of
registered nurses].
PMID- 9400153
TI - [Psychosomatics].
PMID- 9400154
TI - [Growing and doing yesterday and today. The disabled also can harvest].
PMID- 9400155
TI - [Alzheimer's dementia--a challenge to patients, family, physicians and society].
PMID- 9400156
TI - [Psychological aspects of the diagnostic process].
PMID- 9400157
TI - [Psychotherapeutic care of family and patients].
PMID- 9400158
TI - [Milieu therapy--a successful start].
PMID- 9400159
TI - [Alzheimer dementia: new perspectives in drug therapy].
PMID- 9400160
TI - [Laparoscopic "gastric banding" intervention for the treatment of pathologic
obesity].
PMID- 9400161
TI - [The situation of skin tumors in Germany].
PMID- 9400162
TI - [Patients with skin diseases were made scapegoats of the health care system].
PMID- 9400163
TI - [Quality of life as an important condition in therapy--is it only a fad in
medicine? Leaving decisions to the patients].
PMID- 9400164
TI - [Death--an everyday occurrence].
PMID- 9400165
TI - [Listening as an art and hard work. Why don't you ever listen to me?].
PMID- 9400166
TI - [When the Internet grows tiresome].
PMID- 9400167
TI - [Psychosomatics--2].
PMID- 9400168
TI - [Moving and touching to the end].
PMID- 9400170
TI - [What to do about the patients' sexual needs?].
PMID- 9400169
TI - [Sexuality of psychiatric patients. Neither nuns nor sex monsters].
PMID- 9400171
TI - [Nurses from a hundred cultures with common problems].
PMID- 9400173
TI - [A thought journey].
PMID- 9400172
TI - [Report from the Council of National Representatives, the legislative organ of
the International Council of Nurses. How to achieve a fair representation of all
the countries?].
PMID- 9400174
TI - [What is the role of the occupational nurse? "We play the role of catalysts"].
PMID- 9400175
TI - [Congress 1997: impressions. Health, a challenge to be shared].
PMID- 9400176
TI - [Nursing education in the year 2000. Towards clinical teaching].
PMID- 9400177
TI - [Visit by Madeleine Leininger, June 1997. "In Switzerland transcultural nursing
is indispensible"].
PMID- 9400178
TI - [Improving teaching with clinical research].
PMID- 9400179
TI - [The importance of prevention].
PMID- 9400180
TI - [Collaboration in a project of prevention. The risk of falling in the elderly].
PMID- 9400181
TI - [... an unexpected change of contract].
PMID- 9400182
TI - [Three months colic. Your tips and experiences].
PMID- 9400183
TI - [A place at the feed bowl].
PMID- 9400184
TI - [Interdisciplinary cooperation by the 3 basic outpatient services. Each for
himself and all together].
PMID- 9400185
TI - [Evolving nursing concepts and standards. Concrete measures for quality
assurance].
PMID- 9400186
TI - [Quality in the treatment of dialysis patients].
PMID- 9400187
TI - [Time spaces].
PMID- 9400188
TI - [Support in psychosocial areas of life--but how and when?].
PMID- 9400189
TI - [The elbow ... the turning point].
PMID- 9400190
TI - [Challenges for the future].
PMID- 9400191
TI - [A concept of interdisciplinary treatment for patients with nutrition disorders.
The obsession with being thin].
PMID- 9400192
TI - [Reform of the teaching system and implications for nursing. Toward a better
professional education].
PMID- 9400193
TI - Mental health care.
PMID- 9400194
TI - Behind the bare statistics.
AB - The findings of the Mental Health Care stress survey will come as no surprise to
nurses working on the front-line. But the statistics tell only half the story.
PMID- 9400195
TI - Boateng gets down to business.
AB - With his background in law and race relations, Paul Boateng was a surprise
appointment as junior health minister. But he has quickly mastered his brief.
PMID- 9400196
TI - Pathway to employment.
PMID- 9400197
TI - Stress in mental health nursing: findings from the Mental Health Care survey.
AB - Organisational and administrative concerns topped the list of stressors reported
by a national sample of hospital and community mental health nurses. Seven of the
ten top stressors were listed by both groups. Community nurses also listed
inadequate service provision and lack of time to plan treatment. Hospital nurses
were most stressed by inadequacy of staffing cover in potentially dangerous
situations and low morale at work. Jerome Carson et al believe the findings
indicate an urgent need for change at senior NHS management and administration
level.
PMID- 9400198
TI - Management strategies to tackle stress in mental health nursing.
AB - Increased workloads, under-staffing, job insecurity and continuing, rapid
organisational change have all been identified as major sources of stress among
mental health nurses. So too has the increasing intensity of work, with more
highly disturbed and potentially violent or suicidal patients. But, BEN THOMAS
argues, trusts themselves could do much more by tackling poor management practice
and introducing effective policies and procedures to deal with stress at both
organisational and individual levels.
PMID- 9400199
TI - Pressures and rewards of working in community mental health teams.
AB - Community mental health teams (CMHTs) are widely regarded as the mainstay of
community services, bringing health and social services professionals together to
target people with severe mental health problems. Heather Harper and Edana
Minghella report the findings of a recent survey looking at the pressures and
rewards of working in these community-based, multi-disciplinary teams.
PMID- 9400200
TI - Sharing medication information with patients.
AB - Prompted by its user members, the Salford adult mental health services clinical
audit group decided to review the information on medication available to clients.
Here Mick Renoden, a service user on the clinical audit group with a 22 year
history of contact with mental health services, describes his own experiences
with clinicians and medication. Then Jeff Withington reports the results of a
survey of users' views, which revealed a strong demand for information about
medication that could be easily understood and trusted, and led to the production
of a range of leaflets.
PMID- 9400202
TI - Fighting fire with fire.
AB - Post-traumatic stress disorder (PTSD) is a relatively recent diagnostic category,
but it has long been recognised that trauma can produce persistent psychological
sequelae. Paul Wheble describes how he successfully used cognitive behavioural
therapy to help Alec, a fire-fighter, come to terms with an horrific accident 16
years previously.
PMID- 9400201
TI - Epilepsy, learning disability and anti-convulsant drug status.
AB - Epilepsy is frequently associated with learning disability, and can add
considerably to the difficulties this client group experiences. However
behavioural and daily living difficulties can be exacerbated by the seemingly
common practice of polypharmacy, as this small-scale study shows. Barry Coughlan
calls for further, detailed research into the appropriate administration of anti
convulsant drugs to children and adults with learning disabilities and epilepsy.
PMID- 9400203
TI - Door to opportunity.
PMID- 9400204
TI - UK nurses have no right to feel complacent about the recent revelations that
people with learning disabilities.
PMID- 9400205
TI - Telling rights from wrong.
AB - Is it right to medicate patients without their knowledge and consent? Or to tell
an adult woman what she can eat? The UKCC is producing new guidance specifically
to help mental health and learning disabilities nurses with the daily dilemmas of
clinical practice.
PMID- 9400206
TI - Bribery and co-operation.
AB - NHS trusts are still looking for ways to maintain intensive continuing care in
the community for people with severe mental illness. The US model of assertive
community treatment (ACT) may be the answer.
PMID- 9400207
TI - One hell of a trip.
AB - In 1989 the uprising against the Ceausescu regime blew the lid off the hidden
horrors of Romania's mental hospitals. Aid poured in from western agencies and
charities. Eight years on, with attention switched elsewhere, how much has
changed?
PMID- 9400208
TI - Two tales of Mabel.
PMID- 9400209
TI - Pulling together: multi-disciplinary training for mental health nursing.
AB - In 1995 the Sainsbury Centre for Mental Health commissioned a major review of all
specialist mental health training. The current, largely uni-disciplinary approach
to training was felt to be failing to equip professionals with the necessary
skills for today's multi-disciplinary, integrated, community-based service, where
users and their carers expect an equal partnership and sharing of information.
Kevin Gournay and Susannah Strong outline the findings and recommendations of the
review, and its implications for mental health nurse education, which make a case
for its separation from the rest of the nursing profession.
PMID- 9400210
TI - Multi-disciplinary audit and the mental health nurse.
AB - Research advances knowledge; audit is a way of ensuring that this new knowledge
is applied to practice. Uni-disciplinary audit is well-established; multi
disciplinary audit presents other challenges. Jonathan Ash outlines and
illustrates how nurses working in a multi-disciplinary mental health team can
initiate, design and use audit to improve the quality of the service, and to
ensure it meets users' wants and needs.
PMID- 9400211
TI - How do you identify people with severe mental illness in rural communities?
AB - Mental health trusts serving scattered rural communities face particular
challenges when attempting to identify and meet unmet need. A number of social,
geographical and practical factors are involved. Kim Kirkwood and David Peck
describe one such survey, carried out by the Highland Communities NHS Trust, the
failure of which raises a number of important issues for practitioners and
service planners.
PMID- 9400212
TI - Love and friendship.
AB - People with learning disabilities need to know about sexual health issues, and
HIV/AIDS in particular. But how to convey complex and sensitive information in a
clear and simple written format? Joelle Brogan shows it can be done.
PMID- 9400213
TI - Disability discrimination.
PMID- 9400214
TI - Finding a home.
PMID- 9400215
TI - Learning together.
PMID- 9400216
TI - Nurses promote breast health.
PMID- 9400217
TI - The nurse's role in promoting breast cancer screening.
AB - Early detection offers women the best chance of finding breast cancer early when
it is most treatable. Both the ACS and the NCI now recommend mammography and CBE
for women ages 40 and older. These organizations also recommend monthly BSE as a
positive health practice. Nurses can play an important role in promoting
screening by: (a) teaching women about screening guidelines, the benefits and
limitations of screening, and risk factors for breast cancer and (b) helping
women to reduce or eliminate barriers to screening.
PMID- 9400218
TI - The diagnosis of breast abnormalities: nursing implications.
PMID- 9400219
TI - Navigating the maze of breast cancer treatment.
PMID- 9400220
TI - The New World of survivorship and rehabilitation.
PMID- 9400221
TI - Breast cancer as a family disease.
PMID- 9400222
TI - The impact of breast cancer on sexuality.
PMID- 9400223
TI - Breast cancer and women partnering with women.
PMID- 9400224
TI - Lesbian couples and cancer.
PMID- 9400225
TI - Culturally competent nursing care related to breast cancer.
PMID- 9400226
TI - Fear of recurrence: what you should know.
PMID- 9400227
TI - But what about work?
PMID- 9400228
TI - Spirituality and the nurse.
PMID- 9400229
TI - Finding joy and freedom in the challenge of cancer.
PMID- 9400230
TI - Down a twisted path.
PMID- 9400231
TI - Internet breast cancer related resources.
PMID- 9400232
TI - Driver's license: a model for future nursing regulation.
PMID- 9400233
TI - A quest for independent living: a profile of Tim Kolb.
PMID- 9400234
TI - Emphasis on employment.
PMID- 9400235
TI - Female genital mutilation: the penultimate abuse experience.
PMID- 9400236
TI - Visit from Japan.
PMID- 9400237
TI - Oklahoma Nurses Association position statement unlicensed assistive personnel.
PMID- 9400239
TI - One student's perspective.
PMID- 9400238
TI - Prenatal weight gain and birth weight among Oklahoma mothers.
PMID- 9400240
TI - A hospital's view of recovering nurses.
PMID- 9400241
TI - Oklahoma Board of Nursing creates plan for regulation of unlicensed assistive
personnel.
PMID- 9400243
TI - AHCPR and private groups partner on pilot evidence reports. Agency for Health
Care Policy and Research.
PMID- 9400242
TI - Community partnership brings a response to health care concerns.
PMID- 9400244
TI - Family Medical Leave Act.
PMID- 9400245
TI - Political action committees: the work of ANA-PAC and ONA-PAC.
PMID- 9400246
TI - Advanced practice nurses see rules and regulations approved by physicians.
PMID- 9400247
TI - Smoking in Oklahoma: the 7-year trend.
PMID- 9400248
TI - Oklahoma pregnancy risk assessment monitoring system.
PMID- 9400249
TI - SWOSU nursing students working to increase awareness of the RN leaving the
bedside.
PMID- 9400250
TI - Every patient deserves a nurse every patient deserves you.
PMID- 9400251
TI - A "caring" heart.
PMID- 9400252
TI - "Tasks".
PMID- 9400253
TI - Roles, functions of Oregon's clinical nurse specialists.
PMID- 9400254
TI - ONA assisted suicide guidelines.
PMID- 9400255
TI - ONA provides guidance on nurses' dilemma.
PMID- 9400256
TI - Summary of ONA's top legislative priorities.
PMID- 9400257
TI - NIOSH alerts health care workers to risk of developing latex allergy.
PMID- 9400258
TI - Would you be ready to design your health care benefits?
PMID- 9400259
TI - Antibiotic resistance: nursing implications for the '90s.
PMID- 9400260
TI - ONA promotes image of nursing.
PMID- 9400262
TI - [From the bed onto the operating table. The transfer of patients from their bed
to the operating table].
AB - Perioperative nursing is still a much neglected area among the various fields of
direct nursing care. This investigation was carried out within a framework of
reevaluation and actualization of this area of care. The results show that in
particular because of the working conditions of perioperative nursing high
standards of professionally both with respect to details of care as well as to
recognition of the overall situation of a patient are required.
PMID- 9400261
TI - [Head outside--feet within. How do patients from differing cultures experience
the German health care delivery system?].
PMID- 9400263
TI - [Linguistic confusion about nursing standards. A literature study].
AB - This paper takes a close look at nursing publications that are concerned with the
theoretical knowledge of "standards". The central question is: "What are the
intentions and characteristics to which standards are linked in nursing
literature?" Diverse definitions and synonyms of standards are discussed as well.
There is a considerable irregularity in the terminology of standards and similar
terms in the investigated literature. Therefore, the term "standard" is treated
by the author as a general one that embraces many definitions and has to be
differentiated for a closer approach. Thus, four different kinds of features have
been developed in the course of the analytic work: "intentions", "range of
validity", "contents" and "structure". These four areas form a basis for a more
definite description of the various kinds of standards. Based on her findings,
the author give recommendations on how the actual linguistic confusion can be
effectively dealt with.
PMID- 9400264
TI - [Patterns of independent activities of daily living in the frail and disabled
elderly: correlations with health and a socio-ecological context].
AB - The following contribution is focussing on independence in everyday life of 626
frail and disabled elderly people. The impact of medical and social factors on
independence as well as different patterns of independence are examined. Results
show that--besides medical factors--ecological living conditions (e.g. housing)
strongly influence independence. Furthermore, four different patterns of
independence with a high heterogenity in objective and subjective aspects of
living conditions are analyzed. Finally, conclusions regarding nursing science
and nursing practice are discussed.
PMID- 9400265
TI - [Normative dimensions of nursing practice--the ethical relevance of the body].
AB - A combination of preliminary considerations concerning a theory of action and a
philosophy of science illustrates the determining influence of the scientific
preconception of the subject matter, and of the approach which is presupposed by
this preconception, on the normative orientation of nursing practice. The
specific physical nearness involved in nursing practice ("body to body") holds
problems with regard to an appropriate theoretical frame of reference and
corresponding practical convictions. This background provides the context for a
concluding critical examination of several representative nursing theories with
regard to their implicit, normative premises.
PMID- 9400266
TI - [Communication in the hospital. A qualitative study of the communication behavior
within the nursing service between the wards of a psychiatric department of a
general hospital].
AB - In this project the behaviour of communication was examined of the nursing staff
of a psychiatric clinic of a university hospital in Germany dealing with the
staff of the other units. For this project qualitative methods of research with
characteristics of the "Grounded Theory" have been used. The results show among
others that communication barriers with regard to a cooperative communication
process have existed in the past and are still showing some influence on todays'
nursing staff. The interviewed nurses intend to realize a more cooperative
communication and interaction on and between the units. A critical reflection of
the "nursing conference", the "job rotation" or the "coaching of the team
sessions by a neutral presenter" are examples of recommendations to improve and
support the development of the communication process among the nurses.
PMID- 9400267
TI - [Production of a classification system for nursing science for the library of
Bremen University. A contribution to the development of nursing as a science].
AB - Nursing has taken important steps towards becoming a scientific discipline in
Germany. The systematic registration and filing of the available literature in
libraries needs to be enhanced in order to consolidate scientific infrastructures
which can support activities in research, theory and international integration.
In the course of teaching training studies in nursing science, a project was
initiated to develop a classification system for nursing science literature at
the University Library in Bremen. This article describes the genesis of the
project, the basic conditions which were taken into account, the background and
the developmental steps of the classification.
PMID- 9400268
TI - [5 ambulances arrive too late].
PMID- 9400269
TI - [Narcotic abuse treatment--in contact with the mentally ill patient].
PMID- 9400270
TI - [Dr Jekyll and Mr. Hyde in the nursing home].
PMID- 9400271
TI - [Quality in the acute stage].
PMID- 9400272
TI - [Shallow network of ombudsman health visitors].
PMID- 9400273
TI - [At one's own responsibility].
PMID- 9400274
TI - [Rehabilitation in brain injury--the goal is independent activities].
PMID- 9400275
TI - [FS 25 (Professional Association 25) is dissolved].
PMID- 9400276
TI - [WHO--both private and public sector have a responsibility].
PMID- 9400277
TI - [Falck--lack of control].
PMID- 9400278
TI - [Velje district wants to ensure control with Falck].
PMID- 9400279
TI - [Relationship between profession and salary].
PMID- 9400280
TI - [Russia--neighbor in need].
PMID- 9400281
TI - [Russia--team nursing and strange therapies].
PMID- 9400282
TI - [Russia--the sick person in the East].
PMID- 9400283
TI - [Russia--outbreak of infectious diseases].
PMID- 9400284
TI - [Russia--a health system from the turn of the century].
PMID- 9400285
TI - [Russia--Finnish and Russian nurses cross borders].
PMID- 9400286
TI - [Russia--an indomitable ability to survive. Interview by Susanne Bloch Kjeldsen].
PMID- 9400287
TI - [Russia--new nurses for the new Russia].
PMID- 9400288
TI - [First Russian nurses' organization].
PMID- 9400289
TI - [Executive Board--education connection does not balance].
PMID- 9400290
TI - [Fast forward].
PMID- 9400291
TI - [Alcohol--personnel should intervene].
PMID- 9400292
TI - [Education--nursing theory: more freedom for patients].
PMID- 9400293
TI - [Early retirement--occupational ability only theoretical].
PMID- 9400294
TI - [Consultants should counsel on AMS].
PMID- 9400295
TI - [Russia--the good circle].
PMID- 9400296
TI - [Russia--exemplary home care].
PMID- 9400297
TI - [Russia--daily struggle to provide medicines].
PMID- 9400298
TI - [Russia--motivation has severe conditions].
PMID- 9400299
TI - [Russia--hope for Russian health].
PMID- 9400300
TI - [Organization--introduction to the debate--daring to act].
PMID- 9400301
TI - [Organization--watch out--the others are more dangerous!. Interview by Helle
Broberg Nielsen].
PMID- 9400302
TI - [Organization--"Now we do it!". Interview by Helle Broberg Nielsen].
PMID- 9400303
TI - [Organization--troika management--an obsolete construction?. Interview by Helle
Broberg Nielsen].
PMID- 9400304
TI - [Organization--ombudsman course: new wage forms take time. Interview by Soren
Palsbo].
PMID- 9400305
TI - [Organization--ombudsman course: it is a change in system. Interview by Soren
Palsbo].
PMID- 9400306
TI - [Organization--ombudsman course: ombudsman fully in front. Interview by Soren
Palsbo].
PMID- 9400307
TI - [Organization--ombudsman course: an opportunity for the profession. Interview by
Soren Palsbo].
PMID- 9400308
TI - [The little therapist].
PMID- 9400309
TI - [Quality assurance--we don't allow pressure sores here].
PMID- 9400310
TI - [Competence gap].
PMID- 9400312
TI - [Viewpoint from the medical technician. Interview by Marit Fonn].
PMID- 9400311
TI - [Hospital administrator challenges "the system". Interview by Kjelle Arne Bakke].
PMID- 9400313
TI - [I had a uniform and nameplate].
PMID- 9400314
TI - [Closeup: Gerd Fadnes, coordinator for reception of the sexually abused in Bergen
emergency department. Supportive contact. Interview by Marit Fonn].
PMID- 9400315
TI - [Work environment--report use of overtime to Industrial Inspection. Interview by
Tone Kristiansen].
PMID- 9400316
TI - [My workplace: home treatment team for HIV/AIDS patients, Uleval Hospital, Oslo-
persons one gets to like. Interview by Kari Anne Aase].
PMID- 9400317
TI - [From times past--nurses' status in society].
PMID- 9400318
TI - [A split in the AF (Joint Academicians' Organization) could benefit NSF
(Norwegian Nurses' Association). Interview by Kjell Arne Bakke].
PMID- 9400319
TI - [Sunnaas--State takes over TRS Center (Training and Counseling Center). Interview
by Kari Anne Aase].
PMID- 9400320
TI - [Great pursuit of TSS (Telemark Central Hospital). Interview by Tone
Kristiansen].
PMID- 9400321
TI - [National budget--a proposal ... and and explanation].
PMID- 9400322
TI - [Chronic lung disease--morning nap gives breathing a respite. Interview by Kjell
Arne Bakke].
PMID- 9400323
TI - [France--vast differences between North and South].
PMID- 9400325
TI - [Overcoming crisis--a coping model with stress on feelings].
PMID- 9400326
TI - [Consumer participation--in focus groups patients are included in counseling].
PMID- 9400324
TI - [WHO--different ages for women and men].
PMID- 9400327
TI - [Competence--increased number of courses provide better professional
development].
PMID- 9400328
TI - [Is behaviorism dangerous for nursing?].
PMID- 9400329
TI - The legacy of epidemiology in the Department of Social and Preventive Medicine. A
commemoration of the sesquicentennial of the State University of New York at
Buffalo School of Medicine and Biomedical Sciences.
PMID- 9400330
TI - Observations on the history of epidemiology in western New York, 1843-1960.
AB - Epidemiology has a rich tradition in western New York State, beginning with the
classic study by Austin Flint of a waterborne typhoid fever outbreak in North
Boston in 1843. Other important investigations included the study of the Buffalo
poliomyelitis epidemic of 1912, by Wade Hampton Frost, which provided a
comprehensive characterization of the epidemiology of the disease, and the first
case-control study of cigarette smoking and lung cancer, by Morton L. Levin et
al., conducted at the Roswell Park Memorial Cancer Institute in the 1940s. Other
studies carried out before 1960 and included in the review deal with additional
typhoid fever outbreaks, tuberculosis, breast cancer, and coronary heart disease.
PMID- 9400331
TI - Current problems that are likely to affect the future of epidemiology.
AB - The current discussion focuses on criticism as a positive force for improving
epidemiologic practice through periodic reexamination of the basic approach to
the discipline and the strategy for meeting the future educational needs of
students and practicing epidemiologists. The types of epidemiologic research
conducted and the settings within which the research will be conducted are also
discussed. Epidemiology can be expected to play a major role in new areas of
research that are created by changes in the medical care system and the
development of large data systems associated with these approaches to health care
delivery. This paper also discusses the growing threat to data access, the
problems of communicating epidemiologic research findings to the public through
the media, and the expanding interface between epidemiologic research and the
legal system. The role of epidemiologic organizations in helping to shape the
discipline's response to these issues and the opportunities these issues or
problems present for improving epidemiologic research are also discussed.
PMID- 9400332
TI - Toward an integrated approach to molecular epidemiology.
AB - The emergence of "molecular epidemiology" as a scientific approach within the
fields of epidemiology and toxicology has led to spirited discussion within the
biomedical community, particularly in the area of cancer research. At scientific
meetings and in peer-reviewed journals, numerous issues have been raised not only
with regard to the practice of molecular epidemiology, but also with regard to
its role in traditional epidemiology, toxicology, and risk assessment.
Furthermore, the utility of information gleaned from such studies and the
implications for public health have been the subject of considerable debate.
Conceptual differences in how one views the function of epidemiologic and
laboratory research may be reflected in discussions on the merits of molecular
epidemiology. This commentary reviews some of the prevailing attitudes toward
molecular epidemiology, with the goal of identifying areas of concern and
suggesting means of achieving harmonization. The need for cross-training of
epidemiologists and laboratory scientists is discussed, and suggestions are made
for building successful collaborative relations across disciplines.
PMID- 9400333
TI - Body mass index and mortality in a general population sample of men and women.
The Buffalo Health Study.
AB - The objective of this research was to investigate the long-term relation between
body mass index (BMI) and mortality from all causes and from specific causes in
the general population. A 29-year follow-up study was conducted in a random
sample of white men (n = 611) and women (n = 697) aged 20-96 years who were
residents of Buffalo, New York, in 1960. At baseline, height and weight were
determined by self-report. BMI was calculated as weight (kg)/height (m2). During
the follow-up period, 295 (48.3 percent) men and 281 (40.3 percent) women died.
With the Cox proportional hazards model and adjustment for age, education, and
cigarette smoking, a significant linear association was found between BMI and all
cause mortality in men less than age 65 years at baseline (relative risk (RR) =
1.06, 95 percent confidence interval 1.02-1.09), but not in women (RR = 1.02, 95
percent confidence interval 0.99-1.05). In men age 65 years and older, the
relation was quadratic in form (p = 0.02), with the lowest risks appearing in the
BMI range of 23-27. BMI was most strongly related to cardiovascular disease (CVD)
and coronary heart disease mortality in women and younger men. No such
associations were observed in older men. BMI was not related to an increased risk
of death from non-CVD or cancer in either sex. These findings illustrate the
importance of BMI as a risk factor for CVD and coronary heart disease mortality
in certain gender-age groups and indicate that the majority of the impact of BMI
on overall mortality is due to the strong relation between relative weight and
these specific causes of death.
PMID- 9400334
TI - Lactation history and breast cancer risk.
AB - Lifetime lactation in relation to breast cancer risk was examined in a case
control study in two counties in western New York. Cases were women age 40 years
and over with incident, primary, histologically confirmed breast cancer. Controls
were age- and county-frequency matched, selected from New York State driver's
license records (for those less than age 65 years) and from Health Care Finance
Administration Records (for those age 65 or more). Included were women with at
least one livebirth (253 premenopausal and 367 postmenopausal cases and 266
premenopausal and 427 postmenopausal controls). Breast cancer risk was very
weakly associated with long duration of lactation among premenopausal women; the
odds ratio for at least 20 months lifetime lactation was 0.50 (95% confidence
interval 0.21-1.12). Among postmenopausal women, the protective effect of
lactation was restricted to women with first lactation before age 25 years (odds
ratio = 0.67, 95% confidence interval 0.46-0.95). However, age at first birth was
highly correlated with age at first lactation. Neither insufficient milk as a
reason for not breastfeeding nor having received medication to stop milk flow was
associated with increased risk. These findings are in accordance with
accumulating evidence that lactation may have a weak protective effect on breast
cancer risk.
PMID- 9400335
TI - Oxidative stress and lung function.
AB - It has been suggested that lung function can be altered by both free radical and
oxidant exposure, while antioxidant vitamin intake is positively related to lung
function. However, the information on the relation of blood levels of oxidants
and antioxidants to lung function is sparse. The present cross-sectional study,
conducted from September 1995 to May 1996, analyzes the association between lung
function measured as forced expiratory volume in 1 second (FEV1) with 1) levels
of thiobarbituric acid-reactive substances in plasma (p-TBARS) and in low and
very low density lipoprotein cholesterol (LDL cholesterol/VLDL cholesterol-TBARS)
as indicators of lipid peroxidation and 2) compounds with antioxidant activity,
erythrocytic glutathione, plasma glutathione peroxidase, trolox equivalent
antioxidant capacity, and serum bilirubin, which may protect against lipid
peroxidation. The analysis was carried out in 132 nonsmoking subjects aged 37-73
years who were randomly selected from the residents of Erie and Niagara counties,
New York. FEV1 in percent of the predicted value (FEV1%) was negatively and
statistical significantly associated with p-TBARS (r = -0.19). A negative
association with borderline statistical significance was observed between FEV1%
with low density lipoprotein cholesterol/very low density lipoprotein cholesterol
TBARS (r = -0.16) and glutathione (r = -0.16), while FEV1% was positively related
to serum bilirubin (r = 0.15). Participants in the lowest quartile of FEV1%
showed significantly higher levels of p-TBARS (p = 0.02) and lower levels of
bilirubin (p = 0.04) than did those in the highest quartile. Our results suggest
that increased lipid peroxidation is associated with pulmonary airway narrowing
in the general population.
PMID- 9400336
TI - Consumption of contaminated sport fish from Lake Ontario and time-to-pregnancy.
New York State Angler Cohort.
AB - Sport fish from the Great Lakes are contaminated with halogenated organics, heavy
metals, and pesticides, thus serving as a route of exposure for fish-consuming
populations. These contaminants are recognized reproductive toxicants in animals;
few human studies are available. The purpose of this study was to assess
consumption of contaminated fish in relation to time-to-pregnancy (TTP) among
women in the New York State Angler Cohort. In 1993, structured telephone
interviews were conducted with 2,445 of 2,977 (82%) female cohort members aged 18
40 years who stated upon enrollment in the cohort in 1991 that they were
considering pregnancy over the next 3 years. Among the 1,234 women who reported
being pregnant, 874 (71%) had a known TTP and comprise the study sample. After
descriptive analyses, log transformations of the number of years of fish
consumption (duration) and TTP were performed and entered into multiple
regression models that also included other covariates. Duration of fish
consumption and maternal age accounted for only a small percentage of the
explained variance in TTP (R2 = 0.005), even after the analysis was restricted to
women who reported eating fish (R2 = 0.006). All beta coefficients were positive.
These preliminary findings do not support an adverse effect of contaminated fish
consumption on TTP.
PMID- 9400337
TI - Consumption of PCB-contaminated freshwater fish and shortened menstrual cycle
length.
AB - Highly contaminated Lake Ontario sport fish represent an important human dietary
exposure to polychlorinated biphenyls (PCBs) and other toxic contaminants that
may disrupt endocrine pathways. New York State Angler Cohort women interviewed by
telephone in 1993 provided menstrual cycle length (n = 2,223). Fish consumption
at cohort enrollment in 1991 was categorized by duration and frequency and was
used to calculate a PCB exposure index. Multiple regression analyses identified
significant cycle length reductions with consumption of more than one fish meal
per month (1.11 days) and moderate/high estimated PCB index (-1.03 days). Women
who consumed contaminated fish for 7 years or more also had shorter cycles (-0.63
days).
PMID- 9400338
TI - Physical activity, obesity, and diabetes in pregnancy.
AB - Gestational diabetes mellitus (GDM) is the most common medical complication of
pregnancy. Women with GDM are at elevated for numerous maternal health
complications, and their infants are at elevated risk for death and morbidity.
Management of GDM has traditionally been through diet and close monitoring of
glucose levels, with initiation of insulin therapy when diet alone fails to
maintain euglycemia. Recently, however, it has been suggested that alternative
treatment modalities, such as exercise, may overcome a peripheral resistance to
insulin, thus preventing GDM or controlling hyperglycemia in women with GDM. In
this study, conducted from October 1995 to July 1996, the authors used a
population-based birth registry to determine whether exercise has a preventive
role in the development of GDM in women living in central New York State. They
used contingency tables and chi-square statistics to examine bivariate
differences among maternal and demographic variables and the occurrence of GDM.
When stratified by prepregnancy body mass index category, exercise was associated
with reduced rates of GDM only among women with a body mass index greater than 33
(odds ratio = 1.9, 95% confidence interval 1.2-3.1). The effect of exercise in
obese women was further complicated by insurance status. When the data were
stratified by insurance status, it appeared that women of higher socioeconomic
status who were obese and did not exercise were at a significantly elevated risk
of GDM compared with their counterparts of lower socioeconomic status. The
results of this study suggest that for some women exercise may play a role in
reducing the risk that they will develop GDM during pregnancy.
PMID- 9400339
TI - Gender differences in the relation between depressive symptoms and alcohol
problems: a longitudinal perspective.
AB - Longitudinal relations between depressive symptoms and alcohol problems have been
examined infrequently in community-based studies, and gender-specific findings to
date appear to be inconclusive. Study hypotheses were that depressive symptoms
predicted subsequent alcohol problems for females, whereas alcohol problems
predicted subsequent depressive symptoms for males. The authors examined these
relations in a random sample of household adults (aged 19 years or more) from
Erie County, New York, assessed in 1986, 1989, and 1993 (n = 1,306). Measures of
alcohol problems (in the previous year) incorporated an alcohol abuse/dependence
diagnosis and a heavy alcohol use index. The Center for Epidemiologic Studies
Depression Scale was used to assess depressive symptoms over a 1-month time
frame. Comprehensive logistic regression models incorporated prior depressive
symptoms, prior alcohol problems and sociodemographic variables (age, race,
education, marital status, employment, total family income, and number of
children living at home). For females, depressive symptoms predicted subsequent
alcohol problems over 3 years (odds ratio = 3.04, 95% confidence interval 1.35
6.80, p < 0.01) and 4 years (odds ratio = 2.42, 95% confidence interval 1.14
5.12, p < 0.05), but not for 7 years. There was no evidence to support the
hypothesis for males. This study clarifies and extends prior investigations of
relations between these two prevalent mental health problems in a community-based
sample.
PMID- 9400340
TI - Test-retest reliability of the cognitive lifetime drinking history.
AB - A new measure of lifetime alcohol consumption, the Cognitive Lifetime Drinking
History (CLDH) uses beverage-specific questions on drink sizes and assesses
drinking patterns to enhance recall. Two methods of establishing drinking
intervals were examined: 1) floating--the respondent's report of when drinking
changed, and 2) fixed--defined in terms of decades. Test-retest reliability for
lifetime ounces of alcohol consumed and times intoxicated in lifetime estimated
at visits 1 week or more apart was assessed in postmyocardial infarction patients
(n = 81) and controls (n = 138) who had had at least 12 drinks in a year during
their lifetimes. No significant differences in estimates of lifetime ounces of
alcohol or times intoxicated were observed. Spearman's r ranged between 0.85 and
0.92 for the floating and fixed versions of the CLDH administered at a single
visit and between 0.74 and 0.85 for the floating or fixed administered at both
visits. Time between visits did not influence correlations. Intervals reported on
the floating CLDH were comparable for postmyocardial infarction patients and
controls. It took approximately 5 minutes longer to administer the floating CLDH
than the fixed CLDH. Findings support use of the CLDH for case-control studies
and suggest that the floating and fixed versions would yield comparable results.
PMID- 9400341
TI - Cognitive aspects of recalling and reporting health-related events: Papanicolaou
smears, clinical breast examinations, and mammograms.
AB - This paper reports an examination of cognitive processes used by 178 women aged
50 years and older in retrieving information about the frequency with which they
received Papanicolaou smears, mammograms, and clinical breast examinations. Women
were selected from a health maintenance organization in which they had been
enrolled for at least 5 1/2 years. The literature suggested that reporting of
regular events such as these kinds of tests is likely to be based on schemas,
which is an estimation technique in which events are reported in a format with
generic content. Thus, if the procedure is believed to occur annually, the
respondent will report receiving five tests in 5 years. The study attempted to
evaluate whether use of episodic recall, in which respondents are forced to
report individual events, would be more accurate than reports based on estimation
using a schema format. The results indicated that most of the errors occurred in
Papanicolaou smear reporting, which is consistent with the literature, and that
the fewest errors occurred with mammograms. Regardless of the questionnaire
format, respondents persisted in using schemas based on the date of annual
physical examination. Most reporting errors occurred because the interval between
examinations was estimated incorrectly.
PMID- 9400342
TI - Clinical efficacy of methylphenidate in conduct disorder with and without
attention deficit hyperactivity disorder.
AB - BACKGROUND: Stimulants are not considered appropriate for the treatment of
children with conduct disorders (CDs). The postulated differences in stimulant
effect between children with attention deficit hyperactivity disorder (ADHD) and
CD led to the hypothesis that methylphenidate hydrochloride, which is effective
in ADHD, would not significantly improve symptoms of CD. METHODS: We randomly
assigned 84 children with CD, between the ages of 6 and 15 years, to receive
methylphenidate hydrochloride (up to 60 mg/d) or placebo for 5 weeks. Behavior
was evaluated by parent, teacher, and clinician reports and by direct classroom
observations. Two thirds of the children also met criteria for ADHD. RESULTS:
Contrary to prediction, ratings of antisocial behaviors specific to CD were
significantly reduced by methylphenidate treatment. The magnitude of
methylphenidate effect indicated meaningful clinical benefit. Partialling out
severity of ADHD did not alter the significant superiority of methylphenidate on
CD ratings specifically (P < .001). CONCLUSIONS: Methylphenidate has short-term
positive effects on children and adolescents with CD. Key aspects of antisocial
adjustment appear to be treatment responsive. This effect was independent of
severity of the children's initial ADHD symptoms.
PMID- 9400343
TI - Fluoxetine and impulsive aggressive behavior in personality-disordered subjects.
AB - BACKGROUND: Evidence of an inverse relationship between central serotonergic
(serotonin [5-hydroxytryptamine]) system function and impulsive aggressive
behavior has been accumulating for more than 2 decades. If so, pharmacological
enhancement of serotonin activity should be expected to reduce impulsive
aggressive behavior in subjects in whom this behavior is prominent. METHODS: A
double-blind, placebo-controlled trial of the selective serotonin-uptake
inhibitor fluoxetine hydrochloride was conducted in 40 nonmajor-depressed,
nonbipolar or schizophrenic, DSM-III-R personality-disordered individuals with
current histories of impulsive aggressive behavior and irritability. Measures
included the Overt Aggression Scale-Modified for Outpatients, Clinical Global
Impression Rating of Improvement, and several secondary measures of aggression,
depression, and anxiety. RESULTS: Fluoxetine, but not placebo, treatment resulted
in a sustained reduction in scores on the Irritability and Aggression subscales
of the Overt Aggression Scale-Modified for Outpatients that was first apparent
during months 2 and 3 of treatment, respectively. Fluoxetine was superior to
placebo in the proportion of "responders" on the Clinical Global Impression
Rating of Improvement: first at the end of month 1, and then finally
demonstrating a sustained drug-placebo difference from the end of month 2 through
the end of month 3 of treatment. These results were not influenced by secondary
measures of depression, anxiety, or alcohol use. CONCLUSION: Fluoxetine treatment
has an antiaggressive effect on impulsive aggressive individuals with DSM-III-R
personality disorder.
PMID- 9400344
TI - Dopamine receptor transcript expression in striatum and prefrontal and occipital
cortex. Focal abnormalities in orbitofrontal cortex in schizophrenia.
AB - BACKGROUND: The identification of novel subtypes of the dopamine receptors has
renewed interest in the involvement of dopaminergic mechanisms in schizophrenia.
We determined the expression of transcripts encoding the dopamine receptors in
the brains of schizophrenic patients. METHODS: The levels of the messenger RNA
molecules encoding the 5 dopamine receptors were quantified in postmortem brain
samples from 16 schizophrenic patients and 9 control subjects. Samples from
multiple regions of the prefrontal cortex, primary visual cortex, and striatum
were subjected to in situ hybridization followed by quantitative image analysis.
RESULTS: Expression of dopamine receptor transcripts did not differ between
schizophrenic patients and controls in striatum or visual cortex. Dramatic
decreases of dopamine receptor transcripts were found in the prefrontal cortex,
but these changes were restricted to the D3 and D4 receptors, and localized to
Brodmann area 11 (orbitofrontal cortex). CONCLUSIONS: Cortical dopaminergic
neurotransmission may be disrupted in schizophrenia at the level of receptor
expression. There appears to be a focal abnormality of D3 and D4 messenger RNA
expression in the prefrontal cortex, with down-regulation of both, consistent
with prefrontal cortical hypodopaminergia in schizophrenia.
PMID- 9400346
TI - Structural magnetic resonance imaging abnormalities in men with severe chronic
schizophrenia and an early age at clinical onset.
AB - BACKGROUND: Early age at onset of schizophrenia often signifies a more severe
form of the illness. However, the relationship between age at onset and brain
abnormalities has not been established. We assessed temporal-limbic morphometry
in severely ill men with chronic schizophrenia who had a relatively early onset
of illness and examined the relationships among regional brain volumes, clinical
symptoms, and age at illness onset. METHOD: Temporal lobe, superior temporal
gyrus, hippocampus, temporal horn, lateral ventricles, third ventricle, and
frontoparietal volumes were measured on magnetic resonance imaging data from 56
schizophrenic men (mean [SD] age at illness onset, 16.6 [4.2] years) recruited
from a state hospital and 52 age- and range-matched healthy control men. RESULTS:
Patients had significantly smaller gray matter volumes in the temporal lobe,
superior temporal gyrus, and frontoparietal regions; smaller temporal lobe white
matter volumes; and larger cerebrospinal fluid volumes for temporal lobe sulci
and the 3 ventricular measures. There were no group differences in hippocampal
volumes. Psychotic symptom subscores from the Brief Psychiatric Rating Scale were
selectively correlated with smaller left posterior superior temporal gyrus gray
matter volumes. None of the brain measurements were significantly correlated with
age at illness onset. CONCLUSIONS: Data from this unique sample of severely ill
schizophrenic men emphasize a pattern of structural abnormalities involving the
cortex, but not the hippocampus, in schizophrenia. Furthermore, these data
support theories suggesting that superior temporal gyrus abnormalities contribute
selectively to psychotic symptoms and that the extent of structural abnormalities
is unrelated to age of clinical symptom onset.
PMID- 9400345
TI - The New York High-Risk Project. Prevalence and comorbidity of axis I disorders in
offspring of schizophrenic parents at 25-year follow-up.
AB - BACKGROUND: The New York High-Risk Project is a study of offspring of patients
with schizophrenia (HRSz group) or affective illness (HRAff group) and
psychiatrically normal parents (NC group) observed prospectively from childhood
to adulthood. We herein present lifetime prevalence and comorbidity rates of Axis
I disorders in subjects and their siblings from sample A of the project. METHODS:
Schedule for Affective Disorders and Schizophrenia-Lifetime Version interviews
conducted with the offspring in adulthood were used to obtain diagnoses of Axis I
disorders. RESULTS: Schizophrenia and unspecified psychoses occurred only in the
HRSz group. However, schizoaffective and psychotic affective disorders occurred
equally in the HRSz and HRAff groups. Total rates of psychosis in these groups
were significantly higher than in the NC group. All groups had similar rates of
nonpsychotic affective and substance abuse disorders. The HRAff group, however,
had significantly more total affective illness than the NC group and tended to
have more anxiety disorders than the other groups. Comorbidity rates in the HRSz
and HRAff groups were nearly twice those of the NC group. CONCLUSIONS: The
familial liabilities to schizophrenia and affective disorders show specificities
and commonalities, differing markedly from each other in their expression of some
disorders and sharing others. Patterns of comorbidity are generally, although not
entirely, similar to these liabilities.
PMID- 9400347
TI - Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high
risk of major depressive disorder.
AB - BACKGROUND: Altered serotonergic function has been observed in prepubertal
children and adults with an acute episode of major depressive disorder (MDD).
However, it is not known whether these alterations are present prior to the onset
of MDD. METHODS: A serotonergic precursor, 5-hydroxy-L-tryptophan (L-5HTP)
(oxitriptan) (0.8 mg/kg), was administered through an indwelling catheter to 36
children at high risk of MDD (with high family loading for MDD), 31 children with
MDD, and 23 low-risk normal controls (with low family loading for mood disorders
and no history of psychopathology). Blood samples for cortisol, prolactin (PRL),
and growth hormone were obtained every 15 minutes for 180 minutes, beginning 30
minutes before L-5HTP infusion. RESULTS: Children at high risk of MDD and
children with MDD had similar hormonal responses following L-5HTP infusion. After
controlling for baseline values, both groups secreted significantly less cortisol
and more PRL than did the low-risk normal controls, with the PRL finding being
limited to girls. There were no between-group differences in baseline cortisol,
PRL, or growth hormone secretion measures. CONCLUSIONS: Before the onset of
affective illness, high-risk children had the same pattern of neuroendocrine
response to the L-5HTP challenge as did children with MDD. These results extend
earlier findings of altered serotonergic regulation in association with early
onset depression and indicate that these alterations may represent a trait marker
for depression in children.
PMID- 9400348
TI - What is the 'right' statistical measure of twin concordance (or diagnostic
reliability and validity)?
PMID- 9400349
TI - Another view on the 'right' statistical measure of twin concordance.
PMID- 9400350
TI - The safety profile of naltrexone in the treatment of alcoholism. Results from a
multicenter usage study. The Naltrexone Usage Study Group.
AB - BACKGROUND: Naltrexone hydrochloride is the first medication approved in the
United States for the treatment of alcohol dependence in almost 50 years. This
study was designed to collect safety data in a setting that reflected the
expected clinical use of naltrexone. METHODS: This was a 12-week, nonrandomized,
open-label usage study conducted in 40 alcoholism treatment centers throughout
the United States, including free-standing alcoholism treatment programs,
university clinics, Veterans Administration hospitals, and office-based primary
care practices. Eligible patients were assigned, at the investigators'
discretion, to a naltrexone treatment group or to a reference group that did not
receive study medication. At study entry, patients must have been abstinent from
alcohol for 1 to 6 weeks and enrolled in a psychosocial treatment program for
alcoholism. Patients often underrepresented in controlled clinical trials,
including women and patients with comorbid medical and psychiatric illness, were
eligible. Patients with polysubstance abuse or infection with the human
immunodeficiency virus were not excluded. RESULTS: Of 865 patients enrolled, 570
received naltrexone and 295 were in a reference group. The most common new-onset
adverse clinical events in the naltrexone group were nausea (9.8%) and headache
(6.6%). Naltrexone was discontinued in 15.0% of patients because of adverse
events, most frequently nausea. The results of liver function tests in the
naltrexone group were similar to those in the reference group. No death occurred
during the study. CONCLUSIONS: This is the largest study to date describing the
safety of naltrexone in a heterogeneous population of persons with alcoholism. No
new safety concerns were identified.
PMID- 9400351
TI - Hypercortisolism associated with social subordinance or social isolation among
wild baboons.
AB - BACKGROUND: The phenomena of basal hypercortisolism and of dexamethasone
resistance have long intrigued biological psychiatrists, and much is still
unknown as to the causes and consequences of such adrenocortical hyperactivity in
various neuropsychiatric disorders. We have analyzed basal cortisol
concentrations and adrenocortical responsiveness to dexamethasone in a population
of wild baboons living in a national park in Kenya. We tested whether social
subordinance in a primate is associated with dexamethasone resistance.
Furthermore, we examined whether individual differences in adrenocortical
measurements were predicted by the extent of social affiliation in these animals.
METHODS: Seventy yellow baboons (Papio cynocephalus) were anesthetized and
injected with 5 mg of dexamethasone; the cortisol response was monitored for 6
hours. The animals were of both sexes in a range of ages and had known ranks in
the dominance hierarchies within their troops. Extensive behavioral data were
available for a subset of 12 adult males who were anesthetized under
circumstances that also allowed for the determination of basal cortisol
concentrations. RESULTS: The socially subordinate baboons were less responsive to
dexamethasone than were the dominant ones; as one manifestation of this,
postdexamethasone cortisol values were more than 3 times higher in the dozen
lowest-ranking animals compared with the dozen highest. In addition, socially
isolated males had elevated basal cortisol concentrations and showed a trend
toward relative dexamethasone resistance. CONCLUSIONS: Our findings indicate that
social status and degree of social affilitation can influence adrenocortical
profiles; specifically, social subordinance or social isolation were associated
in our study with hypercortisolism or feedback resistance.
PMID- 9400352
TI - Autopsy-proven Alzheimer disease in a patient with dementia who retained musical
skill in life.
PMID- 9400353
TI - Nobel Prize in Physiology or Medicine for 1997 Awarded to Stanley B. Prusiner,
MD.
PMID- 9400354
TI - Abnormal expression of laminin beta 1 chain in skeletal muscle of adult-onset
limb-girdle muscular dystrophy.
AB - BACKGROUND: Laminin 2 is a major component of the basal lamina of skeletal muscle
cells. It is a heterotrimer composed of 3 chains: merosin (laminin alpha 2
chain), beta 1, and gamma 1. Deficiency of merosin, with or without laminin beta
1 chain reduction, is associated with some forms of congenital muscular
dystrophy. Deficient expression of laminin beta 1 chain is also associated with
some cases of merosin-positive congenital muscular dystrophy. The expression of
laminin 2 subunits has not been well studied in the skeletal muscle of limb
girdle muscular dystrophy (LGMD), nor has much attention been given to the
significance of reduction of individual laminin 2 subunits, such as beta 1.
OBJECTIVES: To examine the expression of laminin 2 subunits in skeletal muscle in
patients with LGMD and to define the clinical features of patients with LGMD who
have abnormal expression of laminin 2 subunits. METHODS: We studied muscle biopsy
specimens from 18 patients with LGMD using immunofluorescence with antibodies
against dystrophin C-terminus, beta-dystroglycan, alpha-sarcoglycan, gamma
sarcoglycan, and the laminin subunits merosin, beta 1, and gamma 1. Of the 18
biopsy specimens, 9 were available for electron microscopic examination of the
muscle basement membrane. The clinical features associated with abnormal laminin
beta 1 chain immunoreactivity were further described. RESULTS: Laminin beta 1
chain was either barely detectable or severely reduced in 3 cases of patients
with LGMD in which the biopsy specimens showed normal staining with the other
antibodies. Patients in all 3 cases had common clinical features consistent with
a slowly progressive, adult-onset LGMD. Specimens from 2 of the 3 cases that were
available for ultrastructural examination showed significant abnormalities of the
muscle fiber basement membrane. CONCLUSIONS: Abnormal expression of laminin beta
1 chain without concomitant deficiency of alpha-sarcoglycan in skeletal muscle
has not been previously described in LGMD. Reduced laminin beta 1 chain
immunoreactivity may potentially serve as a marker for defining subsets of
individuals with LGMD, in particular those with slowly progressive, adult-onset
pelvifemoral presentation. The abnormality of muscle fiber basement membranes in
specimens from cases that were available for ultrastructural study suggests that
defects in the extracellular matrix may play a role in the pathogenesis of this
subset of LGMD.
PMID- 9400355
TI - Total quality improvement method for reduction of delays between emergency
department admission and treatment of acute ischemic stroke. The National
Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.
AB - OBJECTIVE: To develop an approach for reducing time between emergency department
(ED) admission and treatment in patients with acute ischemic stroke to meet the
challenge of providing tissue plasminogen activator treatment within 180 minutes.
DESIGN: An observational study. SETTING: Forty trial-affiliated hospitals,
including 30 community hospitals. PARTICIPANTS: A total of 17,324 consecutive
patients admitted to trial-affiliated hospital EDs within 24 hours of possible
stroke, from January 1991 through October 1994. INTERVENTION: Appraisal of the
process of triage, evaluation, diagnosis, and treatment by means of total quality
improvement techniques in each hospital. Staff participating in the process
identified sources of variation and modifications by flow charting the process.
MAIN OUTCOME MEASURE: Time between ED admission and treatment with study
medication. RESULTS: Total quality improvement methods identified hospital
specific process improvements. Many improvements were administrative, requiring
no additional resources. More than 50% of screened patients arrived too late to
be treated. Only 1268 patients were admitted between 0 and 125 minutes from
stroke onset with no other trial exclusion criteria; 48% were treated. Of 243
patients admitted between 126 and 170 minutes from stroke onset with no exclusion
criteria, 4% were treated. Mean time from ED admission to treatment was similar
in teaching and community hospitals. CONCLUSIONS: Total quality improvement
methods identified ED-specific sources of process variability and reduced time
between ED admission and treatment. Therefore, these methods should be considered
in developing and monitoring emergent stroke treatment protocols.
PMID- 9400356
TI - The quality-of-life effects of interferon beta-1b in multiple sclerosis. An
extended Q-TWiST analysis.
AB - BACKGROUND: A recombinant form of interferon beta-1b (Betaseron) was given Food
and Drug Administration approval for use in the treatment of relapsing-remitting
multiple sclerosis in 1993 based on a documented reduction in exacerbation rate.
However, its effect on disease progression is less clear. It costs $11,000 per
year and has documented adverse effects such as fatigue, feverlike symptoms, and
depression. OBJECTIVES: To evaluate a recombinant form of interferon beta-1b in
the treatment of relapsing-remitting multiple sclerosis and to discuss treatment
trade-offs and comprehensive quality-of-life (QOL) outcomes. METHODS: We present
a randomized evaluation of treatment with a recombinant form of interferon beta
1b in 79 patients with multiple sclerosis who participated in a random allocation
lottery and were followed up for 12 months, during which data on QOL and clinical
outcomes were collected. The data were analyzed using the Extended Quality
Adjusted Time Without Symptoms and Toxicity (Q-TWiST) method, which evaluates
treatment trade-offs by incorporating several QOL domains and patient preferences
regarding these domains. RESULTS: Over the 12 months of follow-up, the case
patients reported 10.6 months of quality-adjusted time, while the control
patients reported 10.4 months of quality-adjusted time (P = .50). CONCLUSIONS:
Thus, the first year of treatment with interferon beta-1b did not significantly
improve or detract from QOL. Results are discussed in terms of acceptable trade
offs depending on the nature of therapy. Future observational and clinical
studies should incorporate measures of patient preference.
PMID- 9400357
TI - A magnetic resonance imaging study of planum temporale asymmetry in men with
developmental dyslexia.
AB - BACKGROUND: Imaging studies have suggested anomalous anatomical asymmetries in
language-related regions of the temporal and parietal lobes in individuals with
developmental dyslexia. Autopsy studies have reported unusual symmetry of the
planum temporale (PT) in patients with dyslexia. Methodological limitations
characterize much of this literature, however. OBJECTIVE: To examine the size and
asymmetry of the PT and its extension into the parietal lobe (planum parietale
[PP]) in men with well-characterized, persistent dyslexia by using magnetic
resonance imaging and 3-dimensional surface rendering techniques. METHODS: The
brains of 16 right-handed dyslexic men aged 18 to 40 years and 14 matched control
subjects were studied with magnetic resonance imaging. Most of these subjects
were previously studied with positron emission tomography, which demonstrated
functional abnormalities in temporal and parietal brain regions in the dyslexic
group. The area of the PT was determined with the aid of 3-dimensional surface
rendering techniques. The size of the PP was estimated by measuring the length of
the posterior ascending ramus on 3 parasagittal slices. RESULTS: Approximately
70% to 80% of both groups showed equivalent leftward (left > right) asymmetries
of the PT; approximately 50% to 60% showed equivalent rightward (right > left)
asymmetries of the PP. These asymmetries showed equivalent moderate inverse
correlations with each other in both groups. CONCLUSIONS: These results challenge
the notion that anomalous asymmetry of the PT is strongly associated with
developmental dyslexia. Given the heterogeneity of the dyslexic population, some
subgroup of dyslexic individuals (i.e., those with developmental language
disorders) may show unusual symmetry or reversed asymmetry in this region.
However, anomalous asymmetry of the planum did not contribute to functional
abnormalities demonstrated in these patients by positron emission tomography.
PMID- 9400358
TI - Dichotic-listening performance and intracarotid injections of amobarbital in
children and adolescents. Preoperative and postoperative comparisons.
AB - BACKGROUND: Dichotic listening (DL) to consonant-vowel syllables is frequently
used in clinical and experimental studies of brain laterality. However, the
paradigm of consonant-vowel syllables has not been thoroughly validated through a
comparison with injections of amobarbital sodium (Amytal). OBJECTIVE: To validate
the DL test for hemisphere dominance preoperatively vs postoperatively with the
results from intracarotid injections of amobarbital (i.e., the Wada test) in
epileptic children and adolescents. DESIGN AND MAIN OUTCOME MEASURES: Patients
were tested with DL preoperatively and at 6-month follow-up. Correct reports in
the DL tests were entered in a stepwise discriminant analysis for calculation of
correct classification of hemisphere dominance with the results from the
injections of amobarbital as the grouping variable. Correct reports from the
right and left ears on the consonant-vowel DL test were compared preoperatively
and postoperatively, separated for the subjects with regard to language dominance
in the left and right hemispheres. SETTING: The Department of Pediatrics, Ostra
Hospital, University of Goteborg, Goteborg, Sweden. PATIENTS: Thirteen children
and adolescents between the ages of 10 and 19 years, who were surgically treated
for resistant epilepsy, were included in the study. The operated area
corresponded with morphological changes and functional dysfunctions according to
findings from computed tomography, magnetic resonance imaging, single photon
emission computed tomography, and electroencephalography. RESULTS: The results of
the Wada tests revealed that 10 subjects had left hemisphere language dominance,
with 3 subjects having right hemisphere language dominance. All 3 subjects with
right hemisphere language dominance showed a left ear advantage on the DL test
preoperatively and postoperatively, with 8 and 7 of the 10 subjects with left
hemisphere dominance showing a right ear advantage, preoperatively and
postoperatively, respectively. However, according to discriminant analysis,
knowledge of the DL performance led to a correct classification according to the
Wada test results in 12 (92%) of the 13 subjects. CONCLUSIONS: A quantitative
classification procedure like discriminant analysis may be more sensitive when
predicting hemisphere speech dominance from DL data than a qualitative procedure
based on the ear advantage dichotomy. The ear advantage dichotomy may actually
introduce arbitrary left-right categories that do not correspond to the actual
clustering of the data.
PMID- 9400359
TI - Prose recall in dementia. A comparison of delay intervals.
AB - OBJECTIVE: To explore one methodological variation, delay length, that may
contribute to contradictory findings in the literature regarding the use of
delayed recall in the detection of early-stage dementia of the Alzheimer type.
DESIGN: Comparison of participants with dementia and without dementia on a prose
recall task at both 10- and 30-minute delay intervals. SETTING: Washington
University Alzheimer's Disease Research Center, St Louis, Mo. PARTICIPANTS:
Participants with very mild dementia of the Alzheimer type (n = 136) and
uncompromised elderly individuals (n = 197). MAIN OUTCOME MEASURES: Results of
the Logical Memory subtest from the Wechsler Memory Scale with immediate recall
and 10- and 30-minute delayed recall. RESULTS: Participants with dementia
recalled significantly less material than elderly controls at both immediate and
delayed recall (P < .001). Multiple regression analyses revealed that dementia
classification failed to account for additional variance in the 30-minute delayed
score beyond that which could be accounted for by the immediate score. A small
but significant proportion of variance was accounted for in the 10-minute delayed
score beyond that which could be accounted for by the immediate recall score.
CONCLUSION: Delayed recall of a prose passage does not appear to enhance the
differentiation of very mild dementia of the Alzheimer type from normal aging in
a meaningful way, whether the recall delay is 10 or 30 minutes.
PMID- 9400360
TI - Predictors of intracranial pathologic findings in patients who seek emergency
care because of headache.
AB - BACKGROUND: Clinical criteria to select patients with headache in whom structural
diagnostic studies (computed tomography) have a high yield disclosing
intracranial pathologic findings, independent of abnormal findings on neurologic
examination, have not been defined. OBJECTIVE: To determine which clinical
characteristics predict the presence of intracranial pathologic findings,
independently of neurologic examination, in patients with headache. DESIGN: Case
control, consecutive sample. SETTING: Major metropolitan trauma center emergency
department. PATIENTS AND MATERIALS: Hospital records of 139 hospitalized and 329
randomly selected patients from 1720 nonhospitalized adult patients,
consecutively evaluated for headache in the emergency department, were reviewed.
Demographic data, clinical characteristics of the headache, results of neurologic
and physical examinations, and diagnostic radiologic and laboratory results were
correlated with final diagnosis and outcome at 6 months after emergency
department visit. DATA ANALYSIS: Nonparametric statistical analysis. RESULTS:
Intracranial pathologic findings were found in 18 (3.8%) of 468 patients. Acute
onset and occipitonuchal location of headache, presence of associated symptoms,
and patient age of 55 years or older were significantly associated with the
finding of intracranial pathology, independently of the findings from neurologic
examination. Abnormal findings on neurologic examination alone, whether focal or
nonfocal, had a highly significant association and a positive predictive value
for intracranial pathology of 39%. CONCLUSIONS: Abnormal results from neurologic
examination are the best clinical parameters to predict structural intracranial
pathology; however, in patients 55 years or older with headache of acute onset
located in the occipitonuchal region that has associated symptoms, computed
tomographic scan of the head is justified as part of their clinical evaluation
independently of the findings of the neurologic examination.
PMID- 9400361
TI - 'Complete' spinal cord injury does not block perceptual responses to genital self
stimulation in women.
AB - BACKGROUND: A priori hypothesis: vaginal and/or cervical self-stimulation will
not produce perceptual responses in women with "complete" spinal cord injury
(SCI) at or above the highest level of entry of the hypogastric nerves (T10-12)
but will produce perceptual responses if SCI is below T-10. DESIGN: Women with
complete SCI were assigned to a group with "upper" (T-10 and/or above) (n = 6) or
"lower" (below T-10) (n = 10) SCI; uninjured women (n = 5) constituted a control
group. Perceptual response to vaginal and/or cervical self-stimulation was
quantified as magnitude of analgesia to calibrated finger compressive force.
SETTING: Rutgers, The State University of New Jersey, Human Physiology
Laboratory, College of Nursing, Newark. PARTICIPANTS: Consecutive samples of
first 16 of 34 women with SCI who responded to nationwide advertisements, met
inclusion criteria, and volunteered; control group was the first 5 respondents.
INTERVENTION: Vaginal or cervical (cervix uteri) self-stimulation applied for 12
minutes, interspersed with non-stimulation periods, while measuring analgesia.
MAIN OUTCOME MEASURE: Quantify analgesia magnitude to vaginal or cervical self
stimulation. RESULTS: Significant analgesia was produced in the uninjured group
and the group with lower SCI, supporting the hypothesis. Unexpectedly,
significant analgesia was also produced in the group with upper SCI. Women in the
group with upper SCI also experienced menstrual discomfort, awareness of vaginal
and/or cervical stimulation per se, and orgasms. CONCLUSIONS: (1) Genitospinal
visceral afferent pathways function in the women in the group with upper SCI,
although unrecognized by the American Spinal Injury Association criteria, and/or
(2) there exists a functional genital afferent pathway that bypasses the spinal
cord and projects directly to the brain, which we propose to be via the vagus
nerves.
PMID- 9400362
TI - Volumetric magnetic resonance imaging. Clinical applications and contributions to
the understanding of temporal lobe epilepsy.
AB - In recent years, magnetic resonance imaging-based volumetric measurements of the
amygdala and hippocampus have proved useful in the diagnosis and treatment of
patients with temporal lobe epilepsy. This imaging modality allows amygdaloid and
hippocampal volumes to be correlated with neurophysiological, neuropathological,
and neuropsychological findings, surgical outcome, and clinical findings. We
evaluated the technical and anatomical aspects underlying the successful use of
the modality that were reported in previous studies. We also evaluated issues
such as the sensitivity and specificity of volumetric magnetic resonance imaging,
its use in bilateral temporal lobe epilepsy, and the debate concerning the
sensitivity of qualitative visual analysis vs quantitative volumetric analysis of
magnetic resonance images. Volumetric magnetic resonance imaging, when used in
conjunction with video electroencephalographic monitoring, neuropsychological
studies, and other neuroimaging studies, will enable patients with temporal lobe
epilepsy to be treated in an appropriate, efficient, and cost-effective manner.
PMID- 9400363
TI - Adult-onset Niemann-Pick type C disease. Clinical, biochemical, and genetic
study.
AB - BACKGROUND: Niemann-Pick type C disease is an autosomal recessive neurometabolic
disorder of unknown origin mapped to chromosome 18q11-12 in most of the studied
families. In contrast to the sphingomyelin lipidoses, in Niemann-Pick type C
disease, fibroblasts are impaired in intracellular homeostatic responses to
exogenous low-density lipoprotein (LDL) cholesterol. Biochemical heterogeneity of
the disorder in relation to abnormal LDL processing is associated with various
clinical presentations, but adult-onset Niemann-Pick type C disease is rare and
has not been comprehensively characterized. OBJECTIVE: To describe clinical,
biochemical, and genetic features of adult-onset Niemann-Pick type C disease in 3
siblings. DESIGN AND SETTING: Case series in a tertiary care center. PATIENTS:
The 3 siblings manifested a variable combination of vertical supranuclear
ophthalmoplegia, ataxia, and splenomegaly. Brain magnetic resonance imaging
showed cerebellar atrophy; brainstem auditory evoked responses were unobtainable,
and bone marrow examination disclosed typical foam cells. The patients were 20,
26, and 28 years old and belonged to a sibship of 13 born of consanguineous
healthy parents. METHODS: Esterification of exogenous LDL cholesterol in cultured
skin fibroblasts and filipin staining for free intracellular cholesterol.
Polymerase chain reaction-based DNA linkage study using AC microsatellite markers
D18S40, D18S44, D18S480, and D18S66. RESULTS: Fibroblasts of the 3 patients
showed a 23% to 58% block in the induced cholesterol esterification after 4 1/2
hours and a mild to moderate accumulation of free cholesterol. DNA study
demonstrated linkage to the major 18q11-12 Niemann-Pick type C locus and
identified unaffected carriers. CONCLUSIONS: These results confirm the diagnosis
of the least biochemically affected Niemann-Pick type C phenotype in this family
with adult-onset disease and support a correlation between the mild laboratory
and clinical findings in this age group.
PMID- 9400364
TI - Four legs. Illusory reduplication of the lower limbs after bilateral parietal
lobe damage.
AB - OBJECTIVE: To report an unusual disorder of body schema and its neurologic and
neuropsychological correlates. DESIGN AND METHODS: We describe a patient with a
reduplicative phantom illusion of her lower limbs. Motor and sensory functions,
as well as mental representation of body and space, were studied during the
reduplication experience until its resolution. SETTING: Clinical neurology
department in a primary care hospital. PATIENT: A 64-year-old, left-handed woman
who experienced the uncontrollable and distressing feeling of having 4 legs,
without delusional belief, after surgical removal of a right-predominant
parasagittal parietal meningioma. This phenomenon spontaneously resolved after 2
weeks. INTERVENTION: None. MAIN OUTCOME MEASURES: Clinical neurologic
examinations and standardized neuropsychological tests, with emphasis on tests
assessing orientation to body parts, right-left discrimination, and mental
orientation in space. RESULTS: The patient had severe weakness and proprioceptive
sensory loss in both lower limbs. She had no disturbances of body schema
knowledge but a striking impairment in tasks requiring mental orientation in
space, particularly for right-left laterality discrimination. Resolution of the
reduplication experience correlated with improvement in the affected spatial
abilities, while motor, sensory, and other cognitive functioning did not
significantly change. CONCLUSION: This patient's reduplicative phantom illusion
might be related to the combination of the severe somatosensory loss with an
underlying impaired mental representation of relative positions in space.
PMID- 9400365
TI - Model of a quinary structure between Krebs TCA cycle enzymes: a model for the
metabolon.
AB - The enzymes which are responsible for catalyzing sequential reactions in several
metabolic pathways have been proposed to be highly organized in supramolecular
complexes termed metabolons. However, the in situ existence of these weak
complexes is difficult to demonstrate because many of them are dissociated during
isolation due to dilution effects. Consequently, the metabolon concept is subject
to controversy. A model system consisting of genetically prepared bienzymatic
fusion proteins has been used to immobilize sequential metabolic enzymes in close
proximity and to demonstrate possible kinetic advantages of metabolons. These
experiments use the sequential Krebs TCA cycle enzymes from yeast mitochondrial
malate dehydrogenase (MDH), citrate synthase (CS), and aconitase (ACO). Using the
porcine high-definition structures of these three enzymes, we have performed
computer-modeling studies in order to understand how the molecules may interact.
Among the thousands of docking orientations we have tried, one was found to
respond to the structural and experimental constraints from the results obtained
with the yeast fusion proteins. Interestingly, this quinary structure model shows
substantial interacting surface areas with spatial and electrostatic
complementarities which make the complex thermodynamically stable. This structure
also contains an unbroken electrostatically favorable channel connecting the
active sites of ACO and CS, as well as the one previously reported between CS and
MDH active sites. Charged amino acids which could be involved in interactions
stabilizing the complex have been identified. This model will be used as the
basis for further experimental work on the structure of the Krebs TCA cycle
metabolon.
PMID- 9400366
TI - An early intermediate in the folding reaction of the B1 domain of protein G
contains a native-like core.
AB - The folding kinetics of a 57-residue IgG binding domain of streptococcal protein
G has been studied under varying solvent conditions, using stopped-flow
fluorescence methods. Although GB1 has been cited as an example of a protein that
obeys a two-state folding mechanism, the following kinetic observations suggest
the presence of an early folding intermediate. Under stabilizing conditions (low
denaturant concentrations, especially in the presence of sodium sulfate), the
kinetics of folding shows evidence of a major unresolved fluorescence change
during the 1.5 ms dead time of the stopped-flow experiment (burst phase).
Together with some curvature in the rate profile for the single observable
folding phase, this provides clear evidence of the rapid formation of compact
states with native-like fluorescence for the single tryptophan at position 43. In
refolding experiments at increasing denaturant concentrations, the amplitude of
the sub-millisecond phase decreases sharply and the corresponding slope (m value)
is only about 30% lower than that of the equilibrium unfolding curve indicative
of a pre-equilibrium transition involving cooperative unfolding of an ensemble of
compact intermediates. The dependence on guanidine hydrochloride concentration of
both rates and amplitudes (including the equilibrium transition) is described
quantitatively by a sequential three-state mechanism, U [symbol: see text] I
[symbol: see text] N, where an intermediate (I) in rapid equilibrium with the
unfolded state (U) precedes the rate-limiting formation of the native state (N).
A 66-residue fragment of GB1 with an N-terminal extension containing five apolar
side chains exhibits three-state kinetic behavior virtually identical to that of
the 57-residue fragment. This is consistent with the presence of a well-shielded
native-like core excluding the N-terminal tail in the early folding intermediate
and argues against a mechanism involving random hydrophobic collapse, which would
predict a correlation between overall hydrophobicity and stability of compact
states.
PMID- 9400367
TI - Cysteine-scanning mutagenesis of helix IV and the adjoining loops in the lactose
permease of Escherichia coli: Glu126 and Arg144 are essential. off.
AB - Cys-scanning mutagenesis has been applied to the remaining 45 residues in lactose
permease that have not been mutagenized previously (from Gln100 to Arg144 which
comprise helix IV and adjoining loops). Of the 45 single-Cys mutants, 26
accumulate lactose to > 75% of the steady state observed with Cys-less permease,
and 14 mutants exhibit lower but significant levels of accumulation (35-65% of
Cys-less permease). Permease with Phe140-->Cys or Lys131-->Cys exhibits low
activity (15-20% of Cys-less permease), while mutants Gly115-->Cys, Glu126-->Cys
and Arg144-->Cys are completely unable to accumulate the dissacharide. However,
Cys-less permease with Ala or Pro in place of Gly115 is highly active, and
replacement of Lys131 or Phe140 with Cys in wild-type permease has a less
deleterious effect on activity. In contrast, mutant Glu126-->Cys or Arg144-->Cys
is inactive with respect to both uphill and downhill transport in either Cys-less
or wild-type permease. Furthermore, mutants Glu126-->Ala or Gln and Arg144-->Ala
or Gln are also inactive in both backgrounds, and activity is not rescued by
double neutral replacements or inversion of the charged residues at these
positions. Finally, a mutant with Lys in place of Arg144 accumulates lactose to
about 25% of the steady state of wild-type, but at a slow rate. Replacement of
Glu126 with Asp, in contrast, has relatively little effect on activity. None of
the effects can be attributed to decreased expression of the mutants, as judged
by immunoblot analysis. Although the activity of most of the single-Cys mutants
is unaffected by N-ethylmaleimide, Cys replacement at three positions (Ala127,
Val132, or Phe138) renders the permease highly sensitive to alkylation. The
results indicate that the cytoplasmic loop between helices IV and V, where
insertional mutagenesis has little effect on activity [McKenna, E., et al. (1992)
Proc. Natl. Acad. Sci. U.S.A. 89, 11954-11958], contains residues that play an
important role in permease activity and that a carboxyl group at position 126 and
a positive charge at position 144 are absolutely required.
PMID- 9400368
TI - Crystal structure of phenylmethanesulfonyl fluoride-treated human chymase at 1.9
A.
AB - The X-ray crystal structure of human chymase has been determined to 1.9 A
resolution using molecular replacement methods. This first structure of human
chymase is present as the Ser 195 ester of alpha-toluenesulfonic acid. The
refined structure (Rcryst = 0.183) shows that the inhibitor phenyl moiety lies at
the top of the major specificity pocket, S1, while the sulfur is covalently
linked to Ser 195-O gamma. The sulfonyl oxygens interact with the oxyanion hole
and with His 57-N delta 1. The presence of the inhibitor disturbs the usual
gauche position of His 57 and forces it to the trans conformer. Though the
primary binding pockets are similarly specific in chymase and chymotrypsin,
examination of the extended substrate binding sites reveals the structural basis
for chymase's greater discrimination in choosing substrates. The larger 30s loop
and its proximity to the active site indicates that it contacts substrate
residues C-terminal to the scissile bond. Modeling of substrate at the chymase
active site suggests that binding energy may be gained by three main-chain
hydrogen bonds provided by substrate residues P2' and P4' and that discriminating
interactions with substrate side chains are also likely. The presence of Lys 40
in S1' of human chymase explains its preference for Asp/Glu at P1'. Moreover, the
cationic nature of S1' provides a structural basis for human chymase's poor
catalytic efficiency when angiotensin II is the substrate.
PMID- 9400369
TI - Increased pressure induces sustained protein kinase C-independent herbimycin A
sensitive activation of extracellular signal-related kinase 1/2 in the rabbit
aorta in organ culture.
AB - The 42- and 44-kD mitogen-activated protein kinases, also referred to as
extracellular signal-related kinase (ERK) 2 and 1, respectively, may be
transiently activated by stretching vascular smooth muscle cells (VSMCs). Using
an organ culture model of rabbit aorta, we studied short- and long-term ERK1/2
activation by intraluminal pressure (150 mm Hg). Activation of ERK1/2 was
biphasic: it reached a maximum (217.5 +/- 8.4% of control) 5 minutes after
pressurizing and decreased to 120.7 +/- 5.1% of control after 2 hours.
Furthermore, after 24 hours of pressurizing, ERK1/2 activity was as high (241.8
+/- 14.7% of control) as in the acute phase. Long-term pressure-induced ERK1/2
activation correlated with stimulation of tyrosine phosphorylation of proteins in
the 125- to 140-kD range. Neither protein kinase C inhibitors (1 mumol/L
staurosporine or 50 mumol/L bisindolylmaleimide-I) nor tyrosine kinase inhibitors
(50 mumol/L tyrphostin A48 or 50 mumol/L genistein) affected pressure-induced
ERK1/2 activation. However, the Src-family tyrosine kinase inhibitor herbimycin A
(500 nmol/L) did reduce both 5-minute (by 92 +/- 8%) and 24-hour (by 63 +/- 7%)
pressure-induced ERK1/2 activation. Thus, our results demonstrate a sustained
activation of ERK1/2 and tyrosine kinases by intraluminal pressure in the
arterial wall. Pressure-induced ERK1/2 activation is PKC independent and Src
family tyrosine kinase dependent and possibly includes activation of
extracellular matrix-associated tyrosine kinases.
PMID- 9400370
TI - Activation of MAP kinase in vivo follows balloon overstretch injury of porcine
coronary and carotid arteries.
AB - Vascular restenosis involves contraction, proliferation, and remodeling of the
arterial wall in response to overstretch injury. Mitogen-activated protein
kinases (MAPKs) are implicated in both contraction and proliferation of vascular
smooth muscle (VSM), and studies of porcine carotid arterial muscle strips have
shown that mechanical stretch leads to the activation of the extracellular signal
regulated kinase (ERK) family of MAPKs in vivo. We, therefore, analyzed the acute
effect of mechanical overstretch injury on ERK-MAPK (herein referred to simply as
MAPK) activity in porcine coronary and carotid arteries in vivo. Balloon
angioplasty catheters were inflated to 6 atm three times over 5 minutes at a
balloon-artery ratio of 1.2:1 in either porcine coronary or carotid arteries. The
arteries were snap-frozen after angioplasty, and MAPK activity was measured.
Angioplasty of the left anterior descending (LAD, n = 5), left circumflex (LCx, n
= 5), and carotid (n = 5) arteries effected an increase in MAPK activity compared
with the activity in uninstrumented right coronary arteries (RCAs) or carotid
arteries from the same animals used for controls. Balloon angioplasty of carotid
arteries led to an increase in MAPK activity that was 7.7-fold over the activity
in control arteries and comparable to the activity in stretched carotid arterial
muscle strips in vivo. The increase in coronary artery kinase activity on
angioplasty was variable from animal to animal. The increase in MAPK activity
over that in control arteries ranged from 4.5- to 31.7-fold (mean +/- SEM, 10.7
+/- 5.3) in the LAD and 1.8- to 31.3-fold (mean +/- SEM, 9.7 +/- 5.7) in the LCx.
There were no apparent inherent differences in the levels of MAPK activity in the
three different types of coronary arteries (RCA, LAD, and LCx) without
instrumentation. MAPK activation occurs rapidly during angioplasty, suggesting
that this kinase may play an early role in initiating the injury response in both
porcine coronary and carotid arteries. MAPKs may be key enzymes targeted to treat
or prevent restenosis.
PMID- 9400371
TI - Transcriptional regulation of inducible nitric oxide synthase in cultured
neonatal rat cardiac myocytes.
AB - Previous work has demonstrated that inducible NO synthase (iNOS) can be expressed
in cardiac myocytes. In this study, we investigated transcriptional regulation of
the iNOS gene in these cells. Lipopolysaccharide (LPS) induced iNOS mRNA and
protein in cultured neonatal rat cardiac myocytes. H-89, dexamethasone,
herbimycin, genistein, staurosporine, or pyrrolidine dithiocarbamate (PDTC)
attenuated the iNOS induction by LPS. Forskolin, interleukin (IL)-6, tumor
necrosis factor (TNF)-alpha, or interferon (IFN)-gamma enhanced the LPS-induced
iNOS expression. Combined stimulation of IL-6 and TNF-alpha also induced iNOS.
The 5'-upstream sequence of the rat iNOS gene contains the nuclear factor-kappa B
(NF-kappa B) site, CAAT box, IFN-gamma activation site (GAS), and IFN regulatory
factor (IRF) site. DNase I footprinting assay revealed that the nuclear factors
binding to these elements were increased by LPS exposure. Transient transfection
assay suggested that these elements were indispensable for transcriptional
regulation of the iNOS induction. Electrophoretic mobility shift assay revealed
that LPS or TNF-alpha increased binding activity for the NF-kappa B site. A
slower-migrating complex binding to the CAAT box gave rise after exposure to LPS
or forskolin. Competition assay suggested that this slower-migrating complex
consisted of a heterodimer between a member of CAAT box/enhancer binding (C/EBP)
protein family and cAMP responsive element binding protein (CREB). LPS or IL-6
increased binding complexes for the IRF site, which was compatible with induction
of IRF-1. LPS, IL-6, or IFN-gamma induced a novel binding complex for GAS, which
also existed in the 5'-flanking region of the IRF-1 gene. These data suggest that
(1) iNOS induction simultaneously requires both NF-kappa B activation and IRF-1
induction, and (2) the heterodimer between C/EBP and CREB has synergistic effects
on the iNOS induction via the CAAT box.
PMID- 9400372
TI - Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to
cultured endothelial cells.
AB - The objectives of this study were to (1) determine the time course of neutrophil
adhesion to monolayers of human umbilical vein endothelial cells (HUVECs) that
were exposed to 60 minutes of anoxia followed by 30 to 600 minutes of
reoxygenation and (2) define the mechanisms responsible for both the early
(minutes) and late (hours) hyperadhesivity of postanoxic HUVECs to human
neutrophils. The results clearly demonstrate that anoxia/reoxygenation (A/R)
leads to a biphasic increase in neutrophil adhesion to HUVECs, with peak
responses occurring at 30 minutes (phase 1) and 240 minutes (phase 2) after
reoxygenation. Oxypurinol and catalase inhibited phase-1 adhesion, suggesting a
role for xanthine oxidase and H2O2. In comparison, platelet activating factor
(PAF) contributed to both phases of neutrophil adhesion. Anti-intercellular
adhesion molecule-1 (ICAM-1) and anti-P-selectin antibodies (monoclonal
antibodies [mAbs]) attenuated phase-1 neutrophil adhesion, consistent with roles
for constitutively expressed ICAM-1 and enhanced surface expression of preformed
P-selectin. Phase-2 neutrophil adhesion was attenuated by an anti-E-selectin mAb,
indicating a dominant role of this adhesion molecule in the late phase response.
Pretreatment with actinomycin D and cycloheximide or with competing ds
oligonucleotides containing the nuclear factor-kappa B or activator protein-1
cognate DNA sequences significantly attenuated phase-2 response, suggesting a
role for de novo macromolecule synthesis. Surface expression of ICAM-1, P
selectin, and E-selectin on HUVECs correlated with the phase-1 and -2 neutrophil
adhesion responses. Collectively, these findings indicate that A/R elicits a two
phase neutrophil-endothelial cell adhesion response that involves transcription
independent and transcription-dependent surface expression of different
endothelial cell adhesion molecules.
PMID- 9400373
TI - Vascular endothelial growth factor increases the mitogenic response to fibroblast
growth factor-2 in vascular smooth muscle cells in vivo via expression of fms
like tyrosine kinase-1.
AB - Vascular endothelial growth factor (VEGF) has traditionally been considered an
endothelial cell-specific factor inducing angiogenesis and vascular permeability
in vivo. In the present study, expression of VEGF and its receptors, fetal liver
kinase-1 (flk-1) and fms-like tyrosine kinase-1 (flt-1), was examined in rat
carotid arteries after balloon injury. Although VEGF and flk-1 were not
detectable, high levels of flt-1 mRNA and protein were expressed by smooth muscle
cells (SMCs) in the neointima, as demonstrated by en face in situ hybridization
and Western blotting. Intimal SMC proliferation in chronically denuded rat
carotid arteries was unaffected by intraluminal infusion of VEGF, whereas
fibroblast growth factor (FGF)-2 increased the number of replicating SMCs 4-fold.
Pretreatment with VEGF doubled the mitogenic response to infused FGF-2 by
increasing SMC replication in deeper layers of the intima. VEGF increased the
permeability of chronically denuded vessels to plasma proteins but had no effect
on the uptake of locally infused biotinylated FGF-2. These findings demonstrate
that vascular SMCs express functional flt-1 receptors after arterial injury and
that VEGF has synergistic effects with FGF-2 on SMC proliferation. These effects
are likely to be mediated by a VEGF-mediated increase in permeability as well as
a direct interaction between the VEGF and FGF signaling pathways.
PMID- 9400374
TI - Smooth muscle cells isolated from discrete compartments of the mature vascular
media exhibit unique phenotypes and distinct growth capabilities.
AB - Heterogeneity of smooth muscle cell (SMC) phenotype and function is rapidly
emerging as an important concept. We have recently described that phenotypically
distinct SMC subpopulations in bovine pulmonary arteries exhibit unique
proliferative and matrix-producing responses to hypoxic pulmonary hypertension.
To provide better understanding of the molecular mechanisms contributing to this
phenomenon, experimental studies will require a reliable in vitro model. The
purpose of the present study was first to determine if distinct SMC
subpopulations, similar to those observed in vivo, could be selectively isolated
from the mature arterial media, and then to evaluate whether select SMC
subpopulations would exhibit heightened responses to growth-promoting stimuli and
hypoxia. We were able to reproducibly isolate at least four phenotypically unique
cell subpopulations from the inner, middle, and outer compartments of the
arterial media. Differences in cell phenotype were demonstrated by morphological
appearance and differential expression of muscle-specific proteins. The isolated
cell subpopulations exhibited markedly different growth capabilities. Two SMC
subpopulations grew slowly in 10% serum and were quiescent in plasma-based
medium. The other two cell subpopulations, exhibiting nonmuscle characteristics,
grew rapidly in 10% serum and proliferated in plasma-based medium and in response
to hypoxia. Certain colonies of the nonmuscle-like cell subpopulations were found
to grow autonomously under serum-deprived conditions and to secrete mitogenic
factors. Our data, demonstrating that phenotypically distinct cells with enhanced
growth potential exist within the normal arterial media, support the idea that
these unique cells could contribute selectively to the pathogenesis of vascular
disease.
PMID- 9400375
TI - Mechanisms of action of troglitazone in the prevention of high glucose-induced
migration and proliferation of cultured coronary smooth muscle cells.
AB - Recent findings suggest that high glucose levels may promote atherosclerosis in
coronary vascular smooth muscle cells (VSMCs). To explore the intracellular
mechanisms of action by which troglitazone affects this process, we examined the
effect of troglitazone on the migration and growth characteristics of cultured
rabbit coronary VSMCs. Treatment with chronic high glucose medium (22.2 mmol/L)
for 5 days increased VSMC migration by 92%, [3H]thymidine incorporation by 135%,
and cell number by 32% compared with VSMCs treated with normal glucose (5.5
mmol/L glucose + 16.6 mmol/L mannose) medium. Trolitazone at 100 nmol/L and 1
mumol/L significantly suppressed high glucose-induced VSMC migration by 34% and
42%, respectively, the proliferative effect (as measured by cell number) by 17%
and 27%, and [3H]thymidine incorporation by 45% and 60% (n = 6, P < .05). The
high glucose-induced impairment of insulin-mediated [3H]deoxyglucose uptake was
blocked by a protein kinase C (PKC) inhibitor (calphostin C, 1 mumol/L) and was
also improved by troglitazone without any change in insulin receptor number and
affinity. The high glucose-induced insulin-mediated increase in cell number and
in [3H]thymidine incorporation was suppressed by troglitazone. Troglitazone (1
mumol/L) also suppressed high glucose-induced phospholipase D activation,
elevation of the cytosolic NADH/NAD+ ratio (as measured by the cytosolic ratio of
lactate/pyruvate), and membrane-bound PKC activation. Flow cytometric DNA
histogram analysis of cell cycle stage showed that high glucose-induced increase
in the percentage of cells in the S phase was suppressed by 1 mumol/L
troglitazone. These findings suggest that PKC may be a link between impairment of
insulin-mediated glucose uptake and the increase in migration and proliferation
induced by high glucose levels and that troglitazone may be clinically useful for
the treatment of high glucose-induced coronary atherosclerosis.
PMID- 9400376
TI - Mevalonate-dependent inhibition of transendothelial migration and chemotaxis of
human peripheral blood neutrophils by pravastatin.
AB - Pravastatin, a hydrophilic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A
reductase, has been reported to beneficially affect atherogenesis, plaque
stability, and transient myocardial ischemia in significant coronary artery
disease by influencing lipid metabolism and by intracellular signaling via
mevalonate pathway products other than cholesterol. Leukocytes are implicated to
play a pathophysiological role in these events. We were interested in finding out
whether pravastatin could affect transendothelial migration (TEM), chemotaxis,
and respiratory burst activity of the neutrophil ex vivo. In addition, effects on
monocyte and T-lymphocyte chemotaxis were tested. For TEM assays, monolayers of
human umbilical vein endothelial cells (HUVECs) were grown to confluence on
polycarbonate filters bearing 5-microns pores in Transwell (Costar) culture plate
inserts. Chemotaxis experiments were performed using modified Boyden chambers
with cellulose nitrate micropore filters. Respiratory burst activity was measured
fluorometrically. Treatment of neutrophils and monocytes with pravastatin at 2 to
200 mumol/L and 10 to 1000 mumol/L, respectively, significantly decreased
chemotaxis triggered by fMet-Leu-Phe. This effect was abolished in the presence
of mevalonic acid (500 mumol/L); no effect of pravastatin was seen on T
lymphocyte chemotaxis triggered by interleukin-8. Preincubation of neutrophils
with pravastatin (200 mumol/L) also resulted in a significant reduction in the
number of neutrophils that transmigrated a tumor necrosis factor-stimulated or
lipopolysaccharide-stimulated HUVEC monolayer. At none of the concentrations
tested (2 pmol/L to 200 mumol/L) did pravastatin affect neutrophil respiratory
burst activity. We conclude that pravastatin may alter monocyte chemotaxis and
neutrophil-endothelial interactions in migratory responses at concentrations
obtained in vivo with cholesterol-lowering doses.
PMID- 9400377
TI - Angiotensin II induces apoptosis of human endothelial cells. Protective effect of
nitric oxide.
AB - Angiotensin II (Ang II) importantly contributes to the pathobiology of
atherosclerosis. Since endothelial injury is a key event early in the
pathogenesis of atherosclerosis, we tested the hypothesis that Ang II may injure
endothelial cells by activation of cellular suicide pathways leading to
apoptosis. Human umbilical venous endothelial cells (HUVECs) were incubated with
increasing doses of Ang II for 18 hours. Apoptosis of HUVECs was measured by
ELISA specific for histone-associated DNA fragments and confirmed by DNA
laddering and nuclear staining. Ang II dose-dependently induced apoptosis of
HUVECs. Simultaneous blockade of both the AT1 and AT2 receptor prevented Ang II
induced apoptosis, whereas each individual receptor blocker alone was not
effective. Selective agonistic stimulation of the AT2 receptor also dose
dependently induced apoptosis. Ang II-mediated as well as selective AT2 receptor
stimulation-mediated apoptosis was associated with the activation of caspase-3, a
central downstream effector of the caspase cascade executing the cell death
program. Specific inhibition of caspase-3 activity abrogated Ang II-induced
apoptosis. In addition, the NO donors sodium nitroprusside and S
nitrosopenicillamine completely inhibited Ang II-induced apoptosis and eliminated
caspase-3 activity. Thus, Ang II induces apoptosis of HUVECs via activation of
the caspase cascade, the central downstream effector arm executing the cell death
program. NO completely abrogated Ang II-induced apoptosis by interfering with the
activation of the caspase cascade.
PMID- 9400378
TI - Nitric oxide-independent dilation of conductance coronary arteries to
acetylcholine in conscious dogs.
AB - NO and prostacyclin formation cannot entirely account for receptor-operated
endothelium-dependent dilation of coronary vessels, since vasodilator responses
are not completely suppressed by inhibitors of these agents. Therefore, we
considered that another factor, such as an endothelium-derived hyperpolarizing
factor described in vitro, may participate in NO- and prostacyclin-independent
coronary dilator responses. In conscious instrumented dogs, intracoronary
acetylcholine (ACh, 30.0 ng.kg-1.min-1) increased the external epicardial
coronary diameter (CD) by 0.18 +/- 0.03 mm (from 3.44 +/- 0.11 mm) when increases
in coronary blood flow (CBF) were prevented and increased the CD by 0.20 +/- 0.05
when CBF was allowed to increase. After the administration of intracoronary N
omega-nitro-L-arginine methyl ester (L-NAME), CBF responses to ACh were
abolished, but CD responses (0.23 +/- 0.05 from 3.22 +/- 0.09 mm) were
maintained. Blockade of NO formation was confirmed by reduced CD baselines and
blunted flow-dependent CD responses caused by adenosine and transient coronary
artery occlusions after L-NAME administration. ACh-induced CD increases resistant
to L-NAME and indomethacin were reduced after the administration of intracoronary
quinacrine, an inhibitor of phospholipase A2, or proadifen, an inhibitor of
cytochrome P-450. Quinacrine or proadifen alone (without L-NAME) did not alter CD
responses to ACh, but L-NAME given after proadifen blunted ACh-induced increases
in CD. The increases in CD caused by arachidonic acid given after L-NAME +
indomethacin were antagonized by proadifen but not altered by quinacrine. Thus, a
cytochrome P-450 metabolite of arachidonic acid accounts for L-NAME-resistant and
indomethacin-resistant dilation of large epicardial coronary arteries to ACh.
Conversely, NO formation is the dominant mechanism of ACh-induced dilation after
blockade of the cytochrome P-450 pathway.
PMID- 9400379
TI - Venous myogenic tone and its regulation through K+ channels depends on chronic
intravascular pressure.
AB - In this study, we compared the level of myogenic tone and its negative-feedback
control through specific K+ channels in two types of human veins (saphenous [SV]
and cephalic [CV] veins), which experience different ranges of pressure in vivo.
We also investigated whether an experimental model of increased venous pressure
in rats exposed to head-up tilt for 2 weeks produced changes similar to those
observed in the human veins. Cylindrical vein segments were cannulated, their
diameters were measured, and the intraluminal pressure was set at different
levels (2 to 30 mm Hg) in vitro. Acetylcholine test showed that during the
regular harvesting process 76% of the human SVs exposed for coronary bypass
grafts had no functional endothelium. We found significant myogenic tone in the
human SV, where the in vivo pressure is high, but it was not present in the human
CV, where the in vivo pressure is low. The nonspecific K+ channel antagonist,
tetraethylammonium (TEA), decreased the diameter of the human SV but not the CV.
Iberiotoxin and 4-aminopyridine, blockers of the Ca(2+)-sensitive (KCa) and
voltage-gated K+ (KV) channels, also decreased the diameter of the human SV by
10.2 +/- 4.8% and 19.5 +/- 4.7%, respectively. In the rat SV, significant
myogenic tone was found, but TEA had no effect, even after 2 weeks of in vivo
pressure increase in the hindlimb by head-up tilt. We conclude that (1) an
increased venous myogenic tone correlates with higher chronic intraluminal
pressure loads, (2) KCa and KV channels counterregulate the myogenic tone in
human, but not in rat, saphenous vein, (3) the counterregulatory effect is more
effective at high than at low intraluminal in vitro pressure levels, and (4) its
development is probably a long-term process.
PMID- 9400380
TI - Increased myogenic tone and diminished responsiveness to ATP-sensitive K+ channel
openers in cerebral arteries from diabetic rats.
AB - Diabetes mellitus has profound adverse effects on vascular and, in particular,
endothelial function. Although pressure-induced constriction ("myogenic tone") is
a major contributor to the regulation of blood flow, little is known about the
effects of diabetes on this response. Diabetes has been shown to diminish the
dilation of cerebral arteries to synthetic ATP-sensitive K+ (KATP) channel
openers. In this study, we explored the effects of diabetes induced in rats by
streptozotocin on cerebral artery (250 to 300 microns) myogenic tone and on
vasodilations to the synthetic KATP channel openers pinacidil and levcromakalim.
Elevation of intravascular pressure caused a graded membrane potential
depolarization and constriction, which was greater in arteries from diabetic rats
compared with normal rats (at 60 mm Hg, 5 mV more depolarized and 22 microns more
constricted). Pressurized arteries (at 60 mm Hg) from diabetic rats were 5- to 15
fold less sensitive to pinacidil and levcromakalim than were control arteries
(EC50 values for pinacidil and levcromakalim were 1.4 and 0.6 mumol/L,
respectively, in diabetic animals and 0.3 and 0.04, respectively, in control
animals; P < .05). Removal of the endothelium or addition of a NO synthase
inhibitor, NG-nitro-L-arginine (LNNA), in control arteries decreased the
sensitivity to KATP channel openers and depolarized and constricted control
arteries to levels similar to those observed in arteries from diabetic animals.
Sodium nitroprusside caused a membrane potential hyperpolarization and enhanced
the response to pinacidil in arteries from diabetic animals. Removal of the
endothelium or LNNA had little effect on the apparent KATP channel opener
sensitivity, the membrane potential, and pressure-induced constrictions of
arteries from diabetic animals. The results are consistent with the hypothesis
that this type of diabetes leads to a decrease in tonic NO release from the
endothelium, which in turn causes membrane potential depolarization and
vasoconstriction, resulting in a diminished response to KATP channel openers.
PMID- 9400381
TI - Targeted ablation of the murine alpha-tropomyosin gene.
AB - We created a mouse that lacks a functional alpha-tropomyosin gene using gene
targeting in embryonic stem cells and blastocyst-mediated transgenesis.
Homozygous alpha-tropomyosin "knockout" mice die between embryonic day 9.5 and
13.5 and lack alpha-tropomyosin mRNA. Heterozygous alpha-tropomyosin knockout
mice have approximately 50% as much cardiac alpha-tropomyosin mRNA as wild-type
littermates but similar alpha-tropomyosin protein levels. Cardiac gross
morphology, histology, and function (assessed by working heart preparations) of
heterozygous alpha-tropomyosin knockout and wild-type mice were
indistinguishable. Mechanical performance of skinned papillary muscle strips
derived from mutant and wild-type hearts also revealed no differences. We
conclude that haploinsufficiency of the alpha-tropomyosin gene produces little or
no change in cardiac function or structure, whereas total alpha-tropomyosin
deficiency is incompatible with life. These findings imply that in heterozygotes
there is a regulatory mechanism that maintains the level of myofibrillar
tropomyosin despite the reduction in alpha-tropomyosin mRNA.
PMID- 9400382
TI - Lipopolysaccharide depresses cardiac contractility and beta-adrenergic
contractile response by decreasing myofilament response to Ca2+ in cardiac
myocytes.
AB - Lipopolysaccharide (LPS) plays a key role in the pathogenesis of sepsis. Cardiac
function and the inotropic response to beta-adrenergic stimulation are impaired
in sepsis. We hypothesized that LPS, in clinically relevant levels (1 ng/mL),
directly depresses contractility and beta-adrenergic responses in cardiac
myocytes. Cardiac myocytes were isolated from the left ventricle of adult rabbits
using digestive enzymes (collagenase and protease). We depyrogenated the enzymes
(LPS contamination lowered from 100 to 300 ng/mL to < 0.7 ng/mL) to minimize
development of LPS tolerance during cell isolation. After 6 hours of incubation
with 1 ng/mL LPS, there was a decrease in the extent of active cell shortening
with no change in Ca2+ transients (measured with indo 1 fluorescence), indicating
decreased myofilament responsiveness to Ca2+. This was related to NO pathways,
since cGMP (a second messenger of NO) increased in cardiac myocytes and LPS
effects were completely reversed with a 1 mmol/L NG-monomethyl-L-arginine (L
NMMA, a NO synthase inhibitor). LPS did not alter the intracellular Ca2+ response
to beta-adrenergic stimulation with isoproterenol but attenuated the contractile
response (maximal cell shortening, 15.5 +/- 1.0% versus 23.3 +/- 1.1% in control
myocytes; P < .001). LPS attenuation of the contractile response to isoproterenol
was restored completely by L-NMMA and almost completely restored (to 86% of the
control response) by an inhibitor of cGMP-dependent protein kinase. We conclude
that LPS depresses cardiac contractility and the contractile response to beta
adrenergic stimulation by a NO-cGMP-mediated decrease in myofilament
responsiveness to Ca2+. The direct effects of low levels of LPS on cardiac
myocytes may contribute to cardiac depression and hemodynamic decompensation
during sepsis.
PMID- 9400383
TI - beta-Arrestin1 knockout mice appear normal but demonstrate altered cardiac
responses to beta-adrenergic stimulation.
AB - beta-Arrestin1 knockout mice were studied to define the physiological role of
beta-arrestin1 in the regulation of G protein-coupled receptors. beta-Arrestin1
is thought to be involved in the desensitization of many G protein-associated
cell surface receptors, particularly beta-adrenergic receptors. Homozygous
knockout mice are overtly normal. Resting cardiovascular parameters modulated by
beta-adrenergic receptors such as heart rate, blood pressure, and left
ventricular ejection fraction are not changed. However, homozygous mutants are
more sensitive to beta-receptor agonist-stimulated increases in ejection
fraction, consistent with a role of beta-arrestin1 in beta-adrenergic receptor
desensitization. We conclude that beta-arrestin1 is important for in vivo G
protein-coupled receptor desensitization and that this aspect of desensitization
represents a mechanism for fine-tuning responses. However, beta-arrestin1 does
not appear to be required for development or for other essential biological
functions.
PMID- 9400384
TI - Experimental diabetes is associated with functional activation of protein kinase
C epsilon and phosphorylation of troponin I in the heart, which are prevented by
angiotensin II receptor blockade.
AB - A cardiomyopathy that is characterized by an impairment in diastolic relaxation
and a loss of calcium sensitivity of the isolated myofibril has been described in
chronic diabetic animals and humans. To explore a possible role for protein
kinase C (PKC)-mediated phosphorylation of myofibrillar proteins in this process,
we characterized the subcellular distribution of the major PKC isoforms seen in
the adult heart in cardiocytes isolated from diabetic rats and determined
patterns of phosphorylation of the major regulatory proteins, including troponin
I (TnI). Rats were made diabetic with a single injection of streptozotocin, and
myocardiocytes were isolated and studied 3 to 4 weeks later. In nondiabetic
animals, 76% of the PKC epsilon isoform was located in the cytosol and 24% was
particulate, whereas in diabetic animals, 55% was cytosolic and 45% was
particulate (P < .05). PKC delta, the other major PKC isoform seen in adult
cardiocytes, did not show a change in subcellular localization. In parallel, TnI
phosphorylation was increased 5-fold in cardiocytes isolated from the hearts of
diabetic animals relative to control animals (P < .01). The change in PKC epsilon
distribution and in TnI phosphorylation in diabetic animals was completely
prevented by rendering the animals euglycemic with insulin or by concomitant
treatment with a specific angiotensin II type-1 receptor (AT1) antagonist. Since
PKC phosphorylation of TnI has been associated with a loss of calcium sensitivity
of intact myofibrils, these data suggest that angiotensin II receptor-mediated
activation of PKC may play a role in the contractile dysfunction seen in chronic
diabetes.
PMID- 9400385
TI - Low efficiency of Ca2+ entry through the Na(+)-Ca2+ exchanger as trigger for Ca2+
release from the sarcoplasmic reticulum. A comparison between L-type Ca2+ current
and reverse-mode Na(+)-Ca2+ exchange.
AB - It has been proposed that Ca2+ entry through the Na(+)-Ca2+ exchanger can
contribute significantly to the trigger for Ca2+ release from the sarcoplasmic
reticulum (SR). We have compared the characteristics of Ca2+ release triggered by
reverse-mode Na(+)-Ca2+ exchange and by L-type Ca2+ current (ICaL) during
depolarizing steps in single guinea pig ventricular myocytes (whole-cell voltage
clamp, fluo 3 and fura-red as [Ca2+]i indicators, 36 +/- 1 degrees C, K(+)-based
pipette solution with 20 mmol/L [Na+]). Conditioning pulses to +60 mV ensured
comparable Ca2+ loading of the SR. In the presence of ICaL, [Ca2+]i transients
typically have an early and rapid rising phase reflecting Ca2+ release, which has
a bell-shaped voltage dependence with a peak at +10 mV. With Ca2+ entry through
Na(+)-Ca2+ exchange only (20 mumol/L nisoldipine), Ca2+ release flux from the SR
is decreased and directly related to the amplitude of the depolarizing step. Ca2+
release is preceded by a significant delay (81 +/- 21 ms at +20 mV, 24 +/- 4 ms
at +70 mV) related to Ca2+ entry through the exchanger. Triggered release
interrupts Ca2+ entry, as evidenced by reversal of the exchanger current. At
potentials positive to +40 mV, Ca2+ influx through Na(+)-Ca2+ exchange,
calculated from the outward exchange current, reaches magnitudes comparable to
ICaL, but Ca2+ release due to reverse-mode Na(+)-Ca2+ exchange still has a
significant delay. We calculated trigger efficiency as the ratio between the
maximal rate of Ca2+ release and the Ca2+ influx preceding this release;
efficiency of reverse-mode Na(+)-Ca2+ exchange is approximately four times less
than that of ICaL. With both ICaL and reverse-mode Na(+)-Ca2+ exchange present,
Ca2+ release is triggered by ICaL, and a contribution of reverse-mode Na(+)-Ca2+
exchange to the trigger could not be detected at potentials below +60 mV. These
characteristics of reverse-mode Na(+)-Ca2+ exchange predict that its role as a
trigger for Ca2+ release during the action potential is likely to be negligible.
PMID- 9400386
TI - Tachycardia-induced changes in Na+ current in a chronic dog model of atrial
fibrillation.
AB - We have previously shown that chronic rapid atrial activation (400 bpm) reduces
atrial conduction velocity in dogs, contributing to the development of a
substrate supporting sustained atrial fibrillation (AF). However, the cellular
and ionic mechanisms underlying these functional changes have not been defined.
We applied whole-cell patch-clamp techniques to atrial myocytes from dogs
subjected to atrial pacing at 400 bpm for 7 days (P7, n = 6) and 42 days (P42, n
= 5) and compared the results with those from sham-operated dogs similarly
instrumented but without pacemaker activation (P0, n = 6). Rapid atrial pacing
allowed for the induction of sustained AF in 67% and 100% of dogs paced for 7 and
42 days, respectively, and significantly decreased conduction velocity under P7
and P42 conditions. In dogs paced for 7 days, Na+ current (INa) density was
reduced by 28% at -40 mV (P < .0001, n = 59 cells). INa changes were even more
decreased under P42 conditions, by approximately 52% at -40 mV (P < .0001): from
78.7 +/- 4.6 pA/pF (P0, n = 28 cells) to -37.7 +/- 3.0 pA/pF (P42, n = 43 cells).
INa was significantly reduced at all voltages ranging from -65 to -10 mV. Voltage
dependent activation and inactivation properties, activation kinetics, and
recovery from inactivation were not altered by rapid atrial pacing; however,
inactivation kinetics were slowed. AF duration was related to mean INa in each
dog (r2 = .573, P < .001). We conclude that rapid atrial activation significantly
reduces both conduction velocity and INa density. Since INa is a major
determinant of conduction velocity, our data point to INa reduction as a
potentially important mechanism contributing to the substrate for AF in this
model.
PMID- 9400387
TI - Molecular determinants of stereoselective bupivacaine block of hKv1.5 channels.
AB - Enantiomers of local anesthetics are useful probes of ion channel structure that
can reveal three-dimensional relations for drug binding in the channel pore and
may have important clinical consequences. Bupivacaine block of open hKv1.5
channels is stereoselective, with the R(+)-enantiomer being 7-fold more potent
than the S(-)-enantiomer (Kd = 4.1 mumol/L versus 27.3 mumol/L). Using whole-cell
voltage clamp of hKv1.5 channels and site-directed mutants stably expressed in
Ltk- cells, we have identified a set of amino acids that determine the
stereoselectivity of bupivacaine block. Replacement of threonine 505 by
hydrophobic amino acids (isoleucine, valine, or alanine) abolished
stereoselective block, whereas a serine substitution preserved it [Kd = 60
mumol/L and 7.4 mumol/L for S(-)- and R(+)-bupivacaine, respectively]. A similar
substitution at the internal tetraethylammonium binding site (T477S) reduced the
affinity for both enantiomers similarly, thus preserving the stereoselectivity
[Kd = 45.5 mumol/L and 7.8 mumol/L for S(-)- and R(+)-bupivacaine, respectively].
Replacement of L508 or V512 by a methionine (L508M and V512M) abolished
stereoselective block, whereas substitution of V512 by an alanine (V512A)
preserved it. Block of Kv2.1 channels, which carry valine, leucine, and
isoleucine residues at T505, L508, and V512 equivalent sites, respectively, was
not stereoselective [Kd = 8.3 mumol/L and 13 mumol/L for S(-)- and R(+)
bupivacaine, respectively]. These results suggest that (1) the bupivacaine
binding site is located in the inner mouth of the pore, (2) stereoselective block
displays subfamily selectivity, and (3) a polar interaction with T505 combined
with hydrophobic interactions with L508 and V512 are required for stereoselective
block.
PMID- 9400388
TI - Reduced adenosine A1 receptor and G alpha protein coupling in rat ventricular
myocardium during aging.
AB - Adenosine A1 receptor (A1-AdoR) function in rat ventricles has previously been
shown to decrease with age. In the present study, using the ligand [3H]8
cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX) and coimmunoprecipitation of A1
AdoRs with their associated G proteins, we determined the specific binding of A1
AdoR and A1-AdoR/G protein coupling in ventricular myocardium of 6- to 24-month
old Fischer 344 rats. The densities (Bmax) of A1-AdoRs were 5.8 +/- 0.8 fmol/mg
protein in 6-month-old rats and 6.1 +/- 1.4 fmol/mg protein in 24-month-old rats,
and the dissociation constants (Kd) were 0.32 +/- 0.04 nmol/L in 6-month-old rats
and 0.34 +/- 0.05 nmol/L in 24-month-old rats (P > .05). Analysis of the dose
dependent displacement of [3H]DPCPX binding by the selective A1-receptor agonist,
N6-p-sulfophenyladenosine (SPA), yielded two affinity binding sites in both 6-
and 24-month-old rats. However, the proportion of high-affinity A1-AdoRs was
significantly lower in 24-month-old rats (23.5%) compared with 6-month-old rats
(54.9%) (P < .05). In solubilized ventricular membranes, specific [3H]DPCPX
binding sites were detected in immunoprecipitates of G alpha i3 and G alpha o
antisera but not with antibodies for other G alpha proteins. The basal
coimmunoprecipitation of A1-AdoR with G alpha i3 and G alpha o proteins decreased
by 22% and 21%, respectively, in ventricular membranes of 24-month-old rats
compared with that in 6-month-old animals. A1-AdoR stimulation with SPA increased
the coprecipitation of A1-AdoR with G alpha i3 and G alpha o proteins by 287% and
245%, respectively, in 6-month-old rats but only by 129% and 140%, respectively,
in 24-month-old rats (P < .01). In the absence of changes in A1-AdoR density and
G alpha protein levels, an age-related decline in high-affinity A1-AdoR binding
sites and a reduction in the association of A1-AdoR with G alpha proteins suggest
that the age-related decrease in ventricular A1-AdoR-mediated response is related
to a reduction in the coupling between A1-AdoR and their G proteins.
PMID- 9400389
TI - Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP
sensitive K+ channels. Possible mechanism of cardioprotection.
AB - Previous studies showed a poor correlation between sarcolemmal K+ currents and
cardioprotection for ATP-sensitive K+ channel (KATP) openers. Diazoxide is a weak
cardiac sarcolemmal KATP opener, but it is a potent opener of mitochondrial KATP,
making it a useful tool for determining the importance of this mitochondrial
site. In reconstituted bovine heart KATP, diazoxide opened mitochondrial KATP
with a K1/2 of 0.8 mumol/L while being 1000-fold less potent at opening
sarcolemmal KATP. To compare cardioprotective potency, diazoxide or cromakalim
was given to isolated rat hearts subjected to 25 minutes of global ischemia and
30 minutes of reperfusion. Diazoxide and cromakalim increased the time to onset
of contracture with a similar potency (EC25, 11.0 and 8.8 mumol/L, respectively)
and improved postischemic functional recovery in a glibenclamide (glyburide)
reversible manner. In addition, sodium 5-hydroxydecanoic acid completely
abolished the protective effect of diazoxide. While-myocyte studies showed that
diazoxide was significantly less potent than cromakalim in increasing sarcolemmal
K+ currents. Diazoxide shortened ischemic action potential duration significantly
less than cromakalim at equicardioprotective concentrations. We also determined
the effects of cromakalim and diazoxide on reconstituted rat mitochondrial
cardiac KATP activity. Cromakalim and diazoxide were both potent activators of K+
flux in this preparation (K1/2 values, 1.1 +/- 0.1 and 0.49 +/- 0.05 mumol/L,
respectively). Both glibenclamide and sodium 5-hydroxydecanoic acid inhibited K+
flux through the diazoxide-opened mitochondrial KATP. The profile of activity of
diazoxide (and perhaps KATP openers in general) suggests that they protect
ischemic hearts in a manner that is consistent with an interaction with
mitochondrial KATP.
PMID- 9400390
TI - Enhanced Na(+)-Ca2+ exchange in the infarcted heart. Implications for excitation
contraction coupling.
AB - Cellular Ca2+ regulation is abnormal in diseased hearts. We designed this study
to assess the role of the Na(+)-Ca2+ exchanger in excitation-contraction coupling
in surviving myocardium of the infarcted heart. We measured cellular contractions
and whole-cell currents in single left ventricular myocytes isolated from the
hearts of rabbits with healed myocardial infarction (MI). Eight weeks after MI,
rabbits had left ventricular dysfunction without overt heart failure. Myocytes
isolated from regions adjacent to the infarcted zone were significantly longer
than cells from control hearts. At low stimulation rates (0.5 Hz), the amplitude
of field-stimulated contractions was increased (11.6 +/- 0.5% versus 10.2 +/-
0.6% resting cell length), whereas the time to peak shortening and action
potential duration were prolonged in the MI cells. When stimulation frequency was
increased to 2.0 Hz, cellular shortening did not change or decreased in myocytes
from infarcted hearts, whereas control cells had a positive shortening-interval
relationship. Cells from infarcted hearts had a significantly decreased (31%) L
type Ca2+ current (ICa) density but no change in the current-voltage relationship
or the kinetics of ICa inactivation. Maximal Na(+)-Ca2+ exchange current density
was significantly increased (32%) in the cells from infarcted hearts.
Sarcoplasmic reticulum (SR) Ca2+ content during a stable train of contractions,
as estimated from caffeine-induced inward currents, was slightly increased (P =
NS) in the MI myocytes. To determine whether Na(+)-Ca2+ exchange influenced SR
Ca2+ content, cells were clamped at potentials between -70 and +90 mV for 400 ms.
The amplitude of the contraction during a subsequent clamp step to +10 mV was
then measured as an index of SR loading that occurred during the preceding clamp
step. Steps to positive potentials produced greater augmentation of the
subsequent contraction in MI than in control myocytes. In myocytes from the
infarcted heart, increased activity of the Na(+)-Ca2+ exchanger may promote Ca2+
entry or decrease Ca2+ extrusion. This relative augmentation of inward Ca2+ flux
by the exchanger may enhance SR Ca2+ loading and thus support contractility that
would otherwise be impaired as a result of decreased Ca2+ current. However, Ca2+
influx by the exchanger may contribute to the prolongation of contractions in
myocytes from infarcted hearts.
PMID- 9400392
TI - Students get gritty introduction to reality of HIV/AIDS.
PMID- 9400391
TI - The protective effect of late preconditioning against myocardial stunning in
conscious rabbits is mediated by nitric oxide synthase. Evidence that nitric
oxide acts both as a trigger and as a mediator of the late phase of ischemic
preconditioning.
AB - Seventy-four conscious rabbits undergoing a sequence of six 4-minute coronary
occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3)
were assigned to nine groups. In group I (controls, n = 8), the recovery of
systolic wall thickening (WTh) after the sixth reperfusion was markedly improved
on days 2 and 3 compared with day 1, indicating late preconditioning (PC) against
myocardial stunning; the total deficit of WTh after the sixth reperfusion was
reduced by 56% on day 2 and 50% on day 3 compared with day 1 (P < .01).
Administration on day 2 of the nonselective NO synthase (NOS) inhibitor N omega
nitro-L-arginine (L-NA) (group II, n = 8) or of the selective inducible NOS
inhibitors aminoguanidine (AG) (group IV, n = 8) and S-methylisothiourea sulfate
(SMT) (group VI, n = 6) completely abrogated late PC against stunning on day 2.
On day 3, the expected PC effect became manifest in all groups. Administration of
L-NA, AG, or SMT on day 1 (groups III [n = 7], V [n = 6], and VII [n = 5],
respectively) had no discernible effect on the deficit of WTh on day 1,
indicating that these agents do not augment the severity of myocardial stunning
in nonpreconditioned myocardium. In group VIII (n = 7), the abrogation of late PC
by SMT on day 2 was completely reversed by the concomitant administration of L
arginine (595 mg/kg IV), indicating that it was not due to nonspecific NOS
unrelated actions. Administration of L-arginine alone on day 2 (group IX [n = 5])
had no effect on the deficit of WTh. Furthermore, administration of L-NA on day 1
(group III) prevented the appearance of the PC effect on day 2, whereas AG (group
V) and SMT (group VI) did not, suggesting that the development of late PC on day
1 is triggered by the endothelial (type III) isoform of NOS. This study
demonstrates that three structurally different NOS inhibitors (L-NA, AG, and
SMT), given 24 hours after the PC ischemia, consistently abrogate late PC against
myocardial stunning in conscious rabbits, indicating that this cardioprotective
effect is mediated by the activity of NOS. The results obtained with AG and SMT
specifically implicate the inducible (type II) isoform as the mediator of the
protection on day 2. Previous studies have shown that NO triggers the development
of late PC. The present results indicate that NO plays a dual role in late PC
against stunning, acting initially as the trigger and subsequently as the
mediator of the protection.
PMID- 9400393
TI - Ontario's HSOs have not failed!
PMID- 9400394
TI - Ontario's HSOs have not failed!
PMID- 9400395
TI - CPGs: to reach the unreachable goal?
PMID- 9400396
TI - Addressing needle-stick concerns.
PMID- 9400397
TI - The US attack on Cuba's health.
PMID- 9400398
TI - The US attack on Cuba's health.
PMID- 9400399
TI - The US attack on Cuba's health.
PMID- 9400400
TI - Shedding light on sunscreen use.
PMID- 9400401
TI - Signing up with ADD.
PMID- 9400402
TI - Cervical cancer screening.
PMID- 9400404
TI - Why?
PMID- 9400403
TI - The many faces of pheochromocytoma.
PMID- 9400405
TI - Why?
PMID- 9400406
TI - Induction of labour versus expectant management for prelabour rupture of the
membranes at term: an economic evaluation. TERMPROM Study Group. Term Prelabour
Rupture of the Membranes.
AB - BACKGROUND: As the interval between rupture of the fetal membranes at term and
delivery increases, so may the risk of fetal and maternal infection. Recently the
TERMPROM (Term Prelabor Rupture of the Membranes) Study Group reported the
results of a randomized controlled trial comparing 4 management strategies:
induction with oxytocin (IwO), induction with prostaglandin (IwP), and expectant
management and induction with either oxytocin (EM-O) or prostaglandin (EM-P) if
complications developed. The study found no statistically significant differences
in neonatal infection and cesarean section rates between any of the 4 groups.
OBJECTIVE: To conduct an economic evaluation comparing the cost of (a) IwO and EM
O, (b) IwP and EM-P and (c) IwO and IwP. DESIGN: An economic analysis, conducted
alongside the clinical trial, using a third-party payer perspective. Analysis
included all treatment costs incurred for both the mother and the baby.
Information on health care utilization and outcomes was collected for all study
participants. Three countries (Canada, the United Kingdom and Australia),
corresponding to the largest study recruitment, were chosen for calculation of
unit costs. For each country, the base, low and high estimates of unit cost for
each service item were generated. Intention-to-treat analysis. Extensive
statistical and sensitivity analyses were performed. RESULTS: The median cost of
IwO per patient was significantly lower statistically than that of EM-O and IwP.
This result held in all 3 countries compared -$114 and -$46 in Canada, -113
Pounds and -63 Pounds in the UK, and -A$30 and -A$49 in Australia) and after an
extensive sensitivity analysis. There was no statistically significant difference
in median cost per patient between IwP and EM-P. CONCLUSION: Although the
clinical results of the TERMPROM study did not find IwO to be preferable to the
other treatment alternatives, the economic evaluation found it to be less costly.
However, these cost differences, even though statistically significant, are not
likely to be important in many countries. When this is the case, the authors
recommend that women be offered a choice between management strategies.
PMID- 9400407
TI - Alcohol disorders in Canada as indicated by the CAGE questionnaire.
AB - OBJECTIVE: To describe alcohol disorders in the general Canadian population,
using as a standard indicator the CAGE questionnaire (Have you felt you needed to
cut down on your drinking? Have you felt annoyed by criticism of your drinking?
Have you felt guilty about drinking? Have you felt you needed a drink first thing
in the morning [eye-opener]?). DESIGN: Secondary analysis of data from Canada's
Alcohol and Other Drugs Survey (CADS), a national telephone survey conducted in
1994 of a representative sample of 12,155 people aged 15 years or more.
PARTICIPANTS: The CAGE questionnaire was administered to 5894 drinkers who had
consumed alcohol in the 12 months before the CADS survey. MAIN OUTCOME MEASURES:
Respondents with positive (2 or more affirmative responses) and negative results
on the CAGE questionnaire were compared as to demographic characteristics,
alcohol consumption and harmful consequences of their drinking. Independent
predictors of a positive result were identified by means of logistic regression
analysis. RESULTS: A total of 5.8% of CAGE-tested current drinkers had a positive
result on the past-year CAGE in 1994. The proportion of respondents reporting
alcohol-related problems in one or more areas of their life was 7 times greater
among drinkers with a positive result on the CAGE questionnaire than among those
with a negative result (66.8% v. 9.5%) (p < 0.0001). When all demographic
characteristics were controlled for simultaneously, male sex, residence in the
Atlantic provinces, Quebec or the Prairies, single/never married or
divorced/separated marital status, and low education level were found to be
independent risk factors for a positive result on the CAGE questionnaire. About
85% of the respondents with a positive result had not sought help for their
drinking. Applying the estimated sensitivity and specificity of the CAGE
questionnaire in detecting alcohol dependence, as per criteria of the Diagnostic
and Statistical Manual, in a general US population, the authors estimated that
4.1% of Canadians had an alcohol dependence in 1994. CONCLUSION: The large
proportion of current drinkers with a positive result on the CAGE questionnaire
who did not seek help for their drinking underscores the need for identification
and brief interventions by physicians. Further research is needed to elucidate
the underlying reasons for regional differences in CAGE status.
PMID- 9400408
TI - Responding to our abused patients.
PMID- 9400409
TI - Premature rupture of membranes at term: a medical and economic rationale for
active management.
PMID- 9400410
TI - Alcohol disorders in Canada: the need for intervention.
PMID- 9400411
TI - Avoiding the mismeasurement of medicine and improving care.
PMID- 9400412
TI - More than meets the eye: recognizing and responding to spousal abuse.
PMID- 9400413
TI - Medical classification systems in Canada: moving toward the year 2000.
AB - The use of different standards for coding diagnoses and procedures has been
identified as a major obstacle to the collection and analysis of data across the
various jurisdictions in Canada. In this article the authors briefly describe the
current and future situation of medical classification systems in Canada and
discuss some of the potential benefits and implications of adopting the 10th
revision of the International Statistical Classification of Diseases and Related
Health Problems and a revised procedure classification, the Canadian
Classification of Health Interventions, as national standards for classification
systems in Canada. They further describe some of the key features of the proposed
new classification systems and highlight some of the actions being taken by the
Canadian Institute for Health Information to support implementation of these
standards in Canada over the next few years.
PMID- 9400414
TI - A curriculum for the times: an experiment in teaching health policy to residents
in family medicine.
AB - The Department of Family Medicine at Queen's University in Kingston, Ont.,
recently undertook a pilot project to familiarize residents in family medicine
with physician-related health policy issues. The objective of the project was to
ease the residents' transition into practice and to equip them to participate
effectively in future policy debates. All first-year residents assigned to a 4
month clinical rotation in the Department of Family Medicine took part in the
program, which consisted of 5 weekly 1-hour lecture and discussion sessions. The
program was offered as one component of the 130-hour core curriculum for first
year residents. Participants evaluated the program as highly informative and
extremely relevant to their career plans. The authors conclude that health policy
is a subject that can be incorporated into the core curriculum of residency
training programs.
PMID- 9400415
TI - Amantadine use in influenza outbreaks in long-term care facilities.
PMID- 9400416
TI - MDs have key role in bringing ugly secret of wife abuse out of closet.
PMID- 9400417
TI - Mother's rights can't be infringed to protect fetus, Supreme Court's landmark
ruling states.
AB - Cases involving child abuse have received wide coverage lately, as has a case
involving possible risk to a fetus because of a mother's addiction to solvents.
Lawyer Karen Capen discusses the legal issues facing doctors over the reporting
of child abuse and outlines their obligations and responsibilities.
PMID- 9400418
TI - Move into hospital sector another sign of complementary medicine's growing
popularity.
AB - Growing demand has led some Canadian hospitals to offer alternative therapies to
patients, even though many physicians still question their efficacy. Anita Elash
visited Toronto's Sunnybrook Health Science Centre, where staff physicians have
been debating the issue. One physician said hospitals have no choice but to offer
the treatments. "If you believe in the primacy of patients making their own
decisions and you believe in the fundamental of informed consent, you cannot deny
them access to this treatment."
PMID- 9400419
TI - Work by Alberta researchers may free MDs from awkward fitness-to-drive decisions.
AB - An Alberta researcher has developed tests that determine whether a senior citizen
with cognitive impairment is fit to drive. The issue is important to the medical
profession because these drivers sometimes cause accidents and physicians often
have to decide whether they should still be allowed to get behind the wheel.
PMID- 9400420
TI - Common cancers--immunotherapy and multidisciplinary therapy: Parts III and IV.
AB - The refractoriness of many solid tumors to cytotoxic chemotherapy has led to the
exploration of new therapeutic modalities, including immunotherapy. Immunotherapy
does not have a direct cytotoxic effect on the cancer cell but is an attempt to
promote rejection of the tumor by the host, chiefly through the cellular arm of
the immune system. The clinical success with immunotherapy (primarily adoptive
immunotherapy) among patients with unresectable malignant melanoma and cancer of
the kidney has not been marked by the large numbers of patients responding but by
occasional dramatic effectiveness of therapy for these cancers, which usually are
refractory to chemotherapy. Long-lasting responses and even complete
disappearance of all known metastases are possible for a small percentage of
patients with melanoma or renal cell carcinoma who undergo immunotherapy. A
reasonable approach for patients with good performance status (no symptoms or
ambulatory with symptoms but not bedridden) is entrance to clinical trials,
especially trials examining adoptive or active immunotherapy for melanoma or
adoptive immunotherapy for renal cancer. The overall treatment of patients with
cancer has changed. Primary-care physicians detect almost all cancers. The days
when "taking it out" is the best we could offer a patient are over. As we learn
more about the use of adjuvant or neoadjuvant chemotherapy and radiation therapy,
it is likely one or both of these modalities will be incorporated into the
treatment of additional solid tumors previously managed solely with surgical
resection. Increasingly, additional therapy is being given for earlier-stage
disease as we define how to maximize the potential for cure with minimal
toxicity. Many new therapies are on the horizon, including the use of
noncytotoxic treatments as an adjunct to a surgical procedure. Such therapies
include the use of angiogenesis inhibitors, tumor vaccines, and immunotherapy.
Now and in the future, patients will be best served when treated in an
environment that can integrate medical, surgical, and radiation oncology
actively.
PMID- 9400421
TI - Carboxy-terminal domain mediates assembly of the voltage-gated rat ether-a-go-go
potassium channel.
AB - The specific assembly of subunits to oligomers is an important prerequisite for
producing functional potassium channels. We have studied the assembly of voltage
gated rat ether-a-go-go (r-eag) potassium channels with two complementary assays.
In protein overlay binding experiments it was shown that a 41-amino-acid domain,
close to the r-eag subunit carboxy-terminus, is important for r-eag subunit
interaction. In an in vitro expression system it was demonstrated that r-eag
subunits lacking this assembly domain cannot form functional potassium channels.
Also, a approximately 10-fold molar excess of the r-eag carboxy-terminus
inhibited in co-expression experiments the formation of functional r-eag
channels. When the r-eag carboxy-terminal assembly domain had been mutated, the
dominant-negative effect of the r-eag carboxy-terminus on r-eag channel
expression was abolished. The results demonstrate that a carboxy-terminal
assembly domain is essential for functional r-eag potassium channel expression,
in contrast to the one of Shaker-related potassium channels, which is directed by
an amino-terminal assembly domain.
PMID- 9400422
TI - Acute and long-lasting effects of neonatal hypoxia on (+)-3-[125I]MK-801 binding
to NMDA brain receptors.
AB - The NMDA receptor subtype is the major excitatory mediator for glutamate
neurotoxicity. To assess its participation in the noxious effects of postnatal
hypoxia, we have characterized the binding of the ionophoric marker of NMDA
receptor, dizocilpine (MK-801). Binding of (+)-3-[125I]MK-801 to NMDA brain
receptors under nonequilibrium conditions was quantified by in vitro
autoradiography in rats exposed to hypoxia induced by 93% N2/6.5% O2 exposure for
70 min on Postnatal Day 4. Acute and long-lasting effects were investigated at 4
h after injury and on Postnatal Day 40. At the acute stage, a transient decrease
in binding was found in several specific brain areas, hypothalamus, amygdaloid
nuclei, entorhinal cortex, perirhinal cortex, and hippocampus, and no differences
were found in temporal cortex, thalamus, and geniculate nucleus, when compared to
sham-treated animals. At this early age, there was no increase of binding when
slices from both groups were incubated in the presence of glutamate and glycine
(Glu/Gly), positive allosteric modulators of MK-801 binding. In the 40-day-old
brains, the binding to the NMDA receptors of hypoxiatreated animals was not
different with respect to controls in most of the areas studied, but the Glu/Gly
stimulation of binding in hypoxic rats showed a reduced, or absent, response to
the allosteric modulators. In contrast, control rats showed a remarkable increase
of the specific binding induced by the presence of the modulators in the
incubation buffer. Binding of (+)-3-[125I]MK-801 was also performed at a higher
concentration to clarify whether the altered response to Glu/Gly may be due to
differences in the number of channels; however, the density of NMDA receptors at
this concentration was similar in both control and hypoxia-treated rats. We
conclude that the effect of exposure of newborn rats to hypoxia can generate
acute and long-lasting effects on the NMDA receptor. The deleterious action of
this kind of noxa on the CNS could be exerted by interference with normal
glutamatergic transmission and hence over normal growth and development.
PMID- 9400423
TI - Spinal cord transection--no loss of distal ventral horn neurons. Modern
stereological techniques reveal no transneuronal changes in the ventral horns of
the mouse lumbar spinal cord after thoracic cord transection.
AB - Anterograde transneuronal degeneration is caused by the loss of afferent input to
the nerve cells and may occur in a number of neuronal systems. Transection of the
adult spinal cord, causing anterograde transneuronal degeneration in ventral horn
neurons, distal to the lesion, has been reported by some authors, while others
contend that no such changes take place. The present study was undertaken in
order to investigate whether transection of adult mouse thoracic spinal cord
induces neuronal death in the ventral horns distal to the lesion. By means of
modern stereological techniques such as the optical dissector, the total number
of cells in the lumbar ventral horns was estimated 7 weeks after transection. The
mean numbers of neurons and glial and endothelial cells were 82,000 versus
89,000, 259,000 versus 301,000, and 129,000 versus 144,000 in the transected (n =
6) and sham-operated animals (n = 5), respectively. These differences were not
statistically significant. Furthermore, neuronal soma volume was estimated by
another stereological method, the vertical rotator. Mean neuronal soma volume was
not significantly different between transected (2762 microns 3) and sham-operated
(2617 microns 3) mice. Although no reduction in cell number or neuronal soma
volume was observed, the mean volume of the ventral horns in the lumbar segments
was significantly less in transected than in sham-operated animals, 2.49 mm3
versus 3.05 mm3 (P < 0.05). In conclusion, the transection of adult mouse
thoracic spinal cord does not induce neuronal degeneration in the lumbar ventral
horns.
PMID- 9400424
TI - Re: Unstable trinucleotide repeats in Alzheimer's disease?
PMID- 9400425
TI - Autologous cell transplantation for urologic reconstruction.
PMID- 9400426
TI - Interpretation of free prostate specific antigen clinical research studies for
the detection of prostate cancer.
AB - PURPOSE: We reviewed the use of percent free prostate specific antigen (PSA) to
enhance specificity of PSA testing and aid in the discrimination of benign and
malignant prostate disease. We present proposed percent free PSA cut points and
probability factors, and discuss factors that are believed to affect study
outcomes and conclusions. MATERIALS AND METHODS: We reviewed the literature with
respect to PSA and free PSA with particular emphasis on clinical use of percent
free PSA and factors that may affect study outcomes. RESULTS: Percent free PSA
may increase the specificity of PSA testing without sacrificing the cancer
detection rate. Differences in study designs and subject populations may account
for the confusion in the current literature. Specific factors that may influence
study outcomes include sample size, PSA range, age, race, digital rectal
examination findings, prostate size, tumor size and pathology, as well as
treatment history, sample collection and storage conditions, and the particular
assays used to determine free and total PSA values. CONCLUSIONS: The use of
percent free PSA to enhance the specificity of prostate cancer screening is
thought to provide useful information to aid in the differentiation of benign and
malignant prostate diseases. There is evidence to suggest a benefit cost
advantage to a tailored biopsy approach based on percent free PSA. However,
statistically valid multisite clinical trials that take into account influencing
factors are needed to set assay specific cut points and probability
determinations.
PMID- 9400428
TI - Holmium:YAG lithotripsy yields smaller fragments than lithoclast, pulsed dye
laser or electrohydraulic lithotripsy.
AB - PURPOSE: The mechanism of lithotripsy differs among electrohydraulic lithotripsy,
mechanical lithotripsy, pulsed dye lasers and holmium:YAG lithotripsy. It is
postulated that fragment size from each of these lithotrites might also differ.
This study tests the hypothesis that holmium:YAG lithotripsy yields the smallest
fragments among these lithotrites. MATERIALS AND METHODS: We tested 3F
electrohydraulic lithotripsy, 2 mm. mechanical lithotripsy, 320 microns pulsed
dye lasers and 365 microns. holmium:YAG fiber on stones composed of calcium
hydrogen phosphate dihydrate, calcium oxalate monohydrate, cystine, magnesium
ammonium phosphate and uric acid. Fragments were dessicated and sorted by size.
Fragment size distribution was compared among lithotrites for each composition.
RESULTS: Holmium:YAG fragments were significantly smaller on average than
fragments from the other lithotrites for all compositions. There were no
holmium:YAG fragments greater than 4 mm., whereas there were for the other
lithotrites. Holmium:YAG had significantly greater weight of fragments less than
1 mm. compared to the other lithotrites. CONCLUSIONS: Holmium:YAG yields smaller
fragments compared to electrohydraulic lithotripsy, mechanical lithotripsy or
pulsed dye lasers. These findings imply that fragments from holmium:YAG
lithotripsy are more likely to pass without problem compared to the other
lithotrites. Furthermore, the significant difference in fragment size adds
evidence that holmium:YAG lithotripsy involves vaporization.
PMID- 9400427
TI - Historical milestones regarding torsion of the scrotal organs.
AB - PURPOSE: The clinical syndrome of the acute scrotum, whereby the spermatic cord
or appendix testis becomes twisted, commonly affects young men. Our knowledge of
this condition, however, is of relatively recent origin. MATERIALS AND METHODS:
We performed an historical survey of torsion of the scrotal organs dating back to
1703. In Bologna in 1703 Morgagni observed the first hydatid on the caput
epididymis. He described 10 hydatid cases of the testis and epididymis producing,
in his opinion, the fluid of hydroceles. The first illustration of appendix
testis dates from Cooper 1841. Later these testicular appendages, or hydatids,
were shown to be vestigial remnants of either the mullerian duct or the wolffian
structures, depending on location. Actual torsion of the appendix testis was
mentioned by Ombredanne in 1913 but the first case report was published in 1922
by Colt. Appendix testis torsion was first schematically illustrated in 1923 by
Mouchet and was characterized by Dix in 1931 in a manner that is still valid
today. Interestingly, the great majority of case reports since 1932 have
originated from America. In 1810 Hunter described a typical case of testicular
torsion, and in 1840 Delasiauve presented the first case of surgically treated
testicular torsion. A schematic and original illustration of a contorted
undescended testis was published in 1894 by Lauenstein. RESULTS: Testicular
torsion was, and still is, a true urological emergency but the historical
survival rate of the testis was extremely low. Searching for improvement in
clinical diagnosis, physicians have noted helpful specific signs, 1 of which is
that the period of ischemia determines loss of the testis. CONCLUSIONS: The
historical development of diagnosis of torsion of the appendix testis and
spermatic cord highlights the ever present need for careful examination, a high
index of suspicion and timely therapy.
PMID- 9400429
TI - Efficacy and cost-effectiveness of extracorporeal shock wave lithotripsy for
solitary lower pole renal calculi.
AB - PURPOSE: We determined the efficacy of extracorporeal shock wave lithotripsy
monotherapy and compared its cost-effectiveness with percutaneous nephrolithotomy
for the management of lower pole renal calculi. MATERIALS AND METHODS: The
efficacy (stone-free rates at 3-months posttreatment) of shock wave lithotripsy
with the modified Dornier HM3* machine was determined retrospectively in 114
patients with solitary lower pole renal calculi. Using cost data available from
patient billing charges and efficacy data from the literature, the cost
effectiveness for percutaneous nephrolithotomy and shock wave lithotripsy as
primary therapy was evaluated. To make this cost-effectiveness comparison, we
developed a decision analysis model in which a patient in whom primary therapy
failed was rendered stone-free with a secondary percutaneous nephrolithotomy
procedure. RESULTS: The stone-free rates of solitary lower pole stones with a
size range of less than 10, 11 to 20 and greater than 20 mm. were 76, 74 and 33%,
respectively, with a single shock wave lithotripsy treatment. Based on average
treatment costs for shock wave lithotripsy and percutaneous nephrolithotomy, the
model results show that for stone sizes less than 2 cm. primary lithotripsy
therapy followed by nephrolithotomy for failed cases is the least costly
approach. For stone sizes greater than 2 cm. primary percutaneous nephrolithotomy
may be more cost-effective. CONCLUSIONS: Whereas shock wave lithotripsy with the
Dornier HM3 should be considered the initial treatment choice for most lower pole
stones less than 2 cm., primary percutaneous nephrolithotomy should be considered
for stones larger than 2 cm.
PMID- 9400430
TI - A placebo controlled study of mycophenolate mofetil used in combination with
cyclosporine and corticosteroids for the prevention of acute rejection in renal
allograft recipients: 1-year results. The European Mycophenolate Mofetil
Cooperative Study Group.
AB - PURPOSE: We performed a randomized, double-blind, multicenter, placebo controlled
study to compare the efficacy and safety of 2 oral doses of mycophenolate mofetil
with placebo for prevention of acute rejection episodes following first or second
cadaveric renal allograft transplantation. MATERIALS AND METHODS: A total of 491
patients were enrolled in the study and randomly allocated to receive placebo
(166), 1 gm. mycophenolate mofetil twice daily (165) or 1.5 gm. mycophenolate
mofetil twice daily (160). Patients were given concomitant immunosuppression with
cyclosporine and corticosteroids. Treatment with mycophenolate mofetil was
initiated within 72 hours of transplantation and was continued for at least 1
year. RESULTS: The percentages of patients who experienced biopsy proved
rejection or withdrew early from the trial for any reason were significantly
reduced with 2 gm. (30.3%) and 3 gm. (38.8%) mycophenolate mofetil compared to
placebo (56.0%) (p < 0.001). The biopsy proved rejection rates of the placebo,
and 2 gm. and 3 gm. mycophenolate mofetil treatment arms were 46.4, 17.6 and
13.8%, respectively. There were fewer patients in the 2 gm. (28.5%) and 3 gm.
(24.4%) mycophenolate mofetil groups compared to the placebo (51.8%) group, who
received full courses of corticosteroids or antilymphocyte agents for treatment
of rejection episodes in the first 6 months after renal transplantation. There
was a greater incidence of gastrointestinal adverse events, leukopenia and
opportunistic events in the mycophenolate mofetil treatment groups. CONCLUSIONS:
Mycophenolate mofetil was shown to reduce significantly the number of patients
who experienced biopsy proved rejection episodes or treatment failure during the
first year after renal transplantation, and was well tolerated.
PMID- 9400431
TI - Endoluminal stent placement after percutaneous transluminal angioplasty in the
treatment of post-transplant renal artery stenosis.
AB - PURPOSE: We report our experience with endoluminal stent placement after
percutaneous transluminal angioplasty for the treatment of post-transplant renal
artery stenosis. MATERIALS AND METHODS: From October 1992 to September 1996, 8
stents were successfully implanted in 7 patients affected by resistant transplant
renal artery stenosis. All transplanted kidneys were procured from cadaver
donors. The patients were routinely evaluated with duplex sonography and the
median interval between transplantation and stenosis detection was 7.4 months
(range 0.5 to 17). When serious renal stenosis was diagnosed (greater than 50%),
selected angiography and percutaneous transluminal angioplasty were performed. In
8 cases (7 patients) an endoluminal metallic Palmaz stent was placed in the site
of the restenosis. One patient received 2 stents repeatedly positioned in
different stenosis sites. RESULTS: No major complications occurred. Clinical
outcome was positive in 5 patients (71.4%) and Stenosis recurred in 2 (28.5%)
(less than 50% and less than 35%, respectively). Median followup after stent
placement was 14.8 months (range 1 to 37). CONCLUSIONS: Percutaneous endoluminal
stent procedures after resistant transplant renal artery stenosis or for ex novo
treatment for severe anastomotic stenoses appears to be promising. Longer
followup periods are necessary for true evaluation of this procedure.
PMID- 9400433
TI - Bilateral open transperitoneal cyst reduction surgery for autosomal dominant
polycystic kidney disease.
AB - PURPOSE: We reviewed our experience with open transperitoneal bilateral renal
cyst reduction surgery in patients with symptomatic autosomal dominant polycystic
kidney disease to define perioperative morbidity and mortality, and to suggest
that others consider this mode of therapy when more conservative methods fail to
provide relief from pain or early satiety. MATERIALS AND METHODS: A total of 28
patients underwent 30 transperitoneal bilateral renal cyst reduction
decompression operations between May 1987 and June 1996. Ten procedures included
surgical treatment of concomitant liver cysts (8 by liver cyst marsupialization
and 2 by partial hepatic resection). Records were reviewed for hospital stay,
perioperative morbidity, changes in renal function and hypertension control.
RESULTS: Hospitalization averaged 9 days. Treatment of hepatic cysts, age and
renal insufficiency did not extend hospitalization. A transient reduction in
renal function occurred after 20 procedures. The most frequently encountered
perioperative morbid events were ileus in 4 patients and cardiac arrhythmias in
3. The most significant complications were myocardial infarction in 1 patient and
fatal adult respiratory distress syndrome after partial liver resection in
another. Preoperative renal insufficiency, age and treatment of hepatic cysts
were not associated with increased morbidity. Six patients had improvement in
hypertension and none had sepsis. CONCLUSIONS: Bilateral transperitoneal renal
cyst reduction surgery is a relatively safe and effective treatment for
individuals with symptomatic polycystic kidney disease in whom more conservative
therapies have failed.
PMID- 9400432
TI - Urological complications after kidney-pancreas transplantation.
AB - PURPOSE: Urological complications are common after kidney-pancreas
transplantation. Predictors of urological complication after transplantation have
not been established. We studied the impact of urological complications on
allograft function. In addition we evaluated age at transplantation, diabetic
years before transplantation and preoperative bladder function as predictors of
allograft pancreatitis, postoperative retention and urine leaks. MATERIALS AND
METHODS: Urological complications in 65 cases (38 men, 27 women, mean diabetic
years 21 +/- 6, mean age 33 +/- 7 years) who had transplants between December
1987 and January 1995 were reviewed. Preoperative urodynamics in 50 patients
(77%) and voiding cystourethrogram in 40 (62%) were analyzed. Kidney-pancreas
transplantation was completed using bladder drainage techniques. RESULTS: Mean
followup was 44 +/- 27 months (median 40, range 1 to 93). Urological
complications in 51 patients (79%) included urinary tract infection in 59%,
hematuria in 26%, allograft pancreatitis in 19%, duodenal leaks in 17%, ureteral
lesions in 9% and urethral lesions in 6%. Eleven duodenal leaks (8 leaks in less
than 1 month) required surgical treatment. Nine leaks recurred in 7 patients.
Allograft pancreatitis occurred 32 times (range 1 to 9) in 12 patients. Three
patients had ureteral obstruction and 3 had ureteral leaks. Preoperative
urodynamics included detrusor hyperreflexia in 8 patients, detrusor areflexia in
19, indeterminate in 5 and normal in 18. The 1-year patient, kidney and
pancreatic allograft survival rates were 92, 91 and 86%; 2-year survival rates
were 89, 88 and 80%, and 5-year survival rates were 61, 59 and 55%, respectively.
CONCLUSIONS: Urological complications were common after transplantation but did
not adversely affect allograft survival in our series. Age at transplantation,
diabetic years preceding transplantation and preoperative bladder function were
not significantly correlated with allograft pancreatitis, postoperative urinary
retention or urine leaks. A prospective analysis of postoperative bladder
function should be completed to improve understanding and possibly reduce
morbidity of urological complications after transplantation.
PMID- 9400434
TI - Monoclonal antibodies against renal tumors: the potential application in
discrimination of ambiguous adenocarcinoma or transitional cell carcinoma of
kidney.
AB - PURPOSE: We tested the discrimination ability of 2 monoclonal antibodies, mAB 90
and 2-2, in renal carcinomas, including renal cell carcinoma and transitional
cell carcinoma of the kidney. MATERIALS AND METHODS: Two monoclonal antibodies
raised in renal adenocarcinoma (mAB 90, IgG3 subclass and mAB 2-2, IgG1
subclass), have been generated in our laboratory by hybridoma technique. The
tumor associated antigens recognized by these IgG subclass monoclonal antibodies
are located in the cell membrane of tumor cells. Antibodies were purified from
mice ascites through protein A-Sepharose 4B affinity column and then conjugated
with fluorescein isothiocyanate fluorescence by dimethyl sulfoxide method. The
binding activity of these antibodies was measured by direct immunofluorescence
method and analyzed in a flow cytometer. Forty-five cases of renal cell carcinoma
and 16 cases of transitional cell carcinoma of the renal pelvis were collected,
and the recognition power of these 2 antibodies was tested. Frozen tumor tissues
were prepared and allocated into single cell suspensions in phosphate buffered
saline before adding diluted (1:10) conjugated antibodies. Irrelevant antibody
and negative tumor cell lines without any reaction with these antibodies were
used as background fluorescence control. RESULTS: Reactivities of mAB 90 and mAB
2-2 for renal cell carcinoma tissues were 80 and 91%, respectively. On the
contrary the reactivities of mAB 90 and mAB 2-2 for transitional cell carcinoma
of renal pelvis tissues were 0 and 69%, respectively. mAB 90 (+)/mAB 2-2 (-)
expression pattern had 76% accurate diagnostic rate for renal cell carcinoma and
mAB 90 (+)/mAB 2-2 (+) pattern had 69% accurate diagnostic rate for transitional
cell carcinoma of the kidney. CONCLUSIONS: When facing pathologically ambiguous
kidney tumors, the binding specificity of mAB 90 and mAB 2-2 may be useful for
discrimination between renal cell carcinoma tumors and transitional cell
carcinoma of the renal pelvis.
PMID- 9400435
TI - Secondary ureteroscopy: results and management strategy at a referral center.
AB - PURPOSE: In an era when extracorporeal shock wave lithotripsy occupies a dominant
place in the treatment of urolithiasis ureteroscopy retains an important role in
certain circumstances. While often a definitive procedure, ureteroscopy can be
associated with potential risks and complications. The treatment of patients who
have undergone a failed attempt at ureteroscopic stone retrieval or have a
complication may be complex. As a tertiary care stone referral center we review
our experience with performing salvage ureteroscopy following a previous
unsuccessful attempt at endoscopic stone removal. MATERIALS AND METHODS: Between
May 1990 and February 1996, 79 patients were referred following an unsuccessful
attempt at retrograde endoscopic or basket manipulation for ureteral calculi. A
retrospective review of the outcomes of these patients was conducted. Of the
patients 11 presented with associated complications, which included ureteral
perforation (4), intramural false passage (1) and fever or sepsis (6).
Complications were managed by early establishment of urinary tract drainage by
stenting or nephrostomy. Among patients without complications elective salvage
ureteroscopy was performed. RESULTS: Ureteroscopy was used in 79 patients with a
successful outcome (stone-free) in 75 (95%). Followup imaging with renal
ultrasound or excretory urography at least 3 months after secondary ureteroscopy
was available in 65 patients and showed no evidence of hydronephrosis or delayed
stricture formation. CONCLUSIONS: Treating the patient who undergoes a failed
attempt at ureteroscopy may be problematic and requires access to a wide array of
endourological equipment. Each subsequent treatment should be individualized with
consideration given to stone size, location and general health. In the presence
of a ureteral injury establishment of early urinary tract drainage is essential.
Following stabilization, secondary ureteroscopy can be performed yielding high
stone-free rates with minimal complications.
PMID- 9400436
TI - Endopyelotomy for primary ureteropelvic junction obstruction: risk factors
determine the success rate.
AB - PURPOSE: We prospectively assessed the feasibility, complications, and short-term
and long-term results of endopyelotomy for primary ureteropelvic junction
obstruction. MATERIALS AND METHODS: In 80 consecutive patients primary
ureteropelvic junction obstruction was diagnosed by excretory urogram or
nephrostomogram, retrograde pyelography, diuresis renography and the Whitaker
test in ambiguous cases. In all patients antegrade endopyelotomy was performed
with a cold knife and an indwelling stent was left for 6 weeks. At 6 and 24
months postoperatively results were assessed clinically by an excretory urogram
and/or diuretic renography and later by questionnaire and ultrasound. RESULTS:
The primary success rate was 89% (71 of 80 patients) after the first
endopyelotomy and increased to 91% (73 of 80 patients) after 2 patients had a
second endopyelotomy. After median followup of 26 months (range 1.5 to 72) 6 of
the 73 initially successfully treated patients had relapse. Two were successfully
re-treated by a second endopyelotomy, resulting in an overall success rate of 81%
(65 of 80 patients) after 1 procedure and 86% (69 of 80 patients) after a second
endopyelotomy in 4 patients. Mean preoperative pyelocaliceal volume decreased
from 64 +/- 33 to 41 +/- 20 ml. (p = 0.0003) 6 months after endopyelotomy and did
not change during the following 18 months. The probability of successful
endopyelotomy was better in patients with a preoperative pyelocaliceal volume
less than 50 ml. (87%) and worse in patients with a volume greater than 50 ml.
(76%). A crossing vessel to the lower pole of the kidney causing persistent
functional obstruction of the ureteropelvic junction was found in 6 of the 10
patients re-treated by open pyeloplasty (9) or nephrectomy (1). Preoperative mean
renal function as determined by diuretic renography was significantly lower in
patients with failed endopyelotomy than in successfully treated patients.
Successfully treated patients showed no change in renal function 6 and 24 months
postoperatively. CONCLUSIONS: Endopyelotomy in primary ureteropelvic junction
obstruction is a safe, minimally invasive procedure with a high primary success
rate and a low relapse rate. Open pyeloplasty could be avoided in 86% of our
patients. Endopyelotomy is less invasive, has less functional and esthetic
sequelae than open pyeloplasty and does not compromise open surgery if that
becomes necessary. We recommend endopyelotomy as first line treatment for
patients with primary ureteropelvic junction obstruction.
PMID- 9400437
TI - Retrospective analysis of the effect of crossing vessels on successful retrograde
endopyelotomy outcomes using spiral computerized tomography angiography.
AB - PURPOSE: Using spiral computerized tomography (CT) angiography, we sought to
evaluate the incidence of a crossing vessel in a group of adults with primary
ureteropelvic junction obstruction who had previously undergone successful
retrograde endopyelotomy. MATERIALS AND METHODS: A total of 16 patients who had
undergone successful Acucise balloon incision endopyelotomy for ureteropelvic
junction obstruction, all with followup greater than 2 years, underwent a spiral
CT angiogram with intravenous contrast material to identify those with a crossing
vessel. Contrast enhanced CT was performed with dual phase technique on a Somatom
Plus-S CT scanner using prototype software. After 180-degree linear interpolation
of the projection data, transaxial images of the affected kidney were
reconstructed. In addition, at the time of the study all patients completed
analog followup pain scales and quality of life assessment questionnaires.
RESULTS: Among the 16 patients 6 (38%) had anterior or posterior crossing vessels
based on spiral CT angiography. No patient had both types. By analog pain scale
patients had 80% mean improvement in pain (range 63 to 100). CONCLUSIONS: In our
series nearly 40% of patients with anterior or posterior crossing vessels had a
long-term (greater than 2 years) successful outcome with retrograde
endopyelotomy. Endopyelotomy continues to be our initial mode of therapy among
adults with primary ureteropelvic junction obstruction. In our opinion the
adverse influence of the crossing vessel is not sufficient to justify the added
expense of preoperative angiography, spinal CT or endoluminal ultrasound.
PMID- 9400438
TI - Endopyelotomy--a panacea for ureteropelvic junction obstruction?
PMID- 9400439
TI - Ureteropelvic junction disruption secondary to blunt trauma: excretory phase
imaging (delayed films) should help prevent a missed diagnosis.
AB - PURPOSE: Ureteropelvic junction disruption is a rare condition which is often
diagnosed after some delay. The aim of this study is to examine the current
status of this entity and to determine if improvements could be made in the
diagnosis. MATERIALS AND METHODS: We evaluated 5 consecutive adult cases of
ureteropelvic junction disruption secondary to blunt trauma and compared the
findings to those reported in literature. RESULTS: The diagnosis was delayed by
at least 24 hours in 4 of the 5 cases (80%). Compared to the literature, in which
most delays in diagnosis were the result of genitourinary tract imaging being
omitted, most of our delays (3 cases) were a result of the initial contrast
enhanced spiral (helical) computerized tomography (CT) failing to provide the
diagnosis. This failure occurred because of either absence of contrast
extravasation (2 cases) or only subtle extravasation (1 case), which was not
recognized by the radiologist. The delay in diagnosis resulted in added morbidity
in all circumstances. CONCLUSIONS: Ureteropelvic junction disruption continues to
be diagnosed late in a large proportion of cases. Absence of gross contrast
extravasation on nephrogram phase scanning using spiral CT may not exclude a
major injury of the ureteropelvic junction. Addition of delayed CT of the kidney
5 to 8 minutes or longer after contrast material injection (during the excretory
phase) may increase the probability of extravasation being demonstrated and,
thus, reduce the possibility of missing a ureteropelvic junction disruption.
PMID- 9400440
TI - New techniques for the administration of topical adjuvant therapy after
endoscopic ablation of upper urinary tract transitional cell carcinoma.
AB - PURPOSE: We evaluated the role of combining ureteroscopic tumor ablation and new
methods of administering topical adjuvant therapy in select patients with
transitional cell carcinoma of the upper urinary tract. MATERIALS AND METHODS:
Patients with upper tract transitional cell carcinoma and indications for
preserving renal function initially underwent ureteroscopic evaluation and tumor
ablation. We treated 17 renal units in 13 patients. Three patients with distal
ureteral lesions underwent uncomplicated adjuvant bacillus Calmette-Guerin
therapy by the combination of Double-J stent placement and bladder instillations
in the Trendelenburg position. In the remaining 14 renal units adjuvant topical
therapy was administered by low pressure weekly instillations through a
transvesical single-J stent whose curl was positioned in an upper calix. Patients
were regularly followed with office flexible ureterorenoscopy under local
anesthesia and cytology washings once they were confirmed to be tumor-free.
RESULTS: Complete ureteroscopic tumor ablation was possible in all patients. Two
sessions were needed due to tumor burden in 3 patients. There were intercurrent
urinary infectious complications with Candida albicans in the 3 patients treated
with bacillus Calmette-Guerin through the single-J stent, including 1 who
received only 3 instillations due to persistent unexplained fevers but who
remains disease-free at 24 months. In 2 of the 17 renal units multifocal tumor
recurred within 12 months, which was treated with nephroureterectomy. At short
followup (mean 14.6 months) 15 renal units have been preserved and remain tumor
free. CONCLUSIONS: The new techniques of administering adjuvant topical agents
for upper tract transitional cell carcinoma after ureteroscopic tumor ablation in
select cases described provide a useful and simple alternative to the
percutaneous method preferred in the past. Short-term responses have been
favorable but the true value of adjuvant therapy remains uncertain at present.
The 2 recurrences within 12 months of treatment were readily detected by
outpatient ureterorenoscopy with the patient under local anesthesia using 7.5F
flexible endoscopes.
PMID- 9400441
TI - Isolated retrovesical and extrarenal retroperitoneal hydatidosis: clinical study
of 10 cases and literature review.
AB - PURPOSE: Isolated extrarenal retroperitoneal echinococcal cyst is a rare
manifestation of hydatid disease. We review the clinical findings of a series of
isolated retrovesical and retroperitoneal hydatid cysts in an endemic area, with
special emphasis on diagnostic pitfalls. MATERIALS AND METHODS: A retrospective
15-year review in a rural area of central Spain (600,000 population), with a
global incidence of hydatidosis of 10 new cases per 100,000 population per year,
revealed 10 patients (0.1 cases per 100,000 per year) with surgically treated
primary extrarenal retroperitoneal echinococcosis and absence of other hydatid
cysts in any organ. Clinical, radiological and laboratory data are analyzed. The
literature of the last 15 years on hydatid disease with a primary retroperitoneal
and retrovesical location is reviewed. RESULTS: A total of 42 cases of isolated
retrovesical (25) and retroperitoneal (17) hydatidosis was compiled. Male
predominance of 2.5:1 was noted and age ranged from 8 to 79 years (mean 42.2 +/-
5.4). The most frequent presentation was a palpable mass in 29% of the cases
followed by flank pain in 24%, frequency in 17% and urinary retention in 14% of
the cases. Hydatiduria of the urinary tract was present in 9.5% of the cases.
Different serological investigations were performed in 45% of the cases with
positive results in 68%. The lesion had been surgically removed in all cases.
Therapy and followup of each patient were analyzed. CONCLUSIONS: An isolated
retrovesical, retroperitoneal or even retrocrural cyst can be the unique
manifestation of hydatid disease. Although difficult, preoperative diagnosis is
desirable for the selection of a surgical approach and prevention of allergic
reactions and operative spillage. A diagnostic algorithm and several therapeutic
guidelines are proposed.
PMID- 9400442
TI - Bladder petechiae after cystoscopy and hydrodistension in men diagnosed with
prostate pain.
AB - PURPOSE: We determined if men with prostate pain syndromes have petechiae in the
bladder after hydrodistension. MATERIALS AND METHODS: A total of 60 men with the
diagnosis of prostate pain and without bacteriuria underwent cystoscopy and
hydrodistension under a general or regional anesthetic. RESULTS: Of the 60 men 35
(58%) had moderate to severe petechiae similar in appearance to women with
interstitial cystitis after hydrodistension. Men with moderate to severe bladder
petechiae had fewer leukocytes in expressed prostatic secretions, smaller bladder
capacities and less often testicular pain than men with more normal appearing
bladders after hydrodistension. Symptomatic improvement 2 to 6 weeks after
hydrodistension was more common in men with moderate to severe petechiae than in
those with fewer petechiae. Absence of rectal pain predicted symptomatic
improvement after hydrodistension. CONCLUSIONS: We suggest that bladder
petechiae, and possibly interstitial cystitis or a related condition, may be more
frequently associated with prostate pain syndromes in men than previously
appreciated.
PMID- 9400443
TI - Lack of evidence for a role of human papillomaviruses in transitional cell
carcinoma of the bladder.
AB - PURPOSE: In view of the conflicting results reported in the literature, we
assessed the involvement of human papillomaviruses (HPV) in the development of
transitional cell carcinoma of the bladder. MATERIALS AND METHODS: A total of 58
bladder papillomatous proliferations was histologically examined and analyzed for
the presence of HPV deoxyribonucleic acid (DNA) sequences by Southern blot
hybridization and the polymerase chain reaction (PCR) method. RESULTS: Typical
features of condyloma acuminatum were observed in the bladder specimen of a
patient with urethral condylomatosis. Of the specimens 57 had histological
features of transitional cell carcinoma but no known signs of HPV infection. HPV
6 DNA was detected in the condylomatous tumor. However, no HPV DNA was detected
in the 57 bladder cancers by Southern blot hybridization and polymerase chain
reaction. CONCLUSIONS: These findings do not support an etiological role of HPV
in the development of transitional cell bladder cancer.
PMID- 9400444
TI - The influence of the level of lamina propria invasion and the prevalence of p53
nuclear accumulation on survival in stage T1 transitional cell bladder cancer.
AB - PURPOSE: We assessed the influence of the level of lamina propria invasion and
the prevalence of p53 nuclear immunoreactivity on the survival of patients with
stage T1 transitional cell bladder cancer. MATERIALS AND METHODS: All patients
presenting with stage T1 bladder cancer were prospectively and routinely grouped
according to the level of lamina propria invasion. Invasion of the tumor stalk
was defined as stage T1a, invasion of the lamina propria proper superficial to
the level of muscularis mucosa as stage T1b and into or deeper than the
muscularis mucosa as stage T1c. The p53 nuclear immunoreactivity was determined
with antibody PAB 1801. RESULTS: The study comprised 143 patients including 31
(22%) with stage T1a disease, 60 (42%) with stage T1b and 52 (36%) with stage
T1c. Mean patient age was 67 years (range 38 to 92) and mean followup was 4.7
years (range 2.4 to 9.7). Tumor grade related to the depth of lamina propria
invasion (p < 0.05) and the prevalence of dysplasia in random mucosal biopsies
was higher in stage T1b and T1c tumors than in stage T1a. Of all tumors 42%
expressed p53 nuclear reactivity which correlated with tumor grade (p < 0.05).
Also the prevalence of nuclear p53 was higher in stages T1b and T1c compared with
T1a disease. Of the patients 115 were treated with transurethral resection alone
and 28 underwent radical cystectomy. Overall survival was 60.1%. Age was the only
independent predictor of survival in patients older than 75 years. For patients
up to 75 years old survival related to age, level of lamina propria invasion and
presence of p53 nuclear accumulation. For this subpopulation overall survival was
67%, and 79% for stage T1a, 70% for stage T1b and 57% for stage T1c (p < 0.05).
Survival was higher in patients with p53 negative (73%) than in those with p53
positive (61%) tumors (p < 0.05). A multivariate analysis of the influence of
lamina propria invasion and nuclear p53 status on survival histology was found to
be the only independent predictor of survival. CONCLUSIONS: Immediate radical
cystectomy should be considered for patients with stage T1c tumors and for some
patients with stage T1b disease, particularly those with tumors expressing p53
nuclear reactivity and with dysplasia in the random mucosal biopsies.
PMID- 9400446
TI - Transurethral ultrasound: evaluation of anatomy and function of the
rhabdosphincter of the male urethra.
AB - PURPOSE: A combined anatomic-sonographic study was undertaken to investigate
whether the anatomical arrangement and the contractions of the rhabdosphincter of
the male urethra could be visualized by transurethral ultrasound. Furthermore,
this new technique was compared with standard urodynamic tests. MATERIALS AND
METHODS: In 7 cadavers transurethral ultrasound was performed to define sono
morphological criteria of the rhabdosphincter, and the sonographic pictures were
then compared to histological sections. In 48 patients the rhabdosphincter of the
male urethra was investigated by transurethral ultrasound and urodynamic
techniques. Of these patients 40 were completely continent after radical
prostatectomy and 8 presented with urinary stress incontinence after
transurethral resection of the prostate or radical prostatectomy. The decrease of
the distance between the rhabdosphincter and the transducer during contraction
served as quantitative parameter for the contractility of the muscle. RESULTS:
The anatomical arrangement and contractions of the rhabdosphincter loop could be
clearly visualized on transurethral ultrasound (during contraction the
rhabdosphincter retracts the urethra, pulling it towards the rectum). Ultrasound
showed scars in 3 patients with postoperative urinary stress incontinence,
thinning of the muscle in 3 complete atrophy of the rhabdosphincter in 2 and
minimal contractions of the rhabdosphincter in 1. Urethral closure pressures were
decreased and decrease in rhabdosphincter-transducer distance was statistically
significantly decreased in the incontinent patients. CONCLUSIONS: Our sono
morphological data and anatomical histological results strongly suggest that the
rhabdosphincter constitutes the main component of the continence mechanism in
post-prostatectomy patients. Unlike urethral pressure profiles, which can only
reveal zones of higher intraluminal pressure between the bladder and the penile
urethra, transurethral ultrasound is highly specific for measurement of the
function of the rhabdosphincter.
PMID- 9400445
TI - Feasibility of transurethral resection for muscle infiltrating carcinoma of the
bladder: long-term followup of a prospective study.
AB - PURPOSE: We analyzed the long-term results of radical transurethral resection for
the treatment of a large series of patients with muscle infiltrating bladder
cancer entered into a prospective study to determine progression predictive
factors. MATERIALS AND METHODS: The study included 133 patients with invasive
bladder cancer treated by radical transurethral resection who had negative
biopsies of the muscle layer of the tumor bed. Followup was more than 5 years for
all subjects and more than 10 years in 59 (44.4%). A comparative nonrandomized
study was performed of a control group of 76 patients with invasive pathological
stage pT2-3a, N0-3 bladder cancer treated by cystectomy. In those patients
treated by radical transurethral resection univariate and multivariate analyses
were performed to establish clinical progression predictive factors. RESULTS: At
5 and 10 years of followup cause specific survival rates were 80.5 and 74.5%, and
bladder preservation rates were 82.7 and 79.6%, respectively. No significant
difference was noted in terms of cause specific survival, with respect to the
control group. The initial presence of associated bladder carcinoma in situ was
the only independent progression predictive factor. CONCLUSIONS: For patients
with invasive bladder cancer radical transurethral resection is justified when
the tumor is clinically limited to the muscular layer and when all biopsies of
the periphery and depth of the tumor bed show muscular tissue negative for tumor
cells. Patients with initial associated bladder carcinoma in situ should not be
excluded from this treatment but endovesical bacillus Calmette-Guerin
immunotherapy should be administered and a closer followup is recommended.
PMID- 9400447
TI - A followup on transurethral collagen injection therapy for urinary incontinence.
AB - PURPOSE: Transurethral collagen injection therapy has been used successfully in
treating stress urinary incontinence due to intrinsic sphincter deficiency since
United States Food and Drug Administration approval in October 1993. MATERIALS
AND METHODS: Telephone interview and chart review were performed on 139 women
with intrinsic sphincter deficiency documented using video urodynamics, of whom
73% had grade 3 incontinence (leakage without effort). Median followup was 18
months (range 6 to 36). Median patient age was 72 years. RESULTS: A total of 103
patients (74%) was substantially improved after collagen therapy, 29 (20%) were
improved and 7 had no improvement. Of the substantially improved group 72%
obtained continence after 2 or fewer injections. Of the patients 11% required a
"booster" injection more than 6 months after initial treatment. Complications,
such as hematuria, urinary tract infections or transient urinary retention, were
rare. CONCLUSIONS: Our results confirm the safety and efficacy of transurethral
collagen. Once continence is achieved further collagen therapy is rarely
necessary.
PMID- 9400448
TI - Hemodynamic patterns of pharmacologically induced erection: evaluation by color
Doppler sonography.
AB - PURPOSE: Penile erection is achieved through hemodynamic mechanisms that can be
assessed best with color flow imaging and Doppler waveform analysis. We performed
dynamic studies using computer assisted analysis to assess the hemodynamic
patterns of pharmacologically induced erection. MATERIALS AND METHODS: A total of
73 color Doppler ultrasound studies was performed in 66 patients with erectile
dysfunction. Various blood flow parameters, including peak systolic velocity, end
diastolic velocity, mean flow rate, resistive index and artery diameter, were
observed continuously and recorded frequently for about 30 minutes after
intracorporeal injection of papaverine/phentolamine/prostaglandin E1 mixture. A
computerized Doppler waveform analysis of 3 curves or greater was performed for
each recording to minimize error. A second injection was administered if the
first injection failed to induce a rigid erection. Status of the erection was
observed and recorded throughout the study. A computerized graph was generated
for each corpus. RESULTS: After intracorporeal injection the time to reach normal
or peak velocity varied from 1 to 24 minutes. Among 146 corpus units in 73 color
Doppler ultrasound studies we observed the following hemodynamic patterns: I
normal maximal peak systolic velocity (35 cm. per second or greater), sustained;
Ia-end diastolic velocity 0 or less with complete erection response (19 units);
Ib-end diastolic velocity greater than 0 or incomplete erection response (14
units); II-normal maximal peak systolic velocity (35 cm. per second or greater),
transient; IIa-end diastolic velocity 0 or less with complete erection response
(21 units); IIb-end diastolic velocity greater than 0 or incomplete erection
response (12 units); III-borderline maximal peak systolic velocity (30 to 35 cm.
per second); IIIa-end diastolic velocity 0 or less with complete erection
response (10 units); IIIb-end diastolic velocity greater than 0 or incomplete
erection response (8 units); IV-low maximal peak systolic velocity (less than 30
cm. per second); IVa-end diastolic velocity 0 or less with complete erection
response (24 units); and IVb-end diastolic velocity greater than 0 or incomplete
erection response (38 units). CONCLUSIONS: Erection is a complex and dynamic
process. A new classification of hemodynamic patterns is presented that aids in
assessing and interpreting more thoroughly blood flow parameters to stratify more
precisely the hemodynamic patterns of erectile dysfunction.
PMID- 9400449
TI - Genital plus audiovisual sexual stimulation following intracavernous vasoactive
injection versus re-dosing for erectile dysfunction--results of a prospective
study.
AB - PURPOSE: We assessed whether re-dosing of a vasoactive agent or the combination
of a vasoactive injection and genital plus audiovisual sexual stimulation caused
the greatest erectile effect to determine which of the 2 procedures would be
better for dynamic penile color Doppler sonography in patients with erectile
dysfunction. MATERIALS AND METHODS: A total of 20 consecutive patients with
erectile dysfunction underwent 2 sessions under real-time RigiScan* recording of
penile erection. Session 1 consisted of adaptation in 10 minutes, intracavernous
injection of 10 micrograms. alprostadil in 10 minutes and re-dosing of 10
micrograms. alprostadil in 10 minutes. Session 2 consisted of adaptation in 10
minutes, injection of 10 micrograms. alprostadil in 10 minutes and genital plus
audiovisual sexual stimulation in 10 minutes. The total duration of each session
was 30 minutes. The order of the 2 sessions was randomly assigned with a week
interval between each session. RESULTS: Re-dosing and genital plus audiovisual
sexual stimulation caused a significant increase in erectile response compared to
the result seen after the first injection (re-dosing p < 0.05, injection plus
stimulation p < 0.01). However, erectile response after the genital stimulation
session was significantly greater than that after re-dosing (p < 0.01). An
erection comparable to the greatest spontaneous erection reported by the patient
was much more frequently achieved after genital stimulation than after the re
dosing session (p < 0.01). CONCLUSIONS: The combination of injection and
stimulation caused a significantly greater erectile response than re-dosing. We
suggest that the former should always be used during color Doppler sonography to
optimize the accuracy of the test. Re-dosing is suggested when an incomplete
erectile response occurs after the injection plus stimulation phase.
PMID- 9400450
TI - Double-blind multicenter study comparing alprostadil alpha-cyclodextrin with
moxisylyte chlorhydrate in patients with chronic erectile dysfunction.
AB - PURPOSE: We compared the efficacy and safety of alprostadil alpha-cyclodextrin
and moxisylyte chlorhydrate to induce erections adequate for sexual intercourse
in a prospective, randomized, parallel double-blind study in patients with
erectile dysfunction. MATERIALS AND METHODS: A total of 156 men with erectile
dysfunction due to organic, nonorganic and mixed origin was randomized into 2
parallel treatment groups receiving titrations of an individual optimum dose of
alprostadil alpha-cyclodextrin or moxisylyte chlorhydrate. Erectile response was
measured by the buckling test. A positive test was associated with axial erection
rigidity that did not buckle/deform to 1.0 kg. load. The buckling test was
repeated every 10 minutes for up to 60 minutes. RESULTS: A total of 56 patients
(75%) in the alprostadil alpha-cyclodextrin group and 32 patients (40%) in the
moxisylyte chlorhydrate group responded with at least 1 positive buckling test
during the office period. Investigators assessed erections after alprostadil
alpha-cyclodextrin to be adequate for sexual intercourse in 61 patients (81%)
compared to 37 patients (46%) after moxisylyte chlorhydrate. All efficacy
parameters in office reached statistical significance of p < 0.001 in favor of
alprostadil alpha-cyclodextrin. During self-injection therapy at home 58 patients
(85%) reported at least 1 rigid erection after alprostadil alpha-cyclodextrin
compared to 37 patients (61%) after moxisylyte chlorhydrate. Patient and partner
opinion of treatment achieved statistically significantly better scores in the
alprostadil alpha-cyclodextrin group compared to the moxisylyte chlorhydrate
group. CONCLUSIONS: Alprostadil alpha-cyclodextrin is significantly more
effective than moxisylyte chlorhydrate in producing full penile rigidity in
office and at home. Injection related side effects occur with the same frequency
but moxisylyte results in more systemic side effects and alprostadil results in
more painful and prolonged erections. Patients and partners are significantly
more satisfied with alprostadil alpha-cyclodextrin.
PMID- 9400451
TI - After the gold rush--advancing research based care for patients with erectile
dysfunction.
PMID- 9400452
TI - Therapeutic effects of high dose yohimbine hydrochloride on organic erectile
dysfunction.
AB - PURPOSE: We evaluated men with organic erectile dysfunction treated with placebo
and high dose oral yohimbine hydrochloride. MATERIALS AND METHODS: We selected 22
patients with organic erectile dysfunction (mean age 58 years) for treatment in
the andrology outpatient clinic. These patients had been previously undergone
neurological, vascular, hormonal and psychological testing, and were treated
during an equal period of 30 days with placebo and daily single dose oral 100 mg.
yohimbine. The response to treatment was evaluated via a questionnaire that
comprised the outcome items of complete--normal penile rigidity enabling vaginal
penetration, partial--erection improved but not sufficiently for appropriate
vaginal penetration, none--no improvement and worse--erection deteriorated. The
patients consented to treatment after being told of the severe adverse effects
that might occur. RESULTS: The most common side effects were anxiety, increase in
cardiac frequency, increased urinary output and headache but in no case was
treatment discontinued. Of the patients 3 (13.6%) and 12 (54.5%) reported
complete or partial response to treatment, respectively. However, statistical
analysis disclosed no significant difference when yohimbine was compared to
placebo (p < 0.05). CONCLUSIONS: Oral 100 mg. single dose daily yohimbine
promotes no improvement in patients with organic erectile dysfunction.
PMID- 9400453
TI - Management of severe corporeal fibrosis with implantation of prosthesis via a
transverse scrotal approach.
AB - PURPOSE: We reviewed our experience in the management of severe corporeal
fibrosis with placement of the AMS 700 CXM* prosthesis to determine the efficacy
of this approach. MATERIALS AND METHODS: The records of 26 men with severe
corporeal fibrosis who underwent placement of the AMS 700 CXM prosthesis via a
transverse scrotal approach between August 1991 and July 1996 were reviewed.
RESULTS: In all cases the AMS 700 CXM prosthesis was successfully implanted with
primary closure of the tunica albuginea, although 2 patients required extended
corporotomies. Followup data were available on all 26 men. At a mean followup of
22.5 months (range 3 to 63) 24 of the 26 men had a functional device (92%). One
patient required explantation for infection and 1 underwent explantation for
cylinder cross-over. CONCLUSIONS: Implantation of the AMS 700 CXM prosthesis in
patients with severe corporeal fibrosis produced good results at approximately 2
years of followup.
PMID- 9400454
TI - Use of a prefabricated tunica vaginalis fascia flap to reconstruct the tunica
albuginea after recurrent penile prosthesis extrusion.
AB - PURPOSE: Although a penile prosthesis usually perforates into the urethra, it can
extrude through the glans or corporeal shaft. Various materials have been used to
reconstruct tunica albuginea but no method of repair has been satisfactory in
such difficult cases. Repair of the weakened tunica albuginea should ideally be
performed with autogenous tissues. Inasmuch as the scarred tissue bed is
inadequate to ensure graft survival and no local flaps are available for this
purpose, prefabrication of a local flap has been designed. MATERIALS AND METHODS:
We present 2 cases in which the distal corpus was reconstructed with a
prefabricated tunica vaginalis fascia flap. The first stage involves grafting
rectus fascia onto the external tunica vaginalis of the testicle. At the second
stage the prefabricated tunica vaginalis fascia flap is transposed to the distal
corpus, placing it as a buttress between the cylinder and urethra medially or
between the cylinder and thin lateral and distal tunica albuginea. The flap also
replaces part of the tunica albuginea. RESULTS: In both patients repair of the
tunica albuginea was successful and each has a functioning inflatable penile
prosthesis at 2 1/2 1 1/2 years postoperatively, respectively. CONCLUSIONS:
Reconstruction of the weak tunica albuginea with a prefabricated tunica vaginalis
fascia flap is an excellent procedure in these difficult cases.
PMID- 9400455
TI - Teratoma with malignant transformation: diverse malignant histologies arising in
men with germ cell tumors.
AB - PURPOSE: Teratoma with malignant transformation refers to a form of germ cell
tumor in which a somatic teratomatous component becomes morphologically malignant
and develops aggressive growth. We evaluated the spectrum of histologies,
chromosomal abnormalities and clinical outcome in patients with teratoma with
malignant transformation. MATERIALS AND METHODS: We identified 46 patients with
germ cell tumor meeting morphologic criteria for malignant transformation.
Histology, disease extent and treatment were correlated with survival. Tumors in
12 patients were studied by conventional cytogenetics or molecular genetic
techniques for the isochromosome 12p [i(12p)], a marker for germ cell tumor, as
well as other chromosomal abnormalities. RESULTS: The site of first detection of
malignant transformation occurred in the primary tumor of 21 cases (44%), at a
metastatic site in 20 (43%) and in both sites in 5 (10%). Sarcoma was the most
frequent histology, identified in 29 patients (63%) with rhabdomyosarcoma the
most common subtype. Seventeen tumors (37%) contained a solid tumor histology
other than sarcoma, with adenocarcinoma and primitive neuroectodermal tumor as
the most common histologies. Four patients with mediastinal germ cell tumor
containing sarcoma also had hematological malignancies, including a focus of
nonHodgkin's lymphoma in the mediastinal primary tumor (1) and nonlymphocytic
leukemia in spleen or bone marrow (3). Patients who had teratoma with malignant
transformation components confined to the testis or retroperitoneum completely
resected experienced a longer survival than those with distant metastases or
incompletely resected tumors (p = 0.003). Chromosomal abnormalities associated
with germ cell tumor (i[12p]) were identified in 11 of 12 tumors containing
adenocarcinoma, primitive neuroectodermal tumor, sarcoma and leukemia. In
addition to i (12p), chromosomal rearrangements characteristic of the transformed
histology were detected in 4 tumors. CONCLUSIONS: A variety of nongerm cell
histologies, including sarcoma, adenocarcinoma, primitive neuroectodermal tumor
and leukemia, may occur in association with germ cell tumor. Chromosomal
abnormalities in these tumors include i (12p), reflecting germ cell tumor
clonality, as well as chromosomal abnormalities associated with the transformed
histology. These tumors do not respond like germ cell tumor to cisplatin
containing chemotherapy regimens. Treatment should be tailored according to that
used in standard management of the transformed histology, and surgical resection
is the mainstay of therapy.
PMID- 9400456
TI - Microsurgical repair of iatrogenic injury to the vas deferens.
AB - PURPOSE: We determined the incidence of iatrogenic injuries to the vas deferens
at a tertiary care university infertility center and the results of surgical
repair. MATERIALS AND METHODS: Records of 472 patients surgically explored for
obstructive azoospermia between 1984 to 1996 were reviewed. Enrollment criteria
included history of inguinal, pelvic and scrotal (other than vasectomy) surgery.
Conventional ipsilateral and crossover vasovasostomies and vasoepididymostomies
were performed. Patency rate was defined as presence of complete sperm with tails
in a postoperative semen analysis. Followup included a minimum of 2 semen
analyses. Only naturally conceived pregnancies were included. RESULTS: Of 472
patients 34 (7.2%) had an iatrogenic injury to the vas deferens with a mean
obstruction interval of 20.5 +/- 1.9 years. Mean patient age was 36.7 +/- 1.8
years. Iatrogenic injury to the vas deferens was secondary to bilateral inguinal
hernia repair in 19 patients, unilateral hernia repair in 11, renal
transplantation in 2, appendectomy in 1 and spermatocelectomy in 1. Pediatric
inguinal hernia repair was the most common etiology of the vasal injury (20
patients), followed by adult inguinal hernia repair (10). A total of 36
microsurgical reconstructive procedures were performed, including 20 ipsilateral
and 16 crossed vasovasostomies and vasoepididymostomies. There were 26 patients
(29 procedures) available for followup (mean 21.0 +/- 3.7 months). Total patency
rate per procedure was 65% and pregnancy rate was 39%. Patency and pregnancy
rates per conventional ipsilateral procedures were 62.5 and 35.7% and per
crossover procedures 64.2 and 42.8%, respectively. CONCLUSIONS: Pediatric
inguinal hernia repair is the most common cause of iatrogenic injury to the vas
deferens. Results of treatment of iatrogenic injury to the vas deferens are
somewhat lower than for patients with obstructive azoospermia due to vasectomy.
Iatrogenic injuries are associated with longer vasal defects, impaired blood
supply and longer obstructive intervals frequently resulting in secondary
epididymal obstruction. Crossover reconstruction is particularly useful when
contralateral testicular atrophy is present. Intraoperatively aspirated sperm
should be cryopreserved for later use in case the reconstruction fails.
PMID- 9400457
TI - Three-dimensional stereotactic posterior ischiorectal space computerized
tomography guided brachytherapy of prostate cancer: a preliminary report.
AB - PURPOSE: A 3-dimensional (D) stereotactic posterior ischiorectal space
computerized tomography (CT) guided approach is presented for brachytherapy of
localized prostate adenocarcinoma. MATERIALS AND METHODS: During the last 2 years
130 patients 49 to 90 years old (median age 71) with clinical stage A, B or C
adenocarcinoma have been treated by this method. The initial prostate specific
antigen profile was range 0.9 to 143 ng./ml., mean, 16.25 and median 13.0. Range
of initial prostatic volume was 30 to 156 cm.3, with a (median 62 and mean 65).
Of the patients 15% had signs and symptoms of urinary obstruction, that is with
residual urine greater than 100 cc and significant nocturia and frequency.
Transurethral resection of the prostate defects were present in 20% of the
patients. Volume and treatment planning is performed by CT. Placement of the
after loading needles is accomplished with a 3-D stereotactic system mounted on a
CT table. The prescribed dose is 12,000 cGy. for 103Palladium seeds and 16,000
for 125I. The dosage is achieved by spacing the after loading needles 10 mm.
apart with the seeds averaging 10 mm. apart from center to center. RESULTS:
Prostate specific antigen levels decreased to less than 2 ng./ml. in 95% of the
patients including those at high risk 6 to 24 months after the procedure. Except
for treatment related transient symptoms of urethritis and proctitis, there have
been no complications. No patients had incontinence, acute infection, hemorrhage
or radiation damage to the rectum. No patients required post-implant
transurethral resection of the prostate. There was significant clinical
improvement in patients with obstructive uropathy. CONCLUSIONS: The 3-D
stereotactic CT guided posterior ischiorectal space approach for brachytherapy is
not limited by prostate size, transurethral prostatic resection defects or public
arch interference, and it allows for needle verification and correction if
necessary. Initial clinical and biochemical results in patients treated with this
method are promising.
PMID- 9400458
TI - Kaposi's sarcoma associated herpesvirus deoxyribonucleic acid sequences: lack of
detection in prostatic tissue of human immunodeficiency virus-negative
immunocompetent adults.
AB - PURPOSE: A recent study argued that Kaposi's sarcoma associated herpesvirus is
ubiquitous, as reflected by the frequent detection of its deoxyribonucleic acid
(DNA) sequences in the prostatic tissue of healthy Italian men. Because these
findings are discordant with serological data, our objective was to reassess the
prevalence of this virus in prostate tissue from immunocompetent men. MATERIALS
AND METHODS: Normal tissue samples from 45 human immunodeficiency virus-negative
men undergoing radical prostatectomy for prostate carcinoma were snap frozen. DNA
was extracted from normal noncancerous tissue. DNA was confirmed to be polymerase
chain reaction amplifiable. Then, using multiple primer sets, extracted prostatic
DNA was blinded, polymerase chain reaction amplified and screened for Kaposi's
sarcoma herpesvirus by Southern blot. RESULTS: Kaposi's sarcoma herpesvirus DNA
sequences were not detected in either the 45 prostatic DNA or in blinded internal
negative controls, but they were consistently identified in all positive internal
controls. CONCLUSIONS: Since Kaposi's sarcoma herpesvirus was undetectable in any
of the prostatic samples despite high assay sensitivity, it is unlikely that the
prostate serves as a reservoir for this virus in immunocompetent North American
men. These findings also suggest that Kaposi's sarcoma herpesvirus is not
ubiquitous.
PMID- 9400459
TI - High dose bicalutamide for androgen independent prostate cancer: effect of prior
hormonal therapy.
AB - PURPOSE: A pilot study of the antiandrogen bicalutamide at 150 mg. a day for
androgen independent prostate cancer was performed. This study was based on the
possibility that androgen independent cases might display responses to additional
hormonal agents. MATERIALS AND METHODS: The study included 31 androgen
independent cases with an increasing prostate specific antigen (PSA) and
progressive disease. PSA measurements were used as the primary method of
assessing response. However, PSA decline was also correlated with clinical
status. RESULTS: Seven patients demonstrated PSA declines of greater than 50% for
2 months or more, for an overall response rate of 22.5%. Responses were observed
almost exclusively in patients treated with long-term flutamide as part of a
complete androgen blockade regimen (43% response rate) in contrast to patients
treated with androgen deprivation without flutamide (6% response rate). Of the 7
PSA responding patients bicalutamide resulted in a significant improvement in
performance status and a decrease in analgesic requirement in 4 and 3 remained
asymptomatic. Bicalutamide at 150 mg. a day was well tolerated, with the most
frequent side effect being mild exacerbation of hot flashes. CONCLUSIONS:
Bicalutamide at this dose is modestly effective for some patients with androgen
independent prostate cancer, particularly for those previously treated with long
term flutamide. This study indicates that previous antiandrogen therapy alters
the response to subsequent hormonal agents.
PMID- 9400460
TI - Bupivacaine infiltration into the neurovascular bundle of the prostatic nerve
does not improve postoperative pain or recovery following transvesical
prostatectomy.
AB - PURPOSE: We assessed the effect of intraoperative bupivacaine infiltration into
the neurovascular bundle of the prostatic nerve on postoperative pain and patient
outcome. MATERIALS AND METHODS: The study included 40 American Society of
Anesthesiologists physical status I to III patients undergoing transvesical
prostatectomy. Following surgical resection of the prostate the neurovascular
bundle of the prostatic nerve was infiltrated with either 10 ml. bupivacaine 0.5%
or saline. Postoperative pain intensity was assessed using a patient generated
100 mm. visual analog scale and a patient controlled analgesia device. Additional
analgesic requirements, time to ambulation, length of hospitalization and return
to normal activity were also recorded. RESULTS: There were no differences in
visual analog scale for pain, patient controlled analgesia demands or actual
morphine delivered. Similarly, saline versus bupivacaine infiltration did not
influence ambulation time (21.3 +/- 2.7 versus 25.0 +/- 11.8 hours,
respectively), length of hospitalization (7.06 +/- 0.8 versus 7.11 +/- 0.6 days,
respectively), return to normal activity (14.4 +/- 8.8 versus 14.2 +/- 8.2 days,
respectively) or patient satisfaction. On postoperative days 1 and 2 more
patients in the saline treatment group requested additional oral analgesia
compared to the bupivacaine treatment group. However, no statistical difference
was demonstrated. CONCLUSIONS: Following transvesical prostatectomy, prostatic
nerve blockade has no beneficial effects on postoperative pain or patient
outcome.
PMID- 9400461
TI - Assessment of patient preferences among men with prostate cancer.
AB - PURPOSE: We developed a self-administered paper based instrument to assess
patient preferences quantified as utilities for common outcomes associated with
the management of prostate cancer. MATERIALS AND METHODS: A total of 50 patients
was invited to test a self-administered paper based instrument designed to assess
preferences for health outcomes associated with the management of localized
prostate cancer. The 50 patients were selected from a group of 625 randomly
identified men with prostate cancer who responded to a survey instrument designed
to assess health related quality of life. The 50 patients selected for this pilot
project were chosen because of the wide range of responses to the quality of life
survey. Patient utilities were assessed for the 5 health states of overall
quality of life, problems related to prostate cancer, and problems related to
urinary, bowel and sexual dysfunction. RESULTS: Patients were able to complete
the assigned tasks. The self-administered instrument had high test-retest
reliability. In addition results obtained from this instrument showed a
correlation with results obtained from assessments using other instruments,
including an analog scale, a computer based system known as U-Titer, a quality of
life survey and the Health Utility Index:3. CONCLUSIONS: A self-administered
paper based instrument can be used to assess patient utilities for health states
associated with prostate cancer management. Results from the instrument tested
appear to be reliable and valid, and are comparable to those obtained from other
assessment techniques. A self-administered paper based instrument has distinct
advantages when conducting large survey studies because it can be incorporated at
relatively low cost.
PMID- 9400462
TI - Adjuvant radiation therapy does not cause urinary incontinence after radical
prostatectomy: results of a prospective randomized study.
AB - PURPOSE: We analyzed the potential influence of adjuvant radiotherapy on urinary
continence after radical prostatectomy. MATERIALS AND METHODS: A total of 100
patients with N0M0 prostate cancer randomized in a prospective study on
postoperative radiotherapy for locally advanced disease (positive surgical
margin, capsular perforation and/or seminal vesicle infiltration) were studied.
Objective pad weighing tests corroborated by direct personal interviews were used
to evaluate urinary continence at regular postoperative intervals. RESULTS: Of
the patients 48 received 60 Gy. external radiotherapy with 18 MV photon beams
between 12 and 16 weeks postoperatively, and 52 were followed expectantly. Risk
factors were similar in both groups. With a mean followup of 24 months, no
difference in complete urinary continence was observed. Of the irradiated group
77% and of the surveillance group 83% were totally dry. The fate of the bladder
neck had no significant influence on final continence status, although there was
a trend for faster recovery when the bladder neck was preserved. CONCLUSIONS: In
this prospective randomized study 60 Gy. external radiation therapy administered
between 3 and 4 months after radical prostatectomy for pathologically locally
advanced prostate cancer had no significant influence on urinary continence.
PMID- 9400463
TI - Radical retropubic prostatectomy outcomes at a community hospital.
AB - PURPOSE: We reviewed a 6-year experience performing radical retropubic
prostatectomy at 2 community hospitals (for-profit and not-for-profit) to assess
outcomes and to compare them to the published literature reflecting outcomes from
major academic hospitals. MATERIALS AND METHODS: Charts of 116 patients who
underwent radical retropubic prostatectomy (nerve sparing in select cases)
between 1990 and 1996 were reviewed for clinical and pathological outcomes as
well as hospital charges. Subjective patient reports of urinary continence,
potency and satisfaction were evaluated postoperatively. RESULTS: Average patient
age was 66.6 years and average preoperative prostate specific antigen level was
9.6 ng./ml. Of the patients 43% had T1c disease, 63% pT2 and 37% pT3. Positive
margins were present in 17.2% of the specimens and 66% of the patients had
Gleason scores of 5 and 6. No deaths occurred. Major complications occurred in
5.4% of patients and included deep venous thrombosis (1.8%), pulmonary embolism
(1.8%), rectal injury requiring ileostomy (0.9%) and fascial dehiscence (0.9%).
Mean blood loss was 872 cc and mean blood transfusion rate was 1.7 units (almost
exclusively autologous blood). Hospital charges decreased at the not-for-profit
hospital to $13,233 in 1996 from $17,743 in 1990 to 1995, whereas charges
increased at the for-profit hospital to $25,979 in 1996 from $24,481 in 1990 to
1995. Mean length of stay decreased from 5 days in 1990 to 1995 to 3 days in
1996. Of the patients 80% were totally continent (pad-free), 12% wore a
protective pad once per day for minimal incontinence and 8% wore 2 or more pads.
Of the men who were potent preoperatively 18% retained potency and 46% remained
sexually active postoperatively either spontaneously or with assistance. Of the
patients 84% were satisfied with surgical outcomes, 11% were somewhat satisfied
and 5% were dissatisfied. CONCLUSIONS: Radical retropubic prostatectomy can be
performed safely and with acceptable clinical and pathological outcomes at a
community hospital. Impotence continues to be one of the most bothersome
morbidities, particularly in older men. Increasing cost awareness, coincident
with the proliferation of managed care, has led to reductions in length of
hospital stay and charges at certain hospitals.
PMID- 9400464
TI - Prostate cancer outcomes studies--the pathway to improvement.
PMID- 9400465
TI - Long-term results of radiation therapy for prostate cancer recurrence following
radical prostatectomy.
AB - PURPOSE: Following radical prostatectomy, radiation therapy may be beneficial in
select patients with isolated local recurrence. Pathological stage, Gleason score
and the timing of prostate specific antigen (PSA) elevation are useful in
distinguishing men with local recurrence from those with distant metastases. We
test the ability of these criteria to predict long-term suppression of PSA
recurrence following post-prostatectomy radiation therapy. MATERIALS AND METHODS:
Of 1,699 men treated with radical prostatectomy from 1982 to 1995, 82 with an
isolated PSA elevation or local recurrence following surgery underwent radiation
therapy to the prostatic bed and were followed for at least 2 years. No patient
had evidence of metastases at the time of radiation. RESULTS: Of the men 17 (21%)
had an undetectable PSA (less than 0.2 ng./ml.) for 2 or greater years following
radiation. The 5-year actuarial PSA recurrence-free rate after radiation was 10%.
PSA remained at undetectable levels for 2 or greater years in no patients with
Gleason score 8 or greater (12 cases), positive seminal vesicles (12) or positive
lymph nodes (3), and in only 1 of 16 men (6%) who had a PSA recurrence within 1
year of prostatectomy. As the interval to PSA recurrence increased, the
likelihood of responding to radiotherapy increased to 44% if initial disease
detection occurred 5 or more years after prostatectomy. There was no demonstrated
advantage to radiating men with an isolated PSA elevation before a documented
local recurrence. CONCLUSIONS: Patients with Gleason score 8 or greater, positive
seminal vesicles or lymph nodes, or a PSA recurrence within the first year
following surgery rarely benefit from radiation therapy. As the interval to PSA
recurrence increases, the likelihood of responding to radiation therapy increases
substantially. These parameters are useful in the selection of patients with
prostate cancer recurrences who are likely to benefit from radiation to the
prostatic bed.
PMID- 9400466
TI - The use of 2 ipsilateral ureteral stents for relief of ureteral obstruction from
extrinsic compression.
AB - PURPOSE: We present our early experience with the novel approach of placing 2
parallel stents simultaneously in extrinsically obstructed ureters in which
single stents had failed. The increased stiffness of 2 stents reduces kinking and
luminal compression, and the potential space between the stents likely preserves
flow around as well as through them. MATERIALS AND METHODS: Four patients
recently presented with ureteral obstruction secondary to nonurinary tract
malignancies. Previous stenting with a single 6F Double-J* stent had failed in
all cases. Three patients experienced flank pain and 1 had persistent azotemia
within 3 days of initial stent placement. All patients had significant residual
sonographic hydronephrosis despite good stent position. In all cases
cystoscopy/stent exchange was performed under local anesthesia with intravenous
sedation. Parallel 4.7F Double-J stents were placed simultaneously over 2, 0.035
hydrophilic coated glide wires under fluoroscopic guidance after removal of the
malfunctioning 6F stent. RESULTS: Stent placement was uneventful in all 4
patients with prompt drainage of contrast material seen after parallel
ipsilateral stent placement. Patients tolerated the double 4.7F parallel stents
with no discernible difference in irritative symptoms compared to single 6F
stents. Flank pain and azotemia resolved in 3 patients, and hydronephrosis
improved in all 4 after placement of parallel Double-J stents. All patients
remain alive with a mean followup of 5.8 months (range 4 to 8). Except for 1
patient who later underwent ureterolysis, each has subsequently had the stent
changed every 3 months. No patient has required proximal urinary diversion (that
is percutaneous nephrostomy tube). CONCLUSIONS: Placement of 2 ipsilateral
parallel ureteral stents simultaneously is an easy technique. It may obviate
percutaneous nephrostomy tube placement in patients in whom drainage with a
single stent failed, especially in cases of extrinsic ureteral compression.
PMID- 9400467
TI - Inguinal scrotal incision for penile fracture.
AB - PURPOSE: We report a new incision for repair of penile fracture. MATERIALS AND
METHODS: We describe 2 cases in which the inguinal scrotal incision was used for
repair of penile fracture. The preoperative evaluation as well as the technical
case and rationale for use of this incision are discussed. RESULTS: Preoperative
cavernosogram delineated the site of the fracture. Immediate repair of the
fracture using the inguinal scrotal incision was successful. CONCLUSIONS: The
inguinal scrotal incision should be entertained for cases of penile fracture. It
avoids incision into markedly edematous penile skin and allows for excellent
visualization of the fracture site.
PMID- 9400468
TI - Primary skin closure of a large groin defect after inguinal lymphadenectomy for
penile cancer using a skin stretching device.
AB - PURPOSE: We describe a method of primary closure of a large skin defect.
MATERIALS AND METHODS: A 44-year-old man was treated for penile cancer. After
left inguinal lymphadenectomy a large skin defect in the groin remained that
could not be closed primarily. Allowing skin to stretch beyond its inherent
extensibility with a skin stretching system (Sure-Closure) the wound edges were
closed without tension. RESULTS: Primary closure of a large skin defect was
possible after cyclic stretching and relaxation of the skin with a skin
stretching device. CONCLUSIONS: Large skin defects can be closed primarily using
a skin stretching device. The primary advantage of the procedure are its
simplicity and avoidance of the need for more complicated reconstructive surgery.
PMID- 9400469
TI - Microsurgical vasovasostomy: the microdot technique of precision suture
placement.
AB - PURPOSE: A technique of vasovasostomy that facilitates precision suture placement
is presented. MATERIALS AND METHODS: The technique involves mapping of the
planned suture exit points with "microdots" placed on the cut ends of the vas
deferens with a microtip marking pen. Microdots are placed at 12, 3, 6 and 9
o'clock positions. Four additional dots are placed between each of the previous 4
dots. Exactly 8 mucosal sutures (double armed 10-zero monofilament sutures) are
used for each anastomosis. The anastomosis is completed with 8 muscularis sutures
(9-zero monofilament) and 6 to 8 sutures (6-zero monofilament) approximating the
vasal sheath. RESULTS: In a series of 194 consecutive vasovasostomy procedures
using this technique a patency rate of 99.5% was achieved. Pregnancy rates of 54%
(crude) and 64% (excluding female factor infertility) were observed for the first
100 subjects of this cohort. CONCLUSIONS: The microdot technique ensures
precision suture placement and facilitates the anastomosis of lumens of
discrepant diameters by exact mapping of each planned suture. The microdot method
separates the planning from the placement. Patency rates using the microdot
technique approach 100%.
PMID- 9400470
TI - Morbidity of the evaluation of the lower urinary tract with transurethral
multichannel pressure-flow studies.
AB - PURPOSE: The aim of this prospective study was to determine morbidity and
complication rate of invasive urodynamic evaluation of the lower urinary tract
after transurethral multichannel pressure-flow studies. MATERIALS AND METHODS:
The study included 63 men with the clinical diagnosis of benign prostatic
hyperplasia and 56 women with stress urinary incontinence. All patients underwent
routine pressure-flow study as part of the urodynamic evaluation. A week later
the patients returned for followup which also included a detailed interview on
post-evaluation morbidity. RESULTS: The overall complication rate, including
urinary retention, gross hematuria, urinary tract infection and fever, was 19.0%
(12 of 63) for men and 1.8% (1 of 56) for women. In men there was no
statistically significant correlation between post-void residual urine or age and
complication rate (p > 0.05). Of the men 4.8% experienced post-investigational
urinary retention and all of them had significant bladder outflow obstruction. In
addition, obstructed men reported a higher incidence of dysuria and pain (76.2%,
32 of 42) compared to those without obstruction (57.1%, 12 of 21), whereas only
53.6% of women reported these complaints. Of the 63 men 4 (6.2%) had significant
urinary tract infections, while only 1 woman (1.8%) had infections. CONCLUSIONS:
Invasive urodynamic investigation is associated with a considerable rate of
complications and morbidity, particularly in men with infravesical obstruction.
These facts must be considered and discussed with the patient before urodynamic
testing.
PMID- 9400471
TI - Renal autotransplantation and pyelocystostomy for the treatment of urothelial
tumors of the upper urinary tract.
PMID- 9400472
TI - Hypogastric arterial-ureteral fistula.
PMID- 9400473
TI - Laparoscopic urinary undiversion.
PMID- 9400474
TI - Massive bleeding from ileal conduit peristomal varices: successful treatment with
the transjugular intrahepatic portosystemic shunt.
PMID- 9400475
TI - Gastric neobladder for treatment of tuberculosis cystitis.
PMID- 9400476
TI - Extensive squamous cell carcinoma in situ of the bladder masking deeply invasive
disease.
PMID- 9400477
TI - Transitional cell carcinoma of the bladder with involvement of vasa deferentia.
PMID- 9400478
TI - Simultaneous bilateral testicular torsion in an adult.
PMID- 9400479
TI - Re: Epithelial inclusion cyst formation after free vaginal wall swing sling
procedure for stress urinary incontinence.
PMID- 9400480
TI - Re: The resistance index represents the corporeal pressure and not the cavernous
wall resistance.
PMID- 9400481
TI - Re: Possible mechanisms of action of transurethral needle ablation of the
prostate on benign prostatic hyperplasia symptoms: a neurohistochemical study.
PMID- 9400482
TI - Re: The safety of overnight hospitalization for transurethral prostatectomy: a
prospective study of 200 patients.
PMID- 9400483
TI - Constant elevation in renal pelvic pressure induces an increase in urinary N
acetyl-beta-D-glucosaminidase in a nonobstructive porcine model.
AB - PURPOSE: To clarify the physiological significance of renal pelvic pressure
elevations encountered in the evaluation of hydronephrotic kidney we examined the
effects of different levels of renal pelvic pressure on the induction of renal
injury. MATERIALS AND METHODS: A nonobstructive porcine model was created in
which the urine drained against a constant predetermined pressure gradient. Renal
pelvic pressure of 10, 20 and 40 cm. was created in 2, 2 and 4 animals,
respectively. During 18 to 23 hours serial urinary N-acetyl-beta-D
glucosaminidase levels were determined as an indicator of renal tubular injury.
Tissue specimens were examined histologically and renal arterial blood flow was
monitored. RESULTS: Urinary N-acetyl-beta-D-glucosaminidase levels in the kidneys
subjected to 10 cm. water remained essentially unchanged. However, at 20 and 40
cm. water statistically significant increases were observed. Similarly, renal
arterial blood flow was unchanged at 10 cm. water but it became significantly
lower than in controls at 20 and 40 cm. water. Histological evaluation revealed
mild to moderate tubular dilatation in the kidneys subjected to 20 and 40 cm.
water. CONCLUSIONS: Excessively high collecting system pressure induced renal
cellular injury, as reflected by an increase in urinary N-acetyl-beta-D
glucosaminidase levels. While renal pelvic pressure up to 10 cm. water appeared
to be innocuous, renal cellular injury was evident within as little as 1 hour at
renal pelvic pressures 20 cm. water or greater. The degree of N-acetyl-beta-D
glucosaminidase in the urine also correlated with a decrease in renal arterial
blood flow.
PMID- 9400484
TI - Diagnosing the combination of renal dysgenesis, Gartner's duct cyst and
ipsilateral mullerian duct obstruction.
AB - PURPOSE: We describe the differential points in the diagnosis of the combination
of renal dysgenesis, Gartner's duct cyst and ipsilateral mullerian duct
obstruction. Various imaging studies and urological procedures were performed. We
report our experience in detecting these anomalies in 10 girls and review the
literature. MATERIALS AND METHODS: Ten girls, 7 to 13 years old, with this
combination of anomalies were identified in the last 10 years. Imaging studies as
well as urological procedures were selectively performed, especially at puberty
following menarche. Patients received long-term followup with ultrasound.
RESULTS: Cystic dilation of Gartner's duct protruded into the bladder and
presented as a ureterocele in 5 patients and posterior to the bladder in 5.
Surgical removal of a partial portion of a Gartner's duct cyst was performed in 5
patients for alleviation of urinary symptoms. Unilateral mullerian duct
obstruction was demonstrated in all 10 patients. Excision of the vaginal septum
was performed in 6 patients for relief of genital obstruction. CONCLUSIONS: When
cystic dilatation of the pelvis, especially a ureterocele-like cyst without
ureteral dilatation, is found in girls with ipsilateral renal dysgenesis, the
possibility of a Gartner's duct cyst should be considered. For early detection
and treatment of unilateral obstruction of duplicated mullerian ducts pelvic
sonography should be performed at puberty, especially just after menarche, in
girls with renal dysgenesis and ipsilateral Gartner's duct cyst.
PMID- 9400486
TI - Retroperitoneal fibrosis mimicking recurrent leukemia in a 7-year-old boy.
PMID- 9400485
TI - Surgery versus observation for managing obstructive grade 3 to 4 unilateral
hydronephrosis: a report from the Society for Fetal Urology.
AB - PURPOSE: The Society for Fetal Urology has undertaken the first multicenter
prospective randomized study of high grade obstructive unilateral hydronephrosis
to evaluate the natural history of untreated obstruction and compare it to the
benefits of pyeloplasty. MATERIALS AND METHODS: Since 1991, infants with isolated
unilateral Society for Fetal Urology grade 3 hydronephrosis and ipsilateral
obstruction with greater than 40% differential renal function on well tempered
renography were studied. Patients were randomly assigned to observation or
pyeloplasty groups. Renal ultrasound and well tempered renography were performed
biannually for 1 year and yearly thereafter. Crossover criteria for surgery
included concurrent worsening of isotope washout and increasing grade of
hydronephrosis or a greater than 10% point loss in percent differential renal
function that was noted between studies. The end point of the study was the 3
year anniversary of randomization. RESULTS: A total of 32 infants from 10 centers
were randomized equally to 2 groups. The starting grade of hydronephrosis and
percent differential renal function were similar between the 2 groups. At 6
months and 1 year the grade of hydronephrosis was significantly reduced (p <
0.02) and well tempered renography was significantly more likely to demonstrate
no obstruction (p < 0.03) in the surgical group compared with the observation
group. The mean percent differential renal function remained stable and similar
in both groups. Reduced hydronephrosis and resolution of obstruction in the
surgery group persisted as a trend at the 2 and 3-year anniversaries. In the
observation group 4 patients (25%) showed enough renal deterioration to qualify
for crossover to surgery. CONCLUSIONS: Infant pyeloplasty significantly improved
the grade of hydronephrosis and drainage pattern at 6 months and 1 year
postoperatively, when compared with observation. Renal function stabilization was
similar for either management approach. However, 25% of the patients satisfied
objective criteria of status deterioration requiring pyeloplasty.
PMID- 9400487
TI - Subclinical changes in bladder function in children presenting with nonurological
symptoms of the tethered cord syndrome.
AB - PURPOSE: We evaluated the urodynamic findings in myelodysplastic children with
the tethered cord syndrome without urological symptoms to determine if occult
bladder changes occur or if routine preoperative urodynamic evaluation is not
indicated for this select population. MATERIALS AND METHODS: Preoperative and
postoperative urodynamic studies were performed on children with myelodysplasia
and the tethered cord syndrome between 1988 and 1994. Inclusion criteria were
neurological or musculoskeletal surgical indications only, without urological
status changes, radiographic confirmation of the tethered cord syndrome, and
water cystometry performed preoperatively within 1 week and again postoperatively
within 6 months. The parameters of interest included total bladder capacity and
pressure, leak point pressure, compliance, uninhibited contractions,
electromyelogram activity and sensation. RESULTS: A total of 20 children, 11
girls and 9 boys, 2.3 to 17.3 years old were included in the study. Worsening
scoliosis and lower extremity weakness were the most common presentations.
Urodynamic studies were conducted 1.8 days preoperatively (mean) and 104.3 days
postoperatively (mean). Results were analyzed with regard to improvement or
deterioration between preoperative and postoperative urodynamic studies. Of the
20 children 15 (75%) demonstrated improvement between the 2 urodynamic studies,
including 10 who improved in 1 parameter (most often with resolution of
uninhibited contractions), 3 in 2, 1 in 3 and 1 in 4. There were no significant
postoperative changes for any of the specific parameters. Urodynamic studies
identified 7 children with preoperative leak point pressures above 40 cm. water,
of whom only 2 had decreased pressures below 40 cm. water, 2 had postoperative
deterioration of compliance and 1 had preoperative detrusor-sphincter
dyssynergia. CONCLUSIONS: Routine preoperative and postoperative urodynamic
evaluations in children with the tethered cord syndrome without clinical changes
to urological status may be important. The majority of clinically asymptomatic
children will demonstrate preoperative urodynamic findings that improve
postoperatively, which serves as another marker of progress after spinal cord
untethering. Moreover, some asymptomatic children will demonstrate changes to the
urinary tract that merit management changes, such as detrusor-sphincter
dyssynergia, elevated bladder storage pressures and poor compliance, which may
have otherwise been delayed in recognition.
PMID- 9400488
TI - Fluorescence in situ hybridization on nuclei from paraffin-embedded tissue in low
stage pure embryonal carcinoma of the testis.
AB - Approximately 30% of patients who present with clinical stage A nonseminomatous
testis cancer are in fact pathologic stage B. In previous studies an increasing
volume of embryonal carcinoma in the orchiectomy specimen was associated with a
higher likelihood of being pathologic stage B. However, not all patients with
pure embryonal carcinoma in the primary tumor were pathologic stage B. In an
effort to discriminate patients with pure embryonal carcinoma in the testicular
specimen relative to pathologic stage, archival specimens from patients
presenting with clinical stage A pure embryonal carcinoma were examined by
fluorescence in situ hybridization (FISH) with newly developed probes for
chromosome arms 12p and 12q. Whole nuclei from archival material from 14 patients
(six pathologic stage A, seven pathologic stage B and one stage C) with 100%
embryonal carcinoma in the orchiectomy specimen were studied using bicolor FISH
with chromosome arm 12p- and 12q-specific painting probes developed by chromosome
microdissection. In all cases a blinded analysis showed distinct regions of 12p
and 12q probe hybridization simultaneously and allowed identification of probable
normal chromosomes 12, as well as regions of amplification of 12p sequences,
including possible i(12p). In 5/14 specimens, a distinct and peculiar pattern of
12p hybridization was observed which resembled 12p "disarray" or "multifocal
12p". Of the five specimens demonstrating multifocal 12p, four were pathologic
stage B, while one was pathologic stage A. Whether the trend toward multifocal
12p predicts metastatic potential in primary testicular embryonal carcinoma will
need to be assessed using a larger series of patients.
PMID- 9400489
TI - Low frequency of positive telomerase activity in a chromophobe subtype of renal
cell carcinoma.
AB - PURPOSE: In malignant tumors, telomerase reactivation plays an important role in
the acquisition of cellular immortality. We evaluated the telomerase activity in
renal cell carcinomas (RCCs) with special reference to their clinicopathologic
features. MATERIALS AND METHODS: Telomerase activity was examined in 47 RCCs and
9 RCC cell lines by telomeric repeat amplification protocol assay (TRAP). The
telomere lengths were assessed by Southern analysis of terminal restriction
fragments (TRFs) generated by Hinfl-digested DNA. RESULTS: Thirty-six (77%) of
the 47 RCCs and all 9 RCC cell lines showed telomerase activity, whereas no
activity was detected in any of 30 normal kidneys. When the tumors were
histopathologically classified, only one (17%) of the 6 chromophobe cell
carcinomas was telomerase-positive. This frequency was significantly low (p <
0.001) when compared with those in clear cell RCCs (93%; 26/28). In 40 of the 47
patients, DNA from the tumor tissues and the paired normal kidneys was available
for analysis of the TRF lengths. No tumor showed elongated TRF length compared to
its paired normal kidney. Regarding the relationship between telomere length and
telomerase activity, 23 (74%) of the 31 telomerase-positive RCC and 6 (67%) of
the 9 telomerase-negative RCC exhibited reduced TRF. There was no significant
correlation between the telomere reduction and telomerase activity. CONCLUSION:
The mechanism for preventing telomere shortening may differ according to RCC
subtype. Alternatively, telomerase-negative tumors may have yet to reach the
immortal stage when they progress to clinical cancer. The telomerase activity
status may contribute to the biological potential and the prognosis of RCCs.
PMID- 9400490
TI - Bethanechol activates a post-receptor negative feedback mechanism in rabbit
urinary bladder smooth muscle.
AB - PURPOSE: Recent studies using vascular and gut smooth muscles indicate that
contractile receptor agonists may activate post-receptor down-regulatory
mechanisms causing a temporary reduction in the strength of subsequent
contractions. Our data indicate a similar mechanism exists in detrusor smooth
muscle of the urinary bladder. MATERIALS AND METHODS: Each isolated strip of
female rabbit detrusor was placed in a tissue bath, secured to an isometric force
transducer, and length-adjusted until depolarization with 110 mM KCl produced a
maximum contraction (S0). Subsequent contractions were normalized to S0 (S/S0) or
to a first stimulus with 30 mM KCl or caffeine (S/S1). Tissues were pretreated
with the muscarinic receptor agonist, bethanechol (BE), then stimulated with KCl,
caffeine, or Bay k 8644 to identify potential post-receptor down-regulation.
RESULTS: Contractions induced by 30 mM KCl had three phases labeled fast peak
(FP), slow peak (SP) and steady-state (SS). In tissues exposed for 30 min. to a
maximum BE concentration then washed for 5 min., the KCl-induced FP and SP, but
not SS, responses were reduced by approximately 40%. Smaller reductions in peak
KCl-induced contractions occurred in tissues pretreated for a shorter duration or
with a 100-fold lower BE concentration. This down-regulation induced by
bethanechol pretreatment was reversible, lasting approximately 1-2 h. Not only
were KCl-induced contractions reduced by BE pretreatment, but also those produced
by the intracellular Ca(2+)-mobilizer, caffeine, and the L-type Ca2+ channel
agonist, Bay k 8644. CONCLUSIONS: Pretreatment of isolated strips of rabbit
detrusor with a muscarinic receptor agonist produced short-term down-regulation
of KCl-induced peak contractions that may have involved inhibition of both influx
of extracellular Ca2+ and release of intracellular Ca2+. Reductions in the degree
of this novel modulatory response during disease conditions and aging could
enhance contractile activity, possibly causing detrusor instability.
PMID- 9400491
TI - Detailed interstitial temperature mapping during treatment with a novel
transurethral microwave thermoablation system in patients with benign prostatic
hyperplasia.
AB - PURPOSE: To delineate in detail the temperature changes in the prostate gland and
adjacent structures during treatment with a newly designed microwave
thermoablation system in patients with benign prostatic hyperplasia (BPH).
MATERIALS AND METHODS: Microwave thermoablation treatment was administered to 22
BPH patients at two centers in the U.S. and Argentina using the Urologix Targis
targeted transurethral thermoablation system. Continuous temperature measurements
were made with widely spatially dispersed fiber optic thermosensors at 11 to 24
prostatic sites in each patient using a recently described accurate stereotactic
method. Urethral and rectal temperatures were also measured. RESULTS: Treatment
using the microwave thermoablation system resulted in marked elevation of
intraprostatic temperatures to as high as 80C in some patients with little or no
elevation of urethral or rectal temperatures. Average temperature increased with
radial distance from the urethra to a peak at 5 to 7 mm. and declined
exponentially at greater distances. Higher maximum intraprostatic temperatures in
individual patients were associated with a larger zone, up to 24.0 mm. in radius,
of prostatic tissue exposed to thermoablative temperatures of 45C and higher.
Along the longitudinal axis of the microwave treatment catheter, thermoablative
temperatures were confined to a zone of 11.5 mm. from the microwave antenna
midpoint apically and 11.3 mm. basally, that is, a range shorter than the length
of the treatment catheter's microwave antenna (2.8 to 3.5 cm.). The mean
temperature in the posterior sector of the prostate gland during treatment
(43.6C; 95% CI, 41.1 to 46.1C) was significantly lower (p < 0.05) by 6.7C than
that in the anterolateral prostate (50.3C; 95% CI, 48.3 to 52.3C), as a
consequence of the preferential heating design of the treatment catheter.
Intraprostatic mean temperature during treatment, as measured at all thermosensor
sites without respect to spatial location, was 47.1C (95% CI, 44.2 to 50.0C), a
value significantly higher (p < 0.05) than that measured in the urethra (39.6C;
95% CI, 36.6 to 42.6C) or rectum (37.7C; 95% CI, 36.7 to 38.7C). There was a
strong correlation between the temporal pattern of fluctuation in urethral
temperature and that of prostate temperature (r = 0.83; p < 0.001) during
treatment. CONCLUSIONS: Treatment with the microwave thermoablation system
fulfilled the requirements for an effective and safe microwave-based BPH
treatment modality by exposing obstructive tissue to high temperatures without
endangering vulnerable adjacent tissues.
PMID- 9400492
TI - Does topical instillation therapy influence chromosomal aberrations in
superficial bladder cancer?
AB - PURPOSE: Patients with a high risk for superficial bladder cancer are treated by
topical immuno-or chemotherapy after transurethral resection to reduce the chance
of recurrence and/or progression. The aim of this study was to analyse if
cytogenetical abnormalities, which are known to be constantly related to bladder
cancer, are modified or eliminated by topical immuno- or chemotherapy. MATERIALS
AND METHODS: Using fluorescence in situ hybridization (FISH), the influence of
topical instillation therapy with Bacillus Calmette-Guerin (BCG) and Mitomycin C
(MMC) on numerical aberrations of chromosomes 7, 9 and 17 was investigated in 25
patients with transitional cell cancer (TCC) of the bladder. Data were compared
with histological and clinical outcome. Fifteen TCC patients with similar
histological criteria without instillation therapy served as controls. Median
follow-up was 30 +/- 2 months. RESULTS: After BCG treatment 10 of 15 patients
(66.6%) developed recurrent and 2/15 (13.3%) progressive disease. Three of 15
patients (20.0%) had no evidence of disease. Numerical aberrations did not change
in 8 of the 15 BCG patients (53.3%) and changed to a more aggressive pattern in
40.0% (6/15). Five of 10 MMC treated patients (50.0%) developed a recurrent
tumor, 2/10 (20.0%) progressed and 3/10 (30.0%) had no evidence of disease. Four
of 10 (40.0%) of these patients showed stable and 5/10 (50.0%) progressive
chromosomal patterns. Only one patient in each group with primary chromosomal
alterations changed to a regular diploid chromosomal pattern after therapy
according to a complete clinical remission. CONCLUSION: Even though topical
immuno- and chemotherapy may be useful to delay recurrence and progression,
chromosomal patterns remain basically unstable.
PMID- 9400493
TI - Enhanced expression of the mesenchymal marker, vimentin, in hyperplastic versus
normal human prostatic epithelium.
AB - A total of 20 benign prostatic hyperplasia (BPH) tissue samples from 13 patients
were evaluated for the coexpression of cytokeratins and vimentin intermediate
filaments in the glandular epithelium. Vimentin expression was significantly
increased (p < 0.001) in BPH epithelium compared to adjacent "normal" epithelium.
The data imply that epithelial/mesenchymal (E/M) transformations may play a role
in the pathogenesis of BPH.
PMID- 9400494
TI - The effects of brefeldin A (BFA) on cell cycle progression involving the
modulation of the retinoblastoma protein (pRB) in PC-3 prostate cancer cells.
AB - PURPOSE: To investigate the effects of brefelding A (BFA) on the growth of the
androgen-independent human prostate cancer PC-3 cells, focusing on cell cycle
regulation. MATERIALS AND METHODS: BFA is a fungal macrocyclic lactone with an
antiviral activity. PC-3 cells were cultured with various concentrations of BFA
for indicated times and cell growth was monitored at each time point. Cell cycle
analysis was performed to explore the mechanism of BFA-induced growth inhibition.
To further investigate the cell cycle regulation, cell cycle-controlling factors,
such as the retinoblastoma gene product (pRB) and its regulatory components cdk2,
cdk4, and cyclin D1, were analyzed by Western immunoblots. RESULTS: BFA was a
potent growth inhibitor at a concentration of 30 ng./ml., resulting in a > 70%
reduction in cell number at 3 days. Cell cycle analysis revealed a cell arrest in
the G1 to S phase transition. Western blots further showed that BFA induced
dephosphorylation of pRB accompanied by down regulation of cdk2, cdk4, and cyclin
D1 expression. The extended pRB dephosphorylation in control cell lysates was
also observed by the addition of BFA-treated lysates, but was prevented by the
inclusion of phosphatase inhibitors in assay mixtures. CONCLUSION: These results
suggest that BFA may be a potent cell cycle modulator, which post-translationally
regulates pRB phosphorylation possibly by down-regulating cdk2, cdk4, and cyclin
D1 and/or by up-regulating a phosphatase(s) capable of dephosphorylating pRB.
Thus, BFA-induced growth inhibition in PC-3 cells appears to be at least
partially due to the modulation of a pRB-mediated growth pathway.
PMID- 9400495
TI - Polymerase chain reaction amplification of bacterial 16S rRNA genes in
interstitial cystitis and control patient bladder biopsies.
AB - PURPOSE: Several characteristics of the chronic bladder disease called
interstitial cystitis (IC) suggest an infectious etiology. However, a single
causative organism has not been convincingly cultured in vitro, and DNA for a
variety of microorganisms has been found inconsistently in bladder biopsies from
IC patients. We therefore looked for a possible bacterial cause for IC by using a
sensitive nested PCR assay on cystoscopic bladder biopsy specimens obtained from
IC patients and controls. MATERIALS AND METHODS: Bladder biopsies were obtained
at cystoscopy from 6 IC patients and 6 controls. DNA was extracted from these
specimens and PCR with 2-round amplification performed using nested primers from
a highly conserved region of the bacterial 16s rRNA gene. Amplified DNA was
purified and sequenced using the Sequenase PCR Product Sequencing Kit, and the
sequences obtained were compared with bacterial rRNA gene sequences recorded in
GenBank. RESULTS: Biopsy specimens from all 6 patients and 6 controls were
positive by PCR for DNA encoding bacterial 16s rRNA. Sequence data indicated a
predominant microorganism in 10 of the 12 specimens, with > 95% homology to DNA
from several different genera of bacteria including Acinetobacter,
Propionobacterium, Salmonella, and Escherichia. None of the organisms identified
by PCR had been cultured from tissue or urine obtained simultaneously from these
persons, using sensitive culture techniques. CONCLUSIONS: These data indicate no
difference between IC patients and controls in the proportion of bladder biopsies
with PCR positivity or the type(s) of organism present, providing additional
evidence that IC is not associated with infection by a particular type of
bacterium.
PMID- 9400496
TI - Autologous transplantation of urothelium into demucosalized gastrointestinal
segments: evidence for epithelialization and differentiation of in vitro expanded
and transplanted urothelial cells.
AB - PURPOSE: Our study established a technique for in vitro expansion and subsequent
transplantation of autologous urothelial cells into vascularized seromuscular
segments from stomach and colon in sheep. The proof of proliferation and
differentiation of the transplanted urothelium in the absence of resident
urothelium is considered to be a prerequisite for use of this technique in
bladder augmentation. MATERIALS AND METHODS: Autologous sheep urothelial cells
were expanded in vitro and grown on collagen membranes for sheet grafting. Using
a vital stain, viability and confluency status of the urothelial graft were
determined before transplantation into demucosalized segments isolated from the
sheep stomach and colon gastrointestinal pouches. The gastrointestinal segments
were sewn up and remained in the abdomen as small pouches stiched to the
abdominal wall. Take and differentiation of transplanted cells within the pouch
were assessed two and three weeks later using histological and immunohistological
means. RESULTS: Urothelial cells grew well on collagen membranes. A confluency
status > 40% and co-culturing with 3T3 feeder cells favored successful
transplantation. Two weeks after transplantation a multilayered urothelial-like
epithelium was found to line the lumen of the pouch. The epithelium was
characterized by a distinct urothelium-typical distribution of basal and luminal
keratins and the expression of the umbrella cell-specific marker uroplakin III.
Moreover, the epithelium had an underlying basal lamina which focally contained
collagen type IV. CONCLUSIONS: The data indicate that in vitro expanded
urothelial cells are capable of epithelializing demucosalized gastrointestinal
segments forming a genuine, differentiated "neo" urothelium.
PMID- 9400497
TI - Expression of transforming growth factor alpha and epidermal growth factor
receptor in adult polycystic kidney disease.
AB - Adult polycystic kidney disease (APKD) is a common genetic disease with a
frequency of 1:1000. Evidence suggests that transforming growth factor alpha (TGF
alpha) signaling may contribute to the hyperproliferation of the cystic epithelia
in APKD. TGF alpha and epidermal growth factor (EGF) are well known mitogens
expressed in the kidney and both exert their biological activities through
binding to the same EGF receptor. A transgenic mouse that over-expressed TGF
alpha developed renal cysts; raised levels of TGF alpha and EGF receptor mRNA
were found in kidneys from two autosomal dominant APKD patients. To study the
role of TGF alpha in cyst formation, we analyzed nine anatomically diagnosed
adult polycystic kidneys and four normal kidneys using immunohistochemistry. We
also traced the possible origins of the cysts by staining with the proximal
convoluted tubule (PCT) marker, gp330, and the distal convoluted tubule (DCT) and
collecting tubule (CT) marker, peanut agglutinin (PNA). In normal kidneys, TGF
alpha protein was concentrated in the DCT and CT and EGF receptor protein in all
three tubule types. In the early cysts of APKD, the cystic epithelia showed
strong positive staining with TGF alpha, EGF receptor and gp330 but negative with
PNA. Strong TGF alpha and EGF receptor staining was also found in the mixture of
advanced cysts in the end-stage cystic kidneys although the cysts are likely to
be derived from different segment of the renal tubules. This increased TGF alpha
and EGF receptor expression in all cases and all types of cysts suggests that
autocrine/paracrine stimulation by TGF alpha may be a common mechanism in cyst
development in APKD.
PMID- 9400498
TI - Prostate-specific antigen forms complexes with human alpha 2-macroglobulin and
binds to the alpha 2-macroglobulin receptor/LDL receptor-related protein.
AB - PURPOSE: To investigate the binding of the prostate-specific antigen (PSA) to
human alpha 2-macroglobulin (alpha 2-M) and to alpha 1-antichymotrypsin (ACT).
MATERIALS AND METHODS: Binding analysis was evaluated by electrophoresis, Western
blotting, enzyme-linked immunosorption assay (ELISA) and size exclusion
chromatography. Quantification of PSA and of different forms of alpha 2-M was
performed using commercial test kits. The cleavage site of PSA in alpha 2-M was
analyzed by SDS-PAGE and microsequencing. RESULTS: Binding of PSA to alpha 2-M is
initiated by the cleavage of the peptide bond between amino acids Tyr 686 and Glu
687 of the bait region indicating a chymotrypsin-like activity of the PSA. The
PSA's proteolytic cleavage triggers the transformation of alpha 2-M as detected
by conformation-specific monoclonal antibodies. Kinetic analysis revealed faster
binding of PSA to alpha 2-M than to ACT. The PSA bound to alpha 2-M is caged by
the inhibitor and thus escapes detection by antibodies. This results in an
incorrect calculation of the level of PSA when released from prostate into the
blood. Complexes of PSA-alpha 2-M and PSA-ACT were found to bind to the alpha 2
macroglobulin receptor/LDL receptor-related protein (alpha 2-M-R/LRP) which may
be the clearance receptor for PSA. CONCLUSIONS: Quantifying free PSA and PSA-ACT
complexes, as routinely done in managing prostate-associated diseases, does not
represent the total secretion capacity of the prostate. The proteinase inhibitor
alpha 2-M has to be considered as a main contributor to PSA complex formation in
the blood.
PMID- 9400499
TI - Patient-reported impotence and incontinence after nerve-sparing radical
prostatectomy.
PMID- 9400500
TI - Endoluminal sonographic evaluation of ureteral and renal pelvic neoplasms.
PMID- 9400501
TI - Mysterious, unseen, and quite possibly unpleasant.
PMID- 9400502
TI - Recommendations on folate intake.
PMID- 9400503
TI - Counselling in primary care.
PMID- 9400504
TI - Vancomycin-resistant Staphylococcus aureus: apocalypse now?
PMID- 9400506
TI - Half-way at Kyoto--but to where?
PMID- 9400505
TI - European perspectives on general medicine.
PMID- 9400507
TI - Communicating drug-safety information.
PMID- 9400508
TI - Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults:
meta-analysis of individual data. Sarcoma Meta-analysis Collaboration.
AB - BACKGROUND: Individually, randomised trials have not shown conclusively whether
adjuvant chemotherapy benefits adult patients with localised resectable soft
tissue sarcoma. METHODS: A quantitative meta-analysis of updated data from
individual patients from all available randomised trials was carried out to
assess whether adjuvant chemotherapy improves overall survival, recurrence-free
survival, and local and distant recurrence-free intervals (RFI) and whether
chemotherapy is differentially effective in patients defined by age, sex, disease
status at randomisation, disease site, histology, grade, tumour size, extent of
resection, and use of radiotherapy. FINDINGS: 1568 patients from 14 trials of
doxorubicin-based adjuvant chemotherapy were included (median follow-up 9.4
years). Hazard ratios of 0.73 (95% CI 0.56-0.94, p = 0.016) for local RFI, 0.70
(0.57-0.85, p = 0.0003) for distant RFI, and 0.75 (0.64-0.87, p = 0.0001) for
overall recurrence-free survival, correspond to absolute benefits from adjuvant
chemotherapy of 6% (95% CI 1-10), 10% (5-15), and 10% (5-15), respectively, at 10
years. For overall survival the hazard ratio of 0.89 (0.76-1.03) was not
significant (p = 0.12), but represents an absolute benefit of 4% (1-9) at 10
years. These results were not affected by prespecified changes in the groups of
patients analysed. There was no consistent evidence that the relative effect of
adjuvant chemotherapy differed for any subgroup of patients for any endpoint.
However, the best evidence of an effect of adjuvant chemotherapy for survival was
seen in patients with sarcomas of the extremities. INTERPRETATION: The meta
analysis provides evidence that adjuvant doxorubicin-based chemotherapy
significantly improves the time to local and distant recurrence and overall
recurrence-free survival. There is a trend towards improved overall survival.
PMID- 9400509
TI - Human herpesvirus 8 variants in sarcoid tissues.
AB - BACKGROUND: The cause of sarcoidosis is unknown, although mycobacteria have been
implicated. We examined sarcoid tissues for human herpesvirus 8 (HHV-8) in
addition to mycobacterial genomic sequences. METHODS: Biopsy samples from 17
patients with sarcoidosis were studied (eight transbronchial, 27 lymph node, two
skin, and two oral mucosa). We used tissues (n = 137) from 96 patients without
sarcoidosis as negative controls. A nested PCR was applied to amplify a segment
of open reading frame (ORF) 26 of the HHV-8 genome, and a heminested PCR was to
amplify a segment of ORF 25 of HHV-8 and of the 16 S rRNA gene of mycobacteria.
Differences in base sequences of the amplified fragments were resolved with
single-strand conformation polymorphism and dideoxy sequencing. FINDINGS: HHV-8
ORF 26 DNA was detected in significantly higher proportions of sarcoid than of
non-sarcoid tissue samples from lung (8/8 vs 0/54; p < 0.0001), lymph nodes
(26/27 vs 6/29; p < 0.0001), skin (2/2 vs 0/17; p = 0.006), and oral tissues (2/2
vs 1/13; p = 0.029). 31 (82%) of the 38 ORF 26 DNA-positive sarcoid specimens
were also positive for ORF 25 DNA. For mycobacteria-like 16 S rRNA DNA, the
proportion positive was significantly higher in sarcoid than non-sarcoid tissues
for lymph node samples (11/27 vs 2/29; p = 0.003) but not for other tissues (lung
3/8 vs 22/54; skin 2/2 vs 15/17; and oral tissues 1/2 vs 0/13). Overall, the
prevalence of HHV-8 ORF 26 sequences was higher in sarcoid tissues than in non
sarcoid tissues (p < 0.0001). When patients whose tissues were included in a
masked phase of the study were treated as units of analysis, eight of eight
sarcoidosis patients were positive for HHV-8 ORF 26 DNA, compared with three of
56 control patients (p < 0.0001); for mycobacteria-like sequences, three of eight
sarcoidosis patients were positive, compared with four of 56 controls (p =
0.0464). The HHV-8 ORF 26 sequences, ten of which were unique, could be
segregated into four groups according to peptide motifs. In seven of nine
patients from whom biopsy samples were taken from various sites, different
sequences were recovered. The mycobacterial sequences amplified from sarcoid
tissues were also varied, but none was homologous to those of known species.
INTERPRETATION: Variant HHV-8 DNA sequences are found in a wide range of sarcoid
but not non-sarcoid tissues. Mycobacteria-like 16 S rRNA sequences are more
frequently present in sarcoid lymph nodes and not in other tissue types, but do
not indicate infection by a particular mycobacterial species.
PMID- 9400510
TI - Randomised controlled assessment of non-directive psychotherapy versus routine
general-practitioner care.
AB - BACKGROUND: We compared the efficacy of and patients' satisfaction with general
practice-based psychotherapists with those of general practitioners in providing
treatment to people with emotional difficulties. METHODS: We carried out a
prospective, randomised, controlled trial of brief, non-directive psychotherapy
and routine general-practice care. Therapists adhered to a non-directive Rogerian
model of psychotherapy. Between one and 12 sessions of psychotherapy were given
over 12 weeks in 14 general practices in north London, UK. Of 136 patients with
emotional difficulties, mainly depression, 70 patients were randomly assigned to
the therapist and 66 to the general practitioner. Depression, anxiety, other
mental-disorder symptoms, and social adjustment were measured by self-report at
baseline, 3 months, and 9 months. Patients' satisfaction was also measured by
self-report at 3 and 9 months. FINDINGS: All patients improved significantly over
time. There were no significant differences between the groups receiving brief
psychotherapy and routine general-practitioner care. Patients assigned brief
psychotherapy were more satisfied with the help they received than those assigned
to the general practitioner at both 3 and 9 months' follow-up (mean scores on
satisfaction scale 50.9 [SD 7.9] vs 44.4 [9.8] and 45.6 [9.4] vs 37.1 [11.2],
respectively). INTERPRETATION: General-practitioner care is as effective as brief
psychotherapy for patients usually referred by doctors to practice-based
psychotherapists. Patients with emotional difficulties prefer brief psychotherapy
from a counsellor to care from their general practitioner.
PMID- 9400511
TI - Minimum effective dose of folic acid for food fortification to prevent neural
tube defects.
AB - BACKGROUND: Although a daily supplement of 400 micrograms folic acid has been
shown to prevent neural-tube defects (NTD), most women do not take the
recommended supplement. Thus, food fortification is to be introduced in the USA
and is being considered in the UK. Because of safety concerns, the USA has chosen
a level of fortification that will increase the average woman's intake by only
100 micrograms. Such an increase, although safe, may be ineffective; but a trial
to assess its efficacy would be unethical. Because women with red-cell folate
concentrations above 400 micrograms/L have a very low risk of NTD, we undertook a
randomised trial of several folic acid doses to find out how much is needed to
reach this protective concentration. METHODS: We screened 323 women. 172 with red
cell folate between 150 micrograms/L and 400 micrograms/L were invited to take
part in the trial. 121 women were randomly assigned placebo or 100 micrograms,
200 micrograms, or 400 micrograms daily of additional folic acid. Compliance was
monitored by having the women sign a dated sheet when taking the tablet. 95 women
completed the 6-month study. FINDINGS: There were significant increases in red
cell folate in all folic acid groups. The placebo group showed no significant
change. The median incremental changes and median post-treatment concentrations
were 67 micrograms/L (95% CI 43-120) and 375 micrograms/L (354-444) in the 100
micrograms/day group, 130 micrograms/L (108-184) and 475 micrograms/L (432-503)
in the 200 micrograms/day group, and 200 micrograms/L (125-312) and 571
micrograms/L (481-654) in the 400 micrograms/day group. INTERPRETATION: A
fortification programme that delivered 400 micrograms folic acid daily to women
would protect against NTD, but at the expense of unnecessarily high exposure for
many people. Delivery of 200 micrograms daily is also effective against NTD and
safer for the general population. Based on projections from the positive folate
balance in the group that received 100 micrograms daily, this dose taken
continually, as it will be in fortified food, will also produce an important
decrease in NTD.
PMID- 9400512
TI - Dissemination in Japanese hospitals of strains of Staphylococcus aureus
heterogeneously resistant to vancomycin.
AB - BACKGROUND: Since the discovery of the vancomycin-resistant Staphylococcus aureus
(VRSA) strain Mu50 (minimum inhibitory concentration [MIC] 8 mg/L), there has
been concern about the potential spread of such strains throughout Japanese
hospitals. Two important questions need to be answered: (1) what is the
prevalence of VRSA, and (2) by what mechanism does vancomycin resistance occur.
METHODS: The vancomycin susceptibilities of three methicillin-resistant S aureus
(MRSA) strains (Mu50, Mu3, and H1) and the methicillin-susceptible S aureus type
strain FDA209P were compared by MIC determinations and population analysis. Mu3
(MIC 3 mg/L) was isolated from the sputum of a patient with pneumonia after
surgery who had failed vancomycin therapy. H1 (MIC 2 mg/L), which is a
representative vancomycin-susceptible MRSA strain, was isolated from a patient
with pneumonia who responded favourably to vancomycin therapy. Subclones of Mu3
with increased resistance against vancomycin were selected with serial
concentrations of vancomycin and their MICs were determined. The prevalence of
VRSA and Mu3-like strains in Japanese hospitals was estimated by population
analysis from 1149 clinical MRSA isolates obtained from 203 hospitals throughout
Japan. The genetic traits of the Mu3 and Mu50 strains were compared with
clonotypes of MRSA from around the world. FINDINGS: Mu3 and Mu50 had an identical
pulsed-field gel electrophoresis banding pattern. When grown in a drug-free
medium, Mu3 produced subpopulation of cells with varying degrees of vancomycin
resistance, thus demonstrating natural heterogeneity, or variability, in
susceptibility to vancomycin. In the presence of vancomycin, Mu3 produced
subclones with resistance roughly proportional to the concentrations of
vancomycin used. Selection of Mu3 with 8 mg/L or more of vancomycin gave rise to
subclones with vancomycin resistance equal to that of Mu50 (MIC 8 mg/L) at a
frequency of 1/1,000,000. During screening of Japanese MRSA strains, no strain of
VRSA additional to Mu50 was found. The prevalence of MRSA isolates
heterogeneously resistant to vancomycin was 20% in Juntendo University Hospital,
9.3% in the other seven university hospitals, and 1.3% in non-university
hospitals or clinics. INTERPRETATION: Heterogeneously resistant VRSA is a
preliminary stage that allows development into VRSA upon exposure to vancomycin.
Heterogeneously resistant VRSA was found in hospitals throughout Japan. This
finding could explain, at least partly, the frequent therapeutic failure of MRSA
infection with vancomycin in Japan.
PMID- 9400513
TI - Fever, haematuria, proteinuria, and a parrot.
PMID- 9400514
TI - Stimulation of subthalamic nucleus alleviates tremor in Parkinson's disease.
PMID- 9400515
TI - Chronic stimulation of subthalamic nucleus improves levodopa-induced dyskinesias
in Parkinson's disease.
PMID- 9400516
TI - Fever associated with intravenous antibiotics in adults with cystic fibrosis.
PMID- 9400517
TI - Vocal cord haematoma after thrombolysis.
PMID- 9400518
TI - Spherocytosis, splenectomy, strokes, and heat attacks.
PMID- 9400519
TI - Sweat electrolyte concentrations in children with atopic dermatitis.
PMID- 9400520
TI - Synovial sarcoma of bone delineated by spectral karyotyping.
PMID- 9400522
TI - Field trial of a rapid card test for Wuchereria bancrofti.
PMID- 9400521
TI - Non-cardiovascular disease mortality and diabetes mellitus.
PMID- 9400523
TI - Exhaled nitric oxide during lung transplantation.
PMID- 9400525
TI - HIV epidemic could number 40 million by year 2000.
PMID- 9400524
TI - Penile rigidity in erectile dysfunction treated with alprostadil.
PMID- 9400526
TI - Trial to reduce vertical transmission of HIV-1 on schedule in Uganda.
PMID- 9400528
TI - Final Krever report paints picture of regulatory dysfunction.
PMID- 9400527
TI - Salt and hypertension: consensus or controversy?
PMID- 9400529
TI - Irritable bowel syndrome.
PMID- 9400530
TI - Development of a malaria vaccine.
AB - Development of an effective malaria vaccine poses a major scientific challenge
both in the laboratory and in the field. Such a vaccine is necessary because of
the massive disease burden of malaria in the developing world, the global spread
of drug resistance, and the difficulty of sustainable control of the mosquito
vector. Animal models have shown the immunological feasibility of vaccines
targeted against different stages of parasite development, and studies in human
volunteers have shown that a recombinant protein vaccine can protect against
challenge with the homologous strain of parasite. However, both natural and
vaccine-induced immunity are hampered by the remarkable capacity of the parasites
to vary critical antigenic structures; large field trials of a synthetic peptide
vaccine gave equivocal results. In an attempt to overcome the dual difficulty of
poor immunogenicity and parasite diversity, much experimental work is now focused
on complex antigenic constructs, delivered as DNA vaccines or in live vectors
such as vaccinia, with multiple targets at each stage of parasite development.
PMID- 9400531
TI - Modest salt restriction in older people.
PMID- 9400532
TI - Modest salt restriction in older people.
PMID- 9400533
TI - Modest salt restriction in older people.
PMID- 9400534
TI - New-variant Creutzfeldt-Jakob disease and treatment of haemophilia. Executive
Committee of the UKHCDO. United Kingdom Haemophilia Centre Directors'
Organisation.
PMID- 9400535
TI - Hormone replacement therapy and biological aggressiveness of breast cancer.
PMID- 9400536
TI - Ventricular remodelling in dilated cardiomyopathy.
PMID- 9400537
TI - Ventricular remodelling in dilated cardiomyopathy.
PMID- 9400538
TI - Ventricular remodelling in dilated cardiomyopathy.
PMID- 9400539
TI - Meningococcal vaccine in sub-Saharan Africa.
PMID- 9400540
TI - Meningococcal vaccine in sub-Saharan Africa.
PMID- 9400541
TI - Meningococcal vaccine in sub-Saharan Africa.
PMID- 9400542
TI - Meningococcal vaccine in sub-Saharan Africa.
PMID- 9400543
TI - Sickle-cell disease.
PMID- 9400544
TI - Continuing increase in invasive methicillin-resistant infection.
PMID- 9400545
TI - End-of-life decisions in Dutch paediatric practice.
PMID- 9400546
TI - Sex and examination results.
PMID- 9400547
TI - Sex and examination results.
PMID- 9400548
TI - Quality of essential drugs.
PMID- 9400549
TI - Terathanasia or teratothanasia?
PMID- 9400550
TI - The association of antihypertensive agents with MRI white matter findings and
with Modified Mini-Mental State Examination in older adults.
AB - OBJECTIVES: To examine the association of antihypertensive regimen with magnetic
resonance imaging (MRI) white matter hyperintensity and with cognitive impairment
in older adults. DESIGN: Cross-sectional study. SETTING: The Cardiovascular
Health study, an observational prospective cohort study of risk factors for
coronary heart disease and stroke in men and women 65 years of age and older.
PARTICIPANTS: 1268 men and women with pharmacologically treated hypertension.
MEASUREMENTS: Information on medication use, medical history, and health habits
was collected at clinic examinations. Participants completed the Modified Mini
Mental State Examination (3MS) and underwent MRI examination. Without clinical
information, study neuroradiologists assigned an overall grade of white matter
signal intensity on MRI on a scale from 0 (no findings) to 9 (extensive
findings). RESULTS: Adjusted mean white matter grade was higher for users of
calcium channel blockers (2.59, P = .007) and users of loop diuretics (2.60, P =
.015) than for users of beta blockers (2.12). The association was present for
both dihydropyridine and non-dihydropyridine calcium channel blockers. Adjusted
mean 3MS scores were lower for users of calcium channel blockers (89.6, P <
.002), especially dihydropyridines, and users of loop diuretics (89.7, P < .006)
than for users of beta blockers (92.3). No statistically significant association
could be shown for users of other drug regimens, including thiazides and ACE
inhibitors. CONCLUSION: In this study, users of antihypertensive regimens which
included calcium channel blockers or loop diuretics had more severe white matter
hyperintensity on MRI and worse performance on 3MS than users of beta blockers.
PMID- 9400551
TI - Cerebral white matter changes (leukoaraiosis), stroke, and gait disturbance.
AB - OBJECTIVES: Leukoaraiosis, a radiological change of cerebral white matter thought
to be caused by ischemia, is associated with gait disturbance. However, because
of concomitant stroke and cerebral atrophy, the clinical relevance of
leukoaraiosis is uncertain. We, therefore, sought to determine if leukoaraiosis
is a predictor of gait disturbance after accounting for cerebral atrophy and
stroke in patients with a high prevalence of cerebrovascular disease. DESIGN:
Cross-sectional observational study. SETTING: Neurology service (inpatient and
outpatient) of a Department of Veterans Affairs Hospital. PARTICIPANTS:
Consecutive sample of 130 patients, 127 men and three women. MEASUREMENTS: The
findings of a gait scale were correlated to vascular risk factors, neurological
examination as quantified by the NIH stroke scale and supplemental motor scale,
and to brain CT findings. Brain CT scans were rated for leukoaraiosis, cerebral
infarction, and cerebral atrophy. RESULTS: Gait disturbance was more frequent and
more severe in subjects with leukoaraiosis, of whom 31% had mild and 49%
moderate/severe gait disturbance compared with 27% with mild and 12% with
moderate/severe gait disturbance in subjects without leukoaraiosis (P < .001).
Leukoaraiosis, cerebral atrophy, a history of multiple strokes, and weakness and
ataxia of the legs were independent predictors of gait disturbance. The
proportion and severity of leukoaraiosis increased with increasing gait
disturbance in subgroups without leg deficit (P < .001) and without multiple
strokes (P < .001), but no association with leukoaraiosis was shown in patients
with leg deficit or a history of multiple strokes (P = .037 and P = .186,
respectively). Gait disturbance was more severe when both leukoaraiosis and
cerebral atrophy were present (P = .019). CONCLUSION: In our Veteran population,
leukoaraiosis is an independent predictor of gait disturbance after accounting
for stroke and cerebral atrophy. Although leukoaraiosis is a form of
cerebrovascular disease, it appears to be most closely associated to gait
disturbance in the absence of symptomatic stroke or leg deficit.
PMID- 9400552
TI - Physical activity and the changes in maximal isometric strength in men and women
from the age of 75 to 80 years.
AB - OBJECTIVE: To research the natural changes in maximal isometric strength, over a
period of 5 years, in men and women aged 75 at baseline, and to study the effect
of everyday physical activity on strength alterations. DESIGN: A 5-year
longitudinal study. SETTING: Exercise laboratory. PARTICIPANTS: The target group
in 1989 was the total 75-year-old population of Jyvaskyla. One hundred one men
(81%) and 186 women (75%) participated in baseline strength tests, and after 5
years, 55 men and 111 women (70% and 72% of the survivors) took part in the
follow-up measurements. METHODS: Maximal isometric hand grip, arm flexion, knee
extension, trunk flexion, and trunk extension forces were measured using
dynamometers. Self-rated physical activity was recorded using a scale by Grimby
(1986). Strength changes were compared between groups based on the amount of
everyday physical activity: (1) remained active (AA, 24 men, 24 women); (2)
remained sedentary (SS, 11 men, 43 women); (3) decreased activity (AS, 11 women);
and (4) increased activity (SA, 32 women). AS and SA could be formed for women
only because of the small number of men. All analyses were stratified by gender.
MAIN RESULTS: The average percentage change in strength over 5 years among
survivors varied from a 4% increase in knee extension strength observed in men
and women to a 16% decrease in grip strength in women. The grip strength decrease
was greater in women than men. The AA men maintained their trunk extension
strength at a higher level than the SS men. Time by group interactions in men
were not significant. In women, the rate of decline in AS was 32% in grip and 27%
in elbow flexion strength, which was greater than in the other activity groups.
The AA women retained their knee extension strength at a higher level than the
other groups. Those who died before follow-up tests exhibited poorer strength
test results at baseline. Physical activity decreased over follow-up.
CONCLUSIONS: Strength alterations with age differed between muscle groups.
Undertaking everyday physical activities such as household work, walking, and
gardening, which are also the most common physically demanding activities of
older people, may play an important role in maintaining strength at an adequate
level for independent living.
PMID- 9400553
TI - Effects of age, physical training, and physical fitness on coronary heart disease
risk factors in older track athletes at twenty-year follow-up.
AB - OBJECTIVE: To compare current coronary heart disease (CHD) risk factor values in
older athletes with mid-life measures and to examine the associations between
changes in CHD risk factors with aging, physical training, and physical fitness.
DESIGN: Prospective study with three longitudinal evaluation points: initial
(T1), 10-year (T2), and 20-year (T3). Subjects were selected because of their
elite status in Masters track competition. SETTING: University and medical center
laboratories. PARTICIPANTS: Participants were 60 to 92 years of age and included
21 of the initial 27 subjects. At T3, subjects were divided into three groups,
based on physical activity levels: high intensity (H), remained elite in national
and international competition (n = 9); moderate intensity (M) continued frequent
rigorous endurance training but rarely competed (n = 10); and low intensity (L)
greatly reduced their training volume and intensity (n = 2). MEASUREMENTS:
Smoking history; family history of coronary or cerebrovascular disease; resting
blood pressure; resting electrocardiogram (ECG); serum total cholesterol, plasma
glucose; body weight, % body fat, body mass index, waist:hip ratio; training pace
and mileage; maximal oxygen consumption VO2 max). MAIN RESULTS: Several risk
factors (smoking, diabetes, obesity) were never present, and the prevalence of
other risk factors (family history of cardiovascular disease, abnormal resting
ECG) remained low through T3 (< or = 14% of subjects). Mean systolic and
diastolic blood pressure remained low without medication, but diastolic blood
pressure measurements had the greatest redistribution between evaluation periods
of any risk factor (r = .16, P = .479, T1 to T2). Mean total cholesterol was
lower at T2 (-13%, P = .005) and T3 (-14%, P = .019) compared with T1. Change in
VO2 max was correlated with changes in body weight (r = -.44, P = .048) and % fat
(r = -.52, P = .015) from T1 to T2, whereas age was correlated to changes in
systolic blood pressure (r = -.61, P = .003) and total cholesterol (r = -.49, P =
.023) from T2 to T3. CONCLUSIONS: The prevalence of CHD risk factors remained
low, and mean risk factor values remained low and generally stable in older
athletes who had maintained habitual exercise training.
PMID- 9400554
TI - Hypokalemia and potassium excretion in stroke patients.
AB - OBJECTIVES: To determine (1) the prevalence of hypokalemia (plasma potassium < or
= 3.4 mmol/L) in a group of stroke patients in comparison with age- and sex
matched groups of patients having sustained a myocardial infarction or having
mild hypertension and (2) the association between plasma potassium concentration
and stroke outcome. DESIGN: Observational study. PARTICIPANTS: A total of 421
consecutive stroke patients admitted to a teaching hospital, 150 consecutive
patients 50 years or older with myocardial infarction admitted to the hospitals
Coronary Care Unit, and 161 out-patients 60 years or older with borderline and
established hypertension. MEASUREMENTS: All stroke and cardiac patients had
plasma urea and electrolytes estimated within 2 hours of hospital admission; in
the hypertensive group blood samples were taken in clinic. Stroke patients had
blood pressure, stroke severity (Barthel score) and smoking status recorded. A
sub-group of 61 stroke patients and all 79 hypertensive patients not taking
antihypertensive medication had 24-hour urine electrolyte excretion measured.
Outcome (independent, dependent, or dead) at 3 months post-stroke was established
in 349 patients. RESULTS: Hypokalemia occurred more frequently in stroke patients
than in patients with myocardial infarction (84 (20%) vs 15 (10%), P = .008) or
patients with hypertension (84 (20%) vs 13 (8%), P < .001), even when patients
taking diuretics were excluded from analysis (56 (19%) vs 12 (9%) of cardiac
group, P = .014 and 56 (19%) vs 4 (5%) of hypertensive group, P = .005,
respectively). 24-hour urine excretion of potassium and the potassium:creatinine
ratio was lower in stroke patients than in hypertensive patients (41 +/- 21 vs 62
+/- 25 mmol/24 hour, P = .001, 5.5 +/- 2.2 vs 7.4 +/- 2.6 mmol/24 hour, P = .001,
respectively). On survival analysis, a lower plasma potassium on admission to
hospital was associated with an increased chance of death, independent of age,
stroke severity, history of hypertension, blood pressure level, or smoking
history (hazard ratio 1.73 (95% CI: 1.03-2.9) for a 1 mmol/L lower plasma
potassium concentration). CONCLUSIONS: Hypokalemia post stroke is common and may
be associated with a poor outcome.
PMID- 9400555
TI - The effect of specific medical conditions on functional decline.
AB - OBJECTIVES: To examine how functional status among older community-dwelling
residents differs over time between those with and those without specific medical
conditions. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 1060
community-dwelling Massachusetts residents aged 65 or older who were not totally
functionally dependent at baseline assessment. MEASUREMENTS: Functional status,
five medical conditions (heart problem, arthritis, diabetes, cancer, and stroke),
and the total number of these five medical conditions. Assessments were done at
baseline and at two annual follow-ups. RESULTS: Adjusted repeated measures
analysis of covariance revealed a time difference (P < .001) for all five medical
conditions and group differences for diabetes (P = .006) and stroke (P < .001).
Functional abilities declined over time and those with specific medical
conditions were more impaired initially, but the rate of decline did not
significantly differ from those free of the condition. The presence of each
additional medical condition resulted in additional impairment (P < .001), but
the rate of decline over time did not differ by number of medical conditions.
CONCLUSIONS: Efforts to reduce or prevent the development of specific medical
conditions are essential to maintaining functional independence of older people
as well as to reducing use of supportive services and admission rates to nursing
homes. Particular attention should be directed toward preventing stroke since its
consequences are the most functionally disabling.
PMID- 9400556
TI - The synergy of low lung function and low body mass index predicting all-cause
mortality among older Japanese-American men.
AB - OBJECTIVE: To assess the joint characteristics of low standardized weight and
compromised pulmonary function in predicting all-cause mortality. DESIGN: A
population-based, prospective cohort study. SETTING: Oahu Island, Hawaii.
PARTICIPANTS: Surviving Japanese-American men of the Honolulu Heart Program
cohort, 71 to 93 years of age (N = 3059). MEASUREMENTS: Body mass index (BMI
weight in kilograms/square of height in meters) and 1-second forced expiratory
volume (FEV1) as a percentage of age- and height-predicted FEV1 from the 1991 to
1993 examination of the cohort. Mortality data derived from the ongoing tracking
of deaths of the cohort. Relations of selected risk factors among joint levels of
BMI (< or = 21, > 21 to < 25, > or = 25 kg/m2) and percent predicted FEV1 (< or =
70%, > 70%) were determined. The impact of these covariates on relations between
joint BMI/percent predicted FEV1 levels and subsequent all-cause mortality was
assessed. RESULTS: The highest age-adjusted mortality rate (91.9 deaths per 1000
person-years) was noted among men characterized by the joint conditions of
percent predicted FEV1 < or = 70% and BMI < or = 21 kg/m2. This rate was 4.0
times the mortality rate of a "healthy" reference group characterized by percent
predicted FEV1 > 70% and 21 < BMI < 25 kg/m2. This rate ratio is attenuated to
3.2 upon statistical control for measures of current and past smoking behavior.
Among the three strata of BMI, statistical interaction is reflected in a
heterogeneity of mortality rate differences (49.7, 21.8, -9.6 deaths/person-year,
respectively) and rate ratios (2.18, 1.98, .66, respectively) comparing men with
percent predicted FEV1 < or = 70% to > 70%. CONCLUSION: Joint loss of pulmonary
function and relative weight is predictive of subsequent all-cause mortality in
excess of additive or multiplicative effects of each condition separately.
Smoking behavior may contribute to this observation.
PMID- 9400557
TI - Mortality over four years in SHEP participants with a low ankle-arm index.
AB - OBJECTIVES: To assess the risk of total and cardiovascular mortality in older
adults with systolic hypertension and with a low ankle-arm index (AAI) as a
marker of subclinical peripheral arterial disease (PAD). DESIGN: Prospective
observational study PARTICIPANTS: A subgroup of 1537 participants in the Systolic
Hypertension in the Elderly Program (SHEP) were screened for lower extremity
arterial disease using the AAI. Participants were evaluated at 4 years to
determine vital status and cause of death. Total and cardiovascular disease (CVD)
mortality rates were assessed in relationship to clinical CVD at baseline,
cardiovascular risk factors and the presence of a low AAI (subclinical PAD).
RESULTS: Total mortality rates increased as the AAI decreased in those with and
without clinical CVD at baseline. In those without clinical CVD at baseline, the
presence of an AAI < or = .9 was associated with an age-adjusted relative risk
(RR) of 3.00 for total mortality in men and 2.67 in women. Results were similar
for CVD mortality and persisted after adjustment for cardiovascular risk factors
including the presence of an abnormal electrocardiogram. CONCLUSIONS: A low ankle
arm-index predicted a two to three-fold increase in total and cardiovascular
mortality in older adults with systolic hypertension of risk for incident
cardiovascular disease. In this study of older adults with systolic hypertension,
19.7% of the participants had subclinical PAD. Risk factor modification could be
targeted to older adults based on markers of asymptomatic atherosclerosis.
PMID- 9400558
TI - The impact of kyphosis on daily functioning.
AB - OBJECTIVES: To determine whether moderate or severe kyphosis is associated with
decrements in physical function, especially mobility. DESIGN: Cross-sectional
analysis of a cohort study. SETTING: The Johns Hopkins Functional Status
Laboratory, a multidisciplinary, standardized, quantitative assessment center.
PARTICIPANTS: A total of 231 community-dwelling volunteers aged 59 and older who
participated in a 1-day evaluation. MEASUREMENTS: Age, gender, self report of
physical function, standardized measurement of: kyphosis (both qualitatively
clinical criteria and quantitative assessment), time to walk 5 meters (0.1
seconds), and time to climb a flight of stairs (0.1 seconds) at usual pace.
RESULTS: Using multivariate step-wise regression analysis, the presence and
severity of kyphosis, measured qualitatively, was independently associated with
time to walk 5 meters and to climb a flight of stairs (P = .015, P < .001,
respectively), adjusting for moderate-severe scoliosis, heart rate response to
exercise, arthritis, vertigo, age, and gender. Similarly, quantitative kyphosis
was associated independently with stair climb time (P = .005). Qualitative
kyphosis was also associated with difficulty reaching (OR = 2.21 (95% CI: 1.14 to
4.29)) and difficulty performing heavy housework (OR = 1.64 (95% CI: 1.03 to
2.61)), adjusting for prior diagnosis of moderate-severe scoliosis, prior
diagnosis of arthritis, age, and gender. CONCLUSION: Kyphosis, by both clinical
and quantitative assessment, is associated with diminished function, especially
performance of mobility tasks. This association should be verified prospectively.
If predictive, the impact of kyphosis on physical function should be considered
in osteoporosis prevention and treatment counseling.
PMID- 9400559
TI - Differences in psychosocial and health correlates of major and minor depression
in medically ill older adults.
AB - OBJECTIVES: To compare the differences in correlates of different levels of
depression in medically ill hospitalized older adults. DESIGN, SETTING, AND
PARTICIPANTS: A consecutive series of 542 patients aged 60 or older admitted to
the medical inpatient services of Duke Hospital underwent a structured
psychiatric evaluation administered by a psychiatrist. MEASUREMENT: A wide range
of demographic, social, psychiatric, and physical health data were collected, and
associations with major and minor depression were assessed. RESULTS: Compared
with patients without depression, those with major depression were more likely to
have a history of prior episodes of depression, higher dysfunctional attitude
scores, greater overall severity of medical illness, cognitive impairment, and
symptoms of pain or other somatic complaints. Specific medical diagnosis was less
important a predictor of major depression than overall severity of medical
illness. Compared with patients without depression, those with minor depression
were more likely to report non-health-related stressors during the year before
hospital admission, have a diagnosis of immune system disorder, and have greater
severity of medical illness. When major and minor depression were compared
directly, on the other hand, no significant differences were observed except for
history of depression, and that relationship was weak and present only when the
etiologic approach to diagnosis was used. CONCLUSION: During hospital admission,
certain psychosocial, psychiatric, and physical health characteristics of older
medical patients place them at high risk for different levels of depression.
Patients with major and minor depression resemble each other more than they do
patients without depression. These findings may help clinicians better understand
the causes of different types of depression in this setting and lead to improved
diagnosis and treatment.
PMID- 9400560
TI - Older women and hormone replacement therapy: factors influencing late life
initiation.
AB - OBJECTIVE: To describe factors associated with initiation of hormone replacement
therapy (HRT) by older women. DESIGN: A cross-sectional study of 671 randomly
selected women aged 65 to 80 who participated in a larger telephone survey on
preventive health behaviors. SETTING: A large health maintenance organization
(HMO) in Seattle, Washington. PARTICIPANTS: Of the 521 women who responded (78%),
51 had begun taking HRT at age 60 or older and were identified as initiators.
Women who had never used HRT or past users who had begun HRT before age 60 were
classified as noninitiators (n = 362). Current users who started HRT before age
60 (n = 108) were excluded. MEASUREMENTS: Sources included the telephone survey,
automated HMO pharmacy data, and HMO utilization and provider databases. RESULTS:
Initiators were similar to noninitiators with respect to age, marital status,
education, and health status. Initiators were more likely to have had a
hysterectomy at age 60 or later than noninitiators. Sixty-two percent of the non
initiators said they had received no information about the benefits of HRT from
their providers compared with 18% of initiators. HRT initiation was associated
with belief in prevention benefits of HRT for fractures and cardiovascular
disease and with reported encouragement from the physician to use HRT.
CONCLUSIONS: Other than hysterectomy status, there were few sociodemographic or
health characteristics that markedly distinguished older initiators from
noninitiators. Our findings show the importance of physician counseling in an
older woman's decision to initiate HRT.
PMID- 9400561
TI - Antidepressant use over time in a rural older adult population: the MoVIES
Project.
AB - OBJECTIVE: To examine the use of antidepressant drugs over time among community
based older persons. DESIGN: A longitudinal community study with four
approximately biennial data collection waves (1987-1996). SETTING: A low
socioeconomic status rural older community-based population in Southwestern
Pennsylvania. PARTICIPANTS: A total of 1681 individuals with a mean age of 72.9
years at study entry, MEASUREMENTS: Antidepressant drug use, demographics, and
health services utilization by self-report. RESULTS: Antidepressant use was
reported by less than 5% of the population during all four waves. It was
associated with female gender, use of mental health services, presence of five or
more depressive symptoms, and use of five or more prescription drugs, but not
with age. During the four waves, tricyclics accounted for 84.6%, 85.3%, 78.4%,
and 45.5% of total antidepressants used, whereas selective serotonin reuptake
inhibitors (SSRIs) accounted for 2.6%, 11.8%, 8.1%, and 36.4%. CONCLUSIONS:
Overall, our data on antidepressant use in this rural older population mirror
national trends away from tricyclics and towards SSRIs. Our findings also suggest
underutilization of mental health services and antidepressant drugs in this
population.
PMID- 9400562
TI - Preserved antilipolytic insulin action is associated with a less atherogenic
plasma lipid profile in healthy centenarians.
AB - OBJECTIVE: Recent studies have demonstrated that centenarians have a preserved
glucose tolerance and insulin action and a more favorable body composition and
fat distribution than aged subjects. The strong relationship among glucose
tolerance, insulin action, plasma lipid concentration, and lipoprotein metabolism
would lead to the hypothesis that healthy centenarians may also have a less
atherogenic profile than aged subjects less than 100 years old. DESIGN:
Investigation of the relationship between insulin action and lipid metabolism in
healthy centenarians. PARTICIPANTS: Fifty-six subjects were categorized into
three groups: Adults (< or = 50 years old; n = 20); Aged (> or = 75 years old; n
= 22); Centenarians (> or = 100 years old; n = 14). The latter represented a
select group of individuals free of major age-related diseases. MEASUREMENTS:
Anthropometric measurements were made in all subjects, fasting blood samples were
drawn for metabolite determinations, and an euglycemic glucose clamp was
performed. RESULTS: Compared with aged subjects, healthy centenarians appeared to
have a less atherogenic plasma lipid profile. Fasting plasma LDL cholesterol (2.4
+/- 0.6 vs 3.7 +/- .6 mmol/L P < .010) was significantly higher in aged subjects
than in centenarians, whereas fasting plasma HDL cholesterol (1.0 +/- 0.4 vs 1.7
+/- .4 mmol/L P < .005) had an opposite trend. In centenarians, insulin-mediated
glucose uptake was greater (34.6 +/- 0.5 vs 23.3 +/- .05 mumol/Kg FFM x min P <
.010) than in aged subjects and correlated with fasting plasma triglycerides,
FFA, LDL, and HDL cholesterol, Apo B, and Apo A1 concentrations. Finally, insulin
infusion suppressed plasma FFA concentration in similar ways in adults and
centenarians. CONCLUSION: Our study demonstrates that centenarians have a less
atherogenic plasma lipid and lipoprotein profile than aged subjects.
PMID- 9400563
TI - Development and validation of a clinical prediction rule for prolonged nursing
home residence after hip fracture.
AB - OBJECTIVES: To develop and validate a clinical prediction rule for nursing home
residence 6 months after a hip fracture. DESIGN: Two prospective cohort studies,
a development study (DS) and a validation study (VS). SETTING: The DS included
hip fracture patients admitted to 92 rehabilitation units or skilled nursing
facilities; the VS included hip fracture patients from 11 integrated healthcare
systems. PARTICIPANTS: A total of 344 community-dwelling hip fracture patients
aged 65 and older participated in the DS; 239 similar patients were enrolled in
the VS. INTERVENTION: None. MEASUREMENTS: The acute hospital record, nursing
evaluations, and patient questionnaires provided information about demographics,
physical and neuropsychological function, and comorbidity. Residence 6 months
after fracture was determined by phone interview. Multivariate analysis
identified predictors for a risk score to assess the likelihood of nursing home
residence. RESULTS: 18.7% of patients in the DS resided in nursing homes 6 months
after hip fracture. The four independent risk factors for institutionalization
were (1) being unmarried (OR = 6.7 [95% CI 2.4 to 19]), (2) incontinence (OR =
2.3 [CI 1.2 to 4.7]), (3) dependence in ambulation (OR = 5.0 [CI 2.1 to 12.3]),
and (4) cognitive impairment (OR = 6.6 [CI 3.3 to 13.2]). Of patients with all
four risk factors, 73.2% were institutionalized at 6 months, compared with 0% of
patients with no risk factors. In the VS, 6.1% of patients resided in nursing
homes after 6 months, with a range from 50.0% of patients with four risk factors
to 0% of those with no risk factors. Areas under receiver-operating
characteristic curves for the prediction rule were 0.84 +/- .03 in the DS, and
0.81 +/- .06 in the VS. CONCLUSION: A clinical prediction rule using four easily
measurable characteristics can identify individuals at high or low risk of
nursing home residence 6 months after hip fracture.
PMID- 9400564
TI - Geropsychiatric restraint use.
AB - OBJECTIVES: To investigate predictors and reasons for restraint use with
geropsychiatric patients. DESIGN: A prospective, correlational study. SETTING:
The geriatric unit of an acute-care psychiatric hospital. PARTICIPANTS: Twenty
one staff nurses and 131 patients admitted consecutively over a period of 6
months. MEASUREMENTS: Disruptive behaviors were measured with the Nursing Home
Behavior Problem Scale (NHBPS), cognitive function was measured with the Mini
Mental State Examination (MMSE), mobility was measured with a Functional Mobility
Screen (FMS), and reasons for restraint use were obtained with a questionnaire
completed by nurses. RESULTS: Patients with a diagnosis of dementia, impaired
mobility, or behavioral problems were more likely to be restrained. The most
frequent reasons given by staff for restraint use were an unsteady gait and a
risk of falling. The incidence of restraint use was 27.1%. CONCLUSIONS: The use
of restraint with geropsychiatric patients may be more common than previously
reported and requires further investigation.
PMID- 9400565
TI - Health care for older persons, a country profile: Italy.
PMID- 9400566
TI - A model for nurse case-managed home care using televideo.
PMID- 9400567
TI - Antihypertensive drugs, brain structure, and cognitive function: more research is
necessary.
PMID- 9400568
TI - High tech comes to high touch.
PMID- 9400569
TI - Do older individuals need more than usual physical activities to maintain muscle
strength and function?
PMID- 9400570
TI - Apolipoprotein E level in cerebrospinal fluid increases with aging.
PMID- 9400571
TI - Increased oxidative damage in lymphocytes of Alzheimer's disease patients.
PMID- 9400572
TI - Renal failure in older people: a preventable hospital admission and ageism in
decision making.
PMID- 9400574
TI - Size and structure of the thyroid in old age.
PMID- 9400573
TI - Nutrition and immunity in older people.
PMID- 9400575
TI - Squalor syndrome.
PMID- 9400576
TI - Interviewing adolescents.
AB - Incorporating a functional approach within the traditional structure of the
medical interview allows for improved communication with adolescent patients.
Using these techniques results in improved patient satisfaction, more accurate
psychosocial diagnosis, and better adherence to treatment recommendations. Many
physicians think that using patient-centered interviewing techniques is time
consuming and inefficient, but, in fact, a higher quality and quantity of
information usually is obtained per unit time using these techniques. An
additional benefit is that this approach is more satisfying for the physician;
the enhancement of the therapeutic relationship works both ways. Adolescents
become more interesting as people; communication barriers become challenges to be
creatively solved rather than annoyances to complain about. Adolescents need and
deserve high-quality health care to grow into physically and mentally healthy
adults, and effective physician-patient communication skills are the key to
delivering that care.
PMID- 9400577
TI - Integrating comprehensive adolescent preventive services into routine medicine
care. Rationale and approaches.
AB - Relying on therapeutic interventions to address health problems after they occur
has proven costly and does not address the need to reduce the number of youth who
develop these health problems. Primary care physicians have an important role to
play in promoting adolescent health through a strategy of providing health
guidance to adolescents and parents, screening, and promoting immunizations.
Reducing the health risk behaviors of adolescents is a challenge that is best
accomplished with the support of other preventive initiatives. Clinical
preventive services should complement and reinforce preventive efforts in schools
(i.e., comprehensive school health programs) and communities (i.e., mass media
campaigns and health regulations). GAPS recommendations developed by the AMA and
recommendations from other groups provide a model for organizing the content and
delivery of comprehensive preventive services for adolescents. Physicians and
other primary care health providers may use these recommendations to expand the
quantity and quality of preventive services they offer to adolescents. Additional
information about preventive services and GAPS, including a complete list of the
recommendations, dates for future GAPS training, a description of the materials
developed to help implement preventive services, other national efforts in
adolescent preventive services, and current articles in scientific literature,
can be reviewed on the AMA web site (http:/(/)www.AMA-Assn.Org/Adolhlth/Adolhlth+
++.htm).
PMID- 9400578
TI - The pediatrician and the sexually active adolescent. Sexual activity and
contraception.
AB - Sexuality and its resultant consequences continue to be major issues for
adolescents and for those who provide their health care. This article discusses
current sexual behavior in adolescents and describes the various forms of
hormonal contraception that sexually active adolescents should use.
PMID- 9400579
TI - The pediatrician and the sexually active adolescent. Treatment of common
menstrual disorders.
AB - Menstrual disorders in adolescents are a common medical problem. For young
adolescents, the onset of menses is a time of dramatic physical and psychological
change. Providing education to young women regarding the normal process of
puberty helps ease some of the anxiety regarding this change. Health
professionals can participate in the education of young women by defining the
normal process of puberty and menstruation. Menstrual disorders, such as
dysmenorrhea, irregularities in menstrual flow, and premenstrual symptoms, can be
effectively diagnosed and treated in the adolescent population.
PMID- 9400581
TI - Office approach to drug abuse prevention.
AB - The onset of tobacco, alcohol, and other drug use generally occurs during
adolescence. While many teens experiment with these substances, a significant
number use them to the point that their behavior interferes with school, family,
social relationships, and general productivity. It is the pediatrician's
responsibility to identify young people who are at risk for the subsequent use of
these substances and initiate a carefully designed prevention program in the
office setting.
PMID- 9400580
TI - The pediatrician and the sexually active adolescent. A primer for sexually
transmitted diseases.
AB - Sexual activity is a common practice among young adolescents, placing them at
high risk for STDs, many of which have long-term consequences. Early diagnosis
and treatment are essential to limit both the consequences and the spread of
these infections. The clinician has a responsibility to the adolescent patient to
recognize and treat these diseases. Using history and physical examination, the
clinician should be able to determine an adolescent's risk for an STD, and, based
on this risk, undertake the appropriate evaluations. Patient treatment, follow
up, and management of sex partners are then guided by the results of either
presumptive or definitive diagnostic tests.
PMID- 9400582
TI - The rebellious adolescent. Evaluation and management of oppositional and conduct
disorders.
AB - A wide variety of management options are available to the primary care physician
who is presented with a rebellious adolescent. After a careful assessment, the
clinician and other health care professionals can choose a diverse combination of
interventions: individual therapy, family therapy, youth-centered programs,
community-centered programs, psychopharmacology, and others. Rebellious
adolescents need access to comprehensive medical and mental health care, academic
education (including sexuality education), and full employment opportunities.
Primary care physicians can play a vital and sometimes pivotal role coordinating
services and helping parents, school personnel, and therapists work with these
youth. Even when dealing with the very difficult and resistant group of youth
with CD and ODD, optimism for improvement should always be maintained by the
clinician.
PMID- 9400583
TI - Juvenile mood disorders and office psychopharmacology.
AB - Mood disorders afflict pediatric patients, cause significant impairment, and
interfere with normal development. Increasingly, pediatricians are called on to
assess and collaborate with mental health practitioners in medicating children
and adolescents with mood disorders. Approaching the juvenile with a primary
emphasis on clarifying the diagnoses, determining environmental antecedents and
sequelae, and investigating suicide risk enables the pediatrician to institute
appropriate treatment. Despite limited data from controlled studies,
psychotherapy often is used for mild to moderate depression. Pharmacotherapy is
indicated in cases unresponsive to psychotherapy and in severe or suicidal cases.
First-line pharmacotherapy for depressed adolescents is usually an SRI followed
by the atypical or TCA antidepressants. Bipolar disorder typically requires an
aggressive medication regimen, including anticonvulsants, lithium, or a
combination, as well as environmental modifications. With severe, difficult, or
refractory cases, mental health consultation is recommended to clarify diagnoses
and to provide psychotherapy and medication input.
PMID- 9400584
TI - Acne. What every pediatrician should know about treatment.
AB - Acne is one of the most common and easily treated diseases of adolescents.
Scarring can be prevented in most cases with early and vigorous treatment. But
such treatment requires patience, skill, and a commitment to good counseling.
PMID- 9400585
TI - The preparticipation sports examination.
AB - Although not a comprehensive health evaluation, the PSE is viewed as such by many
parents and adolescents. In this regard, these athletes are getting a lower
standard of care than recommended; however, the mechanism wherein the PSE can
become a cost-effective comprehensive examination has not been established. The
PSE is one method of injury prevention in that it is designed to identify medical
conditions that would be worsened by participation in exercise and sports.
Pediatricians should use this examination as a quality control point during the
year to assess how medical conditions and musculoskeletal injuries have been
diagnosed and managed in the context of sports.
PMID- 9400586
TI - What every pediatrician should know about infectious mononucleosis in
adolescents.
AB - Infectious mononucleosis (IM) is one of the most common diseases occurring during
adolescence. Appreciation of IM's varied clinical presentations, its differential
diagnosis, and the difficulties involved in making the laboratory diagnosis will
enable clinicians to treat teenagers more effectively in their office practices.
PMID- 9400587
TI - Psychosomatic problems and stress in adolescence.
AB - Psychosomatic problems are common in adolescents, and stress frequently plays a
role in their development and maintenance. Armed with an understanding of the
stressors experienced by adolescents, the individual's vulnerabilities and
competencies and their level of social support, the physician can systematically
assess each of these factors. Once the assessment is complete, a management plan
can be formulated to address the particular psychosomatic problem. Symptom
relief, stress reduction, and promotion of competence are important interventions
that can be initiated by the primary care physician. When referrals are made for
counseling and other stress management techniques, the primary care physician
should maintain contact with the patient and family and remain an integral part
of the management team. Incorporating brief discussions about the potential role
of stress in health and illness into anticipatory guidance sessions may also help
prevent the development of psychosomatic problems in adolescents.
PMID- 9400588
TI - Evaluation of hematuria, proteinuria, and hypertension in adolescents.
AB - Signs or symptoms of renal disease in adolescents deserve prompt attention and
appropriate evaluation. Adolescents are susceptible to a variety of urinary tract
disorders. The key issue in the evaluation of hematuria or proteinuria in
adolescents is the existence of concomitant signs of renal disease. For isolated
hematuria or proteinuria, demonstration of persistence and a reasoned evaluation
are in order. Hypertension in adolescents must be carefully documented and, when
present, considered seriously. The fact that most teens with persistent elevated
blood pressures have essential hypertension is still a great concern because for
most of these adolescents the hypertension will be lifelong and, if left
untreated, can be associated with significant morbidity and mortality in the
adult years.
PMID- 9400589
TI - Common cardiac diseases in adolescents.
AB - Adolescent patients frequently present with symptoms potentially referable to the
cardiovascular system; however, patients rarely have true cardiovascular disease.
In many patients, the history is the key to determining whether additional
testing or referral is necessary. Even though the history, physical examination,
and preliminary laboratory data may indicate a benign cause, occasionally a
referral to a cardiologist is necessary because of patient or parental anxiety.
Patients with true cardiac pathology should be followed by a cardiologist in
conjunction with the primary care physician.
PMID- 9400590
TI - Immunity to rotavirus in T cell deficient mice.
AB - Rotavirus infection was studied in adult nude mice (BALB/c background), alpha
beta or gamma delta and alpha beta/gamma delta T cell receptor (TCR) knockout (-/
) mice (C57BL/6 and C57BL/6 x 129 backgrounds), and SCID mice (C57BL/6
background). The gamma delta TCR -/- mice cleared infection just like control
mice. All of the nude mice, alpha beta, and alpha beta/gamma delta TCR -/- mice
cleared primary rotavirus infection, with a short delay, compared to
immunocompetent control mice and developed a rotavirus-specific intestinal IgA
measured by ELISA. Elispot analysis with spleen and lamina propia cells showed
that the virus-specific intestinal IgA response in immunocompetent C57BL/6 mice
was similar to the gamma delta TCR -/- mice and 7- to 60-fold higher than in the
alpha beta TCR -/- and alpha beta/gamma delta TCR -/- mice. Likewise, the
response of nude +/- mice was 20 times greater than that of nude -/- littermates.
While the intestinal IgA antibodies of C57BL/6 mice, gamma delta TCR -/- mice,
and nude +/- mice recognized insect cells infected with recombinant baculovirus
expressing rotavirus VP6 and VP4 proteins, those of the alpha beta TCR -/-, alpha
beta/gamma delta TCR -/-, and nude -/- mice recognized only VP6. Immunocompetent
C57BL/6 mice depleted of CD4+ T cell developed similar levels of rotavirus
specific intestinal IgA as the alpha beta TCR -/- mice, suggesting that this T
cell-independent IgA response is present in normal mice. In contrast to
previously published results with BALB/c SCID and RAG 2 -/- (C57BL/6 x 129
background) mice, all of which become chronically infected with murine rotavirus,
40% of the C57BL/6 SCID mice cleared primary rotavirus infection. These results
suggest that both a T cell-independent antibody response and innate mechanisms
can contribute to immunity to murine rotavirus and show that gamma delta T cells
are not necessary for efficient clearance of primary rotavirus infection in mice.
PMID- 9400591
TI - Apoptosis of CD4+ and CD19+ cells during human immunodeficiency virus type 1
infection--correlation with clinical progression, viral load, and loss of humoral
immunity.
AB - Enhanced rates of programmed cell death (apoptosis) have been detected in T cells
and B cells from human immunodeficiency virus type 1 (HIV-1)-infected
individuals. To evaluate the possible relevance of this event to HIV pathogenesis
and disease progression, apoptosis in CD4+ T lymphocytes and CD19+ B lymphocytes,
viral load, and neutralizing antibody titers were assayed in HIV-1-infected slow
progressors and progressors. A correlation was found between progressive disease
and apoptosis of CD4+ T cells. The extent of apoptosis in CD4+ cells was similar
in slow progressors and seronegative control subjects. By contrast, we found
elevated levels of B-cell apoptosis in all HIV-1-infected individuals compared
with seronegative control subjects, with a tendency toward increased levels of
apoptosis with progressive disease. Apoptosis in CD4+ T cells and CD19+ B cells
correlated with viral RNA levels in plasma. Furthermore, higher rates of B-cell
apoptosis were observed in individuals with poor neutralizing activity against a
panel of six clinical HIV-1 isolates. From these results we conclude that the
extent of apoptosis in cultured CD4+ cells and CD19+ cells appears to parallel
the decline in CD4 cell counts in infected individuals. The finding of a relation
between apoptosis in B cells and poor neutralizing capacity suggests that
apoptosis may be related to loss of immune function. A role for apoptosis in the
pathogenesis of AIDS is also supported by the strong correlation between viral
load and rates of apoptosis in CD4+ T cells.
PMID- 9400592
TI - Interferon-gamma protects against herpes simplex virus type 1-mediated neuronal
death.
AB - Host inflammatory mediators, such as interferons, play a protective role in
infection, but the mechanism is undefined and may differ between tissue
compartments. To determine whether interferon-gamma (IFN-gamma) elicitation
prevents destructive encephalitis in herpes simplex virus type 1 (HSV-1)
infection of the central nervous system, IFN-gamma-knockout (GKO) mice were
challenged intravitreally with HSV-1 strain F, inciting infection of the eyes and
the brain. Indeed, the GKO mice showed encephalitis with ataxia, whereas
nontransgenic controls remained asymptomatic. Morphology and digoxigenin labeling
of DNA fragments revealed increased apoptosis in the brains of GKO mice compared
with controls, although viral replication was not influenced at early stages of
infection. Greater numbers of apoptotic cells in the brains of GKO mice
correlated with neurological symptoms, as well as lower expression of the
protective protooncogene bcl-2. Thus, IFN-gamma inhibits apoptosis, affording
neuronal protection from destructive encephalitis during viral infection of the
central nervous system.
PMID- 9400593
TI - Host range and cytopathogenicity of the highly attenuated MVA strain of vaccinia
virus: propagation and generation of recombinant viruses in a nonhuman mammalian
cell line.
AB - Modified vaccinia virus Ankara (MVA), attenuated by over 500 passages in primary
chick embryo fibroblasts (CEF), is presently being used as a safe expression
vector. We compared the host ranges of MVA and the parental Ankara strain in CEF
and 15 permanent cell lines. The cells could be grouped into three categories:
permissive, semipermissive, and nonpermissive. For MVA, the permissive category
consisted of primary CEF, a quail cell line derived from QT6, and the Syrian
hamster cell line BHK-21. Only in BHK-21 cells did the virus yield approach that
occurring in primary CEF. The semipermissive category included two African green
monkey cell lines: BS-C-1 and CV-1. The nonpermissive category for MVA consisted
of three human cell lines HeLa, 293, and SW 839; one rhesus monkey cell line FRhK
4; two Chinese hamster cell lines CHO and CHL; one pig cell line PK(15); and
three rabbit cell lines RK13, RAB-9, and SIRC. The grouping for MVA with a
restored K1L host range gene was similar except for the inclusion of RK13 cells
among permissive lines. The grouping for the Ankara strain, however, was quite
different with more permissive and semipermissive cell lines. Nevertheless, in
cells that were permissive for MVA, the virus replicated to higher levels than
Ankara, consistent with both positive and negative growth elements associated
with the adaptation of MVA. The cell lines were also characterized according to
their susceptibility to MVA-induced cytopathic effects, expression of a late
promoter regulated reporter gene by an MVA recombinant, and stage at which virion
morphogenesis was blocked. Finally, the permissive BHK-21 cell line was shown to
be competent for constructing and propagating recombinant MVA, providing an
alternative to primary CEF.
PMID- 9400594
TI - Phylogenetic analysis of simian T-lymphotropic virus Type I (STLV-I) in common
chimpanzees (Pan troglodytes): evidence for interspecies transmission of the
virus between chimpanzees and humans in Central Africa.
AB - Serum and peripheral blood leukocytes from the chimpanzees (Pan troglodytes) of
the colony of the Laboratory of Central Nervous System Studies, National
Institute of Neurological Disorders and Stroke, NIH, were tested for the presence
of STLV-I-specific antibodies and proviral DNA. Antibodies were determined by
gelatin particle agglutination and Western blot (WB) assays utilizing HTLV-I
antigens. Proviral DNA was detected by four PCR assays targeting three different
regions of STLV-I genome: the fragments of the env and pol genes and LTR. Twenty
of twenty-two DNA samples from WB-positive animals were PCR positive. None of the
DNA samples from WB-negative (n = 5) and WB-indeterminate (n = 4) animals was PCR
positive. The results of the nested and double nested env PCR tests were fully
concordant; the seminested LTR PCR test was much less sensitive. The DNA
sequences from the env (483 bp) and the pol (200 bp) genes and LTR (705 bp) were
determined for six, two, and two chimpanzee STLV-I isolates, respectively.
Phylogenetic analysis revealed that chimpanzee STLV-I isolates can be attributed
to three clades. The first of these clades (SS-PTR1/CSA) included STLV-I isolates
from the chimpanzees and West African subspecies of African green monkeys
(Cercopithecus a. sabaeus). The other clades (S-PTR2 and S-PTR3) included STLV-I
isolates only from chimpanzees. However, both S-PTR2 and S-PTR3 clustered
together with Central African HTLV-I comprising the human/simian clade (HS
HSA/PTR). This pattern of phylogenetic clustering suggests that interspecies
transmission of STLV-I occurred between chimpanzees and African green monkey
subspecies as well between chimpanzees and human populations in Central Africa.
PMID- 9400595
TI - Interactions between Tat of HIV-2 and transcription factor Sp1.
AB - Tat of HIV-2 (Tat-2) requires host cellular factors for optimal function. We show
that transactivation by Tat-2 of the HIV promoter requires cis-acting binding
sites for Sp1 or Sp1 brought to the promoter via a heterologous system. We
demonstrate that an activation domain in Tat-2 consists of one of two potential
alpha-helices in the amino-terminal region, the cysteine-rich region, and the
core region and that this independent activation domain requires cis-acting Sp1
binding sites for function. Tat-2 interacts with Sp1 in in vitro binding assays,
and these interactions require basic residues outside of the Tat-2 activation
domain. The regions in Sp1 sufficient for functional synergy with Tat are the Sp1
activation domains, while the DNA-binding region is dispensable. Substitution
mutations of a glutamine-rich region in one Sp1 activation domain, which
eliminate interactions with a TBP-associated factor, also significantly decrease
synergy with Tat. Thus, the functional synergy between Tat-2 and Sp1 localizes to
domains in each activator that interact with components of the transcription
complex. We suggest that these interactions, rather than direct Tat/Sp1 binding,
result in highly processive RNA polymerase II complexes and full-length viral
transcripts.
PMID- 9400596
TI - Direct effect of type 1 human immunodeficiency virus (HIV-1) on intestinal
epithelial cell differentiation: relationship to HIV-1 enteropathy.
AB - Human immunodeficiency virus (HIV)-infected patients display severe impairments
of gastrointestinal functions, including diarrhea and malabsorption, even in the
absence of opportunistic infections. Since HIV-1 proteins and nucleic acids have
been detected in several cell types of the intestinal mucosa, it has been
postulated that HIV-1 itself could alter enterocytic functions. In the present
study, we analyzed the effect of HIV-1 on the differentiation process of the
epithelial intestinal cell clone HT-29-D4, which mimics the maturation of
enterocytes along the crypt-villus axis of the small intestine. We found that HIV
1 infection impairs cellular differentiation (i) by affecting the barrier
function of the epithelium, as evidenced by a decrease in the transepithelial
electrical resistance, and (ii) by inhibiting the activity of one major glucose
absorption function, i.e., sodium/glucose cotransport. At the morphological
level, HIV-1 infection of HT-29-D4 cells was associated with the formation of
lumina, which are representative of a defect in cellular organization. These
morphofunctional perturbations induced by HIV-1 could be mimicked by nocodazole,
a microtubule-disrupting agent. Correspondingly, HIV-1 exposure of HT-29-D4 cells
evoked a massive disruption of microtubules, as revealed by alpha-tubulin
indirect immunofluorescence staining. A similar effect was observed after
incubation of the cells with either recombinant gp120 or a monoclonal antibody
against galactosylceramide (GalCer), the intestinal receptor for HIV-1 gp120,
suggesting that the effect of HIV-1 was mediated by the binding of gp120 to
GalCer. Based on these data, we propose that HIV-1 may selectively alter
enterocytic functions through a direct effect on the intracellular architecture
of the cells. In contrast with previous theories for HIV-1 enteropathy, our data
support the concept that HIV-1 may perturb intestinal functions without
necessarily infecting intestinal epithelial cells.
PMID- 9400597
TI - Liquefaction of Autographa californica nucleopolyhedrovirus-infected insects is
dependent on the integrity of virus-encoded chitinase and cathepsin genes.
AB - We examined the role of the Autographa californica nucleopolyhedrovirus (AcMNPV)
encoded chitinase in virus pathogenesis in Trichoplusia ni larvae. In conjunction
with the AcMNPV-encoded cathepsin, it promotes liquefaction of the host in the
latter stages of infection. Insects infected with virus mutants lacking either
the chitinase A gene (chiA) or cathepsin gene (cath) remained intact several days
after death. However, if both viruses were used to infect insects, liquefaction
of the host was restored. Chitinase was readily detected in AcMNPV-infected
insects using a chitinase-specific antibody, but it was absent from insects
infected with a chiA deletion mutant (AcchiA-). The chitinase was also detected
in polyhedra purified from AcMNPV-infected insects but not in those from AcchiA-.
However, polyhedra derived from a virus lacking an intact chiA were no less
effective in initiating an infection in second instar T. ni larvae than those of
the unmodified AcMNPV. It was also demonstrated that the virus chitinase retained
high levels of activity between pH 3.0 and 10.0. In contrast, chitinases isolated
from Serratia marcescens, although active under acidic conditions, rapidly lost
activity above pH 7.0 illustrating that despite 57% sequence identity, the two
proteins have distinct enzymic activities.
PMID- 9400598
TI - Passage of HIV-1 molecular clones into different cell lines confers differential
sensitivity to neutralization.
AB - In this study, progeny viruses of four HIV-1 molecular clones were tested for
sensitivity to neutralization following prolonged passage in peripheral blood
mononuclear cells (PBMC) and MT-2, H9, and CEM T-lymphoid cell lines. Two of the
viruses were able to establish persistent infection with no cytopathic effect in
H9 and CEM cells. Such adaptation conferred increased sensitivity to
neutralization by a panel of human sera obtained from HIV-1-infected asymptomatic
individuals, by soluble CD4 and by monoclonal antibodies directed to a linear
epitope in the V3 region (268-D) and a conformational epitope in the CD4 binding
site of the envelope gp 120 (1.5e). Increased sensitivity to neutralization was
paralleled by increased binding of these mAbs to native envelope glycoproteins
and by increased binding capacity to CD4 expressed on the cell surface. Our
results show that virus-host cell interactions are important in influencing
sensitivity to neutralization of HIV-1. In primary PBMC or in cytopathic
interactions in cell lines, like in MT-2 cells, envelope epitopes important for
neutralization remain masked. In contrast, noncytopathic but productive virus
host cell interactions may lead to an increased exposure of neutralizing epitopes
and more efficient binding capacity to CD4 resulting in an increased sensitivity
to neutralization.
PMID- 9400599
TI - Mutations affecting the sensitivity of the influenza virus neuraminidase to 4
guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid.
AB - 4-Guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid (4-guanidino
Neu5Ac2en) specifically inhibits the influenza virus neuraminidase (NA) through
interaction of the guanidino group with conserved Glu 119 and Glu 227 residues in
the substrate binding pocket of the enzyme. To understand the mechanism by which
influenza viruses become resistant to 4-guanidino-Neu5Ac2en, we investigated
mutations at amino acid residues 119 and 227 in the influenza virus NA for their
effects on this compound and on NA activity. The NA gene was cloned from the NWS
G70c virus, and mutations were introduced at the codon for amino acid residue 119
or 227. All of the 13 mutants containing a change at residue 119 were transported
to the cell surface, although their expression levels ranged from 68.2 to 91.3%
of wild type. Mutant NAs that retained at least 20% of the wild-type enzymatic
activity were tested for their sensitivity to 4-guanidino-Neu5Ac2en and found to
be sevenfold less sensitive to this compound than was the wild-type NA. By
contrast, only 6 of 13 mutants defined by modifications at residue 227 were
transported to the cell surface, and those NAs lacked substantial enzymatic
activity (9% of wild type, at most). These results suggest that only a limited
number of resistant viruses arise through mutations at Glu 119 and Glu 227 under
selective pressure from 4-guanidino-Neu5Ac2en and that the development of
compounds which interact with 227 Glu more strongly than does 4-guanidino
Neu5Ac2en may reduce the likelihood of drug-resistant viruses still further.
PMID- 9400600
TI - Insights into the interaction between tRNA and primer binding site from
characterization of a unique HIV-1 virus which stably maintains dual PBS
complementary to tRNA(Gly) and tRNA(His).
AB - Previously our laboratory constructed an HIV-1 which stably maintained a primer
binding site (PBS) complementary to tRNA(His) by mutating the region of the
provirus within U5 postulated to interact with the anticodon of tRNA(His) (J.
Wakefield, S-M Kang, and C. D. Morrow, 1996, J. Virol, 70, 966-975). From the
analysis of the virus obtained after long-term culture, we identified an unusual
proviral DNA in which the U5-PBS region contained a dual PBS complementary to
tRNA(Gly) and tRNA(His), respectively, separated by a 21-nucleotide intervening
sequence. To determine if this U5-PBS region containing the dual PBS would give
rise to an infectious virus, the mutant U5-PBS containing the dual PBS was
subcloned into an infectious HIV-1 proviral clone, pHXB2; the resultant proviral
DNA was designated as pHXB2(Gly-His). Transfection of pHXB2(Gly-His) into cells
gave rise to infectious virus. Analysis of the U5-PBS region revealed that the
virus stably maintained the dual PBS rather than revert back to the wild-type
PBS. In addition to genomes with the PBS complementary to tRNA(Gly) and
tRNA(His), proviral genomes were identified after extended in vitro culture which
contained dual PBS complementary to tRNA(Gly) and tRNA(Phe). To determine which
PBS could be used for reverse transcription, we utilized an endogenous reverse
transcription/PCR method which could discriminate (based on molecular size of the
products) between the minus strand DNA initiated from the two PBSs. The results
of this assay demonstrated that either the PBS complementary to tRNA(Gly) or
tRNA(His) could be used for the initiation of reverse transcription. The results
of our study highlight the complex interrelationship between U5-PBS and primer
tRNA required for positioning the tRNA at the PBS and provides new insights into
how the tRNA primer used to initiate reverse transcription is selected.
PMID- 9400601
TI - A glycine to alanine substitution in the paramyxovirus SV5 fusion peptide
increases the initial rate of fusion.
AB - Simian virus 5 fusion (F) protein mutant F-G3A, which contains a glycine-to
alanine substitution at position 3 in the conserved hydrophobic fusion peptide at
the N-terminus of the F1 subunit, has been shown previously to cause increased
syncytium formation compared to wild-type (wt) F protein, when expressed using an
SV40 recombinant virus vector system (C. M. Horvath and R. A. Lamb (1992) J.
Virol. 66, 2443-2455). The wt F and the F-G3A proteins were expressed in
eukaryotic cells using the vaccinia virus-bacteriophage T7 RNA polymerase (vac
T7) expression system, and they showed similar cell surface expression levels as
determined by flow cytometry. The final extent of fusion when the vac-T7
expression system was used was not found to be greatly different when examined
with a reporter gene activation assay. However, the initial rate of fusion was
found to be five- to sixfold higher for the F-G3A mutant protein than the wt F
protein, when examined using a quantitative assay for lipid mixing based on
relief of self-quenching of fluorescence of the lipid probe octadecyl rhodamine
(R18). A microscopic fluorescent dye transfer assay also showed a much earlier
spread of dye from R18-labeled red blood cells to the cells expressing the mutant
F-G3A protein than the wt F protein. Thus, these data indicate that a single gly
to-ala mutation in the fusion peptide domain, although not affecting the final
extent of fusion, significantly increased the rate of fusion. Possible mechanisms
for the increased rate of fusion are discussed.
PMID- 9400602
TI - Analysis of a peptide inhibitor of paramyxovirus (NDV) fusion using biological
assays, NMR, and molecular modeling.
AB - To investigate the molecular mechanisms involved in paramyxovirus-induced cell
fusion, the function and structure of a peptide with a 20-amino-acid sequence
from the leucine zipper region (heptad repeat region 2) of the Newcastle disease
virus fusion protein (F) were characterized. A peptide with the sequence
ALDKLEESNSKLDKVNVKLT (amino acids 478-497 of the F protein) was found to inhibit
syncytia formation after virus infection and after transfection of Cos cells with
the HN (hemagglutinin-neuraminidase) and F protein cDNAs. Using an F protein gene
that requires addition of exogenous trypsin for cleavage, it was shown that the
peptide exerted its inhibitory effect prior to cleavage. The three-dimensional
conformation of the peptide in aqueous solution was determined through the use of
NMR and molecular modeling. Results showed that the peptide formed a helix with
properties between an alpha-helix and a 3(10)-helix and that leucine residues
aligned along one face of the helix. Side chain salt bridges and hydrogen bonds
likely contributed to the stability of the peptide secondary structure. Analysis
of the aqueous solution conformation of the peptide suggested mechanisms for
specificity of interaction with the intact F protein.
PMID- 9400603
TI - Interaction of endocytic signals from the HIV-1 envelope glycoprotein complex
with members of the adaptor medium chain family.
AB - The envelope glycoprotein (Env) complex of HIV-1 undergoes rapid internalization
from the plasma membrane of human cells by virtue of a tyrosine-based endocytic
signal (RQGYSPL, residues 704-710) in the cytosolic tail of the protein (J. F.
Rowell et al., J. Immunol. 155, 473-488, 1995). Here we demonstrate that this
tyrosine-based signal interacts with the mu 2 (medium) chain of the AP-2 clathrin
associated adaptor, a protein complex involved in endocytosis of cell surface
receptors. The same signal is also capable of interacting with two other members
of the adaptor medium chain family, mu 1 and mu 3A, which are components of the
AP-1 and AP-3 adaptor complexes, respectively. Interactions with mu 1 and mu 3A
might be responsible for the targeting of the internalized envelope glycoprotein
to lysosomes or to the basolateral plasma membrane of polarized epithelial cells.
A second potential tyrosine-based signal (LFSYHRL, residues 760-766) also
interacts with mu 1, mu 2, and mu 3A, although it is less important for
internalization in vivo probably due to its position within the cytosolic tail.
Overexpression of chimeric proteins having the HIV-1 Env cytosolic tail increases
expression of the transferrin receptor on the cell surface, probably due to
saturation of the cellular pool of mu 2 by the overexpressed proteins. These
observations suggest that HIV-1 Env utilizes the protein sorting machinery of the
host cells for internalization and sorting at various steps of the endocytic and
biosynthetic pathways.
PMID- 9400604
TI - Differential replication of ovine lentivirus in endothelial cells cultured from
different tissues.
AB - Blood-brain barrier dysfunction has been postulated to be important in the
pathogenesis of HIV dementia. This study used an in vitro model of the blood
brain barrier to determine the effects of ovine lentivirus (OvLV) infection on
endothelial cells. The replication of two American OvLV isolates and two
lcelandic OvLV isolates in pure cultures of endothelial cells isolated from brain
was compared to replication in endothelial cells from adipose, lung, and aorta.
Inoculation with the two American isolates resulted in 100 times greater reverse
transcriptase (RT) activity in supernatant of the microvascular endothelial cells
(brain, lung, and adipose) than in the macrovascular endothelial cells (aorta).
Conversely, inoculation with the two lcelandic isolates resulted in 100 times
higher RT activity in aortic, lung, and adipose endothelial cells than in the
brain endothelial cells. Transmission electron microscopy of the brain capillary
endothelial cells infected with the American isolates revealed polarized viral
budding from the lateral cell membrane and a loss of tight junctions. Replication
of OvLV in brain capillary endothelial cells could play a role in the
pathogenesis of lentiviral encephalitis by altering blood-brain barrier
integrity.
PMID- 9400605
TI - Efficacy of replication-defective adenovirus-vectored vaccines: protection
following intramuscular injection is linked to promoter efficiency in muscle
representative cells.
AB - To investigate the respective role of transduced cells in the induction of immune
response following intramuscular inoculation of adenovirus-based vaccines, we
generated several replication-defective adenoviruses expressing the glycoprotein
D gene of pseudorabies virus under the control of four different promoters: major
late promoter of adenovirus type 2, human cytomegalovirus immediate-early
promoter/enhancer (CMV), Rous sarcoma virus-long terminal repeat promoter, and
human desmin gene 5' regulatory region (DES). All the adenovirus constructs were
able to fully protect mice, in the contrary of direct DNA inoculation of plasmids
harboring the same transcription units. The far most effective adenovirus
constructs, on the criterion of protective doses and specific antibody response
induction, were those in which the foreign gene was driven by the DES or CMV
promoter. Wide variations in promoter strength in vitro were evidenced in several
cell culture types representative of putative target cells following muscular
inoculation (myoblasts, myotubes, fibroblasts, macrophages, and endothelial
cells). The level of efficacy in vivo, was not correlated with the level of
expression in vitro in myotubes, but paralleled the level of expression in
endothelial cells and in myoblasts. Together with previously published data,
these results suggest that, following adenovirus injection, locally produced
cytokines may induce myoblasts to act as local antigen presenting cells.
PMID- 9400606
TI - Serial in vivo passage of HIV-1 infection in Macaca nemestrina.
AB - In an earlier study we found that pigtailed macaques (Macaca nemestrina) that
were experimentally infected with human immunodeficiency virus type 1 (HIV-1)
initially became viremic and seroconverted, but HIV-1 replication diminished
markedly over time. In an attempt to develop a longer term pathogenic model,
blood from HIV-1-infected macaques was serially transfused into three groups of
naive macaques. Transfer was successful through two transfusions as shown by
repeated virus isolations and confirmed by the development of cell-free plasma
viremia and by seroconversion. Three to five weeks after transfusion, plasma
levels of HIV-1 RNA from several macaques in the first two groups exceeded those
of the initially inoculated macaques. However, animals in the third group had
diminished RNA levels, were virus culture negative, and did not seroconvert.
Sequence analyses of env-region clones from infected animals revealed only
minimal changes over the course of the passages. These results confirm HIV-1
replication in M. nemestrina during the acute phase of infection. However,
adaptation of HIV-1 to a macaque-pathogenic variant did not occur during serial
passage, possibly because the animals were able to restrict HIV-1 replication
below a level required for a pathogenic variant to emerge. Whether such
containment is a function of the host's immune response or a virus cell
incompatibility remains to be determined.
PMID- 9400607
TI - Epstein-Barr virus induces GM-CSF synthesis by monocytes: effect on EBV-induced
IL-1 and IL-1 receptor antagonist production in neutrophils.
AB - Neutrophils play an important role in the control of viral infections by
releasing a variety of potent agents. We previously demonstrated that Epstein
Barr virus (EBV) binds to human neutrophils and stimulates cytokine synthesis
including interleukin-1 (IL-1) and IL-1 receptor antagonist (IL-1Ra). Since
neutrophil functions are known to be modulated by the priming effect of
granulocyte-macrophage colony-stimulating factor (GM-CSF), we therefore
investigated the cellular source of GM-CSF synthesis following treatment of
leukocytes with EBV and the effect of GM-CSF on the production of IL-1, IL-1Ra,
and superoxide by EBV-treated neutrophils. In enriched-cell populations, only
monocytes were found to produce GM-CSF in response to EBV, which was maximal
after 12 h of incubation. The results obtained with UV-irradiated particles or
EBV neutralized with monoclonal antibody 72A1 suggest that contact between the
cell and the gp350 of the viral envelope is sufficient to induce the release of
GM-CSF. On the other hand, GM-CSF differentially upregulated EBV-induced IL-1 and
IL-1Ra production by neutrophils. Pretreatment of neutrophils with GM-CSF prior
to EBV activation synergistically enhanced the production of IL-1 alpha and IL-1
beta, but only marginally affected IL-1Ra synthesis. In addition, GM-CSF was also
found to synergistically enhance the superoxide production by neutrophils in
response to EBV. Molecular analysis showed that GM-CSF did not alter the IL-1
beta and IL-1Ra mRNA synthesis induced by EBV, suggesting that GM-CSF could act
at a posttranslational level. Local production of GM-CSF by monocytes in tissues
invaded by EBV could serve to potentiate the host defense mechanisms directed
toward the destruction of the infectious virus.
PMID- 9400608
TI - Nucleotide sequence and genomic organization of Acyrthosiphon pisum virus.
AB - The nucleotide sequence of the genomic RNA of Acyrthosiphon pisum virus was
determined. The APV genome is 10,016 nucleotides in length, excluding the 3'-end
poly(A) track, and contains two large open reading frames (ORFs), encoding
proteins of 296,340 and 63,279 Da. The ORF1 is preceded by an untranslated leader
sequence of 267 nucleotides. The ORF1 product contains sequence motifs
characteristic of RNA-dependent RNA polymerases, chymotrypsin-like proteases, and
helicases. Interviral sequence comparison revealed significant similarities with
viruses belonging to the so-called picornavirus superfamily. The ORF2 is most
likely expressed by a -1 translational frameshift and is followed by an
untranslated sequence of 222 nucleotides. Internal amino acid sequences of three
capsid proteins (66K, 34K, 23/24K) were determined. Comparison of the obtained
amino acid sequences with the APV sequence disclosed that the structural proteins
are located in the 3'-terminal half of the genome. The 34K protein is encoded by
the ORF1, while the 66K protein contains both ORF1-(34K) and ORF2-derived
sequences and is probably expressed by a translational frameshift. The 23/24K
proteins most likely arise by proteolytic breakdown of the 34K protein. Although
the deduced APV genomic organization in some aspects resembles that of the
picornaviruses, its overall genomic organization indicates that APV is a distinct
species only distantly related to the Picornaviridae.
PMID- 9400609
TI - Heterogeneity and common features of defective hepatitis B virus genomes derived
from spliced pregenomic RNA.
AB - Defective hepatitis B virus (HBV) genomes derived from packaging and reverse
transcription of spliced RNA pregenomes were reported to be associated with
progression to chronic infection. Since only two types with similarly spliced
regions were characterized so far we reasoned that additional "spliced" genome
variants may exist. Therefore, we isolated a large number of defective HBV
genomes from sera of seven chronic carriers by full-length PCR. Forty-eight were
found to contain deletions caused by splicing as identified by cloning,
subgenomic PCR, and sequencing. In total, 11 types of spliced genomes derived
from excision of 10 different introns were present in various combinations in
each serum. This diversity resulted from alternative usage of five splice donor
and four acceptor sites present in most but not all HBV genotypes. All spliced
genomes shared sequence elements essential for replication as well as for
transcription of the pre-C and pregenome/C mRNAs and the X mRNA. Moreover, all
contained the coding regions for the X protein and for precore/core or precore/
core fusion proteins but lacked the pre-S/S gene promoters. These data
demonstrate substantial and HBV genotype-dependent diversity of spliced genomes
from which a variety of aberrant precore/core fusion proteins and normal X
protein but no functional envelope and P proteins could be expressed. These
genomes and the encoded proteins may play a role in the viral life cycle,
persistence, and pathogenesis.
PMID- 9400610
TI - Negative regulation of a heterologous promoter by human cytomegalovirus immediate
early protein IE2.
AB - The HCMV IE2 protein promiscuously activates transcription of many viral and
cellular genes. IE2 also negatively autoregulates its own expression by binding
to a strategically positioned IE2 binding site, called CRS, located immediately
downstream of the TATA box of the HCMV major IE promoter. Here we show that IE2
is able to repress transcription driven by a heterologous promoter, RSV LTR.
Repression of RSV LTR by IE2 is completely dependent of DNA sequences downstream
of the TATA box of RSV LTR. A DNA sequence, 5'-CGATACAATAAACG-3', evidently
matching the proposed CRS consensus sequence, is located between nucleotides -13
and +1 (relative to the transcription start site) of RSV LTR. Three lines of
evidence support the notion that this RSV CRS element is involved in the IE2
mediated repression of RSV LTR. First, introduction of mutation to the RSV CRS
element renders to the mutant RSV LTR resistance to IE2-mediated repression.
Second, a mutant IE2 defective in DNA binding cannot downregulate transcription
from RSV LTR. Third, IE2 specifically binds to the wild-type, but not the mutant,
RSV CRS element in vitro. These data, in conjunction with previous works,
demonstrate that IE2 can passively repress transcription of homologous and
heterologous promoters that contain a CRS element.
PMID- 9400611
TI - Hantavirus pulmonary syndrome: CD8+ and CD4+ cytotoxic T lymphocytes to epitopes
on Sin Nombre virus nucleocapsid protein isolated during acute illness.
AB - In 1993 a number of cases of unexplained adult respiratory syndrome occurred in
the southwestern United States. The illness was characterized by a prodrome of
fever, myalgia, and other symptoms followed by the rapid onset of a capillary
leak syndrome with hemoconcentration, thrombocytopenia, and pulmonary edema.
Viral RNA sequences in the lungs identified a new member of the hantavirus genus,
Sin Nombre virus (SNV), unique to North America. Pulmonary endothelial cells were
heavily infected but were not necrotic. We speculated that this capillary leak
syndrome was initiated by immune responses to the SNV-infected pulmonary
endothelial cells. We isolated a CD8+ cytotoxic T lymphocyte (CTL) clone directly
from the blood of a patient with the acute hantavirus pulmonary syndrome (HPS)
which recognizes a SNV specific epitope on the virus nucleocapsid protein (aa 234
242) that is restricted by HLA C7 and produces IFN gamma but not IL-4. We
identified a second CD8+ CTL epitope located within another site aa 131-139 on
the nucleocapsid protein, which is HLA B35 restricted, and a CD4+ CTL epitope
located on a third site on nucleocapsid protein aa 372-380 using lymphocytes
obtained during HPS from another patient that were stimulated in vitro.
Hantavirus specific CD8+ and CD4+ CTL may contribute to the immunopathology and
capillary leak syndrome observed in the HPS.
PMID- 9400612
TI - Analysis of a temperature-sensitive vaccinia virus mutant in the viral mRNA
capping enzyme isolated by clustered charge-to-alanine mutagenesis and transient
dominant selection.
AB - We have previously reported the successful development of a targeted genetic
method for the creation of temperature-sensitive vaccinia virus mutants [D. E.
Hassett and R. C. Condit (1994) Proc. Natl. Acad. Sci. USA 91, 4554-4558]. This
method has now been applied to the large subunit of the multifunctional vaccinia
virus capping enzyme, encoded by gene D1R. Ten clustered charge-to-alanine
mutations were created in a cloned copy of D1R. Four of these mutations were
successfully transferred into the viral genome using transient dominant
selection, and each of these four mutations yielded viruses with plaque
phenotypes different from that of wild-type virus. Two of the mutant viruses, 516
and 793, were temperature sensitive in a plaque assay. Mutant 793 was also
temperature sensitive in a one-step growth experiment. Phenotypic
characterization of the 793 virus under both permissive and nonpermissive
conditions revealed nearly normal patterns of viral protein and mRNA synthesis.
Under nonpermissive conditions the 793 virus was defective in telomere resolution
and blocked at an intermediate stage of viral morphogenesis. In vitro assays of
various capping enzyme activities revealed that in permeabilized virions, enzyme
guanylylate intermediate formation was reduced and methyltransferase activity was
thermolabile, while in solubilized virion extracts enzyme guanylylate activity
was reduced and both guanylyltransferase and methyltransferase activities were
absent. Thus, the 793 mutation affects at least two separate enzymatic activities
of the capping enzyme, guanylyltransferase and methyltransferase, and when
incorporated into the virus genome, the mutation yields a virus that is
temperature sensitive for growth, telomere resolution, and virion morphogenesis.
PMID- 9400613
TI - Interaction of the human protein kinase PKR with the mouse PKR homolog occurs via
the N-terminal region of PKR and does not inactivate autophosphorylation activity
of mouse PKR.
AB - The RNA-dependent protein kinase (PKR) is implicated in the antiviral and
antiproliferative actions of interferon. Mutant forms of human PKR display a
transdominant behavior when expressed in transfected cells. The potential for the
human PKR protein to physically interact with the mouse PKR homolog has therefore
been examined. The yeast two-hybrid system was used to probe the association
between mouse and human PKR proteins as measured by activation of two Gal4
responsive reporter genes, HIS3 and IacZ. Expression of full-length wild-type
mouse PKR(1-515)WT as a Gal4 fusion protein did not exhibit the growth
suppression phenotype in yeast characteristic of wild-type human PKR(1-551)WT.
Coexpression of mouse PKR(1-515)WT as a Gal4 DNA-binding domain fusion with
either the catalytic-deficient human PKR(1-551) K296R mutant, the RNA-binding
deficient human PKR(1-551)K64E/K296R double mutant, or wild-type mouse PKR(1
515)WT as full-length PKR-Gal4 activation domain fusions resulted in activation
of the HIS3 and lacZ reporters. The N-terminal RNA-binding region of human PKR,
both WT and the K64E RNA-binding-deficient mutant, also interacted with mouse
PKR(1-515)WT sufficiently to activate the reporters but the human catalytic
region did not. Mouse and human full-length PKR proteins expressed as glutathione
S-transferase (GST) fusions in Escherichia coli were purified on Sepharose beads.
Using GST-PKR fusion chromatography, direct physical interaction between the
mouse and human PKR homologs was established. Intraspecies PKR interactions were
more efficient than interspecies PKR interactions, and interactions between RNA
binding-sufficient PKR proteins were more efficient than those involving an RNA
binding mutant as measured by binding to GST-PKR protein Sepharose beads. The N
terminal region of human PKR within amino acids 1-184 was sufficient for binding
mouse PKR. Purified mouse full-length PKR(1-515)WT GST fusion protein retained
kinase activity on Sepharose beads, but the activity was not impaired by
association with either the full-length or the N-terminal region of human PKR.
PMID- 9400614
TI - A point mutation in the Sendai virus accessory C proteins attenuates virulence
for mice, but not virus growth in cell culture.
AB - A mutant Sendai virus (SevMVC), which grows much better than its progenitor virus
(SeVM) in cell culture, but, in strong contrast to SeVM, is totally avirulent for
mice, has been described. SeVMVC contains two amino acid substitutions relative
to SeVM, namely, F170S in the C protein and E2050A in the L protein. We have
examined which substitutions were responsible for the above phenotypes by
exchanging the C gene of our reference strain Z with those of SeVH (another
reference strain), SeVM, and SeVMVC, in turn. We have found that the F170S
mutation in the CMVC protein is responsible both for enhanced replication in cell
culture and for avirulence in mice. Avirulence appeared to be due to restricted
viral replication primarily after day 1, implicating some aspect of innate
immunity in this process. The SeV C proteins thus appear to be required for
multiple cycles of replication in mice.
PMID- 9400615
TI - Increasing the ratio of PP2A core enzyme to holoenzyme inhibits Tat-stimulated
HIV-1 transcription and virus production.
AB - We demonstrated previously that PP2A exists in many cell types as two abundant
forms: (1) holoenzyme composed of two regulatory subunits, A and B, and a
catalytic subunit C; and (2) core enzyme consisting of the A and C subunits.
These two forms have different substrate specificities. Since published data
suggested that HIV-1 transcription may be regulated by a cellular protein
phosphatase, it was of interest to determine whether changing the ratio between
PP2A core and holoenzyme affects HIV-1 gene expression. This question was
addressed by expression in COS cells of an N-terminal mutant of the A subunit, A
delta 5, which binds the C but not the B subunit. This resulted in an increase in
the amount of core enzyme and a decrease in the amount of holoenzyme concomitant
with the expected change in phosphatase activity. Tat-stimulated transcription
from the HIV-1 LTR was inhibited 5-fold by mutant A delta 5, whereas mRNA
synthesis directed by the actin promoter was not affected. Furthermore, virus
production in COS, HeLa, and Jurkat T cells was inhibited 45-, 5-, and 3-fold,
respectively, by mutant A delta 5. These results demonstrate that the balance
between PP2A holoenzyme and core enzyme is important for HIV-1 gene expression
and virus production.
PMID- 9400616
TI - Construction and characterization of vaccinia direct ligation vectors.
AB - Poxvirus vectors are extensively used as expression vehicles for protein and
antigen expression in eukaryotic cells. Customarily, the foreign DNA is
introduced into the poxvirus genome by homologous recombination. An alternative
method using direct ligation vectors has been used to efficiently construct
chimeric genomes in situations not readily amenable for homologous recombination.
We describe the construction and characterization of a new set of direct ligation
vectors designed to be universally applicable for the generation of chimeric
vaccinia genomes. These vectors contain the pair of unique restriction sites NotI
and ApaI to eliminate religation of poxvirus arms and fix the orientation of the
insert DNA behind strongly expressing constitutive vaccinia promoters. The
insertion cassette has been placed at the beginning of the thymidine kinase gene
in vaccinia to use drug selection in the isolation of recombinants. These viruses
provide a set of universally applicable direct ligation poxvirus cloning vectors,
extending the utility of poxvirus vectors for construction and expression of
complex libraries.
PMID- 9400617
TI - Molecular studies on bromovirus capsid protein. IV. Coat protein exchanges
between brome mosaic and cowpea chlorotic mottle viruses exhibit neutral effects
in heterologous hosts.
AB - Two members of the bromovirus group, brome mosaic virus (BMV) and cowpea
chlorotic mottle virus (CCMV), selectively infect barley and cowpea,
respectively, and also differ in their ability to systemically infect a common
permissive host, Chenopodium quinoa. CCMV is confined to inoculated leaves of C.
quinoa, whereas BMV causes rapid systemic mottling. To examine whether host
specific determinants for systemic movement of BMV and CCMV in each of these
hosts are localized in the coat protein (CP), sequences encoding this gene were
exchanged between biologically active clones of BMV RNA3 (B3) and CCMV RNA3 (C3)
to create chimera expressing heterologous CP genes (B3/CCP and C3/BCP).
Inoculation of each chimera with its respective wild-type (wt) RNAs 1 and 2 to
barley or cowpea or C. quinoa plants resulted in symptom phenotype and long
distance movement characteristics similar to those of the parental virus donating
RNAs 1 and 2. These observations suggest that neither BMV CP nor CCMV CP has host
specific determinants for long distance movement. Inoculation of additional
recombinant viruses, constructed by reassorting wt genomic RNAs 1 and 2 of BMV
and CCMV with either heterologous wt RNA3 (i.e., B1 + B2 + C3 and C1 + C2 + B3)
or heterologous chimeric RNA3 (i.e., B1 + B2 + C3/BCP and C1 + C2 + B3/CCP), to
susceptible hosts resulted only in localized infections. The significance of
these observations in relation to bromovirus movement is discussed.
PMID- 9400618
TI - The RNA binding region of the paramyxovirus SV5 V and P proteins.
AB - The V/P gene of simian virus 5 (SV5) encodes two proteins, V (222 residues) and
the phosphoprotein P (392 residues). The V and P proteins are amino coterminal
for 164 residues, but they have unique carboxy termini due to addition of two
nontemplated G residues to the P mRNA during transcription. We have shown that
the V and P proteins bind RNA by using both Northwestern blot analysis and
ultraviolet-light crosslinking. The RNA-binding region has been mapped to a
region in the P and V proteins which contains five basic residues (K74, K76, K77,
R79, K81). Either deletion of the basic residues or substitution of the basic
residues with alanine inhibited RNA binding by the V or P proteins.
PMID- 9400619
TI - Analysis in vivo of turnip crinkle virus satellite RNA C variants with mutations
in the 3'-terminal minus-strand promoter.
AB - Turnip crinkle virus and its associated RNA, sat-RNA C, share similar, but not
identical hairpins near their 3' ends and terminate with CCUGCCC-OH, which forms
a single-stranded tail. With an in vitro transcription system containing
partially purified TCV RdRp, the 3'-terminal 29 bases making up the hairpin and
single-stranded tail were previously demonstrated to be required for
transcription, and alterations in the stem, but not the loop, could affect
template activity (C. Song and A. E. Simon, 1995, J. Mol. Biol. 254, 6-14). We
have now analyzed sat-RNA C mutants in the 3' hairpin for ability to accumulate
in vivo. While active templates in vitro were able to accumulate in vivo, some
very weak templates in vitro were also able to accumulate in vivo without
reversion or second-site alterations. Computer models of hairpin structure
indicated that biologically active promoters could have hairpins less stable than
wild type, with loops of variable length and sequence, and without a need for a 6
base single-stranded tail. In addition, transcripts containing compensatory
exchanges in the upper stem region that had limited activity in vitro were
biologically active in vivo, indicating that positioning of specific bases in the
stem is not required to produce an active minus-strand promoter.
PMID- 9400620
TI - The coat protein of turnip crinkle virus is involved in subviral RNA-mediated
symptom modulation and accumulation.
AB - Some satellite (sat-) and defective interfering (DI) RNAs associated with plant
viruses intensify or ameliorate the symptoms of the virus. We recently
demonstrated that the TCV coat protein (CP) is involved in symptom modulation by
sat-RNA C. Two additional subviral RNAs have now been tested for effect of the CP
on symptom modulation. DI RNA G, which normally intensifies the symptoms of TCV,
is able to attenuate symptoms if the TCV CP is replaced with the CP of cardamine
chlorotic fleck virus. DI RNA G had no effect on the symptoms of TCV with a
single base alteration in the CP open reading frame, unlike sat-RNA C, which was
able to ameliorate the symptoms of the mutant TCV. Using a hybrid sat-RNA
constructed from sat-RNA C and TCV (which shares a similar 3'-end region with DI
RNA G), the 3'-terminal 53 bases of sat-RNA C were found to be involved in
symptom attenuation, which was directly correlated with the lack of detectable
viral genomic RNA in whole plants. Sat-RNA D had no effect on the symptoms of
mutant or wild-type TCV. The accumulation of TCV subviral RNAs in plants and
protoplasts was also found to be strongly influenced by the presence or absence
of the wild-type TCV CP.
PMID- 9400621
TI - Sialyl-Lewis(x) sequence 6-O-sulfated at N-acetylglucosamine rather than at
galactose is the preferred ligand for L-selectin and de-N-acetylation of the
sialic acid enhances the binding strength.
AB - Oligosaccharide sequences based on sialyl-Lewis(x) with 6-O-sulfation at
galactose (6'-sulfo) or at N-acetylglucosamine (6-sulfo) and expressed on high
endothelial venules are considered likely endogenous ligands for the leukocyte
adhesion molecule, L-selectin. In the course of high performance TLC of three
hexaglycosylceramides 6'-sulfo sialyl Lewis(x), 6-sulfo sialyl Lewis(x), and 6',6
bis-sulfo sialyl Lewis(x), synthesized chemically for selectin recognition
studies, two minor byproducts were detected and isolated from each parent
compound. By liquid secondary ion mass spectrometry these were identified as
isomers containing a de-N-acetylated sialic acid or having a modified carboxyl
group. Binding experiments with the parent compounds and the non-sulfated sialyl
Lewis(x) glycolipid show that 6-sulfation potentiates, whereas 6'-sulfation
virtually abolishes L-selectin binding. Thus the hierarchy of binding strengths
were 6-sulfo sialyl > sialyl = 6',6-bis-sulfo sialyl >> 6'-sulfo sialyl Lewis(x).
Whereas modification of the sialic acid carboxyl group markedly impaired L
selectin binding, de-N-acetylation resulted in enhanced binding. The natural
occurrence on high endothelial venules of this 'super-active' de-N-acetylated
form of 6-sulfo sialyl Lewis(x), and related structures, now deserves
investigation.
PMID- 9400622
TI - Detection of molecular determinants and epitope mapping using MALDI-TOF mass
spectrometry.
PMID- 9400623
TI - Cytokine mRNA profiles during the course of experimental Haemophilus influenzae
bacterial meningitis.
AB - Intraperitoneal inoculation of Haemophilus influenzae type b (Hib) to 3-week-old
Sprague-Dawley rats resulted in nonlethal meningitis with high levels of
leukocytes in the cerebrospinal fluid (CSF) and positive bacterial culture. Using
in situ hybridization, levels of cytokine mRNA-expressing cells were determined
in the brain, CSF, and spleen from Hib-inoculated and uninfected control rats.
IFN-gamma, IL-1 beta, IL-4, IL-6, IL-10, IL-12, and TNF-alpha mRNA levels were
elevated at 12 hr postinoculation (pi) in spleen and CSF. At this time point,
strong expression of IL-6 and TGF-beta was detected in the brain, and also of IL
10 at 48 hr while IFN-gamma and IL-12 were expressed at very low levels
throughout the observation time. Delayed cytokine induction occurred in CSF
compared to spleen and brain. TGF-beta was high in CSF at 48 hr, and some
elevation of IL-1 beta, IL-6, IL-10, TNF-alpha, IFN-gamma, and IL-12 was evident
at 72 hr pi. This may suggest measures that promote production of TGF-beta and/or
IL-10 should be evaluated in treatment of bacterial meningitis.
PMID- 9400624
TI - Synchronous decline of serum-soluble HLA class I antigen and beta-cell function
in insulin-dependent diabetes mellitus.
AB - Serum-soluble HLA class I molecules (sHLA) have immunomodulatory functions and
their serum levels correlate with the HLA class I phenotype. We studied
longitudinal changes of serum sHLA levels in insulin-dependent diabetes mellitus
(IDDM). A total of 198 serum samples were obtained from 40 IDDM patients before
and after IDDM onset. sHLA was assayed by a sandwich ELISA. sHLA levels in IDDM
patients at the initiation of insulin therapy (IDDM onset) were markedly reduced
compared with those in normal controls (334.2 +/- 26.3 ng/ml vs 492.4 +/- 55.5
ng/ml, mean +/- SEM, P = 0.0038). They fell sharply during 6 months before and
after the onset of IDDM. The dynamic profile of sHLA and the time course of beta
cell loss were different between IDDM patients with and without HLA-A24. In those
with HLA-A24, sHLA became significantly lower than normal controls with HLA-A24
at IDDM onset. Recovery of their sHLA values occurred at 3 years from IDDM onset.
On the other hand, in those without HLA-A24, sHLA levels began to decrease since
the onset of IDDM and became significantly lower than normal controls without HLA
A24 at 4 years after the onset. Recovery of sHLA occurred at more than 6 years
from the onset. An early (within 18 months), complete loss of beta-cell function
occurred in 5 of 13 IDDM patients with HLA-A24 compared with 1 of 14 of those
without HLA-A24 (P = 0.077). A late (more than 36 months after the onset of
IDDM), complete loss of beta-cell function occurred in 7 of 14 IDDM patients
without HLA-A24 but in none of 13 of those with HLA-A24 (P = 0.0058). These
results indicate that the decline of sHLA is synchronous with massive beta-cell
destruction, and that these events occur during a short period in IDDM patients
with HLA-A24, whereas they occur during a relatively long period in those without
HLA-A24.
PMID- 9400625
TI - Evaluating the role of Th0 and Th1 clones in autoimmune thyroid disease by use of
Hu-SCID chimeras.
AB - To study the role of Th0 and Th1 cells in autoimmune thyroid disease, thyroid
tissues from patients with Graves' disease (GD), Hashimoto's thyroiditis (HT),
and colloid nodular disease were xenografted into SCID mice, followed by ip
injection of peripheral blood mononuclear cells (PBMC), T cell lines, and T cell
clones (TCC). The antigen-specific TCC reactive to TSH receptor (TSH-R), thyroid
peroxidase (TPO), or thyroglobulin (Tg), and their respective peptides, were
classified into Th0 (secreting IL-4 and/or IL-5 and IFN-gamma) and Th1 (secreting
IFN-gamma) according to their cytokine profile. Engraftment of autologous or HLA
matched allogeneic CD4+ thyroid-specific clones with Th0 or Th1 phenotypes
induced the production of total IgG and thyroid-specific autoantibodies by B
cells present in xenografted thyroid tissues. TSH-R-specific clones mainly
enhanced thyroid-stimulating antibodies (TSAb) production, while clones reactive
to TPO and Tg increased the synthesis of TPO and Tg autoantibodies. Total IgG
production, but not TSAb, was also stimulated by PBMC and TSH-R lines. TSAb
correlated with the viability and hyperplasia of thyroid follicles, but not with
the serum T3 levels, which were normal. Thyroid tissue viability was maintained
or increased by antigen-specific Th0 clones, and decreased by Th1 clones reactive
to TSH-R or TPO. Thyroid lymphocytic infiltration was variable; however, Th0 and
Th1 clones from HT patients caused high degree of lymphocytic infiltration
compared to the control groups. These results demonstrate for the first time that
T cells clones reactive to specific epitopes of TSH-R, TPO, or Tg can generate
antibody-mediated and/or cell-mediated responses in the xenografted thyroid
tissue microenvironment. Such effects depend on clonal specificity, HLA class II
restriction, and cytokine profile of the clone. Th0 clones reactive to TSH-R
stimulate both total IgG production and TSAb in SCID mice engrafted with thyroid
tissue from GD patients. Th0 and Th1 clones specific for TPO and Tg also function
as helper T cells, stimulating total IgG synthesis and autoantibodies against TPO
and Tg. Th1 clones may also cause tissue destruction in GD and HT.
PMID- 9400626
TI - Dinitrophenyl-modified autologous melanoma vaccine induces a T cell response to
hapten-modified, melanoma peptides.
AB - Active specific immunotherapy with dinitrophenyl (DNP)-modified autologous
melanoma vaccine elicits inflammatory responses in metastatic tumor sites.
Postsurgical adjuvant immunotherapy with this vaccine prolongs survival in stage
III melanoma patients. We have reported that, after administration of DNP
modified melanoma vaccine, T cell responses to DNP-modified autologous tumor
cells are demonstrable in vivo and in vitro. These responses are hapten specific
and MHC restricted. To elucidate this phenomenon, we investigated the immune
response to DNP-modified peptides eluted from autologous cells. Short peptides
were extracted from DNP-modified and unmodified autologous melanoma cells by an
acid elution technique and HPLC fractionation. Peptides were also extracted from
DNP-modified and unmodified, EB virus-transformed, autologous B lymphoblasts.
These various peptide fractions were loaded onto autologous B lymphoblasts and
tested for ability to elicit a response by a DNP-specific T cell line as measured
by IFN-gamma production. Unexpectedly, stimulatory activity of peptides from DNP
modified melanoma cells was confined to a single HPLC fraction. Spectrometric
analysis of this fraction confirmed modification of peptides with DNP. A weaker T
cell response was observed to a single HPLC fraction of DNP-modified peptides
from the patient's B lymphoblasts. No T cell response was elicited by
corresponding fractions of peptides eluted from unmodified melanoma cells or B
lymphoblasts. These findings demonstrate the human T cell response to DNP
modified autologous melanoma cells is mediated by hapten-modified, MHC-associated
peptides. Further investigation of these peptides could lead to a new strategy
for peptide-based cancer immunotherapy.
PMID- 9400627
TI - Lymphocyte phenotyping in infants: maturation of lymphocyte subpopulations and
the effects of HIV infection.
AB - Changes in the distribution of lymphocyte subpopulations in infants with
perinatally acquired HIV infection are confounded by the rapid changes that are
the result of normal maturation of the immune system. We describe the changes in
seven lymphocyte phenotypes (CD3+ CD4+, CD3+ CD8+, CD8+ HLA- DR+, CD8+ CD38+,
CD8+ CD57+, CD3-/ CD16+ 56+, and CD19+) over the first 2 years of life in 390 HIV
1 exposed but uninfected and 98 HIV-1-infected infants enrolled in the Women and
Infants Transmission Study. The greatest changes in uninfected infants were
declines in the CD3+ CD4+ lymphocytes and increases in CD8+ HLA- DR+ and CD19+
lymphocytes. All phenotypes were affected by HIV infection but the greatest
changes were declines in the CD3+ CD4+ subset and increases in the CD3+ CD8+ and
CD8+ HLA- DR+ subsets. Thus, this study provides reference data for the
maturational changes in lymphocyte phenotypes in HIV-exposed but uninfected
infants and describes the overall changes that occur with perinatally acquired
HIV infection.
PMID- 9400628
TI - Role of T-cell subsets in acute and persistent E-55+ murine leukemia virus
infection in susceptible progressor and resistant long-term nonprogressor mouse
strains. Women and Infants Transmission Study.
AB - Previous studies from this laboratory have demonstrated that E-55+MuLV-infected
BALB/c-H-2k (BALB.K) mice progress to develop thymic lymphoma about 7 months
after infection whereas infected C57BL/10-H-2k (B10.BR) mice are long-term
nonprogressors that fail to develop disease even after 2 years of infection. Both
resistant long-term nonprogressor (B10.BR) and progressor (BALB.K) mice generate
an early immune response that results in a dramatic decrease in the number of
virus-infected cells. Despite this early immune response, mice from both strains
become persistently infected. However, resistant B10.BR mice also demonstrate a
late T-cell-mediated response that may be causally related to long-term
nonprogression whereas susceptible BALB.K mice fail to demonstrate this late T
cell response. In the present studies, the T-cell subsets involved in the
effective early immune response in both B10.BR and BALB.K mice as well as the
late T-cell response in B10.BR mice were determined by in vivo antibody-mediated
depletion. Results from these studies demonstrate that during the early acute
phase of infection, elimination of CD4+ T cells ablated the ability of both
BALB.K and B10.BR mice to decrease the burden of virus-infected cells. However,
elimination of CD8+ T cells ablated this result in BALB.K but not B10.BR mice.
Thus, despite the fact that both immunocompetent B10.BR and BALB.K mice are able
to decrease the number of virus-infected cells during the early acute phase of
infection, there is a difference in the T-cell subsets that mediate this effect
in these strains of mice. In addition, characterization of the late immune
response that keeps virus at very low levels during the persistent stage of virus
infection in resistant B10.BR mice demonstrated that simultaneous elimination of
both CD4+ and CD8+ T cells allowed the emergence of virus-infected cells whereas
the elimination of either subset alone showed no effect compared to untreated
control mice that are immunologically intact. Since B10.BR and BALB.K are
identical with respect to their H-2k-haplotypes, it appears that the differences
between these strains with respect to the generation of effective early and late
anti-virus immune responses are regulated by a non-H-2-linked gene(s).
PMID- 9400629
TI - Anti-gliadin antibodies in patients with celiac disease cross-react with
enterocytes and human calreticulin.
AB - One of the characteristic features of celiac disease is an increase in anti
gliadin antibodies (Abs). Recently we found that some of the monoclonal Abs to
gliadin cross-react with molecules on rat enterocytes. One of these cross
reacting molecules was identified as rat calreticulin. This study shows that the
levels of serum IgA Abs to gliadin, rat, and human enterocytes; purified
enterocyte antigens; and calreticulin in sera from patients with active disease
were significantly higher than in patients on a gluten-free diet and healthy
controls (P < 0.001). Anti-gliadin Abs were isolated by affinity chromatography
from the sera of six active celiac patients. The reactivity of these anti-gliadin
Abs was demonstrated to be significantly higher (P < 0.05) with human enterocytes
and human calreticulin than with other antigens tested. Furthermore, using
isolated patients' anti-gliadin Abs bound to Sepharose 2B, two main proteins of
molecular mass 62 and 66 kDa were purified from a lysate of human enterocytes.
The 62-kDa enterocyte antigen was identified as human calreticulin. These
findings suggest that anti-gliadin Abs may play a pathogenic role in celiac
disease by cross-reacting with enterocytes. Calreticulin in enterocytes may be
one of the putative targets for autoimmune reactions.
PMID- 9400630
TI - Interactions of lymphocytes from patients with psoriatic arthritis or healthy
controls and cultured endothelial cells.
AB - Psoriatic arthritis (PA) is an inflammatory rheumatic disease that can
concomitantly occur in patients with psoriasis vulgaris. Psoriatic synovitis
shows alterations of the synovial microvasculature. Inflammatory cells adhere to
endothelial cells (EC) and migrate through the vascular wall of postcapillary
venules located in the subintimal layer of the synovial membrane. The aim of our
study was to investigate, first, the phenotype of lymphocytes (LC) of PA patients
using flow cytometry (FC) with regard to activation antigens and adhesion
molecules; second, the adhesion of LC of PA patients on cultivated resting or
activated (with thrombin, LPS, IFN-gamma, or TNF-alpha) human umbilical vein
endothelial cells (HUVEC) by counting the Feulgen-stained nuclei of both adherent
LC and HUVEC using image analysis; and third, the synthesis of IL-6 and IL-8 in
both LC and HUVEC 24 hr after cell contact. These cytokines were determined
qualitatively by immunofluorescence and quantitatively at the single-cell level
by FC as well as in the supernatants of the cultures using commercial cytokine
ELISAs. Fourth, we investigated whether or not the LC adhesion on HUVEC as well
as the cytokine production could be inhibited by monoclonal antibodies against LC
or EC-specific adhesion molecules. In contrast to controls PA patients showed an
increased surface expression of CD11a, b, and c as well as of CD44 but a reduced
surface expression of CD49d/CD29, and CD49e/CD29, and cell-bound fibronectin on
CD3+ LC. The activation markers CD25 and HLA-DR were found to be slightly
enhanced in PA. The cell adhesion was generally enhanced in PA patients vs
controls. It could be reduced with monoclonal antibodies (MoAbs) against CD11a
and CD18 on IFN-gamma- or TNF-alpha-activated HUVEC but was generally enhanced
after treatment of HUVEC with MoAbs against CD54, CD62E, or CD106. Due to LC
adhesion on HUVEC IL-6 and IL-8 were produced in significantly higher amounts in
PA patients compared to controls. This effect occurred already in resting but was
enhanced in activated HUVEC. While IL-6 is mainly produced by HUVEC but also in
smaller quantities by LC, IL-8 is synthesized only by HUVEC and could be modified
by preincubation with MoAbs against LC- or EC-specific adhesion molecules in
parallel to the cell adhesion. The experiments show that the main adhesion
pathway in LC homing of PA patients is the interaction of the LC adhesion
molecule CD11a/CD18 with CD54 on EC followed by an enhanced synthesis of
proinflammatory and chemotactic cytokines. These results favor the hypothesis
that the pathological alterations of the microvasculature in PA patients are
generated by altered homing processes.
PMID- 9400631
TI - Adoptively transferred EAE in mice bearing the lpr mutation.
AB - We have recently developed approaches for the generation of encephalitogenic T
cell clones from mouse strains considered resistant to experimental allergic
encephalomyelitis (EAE). By allowing for the direct use of knockout and mutant
strains of mice, such clones allow for the efficient characterization of the
relevance of specific gene products in the effector phase of EAE. Recent studies
have suggested that Fas/FasL-mediated cell death may play a role in the
pathogenesis of MS. To assess the role of Fas/FasL in EAE, we have tested the
ability of wild-type C57BL/6-derived, encephalitogenic T cell clones to mediate
adoptively transferred EAE in Fas-deficient C57BL/6-lpr mice. We now report that
mice with the lpr mutation are fully susceptible to the adoptive transfer of EAE.
Our results suggest that Fas/FasL-mediated cell death in the central nervous
system does not play an integral role in the effector phase of acute EAE.
PMID- 9400632
TI - Patterns of in vitro anti-human immunodeficiency virus type 1 antibody production
in long-term nonprogressors.
AB - With the aim of evaluating the specific pattern of in vitro antibody production
(IVAP) in human immunodeficiency virus type 1 (HIV-1)-infected long-term non
progressors (LTNPs), we tested 20 subjects who had remained asymptomatic for more
than 8 years with a CD4+ cell count higher than 500/microliter and 59 patients at
different stages of HIV-1 infection as controls. In cell cultures, IVAP was
detected in 14 out of 20 LTNPs (70%), in 5 out of 6 recent seroconverters (83%),
and in all the other control patients. Anti-p24 antibody production was
significantly lower in LTNPs than in asymptomatic patients with a more recent
infection. Recent seroconverters and patients with AIDS did not produce anti-p24
antibodies (P = 0.02). Anti-gp160 antibodies were produced by peripheral blood
mononuclear cells from LTNPs in 12/20 cases. CD4+ cell count was significantly
higher in IVAP-negative than in IVAP-positive LTNPs (P = 0.013), while the viral
load was not significantly different. Specific anti-HIV-1 antibody production did
not seem to be a correlate of long-term nonprogression.
PMID- 9400633
TI - The use of clinical practice guidelines (CPGs) to evaluate practice and control
costs in ventriculoperitoneal shunt management.
AB - BACKGROUND: As a step toward maximizing the quality and cost-effectiveness of
neurosurgical care, we designed clinical practice guidelines (CPGs) for the
management of VP shunt malfunctions and infections at a tertiary care pediatric
teaching institution. The detailed CPGs determine the use of radiographic
studies, laboratory tests, and invasive procedures in the management of this
problem. One purpose of the CPGs is to provide clear clinical guidelines for the
medical trainee, thereby reducing variability in care and unnecessary utilization
of resources. METHODS: The CPGs were developed in stages over a 2-year period.
The practice patterns in our institution for the management of shunt malfunctions
and infections were articulated. They were compared with those published in the
neurosurgical literature, and areas of clinical decision-making variability were
identified. Preliminary guidelines were formulated, and data regarding patient
care were prospectively collected. Based on this data, final CPGs were formulated
and implemented. Total and itemized hospital charges for patients managed
according to the CPGs were compared with those for patients in the 3 years before
CPG implementation. RESULTS: CPG-managed patients had generally lower total and
itemized charges as compared with control patients. Decreased charges per
hospital day and charges for shunt films in the CPG group were statistically
significant. CONCLUSIONS: The process by which the CPGs were developed and
implemented, as well as the CPGs themselves, are described. We also present the
clinical, demographic, and financial data that were prospectively collected for
all patients managed within the CPGs over an initial 1-year period and compare it
with data obtained for control groups of shunt malfunction patients admitted
during the 3 years before implementation of the CPGs. We find a trend toward
reduction of charges after implementation of the CPG.
PMID- 9400634
TI - Stereotaxy reduces cost of brain tumor resection.
AB - BACKGROUND: Health care professionals are under increasing pressure to contain
the cost of health care. Simultaneously, medical technology continues to advance.
Medical institutions must therefore consider the costs and benefits before using
a new technology. Using a direct costing system, we determined the cost efficacy
of stereotaxy applied to the resection of brain mass lesions. METHODS: Twenty
nine patients underwent a stereotactically guided craniotomy and brain tumor
resection. Fifteen of them underwent general and fourteen received local
anesthesia. Twelve other patients, comprising a historical reference group,
underwent a standard craniotomy and brain tumor resection under general
anesthesia. costs were determined for every hospital charge item in all patients.
Cost efficiency was then compared between the two groups. RESULTS: Patients
treated stereotactically incurred additional costs in frame placement and
neuroimaging. These costs were offset by savings in operating room time, patient
acuity, length of stay, respiratory care, and medications. Savings were greatest
for patients who had local anesthesia. Overall, patients treated by stereotactic
craniotomy had a total hospitalization cost of $8,495.19, whereas those treated
with standard craniotomy incurred a cost of $11,365.23 (p < 0.001). CONCLUSION:
Stereotaxy is cost effective for the surgical treatment of brain tumors. Accurate
estimates of cost can justify the use of medical technology. Directly measured
cost data is a useful index for any cost containment program.
PMID- 9400635
TI - Lumbar disc surgery in a fixed compensation population: a model for influence of
secondary gain on surgical outcome.
AB - BACKGROUND: Reported outcomes in patients undergoing surgical procedures for
lumbar disc herniation are poorer in patients eligible for workers' compensation
or with pending litigation. In the civilian community, the amount of compensation
for one's disability is variable and thus its influence on surgical outcome is
difficult to quantify. In the military, all members are covered by a standardized
workers' compensation system, and have generally standardized work requirements,
a standard pay scale, and third party evaluation of disability based on the
Veterans Affairs rating system. This made the military a good system in which to
study the effect of potential compensation on surgical outcome. METHODS: The
study population consisted of active duty military members who underwent
sequential lumbar microdiscectomies over a 31-month period. Omitted were lumbar
fusions, decompressive laminectomies, and far lateral discectomies. Clinical and
demographic variables, along with financial data for each patient were derived
from these data. A good result was defined as return to active military duty.
RESULTS: Three hundred forty-nine lumbar discectomies were performed in 348
active duty military members. Overall, 75.3% (262) of the 348 patients were able
to return to full military duty after surgery, and 24.7% (86) received disability
compensation. Chi-square univariate analysis showed higher compensation incentive
was a significant determinant of poor surgical outcome (p = 0.0021). The
influence of compensation incentive was proportional to the amount of anticipated
payout, and relative to a military service member's usual income. In mutivariate
analysis, lower base pay (0.0005) and female gender (p = 0.038) were predictive
of poor outcome. CONCLUSIONS: Secondary gain in the form of disability pay has a
proportionally adverse effect on outcome following lumbar disc surgery. Although
studying this issue in the military system allowed standardization of secondary
gain values, the influence of other factors could not be eliminated entirely.
Potential disability pay is proportionally greater in lower ranked service
members. Thus, other variables such as income level, education, and job
satisfaction may contribute to the poorer results in this subgroup of military
members.
PMID- 9400636
TI - Cost advantages of two-level anterior cervical fusion with rigid internal
fixation for radiculopathy and degenerative disease.
AB - BACKGROUND: Conventional anterior cervical discectomy with fusion is thought to
require postoperative neck immobilization for the promotion of bony fusion. Rigid
internal fixation with anterior cervical plates may decrease graft-related
complications and provide immediate stability. This stability may obviate
postoperative external immobilization. METHODS: This report reviews one surgeon's
experience with the use of rigid internal fixation for two-level anterior
cervical discectomy and fusion for radiculopathy to promote early mobilization
without external bracing. It compares outcomes and costs with a similar
population of patients treated with anterior cervical discectomy and fusion who
did not undergo rigid internal fixation. We compared patients who underwent two
level allograft anterior cervical discectomy and fusion with or without rigid
internal fixation between 1989 and 1994 performed by a single surgeon (FJP) to
evaluate the cost advantages and outcome of each procedure. All patients had
clinical evidence of cervical radiculopathy unresponsive to medical therapy with
magnetic resonance imaging confirmation of the appropriate nerve root
impingement. Thirty-nine patients underwent two-level Cloward allograft fusion
using Synthes anterior cervical locking plates, 25 underwent identical fusion
without plating. Follow-up was 6 months to 4 years (mean, 31 months). RESULTS:
Twenty-three of 25 patients in the nonplated group and 36 of 39 patients in the
plated group achieved excellent or good outcomes using the Odom criteria. There
were six complications (two major and four minor) in each group. Patients who
underwent plating returned to light activities (mean, 17 vs. 29 days), driving
(28 vs. 57 days), and unrestricted work (66 vs. 136 days) sooner than non-plated
patients (p < 0.05, paired t test). No patient with plates was given external
immobilization. CONCLUSIONS: Two-level anterior cervical discectomy and fusion
with anterior plating for radiculopathy is safe, effective, and seems to provide
shorter convalescence compared with conventional anterior cervical discectomy and
fusion. Patients returned to unrestricted work sooner, thus reducing short-term
disability. Rigid internal fixation may provide cost advantages to patients and
insurance disability providers. The authors conclude that the increased cost of
treatment for rigid internal fixation is more than offset by the benefits of
earlier mobilization.
PMID- 9400637
TI - Spinal instrumentation with a low complication rate.
AB - BACKGROUND: Spinal instrumentation has become an increasing part of the
armamentarium of neurosurgery and neurosurgical training. For noncontroversial
indications for spine fusion the arthrodesis rate seems to be better. For both
noncontroversial and controversial indications, the reported complication rate
with spinal instrumentation tends to be greater than that with noninstrumented
spine surgeries. These reported complications include a 2-3% neurologic injury
rate, 3-45% reoperation rate for implant failure, and inflection rates of 5-10%.
Therefore, we report on 299 cases that have undergone spinal instrumentation
placed exclusively by neurosurgeons with a very low complication rate. METHODS:
Two hundred ninety-nine consecutive spinal instrumentation cases performed
exclusively by neurosurgeons at Indiana University Medical Center were analyzed
for complications related to spinal instrumentation. The spinal instrumentation
placed consisted of 195 anterior cervical locking plates, 22 cases of posterior
cervical instrumentation, 9 cases of combined anterior locking plates with
posterior cervical instrumentation, 14 anterior thoracolumbar plates, 51
posterior thoraco-lumbar instrumentation cases, and 8 combined anterior/posterior
thoracolumbar instrumentation cases. RESULTS: The mean follow-up is 40 months (6
95). There was one perioperative death unrelated to the spinal instrumentation.
There were no neurologic injuries and there has been no hardware infection to
date. There were two dural tears, three superficial wound infections, and three
minor wound breakdowns successfully treated. Hardware complications included
three cervical plate/screw extrusions reoperated, one cervical plate fracture
reoperated, one posterior cervical screw backout not reoperated, one case of
broken pedicle screw not reoperated, one vertebral body failure not reoperated,
and one posterior rod case reoperated for excessive rod length and protrusion.
The overall complication rate attributable to placement of spinal instrumentation
was 10/299 (3%) with a reoperation rate of 2%. The arthrodesis rate was 298/299
(99%). CONCLUSION: The complication rate for using spinal instrumentation can be
less than previously reported. Lessons learned and discussed should reduce the
rate even more. Spinal instrumentation is a safe and useful adjunct to fusion in
treating degenerative, traumatic, infectious, and neoplastic diseases of the
spine.
PMID- 9400638
TI - Symptomatic pneumocephalus after transsphenoidal surgery.
AB - BACKGROUND: Symptomatic pneumocephalus after transsphenoidal surgery, though
reported, is a rare phenomenon. We report three cases of pneumocephalus in a
series of 300 transsphenoidal operations for sellar/suprasellar mass lesions done
over the past 12 years. METHODS AND RESULTS: Three cases of symptomatic
pneumocephalus occurring after transsphenoidal surgery are presented to
illustrate the causative factors, methods of prevention, and management. In case
1, an intraoperative cerebrospinal fluid (CSF) leak occurred and drainage of CSF
through a lumbar subarachnoid drain resulted in pneumocephalus, in spite of
repair of the sellar floor. In case 2, partial excision of tumor and subsequent
reduction of intracranial pressure due to a ventriculoperitoneal (VP) shunt led
to pneumocephalus. In case 3, radiotherapy-induced shrinkage of a partially
excised tumor resulted in pneumocephalus. The sellar floor had not been repaired
in cases 2 and 3 as there was no intraoperative CSF leak and only a partial
excision had been done. Conservative management failed in the two patients in
whom it was tried. Repair of the sella and sphenoid sinus had to be done in all
three cases. CONCLUSIONS: Repair of the sellar floor should be done after a
transphenoidal approach in all cases, even when no intraoperative leak has been
identified and only a partial excision of tumor has been done. Once
pneumocephalus has occurred, the sellar floor and sphenoid sinus should be
repaired early before reducing the intracranial pressure (ICP) by tapping
ventricular air and draining or diverting CSF.
PMID- 9400639
TI - Prediction of consistency of meningiomas with preoperative magnetic resonance
imaging.
AB - BACKGROUND: The consistency of a meningioma is one of the important factors in
determining the surgical outcome. If the surgeon is aware of the consistency of a
meningioma preoperatively, the surgical plans will be influenced. A few papers
have described the correlation between consistency of meningiomas and their
magnetic resonance imaging (MRI) findings. However, prediction of consistency
with MRI is still difficult. We have tried to predict the consistency of
meningiomas with MRI findings more precisely. METHODS AND RESULTS: Fifty patients
diagnosed as having intracranial meningiomas were studied with 1.5 Tesla MRI. We
compared the MRI findings with tumor consistency. The intensities of the tumors
were categorized into three grades (low, iso, and high) compared to that of the
gray matter. T1-weighted images had no specifics, but T2-weighted images and
proton density images were useful for the prediction of tumor consistency.
Hyperintensity on protein density (PD) and T2-weighted images was a sign of a
soft tumor. CONCLUSION: We presume that T2 and PD are useful for predicting
consistency of meningiomas, and their water content is one of the main factors in
their consistency. Histology may be one of the factors helpful in defining the
consistency of a tumor. In this series, we found no relationship between
histology and MRI findings, nor between histology and consistency. If the
meningioma is believed to be hard, preoperative endovascular embolization is
beneficial, which will induce necrosis of the meningioma and make it soft enough
to be removed more easily and safety.
PMID- 9400640
TI - Pathologic significance of meningeal enhancement ("flare sign") of meningiomas on
MRI.
AB - BACKGROUND: The purpose of this study was to clarify the pathologic features and
clinical significance of the meningeal enhancement surrounding meningiomas
("flare sign") on contrast-enhanced T1-weighted magnetic resonance images (MRI).
METHODS: The marginal dura mater of tumors was resected from nine cases of
meningioma exhibiting a flare sign and used for histopathologic evaluation.
RESULTS: Connective tissue proliferation was found in the dura mater in all
cases, vascular proliferation was found in three, and tumor cell nests were
observed in four cases. In one case, tumor cells were found 4.5 mm from the edge
of the tumor. In another case, a meningothelial cell cluster was found.
CONCLUSIONS: These results suggest that tumor cell nests are present frequently
in dura mater that exhibits the flare sign, and that the dura mater near these
lesions should be resected as widely as possible.
PMID- 9400641
TI - Resection of a recurrent parasagittal meningioma with cortical vein anastomosis:
technical note.
AB - BACKGROUND: Simpson Grade I resection of parasagittal meningiomas is not always
feasible because of the involvement of the sagittal sinus and cortical veins.
Complete resection requires reconstruction of the sagittal sinus and cortical
veins. This report describes a surgical technique to preserve patency of the
cortical veins. CASE REPORT: A recurrent parasagittal meningioma completely
occupied the superior sagittal sinus and encased several large cortical veins.
The tumor in the sagittal sinus was totally resected and the roof of the sinus
was sutured. To avoid thrombotic cortical vein occlusion, two cortical veins
encased by the meningioma were anastomosed end-to-end, regardless of their flow
directions. The postsurgical course was uneventful and patency of the anastomosed
veins was confirmed by postoperative angiography. CONCLUSIONS: End-to-end
anastomosis of cortical veins was a useful surgical technique for radical
resection of a parasagittal meningioma.
PMID- 9400642
TI - Classification and treatment of vertebral dissecting aneurysm.
AB - BACKGROUND: For many years, dissecting aneurysms of the intracranial vertebral
artery were believed to be quite rare. In recent years, because vascular
disorders have been studied more thoroughly by three dimensional-computed
tomography (3D-CT), angiographically and pathologically, these aneurysms are
being reported with more frequency. METHODS: Among the 45 patients diagnosed to
have aneurysms arising from the vertebral artery or its branches over a 20-year
period, 16 had dissecting aneurysms. The authors present their therapeutic
strategy for these patients. Surgery was performed in the 16 patients, the most
common technique being clip-occlusion or trapping of the parent artery wherever
feasible, in an attempt to optimize cerebral blood flow. The dissecting aneurysms
of the vertebral artery were classified into two groups for the purpose of
determining a therapeutic approach, namely unilateral and circumferential groups.
In the unilateral group, the dissection seemed to involve only on one side of the
vessel according to the conventional cerebral angiogram. These patients underwent
surgical reconstruction of the vertebral artery by direct clipping. In the
circumferential group, the dissection was all around the artery. Proximal
clipping or trapping was performed in this group. RESULTS: In six out of eight
patients with unilateral dissecting aneurysms, vascular reconstruction was
possible by direct clipping. Of these six patients, the surgical outcome was
considered excellent in four, fair in one, and one patient died of cardiac
failure after 12 days as his preoperative morbid condition remained the same
after surgery. Two other patients with unilateral dissecting aneurysms were
treated with trapping technique and the surgical outcome was excellent in one
patient and good in the other patient. Both patients resumed a normal social
life. In five out of eight patients with circumferential dissecting aneurysms,
trapping or proximal clipping was performed and the surgical outcome was
excellent in two patients, good in one and fair in one patient. One patient with
preoperative brain stem infarction died of aspiration pneumonitis after 8 months.
Two patients who were noted to have an increase in the size of aneurysm during
follow-up angiography underwent a craniotomy with clipping and wrapping of the
aneurysm. There was a favorable surgical outcome in both patients. The remaining
three patients had Grade IV subarachnoid hemorrhage (SAH) prior to surgery and at
autopsy a disturbed vascular wall was detected. CONCLUSION: The authors'
experience suggests that when surgically feasible, direct clipping is an
effective alternative approach in the treatment of dissecting aneurysms of the
vertebral artery in which blood flow in the parent artery is to be preserved.
PMID- 9400643
TI - Spontaneous occlusion of a giant basilar tip aneurysm and a basilar artery due to
the dissection of both structures: case report.
AB - BACKGROUND: Spontaneous occlusion of a giant aneurysm with its parent artery is
relatively rare. Complete occlusion of a giant aneurysm at the basilar
bifurcation and a basilar artery due to the dissection of the basilar artery has
never been reported. CASE DESCRIPTION: This 62-year-old man presented with left
hemiparesis and right oculomotor palsy. Radiographic study showed a giant
aneurysm at the basilar artery bifurcation with hemorrhage in its wall and an
ischemic area in the right midbrain. Subsequent study revealed that thrombosis of
the aneurysm rapidly progressed and that the parent basilar artery caused the
dissection. Finally the giant aneurysm and the basilar artery were completely
thrombosed. CONCLUSION: The dissection was considered to occur in the aneurysm
wall first by the hemorrhage in it and progress proximally along the basilar
artery. Intramural hemorrhage in the wall of a giant aneurysm can be a cause of
dissection of its parent artery. This seems to be one of the mechanisms by which
a giant aneurysm and its parent artery are spontaneously thrombosed.
PMID- 9400644
TI - Brain cavernoma: a dynamic lesion.
AB - BACKGROUND: Although the prevalence of brain cavernomas is high (0.50%), for
unknown reasons, only a few of them display aggressive clinical behavior.
METHODS: From a personal series of 65 operated and histopathologically verified
cavernomas, we have conducted a long-term study, both retrospectively and
prospectively, of the main features that cause some cavernomas to be dynamic
lesions. RESULTS: Hemorrhage is the most common phenomenon. Extralesional
bleeding due to the rupture of peripheral caverns is most often observed. These
are never as immediately devastating as hemorrhages originating from a high-flow,
high-pressure AVM. Extralesional hemorrhages tend toward spontaneous resorption,
but the risk of recurrence exists and may lead to permanent disability or death
(especially when the lesion is located in the brain stem). Intralesional bleeding
caused by rupture of contiguous caverns is less frequently observed. This may
lead to the formation of large cysts. Calcifications are mostly observed in
patients presenting with chronic epilepsy. The bleeding risk of calcified
cavernomas is low, but it can exist and should be taken into account in the
surgical decision making. The growth of the cavernomatous matrix was obvious in
three large cavernomas (two with calcification). No bleeding was found inside the
lesions, suggesting a pure "intrinsic" growth. The role of pathologic angiogenic
factors is highly probable in these cases. "De novo" appearing lesions were
observed in five cases (four belonging to familial forms) on the magnetic
resonance imaging survey of operated patients. Perilesional atrophy was observed
in three cases (two operated) in patients with a long-lasting evolution. It
suggests that the brain metabolism can be disturbed by slow, chronic effusion of
blood around the cavernoma. CONCLUSIONS: The dynamism of cavernomas is determined
by extrinsic factors, mainly hemorrhage (with its own consequences); and by
intrinsic factors: the pseudotumoral growth of the cavernous matrix. Therefore,
when they are symptomatic, cavernomas should be totally removed.
PMID- 9400645
TI - Anastomosis of the superficial temporal artery to the middle cerebral artery with
the interposed occipital artery graft in moyamoya disease: case report.
AB - BACKGROUND: Although there have been various interposed bypass grafts used for
cerebral revascularization, the occipital artery has never been used as a graft.
Interposed occipital artery bypass graft in an adult case with moyamoya disease
after failed indirect revascularization is presented. CASE DESCRIPTION: This 34
year-old woman with moyamoya disease, who had suffered from cerebral ischemic
symptoms since the age of 6 years, was admitted to our hospital because of an
intracerebral hemorrhage on the left side. She had undergone superficial temporal
to-middle cerebral artery anastomosis, encephalo-galeo-synangiosis on the right
side, and encephalo-duro-arterio-synangiosis on the left side at age 29 years.
Four months after the intracerebral hemorrhage, she still had cerebral ischemic
symptoms in the left hemisphere where cerebral revascularization was poor. Since
neither the superficial temporal nor occipital artery could be used for direct
anastomosis because of spontaneous transdural anastomoses of the superficial
temporal artery and the short length of the occipital artery, anastomosis between
the left superficial temporal artery and left posterior parietal artery was
performed using a left occipital artery graft 6 months after the hemorrhage.
Postoperative external carotid angiograms showed good patency of the graft.
CONCLUSION: In cases in which direct anastomosis is infeasible for cerebral
revascularization, the occipital artery could successfully be used as a bypass
graft.
PMID- 9400646
TI - Vasoreconstructive surgery for radiation-induced vasculopathy in childhood.
AB - BACKGROUND: Cerebral vasculopathy associated with the appearance of netlike
vessels can develop following irradiation therapy for parasellar brain tumors,
especially in children. However, little is known regarding the clinical course of
this disease or the appropriate therapy for it. CASE REPORTS: We experienced two
surgically-treated patients with radiation-induced vasculopathy and reviewed the
previously reported cases. Both of our patients were treated with encephalo-duro
arterio-myo-synangiosis combined with superficial temporal artery to middle
cerebral artery (STA-MCA) bypass. Their ischemic symptoms improved following the
surgery, associated with a good angiographic neovascularization from the STA-MCA
bypass, as well as dural and muscular arteries. CONCLUSION: Our findings and the
review of the previous reports suggested that surgical therapy may be beneficial
for the patients with radiation-induced vasculopathy with the appearance of
netlike vessels.
PMID- 9400647
TI - Transcondylar approach for dural arteriovenous fistulas of the cervicomedullary
junction.
AB - BACKGROUND: Spinal dural arteriovenous fistulas are abnormal arteriovenous
connections on the surface of the dura. The site of the fistula is most commonly
in the thoracic and lumbosacral regions and they are rarely located in the
cervical region. CASES: The patients had two asymptomatic dural arteriovenous
fistulas of the cervicomedullary junction fed by the left posterior meningeal
artery and draining to the dilated coronal venous plexus and the
radiculomedullary vein. RESULTS: The lesions were successfully treated by
surgical interruption of the intrathecal vein with coagulation via a suboccipital
transcondylar approach and a condylar fossa approach. Both patients left the
hospital without significant deficits. CONCLUSIONS: We recommend that dural
arteriovenous fistulas in the cervical region be surgically treated.
PMID- 9400648
TI - Cranial titanium osteosynthesis systems.
PMID- 9400649
TI - Pitfalls of facial nerve enhancement on MRI.
PMID- 9400650
TI - The Visible Human Project.
PMID- 9400651
TI - Reducing the costs of health care: the other side of the equation.
PMID- 9400652
TI - Migration of nitrosamines from condoms to physiological secretions.
PMID- 9400653
TI - Elevated dentine lead levels in adult teeth of First Nation people from an
isolated region of northern Ontario, Canada.
PMID- 9400654
TI - Trace element pollution of soils collected near a municipal solid waste
incinerator: human health risk.
PMID- 9400655
TI - Vapor phase and particulate bound polycyclic aromatic hydrocarbons in the smoke
of mosquito coils.
PMID- 9400656
TI - HCH and DDT residues in drinking water from the South of Spain, 1991-1994.
PMID- 9400657
TI - Volatilization of arsenic in contaminated cattle dipping vat soil.
PMID- 9400658
TI - Effect of antioxidants on UV-induced DNA breakage in human peripheral
lymphocytes.
PMID- 9400659
TI - Effect of methacrylonitrile on rat lung antioxidant enzymes.
PMID- 9400660
TI - Biodisposition study of the organophosphorus pesticide, methyl-parathion.
PMID- 9400661
TI - Determination of pentachlorophenol in environmental samples of the S. Euboic
Gulf, Greece.
PMID- 9400662
TI - Monitoring of the pesticide levels in natural waters of Greece.
PMID- 9400663
TI - Phototransformation of 2-chloroaniline in aqueous solution.
PMID- 9400664
TI - Biodegradation of endosulfan by a bacterial coculture.
PMID- 9400665
TI - Adsorption characteristics of trihalomethanes onto activated carbon fiber from
quarternary mixture solution.
PMID- 9400666
TI - Improved blue rayon hanging technique that can measure a time-weighted average
concentration of benzo(a)pyrene in sea water.
PMID- 9400667
TI - Response of the stonefly Pteronarcys dorsata in enclosures from an urban North
Carolina stream.
PMID- 9400668
TI - Sensitivity of chironomus plumosus larvae to V5+, Mo6+, Mn2+, Ni2+, Cu2+, and Cu+
metal ions and their combinations.
PMID- 9400669
TI - Comparative acute toxicity of some pesticides, metals, and surfactants to
Gammarus italicus Goedm. and Echinogammarus tibaldii pink. and stock (Crustacea:
Amphipoda).
PMID- 9400670
TI - Bioconcentration of chlorpyrifos, chlorfenvinphos, and methidathion in Mytilus
galloprovincialis.
PMID- 9400671
TI - Species variation and some properties of renal glutathione S-transferase of fish
from Arabian gulf.
PMID- 9400672
TI - Comparative study on the acute toxicities of alpha, beta, gamma, and delta
isomers of hexachlorocyclohexane to freshwater fishes.
PMID- 9400673
TI - Effect of naphthalene on carbohydrate metabolism during vitellogenesis in marine
edible crab, Scylla Serrata.
PMID- 9400674
TI - Effect of selenium on mercury methylation in anaerobic lake sediments.
PMID- 9400675
TI - Assay for toxic chemicals using bacteria.
PMID- 9400676
TI - Gastro-oesophageal reflux disease and asthma.
AB - Gastro-oesophageal reflux disease (GOR) and asthma are both common medical
conditions that often co-exist. Studies using oesophageal manometry and 24 h
ambulatory pH monitoring have shown that up to 80% of asthmatics have abnormal
GOR. A number of mechanisms whereby GOR may trigger asthma have been proposed,
and it is believed that acid reflux may stimulate vagal receptors in the lower
oesophagus causing reflex bronchoconstriction. However, GOR may be worsened by
asthma causing abnormal diaphragm mechanics and by its treatment. Formal
evaluation of GOR should be considered a part of asthma assessment, particularly
if asthmatic symptoms are precipitated by factors known to trigger GOR such as
reclining, alcohol ingestion, and the use of theophylline. Twenty-four hour
ambulatory intra-oesophageal pH monitoring remains the gold standard for the
diagnosis of GOR. Medical therapy with anti-reflux medications, such as acid
suppressive agents and prokinetic agents may improve both GOR and asthma control.
In those who fail medical therapy, anti-reflux surgery may be warranted in some.
PMID- 9400677
TI - Environment and the ageing lung.
AB - A brief review of changes in the morphology, physiology and defence mechanism in
the ageing lung is presented. During the ageing process, the lung is also
affected by environmental insults, which can be exogenous or endogenous.
Exogenous factors include infection, climate, air pollution and mechanical
injuries, whereas endogenous environments are certain system diseases (e.g.
diabetes mellitus and thromboembolism) as well as infectious diseases (e.g.
tuberculosis).
PMID- 9400678
TI - Non-invasive ventilation in the management of respiratory failure.
AB - Non-invasive positive pressure ventilation (NIPPV) has been used increasingly to
treat various forms of respiratory failure, with benefits in terms of gas
exchange improvement, avoidance of endotracheal intubation and a decreased
mortality. This review will focus on the recent developments and recommendations
in the use of NIPPV in the treatment of acute and chronic respiratory failure,
the methodology in the application of NIPPV, and briefly on its proposed
mechanism of action.
PMID- 9400679
TI - Surgical results of 29 patients with benign tracheobronchial lesions.
AB - This study was carried out in order to evaluate the surgical results of benign
tracheobronchial diseases. Between July 1988 and March 1996, tracheobronchial
surgery was performed on 29 patients with a variety of benign diseases. The
primary diseases were post intubation or post tracheostomy tracheal stenosis (n =
12), tuberculous stenosis (n = 7), congenital tracheal stenosis with or without
vascular ring (n = 4), tracheobronchial tumour (n = 2), oesophageal tumour (n =
1), and miscellaneous conditions (n = 3). Thirty-one operative procedures
included sleeve lobectomy (n = 7), sleeve resection of trachea (n = 17) and
bronchus (n = 2), and plastic surgery of trachea (n = 4) and bronchus (n = 1).
There was one operative death, which put the mortality rate at 3.4%. There were
five postoperative complications in this series (17.2%), including anastomotic
disruption of trachea (n = 1), bilateral vocal cord palsy (n = 1), prolonged
endotracheal intubation (n = 1) and overgrowth of granulation (n = 2). The
complication of anastomotic disruption of trachea was treated by insertion of a
tracheal T-tube, and the granulation was treated by bronchoscopic excision. We
suggest that tracheobronchoplasty is a safe procedure in carefully selected
patients with benign diseases.
PMID- 9400680
TI - Hepatocyte growth factor promotes growth and lumen formation of fetal lung
epithelial cells in primary culture.
AB - Mesenchyme-epithelium interactions are generally considered critical for fetal
lung development. Hepatocyte growth factor (HGF), a mesenchyme-derived mitogen
active on a variety of epithelial cells, appears to be involved in the
morphogenesis of fetal liver and kidney. During lung development, HGF and its
receptor, c-Met, are expressed in close proximity in mesenchymal cells and
epithelial cells, respectively. To examine the role of HGF in fetal lung
development, we investigated the effects of HGF on lung epithelial cells derived
from a 15-day-old mouse fetus. First, HGF induces a 45% increase in [3H]thymidine
incorporation and a 65% increase in cell number by crystal violet analysis at 10
ng/mL concentration, and the increase is dose dependent. Second, HGF facilitates
the formation of an organotypic arrangement of the fetal epithelial cells on a
basement membrane extract (Matrigel) that resembles alveolar structures in vivo,
and the maximum increase is about twice the control level at 10 ng/mL. These
results suggest that HGF may be implicated in fetal lung development through the
regulation of mesenchyme-epithelium interactions.
PMID- 9400682
TI - A case of malignant pleural mesothelioma following exposure to atomic radiation
in Nagasaki.
AB - We report the case of a 75-year-old Japanese man who developed malignant
mesothelioma in the left hemithorax 50 years after the dropping of the atomic
bomb on Nagasaki in 1945. This may be the first reported case of malignant
mesothelioma following exposure to atomic radiation. Asbestos is the leading
cause of malignant mesothelioma, but radiation therapy is the primary non
asbestos-related cause. In the case of radiation therapy, the interval between
exposure and the occurrence of malignant mesothelioma tends to be many years.
This patient was at a high risk of malignant mesothelioma as he had been exposed
to radiation from the atomic bomb and may also have had a history of asbestos
exposure at the munitions factory where he was employed as a shipbuilder for 2
years. It has been suggested that combined exposure to atomic radiation and
asbestos is associated with an increased incidence of malignant mesothelioma. If
thickening of the pleura or pleural effusion is found in atomic bomb survivors,
malignant mesothelioma should be considered as one of the options in the
differential diagnosis, even although the atomic bomb attacks occurred several
decades ago.
PMID- 9400681
TI - Tachykinins contribute to the acute airways response to allergen in sheep
actively sensitized to Ascaris suum.
AB - Tachykinins, found in sensory nerves, have effects in the airways which suggest
that they may contribute to the pathogenesis of asthma. We aimed to find evidence
for tachykinin involvement in the immediate airway response to allergen in a
sheep model of experimental asthma. Twenty-four sheep were actively sensitized to
Ascaris suum, then challenged with nebulized Ascaris extract in a dose-response
fashion. Change in lung resistance (RL) in response to challenge was measured.
Responder sheep (those with an increase in RL of > or = 100% over baseline) that
had reproducible responses over three challenges were identified (n = 4 sheep)
and a PC100 (number of breaths of extract required to induce a 100% increase in
RL) was determined. The effect of the neutral endopeptidase inhibitor
phosphoramidon, the NK-1 receptor-specific antagonist CP 96, 345 and capsaicin
desensitization on the RL response to Ascaris challenge was then assessed.
Administration of phosphoramidon before Ascaris decreased the PC100 to 31 +/- 7%
of the PC100 seen with Ascaris alone (P < 0.05), whereas CP 96,345 and capsaicin
desensitization increased the PC100 to 285 +/- 41% and 555 +/- 93% respectively
(P < 0.05 for both). These findings suggest that endogenous tachykinins are
released in response to allergen challenge and that they contribute to the
immediate increase in RL.
PMID- 9400683
TI - Tuberculosis and HIV infection: global perspectives.
AB - This paper reviews the epidemiological and clinical aspects of the interaction
between Mycobacterium tuberculosis and HIV infection. The incidence of HIV
associated tuberculosis is increasing worldwide and is expected to increase
further, especially in Africa and parts of Asia. HIV infection appears to
increase the likelihood that tuberculous infection will occur after tubercle
bacilli are inhaled into the lungs. Moreover, there is persuasive evidence that
in the presence of HIV infection, new-onset tuberculous infection will progress
rapidly to clinically significant disease and the probability that latent
tuberculous infection will reactivate is enormously increased. The accelerating
and amplifying influence of HIV infection is also contributing to the increasing
incidence of disease caused by multidrug-resistant strains of M. tuberculosis.
Neither clinical nor radiographic features reliably distinguish the majority of
patients with HIV-associated tuberculosis from those who are non-HIV-infected.
Some HIV-infected patients, however, have atypical manifestations and are
difficult to diagnose. Chemotherapy for 6 months with conventional
antituberculosis drugs cures most patients, but many died during or after
treatment of other AIDS-related complications. HIV is contributing heavily to the
worldwide increase in tuberculosis. There is also mounting evidence that
tuberculosis accelerates the course of co-existing HIV disease.
PMID- 9400684
TI - Current issues in the management of chronic obstructive pulmonary diseases.
AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and
mortality, especially among smokers. Many guidelines that have recently been
issued emphasize that COPD is not inaccessible to therapeutic measures: although
few interventions are capable of affecting its natural history (i.e. smoking
cessation and, in patients with severe resting hypoxaemia, oxygen therapy),
several others have a demonstrated effect on symptoms and, thereby, quality of
life. The effects of inhaled corticosteroids, and alpha 1-antitrypsin replacement
therapy in emphysema due to alpha 1-antitrypsin deficiency are currently being
studied. When there is a marked increase in mucus production, chest physiotherapy
using controlled expiration and directed cough may be useful. Inhaled
bronchodilators are frequently effective on dyspnoea, anticholinergic agents
being more suitable for continuous symptoms. Rehabilitation, which includes
education and psychosocial care, chest physiotherapy, nutritional care and
exercise training, also improves quality of life. When there is persistent severe
alveolar hypoventilation despite oxygen therapy, long-term mechanical ventilation
may be considered. Surgical options in the treatment of emphysema include
resection of giant bullae and lung volume reduction surgery. Lung transplantation
should be proposed only in patients with end-stage disease, the difficulty here
being to define what 'end-stage' means. Finally, all preventive and some
therapeutic interventions are likely to be more effective early in the course of
the disease. Thus, efforts should be made to detect airways obstruction early in
subjects at risk, such as smokers.
PMID- 9400685
TI - Applications of colour Doppler ultrasound in the diagnosis of chest diseases.
AB - Colour Doppler ultrasound (US) or colour Doppler imaging is a new imaging
modality that can simultaneously display blood flow information and Doppler
spectral analysis. This new technique provides an opportunity to assess pulmonary
blood flow and perfusion non-invasively. Colour Doppler US has many potential
applications in diseases of the chest. Colour Doppler imaging is useful in
assisting the diagnosis of pulmonary arteriovenous malformation and pulmonary
sequestration. The 'fluid colour sign' can be used to detect minimal effusion
amenable to thoracentesis. Colour Doppler US can be used to assess the
angiogenesis of a lung tumour and may be helpful in differentiating a malignant
tumour from a benign one. Colour Doppler US can be used to guide a transthoracic
needle biopsy and improve the safety of this invasive procedure. Colour Doppler
US can demonstrate the vascular patterns and assess the regional haemodynamic
changes of a pulmonary consolidation. The information of spectral wave analysis
is helpful for understanding the haemodynamic changes of a pulmonary
consolidation. Colour Doppler US is useful in assessing perfusion and reperfusion
status of a pulmonary infarction. The recent advent of amplitude US angiography
further improved the sensitivity of colour Doppler US in detecting blood flow
signal without angle restriction. The potential application of these new
techniques in chest diseases may need further exploration.
PMID- 9400686
TI - Role of endogenous nitric oxide in the pathogenesis of bronchial asthma.
PMID- 9400687
TI - ATS standards for the optimal management of chronic obstructive pulmonary
disease.
AB - Tobacco smoking is the main cause of chronic obstructive pulmonary disease
(COPD), and the provision of encouragement and support in smoking cessation is
the best way to help patients with COPD. The three major goals of COPD management
are to lessen airflow limitation, to prevent and treat secondary medical
complications and to decrease respiratory symptoms and improve quality of life.
Outpatient pharmacotherapy should be organized in a stepwise manner according the
severity of disease, the aims being to induce bronchodilation, reduce
inflammation and facilitate expectoration, although the role of anti-inflammatory
and mucolytic treatment in COPD has not been clearly established. Patients who
are not well controlled on optimal pharmacotherapy are candidates for enrollment
in a pulmonary rehabilitation programme. Correction or prevention of hypoxaemia
is a priority, and long-term oxygen therapy may prolong survival in hypoxaemic
patients. With only limited data on criteria for hospital admission and the
objectives of hospitalization, the published ATS standards on the management of
COPD include expert consensus statements on these aspects of hospital care.
Special considerations, such as surgery in the COPD patient, sleep disorders,
nutrition, air travel, and ethical issues, are discussed.
PMID- 9400688
TI - Efficacy and safety of inhalation therapy in chronic obstructive pulmonary
disease and asthma.
AB - The inhaled route has a number of well-recognized advantages over other routes
for administration of drugs to the lungs. As the drug is delivered directly to
its required site of action, only a small quantity is required for an adequate
therapeutic response. Consequently, there is a low incidence of systemic side
effects compared with oral or intravenous administration. In addition, the onset
of action of inhaled drugs is generally faster than that achieved by oral
administration. Factors that can affect the quantity of inhaled particles
reaching the lungs and their topographical distribution are manner of inhalation,
aerosol characteristics and subject characteristics. The main types of inhaler
device are metered-dose inhalers (MDIs), dry powder inhalers (DPIs) and
nebulizers (jet and ultrasonic). There are advantages and disadvantages
associated with all types of currently available inhaler device and there is
still a clear need to develop more efficient devices that are easy to use.
Respimat (Boehringer Ingelheim) is a novel soft mist inhaler that operates via a
mechanism utilizing mechanical power rather than gas propellants, and represents
an exciting development in this field.
PMID- 9400689
TI - Choice of bronchodilator therapy in chronic obstructive pulmonary disease.
AB - The majority of patients with chronic obstructive pulmonary disease may derive
benefit from bronchodilator therapy, particularly those patients with severe
disease. Currently, three classes of bronchodilator are available:
anticholinergics, beta 2-adrenergic agonists and methyl-xanthines. Several
factors should be considered when choosing a bronchodilator. Inhaled therapy is
generally preferred over oral treatment as the inhaled route reduces systemic
exposure to the drug, whereas oral therapy has the advantages of convenience and
ease of use. The anticholinergics (e.g. ipratropium bromide) and beta 2-agonists
(e.g. salbutamol) are used via the inhaled route and have approximately
equivalent acute bronchodilator effects; they differ pharmacokinetically in onset
of effect and duration of action and the anticholinergic may be superior in its
long-term effects on lung function.
PMID- 9400690
TI - Combined anticholinergic therapy in the management of acute asthma.
AB - In a hospital setting, first-line drugs for treatment of acute severe asthma are
usually nebulized short-acting beta 2-agonists and systemic corticosteroids.
Combining a nebulized beta 2-agonist with the anticholinergic agent ipratropium
bromide may produce better bronchodilation than either drug alone, particularly
in patients with more severe episodes. A recent study from New Zealand compared
nebulized beta 2-agonist alone or in combination in patients presenting with
acute severe asthma to the emergency department. Combined treatment produced a
significantly greater change in forced expiratory volume in 1 s (FEV1) than
salbutamol alone. Factors predicting a poor bronchodilator response (irrespective
of study drug received) were frequent use of inhaled beta 2-agonist before
presenting at the emergency department, increased severity and duration of attack
and older age. Patients presenting with more severe asthma had taken more inhaled
bronchodilator before presentation and were therefore likely to be higher on the
dose-response curve and thus less likely to derive benefit from additional
bronchodilator therapy. The patients most likely to benefit from the addition of
nebulized ipratropium bromide were those who had taken less inhaled beta 2
agonist in the previous 6 h. A combined analysis of three large studies on
anticholinergic therapy, including the New Zealand study, has shown a 17%
reduction in risk of subsequent admission (R = 0.83, 95% CI 0.63-1.1). Thus,
nebulized ipratropium bromide imparts a small improvement in lung function when
compared with salbutamol alone; however, further studies are needed to determine
if multiple doses of combined anticholinergic/beta 2-agonist treatment reduce
need for admission.
PMID- 9400691
TI - Combined bronchodilator therapy in the management of chronic obstructive
pulmonary disease.
AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of death and
disability. There is now a better understanding of the pathophysiology of COPD
and of the effectiveness of various treatment strategies in controlling symptoms
and progression of disease. Although cessation of smoking is of primary
importance, the growing realization in recent years that airflow limitation in
COPD can be significantly relieved with the use of bronchodilators has changed
the clinical approach to treating this disease. As a result, inhaled
bronchodilators have become the therapy of choice in new pharmacological
treatment algorithms for COPD. Additionally, the improvement in airflow
limitation seen with bronchodilators, if maintained by patient compliance, can
result in an improved level of lung function. Inhaled beta 2-adrenergic agonists
are effective bronchodilators with a relatively rapid onset of action. They may
also have additional value in that they can increase mucociliary clearance in the
airways. Inhaled anticholinergic bronchodilators, such as ipratropium bromide,
have been shown to be more effective bronchodilators than beta 2-agonists in
COPD; they are associated with a low incidence of side-effects and may decrease
the number of pulmonary exacerbations. The use of the combination of these two
classes of inhaled bronchodilators provides superior bronchodilation than
treatment with either of the individual components without added side-effects or
loss of the positive effects of ipratropium bromide including reduced
exacerbation frequency and lack of tachyphylaxis. The use of combination therapy
also improves cost-effectiveness and patient compliance. Combination therapy
should be considered as an important component of a treatment algorithm of COPD.
PMID- 9400692
TI - Mineral properties and their contributions to particle toxicity.
AB - It has been recognized since at least as early as the mid-1500s that inhaled
minerals (i.e., inorganic particles) can pose a risk. Extensive research has
focused on the biological mechanisms responsible for asbestos- and silica-induced
diseases, but much less attention has been paid to the mineralogical properties
and geochemical mechanisms that might influence a mineral's biological activity.
Several important mineralogical characteristics control a mineral's reactivity in
geochemical reactions and are likely to determine its biological reactivity. In
addition to the traditionally considered variables of particle size and shape,
mineralogical characteristics such as dissolution behavior, ion exchange,
sorptive properties, and the nature of the mineral surface (e.g., surface
reactivity) play important roles in determining the toxicity and carcinogenicity
of a particle. Ultimately, a mineral's species (which provides direct information
on a mineral's structure and composition) is probably one of the most significant
yet most neglected factors that must be considered in studies of toxicity and
carcinogenicity.
PMID- 9400694
TI - Chemical characterization and reactivity of iron chelator-treated amphibole
asbestos.
AB - Iron in amphibole asbestos is implicated in the pathogenicity of inhaled fibers.
Evidence includes the observation that iron chelators can suppress fiber-induced
tissue damage. This is believed to occur via the diminished production of fiber
associated reactive oxygen species. The purpose of this study was to explore
possible mechanisms for the reduction of fiber toxicity by iron chelator
treatments. We studied changes in the amount and the oxidation states of bulk and
surface iron in crocidolite and amosite asbestos that were treated with iron
chelating desferrioxamine, ferrozine, sodium ascorbate, and phosphate buffer
solutions. The results have been compared with the ability of the fibers to
produce free radicals and decompose hydrogen peroxide in a cell-free system in
vitro. We found that chelators can affect the amount of iron at the surface of
the asbestos fibers and its valence, and that they can modify the chemical
reactivity of these surfaces. However, we found no obvious or direct correlations
between fiber reactivity and the amount of iron removed, the amount of iron at
the fiber surface, or the oxidation state of surface iron. Our results suggest
that surface Fe3+ ions may play a role in fiber-related carboxylate radical
formation, and that desferrioxamine and phosphate groups detected at treated
fiber surfaces may play a role in diminishing and enhancing, respectively, fiber
redox activity. It is proposed that iron mobility in the silicate structure may
play a larger role in the chemical reactivity of asbestos than previously
assumed.
PMID- 9400693
TI - Surface reactivity in the pathogenic response to particulates.
AB - The peculiar characteristics of dust toxicity are discussed in relation to the
processes taking place at the particle-biological medium interface. Because of
surface reactivity, toxicity of solids is not merely predictable from chemical
composition and molecular structure, as with water soluble compounds. With
particles having the same bulk composition, micromorphology (the thermal and
mechanical history of dust and adsorption from the environment) determines the
kind and abundance of active surface sites, thus modulating reactivity toward
cells and tissues. The quantitative evaluation of doses is discussed in
comparisons of dose-response relationships obtained with different materials.
Responses related to the surface of the particle are better compared on a per
unit surface than per-unit weight basis. The role of micromorphology,
hydrophilicity, and reactive surface cations in determining the pathogenicity of
inhaled particles is described with reference to silica and asbestos toxicity.
Heating crystalline silica decreases hydrophilicity, with consequent
modifications in membranolytic potential, retention, and transport. Transition
metal ions exposed at the surface generate free radicals in aqueous suspensions.
Continuous redox cycling of iron, with consequent activation-reactivation of the
surface sites releasing free radicals, could account for the long-term
pathogenicity caused by the inhalation of iron-containing fibers. In various
pathogenicities caused by mixed dusts, the contact between components modifies
toxicity. Hard metal lung disease is caused by exposure to mixtures of metals and
carbides, typically cobalt (Co) and tungsten carbide (WC), but not to single
components. Toxicity stems from reactive oxygen species generation in a mechanism
involving both Co metal and WC in mutual contact. A relationship between the
extent of water adsorption and biopersistence is proposed for vitreous fibers.
Modifications of the surface taking place in vivo are described for ferruginous
bodies and for the progressive comminution of chrysotile asbestos fibers.
PMID- 9400695
TI - Study of the stability of a paramagnetic label linked to mesoporous silica
surface in contact with rat mesothelial cells in culture.
AB - Stable radicals detectable by electron paramagnetic resonance (EPR) may be use in
the investigation of early events in cell-particle toxicity. Piperidine-N-oxyl
derivatives (nitroxides), covalently linked to the surface of a high surface area
silica (used as model solid for the technique), served as probes in the
investigation of the effects of incubation of silica particles with mesothelial
cells. A mesoporous silica (MCM-41), prepared by precipitation from a micellar
solution, was the most appropriate silica-based particle for this purpose, as its
channels allow direct contact with small molecules but not with macromolecules.
The cytotoxicity of this amorphous silica is very low, allowing relatively high
particle loading in the cell cultures. Both the high surface area of the sample
and the large amount of inorganic material extracted from the cell culture
provide enough material to run reasonably intense EPR spectra. Computer-aided
analysis of the EPR spectra of silica-bound nitroxides provided information on
the sensitivity of the labeled silica monitoring different environments, e.g., to
follow the path of particles in a mammalian cell culture. Upon contact of the
particles with mesothelial cells, the mean distance among the labels at the
silica surface decreased as a consequence of the release of oxidizing and/or
radical moieties from the cells.
PMID- 9400696
TI - Demonstration of nitric oxide on asbestos and silicon carbide fibers with a new
ultraviolet spectrophotometric assay.
AB - Nitric oxide (NO) has a number of important functions in biological systems and
may play a role in the toxicity of mineral fibers. We investigated whether NO
might be present on the surface of mineral fibers and if crocidolite could adsorb
NO from NO gas or cigarette smoke. NO was determined with a new gas
chromatography-ultraviolet spectrophotometric technique after thermal desorption
from the fiber surface and injection in a gas flow cell. NO was found in
different amounts on chrysotile B, crocidolite, amosite, and silicon carbide
whiskers. There was a strong correlation between the amount of NO and the
specific surface area of these fibers (r = 0.98). NO could not be demonstrated on
rockwool fibers [man-made vitreous fiber(s) (MMVF)21 and MMVF22] or silicon
nitride whiskers. NO on crocidolite, amosite, and silicon carbide whiskers was
readily desorbed from the fibers at increased temperature, while NO on chrysotile
B seemed to be more firmly adsorbed to the fiber and required a longer period of
time to be desorbed. The amount of NO bound to crocidolite increased from 34
micrograms/g fiber to 85 and 474 micrograms/g after exposing the fibers to
cigarette smoke and NO gas, respectively. These findings indicate that a) NO
adsorbs to fiber surfaces, b) some fibers adsorb more NO than others, c) some
fibers adsorb NO more strongly than others, and d) the amounts of NO on fibers
may be increased after exposure of the fiber to cigarette smoke or other sources
of NO. The biological significance of NO on mineral fibers remains to be
investigated.
PMID- 9400697
TI - Can microwave radiation at high temperatures reduce the toxicity of fibrous
crocidolite asbestos?
AB - Exposure of animals and humans to crocidolite asbestos fibers produces fibrosis
and two types of cancers: bronchogenic carcinoma and mesothelioma. It is
therefore desirable to reduce toxicity of these fibers without affecting their
other characteristics. In this study, commercial crocidolite asbestos fibers were
radiated with microwave radiation at different temperatures. Radiated fibers and
nonradiated original fibers were then studied by Mossbauer spectroscopy to
quantify the amount of ferric and ferrous ions present at structurally different
sites in each crocidolite sample. They were also studied for their ability to
initiate the peroxidation of linoleic acid to assess the effect of radiation on
this process. Results showed that microwave radiation reduced the total Fe2+/Fe3+
ratio. This reduction produced a concomitant decrease in the ability of the
radiated samples to peroxidize linoleic acid.
PMID- 9400698
TI - Significance of the biodurability of man-made vitreous fibers to risk assessment.
AB - It is generally agreed that the biodurability of man-made vitreous fibers is a
major factor for the characterization of potential health effects. As there is
currently no standardization of experimental protocols to determine biodurabilty,
the results of the clearance assays have not been used up to now for regulatory
purposes. Methods used to analyze biodurability in animal models are short-term
inhalational exposure and intratracheal instillation of rat respirable fibers.
Both test methods have strengths and limitations for regulatory purposes. We
outline recommended procedures for standardized biodurability assays that can be
used to compare different fiber types. In animal experiments, biodurability is
difficult to separate from biopersistence, as mucociliary and macrophage-mediated
clearance occur simultaneously with dissolution and disintegration. For
intratracheal instillation, a sized rat respirable sample must be used.
Precautions should be taken to prevent aggregation of fibers in the lungs.
Although from a scientific point of view questions remain about quantifying the
influence of fiber length, diameter, dose, and exposure route, consistent data on
the biodurability of vitreous glass fibers are available which may be used for
regulatory purposes.
PMID- 9400699
TI - Investigations on health-related properties of two sepiolite samples.
AB - Published i.p. injection studies have shown different biological behavior of
different sepiolite samples. There was no evidence for carcinogenic potential of
sepiolite from Vicalvaro, Spain, whereas a high tumor incidence was reported for
sepiolite from Finland. The low biological activity of the sepiolite from
Vicalvaro, compared to the Finnish sample, could be caused by low in vivo
persistence or by the short length of the fibers, or both. In this study a
further sepiolite sample, obtained as a commercial sample originating from China,
was investigated. This sample contained a higher fraction of fibers longer than 5
microns, comparable to the Finnish sepiolite sample. The fraction of fibers with
a length > 5 microns was 0.12 and 2.2% for the Vicalvaro and Chinese sepiolite,
respectively. For the fiber fraction longer than 8 microns, the corresponding
values were 0.0045 and 0.82%. The in vivo persistence of the sepiolite samples
from China and Vicalvaro was analyzed after intratracheal instillation of 2 mg in
female Wistar rats. Fiber retention in the lungs was analyzed by transmission
electron microscopy at different sacrifice dates up to 12 months after
application. For the Vicalvaro sepiolite, a splitting of fiber bundles was found
during retention time in the lung. Therefore, no half-time of the fiber clearance
could be calculated from the number of fibers. The decrease of the calculated
retained fiber mass was faster for the Vicalvaro sepiolite (T1/2 = 89 days)
compared to the Chinese sepiolite (T1/2 = 129 days). For 2 or 3 rats per group,
at sacrifice date 12 months after i.p. injection, the lung was investigated by
histopathology. The main difference between both treatment groups was a more
pronounced fibrotic response in the Chinese sepiolite-treated rats compared to
those treated with Vicalvaro sepiolite. It is concluded that both the higher
fraction of long sepiolite fibers and the slower elimination rate of the fiber
mass in the Chinese sample were important factors for the different biological
reaction in comparison with Vicalvaro sepiolite.
PMID- 9400700
TI - Bioavailable transition metals in particulate matter mediate cardiopulmonary
injury in healthy and compromised animal models.
AB - Many epidemiologic reports associate ambient levels of particulate matter (PM)
with human mortality and morbidity, particularly in people with preexisting
cardiopulmonary disease (e.g., chronic obstructive pulmonary disease, infection,
asthma). Because much ambient PM is derived from combustion sources, we tested
the hypothesis that the health effects of PM arise from anthropogenic PM that
contains bioavailable transition metals. The PM samples studied derived from
three emission sources (two oil and one coal fly ash) and four ambient airsheds
(St. Louis, MO; Washington; Dusseldorf, Germany; and Ottawa, Canada). PM was
administered to rats by intratracheal instillation in equimass or equimetal doses
to address directly the influence of PM mass versus metal content on acute lung
injury and inflammation. Our results indicated that the lung dose of bioavailable
transition metal, not instilled PM mass, was the primary determinant of the acute
inflammatory response for both the combustion source and ambient PM samples.
Residual oil fly ash, a combustion PM rich in bioavailable metal, was evaluated
in a rat model of cardiopulmonary disease (pulmonary vasculitis/hypertension) to
ascertain whether the disease state augmented sensitivity to that PM. Significant
mortality and enhanced airway responsiveness were observed. Analysis of the
lavaged lung fluids suggested that the milieu of the inflamed lung amplified
metal-mediated oxidant chemistry to jeopardize the compromised cardiopulmonary
system. We propose that soluble metals from PM mediate the array of PM-associated
injuries to the cardiopulmonary system of the healthy and at-risk compromised
host.
PMID- 9400701
TI - Oncogenes and tumor-suppressor genes in mesothelioma--a synopsis.
AB - Invariably mesothelioma is diagnosed late in the development of the disease when
treatment is no longer effective. Therefore, a key to reducing the mortality rate
of this neoplasm is knowledge of the general sequence of genetic events between
initiation of mesothelial cells and the emergence of the metastatic tumor cells.
Unfortunately, relatively little is known about the early changes in the genesis
of this disease. Of the known changes, the most frequent are in the tumor
suppressor genes p16INK4a and NF2 and possibly the SV40 virus large T-antigen
oncogene. The molecular nature of the changes in these genes as well as other
alterations are addressed in this overview.
PMID- 9400702
TI - Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite
asbestos fibers.
AB - Exposure of mesothelial cells to asbestos fibers in vitro has been shown to
induce DNA damage mediated by oxidants. An early cellular response to DNA damage
is increased expression of the p53 protein. This protein induces transcription of
genes that activate cell cycle checkpoints or induce apoptosis. A murine
mesothelial cell line that spontaneously acquired a point mutation in the p53
gene shows increased sensitivity to DNA damage induced by crocidolite asbestos
fibers. It is hypothesized that p53-deficient mice will show increased
sensitivity to the genotoxic effects of asbestos and accelerated development of
malignant mesotheliomas.
PMID- 9400704
TI - Malignant transformation of immortalized human bronchial epithelial cells by
asbestos fibers.
AB - Although asbestos is a well-established lung carcinogen, there currently is no
suitable human cell model in which to examine the underlying cellular and
molecular changes associated with fiber-mediated bronchial carcinogenesis. Using
a recently established transformation model based on a human papillomavirus
immortalized human bronchial epithelial cell line, we successfully transformed
these BEP2D cells after a single, 7-day treatment with a 20-microgram/ml (4
micrograms per cm2 area) dose of Union Internationale Contre le Cancer (UICC)
Rhodesian chrysotile fibers. Asbestos treatment resulted in a surviving fraction
of 0.18 compared to control cells. Transformed cells developed through a series
of sequential steps, including altered growth kinetics, resistance to serum
induced terminal differentiation, and anchorage-independent growth, before
becoming tumorigenic to form progressively growing tumors in nude mice. Seven
tumorigenic cell lines were isolated and determined to be of human epithelial
origin based on immunofluorescent staining of keratin and isozyme analysis.
Analysis of tumor DNA revealed no mutations at either codon 12 or 13 in any the
ras oncogenes. An independent role for K-ras mutation in fiber carcinogenesis,
therefore, cannot be confirmed. This model provides a unique opportunity to study
the cellular and molecular changes at the various stages in fiber-mediated
neoplastic transformation of human bronchial epithelial cells.
PMID- 9400703
TI - Mechanisms of fiber-induced genotoxicity.
AB - The mechanisms of particle-induced genotoxicity have been investigated mainly
with asbestos fibers. The results are summarized and discussed in this paper. DNA
damage can be produced by oxidoreduction processes generated by fibers. The
extent of damage yield depends on experimental conditions: if iron is present,
either on fibers or in the medium, damage is increased. However, iron reactivity
does not explain all the results obtained in cell-free systems, as breakage of
plasmid DNA was not directly associated with the amount of iron released by the
fibers. The proximity of DNA to the site of generation of reactive oxygen species
(ROS) is important because these species have an extremely short half-life.
Damage to cellular DNA can be produced by oxidoreduction processes that originate
from cells during phagocytosis. Secondary molecules that are more stable than ROS
are probably involved in DNA damage. Oxidoreduction reactions originating from
cells can induce mutations. Genotoxicity is also demonstrated by chromosomal
damage associated with impaired mitosis, as evidenced by chromosome
missegregation, spindle changes, alteration of cell cycle progression, formation
of aneuploid and polyploid cells, and nuclear disruption. In some of these
processes, the particle state and fiber dimensions are considered important
parameters in the generation of genotoxic effects.
PMID- 9400705
TI - Neutrophils amplify the formation of DNA adducts by benzo[a]pyrene in lung target
cells.
AB - Inflammatory cells and their reactive oxygen metabolites can cause mutagenic
effects in lung cells. The purpose of this study was to investigate the ability
of activated neutrophils to modulate DNA binding of benzo[a]pyrene (B[a]P), a
known carcinogen, in lung target cells. Equivalent numbers of rat lung epithelial
cells (RLE-6TN cell line) and freshly isolated human blood neutrophils (PMN) were
coincubated in vitro for 2 hr after addition of benzo[a]pyrene (0.5 microM) or
two of its trans-diol metabolites, with or without stimulation with phorbol
myristate acetate (PMA). DNA adducts of B[a]P-metabolites were determined in
target cells using 32P-postlabeling; oxidative DNA damage (7-hydro-8-oxo-2'
deoxyguanosine [8-oxodG]) was evaluated by high performance liquid chromatography
with electrochemical detection. Increased DNA adducts were observed in lung cells
coincubated with polymorphonuclear leukocytes (PMN). Activation of PMN with PMA,
or addition of more activated PMN in relation to the number of lung cells,
further increased the number of adducts, the latter in a dose-response manner.
Incubation with B[a]P-4,5-diol did not result in any adduct formation, while
B[a]P-7,8-diol led to a significant number of adducts. Moreover, PMA-activated
PMN strongly enhanced adduct formation by B[a]P-7,8-diol, but not 8-oxodG, in
lung cells. The addition of antioxidants to the coincubations significantly
reduced the number of adducts. Results suggest that an inflammatory response in
the lung may increase the biologically effective dose of polycyclic aromatic
hydrocarbons (PAHs), and may be relevant to data interpretation and risk
assessment of PAH-containing particulates.
PMID- 9400706
TI - A new mechanism for DNA alterations induced by alpha particles such as those
emitted by radon and radon progeny.
AB - The mechanism(s) by which alpha (alpha) particles like those emitted from inhaled
radon and radon progeny cause their carcinogenic effects in the lung remains
unclear. Although direct nuclear traversals by alpha-particles may be involved in
mediating these outcomes, increasing evidence indicates that a particles can
cause alterations in DNA in the absence of direct hits to cell nuclei. Using the
occurrence of excessive sister chromatid exchanges (SCE) as an index of DNA
damage in human lung fibroblasts, we investigated the hypothesis that alpha
particles may induce DNA damage through the generation of extracellular factors.
We have found that a relatively low dose of alpha-particles can result in the
generation of extracellular factors, which, upon transfer to unexposed normal
human cells, can cause excessive SCE to an extent equivalent to that observed
when the cells are directly irradiated with the same irradiation dose. A short
lived, SCE-inducing factor(s) is generated in alpha-irradiated culture medium
containing serum in the absence of cells. A more persistent SCE-inducing
factor(s), which can survive freeze-thaw and is heat labile is produced by
fibroblasts after exposure to the alpha-particles. These results indicate that
the initiating target for alpha-particle-induced genetic changes can be larger
than a cell's nucleus or even a whole cell. How transmissible factors like those
observed here in vitro may extend to the in vivo condition in the context of a
particle-induced carcinogenesis in the respiratory tract remains to be
determined.
PMID- 9400707
TI - Fiber-specific molecular features of tumors induced in rat peritoneum.
AB - Molecular markers such as mutational spectra or mRNA expression patterns may give
some indication of the mechanisms of carcinogenesis induced by fibers and other
carcinogens. In our study, tumors were induced by application of crocidolite
asbestos or benzo[a]pyrene (B[a]P) to rat peritoneum. DNA and RNA of these tumors
were subjected to analysis of point mutations and to investigation of mRNA
expression patterns. With both assays we found typical features depending on the
type of carcinogen applied. The analysis of point mutations in the tumor
suppressor gene p53 revealed mutations in the B[a]P-induced tumors. However, in
the tumors induced by crocidolite asbestos that were of the same tumor type as
those induced by B[a]P, mutations in p53 were not detectable. Every mutation
detected on the DNA level causes an amino acid substitution within one of the
functional domains of the tumor suppressor protein. Therefore, these mutations
seem to be of biological relevance for tumor progression and indicate a
difference in the carcinogenesis regarding the type of the carcinogenic
substance. An additional specificity of crocidolite-induced tumors was detectable
by analyzing the mRNA expression of the tumor suppressor gene WT1, which is known
to be expressed in human mesothelial and mesothelioma cells. A relatively high
amount of WT1 mRNA was measured by quantitative competitive reverse transcription
polymerase using RNA extracted from crocidolite-induced tumors. However, WT1
seems to be expressed on a rather low level in tumors induced by B[a]P.
PMID- 9400708
TI - Mechanism of asbestos-mediated DNA damage: role of heme and heme proteins.
AB - Several observations, including studies from this laboratory, demonstrate that
asbestos generates free radicals in the biological system that may play a role in
the manifestation of asbestos-related cytotoxicity and carcinogenicity. It has
also been demonstrated that iron associated with asbestos plays an important role
in the asbestos-mediated generation of reactive oxygen species. Exposure to
asbestos leads to degradation of heme proteins such as cytochrome P450-releasing
heme in cytosol. Our simulation experiments in the presence of heme show that
such asbestos-released heme may increase lipid peroxidation and can cause DNA
damage. Further, heme and horseradish peroxidase (HRP) can cause extensive DNA
damage in the presence of asbestos and hydrogen peroxide/organic
peroxide/hydroperoxides. HRP catalyzes oxidation reactions in a manner similar to
that of prostaglandin H synthetase. Iron released from asbestos is only partially
responsible for DNA damage. However, our studies indicate that DNA damage
mediated by asbestos in vivo may be caused by a combination of effects such as
the release and participation of iron, heme, and heme moiety of prostaglandin H
synthetase in free radical generation from peroxides and hydroperoxides.
PMID- 9400709
TI - Asbestos, asbestosis, and lung cancer: observations in Quebec chrysotile workers.
AB - One prospective epidemiologic study of asbestos cement workers with radiological
small opacities has been cited as a rationale for attributing excess lung cancer
to asbestosis. This approach could have considerable practical value for disease
attribution in an era of decreasing exposure. However, a recent International
Agency for Research on Cancer review concludes that the mechanism of production
of asbestos-related lung cancer are unknown. Asbestosis, therefore, cannot be a
biologically effective dose marker of lung cancer susceptibility. Asbestosis
nonetheless would be useful in identifying asbestos-attributable lung cancer
cases if it could be proven an infallible exposure indicator. In this study, we
tested this hypothesis in the chrysotile miners and millers of Quebec, Canada. We
examined exposure histories, autopsy records, and lung fiber content for 111
Quebec chrysotile miners and millers. If the hypothesis of an asbestosis
requirement for lung cancer attribution were accurate, we would expect as
asbestosis diagnosis to separate those with lung cancer and high levels of
exposure from those with lower levels of exposure in a specific and sensitive
manner. This is the first such study in which historical job-based individual
estimates based on environmental measurements, lung fiber content, exposure
timing, and complete pathology records including autopsies were available for
review. We found significant excesses of lung tremolite and chrysotile and
estimated cumulative exposure in those with lung cancer and asbestosis compared
to those with lung cancer without asbestosis. However, when the latter were
directly compared on a case-by-case basis, there was a marked overlap between
lung cancer cases with and without asbestosis regardless of the measure of
exposure. Smoking habits did not differ between lung cancer cases with and
without asbestosis. In regression models, smoking pack-years discriminated
between those with the without lung cancer, regardless of asbestosis status. Most
seriously, the pathologic diagnosis of asbestosis itself seemed arbitrary in many
cases. We conclude that although the presence of pathologically diagnosed
asbestosis is a useful marker of exposure, the absence of this disease must be
regarded as one of many factors in determining individual exposure status and
disease causation.
PMID- 9400710
TI - Cell signaling pathways elicited by asbestos.
AB - In recent years, it has become apparent that minerals can trigger alterations in
gene expression by initiating signaling events upstream of gene transactivation.
These cascades may be initiated at the cell surface after interaction of minerals
with the plasma membrane either through receptorlike mechanisms or integrins.
Alternatively, signaling pathways may be stimulated by active oxygen species
generated both during phagocytosis of minerals and by redox reactions on the
mineral surface. At least two signaling cascades linked to activation of
transcription factors, i.e., DNA-binding proteins involved in modulating gene
expression and DNA replication, are stimulated after exposure of lung cells to
asbestos fibers in vitro. These include nuclear factor kappa B (NF kappa B) and
the mitogen-activated protein kinase (MAPK) cascade important in regulation of
the transcription factor, activator protein-1 (AP-1). Both NF kappa B and AP-1
bind to specific DNA sequences within the regulatory or promoter regions of genes
that are critical to cell proliferation and inflammation. Unraveling the cell
signaling cascades initiated by mineral dusts and pharmacologic inhibition of
these events may be important for the control and treatment of mineral-associated
occupational diseases.
PMID- 9400711
TI - Possible role of lipid peroxidation in the induction of NF-kappa B and AP-1 in
RFL-6 cells by crocidolite asbestos: evidence following protection by vitamin E.
AB - Asbestos fibers cause persistent induction of the oxidative stress sensitive
transcription factors nuclear factor kappa-B (NF-kappa B) and activator protein-1
(AP-1) in mammalian cells. These transcription factors play an important role in
the regulation of cellular activity. Lipid peroxidation, mediated by reactive
oxygen species, is thought to be a possible mechanism in the pathogenicity of
asbestos fibers. These studies were designed to determine if crocidolite asbestos
induced lipid peroxidation plays a role in the mechanism of formation of NF-kappa
B and AP-1. Treatment of a rat lung fibroblast cell line (RFL-6) with crocidolite
asbestos in the presence and absence of the membrane antioxidant vitamin E
decreased the levels of crocidolite-induced AP-1 and NF-kappa B to background
levels. Preincubation of RFL-6 cells with 5,8,11,14-eicosatetraynoic acid, an
inhibitor of arachidonic acid metabolism, prior to exposure to crocidolite,
abrogated crocidolite-induced NF-kappa B DNA-binding activity to background
levels. Coincubation with indomethacin, a cyclooxygenase inhibitor, had no effect
on NF-kappa B DNA-binding activity induced by crocidolite. However,
nordihydroguaiaretic acid, a lipoxygenase inhibitor, decreased levels of NF-kappa
B to background levels. This would suggest that lipoxygenase metabolites of
arachidonic acid, produced following lipid peroxidation, are involved in the
cellular signalling events to NF-kappa B transcription factor induction by
asbestos.
PMID- 9400713
TI - Asbestos and silica-induced changes in human alveolar macrophage phenotype.
AB - The mechanism by which fibrogenic particulates induce inflammation that can
progress to lung fibrosis is uncertain. The alveolar macrophage (AM) has been
implicated in the inflammatory process because of its function and reported
release of inflammatory mediators when isolated from fibrotic patients. It has
been recently shown that fibrogenic, but not nonfibrogenic, particulates are
highly potent in inducing apoptosis of human AM. In this study, we tested the
hypothesis that fibrogenic particulates could shift the phenotypic ratio of human
AM to a more inflammatory condition. The macrophage phenotypes were characterized
by flow cytometry targeting the RFD1 and RFD7 epitopes. Results demonstrated that
chrysotile and crocidolite asbestos, as well as crystalline silica, but not
titanium dioxide or wollastonite, increased the RFD1+ phenotype (inducer or
immune activator macrophages) and decreased the RFD1+ RFD7+ phenotype (suppressor
macrophages). These results provide a mechanistic explanation that may link
apoptosis (namely, suppressor macrophages) to a shift in the ratio of macrophage
phenotypes that could initiate lung inflammation.
PMID- 9400712
TI - Increased focal adhesion kinase- and urokinase-type plasminogen activator
receptor-associated cell signaling in endothelial cells exposed to asbestos.
AB - Exposure of low-passage endothelial cells in culture to nonlethal amounts of
asbestos, but not refractory ceramic fiber-1, increases cell motility and gene
expression. These changes may be initiated by the fibers mimicking matrix
proteins as ligands for receptors on the cell surface. In the present study, 1-
to 3-hr exposures of endothelial cells to 5 mg/cm2 of chrysotile asbestos caused
marked cell elongation and motility. However, little morphological change was
seen when chrysotile was added to cells pretreated with either mannosamine to
prevent assembly of glycophosphatidylinositol (GPI)-anchored receptors or with
herbimycin A to inhibit tyrosine kinase activity. Affinity purification of GPI
anchored urokinase-type plasminogen activator receptor (uPAR) from chrysotile
exposed cells demonstrated that asbestos altered the profile of proteins and
phosphoproteins complexed with this receptor. Tyrosine kinase activities in the
complexes were also increased by asbestos. Immunoprecipitations with selective
monoclonal antibodies demonstrated that both chrysotile and crocidolite asbestos
increase kinase activities associated with p60 Src or p120 focal adhesion kinase
(FAK). Further, chrysotile also changed the profile of proteins and
phosphoproteins associated with FAK in intact cells. These data suggest that
asbestos initiates endothelial cell phenotypic change through interactions with
uPAR-containing complexes and that this change is mediated through tyrosine
kinase cascades.
PMID- 9400714
TI - p53, Cip1, and Gadd153 expression following treatment of A549 cells with natural
and man-made vitreous fibers.
AB - DNA damage induced by chemicals and ionizing radiation is associated with the
expression of negative regulators of the cell cycle. The arrest of cells in G1
and G2 phases of the cell cycle provides time for DNA repair. Asbestos fibers are
carcinogenic when inhaled by both humans and animals; however, the mechanism by
which the fibers exert their effect is unknown. This work was undertaken to
determine whether the expression of DNA damage-inducible genes differs between
crocidolite, a fiber positive for lung tumors, and JM 100 glass microfiber, which
is negative for lung tumors when inhaled by rats. Temporal and dose-related
expressions of p53, Cip1, and Gadd153 proteins were determined in cultured A549
cells treated with either Union Internationale Contre le Cancer crocidolite or JM
100 for 20 hr and cultured in fresh media. Immunolabeled cells were analyzed by
flow cytometry, and the increased number of protein-expressing cells was
determined by subtracting the expression in unexposed cells from exposed cells.
Crocidolite induced the expression of all three proteins with a maximum
expression after approximately 18 hr in fresh media. At a similar time point, JM
100 did not markedly induce the three proteins. Crocidolite also induced a dose
dependent increase in the number of cells in the G2 phase of the cell cycle.
These results show that asbestos behaves like ionizing radiation and genotoxic
chemicals by inducing proteins associated with DNA damage and cell-cycle arrest.
The clear difference in response between crocidolite and JM 100 may help
elucidate the mechanism of action of toxic and nontoxic fibers.
PMID- 9400715
TI - Crocidolite asbestos induces apoptosis of pleural mesothelial cells: role of
reactive oxygen species and poly(ADP-ribosyl) polymerase.
AB - Mesothelial cells, the progenitor cells of the asbestos-induced tumor
mesothelioma, are particularly sensitive to the toxic effects of asbestos,
although the molecular mechanisms by which asbestos induces injury in mesothelial
cells are not known. We asked whether asbestos induced apoptosis in mesothelial
cells and whether reactive oxygen species were important. Rabbit pleural
mesothelial cells were exposed to crocidolite asbestos or control particles (1-10
micrograms/cm2) over 24 hr and evaluated for oligonucleosomal DNA fragmentation,
loss of membrane phospholipid asymmetry, and nuclear condensation. Asbestos
fibers, not control particles, induced apoptosis in mesothelial cells by all
assays. Induction of apoptosis was dose dependent; crocidolite (5 micrograms/cm2)
induced apoptosis (15.0 +/- 1.1%, mean +/- SE; n = 12) versus control particles
(< 4%), as measured by appearance of nuclear condensation. Apoptosis induced by
asbestos, but not by actinomycin D, was inhibited by extracellular catalase,
superoxide dismutase in the presence of catalase, hypoxia (8% oxygen),
deferoxamine, and 3-aminobenzamide (an inhibitor of the nuclear enzyme,
poly(adenosine diphosphate-ribosyl) polymerase). We conclude that asbestos
induces apoptosis in mesothelial cells via reactive oxygen species. We speculate
that escape from this pathway could allow the abnormal survival of mesothelial
cells with asbestos-induced mutations.
PMID- 9400716
TI - Alterations in protein glycosylation in PMA-differentiated U-937 cells exposed to
mineral particles.
AB - Carbohydrate moieties of cell glycoconjugates play a pivotal role in molecular
recognition phenomena involved in the regulation of most biological systems and
the changes observed in cell surface carbohydrates during cell activation or
differentiation frequently modulate certain cell functions. Consequently, some
aspects of macrophage response to particle exposure might conceivably result from
alterations in glycosylation. Therefore, the effect of mineral particles on
protein glycosylation was investigated in phorbol myristate acetate (PMA)
differentiated U-937. Jacalin, a lectin specific for O-glycosylated structures,
showed a global increase in O-glycosylation in particle-treated cells. In
contrast, no significant modifications were observed with concanavalin A, a
lectin that recognizes certain N-glycosylated structures. The sialic acid
specific lectins Sambucus nigra agglutinin and Maackia amurensis agglutinin and
the galactose-specific lectin Ricinus communis agglutinin revealed a complex
pattern of alterations in glycoprotein glycosylation after crystalline silica or
manganese dioxide treatments. Expression of sialyl Lewis(x), a glycosylated
structure implicated in leukocyte trafficking, could not be detected in control
or treated cells. This finding was consistent with the decrease in sialyl
Lewis(x) expression observed during PMA-induced differentiation. In conclusion,
various treatments used in this study induced quantitative as well as qualitative
changes in protein glycosylation. Whether these changes are due to glycosidase
release or to an alteration in glycosyltransferase expression remains to be
determined. The potential functional implications of these changes are currently
under investigation.
PMID- 9400717
TI - Cytokines and particle-induced inflammatory cell recruitment.
AB - The inflammatory response is a key component of host defense. However, excessive
or persistent inflammation can contribute to the pathogenesis of disease.
Inflammation is regulated, in part, by cytokines, which are small, typically
glycosylated proteins that interact with membrane receptors to regulate cellular
processes such as proliferation, differentiation, and secretion. During the past
10 years studies in humans and experimental animals have demonstrated that a
cytokine called tumor necrosis factor alpha (TNF-alpha) plays a key role in the
initiation of inflammatory responses in the lung and other tissues, including
inflammation resulting from inhalation of noxious particles. There is now
compelling evidence that one of the pathways by which inhaled particles stimulate
the recruitment and subsequent activation of inflammatory cells is through the
activation of lung macrophages to release TNF-alpha. TNF-alpha then acts via
paracrine and autocrine pathways to stimulate cells to release other cytokines
known as chemokines, which are directly chemotactic to leukocytes and other cells
that participate in inflammatory and wound healing responses. In addition to a
TNF-alpha-mediated pathway, there is growing evidence that some particles such as
quartz and crocidolite can directly activate lung epithelial cells to release
chemokines such as macrophage inflammatory protein-2, cytokine-induced neutrophil
chemoattractant, and interleukin-8. A direct stimulatory effect of particles on
lung epithelium may represent an additional or alternate pathway by which inhaled
particles may elicit inflammation in the lung. Recent studies have suggested that
oxidative stress may be a component of the mechanism by which particles activate
cytokine production in cells such as macrophages and epithelial cells. The
contribution of oxidative stress to particle-induced cytokine gene expression
appears to be mediated, at least in part, through activation of the transcription
factor nuclear factor kappa B.
PMID- 9400718
TI - Analyzing the genes and peptide growth factors expressed in lung cells in vivo
consequent to asbestos exposure and in vitro.
AB - Inhalation of fibrogenic particles causes injury to the bronchiolar-alveolar
epithelium. Consequently, there is a rapid proliferative response as the
epithelium recovers and interstitial mesenchymal cells divide and produce
connective tissue. In our model of brief (5-hr) exposure to chrysotile asbestos
(approximately 1000 fibers/cc) in rats and mice, these events result in focal
scarring at the bronchiolar-alveolar duct junctions in a histopathologic pattern
identical to that seen in asbestos-exposed individuals. After 3 consecutive days
of exposure, these lesions persist for at least 6 months postexposure. We
postulate that cell proliferation and production of extracellular matrix is
mediated in large part by three peptide growth factors, transforming growth
factors alpha and beta (TGF-alpha and -beta), and platelet-derived growth factor
(PDGF) A- and B-chains. To test this hypothesis in part, we have asked whether
the genes that code for these growth factor proteins are activated at sites of
asbestos-induced lung injury. If these genes were not activated, it would be
reasonable to suspect that other potent growth factors and cytokines released
during lung injury could be the primary mediators of fibroproliferative lung
disease. In the studies reported here, we show, by in situ hybridization (ISH)
and immunohistochemistry, that the four genes and their concomitant proteins are
expressed within 24 hr in the bronchiolar-alveolar epithelium and underlying
mesenchymal cells. RNase protection assay and ISH showed that the PDGF gene was
upregulated during the first 5 hr of exposure and all the gene products remained
above control levels for at least 2 weeks postexposure. TGF-alpha is a potent
mitogen for epithelial cells, whereas the PDGF isoforms are potent growth factors
for mesenchymal cells. TGF-beta retards fibroblast growth but stimulates
extracellular matrix synthesis. Further studies using gene knockouts, appropriate
antibodies, or antisense technology will be necessary to prove whether any of the
growth factors are playing a significant role in fibrogenic lung disease. In
addition, we have carried out a series of studies using type II alveolar
epithelial cells purified from adult mouse lungs and maintained for up to 8 weeks
in serum-free culture. These cells exhibit high transepithelial resistance values
and they release TGF-beta 1 and -beta 2. This cell type also has been cultured
from TGF-alpha knockout mice, resulting in monolayers with increased
transepithelial resistance. This combination of studies in vivo and in vitro will
allow us to pursue the mechanisms through which growth factors mediate lung
fibrosis.
PMID- 9400719
TI - Effects of mineral fibers on the expression of genes whose product may play a
role in fiber pathogenesis.
AB - To determine which factors are useful for the risk assessment of man-made fibers,
we examined the gene expression of proinflammatory cytokines, growth factors,
manganese superoxide dismutase (MnSOD), and inducible nitric oxide synthase
(iNOS) in mineral fiber-exposed rats by means of reverse transcription-polymerase
chain reaction (RT-PCR). Male Wistar rats received a single intratracheal
instillation of either saline (control) or two types of fibers (2 mg of Union
Internationale Centre le Cancer (UICC) chrysotile or alumina silicate refractory
ceramic fiber [RCF]). Expression of interleukin-1 alpha (IL-1 alpha), interleukin
6 (IL-6), tumor necrosis factor alpha (TNF-alpha), platelet-deriving growth
factor-A, (PDGF-A), platelet-deriving growth factor-B (PDGF-B), transforming
growth factor beta 1 (TGF-beta 1), basic fibroblast growth factor (bFGF), MnSOD,
and iNOS mRNA from lung and lipopolysaccharide (LPS)-stimulated alveolar
macrophages (AM) were assessed by RT-PCR. Among these factors, IL-1 alpha, TNF
alpha, IL-6, bFGF, and iNOS would be the possible parameters for the risk
assessment of fibers. In a follow-up study, we investigated the time course (3
days, 1 week, 1 month, and 3 months) of expression of IL-1 alpha and TNF-alpha by
LPS-stimulated AM exposed to mineral fibers in vivo. Male Wistar rats were
instilled intratracheally with saline or fibers (2 mg of Union Internationale
Contre le Cancer UICC crocidolite or potassium octatitanate whisker [TW]). The
expression of IL-1 alpha mRNA by fibers was greatest in TW, crocidolite,
chrysotile, and RCF-instilled rat AM, in that order. The increase of IL-1 alpha
and TNF-alpha mRNA in AM peaked at 1 month and 3 days after exposure to
crocidolite or TW, respectively. The expression of IL-1 alpha by fibers
(crocidolite, chrysotile, TW, and RCF) may be a good indicator of the pathologic
potential of fibers.
PMID- 9400720
TI - Particulate-cell interactions and pulmonary cytokine expression.
AB - The type II cell plays an important role in the response of the alveolar
epithelium after lung injury through its synthesis and secretion of pulmonary
surfactant, and by acting as the stem cell for the replacement of damaged type I
epithelial cells. The nonciliated bronchiolar epithelial (Clara) cell is thought
to play a similar role during repair of the bronchiolar epithelium. Recent
evidence has suggested that epithelial cells may participate in aspects of the
inflammatory response and regulation of fibroblast growth during pulmonary
fibrosis through the production of and response to specific growth factors and
cytokines. The cellular and molecular responses of epithelial cells and how they
lead to the progression of events that defines the pulmonary parenchymal response
to a class of particles is unclear. We used particles differing in size, chemical
composition, and fibrogenicity in vivo and in vitro to elucidate early changes in
proinflammatory and profibrotic cytokine and antioxidant gene expression in lung
cells. Early increases in mRNA and protein for the proinflammatory cytokines
interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha have been observed
in epithelial cells following exposure. These are accompanied by changes in
specific epithelial genes including surfactant protein C and Clara cell secretory
protein. The data indicate that effects on the epithelium are due to direct
interactions with particles, not a result of macrophage-derived mediators, and
suggest a more significant role in the overall pulmonary response than previously
suspected. These results suggest that type II cell growth factor production may
be significant in the pathogenesis of pulmonary fibrosis.
PMID- 9400721
TI - Localization of intercellular adhesion molecule-1 (ICAM-1) in the lungs of silica
exposed mice.
AB - Intercellular adhesion molecule-1 (ICAM-1) is expressed on a variety of cells
including endothelial cells, alveolar epithelial cells, and alveolar macrophages.
Endothelial/epithelial cell ICAM-1 participates in the migration of leukocytes
out of the blood in response to pulmonary inflammation, whereas alveolar
macrophage ICAM-1 may represent cell activation. Our previous studies have shown
that there is increased expression of ICAM-1 in lung tissue during acute
inflammation following intratracheal injection with silica particles (2
mg/mouse). This increased expression was shown to play a role, in part, in the
migration of neutrophils from the circulation into the tissue parenchyma. The aim
of the current work is to localize expression of ICAM-1 during acute inflammation
in lungs of mice exposed to either silica or the nuisance dust, titanium dioxide.
In silica-exposed mice, a significant increase in ICAM-1 was detected on day-1
and localized by immunohistochemistry to aggregates of pulmonary macrophages and
to type II epithelial cells. Areas of the lung with increased ICAM-1 expression
also showed increased tumor necrosis factor alpha expression. Immunocytochemical
staining of bronchoalveolar lavage (BAL) cells demonstrated increased ICAM-1
expression associated with alveolar macrophages 3, 5, and 7 days following silica
exposure. Finally, soluble ICAM-1 levels in the BAL fluid were significantly
increased in mice exposed to silica on the same days. Titanium dioxide exposure
elicited a minimal increase in expression of ICAM-1 in the lungs. These data
demonstrate that exposure to the toxic particle silica specifically increases
ICAM-1 expression localized to pulmonary macrophages and type II epithelial
cells.
PMID- 9400722
TI - Alveolar macrophage interaction with air pollution particulates.
AB - We applied flow cytometric analysis to characterize the in vitro response of
alveolar macrophages (AM) to air pollution particulates. Normal hamster AM were
incubated with varying concentrations of residual oil fly ash (ROFA) or
concentrated ambient air particulates (CAP). We found a dose-dependent increase
in AM-associated right angle light scatter (RAS) after uptake of ROFA (e.g., mean
channel number 149.4 +/- 6.5, 102.5 +/- 4.1, 75.8 +/- 3.5, and 61.0 +/- 4.6 at
200, 100, 50, and 25 mg/ml, respectively) or CAP. A role for scavenger-type
receptors (SR) in AM uptake of components of ROFA and CAP was identified by
marked inhibition of RAS increases in AM pretreated with the specific SR
inhibitor polyinosinic acid. We combined measurement of particle uptake (RAS)
with flow cytometric analysis of intracellular oxidation of dichlorofluorescin.
Both ROFA and CAP caused a dose-related intracellular oxidant stress within AM,
comparable to that seen with phorbol myristate acetate (PMA) (e.g., fold increase
over control, 6.6 +/- 0.4, 3.6 +/- 0.4, 4.6 +/- 0.5, 200 mg/ml ROFA, 100 mg/ml
ROFA, and 10(-7) M PMA, respectively). We conclude that flow cytometry of RAS
increases provides a useful relative measurement of AM uptake of complex
particulates within ROFA and CAP. Both ROFA and CAP cause substantial
intracellular oxidant stress within AM, which may contribute to subsequent cell
activation and production of proinflammatory mediators.
PMID- 9400724
TI - Early mesothelial cell proliferation after asbestos exposure: in vivo and in
vitro studies.
AB - There is some evidence that proliferation of pleural mesothelial cells (MC)
occurs soon after deposition of asbestos fibers. To study this effect, we
instilled a single dose of 0.1 mg crocidolite into the lungs of mice for 1 and 6
weeks and counted labeled nuclei after 3H-thymidine (3HT) injection. Short fibers
(< 1 micron) induced little change in the lung; they were mostly phagocytized and
had a minimal effect on MC labeling. Long fibers up to 20 microns damaged the
bronchiolar epithelium and were incorporated into connective tissue. Increased
3HT uptake was seen in fibroblasts and epithelial cells and also in MC, which
peaked at 2% labeled at 1 week compared to near 0% labeling in controls. No
fibers were found in or near labeled MC, which suggested that a cytokine
generated in the lung during the early response phase might induce MC
proliferation. To look for a cytokine effect in vitro, we instilled asbestos into
rat lungs and, after 1 and 6 weeks, bronchoalveolar and pleural lavage fluids as
well as macrophages were collected. Alveolar macrophages contained fibers, but
pleural macrophages (PM) did not. After short-term culture, macrophage
supernatants and the lavage fluids were tested on rat lung MC in culture. At 1
week, PM secreted growth factor(s) for MC, and the mitogenic effect was more
pronounced with lavage fluids. No effects on MC were found using material
prepared 6 weeks after asbestos. The early MC growth increase was not blocked by
antibodies to cytokines, such as platelet-derived growth factor, fibroblast
growth factors, or tumor necrosis factor, but was inhibited by anti-keratinocyte
growth factor (anti-KGF). The results show that an early growth phase of MC after
asbestos exposure appears unrelated to particle translocation to the pleura but
is associated with cytokine release, most likely KGF, by lung cells.
PMID- 9400723
TI - Immunohistochemical localization of transforming growth factor beta isoforms in
asbestos-related diseases.
AB - Transforming growth factor beta (TGF-beta), a multifunctional cytokine and growth
factor, plays a key role in scarring and fibrotic processes because of its
ability to induce extracellular matrix proteins and modulate the growth and
immune function of many cell types. These effects are important in inflammatory
disorders with fibrosis and cancer. The asbestos-related diseases are
characterized by fibrosis in the lower respiratory tract and pleura and increased
occurrence of lung cancer and mesothelioma. We performed immunohistochemistry
with isoform-specific antibodies to the three TGF-beta isoforms on 16 autopsy
lungs from Quebec, Canada, asbestos miners and millers. There was increased
immunolocalization of all three TGF-beta isoforms in the fibrotic lesions of
asbestosis and pleural fibrosis. The hyperplastic type II pneumocytes contained
all three isoforms. By contrast, there was differential spatial immunostaining
for the TGF-beta isoforms in malignant mesothelioma, with TGF-beta 1 in the
stroma but TGF-beta 2 in the tumor cells. These data are consistent with an
important role for TGF-beta in accumulation of extracellular matrix and cell
proliferation in asbestos-related diseases.
PMID- 9400725
TI - Comparison of pleural responses of rats and hamsters to subchronic inhalation of
refractory ceramic fibers.
AB - In the present subchronic study, we compared pleural inflammation, visceral
pleural collagen deposition, and visceral and parietal pleural mesothelial cell
proliferation in rats and hamsters identically exposed to a kaolin-based
refractory ceramic fiber, (RCF)-1 by nose-only inhalation exposure, and
correlated the results to translocation of fibers to the pleural cavity. Fischer
344 rats and Syrian golden hamsters were exposed to 650 fibers/cc of RCF-1, for 4
hr/day, 5 days/week for 12 weeks. Following 4 and 12 weeks of exposure, and after
a 12-week recovery period, pleural lavage fluid was analyzed for cytologic and
biochemical evidence of inflammation. Visceral and parietal pleural mesothelial
cell proliferation was assessed by immunocytochemical detection of
bromodeoxyuridine incorporation. Pleural collagen was quantitated using
morphometric analysis of lung sections stained with Sirius Red. Fiber-exposed
rats and hamsters had qualitatively similar pleural inflammation at each time
point. Mesothelial cell proliferation was more pronounced in hamsters than in
rats at each time point and at each site. In both species, the mesothelial cell
labeling index was highest in the parietal pleural mesothelial cells lining the
surface of the diaphragm at each time point. Hamsters but not rats had
significantly elevated collagen in the visceral pleura at the 12-week
postexposure time point. Fibers were found in the pleural cavities of both
species at each time point. These fibers were generally short and thin. These
results suggest that mesothelial cell proliferation and fibroproliferative
changes in the pleura of rodents following short-term inhalation exposure are
associated with fiber translocation to the pleura and may be predictive of
chronic pleural disease outcomes following long-term exposure.
PMID- 9400726
TI - Mechanisms of mineral dust-induced emphysema.
AB - Mineral dust exposure can result in emphysema and chronic airflow obstruction. We
postulated that dust-induced emphysema has a pathogenesis similar to that in
cigarette smoke-induced emphysema, namely, excess release of proteolytic enzymes
from dust-evoked inflammatory cells, and inactivation of alpha-1-antitrypsin
(A1AT) by dust-catalyzed formation of oxidants. To test this theory we examined
the antiproteolytic activity of A1AT exposed to quartz in vitro and found that it
was decreased in a dose-response fashion. Catalase prevented this effect, which
suggested that it was mediated by quartz-generated hydrogen peroxide. We also
showed that a variety of dusts could oxidize methionine to methionine sulfoxide
in vitro, using either pure amino acid or whole protein. The relative order of
activity was coal > quartz > titanium dioxide. Lastly, we used a new high
performance liquid chromatography technique to demonstrate that quartz, coal, and
titanium dioxide produced connective tissue breakdown in rat lungs, as determined
by the appearance of desmosine and hydroxyproline in lavage fluid after dust
instillation. On a particle-for-particle basis, the order of dust potency was
similar to that for methionine oxidation. Connective tissue breakdown was
associated with elevations of both polymorphonuclear leukocytes and macrophages
in lavage fluid, and it is unclear whether one or both of these types of
inflammatory cell mediates this process. These observations support our theory
that dust-induced emphysema and smoke-induced emphysema occur through similar
mechanisms.
PMID- 9400727
TI - Lung proliferative and clearance responses to inhaled para-aramid RFP in exposed
hamsters and rats: comparisons with chrysotile asbestos fibers.
AB - This study compared pulmonary effects of para-aramid respirable-sized, fiber
shaped particles (RFP) (p-aramid fibrils) and chrysotile asbestos fiber exposures
in rats. Additional p-aramid inhalation studies were conducted in hamsters to
compare species responses. The hamster results are preliminary. The parameters
studied were clearance/biopersistence of inhaled p-aramid RFP or size-separated
asbestos fibers as well as pulmonary cell proliferation and inflammation indices
after 2-week inhalation exposures. Rats were exposed nose only to chrysotile
asbestos fibers at concentrations of 459 and 782 fibers/ml or to p-aramid RFP at
419 or 772 fibrils/ml. Hamsters were exposed whole body to p-aramid RFP at
concentrations of 358 and 659 fibrils/ml. Subsequently, animals were assessed
immediately (time 0) as well as 5 days (10 days for hamsters), 1, 3, 6, and 12
months postexposure. Lung burdens for the p-aramid-exposed rats were 4.8 x 10(7)
and 7.6 x 10(7) fibrils/lung, with similar numbers of chrysotile fibers > 5
microns recovered from the lungs of asbestos-exposed rats. In comparison, 1.4 x
10(6) fibrils/lung were recovered in the high-dose hamster group. Biopersistence
studies in p-aramid-exposed rats and hamsters demonstrated an initial increase
(relative to time 0) in retained p-aramid fibrils during the first month
postexposure, which indicated breakage or shortening of inhaled fibrils. This
result was associated with a progressive reduction, and increased residence time
in the lung, in the mean lengths of the fibrils, which signified biodegradability
of inhaled p-aramid fibrils in both species. In contrast, clearance of short
chrysotile asbestos fibers was rapid, but clearance of the long chrysotile fibers
was slow or insignificant, as evidenced by a progressive increase over time in
the mean lengths of fibers recovered from the lungs of exposed rats. Two-week,
high-dose exposures to p-aramid in both rats and hamsters produced transient
increases in pulmonary inflammatory and cell proliferative responses. In
contrast, inhalation of size-separated chrysotile asbestos fibers in rats
produced persistent increases in cell labeling indices of airway, alveolar, and
subpleural cells measured through a period of 1 to 3 months postexposure. These
results suggest that inhaled p-aramid RFP are biodegradable in the lungs of
exposed rats and hamsters. In contrast, exposures to chrysotile asbestos fibers
in rats resulted in a selective pulmonary retention of long chrysotile fibers.
PMID- 9400728
TI - Chronic inhalation study of fiber glass and amosite asbestos in hamsters: twelve
month preliminary results.
AB - The effects of chronic inhalation of glass fibers and amosite asbestos are
currently under study in hamsters. The study includes 18 months of inhalation
exposure followed by lifetime recovery. Syrian golden hamsters are exposed, nose
only, for 6 hr/day, 5 day/week to size-selected test fibers: MMVF10a (Schuller
901 insulation glass); MMVF33 (Schuller 475 durable glass); amosite asbestos
(three doses); or to filtered air (controls). Here we report interim results on
airborne fiber characterization, lung fiber burden, and pathology (preliminary)
through 12 months. Aerosolized test fibers averaged 15 to 20 microns in length
and 0.5 to 1 micron in diameter. Target aerosol concentrations of World Health
Organization (WHO) fibers (longer than 5 microns) were 250 fibers/cc for MMVF10a
and MMVF33, and 25, 125, or 250 fibers/cc for amosite. WHO fiber lung burdens
showed time-dependent and (for amosite) dose-dependent increases. After a 12
month exposure, lung burdens of fibers longer than 20 microns were greatest with
amosite high and mid doses, similar for low-dose amosite and MMVF33, and smaller
for MMVF10a. Biological responses of animals exposed for 12 months to MMVF10a
were limited to nonspecific pulmonary inflammation. However, exposures to MMVF33
and each of three doses of amosite were associated with lung fibrosis and
possible mesotheliomas (1 with MMVF33 and 2, 3, and 1 with amosite low, mid, and
high doses, respectively). Pulmonary and pleural changes associated with amosite
were qualitatively and quantitatively more severe than those associated with
MMVF33. As of the 12-month time point, this study demonstrates that two different
fiber glass compositions with similar fiber dimensions but different durabilities
can have distinctly different effects on the hamster lung and pleura after
inhalation exposure. (Preliminary tumor data through 18 months of exposure and 6
weeks of postexposure recovery became available as this manuscript went to press:
No tumors were observed in the control or MMVF10a groups, and no additional
tumors were observed in the MMVF33 group; however, a number of additional
mesotheliomas were observed in the amosite groups.
PMID- 9400729
TI - Sites of particle retention and lung tissue responses to chronically inhaled
diesel exhaust and coal dust in rats and cynomolgus monkeys.
AB - The usefulness of pulmonary carcinogenicity data from rats exposed to high
concentrations of particles for quantitatively predicting lung cancer risk in
humans exposed to much lower environmental or occupational concentrations has
been questioned. The results of several chronic inhalation bioassays of poorly
soluble, nonfibrous particles have suggested that rats may be more prone than
other rodent species to develop persistent pulmonary epithelial hyperplasia,
metaplasia, and tumors in response to the accumulation of inhaled particles. In
addition, rats and primates differ in their pulmonary anatomy and rate of
particle clearance from the lung. This paper reviews results of recent Lovelace
Respiratory Research Institute (Albuquerque, NM) investigations that directly
compared the anatomical patterns of particle retention and the lung tissue
responses of rats and monkeys exposed chronically to high occupational
concentrations of poorly soluble particles. Lung sections from male cynomolgus
monkeys and F344 rats exposed 7 hr/day, 5 days/week for 24 months to filtered
ambient air, diesel exhaust (2 mg soot/m3), coal dust (2 mg respirable
particulate material/m3), or diesel exhaust and coal dust combined (1 mg soot and
1 mg respirable coal dust/m3) were obtained from a study conducted at the U.S.
National Institute for Occupational Safety and Health and examined
histopathologically and morphometrically. Within each species, the sites of
particle retention and lung tissue responses were the same for diesel soot, coal
dust, and combined material. Rats retained a significantly greater portion of the
particulate material in the lumens of alveolar ducts and alveoli than monkeys.
Conversely, monkeys retained a significantly greater portion of the particulate
material in the interstitium than rats. Rats, but not monkeys, had significant
alveolar epithelial hyperplastic, inflammatory, and septal fibrotic responses to
the retained particles. These results suggest that anatomic patterns of particle
retention and lung tissue reactions in rats may not be predictive of retention
patterns and tissue responses in primates that inhale poorly soluble particles at
concentrations representing high occupational exposures.
PMID- 9400730
TI - Short-term inhalation and in vitro tests as predictors of fiber pathogenicity.
AB - A wide range of fiber types was tested in two in vitro assays: toxicity to A549
epithelial cells, as detachment from substrate, and the production of the
proinflammatory cytokine tumor necrosis factor (TNF) by rat alveolar macrophages.
Three of the fibers were also studied in vivo, using short-term inhalation
followed by a) bronchoalveolar lavage to assess the inflammatory response and b)
measurement of cell proliferation in terminal bronchioles and alveolar ducts,
using incorporation of bromodeoxyuridine (BrdU). The amount of TNF produced by
macrophages in vitro depended on the fiber type, with the man-made vitreous
fibers, and refractory ceramic fibers being least stimulatory and silicon carbide
(SiC) whiskers providing the greatest stimulation. In the epithelial detachment
assay there were dose-dependent differences in the toxicity of the various
fibers, with long amosite being the most toxic. However, there was no clear
relationship to known chronic pathogenicity. Fibers studied by short-term
inhalation produced some inflammation, but there was no clear discrimination
between the responses to code 100/475 glass fibers and the more pathogenic
amosite and SiC. However, measurements of BrdU uptake into lung cells showed that
amosite and SiC produced a greater reaction than code 100/475, which itself
caused no more proliferation than that seen in untreated lungs. These results
mirror the pathogenicity ranking of the fibers in long-term experiments. In
conclusion, the only test to show potential as a predictive measure of
pathogenicity was that of cell proliferation in lungs after brief inhalation
exposure (BrdU assay). We believe that this assay should be validated with a
wider range of fibers, doses, and time points.
PMID- 9400731
TI - Silica-induced apoptosis in alveolar and granulomatous cells in vivo.
AB - Silica is a toxicant that can stimulate cells to produce various cellular
products such as free radicals, cytokines, and growth factors. Silica and its
induced substances may induce apoptosis to regulate the evolution of silica
induced inflammation and fibrosis. To examine this hypothesis, groups of Wistar
male rats were intratracheally instilled with different doses of Min-U-Sil 5
silica (Silica, Berkeley Springs, WV). Ten days after the instillation, we
obtained cells by bronchoalveolar lavage and placed them on slides by cytospin
preparation. The slides were stained with Diff-Quik (Lab Aids, Sydney, NSW,
Australia) and examined under oil immersion. A substantial number of cells with
apoptotic features were identified in all silica-instilled rats and the apoptosis
was confirmed by agarose gel electrophoresis. The number of apoptotic cells was
clearly related to silica dosage. Engulfment of apoptotic cells by macrophages
was also noted. Neutrophil influx in silica-instilled rats could be saturated
with the increase of silica dosage and the number of macrophages in different
dose groups changed in parallel with the proportion of apoptotic cells. Fifty-six
days after instillation, morphologically apoptotic cells could be identified in
granulomatous cells of lung tissue from silica-instilled rats. We conclude that
intratracheal instillation of silica could induce apoptosis in both alveolar and
granulomatous cells, and the apoptotic change and subsequent engulfment by
macrophages might play a role in the evolution of silica-induced effects.
PMID- 9400732
TI - Expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases,
and extracellular matrix mRNA following exposure to mineral fibers and cigarette
smoke in vivo.
AB - To determine the effect of mineral fibers and cigarette smoke on remodeling of
lung tissues, we examined matrix metalloproteinase-1 (MMP-1), MMP-2, tissue
inhibitors of metalloproteinase-1 (TIMP-1), TIMP-2, and types I and IV collagen
mRNA levels from rat lungs exposed to mineral fibers and/or cigarette smoke in
vivo. Male Wistar rats (10 weeks of age) were given a single intratracheal
instillation of 2 mg of chrysotile or alumina silicate ceramic fibers (RCF).
Animals were then exposed to cigarette smoke (side stream) 5 days per week for 4
weeks. Transcriptional levels of mRNA extracted from the lungs were assessed by
semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).
Exposure to cigarette smoke induced increases in MMP-1 and TIMP-1 mRNA levels and
decreased TIMP-2 and type I collagen mRNA levels in lung. Chrysotile or RCF
stimulated the expression of MMP-1 mRNA in the lung. The mineral fibers and
cigarette smoke had more than additive effects on the expression of MMP-2 and
TIMP-1 in the lung. These data suggest that the imbalance of the expression of
MMPs, TIMPs, and extracellular matrix may be associated with the remodeling of
lung tissues induced by mineral fibers and/or cigarette smoke.
PMID- 9400733
TI - Dose-response relationship of fibrous dusts in intraperitoneal studies.
AB - The relationship between the number of fibers injected intraperitoneally and the
occurrence of peritoneal mesotheliomas in rats was investigated using data from a
series of carcinogenicity studies with several fibrous dusts. Based on observed
tumor incidences ranging between 10 and 90%, the hypothesis of a common slope of
dose-response relationships (parallel probit lines in probit analysis) cannot be
rejected. In general, parallelism of probit lines is considered an indication of
a common mode of action. Analysis of the shape of the dose-response relationship,
with one apparent exception, shows virtually linear or superlinear behavior,
i.e., from these data, there is no indication of a decrease in carcinogenic
potency of an elementary carcinogenic unit at lower doses.
PMID- 9400735
TI - Cell size of alveolar macrophages: an interspecies comparison.
AB - Alveolar macrophages (AM) play a critical role in the removal of inhaled
particles or fibers from the lung. Species differences in AM size may affect the
number and size range of particles/fibers that can be actually phagocytized and
cleared by AM. The purpose of this study was to compare the cell size of rat,
hamster, monkey, and human AM by selective flow cytometric analysis of cell
volume. Resident AM from CD rats, Syrian golden hamsters, cynomolgus monkeys, and
nonsmoking, healthy human volunteers were harvested by standard bronchoalveolar
lavage procedures. Morphometric analysis of AM was performed using a flow
cytometer that generates volume signals based on the Coulter-type measurement of
electrical resistance. We found that hamster and rat AM had diameters of 13.6 +/-
0.4 microns (n = 8) and 13.1 +/- 0.2 microns (n = 12), respectively.
Comparatively, the AM from monkeys (15.3 +/- 0.5 microns, n = 7) and human
volunteers (21.2 +/- 0.3 microns, n = 10) were larger than those from rats and
hamsters. The AM from humans were significantly larger (p < 0.05) than those from
all other species studied, corresponding to a 4-fold larger cell volume of human
AM (4990 +/- 174 microns 3) compared to hamster (1328 +/- 123 microns 3) and rat
(1166 +/- 42 microns 3) AM. In summary, we have found marked species differences
in the cell size of AM. We suggest that the number and size range of
particles/fibers that can be phagocytized and cleared by AM may differ among
species due to inherent or acquired species differences in AM cell size.
PMID- 9400734
TI - Pleural macrophage recruitment and activation in asbestos-induced pleural injury.
AB - The pathogenesis of asbestos-induced pleural fibrosis is poorly understood.
Moreover, there has been a long-standing controversy regarding the relative
potential of different commercial types of asbestos to cause pleural disease. We
postulated that inhaled asbestos fibers translocate to the pleural space where
they stimulate the recruitment and activation of pleural macrophages. To test
this hypothesis, and to determine whether there are differences between inhaled
amphibole and serpentine asbestos, Fischer 344 rats were exposed by intermittent
inhalation (6 hr/day for 5 days/week over 2 weeks) to either National Institute
of Environmental Health Sciences (NIEHS) crocidolite (average concentration 7.55
mg/m3) or NIEHS chrysotile fibers (average concentration 8.51 mg/m3). Comparisons
were made with sham-exposed rats. The rats were sacrificed at 1 and 6 weeks after
the cessation of exposure. More pleural macrophages were recovered at 1 and 6
weeks after crocidolite and chrysotile exposure than after sham exposure. Small
numbers of crocidolite fibers (approximately 1 per 4000 cells) were detected in
the pleural cell pellet of one crocidolite-exposed rat by scanning electron
microscopy. Pleural macrophage supernatants were assayed for production of nitric
oxide (NO) (by the Griess reaction) and tumor necrosis factor alpha (TNF-alpha)
(by an enzyme-linked immunosorbent assay method). Significantly greater amounts
of NO as well as TNF-alpha were generated by pleural macrophages at 1 and 6 weeks
after either crocidolite or chrysotile inhalation than after sham exposure.
Conceivably, translocation of asbestos fibers to the pleural space may provide a
stimulus for persistent pleural space inflammation, cytokine production, and the
generation of toxic oxygen and nitrogen radicals. Enhanced cytokine secretion
within the pleural space may in turn upregulate adhesion molecule expression and
the synthesis of extracellular matrix constituents by pleural mesothelial cells.
Thus, our findings may have significance for the development of asbestos-induced
pleural injury.
PMID- 9400736
TI - Intratracheal instillation versus intratracheal inhalation: influence of
cytokines on inflammatory response.
AB - Our laboratory has developed a method of particle exposure whereby anesthetized
rats intratracheally inhale, at a regulated breathing rate and pressure, an
aerosolized test material. This method is capable of delivering considerable
doses in a short time period and, unlike the commonly used method of
intratracheal instillation, does so with an even particle distribution throughout
the lung. Early studies comparing the response of male Fischer 344 rats exposed
to TiO2 particles of two differing primary particle sizes showed that at similar
particle doses animals exposed by the two methods showed differences in response,
as measured by bronchoalveolar lavage (BAL) parameters. Building on this, we
sought to study the roles that macrophage inflammatory protein-2 (MIP-2) and
tumor necrosis factor alpha (TNF-alpha), two cytokines thought to have
proinflammatory roles in the lung, may play in the differences observed.
Increases in MIP-2 protein levels in the lavaged cells, but not the supernatant,
were observed in those groups where increased polymorphonuclear cells (PMN) in
the lung lavage were found, but not in those where no increase in PMN levels was
observed. BAL TNF-alpha levels, measured by enzyme-linked immunosorbent assay,
showed no apparent correlation with cellular or biochemical BAL parameters for
either particle size or dosing method. Increases in immunocytochemical staining
for TNF-alpha, compared to unexposed controls, were observed in several particle
exposed groups. Thus, it appears that increased BAL MIP-2 protein levels, but not
TNF-alpha, correlate well with the inflammatory response, as measured by PMN
numbers in lavaged cells, for both exposure systems.
PMID- 9400737
TI - Efflux of reduced glutathione after exposure of human lung epithelial cells to
crocidolite asbestos.
AB - This study investigated glutathione (GSH) homeostasis in human lung epithelial
cells (A549) exposed to crocidolite. Exposure of A549 cells to 3 micrograms/cm2
crocidolite resulted in a decrease in intracellular reduced glutathione by 36%
without a corresponding increase in GSH disulfide. After a 24-hr exposure to
crocidolite, 75% of the intracellular GSH lost was recovered in the extracellular
medium, of which 50% was in reduced form. Since the half-life of reduced GSH in
culture medium was less than 1 hr, this suggests that reduced GSH was released
continuously from the cells after treatment. The release of GSH did not appear to
result from nonspecific membrane damage, as there was no concomitant release of
lactate dehydrogenase or 14C-adenine from loaded cells after crocidolite
treatment for 24 hr. Crocidolite exposure resulted in the formation of S
nitrosothiols but no increase in the level of GSH-protein mixed disulfides or GSH
conjugates. Exposure of A549 cells to crocidolite for 24 hr decreased gamma
glutamylcysteine synthetase (gamma-GCS) activity by 47% without changes in the
activities of GSH reductase, GSH peroxidase, GSH S-transferase, or glucose-6
phosphate dehydrogenase. Treatment of cells with crocidolite pretreated with the
iron chelator desferrioxamine B resulted in the same level of intracellular GSH
depletion and efflux and the same decrease in gamma-GCS activity as treatment
with unmodified crocidolite, which suggests that iron-catalyzed reactions were
not responsible for the GSH depletion.
PMID- 9400738
TI - In vivo and in vitro proinflammatory effects of particulate air pollution (PM10).
AB - Epidemiologic studies have reported associations between fine particulate air
pollution, especially particles less than 10 mm in diameter (PM10), and the
development of exacerbations of asthma and chronic obstructive pulmonary disease.
However, the mechanism is unknown. We tested our hypothesis that PM10 induces
oxidant stress, causing inflammation and injury to airway epithelium. We assessed
the effects of intratracheal instillation of PM10 in rat lungs. The influx of
inflammatory cells was measured in bronchoalveolar lavage (BAL). Airspace
epithelial permeability was assessed as total protein in bronchoalveolar lavage
fluid (BALF) in vivo. The oxidant properties of PM10 were determined by their
ability to cause changes in reduced glutathione (GSH) and oxidized glutathione
(GSSG). We also compared the effects of PM10 with those of fine (CB) and
ultrafine (ufCB) carbon black particles. Six hours after intratracheal
instillation of PM10, we noted an influx of neutrophils (up to 15% of total BAL
cells) in the alveolar space, increased epithelial permeability, an increase in
total protein in BALF from 0.39 +/- 0.01 to 0.62 +/- 0.01 mg/ml (mean +/- SEM)
and increased lactate dehydrogenase concentrations in BALF. An even greater
inflammatory response was observed after intratracheal instillation of ufCB, but
not after CB instillation. PM10 had oxidant activity in vivo, as shown by
decreased GSH in BALF (from 0.36 +/- 0.05 to 0.25 +/- 0.01 nmol/ml) after
instillation. BAL leukocytes from rats treated with PM10 produced greater amounts
of nitric oxide, measured as nitrite (control 3.07 +/- 0.33, treated 4.45 +/-
0.23 mM/1 x 10(6) cells) and tumor necrosis factor alpha (control 21.0 +/- 3.1,
treated 179.2 +/- 29.4 unit/1 x 10(6) cells) in culture than BAL leukocytes
obtained from control animals. These studies provide evidence that PM10 has free
radical activity and causes lung inflammation and epithelial injury. These data
support our hypothesis concerning the mechanism for the adverse effects of
particulate air pollution on patients with airway diseases.
PMID- 9400739
TI - Free radical activity of PM10: iron-mediated generation of hydroxyl radicals.
AB - The purpose of this study was to test the hypothesis that particulate matter < or
= 10 microns in aerodynamic diameter (PM10) particles have the ability to
generate free radical activity at their surface. We collected PM10 filters from
the Edinburgh, United Kingdom, Enhanced Urban Network sampling site, removed
particles from the filter, and tested their ability to cause free radical damage
to supercoiled plasmid DNA. We found that the PM10 particles did cause damage to
the DNA that was mediated by hydroxyl radicals, as shown by inhibition of the
injury with mannitol. The PM10-associated hydroxyl radical activity was confirmed
using a high-performance liquid chromatography-based assay to measure the
hydroxyl radical adduct of salicylic acid. Desferrioxamine abolished the hydroxyl
radical-mediated injury, which suggests that iron was involved. Analysis of PM10
filters confirmed the presence of large amounts of iron and leaching studies
confirmed that the PM10 samples could release substantial amounts of Fe(III) and
lesser amounts of Fe(II). To investigate the size of the particles involved in
the hydroxyl radical injury, we centrifuged the suspension of PM10 to clarity,
tested the clear supernatant, and found that it had all of the suspension
activity. We conclude, therefore, that the free radical activity is derived
either from a fraction that is not centrifugeable on a bench centrifuge, or that
the radical generating system is released into solution.
PMID- 9400740
TI - Formation and persistence of 8-oxoguanine in rat lung cells as an important
determinant for tumor formation following particle exposure.
AB - Exposure of rats to quartz (or various other particles) can lead to the
development of lung tumors. At the moment, the mechanisms involved in particle
induced tumor formation are not clarified. However, it is suggested that
inflammation, in conjunction with the production of reactive oxygen species (ROS)
and an enhancement of epithelial cell proliferation, may play a key role in the
development of lung tumors. ROS induces 8-oxoguanine (8-oxoGua) and other
mutagenic DNA oxidation products, which can be converted to mutations in
proliferating cells. Mutation formation in cancer-related genes is a critical
event with respect to tumor formation. In this study we investigated the effects
of quartz (DQ12) and of the nontumorigenic dust corundum on the induction of 8
oxoGua in the DNA of rat lung cells, as well as on cell proliferation and
pulmonary inflammation. Wistar rats were exposed by intratracheal instillation to
quartz (2.5 mg/rat) or corundum (2.5 mg/rat) suspended in physiological saline;
control animals exposed to physiological saline or left untreated. Measurements
were carried out 7, 21, and 90 days after the exposures. 8-oxoGua levels were
determined in lung tissue sections at the single cell level by immunocytological
assay using a rabbit anti-8-oxoGua antibody. After exposure to quartz, 8-oxoGua
levels were significantly increased at all time points of investigation.
Additionally, we observed inflammation and an enhanced cell proliferation.
Exposure to corundum had no adverse effects on the lung; neither increased 8
oxoGua levels nor enhanced cell proliferation or inflammation were detected.
These observations support the suggestion that inflammation associated with
increased 8-oxoGua levels in lung cells and increased cell proliferation is an
important determinant for particle-induced development of lung tumors in the rat.
PMID- 9400741
TI - Expression of inducible nitric oxide synthase and formation of nitric oxide by
alveolar macrophages: an interspecies comparison.
AB - Nitric oxide (NO) is suggested to play a role in mediating pulmonary injury.
However, interspecies differences appear to exist in the ability of alveolar
macrophages (AM) to express the inducible nitric oxide synthase (iNOS) and to
generate NO. The purpose of this study was to compare iNOS expression and NO
production by rat, hamster, monkey, and human AM using the identical experimental
conditions in vitro. As AM donors, CD rats, Syrian golden hamsters, cynomolgus
monkeys, and nonsmoking, healthy human volunteers were used. The AM were obtained
by bronchoalveolar lavage and stimulated in vitro with various concentrations and
combinations of lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). The
oxidation product of NO, nitrite, was measured in the AM supernatant by the
Griess reaction. The expression of iNOS in AM was detected using
immunocytochemistry and immunoblotting. The expression of iNOS mRNA was assessed
by reverse transcriptase-polymerase chain reaction (RT-PCR). Rat AM, stimulated
with either LPS or IFN-gamma, produced nitrite in a time- and dose-dependent
manner. Combination of LPS and IFN-gamma resulted in a significantly enhanced
nitrite formation. However, none of the treatments was able to induce hamster,
monkey, or human AM to release measurable amounts of nitrite. Whereas expression
of iNOS protein was only detected in stimulated rat AM, expression of iNOS mRNA
was found in unstimulated and stimulated rat AM, slightly in stimulated hamster
AM, but not in monkey and human AM. In conclusion, our findings point to distinct
regulatory mechanisms of the NO pathway in AM from these four different species.
PMID- 9400742
TI - The role of reactive oxygen and nitrogen species in the response of airway
epithelium to particulates.
AB - Epidemiologic and occupational studies indicate adverse health effects due to
inhalation of particulate air pollutants, but precise biologic mechanisms
responsible have yet to be fully established. The tracheobronchial epithelium
forms the body's first physiologic barrier to such airborne pollutants, where
ciliary movement functions to remove the offending substances caught in the
overlying mucus layer. Resident and infiltrating phagocytic cells also function
in this removal process. In this paper, we examine the role of reactive oxygen
and nitrogen species (ROS/RNS) in the response of airway epithelium to
particulates. Some particulates themselves can generate ROS, as can the
epithelial cells, in response to appropriate stimulation. In addition, resident
macrophages in the airways and the alveolar spaces can release ROS/RNS after
phagocytosis of inhaled particles. These macrophages also release large amounts
of tumor necrosis factor alpha (TNF-alpha), a cytokine that can generate
responses within the airway epithelium dependent upon intracellular generation of
ROS/RNS. As a result, signal transduction pathways are set in motion that may
contribute to inflammation and other pathobiology in the airway. Such effects
include increased expression of intercellular adhesion molecule 1, interleukin-6,
cytosolic and inducible nitric oxide synthase, manganese superoxide dismutase,
cytosolic phospholipase A2, and hypersecretion of mucus. Ultimately, ROS/RNS may
play a role in the global response of the airway epithelium to particulate
pollutants via activation of kinases and transcription factors common to many
response genes. Thus, defense mechanisms involved in responding to offending
particulates may result in a complex cascade of events that can contribute to
airway pathology.
PMID- 9400743
TI - Interspecies comparison of rat and hamster alveolar macrophage antioxidative and
oxidative capacity.
AB - Generation of oxidants has been implicated in lung injury and disease caused by a
variety of inhaled agents such as ozone, particles, and mineral fibers.
Antioxidants in the pulmonary system presumably provide the initial defense
against such oxidants. We designed the present study to assess the oxidative and
antioxidative capacity of alveolar macrophages (AM) from rats and hamsters. These
two laboratory animal species commonly used in biomedical research are well known
for their disparate response to pulmonary irritants/toxicants. AM from CD rats
and Syrian golden hamsters were obtained by bronchoalveolar lavage. We assessed
AM antioxidant levels by measuring the catalase and superoxide dismutase (SOD)
activity and the intracellular concentrations of total glutathione, ascorbic
acid, and alpha-tocopherol. We determined the AM oxidative capacity by assessing
the ability of AM to oxidize extracellular glutathione (GSH) and to release
superoxide anions. There were no significant differences in the intracellular
antioxidant levels, except for catalase activity that was significantly (p <
0.05) higher in hamster AM than in rat AM. However, AM oxidative capacity was
markedly different between the two species studied. The amount of spontaneous and
phorbol myristate acetate (PMA)-induced GSH oxidation was about 5-fold higher in
rat AM than in hamster AM, whereas the PMA-induced superoxide anion release did
not differ significantly between the two rodents. In summary, our data suggest
that species variation exists between the oxidative capacity of rat and that of
hamster AM. Whereas the oxidative capacity of hamster AM appears to be based
mainly on the formation of reactive oxygen species, it is suggested that rat AM
possess an additional oxidative system.
PMID- 9400744
TI - Free radical activity of industrial fibers: role of iron in oxidative stress and
activation of transcription factors.
AB - We studied asbestos, vitreous fiber (MMVF10), and refractory ceramic fiber (RCF1)
from the Thermal Insulation Manufacturers' Association fiber repository regarding
the following: free radical damage to plasmid DNA, iron release, ability to
deplete glutathione (GSH), and activate redox-sensitive transcription factors in
macrophages. Asbestos had much more free radical activity than any of the man
made vitreous fibers. More Fe3+ was released than Fe2+ and more of both was
released at pH 4.5 than at pH 7.2. Release of iron from the different fibers was
generally not a good correlate of ability to cause free radical injury to the
plasmid DNA. All fiber types caused some degree of oxidative stress, as revealed
by depletion of intracellular GSH. Amosite asbestos upregulated nuclear binding
of activator protein 1 transcription factor to a greater level than MMVF10 and
RCF1; long-fiber amosite was the only fiber to enhance activation of the
transcription factor nuclear factor kappa B (NF kappa B). The use of cysteine
methyl ester and buthionine sulfoximine to modulate GSH suggested that GSH
homeostasis was important in leading to activation of transcription factors. We
conclude that the intrinsic free radical activity is the major determinant of
transcription factor activation and therefore gene expression in alveolar
macrophages. Although this was not related to iron release or ability to deplete
macrophage GSH at 4 hr, GSH does play a role in activation of NF kappa B.
PMID- 9400745
TI - Augmentation of pulmonary reactions to quartz inhalation by trace amounts of iron
containing particles.
AB - Fracturing quartz produces silica-based radicals on the fracture planes and
generates hydroxyl radicals (.OH) in aqueous media. .OH production has been shown
to be directly associated with quartz-induced cell damage and phagocyte
activation in vitro. This .OH production in vitro is inhibited by desferrioxamine
mesylate, an Fe chelator, indicating involvement of a Fenton-like reaction. Our
objective was to determine if Fe contamination increased the ability of inhaled
quartz to cause inflammation and lung injury. Male Fischer 344 rats were exposed
5 hr/day for 10 days to filtered air, 20 mg/m3 freshly milled quartz (57 ppm Fe),
or 20 mg/m3 freshly milled quartz contaminated with Fe (430 ppm Fe). High Fe
contamination of quartz produced approximately 57% more reactive species in water
than quartz with low Fe contamination. Compared to inhalation of quartz with low
Fe contamination, high Fe contamination of quartz resulted in increases in the
following responses: leukocyte recruitment (537%), lavageable red blood cells
(157%), macrophage production of oxygen radicals measured by electron spin
resonance or chemiluminescence (32 or 90%, respectively), nitric oxide production
by macrophages (71%), and lipid peroxidation of lung tissue (38%). These results
suggest that inhalation of freshly fractured quartz contaminated with trace
levels of Fe may be more pathogenic than inhalation of quartz alone.
PMID- 9400746
TI - Involvement of protein kinase C, phospholipase C, and protein tyrosine kinase
pathways in oxygen radical generation by asbestos-stimulated alveolar macrophage.
AB - Although asbestos stimulates oxygen radical generation in alveolar macrophages,
the exact mechanism is still not clear. The purpose of this study was to compare
the ability of three asbestos fibers (amosite, chrysotile, and crocidolite) to
generate oxygen radicals in macrophages and examine the mechanism of this action.
All asbestos fibers were able to induce chemiluminescence but chrysotile induced
maximal chemiluminescence at higher concentrations than amosite and crocidolite.
Protein kinase C (PKC) inhibitors (sphingosine and staurosporine) suppressed the
ability of asbestos to induce oxygen radical generation. Phospholipase C (PLC)
inhibitors (U73122 and neomycin) and protein tyrosine kinase (PTK) inhibitors
(erbstatin and genistein) decreased oxygen radical generation of asbestos
stimulated alveolar macrophages. Oxygen radical generation was not suppressed by
an adenylate cyclase activator (forskolin), a protein kinase A inhibitor (H-8),
and a protein serine-threonine phosphatase inhibitor (okadaic acid). PLC and PTK
inhibitors suppressed the increment of phosphoinositide turnover by amosite.
These results suggest that asbestos fibers induce the generation of oxygen
radicals through PTK, PLC, and PKC pathways in a dose-response pattern.
PMID- 9400747
TI - Approaches to characterizing human health risks of exposure to fibers.
AB - Naturally occurring and man-made (synthetic) fibers of respirable sizes are
substances that have been identified by the U.S. Environmental Protection Agency
(U.S. EPA) as priority substances for risk reduction and pollution prevention
under the Toxic Substances Control Act (TSCA). The health concern for respirable
fibers is based on the link of occupational asbestos exposure and environmental
erionite fiber exposure to the development of chronic respiratory diseases,
including interstitial lung fibrosis, lung cancer, and mesothelioma in humans.
There is also considerable laboratory evidence indicating that a variety of
fibers of varying physical and chemical characteristics can elicit fibrogenic and
carcinogenic effects in animals under certain exposure conditions. This paper
discusses key scientific issues and major default assumptions and uncertainties
pertaining to the risk assessment of inhaled fibers. This is followed by a
description of the types of assessment performed by the U.S. EPA to support risk
management actions of new fibers and existing fibers under TSCA. The scope and
depth of these risk assessments, however, vary greatly depending on whether the
substance under review is an existing or a new fiber, the purpose of the
assessment, the availability of data, time, and resources, and the intended
nature of regulatory action. In general, these risk assessments are of
considerable uncertainty because health hazard and human exposure information is
often incomplete for most fibers. Furthermore, how fibers cause diseases and what
specific determinants are critical to fiber-induced toxicity and carcinogenicity
are still not completely understood. Further research to improve our knowledge
base in fiber toxicology and additional toxicity and exposure data gathering are
needed to more accurately characterize the health risks of inhaled fibers.
PMID- 9400748
TI - Relevance of particle-induced rat lung tumors for assessing lung carcinogenic
hazard and human lung cancer risk.
AB - Rats and other rodents are exposed by inhalation to identify agents that might
present hazards for lung cancer in humans exposed by inhalation. In some cases,
the results are used in attempts to develop quantitative estimates of human lung
cancer risk. This report reviews evidence for the usefulness of the rat for
evaluation of lung cancer hazards from inhaled particles. With the exception of
nickel sulfate, particulate agents thought to be human lung carcinogens cause
lung tumors in rats exposed by inhalation. The rat is more sensitive to
carcinogenesis from nonfibrous particles than mice or Syrian hamsters, which have
both produced false negatives. However, rats differ from mice and nonhuman
primates in both the pattern of particle retention in the lung and alveolar
epithelial hyperplastic responses to chronic particle exposure. Present evidence
warrants caution in extrapolation from the lung tumor response of rats to inhaled
particles to human lung cancer hazard, and there is considerable uncertainty in
estimating unit risks for humans from rat data. It seems appropriate to continue
using rats in inhalation carcinogenesis assays of inhaled particles, but the
upper limit of exposure concentrations must be set carefully to avoid false
positive results. A positive finding in both rats and mice would give greater
confidence that an agent presents a carcinogenic hazard to man, and both rats and
mice should be used if the agent is a gas or vapor. There is little justification
for including Syrian hamsters in assays of the intrapulmonary carcinogenicity of
inhaled agents.
PMID- 9400749
TI - Pulmonary carcinogenicity of inhaled particles and the maximum tolerated dose.
AB - Chronic inhalation bioassays in rodents are used to assess pulmonary
carcinogenicity for purposes of hazard identification and potentially for risk
characterization. The influence of high experimental doses on tumor development
has been recognized for some time and has led to the concept of maximum tolerated
dose (MTD) for dose selection, with the highest dose being at the MTD. Exposure
at the MTD should ensure that the animals are sufficiently challenged while at
the same time the animal's normal longevity is not altered from effects other
than carcinogenicity. A characteristic of exposure-dose-response relationships
for chronically inhaled particles is that lung tumors are significantly increased
only at high exposure levels, and that lung tumors are seen in rats only but not
in mice or hamsters. This lung tumor response in rats is thought to be secondary
to persistent alveolar inflammation, indicating that the MTD may have been
exceeded. Thus, mechanisms of toxicity and carcinogenicity may be dose dependent
and may not operate at lower doses that humans normally experience. Despite
awareness of this problem, carcinogenicity bioassays that evaluate particulate
compounds in rodents have not always been designed with the MTD concept in mind.
This is due to several problems associated with determining an appropriate MTD
for particle inhalation studies. One requirement for the MTD is that some
toxicity should be observed. However, it is difficult to define what degree of
toxic response is indicative of the MTD. For particle inhalation studies, various
noncancer end points in addition to mortality and body weight gain have been
considered as indicators of the MTD, i.e., pulmonary inflammation, increased
epithelial cell proliferation, increased lung weight, impairment of particle
clearance function, and significant histopathological findings at the end of a
subchronic study. However, there is no general agreement about quantification of
these end points to define the MTD. To determine whether pulmonary responses are
indicative of the MTD, we suggest defining an MTD based on results of a multidose
subchronic and chronic inhalation study with a known human particulate
carcinogen, e.g., asbestos or crystalline silica. Quantification of effects in
such a study using the noncancer end points listed above would identify a dose
level without significant signs of toxicity at the end of the subchronic study.
If this dose level still results in significant lung tumor incidence at the end
of the chronic study. We will have a sound basis for characterizing the MTD and
justifying its use in future particle inhalation studies. Also, a better
understanding of cellular and molecular mechanisms of particle-induced lung
tumors is needed to support the MTD concept.
PMID- 9400750
TI - Strategies for setting occupational exposure limits for particles.
AB - To set occupational exposure limits (OELs) for aerosol particles, dusts, or
chemicals, one has to evaluate whether mechanistic considerations permit
identification of a no observed effect level (NOEL). In the case of carcinogenic
effects, this can be assumed if no genotoxicity is involved, and exposure is
considered safe if it does not exceed the NOEL. If tumor induction is associated
with genotoxicity, any exposure is considered to be of risk, although a NOEL may
be identified in the animal or human exposure studies. This must also be assumed
when no information on the carcinogenic mechanism, including genotoxicity, is
available. Aerosol particles, especially fibrous dusts, which include man-made
mineral fiber(s) (MMMF), present a challenge for toxicological evaluation. Many
MMMF that have been investigated have induced tumors in animals and genotoxicity
in vitro. Since these effects have been associated with long-thin fiber geometry
and high durability in vivo, all fibers meeting such criteria are considered
carcinogenic unless the opposite has been demonstrated. This approach is
practicable. Investigations on fiber tumorigenicity/genotoxicity should include
information on dose response, pathobiochemistry, particle clearance, and
persistence of the material in the target organ. Such information will introduce
quantitative aspects into the qualitative approach that has so far been used to
classify fibrous dusts as carcinogens. The rationales for classifying the
potential carcinogenicity of MMMF and for setting OELs used by the different
European committees and regulatory agencies are described.
PMID- 9400752
TI - Laser photocoagulation for central serous retinopathy.
PMID- 9400751
TI - Use of mechanistic data in assessing human risks from exposure to particles.
AB - The ultimate goal of toxicologic investigations of both natural and man-made
fibrous and nonfibrous particles is to provide essential input for the assessment
of potential human risks from exposure to these materials. The development of
risk assessment procedures for airborne particles has evolved over the years. The
earliest assessments for naturally occurring materials used direct human
observations and incorporated safety factors to arrive at allowable human
exposures. More recently, there has been a need to assess the potential risk
associated with production and use of certain man-made materials for which human
data are not available or are inadequate. For these materials, it has been
necessary to assess human risks using data obtained from studies conducted in
laboratory animals and with cells or tissues. During the last several decades, it
has been suggested that data on the mechanisms by which particles cause disease
could be used to reduce the uncertainty in estimates of human risks of particle
exposures. This article provides comments on the use of mechanistic data in the
risk assessment process and suggestions for increasing the successful development
and use of mechanistic data in risk assessments conducted in the future.
PMID- 9400753
TI - Complications of hydroxyapatite implants.
PMID- 9400754
TI - Annular peripheral choroidal detachment after glaucoma surgery.
PMID- 9400755
TI - Reappraising the risk and benefits of aggressive glaucoma therapy.
PMID- 9400756
TI - Incidence and progression of cortical and posterior subcapsular opacities: the
Longitudinal Study of Cataract. The LSC Group.
AB - OBJECTIVE: The purpose of the study is to estimate incidence and progression
rates of cortical and posterior subcapsular (PSC) opacities in the Longitudinal
Study of Cataract (LSC). DESIGN: An epidemiologic study of the natural history of
lens opacities in a clinic-based population. PARTICIPANTS: The LSC was based on
764 participants in an earlier case-control study of lens opacities. MAIN OUTCOME
MEASURES: Baseline data, collected until 1988, included color slit and
retroillumination photographs. The same data were collected at follow-up visits
from 1989 to 1993. The Lens Opacities Classification System III (LOCS III) was
used to assess lens changes between baseline and follow-up photographs. The
product-limit method was used to estimate the incidence and progression rates.
RESULTS: After 5 years of follow-up, the incidence rates for developing cortical
and PSC opacities were 7.7% and 4.3%, respectively. The progression rate of pre
existing cortical opacities was 16.2% after 5 years, and was twice as high as the
incidence rate. The progression of pre-existing PSC opacities was much higher,
and reached 55.1% after 5 years of follow-up. The incidence of newly developed
cortical or PSC opacities increased with age. The incidence of PSC opacities also
increased when coexisting opacities were present at baseline. CONCLUSIONS: After
5 years, 1 in every 13 patients developed new cortical opacities, and 1 in 24
developed new PSC opacities. The 5-year progression rates for cortical and PSC
opacities were much higher than the incidence rates. These results can be used to
estimate the rate of cortical and PSC changes in similar populations.
PMID- 9400757
TI - Clinical findings and hemodynamic changes associated with severe occlusive
carotid artery disease.
AB - OBJECTIVE: The purpose of the study was to evaluate the ophthalmologic findings
and to analyze the retrobulbar hemodynamics of patients with severe (greater than
70% stenosis) occlusive carotid artery disease (OCAD) by means of color Doppler
imaging (CDI). DESIGN: A case-controlled study. PARTICIPANTS: Fifty-six
consecutive patients with severe OCAD and an age- and sex-matched control group
consisting of 56 healthy patients without OCAD were studied. INTERVENTION: All
112 patients underwent a complete ophthalmologic examination. Color Doppler
imaging of both orbits was performed by one masked investigator. MAIN OUTCOME
MEASURES: Peak systolic velocity, end diastolic velocity, and the resistive index
of the ophthalmic, central retinal, and temporal short posterior ciliary arteries
were measured. The authors compared the hemodynamic parameters measured in
patients with severe OCAD with those obtained in the control group. The
hemodynamic parameters of patients with asymmetric OCAD (stenosis > 70% in one
internal carotid artery and stenosis < 50% in the contralateral artery) were also
compared. In an attempt to determine risk factors associated with the ocular
ischemic syndrome (OIS), the authors compared patients with severe OCAD and OIS
with patients with severe OCAD without OIS. RESULTS: Peak systolic and end
diastolic velocities in the ophthalmic, central retinal, and temporal short
posterior ciliary arteries were significantly lower in patients with severe OCAD
(P < 0.01). The mean resistive indices in the central retinal and temporal short
posterior ciliary arteries were higher in the group with severe OCAD (P < 0.01).
Similar results were obtained in the analysis of 25 patients with asymmetric
carotid stenosis. Younger age (P = 0.012), severe bilateral OCAD (P = 0.01), high
grade carotid stenosis (P = 0.013), and reversed ophthalmic artery flow (P =
0.038) were significant risk factors for OIS. CONCLUSIONS: Patients with severe
OCAD show hemodynamic changes that suggest reduced retrobulbar blood flow.
Patients with severe bilateral OCAD, high-grade carotid stenosis, and reversed
ophthalmic artery flow may have a greater risk of developing OIS.
PMID- 9400758
TI - A comparison of retrobulbar versus sub-Tenon's corticosteroid therapy for cystoid
macular edema refractory to topical medications.
AB - OBJECTIVE: The objective is to compare the effectiveness of retrobulbar and
posterior sub-Tenon's injection of corticosteroids for treatment of post-cataract
cystoid macular edema that was refractory to topical medications. DESIGN: A
retrospective study was performed. PARTICIPANTS: A total of 48 patients (49 eyes)
with post-cataract cystoid macular edema refractory to topical medications was
studied. INTERVENTION: Patients received either a single retrobulbar injection
(18 eyes) or 3 biweekly posterior sub-Tenon's injections (31 eyes) of
corticosteroids. MAIN OUTCOME MEASURES: Patients were observed for clinical
resolution of the cystoid macular edema, visual acuity, and intraocular pressure.
RESULTS: Both treatment methods resulted in significant improvement in visual
acuity. The posterior sub-Tenon's group had a visual improvement from 20/92
pretreatment to 20/50 post-treatment (P = 0.0001) with a median follow-up of 12
months. The retrobulbar group had a visual improvement from 20/97 pretreatment to
20/58 post-treatment (P = 0.035) with a median follow-up of 10 months. The visual
improvement was not significantly different between the two groups. The average
intraocular pressure increased from a pretreatment level of 14.1 mmHg to a high
of 17.7 mmHg (P < 0.00005) in the sub-Tenon's group. The average intraocular
pressure increased from 15.1 mmHg to a high of 17.6 mmHg (P = 0.04) in the
retrobulbar group. CONCLUSIONS: Cystoid macular edema that persists after
treatment with topical medications may improve after retrobulbar or posterior sub
Tenon's corticosteroid injections. There was no significant difference in outcome
between the two treatment groups.
PMID- 9400759
TI - Outpatient postoperative fluid-gas exchange after early failed vitrectomy surgery
for macular hole.
AB - BACKGROUND: Vitrectomy surgery with fluid-gas exchange and prone positioning has
been shown to close macular holes and improve vision. In those eyes that have
failed surgery, repeat vitrectomy has been advocated. As an alternative, the
authors performed an outpatient postoperative fluid-gas exchange on eyes when the
macular hole failed to close after vitrectomy surgery. METHODS: The authors
reviewed all cases of failed vitrectomy surgery for macular holes that underwent
a postoperative fluid-gas exchange. Eyes were considered to have failed initial
surgery if a rim of subretinal fluid surrounded an open full-thickness macular
hole. RESULTS: Twenty-three consecutive eyes underwent outpatient fluid-gas
exchange 1 week to 8 weeks after vitrectomy surgery. In 17 eyes (74%), fluid-gas
exchange resulted in flattening and closure of the macular hole. In all 17 eyes,
visual acuity improved 2 or more lines, with 8 (35%) of the 23 eyes achieving
20/50 or better visual acuity. CONCLUSIONS: Postoperative fluid-gas exchange may
achieve successful closure of macular holes and improve vision in eyes that have
failed surgery for full-thickness macular holes and should be considered as a
cost-effective alternative to repeat vitrectomy.
PMID- 9400760
TI - A multivariate analysis of anatomic success of recurrent retinal detachment
treated with pneumatic retinopexy.
AB - PURPOSE: The purpose of the study is to determine the success rate of pneumatic
retinopexy (PR) after failed scleral buckling and to elucidate the predictors for
anatomic failure by multiple logistic regression analysis. METHODS: Thirty-six
eyes with recurrent retinal detachment after failed scleral buckling underwent
PR. Intraocular tamponade was attained with SF6 (20 eyes), C3F8 (13 eyes), and
air (3 eyes). Median follow-up was 14 months. RESULTS: Retinal reattachment was
obtained in 69.4%. Multivariate analysis identified two risk factors for failure:
location of retinal break either on the posterior slope or posterior to buckle (P
= 0.01) and extent of retinal detachment greater than two quadrants (P = 0.02).
CONCLUSIONS: Pneumatic retinopexy is an effective alternative to revision
surgical operations if the leaking retinal break is located on the buckle.
PMID- 9400761
TI - Quantitative analysis of macular holes with scanning laser tomography.
AB - OBJECTIVE: The purpose of the study is to establish objective, quantitative, and
reproducible three-dimensional analysis for macular holes with scanning laser
tomography and to correlate measurements with visual acuity. DESIGN: The authors
performed a cross-sectional, nonrandomized study. PARTICIPANTS: The authors
examined 28 full-thickness macular holes of 23 patients aged 61 to 84 years.
INTERVENTION: Confocal infrared imaging with scanning laser tomography using the
TopSS (790 nm, 10 degrees field) three-dimensional measurements and macular hole
analysis were performed. MAIN OUTCOME MEASURES: Area, depth, and volume
parameters for both macular holes and rims were obtained in two ways: (1)
reference plane for analysis equal to height of the retina (offset surface
distance [OSD] 0) or (2) equal to height of the surrounding edematous rim of the
hole (OSD user). Correlation of measurements with visual acuity and groups of
macular holes was performed. Reproducibility from three image series per subject
and intraobserver variability from ten measurements in four subjects were
computed. RESULTS: Scanning laser tomography could detect macular hole and rim
features in all subjects. Infrared images provided clinically useful information
that may help explain macular hole pathophysiology. Based on quantitative, three
dimensional measurements, holes were assigned to four groups: large, small,
shallow, and average. Groups varied significantly (P < 0.05) for the majority of
measurements. Visual acuity correlated significantly (P < 0.05) with macular hole
volume, depth, slope, and rim height with OSD user only, but not with hole area.
Holes computed with OSD user were deeper and of greater volume. Reproducibility
was excellent for hole area, slope, and rim area; good for hole volume and depth;
variable for rim volume; and improved with OSD user. Intraobserver variability
was low in each group. CONCLUSIONS: Scanning laser tomography is a reproducible
three-dimensional imaging technique providing objective and quantitative clinical
information in assessing, grouping, and managing macular holes. By setting the
OSD to rim height, additional information of rim height and hole volume was
provided and correlated with visual acuity. In addition, more reliable
differences among macular hole groups were found. Axial measurements such as
macular hole depth, volume, and rim height may be more important for visual
acuity than hole area indicating their possible predictive value for outcome
measures.
PMID- 9400762
TI - The treatment of macular disease using a micropulsed and continuous wave 810-nm
diode laser.
AB - OBJECTIVE: The purpose of the study is to determine whether the 810-nm diode
wavelength using a rectangular waveform is clinically effective in the treatment
of choroidal neovascularization from age-related macular degeneration and to
determine whether macular edema secondary to branch vein occlusion or diabetic
retinopathy can be effectively treated with this laser using the micropulse
waveform. DESIGN: Review of consecutive nonrandomized patients whose eyes were
treated with the diode laser over a 30-month period. PARTICIPANTS: Fifty-three
patients with an initial presentation of choroidal neovascularization located
subfoveally (77%), extrafoveally (17%), and juxtafoveally (6%); 14 patients with
macular edema from a branch vein occlusion; and 59 patients with diabetic macular
edema, 40 of which were treated for the first time. INTERVENTION: Ablative
rectangular wave laser photocoagulation was applied to the choroidal neovascular
membranes and very light threshold treatment was applied in a macular grid to
treat retinal edema. Microaneurysms were not targeted. MAIN OUTCOME MEASURES:
Anatomic resolution of macular edema or choroidal neovascularization and visual
acuity. RESULTS: Sixty percent of eyes treated for choroidal neovascularization
had no persistence or recurrence at 6 months, and 72% achieved visual
stabilization. In 8% of eyes, some localized bleeding occurred during
photocoagulation. Clinical resolution of macular edema from branch vein occlusion
occurred by 6 months in 92% of eyes, and 77% had stabilization of visual acuity.
At 6 months, 76% of newly treated patients with diabetic macular edema and 67% of
previously treated patients had clinical resolution of their edema. Vision was
improved or stabilized in 91% and 73% of newly treated and retreated patients at
6 months, respectively. CONCLUSIONS: The micropulsed 810-nm diode laser is
clinically effective in the treatment of macular edema from venous occlusion and
diabetic retinopathy, and the rectangular (normal) mode diode laser can be used
in many eyes with choroidal neovascularization.
PMID- 9400763
TI - Visual acuity outcomes among patients with appositional suprachoroidal
hemorrhage.
AB - OBJECTIVE: The purpose of the study is to investigate visual acuity outcomes
among patients with appositional suprachoroidal hemorrhage and to identify
clinical features associated with visual prognosis. DESIGN: The study design was
a retrospective chart review. PARTICIPANTS: All patients whose ocular echographic
examination results showed appositional suprachoroidal hemorrhage at the Bascom
Palmer Eye Institute between January 1, 1987, and December 31, 1996 were
included. Fifty-one patients were identified. INTERVENTION: Demographic and
clinical data were abstracted from patients' medical records. MAIN OUTCOME
MEASURES: Visual acuity at 3, 6, and 12 months posthemorrhage and clinical
features associated with visual prognosis were defined. RESULTS: At final follow
up fifteen (29.4%) patients achieved either their prehemorrhage visual acuity (n
= 7) or a visual acuity of 20/200 or better (n = 8), but 14 (27.5%) patients had
no light perception. Predictors of a poor visual outcome include vitreous
incarceration in the wound/bleb (P = 0.014), concurrent or delayed retinal
detachment (P = 0.003), and afferent pupillary defect on presentation (P =
0.002). Poorer visual acuity on presentation (r = 0.37, P = 0.008) and longer
duration of central retinal apposition (r = 0.51, P < 0.001) also were
significantly associated with poor final visual acuity. Patients in whom the
suprachoroidal hemorrhage maintained an appositional configuration for more than
14 days were more likely to have worse final visual acuities than were patients
with appositional choroidals for fewer than 14 days (P = 0.006). The association
between duration of apposition and final visual acuity was significant, both
among patients whose suprachoroidal hemorrhages were observed (n = 26, r = 0.60,
P = 0.001) and among patients who underwent secondary surgical intervention (n =
23, r = 0.66, P = 0.001). Patients with postoperative suprachoroidal hemorrhages
achieved better final visual acuities than did patients in whom suprachoroidal
hemorrhages developed intraoperatively or after trauma (P = 0.038). CONCLUSIONS:
Appositional suprachoroidal hemorrhage is a serious ocular complication with a
guarded visual prognosis. A variety of clinical features, including vitreous
incarceration in the wound/bleb, concurrent or delayed retinal detachment,
afferent pupillary defect, presenting visual acuity, and duration of central
retinal apposition, may help predict visual outcome.
PMID- 9400764
TI - Vitreous surgery for chronic macular holes.
AB - OBJECTIVE: The purpose of the study is to compare the results of vitreous surgery
for a group of patients with chronic macular holes with a group of patients with
acute-onset macular holes undergoing identical surgery. DESIGN: A case-control
study design was used. PARTICIPANTS: The duration of symptoms of visual loss due
to macular holes was greater than 1 year's duration in 11 eyes in each group
consecutively operated on within a few days. INTERVENTION: All patients underwent
macular hole surgery. MAIN OUTCOME MEASURES: Ophthalmoscopic resolution of the
macular hole, improvement of 2 lines of visual acuity or greater, improvement in
mean and median visual acuity, and rate of 20/40 or greater final visual acuity.
RESULTS: The hole resolved in 9 of 11 eyes in the chronic group and 10 of 11 eyes
in the acute group. The mean (median) preoperative visual acuity was 20/151
(20/200) in the chronic group and 20/139 (20/200) in the acute group. The 3-month
mean (median) postoperative visual acuity was 20/85 (20/80) in the chronic group
and 20/62 (20/63) in the acute group. The final mean (median) postoperative
visual acuity was 20/96 (20/ 100) in the chronic group and 20/48 (20/50) in the
acute group (P = 0.022). The mean interval to final follow-up examination was 70
weeks for the chronic group and 44 weeks for the acute group. Five (45%) of 11
eyes with chronic holes and 8 (73%) of 11 eyes in the acute group had a final
visual acuity of 2 lines or better than the preoperative visual acuity. Cataract
extraction had been performed by the final follow-up examination in 7 chronic
eyes (64%) and 2 acute eyes (18%). CONCLUSIONS: Chronic macular holes have a
similar anatomic success rate, but a poorer visual prognosis than acute holes
after macular hole surgery. Vitreous surgery benefits some patients with
idiopathic macular holes of greater than 1 year's duration.
PMID- 9400765
TI - Laser photocoagulation for retinal detachments and retinal tears in
cytomegalovirus retinitis.
AB - OBJECTIVE: Retinal detachment complicates the course of cytomegalovirus (CMV)
retinitis in nearly 30% of human immunodeficiency virus-infected patients. The
study goal was to evaluate laser photocoagulation in the treatment of CMV
retinitis-related retinal detachments and retinal tears. DESIGN: Nonrandomized,
observational cohort study. PARTICIPANTS: Sixty-three patients with CMV retinitis
related retinal detachments and nine patients with peripheral retinal tears in
eyes with CMV retinitis were studied. INTERVENTION: Of the 63 eyes with retinal
detachment, 23 patients were treated with demarcating laser photocoagulation, 24
patients underwent vitrectomy with silicone oil, and 16 patients were observed
without treatment. All nine patients with peripheral retinal tears received laser
photocoagulation. MAIN OUTCOME MEASURES: Time to progression of retinal
detachment, final visual acuity, and need for vitrectomy surgery were studied.
RESULTS: Median time to progression of the retinal detachment in the laser
treated patients was 175 days versus 39 days in observed patients (P = 0.012).
Both initial (P < 0.001) and final (P = 0.005) visual acuities were better in the
patients with laser-treated detachment than in the observed or vitrectomy
patients. The retinal detachment groups were comparable in follow-up, zone and
location of detachment, and size of holes, but the vitrectomy and observed groups
had more cases with extensive CMV retinitis. Vitrectomy surgery was required in 9
of 16 (56%) in the observed group and 7 of 23 (30%) in the laser group. Two of
nine patients (22%) who failed to respond to laser treatment for retinal breaks
required vitrectomy surgery. CONCLUSIONS: Laser photocoagulation of selected
retinal detachments and retinal tears delayed or avoided vitrectomy with silicone
oil. It may be an important treatment modality for patients with nonmacular
detachments and for those who are receiving local anti-CMV therapy with
intravitreal injections or pellets, in whom silicone oil may affect the efficacy
of the local treatment.
PMID- 9400766
TI - Laser photocoagulation repair of macula-sparing cytomegalovirus-related retinal
detachment.
AB - OBJECTIVE: The purpose of the study is to investigate the role of laser
photocoagulation in the treatment of macula-sparing cytomegalovirus (CMV)-related
retinal detachment (CMVRD) in patients with acquired immune deficiency syndrome
(AIDS). DESIGN: Seven macula-sparing CMVRD identified between July 1995 and
February 1997 were managed with laser photocoagulation and observed prospectively
(group I). Seven CMVRD reattached with pars plana vitrectomy (PPV) and silicone
oil injection (group II) between January 1992 and June 1996 were analyzed
retrospectively. PARTICIPANTS: Patients with AIDS with macula-sparing
rhegmatogenous CMVRD with no proliferative vitreoretinopathy and visual acuity
better than 20/30 were studied. INTERVENTION: Demarcation laser photocoagulation
(group I) or PPV with silicone oil injection (group II) was performed. MAIN
OUTCOME MEASURES: Postoperative best-corrected visual acuity (BCVA), temporary or
permanent visual loss, CMVRD progression or recurrence, and cataract were
measured. RESULTS: Follow-up ranged from 2 to 19 months (mean, 9 months) in group
I. Post-treatment BCVA was unchanged in all eyes after laser. One retina
redetached 9 months after laser treatment. Final visual acuity was less than
20/40 in one eye because of progressive CMV retinitis. Follow-up ranged from 2 to
24 months (mean, 10.4 months) in group II. All group II RDs were reattached
successfully with PPV and silicone oil injection. Best-corrected visual acuity
was an average of 1.6 lines worse after vitrectomy. Silicone-induced hyperopic
shift caused temporary visual loss in all eyes (mean duration, 5.6 weeks).
Delayed visual loss due to cataract formation occurred in five eyes. Three eyes
had cataract extraction within 6 months. Two partial redetachments developed. One
was repaired with repeat vitrectomy. Final visual acuity was less than 20/40 in
five of seven eyes because of progressive CMV retinitis (1), dense cataract (2),
uncorrected refractive error (2), and uncertain cause (1). CONCLUSIONS:
Demarcation laser photocoagulation appears to be an effective treatment for many
macula-sparing CMVRD. Loss of BCVA, temporary postoperative visual loss due to
silicone-induced refractive error, and delayed visual loss due to cataract after
vitrectomy with silicone oil injection may be avoided. Demarcation laser
photocoagulation may be an effective alternative to vitrectomy in macula-sparing
CMVRD.
PMID- 9400768
TI - Analysis of videokeratography after penetrating keratoplasty: topographic
characteristics and effects of removing running sutures.
AB - OBJECTIVE: Previous studies have shown that removal of running sutures after
penetrating keratoplasty causes unpredictable changes in astigmatism. The current
study was conducted to investigate whether computer-assisted videokeratography is
beneficial for predicting visual outcomes after running sutures are removed.
DESIGN: The design was that of a prospective clinical study. PARTICIPANTS: The
authors prospectively studied 29 consecutive eyes undergoing a 10-0 nylon running
suture removal after penetrating keratoplasty. INTERVENTIONS: Videokeratography
was performed before, 1 week, 1 month, and 3 months after removal of sutures.
MAIN OUTCOME MEASURES: Changes in refractive and topographic astigmatism after
suture removal were measured. Topographic patterns and their quantitative
descriptors also were analyzed. RESULTS: An asymmetric bowtie was the most common
videokeratography pattern both before and after suture removal. After suture
removal, the incidence of peripheral corneal steepening increased significantly
(2 vs. 21 eyes, P < 0.0001), and that of focal flattening of the midperipheral
cornea decreased (13 vs. 5 eyes, P = 0.046). The mean topographic astigmatism,
surface regularity index, and corrected visual acuity were improved significantly
by suture removal in eyes that had localized flattening but not in eyes without
this finding. Eyes having either skewed axis in astigmatism or topographic
astigmatism of more than 9 diopters also showed significant decreases in
astigmatism. CONCLUSIONS: Suture removal after keratoplasty is advantageous for
both reducing astigmatism and normalizing topography, especially in eyes that
have localized flattening of the midperipheral cornea. Predictability of visual
outcomes of a running suture removal in postkeratoplasty eyes may be improved by
the use of videokeratography.
PMID- 9400767
TI - Amniotic membrane transplantation for ocular surface reconstruction in patients
with chemical and thermal burns.
AB - OBJECTIVE: The purpose of the study is to examine the usefulness of preserved
human amniotic membrane transplantation in patients with chemical and thermal
burns. DESIGN: The study design was a nonrandomized clinical trial. PARTICIPANTS:
Seven eyes of six patients with severe chemical (n = 5) and thermal (n = 2) burns
were studied. INTERVENTION: Eyes were treated with excision of cicatricial
tissues followed by a placement of amniotic membrane on the sclera.
Transplantation of limbal grafts from an opposite eye (n = 4) or from donor eyes
preserved at -80 degrees C (n = 2) was performed simultaneously. MAIN OUTCOME
MEASURES: Reconstruction of ocular surface epithelia and visual acuity were
measured. RESULTS: With the mean observation period of 53.3 weeks, central
corneal epithelium was reconstructed successfully in all eyes. Neither amniotic
membrane nor limbal grafts were rejected. A persistent epithelial defect
developed in one eye, which was treated successfully by tarsorrhaphy. After
surgery, the corneal epithelium showed normal arrangements on specular
microscopy, and its barrier function recovered to seminormal. Corrected visual
acuity markedly improved in each eye. Regenerated conjunctiva on the amniotic
membrane was stable and uninflammed with minimum-to-mild scarring. Slight
recurrence of conjunctivalization was noted in three eyes. However, because these
eyes were stable and central cornea was clear, no further surgery was needed.
CONCLUSIONS: Amniotic membrane transplantation promotes normal conjunctival
epithelialization while suppressing fibrosis formation. The procedure, especially
when performed with limbal autograft transplantation, appears to be effective for
the treatment of chemical or thermal burns of the ocular surface.
PMID- 9400769
TI - Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: a
multicenter experience.
AB - OBJECTIVE: The purpose of the study is to evaluate the efficacy and risks of
topical mitomycin C (MMC) for conjunctival-corneal intraepithelial neoplasia
(CCIN). DESIGN: The study design was a clinical case series of CCIN.
PARTICIPANTS: Seventeen patients, 16 with biopsy-confirmed CCIN and 1 with
invasive squamous cell carcinoma (SCC), were included in the study. INTERVENTION:
Patients received topical drops of MMC 0.02% to 0.04% four times daily from 7 to
28 days. Retreatment was done in cases of lesion recurrence. MAIN OUTCOME
MEASURES: The size of the CCIN before and after the treatment and ocular
complications post-MMC application were evaluated. RESULTS: Ten patients remained
disease-free after one course of MMC application. In one case, residual CCIN
remained very small without regrowth. In the one patient with invasive SCC and in
five patients with CCIN, regrowth occurred within 6 months of the first
treatment. After retreatment, invasive SCC and CCIN in an additional two patients
were eradicated. In two cases, although the size of the lesions decreased after
two and three applications of MMC, regrowth occurred, and the CCIN returned to
its original size. In the final case, limited recurrence has occurred and no
retreatment has been done. The complications of MMC use included mild-to-moderate
conjunctival hyperemia and mild allergy, which resolved after discontinuation of
the treatment. Severe pain manifested when treatment was longer than 14 days.
CONCLUSIONS: Application of topical MMC is an efficient treatment for most but
not all cases of CCIN.
PMID- 9400770
TI - Orbital involvement in allergic fungal sinusitis.
AB - BACKGROUND: Although allergic fungal sinusitis is a relatively common,
noninvasive form of paranasal sinus mycosis, and despite frequent orbital
involvement, there have been few reports of this condition in the ophthalmic
literature. METHODS: Two cases of allergic fungal sinusitis having orbital
symptoms are described. The current classification, typical presentation, and
ideal management of fungal sinusitis are reviewed. RESULTS: Distinguishing
radiologic and pathologic features were present in both patients. Aspergillus
flavus was cultured in one case, and Bipolaris spicifera was cultured in the
other. CONCLUSIONS: Allergic fungal sinusitis is a unique subset of sino-orbital
disease with highly characteristic clinical, radiologic, and pathologic features.
Unlike invasive forms of mycotic disease, allergic fungal sinusitis may be
managed adequately with surgical debridement, aeration of the involved sinuses,
and systemic and topical corticosteroids.
PMID- 9400771
TI - Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma.
AB - OBJECTIVE: The purpose of the study is to investigate chemoreduction and adjuvant
treatment (AT) for retinoblastoma and its effect on complete retinal tumor
control, vitreous seed control, and subretinal seed control. DESIGN: The study
design was a prospective, nonrandomized clinical trial. PARTICIPANTS: There were
130 intraocular retinoblastomas in 52 eyes of 32 consecutive patients observed
for at least 1 year after initiation of treatment. INTERVENTION: Treatment with
chemoreduction using vincristine, etoposide, and carboplatin (VEC) and adjuvant
treatment (+ AT) (cryotherapy, laser photocoagulation, thermotherapy,
chemothermotherapy, plaque radiation therapy, or external beam radiation therapy)
were assessed. MAIN OUTCOME MEASURES: The effect of chemoreduction for 6 cycles
(VEC x 6) versus fewer than 6 cycles (VEC x <6) on retinoblastoma control was
analyzed. Furthermore, the impact of adjuvant treatment (+ AT) versus no adjuvant
treatment (no AT) on retinoblastoma control was analyzed. RESULTS: Retinal tumors
showed favorable initial regression with chemoreduction. Adjuvant treatment was
applied to 93% of the retinal tumors after chemoreduction and only 2% recurred
over the mean follow-up of 17 months (range 13-27 months). Vitreous seeds and
subretinal seeds showed initial regression and often complete disappearance with
chemoreduction. In those eyes with seeds before treatment, the addition of AT to
VEC for 6 cycles decreased the vitreous seed recurrence from 75% to 0% (P = 0.04)
and also decreased the subretinal seed recurrence from 67% to 0% (P = 0.003).
More important, when considering that enucleation or external beam radiation
therapy was the only other treatment option for these 52 eyes, the authors were
successful in avoiding these methods in 42% of cases. Of the 36 eyes classified
as Reese-Ellsworth group 5, there was 78% ocular salvage, and external beam
radiation therapy was avoided in 25% of these eyes. There was a 100% ocular
salvage in the group 5 eyes that received VEC for 6 cycles + AT to retinal tumors
and seeds. CONCLUSIONS: Chemoreduction and AT to intraocular retinoblastoma and
its seeds provides good retinal tumor control, even in eyes with advanced
disease. Chemoreduction alone generally is not adequate to achieve complete tumor
seed control. Cautious follow-up of affected patients is recommended because the
risk for recurrent vitreous and subretinal seeds is substantial and proper
treatment is critical for salvaging the eye.
PMID- 9400772
TI - Ocular-hypertensive response to topical steroids in children.
AB - OBJECTIVE: The purpose of the study is to investigate the rate and degree of
ocular-hypertensive response to topical steroids in Chinese children. DESIGN: The
study design was an institutional, randomized, clinical trial. PARTICIPANTS: A
total of 19 consecutive patients were studied. INTERVENTION: Topical steroids
were administered to Chinese children younger than 10 years of age who underwent
bilateral strabismus surgery. One eye was randomized to receive topical 0.1%
dexamethasone (DMS), whereas the fellow eye received 0.1% fluorometholone (FML)
six times per day for up to 4 weeks. Intraocular pressure (IOP) was measured on
the day before operation and at postoperative days 1, 3, 6, 10, 13, and 27, then
every 2 weeks thereafter until the IOP fell to preoperative levels. Topical
steroids would be stopped if IOP was 30.00 mmHg or greater. MAIN OUTCOME
MEASURES: Peak IOP and maximal change of IOP from baseline were measured and
categorized into low, intermediate, and high levels. Time to peak IOP also was
studied. RESULTS: A total of 16 patients were included. The peak IOP for DMS
treated eyes was 30.66 +/- 8.35 mmHg (range, 13.00-48.00 mmHg), whereas that in
FML-treated eyes was significantly lower at 20.66 +/- 6.03 mmHg (range, 11.30
36.30 mmHg) (P = 0.001). The maximal change in IOP ranged from -2.60 to +31.00
mmHg in DMS-treated eyes (mean, 15.48 +/- 8.71 mmHg), almost double that of FML
treated eyes (range, +1.00 to +17.00 mmHg; mean, 5.83 +/- 4.96 mmHg) (P = 0.001).
When the ocular-hypertensive responses of both DMS and FML groups were
categorized into three levels of severity, significant differences were found
between the two treatment groups (P = 0.001). In the DMS group, nine patients
(56.25%) were high responders and six patients (37.5%) were intermediate
responders. In the FML group, only one patient (6.25%) was a high responder.
CONCLUSIONS: The ocular-hypertensive response to topical DMS in children occurs
more frequently, more severely, and more rapidly than that reported in adults. A
total of 56% of the studied children, all younger than 10 years of age, were high
responders to topical DMS. Of these, 89% attained their peak IOP within 8 days.
Its use in children should best be avoided if possible. It would be desirable to
monitor the IOP when it is being used. Conversely, FML produced a much less
ocular-hypertensive effect and therefore poses an acceptable risk of clinically
significant pressure elevation.
PMID- 9400773
TI - Bleb-related ocular infection in children after trabeculectomy with mitomycin C.
AB - OBJECTIVE: The purpose of the study is to report the clinical course of bleb
related ocular infection in children after trabeculectomy with adjunctive
mitomycin C. DESIGN: The study design was a retrospective review of all patients
with a diagnosis of bleb-related ocular infection after trabeculectomy with
adjunctive mitomycin C. PARTICIPANTS: Three children were identified in whom late
postoperative bleb-related ocular infection developed. INTERVENTION: Treatment
consisted of vitreous biopsy with intravitreous antibiotic and corticosteroid
injection and/or bleb culture with topical and intravenous antibiotic
administration. MAIN OUTCOME MEASURES: Visual acuity and intraocular pressure
were measured. RESULTS: Bleb-related ocular infection developed an average of
16.7 +/- 10.9 months after trabeculectomy (range, 4-23 months). The mean age at
presentation was 7.0 +/- 2.6 years (range, 4-10 years). Vitreous cultures were
positive for staphylococci in two cases. A bleb culture from the third case also
grew staphylococcus. All of the children recovered their initial vision after
treatment of infection. However, one lost six lines of vision after a subsequent
retinal detachment. Additional glaucoma surgery was required in one patient.
CONCLUSIONS: Late bleb-related ocular infection may occur in children after
trabeculectomy with mitomycin C and is characterized by abrupt onset, bleb
infiltration, and rapid progression. Despite early preservation of vision after
treatment of infection, significant late visual loss can occur.
PMID- 9400774
TI - Clinical experience of trabeculotomy for the surgical treatment of aniridic
glaucoma.
AB - OBJECTIVE: The purpose of this study is to determine the efficacy of initial
trabeculotomy in the patient with aniridic glaucoma. DESIGN: Clinical charts were
reviewed. PARTICIPANTS: Twenty-nine eyes of 16 patients with aniridia were
studied. INTERVENTION: Glaucoma surgery was performed. As an initial procedure,
trabeculotomy was performed in 12 eyes, other surgery was performed in 17 eyes
(trabeculectomy, 5; goniotomy, 5; other, 7). MAIN OUTCOME MEASURES: Success was
defined as an intraocular pressure (IOP) of 21 mmHg or lower, and no further
surgery was performed. RESULTS: Ten (83%) of 12 eyes obtained IOP control after
first (6 eyes) or second (4 eyes) trabeculotomy with a mean follow-up period of
9.5 years. Five eyes maintained visual acuity of 20/40 to 20/200. No serious
complications were found after trabeculotomy. Three (18%) of 17 eyes were
controlled with the first glaucoma surgery other than trabeculotomy (goniotomy,
trabeculectomy, trabeculectomy combined with trabeculotomy, and Molteno implant).
Good IOP control was obtained in 8 (47%) of 17 eyes after several surgeries with
a mean follow-up period of 10.4 years. Four of 17 eyes became phthisical.
CONCLUSION: This study suggests that trabeculotomy is the preferred initial
operation for uncontrolled glaucoma with aniridia.
PMID- 9400775
TI - The effect of adjunctive mitomycin C in Molteno implant surgery.
AB - PURPOSE: The purpose of the study is to assess the effect of adjunctive
intraoperative mitomycin C (MMC) in Molteno drainage device implantation for
patients with recalcitrant glaucomas. METHOD: Forty-nine eyes of 49 patients who
underwent one-stage, single-plate Molteno device implantation with adjunctive
intraoperative MMC (0.5 mg/ml) for 3 to 5 minutes (MMC group) were compared to a
historic control group of 51 eyes of 51 patients (control group) who received one
stage, single-plate Molteno device implantation without MMC. Success (survival)
was defined as an intraocular pressure (IOP) between 6 and 21 mmHg, inclusive,
with (qualified success) or without (complete success) glaucoma medications and
with no additional glaucoma surgery, phthisis, implant removal, or loss of light
perception. RESULTS: Preoperative conditions were similar between the two groups.
There was no significant difference in surgical survival rate between the two
groups (P = 0.13, log-rank test). There also were no significant differences in
the postoperative IOP levels and numbers of antiglaucoma medications between the
two groups at all times (P > 0.05). Visual acuity was improved or remained within
one line of preoperative visual acuity in 76.1% of the MMC group and 78.7% of the
control group at 1 year after surgery (P = 0.76, chi-square test). Complications
and reoperation for complications were similar in both groups (P > 0.05, chi
square test) except for the incidence of early postoperative hypotony and the
total number of eyes with complications not requiring reoperation, which were
more common in the MMC group (P = 0.027, 0.005, respectively, chi-square test).
The most common complications included hypotony with or without a flat anterior
chamber or choroidal detachment, followed by hyphema and tube plugging.
CONCLUSION: Molteno device implantation with adjunctive intraoperative MMC in
patients with complicated glaucoma may not offer a better chance of surgical
success compared with Molteno implantation without MMC.
PMID- 9400776
TI - Pattern electroretinogram and spatial contrast sensitivity in primary congenital
glaucoma.
AB - OBJECTIVE: The authors investigated the temporal and spatial characteristics of
pattern electroretinogram (PERG) and spatial contrast sensitivity (CS) in primary
congenital glaucoma (PCG) to determine whether the PERG and CS could be useful
tools in the diagnosis of childhood glaucoma, especially PCG. PARTICIPANTS: The
PERGs were evaluated in eyes from ten patients with PCG and nine age-matched
visually normal subjects. INTERVENTION: All patients received complete
ophthalmologic evaluations including visual field testing. MAIN OUTCOME MEASURES:
The PERGs were recorded using phase-alternating (2, 4, and 16 reversals per
second [rps]) checkerboard patterns (30' and 60' checks). RESULTS: The patients
with PCG exhibited decreased CS when compared with that of control subjects.
Significant PERG deficits also were detected in these patients. However, PERG
amplitude in patients with PCG almost reached control subject levels at high (16
rps) temporal frequency. This was true for both 30' and 60' checks. Taken
together, these observations on PERG amplitude suggest a more important
deficiency of the neural response of the retinal cells at lower temporal
frequency (rps) in patients with PCG. This is unlike primary open-angle glaucoma
(POAG) in which significant PERG deficits are observed at high temporal
frequencies. CONCLUSIONS: The PERG amplitude is reduced in patients with PCG, and
this is consistent with a loss of CS and visual field changes in these patients.
However, the spatiotemporal characteristics of the PERG deficits in PCG differ
from those of POAG. This could suggest a difference in the mechanisms mediating
retinal ganglion cell dysfunction in the two types of glaucoma.
PMID- 9400777
TI - Full-time atropine, intermittent atropine, and optical penalization and binocular
outcome in treatment of strabismic amblyopia.
AB - OBJECTIVE: The purpose of the study is to evaluate the monocular and binocular
outcome of three types of "penalization" (blurring of the sound eye) treatment of
amblyopia: traditional full-time atropine or optical penalization and a new
intermittent atropine regimen involving atropine instillation 1 to 3 days a week.
DESIGN: The study design was a retrospective study. PARTICIPANTS: A total of 163
patients with strabismic amblyopia treated by full-time atropine (n = 38),
intermittent atropine (n = 73), or optical (n = 52) penalization participated.
MAIN OUTCOME MEASURES: Logarithm of the minimum angle of resolution (logMAR)
visual acuity, and binocularity index were determined. RESULTS: All three forms
of penalization produced statistically significant mean reduction in amblyopia
(1.7-2.7 logMAR lines) and mean improvement in binocularity by the end-of
treatment or long-term follow-up visit or both, with minimal mean loss after
discontinuation or slight mean improvement on these measures at long-term mean
follow-up of 1.9 to 4 years across groups. Few patients achieved high-grade
stereoacuity. Compliance was high. Comparable efficacy was found for all three
treatment groups after controlling for age, depth of amblyopia, and binocularity
at the initial visit. Initial-visit amblyopia depth was strongly and
significantly associated with amblyopia depth at both post-treatment visits.
Pretreatment and post-treatment binocularity showed a similar strong
relationship. Surprisingly, however, there was no consistent or significant
association found between depth of amblyopia and binocularity in any visit
combination. Post-treatment measures of these two variables also were not
associated with initial-visit age or refractive error at any clinically
significant level. Mean treatment duration was 1.1 to 2.9 years and was not found
to be associated with visual outcome. Amblyopia reversal was found in one (full
time atropine) case at a clinically important level. CONCLUSIONS: The authors
confirmed previous reports of penalization's efficacy as a primary treatment of
moderate amblyopia (20/100 or better acuity) and, in some cases, relatively
severe amblyopia (>20/100) and also confirmed its ability to significantly
improve mean binocularity. Amblyopia and binocularity appear to respond to
treatment independently and, within the postinfancy age range of the sample
studied, the responses appear to be independent of initial-visit age. The high
acceptability to patients and parents of atropine penalization, and particularly
of the intermittent regimen introduced here, suggests the need for prospective
study-based re-evaluation of the relative merits of penalization and occlusion as
the standard of care for mild-to-moderate amblyopia.
PMID- 9400778
TI - Penalization versus part-time occlusion and binocular outcome in treatment of
strabismic amblyopia.
AB - OBJECTIVE: The purpose of the study is to compare the visual outcome of occlusion
versus penalization treatment of strabismic amblyopia, with particular attention
to binocularity outcome. DESIGN: The study design was a retrospective study.
PARTICIPANTS: Patients with strabismic amblyopia, 75 receiving penalization
alone, 87 with a history of occlusion treatment who were later treated by
penalization, and 30 treated by means of part-time occlusion (2 to 6 hours/day)
participated in this study. MAIN OUTCOME MEASURES: Logarithm of the minimum angle
of resolution (logMAR) visual acuity and binocularity index were measured.
RESULTS: No statistically significant difference was found between outcomes for
the penalization groups with and without a history of occlusion, either by
univariate analysis or by multivariate analysis controlling for initial-visit
age, acuity, and binocularity status. One marginally significant outcome
difference was found between the pure penalization and part-time occlusion groups
by univariate analysis, but no significant difference was found in the
multivariate analyses controlling for the same three variables at the initial
visit. All visual outcome differences between the pure penalization and part-time
occlusion groups were less than 1 logMAR line visual acuity or less than a half
unit on the binocularity index. CONCLUSIONS: The study provided no evidence of a
difference in visual function outcome between penalization and occlusion, in
terms of either statistical or clinical significance, although limitations of the
patient samples used preclude these data from showing conclusively that there was
no such difference. The lack of any other study adequately comparing these two
treatment methods, in combination with the current study's demonstration of the
difficulty of making adequate retrospective-based comparison despite a large
patient base (n = 1413), suggests that a large prospective, randomized
comparative treatment trial is needed. If atropine penalization, with its high
acceptability to patients and parents, is found to produce results comparable
with those of occlusion in cases of mild-to-moderate amblyopia, as the current
and previous smaller studies suggest, then reconsideration of the standard of
care for such amblyopia cases is indicated.
PMID- 9400779
TI - Automated pupil perimetry in amblyopia: generalized depression in the involved
eye.
AB - OBJECTIVE: This study was designed to determine whether the relative afferent
pupillary defects observed commonly in amblyopic eyes are associated with a
uniform depression of the pupillary light reflex throughout the visual field or
solely by a focal decrease in pupillary response near fixation. DESIGN: The
authors used pupil perimetry to evaluate the contraction amplitude of the pupil
in response to focal light stimuli at 76 points throughout the 30 degrees field
in each eye of 28 patients with amblyopia. The "pupil fields" were recorded using
a computerized infrared pupillograph linked to a Humphrey Field Analyzer, so that
the pupil contraction could be recorded in response to perimetric light stimuli.
PARTICIPANTS: Nine patients had strabismic amblyopia, ten had anisometropia, six
had a combination of anisometropia and strabismus, and three had deprivation
amblyopia due to monocular congenital cataract. MAIN OUTCOME MEASURES: Mean
pupillary contraction amplitude for the entire field and focal amplitudes at each
tested location were compared. Mixed-model analysis of variance was used to
assess effects of perimetry location, type of amblyopia, and interaction effects.
RESULTS: The overall average of all the pupil contractions throughout the 30
degrees field was less for the amblyopic eye compared with that of the fellow
eye. This decrease in focal pupil response for amblyopic eyes was present in each
type of amblyopia and was greatest for deprivation amblyopia. The contraction
amplitude was depressed diffusely throughout the pupil field and showed neither
focal deficits nor a selective depression about fixation. CONCLUSION: Amblyopia
produces a global depression of focal pupillary responses across the entire 30
degrees field.
PMID- 9400780
TI - Posterior capsulectomy in pediatric cataract surgery: the necessity of a choice.
AB - OBJECTIVE: The purpose of the study is to evaluate whether a posterior
capsulectomy combined with anterior vitrectomy is a necessity in pediatric
cataract. DESIGN: The incidence of posterior capsule opacification, the need for
additional surgical interventions, and the influence of a primary posterior
capsulectomy after cataract surgery in children were evaluated. The analysis was
carried out by studying patients' records retrospectively or after prospective
follow-up. PARTICIPANTS: In 94 eyes (69 aphakic and 25 pseudophakic), the medical
records were studied retrospectively. Twenty-eight eyes (18 aphakic and 10
pseudophakic) were observed prospectively during 1 year after surgery. In 20 eyes
(6 aphakic and 14 pseudophakic) of 10 patients with bilateral cataract, a
prospective comparison between the 2 eyes of the same patient also was carried
out. INTERVENTION: Cataract surgery through the limbus with or without a primary
posterior capsulectomy was performed in 114 eyes (43 of these received a
posterior chamber intraocular lens [IOL] and 71 remained aphakic). In 28 eyes,
the surgery was carried out by way of the pars plana (6 eyes received an anterior
chamber IOL and 22 remained aphakic). MAIN OUTCOME MEASURES: Incidence of
posterior capsule opacification, the need for secondary surgical intervention,
and visual acuity were measured. RESULTS: Opacification of the posterior capsule
is observed in all children's eyes when a primary posterior capsulectomy
(combined with an anterior vitrectomy) was not carried out. Earlier secondary
cataract formation is associated with a younger age and with implantation of an
IOL. Eyes undergoing a primary opening of the posterior capsule during the
initial surgery of children with bilateral cataract achieved, in most cases, a
better visual acuity than did their fellow eyes. CONCLUSION: Although possibly a
choice in older children, a primary posterior capsulectomy combined with anterior
vitrectomy is a must in younger children and particularly when implantation of an
IOL is planned.
PMID- 9400781
TI - Trichotillomania.
AB - PURPOSE: Trichotillomania is characterized by an irresistible urge to pull one's
hair, and may involve the eyelashes or eyebrows. The authors present four cases
of trichotillomania, and review the management of this unusual disorder. METHODS:
The cases of four patients with trichotillomania were reviewed retrospectively.
RESULTS: All four patients had characteristic areas of broken lashes along the
lid in the absence of other signs of disease. Three of the four knew they were
plucking the hair, yet could not control it. In the fourth, it was only after a
lengthy observation period that she was discovered plucking. CONCLUSIONS:
Trichotillomania has been infrequently reported in the ophthalmic literature.
Management can be difficult. Many of these patients are aware of their behavior,
but are unable to curtail it. Others may conceal or deny their habit. Psychiatric
counseling may be of some benefit if patients are willing to undergo it.
PMID- 9400782
TI - Parapapillary chorioretinal atrophy in patients with ocular hypertension. I. An
evaluation as a predictive factor for the development of glaucomatous damage.
AB - OBJECTIVE: To determine whether parapapillary chorioretinal atrophy is a risk
factor for the development of glaucomatous optic disc or visual field damage.
METHODS: The initial morphometric parameters of the optic disc and parapapillary
atrophy were retrospectively investigated in 350 eyes of 175 patients with ocular
hypertension. The prognostic value of parapapillary atrophy at the baseline
examination and its relationship with known risk factors for the development of
glaucomatous damage were analyzed by multivariate analysis. RESULTS: Visual field
loss, optic disc damage, or both were detected in 98 eyes of 53 patients during
the follow-up period of at least 10 years. By univariate analysis, the presence
of parapapillary atrophy, as well as higher parapapillary atrophy area-disc area,
zone beta area-disc area, and parapapillary atrophy length-disc circumference
ratios, at the baseline examination was associated with the conversion to
glaucoma. In addition, higher intraocular pressure, larger vertical cup-disc
ratio, and smaller neural rim area-disc area ratio at the baseline examination
were associated with subsequent glaucomatous optic nerve damage. In a
multivariate regression model adjusted for other factors, intraocular pressure
(relative risk, 1.19), neural rim area-disc area ratio (relative risk, 0.72), and
zone beta area-disc area ratio (relative risk, 1.32) were found to be associated
with the development of optic disc damage, visual field damage, or both.
CONCLUSION: The presence and the size of parapapillary atrophy are related to the
development of subsequent optic disc or visual field damage in patients with
ocular hypertension.
PMID- 9400783
TI - Parapapillary chorioretinal atrophy in patients with ocular hypertension. II. An
evaluation of progressive changes.
AB - OBJECTIVE: To determine whether parapapillary chorioretinal atrophy in patients
with ocular hypertension remained stationary or progressed along with
glaucomatous optic nerve damage. METHODS: The morphometric parameters and
progression of parapapillary atrophy were retrospectively investigated, using
serial photographs, in 350 eyes of 175 patients with ocular hypertension. The
association of parapapillary atrophy progression with subsequent glaucomatous
conversion and with other baseline patient- and eye-specific characteristics was
analyzed. RESULTS: Progression in the area and extension of parapapillary atrophy
before noticeable optic disc or visual field changes was observed in 48 (49.0%)
of 98 eyes that converted to glaucoma, while parapapillary atrophy progression
was noted in 25 (9.9%) of 252 ocular hypertensive eyes that did not develop
glaucomatous damage (P<.001). The predictive sensitivity and specificity of this
observation were 49% and 90%, respectively. In a logistic multiple regression
model, the progression of parapapillary atrophy was associated with a family
history of glaucoma (odds ratio, 2.7) and the initial size of zone beta (odds
ratio, 1.64, for an increase of 0.10 of the zone beta area-disc area ratio).
CONCLUSION: The progression of parapapillary chorioretinal atrophy may be an
early glaucomatous finding in some patients with ocular hypertension.
PMID- 9400784
TI - Effect of cataract extraction on the results of automated perimetry in glaucoma.
AB - OBJECTIVE: To investigate the effect of cataract extraction on the results of
automated perimetry in persons with glaucomatous visual field loss. SUBJECTS:
Subjects from a retrospective study of visual field progression who underwent
cataract extraction during follow-up were identified. Subjects came from the
glaucoma service of a hospital-based tertiary referral center. METHODS: Subjects
had at least 7 Humphrey 24-2 or 30-2 visual fields over 5 years or more, with an
abnormal glaucoma hemifield test result on the first 2 examinations. Visual field
data were transferred to a microcomputer and comparison of the visual fields
immediately before and after cataract extraction was performed. RESULTS: Sixty
five eyes of 50 subjects (mean age, 71.8 years) were included in the analysis. A
mean improvement in mean deviation (MD) of 1.68 dB (P<.001), and a mean worsening
in corrected pattern SD (CPSD) of 0.54 dB (P=.09) was observed. The mean
unweighted change in threshold in the 52 points of program 24-2 was 1.58 dB,
corresponding to a 43.9% increase in sensitivity. A significant correlation
between improvement in visual acuity and improvement in MD was also found. A mean
increase in CPSD of 1.61 dB (P=.005) occurred in subjects with dense scotomas
(minimum threshold value < or = 5 dB) and preoperative CPSD of 8 dB or less.
CONCLUSIONS: In persons with glaucomatous visual field defects, cataract
extraction produces only a modest improvement in MD. After cataract surgery, the
CPSD index worsened in many subjects with dense scotomas. This suggests that the
development of cataract can mask progressive glaucomatous visual field loss in
such persons.
PMID- 9400785
TI - Factors associated with intraocular pressure-induced acute visual field
depression.
AB - OBJECTIVE: To determine the factors associated with visual field depression
produced by artificial elevation of intraocular pressure (IOP). METHODS: The
visual threshold was determined at 26 locations in the central visual field at a
spontaneous IOP, at 30 mm Hg, at 40 mm Hg, and at the IOP immediately following
release of the suction cup used to elevate the IOP artificially in 33 subjects
with and without glaucoma. The net decrease in threshold sensitivity at each IOP
level relative to sensitivity obtained at the spontaneous IOP was calculated
(acute visual field depression). RESULTS: Factors potentially influencing the
acute visual field depression between subjects were determined with stepwise
regression. The reciprocal of ocular perfusion pressure, a clinical measure, was
strongly correlated with acute visual field depression (dependent variable),
particularly at 40 mm Hg (at 30 mm Hg, r=0.412, P=.02, n=32; and at 40 mm Hg,
r=0.813, P<.001, n=33). When a second variable, the diagnosis of glaucoma, was
included in the regression at 40 mm Hg, it contributed significantly (partial
r=0.650, P<.001, n=26). The degree of glaucomatous damage (vertical cup-disc
ratio or baseline Humphrey 24-2 visual field mean deviation) failed to correlate
with acute field depression, with or without correction for ocular perfusion
pressure. CONCLUSIONS: The elevation of IOP produces acute, reversible visual
field depression. This depression is largely dependent on the subject's ocular
perfusion pressure. The degree of depression is greater in those with glaucoma
but is not strictly related to the degree of glaucomatous damage.
PMID- 9400786
TI - MSL-109 adjuvant therapy for cytomegalovirus retinitis in patients with acquired
immunodeficiency syndrome: the Monoclonal Antibody Cytomegalovirus Retinitis
Trial. The Studies of Ocular Complications of AIDS Research Group. AIDS Clinical
Trials Group.
AB - OBJECTIVE: To evaluate the efficacy and safety of an intravenous human monoclonal
antibody to cytomegalovirus (CMV), MSL-109, as adjuvant treatment for CMV
retinitis. METHODS: Two hundred nine patients with acquired immunodeficiency
syndrome and active CMV retinitis were enrolled in a multicenter, phase 2/3,
randomized, placebo-controlled clinical trial. Patients received adjuvant
treatment with MSL-109, 60 mg intravenously every 2 weeks, or placebo.
Randomization was stratified on the basis of whether patients had untreated or
relapsed retinitis. Primary drug therapy for CMV retinitis was determined by the
treating physician. RESULTS: The rates of retinitis progression, as evaluated in
a masked fashion, were 3.04/person-year in the MSL-109-treated group and
3.05/person-year in the placebo-treated group (P=.98; Wald test); the median
times to progression were 67 days in the MSL-109-treated group and 65 days in the
placebo-treated group. No differences between the 2 groups were noted in the
rates of increase in retinal area involved by CMV, visual field loss, or visual
acuity outcomes. The mortality rate in the MSL-109-treated group was 0.68/person
year, and in the placebo-treated group, 0.31/person-year (P=.01). The mortality
difference was not explained by differences in baseline variables or in
concurrent antiretroviral therapy. Among patients with newly diagnosed retinitis,
mortality rates were similar (MSL-109, 0.41/person-year; placebo, 0.42/person
year; P=.95), whereas among patients with relapsed retinitis the MSL-109-treated
group had a greater mortality rate (MSL-109, 0.83/person-year; placebo,
0.24/person-year; P=.003). However, the mortality rate in the placebo-treated
patients with relapsed CMV retinitis was lower than that in the placebo-treated
patients with newly diagnosed CMV retinitis and lower than that in other trials
of patients with relapsed CMV retinitis. CONCLUSIONS: Intravenous MSL-109, 60 mg
every 2 weeks, appeared to be ineffective adjuvant therapy for CMV retinitis. The
mortality rate was higher in the MSL-109-treated group, but the reasons for this
difference remain uncertain.
PMID- 9400787
TI - Factors predictive of growth and treatment of small choroidal melanoma: COMS
Report No. 5. The Collaborative Ocular Melanoma Study Group.
AB - OBJECTIVES: To describe time to tumor growth of a prospectively followed group of
patients with small choroidal melanoma and to determine baseline clinical and
photographic characteristics associated with time to growth. METHODS: The
Collaborative Ocular Melanoma Study (COMS) is a set of clinical trials designed
to compare radiotherapy and enucleation in the treatment of medium- and large
size choroidal melanoma. From December 1986 to August 1989, patients with small
choroidal melanoma, not large enough to be eligible for the COMS clinical trials,
were offered participation in a nonrandomized prospective follow-up study. Small
choroidal melanomas were defined as 1.0 to 3.0 mm in apical height and 5.0 to
16.0 mm in largest basal dimension. A total of 204 patients were enrolled in the
study and were followed up annually through August 1989. An assessment of current
size of tumor, treatment status, and vital status was conducted in 1993-1994; an
additional assessment of treatment and vital status was performed in 1995-1996.
RESULTS: Of 188 small tumors not treated at the time of study enrollment, 46 grew
during follow-up to a size that was large enough to be eligible for the COMS
clinical trials. The Kaplan-Meier estimates of proportion of tumors that grew
were 21% (95% confidence interval, 14%-27%) by 2 years and 31% (95% confidence
interval, 23%-39%) by 5 years. Factors significantly associated with time to
growth in a Cox proportional hazards regression model were greater initial tumor
thickness and diameter, presence of orange pigment, absence of drusen, and
absence of areas of retinal pigment epithelial changes adjacent to the tumor.
CONCLUSIONS: Of small choroidal melanomas initially managed by observation, 21%
demonstrated growth by 2 years and 31% by 5 years. The clinical and photographic
features of these tumors confirm previous findings and are useful in identifying
patients with small tumors at highest risk of short-term growth.
PMID- 9400788
TI - Visual function 5 years after optic neuritis: experience of the Optic Neuritis
Treatment Trial. The Optic Neuritis Study Group.
AB - OBJECTIVE: To assess the 5-year visual course, including the incidence of
recurrent optic neuritis, in 454 patients enrolled in the Optic Neuritis
Treatment Trial. METHODS: Five-year follow-up vision testing, which included
measures of visual acuity, contrast sensitivity, visual field, and color vision,
was completed for 397 (87%) of the 454 patients. RESULTS: Visual function test
results in the eyes that experienced optic neuritis at study enrollment (affected
eyes) were normal or only slightly abnormal after 5 years in most patients; the
results did not significantly differ by treatment group (P=.37 for visual
acuity). The visual acuity in the affected eyes was 20/25 or better in 87%, 20/25
to 20/40 in 7%, 20/50 to 20/190 in 3%, and 20/200 or worse in 3%. The recurrence
of optic neuritis in either eye occurred in 28% of the patients and was more
frequent in patients with multiple sclerosis (P=.001) and in patients without
multiple sclerosis who were in the prednisone treatment group (P=.004). Most eyes
with a recurrence retained normal or almost normal visual function. CONCLUSIONS:
Most patients retained good to excellent vision in the 5 years following an
attack of optic neuritis, even if the optic neuritis recurred. Recurrences were
more frequent in patients with multiple sclerosis and in those treated with oral
prednisone alone. The completion of the 5-year follow-up by the Optic Neuritis
Treatment Trial cohort has not altered our management recommendations based on
the results we reported earlier.
PMID- 9400789
TI - Systemic hyperoxia decreases vascular endothelial growth factor gene expression
in ischemic primate retina.
AB - OBJECTIVES: To determine whether systemic hyperoxia can reverse retinal hypoxia
and decrease vascular endothelial growth factor (VEGF) gene expression in
ischemic nonhuman primate retina. METHODS: Six eyes of 3 cynomolgus monkeys were
studied. Retinal ischemia was induced via laser vein occlusion and confirmed with
fluorescein angiography. Animals were randomly assigned to treatment with either
21% or 100% inhaled oxygen. Arterial PO2 was monitored while systemic acid-base
status was maintained. An oxygen microelectrode on a micromanipulator was used to
measure preretinal oxygen concentrations in ischemic and nonischemic retina in
situ. RNA was isolated from fresh whole retinas, and VEGF messenger RNA levels
were quantified with Northern blotting. RESULTS: The preretinal PO2 in ischemic
retina was less than the PO2 in nonischemic retina in animals breathing 21%
oxygen (intervascular zone PO2, 14.3+/-0.53 vs 21.8+/-0.55 mm Hg; P=.002). After
8 hours of systemic hyperoxia (arterial PO2, 512+/-18 mm Hg), the preretinal PO2
in ischemic retina increased to 166.2+/-15.6 mm Hg (21.8% oxygen) and retinal
VEGF messenger RNA levels were reduced by an average of 55%. CONCLUSIONS: These
data demonstrate that systemic hyperoxia can lower retinal VEGF gene expression
and reoxygenate ischemic adult primate retina.
PMID- 9400790
TI - Apoptosis in patients with posterior uveitis.
AB - BACKGROUND: Apoptosis plays a part in the pathogenesis of autoimmune diseases.
OBJECTIVE: To investigate the expression of apoptotic markers in the eyes of
patients with uveitis. METHODS: With the use of immunohistochemical and in situ
apoptotic detection techniques, apoptotic molecules (Fas or Fas ligand [FasL])
and nuclear DNA fragmentation were examined in 8 enucleated eyes with Behcet's
disease (1), sarcoidosis (1), subretinal fibrosis and uveitis (1), sympathetic
ophthalmia (4), and the Vogt-Koyanagi-Harada syndrome (1); in 5 chorioretinal
biopsy specimens with acute retinal necrosis (2), multifocal choroiditis (1),
sarcoidosis (1), and subretinal fibrosis and uveitis (1); and in 3 normal control
eyes. RESULTS: Fas and FasL were constitutively expressed in the normal human
retina, but they were expressed much less in the choroid. Increased expression of
Fas and FasL was found in the retina, chorioretinal scar, and choroidal
granulomas in uveitic eyes. However, Fas and FasL expression was absent in the
biopsy specimens with acute retinal necrosis, and little Fas or FasL was noted on
infiltrating lymphocytes. DNA fragmentation was also identified in eyes with
chorioretinal scar and gliosis. CONCLUSIONS: Apoptosis occurs in uveitic eyes and
may play a regulatory role in limiting ocular inflammation. In uveitic eyes, a
dysregulation of the Fas-FasL apoptotic pathway may lead to gliosis and fibrosis.
PMID- 9400791
TI - Sorsby fundus dystrophy: reevaluation of variable expressivity in patients
carrying a TIMP3 founder mutation.
AB - Interfamilial phenotypic variations in Sorsby fundus dystrophy (SFD) have given
rise to controversy as to whether SFD constitutes more than 1 nosologic entity.
The recent identification of the tissue inhibitor of metalloproteinases-3 (TIMP3)
as the gene causing SFD has made it possible to readdress the question of genetic
and clinical heterogeneity. In this study, we have extended previous findings on
a Ser181Cys founder mutation in SFD families from the British Isles and show that
carriers of this mutation residing in Canada, the United States, and South Africa
likewise are descendants of the British ancestor. In addition, we have
reevaluated the question of variable SFD phenotypes by analyzing the available
clinical data on carriers of the Ser181Cys mutation.
PMID- 9400792
TI - Associations with intraocular pressure in the Barbados Eye Study.
AB - OBJECTIVE: To evaluate the demographic, medical, ocular, familial, and other
factors possibly associated with intraocular pressure (IOP) in a black
population, after excluding persons with any type of glaucoma. DESIGN: The
Barbados Eye Study was a population-based study of a random sample of residents
of Barbados, West Indies, aged 40 to 84 years. PARTICIPANTS: A subset of the
Barbados Eye Study population consisting of 3752 black Barbados Eye Study
participants without glaucoma. DATA COLLECTION: A standardized protocol included
applanation tonometry and other ocular data, blood pressure measurements,
anthropometry, complexion pigmentation gradings, and a comprehensive interview.
MAIN OUTCOME MEASURE: Intraocular pressure was based on the average of 3
measurements at the Barbados Eye Study visit. Multiple linear regression was used
to evaluate factors associated with IOP. RESULTS: Systolic blood pressure (or
hypertension), diabetes history, and age were the major factors positively
associated with IOP (P<.01). Other positively related factors were female gender,
darker complexion, pulse rate, higher body mass, seasonality, family history of
glaucoma, current alcohol use, and current smoking. These factors explained 10%
of the variation in IOP. CONCLUSIONS: By identifying risk factors, these results
define specific subgroups most likely to have an elevated IOP. The high IOP in
this population may be linked to the high prevalence of hypertension and
diabetes. Aside from age and a family history of glaucoma, none of the risk
factors for high IOP evaluated in this study was similar to those associated with
open-angle glaucoma.
PMID- 9400793
TI - Small choroidal melanoma.
PMID- 9400794
TI - Maximal medical therapy for glaucoma.
PMID- 9400795
TI - Melanogenic neuroectodermal tumor of the retina (primary malignant melanoma of
the retina).
AB - A 35-month-old girl with leukocoria was clinically diagnosed with unilateral
sporadic retinoblastoma. Macroscopic examination of her enucleated eye disclosed
a white retinal tumor that appeared to be a retinoblastoma. Histopathologic
examination, however, revealed that the tumor was composed of poorly
differentiated neuroblastic cells, larger spindle-shaped cells, and anaplastic
epithelioid cells, which is inconsistent with retinoblastoma. Immunohistochemical
testing disclosed that the tumor cells were immunoreactive for melanoma-specific
antigen HMB-45, while electron microscopy showed premelanosomes in the tumor
cells, both of which are consistent with melanogenesis. To our knowledge, such an
ocular tumor has not been reported previously.
PMID- 9400796
TI - Primary basal cell carcinoma of the caruncle.
AB - Basal cell carcinomas (BCCs) of the caruncle are rare. We report a case of a
primary BCC of the caruncle in a 74-year-old man who was seen with a medial
interpalpebral lesion. He had a history of sun exposure and multiple malignant
neoplasms of the skin. The lesion was excised and histological examination showed
a BCC of the caruncle. The clinical history, examination findings, and
histological features are given.
PMID- 9400797
TI - Myoepithelioma of the lacrimal gland.
AB - A right orbital tumor was excised from a 76-year-old woman. Pathological
examination showed that the tumor was composed of spindle to cuboidal cells
arranged in a solid to trabecular pattern. Immunohistochemical stains were
positive for S-100 protein, muscle-specific actin, cytokeratins MAK6 and AE1,3,
and glial fibrillary acid protein and negative for CD34 in tumor cells.
Ultrastructural features of tumor cells included microvillous processes,
intercellular junctions, and intracytoplasmic filaments with electron densities.
To our knowledge, this is the first non-spindle cell myoepithelioma noted to
arise in the lacrimal gland. This tumor likely has a similar biological behavior
to pleomorphic adenoma (benign mixed tumor).
PMID- 9400798
TI - Pseudomembranous conjunctivitis following topical gentamicin therapy.
PMID- 9400799
TI - Bilateral corneal infection as a complication of laser in situ keratomileusis.
PMID- 9400800
TI - Hypertensive retinopathy simulating Leber idiopathic stellate neuroretinitis.
PMID- 9400801
TI - Inflammatory mass of the optic nerve head associated with systemic Bartonella
henselae infection.
PMID- 9400802
TI - Epiretinal membrane delamination with a diamond knife.
AB - Removal of membranes from the retinal surface is an integral part of many
vitreoretinal surgical procedures. Two-handed tissue delamination with a knife
allows precise and accurate control of dissection planes. A newly designed
diamond knife provides the consistently sharp cutting edge required for this
technique.
PMID- 9400803
TI - Conjunctival squamous cell carcinoma treated with topical 5-fluorouracil.
PMID- 9400804
TI - Familial trichomegaly.
PMID- 9400805
TI - What is the evidence supporting chemotherapy for intraocular retinoblastoma?
PMID- 9400806
TI - A case of primary choroidal melanoma in a patient with previous cutaneous
melanoma.
PMID- 9400807
TI - Should we patch corneal erosions?
PMID- 9400808
TI - Women in ophthalmology.
PMID- 9400809
TI - Natural killer cells: endothelial interactions, migration, and target cell
recognition.
AB - Natural killer (NK) cells form a unique third group of lymphocytes that differs
from T and B cells in surface phenotype, target recognition, and function. By
producing cytokines and exerting cytotoxicity, NK cells participate in the
resistance against microbial infections and malignant disease. The research on
the molecular mechanisms of migration and target cell recognition by NK cells has
recently developed rapidly. NK cells express a number of adhesion molecules
common to hematopoietic lineage, bind to endothelium, extravasate, and respond to
chemotactic stimuli, much resembling T cells in those respects. However, NK cells
are probably capable of transmigration and infiltration merely through activation
by cytokines and chemokines, as opposed to the requirement of antigen
presentation in the initial activation of T cells. Target cell recognition and
ensuing cytotoxicity of NK cells is a sum effect of a delicate balance between
the effects of inhibitory and activating NK cell receptors. NK cells express
several well-defined MHC I-recognizing receptors that inactivate their functions.
In pathological alterations of MHC I expression, the inhibitory receptors do not
engage and thus permit the lysis of the target cell. The receptors that trigger
the cytolytic machinery of NK cells are less well known. Some candidate
triggering receptors have been identified and it seems that NK cell triggering is
mediated by multiple receptors, as is the inhibition of cytotoxicity. For
example, NK cells clearly detect target cell-bound antibodies and thus mediate
antibody-dependent cytotoxicity. They may also detect carbohydrate moieties,
normal but pathologically distributed adhesion molecules, as well as ligands for
a number of co-stimulatory receptors.
PMID- 9400810
TI - Elimination, blocking, and activation of macrophages: three of a kind?
AB - In mammals, macrophages are multifunctional cells. Apart from their scavenger
role in the clearance of non-self materials such as microorganisms and altered
self materials such as apoptotic cells, senescent erythrocytes, immune complexes,
and inflammatory products, they play a crucial role in the regulation of both
innate and acquired immunity. Whereas the former activity is based on
phagocytosis and intracellular degradation, the latter activity largely depends
on the production and secretion of a panel of regulatory molecules such as
cytokines, chemokines, and nitrogen oxide (NO). Depletion of macrophages and
blocking of phagocytosis form important approaches to study the role of these
cells in various host defense mechanisms. Moreover, the efficacy of drug- and
gene-targeting, based on the application of particulate carrier devices, can be
improved in this way. However, compounds originally described as efficacious
blockers of phagocytosis simultaneously activate their production of cytokines
and NO. Moreover, elimination, blocking, as well as activation of macrophages are
all dependent on the concentration of such compounds. When administered in vivo,
they will reach some macrophages in a high and others in a low concentration. As
a consequence, the former cells may be eliminated or blocked, whereas the latter
are activated by the same treatment. In this review, the various methods for
suppression of macrophage functions are compared and requirements for the
development of new, selective, and organ-specific macrophage-suppressing devices
are discussed.
PMID- 9400812
TI - Effect of alterations of blood cholesterol levels on macrophages in the
myocardium of New Zealand White rabbits.
AB - We investigated the effect of alterations of blood cholesterol levels on
macrophages (mphi) in the myocardium of New Zealand White (NZW) rabbits. Three
groups of NZW rabbits were used: controls, rabbits fed a 0.5% cholesterol
enriched diet (CH-D) for 96 days, and rabbits fed a 0.5% CH-D for 96 days
followed by normal chow for 4 months. Immunohistochemical analysis by mAbs
directed against mphi (RAM-11) and Mn superoxide dismutase (MnSOD) were
quantified by computer-assisted morphometry. Using cultured human and rabbit
mphi, a cross-reaction of the human MnSOD mAbs was found as well as the
predominant localization of MnSOD-immunoreactivity (IR) in mitochondria. In group
1, only a very few RAM-11-immunoreactive (ir) mphi occurred in the interstitial
space of the myocardium. In group II blood cholesterol levels significantly
increased in parallel with the numbers of mphi, which often contained lipid
droplets (foam cells). Although blood cholesterol concentrations regressed about
10-fold in group III, mphi in the myocardium were found to be reduced only about
20%. Most mphi were also MnSOD-ir. In atherosclerotic coronary arteries RAM-11-IR
was located in mphi and also extracellularly, whereas MnSOD-IR was found only in
mphi. Drastically induced MnSOD in the mitochondria of mphi is suggested as an
indicator of increased oxidative stress caused by in vitro conditions or by
phagocytosis of low-density lipoprotein in vivo. Elevation of the cholesterol
level leads to a long-term increase and its regression results in a delayed
reduction of such mphi, which seem to play a key role in the atherogenesis of the
coronary arteries as well.
PMID- 9400811
TI - Immunomodulatory action of G-CSF in a rat model of endotoxin-induced liver
injury: an intravital microscopic analysis of Kupffer cell and leukocyte
response.
AB - In contrast to the anticipation that in sepsis granulocyte colony-stimulating
factor (G-CSF) would overactivate the nonspecific immune system by recruiting and
priming leukocytes with consequent aggravation of inflammatory tissue lesions,
recombinant (r) G-CSF pretreatment was protective in various experimental non
neutropenic models of inflammation. The mechanisms of protection, however, are
not fully understood. Using intravital fluorescence microscopy, we show that rG
CSF enhances leukocyte endothelial cell interaction within the microvasculature
of normal rat livers, whereas rG-CSF pretreatment of animals exposed to
lipopolysaccharide (LPS) attenuates the LPS-induced leukocytic response,
including stasis in sinusoids as well as rolling and adherence in postsinusoidal
venules with subsequent tissue infiltration. Moreover, rG-CSF, which did not
affect Kupffer cell activity in normal rat livers, reduced the immediate
activation of Kupffer cells on LPS exposure, as indicated in vivo by the delayed
adherence/phagocytosis of intra-arterially administered latex particles
associated with attenuation of proinflammatory cytokine release (tumor necrosis
factor alpha and interleukin-6). Finally, rG-CSF reduced LPS-induced nutritive
perfusion failure and hepatocellular excretory dysfunction. This study provides
evidence for a distinct, possibly tumor necrosis factor alpha-dependent
modulation of LPS-induced cellular response within the liver by rG-CSF, thereby
achieving protection against microcirculatory perfusion failure and hepatic
dysfunction.
PMID- 9400813
TI - Innate resistance to Listeria monocytogenes in tumor-bearing mice.
AB - We have previously described the isolation, cloning, and characterization of a
tumorigenic murine fibrosarcoma, designated JBS. Growth of JBS tumors in
syngeneic mice initiates an anti-tumor immune response that initially manifests
as progressive splenic hyperplasia and an increased proliferative ability in
cultured splenocytes. In animals with tumors progressing beyond the 2 cm stage
there is a reduction in spleen size and a gradual decrease in splenocyte
proliferative abilities, leading to anergy at heavy tumor burdens (>3.5 cm).
During the phase of immune hyperresponsiveness in tumor-bearing mice clearance of
Listeria monocytogenes by components of the innate immune system is increased.
This heightened resistance to infection is most likely macrophage-mediated
because these mice demonstrate an increased ability to recruit macrophages to the
peritoneal cavity during Listeria infection. In addition, these macrophages are
highly activated in vivo as evidenced by an elevated capacity to express class II
MHC (Ia) molecules. This increase in macrophage activation status is coincident
with an increased capacity of splenocytes from tumor-bearing mice to secrete IFN
gamma. In mice with much heavier tumor burdens (>3.5 cm), down-regulation of the
immune response leads to a reduction in peritoneal macrophage numbers, decreased
macrophage Ia expression, and diminished splenic clearance of L. monocytogenes.
Our data demonstrate that activation of macrophages distal to the tumor site
occurs as an initial consequence of tumor growth. It is only in mice with very
heavy tumor burdens that functionality of macrophages is sufficiently suppressed
to allow increased splenic growth of L. monocytogenes.
PMID- 9400814
TI - Effects of acute ethanol exposure on cellular immune responses in a murine model
of thermal injury.
AB - To test the effects of acute ethanol exposure on immune function after thermal
injury, mice with blood alcohol levels of 100 mg/dL were given a 15% total body
surface area dorsal scald or sham injury. Bacterial challenge resulted in 100 and
40% mortality in burn + ethanol- and burn + vehicle-treated mice, respectively.
Delayed-type hypersensitivity responses were also significantly suppressed in
burn + ethanol-treated mice. At 1 and 4 days post-burn, concanavalin A (ConA)
induced total splenocyte proliferation in burn + ethanol-treated groups was
significantly decreased (P < 0.01) compared with burn + vehicle- or sham-treated
animals. This decrease was not observed in total splenocytes cultured with anti
CD3epsilon or among adherence-depleted splenocytes given ConA or anti-CD3epsilon.
FACS analyses revealed no changes in splenocyte sub-type ratios in burn + ethanol
mice. The data herein demonstrate that acute ethanol exposure before thermal
injury results in enhanced susceptibility to bacterial infection and markedly
suppressed cellular immunity, which appears to be macrophage dependent.
PMID- 9400815
TI - Rat monocytes up-regulate NKR-P1A and down-modulate CD4 and CD43 during
activation in vivo: monocyte subpopulations in normal and IFN-gamma-treated rats.
AB - LEW rats were treated intravenously with recombinant rat interferon-gamma (IFN
gamma) for 3 days to achieve intravascular accumulation, proliferation, and
activation of monocytes. Monocytes, defined by their expression of the ED1, ED9,
and Ox41 antigens, were recovered from the vasculature by perfusion with
PBS/EDTA, subsequently depleted of erythrocytes and granulocytes by Percoll
density gradient centrifugation, and analyzed by flow cytometry and
immunocytology. In untreated and control-infused specified pathogen-free (SPF)
rats, lymphocytes and monocytes formed overlapping cell populations with respect
to size and internal granularity. At least two intravascular monocyte subsets,
probably central and marginating cells, were distinguished by their size and
differential expression of CD43, CD4, CD11a, CD18, and L-selectin. It is
interesting to note that a fraction of the monocytes in normal and control
infused animals carried the NKR-P1A molecule. IFN-gamma treatment provoked a
duplication of monocyte size and granularity. Both the number of positive
monocytes and the level of expression of NKR-P1A strongly increased after IFN
gamma infusion, whereas CD43 (leukosialin) and CD4 were impressively down
regulated. NKR-P1A+ L-selectin+ CD43low CD4- monocytes also occur in the
vasculature of rats during immune reactions in vivo. We speculate that these
cells are involved in organ damage and that their number is controlled by
activation-induced cell death within the vessels.
PMID- 9400816
TI - Increased expression of an endopeptidase (gamma-EGE/IDE) hydrolyzing beta
endorphin during differentiation and maturation of bone marrow macrophages.
AB - The presence and regulated expression of peptidase activity is a powerful
mechanism with the potential to terminate or alter receptor recognition, cell
membrane signal transduction, and physiological responses of immune cells to
exogenous opioid peptides. In this study, the expression of an endopeptidase that
hydrolyzes beta-endorphin to gamma-endorphin and other peptide products was
investigated during in vitro differentiation and maturation of recombinant
granulocyte-macrophage colony-stimulating factor (rGM-CSF) -derived, bone marrow
derived macrophages. In freshly isolated intact isolated mouse bone marrow cells
the rate of beta-endorphin hydrolysis is undetectable (<0.1 nmol beta-endorphin
hydrolyzed/h/10[6] cells). However, total intracellular beta-endorphin hydrolytic
activity was increased significantly to 20.0 +/- 1.7 nmol/h/10(6) cells in the
mature mouse macrophages derived in vitro by culture with rGM-CSF. rGM-CSF
derived macrophages expressed significantly higher levels of both protein and
mRNA for the major beta-endorphin endopeptidase, gamma-endorphin-generating
enzyme/insulin-degrading enzyme (gamma-EGE/IDE). Moreover, this enzymatic
activity appears to be responsible for cleavage of exogenous beta-endorphin by
intact rGM-CSF-derived macrophages or peritoneal macrophages to generate gamma
endorphin and other peptide products.
PMID- 9400817
TI - Tumor site-selective localization of an adoptively transferred T cell line
expressing a macrophage lectin.
AB - CTLL-2 cells were transfected with an expression vector that contained cDNA of a
mouse macrophage galactose/N-acetylgalactosamine-specific calcium-type lectin
(MMGL) and a stable transfectant (CTL-ML) was established. These cells and mock
transfectant cells (CTL-CEP) were labeled with a long-term fluorescent cell
tracer, DiI. The labeled cells were intravenously injected into mice that
contained established lung metastases produced by OV2944-HM-1 ovarian tumor
cells. Analyses with fluorescence microscopy of a series of frozen lung sections
from the recipient mice revealed that CTL-ML preferentially accumulated in the
lung metastatic nodules, whereas CTL-CEP did not. Time course studies showed that
the preferential accumulation was evident 3 days after adoptive transfer. We also
found that OV2944-HM-1 cells bound peanut agglutinin and Vicia villosa agglutinin
B4, whose sugar specificity overlaps with the specificity of MMGL. These results
suggested that MMGL molecules expressed on CTLL-2 cells contributed to their
selective trafficking or retention in tumor foci possibly through recognition of
tumor-associated cell surface carbohydrate antigens. These results also suggested
that MMGL could be used for the selective targeting of effector cells in adoptive
immunotherapy.
PMID- 9400818
TI - Dietary fish oil diminishes the antigen presentation activity of rat dendritic
cells.
AB - Rats were fed for 6 weeks on a low fat (LF) diet or on high fat diets containing
safflower oil [SO; rich in n-6 polyunsaturated fatty acids (PUFAs)] or fish oil
(FO; rich in n-3 PUFAs). Lymph-borne dendritic cells (L-DC) were isolated after
cannulation of the thoracic duct and were used as antigen [keyhole limpet
hemocyanin (KLH)]-presenting cells in an ex vivo assay that used KLH-sensitized
spleen lymphocytes as the responder cells. FO feeding significantly diminished
the antigen presentation activity of L-DC compared with L-DC from rats fed each
of the other diets. The antigen presentation activity of L-DC from rats fed the
SO diet was greater than that of L-DC from rats fed the LF diet. Feeding the FO
diet significantly reduced both the proportion of CD2-positive L-DC and the level
of CD2 expression on L-DC compared with feeding each of the other diets; the
proportions of L-DC staining positive for CD40, CD18, CD54, CD11a, and MHC II
were unaffected by diet. However, FO feeding reduced the level of expression of
CD18, CD11a, MHC II, and CD54 on L-DC compared with feeding the other two diets;
the level of expression of CD40 was unaffected by diet. This is the first study
to report effects of dietary fatty acids on dendritic cells. The suppressive
effect of FO feeding may account for some of the beneficial effects of n-3
polyunsaturated fatty acids observed in clinical settings, such as prolonged
survival of grafts and diminished chronic inflammatory responses. However, such
an effect may also be detrimental because host defense toward bacterial and other
antigens could be compromised.
PMID- 9400819
TI - Effects of inhibitors of inflammatory mediators and cytokines on eosinophil and
neutrophil accumulation induced by Mycobacterium bovis bacillus Calmette-Guerin
in mouse pleurisy.
AB - In this work we characterize the Mycobacterium bovis bacillus Calmette-Guerin
(BCG) -induced pleurisy and investigate the role of chemical mediators and
cytokines in BCG-induced granulocyte accumulation at 24 h. Intrathoracic
injection of BCG in C57B1/6 mice induces a biphasic inflammatory reaction with
intense leukocyte accumulation at 24 h and 15 days. Neutrophils were observed in
the pleural cavity at 4-24 h, mononuclear cells and eosinophils after 24 h. A new
wave of mononuclear cells and neutrophils were observed after 15 days.
Pretreatments with dexamethasone, BW 755C, BW A4C, WEB 2170, L-NAME, and
monoclonal antibody (mAb) anti-interleukin-5 (IL-5; TRFK-5) had inhibited the
eosinophil accumulation. On the other hand, only the pretreatments with
dexamethasone, L-NAME, or mAb anti-tumor necrosis factor alpha (TNF-alpha; MP6
XT3) had inhibited the neutrophil influx. These results suggest the involvement
of leukotrienes, platelet-activating factor, nitric oxide, and IL-5 in the
eosinophil accumulation, and a role for nitric oxide and TNF-alpha in the
neutrophil influx induced by BCG.
PMID- 9400820
TI - Phagocytosis of gram-negative bacteria by a unique CD14-dependent mechanism.
AB - THP-1-derived cell lines were stably transfected with constructs encoding
glycophosphatidylinositol (GPI)-anchored or transmembrane forms of human CD14.
CD14 expression was associated with enhanced phagocytosis of serum (heat
inactivated)-opsonized Escherichia coli (opEc). Both the GPI-anchored and
transmembrane forms of CD14 supported phagocytosis of opEc equally well.
Lipopolysaccharide-binding protein (LBP) played a role in CD14-dependent
phagocytosis as evidenced by inhibition of CD14-dependent phagocytosis of opEc
with anti-LBP monoclonal antibody (mAb) and by enhanced phagocytosis of E. coli
opsonized with purified LBP. CD14-dependent phagocytosis was inhibited by a
phosphatidylinositol (PI) 3-kinase inhibitor (wortmannin) and a protein tyrosine
kinase inhibitor (tyrphostin 23) but not a protein kinase C inhibitor (bisindolyl
maleimide) or a divalent cation chelator (ethylenediaminetetraacetate). Anti-LBP
mAb 18G4 and anti-CD14 mAb 18E12 were used to differentiate between the pathways
involved in CD14-dependent phagocytosis and CD14-dependent cell activation.
F(ab')2 fragments of 18G4, a mAb to LBP that does not block cell activation,
inhibited ingestion of opEc by THP1-wtCD14 cells. 18E12 (an anti-CD14 mAb that
does not block LPS binding to CD14 but does inhibit CD14-dependent cell
activation) did not inhibit phagocytosis of LBP-opEc by THP1-wtCD14 cells.
Furthermore, CD14-dependent phagocytosis was not inhibited by anti-CD18 (CR3 and
CR4 beta-chain) or anti-Fcgamma receptor mAb.
PMID- 9400821
TI - Effector molecules in expression of the antimicrobial activity of macrophages
against Mycobacterium avium complex: roles of reactive nitrogen intermediates,
reactive oxygen intermediates, and free fatty acids.
AB - We studied microbicidal activities of reactive nitrogen intermediates (RNI), free
fatty acids (FFA), and reactive oxygen intermediates (ROI) against Mycobacterium
avium complex (MAC) and the mode of macrophage (mphi) production of these
effectors. (1) Intracellular growth of MAC in murine peritoneal mphis was
accelerated by scavengers for ROI or RNI and inhibitors of nitric oxide synthase
or phospholipase A2, indicating roles of ROI, RNI, and FFA in mphi anti-MAC
functions. (2) Acidified NaNO2-derived RNI, FFA (linolenic and arachidonic
acids), and the H2O2-mediated halogenation system exhibited a significant anti
MAC bactericidal activity. The combination of RNI with FFA showed a synergistic
effect. However, the H2O2-halogenation system in combination with either RNI or
FFA showed an antagonism. When Listeria monocytogenes (Lm) was used as a target
organism, the combinations of RNI + FFA and RNI + H2O2-halogenation gave a
synergistic effect, whereas FFA + H2O2-halogenation showed an antagonism in
exerting bactericidal activity. In addition, when ROI generated by the xanthine
oxidase-acetaldehyde system was combined with RNI, anti-Lm but not anti-MAC
activity was potentiated. (3) ROI production by murine peritoneal mphis was
observed immediately after contact with MAC organisms (MAC stimulation) and
ceased within 2 h. FFA release was seen 1-24 h after MAC stimulation. RNI
production was initiated from 3 h and increased during the first 36 h and
continued at least for 4 days. These findings suggest that RNI and FFA rather
than ROI are important effectors of anti-MAC functions of mphis, and the
collaborating action of RNI with FFA temporarily participates in mphi-mediated
killing of MAC in the relatively early phase after MAC stimulation.
PMID- 9400822
TI - Modulation of human neutrophil inflammatory responses by nitric oxide: studies in
unprimed and LPS-primed cells.
AB - Because nitric oxide (NO) can act both as a regulatory and as a toxic molecule,
we have studied N-formyl-methionyl-leucyl-phenylalanine (fMLF)-stimulated
responses of human neutrophils (PMNs) during various conditions of NO modulation
in unprimed and bacterial lipopolysaccharide (LPS) -primed cells. Effects of
various NO modulators were assessed on stimulated superoxide (O2-) generation,
granule exocytosis, homotypic aggregation, and rises in intracellular free Ca2+
([Ca2+]i). Significant differences in the effects of various NO modulators on
inflammatory responses of PMNs kept in stirred suspension versus those kept under
static and/or adherent conditions, were observed. L-arginine, the physiological
substrate for NO synthase (NOS), and NG-nitro-L-arginine methyl ester, an
inhibitor of NOS, both caused a 40-50% inhibition of LPS-induced priming of O2-
generation in PMNs in stirred suspension, but not in LPS-primed PMNs under static
or adherent conditions. The NO donors, sodium nitroprusside and S-nitroso-N
acetylpenicillamine, completely abrogated the LPS-induced priming of O2-
generation in PMNs in suspension, while causing only a 40-50% inhibition in PMNs
under static or adherent conditions. The Ca2+ ionophore, A23187, prevented the
LPS-induced priming of O2- generation without affecting O2- generation in
unprimed PMNs. LPS priming of PMNs induced about a twofold increase in fMLF
stimulated homotypic aggregation, exocytosis of secondary granules, and rises in
[Ca2+]i. In related studies, we also provide definitive evidence for enzymatic
formation of NO in human PMNs and demonstrate a significant decrease in NO levels
in LPS-primed PMNs. Taken together, these findings indicate that NO modulates PMN
inflammatory responses and plays a protective role in priming and activation
processes of inflammatory PMNs.
PMID- 9400823
TI - Rapid induction of neutrophil apoptosis by sulfasalazine: implications of
reactive oxygen species in the apoptotic process.
AB - Accumulating evidence indicates that neutrophils are crucially involved in the
pathogenesis of inflammatory bowel diseases and rheumatoid arthritis. We
therefore investigated the effect of sulfasalazine (SSZ), which is widely used in
the treatment of these diseases, on neutrophil apoptosis in vitro. The apoptosis
of neutrophils was determined by morphology, a DNA histogram of propidium iodide
stained nuclei, and DNA fragmentation. SSZ rapidly accelerated the rate of
spontaneous neutrophil apoptosis within clinically relevant concentrations. This
effect is unique to neutrophils because other types of leukocytes and a number of
leukocyte cell lines are resistant to SSZ. Neutrophil apoptosis caused by SSZ was
abrogated by a tyrosine kinase inhibitor, a protein kinase A inhibitor, and
antioxidants. The subsequent results provided pharmacological evidence that the
phosphorylation of tyrosine kinase and protein kinase A and generation of
reactive oxygen species are involved in SSZ-mediated neutrophil apoptosis. These
data suggest that SSZ-induced neutrophil apoptosis may account, in part, for the
clinical benefits of SSZ on inflammatory bowel diseases and rheumatoid arthritis.
PMID- 9400824
TI - Anti-inflammatory action of dapsone: inhibition of neutrophil adherence is
associated with inhibition of chemoattractant-induced signal transduction.
AB - Dapsone has clinical utility as an anti-inflammatory agent but the mechanism of
this action remains unknown. We have previously reported that dapsone inhibits
beta2 integrin (CD11b/CD18)-mediated adherence of human neutrophils in vitro and
now describe studies designed to discover how dapsone-mediated inhibition of this
neutrophil function occurs. Results indicate that dapsone interferes with the
activation or function of the G-protein (Gi type) that initiates the signal
transduction cascade common to chemotactic stimuli. They also show that dapsone
mediated suppression of this pathway inhibits the generation of second messengers
essential to the activation of beta2 integrin molecules, as well as respiratory
and secretory functions of neutrophils exposed to chemoattractants. We propose
that the inhibition of chemoattractant-induced signal transduction by dapsone
suppresses neutrophil recruitment and local production of toxic respiratory and
secretory products in the affected skin of dermatitis herpetiformis and other
neutrophilic dermatoses.
PMID- 9400825
TI - Maintenance and down-regulation of primed neutrophil chemiluminescence activity
in human whole blood.
AB - Priming of polymorphonuclear neutrophils (PMN) in whole blood (by tumor necrosis
factor alpha and interleukin-8 for enhancement of luminol-dependent
chemiluminescence induced by human complement-opsonized zymosan) was stable for
120 min. In contrast, priming of isolated PMN in plasma-free suspension for
responses to opsonized zymosan, formyl-methionyl-leucyl-phenylalanine, and
phorbol myristate acetate was markedly less stable. Decay of priming was not due
to irreversible inactivation of the terminal CL production machinery because PMN
could be reprimed by platelet-activating factor or leukotriene B4. The tumor
necrosis factor-alpha-primed state of isolated PMN was stabilized by host plasma
in a concentration-dependent fashion. We conclude that PMN priming results in a
dynamic state that is reversible. Our findings suggest the existence of blood
borne components that may act to stabilize or modify PMN priming.
PMID- 9400826
TI - Induction and modulation of macrophage Ia antigen expression by platelet
activating factor.
AB - Expression of major histocompatibility complex class II molecules, Ia, can be
significantly augmented by interferon-gamma (IFN-gamma) in macrophages. In this
study we demonstrate that platelet-activating factor (PAF) was also a potent
inducer of Ia antigen expression on macrophages. PAF-induced Ia expression was
both time- and dose-dependent. Maximal Ia expression was induced with 25 nM PAF
after 3-h exposure to PAF. Ia expression in macrophages stimulated with PAF for
24 h was not significantly greater than unstimulated macrophages. Treatment of
macrophages with IFN-gamma and PAF did not affect either the kinetics or
concentration required for maximal Ia expression induced by either IFN-gamma or
PAF. PAF-induced Ia expression was inhibited by the specific PAF receptor
antagonists, WEB 2086, Ro 24-0238, and Ro 24-4637, indicating a receptor-mediated
event. Like IFN-gamma-induced Ia expression, PAF activity was inhibited by
prostaglandin E2 (PGE2). However, that expression was only inhibited after 24 h
when macrophages were treated with the PGE2 synthesis inhibitors, flurbiprofen
and indomethacin. These findings demonstrate that PAF, along with its role as a
potent proinflammatory mediator, was also capable of inducing Ia expression on
macrophages through the PAF receptor and that expression was altered by PGE2.
PMID- 9400827
TI - Epithelioid cells from foreign-body granuloma selectively express the calcium
binding protein MRP-14, a novel down-regulatory molecule of macrophage
activation.
AB - The S-100 proteins MRP-8 and MRP-14 are expressed by cells of the myelomonocytic
lineage, either alone or simultaneously during certain stages of cellular
differentiation. We demonstrate that MRP-14 but not MRP-8 was detected by
immunostaining in the cytoplasm of epithelioid cells on the surface of round
coverslips implanted for 14 days into the subcutaneous tissue of mice. Using this
experimental model, our laboratory has previously shown that epithelioid
macrophages are poor phagocytic cells that release a macrophage-deactivating
factor (MDF) in short-term cultures. The full chemical characterization of MDF
has not been achieved so far. We provide evidence that the calcium-binding
protein MRP-14 was also released by epithelioid macrophages in short-term
cultures and that its neutralization from the culture medium after addition of
monoclonal antibody anti-MRP-14 abolished the MDF activity of the conditioned
medium. Purified or recombinant human MRP-14 but not MRP-8 inhibits the
respiratory burst of BCG-activated macrophages. Recombinant mouse MRP-14 also
down-regulate macrophage activation in vitro, and PMA does not revert the
inhibitory effect induced by MRP-14. It is thus concluded that epithelioid cells
from foreign-body granuloma express and release MRP-14 in short-term cultures and
that this molecule is endowed with MDF activity.
PMID- 9400828
TI - Bacterial LPS and IFN-gamma trigger the tyrosine phosphorylation of vav in
macrophages: evidence for involvement of the hck tyrosine kinase.
AB - We and others have previously reported that tyrosine kinases play key roles in
the activation of macrophages by both bacterial lipopolysaccharide (LPS) and
interferon-gamma (IFN-gamma). However, little is known regarding the substrates
of tyrosine phosphorylation that mediate macrophage activation and the resultant
production of inflammatory mediators. In lymphocytes and other hematopoietic
lineages, tyrosine phosphorylation of the proto-oncogene vav appears to be an
essential component of cell activation. In this study, we demonstrate that both
LPS and rIFN-gamma trigger the prompt, dose-dependent tyrosine phosphorylation of
vav in murine RAW 264.7 macrophages. In addition, vav is physically associated
with the src-related kinase hck in murine macrophages, and antisense
oligonucleotides specific for murine hck block both LPS and rIFN-gamma-mediated
vav phosphorylation. These findings suggest that hck probably mediates vav
tyrosine phosphorylation during macrophage activation and that LPS and rIFN-gamma
mediated signaling pathways partially overlap.
PMID- 9400829
TI - PGG-Glucan activates NF-kappaB-like and NF-IL-6-like transcription factor
complexes in a murine monocytic cell line.
AB - PGG-Glucan (Betafectin) is a novel soluble beta-glucan immunomodulator that
enhances leukocyte microbicidal activities without inducing inflammatory
cytokines. Although several different receptors for soluble and particulate beta
glucans have been described, the signal transduction pathway(s) used by soluble
beta-glucans have not been elucidated. We report that in a murine monocytic cell
line (BMC2.3) PGG-Glucan activates nuclear factor-kappaB (NF-kappaB)-like and NF
interleukin-6 (IL-6)-like transcription factors. Electrophoretic mobility shift
assays showed that PGG-Glucan activation of the factors is time- and
concentration-dependent. The NF-kappaB-like complex includes subunit p65 (rel-A)
as one of its components, but apparently not p50 (kappaB1), p52 (kappaB2), p68
(rel-B), or p75 (C-rel) family members. The NF-IL-6-like complex contains subunit
C/EBP-beta (NF-IL-6alpha) as one of its components, but apparently not C/EBP
alpha or C/EBP-delta (NF-IL-6beta). As expected, lipopolysaccharide (LPS)
activated p65/p50 NF-kappaB and C/EBP-beta NF-IL-6 complexes, increased the
nuclear titer of p65 and p50 antigens, and increased cytokine (IL-1beta, tumor
necrosis factor alpha) mRNA production. In contrast, PGG-Glucan increased the
nuclear titer of p65, but apparently not p50, and did not induce cytokine mRNA
production. These data demonstrate that PGG-Glucan utilizes signal transduction
pathways different from those used by LPS. The data suggest that activation of
the PGG-Glucan-stimulated factors is not sufficient to stimulate cytokine mRNA
transcription.
PMID- 9400830
TI - Signal transduction in Jurkat T lymphocytes. Evidence for early Ca2+ movements
between the cytoplasm and the nucleoplasm in activated cells.
AB - Spatial analyses of the distribution of Ca2+ in resting and activated T and B
lymphocytes have shown that the bulk of increased [Ca2+]i appears to be
associated with the nuclear region. These observations suggest that Ca2+ is
released from the perinuclear space or that it diffuses to the nucleoplasm, or
both. We have used laser scanning confocal microscopy to assess whether
cytoplasmic diffusion of Ca2+ could contribute to the rise in nuclear Ca2+. We
found that the activation of individual Jurkat cells by use of an anti-Ti (beta
subunit) mAb induced a nucleus-associated increase in [Ca2+]i. In cells loaded
with the InsP3 receptor antagonist heparin, the nuclear Ca2+ response was
abolished but not the response to thapsigargin. Evidence for a cytoplasmic Ca2+
response was obtained by loading Jurkat cells with a cytoplasm-restricted Ca2+
probe (Calcium Green-1-Dextran). These observations suggested that a process of
diffusion of cytoplasmic Ca2+ contributed to the rise of nuclear Ca2+ in Jurkat T
cells. This interpretation was supported by the findings (1) that rapid scanning
of thapsigargin-released Ca2+ showed an inverse relationship between the levels
of cytoplasmic and nuclear Ca2+ and (2) that modulation of the external
concentration of Ca2+ in thapsigargin-treated Jurkat cells showed a time
dependent decrease of fluorescence from the nucleoplasm that was reversed by
raising the concentration of external Ca2+. We conclude that Ca2+ can rapidly
diffuse between the cytoplasm and the nucleoplasm in activated Jurkat T
lymphocytes and that hydrophilic Ca2+ probes largely partition to the
nucleoplasm, thus giving rise to distorted nucleus-to-cytoplasm fluorescence
ratios.
PMID- 9400831
TI - Induction of endotoxin tolerance depletes nuclear factor-kappaB and suppresses
its activation in rat alveolar macrophages.
AB - To investigate the mechanism of endotoxin tolerance in macrophages, a rat
alveolar macrophage cell line (NR8383) was rendered endotoxin tolerant by
treatment with endotoxin at 40 ng/mL for 48 h. This treatment induced a state of
tolerance such that subsequent exposure to high-dose endotoxin (5 microg/mL)
resulted in decreased production of macrophage inflammatory protein-2, tumor
necrosis factor alpha, and nitric oxide compared to endotoxin-sensitive cells.
Suppressed mediator production by endotoxin-tolerant cells was associated with
impaired activation of nuclear factor-kappaB (NF-kappaB) in response to treatment
with 5 microg/mL of endotoxin. This impairment of NF-kappaB activation was found
to be associated with depletion of latent NF-kappaB (both RelA and p50) in the
cytoplasm of endotoxin-tolerant cells. These data suggest that a mechanism of
endotoxin tolerance is depletion of RelA/p50, which could limit the amount of NF
kappaB available for activation by subsequent stimuli and thereby inhibit
transcription of NF-kappaB-dependent genes. Limiting NF-kappaB-dependent
inflammatory gene transcription by inducing endotoxin tolerance is a potential
therapeutic strategy for diseases where excessive production of inflammatory
mediators leads to tissue injury.
PMID- 9400832
TI - The cytoplasmic domains of complement regulatory protein CD46 interact with
multiple kinases in macrophages.
AB - Membrane cofactor protein (CD46), which normally protects autologous cells from
complement lysis, is the human cell receptor for measles virus (MV). Interaction
between MV and CD46 on monocytes can lead to suppression of monocyte activation.
We have investigated the interaction between the cytoplasmic sequences of CD46
and kinases in a mouse macrophage cell line. Glutathione-S-transferase (GST)
fusion proteins bearing the Cyt1 or Cyt2 alternative cytoplasmic domain of CD46
associate with macrophage kinase activity, which phosphorylates multiple proteins
co-purified with the GST fusion proteins. Association with the macrophage kinase
activity correlates with tyrosine phosphorylation of the CD46 cytoplasmic
domains. Removing the CD46 sequences or introducing a frame-shift mutation
abrogates the association with macrophage kinase activity. Renaturation studies
reveal multiple kinases with apparent molecular mass of 82, 79, 58, and 50/49
kDa, which associate specifically with both CD46 cytoplasmic domains. Alanine
substitutions at a juxtamembrane Tyr-X-X-Leu motif in the Cyt1 domain completely
abrogate the association with macrophage kinases and tyrosine phosphorylation of
Cyt1; but similar substitutions in the Cyt2 domain only partially reduce the
association with kinases and tyrosine phosphorylation of Cyt2. These results
reveal a specific interaction between complement regulatory protein CD46 and
macrophage kinases. These findings may provide an important clue for
understanding immune modulation by MV.
PMID- 9400833
TI - Agonist-specific tyrosine phosphorylation of Cbl in human neutrophils.
AB - The effects of soluble and particulate agonists on the tyrosine phosphorylation
levels of the proto-oncogene Cbl in human neutrophils were examined. Experimental
conditions allowing the maintenance of Cbl as well as of its tyrosine
phosphorylation status were first established. Their use allowed us to observe
that Cbl was tyrosine phosphorylated in response to some (FcgammaRII ligation,
opsonized bacteria and zymosan, granulocyte-macrophage colony-stimulating factor,
monosodium urate, and calcium pyrophosphate microcrystals), but not all (fMet-Leu
Phe, interleukin-8) neutrophil agonists. Cbl was also shown to account for a
varying proportion of the 120-kDa phosphoprotein(s) observed in response to the
above stimuli. These data establish that Cbl is present in human neutrophils and
that its level of tyrosine phosphorylation is modulated by some of these cells'
agonists, and in particular by phagocytic particles. Furthermore, the signaling
pathways activated by chemotactic factors and the other neutrophil stimuli tested
in this investigation diverge at or downstream from the tyrosine phosphorylation
of Cbl.
PMID- 9400834
TI - Monocyte chemoattractant protein-2 is a potent agonist of CCR2B.
AB - The binding and functional activity of the CC chemokines monocyte chemoattractant
protein-1 (MCP-1), MCP-2, and MCP-3 have been characterized using Chinese hamster
ovary DXB-11 cells transfected with the chemokine receptor CCR2B. Receptor
binding studies demonstrated that 125I-labeled MCP-1 bound to a single class of
high-affinity receptors with a Kd of 0.14 (0.07-0.32) nM. In competition studies
MCP-1, MCP-2, and MCP-3 completely inhibited 125I-labeled MCP-1 binding with Ki
values of 0.3 (0.16-0.46), 8.8 (3.4-26), and 12.2 (0.6-22) nM, respectively. In
calcium mobilization studies, MCP-1 and MCP-3 induced robust elevations in
intracellular calcium concentrations, whereas MCP-2 was only weakly active. In
contrast, using changes in extracellular acidification rate as a functional
readout, all three chemokines were identified as potent agonists of CCR2B. These
data demonstrate that MCP-2, in addition to MCP-1 and MCP-3, is a potent agonist
of CCR2B and furthermore that MCP-2 activates either different or a subset of the
signaling pathways activated by MCP-1 and MCP-3.
PMID- 9400836
TI - Multiresolution, model-based segmentation of MR angiograms.
AB - During the last decade, the quality of MR angiograms has risen substantially and
their clinical utility has been demonstrated progressively. This acceptance has
created a need for tools with which to summarize and display the information
available. We have used a model-based segmentation technique to extract vascular
morphology and local flow parameters from phase contrast MR angiograms. A
multiresolution data structure is used as the basis of recursive decision-making
to identify regions of blood flow. The resulting data representation allows more
efficient data handling in subsequent processing and visualization and is
directly applicable to the creation of a connected graph model of vascular
regions. We describe this flow feature extraction algorithm and demonstrate the
utility of the results.
PMID- 9400835
TI - SPIO-enhanced 2D-TOF MR angiography of the portal venous system: results of an
intraindividual comparison.
AB - The purpose of this study was to investigate whether MR angiography (MRA) of the
portal venous system may be improved by means of superparamagnetic iron oxides
(SPIOs) during accumulation phase imaging and to study the underlying contrast
mechanisms. MRA of the portal venous system was performed on 48 patients before
and after intravenous injection of a new SPIO (Resovist, Schering AG, Berlin,
Germany). Resovist, as a predominantly liver parenchymal darkening agent on T2
weighted MR images with uptake into the reticuloendothelial cell system, was
administered intravenously by bolus injection of 8 to 12 micromol Fe/kg body
weight. Patients were scanned with breath-hold coronal and axial two-dimensional
(2D) time of flight (TOF) MRA (TR = 31.0 msec, TE = 9.8 msec, flip angle (FA) =
50 degrees, and 6.9-second acquisition time per section) sequences. Signal
intensity values of liver parenchyma, the portal venous system, and background
were obtained for quantitative analysis. The clinical relevance of additional
plain and contrast-enhanced MRA studies for surgical planning was assessed by
independent reading of three readers. Liver signal-to-noise ratio (SNR)
significantly decreased following iv injection of Resovist; however, SNR values
of the portal veins or hepatic veins did not change significantly. Visibility of
the portal venous system improved significantly (tertiary branches visible: pre
in 15.2% versus post in 87.0% of patients). Resovist-enhanced 2D-TOF MRA may
improve planning of liver resections by better demonstrating the relationship of
central liver lesions and vessels on source images. The decrease in liver SNR at
a constant vessel SNR after iv injection of Resovist improves MRA of the liver.
SPIO-enhanced 2D-TOF MRA scans are superior to plain 2D-TOF MRA studies and may
be added for the workup of preoperative patients.
PMID- 9400838
TI - Intravascular contrast agent improves magnetic resonance angiography of carotid
arteries in minipigs.
AB - This study was designed to optimize three-dimensional (3D) time-of-flight (TOF)
magnetic resonance angiography (MRA) sequences and to determine whether contrast
enhanced MRA could improve the accuracy of lumen definition in stenosed carotid
arteries of minipigs. 3D TOF MRA was acquired with use of either an intravascular
(n = 13) and/or an extravascular contrast agent (n = 5) administrated at 2 to 4
weeks after balloon-induced injury to a carotid artery in 16 minipigs. Vascular
contrast, defined as signal intensity differences between blood vessels and
muscle normalized to the signal intensity of muscle, was compared before and
after the injection of each contrast agent and between the two agents. Different
vascular patencies were observed among the animals, including completely occluded
vessels (n = 5), stenotic vessels (n = 3), and vessels with no visible stenosis
(n = 8). Superior vascular contrast improvement was observed for small arteries
and veins and for large veins with the intravascular contrast agent when compared
with the extravascular contrast agent. In addition, preliminary studies in two of
the animals showed a good correlation for the extent of luminal stenosis defined
by digital subtraction angiography compared with MRA obtained after
administration of the intravascular contrast agent (R2 = .71, with a slope of .96
+/- .04 by a linear regression analysis). We concluded that use of an
intravascular contrast agent optimizes 3D TOF MRA and may improve its accuracy
compared with digital subtraction angiography.
PMID- 9400839
TI - Use of k-space segmentation in MR velocity mapping for rapid quantification of
CSF flow.
AB - In this work, a k-space segmentation technique for quantitative studies of
pulsatile cerebrospinal fluid (CSF) flow is suggested. Three k-space lines are
sampled for each of two interleaved gradient-echo sequences (velocity-compensated
and velocity-encoded) within each repetition interval. Nine cardiac phases are
obtained at a heart rate of 60 bpm with maintained nominal resolution and a
factor of 3 in reduction of acquisition time relative to our conventional
nonsegmented flow quantification protocol. Segmented and conventional sequences
were compared in phantoms, in healthy volunteers, and in two patients with
clinically suspected normal pressure hydrocephalus. Good agreement between flow
curves obtained with the two sequences was demonstrated in vitro as well as in
vivo. A slight underestimation of flow values in volunteers was attributed to
data filtering when using the segmented sequence. Because the CSF circulation is
complex and tightly connected to the vascular circulation, specific clinical
applications may require flow studies at multiple positions and with different
velocity encoding. In such cases, the proposed sequence can be used to gain time,
but alternatively, the segmentation technique can be used to further increase
spatial resolution within reasonable examination times.
PMID- 9400837
TI - Ultrasmall superparamagnetic iron oxide particles (AMI 227) as a blood pool
contrast agent for MR angiography: experimental study in rabbits.
AB - The purpose of this study was to evaluate the contribution of an ultrasmall
superparamagnetic iron oxide particles (USPIOs) based contrast agent (AMI 227),
in a transverse three-dimensional time-of-flight TONE MR angiography sequence of
abdominal aorta in rabbits. The main goal was to assess improvement in the
visualization of small arteries such as renal arteries, when using such a
sequence. Imaging experiments were performed on a 1.5 T magnet, using a
transverse 3D time-of-flight (TOF) tilted optimized nonsaturating excitation
(TONE) sequence with magnetization transfer suppression. The contrast media used
were composed of a USPIO core surrounded by a dextran-surfactant (AMI 227).
Different concentrations of AMI 227 were evaluated in 12 rabbits. Concentrations
varied within the range 8.5-34 micromol Fe/kg - bw: 8.5 micromol Fe/kg (three
rabbits); 17 micromol Fe/kg (three rabbits); 25.5 micromol Fe/kg (three rabbits);
34 micromol Fe/kg (three rabbits). A visual analysis based on the improvement of
visualization of small arteries (renal arteries) on MIP images and a quantitative
analysis based on the percentage of contrast enhancement of the aorta plotted
against distance in the slab from the top edge of the acquisition volume were
obtained. A signal-to-noise ratio enhancement of the distal part of the aorta and
only improvement in the delineation of the renal arteries were noted when using
low concentrations of the contrast media. A loss of signal-to-noise ratio of the
aorta and a decrease in arterial visualization were respectively noted with
higher concentration of contrast media. In this experimental study, using a
transverse three-dimensional TOF TONE MR angiography sequence of renal arteries,
in which sequence the saturation effect is minimized, the use of AMI 227 allows
only improvement in the delineation of small arteries when using low
concentrations of contrast media.
PMID- 9400840
TI - Coronary MR angiography during peak-systole: work in progress.
AB - The purpose of this study is to compare the quality of images of coronary
arteries obtained with two-dimensional breath-hold coronary MR angiography during
peak systole and mid diastole. Two-dimensional coronary MR angiography was
performed in eight normal volunteers at peak systole and in mid diastole with a
commercial 1.5-T MR imager. An ultrafast gradient-echo sequence with incremented
flip angle series and k-space segmentation was used. The image quality grade,
length, and proximal diameter of each visualized coronary artery were measured.
The highest quality images in systole and diastole were compared. Coronary MR
angiography provided high quality images in systole and diastole in 14 of 16
coronary vessels (87.5%). In 8 of 14 vessels (57%), there was no visible coronary
MR angiogram image degradation when comparing peak systolic with mid-diastolic
images. In 4 of 14 vessels (29%), there was mild MR image degradation. There was
significant MR image degradation in only one case (7%). And in one case (7%),
there was mild image improvement during systole. The width and length of the
visualized coronary vessels did not change significantly from diastole to
systole. Existing two-dimensional breath-hold coronary MR angiography provides MR
images during peak systole and mid-diastole with little or no perceptible
difference in quality.
PMID- 9400841
TI - MRI for the evaluation of regional myocardial perfusion in an experimental animal
model.
AB - Myocardial perfusion was assessed in nine pigs using ultrafast gradient-echo MRI
(.5 T, 15-mT/m gradients) at different levels of myocardial blood flow (range,
.005-1.84 ml/min/g), generated either by adenosine infusion or by a mechanical
occluder, and measured independently using radiolabeled microspheres. Sixty-four
consecutive, ECG-triggered, diastolic, short axis images of the left ventricle
were obtained during intravenous bolus injections (n = 30) of .05 mmol/kg of
gadopentetate dimeglumine. Relative changes in peak intensity, time to peak
intensity, washin slope, correlation coefficient, and cross-correlation
coefficient were computed from the time-intensity curves obtained from four
regions of interest, namely septal, anterior, lateral, and inferior walls. The
values from the inferior wall acted as reference for evaluating relative changes
in the other three regions. The cross-correlation coefficient (P < .001, rho =
.60) and the peak intensity (P < .001, r = .72) showed the best correlation with
myocardial blood flow. The washin slope showed a weak positive trend (P < .05),
but the low value of r (r = .28) indicated that the use of this parameter to
predict flow was invalid; the correlation coefficient and time to peak intensity
were not correlated (P = ns). In conclusion, this study shows that it is possible
to evaluate relative myocardial perfusion after the first pass of a an
intravenously injected bolus of gadopentetate dimeglumine, using dynamic MRI on a
conventional medium field MRI system. The cross-correlation coefficient and the
peak intensity resulted in more efficient parameters to evaluate relative
inhomogeneity of regional myocardial perfusion.
PMID- 9400842
TI - Novel application of breath-hold turbo spin-echo T2 MRI for detection of acute
myocardial infarction.
AB - To assess the clinical utility of the breath-hold turbo spin-echo T2-weighted MRI
in patients with acute myocardial infarction, the results of MRI were compared
with those of electrocardiography, coronary angiography, and thallium-201 single
photon emission tomography (SPECT) in 23 patients and 5 healthy volunteers. To
compare MRI and thallium-SPECT, the left ventricle was divided into five
segments, and the presence of myocardial infarction was determined in each
segment. MRI demonstrated an abnormally bright signal in 49 of 140 segments (five
segments each from 23 patients and 5 volunteers); thallium-SPECT showed a fixed
perfusion defect in 52 segments, for an 85% diagnostic concordance rate. The size
of the myocardial infarction measured on MRI corresponded well to that measured
on thallium-SPECT (r = .70, P < .01). Breath-hold turbo spin-echo T2 MRI can be
used for detection of acute myocardial infarction in conjunction with thallium
SPECT, especially when accurate localization of lesion, increased spatial
resolution, and anatomic landmarks are needed.
PMID- 9400843
TI - Water-fat imaging with direct phase encoding.
AB - A new method is introduced for water-fat imaging. With three acquisitions, a
general direct phase encoding (DPE) of the chemical shift information is
achieved. Pixels containing both water and fat are solved directly. Pixels with
only a single component are resolved with local and global orientation filters,
which use phase information from neighboring pixels. The fact that a single
component is more likely to be water than fat in living tissues is also useful. A
second pass solution yields water and fat images with superior signal-to-noise
ratio. Unlike other methods, DPE does not rely on the error-prone phase
unwrapping; also, it easily handles disconnected tissues. Because the
magnetization vectors of water and fat are sampled not only at parallel or
antiparallel, they can be not only separated but also identified respectively,
which is desirable for routine clinical work. DPE has been implemented on several
imagers at various field strengths and has been demonstrated in a large number of
clinical cases to be useful and robust in various parts of the body.
PMID- 9400844
TI - Multifeature analysis of Gd-enhanced MR images of breast lesions.
AB - The objective of this study was to determine whether linear discriminant analysis
of different independent features of MR images of breast lesions can increase the
sensitivity and specificity of this technique. For MR images of 23 benign and 20
malignant breast lesions, three independent classes of features, including
characteristics of Gd-DTPA-uptake curve, boundary, and texture were evaluated.
The three classes included five, four and eight features each, respectively.
Discriminant analysis was applied both within and across the three classes, to
find the best combination of features yielding the highest classification
accuracy. The highest specificity and sensitivity of the different classes
considered independently were as follows: Gd-uptake curves, 83% and 70%; boundary
features, 86% and 70%; and texture, 70% and 75%, respectively. A combination of
one feature each from the first two classes and age yielded a specificity of 79%
and sensitivity of 90%, whereas highest figures of 93% and 95%, respectively,
were obtained when a total of 10 features were combined across different classes.
Statistical analysis of different independent classes of features in MR images of
breast lesions can improve the classification accuracy of this technique
significantly.
PMID- 9400845
TI - MRI of pelvic masses: efficacy of the rectal superparamagnetic contrast agent
Ferumoxsil.
AB - The purpose of this study was to determine the potential value of rectally
administered Ferumoxsil for pelvic MRI. Twenty patients with suspected
rectosigmoid and ovarian tumors were prospectively examined before and after
rectal administration of 300 to 600 ml of the superparamagnetic contrast agent
Ferumoxsil. Imaging parameters (1.5-T system, phased-array coil, transverse T1
weighted spin echo (SE) and T2-weighted turbo-SE sequences, 6-mm slice thickness,
350-mm field of view [FOV], 512 x 512 matrix) were kept constant. Images were
evaluated for tumor presence, lymphadenopathy, bowel involvement, and peritoneal
implants. Precontrast and postcontrast studies were rated for bowel delineation,
lesion/organ-to-bowel differentiation, presence of artifacts, and confidence of
diagnosis. Delineation of rectum and sigmoid colon (P < .001) as well as
separation of bowel and vagina, uterus/adnexa, dome of the urinary bladder, lymph
nodes, and vessels improved significantly (P < .01) on both T1-weighted and T2
weighted postcontrast sequences. The rectal contrast agent did not increase the
level of artifacts. Changes in diagnosis in 7 of 20 patients were mainly due to
identification of colorectal tumors or bowel involvement on postcontrast images.
The readers' diagnostic confidence was significantly higher on contrast-enhanced
than on unenhanced studies (93 +/- 6.4% vs 68 +/- 25.2%). Rectal application of
Ferumoxsil improves lesion/organ-to-bowel delineation and overall diagnostic
confidence in pelvic MRI.
PMID- 9400846
TI - Rapidly enhancing hepatic hemangiomas at MRI: distinction from malignancies with
T2-weighted images.
AB - The purpose of this study is to describe a subset of atypical hepatic hemangiomas
that enhance rapidly and diffusely and to determine whether heavily T2-weighted
images could distinguish between atypically enhancing liver hemangiomas and
hypervascular malignancies. A retrospective search of MR records identified seven
patients with liver hemangiomas that demonstrated diffuse early enhancement and
23 patients with biopsy-proven malignant liver lesions that were hypervascular on
dynamic gadolinium-enhanced MR images. Quantitative analysis of signal intensity
measurements was performed on the T2-weighted images, heavily T2-weighted (TE >
140), and dynamic gadolinium-enhanced images. Blinded reader comparison of the T2
weighted images and gadolinium-enhanced images was performed. Hypervascular
hemangiomas enhanced to a greater degree than hypervascular malignant liver
lesions on the early phase gadolinium-enhanced images. Perilesional parenchymal
enhancement was demonstrated in five cases of rapidly enhancing hemangiomas.
Signal intensity and contrast-to-noise ratios on the heavily T2-weighted images
of the hemangiomas were significantly greater than that of the hypervascular
malignant lesions (P < .05). Hemangiomas were differentiated from the
hypervascular malignant liver lesions with high accuracy (97-100%) by three
blinded readers based on the T2-weighted images. A subset of hemangiomas have
atypical rapid diffuse enhancement on dynamic gadolinium-enhanced images. These
atypical hemangiomas can be distinguished from hypervascular malignant liver
lesions on T2-weighted MR images.
PMID- 9400847
TI - Liver lesion detection, characterization, and effect on patient management:
comparison of single-phase spiral CT and current MR techniques.
AB - This study compares liver lesion detection, characterization, and effect on
patient management between single-phase spiral CT and MRI using spoiled gradient
echo (SGE), T2-weighted fat-suppressed spin echo, and serial post gadolinium SGE.
All patients with suspected liver lesions who underwent spiral CT and MRI within
a 1-month period between January 1993 and September 1996 were included in the
study. Spiral CT and MRI were interpreted prospectively in a blinded fashion by
separate individual experienced investigators, and lesion detection and
characterization were determined. Confirmation was obtained by surgery (6
patients), biopsy (18 patients), imaging follow-up (36 patients), or combined
reading of all imaging studies and clinical follow-up (29 patients). Effect on
patient management was determined by combined chart review and interview of the
patients' physicians and by retrospective clinical assessment performed by a
surgical oncologist and medical oncologist separately. Eighty-nine patients were
included in the study. Regarding true positive lesion detection, 295 and 519
lesions were detected on spiral CT and MR images, respectively, which was
significantly different on a patient-by-patient basis (P < .001). More lesions
were detected on MR than on spiral CT in 44 of 89 patients (49.4%), and 11 of
these 44 patients had lesions shown on MRI in whom no lesions were apparent on CT
images. No patients had true positive lesions shown on spiral CT that were not
shown on MRI. Regarding lesion characterization, 129 and 466 lesions were
characterized on spiral CT and MRI images, respectively, which was significantly
different on a patient-by-patient basis (P < .001). More lesions were
characterized on MR than CT images in 67 patients (75.3%). Regarding effect on
patient management, chart review with physician interview demonstrated that
findings on MRI provided information that altered patient management as compared
with findings on spiral CT in 57 patients. Retrospective clinical evaluation by
the surgical and medical oncologist showed that MRI was considered to have a
greater effect on patient management than spiral CT in 58 and 55 patients,
respectively. Comparing current MRI technique to single-phase spiral CT, MRI
detected more lesions in 49.4% and characterized more lesions in 75.3% of
patients investigated for focal liver disease. MRI had a greater effect on
patient management in each of the three methods than single-phase spiral CT in
more than 61% of patients.
PMID- 9400848
TI - RARE imaging of PCr in human forearm muscles.
AB - Rapid acquisition with relaxation enhancement (RARE) sequences have been used to
map the 31P phosphocreatine (PCr) signal in human forearms at 4.7 T. Signal-to
noise levels of approximately 10 were achieved from the major muscle groups in
5.5-minute scan times with a spatial resolution of 4 x 2 x 2 cm3. Exercise caused
demonstrable reductions in PCr signal from activated muscles, which correlated
with affected muscle groups in T2-weighted proton images. RARE imaging of the PCr
signal at 4.7 T is feasible and, with technically achievable improvements in
signal-to-noise ratio, should prove useful in studying energy metabolism in
muscle and other organs.
PMID- 9400849
TI - High resolution, short echo time sodium imaging of articular cartilage.
AB - The sodium present in articular cartilage interacts with the negatively charged
proteoglycan aggregates in the matrix of the cartilage. Sodium images of short
echo time may be useful for detecting changes that occur in the proteoglycan
content of the cartilage. Such changes are indicative of early osteoarthritic
damage, for example. Using an asymmetric short echo technique, sodium images of
high resolution and signal-to-noise ratio that demonstrate anatomic features of
the cartilage are presented. These images were obtained with echo times as short
as 1 msec, at an in-plane resolution of 39 microns by 117 microns and signal-to
noise ratios of up to 40:1.
PMID- 9400850
TI - A segment-interleaved motion-compensated acquisition in the steady state
(SIMCAST) technique for high resolution imaging of the inner ear.
AB - MRI, with ever-increasing spatial resolution, recently has depicted progressively
more anatomic details of the inner ear and is playing an important role in the
diagnostic evaluation of patients with sensorineural hearing loss. We present a
three-dimensional (3D) segment-interleaved, motion-compensated acquisition in
steady state (SIMCAST) sequence that allows further increase in spatial
resolution in reasonable scan times minimizing artifacts due to susceptibility
and motion. The sequence uses gradient moment nulling over TR and segmented
interleaved acquisition of multiple data sets with different radiofrequency (RF)
phase-cycling schemes. Combination of data from multiple acquisitions by
averaging and maximum intensity projection were compared. Images of phantoms and
in vivo inner ears were obtained with both full and fractional echoes and
compared with other high resolution techniques such as three-dimensional gradient
echo and two-dimensional (2D) and three-dimensional fast spin-echo (FSE)
sequences. The new sequence achieves improved signal-to-noise ratio (SNR) and
spatial resolution resulting in improved depiction of inner ear structures.
PMID- 9400851
TI - Brain atrophy progression measured from registered serial MRI: validation and
application to Alzheimer's disease.
AB - In this paper, we validate the brain boundary shift integral (BBSI) as a measure
of brain atrophy and demonstrate its application in Alzheimer's disease (AD).
Nineteen normal subjects and nine patients with AD underwent serial three
dimensional MRI (6- to 30-month scan intervals). Repeat studies were registered
to the baseline studies. The accuracy of the BBSI was assessed by comparison with
simulated atrophy and with segmentation; it was also tested for reproducibility,
linearity, and its ability to discriminate patients with AD from healthy
controls. The BBSI correlated closely with simulated volumes of atrophy (r =
1.000). The mean absolute difference between repeat measures was 1.51 ml or .13%
of mean brain volume. Rates of atrophy from all 18 AD scan pairs were widely
separated from those of all 31 control pairs. In matched subgroups, the mean (SD)
annual rate of brain atrophy in nine controls was .24% (.32%), compared with
2.78% (.92%) in nine patients with AD. We conclude that the BBSI is a linear and
highly reproducible measure of atrophy with potential uses in the early diagnosis
and measurement of progression in Alzheimer's disease.
PMID- 9400852
TI - Magnetization transfer fast imaging of implanted glioma in the rat brain at 4.7
T: interpretation using a binary spin-bath model.
AB - C6 glioma cells were implanted in the left caudate nucleus of the rat brain.
Histologic studies confirmed the presence of neoplastic tissue surrounded by a
thin edematous region. Proton magnetization transfer contrast (MTC) fast imaging,
using continuous wave off-resonance irradiation, was performed in vivo at 4.7 T
with the rapid acquisition with relaxation enhancement (RARE) sequence. The
observed MTC allowed very clear distinction of the tumoral region, in which
magnetization transfer (MT) ratios were lower than in healthy tissues. Contrasts
were analyzed as a function of the offset frequency and the amplitude of the
radiofrequency (RF) irradiation. The contrast was higher between the
contralateral basal ganglia and the tumor and lower between the tumor and the
temporal lobe. Modeling of MT in the three brain regions was performed using a
system including free water and a pool of protons with restricted motions. The
rate of exchange between the two pools exhibited a decreasing hierarchy from the
basal ganglia to the tumor. T2B values for the immobile protons ranged from 9.3
microsec in the basal ganglia to 7.5 microsec for the glioma. The acquisition
conditions leading to the highest contrasts between the tumor and the healthy
tissues correspond to 3,000 Hz offset frequency and 300 to 700 Hz RF irradiation
amplitude.
PMID- 9400853
TI - Dynamic imaging of intracranial lesions using fast spin-echo imaging:
differentiation of brain tumors and treatment effects.
AB - The purpose of this study was to develop a technique for differentiating between
recurrent brain tumors and treatment-related changes, such as radiation necrosis,
using dynamic MRI. Ninety-five patients with intracranial mass lesions were
evaluated using T1-weighted fast spin-echo (FSE) MRI at 1.5 T. Pathologies
included treatment-related changes (n = 32), primary tumors (n = 41), metastatic
tumors (n = 5), meningiomas (n = 4), and mixed primary/treatment related changes
(n = 13). Signal enhancement-time curves were analyzed by fitting to a sigmoidal
exponential function. Maximal enhancement rates were calculated as the first
derivative of the fitted curve. Based on the maximal enhancement rates, treatment
related changes could be differentiated from primary tumors, metastatic tumors,
and meningiomas at the P < .05 confidence level. Lesions of mixed tumor and
treatment-related change had intermediate values. Dynamic MRI can be used to
differentiate treatment-related changes from primary tumors in previously treated
patient populations based on maximal enhancement rates. Individual case studies
demonstrate the clinical significance of these findings.
PMID- 9400854
TI - Fuzzy clustering of gradient-echo functional MRI in the human visual cortex. Part
I: reproducibility.
AB - Reproducibility of human functional MRI (fMRI) studies is essential for clinical
and neuroresearch applications of this new human brain mapping method. Based on a
recently presented study on reproducibility of gradient-echo fMRI in the human
visual cortex (Moser et al. Magn Reson Imaging 1996; 14:567-579), comparing the
performance of three different threshold strategies for correlation analysis, we
demonstrate that (a) fuzzy clustering is a robust, model-independent method to
extract functional information in time and space; (b) intertrial reproducibility
of cortical activation is significantly improved by the capability of fuzzy
clustering to separate signal contributions from larger vessels, running
perpendicular to the slice orientation, from activation apparently close to the
primary visual cortex; and (c) for repeated single subject studies, SDs of <20%
for signal enhancement in approximately 80% of the studies and SDs of <30% for
activated area size in approximately 65% of the studies are obtained. This,
however, depends also on signal-to-noise ratio, (motion) artifacts, and subject
cooperation.
PMID- 9400855
TI - Fuzzy clustering of gradient-echo functional MRI in the human visual cortex. Part
II: quantification.
AB - Fuzzy cluster analysis (FCA) is a new exploratory method for analyzing fMRI data.
Using simulated functional MRI (fMRI) data, the performance of FCA, as
implemented in the software package Evident, was tested and a quantitative
comparison with correlation analysis is presented. Furthermore, the fMRI model
fit allows separation and quantification of flow and blood oxygen level dependent
(BOLD) contributions in the human visual cortex. In gradient-recalled echo fMRI
at 1.5 T (TR = 60 ms, TE = 42 ms, radiofrequency excitation flip angle [theta] =
10 degrees-60 degrees) total signal enhancement in the human visual cortex, ie,
flow-enhanced BOLD plus inflow contributions, on average varies from 5% to 10% in
or close to the visual cortex (average cerebral blood volume [CBV] = 4%) and from
100% to 20% in areas containing medium-sized vessels (ie, average CBV = 12% per
voxel), respectively. Inflow enhancement, however, is restricted to intravascular
space (= CBV) and increases with increasing radiofrequency (RF) flip angle,
whereas BOLD contributions may be obtained from a region up to three times larger
and, applying an unspoiled gradient-echo (GRE) sequence, also show a flip angle
dependency with a minimum at approximately 30 degrees. This result suggests that
a localized hemodynamic response from the microvasculature at 1.5 T may be
extracted via fuzzy clustering. In summary, fuzzy clustering of fMRI data, as
realized in the Evident software, is a robust and efficient method to (a)
separate functional brain activation from noise or other sources resulting in
time-dependent signal changes as proven by simulated fMRI data analysis and in
vivo data from the visual cortex, and (b) allows separation of different levels
of activation even if the temporal pattern is indistinguishable. Combining fuzzy
cluster separation of brain activation with appropriate model calculations allows
quantification of flow and (flow-enhanced) BOLD contributions in areas with
different vascularization.
PMID- 9400856
TI - Perfusion-weighted MRI using gadobutrol as a contrast agent in a rat stroke
model.
AB - The purpose of this study was to examine the new nonionic contrast agent
gadobutrol in MR perfusion-weighted imaging, including the influence of different
concentrations and dosages of the agent on the sensitivity to perfusion
alterations. Sixteen rats were examined within 35 to 105 minutes after
endovascular occlusion of the middle cerebral artery. A fast T2*-weighted fast
low-angle shot (FLASH) sequence was used to acquire four images before and 16
images after bolus injection of .1, .2, .3, and .4 mmol/kg gadobutrol as .5 molar
and 1.0 molar formulation. From user-defined regions, we obtained the maximum
signal decrease, the relative regional cerebral blood volume, and the bolus
delay. Contrast between ischemic and nonischemic regions during bolus passage
increased with dose and concentration of the contrast agent. For low doses (.1
and .2 mmol/kg), the ischemic lesion could not or could barely be discerned. For
higher doses (.3 and .4 mmol/kg), administration of the 1 molar contrast agent
yielded a better contrast between ischemic and nonischemic tissue. Our results
suggest that administration of gadobutrol at higher dosage and higher
concentration increases sensitivity to perfusion alterations. These results are
potentially useful for perfusion-weighted imaging of the human brain, because the
volume of contrast agent will be reduced if a solution with higher concentration
is used. When using contrast agents in higher concentrations for human
examinations, a significant signal decrease may be achieved also with the low
doses (.1-.15 mmol/kg).
PMID- 9400857
TI - Discrimination of metabolite from lipid and macromolecule resonances in cerebral
infarction in humans using short echo proton spectroscopy.
AB - Short-echo proton spectroscopy allows the noninvasive study of metabolites,
lipids, and macromolecules in stroke patients, but spectra are difficult to
interpret and quantify because narrow metabolite peaks are added to a broad
background of lipid and macromolecule peaks. "Metabolite nulling" was used to
distinguish the lactate peak from underlying lipid and macromolecule peaks.
Increases in the lipid and macromolecule peaks were initially observed within the
region of infarction in all patients, and further increases in lipid peaks were
seen in five of the six patients during the following 6 weeks. The initial high
lactate concentration decreases during the first 2 weeks after stroke, whereas
lipid and macromolecule signals show a persistent elevation during the same
period. Differences in the time courses of the observed changes suggest that
lipid, macromolecule, and lactate signals arise from more than one source.
PMID- 9400858
TI - Centric ordering is superior to gradient moment nulling for motion artifact
reduction in EPI.
AB - Echo-planar imaging (EPI) is sensitive to motion despite its rapid data
acquisition rate. Compared with traditional imaging techniques, it is more
sensitive to motion or flow in the phase-encode direction, which can cause image
artifacts such as ghosting, misregistration, and loss of spatial resolution.
Consequently, EPI of dynamic structures (eg, the cardiovascular system) could
benefit from methods that eliminate these artifacts. In this paper, two methods
of artifact reduction for motion in the phase-encode direction are evaluated.
First, the k-space trajectory is evaluated by comparing centric with top-down
ordered sequences. Next, velocity gradient moment nulling (GMN) of the phase
encode direction is evaluated for each trajectory. Computer simulations and
experiments in flow phantoms and rabbits in vivo show that uncompensated centric
ordering produces the highest image quality. This is probably due to a shorter
readout duration, which reduces T2* relaxation losses and off-resonance effects,
and to the linear geometry of phantoms and vessels, which can obscure centric
blurring artifacts.
PMID- 9400859
TI - The effects of incomplete breath-holding on 3D MR image quality.
AB - The purpose of this study was to investigate how fast three-dimensional (3D) MR
image quality is affected by breath-holding and to develop an optimal breath
holding strategy that minimizes artifact in the event of an incomplete breath
hold. A computer model was developed to study variable-duration breath-holds
during fast 3D imaging. Modeling was validated by 3D gradient-echo imaging
performed on 10 volunteers. Signal-to-noise ratio (SNR) and image blur were
measured for both simulated and clinical images. Insights gained were applied to
clinical 3D gadolinium-enhanced MR angiography. Breath-holding significantly
improved abdominal 3D MR image quality. Most of this benefit could be achieved
with a breath-hold fraction of 50% if it occurred during acquisition of central k
space. Breath-holding during peripheral k-space acquisition, however, had no
significant benefit. Respiratory motion artifact on fast 3D MRI occurring when a
patient fails to suspend respiration for the entire scan duration can be
minimized by collecting central k space first (centric acquisition) so that
premature breathing affects only the acquisition of peripheral k space.
PMID- 9400860
TI - Uptake of dextran-coated monocrystalline iron oxides in tumor cells and
macrophages.
AB - Although several dextran-coated iron oxide preparations are in preclinical and
clinical use, little is known about the mechanism of uptake into cells. As these
particles have been shown to accumulate in macrophages and tumor cells, we
performed cellular uptake and inhibition studies with a prototypical
monocrystalline iron oxide nanoparticle (MION). MION particles were labeled with
fluorescein isothiocyanate or radioiodinated and purified by gel permeation
chromatography. Two preparations of MION particles were used in cell experiments:
nontreated MION and plasma-opsonized MION purified by gradient density
purification. As determined by immunoblotting, opsonization resulted in C3,
vitronectin, and fibronectin association with MION. Incubation of cells with
fluorescent MION showed active uptake of particles in macrophages both before and
after opsonization. In C6 tumor cells, however, intracellular MION was only
detectable in dividing cells. Quantitatively, 125I-labeled MION was internalized
into cells with uptake values ranging from 17 ng (in 9L gliosarcoma) to 970 ng
iron per million cells for peritoneal macrophages. Opsonization increased MION
uptake into macrophages sixfold, whereas it increased the uptake in C6 tumor
cells only twofold. Results from uptake inhibition assay suggest that cellular
uptake of nonopsonized (dextran-coated) MION particles is mediated by fluid-phase
endocytosis, whereas receptor-mediated endocytosis is presumably responsible for
the uptake of opsonized (protein-coated) particles.
PMID- 9400862
TI - Detection of primary breast cancer in women with known adenocarcinoma metastatic
to the axilla: use of MRI after negative clinical and mammographic examination.
AB - The purpose of this study was to evaluate the ability of MRI to identify a
primary site of malignancy in the breast of patients who present clinically with
ipsilateral lymph nodes containing metastatic carcinoma but whose physical and
mammographic examination are negative. MRI of the breast was performed on four
patients using a variety of imaging parameters, all with and without gadolinium
contrast. All patients had biopsy-proven adenocarcinoma of the ipsilateral
axilla, with negative physical and mammographic examinations. Foci of enhancement
assessed visually on precontrast and postcontrast scans (n = 1) and on
subtraction studies (n = 3) were considered suspicious under the clinical
circumstances defined for this study. Lesions identified on MRI were re
identified on ultrasound examination and either preoperative localization for
excisional biopsy or tissue sampling was performed. Surgery was performed and
histopathologic correlation was obtained in all cases. Primary sites of breast
carcinoma were identified in all four patients, with multiple sites of malignancy
identified in three of four patients. Breast conservation therapy was made
possible for three of four patients based on the results of the MRI study showing
sites of malignancy and no features of cancer elsewhere in the breast. Follow-up
data of 1, 2, and 5 years of these patients show no evidence of recurrent
disease. MRI of the breast is a useful technique for identifying primary sites of
malignancy in patients presenting with ipsilateral lymph nodes positive for
metastatic adenocarcinoma when the physical and mammographic examinations are
negative.
PMID- 9400861
TI - Volume MRI and MRSI techniques for the quantitation of treatment response in
brain tumors: presentation of a detailed case study.
AB - Patients with primary brain tumors may be considered for several different
treatments during the course of their disease. Assessments of disease progression
and response to therapy are typically performed by visual interpretation of
serial MRI examinations. Although such examinations provide useful morphologic
information, they are unable to reliably distinguish active tumor from radiation
necrosis. This poses a particular problem in the assessment of response to
localized radiation therapies such as gamma knife radiosurgery. In this paper, we
present methodology for evaluating changes in tissue morphology and metabolism
based on serial volumetric MRI and magnetic resonance spectroscopic imaging
(MRSI) examinations. Registration and quantitative analysis of these data provide
measurements of the temporal and spatial distributions of gadolinium enhancement
and of N-acetylasparate, choline, creatine, and lactate/lipid. The key features
of this approach and the potential clinical benefits are illustrated by a
detailed analysis of six serial MRI/MRSI examinations and three serial 1-[F-18]
fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies on a
patient with a recurrent anaplastic astrocytoma.
PMID- 9400863
TI - First pass MRA of the abdomen: ultrafast, non-breath-hold time-of-flight imaging
using Gd-DTPA bolus.
AB - The authors describe a new fast imaging sequence that can produce projection
angiograms of the abdominal vessels at a rate of 2 to 3 frames per second. The
result is a versatile imaging technique that can track the arrival of a bolus of
contrast in major vessels. With very fast data acquisition, gross patient motion
is not a problem, and routine vascular projection studies may be performed
without the need for breath-holding. This method is compatible with later high
resolution three-dimensional gradient echo studies using contrast agents and may,
in fact, be used as an accurate timing protocol to gauge the arrival time of
contrast in various segments of the abdominal vessels. Compared with echo planar
imaging, this method has the advantages of avoiding susceptibility artifacts and
depicting retroperitoneum and other abdominal fat-containing landmarks and does
not require extensive hardware modifications for a clinical system.
PMID- 9400864
TI - Breath-hold R2* mapping with a multiple gradient-recalled echo sequence:
application to the evaluation of intrarenal oxygenation.
AB - Blood oxygenation level dependent (BOLD) MRI is sensitive to changes in regional
oxygen supply versus demand and is therefore potentially useful in evaluating
susceptibility to ischemic injury. Recently, we have demonstrated the use of BOLD
MRI to evaluate intrarenal oxygenation using single shot echo-planar imaging
(EPI). Here, we present an alternate implementation of BOLD MRI sequence, using
multiple gradient echoes, that does not require any specialized hardware.
PMID- 9400865
TI - Elimination of Nyquist ghosts in MRI by using fast linogram imaging.
AB - Timing inaccuracies between the even and odd echoes lead to the formation of
Nyquist ghosts in conventional (blipped) echo-planar imaging (EPI). A fast radial
scanning method based on the linogram sampling geometry was designed and
implemented. No ghosting effects are seen with this scheme, and correction for
timing inaccuracies is performed using simple postprocessing steps before
reconstruction.
PMID- 9400867
TI - Aboriginal reconciliation: a role for psychiatrists?
AB - Australian Aboriginal people are marginalised, severely disadvantaged and subject
to discrimination. The Report of the National Inquiry into the Separation of
Aboriginal and Torres Strait Islander Children from their Families has focused
international attention on their plight. However, the Council for Aboriginal
Reconciliation and the High Court Mabo decision provide avenues for change. This
paper asks: is there a role for psychiatrists in the reconciliation process?
PMID- 9400866
TI - The effect of mechanical deformation on magnetic properties and MRI artifacts of
type 304 and type 316L stainless steel.
AB - The purpose of this study was to evaluate the influence of composition and
deformation of biomedical stainless steels on mechanical properties, magnetic
properties, and MRI artifacts. Type 304 and Type 316L samples were prepared using
standard wire-drawing techniques. Mechanical properties were determined using
standard test methods. The amount of ferromagnetic phase present was estimated
using a Severn Gage and x-ray diffraction. Magnetic field attraction and
artifacts were determined using previously described techniques. The strength of
both steels increased significantly with increasing deformation. None of the type
316L wires transformed to the magnetic phase. The amount of magnetic phase in the
type 304 wires increased with increasing deformation. There was no magnetic field
attraction, and artifacts were minimal for all of type 316L wires and the
undeformed type 304 wire. Deflection and artifacts were significant for the
deformed type 304 stainless steel. These results provide guidance regarding the
use of type 304 and type 316L stainless steels for bioimplants. In this regard,
type 316L stainless steel seems to be a more acceptable material with respect to
MR compatibility.
PMID- 9400868
TI - The NHMRC Psychiatric Epidemiology Research Centre. National Health and Medical
Research Council.
PMID- 9400869
TI - Training in psychiatry: an examination of trainee perceptions. Part 1.
AB - OBJECTIVE: To look at the perceptions of New South Wales (NSW) psychiatric
trainees in relation to their training experiences and the role and quality of
the consultant-registrar relationship. METHODS: A self-report questionnaire was
developed to probe trainee perceptions of the consultant-trainee relationship in
all those who had completed at least 1 year of training in psychiatry (n = 138)
in NSW, as well as all consultants who had completed their training in the last 5
years (n = 95). Test-retest reliability was assessed at 3 months for each of the
subscales (r = 0.70-0.89) and found to be acceptable. Validity issues are
discussed. RESULTS: The results are discussed with special reference to the
perceived competence, availability, breadth of knowledge and willingness to
accept responsibilities of the supervising consultant. Consultant competence as a
clinician was consistently rated as more important than being emotionally
supportive. CONCLUSION: In addressing these issues, we aim to increase the degree
of self-consciousness and reflectiveness of the profession of psychiatry within
the Australian context. If there is to be a substantial shift for the better in
trainees' perceptions of consultants, it is likely that the general consultant
experience will have to be improved rather than providing small amounts of
exposure to high quality consultants.
PMID- 9400870
TI - Adverse experiences in psychiatric training. Part 2.
AB - OBJECTIVE: To examine the perceptions of New South Wales (NSW) psychiatric
trainees in relation to their training, the adverse events they experienced and
the role and quality of the consultant-registrar relationship. METHOD: A self
report questionnaire was developed to probe trainee perceptions of the consultant
trainee relationship and adverse events during training in all those who had
completed at least 1 year of training in psychiatry (n = 138) in NSW, as well as
all consultants who had completed their training in the last 5 years (n = 95).
All subjects were asked to rate the frequency and relative impact of 20 adverse
experiences with the opportunity to proffer adversities not listed. They were
also asked to rate their experience of their consultants in relation to the
adversity. RESULTS: The results from The Training Impact Study exploring adverse
events experienced by NSW trainees are presented. Assault by a patient and
suicide of a patient are identified as the most stressfull adversities of
training in psychiatry. However, more general concerns such as educational and
emotional neglect by supervisors, observing consultant maltreatment of patients,
exam failure and conflict between consultants were also identified and discussed.
CONCLUSIONS: The high response rate of both trainees and consultants gives these
results a level of representative validity. Recommendations in relation to future
training and research are put forward. Specific training in the management of
potentially assaultive patients and facilitating trainee recovery from assault or
threat of assault should be a priority of the Royal Australian and New Zealand
College of Psychiatrists. Support and education in relation to patient suicide is
also important. Training and recognition of teachers within the College should be
encouraged.
PMID- 9400871
TI - Peer review groups: problems and solutions.
AB - OBJECTIVE: To elucidate and delineate principles for dealing with problems
encountered in peer review groups. METHOD: A workshop format was utilised in
which a number of interested psychiatrists were invited to role-play specific
problems which occurred in established peer review groups, and reported in recent
research studies. Process notes or videotapes were used to record proceedings.
Principles were delineated for the management of five specific problems via role
play and discussion. RESULTS: Principles have been delineated for the management
of the following problems reported by peer review groups: dominating group
member; member with disturbing behaviour; member providing inadequate treatment;
member transgressing treatment boundaries; and group members strongly disagreeing
about the management of a case. CONCLUSION: Problems encountered within peer
review groups were adequately replicated during role-played enactments. The
workshop format offered a means of engaging with these, allowing exploration and
subsequent resolution of problems which had not proved resolvable in the real
group peer review situation.
PMID- 9400873
TI - Experience, knowledge and attitudes of child psychiatrists regarding
electroconvulsive therapy in the young.
AB - OBJECTIVE: To ascertain the experience, knowledge and attitudes of Australian and
New Zealand child psychiatrists in relation to electroconvulsive therapy (ECT) in
the young in order to determine whether they would be willing and able to provide
an opinion if consulted about children or adolescents in whom ECT is proposed.
METHOD: A 28-item questionnaire was posted to all members of the Faculty of Child
and Adolescent Psychiatry living in Australia or New Zealand. RESULTS: Eighty
three percent (n = 206) answered the questionnaire. Forty percent rated their
knowledge about ECT in the young as nil or negligible. Having had patients
treated with ECT was the best predictor of possessing some knowledge. Thirty-nine
percent believed that ECT was unsafe in children compared to 17% for adolescents
and 3% for adults. Almost all (92%) respondents believed child psychiatrists
should be consulted in all cases of persons under 19 in whom ECT was recommended.
The vast majority believed the Faculty or College should have guidelines relating
to ECT use in this group and that it would be useful to have a national register
of young persons treated with ECT. CONCLUSIONS: Child and adolescent
psychiatrists wish to be involved in the process of ECT treatment in young
people. At the same time, there are gaps in their knowledge. This will need to be
remedied, particularly if formal guidelines advocating their involvement are
introduced.
PMID- 9400872
TI - The relationship between low family income and psychological disturbance in young
children: an Australian longitudinal study.
AB - OBJECTIVE: This study examines the relationship between low family income (LFI)
experienced at different points in time, chronic low income status and its impact
on child behaviour measured at 5 years of age. METHOD: Longitudinal data from the
Mater University Study of Pregnancy were used to measure LFI in families at three
points in time (the antenatal period, 6 months post birth and at 5 years cf age).
Outcome variables were three independent groups of behaviour problems labelled as
externalising, social, attentional and thought (SAT) problems, and internalising
problems. These groups were developed from the Child Behaviour Checklist. An
analysis based on logistic regression modelling was carried out examining the
relationship between LFI and a range of intermediate variables known to be
associated with child behaviour problems. RESULTS: The more often families
experienced low income, the higher the rate of child behaviour problems at age 5.
Low family income was still independently associated with SAT behaviour problems
after controlling for smoking in the first trimester, parenting styles, maternal
depression and marital dysharmony at age 5. The association between LFI and
internalising and externalising behaviour problems was largely mediated by
maternal depression. CONCLUSION: Low family income is a significant factor in the
aetiology of a variety of child behaviour problems. The mechanisms involved in
the link between LFI and childhood internalising and externalising behaviours
involve the exposure of the children to maternal depression. However, the
relationship between LFI and SAT behaviour problems remains to be elucidated.
PMID- 9400874
TI - A profile of children and adolescents in a psychiatric unit: multidomain
impairment and research implications.
AB - OBJECTIVE: The scientific literature has not kept pace with the evolution of
child and adolescent psychiatric inpatient units, including their nature, patient
profile, philosophical orientation and efficacy. This study aims to establish a
comprehensive, multimodal description of the population served by an inpatient
psychiatric treatment facility for children and adolescents. METHOD: A
multidisciplinary assessment regime including psychiatric, medical, speech and
language examination, observer rating and patient self-report of psychopathology
was used to assess 58 consecutive patients over a 20-month period. RESULTS: In
addition to a prevalence of disruptive behaviour disorders of 67% and a high rate
of comorbidity with other psychiatric conditions, a breadth of impairment was
demonstrated in many areas. Significantly decreased measures of socialisation,
communication, daily living skills, self-esteem, intelligence and physical health
are reported. Moderate to severe language handicap was found in 40% of patients.
CONCLUSIONS: The inpatient population of children and adolescents exhibited not
only a high rate of disruptive behaviour disorders, frequently comorbid with
other psychiatric conditions, but also high levels of physical, speech, language
and living skills impairment. This finding supports the need for multimodal,
multidisciplinary evaluation and treatment in this population. Outcome research
evaluating treatment effectiveness must also account for the wide-ranging
disabilities of these children and adolescents.
PMID- 9400875
TI - Paradox, persecution and the double game: psychotherapy in anorexia nervosa.
AB - OBJECTIVE: In anorexia nervosa, the interface between psychotherapy and effective
physical management continues to arouse dissent. For this reason, theoretical
underpinnings and their practical applications were explored. METHOD: A selective
review of the literature was based on the authors' clinical experience in
hospital treatment settings. RESULTS: The psychosomatic paradigm, the threat to
life, the reward characteristics and the developmental trajectory of anorexia
nervosa necessitate a particular form of integrated psychotherapy. CONCLUSIONS:
The approach is essentially that of self psychology but with an important
departure which must be addressed in the therapeutic process. This is exemplifed
in the paradox of persecution by refeeding and the curious double game that
evolves.
PMID- 9400876
TI - The comorbidity of anxiety and depression.
AB - OBJECTIVE: This study explored the effect of comorbid anxiety disorders in
patients admitted to an inpatient specialist Mood Disorders Unit for the
treatment of a primary major depressive episode. METHOD: Subjects were assessed
on admission and discharge. DSM-III-R diagnoses for major depression and anxiety
disorders were established using CIDI-Auto; comorbid anxiety disorders were
coexistent in time with the major depression, with both conditions meeting
diagnostic criteria at the time of assessment. Severity of illness was assessed
using the Hamilton Depression/Melancholia Scale, the revised Hamilton Anxiety
Scale and the revised Beck Depression Inventory. RESULTS: For the analysis, the
study cohort was divided into three groups: depression alone (n = 33), one
comorbid anxiety disorder (n = 15), and two or more comorbid anxiety disorders (n
= 24). No particular anxiety disorder predominated. Interestingly, the presence
or absence of comorbid anxiety with severe major depression made no significant
difference to treatment choice or outcome results. Specifically, there was no
significant difference between the three groups in the utilisation of
electroconvulsive therapy and pharmacotherapy (including antidepressants,
benzodiazepines and neuroleptics); all subjects improved significantly on both
depression and anxiety ratings, and length of inpatient stay did not vary
significantly between the three groups. CONCLUSIONS: The existence of comorbid
anxiety disorders in those patients who presented for treatment of a primary
major depressive episode did not significantly effect choice of treatment or
treatment outcome, suggesting that there is a close interrelationship between the
two conditions.
PMID- 9400877
TI - The molecular genetics of schizophrenia: an update.
AB - OBJECTIVE: This paper aims to summarise the latest molecular genetic findings in
schizophrenia, while providing background information on a number of relevant
methodological issues. METHOD: Accumulative genetic data indicate that
schizophrenia is a genetically complex disease with an unclear mode of
transmission. The development and rapid progression of molecular genetics have
provided a wide variety of methods to search for genes predisposing to human
disease. The genetic basis for a number of the simpler diseases has been
identified and characterised using these methods. More recently, progress has
been made in identifying genes predisposing to the genetically more complex
diseases such as diabetes mellitus, multiple sclerosis, bipolar disorder and
schizophrenia. RESULTS: The latest findings on chromosomes 3, 6, 8, 13, 18 and 22
and on the X chromosome are reviewed. CONCLUSIONS: There is now suggestive
support for three susceptibility loci (6p24-22, 8p22-21 and 22q12-q13.1) for
schizophrenia, and it is likely that other regions will emerge from studies now
in progress. Finding and then characterising genes within these loci will require
long-term commitment and systematic efforts in clinical, laboratory and
analytical fields.
PMID- 9400879
TI - Adverse psychological impact of operative obstetric interventions: a prospective
longitudinal study.
AB - OBJECTIVE: This paper reports the findings of a prospective longitudinal study of
272 nulliparous pregnant women, which investigated as one of its objectives the
psychological sequelae of obstetric procedures. METHOD: Participants completed
structured interviews and standardised, published psychometric questionnaires,
including the Rosenberg Self-Esteem Scale and the Profile of Mood States late in
pregnancy and again early in the postpartum period. RESULTS: Little evidence was
found to support the notion that the total number of obstetric interventions was
linked to a deterioration in postpartum mood. Significant adverse psychological
effects were associated with the mode of delivery. Those women who had
spontaneous vaginal deliveries were most likely to experience a marked
improvement in mood and an elevation in self-esteem across the late pregnancy to
early postpartum interval. In contrast, women who had Caesarean deliveries were
significantly more likely to experience a deterioration in mood and a diminution
in self-esteem. The group who experienced instrumental intervention in vaginal
deliveries fell midway between the other two groups, reporting neither an
improvement nor a deterioration in mood and self-esteem. CONCLUSIONS: The
findings of this study suggest that operative intervention in first childbirth
carries significant psychological risks rendering those who experience these
procedures vulnerable to a grief reaction or to posttraumatic distress and
depression.
PMID- 9400878
TI - An evaluation of the effectiveness of a consultation-liaison psychiatry service
in general practice.
AB - OBJECTIVE: This study evaluated the 6-month outcome of patients referred by their
general practitioner (GP) to a consultation-liaison (C-L) psychiatry service
provided to eight group general practices. METHOD: Over a 12-month period, there
were 307 referrals to the C-L psychiatry service of whom 86 consented to take
part in an outcome study. Two different control groups were examined comprising
patients seen by the same GPs but not referred to the C-L service, who were
matched with the C-L referrals on the basis of either demographic characteristics
(n = 86) or initial symptomatology (n = 59). Clinical interviews were conducted
at recruitment to the outcome study using the Composite International Diagnostic
Interview (CIDI), while postal questionnaires were used at both the initial and 6
month assessments. RESULTS: Data reported include DSM-III-R clinical audit and
CIDI diagnoses, changes in current symptomatology (SCL-90-R) and changes in
global ratings of physical health, emotional health, social relationships and
ability to perform everyday duties. Consultation-liaison referrals without
symptom-matched controls (n = 27), being patients with higher levels of symptoms
initially, were more likely to be referred to other psychiatric services for
treatment. They also showed more marked improvement over time on the selected
outcome measures. However, there were no significant differences in the patterns
of change over time between symptom-matched C-L referrals and their non-referred
controls. CONCLUSIONS: The findings from the 6-month outcome study raise doubts
about the overall benefit of the current C-L service relative to usual GP care.
Improving the quality of psychiatric care in general practice is likely to
require a range of interrelated strategies, including C-L psychiatry services, GP
education and well-functioning links with public mental health services.
PMID- 9400880
TI - Using action research to facilitate organisational change in mental health
service delivery.
AB - OBJECTIVE: To report how well a particular mental health service was responding
to National and State mental health policies by emphasising community-based
clinical care for patients. METHOD: The method involved analysis and action in
response to information obtained from a consecutive sample of 100 people admitted
to a psychiatric hospital ward from a geographical catchment area. RESULTS: It
was found that community mental health staff were working without adequate
support and were not able to effectively implement early intervention and relapse
prevention strategies. Concern about these findings led to organisational change
using action research methodology and some of these changes are discussed.
CONCLUSIONS: Such methodology was a useful tool to identify and achieve
organisational change in psychiatric services.
PMID- 9400882
TI - The case-conferencing project: a first step towards shared care between general
practitioners and a mental health service.
AB - OBJECTIVES: The objectives of this study were: (i) to improve general
practitioners' knowledge of the mental disorders they commonly treat, and to
increase their confidence in managing people with these disorders; and (ii) to
increase general practitioners' familiarity with the Logan-Beaudesert Mental
Health Service. METHOD: Eleven general practitioners met with psychiatrists from
the Logan-Beaudesert Mental Health Service in six 2-hour sessions held at monthly
intervals. Each session comprised a teaching component, a consumer interview and
a case-conference. Outcomes were measured using an objective test of general
practitioners' knowledge, a subjective test of their confidence in dealing with
mental health problems, and satisfaction surveys for participating consumers,
general practitioners and psychiatrists. RESULTS: On the objective test, the
scores of 10 out of the 11 general practitioners improved (p < 0.05). On the
subjective test, the ranked scores improved in nine out of the 11 cases (p <
0.05). Consumers, general practitioners and psychiatrists expressed their
satisfaction with the format and content of the course. CONCLUSIONS: Having
improved the knowledge of a group of general practitioners who are familiar with
the functioning of the Logan-Beaudesert Mental Health Service, the stage is now
set to proceed to the next step: the shared-care project.
PMID- 9400881
TI - Who is a heavy service user? Preliminary development of a screening instrument
for prospective consumers of a mobile intensive treatment team.
AB - OBJECTIVE: The mobile intensive treatment team (MITT) of the Valley Integrated
Adult Mental Health Service in Brisbane, Australia, aims to provide services in
the community to people with severe and persistent mental illness who have
traditionally been heavily reliant on inpatient services (i.e. heavy service
users). The MITT screening instrument (MITTSI) was developed to provide an
objective measure to appropriately identify patients for referral to the service.
METHOD: A literature review and a panel of multidisciplinary clinicians were
consulted to identify a list of specific attributes that would assist in the
detection of heavy service users. These attributes were then formulated into an
easy-to-administer screening instrument entitled the MITTSI. The MITTSI was
administered in an interview format to MITT case managers (intensive case
management) and to case managers in standard case management with prospective
MITT patients (prospective heavy service users). RESULTS: Analyses of the
responses indicated support for the MITTSI as a valid screening instrument in
identifying heavy service users and for determining appropriate patients for
referral to the MITT. CONCLUSION: The MITTSI is an easy-to-administer screening
instrument which provides clear guidelines for inclusion and exclusion, and is an
objective measure regarding the patients' urgency for referral to the MITT.
Follow-up of the MITTSI within a broader, longer-term project will attempt to
further refine the MITTSI and to further determine its validity. Outcomes will be
published at a later stage.
PMID- 9400883
TI - How are psychotic symptoms perceived? A comparison between patients, relatives
and the general public.
AB - OBJECTIVE: The aim of this study is to compare patients with schizophrenia with
their relatives and the general public in their attitudes towards schizophrenic
psychotic symptoms. METHOD: We used a case vignette depicting a person with
typical schizophrenic psychotic symptoms and compared the attitudes of 44
inpatients and 47 outpatients with schizophrenia, 48 of their relatives and 43
members of the general public. We also compared the attitudes of patients with
schizophrenia to their own symptoms and the symptoms described in the vignette.
RESULTS: Subjects from the general public tended not to recognise psychotic
symptoms as features of mental illness and tended not to consider drug treatment
and hospitalisation as required. Sex, education level as well as previous contact
with the mentally ill were found to be significant determinants of attitude. The
levels of symptom awareness in patients with schizophrenia and their relatives
are higher but still relatively low. In addition, we found that patients with
schizophrenia who correctly appraised psychotic symptoms in another person were
also aware of their own mental symptoms and need of treatment. CONCLUSIONS: The
level of recognition of psychotic symptoms and awareness of a need for treatment
are low in the general public, as well as in patients with schizophrenia and
their relatives. These findings are discussed in relation to the assessment of
insight in patients and a need for psychoeducational programs for each group.
PMID- 9400884
TI - Psychosis following acute alteration of thyroid status.
AB - OBJECTIVE: Mania with psychotic features presenting following abrupt
normalisation of thyroid function from severe Graves's disease is reported.
CLINICAL PICTURE: A 33-year-old man with severe, untreated Graves's disease was
treated aggressively, with rapid restoration of normal serum thyroid hormone
levels. Symptoms of mania and psychosis then developed. TREATMENT: Time limited
antipsychotic medication and continuing medical treatment. OUTCOME: There was
resolution of psychiatric symptoms. CONCLUSIONS: The association of mania and
psychosis with thyroid disease is rare, but aggressive medical treatment and
rapid restoration of normal serum thyroid levels may increase the risk of the
emergence of such symptoms.
PMID- 9400885
TI - Erotomania associated with temporal lobe abnormalities following radiotherapy.
AB - OBJECTIVE: The aetiology of primary erotomania is usually discussed in terms of
psychological disturbance in the patient. A case associated with demonstrable
left temporal lobe abnormalities is described. CLINICAL PICTURE: An elderly
female patient presented with the delusion of being loved by a physician who had
treated her previously. She had received radiotherapy to her left periorbital
area in childhood. Structural and functional neuroimaging revealed medial
temporal lobe damage. TREATMENT AND OUTCOME: She was treated with haloperidol
with moderate improvement in her distress. CONCLUSIONS: This case illustrates the
contribution of both cerebral injury and psychosocial factors in the eventual
development of this unusual psychiatric syndrome.
PMID- 9400886
TI - Charles Bonnet syndrome with major depression in a Chinese middle-aged man.
AB - OBJECTIVE: To describe a middle-aged patient with Charles Bonnet syndrome (CBS)
suffering from concurrent major depression. CLINICAL PICTURE: A 41-year-old
Chinese man with retinitis pigmentosa developed complex and vivid visual
hallucinations. This was followed by the onset of major depressive illness. His
visual hallucinations were greatly influenced by his cultural background and
changed during the course of his depression. TREATMENT: The patient was treated
with imipramine. OUTCOME: The patient had a relapse of depression due to his non
compliance. He recovered after the resumption of imipramine but the visual
hallucinations persisted. CONCLUSIONS: Patients suffering from CBS can have
another concurrent psychiatric illness. The content and form of this patient's
visual hallucinations were modified by his cultural background and depressive
illness. Sensory deprivation is suggested to be the pathogenic mechanism of his
visual hallucination.
PMID- 9400887
TI - Obsession with infidelity: another case and some views.
PMID- 9400888
TI - Existing brain condition may predispose to SSRI-induced extrapyramidal symptoms.
PMID- 9400889
TI - Hired guns.
PMID- 9400890
TI - Legalistic abuse of psychiatric diagnoses and our own future.
PMID- 9400891
TI - Urinary tract infection and delusion of pregnancy.
PMID- 9400892
TI - Introduction: COPD--the role of infection.
PMID- 9400893
TI - Defining subsets of patients with chronic bronchitis.
PMID- 9400894
TI - Guidelines for the treatment of acute exacerbations of chronic bronchitis.
PMID- 9400895
TI - Antibiotic selection and dosing for the treatment of acute exacerbations of COPD.
PMID- 9400896
TI - Introduction: surviving septic shock.
PMID- 9400897
TI - Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis
of septic shock.
PMID- 9400898
TI - New therapies in sepsis.
PMID- 9400899
TI - Current status of clinical trials with anti-TNF.
PMID- 9400900
TI - Ethical considerations on the use of monoclonals in the managed care environment.
PMID- 9400901
TI - The SYST-EUR Study--calcium channel blockers coming of age? European Trial on
Isolated Systolic Hypertension in the Elderly.
PMID- 9400902
TI - Pseudo-hypertension in the elderly: still hazy, after all these years.
PMID- 9400903
TI - Stroke, blood pressure and antihypertensive therapy.
PMID- 9400904
TI - Moxonidine: a review.
AB - Moxonidine is an imidazoline compound which acts on I1 imidazoline 'receptors' in
the central nervous system to reduce blood pressure. This novel mechanism of
action is claimed to lead to fewer adverse effects than the older centrally
acting agents such as clonidine. In this review we examine the drug's
pharmacology, clinical pharmacokinetics, efficacy as an antihypertensive agent
including comparative studies with pre-existing drugs, and adverse effect
profile. With a growing number of effective antihypertensive agents already
available to the clinician, it is not yet clear whether moxonidine represents a
significant advance in hypertension management.
PMID- 9400905
TI - Effects of antihypertensive agents on circadian blood pressure in hypertensive
patients with previous brain infarction.
AB - To evaluate the effects of antihypertensive agents on the circadian blood
pressure (BP) of patients with previous brain infarction, the ambulatory BP was
measured non-invasively for 24 h before and after administration of
antihypertensive agents. One hundred milligrams of acebutolol twice daily (n =
15) is effective in lowering the BP during the daytime, but has little effect
during the night and the morning. Twenty milligrams of slow-release nifedipine
twice daily (n = 14) produced a consistent reduction in the BP over the entire 24
h period and effectively blunted the rise in BP in the morning. Captopril (12.5
mg) twice daily (n = 15) produced a mild reduction in BP with little change in
the circadian pattern. The slow-release nifedipine group had the greatest
decrease in mean systolic and diastolic BP. The heart rate significantly
increased after administration of slow-release nifedipine and decreased after
administration of acebutolol. To reduce stroke recurrence, we should consider the
effects of antihypertensive agents on circadian BP in hypertensive patients with
previous brain infarction.
PMID- 9400906
TI - The effectiveness of exercise training in lowering blood pressure: a meta
analysis of randomised controlled trials of 4 weeks or longer.
AB - OBJECTIVE: To identify the features of an optimal exercise programme in terms of
type of exercise, intensity and frequency that would maximise the training
induced decrease in blood pressure (BP). DATA IDENTIFICATION: Trials were
identified by a systematic search of Medline, Embase and Science Citation Index
(SCI), previous review articles and the references of relevant trials, from 1980
until 1996, including only English language studies. STUDY SELECTION: The
inclusion criteria were limited to randomised controlled trials of aerobic or
resistance exercise training conducted over a minimum of 4 weeks where systolic
and diastolic BP was measured. RESULTS: A total of 29 studies (1533 hypertensive
and normotensive participants) were included, 26 used aerobic exercise training,
two trials used resistance training and one study had both resistance and aerobic
training groups. Aerobic exercise training reduced systolic BP by 4.7 mm Hg (95%
CI: 4.4, 5.0) and diastolic BP by 3.1 mm Hg (95% CI: 3.0, 3.3) as compared to a
non-exercising control group, however, significant heterogeneity was observed
between trials in the analysis. The BP reduction seen with aerobic exercise
training was independent of the intensity of exercise and the number of exercise
sessions per week. The evidence for the effect of resistance exercise training
was inconclusive. CONCLUSIONS: Aerobic exercise training had a small but
clinically significant effect in reducing systolic and diastolic BP. Increasing
exercise intensity above 70% VO2 max or increasing exercise frequency to more
than three sessions per week did not have any additional impact on reducing BP.
PMID- 9400907
TI - Efficacy and position of endurance training as a non-drug therapy in the
treatment of arterial hypertension.
AB - Regular conditioning has been well documented to exert a beneficial effect on
cardiovascular risk factors and to improve overall cardiovascular health and to
reduce the incidence of coronary disease. There are conflicting results
concerning the effect of physical exercise on blood pressure (BP) in hypertensive
patients and its importance in the treatment of hypertension. Therefore 10 male
patients with mild arterial hypertension were studied in order to define the BP
response to long-term aerobic training (60 min twice a week) under resting
conditions, during standardised ergometric workload, during isometric exercise,
during cold pressor testing and during 24-h BP monitoring. After 18 months of
regular training there were significant reductions in arterial pressures at rest,
during and after standardised ergometry and during isometric and cold pressor
testing when compared with pre-training. The heart rate also decreased
significantly during exercise testing thus implying a decrease in myocardial
oxygen consumption. After long-term training, a reduction in systolic and
diastolic BP could also be shown during 24-h ambulatory BP monitoring. These
results demonstrate that long-term aerobic training leads to a decrease in
systolic and diastolic BP at rest, during exercise and during 24-h BP monitoring
and imply a beneficial effect in the management of hypertension that is nearly
comparable to that of drug therapy.
PMID- 9400908
TI - Avoiding the supine position during sleep lowers 24 h blood pressure in
obstructive sleep apnea (OSA) patients.
AB - Obstructive sleep apnea (OSA), is a common clinical condition affecting at least
2-4% of the adult population. Hypertension is found in about half of all OSA
patients, and about one-third of all patients with essential hypertension have
OSA. There is growing evidence that successful treatment of OSA can reduce
systemic blood pressure (BP). Body position appears to have an important
influence on the incidence and severity of these sleep-related breathing
disturbances. We have investigated the effect of avoiding the supine position
during sleep for a 1 month period on systemic BP in 13 OSA patients (six
hypertensives and seven normotensives) who by polysomnography (PSG) were found to
have their sleep-related breathing disturbances mainly in the supine position. BP
monitoring was performed by 24-h ambulatory BP measurements before and after a 1
month intervention period. We used a simple, inexpensive method for avoiding the
supine posture during sleep, namely the tennis ball technique. Of the 13
patients, all had a reduction in 24-h mean BP (MBP). The mean 24-h
systolic/diastolic (SBP/DBP) fell by 6.4/2.9 mm Hg, the mean awake SBP/DBP fell
by 6.6/3.3 mm Hg and the mean sleeping SBP/DBP fell by 6.5/2.7 mm Hg,
respectively. All these reductions were significant (at least P < 0.05) except
for the sleeping DBP. The magnitude of the fall in SBP was significantly greater
in the hypertensive than in the normotensive group for the 24 h period and for
the awake hours. In addition, a significant reduction in BP variability and load
were found. Since the majority of OSA patients have supine-related breathing
abnormalities, and since about a third of all hypertensive patients have OSA,
avoiding the supine position during sleep, if confirmed by future studies, could
become a new non-pharmacological form of treatment for many hypertensive
patients.
PMID- 9400909
TI - Autonomic nervous system activity in essential hypertension: a comparison between
dippers and non-dippers.
AB - The present study was undertaken to investigate the changes in autonomic nervous
system activity in essential hypertension. Fourteen normotensive controls and 33
age-matched untreated hypertensive subjects, diagnosed by ambulatory blood
pressure (ABP) measurement (24-h systolic ABP value over 140 mm Hg or 24-h
diastolic ABP over 90 mm Hg, or both) were recruited. ABP and 24-h
electrocardiogram were monitored simultaneously. Power spectral analysis of the R
R interval was performed by a fast Fourier transformation method and the powers
of low frequency (LF; 0.04 to 0.15 Hz) and high frequency (HF; 0.15 to 0.4 Hz)
components were obtained. Hypertensive subjects were divided into 'dippers',
whose night-time systolic ABP fell by more than 10% of their daytime ABP, and
'non-dippers' in whom this phenomenon was absent. In hypertensive subjects,
electrocardiogram monitoring and power spectral analysis were also performed for
5 min before and during 90 degrees tilt. There were no significant differences in
the 24-h mean LF/HF power ratio, LF power or HF power between normotensive and
hypertensive subjects. A significant negative correlation between the night-time
systolic ABP level and the 24-h LF/HF power ratio was found (r= -0.36, P < 0.05)
in the hypertensive subjects. A significant positive correlation was found
between the 24-h LF/HF power ratio and the percentage nocturnal reduction of the
daytime systolic ABP in hypertensive subjects (r = +0.40, P < 0.01). The 24-h
LF/HF power ratio was significantly lower in non-dippers than in dippers (2.09 +/
1.06 vs 3.24 +/- 0.97, P < 0.01). The mean daytime LF/HF power ratio was
significantly lower in non-dippers than in dippers (2.50 +/- 1.43 vs 4.08 +/-
1.27, P < 0.01). The night-time LF/HF power ratio was not significantly different
between the two groups. The LF/HF power ratio increased significantly in dippers
(from 1.32 +/- 1.95 to 4.65 +/- 1.54, P < 0.001) during 90 degrees tilt, but
there was no significant change in the LF/HF power ratio in non-dippers during
tilt (from 1.13 +/- 0.28 to 1.36 +/- 0.78, NS). The 24-h LF/HF power ratio
decreased according as the night-time systolic BP elevated in hypertensive
subjects. During ambulatory monitoring, the non-dippers showed a significantly
lower LF/HF power ratio than the dippers. The LF/HF power ratio increased
significantly in dippers, but not in non-dippers during tilting. These results
suggest that impaired cardiovascular reflexes might contribute to the decreased
sympathovagal balance in non-dipper type hypertension.
PMID- 9400910
TI - For how many days should blood pressure be measured at home in older patients
before steady levels are obtained?
AB - This study investigated the period of time that blood pressure (BP) should be
measured at home in older patients in order to obtain steady BP values. Thirty
six men and 38 women (> or =60 years) were recruited at one family practice. At
one office visit the family physician measured supine, sitting and standing BPs
three times consecutively in each position. During 10 consecutive days, BP was
measured at home five times daily. The supine and standing BPs were measured once
in the morning and in the evening and the sitting BP once at noon. These home BP
values were averaged over the first day (1-day), over the first 3 days (3-day)
and all 10 days (10-day) of measurements. In both the supine (-5.1 mm Hg) and
sitting (-3.8 mm Hg) positions the 10-day average systolic home BP was
significantly lower than the corresponding office BP. The opposite was observed
for the 10-day average standing home BP values (+7.3/+3.4 mm Hg). Comparison of
the 3-day and 10-day average home BP values showed only a significantly lower 10
day than 3-day systolic BP level in the supine position (-1.1 mm Hg, 95% CI -1.9
to -0.2 mm Hg). Repeated measures ANOVA, showed a small but significant decrease
over time only for the supine systolic home BP (-0.29 mm Hg per day, 95% CI -0.49
to -0.08 mm Hg per day). We conclude that in older subjects, 3 days of home
measurements may suffice to obtain steady values for the sitting and standing
BPs. A longer interval might be required for the supine BP.
PMID- 9400911
TI - Epidemiological study of hypertension and its determinants in an urban population
of North India.
AB - OBJECTIVES: To determine age-specific prevalence of hypertension and blood
pressure (BP) levels in relation to diet and lifestyle factors in North Indians.
DESIGN AND SETTING: Cross-sectional survey in 20 randomly selected streets in
Moradabad, North India. SUBJECTS AND METHODS: A total of 1806 subjects from North
India (904 males and 902 females) age range 25-64 years. The survey methods were
as follows: dietary diaries for 7 days food intake record; BP measurements;
physician administered questionnaire and anthropometric measurements. Diagnosis
of hypertension was based on new World Health Organization/International Society
of Hypertension (WHO/ISH) criteria. Risk factors were assessed based on WHO
guidelines. RESULTS: The prevalence of hypertension according to WHO/ISH criteria
was 23.7% and by old WHO criteria 13.3%. In the WHO/ISH hypertensive group,
isolated diastolic hypertension was present in 47.3% males and 40.6% females.
Males have a slightly higher prevalence than females in the young age group,
however, the prevalence rates are comparable in the older age groups. In both
sexes, the prevalence rates and BP level increased with older age. Multivariate
analysis revealed that age, higher body mass index, central obesity and higher
socioeconomic status were independently and strongly associated with hypertension
in both sexes. Higher dietary fat and salt intake and lower physical activity
were weakly but significantly associated with hypertension. CONCLUSION:
Association of higher socioeconmic status, higher body mass index and central
obesity in North Indian adults with higher fat intake, lower physical activity
and higher prevalence and level of hypertension indicate that these populations
may benefit by decreasing the dietary fat intake and increasing physical
activity, with an aim to decrease central obesity for decreasing hypertension in
North Indians.
PMID- 9400912
TI - Fibromuscular dysplasia.
PMID- 9400913
TI - Intensified insulin therapy--is there anything left to argue?
PMID- 9400914
TI - Update of tacrolimus in pancreas transplantation.
AB - Pancreas transplantation for the better treatment of diabetes mellitus is
becoming an important part of the service offered to diabetic patients requiring
renal transplantation. Improvements in surgical technique make this a useful
option. A major problem, limiting more extensive use of pancreas transplantation
to other diabetic patients, remains the inadequacies of present immunosuppressive
regimens. A relatively new agent, FK506 or tacrolimus, is being used increasingly
because of perceived benefits over older therapeutic agents. There are concerns
about the diabetogenic effect of tacrolimus. These may be dose-related, and low
dose tacrolimus regimens, by allowing reduction in dosage of other diabetogenic
immunosuppressive agents, have produced encouraging results in pancreas
transplantation in many centres. Further improvements in immunosuppressive
regimens may widen the clinical implications for pancreas transplantation but
identifying the patient group who will most benefit remains a priority.
PMID- 9400915
TI - Risk of adverse effects of intensified treatment in insulin-dependent diabetes
mellitus: a meta-analysis.
AB - While the benefits of intensified insulin treatment in insulin-dependent (Type 1)
diabetes mellitus (IDDM) are well recognized, the risks have not been
comprehensively characterized. We examined the risk of severe hypoglycaemia,
ketoacidosis, and death in a meta-analysis of randomized controlled trials. The
MEDLINE database, reference lists, and specialist journals were searched
electronically or by hand to identify relevant studies with at least 6 months of
follow-up and the monitoring of glycaemia by glycosylated haemoglobin
measurements. Logistic regression was used for calculation of combined odds
ratios and 95% confidence intervals (95% CI). The influence of covariates was
examined by including covariate-by-treatment interaction terms. Methodological
study quality was assessed and sensitivity analyses were performed. Fourteen
trials were identified. These contributed 16 comparisons with 1028 patients
allocated to intensified and 1039 allocated to conventional treatment. A total of
846 patients suffered at least one episode of severe hypoglycaemia, 175 patients
experienced ketoacidosis and 26 patients died. The combined odds ratio (95% CI)
for hypoglycaemia was 2.99 (2.45-3.64), for ketoacidosis 1.74 (1.27-2.38) and for
death from all causes 1.40 (0.65-3.01). The risk of severe hypoglycaemia was
determined by the degree of normalization of glycaemia achieved (p=0.005 for
interaction term), with the results from the Diabetes Control and Complications
Trial (DCCT) in line with the other trials. Ketoacidosis risk depended on the
type of intensified treatment used. Odds ratios (95% CI) were 7.20 (2.95-17.58)
for exclusive use of pumps, 1.13 (0.15-8.35) for multiple daily injections and
1.28 (0.90-1.83) for trials offering a choice between the two (p = 0.004 for
interaction). Mortality was significantly (p = 0.007) increased for causes
potentially associated with acute complications (7 vs 0 deaths, 5 deaths
attributed to ketoacidosis, and 2 sudden deaths), and non-significantly (p =
0.16) decreased for macrovascular causes (3 vs 8 deaths). We conclude that there
is a substantial risk of severe adverse effects associated with intensified
insulin treatment. Mortality from acute metabolic causes is increased; however,
this is largely counterbalanced by a reduction in cardiovascular mortality. The
excess of severe hypoglycemia in the DCCT is not exceptional. Multiple daily
injection schemes may be safer than treatment with insulin pumps.
PMID- 9400916
TI - Symptomatic and physiological responses to hypoglycaemia induced by human soluble
insulin and the analogue Lispro human insulin.
AB - The aim of this study was to compare the glycaemic threshold for onset of the
clinically detectable sympatho-adrenal (autonomic) reaction (defined as 'R') to
hypoglycaemia induced by Lispro human insulin, with that induced by human soluble
insulin (HS). The hypoglycaemia symptom profile, counterregulatory hormonal
responses, and cognitive performance at R were also compared. Sixteen patients
with IDDM, aged 32.5 (20-45) (median (range)) years and duration of IDDM 3.0 (0.5
4.5) years participated in a randomized, double-blind study during which
intravenous infusions of either Lispro or HS insulin (2.0 mU kg(-1) min(-1)) were
used on separate occasions to lower the blood glucose to the level at which R was
induced. For both HS and Lispro, significant increments in systolic blood
pressure (p<0.05), heart rate (p<0.05), and in autonomic (p<0.05) and
neuroglycopenic symptom scores (p<0.05) occurred at R, and a significant
deterioration was observed in cognitive performance (p<0.05). In response to
hypoglycaemia, a significant increase from baseline occurred in plasma
concentrations of all of the counterregulatory hormones (p<0.01) and the
magnitude of response and temporal pattern did not differ, nor were any
significant differences apparent between HS and Lispro insulins for any of the
variables studied. The autonomic reaction occurred at a blood glucose (mean +/-
SD) of 2.0 (+/- 0.6) mmol(-1) for Lispro and 1.9 (+/- 0.6) mmol(-1) for HS, which
did not differ significantly. Thus, at the autonomic reaction to hypoglycaemia no
significant differences were evident in the glycaemic threshold, symptom profile,
physiological responses, and counterregulatory hormonal responses between Lispro
and human soluble insulin in IDDM patients.
PMID- 9400917
TI - Plasma leptin in non-diabetic Asian Indians: association with abdominal
adiposity.
AB - Plasma leptin concentrations were measured in 144 non-diabetic men and women (age
21-73 years, BMI 14.8-37.7 kg m(-2)), in fasting samples collected during a
population survey for diabetes mellitus. Leptin, fasting and 2-h post-glucose
load plasma concentrations of glucose and immunoreactive insulin were measured.
In a subset of 50 normoglycaemic individuals, subcutaneous fat (SF) and visceral
fat (VF) areas at L4-L5 level were also measured by CT. As in other populations,
women had significantly higher plasma leptin concentrations than men (p < 0.001)
but the values were similar in normal (NGT) and impaired glucose tolerance (IGT).
Geometric mean concentrations of leptin in men and women with NGT were 4.8 and
17.7 ng ml(-1), respectively, and the corresponding values in IGT were 6.2 and
19.0 ng ml(-1). Multiple regression analysis in the total group showed that the
leptin concentration (log-transformed) was strongly dependent on sex (R2 =
53.4%), BMI (R2 = 17.4%), and to a lesser degree on the 2-h plasma insulin (R2 =
2.4%) and the WHR (R2 = 0.8%). In men, the total abdominal fat showed a strong
association with leptin (R2 = 49.3%) and in women the subcutaneous fat area
showed a similar effect (R2 = 39.5%). It is likely that subcutaneous and not
visceral fat may be a determinant of plasma leptin in Asian Indians, and the
correlation between leptin and insulin resistance may be less strong than in
other ethnic groups.
PMID- 9400918
TI - Is an exaggerated postprandial triglyceride response associated with the
component features of the insulin resistance syndrome?
AB - To investigate whether individual component features of the insulin resistance
syndrome were associated with the postprandial triglyceride response, 57 healthy
Caucasian men between 57 and 70 years of age underwent a fat tolerance test
lasting 8 h. Fasting triglyceride concentrations were associated with the total
unfractionated postprandial triglyceride response (r(s) = 0.54, p < 0.001) and
the triglyceride-rich lipoprotein (TGRLP) fraction (d < 1.006) at 8 h was
associated with the maximum non-esterified fatty acid concentration (NEFA) (r(s)
= 0.33, p = 0.01). Measures of obesity (BMI and WHR) were not associated with the
postprandial triglyceride response but were inversely related to NEFA suppression
(NEFA nadir and BMI, r(s) = 0.31, p = 0.02; and NEFA nadir and WHR, r(s) = 0.36,
p = 0.006). Other component features of the IRS, including glucose tolerance and
two proxy measures of insulin resistance (fasting insulin concentration and HOMA
measurement) were not associated with the postprandial triglyceride response
despite being strongly associated with fasting triglyceride concentration.
Current smoking habit, chronic alcohol consumption and birth weight were also not
associated with an altered postprandial triglyceride response. In conclusion
these results show that although component features of the IRS were associated
with increased fasting triglyceride concentrations many of these features,
including two proxy measures of insulin sensitivity were not associated with an
exaggerated postprandial triglyceride response.
PMID- 9400919
TI - A 3-19-year follow-up study on diabetic retinopathy in patients diagnosed in
childhood and treated with conventional therapy.
AB - Few data are available from follow-up studies on diabetic retinopathy in patients
diagnosed with insulin-dependent (Type 1) diabetes mellitus in childhood and
treated with conventional therapy. We report the results of conventional insulin
therapy on development of diabetic retinopathy in 100 children and adolescents
(47 females and 53 males), aged 8.3 +/- 3.5 (1.2-16.4) years at diagnosis of
disease. Oral or intravenous fluorescein angiography was performed during a 3-19
year follow-up in all patients. Retinopathy was staged according to the criteria
of the Italian Society of Diabetology (SID). During follow-up, retinopathy was
observed in 28 patients (28%). At the end of follow-up, retinopathy was present
in 23 patients and had disappeared in 5. Life-table analysis showed a median
disease-free interval of 10.8 years. At 10 years from diagnosis the percentage of
patients free of retinopathy was 66%. Poor metabolic control, age, and degree of
pubertal development at diagnosis were the most important risk factors.
PMID- 9400920
TI - Effect of insulin on blood rheology in non-diabetic subjects and in patients with
Type 2 diabetes mellitus.
AB - We evaluated the effect of insulin on platelet function, blood viscosity, and
filterability in healthy subjects and in patients with Type 2 (non-insulin
dependent) diabetes mellitus. Fifteen diabetic patients were free from
cardiovascular complications (group A), while the other 15 patients had both
clinical and measured evidence of coronary or peripheral vascular disease (group
B); 15 non-diabetic subjects served as controls. On blood samples taken without
stasis, maximal platelet aggregation to 1.25 micromol l(-1) ADP, blood and plasma
viscosity, and blood filterability were measured in basal conditions, and after
incubation of blood, plasma or platelet-rich plasma with insulin at two
physiological concentrations (120 and 480 pmol l(-1)). Compared with healthy
subjects, the diabetic patients of group B had higher values of blood (p < 0.01)
and plasma (p < 0.05) viscosity, and platelet aggregation response to ADP (p <
0.01), as well as lower values of blood filterability (p < 0.01). The diabetic
patients of group A had values intermediate between normal subjects and the
patients of group B. In non-diabetic subjects, insulin significantly decreased
platelet aggregation and blood viscosity at low shear rates (22.5 s(-1)) (p <
0.01 for both), and had no significant effects on other parameters. In the
diabetic patients of group A, insulin decreased blood viscosity at high (225 s(
1)) rates of shear (p < 0.01) and increased blood filterability (p < 0.01). The
effects of insulin were not dose-related. In the diabetic patients of group B,
none of the parameters evaluated was significantly influenced by insulin. Type 2
diabetic patients present many abnormalities of the rheologic properties of
blood. The beneficial effects of insulin on platelet aggregation and blood
viscosity are not evident in Type 2 diabetic patients, especially those with
vascular complications and this may be relevant to the development of those
complications.
PMID- 9400921
TI - Comparison of incidence of insulin-dependent diabetes mellitus in children and
young adults in the Province of Turin, Italy, 1984-91. Piedmont Study Group for
Diabetes Epidemiology.
AB - To document the incidence of IDDM in the Province of Turin (Italy) in the 8-year
period 1984-91 in children (0-14 years) and young adults (15-29 years), in
relation to age, sex, monthly-seasonal variability, calendar year and urban/rural
area, (all newly diagnosed cases (502) were ascertained through primary and
secondary data sources and completeness of ascertainment estimated with the two
sample capture-recapture method (99% in childhood and 95% in young adults). The
independent effect of age, sex, calendar year, and urban/rural area was estimated
with a Poisson regression model. Age-specific incidence rates were 8.42/100,000
(95% CI 7.37-9.62) and 6.72/100,000 (95% CI 5.96-7.58), respectively, in the age
groups 0-14 and 15-29 years. Sex differences were evident in young adults, with
an almost 1.5-fold increased risk in men (8.37/100,000, 95% CI 7.21-9.71 vs
5.00/100,000, CI 4.09-6.10). Seasonal trend was evident in childhood. Predictors
of incidence rates were age, place of residence and interaction between sex and
age; no temporal trend was detected. No significant differences were found in the
two age-groups with respect to glycaemia, glycosuria, ketonuria, and fasting C
peptide levels. In conclusion, this study shows sex differences in IDDM risk in
young adults; 55% of incident cases occurring in young adults; an independent
contribution of urban/rural differences to IDDM risk; no temporal trend in 1984
91; a seasonal pattern of incidence in children; no significant differences in
clinical presentation between age groups.
PMID- 9400922
TI - Can digitised colour 35 mm transparencies be used to diagnose diabetic
retinopathy?
AB - Retinal photography is an adjunct to ophthalmoscopy in screening for diabetic
retinopathy (DR). Digital retinal cameras allow a retinal image to be displayed
immediately on a high resolution video display monitor. We conducted a pilot
study to investigate the agreement in retinopathy grading from digitized images
in comparison to original colour transparencies as 35 mm slides. One hundred and
fifty macula-centred, 45 degree, non-stereoscopic retinal images were digitized
onto CD ROM by Kodak at base resolution of 768 x 512 pixels. The anonymized
images were displayed on a 17" monitor running Windows at 800 x 600 resolution in
64,000 colours (PC images) and graded in random order. Alternatively the
transparencies were graded on a Slidex viewer. A quality control set were also
graded with exact agreement in 93% of cases (91% (73/80) of PC images and 94%
(75/80) of slide images). Compared to colour transparencies, 95% (84/88) of sight
threatening diabetic retinopathy (STDR) and 100% (62/62) of non-STDR cases were
diagnosed using the PC. One case of pre-proliferative DR and three cases of non
proliferative DR were graded as non-STDR from the PC. There was good agreement
between PC displayed digitized retinal images and 35 mm colour transparencies.
PMID- 9400923
TI - Low-density lipoprotein size, high-density lipoprotein concentration, and
endothelial dysfunction in non-insulin-dependent diabetes.
AB - We examined endothelial function (nitric-oxide mediated) in 29 men with diet
treated non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 18 male age
matched controls. Forearm blood flow was measured by venous occlusive
plethysmography during intra-arterial administration of acetylcholine (ACh, 7.5
and 15 microg min(-1)) and sodium nitroprusside (SNP, 3 and 10 microg min(-1)).
LDL particle size was estimated by non-denaturing gel electrophoresis. Serum
lipids, blood pressure, and glycated haemoglobin were also measured. LDL particle
size was smaller (p = 0.048) in the diabetic patients than controls. In the
diabetic patients, LDL particle size was a significant positive predictor (p =
0.01) of the area under the dose-response curve for ACh, after adjusting for age,
HbA1c, systolic BP, and cholesterol (R2 0.20). In stepwise regression including
serum lipid and lipoprotein concentrations and LDL particle size, decreased HDL
cholesterol was the best predictor of an impaired vasodilatory response to ACh.
Vasodilatory responses to sodium nitroprusside were not significantly correlated
with LDL particle size or serum lipid and lipoprotein concentrations. We conclude
that in men with NIDDM, small, dense LDL particle size is associated with
abnormal endogenous release of nitric oxide. The contribution of small, dense LDL
particles to the development of endothelial dysfunction and early diabetic
vasculopathy may not, however, be as great as decreased HDL cholesterol.
PMID- 9400924
TI - Return of beta-adrenergic sensitivity in a patient with insulinoma after removal
of the tumour.
AB - Beta-adrenergic sensitivity and counterregulatory hormone and symptomatic
responses to hypoglycaemia were studied in a 22-year-old man before and 3 and 34
weeks after removal of an insulinoma. The beta-adrenergic sensitivity was
measured by the effect of an isoprenaline infusion on the heart rate, and the
dose needed to increase the heart rate by 25 beats min(-1) (I25) calculated from
regression lines. The glucose thresholds for the hormonal responses and symptoms
were studied during a gradual fall in plasma glucose using a hypoglycaemic clamp
technique. As compared with preoperative values, beta-adrenergic sensitivity was
unchanged 3 weeks after surgery, but showed a marked improvement after 34 weeks,
the I25 (in microg isoprenaline) being 0.96, 0.86, and 0.56, respectively. The
hormone responses to hypoglycaemia were earlier, but with no improvement in
symptom generation at 3 weeks. After 34 weeks, the thresholds for both hormone
release and symptom generation occurred at a plasma glucose approximately 1 mmol
l(-1) higher than before surgery. Thus, in our patient, there was a marked
improvement in beta-adrenergic sensitivity, an earlier release of
counterregulatory hormones, and an earlier recognition of hypoglycaemic symptoms
after surgery. However, the restoration of these responses took more than 3
weeks.
PMID- 9400926
TI - Diabetes information in the Cochrane Library.
PMID- 9400925
TI - Selective intra-arterial calcium injection in the investigation of adult
nesidioblastosis: a case report.
AB - A 69-year-old man with recurrent hypoglycaemia had inappropriately elevated
plasma insulin level during a symptomatic hypoglycaemia, but had a negative
prolonged fast. Computerized tomography (CT) of the abdomen revealed a nodular
lesion over the body of pancreas, whereas pancreatic arteriography failed to show
tumour blush. Hence, arterial stimulation (with calcium) and venous sampling
(ASVS) was performed and a brisk response of plasma insulin level was found when
calcium was injected both into the splenic and the superior mesenteric arteries.
Since no tumour was found during the operation, the patient received subtotal
distal pancreatectomy. Pathological examination of the resected tissue disclosed
a typical finding of nesidioblastosis. We suggest that selective intra-arterial
calcium injection with hepatic venous sampling for insulin gradients is useful
for the diagnosis of adult nesidioblastosis.
PMID- 9400927
TI - Ketosis-onset diabetes in young adults with subsequent non-insulin-dependency, a
link between IDDM and NIDDM?
PMID- 9400929
TI - In defence of twin studies: look to the phenotype.
PMID- 9400928
TI - Soluble selectins in IDDM: possible association with lipids?
PMID- 9400930
TI - Poor glycaemic control and retinopathy in non-insulin-dependent diabetes
mellitus.
PMID- 9400931
TI - A miracle of salamization: positive divided by two equals negative.
PMID- 9400932
TI - Combined inhibition of topoisomerases I and II--is this a worthwhile/feasible
strategy?
PMID- 9400933
TI - Circulating soluble adhesion molecules E-cadherin, E-selectin, intercellular
adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in
patients with gastric cancer.
AB - The concentrations of the soluble adhesion molecules E-cadherin, E-selectin,
intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1
(VCAM-1) were investigated in 45 patients with gastric cancer before treatment
and their correlation with clinical, histological and routine laboratory
parameters was examined. Data were collected on tumour stage at presentation,
presence and sites of metastatic disease, tumour pathology, survival and results
of routine laboratory tests. Serum concentrations of ICAM-1 and VCAM-1 were
significantly elevated in the patients with gastric cancer in comparison with the
group of healthy subjects (P < 0.00001 and P < 0.0001 respectively). Increased
serum concentrations of VCAM-1 were associated with locally advanced and
metastatic disease whereas ICAM-1 was significantly elevated both in local and in
advanced/metastatic disease. Soluble E-cadherin and E-selectin concentrations did
not show any significant elevation in gastric cancer patients. Concentrations of
soluble adhesion molecules showed significant correlation with each other (except
E-selectin and VCAM-1) and with alkaline phosphatase. Soluble ICAM-1 and VCAM-1
were significantly associated with an elevated total white cell count. Patients
with elevated VCAM-1 had significantly poorer survival in comparison with
patients with normal serum levels (P = 0.0361).
PMID- 9400934
TI - The RB1 gene mutation in a child with ectopic intracranial retinoblastoma.
AB - The RB1 gene mutation was investigated in a child with ectopic intracranial
retinoblastoma using DNA obtained from both the pineal and retinal tumours of the
patient. A nonsense mutation in exon 17 (codon 556) of the RB1 gene was found to
be present homozygously in both the retinal and the pineal tumours. The same
mutation was present heterozygously in the DNA from the constitutional cells of
the patient, proving it to be of germline origin. The initial mutation was shown
to have occurred in the paternally derived RB1 allele. The mutation is in an area
of the gene that encodes the protein-binding region known as the 'pocket' region
and has been detected in other cases of retinoblastoma.
PMID- 9400935
TI - Angiogenesis is associated with vascular endothelial growth factor expression in
cervical intraepithelial neoplasia.
AB - Squamous cell carcinoma of the cervix (SCC) is preceded by a premalignant
condition known as cervical intraepithelial neoplasia (CIN). The majority of
cases of CIN regress spontaneously; however, methods are needed to identify those
lesions likely to progress. Increased blood vessel density, signifying
angiogenesis, is an independent prognostic indicator in a number of cancers,
although little is known about its significance in premalignant lesions. The aim
of the present study was to determine the relationship between vessel density,
expression of the potent angiogenic factor vascular endothelial growth factor
(VEGF) and CIN grade. Using immunohistochemistry, mean vessel density (MVD) and
VEGF expression were assessed in samples from 54 patients who had undergone cone
biopsy for CIN or hysterectomy for SCC and from 16 patients with no cervical
pathology. There were significant increases in MVD and VEGF expression from
normal cervix through CIN I to CIN III to invasive SCC, but no difference in mean
vessel diameter between groups. There was a strong correlation between mean
vessel density and VEGF expression, and both were associated with histological
grade of CIN. The original MVDs for a small group of patients later presenting
with recurrent disease were found to be equal to or greater than the mean for
their histological grade. We conclude that the onset of angiogenesis is an early
event in premalignant changes of the cervix due, in part, to enhanced expression
of VEGF by the abnormal epithelium.
PMID- 9400936
TI - Prognostic value of loss of heterozygosity at BRCA2 in human breast carcinoma.
AB - To confirm several recent studies pointing to loss of heterozygosity (LOH) at
BRCA2 as a prognostic factor in sporadic breast cancer, we examined this genetic
alteration in a large series of human primary breast tumours for which long-term
patient outcomes were known. LOH at BRCA2 correlated only with low oestrogen and
progesterone receptor content. Univariate analysis of metastasis-free survival
and overall survival (log-rank test) showed no link with BRCA2 status (P = 0.34,
P = 0.29 respectively). LOH at BRCA2 does not therefore appear to be a major
prognostic marker in sporadic breast cancer.
PMID- 9400937
TI - Down-regulation of a novel form of fibroblast growth factor receptor 1 in human
breast cancer.
AB - Monoclonal antibodies against two epitopes of FGFR-1 have been used to
investigate FGFR-1 expression in the normal and neoplastic human breast.
Different forms are detected in the different cell types constituting the normal
breast. Moreover, breast cancer cells lack one form of FGFR-1. Western blot
analysis showed 115-kDa and 106-kDa forms of FGFR-1 within the human breast. The
115-kDa band corresponds to the beta form of FGFR-1, whereas the 106-kDa band is
truncated at the carboxyl terminus. The 106-kDa form of FGFR-1 is the major form
present in breast fibroblasts and myoepithelial cells, whereas epithelial cells
contain equal amounts of the 115-kDa and 106-kDa forms. Breast cancer cells,
however, appear to contain only the 115-kDa form of FGFR-1. This expression
pattern is reflected in malignant and non-malignant tissue samples. Using reverse
transcription polymerase chain reaction (RT-PCR) analysis, we have shown that the
106-kDa FGFR-1 isoform is not the previously described alpha 2 receptor that
arises from a 25-base pair insertion in the second kinase domain. It is probable
that the 106-kDa FGFR-1 has different signalling properties to the full-length
receptor, having lost at least one tyrosine at amino acid 766, which is required
for phospholipase C activation. This form of FGFR-1 appears to be lost in all
breast cancer cells analysed and its absence may have a bearing on malignancy.
PMID- 9400938
TI - Germline BRCA2 mutations in men with breast cancer.
AB - Breast cancer in men is rare and is clearly due in some cases to an inherited
predisposition. A total of 28 male breast cancer patients were tested for BRCA2
mutations; two frameshifts and one putative missense mutation were identified.
One of the frameshifts was detected in the same position as a mutation estimated
to be responsible for 40% of all male breast cancer cases in Iceland.
PMID- 9400939
TI - The effect of hypoxia and hyperoxia on nucleoside triphosphate/inorganic
phosphate, pO2 and radiation response in an experimental tumour model.
AB - This study has evaluated the effect of breathing 100% oxygen, carbogen and carbon
monoxide (at 660 p.p.m.) on the bioenergetic and oxygenation status and the
radiation response of 200-mm3 C3H mammary carcinomas grown in the feet of CDF
mice. Bioenergetic status was assessed by 31P magnetic resonance spectroscopy
(MRS) using a 7-tesla spectrometer with both short (2 s) and long (6 s) pulse
repetition times. Tumour partial pressure of oxygen (PO2) was measured with an
Eppendorf polarographic electrode; the oxygenation parameters were the median pO2
and fraction of pO2 values < or = 2.5 mmHg. The radiation response was estimated
using a tumour growth delay assay (time to grow three times treatment volume).
Carbon monoxide breathing decreased tumour pO2 and compromised the radiation
response, but the beta-nucleoside triphosphate (NTP)/Pi ratio was unchanged. Both
carbogen and oxygen (100%) increased tumour pO2 and beta-NTP/Pi and enhanced the
radiation response, the effects being similar under the two gassing conditions
and dependent on the gas breathing time. Thus, in this tumour model, 31P-MRS can
detect hyperoxic changes, but because cells can remain metabolically active even
at low oxygen tensions the beta-NTP/Pi did not correlate with low tissue
oxygenation. An analysis of variance showed that gas breathing time induced a
significant systematic effect on beta-NTP/Pi, the MRS pulse repetition time had a
significant effect on beta-NTP/Pi change under hypoxic but not under hyperoxic
conditions and the type of gas that was inhaled had a significant effect on beta
NTP/Pi.
PMID- 9400940
TI - Differential level of DSB repair fidelity effected by nuclear protein extracts
derived from radiosensitive and radioresistant human tumour cells.
AB - A cell-free plasmid reactivation assay was used to determine the fidelity of DNA
double-strand break (DSB) repair in a panel of eight DSB repair-proficient human
tumour cell lines. Nuclear protein extracts derived from radiosensitive tumour
cells were less capable of correctly rejoining EcoRI-induced DSBs than were
similar extracts from radioresistant tumour cells. Linear regression analysis
suggests that there was a significant (r2 = 0.84, P = 0.001, d.f. = 6)
correlation between the fidelity of DSB rejoining and the SF2 values of the cell
lines studied. This cell-free assay is clearly sensitive to differences in the
nuclear protein composition that reflect the clinically relevant radiosensitivity
of these cell lines. The fact that our cell-free assay yielded similar results to
previous studies that used intracellular plasmid reactivation assays suggests
that those differences in DSB mis-rejoining frequencies in radiosensitive and
radioresistant cell lines may be due to inherent differences in nuclear protein
composition and are not directly attributable to differences in proliferation
rates between cell lines. The underlying cause for this association between DSB
mis-rejoining frequencies and radiosensitivity is presently unknown, however
restriction endonuclease mapping and polymerase chain reaction (PCR)
amplification analysis revealed that approximately 40% of the mis-rejoined DSBs
arose as a result of the deletion of between 40 and 440 base pairs. These data
raise the possibility that the radiosensitivity of DSB repair-proficient human
tumour cell lines may be partly determined by the predisposition of these cell
lines to activate non-conservative DSB rejoining pathways.
PMID- 9400941
TI - Similarity of apoptosis induction by 2-chlorodeoxyadenosine and cisplatin in
human mononuclear blood cells.
AB - The purine analogue 2-chlorodeoxyadenosine (CdA) is unique compared with
traditional antimetabolite drugs, as it has shown equal activity in dividing and
resting lymphocytes. Poly(ADP-ribose)polymerase (PARP) activation and consecutive
NAD+ consumption have been associated with the induction of apoptosis in resting
cells. The potential of CdA to induce the p53-dependent DNA damage response was
assessed in resting and phytohaemagglutinine (PHA)-activated peripheral blood
mononuclear cells (PBMCs) and compared with cisplatin (DDP), a cell cycle
dependent and DNA-damaging agent that is mainly used in the treatment of solid
tumours. Both drugs induced transactivation of the p53 target genes waf1 and
mdm2, NAD+ consumption and apoptotic death. The expression pattern of p53 and
waf1 suggests a partly p53-independent induction of waf1. The expression of c-myc
and PARP, which both have a dual role in proliferation and apoptosis, was
selectively induced by CdA. Cell cycle stimulation increased the cytotoxic
activity of both drugs. These data show that DDP is also a potent inducer of
apoptosis in resting and proliferating peripheral blood mononuclear cells.
Activation of the p53-dependent DNA damage response seems to be an important
component of the toxic effect of CdA.
PMID- 9400942
TI - Allelotype analysis of adenocarcinoma of the gastric cardia.
AB - To identify chromosomal loci involved in the development of proximal gastric
adenocarcinoma, this study delineated the pattern of allelic imbalance in a
series of 38 adenocarcinomas arising in the gastric cardia. A total of 137
microsatellite markers covering all autosomal arms, excluding acrocentric arms,
were analysed. A mean of 35 out of a total of 39 chromosomal arms studied were
informative for each patient. The tumour group demonstrated a high level of
allelic imbalance, with an observed median fractional allelic imbalance of 0.47
for the 29 intestinal-type adenocarcinomas and 0.54 for the nine diffuse-type
adenocarcinomas. Allelic imbalance was detected in >50% of informative cases in
both histological subtypes on a number of chromosomal arms. In the intestinal
subtype, these included, 3p (61%), 4q (71%), 5q (59%), 8p (60%), 9p (65%), 9q
(83%), 12q (52%), 13q (52%), 17p (78%) and 18q (70%). A higher incidence of
allelic imbalance was detected on chromosome 16q in tumours of the diffuse type
relative to those of the intestinal type. A more detailed mapping on chromosomes
4q and 6q identified a number of cases with subchromosomal breakpoints. In
conclusion, this analysis has indicated regions of the genome potentially
involved in the development of proximal gastric carcinomas.
PMID- 9400943
TI - Platinum-DNA adduct formation in leucocytes of children in relation to
pharmacokinetics after cisplatin and carboplatin therapy.
AB - Platinum (Pt)-DNA adducts were measured in peripheral blood leucocytes (PBLs)
from 24 children with solid tumours after standard cisplatin and/or carboplatin
treatment. The relationship between Pt-DNA adduct levels and pharmacokinetics of
cisplatin and carboplatin was investigated. Adduct measurements were performed by
competitive enzyme-linked immunosorbent assay (ELISA) and plasma unbound Pt
concentrations were measured by atomic absorption spectrophotometry (AAS). There
was considerable interindividual variation in Pt-DNA adduct level that was weakly
correlated (r2 = 0.32) with the area under the unbound drug concentration vs time
curve (AUC) at 6 h after the start of cisplatin infusion, indicating that the
variation in Pt-DNA adduct levels was primarily determined by factors other than
AUC. No clear relationship between AUC and adduct levels was seen at 24 and 48 h
after cisplatin or at 6, 24 or 48 h after carboplatin. Carboplatin produced lower
levels of immunoreactive adducts than did cisplatin (1.3 +/- 0.6 nmol Pt g-1 DNA
vs 3.2 +/- 1.7 nmol Pt g-1 DNA), despite a 20-fold higher unbound drug AUC for
carboplatin (8.0 +/- 3.5 mg ml-1 min vs 0.4 +/- 0.2 mg ml-1 min). This study
demonstrates that, after cisplatin and carboplatin treatment the drug-target
interaction is determined by both pharmacokinetic and, predominantly, cellular
factors. Intrinsic differences between the two complexes, primarily reactivity,
probably explain the lower adduct levels observed after carboplatin treatment.
PMID- 9400944
TI - A phase I/II study of a hypoxic cell radiosensitizer KU-2285 in combination with
intraoperative radiotherapy.
AB - A fluorinated 2-nitroimidazole radiosensitizer KU-2285 was given before
intraoperative radiotherapy (IORT) to 30 patients with unresectable, unresected
or macroscopic residual tumours. Twenty-three patients had pancreatic cancer and
five had osteosarcoma. The IORT dose was 30 Gy for unresectable pancreatic cancer
and 60 Gy for osteosarcoma. The dose of KU-2285 administered ranged from 1 to 9 g
m-2. Four patients received a dose of 9 g m-2, and ten received 6.8-7 g m-2. All
patients tolerated KU-2285 well, and no drug-related toxicity was observed. The
average tumour concentration of KU-2285 immediately after IORT was 166 microg g-1
at dose of 6.8-7 g m-2 and 333 microg g-1 at 9 g m-2. The average tumour-plasma
ratio was > or = 0.82. Eleven patients with unresectable but localized pancreatic
cancer treated with KU-2285 plus IORT and external beam radiotherapy had a median
survival time of 11 months and 1-year local control rate of 50%, which compares
favourably with those of 8 months (P = 0.26) and 28% (P = 0.10) for 22 matched
historical control patients. The five patients with osteosarcoma attained local
control. The results of this first study on KU-2285 and IORT appear encouraging,
and further studies of this compound seem to be warranted.
PMID- 9400945
TI - Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and
bile.
AB - Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that
this prodrug could be used to overcome the solubility limitations and erratic
bioavailability of oral etoposide. To investigate the possibility of prodrug
conversion to etoposide within the gastrointestinal lumen, etoposide phosphate
was dissolved in water and incubated with human gastric juice or human bile in
vitro. Samples were collected during 150 min and analysed for etoposide
concentration with high-performance liquid chromatography. Conversion of prodrug
to etoposide during incubation with gastric juice was negligible. There was
significant conversion during incubation with bile at pH 7-8. The percentage of
prodrug converted to etoposide at pH 8 after 60 min was 78 +/- 18% (mean +/-
S.D.) for a 0.1 mg ml-1 prodrug solution and 36 +/- 26% for 0.5 mg ml-1. At pH 7,
after 60 min 22% of prodrug was converted to etoposide when incubated at 0.1 mg
ml-1 and 10% at 0.5 mg ml-1. No conversion was found after inactivation of
alkaline phosphate (AP) by overnight heating of bile at 65 degrees C or by the
addition of disodium edetate to the bile. In conclusion, because of AP in bile,
variable conversion of etoposide phosphate to etoposide can be expected within
the intestinal lumen after oral administration. This could have important
pharmacokinetic consequences.
PMID- 9400946
TI - A prospective study of surgery and adjuvant chemotherapy for primary gastric
lymphoma stage II.
AB - The standard management of primary gastric lymphoma (PGL) (stage II) has not been
established despite the use of various treatment modalities. The present
prospective trial of combined surgery and chemotherapy for the treatment of PGL
(stage II) included 25 consecutive patients treated between July 1978 and
December 1993. Twenty-one patients were treated with total gastrectomy and four
with partial gastrectomy; this was followed by post-operative chemotherapy with m
VEPA (vincristine, cyclophosphamide, prednisolone and doxorubicin), followed by
consolidation chemotherapy with VEMP (vindesine, cyclophosphamide, methotrexate
and prednisolone) or VQEP (vindesine, carbazilquinone, cyclophosphamide and
prednisolone). Twenty-one of the 25 patients who completed post-operative
chemotherapy were free of relapse 26-203 (median 94) months after the
gastrectomy. Of the four patients who did not complete the projected
chemotherapy, two relapsed and died of lymphoma. Another patient with recurrent
lymphoma died in an accident, and the fourth patient was in remission at 54
months after surgery. The post-operative overall and disease-free survival rates
at 10 years for the 25 evaluable patients were 81.6% and 92.0% respectively.
Major surgical complications and treatment-related death after chemotherapy were
not observed. PGL (stage II) appears to be curable when treated with gastrectomy
and adjuvant chemotherapy.
PMID- 9400947
TI - Phase I study of gemcitabine using a once every 2 weeks schedule.
AB - Gemcitabine (2',2'-difluorodeoxycytidine) is a novel nucleoside analogue. As part
of a series of studies to determine the maximum tolerated dose (MTD) of
gemcitabine and the most appropriate schedule, a two-centre phase I study of
gemcitabine was undertaken in patients with advanced refractory solid tumours
using a once every 2 weeks schedule. Fifty-two patients were entered into the
study at 14 different dose levels (40-5700 mg m-2). Weekly evaluations for
toxicity were performed and the MTD for this once every 2 weeks schedule was 5700
mg m-2. The dose-limiting toxicity was myelosuppression, with neutropenia being
most significant. Other toxicities were nausea, vomiting, fever and asthenia. One
minor response was seen in a heavily pretreated breast cancer patient treated at
1200 mg m-2. Preclinical studies suggest that the efficacy of gemcitabine is more
schedule than dose related, and it is concluded that this is not the most
appropriate dosing schedule for gemcitabine. However, this study demonstrates the
safety profile of gemcitabine, as doses over fourfold greater than that
recommended for the weekly schedule of 1000 mg m-2 could be tolerated.
PMID- 9400948
TI - Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan)
and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung
cancer.
AB - We conducted a phase I study of irinotecan (CPT-11) and etoposide (VP-16) given
sequentially to untreated patients with metastatic non-small-cell lung cancer.
Arm A: CPT-11 was given over 90 min on days 1-3 and VP-16 was given over 60 min
on days 4-6. Arm B: VP-16 was given on days 1-3 and CPT-11 on days 4-6. G-CSF was
given to all patients daily on days 7-17. Twenty-seven patients were entered
randomly at the two arms. The major dose-limiting toxicities in arms A and B were
granulocytopenia and diarrhoea. Transient elevations of transaminases and
bilirubin were observed in both arms. The degree of the toxicities did not differ
between the two arms. The maximum tolerated doses (MTDs) were 60 mg m-2 CPT-11
and 60 mg m-2 VP-16 in both arms. Of the 13 patients who received more than two
cycles, two out of five achieved partial response (PR) at the first level of arm
A and one out of four achieved PR at the second level of arm B. We conclude that
these schedules of sequential CPT-11 and VP-16 administration were inappropriate
because of severe toxicities.
PMID- 9400949
TI - Phase I and pharmacological study of sequential intravenous topotecan and oral
etoposide.
AB - We performed a phase I and pharmacological study to determine the maximum
tolerated dose (MTD) and dose-limiting toxicities (DLT) of a cytotoxic regimen of
the novel topoisomerase I inhibitor topotecan in combination with the
topoisomerase II inhibitor etoposide, and to investigate the clinical
pharmacology of both compounds. Patients with advanced solid tumours were treated
at 4-week intervals, receiving topotecan intravenously over 30 min on days 1-5
followed by etoposide given orally twice daily on days 6-12. Topotecan-etoposide
dose levels were escalated from 0.5/20 to 1.0/20, 1.0/40, and 1.25/40 (mg m-2 day
1)/(mg bid). After encountering DLT, additional patients were treated at 3-week
intervals with the topotecan dose decreased by one level to 1.0 mg m-2 and
etoposide administration prolonged from 7 to 10 days to allow further dose
intensification. Of 30 patients entered, 29 were assessable for toxicity in the
first course and 24 for response. The DLT was neutropenia. At doses of topotecan
etoposide 1.25/40 (mg m-2)/(mg bid) two out of six patients developed neutropenia
grade IV that lasted more than 7 days. Reduction of the treatment interval to 3
weeks and prolonging etoposide dosing to 10 days did not permit further dose
intensification, as a time delay to retreatment owing to unrecovered bone marrow
rapidly emerged as the DLT. Post-infusion total plasma levels of topotecan
declined in a biphasic manner with a terminal half-life of 2.1 +/- 0.3 h. Total
body clearance was 13.8 +/- 2.7 l h-1 m-2 with a steady-state volume of
distribution of 36.7 +/- 6.2 l m-2. N-desmethyltopotecan, a metabolite of
topotecan, was detectable in plasma and urine. Mean maximal concentrations ranged
from 0.23 to 0.53 nmol l-1, and were reached at 3.4 +/- 1.0 h after infusion.
Maximal etoposide plasma concentrations of 0.75 +/- 0.54 and 1.23 +/- 0.57
micromol l-1 were reached at 2.4 +/- 1.2 and 2.3 +/- 1.0 h after ingestion of 20
and 40 mg respectively. The topotecan area under the plasma concentration vs time
curve (AUC) correlated with the percentage decrease in white blood cells (WBC)
(r2 = 0.70) and absolute neutrophil count (ANC) (r2 = 0.65). A partial response
was observed in a patient with metastatic ovarian carcinoma. A total of 64% of
the patients had stable disease for at least 4 months. The recommended dose for
use in phase II clinical trials is topotecan 1.0 mg m-2 on days 1-5 and etoposide
40 mg bid on days 6-12 every 4 weeks.
PMID- 9400951
TI - The role of occupation and a past history of malaria in the etiology of classic
Kaposi's sarcoma: a case-control study in north-east Sardinia.
AB - A case-control study was performed to determine the role of rural factors
including occupation and previous malaria exposure in the development of classic
Kaposi's sarcoma (CKS) in a high incidence area of Europe. The occurrence of CKS
association with other malignancies was also examined. The results showed that
the risk of having CKS was significantly increased in subjects farming cereals,
while a previous history of malaria did not influence the risk of developing CKS.
A near-significant increase in associated tumours was found.
PMID- 9400950
TI - Cisplatin and vinorelbine followed by ifosfamide plus epirubicin vs the opposite
sequence in advanced unresectable stage III and metastatic stage IV non-small
cell lung cancer: a prospective randomized study of the Southern Italy Oncology
Group (GOIM).
AB - A multicentric, prospective phase III study was carried out with the aim of
testing the so-called 'worst drug rule' hypothesis, which suggests the use of an
effective but 'less active' regimen that first eradicates tumoral cells resistant
to a second effective and 'more active' regimen. With respect to this hypothesis,
we considered the cisplatin plus vinorelbine regimen (CCDP/VNR) as the more
active regimen compared with the non-cisplatin-containing regimen of ifosfamide
plus high-dose epirubicin (IFO/EPI). Thus, a randomized study was carried out to
compare the sequencial strategy of three cycles of CDDP/VNR followed by three
cycles of IFO/EPI with the opposite sequence in advanced non-small-cell lung
cancer. A total of 100 consecutive previously untreated patients with stage III
IV non-small-cell lung cancer were centrally randomized in two arms according to
stage of disease and the performance status. Patients allocated to arm A received
CDDP (100 mg m-2 on day 1) plus VNR (25 mg m-2 i.v. on days 1 and 8) every 21
days for three cycles (step 1) followed, after restaging, by three cycles of IFO
(2.5 g m-2 with mesna on day 1) plus high-dose EPI (100 mg m-2 on day 1) every 21
days (step 2). Patients in arm B received the opposite sequence. Type and rates
of objective response were evaluated after step 1 and step 2 in agreement with
WHO criteria and an intent-to-treat analysis. Patients were also analysed for
toxicity patterns, time to progression and survival. After the first three cycles
(step 1), overall response rate (ORR), calculated according to an intent-to-treat
analysis, was 47% and 21% for arm A and arm B respectively (P = 0.0112). ORR for
stage III patients was 55% and 14% for arm A and B respectively (P = 0.0097). In
stage IV patients ORR was higher in arm A than in arm B (42% vs 28%) but not
statistically significant (P = 0.4). Clinical responses to the shift of
chemotherapy (step 2) showed that no patient pretreated with CDDP/VNR and
subsequently treated with IFO/EPI showed further response, whereas in the inverse
sequence arm CDDP/VNR was able to induce 26% partial response (PR) rate in
patients pretreated with IFO/EPI. This difference was statistically significant
(P = 0.037). The overall median time to progression (TTP) of arm A and arm B did
not significantly differ (6 vs 4 months; P = 0.665). However, median TTP of stage
III patients was, respectively, 7 months for arm A and only 3 months for arm B.
This difference was statistically significant (P = 0.049). Median overall
survival (OS) was 9 and 7 months respectively for arm A and arm B. Despite this
trend the difference was not significant (P = 0.328). Median OS of stage III
patients showed a statistically significant advantage for arm A over arm B (13 vs
7 months, P = 0.03). In addition, no statistically significant difference in OS
was recorded for stage IV patients (both arms 7 months, P = 0.526). Our data do
not confirm Day's 'worst drug rule' hypothesis, at least in patients with
advanced non-small-cell lung cancer treated with the above-mentioned regimens.
The combination of CDDP and VNR seems more active, at least in terms of response
rate, than the IFO/EPI, which performed poorly.
PMID- 9400952
TI - Melanoma risk and residence in sunny areas. EORTC Melanoma Co-operative Group.
European Organization for Research and Treatment of Cancer.
AB - Melanoma risk among subjects from Germany, France and Belgium who had lived for 1
year or more in sunny climates was examined in a one-to-one unmatched case
control study conducted among white subjects 20 years old or more. A total of 412
consecutive patients with melanoma diagnosed from 1 January 1991 onwards, were
derived from hospital registers; 445 controls were randomly chosen in the same
municipality as the cases. After adjustment for host characteristics, melanoma
risk associated with residence in a sunny area was 2.7 (95% CI: 1.4-5.2),
increasing to 4.7 (95% CI: 1.4-13.5) if subjects sought a suntan when residing in
sunny climates, and to 4.3 (95% CI: 1.7-11.1) if subjects arrived before the age
of 10 years in the sunny area. Residence in sunny areas and recreational sun
exposure seemed to combine their effects on melanoma risk. Increase in melanoma
risk conveyed by deliberate sun exposure during adulthood was highest among
subjects who had lived in sunny areas as a child or adolescent and lowest among
subjects who had never resided in sunny areas. Our results support conclusions
from migrant studies that indicated that childhood is a critical period of either
vulnerability to solar radiation or more frequent exposures to melanoma risk
factors. They also suggest that moderate sun exposure of an adult who was heavily
sun exposed in childhood is associated with a higher melanoma risk than that of
high sun exposure of an adult who was sun protected in childhood.
PMID- 9400953
TI - Childhood cancer and parental use of tobacco: deaths from 1971 to 1976.
AB - Parental smoking data have been reabstracted from the interview records of the
Oxford Survey of Childhood Cancers (deaths from 1971 to 1976). Reported smoking
habits for the parents of 2587 children who died with cancer were compared with
similar information for the parents of 2587 healthy controls (matched pairs
analysis). Maternal daily consumption of cigarettes and paternal use of pipes or
cigars were unimportant, but there was a statistically significant positive trend
between paternal daily consumption of cigarettes and the risk of childhood cancer
(P < 0.001). This association could not be explained by maternal smoking, social
class, parental ages at the birth of the survey child, sibship position or
obstetric radiography. Relations between maternal consumption of cigarettes and
birth weights suggested that (maternal) smoking data were equally reliable for
case and control subjects. About 14% of all childhood cancers in this series
could be attributable to paternal smoking. These data were combined with smoking
data from two previously published reports from the Oxford Survey (deaths from
1953 to 1955, deaths from 1977 to 1981) to obtain further information on risks
for different types of cancer and different ages at onset of disease. Paternal
cigarette smoking emerged as a potential risk factor both for the generality of
childhood cancer and for all ages at onset.
PMID- 9400955
TI - Efficient protein production using a Bombyx mori nuclear polyhedrosis virus
lacking the cysteine proteinase gene.
AB - Infection by a baculovirus (Bombyx mori nuclear polyhedrosis virus, BmNPV) in
silkworm (Bombyx mori) larvae is highly efficient as an expression system for the
production of useful proteins. However, the amount of the protein of interest
expressed tends to decrease in the later stages of infection presumably due, in
part, to a proteinase produced in the larval haemolymph. The N-terminal amino
acid sequence of a proteinase purified from the haemolymph of BmNPV-infected
larvae was identical to the internal amino acid sequence of the viral cysteine
proteinase gene of BmNPV, suggesting that the cysteine proteinase in the
haemolymph originated from the BmNPV gene. We constructed a mutant virus (CPd)
which had a deletion in the cysteine proteinase gene. No proteinase activity
corresponding to this proteinase was detected in the haemolymph of silkworm
larvae infected with CPd. The firefly luciferase and the human growth hormone
genes were separately introduced into CPd under control of the polyhedrin
promoter. These constructs produced these proteins very efficiently, because of a
greatly reduced degree of degradation of these proteins. A BmNPV vector system
using CPd enhances the stability of foreign expressed proteins, especially for
those that are cysteine proteinase-sensitive.
PMID- 9400954
TI - Alcohol, tobacco and recreational drug use and the risk of non-Hodgkin's
lymphoma.
AB - A population based case-control study was conducted to determine whether risk of
non-Hodgkin's lymphoma (NHL) in the absence of HIV infection is related to the
previous use of tobacco, alcohol or recreational drugs. A total of 378 residents
of Los Angeles County who were diagnosed with high- or intermediate-grade NHL
were compared with individually age-, race- and sex-matched neighbourhood control
subjects with regard to history of use of tobacco products, alcohol and ten
specific recreational drugs. Risk of NHL among women decreased with increased
consumption of alcoholic beverages (trend P = 0.03), with risk 50% lower among
those consuming five or more drinks per week than among non-drinkers. Cocaine,
amphetamines, Quaaludes and lysergic acid diethylamide (LSD) were each associated
with a significantly increased risk of NHL in men with risk greater among those
with more frequent use of these drugs. Confounding factors could not be excluded
in these findings. The use of multiple types of drugs was also associated with a
significantly increased risk of NHL in men (trend P = 0.005) with risk greatest
among those using five or more types of drugs (odds ratio = 5.8, 95% confidence
limits = 1.2-28.4); among these drugs, cocaine use appeared to account for the
elevated risk of NHL among men based on multivariable analyses.
PMID- 9400956
TI - Binding and fusion of Autographa californica nucleopolyhedrovirus to cultured
insect cells.
AB - Binding of baculoviruses to insect cells and fusion of the virus envelope to cell
membranes are early events suggested to be affected by baculovirus enhancins. The
binding of Autographa californica nucleopolyhedrovirus (AcMNPV) to the Spodoptera
frugiperda cell line Sf21 and the fusion of the virus envelope to cell membranes
were characterized. Virus binding assays demonstrated that AcMNPV budded virus
(BV) bound to specific binding sites on Sf21 cells with an avidity of 2.3 x
10(10) M(-1). The cells displayed 3.1 x 10(3) specific binding sites per cell in
a confluent monolayer. In addition, the effects of pH, buffer composition and
cation concentration on the binding were examined. Using a fluorescent probe
(R18) and fluorescence microscopy, the fusion of AcMNPV BV envelope to the cell
membrane was directly visualized in living cells. It has been reported that
Trichoplusia ni nucleopolyhedrovirus enters Sf21 cells by membrane fusion at the
cell surface; however, the present studies confirmed the well established concept
that adsorptive endocytosis is the major entry pathway for baculovirus BV
infection. Membrane fusion kinetics and fluorescence microscopy demonstrated and
verified that the envelope-cell membrane fusion was triggered by acidification.
The effect of a T. ni granulovirus enhancin on virus binding and membrane fusion
was examined, and no increase in activity was observed.
PMID- 9400957
TI - Analysis of p74, a PDV envelope protein of Autographa californica
nucleopolyhedrovirus required for occlusion body infectivity in vivo.
AB - In nature, nuclear polyhedrosis viruses (NPV) are transmitted when susceptible
insect larvae ingest viral occlusion bodies (OB). These dissociate in the
alkaline environment of the midgut and release encapsulated virions (PDV) which
bind to midgut epithelial cells and initiate an infection. A previous study
showed that expression of the Autographa californica NPV (AcMNPV) p74 gene during
replication is essential for the production of infectious OB. A set of p74
deletion and overexpression recombinants was used for the production and
screening of monoclonal antibodies, and for an investigation of gross
cytopathology and localization of p74. No differences in virus structure or
morphogenesis were observed in infected cells when the p74 gene of AcMNPV was
deleted, even though the infectivity of OB harvested from the cells was abolished
when they were fed to Trichoplusia ni larvae. Mutant OB released virus particles
and degraded insect peritrophic membrane as in infections with wild-type virus;
in addition, virions purified from mutant OB were infectious when injected into
the haemocoel of T. ni larvae. Western blot analysis confirmed that p74 was
associated with the PDV and could not be detected in the budded form virion
phenotype. The polypeptide was readily degraded by treatment of purified PDV with
proteinase K, in the presence and absence of detergent, and could be extracted
from PDV by a non-ionic detergent treatment. The data are consistent with p74
being a structural polypeptide of the PDV phenotype, most probably as a component
associated with the outside surface of the virion envelope. Its presence is shown
to be essential for primary infection of midgut cells of insect larvae.
PMID- 9400958
TI - Characterization of a putative Spodoptera exigua multicapsid nucleopolyhedrovirus
helicase gene.
AB - Putative baculovirus helicases have been implicated as playing an important role
in viral DNA replication and host specificity. The Spodoptera exigua multicapsid
nucleopolyhedrovirus (SeMNPV) helicase is therefore of interest since the virus
only infects the beet army worm. Sequence analysis of the SeMNPV lef5-p39 (mu
46.5-55.1) region, which is collinear with the 39K-lef5 area in Autographa
californica MNPV (AcMNPV), revealed an open reading frame (ORF) of 3666 bp
potentially encoding a protein with a molecular mass of 143 kDa. This protein had
considerable amino acid sequence similarity (58%) to AcMNPV p143, including seven
conserved motifs characteristic of helicases. In cultured insect cells, this
SeMNPV ORF is expressed from 4 to 12 h postinfection and its major transcript of
4 kb starts 11 to 12 nt upstream of the putative translational initiation site
(ATG). To study their possible role in the specificity of baculovirus DNA
replication, the putative AcMNPV and SeMNPV helicase genes were tested for their
ability to replicate homologous regions (hrs; putative origins of DNA
replication) in a transient DNA replication assay in insect cells. All viral cis-
and trans-acting factors were provided as plasmids using either Achr2 or Sehr1 as
the DNA replication origin. SeMNPV p143 could not substitute for AcMNPV p143 in
the transient assays supplemented with either hr. Similar results were obtained
when the SeMNPV and AcMNPV ie1 genes were exchanged. None of the essential AcMNPV
trans-acting factors could be complemented by SeMNPV infections to support DNA
replication of hrs. These data suggest a specific interaction between baculovirus
DNA replication factors to form the replisome and/or between the replisome and
the origin of DNA replication.
PMID- 9400959
TI - Mapping of the Heliothis armigera entomopoxvirus (HaEPV) genome, and analysis of
genes encoding the HaEPV spheroidin and nucleoside triphosphate phosphohydrolase
I proteins.
AB - The genome of Heliothis armigera entomopoxvirus (HaEPV) has been mapped with four
restriction endonuclease enzymes (BamHI, HindIII, PstI and XhoI), and its length
estimated at 233 kbp. An EcoRI-generated HaEPV genomic fragment hybridized to all
fragments identified as genomic termini, providing the first experimental
evidence for the presence of terminal repeat elements in an EPV genome. The HaEPV
spheroidin and nucleoside triphosphate phosphohydrolase I (NPHI) genes have been
cloned and sequenced, and their deduced products shown to possess high levels of
identity with homologues from other Genus B entomopoxviruses (EPVs). The genomic
locations of these and other HaEPV genes and open reading frames have been
determined; comparison of their locations with those of homologues in the Amsacta
moorei EPV genome largely supports an hypothesis that the Genus B EPVs share a
conserved genomic organization which differs from that of chordopoxviruses. It is
proposed that genes of EPVs can be assigned to five actual or predicted homology
based groups, a categorization which is useful for directing and interpreting
investigations of EPV gene functions and relationships.
PMID- 9400961
TI - Hypothesis on particle structure and assembly of rice dwarf phytoreovirus:
interactions among multiple structural proteins.
AB - To study the morphogenesis and packaging of rice dwarf phytoreovirus (RDV), the
interactions among multiple structural proteins were analysed using both the
yeast two-hybrid system and far-Western blotting analysis. The following protein
protein interactions were observed. P3 (major core protein) bound to itself as
well as to P7 (nucleic acid-binding protein) and P8 (major outer capsid protein).
P7 bound to P1 (RNA-dependent RNA polymerase) and P8, in addition to P3. Based on
these findings, we hypothesize that the core shell structure is based on P3-P3
interactions and that P7 has the ability to bind to multiple structural proteins
as well as to genomic RNAs during viral particle assembly. Based on the observed
protein-protein interactions and on computer-aided analysis of the numbers of
structural proteins per particle, possible RDV assembly events are proposed.
PMID- 9400960
TI - Excision of the polydnavirus chromosomal integrated EP1 sequence of the
parasitoid wasp Cotesia congregata (Braconidae, Microgastinae) at potential
recombinase binding sites.
AB - Cotesia congregata polydnavirus (CcPDV) is essential for successful parasitism of
Manduca sexta larvae by the braconid wasp Cotesia congregata. To determine the
molecular mechanisms for the vertical transmission of CcPDV in the wasps, we
analysed the different forms of the virus sequences containing the gene encoding
the early parasitism-specific protein 1 (EP1). By a detailed molecular analysis,
we demonstrated that the EP1 sequences are present in wasp DNA in two forms: a
circular form as seen in the virus particles and a form integrated into the wasp
genome. Moreover, we showed that the integrated form of the EP1 sequences is able
to excise in the ovary cells. A fragment corresponding to an EP1 'empty locus'
(without the viral sequence) was PCR-amplified from ovarian DNA. Comparison of
the sequences isolated from the EP1 circle, the integrated form and the empty
locus revealed that the extremities of the EP1 genomic sequences constitute a
direct repeat. Strikingly, these sequences contain a potential binding site for a
recombinase of the Hin family located in close vicinity to the position where the
DNA strand exchange occurs. Thus, the data bear upon the possibility that the
bracovirus circles are excised via a mechanism related to the Hin mediated
Conservative Specific-Specific Recombination (CSSR) of prokaryotes.
PMID- 9400962
TI - Infectious in vivo and in vitro transcripts from a full-length cDNA clone of PVY
N605, a Swiss necrotic isolate of potato virus Y.
AB - A full-length cDNA clone of the potato virus Y (PVY) genome was obtained after
cloning difficulties in Escherichia coli were overcome. These difficulties were
mainly due to the expression of the CI gene from upstream prokaryotic promoter
like elements within the PVY genome. To overcome this problem, PVY cDNA was
maintained in two subclones which were ligated before infection. A plasmid in
which these two fragments were contained could be propagated in some E. coli
strains but was unstable and yielded only low levels of plasmid DNA. Replacement
of the 35S promoter by the SP6 promoter slightly increased the stability of the
plasmid and its RNA transcripts were infectious when capped with m7G(5')ppp(5')G.
Using two inoculation methods (mechanical or biolistic) the cDNA and its RNA
transcript proved infectious on three Nicotiana species and on Solanum tuberosum.
PMID- 9400963
TI - 35S promoter-driven cDNAs of barley mild mosaic virus RNA1 and RNA2 are
infectious on barley plants.
AB - Full-length cDNAs of barley mild mosaic bymovirus RNA1 and RNA2 were cloned
downstream of a modified cauliflower mosaic virus 35S promoter with double
enhancer. Mechanical inoculation of barley seedlings with a mixture of both cDNAs
resulted in systemic mosaic symptoms, typical of barley mild mosaic virus
infection. The presence of both RNA species and their gene products in the
systemically infected leaves was demonstrated by RT-PCR and Western blot
analyses, respectively. Virions were detected by immunogold labelling,
demonstrating that the RNAs are encapsidated. This is the first report of the 35S
promoter used in successfully infecting a monocot plant host with cDNA from a
strictly monocot plant RNA virus.
PMID- 9400964
TI - Variability of geographically distinct isolates of maize rayado fino virus in
Latin America.
AB - We have examined the molecular epidemiology of the leafhopper-borne maize rayado
fino virus (MRFV) in Latin America. The coat protein gene and 3' non-translated
region of 14 isolates of MRFV collected from Latin America and the United States
were sequenced and phylogenetic relationships examined. The nucleotide sequence
revealed remarkable conservation, with a sequence similarity of 88-99%.
Phylogenetic analysis of sequence data obtained from a 633 bp fragment showed
that MRFV has diverged into three main clusters, i.e. the geographically distinct
northern and southern isolates and the Colombian isolates. Significant
differences between the isolates collected from Colombia, previously named maize
rayado colombiana virus, based upon differences in symptomatology and serological
relationships to MRFV, and the other MRFV isolates, provides additional evidence
supporting its designation as a unique strain of MRFV.
PMID- 9400965
TI - Beet soil-borne virus RNA 1: genetic analysis enabled by a starting sequence
generated with primers to highly conserved helicase-encoding domains.
AB - The complete sequence of the 5834 nucleotides of RNA 1 of beet soil-borne
furovirus (BSBV, Ahlum isolate) was determined using a PCR product obtained with
primers to highly conserved coding regions for helicase-like proteins in RNA 1 of
furo-, hordei- and tobraviruses as a starting sequence. Unknown parts of the
sequence upstream and downstream of this starting sequence were amplified by
means of RT-PCR techniques using combinations of specific and random primers.
BSBV RNA 1 contains one large ORF for a readthrough protein with a molecular mass
of 204 kDa (204K protein) which is interrupted internally by a UAA stop codon
terminating the coding region for a protein of 145 kDa (145K protein). The N- and
C-terminal parts of the 145K protein and the readthrough domain of the 204K
protein contain methyltransferase, helicase and RNA-dependent RNA polymerase
motifs, respectively. Unlike other furo- and tobraviruses BSBV contains no
further genes on its RNA 1.
PMID- 9400966
TI - Isolation and characterization of tubular structures of cowpea mosaic virus.
AB - Tubular structures involved in the cell-to-cell movement of cowpea mosaic virus
(CPMV) were partially purified from infected cowpea protoplasts to identify the
structural components. A relatively pure fraction could be obtained by
differential centrifugation and this was analysed by PAGE and immunoblotting.
Besides the movement protein (MP) and capsid proteins (CP) of CPMV, no other
major infection-specific proteins could be detected, suggesting that host
proteins are not a major structural component of the movement tubule.
PMID- 9400967
TI - Replication of alfalfa mosaic virus RNA 3 with movement and coat protein genes
replaced by corresponding genes of Prunus necrotic ringspot ilarvirus.
AB - Alfalfa mosaic virus (AMV) and Prunus necrotic ringspot virus (PNRSV) are
tripartite positive-strand RNA plant viruses that encode functionally similar
translation products. Although the two viruses are phylogenetically closely
related, they infect a very different range of natural hosts. The coat protein
(CP) gene, the movement protein (MP) gene or both genes in AMV RNA 3 were
replaced by the corresponding genes of PNRSV. The chimeric viruses were tested
for heterologous encapsidation, replication in protoplasts from plants
transformed with AMV replicase genes P1 and P2 (P12 plants) and for cell-to-cell
transport in P12 plants. The chimeric viruses exhibited basic competence for
encapsidation and replication in P12 protoplasts and for a low level of cell-to
cell movement in P12 plants. The potential involvement of the MP gene in
determining host specificity in ilarviruses is discussed.
PMID- 9400968
TI - Hop stunt viroid (HSVd) sequence variants from Prunus species: evidence for
recombination between HSVd isolates.
AB - Hop stunt viroid (HSVd) is able to infect a number of herbaceous and woody hosts,
such as grapevine, Citrus or Prunus plants. Previous phylogenetic analyses have
suggested the existence of three major groups of HSVd isolates (plum-type, hop
type and citrus-type). The fact that these groups often contain isolates from
only a limited number of isolation hosts prompted the suggestion that group
discriminating sequence variations could, in fact, represent host-specific
sequence determinants which may facilitate or be required for replication in a
given host. In an effort to further understand the relationships between HSVd and
its different hosts, HSVd variants from eight naturally infected Prunus sources,
including apricot, peach and Japanese plum have been cloned and sequenced. In
total, ten molecular variants of HSVd have been identified, nine of which have
not been described before. A detailed phylogenetic analysis of the existing HSVd
sequences, including the new ones from Prunus determined in this work, points
towards a redefinition of the grouping of variants of this viroid, since two new
groups were identified, one of them composed of sequences described here. A bias
for the presence of certain sequences and/or structures in certain hosts was
observed, although no conclusive host-determinants were found. Surprisingly, our
analysis revealed that a number of HSVd isolates probably derived from
recombination events and that the previous hop-type group itself is likely to be
the result of a recombination between members of the plum-type and citrus-type
groups.
PMID- 9400969
TI - Characterization of genotype-specific epitopes of the HN protein of mumps virus.
AB - The SBL-1 strain of mumps virus, grouping with genotype A on the basis of the
small hydrophobic protein gene sequence, was grown in the presence of three
different monoclonal antibodies. The monoclonal antibodies were directed against
the haemagglutinin-neuraminidase (HN) protein and they inhibited
haemagglutinating activity and infectivity of the virus. The HN genes of the nine
neutralization-escape virus mutants were sequenced and the predicted amino acid
sequences were compared with that of the parental virus. Amino acid substitutions
were found at positions 269, 352 and 354, respectively, of the 582 amino acid
long protein. The three monoclonal antibodies did not react with 35 virus strains
isolated in Stockholm during the years 1970 to 1985. Thirteen and four of the
strains were found to belong to the D and C genotypes, respectively. A type
specific neutralization antibody response was also found in sera of rabbits
hyperimmunized with purified virions of genotype A and D. The genotype-specific
difference in neutralizing activity in mice and rabbits was not corroborated by
an overall difference in the amino acid sequence of the HN protein of the
different genotypes. Further studies are needed to explore the efficacy of mumps
virus vaccines for protection against homologous and heterologous genotypes of
mumps virus.
PMID- 9400970
TI - Recombinant vaccinia viruses expressing the F, G or N, but not the M2, protein of
bovine respiratory syncytial virus (BRSV) induce resistance to BRSV challenge in
the calf and protect against the development of pneumonic lesions.
AB - The immunogenicity and protective efficacy of recombinant vaccinia viruses (rVV)
encoding the F, G, N or M2 (22K) proteins of bovine respiratory syncytial virus
(BRSV) were evaluated in calves, the natural host for BRSV. Calves were
vaccinated either by scarification or intratracheally with rVV and challenged 6
to 7 weeks later with BRSV. Although replication of rVV expressing the F protein
in the respiratory tract was limited after intratracheal vaccination, the levels
of serum and pulmonary antibody were similar to those induced following
scarification. The serum antibody response induced by the F protein was biased in
favour of IgG1 antibody, whereas the G and the N proteins induced similar levels
of IgG1:IgG2, and antibody was undetectable in calves primed with the M2 protein.
The F protein induced neutralizing antibodies, but only low levels of complement
dependent neutralizing antibodies were induced by the G protein, and antibody
induced by the N protein was not neutralizing. The F and N proteins primed calves
for BRSV-specific lymphocyte proliferative responses, whereas proliferative
responses were detected in calves primed with the G protein only after BRSV
challenge. The M2 protein primed lymphocytes in only one out of five calves.
Although there were differences in the immune responses induced by the rVVs, the
F, G and N, but not the M2, proteins induced significant protection against BRSV
infection and, in contrast with the enhanced lung pathology seen in mice
vaccinated with rVV expressing individual proteins of human (H)RSV, there was a
reduction in lung pathology in calves.
PMID- 9400971
TI - Isolation of an avirulent mutant of Sendai virus with two amino acid mutations
from a highly virulent field strain through adaptation to LLC-MK2 cells.
AB - A field strain of Sendai virus (SeV) Ohita-M1 (M1) was isolated from an epidemic
in an animal laboratory by passaging in mice. A mutant strain, Ohita-MVC11
(MVC11), was then obtained by passaging M1 in rhesus monkey (LLC-MK2) cells.
MVC11 was adapted to LLC-MK2 cells and produced 20 times higher levels of
infectious virus than M1. This increased production of infectious virus in LLC
MK2 cells was associated with enhanced viral gene expression. However, MVC11
could not replicate efficiently in mouse lung and was not lethal to mice even
when inoculated at a titre of 8 x 10(5) cell-infecting units (CIU) per mouse. On
the other hand, with an inoculum of only 4 x 10(1) CIU per mouse, corresponding
to 1 LD50, M1 replicated well in mouse lung and was highly virulent to mice.
Nucleotide and deduced amino acid sequence analyses of the entire genomes of M1
and MVC11 revealed that adaptation to LLC-MK2 cells and the attenuation of mouse
pathogenicity of MVC11 were associated with only two amino acid substitutions;
one on the C protein (Phe substituted by Ser at position 170) and the other on
the RNA polymerase, the L protein (Glu substituted by Ala at position 2050).
PMID- 9400972
TI - Cell cycle arrest rather than apoptosis is associated with measles virus contact
mediated immunosuppression in vitro.
AB - Acute measles is associated with pronounced immunosuppression characterized both
by leukopenia and impaired lymphocyte functions. In an earlier study, we found
that mitogen-dependent proliferation of uninfected human peripheral blood
lymphocytes (PBLs) and spontaneous proliferation of human cell lines of
lymphocytic or monocytic origin was impaired after contact with UV-inactivated,
measles virus (MV)-infected cells, UV-inactivated MV or with cells transfected
with MV glycoproteins (gp) F and H. We now show that mitogen-stimulated PBLs and
Jurkat cell clones either highly sensitive or resistant to CD95-induced apoptosis
have a similar sensitivity to MV-induced inhibition and do not undergo apoptosis.
Moreover, unimpaired mitogen-dependent upregulation of important activation
markers, including IL-2R, was observed in PBL cultures after contact with MV
infected, UV-irradiated presenter cells. This indicates that the cells were
indeed viable and acquire a state of activation. Less IL-2 was released from PBLs
after contact with MV-infected presenter cells when compared with that released
after contact with uninfected cells. However, mitogen-induced proliferation of
PBLs was not restored by addition of IL-2 under these conditions. It appeared
that a higher fraction of mitogen-stimulated PBLs accumulated in the G0/G1 phase
of the cell cycle after contact with MV-infected cells. Thus, the mitogen
unresponsiveness of PBLs seen after contact with MV-infected cells is due to cell
cycle arrest rather than apoptosis.
PMID- 9400973
TI - Fine specificity of the antibody response to a synthetic peptide from the fusion
protein and protection against measles virus-induced encephalitis in a mouse
model.
AB - A synthetic peptide representing residues 397-420 from the measles virus (MV)
fusion (F) protein was tested for its structure, immunogenicity and protective
capacity against intracerebral challenge with a neuroadapted strain of MV.
Analysis of the peptide by mass spectrometry showed that it was linear, despite
the presence of two cysteine residues in the sequence. Circular dichroism
spectroscopy highlighted a weak preference for the peptide to adopt an alpha
helical conformation. The peptide was shown to be immunogenic in BALB/c and
C57BL/6 mice after intraperitoneal immunization in Freund's adjuvant, and anti
peptide antibodies from both strains of mice reacted with the MV as a solid phase
antigen on an ELISA plate. When the fine specificity of the anti-peptide antibody
response was examined using overlapping 8-mer peptides, serum antibodies from
BALB/c mice recognized the region between residues 407-417 whereas antibodies
from C57BL/6 mice recognized the region 408-420 of the 397-420 peptide sequence.
Although anti-397-420 antibodies had no demonstrable neutralizing activity,
protection against challenge with a neuroadapted strain of MV was demonstrated
following active immunization with peptide in C57BL/6 mice or after passive
transfer of anti-peptide antibodies in BALB/c mice. These findings highlight the
importance of the 397-420 region in the induction of protective antibodies in the
MV encephalitis mouse model, and suggest that this epitope might be a good
candidate for inclusion in a future MV synthetic peptide vaccine.
PMID- 9400974
TI - Biosynthesis, intracellular transport and enzymatic activity of an avian
influenza A virus neuraminidase: role of unpaired cysteines and individual
oligosaccharides.
AB - Intracellular transport, glycosylation, tetramerization and enzymatic activity of
the neuraminidase (NA) of fowl plague virus (FPV) were analysed in vertebrate
cells after expression from a vaccinia virus vector. Tetramerization occurred
with a half-time of 15 min, whereas passage through the medial Golgi apparatus
and transport to the plasma membrane occurred with half-times of 2 and 3 h,
respectively, suggesting a step in NA maturation beyond tetramerization that
limits the rate of transport to the medial Golgi. NA transport rates were about
fourfold slower than those of haemagglutinin (HA). Slow transport and processing
of FPV NA was not altered by coexpression of FPV HA, nor was the transport rate
of HA influenced by NA. The slow transport kinetics of NA were also observed in
FPV-infected CV-1 cells. As deduced from the coding sequence, FPV NA has the
shortest stalk of all naturally occurring NAs described to date and contains only
three potential N-glycosylation sites, which are all located in the globular head
domain. Elimination of each of the three N-glycosylation sites revealed that the
two oligosaccharides at positions 124 and 66 are of the complex type, whereas the
one at Asn-213 remains in mannose-rich form. The glycosylation mutants showed
also that oligosaccharides at positions 124 and 213 of FPV NA modulate enzymatic
activity. Transport of NA is not influenced by single elimination of any of the
three oligosaccharide attachment sites. Mutational analysis of the three Cys
residues not involved in intrachain disulfide pairing revealed that Cys-49 in the
stalk of the NA molecule is responsible for the formation of disulfide-linked
dimers. Analysis of cysteine mutants of FPV NA also demonstrated that disulfide
linked dimers are not absolutely necessary for the formation of enzymatically
active tetramers but may stabilize the quaternary structure of NA.
PMID- 9400975
TI - Identification of a single genotype of hepatitis G virus by comparison of one
complete genome from a healthy carrier with eight from patients with hepatitis.
AB - Different isolates of a putative hepatitis virus called hepatitis GB virus C or
hepatitis G virus (HGV) have been cloned recently from patients with hepatitis.
This virus has also been found commonly in healthy carriers. We have cloned and
sequenced a complete HGV genome, designated HGVCN, from a healthy Chinese blood
donor. HGVCN shares 85.8-90.0% nucleotide sequence identity and 95.4-97.5% amino
acid identity with the eight available full-length HGV genomes. Furthermore, the
majority (82.8%) of the nucleotide substitutions found in HGVCN were synonymous
and a fairly uniform distribution of changes was found across the entire genome
without identification of any hypervariable region. When compared with the
African isolates GBVC and GBVC-EA, the HGVCN-encoded polyprotein contained a 31
amino acid N-terminal extension which was predicted to be a defective core-like
sequence. The sequences of the HGV E1 and E2 proteins displayed unique motifs and
were highly conserved. Phylogenetic analysis revealed that all nine complete HGV
isolates were closely related and that HGVCN grouped with the other Chinese HGV
isolate (HGVC964). Taken together, our findings suggest that there is one single
genotype of HGV and that the HGV genome cloned from the healthy carrier is not
significantly different from those derived from patient sera.
PMID- 9400976
TI - Molecular analysis of the differential restriction of human immunodeficiency
virus type 1 replication in neuronal cell lines.
AB - Human immunodeficiency virus type 1 (HIV-1) replication is restricted partially
in SK-N-MC and completely in SK-N-SH neuronal cells. To investigate the molecular
mechanism of this differential restriction of HIV-1 replication, cells infected
with HIV-1 were analysed for their steady-state levels of: total and unintegrated
HIV-1 DNA by DNA PCR, different species of HIV-1 RNA by RT-PCR, and HIV-1 p24
protein production by an ELISA procedure. We found that the kinetics of the
infection were slower and there was a lower level of accumulation of HIV-1
macromolecules (total and unintegrated circular DNA, unspliced and spliced RNAs
and viral proteins) in the SK-N-MC cells than in the permissive CEM cells. In SK
N-SH cells, HIV-1 DNA was only transiently detected during the first 24 h post
infection, and the unspliced RNA was detected up to 1 week post-infection.
However, the HIV-1 spliced RNAs and the 2-LTR circular DNA were not detected at
all during the course of infection. Both SK-N-MC and SK-N-SH cells showed higher
levels of HIV-1 DNA, RNA and p24 protein when infected with an HIV-1 (amphotropic
retrovirus) pseudotype, HIV-1B. However, the level of HIV-1 replication was still
lower in SK-N-SH than in SK-N-MC cells. Moreover, although the kinetics of viral
protein production were comparable in SK-N-MC cells infected with HIV-1B and CEM
cells infected with HIV-1, the overall level of virus replication was still much
lower in HIV-1B-infected SK-N-MC cells. These data suggest that the restriction
of HIV-1 replication in neuronal cell lines takes place at both virus-entry and
post-entry levels, and cellular factors may be involved in the differential
restriction of HIV-1 replication in these cells.
PMID- 9400977
TI - Salmonella typhimurium aroA recombinants and immune-stimulating complexes as
vaccine candidates for feline immunodeficiency virus.
AB - Two experimental feline immunodeficiency virus (FIV) vaccines were tested, either
alone or in combination, in four groups of cats (A-D). One vaccine (SL3261-FIV)
was composed of live attenuated Salmonella typhimurium aroA (SL3261) strains
expressing the capsid (Gag) and part of the envelope (Env) proteins of FIV. The
other was composed of FIV Gag and Env proteins incorporated into immune
stimulating complexes (iscom-FIV). Cats of group A were immunized four times with
SL3261-FIV. Cats of group B were immunized twice with SL3261-FIV and then twice
with iscom-FIV. Cats of group C were immunized twice with SL3261 expressing the B
subunit of cholera toxin (SL3261-CtxB) and then twice with iscom-FIV. Cats of
group D, which served as negative controls, were immunized twice with SL3261-CtxB
and then twice with iscom into which the Gag and Env proteins of simian
immunodeficiency virus (SIV) had been incorporated (iscom-SIV). Two weeks after
the last immunization, all cats were challenged with FIV. At this time, cats
immunized with iscom-FIV (groups B and C) showed strong plasma antibody responses
to Gag and Env, whilst these responses were weak or undetectable in the cats
immunized four times with SL3261-FIV (group A). Seven weeks after FIV challenge,
Env-specific antibody responses had increased considerably in cats of all groups
except group A. The mean virus loads in the cats of this group proved to be lower
than those of the other groups at all time points, indicating partial protection.
PMID- 9400979
TI - Regulatory interactions of transcription factor YY1 with control sequences of the
E6 promoter of human papillomavirus type 8.
AB - Human papillomavirus type 8 (HPV-8) is a strictly cutaneous oncogenic virus known
to induce malignant skin lesions in epidermodysplasia verruciformis patients. Our
study shows that sequences surrounding transcription start sites of the HPV-8
oncogene E6 (nt 175-179) and comprising the presumable CCAAC and TATA boxes of
the E6 promoter P175 contain a cluster of four motifs similar to the DNA
recognition site of the multifunctional cellular transcription factor yin-yang 1
(YY1). Using DNase I footprinting and gel retardation tests it could be
demonstrated that three of these motifs indeed act as YY1 binding sites. To test
their functional relevance for P175 activity, engineered YY1 binding site mutants
were analysed in the context of a P175 test vector using transient expression
assays with human keratinocytes. YY1 turned out to exert both positive and
negative effects upon the activity of the HPV-8 E6 promoter; binding of YY1 to a
site upstream of the promoter's cap-position (BS1) activated transcription,
whereas the downstream site (BS2) mediated repression. The second downstream YY1
binding site (BS3) seemed to play an auxiliary role, enhancing the negative
effect of YY1 BS2. These observations define YY1 as an important cellular protein
involved in the control of E6 oncogene expression of the skin-specific 'high
risk' HPV-8 and emphasize the potential regulatory role of sequences located
downstream of the transcription start site.
PMID- 9400978
TI - Role of the Fas/Fas ligand pathway in apoptotic cell death induced by the human T
cell lymphotropic virus type I Tax transactivator.
AB - Two distinct human diseases have been described in association with human T cell
lymphotropic virus type I (HTLV-I) infection: adult T cell leukaemia and tropical
spastic paraparesis/HTLV-I-associated myelopathy. Although comprehensive
understanding of specific mechanisms underlying pathogenesis of either disease
has not yet been achieved, the viral regulatory protein Tax is believed to play a
significant role. Previous studies demonstrated the potential of Tax to transform
host cells. Here, it is shown that the Tax transactivator has in addition the
potential to induce T cell death by apoptosis. Using an inducible system (Jurkat
cell line JPX-9), significant apoptotic cell death upon Tax expression was
observed. In an attempt to detect the cellular genes mediating this effect, it
was found that induction of Tax was associated with marked upregulation of the
Fas ligand (FasL) gene. Tax-induced apoptosis was inhibited when the Fas/FasL
pathway was interrupted by YVAD-cmk, the inhibitor of ICE-like proteases.
Transient expression experiments provided additional support for the putative
role of endogenous FasL in Tax-induced apoptosis. Upon cotransfection with Tax
expressing plasmid, the transcriptional activity of the FasL promoter was found
to be significantly upregulated in Jurkat cells and several other cell lines, as
measured by reporter gene expression. Furthermore, cotransfection using different
Tax mutants demonstrated that both CREB and NF-kappaB activation domains of Tax
protein were required for the transactivation to take effect.
PMID- 9400980
TI - Preferential virosomal location of underphosphorylated H5R protein synthesized in
vaccinia virus-infected cells.
AB - The phosphorylation state of vaccinia virus (VV) protein H5R synthesized in
infected cells was investigated by two-dimensional gel electrophoresis. Most of
the H5R protein was underphosphorylated (pI 5.9 to 6.8) and, on centrifugation of
cell lysates, was associated with virosomes sedimenting with nuclei. However,
about a quarter of the H5R protein synthesized was highly phosphorylated (pI
5.5), and this was the major form of the H5R protein present in cytoplasmic
extracts. Immunofluorescence of VV-infected cells in the absence of DNA
replication showed that underphosphorylated H5R protein, specifically recognized
by antibody, was abundantly distributed throughout the cytoplasm but also present
in punctate particles, whereas most of the B1R protein detected was in the
punctate particles. Late gene expression was not required for the H5R protein to
accumulate in virosomes--viral DNA synthesis was sufficient. The different
phosphorylation states and cytological locations of the H5R protein suggest it
has multiple roles in VV development.
PMID- 9400981
TI - Effective priming of neonates born to immune dams against the immunogenic
pseudorabies virus glycoprotein gD by replication-incompetent adenovirus-mediated
gene transfer at birth.
AB - One of the main limitations of the vaccination of neonates from vaccinated or
infected mothers is the interference by inherited maternal antibodies, which are
known to inhibit the immune response against both live and inactivated vaccines.
The efficiency of bypassing this inhibition by the transfer of an immunogenic
glycoprotein gene, the gD gene of pseudorabies virus (PRV), into neonates was
explored. The experiments were conducted in 1-day-old piglets, which are
immunocompetent at birth. The same transcription unit (gD of PRV under the
control of the adenovirus major late promoter) was delivered intramuscularly at
birth either in the form of naked DNA or cloned in the genome of a replication
defective adenovirus. A booster injection of a conventional live PRV vaccine
strain was given at 10 weeks of age, the replication of which was greatly
restricted by the residual amounts of colostral antibodies in control animals.
Piglets were challenged at the age of 16 weeks with a virulent PRV strain. The
replication-defective adenovirus was able to efficiently prime piglets born to
immune dams against gD in such a way that inoculation with the Bartha strain
protected them against a subsequent challenge with the same level of efficacy in
piglets born to naive or immune dams. In contrast, piglets born to immune dams
into which the gD gene was not transferred, or transferred as naked DNA at birth,
were not protected. These results open the way for early immunization of neonates
born to vaccinated or infected mothers.
PMID- 9400982
TI - Biologically safe, non-transmissible pseudorabies virus vector vaccine protects
pigs against both Aujeszky's disease and classical swine fever.
AB - Envelope glycoprotein D (gD) of pseudorabies virus (PRV) is essential for
penetration but is not required for cell-to-cell spread. When animals are
inoculated with a phenotypically complemented PRV gD mutant, the virus is able to
spread locally by means of direct cell-to-cell transmission, but progeny virions
released by infected cells are non-infectious because they lack gD. Therefore,
the virus cannot be transmitted from inoculated animals to other animals. This
property makes a PRV gD mutant an attractive candidate as a safe vaccine vector.
To examine whether a self-restricted, non-transmissible PRV mutant can be used as
a biologically safe vaccine vector, a gD/gE-negative PRV recombinant virus which
expresses envelope glycoprotein E2 of classical swine fever virus was
constructed. Vaccination of pigs showed that the recombinant virus was able to
protect pigs against both Aujeszky's disease and classical swine fever.
PMID- 9400983
TI - Cytokine production in the nervous system of mice during acute and latent
infection with herpes simplex virus type 1.
AB - Immunocytochemistry on serial paraffin sections was used to monitor the
production dynamics of cytokines (IL-2, IL-4, IL-6, IL-10, IFN-gamma and TNF
alpha) and viral antigens in the trigeminal ganglion (TG) and the central side of
the dorsal root entry zone (DRE) of mice, following infection of the cornea with
herpes simplex virus type 1. In normal TG, scattered satellite cells were TNF
alpha+ and in the DRE, TNF-alpha+ and/or low numbers of IL-6+ cells were
detected. On day 3 after infection, foci of TG neurons with viral antigens were
surrounded by large numbers of TNF-alpha+ and/or IL-6+ cells and low numbers of
IFN-gamma+ cells. IL-2+ and/or IL-4+ cells appeared later, when viral antigens
had almost cleared. In the TG, the most striking changes occurred with TNF-alpha,
with respect to its source (satellite cells, Schwann cells and infiltrating
cells) and the extent and long duration of its production. TNF-alpha was the
predominant cytokine throughout acute and latent infection and even by day 30,
numbers of satellite cells expressing this cytokine were three times higher than
those in normal ganglia. Moreover, in the DRE, TNF-alpha was the only cytokine
detected during virus clearance and again, its production continued, along with
that of IL-6, on days 20 to 30, in both infiltrating cells and astrocytes. Thus,
cytokines, particularly TNF-alpha and perhaps IL-6, from infiltrating cells and
resident glial cells may have a role both in virus clearance and in normal
homeostatic mechanisms in the nervous system such as repair and protection of
neurons from damage.
PMID- 9400984
TI - Herpes simplex virus type 1 immediate early protein IE63 shuttles between nuclear
compartments and the cytoplasm.
AB - Herpes simplex virus type 1 (HSV-1) immediate early protein IE63, an essential
nuclear protein, is pleiotropic in function and, at the post-transcriptional
level, inhibits RNA splicing, interacts with cellular splicing small nuclear
ribonucleoprotein particles (snRNPs), binds RNA and prevents the
nucleocytoplasmic transport of intron-containing mRNAs. Here it is reported that
IE63 is a nucleocytoplasmic shuttle protein able to travel from snRNP- and RNA
rich nuclear foci to the cytoplasm, where it accumulates during actinomycin D
treatment. This newly identified property suggests that IE63 facilitates nuclear
export of HSV-1 transcripts, in addition to retaining intron-containing
transcripts in the nucleus. The mechanism by which IE63 controls RNA export has
yet to be defined.
PMID- 9400985
TI - Herpes simplex virus 1716, an ICP 34.5 null mutant, is unable to replicate in CV
1 cells due to a translational block that can be overcome by coinfection with
SV40.
AB - Herpes simplex virus (HSV) mutants lacking the gene encoding infected cell
protein (ICP) 34.5 exhibit an attenuated phenotype in models of pathogenesis and
have been used for experimental cancer therapy. Recently it was shown that the
HSV ICP 34.5 protein functions to prevent the host cell-induced double-stranded
RNA-activated protein kinase (PKR)-dependent translational block that normally
occurs during virus infection. We now report that an HSV ICP 34.5 mutant called
HSV-1716 is unable to replicate in the simian kidney cell-derived line CV-1, due
to a translational block. Moreover, we find that this block can be overcome by
simian virus 40 (SV40). This has been shown directly by infecting CV-1 cells with
SV40 and HSV-1716 simultaneously, and indirectly via HSV-1716 infection of COS-1
cells (CV-1 cells transformed by an origin-defective mutant of SV40 that codes
for wild-type T antigen). The translational block is restored when infections are
done in the presence of the phosphatase inhibitor okadaic acid. These results
support, but do not directly prove, contentions that HSV ICP 34.5 interacts with
the PKR pathway to restore translation in non-permissive cells, and that SV40
large T antigen has a similar functional role, but acts downstream of the site of
ICP 34.5 interaction (eIF2alpha) in the pathway. Study of this CV-1/COS-1 system
should allow further clarification of the virus-host interactions that underlie
the restricted replication of HSV-1 ICP 34.5 gene null mutants.
PMID- 9400987
TI - Development of a model for cytomegalovirus infection of oligodendrocytes.
AB - The well-characterized human oligodendroglioma (HOG) cell line, cells of which
resemble immature oligodendrocytes, was used to investigate the level of
permissiveness to human cytomegalovirus (CMV) infection. Expression of CMV genes
was incomplete following exposure of HOG cells to CMV, in contrast with results
observed with the astroglioma cell line U373-MG (used as a positive control).
However, treatment with phorbol 12-myristate 13-acetate (PMA) or with dibutryl
cAMP (dbcAMP) plus the phosphatase inhibitor 1-isobutyl-3,3-methyl xanthine
(IBMX) rendered the HOG cells fully permissive to CMV; down-regulation of HLA
class I and production of virions were only observed under these conditions. In
contrast to the findings seen with the HOG cell line, treatment of U373-MG cells
with dbcAMP/IBMX or PMA did not interfere with CMV-induced down-regulation of HLA
class I. However, these chemical stimulators reduced virus production in U373-MG
cells by 30 and 70%, respectively.
PMID- 9400986
TI - Analysis of cyclin-dependent kinase activity after herpes simplex virus type 2
infection.
AB - Small DNA viruses (adenoviruses, simian virus 40, or human papillomaviruses)
induce S-phase progression but prevent cell division to provide precursors for
viral DNA replication. Herpes simplex viruses types 1 or 2 (HSV-1 or HSV-2)
contain genes which encode DNA-metabolizing enzymes, for example, ribonucleotide
reductase, thymidine kinase and dUTPase, suggesting that S-phase factors are not
required for an efficient infection. However, several studies indicated that HSV
induces some events that occur during cell-cycle progression. To determine if HSV
2 induces S-phase entry, we examined serum-arrested African green monkey kidney
cells (CV-1) after infection. Two hours after infection steady-state levels of
the S-phase-specific cyclin, cyclin A, increased. S-phase cyclin-dependent kinase
activity (CDK2) was stimulated 10-fold 8 h after infection but decreased at 16 or
24 h after infection. Mitotic CDK activity (CDC2) was not activated after
infection, in part due to decreases in CDC2 protein levels and inactivation of
enzymatic activity resulting from tyrosine phosphorylation of CDC2. Furthermore,
CDK4 activity was not dramatically affected by infection. These studies indicate
that HSV-2 infection selectively activates CDK2 after infection but cell-cycle
progression does not occur. We hypothesize that infection activates certain
components of the cell cycle which enhance viral gene expression and DNA
replication.
PMID- 9400988
TI - PCR amplification is more sensitive than tissue culture methods for Epstein-Barr
virus detection in clinical material.
AB - In this study we have compared the use of PCR and conventional tissue culture
methods to detect Epstein-Barr virus (EBV) in peripheral blood mononuclear cells
and throat wash samples. The study population included 29 healthy adult and 20
immunocompromised EBV-seropositive donors. The results show significantly higher
EBV detection rates by PCR than the tissue culture methods in throat wash samples
from both donor groups (P < 0.01 in healthy donors and P < 0.009 in the
immunocompromised donors) and in peripheral blood from the immunocompromised but
not from the healthy donors (P < 0.008). Furthermore, when EBV DNA detection
rates in throat wash cell pellet and supernatant fluid were compared, a higher
positive result was obtained with the cell pellets which reached statistical
significance in the immunocompromised group (P < 0.02). No correlation was found
between positivity in throat wash and peripheral blood from the same donors.
PMID- 9400989
TI - Expression of Epstein-Barr virus BMRF-2 and BDLF-3 genes in hairy leukoplakia.
AB - The high level of Epstein-Barr virus (EBV) replication found in hairy leukoplakia
(HL) provides a unique opportunity to study EBV expression in the oral
epithelium. Screening of a cDNA library from an HL biopsy revealed expression of
two genes not previously described in vivo: BMRF-2 and BDLF-3. Sequence analysis
of the cDNAs demonstrated several nucleotide changes from the B95-8 sequence. In
all six different HL strains studied, only one amino acid change was found in
BMRF-2 relative to B95-8 and two amino acid changes were found in the BDLF-3 ORF.
mRNA expression of both genes was localized to the lower prickle cell layer of
the tongue epithelium. BMRF-2 protein expression was primarily detected in the
cell nuclei of the upper prickle cell layer; immunoelectron microscopy revealed
that BMRF-2 was associated with the nuclear chromatin. BDLF-3 protein expression
was observed in the perinuclear space and cytoplasm of the prickle cells. BDLF-3
has recently been identified as a virion-associated protein, but the functions of
BMRF-2 and BDLF-3 have not been elucidated.
PMID- 9400990
TI - Involvement of cdc2-mediated phosphorylation in the cell cycle-dependent
regulation of p185neu.
AB - We previously reported cell cycle-dependent negative regulation of p185neu
(decreased tyrosine phosphorylation and kinase activity, with electrophoretic
mobility retarded by serine/threonine phosphorylation) in M phase and the escape
of mutation-activated p185neu* from this regulation. Our present results showed
that retardation of electrophoretic mobility occurs independently of the cells'
transformed status. We found that normal p185neu lost its ability to dimerize in
the M phase. We demonstrated a physical association between cdc2 (a
serine/threonine kinase, active in M phase) and p185neu. We showed that the
carboxy terminal portion of p185neu is phosphorylated in vitro by cdc2. Many
phosphopeptides (at least three phosphoserine residues) unique to the M phase
were identified, and the in vivo and in vitro phosphopeptide patterns were
superimposable. In contrast, mutation-activated p185neu* dimerized in the M phase
with no changes in electrophoretic mobility, failed to associate with cdc2 and no
unique phosphoserine residues could be identified in the M phase (data not
shown), consistent with the escape of p185neu* from cell cycle-dependent
regulation. Our results suggest that this escape is an intrinsic property of the
mutation-activated p185neu* independent of its ability to transform cells. Our
results also suggest the involvement of serine/threonine kinases such as cdc2 in
the cell cycle-dependent negative regulation of p185neu.
PMID- 9400991
TI - Modular organization of the E2F1 activation domain and its interaction with
general transcription factors TBP and TFIIH.
AB - The transcriptional activator E2F1 regulates the expression of genes at the G1/S
boundary. We have characterized interactions of the E2F1 activation domain with
two general transcription factors, the TATA-box binding protein (TBP) and TFIIH.
Two distinct binding sites on E2F1 were identified for TBP (amino acids 386-417
and 415-437) each of which supported activation in mammalian cells when expressed
as a fusion to a heterologous DNA-binding domain. Neither of these minimal
activation domains independently bound TFIIH; rather, the TFIIH binding site of
E2F1 overlaps both domains. Loss of TFIIH-binding by E2F1 resulted in a 60-65%
reduction in transactivation, suggesting that the E2F1/TFIIH interaction is
important, but not essential, for transactivation. The retinoblastoma protein
(Rb) binds directly to E2F1 and represses E2F1-mediated transactivation. We have
demonstrated that recombinant Rb can compete with TBP and the p62 subunit of
TFIIH for binding to immobilized E2F1. A tumorigenic form of Rb deficient in
repressing E2F1-mediated transactivation is likewise deficient in displacing TBP
from E2F1. We propose that competition between Rb and both TBP and TFIIH for
binding to E2F1 is a mechanism by which Rb inhibits transactivation by E2F1.
PMID- 9400992
TI - Influence of ATM function on telomere metabolism.
AB - The ATM gene product, which is defective in the cancer-prone disorder ataxia
telangiectasia, has been implicated in mitogenic signal transduction, chromosome
condensation, meiotic recombination and cell cycle control. The ATM gene has
homology with the TEL1 gene of yeast, mutations of which lead to shortened
telomeres. To test the hypothesis that the ATM gene product is involved in
telomere metabolism, we examined telomeric associations (TA), telomere length,
and telomerase activity in human cells expressing either dominant-negative or
complementing fragments of the ATM gene. The phenotype of RKO colorectal tumor
cells expressing ATM fragments containing a leucine zipper (LZ) motif mimics that
of ataxia telangiectasia (A-T) cells. These transfected RKO cells relative to
transfected controls had a higher frequency of cells with TA and shortened
telomeres, but no detectable change in telomerase activity. In addition, the
percentage of cells with TA after gamma irradiation was higher in the transfected
RKO cells with dominant negative activity of the ATM gene, compared to control
cells. SV40 transformed fibroblasts derived from an A-T patient and transfected
with a complementing carboxyl terminal kinase region of the ATM gene had a
reduced frequency of cells with TA, with no effect on the telomere length or
telomerase activity. The present studies using isogenic cells with manipulated
ATM function demonstrate a role for the ATM gene product in telomere metabolism.
PMID- 9400993
TI - High frequency of p53 mutations in human oral epithelial dysplasia and primary
squamous cell carcinoma detected by yeast functional assay.
AB - To determine the timing and actual incidence of p53 mutations in oral epithelial
lesions, we examined 33 primary squamous cell carcinomas (SCCs), 14 dysplasias
and six hyperplasias from Japanese patients by a combination of yeast functional
assay and DNA sequencing. The assay detects mutations of p53 mRNA between codons
67 and 347 on the basis of the DNA-binding activity of the protein. Twenty-six
SCCs (79%) and five dysplasias (36%) were positive for p53 mutation, while all
six hyperplasias were negative for the mutation. Human papillomavirus type 16 E6
mRNA was detected in one of seven p53 mutation-negative SCCs by reverse
transcription polymerase chain reaction (RT-PCR). We further examined p53
mutations in 17 Sri Lankan oral SCCs using the yeast functional assay and the
single-strand conformation polymorphism analysis of PCR-amplified DNA fragments
(PCR-SSCP) of exon 5-8. The mutations were confirmed by DNA sequencing and the
detection sensitivity was compared between the two methods. Six samples (35%)
were positive for p53 mutation in PCR-SSCP analysis, while nine samples (53%)
were positive in yeast functional assay. This suggests that the incidence of p53
mutations has been considerably underestimated in the conventional SSCP analysis.
The present data indicate that p53 mutations are extremely frequent in oral
cancers in the Japanese, and suggest that the timing and significance of p53
mutation in oral tumor progression vary in different ethnic populations and
areas.
PMID- 9400994
TI - Identification and characterization of R-ras3: a novel member of the RAS gene
family with a non-ubiquitous pattern of tissue distribution.
AB - Members of the Ras subfamily of GTP-binding proteins, including Ras (H-, K-, and
N-), TC21, and R-ras have been shown to display transforming activity, and
activating lesions have been detected in human tumors. We have identified an
additional member of the Ras gene family which shows significant sequence
similarity to the human TC21 gene. This novel human ras-related gene, R-ras3,
encodes for a protein of 209 amino acids, and shows approximately 60-75% sequence
identity in the N-terminal catalytic domain with members of the Ras subfamily of
GTP-binding proteins. An activating mutation corresponding to the leucine 61
oncogenic lesion of the ras oncogenes when introduced into R-ras3, activates its
transforming potential. R-ras3 weakly stimulates the mitogen-activated protein
kinase (MAPK) activity, but this effect is greatly potentiated by the co
expression of c-raf-1. By the yeast two-hybrid system, R-ras3 interacts only
weakly with known Ras effectors, such as Raf and RalGDS, but not with RglII. In
addition, R-ras3 displays modest stimulatory effects on trans-activation from
different nuclear response elements which bind transcription factors, such as
SRF, ETS/TCF, Jun/Fos, and NF-kappaB/Rel. Interestingly, Northern blot analysis
of total RNA isolated from various tissues revealed that the 3.8 kilobasepair
(kb) transcript of R-ras3 is highly restricted to the brain and heart. The close
evolutionary conservation between R-ras3 and Ras family members, in contrast to
the significant differences in its biological activities and the pattern of
tissue expression, raise the possibility that R-ras3 may control novel cellular
functions previously not described for other GTP-binding proteins.
PMID- 9400995
TI - Upregulation of the angiogenic factors PlGF, VEGF and their receptors (Flt-1, Flk
1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed
rats suggest a TSH-dependent paracrine mechanism for goiter hypervascularization.
AB - Placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF)
represent two closely related angiogenic growth factors active as homodimers or
heterodimers. Since goiters of the thyroid gland are extremely hypervascular, we
investigated the expression of PlGF, VEGF and their receptors, Flt-1 and Flk
1/KDR, in a small panel of human goiters from patients with Graves's disease, in
an animal model of thyroid goitrogenesis and in in vitro cultured thyroid cells.
Here we report that the mRNA expression of PlGF, VEGF and their receptors is
markedly enhanced in biopsies of goiters resected from Graves's patients. In vivo
studies demonstrated that in the thyroid gland of thiouracil-fed rats, increased
mRNA and protein expression of PIGF, VEGF, Flt-1 and Flk-1/KDR occurred
subsequent to the rise in the serum thyroid stimulating hormone (TSH) levels and
in parallel with thyroid capillary proliferation. In vitro studies confirmed the
existence of such TSH-dependent paracrine communication between thyroid
epithelial cells and endothelium since the conditioned medium collected from TSH
stimulated thyrocytes acquired mitogenic activity for human umbilical vein
endothelial (HUVE) cells. Altogether, these data suggest that PlGF and VEGF,
released by thyrocytes in response to the chronic activation of the TSH receptor
pathway, may act through a paracrine mechanism on thyroid endothelium.
PMID- 9400996
TI - Wig-1, a new p53-induced gene encoding a zinc finger protein.
AB - Wild type p53 expressed from a temperature-sensitive (ts p53) construct induces
both G1 cell cycle arrest and apoptosis in the p53-negative J3D mouse T lymphoma
line (Wang et al., 1995). Using differential display analysis, we have identified
one new p53-induced gene, wig-1 (for wild type p53-induced gene 1), whose 7.6 kb
and 2.2 kb transcripts are upregulated in ts p53-transfected J3D cells following
induction of wild type p53 expression by temperature shift to 32 degrees C. The
wig-1 transcripts were also induced in irradiated NIH3T3 and p21-/- fibroblasts
but not in irradiated p53-/- fibroblasts. Whole body gamma irradiation caused
induction of both wig-1 transcripts in mouse brain, testis, kidney, spleen and
lung. A basal wig-1 expression was detected in brain, testis and kidney. The WIG
1 protein contains three zinc finger motifs and a putative nuclear localization
signal.
PMID- 9400997
TI - ErbB kinases and NDF signaling in human prostate cancer cells.
AB - Prostate carcinoma (PCA) is the most commonly diagnosed malignancy in American
men. Our knowledge of PCA growth regulation lags behind that of other cancers,
such as breast and colon carcinomas. Among receptor tyrosine kinases, the ErbB
family is most frequently implicated in neoplasia. We report here the expression
of ErbB family kinases and their ligands in PCA cell lines and a xenograft. While
ErbB1/EGFR, ErbB2/NEU, and ErbB3 were always observed in a distinct pattern,
ErbB4 was not observed. Interestingly, while TGF-alpha was expressed in the
majority of PCA lines, the ligand Neu Differentiation Factor/Heregulin (NDF) was
expressed only in an immortalized, non-transformed prostate epithelial line.
Concomitantly, there was a significant difference in biological response to these
ligands. NDF inhibited LNCaP growth and induced an epithelial-like morphological
change, in contrast to TGF-alpha, which accelerated cell growth. We also
performed the first comprehensive analysis of NDF signaling in a prostate line.
LNCaP stimulated with NDF demonstrated crosstalk between ErbB3 and ErbB2 which
did not involve ErbB1. NDF also turned on several cascades, including those of
PI3-K, ERK/MAPK, mHOG/p38 and JNK/SAPK, but not those of PLCgamma or the STAT
family. This signaling pattern is distinct from that of TGF-alpha. The activation
of mHOG by ErbB2 or ErbB3 has not been reported, and may contribute to the
unusual phenotype. PI3-K activation is characterized by the formation of a
striking 'activation complex' with multiple tyrosine-phosphorylated species,
including ErbB3. Our studies provide a framework in which to dissect the growth
and differentiation signals of prostate cancer cells.
PMID- 9400998
TI - Induction of Mdm2 and enhancement of cell survival by bFGF.
AB - Basic fibroblast growth factor (bFGF) can exert mitogenic and viability-promoting
effects in a wide range of biological systems. The biochemical activities
mediating the cell survival function of bFGF are largely unknown. We report here
that exposure of fibroblasts to bFGF, which confers upon them increased survival,
also causes at the same time an increase in cellular levels of the Mdm2
oncoprotein. Cells constitutively exposed to a bFGF autocrine loop are more
refractory to killing by cisplatin. This increased chemoresistance coincides with
elevated Mdm2 and reduced activation of the endogenous p53, resulting in
inefficient transcriptional activation of the bax gene promoter. Importantly,
unlike Mdm2 accumulation in fibroblasts exposed to DNA damage, induction of Mdm2
by bFGF does not occur through a p53-mediated pathway. The role of p53 in DNA
damage-induced apoptosis and the ability of Mdm2 to block p53-mediated cell death
are well established. These findings therefore suggest that induction of Mdm2 and
the subsequent inhibition of p53 function may contribute, at least partially, to
the anti-apoptotic effects of bFGF and possibly some other survival factors.
PMID- 9400999
TI - Loss of heterozygosity on the long arm of human chromosome 7 in sporadic renal
cell carcinomas.
AB - Cytogenetic and molecular analysis of DNA sequences with highly polymorphic
microsatellite markers have implicated allele loss in several chromosomal regions
including 3p, 6p, 6q, 8p, 9p, 9q, 11p and 14q in the pathogenesis of sporadic
renal cell carcinomas (RCCs). Deletions involving the long arm of chromosome 7
have not been described in RCCs although they have been seen in several other
tumor types. However, there have been no detailed analysis of loss of
heterozygosity (LOH) of 7q sequences in sporadic RCCs. We therefore studied LOH
for DNA sequences on 7q with 10 highly polymorphic markers in 92 matched
normal/tumor samples representing sporadic RCCs including papillary,
nonpapillary, and oncocytomas in order to determine whether allelic loss could be
detected in a tumor type with no visible 7q rearrangements at the cytogenetic
level. We found chromosome 7q allele loss in 59 of 92 cases (64%) involving one,
two, or more microsatellite markers. The most common allele loss included loci
D7S522 (24%) and D7S649 (30%) at 7q31.1-31.2, a region that contains one of the
common fragile sites, FRA7G. By comparative multiplex PCR analysis, we detected a
homozygous deletion of one marker in the 7q 31.1-31.2 region in one tumor, RC21.
These results support the idea that a tumor suppressor gene in 7q31 is involved
in the pathogenesis of sporadic renal cell carcinomas.
PMID- 9401000
TI - Pim1 cooperates with E2a-Pbx1 to facilitate the progression of thymic lymphomas
in transgenic mice.
AB - Mice transgenic for the leukemia oncogene E2A-PBX1 invariably develop lethal,
high-grade T-cell lymphomas by 5 months of age. In this study, retroviral
insertional mutagenesis was employed to identify oncogenes that cooperate with
the E2A-PBX1 transgene in lymphomagenesis. Neonatal retroviral infection
substantially reduced length of survival due to accelerated development of
lymphomas (81 versus 130 days). The Pim1 gene was targeted by retroviral
insertions in 48% of accelerated lymphomas whereas less than 5% contained
activated c-Myc and none contained activated Pim2. However, Pim1 DNA
rearrangements were frequently sub-stoichiometric and not present at all sites of
involvement in an otherwise monoclonal lymphoma indicating that Pim1 activation
occurred late in the course of lymphomagenesis. Tumor subpopulations containing
activated Pim1 alleles displayed a substantial growth advantage over Pim1
negative cells following serial transfer to secondary, syngeneic recipients.
Cooperative interactions were observed in intercrossed Pim1 and E2A-PBX1
transgenic mice in which all double transgenic progeny developed lethal, diffuse
T lineage lymphomas by 3 months of age, whereas only 13% of E2A-PBX1 and none of
Pim1 single transgenic intercross progeny developed lymphomas by 1 year. Tumors
from double transgenic mice were monoclonal providing evidence that additional
genetic events were required for transformation. Therefore, Pim1 and E2a-Pbx1
cooperate in T lineage lymphomagenesis but they are not sufficient and the role
of Pim1 is more likely to be associated with tumor progression.
PMID- 9401001
TI - Differences in the mechanisms of growth control in contact-inhibited and serum
deprived human fibroblasts.
AB - In the present work we studied mechanisms of growth control in contact-inhibited
and serum-deprived human diploid fibroblasts. The observation that the effects on
[3H]thymidine incorporation and reduction of retinoblastoma gene product
phosphorylation were additive when contact-inhibition and serum-deprivation were
combined led us to the conclusion that the underlying mechanisms might be
different. Both contact-inhibition and serum-deprivation led to a strong decrease
of cdk4-kinase-activity and cdk2-phosphorylation at Thr 160, while the total
amounts of cdk4 and cdk2 remained constant. In contact-inhibited cells, we
revealed a strong protein accumulation of the cdk2-inhibitor p27 and a slight,
but significant increase of the cdk4-inhibitor p16. In serum-deprived cells, the
protein levels in p27 and p16 remained low. In contrast, we detected a rapid
decrease of cyclin D1 and cyclin D3 which did not occur in contact-inhibited
cells. These results indicate that serum-deprivation and contact-inhibition have
different mechanisms although they affect the same pathway cyclin D-cdk4, pRB,
cyclin E-cdk2.
PMID- 9401002
TI - Cell cycle re-entry following chemically-induced cell cycle synchronization leads
to elevated p53 and p21 protein levels.
AB - Mimosine (MIM) and aphidicolin (APH) are two agents frequently used in tissue
culture-based experiments to achieve cell synchronization at late G1 and S
phases. Following MIM or APH treatment of human cancer cell lines, a reversible
growth arrest in late G1 and S phases of the cell cycle was correlated with
moderate increases in p53 and p21 protein levels. Both p53-dependent and
independent increases in p21 were observed following treatment with either agent.
However, a striking increase in p21 protein levels and a continuous elevation in
both p53 and p21 protein levels were observed over 48 h after cells re-entered
the cell cycle following the chemically-induced synchronization. In addition, the
increase in p21 protein levels typically seen following treatment of cells with
DNA damaging agents, was enhanced when cells were treated with genotoxic agents
following MIM or APH synchronization. These findings suggest that caution should
be exercised when interpreting results from experiments using cell
synchronization agents, in particular, studies designed to investigate p53- and
p21-regulatory pathways.
PMID- 9401003
TI - Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies.
AB - Fibrillin is the major component of extracellular microfibrils and is widely
distributed in connective tissue throughout the body. Mutations in the fibrillin
1 (FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a
dominantly inherited disorder characterised by clinically variable skeletal,
ocular, and cardiovascular abnormalities. Fibrillin-1 mutations have also been
found in several other related connective tissue disorders, such as severe
neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic
aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg
syndrome. Mutations are spread throughout the gene and, with the exception of
neonatal Marfan syndrome, show no obvious clustering or phenotypic association.
PMID- 9401004
TI - Molecular basis of heat labile hexosaminidase B among Jews and Arabs.
AB - Genotyping individuals for Tay-Sachs disease (TSD) is mainly based on the heat
lability of beta-hexosaminidase (Hex) A (alphabeta) and the heat stability of Hex
B (betabeta). Mutations in the HEXB gene encoding the beta-subunits of Hex that
result in heat-labile Hex B thus may lead to erroneous enzymatic genotyping
regarding TSD. Utilizing single strand conformation polymorphism (SSCP) analysis
for all 14 exons of HEXB followed by direct sequencing of aberrant fragments, we
screened individuals whose Hex B was heat labile. A novel heat labile mutation,
previously concluded to exist in the HEXB gene, was identified among Jews and
Arabs as 1627 G-->A. One individual with heat labile Hex B (HLB) was negative for
this novel mutation and for the known 1514 G-->A HLB mutation, proving that there
exists at least one other unidentified HLB mutation. Based on these results, it
is advisable to perform DNA tests for 1627 G-->A mutation in suspected HLB
individuals.
PMID- 9401005
TI - Analysis of mutations and chromosomal localisation of the gene encoding RFX5, a
novel transcription factor affected in major histocompatibility complex class II
deficiency.
AB - MHC class II deficiency is a severe primary immunodeficiency characterised by the
absence of major histocompatibility complex class II (MHC-II) gene expression. It
is genetically heterogeneous and can result from defects in at least four
different trans-acting regulatory genes required for transcription of MHC-II
genes. One of these genes has recently been shown to encode a novel DNA binding
protein called RFX5, which is one subunit of a heteromeric protein complex (RFX)
that binds to the promoters of MHC-II genes. We have characterised the mutations
in all four patients known to harbour a defect in the RFX5 gene and have mapped
this new human disease gene to chromosome 1 band q21, a region frequently
exhibiting chromosomal aberrations in a variety of preneoplastic and neoplastic
diseases.
PMID- 9401006
TI - Cystic fibrosis mutation frequencies in upstate New York.
AB - Upstate New York patients (100) with cystic fibrosis (i.e., 200 CF chromosomes),
72 from the CF center in Syracuse and 28 from a Buffalo CF center, were analyzed
for their CF-causing mutations using restriction enzyme digest, single-strand
conformation analysis (SSCA), and Heteroduplex (HA) analysis. Polymerase chain
reaction (PCR) amplified products from all 27 CFTR exons using primers that
included flanking intron junction sequence were investigated. More than 120 known
cystic fibrosis transmembrane conductance regulator (CFTR) disease-causing
mutations were screened. Four novel CFTR disease-causing mutations were
identified (N287Y in exon 6b, 1259insA in exon 8, R1070P in exon 17b, and
CF?20kbdel14b-18). A detection rate of 96% of the combined Syracuse and Buffalo
population CF chromosomes was obtained.
PMID- 9401007
TI - Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities:
characterization of 14 Cx32 mutations in 35 families.
AB - Charcot-Marie-Tooth disease can be inherited either autosomal dominantly or
recessively or linked to the X chromosome. X-linked dominant Charcot-Marie-Tooth
disease (CMTX) is a sensorimotor peripheral neuropathy in which males have
usually more severe clinical symptoms and decreased nerve conduction velocities
than do females. CMTX is usually associated with mutations in exon 2 of the
connexin 32 (Cx32) gene. DNA from 35 unrelated CMT patients, without the 17p11.2
duplication, but with median nerve conduction between 30 and 40 m/s, were tested
for the presence of Cx32 mutations. The entire coding sequence of the Cx32 gene
was explored using a rapid nonradioactive technique to detect single-strand
conformation polymorphisms (SSCP) on large PCR fragments. Thirteen abnormal SSCP
profiles were detected and characterized by sequencing. In addition, systematic
sequencing of the entire Cx32 coding region in the remaining index cases revealed
another mutation that was not detected by SSCP. A total of 14 mutations were
found, five of which were not previously reported. These results demonstrate the
high frequency (40%) of mutations in the coding region of the Cx32 gene in CMT
patients with intermediate MNCV, without 17p11.2 duplications. Most of these
mutations (93%) can be detected by SSCP.
PMID- 9401008
TI - Two mutated HEXA alleles in a Druze patient with late-infantile Tay-Sachs
disease.
AB - Two affected HEXA alleles were found in an Israeli Druze Tay-Sachs child born to
first-cousin parents. His paternal allele contained two adjacent changes in exon
5: delta496C, which resulted in a frameshift and premature termination codon 96
nucleotides downstream, and 498C-->G, a silent mutation. The maternal allele had
a 835T-->C transition in exon 8 (S279P). Phosphoimaging quantitation of the
parents' RNAs showed that the steady-state levels of mRNAs of the mutant exons 5
and 8 were 5% and 50%, respectively, of normal levels. The exon 5 mutated allele
with the premature translation termination resulted in severe deficiency of Hex
A. Transient expression of the exon 8 mutated alpha-chain cDNA in COS-1 cells
resulted in deficiency of enzymatic activity. The child exhibited a late
infantile-type disease.
PMID- 9401009
TI - Analysis of (CAG)n size heterogeneity in somatic and sperm cell DNA from
intermediate and expanded Huntington disease gene carriers.
AB - The length of the CAG repeat responsible for Huntington disease has been analysed
by two PCR methods in blood and sperm DNA of 13 expansion carriers, two carriers
of intermediate alleles, and four normal subjects. The two methods consistently
confirmed size heterogeneity, more pronounced in sperm and confined to the CAG
stretch. Based on densitometric scanning of films, four indexes addressed to
different features of the PCR pattern were used to quantitate mosaicism. These
revealed strong correlations with CAG size and intergenerational instability.
However, mosaicism did not show a greater similarity in sibs who shared the same
HD chromosome, nor was correlated with instability in the proband's pedigree. Our
data do not support the hypothesis that cis-acting factors play a major role in
the instability and leave the CAG size per se as the major determinant of sperm
cell CAG instability.
PMID- 9401010
TI - Familial lipoprotein lipase (LPL) deficiency: a catalogue of LPL gene mutations
identified in 20 patients from the UK, Sweden, and Italy.
AB - The aim of this study was to identify mutations in the lipoprotein lipase (LPL)
gene in 20 unrelated patients with familial lipoprotein deficiency (FLLD) and to
investigate the genotype/phenotype relationship. The previously reported G188E
mutation (Monsalve et al., J Clin Invest 86:728-734, 1990) was screened for and
found to be present in seven individuals (12/40 alleles). In addition, three
patients were heterozygous for the 2.0 kb insertion (Langlois et al., Proc Nalt
Acad Sci US 86:948-952, 1989). Two approaches were taken for new mutation
detection; single-strand conformation polymorphism and sequencing to identify
micro-mutations in the proximal promoter and exons 1-9 of the LPL gene and
Southern blotting to identify gross mutations. Ten different point mutations were
found (W86G, A158T, H183Q, G188E, S193R, P207L, L252X, N291S, M301T, L303P).
Additionally, a two nucleotide deletion in exon 6 (delta1006-1007), a six
nucleotide deletion in exon 8 (delta1441-1447), and a silent substitution in the
wobble position of codon E118 were identified. In vitro mutagenesis and
expression in COS-B cells suggested that the A158T and S193R substitutions
virtually abolished enzyme activity. In analysing the genotype/phenotype
relationship, there was no strong association between age at diagnosis, severity
of symptoms, lipid levels, and the nature/position of the mutation. Triglyceride
levels, however, were higher in compound heterozygotes compared to true
homozygotes, possibly reflecting increased instability of heterodimers. Overall,
29 of 40 (72.5%) mutant alleles were identified. Failure to identify the mutation
in 11 alleles might reflect the inadequacy of the method or the possibility that
mutations lie within regions of the gene not screened in the study because of
lack of availability of sequence.
PMID- 9401011
TI - Mutation of hMSH3 and hMSH6 mismatch repair genes in genetically unstable human
colorectal and gastric carcinomas.
AB - Mutations within microsatellite sequences, consisting of additions or deletions
of repeat units, are known as the replication/repair error positive (RER+)
phenotype or micorsatellite instability (MI). Microsatellite instability has been
demonstrated in hereditary and sporadic colorectal carcinomas and is usually
observed in noncoding regions of genomic DNA. However, relatively few coding
region targets of MI have been identified thus far. Using PCR, we amplified
regions encompassing (A)8 and (C)8 microsatellite tracts within hMSH3 and hMSH6
from 31 RER+ sporadic colorectal tumors, 8 hereditary colon cancers, 23 RER+
gastric carcinomas, and 32 RER- gastric tumors. Mutations were found in 11 (36%)
of 31 sporadic colon carcinomas, 4 (50%) of 8 hereditary colorectal cancers, and
5 (22%) of 23 RER+ gastric carcinomas, but in only 2 (6%) of 32 RER- gastric
carcinomas. These frameshift mutations cause premature stop codons downstream
that are predicted to abolish normal protein function. Our results and those of
others suggest that DNA mismatch repair genes, such as hMSH3 and hMSH6, are
targets for the mutagenic activity of upstream mismatch repair gene mutations and
that this enhanced genomic instability may accelerate the accumulation of
mutations in RER+ tumors.
PMID- 9401012
TI - Identification of 16 sulfamidase gene mutations including the common R74C in
patients with mucopolysaccharidosis type IIIA (Sanfilippo A).
AB - Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo A disease) is a storage
disorder caused by deficiency of the lysosomal enzyme sulfamidase. Mutation
screening, using SSCP/heteroduplex analyses on cDNA and genomic DNA fragments,
was performed in a group of 42 European patients. Sixteen of the 17 different
gene mutations characterized have not been previously described. The spectrum of
gene lesions consists of two 1-bp deletions (1091delC, 1093delG), an 18-bp
duplication (421ins18), a splice site mutation (IVS2-2A-->G), and 13 different
missense point mutations. As in other lysosomal storage disorders, the phenotypic
heterogeneity is associated with a considerable genetic heterogeneity. The
missense mutation R74C, which alters an evolutionary conserved amino acid in the
active site of the enzyme, was found on 56% of alleles of 16 Polish patients,
whereas it was less frequent among German patients (21% of disease alleles).
R245H, a previously reported common mutation, represents 35% of disease alleles
in German patients, but only 3% in Polish patients. As the combined frequency of
the common mutations (R74C and R245H) in German and Polish populations exceeds
55%, screening for these two mutations will assist molecular genetic diagnosis of
MPS IIIA and allow heterozygote testing in these populations.
PMID- 9401013
TI - The repeat expansion detection method in the analysis of diseases with CAG/CTG
repeat expansion: usefulness and limitations.
AB - The repeat expansion detection (RED) method was described to detect expansions of
trinucleotide repeats of unknown chromosomal location. We have improved the RED
method by the use of 8-mer oligonucleotides and assessed its usefulness in 30
samples from patients with spinocerebellar ataxia type 1 (SCA1), Huntington's
disease (HD), and Machado Joseph's disease (MJD), for which the number of CAG/CTG
repeats was determined by sequencing. There was a good correlation between the
number of repeats detected by sequencing and those identified by RED. However, in
17% of samples, the RED gave additional fragments for ligation products of
different size than the CAG/CTG repeat expansion detected in the sample by
sequencing. The same was observed in a group of control subjects (n = 78) without
known clinical abnormalities in which products of more than 40 repeats were
detected in 27% of them, indicating that CAG/CTG repeat expansions are common in
the general population. Wether this corresponds to unidentified loci with
expansions deserves further investigation.
PMID- 9401014
TI - Method for in situ investigation of mitochondrial DNA deletions.
AB - A number of mitochondrial DNA (mtDNA) deletions have been recently identified in
the tissues of patients with mitochondrial diseases and in elderly individuals.
To investigate the distribution of mutant mitochondrial genomes within any
particular tissue, we have developed a sensitive method based on indirect in situ
PCR. Our experiments have shown that the new method had the advantage of
selectively amplifying only mtDNA bearing the 4,977 bp deletion. We show that
this method is more sensitive than in situ hybridization for detecting the 4977
bp mtDNA deletion while using only a low number of PCR cycles that minimize
damage to tissue architecture. By using this method, we have demonstrated that
the mutation does not occur uniformly among the cells of a given tissue/organ.
This technique will be useful studying the distribution/localization of mtDNA
mutations in individual cells of tissues and when combined with enzyme
histochemical procedures in adjacent sections will enable the correlation between
mtDNA mutations and bioenergy defects in single cells.
PMID- 9401015
TI - An improved methodology for the detection of the common mutation in the FGFR3
gene responsible for achondroplasia.
AB - Homozygous achondroplasia is a neonatal lethal condition which can only be
diagnosed in the first trimester of pregnancy by molecular analysis. The vast
majority of patients with achondroplasia have a G-->A substitution at position
1138 of the fibroblast growth factor receptor (FGFR3) cDNA sequence, resulting in
the substitution of an arginine for a glycine residue at position 380 of the
FGFR3 protein. This mutation has typically been detected by SfcI digestion of
amplified genomic DNA. We have demonstrated that the SfcI digestion protocol does
not consistently distinguish between DNA samples heterozygous and homozygous for
the G1138A substitution, and illustrates how the misdiagnosis of a homozygous
affected fetus for one carrying only one copy of the G1138A mutation could occur.
We report here an improved, simple nonradioactive technique which can reliably
and consistently detect the presence of the G1138A mutation both in the
heterozygous and homozygous state.
PMID- 9401016
TI - Biosynthesis of phosphatidic acid in lipid particles and endoplasmic reticulum of
Saccharomyces cerevisiae.
AB - Lipid particles of the yeast Saccharomyces cerevisiae harbor two enzymes that
stepwise acylate glycerol-3-phosphate to phosphatidic acid, a key intermediate in
lipid biosynthesis. In lipid particles of the s1c1 disruptant YMN5 (M. M. Nagiec
et al., J. Biol. Chem. 268:22156-22163, 1993) acylation stops after the first
step, resulting in the accumulation of lysophosphatidic acid. Two-dimensional gel
electrophoresis confirmed that S1c1p is a component of lipid particles. Lipid
particles of a second mutant strain, TTA1 (T. S. Tillman and R. M. Bell, J. Biol.
Chem. 261:9144-9149, 1986), which harbors a point mutation in the GAT gene, are
essentially devoid of glycerol-3-phosphate acyltransferase activity in vitro.
Synthesis of phosphatidic acid is reconstituted by combining lipid particles from
YMN5 and TTA1. These results indicate that two distinct enzymes are necessary for
phosphatidic acid synthesis in lipid particles: the first step, acylation of
glycerol-3-phosphate, is catalyzed by a putative Gat1p; the second step,
acylation of lysophosphatidic acid, requires S1c1p. Surprisingly, YMN5 and TTA1
mutants grow like the corresponding wild types because the endoplasmic reticulum
of both mutants has the capacity to form a reduced but significant amount of
phosphatidic acid. As a consequence, an s1c1 gat1 double mutant is also viable.
Lipid particles from this double mutant fail completely to acylate glycerol-3
phosphate, whereas endoplasmic reticulum membranes harbor residual enzyme
activities to synthesize phosphatidic acid. Thus, yeast contains at least two
independent systems of phosphatidic acid biosynthesis.
PMID- 9401018
TI - Nucleoid structure and distribution in thermophilic Archaea.
AB - Nucleoid structure and distribution in thermophilic organisms from the Archaea
domain were studied. Combined phase-contrast and fluorescence microscopy of DAPI
(4',6-diamidino-2-phenylindole)-stained Sulfolobus acidocaldarius and Sulfolobus
solfataricus cells revealed that the nucleoids were highly structured. Different
nucleoid distribution within the cells, representing different partition stages,
was observed. The conformation of the nucleoids differed between exponentially
growing and stationary-phase cells. Also, the stationary-phase cells contained
two chromosomes, and the nucleoids occupied a larger part of the interior of the
cells than in the exponentially growing cells. The part of the cell cycle during
which fully separated nucleoids could be detected was short. Since the
postreplication period is long in these organisms, there was a considerable time
interval between termination of chromosome replication and completion of nucleoid
separation, similar to the G2 phase in eukaryotic cells. The length of the
visible cell constriction period was found to be in the same range as that of
eubacteria. Finally, cell-cell connections were observed under certain
conditions. Possible eubacterial, eukaryotic, and unique features of nucleoid
processing and cell division in thermophilic archaea are discussed.
PMID- 9401019
TI - The D-allose operon of Escherichia coli K-12.
AB - Escherichia coli K-12 can utilize D-allose, an all-cis hexose, as a sole carbon
source. The operon responsible for D-allose metabolism was localized at 92.8 min
of the E. coli linkage map. It consists of six genes, alsRBACEK, which are
inducible by D-allose and are under the control of the repressor gene alsR. This
operon is also subject to catabolite repression. Three genes, alsB, alsA, and
alsC, appear to be necessary for transport of D-allose. D-Allose-binding protein,
encoded by alsB, is a periplasmic protein that has an affinity for D-allose, with
a Kd of 0.33 microM. As was found for other binding-protein-mediated ABC
transporters, the allose transport system includes an ATP-binding component
(AlsA) and a transmembrane protein (AlsC). It was found that AlsE (a putative D
allulose-6-phosphate 3-epimerase), but not AlsK (a putative D-allose kinase), is
necessary for allose metabolism. During this study, we observed that the D-allose
transporter is partially responsible for the low-affinity transport of D-ribose
and that strain W3110, an E. coli prototroph, has a defect in the transport of D
allose mediated by the allose permease.
PMID- 9401017
TI - Characterization of genes encoding dimethyl sulfoxide reductase of Rhodobacter
sphaeroides 2.4.1T: an essential metabolic gene function encoded on chromosome
II.
AB - Rhodobacter sphaeroides 2.4.1T is a purple nonsulfur facultative phototrophic
bacterium which exhibits remarkable metabolic diversity as well as genomic
complexity. Under anoxic conditions, in the absence of light and the presence of
dimethyl sulfoxide (DMSO) or trimethylamine N-oxide (TMAO), R. sphaeroides 2.4.1T
utilizes DMSO or TMAO as the terminal electron acceptor for anaerobic
respiration, which is mediated by the molybdoenzyme DMSO reductase. Sequencing of
a 13-kb region of chromosome II revealed the presence of 10 putative open reading
frames, of which 5 possess homology to genes encoding the TMAO reductase (the tor
system) of Escherichia coli. The dorS and dorR genes encode a sensor-regulator
pair of the two-component sensory transduction protein family, homologous to the
torS and torR gene products. The dorC gene was shown to encode a 44-kDa DMSO
inducible c-type cytochrome. The dorB gene encodes a membrane protein of unknown
function homologous to the torD gene product. The dorA gene encodes DMSO
reductase, containing the molybdopterin active site. Mutations were constructed
in each of these dor genes, and the resulting mutants were shown to be impaired
for DMSO-dependent anaerobic growth in the dark. The mutant strains exhibited
negligible levels of DMSO reductase activity compared to the wild-type strain
under similar growth conditions. Further, no DorA protein was detected in DorS
and DorR mutant strains with anti-DorA antisera, suggesting that the products of
these genes are required for the positive regulation of dor expression in
response to DMSO. This characterization of the dor gene cluster is the first
evidence that genes of chromosome CII encode metabolic functions which are
essential under particular growth conditions.
PMID- 9401020
TI - Temperature-sensitive lesions in the Francisella novicida valA gene cloned into
an Escherichia coli msbA lpxK mutant affecting deoxycholate resistance and
lipopolysaccharide assembly at the restrictive temperature.
AB - The valAB locus of Francisella novicida has previously been found to be highly
similar at the deduced amino acid level to msbA lpxK of Escherichia coli. Both
ValA and MsbA are members of the superfamily of ABC transporters, and they appear
to have similar functions. In this study we describe the isolation of a
temperature-sensitive valAB locus. DNA sequence analysis indicates that the only
changes to the ValAB deduced amino acid sequence are changes of S453 to an F and
T458 to an I in ValA. E. coli strains defective in msbA and expressing
temperature-sensitive ValA rapidly ceased growth when shifted from a permissive
temperature to a restrictive temperature. After 1 h at the restrictive
temperature, cells were much more sensitive to deoxycholate treatment. To test
the hypothesis that ValA is responsible for the transport or assembly of
lipopolysaccharide, we introduced gseA, a Kdo (3-deoxy-D-manno-octulosonic acid)
transferase from Chlamydia trachomatis, into a strain with a temperature
sensitive valA allele and a nonfunctional msbA locus. These recombinants were
defective in cell surface expression of the chlamydial genus-specific epitope
within 15 min of a shift to the nonpermissive temperature. Also, there was
enhanced association of the epitope with the inner membrane after a shift to the
nonpermissive temperature. Thus, we propose that ValA is involved in the
transport of lipopolysaccharide to the outer membrane.
PMID- 9401021
TI - The minimal transactivation region of Saccharomyces cerevisiae Gln3p is localized
to 13 amino acids.
AB - Regulated nitrogen catabolic gene transcription in Saccharomyces cerevisiae is
mediated by four positive (Gln3p and Gat1p/Nil1p) and negative (Dal80p/Uga43p and
Deh1p/Nil2p/GZF3p) regulators which function in opposition to one another. All
four proteins contain GATA-type zinc finger domains, and three of them (Gln3p,
Dal80p, and Deh1p) have been shown to bind to GATA sequences situated upstream of
genes whose expression is sensitive to nitrogen catabolite repression (NCR). The
positive regulators, Gln3p and Gat1p, are able to support transcriptional
activation when tethered by LexAp to the promoter of a reporter gene whose
upstream activation sequences have been replaced with one or more lexA operator
sites. Existing data suggest that these four proteins regulate transcription by
competing with one another for binding to the GATA sequences which mediate NCR
sensitive gene expression. We show that the minimal Gln3p domain mediating
transcriptional activation consists of 13 amino acids with a predicted propensity
to form an alpha-helix. Genetic analysis of this region (Gln3p residues 126 to
138, QQNGEIAQLWDFN) demonstrated that alanine may be substituted for the aromatic
and acidic amino acids without destroying transcriptional activation potential.
Similar substitution of alanine for the two hydrophobic amino acids, isoleucine
and leucine, however, destroys activation, as does introduction of basic amino
acids in place of the acidic residues or introduction of proline into the center
of the sequence. A point mutation in the Gln3p activation region destroys its in
vivo ability to support NCR-sensitive DAL5 expression. We find no convincing
evidence that NCR regulates Gln3p function by modulating the functioning of its
activation region.
PMID- 9401023
TI - N-acyl-homoserine lactone-mediated regulation of phenazine gene expression by
Pseudomonas aureofaciens 30-84 in the wheat rhizosphere.
AB - Pseudomonas aureofaciens 30-84 is a soilborne bacterium that colonizes the wheat
rhizosphere. This strain produces three phenazine antibiotics which suppress take
all disease of wheat by inhibition of the causative agent Gaeumannomyces graminis
var. tritici. Phenazines also enhance survival of 30-84 within the wheat
rhizosphere in competition with other organisms. Expression of the phenazine
biosynthetic operon is controlled by the phzR/phzI N-acyl-homoserine lactone
(AHL) response system (L. S. Pierson III et al., J. Bacterial 176:3966-3974,
1994; D. W. Wood and L. S. Pierson III, Gene 168:49-53, 1996). By using high
pressure liquid chromatography coupled with high-resolution mass spectrometry,
the AHL produced by PhzI has now been identified as N-hexanoyl-homoserine lactone
(HHL). In addition, the ability of HHL to serve as an interpopulation signal
molecule in the wheat rhizosphere has been examined by using isogenic reporter
strains. Disruption of phzI reduced expression of the phenazine biosynthetic
operon 1,000-fold in the wheat rhizosphere. Coinoculation of an isogenic strain
which produced the endogenous HHL signal restored phenazine gene expression in
the phzI mutant to wild-type levels in situ. These results demonstrate that HHL
is required for phenazine expression in situ and is an effective interpopulation
signal molecule in the wheat rhizosphere.
PMID- 9401022
TI - cps1+, a Schizosaccharomyces pombe gene homolog of Saccharomyces cerevisiae FKS
genes whose mutation confers hypersensitivity to cyclosporin A and papulacandin
B.
AB - The Schizosaccharomyces pombe cps1-12 (for chlorpropham supersensitive) mutant
strain was originally isolated as hypersensitive to the spindle poison isopropyl
N-3-chlorophenyl carbamate (chlorpropham) (J. Ishiguro and Y. Uhara, Jpn. J.
Genet. 67:97-109, 1992). We have found that the cps1-12 mutation also confers (i)
hypersensitivity to the immunosuppressant cyclosporin A (CsA), (ii)
hypersensitivity to the drug papulacandin B, which specifically inhibits 1,3-beta
D-glucan synthesis both in vivo and in vitro, and (iii) thermosensitive growth at
37 degrees C. Under any of these restrictive treatments, cells swell up and
finally lyse. With an osmotic stabilizer, cells do not lyse, but at 37 degrees C
they become multiseptated and multibranched. The cps1-12 mutant, grown at a
restrictive temperature, showed an increase in sensitivity to lysis by enzymatic
cell wall degradation, in in vitro 1,3-beta-D-glucan synthase activity (173% in
the absence of GTP in the reaction), and in cell wall biosynthesis (130% of the
wild-type amount). Addition of Ca2+ suppresses hypersensitivity to papulacandin B
and septation and branching phenotypes. All of these data suggest a relationship
between the cps1+ gene and cell wall synthesis. A DNA fragment containing the
cps1+ gene was cloned, and sequence analysis indicated that it encodes a
predicted membrane protein of 1,729 amino acids with 15 to 16 transmembrane
domains. S. pombe cps1p has overall 55% sequence identity with Fks1p or Fks2p,
proposed to be catalytic or associated subunits of Saccharomyces cerevisiae 1,3
beta-D-glucan synthase. Thus, the cps1+ product might be a catalytic or an
associated copurifying subunit of the fission yeast 1,3-beta-D-glucan synthase
that plays an essential role in cell wall synthesis.
PMID- 9401024
TI - Involvement of CysB and Cbl regulatory proteins in expression of the tauABCD
operon and other sulfate starvation-inducible genes in Escherichia coli.
AB - Starvation for sulfate results in increased synthesis of several proteins in
Escherichia coli. Among these Ssi (sulfate starvation-induced) proteins are the
products of the tauABCD genes, which are required for utilization of taurine as
sulfur source for growth. In this study, the role of the cbl gene in expression
of tauABCD and other ssi genes was investigated. The protein encoded by cbl shows
high sequence similarity to CysB, the LysR-type transcriptional activator of the
genes involved in cysteine biosynthesis. Strain EC2541, which contains an
internal deletion in cbl, was unable to utilize taurine and other aliphatic
sulfonates as sulfur sources. Two-dimensional sodium dodecyl sulfate
polyacrylamide gel electrophoresis showed that many of the Ssi proteins were not
synthesized in EC2541. Expression of a translational tauD'-'lacZ fusion required
the presence of both cbl and cysB. The interactions of CysB and Cbl with the
promoter region of tauABCD were studied by using gel mobility shift experiments
and DNase I footprinting. CysB occupied multiple binding sites, whereas Cbl
occupied only one site from 112 to 68 bp upstream of the transcription start
site. Acetylserine, the inducer of transcription of CysB-regulated genes,
stimulated binding of CysB but not of Cbl. Sulfate had no effect on binding of
both proteins to the tauABCD promoter region. These results indicate that Cbl is
a transcription factor for genes required for sulfonate-sulfur utilization and
maybe for other genes whose expression is induced by sulfate starvation.
PMID- 9401025
TI - Characterization of the aes gene of Escherichia coli encoding an enzyme with
esterase activity.
AB - malQ mutants of Escherichia coli lacking amylomaltase cannot grow on maltose.
They express the maltose system constitutively and are sensitive to maltose when
grown on another carbon source. In an attempt to isolate a multicopy suppressor
that would result in growth on maltose, we transformed a malQ mutant with a gene
bank of E. coli DNA which had been digested with Sau3a and cloned in pBR322. We
screened the transformants on MacConkey maltose plates. A colony was isolated
that appeared to be resistant to maltose and was pink on these plates, but it was
still unable to grow on minimal medium with maltose as the carbon source. The
plasmid was isolated, and the gene causing this phenotype was characterized. The
deduced amino acid sequence of the encoded protein shows homology to that of
lipases and esterases. We termed the gene aes, for acetyl esterase. Extracts of
cells harboring plasmid-encoded aes under its own promoter exhibit a fivefold
higher capacity to hydrolyze p-nitrophenyl acetate than do extracts of cells of
plasmid-free strains. Similarly, strains harboring plasmid-encoded aes are able
to grow on triacetyl glycerol (triacetin) whereas the plasmid-free strains are
not. The expression of plasmid-encoded aes resulted in strong repression of the
maltose transport genes in malT+ strains (10-fold reduction), but not in a
malT(Con) strain which is independent of the inducer. Also, overproduction of
MalT counteracted the Aes-dependent repression, indicating a direct interaction
between MalT and Aes.
PMID- 9401026
TI - Unliganded maltose-binding protein triggers lactose transport in an Escherichia
coli mutant with an alteration in the maltose transport system.
AB - Escherichia coli accumulates malto-oligosaccharides by the maltose transport
system, which is a member of the ATP-binding-cassette (ABC) superfamily of
transport systems. The proteins of this system are LamB in the outer membrane,
maltose-binding protein (MBP) in the periplasm, and the proteins of the inner
membrane complex (MalFGK2), composed of one MalF, one MalG, and two MalK
subunits. Substrate specificity is determined primarily by the periplasmic
component, MBP. However, several studies of the maltose transport system as well
as other members of the ABC transporter superfamily have suggested that the
integral inner membrane components MalF and MalG may play an important role in
determining the specificity of the system. We show here that residue L334 in the
fifth transmembrane helix of MalF plays an important role in determining the
substrate specificity of the system. A leucine-to-tryptophan alteration at this
position (L334W) results in the ability to transport lactose in a saturable
manner. This mutant requires functional MalK-ATPase activity and the presence of
MBP, even though MBP is incapable of binding lactose. The requirement for MBP
confirms that unliganded MBP interacts with the inner membrane MalFGK2 complex
and that MBP plays a crucial role in triggering the transport process.
PMID- 9401027
TI - rpbA controls transcription of the constitutive phycocyanin gene set in Fremyella
diplosiphon.
AB - Three gene sets encode alpha and beta subunits of the phycobiliprotein
phycocyanin (PC) in the filamentous cyanobacterium Fremyella diplosiphon. The
cpcB1A1 set (encodes PC1) is constitutively expressed, whereas the cpcB2A2 set
(encodes PC2) is expressed only in red light and the cpcB3A3 set (encodes PC3) is
expressed only during sulfur-limited growth. Primary pigment mutant strain FdBM1
is characterized by elevated levels of PC. DNA hybridization analysis showed that
like many pigment mutants in our strain collection, strain FdBM1 harbors an extra
genomic copy of endogenous transposon Tn5469. By direct cloning from FdBM1
genomic DNA, the extra copy of Tn5469 was localized to an open reading frame,
which we have designated the rpbA gene. Complementation experiments correlated
rpbA activity to the phenotype of strain FdBM1. The predicted RpbA protein
contains two regions resembling the characterized helix-turn-helix motif which is
involved in DNA recognition by many bacterial and phage transcription regulator
proteins. RNA hybridization analysis showed that relative to the parental strain
Fd33, the level of transcripts from cpcB1A1, but not cpcB2A2 or cpcB3A3, was
significantly elevated in strain FdBM1. Introduction of the intact rpbA gene into
strain FdBM1 restored the cpcB1A1 transcript level to that of strain Fd33. These
results suggest that the rpbA gene product functions in controlling constitutive
transcription from the cpcB1A1 gene set, possibly as a DNA-binding
transcriptional repressor element.
PMID- 9401028
TI - Cloning, functional analysis, and transcriptional regulation of the Bacillus
subtilis araE gene involved in L-arabinose utilization.
AB - The Bacillus subtilis araR locus (mapped at about 294 degrees on the genetic map)
comprises two open reading frames with divergently arranged promoters, the
regulatory gene, araR, encoding a repressor, and a partially cloned gene, termed
araE by analogy to the Escherichia coli L-arabinose permease gene. Here, we
report the cloning and sequencing of the entire araE gene encoding a 50.4-kDa
polypeptide. The araE gene is monocistronic (as determined by Northern blot
analysis), and its putative product is very similar to a number of prokaryotic
proton-linked monosaccharide transporters (the group I family of membrane
transport proteins). Insertional inactivation of the araE gene leads to a
conditional Ara- phenotype dependent on the concentration of L-arabinose in the
medium. Therefore, we assume that araE encodes a permease involved in L-arabinose
transport into the cell. The araE promoter region contains -10 and -35 regions
(as determined by primer extension analysis) very similar to those recognized by
RNA polymerase containing the major vegetative-cell sigma factor sigmaA, and the
35 region of the transcription start point for araE is located 2 bp from the -35
region of the araR gene. Transcriptional studies demonstrated that the expression
from the araE promoter is induced by L-arabinose, repressed by glucose, and
negatively regulated by AraR. These observations are consistent with a model
according to which in the absence of L-arabinose, AraR binds to a site(s) within
the araE/araR promoter, preventing transcription from the araE promoter and
simultaneously limiting the frequency of initiation from its own promoter; the
addition of L-arabinose will allow transcription from the araE promoter and
increase the frequency of initiation from the araR promoter.
PMID- 9401029
TI - Identification of cysteine and arginine residues essential for the
phosphotransacetylase from Methanosarcina thermophila.
AB - Phosphotransacetylase catalyzes the following reaction: CoASH + CH3CO2PO3(2-)
<==> CH3COSCoA + HPO4(2-) (where CoA is coenzyme A). Based on biochemical
characterization of the enzyme from the obligate anaerobe Clostridium kluyveri, a
ternary mechanism was proposed in which an unspecified cysteine abstracts a
proton from CoASH forming a nucleophilic thiolate anion which attacks acetyl
phosphate (J. Henkin and R. H. Abeles, Biochemistry 15:3472-3479, 1976).
Heterologous production in Escherichia coli of the phosphotransacetylase from
Methanosarcina thermophila, an obligately anaerobic methanoarchaeon, allowed site
specific replacements to identify essential residues. All four cysteines present
in the sequence were individually replaced with alanine, and the kinetic
constants of the altered enzymes were determined. The results indicated that only
C159 is essential for activity; however, replacement with serine resulted in a
fully active enzyme. Activity of the unaltered phosphotransacetylase was
sensitive to N-ethylmaleimide. Inhibition kinetics of altered enzymes indicated
that this sensitivity resulted from modification of C312, which is at the active
site but itself is nonessential for catalysis. Five arginines were individually
replaced with glutamine. Kinetic analysis of the altered enzymes identified R310
as essential for activity. Of the four nonessential for activity, R87 and R133
appear to be involved in binding CoA.
PMID- 9401030
TI - Characterization of nicotinamide mononucleotide adenylyltransferase from
thermophilic archaea.
AB - The enzyme nicotinamide mononucleotide (NMN) adenylyltransferase (EC 2.7.7.1)
catalyzes the synthesis of NAD+ and nicotinic acid adenine dinucleotide. It has
been purified to homogeneity from cellular extracts of the thermophilic archaeon
Sulfolobus solfataricus. Through a database search, a highly significant match
was found between its N-terminal sequence and a hypothetical protein coded by the
thermophilic archaeon Methanococcus jannaschii MJ0541 open reading frame (GenBank
accession no. U67503). The MJ0541 gene was isolated, cloned into a T7-based
vector, and expressed in Escherichia coli cells, yielding a high level of
thermophilic NMN adenylyltransferase activity. The expressed protein was purified
to homogeneity by a single-step chromatographic procedure. Both the subunit
molecular mass and the N-terminal sequence of the pure recombinant protein were
as expected from the deduced amino acid sequence of the MJ0541 open reading frame
encoded protein. Molecular and kinetic properties of the enzymes from both
archaea are reported and compared with those already known for the mesophilic
eukaryotic NMN adenylyltransferase.
PMID- 9401031
TI - Transduction of envelope stress in Escherichia coli by the Cpx two-component
system.
AB - Disruption of normal protein trafficking in the Escherichia coli cell envelope
(inner membrane, periplasm, outer membrane) can activate two parallel, but
distinct, signal transduction pathways. This activation stimulates the expression
of a number of genes whose products function to fold or degrade the mislocalized
proteins. One of these signal transduction pathways is a two-component regulatory
system comprised of the histidine kinase CpxA and the response regulator, CpxR.
In this study we characterized gain-of-function Cpx* mutants in order to learn
more about Cpx signal transduction. Sequencing demonstrated that the cpx*
mutations cluster in either the periplasmic, the transmembrane, or the H-box
domain of CpxA. Intriguingly, most of the periplasmic cpx* gain-of-function
mutations cluster in the central region of this domain, and one encodes a
deletion of 32 amino acids. Strains harboring these mutations are rendered
insensitive to a normally activating signal. In vivo and in vitro
characterization of maltose-binding-protein fusions between the wild-type CpxA
and a representative cpx* mutant, CpxA101, showed that the mutant CpxA is altered
in phosphotransfer reactions with CpxR. Specifically, while both CpxA and CpxA101
function as autokinases and CpxR kinases, CpxA101 is devoid of a CpxR-P
phosphatase activity normally present in the wild-type protein. Taken together,
the data support a model for Cpx-mediated signal transduction in which the
kinase/phosphatase ratio is elevated by stress. Further, the sequence and
phenotypes of periplasmic cpx* mutations suggest that interactions with a
periplasmic signaling molecule may normally dictate a decreased
kinase/phosphatase ratio under nonstress conditions.
PMID- 9401032
TI - Cloning of the RHO1 gene from Candida albicans and its regulation of beta-1,3
glucan synthesis.
AB - The Saccharomyces cerevisiae RHO1 gene encodes a low-molecular-weight GTPase. One
of its recently identified functions is the regulation of beta-1,3-glucan
synthase, which synthesizes the main component of the fungal cell wall (J.
Drgonova et al., Science 272:277-279, 1996; T. Mazur and W. Baginsky, J. Biol.
Chem. 271:14604-14609, 1996; and H. Qadota et al., Science 272:279-281, 1996).
From the opportunistic pathogenic fungus Candida albicans, we cloned the RHO1
gene by the PCR and cross-hybridization methods. Sequence analysis revealed that
the Candida RHO1 gene has a 597-nucleotide region which encodes a putative 22.0
kDa peptide. The deduced amino acid sequence predicts that Candida albicans Rho1p
is 82.9% identical to Saccharomyces Rho1p and contains all the domains conserved
among Rho-type GTPases from other organisms. The Candida albicans RHO1 gene could
rescue a S. cerevisiae strain containing a rho1 deletion. Furthermore,
recombinant Candida albicans Rho1p could reactivate the beta-1,3-glucan synthesis
activities of both C. albicans and S. cerevisiae membranes in which endogenous
Rho1p had been depleted by Tergitol NP-40-NaCl treatment. Candida albicans Rho1p
was copurified with the beta-1,3-glucan synthase putative catalytic subunit,
Candida albicans Gsc1p, by product entrapment. Candida albicans Rho1p was shown
to interact directly with Candida albicans Gsc1p in a ligand overlay assay and a
cross-linking study. These results indicate that Candida albicans Rho1p acts in
the same manner as Saccharomyces cerevisiae Rho1p to regulate beta-1,3-glucan
synthesis.
PMID- 9401033
TI - Mutational analysis of the three cysteines and active-site aspartic acid 103 of
ketosteroid isomerase from Pseudomonas putida biotype B.
AB - In order to clarify the roles of three cysteines in ketosteroid isomerase (KSI)
from Pseudomonas putida biotype B, each of the cysteine residues has been changed
to a serine residue (C69S, C81S, and C97S) by site-directed mutagenesis. All
cysteine mutations caused only a slight decrease in the k(cat) value, with no
significant change of Km for the substrate. Even modification of the sulfhydryl
group with 5,5'-dithiobis(2-nitrobenzoic acid) has almost no effect on enzyme
activity. These results demonstrate that none of the cysteines in the KSI from P.
putida is critical for catalytic activity, contrary to the previous
identification of a cysteine in an active-site-directed photoinactivation study
of KSI. Based on the three-dimensional structures of KSIs with and without
dienolate intermediate analog equilenin, as determined by X-ray crystallography
at high resolution, Asp-103 was found to be located within the range of the
hydrogen bond to the equilenin. To assess the role of Asp-103 in catalysis, Asp
103 has been replaced with either asparagine (D103N) or alanine (D103A) by site
directed mutagenesis. For D103A mutant KSI there was a significant decrease in
the k(cat) value: the k(cat) of the mutant was 85-fold lower than that of the
wild-type enzyme; however, for the D103N mutant, which retained some hydrogen
bonding capability, there was a minor decrease in the k(cat) value. These
findings support the idea that aspartic acid 103 in the active site is an
essential catalytic residue involved in catalysis by hydrogen bonding to the
dienolate intermediate.
PMID- 9401034
TI - Regulation of expression of the pilA gene in Myxococcus xanthus.
AB - Type IV pili are required for social gliding motility in Myxococcus xanthus. In
this work, the expression of pilin (the pilA gene product) during vegetative
growth and fruiting-body development was examined. A polyclonal antibody against
the pilA gene product (prepilin) was prepared, along with a pilA-lacZ fusion, and
was used to assay expression of pilA in M. xanthus in different mutant
backgrounds. pilA expression required the response regulator pilR but was
negatively regulated by the putative sensor kinase pilS. pilA expression did not
require pilB, pilC, or pilT. pilA was also autoregulated; a mutation which
altered an invariant glutamate five residues from the presumed prepilin
processing site eliminated this autoregulation, as did a deletion of the pilA
gene. Primer extension and S1 nuclease analysis identified a sigma54 promoter
upstream of pilA, consistent with the homology of pilR to the NtrC family of
response regulators. Expression of pilA was found to be developmentally
regulated; however, the timing of this expression pattern was not entirely
dependent on pilS or pilR. Finally, pilA expression was induced by high nutrient
concentrations, an effect that was also not dependent on pilS or pilR.
PMID- 9401036
TI - Evidence of participation of McrB(S) in McrBC restriction in Escherichia coli K
12.
AB - The McrBC restriction system has the ability to restrict DNA containing 5
hydroxymethylcytosine, N4-methylcytosine, and 5-methylcytosine at specific
sequences. The mcrB gene produces two gene products. The complete mcrB open
reading frame produces a 51-kDa protein (McrB(L)) and a 33-kDa protein (McrB(S)).
The smaller McrB polypeptide is produced from an in-frame, internal translational
start site in the mcrB gene. The McrB(S) sequence is identical to that of McrB(L)
except that it lacks 161 amino acids present at the N-terminal end of the latter
protein. It has been suggested that McrB(L) is the DNA binding restriction
subunit. The function of McrB(S) is unknown, although there has been speculation
that it plays some role in the modulation of McrBC restriction. Studies of the
function of McrB(S) have been challenging since it is produced in frame with
McrB(L). In this study, we tested the effects of underproduction (via antisense
RNA) and overproduction (via gene dosage) of mcrBC gene products on restriction
levels of the mcrBC+ strain JM107. Among the parameters monitored was the
induction of SOS responses, which indicate of DNA damage. Evidence from this
study suggests that McrB(S) is necessary for stabilization of the McrBC
restriction complex in vivo.
PMID- 9401035
TI - Myxococcus xanthus sasS encodes a sensor histidine kinase required for early
developmental gene expression.
AB - Initiation of Myxococcus xanthus multicellular development requires integration
of information concerning the cells' nutrient status and density. A gain-of
function mutation, sasB7, that bypasses both the starvation and high cell density
requirements for developmental expression of the 4521 reporter gene, maps to the
sasS gene. The wild-type sasS gene was cloned and sequenced. This gene is
predicted to encode a sensor histidine protein kinase that appears to be a key
element in the transduction of starvation and cell density inputs. The sasS null
mutants express 4521 at a basal level, form defective fruiting bodies, and
exhibit reduced sporulation efficiencies. These data indicate that the wild-type
sasS gene product functions as a positive regulator of 4521 expression and
participates in M. xanthus development. The N terminus of SasS is predicted to
contain two transmembrane domains that would locate the protein to the
cytoplasmic membrane. The sasB7 mutation, an E139K missense mutation, maps to the
predicted N-terminal periplasmic region. The C terminus of SasS contains all of
the conserved residues typical of the sensor histidine protein kinases. SasS is
predicted to be the sensor protein in a two-component system that integrates
information required for M. xanthus developmental gene expression.
PMID- 9401037
TI - Cloning and expression of a gene from Streptomyces scabies encoding a putative
pathogenicity factor.
AB - We cloned a 9.4-kb DNA fragment from Streptomyces scabies ATCC 41973 that allows
the nonpathogen Streptomyces lividans 66 TK24 to necrotize and colonize potato
tuber slices and produce scab-like symptoms on potato minitubers. Deletion
analysis demonstrated that activity was conferred by a 1.6-kb DNA region.
Sequence analysis of a 2.4-kb DNA fragment spanning the DNA region necessary for
activity revealed three open reading frames (ORFs). The deduced amino acid
sequence of ORF1, designated ORFtnp, showed high levels of identity with the
first 233 amino acids of the putative transposases of the IS1164 elements from
Rhodococcus rhodochrous (71%) and Mycobacterium bovis (68%), members of the
Staphylococcus aureus IS256 family of transposases. No significant homologies to
ORF2 and ORF3 were found in the nucleic acid and protein databases. ORFtnp is
located 5' of ORF3. ORF2 is incomplete and is located 3' of ORF3. Subcloning of
the individual ORFs demonstrated that ORF3, designated nec1, is sufficient for
necrotizing activity in S. lividans 66 TK24. S. lividans 66 TK24 expressing nec1
does not produce thaxtomin A but produces an unidentified extracellular water
soluble compound that causes necrosis on potato tuber discs. The G+C content of
nec1 suggests that it has moved horizontally from another genus. Southern
analysis of ORFtnp and nec1 demonstrate that these genes are physically linked in
Streptomyces strains, including S. scabies and Streptomyces acidiscabies strains,
that are pathogenic on potato and that produce the phytotoxin thaxtomin A. These
data suggest that nec1 may have been mobilized into S. scabies through a
transposition event mediated by ORFtnp.
PMID- 9401038
TI - A glgC gene essential only for the first of two spatially distinct phases of
glycogen synthesis in Streptomyces coelicolor A3(2).
AB - By using a PCR approach based on conserved regions of ADP-glucose
pyrophosphorylases, a glgC gene was cloned from Streptomyces coelicolor A3(2).
The deduced glgC gene product showed end-to-end relatedness to other bacterial
ADP-glucose pyrophosphorylases. The glgC gene is about 1,000 kb from the leftmost
chromosome end and is not closely linked to either of the two glgB genes of S.
coelicolor, which encode glycogen branching enzymes active in different locations
in differentiated colonies. Disruption of glgC eliminated only the first of two
temporal peaks of ADP-glucose pyrophosphorylase activity and glycogen
accumulation and prevented cytologically observable glycogen accumulation in the
substrate mycelium of colonies (phase I), while glycogen deposition in young
spore chains (phase II) remained readily detectable. The cloned glgC gene
therefore encodes an ADP-glucose pyrophosphorylase essential only for phase I
(and it is therefore named glgCI). A second, phase II-specific, glgC gene should
also exist in S. coelicolor, though it was not detected by hybridization
analysis.
PMID- 9401039
TI - Characteristics of Fps1-dependent and -independent glycerol transport in
Saccharomyces cerevisiae.
AB - Eadie-Hofstee plots of glycerol uptake in wild-type Saccharomyces cerevisiae W303
1A grown on glucose showed the presence of both saturable transport and simple
diffusion, whereas an fps1delta mutant displayed only simple diffusion.
Transformation of the fps1delta mutant with the glpF gene, which encodes glycerol
transport in Escherichia coli, restored biphasic transport kinetics. Yeast
extract-peptone-dextrose-grown wild-type cells had a higher passive diffusion
constant than the fps1delta mutant, and ethanol enhanced the rate of proton
diffusion to a greater extent in the wild type than in the fps1delta mutant. In
addition, the lipid fraction of the fps1delta mutant contained a lower percentage
of phospholipids and a higher percentage of glycolipids than that of the wild
type. Fps1p, therefore, may be involved in the regulation of lipid metabolism in
S. cerevisiae, affecting membrane permeability in addition to fulfilling its
specific role in glycerol transport. Simultaneous uptake of glycerol and protons
occurred in both glycerol- and ethanol-grown wild-type and fps1delta cells and
resulted in the accumulation of glycerol at an inside-to-outside ratio of 12:1 to
15:1. Carbonyl cyanide m-chlorophenylhydrazone prevented glycerol accumulation in
both strains and abolished transport in the fps1delta mutant grown on ethanol.
Likewise, 2,4-dinitrophenol inhibited transport in glycerol-grown wild-type
cells. These results indicate the presence of an Fps1p-dependent facilitated
diffusion system in glucose-grown cells and an Fps1p-independent proton symport
system in derepressed cells.
PMID- 9401040
TI - Purification, properties, and sequence of glycerol trinitrate reductase from
Agrobacterium radiobacter.
AB - Glycerol trinitrate (GTN) reductase, which enables Agrobacterium radiobacter to
utilize GTN and related explosives as sources of nitrogen for growth, was
purified and characterized, and its gene was cloned and sequenced. The enzyme was
a 39-kDa monomeric protein which catalyzed the NADH-dependent reductive scission
of GTN (Km = 23 microM) to glycerol dinitrates (mainly the 1,3-isomer) with a pH
optimum of 6.5, a temperature optimum of 35 degrees C, and no dependence on metal
ions for activity. It was also active on pentaerythritol tetranitrate (PETN), on
isosorbide dinitrate, and, very weakly, on ethyleneglycol dinitrate, but it was
inactive on isopropyl nitrate, hexahydro-1,3,5-trinitro-1,3,5-triazine, 2,4,6
trinitrotoluene, ammonium ions, nitrate, or nitrite. The amino acid sequence
deduced from the DNA sequence was homologous (42 to 51% identity and 61 to 69%
similarity) to those of PETN reductase from Enterobacter cloacae, N
ethylmaleimide reductase from Escherichia coli, morphinone reductase from
Pseudomonas putida, and old yellow enzyme from Saccharomyces cerevisiae, placing
the GTN reductase in the alpha/beta barrel flavoprotein group of proteins. GTN
reductase and PETN reductase were very similar in many respects except in their
distinct preferences for NADH and NADPH cofactors, respectively.
PMID- 9401041
TI - Characterization of a DNA polymerase from the uncultivated psychrophilic archaeon
Cenarchaeum symbiosum.
AB - Cenarchaeum symbiosum, an archaeon which lives in specific association with a
marine sponge, belongs to a recently recognized nonthermophilic crenarchaeotal
group that inhabits diverse cold and temperate environments. Nonthermophilic
crenarchaeotes have not yet been obtained in laboratory culture, and so their
phenotypic characteristics have been inferred solely from their ecological
distribution. Here we report on the first protein to be characterized from one of
these organisms. The DNA polymerase gene of C. symbiosum was identified in the
vicinity of the rRNA operon on a large genomic contig. Its deduced amino acid
sequence is highly similar to those of the archaeal family B (alpha-type) DNA
polymerases. It shared highest overall sequence similarity with the crenarchaeal
DNA polymerases from the extreme thermophiles Sulfolobus acidocaldarius and
Pyrodictium occultum (54% and 53%, respectively). The conserved motifs of B
(alpha-)-type DNA polymerases and 3'-5' exonuclease were identified in the 845
amino-acid sequence. The 96-kDa protein was expressed in Escherichia coli and
purified with affinity tags. It exhibited its highest specific activity with
gapped-duplex (activated) DNA as the substrate. Single-strand- and double-strand
dependent 3'-5' exonuclease activity was detected, as was a marginal 5'-3'
exonuclease activity. The enzyme was rapidly inactivated at temperatures higher
than 40 degrees C, with a half-life of 10 min at 46 degrees C. It was found to be
less thermostable than polymerase I of E. coli and is substantially more heat
labile than its most closely related homologs from thermophilic and
hyperthermophilic crenarchaeotes. Although phylogenetic studies suggest a
thermophilic ancestry for C. symbiosum and its relatives, our biochemical
analysis of the DNA polymerase is consistent with the postulated nonthermophilic
phenotype of these crenarchaeotes, to date inferred solely from their ecological
distribution.
PMID- 9401042
TI - Synthesis of nitric oxide from the two equivalent guanidino nitrogens of L
arginine by Lactobacillus fermentum.
AB - Ten strains of Lactobacillus fermentum that differed in origin converted
metmyoglobin to nitrosylmyoglobin [a pentacoordinate nitric oxide (NO) complex of
Fe(II) myoglobin] in MRS broth at pH 4.3. Of the 10 strains, L. fermentum IFO
3956 possessed the strongest capacity to convert metmyoglobin to
nitrosylmyoglobin. This strain synthesizes NO enzymatically from the two
equivalent guanidino nitrogens of L-arginine. To our knowledge, this demonstrates
for the first time the production of NO synthesized from the guanidino nitrogens
of L-arginine by lactic acid bacteria. IFO 3956 may possess a bacterial NO
synthase.
PMID- 9401043
TI - bldA-dependent expression of the Streptomyces exfoliatus M11 lipase gene (lipA)
is mediated by the product of a contiguous gene, lipR, encoding a putative
transcriptional activator.
AB - Extracellular lipase synthesis by Streptomyces lividans 66 carrying the cloned
lipase gene (lipA) from Streptomyces exfoliatus M11 was found to be growth phase
dependent, since lipase was secreted into the medium mainly during the stationary
phase; S1 nuclease protection experiments revealed abundant lipA transcripts in
RNA preparations obtained during the stationary phase but not in those obtained
during exponential growth. Transcription from the lipA promoter was dependent on
the presence of lipR, a contiguous downstream gene with a very high guanine-plus
cytosine content (80.2%). The deduced lipR product consists of a protein of 934
amino acids that shows similarity to known transcriptional activators and has a
strong helix-turn-helix motif at its C terminus; this motif is part of a domain
homologous to DNA-binding domains of bacterial regulators of the UhpA/LuxR
superfamily. The lipR sequence revealed the presence of a leucine residue,
encoded by the rare TTA codon, which caused bldA dependence of lipA transcription
in Streptomyces coelicolor A3(2); replacement of the TTA codon by the alternate
CTC leucine codon alleviated bidA dependence but not the apparent growth phase
dependent regulation of lipA transcription. When lipR expression was induced in a
controlled fashion during the exponential growth phase, by placing it under the
inducible tipA promoter, lipase synthesis was shifted to the exponential growth
phase, indicating that the timing of lipR expression, and not its bldA
dependence, is the main cause for stationary-phase transcription of lipA.
PMID- 9401044
TI - A Mycobacterium smegmatis mutant with a defective inositol monophosphate
phosphatase gene homolog has altered cell envelope permeability.
AB - A bacteriophage infection mutant (strain LIMP7) of Mycobacterium smegmatis was
isolated following transposon mutagenesis. The mutant showed an unusual
phenotype, in that all phages tested produced larger plaques on this strain
compared to the parent strain. Other phenotypic characteristics of the mutant
were slower growth, increased clumping in liquid culture, increased resistance to
chloramphenicol and erythromycin, and increased sensitivity to isoniazid and
several beta-lactam antibiotics. Permeability studies showed decreases in the
accumulation of lipophilic molecules (norfloxacin and chenodeoxycholate) and a
small increase with hydrophilic molecules (cephaloridine); taken together, these
characteristics indicate an altered cell envelope. The DNA adjacent to the
transposon in LIMP7 was cloned and was shown to be highly similar to genes
encoding bacterial and mammalian inositol monophosphate phosphatases. Inositol is
important in mycobacteria as a component of the major thiol mycothiol and also in
the cell wall, with phosphatidylinositol anchoring lipoarabinomannan (LAM) in the
cell envelope. In LIMP7, levels of phosphatidylinositol dimannoside, the
precursor of LAM, were less than half of those in the wild-type strain,
confirming that the mutation had affected the synthesis of inositol-containing
molecules. The impA gene is located within the histidine biosynthesis operon in
both M. smegmatis and Mycobacterium tuberculosis, lying between the hisA and hisF
genes.
PMID- 9401045
TI - Regulation of ornithine utilization in Pseudomonas aeruginosa (PAO1) is mediated
by a transcriptional regulator, OruR.
AB - We have used transpositional mutagenesis of a proline auxotroph (PAO951) to
isolate an ornithine utilization (oru) mutant of Pseudomonas aeruginosa (PAO951
4) that was unable to use ornithine efficiently as the sole carbon and nitrogen
source. DNA sequence analysis of the inactivated locus confirmed that the
transposon had inserted into a locus whose product demonstrated significant
primary sequence homology to members of the AraC family of transcriptional
activators. DNA mobility shift assays affirmed this potential regulatory function
and indicated that the inactivated gene encodes a transcriptional regulator,
which has been designated OruR. In trying to define the ornithine utilization
phenotype further, a similar inactivation was engineered in the wild-type strain,
PAO1. The resulting isolate (PAO1R4) was totally unable to use ornithine as the
sole carbon source. Despite the intensified phenotype, this isolate failed to
demonstrate significant changes in any of the catabolic or anabolic enzymes that
are known to be subject to regulation by the presence of either ornithine or
arginine. It did, however, show modified levels of an enzyme, ornithine
acetyltransferase (OAcT), that was previously thought to have merely an
anaplerotic activity. Definition of this oruR locus and its effects upon OAcT
activity provide evidence that control of ornithine levels in P. aeruginosa may
have a significant impact upon how the cell is able to monitor and regulate the
use of arginine and glutamate as sources of either carbon or nitrogen.
PMID- 9401047
TI - Cloning and characterization of the major outer membrane protein gene (ompH) of
Pasteurella multocida X-73.
AB - The major outer membrane protein (OmpH) of Pasteurella multocida X-73 was
purified by selective extraction with detergents, followed by size exclusion
chromatography. The planar lipid bilayer assay showed that OmpH has pore-forming
function. The average single channel conductance in 1.0 M KCl was 0.62 nS. The
gene (ompH) encoding OmpH has been isolated and sequenced by construction of a
genomic library and PCR techniques. The coding region of this gene is 1,059 bp
long. The predicted primary protein is composed of 353 amino acids, with a 20
amino-acid signal peptide. The mature protein is composed of 333 amino acids with
a molecular mass of 36.665 kDa. The ompH gene encoding mature protein has been
expressed in Escherichia coli by using a regulatable expression system. The ompH
gene was distributed among 15 P. multocida serotypes and strain CU. Protection
studies showed that OmpH was able to induce homologous protection in chickens.
These findings demonstrate that OmpH is a protective outer membrane porin of
strain X-73 and is conserved among P. multocida somatic serotypes.
PMID- 9401046
TI - Cloning and genetic and sequence analyses of the bacteriocin 21 determinant
encoded on the Enterococcus faecalis pheromone-responsive conjugative plasmid
pPD1.
AB - The pheromone-responsive conjugative plasmid pPD1 (59 kb) of Enterococcus
faecalis encodes the bacteriocin 21 (bac21) determinant. Cloning, transposon
insertion mutagenesis and sequence analysis of the bac21 determinant showed that
an 8.5-kb fragment lying between kb 27.1 and 35.6 of the pPD1 map is required for
complete expression of the bacteriocin. The 8.5-kb fragment contained nine open
reading frames (ORFs), bacA to bac1, which were oriented in the same (upstream-to
downstream) direction. Transposon insertions into the bacA to bacE ORFs, which
are located in the proximal half of bac21, resulted in defective bacteriocin
expression. Insertions into the bacF to bac1 ORFs, which are located in the
distal half of bac21, resulted in reduced bacteriocin expression. Deletion mutant
analysis of the cloned 8.5-kb fragment revealed that the deletion of segments
between kb 31.6 and 35.6 of the pPD1 map, which contained the distal region of
the determinant encoding bacF to bac1, resulted in reduced bacteriocin
expression. The smallest fragment (4.5 kb) retaining some degree of bacteriocin
expression contained the bacA to bacE sequences located in the proximal half of
the determinant. The cloned fragment encoding the 4.5-kb proximal region and a
Tn916 insertion mutant into pPD1 bacB trans-complemented intracellularly to give
complete expression of the bacteriocin. bacA encoded a 105-residue sequence with
a molecular mass of 11.1 kDa. The deduced BacA protein showed 100% homology to
the broad-spectrum antibiotic peptide AS-48, which is encoded on the E. faecalis
conjugative plasmid pMB2 (58 kb). bacH encoded a 195-residue sequence with a
molecular mass of 21.9 kDa. The deduced amino acid sequence showed significant
homology to the C-terminal region of HlyB (31.1% identical residues), a protein
located in the Escherichia coli alpha-hemolysin operon that is a representative
bacterial ATP-binding cassette export protein.
PMID- 9401048
TI - msDNA-Ec48, the smallest multicopy single-stranded DNA from Escherichia coli.
AB - Previously we have reported a novel bacterial reverse transcriptase (RT) from
Escherichia coli ECOR58 strains in which the YXDD box was replaced with LVDD (J.
R. Mao, S. Inouye, and M. Inouye, Biochem. Biophys. Res. Commun. 227:489-493,
1996). Here we determined the structure of the multicopy single-stranded DNA
(msDNA) produced by the RT. The msDNA was found to consist of a single-stranded
DNA of 48 nucleotides in length, the shortest msDNA thus far identified from
natural sources. The msDNA, the RT, and the retron are designated msDNA-Ec48, RT
Ec48, and retron-Ec48, respectively. On the basis of the structure of the msr
gene, the RNA molecule of msDNA-Ec48 is predicted to be composed of 119
ribonucleotides; it is the longest RNA among the known msDNAs. Analysis of the
DNA sequences flanking the retron indicates that retron-Ec48 is associated with a
prophage related to phages P2 and P4.
PMID- 9401049
TI - Comparison of the bacterial HelA protein to the F508 region of the cystic
fibrosis transmembrane regulator.
AB - The HelA protein of Rhodobacter capsulatus is the ATP-binding-cassette subunit of
an exporter complex required for cytochrome c biogenesis. By primary sequence
comparisons the F88 residue of HelA is similar to the F508 residue of the cystic
fibrosis transmembrane regulator (CFTR) protein. Previous studies have
established that CFTR F508delta or F508R proteins are defective but F508C is
functional. Our results demonstrate that the HelA F88 mutants functionally mimic
the phenotypes of known CFTR F508 mutants. The phenotypes of additional HelA
mutants and the in vivo steady-state levels of these proteins are also reported.
PMID- 9401050
TI - Dinitrogenase reductase-activating glycohydrolase can be released from
chromatophores of Rhodospirillum rubrum by treatment with MgGDP.
AB - Dinitrogenase reductase-activating glycohydrolase (DRAG), involved in the
regulation of nitrogenase activity in Rhodospirillum rubrum, is associated with
chromatophore membranes in cell extracts. We show that DRAG can be specifically
released by treatment with MgGDP; other nucleotides studied had no effect. The
DRAG activity released corresponds to the release of DRAG protein.
PMID- 9401051
TI - Inner membrane efflux components are responsible for beta-lactam specificity of
multidrug efflux pumps in Pseudomonas aeruginosa.
AB - A major feature of the MexAB-OprM multidrug efflux pump which distinguishes it
from the MexCD-OprJ and MexEF-OprN multidrug efflux systems in Pseudomonas
aeruginosa is its ability to export a wide variety of beta-lactam antibiotics.
Given the periplasmic location of their targets it is feasible that beta-lactams
exit the cell via the outer membrane OprM without interaction with MexA and MexB,
though the latter appear to be necessary for OprM function. To test this,
chimeric MexAB-OprJ and MexCD-OprM efflux pumps were reconstituted in delta mexCD
delta oprM and delta mexAB delta oprJ strains, respectively, and the influence of
the exchange of outer membrane components on substrate (i.e., beta-lactam)
specificity was assessed. Both chimeric pumps were active in antibiotic efflux,
as evidenced by their contributions to resistance to a variety of antimicrobial
agents, although there was no change in resistance profiles relative to the
native pumps, indicating that OprM is not the determining factor for the beta
lactam specificity of MexAB-OprM. Thus, one or both of inner membrane-associated
proteins MexA and MexB are responsible for drug recognition, including
recognition of beta-lactams.
PMID- 9401053
TI - Hepatitis C virus-related lymphomas.
PMID- 9401052
TI - Bordetella bronchiseptica expresses the fimbrial structural subunit gene fimA.
AB - The differential host species specificities of Bordetella pertussis, B.
parapertussis, and B. bronchiseptica might be explained by polymorphisms in
adherence factor genes. We have found that B. parapertussis and B.
bronchiseptica, unlike B. pertussis, contain a full-length gene for the fimbrial
subunit FimA. B. bronchiseptica expresses fimA in a BvgAS-dependent fashion.
PMID- 9401054
TI - Induction of nitric oxide synthase is involved in the mechanism of Fas-mediated
apoptosis in haemopoietic cells.
AB - Induction of nitric oxide synthase (iNOS) and production of the toxic metabolite
nitric oxide (NO) is one of the interferon-gamma (IFN-gamma) and tumour necrosis
factor-alpha (TNF-alpha) regulated effector mechanisms that can lead to apoptosis
of haemopoietic progenitor cells. Fas-receptor (Fas-R) expression can be
stimulated by IFN-gamma and TNF-alpha. Transactivation of iNOS, and possibly Fas
R promoters, by interferon regulatory factor-1 expressed in response to IFN-gamma
may be a part of the iNOS transduction pathway. We investigated whether the
effects of Fas-R triggering in haemopoietic cells were mediated by NO. On Western
blotting, we observed that Fas-receptor agonist, monoclonal antibody CH11.
enhanced expression of iNOS. As shown by the reverse transcription polymerase
chain reaction. CH11 also induced iNOS mRNA expression in purified CD34+ cells.
To determine whether NO was involved in Fas-mediated apoptosis we inhibited iNOS
catalysed production of NO using anti-sense (AS) oligodeoxynucleotides (ODN)
directed against iNOS mRNA. After culture of haemopoietic cells in the presence
of AS-ODN, iNOS expression decreased and was no longer enhanced by Fas. This
effect was associated with the prevention of Fas-mediated apoptosis, as
determined by a DNA fragmentation and terminal deoxynucleotidyl transferase
staining. In colony assays, specific AS-oligonucleotides prevented FAS-mediated
inhibition of colony formation by total bone marrow and CD34+ progenitor cells.
Our data suggest that the inhibitory effects of Fas, including induction of
apoptosis, are mediated by effector mechanisms that may be similar to those
described for IFN-gamma and TNF-alpha.
PMID- 9401055
TI - CD34+ peripheral blood progenitor cell and monocyte derived dendritic cells: a
comparative analysis.
AB - Dendritic cells (DC) have been generated in vitro from either CD34+ haemopoietic
progenitor cells (HPC) or peripheral blood monocytes (Mo) in the presence of
specific cytokine combinations, including granulocyte-macrophage colony
stimulating factor (GM-CSF). Since differences between DC from either source may
be important for the clinical use of these antigen-presenting cells (APC), a
comparative analysis was performed. HPC were expanded in the presence of
interleukin (IL)-3, IL-6 and stem cell factor (SCF) (days 1-7) and subsequently
induced by IL-4+ GM-CSF (days 8-26) to differentiate to Langerhans-type cells
(pLC). The latter cytokines were similarly used to generate Mo-derived LC (mLC).
Maturation of both cell types, pLC and mLC, to interdigitating DC-type cells
(iDC) was induced by tumour necrosis factor-alpha (TNF-alpha) or
lipopolysaccharide (LPS). Analysis of mLC/pLC and miDC/piDC with respect to
morphology, phenotype, antigen uptake and presentation revealed a high similarity
of DC from either source. The majority of mLC, however, exhibited a more mature
differentiation stage, compared to pLC, evidenced from lower numbers of
multilaminar MHC class II compartments and less efficient APC function for
extracellular protein antigens. Although macropinocytosis was performed by LC,
neither LC nor iDC from either source were able to take up > or = 0.5 microm
latex beads. However, phagocytosis of 0.5 microm and 1 microm beads was performed
by Mo that could subsequently be induced to become iDC, thus providing the unique
opportunity to present phagocytosed material in DC-type fashion. Mo may be the
preferential source for clinical use of iDC-type cells since preparation and
culture are easier to perform and are less costly while APC function is similar
to HPC-derived iDC.
PMID- 9401056
TI - Constitutive and inducible expression of megakaryocyte-specific genes in Friend
erythroleukaemia cells.
AB - Friend murine erythroleukaemia cells (MELC) were analysed by semiquantitative RT
PCR for the constitutive and inducible expression of megakaryocyte-specific
genes. Uninduced MELC expressed detectable levels of mRNAs for
acethylcholinesterase (AChE), platelet factor-4 (PF4), glycoprotein IIb (GPIIb)
and von Willebrand factor (VWF), whereas the erythroid alpha- and beta-globin
genes were not transcribed appreciably. However, MELC exposed to 5 mM
hexamethylene bisacetamide (HMBA) or 1.5% dimethyl sulphoxide (DMSO) seemed to be
channelled towards a mixed erythroid/megakaryocytic phenotype characterized by
unaltered levels of VWF mRNA, increased levels of AChE, GPIIb and PF4 mRNA. and
simultaneous induction of the globin genes. Megakaryocyte-related genes were
expressed. in the absence of globin gene transcription, by MELC treated with
either phorbol-12-myristate acetate (PMA; 100 ng/ml) or colcemid (40 nM), an
antimicrotubule agent capable of promoting polyploidization in this model.
Moreover, PMA and colcemid induced also de novo expression of the thrombopoietin
receptor c-mpl. PMA and colcemid did not affect high basal c-myb mRNA levels
which, in turn, were down-regulated upon HMBA or DMSO induction. Additionally,
both uninduced and induced MELC exhibited significant levels of Epo-R and IL-3R
mRNAs, whereas no expression of granulocyte/macrophage-related genes was
detected. Megakaryocyte gene expression of MELC was also compared to that of
other haemopoietic cell populations from normal mice and mice infected with the
anaemic strain of the Friend virus. According to our results, MELC should be seen
as an unique erythro-megakaryocytic model of differentiation, potentially useful
for studying molecular events governing lineage commitment as well as some steps
of megakaryocytopoiesis.
PMID- 9401058
TI - T cells selectively infiltrate bone marrow areas with residual haemopoiesis of
patients with acquired aplastic anaemia.
AB - Aplastic anaemia (AA) is characterized by pancytopenia and bone marrow (BM)
hypocellularity. In some patients AA may be mediated by T cells. To localize
inflammatory cell infiltrates, we carried out a quantitative immunohistochemical
analysis of BM biopsies of AA patients. In five out of eight biopsies,
significantly higher numbers T cells were found in the areas with residual
haemopoiesis (RH). The significantly increased numbers of CD3+ T cells in areas
with RH supports the hypothesis of a site-directed infiltration and/or a local
proliferation of T cells in the BM of patients with AA.
PMID- 9401057
TI - Megakaryocytes derived from CD34-positive cord blood cells produce interleukin-8.
AB - In a serum-free liquid culture, thrombopoietin (TPO) selectively stimulated the
growth of megakaryocytic cells from CD34-positive cord blood cells. Using these
cultured cells, we investigated cytokine production by human megakaryocytes. Day
10 megakaryocytes (2 x 10(5)) secreted > 1000 pg/ml of interleukin (IL)-8, in
contrast to small amounts of IL-1beta and IL-6. A time-course study showed that
the IL-8 production of megakaryocytes occurred at the late phase of the culture
period. The megakaryocyte-conditioned medium had the chemotactic potential of
polymorphonuclear leucocytes, which was abrogated by the addition of anti-IL-8
antibody, suggesting the secretion of biologically active IL-8. The combination
of TPO and IL-1alpha was required for a significant augmentation of the IL-8
secretion. Direct evidence for IL-8 synthesis in megakaryocytes was provided by
reverse transcription-polymerase chain reaction on purified CD41b+ cells and by
the detection of intracellular IL-8 in CD41b+ cells. These results suggest that
TPO stimulates not only the proliferation and differentiation of the progenitors
capable of megakaryocytic lineage expression but also IL-8 release by the
megakaryocytic cells with the aid of IL-1.
PMID- 9401059
TI - Severe aplastic anaemia in association with a unique constitutional translocation
46,XY,t(6;10)(q13;q22)c.
AB - Severe aplastic anaemia (SAA) is an uncommon disorder which may be associated
with several congenital syndromes. However, it has rarely been described in
association with a constitutional karyotypic abnormality. The breakpoint of the
balanced t(6:10)(q13:q22) translocation described here does not disrupt any
currently recognized gene of haemopoietic or stromal importance. This report also
highlights the problems inherent in the use of bone marrow transplantation (BMT)
for treating multiply transfused aplastic anaemia patients.
PMID- 9401060
TI - Total absence of protein 4.2 and partial deficiency of band 3 in hereditary
spherocytosis.
AB - Unlike previously reported cases with total protein 4.2 deficiency due to
mutations in the EPB42 gene, we describe a total deficiency in protein 4.2 with
normal EPB42 alleles. Hereditary spherocytosis (HS) was observed in a Japanese
woman (unsplenectomized) and her daughter (splenectomized). The mother showed a
partial deficiency in band 3 and a proportional reduction in protein 4.2. She was
heterozygous for a novel allele of the EPB3 gene, allele Okinawa, which contains
the two mutations that define the Memphis II polymorphism (K56E, AAG-->GAG, and
P854L, CCG-->CTG) and, additionally, the mutation: G714R, GGG-->AGG, located in a
highly conserved position of transmembrane segment 9. The latter change was
responsible for HS. In trans to allele Okinawa, the daughter displayed allele
Fukuoka: G130R, GGA-->AGA, an allele known to alter the binding of protein 4.2 to
band 3. The daughter presented with a more pronounced decrease of band 3, and
lacked protein 4.2, resulting in aggravated haemolytic features. Although the
father was not available for study, heterozygosity for allele Fukuoka has been
documented in another individual who showed no clinical or haematological signs,
and a normal content of band 3. We suggest that band 3 Okinawa binds virtually
all the protein 4.2 in red cell precursors, band 3 Fukuoka being unable to do so,
and that the impossibility of band 3 Okinawa incorporation into the membrane
leads to degradation of the band 3 Okinawa protein 4.2 complex. In contrast, band
3 Fukuoka, free of bound protein 4.2, could then incorporate normally into the
bilayer. Thus, protein 4.2 would not appear in the daughter's red cell membrane.
PMID- 9401061
TI - Distribution of the cytogenetic abnormality +i(3)(q10) in persistent polyclonal B
cell lymphocytosis: a FICTION study in three cases.
AB - Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare entity characterized
by a moderate but sustained lymphocytosis where some binucleated or bilobulated
circulating forms constitute, even if they are not entirely specific, the
cytological hallmark of the disease. An additional chromosome long arm i(3)(q10)
has recently been reported as a recurrent cytogenetic aberration, contrasting
with a usual polyclonal immunoglobulin expression. To determine more precisely
the distribution of the chromosomal abnormality within the peripheral lymphocyte
population and study the relationship between the +i(3)(q10) and the bilobulated
character, we investigated three new cases of PPBL displaying the cytogenetic
abnormality on the karyotype, using a technique of simultaneous fluorescence
immunophenotyping and interphase cytogenetics (FICTION). We demonstrated that the
+i(3)(q10) was restricted to the B lymphocytes, independently of the kappa or
lambda light chain isotype and was present in both bilobulated and non
bilobulated cells. Therefore it is likely that the cytogenetic abnormality occurs
at an early stage of lymphocyte differentiation in a precursor cell already
committed to the B-cell lineage, before any rearrangement of immunoglobulin genes
has taken place.
PMID- 9401062
TI - Addition of granulocyte colony-stimulating factor to chemotherapy in patients
with AIDS-related lymphoma: effects on neutrophil Fc gamma receptor expression
and soluble Fc gammaRIII plasma levels.
AB - AIDS-related neutropenia and neutrophil dysfunction can (partly) be reversed by
granulocyte-colony stimulating factor (G-CSF). We studied the effect of G-CSF on
neutrophil increment and levels of soluble Fc gamma receptor type III in 15
patients with AIDS-related lymphoma (ARL) undergoing chemotherapy. In six of
these patients we performed a detailed kinetic analysis of the membrane
expression of the functionally important Fc gamma-receptors type I, II and III.
In all these patients G-CSF induced Fc gammaRI positive neutrophils with a
decreased expression of the Fc gammaRIII receptor. These changes were similar to
those seen both in healthy volunteers and in non-HIV-infected individuals treated
with chemotherapy. Interestingly, the mean neutrophil and sFc gammaRIII increment
were significantly lower and more patients had a nadir granulocyte count < 0.5 x
10(9)/l after the first cycle than after the second cycle of chemotherapy. This
may be related to a therapy-associated decrease in HIV-1 viral load. The
conclusion is that patients treated with chemotherapy for ARL have a
qualitatively normal response to G-CSF.
PMID- 9401063
TI - Platelet activity of high-dose factor VIIa is independent of tissue factor.
AB - High-dose recombinant factor VIIa has been successfully used as therapy for
haemophiliacs with inhibitors. The mechanism by which high-dose factor VIIa
supports haemostasis is the subject of some controversy. Postulating a mechanism
in which activity is dependent on tissue factor at the site of injury explains
the localization of activity but not the requirement for high doses. Postulating
a mechanism in which factor VIIa acts on available lipid independently of tissue
factor explains the requirement for high doses but not the lack of systemic
procoagulant activity. We report that factor VIIa bound weakly to activated
platelets (Kd approximately 90 nM). This factor VIIa was functionally active and
could initiate thrombin generation in the presence of plasma concentrations of
prothrombin, factor X, factor V, antithrombin III and tissue factor pathway
inhibitor. The activity was not dependent on tissue factor. The concentration of
factor VIIa required for detectable thrombin generation agreed well with the
lowest concentration of factor VIIa required for efficacy in patients. High-dose
factor VIIa may function on the activated platelets that form the initial
haemostatic plug in haemophilic patients. These observations are in agreement
with clinical trials which have shown that high-dose factor VIIa was
haemostatically effective without causing systemic activation of coagulation.
PMID- 9401064
TI - The effect of thrombin on the dynamic exchange between intraplatelet and
extraplatelet fibrinogen.
AB - We examined the distribution of platelet fibrinogen and the exchange between
intra- and extra-platelet fibrinogen in unstimulated and thrombin-stimulated
platelets. In unstimulated platelets 60% of platelet fibrinogen was found in the
soluble platelet fraction and 40% in the insoluble one. In platelets activated
with thrombin, changes took place in the distribution of intraplatelet fibrinogen
but not in the total fibrinogen content. At > or = 0.5 U/ml of thrombin the
fibrin(ogen) content of the insoluble and soluble fractions was approximately 80%
and 20%, respectively. When we evaluated how extraplatelet fibrinogen affects the
content and distribution of intraplatelet fibrinogen, we found that when
unlabelled fibrinogen was added to unstimulated and thrombin-stimulated platelets
the content and distribution of intraplatelet fibrinogen remained unaltered.
However, when 125I-fibrinogen was added, it was incorporated into unstimulated
and thrombin-stimulated platelets. In unstimulated platelets, 70% of the
incorporated 125I-fibrinogen was in the soluble fraction and 30% in the
insoluble. In thrombin-stimulated platelets the distribution of the incorporated
125I-fibrinogen was 62% and 38% in soluble and insoluble fractions respectively.
MoAb to GPIIb-IIIa produced 80% and 60% inhibition of 125I-fibrinogen
incorporation by unstimulated and thrombin-stimulated platelets. Our data showed
dynamic exchange between intraplatelet and extraplatelet fibrinogen both in
unstimulated and thrombin-stimulated platelets mediated mainly by GPIIb-IIIa.
PMID- 9401065
TI - Brefeldin A inhibits thrombin receptor regeneration in human endothelial cells.
AB - Endothelial cells, once stimulated with thrombin, are resistant to subsequent
stimulation. After a recovery period of about 60 min the cells are sensitized
again for activation by thrombin. The resensitization is independent of the
receptor de novo synthesis. Therefore an intracellular pool of thrombin receptors
that is possibly co-localized with the Golgi apparatus has been assumed.
Brefeldin A (BFA) has been used extensively to investigate the intracellular
sorting of proteins because of its dramatic alteration of the structural and
functional organization of the Golgi apparatus. Accordingly we have examined the
effects of BFA on the regeneration of the thrombin receptor response in human
umbilical vein and artery cells. The von Willebrand factor (VWF) release from
Weibel-Palade vesicles and the intracellular calcium mobilization were used as
physiological parameters of thrombin receptor activation. The addition of BFA (2
microg/ml) to endothelial cells or the reduction of the incubation temperature
from 37 degrees C to 16 degrees C blocked the receptor response regeneration
almost completely.
PMID- 9401066
TI - Fibrinogen Kaiserslautern (gamma 380 Lys to Asn): a new glycosylated fibrinogen
variant with delayed polymerization.
AB - An adult woman diagnosed with cerebral thrombosis following a caesarean section
was found to have severely prolonged thrombin and reptilase times. Five other
family members also had prolonged, but variable, thrombin and reptilase times.
Analysis of purified fibrinogen on reducing SDS-PAGE revealed an additional band,
in all family members, which migrated immediately below the normal B beta band.
Western blotting indicated that this band was a gamma chain and endoglycosidase-F
digestion established that it contained an additional oligosaccharide side chain.
Partial acid hydrolysis localized the new oligosaccharide to the C-terminus of
the gamma chain. Amplification of this region by PCR and subsequent DNA
sequencing demonstrated a single base substitution altering the normal 380 Lys
(AAG) codon to Asn (AAT), producing a new Asn-Lys-Thr glycosylation site. The
propositus and one other family member were homozygous for this mutation but the
remaining four family members were heterozygous. The polymerization of purified
fibrin monomers from the propositus was grossly abnormal; however, the
polymerization curve was almost normalized by the removal of terminal sialic acid
residues. This suggests that the polymerization defect was primarily caused by
additional negatively charged sialic acid residues present on the new
oligosaccharide. Further analysis of the D domain of purified fibrinogen
established that calcium binding to the high affinity site remained unaffected by
the bulky carbohydrate side chain or negatively charged sialic acid residues.
PMID- 9401067
TI - Tumour cell u-PA as a cause of fibrinolytic bleeding in metastatic disease.
AB - Tumour cells may express urokinase type plasminogen activator (u-PA). This may
influence the invasive properties of the cells but has seldom been implicated in
production of a systemic bleeding state. Two patients are described in whom
severe bleeding occurred in association with disseminated malignancies. Thrombin
generation was little disturbed and platelet numbers were insufficient to account
for the bleeding. Florid plasmin generation was evident in the circulation and
the fibrinolytic inhibitor tranexamic acid controlled the bleeding well. Free
active u-PA was demonstrated in the circulation and u-PA antigen on the malignant
cells which invaded the marrow of one of the patients. Tumour cell u-PA may
occasionally be responsible for a bleeding state.
PMID- 9401068
TI - Severe factor XI deficiency in an Arab family associated with a novel mutation in
exon 11.
AB - We investigated an 8-year-old Arab girl with severe factor XI deficiency; one
sibling and her father also have severe factor XI deficiency. Her parents and her
father's parents are first cousins. Restriction analysis and DNA sequencing
excluded the type I, II, III and IV mutations. We demonstrated a previously
undescribed C-->A mutation at nucleotide 1254 in exon 11 resulting in a threonine
to asparagine (T-->N) substitution at amino acid 386. We postulate that this
substitution interferes with folding and secretion of the molecule.
PMID- 9401069
TI - Clotting factor IX levels in C/EBP alpha knockout mice.
AB - Previous studies have indicated that C/EBP alpha is involved in the regulation of
factor IX and mutations of a C/EBP recognition element in the factor IX promoter
result in haemophilia B. We now report that mice homozygous for the deletion of
the c/ebp alpha gene are significantly deficient in factor IX transcription.
PMID- 9401070
TI - A comparison of outcome from febrile neutropenic episodes in children compared
with adults: results from four EORTC studies. International Antimicrobial Therapy
Cooperative Group (IATCG) of the European Organization for Research and Treatment
of Cancer (EORTC).
AB - The object of this study was to determine whether there were any differences
between the 'typical' child with fever and neutropenia and their adult
counterpart with regard to infection type and outcome, by analysis of 3080
patients, including 759 children < 18 years of age and 2321 adults. These
represented patients randomized in previous trials, between 1986 and 1994, which
compared empirical antibiotic regimens for fever in neutropenic patients. There
were fewer childhood acute myeloid leukaemia patients than adults but more acute
lymphoblastic leukaemia cases and more with solid tumours undergoing intensive
myelosuppressive therapy. The children were less likely to be undergoing first
induction therapy but the relative incidence of patients receiving relapse
schedules or maintenance therapies were not significantly different in the two
age groups. Children less frequently had a defined site of infection than adults
and where they had a defined site there were more upper respiratory tract but
fewer lung infections. There was a similar low incidence of shock at presentation
in the two groups but the children's median neutrophil count was lower, and their
median duration of granulocytopenia before the trial was shorter. The incidence
of bacteraemia was similar, but clinically documented infection was less frequent
and fever of unknown origin consequently more common in children. Children
developed more streptococcal bacteraemias and fewer staphylococcal bacteraemias
than adults (P=0.003) but the relative incidence of various gram-negative species
was similar (P=0.57). In general, the children had a better overall success rate
and lower mortality than adults. Death from infection was only 1% in children
versus 4% in adults (P=0.001), and time to defervescence was shorter in children.
In the younger age group, univariate logistic regression models showed high
temperature, prolonged neutropenia before the trial and shock as prognostic
indicators for the presence of bacteraemia. Solid tumour patients were
significantly less likely to have a bacteraemia. Multivariate analysis confirmed
the independent prognostic value of these indicators. Using the logistic equation
of the selected model, the overall discriminant ability was poor. However, it was
possible to identify a small subgroup without shock or high fever and with a
short prior duration of neutropenia which carries a particularly low risk of
bacteraemia, who could be considered for early discharge, monotherapy and
shortened courses of antibodies, in prospective trials.
PMID- 9401071
TI - Comparative genomic hybridization is a powerful tool, complementary to
cytogenetics, to identify chromosomal abnormalities in childhood acute
lymphoblastic leukaemia.
AB - Cytogenetics has a strong prognostic value in childhood acute lymphoblastic
leukaemia (ALL), but results are often incomplete because of the poor chromosome
morphology. To improve this analysis, we tested comparative genomic hybridization
(CGH) for the detection of chromosomal imbalances. 72 children were
retrospectively analysed using CGH. Only 53% of the patients had been fully
banded by standard methods. With CGH, 36 patients retained a normal chromosomal
profile and 36 had unbalanced abnormalities. No amplification was detected.
Fluorescence in situ hybridization (FISH) with centromeric and unique sequence
probes was used in those cases with discrepancies or unsuccessful karyotype to
validate CGH results. CGH enabled clear identification of unbalanced chromosomal
abnormalities, even in some cases which had a normal karyotype. In view of the
strong prognostic value of hyperdiploidy in childhood ALL, CGH appears to be a
powerful technique, complementary to conventional cytogenetics.
PMID- 9401072
TI - The rapid diagnosis of acute promyelocytic leukaemia using PML (5E10) monoclonal
antibody.
AB - Acute promyelocytic leukaemia (APL) is characterized cytogenetically by
t(15;17)(q22:q21) which results in the production of a PML/RAR alpha fusion
protein. Detection of the translocation or the fusion gene product is required
for objective diagnosis of APL. This can be accomplished by conventional
cytogenetic methods, fluorescence in situ hybridization or RT-PCR. Such
techniques are time consuming and not universally available. The intracellular
distribution of the PML protein in promyelocytes is characteristically altered in
APL and this can be detected by immunocytochemistry. We have assessed two
immunocytochemical methods, immunofluorescence and alkaline phosphatase-anti
alkaline phosphatase staining (APAAP), with regard to sensitivity, specificity
and rapidity of diagnosis. 85 patients with AML including 15 cases of APL were
studied. Immunofluorescence PML detection was concordant with RT-PCR for t(15:17)
in 14/15 (93.3%) cases with no false positives. The negative APL case in our
series was a patient with a 5' PML breakpoint who did not express the reciprocal
t(17;15) fusion product. APAAP was concordant in only 6/13 (46%) APL cases with
one false positive. In conclusion, immunofluorescent localization of PML using
5E10 monoclonal antibody is a rapid, sensitive and specific diagnostic tool for
APL.
PMID- 9401073
TI - The significance of trisomy 8 in de novo acute myeloid leukaemia: the
accompanying chromosome aberrations determine the prognosis. German AML
Cooperative Study Group.
AB - Trisomy 8 is the most frequent numerical chromosome aberration in acute myeloid
leukaemia (AML). It occurs either as the sole anomaly or together with other
clonal chromosome aberrations. We investigated whether accompanying chromosome
anomalies influence the clinical outcome in patients with trisomy 8 and de novo
AML. Since 1986, in 713 AML cases treated according to the protocols of the
German AMLCG trials, chromosome analyses have been successfully performed. The
overall incidence of trisomy 8 was 7.6%. Complete clinical follow-up data were
available for 51 patients who were divided into three different categories: group
1: trisomy 8 as the sole cytogenetic anomaly (n = 20); group 2: trisomy 8 in
addition to favourable chromosome aberrations (t(8;21)(q22;q22),
t(15;17)(q22;q21), inv(16)(p13q22)) (n = 10); and group 3: trisomy 8 accompanied
by other anomalies, in most cases of complex type (n = 21). Complete remission
(CR) rates were 70%, 90% and 67% for groups 1, 2 and 3, respectively. Event-free
survival (EFS) at 3 years differed significantly between patients with trisomy 8
only (37.5%), patients with trisomy 8 in combination with favourable aberrations
(55.0%) and patients with trisomy 8 and other accompanying anomalies, mostly
complex chromosome aberrations (9.0%) (group 1 v group 2: P=0.12; group 1 v group
3: P=0.005; group 2 v group 3: P=0.05). In this study patients with +8 as the
sole cytogenetic anomaly had an intermediate prognosis, patients with +8 in
addition to favourable chromosome aberrations maintained a good clinical outcome,
and patients with +8 in combination with other abnormalities showed the worst
prognosis.
PMID- 9401074
TI - Aberrant FHIT transcripts in acute myeloid leukaemia.
AB - Recently the FHIT gene (fragile histidine triad gene) has been identified at
chromosome 3p14.2 and a high frequency of abnormalities in this gene has been
demonstrated in various cancers. To determine the role of the FHIT gene in
leukaemia, bone marrow or peripheral blood from 62 acute myeloid leukaemia
patients and five haemopoietic cell lines (HL60, U937, Raji, KC-1, K562) were
analysed by reverse transcription of the FHIT mRNA followed by PCR amplification
and sequencing of the products. To detect the deletion of the FHIT gene, 17 cases
were evaluated using microsatellite polymorphism analysis. In this study, 17/62
(27%) AML patients expressed aberrant transcripts which lack two or more exons of
the FHIT gene, and all the cell lines exhibited the aberrant FHIT transcripts. No
cases exhibited a loss of the FHIT alleles. Our data indicated that the FHIT gene
may play a role in myeloid carcinogenesis and may be indicated in the late
progression of the disease.
PMID- 9401075
TI - Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological
malignancies.
AB - T-cell cytotoxicity is primarily mediated by two cell surface proteins, Fas
ligand (FasL) and tumour necrosis factor-related apoptosis-inducing ligand
(TRAIL), and intracellular perforin and granzyme granules. FasL-deficient and
perforin-deficient T lymphocytes maintain cytotoxicity but fail to induce graft
versus-host disease (GVHD) when transplanted into mice. suggesting that GVHD and
graft-versus-tumour (GVT) effects can be dissociated, and that TRAIL is not
involved in the pathogenesis of GVHD. Because TRAIL could mediate a favourable
GVT effect it became important to study the spectrum of its activity and to
investigate factors that can dissociate its expression from FasL. TRAIL induced
apoptosis in 11/41 (27%) tumour specimens of haematological origin compared to
16/41 (39%) induced by FasL. Although eight specimens were sensitive to both FasL
and TRAIL, no synergism was observed between these two ligands. TRAIL induced
apoptosis in a dose and time dependent manner with an ED50 of 0.5 microg/ml and
EDmax of 1 microg/ml. TRAIL activity was not reduced by the over-expression of
the multidrug resistant (MDR) protein, and was not enhanced by 9-cis retinoic
acid (RA), which can down-regulate bcl-2 protein. Both ligands were
simultaneously up-regulated in normal peripheral blood lymphocytes in response to
IL-2, IL-15 and anti-CD3 antibody, whereas IL-10 had no effect. Together, our
data show that (1) TRAIL can mediate cell death in a variety of human
haematological malignancies, (2) resistance to TRAIL is not mediated by MDR
protein, (3) the lack of synergy between TRAIL and FasL suggests that either one
is sufficient to mediate T-cell cytotoxicity, and (4) within the panel of
cytokines tested, the expression of TRAIL and FasL could not be dissociated.
PMID- 9401077
TI - Genetic analysis of 8;21 chromosomal translocation without AML1 gene involvement
in MDS-AML.
AB - We have investigated a case of acute myelocytic leukaemia derived from
myelodysplastic syndrome (MDS-AML) with an 8;21 translocation. In this case the
AML1/MTG8 (ETO) fusion transcript was not detected by reverse transcriptase
polymerase chain reaction (RT-PCR), and the rearrangement of the AML1 gene locus
was not detected by Southern blot nor pulse field gel electrophoresis (PFGE)
analyses using specific probes for the AML1 gene. Fluorescence in-situ
hybridization (FISH) study using cosmid probes for 21q22 revealed that the
breakpoint of 21q22 was telomeric to the AML1 gene locus and centromeric from
D21S259, 351, 3421 loci. This is the first report concerning the t(8;21)(q22;q22)
carrying AMLs (de novo AML, MDS-AML and therapy-related AML) to show that the
breakpoint at 21q22 is located outside the AML1 gene locus. It is also noteworthy
that the cell-surface antigen expression pattern of the bone marrow (BM) blasts
was changed from CD7+ CD2+ CD13+ CD33+ CD19- CD11b+ CD14+ CD36+ to CD7- CD2-
CD13+ CD19+ CD11b- CD14- CD33+ CD34+ CD36- CD56+ during leukaemic progression,
and the pattern in leukaemic phase was similar to the characteristic phenotype of
de novo AML cases with t(8;21), when the AML1/MTG8 fusion transcripts are always
detected by RT-PCR.
PMID- 9401076
TI - Oxidative DNA damage in CD34+ myelodysplastic cells is associated with
intracellular redox changes and elevated plasma tumour necrosis factor-alpha
concentration.
AB - Ineffective haemopoiesis in the myelodysplastic syndromes (MDS) is mediated, at
least in part, by apoptosis, though the mechanisms of apoptotic induction are
unclear. Tumour necrosis factor-alpha (TNF-alpha) promotes apoptosis via
intracellular oxygen free radical production, oxidation of DNA and proteins, and
is increasingly implicated in the pathogenesis of MDS. Using single-cell gel
electrophoresis, we have identified oxidized pyrimidine nucleotides in the
progenitor-enriched bone marrow CD34+ compartment from MDS patients (P=0.039),
which are absent in both CD34- MDS cells (P=0.53) and also CD34+ cells from
normal subjects (P=0.55). MDS CD34+ blood cells also showed oxidized pyrimidine
nucleotides compared with CD34- cells (P=0.029). Within normal subjects no
differences were seen between CD34+ and CD34- bone marrow cell compartments.
CD34+ bone marrow cell oxidized pyrimidines were strongly associated with
elevated plasma TNF-alpha and low bone marrow mononuclear cell glutathione
concentrations (5/6 patients) and the inverse relationship was also found (3/4
patients). This data implies a role for intracellular oxygen free radical
production, perhaps mediated by TNF-alpha, in the pathogenesis of ineffective
haemopoiesis in MDS and provides a rationale for the bone marrow stimulatory
effects of antioxidants such as Amifostine in MDS.
PMID- 9401078
TI - Bone marrow fibrosis and disease activity in multiple myeloma monitored by the
aminoterminal propeptide of procollagen III in serum.
AB - Simple bone marrow fibrosis is seen in 10-30% of multiple myeloma (MM) patients.
We investigated the incidence and characteristics of the bone marrow stromal
alterations, in order to characterize the collagens involved by
immunohistochemistry, and to evaluate the use of serum aminoterminal propeptide
of type III procollagen (PIIINP) as a marker of marrow fibrogenesis and disease
activity in MM. 34 consecutive patients with newly diagnosed MM were included
prospectively, and followed for 12-30 months. Compared with the findings in 15
normal individuals we found increased interstitial deposits of collagen III in
48% of MM patients, whereas deposits of collagen I were not increased.
Interstitial fibrosis appeared to be restricted to areas of severe plasma cell
infiltration, but it could also have a more dispersed presentation in the
severely infiltrated marrow. There was a high co-distribution of collagen III
fibrils and reticulin fibres. Serum PIIINP levels were elevated in most patients,
and in the follow-up study serum PIIINP showed a good correlation with the
response to treatment. Patients with resistant or progressive disease had
continually elevated levels of PIIINP. In most patients with responsive disease
serum PIIINP normalized, and we observed no relapses in patients who had normal
serum PIIINP levels. Other patients who responded to treatment by reduced M
component level, but had persistently elevated serum levels of PIIINP, had either
early relapses or developed progression of osteolytic lesions in spite of
unchanged M-component levels. Therefore an elevated serum PIIINP during treatment
might indicate an active malignant clone. Serum PIIINP does not simply follow the
M-component, but gives further information of potential therapeutic value.
PMID- 9401079
TI - Magnetic resonance imaging patterns in patients with multiple myeloma.
AB - Sixty-one consecutive patients with multiple myeloma were studied with magnetic
resonance (MR) imaging of the spine. Sagittal T1-weighted and short inversion
time (TI) inversion recovery (STIR) images were obtained. The MR patterns of the
bone marrow were classified as diffuse (D) (n=26), nodular (N) (n=11), D+N (n=13)
or normal (n) (n=11). Abnormal patterns were seen in 50 (82%) of the 61 patients.
Correlations were found between the MR imaging patterns and some laboratory
findings (WBC, haematocrit, platelet count, serum albumin, and percentage of
marrow plasmacytosis). The survival of the patients with abnormal MRI patterns
was significantly poorer than that of the patients with normal patterns. However,
the survival of patients with a nodular pattern did not differ from those with a
normal pattern. The MR imaging pattern of the bone marrow in patients with
multiple myeloma is a useful factor in the assessment of prognosis.
PMID- 9401080
TI - Malignant histiocytosis-like B-cell lymphoma, a distinct pathologic variant of
intravascular lymphomatosis: a report of five cases and review of the literature.
AB - Malignant histiocytosis (MH)-like B-cell lymphoma (BCL) is a neoplastic
proliferation of large B cells clinically characterized by fever,
hepatosplenomegaly, haemophagocytosis and abnormal laboratory data, without
lymphadenopathy or skin lesions. Interestingly, most cases have been reported in
Asian patients, and it is unclear whether MH-like BCL is biologically distinct
from conventional large B-cell lymphomas. We report five Japanese patients with
MH-like BCL. Biopsied specimens of bone marrow, liver and/or spleen showed
infiltration of neoplastic B cells accompanied by haemophagocytosing histiocytes.
Lymphoma cells were positive for CD19, CD20 and HLA-DR surface antigens, and
negative for CD5 and CD10. In four cases elevated serum levels of interleukin
(IL)-6 and the soluble IL-2 receptor isoform were noted, but not IL-1beta, IL-2
or tumour necrosis factor-alpha. Autopsies of two cases were pathologically
diagnosed as intravascular lymphomatosis (IVL). Based on these observations, the
current and nine previous cases reported as MH-like BCL in Japan were re
evaluated. They appear to form a peculiar variant of IVL, characterized by bone
marrow involvement at presentation, haemophagocytic syndrome, and a rapidly
aggressive clinical course, but rarely neurological complications or skin
lesions. This variant may merit separate consideration because of the problems
posed in the initial diagnosis and therapeutic approaches.
PMID- 9401081
TI - Analysis of p18INK4C in adult T-cell leukaemia and non-Hodgkin's lymphoma.
AB - p18INK4C, a cyclin-dependent kinase inhibitor, is a homologue of p15INK4B and
p16INK4A which are frequently altered in a variety of malignancies. We searched
for structural alterations of the p18INK4C gene in 44 adult T-cell leukaemias
(ATLs), 101 non-Hodgkin's lymphomas (NHLs), two polyclonal B-cell proliferations,
seven ATL cell lines and seven leukaemia/lymphoma cell lines, by Southern blot
and polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP)
analyses. No genomic alterations of the p18INK4C gene were found in any of the
samples. By RT-PCR, p18INK4C was not expressed in three of five ATL cell lines,
whereas it was expressed in all the non-ATL leukaemia/lymphoma cell lines. Tax
did not inhibit the expression of p18INK4C in tax-expressing Jurkat cells.
PMID- 9401082
TI - Bcl-6 gene hypermutations in diffuse large B-cell lymphoma of primary gastric
origin.
AB - The presence of the bcl-6 gene hypermutation was studied in 40 Hong Kong Chinese
patients with diffuse large B-cell lymphoma. The primary sites of involvement
were nodal in 18 cases and gastric in 22. Hypermutations at the E1.11 segment of
bcl-6 gene were detectable in 16/22 (73%) primary gastric and 4/18 (22%) primary
nodal lymphoma (P<0.01). Three of the 22 cases of primary gastric but none of the
nodal lymphoma had mutations at E1.12. The proportion of hypermutated cases in
the group with bcl-6 gene rearrangement was similar to that of the germ-line
group (70% v 75%). High frequency of bcl-6 gene hypermutations was found in
diffuse large B-cell lymphoma of the stomach and they were independent of
rearrangement of the gene as detected by Southern analysis. Unlike gene
rearrangement, hypermutations of the bcl-6 gene did not appear to carry any
prognostic significance clinically.
PMID- 9401083
TI - ALL R-87 protocol in the treatment of children with acute lymphoblastic leukaemia
in early bone marrow relapse.
AB - Seventy-three children with acute lymphoblastic leukaemia (ALL) in first bone
marrow (BM) relapse, occurring within 30 months from complete remission (CR),
were enrolled in an Italian cooperative study (ALL R-87 protocol). This treatment
programme consisted of an induction phase with intermediate-dose cytarabine
(IDARA-C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug
consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved
CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction.
The response rate was significantly higher for children with a first CR duration
> or = 12 months (P=0.0005) and for those with a white blood cell (WBC) count at
relapse < 20 x 10(9)/l (P=0.004). The estimated disease-free survival (DFS +/-
SE) at 82 months was 0.18 +/- 0.05 for all responders, and 0.70 +/- 0.14 for
allotransplanted patients versus 0.05 +/- 0.05 for those autografted (P=0.001).
The estimated probabilities of survival +/- SE and event-free survival (EFS +/-
SE) at 83 months were 0.16 +/- 0.07 and 0.13 +/- 0.04, respectively. for all
enrolled children. Univariate analysis showed that age < 10 years at initial
diagnosis and B-lineage immunophenotype favourably influenced both DFS (P=0.001)
and EFS probabilities (P=0.0014 and P=0.012, respectively), whereas a first CR
duration > or = 12 months and a WBC count at relapse < 20 x 10(9)/l were
associated only with a better EFS rate (P=0.026 and P=0.004, respectively). Our
results show the efficacy of the IDA plus IDARA-C schedule used in the ALL R-87
protocol in high-risk relapsed ALL children. Allogeneic BMT proved effective for
patients with an HLA sibling donor. In a multivariate analysis, age > or = 10
years at initial diagnosis (P=0.016) and WBC count at relapse > or = 20 x 10(9)/l
(P=0.048) were independently associated with a worse disease outcome.
PMID- 9401084
TI - Granulocyte colony-stimulating factor given in addition to interferon-alpha to
mobilize peripheral blood stem cells for autologous transplantation in chronic
myeloid leukaemia.
AB - In order to potentially mobilize and harvest the Ph cells observed in most
patients with chronic myeloid leukaemia (CML) during interferon-alpha (IF-alpha)
therapy, G-CSF (filgrastim), 5 microg/kg/d, was administered subcutaneously
together with IF-alpha to 30 CML patients in haematological remission but with
various degrees of cytogenetic remission, after IF-alpha therapy. Peripheral
blood stem cells (PBSC) were harvested using standard aphereses from day 5 of G
CSF Patients underwent one to four (median three) aphereses. Median total
yields/kg were 7.6 (range 3.8-25) x 10(8) MNC, 3.4 (0-140) x 10(6) CD34+ cells,
and 17 (1.1-107) x 10(4) CFU-GM. No patient had a significant increase in the
percentage of Ph+ cells in the bone marrow under G-CSF therapy. The percentage of
Ph+ cells in apheresis products tended to decrease between the first and the last
apheresis (P = 0.05). 14 patients who were not responsive to IF-alpha were
transplanted after conditioning with busulphan 16 mg/kg and melphalan 140 mg/m2.
Median time to neutrophils > 0.5 x 10(9)/l was 20 d (16-114 d) and to platelets >
50 x 10(9)/l 18 d (12-149 d). Nine patients had a major cytogenetic response post
graft, which correlated with the amount of Ph+ cells reinfused with the graft (P
= 0.02). We conclude that this procedure is feasible, allowing the harvest of
enough PBSC, some of them Ph- in patients who responded to IF-alpha, to allow
autologous transplantation.
PMID- 9401085
TI - Multiple myeloma: reduced plasma cell contamination in peripheral blood
progenitor cell collections performed after repeated high-dose chemotherapy
courses.
AB - The possibility of reducing tumour cell contamination by cytotoxic drug courses
prior to peripheral blood progenitor cell (PBPC) collection was evaluated in two
consecutives groups of multiple myeloma (MM) patient candidates for autograft.
All patients were at disease onset and received two VAD (vincristine, doxorubicin
and dexamethasone) courses as initial debulking. In the first group (44
patients), mobilization and harvest were performed 'upfront', after a single
cyclophosphamide (CY) administration of 4 g/m2; in the second group (17
patients), PBPC were collected at the end of a high-dose sequential chemotherapy
programme, including: CY 5 g/m2, etoposide (VP16) 2 g/m2, a chemotherapy-free
interval with three courses of high-dose dexamethasone, a final mobilizing CY at
7 g/m2. G-CSF was given following each high-dose cytotoxic drug. Cytofluorimetric
analysis was performed to quantify progenitors (CD34+ cells) and plasma cells,
identified by the high CD38 expression and/or CD38 and CD138 coexpression. Large
amounts of PBPC were collected in either group (median harvested CD34+/kg: 15.8 x
10(6) and 13.4 x 10(6), respectively; P=0.9). Circulating plasma cells were
significantly higher in patients mobilized 'upfront' compared to those who
received the high-dose sequence (median peak values of CD38bright/microl: 39 and
10, respectively; P=0.02); a similar difference was observed in the amount of
contaminating plasma cells in the harvest products (median CD38bright/kg: 7.4 x
10(6) and 1.3 x 10(6), respectively; P=0.02). The results demonstrate that an in
vivo purging approach is feasible in myeloma patients through repeated high-dose
chemotherapy courses; this may provide less-contaminated material suitable for
further in vitro purging procedures.
PMID- 9401086
TI - Reduction of heat-induced haemotoxicity in a hyperthermic purging protocol of
murine acute myeloid leukaemic stem cells by AcSDKP.
AB - The tetrapeptide AcSDKP (Goralatide) is a cytokine with known inhibitory effects
on cell proliferation. Many purging agents used in autologous bone marrow
transplantation protocols, including hyperthermia, preferentially kill cycling
cells. A pretreatment with Goralatide offers a possibility to reduce the
haemotoxicity in many purging settings. The impact of Goralatide on the
hyperthermic purging protocol was investigated in normal and myeloid leukaemic
(SA8) murine cells. The median survival time after transplantation (i.e.
leukaemia incidences) was used as an in vivo parameter to determine the effects
on leukaemic cells. The hyperthermic effect on normal and leukaemic cells was
also investigated in vitro using the cobblestone area-forming cell (CAFC) assay.
A heat treatment of 90 min at 43 degrees C resulted in a 4-log depletion of
leukaemic stem cells. For normal progenitor cells (CFU-GM) a 2-log cell kill was
shown. The reduction in proliferative activity of the CFU-GM after an 8 h
incubation with 10(-9) M Goralatide resulted in a decrease in the heat
sensitivity of the progenitor subset to approximately a 1-log cell kill. The
leukaemic precursor cells seem insensitive to Goralatide inhibition, implicating
an increase in the therapeutic window of the hyperthermic purging protocol.
Finally, simulated remission bone marrow (5% leukaemic blasts) was incubated with
Goralatide followed by a heat treatment of 90 min at 43 degrees C. Lethally
irradiated (10 Gy) mice transplanted with heat-treated remission bone marrow
(10(6) normal bone marrow cells versus 5 x 10(4) leukaemic cells) died of aplasia
while Goralatide-pretreated remission bone marrow could rescue the irradiated
mice without revealing leukaemic engraftment. These findings confirmed the
enhanced protection against hyperthermia of the normal haemopoietic subsets by
Goralatide and thus increased the success of the hyperthermic purging protocol.
PMID- 9401087
TI - Antithymocyte globulin for patients with myelodysplastic syndrome.
AB - Twenty-five transfusion-dependent myelodysplastic syndrome (MDS) patients (with <
20% blasts) were treated in a phase II study with antithymocyte globulin (ATG) at
40 mg/kg/d for four doses and then followed with blood counts every 2 weeks and
clinic visits every 3 months, for a median of 14 months (range 1-38 months). 11
(44%) patients responded and became transfusion-independent after ATG, including
three complete responses, six partial responses, and two minimal responses.
Responses were observed in 9/14 patients (64%) with refractory anaemia (RA) and
2/6 patients (33%) with refractory anaemia with excess blasts (RAEB). Median
response duration was 10 months (range 3-38 months). The Kaplan-Meier estimate of
overall survival was 84% at 38 months, with one early death due to pneumonia and
two deaths from disease progression to leukaemia. Side-effects consisted mainly
of mild serum sickness in all patients. A single course of ATG restored
haemopoiesis in some patients with MDS and was well tolerated.
PMID- 9401088
TI - Evans syndrome complicating fludarabine treatment for advanced B-CLL.
PMID- 9401089
TI - CHOP for recurrent TTP.
PMID- 9401090
TI - The presence of the Ph-chromosome in different cell lineages in CML.
PMID- 9401091
TI - Confirmation of frequent somatic deletion of the 13q12.3 locus encompassing BRCA2
in chronic lymphocytic leukaemia.
PMID- 9401092
TI - Hepatitis G virus (HGV) and lymphoproliferative disorders.
PMID- 9401093
TI - Trisomy 14 in association with myeloid malignancies.
PMID- 9401094
TI - Conventional cytogenetics and fluorescence in situ hybridization (FISH)
PMID- 9401095
TI - Activated protein C (APC) resistance: does it exist in Basques?
PMID- 9401096
TI - [Intraoperative pain stimuli change somatosensory evoked potentials, but not
auditory evoked potentials during isoflurane/nitrous oxide anesthesia].
AB - PURPOSE: Evoked potentials are used for intraoperative monitoring to assess
changes of cerebral function. This prospective randomised study assesses the
influence of surgical stimulation on midlatency components of somatosensory
(SEPs) and auditory evoked potentials (AEPs) in anaesthetised patients. METHODS:
After approval of the Ethics Committee and written informed consent 36
orthopaedic patients (34 +/- 15 y, 73 +/- 14 kg. 1.71 +/- 0.07 m, ASA I-II) were
randomly included in the study. Anaesthesia was induced with 1.5 micrograms/kg
fentanyl, 0.3 mg/kg etomidate and 0.1 mg/kg vecuronium. The lungs were intubated
and patients normoventilated in steady state anaesthesia with isoflurane (end
tidal 0.6%) and 66% nitrous oxide. 18 patients (group 1) were assigned to the SEP
group: median nerve stimulation, recording at Erb, C 6 and the contralateral
somatosensory cortex (N20, P25, N35) vs Fz. AEPs were recorded in group 2 (n =
18): binaural stimulation, recording at Cz versus linked mastoid (V, Na, Pa, Nb).
Recordings were performed during 30 min before the start of surgery (baseline:
BL), at skin incision (SURG1) and at the preparation of the periost (SURG2).
Heart rate, mean arterial blood pressure, oxygen saturation, endtidal pCO2 and
isoflurane (PetISO) concentrations were registered simultaneously. Data were
analysed by one-way analysis of variance. Post hoc comparison were made by Mann
Whitney U-Wilcoxon Rank Sum Test with p < 0.05 significant. RESULTS AND
DISCUSSION: During steady state isoflurane anaesthesia surgical stimulation
(SURG2) resulted in significant increases of N20 P25 amplitudes compared with BL
(BL: 1.4 +/- 0.7 microV; SURG2: 2.0 +/- 0.8 microV; p < 0.05). Latencies of SEPs
and midlatency components of AEPs did not change over time. There were no
differences in autonomic parameters between SEP and AEP groups. MAP increased
from 76 +/- 6 mmHg at BL to 93 +/- 16 mmHg at SURG1 and 96 +/- 17 mmHg at SURG2
(n = 36; p < 0.05). HR increased from BL (60 +/- 8 beats/min) to SURG2 (76 +/- 12
beats/min). Increases of amplitudes of midlatency SEP amplitudes indicate
increased nociceptive signal transmission which is not blunted by isoflurane
nitrous oxide anaesthesia. In contrast, unchanged AEPs indicate adequate levels
of the hypnotic components of anaesthesia.
PMID- 9401097
TI - Reduction of post-prandial motility by pinaverium bromide a calcium channel
blocker acting selectively on the gastrointestinal tract in patients with
irritable bowel syndrome.
AB - BACKGROUND: Growing evidence points to irritable bowel syndrome physiologically
as a disease of the enteric nervous system characterised by hypermotility. The
aim of this study was to investigate the action of pinaverium bromide a calcium
channel blocker acting selectively on the gastrointestinal tract on basal and
post-prandial recto-anal motility of 40 irritable bowel syndrome patients in a
random, double blind and placebo controlled trial. METHODS: Pinaverium bromide
(50 mg) or placebo was taken orally t.i.d. with food. Myoelectrical and
mechanical activities of the rectum and the internal anal sphincter were recorded
before treatment for 2 h in the fasting state and for an additional 2 h post
prandial. RESULTS: Post-prandial rectal spike amplitude and frequency as well as
the spontaneous recto-anal inhibitory reflex frequency decreased after pinaverium
bromide (P < 0.01) but not after placebo. CONCLUSIONS: These results suggest that
the calcium channel blockers acting selectively on the gastrointestinal tract may
have a therapeutic role in patients with irritable bowel syndrome.
PMID- 9401098
TI - Syphilitic rectal ulcer associated with perforation of the hard palate: case
report.
AB - We report a case of a patient that presented with a perforated hard palate as a
late complication due to an unsuspected syphilis. This disease first presented as
a rectal ulcer which was misdiagnosed as an amebic proctitis. The patient
received antiamebic treatment with a satisfactory outcome. He did not return for
late control of the latter treatment and returned seeking medical advice six
years later with the former complication. He tested positive for syphilis and
appropriate treatment was performed. In addition, the ORL department recommended
a palate prosthesis.
PMID- 9401099
TI - Serum IgE level and clinical allergic diseases in the United Arab Emirates.
AB - OBJECTIVE: To determine the serum IgE level in population and its association
with allergic diseases in Al-Ain, United Arab Emirates (UAE). DESIGN: This is a
prospective descriptive hospital-based study. SETTING: Al-Ain Medical District,
Tawam Hospital, United Arab Emirates. SUBJECTS: Patients who were seen at Tawam
Hospital for skin, allergic and respiratory diseases during 1996. RESULTS: The
study was based on 228 patients. The sample consisted 95 (41.7%) males and 133
(58.3%) females. The mean and standard deviation of age were 25.89 +/- 15.87
years with range 1 and 72 years. The present study revealed that there were no
statistically significant differences between serum IgE level and age groups,
gender, clinical diagnosis and respiratory symptoms (p > 0.05). Of 59.2% of
patients clinically diagnosed were possible IgE related. There was statistically
significant differences between serum IgE level and cut (p < 0.030). There was a
positive correlation between clinical diagnosis and cut. CONCLUSION:
Consistencies and discrepancies between our findings and those from other studies
with respect to allergic diseases and IgE level which support the hypothesis that
allergic diseases are a multi-factorial diseases related to both familial and
environmental influences.
PMID- 9401100
TI - Floating Harbor syndrome. Case report and further syndrome delineation.
AB - Floating Harbor syndrome was diagnosed in a 9 years old girl on the basis of
short stature, delayed bone age, mild mental retardation, speech problems and
specific craniofacial features. A detailed phenotype description is given and
evaluated together with 18 other published case reports according to the concept
of the Munich Dysmorphology Database (Stengel-Rutkowski et al., 1996) with the
aim to delineate the spectrum of clinical and anthropological features.
PMID- 9401102
TI - Characterization of two extreme variants involving the short arm of chromosome
22: are they identical?
AB - The heteromorphic nature of the short-arms of human acrocentric chromosomes is
considered the norm without any dire consequences. We characterized two highly
unusual chromosome 22 variants with extremely enlarged short arms by routine and
molecular cytogenetic techniques. Routine banding revealed that the two variants
were not alike. Therefore, a characterization by fluorescent in situ
hybridization (FISH) technique became warranted and revealed their remarkable
differences. The first variant apparently had a tandem duplication of bands p11.2
->p13, while the second variant had a loss of the beta-satellite and ribosomal
DNA regions with an apparent amplification of the satellite III region. The
formation of these extremely enlarged regions can occur by a variety of
mechanisms whose clinical significance remains obscure.
PMID- 9401101
TI - Systematic screening for fragile X syndrome in a cohort of 574 mentally retarded
children.
AB - In this study, we evaluated the prevalence of the fragile X syndrome in a cohort
of 574 mentally retarded children. The only inclusion criterion was the diagnosis
of mental retardation according to the DSM-IIIR classification. We used a PCR
based strategy for the diagnosis of fragile X syndrome to facilitate systematic
screening. This diagnostic scheme is based on an initial PCR to eliminate most
fragile X-negative patients followed by Southern blotting for fragile X syndrome
diagnosis. Altogether, 403 boys and 171 girls were tested. The prevalence of this
genetic disorder was 1.9% (11/574) in the whole cohort and 2.5% (10/403) in boys.
Only one case of fragile X syndrome was detected among the 171 girls tested
(0.6%). Clinical examination, especially in the youngest children, was often
unremarkable, and the only reason for suspecting fragile X syndrome was the
presence of mental retardation. Thus, a systematic screening for the fragile X
syndrome in mentally retarded children seems justified because of the importance
of a precise diagnosis in genetic counseling.
PMID- 9401103
TI - A recombination event close to HFE gene in hereditary hemochromatosis.
AB - A candidate gene for Hereditary Hemochromatosis (HFE) has been recently cloned
from a region 4 cM telomeric to HLA-A on the short arm of chromosome 6. This
gene, defined HFE, is mutated in a high proportion of HFE patients. Positional
cloning of HFE has been difficult, because of the extended region of linkage
disequilibrium observed around the gene and of the rarity of recombination events
in this DNA area. Here we describe a crossover in an Italian HFE patient which
occurred close to the HFE gene in a restricted interval between D6S2221 and
D6S2240-D6S2238 markers. The molecular analysis of this event and the segregation
of the HFE mutations in the family are consistent with the position of the HFE
gene telomeric to D6S2221.
PMID- 9401104
TI - Clinical applications of primed in situ labelling (PRINS) rapid identification of
a marker chromosome in a fetus.
AB - Marker chromosomes pose a serious problem in clinical cytogenetic diagnosis since
the conventional banding analyses are often not useful in identifying their
origin or composition. In the absence of information, counseling as to the
clinical significance and prognosis is difficult, especially in prenatal
diagnosis. With the introduction of fluorescence in situ hybridization (FISH)
marker identification has became feasible. However, FISH is relatively time
consuming and expensive. In an effort to overcome these disadvantages, we have
used primed in situ labelling (PRINS) technique as an alternative. Presented here
is one case in which PRINS was useful in rapidly identifying the origin of a
marker chromosome detected on amniotic fluid chromosome analysis. Based on our
experience with this case and others, we propose that PRINS can become a viable
and cost effective alternative to FISH and is as reliable as FISH in terms of
accuracy, specificity, and sensitivity.
PMID- 9401105
TI - 18p monosomy with midline defects and a de novo satellite identified by FISH.
AB - We report a girl with an 18p deletion and showing a total GH deficiency, a single
central maxillary incisor, and a pituitary dysplasia. This suggests that
del(18)(p) could be involved in pituitary dysplasia. We review the association
between midline developmental defects and chromosome 18 anomalies. This case is
due to a de novo satellite resulting from an unbalanced translocation t(18p;13p)
identified by FISH. This is the first case of this cytogenetic mechanism in the
18p monosomy.
PMID- 9401106
TI - High recurrence of recombinants in a family with pericentric inversion of
chromosome 18.
AB - We report a family in which the father carries a pericentric inversion involving
two third of the chromosome 18 (p11.2q22). Of his three children, the proposita
and her youngest brother show partial duplication of the short arm and partial
deficiency of the long arm; the oldest sister shows the other recombinant
(partial duplication of the long arm and partial deficiency of the short arm). In
the literature, we found only one family in which both recombinants of a parental
pericentric inversion were present in the same offspring and none with three
affected and both kinds of recombinants. A review of the reported familial cases
reveals that the risk of aneusomy of recombination, at least for chromosome-18
inversion carriers, may be close to 20% and no only 5-10% as previously reported.
PMID- 9401107
TI - Myotonic dystrophy protein kinase gene expression in skeletal muscle from
congenitally affected infants.
AB - Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disorder
characterized by marked variability of its clinical manifestations. The
mutational basis of DM is an unstable (CTG)n trinucleotide repeat in the 3'
untranslated region of the myotonic dystrophy protein kinase gene (DMPK). We used
quantitative RT-PCR to determine DMPK mRNA levels in muscular biopsies from three
congenitally affected (CDM) and two control infants. The CDM infants had
increased DMPK mRNA levels, which were not correlated to increased expression of
the mutant allele. This increase may be the consequence of a maturational
muscular arrest, which may maintain an elevated level of DMPK mRNA until birth.
PMID- 9401108
TI - A rare case of a liveborn with free, de novo and partial trisomy 12 and an
unusual phenotype.
AB - Individuals with free and total trisomy 12 are rare and always mosaic. Incidences
of partial trisomy 12 are more frequent and are classified into trisomy 12p and
trisomy 12q. The phenotype of both trisomy 12p and trisomy 12q is well described
in the literature. We report here, the rare occurrence of a liveborn with free
and de novo trisomy 12, albeit not the whole chromosome. The clinical description
of this infant includes characteristics of trisomy 12p and trisomy 12q syndromes.
Few additional anomalies present in the infant are unaccounted for by both
syndromes. We anticipate that these characteristics are caused by trisomy 12q13,
which to our knowledge has not been reported in a trisomy before.
PMID- 9401109
TI - Mosaicism in trisomy 8: phenotype differences according to tissular repartition
of normal and trisomic clones.
AB - Three new observations of trisomy 8 mosaicism are presented. In two postnatal
cases, both patients showed agenesis of corpus callosum associated with different
clinical findings. In a third case, the prenatal diagnosis revealed trisomy 8
mosaicism exclusively in chorionic villi (CV) cells long term culture. Normal
results were obtained in CV direct preparation and in cultured amniotic cells. In
lymphocytes, the child showed low level trisomy 8 mosaicism. The only clinical
findings were deep palmar and plantar furrows. The present cases as well as
reports in the literature indicate that the variation in tissular repartition of
normal and trisomic clones in trisomy 8 mosaicism is possibly responsible for the
missing correlation between cytogenetic findings and clinical severity in this
syndrome.
PMID- 9401110
TI - CFTR gene analysis in cystic fibrosis patients: detection of 91% of molecular
defects and identification of the novel mutation D979V.
AB - More than 600 mutations have been identified in the Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR) gene and are known to cause cystic fibrosis (CF).
This large number of mutations makes the search of the molecular defects in CF
patients difficult. We have used the techniques of denaturing gradient gel
electrophoresis (DGGE) and direct DNA sequencing to detect the mutations in 334
CF chromosomes mostly of French origin. The whole coding sequence of the CFTR
gene corresponding to the 27 exons and their exon-intron boundaries was studied.
45 different mutations were identified. This method allowed us to detect the
molecular defect in 90.5% of the mutant alleles and to report a novel mutation
D979V.
PMID- 9401111
TI - Detection of delta F508 mutation in cystic fibrosis patients from northwestern
Mexico.
PMID- 9401116
TI - [Lymphoplasmacellular osteomyelitis].
AB - Chronic lymphoplasmacellular osteomyelitis may occur in children, adolescents and
adults, but has not been found in newborns or babies either in our series or in
the literature. Symptoms suggesting an acute disease like fever are uncommon, but
a primary chronic course with symptomatic and asymptomatic periods is typical.
Pain and swelling are the main symptoms; painless masses are rare. In children
and adolescents the clavicle and metaphyseal regions of long bones are typical
sites of chronic abacterial osteomyelitis. In adults the clavicles or the first
two ribs are mainly affected with synovitis of the adjacent joints, but the long
bones are rarely involved. Laboratory findings are non-specific but important for
the differential diagnosis. The sedimentation rate and c-reactive protein might
be elevated. The X-ray examination shows osteolytic, sclerotic or mixed bony
changes and, in case of a diaphyseal involvement, onionskinlike periosteal bone
formation may be present, suggesting a malignant process. In late stages
sclerotic bone formations may be seen as a rest. Uni- or multifocal lesions can
be detected by bonescan, as can asymptomatic lesions. Magnetic resonance imaging
shows gross signal intensity differences both in the bone and perifocal soft
tissue and involvement of the synovium with gadolinium DPTA enhancement in T1
weighted images. In early stages of the disease granulocytes, microabscesses and
new bone formations might suggest bacterial osteomyelitis that cannot be
differentiated by histology. In intermediate phases lymphocytic and plasma
cellular infiltrates are found, whereas in late phases sclerotic bone formations
and fibrosis of the bone marrow are seen histologically. In chronic
lymphoplasmacellular osteomyelitis, all clinical, radiological and histological
findings, as well as negative bacteriological cultures, are mandatory and will
allow a definitive diagnosis to be made. The disease may be uni- or multifocal,
and new bone lesions may occur over time, as well as skin manifestations, which
can be found years before or after bone involvement. The association with
dermatological diseases and/or synovitis led to the acronym SAPHO syndrome
(synovitis, acne, pustulosis, hyperostosis, osteomyelitis). For the treatment
nonsteroidal anti-inflammatory drugs are effective for pain relief, reduction of
swelling and dysfunction. Antibiotics have been used in several series and are
not effective. Major surgery is not recommended even for recurrences, and the
prognosis for growth and function is excellent in the long term despite
recurrences over several years.
PMID- 9401117
TI - New arguments to explain the high infection rate in posttraumatic spleenless
patients.
AB - To get more information about the high infection rate in splenectomized adult
patients 211 spleenless patients were investigated with regard to clinical and
laboratory data and compared to healthy blood donors. The results show that the
infection rate is markedly increased to 30%. Splenectomized patients have
decreased IgG levels which is due to diminished IgG1 and IgG4. Whereas IgA,
complement factors C3, C4, and transferrin are not changed in patients without
spleen, fibronectin and IgM are significantly reduced and the phagocytosis as
well as the migration of neutrophilic granulocytes is impaired to 50%. With these
changes in laboratory data it is possible to identify patients which bear an
increased risk with regard to infection.
PMID- 9401118
TI - Different roles of flowering-time genes in the activation of floral initiation
genes in Arabidopsis.
AB - We have analyzed double mutants that combine late-flowering mutations at four
flowering-time loci (FVE, FPA, FWA, and FT) with mutations at the LEAFY (LFY),
APETALA1 (AP1), and TERMINAL FLOWER1 (TFL1) loci involved in the floral
initiation process (FLIP). Double mutants between ft-1 or fwa-1 and lfy-6
completely lack flowerlike structures, indicating that both FWA and FT act
redundantly with LFY to control AP1. Moreover, the phenotypes of ft-1 ap1-1 and
fwa-1 ap1-1 double mutants are reminiscent of the phenotype of ap1-1 cal-1 double
mutants, suggesting that FWA and FT could also be involved in the control of
other FLIP genes. Such extreme phenotypes were not observed in double mutants
between fve-2 or fpa-1 and lfy-6 ap1-1. Each of these showed a phenotype similar
to that of ap1-1 or lfy-6 mutants grown under noninductive photoperiods,
suggesting a redundant interaction with FLIP genes. Finally, the phenotype of
double mutants combining the late-flowering mutations with tfl1-2 were also
consistent with the different roles of flowering-time genes.
PMID- 9401119
TI - Genetic analysis of osmotic and cold stress signal transduction in Arabidopsis:
interactions and convergence of abscisic acid-dependent and abscisic acid
independent pathways.
AB - To dissect genetically the complex network of osmotic and cold stress signaling,
we constructed lines of Arabidopsis plants displaying bioluminescence in response
to low temperature, drought, salinity, and the phytohormone abscisic acid (ABA).
This was achieved by introducing into Arabidopsis plants a chimeric gene
construct consisting of the firefly luciferase coding sequence (LUC) under the
control of the stress-responsive RD29A promoter. LUC activity in the transgenic
plants, as assessed by using in vivo luminescence imaging, faithfully reports the
expression of the endogenous RD29A gene. A large number of cos (for constitutive
expression of osmotically responsive genes), los (for low expression of
osmotically responsive genes), and hos (for high expression of osmotically
responsive genes) mutants were identified by using a high-throughput luminescence
imaging system. The los and hos mutants were grouped into 14 classes according to
defects in their responses to one or a combination of stress and ABA signals.
Based on the classes of mutants recovered, we propose a model for stress
signaling in higher plants. Contrary to the current belief that ABA-dependent and
ABA-independent stress signaling pathways act in a parallel manner, our data
reveal that these pathways cross-talk and converge to activate stress gene
expression.
PMID- 9401120
TI - The Arabidopsis deetiolated2 mutant is blocked early in brassinosteroid
biosynthesis.
AB - The Arabidopsis DEETIOLATED2 (DET2) gene has been cloned and shown to encode a
protein that shares significant sequence identity with mammalian steroid 5 alpha
reductases. Loss of DET2 function causes many defects in Arabidopsis development
that can be rescued by the application of brassinolide; therefore, we propose
that DET2 encodes a reductase that acts at the first step of the proposed
biosynthetic pathway--in the conversion of campesterol to campestanol. Here, we
used biochemical measurements and biological assays to determine the precise
biochemical defect in det2 mutants. We show that DET2 actually acts at the second
step in brassinolide biosynthesis in the 5 alpha-reduction of (24R)-24
methylcholest-4-en-3-one, which is further modified to form campestanol. In
feeding experiments using 2H6-labeled campesterol, no significant level of 2H6
labeled campestanol was detected in det2, whereas the wild type accumulated
substantial levels. Using gas chromatography-selected ion monitoring analysis, we
show that several presumed null alleles of det2 accumulated only 8 to 15% of the
wild-type levels of campestanol. Moreover, in det2 mutants, the endogenous levels
of (24R)-24-methylcholest-4-en-3-one increased by threefold, whereas the levels
of all other measured brassinosteroids accumulated to < 10% of wild-type levels.
Exogenously applied biosynthetic intermediates of brassinolide were found to
rescue both the dark- and light-grown defects of det2 mutants. Together, these
results refine the original proposed pathway for brassinolide and indicate that
mutations in DET2 block the second step in brassinosteroid biosynthesis. These
results reinforce the utility of combining genetic and biochemical analyses to
studies of biosynthetic pathways and strengthen the argument that
brassinosteroids play an essential role in Arabidopsis development.
PMID- 9401121
TI - Aux/IAA proteins repress expression of reporter genes containing natural and
highly active synthetic auxin response elements.
AB - A highly active synthetic auxin response element (AuxRE), referred to as DR5, was
created by performing site-directed mutations in a natural composite AuxRE found
in the soybean GH3 promoter. DR5 consisted of tandem direct repeats of 11 bp that
included the auxin-responsive TGTCTC element. The DR5 AuxRE showed greater auxin
responsiveness than a natural composite AuxRE and the GH3 promoter when assayed
by transient expression in carrot protoplasts or in stably transformed
Arabidopsis seedlings, and it provides a useful reporter gene for studying auxin
responsive transcription in wild-type plants and mutants. An auxin response
transcription factor, ARF1, bound with specificity to the DR5 AuxRE in vitro and
interacted with Aux/IAA proteins in a yeast two-hybrid system. Cotransfection
experiments with natural and synthetic AuxRE reporter genes and effector genes
encoding Aux/IAA proteins showed that overexpression of Aux/IAA proteins in
carrot protoplasts resulted in specific repression of TGTCTC AuxRE reporter gene
expression.
PMID- 9401122
TI - The adenylate cyclase gene MAC1 of Magnaporthe grisea controls appressorium
formation and other aspects of growth and development.
AB - Magnaporthe grisea, the causal agent of rice blast disease, differentiates a
specialized infection structure called an appressorium that is crucial for host
plant penetration. Previously, it was found that cAMP regulates appressorium
formation. To further understand the cellular mechanisms involved in appressorium
formation, we have cloned a gene (MAC1) encoding adenylate cyclase, a membrane
bound enzyme that catalyzes the production of cAMP from ATP, by using a
polymerase chain reaction-based strategy. The entire gene was isolated and
subcloned from a large insert bacterial artificial chromosome library. Sequence
characterization showed that MAC1 has a high degree of identity with other
adenylate cyclase genes from several filamentous fungi as well as yeasts. Gene
deletion resulted in reduced vegetative growth, conidiation, and conidial
germination. Transformants lacking MAC1 were unable to form appressoria on an
inductive surface and were unable to penetrate susceptible rice leaves. mac1-
transformants were also sterile and produced no perithecia. Appressorium
formation was restored in the presence of exogenous cAMP derivatives. These
results confirm that cell signaling involving cAMP plays a central role in the
development and pathogenicity of M. grisea.
PMID- 9401123
TI - Antisense suppression of 4-coumarate:coenzyme A ligase activity in Arabidopsis
leads to altered lignin subunit composition.
AB - The phenylpropanoid enzyme 4-coumarate:coenzyme A ligase (4CL) is considered
necessary to activate the hydroxycinnamic acids for the biosynthesis of the
coniferyl and sinapyl alcohols subsequently polymerized into lignin. To clarify
the role played by 4CL in the biosynthesis of the guaiacyl (G) and syringyl (S)
units characteristic of angiosperm lignin, we generated 4CL antisense Arabidopsis
lines having as low as 8% residual 4CL activity. The plants had decreases in
thioglycolic acid-extractable lignin correlating with decreases in 4CL activity.
Nitrobenzene oxidation of cell walls from bolting stems revealed a significant
decrease in G units in 4CL-suppressed plants; however, levels of S lignin units
were unchanged in even the most severely 4CL-suppressed plants. These effects led
to a large decrease in the G/S ratio in these plants. Our results suggest that an
uncharacterized metabolic route to sinapyl alcohol, which is independent of 4CL,
may exist in Arabidopsis. They also demonstrate that repression of 4CL activity
may provide an avenue to manipulate angiosperm lignin subunit composition in a
predictable manner.
PMID- 9401124
TI - EMF genes regulate Arabidopsis inflorescence development.
AB - Mutations in EMBRYONIC FLOWER (EMF) genes EMF1 and EMF2 abolish rosette
development, and the mutants produce either a much reduced inflorescence or a
transformed flower. These mutant characteristics suggest a repressive effect of
EMF activities on reproductive development. To investigate the role of EMF genes
in regulating reproductive development, we studied the relationship between EMF
genes and the genes regulating inflorescence and flower development. We found
that APETALA1 and AGAMOUS promoters were activated in germinating emf seedlings,
suggesting that these genes may normally be suppressed in wild-type seedlings in
which EMF activities are high. The phenotype of double mutants combining emf1-2
and apetala1, apetala2, leafy1, apetala1 cauliflower, and terminal flower1 showed
that emf1-2 is epistatic in all cases, suggesting that EMF genes act downstream
from these genes in mediating the inflorescence-to-flower transition.
Constitutive expression of LEAFY in weak emf1, but not emf2, mutants increased
the severity of the emf phenotype, indicating an inhibition of EMF activity by
LEAFY, as was deduced from double mutant analysis. These results suggest that a
mechanism involving a reciprocal negative regulation between the EMF genes and
the floral genes regulates Arabidopsis inflorescence development.
PMID- 9401125
TI - A strong inhibitor of gene expression in the 5' untranslated region of the pollen
specific LAT59 gene to tomato.
AB - Promoter sequences that direct pollen-specific expression have been previously
identified in the LAT59 (for late anther tomato) gene. Here, we show that the
LAT59 sequences encoding the 5' untranslated region inhibit expression of
reporter genes by > 20-fold in transient expression experiments and up to 300
fold after stable transformation. Inhibition occurred in somatic cells as well as
in pollen. Our results indicate that the inhibitor still functions after pollen
germination and therefore does not modulate the level of the LAT59 protein during
pollen development. The presence of the leader sequence dramatically decreased
mRNA accumulation but without affecting translation rate and mRNA stability. We
believe that the leader inhibits transcription. We mapped the inhibitor to a
region in the leader that coincides with a putative stem-loop and present
evidence that this stem-loop participates in inhibition.
PMID- 9401126
TI - Role of the sulfhydryl redox state and disulfide bonds in processing and assembly
of 11S seed globulins.
AB - Seed legumins contain two conserved disulfide bonds: an interchain bond (IE)
connecting the acidic and basic chains and an intrachain bond (IA) internal to
the acidic chain. Mutant subunits were constructed in which these disulfide bonds
were disrupted. Oxidized glutathione stimulated the rate of assembly of trimers
with unmodified prolegumin subunits. Stimulation was not detected during assembly
of IE mutant subunits and was diminished for the IA mutant. Hexamer assembly with
trimers of mature unmodified subunits required oxidizing conditions. Trimers
composed of mature IE mutants did not form hexamers. Both mutant and non-mutant
subunits accumulated in hexamers when the cDNAs were expressed in tobacco.
Hexamer assembly in seeds probably involved trimers with a mixture of mutant and
non-mutant subunits. Similarly, mixed trimers that were a mixture of mutant and
non-mutant subunits assembled into hexamers in vitro. The results demonstrate the
importance of disulfide bonds during the assembly of 11S globulins.
PMID- 9401127
TI - Satellite RNA-mediated resistance to turnip crinkle virus in Arabidopsis involves
a reduction in virus movement.
AB - Satellite RNAs (sat-RNAs) are parasites of viruses that can mediate resistance to
the helper virus. We previously showed that a sat-RNA (sat-RNA C) of turnip
crinkle virus (TCV), which normally intensifies symptoms of TCV, is able to
attenuate symptoms when TCV contains the coat protein (CP) of cardamine chlorotic
fleck virus (TCV-CPCCFV). We have now determined that sat-RNA C also attenuates
symptoms of TCV containing an alteration in the initiating AUG of the CP open
reading frame (TCV-CPm). TCV-CPm, which is able to move systemically in both the
TCV-susceptible ecotype Columbia (Col-0) and the TCV-resistant ecotype Dijon (Di
0), produced a reduced level of CP and no detectable virions in infected plants.
Sat-RNA C reduced the accumulation of TCV-CPm by < 25% in protoplasts while
reducing the level of TCV-CPm by 90 to 100% in uninoculated leaves of Col-0 and
Di-0. Our results suggest that in the presence of a reduced level of a possibly
altered CP, sat-RNA C reduces virus long-distance movement in a manner that is
independent of the salicylic acid-dependent defense pathway.
PMID- 9401128
TI - A functional S locus anther gene is not required for the self-incompatibility
response in Brassica oleracea.
AB - The self-incompatibility (SI) response in Brassica involves recognition of self
pollen by the papillar cells of the stigma and is mediated by the products of
genes localized at the S (self-incompatibility) locus. Two S locus genes, SRK and
SLG, are thought to encode components of a receptor complex present in the female
partner. The putative gene product of SLA, a third S locus-linked gene that is
expressed specifically in anthers, is a candidate for the male component of the
SI recognition system. The identification of a mutant SLA allele, interrupted by
a large insert resembling a retrotransposon, in self-compatible Brassica napus
initially suggested that SLA played an essential role in the SI response. In this
study, we have characterized an SLA allele from a self-compatible B. oleracea var
acephala line and show that it too is interrupted by a large insert. However,
analysis of seven B. oleracea var botrytis lines exhibiting both self-compatible
and self-incompatible phenotypes showed that these lines carry an S allele very
similar or identical to that of the B. oleracea var acephala line and that the
SLA gene is interrupted by an insert in all seven lines. The insertion of the
putative retrotransposon was shown to interfere with gene expression, with no SLA
transcripts being detected by RNA gel blot analysis in a self-incompatible B.
oleracea var botrytis line carrying an interrupted SLA gene. These data indicate
that a functional SLA gene is not required for the SI response in Brassica.
PMID- 9401129
TI - A developmentally regulated MAP kinase activated by hydration in tobacco pollen.
AB - A novel mitogen-activated protein (MAP) kinase signaling pathway has been
identified in tobacco. This pathway is developmentally regulated during pollen
maturation and is activated by hydration during pollen germination. Analysis of
different stages of pollen development showed that transcriptional and
translational induction of MAP kinase synthesis occurs at the mid-bicellular
stage of pollen maturation. However, the MAP kinase is stored in an inactive form
in the mature, dry pollen grain. Kinase activation is very rapid after hydration
of the dry pollen, peaking at approximately 5 min and decreasing thereafter.
Immunoprecipitation of the kinase activity by an anti-phosphotyrosine antibody is
consistent with the activation of a MAP kinase. The kinetics of activation
suggest that the MAP kinase plays a role in the activation of the pollen grain
after hydration rather than in pollen tube growth.
PMID- 9401130
TI - The impact of personality disorders on behavioral treatment outcome for social
phobia.
AB - The impact of personality disorders (PDs) on exposure in vivo treatment for
social phobia was investigated in three groups of social phobics: social phobia
without any PD (n = 30), social phobia with a single diagnosis of avoidant PD (n
= 18) and social phobia with multiple PDs (n = 13). We hypothesized parallel
change for social phobia with and without an avoidant PD with the latter group
being more impaired before and after treatment. In order to test this hypothesis,
confidence intervals for change were computed. In line with our hypothesis,
social phobics in all three groups improved significantly during treatment and no
interaction effects were found on the repeated MANOVAs. By using a confidence
interval, parallel change was found on most measures. The impact of additional
anxiety and mood disorders on treatment outcome was investigated separately. The
analyses showed that an additional anxiety or mood disorder also did not predict
outcome of exposure treatment.
PMID- 9401131
TI - The perception of bodily sensations, with special reference to hypochondriasis.
AB - Bodily sensations are relevant to problems such as hypochondriasis, but the issue
of whether people are accurate in their perception remains unclear. The accuracy
of perception of bodily sensations was analysed in 20 male and 20 female
volunteers using two methods: a heart beat tracking procedure and the within-S
correlational approach described by Steptoe and Vogele (1992, Behaviour Research
and Therapy, 30, 597-607). The correlational approach involved monitoring of
heart rate, skin conductance level and total respiratory resistance during
relaxation and task periods, and computing correlations between appropriate
physiological parameters and ratings of heart rate, sweaty hands and difficulty
with breathing. In general, subjective ratings of bodily sensations were tied
more closely with feelings of distress than with objective physiological state.
Error scores on the heart beat tracking procedure showed no association with
hypochondriacal concerns or with vigilant and avoidant coping styles measured
with the Mainz Coping Inventory. Individuals varied considerably in accuracy as
assessed with the correlational approach. However, there was a significant
negative association between hypochondriacal concerns and accuracy of perception
of sweat gland activity. The results are discussed in relation to measures of
somatic perception and the experience of bodily sensations.
PMID- 9401132
TI - Attentional biases for negative information in induced and naturally occurring
dysphoria.
AB - Two studies investigated the relationship between attentional biases for negative
information and dysphoria--both induced (Study 1) and naturally occurring (Study
2). In a modified dot probe task a series of word pairs was presented, and Ss
responded to probes that replaced one of the words in each pair. The stimuli
included depression-related, anxiety-related and neutral words. To examine the
time course of the attentional biases, there were three exposure durations of the
word pairs: 14 ms (+ 186 ms mask); 500 ms and 1000 ms. In Study 1, the depressed
mood induction procedure was associated with greater vigilance for depression
related words at 500 ms, with a similar trend at 1000 ms. In Study 2, measures of
depressed mood and vulnerability correlated positively with vigilance for
negative words in the 1000 ms condition. There was no evidence from either study
that depressed mood was associated with a pre-conscious bias for negative words
(i.e. in the 14 ms masked exposure condition). However, this pre-conscious bias
was associated with high trait anxiety in Study 2, consistent with previous
research. The results are discussed in relation to theoretical and empirical work
on cognitive biases in clinical and non-clinical anxiety and depression.
PMID- 9401133
TI - Common childhood fears and their origins.
AB - The present study examined rank orders and characteristics of childhood fears. A
'free option' approach ('What do you fear most?') deviated markedly from the fear
rank order based on the Fear Survey Schedule for Children. A second aim of the
study was to investigate the origins of prevalent childhood fears. In contrast to
the results of Ollendick and King (1991, Behaviour Research and Therapy, 29, 117
123), conditioning was found to be the most commonly reported pathway related to
exacerbation and onset of fears. Finally, special attention was given to the top
intense fear in children, namely fear of spiders. Children who reported 'none',
'some' or 'a lot' of spider fear were compared with each other in terms of
pathways. No differences between the three groups were found with respect to the
frequency of modeling and information experiences. However, high fearful children
more often reported conditioning experiences than low or moderate fearful
children.
PMID- 9401134
TI - Comparison of cognitive style in bulimia nervosa and depression.
AB - This study investigated the global and specific cognitive style associated with
bulimia nervosa. Three groups of women (women with bulimia nervosa, women with
major depression, and controls) completed measures of eating disorder severity,
depression, dysfunctional cognitions and irrational beliefs. The control group
was found to report significantly lower levels of cognitive distortions and
irrational beliefs overall than both women with bulimia nervosa and women with
depression. However, no difference was found between the latter two groups.
Furthermore, the pattern of individual cognitions and beliefs was exactly the
same. When depression was statistically controlled, cognitive style no longer
differentiated between the control group and two clinical groups. These results
have implications for improving the effectiveness of cognitive behaviour therapy
for bulimia nervosa.
PMID- 9401135
TI - Disgust and disgust sensitivity in blood-injection-injury and spider phobia.
AB - Blood-injection-injury (BII) phobics and spider phobics show markedly different
cognitive, psychophysiological, and motoric reactions to activating stimuli.
These observations have led theorists to question whether the emotion of fear
mediates both phobias. The present study examined the role of disgust and disgust
sensitivity in these subtypes of specific phobia. BII phobics, spider phobics,
and nonphobics completed questionnaires and rated pictures of specific objects on
fear and disgust scales. Questionnaire data indicated that phobic participants
were higher than nonphobics on fear, and also on disgust sensitivity. The
reaction of BII phobics to pictures of medical stimuli was one of disgust, rather
than fear. The reaction of spider phobics to pictures of spiders was a
combination of fear and disgust, though fear appeared to predominate. Results are
discussed in view of current theories of emotional factors in specific phobia.
PMID- 9401136
TI - Danger ideation reduction therapy (DIRT): preliminary findings with three
obsessive-compulsive washers.
AB - Three obsessive-compulsive patients received Danger Ideation Reduction Therapy
(DIRT) in an initial treatment trial. All three subjects presented with
contamination/washing concerns but refused to participate in exposure and
response prevention. DIRT is solely directed at decreasing danger-related
expectancies concerning contamination. DIRT procedures do not attempt to address
inflated personal responsibility. In addition, DIRT does not involve direct or
filmed exposure to contamination-related stimuli, or behavioural experiments.
Components of DIRT include corrective information cognitive restructuring, filmed
interviews, microbiological experiments, attentional focusing and Hoekstra's
(1989) probability of catastrophe estimation task. Treatment consisted of between
six and ten 1-hr weekly sessions. At post-treatment, substantial reductions in
scores on the Padua Inventory, Maudsley Obsessional-Compulsive Inventory and two
global rating scales were apparent for all subjects. These improvements were
maintained at a 3-month follow-up. The theoretical and clinical implications of
these preliminary findings are discussed.
PMID- 9401137
TI - The relation between anxiety sensitivity and depression in children and
adolescents referred for anxiety.
AB - Research conducted with adult samples suggests that anxiety sensitivity is
positively related to depression (Otto et al., 1995, Journal of Anxiety
Disorders, 10, 117-123). The Childhood Anxiety Sensitivity Index (CASI, Silverman
et al., 1991, Journal of Clinical Child Psychology, 20 162-168) was used in this
study to provide an examination of the relation between anxiety, anxiety
sensitivity, and depression in a sample of children and adolescents (N = 234)
referred for anxiety disorders. A significant correlation between depression and
anxiety sensitivity was found. This relation remained statistically significant
when controlling for other aspects of anxiety (i.e. worry, physiological anxiety,
and concentration). The similarities between these findings and findings obtained
with adults are discussed, as well as suggestions for future research.
PMID- 9401138
TI - The Reiss Screen for Maladaptive Behavior: confirmatory factor analysis.
AB - We tested the factorial stability of the Reiss Screen for Maladaptive Behavior
(Reiss, 1988a, The Reiss Screen for Maladaptive Behavior test manual). Reasonable
fit was demonstrated in a geographically diverse sample of 448 individuals with
mild, moderate, severe and profound mental retardation according to four measures
of overall fit: RMSEA, ECVI, NNFI, and NFI. The results confirm Reiss' (1988a)
factor solution of this widely used dual diagnosis (mental retardation and mental
illness) screening instrument.
PMID- 9401139
TI - A hospital attachment in restorative dentistry: a valuable but rare opportunity
for general dental practitioners.
PMID- 9401140
TI - Thiomersal sensitivity in health care workers.
PMID- 9401141
TI - Tooth fairies.
PMID- 9401142
TI - Factors influencing the diagnosis and management of periodontal disease by
general dental practitioners.
AB - OBJECTIVE: To identify factors influencing the diagnosis and management of
periodontal disease by general dental practitioners. DESIGN: The study was
conducted in two stages. 1. Analysis of returns to the Scottish Dental Practice
Board. 2. Data collection via a postal questionnaire distributed to 500 general
dental practitioners (27% of Scottish practitioners). RESULTS: 374 (75%)
questionnaires were completed and returned. Analysis revealed the majority of
treatment provided was in the form of simple scale and polishes, with multi-visit
periodontal therapy comprising less than 0.2% of all non-surgical periodontal
treatment. While the majority of respondents were confident in their ability to
diagnose periodontal disease, only 40% were confident in treating it. Patient
related factors were seen as the major hindrance to disease management, although
time factors and the low level of fees were viewed by at least one half of
respondents as major constraints. CONCLUSIONS: Greater efforts are required to
motivate and inform patients of the necessity for and benefits of periodontal
treatment, as is emphasis on appropriate treatment of early to moderate forms of
disease. There is also a need for the development of appropriate, evidence-based
clinical guidelines and fiscal arrangements to facilitate such provision.
PMID- 9401143
TI - Are anterior occlusal radiographs still indicated for orthodontic assessment?
AB - OBJECTIVE: This study examined the question of taking anterior occlusal
radiographs (AO) in addition to a dental panoramic tomogram (DPT) using the
Planmeca PM Proline CC. DESIGN: Retrospective single centre study. SETTING:
Dental hospital radiology department. SUBJECTS: 100 pairs of DPTs and AOs which
had been requested for orthodontic assessment were examined between April and
July 1995. All DPTs were taken on a Planmeca PM Proline CC machine. RESULTS: The
AO was assumed to be the gold standard and the diagnostic validity of the DPT can
be assessed using values of sensitivity and specificity. 21% of DPTs were
identified as requiring a supplementary radiograph to clarify the image of the
anterior maxilla. CONCLUSIONS: A DPT machine with an adjustable focal trough has
significantly reduced the need for supplementary AO radiographs. The AO is
indicated when there is abnormality in the premaxilla or where dental
malocclusion prevents ideal positioning of the patient in the machine.
PMID- 9401144
TI - Prevalence of HCV infection in health care workers of a UK dental hospital.
AB - OBJECTIVE: To determine the prevalence of hepatitis C virus (HCV) antibodies in a
group of dental health care workers (DHCW). DESIGN: Retrospective cross sectional
study. SETTING: A UK dental hospital. SUBJECTS AND METHODS: The sera of 167
unselected DHCW were tested for the presence of IgG antibodies to HCV using two,
third-generation enzyme-linked immunosorbent assays (ELISA). HCV viremia was
determined by reverse transcription polymerase chain reaction (RT-PCR) analysis.
RESULTS: Two (1.2%) of the serum samples were found to be anti-HCV positive; one
was also viremic. The two antibody-positive subjects were a qualified dental
nurse and a student dental nurse, both females, without any known risk factor for
HCV acquisition. No dentist was HCV seropositive. CONCLUSIONS: Since the
prevalence of HCV infection in the UK general population varies between 0.08% and
0.55%, these results suggest that DHCW, and auxiliary staff in particularly, may
have a slightly increased risk of HCV infection.
PMID- 9401145
TI - The evaluation of SafeQuest--a computer-assisted learning program on cross
infection control for the dental team.
AB - OBJECTIVE: Evaluation of a computer-assisted learning (CAL) program (authored by
a general dental practitioner-GDP) on cross-infection control (CIC) for the
dental team. The aims of the evaluation were to determine how easy the program
was to use, to determine if users found the information useful, to ensure that
the content was accurate and to see what improvements could be made. METHODS: 96
questionnaires were distributed to dentists, 57 of whom responded (60%). 66% of
the respondents were GDPs. RESULTS: Compared with earlier evaluations of hospital
produced CAL programs, SafeQuest was equally well received. 96% of respondents
found it easy to use and 93% gave a positive score for their overall impression.
64% felt that the program had extended their knowledge, despite the fact that 74%
rated their knowledge on CIC as being good/excellent before using SafeQuest.
Suggestions on how the content and presentation of the program could be improved
led to changes to the final version. CONCLUSIONS: The SafeQuest program on cross
infection control could be useful as a learning resource in general dental
practice. The program, authored and produced by a GDP, compares favourably with
those written in dental schools.
PMID- 9401146
TI - A survey of dental professionals' health and well-being.
AB - Past research has indicated that working within dentistry may offer a
considerable threat to health. However, no data have previously been published
regarding the general well-being and lifestyles of dental personnel. This
descriptive study, which was undertaken by the BDA, aimed to examine the self
perceived health and well-being of people working in dental surgeries and to
describe their health related behaviours.
PMID- 9401147
TI - Treatment of severe mental illness.
PMID- 9401148
TI - My life on the street.
AB - In this first-person account, the author chronicles her experience of being
mentally ill and homeless in New York and New Jersey in the early 1980s. She
describes surviving numerous traumatic events until she eventually realized her
need for treatment and admitted herself to a mental institution.
PMID- 9401149
TI - Families of borderline patients: a psychoeducational approach.
AB - The development of the psychoeducational form of treatment described in this
article has been prompted by changes in our understanding of borderline
psychopathology and changes in the health care system in which these patients are
treated. After reviewing these background changes, the authors describe the
treatment itself, its form, its purpose, and the preliminary suggestions of its
effectiveness.
PMID- 9401150
TI - Using commercially available films to teach about borderline personality
disorder.
AB - Commercial films on videotape may be helpful in teaching medical students,
residents, and other mental health trainees about various topics in psychiatry.
Recommendations are made on the use of specific films, scenes, and characters to
illustrate the DSM-IV diagnostic criteria for borderline personality disorder
(BPD). The authors list 33 films depicting various aspects of BPD that might be
used for teaching purposes.
PMID- 9401151
TI - Aging and retirement: a difficult issue for individual psychoanalysts and
organized psychoanalysis.
AB - Organized psychoanalysis has a long history of discussing and formulating
policies on retirement, but follow-through has been lax and few analysts retire
unless forced by illness. Institutes tend to avoid and deny the problem of the
impaired analyst. Procedural guidelines are needed for assessing competency and
imposing involuntary retirement. The authors recommend that all institute
appointments be time-limited and that medical clearance specifically addressing
conditions potentially impairing professional functioning be required for
appointment and renewal.
PMID- 9401152
TI - The vision in supervision: transference-countertransference dynamics and
disclosure in the supervision relationship.
AB - The centrality of the supervision experience in the development of the
supervisee's personal and professional capacities is addressed. The supervision
relationship and process are explored in light of the potential effects of
transference-countertransference configurations of supervisor and supervisee.
Parallels between supervision and treatment are highlighted. The importance of
developing and utilizing the capacity for reflectivity is reviewed, as is the
impact of supervisee nondisclosure to supervisor. The direct use of
countertransference experiences in the context of supervision is explored, and
the centrality of self-disclosure is highlighted. It is recommended that
supervisor and supervisee remain receptive to exploring these experiences in the
service of developing a shared subjective sense of the patient, of increasing the
supervisee's capacity to treat his or her patient, and of providing the
supervisee with a novel, growth-enhancing relationship.
PMID- 9401153
TI - The unbearable agony of being: interpreting tormented states of mind in the
psychoanalysis of sexually traumatized patients.
AB - This article focuses on the clinical importance of the disturbing transference
countertransference matrix in the psychoanalysis of patients whose ego
development was decisively influenced by early, traumatic sexual abuse.
Dissociative defensive operations and "automatic" identifications are emphasized
in accounting for the sadomasochistic and other characteristic features of the
"traumatic" transference-countertransference ambiance. Two clinical vignettes
depict the analyst's need to take his or her own disturbing experience as an
object of analytic examination, while illustrating how "here-and-now"
transference cues are used to interpret the patient's efforts to cope with
overwhelming, traumatized states of mind.
PMID- 9401154
TI - Methodological problems encountered in research with psychiatric inpatients: a
case example.
AB - In this article, problems associated with several methods commonly employed in
research with psychiatric inpatients are discussed and the implications that
these problems have for the validity of research with this population are
explored, using an investigation of the relationship between moral reasoning and
aggression among psychiatric inpatients as a case example. Specific issues
examined include the adequacy of hospital records for diagnosing patients, the
difficulty of determining when it is appropriate to approach recently admitted
patients for research, and problems in the measurement of behavioral and
psychological variables such as aggression and moral reasoning. Suggestions and
recommendations for addressing these issues in future research are offered.
PMID- 9401155
TI - Outbreak of Vibrio parahaemolyticus related to raw oysters in British Columbia.
PMID- 9401156
TI - Outbreak of Salmonella enteritidis phage type 8 in a Montreal hotel.
PMID- 9401157
TI - A case of human rabies contracted in Nigeria.
PMID- 9401158
TI - Ciguatera fish poisoning linked to the ingestion of barracuda in a Montreal
restaurant--Quebec.
PMID- 9401159
TI - Transmission of hepatitis C virus infection associated with home infusion therapy
for hemophilia.
PMID- 9401160
TI - Ageism: the quiet epidemic.
PMID- 9401161
TI - Age and depression in a nationally representative sample of Canadians: a
preliminary look at the National Population Health Survey.
AB - There are considerable inconsistencies in the literature concerning the
relationship between age and depression. Recently, however, two independent
studies in the U.S. have shown that the distribution is U-shaped with the lowest
reported levels of depression at ages 45-49. Three reasons for past
inconsistencies are identified and addressed using the 1994 National Population
Health Survey by Statistics Canada. Using both a distress scale and a diagnostic
measure, a substantially different relationship was found. The prevalence of
distress decreased steadily with age until about 65, with only a slight increase
afterwards for both males and females. After the introduction of several
sociodemographic covariates, however, this relationship was clearly negative.
These findings are discussed in terms of future research questions.
PMID- 9401162
TI - Mortality and cognitive status among elderly Canadians living in the community
and in institutions: the Canadian Study of Health and Aging.
PMID- 9401163
TI - Predictors of dietary intake in Ontario seniors.
AB - This study determined the independent association of 24 risk factors with dietary
intake in community-living seniors. The study sample was 5,073 seniors for whom
complete data were available from the 1990 Ontario Health Survey. Risk factors
were items completed on an interviewer-administered health questionnaire. Diet
Score, Mean Adequacy Ratio and energy were the diet outcomes derived from a self
administered food frequency questionnaire. The independent association of risk
factors with these diet outcomes was assessed with multiple linear regression
analyses. Factors that were consistently and positively associated with diet
outcomes included: education, income, social support, perceived health status,
belief in the nutrition/health link, dependence in walking and vision. Factors
that were consistently and negatively associated with diet outcomes included:
chewing status, dentition, hearing, level of happiness and body mass index. These
results provide a basis for the development of a screening tool for the
identification of "at risk" subgroups of seniors.
PMID- 9401164
TI - Nutrient intakes of senior women: balancing the low-fat message.
AB - Nutrient intakes based on six days of food intake were collected from 52 elderly
Nova Scotian women. Mean reported energy intake was 1600 kilocalories, of which
fat contributed 31%. Mean intakes of zinc and Vitamin D were below
recommendations. Other nutrients of concern were protein, calcium, folate, and
vitamins B6 and B12. Nutrition education efforts should be directed at assisting
older people to maintain the generally recommended low fat intake, while
stressing the desirability of a balanced food intake of sufficient quantity,
which includes low-fat milk and dairy products, lean meats and legumes as sources
of nutrients in low supply.
PMID- 9401165
TI - Canadian recommended nutrient intakes underestimate true energy requirements in
middle-aged women.
AB - To examine whether Health Canada's Recommended Nutrient Intakes (RNI) and
FAO/WHO/UNU (Food and Agriculture Organization, World Health Organization, United
Nations University) values provide accurate indices of true energy requirements,
energy expenditure was determined using doubly labelled water (DLW) over 13 days
in a group of 29 middle-aged women. Energy intakes were calculated from weighed
food intake, and energy expenditures and intakes were then compared with
individual calculated RNI requirements. The mean energy requirement as determined
by DLW expenditure (9.56 +/- 0.53 MJ/d) was higher (p < 0.0001) than reported
energy intake (7.08 +/- 0.30 MJ/d) and was higher (p < 0.004) than RNI mean
energy requirement (7.97 +/- 0.18 MJ/d). The mean RNI for energy was also lower
(p < 0.0001) than that derived from FAO data. These results suggest that current
Health Canada RNIs are inadequate in predicting the energy needs of Canadian
middle-aged women.
PMID- 9401166
TI - Creation of priority criteria for corneal transplantation and analysis of factors
associated with surgery following implementation.
AB - PURPOSE: We sought to test the effectiveness and application of a system for
prioritizing corneal disease patients for corneal transplantation. METHODS: All
patients wait-listed for corneal transplantation in British Columbia in April
1995 were followed for 10 months to determine whether they received surgery and
to assess the application of recently introduced priority criteria. RESULTS: The
factors that determined whether a patient had surgery were as follows: having
vision in one eye only, being female, having progressive disease, and
experiencing pain. The surgeon involved was also a factor. Overall, the priority
system did not adequately predict who had surgery and who did not have surgery.
CONCLUSIONS: The priority system needs to be re-structured to reduce the
contribution of months waited and to more adequately take into account patient
need. Furthermore, its application by individual surgeons needs to be
strengthened.
PMID- 9401167
TI - Along the boardwalk: effects of a boardwalk on walking behaviour within a Nova
Scotia community.
PMID- 9401168
TI - Prostate cancer screening in the midst of controversy: Canadian men's knowledge,
beliefs, utilization, and future intentions.
AB - Despite controversy about prostate cancer screening, administrative data show
that the use of prostate specific antigen (PSA) testing in Canada has increased.
This study sought to determine awareness and knowledge of prostate cancer and
screening, use to date, and future intentions to have a digital rectal
examination (DRE) and PSA test among Canadian men aged 40 and over. Data were
collected through a Canada-wide cross-sectional random digit dial telephone
survey of 629 men. Awareness of DRE and PSA, use to date, and future intended use
varied with age and education. Although only 9% of respondents had had PSA
testing for screening, future intentions to undergo this test were higher than
use to date. Knowledge of prostate cancer and screening controversies was low,
and men received more information about PSA from the media than from doctors. Men
would, therefore, benefit from age- and education-specific information regarding
the factors to consider in making an informed choice about prostate cancer
screening.
PMID- 9401169
TI - A perspective on Canadian teenage births, 1992-94: older men and younger women?
AB - This article uses vital statistics relating to births by Canadian mothers between
1992 and 1994 to examine the distribution of age of father by age of mother at
the birth of the child. Over 77% of births to teenage mothers involved males who
were older than the mother. At the time of birth of the child, the mean
difference between age of the teenage mother and the father was 4.1 years,
compared with a mean of 2.6 years for all mothers and fathers. For mothers below
the age of 18 years, 37% of partners were within 2 years of the woman's age, 39%
were 3 to 5 years older, and 24% were six or more years older. Family planning
and sex education programs directed at the prevention of teenage pregnancy,
especially if these programs are given in the elementary or high school system,
would not necessarily reach older males, who make up the majority of partners in
teenage pregnancies.
PMID- 9401170
TI - Taking issue with alternative medicine label.
PMID- 9401171
TI - Taking issue with alternative medicine label.
PMID- 9401172
TI - Factors important in promoting mammography screening among Canadian women.
AB - Among women aged 50 to 69 years, regular screening by mammography in combination
with clinical examination, can substantially decrease the morbidity and mortality
associated with breast cancer by facilitating early detection. Unfortunately,
many Canadian women are not screened in accordance with current guidelines.
Research to date is based primarily on large surveys conducted in the United
States and less is known about the relevance of specific barriers to mammography
screening among Canadian women. Multivariate results from the 1994-95 National
Population Health Survey (NPHS) indicate that younger (40-49) and older (70+)
women, those who are socioeconomically disadvantaged, and minority women are
least likely to report having had a mammogram. Conversely, women with positive
health behaviours, high social support, and positive mental health attributes are
more likely to participate in mammography screening. These findings are discussed
in terms of the implications for developing successful intervention programs for
Canadian women and for setting priorities for further research.
PMID- 9401173
TI - Impact of two cardiovascular disease reduction education programs varying in the
type of nutrition information provided.
AB - The purpose of the study was to determine the impact of two worksite
cardiovascular nutrition education programs. Program 1 focused on information
related to the skills needed to change dietary behaviours (1 session, 45
minutes). Program 2 focused on information related to skills as well as
cardiovascular risk factors (1 session, 60 minutes). The study sample consisted
of office employees at three worksites. The pretest consisted of questions
pertaining to: frequency of consumption of high fat foods, knowledge related to
the risk and skills components of the program, and self-report of family and
personal history of cardiovascular disease. Of employees who completed the
pretest, 67% (55/82) in Program 1, 88% (46/52) in Program 2, and 86% (30/35) in
the control group completed the post-test (six weeks after the programs). The
results of regression analysis indicated that participants of Program 1 (skills
only) reduced their frequency of consumption of high fat foods (p < 0.01); no
other variables were significant. Nutrition education programs for the prevention
of cardiovascular disease should focus on information related to skills when
limited time is available.
PMID- 9401174
TI - Breast milk and the prevention of neonatal and preterm gastrointestinal disease
states: a new perspective.
AB - In this review of the protective properties of human breast milk, a new
perspective is taken to underscore the passive and active protection properties
of breast milk in providing specific protection against selective
gastrointestinal disease affecting the neonate and preterm infant. The normal
protective properties of the gastrointestinal epithelial barrier (immunologic and
nonimmunologic) are considered as is the development of barriers to antigen
absorption in the immature infant human intestine as a background for considering
three accelerated gastrointestinal diseases-necrotizing enterocolitis, intestinal
allergy, and bacterial gastroenteritis. In each of these conditions, the
developmental protective defect is considered and the role of breast milk plays
in filling the protective void discussed. Besides considering passive protection
of breast milk including the new roles assigned to nutrients such as lactoferrin
and nucleotides, and importance of active substances in breast milk such as
growth factors, cytokines and hormones are discussed in the context of actively
stimulating the infant's own intestinal defenses to function as a protective
barrier. Future studies at the cellular and molecular level should be helpful in
designing both preventative and treatment strategies to deal with these diseases.
PMID- 9401175
TI - Growth factors in breast milk and their effect on gastrointestinal development.
AB - Breast milk contains various biologically active factors including, hormones,
peptide growth factors, and cytokines. Epidermal growth factor (EGF) and
insulinlike growth factor-I (IGF-I) are two of the major milk-derived peptide
growth factors. Colostrum contains higher levels of these growth factors than
mature milk does, and, these factors are relatively resistant to proteolysis and
stable in the G-I tract. There are specific receptors found in G-I mucosa.
Luminal EGF and IGF-I stimulate growth and development of gastrointestinal tract.
Intestinal epithelial Caco-2 cells are a good model for studying physiological
roles of exogenous growth factors in the G-I development. Effect of EGF and IGF-I
on proliferation, differentiation, and IGF-binding protein (IGFBP) production of
intestinal Caco-2 cells were studied. Both EGF and IGF-I increased cell
proliferation in dose dependent manner. The number of IGF-I receptors on Caco-2
cells increased after differentiation, in contrast to EGF binding which was
reported to decrease. Caco-2 cells produced at least three IGFBPs, namely IGFBP
2, -3, and -4. The profile of these IGFBPs varied with differentiation. Secretion
of IGFBP-2 and -3 increased with differentiation, but IGFBP-4 diminished. IGF-I
stimulated mainly IGFBP-3 production, while EGF stimulated predominantly IGFBP-4.
The effects of IGF-I and EGF on IGFBP secretion diminished with increasing cell
differentiation. Thus, the interaction between intestinal epithelial cells and
extrinsic growth factors are complex and the stage of differentiation is an
important determinant of this phenomenon.
PMID- 9401176
TI - Breastfeeding practices in Indonesia.
AB - Breastfeeding promotion program was started by the paediatricians and others in
1977, and is becoming a strong activity since 1990 it was declared by the
President of the Republic of Indonesia as a National Movement. One year later the
First Lady stated the importance of every Indonesian mother to breast-feed her
baby, and thereafter many hospitals created the so called "Baby Friendly
Hospital". In this occasion we only limit with eminent topics, i.e., "Exclusive
Breast-feeding" in Indonesia, and "Breastfeeding amongst Working Mothers." In
fact, until now the percentage of mothers who breastfeed exclusively is very low.
Although the ever breastfed babies in Indonesia is 97% (Kodyat, 1996) but the
data of the "Exclusive Breastfeeding" of Indonesia is just like Pakistan and
Thailand, i.e. nearly 2 months, whereas the Philippines and Ceylon showed a
figure of 4 months, and India 5 months. The Home Health Survey (SKRT) data in
1992 showed that 63.7% of the babies were exclusively breast-fed until 3 months.
Three quarter of the quality of the exclusive breastmilk is quite good, enough or
excellent, whereas the other one quarter is poor and this should be interfered by
increasing the quality of the breastmilk and/or adding other formula, to prevent
the baby of getting "failure to thrive" (Suharyono, 1996). Working mothers use to
do "Early Weaning Practices" with very high mixed feeding practices (Matulessy et
al, 1996). Mothers have to go to work because they have to support their family
income, but unfortunately most of them ignore their main task of care their
children. IN CONCLUSION: the experience in Indonesia proves that a very hard work
should still be continued on the effort of promoting breastfeeding, especially
regarding the two issues, i.e. "Exclusive breastfeeding" (we do hope at least
until 4 months) and the other issue is regarding the "Working Mothers".
PMID- 9401177
TI - Blood nutrient indices in breast and formula fed infants: amino acids metabolic
responses.
AB - Human milk is generally considered as nutritionally the best food for infants,
infant formula are usually manufactured to be as similar to human milk as
possible, it may appear logical to attempt a metabolic response of formula fed
infants similar to that of breast fed infants. We conducted a 8 week growth and
metabolic study in 90 healthy term infants fed either human milk, whey dominant
formula or casein dominant formula, each group consisted of 30 infants. Results
revealed no significant differences were observed among the groups with respect
to growth and anthropometric measurements. Serum total protein, albumin were not
differ among breast-fed and formula fed infants. BUN and many plasma essential,
amino acid were significant higher in formula-fed groups. While plasma tryptophan
concentration was lower in two formula fed groups, in addition, plasma taurine
was lower in casein dominant group at 4 weeks of age. These results suggested a
reevaluation of protein quantity and quality in infant formula is needed.
PMID- 9401178
TI - Perspective of a pediatric nephrology program: an 18 year retrospective.
AB - We analyzed the patient profile in a pediatric nephrology training program, along
with data collected over an 18 year period, to determine whether there is merit
in the proposition that clinical training can be obtained equally well in
internal medicine nephrology training programs. We also compared the rate of
patient referral in an U.S. metropolitan area with a population of 1.2 million,
in the first 9 years without the "gatekeeper" health insurance system and the
next 9 years with managed care competition. Finally, we discussed guidelines for
renal biopsy in the child and approaches to treatment as practiced in a pediatric
nephrology program of almost two decades. We used the same NIH clinical data form
throughout the 18 years of data collection to record clinical, laboratory and
biopsy diagnosis, dialysis/ transplantation and other treatment data of patients
entering our outpatient and inpatient services. Between 1977 and 1996, 3,150 new
patients were examined for disorders related to the kidney. Twenty-one per cent
of the patients were in the first year of life and 50% were younger than seven
years of age. The majority of the 389 percutaneous renal biopsies were done in
children under 10 years of age. In addition, almost half of the 112 pediatric
dialysis/transplant patients presented before 10 years of age. Thus, the majority
of patients were in the early years of life, with an unique pattern of renal
diseases and issues regarding therapy which are clearly different from adulthood.
Therefore we concluded that the existing data did not support the proposition
that pediatric nephrology training be absorbed into internal medicine nephrology
programs. The introduction of managed care competition did not affect the rate of
patient enrollment. In fact, the rate of referrals in the latter 9 years
paralleled the first 9 years. The factors which contribute to this outcome are
discussed. Such data should be useful to those trying to meet the challenges of
this competitive era. Finally, we discussed guidelines for renal biopsies in
children and approaches to specific diseases.
PMID- 9401179
TI - Bone fractures in children with chronic cholestasis.
AB - The clinical features, biochemical data, roentgenographical bone changes and
liver histological studies of four children with fractures related to chronic
cholestasis are described. Two of them had Alagille syndrome and the other two,
biliary atresia. Only one patient presented with forearm fracture associated with
typical radiographic evidence of rickets. The others revealed generalized
osteopenia together with fractures in arms, forearms, and wrists respectively. Of
these, one with rickets had hypocalcemia and hypophosphatemia; one had decreased
parathyroid hormone with mild hypocalcemia and hyperphosphatemia; one had
hyperphosphatemia solely. Eucalcemia and euphosphatemia were noted in the
remaining patient. Their bone lesions deteriorated in spite of treatment, except
for the one with clinical rickets. All the patients succumbed eventually. It was
concluded that the real pathogenesis of bone lesions in end-stage liver disease
of chronic cholestatic children remains unclear. However, because rickets may
intervene, continuing efforts to supply vitamin D and calcium since diagnosis of
chronic cholestasis on a long-term basis, to prevent fracture, is still
mandatory.
PMID- 9401180
TI - Patch testing in the detection of cutaneous reactions caused by carbamazepine.
AB - Carbamazepine is a widely used antiepileptic drug associated with various side
effects including skin eruptions. Peroral provocation test with any suspected
drug is a reliable method of investigating the etiology: however, it is both
laborious and potentially dangerous to the patient. Patch testing has been
reported with variable success in skin drug reactions. Four cases (one male,
three females) with epileptic seizures were reviewed; all had received
carbamazepine therapy with appropriate dosage, then suffered from various
cutaneous reactions including maculopapular exanthema, exfoliative dermatitis,
erythema multiforme and Stevens-Johnson syndrome after the initial therapy for
two weeks to one month. Skin patch test was done with 1% and 10% carbamazepine in
petrolatum applied on the back, then read at 48 and 72 hours. All four patients
had positive allergic patch test reactions to carbamazepine. One patient had
extreme (+3), one had strong (+2) and another two had weak (+) reactions. There
were no any skin reaction to vehicle and control cases. This limited study
demonstrates that patch testing may be useful in the detection or confirmation of
any type of exanthematous eruption caused by carbamazepine.
PMID- 9401181
TI - Retinopathy of prematurity in very-low-birthweight neonates: epidemiology and
risk factors.
AB - A retrospective study of 143 very-low-birthweight infants cared in a level III
neonatal intensive care unit who had survived for at least 28 days. Initial eye
ground evaluation was done at the postnatal age between 4 and 6 weeks. Follow-up
evaluation was done every one to two weeks at the discretion of the
ophthalmologists. Thirty-four variables were reviewed for each case. Statistical
analysis was done for each variable, with the development of retinopathy of
prematurity (ROP), severity of ROP and development of threshold ROP as the
dependent variables, by Mann-Whitney U test or X2 test when adequate. Variables
with P-valu < 0.05 were included in multiple regression. One hundred and thirty
eight cases were survived for more than 28 days with their eyes been checked.
Twenty-six (18.8%) of them developed ROP. The prevalence of stage I was 2.2%
(3/138), stage II was 3.6% (5/138), stage III was 12.3% (17/138), and stage V was
0.7% (1/138). Threshold disease, stage 3 (+) and above, was found in 5 cases
(3.6%). Seventeen variables were found to be correlated with the development of
ROP. Only the duration of continuous positive airway pressure (CPAP) was
significantly correlated to the development of ROP in multivariate logistic
regression. Fifteen variables were correlated with the severity of ROP, but only
peak direct bilirublin level, peak total bilirubin level and duration of CPAP
could entered multiple stepwise linear regression. Thirteen variables were
correlated with the development of threshold ROP, but only episodes of septicemia
enter the multivariate logistic regression. We postulate that the longer duration
of CPAP in ROP cases may reflect the severity of apnea and episodes of hypoxic
attacks. Reducing episodes of apnea may prevent the development of ROP. The
number of episodes of septicemia was the only significant variable for threshold
ROP so that infection control is important for the prevention of threshold
disease.
PMID- 9401182
TI - Analysis of total IgE and allergen-specific IgE antibody levels of allergic
children in Taiwan.
AB - With advances in technology, several in vitro screening tests such as MAST and
CAP system have been used for analyzing the allergens involved in allergic
diseases such as bronchial asthma (BA), allergic rhinitis (AR), atopic dermatitis
(AD) and urticaria. In this study, CAP system (Pharmacia, Sweden) was used to
screen the prevalence of allergens responsible for these atopic diseases. A total
of 392 children were enrolled in this study retrospectively, all these atopic
children visited the allergy clinic of the Department of Pediatrics, National
Taiwan University Hospital during the period March 1995 and August 1995. Our
results showed: (1) Among these 392 allergic children, included 82 BA, 70 AR, 22
AD, 156 BA + AR. 8 BA + AD, 12 AR + AD, and 42 AD + AR + AD: (2) House dust mites
(Dermatophagoides pteronyssinus: D. p and Dermatophagoides farinae: D. f) are the
most common allergens triggering atopic disease in the Taiwan area. (3) Total IgE
level is the highest in three combined allergic disease (BA + AR + AD) [2179.9 +/
504.2KU/L] and lowest in single disease (AR) [503.1 +/- 84.8 KU/L]. Mite
specific IgE (D. p + D. f-specific IgE) concentration is also the highest in
three combined disease (BA + AR + AD) [499.1 +/- 86.0KU/L] and lowest in AR
[159.5 +/- 47.5 KU/L], (4) elevated specific IgE antibody to egg white and milk
were found in 68.4% and 47.4% of patients with AD and/or urticaria. In
conclusion, these data suggest that house dust mites, are the most important
allergens in respiratory allergy as well as in atopic dermatitis, while food
allergens play relatively important roles only in skin allergy. Furthermore, the
highest IgE level was noted in children with combined allergic diseases.
PMID- 9401183
TI - Myocarditis with complete atrioventricular block associated with herpes simplex
virus infection: report of one case.
AB - Myocarditis with complete atrioventricular block is a very unusual complication
of the herpex simplex infection. We report a 10-year-old boy infected very likely
by the herpes simplex virus and who presented with high fever, erythema
multiforme, complete atrioventricular block, and Adams-Stokes seizures. Emergent
temporary pacemaker was performed for bradycardia. A sixteen-fold rise in herpes
simplex antibody titer by a complement fixation method occurred within two weeks.
Normal cardiac rhythm recovered 11 days later with a sequela of complete right
bundle branch block after 2 years follow-up.
PMID- 9401184
TI - DiGeorge syndrome with microdeletion of chromosome 22q11.2: report of one case.
AB - DiGeorge syndrome (DGS) is a congenital anomaly involving developmental defects
of the third and fourth pharyngeal pouches. Thymic aplasia or hypoplasia,
parathyroid aplasia or hypoplasia, cardiac malformations, and dysmorphic facies
are characteristics features. We present a case which had thymic aplasia,
hypocalcemia, facial dysmorphism (hypertelorism, low set ears, cleft of soft
palate, fish-like mouth and micrognathia) and congenital heart disease
(ventricular septal defect, perimembranous type). The T-cell immunologic
functions as a percentage of T-cell and phytohemagglutinin stimulation test were
within normal range matched with age. Molecular study showed microdeletion of
chromosome 22q11.2 by genotype analysis, but chromosome study of high-resolution
cytogenetic analysis by G-banding technique was normal. To our knowledge, about
90% of DiGeorge syndrome patients show chromosome abnormalities, most involving
chromosome 22 (monosomy of 22q11.2). In the past, most cases were proven by high
resolution cytogenetic analysis or fluorescence in situ hybridization(FISH). We
report a case of DGS in Taiwan with microdeletion of chromosome 22q11.2 detected
by genotype analysis.
PMID- 9401185
TI - A giant retroperitoneal ganglioneuroma with intraspinal involvement: report of
one case.
AB - A 9-year-old girl was discovered to have had a huge retroperitoneal mass causing
moderate hydronephrosis and anterior displacement of the right kidney and which
was found on a renal ultrasonographic examination. A series of examinations
including (1)IVP, (2) abdominal computed tomography, (3) MRI and(4) incisional
biopsy revealed a giant dumb-bell shaped retroperitoneal ganglioneuroma with
intraspinal involvement. Secondary scoliosis was also noticed. We successfully
resected the huge ganglioneuroma of the right retroperitoneum in a two stage
procedure: her postoperative course was uneventful.
PMID- 9401186
TI - Congenital short bowel syndrome with left acheiria: report of one case.
AB - A case of congenital short bowel syndrome with left acheiria, hemivertebra and
dextrocardia is described. Dilatation of the fetal bowel was observed at the 24th
week of gestation during a routine ultrasonic scan of a healthy 23-year-old
primigravida from a non-consanguineous marriage. Amniocentesis and chorionic
villus sampling were denied. The baby was delivered at 38 weeks of gestational
age. After delivery, multiple anomalies were noted: left acheiria, congenital
short bowel syndrome (15 cm in length of the ileum), pseudo-obstruction of
intestine, dextrocardia, and hemivertebrae. We suspected these abnormalities
might be due to a vascular accident or failure of lateralization during the early
gestational period. To our knowledge, these combinations have not been reported
previously in English literature.
PMID- 9401187
TI - Aplasia cutis congenita: report of one case.
AB - We present a female newborn with a skin defect on the vertex. Aplasia cutis
congenita was diagnosed. No associated anomaly was found. There was no family or
drug history noted. At one-year follow-up, the lesion tended to contract and
became epithelialized. We report this case and also review the literature, and
then we suggest a checklist for aplasia cutis congenita.
PMID- 9401188
TI - Meningococcal disease in students at the University of Southampton: update.
PMID- 9401189
TI - Uptake of influenza vaccine in high risk patients.
PMID- 9401190
TI - Detecting vancomycin intermediate Staphylococcus aureus.
PMID- 9401191
TI - Converting hospital computer systems.
PMID- 9401192
TI - Health care quality leaders address patient confidentiality.
PMID- 9401193
TI - Wireless, infrared "tag" system improves patient care.
PMID- 9401194
TI - A challenge for nursing education.
AB - Computer technology has the potential to help nursing programs to establish
conditions that allow for academic success of special needs students without
compromising the caliber of instruction or academic standards. As the
capabilities of computers have increased in the last decade, a variety of
exciting new tools have been created that have the potential to enhance the
success of students with special needs. Effective instructional methods must be
developed and implemented to make use of the power provided by these tools.
Limited research is available in the nursing and education literature to support
use of computer adaptations for students with special needs. There needs to be
initiation of research based study of the tools and proposed adaptations.
Educators, administrators, and researchers need to collaborate in this effort to
transform the potential of technology into reality.
PMID- 9401195
TI - Presentation hardware options.
PMID- 9401196
TI - Criteria for nursing information systems as a component of the electronic patient
record. An international Delphi study.
AB - In many countries nurses lack an adequate tool to assist in determining the
essentials of an information policy in health care institutions and to outline
the nursing component of the electronic patient record. In the United States
criteria exist for systems that support the nursing process and for the
electronic patient record, and the United Kingdom has the disposal of an
Information Management and Technology Strategy that includes nursing information.
The objective of this study was to determine international criteria for nursing
information systems when such systems become part of the electronic patient
record. Using the Delphi methodology, criteria for nursing information systems
development, content, structure, and use are established by an international
panel of 36 experts in three succeeding rounds. Most criteria gained consensus
and are useful for application in practice for development of information policy
and information systems for nursing. Eventually, the list of criteria will be
included in a nursing information reference model. Nursing will benefit from the
application of the reference model and the criteria to develop adequate
information and communication technology.
PMID- 9401197
TI - Nursing the community in cyberspace.
AB - As nursing expands more into the community, the role of health promotion is
finding its way on the information superhighway. Through NetWellness, nursing
faculty experts at the University of Cincinnati College of Nursing and Health are
providing health care information via the internet. Not only is the world wide
web a site of their nursing practice, but also faculty are identifying new
linkages to add to the College's curriculum.
PMID- 9401198
TI - Learning environment in information technology. The views of student nurses.
PMID- 9401199
TI - Validation by school nurses of the Nursing Intervention Classification for
computer software.
AB - Validation of standardized nursing language for use by specialty nurses is
important for the design of computer software. The purposes of this study were to
validate the usefulness of the 433 interventions in the Nursing Intervention
Classification (NIC) for school nurses and to identify interventions that could
be omitted from computer software for school nurses. A school nursing listserv,
SCHLRN-L, was used to recruit volunteers. Ninety-three volunteers from the
listserv also recruited 26 school nurses who were not members of the listserv.
The total sample was 102 school nurses from 25 states and other areas, 76
listserv volunteers, and 26 others. E-mail was used to send and receive the
survey forms to portions of the sample. A majority of interventions (n = 241;
56%) were selected as used by more than 50% of the sample. Of these, 53 direct
care interventions were selected as used by more than 80% of the sample. Fifty
interventions were not used by 100% of the sample. E-mail was a useful means to
obtain a national sample and collect data.
PMID- 9401200
TI - Functions of SH2 and SH3 domains.
PMID- 9401201
TI - Function of PTB domains.
PMID- 9401202
TI - Pleckstrin homology domains.
PMID- 9401203
TI - Structure and function of LIM domains.
PMID- 9401204
TI - WW (WWP) domains: from structure to function.
PMID- 9401205
TI - Modular domains of focal adhesion-associated proteins.
PMID- 9401206
TI - Physiological function of receptor-SH2 interactions.
PMID- 9401207
TI - The IRS-signaling system: a network of docking proteins that mediate insulin and
cytokine action.
PMID- 9401208
TI - PDZ domains and the formation of protein networks at the plasma membrane.
PMID- 9401209
TI - Mechanism and function of signaling by the TGF beta superfamily.
PMID- 9401210
TI - Notch receptors, partners and regulators: from conserved domains to powerful
functions.
PMID- 9401211
TI - Signaling through Grb2/Ash-control of the Ras pathway and cytoskeleton.
PMID- 9401212
TI - Genetic analysis of sevenless tyrosine kinase signaling in Drosophila.
PMID- 9401213
TI - An overview of thyroid carcinoma.
AB - Approximately, 12,000 cases of thyroid carcinoma are diagnosed each year. This
disease entity accounts for 1.5 percent of all malignancies and is clinically
evident in four percent to seven percent of the United States population. This
paper provides an overview of thyroid carcinoma, including types, incidence,
predisposing factors, evaluation, and treatment.
PMID- 9401215
TI - The duPont Hospital for Children: a brief history.
PMID- 9401214
TI - Predicting red blood cell transfusions in very low birth weight infants based on
clinical risk factors.
AB - OBJECTIVE: To describe the clinical factors most predictive of red blood cell
transfusion in very low birth weight (VLBW) infants. STUDY DESIGN: Retrospective
review of VLBW infants cared for at a single level III NICU during a two year
period, n = 199. RESULTS: Overall transfusion requirement was 4.6 +/- 6.2
transfusions/infant/hospital course. Length of hospital stay, days of mechanical
ventilation, requirement for dopamine support, birth weight, initial hematocrit,
periventricular leukomalacia and necrotizing enterocolitis all independently
correlated with number of transfusions and donors. Bronchopulmonary dysplasia and
patent ductus arteriosus were associated with donor but not transfusion number.
CONCLUSIONS: Our data characterize the population of VLBW infants with the
greatest blood transfusion and donor requirement. Further investigation is needed
to target this population for interventions to reduce blood exposure.
PMID- 9401216
TI - The perfect physician.
PMID- 9401217
TI - Surface-marker cluster design criteria for 3-D bone movement reconstruction.
AB - When three-dimensional (3-D) human or animal movement is recorded using a
photogrammetric system, bone-embedded frame positions and orientations are
estimated from reconstructed surface marker trajectories using either nonoptimal
or optimal algorithms. The effectiveness of these mathematical procedures in
accommodating for both photogrammetric errors and skin movement artifacts depends
on the number of markers associated with a given bone as well as on the size and
shape characteristics of the relevant cluster. One objective of this paper deals
with the identification of marker-cluster design criteria aimed at the
minimization of error propagation from marker coordinates to bone-embedded frame
position and orientation. Findings allow for the quantitative estimation of these
errors for any given cluster configuration and suggest the following main design
criteria. A cluster made up of four markers represents a good practical
compromise. Planar clusters are acceptable, provided in quasi-isotropic
distribution. The root mean square distance of the markers from their centroid
should be greater than ten times the standard deviation of the marker position
error. The second objective of this paper deals with the identification of the
optimal cluster position and orientation on the limb aimed at the minimization of
error propagation to anatomical landmark laboratory coordinates. Cluster position
should be selected to minimize skin movement artifacts. The longest principal
axis of the marker distribution should be oriented toward the relevant anatomical
landmark position.
PMID- 9401218
TI - Joint kinematics simulation from medical imaging data.
AB - A method for joint kinematics simulation is described. Kinematics parameters are
determined from the relative displacement of marker sets placed on anatomical
landmarks of surface models generated from medical imaging contour data. The
landmarks are identified manually on fingers in multiple positions. A
mathematical algorithm was then used to ascertain the kinematics axes of motion
of the fingers. Once these axes are located, they are used as the base of a real
time interactive simulation of the finger. The entire simulation was accomplished
in a high-resolution graphics environment. A full complement of interactive tools
(virtual dials and buttons controlled via mouse) was used to enhance the user
interface. The development of the system, the model and the advantages and
disadvantages of the method are discussed.
PMID- 9401219
TI - Simultaneous and nonlinear identification of mechanical and reflex properties of
human elbow joint muscles.
AB - The naturally coexisting intrinsic mechanical and reflex properties of the human
elbow joint were identified simultaneously using nonlinear, time-delay,
continuous-time, and dynamic models. Angular random perturbations of small
amplitude and low bandwidth were applied to the joint using a computer-controlled
servomotor, while the subject maintained various levels of mean background muscle
torque. Joint neuromuscular dynamics were identified from the measured elbow
angle and torque. Stretch reflexes were modeled nonlinearly with both dynamic and
static reflex gains. A continuous-time system identification method was developed
to estimate parameters of the nonlinear models directly from sampled data while
retaining realistic physical or physiological interpretations. Results from six
subjects showed that dynamic stretch reflex gains, joint stiffness, and viscosity
generally increased with mean background muscle torque; and that dynamic stretch
reflex gain was higher during muscle stretch than that during muscle shortening.
More importantly, the study provided realistic simultaneous estimates of the
relative contributions of intrinsic mechanical and reflex actions to net joint
torque. In particular, reflexively-mediated stiffness generated a significant
portion of the total joint stiffness and the percentage varied systematically
with background muscle torque.
PMID- 9401220
TI - An advanced demultiplexing system for physiological stimulation.
AB - A CMOS very large scale integration (VLSI) chip has been designed and built to
implement a scheme developed for multiplexing/demultiplexing the signals required
to operate an intracortical stimulating electrode array. Because the use of radio
telemetry in a proposed system utilizing this chip may impose limits upon the
rate of data transmission to the chip, the scheme described herein was used to
reduce the amount of digital information which must be sent to control a large
quantity (up to several hundred) of stimulating electrodes. By incorporating
multiple current sources on chip, many channels may be stimulated simultaneously.
By incorporating on-chip timers, control over pulse timing is assigned to the
chip, reducing by up to fourfold the amount of control data which must be sent.
By incorporating on-chip RAM, information associated with the desired stimulus
amplitude and pulse timing can be stored on chip. In this manner, it is necessary
to send control information to the chip only when the information changes, rather
than at the stimulus repeat rate for each channel. This further reduces the data
rate by a factor of five to ten times or more. The architecture described here,
implemented as an eight-channel stimulator, is scalable to a 625-channel
stimulator while keeping data transmission rates under 2 Mbps.
PMID- 9401221
TI - Noninvasive glucose sensing utilizing a digital closed-loop polarimetric
approach.
AB - A polarimetric glucose sensor utilizing a digital closed-loop controller was
designed and implemented during this study. Its potential as a noninvasive
glucose sensor was evaluated in vitro for both glucose-doped water and bovine
aqueous humor mediums. A physiological hyperglycemic concentration range was used
in both calibration and validation of each set of experiments. Ideally, the end
application of this system could estimate blood glucose concentrations indirectly
by measuring the amount of rotation of a light beam's polarization state after it
propagates through the aqueous humor contained within the anterior chamber of the
eye. The polarimeter designed in this study differs from similar investigated
systems in that it utilizes a digital closed-loop control system. This type of
controller was implemented in order to further improve system repeatability and
stability without sacrificing accuracy. Unique to this investigation, independent
validation sets other than those used to create each respective calibration model
were obtained. The results of the glucose-doped water experiments yielded mean
standard errors of prediction for calibration and validation of 6.91 and 8.84
mg/dl, respectively. The mean standard errors of prediction during calibration
and validation of the glucose-doped aqueous humor experiments were higher at
27.20 and 27.47 mg/dl, respectively, due to medium degradation over time while
exposed to air.
PMID- 9401222
TI - Real-time multichannel computerized electrogastrograph.
AB - The purpose of this study was to develop a real-time multichannel computerized
electrogastrograph (EGG) to measure and analyze electrical signals from the human
abdominal surface. A soft-contact matrix composed of 25 cutaneous electrodes is
embedded evenly in a latex mat. The mat can be firmly attached to the abdominal
surface by drawing a vacuum between the matrix and the stomach. Twenty-five high
amplification filter/amplifiers provide a high signal-to-noise ratio and flat
amplitude response for a signal between 0.02 and 0.12 Hz (1.2-7.2 cpm). The
computer program provides waveform and frequency analysis for any chosen channel
and mapping analyses for all 25 channels. A two-dimensional propagation
exploration program was also developed. Using four different mapping analysis
program subroutines, the optimal points for analyzing the EGG signals can be
reliably found and variability of these locations can be observed easily. Results
show differences in the EGG mappings of normal and abnormal subjects.
PMID- 9401223
TI - An integral equation model for intracardiac electrogram sensing.
AB - Electrogram sensed by an intracardiac electrode has long been characterized based
on two approaches: 1) presume that the electrode is very small and does not
disturb the potential prior to applying the electrode, and 2) take an average of
the prior potential over the electrode surface. In fact, any intracardiac sensing
electrode has a finite surface area where electrical charges are induced and
disturb the external potential field, thus, the sensed potential is different
from the potential prior to placing the electrode. In this paper, an integral
equation model is proposed based on the current continuity equation in
homogeneous myocardial medium. The new model can accurately characterize the
electrogram sensed by an electrode with a non-negligible surface area and a load
impedance. The new model can be solved numerically via the method of moments to
obtain the potential induced on the electrode surface by an arbitrary dipole
volume source. As an application of the proposed theory, several electrode
configurations with different loads have been analyzed with an intent to show
that a finite electrode surface will significantly reduce the electrogram peak
amplitude and slope, and a load impedance lower than 20 k omega will also degrade
the electrogram sensitivity.
PMID- 9401224
TI - An efficient algorithm for computing multishell spherical volume conductor models
in EEG dipole source localization.
AB - Computationally localizing electrical current sources of the
electroencephalographic signal requires a volume conductor model which relates
theoretical scalp potentials to the dipolar source located within the modeled
brain. The commonly used multishell spherical model provides this source
potential relationship using a sum of infinite series whose computation is
difficult. This paper provides a closed-form approximation to this sum based on
an optimal fitting to the weights of the Legendre polynomials. The second-order
(third-order) approximation algorithm, implemented by a provided C-routine,
requires only 100 (140) floating point operations to compute a single scalp
potential in response to an arbitrary current dipole located within a four-shell
spherical volume conductor model. This cost of computation represents only 6.3%
(8.9%) of that required by the direct method. The relative mean square error,
measured by using 20,000 random dipoles distributed within the modeled brain, in
only 0.29% (0.066%).
PMID- 9401225
TI - ECG coding by wavelet-based linear prediction.
AB - This paper presents a novel coding scheme for electrocardiogram (ECG). Following
beat delineation, the periods of the beats are normalized by multirate
processing. After amplitude normalization, discrete wavelet transform is applied
to each beat. Due to the period and amplitude normalization, the wavelet
transform coefficients bear a high correlation across beats at identical
locations. To increase the compression ratio, the residual sequence obtained
after linear prediction of the significant wavelet coefficients is transmitted to
the decoder. The difference between the actual period and the mean beat period,
and that between the actual scale factor and the average amplitude scale factor
are also transmitted for each beat. At the decoder, the inverse wavelet transform
is computed from the reconstructed wavelet transform coefficients. The original
amplitude and period of each beat are then recovered. The approximation achieved,
at an average rate of 180 b/s, is of high quality. We have evaluated the
normalized maximum amplitude error and its position in each cycle, in addition to
the normalized root mean square error. The significant feature of the proposed
technique is that, while the error is nearly uniform throughout the cycle, the
diagnostically crucial QRS region is kept free of maximal reconstruction error.
PMID- 9401226
TI - A noninvasive technique for detecting obstructive and central sleep apnea.
AB - A new noninvasive method to detect obstructive and central sleep apnea [(OSA) and
(CSA)] events is described. Data were collected from ten volunteer subjects with
a previous diagnosis of OSA while they were titrated for continuous positive
airway pressure (CPAP) therapy. Apneic events were identify by analyzing of
estimated airway impedance determined from pressure and airflow signals delivered
from CPAP. To enhance performance of this technique, a single-frequency (5 Hz
with 0.5 cmH2O peak-to-peak amplitude) probing signal was superimposed on the
applied CPAP pressure. The results indicated that estimated airway impedance
during OSA (mean: 17.9, SD: 3.4, N = 50) was significantly higher then during CSA
(mean: 4.1, SD: 1.7, N = 50). When the estimated impedance of OSA and CSA events
were compared to a fixed threshold, 100% of all events can be correctly
categorized. These results indicate that it may be possible to diagnose OSA and
CSA noninvasively based upon this technique. The instrument and the algorithm
required are relatively simple and can be incorporated in a home-based device. If
this method was used for prescreening apnea patients, it could reduce cost,
waiting time, and discomfort associated with traditional diagnostic procedures.
PMID- 9401227
TI - Separation of discontinuous adventitious sounds from vesicular sounds using a
wavelet-based filter.
AB - The separation of pathological discontinuous adventitious sounds (DAS) from
vesicular sounds (VS) is of great importance to the analysis of lung sounds,
since DAS are related to certain pulmonary pathologies. An automated way of
revealing the diagnostic character of DAS by isolating them from VS, based on
their nonstationarity, is presented in this paper. The proposed algorithm
combines multiresolution analysis with hard thresholding in order to compose a
wavelet transform-based stationary-nonstationary filter (WTST-NST). Applying the
WTST-NST filter to fine/coarse crackles and squawks, selected from three lung
sound databases, the coherent structure of DAS is revealed and they are separated
from VS. When compared to other separation tools, the WTST-NST filter performed
more accurately, objectively, and with lower computational cost. Due to its
simple implementation it can easily be used in clinical medicine.
PMID- 9401228
TI - Simulations of the behavior of synaptically driven neurons via time-invariant
circuit models.
AB - This paper describes computer simulations of the behavior of Hodgkin-Huxley
neurons, based on a redefinition of membrane and synaptic connections as time
invariant circuit elements. Examples are given showing that this self-consistent
equivalent circuit representation allows very efficient computer simulations and
could facilitate the introduction of detailed biological neurons into formal
neural networks.
PMID- 9401229
TI - Reliability of percent distribution of power of the electrogastrogram in
recognizing gastric electrical uncoupling.
AB - The aim of this study was to examine the reliability of percent distribution of
electrogastrographic (EGG) power in recognizing gastric electrical uncoupling.
Sixteen anaesthetized dogs underwent laparotomy and implantation of six pairs of
stainless-steel wire electrodes. Distal stomach was measured and three sections
with approximately equal lengths were defined. Two pairs of electrodes were
implanted in each section. Eight-channel EGG was also recorded. Three separate
half-hour recordings were made: in the basal state; after a full circumferential
separation of the distal antral section from the rest; after a second
circumferential cut completely separating the middle from the proximal sections.
EGG digital power spectra were split into three frequency ranges and dynamics of
percent distribution of power was statistically examined. After the first cut,
changes in the percent distribution of EGG power in the normal range were not
significant (p = 0.2). Significant changes in the low range were noted (p < 0.05)
and changes in the high range were borderline nonsignificant (p = 0.056). After
the second cut, changes in percent distribution in the normal and the high range
became significant (p < 0.01) while changes in the low range were insignificant
(p = 0.075). Severe uncoupling was reflected in EGG by significant changes in the
high-frequency range without internal tachygastria necessarily being present.
PMID- 9401230
TI - Changing trend of Salmonella infection.
PMID- 9401231
TI - Oxidants, antioxidants and diseases--a brief review.
AB - Although oxygen (O2) is needed to the body, partially reduced forms of O2 and
some of their derivatives collectively called reactive oxygen species (ROS), are
highly toxic prooxidants to the body. To prevent ROS toxicity body's endogenous
and exogenous antioxidants (AOS) act in concert. To maintain health a balance
between pro and anti oxidants is very necessary.
PMID- 9401232
TI - Evaluation of transperineal template implant technique in Indian cervical
carcinoma patients.
AB - The prognosis in advanced cervical cancer patients is poor specially in presence
of distorted anatomy, gross residual growth etc. In these cases template implant
offers good option for treatment. We have carried out the procedure in 19
patients with acceptable level of complication. Preliminary results have been
described.
PMID- 9401233
TI - Anti-neutrophil cytoplasmic antibody (ANCA)--a review.
PMID- 9401234
TI - Clinton to apologize for tests.
PMID- 9401235
TI - Costly medicines only for staff--patient sues NDMC hospital for Rs. 25,000.
PMID- 9401236
TI - Diagnosis and monitoring of thyroid diseases.
PMID- 9401237
TI - UV-dependent melanocyte plasticity--the structure-function relationship.
AB - The UV response of marginal melanocytes in vitiliginous skin was studied using a
whole skin organ culture technique. This method assesses the plasticity of
melanocytes in response to UV. It is observed that there is a sequential increase
in catecholoxidase production and in the volume and dendricity of the melanocytes
on exposure to a single pulse of UV, reaching a peak at 3 1/2 h. From this study
it is evident that the melanocyte shows a prominent structural and functional
plasticity in response to UV. Implicit is the utilisation and transduction of UV
energy by the melanocyte, for transcriptional and translational activity,
enhancing catecholoxidase and cell structural protein production.
PMID- 9401238
TI - Prevalence of bacterial prostatitis in benign prostatic hyperplasia.
AB - To define the prevalence of bacterial prostatitis and urinary tract infection
(U.T.I) among benign prostatic hyperplasia patients (B.H.P) undergoing
prostatectomy trans urethral resection of prostate (T.U.R.P.), 100 consecutive
patient has their preoperative and post-operative urine cultures along with
tissue culture of the resected prostatic tissue. Our data suggests that
significant incidence (42%) of bacterial growth in prostatic tissue-occurs in
patients with B.H.P. Pre-existing U.T.I. is not a reliable indicator by which
this group could be identified pre-operatively and prostatic infection could be
treated.
PMID- 9401240
TI - Characterisation of Vibrio cholerae 0139 isolated from diarrhoeal stools.
AB - A total of 174 samples of acute diarrhoeal stools received over a period of seven
months, yielded 101 isolated morphologically and biochemically resembling Vibro
cholerae. Serologically, 57(56.4 per cent) of the 101 isolates were identified as
V. cholerae 01 and remaining 44 (43.6 per cent) as V. cholerae 0139. Keeping in
mind the unique potential of 0139 among non 01 vibrio to cause epidemics, we
decided to undertake the study of biochemical characters and physiological
behaviour of all the 44 V. cholerae 0139 isolates. All the stains were Voges
Proskauer's test positive' haemagglutinating and grew in the presence of 6 per
cent sodium chloride. 13 (29.5 per cent) strains showed haemolytic activity. Nine
(20.5 per cent) were polymyxin-B sensitive and 4 (9.0 per cent) fermented
lactose. All the isolates showed considerable degree of homogeneity in their
biochemical and physiological properties, some characters define them to be
closer to El Tor biotype.
PMID- 9401239
TI - Anaerobic and aerobic microflora of pouch of Douglas aspirate v/s high vaginal
swab in cases of pelvic inflammatory disease.
AB - The anaerobic and aerobic bacterial flora in pouch of Douglas (POD) aspirate and
high vaginal swabs (HVS) was studied in 43 cases of pelvic inflammatory disease
(PID) using standard techniques. High vaginal swabs from 20 healthy women were
included as controls. Anaerobic and aerobic bacteria were isolated from 37 (86%)
HVS and 31 (72%) POD aspirates from these 43 women. A total of 100 aerobic and 10
anaerobic bacterial strains were recovered from both the sites. Coagulase
negative staphylococci (28), Escherichia coli (23) and Streptococcus faecalis
(14) were predominant aerobic bacteria. Of the anaerobes, peptostreptococci
species and Bacteroides species were more common, polymicrobial flora (more than
one type of organism) was present in a total of 27 specimens. However mixture of
anaerobic and aerobic bacteria were seen in only 5 specimens. Of the 20 control
specimens, ten were positive for organisms. Ten aerobic and 3 anaerobic bacterial
strains were recovered.
PMID- 9401241
TI - Study of pathogenicity markers of staphylococci isolated from clinical specimens.
AB - A total of 165 strains of coagulase positive staphylococci (CPS) and 39 strains
of coagulase negative Staphylococci (CNS) isolated from various clinical
specimens studied for biochemical and enzyme profile showed overlapping of the
key characters of pathogenicity. Anaerobic mannitol fermentation (69.20%),
phosphatase (58.97%) and penicillinase (58.97%) production was remarkable amongst
CNS. Both CPS and CNS showed increased resistance to penicillin and other
antimicrobials. Besides increased frequency of isolation of CNS from pathological
specimens, they elaborate singly or in combination, the recognized virulence
factors.
PMID- 9401242
TI - Pulmonary infection caused by Mycobacteria other than M. tuberculosis in and
around Calcutta.
AB - A study was undertaken to determine the prevalence rate of atypical mycobacteria
in indolent fibrocavitary pulmonary diseases. 450 sputum specimens were examined
and cultured, of which 15 were identified as atypical mycobacteria on repeated
culture. No previous study was recorded from Calcutta. Compared to the results of
previous workers from different regions of India, the prevalence rate seems high
in this part of the country.
PMID- 9401243
TI - Seroprevalence of syphilis by TPHA test.
AB - A total of 1074 sera obtained from clinically suspected cases of Syphilis and
various risk groups were screened for antitreponemal antibodies by Treponema
pallidum Haemagglutination (TPHA) test and cardiolipin antibodies by the Venereal
Disease Research Laboratory (VDRL) tests. The TPHA test was positive in 291
(27.09) per cent. The TPHA was positive in 53.31 per cent (161 out of 302)
patients of primary syphilis, 54.17 per cent (26 out of 48) of secondary, 32.76
per cent (19 out of 58) of tertiary syphilis, 17.12 per cent (19 out of 111) of
other Sexually Transmitted Disease (STD) patients, 25.32 per cent (60 out of 237)
pregnant women and 1.89 per cent (6 out of 318) healthy individuals. TPHA was
found to be superior to VDRL test in all the study groups. Almost a total
agreement was seen between the TPHA test and VDRL test with a titre of 1 in 16 &
above; while in as many as 32.39 per cent sera with VDRL titre of 1 in 8 TPHA was
negative indicating that the VDRL titres above 1 in 8 should be considered as
true reactives to minimize the biological false positive reactions.
PMID- 9401244
TI - Trends of HIV infection in the blood donors of Delhi.
AB - Screening of HIV Infection was made mandatory for every unit of blood collected
for transfusion in Delhi, India since 1989. Ten Zonal Blood Testing Centres have
been identified which test all the blood collected for HIV by 29 blood blanks for
the city. Reports from these testing centres have been analysed yearwise to find
out the magnitude and trends of HIV infection in different groups of blood
donors. Although initially there was no difference in HIV Sero-reactivity in
different blood donors categories (between 1 & 2 per 1000 blood donors samples
tested) but subsequently there is significant increase (5.24/1000 in 1992 &
7.48/1000 in 1993) in the HIV sero-reactivity in replacement donor category
possibly because professional donors donate blood in the guise of being
replacement donors. The fact which comes out clearly is that HIV infection is
present in all sections of the population in Delhi and mandatory HIV Screening of
all blood collected for transfusion is justified.
PMID- 9401245
TI - Coronary artery-intramyocardial sinusoid communication in a case of pulmonary
atresia with intact ventricular septum.
AB - Intramyocardial sinusoid--coronary artery fistulous communications are well
established channels in pulmonary atresia with intact ventricular septum.
Angiographically flow can be demonstrated from the right ventricular cavity into
the coronary arteries. We have histologically demonstrated such a communication
in a case of pulmonary atresia with intact septum.
PMID- 9401246
TI - Hepatoblastoma with complete regeneration of liver and with metastasis to lungs
and brain within six months after partial hepatectomy--a case report.
PMID- 9401247
TI - Post-transplantation epididymitis associated with cytomegalovirus.
AB - Cytomegalovirus (CMV) infection, though usually systemic, has been known to cause
localised involvement of organs like lung, liver, testis and gastrointestinal
tract. We report a case of cytomegaloviral infection involving the epididymis
without systemic manifestations in an young male one month after renal
transplantation. The diagnosis was made on histopathologic examination of the
epididymo-orchidectomy specimen. Clinical improvement occurred after the
emergency epididymo-orchidectomy. To the best of our knowledge, only three cases
of CMV epididymitis have been described in the world literature--two in
transplant patients and one in an AIDS patient.
PMID- 9401248
TI - Echinococcosis involving the breast: diagnosis by fine needle aspiration
cytology.
PMID- 9401249
TI - Cytologic diagnosis of neurilemomas of male breast by fine needle aspiration.
AB - Among 217 cases of male breast lesions subjected to fine needle aspiration
cytology(FNAC) over a period of nine years, three cases were found to be having
neurilemomas, The review of literature reveals the first case of neurilemoma of
male breast diagnosed by FNAC was reported in 1992. Very scanty literature is
available on this rare tumour of male breast. The aspirates yielded cellular
smears composed of clusters of spindle shaped cells and Verocay bodies.
Histopathological examination of the excised masses confirmed the cytological
diagnosis.
PMID- 9401250
TI - Childhood cancer: where do we stand?
PMID- 9401251
TI - Effect of zinc supplementation on cell-mediated immunity and lymphocyte subsets
in preschool children.
AB - OBJECTIVE: In a zinc supplementation trial (with a significant impact on
diarrheal morbidity), to evaluate effect of zinc supplementation on cellular
immune status before and after 120 days of supplementation. DESIGN: A double
blind, randomized controlled trial with immune assessment at baseline and after
120 days on supplement. SETTING: Community based study in an urban slum
population. SUBJECTS: Randomly selected children (zinc 38, control 48), had a
Multitest CMI skin test at both times. In 66 children (zinc 22, control 34),
proportions of CD3, CD4, CD8, CD16, CD20 cells and the CD/CD8 ratio were also
estimated using a whole blood lysis method and flowcytometry. INTERVENTION: Zinc
gluconate to provide elemental zinc 10 mg daily and 20 mg during diarrhea. MAIN
OUTCOME RESULTS: Regarding CMI, the percentage of anergic or hypoergic children
(using induration score) decreased from 67% to 47% in the zinc group, while in
the control group it remained unchanged (73% vs 71%) (p = 0.05). The percentage
of children deteriorating between first and second tests was significantly lower
in the zinc group (13% vs 33%, p = 0.03). Regarding lymphocyte subsets, the zinc
group had a significantly higher rise in the geometric means of CD3 (25%, p =
0.02), CD4 (64% p = 0.001), and CD4/CD8 ratio (73% p = 0.004) with no difference
in CD8 and CD20. The rise in CD4 was significantly higher in the zinc as compared
to the control group; the ratio of geometric means was 1.45 (95% CI, 1.03-2.01).
CONCLUSION: Zinc supplementation improves cellular immune status, which may have
been one of the mechanisms for observed impact of zinc supplementation on
diarrheal morbidity.
PMID- 9401252
TI - Prevalence of malnutrition and intestinal parasites in preschool slum children in
Lucknow.
AB - OBJECTIVE: To assess the point prevalence of intestinal parasites and their
association with nutritional parameters. SETTING: Anganwadi centers under the
Integrated Child Development Scheme (ICDS) in Lucknow, North India. DESIGN: Cross
sectional survey. METHODS: By random draw, 32 out of 153 Anganwadi centers were
selected. All eligible subjects registered with the Anganwadi worker were
enrolled. These were 1061 children (48.3% girls and 51.7% boys) between the ages
of 1.5 to 3.5 years. RESULTS: Of these, 67.6% were underweight (weight for age <
2 SD), 62.8% were stunted (height for age < -2 SD) and 26.5% were wasted (weight
for height < -2 SD). Parasites were detected in 17.5% (95% CI 15.3%-19.9%)
children by a single direct fecal smear examination. Of these, Ascaris
lumbricoides was found in 124 (68.1%) and Giardia lamblia in 60 (32.9%). There
was no association between weight or height and parasite positivity. The mean
hemoglobin levels for children who were smear positive versus smear negative for
ascaris or giardia were 9.1 g/dl and 9.6 g/dl, respectively (p < 0.0001).
CONCLUSION: In the urban slums the point prevalence of intestinal parasites is
17.5% in the preschool children. Malnutrition and low hemoglobin levels are also
widely prevalent. Urgent remedial steps are needed on community basis to improve
their nutritional status and control parasitic infestation.
PMID- 9401253
TI - Cardiovascular responses to treadmill exercise testing in anemia.
AB - OBJECTIVE: To study exercise performance on a treadmill in anemic children.
DESIGN: Prospective case control study. SETTING: Department of Pediatrics and
Intensive Care Unit, Department of Medicine, King George's Medical College,
Lucknow. SUBJECTS: The study population consisted of 41 cases of anemia (10 mild,
21 moderate and 10 severe) and 11 normal age and height matched children aged
between 7-12 years. METHODS: These subjects were exercise tested on Quinton Model
Q5000 treadmill using Modified Naughton Q5000 protocol. Heart rate, systolic
blood pressure, double product, ECG changes, exercise duration and metabolic
equivalents achieved during peak exercise were studied. Statistical analysis was
performed using analysis of variance (ANOVA) test. RESULTS: No significant
difference was observed in values of resting heart rate, heart rate at peak
exercise, recovery heart rate, blood pressure response, resting double product,
double product at peak exercise, recovery double product and ECG changes in any
of the study groups (p > 0.05). However, the gain in heart rate at peak exercise
compared to basal value, and double product, total exercise duration and
metabolic equivalent (MET) values at peak exercise were significantly low in
anemic children on comparison to normal controls (p < 0.001). CONCLUSIONS:
Cardiovascular responses are blunted in anemia, mainly because of depleted
cardiac reserve.
PMID- 9401254
TI - Alkali therapy for neonates: where does it stand today?
PMID- 9401255
TI - Measles control in India: additional immunization strategies.
PMID- 9401257
TI - Clinical profile of persistent diarrhea in a DTTU.
PMID- 9401256
TI - Prevalence of underweight, stunting and wasting.
PMID- 9401258
TI - Maternal abortions and birth of Down syndrome offspring.
PMID- 9401259
TI - Propionic acidemia in the newborn.
PMID- 9401260
TI - Valvular heart disease: rheumatic or rheumatoid?
PMID- 9401261
TI - Congenital chylothorax.
PMID- 9401262
TI - Tuberculosis verrucosa cutis.
PMID- 9401263
TI - Age for typhoid vaccination.
PMID- 9401264
TI - Aluminium phosphide poisoning: a growing concern in pediatric population.
PMID- 9401265
TI - Neonatal skin lesions.
PMID- 9401266
TI - A cheap alternative to a stadiometer.
PMID- 9401268
TI - Consumer Protection Act and the pediatrician.
PMID- 9401267
TI - Safe bilirubin level for term babies with non-hemolytic jaundice.
PMID- 9401269
TI - Placenta: an alternative source of hematopoietic stem cells.
PMID- 9401270
TI - Antimalarial vaccine.
PMID- 9401271
TI - Sunlight exposure in young infants.
PMID- 9401272
TI - HTLV-1-associated diseases.
AB - HTLV-1-infection is associated with a variety of human diseases including adult T
cell leukemia (ATL) and non-neoplastic inflammatory diseases. The latter includes
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and HTLV-1
uveitis (HU) and other diseases with unestablished associations such as
arthropathy, pneumopathy, dermatitis, exocrinopathy and myositis. ATL is defined
as neoplastic clonal growth of HTLV-1-infected T-cells and is characterized by
unique clinical features including hypercalcemia and severe organ infiltration of
leukemic cells. HAM/TSP and HU are characterized by infiltration of HTLV-1
infected lymphocytes and dysregulated production of cytokines. Four major
subtypes (genotypes) of HTLV-1 have been identified, which depend more on
geography than disease. No disease-specific variants or mutations have been
identified to date. A viral transcriptional regulator, Tax, regulates virus and
cellular gene expression through binding to transcription factors or other
cytoplasmic cellular molecules. Aberrant expression of cellular genes will affect
fundamental cellular functions. The interaction between HTLV-1-infected cells and
different kinds of cells in the host appears to be one of the basic mechanisms
underlying the development of HTLV-1-associated diseases. This interaction may
play a major role in determining tumorigenicity and in forming clinical features
of the disease. Increased provirus load found in patients with HAM/TSP and HU
results from clonal expansion of the HTLV-1-infected T-cells, which has been
implicated in the pathogenesis of HTLV-1-associated diseases. Regulatory
mechanisms of clonal growth remain unknown. Efforts to characterize functions of
the viral proteins and the virus-infected cells and to understand the natural
history of the HTLV-1-infection are required to determine the mechanisms of HTLV
1 viral pathogenesis.
PMID- 9401273
TI - Infections in patients with hematological diseases: recent advances in
serological diagnosis and empiric therapy.
AB - Recent advances in the diagnosis and therapy of infections in patients with
hematological diseases are reviewed. In general, 40-60% of febrile episodes lack
clinical or microbiological evidence of infection and are thus treated
empirically. Among the cases of microbiologically documented bacteremia treated
in our department, the incidence of Gram-negative bacteria was high (47.1%) and
the incidence of Gram-positive bacteremia is increasing. To improve the
diagnostic rate of Gram-negative sepsis, the measurement of plasma endotoxin was
performed. Of 147 febrile neutropenic episodes, endotoxemia was observed in 58
(39.5%) and the causative microorganisms of these infections were deemed Gram
negative bacteria. The measurement of plasma (1-->3)-beta-D-glucan, a ubiquitous
component of fungi, was also performed for making early diagnosis of deep
mycosis; the sensitivity of this assay was 90% and the specificity was 100%. The
detection of (1-->3)-beta-D-glucan appears to be useful as a screening test of
deep mycosis. The effects of the concomitant use of granulocyte-colony
stimulating factor (G-CSF) and empiric antibiotic therapy for febrile neutropenia
were studied in a randomized fashion. G-CSF did not affect the rate of the
response to the empiric antibiotic therapy, although a significant effect of G
CSF on neutrophil recovery was observed. Guidelines for empiric antibiotic and
antifungal therapy combined with serological diagnosis are proposed.
PMID- 9401274
TI - HLA DR2: a predictive marker in response to cyclosporine therapy in aplastic
anemia.
AB - The effect of immunosuppressive agents on HLA DR2-aplastic anemia (AA) has
recently been investigated by different groups. In the present report, we
analyzed 40 Turkish AA patients, who received immunosuppressive therapy (IST) and
12 AA's who were transplanted from HLA matched siblings. HLA DR2 frequency was
0.442 and significantly higher in AA's when compared to an unrelated healthy
control group (RR: 2.93, 95% confidence interval 1.48-5.77, P = 0.001. Patients
received antithymocyte or antilymphocytic globulin (AT/LG) or AT/LG plus
cyclosporine-A (CsA) or CsA alone. In DR2+ and DR2- patients overall response
rates were 73.3 and 30%, respectively (P = 0.03). When patients were analyzed
separately, CsA administration either alone or in combination with AT/LG gave
favorable results in the DR2+ group (P = 0.02). In contrast AT/LG presence alone
was shown to be inadequate.
PMID- 9401275
TI - Granulocyte colony-stimulating factor-combined marrow-ablative chemotherapy and
autologous blood cell transplantation for the treatment of patients with acute
myelogenous leukemia in first remission. The Fukouka Bone Marrow Transplant
Group.
AB - We conducted a clinical trial to increase the chemosensitivity of residual
leukemic cells by combining G-CSF to marrow-ablative chemotherapy, including
cytosine arabinoside (Ara-C), and facilitated by autologous blood cell
transplantation (ABCT) for treatment of acute myelogenous leukemia (AML) in first
complete remission. A total of 16 patients were consecutively treated with
granulocyte colony-stimulating factor (G-CSF)-combined high-dose chemotherapy
(busulfan, etoposide and Ara-C) followed by autotransplantation of peripheral
blood progenitor cells, which had been collected after the consolidation
chemotherapy. At a median follow-up time of 44.5 months, the probability of 5
year event-free survival was 74.5% with only three leukemic relapses. This
preliminary observation suggests the effectiveness of G-CSF-combined conditioning
and ABCT as a post-remission therapy for AML.
PMID- 9401276
TI - Determining the optimal time for peripheral blood stem cell harvest by detecting
immature cells (immature leukocytes and immature reticulocytes) using two newly
developed automatic cell analyzers.
AB - To determine the optimal time of peripheral blood stem cell harvest (PBSCH), we
evaluated the usefulness of the detection of immature hematopoietic cells
(immature leukocytes and reticulocytes) using newly developed automatic cell
analyzers, and compared the results with those of conventional CD34 measurement
by flow cytometry (FCM). The presence of immature leukocytes and reticulocytes
was calculated as immature leukocyte information (IMI)-positive rate and high
fluorescence reticulocyte (HFR)-positive rate by multi-item autoanalyzers. Both
the IMI-positive rate and HFR-positive rate positively correlated with the CD34
positive rate and was more highly correlated with the colony forming units-mixed
(CFU-Mix) count in peripheral blood. In addition, they positively correlated not
only with the CD34-positive rate, but also with the colony forming units
granulocyte/macrophage (CFU-GM) count and CFU-Mix count in harvested stem cell
juice. These findings imply that the parameters of IMI and HFR could be used for
determining the optimal time of PBSCH, and could also be useful for quantifying
stem cells.
PMID- 9401277
TI - Flow cytometric analysis of Thy-1 expression in CD34-positive acute leukemia.
AB - We analyzed the expression of the Thy-1 antigen (CD90) in CD34+ acute leukemia
using two-color flow cytometry. Leukemic cells were obtained from the bone marrow
(BM) and/or the peripheral blood (PB) of 57 patients: 37 with acute myelogenous
leukemia (AML) including nine with secondary AML following myelodysplastic
syndrome (MDS/AML), and 20 with acute lymphoblastic leukemia (ALL) including
three with chronic myelogenous leukemia in blast crisis (CML-BC) of the lymphoid
type. Among these patients, one (3.6%) with de novo AML, two (22.2%) with
MDS/AML, three (17.6%) with de novo ALL, and two (66.7%) with CML-BC coexpressed
CD34 and Thy-1 (CD34+ Thy-1+) on more than 20% of the mononuclear cells within
'lymph' plus 'blast' window. Thy-1 was rarely expressed in de novo acute leukemia
especially in AML. Interestingly, in 1 patient with CML-BC, the leukemic cells in
BM were divided into two subpopulations (CD34+ Thy-1low and CD34+ Thy-1high),
whereas most of the CD34+ leukemic cells in PB were Thy-1high. However, the
mechanism for the mobilization of CD34+ Thy-1high leukemic cells into the PB is
unknown.
PMID- 9401278
TI - Rationale and hematologic target points in response-oriented individualized
induction chemotherapy for acute myeloid leukemia.
AB - Response-oriented individualized induction chemotherapy (ROIIC) has been reported
to achieve a high complete remission (CR) rate in acute myeloid leukemia (AML).
In ROIIC, drug dose is modified for each patient to achieve hematologic target
points, based on the concept that this achievement, not a preset drug dose,
increases the likelihood of attaining CR. However, the existing target points
lack objectivity, therefore prohibiting worldwide use of ROIIC. In addition, the
achievement of these target points does not statistically relate to CR, which
contradicts the concept of ROIIC. To solve these problems, we evaluated various
parameters of 117 AML cases treated by ROIIC to identify the factors relating to
CR. Of 117 AML subjects, 75 achieved CR with ROIIC and most cases achieving CR
did so with one ROIIC course. Not the administered dose of drugs but several
hematologic parameters at the end of ROIIC correlated significantly with CR. A
total of four parameters, all related to the leukemic cell mass, were independent
predictive factors of CR. A formula consisting of these parameters predicted CR
cases with high sensitivity (98%) and non-CR cases with high specificity (96%).
Based on this formula, an objective target point (a bone marrow blast mass ratio
between before and after ROIIC of below 0.15), valid for dose modification during
ROIIC, was established. These results validate the concept of ROIIC and enable
objective dose modification in ROIIC and universal application of this therapy.
Further, the formula predicting non-CR cases at the end of ROIIC is useful for
deciding early therapeutic intervention for such cases.
PMID- 9401279
TI - Differentiation induction in non-lymphocytic leukemia cells upon treatment with
mizoribine.
AB - Inosine-5'-monophosphate (IMP) dehydrogenase catalyzes the rate-limiting reaction
of guanine nucleotide biosynthesis and has been implicated in the reaction of
cell growth and differentiation. We examined the ability of mizoribine, an IMP
dehydrogenase inhibitor, to induce differentiation in HL-60 and U937 cells as
well as in fresh leukemic blast cells from patients with non-lymphocytic
leukemia. Treatment with mizoribine reduced intracellular GTP levels and induced
morphologic and functional differentiation in these two cell lines in a dose
dependent manner. HL-60 and U937 cells developed polymorphic nuclei and
macrophage-like cytoplasm, respectively, as well as expression of CD11b and CD14
antigens and the ability to oxidize NBT. These changes became evident when
intracellular GTP levels decreased to approximately 30% of untreated controls and
were abrogated by addition of guanosine to the media. However, in fresh leukemic
cells, the cells showing maturation in response to mizoribine were limited in
those derived from two of ten patients having non-lymphocytic leukemia. These
findings suggest mizoribine could induce differentiation in HL-60 and U937 cells
through a decrease of intracellular GTP levels. Further study is required to
determine its clinical use in patients with acute non-lymphocytic leukemia.
PMID- 9401280
TI - Correlation between immunological abnormalities and prognosis in myelodysplastic
syndrome patients.
AB - Immunological abnormalities (IA) are frequently observed in patients with
myelodysplastic syndromes (MDS). Although there have been a number of analyses of
the prognostic factors, there have been few studies, if any, to determine whether
IA affects prognosis. We investigated the prognosis of 153 MDS patients with or
without IA who were treated at a single Japanese institute for 10 years. Nineteen
of 153 patients (12%) developed autoimmune disorders. One hundred of 153 patients
(63%) had an abnormality in at least one immunological laboratory test.
Hypergammaglobulinemia was found in 50 of 128 (39%) patients tested,
hypogammaglobulinemia was observed in 10 of 128 (8%), positivities of antinuclear
antibody, RA factor. DNA antibody, and direct antiglobulin test were observed in
30%, 14%, 7% and 12%, respectively, and a CD4/CD8 ratio < 1 was observed in 20%.
There was no significance in the distribution of age, MDS subtype, or sex between
patients with and without IA. The survival of MDS patients without IA was
significantly better than that of patients with IA, and the survival of patients
with a CD4/CD8 ratio > 1 was also significantly superior to the survival of those
with an inverted CD4/CD8 ratio. Patients with IA tended to die of infection or
leukemic progression in comparison with those without IA, suggesting that IA may
be associated with susceptibility to opportunistic infection and disease
progression.
PMID- 9401281
TI - Hypercalcemia in children presenting with acute lymphoblastic leukemia.
AB - Although hypercalcemia is a well-recognized complication in malignant disorders,
neither the incidence and prognostic significance of hypercalcemia, nor the role
of parathormone related peptide (PTHrP) in pediatric acute lymphoblastic leukemia
(ALL) have been clarified. Of 83 newly diagnosed pediatric ALL patients with
early pre-B cell phenotype treated at our hospital during the last 8 years, four
patients were diagnosed as having hypercalcemia (> 14 mg/dl). In these 4
hypercalcemic ALL patients at onset, serum calcium levels ranged from 14.6 to
20.8 mg/dl (normal 7.4-9.0 mg/dl), and serum PTHrP levels were markedly elevated
to 112-240 pmol/l (normal range: 17.6-61.2 pmol/l). Unlike patients with ordinary
ALL in childhood, gastrointestinal symptoms (nausea, vomiting, abdominal pain)
and skeletal symptoms (bone pain, gait disturbance) were the chief complaints.
Because of these characteristic symptoms, bone marrow aspiration was carried out
in two patients in an attempt to diagnose ALL before leukemic cells appeared in
peripheral blood. Serum calcium levels were promptly normalized by induction
chemotherapy. The four patients have been in complete remission from 35+ to 125+
months. Based on these results, the incidence of hypercalcemia in pediatric ALL
patients with early pre-B cell phenotype at our institute is calculated to be
about 4.8%. Gastrointestinal and skeletal problems are the characteristic initial
symptoms, and hypercalcemia does not seem to be significant in the prognosis of
these patients.
PMID- 9401282
TI - A case of mu-heavy chain disease: combined features of mu-chain disease and
macroglobulinemia.
AB - A case of mu-heavy chain disease (HCD) is described. The patient, a 40-year-old
man, presented with an intracranial tumor. The bone marrow of this patient showed
infiltration with both plasma cells and lymphocytes. The majority of plasma cells
were vacuolated and the result of immunoelectrophoresis of serum protein revealed
an arc with anti-IgM antiserum and an additional rapid migrating arc of different
mobility with anti-kappa antiserum. The urine contained a kappa-type Bence Jones
protein. An enzyme-linked antibody study showed that the majority of plasma cells
in bone marrow contained both mu and kappa antigenic determinants in their
cytoplasm. On Sephadex G-200 gel filtration, the monoclonal IgM-kappa protein and
the mu-chain fragment were detected in the serum, suggesting the combined
features of mu-HCD and macroglobulinemia. The molecular weight of the mu-chain
fragment was approximately 45,000 daltons. The intracranial tumor completely
disappeared after irradiation therapy. However, he died 1 year later after
development of a huge abdominal tumor.
PMID- 9401283
TI - Serum soluble IL-6 receptor concentrations correlate with stages of multiple
myeloma defined by serum beta 2-microglobulin and C-reactive protein.
AB - Serum soluble interleukin-6 receptor (sIL-6R) concentrations were measured in 52
patients with multiple myeloma (MM) and 24 normal controls, using a commercially
available immunoenzymatic assay kit. Patients were staged according to the
Bataille et al. myeloma staging system based on the levels of patients' serum
beta 2-microglobulin and C-reactive protein. Twenty-one patients were at stage A
of disease, 19 at stage B and 12 at stage C at the time of serum collection for
sIL-6R determination. Serum sIL-6R concentrations ranged from 15 to 176 ng/ml
with a mean of 64.8 +/- 35.9 ng/ml and a median of 58 ng/ml in the entire group
of patients studied. These values were significantly higher than those of 34.4 +/
13.4 ng/ml found in the controls (P < or = 0.001). Patients of stage C had
higher sIL-6R levels (94.8 + 41.2 ng/ml) than patients of stage B (67.7 +/- 31.0
ng/ml) (P < 0.01), and markedly higher than patients of stage A (45.0 +/- 23.1
ng/ml) (P < 0.001). Serum levels of sIL-6R in patients with stage A disease did
not differ statistically from those of the controls. A linear positive
correlation was observed between serum levels of the receptor and the stage of MM
(r = 0.539, P < 0.001). These data strongly suggest that serum sIL-6R
concentrations correlate with the stages of MM and may be used as an indicator of
the activity of the disease.
PMID- 9401284
TI - Effect of thrombopoietin (c-Mpl ligand) alone and in combination with other
hematopoietic growth factors on human megakaryocytopoiesis in serum-free
cultures.
AB - The effect of human recombinant (hr) thrombopoietin (TPO) on human
megakaryocytopoiesis was studied in a serum-free system. hrTPO induced
megakaryocyte colony formation by purified CD 34-positive cells and
polyploidization of megakaryocytes by purified CD41a-positive cells. hrTPO gave
rise to much smaller colonies which appeared at an earlier time compared to the
use of human recombinant interleukin-3 (hrIL-3), suggesting that hrTPO
predominantly affects the population of megakaryocyte progenitor cells in the
late stage. hrIL-3 additively increased the hrTPO-induced megakaryocyte colony
formation by CD34-positive cells. The hrTPO-induced megkaryocyte colony formation
was also increased by the presence of hrIL-6, hrIL-11, human recombinant
erythropoietin (hrEpo) or human recombinant stem cell factor (hrSCF), none of
which stimulated megakaryocyte colony growth when added alone. The combined
addition of hrTPO, hrIL-3 and hrSCF to CD34-positive cells markedly stimulated
megakaryocyte colony formation and produced large numbers of megakaryocytes.
hrTPO stimulated the polyploidization of CD34-positive cell-derived
megakaryocytes in liquid culture. However, the addition of hrIL-6, hrIL-11 or
hrEpo to hrTPO did not further enhance the hrTPO-induced polyploidization. These
findings indicate that at the megakaryocyte progenitor cell level, the effect of
hrTPO can be promoted by the presence of various hematopoietic growth factors
involved in human megakaryocytopoiesis.
PMID- 9401285
TI - Rapid progression of chronic myelomonocytic leukemia following diaminodiphenyl
sulphone treatment for dermatitis herpetiformis.
AB - A 41-year-old patient with dermatitis herpetiformis (DH) developed steroid
resistant blebs as a sign of exacerbating DH. The skin symptoms were resolved
after 2 weeks of oral administration of diaminodiphenyl sulphone (DDS). However,
3 weeks after the start of DDS, he suffered from edematous eruption on the cheeks
and neck, enlargement of the pharynx, systemic lymphoadenopathy and hepatomegaly.
In addition, his leukocyte count increased rapidly from 10.1 x 10(9)/l with 13%
monocytes just before the start of DDS, to 24.6 x 10(9)/l with 28% monocytes.
Bone marrow aspirate showed trilineage dysplasia and chronic myelomonocytic
leukemia (CMML) was diagnosed. The patient died from septic shock during
neutropenia following cytotoxic chemotherapy. In this case, CMML was complicated
with DH and the administration of DDS accelerated the progression of CMML with
the manifestations of DDS syndrome. Although DDS is a well-established drug for
DH, DDS should be used with great caution when a hematological malignancy
coexists.
PMID- 9401286
TI - Distribution of endogenous endonuclease activities capable of producing
internucleosomal DNA cleavage in hematopoietic cells.
PMID- 9401287
TI - Kaposi's sarcoma--associated herpesvirus-like DNA sequences are not present in
adult T-cell leukemia.
PMID- 9401288
TI - Glutathione S-transferase theta 1 gene (GSTT1) defect in Japanese patients with
myelodysplastic syndromes.
PMID- 9401290
TI - Pelton & Crane Light alert.
PMID- 9401289
TI - Poor kids' teeth: a crying shame.
PMID- 9401291
TI - Dental benefits issues.
PMID- 9401292
TI - Dental hygiene.
PMID- 9401293
TI - CDA opposes proposed HBV recommendations.
PMID- 9401294
TI - Health Canada issues warning letter on lead shielding.
PMID- 9401295
TI - Supreme Court of Delaware rules in favor of HIV-positive dentist.
PMID- 9401296
TI - The business of dentistry.
PMID- 9401297
TI - Guidelines on the use of space maintainers following premature loss of primary
teeth.
AB - OBJECTIVE: To formulate evidence-based guidelines on the appropriate use of space
maintaining appliances to prevent or reduce the severity of malocclusion in the
permanent dentition following the premature loss of primary teeth. OPTIONS:
Placement of lingual arch, palatal arch, band-loop, crown-loop, and intra
alveolar space maintainers. OUTCOMES: Reduced prevalence or severity of space
loss in the primary or mixed dentition, reduced prevalence or severity of
malocclusion in the permanent dentition measured as significant changes in:
crowding, ectopic eruption, impacted teeth, Angle's class II or III occlusion,
crossbite, deep overbite, deep overjet, or midline shift. EVIDENCE: Articles
published from 1966 to 1996, located though Medline searches. Only clinical
trials, cohort studies, case-control studies, or large case series were
considered. VALUES: Relevant clinical findings were evaluated and categorized
using evidence-based methods and values established by the Canadian Task Force on
the Periodic Health Examination. A recommendation was developed for the use of
space maintainers. BENEFITS, HARMS AND COSTS: The potential benefits of using
space maintaining appliances include reduced prevalence or severity of: crowding,
ectopic eruption, tooth impaction, crossbite, excessive overbite and overjet, and
poor molar relationship. Other advantages include the potential for considerable
cost savings by reducing the need for future orthodontic treatment. The potential
disadvantages of using space maintaining appliances include soft tissue
impingement, interference with eruption of adjacent teeth, pain, plaque
accumulation, caries, and broken, dislodged or lost appliances. RECOMMENDATIONS:
There is poor evidence to recommend for or against the use of space maintainers
to prevent or reduce the severity of malocclusion in the permanent dentition (see
Table 1, Recommendation C) Decisions regarding the use of space maintainers must
therefore be guided by factors other than scientific evidence.
PMID- 9401298
TI - Anatomically correct soft tissue profiles using fixed detachable provisional
implant restorations.
AB - For the past decade, the dental profession has given very little thought to the
design of fixed detachable restorations with anatomically correct emergence
profiles. Over-contoured implant restorations are frequently seen, and they may
be challenging for patients to maintain. This article will address the most
common techniques used to improve the soft tissue profile, and will show how
implant-borne provisional restorations allow ideal soft tissue profiles to be
achieved.
PMID- 9401299
TI - Denturists: do they really provide more affordable care in Ontario?
AB - The 1996 Denturist Association of Ontario fee guide and the Ontario Dental
Association Fee Guide for General Practitioners were examined to identify
variations in the fees charged for a range of removable prosthodontic services.
Fee guides were selected for this analysis as third-party insurers and government
dental plans frequently use them to establish fee schedules and levels of
reimbursement. However, it is recognized that dentists set their own fees, which
may be higher or lower than the fees suggested in the guide. Although the
descriptions of the specific services listed in the guides were similar in many
cases, no attempt was made to examine variations in the quality of care provided
by dentists and denturists, or the approach to treatment offered by their
respective professions. The analysis revealed that a number of procedure fees
were, on average, 15 per cent higher in the Ontario Dental Association (ODA) fee
guide compared to the denturists' fee guide. However, a wide range of prosthetic
services, including partial dentures, were less expensive in the ODA fee guide.
Based on this analysis, there appears to be no substantial cost differential
between the services provided by dentists and denturists six years after the
proclamation of the new Regulated Health Professions Act in Ontario, as the
denturists have claimed. The denturist association's further claims of greater
choice and improved access may also be questionable, and should be reexamined in
light of these findings.
PMID- 9401300
TI - Dental unit waterline microbiology: a cautionary tale.
AB - The question of dental unit waterline contamination now concerns the dental
profession on a number of levels and has become part of the landscape in
dentistry. Researchers have identified the problem, studied it, and published
their results. Official organizations have reacted to the problem by issuing
press releases and recommendations. In the mean time, dental companies have
jumped into the fray, ensuring a proliferation of products designed to mitigate a
problem that certain people feel is imaginary are artificially inflated. Despite
the number of publications describing waterline contamination, we still face the
challenge of determining whether are picture of the problem is truly accurate.
For example, it has become almost customary to use the term contamination when
talking about waterlines, even though it is inadequate. In addition, we are
moving ahead with water quality standards for dental units at a time when certain
fundamental questions remain unanswered. What should we be measuring and what
methods should we be using? Do certain disinfection procedures have an opposite
effect to the one desired? Finally, the question of health risks linked to the
colonization of waterlines has not been adequately addressed by researchers.
PMID- 9401301
TI - Stabilization of rubber dam for child patients and fibre-reinforced
postorthodontic retainer.
PMID- 9401302
TI - Getting what we are worth.
PMID- 9401304
TI - Nursing centers--models of professional practice.
PMID- 9401303
TI - Future organizational leadership.
PMID- 9401305
TI - Fighting success--facilitation of senior faculty.
PMID- 9401306
TI - Education and practice partnerships in California.
AB - As the most populous state in the United States, California often serves as a
bellwether of events to come. The following describes nursing work force issues
in California, examples of how nurse educators are responding to health care
system changes, and how practice colleagues are joining educators to prepare
nurses for meeting the health needs of the people of California. The discussion
begins with historical perspectives from the late 1980s to the present, the
founding of the California Strategic Planning Committee for Nursing and its work,
the Robert Wood Johnson Colleagues in Caring project for developing a master plan
for nursing in California, and examples of existing programs in California that
serve as models for preparing the best care providers to meet the health care
needs of the population.
PMID- 9401307
TI - Student and preceptor perceptions of factors in a successful learning
partnership.
AB - Thirty-two registered nurse preceptors and 42 senior undergraduate nursing
students completed a survey ranking factors related to both participants in the
clinical learning partnership. Mann-Whitney U-Wilcoxon Rank Sum W tests showed
statistically significant differences in the ranking of four factors (the ability
to give and receive criticism, knowledge of the preceptoring process, clinical
competence, and compatibility) that contribute to successful learning
partnerships. Nurse educators and professional nurses should acknowledge these
perceptual differences and include these in student and preceptor orientation
programs to promote a positive teaching and learning partnership.
PMID- 9401308
TI - Mid-life women doctoral students rediscover "voice" in a community of scholarly
caring.
AB - Recent research indicates that doctoral study is for many "an excessively painful
rite of passage" for which an "indefensible human price is exacted." For mid-life
women doctoral students in nursing and education doctoral programs, this human
price is sometimes paid in the currency of loss of personal voice. Because they
often assume leadership positions after graduation, it is a significant loss to
the professions when these women's mature voices are lost or even temporarily
silenced. This article describes the design, findings, evaluation, and
implications of an emancipatory inquiry entitled "Gifted Women: Doctoral Study As
Heroic Journey." Simultaneously a participatory research project and curricular
innovation, this unique 18-month project joined facilitators and participants as
coresearchers in a workshop and four reunions that integrated feminist process
with expressive, esthetic approaches. The results of this emancipatory inquiry
showed that viewing doctoral study as a heroic journey enlightened these mid-life
women participants to reclaim their personal voices, empowered them with the
support of a community of scholarly caring, and emancipated them to undertake
personally meaningful and scholarly dissertation research.
PMID- 9401309
TI - Cognitive pathways and historical research.
AB - The nursing literature is replete with articles detailing the logical reasoning
processes required by the individual scientist to implement the rigors of
research and theory development. Much less attention has been focused on creative
and critical thinking as modes for deriving explanations, inferences, and
conclusions essential to science as a product. Historical research, as a
particular kind of qualitative research, is dependent on and compatible with such
mental strategies as logical, creative, and critical thinking. These strategies
depict an intellectual framework for the scientist examining archival data and
offer a structure for such inquiry. A model for analyzing historical data
delineating the cognitive pathways of logical reasoning, creative processing, and
critical thinking is proposed.
PMID- 9401310
TI - Management of comorbid depression and heart disease: the time has (almost) come.
PMID- 9401312
TI - Post-traumatic stress disorder and serotonin: new directions for research and
treatment.
AB - The overlap in clinical phenomenology and morbidity between post-traumatic stress
disorder (PTSD) and such conditions as major depression, anxiety disorders and
aggression, in which a serotonin dysfunction is implicated, suggests a role for
serotonin in the pathophysiology of PTSD. In this paper, we review current
knowledge concerning the role of serotonergic mechanisms and interventions in
PTSD. Since there is no clearly effective pharmacologic intervention for this
disorder, the underlying neurochemical dysfunction needs to be carefully defined
so that more effective treatment can be developed. Preclinical and clinical
studies of the serotonergic mechanisms in the pathophysiology of PTSD and
treatment trials involving serotonergic agents are limited, but indicate
considerable promise. Further investigation of a serotonergic dysfunction in PTSD
and of its treatment with serotonergic agents is warranted.
PMID- 9401313
TI - Refractory depression: treatment strategies, with particular reference to the
thyroid axis.
AB - In the last few years, it has become evident that major depressive disorder often
runs a chronic and recurrent course. Early effective intervention may increase
the liklihood of a good long-term prognosis. The main treatment options for
patients who fail to respond to antidepressant therapy and the relative
advantages of each are critically reviewed. These include substitution, replacing
one antidepressant with another, and augmentation/combination, in which a second
antidepressant is added to the first. Particular emphasis is placed on the role
of triiodothyronine (T3) in augmentation therapy. The theoretic rationale for
using augmentation/combination therapy and its relative advantages and
disadvantages over substitution therapy are critically reviewed.
PMID- 9401314
TI - Effects of citalopram treatment on behavioural, cardiovascular and neuroendocrine
response to cholecystokinin tetrapeptide challenge in patients with panic
disorder.
AB - Eight patients with panic disorder were administered 20 micrograms of
cholecystokinin tetrapeptide (CCK-4) before and after 8 weeks of treatment with
the selective serotonin reuptake inhibitor (SSRI) citalopram. All patients
responded to treatment by showing a significant general improvement and reaching
a panic-free state for 2 weeks. At the rechallenge with CCK-4, patients displayed
a marked reduction in the intensity and number of panic symptoms. The frequency
of panic attacks induced with CCK-4 decreased by 50% after treatment. Citalopram
treatment had no substantial effect on cardiovascular (heart rate and blood
pressure) or hormonal (cortisol, prolactin and growth hormone) responses to CCK
4. Patients who still had panic attacks after treatment demonstrated a blunted
growth hormone response to CCK-4 that was not seen in those who did not have
panic attacks. This study suggests that treatment with an SSRI can reduce an
enhanced sensitivity to CCK-4 without modifying cardiovascular and neuroendocrine
responses to CCK-4 in patients with panic disorder.
PMID- 9401316
TI - Successful treatment of steroid-induced panic disorder with fluvoxamine.
PMID- 9401315
TI - Effective treatment of mania with olanzapine: 2 case reports.
PMID- 9401311
TI - Galanin-acetylcholine interactions in rodent memory tasks and Alzheimer's
disease.
AB - Galanin is a 29-amino-acid neuropeptide that is widely distributed in the
mammalian central nervous system. Galanin-immunoreactive cell bodies, fibres and
terminals, and galanin binding sites, are located in the basal forebrain of rats,
monkeys and humans. Galanin fibres hyperinnervate the surviving cholinergic cell
bodies in patients with Alzheimer's disease (AD). In rats, galanin inhibits
acetylcholine release and produces deficits in learning and memory. These
findings suggest that overexpressed galanin may contribute to the cognitive
impairments exhibited by patients with AD. This paper reviews the literature on
galanin distribution and function in light of its putative role in the mnemonic
deficits in patients with AD, the effects of galanin on tests of learning and
memory, and preliminary experiments with galanin antagonists in animal models of
AD.
PMID- 9401317
TI - Distinguishing anxiety disorders psychometrically.
PMID- 9401318
TI - Mania in children with PDD.
PMID- 9401319
TI - ADHD/thyroid dysfunction.
PMID- 9401320
TI - Immunology of TS/OCD.
PMID- 9401321
TI - Pemoline in ADHD.
PMID- 9401322
TI - Childhood mania in India.
PMID- 9401323
TI - Domestic violence and psychopathology.
PMID- 9401324
TI - Behavioral effects of hypoglycemia.
PMID- 9401325
TI - Looking at the future through orange-colored glasses.
PMID- 9401326
TI - Mental retardation: a review of the past 10 years. Part I.
AB - OBJECTIVE: To review the literature over the past decade on mental retardation,
particularly as regards its definition, prevalence, major causes, and associated
mental disorders. METHOD: A computerized search was performed for articles
published in the past decade, and selected papers were highlighted. RESULTS: The
study of mental retardation has benefited considerably by advances in medicine
generally and by developments in molecular neurobiology in particular. Increasing
awareness of psychiatric comorbidity in the context of intellectual disability
highlights the need for studies of the phenomenology and treatment of mental
disorders in this population. CONCLUSIONS: Although the study of developmental
disorders has advanced significantly over the past decade, considerable work
remains. Mental retardation is a model for the utility of the biopsychosocial
approach in medicine.
PMID- 9401327
TI - Mental retardation: a review of the past 10 years. Part II.
AB - OBJECTIVE: To review the literature over the past decade on mental retardation,
particularly with respect to genetics and behavioral phenotypes. METHOD: A
computerized search was performed for articles published in the past decade, and
selected papers were highlighted. RESULTS: The study of mental retardation has
benefited considerably by advances in medicine generally, and by developments in
molecular neurobiology in particular. These advances in genetics have led to new
insights regarding the causes of mental retardation, as well as a growing
appreciation of behavioral phenotypes associated with some mental retardation
syndromes. CONCLUSIONS: Although the study of developmental disorders has
advanced significantly over the past decade, considerable work remains. Mental
retardation should remain the model for the utility of the biopsychosocial
approach in medicine.
PMID- 9401328
TI - Evolution and revolution in child psychiatry: ADHD as a disorder of adaptation.
AB - Current knowledge about early plasticity and children's responsiveness to
environmental modifications as well as the atheoretical nature of current
nosological systems necessitate alternative models to explain the phenomena of
childhood behavioral and emotional disturbances. Evolutionary biology provides
one such framework. It organizes data from the behavioral and cognitive sciences
and parallels similar efforts in other areas of medicine and biology. Through an
evolutionary biological lens, some mental disorders are better viewed as an
adaptive response to early pathogenic environments and/or reflect the
optimization of brain function to some environments at the cost of poorer
response to the demands of other environments. As an example, the authors examine
attention-deficit/hyperactivity disorder (ADHD) in relation to evolutionary
theories of psychology and biology and clarify the potentially adaptive nature of
characteristics of inattention, impulsivity, and motoric hyperactivity, depending
on the nature of child's environments. Reframing ADHD characteristics according
to evolutionary theory has important treatment implications for clinicians and
offers researchers opportunities for novel scientific discoveries.
PMID- 9401329
TI - Correspondence between DSM-III-R and DSM-IV attention-deficit/hyperactivity
disorder.
AB - OBJECTIVE: To evaluate the correspondence between DSM-III-R and DSM-IV
definitions of attention-deficit/hyperactivity disorder (ADHD) in clinically
referred children. Results of the field trials led to the hypothesis that there
would be a strong correspondence between DSM-III-R and DSM-IV subtypes. METHOD:
The sample consisted of all children and adolescents consecutively referred to a
pediatric psychopharmacology clinic (N = 405). Children were comprehensively
evaluated with structured diagnostic interviews assessing both DSM-III-R and DSM
IV ADHD. DSM-III-R symptoms were used to approximate DSM-IV subtypes. Kappa
statistics and conditional probabilities were used to examine the correspondence
between DSM-III-R and DSM-IV ADHD. RESULTS: Ninety-three percent of children who
received a DSM-III-R diagnosis of ADHD also received a DSM-IV ADHD diagnosis. The
kappa coefficient assessing the agreement between DSM-III-R and DSM-IV ADHD was
.73 (z = 14.6, p < .0001). The kappa coefficient assessing the agreement between
the DSM-III-R-approximated subtypes and the actual DSM-IV subtypes was .71 (z =
15, p < .0001). CONCLUSION: These results confirm previous findings and indicate
that the change from DSM-III-R to DSM-IV results in minimal changes in case
identification and provides support for diagnostic continuity between the two
classification systems.
PMID- 9401330
TI - Noradrenergic mechanisms in ADHD children with and without reading disabilities:
a replication and extension.
AB - OBJECTIVE: To examine noradrenergic (NA) function in children with attention
deficit hyperactivity disorder (ADHD) by replicating and expanding upon a
previous finding that ADHD children with and without reading disabilities (RD)
differ in plasma levels of the NA metabolite 3-methoxy-4-hydroxyphenylglycol
(MHPG). METHOD: Plasma levels of MHPG were compared in ADHD children who were
subdivided on the basis of the presence or absence of RD. Subsequently, this
replication sample was combined with a previously studied sample to further
explore the relationship between plasma MHPG levels and measures of cognitive
function in children with ADHD. RESULTS: Plasma levels of MHPG were significantly
lower in ADHD children without RD, compared with those with RD, replicating a
published finding. Analyses in the combined sample indicated that, among children
with ADHD, plasma MHPG levels were inversely associated with measures of academic
achievement and verbal processing, but not parent or teacher ratings of behavior
or continuous performance test measures of attention and impulsivity.
CONCLUSIONS: These data indicate that children with ADHD are not homogeneous with
regard to NA function and that neurochemical variation is closely associated with
differences in clinical characteristics of the children.
PMID- 9401331
TI - Affective valence and arousal in ADHD and normal boys during a startle
habituation experiment.
AB - OBJECTIVE: To measure two dimensions of emotion (affective valence and arousal)
in 29 boys with attention-deficit hyper-activity disorder (ADHD) and 32 normal
boys. METHOD: After a startle habituation experiment during which these subjects
heard 40 startling sounds while watching a silent interesting movie, they were
asked 12 questions (categorized a priori into questions relating to affective
valence and to arousal) about their emotional reactions to these putatively
unpleasant and pleasurable stimuli. Responses were recorded for the two
dimensions of emotion, using two cartoon strips in each of which five expressions
of a cartoon character varied linearly from happy to unhappy (affective valence
dimension) and calm to excited (arousal dimension). RESULTS: Factor analyses of
the 12 responses revealed four factors in which the highest loadings were for
affective valence to the startle responses, affective valence to the silent
movie, arousal, and scary feelings. Relative to the normal group, the responses
of the ADHD group were significantly biased toward pleasurable valence to the
startling stimuli and to the silent movie, with a trend toward hypoarousal.
Startle magnitude and habituation were similar in both groups. The normal tonic
heart rate acceleration throughout the experimental session was not sustained in
the ADHD group. CONCLUSIONS: The self-reports of affective valence biased in the
direction of pleasure and away from displeasure and the trend toward hypoarousal
suggest an emotional dysfunction in ADHD.
PMID- 9401332
TI - Gender differences in children with ADHD, ODD, and co-occurring ADHD/ODD
identified in a school population.
AB - OBJECTIVE: To examine gender differences among children with disruptive behavior
disorders (DBDs) from an ethnically diverse school sample. METHOD: From 2,984
children, children with attention-deficit/hyperactivity disorder, combined type
(ADHD-C) (46 boys, 11 girls), oppositional defiant disorder (ODD) (59 boys, 35
girls), and co-occurring ADHD-C/ODD (76 boys, 27 girls), diagnosed by teacher
rated DSM-IV symptoms, were compared with each other and with 254 controls on
teacher ratings of symptoms, social functioning and Achenbach Teacher's Report
Form scales. RESULTS: Children with ADHD-C/ODD received the poorest ratings on
all variables. In "pure" groups, children with ODD were rated as learning more,
working harder, and being less inattentive than children with ADHD-C; only the
ODD group showed more internalizing problems than controls. For ADHD-C and ODD
groups, ratings of aggression and some individual symptoms were higher in boys
than girls. Girls with ODD were rated as more appropriate and less inattentive,
but unhappier and more socially impaired than boys with ODD. Overall, girls
received higher peer dislike scores than boys. CONCLUSIONS: Comorbidity and
gender issues affect the correlates of DBDs, with learning problems higher in
ADHD-C, internalizing problems associated only with ODD, and greatest impairment
for ADHD-C/ODD groups. Despite having similar or less behavioral dysfunction,
girls with DBDs may have more social problems than boys with DBDs.
PMID- 9401333
TI - Impact of comorbid oppositional or conduct problems on attention-deficit
hyperactivity disorder.
AB - OBJECTIVE: To investigate whether the presence of comorbid oppositional defiant
disorder (ODD) or conduct disorder (CD) alters the correlates of attention
deficit hyperactivity disorder (ADHD). METHOD: Three groups of children (33
"pure" ADHD, 46 ADHD + ODD, and 12 ADHD + CD) were compared on measures of ADHD,
aggression, anxiety, parental psychopathology, self-esteem, school, and social
emotional functioning. RESULTS: Findings indicated that the presence of comorbid
oppositional or conduct problems in children with ADHD altered the correlates of
ADHD across a number of areas, including greater ADHD symptom severity and social
dysfunction. Nevertheless, some correlates were more closely linked with the
comorbid condition of ADHD + CD (e.g., higher aggression, anxiety, and maternal
pathology, as well as decreased self-esteem), while others appeared more closely
linked with ADHD + ODD (e.g., social withdrawal, elevated academic achievement
paired with higher perceived scholastic competence). CONCLUSIONS: Findings
support the distinctive profiles of the disruptive behavior disorder groups and
emphasize the deleterious effects on the quality of life experienced by the
comorbid conditions. The need for syndrome-specific interventions is stressed.
PMID- 9401334
TI - A prospective study of hyperactive boys with conduct problems and normal boys:
adolescent and adult criminality.
AB - OBJECTIVE: To examine the relationship between attention deficit disorder with
hyperactivity in childhood and criminality in adolescence and adulthood in 89
hyperactive and 87 normal control subjects. METHOD: In this prospective study,
adolescent follow-up intervals ranged from 13 to 21 years and adult follow-up
ranged from 18 to 23 years. The official arrest records for all subjects were
obtained. RESULTS: Hyperactive subjects had significantly higher juvenile (46%
versus 11%) and adult (21% versus 1%) arrest rates. Juvenile and adult
incarceration rates were also significantly higher. Childhood conduct problems
predicted later criminality, and serious antisocial behavior in adolescence
predicted adult criminality. CONCLUSIONS: Hyperactive children are at risk for
both juvenile and adult criminality. The risk for becoming an adult offender is
associated with conduct problems in childhood and serious antisocial behavior
(repeat offending) in adolescence. Hyperactive children who do not have conduct
problems are not at increased risk for later criminality.
PMID- 9401335
TI - Childhood cancer: a two-year prospective study of the psychological adjustment of
children and parents.
AB - OBJECTIVE: To follow prospectively the psychological adjustment of young
children, parents, and families during the first 2 years after the children's
diagnosis of cancer. METHOD: Children aged 2 to 5 years with cancer diagnoses and
their parents and families (n = 38) were assessed immediately after diagnosis, 1
year after diagnosis, and 2 years after diagnosis. At each assessment, the
psychological adjustment of the children and their families was compared with the
adjustment of a cohort of children and families in the general community (n =
39). RESULTS: Children with cancer and their parents experienced significantly
more emotional distress than children and parents in the community during the
period immediately after diagnosis. However, the number of problems experienced
by the children with cancer and their parents declined during the first year
after the children's diagnosis and stabilized at a level comparable with that
found among children and parents in the general community. CONCLUSION: Although
the results are consistent with reports that suggest that in the longer term the
prevalence of psychological problems among children with cancer is similar to
that found among children in the general community, they also highlight the
considerable distress experienced by children and parents during the period
immediately after the children's diagnosis.
PMID- 9401336
TI - Traumas and other adverse life events in adolescents with alcohol abuse and
dependence.
AB - OBJECTIVE: Clinical observation suggests that adolescents with alcohol use
disorders often have complex histories that include childhood maltreatment and
other traumas. The aim of this study was to determine the relationships among
adolescent alcohol use disorders and a broad range of traumas and adverse life
events. METHOD: The subjects were 132 adolescents with alcohol dependence, 51
adolescents with alcohol abuse, and 73 adolescents recruited from the community
as a control group. Trauma history was assessed by a semistructured interview and
other adverse life events by questionnaire. RESULTS: Traumatic events reflecting
interpersonal violence had occurred in many of the adolescents with alcohol
dependence and abuse and few of the control adolescents. Adolescents with alcohol
abuse or dependence, compared with control subjects, were 6 to 12 times more
likely to have a physical abuse history and 18 to 21 times more likely to have a
sexual abuse history. Sexual abuse was more common in females, and victimization
by other violent acts was more common in males. Many other adverse life events
were also significantly more common in the alcohol use disorder groups than in
the control group, including having a close friend die, arguments within the
family, and legal difficulties. CONCLUSIONS: These results demonstrate that
trauma and other adverse life events are strongly associated with alcohol use
disorders in adolescents. Clinical screening of adolescents with alcohol use
disorders for a range of traumatic events is recommended.
PMID- 9401337
TI - Axis II psychopathology as a function of Axis I disorders in childhood and
adolescence.
AB - OBJECTIVE: To examine the occurrence of elevated personality disorder (PD)
dimensional scores in a community sample of young adults as a function of the
occurrence of Axis I disorders through age 18 years. METHOD: 299 individuals who
had been interviewed regarding Axis I disorders twice while in adolescence (first
when 14 through 18 years of age) were carefully assessed regarding Axis I and II
psychopathology at age 24. RESULTS: The prevalence of PD diagnoses was relatively
low (3.8% in participants with a history of Axis I versus 1.7% in participants
with no Axis I history). The occurrence of all four Axis I diagnostic categories
(major depression, anxiety disorders, disruptive behavior disorders, substance
use disorders) in childhood and adolescence was associated with elevated PD
dimensional scores. The likelihood of elevated PD dimensional scores increased as
a function of the number of Axis I disorders. Elevated PD scores were
significantly associated with a negative course of major depression. CONCLUSIONS:
Although the rates of PDs were low, the findings suggest a substantial degree of
association between early-onset Axis I disorders and Axis II psychopathology in
young adulthood. More research is needed to develop assessment and treatment
recommendations addressing the early manifestations of PDs.
PMID- 9401338
TI - Antecedents of preschool children's internalizing problems: a longitudinal study
of low-income families.
AB - OBJECTIVE: To examine antecedents of young children's internalizing problems
using research related to emotion regulation to guide prediction. METHOD:
Longitudinal data were collected on 86 low-income mother-child dyads to examine
risk factors related to early internalizing problems as measured by the Child
Behavior Checklist (CBCL). RESULTS: The following risk factors, assessed during
infancy, were related to the development of preschool-age internalizing problems:
negative emotionality, disorganized attachment classification, negative life
events, exposure to child-rearing disagreements, and parenting hassles. In
addition, the interaction of high negative emotionality and exposure to parental
conflict added unique variance to the prediction of scores on the CBCL Withdrawal
and Depression/Anxiety subscales. CONCLUSIONS: Children's preschool-age
internalizing problems can be identified during infancy from multiple domains
related to the development of emotion regulation. Further longitudinal work is
encouraged that incorporates direct measurement of children's negative
emotionality, parenting, and family factors that influence both parenting and
children's emotion regulation.
PMID- 9401339
TI - Is psychopathology associated with the timing of pubertal development?
AB - OBJECTIVE: This investigation tested whether the timing of pubertal development
was associated with concurrent and prior experiences of psychopathology (symptoms
and disorders) in adolescent boys and girls. METHOD: A large (N = 1,709)
community sample of high school students were interviewed using the Schedule for
Affective Disorders and Schizophrenia for School-Age Children as adapted for use
in epidemiological studies. Adolescents also completed a questionnaire battery
covering a range of psychosocial variables. RESULTS: Analyses tested whether
pubertal timing was associated with present and lifetime history of mental
disorders, psychological symptoms, and psychosocial functioning. As hypothesized,
early-maturing girls and late-maturing boys showed more evidence of
psychopathology than other same-gender adolescents. CONCLUSIONS: Early-maturing
girls had the poorest current and lifetime history of adjustment problems,
indicating that this pattern of pubertal development merits attention by mental
health providers and researchers.
PMID- 9401340
TI - AACAP Official Action. Summary of the practice parameters for child custody
evaluation.
AB - This summary is presented as a guide for clinicians evaluating the often delicate
and complex issues surrounding a child custody dispute. The historical basis of
child custody and the various judicial presumptions that have guided courts, as
well as the differences between performing child custody evaluation and engaging
in traditional clinical practice, are reviewed in the complete document. Issues
that are common to all child custody disputes are presented, including continuity
and quality of attachments, preference, parental alienation, special needs of
children, education, gender issues, sibling relationships, parents' physical and
mental health, parents' work schedules, parents' finances, styles of parenting
and discipline, conflict resolution, social support systems, cultural and ethnic
issues, ethics and values, and religion. In addition, special issues that
complicate custody evaluations are presented, including infants in custody
disputes, homosexual parents, grandparents' rights, parental kidnapping,
relocation problems, allegations of sexual abuse, and advances in reproductive
technology, such as frozen embryos, oocyte donation, and artificial insemination.
PMID- 9401341
TI - Back to the future: revisiting the 40-63-1988 syndrome.
PMID- 9401342
TI - Communicating with our patients: the goal of bioethics.
AB - Listening, teaching, understanding, exploring, explaining: these are the
foundations of a sound patient-physician relationship. From these skills, we can
then proceed to discussions on difficult topics such as preferences for end-of
life care. We can share bad news without destroying hope. We can show what makes
the medical profession unlike any other. This issue of The Journal addresses the
handling of medical errors, the termination of mechanical ventilatory support,
ethical problems in managed care, and confidentiality issues in the computer era.
Guidelines for institutional ethics committees also are presented. These are only
a sampling of topics that cut to the heart of bioethics, patient communication,
and contemporary medical practice. The more that we study such issues, the more
we understand the contributions of medical ethics to medical practice, and the
better we serve our patients.
PMID- 9401343
TI - The new health care triangle: the ethics of managed care.
PMID- 9401344
TI - Electronic health data and the challenges of medical confidentiality.
PMID- 9401345
TI - Disconnecting the ventilator: life saving or death delaying?
AB - Mechanical ventilators have supported patients with respiratory failure from the
era of the polio epidemics to the present. While ventilators can clearly be life
saving, many patients receiving this intervention do not survive. In such
patients, this treatment is not life saving, but death delaying. Other patients
treated with mechanical ventilation may survive, but do not improve to the point
where they can become independent of the ventilator. This paper is a review of
the prognosis and cost of respiratory failure, ethical issues in removing
patients from the ventilator and methods of discontinuing respiratory support.
PMID- 9401346
TI - A perspective from clinical and business ethics on adverse events in hospitalized
patients.
AB - Adverse events occur in a significant, but undetermined, number of hospitalized
patients. These types of patient injuries are more often the result of faulty
systems than human maleficence. A culture exists among health care providers that
discourages the reporting of such events and resists the implementation of formal
efforts to eliminate them. This resistance serves to perpetuate the problem. Both
business and clinical ethics argue that sound reasons exist for hospitals to
reduce, if not eliminate, adverse events. To do so is cost effective,
particularly in a managed care environment. It is also at the heart of
responsible professional behavior. Physicians are afforded an opportunity to be
at the forefront in this quality improvement effort.
PMID- 9401347
TI - Synopsis of a practical guide: guidelines for ethics committees.
PMID- 9401348
TI - Medicine and money: an approach to compensating university physicians.
AB - Academic medical centers have been restructuring faculty compensation plans
because decreasing clinical revenues have created budgetary problems. We propose
an overall compensation strategy designed to reward high performance of
university physicians. The approach incorporates Management by Objectives to
improve communication of expectations within the organization and provide college
of medicine leadership with much needed mechanisms to align faculty compensation
with productivity.
PMID- 9401349
TI - Nonstationarity in epileptic EEG and implications for neural dynamics.
AB - In this paper, we use a recently developed method to analyze the nonstationarity
in time series from intracranial depth and subdural recordings of patients with
temporal lobe epilepsy. We show that the nonstationarity in the signal can be
accounted for by the variation of a single parameter. We then show that the
various dominant nonlinear waveforms observed in different electrodes can be
explained by a simple stochastic model in which the mesoscopic collection of
neurons, whose potential the electrodes measure, can be on one of two states. The
nonstationarity observed in our analysis is a consequence of a time-dependent
transition probability between these two states. In general, this transition
probability increases as a seizure is approached. The model that we propose
incorporates this bistability. We find good agreement between real data and
simulated data generated by our model. We understand that this mesoscopic
bistability may be associated with the existence of excitation waves traversing
the brain in these patients.
PMID- 9401350
TI - The effect of community structure on the immunity coverage required to prevent
epidemics.
AB - Estimation of the immunity coverage required to effectively control disease
transmission is an important public health problem. Using data on the eventual
size of a major epidemic, we compare estimates based on the simplifying
assumption that the community consists of uniformly mixing individuals with
estimates obtained when the more complex community structure is acknowledged. The
alternative community structures considered include households and localities
that are quite separate. Several inequalities are established for estimates of
the critical immunity coverage. For several settings, the coverage estimated by
assuming an oversimplified community structure is found to actually be an
underestimate. A serious consequence of this finding is that we may be misled
into believing that we have estimated an immunity coverage that can prevent
epidemics when it in fact cannot. The conclusion is that the heterogeneity in the
community must be taken into account when estimating the critical immunity
coverage.
PMID- 9401351
TI - A mathematical model of drug resistance: heterogeneous tumors.
AB - A mathematical model is developed to describe the growth and control of a
heterogeneous tumor. The main aspect of the model is that it takes into account
induced drug resistance. The mathematical model is a system of two ordinary
differential equations that describes the growth of the cancer along with the
effects of chemotherapy. The model is analyzed to determine what some of the
critical parameters are; how we determine an effective treatment; how combination
chemotherapy should be delivered; and how this model may help us develop more
effective cancer chemotherapeutic treatments.
PMID- 9401352
TI - Modeling the covarion hypothesis of nucleotide substitution.
AB - A "covarion" model for nucleotide substitution that allows sites to turn "on" and
"off" with time was proposed in 1970 by Fitch and Markowitz. It has been argued
recently that evidence supports such models over later, alternative models that
postulate a static distribution of rates across sites. However, in contrast with
these latter well-studied models, little is known about the analytic properties
of the former model. Here we analyze a covarion-style model and show (i) how to
obtain the evolutionary distance between two species from the expected proportion
of sites where two species differ, (ii) that the covarion model gives identical
results to a suitably chosen rates-across-sites model if several sequences are
compared in pairs by using only the expected proportion of sites at which they
differ, (iii) conditions under which the two models will give identical results
if the full joint probability matrix is examined, and (iv) that the two models
can, in principle, be distinguished when there are at least four monophyletic
groups of species. This last result is based on a distance measure that is tree
additive under certain versions of the covarion model but, in general, will not
be additive under a rates-across-sites model. The measure constructed does not
require knowledge of the parameters of the model and so shows that sequences
generated by the covarion model do in fact contain information about the
underlying tree.
PMID- 9401353
TI - Dynamic balance of segregation distortion and selection maintains normal allele
sizes at the myotonic dystrophy locus.
AB - Myotonic dystrophy (DM), an autosomal dominant neurological disorder, is caused
by CTG-repeat expansions at the DMPK locus, with affected individuals having > or
= 50 repeats of this trinucleotide. Reduced reproductive fitness of affected
individuals and decreased viability of congenital DM have been noted. Expanded
CTG-repeat alleles are highly unstable, predominantly yielding even higher repeat
sizes. Preferential transmission of longer alleles from heterozygous mothers
within the normal size range of alleles also is observed. In view of these
observations, it is worth examining how DM has been maintained in human
populations for hundreds of generations. We present an analysis of the dynamic
properties of a model of joint effects of segregation distortion and selection
(intensity of which increases with allele sizes of an individual's genotype). Our
mathematical formulation and numerical analyses demonstrate that a weak
segregation distortion during female meiosis, together with selection of
comparable intensity (within the normal allele size range), can maintain an
equilibrium distribution of allele frequencies. Genetic drift, acting in
conjunction with the occasional contraction of alleles by mutation, can
contribute to the balance of segregation distortion and mutation, in the sense
that even weaker selection can explain the observed allele frequencies. The model
is applied to CTG-repeat size distributions at the DMPK locus, observed in normal
individuals from world populations.
PMID- 9401354
TI - Spatially varying equilibria of mechanical models: application to dermal wound
contraction.
AB - Mechanochemical models based on the Oster-Murray continuum framework have been
applied to a variety of biological settings to obtain an understanding of the
morphogenesis of living tissues. Wound-healing in mammalian skin is an important
example, because a complex sequence of biochemical and biomechanical responses
are orchestrated to close a wound by a combination of new tissue formation and
wound contraction. Mechanical interactions between dermal fibroblastic cells and
the collagen-rich extracellular matrix are crucial in the development of a
contracted wound state. We and others have previously proposed mechanochemical
models for wound repair to gain a greater understanding of both normal and
abnormal healing. In the present work, the existence of spatially varying
equilibria of these models is investigated by using a small-stain approximation
and phase-plane techniques, with numerical simulations to confirm the analytical
predictions. These results are sources of novel insight into the roles of key
biological parameters in determining the mechanical properties of a contracted
wound. These methods may also be relevant to other morphogenetic scenarios for
which similar mechanochemical models have been proposed.
PMID- 9401355
TI - Four years experience of primary intra-arterial chemotherapy (PIAC) for locally
advanced and recurrent breast cancer.
AB - AIMS: To find a means of achieving operability very quickly without the
additional discomfort of prolonging systemic chemotherapy. To improve the
patient's quality of life by obtaining quick tumor reduction and decreasing
systemic toxicity. MATERIALS AND METHODS: From January 1991 to January 1995, 13
patients with locally advanced breast cancer (LABC) and 8 patients with recurrent
breast cancer (RBC), were treated by transfemoral Seldinger technique, with the
catheter tip placed into the subclavian artery at the basis of the internal
mammary artery. The patients received 5-fluorouracil (5FU) 1000 mg, epirubicin
(EPI) 30 mg/m2, mitomycin (MMC) 7 mg/m2 over an infusion for 30 minutes. The
cycle was repeated every two weeks for three times. RESULTS: The overall response
rate was 62%. Stage IIIb and RBC patients had a response rate of 100% and 25%
respectively. In respondent patients a measurable response was seen after the
first cycle. Ten patients were radically operated. After a media follow-up of 21
months, the overall survival is 52% at 48 months (68% at 48 months and 65% at 34
months for stage IIIb and RBC patients respectively). CONCLUSIONS: PIAC is
feasible and effective. In LABC patients it reaches 100% of response rate.
Systemic toxicity was absent and the local one was mild. The interval between the
starting of PIAC and operation is short. There was an optimal compliance of the
patients.
PMID- 9401357
TI - Isolated agenesis of the gallbladder. An intraoperative problem.
AB - Agenesis of the gallbladder and cystic duct is a rare congenital malformation. In
40-70% of cases this anomaly is associated with other gastrointestinal, skeletal,
cardiovascular and genitourinary malformations. Lithiasis of the common bile duct
is present in 25-50% of cases. In the majority of cases patients are asymptomatic
or have symptoms compatible with a biliary disorder. A preoperative diagnosis is
extremely difficult and the absence of the gallbladder is often an intraoperative
finding. The authors report a case of isolated agenesis of the gallbladder. The
relative embryology, development, diagnostic pitfalls, intraoperative behaviour
and therapeutic strategies are discussed.
PMID- 9401356
TI - Classical corticosteroids and new lipid peroxidation inhibitors in the therapy of
multiple organ failure (MOF).
PMID- 9401358
TI - Tuberculin test and tuberculosis control in a low-prevalence country today.
PMID- 9401359
TI - Transbronchial lung biopsy: an analysis of 530 cases with reference to the number
of samples.
AB - To evaluate the diagnostic yield (DY) of transbronchial lung biopsies (TBBs), as
the relationship between the DY and the number of tissue specimens taken per TBB,
we reviewed the histological and clinical data of 530 consecutive TBBs performed
in 516 immunocompetent patients, having either a chronic diffuse lung infiltrate,
a localized peripheral lung lesion or hilar adenopathies. The DY (positive
TBBs/performed TBBs) varied significantly according to the radiographic pattern
and the underlying disease. For chronic diffuse pulmonary infiltrates (n = 244),
the overall DY was 50%, but higher figures were obtained for hypersensitivity
pneumonitis (92%), sarcoidosis stage II-III (75%), lymphangitic carcinomatosis
(68%) and pneumoconiosis (54%). The DY was lower in diffuse tuberculosis (38%)
and interstitial pulmonary fibrosis (27%). For localized peripheral lung lesions
(n = 205), the overall DY was only 29%, while for sarcoidosis stage I it was 56%
(n = 63). Data analysis shows that there is a direct correlation between the
number of samples obtained per TBB and the overall DY (i.e. 38% with one to three
tissue fragments versus 69% with six to 10, p < 0.01). The increment itself
depends on the radiographic pattern and/or the underlying disease which indicates
that the probability of diagnostic confirmation per individual tissue sample is
not always the same. The clinical implication of these findings is that whereas
for some pulmonary diseases the DY is already good with few samples, more samples
are to be taken to warrant a satisfactory overall DY. Accordingly, we recommend
that at least five to six specimens per TBB should be taken. This number should
allow a quite good overall DY in patients with diffuse lung infiltrate. On
theoretical grounds, more specimens (seven to 10) should be taken for an optimal
DY of localized peripheral lung lesions and of sarcoidosis at stage I. In these
indications the clinician should therefore compare the risk-benefit of TBB with a
high number of biopsies to the results of other diagnostic procedures.
PMID- 9401360
TI - Management of concurrent pleural effusion in patients with lymphoma: thoracoscopy
a useful tool in diagnosis and treatment.
AB - Pleural effusion represents a frequent feature both of Hodgkin's (HL) and non
Hodgkin's (NHL) lymphoma. The aims of the present study were: 1) to analyse the
diagnostic accuracy of thoracoscopy as compared to pleural cytology in patients
with lymphoma and concurrent pleural effusion; and 2) to evaluate the
effectiveness of chemical pleurodesis with the tetracycline derivative,
rolitetracycline. Seventeen patients with pleural effusion and concurrent
lymphoma (10 NHL and seven HL) were studied. Analysis of pleural fluid revealed
the presence of lymphoma cells in six cases (four NHL and two HL);
histopathological examination of samples obtained by thoracoscopy was consistent
with pleural infiltration by NHL in eight cases and by HL in six cases. Overall
sensitivities of pleural cytology and histology were 35 and 82%, respectively.
Following chemical pleurodesis, complete response was observed in five of the 17
cases (two NHL and three HL), partial response in four cases (two NHL and two
HL), whereas failure was observed in the remaining eight cases. Two patients who
had presented failure underwent subsequent pleurectomy by thoracotomy (one case
of HL) or video-thoracoscopy (one case of NHL). Complete response was observed in
both cases following this treatment. No major complication was recorded after
chemical pleurodesis or pleurectomy. Thoracoscopy may be considered a useful tool
to evaluate the involvement of pleural space in patients presenting with pleural
effusion in the course of lymphoma. Chemical pleurodesis plays an important role
in the palliative treatment of this condition. Further studies are necessary to
assess the role of pleurectomy in the treatment of such patients.
PMID- 9401361
TI - Assessment of the value of fibronectin as a tumour marker in malignant pleural
mesothelioma.
AB - Fibronectin concentrations both in plasma and pleural effusion were prospectively
determined in 60 patients with exudative pleural effusions. Fibronectin
concentrations in plasma and pleural fluid in 12 patients with infectious and
exudative pleural effusions (mean +/- SD) were 240 +/- 103 and 212 +/- 115
micrograms.mL-1, in 17 patients with primary or metastatic lung carcinoma 242 +/-
104 and 210 +/- 82 micrograms.mL-1, in 13 patients with pleural tuberculosis 246
+/- 77 and 231 +/- 133 micrograms.mL-1, and in 18 patients with confirmed
malignant pleural mesothelioma 261 +/- 119 and 276 +/- 188 micrograms.mL-1. There
were no significant differences either in the plasma or serum concentrations of
fibronectin between groups (p > 0.05). Although pleural fluid fibronectin content
appeared to have high specificity (85%), it was found to be an inefficient
biological marker for differentiating nonmalignant from malignant pleural
effusions due to its low sensitivity (6%).
PMID- 9401362
TI - Near fatal asthma and psychopathological characteristics: a group-control study.
AB - Psychological factors may play a role in asthma. In particular, emotional upsets
have been correlated with fatal asthma attacks, and an abnormal personality
attitude is considered to be a risk factor in fatal asthma. Moreover, some
authors have recently reported favourable asthma outcome in patients with severe
asthma and psychiatric abnormalities, when psychoactive treatment was initiated.
On the understanding that people with fatal and "near fatal asthma" (NFA) are
components of the same subset of the asthmatic population, we undertook a study
aimed at assessing the importance of personality and psychiatric factors in
asthma mortality. Between June 1991 and December 1993, a sample of 17 patients
with asthma who had experienced one or more near fatal asthma attacks
(respiratory arrest, or need for respiratory assistance, or altered conscious
state, or arterial carbon dioxide tension (Pa,CO2) > 6.7 kPa (50 mmHg)), and 17
control patients with asthma who had never experienced such an attack (control
group) were enrolled. All patients underwent: 1) an interview concerning their
personal and family psychiatric history; 2) a psychodiagnostic investigation by a
battery of four of the most widely used psychiatric tools: Hamilton scales for
anxiety and depression; Zung scales for anxiety and depression; and Minnesota
Multiphasic Personality Inventory. No statistical difference was found in
psychodiagnostic tests between study and control groups. The psychiatric history
was similar in the two groups. Our results suggest that personality
characteristics and psychiatric history are not related to asthma outcome, and
that the psychiatric approach is not expected to be useful in preventing
mortality in asthma.
PMID- 9401363
TI - Severe haemorrhagic diathesis in an adult patient with cystic fibrosis after long
term antibiotic treatment of pulmonary infection.
AB - We describe the case of a 22 yr old male patient with cystic fibrosis, who, after
long-term antibiotic treatment of pulmonary infection, developed a haemorrhagic
diathesis with severe bleeding from the mucus membrane of the mouth, and
haematuria. Rapid recovery was observed after infusion of vitamin K. During 8
months of follow-up, no evidence of recurrence of the clotting disturbances and
anaemia were noted. The combination of impaired absorption of vitamin K due to
underlying disease with the antibiotic-induced suppression of vitamin K synthesis
by intestinal bacteria could be a possible explanation for this disorder.
PMID- 9401364
TI - Epithelioid haemangioendothelioma of the lung imitating clinical features of
pulmonary histiocytosis X.
AB - A young male who was a heavy smoker presented with spontaneous right
pneumothorax. A high resolution computed tomography scan showed disseminated
nodules up to 1 cm in diameter; the greatest majority of which were sited in the
centrilobular zone, though some abutted on the pleural surface. Surgical lung
biopsies allowed a diagnosis of epithelioid haemangioendothelioma. The neoplastic
tissue infiltrated the wall of bronchioles, partially obliterating them and the
visceral pleura. These two histological aspects could be considered as
concomitant mechanisms for the appearance of spontaneous pneumothorax.
Epithelioid haemangioendothelioma should be added to the list of lung diseases in
young heavy smokers that can begin with a spontaneous pneumothorax.
PMID- 9401365
TI - Prevalence of tuberculous infection among students in Naples.
AB - The aim of this study was to estimate the prevalence of tuberculous (TB)
infection in Naples, Italy. The target population was defined as pupils aged 6, 9
and 13 yrs, studying in state and private schools in Naples. A stratified cluster
sampling design was used. The stratification criteria were: age (6, 9, 13 yrs);
type of school (state or private); and district within the town. Prevalence of TB
infection was assessed through a tuberculin Tyne test. Some individual risk
factors of tuberculous infection were also investigated by means of a simple
questionnaire given to pupils' parents. Among observers reproducibility of test
reading was also evaluated. An overall prevalence of TB infection of 5.7% (95%
confidence interval (95% CI) 4.6-6.8) was observed in the 1,597 sampled subjects.
Skin-test positivity was highly variable with age, ranging from 2.8 (95% CI 1.0
4.6) at 6 yrs to 9.4% (95% CI 7.1-11.7) at 13 yrs. In 458 children (28.7%)
response was blindly assessed by three independent observers. Reproducibility of
tuberculin skin-test reading was good, with an overall kappa value of 0.718. Only
parents' drug abuse was found to be significantly associated with infection. This
is the first study to evaluate the prevalence of tuberculous infection in Naples.
PMID- 9401366
TI - Pharmacological treatment of exertional dyspnoea in stable COPD patients.
AB - Exertional dyspnoea is one of the most common and disabling symptoms in patients
with stable chronic obstructive pulmonary disease (COPD). Because little can be
done for its resolution, the idea of its symptomatic treatment is attractive.
There is no gold standard for the pharmacological management of exertional
dyspnoea in stable COPD. A reassessment of the available literature shows the
current perspectives and limits.
PMID- 9401367
TI - Cystic fibrosis respiratory infections: interactions between bacteria and host
defence.
AB - In cystic fibrosis, impaired mucociliary clearance leads to chronic endobronchial
bacterial infection, mostly caused by Pseudomonas aeruginosa. In the early stage
of infection, the pathogen produces several extracellular protein toxins which
may contribute to its multifactorial virulence before specific antibodies are
produced. P. aeruginosa successfully resists phagocytosis by neutrophils, which
dominate the local inflammatory response, by switching from a nonmucoid variant
to a mucoid phenotype. Chronic infection and inflammation are characterized by
neutrophil-released proteinases which may provide favourable growth conditions
for the bacterial opportunist. Aerosol therapy with serine proteinase inhibitors
is being investigated in cystic fibrosis.
PMID- 9401368
TI - Forced expiratory manoeuvres to increase transport of bronchial mucus: a
mechanistic approach.
AB - Mucus hypersecretion and impaired mucus clearance are well-known symptoms in
patients with chronic obstructive pulmonary disease and cystic fibrosis. These
symptoms should not be considered as innocent but they deserve treatment. A well
known therapy to improve mucus transport is chest physiotherapy. Forced
expiratory manoeuvres are probably the most effective part of chest
physiotherapy. Essential in the application of forced expiratory manoeuvres to
improve mucus transport is whether airway compression should be used or
prevented. The variables that influence the localization and degree of airway
compression are expiratory force, lung volume and possibly mouth pressure. With
these variables the patient should learn the most efficient form of forced
expiration, according to the individual condition of the patient.
PMID- 9401369
TI - Aspects of HIV infection: current infection control policies for HIV.
AB - A coherent infection control policy within healthcare facilities designed for
patients with human immunodeficiency virus (HIV) infection requires the
application of a risk management strategy. The central feature is the adoption of
universal precautions whereby it is assumed that all patients could potentially
be infected by HIV. The major tenets of this are the adoption of good clinical
hygiene and the adoption of agreed infection control policies with a consistent
approach throughout the institution. This involves a teaching and training
programme, and clearly defined policies to protect individuals from HIV infection
itself and infection with other pathogens, in particular tuberculosis. Special
attention is required for bronchoscopy and lung function, as well as a coherent
and proactive policy regarding chemoprophylaxis for HIV infection following
accidental injury such as needlestick.
PMID- 9401370
TI - Tropical infection and the lung.
AB - The term "tropical lung" has been used to describe the lungs that are vulnerable
to those indigenous diseases that occur with particular prevalence in tropical
countries. International travel, student and cultural exchanges and changing
immigration patterns are insidiously transforming the face of medicine in Europe
and other developed countries. The climates of tropical countries provide an
ideal environment for pathogenic organisms, and their vectors and intermediate
hosts, to flourish. In an average out-patient department, 20-40% of patients have
been seen with respiratory complaints, and 20-30% of hospital medical admissions
are for disorders predominantly affecting the lungs. Pulmonary tuberculosis is
common in tropical countries as well as the rest of the world. The other
principal environmentally related tropical pulmonary diseases are melioidosis,
paragonimiasis, amoebiasis, leptospirosis, gnathostomiasis and tropical
eosinophilia. It is essential that the practising clinician be aware of the
increasing prevalence of various new and exotic tropical lung diseases.
Clinicians in developing countries can now use their clinical skills together
with recent developments in immunology, molecular biology and biochemistry to
improve the diagnostic accuracy and therapeutic effectiveness related to tropical
lung infections. Treatment, if inappropriate, may not only be worthless but, in
many cases, extremely harmful and even fatal.
PMID- 9401371
TI - Inspiratory muscle dysfunction as a cause of death in COPD patients.
AB - Although fatigue of the inspiratory muscles has been well documented, its
prevalence in patients with chronic obstructive pulmonary disease (COPD) and its
influence on mortality are unknown, because of the lack of a simple, clinically
available diagnostic test. The hypothesis and experimental evidence relating
inspiratory muscle dysfunction to the development of hypercapnia and hypercapnic
ventilatory failure are reviewed. Since a poor prognosis in COPD is associated
with carbon dioxide retention, inspiratory muscle weakness and/or fatigue may
have an association with survival in these patients.
PMID- 9401372
TI - How women and youth are targeted by the tobacco industry.
AB - Women and youth are fast becoming casualties of the cigarette epidemic. Although
global male smoking rates are almost four times higher than female rates (47
versus 12%), male rates are declining, while female smoking rates are increasing.
With the significant decline in tobacco consumption over the past two decades in
Western countries, the tobacco industry has responded by developing new markets.
The main targets of the tobacco industry are women and youth: in developing
countries, in lower socioeconomic groups, and those with independent careers. The
tobacco industry recognizes that women and youth represent a major untapped
market and are targeting them with aggressive advertising, marketing and
promotional campaigns, sponsorship, and employment in the growing tobacco
industry. In addition, they are applying political and commercial pressure to
open new markets in developing countries. These initiatives of the tobacco
industry have resulted in an increase in tobacco use among women and youth. The
economic arguments put forward by the tobacco industry of providing employment
for many people have to be balanced against the social and financial drain that
tobacco costs the economy in the health area, and the human suffering from
preventable diseases resulting from smoking.
PMID- 9401373
TI - Influence of a secondary genetic factor in cystic fibrosis genotype-phenotype
correlations.
PMID- 9401374
TI - Bronchoscopic biopsy techniques in the diagnosis and staging of lung cancer.
AB - In a review of the bronchoscopic biopsy techniques currently available for the
diagnosis and staging of lung cancer, the author individually analyses the
sampling instruments and procedures used in cancer of the central airways,
peripheral lung lesions, and in the study of hilar and mediastinal lymph nodes.
With regard to central bronchial lesions, data concerning diagnostic yield, the
advantages and limits of forceps biopsy, brushing, washing and transbronchial
needle aspiration are reported. With the integration of two or more of the
sampling methods, a cytohistological diagnosis can be obtained in almost all
cases. In the field of peripheral lung cancer, the diagnostic possibilities of
the transbronchial approach are described. The experience of the Regional
Hospital of Ancona, Italy on 1,027 patients affected by peripheral pulmonary
nodules or masses is reported. The biopsy technique is based on the integration
of transbronchial (using forceps biopsy and transbronchial needle aspiration) and
percutaneous approaches, and on a team approach with the close co-operation of a
pulmonologist, a radiologist and a cytopathologist, all simultaneously present in
the diagnostic suite during the procedures. On the basis of the results obtained,
the author suggests that, in peripheral pulmonary lesions, the transbronchial
approach should generally be performed before the percutaneous needle aspirate,
especially in patients who are candidates for surgery. The transbronchial
approach has the advantages of allowing an examination of the tracheobronchial
tree and staging of lymph nodes with a lower incidence of complications. In
addition, the diagnostic yield of transbronchial needle aspiration in the study
of hilar and mediastinal lymph nodes is analysed. This method, if positive, plays
a major role in the staging of lung cancer and makes it possible to avoid
unnecessary surgical procedures. Knowledge of the advantages and limits of
different sampling instruments and procedures, and of their integration, is
essential to optimize the diagnostic management of each patient with lung cancer.
The goal is to maximize the diagnostic possibilities whilst minimizing risk and
reducing costs.
PMID- 9401375
TI - Improved simulation system for routine cardiopulmonary exercise test equipment.
Part II: A new metabolic simulator system: practical applicability. The European
Coal and Steel Community (ECSC) Working Group on Standardization of Stress-test
Methods.
AB - The utilization in clinical practice of an improved metabolic calibrator was
tested. The morphological characteristics and integration patterns of the signals
were checked with a reference stress-test instrument and compared with
physiological recordings. No significant differences were observed. Conversion
formulae were developed to compare the calibrator's data with those produced by
routine instruments. Simultaneous graphical representations of erroneous and
reference signals and computer processing of data allowed on-line detection of
even minimal sources of error in dynamic working conditions.
PMID- 9401376
TI - Vaccination and the eradication of infectious diseases.
PMID- 9401377
TI - Unreported trials: an opportunity.
PMID- 9401378
TI - Comparison of methods to assess coronary heart disease prevalence in South
Asians.
AB - BACKGROUND: Migrants from the Indian subcontinent (South Asian migrants) in the
United Kingdom have high mortality from coronary heart disease (CHD) in
comparison to the indigenous population. Few studies have assessed the prevalence
of CHD in South Asians, and the applicability of conventional survey methods in
this population is not known. In this pilot random population survey of South
Asian men and women living in West London, the prevalence of CHD as judged by the
Rose questionnaire, past cardiac history, cardiologist and resting
electrocardiogram were compared. METHODS: Subjects aged 30-64 years from randomly
selected households were invited for a cardiological assessment. A lay person
administered the Rose questionnaire and recorded the past cardiac history. A
cardiologist also made an independent assessment and a 12-lead electrocardiogram
was recorded and analysed according to the Minnesota code. RESULTS: Three hundred
and seventy-six individuals (192 men and 184 women) were assessed. The prevalence
of angina in men and women, respectively, was 3.1% and 4.9% by the Rose
questionnaire; 2.6% and 2.2% by past cardiac history; and 4.2% and 0.5% according
to the cardiologist. The prevalence of myocardial infarction in men and women,
respectively, was 5.2% and 2.2% by the Rose questionnaire, 3.6% and zero by past
cardiac history and 3.6% and 0.5% by the cardiologist. Q/QS codes were present in
1.6% men and 0.5% women and ischaemic codes in 13% men and 14% women. Ischaemic
changes were not associated with any cardiac history in 72% of men and 92% of
women. For a diagnosis of CHD in men, there was poor agreement between the Rose
questionnaire and either the past cardiac history or the cardiologist's
assessment, but moderate agreement between the past cardiac history and the
cardiologist. Agreement was poor between all three methods for a positive
diagnosis of CHD in women. CONCLUSION: Current accepted epidemiological methods
for assessing CHD prevalence may be inaccurate in South Asians, especially women.
Electrocardiogram abnormalities suggestive of ischaemia are common in South
Asians and are usually not associated with evidence of CHD. Thus, their value as
indicators of CHD is questionable.
PMID- 9401379
TI - Modified Glasgow Coma Scale to predict mortality in children with acute
infections of the central nervous system.
AB - BACKGROUND: This study aimed to identify the predictors of hospital mortality in
children with acute infective disorders of the central nervous system using an
aggregate Modified Glasgow Coma Scale (MGCS) score and other clinical variables
assessed within 24 hours of hospitalization. METHODS: We did a prospective cohort
study in a teaching and referral hospital in Lucknow, North India. Consecutive
children aged 1 month to 12 years of age admitted with acute infective disorders
of the central nervous system were included in the study. The diagnosis was based
on the presence of symptoms of fever, headache or irritability with or without
vomiting, and either altered sensorium or first episode of seizures or both. The
main outcome measure was hospital-based mortality. RESULTS: Of the 230 patients
included in the study, 42.2% had pyogenic meningitis, 36.9% had tuberculous basal
meningitis and 20.9% had meningo-encephalitis. There were 43 (18.7%) deaths of
which 44.2% were within 3 days of admission. Death was associated with the day 1
aggregate MGCS score only. The area under the curve of four strata of aggregate
MGCS was 0.63 (SE 0.05). The likelihood ratio for discharge with an aggregate
MGCS score of < 5 was 0.52 (95% CI:0.29-0.95) and > 10 was 5.52 (9% CI:1.02
31.96). CONCLUSION: The MGCS can be used to predict discharge in patients with
acute infective disorders of the central nervous system within 24 hours of
hospitalization. The scale is simple, can be applied at the bedside and does not
depend on any investigations. In developing countries with limited investigative
facilities it can be used for identification and selective referral of patients
with a higher risk of death to specialized centres. This study validates the
predictive value of the MGCS.
PMID- 9401381
TI - Microbial resistance to drugs--a universal problem in urgent need of a
comprehensive approach.
AB - The last two decades have seen an increase in bacterial resistance to commonly
used antibiotics all over the world. In the past five years the emergence of
vancomycin-resistant Enterococcus and multidrug-resistant Streptococcus
pneumoniae was particularly notable. Several factors have contributed to this,
including inappropriate use of readily available antibiotics, survival of high
risk patients in critical care units, burn wards and cancer centres following
treatment with multiple antibiotic combinations, increasing poverty and worsening
of living conditions. The data available from South-east Asia, albeit limited,
indicate that prevalence of antibiotic resistance in bacteria isolated from human
and animal sources is higher than that reported from western countries. To combat
this global problem, a multi-pronged approach is needed. Accurate antibiotic
susceptibility data will be required to define the extent of the problem. Medical
experts and scientific organizations will have to develop guidelines for the use
of antibiotics in ambulatory, inpatient and animal husbandary areas. Cooperation
between the medical community, regulating agencies and pharmaceutical industry
will be needed to define policies governing the sale of antibiotics, drug
promotional materials, physician education programmes and consumer education
regarding the hazards of inappropriate antibiotic use. For long term control of
infectious diseases, it is imperative that existing vaccines be appropriately
utilized and new vaccines developed.
PMID- 9401380
TI - Distribution of vascular lesions in ischaemic stroke: a magnetic resonance
angiographic study.
AB - BACKGROUND: Carotid endarterectomy is now an accepted modality for reducing the
threat of recurrence of ischaemic strokes in patients with severe carotid artery
stenosis. However, the incidence of carotid artery stenosis, and hence the
applicability of carotid endarterectomy in the Indian population is not known. We
conducted a prospective study to detect and quantify extracranial and
intracranial arterial lesions using magnetic resonance angiography in consecutive
patients with ischaemic strokes. METHODS: All patients with recent onset of
ischaemic stroke (< 4 months) had a magnetic resonance angiography done to
evaluate the neck vessels as well as the circle of Willis and its branches. The
degree of stenosis of the internal carotid or common carotid artery was measured
according to the criteria described by the North American Symptomatic Carotid
Endarterectomy Trial (NASCET) collaborators. The site and extent of the
extracranial and intracranial arterial lesions were correlated with the clinical
features and the pattern of infarcts on magnetic resonance imaging or
computerized tomographic scan of the brain. RESULTS: The magnetic resonance
angiography was abnormal in 56 out of 100 patients included in the study. Severe
stenosis (> 70%) of the extracranial carotid arteries was seen in 26 patients.
Lesions suitable for carotid endarterectomy were present in only 11 patients
(42.3% of those with severe stenosis). CONCLUSION: Our results are in contrast to
those reported from western countries where the likelihood of a surgically
correctable lesion being present is 60%-70%. We found operable lesions in only
11%. Intracranial atherosclerotic disease causing strokes is probably more common
in India. Therefore, although carotid endarterectomy is the only accepted
surgical procedure for secondary prophylaxis of stroke, there is a need to find
an alternative surgical intervention for the predominantly intracranial pathology
found in the Indian population.
PMID- 9401382
TI - Gender differences in depression in relation to life events.
PMID- 9401383
TI - The prognosis for very tiny neonates.
PMID- 9401384
TI - The enigma of pituitary abscess.
PMID- 9401385
TI - Chest pain.
PMID- 9401386
TI - Ageing.
PMID- 9401388
TI - Making an ass of the law.
PMID- 9401387
TI - Multimedia in health.
PMID- 9401389
TI - The Scottish Health Survey--alcohol consumption in Scotland.
PMID- 9401391
TI - Armed Forces Medical College, Pune.
PMID- 9401390
TI - How can we help today's youth?
PMID- 9401392
TI - Research methods in cancer: clinical trials, epidemiology and audit, Tata
Memorial Hospital, Mumbai, 28 February and 1 March 1997.
PMID- 9401393
TI - Diphtheritic conjunctivitis.
PMID- 9401395
TI - Health services for India's urban poor.
PMID- 9401394
TI - Susceptibility of Staphylococcus aureus at a rural clinic.
PMID- 9401396
TI - Chemical injury due to colours used at the festival of Holi.
PMID- 9401397
TI - A new method for quantifying the cognitive impairment. Its application in
patients with vascular dementia.
AB - Seven-three patients diagnosed with vascular dementia (VD) left to their natural
evolution have been observed during a period of time of one year. The objective
of this study is to find an index to quantify the degree of loss of cognitive
capabilities in patients affected by VD, as well as to define the minimum loss of
punctuation in this index, that can only be caused by an unfavourable evolution
of the disease. This index, which we call Percentual Variation Index (PVI), is
based on the evolution of the punctuations of the Cognoscitive Mini-Exam (CME)
after a follow-up of one year. Our definition states that in order to consider
patients as having cognitive impairment of vascular origin, they must lose more
than 10% of their basal CME score in one year. This method could be useful in
assessing the therapeutic efficacy of drugs used in treating such illnesses.
PMID- 9401398
TI - Intracranial meningioma recognition following general anesthesia: a surprisingly
acute form of presentation.
PMID- 9401399
TI - Diurnal enuresis.
AB - Daytime wetting is a common problem in childhood; in most cases, it is an
intermittent or self-limited problem with a benign and easily identifiable cause.
The history is the most important aspect of the assessment. A urinalysis is
helpful to look for UTI, and ultrasonography of both the kidney and the bladder
is an excellent noninvasive screening study. More invasive diagnostic imaging
studies are necessary only if the patient has symptoms or signs suggestive of
urethral obstruction, neurogenic bladder, Hinman syndrome, or ectopic ureter.
With time and appropriate treatment, the prognosis is excellent for the majority
of patients.
PMID- 9401400
TI - Child occupant protection in motor vehicles.
PMID- 9401401
TI - What's new in pediatric emergency medicine.
PMID- 9401402
TI - Musculoskeletal injury in children.
PMID- 9401403
TI - Tobacco.
PMID- 9401404
TI - Poor growth after cranial irradiation.
PMID- 9401405
TI - Is fever bad?
PMID- 9401406
TI - Role of Ito cells in the liver function.
AB - Ito cells (perisinusoidal fat-storing cells, stellate cells, lipocytes) of the
liver are mesenchymal cells located in the space of Disse. They are the main
place of vitamin A storage in characteristic lipid droplets. Moreover, they
demonstrate synthetic activity of collagens and other extracellular matrix
proteins involved in hepatic fibrosis. Their long, contractile cytoplasmic
processes encompass the sinusoids and can affect sinusoidal blood flow. Because
of their location in the space of Disse and connection with other sinusoidal and
parenchymal cells, they are probably involved in local neurotransmission and
paracrine regulation of numerous liver functions. As a source of cytokines,
prostaglandins and other bioactive substances, produced in the response to
noxious agents, they play a crucial role in the mechanisms of liver injury,
regeneration and fibrosis. This article is a review of the current state of
knowledge on Ito cells structure and function.
PMID- 9401407
TI - Liver cell dysplasia in liver cirrhosis and hepatocellular carcinoma.
AB - The aim of the study was to assess the incidence of both types of liver cell
dysplasia and concomitance with cirrhosis, hepatocellular carcinoma (HCC) and
positive reaction for HBsAg in the autopsy material and an attempt to determine a
relationship between these two types of liver cell dysplasia and hepatocellular
carcinoma. Autopsy material included 102 cases of hepatocellular carcinoma, 101
cases of hepatocirrhosis without accompanying cancer and 106 control cases.
Histological specimens stained with HE were analyzed for the presence of large
liver cell dysplasia (LLCD) according to Anthony et al., small liver cell
dysplasia (SLCD) according to Watanabe et al., the presence of macroregenerative
nodules (< 8 mm) and antigen HBs (stained with orcein according to Shikata). The
detected LLCD were also assessed semiquantitatively taking into account the
number of dysplastic areas in a given case. Statistical significance of the
results was tested with the chi square test. LLCD was most frequently detected in
HCC with concomitant cirrhosis (55.3%), then in cirrhosis without HCC (40.6%),
and in HCC without cirrhosis only in 12.5%. LLCD was found significantly more
frequently (p < 0.05) in cirrhosis with HCC than in cirrhosis without HCC.
Antigen HBs was found in 25.6% of cirrhoses and/or HCC. No significant
differences in the presence of HBsAg were seen between the analyzed groups. The
incidence of LLCD and HBsAg in controls was significantly lower than in other
groups. A mean age at death in case of cirrhosis with HCC subdivided into that
with or without LLCD was not significantly different, whereas in case with
cirrhosis with LLCD age at death was 10.8 years higher (the difference
statistically significant). Analysis of material with respect to gender revealed
a high proportion of men in case of HCC with concomitant cirrhosis but without
LLCD (13:1). A strong relationship was seen between the presence of positive
reaction for HBsAg and LLCD (p < 0.001). Also the intensity of LLCD positively
correlated with the presence of HBsAg. Furthermore, a positive correlation was
seen between the presence of LLCD and macronodular cirrhosis (posthepatitic). The
present findings suggest a closer relation between HBV infection and LLCD than
between cirrhosis or HCC and LLCD. Also morphological patterns of LLCD foci do
not confirm the hypothesis of some investigators about the precancerous character
of these lesions. In the whole current material only seven cases of SLCD were
detected. They were all present in cirrhotic livers with concomitant HCC. Both
the morphological pattern of these lesions and their sometimes discerned close
spatial relation with HCC foci indicate that SLCD is an alternative way of HCC
development.
PMID- 9401408
TI - Gastric fundic gland polyps (Elster's polyps) and Helicobacter pylori-induced
gastritis.
AB - In a series of 555 gastric polyps characteristic Elster's polyps were identified
in 31 cases. Spiral bacteria (Helicobacter pylori) in these polyps were sporadic,
much less frequent (9.7%) than in hyperplastic polyps (35%) in the present series
and in relation to the bacteria frequency found in our randomly chosen gastric
biopsy specimens (43%). The present results indicate that Elster's polyps are not
readily colonized by Helicobacter pylori and accordingly, they do not show the
signs of active gastritis. The reasons for this are unknown. One of the
mechanisms preventing from bacterial colonization may be a different from normal
gastric mucosa and other polyps character of mucus produced by glandular neck
cells, which was found in our series of gastric fundic gland polyps.
PMID- 9401409
TI - Myelinated axon undergoes complete demyelination in the panencephalopathic--but
it is merely subjected to the Wallerian degeneration in the polioencephalopathic
type of transmissible spongiform encephalopathies.
AB - We report here on axon and myelin changes in panencephalopathic type of
Creutzfeldt-Jakob disease as opposed to polioencephalopathic models of scrapie.
In CJD, myelinated axons presented various pathological changes. Initially the
myelin sheath was separated by cytoplasmic tongues into several concentric bands.
Cellular processes penetrated between layers of myelin and lifted away the
outermost lamellae. Then a complicated labyrinth of concentric cellular
processes, clearly belonging to either astrocytes or macrophages invested
myelinated axons. In terminal stages axons completely denuded of myelin were seen
in the centre of a concentric network of cellular processes or spirals of myelin
were seen surrounded by such processes. The myelin fragments penetrated into
astrocytes or macrophages where they underwent final digestion. Macrophages
containing fragments of axons, paracrystalline lamellar bodies and myelin debris
were abundant in this model. In two models of scrapie myelin dilatation, not
unlike that seen in the panencephalopathic type of CJD was observed. Several
altered axons were also seen, but these presented only typical features of
Wallerian degeneration. Even the most damaged fibres consisted of "empty"
vacuoles (the axon itself was lost) surrounded by a narrow rim of
oligodendroglial cytoplasm. Thus, myelinated fibre degeneration in this
polioencephalopathic model merely represents the sequel to preceding neuronal
degeneration. In conclusion, it seems that myelinated fibres are eventually
denuded of myelin in the panencephalopathic type of CJD but undergo Wallerian
degeneration in polioencephalopathic types of scrapie. Because myelin dilatation
is observed in both pan- and polioencephalopathic type of TSE and because their
formation is probably mediated by cytokines released from astrocytes and
microglia, we hypothesised that this mechanism operates early in the fibre
destruction and must be supplemented later in the course of the disease by other,
currently unknown mechanisms.
PMID- 9401410
TI - Primary IgA nephropathy. Contrasting morphometric insight into glomerular and
interstitial changes in younger and elderly patients.
AB - Twelve patients with primary diffuse IgA nephropathy (IgAN) aged under 45 years
(IgAN < 45), and eleven patients with this glomerulopathy aged over 45 years
(IgAN > 45) for whom both light and electron microscopy as well as
immunofluorescence microscopy and full clinical data were available were examined
quantitatively and compared with fifteen normal controls. Morphometric
investigations were performed by means of a computer image analysis system to
characterize quantitatively IgAN in patients over and below 45 years of age as
well as to study whether changes in quantitatively analyzed glomeruli could
correlate with hematuria, which is thought as the main renal symptom in this
glomerulopathy. The study revealed that the mean values of total glomerular cells
per total glomerular area, total glomerular cells per unit of glomerular area,
mesangium (% of total glomerular area) and relative interstitial volume were in
both IgAN < 45 and IgAN > 45 groups increased in comparison with normal controls,
most of them significantly. The comparison of these parameters between IgAN < 45
and IgAN > 45 groups showed that the mean values of total glomerular cells per
total glomerular area and total glomerular cells per unit of glomerular area were
significantly greater in IgAN < 45 group, but relative interstitial volume was
significantly increased in IgAN > 45 patients. Moreover, there were significant
positive correlations between total glomerular cells per unit of glomerular area
and hematuria, but not between glomerular mesangium (% of total glomerular area)
and hematuria in both IgAN < 45 and IgAN > 45 groups. In conclusion, we found
evident quantitative differences between glomerular and interstitial parameters
in younger and elderly patients. Although close relationship was observed between
glomerular hypercellularity and the degree of hematuria in both younger and elder
patients, this association is not clear and its pathogenesis remains to be shown.
PMID- 9401411
TI - Tumor necrosis factor-alpha induces emphysema-like pulmonary tissue rebuilding.
Changes in type II alveolar epithelial cells.
AB - The effect of repeated doses of TNF-alpha on the histological picture of the
pulmonary tissue was analyzed in the present study. Special attention was paid to
the lung rebuilding processes. TNF-alpha was applied intraperitoneally for two
weeks in a dose of 10 micrograms/0.5 ml PBS/24h. Morphological analysis of the
pulmonary tissue was performed after 1 and 28 days following the last TNF-alpha
dose. The study revealed focal pulmonary tissue rebuilding with emphysema-like
changes twenty eight days following termination of TNF-alpha administration. The
rebuilding processes included interalveolar septal atrophy, collagen accumulation
and damage-repair changes in type II alveolar epithelial cells. It has been
demonstrated that apart from the protease-antiprotease hypothesis of the lung
emphysema, the inflammatory-repair hypothesis should be considered. Both
hypotheses are complementary to each other and interpret the emphysema-like
changes as complications of various pathological conditions of the pulmonary
tissue.
PMID- 9401412
TI - Ultrastructural study of subependymal giant cell astrocytoma: unusual
paracrystalloid inclusions in tumour cells.
AB - Subependymal giant cell astrocytoma (SEGA) is a tumour with a broad range of
morphological, immunohistochemical and ultrastructural neoplastic cellular
features. We report here the presence of this tumor in two 7-year-old-boys
presented with a lateral intraventricular mass. Further clinical investigation
confirmed the diagnosis of tuberous sclerosis. Ultrastructural and
immunohistochemical investigation revealed that glial differentiation was more
pronounced in these cases. Interestingly, tumour cells containing unusual
paracrystalline inclusions, infrequently described in SEGA, were identified
ultrastructurally. These inclusions are probably not related to other cellular
organelles.
PMID- 9401413
TI - A case of mitochondrial myopathy with MELAS-like features and polyneuropathy:
ultrastructural and molecular studies.
PMID- 9401414
TI - Multiple fundic gland polyps in duodenal mucosa not associated with colonic
polyposis.
AB - One of extracolonic manifestations of Gardner's syndrome and familial adenomatous
polyposis (FAP) are fundic gland polyps (FGP) located typically in the gastric
body. Rarely FGP develop in the absence of intestinal polyposis. A case of FGP in
the duodenal bulb without associated pathological changes in the large bowel has
been reported.
PMID- 9401415
TI - Primary malignant melanoma of the esophagus. A case report.
AB - A case of primary malignant melanoma of the esophagus has been reported. This
rare entity accounts for less than 0.2% of all esophageal neoplasms. A polypoid,
deep blue and tough tumour was present on endoscopic examination during which a
few samples were taken. Microscopically melanotic tissue occupied the whole
submucosa and scanty deposits of melanin pigment were dispersed. Positive
immunohistochemical stain with HMB-45 antibody confirmed the diagnosis of
malignant melanoma. The patient was admitted to the Oncological Center for
resection of the tumour, which is the treatment of choice in such cases.
PMID- 9401416
TI - Iron crosses the endosomal membrane by a carrier-mediated process.
PMID- 9401417
TI - Whole-heart modeling: progress, principles and applications.
PMID- 9401418
TI - alpha-Amylase family: molecular biology and evolution.
PMID- 9401419
TI - Heart rate variability: origins, methods, and interpretive caveats.
AB - Components of heart rate variability have attracted considerable attention in
psychology and medicine and have become important dependent measures in
psychophysiology and behavioral medicine. Quantification and interpretation of
heart rate variability, however, remain complex issues and are fraught with
pitfalls. The present report (a) examines the physiological origins and
mechanisms of heart rate variability, (b) considers quantitative approaches to
measurement, and (c) highlights important caveats in the interpretation of heart
rate variability. Summary guidelines for research in this area are outlined, and
suggestions and prospects for future developments are considered.
PMID- 9401420
TI - Cardiovascular recovery from stress and hypertension risk factors: a meta
analytic review.
AB - Recent research has suggested that cardiovascular recovery from stress can play a
potential role in hypertension pathogenesis. Sixty-nine studies were included in
a meta-analytic review to evaluate the effect of various hypertension risk
factors (e.g., race, lack of exercise) on cardiovascular recovery from stress.
Small mean effect sizes were observed for studies examining hypertension status
and race as risk factors associated with delayed diastolic blood pressure
recovery. Lack of fitness was also associated with delayed heart rate recovery.
These results revealed that, for the specified risk factors and cardiovascular
variables, high-risk individuals exhibited delayed cardiovascular recovery as
compared with low-risk individuals. Further, the relationships between
hypertension status, race, and cardiovascular recovery were typically associated
with the use of "active" laboratory stressors. The relationship between lack of
fitness and cardiovascular recovery was also associated with the use of "active"
and exercise laboratory stressors.
PMID- 9401421
TI - When syntax meets semantics.
AB - Three experiments concerning the processing of syntactic and semantic violations
were conducted. Event-related potentials (ERPs) showed that semantic violations
elicited an N400 response, whereas syntactic violations elicited two early
negativities (150 and 350 ms) and a P600 response. No interaction between the
semantic and early syntactic ERP effects was found. Sentence complexity and
violation probability (25% vs. 75%) affected only the P600 and not the early
negativities. The probability effect was taken as evidence that the P600
resembles the P3b. The temporal order of word processing in a sentence as
suggested by the data was such that a more automatic syntactic analysis was
performed (earlier syntactic-related negativities) in parallel with a semantic
analysis (N400), after which a syntactic reanalysis was performed (P600). A
reanalysis interpretation of the P600 could explain why the extent of the
reanalysis differed with syntactic complexity and probability of
ungrammaticality.
PMID- 9401422
TI - Development and topography of auditory event-related potentials (ERPs): mismatch
and processing negativity in individuals 8-22 years of age.
AB - How do event-related potentials (ERPs) reflecting auditory processing develop
across adolescence? Such development was described for five ERP components in
four groups of 11 healthy participants with mean ages of 10, 14, 17, and 21
years. Data from 19 sites during diffuse (passive) and focused (discrimination)
attention in a three-tone oddball were analyzed to see how ERP loci varied with
age for tone type, attention condition, and for four types of difference waves
reflecting nontarget and target comparisons. Age interacted with site for most
components. P1 loci sensitive to rare tones moved posteriorly and N1 loci lost
their right bias in early puberty. The P2 loci did not move anterior to Cz until
adulthood. N2 amplitude, sensitive to attention condition, developed a frontal
focus by 17 years. Right-biased P3 loci moved to the midline with focused
attention similarly in all age groups. Difference waves developed in three
stages: In 10-year-old participants, early deflections (< 150 ms) were diffusely
distributed; in midadolescent participants, the main frontal negative component
(150-300 ms) became well formed and lost an earlier right bias; and for
participants 17 years old and older, the late positive complex developed a right
bias in target-derived waves. Latency decreases for early frontal components were
marked in participants 10-14 years old and for later posterior components in
participants 14-17 years old. Major developments appeared at the onset of
adolescence in early stimulus selection processes and during adolescence in the
differential use of this information (N2- and P3-like latencies).
PMID- 9401423
TI - Mismatch negativity during objective and subjective sleepiness.
AB - The mismatch negativity (MMN) and P3 of auditory event-related potentials were
studied during subjectively and objectively (physiologically) defined sleepiness
under optimal stimulus conditions for MMN elicitation. The MMN and P3 were
elicited by either small or large unattended auditory deviants presented to the
left ear. The participant's task was to detect either rare auditory targets
presented to the right ear or rare changes in the light flashes. Eleven young
adults served as participants in a nighttime experiment. The MMN declined
especially at Fz and Cz but not so markedly at the right mastoid as either
subjective or objective alertness decreased. The amplitude of P3 also decreased
during sleepiness. The attenuation of the MMN was paralleled by a decline in
behavioral performance. The results show that the MMN is attenuated by a decrease
in alertness even before an actual sleep state is reached.
PMID- 9401424
TI - Effects of attentional and stressor manipulations on the P50 gating response.
AB - The decline in amplitude of the P50 component of the event-related potential to
the second of paired clicks has been suggested as a measure of preattentional
gating. Two experiments were conducted to assess the effects of attention and a
psychological stressor on P50. Experiment 1 included two choice reaction time
tasks designed to direct attention selectively to the first or second click in
each pair. Results suggest that the N100 component was responsive to attentional
manipulations, whereas P50 was not affected. Experiment 2 examined the impact of
a brief psychological stressor on the P50 response. Parallel mental arithmetic
tasks were administered silently and orally. Self-report and measures of
autonomic activity were used to assess the level of stress occurring during the
performance of the mental arithmetic tasks. Results indicate that P50 suppression
was sensitive to the acute stressor, the oral mental arithmetic task.
Implications of these findings for studies of P50 suppression in schizophrenia
are discussed.
PMID- 9401425
TI - Storage of feature conjunctions in transient auditory memory.
AB - The purpose of this study was to determine whether feature conjunctions are
stored in transient auditory memory. The mismatch negativity (MMN), an event
related potential that is elicited by stimuli that differ from a series of
preceding stimuli, was used in this endeavour. A tone that differed from the
preceding series of stimuli in the conjunction of two of its features, both
present in preceding stimuli but in different combinations, was found to elicit
the MMN. The data are interpreted to indicate that information about the
conjunction of features is stored in the memory.
PMID- 9401426
TI - An in vivo comparison of two circumferential penile strain gauges: the
introduction of a new calibration method.
AB - This study assessed the comparability of two types of penile strain gauges using
both a circular and a newly developed oval calibration device. A group of 25
sexually functional participants placed both an electromechanical and an
indium/gallium-in-rubber strain gauge on the penis and viewed an erotic film. The
electromechanical gauge as calibrated on the circular device resulted in greater
penile circumference changes than the indium/gallium-in-rubber gauge. Mean
circumference changes were not different for the two strain gauges when the oval
calibration device was used. The use of an oval calibration device improves
ecological validity of calibration of penile strain gauges. Standard inclusion of
this method in studies on male sexual response will increase comparability of
research findings.
PMID- 9401427
TI - Suppression of sleepiness in drivers: combination of caffeine with a short nap.
AB - Previous research has shown that caffeine and a < 15-min nap effectively and
separately reduce sleepiness in drivers for 1 hr. In the present study, we
examined in 12 sleepy individuals the treatments combined, taken during a 30-min
break, prior to a longer (2 hr) continuous monotonous afternoon drive in a car
simulator. Nonnap comparisons were 200 mg caffeine only and placebo. For placebo,
driving incidents, subjective and electroencephalographic measures of sleepiness
all reflected a mid-afternoon peak. This peak was significantly reduced by
caffeine and eliminated by the combined treatment, which reduced incidents to 9%
of placebo levels versus 34% of placebo levels for caffeine alone. Naps
comprising "nonsleep dozing" were still effective.
PMID- 9401428
TI - Startle reflex modulation by pleasant and unpleasant odors in a between-subjects
design.
AB - Participants were presented with an acoustic startle probe while they smelled
either a pleasant odor or an unpleasant odor (n = 40 per condition). Within each
condition, participants were presented with four blocks in which odor was present
and four in which odor was not present (no-odor control). Significant differences
were found in both conditions between the odor and no-odor blocks. In the
unpleasant odor condition, blink magnitude was greater during the odor blocks; in
the pleasant odor condition, blink magnitude was smaller during the odor blocks.
PMID- 9401429
TI - Interaction of the von Willebrand factor with platelets and thrombosis.
AB - The human von Willebrand factor (vWf) is a multimeric glycoprotein present in
plasma, platelets, endothelial cells and subendothelium and synthesized in
endothelial cells and megakaryocytes. vWf plays a pivotal role in the mechanisms
of blood clotting and platelet thrombus formation; quantitative and qualitative
abnormalities of vWf cause the most common congenital bleeding disorder in man,
the von Willebrand disease. vWf stabilizes factor VIII and interacts with
subendothelial components and with platelet membrane receptors. The multimeric
structure of vWf provides an array of binding sites which allows multivalent
interactions with its ligands, thus supporting the formation of stable platelet
aggregates at the site of vascular injury, particularly under flow conditions
characterized by high shear stress. In the last years, remarkable progress has
been made toward understanding the structure of vWf protein and gene, and the
elucidation of many structure-function relationships, which may result in
improved therapeutic intervention for vWD patients, and in the development of
effective strategies for antithrombotic therapy.
PMID- 9401430
TI - Acute intravascular haemolysis with massive microspherocytosis in a 75-year-old
woman.
AB - Acute intravascular haemolysis (AIH) sometimes occurs in patients with sepsis or
bacteraemia, mainly due to clostridia or Salmonella sp., and may be a life
threatening condition. We describe a case of AIH in a 75-yr-old woman with
chronic cholelithiasis. Blood and stool cultures were repeatedly negative, but
the massive microspherocytosis, typically observed in clostridia infections,
oriented our diagnosis. The patient was treated with antibiotics and for a rapid
worsening of her conditions, which could have led to the onset of a multi-organ
dysfunction syndrome (MODS), with plasma exchange and, subsequently,
haemodialysis, with satisfactory results.
PMID- 9401431
TI - Influence of alcohol consumption on the initial development of chronic
pancreatitis.
AB - The aim of our study was to analyze the influence of alcohol consumption on the
early clinical manifestations of alcoholic chronic pancreatitis of the 517
patients in whom chronic pancreatitis was initially suspected, 158 were diagnosed
with this disease; of these, alcohol was considered the cause in 136 (86.1%).
Alcohol was considered a major etiologic factor when mean consumption was > or =
60 grams per day for at least 4 years. Alcohol consumption, initial clinical
manifestations and time of onset were considered up until the moment of diagnosis
in all patients. The sex distribution was 133 men (97.8%) and 3 women (2.2%). The
average age was 22 +/- 6.5 years at onset of alcoholism, 38 +/- 9.4 years at
onset of clinical features, and 44 +/- 9.4 years at diagnosis. The interval
between the onset of alcoholism and the initial clinical manifestations was 15.8
+/- 8.8 years, and the interval between the latter and diagnosis was 6.1 +/- 4.9
years. Average alcohol consumption was 162 +/- 8 grams/day and total consumption
was 1312 +/- 1017 kg. A statistically significant relationship was found only for
mean alcohol consumption and abdominal pain. We found a higher frequency of acute
pancreatitis outbreaks, calcifications, steatorrhea and diabetes until the moment
of diagnosis in the higher alcohol consumption groups, although the relationship
was not statistically significant.
PMID- 9401432
TI - Laparoscopic gastroplasty. Technique and preliminary results in patients with
morbid obesity.
AB - Morbid obesity is an aesthetic, social and psychological problem, with
characteristic morbidity and mortality. Surgical treatment has been developed due
to the high failure rate of medical treatment. In our previous experience with 40
patients, open transverse gastroplasty reinforced with mesh, has been found to be
a good procedure to deal with this problem, with very few postoperative
complications. In March 1995 we started a prospective study to evaluate the
feasibility and results of the same technique done laparoscopically. We operated
on 10 morbid obesity patients with several failed medical treatments.
Laparoscopic surgery was felt to be easier and faster than the open technique.
Weight loss was similar to that in our previous patients with open surgery, but
postoperative pain and complications were less frequent, and the aesthetic
results were better. More patients and a longer follow-up will be needed to
provide definitive conclusions.
PMID- 9401433
TI - Multiple colon tumors. Diagnosis and follow-up of 450 patients with colorectal
carcinoma.
AB - OBJECTIVE: Failure to diagnose synchronous tumors leads to errors in patient
treatment and prognosis. The existence of metachronous tumors requires strict
patient follow-up to ensure early identification of the second tumor. The present
study evaluates the results obtained in the application of a structured procedure
for the diagnosis and follow-up of multiple colorectal carcinoma. MATERIALS AND
METHODS: A structured procedure was used to follow for 5 years a group of 12
patients with multiple colorectal tumors (7 synchronous and 5 metachronous) of a
series of 450 colorectal neoplasms. RESULTS: Six synchronous tumors were
diagnosed preoperatively and one intraoperative. Of the 5 metachronous neoplasms,
4 strictly adhered to the follow-up protocol, as a result of which the second
tumor was detected at an early stage. The remaining case involved no follow-up,
and the second tumor was diagnosed in an advanced stage as a result of bowel
occlusion. The left colon was predominantly involved; polyps were detected in 9
cases, while two patients had 3 malignancies detected by histopathological study.
COMMENTS: We emphasize the need for a full evaluation of the colon in all
patients with colorectal carcinoma. In the case of incomplete preoperative
evaluation, intraoperative colonoscopy is to be considered; if this is not
feasible it should be performed one month after surgery. A structured follow-up
procedure permits the early detection of these tumors, there by improving patient
prognosis.
PMID- 9401434
TI - Hepatic tumors in patients with cirrhosis: an autopsy study.
AB - The incidence and characteristics of hepatic tumors -primitive or secondary- were
analyzed in a series of 596 patients with cirrhosis and on whom an autopsy was
carried out. A hepatic tumor was discovered in 43.6%: 96.5% with histological
findings of malignant disease and only 3.4% with benign disease. The tumors
discovered showed the following in order of frequency: hepatocellular carcinoma
(90.3%), hepatic metastases (4.2%), cholangiocarcinoma (2.3%), adenoma (1.5%),
hemangioma (1.2%) and hamartoma (0.8%). Therefore, 10% of the neoplasms located
in the cirrhotic liver were different from the hepatocellular carcinoma. In 2% of
the subjects with hepatic tumors, two histologically different lesions were found
to co-exist in the liver, and in every case it was found to be a hepatocellular
carcinoma related to another tumor, which further complicated the diagnosis. The
most frequent type of hepatocellular carcinoma was multinodular, although diffuse
tumors most frequently developed metastases. When the hepatocellular carcinoma
was uninodular and small, distal spread was exceptional. Metastatic infiltration
of the liver by neoplasms of different origin, characteristically infrequent in
cirrhosis, was always accompanied by spread to other organs and did not appear as
a single nodule in any case. We conclude that the correct diagnosis of tumor
related lesions located, in a cirrhotic liver is occasionally difficult during
life, especially when the neoplasms are different from the hepatocellular
carcinoma.
PMID- 9401435
TI - New numbers to define a common plague.
PMID- 9401436
TI - Nonsteroidal anti-inflammatory drug induced duodenal web.
AB - Duodenal webs represent an unusual cause of intestinal obstruction in adults.
These anomalies are generally considered to be congenital in origin and usually
present in infancy. However, they occasionally become symptomatic in adulthood.
In these cases, because of the delay in symptoms, the etiology of duodenal webs
in adults is uncertain. Gastrointestinal webs in adults have also been reported
in the small intestine and colon. It is generally accepted that these lesions are
an acquired defect related to long term nonsteroidal anti-inflammatory drug
(NSAID) use. We report a patient with a history of long term NSAID use who
presented with symptoms of gastric outlet obstruction due to the presence of a
duodenal web.
PMID- 9401437
TI - Life would be better if we faced our fear of death.
PMID- 9401438
TI - Molecular medicine: a primer for clinicians. Part X: Clinical implications of the
new genetics--I.
AB - The mendelian concepts of genetic inheritance remain valid and are well
recognized. However, there are a number of diseases or syndromes that do not
follow mendelian rules. These are designated "non-traditional patterns of
inheritance" and will be the subject of the current and subsequent installments
in this series.
PMID- 9401439
TI - Appropriate antibiotic use in long-term care facilities.
PMID- 9401440
TI - Tell your patients to stop smoking!
PMID- 9401441
TI - Do the right thing for our kids.
PMID- 9401442
TI - A brief history of tobacco.
PMID- 9401443
TI - Tobacco update 1997: "global settlement" on hold.
PMID- 9401444
TI - Tobacco update 1997: tobacco use by kids increases.
PMID- 9401445
TI - Trends in lung cancer mortality among men and women, Wisconsin and the United
States, 1979-1994.
PMID- 9401446
TI - Smoke-free workplaces, Wisconsin municipal and county government buildings, 1996.
PMID- 9401447
TI - Enforcement of minor tobacco laws: Wisconsin, 1996.
AB - The objective of this project was to profile the statewide enforcement of laws
prohibiting sales of tobacco to minors and purchasing/possession of tobacco by
minors in 1996. A sample of Wisconsin cities or villages (n = 86) were surveyed
on adoption of pertinent state statutes as local ordinances and the number of
recorded violations. About 70% of municipalities have passed illegal sales
ordinances and about 80% have passed purchase/possession ordinances. Over 6,000
citations were issued to minors in 1996 for purchase/possession of tobacco and 67
citations were issued for illegal sales to minors. By extrapolation, we estimate
that there is approximately one commercial selling citation issued for every
112,000 packs of cigarettes sold to minors. We discuss this disparity and submit
that a shift in enforcement, to commercial sellers, is needed to help reduce the
increasing use of tobacco by minors.
PMID- 9401448
TI - Recent advances in MR spectroscopy expand its applications in neurologic disease.
AB - MRS extends the diagnostic power of MRI by displaying the biochemical composition
of a selected tissue or region. When MR imaging shows a lesion, the evaluation of
the chemical composition by MRS can help determine whether biopsy, observation or
medical treatment is indicated. It can save some patients from biopsy prior to
radiation or chemotherapy. In the future, both the image information and the
spatial distribution of chemical constituents throughout the brain will be
displayed with techniques such as chemical shift imaging (CSI). MRS improves the
accuracy of MRI diagnosis and prognosis. MRS is performed at many sites in the
country and is reimbursed by many insurers. MRS has been approved by the AMA for
a CPT-4 code for reimbursement.
PMID- 9401449
TI - Status epilepticus after cranial CT with contrast media.
AB - This case illustrates intravenous radiographic contrast material as an unusual
and little known etiology of seizure. A brief review of the literature is
provided in which the incidence of contrast induced seizures and the potential
risk factors for their development are discussed.
PMID- 9401450
TI - What's new in ... pediatric tertiary care.
PMID- 9401451
TI - Combating the fraud squad: corporate compliance programs are of utmost
importance.
PMID- 9401452
TI - The perception of shape and curvedness from binocular stereopsis and structure
from motion.
AB - The integration of binocular stereopsis and kinetic depth was measured for two
distinct aspects of 3-D structure: (1) shape index, which is a measure of scale
independent structure, and (2) curvedness, which is a measure of scale-dependent
structure. We found that motion contributes significantly more to judged shape
index than it does to judged curvedness, and stereo contributes significantly
more to judged curvedness than it does to judged shape index. This suggests that
the differences in the relative contribution of motion and stereo reported here
occurred because these two sources do not equally specify the scale-dependent and
scale-independent aspects of surface structure. Furthermore, these results seem
to be inconsistent with integration models in which the different visual cues all
initially contribute to the same single representation of 3-D structure.
PMID- 9401453
TI - The representation of auditory source characteristics: simple geometric form.
AB - Two experiments examined listeners' ability to discriminate the geometric shape
of simple resonating bodies on the basis of their corresponding auditory
attributes. In cross-modal matching tasks, subjects listened to recordings of
pairs of metal bars (Experiment 1) or wooden bars (Experiment 2) struck in
sequence and then selected a visual depiction of the bar cross sections that
correctly represented their relative widths and heights from two opposing pairs
presented on a computer screen. Multidimensional scaling solutions derived from
matching scores for metal and wooden bars indicated that subjects' performance
varied directly with increasing differences in the width/height (W/H) ratios of
both sets of bars. Subsequent acoustic analyses revealed that the frequency
components from torsional vibrational modes and the ratios of frequencies of
transverse bending modes in the bars correlated strongly with both the bars' W/H
ratios and bar coordinates in the multidimensional configurations. The results
suggest that listeners can encode the auditory properties of sound sources by
extracting certain invariant physical characteristics of their gross geometric
properties from their acoustic behavior.
PMID- 9401454
TI - Temporal binding errors are redistributed by the attentional blink.
AB - When one searches for a target among nontargets appearing in rapid serial visual
presentation (RSVP), one's errors in performance typically involve the
misreporting of neighboring nontargets. Such illusory conjunctions or intrusion
errors are distributed differently around the target, depending on task or
stimulus variables. It is shown here that shifts in intrusion error patterns can
be produced by the manipulation of attention alone. In a dual-task paradigm, the
magnitude and distribution of intrusion errors changed systematically as a
function of available attentional resources. Intrusion errors in RSVP tasks
reflect internal capacity limitations for binding independent features. The
present results support a two-stage model of RSVP target processing.
PMID- 9401455
TI - Differential effects of stimulus context on perceived length: implications for
the horizontal-vertical illusion.
AB - Six experiments examined orientation-specific effects of stimulus context on the
visual perception of horizontal and vertical lengths: Using a paired-comparison
method, Experiments 1-5 showed that the probability of judging a given vertical
line to be longer than a given horizontal line was relatively great when the
stimulus set comprised relatively long horizontals and short verticals, and
relatively small when the stimulus set comprised short horizontals with long
verticals. To the extent that stimulus context exerts orientation-specific
effects on perceived length, it thereby modulates the degree to which verticals
appear longer than physically equivalent horizontals: the horizontal-vertical
illusion (HVI). Under various contextual conditions, the HVI was as small as 3%
(horizontals had to be 3% greater than verticals to be perceived as equally long)
and as great as 15%, equaling about 12% in a "neutral" context. In Experiment 6,
subjects judged the absolute physical length of each stimulus, and the results
indicated that stimulus context acted largely by decreasing perceived lengths.
The results are consistent with the hypothesis that differential effects of
context reflect a process of stimulus-specific perceptual attenuation.
PMID- 9401456
TI - A multidimensional scaling analysis of vowel discrimination in humans and
monkeys.
AB - Multidimensional scaling (MDS) was used to compare perceptual maps for 10
synthetic English vowels in humans and Old World monkeys (Macaca fuscata and
Cercopithecus albogularis). Subjects discriminated among the vowels using a
repeating background procedure, and reaction times were submitted to an MDS
analysis to derive measures of perceive similarity. The dimensions that emerged
related to the frequencies of the first (F1), second (F2), and third (F3)
formants. Human data indicated a good match to previous MDS studies using rating
procedures or confusion matrices: The dominant dimension mapped onto vowel F2,
the phonetically most important formant, and the second and third dimensions
mapped onto F1 and F3, respectively. For monkeys, equal weightings occurred for
F1 and F2, and F3 was not clearly represented. Monkey sensitivity to the formants
appeared to relate to formant amplitudes. If monkeys are giving an accurate
representation of the psychoacoustic relations among the formants, then our human
results suggest that species-specific mechanisms, reflecting the salience of the
phonetic feature of advancement, may contribute to vowel coding in humans.
PMID- 9401457
TI - Haptic curvature discrimination at several regions of the hand.
AB - Static haptic discrimination of the curvature of convex, concave, or straight 20
cm-long strips was investigated for nine placements on the hand. In one
condition, the strips were touched with the palmar side of the hand, and in the
other condition, with the dorsal side. The influence of the lengths of the
strips, and thus of contact lengths, was also investigated. For all placements,
discrimination was poorer in the dorsal than in the palmar condition, owing to
poorer cutaneous resolution on the dorsal side of the hand (the kinesthetic
stimulation was the same in both conditions). Thus cutaneous stimulation is
important. In both experiments, performance appeared to depend primarily on
contact length. Moreover, the discrimination thresholds for all different
placements and contact lengths followed the same trend. We conclude that in these
experiments the effective stimulus for the discrimination of curved strips is the
total difference of local surface attitude--that is, the slope difference over
the far ends of the stimulus.
PMID- 9401458
TI - Does IOR occur in discrimination tasks? Yes, it does, but later.
AB - When a stimulus appears in a previously cued location several hundred
milliseconds after the cue, the time required to detect that stimulus is greater
than when it appears in an uncued location. This increase in detection time is
known as inhibition of return (IOR). It has been suggested that IOR reflects the
action of a general attentional mechanism that prevents attention from returning
to previously explored loci. At the same time, the robustness of IOR has been
recently disputed, given several failures to obtain the effect in tasks requiring
discrimination rather than detection. In a series of eight experiments, we
evaluated the differences between detection and discrimination tasks with regard
to IOR. We found that IOR was consistently obtained with both tasks, although the
temporal parameters required to observe IOR were different in detection and
discrimination tasks. In our detection task, the effect appeared after a 400-msec
delay between cue and target, and was still present after 1,300 msec. In our
discrimination task, the effect appeared later and disappeared sooner. The
implications of these data for theoretical accounts of IOR are discussed.
PMID- 9401459
TI - The effect of shape and location on temporal masking of spatial vibrotactile
patterns.
AB - Target patterns presented to uncued locations on a single fingerpad were followed
by either same-shape (SS) maskers or different-shape (DS) maskers presented to
either the same location (SLoc) or a different location (DLoc). DS maskers
interfered with identification more when they were at SLoc than when they were at
DLoc, but the reverse was true for SS maskers; they interfered more at DLoc than
at SLoc. When targets were presented to cued locations, performance in the
absence of maskers improved, but the pattern of interference from maskers
resembled that for uncued presentation. The proportion of masker responses on
incorrect trials revealed that both temporal masking and response competition may
be involved in the effects of location on pattern identification.
PMID- 9401460
TI - Monocular discrimination of rigidly and nonrigidly moving objects.
AB - We measured thresholds for the monocular discrimination of rigidly and nonrigidly
moving objects defined by motion parallax. The retinal projections of rigidly
moving objects are subject to certain constraints. By applying smooth 2-D
transformations to the projections of rigidly moving objects, we created stimuli
in which these constraints were affected. Thresholds for (generic) nonrigid
transformations that in theory can be detected from rigid ones by processing
pairs of views depended not only on the extent to which the rigidity constraints
were affected, but also on the structure and the movement of the simulated
object. Nonrigid transformations under which every three successive views had a
rigid interpretation were not discriminable from rigid transformations, except in
cases where the distortions were very large. Under the rigidity assumption, this
would mean that a large class of nonrigidly moving objects is erroneously
perceived as rigidly moving.
PMID- 9401461
TI - Is visual image segmentation a bottom-up or an interactive process?
AB - Visual image segmentation is the process by which the visual system groups
features that are part of a single shape. Is image segmentation a bottom-up or an
interactive process? In Experiments 1 and 2, we presented subjects with two
overlapping shapes and asked them to determine whether two probed locations were
on the same shape or on different shapes. The availability of top-down support
was manipulated by presenting either upright or rotated letters. Subjects were
fastest to respond when the shapes corresponded to familiar shapes--the upright
letters. In Experiment 3, we used a variant of this segmentation task to rule out
the possibility that subjects performed same/different judgments after
segmentation and recognition of both letters. Finally, in Experiment 4, we ruled
out the possibility that the advantage for upright letters was merely due to
faster recognition of upright letters relative to rotated letters. The results
suggested that the previous effects were not due to faster recognition of upright
letters; stimulus familiarity influenced segmentation per se. The results are
discussed in terms of an interactive model of visual image segmentation.
PMID- 9401462
TI - The tactual horizontal-vertical illusion depends on radial motion of the entire
arm.
AB - We sought to clarify the causes of the tactual horizontal-vertical illusion,
where vertical lines are overestimated as compared with horizontals in L and
inverted-T figures. Experiment 1 did not use L or inverted-T figures, but
examined continuous or bisected horizontal and vertical lines. It was expected
that bisected lines would be perceived as shorter than continuous lines, as in
the inverted-T figure in the horizontal-vertical illusion. Experiment 1 showed
that the illusion could not be explained solely by bisection, since illusory
effects were similar for continuous and bisected vertical and horizontal lines.
Experiments 2 and 3 showed that the illusory effects were dependent upon stimulus
size and scanning strategy. Overestimation of the vertical was minimal or absent
for the smallest patterns, where it was proposed that stimuli were explored by
finger movement, with flexion at the wrist. Larger stimuli induce whole-arm
motions, and illusory effects were found in conditions requiring radial arm
motion. The illusion was weakened or eliminated in Experiment 4 when subjects
were forced to examine stimuli with finger-and-hand motion alone, that is, their
elbows were kept down on the table surface, and they were prevented from making
radial arm motions. Whole-arm motion damaged performance and induced perceptual
error. The experiments support the hypothesis that overestimation of the vertical
in the tactual horizontal-vertical illusion derives from radial scanning by the
entire arm.
PMID- 9401463
TI - Antiphase flicker induces depth segregation.
AB - We examined the influence of the temporal phase of flickering stimuli on
perceptual organization. When two regions of a uniform random-dot field are
flickered in temporal alternation with the same flicker rate, one of the regions
appears to lie in front of the other. Within the range of temporal frequencies
used in the present experiments, depth perception was maximal between 5 and 31.3
Hz. Which region of the two is perceived as lying in front is different from
person to person and sometimes fluctuates within the same subject, but when two
regions are of different sizes, the smaller region tends to be perceived in front
for longer than the larger region. The depth segregation was not due to a
luminance difference, because the average temporal luminance of the regions was
kept equal. Strikingly, the illusory depth segregation is perceived even between
two adjacent regions whose densities of dots, sizes, shapes, and flicker rates
are identical. This result suggests that a difference of temporal phase between
two flickering regions is crucial for this new depth perception.
PMID- 9401464
TI - Isoluminance and contingent color aftereffects.
AB - In the typical induction of the orientation-contingent color aftereffect (CCAE),
the stimuli are composed of elements that differ in both color and luminance.
Three experiments are reported that show that chromatic contrast between stimulus
elements is insufficient for the induction of the orientation-CCAE and that
luminance contrast is necessary. These experiments expand on previous research
concerned with the role of luminance contrast in the induction of orientation
CCAEs by eliminating alternative explanations.
PMID- 9401465
TI - Nucleotide sequence of cDNA and the gene expression of testis-specific protein Y
in the Japanese monkey.
AB - We cloned the cDNA for Japanese monkey Testis-Specific Protein Y (TSPY). The cDNA
contained an open reading frame of 246 amino acids. This coding fragment shared
89% nucleotide sequence identity and 81% amino acid sequence identity with the
homologous fragment of previously isolated human TSPY cDNA. Monkey TSPY was
assumed to be a molecular mass of 28 kDa and an isoelectric point of pH 5.35.
This protein was hydrophilic and contained an Arg and Lys-rich region which was a
potential DNA binding site. Expression of the TSPY gene examined by reverse
transcription PCR showed that the transcript was detectable only in testis,
suggesting that TSPY plays an important role in spermatogenesis of primates.
PMID- 9401466
TI - Bombyxin F1 gene: structure and expression of a new bombyxin family gene that
forms a pair with bombyxin B10 gene.
AB - Bombyxin F1 gene, a new bombyxin family gene, has been identified. The F1 gene
forms a pair with bombyxin B10 gene with an opposite transcriptional orientation
and the gene pair F1/B10 is located between bombyxin gene pairs B9/C1 and A7/B7
in a bombyxin gene cluster. The nucleotide sequence of the F1 gene and its
deduced amino acid sequence deviate moderately from those characterized
previously for the family-A, family-B, family-C, family-D, and family-E bombyxin
genes; the bombyxin F1 gene and preprobombyxin F1 share no more than 62% and 53%
sequence identities with other bombyxin members, respectively. Harr-plot analysis
indicated that the spacer of the F1/B10 gene pair has low sequence similarity
with that of other bombyxin gene pairs characterized. The bombyxin F1 mRNA in
Bombyx mori brain was shown to locate in four pairs of medial neurosecretory
cells, which also produce other bombyxin family mRNAs. Genomic Southern
hybridization indicated that the Bombyx haploid genome contains a single copy of
the family-F bombyxin gene.
PMID- 9401467
TI - groE-homologous operon of Wolbachia, an intracellular symbiont of arthropods: a
new approach for their phylogeny.
AB - Wolbachia, a member of rickettsia found in the cells of many arthropod species,
are cytoplasmically inherited bacteria which interfere with host's sexuality and
reproduction. Wolbachia strains have been phylogenetically divided into A and B
groups based on the nucleotide sequences of their ftsZ genes. In an attempt to
further define the phylogenetical relationship among these endosymbionts, we
cloned and sequenced the entire length of the groE operon of a Wolbachia harbored
by a cricket. The operon encoded two heat shock proteins, which represented the
third and fourth proteins of any Wolbachia ever characterized. Also, 800 bp
stretches of the groE operons of several other Wolbachia were sequenced, and a
phylogenetic tree was constructed based on the results. The groE tree defined the
relationship among A group Wolbachia strains that had not been successfully
resolved by the ftsZ tree, and suggested unexpected horizontal transmission of
these bacteria.
PMID- 9401468
TI - Cross purposes. Interview by Michele Bitoun Blecher.
PMID- 9401469
TI - A lot is not enough. For foundations spun off by hospital sales, even billions go
only so far.
PMID- 9401470
TI - Founders' keepers.
PMID- 9401471
TI - Is medical research doomed?
AB - Managed care has stepped on the oxygen line of academic medicine, cutting patient
revenue needed for research basics and delaying clinical trials. If that isn't
worry enough, private firms and foreign universities are grabbing market share
from academic medical centers in the United States.
PMID- 9401472
TI - Pay-block time.
AB - Primary care doctors pocketed huge raises five years ago, when HMOs drove up
demand for their services and hospitals began snapping up their practices. But
the pay party has ended, as this Executive Chartbook exclusive shows.
PMID- 9401473
TI - Gold in goldenseal.
AB - Healing herbs and alternative therapies already represent a market as big as $40
billion a year--with consumers paying most of the tab. That's why hospitals and
entrepreneurs aren't waiting for insurers to expand coverage before venturing
into alternative medicine.
PMID- 9401474
TI - Contract management. Call somebody who can.
AB - Specialized expertise remains the top draw for outsourcing, according to our 1997
survey of contract services. But the popularity of the most heavily penetrated
services is hardly a welcome mat for expansion. In fact, it means slower growth.
PMID- 9401475
TI - Contract management. Special import.
PMID- 9401476
TI - Elder care. Close, but no panacea.
PMID- 9401477
TI - Mental health parity. Another voice breaks the silence.
PMID- 9401478
TI - Clinical guidelines. An agency for change.
PMID- 9401479
TI - Managed care watch. Who's on first--patients or PR?
PMID- 9401480
TI - Antibiotic resistance. Of bugs and drugs.
PMID- 9401481
TI - Prenatal care. Open doors, open minds.
PMID- 9401482
TI - [Structure of the natural plasminogen activator (t-PA) and of reteplase.
Controversies on thrombolytic therapy. 45th yearly session of the American
College of Cardiology. Orlando, Fla. March 1996].
PMID- 9401483
TI - Trends in leprosy case detection rates.
AB - BACKGROUND: A systematic review of the trends in leprosy incidence is lacking.
The question of whether leprosy transmission has declined remains, therefore,
unanswered. This study investigates trends in new case detection rates (NCDRs) in
selected leprosy-endemic areas from different continents. METHODS: A literature
search using specific inclusion criteria was performed. Average annual rates of
change in NCDRs were obtained by exponential curve fitting. The variation in
trends within individual areas was investigated using direct and indirect
information on leprosy control activities. RESULTS: This review covers 16 areas
in the Pacific, Asia, Africa and Latin America. For 10 out of the 16 areas, the
trend was seen to be declining consistently over the last 10 years or longer.
Near stabilization or stabilization after decline was observed for two areas. For
three areas, interpretation of recent NCDRs was difficult due to changes in
control, but two of them showed a decline over the study period. A consistently
increasing trend was observed over the last 20 years in the one remaining area.
The observed downward trends could not be attributed to reduced control
activities or changed diagnostic criteria. A general acceleration of downward
trends in the NCDR after the introduction of multidrug therapy (MDT) has not so
far occurred. CONCLUSION: Our main conclusion is that despite many differences
between the studies and study areas, the review demonstrates a considerable
tendency of downward NCDR trends. Lack of information and changing control
conditions necessitate caution in interpreting NCDR trends in individual areas. A
general impact of MDT on NCDR trends is so far not visible. The coming years will
be crucial for MDT-based control to prove its ability to reduce leprosy
incidence.
PMID- 9401484
TI - A follow-up study of multibacillary Hansen's disease patients treated with
multidrug therapy (MDT) or MDT + immunotherapy (IMT).
AB - Multibacillary (MB) leprosy patients treated with multidrug therapy (MDT) or MDT
+ immunotherapy (IMT) with BCG + heat-killed Mycobacterium leprae were tested
annually for their ability to proliferate in vitro to the mycobacterial antigens
BCG, M. leprae soluble extract, and intact M. leprae. IgM antibody responses to
phenolic glycolipid I (PGL-I) were measured, as well as serum nitrite levels in
patients' sera, before, during and after treatment. Patients who received only
MDT did not present cellular reactivity to intact M. leprae antigens, in contrast
to the results obtained with BCG, which elicited reactivity at time zero, that
increased after treatment. Regarding PGL-I antibody variations in relation to the
initial value, we observed a statistically significant marked decrease at the end
of 2 years which continued to fall in successive evaluations. MB patients showed
high initial serum nitrite concentrations which dropped drastically with
treatment. This decay was apparently associated with the bacillary load present
in these patients. The group submitted to IMT + MDT showed high and long-lasting
T-cell responses to mycobacterial antigens in a significant number of initially
unresponsive MB patients. There was a marked increase to M. leprae soluble
extract and BCG, as well as a more variable response to whole bacilli. The
antibody levels in this group of patients are sustained for a somewhat longer
period and decreased more slowly during the 5-year follow up.
PMID- 9401485
TI - Progress of impairment scores following commencement of chemotherapy in
multibacillary leprosy patients.
AB - STUDY AIM: To investigate the progress of impairment over time in multibacillary
(MB) leprosy patients. STUDY DESIGN: Retrospective cohort study. STUDY
POPULATION: One-thousand-eighty-two MB patients newly registered in nine field
clinics in the Western Region of Nepal between 1980 and 1993. METHODS: Data on
impairment at diagnosis and at yearly intervals afterward were collected from
patient records of MB patients already released from multidrug therapy (MDT). The
World Health Organization (WHO) 1988 "disability" grading scale (0-2, for both
eyes, hands and feet--six sites) was used as a measure of impairment. For the
analysis we summed the WHO grading for the six sites into an eyes-hands-feet
(EHF) sum score (minimum 0, maximum 12). The EHF score at 2 years of follow up
was used to compute the main outcome measures: impairment at 2 years, yes or no,
and deterioration of impairment compared with diagnosis. The combined effect of
age, sex, classification and impairment status at diagnosis on the outcome was
examined with logistic regression. RESULTS: At diagnosis, 55.8% of the patients
had some impairment. This proportion decreased over 2 years to 43.9%. Among
patients without initial impairment, 31/310 (10%) developed impairment during the
study period. This was 81/396 (20.5%) among patients with impairment at
diagnosis. The adjusted odds ratio (OR) for developing impairment was 1.87 [95%
confidence interval (CI) 1.06-3.32] for patients with initial sensory impairment
(WHO grade 1). and 1.98 (95% CI 1.15-3.4) for those with initial visible
deformity (WHO grade 2). Among patients with impairment at diagnosis, 195/396
(49.2%) had improved after 2 years. CONCLUSIONS: The proportion of patients with
impairment after 2 years of antileprosy treatment was 12% less than at diagnosis.
Among patients without initial impairment, 10% had developed some impairment
after 2 years. The risk of developing impairment was almost double for those with
sensory impairment or visible deformity at diagnosis. For purposes of monitoring,
evaluation and planning, both the proportion of patients with sensory impairment
(WHO grade 1) and the proportion with visible deformity (WHO grade 2) should be
reported at diagnosis and at release from treatment.
PMID- 9401486
TI - Steroid therapy for paralytic deformities in leprosy.
AB - One-hundred-forty-nine patients with 272 nerve paralyses, with visible deformity
and gross disability, were prospectively followed up with steroid therapy. Out of
151 ulnar paralyses, 101 recovered (67%). Out of 52 median nerve paralyses, 45
recovered (86%); out of 69 foot drops, 54 recovered (78%) for an overall
improvement of 73%. Serious side effects were few. Hence, steroid therapy should
be widely encouraged for the treatment of early nerve damage to prevent permanent
deformity/disability, and vigilance in spotting complications of steroid therapy
is emphasized.
PMID- 9401487
TI - Studies on therapeutic activity of benzoxazinorifamycin KRM-1648 in combination
with other antimicrobial agents and biological response modifiers interferon
gamma and granulocyte-macrophage colony-stimulating factor against M. leprae
infection in athymic nude mice.
AB - In the present study, we evaluated the in vivo anti-Mycobacterium leprae
activities of KRM-1648 (KRM) given at long intervals in combination with
ofloxacin (OFLX), clofazimine (CFZ), and dapsone (DDS). We also examined the
combined effects of two biological response modifiers (BRMs), gamma interferon
(IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF), on the
therapeutic efficacy of KRM. KRM exhibited potent therapeutic efficacy against M.
leprae infection in mice even when given at 4-week intervals. KRM displayed
increased efficacy in combination with OFLX, CFZ, and DDS (given three or six
times per week) when given to mice in the multidrug combination KRM + OFLX + CFZ
+ DDS. The therapeutic efficacy of KRM given at 4-week intervals was increased by
combined use with IFN-gamma but not by GM-CSF. Adoptive transfer of M. leprae
antigen-primed lymphocytes of euthymic mice to recipient athymic nude mice with
progressive M. leprae infection markedly enhanced host resistance.
PMID- 9401488
TI - M. leprae binds to a 28-30-kDa phosphorylated glycoprotein of rat peripheral
nerve.
AB - To understand Mycobacterium leprae-peripheral nerve interaction, we have
investigated the binding of M. leprae to rat peripheral nerve proteins in an in
vitro model using 32P-phosphorylated proteins of the peripheral nerve. Intact M.
leprae binds to a major phosphorylated protein of 28-30 kDa and, to a minor
extent, to a few proteins of molecular weight 45-55 kDa. This binding was more
specific for M. leprae since only insignificant binding was observed with other
bacteria, such as M. bovis or Escherichia coli. M. leprae did not show binding to
several phosphorylated proteins of the rat brain. The 28-30-kDa binding protein
of the rat peripheral nerve was found to be a glycoprotein by concanavalin A
Sepharose column chromatography.
PMID- 9401489
TI - A comparison of the expression of NGFr, PGP 9.5 and NSE in cutaneous lesions of
patients with early leprosy using immunohistochemistry.
AB - We examined the immunohistochemical expression of the neuronal proteins NGFr, PGP
9.5, and NSE in cutaneous lesions of patients with early leprosy and in the skin
of normal individuals. PGP 9.5- and NSE-immunoreactive nerve fibers were
decreased in the skin of leprosy patients. This reduction was topographically
unrelated to the early leprosy infiltrate. However, no difference in the
expression of NGFr was found between the leprosy patient and normal groups. It
was shown that there is a selective alteration in the expression of neuronal
proteins in early leprosy lesions which seems to be unrelated to the inflammatory
infiltrate in the initial stages of leprosy. Pathogenic mechanisms other than
inflammation, which are intrinsic to the Mycobacterium leprae-nerve relationship,
may thus contribute to the nerve damage in leprosy neuropathy.
PMID- 9401490
TI - Disseminated intravascular coagulopathy as an adverse reaction to intermittent
rifampin schedule in the treatment of leprosy.
PMID- 9401491
TI - Silicone oil prevention of insensitive pressure ulcers.
PMID- 9401492
TI - Histoid nodules of leprosy on the lip.
PMID- 9401493
TI - Minimal inhibitory concentrations of lomefloxacin and minocycline against drug
sensitive and drug-resistant isolates of M. tuberculosis compared on L-J and 7H11
media.
AB - The in vitro activity of lomefloxacin and minocycline was tested against 46
strains of M. tuberculosis resistant to streptomycin (S), isoniazid (H) and
rifampin (R) or SHR and 51 strains sensitive to SHR by the minimal inhibitory
concentration (MIC) method on two different media, namely, Lowenstein-Jensen (L
J) and Middlebrook 7H11. The results of the study showed that, irrespective of
the medium used, minocycline had little activity against the strains tested and
the MIC was > 64 micrograms/ml. The MIC of lomefloxacin in 7H11 medium ranged
from 2 to 16 micrograms/ml. There were highly significant differences in the MICs
of lomefloxacin in L-J compared with 7H11. The results suggest that the activity
of lomefloxacin against M. tuberculosis merits further study.
PMID- 9401494
TI - The impact of molecular cytogenetics on chronic lymphoid leukaemia.
AB - Chronic lymphoid leukaemias are clonal expansions of B and T cells with mature
membrane phenotype. Cytogenetic study of these cases usually requires mitogenic
stimulation and can often be hindered by a lack of response of the tumour cells
to mitogen, poor quality metaphases, complex markers and proliferation of normal
cells. In situ hybridisation with fluorescence-labelled chromosome-specific
centromeric DNA probe, single or low copy sequences and whole chromosome paints
which hybridise to complementary sequences allow the detection of numerical and
structural abnormalities on metaphase and interphase cells with much greater
efficiency. Comparative genomic hybridisation uses whole genomic tumour DNA as
probe which is hybridised to normal metaphases. It is particularly useful for
detecting chromosomal changes without being dependent on the dividing tumour
cells. The application of these techniques to the investigation of chronic
lymphoid leukaemias is reviewed with emphasis on the work done in our laboratory
on trisomy 12 and the tumour suppressor region 13q14 in chronic lymphocytic
leukaemia, translocation t(11;14) (q13;q32) in mantle cell lymphoma and other
chronic B cell leukaemias, inv(14) (q11q32), i(8q) and complex markers in T
prolymphocytic leukaemia.
PMID- 9401495
TI - Levels of Hb A2 in heterozygotes and homozygotes for beta-thalassemia mutations:
influence of mutations in the CACCC and ATAAA motifs of the beta-globin gene
promoter.
AB - The author summarizes the Hb A2 levels in over 600 beta-thalassemia heterozygotes
with 32 different base changes or frameshifts and in 22 heterozygotes for 1 of 5
large deletions. Three major groups are recognized: persons with beta zero
thalassemia or beta (+)-thalassemia (severe) have Hb A2 levels between 4.5 and
5.5%, those with mild beta (+)-thalassemia alleles have levels between 3.6 and
4.2%, with still lower values for those with silent mutations. High values were
observed in subjects with the 2 mild beta + alleles with mutations in the beta
globin gene promoter (-88, C-->T and -29, A-->G); unusually high Hb A2 values
were also present in several -88 and -29 homozygotes. Data for several members of
8 families in which the -88 (C-->T) or the -29 (A-->G) mutation, or the -1,393-bp
deletion, is present in cis or in trans to a delta-globin gene mutation support
earlier observations that an increase in delta-chain synthesis occurs in cis to
either one of these 3 alleles. A review of these data confirms the suggestion
that the increase in Hb A2 levels results from at least two mechanisms: in a
posttranslational system, the formation of alpha delta-dimers is promoted when
excess alpha-chains are available, while certain promoter mutations increase the
transcription of the delta-globin gene in cis because of a change in the binding
of transcription factors.
PMID- 9401496
TI - The characterisation of leukaemias with the Sysmex NE-8000.
AB - Blood samples from 118 patients with acute and chronic leukaemia and with more
than 50% leukaemic cells were processed with the automated haematology analyser
Sysmex NE-8000. For 92 out of these 118 the differences in the histograms and
scattergrams of the NE-8000 could be used in an attempt to characterise the
leukaemia. This interpretation of the histograms and scattergrams appeared to be
highly suggestive of the distinction between lymphatic leukaemia and myeloid
leukaemia, and could be indicative of the presence of either the chronic or acute
form of both the lymphatic and myeloid leukaemias.
PMID- 9401497
TI - Recombinant erythropoietin trial in children with transfusion-dependent
homozygous beta-thalassemia.
AB - Augmentation of gamma-gene synthesis by using recombinant human erythropoietin (r
Hu-EPO) represents a new approach to the therapy of beta-thalassemia. A
prospective study was conducted in 26 transfusion-dependent beta-thalassemia
major patients. r-Hu-EPO (Eprex/Cilag, Switzerland) was given to the patients at
an initial dose of 500 IU/kg s.c. 3 times a week for at least 2 months during
which no transfusion was applied. A sustained hemoglobin (Hb) level greater than
8 g/dl was considered as a response to EPO treatment. In the patients whose Hb
levels remained under 8 g/dl or did not increase in comparison to pretreatment
levels within 4 weeks, the dose of r-Hu-EPO was increased to 1,000 IU/kg 3 times
a week and applied for another 4 weeks. Only 16 cases also received oral iron
supplementation. The whole blood and reticulocyte counts, the biochemical tests
including BUN, creatinine, AST, ALT, alkaline phosphatase and ferritin were done
and the percentages of HbF and F cells were analyzed regularly. At the end of the
2nd month, 6 cases qualified to continue with the trial. At the end of the 6th
month, r-Hu-EPO therapy was ceased in 3 cases of the 6 since their Hb levels had
decreased below 7 g/dl. Only 3 cases (11.5%) continued with the r-Hu-EPO therapy
without transfusion for up to 12 months. In conclusion, r-Hu-EPO may be useful in
some selected transfusion-dependent patients with beta-thalassemia major.
Selection criteria should include a mild beta-genotype of coinheritance of alpha
thalassemia, splenectomy and pretreatment reticulocyte response of the patients
as well as the patients' compliance.
PMID- 9401498
TI - Recombinant human erythropoietin in the treatment of multiple myeloma-associated
anemia.
AB - Multiple myeloma (MM) is commonly associated with anemia. Several causes have
been implicated but inadequate erythropoietin (Epo) production appears to be
important. This single-institute open-label, non-comparative clinical trial was
undertaken in order to evaluate serum Epo levels in patients with MM and to study
the efficacy and toxicity of recombinant human Epo (rHuEpo) in the treatment of
MM-associated anemia. MM patients with a baseline hemoglobin (Hb) level of < 11
g/dl received rHuEpo 150 U/kg 3 times/week subcutaneously, with a possible dose
increase to 300 U/kg if no response was observed after 4 weeks. The study was
designed for 12 weeks, although some responders continued rHuEpo. The study
endpoints were determined by an increase in Hb and a decrease in blood
transfusion requirements (BTR). Seventeen patients were enrolled in the study.
The median serum Epo level was 150 mU/ml (range 11-232). Four patients did not
complete the study for reasons unrelated to rHuEpo, but to their underlying MM.
Twelve patients (70.6%) responded with an increase in their Hb levels. One
patient (5.9%) responded partially. The median Hb level rose from 9.4 g/dl (range
7.3-10.7) at study commencement to 12.5 g/dl (range 9.0-15.2). Six of the 11
patients who were transfusion dependent enjoyed a complete abolition of BTR. The
response was also interpreted as an improved quality of life: 3 patients reported
a decrease of 1 level in their WHO performance status (PS) score; in 8 patients,
the PS declined by 2 grades and 1 patient enjoyed PS reduction by 4 scores. Six
patients continue to receive rHuEpo up to 18 months, with a good response and a
smaller maintenance dose. Four patients reported flu-like symptoms, 2 suffered
from a local irritation and 1 experienced a transient controlled elevation of
blood pressure. SUMMARY: (1) Pretreatment endogenous serum Epo levels were
relatively low in all patients studied with MM-associated anemia; (2) rHuEpo was
well tolerated in these patients; (3) rHuEpo was highly effective in the
treatment of anemia in MM, and (4) the response to rHuEpo is characterized by an
increase in Hb levels, a reduction in BTR and an improvement in the WHO PS score.
PMID- 9401499
TI - Ticlopidine-induced aplastic anemia: report of three Chinese patients and review
of the literature.
AB - In this study, three Chinese patients with ticlopidine-induced aplastic anemia
were reported and another 13 patients in the English literature were reviewed. We
attempted to find underlying similarities, evaluate the risk factors, and
identify appropriate treatment for this complication. All but one of the patients
were over 60 years old, and the 6 who died were all older than 65. Therefore, old
age may be a risk factor for developing this complication. Agranulocytosis
occurred 3-20 weeks after initiation of ticlopidine, so frequent examination of
white cell count during treatment is recommended. There seemed to be no direct
correlation between the dose or duration used and the severity of bone marrow
suppression. Treatment for ticlopidine-induced aplastic anemia with colony
stimulating factors seemed to have little effect. The fact that 5 of the 6
patients who received concurrent calcium channel blockers died, should alert
clinicians to be more cautious when using these two drugs simultaneously.
PMID- 9401500
TI - Thyroid tumor as initial presentation of Hodgkin's disease: a case report
including an immunophenotypic characterization.
AB - A rare case of Hodgkin's disease which initially presented with a thyroid tumor
in an 18-year-old-man is reported. The tumor involved most of the thyroid gland
but was well demarcated, and the border between the tumor and the remnants of the
thyroid gland was relatively clear, suggesting secondary Hodgkin's disease
involving the thyroid gland. Histologic examination of the tumor revealed nodular
sclerosing Hodgkin's disease composed of many peculiar osteoclast--like giant
cells and a few typical Reed--Sternberg cells in the background of dominant
eosinophils. With an immunophenotypic study it was shown that these giant cells
were positive for the monoclonal antibodies LeuM1 and BerH2, but negative for
LCA. Thus the histological diagnosis was clearly confirmed.
PMID- 9401501
TI - Acquired immune thrombocytopenia caused by IgG antiglycoprotein Ib antibody in a
patient with Hodgkin's disease.
AB - We studied a patient with thrombocytopenia associated with Hodgkin's disease
(HD). The megakaryocyte number in the bone marrow and the level of platelet
associated IgG were both increased in the patient. Intravenous gamma-globulin
therapy and chemotherapy for HD dramatically normalized the platelet count,
suggesting that antibody produced by lymphoma cells is likely to account for the
thrombocytopenia. Antigen-captured ELISA and Western blotting showed that the
patient's serum had an IgG autoantibody against platelet membrane glycoprotein
Ib. The patient's plasma had no inhibitory effect on normal platelet aggregation
induced by ristocetin. These findings suggest that the autoantibody found in the
patient had a pathogenetic role in the thrombocytopenia, but not in platelet
dysfunction.
PMID- 9401502
TI - A diagnostic dilemma: chronic myelomonocytic leukemia versus atypical chronic
myeloid leukemia. A case report and review of the literature.
AB - There exists a great deal of overlap between many myelodysplastic syndromes and
myeloproliferative disorders. This is most evident in the spectrum of disorders
classified under the term chronic myeloid leukemia. These include chronic
granulocytic leukemia, atypical chronic myeloid leukemia and chronic
myelomonocytic leukemia. Current classification often does not clearly separate
these entities since they share many features, both clinically and
hematologically. We report here a case that satisfies criteria for both chronic
myelomonocytic leukemia and atypical chronic myeloid leukemia, appearing to
fluctuate between the two. This lends further evidence for the heterogeneity of
these disorders and the need for better definition. An improved classification
scheme would allow for more accurate reporting and research into etiology and
treatment. The complex cytogenetic abnormalities of the case are unique and to
our knowledge have not been reported previously. Also, this case report
underscores the importance of cytochemical stains when such disorders are under
consideration.
PMID- 9401503
TI - Cytomegalovirus infection as cause of severe thrombocytopenia in a
nonimmunosuppressed patient.
PMID- 9401504
TI - Health risk assessment of mould allergen exposure.
PMID- 9401505
TI - Dietary management of acute diarrhea with local foods in a Guatemalan rural
community.
AB - A community-based, randomized trial was conducted to evaluate a locally available
diet for the management of acute diarrhea (n = 99 episodes) in 90 Guatemalan
children, 4-42 months of age. The Test Diet (TD), a combination of a semi-solid
pap (maize flour, black beans, oil) and a liquid gruel, Incaparina (maize flour,
cotton seed flour, sugar), in addition to breast-milk and other home foods (group
TD, n = 45 episodes) was offered for 14 d and compared to usual home feeding
(group HF, n = 54 episodes). Diarrhea episodes after admission were significantly
shorter for group TD (median 2.0 d) than group HF (median 4.4 d, p = 0.003) after
adjusting for potential confounders. Weight gains did not differ significantly
between groups. We conclude that community-based dietary management of acute
childhood diarrhea using energy-dense, locally available foods is feasible and
may shorten diarrhea duration. This may encourage mothers to follow
recommendations for continued feeding during diarrhea in developing country
environments.
PMID- 9401506
TI - Failure to thrive: the earliest feature of cystic fibrosis in infants diagnosed
by neonatal screening.
AB - The benefits of early treatment of nutritional and respiratory problems in the CF
infant and of genetic counselling for the parents are widely recognized. However,
clinical diagnosis of CF is often delayed despite early onset of symptoms and the
usefulness of neonatal population screening as a preventive measure is still
under debate. This study analyses the clinical history of CF patients diagnosed
exclusively on the basis of positive neonatal screening tests with the aim of
identifying the earliest markers of the disease. We studied 103 CF infants born
in north-east Italy, diagnosed following neonatal screening: assay of
immunoreactive trypsin (IRT) from a heel-prick blood sample followed by a
measurement of meconium lactase in cases with raised IRT. Diagnosis was confirmed
by sweat test at an average age of 39 days. Eighty-one patients (79%) had
symptoms strongly suggestive of CF at diagnosis, and signs and/or symptoms of
pancreatic insufficiency were present in 16 of the remaining 22 cases. The most
frequent symptom was growth failure (69% of infants) and of these, 44% weighed
the same as at birth or less. Pancreatic insufficiency was confirmed by the low
level of faecal chymotrypsin found in 85% of cases. IRT was elevated in all
cases. CF had not been suspected in any symptomatic infant, although most of the
infants had been monitored by a paediatrician. In conclusion, most infants with
CF diagnosed by neonatal screening are already symptomatic in the first six weeks
of life and the most frequent symptom is failure to thrive; pancreatic
insufficiency was already present in most cases. In areas without CF neonatal
screening programs, the disease should be excluded by differential diagnosis in
all cases with growth failure notwithstanding adequate caloric intake in the
first months of life. The high sensitivity, low cost and simple execution of IRT
and fecal chymotrypsin tests make them an ideal first step in suspect cases
before proceeding to the sweat test, often performed late because of limited
availability.
PMID- 9401507
TI - Age governs gender-dependent islet cell autoreactivity and predicts the clinical
course in childhood IDDM.
AB - Most IDDM patients temporarily restore some of their beta-cell function following
the initiation of insulin therapy. The aim of this study was to analyse the
influence of age, gender, metabolic state at diagnosis and presence of
autoantibodies (GAD65 antibodies and ICA) on the duration of the clinical partial
remission. In total, 149 consecutively diagnosed IDDM children, 0-16 y old (70F,
79M, mean age 9.5 y) were studied. Partial remission was arbitrarily defined as
the period when the insulin dose was below 0.5 U/BW 24 h-1 and HbA1c below 7.5%,
and occurred in 119/149 patients with a duration between 1 and 38 months. Cox's
regression analysis showed that the factors significantly associated with the
duration of remission were age, gender, interaction between age and gender, ICA
and a high initial HbA1c, whereas GAD65Ab had no influence. Young boys had the
shortest remission period, while adolescent boys had the longest, as compared to
young and adolescent girls. The ICA-negative patients (n = 42) had a longer
remission period (median 9.7 months) than the ICA-positive children (n = 107; 5.0
months; p = 0.0001), regardless of GAD65Ab status. We speculate that the relative
insulin resistance, which is more pronounced in pubertal girls than in boys, may
be associated with a more rapid increase of exogenous insulin requirement. These
findings are important when evaluating the effect of islet cell autoreactivity on
the clinical course of IDDM in children.
PMID- 9401508
TI - Sub-clinical cerebral oedema does not occur regularly during treatment for
diabetic ketoacidosis.
AB - Fulminant cerebral oedema is an uncommon, fatal complication of diabetic
ketoacidosis (DKA) in children. This study aimed to find out whether the sub
clinical compression of the brain ventricles found by an earlier study, is a
general phenomenon during intravenous treatment for DKA. Four boys and four girls
were examined. Blood glucose values ranged from 40 to 24.6 mmol/l, base excess
34.6 to -13.6 and capillary blood pH 6.89-7.22. The patients received fluids
containing both glucose and electrolytes, and insulin intravenously. After about
10h, blood glucose was 8.7-21.8 mmol/l and base excess had decreased
substantially (-9.5 to -2.9) in seven of the eight cases. Computerized tomography
of the brain was then performed, and again after full recovery. Only two of the
patients had an initial decrease in intercaudate distance, which exceeded the
variability found in a reference group. Compression of the cerebral ventricles
does not occur regularly during treatment for DKA.
PMID- 9401509
TI - Loperamide test: a simple and highly specific screening test for hypercortisolism
in children and adolescents.
AB - The overnight dexamethasone (DXM) test can give false-positive results in a few
conditions (e.g. stress, strenuous exercise, depression, anorexia, anxiety,
anticonvulsive therapy) in diagnosing simple obesity and hypercortisolism (HC).
The loperamide (LP; a peripheral opioid agonist) test has proven useful in such
conditions in adults. Thirty-one obese subjects (age 10.0-19.7 y) were studied by
both overnight DXM test and LP test (8 mg orally, samples for cortisol at 0, 90,
150, 180 and 210 min) on 2 separate days. LP suppressed cortisol (< or = 138 nmol
l-1) at a dose of 0.1 mg kg-1 bw (half the minimum recommended dose for the
drug's antidiarrhoea effect) in 14 subjects who had normal urinary (< 4970 nmol l
1) and serum (< 552 nmol l-1) cortisol, in the absence of signs and symptoms of
HC (group A). The DXM test failed to suppress cortisol in three subjects in group
A, two of whom were on anticonvulsive treatment. The LP test suppressed cortisol
in all of 13 subjects with elevated urinary and/or serum cortisol and/or with
signs or symptoms of HC (but in whom HC was subsequently excluded on clinical
grounds) (group B), while the DXM test failed to suppress cortisol in three
subjects of this group. One of these was under anticonvulsive treatment and one
suffered from anxiety and depression. In four patients with Cushing's syndrome
(group C) neither DXM nor LP could suppress cortisol levels. Therefore, the
sensitivity was 100% for both DXM and LP, while the specificity was 84% for DXM
and 100% for LP. No side-effects were observed with either drug. In conclusion,
LP is a useful alternative to DXM in those particular conditions that can affect
its specificity in children.
PMID- 9401510
TI - Moisture and mould problems in schools and respiratory manifestations in
schoolchildren: clinical and skin test findings.
AB - OBJECTIVE: We performed a clinical study in 99 children attending schools with
moisture problems and compared the findings with those of 34 children from a
reference school. The aim of the study was to evaluate the possible association
between respiratory or allergic diseases in the pupils and moisture or mould
problems in the school buildings. RESULTS: Asthma was diagnosed in nine (6.7%)
children: eight of them came from the moisture-problem schools and all were over
10 y old. In addition, 17 non-asthmatic children had suffered from wheezing and
21 from long-term cough, both symptoms being suggestive of occult asthma. If
moisture problems were observed both at home and in the school, the frequency of
asthma was 21% and the combined frequency of asthma and wheezing was 43%. The
presence of allergic rhinoconjuntivitis or atopic dermatitis had no association
with moisture or mould problems. We performed skin-prick tests to 13 moulds in
all the 133 children. A positive reaction (> 3 mm) was observed in only six (5%)
of them. All six positive children reacted to at least one moisture-indicative
mould, Fusarium roseum, Aspergillus fumigatus, Phoma herbarum or Rhodotorula
rubra. None of these cases came from the reference school. There was a
significant association between positive reactions to moisture-indicative moulds
and asthma; four (44%) of the nine children with asthma had such reactions. In
addition, all the 6 reactive children had either asthma or wheezing. CONCLUSIONS:
We report preliminary evidence for an association between moisture or mould
problems in the school building and the presence of manifest and occult asthma in
the pupils. Our results show that skin-test positivity to moulds is rare in
children. However, reactivity to moisture-indicative moulds seems to be
associated with the occurrence of asthma or wheezing.
PMID- 9401511
TI - The development of atopic sensitization in Estonian infants.
AB - In a prospective study, 251 infants were followed from birth up to 12 months of
age, recording manifestations of allergy by questionnaires at 3, 6, 9 and 12
months and by clinical examinations at 6 and/or 12 months. Blood samples were
obtained at birth and at 6 and 12 months and analysed for serum IgE levels. The
children were skin-prick tested with foods at 6 and 12 months of age and with
inhalant allergens at 12 months. Blood samples from SPT-positive individuals and
controls were analysed for the presence of IgE antibodies to common inhalant
allergens and their cord sera for the presence of IgE antibodies to cow's milk
and egg. Twelve infants (7%) were sensitized against foods [3 to cow's milk (CM)
and 9 to egg white (EW)] at 6 months and 11 (5%) (2 to CM and 9 to EW) at 12
months. Seventeen infants (7%) had IgE antibodies against inhalant allergens at 6
and/or 12 months, as determined by either SPT and/or the demonstration of
circulating IgE antibodies. Out of 30 children with positive SPT and/or
circulating IgE antibodies against foods and inhalant allergens at any age, 6 had
atopic dermatitis, 4 gastrointestinal food allergy, 1 urticaria and 4 probable
allergy, while 15 had no clinical manifestation of allergy. Immunoglobulin E
antibodies against Ascaris were detected in 17% of the infants with S-IgE levels
> 20 kU/l. The study indicates that the incidence of sensitization and
manifestations of allergic disease is similar among Estonian and Scandinavian
infants during the first year of life. Given earlier findings indicating a
significantly higher prevalence of atopic disease in Scandinavian school-children
relative to their counterparts in Eastern Europe, the present study suggests that
the key events which determine disease expression do not occur exclusively during
the first year of life.
PMID- 9401512
TI - Usefulness of chest physiotherapy with positive expiratory pressure (PEP)-mask in
HIV-infected children with recurrent pulmonary infections.
AB - Eight children with human immunodeficiency virus (HIV) and recurrent bacterial
pulmonary infections were treated using a Positive Expiratory Pressure (PEP)-mask
twice a day for 12 months. At the end of the study, a reduction in the number of
pulmonary infections [mean (SD) 2.1 (0.9) vs 4.5 (1) p < 0.0001] and antibiotic
courses [mean (SD) 1.5 (0.7) vs 2.4 (0.9) p < 0.021] was noted. The PEP-mask is a
chest physiotherapy technique for removing infected secretions and optimizing
airway functions that is also useful in HIV-infected children.
PMID- 9401513
TI - Soluble receptors to tumour necrosis factor and interleukin-6 in urine during
acute pyelonephritis.
AB - We compared the urinary concentrations of soluble TNF-I (sTNF-RI), TNF-II
receptors, and soluble IL-6 receptor (sIL-6R) standardized to urinary creatinine
concentrations, in children with acute pyelonephritis, in children with non-renal
fever and in healthy controls. These levels were related to the acute
inflammatory response in the kidneys and later renal scarring, as determined by
acute and 1-y follow-up with 99mTC-dimercaptosuccinic acid scintigraphy (DMSA).
The concentrations of the soluble receptors were measured using enzyme
immunoassay (EIA). The urinary levels of sTNF-RI were significantly higher in
children with acute pyelonephritis (median 1320 pg/mmol) than in children with
non-renal fever, children 6 weeks after acute pyelonephritis and healthy controls
(873, 251 and 477 pg/mumol, respectively). Median sTNF-RII urine levels were also
higher in acute pyelonephritis (4123 pg/mumol) than in the three control groups
(2000, 964 and 1850 pg/mumol, respectively). In contrast, the highest urinary sIL
6R concentrations were found in healthy children (median 420 pg/mumol), compared
to those with acute pyelonephritis (235 pg/mumol), children with non-renal fever
and children 6 weeks after pyelonephritis (137 and 50 pg/mumol, respectively). No
significant difference was found in any of the urinary soluble receptor levels in
children with or without DMSA uptake defects at the acute or the 1-y follow-up
scintigraphy. In conclusion, although the urinary soluble TNF receptor levels
were higher during acute pyelonephritis, this observation was not useful for
deciding which children needed follow-up after acute pyelonephritis.
PMID- 9401514
TI - Cholesterol and carotid artery wall in children and adolescents with familial
hypercholesterolaemia: a controlled study by ultrasound.
AB - The carotid artery wall was studied with ultrasound in 23 children and
adolescents with familial hypercholesterolaemia and in 23 age-matched healthy
controls. The study revealed changes in the carotid artery wall related both to
familial hypercholesterolaemia and to age. In the control subjects, the carotid
artery wall became stiffer with age. In the patients with hypercholesterolaemia,
no clear age-dependence was found, but wall stiffness correlated with total and
low-density lipoprotein cholesterol. The intimal-medial wall thickness was
associated with serum total cholesterol, low-density lipoprotein and triglyceride
concentrations, and correlated inversely with the ratio of high-density
lipoprotein to total cholesterol. Carotid artery wall properties seem to be
associated with the degree of hypercholesterolaemia and the high-density
lipoprotein-to-total cholesterol ratio even in children. In childhood and
adolescence it is already possible, with ultrasound, to detect changes in the
arterial wall related both to familial hypercholesterolaemia and to age.
PMID- 9401515
TI - Sequelae of recurrent acute otitis media. Ten-year follow-up of a prospectively
studied cohort of children.
AB - In a cohort of 113 children prospectively followed from birth to the age of 3,
two subgroups were discerned: one with recurrent acute otitis media (rAOM), the
other subgroup with no AOM at all ("healthy" children). At further follow-up at
the age of 10, no child had AOM or secretory otitis media (SOM), but between 3
and 7 y of age the rAOM subgroup was characterized by a significantly higher
incidence of AOM as well as protracted secretory otitis media (SOM) episodes than
was the "healthy" subgroup. The two subgroups did not differ significantly in
hearing-thresholds at pure tone audiometry. After the age of 7, the incidence of
AOM was the same in both groups. It is concluded that children with frequent AOM
episodes before the age of 3 need long-term follow-up to school age, but seem not
be predisposed to chronic SOM.
PMID- 9401516
TI - Perinatally acquired brachial plexus palsy--a persisting challenge.
AB - The aim of this investigation was to study the contemporary pattern of
perinatally acquired brachial plexus palsy (BPP) in Sweden. National incidence
data were collected from the Swedish Medical Birth Registry. The clinical pattern
of BPP was studied in the county of Skaraborg. All children (n = 52) with
confirmed neonatal BPP in 1981-89 were assessed 4-14 y after birth using routine
neonatal and follow-up documentation for retrospective analysis and an assessment
battery for the clinical evaluation of impairment. The mothers' recollection of
the birth process was recorded by interview and compared with two control groups.
The incidence of BPP in Sweden increased significantly from 1.4 per mill in 1980
to 2.3 per mill in 1994. The incidence was 45 times higher at a birthweight of >
4500 g than at a birthweight of < 3500 g. Fifty percent had a birthweight
exceeding the mean +2 SD. In the Skaraborg series, half the children had
normalized arm-hand function after 6 months (mean) and half had stationary
impairment from 15 months (mean). Twenty-two percent of the children had severe
stationary impairment of arm-hand function according to the criteria. There was
no correlation between birthweight and the level of impairment. One-third of the
newborn infants with BPP had neonatal care related to the difficult birth process
and perinatal distress. The mothers of the children recalled the birth process as
being difficult or very difficult in 77% compared with 20 and 27%, respectively,
in the two control groups. This population-based investigation has revealed an
unexpected increase in BPP in Sweden and has confirmed that BPP continues to be a
significant cause of motor handicap in children.
PMID- 9401517
TI - First-trimester invasive procedures and congenital abnormalities.
AB - A prospective study was undertaken to determine whether first-trimester
amniocentesis or chorion villus sampling was associated with an increased
incidence of congenital anomalies. The infants of mothers who had undergone first
trimester amniocentesis (EA) (n = 352), chorion villus sampling (CVS) (n = 348)
or no invasive antenatal procedure (controls) (n = 264) were examined at a median
age of 5 months. Both the EA and CVS groups had a higher proportion of infants
with congenital anomalies (n = 18 and n = 22, respectively) than the control
group (n = 4) (p < 0.01). Certain of the abnormalities, however, affected only
single infants. Compression abnormalities were more common in the EA group than
in the controls (p < 0.05), but not in the CVS group. The isolated limb
abnormalities which occurred were minor anomalies affecting the digits and were
seen in both the CVS (n = 6) and EA (n = 3) groups. First-trimester invasive
procedures are thus associated with an excess of congenital anomalies.
PMID- 9401518
TI - Is smoking in pregnancy interrelated between generations?
AB - In order to compare pregnancy smoking habits in two generations, data on first
generation deliveries in 1964-67 were obtained from prospective questionnaires.
By record linkage with the Swedish Medical Birth Registry, data on daughters
giving second generation births (n = 1659) were obtained, including prospective
smoking information. The catchment area was that of Helsingborg County Hospital
(population 145,000). Second generation births until December 31, 1993 were
identified in all of Sweden. The odds ratio of maternal smoking in the first
generation for pregnancy smoking among the daughters was significantly increased
and approximately doubled. Adjustment for confounders was made using the Mantel
Haenszel method. Similar odds ratios remained after stratification either for a
social environment index of the first generation or the educational level of the
second generation. Thus, our data suggest a biological association between
pregnancy smoking habits over generations. Research on causative mechanisms could
help design more efficient intervention programs. In a separate analysis of two
parturient cohorts in Helsingborg 30 y apart, we found that the prevalence of
maternal smoking had decreased comparatively more among younger than older women.
PMID- 9401519
TI - Endogenous nitric oxide in the upper airways of premature and term infants.
AB - Concentrations of endogenous nitric oxide (NO) were measured in premature (n =
18) and term infants (n = 7). Nasal gas was aspirated continuously and after
timed occlusions, 15 s and 60 s, by a fast-response chemiluminescence analyser.
The sampling flow rate was 20 ml min-1. Typical NO recordings consisted of
plateaux and postocclusive peaks. In term infants peak NO concentrations (60 s
occlusion) were 2.71 +/- 0.44 parts per million (ppm) within 10 min after birth,
increasing (p < 0.05) to 3.81 +/- 0.25 ppm at 4-7 d postnatally. Peak NO values
(15 s occlusion) averaged 1.22 +/- 0.16 ppm in premature infants
(postconceptional age 25-37 weeks, body weight 623-2844 g) and the NO
concentrations increased significantly with postconceptional age (p < 0.05).
Nasal excretion rate, estimated from plateau NO concentrations and sampling flow
rate, was 0.10 +/- 0.01 nmol min-1 kg-1 in both groups. We conclude that
premature and term newborn infants excrete considerable amounts of NO in the
upper airways, with hitherto not fully known functions.
PMID- 9401520
TI - Maturation of hepatosomal mono-oxygenation and glucuronidation activities in pre-
and full-term infants as studied using the [15N]methacetin urine test.
AB - The non-distressing [15N]methacetin liver function test was modified and applied
to newborn healthy infants in order to measure both the total [15N]methacetin
metabolites excreted in the urine (total elimination capacity) and the proportion
of glucuronated metabolite. By studying pre- and full-term normotrophic neonates
3-168 days old, the age-dependent maturation of the two developing liver function
processes can be compared on the basis of either postnatal or postmenstrual age.
When solely considering postnatal age, no significant differences between the pre
and full-term infants were observed in the development of the total elimination
capacity. However, when postmenstrual age was considered, it became apparent that
this development starts earlier in pre-term infants and continues at the same
rate as their full-term counterparts, up to the postmenstrual age of
approximately 280 days. This increase subsequently diminishes in the pre-terms.
In the same study group, the proportion of glucuronidation, another indicator of
the hepatic detoxification system, appears to develop at a lower rate in pre-term
than in full-term infants. When postmenstrual age is taken into consideration,
glucuronidation development is also observed to begin earlier in pre-term infants
and the slower maturation is more pronounced. Although these results are not
generally applicable, they contribute to a better interpretation of the
[15N]methacetin liver function test--for instance when estimating effects due to
environmental exposure or accurately calculating age-related drug dosage for
neonates.
PMID- 9401521
TI - Effects of volume expansion on cardiac output in the preterm infant.
AB - Clinical and echocardiographic haemodynamic evaluations of response to volume
expansion are described in 12 preterm neonates aged < 7 days presenting without
cardiac dysfunction and with a low cardiac output. They received 10% albumin
solution (20 ml kg-1) for 3 h. Measurements were made before infusion, at volumes
5, 12.5 and 20 ml kg-1 and 1 h later. All infants increased significantly their
cardiac output (CO) (from a median of 177 to 283 ml kg-1 min-1). The rise of CO
decreased with the volume infused. The index of systemic vascular resistance (SVR
= ratio of mean arterial pressure to the CO) decreased for the six patients
without PDA (from 272 to 193 mmHg l-1 kg-1 min-1, p < 0.05) showing that the
hypovolaemic preterm infant is able to shut down peripherally in response to
hypovolaemia. The four hypotensive infants responded by increasing mean arterial
blood pressure (from 29 to 44 mmHg). Cutaneous refilling time decreased during
infusion (from 6.7 to 3.8 s. p < 0.01). One infant had an haemodynamically
significant ductus arteriosus revealed by volume expansion, another one developed
myocardial dysfunction.
PMID- 9401522
TI - Comparison of two methods of measurement of whole blood glucose in the neonatal
period.
AB - The purpose of this study was to compare the performance and accuracy of the
HemoCue B-Glucose photometer system and reagent strip tests used in conjunction
with reflectance photometry against a reference plasma glucose method. One
hundred consecutive babies admitted to the neonatal unit over a 6-month period
were enrolled in the study. Each baby had a heelprick capillary glucose measured
by HemoCue and reagent strip tests. At the same time venous plasma glucose and
haematocrit were measured. The mean difference between the reagent strip test and
plasma glucose was significantly less than the corresponding value for the
HemoCue (0.015 +/- 1.41 vs 0.837 +/- 1.565 mmol l-1, mean +/- SD); however, the
agreement limits between both methods and plasma glucose were wide. No
significant effect of haematocrit was detected on either method. The HemoCue
photometer does not offer any advantage over the widely used reagent strip tests
in the neonatal period. However, the limits of agreement of both methods compared
with plasma glucose are too wide to be clinically acceptable in the neonatal
period.
PMID- 9401523
TI - Audit of neonatal intensive care transport--closing the loop.
AB - To audit the effectiveness of changes in transport arrangements, data on babies
ventilated during transfer into a neonatal unit were compared between two
periods. During the first period, August 1991-February 1993, an ad hoc transport
team operated. Transport practice was changed in 1993 by forming a nine-person
nursing transport team, improving training and upgrading monitoring. The second
audit period was January 1994-July 1995. The groups were not significantly
different for birthweight, gestation or levels of ventilation. Physiological
variables were assessed with a "transport score". Improved scores for temperature
and pH were achieved on completion of transfer in 1994-95 compared to 1991-93.
Stabilizing prior to transfer took longer in the 1994-95 period. No serious
deteriorations occurred in transit in the 1994-95 period, three in 1991-93. Audit
facilitates identification of problems in transport. Staff, education and
equipment changes were associated with improved audited outcomes.
PMID- 9401524
TI - The prevalence and associated factors of epilepsy in children in Calicut
District, Kerala, India.
AB - To determine the prevalence of epilepsy and its association with indices of
malnutrition, infection and perinatal complications in children in Calicut
District, Kerala, India, a door-to-door two-stage survey was conducted in two
local government districts. Among the random sample of 1172 children aged 8-12 y,
26 conformed to the definition of epilepsy giving a 5-y period prevalence of
22.2/1000. A history of perinatal complications, low BMI and recent physical
symptoms were independently associated with active epilepsy. The results suggest
epilepsy is highly prevalent in this population of children and that further
research is needed into its cause.
PMID- 9401525
TI - Oral desmopressin treatment of central diabetes insipidus in children.
AB - To assess the efficacy of treatment with oral desmopressin (DDAVP), 20 patients,
aged 5-20 y, with central diabetes insipidus were studied during 3 d of
hospitalization and for 3 months at the outpatient clinic. At baseline the median
rate of diuresis was 12.7 ml kg-1 h-1. Urinary output decreased significantly
under treatment with an increase in urinary osmolality, normalization of plasma
osmolality and absence of nocturia. Patients were discharged from hospital with a
median dose of 500 micrograms d-1 (100-1200 micrograms d-1). An adjustment in
dosage was necessary in seven patients during follow-up, resulting in a final
dose of 600 micrograms d-1. Body weight and DDAVP doses (r = 0.75, p = 0.001) and
body surface and DDAVP doses (r = 0.72, p < 0.001) were significantly correlated.
The average dosage was 474 +/- 222 micrograms m-2 d-1 (mean +/- SD). The oral
DDAVP treatment remained effective during the 3 months of follow-up. This therapy
offers an alternative for the treatment of central diabetes insipidus in
children.
PMID- 9401526
TI - Severe skin loss after meningococcal septicaemia: complications in treatment.
AB - Meningococcal septicaemia can lead to purpura fulminans with subsequent full
thickness skin loss and deep muscle damage. The case reports on two infants who
recovered from such a severe episode are used to describe post-septicaemic
procedures and complications encountered in nursing care, psychological support
and rehabilitation, with the main focus on surgery. Skin grafting is complicated
by contaminated and contracting wound areas. Extensive tissue necrosis required
leg amputations. Cultured keratinocytes in one of the patients were found to be
too vulnerable. It has still to be proven whether more radical early-stage
fasciotomies can limit skin and muscle necrosis. Patients with meningococcal
septicaemia are subject to a high number of complications that are optimally
treated in a burns unit. These patients require up-to-date knowledge of
constantly evolving treatment possibilities and a high-level collaboration of all
medical fields involved.
PMID- 9401527
TI - Systemic candidiasis with acute Epstein-Barr virus infection.
AB - Systemic Candida infections are usually encountered as opportunistic infections
in a setting of immunologic depression. Sepsis or arthritis due to Candida is not
expected in healthy people. Epstein-Barr virus may infect B cells, but does not
cause immunosuppression of any clinical significance. As far as we know, invasive
non-albicans Candida infection complicating Epstein-Barr virus infection has not
been reported in previously healthy children. In this report, two previously
healthy children, one with sepsis due to Candida species and the other sepsis and
arthritis due to Candida parapsilosis are described. Both patients were male and
were aged 2 and 9 y. The diagnosis was confirmed by culture. Both children also
had coincidental acute Epstein-Barr virus infection, confirmed by Epstein-Barr
virus viral capside antigen-IgM. They were both cured with fluconazole given for
21 days and 48 days, respectively.
PMID- 9401528
TI - Multicore myopathy with restrictive cardiomyopathy.
AB - A 10-y-old girl is presented who suffered mild muscular weakness and exercise
intolerance from the age of 1 y onwards, with progression appearing from the age
of about 8 y. Multicore myopathy and restrictive cardiomyopathy were diagnosed.
Literature concerning the coexistence of multicore myopathy and cardiomyopathy is
reviewed.
PMID- 9401529
TI - Body surface and airway triggered ventilation in extremely premature infants.
PMID- 9401530
TI - Feeding difficulties in children with cerebral palsy II.
PMID- 9401531
TI - New growth hormone assays: potential benefits.
AB - Three recently published new assays are described for the measurement of growth
hormone (GH). Two of these--the eluted stain assay (ESTA) and the
immunofunctional assay (IFA)--have been developed to measure the bioactivity of
GH, rather than the immunoactivity as measured by conventional radioimmunoassays
(RIAs). The third assay--the 22 kDa exclusion assay (22 k GHEA)--is designed to
measure the concentrations of the different isoforms of GH present in the
circulation. The ESTA is a variant of the Nb2 bioassay for lactogenic hormones,
but has been adapted for specific GH measurement in serum samples. It has a lower
detection limit than previous bioassays and permits the quantification of GH in
large series of samples. The IFA uses a binding-site-specific antibody in
combination with GH-binding protein (GHBP) in order to quantify only those GH
molecules that are able to dimerize the extracellular domain of the GH receptor
(GHBP), which is a prerequisite for GH signal transduction in target cells. The
IFA is as convenient to use as immunoassays and can be employed routinely for GH
determinations. The clinical usefulness of the 22 k GHEA has not been
established, but it should provide a means of augmenting our understanding of the
regulation of GH and its various isoforms. Once the ESTA bioassay or the IFA
become commercially and widely available, either could replace the RIA as the
standard reference method for measuring GH, as both more closely reflect the
biologically active proportion of GH in serum samples than that measured by RIA.
PMID- 9401532
TI - Neuropharmacological assessment of growth hormone secretion.
AB - The biochemical diagnosis of individuals who are either deficient in growth
hormone (GH) or who have alterations in the normal pattern of GH secretion is
difficult. The uncertainty surrounding diagnosis reflects the lack of a thorough
understanding of the physiology of GH secretion and of the hypothalamic hormones
involved. At least three hormones are implicated: GH-releasing hormone (GHRH),
somatostatin and the endogenous ligand of the GH secretagogue receptor, although
the role that each plays in the release of GH is not clear from the available
experimental evidence. In such a situation, most of the dynamic tests of GH
secretory capacity in humans need to undergo a 'trial and error' process before
being validated. The search for the 'gold standard' test of GH secretion is
ongoing, and the combination of GHRH plus GH secretagogues will probably play an
important role in future clinical diagnosis.
PMID- 9401533
TI - An endocrinologist's approach to the growth hormone--insulin-like growth factor
axis.
AB - Gene knockout studies in mice, and a recent case report, have demonstrated that
insulin-like growth factors (IGFs) are major mediators of pre- and postnatal
growth, whereas the growth-promoting role of growth hormone (GH) appears to be
confined largely to the postnatal period. The IGF axis is now known to consist of
the growth factors themselves and at least seven, and probably ten, IGF-binding
proteins. These act either by regulating the availability of IGFs to their
receptors, or directly on their target cells. Because of the difficulties
associated with GH provocative testing, the central role of IGFs in pre- and
postnatal growth, and the ease of assaying the various components of the IGF
axis, it is suggested that the differential diagnosis of short stature should be
based on the concept of IGF deficiency rather than on GH secretory status.
PMID- 9401534
TI - Secular changes in growth and maturation: an update.
AB - Secular changes in growth and maturation in recent decades have been reviewed for
various populations. The secular increase in attained height during the growth
period is continuing in most countries, but has slowed down. The increase in
adult stature over the past decades has varied between 0.3 and 3.0 cm/decade. The
secular trend in the tempo of growth (earlier menarche and peak height velocity,
and shortening of the growth cycle) has come to a halt in some populations, but
is continuing or has been reversed in others. The secular trend in attained
height and in the tempo of growth is usually more pronounced in children from low
socioeconomic backgrounds, in those with poorly educated parents or in those from
rural areas. It is concluded that updates of growth standards are required in all
populations. More marked secular changes appear to occur in the lower height
centiles, which may have direct implications on the future definition of 'short
stature' in a population.
PMID- 9401536
TI - The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation
in the GH-releasing hormone receptor gene.
AB - We report the discovery of a cluster of severe familial dwarfism in two villages
in the Province of Sindh in Pakistan. Dwarfism is proportionate and occurs in
members of a kindred with a high degree of consanguinity. Only the last
generation is affected, with the oldest dwarf being 28 years old. The mode of
inheritance is autosomal recessive. Phenotype analysis and endocrine testing
revealed isolated growth hormone deficiency (GHD) as the reason for growth
failure. Linkage analysis for the loci of several candidate genes yielded a high
lod score for the growth hormone-releasing hormone receptor (GHRH-R) locus on
chromosome 7. Amplification and sequencing of the GHRH-R gene in affected
subjects demonstrated an amber nonsense mutation (GAG-->TAG; Glu50-->Stop) in
exon 3. The mutation, in its homozygous form, segregated 100% with the dwarf
phenotype. It predicts a truncation of the GHRH-R in its extracellular domain,
which is likely to result in a severely disabled or non-existent receptor
protein. Subjects who are heterozygous for the mutation show mild biochemical
abnormalities in the growth hormone-releasing hormone (GHRH)--growth hormone-
insulin-like growth factor axis, but have only minimal or no growth retardation.
The occurrence of an offspring of two dwarfed parents indicates that the GHRH-R
is not necessary for fertility in either sex. We conclude that Sindh dwarfism is
caused by an inactivating mutation in the GHRH-R gene, resulting in the inability
to transmit a GHRH signal and consequent severe isolated GHD.
PMID- 9401535
TI - Genes regulating hypothalamic and pituitary development.
AB - Several pituitary transcription factors have been identified in the last 3 years.
They offer new insights into the processes that direct organogenesis, cell
commitment, proliferation and differentiated function. All are DNA-binding
proteins, but they have ties to different families of homeodomain proteins. They
differ in their distribution and in the timing of their appearance and
extinction. The Rathke's pouch homeobox protein (Rpx) has a paired-like
homeodomain. In mice, it appears on embryonic day 8.5 (day e8.5) and is gone by
day e14.5. Its targets for activation are unknown. Pituitary OTX has a tryptophan
-phenylalanine--lysine motif in its homeodomain. It appears early and persists.
It shows independent activation of the alpha-glycoprotein subunit (alpha-GSU) and
pro-opiomelanocortin genes and co-operates with Pit-1 in activation of the growth
hormone and prolactin genes. Pituitary Lim (P-Lim) protein also acts
independently on the alpha-GSU gene, and acts in concert with Pit-1 to activate
other genes. A fourth protein, termed the 'Prophet of Pit-1', or Prop-1, is the
recently discovered cause of Ames dwarfism in mice. This paired-like protein is
necessary for the subsequent expression of Pit-1 in somatotrophs, lactotrophs and
thyrotrophs. Any or all of the newly discovered pituitary genes are candidates
for mutations causing hypopituitarism in humans. As several are expressed
transiently in tissues other than the pituitary during organogenesis, the
phenotypes produced by mutations in these genes may prove to be complex.
PMID- 9401537
TI - Insulin-like growth factor I gene deletion causing intrauterine growth
retardation and severe short stature.
AB - The first human case of a homozygous molecular defect in the gene encoding
insulin-like growth factor I (IGF-I) is described. The patient was a 15-year-old
boy from a consanguineous pedigree who presented with severe intrauterine growth
failure, sensorineural deafness and mild mental retardation. Endocrine evaluation
of the growth hormone (GH)--IGF-I axis revealed elevated GH secretion,
undetectable serum IGF-I and normal serum IGF-binding protein-3, acid-labile
subunit, and GH-binding activity. Analysis of the IGF-I gene revealed a
homozygous partial IGF-I gene deletion involving exons 4 and 5, which encodes a
severely truncated mature IGF-I peptide. This patient demonstrates that complete
disruption of the IGF-I gene in man is compatible with life, and indicates a
major role for IGF-I in human fetal growth. In addition, his neurological
abnormalities suggest that IGF-I may be involved in central nervous system
development.
PMID- 9401538
TI - A molecular approach to sex determination in mammals.
AB - Mammalian sex determination occurs in the gonad of the developing embryo. This
process is dependent on the Y-chromosome-encoded Sry gene that acts in the
somatic cells of the genital ridge. The transient nature of Sry gene expression
suggests that it acts as a switch from one cell fate to another. One of the roles
of Sry is to initiate the differentiation of Sertoli cells, which are the first
cell type of the testis to be formed. Two genes are thought to be important in
Sertoli cell differentiation and function, Sox9, an Sry-related gene, and SF-1, a
nuclear hormone receptor. Sox9 is expressed in Sertoli cells throughout
development of the mouse embryo, and inactivating mutations in this gene in
humans give rise to XY females. SF-1 is also expressed in Sertoli cells and is
thought to activate the AMH gene--an early marker of these cells. DAX-1, an X
linked member of the nuclear hormone superfamily, is a candidate for a human
condition in which duplication of regions of the X chromosome results in XY
females. Expression of this gene during mouse development is associated with
ovary development and is down-regulated in the differentiating testis. Mutations
in DAX-1 in humans have shown that this gene is not necessary for testis
development. The properties of the DAX-1 gene suggest that it is important in
ovary determination and might therefore be antagonistic to the action of the Sry
gene.
PMID- 9401539
TI - Prader-Willi syndrome and the hypothalamus.
AB - Dysfunction of various hypothalamic systems may be the basis of a number of
symptoms in Prader-Willi syndrome. The often abnormal position of the baby in the
uterus at the onset of labour, the high percentage of infants with asphyxia and
the high proportion of children born prematurely or post-maturely may all be
related to abnormal fetal hypothalamic systems, as the fetal hypothalamus plays a
crucial role in labour. Abnormal luteinizing hormone-releasing hormone neurones
are thought to be responsible for the decreased levels of sex hormones, resulting
in non-descended testes, undersized sex organs and insufficient growth during
puberty. A lack of growth hormone-releasing hormone may also contribute to the
short stature of patients with Prader-Willi syndrome. In addition, the aberrant
control of body temperature and daytime hypersomnolence may result from
hypothalamic disturbances. The number of oxytocin neurones--the putative satiety
neurones--in the hypothalamic paraventricular nucleus is markedly decreased in
Prader-Willi syndrome. This is presumed to be the basis of the insatiable hunger
and obesity of patients with the syndrome.
PMID- 9401540
TI - The genetic basis for Prader-Willi syndrome: the importance of imprinted genes.
AB - The genetic basis of Prader-Willi syndrome involves imprinted genes on the
proximal long arm of chromosome 15. The basic defect appears to be the absence of
function of genes that are normally expressed in a monoallelic fashion only from
the paternal chromosome. In 60-70% of patients with Prader-Willi syndrome, the
genetic defect is a deletion in the area of 15q11-13 on the paternal chromosome.
A further 25-30% of patients with Prader-Willi syndrome do not have paternal
deletions, the defect being due to uniparental disomy (UPD) for maternal
chromosome 15. Paternal deletions and maternal UPD are functionally equivalent,
as they both result in the absence of a paternal contribution to the genome in
the 15q11-13 region. The SNRPN (small nuclear ribonucleoprotein-associated
polypeptide N) gene has a critical role in the 15q11-13 region, as it is probably
part of the putative imprinting centre that regulates the expression of several
genes in the Prader-Willi syndrome transcriptional domain. Two further rare
causes of Prader-Willi syndrome are imprinting mutations, which are
microdeletions or point mutations in the putative imprinting control region, and
translocations with their breakpoints in the Prader-Willi syndrome region.
PMID- 9401541
TI - Hypogonadism and endocrine metabolic disorders in Prader-Willi syndrome.
AB - Disturbances of the hypothalamic-pituitary-gonadal axis are reviewed in patients
with Prader-Willi syndrome, and a brief account is given of thyroid function,
adrenal function and glucose metabolism in such patients. Cryptorchidism,
hypoplastic external genitalia and delayed or incomplete pubertal development in
most patients with Prader-Willi syndrome suggest dysfunction of the hypothalamic
pituitary-gonadal axis. Decreased levels of gonadotrophins, consistent with
hypogonadotrophic hypogonadism, have been found in some patients, whereas others
appear to have hypergonadotrophic hypogonadism secondary to cryptorchidism and
its treatment. Gonadal function is normal in a small number of patients with the
syndrome. Although most clinicians agree that cryptorchidism should be corrected
in early childhood, in practice the surgery is often not performed. In addition,
most patients do not receive sex hormone replacement therapy. It is therefore
suggested that more aggressive endocrine treatment strategies for hypogonadism
are warranted in both children and adults with Prader-Willi syndrome. Both
thyroid function and adrenal function appear to be normal in most patients, and
glucose metabolism is similar to that in normal obese individuals.
PMID- 9401542
TI - Effects of growth hormone treatment on growth and body composition in Prader
Willi syndrome: a preliminary report. The Swedish National Growth Hormone
Advisory Group.
AB - A controlled, randomized study was conducted to assess the effect of growth
hormone (GH) treatment on growth, body composition and behaviour in prepubertal
children (3-12 years of age) with Prader-Willi syndrome. GH treatment was given
to one group of 15 patients (group A) at a dose of 0.1 IU/kg/day for 2 years. The
second group (group B; n = 12) was not treated for the first year and was then
given GH at a dose of 0.2 IU/kg/day for the second year. All patients had low 24
hour levels of GH and insulin-like growth factor I before GH treatment. Height
velocity SDS increased from -1.9 +/- 2.0 to 6.0 +/- 3.2 during the first year of
GH treatment in group A, and from -1.4 +/- 1.2 to 10.1 +/- 3.9 in the second year
of the study in group B. When GH treatment was stopped, height velocity declined
dramatically. Height SDS followed a similar pattern. GH treatment reduced the
percentage body fat and increased the muscle area of the thigh. Isometric muscle
strength was also increased. In addition, GH treatment appeared to have
psychological and behavioural benefits, which were reversed after cessation of
treatment. It was concluded that GH treatment improves growth, body composition
and behaviour in children with Prader-Willi syndrome.
PMID- 9401543
TI - Effect of 6 months of growth hormone treatment in young children with Prader
Willi syndrome.
AB - Nine prepubertal children with Prader-Willi syndrome were treated with growth
hormone (GH; 24 IU/m2/week) for 6 months. Mean height increased by 0.8 SD and
mean weight for height decreased by 0.7 SD over this 6-month treatment period.
Body fat, measured by dual-energy X-ray absorptiometry, decreased by 22.5% over
the period of GH treatment, whereas fat-free mass increased by 14%. These
preliminary results indicate that GH is effective in increasing height and
normalizing body composition in patients with Prader-Willi syndrome.
PMID- 9401544
TI - Growth hormone, insulin-like growth factor and the immune system.
PMID- 9401546
TI - Effects of growth hormone and insulin-like growth factor I on T- and B
lymphocytes and immune function.
AB - The concept of a neuro-endocrine-immune axis was proposed more than 50 years ago.
Growth hormone (GH), a central component of this axis has many functions at both
a molecular and cellular level, including thymocyte proliferation, stimulation of
the cytotoxic activity of natural killer cells and induction of lymphocyte
proliferation. Binding of GH to its receptors on lymphocytes stimulates the
production of insulin-like growth factor I (IGF-I), which mediates the effects of
GH on cell proliferation. Other effects of GH on the immune system appear to be
direct, such as priming monocytes for enhanced production of hydrogen peroxide in
response to phorbol esters, and stimulating neutrophils to secrete superoxide
anions associated with enhanced phagocytic activity. Many of the effects of GH
are shared by IGF-I. Despite these observations, and the fact that GH is produced
and secreted in immunological tissues such as the thymus and spleen, immune
deficiency is not characteristic of GH deficiency in humans. The question remains
as to whether GH and IGF-I could be used as immunotherapy. Currently, both agents
have been used in adults to diminish wasting due to acquired immunodeficiency
syndrome, and GH has been shown to stimulate CD8+ cell counts. However, they had
little impact on CD4+ cell counts, which may be due to IGF-I and GH resistance in
these individuals. The use of GH and IGF-I as immunotherapies merits further
study.
PMID- 9401545
TI - Pituitary hormones and immune function.
AB - The pituitary gland plays a key role in the regulation of growth, differentiation
and function of all cells in the body, including immunocytes. Immune reactions
are generated through the proliferation of antigen-specific lymphocyte clones.
Growth hormone and prolactin are required for the development of mature
lymphocytes and for the maintenance of immunocompetence. These hormones enable
lymphocytes to respond to antigen, which is delivered as an adherence signal in
the context of major histocompatibility surface molecules of antigen-presenting
cells. Numerous other adhesion molecules play a role in the regulation of
lymphocyte activation. The activation process is completed by cytokine
signalling, after which lymphocyte proliferation, differentiation and functional
maturation take place. Interleukins, hormones and growth factors may all function
as cytokines. Many lymphocytes exist in the body in a quiescent state, with
minimal metabolic activities. These cells are maintained by competence hormones
and insulin-like growth factor 1, which are present in the systemic and local
environment. Apparently, some steroid hormones, opioid peptides and
catecholamines are capable of modulating delivery of the signal from the
lymphocyte membrane receptor to the nucleus. Steroid and thyroid hormones control
nuclear transcription factors as their receptors, and thus are powerful
regulators of lymphocyte signalling at the nuclear level. The bioactive forms of
thyroid hormone and of several steroid hormones are generated locally by
immunocytes. These important hormonal immunoregulators function both at systemic
and local levels. Glucocorticoids are major regulators of cytokine production,
and alpha-melanocyte-stimulating hormone functions as a powerful cytokine
antagonist. The hormones secreted or regulated by the pituitary gland therefore
regulate every level of immune activity, including the competence of lymphocytes
to respond to immune/inflammatory stimuli, signal transduction, gene activation,
the production and activity of cytokines and other immune effector functions.
PMID- 9401547
TI - Effects of growth hormone and insulin-like growth factor I binding to natural
killer cells.
AB - Human growth hormone (GH) and insulin-like growth factor I (IGF-I) are known to
bind to, and exert modulatory effects on, different immunocompetent cells,
including CD16+/CD3- natural killer (NK) cells. NK cells are involved in various
non-major-histocompatibility-complex-restricted actions of the immune system.
Although no clinically significant defect in tumour or virus defence has been
reported in GH-deficient patients, the data available indicate decreased NK cell
activity in these patients. In most studies, the absolute number and percentage
of NK cells have been found to be normal. Substitution with GH has been reported
to normalize the decreased NK cell activity in GH-deficient patients. In a cross
sectional study in GH-deficient adults, decreased basal and interferon-beta (IFN
beta)-stimulated NK cell activity in vitro. Preliminary data on GH binding to NK
cells indicate enhanced binding in GH-deficient patients when compared with
normal controls.
PMID- 9401548
TI - Role of B-cells in growth hormone-immune interactions.
AB - Cells demonstrating cell surface markers for B-cells tend to be normal in growth
hormone (GH)-deficient children. Treatment with pituitary-derived or recombinant
human GH, however, produces a significant, albeit transient, decrease in the
number of these cells both in vitro and in vivo. Receptors for GH have been
detected on numerous cells of the immune system, notably B-cells and monocytes.
Recent studies have shown that cells of the immune system are able to produce
peptide hormones, such as GH, and studies in the rat (which have yet to be
confirmed in humans) suggest that the B-cell is the cell type most involved in
this production. These findings suggest that the B-cell has a significant role in
the bi-directional communication network between the endocrine and immune
systems.
PMID- 9401549
TI - Effects of growth hormone on natural killer cells.
PMID- 9401550
TI - The development of 'impervious peptides' as growth hormone secretagogues.
AB - The discovery and development of growth hormone (GH) secretagogues is briefly
reviewed. GH-releasing peptide-6 (GHRP-6) was the first GHRP to be developed that
was active in vivo. Smaller peptides were found to have no GH-releasing activity
in vivo, even though they were potent releasers of GH in vitro. Substituting Trp
with 2-Me-Trp led to the development of orally active hexarelin and other,
smaller, peptides. Although they showed oral activity, absorption rarely exceeded
1% of the administered dose. Nonpeptide GH secretagogues have now been developed
that combine reasonable oral absorption with high potency. The next development
will be to produce GH secretagogues that overcome the lack of specificity shown
by the present molecules.
PMID- 9401551
TI - Hypothalamic targets for growth hormone secretagogues.
AB - Various novel growth hormone (GH) secretagogues have been developed. GH
secretagogues release GH directly from the pituitary via a pathway distinct from
that involving GH-releasing hormone (GHRH). However, they also act centrally to
activate hypothalamic neurones, and require an intact GHRH system for potent in
vivo activity. Both normal and transgenic growth-retarded (Tgr) rats release GH
in response to GH secretagogues, and their responses are sensitive to the pattern
of secretagogue administration. GH secretagogues are not completely specific for
GH release, but also activate the adrenocorticotrophin-adrenal axis, implying
that they have additional central actions. The recent cloning of an endogenous
receptor for GH secretagogues now makes it possible to identify central targets
for their action. An endogenous receptor implies the existence of an endogenous
ligand, but its site of production, relationship to the xenobiotic
pharmacological agents and its underlying physiological relevance remain unclear.
PMID- 9401552
TI - Age-related growth hormone-releasing activity of growth hormone secretagogues in
humans.
AB - Growth hormone-releasing peptides (GHRPs) are synthetic molecules with strong,
dose-related and reproducible growth hormone (GH)-releasing activity in humans.
GHRPs act at both the pituitary and the hypothalamic level, where specific
receptors have been located. In adults, GHRPs release more GH than does GH
releasing hormone (GHRP), whilst their co-administration has a synergistic
effect, indicating that they have, at least partially, different mechanisms of
action. However, normal activity of GHRH-secreting neurones is needed to achieve
the full GH-releasing effect of GHRPs. In contrast to GHRH, the GH-releasing
activity of GHRPs is not further increased by substances acting via inhibition of
hypothalamic somatostatin, and is only blunted by substances that stimulate
hypothalamic somatostatin release. Even free fatty acids and exogenous
somatostatin, which act directly on somatotrophs, do no more than blunt the
effect of GHRPs. Thus, the GH-releasing activity of GHRPs is partially refractory
to inhibitory influences, GHRPs act, at least in part, by antagonism of
somatostatin activity, both at the pituitary and the hypothalamic level. The GH
releasing effect of GHRPs is not dependent on gender, but undergoes age-related
variations. Gonadal steroids seem to influence the activity of GHRPs only in
childhood. The reduced GH response to GHRPs in the elderly is probably due mainly
to concomitant GHRH hypoactivity and somatostatinergic hyperactivity. A preserved
GH-releasing effect of GHRPs has been reported in acromegaly, anorexia nervosa,
hyperthyroidism and in critically ill patients. GHRPs have also been found to
increase GH release in children with idiopathic short stature, in GH deficiency
and in obese patients, in whom there is a well-known reduction of somatotroph
function. The GH response to GHRPs is markedly reduced in hypothyroidism and
Cushing's syndrome.
PMID- 9401553
TI - Growth hormone secretagogues in pathological states: diagnostic implications.
AB - The identification and cloning of the receptor for synthetic growth hormone (GH)
secretagogues, even before the endogenous ligand has been identified or its
precise physiological role established, suggests that there is a novel target of
action for this class of drug. In an attempt to select patients who will benefit
from GH treatment, GH secretagogues are being evaluated for their usefulness in
diagnosing GH deficiency. The effects of GH-releasing peptides (GHRPs) on GH
release as a function of age and metabolic status, and in different
neuroendocrine pathologies, are described, as are the different mechanisms of
action, potency and reproducibility of the response to GHRPs compared with GH
releasing hormone (GHRH). GHRPs offer the advantage over GHRH in natural models
of deranged GH secretion in that, in various metabolic states (e.g. obesity,
anorexia nervosa and non-insulin-dependent diabetes mellitus), the GH response to
GHRH is more impaired than it is to GHRPs. However, in some neuroendocrine
pathologies, the reverse is true. Thus, both secretagogues provide separate
information on the physiological status of somatotrophs.
PMID- 9401554
TI - Growth hormone secretagogues in children with altered growth.
AB - A diagnostic test was devised to evaluate pituitary growth hormone (GH) secretory
potential. GH secretory dynamics were assessed in children with and without GH
deficiency. The GH response was measured to GH-releasing hormone (GHRH) and the
GH-releasing peptide GHRP-2, administered sequentially. The mean (+/- SEM) peak
GH response to GHRP-2 was 20.1 +/- 5.5, 63.6 +/- 24.9 and 42.2 +/- 4.3
micrograms/l for GH-deficient, slowly growing non-GH-deficient and control
children, respectively (p < 0.02 and p < 0.05 for GH-deficient vs controls and
slowly growing children, respectively). Corresponding values for area under the
curve (AUC) were 995 +/- 371. 2460 +/- 953 and 1598 +/- 274 micrograms/l x
minute. Peak GH (and AUC) responses to GHRH were 19.6 +/- 5.1 micrograms/l (924
+/- 232 micrograms/l x minute), 31.4 +/- 8.4 micrograms/l (1544 +/- 449
micrograms/l x minute) and 39.8 +/- 7.8 micrograms/l (2201 +/- 437 micrograms/l x
minute) for the same three groups, respectively (p < 0.05 for peak GH in GH
deficient patients vs controls, and p < 0.02 and p < 0.01 for AUC in GH-deficient
vs slowly growing children and controls, respectively). The ratio of the peak GH
response to GHRP-2 and GHRH was similar in all three groups. As these
secretagogues stimulate different aspects of hypothalamic function (i.e., they
are functional complements), robust GH secretion in response to GHRH or GHRP
could suggest adequate endogenous GHRP or GHRH, respectively. A poor response to
either GH secretagogue administered individually could represent inadequacy of
its endogenous complement. The integrity of functional pituitary elements could
be differentiated from inadequate complements by administering both GH
secretagogues simultaneously. Application of these principles should allow a
better definition of the underlying disorder and provide the basis for
therapeutic strategies for those patients with abnormal GH production and/or
secretion.
PMID- 9401555
TI - The biology of bone maturation and ageing.
AB - The only indicator of development that is available from birth to maturity is
skeletal age. This short review discusses how standard bone ages have been
developed from assessment of radiographs, and describes the advantages and
disadvantages of the 'atlas' approach as developed by Greulich and Pyle, and the
bone by bone approach, as developed by Tanner. As the standards currently
available are based mainly on historical series of radiographs from particular
populations, it is stressed that national standards should be established and
updated regularly if bone ages are to be used to assess development. The question
of the clinical relevance of using bone age assessments of the hand and wrist to
determine the state maturation of the whole skeleton and particularly, the growth
potential is also discussed. It is concluded that, despite the difficulties of
assessing bone age, and the assumptions on which the various methods are based,
determination of skeletal development is clinically relevant in that it provides
the only means of assessing rates of maturational change throughout the growing
period.
PMID- 9401556
TI - Variation of bone age progression in healthy children.
AB - Bone age assessments were related to auxological variables in 407 Italian boys,
between 7 and 12 years of age, in order to elucidate the factors that affect the
rate of skeletal maturation and to examine the possibility of using measures of
skeletal maturation of evaluate individual patients. Using the radius-ulna-short
bones (RUS) method of assessment, bone age velocity was greater in the Italian
boys than for the UK reference standards, although there was considerable
interindividual dispersion around the mean. Bone age velocity and height velocity
were poorly correlated, and there was little correlation between skeletal and
pubertal maturation. There was a slight positive correlation between bone age
velocity and height SDS and between bone age velocity and body mass index. Bone
age estimations using RUS were greater than those obtained using the carpus. In
conclusion, the marked interindividual deviation in measured bone ages makes it
difficult to relate data on an individual basis to other measures of growth and
maturation
PMID- 9401557
TI - Population-specific reference values for bone age.
AB - Contemporary reference values for assessing skeletal maturity have been obtained
for the Japanese population. These were used to compare skeletal maturation with
populations from the UK. Belgium, North India and South China. Japanese children
were found to attain skeletal maturity, based on measurements of the radius, ulna
and short bones of the left hand and wrist, 1 or 2 years earlier than present-day
European and Chinese children. A relative lack of data for the North Indian
population made comparison impossible.
PMID- 9401558
TI - Clinical usefulness of bone age determination in the management of tall stature.
AB - Measurements of skeletal maturation are used in the study and management of
growth and growth disorders because of the correlation between the degree of
skeletal maturation and the potential for further growth. In a study of 147 tall
girls, final height was overpredicted by 0.7 +/- 2.5 cm (mean +/- SD) when based
on the Bayley-Pinneau method. The radius-ulna-short bones (Tanner-Whitehouse 2)
mark II method of assessment produced an underprediction of final height by 0.8
+/- 2.9 cm and 1.0 +/- 2.8 cm when the rating was performed by a skilled human or
by a computer-aided system, respectively. These errors in prediction were
considered acceptable, although when predictions were made on five girls below 11
years of age, they were less accurate.
PMID- 9401559
TI - Diagnosis of severe growth hormone (GH) deficiency in young adults who received
GH replacement therapy during childhood.
AB - Between 20% and 87% of young adults who had completed growth hormone (GH) therapy
in childhood for a putative diagnosis of GH deficiency (GHD) had normal GH
responses to provocative tests when they were retested. Patients with isolated
idiopathic GHD were more likely to exhibit normal GH responses at retest in young
adult life than were patients with multiple pituitary hormone deficits. When
determining which patients should receive GH therapy in adult life, those who
have isolated GHD should undergo two tests of GH status, while those with
multiple anterior pituitary hormone deficits require only one test. Most
information is available for the insulin tolerance test, the arginine stimulation
test and the glucagon stimulation test, but more recent methods, such as GH
releasing hormone in combination with pyridostigmine, are showing promise in the
investigation of GHD. In young adults with childhood-onset GHD, the serum
concentration of insulin-like growth factor I is a useful marker of GH status,
and can be used in conjunction with a GH provocative test. The choice of GH
provocative test should ultimately depend on the experience and policy developed
at the centre performing the assessment. Whichever tests are chosen, each should
be validated in subjects known to have hypothalamic-pituitary disease as well as
in normal individuals.
PMID- 9401560
TI - Can we predict and prevent adult morbidity in males with childhood-onset growth
hormone deficiency?
AB - In order to achieve an optimal quality of life and minimize morbidity in
adulthood, the therapeutic management of patients with childhood-onset growth
hormone deficiency (GHD) should follow strict guidelines. Optimal final height
should be obtained by the early diagnosis of GHD and subsequent adequate growth
hormone (GH) dosing and duration of treatment. Moreover, particularly in males
with associated gonadotrophin deficiency, the psychosexual maladjustment could be
prevented by the earlier induction of puberty, completion of the male phenotype
and testicular stimulation with gonadotrophins or luteinizing hormone-releasing
hormone. Finally, a satisfactory peak bone mass could be attained by continuation
of GH treatment for some years after cessation of linear growth.
PMID- 9401561
TI - Conditions spanning paediatric and adult endocrine practice--the adult
perspective.
AB - Close liaison between paediatric and adult endocrinologists is essential for
optimum care in a variety of clinical conditions. The increasingly recognized
importance of growth hormone deficiency (GHD) in the adult is a further
indication for maintaining long-term follow-up of patients with isolated GHD,
which remains demonstrable when linear growth is complete, in addition to those
patients presenting in childhood with evidence of structural pituitary disease
and anterior pituitary failure. Additional areas in which liaison is desirable
include congenital adrenal hyperplasia, precocious puberty, gonadal dysgenesis
and other disorders of primary and secondary sexual development, thyroid
dysfunction, diabetes mellitus, inherited neoplasia syndromes and those
conditions, for example Cushing's syndrome, which present in childhood but are
more common in adult clinical endocrine practice. In this brief review, the
diagnostic spectrum of the paediatric/adult interface is described and the
rationale for an integrated approach to treatment and follow-up is outlined.
PMID- 9401562
TI - When and how to transfer patients from paediatric to adult endocrinologists:
experience from St Bartholomew's Hospital, London.
PMID- 9401563
TI - Endocrine and nutritional regulation of prenatal growth.
AB - Fetal growth in late gestation is primarily determined by the functional status
of the pathways by which nutrients are transferred from the maternal compartment,
across the placenta, and taken up by the fetal tissues. Both the maternal and
fetal endocrine systems can influence this pathway at several levels, including
regulation of placental metabolism. The primary fetal axis involved in the
regulation of fetal growth is the glucose-insulin-insulin-like growth factor I
axis.
PMID- 9401564
TI - Early influences on embryonic and placental growth.
AB - Growth of the placenta is influenced by events before and during early pregnancy.
Some of these events set the growth trajectory of the placenta and the fetus for
the remainder of the pregnancy. Maternal size and nutrition, and the local
metabolic, cytokine and hormonal environment of the embryo all affect growth of
the placenta.
PMID- 9401565
TI - Morphometry of fetal growth.
AB - Intrauterine growth retardation (IUGR) complicates about 5% of all pregnancies
and is responsible for substantial perinatal mortality and morbidity. With
ultrasound, it is possible to assess fetal brain growth indirectly by measurement
of the biparietal diameter, head circumference and transcerebellar diameter. As
liver size is affected most profoundly by IUGR, measurement of the abdominal
circumference of the fetus provides the earliest evidence of fetal growth
restriction. Placental size, assessed with ultrasound, can also indicate the
severity of the condition. Once a fetus is diagnosed as having IUGR, its well
being can be monitored with standard heart-rate testing and ultrasound assessment
of fetal behaviour. Doppler analysis of the wave form of the fetal arterial and
venous circulation hold the greatest promise for managing pregnancies complicated
by IUGR.
PMID- 9401566
TI - Pathophysiology of intrauterine growth retardation: role of the placenta.
AB - The placenta is essential for normal fetal development. Failure of the placenta
can result in many fetal conditions, for example, intrauterine growth retardation
(IUGR). Placentas from pregnancies complicated by IUGR show vascular damage,
which may lead to the onset of pregnancy-induced maternal hypertension. Accurate
placental assessment may, therefore, indicate which fetuses are at risk of IUGR
and so improve clinical evaluation and management of both the fetus and the
mother. Placental development and function can be assessed by a number of
methods, including measurement of placental weight at mid-gestation (placental
growth in the second trimester correlates strongly with placental weight at
birth), assessment of fetal and placental circulation (an association between
perinatal morbidity and abnormal blood velocity profiles has been established)
and assessment of placental metabolism and nutritional transfer (a reduction in
transfer of nutrients may be an early indicator of IUGR.
PMID- 9401567
TI - Aetiology, morphology and body composition of infants born small for gestational
age.
AB - Infants born small for gestational age (SGA) are a heterogeneous group. Both the
timing and duration of the intrauterine insult determine the physical condition
and body composition of the infant at birth. Infants with symmetrical
intrauterine growth retardation (IUGR) have a similar body composition at birth
to weight-matched infants born appropriate for gestational age. However, these
infants are more likely to remain shorter and lighter than normal infants. In
contrast, infants with asymmetrical IUGR have reduced fat deposition but are more
likely to exhibit catch-up growth during the first few months of life. The low
mortality and morbidity rates in infants born SGA observed in recent studies are
linked to their appropriate perinatal management, including adequate early
nutritional support.
PMID- 9401568
TI - Intrauterine programming of coronary heart disease and stroke.
AB - We have become accustomed to the idea that the major disorders of adult life,
including coronary heart disease, stroke and diabetes, arise from an interaction
between influences in our adult lifestyle and a genetically determined
susceptibility. Recent research, however, suggests that growth in utero may also
play an important role.
PMID- 9401569
TI - Metabolic consequences of intrauterine growth retardation.
AB - Epidemiological studies have revealed strong and reproducible links between
indices of poor fetal, and possibly infant, growth and susceptibility to the
development of glucose intolerance and insulin resistance syndrome in adult life.
The 'thrifty phenotype' hypothesis has been proposed to explain these
associations. Key features of the hypothesis are: (i) intrauterine growth
retardation has a nutritional basis and the resulting altered fetal environment
permanently alters the development and metabolic functions of organs: (ii) these
alterations are beneficial to survival in a poor nutritional environment, but may
lead to diseases such as non-insulin-dependent diabetes mellitus if nutrition is
abundant and obesity occurs in adult life. Tests of this hypothesis in an animal
model in which pregnant and/or lactating rats were fed a diet with a reduced
protein content have shown that liver metabolism in the offspring is permanently
altered despite their being weaned onto a normal diet. The longevity of male
offspring may be significantly increased or decreased depending on whether growth
retardation is restricted to the period of suckling or pregnancy, respectively.
The latter finding raises questions about potentially detrimental effects of
'catch-up' growth.
PMID- 9401570
TI - Hormonal status of short children born small for gestational age.
AB - The present study was undertaken to evaluate the hormonal status in a subgroup of
prepubertal children born small for gestational age (SGA) who lacked postnatal
catch-up growth. In this subgroup, a reduced rate of growth hormone (GH)
secretion was found, compared with reference groups of healthy children born
appropriate for gestational age, of either normal or short stature at the time of
investigation. In addition, an abnormal pattern of GH secretion was observed in
short children born SGA, which was most pronounced in the younger children, and
involved an increased frequency of GH peaks of low amplitude, combined with
increased baseline secretion. Levels of insulin-like growth factor I (IGF-I) and
IGF-binding protein-3 were also reduced in short children born SGA, compared with
the reference groups. These findings may explain, in part, the lack of postnatal
catch-up growth in short children born SGA.
PMID- 9401571
TI - Postnatal growth of children born small for gestational age.
AB - A large, population-based representative study (n = 3656) has shown that the vast
majority of healthy, full-term, singleton infants born small for gestational age
(SGA) achieve catch-up growth during the first 2 years of life. Indeed, most of
the increase in height SDS occurs by 2 months of age. Children born SGA who do
not show postnatal catch-up growth and so remain short at 2 years of age, have a
higher risk of short stature (< -2 SDS) in later life, with a relative risk at 18
years of age of 5.2 if born light and of 7.1 if born short.
PMID- 9401572
TI - Antenatal therapy for intrauterine growth retardation.
AB - Currently, there is no effective antenatal therapy for intrauterine growth
retardation (IUGR). Although the IUGR fetus is undernourished in utero and there
have been many attempts to treat IUGR with nutritional supplements, most studies
have been poorly controlled, and there is no evidence to date that nutrient
supplements can reverse the process of IUGR once it is established. Nutrient
supplementation is also potentially risky and a combination of nutrients is
likely to be needed. Alternative approaches to antenatal therapy for IUGR that
show promise include fetal growth hormone and insulin-like growth factor I
treatment to improve fetal growth. Fetal and maternal hormone supplements may
also prove useful in IUGR by improving placental function and thus fetal
substrate supply. Fetal enteral supplementation by the administration of growth
factors and/or nutrients into the amniotic fluid may also prove effective and
clinically feasible. It seems likely that combinations of these approaches will
be required before effective therapy can be devised for the IUGR fetus in utero.
PMID- 9401573
TI - Nutritional management and growth hormone treatment of preterm infants born small
for gestational age.
AB - In severe cases of intrauterine growth retardation, elective preterm delivery may
provide the possibility for nutritional intervention to prevent some of the long
term consequences of the catabolic condition in utero. Neonatal nutritional
management is aimed at providing a high protein intake of up to 4 g/kg/day in
order to obtain the rapid increase in protein that is seen in normally growing
infants during the early postnatal period. Unfortunately, due to impaired
production of urea, high plasma levels of ammonia, which may be rate limiting
with respect to an optimal gain in protein, are often observed in the preterm
infant born small for gestational age (SGA). In an attempt to stimulate protein
synthesis in preterm infants born SGA, growth hormone (GH) treatment was given to
seven such infants during the early postnatal period. The infants received daily
subcutaneous injections of GH (1.0 IU/kg/day) from postnatal day 7 until a body
weight of 2000 g was reached (postnatal week 7-8). A further seven preterm
infants born SGA were studied as controls. GH treatment had no significant
effects on growth, body composition, net protein gain and glucose metabolism.
Furthermore, plasma levels of insulin-like growth factor I (IGF-1) and IGF
binding protein-3 revealed a normal developmental increase and were not
significantly altered by GH treatment. These results may be explained by a
relative GH insensitivity or resistance during this period of early preterm life.
PMID- 9401574
TI - Growth hormone treatment of short children born small for gestational age:
reappraisal of the rate of bone maturation over 2 years and metanalysis of height
gain over 4 years.
AB - A minority of children born small for gestational age (SGA) fail to achieve
sufficient catch-up growth during infancy and remain short throughout childhood,
apparently without being growth hormone (GH) deficient. A previous metanalysis of
four trials revealed that GH treatment over a period of 2 years induced a dose
dependent acceleration of linear growth and, to a lesser extent, of the rate of
bone maturation in short, prepubertal children born SGA. The rate of bone
maturation and the change in height SDS for bone age from the previous 2-year
metanalysis have been re-analysed according to chronological age (two prepubertal
age groups: group A, 3.0-5.9 years old; group B, 6.0-8.9 years old). The rate of
bone maturation was slower in younger than in older prepubertal children; this
difference was more marked in children receiving high-dose (0.2 or 0.3 IU/kg/day)
GH treatment (p < or = 0.01). Accordingly, the change in height SDS for bone age
was increased by high-dose GH treatment in both age groups (p < or = 0.01), and
was more pronounced in younger than in older children (1.45 +/- 0.28 versus 0.63
+/- 0.20; p < or = 0.01). Height SDS data from 100 short, prepubertal children
born SGA have been analysed over 4 years. The change in height SDS appeared to be
related to the average dose of GH. A mean GH dose of 0.1 IU/kg/day over 4 years
was administered either as 0.1 IU/kg/day for 4 years (continuous) or as 0.2
IU/kg/day for 2 years, followed by 2 years without GH treatment (discontinuous).
After 4 years of treatment, the increase in height SDS for the continuous and
discontinuous treatment schedules was similar, being 1.42 +/- 0.10 SDS and 1.58
+/- 0.17 SDS, respectively. In a second regimen, a mean GH dose of 0.2 IU/kg/day
over 3 years was administered either as 0.2 IU/kg/day for 3 years (continuous) or
as 0.3 IU/kg/day for 2 years, followed by 1 year without GH treatment
(discontinuous). After 3 years, the increase in height SDS with the continuous
and discontinuous treatment schedules was similar, being 2.01 +/- 0.18 SDS and
2.22 +/- 0.16 SDS, respectively. GH administration was well tolerated in all
treatment groups. In conclusion, the rate of bone maturation in short,
prepubertal children born SGA treated with GH appeared to depend not only on the
dose of GH, but also on the age of the child. GH treatment resulted in a
prolonged increase in height SDS, the magnitude of the rise being dependent on
the average GH dose rather than on the continuous or discontinuous mode of GH
administration.
PMID- 9401575
TI - Growth hormone treatment of short children born small for gestational age.
AB - The administration of growth hormone (GH) for a short period to short children
born small for gestational age increases growth velocity. Children receiving 2-3
times the replacement dose gained nearly 2.0 SDS in height over a 3-year
treatment period. This treatment is well tolerated, without significant side
effects. Further studies of the growth rate following cessation of GH treatment
will reveal whether the gain in height is maintained, and whether the final
height prediction is improved.
PMID- 9401576
TI - Intrauterine growth retardation: our current understanding and future directions.
PMID- 9401577
TI - Can reactive oxygen species precondition the isolated rat heart against
arrhythmias and stunning?
AB - Ischaemic preconditioning has cardioprotective effects. Reactive oxygen species
may be possible mediators. The present study investigated whether low doses of
exogenous hydrogen peroxide could mimic preconditioning in isolated, Langendorff
perfused rat hearts. Hearts were subjected to two episodes of 3 min global
ischaemia and 5 min reperfusion (n = 17), or were given 10 (n = 15), 20 (n = 10),
30 (n = 20), 40 (n = 18), 80 (n = 17) or 160 microM (n = 10) hydrogen peroxide
for 10 min, followed by 10 min recovery, before 25 min global ischaemia and 60
min reperfusion, and compared with ischaemic controls of matching perfusion time
(n = 17 and n = 23). Cardiac performance was assessed by heart rate, left
ventricular systolic, end-diastolic and developed pressures, and coronary flow.
Severe reperfusion arrhythmias occurred frequently in control hearts, and was
attenuated by ischaemic preconditioning. All hearts pretreated with 160 microM
hydrogen peroxide had severe arrhythmias throughout reperfusion, while these were
not seen in any heart perfused with 20 microM hydrogen peroxide (P < 0.01
compared to controls). Ischaemia and reperfusion induced a minor decrease in
heart rate, left ventricular systolic and developed pressures, and increased end
diastolic pressure. Ischaemic preconditioning attenuated the decrease of heart
rate and the increase of end-diastolic pressure, and increased coronary flow,
while hydrogen peroxide did not significantly attenuate these changes. In
conclusion, a low dose of exogenous hydrogen peroxide before global ischaemia
inhibited severe reperfusion arrhythmias, but had no other protective effects.
The present work does not suggest that reactive oxygen species are important
mediators of the preconditioning effects on stunning and arrhythmias in the rat
heart.
PMID- 9401579
TI - Vasomotion in rat diaphragm microcirculation at rest and during stepwise arterial
pressure reduction.
AB - The effect of haemorrhagic hypotension on the incidence, frequency and relative
amplitude of vasomotion in rat diaphragm microcirculation was assessed by laser
Doppler flowmetry (LDF). Graded bleeding to four hypotension levels (80, 60, 40
and 30% of the control state) were performed in 24 Sprague-Dawley rats. The
incidence of vasomotion was 83% in the control state, 96% at the 80% level, 100%
at the 60% level, 96% at the 40% level, and 46% at the 30% level. The median
fundamental frequency of vasomotion determined manually during the control state
and at the hypotension levels (in descending order) was 4.11 (range, 3.29-5.58)
cycles min-1 (cpm), 4.48 (3.21-5.92) cpm, 4.20 (3.5-5.56) cpm, 4.01 (3.33-5.36)
cpm, 3.71 (3.25-4.49) cpm (P < 0.01 from the fundamental frequency at 80 and 60%
hypotension levels). The median relative amplitudes determined manually during
the control state and descending hypotension levels were 44.5% (range, 24.9
135.9%), 69.4% (26.6-147.2%), 84.0% (40.3-177.1%) (P < 0.01 from resting and last
stage of bleeding), 90.40% (26.2-189.6%) (P < 0.01 from resting and last stage of
bleeding), 69.2% (35.6-93.2%). We concluded first that during the resting
condition, vasomotion was frequently present in diaphragm microcirculation, which
is distinct from other vascular beds of skeletal muscles. Second, the relative
amplitude of vasomotion during haemorrhagic hypotension plotted against
decreasing blood pressure exhibited a reverse U-shaped curve with a maximum at 40
60% of the control blood pressure, while the frequency of vasomotion remained
relatively constant until the last stage of haemorrhage and centred around 3-5
cpm.
PMID- 9401580
TI - Acute microcirculatory changes after scalding of the rat paw.
AB - A scalding model in the anaesthetized rat was used to measure acute circulatory
reactions after heat exposure. Local blood flow of both hindpaws was recorded
simultaneously and continuously by laser Doppler flowmetry before, during and for
2 hours following scalding. The scalding injury was inflicted by dipping the
right hindpaw into hot water at 60 degrees C for 20 s. Concomitantly, the mean
arterial blood pressure (MAP) was displayed on a chart recorder. MAP was obtained
by cannulation of the common carotid artery. Oedema formation was calculated by
measuring the volume changes of the hindpaws in a plethysmometer before and 30,
60 and 120 min after scalding. Scalding was followed by a biphasic increase of
cutaneous circulation. During the first minute after heat provocation, an
immediate increase in blood perfusion of about 400% was recorded, followed by a
slow decrease of circulation. At 30 min after scalding, there was a secondary
phase of increased microcirculation of approximately 230%. A slow decline of
cutaneous circulation then followed, and after about 60 min the value was
stabilized at approximately 100% above pre-burn level throughout the observation
time. Almost no change of perfusion was observed on the contralateral unscalded
paw. The scalding injury was followed by a progressive oedema formation on the
scalded paw, measured by a volume increase of approximately 72% during the
observation period, whereas the non-scalded paw showed no change. MAP remained at
a stable level throughout the experiment except for a short-lasting transient
increase of approximately 10% at the same time as the first peak of blood
perfusion. We could thus confirm that scalding in the present model is
accompanied by an immediate and marked increase in the peripheral circulation of
the scalded paw followed by a later propagation of oedema, and that these
inflammatory changes do not appear to be related to central haemodynamic
alterations.
PMID- 9401578
TI - Effects of stimulation and inhibition of protein kinase C on the cytosolic
calcium concentration in rabbit afferent arterioles.
AB - The effect of the protein kinase C (PKC) inhibitor chelerytrine (Ch) and the PKC
activator 12-0-tetradecanoyl-phorbol-13-acetate (TPA) on the cytosolic calcium
concentration ([Ca2+]i) in isolated intact rabbit afferent arterioles was
investigated. [Ca2+]i was measured in the proximal and distal parts of the
arteriole. Administration of 1 microM Ch gave rise to a peak followed by an
elevated level of [Ca2+]i in both these parts. Neither the peak nor the elevated
level of [Ca2+]i was significantly reduced by 1 microM nifedipine. The relative
peak increase in [Ca2+]i in response to 1 microM noradrenaline (NA) or to 10 nM
angiotensin II (AII) was significantly blunted in both parts after preincubation
with 1 microM Ch. Depolarization with 25 mM K+ increased [Ca2+]i in both parts.
Preincubation with Ch did not affect the increase in [Ca2+]i induced by 25 mM K+.
TPA (10 and 100 nM) did not significantly affect the basal [Ca2+]i in the
afferent arteriole. The [Ca2+]i response to NA or 25 mM K+ was not affected by
TPA. We conclude that blockade of PKC increases [Ca2+]i in afferent arteriolar
smooth muscle by a mechanism independent of L-type voltage-sensitive calcium
channels. Inhibition of PKC blunts the relative increase in [Ca2+]i in response
to AII and, to a lesser extent, that induced by NA. We conclude that PKC might be
important in modulating the calcium changes that occur in response to these
vasoconstrictors.
PMID- 9401581
TI - Radiotelemetrically recorded blood pressure and heart rate changes in relation to
plasma catecholamine levels during parturition in the conscious, unrestrained
goat.
AB - The aim of this study was to investigate the extent of sympathetic nervous system
activation during parturition in four unrestrained goats. Chronically implanted
radiotelemetry devices registered heart rate and arterial blood pressure around
the clock and blood was sampled for determination of plasma adrenaline and
noradrenaline concentrations before, during and after labour. Two goats delivered
two kids after moderately intensive abdominal contractions. A third goat had
dystocia, and was treated with prostaglandin F2 alpha. One normal kid and one
mummified foetus were delivered manually. After milking, a third kid was born
spontaneously. The fourth goat experienced severe abdominal contractions and
delivered one kid. Mean blood pressure was 69 +/- 2 mmHg the day before
parturition, increased gradually during the labour pains, and reached a maximal
value of 120 +/- 7 mmHg when the head of the first kid was visible (P < or =
0.05). Heart rate was 134 +/- 4 beats min-1 the day before parturition and peaked
when the first kid was born (159 +/- 6 beats min-1, P < or = 0.05), as did plasma
adrenaline concentration (from 0.4 +/- 0.2 nmol L-1 to 2.7 +/- 1.2 nmol L-1, P <
or = 0.05). The concentration of noradrenaline increased from 4.8 +/- 2.3 nmol L
1 to 12.2 +/- 8.4 nmol L-1 (P < or = 0.05), when the head of the first kid was
visible. Expulsion of the second and third kids caused relatively smaller
increases in blood pressure, heart rate and catecholamines than those seen with
the first born kid. It is concluded that changes in pressure, heart rate and
catecholamines during parturition are related to the different phases of labour
and not to its duration or severity.
PMID- 9401582
TI - Importance of nitric oxide in hepatic arterial blood flow and total hepatic blood
volume regulation in pigs.
AB - The importance of nitric oxide in regulating basal arterial blood flow has been
examined in several different vascular beds by intra-arterial infusion of
inhibitors of nitric oxide synthesis, but not in the arterial vascular bed of the
liver. In the present study, N(G)-nitro-L-arginine (L-NNA), in a dose of 0.5 and
1.0 mumol mL-1 of hepatic arterial blood flow, was infused for 5 min into the
hepatic artery in seven pigs anaesthetized with pentobarbital sodium. The
haemodynamic effects observed by the first infusion were not further enhanced by
the second infusion. Hepatic arterial resistance increased by 143 +/- 38% and
hepatic arterial blood flow declined by 38 +/- 10%. A systemic effect due to
'spillover' was observed, as evidenced by an increase in mean aortic blood
pressure of 24 +/- 4 mmHg. However, no significant increase in arterial
mesenteric resistance was observed and total liver blood flow remained unchanged.
Hepatic arterial vasodilation in response to occlusion of the portal vein, the
arterial buffer response, remained intact after inhibition of nitric oxide
synthesis. Liver lobe thickness, measured by an ultrasonic technique, was not
found to change with inhibition of arterial nitric oxide synthesis, excluding a
significant direct effect of arterial nitric oxide on liver capacitance. In
conclusion, nitric oxide is an important regulator of hepatic arterial
resistance, but does not mediate the hepatic arterial buffer response and was not
found to play any significant role in total hepatic capacitance regulation.
PMID- 9401583
TI - Effect of inhaled nitric oxide on endotoxin-induced hypoxaemia in rabbits.
AB - In five mechanically ventilated rabbits, we studied the property of inhaled
nitric oxide in helping to treat hypoxaemia which was induced by intravenous
endotoxin (Escherichia coli-derived lipopolysaccharide, serotype 0111: B4). We
used measurements of arterial partial pressure of oxygen to check a therapeutic
nitric oxide benefit. Pulmonary artery pressure was continuously monitored.
Furthermore, we determined the single-breath diffusing capacity for nitric oxide.
Measurements of plasma nitrite/nitrate concentration served as an indicator of
endogenous nitric oxide output. The first infusion of endotoxin led to a
transient pulmonary vasoconstriction, whereas arterial partial pressure of oxygen
was permanently reduced by 30 +/- 10 mmHg (mean +/- SD), attaining minimal values
of 48 +/- 3.4 mmHg due to additional endotoxin. Single-breath diffusing capacity
for nitric oxide declined by 20 +/- 5.5% of baseline values until the experiments
were concluded. Endotoxin induced an increase in plasma nitrite/nitrate
concentration in the five rabbits as well as in the control animals (four
rabbits) without exogenous nitric oxide supply. During the 25 inhalations of
nitric oxide (3-50 ppm), arterial oxygenation did not change significantly. Thus
endotoxin permanently impaired pulmonary gas exchange without inducing pulmonary
hypertension. Inhaled nitric oxide did not improve arterial oxygenation during
endotoxaemia.
PMID- 9401584
TI - Effects of the beta 2-adrenergic agonist clenbuterol on capillary geometry in
cardiac and skeletal muscles in young and middle-aged rats.
AB - The effects of 10 day clenbuterol administration on cardiac and skeletal muscle
capillarities were studied, particularly in terms of the distribution of
arteriolar and venular capillaries and their capillary density, in young (10-week
old) and middle-aged (37-week-old) male Wistar rats. Rats of the treated groups
were fed a diet containing 2 mg kg-1 clenbuterol hydrochloride. In both young and
middle aged rats, clenbuterol treatment increased the body wt and the weights of
the heart and hindlimb muscles. The mean fibre cross-sectional area was
significantly increased after the treatment in the left ventricle, soleus,
plantaris and both deep and superficial portions of gastrocnemius (P < 0.01). In
the left ventricle, the total capillary density and the density of venular
capillaries were decreased after the treatment in both young (9 and 13%,
respectively) and middle-aged rats (10 and 11%, respectively). A decrease in
total capillary density was also observed in all skeletal muscles examined. In
both young and middle-aged rats, the capillary-to-fibre (C:F) ratio and the
proportion of each capillary did not change after the treatment in both the left
ventricle and skeletal muscles. Clenbuterol significantly decreased the activity
of succinate dehydrogenase in all skeletal muscles examined (P < 0.01). These
results suggest that clenbuterol increased the diffusion distance for oxygen in
the left ventricle and skeletal muscles. These changes may reduce the oxygen
supply to tissues and increase muscle fatigability.
PMID- 9401585
TI - Time-dependent effects of ischaemia on neuropeptide Y mechanisms in pig renal
vascular control in vivo.
AB - We have investigated the effects of ischaemia on neuropeptide Y (NPY) mechanisms
involved in sympathetic vascular control of the pig kidney in vivo. Reperfusion
after 2 h of renal ischaemia was associated with local overflow of noradrenaline
(NA) but not of NPY-like immunoreactivity (-LI). Renal sympathetic nerve
stimulation 10 min into reperfusion evoked markedly reduced vasoconstrictor
effects and significantly less overflow of NA (reduced by 70% from the pre
ischaemic conditions), whereas NPY-LI overflow was unaltered. Renal
vasoconstrictor responses to exogenous peptide YY (PYY), phenylephrine and
angiotensin II were strongly attenuated after this ischaemic period, while
vasoconstriction to alpha, beta-methylene ATP was maintained to a larger extent.
The renal vascular responses and NA overflow had become partially normalized
within a 2 h recovery period. In contrast, the renal vasoconstrictor response and
the overflow of NPY-LI upon sympathetic nerve stimulation were enhanced after 15
min of renal ischaemia. In parallel, the PYY-evoked renal vasoconstriction was
selectively and markedly prolonged after the 15 min of ischaemia. In the presence
of the NPYY1 receptor antagonist BIBP 3226, the augmented vascular response to
nerve stimulation was significantly attenuated. We conclude that reperfusion
after 2 h of renal ischaemia is associated with local overflow of NA, whereas the
sympathetic nerve-evoked release of NA and the reactivity of the renal
vasculature to vasoconstrictor stimuli are reversibly reduced. Furthermore,
possibly due to an impaired local degradation, the role of neurogenically
released NPY in renal sympathetic vasoconstriction is enhanced after short-term
(15 min) ischaemia compared with control conditions.
PMID- 9401586
TI - Effects of aminoguanidine and L-NAME on histamine-induced blood pressure drop in
the rat.
AB - Mean arterial blood pressure changes in response to i.v. administration of
histamine were monitored in the anaesthetized rat in the absence or presence of
the diamine oxidase (DAO) inhibitor aminoguanidine (AMG, 10 mg kg-1). AMG
prolonged the duration of the transient drop in blood pressure induced by a bolus
injection of histamine (0.05 mg kg-1) by 34%. In animals pretreated with AMG, no
potentiation of the decrease in pressure in response to a 10 min infusion of
histamine was observed. However, when infusion was stopped, the time needed for
pressure recovery was twice as long in animals treated with AMG as in controls.
Blood samples were taken prior to infusion and during the recovery phase and the
quantities of histamine were determined by liquid chromatography. The prolonged
recovery phase observed in animals pretreated with AMG was associated with five
times higher levels of histamine. The duration of histamine-induced hypotension
(0.01 mg kg-1) was 50% shorter in the presence of the nitric oxide synthase
inhibitor L-NAME (10 mg kg-1). We suggest that DAO, through elimination of
histamine from the bloodstream, is important for the recovery from histamine
induced hypotension, and that the duration of histamine-induced pressure drop is
influenced by formation of nitric oxide.
PMID- 9401587
TI - Rate of oxidative phosphorylation in isolated mitochondria from human skeletal
muscle: effect of training status.
AB - Muscle oxidative function has been investigated in subjects with various training
status (VO2 max, 41-72 mL O2 kg-1 body wt min-1, n = 10). Mitochondria were
isolated from biopsies taken from m. vastus lateralis. Maximal mitochondrial
oxygen consumption (QO2) and ATP production (MAPR) were measured with
polarographic and bioluminometric techniques, respectively. The yield of
mitochondria, calculated from the fractional activity of citrate synthase (CS),
averaged 26%. With pyruvate + malate, the respiratory control ratio was 5.7 +/-
0.4 (X +/- SE) and the P/O ratio was 2.83 +/- 0.02, which demonstrates that the
isolated mitochondria were functionally intact. QO2 was significantly correlated
to aerobic training status expressed as muscle CS activity (r = 0.86), VO2 max (r
= 0.84) and lactate threshold (r = 0.83) but not to the fibre type composition. A
highly significant correlation (r = 0.93) was observed between ATP production
calculated from QO2 and MAPR, but ATP production derived from QO2 was higher than
MAPR both for pyruvate + malate (255%) and for alpha-ketoglutarate (23%). QO2
extrapolated to a temperature of 38 degrees C averaged 68 mL O2 min-1 kg-1 wet
wt, which is similar to previous findings in vitro and in vivo during the post
exercise period. However, calculated muscle O2 utilization during exercise was
three- to fivefold higher than QO2 measured on isolated mitochondria. It is
suggested that additional factors exist for activation of mitochondrial
respiration during exercise. It is concluded that muscle oxidative function can
be quantitatively assessed from the respiration of mitochondria isolated from
needle biopsy specimens and that QO2 is closely correlated to whole-body VO2 max.
PMID- 9401588
TI - Central and peripheral components of diaphragmatic fatigue during inspiratory
resistive load in cats.
AB - The development of fatigue was investigated in the diaphragm of anaesthetized,
tracheostomized, spontaneously breathing cats during restricted air flow.
Ventilation, transdiaphragmatic pressure (Pdi), integrated electrical activity of
diaphragm (Edi) and phrenic nerve (Eph) were measured simultaneously and
expressed as a percentage of values at unloaded breathing. Inspiratory loads were
60, 70 and 80% of Pdi max. The Pdi max was measured by airway occlusion at
functional residual capacity. The duration of loads was 40-60 min. The
diaphragmatic fatigue developed only during heavy inspiratory loading (80% Pdi
max). During the first 10 min of heavy load Pdi, Edi and Eph increased to 905 +/-
60%, 248 +/- 20% and 229 +/- 24%, respectively (P < 0.01), and then began to fall
gradually. Ventilation declined to 39 +/- 3% after 60 min of heavy load (P <
0.01), resulting in acute hypercapnia and hypoxia. Initial fatigue appeared as a
decrease in Pdi (to 781 +/- 63%) and parallel decline in Edi (to 233 +/- 21%)
after 30 min of load (P < 0.05). Phrenic nerve activity did not change during
this stage. These data suggest a peripheral basis of diaphragmatic fatigue,
related to disorders in neuromuscular transmission. After 60 min of heavy load,
Pdi fell to 675 +/- 49%, Edi declined to 209 +/- 28% and Eph decreased to 189 +/-
25%. We interpret the decrease in phrenic nerve activity as a weakening of
central inspiratory drive and development of the central component of
diaphragmatic fatigue in the last stage.
PMID- 9401589
TI - Intramuscular EMG from the hip flexor muscles during human locomotion.
AB - The purpose was to investigate the activation pattern of five major hip flexor
muscles and its adaptation to changing speed and mode of progression. A total of
11 healthy subjects performed walking and running on a motor-driven treadmill at
speeds ranging from 1.0 to 6.0 m s-1. Intramuscular fine-wire electrodes were
used to record myoelectric signals from the iliacus, psoas, sartorius, rectus
femoris and tensor fascia latae muscles. The basic pattern, with respect to
number of activation periods, remained the same irrespective of speed and mode of
progression. However, differences in the relative duration and timing of onset of
activation occurred between individual muscles. Over the speed range in walking,
a progressively earlier onset was generally seen for the activation period
related to hip flexion. Changes in EMG amplitude were measured in the iliacus and
psoas muscles and showed a marked increase and difference between walking and
running at speeds above 2.0 m s-1. Thus, the alternating flexion-extension
movements at the hip during locomotion appear to be governed by a rather fixed
'neural program' which normally only needs minor modulations to accomplish the
adjustments accompanying an increase in speed of progression as well as a change
from walking to running.
PMID- 9401590
TI - Influence of muscle mass and work on post-exercise glucose and insulin responses
in young untrained subjects.
AB - The 18 h post-exercise glucose and insulin responses of six male and six female
subjects were measured following one- or two-leg cycling to determine the
influence of muscle mass involvement and work. Each subject performed three
exercise trials on a Cybex Met 100 cycle ergometer: (1) two-leg exercise for 30
min at 60% of the two-leg VO2 max; (2) one-leg exercise for 30 min at 60% of one
leg VO2 max; and (3) one-leg exercise (one-leg TW) at 60% of the one-leg VO2 max
with the total work performed equal to that of the two-leg trial (duration
approximately 50 min). These trials were preceded by 2 days of inactivity and
followed by an 18 h post-exercise 75 g oral glucose tolerance test (OGTT). The
glucose response during the baseline OGTT demonstrated that the subjects had
normal glucose tolerance with fasting serum glucose levels of 5.1 mM, and 1 and 2
h serum glucose less than 7.8 mM, respectively. The 18 h post-exercise glucose
responses were significantly lower following the two-leg trial (P < 0.05), with
the area under the curve values being 129.9 mM h-1 less than the resting control
level. The 18 h post-exercise insulin AUC response of the two-leg trial was
significantly lower than either of the one-leg responses (14.7 pM below the one
leg and 5.0 pM below the one-leg TW) but was not associated with a change in C
peptide. The 18 h post-exercise insulin levels of the one-leg and one-leg TW
trials were above or near the resting control values, but were not accompanied by
a significant change in C-peptide. In conclusion, the data presented here show
that the amount of muscle tissue utilized during an exercise bout can influence
both the glucose and insulin responses, whereas the amount of total work employed
during the exercise had no effect on either of these parameters.
PMID- 9401591
TI - Effects of ubiquinone-10 supplementation and high intensity training on physical
performance in humans.
AB - This study investigated the effects of oral supplementation with ubiquinone-10
(Q10) (n = 9) compared with a placebo (n = 9) on aerobic and anaerobic physical
performance over 22 days of supplementation. The supplementation period included
5 days of high intensity anaerobic training between days 11 and 14. The results
demonstrated, that on an anaerobic (10 x 10 s) cycling test, the placebo group
showed a significantly greater improvement than the Q10-group after a
supplementation and training period (P < 0.001). Further, the Q10 group had a
significantly lower increase in total work performed during the seven training
sessions (15 x 10 s) compared with the placebo group (P < 0.001). There was a
significant increase in maximal blood lactate accumulation during cycling in the
both groups, when compared with levels before the training and recovery period.
There was no significant difference between the groups, either in VO2max
determined during running, or in submaximal and peak VO2, Rate of Perceived
Exertion, respiratory quotient, blood lactate concentration or heart rate
determined during submaximal and maximal cycling. Although insignificant (P = 0.1
0.3), there was evidence of higher submaximal VO2 (55-80% of VO2peak) during
cycling in the Q10-group compared with the placebo group after training and
recovery. It is concluded that with high intensity anaerobic training, there was
a significantly greater increase in anaerobic performance in the placebo group
compared with the Q10 group. The results suggest less increase in physical
performance with Q10 supplement and high intensity anaerobic training, compared
with placebo.
PMID- 9401592
TI - Blubber and flipper heat transfer in harp seals.
AB - The trunk of marine mammals is encased in a blubber layer which provides thermal
insulation that can be changed by circulatory adjustments. The extremities, on
the other hand, are poorly insulated but have vascular arrangements constructed
for prevention or promotion of heat loss depending on the thermal state of the
animal. We have studied the importance of different body parts as sites for heat
dissipation and also assessed the effect of circulatory adjustments on heat
transfer through blubber, by combining direct measurements of heat flux from the
flippers and trunk with simultaneous recordings of temperature gradients through
the blubber and metabolic rates of harp seals (Phoca groenlandica) subjected to
water temperatures between 1 and 24 degrees C. We also determined the thermal
conductivity of blubber samples from the same animals after death, and compared
this with the insulative properties of live blubber. At the lowest water
temperatures, the insulative properties of live blubber were similar to those of
dead blubber, and heat loss from the flippers only accounted for 2-6% of the
metabolic heat production. As heat load increased with increasing water
temperatures, the fraction of heat lost from the flippers increased, to 19-48% at
24 degrees C, while the fraction lost from the trunk decreased, despite an
increase in the convective (circulatory) heat transfer through the blubber layer.
PMID- 9401593
TI - Circadian variation of sweating responses to passive heat stress.
AB - The aim of present study was to examine whether sweating responses to passive
heat stress change with the circadian rhythm of internal temperature. Six men had
their legs immersed in water at 42 degrees C for 60 min in an ambient temperature
of 28 degrees C on four separate days. Experiments were conducted at four
different times [06.00 h (morning), 12.00 h (daytime), 18.00 h (evening) and
24.00 h (night)]. We measured oesophageal temperature (Toes), mean body
temperature (Tb), local sweating rate (msw) on the forehead, back, forearm and
thigh, the densities of activated sweat gland (ASG) on the back, forearm and
thigh, and the frequency of sweat expulsion per minute (Fsw) which has been
suggested to represent central sudomotor activity. Sweat gland output (SGO) on
each site was calculated by dividing msw by ASG. ASG was significantly higher on
the forearm than on the back and thigh, and SGO was significantly lower on the
forearm than on the back and thigh. However, ASG and SGO did not significantly
change over the day. Tb and Toes thresholds for the onset of sweating showed a
significant change with both the temperature rhythms at rest prior to each
procedure, while the slopes of the relationships Fsw-Tb and msw-Fsw showed no
significant difference over the day. We suggest that the circadian variation of
sweating response to passive heat stress is regulated by a central sudomotor
mechanism rather than by sweat gland function.
PMID- 9401594
TI - Effects of pretreatment with an indeno-indole compound on lipid peroxidation in
the cortex and medulla of rabbit kidneys after ischaemia-reperfusion.
AB - The effects of 60 min of ischaemia with or without reoxygenation in vivo or in
vitro on lipid peroxidation in cortical and medullary tissue from rabbit kidneys
were measured as production of thiobarbituric acid-reactive substances (TBARS).
Lipid peroxidation was more pronounced in medullary tissue compared with cortical
tissue. The highest TBARS production was found in medullary slices subjected to
reoxygenation in vitro immediately after 1 h of ischaemia. Reperfusion in vivo
before reoxygenation in vitro attenuated the TBARS formation during subsequent in
vitro incubation. Pretreatment of the rabbits with an indeno-indole compound
(code name H 290/51) reduced the TBARS formation after 60 min of ischaemia and
reoxygenation in vitro towards control values.
PMID- 9401595
TI - CGRP, but not substance P, induces an increased negativity of the interstitial
fluid pressure in rat trachea.
AB - Neurogenic inflammation is mediated by neuropeptides released from sensory nerves
following electrical stimulation of the vagal nerve or by capsaicin. The released
neuropeptides are, among others, calcitonin gene-related peptide and substance P,
which both induce vasodilation, while only substance P induces plasma
extravasation. Electrical stimulation of the vagal nerve induces increased
negativity of interstitial fluid pressure (Pif), which will contribute to enhance
oedema formation. Pif was measured, on the abluminal side of the surgically
exposed trachea, with sharpened glass capillaries (4-10 microns) connected to a
servo-controlled counterpressure system. Measurements were performed after
circulatory arrest, since the oedema formation associated with acute inflammation
will increase Pif in a positive direction, which may potentially underestimate
the increased negativity of Pif. Experiments were carried out in pentobarbital
anaesthetized (50 mg kg-1) Wistar-Moller rats. Pif in control rats averaged -1.2
+/- 0.9 (SD) mmHg (n = 9). Intravenous injection of capsaicin (65.0 nmol) and
calcitonin gene-related peptide (1.3 nmol) increased the negativity of Pif to
4.0 +/- 1.2 mmHg (n = 8) (P < 0.01) and -4.7 +/- 2.0 mmHg (n = 9) (P < 0.01),
respectively. Intravenous injection of substance P (7.4 nmol, n = 9; and 37.0
nmol, n = 8) did not affect Pif compared to control (P > 0.05). Similarly,
potentiation of the available substance P with thiorphan or captopril did not
increase the negative Pif, nor did injection of stable substance P analogues.
Thus, the present study seems to support the theory that, in rat trachea, the
increased negativity of Pif after intravenous injection of capsaicin and after
vagal stimulation is caused by calcitonin gene-related peptide.
PMID- 9401596
TI - The activation pattern in normal humans during suppression, imagination and
performance of saccadic eye movements.
AB - The distribution of activated cerebral regions was examined in nine normal
subjects during four different eye movement-related conditions: (1) fixation
fixation on a central light emitting diode; (2) saccadic suppression-fixation on
a diode in the presence of flashing lateral targets; (3) reflexive/volitional
saccades-performance of overt eye movements to two laterally lit targets and back
to the centre; and (4) imagined saccades-imagining, but not performing, the same
eye movements. The regional neural activity was measured indirectly using
repetitive bolus injections of oxygen-15-labelled water and positron emission
tomography (PET) to yield time-integrated images of the normalized count
distribution. These were aligned and anatomically normalized to a standard
stereotactic space and the averages of each condition were analysed categorically
using statistical parametric mapping. Compared to central fixation,
reflexive/volitional saccades significantly activated regions in the classically
known cortical oculomotor regions. The most notable activation during the saccade
suppression task, compared to central fixation alone, was a bilateral activation
of the parietal cortex with a right-sided preponderance, activation of the
supplementary eye field/caudal cingulate regions, and activation of frontal
regions close to the frontal eye fields. Imagined performance of eye movements
without overt eye movements activated the supplementary eye field and frontal eye
fields identically to regions involved in overt eye movements, thus demonstrating
that over eye movements are not a prerequisite of the activation of these regions
in normal humans.
PMID- 9401597
TI - Increased activity of citrate synthase in human skeletal muscle after a single
bout of prolonged exercise.
PMID- 9401598
TI - James Paget Henry. 12/7 1914--20/11 1996.
PMID- 9401599
TI - Psychological and physiological responses to stress: the right hemisphere and the
hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding.
AB - In addition to repeated reexperiencing of the event, the delayed effects of
severe psychological trauma, i.e., post traumatic stress disorder (PTSD), present
a paradoxical mix of symptoms. There is enhancement of the self-preservative
catecholamine states; anger and fear with a contrasting sense of meaninglessness
and blunting of the emotional responses of the attachment behavior so critical
for species preservation. Hormonally, there is a striking separation of the
catecholamine response, which stays elevated and that of the hypothalamo
pituitary-adrenal (HPA) axis, which may remain at normal levels.
Pathophysiologically, the reexperienceing of the trauma and the arousal may be
associated with dysfunction of the locus coeruleus, amygdala and hippocampal
systems. This article explores the consequences of an additional dysfunction: a
dissociation of the hemispheres that appears to be responsible for the
alexithymic avoidance and failure of the cortisol response that so often follow
severe psychological trauma. There is neurophysiological evidence that the left
the right hemispheres subserve different emotional sets that correspond to
"control" and "appraisal," i.e., very approximately to the self and species
preservative behavioral complexes, respectively. Several studies point to
physiological dissociation of hemispheric functions during alexithymia. This
raises the question: What has been lost if in this condition the right side no
longer fully contributes to integrated cerebral function? Right hemispheric
damaged children lose critical social skills and in adults the related sense of
familiarity critical for bonding is lost. Such losses of social sensibilities may
account for the lack of empathy and difficulties with bonding found in sociopathy
and borderline personality: conditions now believed to result from repeated
psychological trauma during development. On the other hand, systems that promote
right hemispheric contributions provide solacing access to a "Higher Power." They
also appear to protect against socially disordered behavior, substance abuse, the
failure of the HPA axis and some aspects of the pathophysiology of chronic
disease.
PMID- 9401600
TI - James Paget Henry--a retrospective.
AB - James Paget Henry really began his productive research career at the outset of
the second world war. His studies of acceleration and the anoxia of high altitude
were supported by the development of then new techniques of measuring and
recording critical physiologic parameters such as vascular pressures, respiratory
functions and haemoglobin saturation. His inquisitive mind made productive use of
the instruments that had to be made by skilled instrument makers working in
university shops. Much of this instrumentation has now found its way into the
clinical arena where it is now the main armamentarium of cardiac diagnostic and
respiratory function laboratories. His work in the space program preceeded that
of the Russians but did not get recognition until Sputnik awakened the world to
the possibilities of space flight. His development of the concept of a
cardiovascular basis for fluid volume control and the supportive investigative
work undertaken constitute a milestone in the annals of experimental physiology.
The chimpanzees used in Project Mercury were found to be hypertensive which was
related to the method of capture used by the commercial suppliers. This lead Jim
to study the effect of early experience on resting blood pressure, an effort that
soon developed into provocative studies of the biological basis of the stress
response.
PMID- 9401601
TI - Shifting the circulatory control paradigm.
AB - The current paradigm regards circulatory control as mediated by discrete
cardiovascular receptor stimuli, through an array of relatively independent
reflexes, with the arterial baroreflex the centrepiece of this schema. However,
it is often difficult to fit the linear control model to the observed responses
of the intact organism. Hence the need for a more realistic approach. A given
disturbance acting on the body stimulates not only baroreceptors, but many other
receptors, as well as providing the central nervous system (CNS) with behavioral
cues, etc. The mix of stimuli is characteristic of the type and severity of the
particular disturbance. The first task for the CNS, is recognition of the pattern
of stimuli, which is often a non-linear process. This is mediated through a
number of "integrative" centres in different parts of the brain, which compare
the magnitude of stimuli from the various sources. The sum of excitatory and
inhibitory influences in the efferents from these integrative centres project to
"command" centres, e.g. in hypothalamus, amygdala or hindbrain. These generate
the output patterns through activation of particular pools of autonomic
motoneurons and by altering secretion of hormones. Both the recognition of
afferent stimuli (including behaviour) and of the effector patterns, involve
mechanisms above and below the pons.
PMID- 9401602
TI - Physiological aspects of the "defence" and "defeat" reactions.
AB - By means of tele-receptor signals (vision, hearing, olfaction) the mammalian
brain is almost continuously informed about environmental events, and whenever
these are interpreted as positive or negative challenges the cerebral "super
controller" can, for coping with the anticipated situation, select the most
appropriate among a number of pre-formed hypothalamic reaction patterns. These
are organized as combined engagements of the somatomotor, visceromotor and
hormonal efferent links, whereby a variety of behavioural responses can be
elicited, where each is accompanied by appropriate adjustments of inner organ
systems, metabolism, etc., to achieve optimal performance. For eons of time these
"emotionally charged" reactions, common for all mammals, have served to protect
the individual and species in a merciless environment, and they certainly remain
principally the same also when Homo Sapiens faces modern society. As then the
ancient "defence" and "defeat" reactions, intended for quite different
situations, are often activated by the many artificial stimuli and symbolic
threats inherent in today's hectic and competitive life, their principal
organisation and functional consequences are the main topic of this survey. They
are, for example, also marginally engaged along with ordinary shifts in mood
during events in daily-life but are probably in this mild form fairly harmless
and actually often supportive for efficient performance. However, when intensely
engaged over longer periods they can, indeed, profoundly disturb inner organ
systems and metabolic events, often resulting in disorder and even in premature
death, as particularly convincingly shown by Henry and co-workers in studies on
rodent "micro-societies". Transferred to man's situation in modern life, these
model studies have been crucial for insight into the indeed complex mechanisms
involved when long-term psychosocial stress in predisposed or particularly
exposed individual contributes to some of today's most important "disorders of
civilisation".
PMID- 9401603
TI - Oxytocin linked antistress effects--the relaxation and growth response.
AB - Stress or noxious stimuli of various kind may induce the fight-flight response.
In this situation a number of physiological and behavioural adaptations leading
to defense of the organism occur. At a central level increased activity in the
noradrenergic locus coeruleus (LC) and an enhanced secretion of corticotrophin
releasing factor (CRF) and vasopressin produced in the paraventricular nucleus
(PVN) integrate stress response. Here the existence of an opposite psycho
physiological pattern associated with relaxation and growth and which is
activated by certain types of non-noxious stimuli and integrated by oxytocin is
proposed. In support of this, administration of oxytocin to male and female rats
gives rise to effects of antistress nature in particular after repeated
administration. Thus a five day treatment period with oxytocin 1 mg/kg s.c. or 1
micro g/kg i.c.v gives rise to sedation, lowering of blood pressure, increased
withdrawal latency in the tail flick test and also a decrease of corticosterone
levels and a rise of certain vagally controlled hormones. Weight gain is also
increased under certain conditions. These effects persist several weeks after
administration of oxytocin and cannot be reversed by oxytocin antagonists when
established, suggesting that secondary mechanisms have been activated. Naloxone
temporarily reverses the increased withdrawal of the tail flick test suggesting
that opioid mechanisms have been activated to cause this particular effect. In
contrast the sedative and blood pressure lowering effect seems to be induced by
an enhanced activity in central alpha 2 receptors. Oxytocin levels increase in
blood and CSF after various kinds of non-noxious sensory stimulation such as
touch, light pressure and warm temperature in both female and male rats. It is
suggested that other types of non-noxious stimuli as well may increase oxytocin
release. If so, a release of oxytocin could be responsible for not only the
antistress effects occurring during lactation but also why relationships, social
contact and networks may have health promoting effects in particular by
preventing cardiovascular disease.
PMID- 9401604
TI - Stress and immunity: what have we learned from psychoneuroimmunology?
AB - The old concept that stress depresses immunity must be qualified. There is now
evidence that in the same way that different perceptions of stress have different
physiological consequences, different ways of coping with stress result in
different consequences on immunity, the nature and outcome of which depend on the
type of immune response. The mechanisms that are involved in these effects
involve neuroendocrine and autonomic pathways. These pathways are actually part
of a network of bidirectional interactions between the central nervous system and
the immune system, which plays an important role in the physiological regulation
of immunity.
PMID- 9401605
TI - Physical exercise, endogenous opioids and immune function.
AB - The experimental data available today strongly indicate that various types of
physiological stressors, including physical exercise and emotional stress, can
influence immune function. Natural immunity represents a first line of defence in
viral infections and cytotoxicity to a variety of tumour cells. Natural immunity
is strongly influenced by chronic exercise and this regulation includes
interaction between the nervous, endocrine and immune systems. Central mechanisms
including the endogenous opioids are of great interest. Chronic activation of
endogenous opioid systems augments natural cytotoxicity and the possible
involvement the opioids in the exercise-induced enhancement of natural immunity
is discussed. Also, catecholamines seem to play an important role in the
regulation of immune function, both after chronic exercise and emotional stress.
The physiological significance of the reported changes in natural cytotoxicity
after exercise-training is as yet unclear.
PMID- 9401607
TI - The right hemisphere and the human stress response.
AB - Evidence is presented that most components of the human stress response are
influenced asymmetrically by the cerebral hemispheres. The right hemisphere is
endowed with a unique response system preparing the organism to deal efficiently
with external challenges. Therefore, both the hypothalamic-pituitary
adrenocortical (HPA) axis and the sympathetic-adrenomedullary (SA) axis seem to
be under the main control of the right hemisphere.
PMID- 9401606
TI - The role of the central amygdala in stress and adaption.
AB - Recent views on stress emphasise the existence of more than one response pattern
to stressful events, and the importance of individual differences in coping with
environmental challenges. Therefore, in the evaluation of the specific
contribution of the central nucleus of the amygdala (CEA) in stress and
adaptation it has to be considered whether the stress is acute or conditioned,
and whether it requires active or passive styles of coping. Based on series of
our own studies, we propose that the CEA is consistently involved in the
organisation of processes of passive coping, reflected in immobile behaviour and
parasympathetic activity. Furthermore, a differential regulation of the CEA via
its peptidergic neuronal input may underlie the distinct behavioural and
physiological stress patterns accompanying the different styles of coping.
Additionally, the involvement of the CEA in neuroendocrine control is addressed.
The CEA exerts a general, modulatory influence on the neuroendocrine control to
acute stressors, whereas this output during conditioned stress seems to be
independent of the CEA. The neuroendocrine state as achieved during acute stress
is, via feedback to the brain, of importance in learning about the situation, and
to consolidate the experience. In this review an attempt is made to provide an
integrated model of CEA functioning in relation to stress and adaptation.
PMID- 9401608
TI - Cerebral laterality, repressive coping, autonomic arousal, and human bonding.
AB - Jim Henry wrote extensively about emotional expressive styles, such as
alexithymia which is characterized by reduced awareness of one's own or others'
feelings and emotions, and their relation to cerebral hemispheric asymmetries.
The repressive coping style is a stable individual characteristic, which is
marked by reduced and minimized reports of stress coupled with higher levels of
autonomic, somatic, and behavioural responsivity. The apparent dissociation
between subjective and physiological response may be associated with a functional
disconnection between the two cerebral hemispheres and with greater cerebral
lateralization. To test this hypothesis, we reexamined data from a study in which
emotional and neutral slides were presented unilaterally to the left and right
hemisphere. Exposure duration was 200 ms. Subjects were divided into four
different coping styles based on their defensiveness and anxiety scores.
Repressive copers were the only group to show a significant cardiac response
(heart rate deceleration) to emotional material when it was presented to the
right but not to the left hemisphere. These findings and the fact that repressive
copers have a high need for social approval support Henry's views about the role
of the right hemisphere in affiliation and human bonding.
PMID- 9401609
TI - Genetic influences on the responses to psychosocial challenges in rats.
AB - "Psychosocial stress can induce chronic hypertension in normotensive strains of
rats" (Henry et al. 1993). This effect is however variable among different
strains. Factor analysis of the relationships between temperamental dimensions
measured in social and nonsocial settings shows that sensitivity to chronic
social stress loads on a "social reactivity" factor different from spontaneous
aggressive tendencies. Furthermore an "end-organ" sensitivity of the
cardiovascular system also seems to be necessary to explain individual
vulnerability to psychosocial stress-induced hypertension. These psychological
and pathophysiological characteristics combine with situational components that
are not yet fully defined. The advent of telemetry techniques to monitor heart
rate and blood pressure continuously without any disturbance to the animals
should facilitate the analytical approach of this complex, multifactorial
condition.
PMID- 9401610
TI - Social stress in rats and mice.
AB - This paper summarizes some of the highlights of our current social stress
research in rodents as it was inspired by the work of Jim Henry. First, it is
argued that social defeat can be considered as one of the most severe stressors
among a number of laboratory stressful stimuli in terms of neuroendocrine
activation. Moreover, the stress response induced by defeat in particular is
characterized by a strong sympathetic dominance. Depending on the stress
parameter, the stress response induced by a single social defeat may last from
hours to days and weeks. As a long term consequence of a single defeat
experience, the animal becomes sensitized to subsequent minor stressors. Finally,
the importance of individual differences in coping style in relation to stress
vulnerability is discussed.
PMID- 9401611
TI - Effects of cage enrichment on territorial aggression and stress physiology in
male laboratory mice.
AB - The activation of different neuroendocrine subsystems depends on the individual
perception and coping with the challenging situation, the formulation of these
relations by J.P. Henry represents a most useful concept also for the assessment
of welfare consequences of particular caging variables. We investigated effects
of cage enrichment on behaviour and neuroendocrine activations of male laboratory
mice. Mice in enriched cages behaved more aggressive, lacked stable dominance
hierarchies and exhibited neuroendocrine alterations depending on their
individual social position. Subdominant passive mice were characterized by an
augmented adrenal capacity to synthesize epinephrine despite low activities of
the tyrosine hydroxylase. Dominant mice showed elevated circulating
corticosterone concentrations despite high tyrosine hydroxylase-activities.
Findings showed a dissociation of neurosympathetic and adrenomedullary components
in subdominant passive mice and a simultaneous activation of sympathetic
adrenomedullary and hypothalamo-adrenocortical components in dominant mice.
Within the conceptual framework of the Henry model this would suggest different
deteriorations of welfare in dominant and subdominant passive mice. In the
situation of intensified aggression in the enriched cages the increased
epinephrine synthesis in subdominant mice reflect their more frequent receipt of
attacks and the elevated corticosterone secretion in dominant mice reflect their
hindered ability to control the dominant position.
PMID- 9401612
TI - Social relations and their health impact in tree shrews.
AB - In the wild, tree shrews (Tupaia belangeri) live in pairs in territories which
they defend vigorously against strange conspecifics. The paper gives an overview
on some of our laboratory studies with tree shrews, which demonstrate the great
relevance the concepts of Jim Henry have in understanding the biological
relevance of mammalian social behavior. A basic result of these studies is that
the physiological consequences of social relations between mammals depend on the
appraisal of the situation by the animals and their coping behavior. Appraisal of
a stimulus or a situation, as well as the resulting coping behavior, are
basically psychological processes. There are, therefore, no simple relationships
between stimuli imposed on individuals and their physiological responses; rather
the behavioral, psychological and, thus, the physiological responses of
individuals to stimuli differ depending on their genetics, prenatal influences
and postnatal learning processes. This means, to understand the consequences of
social relations between individuals, an integrated approach is required to
assess which factors, including social rank and bonds to conspecifics, interact
to affect an individual's fertility and health, as has been so clearly
demonstrated in the work of Jim Henry.
PMID- 9401613
TI - The social environment, behaviour and stress--a case study in guinea pigs.
AB - In this article we summarize our work on the relationships between the social
environment, behaviour and stress in guinea pigs. We confirm what Jim Henry
predicted to be a general rule for all mammals including man 20 years ago: The
individual's degree of social stress is related to the stability of the pre- and
postnatal social environment in which it lives, to the amount of social support
which it receives from bonding partners and to the social experiences which it
has made during behavioural development.
PMID- 9401614
TI - Individual responses to acute and chronic stress in pigs.
AB - Pigs can be characterised as resistant (R) or non-resistant (NR) at an early age
(1 to 2 weeks) by means of a backtest. In the test the animal is put on its back
and the number of bouts of resistance is used to characterise the animal. The
test is performed twice with 1 week interval and only pigs that show a consistent
response in both tests are classified as either R or NR pigs. On average eighty
percent of a population can be classified by this test. R and NR pigs show
consistent behavioural, physiological and immunological differences when tested
in various challenge test in later life. The R pigs are more sympathetically
dominated and showing an active coping style (fight/flight) as described in rats
and mice. The NR pigs are more para-sympathetically dominated, resembling the
passive coping style (conservation/withdrawal). In intensive husbandry, breeding
sows are housed individually and often tethered. After long term tethering these
sows show signs of chronic stress; overreaction of the sympathetic nervous
system, hypercortisolaemia and disturbed behaviour. The most common disturbed
behaviour found in tethered sows is stereotyped behaviour. Most sows develop
stereotypies within 1 month after first tethering. Again great differences are
found in the amount of stereotypies shown between sows. Some sows spent up to 80%
of their active time on this behaviour while others hardly develop stereotypies.
Sows showing high levels of stereotypies manage to counteract the sympathetic
overreaction caused by the chronic stress of tethering as was shown by a decrease
in heart rate during bouts of stereotyped behaviour. In this view stereotypies
help the animal to cope with the averse situation of tethering. However, after 8
months of tethering stereotypies are no longer effectively attenuating heart
rate. The effect of stereotypies is limited to the initial phase of chronic
stress when the animal is striving to regain control. When chronic stress
persists stereotypies get dissociated from their effect on the sympatho-adreno
medullary system and the animal loses control.
PMID- 9401615
TI - Physiological and neuroendocrine correlates of social position in normotensive
and hypertensive rat colonies.
AB - The hypothesis to be tested was that socially dominant (D) males in a mixed
gender rat colony will have: higher blood pressure (BP) decreased hypothalamic
pituitary axis (HPA) activity measured by plasma corticosterone (C) and increased
sympathetic activity measured by plasma noradrenaline (NA) as compared to
socially subordinate (S) males. BP was measured continuously by implanted aortic
telemetry (Data Sciences, MN), plasma noradrenaline measured by HPLC with
electrochemical detection and plasma C by RIA. Colonies were established using 8
of each sex of 4 strains: SHR, WKY, and our two Y chromosome congenic strains,
SHR/y and SHR/a. Social ranking was determined by physical scarring scores,
overall locomotor activity and patrol behaviour. D males had higher BP (active
dark cycle) across strains compared to subordinates S: SHR-180 vs 148 mmHg, WKY
145 vs 142 mmHg, SHR/y-185 vs 145 mmHg, SHR/a-180 vs 160 mmHg. Using an acute
stressor, BP responsiveness was higher in D than in S SHR and SHR/y males. D
males had higher NA levels than S males across strains: (SHR-76% increase, WKY
31% increase, SHR/y-29% increase, SHR/a-40% increase). S males had significantly
higher C levels than D males across strains (SHR-29% increase, WKY-123% increase,
SHR/y-25% increase, SHR/a-61% increase). The hypertensive Y chromosome (SHR or
SHR/y) produced higher SBP during the active dark cycle in D males than in D
males with a normotensive Y chromosome (WKY or SHR/a). In conclusion, D males
from related hypertensive strains showed elevated sympathetic activity measured
by plasma NA and reduced HPA activity measured by plasma C as compared to S
males. (Supported by HL-48072-04).
PMID- 9401616
TI - Using ethological principles to study psychosocial influences on coronary
atherosclerosis in monkeys.
AB - Studies with male cynomolgus monkeys suggest that atherosclerosis is potentiated
among individuals that are habitually successful in their aggressive encounters
with social strangers, thereby retaining dominant social status in an unstable
environment. Further, the increased risk of atherosclerosis experienced by such
animals is related, in part, to the autonomic (sympathetic) adjustments they make
while responding to the demands of retaining dominant status. These data provide
clear support for the hypothesis that psychosocial factors influence disease
pathogenesis via neuroendocrine mediation. Additionally, they provide initial
evidence in favor of Jim Henry's suggestion that the pattern of neuroendocrine
response to environmental challenge depends on the type and degree of control an
animal can exert in such circumstances (Henry & Stephens 1977).
PMID- 9401617
TI - The role of psychosocial factors in human disease: lessons from animal models.
AB - Studies with humans have identified certain psychosocial characteristics that are
associated with increased risk of developing life-threatening illnesses, as well
as biological and behavioral mechanisms whereby risk is mediated. In this paper I
review research wherein the use of animal models increases our understanding of
the mechanisms acting in humans, using research on psychosocial risk factors and
the "SES gradient" as examples.
PMID- 9401618
TI - A biopsychosocial approach to etiology and pathogenesis.
AB - The interactive etiological and pathogenic processes between physical and
psychosocial environ-mental stimuli, the individual's appraisal of these
influences, and his or her reactions to them in terms of emotion, cognition,
behaviour, and physiology; the modification of these reactions through coping,
social support, and other interacting variables; and the resulting changes in
health and well-being--are extremely complex and poorly understood. Against this
background, this paper argues for a biopsychosocial approach, based on an
ecological model influenced by, and influencing, James P. Henry's related
approaches. This approach is exemplified in six studies carried out by our group
and briefly reviewed in this paper.
PMID- 9401619
TI - Fighting for and losing or gaining control in life.
AB - In JP Henry's work, fighting for and losing control were important concepts in
the interpretation of energy mobilization in psychosocial conditions. Attachment
and support were important protective and salutogenic factors. These concepts
have been applied in a series of epidemiological and psychophysiological real
life studies. Job conditions which force the worker to mobilize energy and
concomitantly inhibit anabolism could be identified at least partly by means of
the demand-control-support model originally proposed by Karasek. The most adverse
conditions at work arise when psychological demands are high and at the same time
the decision latitude is low. This combination is associated with changes in the
regulation of endocrine parameters as well as with increased morbidity--heart
disease, functional gastrointestinal symptoms and musculoskeletal disorders.
Examples of studies of physiological correlates of psychosocial processes leading
to fight for control are also described from outside work activities.
PMID- 9401620
TI - Linking sociological with physiological data: the model of effort-reward
imbalance at work.
AB - While socio-epidemiologic studies documented impressive associations of
indicators of chronic psychosocial stress with cardiovascular (c.v.) disease
evidence on patho-physiologic processes is still limited. In this regard, the
concept of heightened c.v. and hormonal reactivity (RE) to mental stress was
proposed and explored. While this concept is a static one we suggest a more
dynamic two-stage model of RE where recurrent high responsiveness (stage 1) in
the long run results in attenuated, reduced maximal RE due to functional
adaptation (stage 2). We present results of an indirect test of this hypothesis
in a group of 68 healthy middle-aged men undergoing a modified Stroop Test: in
men suffering from high chronic work stress in terms of effort-reward imbalance
significantly reduced RE in heart rate, adrenaline and cortisol was found after
adjusting for relevant confounders. In conclusion, results underscore the
potential of linking sociological with physiological data in stress research.
PMID- 9401621
TI - The sympathetic nervous system in human hypertension.
AB - While animal models of hypertension have clearly shown an increase in sympathetic
activity, a similar demonstration in humans has been more difficult to obtain for
methodological reasons. There is now clear evidence, however, of an increase
sympathetic activity in essential hypertension by the finding of either an
increase in plasma norepinephrine and an increase in muscle sympathetic nerve
traffic. Among the mechanisms responsible for this sympathetic activation the
arterial baroreflex may play a role although probably a non specific and late
one. Central neural influences associated with an excessive hypothalamic response
to stress may also be involved, but conclusive evidence is still lacking due to
the difficulty of assessing cardiovascular reactivity to stress in man. A deeper
insight into the features of human sympathetic cardiovascular control may be
offered now by new techniques which allow neural cardiovascular regulation to be
assessed in daily life through computer analysis of noninvasive ambulatory beat
by-beat blood pressure and heart rate recordings.
PMID- 9401622
TI - Continuing on J.P. Henry's path; studies of physiology and pathophysiology of
cardiopulmonary receptors in humans.
AB - The seminal work of Henry and Gauer lead us to a) show that in healthy humans
cardiopulmonary receptors (CPR) regulate renin release, b) that low renin
hypertension is associated with an expanded cardiopulmonary volume. This
suggested that the low renin state in hypertension may be due to excessive
inhibition of renin by the CPR. In the course of these experiments we uncovered
an undescribed pressor reflex which was used to investigate the effect of
intermittent pressor episodes on cardiac structure in dogs. Finally, in recent
years, we used unloading of CPR to show that reflex vasoconstriction causes acute
insulin resistance in the human forearm.
PMID- 9401623
TI - The effects of occupational stress on blood pressure in men and women.
AB - Human hypertension is the end result of a number of genetic and environmental
influences, and typically develops gradually over many years. The sympathetic
nervous system appears to play a role in the early stages, with structural
changes in the resistance vessels becoming dominant later on. The extent to which
increased sympathetic actively may be the result of environmental stress is
uncertain. Animal studies have suggested that chronic stress can raise blood
pressure. Human epidemiological studies have shown that the prevalence of
hypertension is strongly dependent on social and cultural factors. Blood pressure
tends to be highest at work, and studies using ambulatory monitoring have shown
that occupational stress, measured as job strain, can raise blood pressure in
men, but not women. This may be associated with increased left ventricular mass.
The diurnal blood pressure pattern in men with high strain jobs shows a
persistent elevation throughout the day and night, which is consistent with the
hypothesis that job strain is a causal factor in the development of human
hypertension.
PMID- 9401624
TI - Stress hypertension: the "wrong" genes in the "wrong" environment.
AB - Jim Henry demonstrated an animal's society can induce an increase in blood
pressure and its cardiovascular sequale. He recognized that the stress required
to elevate blood pressure was a function of the genetically determined behavioral
traits of the mice used. He termed some strains aggressive, others peaceable.
Being highly inbred (indeed isogenic strains) it was intriguing to find that the
behavior of these genetically identical individuals could differ markedly once
placed in a society that decreased territory. A dominant or "king" mouse emerged.
Other non-dominant males were aggressive and striving to be king. Adrenal
medullary systems were activated and renins high. Others huddled in one cage and
appeared to have given up. Jim called them depressed. Their adrenal cortex was
hyperplastic suggesting pituitary adrenal axis activation as in depression, their
renin was low and corticosterone high. In rats, careful selection of a strain
genetically aggressive had to be combined with titration of societal stress to
reliably induce hypertension. Its likely that humans retain some, if not all, of
these variations, i.e. some respond to stress with an increase in blood pressure
and others do not, some respond via the sympathetic pathway and others by adrenal
cortical activation. The suggestion that African American's high blood pressures
is due to stress is relevant to the Henry paradigm and the known genetic
influences on sodium retention in blacks. The integration of this paradigm with
the genetically increased sensitivity to the blood pressure raising effects of
dietary sodium in blacks is proposed and discussed.
PMID- 9401625
TI - Do environmental effects on human emotions cause cardiovascular disorders?
AB - Environmental influences on human health include the effects of toxic materials
and adverse ecological factors. Natural milieu stressors also affect emotions
that may adversely affect cardiovascular function and precipitate or otherwise
contribute to complications of cardiovascular diseases. However, although
variously hypothesized, there is inadequate evidence that they directly
contribute to the pathogenesis of sustained hypertension or coronary
atherosclerosis.
PMID- 9401626
TI - Blood pressure trend and psychosocial factors: the case of the nuns in a secluded
order.
AB - The powerful effect of psychosocial and acculturating influences on population
blood pressure trends seems to be confirmed, through longitudinal observations in
the nuns in a secluded order. After initial observation had been made on culture,
body form, blood pressure, diet, and other variables in 144 nuns and 138 lay
women, included as a control group, a 30-year follow-up study was undertaken.
Most striking were opposite trends noted between the two groups in blood pressure
trend. During the follow-up period blood pressure remained remarkably stable
among the nuns. None showed a rise in diastolic blood pressure to above 90 mmHg.
By contrast, the control women showed the expected increase in blood pressure
with age. This resulted in a gradually greater difference (A > 30/15 mmHg) in
systolic and diastolic blood pressure between the two groups, which was
statistically significant. It appears reasonable to attribute much of the
difference in blood pressure to the different burden in psychosocial factor and
to the preserved peaceful lifestyle of the nuns.
PMID- 9401627
TI - Visceral responses to the social environment.
AB - Twenty-five hundred years ago, Hippocrates, recognizing the impact of life
experience on health wrote: "those things which one has been accustomed to for a
long time, although worse than things to which one is not accustomed, usually
give less disturbance" (Bruhn & Wolf 1978). Since Hippocrates, much evidence has
emerged to suggest that social stability is conducive to health, while social
change, especially rapid change, may predispose to illness. The idea that sensory
information from ordinary life experiences contributes in a major way to shaping
the activities of the brain, took root in the 18th century with Pierre Gassendi
and John Locke. A mechanism whereby the vast numbers of neurons in the brain
could be rapidly rearranged and organized to respond to a host of different
external stimuli emerged from the work of Santiago Ramon y Cajal who discovered
the axonal growth cone and its capacity to elongate and guide an axon a
considerable distance to a target dendrite (Cajal 1890). Thereby, with very rapid
shifts in attention and perception, a wide range of responses, emotional, and
physiological can be elicited. With this and other evidence at hand that the
intracranial regulatory mechanisms can reorganize in response to environmental
change including social change, we undertook a 30 year (1962-1992) prospective
study of the effects of social patterns on health in Roseto, a closely knit
Italian-American incorporated town in Pennsylvania. It was settled in 1882 by
Italians from Roseto val Fortore, a town in southern Italy near the Adriatic Sea.
We found a sharp increase in myocardial infarction among Rosetans when long
established cohesive social patterns began to weaken and be replaced by more
egocentric attitudes.
PMID- 9401628
TI - Stress and cardiovascular disease.
AB - The statistical associations between stress and cardiovascular and other
prevalent diseases have not been explained. Perceived stress, resulting in an
uncontrollable defeat reaction, has been shown by James Henry (Henry 1993) to be
followed by specific endocrine abnormalities, including sensitization of the
hypothalamo-pituitary-adrenal (HPA) axis, and inhibited sex steroid and growth
hormone secretions. With an elevated waist/hip circumference ratio (WHR)--a
simple, surrogate, measurement of intraabdominal, visceral fat masses--combined
with insulin resistance, similar endocrine perturbations are found. Based on
considerable evidence, such endocrine abnormalities seem to be followed by
accumulation of intraabdominal, visceral fat masses and insulin resistance, both
powerful risk factors for cardiovascular disease, diabetes and stroke. A
postulated chain of events is therefore that the endocrine perturbations are
primary factors, followed by visceral fat accumulation, insulin resistance and
other risk factors dependent on the hyperinsulinemia following insulin
resistance. This highlights the importance of elucidating the cause(s) to the
endocrine abnormalities. These are identical to those described by Henry (1993)
to follow a stress reaction of a defeat type. Findings of several psychosocial
and socio-economic handicaps might provide a basis for such a reaction, supported
by experimental studies in primates. Furthermore, depression, anxiety, alcohol
consumption and smoking, all known activators of the HPA axis, are also often
found. The low sex steroid and growth hormone secretions might be secondary to
the hypersensitive HPA-axis. They could also be caused by other factors, and are,
each alone, capable of causing both visceral fat accumulation and insulin
resistance. Visceral fat accumulation is only an indirect, surrogate measurement
of the underlying endocrine abnormalities, but is useful for screening purposes
on a population basis. Developments of novel techniques for sensitive, yet simple
measurements of HPA axis activity under undisturbed conditions seem to allow a
better definition of pathogenetic factors. Utilizing such methods, subgroups of
the syndrome including visceral fat accumulation, insulin resistance and other
associated risk factors (Metabolic Syndrome), are beginning to emerge. A more
detailed information on noxious factors in society leading to a defeat reaction
to perceived stress, endocrine abnormalities and the Metabolic Syndrome, with
increased risk for prevalent disease may hopefully be developed by these new
methods.
PMID- 9401629
TI - Heart disease mortality and economic changes; including unemployment; in Western
Germany 1951-1989.
AB - Research over the last two decades has indicated that changes in cardiovascular
disease mortality rates have been influenced by those in national economic
indicators as well as by measures of consumption of tobacco, animal fats and
alcohol. These findings predominantly involved the United States, United Kingdom
and Scandinavian countries. The economic indicators included real per capita
income and social welfare expenditures (beneficial relationships to mortality
rates), and unemployment rates and business failure rates (detrimental
relationships to mortality). James Henry's formulations have emphasized that many
different illnesses respond to emotional stresses in different
psychophysiological patterns depending on the specific constellations of emotions
aroused. On the assumption that the impact of national economic changes on
cardiovascular mortality reflects emotional stresses, losses, frustrations and
deprivations, similar tests were undertaken using Western German heart disease
mortality rate data over 1951-1989. Time-series regression analysis showed that,
holding constant the effects of tobacco, animal fats and alcohol, increased
income and social welfare expenditures are related to heart disease mortality
rate declines, whereas increased unemployment and business failure rates are
related to heart disease mortality rate increases over more than a decade.
PMID- 9401630
TI - Exhausted subjects, exhausted systems.
AB - A state of 'vital exhaustion', characterized by unusual tiredness, increased
irritability and feelings of demoralization has been found to preceed the onset
of myocardial infarction and to increase the risk of a new coronary event after
angioplasty. Probably this state reflects a decreased activity of the
hypothalamic-pituitary-adrenal axis as part of an homeostatic reaction to
prolonged stress and inflammation.
PMID- 9401631
TI - Stress management & hypertension.
AB - Review of literature suggests that emotional and social stress is a contributory
factor to the development of hypertension. If so, relaxation and stress
management therapy may reduce high blood pressure (BP) and its complications. In
a series of studies I and my colleagues have shown that this may be so. These
studies have been published elsewhere and are briefly summarized here.
PMID- 9401632
TI - Changes in cardiovascular risk factors and hormones during a comprehensive
residential three month kriya yoga training and vegetarian nutrition.
AB - In participants of a comprehensive residential three month yoga and mediation
training programme living on a low fat lacto-vegetarian diet changes in
cardiovascular risk factors and hormones were studied. Substantial risk factor
reduction was found. Body mass index, total serum and LDL cholesterol,
fibrinogen, and blood pressure were significantly reduced especially in those
with elevated levels. Urinary excretion of adrenaline, noradrenaline, dopamine,
aldosterone, as well as serum testosterone and luteinizing hormone levels were
reduced, while cortisol excretion increased significantly.
PMID- 9401633
TI - The consequences of having experienced overwhelming stress.
PMID- 9401634
TI - Traumatic stress and attachment.
AB - Traumatic stress in the normal individual results in activation of the sympatho
adrenal system causing a rise in noradrenaline and adrenaline, stimulation of the
thyroid system causing increased secretion of thyroid hormones and activation of
the hypothalamic-pituitary-adrenocortical (HPA) system resulting in elevated
levels of cortisol. Studies in animals and in humans with posttraumatic stress
disorder indicate that chronic traumatic stress can result in dissociation of the
sympatho-adrenal medullary and the HPA system resulting in sustained elevations
of the former system but suppressed or altered ACTH-corticoid responsivity. As
reviewed by Henry, self preservative behavior with its emphasis on power and
control, is associated with catecholamines, thyroid hormones and left hemispheric
functioning while species preservative behavior, with its emphasis on attachment,
familiarity, reverence and synchronicity, is associated with cortisol, oxytocin
and right hemispheric functioning. Traumatic stress seems to disturb this
hemispheric balance which is reflected in the suppression of cortisol and loss of
attachment behavior and other species preservative right hemispheric functions.
PMID- 9401635
TI - James P. Henry. Revisited in reference to his Instincts, Archetypes, and Symbols:
an approach to the physiology of religious experience.
AB - In his Instincts, Archetypes, and Symbols James P. Henry places physiological
aspects of religious experience in the context of cultural anthropology and
religious philosophy. His approach is Jungian. Of major concern is the liberation
of the human mind from privatizations of goodness (privatio boni). Henry
characterizes optimal natural conditions for a healthy psyche substantiated by
physiological research.
PMID- 9401636
TI - James Paget Henry: a man for all seasons.
AB - Jim Henry is best known for his seminal research on psychosocial stress and
cardiovascular disease, and studies of the neuroendocrine correlates of animal
behaviors during stress. However, he had a wide range of interests, made
important contributions in many other areas, and served as a remarkable catalyst
in advancing the work of other scientists. These numerous and less appreciated
accomplishments could not possibly be covered in an article of this length.
Hopefully, some personal observations, and a brief sketch of his extension of
Carl Jung's research and his involvement in the U.S. space program, may help to
illustrate the superb character and qualities of this modest and multifaceted
individual, as well as a few of his lesser known, but equally meaningful
achievements.
PMID- 9401637
TI - Jim Henry's world revisited--environmental "stress" at the psychophysiological
and the molecular levels.
AB - Ever increasing applications of sophisticated technologies in western
civilization have placed great and growing demands for the rapid and accurate
processing of multi-modal sensory information. These information streams may
exceed an individual's performance capabilities. Failure to respond appropriately
may have serious consequences, not only for the individual but also for others,
as in command situations in the aerospace environment. There are, for example,
consistent patterns common to EEG records in a population of astronaut
candidates, when exposed to increasing visual information overload, simulating
hazardous flight conditions. The records are dominated at the point of
"information overload" by sharply and progressively increased theta wave (4-7 Hz)
activity in temporal regions, major increments in frontal beta (> 14 Hz)
activity, and markedly reduced occipital alpha (8-12 Hz) levels. These responses
to a simulated stress raise questions about the brain's ability to distinguish
natural reality from the mediated reality in modern life. It has been
hypothesized that an individual's reactions with computers, television and new
media are fundamentally social and natural, just as in interactions in real life.
Also immune responses may here offer valuable benchmarks concerning reactions to
mentally stressful stimuli. Another type of environmental influences in modern
society is that of electromagnetic fields. Even fairly weak (athermal)
electromagnetic fields have proven to be useful tools to study regulatory
mechanisms in cells from brain and other tissues. There is growing evidence that
nitric oxide may influence normal EEG patterns and that it may also participate
in the pathophysiology of oxidative stress disturbances, including influences in
e.g. Parkinson's and Alzheimer's diseases, then behaving as a free radical with
reactive-oxygen-species or reactive-nitrogen-species. As a free radical, nitric
oxide is sensitive to a variety of imposed magnetic fields, with theoretical and
experimental evidence that its actions in regulating the rate and amount of
product of cerebral biochemical reactions may also be modulated by imposed
magnetic fields.
PMID- 9401638
TI - Transcription factor abnormalities as a cause of beta cell dysfunction in
diabetes: a hypothesis.
AB - Well-characterized defects in insulin secretion, most notably a loss of glucose
induced insulin secretion, are found in virtually all forms of NIDDM, as well as
in early IDDM. Similar abnormalities have been found in all animal models of
diabetes in which they have been studied. A novel hypothesis is being proposed to
explain the mechanisms responsible for these alterations. Many abnormalities in
the various steps of glucose-induced insulin secretion have been identified in
rodent models of diabetes, but none by itself seems sufficient to explain the
defects. These include a loss of GLUT2, glycogen accumulation, glucose recycling,
abnormal glucokinase or hexokinase, altered mitochondrial glycerol phosphate
dehydrogenase (mGPDH) activity, abnormal ion channel function and beta cell
degranulation. We propose that optimal secretory function is dependent upon the
unique differentiation of beta cells that is maintained by a set of transcription
factors and that this control is disrupted by the diabetic state. Therefore, we
propose that key transcription factors are affected even when beta cells are
stressed by insulin resistance in very earliest stages of diabetes and that the
abnormality becomes more severe as full-blown diabetes develops, which leads to
loss of beta cell differentiation and a resultant derangement of insulin
secretion.
PMID- 9401639
TI - Islet autoantibodies and their use in predicting insulin-dependent diabetes.
PMID- 9401641
TI - Prevalence and 4-year incidence of insulin-dependent diabetes mellitus in the
province of Oristano (Sardinia, Italy).
AB - The aims of this study were: (1) to estimate the prevalence of insulin-dependent
diabetes mellitus (type I) among the population of 0-29-years-old residents in
the province of Oristano on 31/12/96; (2) to estimate the incidence of type I
diabetes among the population of 0-29-years-old residents in the province of
Oristano between 1993 and 1996. Data concerning the cases were collected from two
independent sources. The capture-recapture method was utilised to estimate
ascertainment probability. Demographic data for the resident population were
supplied by 78 communes in the province. The completeness of the primary data
source for prevalence was 97.1%; the estimated prevalence was 4.61 per thousand.
The number of type I diabetic subjects identified in a population of 60,095
people aged 0-29 years was 276, i.e. a prevalence of 4.59 per thousand (95%
confidence intervals [CI] 4.07-5.17). No cases were found in the commune of
Arborea, where a large percentage (65%) of immigrants from the Veneto region live
(total population < 30 years of age = 1706; 8 expected cases; P < 0.001). The M/F
ratio was 1.12. The completeness of primary source of incidence data was 100%.
Between 1993 and 1996, the number of new type I diabetic subjects was 86, with a
M/F ratio of 1.00. The age-standardised incidence rates were: 54.4 (95% CI 41.3
70.1) in the 0-14-year-age group, 22.0 (95% CI 15.2-30.5) in the 15-29-year-age
group and 38.2 (95% CI 31.0-46.4) in the 0-29 year age group, per 100,000 person
years. The incidence and prevalence of type I diabetes mellitus are very high,
ranking the province of Oristano among the highest in Europe.
PMID- 9401640
TI - Accelerated gastric emptying during hypoglycaemia is not associated with changes
in plasma motilin levels.
AB - This study examined whether or not changes in plasma concentrations of motilin
and other gastrointestinal hormones known to affect gastric motility are
associated with the accelerated gastric emptying seen during hypoglycaemia. While
studying gastric emptying by scintigraphy in eight healthy subjects, the plasma
concentrations of glucagon, adrenaline, motilin, gastrin, neuropeptide Y and
somatostatin were measured during normoglycaemia and hypoglycaemia with
simultaneous infusion of either atropine or saline. Blood glucose concentrations
were checked by an insulin-glucose clamp. The plasma levels of glucagon and
adrenaline increased markedly during both hypoglycaemic examinations compared
with normoglycaemia. Neither motilin nor any of the other hormones displayed
considerable changes during hypoglycaemia with and without atropine compared with
normoglycaemia. No further information about the mechanisms behind the
accelerated gastric emptying rate during hypoglycaemia was obtained by analysing
motilin and the other gastrointestinal hormones.
PMID- 9401642
TI - Acute effects of pioglitazone on glucose metabolism in perfused rat liver.
AB - Pioglitazone, a thiazolidinedone derivative, decreases insulin resistance and
improves hyperglycemia in insulin-resistant obese and/or diabetic animals.
However, the mechanisms by which hyperglycemia is improved are not well defined.
We investigated the effects of pioglitazone on hepatic glucose metabolism using a
perfused rat liver model. Perfusion with the buffer containing 1-10 microM
pioglitazone for 20 min dose-dependently increased the hepatic fructose 2,6
bisphosphate content, a potent activator of 6-phosphofructo 1-kinase. The
fructose 2,6-bisphosphate level after 20 min perfusion with 10 microM
pioglitazone was 64.9 +/- 14.5 pmol/mg.protein, significantly higher than the
control (48.3 +/- 10.9 pmol/mg.protein). When the liver from a starved for 48 h
rat was perfused with the buffer containing 2 mM lactate but no glucose, glucose
was generated from lactate via the gluconeogenic pathway and flowed into the
effluent perfusate at a constant rate of 31 +/- 0.6 mumol/g.liver/h. The addition
of 10 microM pioglitazone decreased the glucose output rate to 19.3 +/- 3.8
mumol/g.liver/h. Dose-dependent inhibition of glucose output by pioglitazone was
observed in the 1-10 microM dose range. These results indicate that pioglitazone
may not only stimulate glycolysis but also inhibit gluconeogenesis in the liver.
These acute and insulin-independent effects on hepatic glucose metabolism may
partly account for the diverse anti-diabetic effects of pioglitazone.
PMID- 9401643
TI - Relative weight of glucose, insulin and parathyroid hormone in the urinary loss
of phosphate by chronically diabetic rats.
AB - This report deals with the relationships between glucose (G) and insulin on the
tubular transport of phosphate (P) in chronically diabetic rats with high plasma
levels of parathyroid hormone (PTH). Alloxan-induced diabetes leads to phosphorus
depletion of the soft tissues. This phenomenon appears associated with weight
loss and negative P balances caused by the increased urinary P excretion.
Administration of 2 IU of insulin/100 g body weight (bw) to diabetic rats
normalized their P balance and body weight. The effect of parathyroid function on
the P metabolism of diabetic rats was investigated with balance experiments.
Diabetic rats, intact or thyroparathyroidectomized (TPTX), have a greater urinary
excretion of P than their controls. However, in control rats, the ratio
intact:TPTX for urinary P is 1.0:0.76, showing the antiphosphaturic effect of
parathyroid ablation. For diabetic animals, on the other hand, the ratio is
1.0:1.44. The simultaneous deficit of insulin and PTH thus quadruples the urinary
P loss, instead of compensating for each other. The contribution of insulin
deficit and hyperglycemia to the defect in tubular reabsorption (TRP) was
investigated with clearance experiments (done on anesthetized, perfused rats).
Five experimental groups were used: Controls (C), diabetics (D), controls +
glucose (C + G), diabetics + insulin (D + I) and diabetics + insulin + glucose (D
+ I + G). All experimental groups showed a linear relationship between the TRP of
P and G. The regression equation for C is significantly different (F = 40.1, P <
0.001) from that of D animals. The slope value measure the number of mumoles of P
per mumol of G reabsorbed. For C and D rats, the ratio P:G approximates 1:4 and
1:20, respectively. The increase in P:G ratios represents the competition between
both substrates for tubular resorption. Glycemias up to 11 mM (C and D + I) exist
concurrent with the P:G ratio 1:4 Glycemias above 25 mM (D, C + G and D + I + G)
produce a P:G ratio of 1:20. Fractional excretion of P (FEP) increased
significantly in untreated, chronically diabetic rats (0.47 +/- 0.12 vs controls
= 0.05 +/- 0.01, P < 0.001). After a single intramuscular injection of insulin,
the FEP decreased as a function of insulin levels. To normalize the FEP of
diabetic rats in short-term experiments, insulin had to be administered in doses
that produce plasma insulin levels 25 times greater than normal. The general
information afforded by the present experiments shows that in untreated,
chronically diabetic rats, insulin deficit plays an indirect role. The absence of
PTH enhances the effect of hyperglycemia. The latter and the concurrent tubular
overload of glucose are the cause of hyperphosphaturia in these animals.
PMID- 9401644
TI - Glycosylated hemoglobin as predictor of adverse fetal outcome in type 1 diabetic
pregnancies.
AB - The study aimed to determine whether a consistent dose-response association can
be demonstrated, after adjustment for maternal age and White classification,
between glycosylated hemoglobin (HbA1c) values before conception and in the first
trimester of pregnancy of insulin-dependent diabetic mothers and adverse fetal
outcome (abortions and major malformations). This is a historical follow-up study
based on medical records in a geographically defined catchment area. The study
comprised 60 pregnancies with HbA1c determinations before pregnancy and 161 with
HbA1c in the first trimester in women with type 1 diabetes admitted between 1980
and 1992. Relative risk calculations indicated a highly significant and
consistent correlation between HbA1c values above 6.6% and adverse fetal outcome
after adjustment for differences in maternal age and White classification. Our
data support a clinically significant and consistent relationship between adverse
fetal outcome and HbA1c in the first trimester of pregnancy of type 1 mothers,
without any indication of a cut-off level below which further improvement in
HbA1c was of minor importance.
PMID- 9401645
TI - Erythrocyte Na+/H+ exchange and preclinical abnormalities of the left ventricular
diastolic function in normotensive type 1 (insulin-dependent) diabetic patients.
AB - We assessed the relationship between erythrocyte Na+/H+ antiport activity and
myocardial anatomical-functional parameters (by Doppler echocardiography) in
normotensive IDDM patients, with and without microalbuminuria. We studied 33
normotensive IDDM subjects and 14 matched healthy controls (group 4). Based on
urinary albumin excretion rate (UAER), 23 diabetics were normoalbuminuric, 10
microalbuminuric (group 3). Normoalbuminurics were divided up for normal (group
1, n = 13) or high (group 2, n = 10) antiport activity. We evaluated fasting
glycaemia and 24-h urine glucose output, HbA1c, plasma lipids, urea, creatinine
and electrolyte clearances, UAER, erythrocyte Na+/H+ countertransport, M-Mode and
2D echocardiograms with Doppler analysis. Antiport, which was higher in diabetics
than controls, was significantly overactive in groups 2 and 3 vs group 4,
independently from UAER. Diabetics showed left ventricular volume, cardiac mass
and systolic function within the control range. In left ventricular diastolic
filling, while peak E was similar in diabetic and healthy people, the late peak
transmitral flow velocity (peak A) was significantly higher in diabetics than
controls, and this was also true in groups 2 and 3 vs group 4. Antiport activity
was positively related to peak A (p < 0.03). These observations suggest that (a)
the Na+/H+ antiport may be overactive in diabetes, apart from microalbuminuria;
(b) increased Na+/H+ antiport activity, in normotensive IDDM people, may be
associated with preclinical diastolic myocardial dysfunction ("incipient diabetic
cardiomyopathy"?).
PMID- 9401646
TI - A liquid mixed meal or exogenous glucagon-like peptide 1 (GLP-1) do not alter
plasma leptin concentrations in healthy volunteers.
AB - Glucagon-like peptide 1 [7-36 amide] (GLP-1) and the obese gene product (leptin)
are thought to be involved in the central regulation of feeding. Both may act
from the peripheral circulation to influence brain function. To study potential
interactions, GLP-1 ([7-36 amide]: 0.4, 0.8 pmol kg-1 min-1 or placebo on
separate occasions) was infused intravenously (from -30 to 240 min) into nine
healthy volunteers [age 26 +/- 3 years, body mass index: 22.9 +/- 1.6 kg/m2,
glycated haemoglobin HbA1c: 5.0% +/- 0.2% (normal: 4.0%-6.2%), creatinine: 1.1 +/
0.1 mg/dl], and (at 0 min) a liquid test meal (50 g sucrose in 400 ml 8% amino
acid, total amino acids 80 g/l) was administered via a nasogastric tube. Plasma
leptin (radioimmunoassay, RIA), glucose, insulin (microparticle enzyme
immunoassay), C-peptide (enzyme-linked immunosorbent assay) and GLP-1 (RIA) were
measured, and statistical analysis was done with repeated-measures ANOVA and
Student's t-test. Plasma leptin concentrations were 31 +/- 6 pmol/l in the basal
state. They did not change within 240 min after meal ingestion nor in response to
the infusion of exogenous GLP-1 [7-36 amide] (P = 0.99 for the interaction of
experiment and time) leading to GLP-1 mean plasma levels of 25 +/- 2 and 36 +/- 3
(basal 6 +/- 1) pmol/l. On the other hand, glucose (from basal 4.7 +/- 0.1 to 6.0
+/- 0.2 mmol/l at 15 min, P < 0.05) and insulin (from basal 28 +/- 2 to 325 +/-
78 pmol/l at 45 min, P < 0.05) increased clearly after the meal with placebo. In
conclusion, (1) plasma leptin levels in normal human subjects show no short-term
changes after feeding a liquid mixed meal and (2) do not appear to be directly
influenced by physiological and pharmacological elevations in plasma GLP-1 [7-36
amide] concentrations. This does not exclude interactions at the cerebral
(hypothalamic) level or on more long-term temporal scales.
PMID- 9401647
TI - Free plasma magnesium following glucose loading in healthy humans.
AB - The recognized existence of a circadian pattern in extracellular magnesium
balance might mirror either an inherent rhythm in the homeostasis of this ion or
dietary factors. Since in vitro insulin enhances cellular magnesium uptake, the
circadian rhythm in extracellular magnesium metabolism might be modulated at
least in part by carbohydrate intake. To assess this hypothesis, the effects of
oral glucose loading on plasma total and ionized magnesium were investigated in
lean healthy humans with a negative family history for essential hypertension and
diabetes mellitus. Plasma total and ionized magnesium was similar before glucose
loading and 30, 60, 90, 180, and 210 min thereafter. It is therefore concluded
that in healthy humans the circadian pattern of extracellular magnesium is not
modulated by the metabolic and hormonal mechanisms that adjust the concentration
of glucose.
PMID- 9401648
TI - Haematoma evacuation does not improve outcome in spontaneous supratentorial
intracerebral haemorrhage: a case-control study.
AB - Surgical intervention in supratentorial intracerebral haemorrhage (ICH) is still
controversial. We assessed the value of haematoma evacuation with a case-control
study. 145 consecutive patients with supratentorial spontaneous ICH without
tumour or vascular abnormalities were analysed. Haematoma evacuation was
performed in 24 patients. Age, sex, Glasgow Coma Scale (GCS), level of
consciousness, pupillary reaction on admission, localisation, aetiology and
volume of the haematoma, presence of ventricular blood, and Glasgow Outcome Scale
(GOS) on discharge were analysed. From statistical analysis 40 patients > 80
years and with haematoma volume < 10 ml, who were always treated conservatively,
were excluded. Prognostic factors retained from a multiple regression model with
the dichotomised GOS scale (GOS 1-3, 4 + 5) as response variable were GCS,
haematoma volume and location. The only difference between all medically treated
and "operated" patients was haematoma volume, which was larger in the "operated"
patients. All 24 evacuated cases could be matched to a medically treated control
regarding age, haematoma volume and location, GCS, and pupillary reaction.
Significant differences between the two groups could not be detected. Outcome was
not different between the two groups. After separating the sample into patients
with and without ventricular haemorrhage, there was no different outcome between
the two groups either. We conclude that haematoma evacuation did not improve
outcome in supratentorial spontaneous ICH. Since haematomas were evacuated mainly
in clinically deteriorating patients, our data suggest that the only effect of
haematoma evacuation is to stop progressive deterioration rather than to improve
overall clinical outcome.
PMID- 9401649
TI - Treatment results of acromegaly as analyzed by different criteria.
AB - Results of treatment of acromegaly are often incomparable due to the different
criteria which have been used for defining cure or control of disease. At the
present time it is widely accepted, that the main criteria of cure must be
normalization of IGF-1 and a GH in the OGTT < 2 ng/ml. In this retrospective
study we investigated the endocrinological results of 56 patients, who were
surgically treated because of a GH-producing pituitary adenoma, by different
criteria. Twelve of our patients had had additional medical treatment after
surgery, two received radiotherapy. At a mean follow-up of 34 months after
surgery 66% of patients had a basal GH < 5 ng/ml, 64% had a GH in the OGTT < 2
ng/ml and 73% had normalization of IGF-1. The combined criteria of OGTT < 2 ng/ml
and IGF-1 normalization have been fulfilled in 59% of patients. None of these
latter patients developed a clinical recurrence during the follow-up period. An
optimal result (endocrinological cure, no permanent surgical complications and
intact pituitary function) was achieved in 43% of patients. Although surgery was
responsible for 19 new pituitary axis deficiencies (7 corticotropic axis, 8
thyrotropic axis and gonadotropic axis), 22 partial deficiencies improved to
normalization after surgery (respectively 6, 3, and 13). Pre-operatively 55% of
patients had no pituitary deficiency, after surgery this was 61%, leaving a net
positive result of 6% less pituitary deficiencies. The authors conclude that
normalization of IGF-1 combined with an OGTT < 2 ng/ml are adequate criteria for
the definition of cure of acromegaly. However, the authors propose to include
post-treatment hypopituitarism as an additional criterion by which treatment of
acromegaly should be evaluated.
PMID- 9401650
TI - Early radiologically proven rebleeding from intracranial cavernous angiomas:
report of 6 cases and review of the literature.
AB - Although intracranial cavernomas are known to cause haemorrhage, data concerning
the frequency, severity and delay of recurrent bleedings are controversial. We
report a series of 6 patients with histologically proven cavernoma, presenting
with early clinical signs and radiological proof of rebleeding, that is occurring
in the first month after initial overt haemorrhage. These 6 cases have been
selected from a series of 142 patients seen between 1980 and 1995 in our
department with cavernous angiomas or so-called AOVMs, of whom 93 presented with
clinical symptoms of haemorrhage (34 patients presented symptoms of one or more
rebleeding, but only 6 had radiological proof). All patients suffered
neurological worsening due to the rebleeding, with an increase of the size of the
haematoma on the CT scan. Five MRIs were performed at the acute stage: 3 showed
evidence of cavernoma (60%). All patients underwent surgery at the acute stage of
the rebleeding, with 5 improvements and 1 stabilization. A cavernous angioma was
found in 5 cases at first surgery, but a further operation was necessary in the
last patient to find and remove the cavernoma, after a second rebleeding
following the first intervention. Our series reveals a high frequency of
rebleeding after a first intracranial haemorrhage from a cavernous angioma, and
highlights the precocity of such rebleedings. Therefore, we advocate early
aggressive surgical management: in cases of cavernoma revealed by a first
clinical overt haemorrhage, when there is strong radiological suspicion at the
acute stage; and in all cases of rebleeding, even without radiological evidence
of malformation, in the absence of vascular risk factors. Surgical indication
must be discussed in particular cases of cavernomas of the brain stem when
neither the haematoma nor the cavernoma reach the surface, and in deep
supratentorial cavernomas, when the neurological status is good, because of the
therapeutic risk.
PMID- 9401651
TI - Ruptured vertebrobasilar junction aneurysm associated with basilar artery
fenestration.
AB - A case of a ruptured saccular aneurysm arising from the proximal portion of a
partially duplicated basilar artery in a 36-year-old woman is reported. CT and
lumbar puncture confirmed subarachnoid haemorrhage. Cerebral angiography detected
a vertebrobasilar junction aneurysm associated with basilar artery fenestration.
The patient underwent successful clipping and coating of the aneurysm by a right
lateral suboccipital osteoclastic approach. Embryological development,
pathogenesis, diagnostic and therapeutic difficulties of this vascular
malformation are discussed in this report.
PMID- 9401652
TI - Growing skull fractures: a clinical study of 41 patients.
AB - Growing skull fractures are rare complications of head injury, occurring almost
exclusively in infants and children under the age of three. A retrospective
review at our Institute yielded 41 patients with this entity over a period of 20
years (1975-1995). The age at presentation ranged from less than 1 year to 62
years, with 33 (80.5%) patients being less than 5 years of age. The cause of
injury was either a fall from a height (93%) or a road traffic accident. The most
common location of a growing skull fracture was either parietal or frontoparietal
(56%). One patient had a posterior fossa growing skull fracture. CT scan was
performed in 19 patients which demonstrated an underlying porencephalic cyst,
hydrocephalus or a cyst communicating with the ventricle. In 5 children, a
ventriculo-peritoneal shunt alone was performed. Twenty four patients underwent a
duro- and cranioplasty while a duroplasty alone was performed in 8 patients. The
material used for cranioplasty included acrylic, wire mesh, steel plates or
autologous bone. Three patients died, one due to an anaesthetic complication and
two as a result of postoperative meningitis. Post-operative CSF leaks occurred in
3 patients, which were managed by a lumbar drain. Six patients had local wound
infection.
PMID- 9401653
TI - Idiopathic normal pressure hydrocephalus: analysis of factors related to
cerebrospinal fluid dynamics determining functional prognosis.
AB - This investigation has been undertaken to analyze the findings with both the
cerebrospinal fluid (CSF) pressure (Pcsf) and CSF pulse pressure (PP) in order to
predict the outcome of patients with the syndrome of idiopathic normal pressure
hydrocephalus (NPH). Accordingly, a prospective clinical study was planned in
which two groups of patients with NPH, having analogous prevalence of several
matched clinical and radiological parameters, were separated on the basis of
their positive or negative response to shunting. Both the resting Pcsf and CSF PP
profiles were compared in these two groups, and between them and normal controls.
CSF PP amplitude and CSF PP latency correlated directly in conditions associated
with either normal or high compliance (controls and patients with Alzheimer-like
disorders), whereas this correlation was inverse in states of low compliance
(NPH). On the other hand, shunt-responders showed a resting Pcsf significantly
higher than both non-responders and controls. The following conclusions were
obtained: 1) CSF PP is a high-amplitude and relative low-latency wave in NPH when
compared with controls: 2) CSF PP amplitude and latency correlate directly in
normal subjects and in those with primary cerebral atrophy; 3) a non-reversible
stage of NPH could be conceived in contradistinction to the reversible one, in
both of which an inverse correlation between the amplitude and the latency takes
place, the main difference between them being the resting Pcsf, which is
significantly lower in the former than in the latter, depending on the degree of
atrophic changes developed.
PMID- 9401654
TI - Costs and effects of microsurgery versus radiosurgery in treating acoustic
neuroma.
AB - This study analyses costs and effects of treating acoustic neuroma patients by
using microsurgery compared to radiosurgery. Radiosurgery is the stereotactic
application of radiotherapy and an innovative medical technology. Cost and effect
estimates of conventional treatment were based on a retrospective study in the
Netherlands. Similar data for a comparable group of patients in Sweden were
collected for radiosurgery, as this treatment option is currently not available
in the Netherlands. Fifty-three acoustic neuroma patients who had been operated
on the University Hospital Rotterdam between November 1990 and February 1995 were
included. This group was compared with 92 acoustic neuroma patients treated with
radiosurgery (Gamma Knife. Stockholm, Sweden) in the same period. Data on health
care use were collected from patient files. To obtain data on production losses
and quality of life, a questionnaire was sent by mail in February 1995. This
booklet consisted of the Health and Labour-questionnaire (HLQ), the Short Form-36
(SF36) and the EuroQol. The response rate was 92%. Direct costs for microsurgery
amounted to Dfl. 20.072,- and for radiosurgery to Dfl. 14.272,-. Indirect costs
were respectively Dfl. 16.400,- and Dfl. 1.020,-. General health rating was
better for radiosurgery than for microsurgery. On the whole, differences in
clinical outcomes between the two patient groups were small. Assuming a
reasonable occupancy rate of the expensive radiosurgery equipment, we
demonstrated that for the short term treating patients with acoustic neuroma with
an extra-meatal tumour diameter of less than 3 centimeters, radiosurgery is more
cost-effective than microsurgery.
PMID- 9401655
TI - Peripheral nerve schwannomas--an analysis of 16 patients.
AB - 16 patients with peripheral nerve neurinomas (benign schwannomas) were operated
upon in our hospital between 1990-1995. The largest tumours were found on
proximal segments of peripheral nerves (brachial plexus: 15 cm, sciatic nerve: 20
cm). The average duration of symptoms was 1 1/2 years (range: 3 months-15 years).
Pain or painful paraesthesias were the main complaints (13/16). Postoperatively,
9 patients were painfree while 4 improved. Similarly, neurological deficits were
favourably influenced by the operation: Out of 5 patients with motor deficits 4
had complete, 1 patient had partial recovery. One out of 4 patients with sensory
deficits had complete recovery, 2 remained unchanged, while 1 worsened. Two
patients developed new motor and 6 patients new sensory deficits, which (in the
course of time) did not disappear completely. New deficits developed
predominantly in patients with large tumours or longstanding symptoms. Tumour
recurrences were not seen during the follow-up period of 23 months. Our findings
revealed that in the majority of cases peripheral nerve neurinomas can be excised
with good results. Patients should be treated by a neurosurgeon with special
expertise in peripheral nerve surgery. The patient should be thoroughly informed
pre-operatively about any eventual new neurological deficits following surgery.
PMID- 9401656
TI - Giant intrasacral schwannomas: report of six cases.
AB - Only 4 of the 30 previously reported cases of giant sacral schwannomas have been
studied with Magnetic Resonance Imaging (MRI). We are reporting 6 more cases, 5
of which had MRI studies. There were 5 women and 1 man (average age 45 years)
with long lasting symptoms consisting of lumbosacral and radicular pain
accompanied by urinary disturbances and dysaesthetic sensations in the lower
limbs. CT clearly defined sacral bone involvement but poorly demonstrated
intraspinal tumour extension which was more evident in MRI studies. MRI also
clearly showed the intrapelvic extension of the tumour, its relationship with the
neighbouring structures and the dumbbell growth pattern due to tumour extension
through sacral foramina which are important data for making a pro-operative
diagnosis and surgical planning. Surgical treatment consisted of piecemeal tumour
resection through a posterior approach in four cases. Two patients underwent
operation through an abdominal transperitoneal approach followed by a sacral
laminectomy. Total intracapsular resection was apparently achieved in 5 cases.
Through an average follow-up period of 9.2 years and despite a rather
conservative approach, the recurrence rate has been very low in our series and
only one patient had to be re-operated on for tumour recurrence.
PMID- 9401657
TI - Primary malignant rhabdoid tumours of the central nervous system: an
immunohistochemical and ultrastructural study.
AB - Three cases of primary rhabdoid tumour of the CNS (RT-CNS) are presented. In case
1 a hemispheric tumour developed in a 10.5 months old girl, who survived for 6
months after incomplete resection, radio- and polychemotherapy. Case 2 was a 4
years and 8 months old boy with a large IIIrd ventricle tumour, who died of
leptomeningeal tumour dissemination 7 months after diagnosis despite
radiotherapy. In case 3 a pineal mass occurring in a 14 month old female was
radioresistant and totally exstirpated. The child died due to tumour recurrence
two months later. Autopsy examination revealed widespread leptomeningeal
dissemination. All three cases fulfilled light and electron microscopic criteria
of RT-CNS including abundant eosinophilic cytoplasm, vesicular nuclei with large
nucleoli and conspicuous anti-vimentin positive filaments. Extensive
immunohistochemical studies showed expression of epithelial (EMA, KL1),
macrophage (alpha-1 antichymotrypsin), neuro-ectodermal (GFAP, NSE, beta-tubulin
III) and myogenic markers (desmin, actin). Different stress proteins (alpha-B
crystallin, HSP70) were also expressed. Tumour cells showed a proliferation
(MIB1) index of 28.4% (case 1) and 33.4% (case 2). From our study it can be
concluded that RT-CNS reveals significant immuno-morphological heterogeneity thus
supporting the view that it is not a specific pathological entity but merely a
phenotypic appearance of different neoplasms, some of which are linked to
primitive neuro-ectodermal tumours.
PMID- 9401658
TI - Cranioplasty with autogenous autoclaved calvarial bone flap in the cases of
tumoural invasion.
AB - When a bone flap is raised in the course of a craniotomy, the ideal is to replace
it at the end of the procedure. When it is invaded by tumoural cells, it cannot
be replaced due to the risk of tumoural recurrence. In these cases we have
autoclaved the bone flap to be able to replace it with no fear of tumoural
recurrence. Between October 1989 and October 1995 sixty-two patients required
autoclaving of the bone flap in the course of a craniotomy due to tumoural
invasion (thirty-five meningiomas, sixteen bone tumours, five metastases, and
eight scalp tumours). The infiltrated bone flaps were removed, cleaned,
autoclaved for 20 minutes at 134 degrees C and 1 kg/cm2 and re-implanted.
Patients were followed-up for 10 to 58 months (average 41 months). At every
follow-up visit skull x-ray studies, clinical examination, and photographs were
done. When needed a CT scan was performed to assess the thickness of the bone
flap. On follow-up roentgenograms partial resorption was observed in twelve cases
(19.3%). CT scan studies showed loss of thickness in another thirty-five cases
(56.4%). Meanwhile the external aspect remained unchanged. In six cases (3.2%)
biopsies of the bone flaps were taken at a second surgical procedure. They showed
newly formed bone partly re-populated by osteocytes but retaining areas of
sequestered bone. We conclude that autoclaved bone, if replaced with direct
contact with living bone, it is gradually repopulated with osteocytes. Cranial
vault autoclaved autologous bone flap is a good alternative when the original
bone flap is invaded but not destroyed by tumoural cells.
PMID- 9401659
TI - Brain spatula with transparent tip: technical note.
AB - A newly developed brain spatula with transparent tip for brain retraction is
introduced. The high-molecular polymer plastic material is used only for the tip
of the new spatula whilst rest of the spatula is made up of the ordinary
malleable metal. The transparent nature of the spatula tip helps us in observing
the retracted brain vessels and cranial nerves in continuity with the main
operating area. The extent of distortion as a result of the retraction can be
directly observed assisting in prevention of an inadvertent injury. The new brain
spatula with transparent tip is helpful for microneurosurgery under high
magnification. Various shapes and sizes of the spatula can be used.
PMID- 9401660
TI - Usefulness of non-woven sheet (clip pad) on scalp incisions: technical note.
AB - As an alternative to the gauze often used on scalp incisions, we prepared a pad
made of non-woven sheets, coated with adhesive on one side. Unlike conventional
gauze, the pad did not slip away from the incision line or become entangled with
the scalp clips, thus demonstrating its high usefulness for this purpose.
PMID- 9401661
TI - Local variations in the cerebral microcirculatory response to hypercapnia and
haemorrhage.
AB - This study evaluates local variations of the cerebral vasomotor responses to
hypercapnia and haemorrhagic hypotension in a pig model. Four laser Doppler flow
probes were used in each pig. There was considerable variation in laser Doppler
signals between the four probes in baseline recordings. The increases in flow
after CO2 administration in 7 pigs had a mean coefficient of variation of 0.43 +/
0.31, and the flow changes after blood loss in another 7 pigs had a mean
coefficient of variation of 0.45 +/- 0.34. The range of flow changes within each
animal was large; the probe with the highest CO2 response showed on the average a
273% +/- 157% larger CO2 response than the probe with the lowest CO2 response.
Correspondingly, the probe with the best preserved blood flow after blood loss
had on the average a flow value of 93% +/- 12% of the baseline value, while the
probe that changed most with haemorrhage had a flow value of 44% +/- 24% of the
baseline value. Single laser Doppler recordings have been used for the monitoring
of cerebral blood flow in neurosurgical critical care, but our results suggest
that a single laser Doppler flow probe is not an adequate method to monitor
vasoreactivity in neurosurgical patients because flow signals from one probe may
be unrepresentative for other sites in the brain.
PMID- 9401662
TI - Initial and postoperative hyponatremia associated with pituitary adenoma: a case
report.
AB - This 67 year-old man experienced 3 episodes of symptomatic hyponatraemia.
Radiological examination revealed a sellar lesion and the tumour was removed via
the transsphenoidal route. Thereafter, he simultaneously developed intractable
diabetes insipidus and serious hyponatraemia with persistent natriuresis. His
level of atrial natriuretic peptide was not significantly elevated, however, his
plasma aldosterone concentration was low. The oral administration of salt
gradually improved his hyponatraemia as well as the coincident symptoms. By the
administration of a mineralocorticoid, fludrocortisone acetate, we succeeded in
maintaining his serum sodium level without salt replacement. We discuss the
mechanism(s) and treatment of hyponatraemia associated with pituitary tumour.
PMID- 9401663
TI - Pituitary apoplexy with spontaneous cure of acromegaly and its possible relation
to Gd-DTPA-administration.
AB - A case of pituitary apoplexy occurring after Gd-DTPA-administration for contrast
enhanced MRI in a patient with an hGH-producing macro-adenoma is presented.
Within days the initially increased hGH level fell to the normal range, the oral
glucose tolerance test (OGTT) showed a normal suppression of hGH and complete
anterior pituitary insufficiency developed. At this time repeated MRI suggested a
haemorrhagic infarction of the macro-adenoma. Fourteen months later re
examination confirmed spontaneous cure of the acromegaly, improvement of
adenopituitary function and shrinkage of the sellar content. The causal linkage
between the pituitary adenoma apoplexy and Gd-DTPA-administration is unclear. It
might be due to contrast induced blood pressure and endothelial permeability
changes, possibly promoted by pre-existing diabetes mellitus associated
vasculopathy.
PMID- 9401664
TI - Fulminant cerebral infarctions caused by nonbacterial thrombotic endocarditis due
to gallbladder cancer.
PMID- 9401665
TI - Genotype- and gender-dependent hepatic alcohol dehydrogenase (ADH) activity in
developing mice.
AB - Ethanol is metabolized in human and rodent liver primarily by the enzyme alcohol
dehydrogenase (ADH). Hepatic ADH activity in adult males and females of seven
inbred strains of mice was determined to examine genotype- and sex-dependent
variability among the strains and the level of sexual dimorphism in each of the
strains. ADH activity varied considerably among the strains, which could be
categorized into high-activity strains C57BL/6, C57Brcd, and Swiss, and
relatively low-activity strains C3H, CBA, and DBA. Adult Swiss, AKR, C57BL/6, and
DBA females exhibited significantly higher levels of hepatic ADH than their male
counterparts, whereas no gender differences were seen in C3H, CBA, and C57Brcd.
Young mice of high and/or low ADH activity strains viz. C57BL/6 and C3H did not
exhibit gender differences in ADH activity at weanling but the enzyme levels
increased by sixth week in females and remained higher thereafter. The progeny of
a high-activity strain with sexual dimorphism (C57BL/6) and a low-activity strain
lacking gender difference (C3H) exhibited intermediate levels of ADH and age
dependent sexual dimorphism.
PMID- 9401666
TI - Ethanol and glutamate effects on intracellular magnesium.
AB - Acutely dissociated rat brain cells were loaded with the magnesium-sensitive
fluorescent dye furaptra. Stimulation with varying concentrations of GLU + 1
microM GLY produced a concentration-dependent increase in free intracellular
magnesium ([Mg2+]i) that was not dependent on the presence of extracellular Mg2+.
Ethanol (50 mM) did not significantly inhibit GLU/GLY-stimulated increases in
[Mg2+]i. However, ethanol alone significantly increased baseline [Mg2+]i.
PMID- 9401667
TI - Dexmedetomidine alleviates ethanol withdrawal symptoms in the rat.
AB - The effect of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on
ethanol withdrawal symptoms was studied in chronically ethanol-fed rats. After a
4-day ethanol intoxication period the rats were given s.c. injections of
dexmedetomidine (3, 10, or 30 micrograms/kg) or saline (control group) at 10, 16,
22, and 39 h after the last dose of ethanol. The severity of ethanol withdrawal
symptoms (rigidity, tremor, irritability, hypoactivity) was rated up to 58 h,
blind to the treatments. The results showed that dexmedetomidine at doses 10 and
30 micrograms/kg significantly diminished the severity of the ethanol withdrawal
reaction as measured by the sum score of the three most specific withdrawal signs
(rigidity, tremor, and irritability). Dexmedetomidine at 10 micrograms/kg was the
most effective dose, especially in the latter half of the withdrawal period (23
58 h after last dose of ethanol). The results suggest that dexmedetomidine in the
treatment of ethanol withdrawal symptoms should be further studied.
PMID- 9401668
TI - Total contractile protein contents and gene expression in skeletal muscle in
response to chronic ethanol consumption in the rat.
AB - An investigation was carried out to determine changes in the contents of skeletal
muscle myofibrillary proteins (i.e., the contractile fraction composed
principally of actin and myosin) and gene expression in skeletal muscle in
response to ethanol feeding. Male Wistar rats were fed a nutritionally complete
liquid diet, which contained 35% of total calories as ethanol. Controls were pair
fed isocaloric amounts of the same diet, in which ethanol was replaced by
isocaloric glucose. Total mixed and contractile protein contents of the
gastrocnemius in ethanol-fed rats were rapidly reduced by ethanol feeding: a
response was discernible as early as 1 week after the commencement of the ethanol
feeding regimen (approx. -10%, p < 0.025 and p = 0.05 for mixed and myofibrillary
proteins, respectively). At 2, 4, and 6 weeks, mixed and myofibrillary protein
contents were further reduced in alcohol-fed rats, by between 12% and 22%,
compared to pair-fed controls. Similar changes occurred in the soluble (i.e.,
sarcoplasmic) protein fractions of skeletal muscle. At 2 weeks the composition of
total messenger RNA and individual messenger RNA species was measured. Total
messenger RNA content per muscle was reduced by 35% (p < 0.05). Messenger RNA
levels for alpha-actin, beta-myosin heavy chain, and carbonic anhydrase III were
not significantly altered. In conclusion, skeletal muscle protein contents are
rapidly reduced by ethanol feeding, compared to pair-fed controls, though mRNA
species encoding specific isoforms of myosin and actin are not affected. It is
possible that chronic ethanol feeding may significantly alter the stability of
mRNAs encoding other contractile proteins, or alternatively, defects in
translation may predominate.
PMID- 9401670
TI - Chronic low doses of ethanol affect brain protein kinase C and ultrasonic calls
in rats.
AB - Few studies have investigated neurobehavioral and neurochemical consequences of
chronic consumption of low doses of ethanol. The present study shows that in rats
exposure to 3% ethanol (v/v in drinking water) for 2 months decreased both
calcium-dependent and -independent protein kinase C (PKC) activities in the
cortex and in the hippocampus. This treatment also reduced ultrasonic calls
(UCs), an index of emotional and motivational states of the animal. In addition,
at cortical level of ethanol-treated rats, we observed a correlation between
calcium-dependent activities and UCs. These results suggest that nonaddicting
doses of ethanol affect brain PKC activities and that this enzyme may be involved
in the ethanol modulation of emotional and motivational behaviors.
PMID- 9401669
TI - The role of ethanol availability on stress-induced increases in ethanol
consumption.
AB - Exposure to stressors can increase ethanol consumption and ethanol can attenuate
the behavioral and biochemical effects of stressors. This study determined
whether the availability of ethanol during the period of exposure to repeated
restraint alters the poststress increase in ethanol intake. Seven days of
restraint increased ethanol intake on the first poststress test only in animals
deprived of ethanol during the restraint period. These results indicate that the
availability of ethanol during exposure to restraint can attenuate the impact of
restraint on ethanol intake. Ethanol intake was also positively related to
novelty-induced locomotion and restraint eliminated this relationship. However,
amphetamine-induced locomotion was not altered by either restraint or EtOH
intake. These results indicate that voluntary ethanol intake can attenuate the
impact of restraint stress and that restraint stress can alter the influence of
ethanol on novelty-induced locomotion. It is suggested that this symmetrical
relationship between ethanol intake and restraint stress may be involved in an
interactive manner that determines stress-induced ethanol consumption.
PMID- 9401671
TI - Biochemical and histopathological changes in arsenic-intoxicated rats coexposed
to ethanol.
AB - The effects of arsenic and ethanol interaction on blood, liver and serum
biochemical indices, and arsenic concentration in soft tissues of rats were
investigated to determine the influence of these substances in inducing
susceptibility to arsenic poisoning. Arsenic, intraperitoneally (100 ppm, once,
daily), ethanol in drinking water (10%), or the combination were administered for
a period of 6 weeks. Both the chemicals had some additive effects in marginally
elevating blood zinc protoporphyrin. Glutathione (GSH) concentrations of blood
and liver were reduced by both arsenic and ethanol; however, there was a more
pronounced depletion of hepatic GSH concentration in animals coexposed to arsenic
and ethanol. Combined arsenic plus ethanol exposure led to significantly more
elevated activities of serum transaminases than in animals administered arsenic
or ethanol alone. Histopathological alterations in kidneys and liver occurred
following arsenic exposure. Arsenic plus ethanol produced more pronounced liver
lesions, whereas kidney changes were the same as with arsenic alone. The
concentrations of arsenic in kidney and liver were higher in rats exposed to
arsenic plus ethanol. The results suggest that animals exposed to arsenic plus
ethanol are more vulnerable to arsenic toxicity.
PMID- 9401672
TI - Prenatal exposure to ethanol in rats: effects on liver energy level and
antioxidant status in mothers, fetuses, and newborns.
AB - The fetal alcohol syndrome is a clinical condition that affects newborns from
alcoholic mothers. It is not clear, however, whether ethanol consumption during
gestation can affect liver functions of fetuses and newborns. In this study, we
aimed to assess the effects of ethanol administration on body weight, liver
energy level, and antioxidant status of mothers, fetuses, and newborns. Pregnant
rats were exposed to ethanol during the third week of gestation. Body weight,
survival, and liver concentration of gluthatione (GSH) and adenosintriphosphate
(ATP) were measured. No differences were observed in body weight or in liver ATP
and GSH between mothers exposed to ethanol and control animals. Conversely,
fetuses from rats exposed to ethanol showed a marked decrease in GSH, ATP, and
body weight when compared to those from control rats. Newborns exposed prenatally
to ethanol were no different from those born to control mothers. This study
suggests that an amount of ethanol that is not sufficient to determine a
significant effect on mothers can, nevertheless, cause a marked decrease in
growth and in liver antioxidant and energy status in fetuses. These parameters,
however, return to control value one week after ethanol discontinuation.
PMID- 9401673
TI - Developmental changes in the inhibitory actions of ethanol on glutamate-induced
translocation of protein kinase C in cerebellar granule neurons.
AB - The effects of increasing concentrations of ethanol (25-200 mM) on the
enhancement of [3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding produced by
different glutamate receptor agonists, indicative of a translocation of the
intracellular enzyme protein kinase C (PKC), were studied in rat cerebellar
granule cells at 2, 4, 8, and 12 days in vitro (DIV). Glutamate-produced
stimulation of [3H]PDBu binding was inhibited by 50 mM ethanol at 2 DIV, whereas
higher ethanol concentrations (> 100 mM) were needed to reduce the increase of
[3H]PDBu binding in cells grown for 4, 8, and 12 DIV. Ethanol significantly
inhibited NMDA-stimulated [3H]PDBu binding in a concentration-dependent fashion
in cells maintained in culture for 4 and 8 days, respectively, with a slightly
less pronounced inhibition by ethanol (50 mM) seen in cells kept for 2 and 12
DIV. Application of higher ethanol concentrations (> 100 mM), inhibited the NMDA
induced stimulation in all cell preparations. Following kainic acid-induced
enhancement of [3H]PDBu binding, ethanol (100 mM) reduced the binding only in
cells maintained for 2 DIV. Even higher ethanol concentrations (200 mM) inhibited
the effects of kainic acid only in cells maintained for 2 and 4 DIV,
respectively. Our data suggest that various subclasses of glutamate receptors
display a developmentally determined differential sensitivity to ethanol at least
in cerebellar granule cells in vitro.
PMID- 9401674
TI - Effect of ethanol drinking and naltrexone on subsequent drinking in rats.
AB - The effects of several days of oral ethanol drinking paired with naltrexone (NTX)
on subsequent ethanol drinking were investigated in rats. We hypothesized that
repeated pairings of NTX combined with forced oral ethanol intake would
extinguish ethanol drinking so that when NTX injections were terminated,
voluntary oral ethanol drinking would be suppressed. Thirty-two male. Long-Evans
rats were provided with alternate days of either 8% ethanol solution or water as
the sole source of fluid. Intraperitoneal injections of 0, 2.5, or 5.0 mg of NTX
hydrochloride were administered on the ethanol days. Following the termination of
injections, rats were returned to unrestricted access to water and ethanol and 24
h measurements of fluid intake were recorded. NTX decreased ethanol intake 4 h,
but not 24 h, after NTX injections. Despite the consumption of significant
amounts of ethanol during NTX treatment, there was no change in voluntary oral
ethanol intake patterns after NTX injections were terminated (reinstatement of
voluntary ethanol drinking). Thus, NTX's reduction in ethanol intake was limited
in duration and did not result in long-term extinction of ethanol drinking
behavior.
PMID- 9401675
TI - Sulpiride-induced increases in serum prolactin levels in female rats exposed
prenatally to alcohol.
AB - We examined the impact of prenatal alcohol exposure on serum prolactin levels and
on the ability of the D2 dopamine antagonist sulpiride to stimulate prolactin
release in Long-Evans rats. Pregnant rats were intubated with alcohol (0, 3, or 5
g/kg/day) from gestational day 8 (GD8) to GD20. Adult female offspring were
screened for estrous cycle stage. At diestrus, the rats were challenged with a
single dose of sulpiride (0, 10, or 40 micrograms/kg) and trunk blood was
collected 20 min later. After prenatal exposure to either dose of alcohol, mean
basal serum levels of prolactin were about 65% less than the 0 g/kg group, and
the 35-40% mean differences from an untreated control group were not significant.
Sulpiride produced dramatic dose-dependent increases in serum prolactin levels in
all prenatal treatment groups. Across all doses of sulpiride, the group given the
higher dose of prenatal alcohol (5 g/kg/day) had significantly lower serum
prolactin levels than all other groups. There was no significant interaction
between prenatal treatment and sulpiride dose. Neither prenatal alcohol exposure
nor sulpiride injections had significant effects on serum corticosterone levels
in this study. Although the current results are unclear regarding a baseline
decrease in prolactin levels after prenatal alcohol exposure, the overall results
suggest that prenatal alcohol exposure decreases prolactin levels but there is no
evidence that it does so by altering dopaminergic tone in hypothalamus of female
rats.
PMID- 9401676
TI - Effects of ethanol on striatal dopamine overflow and clearance: an in vivo
electrochemical study.
AB - Previous studies have shown that the neurotransmitter dopamine (DA) is implicated
in the reinforcing effects of ethanol and other abused drugs. Ethanol also alters
DA overflow and uptake in vivo. Further studies of the role of DA in the
behavioral and neurochemical effects of ethanol may help explain the
pharmacological mechanisms by which these effects are produced. In these studies
we used in vivo electrochemical recordings to investigate the effects of ethanol
(EtOH) on the dynamics of evoked DA overflow and DA uptake in rat dorsal
striatum. Local applications of EtOH from a multibarrel micropipette did not
produce detectable changes in extracellular levels of endogenous DA in the dorsal
striatum. EtOH application did attenuate potassium (K+)-evoked overflow of DA in
a time-dependent fashion. In contrast, tyramine-induced DA overflow, a calcium
independent process thought to be carrier mediated, was not altered by local EtOH
application in the dorsal striatum. Striatal uptake of locally applied exogenous
DA was decreased by nomifensine, an effect that was attenuated by locally applied
EtOH. Taken together, these data suggest that one of the effects of EtOH on DA
containing nerve endings in the rat striatum involves functional changes in the
high-affinity DA transporter associated with these nerve endings.
PMID- 9401678
TI - Sardinian alcohol-preferring rats prefer chocolate and sucrose over ethanol.
AB - The present study was aimed at determining whether the concurrent availability of
highly palatable fluids (i.e., a chocolate-flavored drink and a sucrose solution)
would alter voluntary ethanol drinking in selectively bred, alcohol-preferring sP
and -nonpreferring sNP rats. Ethanol intake occurred under the three-bottle, free
choice regimen between 10% (v/v) ethanol solution, tap water, and the palatable
fluids for 24 h per day. When rats were given ethanol and water, but no
alternative fluids, mean ethanol intake in sP rats ranged between 6 and 7 g/kg
per day and mean preference ratio was steadily higher than 80%, whereas mean
ethanol intake and preference ratio in sNP rats were constantly lower than 0.3
g/kg and 5%, respectively. In the presence of either the chocolate-flavored drink
or sucrose solution, both prepared as isocaloric to the ethanol solution,
absolute ethanol intake in sP rats declined by 60-70%; similarly, the preference
ratio was reduced by 80-90%. Ethanol intake in sNP rats was unaffected by the
simultaneous presentation of either palatable fluids. The results of the present
study closely replicate those previously reported in genetically selected,
ethanol-preferring HAD rats; however, they differ from those of ethanol
preferring P rats, which were reported to maintain high levels of ethanol intake
and preference in the presence of highly palatable fluids. These results are
discussed in terms of a) an alternative reinforcement partially substituting for
the reinforcing properties of ethanol in sP rats, resulting in a less urgent need
of ethanol, and b) genetic animal models of alcoholism diverging in some
neurochemical and behavioral traits (e.g., response to the presentation of
palatable fluids), which might parallel the different types of alcoholism
observed in humans.
PMID- 9401677
TI - Regional CNS densities of serotonin and dopamine receptors in high alcohol
drinking (HAD) and low alcohol-drinking (LAD) rats.
AB - The densities of subtypes of serotonin (5-HT) and dopamine (DA) receptors were
determined in the CNS of male alcohol-naive HAD and LAD lines of rats.
Autoradiographic studies were undertaken to measure the densities of (a) 5-HT1A
sites labelled with 2 nM [3H]8-OH DPAT, (b) 5-HT2A sites labelled with 2 nM [3H]
ketanserin, (c) D1 sites labelled with 1 nM [3H]SCH23390, and (d) D2 sites
labelled with 20 nM [3H]sulpiride. Membrane binding, using tissue combined from
the olfactory bulb, olfactory tubercle, and nucleus accumbens, was carried out to
determine Kd and Bmax values for the binding of 0.25-8.0 nM [3H]7-OH DPAT to D3
sites. Among the 14 regions measured for densities of 5-HT1A sites, no interline
differences were found in the cerebral cortical regions or in the septal nuclei;
however, within the hippocampus, 15-20% lower binding of [3H]8-OH DPAT was
observed in the posterior dorsal CA3 and dentate gyrus of the HAD line. There
were no interline differences in any of the 10 regions examined for
[3H]ketanserin binding to 5-HT2A sites, or in the densities of D1 and D2 sites in
the mesolimbic and nigrostriatal DA systems, except for a 35% higher density of
D2 sites in the substantia nigra pars compacta of the HAD line. There were no
interline differences in the Kd or Bmax values for [3H]7-OH DPAT binding to D3
sites. Overall, these results indicate that no marked interline differences are
evident in the densities of 5-HT1A, 5-HT2A, D1, D2, and D3 receptors within the
mesolimbic system that could be associated with the disparate alcohol drinking
behaviors of the HAD and LAD rats.
PMID- 9401679
TI - Adenosine A1 receptor antisense infused in striatum of rats: actions on alcohol
induced locomotor impairment, blood alcohol, and body temperature.
AB - Previous pharmacological studies show that adenosine receptors in the corpus
striatum may be involved in locomotor coordination. The purpose of this
investigation was to determine whether the adenosine A1 receptor subtype would
alter the locomotor response due to incapacitating doses of alcohol. In these
experiments, an antisense oligodeoxynucleotide (ODN) targeted to the adenosine A1
receptor was used to elucidate its possible role in locomotor function. After
bilateral cannulation of the caudate nuclei of two strains of adult male rats,
the animals were trained to remain on a rotorod for an entire 3-min interval.
Then, a standard dose of 2.0 micrograms per 2.0 microliters of the A1 adenosine
antisense (A1AS), dissolved in a pyrogen-free artificial cerebrospinal fluid
(aCSF), was microinjected four times bilaterally into the caudate nuclei of the
rats at successive 12-h intervals over 2 days. Three sets of controls were
utilized: intragastric gavage with tap water alone: intragastric gavage of 3.5
4.0 g/kg 20% alcohol alone; and the aCSF vehicle alone microinjected identically
in the caudate nuclei. The results showed that the intragastric administration of
20% alcohol in a dose of 3.5-4.0 g/kg caused a complete incapacitation of
locomotor performance. Moreover, the A1AS injected in the striatum failed to
alter significantly the action of alcohol in its impairment of the rats' ability
to negotiate the rotorod. Concurrent measures of blood alcohol and body
temperature taken to validate the efficacy of alcohol administration correlated
precisely with the blockade of locomotor behavior of the animals. These findings
thus suggest that because of the specificity of the A1AS probe, the A1 receptor
in the striatum is not involved in the alcohol-induced incapacitation of
locomotor activity.
PMID- 9401680
TI - Accuracy of localizing radiopaque markers by abdominal radiography and
correlation between their gastric emptying rate and that of a canned food in
dogs.
AB - OBJECTIVES: To determine accuracy of abdominal radiography in locating radiopaque
markers in the gastrointestinal tract and to assess correlation between gastric
emptying rate of radiopaque markers and that of canned food. ANIMALS: 17 healthy
dogs. PROCEDURE: Dogs were fed thirty 1.5-mm markers and ten 5-mm markers mixed
in sufficient food to meet 25% of their daily caloric intake. They were then
euthanatized by administration of an overdose of barbiturate at 1, 2, 5, 8, or 12
hours after eating and the abdomen was radiographed. The stomach, small
intestine, and large intestine were then separated and radiographed in isolation.
The wet and dry weights of the stomach contents were determined. The apparent and
actual locations of the markers and the gastric emptying rates of markers, wet
matter, and dry matter were compared, using rank correlation. RESULTS: All
comparisons indicated significant (P < 0.025), high correlation coefficients (>
0.92). The mean difference between the apparent and actual locations of the
markers was < 3% for all comparisons. The mean difference between the percentage
of small markers and large markers retained in the stomach and that of dry matter
was 7.8 (SD, 6.2; range, 0 to 18%) and 11.9 (SD, 12.5; range, 0 to 44%),
respectively. CONCLUSIONS: The gastric emptying and orocolic transit rates of the
markers were accurately predicted by abdominal radiography. The gastric emptying
rate of the diet and the small markers and, to a lesser extent, the large markers
was closely correlated. CLINICAL RELEVANCE: When fed with a special canned food
diet, radiopaque markers can be used to assess the gastric emptying rate of food
with sufficient accuracy for clinical purposes.
PMID- 9401681
TI - Detection of antibodies to Aspergillus fumigatus in serum of horses with mycosis
of the auditory tube diverticulum (guttural pouch).
AB - OBJECTIVE: To detect antibodies against Aspergillus fumigatus antigens in serum
samples from horses and to evaluate the relevance of this method as an
alternative approach to the diagnosis of mycosis of the auditory tube
diverticulum (guttural pouch mycosis [GPM]). ANIMALS: Twelve clinically normal
horses (controls) and 12 horses with GPM diagnosed by endoscopic observation of
characteristic mycotic plaques. PROCEDURE: Antibodies to A fumigatus antigens
were detected in serum by use of an ELISA and immunoblot analysis with
extracellular antigens. RESULTS: Antibodies against A fumigatus antigens were
found in healthy and diseased horses. Titer of total Aspergillus antibodies was
not diagnostic for GPM. In contrast, immunoblot analysis results indicated that 2
antigens of 22 and 26 kd were constantly recognized by sera from diseased horses.
CONCLUSIONS: Reactivity to 22- and 26-kd A fumigatus antigens, as measured by
immunoblot analysis, seemed to be diagnostic for GPM in horses.
PMID- 9401682
TI - Comparison of radiography, magnetic resonance imaging, and surgical findings in
dogs with elbow dysplasia.
AB - OBJECTIVE: To describe the magnetic resonance imaging (MRI) appearance of medial
coronoid process and humeral condyle lesions in dysplastic cubital joints and to
compare survey radiography and MRI for evaluation of fragmented medial coronoid
process (FMCP) and lesions of the medial aspect of the humeral condyle (MAHC).
ANIMALS: 18 dogs with elbow dysplasia. PROCEDURE: Radiography of 22 cubital
joints was performed. The 22 joints then underwent MRI. The scans were evaluated
with regard to the shape and signal of the coronoid process; articular cartilage
change, subchondral bone disruption of the MAHC. Surgical findings were used as
the standard to calculate accuracy, sensitivity, specificity, and positive- and
negative-predictive values for specific diagnosis of FMCP (free fragment) and
lesions of the MAHC. RESULTS: At surgery, 31.8% of the joints had FMCP (free),
36.4% had nondisplaced unmineralized coronoid process, and 27.2% had nondisplaced
mineralized coronoid process. Eleven joints had lesions of the MAHC, and wear
lesions were observed in 41% of the joints. On radiography, FMCP (free) was
visualized in 9% of the joints and lesions of the MAHC were observed in 23%. MRI
had the highest accuracy (95.5%), sensitivity (100%), and negative-predictive
value (100%) for detection of FMCP (free), and had accuracy (91%), sensitivity
(87.5%), specificity (92.5%), and positive (87.5%)- and negative (92.5%)
predictive values for detection of nondisplaced unmineralized coronoid process.
CONCLUSIONS AND CLINICAL RELEVANCE: Compared with radiography, MRI was useful for
detection of nondisplaced unmineralized coronoid process; images consistently
correlated with surgical findings. The technique is accurate and especially
useful when radiographic findings are inconclusive.
PMID- 9401683
TI - Immunohistochemical diagnosis of pestivirus infection associated with bovine and
ovine abortion and perinatal death.
AB - OBJECTIVE: To establish a reliable, rapid, economical method for detection of
pestivirus infection in bovine and ovine fetuses and to examine participation of
these viruses in abortions and neonatal mortality. ANIMALS: 213 bovine and 31
ovine fetuses, as well as 36 newborn calves and 25 lambs, which had died within 3
days after birth, were tested for bovine viral diarrhea virus (BVDV) and border
disease virus by use of different methods. PROCEDURE: Detection of BVDV in
fetuses was performed by immunohistochemical methods, using a panel of monoclonal
antibodies against pestivirus antigens on cryostat and paraffin sections and by
virus isolation in cell culture; in some instances, an antigencapture ELISA was
performed. Results of the various methods were compared. RESULTS: Sensitivity of
BVDV detection by immunohistochemical methods and virus isolation in cell culture
was equal; however, it decreased in association with autolysis. In autolytic
fetuses, use of formalin-fixed, paraffin-embedded brain sections was the most
favorable method. Antigen detection by ELISA was less sensitive. CONCLUSIONS:
Immunohistochemical analysis of cryostat sections of brain, skin, thyroid gland,
abomasum, and placenta is a rapid, sensitive method for detecting pestiviruses in
fetuses. In the presence of advanced autolysis, this method used on formalin
fixed, paraffin-embedded brain sections is recommended over the other described
methods.
PMID- 9401684
TI - Evaluation of platelet activation and platelet-neutrophil aggregates in ponies
with alimentary laminitis.
AB - OBJECTIVES: To determine whether platelets are hyperaggregable or form platelet
neutrophil aggregates during the prodromal stages of acute laminitis of ponies.
ANIMALS: Healthy adult ponies: 8 experimental and 6 control. PROCEDURES: Acute
laminitis was induced by oral administration of corn starch and wood flour to 8
ponies, and indices of platelet activation were evaluated. Blood samples were
collected before and at 4, 8, 12, 24, 28, and 32 hours after carbohydrate
administration, and PCV, total plasma protein concentration, platelet count,
activated clotting time, whole blood recalcification time, spontaneous platelet
aggregation, ex vivo platelet aggregation responses, and platelet-neutrophil
aggregates were determined. When lameness was first detected, ponies were
euthanatized and arteriography and histologic examination of hooves were
performed. RESULTS: Carbohydrate overload was associated with hyperaggregability
of platelets throughout the prodromal stages of laminitis and increased numbers
of platelet-neutrophil aggregates. Reduction of blood supply to affected hooves
was variable, and blood clots were found in 6 of 11 laminitis-affected hooves.
CONCLUSIONS: Platelets were hyperaggregable throughout the prodromal stages of
carbohydrate-induced laminitis and formed platelet-neutrophil aggregates.
Platelet-neutrophil aggregates may initiate or contribute to development of acute
laminitis. CLINICAL RELEVANCE: Anti-platelet therapy may be useful for treatment
of acute alimentary laminitis in horses.
PMID- 9401685
TI - Effect of congenitally acquired Neospora caninum infection on risk of abortion
and subsequent abortions in dairy cattle.
AB - OBJECTIVES: To estimate the extent to which abortion risk in dairy cattle during
subsequent pregnancies was associated with congenitally-acquired Neospora caninum
infection and previous abortions. ANIMALS: 468 Holstein cattle. PROCEDURE:
Newborn heifer calves were tested for evidence of congenital infection
attributable to N caninum and examined repeatedly until the completion of their
second lactation for serologic status and evidence of abortion. RESULTS: Compared
with noninfected cows, congenitally infected cows had a 7.4-fold higher risk of
abortion during their initial pregnancy and a 1.7-fold higher risk of aborting
the first pregnancy during their first lactation. During the first pregnancy of
their second lactation, congenitally infected cows that had aborted previously
had a 5.6-fold higher risk of abortion, compared with cows that had not
previously aborted and that were seronegative. The fetal risk period for N
caninum-associated death began sooner and extended later during the initial
pregnancy compared with subsequent pregnancies. CONCLUSION: Congenitally acquired
N caninum infection can cause a substantial number of abortions during the
initial pregnancy of heifers, with abortion risk attributable to N caninum
decreasing in subsequent pregnancies, possibly because of selective culling.
Subsequent abortions can be expected in congenitally infected cows that have
aborted previously.
PMID- 9401686
TI - Pulmonary and neutrophil responses to priming effects of platelet-activating
factor in pigs.
AB - OBJECTIVE: To investigate whether platelet-activating factor (PAF) primes the
porcine pulmonary response to lipopolysaccharide (LPS), and what effect PAF
priming has on porcine neutrophil superoxide (SO) release. ANIMALS: 8- to 10-week
old pigs. PROCEDURES: After pigs were anesthetized with sodium pentobarbital and
instrumented for standard cardiopulmonary hemodynamic measurements, they were
randomly assigned to receive PAF (0.1 ng/kg of body weight/min, 0 to 2 hours)
plus saline solution (2 to 6 hours), saline solution (0 to 2 hours) plus LPS
(0.25 microgram/kg/h, 2 to 6 hours), or PAF plus LPS. Cardiopulmonary variables
were measured throughout the study. Neutrophils were isolated from saline- or PAF
treated pigs at 0 (baseline) and 2 hours, and the effect of in vivo PAF exposure
on ex vivo phorbol myristate acetate (PMA)-induced SO release was measured.
Additionally, neutrophils isolated from immune-naive pigs were primed in vitro
for 10 minutes with 10 microM PAF, and PMA-induced SO release was measured.
RESULTS: PAF infusion significantly enhanced the increase in mean pulmonary
arterial pressure, pulmonary vascular resistance, and hypoxemia associated with
LPS administration. The infusion increased ex vivo neutrophil SO release, and in
vitro PAF exposure primed neutrophils for enhanced SO release that was inhibited
by pretreatment of cells with indomethacin. CONCLUSIONS: PAF primes the porcine
pulmonary system for the response to LPS. It primes porcine neutrophils in vivo
and in vitro for PMA-induced SO release, and in vitro priming is mediated by
cyclooxygenase products of arachidonic acid metabolism. CLINICAL RELEVANCE: PAF
may modulate the porcine inflammatory response by acting as a priming agent,
making pigs more responsive to the negative effects of bacterial LPS.
PMID- 9401687
TI - Functional and phenotypic characterization of monoclonal antibodies to bovine L
selectin.
AB - OBJECTIVE: To characterize 2 bovine neutrophil monoclonal antibodies (MAB) as to
effects on bovine neutrophil function and their binding antigens on the cell
surface of bovine neutrophils. ANIMALS: 16 healthy, lactating Holstein cattle, 1
calf with leukocyte adhesion deficiency, and 1 age-matched control calf, 2
healthy ewes, and 2 healthy human beings as neutrophil sources. PROCEDURE:
Neutrophil chemotactic and respiratory burst activities and calcium influx, and
binding properties of the 2 MAB were determined. Molecular mass of corresponding
cell surface antigens also was determined, as was binding of human L-selectin MAB
DREG56 to molecules recognized by MAB 11G10 and 2G8 on the surface of bovine
neutrophils. RESULTS: MAB 11G10 and 2G8 inhibited chemotactic activity of bovine
neutrophils, up-regulated amplitude of native chemiluminescence, and shortened
the time to reach maximal chemiluminescence induced by serum-opsonized zymosan.
Crosslinking both MAB with a second antibody induced rapid increase in
intracellular free calcium concentration. Binding density of MAB 11G10 and 2G8 to
bovine neutrophils treated with trypsin was increased (P < 0.05), compared with
that of untreated neutrophils. Neutrophils treated with phosphatidylinositol
specific phospholipase C had decreased (P < 0.05) binding density of MAB 11G10
and 2G8. Binding of the various MAB to neutrophils from calves with bovine
leukocyte adhesion deficiency was lower (P < 0.05) than binding to neutrophils
from healthy calves. Expression of antigens recognized by the aforementioned MAB
on the surface of bovine neutrophils was decreased (P < 0.05) within 10 minutes.
CONCLUSION: MAB 11G10 and 2G8 recognized L-selectin molecules on bovine
neutrophil membrane. L-Selectin (CD62L) is involved in low-affinity adhesion
reactions between leukocytes and L-selectin ligand on postcapillary venular
endothelial cells.
PMID- 9401688
TI - Infection of bone marrow macrophages by equine infectious anemia virus.
AB - OBJECTIVE: To characterize infection of bone marrow-derived macrophages (BMDM)
with equine infectious anemia virus (EIAV) by determining virus production,
effects on viability, and induction of cytokines. SAMPLE POPULATION: BMDM
obtained from bone marrow of 6 clinically normal adult horses. PROCEDURE: BMDM
were infected with EIAV at a multiplicity of infection of 8. Cell viability,
percentage of cells with detectable viral protein, reverse transcriptase
activity, and concentrations of infective virus (focus-forming units/ml),
interleukin 6, and tumor necrosis factor-alpha were measured in culture
supernatant samples obtained at various days after infection. RESULTS: Cell
viability was decreased on day 4 and was maximally decreased on day 8. The number
of cells with detectable viral protein and supernatant reverse transcriptase
activity increased significantly on day 4 and increased until day 6. Virus
concentration (focus-forming units per milliliter) peaked on day 4 after
infection and was constant thereafter. Infection with EIAV caused significant
induction of interleukin 6 production by BMDM. The maximal difference was seen on
day 4 after infection. Control and infected BMDM produced only negligible amounts
of tumor necrosis factor-alpha. CONCLUSIONS: BMDM are useful, as a cell
population, to study the effects of infection with EIAV, including cell death and
induction of interleukin 6 but not tumor necrosis factor-alpha production.
PMID- 9401689
TI - Quantification of antigen-specific antibody concentrations in tracheal lavage
fluid of horses with summer pasture-associated obstructive pulmonary disease.
AB - OBJECTIVE: To determine whether horses with summer pasture-associated obstructive
pulmonary disease (SPAOPD) have increased concentrations of antigen-specific IgG
and IgE in tracheal lavage fluid, compared with values in clinically normal
horses. ANIMALS: 8 horses (6 females, 2 geldings; 6 Quarter Horses, 2
Appaloosas), 14 to 23 years old and with previous diagnosis of SPAOPD, served as
the principal group; 8 horses (2 females, 6 geldings; 1 Quarter Horse, 7
Thoroughbreds), 6 to 9 years old, with no evidence of respiratory tract disease,
served as the control group. PROCEDURE: Data were collected twice during a 1-year
period: when all SPAOPD-affected horses were manifesting clinical signs of
disease (July), and when all SPAOPD-affected horses appeared clinically normal
(February). On each occasion, clinical evaluations were performed and blood and
tracheal lavage fluid samples were collected. Transtracheal lavage supernatant
was evaluated for mold antigen-specific IgG and IgE concentrations. RESULTS:
Median IgE relative antibody unit (RAU) values were significantly higher in
control, compared with principal, horses. The SPAOPD-affected horses had
increased concentrations of specific IgG for only 1 antigen, during winter sample
collection. CONCLUSION: Antigen-specific IgG and IgE RAU values were not
increased in SPAOPD-affected horses when these horses were manifesting clinical
signs of disease.
PMID- 9401690
TI - Comparison of pulsed-field gel electrophoresis and phage typing for
discriminating poultry strains of Staphylococcus aureus.
AB - OBJECTIVE: To compare pulsed-field gel electrophoresis (PFGE) patterns of
Staphylococcus aureus from chickens in England, Belgium, Bulgaria, Argentina, and
Japan, to assess the value of PFGE for discriminating strains, and to compare
results obtained by PFGE with those obtained by biotyping and phage typing.
SAMPLE POPULATION: 78 S aureus isolates from diseased and healthy chickens.
PROCEDURE: Chromosomal DNA of S aureus was digested with restriction endonuclease
Sma I, and fragments were separated by PFGE in 1% agarose gel. RESULTS: All 78
strains from 5 countries were classified as poultry ecovar according to a
previously established biotyping system. Chromosomal DNA was cut by Sma I into 18
to 23 fragments ranging from about 3 to 685 kb. Seventy-eight strains produced 15
types, arbitrarily designated A to O, and 45 subtypes. Some differences were
observed in PFGE patterns among countries. However, 10 fragments (333, 190, 110,
63, 55, 42, 34, 19, 10, and 3 kb) were highly conserved and were shared by almost
all (> 78%) of the strains examined. The PFGE patterns were compared with those
obtained by phage typing. All 29 strains belonging to avian phage-group II
produced type A and 19 subtypes. Of the 15 strains belonging to phage-group I, 11
produced 8 types (B to H, O) and 5 subtypes that were different from those of
type A. CONCLUSIONS: Genomic DNA fingerprinting by PFGE is an effective technique
for discriminating poultry S aureus strains and appears to be a useful method for
subtyping strains of avian phage groups or the poultry-specific ecovar.
PMID- 9401691
TI - Diagnosis of trichinellosis in swine by enzyme immunoassay, using a synthetic
glycan antigen.
AB - OBJECTIVE: To assess performance of a synthetic carbohydrate antigen for use in
an enzyme immunoassay for diagnosis of trichinellosis in swine. ANIMALS AND
SAMPLE POPULATION: 47 York X Duroc pigs and field sera from 265 farm pigs raised
under various management systems. PROCEDURES: Each of 47 pigs was inoculated with
25 to 500 Trichinella spiralis larvae, and blood samples were obtained weekly. At
postinoculation week 12, pigs were euthanatized, and tissues recovered from the
tongue and diaphragm were digested to determine worm burden. Serum samples from
experimentally infected pigs and sera obtained from pigs on a farm were tested by
enzyme immunoassay, using standard excretory-secretory and synthetic glycan
antigens. RESULTS: Of the 47 pigs, 46 (97.8%), with worm burden ranging from 0.02
to 248.8 larvae/g of tissue in the tongue and diaphragm, tested seropositive
using both antigens. Time of seroconversion varied among pigs and was negatively
correlated with intensity of infection. Minor differences were observed in time
of seroconversion between the 2 antigens in 11 of 46 pigs, suggesting some
differences in the antibody response. One pig with a worm burden of 0.01 larva/g
was not detected by enzyme immunoassay using either antigen. Background values
obtained using the 2 antigens did not differ among confinement-raised pigs, but
background values for pigs raised outdoors on dirt lots were significantly lower
using the glycan antigen Low-level, naturally acquired T spiralis infections in
pigs were detected in most instances by use of both antigens, although there were
some differences in antibody responses of infected pigs. CONCLUSION: The
synthetic glycan antigen has potential for replacing excretory-secretory antigens
as a standardized reagent for diagnosis of trichinellosis in pigs.
PMID- 9401692
TI - Differences between longitudinal and circular smooth muscle in beta-adrenergic
control of motility of isolated equine ileum.
AB - OBJECTIVE: To identify beta-adrenoceptor subtypes involved in motility inhibition
of circular and longitudinal smooth muscle layers of equine ileum. SAMPLE
POPULATION: Isolated strips of equine ileum circular smooth muscle and membrane
preparations from circular and longitudinal muscle layers. PROCEDURE: Functional
assays of circular muscle preparations and radioligand binding assays and
measurements of cAMP production in smooth muscle membranes from circular and
longitudinal layers. RESULTS: Selective beta-adrenergic agonists exerted
inhibitory effects on circular muscle preparations. Binding studies of cell
membranes indicated that the density and distribution of 3 beta-adrenoceptor
subtypes did not differ between longitudinal and circular muscle layers.
Measurement of cAMP production in membrane preparations of longitudinal and
circular muscle after selective beta-stimulation confirmed presence of the 3
adenylate cyclase-coupled beta-adrenoceptor subtypes; however, preparations from
the 2 layers had differing cAMP production efficacy. CONCLUSIONS: The data may
partly explain the differing functional responses between circular and
longitudinal muscle preparations. CLINICAL RELEVANCE: Findings support the
important role of beta-atypical adrenoceptors in the inhibitory regulation of
equine ileum motility.
PMID- 9401694
TI - Insulin-like growth factor I peptide elution profiles from fibrin polymers
determined by use of high-performance liquid chromatography.
AB - OBJECTIVE: To develop a high-performance liquid chromatography (HPLC) assay for
insulin-like growth factor I (IGF-I) and to use it to quantify elution of IGF-I
from polymerized fibrin in an in vitro system. SAMPLE POPULATION: Equine
fibrinogen and calcium-activated bovine thrombin were used to form fibrin
containing human recombinant IGF-I. PROCEDURE: Multiple fibrin disks were formed
from polymerized fibrinogen and thrombin; 6 disks were loaded with 25 micrograms
of recombinant human IGF-I at the time of polymerization, and 4 remained as
unladen controls. The resultant clots were incubated at 37 C and 90% humidity for
22 days. Phosphate-buffered saline solution in each well was replaced daily, and
IGF-I content was assayed by HPLC. Solid-phase separation was used to assay free
IGF-I peptide peaks. A scan was done to determine optimal wavelength for IGF-I
absorbance. Commercially pure IGF-I was used to construct a standard curve, and
the IGF-I content of medium removed from all 10 wells each day was assayed.
RESULTS: Pure unbound IGF-I eluted from the fibrin polymers for 22 days; initial
rapid daily release of 1.6 to 1.7 micrograms of IGF/ml of medium changed after
day 3 to commence an asymptotic decrease to 110 ng of IGF/ml by day 22. The
fibrin disks had dissolved by day 22, and the experiment was terminated. Control
disks did not have detectable IGF-I content at any time. Limit of the HPLC assay
was 25 ng of IGF-I/ml. Retention time for nonprotein-bound IGF-I was 10.3 +/-
0.15 minutes. CONCLUSION: IGF-I (25 micrograms) can be added to polymerized
fibrin and eluted as free ligand over a 22-day period of culture at 37 C. Release
of IGF-I was initially independent of fibrin dissolution, but later appeared to
follow a pattern consistent with fibrin degradation. CLINICAL RELEVANCE: IGF-I
can be incorporated as a depot form in polymerized fibrin and is released over
time in sufficient concentration to effectively stimulate articular chondrocyte
metabolic activity.
PMID- 9401693
TI - Pharmacokinetics of cisapride in horses after intravenous and rectal
administration.
AB - OBJECTIVES: To determine the i.v. pharmacokinetics of cisapride and measure
systemic absorption after rectal administration. ANIMALS: 5 healthy adult mares
(380 to 610 kg). PROCEDURE: Cisapride was administered, i.v., at a dosage of 0.1
mg/kg of body weight. In the same horses, after a 1-week washout period,
cisapride was administered rectally at a dosage of 1 mg/kg by mixing crushed
tablets with propylene glycol and administering the mixture into the rectum.
After each drug administration, a series of blood samples were collected. Plasma
was obtained and analyzed by high-performance liquid chromatography to determine
cisapride concentration profiles after each drug administration. RESULTS: After
i.v. administration, peak plasma concentration was 221.4 ng/ml and harmonic mean
half-life was 1.9 hours. Rectal absorption of cisapride was negligible. Cisapride
was detected in plasma from only 3 of 5 horses for which mean systemic
availability was 1.23%. Mean maximal plasma concentration after rectal
administration of cisapride was 13.5 ng/ml. CONCLUSION AND CLINICAL RELEVANCE:
After i.v. administration of cisapride, plasma concentration is high for
approximately 2 hours. Cisapride mixed with propylene glycol and administered
rectally at a dosage of 1 mg/kg is poorly and incompletely absorbed. Thus,
cisapride is not clinically useful for rectal administration in horses.
PMID- 9401695
TI - Effect of low-dose atropine administration on dobutamine dose requirement in
horses anesthetized with detomidine and halothane.
AB - OBJECTIVE: To determine whether a low dose of atropine is associated with
decreased requirement for cardiovascular supportive treatment in horses given
detomidine prior to maintenance of general anesthesia with halothane. ANIMALS: 3
groups of 10 healthy horses. PROCEDURE: Detomidine (20 micrograms/kg of body
weight, i.m.) was administered to all 30 horses. Then, 10 horses received
atropine (0.006 mg/kg, i.v.) 1 hour after detomidine administration, 10 horses
received atropine (0.012 mg/kg, i.m.) at the time of detomidine administration,
and 10 horses served as a control group. Heart rate was measured prior to
detomidine administration and at fixed intervals throughout anesthesia. The
dobutamine infusion rate necessary to maintain mean arterial blood pressure
between 70 and 80 mm of Hg was recorded. Systemic blood pressures, end-tidal
halothane, end-tidal CO2, and arterial blood gas tensions were measured at fixed
intervals. RESULTS: Mean heart rate was higher among horses receiving atropine
i.v. or i.m., compared with that in control horses. Horses that received atropine
i.v. had higher systemic arterial blood pressure and required a lower dobutamine
infusion rate than did horses of the other groups. CONCLUSION: Detomidine
treated, halothane-anesthetized horses given atropine i.v. required less
dobutamine, compared with horses receiving or not receiving atropine i.m.
Complications, such as colic and dysrhythmias, from use of higher doses of
atropine, were not observed at this lower dose of atropine. CLINICAL RELEVANCE:
i.v. administration of a low dose of atropine prior to induction of general
anesthesia may result in improved blood pressure in horses that have received
detomidine before anesthesia with halothane.
PMID- 9401696
TI - Effects of medetomidine on serum insulin and plasma glucose concentrations in
clinically normal dogs.
AB - OBJECTIVE: To determine the effects of medetomidine, administered i.v., on serum
insulin and plasma glucose concentrations in clinically normal dogs. ANIMALS: 6
healthy adult Beagles. PROCEDURE: Dogs were randomly assigned to each of 3
treatments in a prospective cross-over study design. Serum insulin and plasma
glucose concentrations were determined before and 20, 40, 60, 120, 180, 240, 300,
360, 420, and 480 minutes after i.v. administration of 0.9% NaCl solution
(control) or medetomidine (10 or 20 micrograms/kg of body weight). RESULTS: Mean
serum insulin concentration decreased after medetomidine administration and was
significantly (P < or = 0.05) lower than control values 20, 40, 60, and 120
minutes after drug administration. Mean plasma glucose concentration tended to
increase after medetomidine administration, but did not differ significantly from
control values. CONCLUSIONS: In dogs, i.v. administration of medetomidine at
dosages of 10 and 20 micrograms/kg transiently decreases serum insulin
concentration, but plasma glucose concentration remains within the normal
physiologic range. CLINICAL RELEVANCE: Medetomidine can be given at low,
preanesthetic dosages without significantly altering plasma glucose concentration
in clinically normal dogs.
PMID- 9401697
TI - Evaluation of selected cardiopulmonary and cerebral responses during
medetomidine, propofol, and halothane anesthesia for laparoscopy in dogs.
AB - OBJECTIVES: To compare the dose-sparing effect of medetomidine on the propofol
induction dose and concentration of halothane for maintenance of anesthesia
during laparoscopy and to provide guidelines for effective and safe use of these
anesthetics in dogs to ensure desirable perioperative analgesia. ANIMALS: 14
purpose-bred dogs. PROCEDURE: Cardiopulmonary and electroencephalographic
responses were determined during 2 anesthesia protocols in dogs scheduled for
laparoscopy. Fifteen minutes before anesthesia induction, all dogs received
atropine sulfate (0.02 mg/kg of body weight, i.m.). Seven dogs were then given
propofol (6.6 mg/kg, i.v.); anesthesia was maintained with halothane in oxygen.
The other dogs were given medetomidine hydrochloride (10 micrograms/kg, i.m.) 5
minutes after administration of atropine sulfate; anesthesia was then induced by
administration of propofol (2.8 mg/kg, i.v.) and was maintained with halothane in
oxygen. RESULTS: The halothane concentration required for laparoscopy was lower
in dogs given medetomidine. Anesthetic requirements were significantly increased
during abdominal manipulation in both groups. Total amplitude of the
electroencephalograph in medetomidine-treated dogs was not significantly lower
than that in dogs not given medetomidine. Pulmonary responses were stable
throughout all procedures. The primary cardiovascular response was an increase in
blood pressure associated with the medetomidine-atropine preanesthetic
combination. Significant differences in total amplitude or frequency shifts
(spectral edge) of brain wave activity were not associated with surgical
stimulation. CONCLUSION: Lack of neurologic changes during laparoscopy supports
the efficacy of either medetomidine-propofol-halothane or propofol-halothane
combinations at higher concentrations to provide desirable analgesia and
anesthesia in this group of dogs.
PMID- 9401698
TI - Secondary stress responses to acute handling in striped bass (Morone saxatilis)
and hybrid striped bass (Morone chrysops x Morone saxatilis).
AB - OBJECTIVE: To test the hypothesis that, compared with pure striped bass, hybrid
striped bass have reduced secondary physiologic responses to handling stress. A
secondary objective was to determine whether not feeding fish for a 3-day period
affected responses. ANIMALS: Hatchery-reared adult striped bass (Morone
saxatilis) and adult hybrids of striped bass with white bass (M chrysops), with
mean length of 27.9 cm and mean weight of 487 g. PROCEDURE: Fed and 3-day nonfed
fish, in groups of 6, were held in dip nets above water for 3 minutes. Severity
of response to handling was determined by measuring plasma glucose and chloride
and blood lactic acid, sodium, and potassium concentrations. Terminal samples
were taken from fish before handling (control), immediately after handling, and
after 12, 24, and 48 hours of recovery. RESULTS: Striped bass were hyperglycemic
and lactacidemic after stress and for 12 to 48 hours afterward, whereas glucose
and lactic acid values in hybrids were essentially unchanged. Blood sodium and
chloride concentrations of hybrids decreased after stress, then returned to
control values within 24 hours. Striped bass, however, had a greater decrease in
values for these electrolytes and failed to recover in 48 hours. Blood potassium
concentration remained unchanged in all test groups. Nonfeeding for 3 days before
handling did not appear to affect stress response in striped bass or hybrids.
CONCLUSIONS AND CLINICAL RELEVANCE: Striped bass have an appreciably greater
response to acute handling stresses, such as those that may be experienced in
hatcheries and experimental laboratories, than do hybrid bass. Thus, pure striped
bass require more care in handling. The usual practice of not feeding before
handling does not affect physiologic responses.
PMID- 9401699
TI - Metabolizable energy intake and sustained energy expenditure of Alaskan sled dogs
during heavy exertion in the cold.
AB - OBJECTIVE: To measure energy expenditures of Alaskan sled dogs at rest and during
racing under frigid conditions, using the doubly labeled water (DLW) technique.
ANIMALS: 18 fit Alaskan sled dogs. PROCEDURE: Energy expenditure was measured in
9 dogs during a 490-km sled dog race by use of the DLW technique, whereby dogs
were administered water enriched with nonradioactive isotopes of hydrogen and
oxygen. Energy intake was determined by dietary analysis. Changes in background
abundance of the isotopes 2H and 18O were monitored in 5 dogs that did not
receive isotope-enriched water. RESULTS: Dogs completed the 490-km race at an
average speed of 7 km/h at ambient temperature of -35 to -10 C. Total energy
expenditure, measured by the DLW technique, was 47,100 +/- 5,900 kJ/d (4,400 +/-
400 kJ.kg-0.75/d), and metabolizable energy intake was 44,600 kJ/d (4,100 kJ.kg
0.75/d) during the 70-hour race. CONCLUSIONS: The sustained metabolic rate for
these sled dogs during racing was extraordinarily high for a large mammal. This
study validated use of the DLW technique in dogs with exceptionally high energy
expenditure associated with prolonged exercise in the cold.
PMID- 9401700
TI - Comparison of alveolar ventilation, oxygenation, pressure support, and
respiratory system resistance in response to noninvasive versus conventional
mechanical ventilation in foals.
AB - OBJECTIVE: To compare the efficacy of positive pressure ventilation applied
through a mask versus an endotracheal tube, using anesthetized/paralyzed foals as
a model for foals with hypoventilation. ANIMALS: Six 1-month-old foals.
PROCEDURE: A crossover design was used to compare the physiologic response of
foals to 2 ventilatory techniques, noninvasive mask mechanical ventilation (NIMV)
versus endotracheal mechanical ventilation (ETMV), during a single period of
anesthesia and paralysis. Arterial pH, PaO2, PaCO2, oxygen saturation, end-tidal
CO2 tension, airway pressures, total respiratory system resistance, resistance
across the upper airways (proximal to the midtracheal region), and positive end
expiratory pressures (PEEP) were measured. Only tidal volume (VT; 10, 12.5, and
15 ml/kg of body weight) or PEEP (7 cm of H2O) varied. RESULTS: Compared with
ETMV, use of NIMV at equivalent VT resulted in PaCO2 and pH values that were
significantly higher, but PaO2 was only slightly lower. Between the 2 methods,
peak airway pressure was similar, but peak expiratory flow was significantly
lower and total respiratory resistance higher at each VT for NIMV. Delivery of
PEEP (7 cm of H2O) was slightly better for ETMV (7.1 +/- 1.3 cm of H2O) than for
NIMV (5.6 +/- 0.6 cm of H2O). CONCLUSION: These data suggest that use of NIMV
induces similar physiologic effects as ETMV, but the nasal cavities and mask
contribute greater dead space, manifesting in hypercapnia. Increasing the VT used
on a per kilogram of body weight basis, or the use of pressure-cycled ventilation
might reduce hypercapnia during NIMV. CLINICAL RELEVANCE: Use of NIMV might be
applicable in selected foals, such as those with hypoventilation and minimal
changes in lung compliance, during weaning from endotracheal mechanical
ventilation, or for short-term ventilation in weak foals.
PMID- 9401701
TI - Exercise capacity in young and old mares.
AB - OBJECTIVE: To test the hypothesis that, compared with unfit young horses, unfit
older horses have lower aerobic capacity and reduction in other indices of
exercise capacity. ANIMALS: 6 young (mean +/- SEM, 5.3 +/- 0.8 years and 445 +/-
13 kg) and 6 aged (22.0 +/- 0.4 years and 473 +/- 18 kg) healthy Standardbred and
Thoroughbred mares. PROCEDURES: The mares, accustomed to running on a treadmill,
were tested by use of an incremental exercise test. None of the mares had
received exercise training for at least 4 months prior to the study. During
testing, mares ran up a fixed 6% grade, starting at a speed of 4 m/s, with 1 m/s
increase every 60 seconds (omitting 5 m/s) until they reached fatigue. Maximal
oxygen uptake (VO2max) was measured by use of an open-flow calorimeter. Venous
blood samples (10 ml) were collected during the last 10 seconds of each step and
were used to measure blood lactate concentration and PCV. Calculated performance
indices included velocity at VO2max, maximal velocity, and velocity at lactate
concentration of 4 mmol/L; work rate (watts) at those velocities also was
determined. RESULTS: There were differences (P < 0.05) between old and young
mares for maximal run velocity attained during the test (8.7 +/- 0.5 versus 10.8
+/- 0.5 m/s, respectively), VO2max (89.4 +/- 4.3 versus 117.3 +/- 9.5 ml/kg of
body weight/min, respectively), and velocity at VO2max (8.0 +/- 0.4 versus 9.8 +/
0.7 m/s, respectively). Also, velocity required to reach blood lactate
concentration of 4 mmol/L was lower (P < 0.05) in old (7.5 +/- 0.4 m/s), compared
with young (10.2 +/- 0.7 m/s), mares. CONCLUSION: Older mares have substantially
(-24%) lower maximal aerobic capacity than do young mares. CLINICAL RELEVANCE:
Many horses participate in athletic activities into their late teens and some do
so beyond the age of 20 years; thus, the need exists to explore ways to adjust
training programs for older horses.
PMID- 9401703
TI - The problems of inattention: methods and interpretations.
PMID- 9401702
TI - Rehabilitation of dogs with surgically treated cranial cruciate ligament
deficient stifles by use of electrical stimulation of muscles.
AB - OBJECTIVE: To determine effect of electrical muscle stimulation (EMS) on rate and
degree of return to function of the limb and development of degenerative joint
disease (DJD) after surgical creation and subsequent stabilization of the cranial
cruciate ligament (CrCL)-deficient stifle. ANIMALS: 12 clinically normal adult
large (19.5 to 31.5 kg) dogs. PROCEDURE: Dogs were anesthetized, and the right
CrCL was severed via arthrotomy, destabilizing the stifle. After 3 weeks, the
stifle was surgically stabilized. Three weeks later, 6 dogs were subjected to an
EMS treatment protocol for the thigh muscles. At 5, 9, 13, and 19 weeks after
stifle destabilization, treated (n = 6) and control (n = 6) dogs were evaluated
for return of stifle function. Gross and histologic evaluations of the stifles
were performed at 19 weeks after stifle destabilization. RESULTS: Treated dogs
had significantly (P = 0.001) better lameness score than did control dogs. There
was less palpable crepitation of the stifle in treated dogs (P = 0.06); treated
dogs also had significantly (P = 0.01) fewer radiographic signs of bone changes.
Thigh circumference was significantly (P = 0.02) larger in treated dogs. There
was less gross cartilage damage (P = 0.07) in the EMS-treated dogs, but more
medial meniscal damage (P = 0.058, cranial pole; P = 0.051, caudal pole).
CONCLUSIONS: Improved lameness scores, larger thigh circumference, and decreased
radiographically apparent bony changes observed for the treated group of dogs
support the hypothesis that dogs treated by EMS after surgical stabilization of
the CrCL-deficient stifle had improved limb function, with less DJD, than did
dogs treated with the currently accepted clinical protocol of cage rest and slow
return to normal activity. However, results of force plate evaluation did not
support the hypothesis. Increased meniscal damage in dogs treated by EMS may be
cause for concern.
PMID- 9401704
TI - The switching model of latent inhibition: an update of neural substrates.
AB - Organisms exposed to a stimulus which has no significant consequences, show
subsequently latent inhibition (LI), namely, retarded conditioning to this
stimulus. LI is considered to index the capacity to ignore irrelevant stimuli and
its disruption has recently received increasing interest as an animal model of
cognitive deficits in schizophrenia. Initial studies indicated that LI is
disrupted by systemic or intra-accumbens injections of amphetamine and
hippocampal lesions, and potentiated by systemic administration of neuroleptics.
On the basis of these findings, the switching model of LI proposed that LI
depends on the subicular input to the nucleus accumbens (NAC). Subsequent studies
supported and refined this proposition. Lesion studies show that LI is indeed
disrupted by severing the subicular input to the NAC, and further implicate the
entorhinal/ventral subicular portion of this pathway projecting to the shell
subterritory of the NAC. There is a functional dissociation between the shell and
core subterritories of the NAC, with lesions of the former but not of the latter
disrupting LI. This suggests that the shell is necessary for the expression and
the core for the disruption of LI. The involvement of the NAC has been also
demonstrated by findings that LI is disrupted by intra-accumbens injection of
amphetamine and potentiated by DA depletion or blockade in this structure.
Disruption and potentiation of LI by systemic administration of amphetamine and
neuroleptics, respectively, have been firmly established, and in addition, have
been shown to be sensitive to parametric manipulations of the LI procedure. LI is
unaffected by lesions and DA manipulations of medial prefrontal cortex and
lesions of basolateral amygdala. The implications of these findings for LI as an
animal model of schizophrenia are discussed.
PMID- 9401705
TI - Latent inhibition: the nucleus accumbens connection revisited.
AB - It has been proposed that dopaminergic transmission in the nucleus accumbens
plays a key role in regulating latent inhibition (LI), i.e. the retardation of
conditioning that occurs if a to-be-conditioned stimulus is first presented a
number of times ('preexposure') without other consequence. New evidence in
support of this hypothesis is presented or reviewed here, showing that: (1) intra
accumbens injection of haloperidol at the time of conditioning potentiates LI;
(2) destruction of dopaminergic terminals in the nucleus accumbens potentiates
LI; (3) intra-accumbens haloperidol reverses the blockade of LI caused by
systemic nicotine; (4) intra-accumbens haloperidol reverses the blockade of LI
caused by systemic amphetamine; (5) after a single systemic injection of
amphetamine (insufficient on its own to block LI), a subsequent intra-accumbens
injection of amphetamine at the time of conditioning blocks LI; and (6) intra
accumbens (like systemic) amphetamine administered 15 min before conditioning,
without prior systemic amphetamine, failed to block LI. The difference between
the effects on LI of one and two administrations of amphetamine, respectively, is
interpreted in terms of the need for sensitisation of the response to
amphetamine, with the result that the response to the second administration
includes a component of impulse-dependent dopamine release in the nucleus
accumbens that is otherwise lacking. Data from dialysis experiments suggest that
such impulse-dependent accumbens dopamine release also occurs at relatively long
delays after a single systemic administration of amphetamine. It was accordingly
predicted, and found, that, although LI is intact 15 min after an i.p. injection
(confirming previous results), it is abolished at 90 min after the injection of
amphetamine. This finding is consistent with the effects of amphetamine in human
subjects, in whom LI is blocked 90 min after a single oral administration.
Overall, these results strengthen the case that the blockade of LI by elevated,
and potentiation of LI by decreased, dopaminergic transmission are both due
specifically to actions in the nucleus accumbens; and also add to the
similarities between LI studied in animal and human subjects, respectively.
PMID- 9401706
TI - Amphetamine-induced disruption and haloperidol-induced potentiation of latent
inhibition depend on the nature of the stimulus.
AB - If a stimulus (e.g. light) is repeatedly preexposed without consequences, it
subsequently develops a weaker association with a reinforcer (e.g. foot shock)
than does a non-preexposed stimulus. This retarded conditioning to the preexposed
as compared to the non-preexposed stimulus, is latent inhibition (LI). It is well
documented that LI is disrupted by low doses of amphetamine and potentiated by
neuroleptic drugs, and there is evidence that the action of these agents on LI
can be modified by changes in the parameters of preexposure or conditioning. The
present experiments tested whether the effects of DA agents on LI are influenced
by the nature of the stimulus. In two experiments, LI was assessed using an off
baseline conditioned emotional response (CER) procedure in rats licking for
water, consisting of three stages: preexposure, in which the stimulus (a light)
to be conditioned, was repeatedly presented without being followed by
reinforcement; conditioning, in which the preexposed stimulus was paired with
reinforcement (a foot-shock); and test, in which LI was indexed by animals'
degree of suppression of licking during stimulus presentation. In both
experiments, different groups of animals were preexposed and conditioned with
four different preexposed visual stimuli: three steady side-lights, three
flashing side-lights, one flashing side-light, and a flashing houselight.
Experiment 1 used 40 stimulus preexposures and tested the effects of 1 mg/kg D
amphetamine, whereas experiment 2 used 10 preexposures and tested the effects of
0.1 mg/kg haloperidol. The results showed that of the four stimuli used, both
drugs were effective with only one and the same stimulus, namely, flashing
houselight. This demonstrates that the disruptive effect of amphetamine and the
potentiating effect of haloperidol on LI, are modifiable by manipulating the
nature of the preexposed stimulus.
PMID- 9401707
TI - Disruption of latent inhibition in the rat by the 5-HT2 agonist DOI: effects of
MDL 100,907, clozapine, risperidone and haloperidol.
AB - Latent inhibition (LI), a measure of the ability to learn to ignore irrelevant
stimuli, is disrupted in acute schizophrenics and in rats treated with
amphetamine; antipsychotics prevent amphetamine disruption of LI in rats. The 5
HT2A/C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) has
hallucinogenic properties in humans, and evidence suggests that 5-HT2 antagonism
is an important component of atypical antipsychotic activity. Therefore, the
ability of DOI to disrupt LI in rats was tested, and the ability of clinically
used and putative antipsychotics to reverse DOI disruption of LI was assessed.
The method consisted of four phases. After habituation to the apparatus, thirsty
rats underwent preexposure to a tone stimulus 24 h prior to two tone-shock
conditioning trials. LI was demonstrated at testing (an additional 24 h later) by
reduced lick suppression during tone presentation. When administered at the
preexposure phase only, DOI disrupted LI. However, when administered at both
preexposure and conditioning phases, DOI did not disrupt LI except at the highest
dose, where lick suppression itself was also disrupted. Therefore, disruptive
effects of DOI on LI are not easily dissociated from state-dependent learning
effects. Additional experiments demonstrated that haloperidol, clozapine,
risperidone, and the selective 5-HT2A antagonist MDL 100,907 prevented the
disruptive effects of DOI on LI when administered at preexposure only. These
results agree with findings that these compounds can also prevent other
behavioral effects of DOI. Further experiments will be required to explore the
possible involvement of state-dependent learning effects in the present results.
However, if the disruptive effects of DOI on LI are due to an influence on
attentional processes rather than state-dependent learning, this procedure may
have potential as a method for detection of antipsychotic activity.
PMID- 9401708
TI - WAY100635 and latent inhibition in the rat: selective effects at preexposure.
AB - The influence of the selective, silent 5HT1a antagonist WAY100635 (Wyeth Research
Ltd) on the latent inhibition effect was examined in a within-subject, on
baseline conditioned suppression procedure in rats. WAY100635 was found to
enhance the latent inhibition effect, producing a retardation in the acquisition
of conditioned suppression following a level of stimulus preexposure known to be
insufficient to produce a latent inhibition effect in control animals. This
influence of the drug was restricted to its actions during the preexposure phase
of the experiment, and the drug also abolished the unconditioned suppression of
lever pressing that occurs on the first presentation of a novel auditory
stimulus. These findings are discussed in terms of the possible influence of
serotonergic manipulations on contextual processing, and also have important
implications for current animal models of schizophrenia which stress the role of
dopaminergic mechanisms in latent inhibition.
PMID- 9401709
TI - Bilateral ablation of the auditory cortex in the rat alters conditioned emotional
suppression to a sound as appraised through a latent inhibition study.
AB - Latent inhibition consists of a retardation of conditioning seen when the to be
conditioned stimulus is presented a number of times with no other consequence.
This phenomenon likely reflects processes of selective attention whereby
irrelevant stimuli come to be ignored. Using physiological models for auditory
attention, some investigators have suggested that selective attention acts as a
filtering mechanism capable of inhibiting or gating unattended stimuli relative
to attended ones in the auditory cortex. In the present work, an on-baseline
conditioned suppression response procedure was used to study the effects of
stimulus preexposure in rats submitted to bilateral auditory cortex ablation. Our
results indicate that both auditory cortex lesioned and control animals exhibit
latent inhibition to a sound. However, learning after preexposure to that sound
was particularly slow in animals with bilateral auditory cortex lesion, i.e. in
these animals, the latent inhibition effect appeared to be enhanced. Conditioning
from one day to the next also varied slightly. Thus, the auditory cortex appears
to modulate learning when the conditioned stimulus is a sound.
PMID- 9401710
TI - Fetal hippocampal transplants restore conditioned blocking in rats with dorsal
hippocampal lesions: effect of age.
AB - Previous studies have shown that conditioned blocking of taste aversion learning
in 3-month-old Wistar rats depends on the hippocampal system integrity. Thus, the
aim was to demonstrate that enough connectivity would develop after a graft to
support the attention mechanism required for conditioned blocking. In the first
experiment, bilateral homotopic grafts of 16-17 day-old hippocampal fetal tissue
applied to 3-month-old male Wistar rats after electrolytical lesions of the
dorsal hippocampus reinstated conditioned blocking tested 5 months after the
transplantation. Unexpectedly, an early age-dependent impairment of conditioned
blocking, similar to that induced by hippocampal lesions, was found in the 8
month-old control group. This finding was further supported by the results of the
second experiment. Non-operated 3-month-old but not 8-month-old Wistar rats
showed conditioned blocking. The results are discussed in terms of early
hippocampal vulnerability, prevented by fetal grafts.
PMID- 9401711
TI - Latent inhibition as a measure of learned inattention: some problems and
solutions.
AB - The latent inhibition (LI) paradigm has been used to assess attentional
dysfunction in various pathological groups. The rationale is based on the
assumption that passive stimulus exposure results in the acquisition of an
inattentional response to that stimulus. Consequently, compared to a novel
stimulus in the same new learning situation, the preexposed stimulus is at a
disadvantage. It is argued that methodological and conceptual problems in
constructing procedures and designs have created obstacles in relating disrupted
LI to psychopathology. Specifically, issues associated with within- and between
subject designs, dichotomous dependent variables, ceiling effects, converging
operations, and possible mis-attribution of the LI effect are addressed. Designs
and data from several new human-LI paradigms, with normal, de novo Parkinson, and
schizophrenic subjects are examined. Results from a multi-condition, within
subject visual search procedure suggest that LI, heretofore attributed only to a
deficit in the stimulus preexposed group, may, in part, be due to enhanced
performance in the nonpreexposed group. Implications for the design and
interpretation of LI experiments, particularly with pathologic groups are
discussed.
PMID- 9401712
TI - Latent inhibition and autonomic responses: a psychophysiological approach.
AB - Latent inhibition, retarded learning after preexposure to the to-be-conditioned
stimulus, has been implied as a tool for the investigation of attentional
deficits in schizophrenia and related disorders. The present paper reviews
research that used Pavlovian conditioning as indexed by autonomic responses
(electrodermal, vasomotor, cardiac) to investigate latent inhibition in adult
humans. Latent inhibition has been demonstrated repeatedly in healthy subjects in
absence of a masking task that is required in other latent inhibition paradigms.
Moreover, latent inhibition of Pavlovian conditioning is stimulus-specific and
increases with an increased number of preexposure trials which mirrors results
from research in animals. A reduction of latent inhibition has been shown in
healthy subjects who score high on questionnaire measures of psychosis proneness
and in unmedicated schizophrenic patients. The latter result was obtained in a
within-subject paradigm that holds promise for research with patient samples.
PMID- 9401713
TI - The development of conditioned blocking and monoamine metabolism in children with
attention-deficit-hyperactivity disorder or complex tics and healthy controls: an
exploratory analysis.
AB - Conditioned blocking (CB) measures the transient suppression of learning that a
new stimulus, added during learning, has the same consequences as the conditioned
stimulus already present. Normal CB increases between the age of 8 and 20 years
(Oades, R.D., Roepcke, B. and Schepker, R., A. test of conditioned blocking and
its development in childhood and adolescence: relationship to personality and
monoamine metabolism, Dev. Neuropsychol., 12 (1996) 207-230). In the present
study CB development is compared between healthy children (CN), children with
attention deficit (ADHD) and those with complex tics or Tourette's syndrome (TS)
with mean ages of 10-11 years. All children needed fewer learning trials with
increasing age: the ADHD group showed a slight impairment. Only controls improved
CB with increasing age. A trend for worse CB in the TS than the other groups was
significant for those over 11 years. While ADHD children over 11 years showed
less CB than controls, younger ADHD children showed more. A correlational
analysis of the status of monoamine metabolism in 24 h urine samples showed a
positive relationship for CB with dopamine metabolism in controls and TS
children, but a negative relationship in ADHD children. In contrast, increases of
serotonin metabolism were negatively related to CB in TS but positively in ADHD
patients. In conclusion, when selective information processing abilities
reflected by CB start to develop at puberty-onset, there is a relative worsening
in ADHD patients. But TS patients show an impairment independent of age. Changes
in the balance between dopamine and serotonin systems may contribute to normal
and abnormal cognitive development.
PMID- 9401714
TI - Disruption of the Kamin blocking effect in schizophrenia and in normal subjects
following amphetamine.
AB - The Kamin blocking effect (KBE) is an established animal learning paradigm
measuring selective processing, in which reduced blocking reflects allocation of
greater processing resources to non-relevant information. Two KBE tasks are
described below. Results from studies using the first (between-subjects) task
indicate that KBE is abolished in acute schizophrenics with positive psychotic
symptoms. It is also abolished in the relatives of schizophrenic subjects,
although interpretation of this finding is hampered by poor performance of
subjects in the control condition. The second (within-subjects) task indicated
abolition of KBE in schizophrenic patients with positive psychotic symptoms.
Administration of acute amphetamine to normal human subjects did not
significantly disrupt performance on the first task. Whilst for the second task,
although blocking was limited to placebo subjects, overall pre-exposure effects
are not sufficiently strong to indicate specific drug effects.
PMID- 9401715
TI - Stimulus dimension shifts in patients with schizophrenia, with and without
paranoid hallucinatory symptoms, or obsessive compulsive disorder: strategies,
blocking and monoamine status.
AB - Reversal, and intra-dimensional (ID) and extra-dimensional (ED) nonreversal
discrimination shifts were studied to see if learned inattention to the
irrelevant dimension differentially influenced the efficacy of learning and
stimulus choice strategy. Performance was compared with conditioned blocking (CB)
and monoamine metabolic status between healthy controls, patients with obsessive
compulsive disorder (OCD) or schizophrenia with (PH) or without (NP) active
paranoid hallucinatory symptoms. PH and NP patients improved learning with
practice, but showed an impaired shift on each task. OCD patients were impaired
only on the ED-shift. The NP patient's impairment was nonspecific and, unlike PH
and controls, it related to reversal performance. All subjects acquired an
attentional set for colour reflected in the length of stimulus-response
sequences. Analysis of paired-stimulus choice-strategies showed that while all
patients showed fewer correct win-stay choices, only PH patients perseverated
with lose-stay choices. Learning about the added stimulus in the CB task related
to ID-shift efficiency in NP patients. Increases of dopamine activity related to
delayed learning but more switches of stimulus choice in the shift-tasks.
Increases of serotonin activity correlated with faster learning in controls, OCD
and PH patients. In NP patients the opposite held for dopamine and serotonin
activity. Thus the two learned inattention tasks have different if related
requirements and correlates: the data are consistent with the use of automatic
exogenous attention strategies by NP patients, of inefficient controlled
attention by PH patients and the automatization of endogenous processes in
controls.
PMID- 9401716
TI - Species differences in cardiac thyroid hormone receptor isoforms protein
abundance.
AB - Little is known about the cardiac expression of different thyroid hormone
receptor (TR) isoforms. The aim of the study was to investigate such patterns of
TR expression at the protein level in different species and in some human
tissues. Western blot analysis with specific polyclonal rabbit antibodies to each
TR isoform was performed with samples from myocardium of the left ventricle from
man, dog, guinea pig, rat and mouse, as well as with samples from several human
tissues such as heart, skeletal muscle, brain, liver and thyroid. The TR alpha 1
isoform was present in all of the species examined. The TR alpha 2 was recognized
in human, dog and guinea pig heart, while no such band was recognized in rat and
mouse hearts. TR beta 1 was not detected in the human heart but in the other
species. Similarly to TR alpha 1, TR beta 2 was detected in all of the species
examined. In the human tissues studied, TR alpha 1 was detected in heart and
skeletal muscle, whereas TR alpha 2 was found only in the heart. TR beta 1 was
not detected in any of the examined human tissues, while TR beta 2 was found in
all of them. These results revealed unique distributions of TR variants and they
demonstrate common epitopes in TR in the different species. For the first time,
the presence of a TR beta 2 isoform has been shown in human tissues. TR isoforms
may have a tissue and species specific role in the regulation of gene expression
and may in part explain variable tissue effects of thyroid hormones.
PMID- 9401717
TI - Cloning of the cDNA for a mouse homologue of human PHBP: a novel hyaluronan
binding protein.
AB - The cDNA which encodes the mouse counterpart of human plasma hyaluronan-binding
protein (PHBP) was isolated and characterized. The clone contained an insert of
2153 bp, which contained the 1674-bp open reading frame coding for a polypeptide
of 558 amino acid residues. The amino acid sequence of mouse PHBP predicted from
the nucleotide sequence of cDNA shows reasonable homology to that of human PHBP.
Like human PHBP, the amino acid sequence predicted from the nucleotide sequence
of mouse PHBP cDNA exhibited significant homology to that of human hepatocyte
growth factor activator (HGFA).
PMID- 9401718
TI - Inhibitory effect of oversulfated fucoidan on tube formation by human vascular
endothelial cells.
AB - Fucoidan is a sulfated poly(L-fucopyranose) present in brown marine algae. In
this study, we examined the effect of native and chemically oversulfated
fucoidans (NF and OSF) on the tube structure formation by human umbilical vein
endothelial cells (HUVEC) on the basement membrane preparation, Matrigel. Unlike
NF, OSF significantly decreased the tube formation: maximal inhibition (50% of
control) was obtained with 25 micrograms/ml. The OSF effect was mediated, at
least in part, through the inhibition of HUVEC migration, as determined by the
ability to block chemotaxis in a Transwell chamber assay. Quantitative
immunoreactive assays for tissue-type plasminogen activator (t-PA) and
plasminogen activator inhibitor-1 (PAI-1) in the culture media indicated that OSF
(25 micrograms/ml) increased the accumulation of PAI-1 antigen, but not of t-PA
antigen, 2.7-fold compared with control. The release of both antigens by HUVEC
was slightly affected by the addition of NF. Determination of the media levels of
type IV collagenase activity and tissue inhibitor of metalloproteinase-1 (TIMP-1)
antigen showed that OSF (25 micrograms/ml) decreased the collagenolytic activity
by 50% compared to the control, without alteration of the TIMP antigen level.
However, the collagenase inhibition by OSF was not observed in an assay system
using purified enzyme. NF had no effect on collagenase activity or TIMP-1 antigen
levels. These results indicate that the introduction of sulfate groups into NF
enables it to effectively inhibit the formation of capillary-like structures by
HUVEC on Matrigel by reducing the basement membrane destruction and cell
migration. It is involved as at least one of the mechanisms by which the OSF
induced increase in HUVEC PAI-1 decreases plasmin formation and suppresses the
following pro-collagenase activation.
PMID- 9401719
TI - Inhibition of the metallo-beta-lactamase produced from Serratia marcescens by
thiol compounds.
AB - Low molecular weight thiol compounds have been found to be strong inhibitors of
metallo-beta-lactamase (IMP-1) produced by Serratia marcescens TN9106, which was
expressed by Echerichia coli JM109 cells. Mercaptoacetic acid and 2
mercaptopropionic acid strongly and competitively inhibited IMP-1 with Ki of 0.23
and 0.19 microM, respectively. 2-Mercaptoethanol reversibly inhibited IMP-1 but
did not show simple competitive inhibition.
PMID- 9401720
TI - Separation of sialoglycoprotein fractions having influenza virus-receptor
activity from human meconium and some of their chemical properties.
AB - Three sialoglycoprotein fractions having reactivities against influenza A and B
viruses (IV-A and IV-B) and influenza virus-hemagglutinin (IV-HA), were obtained
by gel filtration using a Sephacryl S-300 column and an Asahipak GS-710 HPLC
column from water-soluble fraction prepared from human meconium (ME-WSF).
Molecular weights of sialoglycoproteins in these fractions were estimated as 746
kDa (P-Fr. 1-3), 4470 kDa (P-Fr. 1-2) and a more than 10,000 kDa (P-Fr. 1-1),
respectively. The other in P-Fr. 2, with molecular weight estimated as 92 kDa,
revealed positive but weak reactivity against IV-HA; however, the fraction did
not show positive reactivity against either IVs-A or -B. All these fractions
contained sialoglycoproteins with a high content of carbohydrates (31.0-59.3%,
w/w). From their carbohydrate compositions, it can be suspected that
sialoglycoproteins having O-glycosidically linked carbohydrate chains were
predominating in the three fractions. In conclusion, it is suggested that at
least three sialoglycoproteins with influenza virus-receptor activity showing
different chemical properties to each other exist in human meconium.
PMID- 9401721
TI - The effect of TRK-530 on experimental arthritis in mice.
AB - TRK-530 is a newly synthesized diphosphonate derivative. We investigated the
effect of TRK-530 on type II collagen-induced arthritis (CIA) in mice in
comparison to that of prednisolone and indomethacin. TRK-530 at a dose of 25
mg/kg showed a tendency to inhibit CIA. TRK-530 at a dose of 50 mg/kg inhibited
the development of the CIA in terms of the progression of footpad swelling, bone
damage and histopathological changes. TRK-530 at a dose of 50 mg/kg also
significantly inhibited the delayed type hypersensitivity (DTH) response to type
II collagen, but not the production of anti-type II collagen IgG antibody in
arthritic mice. To investigate the inhibitory mechanism of TRK-530, the type of
effect of TRK-530 on the production of IL-1 beta in vitro was studied. TRK-530 at
a concentration of 10(-4) M inhibited LPS-induced IL-1 beta production from
J774.1 cells. In conclusion, TRK-530 inhibited CIA in mice. The inhibition of the
DTH reaction to type II collagen and the inhibition of IL-1 beta production may
partly participate the anti-rheumatoid action of TRK-530.
PMID- 9401722
TI - The analgesic and anti-inflammatory effects of shark cartilage are due to a
peptide molecule and are nitric oxide (NO) system dependent.
AB - The present work shows an antinociceptive and dose-dependent effect of shark
cartilage hydrosoluble fraction (HF) on writhing and formalin tests in mice. The
effect was not altered by thalidomide, a known inhibitor of tumor necrosis factor
alfa (TNF-alfa) synthesis. Similarly, the antinociceptive effect did not change
in the presence of naloxone, indicating that the opioid system is not involved.
However, the effect observed was blocked by L-arginine, a NO synthesis substrate,
and it was potentiated by L-NAME, suggesting a role of the NO system in the shark
cartilage antinociceptive effect. Effects similar to those seen with the HF were
detected with peak II from gel filtration chromatography. The increase in
vascular permeability induced by serotonin in rats was significantly abolished by
the HF at the dose of 2 mg/kg, p.o., and again it was not potentiated by
thalidomide. The observed blockade in the vascular permeability increase induced
by histamine was detected only with a higher dose (10 mg/kg, p.o.).
PMID- 9401723
TI - The effects of hange-shashin-to on gastric function in comparison with sho-saiko
to.
AB - The effects of "Hange-shashin-to (TJ-14)" on gastric function were examined in
comparison with "Sho-saiko-to (TJ-9)". Oral treatment with TJ-14 (125-500 mg/kg)
caused dose-dependent suppression of ethanol-induced gastric injury, while it did
not suppress gastric lesions induced by water-immersion stress. TJ-9 (125-500
mg/kg, p.o.) suppressed both water-immersion stress-induced gastric lesions and
ethanol-induced gastric injury in a dose-dependent manner. Intraduodenal
administration of TJ-14 even at 500 mg/kg did not affect gastric juice secretion,
while TJ-9 at 125 to 500 mg/kg dose-dependently suppressed gastric juice
secretion. TJ-14 (125-500 mg/kg, p.o.) accelerated gastric emptying in normal
rats and improved the delayed gastric emptying induced by BaCl2 in a dose
dependent manner, whereas such effect was not noted with TJ-9. Oral treatment
with TJ-14 at 500 mg/kg significantly suppressed apomorphine-induced vomiting,
but it did not affect copper sulfate-induced vomiting. These results suggest that
TJ-14 exhibits an anti-ulcer action (probably based on its ability to protect the
gastric mucosa), improvement of gastric emptying and an anti-emetic action. TJ-9
also showed anti-ulcer effects, probably based on its ability to suppress gastric
secretion and to protect the gastric mucosa. Thus, the present study demonstrated
the effectiveness of TJ-14 and TJ-9 against gastric disease, and provided basic
data which explain the differences in clinical application between these two
kampo medicines.
PMID- 9401724
TI - Protective effect of tetrandrine on normal human mononuclear cells against
ionizing irradiation.
AB - Tetrandrine, an alkaloid isolated from the plant Stephania tetrandra, at low
concentration (2 micrograms/ml) was shown to protect normal human mononuclear
cells in vitro against damage due to a single high-dose of ionizing irradiation
(10 Gy). The cell survival rate increased from 58.3 +/- 2.2% in the irradiated
group to 78.0 +/- 2.6% in the tetrandrine-pretreated group, and similarly, the
percentage of necrotic cells declined from 20.7 +/- 2.5% to 10.7 +/- 1.9%,
respectively. This protective effect of tetrandrine for cell surviving fraction
increased in a dose-dependent manner. Tetrandrine was also found to inhibit
inflammatory responses induced by irradiation including the release of superoxide
(NBT [nitroblue tetrazolium] reduction decreased from 21.3 +/- 2.3% to 10.2 +/-
2.5%) and phagocytic activity (decreased from 80.7 +/- 3.8% to 50.7 +/- 2.3%, the
same range level as that of the control group). However, the alkaloid
demonstrated no effect on the production of nitric oxide. In terms of cell
morphology, only two types were observed-normal or necrotic cells, and there were
no characteristics of programmed cell death. These results indicate that
tetrandrine possesses radioprotective activity against 10 Gy of ionizing
irradiation and could suppress irradiation-induced inflammatory processes.
PMID- 9401725
TI - Studies on kochiae fructus. IV. Anti-allergic effects of 70% ethanol extract and
its component, momordin Ic from dried fruits of Kochia scoparia L.
AB - The 70% ethanol extract (KS-ext) from Kochiae Fructus (dried fruits of Kochia
scoparia L.) has been screened for activity in experimental models of type I-IV
allergy. In type I allergic models, KS-ext at doses of 200 and 500 mg/kg, p.o.
exhibited an inhibitory effect on 48-h homologous passive cutaneous anaphylaxis
(PCA) in rats, which is related to IgE, and 1.5-h heterologous PCA in mice, which
is related to IgG. In a type III allergic model, KS-ext showed an inhibitory
effect on direct passive arthus reaction (DPAR) in rats, while it had no
inhibitory effect on reversed cutaneous anaphylaxis (RCA) in a type II allergic
model. Furthermore, in a type IV allergic model, KS-ext had an inhibitory effect
on the effector phase in picryl chloride-induced contact dermatitis (PC-CD).
Also, its anti-pruritogenic component, momordin Ic (oleanane saponin) exhibited
inhibitory effects on 48-h homologous PCA and PC-CD. These results indicate that
Kochiae Fructus not only inhibits humoral immunity but also influences cellular
immunity, and should be recognized as a material for anti-allergic reactions.
Also, the mode of its anti-pruritogenic activity may be mediated by anti-allergic
action, and its active component may be partially attributed to momordin Ic.
PMID- 9401726
TI - Pharmacological properties of traditional medicines. XXIII. Searching for active
compounds in the blood and bile of rats after oral administrations of extracts of
sansohnin [symbol: see text].
AB - We made a trial of searching for the bioactive substances from Sansohnin [symbol:
see text]. The blood and bile of rats after the oral administration of extracts
of Sansohnin were analyzed by three-dimensional high-performance liquid
chromatography (3D-HPLC). In blood, spinosin and feruloyl spinosin were found
after the oral administration of a butanol extract of Sansohnin. In bile,
spinosin and feruloyl spinosin were also identified after the oral administration
of a water extract of Sansohnin. Spinosin and feruloyl spinosin induced the
prolongation of hexobarbital sleeping time in mice at doses of 50 and 100 mg/kg,
respectively. We concluded that spinosin and feruloyl spinosin were the bioactive
constituents of Sansohnin. It was assumed that spinosin and feruloyl spinosin
circulated through the intestine and liver, therefore, these results will provide
support for the sedative and hypnotic use of this crude drug in Oriental
medicine.
PMID- 9401727
TI - Effect of hachimi-jio-gan on immunoglobulin A producing cells in Peyer's patch by
oral administration.
AB - We investigated here the effect of Hachimi-jio-gan (HJ), a Japanese and Chinese
herbal medicine, on immunoglobulin A (IgA) producing cells in Peyer's patch. The
oral administration of HJ (0.1, 0.2, 1.0 g/kg for 2 d) enhanced the IgA producing
cells almost 2-fold compared with the control group on days 4 and 5 after the
administration. Furthermore, HJ augmented antigen-specific IgA (anti-SRBC IgA)
production. These results suggested that HJ acted as a polyclonal B cell
activator. To characterize its active ingredients, HJ was fractionated by ethanol
precipitation. The crude polysaccharide fraction (EP fraction) showed the ability
to augment IgA production, but low molecular weight fraction (ES fraction) did
not. These results suggest that the crude polysaccharide fraction might be
responsible for the augmentation of IgA production by HJ.
PMID- 9401728
TI - Polysaccharide of Astragali radix enhances IgM antibody production in aged mice.
AB - The effect of Astragali Radix (AR) on IgM antibody production in mice of various
ages (10 weeks, 36 weeks and 60 weeks) was examined. The antibody production
levels in the 36- and 60-week-old mice were significantly decreased to about 70
and 60% of that in the 10-week-old mice. The enhancement effect of a crude
polysaccharide AR fraction on the antibody production was nil in the 10-week-old
mice, but significant enhancement effects were observed in the 36- and 60-week
old mice, compared to the age-matched control. Two polysaccharides active in the
enhancement of the IgM antibody production in the aged mice were isolated from
the high molecular weight fraction of AR by cetavlon precipitation, ion-exchange
and gel permeation chromatography. The molecular masses of these polysaccharides
were calculated by HPLC in salt solution. Only one major peak was observed for
each, and their molecular masses were estimated to be 1.2 x 10(4) and 2.2 x
10(4). The major components of these polysaccharides were neutral carbohydrates
(89.3 and 95.5%), followed by uronic acid and protein; glucose was the
predominant sugar component.
PMID- 9401729
TI - Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. V.
Biological disposition and targeting characteristics of osteotropic estradiol.
AB - An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has
been developed for 17 beta-estradiol (E2) to improve patient compliance in
estrogen replacement therapy of postmenopausal osteoporosis. The biological
disposition and the targeting efficiency of a bisphosphonic prodrug of E2,
disodium [17 beta-(3'-hydroxy-1',3',5'-estratrienyloxy)carbonylpropyl
carboxamidomethylene]bisphosphonate (E2-BP), was investigated in ovariectomized
rats. After intravenous injection, E2-BP was rapidly taken up into the bone and
subsequently cleared from the bone at a half-life of 13.5 d. The bone
concentration of regenerated E2 was maintained throughout 28 d. In contrast, E2
injected intravenously showed extremely low bone distribution and rapid clearance
from the bone, and E2 administered orally showed even lower bone distribution.
Therapeutic availability (TA) and drug targeting index (DTI), which were
calculated on the basis of the AUCs for E2 in the bone and plasma after injection
of E2-BP and E2, were 64.6 and 451, respectively. These results suggest that ODDS
has a potential to improve not only the apparent potency but also the therapeutic
index of E2. As compared with the conventional estrogenic products, E2-BP should
improve patient compliance with lower adverse effects and less frequent
medication in long-term estrogen replacement therapy.
PMID- 9401730
TI - Effect of aging on the intestinal transport of hydrophilic drugs in the rat small
intestine.
AB - The effect of aging on the intestinal transport of hydrophilic drugs (and probe
compounds) was investigated in the rat small intestine. Passive transport was
suggested to be unchanged with aging from 8 (young) to 54 (old) and further to
101 (very old) weeks old, as shown for D-xylose and urea in single-pass
intestinal perfusion (under urethane anesthesia), where steady-state transport
across the intestinal membrane into the blood stream was evaluated. The passive
transports of cephradine, 5-fluorouracil (5-FU) and L-glucose were also
unchanged, though they were compared only between the young and the old.
Consistently, the passive uptake in the intestinal everted sacs, where the entry
process into the membrane was evaluated for 5-FU, D-xylose, urea and polyethylene
glycol (PEG) 900, was unchanged with aging from the young to the very old. The
carrier-mediated transport of cephradine was also unchanged with aging from the
young to the old in perfusion under anesthesia, though that of D-glucose was
declined by about 50% with aging from the young to the old and thereafter
remained constant in the very old. In perfusion in unanesthetized rats, age
independency in passive transport (examined for cephradine, L-glucose and D
xylose) and an age-dependent decline in D-glucose transport were also observed,
suggesting that the findings under anesthesia are not qualitatively distorted.
These results suggest that, although carrier-mediated transport may moderately
decline with aging, the barrier function of the intestinal membrane to passive
permeation of hydrophilic drugs (with molecular weight below 1000) may be
unaffected by aging, supporting the suggestion from our previous in vivo studies
that age-dependent increases in the orally absorbed fraction may be predicted for
incompletely absorbed drugs because of delayed intestinal transit rather than
increased intestinal transport (membrane permeability).
PMID- 9401731
TI - Pharmacokinetics of pentazocine and its occupancy of opioid receptors in rat
brain.
AB - In order to assess quantitatively the pharmacodynamic process of pentazocine
(PTZ), time courses of its plasma concentration and of the occupation of specific
opioid receptors in the brain were investigated after intravenous (i.v.)
administration of PTZ to rats. The plasma concentration of PTZ was determined by
HPLC and the pharmacokinetic parameters were analyzed using nonlinear least
squares analysis. Measurement of ex vivo receptor occupation was made by
comparing the specific [3H]naloxone (opioid receptor antagonist) binding in vitro
to the crude P2-synaptosomal fractions between vehicle-treated rats (control) and
PTZ-treated rats. Following the i.v. administration of PTZ, the occupancy of
specific opioid receptors decreased rapidly until 10 min, depending on the two
pharmacological doses (2.5 and 10 mg/kg). The results strongly suggest the fast
binding kinetics of PTZ in terms of its association with and dissociation from
specific opioid receptor sites in the brain in addition to its fast rate of
disappearance from the brain compartment. Furthermore, we demonstrated that the
time profile of receptor occupancy correlated well (r = 0.8650) with that of the
unbound concentration in plasma until 120 min after the i.v. administration of
PTZ to rats.
PMID- 9401732
TI - Metabolism of pravastatin sodium by 3 alpha-hydroxysteroid dehydrogenase.
AB - When incubated with isolated rat hepatocytes, pravastatin sodium (PS) yielded a
small amount of a metabolite in addition to two major metabolites that have
already been reported. The previously uncharacterized metabolite was found to be
formed by at first being enzymatically dehydrogenated to 6'-keto intermediate (R
104), followed by decomposition to give the aromatized metabolite (R-195),
through spontaneous deesterification with accompanying aromatization. The PS
6'beta-hydroxydehydrogenase activity was localized in cytosolic fraction and
required NADP, preferentially over NAD, as a cofactor. The formation of R-195 by
rat liver cytosol was strongly inhibited by indomethacin, 3 alpha-hydroxysteroids
(but not 3 beta-isomers) and 3-ketosteroids. The results and high substrate
specificity of purified PS-6'beta-hydroxydehydrogenase toward 3 alpha
hydroxysteroids suggested that the enzyme is identical to 3 alpha-hydroxysteroid
dehydrogenase.
PMID- 9401733
TI - Antibacterial activity of (+/-) 6-benzyl-1-(3-carboxypropyl) indane; a possible
way to identify leading novel anti-H. pylori agents.
AB - Magainin 2, isolated from the skin of the Xenopus laevis, is an antimicrobial
peptide which reacts directly with the biological membrane to lyse various
bacteria from negative and positive microorganisms. In a previous report, we
showed that (+/-)1-(4-aminobutyl)-6-benzylindane (PM2), which mimicked the
conformation of the side-chains of a complementary unit on the amino acid
sequence of magainin 2 analogs, expressed the in vitro antibacterial activity not
only against Helicobacter, pylori (ATCC43526, ATCC43579), but also against
Escherichia coli (ATCC25922) and Staphylococcus aureus (ATCC25923). In addition,
PM2 caused human blood red cells (RBCs) to lyse at the minimum inhibitory
concentration (MIC) value. Based on the antibacterial activities of 9
phenylnonanoic acid (pC9c), we further synthesized (+/-)-6-benzyl-1-(3
carboxypropyl) indane (PM2c), which replaced a positive charge of PM2 with a
negative one, and tested the biological activities. PM2c had the ability to
inhibit the growth of H. pylori strains, but its activity to inhibit the growth
of E. coli and S. aureus was not detected and weak, respectively. Moreover, PM2c
showed non-hemolytic activity against RBCs at the MIC value. These results
indicate the possibility that PM2c may be more useful than PM2 either alone or in
combination with well-known therapeutic agents for the treatment of H. pylori
infection.
PMID- 9401734
TI - Determination of methemoglobin and carboxyhemoglobin in blood by rapid
colorimetry.
AB - A sensitive and rapid colorimetry for determination of methemoglobin (MetHb) in
hemolysate of the test blood was devised by measurement of absorbance at 563 nm,
the isosbestic point of spectra of cyanomethemoglobin and oxyhemoglobin, at pH
6.8. MetHb was determined as the difference in absorption caused by cyanide in
the absence of potassium ferricyanide divided by the difference in absorption
caused by cyanide in the presence of the ferricyanide. Carboxyhemoglobin (COHb)
in the blood was also estimated from the absorbance values of the hemolysates
with or without potassium ferricyanide after the addition of cyanide. The method
requires only 3 microliters of test blood and 10 min for determinations of MetHb
and COHb in blood. Results obtained by the method were in satisfactory agreement
with theoretical results for mixture of MetHb, COHb, and oxyhemoglobin. The
method was compared with two other methods using 55 forensic blood samples
containing various amounts of MetHb and COHb, and proved to be suitable for
practical samples.
PMID- 9401735
TI - Characterization of two restriction endonucleases, SenPT14bI and SenPT16I, in
standard phage-type strains of Salmonella enteritidis.
AB - Two restriction endonucleases (ENases) were found by screening 38 standard phage
strains of Salmonella (S.) Enteritidis. An isoschizomer of SacII ENase that
recognizes the sequence 5'-CCGC/GG-3' was identified in S. Enteritidis PT14b, and
an isoschizomer of XmaIII ENase (5'-C/GGCCG-3') was found in S. Enteritidis PT16.
It is of special interest that the recognition specificities of all known ENases
in Salmonella, including those of the S. Enteritidis ENases, are very similar to
each other.
PMID- 9401736
TI - Carbonyl reductase activity exhibited by pig testicular 20 beta-hydroxysteroid
dehydrogenase.
AB - The carbonyl reductase activity exhibited by pig testicular 20 beta
hydroxysteroid dehydrogenase (20 beta-HSD) was examined using a recombinant
enzyme. Kinetic parameters were obtained for 48 carbonyl group-containing
substrates, including aromatic aldehydes, aromatic ketones, cycloketones,
quinones, aliphatic aldehydes and aliphatic ketones. 20 beta-HSD showed a high
affinity towards quinones, such as 9,10-phenanthrenequinone, alpha-naphthoquinone
and menadione (Km values of 4, 2 and 5 microM, respectively), and the substrate
utilization efficiency (Vmax/Km) of the enzyme against these quinones was very
high. Cyclohexanone and 2-methylcyclohexanone were also reduced with a high
Vmax/Km value, but not cyclopentanone or 2-methylcyclopentanone. Various aromatic
aldehydes and ketones including benzaldehyde- and acetophenone-derivatives were
reduced by 20 beta-HSD. Especially, 4-nitrobenzaldehyde and 4-nitroacetophenone
were reduced with high Vmax/Km values in the related compounds. The enzyme also
reduced the pyridine-derivatives, 2-, 3-, and 4-benzoylpyridine, with the Vmax/Km
value for 2-benzoylpyridine being the highest. 20 beta-HSD reduced aliphatic
aldehydes and aliphatic ketones, but was more effective on the former. The
correlation between the structure of carbonyl compounds and their substrate
Vmax/Km is discussed.
PMID- 9401737
TI - Autoradiographic comparison of muscarinic M1 and M2 binding sites in the CNS of
spontaneously hypertensive and normotensive rats.
AB - Spontaneously hypertensive rats (SHR) respond with exaggerated pressor responses
of central origin in response to pharmacologic stimulation of brain muscarinic
receptors when compared with those to normotensive Wistar Kyoto (WKY) rats. At
least part of the enhanced response to central muscarinic stimulation may be due
to alterations in the expression of one or more of the five subtypes of
muscarinic receptors. SHR are also known to exhibit regional alterations in the
levels of mRNA encoding the M1, M2 and M4 receptors. In this study, we estimated
the number of specific muscarinic receptor binding sites in 12-week-old SHR and
WKY by measuring the binding of M1- and M2-selective ligands. Using standard
autoradiographic techniques, coronal sections obtained from 12-week-old SHR and
WKY were incubated with [3H]pirenzepine or [3H]AFDX 384 to label M1 and M2
receptors, respectively. Although both strains exhibited similar distribution
patterns for both binding sites, sections derived from SHR expressed a
significant increase in the number of [3H]pirenzepine binding sites compared to
normotensive WKY in caudate putamen, CA3 region of the hippocampus, cingulate
cortex, substantia nigra, posterior hypothalamic area and tuberomammillary
nucleus. An increased number of [3H]AFDX 384 binding sites in SHR were observed
in the olfactory tubercle, nucleus accumbens, basolateral amygdaloid nucleus,
rostroventrolateral medulla and nucleus paragigantocellularis. Decreases in the
number of [3H]AFDX 384 binding sites in SHR were also observed in the parietal
cortex, medial geniculate, and lateral hypothalamic area. Statistically
significant site-selective differences in binding densities between strains
ranged from 4.0% to 35.5% of WKY means. These alterations in the expression of M1
and M2 binding sites in cardiovascular regions may contribute to the strain's
hyper-responsiveness to cholinergic drugs and possibly to the appearance of other
autonomic or behavioral phenotypes exhibited by SHR, including the hypertensive
state itself.
PMID- 9401738
TI - Mastoparan-induced apoptosis of cultured cerebellar granule neurons is initiated
by calcium release from intracellular stores.
AB - We have recently reported that mastoparan, a peptide toxin isolated from wasp
venom, induces apoptosis in cultured cerebellar granule neurons that can be
blocked by cholera toxin, an activator of Gs. Measurements of intracellular free
calcium concentration ([Ca2+]i) reveal that mastoparan induces a dramatic
elevation of [Ca2+]i that is frequently followed by enhanced leakage of fura-2
out of the neurons, suggesting that this rise in [Ca2+]i may be due to a more
generalized change in membrane permeability. However, the mastoparan-induced
initial elevation of [Ca2+]i is maintained in the absence of extracellular Ca2+,
suggesting that the rise of [Ca2+]i is from intracellular stores. This conclusion
is supported by the observation that depletion of [Ca2+]i stores by pretreatment
with either caffeine or thapsigargin attenuates both the rise in [Ca2+]i and cell
death induced by mastoparan. Phospholipase C (PLC) inhibitors, neomycin and
U73122 block mastoparan-induced increases of [Ca2+]i and protect against neuronal
death. Pretreatment with cholera toxin, but not pertussis toxin, reduced the
mastoparan-induced rise in [Ca2+]i. Taken together, our data suggest that
mastoparan initiates cell death in cerebellar granule neurons by inducing Ca2+
release from intracellular stores, probably via activation of PLC and IP3. A
secondary or parallel process results in disruption of plasma membrane integrity
and may be ultimately responsible for the death of these neurons by mastoparan.
PMID- 9401739
TI - Sensory feedback contributes to early movement-evoked fields during voluntary
finger movements in humans.
AB - Neuromagnetic field changes accompanying voluntary movement in humans ('movement
evoked fields' or MEFs) were recorded over the scalp using a whole-head MEG
system during the performance of self-paced finger movements in order to
determine the contribution of sensory feedback to the generation of these brain
responses. It was found that cooling the subject's arm resulted in delays of 8 ms
or more in the latency of the early movement-evoked field component (MEFI). These
delays were attributed to increases in conduction times in the afferent pathways
as confirmed by electrically evoked somatosensory responses and suggest a
peripheral origin of the MEFI. In a second experiment, we demonstrated the
effects of sensory input to the contralateral hand during a simple button
pressing task in 4 subjects. The results indicated that responses over the
hemisphere ipsilateral to the side of movement which resembled previously
reported ipsilateral MEFs can be elicited by the spread of mechanical stimulation
to opposite side of the body when a mechanical trigger is used. These experiments
provide further evidence that early movement-evoked fields produced by unilateral
finger movements are observed primarily over the contralateral somatosensory
cortex and represent sensory feedback to the somatosensory cortex from the
periphery.
PMID- 9401740
TI - Axonal transport and distribution of cyclophilin A in chicken neurones.
AB - In the course of pulse-label studies on the axonal transport of the small, basic,
actin-binding proteins--actin depolymerizing factor, cofilin and profilin--in
chicken motor neurones, we observed a heavily labelled protein of M(r) 18 kDa and
pI 8.2 on fluorographs of two-dimensional polyacrylamide gels. On the basis of
its M(r), pI and amino acid composition, we tentatively identified it by database
searching as cyclophilin A and subsequently confirmed its identity by
immunostaining. Like actin and its associated proteins, cyclophilin A was
transported in slow component b of axonal transport, but unlike these proteins,
cyclophilin A did not copurify with actin on DNase I. It was not found amongst
labelled proteins transported by fast axonal transported by fast axonal
transport. Immunostaining of chicken dorsal root ganglion cells revealed that it
accumulated in neurites at points of branching, varicosities and growth cones.
Our results raise the possibility that cyclophilin A is important in maintaining
the native folding of actin and associated proteins during transit in axons and
assembly in growth cones.
PMID- 9401741
TI - Neurofibrillary lesions in experimental aluminum-induced encephalopathy and
Alzheimer's disease share immunoreactivity for amyloid precursor protein, A beta,
alpha 1-antichymotrypsin and ubiquitin-protein conjugates.
AB - Neurofibrillary tangles of Alzheimer's disease contain predominantly tau protein
and to a lesser degree amyloid precursor protein (APP), A beta protein, alpha 1
antichymotrypsin (ACT) and ubiquitin. Previously we have demonstrated the
presence of phosphorylated tau and neurofilament proteins in neurofibrillary
degeneration (NFD) induced by aluminum (Al) maltolate in rabbits [Savory et al.,
Brain Res. 669 (1995) 325-329; Savory et al., Brain Res. 707 (1996) 272-281].
Using the same animal system we have now detected APP, A beta, ACT and ubiquitin
like immunoreactivities in NFD-bearing neurons, often colocalizing in the NFD.
Diffuse cytoplasmic staining for APP, A beta and ubiquitin was also present in
neurons without NFD from Al maltolate-treated rabbits. This study provides
additional support for immunochemical similarities between Al-induced NFD in
rabbits and the neurofibrillary tangles in human subjects with Alzheimer's
disease.
PMID- 9401742
TI - Methamphetamine-induced hyperthermia in mice: examination of dopamine depletion
and heat-shock protein induction.
AB - Methamphetamine (METH) is a common drug of abuse and a clinical anoretic which is
known to cause neurotoxicity in rodents as evidenced by a depletion of dopamine
(DA) and by decreased numbers of DA uptake sites in the striatum. It is also
known to cause hyperthermia which is believed to induce the production of the 72
kDa heat-shock protein (HSP-72). In the present study, we evaluated whether METH
induced the production of HSP-72 in both the mouse hippocampus and striatum and
also attempted to correlate this induction with monoamine depletion. Adult male
C57BL/6N mice received METH (20 mg/kg, i.p.) in an ambient temperature of 27
degrees C and body temperatures were monitored up to 240 min after treatment.
Animals were sacrificed 12, 18, 24, 39, and 48 h after treatment. One striatum
was examined for DA, DOPAC, and HVA levels using HPLC-EC and the contralateral
striatum, along with the hippocampus, was prepared for immunoblotting. HPLC-EC
analysis revealed a significant depletion of DA, DOPAC, and HVA at all time
points. There was, however, a significant increase in DA at 48 vs. 39 h. A
biphasic production of HSP-72, in both the hippocampus and striatum, was detected
by immunoblot. HSP-72 production was strong at 12 h which corresponds to neuronal
induction. However, at 18 h in the striatum and 24 h in the hippocampus, the
induction appears to be reduced. A second phase of HSP-72 induction occurred at
39 h in both regions. In a second experiment, mice were dosed according to the
same paradigm and were perfused at 18 h after treatment for immunohistochemical
analysis. HSP-72 immunoreactivity was found in neurons of the CA1 and CA4 regions
of the hippocampus; however, no detectable response was evident in the striatum.
In conclusion, these data demonstrate that a single injection of METH can lead to
hyperthermia which may then result in both the induction of HSP-72 and depletion
of DA concentration.
PMID- 9401743
TI - QX-314 inhibits ectopic nerve activity associated with neuropathic pain.
AB - In animal models of neuropathic pain, transection or constrictive injury to
peripheral nerves produces ectopic discharges originating at both injury sites
and related dorsal root ganglia (DRG). In addition, hyperexcitability is observed
in associated dorsal horn (DH) neurons of the spinal cord. As ectopic discharges
are inhibited by agents that block voltage-sensitive Na+ channels, it has been
postulated that accumulation of Na+ channels in the membrane at nerve injury
sites may contribute to the development of ectopic nerve activity (ENA). The goal
of the present study was to compare the sensitivity of ENA to lidocaine and QX
314, a positively charged lidocaine derivative, which is frequently assumed to be
membrane impermeant. Experiments were performed on adult male Sprague-Dawley rats
in which the common sciatic nerve had been transected 4-10 days earlier.
Extracellular microelectrode recordings were made from DRG and DH neurons, and
neuronal activity was measured in fine bundles of microfilaments teased from
sciatic nerves in anesthetized and paralyzed rats. Comparative effects on heart
rate (HR) and mean blood pressure (MBP) were also studied. To confirm that
externally applied QX-314 is able to inhibit high frequency activity in sensory
nerves, QX-314 was superfused over isolated rat vagus nerves during stimulation
of compound action potentials in C-fibers (C-spikes). As expected, intravenously
administered lidocaine inhibited ENA at all three sites. Lidocaine ED50 values
(expressed as mg/kg, with 95% confidence limits) were: 10.2 (7.8-13.3), 1.4 (0.8
2.4) and 0.9 (0.4-2.0) for neuromas, DRG and DH neurons, respectively. QX-314
also induced dose-dependent inhibition of ENA at neuromas and DRG, but produced
only a small inhibition of DH neuron ENA. QX-314 had the following ED50 values
(mg/kg) for neuromas, DRG and DH neurons, respectively: 2.3 (2.0-2.8), 6.9 (4.7
26.5) and 85.7. QX-314-mediated inhibition of DRG ENA had a slow onset and was
long-lasting, relative to lidocaine. Lidocaine or QX-314 also significantly
reduced HR and MBP in the same dose range as that which reduced ENA in DRG or
neuromas. In isolated rat vagus nerve recordings, QX-314 induced marked use
dependent inhibition of C-spike amplitude, with IC50 values (microM) of 9000
(4600-18,000) and 350 (290-420) for low- (0.03 Hz) and high-frequency (30 Hz) C
spikes, respectively. These data support the hypothesis that Na+ channel
accumulation contributes to the generation of ectopic discharges in neuromas and
DRG, and suggests that intravenous QX-314 can acutely block Na+ channels at these
sites.
PMID- 9401744
TI - Immunolocalization of the receptor tyrosine kinase EphA4 in the adult rat central
nervous system.
AB - EphA4 is a receptor tyrosine kinase of the Eph family previously designated Cek8
in chicken, Tyro1 in rat, and Sek1 in mouse, which is preferentially expressed in
the embryonic and adult nervous system. We have mapped the distribution of EphA4
in the adult rat brain and spinal cord using a polyclonal antibody raised against
a synthetic carboxy-terminal peptide. Immunoblotting experiments revealed that
EphA4 is widely distributed in various regions of the adult rat brain. At the
light microscopic level, intense immunoreactivity was apparent in the cerebral
cortex, hippocampus, matrix compartment of the neostriatum, cholinergic neurons
in the basal forebrain, cerebellar Purkinje cells, and substantia gelatinosa of
the spinal cord. Among white matter tracts, EphA4 expression was detected in the
corpus callosum, fornix, and posterior portion of the anterior commissure, but
not in the lateral olfactory tract, mammillothalamic tract, or optic chiasm.
Interestingly, expression in the optic chiasm is high at postnatal day 6, but
decreases with the maturation of this structure. While in some regions of the
neuropil neuronal cell bodies were prominently labeled, in others EphA4
immunoreactivity was detected in a punctate pattern. This punctuate staining did
not coincide with synaptophysin localization. At the electron microscopic level,
EphA4 immunoreactivity was observed in dendrites in the gray matter, particularly
associated with dendritic spines, and in myelinated axons, but not their myelin
sheaths in the white matter. The widespread distribution and diverse subcellular
compartmentalization of EphA4 suggest that this receptor is important for the
maintenance of multiple structures in the adult nervous system.
PMID- 9401745
TI - A comparison of the effects of concentric versus eccentric exercise on force and
position sense at the human elbow joint.
AB - It is generally accepted that our sense of limb position and movement is
provided, in part, by signals from muscle spindles, while the sense of muscle
force derives from signals in tendon organs. Experiments are described here,
using human subjects, in which the effects of eccentric and concentric exercise
of elbow flexor muscles are compared on the sense of forearm position and the
sense of tension in elbow flexors. Subjects were required to compress a preloaded
spring with one arm, carrying out a concentric contraction in elbow flexors, then
flexors of the other arm released the spring from compression and thereby carried
out an eccentric contraction. The force of the spring was adjusted to be 20%
maximum voluntary contraction (MVC), and each subject carried out a minimum of
120 contractions. Position sense was measured in blindfolded subjects by placing
one forearm at a set angle and asking subjects to match it by positioning the
other arm. Over 4 days postexercise, subjects placed the eccentrically exercised
arms in a more extended position than the concentrically exercised arm suggesting
that they thought the muscle was shorter than it actually was. In a force
matching task, subjects systematically undershot the target 10% MVC with their
eccentrically exercised arm. Since it is known that eccentric exercise is
associated with damage to muscle fibres, it is postulated that this leads to a
disturbance of muscle receptors, the muscle spindles and tendon organs.
PMID- 9401746
TI - Neuromodulation of activity-dependent synaptic enhancement at crayfish
neuromuscular junction.
AB - Action potential-evoked transmitter release is enhanced for many seconds after
moderate-frequency stimulation (e.g. 15 Hz for 30 s) at the excitor motorneuron
synapse of the crayfish dactyl opener muscle. Beginning about 1.5 s after a
train, activity-dependent synaptic enhancement (ADSE) is dominated by a process
termed augmentation (G.D. Bittner, D.A. Baxter, Synaptic plasticity at crayfish
neuromuscular junctions: facilitation and augmentation, Synapse 7 (1991) 235
243'[4]; K.L. Magleby, Short-term changes in synaptic efficacy, in: G.M. Edelman,
L.E. Gall, C.W. Maxwell (Eds.), Synaptic Function, John Wiley and Sons, New York,
1987, pp. 21-56; K.L. Magleby; J.E. Zengel, Augmentation: a process that acts to
increase transmitter release at the frog neuromuscular junction, J. Physiol.
(Lond.) 257 (1976) 449-470) which decays approximately exponentially with a time
constant of about 10 s at 16 degrees C, reflecting the removal of Ca2+ which
accumulates during the train in presynaptic terminals (K.R. Delaney, D.W. Tank,
R.S. Zucker, Serotonin-mediated enhancement of transmission at crayfish
neuromuscular junction is independent of changes in calcium, J. Neurosci. 11
(1991) 2631-2643). Serotonin (5-HT, 1 microM) increases evoked and spontaneous
transmitter release several-fold (D. Dixon, H.L. Atwood, Crayfish motor nerve
terminal's response to serotonin examined by intracellular microelectrode, J.
Neurobiol. 16 (1985) 409-424; J. Dudel, Modulation of quantal synaptic release by
serotonin and forskolin in crayfish motor nerve terminals, in: Modulation of
Synaptic Transmission and Plasticity in Nervous Systems, G. Hertting, H.-C. Spatz
(Eds.), Springer-Verlag, Berlin, 1988; S. Glusman, E.A. Kravitz. The action of
serotonin on excitatory nerve terminals in lobster nerve-muscle preparations, J.
Physiol. (Lond.) 325 (1982) 223-241). We found that ADSE persists about 2-3 times
longer after moderate-frequency presynaptic stimulation in the presence of 5-HT.
This slowing of the decay of ADSE by 5-HT was not accompanied by significant
changes in the initial amplitude of activity-dependent components of enhancement
1.5 s after the train. Measurements of presynaptic [Ca2+] indicated that the time
course of Ca2+ removal from the presynaptic terminals after trains was not
altered by 5-HT. Changes in presynaptic action potential shape, resting membrane
potential or postsynaptic impedance after trains cannot account for slower
recovery of ADSE. Axonal injection of EDTA slows the removal of residual Ca2+ and
the decay of synaptic augmentation after trains of action potentials (K.R.
Delaney, D.W. Tank, A quantitative measure of the dependence of short-term
synaptic enhancement on presynaptic residual calcium, J. Neurosci. 14 (1994) 5885
5902), but has little or no effect on the 5-HT-induced persistence of ADSE. This
also suggests that the time course of ADSE in the presence of 5-HT is not
determined primarily by residual Ca2+ removal kinetics. The slowing of ADSE
recovery after trains by 5-HT reverses with washing in 5-HT-free saline along
with the 5-HT-mediated enhancement of release.
PMID- 9401747
TI - Compartmentally specific effects of quinpirole on the striatal Fos expression
induced by stimulation of D1-dopamine receptors in intact rats.
AB - Injections of the full D1-agonist A-77636 (1.45 mg/kg) were found to induce clear
Fos-like immunoreactivity (FLI) in the striatum of neurologically intact rats.
Pretreatment with the D2-like agonist quinpirole (3 mg/kg) potentiated staining
in the lateral striatum, but actually decreased the number of immunoreactive
cells observed in the medial portion of the rostral striatum. Comparison with
adjacent sections processed for the calcium binding protein calbindin, indicated
that quinpirole pretreatment specifically suppressed staining in the matrix
compartment of the striatum while tending to potentiate it in the striosomes,
resulting in an extremely patchy pattern of labeling. These results suggest that
exogenous stimulation of D2-receptors, although not essential for the induction
of FLI, may play an important role in the compartmental patterning of neuronal
activity within the striatum.
PMID- 9401748
TI - Biphasic modulation in the trigeminal nociceptive neuronal responses by the
intracerebroventricular prostaglandin E2 may be mediated through different EP
receptors subtypes in rats.
AB - To determine which prostaglandin E2 (PGE2) receptor subtypes are involved in the
brain-derived PGE2-induced changes in nociception, we injected synthetic EP1, EP2
and EP3 receptor agonists (0.01 fmol to 10 nmol) into the lateral
cerebroventricle (LCV) of urethane-anesthetized rats and observed the changes in
the responses of the wide dynamic range (WDR) neurons in the trigeminal nucleus
caudalis to noxious pinching of facial skin. The enhancement and suppression of
the nociceptive responses of the WDR neurons were observed after the LCV
injection of MB28767 (an EP3 receptor agonist) at a low dose range (1-100 fmol)
and 17-phenyl-omega-trinor PGE2 (an EP1 receptor agonist) at high doses (1-10
nmol), respectively. Furthermore, the suppression of nociceptive neuronal
responses after the LCV injection of PGE2 (1 nmol) was completely blocked by
SC19220 (an EP1 receptor antagonist, 300 nmol). On the other hand, butaprost (an
EP2 receptor agonist) at any doses tested (0.1 fmol to 1 nmol) had no effect on
the nociceptive responses. The LCV injection of MB28767 (10 fmol) and 17-phenyl
omega-trinor PGE2 (1 nmol), which respectively enhanced and suppressed the
nociceptive neuronal responses, did not affect the responses of the low threshold
mechanoreceptive neurons to innocuous tactile stimuli. These results provide
electrophysiological evidence that brain-derived PGE2 induces mechanical
hyperalgesia and hypoalgesia through EP3 and EP1 receptors, respectively, in the
rat.
PMID- 9401749
TI - The functional anatomy and evolution of hypoglossal afferents in the leopard
frog, Rana pipiens.
AB - Previously, we suggested that afferents are present in the hypoglossal nerve of
the leopard frog, Rana pipiens. The basis for this was behavioral data obtained
after transection of the hypoglossal nerve. These afferents coordinate the timing
of tongue protraction with mouth opening during feeding. The goal of the present
study was to define anatomically these hypoglossal afferents in Rana pipiens.
Retrograde tracing was performed using horseradish peroxidase, fluorescent
dextran amines and neurobiotin. Data show that the cell bodies of hypoglossal
afferents are located in the dorsal root ganglion of the third spinal nerve and
enter the brainstem through its dorsal root. The afferents ascend in the
dorsomedial funiculus and move laterally after they pass the obex. They project
in the granular layer of the cerebellum and the medial reticular formation. The
cervical afferents that travel in this pathway are known to carry proprioceptive
and cutaneous sensory information. We hypothesize that the presence of afferents
in the hypoglossal nerve is a derived characteristic of anurans, which has
resulted from the re-routing of afferent fibers from the third spinal nerve into
the hypoglossal nerve. The appearance of hypoglossal afferents coincides with the
morphological acquisition of a highly protrusible tongue.
PMID- 9401750
TI - Two novel types of L-glutamate receptors with affinities for NMDA and L-cysteine
in the olfactory organ of the Caribbean spiny lobster Panulirus argus.
AB - A subset of olfactory receptor neurons of the Caribbean spiny lobster Panulirus
argus possesses receptors for L-glutamate that can mediate both excitatory and
inhibitory responses (P.C. Daniel, M.F. Burgess, C.D. Derby, Responses of
olfactory receptor neurons in the spiny lobster to binary mixtures are
predictable using a non-competitive model that incorporates excitatory and
inhibitory transduction pathways, J. Comp. Physiol. A 178 (1992) 523-536). In
this study, we have used biochemical and electrophysiological techniques to
understand the role of these receptors in olfactory transduction, and to compare
these olfactory glutamate receptors with peripheral and central L-glutamate
receptors in other animals. Using a radioligand-binding assay with a membrane
rich preparation from the dendrites of olfactory receptor neurons, we have
identified two types of binding sites for L-glutamate. Both sites showed rapid,
reversible, and saturable association with radiolabeled L-glutamate, and their Kd
values (1 nM and 3 microM) are effective in physiological studies of glutamate
sensitive olfactory neurons, suggesting these binding sites are receptors
involved in olfactory transduction. Both sites were completely inhibited by high
concentrations of NMDA and L-cysteine, and only partially inhibited by other L
glutamate analogs and odorants. Electrophysiological recordings from L-glutamate
best olfactory receptor neurons showed that NMDA and L-cysteine are both partial
agonists and antagonists of glutamate receptors. Together, these results suggest
the olfactory L-glutamate receptors of spiny lobsters are novel types of L
glutamate receptors that are functionally important in mediating olfactory
responses.
PMID- 9401751
TI - Lisuride prevents learning and memory impairment and attenuates the increase in
extracellular dopamine induced by transient global cerebral ischemia in rats.
AB - In this experiment, we tested the efficacy of neuroprotection with lisuride, a
dopamine agonist, using the 4-vessel occlusion rat model. Functional improvement
was evaluated with two behavior tests exploring learning and memorization
capacity in the rat, the Morris water maze and the 14-unit T-maze, 18 days after
ischemia. Extracellular dopamine levels during ischemia were determined in search
of a possible neuroprotection mechanism. Dopamine and its metabolites, DOPAC and
HVA, as well as the serotonin metabolite, 5-HIAA, were assayed with HPLC-EC, in
striatal extracellular fluid obtained by in vivo microdialysis in the awake rat.
Lisuride was administered at a total dose of 10 ng by continuous intrastriatal
infusion or at the dose of 0.5 mg/kg by i.p. infusion, 160 minutes before onset
of ischemia for the neurochemical study and at the dose of 0.5 mg/kg via i.p.
infusion, 1 hour before occlusion of the carotid arteries, for the behavior
tests. Behavioral testing showed significantly better recovery in both sets of
behavioral tests, with more pronounced positive results with the 14-unit T-maze,
in comparison with the saline-treated animals. Microdialysis confirmed a
significant attenuation of the ischemia-induced dopamine surge, whatever the mode
of administration, compared with saline-treated animals. These results show that
lisuride offers significant neuroprotection from the effect of experimental
transient global forebrain cerebral ischemia in the rat; the mechanism would
imply, at least in part, reduced levels of extracellular dopamine.
PMID- 9401752
TI - Developmental cholinotoxicity of lead: loss of septal cholinergic neurons and
long-term changes in cholinergic innervation of the hippocampus in perinatally
lead-exposed rats.
AB - The effects of perinatal lead exposure on choline acetyltransferase
immunoreactive (ChAT-IR) cell counts in the medial septum and AChE-positive fiber
counts in the hippocampus were examined in relation to changes in cholinergic
markers in the septohippocampal pathway of the rat. Maternal exposure to 0.2%
lead acetate in drinking water from gestational day 16 through weaning at post
natal day 21 (P21) induced in the offspring a 30% reduction in septal ChAT
activity and a 20% reduction in ChAT-IR cell profile counts in the medial
septum/vertical diagonal band (MS/vDB). These changes were seen as early as P7,
persisted through 2 months post-exposure (P81), and were followed by recovery of
ChAT activity but not the ChAT-IR cell numbers, at 3 months post-exposure (P112).
The loss of ChAT activity and ChAT-IR neurons in the septum was temporally
associated with a reduction of ChAT activity (30%), hemicholinium-3 (HC-3)
binding (40%), and AChE-positive fiber counts (13-15%) in the hippocampus. The
hippocampal ChAT activity and AChE-positive fiber counts returned to control
levels by P112 whereas HC-3 binding was restored to normal levels by P200. These
results indicate that perinatal, low-level lead exposure induces loss of
septohippocampal cholinergic projection neurons in neonate animals, resulting in
a deficit in hippocampal cholinergic innervation that persists into young
adulthood. The disruption of cholinergic septohippocampal system may be an
important factor in lasting cognitive impairments associated with early Pb
exposure.
PMID- 9401753
TI - Morphological and functional characterization of an in vitro blood-brain barrier
model.
AB - Cell culture models have been extensively used for studies of blood-brain barrier
(BBB) function. However, several in vitro models fail to reproduce some, if not
most, of the physiological and morphological properties of in situ brain
microvascular endothelial cells. We have recently developed a dynamic,
tridimensional BBB model where endothelial cells exposed to intraluminal flow
form a barrier to ions and proteins following prolonged co-culturing with glia.
We have further characterized this cell culture model to determine whether these
barrier properties were due to expression of a BBB phenotype. Endothelial cells
of human, bovine or rodent origin were used. When co-cultured with glia,
intraluminally grown endothelial cells developed features similar to in vivo
endothelial cells, including tight junctional contacts at interdigitating
processes and a high transendothelial resistance. This in vitro BBB was
characterized by the expression of an abluminal, ouabain-sensitive Na/K pump, and
thus favored passage of potassium ions towards the lumen while preventing K+
extravasation. Similarly, the in vitro BBB prevented the passage of blood-brain
barrier-impermeant drugs (such as morphine, sucrose and mannitol) while allowing
extraluminal accumulation of lipophylic substances such as theophylline. Finally,
expression of stereo-selective transporters for Aspartate was revealed by tracer
studies. We conclude that the in vitro dynamic BBB model may become an useful
tool for the studies of BBB-function and for the testing of drug passage across
the brain endothelial monolayer.
PMID- 9401754
TI - Effects of noribogaine on the development of tolerance to antinociceptive action
of morphine in mice.
AB - The effects of noribogaine, a metabolite of ibogaine, on the development of
tolerance to the antinociception action of morphine was determined in male Swiss
Webster mice. Ibogaine is an alkaloid isolated from the bark of the African
shrub, Tabernanthe iboga. Morphine tolerance in mice was developed by two
different methods. Mice were rendered tolerant to morphine either by subcutaneous
implantation of a pellet containing 25 mg morphine free base for 4 days or by
injecting morphine (20 mg/kg, s.c.) twice a day for 4 days. Placebo pellet
implanted mice or vehicle injected mice served as controls. To determine the
effect of intraperitoneally administered noribogaine on tolerance development,
the drug was injected in the appropriate dose twice a day. In pellet implanted
mice, a dose of 20 mg/kg of noribogaine attenuated the tolerance to morphine
whereas lower doses had no effect. Similarly, in mice given multiple injections
of morphine, noribogaine attenuated tolerance development at 20 and 40 mg/kg
doses. Previous studies from this laboratory had shown that ibogaine at 40 and 80
mg/kg doses inhibited tolerance to morphine. Because noribogaine could attenuate
morphine tolerance at lower doses than ibogaine, it is concluded that the
attenuating effect of ibogaine on morphine tolerance may be mediated by its
conversion to noribogaine, a more active metabolite.
PMID- 9401755
TI - Effect of aging on psychological stress-induced increases in noradrenaline
release in the rat anterior hypothalamus: an in vivo microdialysis study.
AB - Basal and psychological stress-induced noradrenaline (NA) release were studied by
intracerebral microdialysis in the hypothalamus of rats aged 9 weeks or 12
months. Basal NA output was not significantly different between young (9-week
old; 2.11 +/- 0.22 pg/20 min) and aged (12-month-old; 2.29 +/- 0.34 pg/20 min)
rats. Psychological stress for 20 min significantly increased NA release in both
groups (186% and 142% of baseline at 9 weeks old and 12 months old,
respectively); however, the increase in aged rats was significantly lower than
that in young rats (P < 0.01). This finding suggest that the noradrenergic
neuronal response to psychological stress is attenuated in aged rats.
PMID- 9401756
TI - Distribution of D-amino acid oxidase (DAO) activity in the medulla and thoracic
spinal cord of the rat: implications for a role for D-serine in autonomic
function.
AB - The activity and regional distribution of D-amino acid oxidase (DAO), an enzyme
that inactivates D-serine, were examined in the medulla and spinal cord of the
rat by biochemical and histochemical procedures. DAO activity was noticeably low
or absent in the nucleus of the solitary tract, ventrolateral medulla and
intramediolateral cell column of the spinal cord. This may be indicative of a
neuromodulatory role for endogenous D-serine (at the NMDA-glycine site) in in the
central control of blood pressure.
PMID- 9401757
TI - Potency and kinetics of nitric oxide-mediated vascular smooth muscle relaxation
determined with flash photolysis of ruthenium nitrosyl chlorides.
AB - Flash photolysis of thermally stable, photolabile 'caged' precursors permits
rapid and precise changes of ligand concentration at their site of action. This
approach was used to determine the concentration-dependence and time course of NO
mediated relaxation of aortic smooth muscle, by use of two photolabile NO donors,
trichloronitrosylruthenium (Ru(NO)Cl3) and dipotassium
pentachloronitrosylruthenate (K2Ru(NO)Cl5). At concentrations up to 500 microM,
both compounds were non-toxic before photolysis, and produced non-toxic by
products on photolysis. Photolytic release of NO produced relaxations of intact
and endothelium-denuded aortic rings precontracted with noradrenaline (0.1-0.5
microM), with an EC50 for NO-mediated relaxations of 10.5 nM and 13 nM,
respectively. NO-mediated relaxations were reversibly blocked by 1 microM
oxyhaemoglobin. The time course of NO-mediated relaxation comprised a delay of 3
7 s, followed by a sigmoidal decline in tension with peak rates that were
strongly dependent on NO concentration.
PMID- 9401758
TI - Dilatation by angiotensin II of the rat femoral arterial bed in vivo via
pressure/flow-induced release of nitric oxide and prostaglandins.
AB - 1. The haemodynamic effects of angiotensin II (AII) and, for comparison, arginine
vasopressin (AVP) in the femoral and superior mesenteric artery of urethane
anaesthetized rats were analysed with the ultrasonic transit time shift
technique. 2. I.v. bolus injection of AII (0.1-3 nmol kg-1) and AVP (0.03-1 nmol
kg-1) increased blood pressure which was accompanied by a decrease in blood flow
through the superior mesenteric artery and an increase in femoral blood flow. The
femoral hyperaemia was in part due to vasodilatation as indicated by a rise of
femoral vascular conductance up to 200% relative to baseline. The femoral
vasodilatation caused by AVP, but not AII, was followed by vasoconstriction. 3.
Blockade of angiotensin AT1 receptors by telmisartan (0.2-20 mumol kg-1)
prevented all haemodynamic responses to AII. 4. The femoral dilator responses to
AII and AVP depended on the increase in vascular perfusion pressure since
vasodilatation was reversed to vasoconstriction when blood pressure was
maintained constant by means of a gravity reservoir. However, the AII-evoked
femoral vasodilatation was not due to an autonomic or neuroendocrine reflex
because it was not depressed by hexamethonium (75 mumol kg-1), prazosin (0.25
mumol kg-1) or propranolol (3 mumol kg-1). 5. The AII-induced femoral
vasodilatation was suppressed by blockade of nitric oxide (NO) synthesis with NG
nitro-L-arginine methyl ester (L-NAME, 40 mumol kg-1) and reversed to
vasoconstriction when L-NAME was combined with indomethacin (30 mumol kg-1), but
was left unaltered by antagonism of endothelin ETA/B receptors with bosentan (37
mumol kg-1). 6. These results demonstrate that the effect of AII to increase
systemic blood pressure and the resulting rise of perfusion pressure in the
femoral artery stimulates the formation of NO and prostaglandins and thereby
dilates the femoral arterial bed. This local vasodilator mechanism is sufficient
to mask the direct vasoconstrictor response to AII.
PMID- 9401759
TI - Contrasting effects of carbachol, McN-A-343 and AHR-602 on Ca(2+)-mobilization
and Ca(2+)-influx pathways in taenia caeci.
AB - 1. We compared the binding profiles and contractile mechanisms of putative
muscarinic M1 agonists McN-A-343 and AHR-602 with those of carbachol in smooth
muscle of guinea-pig taenia caeci. 2. McN-A-343 and AHR-602, as well as
carbachol, completely displaced the atropine-sensitive binding of [3H]
quinuclidinyl benzilate to muscarinic receptors present in the membrane
preparation. The potency order for the affinity of these agents for muscarinic
receptors was carbachol > McN-A-343 >> AHR-602. 3. In the presence of 2.2 mM
extracellular Ca2+, McN-A-343 and AHR-602 induced contraction corresponding to 79
and 85%, respectively, of the maximal contraction to 0.1 mM carbachol.
Contractions induced by these agents were mediated via activation of the
muscarinic receptor subtype that had a high affinity for 4-DAMP (M3 selective)
but a low affinity for pirenzepine (M1 selective) and AF-DX 116 (M2 selective).
These contractions were inhibited by an L-type Ca2+ channel blocker, verapamil.
4. In Ca(2+)-free solution containing 2 mM EGTA, carbachol elicited a transient
contraction whereas no contraction was observed in response to McN-A-343 and AHR
602. Application of McN-A-343 or AHR-602 inhibited the carbachol-induced
contraction in Ca(2+)-free solution, and this inhibition was surmounted by a
higher concentration of carbachol. 5. The EC50 value for carbachol-induced
contraction in the presence of extracellular Ca2+ was approximately 175 times
lower than that in the absence of Ca2+. After treatment with
propylbenzilylcholine mustard, carbachol induced contraction only in the presence
of extracellular Ca2+. 6. The results suggest that in the taenia caeci there is a
greater receptor reserve for muscarinic M3 receptor-mediated Ca2+ influx than for
M3 mediated Ca2+ release. The compounds McN-A-343 and AHR-602 are agonists of the
Ca2+ influx pathway, but do not appear to stimulate the Ca2+ release pathway.
PMID- 9401760
TI - Subtypes of endothelin receptors that mediate venous effects of endothelin-1 in
anaesthetized rats.
AB - 1. The subtypes of endothelin receptors that mediate the effects of endothelin-1
(ET-1) on mean arterial pressure (MAP), heart rate (HR), mean circulatory filling
pressure (MCFP), arterial resistance (RA), cardiac output (CO) and venous
resistance (RV) were characterized in 9 groups of pentobarbitone-anaesthetized
rats via the injection of ET-1 in the absence and presence of bosentan (Ro 47
0203, ETA- and ETB-receptor antagonist), PD 142893 (ETA- and ETB-receptor
antagonist) or FR 139317 (ETA-receptor antagonist), as well as injection of the
ETB-receptor agonist, IRL 1620. 2. Cumulative i.v. bolus injections of ET-1 or
IRL 1620 (0.5, 1 and 2 nmol kg-1) dose-dependently increased MAP (ET: by 22, 34
and 44; IRL: 8, 17 and 28 mmHg), RA (ET: 62, 108 and 162; IRL: 51, 63 and 86%
over baseline), RV (ET: 70, 132 and 179; IRL: 81, 89 and 98% over baseline) and
MCFP (ET: 1.1, 1.8 and 1.9; IRL: 0.9, 1.0 and 1.2 mmHg) and reduced CO (ET: -18,
35 and -44; IRL: -24; -26; -25% below baseline). Equimolar doses of ET-1 and IRL
1620 caused similar initial transient depressor responses. Saline did not modify
any haemodynamic variables in the time-control group. 3. Bosentan (10 mg kg-1,
i.v.) inhibited ET-induced increases in MAP, RV, RA and MCFP and decrease in CO.
PD 142893 (22 mg kg-1, i.v.) abolished ET-induced changes on MAP, RV, RA and CO,
but did not alter effects on MCFP. Bosentan alone did not cause haemodynamic
changes, but PD 142893 alone elevated MCFP (0.9 +/- 0.3 mmHg at 1 h after
injection) and did not alter other variables. Both antagonists abolished the
initial depressor effects of ET-1. 4. FR 139317 (1 mg kg-1, i.v.) partially
inhibited the increases in MAP, RV, RA and MCFP and decreases in CO elicited by
ET-1, but did not alter the transient depressor response of ET-1. 5. The results
show that both ETA- and ETB-receptors mediate the arterial and venous constrictor
effects of ET-1. Bosentan is more efficacious than PD 142893 in inhibiting the
venous effects of ET-1.
PMID- 9401761
TI - Morphological heterogeneity with normal expression but altered function of G
proteins in porcine cultured regenerated coronary endothelial cells.
AB - 1. Experiments were designed to investigate whether the pertussis toxin-dependent
endothelial dysfunction following balloon injury is due to a reduced expression
or an insufficient function of G-proteins. 2. Endothelium-dependent responses of
porcine coronary arteries were examined in vitro by use of conventional organ
chambers. Morphological analysis was performed by isolating and culturing the
endothelial cells from these arteries. The expression of Gi-proteins in
regenerated endothelial cells was measured by Western blots and immunolabelling.
The function of G-proteins was assessed by measuring the GTPase activity of
cultured endothelial cells. 3. Eight days following denudation, endothelial
regrowth was confirmed by histological examination and by demonstrating the
presence of endothelium-dependent relaxations to bradykinin and 5
hydroxytryptamine (5-HT). In primary culture, the regenerated endothelial cells
displayed a 'cobblestone' pattern as seen with native endothelial cells. 4.
Twenty eight days after denudation, the endothelium-dependent relaxations induced
by 5-HT were impaired, but those to bradykinin were maintained. However, the
latter were reduced when endothelium-dependent hyperpolarization was prevented.
5. Twenty eight days after denudation, multinucleated giant cells were present in
the regenerated but not in the native cultured endothelial cell populations.
These regenerated endothelial cells incorporated less tritiated thymidine than
native endothelial cells. 6. The intensities of the bands on the immunoblot of
the regenerated endothelial cells, when several antibodies against Gi alpha
1/alpha 2/alpha 3 were used, were the same as those obtained in native
endothelial cells. The immunolabelling with the same antibodies was similar
between the giant cells and the regenerated endothelial cells of normal size. The
hydrolysis of GTP was lower in regenerated than in native endothelial cell
membranes. 7. In conclusion, endothelium-dependent relaxations mediated by Gi
proteins are impaired in balloon denuded coronary arteries. This dysfunction
following regeneration cannot be explained by a reduced expression of Gi proteins
but rather reflects an abnormal function of the G-proteins in the regenerated
endothelium.
PMID- 9401762
TI - Quantification and distribution of alpha 1-adrenoceptor subtype mRNAs in human
vas deferens: comparison with those of epididymal and pelvic portions.
AB - 1. This study was intended to quantify the amounts of the alpha 1-adrenoceptor
subtype mRNAs in human vas deferens, and demonstrate the receptor subtype
responsible for the vas contraction. 2. The RNase protection assay showed that
the mean total amount of alpha 1a mRNA was 7.4 +/- 2.2 pg/5 micrograms of poly
(A)+ RNA (97.0% of the total alpha 1 mRNA) in the epididymal portion (E-vas) and
4.9 +/- 0.8 pg/5 micrograms of poly (A)+ RNA (96.3% of the total) in the pelvic
portion (P-vas). The E-vas showed a tendency to have a greater alpha 1a mRNA
abundance than the P-vas (P = 0.11). The alpha 1b and alpha 1d mRNAs were absent
or of extremely low abundance. 3. By an in situ hybridization, the alpha 1a and
alpha 1d mRNAs were recognized in the smooth muscle cells of the E-vas and the P
vas, and the distribution pattern the same in both tissue. The alpha 1b mRNA
positive site was scarcely detectable in both vas portions. 4. In a functional
study, l-phenylephrine produced concentration-dependent contraction in the E-vas
(Emax = 2.24 +/- 0.70 g; pD2 = 5.32 +/- 0.09) and the P-vas (Emax = 2.46 +/- 0.46
g; pD2 = 5.07 +/- 0.12). KMD-3213, a novel alpha 1A-adrenoceptor-selective
antagonist, caused parallel rightward shifts of the concentration-response curves
for l-phenylephrine. Apparent pKB values were 9.90 +/- 0.16 for the E-vas and
9.71 +/- 0.17 for the P-vas. There was no significant difference in Emax, pD2 or
pKB estimates between the two portions. 5. We have found that alpha 1a mRNA is
predominant in the human vas deferens, and confirmed that contraction of this
organ is mediated by the alpha 1A-adrenoceptor.
PMID- 9401763
TI - Effect of thromboxane A2 antagonists on bronchial hyperresponsiveness induced
immediately after interleukin-8 inhalation in guinea-pigs.
AB - 1. Although repeated intranasal administration of interleukin-8 (IL-8) causes
bronchial hyperresponsiveness (BHR) mediated via thromboxane A2 (TXA2) and airway
neutrophil accumulation in guinea-pigs, the acute effect of inhaled IL-8 is
unclear. We performed this study to clarify the acute effect of IL-8 on bronchial
responsiveness and the role of TXA2. 2. The effects of inhaled IL-8 on bronchial
responsiveness and of the TXA2 antagonists, S-1452 (0.01 and 0.1 mg kg-1) and ONO
NT-126 (1.0 or 10 micrograms kg-1), on IL-8-induced BHR were examined by use of a
modified Konzett-Rossler method in guinea-pigs. 3. Inhaled IL-8 at 100 ng ml-1,
which failed to induce significant changes in Pao (pressure at the airway
opening), enhanced an increase in Pao induced by subsequent inhalations of
ascending doses (50-200 micrograms ml-1) of methacholine and histamine,
suggesting the potentiating effect of IL-8 on bronchial responsiveness. No
significant leukocyte infiltration was observed histologically sixteen minutes
after the IL-8 inhalation. Both S-1452 and ONO-NT-126 reduced the IL-8-induced
BHR. 4. In conclusion, IL-8 rapidly causes BHR via TXA2 release in guinea-pigs.
PMID- 9401764
TI - Fidelity in functional coupling of the rat P2Y1 receptor to phospholipase C.
AB - 1. The rat homologue of the P2Y1 receptor has been heterologously expressed in
1321N1 human astrocytoma cells and in C6 rat glioma cells. 2. As has been shown
previously for the turkey and human P2Y1 receptors, the rat P2Y1 receptor
expressed in either cell type responded to 2MeSATP with increases in inositol
phosphate accumulation that were competitively blocked by the antagonist PPADS.
Neither of the wild type cell lines exhibited inositol phosphate responses to
P2Y1 receptor agonists. 3. Expression of the rat P2Y1 receptor did not confer a
capacity of 2MeSATP to inhibit adenylyl cyclase activity in 1321N1 cells.
Moreover, the inhibition of adenylyl cyclase mediated by an endogenous P2Y
receptor of C6 glioma cells was not enhanced by expression of the rat P2Y1
receptor. The P2Y receptor-mediated inhibition of adenylyl cyclase in C6 glioma
cells expressing both the endogenous P2Y receptor and the rat P2Y1 receptor
remained unaffected by PPADS. 4. Since the P2Y receptor responsible for
inhibition of adenylyl cyclase in C6 glioma cells does not share the
pharmacological or functional properties of the P2Y1 receptor, even when both
receptors originate from the same species and are simultaneously expressed in the
same cell line, it is concluded that the P2Y1 receptor is distinct from an
endogenous P2Y receptor in C6 cells that couples to inhibition of adenylyl
cyclase.
PMID- 9401765
TI - Hexamethonium- and methyllycaconitine-induced changes in acetylcholine release
from rat motor nerve terminals.
AB - 1. The neuronal nicotinic receptor antagonists hexamethonium and
methyllycaconitine (MLA) have been used to study the putative prejunctional
nicotinic ACh receptors (AChRs) mediating a negative-feedback control of ACh
release from motor nerve terminals in voltage-clamped rat phrenic nerve/
hemidiaphragm preparations. 2. Hexamethonium (200 microM), but not MLA (0.4-2.0
microM), decreased the time constant of decay of both endplate currents (e.p.cs)
and miniature endplate currents (m.e.p.cs), indicating endplate ion channel block
with hexamethonium. However, driving function analysis and reconvolution of
e.p.cs and m.e.p.cs indicated that this ion channel block did not compromise the
analysis of e.p.c. quantal content. 3. At low frequencies of stimulation (0.5-2
Hz), hexamethonium (200 microM) and MLA (2.0 microM) increased e.p.c. quantal
content by 30-40%. At high frequencies (50-150 Hz) neither compound affected
e.p.c. quantal content. All effects on quantal content were paralleled by changes
in the size of the pool of quanta available for release. 4. The low frequency
augmentation of e.p.c. quantal content by hexamethonium was absent when
extracellular [Ca2+] was lowered from 2.0 to 0.5 mM. 5. At the concentrations
studied, MLA and hexamethonium produced a small (10-20%) decrease in the peak
amplitude of m.e.p.cs. 6. Neither apamin (100 nM) nor charybdotoxin (80 nM) had
effects on spontaneous or nerve evoked current amplitudes at any frequency of
stimulation. Thus the ability of nicotinic antagonists to augment e.p.c. quantal
content is not due to inhibition of Ca(2+)-activated K(+)-channels. 7. We suggest
that hexamethonium and MLA increase evoked ACh release by blocking prejunctional
nicotinic AChRs. These receptors exert a negative feedback control over evoked
ACh release and are probably of the alpha-bungarotoxin-insensitive neuronal type.
PMID- 9401766
TI - Ethanol inhibition of N-methyl-D-aspartate-activated current in mouse hippocampal
neurones: whole-cell patch-clamp analysis.
AB - 1. The action of ethanol on N-methyl-D-aspartate (NMDA)-activated ion current was
studied in mouse hippocampal neurones in culture using whole-cell patch-clamp
recording. 2. Ethanol inhibited NMDA-activated current in a voltage-independent
manner, and did not alter the reversal potential of NMDA-activated current. 3.
Concentration-response analysis of NMDA- and glycine-activated current revealed
that ethanol decreased the maximal response to both agonists without affecting
their EC50 values. 4. The polyamine spermine (1 microM) increased amplitude of
NMDA-activated current but did not alter the percentage inhibition of ethanol. 5.
Compared to an extracellular pH of 7.0, pH 6.0 decreased and pH 8.0 increased the
amplitude of NMDA-activated current, but these changes in pH did not
significantly alter the percentage inhibition by ethanol. 6. The sulphydryl
reducing agent dithiothreitol (2 mM) increased the amplitude of NMDA-activated
current, but did not affect the percentage inhibition by ethanol. 7. Mg2+ (10,
100, 500 microM), (5, 20 microM) or ketamine (2, 10 microM) decreased the
amplitude of NMDA-activated current, but did not affect the percentage inhibition
by ethanol. 8. The observations are consistent with ethanol inhibiting the
function of NMDA receptors by a non-competitive mechanism that does not involve
several modulatory sites on the NMDA receptor-ionophore complex.
PMID- 9401767
TI - Nitrergic modulation of cholinergic responses in the opossum lower oesophageal
sphincter.
AB - 1. Electrical field stimulation (EFS) of the superfused lower oesophageal
sphincter from opossum (Monodelphis domestica) elicited biphasic responses. The
first phase (relaxation) was strictly dependent on the duration of the EFS. The
second phase (contraction) started following termination of the EFS (< or = 15
Hz). EFS at frequencies above 15 Hz led only to contraction, which started
immediately upon initiation of the stimulation. 2. In the presence of NG-nitro-L
arginine (L-NOARG; 0.1-300 microM), the relaxation phase was abolished and the
contractile response started with the initiation of EFS (at all frequencies) and
was greater in magnitude. The contractile response to EFS was completely blocked
with scopolamine (10 microM). 3. Exogenous acetylcholine (1-100 microM) elicited
concentration-dependent contractions of the sphincter in the presence of
botulinum toxin. These contractions were abolished when EFS was applied during
administration of acetylcholine. This inhibitory effect of EFS was completely
reversed when the tissue was treated with L-NOARG (100 microM). 4. These results
suggest that the cholinergic response in the opossum lower oesophageal sphincter
is under nitrergic control.
PMID- 9401768
TI - Effect of pentoxifylline on the degradation of procollagen type I produced by
human hepatic stellate cells in response to transforming growth factor-beta 1.
AB - 1. Pentoxifylline (PTF) may act as a potential antifibrogenic agent by inhibiting
cell proliferation and/or collagen deposition in cell type(s) responsible for the
accumulation of extracellular matrix. The aim of the present study was to
investigate at which level PTF may affect synthesis and degradation of type I
collagen in human hepatic stellate cells (HSCs), a key source of connective
tissue in fibrotic liver. 2. Procollagen type I synthesis and release were
evaluated in cells maintained in serum free/insulin free medium for 48 h and then
stimulated with transforming growth factor-beta 1 (TGF-beta 1) for different time
periods in the presence or absence of PTF. TGF-beta 1 caused an upregulation of
procollagen I mRNA levels with a peak increase after 3-6 h of stimulation. This
effect was followed by an increase in both the cell associated and the
extracellular levels of the corresponding protein, with a peak effect at 9-12 h
after the addition of TGF-beta 1. Co-incubation with PTF slightly but
consistently reduced basal as well as stimulated procollagen I mRNA levels, with
negligible effects on the cell-associated expression of the corresponding
protein. Conversely, PTF dose-dependently reduced procollagen type I levels
detected in supernatants from unstimulated and stimulated cells. 3. Pulse-chase
experiments employing L-[3H]-proline revealed that PTF was able to induce
significantly the degradation of procollagen, mainly in the extracellular
compartment. We next analysed the effect of PTF on the major pathway involved in
type I collagen degradation. PTF did not affect the expression of
metalloproteinase 1 (MMP-1) mRNA both in basal and stimulated conditions, whereas
it markedly reduced the expression of tissue inhibitor of metalloproteinase 1
(TIMP-1) mRNA. Accordingly incubation with PTF increased the levels of 'activated
MMP-1' in cell supernatants in both basal and stimulated conditions. 4. These
results suggest that the antifibrogenic action of PTF on human HSCs is mainly
mediated by extracellular collagen degradation rather than by a reduction of
collagen synthesis.
PMID- 9401769
TI - Effects of dexamethasone and phorbol ester on P2 receptor-coupled Ca2+ signalling
and lipocortin 1 presentation in U937 cells.
AB - 1. Cell surface bound lipocortin 1 (LC1) is a putative mediator of the
antiproliferative and anti-inflammatory effects of glucocorticoids. This study
assessed the hypothesis that the glucocorticoid, dexamethasone-phosphate (dex-p),
might exert the above effects via an LC1-mediated downregulation of receptor
coupled Ca2+ signalling, using P2-receptor mediated intracellular Ca2+
accumulation in U937 cells as an appropriate model. 2. Addition of ATP (1-100
microM) to cells resulted in a transient increase in cytosolic Ca2+ ([Ca2+]i).
Prior treatment of cells with dex-p (3-24 h) increased the magnitude of this Ca2+
transient at high, but not low concentrations of ATP, and increased thapsigargin
(Tg)-induced Ca2+ influx, indicating that store-operated Ca2+ influx was
potentiated in these cells. For cells treated with dex-p for 24 h, cell surface
levels of LC1 were significantly reduced by 63%. 3. Differentiation of cells with
1 nM phorbol ester (PMA) for 24 h resulted in a 2.4 fold increase in the cell
surface level of LC1 and inhibition of the ATP-induced Ca2+ response. However,
the Tg-induced Ca2+ response was unaffected by long-term PMA treatment, and
incubating cells with LC1 did not alter Tg-induced Ca2+ mobilization and influx,
or the ATP-mediated Ca2+ response. 4. Data from this study suggest that: (1) dex
p does not inhibit P2-receptor-coupled Ca2+ signalling in this cell line, (2) the
observed modulation of the ATP-induced increase in [Ca2+]i by dex-p and PMA, and
store-operated Ca2+ influx by dex-p, is not linked to an increase in the cell
surface level of LC1, and (3) differentiation of U937 cells with PMA
downregulates the ATP-induced Ca2+ response, but does not affect the thapsigargin
sensitive Ca2+ pool or store-operated Ca2+ influx of these cells.
PMID- 9401770
TI - Tranilast inhibits the proliferation, chemotaxis and tube formation of human
microvascular endothelial cells in vitro and angiogenesis in vivo.
AB - 1. First developed as an antiallergic drug, tranilast inhibits chemical mediator
release from mast cells. In the present study, we examine the effects of
tranilast on angiogenesis in vitro and in vivo and discuss the application of
tranilast for angiogenic diseases. 2. Tranilast inhibited significantly the
proliferation (IC50: 136 microM, 95% confidence limits: 134-137 microM) and
vascular endothelium growth factor (VEGF)-induced chemotaxis (IC50: 135 microM,
95% confidence limits: 124-147 microM) of human dermal microvascular endothelial
cells (HDMECs) at concentrations greater than 25 micrograms ml-1. No toxicity to
HDMECs measuring by LDH release and no inhibitory effects on metalloproteinase
(MMP)-2 and MMP-9 activity were observed even at 100 micrograms ml-1 (306
microM). 3. Tube formation of HDMECs cultured on the matrigel as an in vitro
angiogenesis model was inhibited by tranilast in a concentration-dependent
manner. The IC50 value and 95% confidence limits were 175 microM and 151-204
microM, respectively. 4. In vivo angiogenesis was induced in mice by the
subcutaneous injection of matrigel containing 30 ng ml-1 VEGF and 64 micrograms
ml-1 heparin. Tranilast was administered orally twice a day for 3 days. Tranilast
dose-dependently suppressed angiogenesis in the matrigel and a significant change
was observed at a dose of 300 mg kg-1. 5. These results indicate that tranilast
is an angiogenesis inhibitor which may be beneficial for the improvement of
angiogenic diseases such as proliferative diabetic retinopathy, age-related
macular degeneration, tumour invasion and rheumatoid arthritis.
PMID- 9401771
TI - Beta-adrenoceptor-mediated inhibition of alpha 1-adrenoceptor-mediated and field
stimulation-induced contractile responses in the prostate of the guinea pig.
AB - 1. The prostate of the guinea pig responds to electrical field-stimulation (2 s
trains, 0.1 ms pulses at 3-60 Hz, supramaximal voltage) with contractile
responses. At 18 Hz these responses were inhibited (82 +/- 2%) by the L-type Ca2+
channel blocker, nifedipine (10 microM) and (by 100%) by the neurotoxin,
tetrodotoxin (500 nM). The alpha 1A-selective adrenoceptor antagonist, 5
methylurapidil, inhibited responses to field stimulation in the absence and
presence of nifedipine (10 microM) with -log molar (p) IC50 (+/- s.e. mean)
values of 7.95 +/- 0.14 and 7.01 +/- 0.07, respectively. 2. The non-selective
beta-adrenoceptor agonist, isoprenaline, reduced (56 +/- 8%) field stimulation
induced contractile responses (pEC50 6.91 +/- 0.11). The non-selective beta
adrenoceptor antagonist propranolol (50 nM) and the beta 1-adrenoceptor selective
antagonist, atenolol (3 microM), but not the beta 2-adrenoceptor antagonist ICI
118,551 ((+/-)-1 -[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[1
methylethyl)amino ]-2-butanol HCl; 100 nM) antagonized this effect (apparent pKB
values 8.44 +/- 0.22 and 6.92 +/- 0.21, respectively) indicating an effect
mediated through beta 1-like adrenoceptors. In the presence of nifedipine (10
microM) isoprenaline (up to 10 microM) did not inhibit the remaining response to
field-stimulation. 3. Phenylephrine elicited contractile responses (pEC50 4.47 +/
0.30) from preparations of guinea pig prostate which were reduced (63 +/- 25%)
by nifedipine (10 microM). This response was antagonized by 5-methylurapidil (100
nM, apparent pKB 8.24 +/- 0.33), but was not affected by preincubation
chloroethylclonidine (50 microM, 30 min). Responses to phenylephrine (30 microM)
were inhibited (by up to 52 +/- 5%) by isoprenaline (pIC50 6.40 +/- 0.35, the
beta 2-adrenoceptor selective agonist, salbutamol was weakly effective).
Propranolol (300 nM), ICI 118,551 (100 nM) and atenolol (3 microM) shifted
isoprenaline concentration-response curves to the right (apparent pKB +/- s.e.
values 7.68 +/- 1.10; 8.00 +/- 0.72 and 6.62 +/- 0.95, respectively). In the
presence of nifedipine (10 microM) responses to phenylephrine (30 microM,) were
inhibited (by up to 51 +/- 4%) by isoprenaline (pIC50 6.88 +/- 0.17): propranolol
(300 nM) and ICI 118,551 (100 nM), but not atenolol (3 microM) antagonized this
effect (apparent pKB values 8.85 +/- 1.53 and 8.35 +/- 1.18, respectively). Thus
beta 1-like and beta 2-like adrenoceptors may be involved in the isoprenaline
stimulated inhibition of phenylephrine concentration-response curves. 4.
Phenylephrine stimulated [3H]-inositol phosphate accumulation (pEC50 4.47 +/-
0.83), an effect insensitive to chloroethylclonidine pre-treatment (50 microM, 30
min) and to nifedipine (10 microM), but inhibited by 5-methylurapidil (apparent
pKD 7.90 +/- 0.22). Isoprenaline (up to 1 microM) did not affect the
phenylephrine-stimulated maximal increase in [3H]-inositol phosphates but did
increase [3H]-cyclic adenosine monophosphate ([3H]-cAMP) accumulation (pEC50 6.77
+/- 0.66); propranolol (30 nM) and ICI 118,551 (110 nM), but not atenolol (up to
3 microM), antagonized this effect. These responses may therefore be mediated
through beta 2-like adrenoceptors. 5. These results show that the alpha 1
adrenoceptor mediated and field stimulation-induced contractions of the guinea
pig prostate are partly dependent upon intracellular and extracellular sources of
Ca2+. We conclude that both beta 1- and beta 2-like adrenoceptors inhibit
responses to phenylephrine in the prostate of the guinea pig. The beta 1-like
adrenoceptor-mediated inhibition of these responses is evident upon the field
stimulation-induced and nifedipine-sensitive component of the response to
phenylephrine and may not involve the activation of adenylyl cyclase. The beta 2
like adrenoceptor may inhibit both nifedipine sensitive and insensitive
components of the response to phenylephrine, possibly through the activation of
adenylyl cyclase, but not through the i
PMID- 9401772
TI - Calcium mobilization in Jurkat cells via A2b adenosine receptors.
AB - 1. A functional study of cell surface A2b adenosine receptors was performed on
the T cell leukaemia line, Jurkat. 2. A2b receptors were coupled both to the
adenylate cyclase system and to intracellular calcium channels. In fact, the
agonist of A2b receptors, 5'-N-ethylcarboxamidoadenosine (NECA), led to a
transient accumulation of intracellular calcium by an inositol phosphate
independent mechanism. 3. The NECA-induced accumulation of cGMP was not
responsible for the calcium mobilization via A2b receptors. 4. The calcium
response elicited by activation of A2b receptors was independent of that evoked
by activation of the T cell receptor. 5. These findings not only delineate a
novel transduction mechanism for adenosine but also support a specific role for
adenosine in modulating signals elicited via the T cell receptor.
PMID- 9401773
TI - Effect of peroxynitrite on plasma extravasation, microvascular blood flow and
nociception in the rat.
AB - 1. Peroxynitrite (ONOO-) is a cytotoxic species, formed by the reaction between
nitric oxide and superoxide free radicals, that may be involved in inflammation.
In this study we have investigated the effect of peroxynitrite on plasma
extravasation and microvascular blood flow in the dorsal skin and on nociceptive
responses in the hind paw of the rat. 2. Male Wistar rats were anaesthetized and
their dorsal skin shaved. Plasma extravasation was measured by the extravascular
accumulation of 125I-labelled albumin over 0-45 min and 0-240 min. Blood flow was
measured by laser-Doppler flowmetry over 0-240 min. Studies in the hind paw were
carried out in the conscious rat. Hind paw weight changes were determined by
volume displacement and nociception by a mechanical hyperalgesia technique. 3.
Intradermal (i.d.) peroxynitrite (100-200 nmol site-1) produced a significant (P
< 0.01) dose-dependent increase in plasma extravasation in dorsal skin over 0-45
min which was not increased over 45-240 min. Plasma extravasation was
significantly (P < 0.001) decreased in rats pretreated with the anti-inflammatory
steroid dexamethasone (1 mg kg-1, i.v.; -180 min), but not modulated by treatment
with the hydrogen peroxide deactivator catalase (2200 u site-1), or the
superoxide scavenger superoxide dismutase (500 u site-1), effective doses of the
tachykinin NK1 antagonist SR140333 (1 nmol site-1), the cyclo-oxygenase inhibitor
indomethacin (358 mumol site-1), or combined pretreatment with mepyramine
(histamine H1-receptor antagonist; 2.8 nmol site-1) and methysergide (5-HT
antagonist; 1.9 nmol site-1). 4. Microvascular blood flow was significantly (P <
0.05) increased 30 and 120 min after i.d. peroxynitrite (100 nmol site-1) in
dorsal skin and remained raised until the end of the recording period (240 min).
The increase in blood flow was unaffected by dexamethasone (1 mg kg-1, i.v.; -180
min) or indomethacin (10 mg kg-1, s.c.; -30 min). 5. Hind paw volume was
significantly (P < 0.001) increased 30 min after intraplantar peroxynitrite (87.5
and 175 nmol paw-1) and remained raised for the duration of the experiment (360
min). By comparison, nociception was not altered by intraplantar peroxynitrite.
6. These data indicate that peroxynitrite can cause an increase in both plasma
extravasation and blood flow, suggesting that peroxynitrite could be of
biological relevance to microvascular responses. These findings may be of
importance in the pathology of inflammatory diseases in which peroxynitrite
formation occurs.
PMID- 9401774
TI - Interaction of the renin-angiotensin system, bradykinin and sympathetic nerves
with cholinergic transmission in the rat isolated trachea.
AB - 1. The present study was undertaken to investigate the interaction of the renin
angiotensin system (RAS), bradykinin and the sympathetic nervous system with
cholinergic transmission in the rat airways. Experiments were performed on
epithelium-intact and epithelium-denuded preparations of rat isolated trachea
which had been incubated with [3H]-choline to incorporate [3H]-acetylcholine into
the cholinergic transmitter stores. Tracheal preparations were subjected to
electrical field stimulation (trains of 1 ms pulses, 5 Hz, 15 V) and the
stimulation-induced (S-I) efflux taken as an index of transmitter acetylcholine
release. 2. In both epithelium-intact and epithelium-denuded tracheal
preparations, the alpha 2-adrenoceptor agonist UK14304 (0.1 and 1 microM)
inhibited the S-I efflux, in a concentration-dependent manner. The inhibition of
S-I efflux produced by UK14304 (1 microM) was antagonized by the selective alpha
2-adrenoceptor antagonist idazoxan (0.3 microM). Idazoxan (0.3 microM) alone had
no effect on the S-I efflux. 3. Angiotensin II (0.1 and 1 microM) was without
effect on the S-I efflux in either epithelium-intact or epithelium-denuded
tracheal preparations. When angiotensin-converting enzyme was inhibited by
perindoprilat (10 microM), angiotensin II (1 microM) was also without effect on
the S-I efflux. Similarly, in the presence of idazoxan (0.3 microM), to block
prejunctional alpha 2-adrenoceptors, angiotensin II (0.1 and 1 microM) did not
alter the S-I efflux. When added alone, perindoprilat (10 microM) did not alter
the S-I efflux. 4. In epithelium-denuded preparations, bradykinin (0.01-1 microM)
inhibited the S-I efflux. In epithelium-intact preparations, there was also a
tendency for bradykinin (0.1 and 1 microM) to inhibit the S-I efflux but this was
not statistically significant. However, when angiotensin-converting enzyme and
neutral endopeptidase were inhibited by perindoprilat (10 microM) and
phosphoramidon (1 microM), respectively, bradykinin (1 microM) significantly
inhibited the S-I efflux in epithelium-intact preparations as well as in
epithelium-denuded preparations. The inhibition of the S-I efflux produced by
bradykinin, in the combined presence of perindoprilat (10 microM) and
phosphoramidon (1 microM), was unaffected by the additional presence of the cyclo
oxygenase inhibitor indomethacin (10 microM) and/or the nitric oxide synthase
inhibitor NG-nitro-L-arginine (100 microM), in either epithelium-intact or
epithelium-denuded preparations. 5. In conclusion, the findings of the present
study suggest that airway parasympathetic nerves are endowed with alpha 2
adrenoceptors which subserve inhibition of transmitter acetylcholine release.
Under the present conditions, however, transmitter acetylcholine release is not
subject to transneuronal modulation by noradrenaline released from adjacent
sympathetic nerves in the airways. Moreover, angiotensin II and perindoprilat do
not appear to modulate acetylcholine release from parasympathetic nerves of the
airways. In contrast, bradykinin inhibits acetylcholine release from airway
parasympathetic nerves but this action of bradykinin is limited by the activity
of epithelial angiotensin-converting enzyme and/or neutral endopeptidase. The
inhibitory action of bradykinin on cholinergic transmission in the airways does
not appear to involve the liberation of prostaglandins or nitric oxide.
PMID- 9401775
TI - The influence of 5-HT2 and 5-HT4 receptor antagonists to modify drug induced
disinhibitory effects in the mouse light/dark test.
AB - 1. The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the
disinhibitory profile of diazepam and other agents was investigated in male BKW
mice in the light/dark test box. 2. The 5-HT2A/2B/2C receptor antagonists
ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify
mouse behaviour when administered alone, caused dose-related enhancements (4 to 8
fold) in the potency of diazepam to disinhibit behavioural responding to the
aversive situation of the test box. 3. Ritanserin was shown to enhance the
disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold),
temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH
DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3
receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(-)
zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10
fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor
antagonist, devazepide (100 fold). It also reduced the onset of action of
disinhibition following treatment with the 5-HT synthesis inhibitor
parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects
of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist
losarten or the angiotensin converting enzyme inhibitor ceranapril. 4. The 5-HT4
receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related
reductions in the disinhibitory effect of diazepam, returning values to those
shown in vehicle treated controls. The antagonists failed to modify mouse
behaviour when administered alone. 5. GR113808 was also shown to cause a dose
related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8
OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride,
devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. 6. It was
concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor
antagonists when administered alone to modify behaviour in the light/dark test
indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors
and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the
5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of
5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles
in the mouse.
PMID- 9401776
TI - Binding and effects of KATP channel openers in the vascular smooth muscle cell
line, A10.
AB - 1. The ATP-sensitive K+ channel (KATP channel) in A10 cells, a cell line derived
from rat thoracic aorta, was characterized by binding studies with the tritiated
KATP channel opener, [3H]-P1075, and by electrophysiological techniques. 2.
Saturation binding experiments gave a KD value of 9.2 +/- 5.2 nM and a binding
capacity (BMax) of 140 +/- 40 fmol mg-1 protein for [3H]-P1075 binding to A10
cells; from the BMax value a density of binding sites of 5-10 per microns2
plasmalemma was estimated. 3. KATP channel modulators such as the openers P1075,
pinacidil, levcromakalim and minoxidil sulphate and the blocker glibenclamide
inhibited [3H]-P1075 binding. The extent of inhibition at saturation depended on
the compound, levcromakalim inhibiting specific [3H]-P1075 binding by 85%,
minoxidil sulphate and glibenclamide by 70%. The inhibition constants were
similar to those determined in strips of rat aorta. 4. Resting membrane
potential, recorded with microelectrodes, was -51 +/- 1 mV. P1075 and
levcromakalim produced a concentration-dependent hyperpolarization by up to -25
mV with EC50 values of 170 +/- 40 nM and 870 +/- 190 nM, respectively. The
hyperpolarization induced by levcromakalim (3 microM) was completely reversed by
glibenclamide with an IC50 value of 86 +/- 17 nM. 5. Voltage clamp experiments
were performed in the whole cell configuration under a physiological K+ gradient.
Levcromakalim (10 microM) induced a current which reversed around -80 mV; the
current-voltage relationship showed considerable outward rectification.
Glibenclamide (3 microM) abolished the effect of levcromakalim. 6. Analysis of
the noise of the levcromakalim (10 microM)-induced current at -40 and -20 mV
yielded estimates of the channel density, the single channel conductance and the
probability of the channel to be open of 0.14 micron-2, 8.8 pS and 0.39,
respectively. 7. The experiments showed that A10 cells are endowed with
functional KATP channels which resemble those in vascular tissue; hence, these
cells provide an easily accessible source of channels for biochemical and
pharmacological studies. The density of binding sites for [3H]-P1075 was
estimated to be one order of magnitude higher than the density of functional KATP
channels; assuming a plasmalemmal localization of the binding sites this suggests
a large receptor reserve for the openers in A10 cells.
PMID- 9401777
TI - Tumour necrosis factor-alpha expression and cell recruitment in Sephadex particle
induced lung inflammation: effects of dexamethasone and cyclosporin A.
AB - 1. Tumour necrosis factor-alpha (TNF-alpha) is a cytokine with diverse properties
consistent with a possible role in inflammatory disease. We investigated whether
TNF-alpha is induced during the progression of lung inflammation elicited by a
particulate non-antigenic stimulus, and whether pharmacological control of TNF
alpha expression influences recruitment of specific inflammatory cell types. 2. A
single intravenous injection of Sephadex particles into rats led to extensive
granulomatous inflammation in lung alveolar and bronchial tissue that peaked in
intensity after 24-72 h. Mononuclear cells were the principal component of
granulomas, but neutrophils and eosinophils were also abundant. Numbers of
mononuclear cells, neutrophils and eosinophils recovered by bronchoalveolar
lavage (BAL) peaked at 72 h, 48 h and 72 h, respectively. 3. Messenger RNA
encoding TNF-alpha was induced in lung epithelial cells, lung granulomas and BAL
cells 6 h after Sephadex administration and remained elevated for 72 h before
declining to baseline by 7 days. In BAL cell populations TNF-alpha protein was
localized to mononuclear cells at all times points pre- and post-Sephadex
administration. 4. Treatment of rats with dexamethasone significantly reduced the
Sephadex-induced recruitment of mononuclear cells, neutrophils and eosinophils
into the bronchoalveolar cavity, and significantly reduced TNF-alpha mRNA
expression by BAL cells. 5. Treatment of rats with cyclosporin A was without
effect on Sephadex-induced elevations of mononuclear cell numbers and expression
of TNF-alpha, but did reduce significantly recruitment of neutrophils and
eosinophils to BAL cell populations. 6. These results show that a sequential
asthma-like recruitment of neutrophils, eosinophils and mononuclear cells into
lung tissue can be induced by single exposure to a non-antigenic stimulus.
Pharmacological and histological studies reveal that mononuclear cell
mobilization relates closely to induced TNF-alpha expression, whereas
mobilization of neutrophils and eosinophils appears secondary to expression of
the cytokine.
PMID- 9401778
TI - Investigation of the role of nitric oxide and cyclic GMP in both the activation
and inhibition of human neutrophils.
AB - 1. The aim of this study was to establish the role of nitric oxide (NO) and
cyclic GMP in chemotaxis and superoxide anion generation (SAG) by human
neutrophils, by use of selective inhibitors of NO and cyclic GMP pathways. In
addition, inhibition of neutrophil chemotaxis by NO releasing compounds and
increases in neutrophil nitrate/nitrite and cyclic GMP levels were examined. The
ultimate aim of this work was to resolve the paradox that NO both activates and
inhibits human neutrophils. 2. A role for NO as a mediator of N-formyl-methionyl
leucyl-phenylalanine (fMLP)-induced chemotaxis was supported by the finding that
the NO synthase (NOS) inhibitor L-NMMA (500 microM) inhibited chemotaxis; EC50
for fMLP 28.76 +/- 5.62 and 41.13 +/- 4.77 pmol/10(6) cells with and without L
NMMA, respectively. Similarly the NO scavenger carboxy-PTIO (100 microM)
inhibited chemotaxis; EC50 for fMLP 19.71 +/- 4.23 and 31.68 +/- 8.50 pmol/10(6)
cells with and without carboxy-PTIO, respectively. 3. A role for cyclic GMP as a
mediator of chemotaxis was supported by the finding that the guanylyl cyclase
inhibitor LY 83583 (100 microM) completely inhibited chemotaxis and suppressed
the maximal response; EC50 for fMLP 32.53 +/- 11.18 and 85.21 +/- 15.14
pmol/10(6) cells with and without LY 83583, respectively. The same pattern of
inhibition was observed with the G-kinase inhibitor KT 5823 (10 microM); EC50 for
fMLP 32.16 +/- 11.35 and > 135 pmol/10(6) cells with and without KT 5823,
respectively. 4. The phosphatase inhibitor, 2,3-diphosphoglyceric acid (DPG) (100
microM) which inhibits phospholipase D, attenuated fMLP-induced chemotaxis; EC50
for fMLP 19.15 +/- 4.36 and 61.52 +/- 16.2 pmol/10(6) cells with and without DPG,
respectively. 5. Although the NOS inhibitors L-NMMA and L-canavanine (500 microM)
failed to inhibit fMLP-induced SAG, carboxy-PTIO caused significant inhibition
(EC50 for fMLP 36.15 +/- 7.43 and 86.31 +/- 14.06 nM and reduced the maximal
response from 22.14 +/- 1.5 to 9.8 +/- 1.6 nmol O2-/10(6) cells/10 min with and
without carboxy-PTIO, respectively). This suggests NO is a mediator of fMLP
induced SAG. 6. A role for cyclic GMP as a mediator of SAG was supported by the
effects of G-kinase inhibitors KT 5823 (10 microM) and Rp-8-pCPT-cGMPS (100
microM) which inhibited SAG giving EC50 for fMLP of 36.26 +/- 8.77 and 200.01 +/-
43.26 nM with and without KT 5823, and 28.35 +/- 10.8 and 49.25 +/- 16.79 nM with
and without Rp-8-pCTP-cGMPS. 7. The phosphatase inhibitor DPG (500 microM)
inhibited SAG; EC50 for fMLP 33.93 +/- 4.23 and 61.12 +/- 14.43 nM with and
without DPG, respectively. 8. The NO releasing compounds inhibited fMLP-induced
chemotaxis with a rank order of potency of GEA 3162 (IC50 = 14.72 +/- 1.6 microM)
> GEA 5024 (IC50 = 18.44 +/- 0.43 microM) > SIN-1 (IC50 > 1000 microM). This
order of potency correlated with their ability to increase cyclic GMP levels
rather than the release of NO, where SIN-1 was most effective (SIN-1 (EC50 =
37.62 +/- 0.9 microM) > GEA 3162 (EC50 = 39.7 +/- 0.53 microM) > GEA 5024 (EC50 =
89.86 +/- 1.62 microM)). 9. In conclusion, chemotaxis and SAG induced by fMLP can
be attenuated by inhibitors of phospholipase D, NO and cyclic GMP, suggesting a
role for these agents in neutrophil activation. However, the increases in cyclic
GMP and NO induced by fMLP, which are associated with neutrophil activation, are
very small. In contrast much larger increases in NO and cyclic GMP, as observed
with NO releasing compounds, inhibit chemotaxis.
PMID- 9401779
TI - Inhibition by levetiracetam of a non-GABAA receptor-associated epileptiform
effect of bicuculline in rat hippocampus.
AB - 1. Extracellular recording of field potentials, evoked by commissural stimulation
in hippocampal area CA3 of anaesthetized rats, was performed in order to study
the mode of action of the novel antiepileptic drug levetiracetam (ucb LO59). 2.
The amplitude of orthodromic field population spike (PS2) markedly increased and
repetitive population spikes appeared when the recording micropipette contained
either bicuculline methiodide (BMI), or the specific GABAA antagonist gabazine
(SR-95531). 3. BMI-induced increases in PS2 were reduced in a dose-dependent
manner by 1 to 320 mumol kg-1 levetiracetam i.v., with a U-shape dose-response
relationship. However, levetiracetam did not reduce the increases in PS2 produced
by gabazine. 4. Clonazepam (1 mg kg-1, i.p.), carbamazepine (20 mg kg-1, i.p.)
and valproate (200 mg kg-1, i.v.) were ineffective in preventing BMI-induced
increases in PS2, while the calcium channel antagonist flunarizine, 50 mumol kg
1, i.p., reduced PS2 increments caused by BMI. The L-type calcium channel blocker
nifedipine, 100 mumol kg-1, i.p., was without effect. Similar to levetiracetam,
flunarizine did not reduce the increases in PS2 induced by gabazine. 5. These
data suggest that the increased excitability of CA3 neurones, caused by BMI
administered in situ, involves calcium-dependent processes not associated with
blockade of GABAA receptors. The inhibition by levetiracetam of this calcium
dependent effect of BMI might contribute to the antiepileptic effects of the
drug.
PMID- 9401780
TI - Electrophysiological characterisation of tachykinin receptors in the rat nucleus
of the solitary tract and dorsal motor nucleus of the vagus in vitro.
AB - 1. Recent studies have shown antagonists at the NK1 subtype of receptor for
tachykinins are antiemetics and suggested that this may result from blockade of
tachykinin-mediated synaptic transmission at a central site in the emetic reflex.
2. We have used intracellular recording in vitro to study the pharmacology of
tachykinins in the nucleus of the solitary tract (NST) and dorsal motor nucleus
of the vagus (DMNV). 3. Neurones in the NST were depolarized by substance P (SP),
the presumed endogenous ligand for the NK1 receptor and these effects were
mimicked by the NK1 agonists, SP-O-methylester (SPOMe), GR73632 and septide;
however, SP was nearly an order of magnitude less potent than the latter two
agonists. 4. In the DMNV, SP and NK1 receptor agonists evoked similar
depolarising responses but SP appeared to be more potent than in the NST and was
closer in potency to the other agonists. 5. NK1-receptor antagonists blocked
responses to septide and GR73632 in the NST but had little effect on responses to
SP and SPOMe. In contrast, in the DMNV the NK1-receptor antagonists blocked
responses to septide and GR73632 but also reduced responses to SP and SPOMe. 6.
Neurokinin A (NKA) was almost equipotent with septide and GR73632 in depolarizing
both NST and DMNV neurones but these effects were not mimicked by a specific NK2
receptor agonist. Responses to NKA were unaffected by an NK2-receptor antagonist;
however, the depolarizing effects of NKA were blocked by NK1-receptor
antagonists. 7. Neurones in both DMNV and NST were unaffected by the endogenous
NK3-receptor ligand, neurokinin B and by a specific agonist for this site,
senktide. 8. The results with NK1 receptor agonists and antagonists suggest that
the septide-sensitive NK1 site is involved in the excitation of both NST and DMNV
neurones. The 'classical' NK1 receptor may play more of a role in the DMNV and a
third unknown site may be responsible for the depolarizing response to SP in the
NST. The effects of NKA are best interpreted as an action at the septide
sensitive NK1 site. This raises the possibility that anti-emetic action of the
NK1 antagonists may be due to blockade of NKA transmission at the septide
sensitive site.
PMID- 9401781
TI - Cardiac inotropes inhibit the oedema caused by nifedipine in rabbit skin.
AB - 1. We have shown previously that exposing the rat or rabbit microcirculation to
nifedipine increases the permeability of the post-capillary venule, the segment
of microcirculation that is known to control inflammatory oedema. 2. In the
present study modulation by the inotropes isoprenaline, dopexamine and dobutamine
of nifedipine-induced oedema was examined in the rabbit skin microcirculation by
measuring the localised leakage of 125I-radiolabelled albumin after the i.d.
injection of agents. 3. Coinjection of isoprenaline (10(-11) moles per site),
dopexamine (10(-10) moles per site) or dobutamine (10(-10) moles per site)
suppressed significantly (P < 0.05) the oedema response to nifedipine (10(-7.2)
moles per site) in the rabbit dorsal skin microcirculation. 4. To confirm the
oedema suppresser effect of the inotropes, dopexamine or dobutamine were also
coinjected with histamine 10(-8) + PGE2 10(-10) moles per site, or bradykinin 10(
10) + PGE2 10(-10) moles per site. Both inotropes at 10(-10) moles per site
reduced significantly (P < 0.05) the leakage of albumin caused by bradykinin +
PGE2 and histamine + PGE2. 5. When measured by laser Doppler, basal local skin
blood flow increased at 30 min by 57 +/- 14% with nifedipine 10(-7.2) moles per
site and 15 +/- 11% with isoprenaline 10(-11) moles per site. Isoprenaline did
not suppress the blood flow response to nifedipine, the response to coinjection
being 68 +/- 11%. 6. Oedema caused by nifedipine can be suppressed by low
concentrations of beta-adrenergic agonists that do not suppress the blood flow
response to nifedipine. This suggests that cardiac inotropes can influence non
inflammatory changes in microvascular permeability.
PMID- 9401782
TI - Activation of the cAMP transduction cascade contributes to the mechanical
hyperalgesia and allodynia induced by intradermal injection of capsaicin.
AB - 1. The spinal role of the cAMP transduction cascade in nociceptive processing was
investigated in awake behaving rats (male, Sprague-Dawley) by activating or
inhibiting this pathway spinally. Microdialysis fibres were implanted into the
dorsal horn to infuse drugs directly to the spinal cord. 2. Animals, without
peripheral tissue injury, were tested for responses to repeated applications (10
trials) of von Frey filaments and threshold to mechanical stimulation before and
after infusion of 8-bromo-cAMP. In this group of animals treated spinally with 8
br-cAMP (1-10 mM) a dose-dependent hyperalgesia and allodynia were produced. This
was manifested as an increased number of responses to 10 trials of von Frey
filaments (10, 50, 150, 250 mN) and a decrease in mechanical threshold. 3. A
second series of experiments studied the manipulation of the cAMP pathway
spinally in a model of tissue injury induced by intradermal injection of
capsaicin. Animals were either pre- or post-treated spinally with the adenylate
cyclase inhibitor, tetrahydrofuryl adenine (THFA) or the protein kinase A
inhibitor, myrosilated protein kinase (14-22) amide (PKI). Injection of capsaicin
resulted in an increased number of responses to repeated applications of von Frey
filaments and a decrease in threshold to mechanical stimuli outside the site of
injection, secondary mechanical hyperalgesia and allodynia. 4. Pre-treatment with
either THFA (1 mM) or PKI (5 mM) had no effect on the capsaicin-evoked secondary
hyperalgesia and allodynia. 5. In contrast, post-treatment spinally with THFA
(0.01-1 mM) or PKI (0.05-50 mM) dose-dependently reduced the mechanical
hyperalgesia and allodynia produced by capsaicin injection. Furthermore, the
mechanical hyperalgesia and allodynia blocked by the adenylate cyclase inhibitor,
THFA (1 mM), was reversed by infusion of 8-bromo-cAMP (0.01-10 mM) in a dose
dependent manner. 6. Thus, this study demonstrates that activation of the cAMP
transduction cascade at the spinal cord level results in mechanical hyperalgesia
and allodynia and that the secondary mechanical hyperalgesia and allodynia
following intradermal injection of capsaicin is mediated by this same
transduction cascade.
PMID- 9401783
TI - Evidence for a 5-HT3 receptor involvement in the facilitation of peristalsis on
mucosal application of 5-HT in the guinea pig isolated ileum.
AB - 1. The 5-HT receptor involved in the effect of mucosal application of 5-HT to
facilitate peristalsis was investigated in the isolated guinea pig ileum. 2. An
application of 5-HT (3-100 microM) to the mucosal surface (by inclusion of 5-HT
in the Krebs-Henseleit solution passing through the lumen of the ileum) caused a
concentration related facilitation of peristalsis characterized by a reduction in
the peristaltic threshold. 3. Peristalsis was not modified by methiothepine (0.1
microM), ritanserin (0.1 microM), ondansetron (5 microM), granisetron (1 microM)
or SB 204070 (0.1 microM) administered alone to the mucosal surface. 4. The
concentration-response curve to mucosally applied 5-HT was not altered by the
mucosally applied 5-HT1/2 receptor antagonist methiothepine (0.1 microM), the 5
HT2 receptor antagonist ritanserin (0.1 microM) or the 5-HT4 receptor antagonist
SB 204070 (0.1 microM). However, the mucosally applied 5-HT3 receptor antagonists
ondansetron (5 microM) and granisetron (1 microM) shifted the response curves to
mucosally applied 5-HT to the right in a parallel and surmountable manner. The
pD2 values in the absence and presence of ondansetron were 5.42 +/- 0.07 and 4.12
+/- 0.10, respectively, (n = 6) and that of granisetron were 5.45 +/- 0.12 and
4.50 +/- 0.10 respectively, (n = 5). 5. Serosally applied ondansetron (5 microM)
or granisetron (1 microM) had no effect on the concentration-response curve to
mucosally applied 5-HT. However, the serosally applied ondansetron and
granisetron antagonised the facilitatory effect of serosally applied 5-HT (10
microM) when administered in the presence of serosally applied SB 204070 (0.1
microM). 6. It is concluded that the facilitatory effect of mucosally applied 5
HT to reduce the peristaltic threshold in the guinea pig ileum is mediated via a
5-HT3 receptor located on the mucosal and not the serosal side of the ileum.
PMID- 9401784
TI - Intravascular and interstitial degradation of bradykinin in isolated perfused rat
heart.
AB - 1. Bradykinin (BK) has been shown to exert cardioprotective effects which are
potentiated by inhibitors of angiotensin I-converting enzyme (ACE). In order to
clarify the significance of ACE within the whole spectrum of myocardial kininases
we investigated BK degradation in the isolated rat heart. 2. Tritiated BK (3H-BK)
or unlabelled BK was either repeatedly perfused through the heart, or applied as
an intracoronary bolus allowing determination of its elution kinetics. BK
metabolites were analysed by HPLC. Kininases were identified by ramiprilat,
phosphoramidon, diprotin A and 2-mercaptoethanol or apstatin as specific
inhibitors of ACE, neutral endopeptidase 24.11 (NEP), dipeptidylaminopeptidase IV
and aminopeptidase P (APP), respectively. 3. In sequential perfusion passages, 3H
BK concentrations in the perfusate decreased by 39% during each passage.
Ramiprilat reduced the rate of 3H-BK breakdown by 54% and nearly abolished [1-5]
BK generation. The ramiprilat-resistant kininase activity was for the most part
inhibited by the selective APP inhibitor apstatin (IC50 0.9 microM). BK cleavage
by APP yielded the intermediate product [2-9]-BK, which was rapidly metabolized
to [4-9]-BK by dipeptidylaminopeptidase IV. 4. After bolus injection of 3H-BK,
10% of the applied radioactivity were protractedly eluted, indicating the
distribution of this fraction into the myocardial interstitium. In samples of
such interstitial perfusate fractions, 3H-BK was extensively (by 92%) degraded,
essentially by ACE and APP. The ramiprilat- and mercaptoethanol-resistant
fraction of interstitial kininase activity amounted to 14%, about half of which
could be attributed to NEP. Only the product of NEP, [1-7]-BK, was continuously
generated during the presence of 3H-BK in the interstitium. 5. ACE and APP are
located at the endothelium and represent the predominant kininases of rat
myocardium. Both enzymes form a metabolic barrier for the extravasated fraction
of BK. Thus, only interstitial, but not intravascular concentrations of BK are
increased by kininase inhibitors to the extent that a significant potentiation of
BK effects could be explained. NEP contributes less than 5% to the total kininase
activity, but is the only enzyme which is exclusively present in the interstitial
space.
PMID- 9401785
TI - Fc epsilon RI-mediated chloride uptake by rat mast cells: modulation by chloride
transport inhibitors in relation to histamine secretion.
AB - 1. We have examined the role of extracellular chloride in the mast cell secretion
process. The immunologically-directed ligand, antibody to IgE (anti-IgE) required
extracellular chloride ions for optimum secretion from rat peritoneal mast cells.
In contrast, replacement of extracellular chloride did not alter the mast cell
secretory response to compound 48/80, calcium ionophore A23187 or substance P. 2.
Anti-IgE-stimulation of mast cells evoked a significant uptake of chloride ions
compared to non-stimulated cells. The magnitude of chloride uptake correlated
with the magnitude of stimulated histamine secretion. 3. Compound 48/80,
substance P and A23187 did not alter the rate of chloride ion uptake, although
these agents caused significant histamine secretion. 4. The Na+/K+/2Cl-
cotransport inhibitor, furosemide, reduced the rate of anti-IgE-stimulated
chloride uptake at a relatively high concentration (700 microM). However, the
more potent Na+/K+/2Cl- cotransport inhibitors, bumetanide (100 microM) and
piretanide (100 microM) had no effect on the stimulated chloride uptake. 5.
Furosemide inhibited anti-IgE-induced histamine secretion, bumetanide potentiated
the response and piretanide had no effect. This suggests that their respective
action on histamine secretion are unrelated to inhibition of the Na+/K+/2Cl-
carrier. 6. The chloride channel blocker, 5-nitro-2-((3-phenylpropyl)-amino)
benzoic acid (NPPB), reduced both anti-IgE-stimulated chloride uptake and the
corresponding histamine secretion in a dose-dependent manner. The magnitude of
the inhibitory action of the drug on these two cellular processes was comparable,
implying that chloride channel activity is related to the mechanism of histamine
secretion. 7. It is concluded that chloride uptake has a role in the control of
Fc epsilon RI-mediated histamine secretion from rodent mast cells.
PMID- 9401786
TI - Modulation of nicotinic ACh-, GABAA- and 5-HT3-receptor functions by external H
7, a protein kinase inhibitor, in rat sensory neurones.
AB - 1. The effects of external H-7, a potent protein kinase inhibitor, on the
responses mediated by gamma-aminobutyric acid A type (GABAA)-, nicotinic
acetylcholine (nicotinic ACh)-, ionotropic 5-hydroxytryptamine (5-HT3)-,
adenosine 5'-triphosphate (ATP)-, N-methyl-D-aspartate (NMDA)- and kainate (KA)
receptors were studied in freshly dissociated rat dorsal root ganglion neurone by
use of whole cell patch-clamp technique. 2. External H-7 (1-1000 microM) produced
a reversible, dose-dependent inhibition of whole cell currents activated by GABA,
ACh and 5-HT. 3. Whole-cell currents evoked by ATP, 2-methylthio-ATP, NMDA and KA
were insensitive to external H-7. 4. External H-7 shifted the dose-response curve
of GABA-activated currents downward without changing the EC50 significantly (from
15.0 +/- 4.0 microM to 18.0 +/- 5.0 microM). The maximum response to GABA was
depressed by 34.0 +/- 5.3%. This inhibitory action of H-7 was voltage
independent. 5. Intracellular application of H-7 (20 microM), cyclic AMP (1 mM)
and BAPTA (10 mM) could not reverse the H-7 inhibition of GABA-activated
currents. 6. The results suggest that external H-7 selectively and allosterically
modulates the functions of GABAA-, nicotine ACh- and 5-HT3 receptors via a common
conserved site in the external domain of these receptors.
PMID- 9401787
TI - Species differences in brain adenosine A1 receptor pharmacology revealed by use
of xanthine and pyrazolopyridine based antagonists.
AB - 1. The pharmacological profile of adenosine A1 receptors in human, guinea-pig,
rat and mouse brain membranes was characterized in a radioligand binding assay by
use of the receptor selective antagonist, [3H]-8-cyclopentyl-1,3-dipropylxanthine
([3H]-DPCPX). 2. The affinity of [3H]-DPCPX binding sites in rat cortical and
hippocampal membranes was similar. Binding site affinity was higher in rat
cortical membranes than in membranes prepared from guinea-pig cortex and
hippocampus, mouse cortex and human cortex. pKD values (M) were 9.55, 9.44, 8.85,
8.94, 8.67, 9.39 and 8.67, respectively. The binding site density (Bmax) was
lower in rat cortical membranes than in guinea-pig or human cortical membranes.
3. The rank order of potency of seven adenosine receptor agonists was identical
in each species. With the exception of 5'-N-ethylcarboxamidoadenosine (NECA),
agonist affinity was 3.5-26.2 fold higher in rat cortical membranes than in human
and guinea-pig brain membranes; affinity in rat and mouse brain membranes was
similar. While NECA exhibited 9.3 fold higher affinity in rat compared to human
cortical membranes, affinity in other species was comparable. The stable GTP
analogue, Gpp(NH)p (100 microM) reduced 2-chloro-N6-cyclopentyladenosine (CCPA)
affinity 7-13.9 fold, whereas the affinity of DPCPX was unaffected. 4. The
affinity of six xanthine-based adenosine receptor antagonists was 2.2-15.9 fold
higher in rat cortical membranes compared with human or guinea-pig membranes. The
rank order of potency was species-independent. In contrast, three
pyrazolopyridine derivatives, (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)
acryloyl]-2-piperidine ethanol (FK453), (R)-1-[(E)-3-(2-phenylpyrazolo[1,5
a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352) and 6-oxo-3-(2
phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinebutyric acid (FK838) exhibited
similar affinity in human, guinea-pig, rat and mouse brain membranes. pKi values
(M) for [3H]-DPCPX binding sites in human cortical membranes were 9.31, 7.52 and
7.92, respectively. 5. Drug affinity for adenosine A2A receptors was determined
in a [3H]-2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido ade nosine
([3H]-CGS 21680) binding assay in rat striatal membranes. The pyrazolopyridine
derivatives, FK453, FK838 and FK352 exhibited pKi values (M) of 5.90, 5.92 and
4.31, respectively, compared with pKi values of 9.31, 8.18 and 7.57 determined in
the [3H]-DPCPX binding assay in rat cortical membranes. These novel
pyrazolopyridine derivatives therefore represent high affinity, adenosine A1
receptor selective drugs that, in contrast to xanthine based antagonists, exhibit
similar affinity for [3H]-DPCPX binding sites in human, rat, mouse and guinea-pig
brain membranes.
PMID- 9401788
TI - Effect of lacidipine on cholesterol esterification: in vivo and in vitro studies.
AB - 1. Cholesterol esterification and accumulation in the arterial wall is a hallmark
of atherogenesis. Several preclinical studies suggest that calcium antagonists
may exert antiatherosclerotic activity by directly affecting atherogenesis in the
arterial wall. We investigated the effect of the second generation
dihydropyridine calcium antagonist lacidipine on cholesterol metabolism in vivo
in the aortic arch of cholesterol fed rabbits, and in vitro in mouse cultured
peritoneal macrophages. 2. Treatment of cholesterol-fed rabbits with 1, 3 and 10
mg kg-1 day-1 of lacidipine for two months reduced, in a dose-dependent manner,
cholesterol esterification in the aortic arch: 24 +/- 6, 30 +/- 12, and 41 +/- 8%
inhibition, respectively (P < 0.001 vs HC control). Concomitantly, drug treatment
reduced total cholesterol content of the vessel wall. Lacidipine 3 and 10 mg kg-1
day-1 reduced cholesterolaemia (approximately 20%); no effect was observed at the
lowest dose used (1 mg kg-1 day-1). These results suggest that the action of
lacidipine on cholesterol esterification in the arterial wall involves, at least
in part, a direct effect on cellular cholesterol metabolism. Inhibition of
cholesterol esterification in the arterial wall was observed also in a reference
group of animals treated with the specific ACAT inhibitor CI-976. 3. To evaluate
the action of lacidipine on intracellular cholesterol metabolism we performed in
vitro experiments with murine macrophages, the main cell type that accumulates
cholesterol in the arterial wall. Lacidipine almost completely inhibited
cholesterol esterification in cholesterol loaded macrophages in culture. The
effect was observed independently of esterification stimuli and in cell free
homogenates. The drug modified intracellular cholesterol distribution, doubling
the free- to esterified sterol ratio, but did not influence the cellular rate of
cholesteryl ester hydrolysis in the cell. All together these results indicate an
inhibitory effect of lacidipine on cholesterol esterification catalyzed by the
enzyme ACAT in murine macrophages. 4. We concluded that lacidipine influences
cellular cholesterol metabolism. This effect may contribute to the potential
antiatherosclerotic activity of this drug.
PMID- 9401789
TI - Reversal of tolerance to the antitransit effects of morphine during acute
intestinal inflammation in mice.
AB - 1. The aim of investigation was to establish and compare the reversibility of
tolerance to the antitransit effects of morphine by three different procedures:
(a) acute inflammation of the gut, (b) lorglumide a cholecystokininA (CCKA)
receptor antagonist, or (c) MK-801, an N-methyl-D-aspartate (NMDA) receptor ion
channel blocker. The type of interaction between morphine and lorglumide or MK
801 on the inhibition of gastrointestinal transit (GIT) in naive animals was also
evaluated. 2. Male Swiss CD-1 mice were implanted with 75 mg of morphine base or
placebo pellets. Gastrointestinal transit was assessed with a charcoal meal and
results expressed as % inhibition of GIT. Inflammation was induced by the
intragastric (p.o.) administration of croton oil (CO), while controls received
castor oil (CA) or saline (SS). Morphine was administered by subcutaneous (s.c.)
or intracerebroventricular (i.c.v.) injection, to naive and tolerant animals
treated with CO, CA or SS. Dose-response curves for s.c. morphine were also
performed in naive and tolerant mice receiving 5.2 or 7.4 nmol (s.c.) lorglumide
or MK-801, respectively. 3. The ED50 values for inhibition of GIT by s.c.
morphine were: 45.9 +/- 2.7 and 250.1 +/- 3.1 nmol in naive and tolerant animals,
respectively, demonstrating a five fold decrease in the potency of morphine. In
naive animals, inflammation (CO) decreased the ED50 of morphine three times (14.4
+/- 2.2 nmol). However, no tolerance to s.c. morphine (ED50 16.4 +/- 2.6 nmol)
was manifested during intestinal inflammation. After i.c.v. administration, a
similar degree of tolerance to morphine was observed (4.8 fold decrease in
potency). Intestinal inflammation had no effect on the ED50 values of i.c.v.
morphine in naive and tolerant animals, showing that reversal of tolerance is
related to local mechanism/s. Mean values for intestinal pH were 6.9 +/- 0.04 and
6.2 +/- 0.04 in SS and CO treated mice, respectively. In addition, morphine was
74 times more potent by the i.c.v. than by the s.c. route (naive-SS). 4. Morphine
and lorglumide interacted synergistically in naive animals; in addition, the
administration of lorglumide reversed tolerance to s.c. morphine. No interaction
(additivity) was observed in naive animals when morphine and MK-801 were
administered in combination. However, the drug completely reversed tolerance to
the antitransit effects of morphine. 5. The present investigation shows that
acute inflammation of the gut reverses tolerance to the antitransit effects of
s.c. morphine by a peripheral mechanism. Qualitatively similar results were
obtained after the administration of lorglumide or MK-801. Our results suggest
that a local decrease in pH could play an important role during inflammation,
while antagonism of endogenous compensatory systems would explain the reversal of
tolerance induced by lorglumide or MK-801.
PMID- 9401790
TI - Effects of a novel guanylate cyclase inhibitor on nitric oxide-dependent
inhibitory neurotransmission in canine proximal colon.
AB - 1. Previous studies suggested that nitric oxide (NO) may cause hyperpolarization
and relaxation of canine colonic smooth muscle by both cGMP-dependent and cGMP
independent mechanisms. This hypothesis was tested using 1H-[1,2,4]oxadiazolo[4,3
a]quinoxaline-1-one (ODQ), a novel inhibitor of NO-stimulated guanylate cyclase.
2. In the presence of histamine (30 microM), atropine and indomethacin (both at 1
microM), electrical field stimulation of intrinsic neurons (EFS; 5 Hz) produced
inhibition of phasic contractile activity that is due to NO synthesis. ODQ caused
a concentration-dependent block of this response (10 nM to 10 microM). 3.
Inhibitory junction potentials (IJPs) due to NO synthesis were recorded from
muscle cells located near the myenteric border of the circular muscle layer,
using intracellular microelectrodes. IJPs were abolished by ODQ (1-10 microM). 4.
EFS (10-20 Hz) produced frequency-dependent inhibition of electrical slow waves
recorded from cells located near the submucosal surface of the circular muscle
layer. This inhibition is due to NO synthesis, and it was abolished by ODQ (1-10
microM). 5. Hyperpolarization and relaxation produced by an NO donor, sodium
nitroprusside, were abolished by ODQ pretreatment (1-10 microM). In contrast,
inhibitory responses to 8-Br-cGMP (1 mM) were unaffected by ODQ. 6. ODQ alone (1
10 microM) had no significant effect on spontaneous electrical or phasic
contractile activity. In tissues pre-treated with L-NAME (300 microM), ODQ
decreased the amplitude of spontaneous or histamine-stimulated phasic contractile
activity. 7. These results suggest that electrical and mechanical effects of
endogenously released and exogenously applied NO in canine colon are largely due
to cGMP synthesis by ODQ-sensitive soluble guanylate cyclase. No evidence to
support a direct (cGMP-independent) mechanism of NO action was found. ODQ also
appears to cause a non-specific inhibition of muscle contractile activity;
however, this effect does not contribute to block of NO-dependent effects.
PMID- 9401791
TI - Structural requirements for roxatidine in the stimulant effect of rat gastric
mucin synthesis and the participation of nitric oxide in this mechanism.
AB - 1. The structural requirements of the histamine H2-receptor antagonist,
roxatidine (2-acetoxy-N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide
hydrochloride), for the stimulant effect on mucin biosynthesis and their relation
to histamine H2-receptor antagonism were identified by considering the structural
analogues of this drug using an organ culture system of the rat stomach and
competition studies with [125I]iodoaminopotentidine ([125I]-APT) binding to
membranes of the guinea pig striatum. 2. [3H]Glucosamine incorporation into mucin
during 5 h incubation period was stimulated by roxatidine and its structural
analogues A (2-hydroxy-N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide)
and B (N-(3-[m-(1-piperidinylmethyl)phenoxy]-propyl)acetamide). This effect was
seen in mucosal cultures of the corpus, but not antrum, region. 3. Structural
analogues, in which the length of the flexible chain between the benzene ring and
the amide structure differs from that of roxatidine, failed to activate mucin
synthesis. No significant change in mucus synthesis occurred with the addition of
analogues in which the piperidine ring attached to the benzene ring via a
methylene bridge was changed. 4. Specific [125I]-APT binding to the histamine H2
receptor of guinea pig brain membranes was inhibited by roxatidine and all
structural analogues used in this study, except F (N-(3-[m-(N, N-dimethyl
aminomethyl)phenoxy]-propyl)acetamide). 5. Ranitidine at 10(-4) M did not
suppress the roxatidine-induced increase in [3H]glucosamine incorporation into
mucin. 6. Roxatidine-induced stimulation of [3H]glucosamine incorporation into
mucin was completely blocked by the addition of either NG-nitro-L-arginine (10(
5) M) or 2-(4-carboxyphenyl)-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide
sodium salt (10(-5) M). The inhibitory action of NG-nitro-L-arginine was totally
reversed by L-arginine (5 x 10(-3) M). 7. These results suggest that the cardinal
chemical features of roxatidine for the activation of mucin biosynthesis in the
corpus region of the rat stomach are the appropriate length of the flexible chain
between the amide structure and the aromatic ring system bearing the
methylpiperidinyl group at the meta position. The activity of roxatidine and its
analogues to stimulate mucin synthesis is not related to their histamine H2
receptor antagonistic activity. Roxatidine-induced activation of mucin
biosynthesis in the corpus tissue is mediated by nitric oxide.
PMID- 9401792
TI - Acute effects of nitric oxide blockade with L-NAME on arterial haemodynamics in
the rat.
AB - 1. We employed the technique of impedance spectral analysis to investigate the
role of endogenous nitric oxide (NO) in the regulation of steady and pulsatile
haemodynamics in Wistar Kyoto rat (WKY). 2. A total of 12 WKYs was anaesthetized
with pentobarbitol sodium (40 mg kg-1, i.p.) and artificially ventilated with an
animal respirator. The aortic pressure wave was monitored with a high fidelity
Millar sensor, and aortic flow wave with an electromagnetic flow probe. The
pressure and flow waves were subjected to Fourier transform for the analysis of
impedance spectra. 3. The baseline cardiovascular parameters were mean arterial
pressure (APm) 95 +/- 9 mmHg, heart rate (HR) 338 +/- 9 b.p.m., stroke volume
(SV) 0.23 +/- 0.01 ml, cardiac output (CO) 77.8 +/- 1.6 ml min-1, total
peripheral resistance (TPR) 98 +/- 11 (x10(3)) dyne s cm-5, characteristic
impedance (Zc) 2046 +/- 141 dyne s cm-5, arterial compliance at mean AP (Cm) 3.78
+/- 0.22 microliters mmHg-1 and backward pulse wave (Pb) 12.9 +/- 0.6 mmHg. 4. An
NO synthase inhibitor, NG-nitro-L-arginine monomethyl ester (L-NAME) was
administered at graded intravenous doses. This agent caused dose-dependent
increases in AP and TPR with decreases in HR. At an accumulative dose of 10 mg kg
1, APm was increased by 29 +/- 3 mmHg (+31%) and TPR by 49 +/- 6 (x10(3)) dyne s
cm-5 (+50%), while HR was reduced by 37 +/- 5 b.p.m. (-11%) and CO by 10.4 +/-
0.8 ml min-1 (-14%). The pulsatile haemodynamics including Zc and Pb were
slightly increased by 14-15%. Cm was decreased by 1.09 microliters mmHg-1 (-29%).
L-NAME also did not significantly affect the ventricular work including the
steady, oscillatory and total work. 5. Aminoguanidine, a specific inhibitor for
inducible NO synthase (iNOS), in dose 10-60 mg kg-1 i.v. did not alter the AP, HR
and other parameters. The result indicated that blockade of constitutive NOS, but
not iNOS is involved in these changes. 6. Angiotensin II (Ang) in various
infusion doses was used to produce a profile of AP increase similar to that
caused by L-NAME. Ang remarkably increased Zc, while TPR was moderately elevated.
The pattern of haemodynamic changes was different from that following L-NAME. 7.
The results suggest that blockade of the endogenous NO affects predominantly the
arterial pressure and peripheral resistance. The Windkessel functions such as
arterial impedance and pulse wave reflection are slightly increased. Ventricular
works are not significantly altered.
PMID- 9401793
TI - Lipolytic effects of conventional beta 3-adrenoceptor agonists and of CGP 12,177
in rat and human fat cells: preliminary pharmacological evidence for a putative
beta 4-adrenoceptor.
AB - 1. The nature of rat and human fat cell beta 3-adrenoceptors was investigated by
studying the effects of the new beta 3-adrenoceptor selective antagonist, SR
59,230A, on lipolysis induced by the conventional beta 3-adrenoceptor agonists,
CL 316,243 and SR 58,611A, and by the non-conventional partial beta 3
adrenoceptor agonist CGP 12,177 (a potent beta 1- and beta 2-adrenoceptor
antagonist with partial beta 3-adrenoceptor agonist property). 2. In rat fat
cells, the rank order of potency of agonists was: CL 316,243 > isoprenaline > SR
58,611A > CGP 12,177. The three former agents were full agonists whereas CGP
12,177 was a partial agonist (intrinsic activity of 0.70). In human fat cells,
the lipolytic effect of CGP 12,177 reached 25% of isoprenaline effect. CL 316,243
was a poor inducer of lipolysis and SR 58,611A was ineffective. 3. In rat fat
cells, lipolysis induced by CL 316,243 and SR 58,611A was competitively
antagonized by SR 59,230A. Schild plots were linear with pA2 value of 6.89 and
6.37, respectively. Conversely, 0.1, 0.5 and 1 microM SR 59,230A did not modify
the concentration-response curve of CGP 12,177. A rightward shift of the curve
was however observed with 10 and 100 microM of SR 59,230A. The apparent pA2 value
was 5.65. The non-selective beta-adrenergic antagonist, bupranolol, competitively
displaced the concentration-response curve of CGP 12,177 and CL 316,243. Schild
plots were linear with pA2 values of 6.70 and 7.59, respectively. CL316,243
mediated lipolytic effect was not antagonized by CGP 20,712A. In human fat cells,
CGP 12,177-mediated lipolytic effect was antagonized by bupranolol and CGP
20,712A. SR 59,230A (0.1, 1 and 10 microM) did not modify the concentration
response curve of CGP 12,177. A rightward shift was however observed at 100
microM leading to an apparent pA2 value of 4.32. 4. The results suggest that the
non-conventional partial agonist CGP 12,177 can activate lipolysis in fat cells
through the interaction with a beta-adrenoceptor pharmacologically distinct from
the beta 3-adrenoceptor, i.e. through a putative beta 4-adrenoceptor. They
suggest that the two subtypes coexist in rat fat cells whereas only the putative
beta 4-adrenoceptor mediates lipolytic effect of CGP12,177 in human fat cells.
PMID- 9401794
TI - Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory
actions, in a rodent model of permanent middle cerebral artery occlusion.
AB - 1. The aim of this study was to investigate whether delayed treatment with the
anti-oxidant and anti-inflammatory agent ebselen reduces the volume of infarction
in a rodent model of permanent focal cerebral ischaemia. 2. Ebselen (10 or 30 mg
kg-1) or vehicle was administered by gavage 30 min and 12 h after the induction
of cerebral ischaemia by permanent occlusion of the left middle cerebral artery
(MCA). Animals were killed 24 h following MCA occlusion, and the volumes of
ischaemic damage in the ebselen and control groups were evaluated by quantitative
histopathology. 3. Ebselen was quickly absorbed following oral (gavage)
administration and reached peak levels in the plasma by 1 h post-administration
(plasma selenium level of 0.68 +/- 0.04 and 0.84 +/- 0.1 microgram ml-1 for 10
and 30 mg kg-1, respectively, compared to control level of 0.51 +/- 0.02
microgram kg-1). 4. Treatment with the lower dose of ebselen (10 mg kg-1)
significantly (P < 0.01) reduced the volume of infarction in the cerebral
hemisphere and cerebral cortex (by 31.8% and 36.7%, respectively compared with
the placebo group). 5. The neuroprotective efficacy of the higher dose ebselen
(30 mg kg-1) was less than that of the lower dose ebselen (10 mg kg-1). The
volume of ischaemic damage in the cerebral hemisphere was reduced by 23.7% (P <
0.02), and cerebral cortex by 27.5% (P < 0.01). 6. Both doses of ebselen (10, 30
mg kg-1) had no therapeutic efficacy on the caudate nucleus, where ischaemia was
most severe, in this model. 7. Free radical-mediated injury is normally
associated with reperfusion of ischaemic tissue. The present results suggest that
oxidative injury is also a significant contributor to brain damage in models of
maintained (permanent) ischaemia and that ebselen is effective in attenuating
this free radical-induced damage.
PMID- 9401795
TI - Variabilities in the distribution of neurofibrillary tangles in the anterior
parahippocampal gyrus at initial stages of Alzheimer's disease.
AB - The entorhinal region is located in the ventromedial surface of the temporal lobe
on the parahippocampal gyrus. Occurrence of early argyrophilic neurofibrillary
tangles was investigated in brain sections of the left and right entorhinal
region of 9 individuals of both sexes between the age of 26 to 54 years.
Parasagittal serial sections at 100 microns were performed to include the very
anterior part of the entorhinal region. An advanced silver method was used for
staining neurofibrillary changes. The neurofibrillary tangles were counted via
light microscopy, marked on the sections and staged as proposed by Braak and
Braak. In 1 case we found a left-right difference by 1 stage (right: stage I,
left: stage II). The tangle distribution in another case exhibited several
neurofibrillary tangles only in the very anterior part of the entorhinal cortex
on both sides (stage 0). In 3 cases some neurofibrillary tangles occurred in the
very anterior part of the right entorhinal region, while a few are present in
more posterior parts (stage I). The corresponding left hemisphere showed the same
anterior-posterior distribution pattern as on the right in only 1 of these cases.
In the remaining 4 cases, no neurofibrillary changes were visible. In conclusion,
the very anterior part of the entorhinal region is among the earliest sites for
development of neurofibrillary tangles. Distribution of early Alzheimer-related
neurofibrillary changes in the entorhinal region displays variabilities in the
anterior-posterior direction as well as in a left-right comparison.
PMID- 9401796
TI - Acute stroke in a child with miliary tuberculosis.
AB - Neurological symptoms in childhood miliary tuberculosis are generally caused by
underlying tuberculous meningitis (TBM), since the 2 conditions commonly occur
concurrently. Cerebral infarction, a well-recognized complication of TBM, usually
results from tuberculous periarteritis and secondary thrombosis.
Neuropathological studies have demonstrated that the anterior cerebral
circulation is more commonly affected than the arteries of the vertebro-basilar
system, and basilar artery occlusion as a presenting manifestation of childhood
miliary tuberculosis or TBM has not been described before. We report a 13-month
old infant who presented with fever and convulsions, terminating in acute
decerebration after a second prolonged seizure 1 week after the onset of
symptoms. Magnetic resonance (MR) imaging demonstrated density changes compatible
with acute vertebro-basilar ischemia as well as multiple cerebral granulomas. A
chest radiograph showed diffuse miliary tuberculosis. Postmortem examination
confirmed this diagnosis and revealed acute occlusion of the basilar artery by an
infected (septic) thromboembolus showing granulomatous inflammation, which most
likely arose from an endocardial vegetation with identical histology.
PMID- 9401797
TI - Leptomeningeal lipomatous hamartoma overlying a midline cleft of the ventral
pons.
AB - Intracranial lipomatous hamartomas (lipomas) are of maldevelopmental nature and
have a predilection for the midsagittal plane. They are often associated with
malformations of the CNS and other organ systems. It is reported an asymptomatic
lipomatous hamartoma of the ventral pontine leptomeninges and a midline cleft of
the subjacent pons discovered incidentally at autopsy of an 80-year-old man.
Review of the literature shows that this type of lesion at the ventral pons has
not been reported previously.
PMID- 9401799
TI - Light-microscopic study of the beta 1 integrin subunit in human skeletal muscle.
AB - The beta 1 integrin subunit is identical with the CD29 antigen, which is found at
the surface of leukocytes. Integrins are involved in cell-cell and cell-matrix
adhesion, mediate neuronal attachment and neurite outgrowth in response to
extracellular matrix proteins in cell culture systems. A few analyses of beta 1
integrin subunit have been done on developing and regenerating skeletal muscle in
animals; but cell culture systems and animal models differ in some respects from
human skeletal muscle in situ. The expression of a beta 1 integrin subunit
variant in human skeletal muscle was reported merely by Western blot analysis.
Our present study, performed with immunohistochemical procedures, attempts to
demonstrate the expression of the beta 1 integrin subunit in developing, normal
adult, and diseased human skeletal muscles. The results demonstrated that the
beta 1 integrin subunit is expressed in developing, normal adult, regenerating,
and denervated human skeletal muscle. In developing muscle, the beta 1 integrin
subunit was observed in muscle cells at least from 12 to 16 weeks of gestation.
In muscular dystrophy and inflammatory myopathy the beta 1 integrin subunit
staining occurs in basophilic muscle fibers. Furthermore, the beta 1 integrin
subunit is expressed in mature fast twitch type 2 fibers, and in denervated
myocytes in neurogenic muscular atrophy. On serial sections, the beta 1 integrin
subunit, N-CAM (neural cell adhesion molecule) and vimentin are expressed in
identical muscle fibers. However, in mature fast twitch type 2 fibers the beta 1
integrin subunit is expressed exclusively and in neurogenic muscular atrophy
vimentin expression is weak. In conclusion, the beta 1 integrin subunit, in human
skeletal muscles, probably plays a role in the growth morphology and innervation
of developing, regenerating, and denervated myocytes. Furthermore, the
observation that the beta 1 integrin subunit is enriched in mature fast twitch
type 2 fibers indicates that the beta 1 integrin subunits may play a role in
transducing mechanical forces to extracellular matrix proteins.
PMID- 9401800
TI - Pure alexia: clinical-pathologic evidence for a lateralized visual language
association cortex.
AB - Traditional views of pure alexia have held that the disorder results from a
disconnection between the secondary visual cortices of both hemispheres and the
angular gyrus of the dominant hemisphere. Evidence has accumulated, however,
suggesting the importance of the posterior inferior temporal area in visual
language processing. We describe clinical-pathological support for the presence
of a lateralized visual language association area residing in the dominant
posterior inferior temporal lobe.
PMID- 9401798
TI - Adhesion molecules in HIV-related and idiopathic polymyositis:
immunohistochemical studies.
AB - Idiopathic polymyositis (IPM) and HIV polymyositis (HIV-PM) are considered to be
related autoimmune diseases whose target is skeletal muscle. They have been
associated to a T cell-mediated and MHC-I-restricted cytotoxic phenomenon, but
both etiology and physiopathology remain incompletely understood. Their
histological hallmarks are mononuclear leukocyte infiltrates as well as necrosis,
degeneration, and regeneration of muscle fibers. In the present study, we have
investigated the immunohistochemical expression of cell adhesion molecules,
cytokines, and leukocyte surface antigens in biopsies of HIV-PM and IPM patients.
The aim was to better define factors involved in lymphocyte recruitment and in
inflammatory changes seen in PM. Notable upregulation of ICAM-1 and TNF-alpha was
detected on capillary and venular endothelia and on inflammatory cells, whereas
no significant VCAM-1 and ELAM-1 expression was present. LFA-1, the main ICAM-1
counter-receptor, was found to be highly expressed on lymphocytes and monocytes,
especially at the vicinity of damaged fibers. The majority of infiltrating cells
were CD8+CD45 RO-T cells, which are thought to have memory capacities. These
findings suggest that in IPM and HIV-PM, enhanced ICAM-1 and LFA-1 expression
possibly induced by TNF-alpha, may regulate the homing process of selected
lymphocyte clones in muscle tissue. Lymphocyte proliferation and differentiation
into memory subsets may further potentiate tissue-restricted homing capabilities.
PMID- 9401801
TI - p53 status has no prognostic significance in glioblastomas treated with
radiotherapy.
AB - Mutation of the tumor suppressor gene TP53 and accumulation of the p53 protein
are common events in the range of cerebral astrocytic tumors, including
glioblastomas, but it is uncertain whether these events are associated with
prognosis. Evidence suggests that the response of various tumors to radiotherapy
may be influenced by the status of p53 which is involved in control of the cell
cycle and apoptosis. This study tests the hypothesis that p53 governs survival in
patients (n = 62) with glioblastomas who have received radiotherapy. Analysis of
TP53 and p53 immunohistochemistry were undertaken using standard methods. TP53
mutations were present in 27% tumors, while 50% were p53-immunopositive (LI >
3%). A strong correlation (p < 0.0001) was found between a high p53 LI (> 50%)
and the presence of a mutation, but p53 status at the level of gene or protein
was unrelated to survival. Radiation-induced apoptosis that is independent of
p53, and the presence in glioblastomas of genetic abnormalities that are also
involved in the cellular response to radiation, such as deletions and mutations
of pRb, are possible explanations of this result.
PMID- 9401802
TI - Malignant melanoma in the CNS, subtyping and immunocytochemistry.
AB - Paraffin-embedded specimens from 21 patients (mean age 49 years) with malignant
melanocytic tumors of the central nervous system were studied. Extraneuronal
primary tumors were situated at the trunk (38%), the lower (14%) or upper
extremity (10%), and the head/neck region (5%). In 33% no extraneural primary
tumor could be detected. The tumor location was frontal (19%), occipital (19%),
parietal, spinal, multifocally (14%, respectively), or temporal (5%). Four
subtypes were distinguished according to the predominant histological cell type:
pleomorphic, epithelioid, spindle- and mixed-cell tumors. 29% contained no
melanin, most of them belonging to the epithelioid subtype. The morphology and
immunohistochemical reactivity for different antibodies (KL-1, EMA, VIM, HMB-45,
NKI-C3, S-100, and MIB-1/Ki-67) were assessed. Positive staining was demonstrated
for HMB-45 (in 86% of cases), NKI-C3 (100%), S-100 (95%), vimentin (75%), and KL
1 (33%). No expression of the cytokeratin EMA could be detected. The mean
proliferation index measured by MIB-1 immunoreactivity was 21%. The 4
histological subtypes were found to express different antigen patterns. In the
analysis of CNS tumors of unknown origin, the panel of antibodies used for
diagnosis should include HMB-45 as the most specific marker for malignant
melanoma.
PMID- 9401803
TI - Polymerase chain reaction for the detection of Burkholderia pseudomallei.
AB - Melioidosis is a potentially lethal infection of humans and animals in Southeast
Asia and northern Australia. Current methods for detection of the causative
organism, Burkholderia pseudomallei, lack both speed and sensitivity. We report
the development of a highly sensitive polymerase chain reaction-based method that
can detect as few as 35 colony-forming units of B. pseudomallei/mL in saline
suspensions. This polymerase chain reaction test also detected the presence of B.
pseudomallei DNA in culture-negative splenic tissue obtained from mice infected
with the organism, but without clinical evidence of disease. Specificity has been
confirmed using a variety of pathogenic and nonpathogenic organisms, including B.
mallei, B. cepacia, and Pseudomonas species. The clinical usefulness of this test
should be assessed prospectively and compared with conventional diagnostic
techniques.
PMID- 9401804
TI - Transferable antibiotic resistance in nosocomial Stenotrophomonas maltophilia
strain.
AB - Stenotrophomonas maltophilia (298/85) was isolated from the extensively inflamed
conjunctiva of a neonate in a regional hospital in Ostrava, Czech Republic. It
was resistant to all available antibiotics except cefepime and trimethoprim. The
donor S. maltophilia strain 298/85 transferred carbenicillin and cephaloridine
resistance determinants to recipient strains of Escherichia coli K-12 3110 rif+
and Proteus mirabilis P-38 rif+. All transconjugant colonies were co-resistant
also to kanamycin, cefotaxime, and aztreonam. Active hydrolysis of imipenem in
the original strain was inhibited by ethylene diamine tetra-acetic acid, and
hydrolysis of cefotaxime and aztreonam in the original strain and in the E. coli
K-12 transconjugant was inhibited by clavulanate. In contrast, ceftazidime was
hydrolyzed by the original strain and was not inhibited by clavulanate,
indicating a different character of the resistance to cefotaxime or aztreonam and
ceftazidime.
PMID- 9401805
TI - Ciprofloxacin-resistant Escherichia coli emerging in a rehabilitation medical
center.
AB - A retrospective review of laboratory records from 1988 to 1996 has shown an
increased rate of ciprofloxacin-resistant (cip(r)) Escherichia coli in our
rehabilitation center. Resistance increased from 0.6% in 1989 to 5.9% in 1996. Of
7870 E. coli strains isolated during this period, 257 cip(r)-E. coli were
recovered from 257 patients. The majority (96%) of these resistant strains were
isolated from the urine samples. One hundred and twenty strains of cip(r)-E. coli
were also resistant to four other fluoroquinolones. MICs ranging from 64 to 512
micrograms/mL were observed in 75% of the strains and > or = 1028 micrograms/mL
in 6.4% of the strains. Resistance to ciprofloxacin was due to possible mutations
in topoisomerase gyrA.
PMID- 9401806
TI - A comparison of the BioStar Strep A OIA rapid antigen assay, group A Selective
Strep Agar (ssA), and Todd-Hewitt broth cultures for the detection of group A
Streptococcus in an outpatient family practice setting.
AB - In some studies the BioStar Strep A OIA (optical immunoassay) has yielded
inconsistent results, although originally it was reported to be more sensitive
than conventional culture for the detection of group A Streptococcus (GAS). The
Group A Selective Strep Agar with 5% sheep blood (ssA) incubated anaerobically
has been reported to be more sensitive than conventional culture in the detection
of GAS. We compared the BioStar Strep A OIA GAS rapid antigen detection kit to
anaerobic culture on ssA with and without preincubation in Todd-Hewitt broth
(THB) for the detection of GAS. From September 1995 through January 1996, throat
swabs were collected in duplicate from 75 children (< or = 18 years) and 188
adults (> 18 years) who presented with pharyngitis in the outpatient University
of New Mexico Family Practice Clinic. Thirty-one (12%) of the 263 cases were
positive for GAS by culture and/or broth. Compared with anaerobic culture on the
ssA, with and without preincubation in THB, the sensitivity, specificity,
positive predictive value, and negative predictive value of the BioStar Strep A
OIA were 77, 62, 22, and 95%, respectively. Compared with enrichment in THB
followed by subculture on ssA and anaerobic incubation, the sensitivity,
specificity, positive predictive value, and negative predictive value of direct
culture on ssA and anaerobic incubation were 79, 99, 98, and 96%, respectively.
All isolates were serologically grouped. The BioStar Strep A OIA is as sensitive
as direct culture on ssA incubated anaerobically, but the low specificity and low
positive predictive value when the OIA is used in low prevalence populations
could lead to unnecessary antibiotic treatment.
PMID- 9401807
TI - An outbreak of Candida parapsilosis prosthetic valve endocarditis.
AB - Candida parapsilosis, an important nosocomial pathogen and the most common
species of Candida found on the hands of health care workers, is a rare cause of
prosthetic valve endocarditis (PVE). From March through June 1994, four cases of
C. parapsilosis PVE were diagnosed at a 400-bed community hospital. The mean time
to presentation after valve replacement surgery was 148 days (range, 20 to 345).
Three of the four patients died of complications of PVE. Multiple environmental
cultures were performed, and only one was positive for C. parapsilosis. Cultures
from the bypass pump, cell saver, cardioplegia solution, and subsequent valves
were all negative. All valve replacements were performed by the same operating
room team. Interviews with the surgeon and physician assistant, the only
personnel involved in all cases, revealed that their hypoallergenic gloves were
subject to frequent tears during valve replacement procedures, often requiring
several glove changes per procedure. Hand cultures of personnel were obtained,
and cultures from 20 individuals (26%) were positive for C. parapsilosis. Hand
cultures of the surgeon and physician assistant obtained 8 months after the last
case had surgery were negative for yeasts. Molecular typing of the 3 available
case isolates, 14 epidemiologically unrelated patient isolates, 1 environmental
isolate, and 20 hand isolates was performed by electrophoretic karyotyping and
restriction endonuclease analysis of genomic DNA using restriction enzymes BssHII
and EagI followed by pulsed field gel electrophoresis. The three case isolates
were identical by restriction endonuclease analysis of genomic DNA, and two of
the three shared the same electrophoretic karyotyping profile. The remaining
patient, environmental, and hand isolates represented 29 different DNA types and
were distinctly different from the case isolates. All of the isolates tested were
susceptible to amphotericin B, 5FC, fluconazole, and itraconazole. The
circumstantial evidence suggests the probability of glove tears during valve
replacement surgery and subsequent transmission of C. parapsilosis to patients.
PMID- 9401808
TI - A double-blind, randomized study of three antimicrobial regimens in the
prevention of infections after elective colorectal surgery.
AB - The objective of this study was to assess the prophylactic efficacy of cefoxitin,
ceftizoxime, and metronidazole-gentamicin in colorectal surgery. A double-blind,
randomized prospective clinical trial design was used in a Canadian tertiary care
teaching hospital. Patients were randomized to one of three treatment groups and
received three doses of a study drug (30 min preoperative and 2 postoperative
doses at 12 and 24 h). Cefoxitin and ceftizoxime were given as 1000-mg doses.
Metronidazole-gentamicin was given as 500 mg of metronidazole plus 120 mg of
gentamicin in a minibag. High-risk patients (bowel ischemia, diabetic, current
steroid use, etc.) received 10 postoperative doses. Patients with infections,
prior antibiotics, or study drug allergies were excluded. Over 30 months, 153
patients were enrolled. Thirty-one patients were excluded for protocol
violations. Of the 122 evaluable patients (38 ceftizoxime, 45 metronidazole
gentamicin, 39 cefoxitin), there was no difference across groups regarding sex,
age, weight, preoperative Apache II score, and prior history of bowel surgery.
Groups were equivalent regarding surgeon, nursing unit, high-risk status (six
ceftizoxime, seven metronidazole-gentamicin, seven cefoxitin), bowel preparation,
and procedure (including blood loss, drains, organ injury, intraoperative
complications). Clinically significant infection requiring systemic antibiotics
(7-day hospital and 30-day follow-up) was identified in 0% of ceftizoxime, 15% of
metronidazole-gentamicin, and 26% of cefoxitin receiving patients (p = 0.005).
Mean ASEPSIS scores for each group were 2.3 (range 0-15) for ceftizoxime, 9.2
(range 0-45) for metronidazole-gentamicin, and 10.4 (range 0-75) for cefoxitin (p
= 0.01). Ceftizoxime patients tended to have a shorter total hospital stay (12.2
days versus 19.7 days for cefoxitin versus 13.9 days for metronidazole
gentamicin; p = 0.04), although the procedure to discharge interval was not
significantly different (p = 0.09). There was no difference in clinical outcome
according to risk status. Anaerobic bacteria were observed more commonly in the
ceftizoxime and cefoxitin groups, whereas enteric Gram-negative aerobes were
observed most often in the metronidazole-gentamicin group. The study regimens
were generally well tolerated. Drug costs were equivalent between ceftizoxime and
cefoxitin and lowest with the metronidazole-gentamicin regimen. Ceftizoxime
appears to be more effective for the prevention of infection in colorectal
surgery than either cefoxitin or metronidazole-gentamicin in the dosage regimens
studied.
PMID- 9401809
TI - In vitro activity of clarithromycin alone and in combination with ciprofloxacin
or levofloxacin against Legionella spp.: enhanced effect by the addition of the
metabolite 14-hydroxy clarithromycin.
AB - Clarithromycin is metabolized to an active metabolite, 14-hydroxy clarithromycin.
These compounds have demonstrated excellent in vitro activity against Legionella
species, with both agents having significantly lower MICs than erythromycin.
Using a checkerboard assay, the activity of clarithromycin and its hydroxy
metabolite, alone and in combination, was examined against 41 Legionella
organisms. The activity of clarithromycin and 14-hydroxy clarithromycin, in a 2:1
ratio, plus ciprofloxacin or levofloxacin was also determined. Activity of the
antibiotic combinations was determined by calculating the fractional inhibitory
concentration index. An agar dilution method using buffered charcoal yeast
extract media was used for susceptibility and synergy testing. An inoculum of
10(4) CFU/spot was used, with all plates incubated at 35 degrees C for 48 h. The
MIC90 for clarithromycin or 14-hydroxy clarithromycin alone was 0.5, versus 0.25
microgram/mL for the combination. Additive effects were observed with
clarithromycin and its hydroxy metabolite for 61% of the Legionella species, with
fractional inhibitory concentration indices ranging from 0.63 to 1.25. The 14
hydroxy metabolite significantly increased the activity of both
fluoroquinolone/clarithromycin combinations. Based on these data, in vitro
susceptibility testing of agents such as clarithromycin should be reevaluated to
account for the activity of active metabolites.
PMID- 9401810
TI - Comparative in vitro assessment of sparfloxacin activity and spectrum using
results from over 14,000 pathogens isolated at 190 medical centers in the USA.
SPAR Study Group.
AB - Sparfloxacin, a new orally administered fluoroquinolone, was tested against
14,182 clinical strains isolated (generally blood stream and respiratory tract
cultures) at nearly 200 hospitals in the United States (USA) and Canada.
Sparfloxacin activity was compared with 13 other compounds by Etest (AB BIODISK,
Solna, Sweden), broth microdilution, or a standardized disk diffusion method.
Using the Food and Drug Administration/product package insert MIC breakpoint for
sparfloxacin susceptibility (< or = 0.5 microgram/ml), 94% of Streptococcus
pneumoniae (2666 isolates) and 89% of the other streptococci (554 isolates) were
susceptible. However, at < or = 1 microgram/ml (the breakpoint for all
nonstreptococcal species) sparfloxacin susceptibility rates increased to 100% and
98%, respectively, for the two groups of streptococci. Only 50% and 65% of
pneumococci were susceptible to ciprofloxacin (MIC90, 3 micrograms/ml) and
penicillin (MIC90, 1.5 micrograms/ml), respectively. Although there were
significant differences between regions in the USA in the frequency of penicillin
resistant pneumococcal strains, results indicate that the overall sparfloxacin
MIC90 was uniformly at 0.5 microgram/ml. Nearly all (> or = 99%) Haemophilus
species and Moraxella catarrhalis, including those harboring beta-lactamases,
were susceptible to sparfloxacin, ciprofloxacin, and amoxicillin/clavulanic acid.
Only cefprozil and macrolides demonstrated lower potency and spectrum against
these two species. Sparfloxacin was active against oxacillin-susceptible
Staphylococcus aureus (96 to 97%), Klebsiella spp. (95%), and other tested
enteric bacilli (93%). Comparison between broth microdilution MIC and disk
diffusion interpretive results for M. catarrhalis, Staphylococcus aureus, and the
Enterobacteriaceae showed an absolute intermethod categorical agreement of > 95%
using current sparfloxacin breakpoints, in contrast to those of cefpodoxime for
S. aureus where a conspicuous discord (98% versus 59%) between methods was
discovered. These results demonstrate that sparfloxacin possesses sufficient in
vitro activity and spectrum versus pathogens that cause respiratory tract
infections (indications), especially strains resistant to other drug classes such
as the earlier fluoroquinolones, oral cephalosporins, macrolides, and
amoxicillin/clavulanic acid. The sparfloxacin susceptibility breakpoint for
streptococci may require modification (< or = 1 microgram/ml) based on the MIC
population analysis presented here. A modal MIC (0.38 to 0.5 microgram/ml) was
observed at the current breakpoint. Regardless, sparfloxacin inhibited 89%
(nonpneumococcal Streptococcus spp.) to 100% (Haemophilus spp., M. catarrhalis)
of the isolates tested with a median activity of 97% against indicated species.
PMID- 9401811
TI - Antimicrobial activity of 12 broad-spectrum agents tested against 270 nosocomial
blood stream infection isolates caused by non-enteric gram-negative bacilli:
occurrence of resistance, molecular epidemiology, and screening for metallo
enzymes.
AB - A total of 270 recent nosocomial blood stream isolates of non-Enterobacteriaceae
Gram-negative bacilli representing nearly 50 U.S. medical centers were
characterized. The numbers of isolates of individual organisms were: Pseudomonas
aeruginosa (n = 204), Acinetobacter spp. (n = 48), and Stenotrophomonas
maltophilia (n = 18). MICs were determined using the broth microdilution
susceptibility method with 12 antimicrobial agents: piperacillin,
piperacillin/tazobactam, ceftriaxone, ceftazidime, cefepime, imipenem,
ciprofloxacin, ofloxacin, amikacin, gentamicin, tobramycin, and
trimethoprim/sulfamethoxazole. Based on current National Committee for Clinical
Laboratory Standards breakpoints, rates of resistance to cefepime, ceftazidime,
and imipenem were as follows: P. aeruginosa, 3, 9, and 5%; Acinetobacter spp., 2,
37, and 0%; and S. maltophilia, 88.7, 35.3, and 100%, respectively.
Trimethoprim/sulfamethoxazole was the most active agent against S. maltophilia
(100% susceptible). Twenty-eight isolates of P. aeruginosa that expressed high
levels of resistance to ceftazidime (MIC, > 256 micrograms/mL) and imipenem (MIC,
> 32 micrograms/mL) were examined for potential metallo-beta-lactamase production
by polymerase chain reaction and were found to be negative. Molecular typing of
P. aeruginosa isolates revealed many patient-unique strains, but also noted
clustering of infections due to isolates of the same DNA type, suggesting
possible nosocomial transmission in 9 of 14 medical centers. Given the resistance
profile and pathogenic potential of these non-enteric Gram-negative bacilli,
considerable effort should be exerted to develop and enforce infection control
and antimicrobial utilization practices that will limit the spread of these
organisms in the hospital environment.
PMID- 9401812
TI - Intracerebral mass lesions in patients with human immunodeficiency virus
infection and cryptococcal meningitis.
AB - The frequency of intracerebral mass lesions (ICML) in patients with human
immunodeficiency virus (HIV) infection and cryptococcal meningitis (CM) is not
well established. Cryptococcoma seems to be a rare affliction. The objective of
this study was to analyze the etiology of ICML in patients with HIV infection and
CM. The methodology was a retrospective review of cases diagnosed in two Spanish
hospitals between September 1988 and April 1995. Eighteen cases of CM were
identified. Computed tomography was performed on presentation in 17 cases. Only
one patient had ICML, which progressed while on antifungal treatment and
regressed when anti-Toxoplasma treatment was established. During follow-up, two
additional patients developed ICML and were successfully treated as
toxoplasmosis. Overall, 3 out of 17 patients (18%) developed ICML and all three
were cured when anti-Toxoplasma treatment was implemented. In our study, cerebral
toxoplasmosis was the only presumed cause of ICML. In areas of high prevalence of
toxoplasmosis, ICML in patients with CM may not be cryptococcomas. Consequently,
in these areas of high prevalence, a trial of toxo-therapy should be strongly
considered for patients with CM and ICML.
PMID- 9401813
TI - Comparative antistreptococcal activity of two newer fluoroquinolones,
levofloxacin and sparfloxacin.
AB - The objective of this study was to evaluate the in vitro activity of
sparfloxacin, levofloxacin, ofloxacin, and ciprofloxacin against contemporary
strains of streptococci. Susceptibility testing of a panel of 300 recent clinical
isolates of streptococci (100 each of beta-hemolytic, viridans group, and
Streptococcus pneumoniae) using reference broth microdilution methods was
performed, and the results were compared. Sparfloxacin was the most active of the
four tested fluoroquinolones, inhibiting 99-100% of all isolates at
concentrations of < or = 1 microgram/ml, and was two- to eightfold more potent
than the three comparative agents. Levofloxacin was also quite active, inhibiting
98-100% of the isolates at concentrations < or = 2 micrograms/ml. Both
sparfloxacin and levofloxacin possess an improved spectrum and potency against
contemporary strains of streptococci compared to currently available
fluoroquinolones.
PMID- 9401814
TI - In vitro activity of chloramphenicol alone and in combination with vancomycin,
ampicillin, or RP 59500 (quinupristin/dalfopristin) against vancomycin-resistant
enterococci.
AB - Using a checkerboard assay, ampicillin, vancomycin, and RP 59500, each in
combination with chloramphenicol, were tested for synergy against 23 isolates of
vancomycin-resistant enterococci. Additive effects were seen in 62.5% of the
isolates when exposed to chloramphenicol plus RP 59500. Additive effects were
observed in 20% and 15% of isolates with chloramphenicol plus vancomycin or
ampicillin, respectively. No antagonism was noted.
PMID- 9401816
TI - Protection of rat myocardium by mitogenic and non-mitogenic fibroblast growth
factor during post-ischemic reperfusion.
AB - The effects of acidic fibroblast growth factor (FGF-1) and basic fibroblast
growth factor (FGF-2) and a non mitogenic form of FGF1 on myocardial ischemia and
reperfusion were assessed. Rats underwent 10 minutes of coronary artery occlusion
followed by 24 hours of reperfusion. Creatinine kinase content of the affected
myocardium showed that both fibroblast growth factors 1 and 2 effectively
protected against ischemia reperfusion injury (p < 0.01), and that the vasoactive
but nonmitogenic form of the FGF1 was equally protective (p < 0.01 versus control
+ vehicle). The results were confirmed by light and electron-microscopy
histological studies. Histological evaluations after treatment with the non
mitogenic fibroblast growth factor 1 showed that it did not generate the severe
hyperplasia and connective tissue disorganization observed with the native
mitogenic proteins. The possibility of using a non-mitogenic form of fibroblast
growth factor for cardio-protection circumvents many of the potentially
undesirable effects that may derive from systemically introducing broad spectrum
acting fibroblast growth factors in vivo. This myocardial protection observed 24
hours after the treatment with fibroblast growth factors, and the efficacy of the
non-mitogenic form of the protein, also suggest that the protective effect of
fibroblast growth factors may be due to the increased blood flow rather than to
angiogenesis.
PMID- 9401817
TI - Low level expression of basic FGF upregulates Bcl-2 and delays apoptosis, but
high intracellular levels are required to induce transformation in NIH 3T3 cells.
AB - We investigated the roles of basic fibroblast growth factor (bFGF) in the
transformation and survival of NIH 3T3 cells. We constructed NIH 3T3-derived cell
lines expressing human bFGF using retroviral gene transfer with an N2-based
vector. Clonally derived cell lines containing a single copy of the vector
overexpress bFGF mRNA and produce more immunoreactive protein (0.407 +/- 0.010
3.028 +/- 0.087 ng bFGF/10(6) cells) which is biologically active than
nontransduced (0.151 +/- 0.013 ng bFGF/10(6) cells) or N2-transduced (0.211 +/-
0.029 ng bFGF/10(6) cells) NIH 3T3 cells. All cells producing excess amounts of
bFGF achieve greater density at confluence, show delayed apoptosis and increased
survival and have elevated intracellular levels of Bcl-2. However, only cells
expressing from 8-15 times background levels of bFGF are phenotypically
transformed. The transformed cells form dense foci at confluence, have decreased
adherence to tissue culture plates and grow colonies in soft agar. Exogenous bFGF
induces higher Bcl-2 levels in a dose dependent manner and recapitulates the
antiapoptotic effects of the overexpressed species but fails to induce changes
associated with the transformed phenotype. In this study, we demonstrate a
dissociation between phenotypic transformation secondary to bFGF overexpression
and upregulation of cellular Bcl-2 that correlates with a delay in programmed
cell death. Although low level expression of bFGF or exogenous bFGF is sufficient
to upregulate Bcl-2 and delay apoptosis, high intracellular levels are required
for cellular transformation. These data suggest that overexpression of bFGF
modulates cellular transformation and Bcl-2-mediated inhibition of apoptosis
through alternate molecular mechanisms.
PMID- 9401815
TI - Influence of PDGF-BB on proliferation and transition through the MyoD-myogenin
MEF2A expression program during myogenesis in mouse C2 myoblasts.
AB - We have previously demonstrated that PDGF-BB enhances proliferation of C2
myoblasts. This has led us to examine whether the mitogenic influence of PDGF-BB
in the C2 model correlates with modulation of specific steps associated with
myogenic differentiation. C2 myoblasts transiting through these differentiation
specific steps were monitored via immunocytochemistry. We show that the influence
of PDGF on enhancing cell proliferation correlates with a delay in the emergence
of cells positive for sarcomeric myosin. We further monitored the influence of
PDGF-BB on differentiation steps preceding the emergence of myosin+ cells. We
demonstrate that mononucleated C2 cells first express MyoD (MyoD+/myogenin-
cells) and subsequently, myogenin. Cells negative for both MyoD and myogenin (the
phenotype preceding the MyoD+ state) were present at all times in culture and
comprised the majority, if not all, of the cells which responded mitogenically to
PDGF. Additionally, the frequency of the MyoD+/myogenin+ cell phenotype was
reduced in cultures receiving PDGF, suggesting that PDGF can modulate the
transition of the cells into the myogenin+ state. We determined that many of the
myogenin+ cells subsequently become MEF2A+ and this phenomenon is not influenced
by PDGF-BB. FGF-2 also enhanced the proliferation of C2 myoblasts and suppressed
the appearance of the myogenin+ cells, but did not influence the subsequent
transition into the MEF2A+ state. The study raises the possibility that PDGF-BB
and FGF-2 might delay the transition of the C2 cells into the MyoD+/myogenin+
state by depressing a paracrine signal that enhances differentiation.
PMID- 9401818
TI - Controlled release of leukaemia inhibitory factor (LIF) to tissues.
AB - Leukaemia inhibitory factor (LIF) has been shown to effectively enhance skeletal
muscle regeneration after mechanical injury and it may have potential therapeutic
use in the muscular dystrophies as well as peripheral nerve repair after injury.
When LIF is applied systemically to an animal, it is rapidly removed with a
biological half life of only a few minutes, and at high doses it exhibits toxic
effects. Calcium alginate rods have been developed for the purpose of insertion
adjacent to skeletal muscles. These rods, when charged with LIF will release the
growth factor to the muscle at a rate of less than 1% per day and for a period
extending to several months. In addition, tubes of alginate are described which
will be suitable for the continuous supply of LIF to repaired peripheral nerve.
PMID- 9401819
TI - Placenta growth factor and vascular endothelial growth factor are co-expressed
during early embryonic development.
AB - We have used the polymerase chain reaction to identify mouse proteins similar in
primary structure to the endothelial cell mitogen Vascular Endothelial Growth
Factor (VEGF). One amplified product encoded mouse Placenta Growth Factor (PIGF).
The pattern of PIGF gene expression in mouse embryos was studied by in situ
hybridization. Transcripts encoding mouse PIGF were abundant in trophoblastic
giant cells associated with the parietal yolk sac at early stages of
embryogenesis. VEGF transcripts were also detected in trophoblastic giant cells
raising the possibility that these cells may secrete heterodimers consisting of
one PIGF subunit and one VEGF subunit. The secretion of PIGF and VEGF by
trophoblastic giant cells is likely to be the signal which initiates and co
ordinates vascularization in the deciduum and placenta during early
embryogenesis.
PMID- 9401820
TI - Regulation of gamma-glutamyl transpeptidase activity by Ca(2+)- and protein
kinase C-dependent pathways in Sertoli cells.
AB - gamma-Glutamyl transpeptidase (gamma-GTP) activity in Sertoli cells can be
stimulated by FSH. This cAMP-dependent metabolic event can be enhanced when
Sertoli cells are co-cultured with germ cells, suggesting that different signal
transduction pathways may be involved in the regulation of gamma-GTP activity. In
this study we examined the participation of Ca(2+)- and protein kinase C (pkC)
dependent signal transduction pathways in the regulation of basal and FSH
stimulated gamma-GTP activity. Under basal conditions, the increase in
extracellular Ca2+ concentration or the addition of the Ca2+ ionophore 4Br-A23187
produced a decrease in gamma-GTP activity. Conversely, blockage of voltage
dependent Ca2+ channels with verapamil or nifedipine or inhibition of Ca(2+)
calmodulin dependent processes with trifluoperazine resulted in an increase in
gamma-GTP activity. To study the role of a pkC-dependent pathway the effects of
low doses of staurosporine were evaluated. Under these experimental conditions an
increase in gamma-GTP activity was observed. It was then investigated whether
these signal transduction pathways could interact with the FSH-stimulated cAMP
dependent pathway to regulate gamma-GTP activity. Increase in extracellular Ca2+
concentration, the addition of 4Br-A23187 or the blockage of voltage-dependent
Ca2+ channels did not modify FSH-stimulated gamma-GTP activity. However,
staurosporine produced an additional increase in FSH-stimulated gamma-GTP
activity and this effect was also observed when cells were stimulated with
dbcAMP. In summary, our data are consistent with an inhibitory role of Ca(2+)
calmodulin- and pkC-dependent pathways in the regulation of basal gamma-GTP
activity. Similar to what has been shown for other Sertoli cell parameters, a pkC
dependent pathway can interact with the FSH-stimulated cAMP-dependent pathway.
The precise steps involved in this interaction are still unknown.
PMID- 9401821
TI - Influence of oxygen tension on reactive oxygen species production and human sperm
function.
AB - Human spermatozoa were exposed to the reduced form of nicotinamide adenine
dinucleotide phosphate (NADPH) to stimulate endogenous production of reactive
oxygen species (ROS). They were incubated under a gas phase of 5% CO2/90% N2/5%
O2, or 5% CO2/95% air (20% O2) to investigate whether a lower than atmospheric
oxygen tension in the gas phase of the incubator limited the endogenous
production of ROS by human spermatozoa and thus was able to reduce the cytotoxic
effects of ROS on sperm function. Exposure of human spermatozoa or exogenous
NADPH induced an 8-fold higher production of superoxide anion under ambient vs.
low oxygen tension. This marked difference in the stimulation of superoxide anion
generation was associated with significantly different sperm motility parameters,
according to the oxygen tension in the gas phase of the incubator. Whereas under
5% oxygen the percentage of motile spermatozoa was unaffected by the presence of
NADPH, all of the motility parameters recorded under an atmosphere of 5% CO2 in
air were dramatically affected, not only compared to their respective controls,
but also compared to the motility parameters observed under low oxygen tension.
The presence of superoxide dismutase plus catalase protected spermatozoa against
the toxic effects of NADPH, confirming a cause/effect relationship between the
increased superoxide production and reduced sperm function. Even at a
concentration of NADPH which did not alter the percentage of motile spermatozoa,
hyperactivated motility and acrosome reaction were significantly lower under an
atmosphere of 5% CO2 in air compared to a gas phase of 5% CO2/90% N2/5% O2. These
results suggest that there is an advantage in using 5% O2 rather than 20% O2 in
the gas phase of the incubator to prevent the excessive production of ROS by
spermatozoa and related alterations of sperm functions. This may be of clinical
value in fertilization programmes.
PMID- 9401822
TI - Semen analysis performed by different laboratory teams: an intervariation study.
AB - Some recent studies have indicated that sperm concentration has decreased during
the last 50 years. However, comparisons between laboratories have revealed that
geographical differences seem to exist and that any decrease may not be global.
One point of criticism concerning comparison of results from different
laboratories has been that some of the discrepancies detected could reflect the
lack of standardized methods used in the different laboratories. Four teams, each
consisting of one physician and one technician from groups which have recently
published data on semen quality, met in order to evaluate the variability between
their laboratories on semen analysis. Twenty-six fresh semen samples from
unselected men were analysed. The groups analysed the samples according to the
normal practice in their laboratories, using their own equipment. The variation
between laboratories was estimated through a random effects model. For sperm
concentration and semen volume assessment a remarkable consistency between
laboratories was detected, in contrast to the very considerable inter-individual
variation. For sperm motility and morphology assessments interlaboratory
consistency was much poorer. In conclusion, evaluation of sperm motility and
morphology characteristics requires further standardization in order to achieve
comparable data from different laboratories. However, semen volume and sperm
concentration are characteristics which can be compared reliably between
laboratories, when similar methodologies are used.
PMID- 9401823
TI - Sperm counts in semen of farm animals 1932-1995.
AB - In some countries, sperm counts in normal human semen seem to have declined over
the last 50 years. If this decline is real and due to environmental factors,
falls might also be seen in sperm numbers in the semen of farm animals. Sperm
counts are available for bull, boar and ram from the early 1930s, obtained using
techniques similar to those used for human semen. Data have been obtained from
the literature between 1932 and 1995 from 137 studies involving bulls, 76
involving boars and 130 involving rams. All were normal adult animals, from which
semen was collected regularly but at a frequency which would not be likely to
cause a fall in sperm counts. The references were obtained systematically from
Animal Breeding Abstracts, and where possible the original articles were
consulted to obtain mean values for each study; where the original reference was
not easily obtainable, values were taken from the abstract. The bull data showed
no correlation of sperm count with year of publication (r2 = 0.000), for the
boars there was a slight but non-significant positive correlation (r2 = 0.041),
and for the sheep there was a slight, but significant, rise in sperm counts with
time (r2 = 0.124 for sperm counts and 0.126 for total sperm per ejaculate; not
all authors gave both values). It would appear that, if the fall in human sperm
counts is real, then it must be due to something which is not affecting farm
animals.
PMID- 9401824
TI - Estimating familial and genetic contributions to variability in human testicular
function: a pilot twin study.
AB - The biological basis for the remarkably wide variation in sperm output between
and within men remains unclear. Although some contributing factors have been
identified, the familial and genetic contributions to variation in human sperm
output have been little studied, although such sources of variation are known to
be significant in experimental animals. In order to identify such familial and
genetic factors in a classical twin study design, we recruited monozygotic and
dizygotic twins aiming to study the degree of resemblance between genetically
identical and non-identical twins in sperm output, testis size and testicular
endocrine function. From an approach to 160 twin pairs on the Australian Twin
Register database, eventually 17 pairs of male twins (11 monozygotic and six
dizygotic) participated in this study. Sperm concentration and output, right
testis size and SHBG all exhibited a strong familial effect but a genetic
component could not be confirmed. Total and free testosterone exhibited a genetic
component. Although identifying for the first time a clear familial component to
normal human spermatogenesis, this study had insufficient power to determine
whether there was a genetic component, nor could its design distinguish between
genetic or shared (early) environmental determinants for these familial effects.
Implications for future twin studies of human testicular function including
stronger recruitment strategies, multi-centre studies and surrogate variables for
human spermatogenesis are suggested.
PMID- 9401825
TI - Apoptosis as a mechanism of germ cell loss in elderly men.
AB - In comparison with other mammals, human spermatogenesis is known to be an
inefficient process, of which germ cell degeneration is a normal part. This study
was performed to determine the mechanism of cell death in the testes of elderly
men. Testes from 20 patients undergoing orchidectomy for prostate cancer were
fixed, sectioned and processed for the detection of apoptosis using the in situ
end-labelling technique. In addition, the formation of DNA ladders, a hallmark of
apoptosis, was also investigated. Occurrence of apoptosis was not confined to a
particular germ cell population but comprised all types of germ cells. Sertoli
cell apoptosis was not encountered. The numbers of degenerating germ cells were
determined per standard reference area, but no significant relationship was found
between the mean values and age or testis weight. Analysis of the median values
for germ cell death per reference area suggested that apoptosis occurs in
clusters within the testis but is a rare occurrence outside these areas. It is
concluded that spontaneous apoptosis can mediate germ cell death in a variety of
cell types in the aged human testis.
PMID- 9401826
TI - Histochemical demonstration of zinc ions in ejaculated human semen.
AB - A revised in-vitro technique for autometallographic demonstration of chelatable
zinc in the human ejaculate is presented, and the localization of the loosely
bound pool of zinc ions is described in semen smears and at the ultrastructural
level. In semen smears, black autometallographic (AMG) grains indicated the
presence of zinc ions dispersed between the spermatozoa. These AMG grains have
the same size as grains associated with the sperm tail and may have the same
origin. EM analysis of AMG-developed smears fixed in osmium suggested that the
detected zinc ions might be related to huge protein molecules present in semen
and adhering to the surface of the spermatozoa. Spermatozoa in AMG-stained smears
exhibited zinc ions in the midpiece and head, and also joined to the membrane of
the tail. Washed spermatozoa exhibited zinc ions only within the midpiece.
Ultrastructurally, they were found located in the helecine mitochondria. A few
grains were found in the acrosome of the washed spermatozoa. Treatment with the
chelating agent DEDTC resulted in complete bleaching of the zinc staining. These
findings and the fact that calcium EDTA acid blocks the plasma and surface
staining, but not the acrosomal and mitochondrial staining, suggest that
chelatable zinc ions exist in two separate pools in human semen.
PMID- 9401827
TI - Effect of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN
gamma) on human sperm motility, viability and motion parameters.
AB - Male genital tract infections and non-specific inflammatory conditions may be
associated with unexplained infertility. Previous studies have shown the presence
of cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interferon
gamma (IFN-gamma) in the semen of infertile men. However, the mechanism of effect
of these cytokines on human sperm function is still controversial. The present
study was undertaken to investigate the in-vitro effects of TNF-alpha and IFN
gamma on human sperm motion, viability and the hypoosmotic swelling test (HOST).
Washed spermatozoa from normal volunteers (n = 9) were incubated in the
presence/absence of TNF-alpha (1 microgram/mL) plus IFN-gamma (0.1 microgram/mL).
Sperm motility, viability, HOST, and video sequences were recorded at different
time intervals (0, 30, 60 and 180 min). Sperm motion parameters were analysed
using computer-assisted semen analysis. There was a time-dependent negative
effect of TNF-alpha plus IFN-gamma on sperm motility, viability, HOST, and
lateral-head displacement (ALH). The maximum decrease was observed between 60 and
180 min for sperm motility (50.8 +/- 5.6%), viability (52.8 +/- 4.0%), HOST (38
+/- 2%) and ALH (4.7 +/- 0.1 microns) compared to control samples (62.2 +/- 2.8,
62.4 +/- 2.9, 58 +/- 4, and 5.3 +/- 0.4, respectively; All p < 0.05). There was
no significant effect on sperm straight-line velocity and mean linearity when
compared to control. These data suggest that the common inflammatory cytokines
TNF-alpha plus IFN-gamma have only partial detrimental effects on sperm motility,
viability, membrane integrity and lateral head displacement, which may contribute
to the poor fertilizing potential of human spermatozoa during inflammatory
conditions.
PMID- 9401828
TI - Stage-specific degeneration of germ cells in the seminiferous tubules of non
obese diabetic mice.
AB - The cause of fertility problems in insulin-dependent diabetes is largely unknown.
To evaluate the role of autoimmunity-associated phenomena in the testis as a
possible cause of the derangement in spermatogenesis, the stage-specific
apoptosis of germ cells in the insulitis phase of pre-diabetes was quantified in
the testes of non-obese diabetic (NOD) mice. The seminiferous epithelium of
normal BALB/c and NOD mice contained cells positive for in-situ end-labelling
(ISEL) of DNA. ISEL-positive germ cells formed clusters in the seminiferous
epithelium of the NOD mice in marked contrast to the seminiferous epithelium of
the BALB/c mice, which contained only individual cells positive for ISEL. ISEL
positive cells were present in the basal and luminal compartments of the
epithelium. Ultrastructural analysis and demonstration of externalized
phosphatidyl serine confirmed that the cells were undergoing apoptosis. The
ultrastructurally apoptotic cells included spermatogonia, spermatocytes and
spermatids. In cytological squash preparations of segments of seminiferous
tubules from NOD mice aged 17-20 weeks, the number of ISEL-positive cells/mm
tubule was significantly lower in segments at stages I-II of the seminiferous
epithelial wave but higher at stages III-IV in comparison to BALB/c mice. The
numbers of ISEL-positive cells/mm tubule in the other stages were similar in the
two strains of mice. Analysis of 32P-3'-end labelled DNA from the testes showed
that the BALB/c mice had relatively more DNA fragmentation than did the NOD mice.
These data suggest that autoimmune insulitis in the NOD mice is associated with
increased amounts and abnormal stage distribution of apoptosis in the
seminiferous epithelium, resulting in derangement of spermatogenesis.
PMID- 9401829
TI - The safety and tolerability of single intravenous doses of lubeluzole (Prosynap)
in healthy volunteers.
AB - The safety and tolerability of single escalating doses of lubeluzole were
evaluated in healthy male volunteers in 2 studies. In the first of 2 randomized,
single-blind, placebo-controlled, dose-escalation studies, 6 subjects received
single 30-minute infusions of 2.5, 5, and 10 mg of lubeluzole, and 2 additional
subjects received placebo. In the second study 6 different subjects received a 1
hour infusion of 15 mg of lubeluzole, 5 of whom received the 20-mg dose, and 2
received 25 mg of lubeluzole. Two additional subjects received placebo. Small
increases and decreases in PQ, QRS, QT, QTc, and QTm intervals were noted after
infusion of all lubeluzole doses and placebo, however, these changes were within
the normal ranges for these values except for the QTc for the 25-mg dose of
lubeluzole. Significant prolongation of the QTc interval was observed at the end
of the 1-hour infusion in both subjects receiving the 25-mg dose of lubeluzole.
No clinically relevant changes in systolic time intervals, heart rate, blood
pressure, and clinical laboratory values were noted in subjects receiving 2.5-25
mg of lubeluzole or placebo. Adverse experiences, predominantly lightheadedness
and dizziness, were reported by subjects receiving doses of lubeluzole greater
than or equal to 10 mg. Lubeluzole, administered as single intravenous doses of
2.5-15 mg, is safe and well tolerated in healthy male volunteers.
PMID- 9401830
TI - A single and multiple dose bioavailability study with carbamazepine 400 mg retard
tablets with reference to enzyme autoinduction and circadian time differences.
AB - Both single and multiple dose bioequivalence studies are required to assess the
quality of modified release formulations of drugs. In bioequivalence studies of
drugs with enzyme autoinducing properties such as carbamazepine (CBZ), the
standard multiple dose study design must be modified to guarantee equivalence of
drug elimination. This problem was considered with regard to carbamazepine 400
retard AWD (test) whose bioavailability relative to a listed reference (Tegretal
400 retard) was studied in 2 randomized, open, crossover studies both with 18
healthy volunteers of Caucasian origin (20-36 years, 61.5-92 kg, 172-195 cm). The
single dose study was done with 400 mg CBZ. Serum concentration time profiles of
CBZ and its active metabolite CBZ-10,11-epoxide were determined until 144 h after
administration. The multiple dose study was performed with 400 mg CBZ b.i.d. for
15 days (first 2 days: 200 mg b.i.d.) followed by a 7-day study with the
alternative investigational product. 24-hour serum concentration time profiles of
CBZ and its metabolite were measured on days 15 and 22 of the study. The
quantitative drug analysis was done with an HPLC method the quality of which
fulfilled the requirements of bioequivalence studies. Test was considered
bioequivalent to reference with regard to the extent of absorption, if the 90%
confidence intervals of the AUC0-infinity ratio (single dose) and AUC0-24h ratio
(multiple dose) were within the range of 0.80-1.25, and with regard to rate of
absorption if the 90% confidence intervals of the Cmax/AUC ratio (single dose) or
AUCF0-24h ratio were within 0.70-1.43. The point estimators (90% confidence
limits) of the AUC ratio (test/reference) of CBZ were 0.979 (0.94, 1.02) for the
single and 1.01 (0.947, 1.076) for the multiple dose comparison. The point
estimator (90% confidence limits) of the Cmax/AUC ratio was 0.989 (0.959, 1.020)
and of the AUCF0-24h ratio 1.066 (0.937, 1.212). There were no circadian time
differences in any pharmacokinetic parameter. IN CONCLUSION: Carbamazepine 400
retard AWD tablets were bioequivalent to reference with regard to extent and rate
of absorption after both single and multiple dose administration.
PMID- 9401831
TI - An alternative analysis for crossover studies that accounts for between-group
disparities in drug response.
AB - BACKGROUND: In crossover clinical trials comparing completely different
treatments patients tend to fall apart into different populations: those who
respond better to treatment 1 and those who do so to treatment 2. The correlation
between treatment response in such trials is negative. The current ANCOVA
analysis for crossover studies does not allow for correlations being negative,
and is, therefore, not adequate to test this kind of trial. OBJECTIVE OF STUDY:
To study whether matrix algebra provides a more appropriate approach for this
purpose. RESULTS AND CONCLUSIONS: Using a mathematical model as well as
hypothesized examples I demonstrate that matrix algebra of 2 pairs of cells of
the same order not only allows for negative correlations in a crossover design
but also provides enough power to test both treatment and carryover effect.
PMID- 9401832
TI - A reliable and convenient parameter of the rate of paracetamol absorption to
measure gastric emptying rate of liquids.
AB - The rate of paracetamol absorption represents gastric emptying rate (GER) of
liquids. Thus, the liquid GER is assessed by conventional pharmacokinetic
parameters such as the maximum concentration and the time to maximum
concentration after oral administration of paracetamol. However, the conventional
parameters are subject not only to the rate but also to the extent of absorption.
For the reliable assessment of GER we have proposed a new parameter, the
C0.5/C0.25 ratio, for the rate of paracetamol absorption without being affected
by the extent of absorption. Of 15 healthy male volunteers, 9 orally received 10
mg/kg of paracetamol with 200 ml of water as the "normal" GER group, and the
other 6 took 10 mg/kg of paracetamol with 200 ml of a liquid nutrient (200
kcal/200 ml), which delays GER, as the "delayed" GER group. Blood samples were
obtained at t = 0 (pre-dose), 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and
8.0 hours (post-dose). In each subject, GER was assessed by the conventional
parameters, the C0.5/C0.25 ratio, and the Wagner-Nelson method which provides an
accurate estimate of the drug absorption rate. Using the C0.5/C0.25 ratio and the
Wagner-Nelson method we could more clearly differentiate the delayed GER group
from the normal GER group than by using the conventional parameters. This
suggests that the C0.5/C0.25 ratio and the Wagner-Nelson method may be more
reliable than the conventional parameters in detecting a delay in GER. Further,
it should be noted that the C0.5/C0.25 ratio can be calculated from only 2 blood
samples while the Wagner-Nelson method requires repeated blood sampling.
PMID- 9401833
TI - Crossover comparison of the pharmacokinetics of amlodipine and felodipine ER in
hypertensive patients.
AB - The pharmacokinetics of amlodipine 5 mg and felodipine ER (extended release) 5 mg
o.d. after single and 2 weeks of repeated oral doses, were compared in 28
essential hypertensive patients using a crossover design. As a secondary
parameter the effects of the drugs on blood pressure were assessed. Significant
differences were found between all principal pharmacokinetic variables, when
comparing the 2 treatments after both single and repeated dosing. The
coefficients of variation of maximal drug concentration and AUC after single
dosing and at steady-state were significantly higher for felodipine ER than for
amlodipine. After repeated dosing the peak-to-trough plasma concentration ratio
were 1.58 and 4.43 (p < 0.001) for amlodipine and felodipine ER, respectively.
Both drugs lowered systolic and diastolic blood pressure to the same extent after
2 weeks of repeated dosing. No significant differences between the blood pressure
lowering vs time profile of the 2 drugs were encountered. In conclusion, the
interpatient drug concentration variability and the peak-to-trough plasma
concentration ratio were more favorable for amlodipine compared to felodipine ER.
It remains to be established whether these characteristics are also reflected in
a more smooth and consistent blood pressure control.
PMID- 9401834
TI - Metoclopramide plasma concentration in neonates.
AB - During the course of a multiple-dose metoclopramide (M) oral treatment, M plasma
concentrations were measured just before (Cmin) and 1 hour after the
administration (C1h) at steady-state in 5 (3 premature and 2 term) neonates. Mean
Cmin was equal to 91.6 +/- 45.5 ng/ml and higher than C1h (87.4 +/- 43.2 ng/ml),
but not significantly. A significant negative correlation was found between Cmin
plasma concentration and gestational age as well as with postconceptional age,
suggesting that the lower the gestational and postconceptional age, the lower the
metoclopramide dosage should be.
PMID- 9401835
TI - No need to adjust the dose of 311C90 (zolmitriptan), a novel anti-migraine
treatment, in patients with renal failure not requiring dialysis.
AB - 311C90 ("Zomig", zolmitriptan), is a novel and selective, centrally and
peripherally acting 5 HT1B/1D receptor agonist in development for the acute, oral
treatment of migraine. We have conducted a parallel group study in patients with
moderate/severe renal impairment (creatinine clearance < or = 40 ml/min) and age-
and sex-matched healthy volunteers (creatinine clearance > or = 60 ml/min). All
subjects received a single, 10 mg dose of 311C90. Mean peak concentrations of
311C90 and its pharmacologically active N-desmethyl metabolite (183C91) were
similar in both groups although AUC0-infinity for 183C91 was increased by 35% in
the renally impaired patients. Other pharmacokinetic parameters were little
changed apart from the expected reduction in CLR and urinary recovery and a small
increase of 0.9 and 1.0 h, respectively, in the mean half-lives of 311C90 and
183C91. For the 2 inactive metabolites, the N-oxide (1652W92) and the indolacetic
acid (2161W92), mean peak concentrations were approximately 3 times higher in
renally impaired patients than in healthy volunteers and AUC0-infinity was 6-7.5
times higher. CLR for these metabolites was approximately 90% lower in renal
impairment and half-life of both was increased approximately 3-fold. Baseline
blood pressures were higher in the renally impaired group. After 311C90 there was
a transient, small increase in blood pressure in both groups. There was little
difference in the increase in diastolic blood pressure between the groups (16
mmHg in both) but the rise in systolic blood pressure was greater in the renally
impaired group (23 mmHg vs 16 mmHg in healthy subjects). The lack of substantial
changes in the plasma concentrations of both parent compound and 183C91, and the
similarity of the changes in blood pressure, in renally impaired subjects
compared to healthy volunteers suggest that there is no reason to adjust the dose
of 311C90 in patients with renal impairment.
PMID- 9401836
TI - A new route, jet injection for anesthetic induction in children--III. Ketamine
pharmacokinetic studies.
AB - The jet injector route for ketamine was used on 30 children 1-6 years of age
undergoing various surgical procedures. A randomly selected dose of 2.5, 3.5, or
6.0 mg/kg of ketamine was given to induce anesthesia. Peak plasma ketamine levels
did not follow a simple arithmetic increment related to dose. Dosage based on
mg/m2 body surface area or mg/kg body weight provided similar blood levels of
ketamine. The beta-phase t1/2 of ketamine in these children was shorter than that
found in adults. Considerable individual variability was observed in both the
plasma levels to a given dose of jet-injected ketamine and in the beta-phase
t1/2. The ketamine beta-t1/2s were not dose related.
PMID- 9401837
TI - Influence of acute renal failure on FPIA rapid serum assay of midazolam and its
main metabolite.
AB - We recently developed a simple and fast assay technique, providing the
possibility of monitoring of midazolam (M) during sedation. We compared HPLC vs
FPIA for the measurement of the sum M plus alpha 1-hydroxymidazolam (OM), its
main and pharmacologically active metabolite, in the serum of sedated ICU
patients; this activity referred to as M-like. We identified certain patients in
whom M-like activity appeared abnormally high in comparison with HPLC assays.
Their common denominators were: long-term sedation with M, and seriously impaired
renal function. Further, the conjugates of OM (OMG) accumulated in patients with
acute renal failure could contribute to the sedation. We compared the metabolic
and analytic behavior of M, OM, and OMG in 2 groups of sedated patients either
presenting with normal renal functions (group 1) or with a picture of acute renal
failure (group 2). Blood samples were assayed by HPLC and by FPIA and analysis
was performed before and after hydrolysis of OMG. Before hydrolysis there was a
dramatic accumulation of OMG in the patients of group 2, HPLC vs FPIA results
were not different within group 1, while in group 2 the FPIA response exceeded
that of HPLC. After hydrolysis, measurement by HPLC was greatly increased in
group 2, in each group (vs HPLC) and from one group to another, the FPIA signal
(the M-like activity) showed a significant increase. It would be important to
take OMG into account as a coprotagonist in sedation whenever circumstances
predispose to its accumulation.
PMID- 9401838
TI - Straight ileoanal anastomosis with multiple ileal myotomies as an alternative to
pelvic pouch.
AB - An alternative technique of restorative proctocolectomy, by means of straight
ileoanal anastomosis with multiple myotomies (SIAM) of the terminal ileum in 15
patients, nine with familial adenomatous polyposis (FAP) and six with ulcerative
colitis (UC) is reported. SURGICAL TECHNIQUE: Eight to ten longitudinal myotomies
(3-4 cm long, on three different circumferential sites) were performed on the
terminal ileum for a total length of 12-14 cm. CLINICAL RESULTS: At a mean follow
up of 44 months (range 3-84 months) from the closure of the ileostomy, daytime
continence was achieved in all the patients; stool frequency per 24 hours (+/-
SD) was 4.1 +/- 1.8 for FAP patients and 5.8 +/- 1.7 for UC patients; nocturnal
defecation was 1.0 +/- 0.5 and 1.2 +/- 0.8 for FAP and UC patients respectively;
frequent nocturnal soiling was present in 2/5 of UC patients, and in 3/9 of FAP
patients. SIAM failed in one UC patient that was converted to an ileoanal
reservoir because of poor functional result. Signs of ileal mucosal inflammation
were never observed at endoscopic examination. Histopathological assessment
showed no evidence of acute terminal ileitis. MANOMETRIC FINDINGS: A significant
postoperative reduction in anal resting pressure was observed after SIAM. Neither
the absence of anal inhibitory reflex nor the presence of high pressure waves
generated in the terminal ileum during air insufflation were related to the
presence of soiling. The closure of the loop ileostomy was followed by an
increased capacity and distensibility of the terminal ileum. Values of neorectal
compliance were similar in FAP and UC patients although FAP patients were able to
reach higher values of maximum tolerated volume and pressure. CONCLUSIONS: 1)
SIAM can be an alternative to pelvic pouch in patients who have undergone
restorative proctocolectomy when the construction of the pouch is not feasible.
2) The functional result observed after SIAM has been shown to be similar to that
observed after pouch construction.
PMID- 9401839
TI - Risk of invasive carcinoma in colorectal adenomas assessed by size and site.
AB - BACKGROUND: The risk of invasive carcinoma developing in colorectal adenomas is
influenced by a number of characteristics of both patients and adenomas, and the
composition of the sample analysed. PATIENTS AND METHODS: Between 1978 and 1993
more than 20,000 polyps were prospectively documented at the Erlangen Registry of
Colorectal Polyps, and analysed statistically by logistic regression. RESULTS:
The size of the adenomas proved to be the most important factor for adenomas
equal to or larger than 15 mm as compared with smaller lesions. In 5,137
diminutive adenomas (< or = 5 mm) invasive carcinoma was never found. Adenomas in
the right-sided colon had a lower risk than those in the left colon or rectum,
but with increasing adenoma size, the malignancy rate showed a right-sided shift.
In adenomas of up to 36 mm in diameter, invasive carcinoma was found more often
when they were located in the rectum or left colon while adenomas larger than 36
mm were more likely to harbour invasive carcinoma when located in the right or
left colon rather than in the rectum. CONCLUSIONS: A multivariate analysis of
11,380 adenomas detected at the first total colonoscopy showed that the factors
size and site, both of which can be assessed by endoscopic inspection alone, were
found to enable a statistically and clinically adequate assessment of the
malignancy risk.
PMID- 9401840
TI - Extended mesenteric excision in right hemicolectomy for carcinoma of the colon.
AB - Between 1979 and 1989, 169 patients had a curative operation for right sided
colonic cancer. A retrospective analysis of the incidence and degree of lymph
node metastasis was performed in all and survival rate was determined in 144
patients who could be followed over a period of 5 years or more. In all patients,
dissection involved the removal of right colon (i.e., caecum, ascending colon,
and right side of transverse colon). Dissection of regional lymph nodes in 84
patients (group 1) involved the removal of mesocolic lymph nodes related to the
segment of the removed intestine. In 60 patients (group 2) dissection was
extended to the nodes situated anterior to mesenteric and retropancreatic
vessels. Morbidity and mortality rates were similar in the two procedures. The
number of lymph nodes and the level of apical node examined were significantly
different in the two groups. The 5-year survival rates showed no statistically
significant difference, but in group 2 three of the nine patients with metastasis
to N4 nodes are free of disease, surviving at 7, 12 and 14 years, respectively.
The principle of extensive lymph node dissection is proposed as a procedure that
supplies more accurate staging and might reduce the incidence of loco-regional
recurrence.
PMID- 9401841
TI - Magnetic resonance imaging in the management of fistula in ano.
AB - Fistula-in-ano is a common condition in which accurate diagnosis of the fistula
track is essential as inadequate assessment and surgical treatment may lead to
multiple unnecessary operations and may also render the patient incontinent.
Several studies have suggested that Magnetic Resonance Imaging (MRI) can
accurately identify the fistula track in relation to the sphincter complex. The
aim of this study was to investigate the value of the routine use of completely
non-invasive pre-operative MRI in patients with suspected fistula-in-ano. Each
scan was reported by a consultant radiologist on two occasions to determine
whether the radiologist's opinion had changed and/or become more accurate with
further experience. Surgical assessment of the fistula was performed under
general anaesthesia by one surgeon without knowledge of the result of the MRI
scan. The results of the surgical assessment and the MRI scan were compared and
the surgical procedure completed. Thirty three patients with a clinical diagnosis
of fistula-in-ano were treated and 27 subsequently confirmed to have a fistula.
MRI detected 42% of tracks, identified correctly on initial assessment which
increased to 50% at the end of the study, 63% and 74% of internal openings, 33%
and 46% of external openings and 50% and 33% of abscesses. These data suggest
that there is a learning curve for radiologists undertaking MRI scanning for
fistula in ano, this is probably because the pathology of fistula in ano and
anatomy of the anal sphincter complex are relatively new to radiologists. Routine
MRI scanning of patients with fistula-in-ano is not necessary but there may be a
role for MRI in assessing complex or difficult fistulae.
PMID- 9401842
TI - Reliability of pudendal nerve terminal motor latency.
AB - AIM: To evaluate reliability of Pudendal Nerve Terminal Motor Latency (PNTML).
METHODS: Forty healthy subjects, 24 women and 16 men, and eight female patients
were included. Four patients had idiopathic faecal incontinence and 4 an anal
sphincter rupture after child-birth. PNTML measurement was performed by two
observers with the patient in left lateral and supine position. Examinations were
repeated on another day to evaluate intraindividual reproducibility. RESULTS:
Interobserver reproducibility was 92%-116% for PNTML. Degree of agreement for
PNTML between left lateral and supine position was 86%-111%. Intra-individual
reproducibility in the supine and left lateral positions was 89%-109% and 88%
113% respectively. Normal values for mean PNTML were higher in women compared
with men, 1.91 msec (2 SD, 0.52 msec) and 1.74 msec (2 SD, 0.33 msec)
respectively, t = 2.44, 37 DF, P < 0.01. CONCLUSIONS: Reliability of PNTML in
terms of interobserver and intraindividual reproducibility was high. Women had
higher normal values for PNTML than men.
PMID- 9401843
TI - Emergency large bowel surgery: a 15-year audit.
AB - OBJECT: To evaluate the management of patients presenting with colorectal
emergencies. METHOD: Computerized audit of patients undergoing urgent/semi-urgent
surgery in the Colorectal Service, University Department of Surgery, Wellington
School of Medicine, NZ. RESULTS: 246 patients underwent major emergency or semi
emergency operations. Consultants performed 144 operations. The complications of
cancer and diverticular disease were the commonest indications for surgery.
Patients with inflammatory processes required significant perioperative
nutrition. The disease site varied with the pathology. Overall the sigmoid colon
was the commonest. Resection and anastomosis was generally performed for right
sided lesions whereas Hartmann's operation was the commonest procedure for more
distally situated non neoplastic lesions. A loop diverting stoma was used most
commonly in patients with obstructing cancer. The most frequent post-operative
complication was urinary tract infection. Four patients developed pulmonary
embolism, 2 ARDS, 4 myocardial infarction and 1 CVA. Persistent intra-abdominal
sepsis requiring drainage occurred in five patients. There were 6 anastomotic
leaks. 3 patients were re-operated upon to relieve post-operative small bowel
obstruction. The overall post-operative mortality rate was 6.9%. CONCLUSION: A
cautious policy of resecting right sided lesions and either diversion or
resection without anastomosis for patients presenting acutely with left-sided
colonic lesions resulted in a low overall mortality rate.
PMID- 9401845
TI - Ambulatory anorectal manometric findings in patients before and after
haemorrhoidectom.
AB - The physiological abnormalities in piles before and after surgery were studied by
an ambulatory prolonged anorectal manometric technique. Eighteen consecutive
patients (12 men, 6 women; mean age 43.6 [standard error of mean, 3.3] years)
with 3 prolapsed irreducible piles were prospectively recruited.
Haemorrhoidectomy was performed with excision of 3 piles. The anal and rectal
pressures were monitored before and at a mean 7.8 (1.5) weeks after surgery when
the wounds had healed, for a mean period of 361.3 (47.8) min. The maximum anal
pressures dropped significantly from a mean 325 (15.5) mmHg before to 213 (24.9)
mmHg after surgery (P < 0.05). Ultraslow wave activity was clearly identified in
11 of 18 patients (61%) before surgery, but not found on post operative studies.
The maximum rectal pressures were also significantly reduced after surgery (196.8
[23.2] mmHg before, 75.5 [10.6] mmHg after; P < 0.05). These findings help to
confirm that haemorrhoidectomy leads to changes in the anorectal physiological
findings.
PMID- 9401844
TI - Screening for colorectal neoplasia with faecal occult blood testing compared with
flexible sigmoidoscopy directly in a 55-56 years' old population.
AB - Reduced mortality from colorectal cancer may be achieved by screening with faecal
occult blood testing. Screening for neoplasia in the rectum and sigmoid colon
with flexible sigmoidoscopy is suggested to be more effective, particular among
persons between 50 and 60 years of age. A cohort of 6367 persons 55-56 years of
age were randomised to screening with rehydrated Hemoccult II tests (HII group)
or with flexible videosigmoidoscopy directly (FS group). In the HII group 59%
(1893/3183) attended, compared to 49% (1353/3184) in the FS group. Of the 1893
persons who attended in the HII group, 4% had a positive HII test and in 13%
(10/78) of them a neoplasm > or = 1 cm in the rectum or sigmoid colon was
diagnosed by endoscopy. The corresponding rate in the FS group was 2.3%. Overall
the number of persons with a neoplasm > or = 1 cm diagnosed in the HII group was
10 and in the FS group 31. A subgroup in the flexible sigmoidoscopy group, who
also performed rehydrated HII tests, showed a sensitivity of the HII test for
neoplasia > or = 1 cm of 26% and a specificity of 95.6%. To find a neoplasm > or
= 1 cm in the rectum or sigmoid colon, 44 examinations were needed when using
flexible sigmoidoscopy directly and 7 examinations when only those with positive
HII tests were examined. In mass screening for neoplasia in the rectum and
sigmoid colon, the relatively low prevalence of colorectal neoplasia at 55-56
years of age makes primary selection with rehydrated Hemoccult testing an
alternative to the resource-consuming endoscopy of all invited persons.
PMID- 9401846
TI - Is mechanical bowel preparation really necessary for elective left sided colon
and rectal surgery?
AB - The value of mechanical bowel preparation for elective left sided colorectal
surgery is debatable. This retrospective study evaluates the incidence of wound
infection, wound dehiscence, abdominal/pelvic collections and anastomotic
dehiscence between patients who received mechanical bowel preparation [MBP] (n =
61) and those who did not (n = 75). The case notes of 136 consecutive patients
undergoing elective left sided colorectal surgery over a three year period in a
district general hospital were reviewed. The incidence of infective and
anastomotic complications between the two groups was not significantly different.
There were two post-operative deaths, both in patients receiving MBP. We
therefore conclude that the role of MBP in the era of systemic antibiotics must
be questioned. A prospective randomised multicenter trial recruiting an adequate
number of patients undergoing elective left sided colorectal procedures would
clarify this long standing debate. Note: Presented at the Spring Meeting of the
Minnesota Surgical Society in Rochester, Minnesota, USA, May, 1996 and to the
American Society of Colon and Rectal Surgeons (ASCRS), Seattle, Washington, June
1996, and published in abstract form in Diseases of the Colon and Rectum (1996)
39:A47.
PMID- 9401847
TI - Correlation of pudendal nerve terminal motor latency with the results of anal
manometry.
AB - Denervation to the external anal sphincter is commonly found in disordered
defaecation. AIM: To determine whether a correlation exists between pudendal
nerve terminal motor latency (PNTML) and anal manometry and what influence an
external sphincter defect (ESD) has on any correlation. METHOD: Sixty seven
consecutive patients (23 constipated, 44 incontinent) were analysed. All had
results available for PNTML and anal manometry. Anal ultrasound performed in the
later part of the study period was available in 46 patients. RESULTS: A
significant negative correlation was found between the mean PNTML and squeeze
pressures (SP) for incontinent patients (r = -0.32, P = 0.037). No significant
correlation was seen in constipated patients. A coexisting ESD was found in 57%
of the 46 patients studied. In those without an ESD a significant negative
correlation was found between mean PNTML and SP (r = -0.50; P = 0.026). No
correlation was found in patients with an ESD. Age did not significantly affect
the PNTML or SP results, but was associated with a reduced resting pressure (r =
0.34; P = 0.005). CONCLUSIONS: The PNTML was significantly correlated with SP in
patients with incontinence and in the subgroup of patients without an ESD. In the
assessment of disordered defaecation PNTML is therefore recommended as an adjunct
to anal ultrasound.
PMID- 9401848
TI - Electrostimulated gracilis neosphincter for faecal incontinence and in total
anorectal reconstruction: still an experimental procedure?
AB - The possibility of converting an easily fatiguable muscle like the gracilis
muscle into a fatigue-resistant one using chronic electrostimulation has renewed
interest in Pickrell's procedure. Between July 1991 and June 1996, 9 patients (2
M; 7 F) mean age = 45 y (range 14-72) underwent dynamic graciloplasty using
Medtronic electrostimulators. Five patients had faecal incontinence (2
congenitally anomaly, 1 neurological, 2 post-operative) and 4 had a perineal
colostomy performed either simultaneously (two cases) or at 3 to 4 years after
abdominoperineal excision of the rectum. Early post-operative complications
included distal tendon necrosis [1], perineal colostomy breakdown [1], detachment
of the gracilis tendon [2] and seroma in the thigh [1]. Long-term complications
included rectocele with faecal impaction in one patient with imperforate anus,
anal stricture in one patient who had refashioning of a perineal colostomy, and
displacement of the lead from the main nerve in 3 with external expulsion in 2.
The patient with anal stricture was successfully treated with anoplasty but
subsequently returned to an abdominal colostomy due to stricture recurrence 2
years later. The rectocele was successfully treated using a transvaginal
approach. Electrical conversion of the muscle was completed in all patients but
long term functional results are available for only 5 cases. Manometry revealed a
significant improvement in anal pressure under electro-stimulation and the
continence grading scale score significantly improved in 4 patients. The
technique is applicable to a very selected group of patients with no other
options but is still in the experimental phase and should not be performed
outside controlled trials. Repeated hospitalisation and reoperations are often
required although the complication rate may diminish and improve with experience.
PMID- 9401849
TI - Solitary rectal ulcer syndrome--an underdiagnosed condition.
PMID- 9401850
TI - "Rectal hypersensitivity in the irritable bowel syndrome".
PMID- 9401851
TI - Hello out there! Results of J.A.H. readership survey.
PMID- 9401852
TI - Response to "Out of wedlock births: what do the statistics really mean?".
PMID- 9401853
TI - Assaultive violence in the community: psychological responses of adolescent
victims and their parents.
AB - PURPOSE: This article presents an overview of psychological responses to injuries
due to assaultive violence, particularly gunshot wounds, in adolescents and
parents. METHODS: Reviews were conducted of the psychological, medical, and
public health literature to identify studies of violent injury in adolescent
populations. Studies reviewed in this article include those reporting levels of
gunshot and other violent injuries among pediatric patients in urban hospitals
and those examining psychological responses of children and parents to violent
injury and parental responses to potential death of a child. RESULTS: Existing
literature indicates that the number of adolescent victims of assaultive violence
is increasing. Adolescent victims of assaultive violence and their parents may
experience significant psychological distress including school difficulties,
guilt and fears of subsequent injury, and changes in risk behaviors and
perceptions of life. CONCLUSION: Greater awareness of the psychological
repercussions of injury due to assaultive violence for adolescents and their
families is needed among medical professionals. Hospital based interventions,
which may include psychological support for adolescents and their parents and
referrals for academic evaluation and assistance, should be developed for
adolescent trauma victims and their families.
PMID- 9401854
TI - National cancer clinical trials: children have equal access; adolescents do not.
AB - PURPOSE: To determine whether adolescents with cancer, who in comparison to
younger patients have a higher cancer incidence and lower mortality reduction,
have equal access to national cancer clinical trials. METHODS: The ethnic/racial
distribution of 29,859 subjects < 20 years of age entered onto National Cancer
Institute-sponsored clinical trials between January 1, 1991, and June 30, 1994,
was compared with the expected distribution of patients of the same age in the
United States. RESULTS: The Children's Cancer Group and Pediatric Oncology Group
had 29,134 (97.6%) of the total study entries among < 20-year-old subjects during
the 3.5 years of surveillance. The adult cooperative groups accounted for < 3% of
the clinical trials entries in the 15-19-year age range. When analyzed nationally
by region, the under-representation of the older adolescent subjects was
universal. From other analyses, the two pediatric cooperative groups were
estimated to have registered > 94% of the children < 15 years of age who were
expected to have been diagnosed to have cancer, but only 21% of the cancer
patients in the 15-19-year age group. CONCLUSIONS: The national pediatric cancer
cooperative groups allow the majority of American children < 15 years of age and
their families equal opportunity to access clinical cancer trials, regardless of
race or ethnicity. Among patients 15-19 years of age, however, > 75% are not
being enrolled by any cooperative group sponsored by the National Cancer
Institute. Thus, older adolescents are disadvantaged with respect to access to
the national clinical trials, regardless of their race or ethnicity.
PMID- 9401855
TI - Adolescent under enrollment in national clinical research: it is time to ask why.
PMID- 9401856
TI - Obtaining written parent permission for school-based health surveys of urban
young adolescents.
AB - PURPOSE: To document the process and implications of obtaining written parental
consent for school-based health surveys of young adolescents. METHODS: As part of
the evaluation of the Reach for Health prevention program, written parental
permission was obtained for student participation in school-based health surveys
conducted for three cohorts of seventh graders (N = 3253) enrolled in three urban
schools serving predominately economically disadvantaged minority adolescents.
Students in general, bilingual, and special education classes were eligible to
participate. Rates were recorded for the number of forms returned by parents,
parental consents and refusals, student consents and refusals, and surveys
completed. Procedures for achieving acceptable rates of written parental
permission and survey completion included daily communication between research
and school staff during the consent form collection period, student and teacher
incentives, provision of alternate activities for students without consent, and
scheduling of multiple makeup surveys for absentee students. RESULTS: Survey
completion rates met or exceeded preset goals and ranged from a low of 70% for
Cohort A to a high of 83% for Cohort C. At least 89% of the parents in each
cohort returned forms. Of forms returned, parent refusals ranged from a high of
18% (Cohort A) to a low of 12% (Cohort C). CONCLUSIONS: Obtaining written
permission from parents for young adolescents to participate in school-based
health surveys is possible in urban settings and has potential benefits in terms
of community awareness and involvement in research and evaluation studies. It
does, however, require a substantial commitment of program resources as well as
significant planning and data collection prior to actual survey administration.
PMID- 9401857
TI - Human subjects protection and parental permission in adolescent health research.
PMID- 9401858
TI - Adolescents report their need for and use of health care services.
AB - PURPOSE: The goals of this study were to describe student access to health care
services, identify populations of students who remained in need of health care
services, and highlight particular unmet needs for health care identified by
these adolescents. METHODS: Students in Grades 9-12 attending 50 schools in
Oregon completed the Youth Risk Behavior Surveillance Survey (YRBS). Questions
requesting adolescents to report their need for specific types of health care,
and access to general and specific types of care were added to the core YRBS.
Multivariate logistic regression analysis was used to determine independent
relationships between student or community characteristics and health care access
or unmet needs for care. RESULTS: Almost 14,000 adolescents completed surveys, of
whom 75% reported visiting one or more health care provider within the last 12
months. Nineteen percent of adolescents reported that they had not received 1 or
more of 10 specific types of care when needed in the last year. Females, some
racial/ethnic minorities, rural, and sexually active adolescents were more likely
to report unmet needs for health care. Most frequently, adolescents reported they
needed but did not receive care for an illness (7%) or for personal or emotional
problems (6%). In addition, about 400 (3%) students reported they needed birth
control that they did not receive. CONCLUSIONS: A majority of high school-age
adolescents had visited health care providers within the year prior to study.
However, the number of adolescents who reported unmet specific health care needs
within the same time period remained substantial.
PMID- 9401859
TI - Protecting against hopelessness and suicidality in sexually abused American
Indian adolescents.
AB - PURPOSE: The purpose of this study was to identify factors protective against the
adverse health correlates of sexual abuse in reservation-based American Indian
and Alaskan Native adolescents. METHODS: Data were taken from the National
American Indian Adolescent Health Survey administered in 1988-1990 to 13,923
youths. Included in this analysis were 991 females and 166 males who reported a
history of sexual abuse. Chi-square analysis was used to identify significant
protective factors in sexually abused youths who did not report suicidality or
hopelessness. Discriminant function analysis was used to determine which factors
distinguished this group from those who experienced adverse health correlates.
RESULTS: Separate multivariate analyses for boys and girls demonstrated that for
girls, family attention, positive feelings toward school, parental expectations,
and caring exhibited by family, adults, and tribal leaders were associated with
absence of suicidality and hopelessness. For suicidality in boys, significant
protective factors were enjoyment of school, involvement in traditional
activities, strong academic performance, and caring exhibited by family, adults,
school people, and tribal leaders. No significant protective factors against
hopelessness were identified for boys. CONCLUSIONS: To minimize hopelessness and
suicidal involvement among youth who have been sexually abused, strategies should
be planned, implemented, and evaluated that support family caring and
connectedness, strengthen school attachment and performance, and improve tribal
connectedness.
PMID- 9401860
TI - Confidential health care for adolescents: position paper of the Society for
Adolescent Medicine.
PMID- 9401861
TI - Driver education: position paper of the Society for Adolescent Medicine.
PMID- 9401862
TI - Controversies in assisted reproduction and genetics. Does "EPF" have an identity?
PMID- 9401863
TI - An update on the identity of early pregnancy factor and its role in early
pregnancy.
PMID- 9401864
TI - Early pregnancy factor: an unresolved molecule.
PMID- 9401865
TI - An update on the identity of early pregnancy factor and its role in early
pregnancy.
PMID- 9401866
TI - Ethical principles of the Commonwealth Medical Association.
PMID- 9401867
TI - In vitro fertilization with low-dose clomiphene citrate stimulation in women who
respond poorly to superovulation.
AB - PURPOSE: Our experience with IVF using low-dose clomiphene citrate for
stimulation in "non-" and "poor" responders was reviewed and the treatment
outcomes with the previous controlled ovarian stimulation cycles in which hMG and
GnRH agonist were used were compared. METHODS: The treatment outcome in 11 non-
and 20 poor responders having 30 and 53 clomiphene citrate IVF treatment cycles,
respectively, were compared with the treatment outcome in the previous long
protocol buserelin/hMG cycles. RESULTS: The clinical pregnancy rates per oocyte
collection achieved in the first clomiphene citrate cycle in non (9.1%)- and poor
(10%) responders were comparable to those achieved by poor responders (11.9%) who
had buserelin/hMG using the long protocol. Although the numbers were small, a
similar pregnancy rate could still be achieved in poor responders up to the third
attempt using clomiphene citrate. CONCLUSIONS: IVF using long-protocol
buserelin/hMG is more successful than using clomiphene citrate stimulation.
However, this advantage may not be significant in those women with a previous
poor response to buserelin/hMG. It is suggested that for such poor responders,
three attempts of IVF in a clomiphene citrate cycle may offer a viable
therapeutic alternative before reverting to more stressful, expensive, and time
consuming treatment.
PMID- 9401868
TI - The presence of hydrosalpinx may not adversely affect the implantation and
pregnancy rates in in vitro fertilization treatment.
AB - PURPOSE: To evaluate the effects of hydrosalpinx on the outcome of in vitro
fertilization (IVF) treatment, a retrospective study was undertaken at a tertiary
referral center for infertility. METHODS: Results of the first IVF treatment
cycles in 144 patients from 1 January 1993 to 31 December 1995, who had tubal
infertility only and were less than 38 years old, were reviewed. The
duration/dosage of hMG used, serum estradiol level on the day of hCG, number of
oocytes aspirated and fertilized, number of embryos replaced, implantation rate,
clinical pregnancy rate, and pregnancy outcome were compared in patients with and
without hydrosalpinx. RESULTS: The mean implantation rate and clinical pregnancy
rate were similar in patients with or without hydrosalpinx. Both groups had
similar ovarian responses and fertilization rates. There was no increase in
clinical abortion in the hydrosalpinx group but ectopic pregnancies were more
common in patients with hydrosalpinx. CONCLUSIONS: The presence of hydrosalpinx
did not adversely affect the implantation and pregnancy rates in in vitro
fertilization treatment when the results of the first cycle were compared.
However, it can lead to a higher incidence of ectopic pregnancies.
PMID- 9401869
TI - Outcome of IVF in DES-exposed daughters: experience in the 90s.
AB - PURPOSE: The outcome of in vitro fertilization (IVF) in a group of infertile
women with a history of in utero exposure to diethylstilbestrol (DES) was
analyzed. Records from an academic IVF program were retrospectively reviewed.
METHODS: Seventeen infertile women with a self-reported history of exposure to
DES in utero, attending the IVF unit at Massachusetts General Hospital (MGH) for
assisted reproductive technology (ART), underwent 27 IVF cycles. Analysis of the
outcome of IVF including implantation and ongoing pregnancy rates was performed.
The data were compared with results from a group of 20 infertile patients with
idiopathic infertility undergoing 27 IVF cycles at MGH during the same period.
The patients in the two groups were matched for age, basal day 3 levels of
follicle stimulating hormone and serum estradiol, and the number and quality of
embryos transferred. RESULTS: The response to controlled ovarian hyperstimulation
was comparable in the two groups. Significantly lower implantation and ongoing
pregnancy rates following IVF and embryo transfer were seen in the utero DES
exposed group compared to the control patients. CONCLUSIONS: Infertile patients
with a history of in utero exposure to DES exhibit a significantly impaired
implantation rate following IVF, and the outcome of ART remains poor.
PMID- 9401870
TI - Endogenous LH surge versus hCG as ovulation trigger after low-dose highly
purified FSH in IUI: a comparison of 761 cycles.
AB - PURPOSE: The results obtained with a protocol consisting of ovarian stimulation
with low doses of highly purified FSH (FSH HP), administration of a GnRH analogue
to induce an endogenous surge of gonadotropins, and IUI were evaluated. These
results were compared with those seen with similar FSH stimulation and hCG
administration followed by IUI. METHODS: Three hundred sixty-four patients
scheduled for IUI, after inclusion in a total of 345 FSH HP/GnRH-stimulated
cycles and 416 FSH HP/HCG-stimulated cycles, were studied. The stimulation
protocol consisted of daily subcutaneous injection of 75 IU of FSH HP from day 3
or 5 of the cycle, depending on the duration of the spontaneous cycle. hCG was
administered on days 0, +2, and +5 to support the luteal phase. Monitoring was
conducted using circulating estradiol levels and vaginal ultrasonography.
Administration of two s.c. doses of leuprolide acetate (LA) or 7500 IU of i.m.
hCG when at least one 18-mm-diameter follicle was seen and estradiol levels
reached 120 pg/ml per follicle with a diameter > or = 16 mm. Intrauterine
insemination was with semen capacitated by swim-up, thawed at room temperature if
previously frozen. RESULTS: The ovulation rate was 99.28 after hCG and 99.23 with
LA. No significant differences were seen between the estradiol and progesterone
levels of both groups or in the estradiol/progesterone ratio. The duration of the
luteal phase was similar in both groups. Pregnancy rates per cycle were 17.31%
(hCG) and 27.25% (LA), respectively (P = 0.0007), and abortion rates 22.22% (hCG)
and 24.47% (LA), respectively. No cases of ovarian hyperstimulation were seen.
CONCLUSIONS: After FSH HP administration according to a low-dose protocol, the
use of LA to trigger a gonadotropin surge as a means of inducing ovulation in FSH
stimulated women could be a good alternative to improve the results and prevent
ovarian hyperstimulation in IUI cycles.
PMID- 9401871
TI - Incomplete androgen and progesterone suppression following midluteal GnRHa prior
to controlled ovarian hyperstimulation for IVF-ET.
AB - PURPOSE: We aimed to determine if midluteal GnRH agonist (GnRHa) use prior to
controlled ovarian hyperstimulation (COH) results in uniform progesterone and
androgen suppression and whether elevations of these hormones occurring early in
follicular development may adversely effect the outcome of IVF-ET. METHODS: Forty
four COH cycles using midluteal GnRHa were evaluated. Serum gonadotropins (LH and
FSH) and gonadal steroids (E2, A, P4, and T) were measured after 10 days of GnRHa
administration [cycle day 31 (CD 31)] and again on the day of hCG administration,
following COH. Cycle outcomes evaluated were the number of oocytes retrieved,
morphologic grade, fertilization, implantation, pregnancy, and spontaneous
abortion rates. RESULTS: Endogenous serum FSH was uniformly suppressed (6.32 +/-
0.47 IU/L) on CD 31, however, LH was not (23.76 +/- 0.76 IU/L). Five and four
tenths percent of cycles demonstrated low-level P4 elevations (> or = 0.9 ng/ml),
24.4% demonstrated serum androstenedione levels > or = 600 pg/ml, and 39% of
cycles were characterized by serum T levels > or = 200 pg/ml despite evidence of
E2 suppression (< or = 30 pg/ml) and the absence of follicular growth by
sonography. LH levels were not predictive of incomplete P4 or androgen
suppression. Elevations of either P4, A, or T occurring early in the follicular
phase were not found to correlate with an impairment in clinical cycle outcome.
CONCLUSIONS: Midluteal GnRHa use prior to COH may result in incomplete
suppression of circulating progresterone and androgens. However, these relative
elevations, occurring early in the development of the follicular cohort, did not
appear to affect IVF cycle outcome adversely.
PMID- 9401872
TI - Effects of cryopreserved semen quality and timed intrauterine insemination on
pregnancy rate and gender of offspring in a donor insemination program.
AB - PURPOSE: Our purpose was to study the relationship among cryopreserved donor
semen quality, pregnancy rates, and preconception sex selection after
intrauterine insemination. METHODS: We reviewed the records of the 203 women in
our donor insemination program from 1987 to 1994 who became pregnant after more
than one insemination cycle and had no female-factor infertility. They were
categorized according to the number of cycles required for pregnancy. Semen
samples from 54 donors were analyzed before freezing and after thawing. Specimens
resulting in pregnancy were compared to specimens from the same donor that did
not. Semen characteristics were compared to gender of the child. RESULTS: Two
hundred fifty two-women became pregnant of the 422 who were enrolled. The
pregnancy rate per cycle was 13%. Semen quality was not related to pregnancy
outcome or offspring gender. However, more male children (101 vs 83) were born.
CONCLUSIONS: Semen characteristics in good-quality cryopreserved donor semen do
not affect pregnancy rate or offspring gender.
PMID- 9401873
TI - Creatine kinase level and lipid peroxidation rate in human spermatozoa from
patients with cancer.
AB - PURPOSE: The present study assessed whether the poor semen quality in patients
with cancer results from the inhibition of sperm maturation as indicated by
creatine kinase or from increased oxidative stress as assessed by lipid
peroxidation of the sperm membrane. METHODS: Cryopreserved semen specimens from
patients with testicular (n = 10) and nontesticular (n = 12) cancer and normal
healthy donors (n = 14) were analyzed for lipid peroxidation and creatine kinase
levels. RESULTS: The levels of creatine kinase and malonaldehyde did not differ
among testicular or nontesticular patients with cancer or normal healthy donors.
CONCLUSIONS: Poor semen quality in testicular and nontesticular patients with
cancer is not related to creatine kinase or lipid peroxidation levels; it may be
related to other factors.
PMID- 9401875
TI - FISH and the paediatrician.
AB - Cytogenetics with banding techniques has, since the 1970s, identified patients
with chromosome abnormalities and has contributed enormously to the understanding
of phenotype-karyotype correlations. However, one chromosome band could contain
20-50 genes. Fluorescence in situ hybridization (FISH) bridges the gap in the
area between the resolution obtained by conventional chromosome studies and
purely DNA studies. Fluorescence in situ hybridization provides paediatricians
with the ability to delve more deeply into the aetiology of congenital
abnormalities in children. This annotation aims to clarify the current
applications of FISH in paediatric practice.
PMID- 9401874
TI - Culture with Matrigel inhibits development of mouse zygotes.
AB - PURPOSE: It was reported that Matrigel improved hatching of mouse blastocysts
produced in vitro from F1 hybrid-derived zygotes. We investigated whether
Matrigel would be similarly beneficial with outbred strain-derived embryos, which
exhibit a "two-cell" block similar to the developmental blocks of other species.
METHODS: Mouse embryo development was assessed with or without Matrigel in KSOM
medium, which supports the development of blocking strain zygotes in vitro, and
in human tubal fluid (HTF) medium, which normally does not but which is used for
human IVF. RESULTS: Matrigel severely inhibited the development of zygotes to
blastocysts in KSOM and did not improve culture in HTF. There was no effect on
development from the two-cell stage. We were not able to replicate the previous
finding of Matrigel's beneficial effect on hatching of F1-derived zygotes.
CONCLUSIONS: Matrigel may be a deleterious addition to embryo culture or
coculture systems.
PMID- 9401876
TI - Psychosocial impact of chronic illness in children.
AB - Chronic illness is common in childhood and is associated with an increased risk
of psychological difficulties in the child. Current research is focused on the
identification of specific risk and protective factors that may predict
psychological and health outcomes. The challenges faced by physicians caring for
a child with chronic illness are described and contrasted with the medical role
in treating acute illness. The child's adaptation to illness is discussed in a
developmental framework and positive and maladaptive family responses are
identified. It is suggested that chronic illness and/or its treatment may
compromise intellectual development and academic progress.
PMID- 9401877
TI - Paediatric HIV update.
AB - Less than half of the paediatric HIV infections recorded in Australia have
resulted from perinatal transmission, but in recent years this has been the
predominant mode of infection. There are 136 infants who are known to have been
exposed perinatally to HIV in Australia: 49 of these are infected. Caesarean
section is thought now not to reduce the risk of perinatal transmission (PNT);
rather, the risk increases with duration of membrane rupture and rises rapidly
after 4 h of membrane rupture. However, no data exist to show that interventions
to expediate delivery after membrane rupture reduce the risk of PNT. Data such as
these suggest that the majority of perinatal infections (probably about 60%)
occur close to the time of delivery. While the overall risk of PNT for non-breast
fed infants is approximately 20-25%, the risk of infection for the infant is
considerably increased when there is evidence of increased maternal viral burden.
Advanced maternal disease predicts that if the infant is infected there is more
likely to be early progression of HIV than is the case for the less frequently
infected infants of mothers who are asymptomatic. Bottle feeding may prevent
infection of 10% of children exposed perinatally. Use of zidovudine by the mother
in the third trimester and i.v. zidovudine during labour, followed by oral
zidovudine for the infant for 6 weeks can reduce the PNT rate by two thirds, to
about 8%. Approximately 3% of uninfected infants with perinatal HIV exposure may
be found to be transiently virus positive but eventually become antibody negative
and thus appear to have eliminated the virus. The risk of Pneumocystis carinii
pneumonitis (PCP) cannot be predicted on the basis of CD4 count and it is
recommended that all children of infected mothers commence PCP prophylaxis around
the age of 6 weeks-2 months and continue that therapy until the age of 12 months
or until it becomes clear that the infant is uninfected. The cumulative risk of
AIDS increases rapidly during the first year of life to about 20%, then more
slowly at a rate of about 2 or 3% a year. The shape of this curve reveals the
bimodal progression of HIV disease in children. About 15-20% of children rapidly
develop a severe immune deficiency, opportunistic infections and, in most cases,
encephalopathy. There is a very high morbidity rate in this group of children,
most of whom die before the age of 3 or 4 years. In contrast, 80-85% of children
only become immunodeficient after a relatively long period, which is similar to
or perhaps even longer than that in adults. Recent studies indicate that
zidovudine antiviral monotherapy is no longer appropriate. While no clear
alternative to monotherapy has emerged most would, wherever possible, commence
antiretroviral therapy with a combination of two or three drugs including
zidovudine plus didanosine or lamivudine. If a third drug is used it would
probably be a protease inhibitor.
PMID- 9401878
TI - Social skills training for primary school children: a 1-year follow-up study.
AB - OBJECTIVE: To evaluate the effectiveness of the Rochester Social Problem Solving
Program to reduce emotional and behavioural problems amongst primary school
children. METHODOLOGY: Children in years 3 and 4 at primary school were assessed
prior to receiving the program, immediately after the program and 1 year after
the program. At each assessment, the functioning of the children who received the
program was compared to the functioning of children enrolled in years 3 and 4 at
a comparable school who did not receive the program. RESULTS: The program
improved the ability of children to cope with potentially difficult social
situations. However, the program did not reduce the prevalence of teacher
reported or mother-reported childhood emotional and behavioural problems.
CONCLUSIONS: School-based social skills programs may be more effective in
reducing childhood emotional and behavioural problems if they include components
which focus specifically on childhood behaviour problems as well as components
focusing on social skills and peer relationships.
PMID- 9401879
TI - Discrimination of attention deficit hyperactivity disorder by the continuous
performance test.
AB - OBJECTIVE: To investigate the Continuous Performance Test in discriminating a
group of 56 attention deficit hyperactivity disorder (ADHD) children from 56
school children individually matched for age, sex and social class. METHODOLOGY:
The children all completed the Continuous Performance Task (CPT). The mothers and
teachers completed a Conners Parent-Teacher Rating Scale for the clinic children.
RESULTS: The ADHD sample was selected so that the average IQ was 99.8 to match
the school sample. A non-parametric discriminant function showed that the
subtests of the CPT that best discriminated ADHD were age-normalized errors of
commission (NCPTC) and age-normalized mean reaction time (NMNRT). CONCLUSION:
Optimal use of the CPT for discrimination of ADHD should include age
normalization and mean reaction time to targets. Further evoked potential studies
may show brief cortical events involved in reaction time over the course of the
CPT, and the processes involved in behavioural control.
PMID- 9401880
TI - Clinical and endoscopic predictors of histological oesophagitis in infants.
AB - OBJECTIVE: To define the earliest age at which histological changes can be used
to diagnose oesophagitis and to determine the relationships between clinical,
endoscopic and histological features of oesophagitis in infants. METHODOLOGY: The
case records and biopsies of 113 infants aged 2-18 months with clinically
significant gastro-oesophageal reflux (GOR), undergoing oesophagoscopy between
1978 and 1994 were retrospectively reviewed. The biopsies were independently
evaluated and graded by two pathologists. RESULTS: Forty-five cases (40%) had
histological oesophagitis but only 16 (14%) had abnormal endoscopic findings
(excluding erythema). Endoscopy was found to be highly specific (93%) for
histological oesophagitis but lacked sensitivity (25%). Irritability was
inversely related to the presence of endoscopic abnormalities, and there was poor
correlation between symptoms and histological changes with only haematemesis
showing a statistically significant association with histological abnormalities
(P = 0.033). Intraepithelial lymphocytes were the earliest of the histological
features noted and were present before 4 months of age. The numbers of
intraepithelial eosinophils and lymphocytes and the presence of papillary
elongation all increased with age. CONCLUSIONS: The presence of oesophagitis is
difficult to predict on the basis of symptoms. The presence of intraepithelial
lymphocytes is the earliest histological change to be seen in infants with GOR,
and can develop before 4 months of age. Oesophagoscopy without biopsy is
unreliable in the diagnosis of oesophagitis in infants.
PMID- 9401881
TI - Improvement in outcome of children with Wilms' tumour in South Australia over the
last 30 years.
AB - OBJECTIVE: To evaluate the outcome of children with Wilms' tumour over the last
30 years in South Australia. To compare the outcome of children treated before
and after 1982, when standard treatment protocols were introduced. METHODOLOGY:
Management approaches, survival rates and side-effects of treatment were
identified from case notes. Pathology slides were reviewed to ensure all children
were correctly diagnosed with Wilms' tumour. RESULTS: Children treated for Wilms'
tumour prior to 1982 had an overall survival rate of 54%. Since 1982 there has
been a significant improvement in outcome and the current survival rate is now
85%. Children treated since 1982 have also experienced fewer treatment related
side-effects than children treated prior to 1982. CONCLUSIONS: There has been
substantial improvement in survival from childhood Wilms' tumour over the past 30
years in South Australia. This is likely to be due to a combination of factors
including standardization of treatment, tailoring of treatment to stage and
histology, improved perioperative care, enhanced radiological techniques and
higher levels of collaboration between relevant specialists.
PMID- 9401882
TI - Control of temperature during newborn transport: an old problem with new
difficulties.
AB - OBJECTIVE: To explore any changes in temperature control during neonatal
emergency inter-hospital transport between 1977 and 1996. METHODS: Records were
reviewed of all infants undergoing emergency transfer by the statewide Victorian
Newborn Emergency Transport Service (NETS). Per axillary temperatures were
recorded prospectively on arrival of transport team and at conclusion of transfer
for all infants. RESULTS: The rate of hypothermia (< 36.0 degrees C) when NETS
reached the infant has decreased overall (22% in 1977-79 to 7% in 1995-96) and
for all weight groups; although in 1995-96 hypothermia was present in 36% of
infants less than 1000 g when NETS arrived. The rate of hypothermia (< 36.0
degrees C) at the end of the transfer has remained at 3% overall for many years.
The rate of hyperthermia at both times has increased significantly overall (12%
in 1977-79 to 24% in 1995-96 on NETS arrival, 4%-19%, respectively at end of
transfer) and for all weight groups except infants less than 1000 g. The range of
abnormal temperatures has not substantially changed over time. CONCLUSION: There
has been significant improvement in avoidance of hypothermia and cold stress
amongst infants requiring emergency neonatal transport from 1977 to 1996.
However, in order to improve the number of infants transferred who achieve a
temperature in the normal range the need to avoid hyperthermia is highlighted.
Infants who require incubator care for optimal medical management require
continual monitoring of temperature and review of environmental conditions to
optimise the conditions both prior to and during transport.
PMID- 9401883
TI - Chronic oxygen dependency in infants born at 24-32 weeks' gestation: the role of
antenatal and neonatal factors.
AB - OBJECTIVES: To study the incidence of chronic oxygen dependency (COD) among
ventilated survivors born at 24-32 weeks gestation from 1986 to 1994 and to
identify antenatal and neonatal factors that may have changed with time; and to
identify antenatal and neonatal factors that could contribute to the development
of COD in infants born at 24-32 weeks gestation using a case control model.
METHODOLOGY: Infants born at 24-32 weeks gestation in one tertiary referral
centre between 1986 and 1994 and admitted to the neonatal intensive care unit for
respiratory support were studied. Data accumulated prospectively since 1986 in
survivors of ventilation were analyzed to identify antenatal and neonatal factors
that could have changed with time. The cohort of infants who developed COD were
matched for gestation and time of birth with a control group of infants who did
not have COD. Significant factors that could have contributed to the development
of COD were identified using forward logistic regression analysis. RESULTS: The
number of mothers admitted for threatened premature labour (TPL), and pregnancy
induced hypertension decreased with time while the use of antenatal steroids and
maternal antibiotics increased. More infants were delivered by Caesarean section
during the later years. There was an increase in neonatal septicaemia with time
while there were decreases in hyaline membrane disease, pneumothorax, pulmonary
interstitial emphysema, use of high peak inspiratory pressure (PIP) and high
inspired oxygen. The incidence of COD decreased. The case controlled study
revealed a significant positive association between COD and male gender,
birthweight less than the 10th percentile for gestation, PIP over 30 cm H2O,
septicaemia and significant patent ductus arteriosus (PDA) requiring
indomethacin. There was a negative association with TPL. CONCLUSIONS: Further
decrease in COD can be achieved only if septicaemia, PDA and the use of high PIP
can be avoided. The most effective way of reducing the incidence of COD is by
reducing the incidence of prematurity.
PMID- 9401884
TI - The seasonal distribution of infant deaths by age: a comparison of sudden infant
death syndrome and other causes of death.
AB - OBJECTIVE: To examine the possibility that among deaths in infancy the increase
in the winter/summer ratio with increasing age is not peculiar to sudden infant
death syndrome (SIDS). METHODOLOGY: Details of the winter (December
February)/summer (June-August) ratio among deaths in neonates (< 28 days) and
post neonates dying in the United States of America between 1979 and 1990 were
abstracted from published statistics. The primary causes of death were classified
according to the ninth Revision of the International Classification of Diseases.
RESULTS: For every non-traumatic cause of death including SIDS, the winter/summer
ratio was higher among postneonates than neonates. This was not seen for deaths
due to trauma. Cases of SIDS and deaths due to infection had the highest ratios
in both age categories. Causes of death occurring predominantly in the neonatal
period (e.g. anencephaly) had the lowest overall ratios. CONCLUSIONS: Neither the
greater number of SIDS cases in the winter, nor the increasing winter/summer
ratio with increasing age is unique to SIDS.
PMID- 9401885
TI - Primary course immunogenicity and reactogenicity of a new diphtheria-tetanus
whole cell pertussis vaccine (DTPw).
AB - OBJECTIVE: To establish safety, immunogenicity, and batch stability of a
reformulated whole cell pertussis based diphtheriatetanus-whole cell pertussis
(DTP) vaccine (nDTPw) compared to the currently marketed Australian DTPw vaccine
(Triple Antigen) in a three dose 2, 4 and 6 month primary immunization course.
Reformulation was necessary to make the DTPw vaccine suitable for combination
with hepatitis B and Haemophilus influenzae b vaccines. METHODS: Double blind
randomized controlled trial in suburban Melbourne in 812 healthy infants
recruited through maternal and child health centres, of whom 208 received Triple
Antigen and 604 received nDTPw. RESULTS: Results for both reactogenicity and
immunogenicity were similar and were not significantly different for the three
batches of nDTPw. No new, serious, or unexpected adverse effect was recorded.
Nearly twice as many nDTPw infants experienced no general reaction to the third
dose (18%) compared to Triple Antigen (11%, P = 0.06). An elevated temperature (>
or = 38 degrees C axillary) occurred in about three out of 10 babies overall,
with rates being slightly higher for both vaccines after the second vaccination.
Local reaction rates were significantly less common for nDTPw on days 2 and 3
following each of the three vaccinations. After dose three, 30% of nDTPw subjects
experienced no local reaction compared to 20% of Triple Antigen subjects (P =
0.015, 95% Cl on difference 2%, 19%). Swelling after doses one and three occurred
in 30% and 24% of Triple Antigen subjects, compared to 23% (P = 0.07, 95% Cl diff
0%, 13%) and 14% (P = 0.017, 95% Cl diff 2%, 17%) of nDTPw subjects. Tenderness
after doses two and three occurred in 80%, and 78% of Triple Antigen subjects,
compared to 71% (P = 0.04, 95% Cl diff 1%, 17%) and 68% (P = 0.025, 95% Cl diff
2%, 19%) of nDTPw subjects. There was a significantly higher post immunization
diphtheria antitoxin GMT (2.73 IU/mL) for Triple Antigen compared to nDTPw (1.89
IU/mL; P = 0.02), although no subject in either vaccine group had a tetanus or
diphtheria antibody titre less than six times the protective level of 0.01 IU/mL
following immunization. The nDTPw post immunization GMTs were significantly
higher for Agg2, Fha, and pertactin compared to Triple Antigen geometric mean
titres (GMTs). CONCLUSION: nDTPw is a safe and immunogenic vaccine when compared
to Triple Antigen. The reformulated vaccine is an acceptable replacement for the
currently marketed formulation, and for evaluation as a component of future
combination vaccines.
PMID- 9401886
TI - Incidence of apnoea and bradycardia in preterm infants following DTPw and Hib
immunization: a prospective study.
AB - OBJECTIVE: To evaluate the incidence and severity of apnoea and bradycardia in
hospitalized preterm infants following immunization at 2 months of age, and
identify risk factors. METHODOLOGY: A prospective study of 98 preterm infants, of
gestational age 24-31 weeks, immunized at approximately 2 months post natal age
with diphtheria-tetanus-whole cell pertussis vaccine (DTPw) in the neonatal
intensive care unit (NICU) at King George V Hospital Sydney. Half the infants
also received Haemophilus influenzae type b conjugate vaccine (Hib)
simultaneously. All infants were monitored for apnoea and bradycardia in the 24 h
periods pre- and post immunization. RESULTS: Only one infant had apnoea and/or
bradycardia pre-immunization compared with 17 post immunization. For 12 infants
these events were brief, self-limiting and not associated with desaturations
(oxygen saturation < 90%). However, for five infants (30%) these events were
associated with oxygen desaturation and two of these infants required
supplemental oxygen. The group that had apnoea and/or bradycardia and the group
that did not were not significantly different in terms of gestational age, birth
weight and other variables. Infants who received Hib together with DTPw were less
likely to have apnoea and/or bradycardia than those given DTPw alone. CONCLUSION:
When considering immunization for preterm infants, the benefits of early
immunization must be balanced against the risk of apnoea and bradycardia. We
recommend that the cardio-respiratory function of hospitalized infants born at
less than 31 weeks gestation be monitored for 48 h post immunization.
PMID- 9401887
TI - Young Malaysian children with lower respiratory tract infections show low
incidence of chlamydial infection.
AB - OBJECTIVE: The incidence of Chlamydia pneumoniae and Chlamydia trachomatis
infection was studied among infants and young children admitted to hospital for
the management of lower respiratory tract infections, over a 12 month period.
METHODOLOGY: Respiratory secretions were examined for chlamydiae by cell culture,
enzyme-linked immunosorbent assay and polymerase chain reaction-enzyme
immunoassay. Sera were tested by micro-immunofluorescence for chlamydial IgG, IgM
and IgA. Other bacterial and viral pathogens were also looked for by standard
cultural and serological methods. RESULTS: Of 87 patients aged 2 months-3 years,
an aetiologic diagnosis was made in 41 (47.1%). C. pneumoniae and C. trachomatis
were each detected in 1 (1.2%) of the patients. Among common bacterial pathogens,
Haemophilus influenzae (13.8%) and Streptococcus pneumoniae (8.1%) were the most
frequently identified. Respiratory viruses and elevated Mycoplasma pneumoniae
antibodies were found in 10.3% and 9.1% of patients, respectively. CONCLUSION:
Chlamydiae are infrequent causes of community-acquired acute lower respiratory
tract infections in infants and very young children in Malaysia.
PMID- 9401888
TI - The health of a group of young Australians in a New South Wales juvenile justice
detention centre: a pilot study.
AB - OBJECTIVE: To consider the health profile of a sample of young, largely male
Australians as assessed on their admission to a New South Wales Juvenile Justice
Detention Centre. METHOD: A retrospective analysis of primary care nurse health
records for 100 sequential admissions. RESULTS: Of the 97 males and three females
(mean age = 15.9 years), 30 were Aboriginal and 39 did not live with either
parent at the time of admission. Respiratory illness, such as bronchitis and
asthma were common. These diagnoses were overshadowed by histories of significant
physical injury. The sample was at high risk of sexually transmitted disease.
Forty-six per cent had prior contact with a mental health professional, 26%
reported they had thought of suicide and 9% reported having attempted suicide.
There was a high prevalence of substance abuse. CONCLUSION: The health of these
young Australians is at risk from every perspective. Improving the quality of
their health assessments is an important issue for the clinicians who attend them
as individuals and for policy makers who aim to reduce the considerable social
and economic cost of juvenile crime. The discussion of these results from one
centre has revealed opportunities to make such improvements. There is a need for
a gathering of expertise to address the issue, preferably on a national basis.
PMID- 9401889
TI - Acne in Victorian adolescents: associations with age, gender, puberty and
psychiatric symptoms.
AB - OBJECTIVES: This study aimed to examine the associations between the frequency
and severity of self-reported acne and age, gender, puberty and psychiatric
symptoms in Victorian adolescents. METHODOLOGY: A sample of secondary
schoolchildren in Victoria, Australia were surveyed using a computerized
questionnaire. Developmental and psycho-social factors associated with acne were
recorded and analysed using logistic regression. RESULTS: The Victorian
Adolescent Health Survey (1992) recorded the frequency and severity of self
reported acne in 2491 students. Frequency of acne increased with age and pubertal
development. For females commencement of menstruation was associated with
increased frequency of acne. Asian born male students were less likely to report
acne than Australian born males. Acne severity was coded into mild (students
reporting acne sometimes on back or face) and moderate (students reporting acne
often on face or back). Students reporting moderate acne were more likely to
report a high level of psychiatric symptoms and were in the later stages of
puberty. CONCLUSIONS: This study confirms an association between the frequency
and severity of self-reported acne and stage of pubertal development. It showed
also that students reporting moderate acne were more likely to report psychiatric
symptoms of depression and anxiety.
PMID- 9401890
TI - Trends in the health burden due to urinary tract infection in children in
Australia.
AB - OBJECTIVE: To estimate the health burden of urinary tract infection in children
less than 15 years of age in Australia and to ascertain whether any significant
change has occurred during the past decade. METHODOLOGY: The number of children
less than 15 years of age who were admitted in New South Wales for urinary tract
infection between 1981 and 1994 was ascertained from the Department of Health,
and age and sex specific incidence rates were calculated using Australian Bureau
of Statistics population data. Costs for inpatient care were calculated using the
cost weights from Australia National Disease Related Groups Version 3 for urinary
tract infection (DRG 577). The frequency of the four most commonly requested
renal tract imaging procedures in children following urinary tract infection and
which qualified for Medicare reimbursement were obtained from the Health
Insurance Commission for 1984-1994: micturating cystourethrography, intravenous
urography, renal ultrasonography, and nuclear medicine renal studies. RESULTS:
There were 1203 children who were admitted with urinary tract infection in New
South Wales in 1994, at an estimated cost of $A1.6 million. Since 1981, the age
standardized annual incidence of urinary tract infection requiring
hospitalization has increased from 0.5 to 0.9 per 1000 children, largely because
of an increase in the number of young children admitted (from 0.6 to 2.0 per 1000
children less than 5 years of age). In 1994, 46,230 non-inpatient renal imaging
procedures were undertaken in children under 15 years of age at a cost of $A5.3
million. CONCLUSIONS: Urinary tract infection is an important and increasing
health problem for Australian children, particularly for preschool children.
Whether this represents a true increase in the incidence of urinary tract
infection or improved diagnosis and more intensive management is not possible to
establish with this study design. Prospective population based studies are
required to assess more completely the frequency with which urinary tract
infection occurs in children and any changes that may be occurring.
PMID- 9401891
TI - Limitations of school entry immunization certificates.
AB - OBJECTIVE: To compare the immunization certificate submission rate for
kindergarten school children on the Central Coast of New South Wales for 1994 and
1995; to contact individual parents of children with incomplete or missing
immunization certificates by issuing a personalised immunization reminder letter,
and measuring their response. METHODOLOGY: Seventy Central Coast schools were
surveyed. Immunization documentation for 4177 kindergarten enrolements in 1995
were assessed. Children with incomplete or unknown immunization status were
identified. Immunization reminder letters were sent by the schools to parents of
the children that were identified. The school recorded any additional
immunization certificates submitted. RESULTS: In 1995, 79% of kindergarten
children submitted immunization certificates, unchanged from the previous year.
Immunization reminder letters were sent to 856 families of children with no
certificate and 215 families of children with an incomplete certificate. A
further 263 immunization certificates were submitted, representing a 25% response
rate. This intervention increased the percentage of kindergarten children with a
certificate from 79% to 86%. CONCLUSIONS: Education of school staff during the
1994 immunization survey did not change the overall immunization certificate
submission rate. Specifically targeting parents through schools can be an
effective way of increasing immunization certificate submission.
PMID- 9401892
TI - Vascular air embolism: a rare complication of nasal CPAP.
AB - A preterm infant developed bilateral tension pneumothoraces and extensive
vascular air embolism 6 h after being commenced on nasal continuous positive
airway pressure (CPAP). Neonatal clinicians should be aware that catastrophic
vascular air embolism could occur in infants receiving nasal CPAP, a modality of
respiratory support conventionally considered non-invasive and 'safe'.
PMID- 9401893
TI - Epidural haematoma and stroller-associated injury.
AB - We present a severe case of head injury in an infant associated with stroller use
and review similar reports from the literature. A case report and a literature
search of the Medline database from 1966 to 6/1996 using the terms
'perambulator', 'parm', 'stroller', or 'baby carriage'. Reports in English
describing injuries associated with their use are reviewed. We report a case of
epidural haematoma in a 10 months old girl who sustained the injury after falling
from a stroller. Safety harnesses were not worn during the incident. There was no
skull fracture. Complete recovery followed surgical evacuation of the blood clot.
Five reports describing stroller-related injuries were found in the English
literature. Most injuries were mild. Three cases of death were reported of which
two were classified as child abuse. The prevalence of unintentional stroller
associated injury is not clear. Mild injury, mostly to the head region, is
probably common. Life-threatening injuries are rare but these are potentially
preventable if strollers are properly designed and safety recommendations are
followed.
PMID- 9401894
TI - Haemoptysis in healthy children due to unsuspected foreign body.
AB - Haemoptysis in otherwise healthy children is an uncommon event. Two cases of
massive haemoptysis, subsequently requiring lobectomy, are discussed. In each
case, foreign vegetable matter was identified despite previously normal
bronchoscopy and minimal changes on chest radiograph.
PMID- 9401895
TI - A case of kernicterus in New Zealand: a predictable tragedy?
AB - A case of neonatal kernicterus due to glucose-6-phosphate dehydrogenase
deficiency (G6PD) is described. Diagnosis was delayed as the primary healthcare
attendant had no knowledge of this condition and its potential to cause rapidly
escalating levels of bilirubin and as she was reassured by the lack of signs of
systemic illness or anaemia. The baby has been left deaf, blind, intellectually
handicapped, epileptic and paralysed due to athetoid cerebral palsy. The re
organization of perinatal care in New Zealand, which has led to neonates
sometimes being managed solely by primary healthcare attendants with minimal
training in paediatrics may have increased the risk of a late diagnosis of
potentially devastating diseases such as this.
PMID- 9401896
TI - Yellow nail syndrome in infancy.
AB - This report describes an infant with clinical features consistent with the yellow
nail syndrome (YNS), a rare autosomal dominant disorder. He presented at birth
with congenital lymphoedema and was referred at 6 months of age for investigation
of recurrent cough and wheeze. He had clinical and radiological evidence of
bilateral pleural effusions and a pericardial effusion. Following a lung biopsy
and pericardial window these were shown to be manifestations of his lymphatic
abnormality. He also had persisting middle ear effusions causing conductive
deafness requiring hearing aids and secondary immunodeficiency requiring regular
immunoglobulin infusions.
PMID- 9401897
TI - Prevalence of obesity and hypercholesterolaemia in children: a cohort study.
PMID- 9401898
TI - Efficacy of ipratropium bromide by metered dose aerosol and aerochamber in acute
paediatric bronchiolitis.
PMID- 9401899
TI - Increase in asthma severity in the west.
PMID- 9401900
TI - Chronic illness in adolescents: transfer or transition to adult services?
PMID- 9401901
TI - Insulin-dependent diabetes mellitus: a constellation of autoimmune diseases.
PMID- 9401902
TI - Regional variability in the epidemiology of childhood diabetes in Italy.
AB - The incidence rates of IDDM in Italy show remarkable variability. Sardinia, a
region with the second highest incidence rate in the world, co-exists with other
regions with lower rates. We review and compare epidemiologic data on the
incidence of childhood-onset IDDM in Italy. papers published from 1980 to 1996
reporting incidence data in Italian areas were found by search of Medline and non
indexed Italian journals. The incidence data found cover only 57% of the Italian
population. The analysis of our results shows how difficult it is to make a
careful study of epidemiology of IDDM in Italy. The RIDI (the Registry for
Insulin-dependent Diabetes mellitus in Italy) project started in 1996 according
to international guidelines. The aims is to coordinate local IDDM registries, to
promote the start of new registries in uncovered areas, and to standardize
registration and data collection.
PMID- 9401903
TI - Thyroid nodules in childhood and adolescence--thirty years of experience.
AB - In the thirty year period between 1966 and 1996, fifty-two patients underwent
surgery for thyroid nodules at the Royal Children's Hospital, Melbourne. We aimed
to review their presentation, investigation, histology, treatment and to follow
up those who had malignant neoplasms. Forty-one of the fifty-two patients
presented with a single thyroid nodule. Investigations performed included thyroid
function tests (N = 32), thyroid autoantibodies (N = 21), an ultrasound of the
thyroid (N = 26) and 99mTechnetium scanning (N = 32). Thirty-five of the
neoplasms were benign, the follicular adenoma (N = 16) being the most common.
Seventeen patients had malignant neoplasms, seven of whom had papillary and seven
of whom had follicular carcinoma. Three patients had medullary carcinoma of the
thyroid. Nine of the seventeen patients with thyroid malignancy received post
operative 131I treatment. At the time of this review, all patients were living.
PMID- 9401904
TI - Growth pattern and age at menarche of obese girls in a transitional society.
AB - Childhood obesity is an increasing problem in a transitional society such as
Thailand. To study physical growth and puberty in obese children, a cross
sectional survey of growth and age at menarche was carried out in schoolgirls
aged between 8 and 16 years old. The 3,120 girls were divided into two groups
based on weight-for-height criteria. Girls with weight-for-height between 80 and
120% were classified as normal stature (2,625; 84.1%) and those more than 120%
were obese (495; 15.9%). Using probit analysis, age at menarche in obese girls
was 0.9 year earlier than normal stature girls (11.5 years vs 12.4 years). At age
12, obese girls were reaching menarche 2.8 times more when compared with the
normal stature girls. In terms of growth pattern, obese girls were taller and
grew faster during the prepubertal period, and then reached their final height
earlier than the normal stature girls (13 years vs 15 years). The final height in
obese girls was significantly shorter (153.0 cm and 155.0 cm, p = 0.01). We
conclude that: 1) obese girls grow faster, have earlier menarche and then stop
growing earlier, and 2) obese girls tend to be shorter as adults, compared with
normal stature girls.
PMID- 9401905
TI - The GH-releasing effect of Hexarelin, a synthetic hexapeptide, in newborns is
lower than in young adults.
AB - The aim of the present study was to verify the GH-releasing effect of Hexarelin,
a synthetic hexapeptide, in newborns who are known to have GH hypersecretion
likely due to hyperactivity of GHRH-secreting neurons while somatostatinergic
activity seems not fully operative. We studied in 6 newborns (NB, 2.5 +/- 2.1
days), 12 prepubertal children (PC, 9.8 +/- 0.45 yr) and 12 young adults (YA,
28.2 +/- 0.2 yr) the GH response to Hexarelin (HEX, 2 micrograms/kg i.v.)
compared to that observed after GHRH (1 microgram/kg i.v.) in 6 NB (4.2 +/- 0.4
days), 12 PC (9.9 +/- 0.6 yr) and 12 YA (31.0 +/- 1.3 yr). GH levels were assayed
basally and 30 and 60 min after drug administration. In NB, mean (+/- SEM) basal
GH levels were higher while IGF-I levels were lower than those recorded in PC and
YA (GH: 34.8 +/- 1.9 vs 2.8 +/- 0.4 vs 1.4 +/- 0.4 micrograms/l, p < 0.0006; IGF
I: 36.3 +/- 1.9 vs 152.0 +/- 11.5 vs 175.8 +/- 15.3 micrograms/l, p < 0.0007); in
the last two groups GH and IGF-I levels were similar. The mean delta GH peak
after HEX in NB (32.8 +/- 4.7 micrograms/l) was similar to that in PC (34.6 +/-
4.3 micrograms/l) and lower (p < 0.01) than that in YA (56.2 +/- 7.4
micrograms/l). Delta GH peak after GHRH in NB (60.1 +/- 1.5) was higher than
those in PC and YA (20.8 +/- 4.8 and 22.8 +/- 3.4 micrograms/l) (p < 0.005 and <
0.002, respectively). In NB, the GH response to HEX was lower (p < 0.005) than to
GHRH while in PC and YA the somatotrope response to HEX was higher (p < 0.03 and
0.0004, respectively) than to GHRH. These data demonstrate that the GH-releasing
effect of Hexarelin undergoes age-dependent variation being lower in newborns
than in young adults, opposite to that observed after GHRH administration. The
evidence that Hexarelin releases less GH than GHRH in newborns but not in
prepubertal children and in young adults makes unlikely the hypothesis that the
GH-releasing effect of this hexapeptide is mediated via endogenous GHRH release.
PMID- 9401906
TI - Long-acting gonadotropin-releasing hormone agonists in the differential diagnosis
of male precocious puberty.
AB - Male sexual precocity is defined as the development of secondary sexual
characteristics before 9 years of age. It can be classified as gonadotropin
dependent precocious puberty (GnDP) or gonadotropin-independent precocious
puberty (GnIP) and sometimes the differential diagnosis between these entities is
difficult. To determine whether long-acting GnRH agonists (GnRH-a) are effective
in differential diagnosis of male precocious puberty, we measured gonadotropins
and testosterone levels 30 days after a single administration of depot GnRH-a
(triptorelin, gosereline or leuprolide) in 10 boys with sexual precocity of
different etiologies. Testosterone levels 30 days after depot GnRH-a were in the
prepubertal range in patients with GnDP but not in GnIP. We conclude that
measurement of testosterone levels 30 days after long-acting GnRH-a is effective
in the differential diagnosis of male sexual precocity.
PMID- 9401907
TI - Serum lipids during parenteral nutrition with a 10% lipid emulsion with reduced
phopholipid emulsifier content in premature infants.
AB - Fourteen premature infants (range 26 + 0 to 32 + 3), all but two appropriate for
gestational age with a mean body weight of 1196 g (range 860 to 2770 g) received
a 10% lipid emulsion. This lipid emulsion contained half of the formerly used
phospholipid emulsifier concentration reducing the phospholipid/triglyceride
ratio to the ratio used for the 20% lipid emulsion (0.06 instead of 0.12). Lipid
emulsion was given over a 10 day period commencing at the third day of life with
0.5 g/kg/24 h which was increased daily up to a dose of 2.0-2.5 g/kg/24 h which
was reached in all patients at the seventh day of the observation period. During
this time mean serum concentrations of cholesterol increased non-significantly
from 76.1 mg/dl (SD 33.7) before lipid emulsion to 86.1 mg/dl (SD 36.4) on day
seven of the observation period. 13 of the 14 patients (97%) showed no
pathological increase of their serum triglyceride concentration during lipid
infusion. Mean serum triglyceride concentration increased from 65.3 mg/dl (SD
32.0 mg/dl) before the start of lipid emulsion to 102.6 mg/dl (SD 76.5) on day
four (p < 0.05) but with no further significant increase. Lipid emulsions with
10% triglyceride but lower phospholipid content are tolerated without
pathological increase in triglyceride or cholesterol serum concentration in the
vast majority of premature newborns.
PMID- 9401908
TI - Helicobacter pylori infection with parietal cell antibodies in children and
adolescents with insulin dependent diabetes mellitus.
AB - One hundred and seventy-seven patients with insulin dependent diabetes mellitus
(IDDM) diagnosed at the pediatric age were investigated for the presence of
gastric parietal cell autoantibodies (PCA). The objective was to evaluate the
prevalence of PCA seropositivity and to know whether Helicobacter pylori could be
a reason for a higher presence of PCA in IDDM children and adolescents. Twelve of
177 patients (6.77%; confidence interval: 3.1-10.3) had detectable PCA. Gastric
pathology was studied in eight of these patients and in seven patients without
PCA. Diagnosis of H. pylori infection was made on antral biopsies. None of the
patients had an atrophic gastritis. Six of the eight patients with PCA had
gastric mucosa colonization by H. pylori and/or chronic gastritis. According to
these results, we suggest that H. pylori can be the cause of the presence of PCA
positive results in diabetic children and adolescents, and diabetic patients with
detectable PCA should be screened for H. pylori.
PMID- 9401909
TI - Residential treatment for youngsters with difficult-to-manage insulin dependent
diabetes mellitus.
AB - A descriptive outcome study of 52 children with insulin-dependent diabetes
mellitus (IDDM) admitted to a residential treatment program over 6 years.
Criteria for admission included repeated hospitalizations for diabetes-related
problems, excessive school absences, and/or familial disruption. Residential
treatment included individual, group, and family psychotherapy, diabetes
education, and close medical supervision. The design included collection of data
before, during and after treatment. Children admitted to the residential unit
were compared to a population of pediatric IDDM outpatients from the same
geographical area. Treatment was associated with a reduction in diabetes-related
hospitalizations, improved school attendance, decreased glycosylated hemoglobin
levels, weight gain, individualized insulin changes, improved knowledge about
diabetes, and a normalization of attitudes towards this disease.
PMID- 9401910
TI - Psychological indications for treatment of tall stature in adolescent girls.
PMID- 9401911
TI - Hyperthyroidism in a girl with Down's syndrome.
AB - We report an adolescent girl with Down's syndrome, who presented with
hyperthyroidism. Autoimmune thyroid disorders can occur in children with Down's
syndrome, hypothyroidism developing more frequently. Hyperthyroidism can also be
associated with Down's syndrome, and should not be missed.
PMID- 9401912
TI - Successful therapy with 3,5,3'-triiodothyroacetic acid (TRIAC) in pituitary
resistance to thyroid hormone.
PMID- 9401913
TI - Central precocious puberty and chronic renal failure: a reversible condition post
renal transplantation.
AB - A 3 year-old boy with chronic renal failure associated with prune belly syndrome
who developed central precocious puberty is described. He had been maintained on
cyclic peritoneal dialysis from age 13 months with creatinine levels of 400-600
mumol/l. Increased linear growth rate probably began at 18 months, and by 38
months of age he had testicular enlargement and pubic hair consistent with Tanner
stage 2. Elevated levels of serum testosterone (3.6 nmol/l; normal < 0.7 nmol/l)
and luteinizing hormone (LH) (2.8 IU/l; normal < 1.0 IU/l) were demonstrated with
a pubertal response to luteinizing hormone-releasing hormone (LHRH) stimulation
(peak LH 43.5 IU/l). Other endocrine tests demonstrated hyperprolactinemia (170
micrograms/l; normal 3.4-22 micrograms/l), but normal pituitary-thyroid and
pituitary-adrenal functions and normal cranial MR imaging. Despite LHRH-agonist
therapy with leuprolide over the next 8 months, he showed an incomplete response
with only partial inhibition of basal LH and testosterone levels, and continued
significant increments in height standard deviation scores (Ht-SDS) and bone age
estimates. However, the sexual precocity appeared fully reversible following a
successful living-related renal transplant at age 50 months. Despite
discontinuation of leuprolide treatment post-operatively, there was a full
reversal of his serum LH and testosterone to a prepubertal profile as well as
normalization of the serum prolactin levels. Whereas most boys with chronic renal
failure show delayed pubertal development and suppressed linear growth, our
patient presents a unique phenomenon of reversible central precocious puberty.
The effects of leuprolide therapy in the presence of a uremic milieu and the
outcome of successful renal transplantation on sexual precocity are described.
PMID- 9401914
TI - Adipsic hypernatremia syndrome in infancy.
AB - We report on an infant with chronic hypernatremia due to a congenital defect in
osmo-regulation of thirst and the secretion of arginine vasopressin (AVP). A 12
month-old female infant who presented with irritability and signs of dehydration
was found to have hypertonic dehydration; plasma osmolality was 430 mOsm/kg B.W.
Despite rehydration she remained hypernatremic (serum Na+ 152-158 mEq/l). Lack of
signs of thirst led us to the diagnosis of chronic hypernatremia due to adipsia.
Laboratory investigation showed: 1. plasma AVP levels were low for plasma
osmolality; 2. urine osmolality was normal for plasma AVP, and 3, there was a
significant correlation of plasma to urine osmolality (r = 0.72, p < 0.02);
however, the slope was markedly reduced indicating partial destruction of the AVP
osmoreceptors.
PMID- 9401915
TI - Position one analogs of the Saccharomyces cerevisiae tridecapeptide pheromone.
AB - Analogs of the Saccharomyces cerevisiae alpha-mating factor [WHWLQLKPGQPMY], in
which a variety of residues replaced Trp1 were synthesized and assayed for
biological activity and receptor affinity. Analogs containing Gly or Leu or many
different aromatic residues in position 1 of the peptide exhibited bioactivity in
a growth arrest assay slightly greater than, or equal to, that of the parent
pheromone, whereas the Glu1 and Lys1 analogs exhibited significantly lower
bioactivity. Analogs with an aromatic replacement at position 1 had 3- to 6-fold
lower receptor affinity than the parent peptide, whereas analogs with a
hydrophilic residue at the N-terminus exhibited large reductions in receptor
affinity with the peptide with Glu in position 1 showing a 120-fold reduction. N
alpha-Acetylation had little effect on bioactivity but lowered receptor affinity
by 20- to 40-fold. Amidation of the carboxyl terminus resulted in a 10-fold
decrease in activity and a 160-fold decrease in receptor affinity. These results
indicate that the alpha-factor receptor has a large hydrophobic binding pocket,
possibly containing a negatively charged side-chain, which interacts with the N
terminus of alpha-factor. The lack of correlation between activity and binding
and several analogs suggests that small residues near the N-terminus of alpha
factor may be very efficient in triggering isomerization of the receptor to its
activated state in the first step of the signal transduction pathway.
PMID- 9401916
TI - New mild acid-labile protecting groups for the guanidino function of N alpha
fluorenylmethoxycarbonyl-L-arginine in solid-phase peptide synthesis: 10,11
dihydro-5H-dibenzo[a,d]cyclohepten-5-yl, 2-methoxy-10,11-dihydoro-5H
dibenzo[a,d]cyclohepten-5-yl and 5H-dibenzo[a,d]cyclohepten-5-yl groups.
AB - 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl [5-dibenzosuberyl] and 5H
dibenzo[a,d]-cyclohepten-5-yl [5-dibenzosuberenyl] groups have been found to be
useful protecting groups for the guanidino function of arginine in solid-phase
peptide synthesis on Fmoc chemistry. The arginine derivatives (4a,b,c)
derivatized with these groups were easily deprotected with mild acid (less than
30 min with 25% trifluoroacetic acid). Tryptophan-containing peptide sequences,
two hexapeptides (6) and (8), were synthesized in good yield by mild acid
treatment (50% trifluoroacetic acid in 1 h) of the peptide resins (5a,c-f and
7a,c,d) assembled via 4a,b,c using benzotriazol-1-yl-oxy-tris-(pyrrolidino)
phosphonium hexafluorophosphate-1-hydroxybenzotriazole mediated coupling.
PMID- 9401917
TI - Synthesis and biological activities of head-to-tail cyclic bradykinin analogues
of varying ring size.
AB - Syntheses of cyclic kinin analogues with different backbone atom numbers are
described. Cyclization, by either the O-benzotriazolyl-N,N,N',N'
tetramethyluronium tetrafluoroborate/1-hydroxybenzotriazole/diisopropylethyl
amine (TBTU-HOBt-DIPEA) or the diphenylphosphoryl azide (DPPA) procedure of
linear peptides prepared by the solid-phase method based on the g-fluorenyl
methyloxycarbonyl chemistry, was used for preparing cyclo-Gly-Ile-Ile-Gly
bradykinin, cyclo-Lys-kallidin (cyclo-Lys-Lys-bradykinin) and cyclo-des Arg
bradykinin. Peptides were characterized by amino acid analysis, optical rotation,
analytical high-performance liquid chromatography and matrix-assisted laser
desorption ionization-time flight mass spectrometry. Pharmacological experiments
showed that cyclo-Gly-Ile-Ile-Gly-bradykinin (39 backbone atoms) and cyclo-Lys
bradykinin (30 backbone atoms) are about equipotent, when tested on the
relaxation of the isolated rat duodenum preparation. The potency of cyclo-des Arg
bradykinin is at least three orders of magnitude lower. The potency of cyclo-Lys
Lys-bradykinin (33 backbone atoms) is one tenth the activity of bradykinin but
about 10 times higher than the potency of the above-mentioned cyclokinins and
makes the latter analogue the most potent end-to-end cyclic analogue known
currently. The present results, in agreement with data from earlier reports, seem
to indicate that the enhancement of the number of backbone atoms in the cyclic
kinins first increases and subsequently decreases the potency, whereas a
reduction in the atom number from 27 to 24 causes a dramatic decrease in potency.
PMID- 9401918
TI - Conformational investigation of alpha,beta-dehydropeptides. VIII. N-acetyl
alpha,beta-dehydroamino acid N'-methylamides: conformation and electron density
perturbation from infrared and theoretical studies.
AB - The Fourier transform infrared spectra are analyzed in the regions of Vs(N-H),
amide I, amide II and Vs(C alpha = C beta) bands for a series of Ac-delta Xaa
NHMe, where delta Xaa = delta Ala, (Z)-delta Abu, (Z)-delta Leu, (Z)-delta Phe
and delta Val, to determine the predominant solution conformation of these
alpha,beta-dehydropeptide-related molecules and the electron distribution
perturbation in their amide bonds. The measurements were performed in
dichloromethane (DCM). To confirm and rationalize the assignments, the spectra of
the respective series of saturated Ac-Xaa-NHMe, recorded in DCM, and the spectra
of these two series of unsaturated and saturated compounds, recorded in
acetonitrile, were examined. To help interpret the spectroscopic results, the
equilibrium geometrical parameters for some selected amides were used. These were
optimized with ab initio methods in the 6-31G** basis set. Each of the
dehydroamides studied adopted a C5 structure, which in Ac-delta Ala-NHMe is fully
extended and accompanied by the strong C5 hydrogen bond. Interaction with the C
alpha = C beta bond lessened the amidic resonance within each of the flanking
amide groups. The N-terminal C = O bond was noticeably shorter, both amide bonds
were longer than the corresponding bonds in the saturated entities and the N
terminal amide system was distorted. Ac-delta Ala-NHMe constituted an exception.
Its C-terminal amide bond was shorter than the standard one and both amide
systems were prototypically planar.
PMID- 9401919
TI - Reengineering a type II beta-turn as a potential helix nucleator. Part I. Crystal
structure of Boc-Val-Pro-(D)Asp-Asp-Val-OMe monohydrate.
AB - The crystal structure of Boc-Val1-Pro2-(D)Asp3-Asp4-Val5-OMe is described as a
type II beta-turn reengineered into a potential helix nucleator. (D)Asp3 in the
peptide is responsible for the configurationally guided LD chiral type II beta
turn centered at Pro2-(D)Asp3, as well as the partially developed LL chiral type
I beta-turn centered at Asp4-Val5 by acceptance of a conformation nucleating H
bond from Val5NH to its carboxylic oxygen.
PMID- 9401920
TI - Synthetic peptide vaccines: palmitoylation of peptide antigens by a thioester
bond increases immunogenicity.
AB - Synthetic peptides have frequently been used to immunize animals. However,
peptides less than about 20 to 30 amino acids long are poor immunogens. In
general, to increase its immunogenicity, the presentation of the peptide should
be improved, and molecular weight needs to be increased. Many attempts have been
made to couple peptide immunogens to different carrier proteins [e.g. keyhole
limpet haemocyanin (KLH) or ovalbumin]. This leads to very complex structures,
however. We used a controlled conjugation of a peptide to a single long-chain
fatty acid like palmitic acid by a thioester or an amide bond. It was found that
these S-palmitoylated peptides were much more immunogenic than N-palmitoylated
peptides and at least similar to KLH-conjugated peptides with respect to
appearance and magnitude of induced antibodies (canine parvovirus) or
immunocastration effect (gonadotropin-releasing hormone). For chemical synthesis
of thioesters, we established conditions for solution and solid-phase synthesis.
In both phases, Cys(SBut) could only be deprotected efficiently using phosphines,
and S-acylation was accomplished using standard coupling at pH 5. We speculate
that, in vivo, the presence of an appropriate fatty acid chain, chemically linked
through a labile thioester bond, greatly enhances immunogenicity, because it
represents a favourable substrate for cleavage by cellular thioesterases in cells
of the immune system.
PMID- 9401921
TI - Common and differential recognition of structural features in synthetic peptides
by the catalytic domain and the Src-homology 2 (SH2) domain of pp60c-src.
AB - The relative efficiencies of the catalytic domain of the src-family kinase pp60c
src in phosphorylating four peptide substrates including (i) src-optimal peptide
(AEEEIYGEFEAKKKK), (ii) "-YEEI-peptide" (KKTHQEEEEPQYEEIPIYL), (iii) cdc2(6-20)
(KVEKIGEGTYGVVYK), (iv) src-autophosphorylation site peptide (ADFGLARLIEDNEYTARG)
and the relative efficiencies of its SH2 domain in binding the phosphorylated
forms of these peptide substrates were compared. The results show that the src
optimal peptide, "-YEEI-peptide," cdc2(6-20) peptide were phosphorylated by the
catalytic domain with high efficiency and that the phosphorylated form of all
three peptides could bind the SH2 domain of the kinase, confirming the hypothesis
proposed by Songyang and co-workers that the catalytic domain of pp60c-src
phosphorylates sites which are recognized by its own SH2 domain (Songyang et al.
(1995) Nature 373, 536-539). The four peptides were phosphorylated by the kinase
with relative efficiencies in the order of Src-optimal peptide > "-YEEI-peptide"
> cdc2(6-20) >> src-autophosphorylation site peptide. However, the Tyr(P)-Src
optimal peptide and [pY]15cdc2(6-20) bound to the SH2 domain of the kinase with
an affinity at least an order of magnitude lower than that of the tight-binding
peptide, "-pYEEI-peptide." Thus, our study suggests that the catalytic and SH2
domains of pp60c-src recognize overlapping but not identical determinants in the
local structure around the tyrosine phosphorylation site of the substrate
peptides.
PMID- 9401922
TI - Aza-peptides. III. Experimental structural analysis of aza-alanine and aza
asparagine-containing peptides.
AB - To determine the structural perturbations induced by the C alpha H-->N alpha
exchange in aza-peptides, we have examined by 1H NMR and IR spectroscopy various
derivatives of the aza-analogues of alanine, aspartic acid and asparagine in
different organic solvents with increasing polarity. Their general formulas are:
R1-AzXaa-NR2R3, R1-Pro-AzXaa-NR2R3 and R1-AzXaa-Pro-NR2R3 (where AzXaa denotes
the aza-analogue of the amino acid residue Xaa = Ala, Asp, Asn; R1 = Boc, Z; R2,
R3 = H, Me, iPr). The aza-analogue of an amino acid residue appears to be a
strong beta-turn-inducing motif, and the AzAsn carboxamide side-chain is capable
of interacting, as a proton donor, with the preceding peptide carbonyl group.
PMID- 9401923
TI - The nature of trypsin-pancreatic trypsin inhibitor binding: free energy
calculation of Tyr39-->Phe39 mutation in trypsin.
AB - The main goal of this work is the detailed study of the binding interactions in
the trypsin-pancreatic trypsin inhibitor (PTI) complex and, here, we present how
meaningful the Tyr39-Ile19 interaction is to the stability of that particular
complex using free energy methods. This knowledge should be very important in the
design of new inhibitors for trypsin and enzymes homologous to it. In particular,
it could help to decide whether it is possible to produce selective inhibitors
for these enzymes by appropriate mutations of residues in the contact region of
PTI.
PMID- 9401924
TI - Structure and supramolecular packing features of the dipeptide Arg-Val acetate.
AB - The title compound crystallizes in the zwitterionic form. The crystal forms a
supramolecular structure with the peptide molecules organized in head-to-tail
columns in the b direction. The arginine side-chains and acetate ions interact
with neighbor peptides in the c direction. Infinite hydrophobic columns are
present in the a direction; they involve the valine side-chains, the acetate
methyl groups and the methylene groups of the arginine side-chains. This three
dimensional organization is similar to that found in Lys-Val hydrochloride.
PMID- 9401925
TI - Technetium-99m labeled epidermal growth factor-tumor imaging in mice.
AB - We have shown previously that the epidermal growth factor peptide (EGF) may be
radiolabeled with 99mTc at room temperature and neutral pH by using the N
hydroxysuccinimide ester of S-acetyl mercaptoacetyltriglycine (MAG3) as a
bifunctional chelator. By a competition binding assay, we found that MAG3
conjugated EGF retained biological activity. Furthermore, the labeled peptide
exhibited saturation binding to EGF receptor-positive tumor cell lines which
could be inhibited by presaturation of the cells with unlabeled, native EGF.
Biodistribution in normal mice at 3 h postadministration showed rapid clearance
with minimal retention of the label in sampled organs. We have now investigated
the tumor localization properties in mice of this labeled peptide. Nude mice
implanted with the EGF receptor-positive tumors A431 and LS-174T were
administered labeled EGF and a labeled control peptide (BPTI, aprotinin). Tumor
uptake at 12 h postadministration was 0.44% injected dose/g for EGF/g vs. 0.09
for the control. Pretreatment of tumored mice with unlabeled EGF blocked about
half the tumor uptake. Animals were also administered an anti-EGF receptor
antibody labeled with 99mTc via MAG3. Relative to the antibody, tumor-to-muscle
ratios were improved from 6 to 15 and tumor-to-blood ratios from 0.4 to 7 with
EGF. These favorable results along with documented evidence of overexpression of
the EGF receptor in many human tumors suggest that 99mTc-EGF should be considered
further for tumor detection.
PMID- 9401926
TI - Primary structures of proteins characterized by proteinase K digestion and matrix
assisted laser desorption/ionization mass spectrometry.
AB - To improve the sequence ions of a protein in matrix-assisted laser
desorption/ionization mass spectrometry (MALDI-MS), proteinase K was used to
digest the protein followed by MALDI-MS characterization of the peptide
fragments. The primary structures of three proteins, insulin B chain, cytochrome
c and lysozyme, were determined by this method. A series of peptide fragments
including those differentiated by one residue can be produced from the protein by
using proteinase K digestion, thus providing support to the protein sequence. The
peptide fragments liberated from proteinase K proteolysis of the insulin B chain
allow the protein to be partially sequenced. Furthermore, some of the residues
are double or triple checked by generating a variety of fragments. The same
method was used to investigate cytochrome c and lysozyme denaturated in 3 M
guanidine hydrochloride. The success of the method relies on the intrinsic
properties of proteinase K and accurate determination of the peptide fragments by
MALDI-MS.
PMID- 9401928
TI - Periodontal conditions in 35-44-yr-old adults in France, 1993.
AB - A national study was carried out in France in 1993 to assess the periodontal
status of the population aged 35-44 yr. The study took part in the Second
International Collaborative Study of Oral Health Outcomes developed and
coordinated by the World Health Organization. The representative sample was
composed of 1000 subjects. The Community Periodontal Index of Treatment Needs
(CPITN) index was used. Gingivitis prevalence was high (80.4%) while 26.6% of
dentate subjects had shallow pockets (4-5 mm). Deep pockets (> 6 mm) were rare
(1.6%) concerning on average 0.1 sextant per subject; 87.5% of the 994 dentate
adults needed periodontal treatment. Oral health education and scaling should
reduce periodontal pathology in this population group.
PMID- 9401927
TI - Interleukin-6 production in human fibroblasts derived from periodontal tissues is
differentially regulated by cytokines and a glucocorticoid.
AB - Interleukin-6 (IL-6) is thought to be a major mediator of the host's defense
against infection, and it regulates immune responses in inflamed tissue. In this
study, we investigated the regulation of IL-6 production in human gingival
fibroblasts (HGF) and human periodontal ligament fibroblasts (HPLF). Pro
inflammatory cytokines including interleukin (IL)-1 alpha, IL-1 beta and tumor
necrosis factor (TNF)-alpha stimulated IL-6 production in HGF and HPLF in a time-
and dose-dependent manner. This IL-1 alpha, IL-1 beta, or TNF-alpha-induced IL-6
production was enhanced, but the cAMP accumulation they induced was inhibited by
the addition of indomethacin. This result suggests that endogenous prostaglandin
E2 (PGE2) partially inhibits IL-1 or TNF-alpha-induced IL-6 production and that
the enhancement of IL-6 production by IL-1 or TNF-alpha may not be caused through
endogenous PGE2-induced cAMP-dependent pathway. Dexamethasone (DEX), a
glucocorticoid which is a inhibitor of nuclear factor kappa B (NF-kappa B
activation, markedly inhibited IL-1 (alpha or beta) or TNF-alpha-induced IL-6
production; so this production may be partially mediated through NF-kappa B. IL-1
(alpha or beta) and TNF-alpha enhanced IL-6 production synergistically. IL-6
production in HGF or HPLF stimulated with IL-1 beta was augmented by the addition
of interferon (IFN)-gamma, but was slightly suppressed by the addition of IL-4.
Endogenous IL-6 enhanced IL-1 (alpha or beta)-induced IL-6 production in the
presence of IL-6 soluble receptor (IL-6sR). Accordingly, in inflamed periodontal
tissues, gingival fibroblasts and periodontal ligament fibroblasts stimulated
with pro-inflammatory cytokines such as IL-1 or TNF-alpha, may produce IL-6, and
this production can be differentially modulated by endogenous PGE2, IL-6sR, T
cell-derived cytokines such as IFN-gamma or IL-4, and glucocorticoids.
PMID- 9401929
TI - Effect of the NSAID flurbiprofen on remodelling after periodontal surgery.
AB - The aim of the present experiment was to assess the effect of the administration
of the NSAID flurbiprofen (Froben) on tissue healing after periodontal surgery.
Sites from patients with the same treatment modality (modified Widman flap) but
receiving a placebo drug and sites within each patient not exposed to surgery
served as controls. Nineteen patients suffering from moderate to severe
periodontal disease were recruited and they signed informed consent forms. These
patients required periodontal surgery as assessed at the periodontal re
evaluation. The sites chosen for the study were all diagnosed with PPD > or = 5
mm and were bleeding on probing. During the healing phase 10 patients received 50
mg Froben 3 times per day for 30 d whereas 9 patients received a placebo drug.
Two sites with PPD > or = 5 mm after initial therapy and bleeding on probing
served as surgical sites, whereas 2 similar sites were not exposed to surgery.
The study design was set up double-blind. The radiographic examination consisted
of 2-4 standardized vertical bitewings obtained at the periodontal re-evaluation
(BL) at 1, 3 and 6 months post-surgically for digital subtraction and computer
assisted densitometric image analysis (CADIA). The regions of interest analysed
were mesial or distal crestal sites. Minimal remodelling activity was observed
radiographically after periodontal surgery in both patient groups. There were no
statistically significant differences between the four groups of sites regarding
the mean changes in density when analysing the pairs of radiographs 0-1, 0-3, 0-6
months. A frequency analysis was performed to list the number of sites with
different ranges of density change. No differences in the distributions of the
numbers of sites were observed when comparing the 4 site groups (Kolmogorov
Smirnov, p > 0.05). A significant reduction of the probing pocket depth and a
significant amount of clinical attachment gain was noted at the surgically
treated sites irrespective of whether the patients had used flurbiprofen or
placebo. Whereas the pathways leading to bone resorption in periodontally
diseased sites have been shown, in other studies, to be influenced by NSAID, the
results of the present study could not justify general administration of Froben
for the purpose of reduction of bone resorption after periodontal surgical
procedures in patients with adult periodontitis.
PMID- 9401930
TI - Cystatin A in gingival crevicular fluid of periodontal patients.
AB - Cystatins are physiological inhibitors of cysteine proteinases which are widely
distributed in human tissues and fluids. In the present study we analysed both
the cystatin activity and the different cystatin isoforms in gingival crevicular
fluid and saliva samples of nine periodontitis patients. All crevicular fluid
samples, which were collected with filter paper points, showed cystatin activity
ranging from 7-67 units/mg protein. The mean cystatin activity (24 units/mg
protein) was significantly lower (p < 0.05) than that of the saliva samples (mean
93 units/mg protein). The cystatin isoforms in the crevicular fluid were further
characterized by immunoblotting with specific antibodies against cystatin C, S,
SN and A. While they were clearly present in saliva, cystatin C, cystatin S and
cystatin SN could not be detected in any of the crevicular fluid samples.
Remarkably, cystatin A was found in all the crevicular fluids as well as in the
saliva samples. It is concluded that the cystatin activity found in crevicular
fluid is caused, at least partially, by cystatin A. Furthermore, the gingival
crevicular fluid is not a major contributor of cystatin C, S and SN activity in
saliva.
PMID- 9401931
TI - Radiography of spontaneous periodontitis in dogs.
AB - The pattern and distribution of periodontitis were investigated in 162 randomly
selected dogs available for necropsy in veterinary practice. There were 82 males
and 80 females of 50 different breeds (150 dogs were pure-bred and 12 were
mongrels, aged between 7 months and 14 yr. Presence of periodontitis was
determined by assessment of alveolar bone loss on radiographs of the skulls and
jaws. Periodontitis occurred frequently with increasing age, although the
prevalence varied markedly among and within different breeds. Of the breeds most
represented in the sample, periodontitis was most frequently seen in poodles and
dachshunds but was rarely recognized in German shepherd dogs. Regardless of age,
the vast majority of the dogs displayed either one or both of two different
radiographic patterns of alveolar bone loss. One pattern was characterized by
slight, horizontal alveolar bone loss involving interradicular and interdental
areas. The other pattern was one of predominantly crater-like, or narrow,
vertical bone defects which, when advanced, often extended around a single root
or tooth to surround the root apices. The two types of patterns did not seem to
be breed-dependent. The posterior maxillary and mandibular premolars and molars
were the most frequently affected teeth. Alveolar bone loss was most severe in
the maxilla, while corresponding bone loss in the mandible was more often related
to increasing age.
PMID- 9401932
TI - An immunohistochemical study on the localization of Porphyromonas gingivalis,
Campylobacter rectus and Actinomyces viscosus in human periodontal pockets.
AB - The localization and distribution of Porphyromonas gingivalis, Campylobacter
rectus and Actinomyces viscosus were studied in human periodontal pockets. After
obtaining voluntary consent from 9 patients, 12 teeth and their surrounding
periodontal tissue with advanced adult periodontitis were extracted carefully so
as not to change the structure of the periodontal pockets. The specimens were
processed into serial sections. One of the sections was stained with Brown &
Brenn-modified Gram stain to observe the distribution of bacteria. The others
were stained immunohistochemically by the Labelled Streptavidin Biotin method
(LSAB method) using specific rabbit antibodies against selected bacteria. Some
bacteria could be found within epithelial cells. P. gingivalis was found in 9/12
of the samples examined. Small aggregates of P. gingivalis were scattered in all
parts of the periodontal pockets, and some of these aggregates could be seen in
close contact with the epithelium. Conversely, C. rectus was observed in 5/12 of
the samples examined and was predominantly located in the middle and deep pocket
zones. C. rectus tended to form large clumps in both the tooth-attached and
epithelium-associated plaque area. A. viscosus was observed in 7/12 of the
samples examined and was localized predominantly in the tooth-attached plaque
area, especially in the shallow and middle pocket zones. Although unexpected
spills of unattached plaque from periodontal pockets was possible,
immunohistochemical staining with species-specific antibodies was extremely
sensitive and revealed the localization and the distribution of periodontal
disease-associated bacteria in human periodontal pockets.
PMID- 9401933
TI - Polyclonal B cell activators and in vitro induction of auto-antibody reactive
with collagen.
AB - Cells producing autoantibodies are known to be present in chronically inflamed
periodontal tissues. In sites of chronic inflammation, polyclonal B cell
activators (PBA) are known to exhibit adjuvant activity when combined with
foreign antigens. These results prompted an examination of PBA in eliciting an
antibody response to an autoantigen (i.e. collagen type I). Rat lymphocytes were
stimulated with rat collagen (type I), microbial PBA (LPS) or the combination of
LPS plus rat collagen in vitro. Anti-collagen antibody-forming cells (AFC) were
enumerated using an ELISPOT assay. Collagen or LPS alone elicited few anti
collagen AFC but the addition of LPS to collagen resulted in a substantial
adjuvant effect and yielded maximal responses to collagen. Comparisons of anti
collagen AFC from short-term immunized (2-6 wk after booster), non-immunized and
long-term immunized (3-4 months after booster) animals were performed. It
revealed that cells from recently immunized rats were significantly easier to
activate than the other 2 groups. The adjuvant effect of microbial PBA may be
important in anti-collagen antibody production and thus the localization of PBA
in periodontal pockets may explain why anti-collagen AFC are restricted to the
chronically inflamed periodontal tissues.
PMID- 9401934
TI - Maintenance of new cementum formed during cyclosporin A administration after
suspension of the treatment.
AB - The aim of the present investigation was to examine if new cementum (NC) formed
during cyclosporin A (CsA) administration was maintained after suspension of the
treatment. Thirty mg/kg/d of CsA were given to 3 male Sprague-Dawley rats. Three
control rats received oil-based vehicle solution. Nine wk later the drug and
vehicle administration were stopped and the rats continued to be fed with the
same standard laboratory diet and water ad libitum for 5 months. The rats were
anaesthetized, the tissues fixed by intracardiac perfusion of fixative solution
and the mandibles processed for Epon inclusion. Histological, histomorphometric
and ultrastructural analysis revealed that (a) NC covered extensive areas of the
root surfaces; its structural characteristics were identical to those observed in
the rats killed during CsA administration. (b) collagen fibres of the adjacent
connective tissue were functionally inserted into the NC. (c) In the presence of
cervical NC spurs the extent of the apical downgrowth of the junctional
epithelium, measured parallel to the cemento-dentinal junction, was decreased (up
to 64%) compared to the one occurring in areas devoid of NC deposits. These
results suggest that (a) NC deposition and its functional relations with the
adjacent connective tissue are not reversible after cessation of CsA treatment
and (b) in the presence of cervical NC spurs the amount of connective tissue
attachment on the root surfaces is increased.
PMID- 9401935
TI - Attachment loss with postmenopausal age and smoking.
AB - To determine whether postmenopausal bone loss and factors associated with
osteoporosis affect tooth retention, we examined vertebral and proximal femoral
(postcranial) bone mineral density in relation to tooth loss and attachment loss
in a cross-sectional study of 135 postmenopausal women (age range 41-70 yr).
Women had at least 10 teeth and no evidence of moderate or severe periodontal
disease. Full-mouth attachment loss measurements were made using a pressure
sensitive probe, and bone density was determined by dual-energy X-ray
absorptiometry. Attachment loss was correlated with tooth loss (number of
remaining teeth, radiologically determined), but not with vertebral or proximal
femur bone density. Multivariate analysis showed current smoking (p = 0.01),
years since menopause (p = 0.02) and the interaction of age and current smoking
(p < 0.01), to be statistically significant predictors of attachment loss in our
study population.
PMID- 9401936
TI - A hydrogel based on a polyaspartamide: characterization and evaluation of in-vivo
biocompatibility and drug release in the rat.
AB - This paper deals with the characterization of a new microparticulate hydrogel
obtained by gamma irradiation of alpha, beta-poly[N-(2-hydroxyethyl)-DL
aspartamide] (PHEA). When enzymatic digestion of PHEA hydrogel was evaluated
using various concentrations of pepsin and alpha-chymotrypsin no degradation
occurred within 24 h. In-vivo studies showed that this new material is
biocompatible after oral administration to rats. PHEA hydrogel was also studied
as a system for delivery of diflunisal, an anti-inflammatory drug. In-vitro
release studies in simulated gastrointestinal juice (pH 1 or 6.8) showed that
most of the drug was released at pH 6.8. In-vivo studies indicated that
diflunisal-loaded PHEA microparticles significantly improved the gastric
tolerance and oral bioavailability of the drug in comparison with free
diflunisal. These results suggest the potential application of PHEA hydrogel as a
new delivery system for the oral administration of anti-inflammatory drugs.
PMID- 9401937
TI - Effects of different absorption enhancers on the permeation of ebiratide, an ACTH
analogue, across intestinal membranes.
AB - The permeation of ebiratide (H-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH(CH2)8NH2), a
novel ACTH analogue, across the intestinal mucosae has been examined by use of
isolated intestinal membranes from rats in a modified Ussing chamber. Regional
differences were observed in the permeation of ebiratide across intestinal
membranes; the order of membrane permeability was jejunum > ileum > duodenum >
colon. Overall, the permeation of ebiratide was relatively poor. The effects of
various absorption enhancers were examined to increase the intestinal
permeability to ebiratide. Sodium glycocholate and sodium caprate had no
significant enhancing effect on the permeability of the jejunal membrane, but
significantly enhanced the permeation of ebiratide through the colonic membrane.
On the other hand, N-dodecyl-beta-D-maltopyramoside (LM) significantly enhanced
the permeation of ebiratide through both jejunal and colonic membranes. In
general, the absorption-enhancing effects of these agents were more predominant
in the colon than in the jejunum. Membrane damage by the absorption enhancers was
evaluated by measuring the amount of protein released from the intestinal
membrane. It was found that all the absorption enhancers slightly increased the
amount of protein released, but that the amounts of protein released in the
presence of these enhancers were much less than in the presence of
ethylenediaminetetraacetic acid (EDTA), used as a positive control. These
findings suggest that the absorption enhancers, especially LM might be useful
adjuvants for improving the intestinal absorption of peptide and protein drugs,
including ebiratide.
PMID- 9401938
TI - Airway reactivity to inhaled spasmogens 18-24 h after antigen-challenge in
sensitized anaesthetized guinea-pigs.
AB - The anaesthetized allergic guinea-pig was used to assess changes in airway
reactivity to four different inhaled spasmogens: methacholine, 5
hydroxytryptamine (5-HT), histamine and the thromboxane A2 mimetic, 9,11-dideoxy
9 alpha,11 alpha-methano-epoxy-PGF2 alpha (U-46619). Reactivity was determined 18
to 24 h after challenge of ovalbumin-sensitized guinea-pigs with inhaled
ovalbumin. This time coincides with the appearance of a late-phase
bronchoconstriction in these animals. Sensitivity to the spasmogen was assessed
from the concentration-response curve for the increase in pulmonary inflation
pressure (PIP) in ovalbumin- and saline-challenged sensitized animals. When
methacholine, 5-HT or histamine were the spasmogens there was no hyper
reactivity. The geometric mean EC50 values (i.e. the concentrations inducing half
the maximum effect) obtained from the dose-response curves for methacholine (73
(42-129) and 94 (66-134) micrograms mL-1), 5-HT (1.5 (0.81-3.03) and 1.1 (0.51
2.24 micrograms mL-1) and histamine (39 (21-75) and 72 (32-162) micrograms mL-1)
did not differ significantly (P > 0.05) between saline- and ovalbumin-challenged
animals, respectively. However, when U-46619 was the spasmogen, ovalbumin-induced
airway hyper-reactivity was observed as a leftwards shift of the concentration
response curve and the EC50 value for ovalbumin-challenged animals (8.1 (5.1-13)
ng mL-1) was significantly (P < 0.05) less than the value for control animals (39
(21-75) ng mL-1). Our findings suggest that airway hyper-reactivity is not 'non
specific', but instead depends on the chosen spasmogen. The absence of hyper
reactivity with certain spasmogens was not a result of poor delivery, because all
spasmogens caused a bronchoconstriction by the inhaled route. It was also not
associated with the model because ozone has been shown to induce hyper-reactivity
to inhaled methacholine and 5-HT. Because airway hyper-reactivity to both inhaled
histamine and agonists at muscarinic receptors is regularly seen in man, the
anaesthetized guinea-pig might not be the ideal model for assessing airway hyper
reactivity after antigen challenge and its modification by anti-asthma drugs.
PMID- 9401940
TI - Comparison of the effects of cimetidine and ranitidine on the pharmacokinetics of
disopyramide in man.
AB - The widely prescribed antiulcer agents cimetidine and ranitidine have the
potential to affect the absorption, metabolism or renal excretion of
disopyramide. This study investigated the effect of a single oral dose of
cimetidine or ranitidine on the pharmacokinetics of disopyramide and mono-N
dealkyldisopyramide in six healthy volunteers. The treatment was conducted in a
randomized cross-over design. Serum levels and urinary recoveries of disopyramide
and mono-N-dealkyldisopyramide were assayed by HPLC. Cimetidine significantly
elevated the maximum plasma concentration of disopyramide, the area under the
plasma concentration-time curve and the total amount of disopyramide excreted
unchanged in the urine, but the serum profile of mono-N-dealkyldisopyramide was
not significantly affected. The effects of ranitidine on the pharmacokinetics of
disopyramide and mono-N-dealkyldisopyramide were not significant. The interaction
between cimetidine and disopyramide occurred mainly at the site of absorption.
The results indicate that cimetidine, but not ranitidine, significantly increased
the absorption of orally administered disopyramide.
PMID- 9401939
TI - Intestinal absorption of stable cyclic glycylphenylalanine: comparison with the
linear form.
AB - The absorption, especially the stability and transportability, of the cyclic
peptide cyclic glycylphenylalanine (cyclo(Gly-Phe)) and the linear peptides
glycylphenylalanine, glycyl-D-phenylalanine and phenylalanylglycine have been
studied in rat small intestine. Linear peptides were degraded on the mucosal side
and only glycyl-D-phenylalanine appeared on the serosal side. However, cyclo(Gly
Phe) was stable on the mucosal side and appeared on the serosal side.
Furthermore, the absorption clearance of cyclo(Gly-Phe) was higher than that of
glycyl-D-phenylalanine. In the presence of the peptidase inhibitor bestatin, the
degradation of linear peptides was reduced and linear peptides appeared on the
serosal side, but only phenylalanylglycine, which is transported by the
oligopeptide transporter, was absorbed faster than cyclo(Gly-Phe). The absorption
clearance of cyclo(Gly-Phe) was reduced as its concentration was increased from
125 microM to 500 microM. Furthermore, the absorption clearance of cyclo(Gly-Phe)
at 125 microM was reduced at 4 degrees C or in the presence of glycylsarcosine
and cephalexin, which are transported by the oligopeptide transporter. These
results indicated that cyclo(Gly-Phe) was stable enough to be absorbed and was
transported in part by the oligopeptide transporter rather than completely by
passive diffusion.
PMID- 9401941
TI - Pharmacokinetics of N4-octadecyl-1-beta-D-arabinofuranosylcytosine in plasma and
whole blood after intravenous and oral administration to mice.
AB - N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) is a new cytotoxic
derivative of cytosine arabinoside with improved cytotoxic activity and stability
against deamination. Its pharmacokinetics were studied in mice. The drug was
administered intravenously and orally to ICR mice to assess its pharmacokinetic
parameters in plasma and whole blood. The lipophilic drug was administered in
small unilamellar liposomes 100-400 nm in diameter. The concentrations of NOAC in
plasma and erythrocytes were determined by high-performance liquid chromatography
(HPLC). When given orally a rather low amount of the delivered NOAC was absorbed
as the unchanged drug, resulting in a bioavailability of 1.1% from the plasma and
12.9% from whole blood. As shown elsewhere, the amount of drug absorbed is
sufficient to provide excellent cytotoxic activity in the L1210 leukemia and in
human xenograft models after oral administration. The mean residence time of NOAC
after intravenous administration was 3.5 h in plasma and 6 h in whole blood
giving NOAC a terminal half-life in blood substantially longer than that of
cytosine arabinoside. After oral administration the mean residence time was 18 h
in plasma and whole blood. In summary, NOAC has a prolonged half-life after
intravenous administration compared with cytosine arabinoside. The distribution
of NOAC in blood is highly dependent on its mode of administration.
PMID- 9401943
TI - Stereoselective passage of mefloquine through the blood-brain barrier in the rat.
AB - The pharmacokinetics of the enantiomers of mefloquine were studied in the rat
after administration of a racemic mixture and of the separate enantiomers (+)
mefloquine and (-)-mefloquine. When 50 mg kg-1 racemic mixture was administered
orally for 22 days, plasma concentrations of the (+) enantiomer were 2-3 times
higher than those of the (-) enantiomer whereas the opposite was true in every
part of the brain (cerebellum, cortex, hippocampus, hypothalamus and striatum).
Different concentrations of mefloquine were found in the different regions of the
brain; the lowest concentrations of (+/-)-mefloquine (27.0 nmol g-1) were in the
cerebellum and the highest (110.0 nmol g-1) in the hippocampus. The main
metabolite, carboxymefloquine, was detected in plasma but not in the brain. The
results indicate the mefloquine crosses the blood-brain barrier
stereoselectively.
PMID- 9401942
TI - Pharmacokinetics of intragastrically administered digoxin in rabbits with
experimental bile duct obstruction.
AB - A change in the functioning of the liver as a result of experimental cholestasis
could result in a change in the biotransformation of drugs. The aim of this study
was to evaluate the effect of extrahepatic cholestasis on the pharmacokinetics of
digoxin. The investigation was performed on male rabbits randomly divided into
two groups: sham-operated and animals with bile-duct ligation. Digoxin (0.02 mg
kg-1) was administered intragastrically as a single dose. Biomedical and anatomo
pathological tests and pharmacokinetic assays were performed before the operation
and on the 6th day after surgery. A significant increase in area under the serum
concentration-time curve and in mean residence time, a decrease in total body
clearance, a reduction in the volume of distribution and increases in maximum
concentration and the time to reach maximum concentration were observed in
animals with the bile-duct ligation. These results suggest reduced elimination of
digoxin in animals with obstructive cholestasis.
PMID- 9401944
TI - Affinity of the miotic drug, dapiprazole, at alpha 1-adrenoceptor subtypes A, B
and D.
AB - The functional affinities of the alpha 1-adrenoceptor antagonist, dapiprazole,
currently being used to reverse diagnostic pupillary dilation, were determined at
subtype A in rat vas deferens, at subtype B in guinea-pig spleen and at subtype D
in rat aorta and compared with various alpha 1-adrenoceptor subtype
discriminating antagonists. Dapiprazole had relatively high affinity both at rat
vas deferens alpha 1A-adrenoceptors (pA2 = 7.93) and at rat aortic alpha 1D
adrenoceptors (pA2 = 8.26), whereas its affinity at guinea-pig splenic alpha 1B
adrenoceptors (pA2 = 7.13) was lower. The reference antagonists, 5-methylurapidil
and the 5-methylurapidil/flesinoxan hybrid, B8805-033 ((+/-)- 1,3,5-trimethyl
6[[3[4(2(2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin -5-yl)-1
piperazinyl]propyl]-amino]2,4(1H,3H)-pyrimidinedione), were 40- and 1500-fold
selective for the A subtype, whereas spiperone and BMY 7378 (8-[2-[4-(2
methoxyphenyl)-1- piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione diHCI) were
confirmed as selective for the B and D subtypes of alpha 1-adrenoceptors,
respectively. Thus, in functional experiments dapiprazole seems to be moderately
selective (approximately 10-fold) for the A and D over the B subtype of alpha 1
adrenoceptors; the possible therapeutic consequence of this is discussed.
PMID- 9401945
TI - Cold-storage of rabbit thoracic aorta in University of Wisconsin solution reduces
endothelium-independent vasodilation.
AB - Optimum preservation conditions for storage of donor livers and blood vessels are
essential for successful transplantation. The blood vessels are used as vascular
conduits to facilitate anastomosis of the liver to the recipient's systemic
vasculature. Failure of some transplants has been ascribed to thrombosis of these
vascular conduits possibly because of alterations in vascular reactivity owing to
inadequate storage techniques. To restrict data variability previously associated
with studies using a heterogeneous sample of vessels from man, this study
investigated changes in vascular reactivity in segments of rabbit thoracic aorta
from male, age-matched, New Zealand White rabbits stored at 4 degrees C in either
University of Wisconsin solution (UW; Du Pont Pharmaceuticals, UK) or Krebs
Bulbring buffer (KB). Percent vasodilation to acetylcholine remained
significantly greater in UW than in KB at -log (M) concentrations of 7.0 (UW =
47.05 +/- 4.26 compared with KB = 13.20 +/- 7.20%; P < 0.001), 6.5 (UW = 66.82 +/
4.83 compared with KB = 26.60 +/- 9.48%; P < 0.01), and 6.0 (UW = 83.68 +/- 5.26
compared with KB = 31.20 +/- 9.83%; P < 0.001). This was not significantly
different to relaxation in unstored arteries and suggested improved endothelial
function and structure, confirmed by electron microscopy. Percent vasodilation to
sodium nitroprusside was significantly lower in UW than in unstored (D0) arteries
at -log (M) concentrations of 7.5 (D0 = 28.27 +/- 4.02 compared with UW = 15.21
+/- 1.82%; P < 0.01), 7.3 (D0 = 52.58 +/- 5.05 compared with UW = 29.23 +/-
1.94%; P < 0.01), 7.0 (D0 = 69.70 +/- 4.85 compared with UW = 49.72 +/- 2.49%; P
< 0.05), and 6.4 (D0 = 93.16 +/- 2.93 compared with UW = 71.29 +/- 5.20%; P <
0.05). Percent vasodilation was also lower in UW- compared with KB-stored
arteries at -log (M) sodium nitroprusside concentrations of 7.0 (UW = 49.72 +/-
2.49 compared with KB = 64.11 +/- 5.03%; P < 0.05) and 6.4 (UW = 71.29 +/- 5.20
compared with KB = 96.91 +/- 5.96; P < 0.05). Electron microscopy confirmed that
this was not a result of degradation of smooth muscle structure. The nitric oxide
synthase inhibitor L-NG-nitro-L-arginine methyl ester (100 microM) did not
significantly modulate sodium nitroprusside-induced vasodilation in unstored
arteries, when endothelial function was maximum, or in UW-stored arteries,
suggesting that the reduced responses in UW-stored arteries were not because of
increased synthesis of nitric oxide. This reduced relaxation to sodium
nitroprusside was therefore nitric oxide-independent and not a result of
competition between sodium nitroprusside and endothelial 'nitric oxide donation'
for cGMP. In summary, cold-storage preservation with UW reduced endothelium
independent vascular relaxation by mechanisms other than competition with NO;
this requires further evaluation.
PMID- 9401946
TI - Twenty-four-hour variations in the effect of nitrodilators in rat aorta: lack of
influence of the endothelium.
AB - Time-dependent variations of the vasodilator effects of sodium nitroprusside and
glyceryl trinitrate on isolated smooth muscle have been studied on rings of rat
thoracic aorta, both endothelium-intact and endothelium-denuded. For most of the
concentrations of sodium nitroprusside used the induced relaxations were
significantly dependent on the time the tissues were obtained. However,
significant temporal differences were obtained for glyceryl trinitrate-induced
relaxations at lower concentrations only for both endothelium-intact and
endothelium-denuded preparations. EC50 values of sodium nitroprusside and
glyceryl trinitrate (i.e. the concentrations inducing half the maximum response)
were also significantly different and they had quite similar rhythmic features
both in endothelium-intact and in endothelium-denuded preparations. These results
clearly show that the in-vitro sensitivity of rat thoracic aorta to nitrodilator
agents varies over a 24-h period and thus depends on when the animals were
killed; the presence of endothelium does not change the rhythm of nitrodilator
activity. These variations might be a result of circadian rhythm in the guanylate
cyclase-cGMP system which mediates responses to nitrodilator agents.
PMID- 9401947
TI - Effect of ganglionic blocking compounds on in-vivo fluid secretion in the rat
small intestine.
AB - It is well-known that enteric, secreto-motor nerves mediate cholera toxin-induced
fluid secretion in the rat small intestine. This notion is, in part, derived from
experiments on anaesthetized animals in which the response to cholera toxin was
antagonized by the ganglionic nicotinic receptor antagonist, hexamethonium. In
the current study, such anti-secretory action of ganglionic blocking compounds
was analysed in an experiment designed to minimize any possible negative effect
of general anaesthesia on intestinal secretion. Rats were anaesthetized with
ether for 5-10 min, during which time a jejunal loop (10-12 cm) was constructed.
The loop was challenged with one of the secretagogues, cholera toxin,
prostaglandin E1 (PGE1) or okadaic acid. Saline (control) or either of the
ganglionic blockers, hexamethonium and chlorisondamine, was administered
intravenously. The rats were killed 5 h (cholera toxin) or 1.5 h (PGE1 and
okadaic acid) after challenge, and the amount of fluid accumulated in the loops
was determined. Cholera toxin-induced secretion was unchanged by hexamethonium
but reduced by approximately 80% by chlorisondamine. The difference in effect
between the two blockers might relate to the duration of ganglionic blockade.
Chlorisondamine blocked secretion induced by either PGE1 or okadaic acid by
approximately 60%. It is suggested that the anti-secretory effect of ganglionic
blocking compounds might be a result of blockade of secreto-motor nerves but
other mechanisms, for example interference with haemodynamic factors, cannot be
ruled out.
PMID- 9401948
TI - Several receptor subtypes contribute to 5-hydroxytryptamine-induced secretion by
rat ileum in-vitro.
AB - The receptors contributing to 5-hydroxytryptamine (5-HT)-induced secretion by rat
ileum were investigated in-vitro using selective agonists and antagonists. 5-HT
induced a dose-dependent increase in the short-circuit current (SCC) generated by
both intact and stripped sheets of rat ileum. 1-Phenylbiguanide, a selective 5
HT3 agonist, and 5-methoxytryptamine, an agonist that lacks affinity for 5-HT3
receptors, also increased the SCC. In intact sheets 5-HT was more effective than
either 1-phenylbiguanide or 5-methoxytryptamine, whereas in stripped sheets 5-HT
and 5-methoxytryptamine were equipotent, with 1-phenylbiguanide having little
effect. Tetrodotoxin abolished the response of intact sheets to 1-phenylbiguanide
but only reduced the responses to 5-HT and 5-methoxytryptamine by 57% and 54%,
respectively. This inhibition was reduced to 25% in stripped sheets. The 5-HT3
antagonist granisetron abolished the response to 1-phenylbiguanide, but did not
alter the effects of 5-HT. Ketanserin, a 5-HT2 antagonist, had a small effect on
the actions of 5-methoxytryptamine in intact, but not stripped, sheets and no
effect on the response to 5-HT in either preparation. Tropisetron, a 5-HT3 and 5
HT4 antagonist, inhibited the response to 5-methoxytryptamine, but had less
effect on the response to 5-HT. Desensitization to 1-phenylbiguanide inhibited
the response to 5-HT in intact, but not stripped sheets, whereas desensitization
to 5-methoxytryptamine abolished the 5-HT response in stripped sheets, but
induced only 42% inhibition in intact sheets. Previous exposure to a combination
of both 1-phenylbiguanide and 5-methoxytryptamine abolished the 5-HT-induced
increase in SCC in both preparations. The findings suggest that 5-HT-induced
ileal secretion involves more than one 5-HT receptor subtype and that both neural
and non-neural mechanisms contribute to the response.
PMID- 9401949
TI - Stereoselectivity of butylidenephthalide on voltage-dependent calcium channels in
guinea-pig isolated ileum.
AB - Two geometric isomers, the Z- and the E- forms, can be separated from synthetic
mixtures of butylidenephthalide (Bdph). Z-Bdph (50-100 microM) non-competitively
inhibited Ca(2+)-induced contractions in depolarized (K+, 60 mM) guinea-pig ileum
longitudinal smooth muscle, with a pD2' value of 3.88 +/- 0.20 (n = 5). However,
E-Bdph (20-100 microM) competitively inhibited these contractions with a pA2
value of 4.56 +/- 0.18 (n = 5) which was significantly (P < 0.05) greater than
the pD2' value of Z-Bdph. In contrast, the two isomers had no stereoselective
inhibitory action on Ca2+ influx through pre- or post-junctional membranes of
cholinergic nerve endings from which the transmitter acetylcholine is released or
on Ca2+ release from intracellular stores. Therefore, the trans-Z and cis-E forms
of Bdph might have geometric stereoselectivity for voltage-dependent calcium
channels (VDC) in guinea-pig longitudinal smooth muscle. Both isomers might
inhibit more selectively the contractile twitch responses evoked by electrical
stimulation than by cumulative acetylcholine- or carbachol-induced transient
contractions in guinea-pig ileum longitudinal smooth muscle.
PMID- 9401950
TI - Comparison of the intestinal secretory response to 5-hydroxytryptamine in the rat
jejunum and ileum in-vitro.
AB - A secretory response to 5-hydroxytryptamine (5-HT) is observed throughout the
intestinal tract; this investigation has compared the nature of this response in
the jejunum and ileum of the rat in-vitro. Different basal electrical activity
was observed for jejunal and ileal sheets of rat small intestine. In both intact
and stripped preparations the basal short-circuit current (SCC) was greater and
the tissue resistance lower in the jejunum than in the ileum. 5-HT caused
concentration-dependent increases in SCC in intact and stripped preparations of
both regions. EC50 values were similar in the jejunum and ileum, stripped sheets
from both regions showing greater sensitivity. In the ileum the maximum increase
in SCC induced by 5-HT was similar in intact and stripped sheets, but in the
jejunum the response was greater in intact preparations. The jejunal response to
5-HT was reduced in the absence of bicarbonate but unaffected by lack of
chloride, whereas the ileal response was inhibited by removal of chloride but
unaltered in bicarbonate-free conditions. In intact sheets the tetrodotoxin
sensitive neural component was greater in the jejunum. In stripped sheets a
neural component could still be detected in the ileum, but not in the jejunum.
There are, therefore, fundamental differences in the way in which the jejunum and
ileum respond to 5-HT stimulation--the jejunal response is primarily a result of
stimulation of bicarbonate secretion whereas chloride secretion predominates in
the ileum. The myenteric plexus appears to play a more prominent role in the
jejunum; in the ileum other neural elements also contribute to the response.
PMID- 9401951
TI - Screening of hepatoprotective plant components using a HepG2 cell cytotoxicity
assay.
AB - Identification of the active components of plants with hepatoprotective
properties requires screening of large numbers of samples during fractionation
and purification. A screening assay has been developed based on protection of
human liver-derived HepG2 cells against toxic damage. Various hepatotoxins were
incubated with HepG2 cells in 96-well microtitre plates (30,000 cells well-1) for
1 h and viability was determined by metabolism of the tetrazolium dye 3-(4,5
dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulphophenyl)-2H
tetrazolium (MTS). Bromobenzene (10 mM) and 2,6-dimethyl-N-acetyl-p-quinoneimine
(2,6-diMeNAPQI, 200 mM) had greater toxic effects than tert-butyl hydroperoxide
(1.8 mM) or galactosamine (10 mM), reducing mean viability to 44.6 +/- 1.2%
(s.e.m.) and 56.1 +/- 2.1% of control, respectively. Protection against toxic
damage by these agents was tested using a crude extract of a known
hepatoprotective Sri Lankan plant, Osbeckia aspera, and two pure established
hepatoprotective plant compounds, (+)-catechin and silymarin (1 mg mL-1).
Viability was significantly improved by Osbeckia (by 37.7 +/- 2.4%, P < 0.05, and
36.5 +/- 2.1%, P < 0.05, for bromobenzene and 2,6-diMeNAPQI toxicity,
respectively). Comparable values for (+)-catechin were 68.6 +/- 2.9% and 63.5 +/-
1.1%, and for silymarin 24.9 +/- 1.4% and 25.0 +/- 1.6%. This rapid and
reproducible assay should prove useful for the isolation and identification of
active hepatoprotective compounds in crude plant extracts.
PMID- 9401952
TI - Cisplatin-induced changes in adenine nucleotides in rat kidney slices:
amelioration by tiopronin and procaine.
AB - The adenine nucleotides (ATP, ADP and AMP) in rat renal cortical slices exposed
in-vitro to cisplatin, an anticancer drug, were determined by HPLC. Cisplatin had
no effect on total adenine nucleotides in the slices but caused a time- and
concentration-dependent decrease in ATP levels with a concomitant increase in ADP
and AMP levels. The decrease in ATP and increases in ADP and AMP concentrations
became statistically significant after incubation with cisplatin (2 mM) for 90
min or after cisplatin (1 mM) for 120 min. Both tiopronin, a sulphydryl
containing drug, and procaine, an antioxidant, protected against cisplatin
induced changes in the adenine nucleotides. The results indicate a cisplatin
induced defect in cellular energetics that occurs at a relatively late stage in
the process of toxicity to the slices in this in-vitro model. Cisplatin-induced
depletion of ATP in the slices might result from an increase in catabolism of ATP
to ADP and AMP. Maintenance of the normal concentration of ATP in the slices
might be involved in the protection afforded by tiopronin and procaine against
cisplatin-induced nephrotoxicity.
PMID- 9401953
TI - Application of muscle microdialysis to evaluate the concentrations of the
fluoroquinolones pazufloxacin and ofloxacin in the tissue interstitial fluids of
rats.
AB - Muscle microdialysis has been used to determine the unbound concentrations of the
fluoroquinolones, pazufloxacin and ofloxacin, in tissue interstitial fluids
(Cisf,u) of rats under steady state conditions. Cisf,u was estimated from the
concentration in dialysate and the in-vitro permeability rate constant by the
extrapolation method based on the clearance concept. Paper-disks were inserted
under the abdominal skin of rats, and the drug concentrations in the fluids
penetrating into the disks (Cdisk) were measured and compared with Cisf,u. The
Cisf,u of pazufloxacin and ofloxacin in muscle were close to their unbound
concentrations in the venous plasma; these were 75.3% and 77.1%, respectively, of
the total concentrations in plasma at the steady state. The Cdisk of pazufloxacin
and ofloxacin were also close to their Cisf,u. These results indicate that the
unbound concentrations of the fluoroquinolones in the tissue interstitial fluids
were the same as those in the venous plasma. The disk insertion technique seems
to be useful for evaluating drug concentrations in tissue interstitial fluid.
PMID- 9401954
TI - Isoquinoline derivatives isolated from the fruit of Annona muricata as 5-HTergic
5-HT1A receptor agonists in rats: unexploited antidepressive (lead) products.
AB - The fruit and the leaves of Annona muricata (Annonaceae) are used in traditional
medicine for their tranquillizing and sedative properties. Extracts of the plant
have been shown to inhibit binding of [3H]rauwolscine to 5-HTergic 5-HT1A
receptors in calf hippocampus, and three alkaloids, annonaine (1), nornuciferine
(2) and asimilobine (3), isolated from the fruit have been shown to have IC50
values of 3 microM, 9 microM and 5 microM, respectively, although in ligand
binding studies it was not possible to determine whether interaction of these
ligands with the receptor was agonistic or antagonistic. This paper presents the
results of functional assays of the alkaloids. The inhibition of cAMP
accumulation was tested in NIH-3T3 cells stably transfected with the 5-HT1A
receptor from man. None of the alkaloids showed antagonistic properties towards
the 5-HT1A receptors because in the antagonistic tests no influence on the
forskolin-stimulated increase of cAMP level was detected. Full agonistic
properties were measured for all three compounds; the inhibition constants (Ki)
for 1, 2 and 3 were < 10 microM. Inhibition of the binding of the radioligand to
the 5-HT1A receptor was observed in every ligand-binding assay performed with the
alkaloids; the Ki values for 1, 2 and 3 were in the microM range. These results
imply that the fruit of Annona muricata possesses anti-depressive effects,
possibly induced by compounds 1, 2 and 3, and that in the past potent leads for
the development of anti-depressive therapeutics have not been used.
PMID- 9401955
TI - Cirsimarin and cirsimaritin, flavonoids of Microtea debilis (Phytolaccaceae) with
adenosine antagonistic properties in rats: leads for new therapeutics in acute
renal failure.
AB - In traditional medicine Microtea debilis is used against proteinuria. In ligand
binding studies extracts of Microtea debilis have been shown to inhibit the
binding of [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) to adenosine-A1
receptors in rat forebrain membranes. Subsequently, cirsimarin, a flavonoid, was
isolated as the active component and was shown to function as adenosine
antagonist at the adenosine-A1 receptor in-vitro. In this study we have
investigated the adenosine-A2 receptor activity of cirsimarin the in-vivo
inhibition of the effects of adenosine by cirsimarin in rats, the absorption of
cirsimarin and the inhibition of the binding of [3H]DPCPX to the adenosine-A1
receptor by urine samples obtained after oral administration of crude extract of
Microtea debilis, cirsimarin or cirsimaritin to rats. Cirsimarin inhibited the
binding of [3H]5'-N-ethylcarboxamidoadenosine ([3H]NECA) to adenosine-A2
receptors in rat striatum with an inhibition constant, Ki, of 6.5 +/- 0.3 microM.
The decrease of heart rate and blood pressure induced by adenosine was
significantly inhibited by cirsimarin. After oral administration of 8 and 80 mg
kg-1 cirsimarin, the compound could not be detected in either plasma or urine,
but the presence of cirsimaritin was established. By use of beta-glucuronidase,
glucuronides of cirsimaritin were also detected in the urine. The concentrations
of cirsimaritin in the plasma were 0.126 +/- 0.04, 0.138 +/- 0.015, and 0.120 +/-
0.022 microM, respectively, 2, 5 and 12 h after administration of 8 mg kg-1
cirsimarin. The concentrations of cirsimaritin in the urine at the same times
after administration of the same dose were 2.05 +/- 1.86, 5.05 +/- 2.6 and 2.06
+/- 0.09 microM, respectively. The inhibition of the binding of [3H]DPCPX to the
adenosine-A1 receptor by urine samples collected 2, 5 and 12 h after oral
administration of 8 mg kg-1 cirsimarin or a crude extract of Microtea debilis
containing approximately 8 mg kg-1 cirsimarin and 2.8 mg kg-1 cirsimaritin, or
6.8 mg kg-1 cirsimaritin, was not significantly different from that of urine
samples collected from untreated rats, in contrast with urine samples collected 1
and 2 days after oral administration of 80 mg kg-1 cirsimarin. Approximately 3%
of the cirsimarin was excreted in the urine as cirsimaritin. The results indicate
that in the kidney and urinary tract the concentrations of cirsimaritin produced
after ingestion of more than 8 mg kg-1 cirsimarin can be high enough to inhibit
the interaction of adenosine with its receptors; this might explain the
effectiveness of Microtea debilis preparations against proteinuria in traditional
medicine.
PMID- 9401956
TI - Evaluation of the long-term effects of oleum origani on the toxicity induced by
administration of streptozotocin in rats.
AB - Oleum origani, the essential oil of Origanum onites L., is a traditional plant
material used in Turkey for the treatment of several diseases, including diabetes
mellitus. This study has evaluated the effect of oleum origani on streptozotocin
induced tissue injury and haematological changes. The effect of oleum origani on
glycaemia was also studied. Long-term administration of oleum origani resulted in
significant improvement of tissue injury induced by streptozotocin treatment. No
effect on blood glucose levels was detected. In addition, any visible toxicity or
disturbance of haematological parameters and tissue structure attributable to the
long-term use of oleum origani were not established in normal rats. The data
indicate that long-term use of oleum origani might be effective in preventing or
at least in retarding the development of some complications of diabetes mellitus.
Further investigation is required to determine the underlying mechanism(s) of the
protective effect against tissue injury induced by streptozotocin-treatment of
rats.
PMID- 9401957
TI - The development of nao li shen and its clinical application.
AB - The traditional Chinese medicine Nao Li Shen (containing ginseng, gastrodia
tuber, chuanxiong rhizome and red sage root) is used in craniocerebral injury,
cervical spondylosis and cerebrovascular diseases. The preparation, as an orally
administered liquid, was tested in Mongolian gerbils and shown to increase
tolerance to ischaemia and anoxia. Clinical use of the preparation resulted in
improvement in 96% of 202 patients, as judged by right cerebral blood flow, TCD
and CT examination. We conclude that Nao Li Shen has a positive curative effect
upon craniocerebral injury and sequelae of cerebrovascular diseases.
PMID- 9401958
TI - Detection of a black deposit in intravenous fat emulsions.
PMID- 9401959
TI - Kinetic analysis of the phosphorylation-dependent interactions of synapsin I with
rat brain synaptic vesicles.
AB - 1. Synapsin I, a major synaptic vesicle (SV)-associated phosphoprotein, is
involved in the regulation of neurotransmitter release and synapse formation. By
binding to both phospholipid and protein components of SV with high affinity and
in a phosphorylation-dependent fashion, synapsin I is believed to cluster SV and
to attach them to the actin-based cytoskeleton of the nerve terminal. 2. In the
present study we have investigated the kinetic aspects of synapsin I-SV
interactions and the mechanisms of their modulation by ionic strength and site
specific phosphorylation, using fluorescence resonance energy transfer between
suitable fluorophores linked to synapsin I and to the membrane bilayer. 3. The
binding of synapsin I to the phospholipid and protein components of SV has fast
kinetics: mean time constants ranged between 1 and 4 s for association and 9 and
11's for ionic strength-induced dissociation at 20 degrees C. The interaction
with the phospholipid component consists predominantly of a hydrophobic binding
with the core of the membrane which may account for the membrane stabilizing
effect of synapsin I. 4. Phosphorylation of synapsin I by either SV-associated or
purified exogenous Ca2+/calmodulin-dependent protein kinase II (CaMPKII)
inhibited the association rate and the binding to SV at steady state by acting on
the ionic strength-sensitive component of the binding. When dephosphorylated
synapsin I was previously bound to SV, exposure of SV to Ca2+/calmodulin in the
presence of ATP triggered a prompt dissociation of synapsin I with a time
constant similar to that of ionic strength-induced dissociation. 5. In
conclusion, the reversible interactions between synapsin I and SV are highly
regulated by site-specific phosphorylation and have kinetics of the same order of
magnitude as the kinetics of SV recycling determined in mammalian neurons under
comparable temperature conditions. These findings are consistent with the
hypothesis that synapsin I associates with, and dissociates from, SV during the
exo-endocytotic cycle. The on-vesicle phosphorylation of synapsin I by the SV
associated CaMPKII, and the subsequent dissociation of the protein from the
vesicle membrane, though not involved in mediating exocytosis of primed vesicles
evoked by a single stimulus, may represent a prompt and efficient mechanism for
the modulation of neurotransmitter release and presynaptic plasticity.
PMID- 9401960
TI - Evidence of two mechanisms for the activation of the glucose transporter GLUT1 by
anisomycin: p38(MAP kinase) activation and protein synthesis inhibition in
mammalian cells.
AB - 1. Inhibitors of protein synthesis stimulate sugar transport in mammalian cells
through activation of plasma membrane GLUT1, the housekeeping isoform of the
glucose transporter. However, it has been reported that some of these compounds,
in addition to their effect on protein synthesis, also activate protein kinases.
2. In the present study we have explored the role of these two effects on GLUT1
activation. In 3T3-L1 adipocytes and Clone 9 cells, stimulation of sugar
transport by puromycin, a translational inhibitor that does not activate kinases,
was not detectable until 90 min after exposure. In contrast, stimulation by
anisomycin, a potent Jun-NH2-terminal kinase (JNK) agonist, exhibited no lag
phase. An intermediate response was observed to emetine and cycloheximide, weak
activators of JNK. 3. The potency of anisomycin to stimulate transport acutely
(30 min of exposure) was 5- to 10-fold greater than for its chronic stimulation
of transport, measured after 4 h of exposure. The stimulation of transport by a
low concentration of anisomycin (0.3 microM) was transient, peaked at 30-60 min
and it was inhibited (IC50 < 1 microM) by SB203580, which indicates that its
mediator is not JNK, but the homologous p38(MAP kinase) (p38(MAPK)). In contrast,
the responses to 4 h exposure to 300 microM anisomycin or puromycin were
refractory to SB203580. 4. Exposure to anisomycin resulted in rapid activation of
p38(MAPK). Activation of both p38(MAPK) and GLUT1 by 0.3 microM anisomycin was
cancelled by puromycin. 5. We conclude that the activation of GLUT1 in response
to anisomycin includes two components: a delayed component involving
translational inhibition and a fast, puromycin-inhibitable component that is
secondary to activation of p38(MAPK).
PMID- 9401961
TI - Leptin activates ATP-sensitive potassium channels in the rat insulin-secreting
cell line, CRI-G1.
AB - 1. Whole-cell current-clamp recordings demonstrate that leptin (0.3-10 nm)
hyperpolarizes CRI-G1 insulin-secreting cells. This effect is slow on onset and
is not reversed on washout of the leptin. 2. Voltage-clamp recordings indicate
that leptin activates a potassium conductance in the presence of intracellular
ATP (5 mm), but has not effect in its absence. Following activation of ATP
sensitive K+ (KATP) current by diazoxide (0.2 mm), addition of leptin did not
alter cell membrane potential or potassium current further. 3. The leptin-induced
hyperpolarization and increased potassium conductance are completely inhibited by
the application of the sulphonylureas tolbutamide (100 microM) and glibenclamide
(0.5 microM). 4. Cell-attached and inside-out single-channel recordings indicate
that leptin activates tolbutamide-sensitive KATP channels in CRI-G1 insulin
secreting cells.
PMID- 9401962
TI - Epoxyeicosatrienoic acids activate a high-conductance, Ca(2+)-dependent K +
channel on pig coronary artery endothelial cells.
AB - 1. Epoxyeicosatrienoic acids (EETs) have been described as endothelium-derived
hyperpolarizing factors (EDHFs), based on their stimulatory effects on smooth
muscle K+ channels. In order to reveal a putative autocrine effect of EETs on
endothelial channels, we have studied the effects of the four EET regioisomers
(5,6-EET, 8,9-EET, 11,12-EET and 14,15-EET) on the high-conductance, Ca(2+)
dependent K+ (BKCa) channel recorded in inside-out patches of primary cultured
pig coronary artery endothelial cells. Currents were recorded in the presence of
either 500 nm or 1 microM free Ca2+ on the cytosolic side of the membrane. 2. In
81% of experiments, EETs at < 156 nM, applied on the cytosolic side of the
membrane, transiently increased BKCa channel open state probability (PO) without
affecting its unitary conductance, thus providing evidence for direct action of
EETs, without involvement of a cytosolic transduction pathway. 3. The four EET
regioisomers appeared to be equally active, multiplying the BKCa channel PO by a
mean factor of 4.3 +/- 0.6 (n = 15), and involving an increase in the number and
duration of openings. 4. The EET-induced increase in BKCa channel activity was
more pronounced with low initial PO. When the BKCa channel was activated by 500
nM Ca2+, application of EETs increased the initial PO value of below 0.1 by a
factor of 5. When the channel was activated by 1 microM Ca2+, application of EETs
increased the initial PO value by a factor of 3. 5. Our results show that EETs
potentiate endothelial BKCa channel activation by Ca2+. The autocrine action of
EETs on endothelial cells, which occurs in the same concentration range as their
action on muscle cells, should therefore fully participate in the vasoactive
effects of EETs, and thus be taken into account when considering their putative
EDHF function.
PMID- 9401964
TI - A rapidly activating sustained K+ current modulates repolarization and excitation
contraction coupling in adult mouse ventricle.
AB - 1. The K+ currents which control repolarization in adult mouse ventricle, and the
effects of changes in action potential duration on excitation-contraction
coupling in this tissue, have been studied with electrophysiological methods
using single cell preparations and by recording mechanical parameters from an in
vitro working heart preparation. 2. Under conditions where Ca(2+)-dependent
currents were eliminated by buffering intracellular Ca2+ with EGTA, depolarizing
voltage steps elicited two rapidly activating outward K+ currents: (i) a
transient outward current, and (ii) a slowly inactivating or 'sustained' delayed
rectifier. 3. These two currents were separated pharmacologically by the K+
channel blocker 4-amino-pyridine (4-AP). 4-AP at concentrations between 3 and 200
microM resulted in (i) a marked increase in action potential duration and a large
decrease in the sustained K+ current at plateau potentials, as well as (ii) a
significant increase in left ventricular systolic pressure in the working heart
preparation. 4. The current-voltage (I-V) relation, kinetics, and block by low
concentrations of 4-AP strongly suggest that the rapid delayed rectifier in adult
mouse ventricles is the same K+ current (Kv1.5) that has been characterized in
detail in human and canine atria. 5. These results show that the 4-AP-sensitive
rapid delayed rectifier is a very important repolarizing current in mouse
ventricle. The enhanced contractility produced by 4-AP (50 microM) in the working
heart preparation demonstrates that modulation of the action potential duration,
by blocking a K+ current, is a very significant inotropic variable.
PMID- 9401963
TI - Modulation of inwardly rectifying potassium channels in cultured bovine pulmonary
artery endothelial cells.
AB - 1. We have used the patch-clamp technique to study modulation of the inwardly
rectifying K+ current (IK(IR)) in cultured bovine pulmonary artery endothelial
cells (CPAE cells). In whole-cell mode, IK(IR) was defined as the Ba(2+)
sensitive current. In single channel recordings, we observed a strongly inwardly
rectifying and K(+)-selective channel with a conductance of 31 +/- 3 pS. 2.
Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and functional
data suggest that the endothelial IRK is most probably Kir2.1. 3. Intracellular
ATP is required to prevent run-down of IRK in whole-cell mode. Single channel
activity disappeared in inside-out patches exposed to ATP-free solution and in
cell-attached patches on cells exposed to metabolic inhibition (KCN, 2
deoxyglucose). 4. The non-hydrolysable ATP analogues, ATP gamma S and adenylyl
imidodiphosphate (AMP-PNP), did not prevent run-down. Run-down did not occur in
the presence of okadaic acid, a phosphatase inhibitor, but was enhanced in the
presence of protamine, an activator of phosphatase 2A (PP2A). 5. GTP gamma S and
AlF4- inhibited IRK, also in the presence of ATP. GTP beta S antagonized the GTP
gamma S effect. Pretreatment of the cells with PTX did not affect the GTP gamma S
induced inhibition. Okadaic acid, however, slowed this inhibition. 6. Neither
activation of protein kinase A (PKA) nor activation of protein kinase C (PKC)
affected IRK. Additionally, neither cytochalasin B nor a high concentration of
intracellular Ca2+ affected the time course of IRK run-down. 7. We conclude that
run-down of IRK is probably due to dephosphorylation by PP2A. Activation of a PTX
insensitive G protein inhibits this current by a mechanism that is neither
mediated via the PKA and PKC pathways nor by intracellular Ca2+, but supposedly
by a G protein-dependent activation of a phosphatase.
PMID- 9401965
TI - Calcium-induced release of strontium ions from the sarcoplasmic reticulum of rat
cardiac ventricular myocytes.
AB - 1. The effects of strontium ions, Sr2+, on Ca(2+)-dependent feedback mechanisms
during excitation-contraction coupling were examined in voltage-clamped rat
ventricular myocytes in which intracellular [Ca2+] and [Sr2+] were monitored with
the fluorescent indicator, indo-1. 2. Voltage clamp depolarizations and caffeine
applications during superfusion in Ca(2+)-free, Sr(2+)-containing solutions were
employed to exchange intracellular Ca2+ with Sr2+. Myocytes were loaded with Sr2+
by applying voltage clamp depolarizations during superfusion in Na(+)-free,
Sr(2+)-containing solutions. 3. Caffeine applications produced large fluorescence
transients in Sr(2+)-loaded cells. Thus, Sr2+ could be sequestered and released
from the sarcoplasmic reticulum. 4. Ca2+ influx, but not Sr2+ influx, via
sarcolemmal Ca2+ channels evoked ryanodine-sensitive fluorescence transients in
Sr(2+)-loaded cells. These results demonstrated that Ca2+ influx-induced Sr2+
release (CISR) from the sarcoplasmic reticulum occurred in these experiments,
even though Sr2+ influx-induced Sr2+ release was not observed. 5. The amplitude
of the Ca2+ influx-induced fluorescence transient was 17 +/- 1% of the caffeine
induced transient (n = 5 cells), an indication that fractional utilization of
Sr2+ sequestered in the sarcoplasmic reticulum during CISR was low. 6. With
increased Sr2+ loading, the amplitude of Ca2+ influx- and caffeine-induced
fluorescence transients increased, but fractional utilization of sarcoplasmic
reticulum divalent cation stores was independent of the degree of Sr2+ loading.
These data suggest that Ca2+ influx directly activated the release of divalent
cations from the sarcoplasmic reticulum, but mechanisms promoting positive
feedback of Sr2+ release were minimal during CISR. 7. By comparison, in Ca(2+)
loaded myocytes, Ca2+ influx-induced Ca2+ release (CICR) utilized a greater
fraction of caffeine-releasable stores than CISR. Fractional utilization of Ca2+
stores during CICR increased with the degree of Ca2+ loading. 8. Taken together,
these results suggest that Ca(2+)-dependent feedback mechanisms play a major role
in determining the extent of sarcoplasmic reticulum Ca2+ release during cardiac
excitation-contraction coupling under a wide range of conditions.
PMID- 9401966
TI - Calcium homeostatic mechanisms operating in cultured postnatal rat hippocampal
neurones following flash photolysis of nitrophenyl-EGTA.
AB - 1. We examined Ca2+ homeostatic mechanisms in cultured postnatal rat hippocampal
neurones by monitoring the recovery of background-subtracted fluo-3 fluorescence
levels at 20-22 degrees C immediately following a rapid increase in Ca2+ levels
induced by flash photolysis of the caged Ca2+ compound nitrophenyl-EGTA (NP
EGTA). 2. A variety of methods or drugs were used in attempt to block
specifically efflux of Ca2+ by the plasmalemmal Na(+)-Ca2+ exchanger or uptake of
Ca2+ into mitochondria. 3. Many of the experimental manipulations produced a
decrease in intracellular pH (pHi) measured in sister cultures using the pH
sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF).
Accordingly, in each case, we determined the appropriate amount of the weak base
trimethylamine (TMA) required to restore baseline pHi prior to flash photolysis.
4. Blockade of the plasmalemmal Na(+)-Ca2+ exchanger by replacement of external
Na+ with either Li+ or N-methyl-D-glucamine (NMDG) markedly reduced pHi but did
not affect the rate of recovery of fluo-3 fluorescence intensities once pHi was
restored. 5. Inhibition of mitochondrial Ca2+ uptake, using the protonophore
carbonyl cyanide m-chloro-phenylhydrazone (CCCP), resulted in a reduction in pHi,
which could be restored by the addition of 2 mM TMA. Under these conditions the
rate of recovery of Ca2+ levels was significantly slower than in the controls.
Similar results were found using the respiratory chain inhibitor rotenone. 6. We
conclude that, when the potential effects of changes in pHi are taken into
account, mitochondria appear to sequester significant amounts of Ca2+ in the
neuronal preparations used.
PMID- 9401967
TI - A novel slow hyperpolarization-activated potassium current (IK(SHA)) from a mouse
hippocampal cell line.
AB - 1. A slow hyperpolarization-activated inwardly rectifying K+ current (IK(SHA))
with novel characteristics was identified from the mouse embryonic hippocampus x
neuroblastoma cell line HN9.10e. 2. The non-inactivating current activated
negative to a membrane potential of -80 mV with slow and complex activation
kinetics (tau act approximately 1-7 s) and a characteristic delay of 1-10 s (-80
to -140 mV) that was linearly dependent on the membrane potential. 3. Tail
currents and instantaneous open channel currents determined through fast voltage
ramps reversed at the K+ equilibrium potential (EK) indicating that primarily K+,
but not Na+, permeated the channels. 4. IK(SHA) was unaffected by altering the
intracellular Ca2+ concentration between approximately 0 and 10 microM, but was
susceptible to block by 5 mM extracellular Ca2+, Ba2+ (Ki = 0.42 mM), and Cs+ (Ki
= 2.77 mM) 5. In cells stably transformed with M2 muscarinic receptors, IK(SHA)
was rapidly, but reversibly, suppressed by application of micromolar
concentrations of muscarine. 6. At the single channel level K(SHA) channel
openings were observed with the characteristic delay upon membrane
hyperpolarization. Analysis of unitary currents revealed an inwardly rectifying I
V profile and a channel slope conductance of 7 pS. Channel activity persisted in
the inside-out configuration for many minutes. 7. It is concluded that IK(SHA) in
HN9.10e cells represents a novel K+ current, which is activated upon membrane
hyperpolarization. It is functionally different from both classic inwardly
rectifying IKir currents and other cationic hyperpolarization-activated IH
currents that have been previously described in neuronal or glial cells.
PMID- 9401968
TI - Functional nicotinic ACh receptors on interneurones in the rat hippocampus.
AB - 1. Neuronal nicotinic ACh receptors (nAChRs) were studied in the rat hippocampal
slice preparation using whole-cell patch-clamp recording techniques. 2. Responses
to ACh (100 microM) were detected on inhibitory interneurones in the Ca1 field of
the hippocampus proper and in the dentate gyrus, but not on principal excitatory
neurones in either region. The different neuronal types were identified based on
their morphology and location. 3. ACh excited interneurones in the hippocampus
and dentate gyrus in current-clamp recordings. In voltage-clamp recordings, ACh
activated inward currents were recorded from interneurones in the presence of
blockers of synaptic transmission and the muscarinic ACh receptor antagonist
atropine. The zero current potential for this response to ACh was near 0 mV. 4.
The effect of ACh was mimicked by the nAChR-selective agonists nicotine (100
microM) and 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP, 100 microM). The
response to ACh was reversibly antagonized by the neuronal nAChR antagonist
mecamylamine (10 microM). The nAChR alpha 7 subunit-selective antagonists alpha
bungarotoxin (100 nM) and methyllycaconitine (10 nM) also inhibited the response
to ACh. 5. These observations demonstrate the presence of functional nAChRs on
inhibitory interneurones in the rat hippocampus. Thus, a novel mechanism by which
ACh can regulate neuronal activity in the hippocampus is revealed.
PMID- 9401969
TI - Interchangeable discharge patterns of neurons in caudal nucleus tractus solitarii
in rat slices: role of GABA and NMDA.
AB - 1. We characterized in rat brain slices the discharge patterns of spontaneously
active neurons in the caudal region of the nucleus tractus solitarii (cNTS) and
the neuromodulatory role of GABA and glutamate, via GABAA and NMDA receptors. 2.
Spontaneous action potentials recorded intracellularly from cNTS neurons
manifested either a regular or an irregular discharge pattern, alongside
characteristic waveforms of the action potentials. These discharge patterns were
interchangeable, and were highly sensitive to fluctuations in membrane
potentials. In addition, the repolarizing rate of the after-hyperpolarization
(AHP) in cNTS neurons that exhibited a regular discharge pattern was
significantly higher than that of neurons that displayed irregular discharges. 3.
cNTS neurons that manifested a regular discharge pattern were converted to
irregular discharges upon superfusion with GABA (200 microM). This was
accompanied by a reduction in the repolarizing rate of the AHP of both
spontaneous and evoked action potentials. Conversion of discharge patterns in the
opposite direction was elicited by superfusion with NMDA (6.8 microM). 4. The
irregular discharges of spontaneous or evoked cNTS neurons were converted to a
regular discharge pattern by bicuculline (200 microM). Subsequent application of
D(-)-2-amino-5-phosphonopentanoic acid (250 microM) essentially led the neuronal
discharges to revert to an irregular pattern. 5. Our results support the presence
of two interchangeable modes of electrophysiological manifestations from the same
cNTS neuronal population. They also showed that GABA and glutamate, via GABAA and
NMDA receptors, may provide a novel form of neuromodulation at the cNTS by
switching the patterns of neuronal discharges.
PMID- 9401970
TI - Different roles for GABAA and GABAB receptors in visual processing in the rat
superior colliculus.
AB - 1. The superficial grey layer of the superior colliculus (SGS) contains a high
proportion of GABAergic inhibitory neurones. We have investigated the role of
GABA receptors in synaptic transmission of aspects of visual activity in the SGS
that may be driven by inhibitory mechanisms, such as surround inhibition and
response habituation. 2. Multi-barrel glass iontophoretic pipettes were used to
record single neuronal activity in the SGS of urethane-anaesthetized rats. Visual
stimulation was provided by the display of moving bars and stationary spots of
light on a monitor placed in the receptive field. 3. Both ejection of GABA and
the GABAB agonist baclofen reduced responses to moving bars (interstimulus
intervals > or = 8 s). The effects of GABA were reversed by the GABAA antagonist
bicuculline, and the effects of baclofen were antagonized by the GABAB antagonist
CGP 35,348. 4. Surround inhibition was estimated by plotting the response to
flashed spots of increasing diameter. In controls, expanding the spot diameter
beyond the excitatory receptive field caused a decrease in the response. This
inhibitory surround was reversibly reduced by bicuculline, but CGP 35,348 had no
effect. 5. Response habituation is the progressive reduction in the visual
response during repetitive stimulus presentation. In controls, the visual
response was reduced to 44 +/- 3% of its initial level when a stimulus (moving
bar) was presented 5 times with an interstimulus interval of 0.5 s. During CGP
35,348 ejection, response habituation was reversibly reduced. Bicuculline had no
effect on response habituation. 6. The effects of bicuculline on surround
inhibition in the superior colliculus are consistent with similar studies in the
lateral geniculate nucleus which indicate that GABAA receptors mediate this
effect. The function of GABAB receptors in the visual system is less well
researched. The reduction of response habituation with CGP 35,348 demonstrates
that, at least in the SGS, GABAB receptors have an important role in visual
transmission which is distinct from that of GABAA receptors.
PMID- 9401971
TI - Novel glutamate- and GABA-independent synaptic depolarization in granule cells of
guinea-pig hippocampus.
AB - 1. Dual intracellular recordings of granule cells, hilar interneurons and CA3
pyramidal cells were performed in transverse slices of guinea-pig hippocampus. At
resting membrane potential, in the presence of 4-aminopyridine, ionotropic
glutamate receptor antagonists and the GABAA receptor antagonist bicuculline,
granule cells showed spontaneous, large amplitude depolarizations correlated with
synchronous bursting activity of interneurons. 2. Under these conditions,
pyramidal cells exhibited large amplitude monophasic GABAB inhibitory
postsynaptic potentials (IPSPs) synchronous with the GABAergic interneuron burst
discharges. The granule cells also received a GABAB input, which was evident only
when the neurons were depolarized by DC injection. The GABAB receptor antagonist
CGP 55,845A (CGP) blocked the GABAB IPSPs in both pyramidal cells and granule
cells; however, the depolarizing potential in granule cells was unaffected by the
drug. 3. The granule cells depolarization in the presence of CGP was monophasic
and exhibited linear voltage dependence with a reversal potential around -40 mV,
suggesting that it was generated by a synaptic input activating a mixed cationic
current. 4. The granule cell depolarization was abolished following the addition
of tetrodotoxin to the bath. In addition, perfusing the slice with a low Ca(2+)
containing solution (0.5 mM Ca(2+)-10 mM Mg2+) also abolished the granule cell
depolarization, confirming the synaptic origin of the event. 5. (S)-Methyl-4
carboxyphenylglycine, L-(+)-2-amino-3-phosphonopropionic acid, propranolol and
atropine did not affect the granule cell depolarization, indicating that
metabotropic glutamate receptors, beta-adrenergic receptors and muscarinic
cholinergic receptors were not involved in generating the granule cell
depolarizing synaptic response. 6. These findings indicate that, in the absence
of both glutamatergic and GABAergic inputs, synchronous interneuronal activity
can produce a depolarizing synaptic response in granule cells. The neurochemical
responsible for the depolarization is currently under investigation.
PMID- 9401972
TI - Characterization of the inward current induced by metabotropic glutamate receptor
stimulation in rat ventromedial hypothalamic neurones.
AB - 1. Whole-cell patch clamp recordings were made from rat ventromedial hypothalamic
neurones in slices of brain tissue in vitro. Bath application of 50 microM
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) depolarized all
neurones tested by activation of an inward current of approximately 55 pA at -60
mV. 2. The inward current elicited by 1S,3R-ACPD was unaffected by K+ channel
blockade with external Cs+, Ba2+ or TEA. However, the current was significantly
reduced by replacement of the external NaCl with either Tris-HCl or LiCl. 3. The
1S,3R-ACPD-induced current was reduced by the heavy metal ions Ni2+ or La3+ and
also by the Na(+)-Ca2+ exchange current inhibitor 3',4'-dichlorobenzamil. 4. The
effects of 1S,3R-ACPD were mimicked by the group I metabotropic agonist 3,5
dihydroxyphenylglycine (DHPG) but not by the group III selective agonist, L-2
amino-4-phosphonobutanoate (L-AP4). Furthermore, the effects of 1S,3R-ACPD were
inhibited by the metabotropic antagonists alpha-methyl-4-carboxyphenylglycine
(MCPG) and 1-aminoindan-1,5-dicarboxylic acid (AIDA) but not by the presynaptic
metabotropic receptor antagonists alpha-methyl-4-phosphonophenylglycine (MPPG) or
alpha-methyl-4-tetrazolylphenylglycine (MTPG). 5. Photorelease of caged GDP beta
S inside neurones irreversibly blocked the 1S,3R-ACPD-induced current whilst
photolysis of caged GTP gamma S inside neurones irreversibly potentiated this
current. 6. The PLC inhibitor U-73,122 significantly reduced the size of the
inward current induced by 1S,3R-ACPD. This effect was not mimicked by the
inactive analogue U-73,343. 7. Flash photolysis of the caged calcium chelator
diazo-2 inside neurones diminished the response to 1S,3R-ACPD. 8. It is concluded
that group I metabotropic glutamate receptors depolarize neurones in the VMH by
activation of a Na(+)-Ca2+ exchange current through a G-protein coupled increase
in intracellular Ca2+.
PMID- 9401973
TI - Age-related functional changes of the glutamate receptor channels in rat Meynert
neurones.
AB - 1. The developmental changes of glutamate receptors (GluRs) in acutely
dissociated rat Meynert neurones were investigated using the conventional whole
cell and nystatin perforated patch recording modes under voltage-clamp
conditions. 2. The neurones became less responsive to N-methyl-D-aspartic acid
(NMDA) with age, most dramatically between 1 day and 2 weeks, while the responses
to kainic acid (KA) and L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) gradually increased. The metabotropic GluR response appeared a few
days after birth, but thereafter no further change was observed. 3. The decrease
in the NMDA response during postnatal development was due to an abrupt reduction
in the number of receptors without affecting the affinity, voltage-dependent Mg2+
blockade or high Ca2+ permeability (PCa/PCs approximately 7.0). 4. PCa/PCs in the
presence of KA decreased from 2.8 in the 1-day-old (1D) rat neurones to 1.1 and
0.44 in the 2-week-old (2W) and 6-month-old (6M) rat neurones, respectively. The
concentration-response relationship for KA shifted to the left with age. The KA
response was not affected by NS-102, a KA-selective antagonist, thus indicating
that the increased affinity of the receptor for the ligand resulted from the
change in the AMPA receptor channel subunits. 5. The AMPA response in the
presence of 10(-4) M cyclothiazide showed a change in the inward rectifying
current-voltage relationship with age. The KA response was strongly cross
desensitized by the addition of AMPA and was also blocked by 6-cyano-7
nitroquinoxaline-2,3-dione (CNQX), whereas a rapid desensitization of the AMPA
response was removed in a concentration-dependent manner by cyclothiazide. These
results indicate that the non-NMDA receptor channels are assembled from the
subunits of the AMPA receptor family without the GluR-2 subunit, thus resulting
in a high Ca2+ permeability. 6. The L-glutamate (Glu)-induced responses were more
sensitive to DL-2-amino-5-phosphonopentanoic acid (APV) in the 1D rat neurones
than in the adult rat neurones. 7. Both NMDA and KA raised the intracellular Ca2+
concentration ([Ca2+]i) in all neurones of 1D, 2W and 6M rats, though the
charybdotoxin-sensitive Ca(2+)-activated K+ current (IK(Ca)) did not appear in
the 1D rat neurones. An age-related prolongation of both IK(Ca) decay and [Ca2+]i
clearance was also seen after the removal of KA. 8. It was thus concluded that
the age-related changes of ionotropic receptors appear to play a key role in the
activities of immature and mature rat Meynert cholinergic neurones. The KA
induced IK(Ca), which developed with ageing, may thus function as one of the
negative feedback systems, and thereby prevent excess cell excitation and neural
damage, especially in adult rats.
PMID- 9401974
TI - Glycine receptors in cultured chick sympathetic neurons are excitatory and
trigger neurotransmitter release.
AB - 1. Total RNA isolated from embryonic chick paravertebral sympathetic ganglia was
used in a reverse transcription-polymerase chain reaction (RT-PCR) assay with a
pair of degenerate oligonucleotide primers deduced from conserved regions of
mammalian glycine receptor alpha-subunits. Three classes of cDNA were identified
which encode portions of the chicken homologues of the mammalian glycine receptor
alpha 1, alpha 2 and alpha 3 subunits. 2. The presence of functional glycine
receptors was investigated in the whole-cell configuration of the patch-clamp
technique in neurons dissociated from the ganglia and kept in culture for 7-8
days. In cells voltage clamped to -70 mV, glycine consistently induced inward
currents in a concentration-dependent manner and elicited half-maximal peak
current amplitudes at 43 microM. 3. The steady-state current-voltage relation for
glycine-induced currents was linear between +80 and -60 mV, but showed outward
rectification at more hyperpolarized potentials. Reversal potentials of these
currents shifted with changes in intracellular chloride concentrations and
matched the calculated Nernst potentials for chloride. 4. beta-Alanine and
taurine were significantly less potent than glycine in triggering inward
currents, with half-maximal responses at 79 and 86 microM, respectively. At
maximally active concentrations, beta-alanine-evoked currents were identical in
amplitude to those induced by glycine. Taurine-evoked currents, in contrast,
never reached the same amplitude as glycine-induced currents. 5. The classical
glycine receptor antagonist strychnine reversibly reduced glycine-induced
currents, with half-maximal inhibition occurring at 62 nM. Two more recently
characterized glycine receptor antagonists, isonipecotic acid (half-maximal
inhibition at 2 mM) and 7-trifluoromethyl-4-hydroxyquinoline-3-carboxylic acid
(half-maximal inhibition at 67 microM), also blocked glycine-evoked currents in a
reversible manner. The chloride channel blocker picrotoxin reduced glycine-evoked
currents, with half-maximal effects at 348 microM. Inhibition by the glycine
receptor channel blocker cyanotriphenylborate was half-maximal at 4 microM. 6.
Apart from evoking inward currents, glycine occasionally triggered short (< 100
ms) spike-like currents which were abolished by hexamethonium and thus reflected
synaptic release of endogenous acetylcholine. In addition, glycine caused Ca(2+)
dependent and tetrodotoxin-sensitive tritium overflow from neurons previously
labelled with [3H]noradrenaline. This stimulatory action of glycine was reduced
in the presence of strychnine and after treatment with the chloride uptake
inhibitor furosemide (frusemide). 7. In 65% of neurons loaded with the Ca2+
indicator fura-2 acetoxymethyl ester, glycine increased the ratio of the
fluorescence signal obtained with excitation wavelengths of 340 and 380 nm,
respectively, which indicates a rise in intracellular Ca2+ concentration. 8. The
results show that sympathetic neurons contain transcripts for different glycine
receptor alpha-subunits and carry functional heteromeric glycine receptors which
depolarize the majority of neurons to trigger transmitter release.
PMID- 9401975
TI - Adenosine formation in contracting primary rat skeletal muscle cells and
endothelial cells in culture.
AB - 1. The present study examined the capacity for adenosine formation, uptake and
metabolism in contracting primary rat muscle cells and in microvascular
endothelial cells in culture. 2. Strong and moderate electrical simulation of
skeletal muscle cells led to a significantly greater increase in the
extracellular adenosine concentration (421 +/- 91 and 235 +/- 30 nmol (g protein)
1, respectively; P < 0.05) compared with non-stimulated muscle cells (161 +/- 20
nmol (g protein)-1). The ATP concentration was lower (18%; P < 0.05) in the
intensely contracted, but not in the moderately contracted muscle cells. 3.
Addition of microvascular endothelial cells to the cultured skeletal muscle cells
enhanced the contraction-induced accumulation of extracellular adenosine (P <
0.05), whereas endothelial cells in culture alone did not cause extracellular
accumulation of adenosine. 4. Skeletal muscle cells were found to have ecto-forms
of several enzymes involved in nucleotide metabolism, including ATPases capable
of converting extracellular ATP to ADP and AMP. 5. Adenosine added to the cell
medium was taken up by muscle cells and incorporated into the adenine nucleotide
pool so that after 30 min of incubation, over 95% of the adenosine label was
present in ATP, ADP and AMP. A similar extent of incorporation of adenosine into
the nucleotide pool was evident in the endothelial cells. 6. The present data
suggest that contracting muscle cells induce an elevation in the extracellular
adenosine concentration. Addition of endothelial cells to muscle cells enhances
the contraction-induced formation of adenosine. Adenosine taken up by muscle and
endothelial cells from the extracellular space is not likely to be used for
storage in intracellular pools, but may serve to regulate muscle extracellular
adenosine levels.
PMID- 9401976
TI - Modulation of stimulus-secretion coupling in single rat gonadotrophs.
AB - 1. Exocytosis and intracellular [Ca2+] were determined simultaneously in single
anterior pituitary gonadotrophs from ovariectomized female rats. Dispersed cells
were cultured for 2-4 days with or without 0.2 nM oestradiol-17 beta (E2) before
use. Cells were stimulated with either gonadotrophin releasing hormone (GnRH) or
by membrane depolarization. Exocytosis was determined from the change in membrane
capacitance (Cm) using the perforated-patch whole-cell recording technique.
Intracellular [Ca2+] was measured using fura-2 fluorescence. 2. The exocytotic
response to 1 nM GnRH was characterized by a wide spectrum of responses, ranging
from exocytotic bursts to relatively slow, graded increases that were dependent
on the evoked intracellular Ca2+ pattern. A kinetic model is presented that
incorporates the observed steep dependence of exocytosis on measured
intracellular [Ca2+]; simulated exocytosis reasonably approximated observed
exocytotic responses, both kinetically and quantitatively. The model also
suggests that the modulatory effects of E2 are brought about either by a change
in the Ca2+ sensitivity of exocytosis or by a preferential clustering of docked
secretory granules close to sites of Ca2+ release. The results suggest that in
gonadotrophs an oscillatory Ca2+ signal is sensed by the exocytotic apparatus in
a modified form of digital encoding. 3. Exocytosis in E2-treated cells was 3-fold
greater than in non-treated cells for GnRH-evoked secretion, and 38% greater for
depolarization; however, there was no effect of E2 on the intracellular Ca2+
response to either stimulus. The results show that maximum expression of the
effect of E2 on exocytosis requires activation of GnRH-dependent pathways.
PMID- 9401977
TI - Extracellular glucose turnover in the striatum of unanaesthetized rats measured
by quantitative microdialysis.
AB - 1. Steady-state and time-resolved quantitative microdialysis was used to measure
dialysate concentration, extracellular concentration and the in vivo recovery of
glucose in rat striatum. 2. The extracellular concentration of glucose,
determined by the zero net flux method of Lonnroth, was 350 +/- 20 microM and the
in vivo recovery was 39 +/- 2%. 3. Veratridine caused a steep decrease in
dialysate glucose after an initial delay of 7.5 min. When steady-state glucose
levels had been reached in the presence of veratridine the extracellular
concentration was reduced to zero, but there was no significant change in in vivo
recovery. 4. Measurement of the dynamic changes during the administration of
veratridine showed an immediate decrease in extracellular glucose concentration
and a steep rise in in vivo recovery, which accounted for the delay in the delay
in the decrease in dialysate glucose. When extracellular concentration reached
zero, in vivo recovery returned to control levels.
PMID- 9401978
TI - Phasic activity in the human erector spinae during repetitive hand movements.
AB - 1. Phasic activity in the human back muscle erector spinae (ES) was studied
during repetitive hand movements. The hand movements were elicited voluntarily by
the subject or induced passively by the experimenter through a servomotor or
through cyclical electrical stimulation of muscles acting about the wrist. The
aim of the study was to determine whether the rhythmical activation of ES was of
supraspinal, intersegmental or segmental origin. 2. When voluntary rhythmical
hand movements were performed as fast as possible, cyclical ES EMG bursts
occurred at the same frequency. This frequency was significantly higher than that
reached when the task was to contract the back muscles as rapidly as possible.
This suggests that the ES activity during the fast hand movements was not
generated by direct commands descending to the ES muscles from the motor area of
the cerebral cortex responsible for voluntary back muscle activation. 3. During
imposed rhythmical hand movements, ES EMG bursts remained entrained to the hand
movements, even when movement frequencies far exceeded those attainable
voluntarily either for the hand or the back. This showed that ES EMG responses
could be evoked by the hand movements even when these were not generated by
descending neural commands. Two alternative mechanisms of ES activation were
considered: (a) propriospinal transmission of afferent input entering the spinal
cord from the upper extremity; (b) afferent input from ES and other trunk
muscles, responding to local oscillations transmitted mechanically from the hand
to the lower back. 4. Activation of ES via proprioceptive signals from the
forearm was unlikely since (a) simultaneous electrical stimulation of wrist
extensor and wrist flexor muscles did not result in repetitive ES EMG bursting;
(b) cyclical vibration of the wrist extensors did not evoke ES EMG bursting; (c)
when the forearm was constrained and the hand was moved passively, the lower
trunk accelerations and cyclical ES EMG both occurred at a harmonic of the hand
movement frequency. 5. We conclude that the repetitive ES EMG bursting during
hand movements was probably due to a local segmental reflex rather than to
descending commands. Remote mechanical oscillations of the trunk caused by hand
movements evidently elicited proprioceptive reflexes in ES that presumably
contributed to trunk stabilization.
PMID- 9401979
TI - Firing pattern of type-identified wrist extensor motor units during wrist
extension and hand clenching in humans.
AB - 1. Single motor unit activity was investigated in the extensor carpi radialis
muscles during voluntary isometric contraction involving either the coactivation
of the wrist agonist extensor muscles (wrist extension) or the coactivation of
the wrist and finger antagonist extensor and flexor muscles (hand clenching). 2.
The motor units were found to be activated at a similar level of motoneurone pool
drive during both wrist extension and hand clenching, as indicated by the fact
that the EMG activity at which they were recruited was practically the same in
both cases (mean +/- S.D.: 20 +/- 26 and 21 +/- 25 mV, respectively). In
addition, the net excitatory drive exerted on the motoneurones, as assessed from
the mean interspike intervals, did not differ significantly between the two tasks
(mean +/- S.D.: 104.57 +/- 17.24 and 103.01 +/- 16.26 ms, for wrist extension and
hand clenching, respectively). 3. However, the discharge variability, in terms of
the coefficient of variation of the interspike intervals, was slightly but
significantly greater during hand clenching than during wrist extension (0.213 +/
0.049 and 0.198 +/- 0.045, respectively). This increase involved all types of
motor units, regardless of their contractile force. 4. We suggest that the
greater motoneurone discharge variability observed during hand clenching may be
attributable to an increase in the synaptic noise. This increase might be due to
the activation of numerous afferent pathways mediating reciprocal interactions
between antagonist motoneurone pools, as well as to the activation of hand
cutaneous receptors that play a major role in the regulation of handling and
gripping motor activities.
PMID- 9401981
TI - Cross-facial vein grafting in complicated flap reconstructions of the face and
mandible.
AB - Microvascular flap reconstructions of facial and mandibular defects are achieving
increasingly widespread application and, as a result, more patients are
considered for such procedures after large tumors, congenital abnormalities,
previous surgery (including failed and successful microsurgical procedures) and
radiation have compromised potential recipient vessels on the side of the defect.
In three such cases, contralateral facial vessels with vein grafts have been used
to provide flap-recipient vessels. Each flap was successful. Cross-facial vein
grafting is a relatively simple solution for utilizing undamaged vessels as
recipient pedicles in complicated flap reconstructions of the face and mandible.
PMID- 9401980
TI - Reinterpretation of endothelial cell gaps induced by vasoactive mediators in
guinea-pig, mouse and rat: many are transcellular pores.
AB - 1. In response to vascular permeabilizing agents, particulates circulating in the
blood extravasate from venules through endothelial cell openings. These openings
have been thought to be intercellular gaps though recently this view has been
challenged. 2. To define the precise location of endothelial cell gaps, serial
section electron microscopy and three-dimensional reconstructions were performed
in skin and cremaster muscle of guinea-pigs, mice and rats injected locally with
agents that enhance microvascular permeability: vascular permeability factor,
histamine or serotonin. Ferritin and colloidal carbon were injected intravenously
as soluble and particulate macromolecular tracers, respectively. 3. Both tracers
extravasated from venules in response to all three permeability enhancing agents.
The soluble plasma protein ferritin extravasated primarily by way of vesiculo
vacuolar organelles (VVOs), interconnected clusters of vesicles and vacuoles that
traverse venular endothelium. In contrast, exogenous particulates (colloidal
carbon) and endogenous particulates (erythrocytes, platelets) extravasated from
plasma through transendothelial openings. 4. Serial electron microscopic sections
and three-dimensional reconstructions demonstrated that eighty-nine of ninety-two
openings were transendothelial pores, not intercellular gaps. Pore frequency
increased 3- to 33-fold when carbon was used as tracer. 5. The results
demonstrate that soluble and particulate tracers extravasate from venules by
apparently different transcellular pathways in response to vasoactive mediators.
However, some pores may derive from rearrangements of VVOs.
PMID- 9401982
TI - Plasticity and function--the fate of a free, neurovascular muscle graft ten years
post-reconstruction.
AB - A 16-year-old female sustained a subtotal amputation of the left thigh.
Debridement resulted in a bone and soft-tissue defect of 20 cm in length. The
whole quadriceps muscle was lost, and the knee joint was open. The femur was
stabilized by transfer of corticocancellous bone grafts. A latissimus dorsi
muscle was harvested and transferred to reconstruct the lost quadriceps muscle.
The thoracodorsal nerve was coaptated to the motor branch of the femoral nerve.
The years after trauma, the muscle provides excellent motor function. EMG
evaluation reveals no sign of denervation; macro-electromyography reveals only a
moderate enlargement of motor units. There is recruitment of all motor units.
Maximum voluntary torque of the transplanted muscle has decreased, compared to
the contralateral rectus femoris. Histologic evaluation demonstrates a normal
skeletal muscle with typical fiber distribution. These results indicate complete
adaptability of the muscle at an atypical site, with a high degree of functional
and structural plasticity of the skeletal muscle. The decreased voluntary torque
of the transferred latissimus dorsi depends on the lower, total-fiber, cross
sectional area--the result of a parallel fiber structure.
PMID- 9401983
TI - Successful microsurgical tissue transfer in a patient with postsplenectomy
thrombocytosis treated with platelet-phoresis.
AB - With the use of platelet-phoresis, two microsurgical free-tissue transfers were
successfully undertaken in a patient with postsplenectomy thrombocytosis that had
initially caused flap failure. Rapid reduction in the platelet count allowed free
tissue transfer in this patient who required early wound coverage.
PMID- 9401984
TI - Vascularized fibula graft for spinal fusion in severe cervical kyphosis due to
neurofibromatosis.
AB - A successful anterior spinal fusion using vascularized fibula graft in the case
of a 17-year-old male with severe cervical kyphosis due to neurofibromatosis is
reported. Anterior spinal fusion at C2-7 using the fibula graft was performed
with spinous process wiring. The kyphosis was corrected from 85 to 38 degrees.
Bony fusion was obtained in 5 months without loss of correction.
PMID- 9401985
TI - Macrovascular surgery and the microsurgeon.
AB - The improvement of success rates in microsurgery can be attributed as much to
better technical skills, as to the more frequent selection of donor or recipient
sites with consistent, larger-caliber vessels. Often, these vessels may be larger
than major limb source vessels, and anastomoses using loupes can then be
successful, even without requiring an operating microscope Thus, distinguishing
our capabilities from the domain of the general vascular surgeon, who
traditionally deals only with the ravages of disease or trauma to such large
vessels, has become blurred. For some free-tissue transfers, and especially limb
replantations, perhaps it would be appropriate for the microsurgeon sometimes to
enter the realm of the macrovascular surgeon for enhancement of the overall
outcome. A review of our 202 free flaps and pediatric limb revascularizations has
validated this opinion, as significant portions in 19 of these cases required
unequivocal macrovascular surgery. These included vein-graft bypasses (9) of
major segmental arterial defects of limbs (that incidentally improved collateral
circulation, although intended primarily to simplify arterial inflow to a free
flap simultaneously needed to cover a concomitant soft-tissue defect). Similarly,
arterial grafts as part of a "flow-through" free flap (3) were used for immediate
coverage and concurrent limb revascularization. Finally, two toddlers who
sustained disruption of named leg vessels had microsurgical repair after referral
from the vascular service; they believed we were better able to deal with such
diminutive vasculature. These observations are not intended as evidence that
vascular surgery may be better performed by the microsurgeon; rather, that the
best results of microsurgery often will incorporate technical aspects usually
considered as macrovascular surgery.
PMID- 9401986
TI - Magnetic resonance imaging assessment of a microvascular anastomotic device for
ferromagnetism.
AB - Microvascular free-tissue transfers have assumed particular importance as
reconstructive techniques of choice in centers where ablative surgery for primary
and recurrent malignant disease is a focus. In the context of malignant disease,
issues of surveillance for recurrence are paramount. As clinical experience with
the diagnostic imaging characteristics of flap reconstructions has been acquired,
magnetic resonance imaging (MRI) has assumed a prominent role in the evaluation
for recurrent malignant disease. This has provided an important supportive role
for contemporary concepts of immediate reconstruction. The Precise-TM
Microvascular Anastomotic Device (MACD) is based on the friction-fit union of
implant rings composed of high-density polyethylene and surgical stainless steel.
Many characteristics of the device have been described in histologic and
laboratory studies. As yet uncharacterized is the effect of clinical MRI
electromagnetic fields on the device, which is composed, in part, of type 316
stainless steel. The MACD is in wide use in centers where microsurgeons are
experienced with the system and it is designed to facilitate the performance and
reliability of microvascular anastomoses. The implications for MRI as a safe
imaging modality for the acute perioperative evaluation of patients reconstructed
with microvascular free flaps anastomosed with the MACD are obvious. MACD
implants of varying sizes were evaluated for displacement in each of three
orthogonal planes within a 1.5 Tesla magnetic field. No change in displacement
was observed for any of the devices. Magnetic resonance imaging may thus be
considered a safe imaging modality for the acute perioperative diagnostic imaging
of free-tissue transfers that have been anastomosed with the MACD.
PMID- 9401987
TI - Primary flap closure in complex limb injuries.
AB - Free-tissue transfers enable surgeons to reconstruct or salvage limbs injured or
amputated in high-energy traumas which result in extensive damage to soft tissue,
bone, tendons, vessels and nerves. Primary free-tissue transfer is performed
following debridement, bone fixation, and repair of injured structures within 24
hr after injury. Between 1987 and 1996, 57 patients who had complex extremity
traumas were treated with primary free-tissue transfer, or free flaps. Long-term
follow-up ranged from 4 months to 9 years (median: 4.5 years). No flap failure or
serious wound-healing complication occurred using the protocol. Radical
debridement and primary free-flap coverage in extensive extremity injuries can
salvage limbs, provide improved functional and aesthetic results, and
psychologically benefit patients through lowered morbidity. Other benefits
include reduced incidence of free-flap failure, postoperative infection,
secondary operative procedures, and invalidity, as well as shorter hospital
stays, and lowered medical expenses.
PMID- 9401988
TI - Adjunctive measures in microvascular surgery.
AB - Consistently good results following free-tissue transfers require not only basic
skills in small vessel anastomosis, but also the implementation of numerous
adjunctive measures. The pioneers in microsurgery have shared many of their hard
learned lessons and clinical nuggets through texts, papers, and seminars. This
article presents an assemblage of adjunctive measures of proven utility.
PMID- 9401989
TI - Is axonal sprouting able to traverse the conjunctival layers of the peripheral
nerve?
PMID- 9401990
TI - Transrectal ultrasonographically assisted radical retropubic prostatectomy.
AB - Radical prostatectomy is associated with difficulty in determining the division
site of the urethra adjacent to the apical region of the prostate. We present the
results of a feasibility clinical trial in three patients to determine whether
intraoperative transrectal ultrasonography may assist during radical retropubic
prostatectomy. Using this technique the apex is readily identified and a detailed
view of the urethral stump could be obtained. In one case residual apical tissue
was identified and excised. The creation of the vesicourethral anastomosis was
documented and its water tightness was demonstrated. We conclude that transrectal
ultrasonography can be performed during radical retropubic prostatectomy and may
be helpful in selected cases.
PMID- 9401991
TI - Sonographic imaging of the trachea.
AB - We evaluated the feasibility of ultrasonography for imaging of the trachea and
its effectiveness in the diagnosis and follow-up of patients with tracheal
stenosis due to various diseases. Twenty normal volunteers and six adult patients
with tracheal stenosis were included in the study group. Subjects were examined
with ultrasonography in a supine position with the neck hyperextended or in a
sitting position. At the level of the thyroid isthmus, the anterior tracheal wall
thicknesses imaged by ultrasonography were 1.54 +/- 0.22 mm (mean +/- SD) and
1.22 +/- 0.18 mm for normal male and female volunteers, respectively.
Ultrasonography could reveal the intrinsic tracheal wall lesions and extrinsic
lesions compressing the trachea in patients with tracheal stenosis. These
ultrasonographic images correlated with CT images. In conclusion, ultrasonography
may be useful in imaging of the trachea.
PMID- 9401992
TI - Sonographic, magnetic resonance imaging, and mammographic assessments of
preoperative size of breast cancer.
AB - High resolution sonographic (39 cases), magnetic resonance imaging (32 cases),
and mammographic (35 cases) measurements of preoperative size of breast cancer
were correlated with the pathologic size in 39 patients with breast carcinoma to
determine the most accurate imaging technique for breast cancer size. There were
nine T1, 21 T2, four T3, and four T4 tumors. Sonographic and magnetic resonance
imaging measurements of tumor size demonstrated correlation coefficients of 0.92
and 0.93, respectively, both of which were superior to that of mammography
(0.84). Sonographic tumor size evaluation thus is shown to be equivalent to
magnetic resonance imaging in this study. Three of nine (33%), four of seven
(57%), and four of eight (50%) T1 tumors would have been overstaged by
ultrasonography, magnetic resonance imaging, and mammography, respectively. Three
of 21 (14.3%), one of 16 (6.3%), and two of 18 (11.1%) T2 tumors would have been
understaged by ultrasonography, magnetic resonance imaging, and mammography,
respectively. We therefore found ultrasonography to be of value in the diagnosis
and staging of breast cancer.
PMID- 9401993
TI - Birthweight prediction by three-dimensional ultrasonographic volumes of the fetal
thigh and abdomen.
AB - Our validation study examined a three-dimensional ultrasonographic phantom that
contained irregularly shaped volume targets ranging from 0.5 to 76.1 milliliters.
Four different examiners made blinded measurements from volume datasets that were
acquired by 4 and 7 MHz transducers. Birthweight predictions using abdominal and
thigh volumes from 18 term fetuses also were compared with two-dimensional
ultrasonographic methods. In vitro volume measurements were accurate, precise,
and repeatable despite a small systematic overestimation with increasing object
size. Mean systematic error and precision for birthweight predictions by three
dimensional ultrasonography (-0.03% +/- 6.1%) were not significantly different
from those by two-dimensional ultrasonography (-0.60% +/- 8.8%). Conventional
prediction methods yielded three birthweights with greater than 15% error. By
comparison, except for one infant whose birthweight indicated an 11% error, all
predictions based on fetal volume parameters were within 10% of true values.
Accurate birthweight predictions by fetal volume parameters appear to be
technically feasible at term gestation although their practical clinical
application requires further investigation. Birthweight predictions in this
manner may allow remote consultants to evaluate the fetus over wide-area computer
networks despite the physical absence of the patient.
PMID- 9401994
TI - Echogenicity of hepatic versus portal vein walls revisited with histologic
correlation.
AB - The portal vein wall typically is hyperechoic over a wide range of beam-vessel
angles, whereas the hepatic vein wall is hyperechoic only when the incident beam
and the vessel are perpendicular. This has been attributed to marked
discrepancies in mural thickness, collagen content, or perivascular fat between
portal and hepatic veins. We evaluated histologically the walls of portal and
hepatic veins using three cadaveric livers. For vessels with luminal diameter
above 2 to 3 mm, hepatic vein and portal vein wall thicknesses were similar such
that portal vein walls were not more than 50% thicker than those of hepatic veins
of comparable size. Hepatic vein walls were mostly composed of parallel, tightly
packed collagen fibers. In contrast, portal vein walls were composed of loosely
arrayed, nonparallel connective tissue fibers which were separated by multiple
intervening spaces and only a minority of which were collagenous. Perivascular
fat was not identified adjacent to intrahepatic vessels beyond the liver hilus.
The marked differences in echogenicity between portal vein and hepatic vein walls
typically observed at ultrasonography thus cannot be attributed to differences in
mural thickness, collagen content, or perivascular fat between these vessels.
Rather, the distinct composition of the hepatic vein wall renders it a specular
reflector, which is hyperechoic only when the angle between the ultrasound beam
and the vessel wall is close to 90 degrees, whereas the composition of the portal
vein wall enables it to appear hyperechoic at a wide range of beam-vessel angles.
PMID- 9401995
TI - Hemodynamic changes in the early phase of artificially created arteriovenous
fistula: color Doppler ultrasonographic findings.
AB - The objective of this study was to evaluate hemodynamic variables in
arteriovenous fistulas by color Doppler ultrasonography. This study involved 28
patients with chronic renal failure who were sent to surgery clinic for creation
of an arteriovenous fistula of the Brescia-Cimino type. Patients were evaluated
preoperatively and on the first and seventh days postoperatively by a color
Doppler ultrasound machine with a 7.5 MHz linear probe. The distal radial artery
was examined preoperatively and the fistula itself postoperatively. Changes in
the fistula size and the velocity, volume, and resistive index of the distal
radial artery were recorded. Postoperatively the radial artery diameter, systolic
flow rates, and volume flow had increased significantly, especially on the first
day, in comparison to preoperative values. Resistive index values has decreased
significantly at both the first and the seventh days postoperatively. Color
Doppler ultrasonography is a very effective method in the evaluation of
hemodynamics of arteriovenous fistulas in hemodialysis patients. It will allow an
understanding of the pathology in nonfunctioning fistulas or of the cause of
complications that develop secondarily.
PMID- 9401996
TI - Blood flow in functional cysts and benign ovarian neoplasms in premenopausal
women.
AB - To assess the value of transvaginal color Doppler sonography in the
differentiation of functional cysts from benign ovarian neoplasms in
premenopausal women, 100 premenopausal women with the diagnosis of adnexal mass
were enrolled in a prospective study. All patients underwent transvaginal color
Doppler sonography during the follicular phase. We evaluated 107 masses. Tumor
volume and morphology were assessed, as were tumor blood flow location, the
number of vessels, the resistive and pulsatility indices, and the peak systolic
velocity. Patients were followed up after 8 to 10 weeks by transvaginal
sonography. Functional cysts were considered when spontaneous resolution
occurred. Surgery was performed if a tumor enlarged or persisted after two scans.
Thirty-nine (36.5%) cysts regressed spontaneously and 68 (63.5%) were removed
surgically. Seven of the latter were follicular or luteal cysts and were
considered to be functional cysts. No carcinoma was found. Arterial blood flow
was detected in 28 (60.8%) functional cysts and in 42 (68.8%) benign neoplasms (P
= 0.3446). The vessels were located peripherally in 27 (94.6%) functional cysts
and in 37 (88.1%) benign neoplasms (P = 0.2226). No differences were found
between functional cysts and benign neoplasms in mean resistive index (0.65, 95%
confidence interval: 0.59 to 0.71 versus 0.64, 95% confidence interval: 0.60 to
0.69), mean pulsatility index (1.47, 95% confidence interval: 1.17 to 1.84 versus
1.57, 95% confidence interval: 1.26 to 1.86), number of vessels (1.1, 95%
confidence interval: 0.7 to 1.3 versus 1.4, 95% confidence interval: 1.1 to 1.8),
and peak systolic velocity (28.6 cm/s, 95% confidence interval: 24.7 to 34.2
versus 24.9 cm/s, 95% confidence interval: 21.6 to 28.3). We concluded that
transvaginal color Doppler sonography is not useful to discriminate between
functional ovarian cysts and benign ovarian neoplasms in premenopausal women.
PMID- 9401997
TI - Color Doppler ultrasonography in the diagnosis of portal vein invasion in
patients with pancreatic cancer.
AB - We retrospectively evaluated the diagnostic usefulness of color Doppler
ultrasonography for detecting portal vein invasion in 21 patients with pancreatic
cancer who underwent surgical exploration (14 resection, seven inspection). Real
time gray scale ultrasonography, color Doppler ultrasonography, computed
tomography, and angiography were performed in all patients to evaluate portal
vein invasion, and the images were compared with the histopathologic or surgical
inspection findings. On comparison between gray scale ultrasonographic and color
Doppler ultrasonographic images, the tumor-vessel relations were visualized more
clearly on color Doppler ultrasonography than on gray scale ultrasonography in 14
(22.2%) of 63 vessels. The sensitivity of color Doppler ultrasonography, computed
tomography, and angiography for diagnosing portal invasion was 73.7%, 73.7%, and
73.6%, and the specificity was 95.1%, 95.5%, and 90.9%, respectively; the overall
accuracy was 84.1%, 88.9% and 85.7%, respectively. A mosaic signal pattern was
observed in 12 vessels and showed an accuracy of 86.4% for diagnosing portal vein
invasion. In conclusion, compared with gray scale ultrasonography, color Doppler
ultrasonography provided improved images of the tumor and portal vein.
Furthermore, the accuracy of color Doppler evaluation of portal vein invasion
appears to be equal to that of computed tomography and angiography. Therefore,
color Doppler ultrasonography may play an important role as an initial
examination for evaluating portal vein invasion.
PMID- 9401998
TI - Effective ultrasonographically guided intervention for diagnosis of
musculoskeletal lesions.
AB - Current algorithms recommend computed tomography or fluoroscopic guidance rather
than ultrasonography for musculoskeletal intervention. We analyzed our
ultrasonographically guided experience to evaluate its efficacy. Forty-seven
patients underwent needle aspirates or biopsies or both in 13 extremity and 34
axial locations for 12 inflammatory lesions, 23 soft tissue masses, and 12
lesions arising from bone. Four lesions were initially imaged by ultrasonography;
the remaining lesions were identified by computed tomography (25) or magnetic
resonance imaging (18). Forty-six samples were diagnostic; one needle aspirate of
an inflammatory mass yielded no diagnostic material. No complications occurred.
Ultrasonographically guided musculoskeletal aspiration and biopsy are diagnostic
and effective throughout the body, and with appropriate lesion access, they
should be considered as an alternative to computed tomographic-guided procedures.
PMID- 9401999
TI - Sonographic evolution of a living cervical pregnancy treated with intraamniotic
instillation of methotrexate.
PMID- 9402000
TI - Pseudoaneurysm formation in the breast after core needle biopsy.
PMID- 9402001
TI - Iatrogenic creation of a monoamniotic twin gestation in severe twin-twin
transfusion syndrome.
PMID- 9402002
TI - Integrin signaling.
AB - Integrins provide dynamic links between cells and extracellular matrix molecules.
Although integrins were originally viewed as relatively simple adhesion
molecules, it soon became clear that intracellular signal transduction initiated
by integrins is centrally involved in many cellular processes. In fact, a
remarkable number of classical signaling pathways are now known to be activated
or modified by the interactions of cells with matrix proteins via integrins.
These integrin signaling responses can also involve many other extracellular and
intracellular molecules. The following mini-reviews were solicited from some of
the future leaders in the field of integrin signaling. They examine selected
important portions of this field, provide conceptual syntheses from a large and
confusing literature, and then propose novel testable ideas. These ideas should
encourage dialogue and open new avenues of research in this rapidly expanding,
exciting field.
PMID- 9402003
TI - Structural basis of integrin-mediated signal transduction.
AB - Integrins are a family of alpha/beta heterodimers of cell adhesion receptors that
mediate cell-extracellular matrix and cell-cell interactions. Both alpha and beta
subunits have a large extracellular domain and a short cytoplasmic domain. The
alpha subunit has seven sequence repeats of 60-70 residues in its N-terminal
region. The beta-propeller model, in which seven four-stranded beta-sheets are
arranged in a torus around a pseudosymmetry axis, has been proposed as a
structural model of these seven repeats. Several predicted loops critical for
ligand binding have been identified in the upper face of the proposed beta
propeller model. Several alpha subunits (e.g., alpha 2, alpha L and alpha M) have
I-domains of about 200 residues inserted between their second and third repeats.
These I-domains adopt a Rossman-fold structure and have major ligand and cation
binding sites (the MIDAS site) on their surfaces. The beta subunit has an I
domain-like structure in its N-terminal region. This structure includes multiple
sequences/conserved oxygenated residues critical for ligand binding (e.g., Asp
119 in beta 3), and non-conserved residues critical for ligand specificities.
Several "activation-dependent" epitopes have been identified in the Cys-rich
(stalk) region of beta 1. It has yet to be determined how these multiple ligand
binding sites in the alpha and beta subunits are involved in ligand binding, and
how conformational changes on activation/ligand occupancy relate to signal
transduction.
PMID- 9402005
TI - Integrin signaling: building connections beyond the focal contact?
AB - The integrin family of adhesion receptors is notable for its bi-directional
signaling properties, changing extracellular conformation and ligand binding
affinity in response to external agonists, and inducing complex intracellular
events following ligation. The interaction of integrins with intracellular or
transmembrane moieties has been extensively studied in order to define the
mechanisms of bi-directional signaling. In particular, the recruitment of
integrins to focal contacts puts them in proximity with many cytoskeletal and
signaling molecules. The importance of these structures in connecting integrins
and signaling pathways has been well described. However, the purpose of this
minireview is to explore additional protein interactions and how these might
serve as an alternative means in connecting integrins and signaling pathways.
PMID- 9402004
TI - Integrin cytoplasmic domains as connectors to the cell's signal transduction
apparatus.
AB - Integrins mediate the bidirectional transfer of signals across the plasma
membrane. Integrin cytoplasmic domains provide one pathway linking integrin
engagement with the cell's signal transduction apparatus. Recent structure
function studies have defined regions of beta cytoplasmic domains required for
integrin function and have identified distinct roles for individual alpha
cytoplasmic domains in regulating cell behavior. Newly identified proteins that
bind to integrin alpha and beta cytoplasmic domains have provided new insights
and new questions into the mechanisms involved in integrin signaling.
PMID- 9402007
TI - Integrin receptor signaling: the propagation of an alpha-helix model.
AB - Upon ligand binding to integrin receptors, a transmembrane conformation change
occurs, which is required for the engagement of the actin cytoskeleton. Integrin
receptor latency clearly involves the proximal portions of the alpha and beta
cytoplasmic domains. Several experiments suggest that these two regions, which
are highly conserved among integrins, may be associated, and this association is
the structural basis for latency. We propose that ligand binding leads to a
disruption of this association, which allows for the folding of the proximal beta
cytoplasmic domain. Thus, in this model, the alpha chain association keeps the
beta unfolded, and ligand binding leads to the propagation of an alpha helix from
the transmembrane domain through the proximal beta cytoplasmic domain, leading to
signal transduction.
PMID- 9402006
TI - Allostery and proteolysis: two novel modes of regulating integrin function.
AB - Integrins are involved in transmitting signals between the cytoplasm and the
extracellular matrix. Importantly, the transfer of information is bi-directional:
signals flow inside-out and outside-in. Here, I discuss two potential modes by
which integrin function is likely to be regulated. It is hypothesized that the
integrin cytoplasmic tails are proteolytic substrates, and that cleavage of the
cytoplasmic domain regulates the ligand binding affinity of integrins. It is also
hypothesized that the ligand binding site is allosterically regulated by separate
divalent ion binding sites that independently control ligand association and
dissociation rate. Both hypotheses are suggested by reports in the literature and
can be tested experimentally.
PMID- 9402008
TI - Alternatively spliced variants: a new view of the integrin cytoplasmic domain.
AB - A large number of studies have underscored a major role for the integrin alpha
beta cytoplasmic domains in the modulation of cell functions. Cytoplasmic domain
variants of the beta 1, beta 3, beta 4, alpha 3, alpha 6 and alpha 7 subunits
have been described. These molecules are generated by alternative splicing events
and are expressed in a cell- or tissue-type specific manner. Some of these
variants (beta 1C, beta 1D, alpha 6A and alpha 7A) are predominantly expressed
upon differentiation and have been shown to be regulated during development. The
studies on the structure-function relationship of the integrin variant subunits,
published between 1989 and now, will be reviewed here for the first time. The
results demonstrate that differences in the cytoplasmic domain do not affect
either the alpha beta heterodimer formation or the ligand specificity. Instead,
alternatively spliced integrin cytoplasmic domains appear to be essential
modulators of receptor localization, cell proliferation and migration, as well as
phosphorylation of signaling molecules. These observations lead to the current
hypothesis that cell-type specific regulation of alternatively spliced integrin
cytoplasmic domains may provide a highly specialized mechanism to control cell
growth and intracellular signaling pathways.
PMID- 9402009
TI - Focal adhesion kinase in integrin signaling.
AB - Focal adhesion kinase (FAK) has recently been established as a key component of
the signal transduction pathways triggered by integrins. Aggregation of integrins
and the cytoskeletal proteins tensin, paxillin and talin is proposed to be
responsible for FAK activation and autophosphorylation by integrins in cell
adhesion. Activation and autophosphorylation of FAK lead to its binding to a
number of intracellular signaling molecules, including Src, Grb2 and PI 3-kinase.
FAK/Src association activates both kinases, which act on the potential substrates
tensin, paxillin and p130cas. Besides cytoskeletal regulation, FAK
phosphorylation of paxillin and p130cas could also lead to MAP kinase pathway by
adaptor proteins such as Crk and Nck. Recent studies indicated that integrin
signaling through FAK causes increased cell migration and potentially regulates
cell proliferation and survival. Future challenges will include clarifying the
roles of signaling pathways downstream of FAK in cell migration and cell cycle
regulation.
PMID- 9402010
TI - Synthesis and conformational properties of a recombinant C-propeptide of human
type III procollagen.
AB - A cDNA was prepared that coded for the signal peptide of type III procollagen
linked to the complete C-propeptide of the protein. The cDNA was then used to
express the protein in a baculovirus recombinant system. Recombinant protein was
recovered as a trimer from the medium of transfected cells in a yield of 1 to 2.5
mg per liter. Mapping of peptide fragments with and without reduction indicated
that the protein contained the expected interchain disulfide bonds. Analysis by
circular dichroism suggested that the conformation of the protein corresponded to
the native conformation. Therefore, the protein should be appropriate for further
tests of its biological function and analysis of structure by X-ray diffraction.
PMID- 9402011
TI - Non-glycosaminoglycan bearing domains of perlecan and aggrecan influence the
utilization of sites for heparan and chondroitin sulfate synthesis.
AB - Perlecan and aggrecan are proteoglycans that receive primarily heparan sulfate
and chondroitin sulfate side chains, respectively. Their large multidomained core
proteins have little or no homology to each other and their glycosaminoglycan
(GAG) attachment sites are restricted to certain domains only. We examined the
involvement of the non-GAG bearing domains in designating the GAG type added to
the GAG attachment domain by preparing cDNA constructs that expressed
perlecan/aggrecan chimeras as recombinant products in COS-7 cells and then
determining the size and GAG composition of the recombinant products. The results
showed that domain I of perlecan receives primarily (73-81%) heparan sulfate when
coupled with domain II and III of perlecan, but when coupled with the G3 domain
of aggrecan, it receives primarily (59-63%) chondroitin sulfate. Furthermore, the
chondroitin sulfate attachment region of aggrecan received GAG side chains more
readily when coupled to the G3 domain of aggrecan than when coupled to domains II
and III of perlecan. The GAG side chains on all these recombinant products were
small and similar in size. These findings indicate that the utilization of
attachment sites for heparan and chondroitin sulfate or the sulfation of these
GAGs can be influenced, in part, by non-GAG bearing domains.
PMID- 9402012
TI - Differentiation-dependent expression of laminin-8 (alpha 4 beta 1 gamma 1) mRNAs
in mouse 3T3-L1 adipocytes.
AB - We report that laminin-8 (alpha 4 beta 1 gamma 1) is the specific isoform of
laminin synthesized in adipocytes. Reverse transcription-polymerase chain
reaction (RT-PCR) of mRNA from mouse 3T3-L1 cells with paired primers for alpha
1, alpha 2, alpha 3, alpha 4, alpha 5, beta 1, beta 2, beta 3, gamma 1 and gamma
2 laminins yielded amplified fragments only for alpha 4, beta 1 and gamma 1. A
polyclonal antibody against mouse laminin-1 (alpha 1 beta 1 gamma 1) precipitated
alpha 4 in addition to beta 1 and gamma 1, while the antibody against a deduced
peptide sequence of mouse alpha 4 in addition to beta 1 and gamma 1 in addition
to alpha 4. Thus, laminin-8 (alpha 4 beta 1 gamma 1) is the only isoform
expressed in 3T3-L1 cells. Northern blots showed that the levels of alpha 4, beta
1 and gamma 1 mRNAs increased 2.5-fold during adipose conversion of 3T3-L1 cells.
A 1062 bp cDNA fragment cloned by RT-PCR demonstrated a polymorphism in the mouse
alpha 4 gene which would lead to five amino acid changes in the domain G.
PMID- 9402013
TI - The Escherichia coli genome sequence: the end of an era or the start of the FUN?
AB - Our dream of determining the entire Escherichia coli K12 genome sequence has been
realized. This calls for new approaches for the analysis of gene expression and
function in biology's best-understood organism. Comparison of the E. coli genome
sequence with others will provide important taxonomic insights and have
implications for the study of bacterial virulence. Approximately 20% of E. coli
genes have been designated FUN genes, because they have no known function or
homologies to sequence databases. FUN genes promise to have an exciting impact on
bacterial research. The post-genome era requires novel strategies that address
gene regulation at the level of the entire cell. These strategies need to
supersede the reductionist approach to genetic analysis. Only then will the
genome sequence lead us to an understanding of how a bacterial cell really works.
PMID- 9402014
TI - The non-standard genetic code of Candida spp.: an evolving genetic code or a
novel mechanism for adaptation?
AB - A number of yeasts of the genus Candida translate the standard leucine-CUG codon
as serine. This unique genetic code change is the only known alteration to the
universal genetic code in cytoplasmic mRNAs, of either eukaryotes or prokaryotes,
which involves reassignment of a sense codon. Translation of CUG as serine in
these species is mediated by a novel serine-tRNA (ser-tRNACAG), which uniquely
has a guanosine at position 33, 5' to the anticodon, a position that is almost
invariably occupied by a pyrimidine (uridine in general) in all other tRNAs. We
propose that G-33 has two important functions: lowering the decoding efficiency
of the ser-tRNACAG and preventing binding of the leucyl-tRNA synthetase. This
implicates this nucleotide as a key player in the evolutionary reassignment of
the CUG codon. In addition, the novel ser-tRNACAG has 1-methylguanosine (m1G-37)
at position 37, 3' to the anticodon, which is characteristic of leucine, but not
serine tRNAs. Remarkably, m1G-37 causes leucylation of the ser-tRNACAG both in
vitro and in vivo, making the CUG codon an ambiguous codon: the polysemous codon.
This indicates that some Candida species tolerate ambiguous decoding and suggests
either that (i) the genetic code change has not yet been fully established and is
evolving at different rates in different Candida species; or (ii) CUG ambiguity
is advantageous and represents the final stage of the reassignment. We propose
that such dual specificity indicates that reassignment of the CUG codon evolved
through a mechanism that required codon ambiguity and that ambiguous decoding
evolved to generate genetic diversity and allow for rapid adaptation to
environmental challenges.
PMID- 9402015
TI - Molecular mechanisms of Campylobacter fetus surface layer protein expression.
AB - Cells of the Gram-negative bacteria Campylobacter fetus are covered by
monomolecular arrays of surface layer proteins (SLPs) critical for both
persistence in their natural hosts and for virulence. For C. fetus cells,
expression of SLPs essentially eliminates C3b binding and their antigenic
variation thwarts host immunological defences. Each cell possesses multiple
partially homologous and highly conserved SLP gene cassettes, tightly clustered
in the genome, that encode SLPs of 97-149 kDa. These attach non-covalently via a
conserved N-terminus to the cell wall lipopolysaccharide. Recent studies indicate
that C. fetus reassorts a single promoter, controlling SLP expression, and one,
or more, complete open reading frame strictly by DNA inversion, and that
rearrangement is independent of the distance between sites of inversion. In
contrast to previously reported programmed DNA inversion systems, inversion in C.
fetus is recA-dependent. These rearrangements permit variation in protein
expression from the family of SLP genes and suggest an expanding paradigm of
programmed DNA rearrangements among microorganisms.
PMID- 9402016
TI - Non-palindromic attl sites of integrons are capable of site-specific
recombination with one another and with secondary targets.
AB - Genes borne on cassettes are mobile owing to site-specific recombination systems
called integrons, which have created various combinations of antibiotic
resistance genes in R-plasmids. In these processes, the palindromic site, attC
(59-base element), at cassette junctions has been proposed as being essential.
Excised and circularized cassettes have been found to integrate with preference
for an attl site at one end of the conserved sequence in integrons. In this work,
we give evidence that recombination is possible in the absence of the highly
organized attC sites between the more simply organized attl sites. Furthermore,
at a very low frequency representing the background in our recombination assay,
we observed cross-overs between attl and secondary sites. To characterize
recombination excluding the attC sites, we have used naturally occurring attl
variants and constructed mutants. The cross-over point was identified between a
guanine and a thymine in attl using point mutations. Progressive deletions showed
the extent of attl and identified two important regions in the conserved sequence
5' of the cross-over point. A region 27-36 bp 5' of attl influenced recombination
with attC sites only, whereas a sequence 9-14 bp 5' of the cross-over point in
attl was important for recombination with both attl and attC. Recombination
between attl and secondary sites could allow fusion of the conserved sequence
encoding the integron site-specific recombinase to new sequences.
PMID- 9402017
TI - The finM promoter and the traM promoter are the principal promoters of the traM
gene of the antibiotic resistance plasmid R100.
AB - finP multicopy repression and traJ multicopy derepression indicate that the ratio
of sense to antisense transcripts is important in the regulation of R100
conjugation. The extension of R100 traM transcripts into traJ shows that
promoters in traM can affect this ratio, making the regulation of traM
transcription important in the regulation of R100 conjugation. Since R100 traM,
traY and tral proteins bind to the traM promoter region, we examined traM
transcription in R100-1 traM, traY and tral mutants and compared it with traM
transcription in both R100-1 and R100. We verified that the traM and finM
promoters provide virtually all the transcripts originating in the R100-1 traM
gene. When either is deleted, as in VAR22 or VAR30, the remaining promoter is
highly active. We show here that traY positively regulates R100-1 traM
transcription, as has been found for F. We found that tral did not regulate R100
1 traM transcription. The measured activity of the native R100 traM promoter was
12% of that in R100-1, whereas the native R100 finM promoter was 45% of that in
R100-1. These data and data from the R100-1 traY and tral mutants show that the
activities of the two promoters varied independently.
PMID- 9402018
TI - The role of ribosomal RNAs in macrolide resistance.
AB - Macrolides are bacteriostatic antibiotics which interfere with the
peptidyltransfer function of the ribosome. We have investigated the molecular
mechanisms underlying macrolide resistance in Mycobacterium smegmatis, an
eubacterium carrying two rRNA operons. Surprisingly, drug resistance was
associated not with alterations in ribosomal proteins, but with a single point
mutation in the peptidyltransferase region of one of the two 23S RNA genes, i.e.
A2058-->G or A2059-->G. This mutation resulted in a heterozygous organism with a
mutated and a wild-type rRNA operon respectively. Reverse transcriptase
sequencing indicated the expression of both wild-type and mutated rRNAs. The
mutated operon was introduced into genetically engineered rrn- strains of M.
smegmatis carrying a single functional rRNA operon and into parental M. smegmatis
with two chromosomal rRNA operons, using gene transfer as well as gene
replacement techniques. The results obtained demonstrate the dominant nature of
resistance. As exemplified in our results on macrolide resistance, a complete set
of genetic tools is now available, which allows questions of dominance vs.
recessivity and gene dosage effects in eubacterial ribosomal nucleic acids to be
addressed experimentally in vivo.
PMID- 9402019
TI - Cardiolipin is not essential for the growth of Saccharomyces cerevisiae on
fermentable or non-fermentable carbon sources.
AB - Cardiolipin is a unique dimeric phospholipid, which is present throughout the
eukaryotic kingdom and is specifically localized in mitochondrial membranes. It
is widely believed that mitochondria possess an essential requirement for this
phospholipid. To determine whether cardiolipin is essential for yeast growth, we
generated a cardiolipin synthase null mutant by disrupting the CLS1 gene (open
reading frame YDL142c on chromosome IV) of Saccharomyces cerevisiae. Biochemical
analysis of the mutant indicated that it had no cardiolipin synthase activity and
no cardiolipin in its membranes. The enzyme phosphatidylglycerolphosphate
synthase, which catalyses the committed step of the cardiolipin pathway, remained
unaffected in the null mutant. Haploid cells containing the null allele are
viable in media containing glucose, galactose or glycerol/ethanol as the sole
carbon source, although growth in galactose or glycerol/ethanol is somewhat
reduced in the mutant compared with the wild type. These results indicate that
cardiolipin is not essential for the growth of S. cerevisiae in fermentable or
non-fermentable carbon sources.
PMID- 9402020
TI - Regulation of plasmid R1 replication: PcnB and RNase E expedite the decay of the
antisense RNA, CopA.
AB - The replication frequency of plasmid R1 is controlled by an unstable antisense
RNA, CopA, which, by binding to its complementary target, blocks translation of
the replication rate-limiting protein RepA. Since the degree of inhibition is
directly correlated with the intracellular concentration of CopA, factors
affecting CopA turnover can also alter plasmid copy number. We show here that
PcnB (PAPl-a poly(A)polymerase of Escherichia coli) is such a factor. Previous
studies have shown that the copy number of ColE1 is decreased in pcnB mutant
strains because the stability of the RNase E processed form of RNAI, the
antisense RNA regulator of ColE1 replication, is increased. We find that,
analogously, the twofold reduction in R1 copy number caused by a pcnB lesion is
associated with a corresponding increase in the stability of the RNase E
generated 3' cleavage product of CopA. These results suggest that CopA decay is
initiated by RNase E cleavage and that PcnB is involved in the subsequent rapid
decay of the 3' CopA stem-loop segment. We also find that, as predicted, under
conditions in which CopA synthesis is unaffected, pcnB mutation reduces RepA
translation and increases CopA stability to the same extent.
PMID- 9402021
TI - Structural determinants of processing and secretion of the Haemophilus influenzae
hap protein.
AB - Haemophilus influenzae elaborates a surface protein called Hap, which is
associated with the capacity for intimate interaction with cultured epithelial
cells. Expression of hap results in the production of three protein species:
outer membrane proteins of approximately 155 kDa and 45 kDa and an extracellular
protein of approximately 110 kDa. The 155 kDa protein corresponds to full-length
mature Hap (without the signal sequence), and the 110 kDa extracellular protein
represents the N-terminal portion of mature Hap (designated Haps). In the present
study, we examined the mechanism of processing and secretion of Hap. Site
directed mutagenesis suggested that Hap is a serine protease that undergoes
autoproteolytic cleavage to generate the 110 kDa extracellular protein and the 45
kDa outer membrane protein. Biochemical analysis confirmed this conclusion and
established that cleavage occurs on the bacterial cell surface. Determination of
N-terminal amino acid sequence and mutagenesis studies revealed that the 45 kDa
protein corresponds to the C-terminal portion of Hap, starting at N1037. Analysis
of the secondary structure of this protein (designated Hap beta) predicted
formation of a beta-barrel with an N-terminal transmembrane alpha-helix followed
by 14 transmembrane beta-strands. Additional analysis revealed that the final
beta-strand contains an amino acid motif common to other beta-barrel outer
membrane proteins. Upon deletion of this entire C-terminal consensus motif, Hap
could no longer be detected in the outer membrane, and secretion of Haps was
abolished. Deletion or complete alteration of the final three amino acid residues
had a similar but less dramatic effect, suggesting that this terminal tripeptide
is particularly important for outer membrane localization and/or stability of the
protein. In contrast, isolated point mutations that disrupted the amphipathic
nature of the consensus motif or eliminated the C-terminal tryptophan had no
effect on outer membrane localization of Hap or secretion of Haps. These results
provide insight into a growing family of Gram-negative bacterial exoproteins that
are secreted by an IgA1 protease-like mechanism; in addition, they contribute to
a better understanding of the structural determinants of targeting of beta-barrel
proteins to the bacterial outer membrane.
PMID- 9402022
TI - FIS modulates growth phase-dependent topological transitions of DNA in
Escherichia coli.
AB - The Escherichia coli DNA-binding protein FIS serves as a DNA architectural factor
in two unrelated enzymatic reactions, the site-specific inversion of DNA and
transcriptional activation of stable RNA promoters. In both these processes, FIS
facilitates the assembly and dynamic transitions of two structurally distinct
nucleoprotein complexes. We have proposed previously that, in these systems, FIS
stabilizes writhed DNA microloops by binding at multiple helically phased sites
in DNA. However, FIS also binds and bends DNA at many non-specific sites and, at
its maximum levels in the early exponential phase, FIS could potentially occupy a
considerable part of the E. coli chromosome. Here, we show that fis affects
growth phase-specific alterations in the supercoiling level of DNA. Expression of
fis accelerates the accumulation of moderately supercoiled plasmids in stationary
phase, which are stabilized by FIS after nutritional shift-up. In accordance with
such a function, FIS modulates the relaxing and supercoiling activities of
topoisomerases in vitro in a way that keeps DNA in a moderately supercoiled
state. Our results suggest that the primary role of FIS is to modulate
chromosomal dynamics during bacterial growth.
PMID- 9402023
TI - The rap and hor proteins of Erwinia, Serratia and Yersinia: a novel subgroup in a
growing superfamily of proteins regulating diverse physiological processes in
bacterial pathogens.
AB - The enteric bacterium Serratia marcescens is an opportunistic human pathogen. The
strain ATCC39006 makes the red pigment, prodigiosin (Pig), and the beta-lactam
antibiotic carbapenem (Car). Mutants were isolated that were concomitantly
defective for Pig and Car production. These mutants were found to have a mutation
in the rap gene (Regulation of Antibiotic and Pigment). Sequence analysis of the
rap gene revealed a predicted protein product showing strong homology to SlyA,
originally thought to be a haemolytic virulence determinant in Salmonella
typhimurium. Homologues of rap were detected in several bacterial genera,
including Salmonella, Yersinia, Enterobacter, and species of the plant pathogen,
Erwinia. The Erwinia hoeEr (homologue of rap) and the Yersinia horYe genes were
also found to be very similar to rap and slyA. Marker exchange mutagenesis of
horEr revealed that it encoded a regulatory protein controlling the production of
antibiotic and exoenzyme virulence determinants in the phytopathogen, Erwinia
carotovora subspecies carotovora. We have shown that these new homologues of SlyA
form a highly conserved subgroup of a growing superfamily of bacterial regulatory
proteins controlling diverse physiological processes in human, animal and plant
pathogens.
PMID- 9402024
TI - Analysis of the carbapenem gene cluster of Erwinia carotovora: definition of the
antibiotic biosynthetic genes and evidence for a novel beta-lactam resistance
mechanism.
AB - Members of two genera of Gram-negative bacteria, Serratia and Erwinia, produce a
beta-lactam antibiotic, 1-carbapen-2-em-3-carboxylic acid. We have reported
previously the cloning and sequencing of the genes responsible for production of
this carbapenem in Erwinia carotovora. These genes are organized as an operon,
carA--H, and are controlled by a LuxR-type transcriptional activator, encoded by
the linked carR gene. We report in this paper the genetic dissection of this
putative operon to determine the function of each of the genes. We demonstrate by
mutational analysis that the products of the first five genes of the operon are
involved in the synthesis of the carbapenem molecule. Three of these, carABC, are
absolutely required. In addition, we provide evidence for the existence of a
novel carbapenem resistance mechanism, encoded by the CarF and carG genes. Both
products of these overlapping and potentially translationally coupled genes have
functional, N-terminal signal peptides. Removal of these genes from the Erwinia
chromosome results in a carbapenem-sensitive phenotype. We assume that these
novel beta-lactam resistance genes have evolved in concert with the biosynthetic
genes to ensure 'self-resistance' in the Erwinia carbapenem producer.
PMID- 9402025
TI - uvrD mutations enhance tandem repeat deletion in the Escherichia coli chromosome
via SOS induction of the RecF recombination pathway.
AB - It has previously been shown that recombination between tandem repeats is not
significantly affected by a recA mutation in Escherichia coli. Here, we describe
the activation of a RecA-dependent recombination pathway in a hyper-recombination
mutant. In order to analyse how tandem repeat deletion may proceed, we searched
for mutants that affect this process. Three hyper-recombination clones were
characterized and shown to be mutated in the uvrD gene. Two of the mutations were
identified as opal mutations at codons 130 and 438. A uvrD::Tn5 mutation was used
to investigate the mechanism of deletion formation in these mutants. The uvrD
mediated stimulation of deletion was abolished by a lexAind3 mutation or by
inactivation of either the recA, recF, recQ or ruvA genes. We conclude that (i)
this stimulation requires SOS induction and (ii) tandem repeat recombination in
uvrD mutants occurs via the RecF pathway. In uvrD+ cells, constitutive expression
of SOS genes is not sufficient to stimulate deletion formation. This suggests
that the RecF recombination pathway activated by SOS induction is antagonized by
the UvrD protein. Paradoxically, we observed that the overproduction of UvrD from
a plasmid also stimulates tandem repeat deletion. However, this stimulation is
RecA independent, as is deletion in a wild-type strain. We propose that the
presence of an excess of the UvrD helicase favours replication slippage. This
work suggests that the UvrD helicase controls a balance between different routes
of tandem repeat deletion.
PMID- 9402026
TI - Blocking rolling circle replication with a UV lesion creates a deletion hotspot.
AB - UV light irradiation increases genetic instability by causing mutations and
deletions. The mechanism of UV-induced rearrangements was investigated making use
of deletion-prone plasmids. Chimeric plasmids carrying pBR322 and M13 replication
origins undergo deletions that join the M13 replication origin to a random
nucleotide. A restriction fragment was UV irradiated, introduced into such a
hybrid plasmid and deletions formed at the M13 origin were analysed. In most of
the deletant molecules, the M13 replication nick site was linked to a nucleotide
in the irradiated fragment, showing that UV lesions are deletion hotspots. These
deletions were independent of the UvrABC excision repair proteins, suggesting
that the deletogenic structure is the lesion itself and not a repair
intermediate. They were not found in the absence of M13 replication, indicating
that they result from the encounter of the M13 replication fork with the UV
lesion. Furthermore, UV-induced deletions occurred independently of pBR322
replication. We conclude that, in contrast to pBR322 replication forks, M13
replication forks blocked by UV lesions are deletion prone. We propose that the
deletion-prone properties of a UV-arrested polymerase depend on the associated
helicase.
PMID- 9402027
TI - Telomeres of the linear chromosomes of Lyme disease spirochaetes: nucleotide
sequence and possible exchange with linear plasmid telomeres.
AB - Bacteria of the spirochaete genus Borrelia have linear chromosomes about 950 kbp
in size. We report here that these linear chromosomes have covalently closed
hairpin structures at their termini that are similar but not identical to those
reported for linear plasmids carried by these organisms. Nucleotide sequence
analysis of the chromosomal telomeric regions indicates that unique, apparently
functional genes lie within a few hundred bp of each of the telomeres, and that
there is an imperfect 26 bp inverted repeat at the two telomeres. In addition, we
characterize a major chromosomal length polymorphism within the right telomeric
regions of various Borrelia isolates, and show that sequences similar to those
near the right telomere are often found on linear plasmids in B. burgdorferi
(sensu stricto) isolates from nature. Sequences similar to a number of other
regions of the chromosome, including those near the left telomere, were not found
on B. burgdorferi plasmids. These observations suggest that there has been
historical exchange of genetic information between the linear plasmids and the
right end of the linear chromosome.
PMID- 9402028
TI - Repair by recombination of DNA containing a palindromic sequence.
AB - We report here that homologous recombination functions are required for the
viability of Escherichia coli cells maintaining a 240 bp chromosomal inverted
repeat (palindromic) sequence. Wild-type cells can successfully replicate this
palindrome but recA, recB or recC mutants carrying the palindrome are unviable.
The dependence on homologous recombination for cell viability is overcome in sbcC
mutants. Directly repeated copies of the DNA containing the palindrome are
rapidly resolved to single copies in wild-type cells but not in sbcC mutants. Our
results suggest that double-strand breaks introduced at the palindromic DNA
sequence by the SbcCD nuclease are repaired by homologous recombination. The
repair is conservative and the palindrome is retained in the repaired chromosome.
We conclude that SbcCD can attack secondary structures but that repair conserves
the DNA sequence with the potential to fold.
PMID- 9402029
TI - Mammalian heterotrimeric G-protein-like proteins in mycobacteria: implications
for cell signalling and survival in eukaryotic host cells.
AB - Mammalian heterotrimeric GTP-binding protein (G proteins) are involved in
transmembrane signalling that couples a number of receptors to effectors
mediating various physiological processes in mammalian cells. We demonstrate that
bacterial proteins such as a Ras-like protein from Pseudomonas aeruginosa or a 65
kDa protein from Mycobacterium smegmatis can form complexes with human or yeast
nucleoside diphosphate kinase (Ndk) to modulate their nucleoside triphosphate
synthesizing specificity to GTP or UTP. In addition, we demonstrate that bacteria
such as M. smegmatis or Mycobacterium tuberculosis harbour proteins that cross
react with antibodies against the alpha-, beta- or the gamma-subunits of
heterotrimeric G proteins. Such antibodies also after the GTP synthesizing
ability of specific membrane fractions isolated from glycerol gradients of such
cells, suggesting that a membrane-associated Ndk-G-protein homologue complex is
responsible for part of GTP synthesis in these bacteria. Indeed, purified Ndk
from human erythrocytes and M. tuberculosis showed extensive complex formation
with the purified mammalian alpha- and beta-G-protein subunits and allowed
specific GTP synthesis, suggesting that such complexes may participate in
transmembrane signalling in the eukaryotic host. We have purified the alpha-,
beta- and gamma-subunit homologues from M. tuberculosis and we present their
internal amino acid sequences as well as their putative homologies with mammalian
subunits and the localization of their genes on the M. tuberculosis genome. Using
oligonucleotide probes from the conserved regions of the alpha- and gamma-subunit
of M. tuberculosis G-protein homologue, we demonstrate hybridization of these
probes with the genomic digest of M. tuberculosis H37Rv but not with that of M.
smegmatis, suggesting that M. smegmatis might lack the genes present in M.
tuberculosis H37Rv. Interestingly, the avirulent strain H37Ra showed weak
hybridization with these two probes, suggesting that these genes might have been
deleted in the avirulent strain or are present in limited copy numbers as opposed
to those in the virulent strain H37Rv.
PMID- 9402030
TI - Structural principles of prokaryotic gene regulatory proteins and the evolution
of repressors and gene activators.
PMID- 9402031
TI - Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and
transmigration of cytokine- and endotoxin-activated endothelium.
AB - Vascular endothelium activated by endotoxin and cytokines plays an important role
in organ inflammation and blood leukocyte recruitment. Neutrophils, which are a
homogeneous population of effector cells, are rapidly attracted in large numbers
to sites of inflammation where they form an early response to infection or
injury. Excessive production of various interleukins, TNF, arachidonic acid
metabolites, and other substances by neutrophils and macrophages results in
systemic endothelial cell injury, a fundamental problem. In the present study, we
investigated in vitro the effects of thalidomide (THD) on activation of
endothelial cells for enhanced transmigration of neutrophils by
lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF), and interleukin-1
(IL-1). Modulation of endotoxin- and cytokine-induced neutrophil chemotaxis and
respiratory burst by THD were also studied. Treatment of HUVEC with THD in
combination with LPS, TNF, and IL-1, respectively, antagonized LPS-activated
transmigration of neutrophils but stimulated the effects of TNF and IL-1. All of
the agents used-THD, LPS, TNF, and IL-1-inhibited neutrophil chemotaxis. Addition
of THD to the neutrophils had no effect on LPS-inhibited chemotaxis whereas the
TNF- and IL-1-induced chemotaxis was modulated in a bimodal manner. However, THD
failed to influence neutrophil respiratory burst activity. Results demonstrate
that THD differentially affects mediator-induced activation of HUVEC and
neutrophils.
PMID- 9402032
TI - Multiple calcium channels are required for pituitary adenylate cyclase-activating
polypeptide-induced catecholamine secretion from bovine cultured adrenal
chromaffin cells.
AB - The effects of L-, N-, P- and Q-type calcium channel antagonists and (+/-)-BayK
8644 on catecholamine release induced by pituitary adenylate cyclase-activating
polypeptide (PACAP-27) were investigated in bovine cultured adrenal chromaffin
cells. PACAP-27 induced the release of 4-15% of the total cellular catecholamines
over 7 min, with an EC50 of 20 nM and the effect approaching maximum at 100 nM.
Catecholamine release was fully dependent on the presence of extracellular
calcium. The dihydropyridine nitrendipine which inhibits L-type calcium channels
inhibited PACAP-27-induced secretion in a concentration dependent manner with an
inhibition of 20-30% at 1 microM. In contrast, (+/-)-BayK-8644, which prolongs
the opening of L-type calcium channels produced a concentration-dependent
increase in PACAP-27-induced catecholamine release with 1 microM increasing
release by 40-60%. Blockade of N-type calcium channels with omega-conotoxin GVIA
reduced release by 5-15%. Block of P-type channels with low concentrations of
omega-agatoxin IVA (< or = 30 nM) had no significant effect on release, while
higher concentrations (100-300 nM) which block Q-type channels reduced release by
up to 15%. omega-Conotoxin MVIIC, an antagonist of Q-type calcium channels and
also of N- and P-type channels, inhibited release in a concentration-dependent
manner with a near maximum effect of 30-50% produced by 300 nM. The combination
of omega-conotoxin GVIA and omega-agatoxin IVA reduced release by 40-50%.
Addition of omega-conotoxin MVIIC (300 nM) to the combination of omega-conotoxin
GVIA (10 nM) and omega-agatoxin IVA (100 nM) did not inhibit catecholamine
release more than with omega-conotoxin GVIA and omega-agatoxin IVA alone,
indicating that 100 nM omega-agatoxin IVA was sufficient to block the Q-type
calcium channels. When nitrendipine was used together with omega-conotoxin GVIA,
omega-agatoxin IVA and omega-conotoxin MVIIC, catecholamine release induced by 20
nM or 100 nM PACAP-27 was reduced by 70-85%. Taken together these results suggest
that influx of calcium through multiple different voltage-sensitive calcium
channels mediate PACAP-27-induced catecholamine release from bovine chromaffin
cells, and that L-, N- and Q-channels contribute to this response.
PMID- 9402033
TI - Imidazole antimycotics affect the activity of various ion channels and insulin
secretion in mouse pancreatic B-cells.
AB - In the present paper the effects of antimycotics with imidazole structure on the
activity of various ion currents of mouse pancreatic B-cells and insulin
secretion from isolated islets have been studied. Clotrimazole (0.1-10 microM,
bath solution without albumin) reversibly inhibited the whole-cell K + ATP
current studied with the patch-clamp technique and concomitantly depolarized the
membrane potential. Two other structurally related compounds, econazole and
ketoconazole, exhibited similar effects on the whole-cell K + ATP current.
Clotrimazole also inhibited the current through single K + ATP channels measured
in the inside-out configuration. According to these results it seems unlikely
that a cytoplasmic factor is involved in the action of clotrimazole on K + ATP
currents. Clotrimazole (10 microM) also reduced the current through voltage
dependent Ca2+ and K+ channels and altered inactivation kinetics. Moreover,
clotrimazole reversibly abolished a recently described inward current which is
induced by hypotonic cell swelling. The results show that clotrimazole altered
the activity of all ion currents in B-cells investigated in this study.
Clotrimazole (3-100 microM, solution with albumin) irreversibly inhibited insulin
secretion from isolated islets. With econazole and ketoconazole similar effects
on hormone release were observed. The changes in the activity and kinetics of
voltage-dependent Ca2+ and K+ currents are likely to contribute to the observed
inhibition of insulin secretion. However, we cannot entirely rule out that
imidazole antimycotics also interfere with a step in stimulus-secretion coupling
distal to changes in membrane potential.
PMID- 9402034
TI - Stimulated [35S]GTP gamma S binding by 5-HT1A receptor agonists in recombinant
cell lines. Modulation of apparent efficacy by G-protein activation state.
AB - G-protein activation by different 5-HT receptor ligands was investigated in h5
HT1A receptor-transfected C6-glial and HeLa cells using agonist-stimulated [35S]
GTP gamma S binding to membranes in the presence of excess GDP. 5-HT (10 microM)
stimulated [35S]GTP gamma S binding in the C6-glial membrane preparation to a
larger extent than in the HeLa preparation; maximal responses with 30 microM GDP
were 490 +/- 99 and 68 +/- 12%, respectively. With the 5-HT receptor agonists
that were being investigated, the two preparations displayed the same rank order
of potency for stimulation of [35S]GTP gamma S binding. In the C6-glial
preparation at 0.3 microM GDP, the rank order of maximal effects was: 5-HT (1.00)
> 8-OH-DPAT (0.90) = R(+)-8-OH-DPAT (0.87) = 5-CT (0.86) = L694247 (0.84) > S(-)8
OH-DPAT (0.68) = buspirone (0.67) = spiroxatrine (0.67) = flesinoxan (0.64) >
ipsapirone (0.53) = (-)-pindolol (0.50) > SDZ216525 (0.25). However, differences
in maximal response in the C6-glial preparation were magnified by increasing the
GDP concentrations, indicating that the activity state of G-proteins can affect
the maximal response. With the exception of 5-CT and L694247, increasing the
amount of GDP to 30 microM and higher concentrations resulted in an attenuation
of both the ligand's maximal effect (24 to 56%) and apparent potency (6 to 24
fold). Each of the [35S]GTP gamma S binding responses was mediated by a 5-HT1A
receptor as indicated by the competitive blockade by WAY100635 and spiperone.
Only 5-CT and L694247 in some conditions displayed an efficacy similar to that of
5-HT at the h5-HT1A receptor; the other agents with intrinsic activity are
partial agonists at this receptor. The data also suggest that the activity state
of the G-proteins is involved in the maximal effects that can be produced by
activating the h5-HT1A receptor.
PMID- 9402035
TI - Chronic administration of the selective dopamine uptake inhibitor GBR 12,909, but
not cocaine, produces marked decreases in dopamine transporter density.
AB - The chronic continuous infusion of cocaine produces partial behavioral tolerance
to cocaine and tolerance to the inhibition of dopamine uptake by cocaine, without
changing dopamine transporter binding. In order to examine more closely the
dopaminergic contribution to this effect, the selective dopamine uptake inhibitor
GBR 12,909 (30 mg/kg/day), cocaine (50 mg/kg/day), or vehicle, were continuously
infused via osmotic minipump, and their effects on the dopamine transporter
examined. Drug and vehicle pumps were implanted into male Sprague-Dawley rats and
removed after seven days. [3H]WIN 35,428 binding and [3H]dopamine uptake were
measured in caudate putamen and nucleus accumbens at varying intervals after pump
removal. The Bmax for [3H]WIN 35,428 binding was decreased by approximately 75%
in the caudate putamen and by 40% in the nucleus accumbens of GBR 12,909-treated
rats both 1 and 4 days after pump removal, and was still significantly decreased
after 10 days, but had returned to normal by 20 days post-treatment. In contrast,
cocaine did not significantly alter [3H]WIN 35,428 binding. GBR 12,909 produced
both tolerance to the inhibition of [3H]dopamine uptake by cocaine, and a
decrease in total uptake of dopamine, in the caudate putamen, with no change in
the nucleus accumbens. The persistent reduction of [3H]WIN 35,428 binding
following continuous GBR 12,909 does not appear to result from residual drug
binding. These findings suggest that GBR 12,909 and cocaine may bind to and
regulate the dopamine transporter in different ways.
PMID- 9402036
TI - Evaluation of the effects of a specific alpha 2-adrenoceptor antagonist,
atipamezole, on alpha 1- and alpha 2-adrenoceptor subtype binding, brain
neurochemistry and behaviour in comparison with yohimbine.
AB - In the present study we evaluated the alpha 1- and alpha 2-adrenoceptor subtype
binding, central alpha 2-adrenoceptor antagonist potency, as well as effects on
brain neurochemistry and behavioural pharmacology of two alpha 2-adrenoceptor
antagonists, atipamezole and yohimbine. Atipamezole had higher selectivity for
alpha 2- vs. alpha 1-adrenoceptors than yohimbine regardless of the subtypes
studied. Both compounds had comparable affinity for the alpha 2A-, alpha 2C- and
alpha 2B-adrenoceptors, but yohimbine had significantly lower affinity for the
alpha 2D-subtype. This may account for the fact that significantly higher doses
of yohimbine than atipamezole were needed for reversal of alpha 2-agonist
(medetomidine)-induced effects in rats (mydriasis) and mice (sedation and
hypothermia). The effect on central monoaminergic activity was estimated by
measuring the concentrations of transmitters and their main metabolites in whole
brain homogenate. At equally effective alpha 2-antagonising doses in the rat
mydriasis model, both drugs stimulated central noradrenaline turnover (as
reflected by increase in metabolite levels) to the same extent. Atipamezole
increased dopaminergic activity only slightly, whereas yohimbine elevated central
dopamine but decreased central 5-hydroxytryptamine turnover rates. In behavioural
tests, atipamezole (0.1-10 mg/kg) did not affect motor activity but stimulated
food rewarded operant (FR-10) responding (0.03-3 mg/kg) whereas yohimbine both
stimulated (1 mg/kg) and decreased (> or = 3 mg/kg) behaviour in a narrow dose
range in these tests. In the staircase test, both antagonists increased
neophobia, but in the two compartment test only yohimbine (> or = 3 mg/kg)
decreased exploratory behaviour. The dissimilar effects of the antagonists on
neurochemistry and behaviour are thought to be caused by non alpha 2-adrenoceptor
properties of yohimbine. In conclusion, the alpha 2-antagonist atipamezole
blocked all alpha 2-adrenoceptor subtypes at low doses, stimulated central
noradrenergic activity and had only slight effects on behaviour under familiar
conditions, but increased neophobia. The low affinity for the alpha 2D
adrenoceptor combined with its unspecific effects complicates the use of
yohimbine as pharmacological tool to study alpha 2-adrenoceptor physiology and
pharmacology.
PMID- 9402037
TI - Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the
human and guinea-pig hippocampus.
AB - We examined the question of whether cannabinoid receptors modulating
noradrenaline release are detectable in the brain of humans and experimental
animals. For this purpose, hippocampal slices from humans, guinea-pigs, rats and
mice and cerebellar, cerebrocortical and hypothalamic slices from guinea-pigs
were incubated with [3H]noradrenaline and then superfused. Tritium overflow was
evoked either electrically (0.3 or 1 Hz) or by introduction of Ca2+ ions (1.3 mM)
[corrected] into Ca(2+)-free, K(+)-rich medium (25 mM) [corrected] containing
tetrodotoxin 1 microM. Furthermore, the cAMP accumulation stimulated by forskolin
10 microM was determined in guinea-pig hippocampal membranes. We used the
following drugs: the cannabinoid receptor agonists (-)-cis-3-[2-hydroxy-4-(1,1-
dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclo-hexanol (CP-55,940) and
R(+)-[2,3-dihydro-5-methyl-3- [(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4
benzoxazinyl]- (1-naphthalenyl)methanone (WIN 55,212-2), the inactive S(-)
enantiomer of the latter (WIN 55,212-3) and the CB1 receptor antagonist N
piperidino-5-(4-chlorophenyl)- 1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole
carboxamide (SR 141716). The electrically evoked tritium overflow from guinea-pig
hippocampal slices was reduced by WIN 55,212-2 (pIC30% 6.5) but not affected by
WIN 55,212-3 up to 10 microM. The concentration-response curve of WIN 55,212-2
was shifted to the right by SR 141716 (0.032-microM) (apparent pA2 8.2), which by
itself did not affect the evoked overflow. WIN 55,212-2 1 microM also inhibited
the Ca(2+)-evoked tritium overflow in guinea-pig hippocampal slices and the
electrically evoked overflow in guinea-pig cerebellar, cerebrocortical and
hypothalamic slices as well as in human hippocampal slices but not in rat and
mouse hippocampal slices. SR 141716 (0.32 microM) markedly attenuated the WIN
55,212-2-induced inhibition in guinea-pig and human brain slices. SR 141716 0.32
microM by itself increased the electrically evoked tritium overflow in guinea-pig
hippocampal slices but failed to do so in slices from the other brain regions of
the guinea-pig and in human hippocampal slices but failed to do so in slices from
the other brain regions of the guinea-pig and in human hippocampal slices. The
cAMP accumulation stimulated by forskolin was reduced by CP-55,940 and WIN 55,212
2. The concentration-response curve of CP 55,940 was shifted to the right by SR
141716 (0.1 microM; apparent pA2 8.3), which by itself did not affect cAMP
accumulation. In conclusion, cannabinoid receptors of the CB1 subtype occur in
the human hippocampus, where they may contribute to the psychotropic effects of
cannabis, and in the guinea-pig hippocampus, cerebellum, cerebral cortex and
hypothalamus. The CB1 receptor in the guinea-pig hippocampus is located
presynaptically, is activated by endogenous cannabinoids and may be negatively
coupled to adenylyl cyclase.
PMID- 9402038
TI - Caffeine induces central cholinergic analgesia.
AB - The antinociceptive effect of caffeine was examined by using the hot-plate,
abdominal constriction tests in mice and the tail flick and paw-pressure tests in
rats. Caffeine (1-5 mg kg-1 s.c. in mice; 2.5-5 mg kg-1 i.p. in rats) produced
significant antinociception in both species which was prevented by atropine (5 mg
kg-1 i.p.), pirenzepine (0.1 microgram per mouse i.c.v.), hemicholinium-3 (1
microgram/ mouse i.c.v.) and N6-cyclopentyladenosine (5 micrograms/mouse i.c.v.),
but not by naloxone (1 mg kg-1 i.p.), CGP 35348 (100 mg kg-1 i.p.), alpha-methyl
p-tyrosine (100 mg kg-1 i.p.) and reserpine (2 mg kg-1 i.p.).
Intracerebroventricular injection of caffeine in mice at doses (2.5-5 micrograms
per mouse) which were largely ineffective by parenteral routes, induces an
antinociception whose intensity equalled that obtainable s.c. or i.p. In the
antinociceptive dose-range, caffeine did not produce any behavioural impairment
as revealed by the rotarod and Irwing tests. On the basis of the above data, it
can be postulated that caffeine exerts an antinociceptive effect mediated by
central amplification of cholinergic transmission.
PMID- 9402039
TI - Antinociceptive action of DBO 17 and DBO 11 in mice: two 3,8 diazabicyclo
(3.2.1.) octane derivates with selective mu opioid receptor affinity.
AB - Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were
studied for the opioid-like activity. In the rat brain membrane preparation
binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the
mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11
inhibited the nociceptive response in the hot-plate test of mice with ED50 values
of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both
DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive
action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated
treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine
tolerant mice and vice versa. Chronic treatments (three times daily for seven
consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal
syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas
in DBO 11 treated mice abstinence signs were virtually absent. These results
indicate an interesting pharmacological profile that suggests these compounds as
possible new candidates for the clinical treatment of pain.
PMID- 9402040
TI - Differential regulation of corticotropin-releasing factor and vasopressin in
discrete brain regions after morphine administration: correlations with
hypothalamic noradrenergic activity and pituitary-adrenal response.
AB - The changes in the content of corticotropin-releasing factor (CRF) and arginine
vasopressin (AVP) in discrete brain nuclei during chronic opioids administration
have not been well established. We evaluated the effects of acute and chronic
morphine administration on the content of CRF and AVP in different hypothalamic
and extrahypothalamic (bed nucleus of the stria terminalis, BNST) nuclei in rats.
Concomitantly, changes in hypothalamic noradrenaline (NA) turnover [estimated by
the 3-methoxy-4-hydroxyphenylethyleneglycol MHPG/NA ratio] and in plasma
corticosterone release (as a marker of the activity of the hypothalamus-pituitary
adrenal axis) were determined. Male rats were implanted with placebo (naive) or
morphine (tolerant) pellets for 7 days. On day 8, groups of rats received an
acute injection of either saline i.p. or morphine (30 mg/kg i.p.) and were
sacrificed 30 min later. Acute morphine injection to naive rats increased both
the release of corticosterone and the hypothalamic NA turnover. CRF and AVP
showed no modifications in the paraventricular nucleus (PVN) or in the median
eminence (ME). CRF content decreased in the ventromedian nucleus (VMN) and
increased in the BNST, but did not change in the arcuate nucleus (AN). AVP was
elevated in the supraoptic nucleus (SON) but not changed in the suprachiasmatic
nucleus (SCN). In chronic morphine-treated rats, there was a pronounced decrease
in the NA turnover and in the release of corticosterone, which indicates that
tolerance develops to the acute effects of morphine. Correspondingly, CRF and AVP
were enhanced in the PVN and decreased in the ME, when compared with naive rats
injected with morphine. CRF content was decreased in the AN and in the BNST, but
increased in the VMN. The AVP content was decreased in the SON, and no
modifications were seen in the SCN. The present study shows that, in addition to
the modifications in corticosterone secretion and in hypothalamic NA turnover,
chronic morphine administration produces a complex response in the CRF and AVP
systems. These modifications might contribute to the behavioral, emotional and
neuroendocrine alterations produced during opioid tolerance.
PMID- 9402042
TI - Methylene blue induces ongoing activity in rat cutaneous primary afferents and
depolarization of DRG neurons via a photosensitive mechanism.
AB - The dye methylene blue is known as a blocker of guanylyl cyclase and it has been
widely used to deplete cells of internal cyclic GMP. The data presented
demonstrate an activation of adult rat sensory neurons by methylene blue via a
photosensitive mechanism. In single fiber recordings from primary afferents of
the rat skin in vitro, methylene blue, applied to the receptive field, induced
discharge activity: 2/2 A beta-, 2/4 A delta- and 5/7 C-fibers showed
significantly enhanced firing upon 10 microM methylene blue in the presence of
light, whereas the dye was ineffective when illumination was prevented. In whole
cell current clamp experiments with dissociated dorsal root ganglion neurons, 100
microM methylene blue was ineffective in the dark but evoked a membrane
depolarization of 15.3 +/- 3.5 mV (n = 5) accompanied by discharge activity upon
illumination. In whole cell voltage clamp experiments, methylene blue (100
microM) caused a significant slowing of the inactivation of voltage-dependent
sodium currents. In addition, an inhibition of fast and slow outward currents was
observed with prolonged exposure. The impeded sodium inactivation together with
the blockade of potassium currents may contribute to the depolarization and
discharge activity observed in primary afferents in vitro as well as in
dissociated sensory neurons in culture. We therefore suggest that methylene blue
studies with excitable cells or tissues need to be interpreted with caution.
PMID- 9402041
TI - Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal
neurons without altering normal synaptic transmission.
AB - Previous behavioural and electrophysiological studies have indicated that
levetiracetam (ucb LO59) acts as an anticonvulsant drug in vivo. The purpose of
the present study was to investigate the effects of levetiracetam on normal
synaptic transmission and epileptiform activity in vitro. Intracellular
recordings were obtained from the CA3 subfield of the rat hippocampal slice
preparation. Levetiracetam in a concentration of 10 microM did not influence
basic cell properties or normal synaptic transmission evoked by subthreshold and
suprathreshold stimuli to the commissural pathway. However, it strongly inhibited
the development of epileptiform bursting by the gamma-aminobutyric acid (GABA)A
receptor antagonist bicuculline (1-30 microM). Levetiracetam also decreased the
size of bursts previously established by bicuculline. In experiments in which the
glutamate-receptor agonist N-Methyl-D-Aspartate (NMDA) was used to generate
spontaneous bursting, levetiracetam had no effect on the size of the bursts but
decreased bursting frequency. The difference in effects of levetiracetam on
bicuculline- and NMDA-induced bursting appeared to be dependent on the convulsant
used, since in the presence of 10 microM bicuculline, levetiracetam decreased the
size of NMDA-bursts to the same extent as the size of synaptically evoked
bicuculline-bursts but had little effect on bursting frequency. The results show
that under our experimental conditions, levetiracetam did not alter the
components of normal synaptic transmission. However, levetiracetam at the
concentrations studied inhibited epileptiform bursting induced by bicuculline and
NMDA in vitro in a manner consistent with the profile of an antiepileptogenic
drug.
PMID- 9402043
TI - Presynaptic snake beta-neurotoxins produce tetanic fade and endplate potential
run-down during neuromuscular blockade in mouse diaphragm.
AB - The present study investigated the ability of a number of presynaptic snake
neurotoxins (snake beta-neurotoxins) to produce nerve-evoked train-of-four fade,
tetanic fade and endplate potential run-down during the development of
neuromuscular blockade in the isolated mouse phrenic-hemidiaphragm nerve-muscle
preparation. All the snake beta-neurotoxins tested, with the exception of
notexin, produced train-of-four and tetanic fade of nerve-evoked isometric muscle
contractions. Train-of-four fade was not present during the initial depressant or
facilitatory phases of muscle tension produced by the snake beta-neurotoxins but
developed progressively during the final depressant phase that precedes complete
neuromuscular blockade. The 'non-neurotoxic' bovine pancreatic phospholipase A2
and the 'low-toxicity' phospholipase A2 from Naja naja atra venom failed to
elicit train-of-four fade, indicating that the phospholipase activity of the
snake beta-neurotoxins is not responsible for the development of fade.
Intracellular recording of endplate potentials (EPPs) elicited by nerve-evoked
trains of stimuli showed a progressive run-down in EPP amplitude during the train
following incubation with all snake beta-neurotoxins except notexin. Again this
run-down in EPP amplitude was confined to the final depressant phase of snake
beta-neurotoxin action. However when EPP amplitude fell to near uniquantal levels
(< 3 mV) the extent of toxin induced-fade was reduced. Unlike postjunctional
snake alpha-neurotoxins, prejunctional snake beta-neurotoxins interfere with
acetylcholine release at the neuromuscular junction during the development of
neuromuscular blockade. This study provides further support for the hypothesis
that fade in twitch and tetanic muscle tension is due to an underlying rundown in
EPP amplitude resulting from a prejunctional alteration of transmitter release
rather than a use-dependent block of postjunctional nicotinic receptors.
PMID- 9402044
TI - The Y1 antagonist BIBP 3226 inhibits potentiation of methoxamine-induced
vasoconstriction by neuropeptide Y.
AB - We investigated the interaction of neuropeptide Y (NPY) with the alpha 1
adrenoceptor agonist, methoxamine, in control of mean arterial pressure,
renovascular resistance and mesenteric vascular resistance in anaesthetized rats.
Infusion of 3.0 but not 0.3 microgram/kg/min NPY enhanced the elevations of all
three haemodynamic parameters caused by bolus injections of methoxamine (10-100
micrograms/kg). These enhancements largely involved a prolongation of the
methoxamine effects. While infusion of the Y1 NPY receptor-selective antagonist,
BIBP 3226 (10 micrograms/kg/min), alone did not alter methoxamine-induced
vasoconstriction, it inhibited the potentiation by NPY. We conclude that NPY can
potentiate methoxamine-induced vasoconstriction in vivo. This is mediated
predominantly, if not exclusively, via the Y1 receptor. Endogenously released NPY
does not appear to reach sufficient concentrations to cause tonic systemic
vasoconstriction or potentiation thereof in the anaesthetized rat.
PMID- 9402045
TI - Characterization by antagonists of P2-receptors mediating endothelium-dependent
relaxation in the rat aorta.
AB - The receptors through which 2-methylthio ATP (MeSATP), adenosine 5'-O-(2
thiodiphosphate) (ADP beta S), UTP and ATP elicit endothelium-dependent
relaxation of noradrenaline-precontracted rings of the rat aorta were
characterized by means of a series of antagonists. The acetylcholine-induced
relaxation and the degradation of MeSATP, UTP and ATP were also studied. The
potency of the nucleotides at producing relaxation decreased in the order MeSATP
(EC50 0.24 microM) > ADP beta S (0.43 microM) > UTP (1.09 microM) > ATP (3.53
microM). MeSATP, ADP beta S and UTP did not cause relaxation when the endothelium
had been destroyed; high concentrations of ATP still caused some relaxation. The
relaxation by MeSATP, ADP beta S and UTP became very small after treatment of the
rings with NG-nitro-L-arginine methyl ester; the relaxation by ATP was less
affected. Pre-exposure to MeSATP (100 microM) abolished or almost abolished the
relaxation normally elicited by MeSATP and ADP beta S, did not change that
elicited by UTP and slightly enhanced the relaxation elicited by ATP. Of nine
compounds examined as antagonists, six attenuated selectively the effect of some
or all of the nucleotides (as compared to acetylcholine): suramin, reactive blue
2, pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (iso-PPADS),
pyridoxalphosphate-6-azophenyl-2',4'-disulphonate (PPADS), reactive red 2 and
5,5'-(1,1'-biphenyl-4,4'-diylbisazo)-bis-7-amino -6-hydroxy-naphthalene-1,4
disulphonate (NH05). Decreases of maximal relaxations and slopes different from
unity in Schild plots often indicated non-competitive kinetics of the antagonism.
For each of the six 'selective' antagonist, the apparent Kd values against MeSATP
and against ADP beta S were similar: none of the six differentiated between
MeSATP and ADP beta S. Also, for each of four 'selective' antagonists, the
apparent Kd values against UTP and against ATP were similar: none of the four
differentiated between these two nucleotides (two antagonists did not act against
UTP and ATP in the 'selective' concentration range). On the other hand, for five
of the six 'selective' antagonists (the exception being NH05), the apparent Kd
values against MeSATP and ADP beta S were considerably lower than those against
UTP and ATP. At the highest concentrations tested against agonist-evoked
relaxations, the antagonists did not alter the removal from the incubation
medium, by pieces of rat aorta, of MeSATP, UTP and ATP. It is concluded that
nucleotides cause endothelium-dependent relaxation of the rat aorta through two
sites: a P2Y-receptor and a P2U-receptor. The receptors may be pharmacologically
similar to a bovine endothelial P2Y (P2Y1) and a cloned rat P2U (P2Y2) receptor,
respectively. ATP acts mainly through the P2U-receptor. Suramin, reactive blue 2,
iso-PPADS, PPADS and reactive red 2 are more potent at the P2Y- than the P2U
receptor. NH05 does not discriminate between the two receptors but is the most
potent P2U antagonist so far described.
PMID- 9402046
TI - Vasoconstrictor and vasodilator effects of guanine nucleotides in the rat aorta.
AB - Although GTP, like ATP and UTP, is stored in platelet dense granules, little is
known about its vascular effects. The present study was carried out in order to
characterize the effects of GTP and related compounds in the rat aorta.
Contractions were examined in aortic rings at resting tension. In rings with
intact endothelium, GTP, GDP, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S)
and guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) caused small contractions. In
endothelium-denuded rings, the contractions were unchanged or increased and
persisted after desensitization of P2X-receptors by alpha,beta-methylene ATP.
Relaxations were examined in aortic rings precontracted with noradrenaline. In
rings with intact endothelium, GTP (EC50 131 microM), GDP (no maximal effect
obtained), GTP gamma S (EC50 6.8 microM) and guanosine (EC50 822 microM) caused
prominent relaxation, whereas GDP beta S caused further contraction. In
endothelium-denuded rings, the relaxant effect of GTP was greatly reduced, that
of GDP and guanosine was unchanged, and that of GTP gamma S was abolished.
Relaxations by GTP and GTP gamma S in endothelium-intact rings were studied in
more detail. The relaxation by GTP was slightly and the relaxation by GTP gamma S
greatly reduced after treatment with NG-nitro-L-arginine methyl ester. Pre
exposure to a high concentration of the P2Y-receptor agonist 2-methylthio ATP
(MeSATP) did not attenuate the effects of GTP and GTP gamma S. Four compounds
previously identified as antagonists at the P2Y- and P2U-receptors of rat aortic
endothelium--suramin, reactive blue 2, pyridoxalphosphate-6-azophenyl-2',5'
disulphonate (iso-PPADS) and 5,5'-(1,1'-biphenyl-4,4'-diylbisazo)-bis-7-amino-6-
hydroxynaphthalene-1,4-disulphonate (NH05)--were tested against GTP and GTP gamma
S. Suramin, reactive blue 2 and iso-PPADS were much less potent against GTP and
GTP gamma S than previously found against (the P2Y effect of) MeSATP. Suramin,
iso-PPADS and NH05 were about as potent against GTP and GTP gamma S as previously
found against (the P2U effect of) UTP and in particular ATP. It is concluded that
guanine nucleotides can cause both contraction and relaxation of the rat aorta.
The high concentrations of GTP and GDP required, and in the case of contraction
the small size of the response, make a physiological role of the vascular effects
of these nucleotides unlikely. GTP and GTP gamma S elicit endothelium-dependent
relaxation through P2U-receptors. GTP in addition relaxes the aorta through
smooth muscle receptors, possibly by way of its degradation product guanosine.
The stable analog GTP gamma S is a relatively potent and selective agonist for
the endothelial P2U-receptor.
PMID- 9402047
TI - Kinin B1 and B2 receptors in pig vessels: characterization of two monoreceptor
systems.
AB - The coronary artery and renal vein of the adult pig are sensitive and reliable
monoreceptor systems for studying kinin receptors. The pig coronary artery with
intact endothelium is highly sensitive to bradykinin (BK, pEC50 8.6), while being
insensitive to the B1 receptor agonist, LysdesArg9BK. The tissue responds to BK
with concentration-dependent relaxation, which is prevented by B2 receptor
antagonists, particularly DArg[Hyp3, Thi5, DTic7, Oic8]BK (HOE 140, pKB 9.3), (E)
3-(6-acetoamido-3-pyridyl)-N-(N-{2, 4-dichloro-3-[(2-methyl-8-quinolinyl)oxy
methyl]phenyl}-N- methylaminocarbonyl-methyl)acrylamide (FR 173657), a new non
peptide compound (pKB 9.3), while B1 receptor antagonists (e.g.
Lys[Leu8]desArg9BK) are inactive. The order of potency of kinin-related peptides
in this vessel is: LysBK > or = BK > [Hyp3]BK > [Aib7]BK, a sequence typical of a
B2 receptor system. Antagonists such as HOE 140 and FR 173657, at high
concentrations reduce the maximum effect of BK and thus behave as noncompetitive
antagonists. The kinin B1 receptor was studied in the pig renal vein without
endothelium and incubated for several hours in order to allow for the de novo
formation of this functional site. After 7-8 h in vitro incubation, the vessel
shows high sensitivity to LysdesArg9BK (pEC50 8.3) and is insensitive to BK. The
pig renal vein responds to B1 receptor agonists with concentration-dependent
contraction which maintains a stable plateau and is prevented by selective B1
receptor antagonists such as Lys[Leu8]desArg9BK (pKB 6.7). The most active
antagonist has been found to be desArg9HOE 140 (pA2 7.6) which acts as
competitive antagonist in this preparation. Some B2 antagonists (e.g. HOE 140)
show weak (pKB 6.1) anti-B1 receptor activity while the non-peptide compound FR
173657 is inactive on the B1 receptor and therefore acts as a potent and
selective kinin B2 receptor antagonist in the pig. The data obtained in this
study allow us to compare the porcine B2 and B1 receptors with those of other
species including man, and underline some interesting features that are unique to
the porcine functional sites.
PMID- 9402048
TI - Characterization of postjunctional muscarinic receptors mediating contraction in
rat anococcygeus muscle.
AB - The present study was designed to characterize the postjunctional muscarinic
receptors mediating contraction in rat anococcygeus muscle by means of a series
of muscarinic agonists and subtype-preferring key muscarinic antagonists.
Cumulative addition of muscarinic agonists elicited concentration-dependent
contractions with the following rank order of potency (pD2 values): (+)-muscarine
(6.36) > or = oxotremorine M (6.21) > or = arecaidine propargyl ester (APE)
(6.18) > carbachol (5.68) = (+/-)-methacholine (5.65) > 4-(4-chlorophenyl
carbamoyloxy)-2-butynyltrimethylammonium chloride (4-Cl-McN-A-343) (4.28) > 4-(3
chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) (3.89).
(+)-Muscarine, oxotremorine M, carbachol and (+/-)-methacholine behaved as full
agonists, whereas APE, 4-Cl-McN-A-343 and McN-A-343 displayed partial agonism.
The contractile responses of the rat anococcygeus muscle to (+/-)-methacholine
were competitively antagonized by pirenzepine (pA2 = 6.92), 11-[[4-[4
(diethylamino)butyl]-1-piperidinyl]acetyl] 5,11-dihydro-6H-pyrido(2,3-b) (1,4)
benzodiazepine-6-one (AQ-RA 741; pA2 = 6.75), himbacine (pA2 = 7.11), (+/-)-p
fluoro-hexahydro-sila-difenidol (p-F-HHSiD; pA2 = 7.68) and the (R)- and (S)
enantiomers of hexahydro-difenidol [(R)-HHD: pA2 = 8.52; (S)-HHD: pA2 = 6.06]. A
comparison of the pA2 values derived from studies of contraction in rat
anococcygeus muscle with literature binding (pKi values) and functional
affinities (pA2 values) obtained at native M1-M4 receptors strongly suggests that
the postjunctional muscarinic receptors mediating contraction in rat anococcygeus
muscle are of the M3 subtype.
PMID- 9402049
TI - MEN 11420, a potent and selective tachykinin NK2 receptor antagonist in the
guinea-pig and human colon.
AB - We have characterized the action of the novel, water-soluble, tachykinin NK2
receptor antagonist MEN 11420 ([Asn(2-AcNH-beta-D-Glc)-Asp-Trp-Phe-Dap-Leu] c(2
beta-5 beta)) on the circular muscle of the guinea-pig and human colon in vitro
and on the guinea-pig colon in vivo. In organ bath experiments on guinea-pig
colon MEN 11420 produced a concentration-dependent rightward shift of the
concentration-response curve to the NK2 receptor selective agonist, [beta
Ala8]neurokinin A (NKA) (4-10) with a pKB value of 8.1. Up to 1 microM MEN 11420
had no effect on the concentration-response curve to methacholine, to the NK1
receptor selective agonist, [Sar9]substance P (SP) sulfone, to the NK3 receptor
selective agonist, senktide, or on the response to exogenous SP. The response to
exogenous NKA was inhibited, although the shift of the concentration-response
curve to NKA produced by MEN 11420 at 1 microM (dose ratio 5.3) was much smaller
than that produced against [beta Ala8]NKA (4-10) (dose ratio 102), presumably
because NKA also stimulates NK1 receptors at relatively low concentrations. In
sucrose gap, MEN 11420 concentration-dependently inhibited both depolarization
(IC50 0.34 microM) and contraction (IC50 = 0.32 microM) produced by [beta
Ala8]NKA (4-10) (0.3 microM for 10 s) in the guinea-pig colon without affecting
the corresponding responses produced by [Sar9]SP sulfone. When similar
experiments were performed in the circular muscle of the human colon MEN 11420
concentration-dependently inhibited both depolarization and contraction induced
by [beta Ala8]NKA(4-10) with IC50s of 99 and 75 nM, respectively. MEN 11420 (1
microM) had no effect on the nonadrenergic noncholinergic (NANC) depolarization
and contraction produced by a short period of electrical field stimulation (EFS,
10 Hz for 1 s) in the guinea-pig colon and selectively inhibited the sustained
component of depolarization produced during a prolonged period of EFS (3 Hz for 3
min), without affecting the concomitant depolarization. Nifedipine (1 microM)
eliminated the NANC contraction to a short period of EFS and the phasic
contraction in response to a prolonged period of EFS. MEN 11420 (1 microM)
abolished the nifedipine-resistant NANC contraction produced by prolonged period
of electrical field stimulation (EFS, 3 Hz for 3 min). All electrical and
mechanical NANC responses to EFS which were resistant to MEN 11420, either in the
absence or presence of nifedipine, were abolished by the subsequent application
of the NK1 receptor antagonist, SR 140333 (1 microM). Up to 3 microM, MEN 11420
had no significant effect on the cholinergic excitatory junction potential or the
NANC inhibitory junction potential evoked by single pulse EFS, nor did it affect
membrane conductance. In urethane-anaesthetized guinea-pigs MEN 11420 (10-100
nmol/kg i.v.) produced a dose-dependent and long lasting (> 3 h) inhibition of
the contractile response (15 +/- 2 mmHg) of the proximal colon induced by [beta
Ala8]NKA (4-10) (3 nmol/kg i.v.). MEN 11420 (300 nmol/kg i.v.) did not affect the
contraction produced by [Sar9]SP sulfone. MEN 11420 (300 nmol/kg) produced a
limited (Emax about 40% inhibition) and transient (recovery within 60 min)
inhibition of the atropine- and hexamethonium-sensitive phasic contractions of
the proximal colon induced by threshold distension of a colonic balloon. On the
other hand, MEN 11420 (10-300 nmol/kg i.v.) produced a dose-dependent complete
and prolonged (> 2 h from administration) inhibition of the atropine-resistant
and hexamethonium-sensitive phasic contraction induced by suprathreshold
distension of the colonic balloon. We conclude that MEN 11420 is a potent and
selective tachykinin NK2 receptor antagonist devoid of significant inhibitory
activity toward excitatory transmission mediated via tachykinin NK1 or muscarinic
receptors. The present findings indicate that SP and NKA are likely involved in
the preferential activation of NK1 and NK2 receptors during tachykininergi
PMID- 9402051
TI - Mammalian glial cells in culture synthesize acetylcholine.
AB - In the present study we demonstrate that acetylcholine is synthesized by cultured
mammalian glial cells identified by cell-type specific markers. Primary cultures
of rat brain astrocytes or microglia contained 2.0 and 1.6 pmol
acetylcholine/10(6) cells on average respectively. Astrocyte cultures established
from neonatal mouse brain contained even more acetylcholine (about 80 pmol
acetylcholine/10(6) cells). Primary cultures of rat brain astrocytes showed
choline acetyltransferase (ChAT) enzyme activity of 3 nmol/mg protein/h; ChAT
activity was blocked by 10 microM bromoacetylcholine. In conclusion, these data
demonstrate the synthesis of the "neurotransmitter" acetylcholine in cultured
glial cells, a finding which opens a new view upon the role of acetylcholine in
mammalian brain.
PMID- 9402050
TI - NK1- and NK3-receptor mediated inhibition of 5-hydroxytryptamine release from the
vascularly perfused small intestine of the guinea-pig.
AB - The effects of tachykinins on the spontaneous release of 5-hydroxytryptamine (5
HT) from the enterochromaffin cells into the portal circulation was investigated
in vitro using the vascularly perfused isolated guinea-pig small intestine. 5-HT
was determined by HPLC with electrochemical detection. Test substances were
applied intraarterially. Substance P (SP) caused a concentration-dependent
decrease in 5-HT outflow with an EC50 of 50 pmol/l. Similarly, the selective NK1
receptor agonist SP methyl ester (1 nmol/l) significantly inhibited 5-HT outflow
(to 51 +/- 3%). When tetrodotoxin (1 mumol/l) was added to the arterial perfusion
medium, the inhibition by SP of 5-HT outflow was not affected. The selective NK1
receptor antagonist CP 99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2
phenylpiperidine] (0.1 mumol/l) prevented the inhibitory effect of SP (0.1
mumol/l). Neither GR 94800 (PhCO-Ala-Ala-DTrp-Phe-DPro-Pro-NleNH2) (0.1 mumol/l)
nor SR 142801 [(S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3
yl)propyl)-4-phenylpiperidin-4-yl)-N- methylacetamide] (10 nmol/l), which are
selective NK2 and NK3 receptor antagonists, changed the SP-mediated inhibition.
The selektive NK3 receptor agonist senktide (10 nmol/l) also decreased the 5-HT
outflow (to 57 +/- 5%). This inhibition was prevented by SR 142801 (10 nmol/l)
and by tetrodotoxin. CP 99994 (0.1 mumol/l) significantly antagonized the
senktide-mediated inhibition of 5-HT outflow. The outflow of 5-HT was unaffected
when CP 99994, GR 94800 or SR 142801 alone were added to the perfusion medium. It
is concluded that the release of 5-HT from enterochromaffin cells is directly
inhibited by NK1 receptors, and indirectly by neuronal NK3 receptors whose
stimulation leads to the release of SP.
PMID- 9402065
TI - The crystal structure of a type I cohesin domain at 1.7 A resolution.
AB - The quaternary organization of the cellulosome, a multi-enzymatic extracellular
complex produced by cellulolytic bacteria, depends on specific interactions
between dockerin domains, double EF-hand subunits carried by the catalytic
components, and cohesin domains, individual receptor subunits linearly arranged
within a non-catalytic scaffolding polypeptide. Cohesin-dockerin complexes with
distinct specificities are also thought to mediate the attachment of cellulosomes
to the cell membrane. We report here the crystal structure of a single cohesin
domain from the scaffolding protein of Clostridium thermocellum. The cohesin
domain folds into a nine-stranded beta-sandwich with an overall "jelly roll"
topology, similar to that observed in bacterial cellulose-binding domains.
Surface-exposed patches of conserved residues promote extensive intermolecular
contacts in the crystal, and suggest a possible binding target for the EF-hand
pair of the cognate dockerin domain. Comparative studies of cohesin domains
indicate that, in spite of low sequence similarities and different functional
roles, all cohesin domains share a common nine-stranded beta-barrel fold
stabilized by a conserved hydrophobic core. The formation of stable cohesin
dockerin complexes requires the presence of Ca2+. However, the structure of the
cohesin domain reported here reveals no obvious Ca2+-binding site, and previous
experiments have failed to detect high affinity binding of Ca2+ to the unliganded
dockerin domain of endoglucanase CelD. Based on structural and biochemical
evidence, we propose a model of the cohesin-dockerin complex in which the
dockerin domain requires complexation with its cohesin partner for protein
stability and high-affinity Ca2+ binding.
PMID- 9402066
TI - The 1.8 A crystal structure of the dimeric peroxisomal 3-ketoacyl-CoA thiolase of
Saccharomyces cerevisiae: implications for substrate binding and reaction
mechanism.
AB - The dimeric, peroxisomal 3-ketoacyl-CoA thiolase catalyses the conversion of 3
ketoacyl-CoA into acyl-CoA, which is shorter by two carbon atoms. This reaction
is the last step of the beta-oxidation pathway. The crystal structure of
unliganded peroxisomal thiolase of the yeast Saccharomyces cerevisiae has been
refined at 1.8 A resolution. An unusual feature of this structure is the presence
of two helices, completely buried in the dimer and sandwiched between two beta
sheets. The analysis of the structure shows that the sequences of these helices
are not hydrophobic, but generate two amphipathic helices. The helix in the N
terminal domain exposes the polar side-chains to a cavity at the dimer interface,
filled with structured water molecules. The central helix in the C-terminal
domain exposes its polar residues to an interior polar pocket. The refined
structure has also been used to predict the mode of binding of the substrate
molecule acetoacetyl-CoA, as well as the reaction mechanism. From previous
studies it is known that Cys125, His375 and Cys403 are important catalytic
residues. In the proposed model the acetoacetyl group fits near the two catalytic
cysteine residues, such that the oxygen atoms point towards the protein interior.
The distance between SG(Cys125) and C3(acetoacetyl-CoA) is 3.7 A. The O2 atom of
the docked acetoacetyl group makes a hydrogen bond to N(Gly405), which would
favour the formation of the covalent bond between SG(Cys125) and C3(acetoacetyl
CoA) of the intermediate complex of the two-step reaction. The CoA moiety is
proposed to bind in a groove on the surface of the protein molecule. Most of the
interactions of the CoA molecule are with atoms of the loop domain. The three
phosphate groups of the CoA moiety are predicted to interact with side-chains of
lysine and arginine residues, which are conserved in the dimeric thiolases.
PMID- 9402068
TI - Elevated serum macrophage inhibitory factor-related protein (MRP) 8/14 levels in
advanced HIV infection and during disease exacerbation.
AB - To assess the value of MRP 8, MRP 14, and MRP 8/14 serum concentrations as
markers of disease progression in HIV infection and as markers of intercurrent
infections. DESIGN: We measured MRP 8, MRP 14, and MRP 8/14 serum concentrations
in 184 HIV-infected patients in various stages of disease with or without disease
exacerbation and in 50 healthy control subjects. In clinically stable HIV
infection correlations of MRP levels with stage of HIV disease, CD4 counts, p24
antigen, and beta-2 microglobulin levels were studied. In patients with
intercurrent illnesses, correlations of MRP levels with type of disease
exacerbation and with CRP were calculated and compared with those found in stable
HIV infection. RESULTS: MRP 8/14 levels were significantly elevated and MRP 8
levels slightly decreased in stable HIV infection compared with HIV-negative
controls. The CD4 cell count and MRP 8/14 levels correlated significantly in
patients with AIDS. Despite higher values of MRP 8/14 during advanced disease,
these were not significant predictors of progression to death. In patients with
acute infections, MRP 8/14 levels were significantly elevated, compared with
patients with illnesses of noninfectious origin. Levels of MRP 8/14 associated
with acute infections were significantly higher in patients with AIDS than in
patients during earlier stages of HIV infection. CONCLUSIONS: Both stable HIV
infection and advanced immunedeficiency are associated with an elevation of the
MRP 8/14 complex and probably with a decline of MRP 8 serum levels. MRP 8/14 is
preserved as a marker of acute infection in immunecompromised patients.
PMID- 9402067
TI - Antioxidants and dipyridamole inhibit HIV-1 gp120-induced free radical-based
oxidative damage to human monocytoid cells.
AB - Reactive oxygen species (ROS) may play an important role in HIV-1 pathogenesis
and HIV-1 gp120-induced neurotoxicity. Our studies determined the extent to which
gp120 increased ROS production in human monocytic U937 cells and the
effectiveness of various agents, including dipyridamole (DPR), in blocking these
responses. The thiobarbituric acid-reactive substances (TBARS) assay was used as
a measure of recombinant gp120 (HIV-1[3B])-induced oxidative damage to U937
cells. As a control, TBARS production was measured using a hypoxanthine/xanthine
superoxide generating system. There was gp120-induced oxidative damage in U937
cells with a concentration that produces 50% of maximal effect (apparent EC50
value) of 11 pM. Polyclonal antiserum to gp120 significantly (p < 0.05) inhibited
gp120-induced oxidative damage. gp120-induced oxidative damage was significantly
inhibited 81% (p < 0.01) by catalase/superoxide dismutase, 53% (p < 0.05) by (+/
)-alpha-tocopherol, 78% (p < 0.01) by desferrioxamine, and 82% (p < 0.01) by
ethylene diamine tetraacetic acid (EDTA). These results indicate that gp120 is
capable of promoting iron-based oxygen free radical damage to U937 cells. DPR
potently (p < 0.05) inhibited both hypoxanthine/xanthine- and gp120-induced
oxidative damage with concentrations that produce 50% inhibition (apparent IC50
values) of 1.3 microM for hypoxanthine/xanthine and 1.0 microM for gp120.
Therapeutic intervention against ROS production may prevent HIV-1 neurotoxicity.
PMID- 9402069
TI - CCR5del32 in perinatal HIV-1 infection.
AB - CCR5, a chemokine receptor, serves as a coreceptor for macrophage-tropic HIV-1 (1
3). A 32-bp deletion within the gene encoding CCR5, CCR5del32, has been shown to
prevent HIV-1 infection of T cells in the absence of a wild-type allele. This
alteration is present in low frequency in Caucasian populations (4-6). To
investigate the effect of CCR5del32 in perinatal HIV-1 transmission and disease
progression, two cohorts of perinatally exposed infected and uninfected children
were analyzed for the presence of the allele. Polymerase chain reaction (PCR) was
used to identify CCR5del32 in prevalent and prospective cases among 144 African
American children from New York City and 73 Caucasian children from Barcelona,
Spain. HIV-1 transmission; clinical manifestations of disease, including
encephalopathy, opportunistic infections, and death before 2 years of age;
survival; Centers for Disease Control and Prevention (CDC) classification; and
degree of immunosuppression were compared in children with and without CCR5del32.
The allele frequency in HIV-1-infected African Americans (0.016) was lower than
in Catalan children (0.041). No evidence for a dominant protective effect of
CCR5del32 for HIV-1 transmission or disease progression was found in these
cohorts.
PMID- 9402070
TI - Risk of mother-to-infant transmission of HIV-1 is not reduced in CCR5/delta32ccr5
heterozygotes.
AB - To determine if the 32-bp deletion of the chemokine receptor CCR5 (delta32ccr5)
protects against mother-to-infant transmission of HIV-1, specimens from all
uninfected and infected children who were perinatally exposed to HIV-1 and
observed since 1988 and whose mothers did not take zidovudine were assessed for
delta32ccr5. The CCR5 genotype was determined using polymerase chain reaction
(PCR) for 122 subjects, of whom 73 were HIV-1 infected and 49 were perinatally
exposed but uninfected; 70% and 71%, respectively, were Caucasian. Eleven of 73
(15%) infected children and 4 of 49 (8%) exposed uninfected children were
CCR5/delta32ccr5 heterozygotes (p = 0.40). Among subjects who had at least one
Caucasian parent or grandparent, 11 of 51 (22%) HIV-1-infected persons and 4 of
35 (11%) uninfected persons were heterozygotes. None were homozygous for the
delta32ccr5 allele. The estimated relative risk for mother-to-infant HIV-1
transmission in heterozygotes was 2.0. Furthermore, the 95% confidence interval
(0.6, 7.3) suggested that it is unlikely that the true relative risk was <0.6.
Thus, the infant CCR5/delta32ccr5 heterozygous genotype was not associated with a
diminished risk of perinatally acquired HIV-1 infection.
PMID- 9402072
TI - Testosterone replacement treatment options for HIV-infected men.
AB - Hypogonadism is well documented in HIV-infected men, particularly as they
progress to AIDS and in those with symptoms of wasting. Testosterone deficiency
can be diagnosed with simple laboratory tests, and various treatment options
exist. The benefits of androgen replacement are well documented from a large body
of literature and experience with hypogonadal men without HIV infection.
Hypogonadal men who are given testosterone replacement have improved sexual
thoughts and functioning, more energy, and improved mood. Generally, quality of
life improves with such therapy. Testosterone replacement tends to maintain or
improve lean body mass. The benefit, dose, and timing of testosterone replacement
treatment for men with HIV infection, however, are less clear and require further
study. Appropriate history and a high degree of clinical suspicion, coupled with
relatively simple laboratory measurements, can confirm the diagnosis of
hypogonadism in men with HIV. Various options for testosterone replacement,
including injections of testosterone esters and the use of transcutaneous
patches, are discussed, as are the uses of pharmacologic doses of testosterone,
primarily for its potential anabolic effect.
PMID- 9402071
TI - Safety and antiviral activity of combination therapy with zidovudine,
zalcitabine, and two doses of interferon-alpha2a in patients with HIV. AIDS
Clinical Trials Group Study 197.
AB - We conducted a three-arm, randomized, phase II study to evaluate the combination
of zidovudine (600 mg/day) and zalcitabine (2.25 mg/day) alone or with one of two
interferon-alpha2a doses (1 mIU or 6 mIU daily). Primary study endpoints included
toxicity and changes from baseline for plasma HIV-1 RNA, CD4 cells, and
quantitative microculture at weeks 8 and 24. Sixty-three patients with HIV
infection and <400 CD4 cells/mm3 were enrolled; four patients discontinued
therapy within 2 weeks. Adverse event rates were 37%, 32%, and 60%, respectively,
for the nucleoside, 1-mIU interferon, and 6-mIU interferon combination groups.
Increasing doses of interferon resulted in significantly greater hematologic
toxicity (p = 0.03) and peripheral neuropathy (p = 0.02). Plasma HIV-1 RNA
reductions were noted across all treatment groups at week 8 (p < 0.001) but only
for the nucleoside and 1-mIU interferon combination groups at week 24 (p <
0.001). Mean reductions in HIV-1 RNA at week 8 were 0.94, 1.29, and 1.40 log10,
respectively, for the nucleoside, 1-mIU interferon, and 6-mIU interferon
combination groups (p = 0.05); no differences were noted at week 24. No
differences in CD4 cell counts were seen. The addition of interferon-alpha2a to
zidovudine and zalcitabine resulted in transient enhanced decreases in viral load
and increased toxicity.
PMID- 9402073
TI - Risk behavior for HIV infection in participants in preventive HIV vaccine trials:
a cautionary note.
AB - We conducted a longitudinal study of participants in phase I and II HIV vaccine
safety and immunogenicity trials to examine changes in sexual risk behavior that
are associated with risk of HIV transmission. The participants were 48 HIV
negative men and women enrolled in one of two placebo-controlled HIV vaccine
trials conducted at San Francisco General Hospital. There was a significant
increase in insertive unprotected anal intercourse (UAI) from 9% at baseline
(trial entry), to 13% at the month 6 assessment, to 20% at the month 12
assessment (p = .02). The primary predictor of either insertive or receptive UAI
during the vaccine trials was having engaged in this behavior prior to entry (p =
.001). Higher-risk behavior was also seen among participants who were younger and
had multiple sexual partners (each, p = .06) and who indicated that one of their
reasons for participation in the vaccine trial was hope of protection from HIV
infection (p = .07). These findings indicate that despite instructions otherwise,
participants with a history of high-risk behavior or who express hope of
protection from HIV infection by enrolling in vaccine trials may be candidates
for more intensive risk-behavior counseling prior to and during their
participation.
PMID- 9402074
TI - HIV-1 infection in women is associated with severe nutritional deficiencies.
AB - Nutritional deficiencies may contribute to immune dysregulation, and have been
shown to be sensitive markers of HIV-1 disease progression. Only limited
information exists, however, regarding the nutritional profile of HIV-1
seropositive drug abusers. Immune and nutritional measurements were obtained in a
subsample of 125 subjects from a larger cohort of drug users being followed for
HIV-1 infection and cofactors of disease progression. Nutritional deficiencies,
particularly vitamins A, E, and zinc, were widespread with up to 86% of the drug
users exhibiting at least one nutritional alteration. Although immune parameters
(CD4 count, CD8 count, beta2-microglobulin) were similar in the HIV-1-infected
men and women, women had significantly poorer overall nutritional status, as
measured by plasma proteins, which are considered to be sensitive markers of
malnutrition. A comparison of individuals with advanced disease (CD4 count
<200/mm3) revealed significantly lower levels of plasma prealbumin (p < .01),
selenium, (p < .05), and greater deficiency of vitamins A (p < .01) and E (p <
.05) in women than in men. The greater severity of nutritional deficiencies noted
in HIV-1-infected women may be an important determinant of disease progression
and survival.
PMID- 9402075
TI - Relation between soluble CD30 levels measured soon after HIV seroconversion and
disease progression in men with hemophilia.
AB - Soluble CD30 (sCD30) levels within 3 years of HIV seroconversion were studied in
85 hemophilic men infected with HIV. All men were coinfected with hepatitis C
virus (HCV). Levels of sCD30 were elevated in these men when compared with
controls. These elevated levels did not appear to be a result of treatment with
intermediate-purity clotting factor concentrates and were unlikely to be due to
HCV coinfection inasmuch as hemophilic patients infected with HCV alone showed
only mildly elevated sCD30 levels when compared with those of hemophilic controls
uninfected with HCV. Initial sCD30 levels were not significantly associated with
progression to any endpoint, although a tendency was present for those with the
highest initial levels to progress less rapidly than those with lower values.
Despite elevated sCD30 levels in these men, we have not been able to confirm that
high sCD30 levels are associated with more rapid HIV progression.
PMID- 9402076
TI - Mother-to-child transmission of HIV-1.
AB - After reviewing the evidence on the relation of vertical transmission of HIV to
stage of infection in the mother, I developed a stochastic model of transmission
in which the probability of transmission per week is proportional to the virus
load in the mother. The virus load in different stages of the infection is
measured by viral RNA levels or tissue culture infectious virus levels in plasma.
The constant of proportionality is assumed to be different for transmission
during pregnancy, during parturition, and during breast-feeding. Using data on
transmission from mothers who are in the primary stage of infection, I estimated
the constant of proportionality and calculated the probability of transmission
during pregnancy as a function of the time pregnancy starts in relation to the
stage of the infection. For breast-feeding, I calculated the conditional
probability of transmission by breast-feeding for 20 weeks, dependent on the
infant escaping infection during pregnancy and parturition. As might be expected,
the probabilities of transmission are highest if the mother is in the primary
stage of infection or in late stages of the disease and is quite low when the
mother is in the asymptomatic stage of the infection.
PMID- 9402077
TI - The association of herpes simplex virus type 2 (HSV-2), Haemophilus ducreyi, and
syphilis with HIV infection in young men in northern Thailand.
AB - To evaluate the association between sexually transmitted diseases that commonly
may cause genital ulceration and prevalent and incident HIV infections, we
conducted three case control studies in a cohort of 21-year-old male military
conscripts in northern Thailand. The men were evaluated at baseline in 1991 and
semiannually until their discharge 2 years later. Serologic evidence of infection
with herpes simplex virus type 2 (HSV-2), Haemophilus ducreyi, and HIV were more
frequent at baseline in 83 men with a history of genital ulcer than in 97 men
without such a history. Seropositivity to H. ducreyi (odds ratio [OR] = 3.46),
HSV-2 (OR = 3.83), and syphilis (OR = 1.53) were more common in HIV-positive than
HIV-negative men. Men (N = 45) who seroconverted to HIV while in the military
were more often seropositive for H. ducreyi and HSV-2 before HIV seroconversion
and also were more likely to seroconvert to HSV-2 and H. ducreyi during the same
interval as their HIV seroconversion compared with men who remained HIV-negative.
These data suggest that HSV-2 and H. ducreyi may be both markers for high-risk
sexual behavior and risk factors for HIV infection among young men in Thailand.
PMID- 9402078
TI - Staphylococcus aureus nasal colonization in HIV-seropositive and HIV-seronegative
drug users.
AB - Nasal colonization plays an important role in the pathogenesis of Staphylococcus
aureus infections. To identify characteristics associated with colonization, we
studied a cross-section of a well-described cohort of HIV-seropositive and
seronegative active and former drug users considered at risk for staphylococcal
infections. Sixty percent of the 217 subjects were Hispanic, 36% were women, 25%
actively used injection drugs, 23% actively used inhalational drugs, 23% received
antibiotics, and 35% were HIV-seropositive. Forty-one percent of subjects had
positive nasal cultures for S. aureus. The antibiotic susceptibility patterns
were similar to the local hospital's outpatient isolates and no dominant strain
was identified by arbitrarily primed polymerase chain reaction (AB-PCR).
Variables significantly and independently associated with colonization included
antibiotic use (odds ratio [OR] = 0.37; confidence interval [CI] = 0.18-0.77),
active inhalational drug use within the HIV-seropositive population (OR = 2.36;
CI = 1.10-5.10) and female gender (OR = 1.97; CI = 1.09-3.57). Characteristics
not independently associated included injection drug use, HIV status, and CD4
count. The association with active inhalational drug use, a novel finding, may
reflect alterations in the integrity of the nasal mucosa. The lack of association
between HIV infection and S. aureus colonization, which is contrary to most
previous studies, could be explained by our rigorous control for confounding
variables or by a limited statistical power due to the sample sizes.
PMID- 9402079
TI - High cytomegalovirus antigenemia levels and cytomegalovirus syndrome in patients
with AIDS.
PMID- 9402080
TI - Presence of HTLV-I and HTLV-II infection in Honduras.
PMID- 9402081
TI - Various types of injection equipment and risk of HIV infection.
PMID- 9402082
TI - Early effect of aldosterone on the rate of synthesis of the epithelial sodium
channel alpha subunit in A6 renal cells.
AB - Transepithelial Na+ reabsorption across tight epithelia is regulated by
aldosterone. The amiloride-sensitive epithelial sodium channel (ENaC) is a major
target for the natriferic action of aldosterone. In this study, the effect of
aldosterone on ENaC mRNA abundance and the rate of protein synthesis for each of
the three ENaC subunits (alpha, beta and gamma) in the A6 kidney cell line were
examined. In cells grown on plastic, aldosterone induced a large and rapid
increase in epithelial sodium channel (ENaC) beta and gamma subunit mRNA
abundance, but this effect is not translated into the synthesis of the
corresponding proteins. In cells grown on a porous substrate, amiloride-sensitive
electrogenic sodium transport was expressed and was upregulated by aldosterone
(300 nM) as early as 1 h after the addition of the hormone. The alpha, beta, and
gamma mRNA abundance was not changed by aldosterone during the first 3 h of
stimulation, whereas a fourfold increase over control was observed after 24 h.
The rate of synthesis of alpha subunit was significantly increased above control
already 60 min after aldosterone addition, whereas beta subunit synthesis
increased only 6 h after hormone addition, with no significant change for the
gamma subunit. The half-lives of each subunit as assessed by 35S methionine pulse
chase experiments were short (between 40 and 50 min) and were not modified by
aldosterone. Taking into account the short half-life of ENaC protein and assuming
that the synthesis of the alpha subunit is a limiting factor in the assembly and
expression of new channels at the cell surface, it is proposed that the
aldosterone regulation of sodium transport might be, in part, mediated by de novo
synthesis of the channel protein.
PMID- 9402083
TI - Localization of ROMK channels in the rat kidney.
AB - Renal potassium secretion occurs in the distal segments of the nephron through
apically located secretory potassium (SK) channels. SK may correspond to the ROMK
channels cloned from rat kidney. In this study, the localization of ROMK at the
cellular level in the rat kidney was examined using an affinity-purified
polyclonal antibody raised against a C-terminal peptide of ROMK. The specificity
of the antibody was demonstrated by immunoblots of membranes of Xenopus oocytes
expressing ROMK2. Immunoblots of homogenates from rat renal outer medulla and
cortex revealed predominant bands of 70 to 75 kD, which were ablated by
preadsorption with an excess of peptide. These bands were specific for the rat
kidney. Immunolocalization studies revealed that ROMK is expressed in specific
nephron segments in both the cortex and medulla. In the cortex, ROMK was found in
the apical domain of the thick ascending limb of Henle's loop, the connecting
tubule, and in some, but not all, cells of cortical collecting tubules. In the
medulla, expression in the apical membrane of the thick ascending limbs of
Henle's loop was strong, whereas outer medullary collecting ducts were weakly
stained. Expression in the thick ascending limb was also heterogeneous; some
cells that expressed the Na-K-Cl cotransporter were weakly stained with the anti
ROMK antibody. No staining of glomeruli, proximal tubules, or inner medullary
collecting ducts was found. The localization of ROMK agrees well with the
findings of SK in patch-clamp studies and supports the view that ROMK is the SK
channel of the distal segments of the nephron.
PMID- 9402084
TI - Potential role of luminal potassium in tubuloglomerular feedback.
AB - Transport through the Na+-2Cl(-)-K+ cotransporter in the luminal membrane of
macula densa cells is considered critical for tubuloglomerular feedback (TGF).
Although various studies could support the importance of luminal Na+ and Cl-, the
role of luminal K+ in TGF has not been thoroughly addressed. The study presented
here examines this issue in nephrons with superficial glomeruli of anesthetized
male Munich-Wistar-Fromter rats. Ambient Na+ concentration in early distal
tubular fluid was approximately 22 mM, suggesting collection sites relatively
close to the macula densa segment. First, it was found that ambient early distal
tubular K+ concentration is approximately 1.3 mM, i.e., close to the K+ affinity
of the Na+-2Cl(-)-K+ cotransporter in the thick ascending limb. Second, it was
observed that a change in late proximal tubular flow rate, i.e., a maneuver that
is known to induce a TGF response, significantly alters early distal tubular K+
concentration. Third, previous experiments failed to show an inhibition in TGF
response during retrograde perfusion of the macula densa with K+-free solutions.
Because of a potential K+ influx into the lumen between the perfusion site and
the macula densa, however, the K+ channel blocker U37883A was added to the K+
free perfusate. TGF response was assessed as the fall in nephron filtration rate
in response to retrograde perfusion of the macula densa segment from early distal
tubular site. It was observed that luminal U37883A (100 microM) significantly
attenuated TGF. Because adding 5 mM KCl to the perfusate restored TGF in the
presence of U37883A and because the inhibitory action of U37883A on tubular K+
secretion was confirmed, the effect of U37883A on TGF was most likely caused by
inhibition of K+ influx into the perfused segment, which decreased luminal K+
concentration at the macula densa. The present findings support a potential role
for luminal K+ in TGF, which is in accordance with a transmission of the TGF
signal across the macula densa via Na+-2Cl(-)-K+ cotransporter.
PMID- 9402085
TI - A role for P-selectin in neutrophil and platelet infiltration in immune complex
glomerulonephritis.
AB - P-selectin is one of the key early mediators of leukocyte adhesion in
inflammatory conditions. This report examines the role of P-selectin in a
neutrophil- and platelet-mediated model of glomerulonephritis (the concanavalin A
[con A] model). The administration of neutralizing anti-P-selectin antibody (PB
1.3) reduced the platelet influx at 10 min (P < 0.05) and was associated with a
60% reduction in the neutrophil infiltrate and a 50% reduction in the number of
oxidant-producing cells at 3 h within glomeruli. No effect on glomerular monocyte
macrophage accumulation was observed, and proteinuria was reduced by 20% but did
not reach significance. It is concluded that P-selectin plays an important role
in mediating the neutrophil and platelet accumulation in this model and likely
has a role in mediating the glomerular injury.
PMID- 9402086
TI - Cytokines and Fas regulate apoptosis in murine renal interstitial fibroblasts.
AB - Renal fibrosis is characterized by an increased number of fibroblasts and
excessive deposition of extracellular matrix. Apoptotic cell death is a
physiological mechanism to limit cell numbers, and an insufficient rate of death
may contribute to fibroblast accumulation. However, little is known about the
regulation of renal fibroblast survival. The authors have studied the interaction
of cytokines and the Fas receptor in the regulation of apoptosis of renal
fibroblasts and have observed that murine renal fibroblasts express Fas and the
Fas ligand. Tumor necrosis factor alpha (TNFalpha) and agonistic anti-Fas
antibodies induce apoptosis of renal fibroblasts in a time- and dose-dependent
manner. Serum contains survival factors for renal fibroblasts. Both serum
deprivation and TNFalpha increase the sensitivity to Fas-induced death and the
expression of fas mRNA and Fas receptor. By contrast, insulin-like growth factor
1 decreases apoptosis induced by both serum deprivation and Fas activation and
partially prevents the increase in Fas receptor expression induced by serum
deprivation. Murine renal fibroblasts express constitutively both fas ligand mRNA
and cell-surface Fas ligand, but the authors could not demonstrate a role for Fas
ligand in the autocrine regulation of fibroblast survival. These data suggest
that Fas and other cytokines cooperate to regulate renal fibroblast apoptosis.
Modulation of the Fas death-signaling pathway in renal fibroblasts could
represent a new therapeutic target for renal fibrosis.
PMID- 9402087
TI - Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families
with congenital nephrogenic diabetes insipidus.
AB - Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder
characterized by renal tubular insensitivity to the antidiuretic effect of
arginine vasopressin (AVP). In a large majority of the cases, nephrogenic
diabetes insipidus is an X-linked recessive disorder caused by mutations in the
AVP V2 receptor gene (AVPR2). In the remaining cases, the disease is autosomal
recessive or dominant and, for these patients, mutations in the aquaporin 2 gene
(AQP2) have been reported. Fourteen probands belonging to 12 families were
analyzed by single-strand conformational polymorphism and direct sequencing of
the AVPR2 and AQP2 genes. Ten mutations of the AVPR2 gene (six previously
reported mutations and four novel mutations: G107E, W193X, L43P, and 15delC) were
identified. Three mutations of the AQP2 gene were also identified in two
patients: the first patient is homozygous for the R85X mutation and the second is
a compound heterozygote for V168 M and S216P mutations. Extrarenal responses to
infusion of the strong V2 agonist 1-desamino-8-D-arginine vasopressin allowed
AVPR2- and AQP2-associated forms of CNDI to be distinguished in three patients.
This test also identified an unexpectedly high urinary osmolality (614 mosmol/kg)
in a patient with a P322S mutation of AVPR2 gene and a mild form of CNDI.
PMID- 9402088
TI - Arginine vasopressin secretion with mutants of wild-type and Brattleboro rats AVP
gene.
AB - Defects in peptide processing are associated with several disorders, including
central diabetes insipidus (CDI). In the Brattleboro (BB) rat with CDI, the mRNA
and protein of arginine vasopressin (AVP) are present in the hypothalamus, but no
circulating AVP is detectable, thus suggesting a processing defect. The present
study examined AVP secretion in cultured COS cells transfected with various
constructs from wild-type and mutated Brattleboro AVP gene precursors. The
precursor contains three exons encoding for vasopressin (VP), neurophysin (NP),
and glycopeptide (GP). The Brattleboro rat has a deletion of a single base,
guanine (G), in the NP coding region that leads to a frameshift, resulting in the
loss of normal stop codon. The wild-type pcVP (22.0 +/- 5.2 pg/10[-2] U beta
galactosidase [beta-gal]), but not the mutated BB AVP gene pcBB (1.2 +/- 0.4
pg/10[-2] U beta-gal), was associated with AVP secretion from the COS cells as
measured by RIA. The wild-type AVP gene without the GP coding region was
associated with AVP release greater (47.4 +/- 13.5 pg/10[-2] U beta-gal, n = 5, P
< 0.05, versus pcVP) than the pcVP with intact VP, NP, and GP coding regions.
However, the wild-type AVP gene with VP coding region alone was not processed and
secreted. Normalizing the pcBB total length with the insertion of a stop codon at
the site of the normal stop codon was not associated with AVP secretion (3.0 +/-
1.4 pg/10[-2] U beta-gal). However, insertion of a stop codon so that the pcBB
length equaled the length of VP and NP coding regions of the wild type was
associated with AVP secretion (13.5 +/- 4.0 pg/10[-2] U beta-gal). When a stop
codon was inserted into the wild-type NP coding region at the same site as the G
deletion in the pcBB, the AVP secretion was significantly lower (15.1 +/- 5.0
pg/10[-2] U beta-gal) than pcVP with VP + NP but no GP coding regions (47.4 +/-
13.5 pg/10[-2] U beta-gal, n = 5, P < 0.05). In summary, (1) both VP and intact
NP, but not GP, coding regions are necessary for AVP processing and secretion;
(2) decreasing the length of the NP coding region diminishes but does not abolish
AVP processing and secretion; and (3) shortening of the pcBB length with a stop
codon at a site comparable to wild-type VP + NP allows AVP secretion, albeit less
than with wild-type gene precursor. Thus, the CDI in BB rats is caused by the G
deletion in NP coding region. This defect leads to abnormalities that contribute
to the abnormal AVP processing. Specifically, the frameshift and absence of a
stop codon cause a mutated extended C terminus, which, along with the mutated NP,
contribute to the abnormal steps of AVP processing, transport, and secretion in
the BB rat. These defects no doubt impair the folding and configuration necessary
for normal processing of the AVP gene precursor.
PMID- 9402089
TI - Estrogen replacement during hypoalbuminemia may enhance atherosclerotic risk.
AB - Estrogen replacement therapy is considered antiatherosclerotic because it reduces
LDL cholesterol and fibrinogen and increases HDL cholesterol concentrations.
However, exogenous estrogen is also known to increase hepatic triglyceride
production. Hyperlipidemia in the nephrotic syndrome is probably due to increased
lipoprotein secretion into plasma and decreased clearance of lipoprotein
cholesterol and triglycerides. Previously, lipid-lowering effects of ovariectomy
in analbuminemic rats were observed, suggesting that in the presence of
hypoalbuminemia, estrogen replacement may have adverse effects on the lipid
profile. To test this hypothesis, ovariectomized control rats and rats with
Adriamycin-induced nephrotic syndrome were treated with estradiol. In
ovariectomized controls, estradiol reduced plasma LDL cholesterol, apolipoprotein
B, and fibrinogen and increased apolipoprotein A-I and triglycerides. Nephrotic
rats were characterized by a marked decrease in plasma colloid osmotic pressure,
hyperfibrinogenemia, hyperlipidemia, and stimulated hepatic fatty acid synthesis.
The beneficial effects of estradiol on LDL cholesterol, apolipoprotein B, and
fibrinogen found in ovariectomized controls were not present in estradiol-treated
nephrotic rats. This suggests that in hypoalbuminemia, downregulation of the LDL
receptor overrides putative estradiol-induced increases in LDL receptor activity.
Moreover, estrogen replacement in the nephrotic syndrome doubled fatty acid
synthesis and triglyceride secretion, and markedly exacerbated
hypertriglyceridemia, suggesting saturation of triglyceride clearance. Thus,
severe hypoalbuminemia in rats induces an atherosclerotic metabolic response that
is aggravated by estrogen replacement. These findings suggest that estrogen
replacement in hypoalbuminemic subjects could be contra-indicated.
PMID- 9402090
TI - Verocytotoxin inhibits mitogenesis and protein synthesis in purified human
glomerular mesangial cells without affecting cell viability: evidence for two
distinct mechanisms.
AB - Acute renal failure is one of the hallmarks of the hemolytic uremic syndrome
(HUS). Infection with a verocytotoxin (VT)- or Shiga-like toxin (SLT)-producing
Escherichia coli has been strongly implicated in the etiology of the epidemic
form of HUS. The functional receptor for these closely related toxins appears to
be a glycosphingolipid, globotriaosylceramide (Gb3). Endothelial damage in the
glomeruli and arterioles of the kidney induced by VT is believed to play a
crucial role in the pathogenesis of HUS. However, little information is available
regarding the effects of VT on mesangial cells, which also play an important role
in glomerular function. In this study, the effects of VT on human mesangial cells
in vitro were investigated. Mesangial cells were enriched by collecting hillock
shaped outgrowths derived from adult human glomeruli and subsequently purified by
elimination of contaminating epithelial cells by immunoseparation with ulex
europaeus lectin-I (UEA-I)-coated dynabeads. The obtained and subcultured
mesangial cell populations were >98% pure. Their mesangial nature was established
by the presence of a-smooth muscle cell actin in highly confluent cultures and
the absence of cytokeratin or platelet/endothelial cell adhesion molecule-1.
Mesangial cells bound VT to bands of Gb3 and a closely related glycolipid, which
is similar to a glycolipid involved in the VT-dependent cytokine production in
monocytes. VT did not induce the release of cytokines or chemokines in mesangial
cells. In VT-susceptible cells, binding of VT to Gb3 causes cell death by the
inhibition of protein synthesis. Although protein synthesis was inhibited in
mesangial cells, all cells remained viable, both under basal and tumor necrosis
factor-alpha-stimulated conditions. However, the marked reduction in protein
synthesis may impair a proper response of the cells in conditions of increased
demand of newly synthesized proteins. Furthermore, VT markedly inhibited DNA
synthesis and proliferation of mesangial cells. The inhibition of mitogenesis was
also found with the B-subunit of VT-1 alone, albeit to a lesser extent, without a
significant effect on protein synthesis. Because the inhibition of protein
synthesis involves the A-subunit, this suggests that two distinct mechanisms
contribute to the effects of VT on protein synthesis and mitogenesis.
Intracellular routing of VT (A- and B-subunits) may vary between cell types and
result in differential effects on human mesangial cells when compared with other
cell types.
PMID- 9402091
TI - Apolipoprotein B, fibrinogen, HDL cholesterol, and apolipoprotein(a) phenotypes
predict coronary artery disease in hemodialysis patients.
AB - Patients with end-stage renal disease have a markedly elevated risk for coronary
artery disease (CAD). Lipids and most lipoproteins, however, seem to be not
predictive for CAD in these patients. Although there is clear evidence that
lipoprotein(a) [Lp(a)] is significantly elevated in these patients, no study with
a sufficiently large group of hemodialysis patients has investigated the
relationship between CAD and Lp(a), as well as the genetically determined
apolipoprotein(a) [apo(a)] phenotype. This cross-sectional study determines the
prevalence of CAD in relation to the cardiovascular risk profile in an unselected
population of 607 hemodialysis patients, of which 33% were diabetic patients.
Twenty-six percent (n = 158) of all patients suffered from CAD as diagnosed by a
definitive myocardial infarction (n = 102) and/or at least one stenosis >50% of a
coronary artery (n = 143). In univariate analysis, several classic risk factors,
including the concentration of lipids, lipoproteins, apolipoproteins, and
fibrinogen, correlated with CAD. Lp(a) in patients with CAD showed only a
tendency to higher levels, without reaching significance, compared with patients
without CAD (26.6 +/- 30.8 mg/dl versus 22.1 +/- 30.4 mg/dl, P = 0.10). The
frequency of low molecular weight apo(a) isoforms, however, was significantly
greater in the group with CAD (34.8% versus 23.6%, P < 0.01). Stepwise logistic
regression analysis found seven variables associated with CAD: apolipoprotein B,
the low molecular weight apo(a) phenotype, male sex, age, fibrinogen, diabetes
mellitus, and HDL cholesterol. The association of these variables with CAD
differed depending on age. These results indicate that, besides classic risk
factors such as age, sex, and diabetes mellitus, additional factors of the
lipoprotein and fibrinolytic system contribute to the high prevalence of CAD in
hemodialysis patients.
PMID- 9402092
TI - Metabolic consequences of folate-induced reduction of hyperhomocysteinemia in
uremia.
AB - Plasma homocysteine, a well-recognized risk factor for cardiovascular disease, is
elevated in uremic patients on hemodialysis. The authors have recently
demonstrated that one consequence is the reduction in red cell membrane protein
methylation levels, caused by a rise of intracellular adenosylhomocysteine, a
potent inhibitor of methyltransferases. Protein methylation is involved in a
repair mechanism of damaged membrane proteins, and an impairment in methylation
leads to the accumulation of altered proteins. Therapy with folates, cofactors in
the transformation of homocysteine to methionine, is effective in lowering plasma
homocysteine. This article details a study on the metabolic effects of oral
methyltetrahydrofolate, the active form of folic acid, on 14 uremic hemodialysis
patients. Two months of therapy led to a significant reduction of plasma
homocysteine levels, with a proportional response to pre-folate levels. In five
of 13 patients with homocysteine levels above 20 microM, plasma homocysteine
level was reduced to less than 15 microM. After treatment, levels of
adenosylmethionine, the methyl donor in transmethylations, had significantly
increased; levels of adenosylhomocysteine had increased to a smaller extent.
Therefore, the ratio between the two compounds, an excellent indicator of the
presence and the degree of methylation inhibition, was significantly ameliorated.
Methionine plasma levels increased after treatment in all patients and were
correlated with posttreatment adenosylmethionine levels. It was concluded that
treatment with methyltetrahydrofolate brings the plasma homocysteine
concentration back to an "acceptable" level, and the metabolic consequences are
in the direction of an increase in the normal flow of transmethylations, as
monitored by an increase in the [adenosylmethionine]/[adenosylhomocysteine]
ratio.
PMID- 9402093
TI - Total body water and body composition in chronic peritoneal dialysis patients.
AB - In this investigation, total body water (TBW) in ten chronic peritoneal dialysis
patients was studied by deuterium (TBW-2H), skinfold thickness (TBW-ST), Watson
formula (TBW-WA), 58% of body weight (TBW-58%), and bioelectrical impedance (TBW
BIA), and these results were compared with the reference oxygen18 (TBW-18O)
method. We also analyzed the fat-free mass (FFM) by skinfold thickness (FFM-ST),
bioelectrical impedance (FFM-BIA), oxygen18 (FFM-18O), and creatinine kinetics
method (FFM-CK). In addition, resting metabolic rate was measured by indirect
calorimetry. Compared with TBW-18O, TBW-58% and TBW-BIA were significantly
different (P < 0.01). TBW-2H overestimated TBW-18O by 4.3%. TBW-ST and TBW-WA
gave slightly greater values than TBW-18O, although these values were
nonstatistically significant. The best prediction of total body water from these
methods was obtained with the Watson formula. When Kt/V was calculated from these
results, the values obtained were statistically greater (BIA, P < 0.001) and
smaller (58% BW, P < 0.01) than those obtained with either 18O or Watson formula.
The fat-free mass estimation also led to discrepant findings. Indeed, FFM-CK was
significantly lower (P < 0.05) as compared with FFM-ST, FFM-BIA, or FFM-18O.
Resting metabolic rate was strongly correlated with FFM estimated by skinfold
thickness (r = 0.91, P < 0.001), bioelectrical impedance (r = 0.85, P < 0.005),
and 18O (r = 0.77, P < 0.01), but not when fat-free mass was estimated by the
creatinine kinetic method. The water content of fat-free mass estimated by
skinfold thickness was found to be 69.7 +/- 6.9% in these patients, a value lower
than the standard 73.2% found in healthy adults. This study confirms that there
is an abnormal water distribution in chronic peritoneal dialysis patients.
However, when compared with the oxygen18 reference method, the Watson formula
allows a reliable estimation of Kt/V.
PMID- 9402094
TI - Hyaluronan decreases peritoneal fluid absorption in peritoneal dialysis.
AB - Hyaluronan, exhibiting a high resistance against water flow, acts in the tissue
as a barrier against rapid changes in water content. To test whether hyaluronan
has any effect on the peritoneal fluid and solute transport, and, in particular,
on the peritoneal fluid absorption, a 4-h dwell study with an intraperitoneal
volume marker (radiolabeled human serum albumin [RISA]) was conducted in 21 male
Sprague Dawley rats (three groups, seven rats in each group). Each rat was
injected intraperitoneally with 25 ml of 1.36% glucose solution alone (control
group), with 0.005% hyaluronan (HA1 group), or with 0.01% hyaluronan (HA2 group).
Dialysate and blood samples were taken frequently for analyses of fluid and
solute (urea, glucose, and protein) transport. The intraperitoneal volume was
calculated from the dilution of RISA with a correction for RISA disappearance
from the peritoneal cavity. This study shows that adding hyaluronan to peritoneal
dialysis solution significantly (P < 0.01) increased the net peritoneal fluid
removal, mainly due to a significant decrease in the peritoneal fluid absorption
rate (P < 0.01). The diffusive mass transfer coefficients for glucose, urea, and
protein did not differ between the three groups. The peritoneal clearance of urea
increased significantly in the two hyaluronan groups compared with the control
group, due to the increased net fluid removal in the hyaluronan groups. These
results suggest that intraperitoneal administration of hyaluronan during a single
peritoneal dialysis exchange may significantly increase the peritoneal fluid and
solute removal by decreasing peritoneal fluid absorption.
PMID- 9402095
TI - Anemia in hemodialysis patients: variables affecting this outcome predictor.
AB - Despite the prevalent use of recombinant human erythropoietin (rhEPO), anemia is
a frequent finding in hemodialysis patients. The goal of this study was to
evaluate the impact of anemia on patient survival and characterize the
determinants of hematopoiesis that may be amenable to therapeutic manipulation to
enhance rhEPO responsiveness and reduce death risk. Patient characteristics and
laboratory data were collected for 21,899 patients receiving hemodialysis three
times per week in dialysis centers throughout the United States in 1993.
Hemoglobin concentrations (Hb) < or =80 g/L were associated with a twofold
increase in the odds of death (odds ratio = 2.01; P = 0.001) when compared with
Hb 100 to 110 g/L. No improvement in the odds of death was afforded for Hb >110
g/L. Using multiple linear regression, variables of rhEPO administration (rhEPO
dose and percentage of treatments that rhEPO was administered), variables of iron
status (serum iron, transferrin saturation, and ferritin), variables of
nutritional status (serum albumin and creatinine concentration), and the dose of
dialysis (urea reduction ratio) were found to be significantly associated with
hemoglobin concentration (P < 0.001). Age, race, and gender were also found to be
significantly associated with hemoglobin concentrations (P < 0.001). From this
report, the following conclusions may be made. (1) Anemia may be predictive of an
increased risk of mortality in some hemodialysis patients. (2) Hemoglobin
concentrations > 110 g/L are not associated with further improvements in the odds
of death. (3) Laboratory surrogates of iron stores, nutritional status, and the
delivered dose of dialysis are predictive of hemoglobin concentration. Whether
manipulation of the factors that improve anemia will also enhance the survival of
patients on hemodialysis is unknown and should be evaluated by prospective,
interventional studies.
PMID- 9402096
TI - Evaluation of pathologic criteria for acute renal allograft rejection:
reproducibility, sensitivity, and clinical correlation.
AB - This study was designed to evaluate the pathologic criteria used for acute renal
allograft rejection that were developed by a panel of renal pathologists
participating in the Cooperative Clinical Trials in Transplantation, a National
Institutes of Health-supported, multicenter research group. The panel defined
three categories of acute rejection. (1) Type I: mononuclear infiltrate in > or
=5% of cortex, a total of at least three tubules with tubulitis in 10 consecutive
high-power fields from the most severely affected areas, and at least two of the
three following features: edema, activated lymphocytes, or tubular injury. (2)
Type II: arterial, or arteriolar, endothelialitis with or without the preceding
features. (3) Type III: arterial fibrinoid necrosis or transmural inflammation
with or without thrombosis, parenchymal necrosis, or hemorrhage. Using these
criteria, and without any knowledge of the clinical course or original diagnosis,
a rotating panel of three pathologists agreed with the original study
pathologist's diagnosis of the presence or absence of rejection in 259 of the 286
biopsies (91%) used for this analysis (kappa = 0.80). The sensitivity to
establish the diagnosis of rejection was 91% for a single core and 99% for two
cores. To validate the diagnostic criteria, the thresholds for number of tubules
with tubulitis and the percent infiltrate were varied, and the pathologic
diagnosis was compared with the clinical course. The greatest agreement occurred
with a threshold of > or =1 tubule with tubulitis and > or =5% cortex with
interstitial infiltrate (91%). Clinically severe rejection episodes were
correlated with the type of rejection (type I, odds ratio [OR] 6.2; type II, OR
37.9). Type II rejection was more likely to be clinically severe than type I (OR
6.1). Analysis of other individual pathologic features revealed a correlation
with clinical severity for endothelialitis (OR 13.2), interstitial hemorrhage (OR
13.2), and the presence of glomerulitis (OR 3.7) (all P < 0.05). The extent of
tubulitis or of the interstitial infiltrate did not correlate with severity (P >
0.05). It is concluded that these criteria are simple, reproducible, and
clinically relevant. These data should lead to further refinement of the
diagnostic systems for renal allograft rejection.
PMID- 9402097
TI - Family history of end-stage renal disease among incident dialysis patients.
AB - As part of a larger study of genetic risk factors for the occurrence of renal
failure, the prevalence of a family history of end-stage renal disease (ESRD) in
first- and second-degree relatives of all incident dialysis patients treated in
Georgia, North Carolina, and South Carolina (ESRD Network 6) in 1994 was
ascertained. Family histories were obtained from 4365 dialysis patients (83% of
those eligible), and 856 (20%) reported having a family history of ESRD. Among
race-sex groups, 14.1% of Caucasian men, 14.6% of Caucasian women, 22.9% of
African-American men, and 23.9% of African-American women reported a first- or
second-degree relative with ESRD (P = 0.001). The prevalence of relatives with
ESRD varied by the reported etiology: 22.2% in diabetes mellitus; 18.9% in
hypertension, 22.7% in glomerulonephritis; and 13.0% of other etiologies (P =
0.001). Patient characteristics independently associated with family history of
ESRD included race, younger age, higher levels of education, and etiology of
ESRD. In this report, it is concluded that a large proportion of incident ESRD
cases have close relatives with ESRD in whom preventive actions might be
directed. Genetic analyses in multiply affected families may identify the
inherited factors contributing to progressive renal failure.
PMID- 9402098
TI - Blood flow limitations of solute transport across the visceral peritoneum.
AB - In a previous study, no limitations to urea transfer across the parietal
peritoneum were demonstrated with decreases in local blood flow of 70%. It was
hypothesized that the visceral peritoneum would have similar characteristics. To
address this problem at the tissue level, diffusion chambers were affixed to the
serosal side of the stomach, cecum, or liver of anesthetized rats (n = 6 each
tissue), and solutions containing 14C urea were placed in the chamber. During
each experiment, the local chamber blood flow was measured with laser Doppler
flowmetry, and, simultaneously, the disappearance of the tracer versus time was
determined under three conditions: control, after 60 to 70% blood flow reduction,
and postmortem (flow = 0). The results showed no difference in the urea mass
transfer coefficient (MTC; mean +/- SEM; cm/min x 10[3]) between control and
blood flow reduction for the stomach (4.0 +/- 0.4 versus 3.6 +/- 0.3) or for the
cecum (4.6 +/- 0.3 versus 4.0 +/- 0.3). However, the MTC was significantly
decreased by local blood flow reduction in the liver (5.4 +/- 0.2 versus 2.6 +/-
0.2). Postmortem data demonstrated significant reductions in the MTC with blood
flow equal to zero. It is concluded that a 60 to 70% blood flow reduction from
control values does not limit solute transperitoneal transfer in the hollow
viscera but causes significant changes in the mass transfer across the liver
surface. Because the liver makes up only a small portion of the effective
exchange area, overall transperitoneal solute transfer should not be greatly
affected by significant decreases in blood flow.
PMID- 9402099
TI - Congenital nephrogenic diabetes insipidus.
PMID- 9402100
TI - The artificial kidney: a dialyser with a great area. 1944.
PMID- 9402101
TI - Glomerulomegaly and proteinuria in a patient with idiopathic pulmonary
hypertension.
AB - Glomerulomegaly is a histologic finding present in idiopathic pulmonary
hypertension, congenital cyanotic heart disease, morbid obesity associated with
sleep apnea syndrome, sickle cell disease, and polycythemic states. This study
examines the case of a 34-yr-old woman with idiopathic pulmonary artery
hypertension who presented with nephrotic-range proteinuria. Kidney biopsy
revealed enlarged glomeruli with mesangial-proliferative glomerulonephritis. A
review of the pertinent literature and a discussion of the proposed
pathophysiologic mechanisms leading to glomerulomegaly are presented.
PMID- 9402103
TI - Transforming growth factor-beta1 in adult human microglia and its stimulated
production by interleukin-1.
AB - Ameboid microglia express human immunodeficiency virus 1 (HIV-1) more frequently
than do ramified microglia. These two microglial subtypes might also differ in
the frequency with which they express transforming growth factor-beta1 (TGF
beta1), a cytokine that regulates HIV-1 expression in monocytes. Results
described here show that ameboid and ramified microglia express TGF-beta1. In
brain tissues from HIV-1-infected individuals as compared with seronegative
controls, ameboid rather than ramified microglia more frequently expressed TGF
beta1. Ameboid microglia, isolated and cultured from postmortem adult human brain
more frequently expressed TGF-beta1 in presence of interleukin-1(IL-1), a
cytokine that is elevated in brains of HIV-1-infected individuals when compared
with seronegative controls. The stimulation of TGF-beta1 by IL-1 was dose and
time dependent, occurring with ameboid microglia isolated from either frontal
cortex or globus pallidus but not midbrain pons. Ameboid microglia are similar to
the RCA-1-positive cells that form clusters, called microglial nodules, in the
brain of HIV-1-infected individuals. Pathologic conditions, such as disseminated
microglial nodules, are associated with HIV-1 encephalitis, direct infection of
the brain, and moderate to severe neurologic impairment. TGF-beta1 expression in
ameboid microglia may play a role in HIV-1 neuropathogenesis.
PMID- 9402102
TI - Subacute bacterial endocarditis masquerading as type III essential mixed
cryoglobulinemia.
AB - An adult man presented severely ill with vasculitis of his lower extremities and
with impaired kidney function. After detailed evaluation at a local hospital, a
diagnosis of essential type III cryoglobulinemia was made. High-dose steroid and
cyclophosphamide therapy was begun. The patient improved dramatically. However, 6
wk later when his steroid dose was reduced to 30 mg daily, vasculitis recurred.
Intensifying his immunosuppressive therapy only worsened his condition. He was
than transferred to the Ohio State University Medical Center for consideration
for plasmapheresis for the presumed essential type III cryoglobulinemia. However,
our evaluation showed that he had bacterial endocarditis causing his type III
cryoglobulinemia. When immunosuppressive drugs were stopped and antibiotics were
begun, his condition resolved completely. This case illustrates the difficulty of
identifying infectious causes of cryoglobulinemia and emphasizes that an initial,
highly favorable response of vasculitis to immunosuppressive therapy does not
exclude an infectious cause for the vasculitis.
PMID- 9402104
TI - Activity and tolerance of a continuous subcutaneous infusion of interferon
alpha2b in patients with chronic hepatitis C.
AB - We administered interferon-alpha2b (IFN-alpha2b) by continuous subcutaneous
infusion (60,000 IU/h, or 10 million IU/week) over 3 months to 7 patients with
chronic hepatitis C. All had previously responded, as assessed by normalization
of transaminases to the same dose of IFN administered by intermittent injection
over 6 months, but had relapsed after cessation of therapy. The continuous
infusion was tolerated well at the site of infusion, and the systemic side
effects were similar in type but were lesser in intensity than with intermittent
dosage. Four of 7 subjects had normalization of transaminase at the end of week
12 of therapy. Serum HCV RNA and HCV by PCR decreased with treatment, and there
was a prompt and sustained increase in serum beta2-microglobulin and of 2', 5'
OAS activity. The level of the latter appeared to correlate with response of the
transaminase. Serum IFN concentrations were low but detectable throughout
therapy. After stopping IFN administration, the transaminases in responders
increased again to pretreatment levels.
PMID- 9402105
TI - Cytokine modulatable signalling through macrophage HLA class II. 1. IFN-gamma
upregulates the efficiency of Ca2+ mobilization in response to ligation of
macrophage HLA-DP.
AB - The human macrophage line 2MAC, established recently from peripheral blood,
expresses a number of lineage-specific markers as well as a broad array of
intercellular adhesion molecules, including high levels of HLA class I and class
II. We have presented evidence elsewhere that 2MAC can be productively applied to
the study of signal transduction through macrophage HLA class II. Namely, we
showed that ligation of 2MAC HLA class II, but not HLA class I, by monoclonal
antibody (mAb) elicits an increase in free cytoplasmic Ca2+ concentration
[Ca2+]i. Moreover, this Ca2+ flux appears to be functionally relevant: ligation
of HLA-DR, but not HLA class I, by mAb results in the Ca2+ mobilization-dependent
induction of tissue factor, the high-affinity cellular receptor for factor
VII/VIIa. Here we show that 2MAC is uniquely valuable for addressing the
efficiency of signal transduction through HLA class II. Namely, we show here that
prior culture of 2MAC cells with interferon-gamma (IFN-gamma) profoundly
upregulates subsequent Ca2+ mobilization in response to ligation of HLA-DP in the
absence of increased cell surface HLA-DP expression. Because IFN-gamma has no
effect on 2MAC HLA-DP expression, IFN-gamma must upregulate Ca2+ mobilization by
increasing the efficiency of signal transduction through HLA class II (HLA-DP),
by targeting some other component of the macrophage HLA class II signalling
pathway.
PMID- 9402106
TI - Synergistic antitumor effects of a combination of interferon and tamoxifen on
estrogen receptor-positive and receptor-negative human tumor cell lines in vivo
and in vitro.
AB - Solid tumors are relatively resistant to growth inhibition by interferons (IFNs).
To enhance sensitivity, we assessed combinations of IFNs with tamoxifen in
estrogen receptor-positive (ER-positive) and ER-negative human tumor xenografts.
In nude mice, the growth of MCF-7 human breast tumors (ER-positive) and NIH-OVCAR
3 ovarian tumors (functionally ER-negative) was suppressed completely when
tamoxifen and IFN-alpha or IFN-beta was started 2 days after tumor inoculation.
Established, 6-week-old MCF-7 and NIH-OVCAR-3 tumors regressed when treated with
the combination of IFN-beta and tamoxifen but not with single-agent therapy.
Treatment with the combination also resulted in an augmented antitumor response
in vivo in an ER-negative breast tumor (MDA-MB-231), a colon carcinoma (HT-29),
and a melanoma (SK-MEL-1). Antiproliferative studies in vitro suggested that
growth of both MCF-7 and NIH-OVCAR-3 cells was inhibited to a greater degree by
combination treatment with human IFN-alpha and tamoxifen or IFN-beta and
tamoxifen compared with single agents. Median effect analysis defined synergy.
Four ER-negative carcinomas (MDA-MB-231, MDA-MB-468, BT-20, and HT-29) also
exhibited synergistic growth inhibition in response to the drug combination. The
response of these four cell lines was particularly striking. Tamoxifen as a
single agent had little effect (up to 2.0 microM) but caused enhanced
antiproliferative activity when added to IFN-beta. Sequential treatment of MCF-7
cells in vitro with tamoxifen followed by IFN-beta was more effective at
inhibiting growth than treatment with IFN-beta followed by tamoxifen, suggesting
that tamoxifen modulated the anticellular response to IFN-beta rather than the
converse. Similar results were obtained with IFN-alpha. Cell cycle analysis
indicated that 7 days of exposure to the combination resulted in MCF-7 cell
fragmentation and death. Together with our recent studies demonstrating
enhancement of IFN-stimulated gene expression (ISG) by tamoxifen pretreatment in
IFN-resistant cells, these data suggest that combination treatment with tamoxifen
and IFNs may increase ISG expression in IFN-resistant tumors, leading to
augmented antitumor effects. These effects appear to be independent of ER
expression.
PMID- 9402107
TI - Lack of effect of different cytokines on expression of membrane-bound regulators
of complement activity on human uveal melanoma cells.
AB - Tumor cells are protected from antibody-dependent complement-mediated lysis by
membrane-bound regulators of complement activation (m-RCA). m-RCA are expressed
on uveal melanoma cells. We determined whether cytokine treatment affects
expression of m-RCA on these cells in vitro. m-RCA expression on uveal melanoma
cell lines was studied by flow cytometry, using monoclonal antibodies directed
against CD46, CD55, and CD59. Cytokines studied were interferon-alpha (IFN
alpha), IFN-gamma, interleukin-1B (IL-1B), IL-12, and tumor necrosis factor-alpha
(TNF-alpha). All three m-RCA were expressed on the uveal melanoma cell lines
(CD59>>CD46>CD55), although in variable amounts. With a few exceptions, the
cytokines had no effect on m-RCA expression. CD55 expression was not influenced
by any of the cytokines. IFN-gamma downregulated expression of CD46 on one cell
line (p < 0.01). TNF-alpha upregulated CD59 expression on two of the five cell
lines (p < 0.012 and p < 0.001, respectively), which effect was dose dependent.
IFN-alpha, IFN-gamma, IL1-beta, IL12, and TNF-alpha had limited effects on m-RCA
expression on uveal melanoma cells in vitro.
PMID- 9402108
TI - Interferon-induced growth arrest is mediated by membrane structural changes.
AB - Interferon-gamma (IFN-gamma) is an immunomodulator shown to augment the
expression of major histocompatibility (MHC) class I/class II antigens on the
cell surface. In previous studies, we have demonstrated that the enhanced
expression of these antigens on the cell surface is in part due to IFN-gamma
mediated abrogation of antigen shedding. In this study, we demonstrate that IFN
gamma induces structural changes in the cell membrane by altering the
cholesterol/phospholipid ratio. Furthermore, such changes not only mediate
enhanced expression of antigen on the cell surface but may drive the cells to
growth arrest and apoptosis. These results were obtained by employing x-ray
diffraction, electron microscopy, and DNA analysis.
PMID- 9402109
TI - Importance of pretreatment viral load and monitoring of serum hepatitis C virus
RNA in predicting responses to interferon-alpha2a treatment of chronic hepatitis
C. Hanshin Chronic Hepatitis C Study Group.
AB - The aim of this study was to determine what factors correlate with a favorable
response to interferon-alpha2a (IFN-alpha2a) treatment in chronic hepatitis C.
Fifty patients with chronic hepatitis C who received a 26-week treatment with IFN
alpha2a (474 million units in total) were assessed for pretreatment parameters
and biochemical and virologic events during the treatment. According to
biochemical and virologic responses to the treatment, 16 patients (32%) were
categorized as sustained complete responders (SR), 13 (26%) as initial complete
responders (IR), and 21 (42%) as nonresponders (NR). By multivariate analysis, a
low viremia level was the only independent predictor of SR among pretreatment
parameters (p = 0.0088). The percentage of patients showing hepatitis C virus RNA
negativity at 2 and 12 weeks of treatment was significantly higher in SR (94% and
100%, respectively) or IR (69% and 92%, respectively) than in NR (14% and 33%,
respectively) (p = 0.001). In contrast, the normalization of serum alanine
aminotransferase levels at both time points failed to differentiate among SR, IR,
and NR. These results indicate that monitoring of serum hepatitis C virus RNA at
an appropriate time during treatment in addition to determination of pretreatment
viral load is important in predicting responses to IFN-alpha2a treatment.
PMID- 9402110
TI - Cloning and expression of the cDNA for canine interleukin-12.
AB - We cloned the canine interleukin-12 (IL-12) subunit cDNA. Canine IL-12 exhibited
sequence homology to the known sequences of human, mouse, and bovine genes at
nucleotide and amino acid levels. Cotransfection of the p35 and p40 subunits of
canine IL-12 cDNA clones into COS-1 cells resulted in the secretion of IL-12,
which supported proliferation of the stimulated canine lymphocytes, promoted
induction of canine interferon-gamma (IFN-gamma) from canine lymphocytes, and
showed antitumor effect in vitro. The cloned canine IL-12 will be useful for
canine therapeutic applications.
PMID- 9402111
TI - Clinical utility of endoscopic retrograde cholangiopancreatography.
AB - BACKGROUND: ERCP is a frequently performed procedure, but its necessity for
diagnosis and ability to change management plans are unclear in many cases.
METHODS: We prospectively evaluated diagnosis, certainty of diagnosis, and
management recommendations, both before and after ERCP, as well as therapeutic
maneuvers performed during ERCP, in unselected patients undergoing this
procedure. RESULTS: ERCP procedures (1341) were studied at a university hospital,
an ERCP referral center, and two community hospitals. Among patients undergoing
first-time ERCP, the preceding clinical diagnosis was correct for 64% of those
predicted to have bile duct stones, 86% to 89% of those given other biliary
diagnoses, and 88% predicted to be normal. In 35% of cases, diagnostic confidence
improved substantially after ERCP. Endoscopic therapy was successfully completed
in 51%. After ERCP, plans for other invasive procedures changed in 82%:
percutaneous biliary studies and open surgical procedures were recommended less
often and laparoscopic cholecystectomy more often. Endoscopic therapy and overall
clinical utility were most common in patients with cholangitis, jaundice, or bile
leaks. CONCLUSIONS: ERCP is particularly helpful for diagnosis of bile duct
stones but is less likely to change other diagnoses. The endoscopic therapy
commonly carried out during ERCP often changes the treatment plan, leading to
fewer surgical and percutaneous interventions in general, but more laparoscopic
cholecystectomies.
PMID- 9402112
TI - Application of magnifying chromoscopy for the assessment of severity in patients
with mild to moderate ulcerative colitis.
AB - BACKGROUND: A magnifying colonoscope that enables high-power observation of the
colorectal mucosa has been recently developed. The aim of this study was to
investigate the value of the magnifying instrument in determining the severity of
ulcerative colitis. METHODS: Magnifying colonoscopy was performed in 41 patients
with ulcerative colitis, and the findings in the rectum were graded according to
network pattern and cryptal openings. These findings were correlated with
endoscopic, clinical, and histologic severity of the disease. RESULTS: Magnifying
colonoscopy did not detect network pattern in 37% and cryptal opening in 24% of
the subjects. The clinical, endoscopic, and histologic grades of activity were
not different between groups divided by the presence or absence of each finding.
However, when the two features were coupled, patients with visible network
pattern and cryptal opening had a lower clinical activity index and lower grade
of histologic inflammation than those in whom both findings could not be
visualized. CONCLUSIONS: Observation under magnifying colonoscopy can be another
clue to determining the severity of disease in patients with ulcerative colitis.
PMID- 9402113
TI - Endoscopic ultrasonography in the diagnosis of submucosal lesions of the large
intestine.
AB - BACKGROUND: Although reports of colorectal submucosal tumors have increased since
the development of endoscopic examinations, precise diagnosis of these lesions
remains difficult. In this study, we evaluated the usefulness of endoscopic
ultrasonography (EUS) in the diagnosis of submucosal lesions of the large
intestine. METHODS: From September 1989 to June 1996, EUS was performed in 46
patients who were suspected to have submucosal lesions by barium enema or
colonoscopy. Twenty-seven of the 46 cases were confirmed histologically by
endoscopic or surgical resection, and their ultrasonographic images were compared
with resection specimens. RESULTS: Lipomas (n = 15) were visualized as
hyperechoic masses and lymphangiomas (n = 9) visualized as cystic lesions with
septal structures as characteristic findings. The EUS images of leiomyomas (n =
6), leiomyosarcomas (n = 3), and enteric endometriosis (n = 7) were all
hypoechoic masses in the fourth layer. Leiomyosarcomas tended to be larger and
more inhomogeneous than leiomyomas. Enteric endometriosis was shaped like a
spindle or a half-moon, and myogenic tumors were lobulated when the lesions were
large. Recurrences of colorectal carcinoma (n = 3), malignant lymphomas (n = 2),
and an appendiceal mucocele (n = 1) were examined. CONCLUSIONS: EUS is useful in
the diagnosis of submucosal lesions of the large intestine because it provides
precise information about these lesions.
PMID- 9402114
TI - Endosonographic imaging of pancreatic pseudocysts before endoscopic transmural
drainage.
AB - BACKGROUND: Endoscopic drainage of pancreatic pseudocysts has become an
established alternative to surgery. We performed endosonography before endoscopic
drainage to find out whether detailed anatomic information would help in the
selection of appropriate candidates and result in a reduction of complications.
PATIENTS AND METHODS: Between April 1992 and July 1995 endosonography was
performed in 32 patients, referred for endoscopic pseudocyst drainage, to
determine the minimal distance between the pseudocyst and the gut, to identify
interposed vascular structures, and to determine the optimal site for drainage.
RESULTS: Endosonography failed to identify a pseudocyst in 3 patients and in 2
patients the lesion was inconsistent with a pseudocyst. In 7 patients transmural
drainage was considered inappropriate: in 4 the distance between the gut and the
cyst was too large, in 2 varices were present between the cyst and the gut, and
in 1 patient normal pancreatic parenchyma was present between the cyst and the
gut. In 20 patients endosonography was followed by ERCP, and in 19 endoscopic
drainage was attempted. Transmural drainage was successful in 16 patients.
Endosonography changed management in 37.5% of the patients. CONCLUSION:
Endosonography provides essential information prior to endoscopic drainage of
pseudocysts, leading to a change in therapy in one third of patients.
PMID- 9402115
TI - Incidence and clinical findings of benign, inflammatory disease in patients
resected for presumed pancreatic head cancer.
AB - BACKGROUND: The differentiation between cancer and benign disease in the
pancreatic head is difficult. The aim of this study was to examine common
features in a group of patients that had undergone pancreatoduodenectomy for a
benign, inflammatory lesion misdiagnosed as pancreatic head cancer. METHODS:
Among 220 pancreatoduodenectomies performed on the suspiscion of pancreatic head
cancer, an inflammatory lesion in the pancreas or distal common bile duct was
diagnosed in 14 patients (6%). Of these patients, all preoperative clinical
information and radiologic images (ultrasound, endoscopic retrograde cholangio
pancreaticography [ERCP]) were critically reassessed. For each examination, the
suspicion of cancer was scored on a 0/+/++ scale. RESULTS: Clinical presentation
(pain, weight loss, jaundice) raised a suspicion of cancer in 12 patients. On
ultrasound, a tumor (mean size: 2.8 cm) was found in the pancreatic head in 13
patients; 12 of 14 ultrasound examinations raised a suspicion of cancer. ERCP
showed a distal common bile duct stenosis (length: 1 to 4 cm), stenosis of the
pancreatic duct (length: 1 to 5 cm), or a "double duct" stenosis, suspicious for
cancer in 13 evaluable patients. The overall index of suspicion was + in seven
patients and ++ in seven patients, confirming the initial interpretation of
preoperative data. CONCLUSION: When undertaking pancreatoduodenectomy for a
suspicious lesion in the pancreatic head, it is necessary to expect at least a 5%
chance of resecting a benign, inflammatory lesion masquerading as cancer.
PMID- 9402116
TI - Potential risks and artifacts of magnetic resonance imaging of self-expandable
esophageal stents.
AB - BACKGROUND: Several types of coated and uncoated self-expandable stents composed
of various metals are available for palliation of malignant esophageal stenoses
and fistulas. We encountered poor visualization of the mediastinum and skeletal
axis with magnetic resonance imaging in a patient with a Gianturco self
expandable stent. METHODS: To evaluate potential problems, such as stent
migration in the magnetic field of the magnetic resonance scanner (MRI) and
artifacts in the images, we studied four types of expandable stents: the
Ultraflex (titanium alloy), the covered Wall stent (nitinol), the Gianturco stent
(Cook), and the modified Gianturco stent (Song)-the last two being made of
stainless steel. RESULTS: An appreciable attraction force and torque, as measured
ex vivo by suspending the stent in a Perspex device, was found for both Gianturco
stents. In particular, the Gianturco (Cook) stent is pulled toward the head with
a force of 7g; however, it is uncertain whether this is a potential risk for
dislodgement. In addition, gross artifacts in the images, studied by putting the
stents in a cylindric phantom filled with a diluted gadolinium solution, made the
magnetic resonance useless for imaging in a wide area around the Gianturco stents
of stainless steel. No problems with magnetic resonance image quality were
encountered for the titanium-based Ultraflex and Wall stents. CONCLUSIONS:
Specific information on the type of stent is necessary before a magnetic
resonance imaging examination is planned.
PMID- 9402117
TI - Gastrointestinal bleeding in cirrhotic patients with hepatocellular carcinoma
undergoing intrahepatic artery chemotherapy.
AB - BACKGROUND: Hepatocellular carcinoma in cirrhotic patients increases the risk of
variceal bleeding. We sought to characterize bleeding in a cirrhotic patient
population undergoing intrahepatic artery chemotherapy for hepatocellular
carcinoma and to determine the possible influence of this treatment on
gastrointestinal bleeding. METHODS: We retrospectively reviewed 179 patients with
hepatocellular carcinoma who underwent intrahepatic artery doxorubicin and cis
platinum chemotherapy to determine the incidence of gastrointestinal bleeding and
compared them with 434 hepatocellular carcinoma historic controls not undergoing
regional chemotherapy. RESULTS: Of the 179 patients, 27 patients (15.1%)
developed upper gastrointestinal bleeding over a mean follow-up of 15.2 months;
18 of the 27 (66.7%) bled from a variceal source and 9 (33.3%) bled from a
nonvariceal source: ulcer (n = 6), gastropathy (n = 1), Mallory-Weiss (n = 1),
erosive gastritis (n = 1). Twenty-one patients developed bleeding after
initiation of chemotherapy (14 variceal and 7 nonvariceal). The number of
chemotherapy sessions among patients with variceal and nonvariceal bleeding was
similar (2.1 +/- 0.4 and 4.0 +/- 1.2; p = Not significant). Patients with
variceal and nonvariceal bleeding were comparable with respect to Child-Pugh
classification, pTNM stage, age, time to bleeding, and gender. CONCLUSIONS:
Regional intra-arterial chemotherapy for hepatocellular carcinoma is associated
with a low risk of variceal bleeding. Nonvariceal sources of upper
gastrointestinal bleeding in this population account for a significant component
of bleeding episodes.
PMID- 9402119
TI - Randomized controlled trial of rectal tube placement for the management of
abdominal distension following colonoscopy.
AB - BACKGROUND: Traditionally, endoscopists have sought to provide maximum comfort
for patients undergoing colonoscopy but may have been less concerned with the
level of patient discomfort following the procedure. The aim of this study was to
examine the effectiveness of rectal tube placement for abdominal decompression
following colonoscopy in an effort to limit patient discomfort. METHODS: We
conducted a prospective, single-blind, randomized controlled trial in 67
consecutive men undergoing elective colonoscopy. At the end of the procedure,
patients were randomized to rectal tube placement or standard management without
tube placement. Patients were evaluated by standardized criteria 30 minutes after
completion of colonoscopy, and again 24 hours later. RESULTS: Thirty patients
were randomized to rectal tube placement and 37 served as controls. The two
groups were well matched with respect to age, duration of colonoscopy, quality of
bowel preparation, prevalence of diverticulosis, frequency of polypectomy, and
degree of difficulty in colonoscopy. At 30 minutes after colonoscopy, patients'
overall satisfaction rating (mean +/- SD) from a 10-point scale was 9.1 +/- 3.2
in treated patients and 5.7 +/- 3.9 in controls (p < 0.05; 2-tailed unpaired t
test). CONCLUSION: Placement of a rectal tube at the conclusion of colonoscopy
reduces patient discomfort, and improves satisfaction.
PMID- 9402118
TI - Prospective randomized comparative study of bipolar electrocoagulation versus
heater probe for treatment of chronically bleeding internal hemorrhoids.
AB - BACKGROUND: Our purpose was to compare the efficacy, complications, failure
rates, and crossovers of heater and bipolar probe treatments of chronically
bleeding internal hemorrhoids. METHODS: Eighty-one patients (31 female, 50 male)
with mean age of 53 years had large (grade 2 to 3) internal hemorrhoids with
bleeding for a mean of 12 years, had failed medical management, and were
randomized in a prospective study of anoscopic treatments to heater versus
bipolar probes. Failure was defined as a major complication or failure to reduce
the size of all internal hemorrhoids with three or more treatments. RESULTS: With
similar background variables and no difference in treatment times, rectal
bleeding and other symptoms were controlled in a shorter time with the heater
probe than with the bipolar probe (77 versus 121 days). Five complications
(fissures, bleeding, or rectal spasm) occurred with the bipolar probe, and two
occurred with the heater probe. The heater probe caused more pain during
treatments but had significantly fewer failures and crossovers. CONCLUSIONS: For
patients who had failed medical management of chronically bleeding internal
hemorrhoids, the techniques and complications of heater and bipolar probes were
similar, but pain was more common, failures and crossovers were less frequent,
and the time to symptom relief was shorter with the heater probe than with the
bipolar probe.
PMID- 9402120
TI - Segmental balloon cytology for preoperative localization of in situ pancreatic
cancer.
PMID- 9402121
TI - Combined endoscopic and laparoscopic management of chronic gastric volvulus.
PMID- 9402122
TI - Survival with early diagnosis of invasive gastric mucormycosis in a heart
transplant patient.
PMID- 9402123
TI - Clinical utility of percutaneous transhepatic cholangioscopy in defining tumor
extent: a case of mucin-producing bile duct carcinoma originating in the left
caudate lobe.
PMID- 9402124
TI - Acute lower gastrointestinal bleeding from the appendix.
PMID- 9402125
TI - A case of lipoma of the terminal ileum treated by endoscopic removal.
PMID- 9402126
TI - Endoscopic repair by clipping of iatrogenic colonic perforation.
PMID- 9402127
TI - In comes outcomes.
PMID- 9402128
TI - The new endoscopy of ulcerative colitis.
PMID- 9402129
TI - Tapered-tip, triple-lumen papillotome/cannula facilitates cannulation yet accepts
standard guidewires.
PMID- 9402130
TI - Rapid retrieval of small resected polyps.
PMID- 9402131
TI - "Pull" or "push" PEG: the reinsertion of the gastroscope is often unnecessary.
PMID- 9402132
TI - PEG/PEJ tube placement.
PMID- 9402133
TI - Laparoscopically assisted panenteroscopy for gastrointestinal bleeding of obscure
origin.
PMID- 9402134
TI - The Norwegian guidelines for surveillance after polypectomy: 10-year intervals.
PMID- 9402135
TI - Surgical biliary bypass for benign and malignant extrahepatic biliary
obstruction.
PMID- 9402136
TI - Gastrointestinal endoscopy in Israel.
PMID- 9402137
TI - Endoscopy services in Malaysia--a surgical bias.
PMID- 9402138
TI - The T-cell receptor as immunoglobulin: paradigm regained.
AB - The quest to determine the molecular nature of T-lymphocyte receptors for antigen
was a "holy grail" to immunologists for over 25 years. This paper updates a
review written 15 years ago (Marchalonis JJ, Hunt JC. Proc Soc Exp Biol Med
171:127-145, 1982), which proposed that "these molecules apparently do not bear
determinants specified by the major histocompatibility complex, but express Ig
related variable regions and constant regions unique to T-cell products." We
review subsequent contributions from molecular biology, protein chemistry,
peptide immunochemistry, and structural biology establishing that T-cell
receptors (TCRs) are members of the immunoglobulin family restricted to T cells
that share 3-dimensional structural features, sequence homology, antigenic cross
reactivity, and common mechanisms of diversification with conventional
immunoglobulins. These molecules and their light- and heavy-chain siblings
appeared contemporaneously in vertebrate evolution with the emergence of sharks.
We illustrate how extrapolation of concepts from immunoglobulin to T-cell
receptors has aided in the understanding of these often enigmatic molecules, and,
conversely, how concepts derived for T-cell receptors such as the role of
"superantigens" can be directly applied to conventional immunoglobulins. A second
precept that follows from the symmetry of the combining sites of Igs and TCRs is
that MHC-restricted antibodies should exist. Such molecules have in fact been
reported, and the x-ray crystallography for T-cell receptors suggests that the
combining sites recognizing simultaneously MHC and peptide epitopes resemble the
combining sites of antibodies directed against protein determinants. Additional
immunoglobulin molecules of nonmammalian species have been detected and
characterized based upon conserved homology to TCR and Igs, and it is anticipated
that further study will enable the identification of more antigen-specific
members of the family in mammals as well.
PMID- 9402140
TI - Erythropoietin: physiologic and pharmacologic aspects.
AB - The purpose of this review is to give an update of the recent progress in
research on erythropoietin (Epo), the hormone that regulates red blood cell
production. Epo is a glycoprotein with a molecular mass of approx 30 kDa, which
circulates in plasma of the human with 165 amino acids with three N-linked and
one O-linked acidic oligosaccharide side chains in the molecule. Both the alpha
(39% CHO) and beta (24% CHO) forms are available for clinical use, and there does
not appear to be any difference in the pharmacokinetics of these two forms of
Epo. Radioimmunoassays and enzyme-linked immunoabsorbant (ELISA) assays are
available in a kit form. Serum levels of Epo in normal human subjects range
between 1 and 27 mmu/ml or approx 5 pmol/l. It seems clear that the cells in the
adult mammalian kidney which produce Epo are the interstitial cells in the
peritubular capillary bed and the perivenous hepatocytes in the liver. Expression
of the human Epo gene sequences that direct expression in the kidney are located
6-14 kilobases 5' to the gene; whereas the sequences that control hepatocyte
specific expression are located within 0.7 KS to the 3'-flanking region and 0.5
KS to the 5'-flanking region. The signal transduction pathways postulated to be
involved in the expression of Epo are: kinases A, G and C; both a constitutive
factor and a second hypoxia-inducible factor-1 (HIF-1) located in the 5' end of
an hypoxia inducible enhancer region of the Epo gene; and reactive oxygen
species. The primary target cell in the bone marrow acted on by Epo is the colony
forming unit erythroid (CFU-E) which has the highest number of Epo receptors. It
has been postulated that Epo decreases the rate which Epo-dependent progenitor
cells undergo programed cell death (apoptosis). There are two major signal
transduction pathways activated by the Epo receptor: the JAK2-STAT5 pathway and
the ras pathway. Both pathways involve tyrosine phosphorylation. The approved
clinical uses of Epo are the anemias associated with end-stage renal disease,
cancer chemotherapeutic agents, and patients with HIV infection receiving AZT.
Other anemias reported to respond to Epo therapy are anemia of prematurity,
rheumatoid arthritis, and myelodysplasia. Other uses of Epo under investigation
are in perioperative surgery and preoperative autologous blood donation.
PMID- 9402139
TI - Insulin-like growth factor binding protein-1: recent findings and new directions.
AB - In 1988, insulin-like growth factor-binding protein-1 (IGFBP-1) became the first
characterized member of a group of structurally related soluble proteins which
specifically bind and modulate the actions of the IGFs. Since then, a wealth of
information has accumulated regarding the physiology of this dynamic serum
protein. In this review, we update our 1993 summary (Lee PDK et al. Proc Soc Exp
Biol Med 204:4-29) of the status of IGFBP-1 research. The IGFBP-1 protein
sequence contains 12 N-terminal and 6 C-terminal cysteine residues which are
conserved in other mammalian IGFBP-1 sequences and amongst other IGFBPs; both of
the cysteine-rich regions are required for optimal IGF binding. The nonconserved
IGFBP-1 midregion may act as both a hinge which defines ligand binding
characteristics and as a specific target for protease activity. Integrin-binding
and phosphorylation sites within the IGFBP-1 sequence have functional
significance in vitro, but their physiologic relevance in vivo have not been
defined. The human IGFBP-1 and IGFBP-3 genes are contiguous and located in close
proximity to the homeobox A (HOXA) gene cluster on chromosome 7. The other IGFBP
genes, located on chromosomes 2, 12, and 17, are also associated with HOX
clusters, suggesting evolutionary linkage of the IGFBP and HOX gene families.
Similarities between the hIGFBP-1 and phosphoenolpyruvate kinase (PEPCK)
promoters, including regions conferring insulin, glucocorticoid, and cyclic
adenosine-monophosphate responses, are consistent with our previous hypothesis
that IGFBP-1 is involved in regulation of glucose metabolism. The tissue-specific
patterns of IGFBP-1 gene expression in liver, kidney, decidua, and ovary may be
due to stimulation of IGFBP-1 transcription by hepatic nuclear factor 1 (HNF1)
proteins. Clinical and basic studies of IGFBP-1 physiology have been aided by
several recently developed assay methods. Numerous investigations have confirmed
that insulin, via inhibition of IGFBP-1 transcription, is the primary determinant
of IGFBP-1 expression both in vitro and in vivo. IGF-I and IGF-II also have
specific inhibitory effects on IGFBP-1 expression. Glucocorticoids and cAMP
stimulate IGFBP-1 transcription, but these effects are observed only in
conditions of low or absent insulin effect. Other stimulants of IGFBP-1
expression include thyroid hormones and epidermal growth factor. Phorbol ester
stimulation of IGFBP-1 expression can supersede the effects of insulin in
vitro;however, the mechanism and in vivo correlates of this effect have not been
determined. Cytokines and, perhaps, growth hormones may affect IGFBP-1
expression, perhaps by altering the regulatory actions of insulin; this effect
may have important clinical relevance. IGFBP-1 expression is upregulated in liver
and (nonhuman) kidney during postinjury regeneration. The IGF-inhibitory actions
of IGFBP-1 has been confirmed by numerous in vitro studies and several in vivo
animal investigations, including administration of recombinant IGFBP-1 and IGFBP
1 transgenic models. IGFBP-1 has been shown to inhibit somatic linear growth,
weight gain, tissue growth, and glucose metabolism. Moreover, IGFBP-1 appears to
be a primary determinant of free IGF-I levels in serum. Excess levels of IGFBP-1
may contribute to growth failure in intrauterine growth restriction and in
pediatric chronic renal failure, while low IGFBP-1 levels are associated with
obesity and with cardiovascular risk factors in insulin resistance syndromes.
Serum IGFBP-1 measurements may be useful biochemical marker in these pathologic
conditions. IGFBP-1 is expressed in decidualized stromal cells of the uterine
endometrium and in ovarian granulosa cells. IGFBP-1, together with IGFs, insulin,
ovarian steroids, cytokines, and other factors, is involved in a complex system
which regulates menstrual cycles, ovulation, decidualization, blastocyst
implantation, and fetal growth. (ABSTRACT TRUNCATED)
PMID- 9402141
TI - Lysophosphatidic acid and platelet-derived growth factor synergistically
stimulate growth of cultured rat mesangial cells.
AB - Lysophosphatidic acid (LPA) is a structurally simple, platelet-derived
phospholipid, capable of eliciting a variety of physiological responses. We have
demonstrated previously that LPA elicited a marked contractile response in rat
mesangial cells (Inoue CN, Forster HG, Epstein M. Circ Res 77:888-896, 1995). In
the present study, we examined the potential of this vasoactive substance to
induce mesangial cell proliferation. Serum-starved quiescent rat mesangial cells
were incubated with either LPA or in combination with platelet-derived growth
factor (PDGF). DNA synthesis was assessed by [3H]thymidine incorporation after 24
hr, and cell numbers were determined at 0, 4, and 7 days. LPA- (1 nM-30 microM)
stimulated mesangial cell DNA synthesis in a dose-dependent manner. The DNA
synthesis stimulated by PDGF (1-100 ng/ml) was characterized by a bell-shaped
response curve with a maximum at 40 ng/ml PDGF. The ability of LPA (30 microM) to
synergize PDGF was observed over the entire range of PDGF concentrations (1-100
ng/ml). Under optimal concentrations of LPA/PDGF (30 microM40 ng/ml,
respectively), mesangial cells displayed a 67-fold increase in [3H]thymidine
incorporation, and a 1.9-fold (Day 4) and 2.5-fold (Day 7) increase in cell
number as compared with that of quiescent mesangial cells. With an in vitro assay
with myelin basic protein as the substrate, both LPA and PDGF induced stimulation
of mitogen-activated protein (MAP) kinase activity. In addition, LPA augmented
PDGF-induced increase in MAP kinase activity. In summary, these results
demonstrate that LPA is mitogenic alone and also acts synergistically in
combination with PDGF to promote mesangial cell proliferation. We postulate that
these actions of LPA have the potential to play a crucial role in the mitogenic
response of mesangial cells seen in a wide array of inflammatory and thrombotic
glomerular disorders.
PMID- 9402142
TI - Age-related changes in glucose transporter-one mRNA structure and function.
AB - To determine the molecular mechanisms of age-related changes in the expression of
glucose transporter 1 (GLUT-1) mRNA in cerebral tissue, male Fischer 344 rats at
4, 12, and 24 months of age were studied. The GLUT-1 mRNA in cerebral tissue was
not significantly different among the various age groups. The in vitro
translatability of GLUT-1 mRNA of 24-month-old rats (0.867 +/- 0.066 arbitrary
units) was significantly lower than that in 4-month-old (1.403 +/- 0.153) P <
0.01 or 12-month-old rats (1.387 +/- 0.122) P < 0.01. The poly (A) tail length of
GLUT-1 mRNA decreased from 200-350 nt in 4-month-old rats to only 50-100 nt in 24
month-old rats. Twelve-month-old rats also showed reduced poly (A) tail lengths.
The poly (A) tail of G3PDH mRNA was not altered with age. The changes in GLUT-1
mRNA translatability did not correlate with GLUT-1 content in total cerebral
tissue homogenate or in isolated cerebral microvessels, suggesting that GLUT-1
protein turnover is altered with age. It is concluded that aging is associated
with significant changes in the structure and function of GLUT-1 mRNA.
PMID- 9402143
TI - Cytokine dysregulation and increased oxidation is prevented by
dehydroepiandrosterone in mice infected with murine leukemia retrovirus.
AB - The effects of murine leukemia retrovirus infection on production of cytokines
was investigated in mice fed different doses of dehydroepiandrosterone (DHEA).
Young C57BL/6 female mice were injected with LP-BM5 murine retrovirus or were
kept as uninfected controls. Two weeks later, each group was divided into
subgroups: fed unsupplemented AIN 93 diet as the control, or diets supplemented
with 0.02% DHEA (0.9 mg/mouse/day) or 0.06% DHEA (2.7 mg/mouse/day). The
uninfected mice supplemented with 0.06% DHEA showed a significant (P < 0.05)
increase in interleukin-2 (IL-2) and gamma-interferon (IFN-gamma) production, and
hepatic vitamin E levels. Retroviral infection induced severe oxidative stress
that was reduced by DHEAS supplementation in retrovirally infected mice. DHEA
supplementation prevented the retrovirus-induced loss of cytokines (IL-2 and IFN
gamma) secretion by mitogen stimulated spleen cells. DHEA also suppressed the
production of cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF
alpha) by T helper 2 (Th2) cells which were otherwise stimulated by retrovirus
infection. Thus, immune dysfunction and increased oxidation induced by murine
retrovirus infection were largely prevented by DHEA.
PMID- 9402144
TI - Pirfenidone attenuates bleomycin-induced changes in pulmonary functions in
hamsters.
AB - The antifibrotic potential of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) was
examined in a single intratracheal bleomycin dose hamster model of pulmonary
fibrosis. Bleomycin-induced fibrosis and the effectiveness of pirfenidone
treatment were assessed by measuring pulmonary functions (Cqst, TLC, VC, IC, FRC,
RV) and the level of hydroxyproline in whole lung homogenates. Thirty-five male
golden Syrian hamsters were randomized into four experimental groups: saline
instilled and fed a control diet of rat chow (SCD, n = 8); saline instilled and
fed the control diet containing 0.5% (w/w) pirfenidone (SPD, n = 8); bleomycin
instilled and fed the control diet (BCD, n = 7); and bleomycin instilled and fed
the control diet containing 0.5% pirfenidone (BPD, n = 10). Twenty-one days
following bleomycin instillation Cqst/TLC, TLC, VC, and IC were significantly
reduced and total lung hydroxyproline levels were significantly increased in the
BCD and BPD groups as compared with the SCD and SPD groups, respectively.
Pirfenidone ingestion significantly attenuated these bleomycin-induced
pertubations in pulmonary functions and lung hydroxyproline levels (BCD versus
BPD). The data obtained in this study provide evidence of the benefical effects
of pirfenidone in the hamster model of bleomycin-induced pulmonary fibrosis both
at the functional and biochemical level.
PMID- 9402145
TI - Chronic underfeeding increases the positive feedback efficacy of estrogen on
gonadotropin secretion.
AB - Reduced caloric intake has been shown to inhibit reproductive cycles in females
of several mammalian species. Previous studies have shown that increased negative
feedback efficacy of estrogen on gonadotropin secretion may be responsible. The
present study was designed to test the alternate hypothesis that caloric
restriction alters the positive feedback efficacy of estrogen on gonadotropin
secretion. Adult, cycling female rats were placed on reduced food intake (R)
equal to 50% of that consumed by ad/libitum-fed controls (C). When R rats stopped
cycling, both R and C rats were ovariectomized (OVX) and immediately implanted
subcutaneously with a Silastic capsule containing 100 microg 17beta-estradiol
(E2). Blood samples were obtained at 0900-1000 hr and 1600-1730 hr on Days 2, 4,
6, 8, 10, 12, and 14 after OVX and implantation. Follicle-stimulating hormone
(FSH), luteinizing hormone (LH), and E2 were measured by radioimmunoassay in
duplicate aliquots. Results indicate that underfed female rats retain the ability
to respond to elevated estrogen levels with an afternoon surge of gonadotropin
which is present for at least 14 days for LH. By contrast, FSH surges in R rats
became progressively smaller and were no longer significant after Day 10. The
present results also demonstrate that the response of R rats to elevated estrogen
levels is significantly greater than that of C rats on Days 2-4 for FSH and 2-14
for LH. It is concluded that an inability to respond to elevated estrogen levels
with an afternoon LH surge is not the cause of the cessation of normal estrous
cycles. The progressive decrease in the afternoon surge of FSH may be, at least
partly, responsible for the decreased follicular development observed in underfed
rats. Possible explanations of the enhanced LH response to the positive feedback
of estrogen are discussed.
PMID- 9402146
TI - An innate natural antibody is reactive with a cryptic sequence of lactoferrin
exposed on sperm head surface.
AB - Lactoferrin (LF), an 80-kDa glycoprotein of ubiquitous occurrence in body fluids,
is multifunctional and capable of assuming different configurations to serve
those functions. The capacity of LF to undergo endocytosis and the recent
demonstration of LF binding to sequence specific DNA indicate that a function or
capability of LF, in addition to iron chelation, bacteriostasis, and receptor
specific lymphocyte binding, may be that of gene activation or silencing. The
data of this report present a human physiological system, that of sperm entry
into the oocyte in performance of fertilization in which, since LF is a component
of the sperm protein coat, that capability could be expressed. However, the
configuration of LF in that locus is one in which a revealed cryptic sequence
provides the specific binding site for a natural antibody present in the
fertilization milieu. The presence of that antibody suggests that a system of
control of the potential interaction of LF with the intra-ooplasmic DNA, that of
gametes or pronuclei, is operative. The configuration of LF on the sperm surface
and designation of the reactive site for the natural antibody were enabled by a
monoclonal antibody secreted by a hybridoma derived from a human cord blood B
cell. Thus, in addition to information concerning the molecular flexibility of
LF, these observations support the proposition that the repertoire of natural
antibodies provides an innate homeostatic system, with each antibody serving a
specific role.
PMID- 9402147
TI - Xanthine oxidase decreases production of gut wall nitric oxide.
AB - Multiorgan failure is often the lethal outcome of intratracheal aspiration of
acidic gastric juice. The pathogenesis of multiorgan failure may involve a
systemic imbalance between pro-inflammatory and anti-inflammatory factors. In an
anesthetized rat model, intratracheal instillation of HCl elicited intestinal
inflammation which was exaggerated by xanthine oxidase (XO) and attenuated by
nitric oxide (NO). We hypothesized that XO may mediate injury in part by
suppression of NO formation. Therefore, we measured intestinal tissue
concentrations of the stable NO oxidative metabolites (NO2- and NO3-) following
intratracheal (IT) instillation of NaCl or HCl alone or in combination with
interventions aimed at increasing or decreasing XO activity. Compared with IT
NaCl (control treatment) jejunal tissue NO2- and NO2- + NO3- concentrations were
increased by allopurinol pretreatment, which inhibits XO, and were decreased by
systemically administered XO, as well as by IT HCl. The decreased NO2- and NO2- +
NO3- concentrations found following IT HCl were completely reversed by either
allopurinol or by systemically administered L-arginine (the precursor of NO). We
conclude that manipulation of the pro-inflammatory XO system has a reciprocal
effect on the intestinal anti-inflammatory NO system in either the undamaged or
the endobronchially acidified lung model.
PMID- 9402148
TI - The renal handling of IgG in the aging rat and in experimental kidney disease.
AB - The urinary excretion of total protein, low-MW proteins, albumin, high-MW
proteins, and intact IgG was measured in male Wistar rats between the ages of 5
52 weeks, and in rats with experimentally induced glomerular or tubular
proteinuria. About 25% of aging rats spontaneously developed focal
glomerulosclerosis and a mild glomerular proteinuria. By age 52 weeks, total
protein excretion in rats with glomerulosclerosis exceeded that of unaffected
rats by a factor of seven (39.5 vs 5.4 mg/24 hr x 100 g body wt), and albumin
excretion was seven times higher than IgG excretion in affected rats (21.2 vs 2.9
mg/24 hr x 100 g body wt). Rats with chromate toxicity exhibited a reversible
tubular proteinuria, with low-molecular weight protein excretion reaching 16.8
mg/24 hr x 100 g body wt (75% of total protein excretion) at the time of peak
toxicity. IgG excretion remained less than 0.6 mg/24 hr x 100 g body wt.
Aminonucleoside induced a massive but reversible glomerular proteinuria (204
mg/24 hr x 100 g body wt), with IgG excretion reaching 11.4 mg/24 hr x 100 g body
wt (6% of total protein excretion) at the time of peak toxicity. Biochemical and
immunochemical studies showed that, while some intact IgG is present in normal
rat urine, most IgG immunoreactivity is derived from low-molecular weight
catabolic fragments of IgG which interfere with the immunoassay of intact urinary
IgG. One of these fragments, probably Fc fragment, may be involved in the
pathogenesis of focal segmental glomerulosclerosis.
PMID- 9402149
TI - In pursuit of drugs for American trypanosomiasis: evaluation of some "standards"
in a mouse model.
AB - Forty-nine "standard" compounds known to be useful in the treatment of other
diseases were tested for their suppressive activity against the trypomastigotes
of Trypanosoma cruzi-infected mice. The most active was the antidepressant
protriptyline, which was almost three times as effective as the reference drug,
nifurtimox. A major value of the present data is to demonstrate the
refractoriness of the T. cruzi parasite against many of the drug standards that
have known biological activity.
PMID- 9402150
TI - Effect of Alzheimer's brain extracts on dynein immunoreactivity in PC12 cells.
AB - The neurodegenerative process in Alzheimer's disease (AD) has been suggested to
occur as a consequence of microtubule disruption and subsequent loss of
intracellular transport. Structural microtubule-associated proteins (MAPs) have
been investigated for their role in the etiology of AD, but dynein, a force
producing MAP which mediates intracellular transport, has not been examined. In
this report, dynein (MAP1C) immunoreactivity in AD brain tissue homogenates was
observed increased 3.7-fold compared with control brain homogenate preparations.
Similarly, NGF-differentiated PC12 cells cultured in the presence of soluble
extracts prepared from AD brain tissue homogenates, exhibited an approximate 15
fold increase in dynein immunoreactivity compared to that of control brain tissue
extracts. In contrast, AD clarified extracts had little effect upon "kinesin
like" protein immunoreactivity increased (approximately 2-fold); whereas, tau
immunoreactivity was observed to be moderately increased (5-fold) over that of
control brain extract treated PC12 cells. Chemical dephosphorylation and alkaline
phosphatase treatment of AD extract-treated PC12 cell lysate prior to Western
blotting resulted in complete loss of immunoreactivity, suggesting the dynein
being monitored is a phosphorylated isoform. Furthermore, treatment of clarified
brain tissue extracts with trypsin and (NH4)2SO4 suggests the endogenous elements
giving rise to increased PC12 cell dynein intermediate chain immunoreactivity to
be proteinaceous in nature. The observed increase in dynein intermediate-chain
dynein immunoreactivity following exposure of neuronal cells to endogenous
elements of AD brain may be reflective of dynein-microtubular array differences.
Such an approach may be useful in assessing the effect of endogenous biomolecules
on retrograde axonal transport in neuronal culture models.
PMID- 9402151
TI - Stimulation of intestinal growth is associated with increased insulin-like growth
factor-binding protein 5 mRNA in the jejunal mucosa of insulin-like growth factor
I-treated parenterally fed rats.
AB - Surgically stressed rats maintained with total parenteral nutrition (TPN) exhibit
jejunal atrophy, which can be attenuated by insulin-like growth factor-I (IGF-I)
but not by growth hormone (GH) treatment. In order to understand the basis for
the selective action of IGF-I, the levels of mRNAs encoding IGF-I, IGF-binding
proteins (IGFBPs), IGF-I receptor, and GH receptor/binding protein (GHR/GHBP)
were determined in rats given TPN and treated with GH, IGF-I, or GH + IGF-I. GH
treatment significantly stimulated hepatic IGF-I mRNA. IGF-I treatment did not
alter liver IGF-I mRNA, nor was there any evidence for interaction between GH and
IGF-I. Jejunal mucosa IGF-I mRNA was extremely low and was not altered by TPN or
by any of the hormonal treatments. The inability of GH to stimulate jejunal
growth was not associated with a deficiency in GHR/GHBP mRNA. In jejunal mucosa,
IGF-I and GH treatment independently and synergistically stimulated IGFBP-3 mRNA.
IGF-I stimulated jejunal IGFBP-5 mRNA, but GH had no effect on IGFBP-5 mRNA. The
levels of IGF-I receptor and IGFBP-1, 2, 4, and 6 mRNAs were extremely low and/or
were not altered by any of the treatments. These results suggest that the ability
of exogenous IGF-I, but not GH, to induce IGFBP-5 mRNA in jejunal mucosa may lead
to the selective growth-promoting effect of IGF-I. Jejunal mucosa IGFBP-3 mRNA
levels were not correlated with altered growth. We postulate that IGFBP-5
positively modulates the anabolic effects induced by exogenous IGF-I in the
jejunum.
PMID- 9402152
TI - Disruption of rat estrous cyclicity by the environmental estrogen 4-tert
octylphenol.
AB - 4-tert-Octylphenol (OP) is a prevalent environmental pollutant which binds to
estrogen receptors and exerts estrogenic actions in vitro. The effects of OP in
vivo on mammalian female reproduction are not known. We investigated whether (i)
exposure of neonatal rats to OP interfered with the onset of vaginal opening or
their ability to have regular estrous cycles as adults and (ii) exposure of adult
rats to OP interfered with estrous cyclicity and ovulation. Injection of 1 mg OP
in corn oil sc on the day after birth did not affect the day of vaginal opening.
However, 9 of 11 OP-treated rats were in persistent vaginal estrus when examined
at three months after birth compared with 0 of 9 corn oil-injected controls,
which cycled regularly. Ten of eleven neonatal rats injected with 1.7 mg of the
estrogenic pesticide methoxychlor also were in persistent estrus at 3 months
after birth, and all 10 neonatal rats injected with 1 mg of 2,4,5
trichlorophenol, which is apparently nonestrogenic, cycled regularly. Injection
of 20 or 40 mg OP in corn oil vehicle sc three times weekly into previously
untreated adult cyclic rats caused persistent estrus in 2 of 6 and 16 of 21 rats,
respectively. Injections were continued for three more weeks in 5 of the 16 rats
rendered persistent estrus by the 40 mg OP treatment. These rats remained in
persistent estrus for the additional 3-week period. The other 11 persistent
estrous rats in the 40 mg treatment group started to cycle regularly within 5-7
days after the last injection. Unlike pentobarbital, injection of OP into cyclic
rats during the afternoon of proestrus did not block ovulation. These results
provide strong evidence that OP acts like estrogen in vivo in both neonatal and
adult female rats to exert effects that block reproductive cyclicity.
PMID- 9402153
TI - In vitro effects of boron-containing compounds upon glioblastoma cells.
AB - Boron-neutron capture therapy (BNCT) is currently under investigation as a novel
therapeutic modality for glioblastoma. This study was undertaken to determine
whether boron-containing compounds 4-borono-2-fluoro-D,L-phenylalanine (FBPA) and
FBPA-fructose have direct effects upon kinetics of A172, a glioblastoma cell
line. Flow cytometry analyzed cell-cycle distribution and S-phase kinetics (bromo
deoxyuridine [BUdR] incorporation). BUdR incorporation was increased during a 1
hr pulse after 24-hr or 72-hr exposure of cells to varying concentrations of FBPA
or FBPA-fructose. Results suggest that boron-containing compounds may effect cell
kinetics apart from neutron activation, and this effect should be further
evaluated for potential impact upon tumor responsiveness to BNCT.
PMID- 9402154
TI - Heme induces the expression of adhesion molecules ICAM-1, VCAM-1, and E selectin
in vascular endothelial cells.
AB - Heme is an important immunostimulating agent and oxidative factor contributing to
endothelial cell activation. To investigate the mechanism of heme-induced
endothelial cell activation, we analyzed the effect of heme and the inflammatory
cytokine, tumor necrosis factor-alpha (TNF-alpha), on the expression of the heme
degrading stress protein, heme oxygenase (HO), and adhesion molecules in human
umbilical vein endothelial cells (HUVEC). Indirect immunofluorescence double
labeling studies demonstrated a simultaneous increase of ICAM-1 and HO-1 after
exposure of cells to heme for 24 hr. Co-expression of HO-1 and ICAM-1 was also
demonstrated in TNF-alpha-exposed cells. Dot blot immunoassay and quantitative
analysis by ELISA demonstrated that heme treatment for 24 hr caused a 2-fold
increase in ICAM-1 expression (P < 0.002) compared with quiescent cells, while in
cells stimulated by TNF-alpha for 24 hr ICAM-1 gene expression increased by 5
fold. Moreover, heme exposure also resulted in a marked increase in VCAM-1 and E
selectin expression (three and four times over control levels, respectively). On
the other hand, TNF-alpha treatment showed similar expression levels for VCAM-1
and E selectin, compared with stimulation by heme (100 microM). The level of HO
activity in endothelial cells exposed to heme or TNF-alpha was increased from
24.7 +/- 5.7 pmol bilirubin/mg protein/min in control to 70.0 +/- 9.5 and 36.7 +/
3.1 pmol bilirubin/mg protein/min in heme- and TNF-alpha-stimulated cells,
respectively. These results suggest that upregulation of ICAM-1, VCAM-1, and E
selectin expression is associated with oxidative stress induced by
hemoglobin/heme and that HO-1 may play a modulating role via its ability to
degrade heme to a substance with antioxidant properties.
PMID- 9402156
TI - Situation of medical oncology in Hong Kong remains unchanged.
PMID- 9402155
TI - Human embryonic cells raise some hopes, but mainly questions.
PMID- 9402157
TI - Swiss heroin success prompts consideration of liberalization.
PMID- 9402158
TI - Death rates in Russia rise dramatically: worse than under Stalin.
PMID- 9402159
TI - To what extent are cancer clinical trials imperilled in the UK?
PMID- 9402160
TI - Will Jospin solve Villejuif's problems?
PMID- 9402161
TI - Eugenics: did Hitler merely emulate others?
PMID- 9402162
TI - High-dose chemotherapy and autotransplants: a time for guidelines.
PMID- 9402163
TI - Prognostic factors in salvage therapy of ovarian cancer.
PMID- 9402164
TI - Anthracyclines-paclitaxel combinations in the treatment of breast cancer.
PMID- 9402165
TI - Ethical issues in genetic screening for cancer.
AB - Genetically-based diseases with a late onset, such as BRCA1-dependent breast
cancer or Huntington's disease, can be predicted by the screening of relevant
mutations in members of high-risk families. Genetic screening is characterized by
a conflict between respect for autonomy--e.g., the 'right not to know'--and
responsibility toward future generations (the 'duty to know' for the sake of
one's descendants). Other ethical conflicts are related to uncertainty as to
benefits deriving from screening for mutations, since for most conditions no
clearly effective therapeutical strategy has as yet been defined. In addition to
monogenic high-penetrance conditions, polygenic low-penetrance susceptibility is
attracting increasing attention, in particular with respect to environmental
genetic interactions (metabolic polymorphisms). A simple approach to genetic
screening would be to weigh the benefits and costs of genetic screening against
those of primary prevention, and a superficial conclusion might be that genetic
screening is less expensive and, overall, more practicable than restriction of
toxic exposures or other known risk factors for the disease. Economic advantage
notwithstanding, however, giving precedence to screening over primary prevention
would be unacceptable. A serious hazard of genetic screening is the implicit
limitation of research efforts aimed at primary prevention, and a serious
drawback is its potential application for selection of nonsusceptible employees.
The principle of equity is easily violated by genetic screening of workers in
view of the fact that genetically-based metabolic polymorphisms are distributed
unevenly among different ethnic groups.
PMID- 9402166
TI - Four-step high-dose sequential chemotherapy with hematopoietic progenitor-cell
support as induction treatment for patients with solid tumors.
AB - BACKGROUND: Despite recent progress in modern chemotherapy, metastatic solid
tumors still have a poor outcome. The delivery of increased dose intensities of
cytotoxic agents could improve response rates. We assessed the feasibility and
safety of a high-dose sequential chemotherapy program in chemotherapy-naive
patients with solid tumors. PATIENTS AND METHODS: Thirty patients (14 with
carcinoma of unknown primary site, seven with metastatic breast cancer, six with
small-cell lung cancer, and three with other diseases) were treated by an
induction therapy regimen consisting of four cycles of high-dose chemotherapy
with hematopoietic progenitor cell and growth factor support. Peripheral blood
progenitor cells were collected by apheresis as the leukocyte counts recovered
from the nadir induced by the first cycle of chemotherapy (doxorubicin 75 mg/m2,
cyclophosphamide 6000 mg/m2). Patients then received two cycles of etoposide (800
mg/m2) and carboplatin (900 mg/m2) separated by one cycle of doxorubicin (75
mg/m2) and cyclophosphamide (3000 mg/m2). G-CSF (5 microg/kg/d) was given until
engraftment. Cycles were scheduled to be delivered every three weeks. RESULTS: A
total of 108 cycles of chemotherapy were administered. Six patients went off
study before the end of the program (three because of progressive disease, three
because of toxicity). After the first cycle, a median number of 10 x 10(6)/kg
CD34+ cells (range 8-30) were collected. The median number of apheresis
procedures was 1 (range 1-3). From cycle 2 to cycle 4, the median number of days
when there was an absolute neutrophil count of less than 500/microl increased
from three to five, and the median number of days when the platelet count was
less than 25,000/microl increased from three to six. Episodes of febrile
neutropenia occurred in 36%, 50% and 46% of cycles during cycles 2, 3 and 4,
respectively. The median numbers of days between cycle 1 and cycle 2, cycle 2 and
cycle 3, cycle 3 and cycle 4 were 24 (range 20-30), 22 (range 20-36) and 22
(range 18-35), respectively. There were no treatment-related deaths. Non
hematologic toxicity included severe (WHO grades 3 or 4) nausea/vomiting in 19
(18%) cycles, mucositis in 8 (7%) cycles and diarrhea in 7 (6%) cycles.
CONCLUSION: Support with hematopoietic progenitor cells and growth factors allows
the timely administration of repetitive cycles of high-dose chemotherapy in
chemotherapy-naive patients, resulting in a significant increase in dose
intensity. Toxicity is noteworthy but manageable and does not compromise further
therapy.
PMID- 9402167
TI - Multiple cycles of high-dose doxorubicin and cyclophosphamide with G-CSF
mobilized peripheral blood progenitor cell support in patients with metastatic
breast cancer.
AB - BACKGROUND: In a previous study we applied doxorubicin and cyclophosphamide in a
dose-intensive regimen with GM-CSF to patients with metastatic breast cancer
(MBC). That treatment failed to prolong the remission duration compared to
conventional-dose chemotherapy. In the present study we escalated the dosages of
the same agents to: 1) determine the maximum tolerated dosages (MTD) when given
for three cycles with G-CSF mobilised peripheral blood progenitor cell (PBPC)
reinfusion and 2) evaluate the antitumour effect of this regimen. PATIENTS AND
METHODS: For mobilisation of PBPC, G-CSF 15 microg/kg/day was given
subcutaneously (s.c.), and in subsequent cohorts leucapheresis was started on
days 3, 4 or 6. The intention was to treat MBC patients with three cycles of
doxorubicin and cyclophosphamide at a starting dose of doxorubicin 90 mg/m2 and
cyclophosphamide 1000 mg/m2. Dosages were then escalated in subsequent cohorts of
at least three patients. In case of dose-limiting mucositis, only the dose of
cyclophosphamide was escalated in the next cohort. RESULTS: Twenty-one patients
entered this protocol, of which 18 patients received high-dose chemotherapy. The
mobilisation of PBPC using G-CSF only was sufficient for three cycles of high
dose chemotherapy in 10 of 21 (47%) patients. Mucositis precluded dose escalation
of doxorubicin beyond 110 mg/m2. The MTD in this combination was 110 mg/m2 for
doxorubicin, and 4 g/m2 for cyclophosphamide, with haemorrhagic cystitis being
the dose-limiting toxicity. The overall response rate was 78% (95% confidence
interval (95% CI): 57%-97%), with 22% (95% CI: 3%-41%) complete responses.
CONCLUSION: The MTD of this three cycle high-dose regimen was doxorubicin 110
mg/m2 and cyclophosphamide 4 g/m2 with mucositis and cystitis being dose-limiting
toxicities. Although the primary aim was not the evaluation of antitumour effect,
this high-dose regimen does not appear to provide an improvement of treatment
results in comparison with our previous study with the same drugs at moderately
high-dosages without stem cell support.
PMID- 9402168
TI - Predictors of response to subsequent chemotherapy in platinum pretreated ovarian
cancer: a multivariate analysis of 704 patients [seecomments].
AB - BACKGROUND: The probability of response to chemotherapy following platinum based
treatment in ovarian cancer has usually been related to the 'platinum-free
interval'. However, in a recent European-Canadian trial of paclitaxel, serous
histology, tumor bulk, and hemoglobin, but not treatment free interval, were
predictors of response. To determine if these observations were unique to this
study (or this drug), data from other active agents given as second- or third
line treatment in ovarian cancer were obtained and analyzed. METHODS: In the
first part of the study, results of trials in 1185 platinum pretreated ovarian
cancer patients were obtained on six agents: paclitaxel, epirubicin, docetaxel,
carboplatin, irinotecan, and gemcitabine. Response results according to
histology, baseline hemoglobin, tumor size and time from last chemotherapy were
determined for each agent and the Cochran-Mantel-Haenszel procedure was used to
obtain an overall assessment of significance for each factor. In the second part
of the study, individual data from 704 patients in four studies (three agents:
paclitaxel, docetaxel and epirubicin) were pooled for univariate and multivariate
analysis of factors predictive of response. RESULTS: In the analysis of results
of individual agents all factors examined were significant predictors of
response: serous histology (P = 0.001), tumor size < or = 5 cm (P = 0.02), normal
baseline hemoglobin (P = 0.003), and > or = 6 mo since last treatment (P =
0.001). While these results were interesting, they did not supply definitive
answers regarding independent response predictors. Therefore a multifactor
analysis was undertaken on the 704 patients for whom individual data were
available. Of the 11 factors examined in a univariate analysis, 10 met the
criteria for inclusion in a stepwise logistic regression. In the final model only
3 factors remained as significant independent predictors of response: serous
histology (P = 0.009), no. disease sites (P = 0.003), and tumor size (P = 0.001).
Time from last treatment, when evaluated as a continuous variable, was not in the
final model and was highly correlated with tumor size (P = 0.0005). CONCLUSIONS:
On the basis of this analysis, we conclude that tumor burden (as assessed by size
of the largest lesion and number of disease sites) and histology are factors of
importance in response to subsequent chemotherapy in relapsed ovarian cancer.
Time from last treatment was correlated with tumor size in this data set and its
effect on response was dependent on whether it was examined as a categorical or
continuous variable, so we conclude it is not the sole critical factor of
biologic importance. We recommend description of these factors in reports of
phase II studies, confirmation of these findings in other data sets and further
investigation of the mechanism of sensitivity of serous tumors.
PMID- 9402169
TI - Cisplatin-, epirubicin- and paclitaxel-containing chemotherapy in uterine
adenocarcinoma.
AB - PURPOSE: To evaluate the toxic effects and antitumour activity of a multidrug
regimen with cisplatin, epirubicin and paclitaxel (CEP) as initial therapy in
patients with uterine adenocarcinoma. PATIENTS AND METHODS: Forty-nine patients
with histologically-confirmed diagnoses of locally advanced, recurrent or
metastatic cervical or endometrial adenocarcinoma entered the study. Treatment
consisted of epirubicin (E) given at 70 mg/m2 followed by paclitaxel (P) (175
mg/m2 over three hours) and cisplatin (C) (50 mg/m2), repeated every three weeks.
Eligibility criteria also included age < or = 75 years, no previous chemotherapy,
no previous radiotherapy to the tumour parameters, bidimensionally-measurable
lesions, no previous or ongoing cardiac disease, and renal and liver function
within normal limits. Complete blood cell counts were repeated weekly, and tumor
response was assessed every three cycles. A maximum of eight courses was
administered in responding patients. RESULTS: From January 1996 to January 1997,
30 patients with endometrial adenocarcinoma and 19 with cervical adenocarcinoma
entered the study, for a total of 213 cycles of treatment. In patients with
endometrial carcinoma the overall clinical and pathological response rates were
73% (95% CI, range 54%-88%) and 35% (95% CI, range 16%-57%) respectively; in
patients with locally advanced cervical carcinoma the overall clinical and
pathological response rates were 64% and 62%. WHO grade 3-4 neutropenia occurred
in 61% of the patients, with one possible toxic death. Retreatment had to be
delayed for at least one week because of persisting neutropenia in 34% of the
patients. Mild peripheral neuropathy and stomatitis were observed in 46% and 23%
of the patients. One patient presented acute congestive heart failure after the
third cycle of treatment. CONCLUSION: The high antitumour activity and the good
tolerability of CEP suggest that this regimen should be prospectively compared to
standard combinations as initial treatment of advanced endometrial carcinoma.
PMID- 9402170
TI - Effect of age on the characteristics and clinical behavior of non-Hodgkin's
lymphoma patients. The Non-Hodgkin's Lymphoma Classification Project.
AB - BACKGROUND: The goals of this study are to describe the frequency, clinical
characteristics, and outcome of the different non-Hodgkin's lymphomas according
to age. PATIENTS AND METHODS: Patients included in the recently published
analysis of the Non-Hodgkin's Lymphoma Classification Project were analyzed. All
patients had their slides reviewed and classified by five independent expert
hematopathologists. Lymphomas were classified according to the Revised European
American Classification of lymphoid neoplasms. Sufficient data were available on
1283 cases. Five age groups were analyzed: < 35 years, 35-49 years, 50-59 years,
60-69 years, and > or = 70 years. RESULTS: Few differences were observed between
the age groups with regard to lymphoma types and clinical characteristics.
Anaplastic large cell lymphoma, Burkitt's lymphoma, and lymphoblastic lymphoma
were observed more frequently in patients younger than 35 years, whereas small
lymphocytic and lymphoplasmacytoid lymphomas were observed more frequently in
patients older than 70 years. Mantle cell lymphoma and marginal zone lymphomas
were observed more frequently in middle-aged patients. Poor performance status
was more frequent in older patients, as was bone marrow infiltration, whereas
spleen involvement was more frequent in younger patients. Young and older
patients had a slightly worse age-adjusted International Prognostic Index score
(P < 0.01). Complete response rates decreased with age from 68% in the youngest
patients to 45% in the oldest patients (P < 0.0001). Median event-free survival
and overall survival also decreased with age (P < 0.0001). CONCLUSIONS: Elderly
patients have a poorer outcome than younger patients but age alone is not
sufficient to discriminate patients with a poor outcome. However, the histologic
type of lymphoma and clinical characteristics may define a subgroup of patients
with a poor outcome in each age category.
PMID- 9402171
TI - t(11;18)(q21;q21) is the most common translocation in MALT lymphomas.
AB - BACKGROUND: Low grade malignant lymphomas arising from mucosa associated lymphoid
tissue (MALT) represent a distinct clinicopathological entity. The cytogenetic
findings and molecular genetics of MALT lymphomas remain minimally defined.
Cytogenetic studies infrequently constitute part of the diagnostic work-up of
MALT lymphomas, most commonly due to small biopsy size and their extranodal
localization. Only 28 MALT cases with a clonal karyotype have been published to
date. A number of chromosomal abnormalities have been observed with the majority
of the cases featuring trisomy of chromosome 3 which is present in up to 78% of
the cases. MATERIALS AND METHODS: A total of 116 cases of MALT lymphoma were
diagnosed at BCCA between 1988 and 1997. Eleven cases of pathologically confirmed
MALT lymphomas were subjected to cytogenetic analysis at the time of the initial
evaluation. Eight of 11 cases yielded successful cultures and the presence of a
clonal karyotype using standard cytogenetic methodology. In addition, a single
case of orbital MALT lymphoma with a clonal karyotype has been obtained through
our consultative practice from University of Nebraska Medical Center. These nine
cases of MALT lymphoma with a clonal karyotype are the subject of this report.
RESULTS AND CONCLUSION: In this study we report nine cytogenetically studied MALT
lymphomas, three of which feature a novel t(11;18)(q21;q21) translocation which
has also been observed in five other MALT cases described in the literature. This
recurrent translocation is the most common translocation associated with MALT
lymphomas being present in 33% (three of nine) of our cases and 18% (five of 28)
of the previously published cases. The results suggest that a potentially
important gene located at one of these breakpoints may be involved in the
pathogenesis of MALT lymphomas.
PMID- 9402172
TI - Intraclonal molecular heterogeneity suggests a hierarchy of pathogenetic events
in Burkitt's lymphoma.
AB - BACKGROUND: Burkitt's lymphoma is a B-cell neoplasm characterized by a
chromosomal translocation involving the c-myc gene. BL may carry, besides the c
myc translocation, several other lesions including a) mutations in c-myc, b)
mutations in bcl-6, c) mutations in p53 and d) EBV genomes. In this report we
describe a unique study of the timing of these genetic lesions during the
evolution and progression of Burkitt's lymphoma. MATERIALS AND METHODS: From each
of two patients with Burkitt's lymphoma, we established three different cell
lines from different sites or at different times in the clinical course of the
disease (diagnosis and relapse). Chromosomal aberrations were analyzed by
karyotyping and the presence of molecular lesions determined by Southern blot,
PCR, SSCP and sequence analyses. RESULTS: In each patient all the clones carry
identical c-myc translocations, identical bcl-6 status (wild type or mutant) and
the same productive VDJ rearrangement. However, within each individual patient,
we could demonstrate the presence of intraclonal variation with respect to EBV,
p53 mutations and c-myc mutations. CONCLUSIONS: c-myc translocation and bcl-6
mutations appear to be early events, mutations in the coding region of c-myc
occur early but are an ongoing event, while mutations in the p53 gene seem to
occur later. Discrete clonal bands reflecting independent EBV infection were
observed in the cell lines from one HIV-associated Burkitt's lymphoma, suggesting
the possibility that EBV infection may occur as a late event, at least in some
HIV associated lymphomas.
PMID- 9402173
TI - A prospective randomised trial of protracted venous infusion 5-fluorouracil with
or without mitomycin C in advanced colorectal cancer.
AB - BACKGROUND: To compare protracted venous infusion (PVI) 5-fluorouracil (5-FU)
with and without mitomycin C (MMC) in a prospectively randomised study and
analyse for tumour response, survival, toxicity and quality of life (QL).
PATIENTS AND METHODS: Two hundred patients with advanced colorectal cancer
received PVI 5-FU 300 mg/m2/day for a maximum of 24 weeks and were randomised to
PVI 5-FU alone or PVI 5-FU + MMC 10 mg/m2 (7 mg/m2 from June 1995) 6 weekly for 4
courses. RESULTS: Overall response was 54% (95% confidence interval [CI] 44.1%
63.9%) with PVI 5-FU + MMC compared to 38% (95% CI: 28.3%-47.7%) for PVI 5-FU
alone (P = 0.024). The median failure free survival was 7.9 months in PVI 5-FU
plus MMC and 5.4 months with PVI 5-FU alone (P = 0.033) and at one year 31.9% for
the combination compared to 17.7% for PVI 5-FU alone. Median survival was 14
months with MMC and 15 months in 5-FU alone; one-year survival 51.7% vs. 57.2%.
PVI 5-FU + MMC caused more overall haematological toxicity but CTC grades 3/4 was
increased only for thrombocytopaenia. Two patients treated with a cumulative dose
of MMC of 40 mg/m2 developed haemolytic uraemic syndrome warranting the reduction
in cumulative MMC dose to 28 mg/m2. The global QL scores were better for PVI 5-FU
+ MMC arm at 24 weeks, but the remaining QL data showed no differences.
CONCLUSIONS: PVI 5-FU + MMC results in failure-free survival and response
advantage, tolerable toxicity and better QL when compared to PVI 5-FU alone but
no overall survival advantage. There is no irreversible toxicity with MMC at a
cumulative dose of 28 mg/m2.
PMID- 9402174
TI - Phase I study of daily times five topotecan and single injection of cisplatin in
patients with previously untreated non-small-cell lung carcinoma.
AB - BACKGROUND: The objectives were to determine the dose-limiting toxicity of
topotecan in combination with cisplatin, to describe the principal toxicities,
and to define the maximally-tolerated doses of the drugs in previously untreated
patients with advanced non-small-cell lung carcinoma. PATIENTS AND METHODS: The
study was designed to evaluate escalated doses of topotecan (starting at 0.75
mg/m2/day) as a 30-minute infusion daily for five consecutive days with a fixed
clinically-relevant dose of 75 mg/m2 cisplatin given on day 1, every three weeks.
RESULTS: Fifteen chemotherapy-naive patients entered the study and 14 were
evaluable for toxicity. All 11 patients treated at the first topotecan/cisplatin
dose level of 0.75/75 mg/m2, experienced at least one episode of grade 4
neutropenia. For six patients, absolute neutrophil counts were below 500/ml for
more than five days, and two of them developed a grade 4 thrombocytopenia. At the
next higher topotecan/cisplatin dose level (1.0/75 mg/m2), grade 4 neutropenia
lasting longer than five days occurred in all three evaluable patients, including
one patient who expired due to a severe neutropenia associated with sepsis. Non
hematologic toxicities, predominantly nausea and vomiting, were mild to moderate
in severity and manageable. Four patients had partial responses (30.7%; 95%
confidence interval (9%-61%) of relatively short duration. CONCLUSION: Both
severe neutropenia and thrombocytopenia precluded dose escalation of topotecan
and cisplatin administered on this schedule. In previously untreated patients,
the first topotecan/cisplatin dose level (0.75/75 mg/m2), was associated with
intolerable myelosuppression, and, therefore, the dose levels evaluated in this
study cannot be recommended for subsequent phase II investigations. The high
toxicity of this schedule and the recent understanding of the pharmacokinetic
interaction between those drugs may encourage the investigation of the alternate
sequence of cisplatin after TPT in phase II studies.
PMID- 9402175
TI - Long-term survivors of small-cell lung cancer (SCLC): a French multicenter study.
Groupe d'Oncologie de Langue Francaise.
AB - BACKGROUND: The aim of this study was to analyze SCLC patients beyond 30 months,
particularly their outcome, their way of life, and factors which could influence
relapses, second-primary cancers and death. PATIENTS AND METHODS: Between January
1986 and May 1995, 263 SCLC patients who survived longer than 30 months were
included from 52 French institutions. The analysis was performed on the 155 cases
confirmed by a pathologic review. RESULTS: Physical, mental and psychological
states were considered as normal at 30 months in respectively 70.3%, 87.7% and
67.7% of patients, not influenced by prophylactic cranial irradiation, number of
chemotherapy cycles, CCNU or cisplatin. Therapeutic sequelae were neurological
impairment (13%), pulmonary fibrosis (18%) and cardiac disorders (11%) at 30
months. Return to work was possible for 40% of patients in the first two years
following diagnosis. Among 43 relapsing patients, 33 benefited from a second-line
treatment. Their median survival was 12 months since retreatment, and seven
patients have survived again longer than 30 months. Age > 60 at the time of
diagnosis was found as an independent factor increasing the risk of relapse
beyond 30 months (OR = 2.46, IC 95% (1.16-5.26), P = 0.01). The risk of relapse
became less than 10% beyond five years. Twenty patients (13%) developed a second
primary cancer in a mean time of 58.6 months. The risk of second primary cancer
was increased by a number of chemotherapy cycles > 6 (OR = 3.25, IC 95% (1.08
9.8) P = 0.02) and by an age > 60 (OR = 2.92, IC 95% (1.07-7.97), P = 0.03). Five
and 10-year survival rates were respectively 68% and 44%. In these patients
having reached a 30-month survival, three independent factors were predictive of
a survival longer than five years: age < or = 60 at the time of diagnosis (OR =
2.85, IC 95% (1.23-6.6), P = 0.01), chest radiotherapy (OR = 3.1, IC 95% (1.28
7.69), P = 0.006) and absence of relapse (OR = 4.5, IC 95% (1.75-12.5), P =
0.002). This study suggests that: 1) therapeutic sequelae are rather mild,
allowing return to work in 40% of patients; 2) relapsing 30-month survivors can
benefit from second-line treatment; 3) SCLC cure can be achieved with a 10-year
follow-up.
PMID- 9402176
TI - Elevated ocular levels of vascular endothelial growth factor in patients with von
Hippel-Lindau disease.
AB - BACKGROUND: Von Hippel Lindau disease (VHL) is a rare autosomal dominant
inherited disorder characterized by highly vascularized tumors in various organs.
The abundant presence of endothelial cells in VHL tumors strongly suggest a role
of the VHL tumor suppressor gene in the regulation of angiogenesis. Recently, in
vitro studies have shown that the VHL tumor suppressor gene regulates the
expression of vascular endothelial growth factor (VEGF). We investigated whether
VHL patiens have increased levels of VEGF in their body fluids. PATIENTS AND
METHODS: The concentration of VEGF was measured in fluid of the anterior chamber
of the eye, serum, urine, and fluid from renal cysts of VHL patients and
unaffected individuals by ELISA. In addition, levels of basic fibroblast growth
factor (bFGF), interleukin-8 (IL-8) and endothelin-1 (ET-1) were measured in
urine and serum of VHL patients and control subjects. RESULTS: In 80% of the VHL
patients VEGF was detectable in aqueous fluid of the anterior chamber of their
eyes. A strong positive correlation (r = 0.90) was found between the age of VHL
patients and ocular VEGF concentrations. At comparable age, VEGF levels in ocular
fluid of VHL patients were significantly higher (P < 0.001) than in unaffected
subjects. No correlation was found between VEGF concentration and the presence of
retinal angiomas. A 10 and 16 fold increase of VEGF concentration was seen in
fluid from two independent VHL-related cysts as compared with VEGF serum levels
of the same patient. The mean concentration of VEGF in serum of VHL patients (n =
15) (319 +/- 84 pg/ml) was higher than in matched controls (238 +/- 68 pg/ml; P =
NS). The mean concentration of VEGF in urine of VHL patients (128 +/- 36 pg/ml)
was lower than in matched controls (183 +/- 25 pg/ml; P = NS). Concentrations of
VEGF did not correlate with the presence of VHL-related tumors. No differences
were observed between concentrations of bFGF, IL-8 and ET-1 in serum and urine of
VHL patients and matched controls. CONCLUSIONS: These findings support a role for
the VHL tumor suppressor gene in the in vivo regulation of VEGF.
PMID- 9402177
TI - Growth factor profiles of human gliomas. Do non-tumour cells contribute to tumour
growth in glioma?
AB - BACKGROUND: Growth factors play a role in proliferation and motility of malignant
glial cells, through autocrine and paracrine mechanisms. Also, proliferation of
non-tumour cells, e.g., endothelial cells, is likely to be controlled by growth
factors. Several growth factors with their appropriate receptors can be involved,
but studies on tissue specimens evaluating this in glioma are rare. MATERIALS AND
METHODS: We evaluated the potential role of Transforming growth factor-alpha (TGF
alpha) and Epidermal growth factor receptor (EGF-R), the Platelet-derived growth
factor A- and B-chain (PDGF-A and PDGF-B) and its receptors (PDGFR alpha and
PDGFR beta, and basic fibroblast growth factor (bFGF) in gliomas by analysing 86
of these tumours on the single cell level for the presence of immunoreactive
growth factors and receptors. In a few cases double-staining experiments were
done to directly visualize co-expression of factor and receptor. RESULTS:
Multiple growth factors and their receptors are present in astrocytic tumours;
the higher the grade, the more growth factors and the more positive cells are
found. Oligodendroglial tumours and pilocytic astrocytomas showed little
expression. Autocrine and paracrine mechanisms were frequently possible in the
astrocytic tumours, often more than one loop could be involved. Interestingly, it
was also frequently possible that non-tumour cells produced a growth factor for
which the tumour cells expressed the receptor. CONCLUSIONS: Multiple growth
factors appear to be involved in astrocytic tumours, with frequent autocrine and
paracrine loops. Expression of these molecules seems to increase with increasing
grade. The results argue for a contribution of non-tumour cells to the growth of
a tumour.
PMID- 9402178
TI - Complete spontaneous remission in a patient with metastatic non-small-cell lung
cancer. Case report, review of the literature, and discussion of possible
biological pathways involved.
AB - Spontaneous remission of cancer (SR) is defined as a complete or partial,
temporary or permanent disappearance of all or at least some relevant parameters
of a soundly diagnosed malignant disease without any medical treatment or with
treatment that is considered inadequate to produce the resulting regression. We
report the case of a 61-year-old man who presented with extensive metatastic
disease five months after pneumonectomy for poorly differentiated large cell and
polymorphic lung cancer. A vast metastatic tumour mass of the abdominal wall was
confirmed histolologically and there was clinical and radiographic evidence of
liver and lung metastases. Eight months later, the patient was operated on for a
hernia, which had developed in the inguinal biopsy scar and the surgeon confirmed
complete clinical SR of the abdominal wall metastases. Again five months later
there was no longer any radiologic evidence of liver and lung metastases.
Complete remission has persisted more than five years. Histology of the primary
and of the abdominal metastases were reviewed by several independent
pathologists. SR is an extremly rare event in lung cancer. This is the first
documented case of clinically evident visceral metastases of a bronchiogenic
adenocarcinoma developing after complete resection of the primary and then
showing complete SR. The epidemiology of SR is reviewed and possible mechanisms
involved in SR are discussed.
PMID- 9402179
TI - High-dose treatment with lanreotide of patients with advanced neuroendocrine
gastrointestinal tumors: clinical and biological effects.
AB - BACKGROUND: Neuroendocrine tumors usually present with inoperable metastatic
disease and severe hormonal symptoms. Specific chemotherapy, alpha-interferon and
the somatostatin analog octreotide are established therapies in these patients
but all of them eventually fail. Other somatostatin analogs, e.g., RC-160 and
lanreotide, are currently being studied in different doses and modes of
administration. PATIENTS AND METHODS: Nineteen patients with advanced
neuroendocrine gastrointestinal tumors [13 carcinoids and six endocrine
pancreatic tumors (EPT)], liver metastases being present in 18, most of them
heavily pretreated, were included. Seventeen out of 18 patients had somatostatin
receptors demonstrated by octreotide scintigraphy. Lanreotide was given as four
daily subcutaneous injections, starting with 750 microg/d, then increasing every
week up to 12,000 microg/d after six weeks, a dose which was maintained, if
tolerated, for 12 months, or until progression. RESULTS: There was a significant
tumor size response (>50%) in one patient (5%), whereas 12 patients (70%) had
tumor stabilization for 12 months. Bichemical tumor markers were significantly
reduced at six months (urinary 5-hydroxyindoleacetic acid and plasma
chromogranin) and 12 months (chromogranin) and the overall biochemical response
rate was 58% with this high dose of lanreotide. Adverse events were observed and
four patients stopped the treatment due to adverse events. Studies of tumor
biopsies before and during treatment indicated induction of apoptosis in patients
with tumor stabilization and biochemical response. CONCLUSION: High-dose
treatment with lanreotide (12,000 microg/d) produced tumor size response in 5%,
stabilization in 70% and a biochemical response in 58% of patients. These results
should be related to the advanced stage of the disease as indicated by the mean
duration of disease of more than four years, but they do not appear to be better
than those achieved with standard doses of somatostatin analogs. However, in
responding patients we observed induction of apoptosis in the tumors, a
phenomenon not seen with regular doses of somatostatin analogs, but often
produced by chemotherapeutic agents.
PMID- 9402181
TI - Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports.
AB - BACKGROUND: CPT-11 is hydrolyzed to its active metabolite SN-38, which is mainly
eliminated through conjugation by hepatic uridine diphosphate glucuronosyl
transferases (UGTs) to the glucuronide (SN-38G) derivative. Preclinical studies
showed that UGT*1.1 is the isozyme responsible for SN-38 glucuronidation.
Patients with Gilbert's syndrome have deficient UGT*1.1 activity, therefore may
have an increased risk for related CPT-11 toxicity. PATIENTS AND METHODS: Two
patients with metastatic colon cancer and Gilbert's syndrome were treated with
CPT-11 based chemotherapy. CPT-11, SN-38 and SN-38G pharmacokinetics parameters
were obtained. Serum bilirubin was analysed by alkaline methanolysis and HPLC.
RESULTS: Both patients presented grade 4 neutropenia and/or diarrhea (NCI-CTC) in
every treatment cycle. Biliary index (after Gupta et al) values were well above
4000. CONCLUSION: We present the first clinical evidence linking bilirubin
glucuronidation status and CPT-11 related toxicity. The severe toxicity
experienced by the two patients with Gilbert's syndrome treated with CPT-11 based
chemotherapy has a genetic basis. Individuals with Gilbert's syndrome have an
enhanced risk for CPT-11 toxicity. Unconjugated serum bilirubin could be
predictive parameter of CPT-11 toxicity.
PMID- 9402182
TI - Ophthalmic toxicity following paclitaxel infusion.
PMID- 9402180
TI - Cisplatin, gemcitabine and vinorelbine in locally advanced or metastatic non
small-cell lung cancer: a phase I study.
AB - PURPOSE: The objective of this study was to determine the maximally tolerable
doses (MTDs) of vinorelbine (VNR) and gemcitabine (GEM) when combined with a
fixed dose of cisplatin (CDDP). PATIENTS AND METHODS: Chemotherapy-naive patients
with stage IIIB-IV non-small-cell lung cancer (NSCLC) received a fixed dose of
CDDP (50 mg/m2) and escalating doses of VNR (starting from 20 mg/m2) and GEM
(starting from 800 mg/m2) on days 1 and 8, every three weeks. The single
escalation of GEM alone, by 200 mg/m2 at each step, was initially planned up to a
dose of 1,200 mg/m2, to be followed by increments of the VNR dose of 5 mg/m2 at
each step. RESULTS: Thirty-one patients were enrolled at five different dose
levels. The escalation was stopped at level 4 (GEM 1,200 mg/m2 and VNR 25 mg/m2)
since two of six patients of this cohort showed dose-limiting neutropenia at
treatment cycle 1. Two different dose levels, GEM 1,200 mg/m2 + VNR 20 mg/m2, and
GEM 1,000 mg/m2 + VNR 25 mg/m2 were fairly well tolerated. No treatment-related
deaths occurred. Neutropenia was the main toxic effect, occurring in 76% of the
total of 116 cycles delivered, and in 24% of them was of grades 3 or 4. A total
of eight patients (26%) experienced grade 4 neutropenia lasting more than seven
days; in five of them it occurred in the first course. Neutropenic fever was
observed in four cases. Grade 4 thrombocytopenia occurred in only two patients.
Non-hematologic toxicity was a minor problem in all patients but was never dose
limiting. No complete responses were obtained, but sixteen out of 31 (52%)
patients achieved partial responses. The median duration of response was 20
(range 6-56+) weeks, while at a nine-month median follow-up, the median survival
time has not yet been reached. To date, 18 patients are still alive. The one-year
projected survival for all patients was 51%. CONCLUSIONS: Our results show that
CDDP, VNR and GEM can be safely given together without substantial reductions in
their individual dose intensities. In our opinion, the dose level of GEM 1,000
mg/m2 + VNR 25 mg/m2 given in combination with CDDP 50 mg/m2 on days 1 and 8 of a
three-week cycle can be recommended for phase II trials, since it provides a
better balance in dose intensity of GEM and VNR. A phase II randomised study is
underway to establish the activity of this new regimen (at the above-cited dose
level) in chemo-naive NSCLC patients.
PMID- 9402183
TI - Sublingual nitrate provides cause for fear of food in a carcinoid patient.
PMID- 9402184
TI - T1rho-relaxation in articular cartilage: effects of enzymatic degradation.
AB - Spin-lattice relaxation in the rotating frame (T1rho) dispersion spectroscopy and
imaging were used to study normal and enzymatically degraded bovine articular
cartilage. Normal specimens demonstrate significant T1rho "dispersion"
(approximately 60 to approximately 130 ms) in the 100 Hz to 9 kHz frequency
range. Proteoglycan-degraded specimens have 33% greater T1rho values than
collagen-degraded or normal samples. T1rho-weighted images reveal structure not
found in conventional T1- or T2-weighted images. Our results suggest that T1rho
measurements are selectively sensitive to proteoglycan content. The potential of
this method in distinguishing the early degenerative changes in cartilage
associated with osteoarthritis is discussed.
PMID- 9402185
TI - A multiple echo pulse sequence for diffusion tensor imaging and its application
in excised rat spinal cords.
AB - A new imaging sequence for rapid determination of the apparent self-diffusion
tensor of water was developed and tested on fixed excised rat spinal cords. To
reduce the time required to determine the tensor, the sequence utilized a new
single-shot approach with multiple spin echoes. An assumption of cylindrical
symmetry in the sample was made, thus requiring the measurement of only four of
the six unique elements of the tensor. This assumption was found experimentally
to be valid, and the results obtained using the new sequence were found to be
quantitatively the same as results obtained using a standard spin-echo sequence.
PMID- 9402186
TI - Functional MRI BOLD signal coincides with electrical activity in the rat whisker
barrels.
AB - Functional MRI (fMRI) provides a noninvasive method for mapping brain functional
activity based on blood oxygenation level dependent (BOLD) image contrast that is
primarily due to localized increases in perfusion. Recently, Malonek and Grinvald
(Science 272:551-554, 1996) suggested that during sustained functional
activation, the increases in perfusion were spread over a much larger area than
the localized electrical activity. In this study, it is demonstrated that the
spatial distribution of the BOLD fMRI signal during sustained stimulation of rat
whiskers has the same spatial pattern and dimension as that of neuronal
electrical activity in the rat whisker barrels.
PMID- 9402187
TI - Energetics of 3.5 s neural activation in humans: a 31P MR spectroscopy study.
AB - No direct information on brain energetics and energy-related compounds in the
first seconds of physiological activation has been reported to date. In this
study visual cortex high energy phosphate changes were monitored in 11 normal
subjects during 3.5 s activation and the following 23.5 s by a simple 31P
magnetic resonance spectroscopic method. An intraactivation decrease of
phosphocreatine (PCr) was observed in all subjects, with changes in pH in three,
one of them also presenting a change in adenosine triphosphate (ATP). In the
subgroup of eight subjects without changes in pH, the mean rate of mean PCr
decrease (D(PCr)) was 7.24 +/- 0.78%/s, and the postactivation mean rate of mean
PCr recovery was <1/2 D(PCr). Short phasic neural activity requires a large
amount of energy, i.e., at least three times basal consumption, in agreement with
theoretical calculations. Additional energy demands in the visual cortex are
several times those measured by positron emission tomography during prolonged
stimulation studies, implying that mean energy requirements decrease with
increases in duration of stimulation. During short activation, the vascular
responses as detected by brain-mapping techniques (BMT) are preceded by an
important reduction of the intracellular high-energy phosphate content, which
returns to resting values during an interval that corresponds to the
poststimulation return of BMT signals to baseline.
PMID- 9402188
TI - Two-point Dixon technique for water-fat signal decomposition with B0
inhomogeneity correction.
AB - To separate water and lipid resonance signals by phase-sensitive MRI, a two-point
Dixon (2PD) reconstruction is presented in which phase-unwrapping is used to
obtain an inhomogeneity map based on only in-phase and out-of-phase image data.
Two relaxation-weighted images, a "water image" and a "fat image," representing a
two-resonance peak model of proton density, are output. The method is designed
for T1- or density-weighted spin-echo imaging; a double-echo scheme is more
appropriate for T2-weighted spin-echo imaging. The technique is more time
efficient for clinical fat-water imaging than 3PD schemes, while still correcting
for field inhomogeneity.
PMID- 9402189
TI - Simultaneous T2* and diffusion measurements with 3He.
AB - It has recently been demonstrated that magnetic resonance (MR) imaging of human
lungs and airways is possible with hyperpolarized gases such as 3He. Because the
influence of the apparent transversal relaxation (T2* decay) and diffusion in 3He
imaging have not been quantified, an imaging pulse sequence was developed to
measure these two parameters simultaneously. The imaging pulse sequence generates
two series of multiply recalled gradient echo images with both different echo
spacings and diffusion-sensitizing gradients. From differences in exponential
signal decay between the two series, T2* and diffusion coefficients, D, of both
hyperpolarized and unpolarized 3He samples could be measured on a standard
clinical imager using a home-built Helmholtz coil. In a hyperpolarized sample of
pure 3He values of D = (1.8 +/- 0.2) x 10(-4) m2/s and T2* = 36 +/- 13 ms were
measured, while D = (0.3 +/- 0.1) x 10(-4) m2/s and T2* = 136 +/- 66 ms were
found in a Boltzmann-polarized 3He/O2 mixture.
PMID- 9402190
TI - Dynamic 13C NMR analysis of pyruvate and lactate oxidation in the in vivo canine
myocardium: evidence of reduced utilization with increased work.
AB - In this work, substrate selection was monitored in the left ventricle of the
canine myocardium by following pyruvate and lactate oxidation under in vivo
conditions at basal and elevated workloads. These studies were conducted in the
open chest model using dynamic 13C NMR techniques in the presence and absence of
dichloroacetic acid (DCA), a well-known activator of pyruvate dehydrogenase
(PDH). Following the infusion of (3-(13)C) pyruvate or (3-(13)C) lactate into the
left anterior descending artery, highly variable 13C enrichments of glutamate,
alanine, aspartate, and citrate were noted under low (RPP < 14,500 mmHg/min),
intermediate (RPP = 15,000-25,000 mmHg/min), and high (RPP > 25,500 mmHg/min)
rate pressure products (RPP). At low workloads, the myocardium typically oxidized
the infused (3-(13)C) pyruvate or (3-(13)C) lactate and incorporated the labeled
carbon into the glutamate pool as expected. However, in a few notable instances
(n = 3), 13C-enriched pyruvate and lactate were unable to label the glutamate
pool under in vivo conditions even at the lowest RPPs, indicating a lack of
selection for these substrates by the tricarboxylic acid (TCA) cycle.
Nonetheless, the levels of glutamate C4 enrichment observed at low workloads
could usually be enhanced by infusion of DCA. Importantly, 13C NMR extract
analysis revealed that (3-(13)C) pyruvate or (3-(13)C) lactate labeling of the
glutamate pool was reduced (< 20%) at high workloads in spite of increased DCA
concentrations.
PMID- 9402191
TI - 19F NMR monitoring of in vivo tumor metabolism after biochemical modulation of 5
fluorouracil by the uridine phosphorylase inhibitor 5-benzylacyclouridine.
AB - A uridine phosphorylase inhibitor, 5-benzylacyclouridine (BAU), has been utilized
as biochemical modulator of 5-fluorouracil (5-FU) anti-tumor activity in a murine
tumor model. The effect of BAU on 5-FU metabolism has been evaluated using in
vitro and in vivo 19F NMR spectroscopy. The analysis of the NMR data revealed an
increased formation and retention of fluorouracil nucleotides and fluorouridine
in colon 38 tumors treated with the regimen containing BAU and a reduction in 5
FU catabolites (alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta
alanine). In the normal tissues evaluated, the presence of BAU did not
significantly alter the metabolism and presence of fluoropyrimidine species,
indicating a more selective effect on tumor tissues. Therapy experiments on
C57/BL6 mice bearing colon 38 tumor showed that the administration of 120 mg/kg
BAU 30 min before 5-FU at 85 mg/kg, on a weekly basis, resulted in an increased
antineoplastic effect compared to the same dose of 5-FU alone. A smaller dose of
5-FU (60 mg/kg) also administered 30 min after 120 mg/kg BAU caused a reduction
in tumor growth similar to 5-FU alone. The addition of BAU to 5-FU (85 mg/kg)
resulted in a slight increase, although statistically nonsignificant, in host
toxicity without causing any toxic death during the chemotherapeutic treatment.
19F NMR spectroscopy is here shown to be a powerful technique to evaluate changes
in the metabolism of fluoropyrimidines after the use of biochemical modulator and
to allow a correlation between improved therapeutic response with the biochemical
effects generated in tissues.
PMID- 9402192
TI - The effect of perfusion on T1 after slice-selective spin inversion in the
isolated cardioplegic rat heart: measurement of a lower bound of intracapillary
extravascular water proton exchange rate.
AB - Many NMR measurements of cardiac microcirculation (perfusion, intramyocardial
blood volume) depend on some kind of assumption of intracapillary-extravascular
water exchange rate, e.g., fast exchange. The magnitude of this water exchange
rate, however, is still unknown. The intention of this study was to determine a
lower limit for this exchange rate by investigating the effect of perfusion on
relaxation time. Studies were performed in the isolated perfused cardioplegic rat
heart. After slice-selective inversion, the spin lattice relaxation rate of
myocardium within the slice was studied as a function of perfusion and compared
with a mathematical model which predicts relaxation rate as a function of
perfusion and intracapillary-extravascular exchange rate. A linear relationship
was found between relaxation rate T(-1) and perfusion P normalized by
perfusate/tissue partition coefficient of water, lambda: deltaT(-1) = m x
deltaP/lambda with 0.82 < or = m < or = 1.06. Insertion of experimental data in
the model revealed that a lower bound of the exchange rate from intra- to
extravascular space is 6.6 s(-1) (4.5 s(-1), P < 0.05), i.e., the intracapillary
lifetime of a water molecule is less than 150 ms (222 ms, P < 0.05). Based on
this finding, the T1 mapping after slice-selective inversion could become a
valuable noncontrast NMR method to measure variations of perfusion.
PMID- 9402193
TI - Homocarnosine and the measurement of neuronal pH in patients with epilepsy.
AB - Homocarnosine is a dipeptide of gamma-aminobutyric acid (GABA) and histidine
found uniquely in the brain, most likely in a subclass of GABAergic neurons. By
comparison of spectra from the occipital lobe of patients receiving a
homocarnosine elevation drug to normal subjects we have assigned two elevated
resonances in the short TE 1H MRS spectrum to homocarnosine. These resonances are
partially resolved at 7.05 and 8.02 ppm in a short TE spectrum at 2.1 T when
macromolecule resonances are removed by subtraction of a spectrum in which the
metabolite resonances are nulled by inversion recovery. The chemical shift of
both of these resonances is sensitive to pHi. By comparison with a titration
curve the pHi was calculated from the downfield resonance to be 7.06 in the
patient group which is similar to values reported using the P(i) resonance. Based
on the in vivo results and theoretical considerations the potential sensitivity
for using nonelevated homocarnosine to measure pH is similar to that of P(i)
under physiological conditions.
PMID- 9402194
TI - Localized q-space imaging of the mouse brain.
AB - Localized q-space imaging was used to obtain water displacement profiles from
mouse brain. These profiles take the form of unidirectional diffusive
displacement probability distributions. Two groups of mice were studied, a normal
group and a group in which surgery had been performed to produce a unilateral
reduction in the supply of blood to the forebrain. q-Space measurements were made
both in vivo and postmortem. The displacement profiles were characterized using
the summary parameter prob[d < 10], which is the proportion of water molecules
that undergo a net diffusive displacement that is less than +/-10 microm, during
the diffusion period (50 ms). The range of prob[d < 10] values in the normal
group was 0.71 to 0.77 in vivo compared with 0.78 to 0.87 in the impaired
hemisphere of the surgically treated group. An increase in prob[d < 10] occurred
postmortem to yield values in the range 0.79 to 0.81 and 0.80 to 0.89 in the
normal and surgically treated group, respectively. These observations are
consistent with the diffusion-weighted image intensity changes that occur after a
period of ischemia.
PMID- 9402195
TI - MR microimaging of the lung using volume projection encoding.
AB - Radial acquisition (RA) techniques have been extended to produce isotropic, three
dimensional images of lung in live laboratory animals at spatial resolution down
to 0.013 mm3 with a signal-to-noise ratio of 30:1. The pulse sequence and
reconstruction algorithm have been adapted to allow acquisition of image matrices
of up to 256(3) in less than 15 min. Scan-synchronous ventilation has been
incorporated to limit breathing motion artifacts. The imaging sequence permits
randomizing and/or discarding selected views to minimize the consequences of
breathing motion. The signal in lung parenchyma was measured as a function of
flip angle (alpha) for different repetition times and found to follow the
predictions for which there is an optimum excitation (Ernst) angle. A single T1
relaxation value of 780 +/- 54 ms fits all data from six guinea pigs at 2.0 T.
This T1 value parameterizes the signal and allows for a priori optimization, such
as calculation of the Ernst angle appropriate for lung imaging.
PMID- 9402196
TI - Recording of EEG during fMRI experiments: patient safety.
AB - The acquisition of electroencephalograms (EEG) during functional magnetic
resonance imaging (fMRI) experiments raises important practical issues of patient
safety. The presence of electrical wires connected to the patient in rapidly
changing magnetic fields results in currents flowing through the patient due to
induced electromotive forces (EMF), by three possible mechanisms: fixed loop in
rapidly changing gradient fields; fixed loop in a RF electromagnetic field;
moving loop in the static magnetic field. RF-induced EMFs were identified as the
most important potential hazard. We calculated the minimum value of current
limiting resistance to be fitted in each EEG electrode lead for a representative
worst case loop, and measured RF magnetic field intensity and heating in a
specific type of current-limiting resistors. The results show that electrode
resistance should be > or = 13 k(omega) for our setup. The methodology presented
is general and can be useful for other centers.
PMID- 9402197
TI - On the SAR and field inhomogeneity of birdcage coils loaded with the human head.
AB - Birdcage coils are widely used as a radiofrequency (RF) resonator in magnetic
resonance imaging (MRI) because of their capability to produce a highly
homogeneous B1 field over a large volume within the coil. When they are employed
for high-frequency MRI, the interaction between the electromagnetic field and the
object to be imaged deteriorates the B1-field homogeneity and increases the
specific absorption rate (SAR) in the object. To investigate this problem, a
finite-element method (FEM) is developed to analyze the SAR and the B1 field in a
two-dimensional (2D) model of a birdcage coil loaded with a 2D model of a human
head. The electric field, magnetic field, and SAR distributions are shown, and a
comprehensive study is carried out for both linear and quadrature birdcage coils
at 64, 128, 171, and 256 MHz. It is shown that to generate the same value of the
B1 field, the SAR is increased significantly with the frequency, and for the same
imaging method the SAR produced by a quadrature coil is significantly lower than
that of a linear coil. It is also shown that the B1-field inhomogeneity is
increased significantly with the frequency.
PMID- 9402198
TI - Non-Fourier encoding with multiple spin echoes.
AB - The advantages and limitations of multiple spin-echo sequences for non-Fourier
encoding are investigated. Complications caused by improper encoding of alternate
magnetization pathways due to imperfect refocusing pulses are analyzed. It is
shown that mirror image ghosts result if the encoding RF pulse matrix is real
valued. These ghosts can be avoided as long as the rows of the RF pulse matrix
are conjugate symmetric, which implies that spatial profiles are real valued. Non
Fourier encoding using bases derived from wavelet, Hadamard, and other real
valued orthogonal functions does not result in a mirror ghost artifact. A RARE
sequence for non-Fourier encoding has been implemented on a clinical imaging
system and successfully applied for brain imaging.
PMID- 9402199
TI - Magnetization transfer imaging in vivo of the rat brain at 4.7 T: interpretation
using a binary spin-bath model with a superLorentzian lineshape.
AB - Proton magnetization transfer contrast (MTC) imaging, using continuous wave off
resonance irradiation, was performed on the rat brain in vivo at 4.7 Tesla. The
observed MTC was studied in three different brain regions: the corpus callosum,
the basal ganglia, and the temporal lobe. By systematically varying the offset
frequency and the amplitude of the RF irradiation, the observed signal
intensities for each region of interest were modeled using a system including
free water and a pool of protons with restricted motions (R. M. Henkelman, X.
Huang, Q. Xiang, G. J. Stanisz, SD Swanson, M. J. Bronskill, Magn. Res. Med. 29,
759 (1993)). Most of the relaxation parameters of both proton pools remained
fairly constant for the three regions of interest, with a T2 value of about 9
micros for the immobilized protons, whereas the rate of exchange increased
significantly from the temporal lobe to the corpus callosum. The optimal
acquisition parameters for the improved MTC under steady-state saturation were
found to be 2-10 kHz offset frequency and 500-800 Hz RF irradiation amplitude.
Conversely, an irradiation amplitude of 3 kHz at an offset frequency of 12 kHz is
required to minimize the direct effect of off-resonance irradiation. Such an
approach could be extended to human brain imaging with the aim of characterizing
tissue-specific disease.
PMID- 9402200
TI - MRI quantitative myocardial perfusion with compartmental analysis: a rest and
stress study.
AB - K1 (first-order transfer constant from arterial plasma to myocardium for Gd-DTPA)
and Vd (distribution volume of Gd-DTPA in myocardium) were measured in vivo in a
canine model (n = 5) using MRI-derived myocardial perfusion curves and a
compartmental model. Perfusion curves were obtained after a bolus injection of Gd
DTPA (0.04 mM/kg) with an inversion-prepared fast gradient echo sequence.
Myocardium and blood signal intensity were converted to a concentration of Gd
DTPA, according to a model appropriate for short (<1 s) interimage intervals
characteristic of cardiac-triggered acquisitions. Before dipyridamole-induced
stress, K1 and Vd, obtained from the fit of the MRI-derived perfusion curves,
were 6.2 +/- 1.4 (mHz) and 17.5 +/- 4.2%, respectively. After dipyridamole
infusion, a K1 increase of a factor of 2.82 +/- 0.72 was measured (P = 0.003). No
change was observed in Vd (P = 0.98). These results suggest that the K1 increase
after dipyridamole reflects a flow-related effect that can be useful to quantify
the MRI-derived perfusion curves.
PMID- 9402201
TI - Contrast-agent phase effects: an experimental system for analysis of
susceptibility, concentration, and bolus input function kinetics.
AB - A system is presented for experimental arterial input function (AIF) simulation
and for accurate measurement of the concentration, susceptibility effects, and
magnetic moment of paramagnetic MR contrast agents. Signal effects of contrast
agents are evaluated with a stable, well-characterized, and precise experimental
setup. A cylindrical phantom and a closed-loop circulating flow system were
designed for AIF simulation, assessment of the physical determinants of contrast
agent phase effects, and measurement of contrast-agent properties under
controlled conditions. A mathematical model of the AIF dynamics is proposed. From
the experimental phase shift (delta phi), either the concentration or molar
susceptibility, chiM, is determined. The linear dependence of delta phi on
concentration and echo time (TE), the orientation dependence, and the lack of
dependence on T1, T2, and diffusion time are proven precisely for water solutions
under a wide variety of conditions. The measured effective magnetic moment of
Gd+3, mu(eff), was 7.924 +/- 0.015 Bohr magnetons in agreement with the
theoretical value of 7.937.
PMID- 9402202
TI - Phase alignment of multiple surface coil data for reduced bandwidth and
reconstruction requirements.
AB - Multiple element surface coils are often used in clinical MRI to increase the
image signal-to-noise ratio (S/N). Use of multicoils typically requires increased
net sampling bandwidth and data processing for each coil element. A phase
alignment technique is described which combines the signals from all coil
elements before image reconstruction, greatly relaxing the technical requirements
of the standard multicoil methods. Hardware and software implementations allow
reduction of the reconstruction requirement to that of a single coil. The
hardware implementation additionally allows a significant reduction in the net
sampling bandwidth. The method is applicable to high speed MRI techniques, as
demonstrated in phantoms and volunteers.
PMID- 9402203
TI - MR microscopy of perfused brain slices.
AB - To study the origins of signal changes in clinical MRI we have previously studied
isolated single neuronal cells by MR microscopy. To account for the extracellular
environment of the cells, we have developed a prototype perfusion chamber for MR
microimaging of perfused rat hippocampal brain slices. To demonstrate the utility
of this model, brain slices were initially perfused in isotonic solutions and
then subjected to osmotic perturbations via perfusate exchange with 20%
hypertonic and 20% hypotonic solutions. In diffusion weighted images, signal
intensity changes of +16(sigma(n-1) = 11)% (hypotonic) and -26(sigma(n-1) = 10)%
(hypertonic) were observed. No significant variation in response was observed
across the slice when several subregions were examined. These observations are
consistent with the view that contrast changes are driven primarily by changes in
the intra- and extracellular compartmentation of water. This is the first report
of MR microimaging of the isolated brain slice. The technique will enable the
correlation of MR microimaging measurements with microscopic changes using other
modalities and techniques to provide a better understanding of signals in
clinical MRI.
PMID- 9402204
TI - Elimination of eddy current artifacts in diffusion-weighted echo-planar images:
the use of bipolar gradients.
AB - Small gradient fields resulting from incompletely canceled eddy currents can
cause geometric distortion in echo-planar images. Although this distortion is
negligible in most echoplanar applications, the large gradient pulses used in
diffusion-weighted echo-planar imaging can result in significant image
distortion. In this report, it is shown that this distortion can be significantly
reduced by the application of bipolar gradient waveforms. Both bipolar diffusion
sensitizing gradients and an inverted gradient preparatory pulse were examined
for minimizing the eddy currents responsible for these distortions.
PMID- 9402205
TI - Spectrally weighted twisted projection imaging: reducing T2 signal attenuation
effects in fast three-dimensional sodium imaging.
AB - A scheme for the reduction of T2 signal attenuation effects in three-dimensional
twisted projection imaging is presented. By purposely reducing the sample density
at the high spatial frequencies, a considerable reduction in readout time is
achieved. The reduction in readout time leads to decreased T2 signal attenuation
which translates into improved signal-to-noise ratio (SNR). The SNR improvement
is achieved without decreasing the image's resolution since the point spread
function depends on the sample weighting as well as the T2 attenuation. The
results indicate that SNR improvements of up to 40% can be achieved using the
proposed scheme.
PMID- 9402206
TI - k-Space detection and correction of physiological artifacts in fMRI.
AB - Signal phase variations caused by physiology are a major source of instability in
fMRI images produced by multiple RF pulses. k-Space phase variation maps show
cyclic phase variations at the frequency of respiration combined with a cardiac
variation of lower amplitude. The amplitude of the variation increases with
gradient echo time and proximity to the chest, suggesting that the dominant cause
of the phase variation is a B0 shift (approximately 0.01 ppm) produced by
movement of organs in the chest. A simple k-space phase correction method is
proposed and demonstrated for FLASH fMRI. The retrospective method requires no
pulse sequence modification, and is more effective than navigator echo
correction. Physiological noise is dramatically reduced, especially at inferior
slice locations.
PMID- 9402207
TI - Failure.
PMID- 9402208
TI - The antimicrobial dance.
PMID- 9402209
TI - The search for the Holy Grail: a century of anterior cruciate ligament
reconstruction.
AB - A perspective on the history of the development of anterior cruciate ligament
reconstruction is presented. The lack of critical analyses establishing the
relative effectiveness of many previously described procedures is documented.
PMID- 9402210
TI - Bioresorbable fracture fixation in orthopedics: a comprehensive review. Part II.
Clinical studies.
AB - Bioresorbable materials overcome two major disadvantages of the metal alloys most
commonly used in fracture-fixation devices: their extreme stiffness, which causes
stress shielding of the underlying bone, and the necessity, in a significant
number of cases, of removing metallic implants after fracture healing is
complete. The orthopedic surgeon now has the use of polylactic acid, polyglycolic
acid, and polydioxanone implants for the fixation of small cancellous bone
fractures. The currently available bioresorbable materials lack strength and
stiffness and are associated with inflammatory reactions and osteolysis in a
significant number of cases. Surgeons should use the available pins and screws
with extreme care and attention to the characteristics of each individual injury,
particularly its healing characteristics, as well as to the material's initial
mechanical properties, degradation rates, and associated complications.
PMID- 9402211
TI - Treatment of grade III acromioclavicular separations in professional throwing
athletes: results of a survey.
AB - Forty-two team orthopedists representing all 28 major league baseball teams were
surveyed to ascertain their definitive treatment for a hypothetical starting
rotation pitcher who had sustained a grade III acromioclavicular (AC) separation
to his throwing arm 1 week before the season. Twenty-nine (69%) of the physicians
would treat the injury nonoperatively, while 13 (31%) would operate immediately.
Twenty-five (60%) of the orthopedists had actually treated a pitcher or position
baseball player with a grade III AC separation in the throwing arm, the 25
treating a total of 32 patients. Twenty (63%) of these injuries were treated
nonoperatively, and 12 (37%) were treated operatively. The physicians reported
that 16 (80%) of the patients treated nonoperatively regained normal function and
achieved complete relief of pain, while 18 (90%) had normal range of motion after
treatment; of those treated operatively, 11 (92%) regained normal function,
achieved complete relief of pain, and had normal range of motion after surgery.
PMID- 9402212
TI - Anatomic variations of the musculocutaneous nerve in the arm.
AB - To determine the course and anatomic relationships of the musculocutaneous nerve
in the arm, we dissected 54 cadaver arms and measured the length of any
interconnection between the musculocutaneous nerve and the median nerve (36% of
dissections; mean, 1.77 cm) and the distance from the coracoid process to (1) the
musculocutaneous nerve (mean, 0.46 cm distal); (2) the median nerve (mean, 1.91
cm distal); (3) the musculocutaneous nerve's entrance to and exit from the
coracobrachialis muscle (mean, 4.99 cm and 7.55 cm, respectively); and (4) the
musculocutaneous nerve's entrance into the biceps muscle (mean, 11.66 cm). The
high percentage of anomalies found emphasizes the complexities and irregularities
of this anatomic region with regard to surgical approaches.
PMID- 9402213
TI - Propagation of a patellar stress fracture in a basketball player.
AB - Cyclic loading of cortical bone with repetitive, low-intensity loading can result
in damage at its microstructural level. If this damage accumulates over time
without appropriate repair, the strength of bone is reduced. Accumulation of
fatigue damage may be manifest as stress fractures. As a link in the extensor
mechanism of the leg, the patella is subject to complex loading, which varies
with knee flexion and extension. Stress fractures of the patella originate on its
anterior cortex and rarely propagate to completion.
PMID- 9402214
TI - Paraspinal pyomyositis, a rare cause of severe back pain: case report and review
of the literature.
AB - Pyomyositis, a pyogenic infection of skeletal muscle, is rarely reported in
temperate climates. A case of pyomyositis within the paraspinal muscles of a 63
year-old man is reported, with details of diagnostic evaluation and medical and
surgical treatment of the condition. Failure to recognize this clinical entity
can lead to diagnostic delay and inappropriate management.
PMID- 9402215
TI - Bilateral femoral neck stress fractures in an amenorrheic athlete.
AB - Stress fractures in athletes rarely involve the femoral neck. This report
described the diagnosis and treatment of bilateral femoral neck stress fractures
in a 30-year-old amenorrheic triathlete who is lactose intolerant and has a low
caloric intake. The possibility of fatigue fracture should be considered in
patients who have pain in the lower extremities that is exacerbated by activity,
especially if they have hormonal or nutritional disorders.
PMID- 9402216
TI - Syndesmotic ankle injuries in rodeo bull riders.
AB - This report describes five male rodeo bull riders, aged 18 to 32 years, who
sustained syndesmotic ankle injuries during competition. The mechanism of injury
was identical in each case. As the rider attempted to escape after being thrown,
the bull stepped on his lateral ankle, resulting in forced external rotation. All
patients delayed seeking medical care, the interval between the injury and
presentation ranging from 2 days to 4 weeks. All five patients sustained
significant syndesmotic tears, two with associated fibular fractures. Three
patients underwent surgical stabilization, and all riders returned to competitive
rodeo events, often prior to medical clearance. To the authors' knowledge, this
is the first reported association between injuries caused by livestock stepping
and syndesmotic disruptions.
PMID- 9402217
TI - Hyphenated history: the Hueter-Volkmann law.
AB - The language that orthopedic surgeons speak is filled with eponyms. Perhaps more
than any other medical specialty, we speak cryptically to one another using code
words and secret language. Certain hyphenated eponyms are particularly
interesting, because they pique one's curiosity as to how these persons came to
be partners in orthopedic history. We will offer some bits of orthopedic
hyphenated history, outlining the pertinent work of the respective authors as
well as associated background information. This paper focuses on the Hueter
Volkmann law, an important orthopedic concept concerning bone growth. This law
bears the names of the two men credited with enunciating and popularizing it,
Carl Hueter and Richard von Volkmann.
PMID- 9402218
TI - Radius osteotomy assisted by temporary fixation with the Agee-Wristjack.
AB - A modified technique for performing a distal radius osteotomy, using the Agee
WristJack for temporary fixation, is described. The preoperative and
postoperative conditions of a patient, a 26-year-old woman, are illustrated in
radiographs.
PMID- 9402219
TI - AMPA/kainate receptors modulate the survival in vitro of embryonic brainstem
cells.
AB - This study aimed at analyzing the involvement of (RS)-alpha-amino-3-hydroxy-5
methyl-4-isoxazolepropionic acid/kainate (AMPA/kainate) receptors in the survival
of cultured rat embryonic brainstem cells, dissociated on embryonic day 14. The
cell number was estimated after pharmacological manipulation of the receptors by
exposure to agonists or antagonists. The developmental stage at the moment of
drug application was critical for cell survival. We observed after 8 days in
vitro a much stronger decrease in the number of gamma-enolase-positive cells when
the cultures were treated for 3 days with the antagonist 6,7-dinitroquinoxaline
2,3-dione (DNQX) starting on the day of plating than when DNQX was added after 5
days in vitro. Conversely, exposure to the agonists (RS)-2-amino-3-(3-hydroxy-5
tri-fluoromethyl-4-isoxazolyl)-propion ic acid (T-AMPA) or kainate for 3 days
significantly reduced cell survival only when the treatment was initiated after 5
days in vitro. Survival of S-100-positive cells was not affected after exposure
to either agonists or antagonists. Neither agonist nor antagonist treatment
modified cell proliferation, as assessed by 5-bromo-2'-deoxyuridine (BrdU)
staining, suggesting that the decrease in the number of gamma-enolase-positive
cells is essentially due to cell death. If some of the processes we observed in
vitro correspond to analogous events in vivo, then exposure to excitatory amino
acid receptor agonists or antagonists at critical stages of embryogenesis may
alter the development of the central nervous system.
PMID- 9402220
TI - Effect of a long-term nerve growth factor treatment on body weight, blood
pressure, and serum corticosterone in rats.
AB - Nerve growth factor is a well-characterized neurotrophin essential for the
development and maintenance of certain central and peripheral neurons. As many
neurons affected by aging depend for their survival on a constant supply of
neurotrophins, nerve growth factor has been proposed as a possible treatment to
prevent aging-associated neurodegeneration. There is evidence that nerve growth
factor also plays a role in the immune system and modulates certain aspects of
endocrine function. Here we have determined the effects of prolonged peripheral
(intraperitoneal) treatment with nerve growth factor on body weight, blood
pressure, and serum corticosterone levels in the rat. Our data indicate that
intraperitoneally-injected nerve growth factor can affect body weight gain in
rats. This effect may not be mediated by nerve growth factor-induced increases in
serum corticosterone levels, as exogenous administration of corticosterone did
not result in a similar body weight loss. These results show that, as previously
reported for intracerebroventricular treatment with nerve growth factor,
intraperitoneally-injected nerve growth factor also reduces body weight gain in
rats. The data also suggest that exogenous delivery of nerve growth factor as
part of therapeutic regimens is likely to have several effects.
PMID- 9402221
TI - Cytokine regulation of embryonic rat dopamine and serotonin neuronal survival in
vitro.
AB - Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor
alpha (TNF-alpha) are cytokines with pleiotropic effects in the central nervous
system (CNS), including an emerging role in neurodevelopment. This study measured
the effects of cytokines on the survival of tyrosine hydroxylase (TH)
immunoreactive dopamine neurons from the substantia nigra (SN), and 5
hydroxytryptamine (5-HT) immunoreactive serotonin neurons from the rostral raphe
(RR), using cultures from embryonic day 14 (E14) rat brain. IL-1beta, IL-6, and
TNF-alpha were added to cell cultures at 1, 10 and 100 U/ml. After 3 days in
vitro, TH and 5-HT neurons were counted. The survival of 5-HT neurons was
significantly reduced by 20-30% at 10 U/ml of IL-6. IL-1beta and TNF-alpha at
doses of 1 and 10 U/ml appeared to have a similar effect on the survival of these
neurons, but this effect was not statistically significant. Comparable non
significant reductions of survival also occurred for TH neurons at the lower
doses of IL-6 and TNF-alpha. In separate experiments, SN and RR cultures were
exposed to the cytokines at a higher dose (1000 U/ml), causing a significant 30
40% decrease in the survival of TH neurons, but little or no change in 5-HT
neuronal survival. Taken together, these results show that IL-1beta, IL-6, and
TNF-alpha can affect developing monoamine neurons at physiologically relevant
concentrations, and that high doses differentially inhibit the survival of TH and
5-HT neurons after short exposures.
PMID- 9402222
TI - Fetuin expression in the dorsal root ganglia and trigeminal ganglia of perinatal
rats.
AB - Fetuin, a fetal plasma glycoprotein, has been shown previously to be present in
sub-populations of neurons in the developing central and peripheral nervous
system. To gain a more complete description of the time course of the appearance
of fetuin during neurogenesis we have examined fetuin immunoreactivity, and the
presence of fetuin mRNA, in the developing rat trigeminal and dorsal root
ganglia. Fetuin immunoreactivity and its mRNA were first seen at embryonic day 15
in the trigeminal ganglia, and at embryonic day 16 in dorsal root ganglia. In
both trigeminal and dorsal root ganglion, fetuin appeared to be present up until
around the time of birth, and then again between postnatal days 3 and 16. The
results suggest that fetuin first appears at around the time that ganglion cell
axons reach their central targets, which is also approximately when the cell
death period begins. The proportion of ganglion neurons that were fetuin
immunoreactive at different ages was inversely related to the amount of cell
death that is known to occur in these populations, thus it seems that fetuin is
more likely to be associated not with dying cells, but with those that survive
the cell-death period.
PMID- 9402223
TI - Development of serotoninergic chick retinal neurons.
AB - Numerous neurotransmitters have been studied in detail in the developing retina.
Almost all known neurotransmitters and neuromodulators were demonstrated in
vertebrate retinas using formaldehyde-induced fluorescence, uptake
autoradiography or immunohistochemistry procedures. Serotoninergic (5HT) amacrine
neurons were described in the inner nuclear layer (INL) of the retina with their
dendrites spreading within the inner plexiform layer (IPL). The present work
describes the morphological pattern of development of serotoninergic amacrine
neurons with a stratified dendritic branching pattern in the chick retina from
embryonic day 12 to postnatal day 7. Serotoninergic-bipolar neurons are also
described. SHT-amacrine neurons have round or pear-shaped somata and primary
dendritic trees oriented toward the IPL that runs through the INL, showing
several varicosities. Secondary dendrites then go through the INL, without any
collateral branch. At the outer and inner margin of the IPL the primary and
secondary dendrites originate an outer and an inner serotoninergic network,
respectively. When the primary dendritic tree reaches the IPL it deflects
laterally in sublayer 1-the outer serotoninergic network. Tertiary branches then
arise from the secondary dendrite and deflect in the innermost sublayer of the
IPL-the inner serotoninergic network. The final pattern of branching of 5HT
amacrine cells was present at embryonic day 14 and was completely developed at
hatching. Serotoninergic (5HT) bipolar neurons were also present in the INL at
hatching. They are weakly immunoreactive and are probably a subset of bipolar
cells that accumulate serotonin from the intersynaptic cleft and are not "true"
5HT neurons.
PMID- 9402224
TI - Age-dependent changes of presynaptic neuromodulation via A1-adenosine receptors
in rat hippocampal slices.
AB - The presynaptic neuromodulation of stimulation-evoked release of [3H]
acetylcholine by endogenous adenosine, via A1-adenosine receptors, was studied in
superfused hippocampal slices taken from 4-, 12- and 24-month-old rats. 8
Cyclopentyl-1,3-dimethylxanthine (0.25 microM), a selective A1-receptor
antagonist, increased significantly the electrical field stimulation-induced
release of [3H]-acetylcholine in slices prepared from 4- and 12-month-old rats,
showing a tonic inhibitory action of endogenous adenosine via stimulation of
presynaptic A1-adenosine receptors. In contrast, 8-cyclopentyl-1,3
dimethylxanthine had no effect in 24-month-old rats. 2-Chloroadenosine (10
microM), an adenosine receptor agonist decreased the release of [3H]
acetylcholine in slices taken from 4- and 12-month-old rats, and no significant
change was observed in slices taken from 24-month-old rats. In order to show
whether the number/or affinity of the A1-receptors was affected in aged rats,
[3H]-8-cyclopentyl-1,3-dimethylxanthine binding was studied in hippocampal
membranes prepared from rats of different ages. Whereas the Bmax value was
significantly lower in 2-year-old rats than in younger counterparts, the
dissociation constant (Kd) was not affected by aging, indicating that the density
rather than the affinity of adenosine receptors was altered. Endogenous adenosine
levels present in the extracellular space were also measured in the superfusate
by high performance liquid chromatography (HPLC) coupled with ultraviolet
detection, and an age-related increase in the adenosine level was found. In
summary, our results indicate that during aging the level of adenosine in the
extracellular fluid is increased in the hippocampus. There is a downregulation
and reduced responsiveness of presynaptic adenosine A1-receptors, and it seems
likely that these changes are due to the enhanced adenosine level in the
extracellular space.
PMID- 9402225
TI - Transynaptic modulation by insulin-like growth factor I of dendritic spines in
Purkinje cells.
AB - Purkinje cells synthesize insulin-like growth factor I and express insulin-like
growth factor I receptors during their entire life. An additional source of
insulin-like growth factor I for these cells is provided by climbing fiber
afferents originating in the inferior olive nucleus. Recently we found that
insulin-like growth factor I from the inferior olive is necessary for motor
learning processes probably involving Purkinje cell synaptic plasticity. We now
studied whether inferior olive insulin-like growth factor I influences the
synaptic structure of Purkinje cells, because changes in synaptic morphology are
related to neuronal plasticity events. We injected an insulin-like growth factor
I antisense in the inferior olive of adult rats, a procedure which we previously
found to elicit a significant and reversible decrease of insulin-like growth
factor I levels in the contralateral cerebellum. Ultrastructural analysis of the
cerebellar cortex of these animals showed a significant reduction in the size of
dendritic spines on Purkinje cells of antisense-treated rats compared to
controls. The decrease in spine size was linked to a diminished numerical density
of dendritic spines on Purkinje cells, without affecting the numerical density of
synapses in the molecular layer of the cerebellum. This reduction was not due to
a change in the thickness of the molecular layer. Climbing or parallel fiber
terminals were also unaffected. Taken together with previous findings, these
results support a role for insulin-like growth factor I produced in the inferior
olive in the maintenance of Purkinje cell synaptic plasticity.
PMID- 9402226
TI - Neuronal changes in the basolateral complex during development of the amygdala of
the rat.
AB - Neuronal changes in the amygdala basolateral complex were studied during
development and maturation in fetal and postnatal rat brains using morphometrical
methods. Forty brains of animals of various ages were fixed in formalin, frozen
and cut into 25 microm thick sections and stained with cresyl violet or
haematoxylin and eosin (H&E). In cresyl violet preparations, the complex appeared
for the first time on embryonic day (E)17 and was composed of two homogeneous
nuclei lateral and basolateral. On about the seventh postnatal day, each of these
nuclei was divided into two parts the first one into the dorsolateral and
ventromedial and the second one into the anterior and posterior. Morphometric
investigations showed a different increase of the neuronal and nuclear size in
various parts of the basolateral complex up to postnatal day (P)14; after that
time these parameters did not change significantly. The neuronal density and the
total number of neurons stabilized at P7 in all parts of this complex, except for
the dorsolateral part of the lateral nucleus in which a 30% decrease of the total
number of cells was observed. From P14, in all nuclei under study, the total
number of neurons did not change significantly.
PMID- 9402227
TI - Cloning, characterization and developmental expression of alpha2,8
sialyltransferase (GD3 synthase, ST8Sia I) gene in chick brain and retina.
AB - GD3 and GM2 synthases act on ganglioside GM3 at the branching point of the
pathway of synthesis of gangliosides in which the "a", "b" and "c" families are
produced. The relative activities of these enzymes are important for regulating
the ganglioside composition of a given tissue. In the present work, we report the
cloning and characterization of a chick GD3 synthase cDNA. The cloned cDNA
directed the synthesis of a functionally active enzyme in transiently transfected
CHO-K1 cells and was highly homologous to mammalian GD3 synthases. In Northern
blot experiments the cDNA detected a single specific GD3 synthase mRNA of about
9.0 kb both in the chicken brain and retina. The abundance of the specific mRNA
transcript declined steadily from E7-E9 to very low values around PN2. The levels
of enzyme activities measured at the same developmental stages roughly followed
the changes of specific mRNA levels in both tissues. In situ hybridization of
embryonic neural retina cells in culture showed that both glial- and neuron-like
cells expressed the specific GD3 synthase mRNA, although with different
intensities. Results indicate that transcription and/or stability of the specific
GD3 synthase mRNA constitute a level of control of the expression of GD3 synthase
and indirectly of the ganglioside composition in the developing chicken central
nervous system (CNS).
PMID- 9402228
TI - Valproic acid suppresses G1 phase-dependent sialylation of a 65kDa glycoprotein
in the C6 glioma cell cycle.
AB - The influence of valproate on in vitro glycosylation events in C6 glioma has been
investigated, as this major human teratogen restricts proliferation in the mid-G1
phase of the cycle and alters the prevalence and/or glycosylation state of cell
surface glycoproteins with the potential to mediate cell-cell and cell matrix
interactions critical to development. C6 glioma cultured continuously in the
presence of 1 mM valproate exhibited a significant depression of exponential
growth but attained confluency one day later, when the majority of cells entered
the G1 phase of the cycle. Glycoprotein sialyltransferase, which exhibited a four
fold increase during exponential growth and a small decrease at confluency, was
markedly attenuated in valproate-exposed cells in a manner which was indirect.
This was associated with an inhibition of transient alpha2,3 sialylation of a 65
kDa glycoprotein expressed maximally at 4 hr into the G1 phase of the cell cycle.
This effect was cell-cycle phase-specific, as exposure of synchronized cells to
valproate inhibited transient sialylation at 4 and 5 hr into the G1 phase.
Inhibition of the 65 kDa glycoprotein sialylation by valproate is suggested to
arise from impaired signal transduction preceding the eventual arrest by the drug
at a 5-6 hr G1 phase restriction point.
PMID- 9402229
TI - Differential effect of taurine and serotonin on the outgrowth from explants or
isolated cells of the retina.
AB - The sulfur amino acid taurine and the indoleamine serotonin increases and
decreases, respectively, the outgrowth from goldfish retinal explants. Taurine
seems to be acting, at least partially, through an increase in calcium fluxes,
and the serotonin-inhibiting effect appears to be mediated by serotonin1A
receptors and cAMP. Isolated cells of postcrush goldfish retina and of retina
from 5-day-old rats were cultured in the presence of taurine or serotonin. In the
goldfish, the classical morphology of postcrush ganglion cells was observed. An
antibody against the glycoprotein Thy-1 labelled three types of cells in the
cultures of goldfish retina. The number of cells outgrowing and the length of the
main neurite was measured at 5 days in culture in both species. The number of
cells presenting neurites was increased in the goldfish retina by the addition of
taurine, and decreased by serotonin. However, the length of the neurites was
unaffected by the addition of the modulators. In the rat, only a slight decrease
in the number of cells outgrowing was observed in the presence of serotonin. The
incorporation of [3H]thymidine was not modified after 5 days in culture in the
presence of taurine or serotonin, either in the goldfish or in the rat retina.
The antibody Thy 1.1 can label retinal cells of the goldfish in vitro, one of
them being ganglion cells. The trophic effect exerted by taurine in the postcrush
goldfish retina needs the integrity of the tissue favoring the interaction of
cells and factors, because outgrowth increases in retinal explants, but not in
isolated cells.
PMID- 9402230
TI - In vitro pattern formation during neurogenesis in neuroectodermal progenitor
cells immortalized by p53-deficiency.
AB - In vitro neural differentiation was induced in a p53-deficient immortalized
neuroectodermal progenitor cell line, NE-4C, by treatment with retinoic acid [K.
Schlett and E. Madarasz (1997) J. Neurosci. Res. 47, 405-416]. Rearrangement of
nestin filaments was an early marker of neuron-formation. The increase in
neurofilament protein content was accompanied by a decrease in the expression of
nestin filaments in induced precursors. Cells with astroglial features appeared
with a delay of 4-5 days compared to the appearence of neurons. Future neurons
were sorted out from the substrate-attached population of apparently non-induced
cells. The sorting out of future neurons resembled the separation of neural
precursors in vivo. The continuous changes in the shape and also in the position
of the cells resulted in the formation of characteristic morphological patterns.
On the basis of morphological changes, five characteristic stages of in vitro
neural differentiation were distinguished. The analysis of the morphological
changes revealed that cell-to-cell interactions played an essential role in the
cell fate decision made by induced precursors. Our observations indicate that the
NE-4C cell line can serve as an in vitro model to investigate some early steps of
neurogenesis.
PMID- 9402231
TI - Developmental pattern of plasminogen activator activity in chick optic lobe.
AB - Plasminogen activators are serine proteases which play a key role in
morphogenesis and tissue remodelling. Two different molecular types, tissue-type
and urokinase-type, were identified and they were postulated to play a role in
neural development. The developing chick optic lobe plays a central role in
processing visual information. In previous studies we demonstrated the occurrence
of high levels of plasminogen activator activity in this model. The aim of the
present paper is to study the temporal pattern of expression of this activity and
characterize the type of plasminogen activator expressed in the developing optic
lobe. Using soluble fractions derived by ultracentrifugation from Triton X-100
treated membrane fractions we measured the protease activity with a radial
fibrinolytic assay. Employing different inhibitors of fibrinolytic activity and a
zymographic assay, we showed that the developing optic lobe expresses only one
type of plasminogen activator which corresponds to an urokinase-type of 70 kDa.
Our results indicate that peaks of protease activity temporally correlate with
massive neuronal migration, neurite outgrowth and synapse formation and
maturation. This suggests that a plasminogen activator could play a role in these
developmental events. This consistent pattern of variability strongly suggests
that it is developmentally regulated and, if so, it could be a reliable parameter
to study neural plastic changes induced by modifications in the environmental
stimulation.
PMID- 9402232
TI - Development of the tecto-thalamic projection neurons and the differential
expressions of calcium-binding proteins in the rat.
AB - We studied expression of calbindin-D 28 K and parvalbumin in tecto-thalamic
projection neurons and during the formation of their tecto thalamic projections
using a double-labeling with Fluoro-Gold. To discern the completion of these
projections, Fluoro Gold, an opalescent fluorescent dye, was injected into the
dorsal lateral geniculate and/or the lateral posterior nucleus in rats of various
ages from neonates to adults. After one day's survival, the brains were removed
and sections of the brain were immunohistochemically processed using Cy3, a red
fluorescent dye, as a marker for calbindin-D 28 K or parvalbumin. The three types
of tecto thalamic neurons, which have been described previously in the adult
rats, were identified in the present study. The results revealed that in
developing rats: 1) A population of medium-sized neurons (the presumed pyriform
cells) express calbindin-D 28 K as early as the day of birth prior to the
formation of their tecto thalamic projection that occured on postnatal day 4.
Most (over 90%) of them project to the dorsal lateral geniculate nucleus; 2) A
population of large neurons (the presumed wide-field vertical cells) express
calbindin-D 28 K on postnatal day 7, and most of them (over 90%) project to the
lateral posterior nucleus; 3) Another population of medium-sized neurons (the
presumed narrow-field cells) express parvalbumin on post-natal day 17, but only a
half (45%) of them project to the dorsal lateral geniculate nucleus. In the
developing nervous system, calcium ions play important roles in the biological
and molecular events underlying neural development. Changes in the free
intracellular calcium ion level, indicating neuronal activity has been reported
to be correlated with onset of calbindin-D 28 K or parvalbumin-immunoreactivity
that participate in the regulation of intracellular calcium homeostasis in
neurons. Therefore, the present findings may reflect distinct developmental
events in the different classes of tectal relay neurons that form parallel visual
pathways, but which have such different functions as the detection of luminance,
discrimination of direction, and the detection of fast movements.
PMID- 9402233
TI - An automated PACS image acquisition and recovery scheme for image integrity based
on the DICOM standard.
AB - The data quality and completeness of acquired images, which we refer to as
integrity, is considered as the most important requirement in the image
acquisition design of the Picture Archiving and Communication System (PACS). The
Digital Imaging and Communications in Medicine (DICOM) standard significantly
simplifies the task of acquiring radiological images from a DICOM compliant
imaging system into the PACS. However, human interaction with the imaging system
by changing the DICOM communication settings can result in missing images during
the PACS image acquisition. A scheme based on the DICOM Query and Retrieve (Q/R)
service class was developed to automatically identify and recover missing images.
In addition, grouping sequential scanned images such as a CT and MR image series
is another potential process that can miss images because of no indication of the
end of series. Two methods are presented for determining the end of series and
the pros and cons of each method are discussed in detail. Two experiments in a
real clinical environment were conducted; one with and one without the Q/R
implementation. The statistical results indicate two highlights from this work.
First, the Q/R scheme faithfully recovered all missing images caused by human
interaction with the DICOM compliant imaging system. Second, there was no single
image slice missed when grouping slices into a series using the presented
grouping algorithm in the two experimental periods.
PMID- 9402234
TI - "Follow-up" method for processing of brain function MR images.
AB - FMRI with standard 1.5 T scanners requires adapted algorithms because the time
course of intensity signal showed a non-linearity of the baseline. The protocol
contains sequential images covering periods of rest followed periods of
stimulation. The images of each period of rest and stimulation were averaged,
offering a series of averaged images. From this series, we conserved only the
pixels which presented the alternated variations corresponding to the temporal
pattern of the paradigm. A colour scale was used to present the average
percentage of variations of each pixel selected. We have performed activation
paradigms with a classical motor protocol. This simple "follow-up" method appears
effective for the identification of activated areas.
PMID- 9402235
TI - TAGASIST: a post-processing and analysis tools package for tagged Magnetic
Resonance Imaging.
AB - The Magnetic Resonance Imaging technique myocardial tagging allows the tracking
and measurement of local parameters of heart wall motion. Tagging provides
detailed information about regional cardiac function never before available with
non-invasive techniques. The growth of this technique has been limited in part by
the availability of post-processing tools. We introduce the TAGged cine AnalySIS
Tools package (TAGASIST) for the processing of images from this technique.
TAGASIST includes a graphical user interface for image segmentation, kinematic
analysis, plotting of regional averages as well as multiple subjects (or patient
populations) simultaneously, statistical analysis, and a database of all studies
processed.
PMID- 9402236
TI - Maxillary sinus inflammatory disease: ultrasound compared to computed tomography.
AB - Fifty-six patients (age range, 15-79 yr, average, 37.0+/-18.5 yr), with a
clinical and/or radiological diagnosis of acute maxillary sinusitis, were
prospectively studied with ultrasound (US) and computed tomography (CT). The
imaging finding which supported the diagnosis of acute sinusitis with US was the
identification of the hyperechoic posterior antral wall through the hypoechoic
inflammation. The findings were compared to CT (3 mm axial sections). The
sensitivity of US for maxillary sinus disease was found to be 66.7% and the
specificity was 94.9%, which were similar to the plain film ones (65.2 and 96.8%,
respectively). The results of the present study suggest US as the method of first
choice for acute sinusitis of the maxillary antra, particularly for children and
pregnant women.
PMID- 9402237
TI - Dynamic MR imaging of splenic tumor.
AB - Inflammatory pseudotumor and hemangioma of the spleen are rare benign tumors, and
MRI findings of splenic diseases have been reported only rarely. We recently
observed three patients with inflammatory pseudotumor and hemangioma of the
spleen. Abdominal ultrasonography, computed tomography (CT), magnetic resonance
imaging (MRI) and angiography demonstrated within the enlarged spleen. MRI and
dynamic MRI after administration of gadolinium DTPA provide the characterization
of the splenic tumor.
PMID- 9402238
TI - Invasive adenocarcinoma of the uterine cervix: MR imaging.
AB - The detection of adenocarcinoma of the cervix is difficult in clinical
examination, leading to poor prognoses. We evaluated MR appearances of 23
patients with adenocarcinoma of the cervix and appearances of 65 patients with
cervical SCCs were also evaluated for comparison. Both T2-weighted spin echo,
dynamic and postcontrast Gd-DTPA enhanced techniques were obtained at a 1.5 Tesla
MR unit. The results of our study showed that adenocarcinoma of the cervix have
MR imaging features which may permit distinction from SCCs which include: large
tumors with preservation of endocervical epithelium, lesser contrast enhancement,
and greater enhancement of the tumor periphery. Understaging may be more
problematic with adenocarcinoma than SCC.
PMID- 9402239
TI - Multiple, small, intracranial arachnoid cysts.
AB - Arachnoid cysts are CSF-filled intraarachnoidal collections. They are most
commonly located in the middle cranial fossa followed by suprasellar and
quadrigeminal cisterns, posterior fossa, cerebral convexities, and
interhemispheric fissure. We report an incidental, exceptional case with the
coexistence of multiple arachnoid cysts in five different locations including two
in the middle cranial fossae, and the other three in the retroclival region,
quadrigeminal cistern, and cerebral convexity.
PMID- 9402240
TI - Definitive diagnosis of enzymatic deficiencies of steroidogenesis in at-risk
newborns and infants by urinary marker analysis using GC/MS-SIM.
AB - A simplified urinary marker analysis for diagnosis of congenital adrenal
hyperplasia (CAH) and 5alpha-reductase deficiency in infancy by GC/MS-SIM is
introduced. The analysis was performed in 161 patients aged 3-90 days, 99 females
and 62 males. CAH due to 21-hydroxylase deficiency was diagnosed in 61 patients
(42 females and 19 males; in 10 cases simple virilizing form and in 51 patients
salt-wasting form) and CAH induced by 3beta-hydroxysteroid dehydrogenase
deficiency without salt loss in 1 female patient. In 2 full-term newborns and 6
preterm infants, a false-positive diagnosis of CAH, which had been based on serum
steroid evaluation, was made. In these cases, increased excretion of fetal
adrenal zone steroids was confirmed as a possible source of false-positive serum
11-deoxycortisol and 17alpha-hydroxyprogesterone values. Lack of fetal adrenal
zone steroid metabolites in 2 male newborns with salt loss symptoms led to the
diagnosis of adrenal insufficiency due to X-linked adrenal hypoplasia and adrenal
hemorrhage. A single analysis of urinary CAH markers by the very sensitive and
selective GC/MS-SIM method can replace numerous assays of various steroids that
must be carried out for positive diagnosis of abnormal steroidogenesis in
infancy.
PMID- 9402241
TI - Measurement of serum exon 3-retaining growth hormone-binding protein in children
and adolescents by radioimmunoassay.
AB - Recently described assays for the determination of growth hormone-binding protein
(GHBP) show a wide variety of normal ranges. Their results depend on the assay
design and in the case of ligand-immunofunctional assay (LIFA), probably also on
the binding characteristics, i.e. epitope specificity and affinity of the
employed antibody. These facts underline the necessity to look for more accurate
and specific assays. In this report we describe an accurate and simple
radioimmunoassay (RIA) which allows the specific quantitation of the exon 3
retaining GHBP isoform (E3-GHBP). Data of the E3-GHBP RIA were compared to those
of a LIFA measuring undifferentiated functional forms of GHBP. Our results
demonstrate significant relationships between GHBP and age, BMI and IGF-I as
determined by RIA and by LIFA in normal children and adolescents (n = 115, p <
0.001). Moreover, BMI is the only regulating factor of GHBP for both methods as
shown by multiple regression analysis (p < 0.001). All our data suggest a
qualitatively paralleled regulation of E3-GHBP and undifferentiated functional
GHBP forms. This finding was confirmed by a good correlation between RIA and LIFA
data (r = 0.74, p < 0.001). Children with idiopathic short stature (ISS, n = 47)
had significantly lower GHBP levels than normal controls (n = 58) measured by the
E3-GHBP RIA (p < 0.0001) and by LIFA (p < 0.01). We conclude that (1) ISS
children may have a structural or quantitative defect at the level of the GHR,
and (2) the highly specific assay for E3-GHBP immunoreactivity provides a
sensitive diagnostic tool in conditions with partial GH insensitivity.
PMID- 9402242
TI - Growth before and during growth hormone treatment in children operated for
craniopharyngioma.
AB - Height and weight growth before and during treatment with human growth hormone
(hGH) was studied in 46 Dutch patients treated for craniopharyngioma. Weight was
expressed as body mass index (BMI, weight/height). At the time of tumor treatment
mean +/- SD height standard deviation score (SDS) was -1.22 +/- 1.38 and BMI SDS
was 0.56 +/- 1.32. The initial height SDS was inversely related to age (r =
0.38; p < 0.02). Before hGH treatment height SDS decreased to - 1.57 +/- 1.08 (p
< 0.05) and BMI SDS increased to 1.54 +/- 1.58 (p < 0.005) during the first year
after tumor treatment. Changes in height SDS correlated positively with basal
prolactin (PRL) levels (r = 0.46; p < 0.05). Neither tumor localization nor
treatment mode was related to changes in height SDS and BMI SDS. Forty patients
were treated with hGH, started a median interval of 2.0 years after tumor
treatment. At the time of the start of hGH treatment height SDS in these patients
was -1.70 +/- 1.13, and BMI SDS was 1.44 +/- 1.79. During treatment with hGH,
height SDS increased to -1.05 +/- 1.10 (p < 0.001) in the first, and to -0.80 +/-
1.04 (p < 0.001) in the second year. BMI SDS did not change during hGH therapy.
In conclusion, there is a large variation in height SDS and BMI SDS at the time
of initial presentation as well as during spontaneous growth after tumor
treatment. Spontaneous growth is related to serum PRL concentrations. Treatment
with hGH significantly increased height SDS during the first 2 years, whereas BMI
SDS did not change.
PMID- 9402243
TI - Androstenedione, dehydroepiandrosterone sulfate, and estradiol levels throughout
female puberty: relation to height velocity.
AB - Sex steroids are important contributors to the pubertal growth spurt. Both
androgens and estrogens have been related to this moment of rapid growth, but the
role of estrogens is thought to be the most important one. Since exogenous
estrogens are not capable to induce an appropriate growth spurt in girls, there
might be an additional contributing factor involved. In a recent pilot study of
32 healthy pubertal girls, we found that the peak height velocity (HV) is
preceded by relatively high levels of dehydroepiandrosterone sulfate and
androstenedione (delta4A) as compared with the end-pubertal level. In the present
study we evaluated HV in relation to dehydroepiandrosterone sulfate and delta4A
levels in 149 healthy girls of various Tanner stages. HV was correlated with
delta4A and estradiol levels in Tanner stages I-III. These results suggest that,
like estrogens, delta4A might be an important stimulator of the female growth
spurt.
PMID- 9402244
TI - Concomitant evaluation of plasma galanin and catecholamine levels during a cold
pressor test in healthy human male and female subjects.
AB - The neuropeptide galanin (GAL) is localized in the peripheral and central nervous
systems as well as in the adrenal medulla where it coexists with catecholamines.
We evaluated the changes in GAL plasma levels as well as systolic and diastolic
blood pressures and in the plasma levels of epinephrine and norepinephrine (NE)
in normal human male and regularly menstruating female subjects during the
activation of the sympathoadrenal system by a cold pressor test. The test was
performed by immersing the hand of the subject in 1 degree C cold water for 4
min. Blood samples were collected both under basal conditions and at subsequent
intervals during the cold stimulus as well as at the end of the recovery phase.
The values were compared with those obtained when the same subjects were sham
tested. As expected, systolic and diastolic blood pressures increased in both
sexes during the cold test; the systolic blood pressure values were significantly
(p < 0.05) higher in males. Epinephrine and NE levels rose significantly above
baseline in both male and female subjects after the cold stimulus; the NE
increments were significantly (p < 0.05) higher in males. The basal GAL levels
were found to be variable but not sexually dimorphic. In both sexes, during cold
stimulus and recovery phase, GAL values were found to be not significantly
different from those detected during the sham test. These results demonstrate
that the release of GAL in peripheral blood is not associated with that of
catecholamines in response to the cold pressor test.
PMID- 9402245
TI - Final height after growth hormone therapy in short children: correlation with
siblings' height.
AB - Sixteen prepubertal children (10 males, 6 females) were treated with growth
hormone (GH) 0.75 U/kg/week for 4-5 years until final height was attained. Before
initiation of GH therapy height was below 2 SDS for age and gender, growth
velocity was <4.5 cm/year, bone age was more than 2 SD below the mean for age,
and the GH response to provocative tests was more than 10 microg/l. The final
height of 9 patients exceeded their predicted and target heights. The final
height of the treated patients was highly correlated with their siblings' heights
(r = 0.806, p < 0.001) and to a lesser degree with the target or the predicted
height (r = 0.401, p = 0.124 and r = 0.465, p = 0.06, respectively). It is
concluded that the secular trend should be taken into consideration when
evaluating the success of GH therapy.
PMID- 9402246
TI - Surface changes of ram spermatozoa by adsorption of homologous and heterologous
seminal plasma proteins revealed by partition in an aqueous two-phase system.
AB - Ram spermatozoa freed from seminal plasma by a dextran 'swim-up' procedure were
incubated with Tween 20 and fractionated into motile (PEG-rich) and stationary
(dextran-rich) fractions by centrifugal countercurrent distribution (CCCD) in an
aqueous dextran-Ficoll-polyethylene glycol (PEG) two-phase system. Increasing
concentrations of Tween 20 resulted in greater amounts of extracted protein and
lower cell viability. Addition of bull seminal plasma increased the proportion of
live cells, whereas ram seminal plasma increased the proportion of stationary
cells. Proteins isolated from each type of seminal plasma restored the CCCD
profile of treated spermatozoa to the right, this effect being reduced when
proteins were thermally denatured. Bovine serum albumin induced a slight
displacement to the left. No restoration of profile was achieved when ram
spermatozoa were exposed to proteins from bull seminal plasma in the presence of
protein-free ram seminal plasma. Adsorption of seminal plasma proteins by
spermatozoa previously stripped of surface proteins by exposure to detergent
reversed the detergent effect on motility. The findings are consistent with the
concept that ram seminal plasma contains a factor that interferes with protein
adsorption on the cell surface and prevents the protective effect of seminal
plasma proteins on maintenance of cell viability.
PMID- 9402247
TI - Nitric oxide mediates human chorionic gonadotrophin-induced prostaglandin E
generation in rat oocyte-cumulus complexes.
AB - To determine whether nitric oxide (NO) generation mediates human chorionic
gonadotrophin (hCG)-induced prostaglandin E (PGE) secretion by oocyte-cumulus
complexes (OCC), the secretion of PGE by cultured rat OCC in the presence of NO
donors and NO synthase (NOS) inhibitors was characterized. NO donors (sodium
nitroprusside and 3-morpholino-sydnonimine-hydrochloride) increased PGE
accumulation in OCC to values similar to those obtained in the presence of hCG.
The three NOS inhibitors tested (NG-nitro-L-arginine methyl ester, NG-monomethyl
L-arginine and aminoguanidine) prevented the hCG-induced PGE accumulation in
cultured OCC. This effect appears to be specific since D-enantiomers NG-nitro-D
arginine methyl ester and NG-monomethyl-D-arginine had no effect. The present
results suggest that NO mediates the hCG-induced accumulation of PGE in rat OCC,
a process which may occur in vivo in preovulatory follicles prior to ovulation.
PMID- 9402248
TI - Characterization and proteolytic activity of a cathepsin L-like polypeptide in
endometrium and uterine flushings of cycling, pregnant and steroid-treated
ovariectomized gilts.
AB - Cathepsin L has been proposed to be involved with the endothelial-chorial type of
placentation in the cat. Little information concerning the presence and secretion
of cathepsin L is available for a species with noninvasive epitheliochorial
placentation such as the pig. Cathepsin L activity in uterine flushings and
endometrium from gilts during different days of the oestrous cycle and early
pregnancy was analysed through specific substrate metabolism and Western blot
analyses with antiserum against cat endometrial cathepsin L. This antiserum was
utilized to determine the cellular localization of the enzyme within porcine
endometrium. Cathepsin L activity within uterine flushings was elevated on Day 15
of the oestrous cycle and early pregnancy, with activity declining on Day 18. Cat
cathepsin L antiserum cross-reacted with a group of 46, 40 and 38 kDa uterine
proteins and detected a product within the surface and glandular epithelium of
the endometrium. The appearance of the 40 kDa protein was first detected on Day
10 of the oestrous cycle with the 38 kDa proteins appearing on Day 15 and 18 of
pregnancy. The 40 and 38 kDa uterine proteins appear to be steroid regulated as
12 days of progesterone administration is necessary to detect the proteins and
cathepsin L activity.
PMID- 9402249
TI - Localization and synthesis of collagen types III and V during remodelling and
decidualization in rat uterus.
AB - Uteri of pregnant rats on Days 6, 7 and 8 of pregnancy were studied to determine
the histochemical distribution of collagen types III and V and the incorporation
of [3H]glycine into fibrillar collagens during the period of embryonic
implantation. Types III and V had a similar distribution in the non-decidual
stromal region and muscle layers in implantation sites. They were found to have
very low levels in the primary decidual tissue on Day 6 and were not detected in
developing decidual tissues on Days 7 or 8. Following injection of labelled
glycine, collagen was extracted and the specific activity of the collagens
determined by fluorography and 3H incorporated into the collagen bands in the
gels. It was found that incorporation of label into both types I and III was
similar (33.4+/-12.0 and 31.8+/-18.1 cpm microg-1 collagen respectively) but 3.5
times that of type V (7.7+/-5.3 cpm microg-1). These studies suggest that
although fibrillar collagens are metabolized or redistributed in the growing
decidual tissue, they are incorporated rapidly into the extracellular matrix
during remodelling of the outer stroma and muscle tissues.
PMID- 9402250
TI - Perifusion culture system for bovine embryos: improvement of embryo development
by use of bovine oviduct epithelial cells, an antioxidant and polyvinyl alcohol.
AB - Three experiments were conducted in an attempt to improve a continuous flow
perifusion system capable of maintaining embryo development for long periods of
time. Bovine embryos (8-16 cells) obtained from static co-culture with cumulus
cells in a serum-free medium were perifused in an ACUSYST-S cell culture
incubator. Culture chambers of the incubator consisted of a 0.2-mL unit (Chamber
1) connected to a 1.5-mL unit (Chamber 2), with the outflow from Chamber 1 routed
to the inlet to Chamber 2. A bovine embryo culture medium supplemented with 3 mg
mL-1 bovine serum albumin (BSA) and 25 mM HEPES was used as a perifusion culture
medium (PCM). Embryos were perifused in Chamber 2 for 24, 48 and 72 h and further
co-cultured in a static system up to 216 h after insemination. In Experiment 1,
conditioning PCM with frozen-thawed bovine oviduct epithelial cells (BOEC) placed
in Chamber 1 enhanced (P < 0.05) blastocyst formation of embryos in Chamber 2,
after 24, 48 and 72 h of perifusion culture. The proportion of blastocysts was
not further increased by placing BOEC in Chamber 2 along with the embryos. In
Experiment 2, embryos were perifused with PCM conditioned with BOEC in Chamber 1
for 48 h or 72 h. A higher proportion of perifused embryos developed to the
blastocyst stage after addition of 25 U mL-1 or 50 U mL-1 of superoxide dismutase
(SOD) to PCM than in its absence. However, blastocyst formation of embryos
perifused for 72 h was not increased after addition of 50 U mL-1 SOD compared
with its absence. In Experiment 3, the proportions of morulae and blastocysts
were not decreased by replacement of 3 mg mL-1 BSA with 1 mg mL-1 polyvinyl
alcohol (PVA) in a BOEC-conditioned medium containing 50 U mL-1 SOD after
perifusion for 48 h. In conclusion, PCM conditioning with BOEC and addition of an
antioxidant to the perifusion medium improved the developmental capacity of
perifused embryos. PVA is an adequate replacement for BSA in the perifusion
medium.
PMID- 9402251
TI - Isolation, characterization and radioimmunoassay of luteinizing hormone in the
brushtail possum.
AB - Luteinizing hormone (LH) was purified from brushtail possum (Trichosurus
vulpecula) pituitary glands. The purification procedure consisted of ammonium
sulfate precipitation followed by triazinyl-dye chromatography, hydrophobic
interaction chromatography and gel filtration. A yield of 10 microg LH g-1
pituitary with a recovery of 20% was obtained from 1400 pituitary glands (20.3
g). Contamination with possum follicle-stimulating hormone (FSH) was < or =0.05%.
The amino acid analysis and the N-terminal sequencing for 10 cycles revealed
close homology with LH from other mammals. Minor amounts of LH that had been
truncated near the N-terminal were also detected. No contaminating proteins were
found by amino acid sequencing. The potency of possum LH was 20% that of ovine LH
in a receptor assay using possum testicular receptors and 4% that of ovine LH
when bovine corpora lutea receptors were used. Possum LH was able to stimulate
production of cyclic adenosine 3',5'-monophosphate by bovine granulosa cells. A
radioimmunoassay (RIA) for possum LH using 125I-possum LH and an antiserum raised
against ovine LH was developed. The RIA has a sensitivity of 0.15 ng mL-1, a 50%
displacement of 1.9 ng mL-1 and a cross-reactivity of <0.02% against possum FSH.
Plasma concentrations were 0.24+/-0.04 ng mL-1 (n = 8) and 0.39+/-0.12 ng mL-1 (n
= 8) in female and male possums respectively. Administration of mammalian
gonadotrophin-releasing hormone (GnRH) and chicken GnRH II stimulated increases
in plasma LH concentrations in male and female possums. When comparing LH
responses with administration of mammalian GnRH or chicken GnRH II, plasma LH
concentrations remained elevated for a longer period of time in males than in
females (P < 0.01); plasma LH concentrations also remained elevated for longer
after mammalian GnRH than after chicken GnRH II (P < 0.01). Gonadectomy
stimulated an increase in plasma concentrations of LH in both male (P < 0.01) and
female (P < 0.05) possums. The rate of increase in plasma LH concentrations in
males was faster than that in females. In summary, we have purified, partially
characterized, and developed a RIA for possum LH.
PMID- 9402252
TI - Effects of pivalic acid and sodium pivalate on L-carnitine concentrations in the
cauda epididymidis and on male fertility in the hamster.
AB - In this study, administration of pivalic acid or its sodium salt was found to
decrease the L-carnitine concentration in the epididymal lumen of the hamster; it
also tested whether this decrease affected sperm cell motility, chromatin
structure, or fertilizing capacity. Provision of pivalic acid or its sodium salt
(20 mM or 40 mM) in the drinking water of mature male golden hamsters for 30 days
reduced (by 72%, 75%, and 83% in three experiments) the L-carnitine concentration
of the cauda epididymidis but did not inhibit sperm chromatin condensation, as
assessed by flow cytometry. The treatments did not alter the location of motile
sperm in the epididymidis nor did they appreciably affect the motility of sperm
obtained from the distal cauda epididymidis. The numbers and percentage of ova
that reached the 2-cell stage 36-40 h after uterine insemination with spermatozoa
from control and treated hamsters served as a measure of sperm fertility.
Treatment with pivalic acid or sodium pivalate did not render male hamsters
infertile although it appeared to reduce the fertilizing ability of their
spermatozoa. These results suggest that the high concentration of L-carnitine
present in the lumen of the cauda epididymidis is not required for maturation of
sperm chromatin or development of sperm motility.
PMID- 9402253
TI - Evidence that nitric oxide synthase is involved in progesterone-induced acrosomal
exocytosis in mouse spermatozoa.
AB - In a recent work, we detected nitric oxide synthase (NO synthase) in the acrosome
and tail of mouse and human spermatozoa by an immunofluorescence technique. Also,
NO-synthase inhibitors added during sperm capacitation in vitro reduced the
percentage of oocytes fertilized in vitro, suggesting a role for NO synthase in
sperm function. Therefore, in the present study the effect of three NO-synthase
inhibitors, NG-nitro-L-arginine methyl ester (L-NAME), NG-nitro-D-arginine methyl
ester (D-NAME) and L-NG-nitro-arginine (NO2-arg), and of a nitric oxide donor,
spermine-NONOate, on the progesterone-induced acrosome reaction of mouse sperm
was examined. NO-synthase inhibitors were added at 0, 60 or 90 min during
capacitation; at 120 min, mouse epididymal spermatozoa were exposed to 15 microM
progesterone for another 15 min. In another set of experiments, different
concentrations of spermine-NONOate were added to capacitated spermatozoa for 15
min; in these experiments, progesterone was not included. NO2-arg and L-NAME
blocked progesterone-induced exocytosis regardless of the time at which these
inhibitors were added. Moreover, D-NAME did not inhibit exocytosis. In contrast,
spermine-NONOate stimulated the acrosomal exocytosis in vitro directly. These
results provide evidence that mouse sperm NO synthase participates in the
progesterone-induced acrosome reaction in vitro and that nitric oxide induces
this event.
PMID- 9402254
TI - Effect of cytochalasin B and cycloheximide on the activation rate, chromosome
constituent and in vitro development of porcine oocytes following parthenogenetic
stimulation.
AB - Activation rate, chromosome constituent and developmental pattern of porcine
oocytes was examined in the presence and absence of cytochalasin B and
cycloheximide following parthenogenetic stimulation. Treatment with cycloheximide
after ethanol or Ca2+ ionophore treatment increased the incidence of activation.
The percentage of oocytes with two or more female pronuclei was higher (P < 0.05)
in oocytes treated with cytochalasin B than in control or cycloheximide-treated
oocytes. Treatment with both electrical stimulation and cytochalasin B increased
the incidence of diploid chromosome spreads, and accelerated development to the
morula and blastocyst stage compared with the control and cycloheximide-treated
groups, suggesting a role of ploidy in the development of parthenote.
PMID- 9402255
TI - Effects of passive immunization against oestradiol-17beta and inhibin on the
secretion of gonadotrophin in the cyclic golden hamster (Mesocricetus auratus).
AB - To investigate the physiological importance of oestradiol-17beta and inhibin in
the regulation of gonadotrophin secretion in the cyclic golden hamster, females
were passively immunized against two hormones. When 200 microL antiserum against
oestradiol-17beta (oestradiol-AS) was given on Day 3 (Day 1 = day of ovulation),
the preovulatory gonadotrophin surge was completely blocked for 24 h and the
length of the oestrous cycle was also prolonged for one day. In the group given
200 microL oestradiol-AS on Day 3, basal levels of follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) increased slightly and superovulation (19.6+/
0.8, mean+/-s.e.m.) occurred. When 200 microL antiserum against inhibin (inhibin
AS) was given at 1100 hours on Day 3, a dramatic increase in plasma FSH and a
slight increase in LH were noted, resulting in superovulation (38.2+/-2.6) on the
expected Day 1. The present study indicates clearly that inhibin plays a major
role in regulating the specific ovulation rate in the hamster through the control
of FSH secretion. Present results also indicate that oestradiol-17beta suppresses
basal LH secretion. Oestradiol-17beta may act as an indicator of the follicular
maturation, and the high plasma concentration of oestradiol-17beta noted from Day
3 to Day 4 may play an important role in determining the timing of initiation of
the preovulatory gonadotrophin surge.
PMID- 9402256
TI - Collagen in the fetal membranes of sheep: changes throughout gestation and
effects of dexamethasone at 60 days.
AB - The tensile strength of fetal membranes is largely due to their collagen content.
In this study we have examined the changes in collagen in the amniotic and
allantoic membranes of the sheep over a wide gestational range (27-142 days of
gestation; term, 145-150 days). The results have been correlated with volume
changes in normal development, and in particular, the changes in allantois have
been studied after a rapid and extensive increase in allantoic volume, as a
result of maternal dexamethasone treatment (0.76 mg h-1 for 48 h) from Day 60 of
gestation. Electron microscopy and immunohistochemistry were used to delineate
collagen distribution, and gel electrophoresis was used to assess the relative
proportions of each type. In the amnion, collagen content increased from 37 +/-
4% to 50 +/- 1% dry weight of the tissue from 41-102 days and declined slightly
thereafter. In the allantois, collagen content increased from 20 +/- 1% at Day 27
to 50 +/- 6% at Day 142, significantly correlated with a volume increase from 25
+/- 3 mL to 813 +/- 274 mL. Collagen types I (>85%), III (10%) and small amounts
of types IV and V (<5%) were identified in both membranes at all ages. When
allantoic fluid volume was increased rapidly by maternal dexamethasone infusion,
there was a significant decrease in collagen content from 38 +/- 6% to 25 +/- 2%
(P < 0.05). By immunohistochemistry it was observed that both epithelial cells
and fibroblasts were synthesizing collagen.
PMID- 9402257
TI - Male-dependent variability of fertilization and embryo development in two bovine
in vitro fertilization systems and the effects of casein phosphopeptides (CPPs).
AB - This study investigated the effects of semen from five different bulls and two
different ejaculates of the same bull on penetration, cleavage, blastocyst
formation, and cell allocation in bovine blastocysts produced in vitro. Casein
phosphopeptides (CPPs) were tested for their ability to enhance fertilization and
minimize variability among bulls and ejaculates. In Experiment 1, the BO
fertilization system was employed. Penetration and polyspermy both displayed
great variation among bulls and between ejaculates, whereas no significant
differences were observed in cleavage and blastocyst-formation rates. Similar
variability was observed in penetration, polyspermy, cleavage, blastocyst
formation rates and cell allocation and distribution when the two fertilization
systems, TALP and BO, were compared in Experiment 2. The BO-system supported
penetration and polyspermy better (P < 0.05) than the TALP-system, whereas the
TALP-system was superior (P < 0.05) in supporting cleavage and blastocyst
formation. Significant interactions existed between bulls and the fertilization
system employed. It is concluded that the success of in vitro fertilization is
markedly dependent on individual bulls as well as on ejaculates from the same
bull. CPPs are able to enhance penetration and embryo development in certain
bulls or ejaculates and thus contribute to reducing the degree of individual
variability, but they do not generally improve the success of bovine embryo
production in vitro.
PMID- 9402258
TI - Isolation and partial characterization of tammar wallaby luteinizing hormone and
development of a radioimmunoassay.
AB - Tammar wallaby (Macropus eugenii) luteinizing hormone (LH) was purified from
pituitaries collected from wild and captive populations by salt sequential
precipitation, ion exchange chromatography and gel filtration. Pituitary tissue
(5 g) yielded 1.8 mg of purified wallaby luteinizing hormone (ME-14B), as
verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).
A heterologous radioimmunoassay has been developed for measurement of LH in
plasma of marsupials using a monoclonal antibody raised against bovine LH
(518B7). This assay system was able to measure basal LH concentrations in male
and female tammars and detected a significant rise in plasma LH in response to
oestradiol benzoate in female tammars and luteinizing hormone-releasing hormone
(LHRH) in males. Parallel dose-response curves were also obtained from pituitary
extracts from four other species of marsupial (brushtail possum, Trichosurus
vulpecula; brown antechinus, Antechinus stuartii; kowari, Dasyuroides byrnei; and
Eastern pygmy possum, Cercartetus nanus) in this assay, which suggests its
usefulness in the measurement of LH in other marsupial species.
PMID- 9402259
TI - Why pre-eclampisa?
PMID- 9402260
TI - From birds and bees to babies? Can theories on genetic conflict aid the
clinician?
PMID- 9402261
TI - Cervical ripening in guinea-pigs after a local application of nitric oxide.
AB - In humans cervical ripening is an inflammatory reaction accompanied by an
infiltration of white blood cells and the remodelling of the extracellular
matrix. Similar changes occur in guinea-pigs during cervical ripening. Nitric
oxide (NO) is thought to be important in the maintenance of pregnancy because it
is synthesized by the uterus and inhibits contractility. Previous studies in rats
also demonstrated that an NO generating system is present in the cervix and is up
regulated during labour. We studied the local effect of the NO donor sodium
nitroprusside (SNP) on cervical ripening in guinea-pigs during advanced
pregnancy. SNP (5 mg/injection) was administered into the cervical canal in 0.2
ml phosphate-buffered saline containing 3% hydroxycellulose twice a day either
for 1 [on day 42 post coitum (p.c.)] or 2 consecutive days (days 42-43 p.c.; term
day 67 + 3 p.c.). The effects were assessed 24 h after treatment by both
extensibility measurements (force resistance to incremental stretch) and
morphological evaluation (light and electron microscopy after in-situ fixation).
The control animals were treated with the vehicle. In another experiment, the
guinea-pigs were subcutaneously (s.c.) treated on day 43 p.c. with either the
progesterone antagonist onapristone (3 and 10 mg/animal s.c.) or with
prostaglandin E2 (PGE2) (1 and 3 mg/animal s.c.) and the PGE2 analogue
sulprostone (0.03 and 0.1 mg/animal s.c.). The cervical extensibility was
measured 24 h later. One-day SNP treatment tended to reduce cervical resistance,
but not significantly, whereas 2 day treatment with SNP led to a significant
increase in cervical extensiblity (P < 0.05) with little effect on cervical
dilatation (indirect evidence of the absence of uterine contractions). The
effects on cervical resistance were comparable to those achieved with 10 mg
onapristone and high-dose prostaglandins (PG)s (3 mg PGE2 and 0.1 mg sulprostone)
treatment. An electron microscope study of the SNP-treated animals revealed a
dissolution of collagen fibres, stromal oedema, arterial dilatation, and the
infiltration of macrophages, lymphocytes and granulocytes. Numerous mast cells
were also present. The morphological effects of SNP were similar to those
observed during normal cervical ripening at term. We conclude that the local
application of a NO donor effectively induces cervical ripening without inducing
labour in pregnant guinea-pigs.
PMID- 9402262
TI - Splenocytes in early pregnancy promote embryo implantation by regulating
endometrial differentiation in mice.
AB - We have reported that i.v. administration of splenocytes prepared from early
pregnant mice promoted embryo implantation in pseudopregnant CD-1 (ICR) (closed
colony) mice. In this study, the similar effects of splenocytes were confirmed
using an inbred strain, BALB/c mice, and the mechanism was further investigated.
Splenocytes were prepared from pregnancy day 4 (P4-spl) and dioestrus mice (Di
spl), and supernatant of P4-spl suspension (P4-sup) was used as controls. On
pseudopregnancy day 2, splenocytes or supernatant were injected into caudal vein
or endometrial stroma of the recipient mice, and blastocysts were transferred
into the endometrial lumen. In both BALB/c and ICR strains, the implantation
rates per recipient with i.v. and intraendometrial injection were significantly
higher in P4-spl groups. Then, ICR mice were oophorectomized on pseudopregnancy
day 3. After 3 day progesterone supplementation, blastocysts were transferred
with i.v. injection of P4-spl and P4-sup, or s.c. oestradiol injection. Under
progesterone supplementation, successful implantations were observed in the P4
spl- and oestradiol-treated groups, but not in P4-sup-treated group. Reverse
transcriptase-polymerase chain reaction analysis revealed that messenger RNA
expression of leukaemia inhibitory factor in the uterus was induced by P4-spl and
oestradiol, but not by P4-sup. These findings showed that splenocytes of early
pregnant mice promote embryo implantation by regulating endometrial
differentiation.
PMID- 9402263
TI - Ontogeny of gonadotrophin and inhibin secretion in normal girls through puberty
based on overnight serial sampling and a comparison with normal boys.
AB - We measured luteinizing hormone (LH) and follicle stimulating hormone (FSH) by
immunofluorometric assays and alpha-inhibin by radioimmunoassay in serum sampled
every 10 min throughout the night (2100-0500 h) from 44 normal girls. Mean
overnight LH values rose log-linearly from a mean of 0.2 IU/l in prepubertal
girls to 3.0 IU/l in late pubertal girls. Log2 mean overnight FSH rose rapidly
through early puberty and then remained constant; mean FSH rose from 1.0 IU/l in
prepubertal girls to approximately 2.8 IU/l in Tanner III-V girls. Mean overnight
inhibin increased through puberty, rising from 151 ng/l in prepubertal girls to
432 ng/l in fully pubescent girls. Within each of the first three Tanner stages,
LH differed approximately 100-fold between the smallest and largest mean
concentrations but differed <10-fold within stages IV or V. Such within-pubertal
stage variability was less pronounced for FSH, which differed approximately 16
fold among Tanner I subjects and 4-10-fold at later stages, and for inhibin,
which varied approximately 4-fold within each Tanner stage. The frequency of LH
pulses during overnight sampling increased significantly during puberty, but the
frequency of FSH and inhibin pulses remained constant. We compared the results
from girls to those from 50 normal boys [Manasco et al. (1995) J. Clin.
Endocrinol. Metab., 80, 20462052]. At each pubertal stage, girls had
approximately the same mean overnight LH values as boys; girls had higher mean
overnight FSH, particularly during Tanner stages II-IV; and boys had mean
overnight alpha-inhibin immunoreactivity approximately 1.5 times that of girls at
each pubertal stage. Still, hormone concentrations for individuals of both sexes
intergraded at each pubertal stage.
PMID- 9402264
TI - Increased concentrations of renin, aldosterone and Ca125 in a case of
spontaneous, recurrent, familial, severe ovarian hyperstimulation syndrome.
AB - We report for the first time increased concentrations of aldosterone and renin in
a case of spontaneous, recurrent, familial, severe ovarian hyperstimulation
syndrome (OHSS). High concentrations of Ca125 were also found. Our patient was a
26 year old woman, gravida 2, para 1, affected by severe OHSS, who denied having
ever consumed any ovulation drug. Both the patient and her only sister had
suffered from a similar condition in their previous pregnancies. The patient was
treated with i.v. fluid therapy. Paracentesis was performed on one occasion. The
patient was dismissed after 25 days in good condition. Blood count and blood
chemistry confirmed the severity of the clinical picture. We conclude that
spontaneous OHSS, although very rare, may have been underestimated so far. It can
be recurrent and may also be familial. The intra-ovarian prorenin-renin
angiotensin system may play a role in its aetiopathogenesis.
PMID- 9402265
TI - Effect of disruption versus continuation of gonadotrophin-releasing agonist after
human chorionic gonadotrophin administration on corpus luteum function in
patients undergoing ovulation induction for in-vitro fertilization.
AB - Previous studies have described the luteolytic effect of gonadotrophin-releasing
hormone agonist (GnRHa) administered in the early luteal phase. The present work
was undertaken to compare in a prospective and randomized design the effect of
disruption versus continuation of daily GnRHa after human chorionic gonadotrophin
(HCG) administration on corpus luteum function in patients undergoing ovulation
induction for in-vitro fertilization (IVF). Two different studies were designed
and a total of 38 ovum donors, aged 23-30 years, were included. In the first
study, the effect of GnRHa on the early luteal phase of IVF-stimulated cycles was
investigated (n = 27); the patients were divided into two groups, according to
whether they stopped (n = 13) or continued with daily GnRHa injections (n = 14)
for an additional period of 15 days after HCG administration. Blood was drawn
from luteal phase days 2 to 6 (day 0 = day of HCG administration) and oestradiol
and progesterone concentrations were analysed. The second study focused on the
effects of continuation versus disruption of GnRHa administration in the mid-late
luteal phase. A similar design was employed including six patients who stopped
GnRH on day 0 and five other women who continued GnRHa for 15 days after HCG
administration. In this second study, blood was drawn from days 5 to 11 and
oestradiol, progesterone and luteinizing hormone (LH) concentrations were
analysed. IVF parameters were similar in both groups. The results indicate that
continuous GnRHa administration, after HCG injection, does not produce changes in
oestradiol, progesterone and LH concentrations in the early, mid- and late luteal
phases compared to those patients in whom GnRHa is discontinued at the day of HCG
administration. The present work demonstrates that, when ovulation induction is
performed, the corpus luteum is driven primarily by the HCG, regardless of the
administration or disruption of GnRHa in the luteal phase. This suggests that the
lack of differences between continuation versus disruption of GnRHa may be due to
the accumulation of the product over the previous 2-3 weeks of treatment.
PMID- 9402266
TI - Changes in serum concentrations of growth hormone, insulin, insulin-like growth
factor and insulin-like growth factor-binding proteins 1 and 3 and urinary growth
hormone excretion during the menstrual cycle.
AB - Few studies exist on the physiological changes in the concentrations of growth
hormone (GH), insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP)
within the menstrual cycle, and some controversy remains. We therefore decided to
study the impact of endogenous sex steroids on the GH-IGF-IGFBP axis during the
ovulatory menstrual cycle in 10 healthy women (aged 18-40 years). Blood sampling
and urinary collection was performed every morning at 0800 h for 32 consecutive
days. Every second day the subjects were fasted overnight before blood sampling.
Follicle stimulating hormone, luteinizing hormone (LH), oestradiol, progesterone,
IGF-I, IGFBP-3, sex hormone-binding globulin, dihydroepiandrosterone sulphate and
GH were determined in all samples, whereas insulin and IGFBP-1 were determined in
fasted samples only. Serum IGF-I concentrations showed some fluctuation during
the menstrual cycle, with significantly higher values in the luteal phase
compared to the proliferative phase (P < 0.001). Mean individual variation in IGF
I concentrations throughout the menstrual cycle was 13.2% (SD 4.3; range 0.1
18.3%). There were no cyclic changes in IGFBP-3 serum concentrations and no
differences in IGFBP-3 concentrations between the luteal and the proliferative
phases. Mean individual variation in IGFBP-3 concentrations throughout the
menstrual cycle was 8.8% (SD 2.7; range 3.2-14.1). IGFBP-1 concentrations were
inversely associated with insulin concentrations, and showed a significant pre
ovulatory increase that returned to baseline at the day of the LH surge. Fasting
insulin concentrations showed large fluctuations throughout the menstrual cycle
without any distinct cyclic pattern. No cyclic changes in urinary GH excretion
during menstrual cycle were detected. We conclude that, although IGF-I
concentrations are dependent on the phase of the menstrual cycle, the variation
in IGF-I concentrations throughout the menstrual cycle is relatively small.
Therefore, the menstrual cycle does not need to be considered when evaluating IGF
I or IGFBP-3 serum values in women suspected to have GH deficiency.
PMID- 9402267
TI - Utilization of retrieved oocytes as an index of the efficiency of superovulation
strategies for in-vitro fertilization treatment.
AB - An analysis of 581 in-vitro fertilization treatment cycles was carried out to
determine the pattern of utilization of retrieved oocytes. Patients were divided
into five groups depending on the number of retrieved oocytes. The mean
fertilization rate of 57% was broadly similar amongst the groups but the
proportion of retrieved oocytes that produced embryos of a quality suitable for
transfer or cryopreservation (the cycle efficiency index) fell significantly with
increase in the retrieved oocyte number. However, the pregnancy rate increased
with the number of retrieved oocytes (13-38%). It is important to determine the
point at which advantages of multifollicular development are outweighed by the
potential for complications. Increased utilization of retrieved oocytes will
decrease the need for production of a large number of oocytes.
PMID- 9402268
TI - Recombinant human follicle stimulating hormone (r-hFSH; Gonal-F) versus highly
purified urinary FSH (Metrodin HP): results of a randomized comparative study in
women undergoing assisted reproductive techniques.
AB - A prospective, randomized, comparative, assessor-blind study was carried out in
two centres to compare the efficacy and safety of recombinant human follicle
stimulating hormone (r-hFSH; Gonal-F) versus highly purified urinary FSH (u-hFSH
HP; Metrodin HP), both administered s.c. in women undergoing ovarian stimulation
for in-vitro fertilization including intracytoplasmic sperm injection (ICSI). A
total of 235 patients started a long gonadotrophin-releasing hormone agonist
protocol: 119 received r-hFSH and 114 received u-hFSH HP (150 IU/day) for the
first 6 days. Two patients were excluded from the study because they mistakenly
received the incorrect treatment combination. Human chorionic gonadotrophin (HCG;
10000 IU, s.c.) was administered once there was at least one follicle 18 mm in
diameter and two others > or = 16 mm. In all, 119 (100%) and 102 (89%) of the
patients respectively in the r-hFSH and u-hFSH HP groups achieved the criteria
for HCG. The mean numbers (+/- SD) of oocytes recovered (the primary endpoint)
were 12.2 +/- 5.5 and 7.6 +/- 4.4 in the r-hFSH and u-hFSH HP groups respectively
(P < 0.0001). However, the number of FSH treatment days (11.0 +/- 1.6 versus 13.5
+/- 3.7) and the number of 75 IU ampoules (21.9 +/- 5.1 versus 31.9 +/- 13.4)
used were significantly less (P < 0.0001) in the r-hFSH group than in the u-hFSH
HP group. In patients treated using ICSI (63 patients in each group), no
difference in oocyte maturation was observed. The mean numbers of embryos
obtained were 8.1 +/- 4.2 and 4.7 +/- 3.5 (P < 0.0001), in favour of the r-hFSH
group. In the majority of patients (96 and 99% respectively) only one or two
embryos were replaced (mean 2.0 +/- 0.2 and 1.9 +/- 0.1 respectively) in the r
hFSH and u-hFSH HP groups. The clinical pregnancy rates per started cycle and per
embryo transfer were 45 and 36%, and 48 and 47%, respectively in the r-hFSH and u
hFSH HP groups (not significant). There were six (5.1%) and two (1.7%) cases of
ovarian hyperstimulation syndrome respectively. In conclusion, it was found that
r-hFSH was more effective than u-hFSH at inducing multiple follicular
development. However, the high rate of low ovarian response in the u-hFSH group
compared with our general experience was unexpected. The availability of a
gonadotrophin with less inter-batch variation would be beneficial for clinicians.
r-hFSH seems to fulfil such a requirement.
PMID- 9402269
TI - Beta2-glycoprotein I-dependent anticardiolipin antibody in early recurrent
spontaneous abortion.
AB - The objective of this study was to assess the clinical significance of autoimmune
anticardiolipin antibody that can react with cardiolipin only in the presence of
beta2-glycoprotein I (beta2-glycoprotein I-dependent anticardiolipin antibody) in
the pathogenesis of early recurrent abortion. A total of 72 early recurrent
spontaneous aborters and 175 normal healthy women were analysed for the
occurrence of beta2-glycoprotein I-dependent anticardiolipin antibody in serum
samples by an enzyme-linked immunosorbent assay specific for the detection of
beta2-glycoprotein I-dependent anticardiolipin antibody. The incidence of beta2
glycoprotein I-dependent anticardiolipin antibody in the early recurrent
spontaneous aborters was essentially the same as that of normal women. Thus, the
beta2-glycoprotein I-dependent anticardiolipin antibody seemed to have little, if
any, implication in the pathogenesis of early recurrent spontaneous abortion.
PMID- 9402270
TI - Leukocytosis in response to exogenous gonadotrophin stimulation.
AB - Leukocytosis may develop in women undergoing ovulation induction. The production
of blood leukocytes and their numbers in circulation are regulated by complex
interactions involving endogenous haematopoietic cytokines, such as granulocyte
colony stimulating factor (G-CSF), monocyte-colony stimulating factor (M-CSF),
and interleukins. The purpose of this prospective study was to explore the
presence of leukocytosis in women who receive urinary menotrophins, and to
determine whether haematopoietic cytokines are changed in the stimulation
process. Controls were volunteers of the same age range, not taking any
medication, who received daily saline injections. Subjects underwent phlebotomy
at defined points for determination of complete blood counts, G-CSF, M-CSF, and
interleukin-6 concentrations. Baseline white blood cell (WBC) counts were similar
in patients and controls. In menotrophin-treated patients the WBC counts rose
significantly (4.19 +/- 0.28 to 6.37 +/- 0.71) during the stimulation and peaked
in the luteal phase (P = 0.037). In contrast, WBC counts decreased in controls.
Other leukocytic lineages were not affected. In treated patients G-CSF
concentrations rose significantly (P = 0.028 versus controls), while changes in M
CSF and interleukin-6 were not significant.
PMID- 9402271
TI - Is the outcome of in-vitro fertilization and embryo transfer treatment improved
by spontaneous or surgical drainage of a hydrosalpinx?
AB - A pilot study was designed to examine whether the outcome of embryo transfer in
women with a hydrosalpinx might be improved by surgical drainage of the
hydrosalpinx at the time of oocyte collection for in-vitro fertilization
treatment. A comparative, controlled but retrospective analysis of the results
was performed of all women with infective tubal damage aged <40 years old, who
had ovulatory cycles, a normal uterus and a partner with normal spermatozoa. A
standardized treatment regimen was used. A maximum of three embryos were
transferred. Hydrosalpinx was defined by prior hysterosalpingography and/or
laparoscopy with transcervical dye injection. A total of 237 embryo transfer
cycles in women with hydrosalpinges (tubal distension not visible in 151, visible
but not drained in 30 and drained in 56) were compared with 705 embryo transfer
cycles in women with tubal disease but no hydrosalpinx. Results were analysed in
the first three cycles but also separately in the first cycle to check for bias.
Success rates were higher in the first cycle, but did not significantly influence
overall differences. Implantation rates were significantly reduced overall in the
hydrosalpinx group (8.0 versus 13.2% for controls; P < 0.001), being 8.3% (P <
0.01) in the subgroup without evident tubal distension and 7.5% (not significant)
in the drained hydrosalpinx group. This study shows that tubal damage with distal
occlusion is associated with a marked reduction in embryo implantation, even in
the absence of obvious fluid distension. Surgical drainage of distended
hydrosalpinges appears to offer no benefit.
PMID- 9402272
TI - Sonohysterographic evaluation of uterine abnormalities noted on
hysterosalpingography.
AB - Transvaginal sonohysterography was performed on 40 consecutive patients with
infertility or recurrent pregnancy loss and uterine abnormalities on
hysterosalpingography. The findings were correlated with the hysterosalpingogram
and subsequent diagnostic and/or operative hysteroscopy. Hysterosalpingography
was incorrect in nine cases. Sonohysterography was more accurate than
hysterosalpingography and provided more information about uterine abnormalities.
Sonohysterography was in complete agreement with hysteroscopy. Diagnostic
hysteroscopy can therefore be avoided if the sonohysterogram is normal.
Sonohysterography also provides additional information on the relative proportion
of the intracavitary and intramyometrial components of submucus myomas, as well
as extracavitary myomas and the adnexae. This may help in planning the surgical
procedure.
PMID- 9402273
TI - Analyses of meiotic chromosomes in testicular biopsies of infertile patients.
AB - Between 1989 and 1992 meiotic chromosome studies and synaptonemal complex
analyses were evaluated using light and, in part, electron microscopy in 46
infertile males with highly abnormal spermiograms. This examination focused on
whether the breakdown of spermatogenesis could be attributed to pairing anomalies
of bivalents. The study of meiotic chromosomes and synaptonemal complexes
indicated normal spermatogenesis in five patients (11%); in the remainder,
maturation arrest was diagnosed. In 21 individuals (50%) the breakdown was
accompanied by pairing anomalies (asynapsis, fragmented synaptonemal complexes,
X/Y univalence). Thus it is shown that male infertility can often partly be
explained by meiotic disorders.
PMID- 9402274
TI - Treatment for infertility and risk of invasive epithelial ovarian cancer.
AB - The relationship between the use of fertility drugs and the risk of ovarian
cancer was analysed using data from an Italian case-control study. The study
comprised 971 women below the age of 75 years with histologically confirmed
invasive epithelial ovarian cancer diagnosed within the year before the
interview. The controls were 2758 women admitted to the same network of hospitals
where the cases of ovarian cancer had been identified. Five cases (0.5%) and 11
controls (0.4%) reported use of fertility drugs. In comparison with women who had
never used fertility drugs, the multivariate odds ratio (OR) for women who had
taken fertility drugs was 1.1 [95% confidence interval (CI) 0.4-3.3]. The OR were
0.7 (95% CI 0.1-7.9) and 1.0 (95% CI 0.2-3.8) for women who had used fertility
drugs for <6 and > or =6 cycles respectively. Considering the 14 cases and 45
controls reporting difficulty in conception, the risk of ovarian cancer was 0.5
(95% CI 0.1-3.6) for women who reported use of fertility drugs. Considering
nulliparous women only, the estimated OR of ovarian cancer for any fertility drug
use was 0.6 (95% CI 0.1-3.5). Although the present results have limitations in
terms of statistical power and available information, they provide reassuring
evidence of the absence of a strong association between fertility drugs and
subsequent risk of developing epithelial ovarian cancer.
PMID- 9402275
TI - Intrauterine insemination: effect of the temporal relationship between the
luteinizing hormone surge, human chorionic gonadotrophin administration and
insemination on pregnancy rates.
AB - The optimal time period for intrauterine insemination (IUI) in relation to either
luteinizing hormone (LH) surge or human chorionic gonadotrophin (HCG)
administration leading to the best pregnancy rates has not been determined. In
this study, 856 consecutive human menopausal gonadotrophin (HMG)-stimulated and
49 natural unstimulated IUI cycles carried out at a reproductive medicine unit
affiliated with a tertiary centre were analysed in a retrospective fashion. There
were three scenarios in the temporal relationship of the LH surge, HCG
administration and artificial insemination. These were (group A) subjects who had
an endogenous LH surge but were not given HCG; (group B) subjects who were given
HCG after an observed LH surge, and (group C) subjects who were given HCG before
the LH surge. The overall pregnancy rate (PR) was 16% per cycle. The PR was 9% in
group A, 20% in group B and 14% in group C. The PR in group B was significantly
better than group C (P = 0.04). In group B, the longer the time interval between
the LH surge and HCG administration, the better the PR up to 20 h (P = 0.025);
the timing of IUI based on the LH surge was not critical to the achievement of
pregnancy within 3 days. In group C, PR improved with the increasing interval
between HCG and IUI from <28 h up to 60 h. We conclude that a better PR is
achieved if a spontaneous LH surge occurs before HCG administration, especially
where the administration of HCG is delayed 8-20 h after an observed LH surge; the
timing of IUI based on the LH surge is not critical to the achievement of
pregnancy within 3 days.
PMID- 9402276
TI - Thromboembolic disease associated with ovarian stimulation and assisted
conception techniques.
AB - Thromboembolic disease, as a complication of ovarian stimulation and assisted
conception techniques, is generally considered to be a rare complication of
ovarian hyperstimulation syndrome and, by implication, lower limb in origin.
Sporadic cases of unusually sited thromboses, both venous and arterial, have been
reported. This paper aims to draw attention to the relatively large number of
such thromboses reported in the world literature compared with those cited in
previous commentaries, and to emphasize how little is known about their
pathogenesis. It is believed that this is an issue which requires to be addressed
in order to understand the background pathology to such incidents and if possible
to identify women at greatest risk from such potentially debilitating or fatal
complications, such that appropriate prophylactic measures can be taken.
PMID- 9402277
TI - Upper limb thrombosis associated with assisted conception treatment.
AB - Three cases of upper limb deep venous thrombosis occurring in association with
assisted conception treatment are presented. The accepted argument that lower
limb thrombosis occurring in cases of complicated or severe hyperstimulation
syndrome represents the likeliest thrombo-embolic disorder in this situation is
questioned.
PMID- 9402278
TI - Hamster origin of metaphases with multiple chromosome rearrangements in first
cleavage human-hamster embryos.
AB - Laboratories using the human sperm-hamster egg fertilization system to analyse
sperm chromosomes obtain, sporadically, metaphases with multiple aberrations. Due
to the high number of aberrations, these metaphases cannot be fully karyotyped.
In some of them, one or several human chromosomes can be identified, guaranteeing
the human origin of the whole metaphase. However, in others, none of the
chromosomes can be recognized as human. This latter type of grossly rearranged
metaphases is characterized by complex chromatid exchanges, multifragmented
chromosomes and pulverized chromosome material. Using fluorescent in-situ
hybridization techniques (FISH) with either human or hamster genomic DNA probes,
we examined the origin of this second type of metaphase with multiple chromatid
exchanges and fragmented chromosomes. Our study demonstrates that all of them
hybridize with hamster genomic DNA probes and not with human DNA, proving their
hamster origin. Since some of these metaphases seem to be diploid, we suggest
that they may arise from hamster eggs that have failed to complete meiosis and
have not extruded the second polar body.
PMID- 9402279
TI - No evidence for a decreased fertilizing potential after in-vitro fertilization
using spermatozoa from polyzoospermic men.
AB - Polyzoospermia is generally recognized as a male factor contributing to
infertility and/or recurrent abortion. Although a reduced spermatozoal
fertilizing capacity is assumed to be involved, so far there is no conclusive
explanation for the assumed reduced reproductive performance in these patients,
and data on the fertilizing capacity of spermatozoa from polyzoospermic men are
lacking. The present study therefore aimed at analysing the outcome after in
vitro fertilization (IVF)-embryo transfer in polyzoospermic patients.
Retrospective analysis showed that only 0.5% out of 7863 IVF cycles were
performed with spermatozoa from polyzoospermic men. The outcome of these IVF
cycles shows neither a reduction in spermatozoal fertilizing capacity nor an
increase in pregnancy wastage in cycles in which a pregnancy was obtained. These
results may suggest a normal reproductive potential in polyzoospermic patients
and therefore the question may be raised whether polyzoospermia represents a real
pathological entity leading to infertility.
PMID- 9402280
TI - Is transrectal ultrasonography a reliable diagnostic approach in ejaculatory duct
sub-obstruction?
AB - We studied the diagnostic predictive power of transrectal ultrasonography (TRUS)
coupled with semen volume in cases of distal seminal tract sub-obstruction. As a
gold standard for diagnosis we used seminal tract washout (STW). Non-azoospermic
subjects (n = 112) were submitted to transrectal ultrasonography because of
suspected excretory infertility or other andrological pathologies, before
performing STW. STW indicated ejaculatory duct sub-obstruction in 36.6% of the
patients. Seminal vesicle enlargement (anterior-posterior diameter > or = 15 mm)
and seminal vesicle roundish anechoic areas (stasis) were the ultrasonographic
anomalies more often associated with ejaculatory duct sub-obstruction. Stepwise
logistic regression (SLR) analysis revealed that the ultrasonographic evidence of
stasis was highly diagnostic only in the presence of a low semen volume (< or =
1.5 ml) and that ejaculatory duct sub-obstructions may be present but with no
evidence of ultrasonographic anomalies. Therefore, TRUS is a useful approach for
the treatment of suspected ejaculatory duct sub-obstruction, but is not a
reliable diagnostic tool and, before performing transurethral surgery, STW should
be mandatory.
PMID- 9402282
TI - Immunomodulation by human seminal plasma: a benefit for spermatozoon and
pathogen?
AB - The immunosuppressive effect of human seminal plasma and its implications for
sperm survival are reviewed. Human semen contains high concentrations of
prostaglandins that can effect a cytokine-mediated switch away from a cell
mediated immune response. This effect on antigen presenting cells would induce a
state of non-responsiveness to sperm antigens in the female reproductive tract.
It is postulated that the induction of anergy to sperm antigen may be fundamental
to the continuing fecundity of the individual. However, although this immune
system modulation will benefit the spermatozoa, the response to infective agents
present in semen will also be affected, which may play a critical role in the
aetiology and progress of sexually transmitted disease.
PMID- 9402281
TI - Pentoxifylline induces hyperactivation and acrosome reaction in spermatozoa of
golden hamsters: changes in motility kinematics.
AB - Pentoxifylline (PF) is used to enhance motility of spermatozoa from infertile
human subjects. We have previously shown that 0.45 mM PF improved capacitation of
spermatozoa and fertilization of oocytes in vitro in hamsters. The present study
was carried out to assess PF-induced changes in motility kinematics of hamster
spermatozoa by a computer-aided sperm analyser (CASA) and determine the timing of
onset of hyperactivation (HA) and acrosome reaction (AR) in PF-treated
spermatozoa. Motility kinematics were analysed by CASA for 0-8 h in the absence
or presence of 0.45 mM PF in Tyrode's medium supplemented with lactate, pyruvate
and polyvinyl alcohol (TLP-PVA) or in TLP-PVA with bovine serum albumin (TALP
PVA). Conventional assessment was also made on the percentage of motility and
quality of motility of spermatozoa; values were expressed as sperm motility index
(SMI). Both in TALP-PVA and TLP-PVA, PF markedly increased SMI, especially the
quality of motility (P < 0.02) by 2-3 h which was sustained up to 6 h. The
motility kinematic data of PF-treated spermatozoa in TALP-PVA showed that average
path velocity, curvilinear velocity and amplitude of lateral head displacement
significantly (P < 0.05) increased as early as 2 h, with the expected decrease in
straightness (STR) and linearity (LIN). Similar changes were also observed with
PF-treated spermatozoa in TLP-PVA. Moreover, the percentage of hyperactivated
spermatozoa in PF-treated samples was significantly (P < 0.001) higher than the
untreated control at 2 h. To determine whether PF could induce AR, independent of
bovine serum albumin, quantitative AR was assessed by observing the presence or
absence of acrosomal cap on viable spermatozoa. PF significantly (P < 0.001)
increased the percentage of AR as early as 2 h, reaching maximum at 4 h both in
TALP-PVA (P < 0.05) and in TLP-PVA (P < 0.001). These results show that, in
hamsters, PF induces early onset (by 2 h) of HA and AR and increases the
proportion of spermatozoa undergoing physiological maturation.
PMID- 9402283
TI - A simple and objective approach to identifying human round spermatids.
AB - Although round spermatids have been studied extensively using staining techniques
and electron microscopy, little information is available about their appearance
in living conditions. We describe a method of collecting and identifying round
spermatids from ejaculates and testicular biopsies. The validity of the selection
procedure was confirmed by fluorescence in-situ hybridization. Based on cell
size, morphological characteristics of nucleus and cytoplasm, and on the
nucleus/cytoplasm ratio, we harvested a population of cells that was 84% haploid.
This procedure can be applied to select spermatids for clinical or research
purposes.
PMID- 9402284
TI - Microsurgical epididymal sperm aspiration with motile trophozoite cells but no
spermatozoa.
AB - This paper reports on a patient in whom the clinical diagnosis of obstructive
azoospermia was made according to clinical observations, i.e. azoospermia, normal
andrological examination, normal follicle stimulating hormone and a misleading
histopathological report of a testicular biopsy. Microsurgical vasoepididymostomy
failed to restore fertility, and as a last resort, microsurgical sperm aspiration
was performed. Although flagellated cells were observed in the epididymal
aspiration, no spermatozoa were observed and wet preparation of multiple
testicular biopsies failed to demonstrate any spermatozoon. This patient was
diagnosed to have a non-obstructive azoospermia, resulting from maturation arrest
associated with trichomonas infection at the level of the epididymis.
PMID- 9402285
TI - Possible contribution of follicular interleukin-1beta to nitric oxide generation
in human pre-ovulatory follicles.
AB - The aim of this study was to investigate the relationships between follicular
nitric oxide (NO) metabolite concentrations and several related variables, with
special reference to follicular interleukin-1beta (IL-1beta). The follicular
fluid from the leading and secondary follicles was collected individually from 20
women undergoing in-vitro fertilization (IVF) treatment, and the concentrations
of nitrite (NO2-) and nitrate (NO3-) were determined fluorometrically using 2,3
diaminonaphthalene. Both follicular nitrite (r = 0.42, P < 0.01) and nitrate (r =
0.49, P < 0.001) were found to be significantly correlated with follicular IL
1beta concentrations. There were also significant positive correlations between
follicular nitrate and the number of oocytes retrieved (P < 0.01) and serum
oestradiol concentration on the day of human chorionic gonadotrophin (HCG)
administration (P < 0.05). When follicular cells were incubated in vitro with 10
ng/ml of IL-1beta for 24 h, nitrate generation was significantly (P < 0.01)
elevated compared with the control. In conclusion, our study demonstrates that
follicular IL-1beta and the number of developing follicles are significant
variables that affect follicular NO concentrations, and points to the possible
contribution of IL-1beta to NO generation in human preovulatory follicles.
PMID- 9402286
TI - A novel mechanism of vascular endothelial growth factor, leptin and transforming
growth factor-beta2 sequestration in a subpopulation of human ovarian follicle
cells.
AB - This study describes the occurrence of a highly specialized subpopulation of
granulosa and cumulus oophorus cells that accumulate and sequester specific
growth factors by a novel mechanism. These cells are characterized by multiple
balloon-like processes tethered to the cell by means of a slender stalk of plasma
membrane. Time-lapse analyses demonstrate that these tethered structures (TS)
form in minutes and frequently detach from the cell with the bulbous portion
remaining motile on the cell surface. Serial section reconstruction of
transmission electron microscopic images shows a specific and stable
intracellular organization in which an apparent secretory compartment composed of
densely packed vacuoles, vesicles, and cisternae is separated by a thick
filamentous network from a nuclear compartment containing mitochondria,
polyribosomes, lipid inclusions, and rough-surfaced endoplasmic reticulum.
Immunofluorescent analysis performed during the formation of these structures
showed a progressive accumulation of vascular endothelial growth factor, leptin,
and transforming growth factor-beta2 in the bulbous region. TS were identified in
newly aspirated masses of granulosa and cumulus oophorus, and their production
persists for months in culture. Observations of TS-forming cells made over
several days of culture indicates that their production is episodic and factor
release from these cells may be pulsatile. The findings suggest that a novel
method of growth factor storage and release by an apparent apocrine-like
mechanism occurs in the human ovarian follicle. The results are discussed with
respect to possible roles in pre- and post-ovulatory follicular development.
PMID- 9402287
TI - Apoptosis of germ cells during human prenatal oogenesis.
AB - During human oogenesis two contrasting processes can be observed: germ cell
proliferation and differentiation, and contemporaneous germ cell death. It is
well known that apoptosis is a type of physiological cell death that occurs in
proliferating and differentiating tissues. The aim of this study is to
demonstrate, through ultrastructural and in-situ 3' end labelling observations in
intact sections of human fetal ovaries, that germ cell loss during fetal life is
due to a phenomenon of apoptosis. We evaluated the presence of programmed cell
death in female germ cells in fetal ovaries at 18-20 weeks of postconceptional
age. The alterations that occur during apoptosis were detected by the electron
microscope and include cytoplasmic condensation, organelle relocalization and
compaction, chromatin condensation, and finally, production of membrane-enclosed
particles containing intracellular material, known as apoptotic bodies, that are
phagocytosed. The fragmentation of DNA, characteristic of apoptotic cells, was
detected by the use of the in-situ 3' end labelling procedure on histological
sections of ovaries where only some nuclei of germ cells were positively stained.
The parallel use of these two methods on human ovaries of 18-20 weeks
postconceptional age has allowed us to show that the numerical decrease of human
female germ cells during the fetal period is due to an apoptotic phenomenon.
PMID- 9402288
TI - Ultrastructural observations in human oocytes and preimplantation embryos after
zona opening using an erbium-yttrium-aluminium-garnet (Er:YAG) laser.
AB - For more than 3 years we have performed laser-assisted hatching prior to embryo
transfer in patients with recurrent implantation failure using an erbium-yttrium
aluminium-garnet (Er:YAG) laser system that operates in the infrared region of
the light spectrum. The laser beam is guided through a quartz fibre and is
brought into direct contact with the zona pellucida. This study was undertaken to
evaluate the ultrastructural effects of this laser on the zona pellucida and
underlying cell membrane of unfertilized human oocytes and pathologically
fertilized preimplantation embryos using light and scanning electron microscopy.
The Er:YAG laser produces an almost circular zona opening in the shape of a
truncated cone tapering off towards the inside, with a mean diameter of 18 mm.
The exact diameter of the drilled site depends on the diameter of the fibre tip
and the total number of pulses applied. After laser interaction, the zona matrix
and the surface of the underlying ooplasm membrane showed no degenerative
alterations. We conclude that the Er:YAG laser is an effective microsurgical tool
for achieving reproducible, precise zona openings particularly suitable for
purposes of assisted hatching because of their characteristic shape.
PMID- 9402289
TI - Effects of different hyaluronidase concentrations and mechanical procedures for
cumulus cell removal on the outcome of intracytoplasmic sperm injection.
AB - The aim of this study was to compare concentrations of hyaluronidase and
mechanical methods used to denude human oocytes from surrounding cumulus and
corona cells prior to intracytoplasmic sperm injection (ICSI). Cumulus and corona
cells were removed in two pipetting steps: first in a medium containing
hyaluronidase, and then in a medium without enzyme. The first step in the
procedure was investigated. Different hyaluronidase concentrations (78, 39 or 10
IU/ml) and pipettes of different size (inner diameter 250 or > 1000 microm) were
used to remove the cumulus cells. The time required to denude the oocytes was
recorded. Metaphase II oocytes were injected, and the survival, fertilization,
embryo development and pregnancy rates were evaluated. We found that by using a
pipette with an inner diameter of at least 1000 microm we were able to decrease
significantly the time an oocyte is exposed to hyaluronidase, even if the
concentration of enzyme is very low (10 IU/ml). For the different conditions
there was no statistically significant effect on the outcome in terms of
survival, normal fertilization [two pronuclear (2PN)], parthenogenetic activation
(1PN), abnormal fertilization (3PN), embryo development and pregnancy rates after
ICSI. In conclusion, a concentration as low as 10 IU/ml hyaluronidase in
combination with a pipette of at least 1000 microm inner diameter can be used
successfully to denude oocytes for microinjection.
PMID- 9402290
TI - Transcription of tissue-specific genes in human preimplantation embryos.
AB - We have recently detected de-novo transcripts of the predominantly muscle
specific myotonin protein kinase gene in human preimplantation embryos from the 1
cell to the 4-cell stages. Others have shown de-novo transcripts of the Y-linked
genes, ZFY and SRY, in the 1-cell zygote. In order to assess the significance of
early transcription of these predominantly tissue-specific genes in
preimplantation development, we have analysed individual human oocytes and
preimplantation embryos for the presence of transcripts of two further tissue
specific genes, alpha-globin and beta-globin, and two house-keeping genes, HPRT
and APRT. Reverse transcriptase polymerase chain reaction assays were developed
to the required single cell sensitivity, using human red blood cells and
fibroblasts, prior to their application to human oocytes and embryos. As
expected, transcripts of the house-keeping genes, HPRT and APRT, were detected at
all stages of preimplantation development. Transcripts of 'tissue-specific' alpha
globin were readily detected in preimplantation embryos from the 1-cell stage.
However, transcripts of beta-globin were detected only rarely (in only one of the
11 embryos analysed). This difference may be due to the fact that alpha-globin
contains a CpG island. A survey of the data on gene expression in early human
development suggests that CpG-island-containing genes may be expressed in
preimplantation embryos. Expression of these genes in gametes and early embryos
may be involved in the survival of CpG islands in evolution.
PMID- 9402291
TI - The chromosomal constitution of multipronuclear zygotes resulting from in-vitro
fertilization.
AB - We have attempted to analyse the chromosome constitution of 77 multipronuclear
uncleaved zygotes obtained from our in-vitro fertilization programme. Complete
karyotypes could be established for 51 tripronuclear cells and eight zygotes with
four pronuclei. When compiling the results, the varying arrangement of the
chromosome sets was taken into consideration. Eighteen tripronuclear zygotes
showed three separate haploid metaphases (distribution pattern n/n/n), 16 cells
had one haploid and one diploid chromosome set (n/2n), and in 15 zygotes the
individual sets were not distinguishable (3n). Two zygotes were in fact
tetraploid, the distribution of metaphases on the slide being n/3n and n/n/2n,
respectively. In tripronuclear zygotes the sex chromosome ratio XXX:XXY:XYY was
14:16:18, excluding the two tetraploid cells and one zygote with a 23,X/23,X/22,
C or -Y karyotype. Chromosome abnormalities were found in 16 zygotes (31.4%) and
included numerical (six cells), structural (four cells) as well as combinations
of numerical and structural alterations (six cells). Four of the zygotes with
four pronuclei (50%) had numerical and/or structural chromosome aberrations.
Excluding two cells with one uninterpretable metaphase and a 22,-C or -Y
karyotype, respectively, the sex chromosome distribution XXXX:XXXY:XXYY:XYYY was
1:1:2:1 in zygotes with four pronuclei. Another zygote was found to be pentaploid
after fixation. These results suggest that analysis of multipronuclear zygotes
yields valuable information about cytogenetic abnormalities occurring at the
earliest stage of conception.
PMID- 9402292
TI - Prospective randomized study comparing human serum albumin with fetal cord serum
as protein supplement in culture medium for in-vitro fertilization.
AB - The use of human serum albumin (HSA) instead of fetal cord serum (FCoS) as
protein supplement highly simplifies the preparation of culture medium for human
in-vitro fertilization (IVF) but whether they are equivalent in sustaining embryo
development is still controversial. We performed a prospective randomized study
of patients undergoing IVF or intracytoplasmic sperm injection (ICSI) where
embryos were cultured in Earle's balanced salt solution containing either 8%
(v/v) FCoS or 0.4% (w/v) HSA as protein source. Fertilization rates,
morphological embryonic quality and pregnancy rates were compared. A total of
2189 oocytes from 210 cycles were cultured in medium supplemented with HSA in
patient group 1 and 2109 oocytes from 203 cycles in medium supplemented with FCoS
in patient group 2. The fertilization rate, defined as the presence of two
nuclei, for microinjected oocytes was similar in both patient groups (77.4 and
76.7%, respectively). The fertilization rate for inseminated oocyte-cumulus
complexes was significantly higher in the HSA group than in the FCoS group (62.9
versus 53.8%, P < 0.025). The embryonic quality was significantly better after
culture in medium supplemented with HSA than with FCoS (13.7 versus 9.9%
morphologically excellent embryos, P < 0.001). Implantation rates per transferred
embryo were not significantly different (22.5 versus 18.2%), but there was a
significantly higher pregnancy rate per embryo transfer in the HSA group (45.7
versus 35.9%, P < 0.05, respectively). Non-evolutive pregnancy rates were
significantly different (27.4 and 16.7%). Our data demonstrate that the use of
human serum albumin as a protein supplement for culture medium in human IVF
programmes is associated with improved embryonic quality and significantly higher
pregnancy rates. For this reason as well as the additional benefits of being
virus-free and being purified, HSA is preferable to FCoS for the preparation of
culture media in human IVF.
PMID- 9402293
TI - Induction of artificial endometrial cycles with s.c. oestrogen implants and
injectable progesterone in in-vitro fertilization treatment with donated oocytes:
a preliminary report.
AB - Endometrial preparation for embryo implantation in oocyte recipients with
retained ovarian function presents a special problem. In all, 10 women with
preserved ovarian function received donated oocytes in an in-vitro fertilization
programme. In the preparatory cycles with oral oestrogens, all failed to develop
adequate secretory endometrium because of ill-timed early luteinization occurring
during the proliferative phase of the cycle. Subsequently the patients were
treated with s.c. 17-beta oestradiol implants and injectable progesterone. The
implants successfully induced complete down-regulation of the hypothalamus,
pituitary axis, and prevented luteinizing hormone (LH) surge. In these
preparatory cycles, all the treated patients produced adequate secretory
endometrium. Clinical trials of 27 oocyte donation cycles yielded one biochemical
and eight clinical pregnancies.
PMID- 9402294
TI - Endometrial thickness and serum oestradiol concentrations as predictors of
outcome in oocyte donation.
AB - Adequate endometrial preparation with exogenous steroids is mandatory for
successful ovum donation. This study was undertaken to assess the value of
endometrial thickness by ultrasound and serum oestradiol as predictors of ovum
donation outcome and to analyse the correlation between serum oestradiol
concentrations and the endometrial thickness. Endometrial thickness and serum
oestradiol concentrations on the day of oocyte donation were recorded and
compared to several in-vitro fertilization parameters. The cycles (n = 465) were
classified according to serum oestradiol values and endometrial thickness.
Comparison of the groups showed that endometrial thickness was significantly (P =
0.002) higher when serum oestradiol was >400 pg/ml as compared to <100 pg/ml.
Pregnancy and implantation rates did not differ among the groups, women with
serum oestradiol <50 pg/ml having similar outcome to the remaining cases.
Endometrial thickness showed a similar picture in terms of pregnancy and
implantation. Also, women with an endometrium <4 mm in size had normal pregnancy
and implantation rates. There was a positive correlation (P = 0.0044) between
endometrial thickness and implantation, as well as between endometrial thickness
and serum oestradiol (P = 0.0184). None of the parameters examined was able to
predict ovum donation outcome. It is concluded that endometrial thickness is
preferred to serum oestradiol for the monitoring of endometrial development,
although neither is able to predict success in oocyte donation.
PMID- 9402295
TI - Reproductive impact of congenital Mullerian anomalies.
AB - This retrospective longitudinal study was undertaken in order to determine the
incidence and reproductive impact of uterine malformations on women desiring to
conceive during their reproductive years. A total of 3181 patients in whom the
morphology of the uterus was ascertained by hysterosalpingography (HSG) and
laparoscopy/laparotomy during the years 1980-1995 was included in the study. The
population analysed included fertile, infertile and sterile patients. The overall
frequency of uterine malformations was 4.0%. Infertile patients (6.3%) had a
significantly (P < 0.05) higher incidence of Mullerian anomalies, in comparison
with fertile (3.8%) and sterile (2.4%) women. Septate (33.6%) and arcuate (32.8%)
uteri were the most common malformations observed. Each malformation was
individually analysed in fertile and infertile patients, in order to ascertain
its actual reproductive impact. The performance of the unicornuate and didelphys
uteri was similar with a chance of having a living child of 37-40%. The
reproductive potential of the bicornuate uterus showed a live birth rate of 62.5%
and the septate uterus showed a live birth rate of 62%. In all these
abnormalities, early miscarriages (25-38%) and preterm deliveries (25-47%) were
quite common. The arcuate uterus presented a live birth rate of 82.7%. It is
concluded that uterine anomalies are relatively frequent in fertile women, and
more frequent in infertile patients. Nevertheless, fertile patients with normal
reproductive performance do exist, and Mullerian defects can permit an absolutely
normal obstetric outcome. The reproductive performance of the unicornuate and
didelphys uteri was poor, while that of the septate and bicornuate uteri was
better than expected. The arcuate uterus had no impact on reproduction.
PMID- 9402296
TI - The impact of endometriosis in couples undergoing intracytoplasmic sperm
injection because of male infertility.
AB - To assess the impact of endometriosis on intracytoplasmic sperm injection (ICSI)
outcome, we have retrospectively evaluated 980 ICSI cycles, comparing the results
of women with and without endometriosis. A total of 101 cycles was identified in
which various degrees of endometriosis were involved, and in the remaining 879
cycles, male infertility was the only cause of infertility. Ejaculated
spermatozoa were microinjected in all cycles. There was a significant reduction
(P = 0.004) in the number of oocytes retrieved from women with endometriosis as
compared to those without endometriosis. However, there were no significant
differences in either fertilization or pregnancy and implantation rates between
women with or without endometriosis. We conclude that the presence of
endometriosis in patients undergoing ICSI because of severe male infertility does
not affect fertilization, pregnancy and implantation rates, although
significantly fewer oocytes are retrieved from patients with endometriosis.
PMID- 9402297
TI - Intrauterine sonographic assessments of embryonic heart diameter.
AB - Our purpose was to evaluate embryonic heart diameter in early first-trimester
pregnancy using intrauterine sonography with a 20 MHz flexible catheter-based
high-resolution real-time miniature transducer. A total of 40 women about to
undergo therapeutic abortion from 6-9.9 weeks gestational age and one abnormal
pregnancy with fetal hydrops at 9 weeks were studied with a specially developed
catheter-based high-resolution real-time miniature (2.4 mm outer diameter)
ultrasound transducer (20 MHz). A curvilinear relationship was found between the
menstrual age and embryonic heart diameter (R2 = 95.7%), and a normal range of
embryonic heart diameter for estimating the growth of the embryonic heart during
early first-trimester pregnancy was generated. A normogram of menstrual age as
predicted by embryonic heart diameter was also established. There was a good
curvilinear correlation between embryonic heart diameter and crown-rump length
(R2 = 90.1%). The embryonic heart diameter/crown-rump length ratio rapidly
decreased from week 6 to week 7, and remained almost constant thereafter.
Embryonic heart diameter (5.2 mm) in the case of fetal hydrops at 9 weeks was
above the normal range. These results may provide an additional method of
estimating gestational age in the early first trimester of pregnancy. In this
limited series, a single case of embryonic heart enlargement was demonstrated,
suggesting its potential use in the detection of embryonic congestive heart
failure.
PMID- 9402298
TI - Serum levels of folate and cobalamin in women with recurrent spontaneous
abortion.
AB - We evaluated the folate and cobalamin status in 29 non-pregnant women with a
history of recurrent spontaneous abortion (three or more consecutive) of unknown
aetiology in comparison to 29 healthy nulligravidae of similar reproductive age
(controls). Serum concentrations of folate and cobalamin showed no significant
differences between the two groups. No correlation between age and vitamin
concentrations was found. In the study group there was a significant negative
correlation of the number of previous abortions and the concentration of serum
folate. Patients with at least four previous miscarriages had significantly lower
serum values of folic acid than women with three abortions, but not than
controls. The underlying cause of this finding remains unclear. In conclusion,
the serum concentrations of folic acid and vitamin B12 are not significantly
altered in women with unexplained recurrent spontaneous abortions, and an
association between a deficiency of these vitamins and an increased risk of
pregnancy loss appears to be questionable in the majority of gestations.
PMID- 9402299
TI - Remodelling of guinea-pig aorta during pregnancy: selective alteration of
endothelial cells.
AB - It is known that aortic blood flow is increased during pregnancy, which may be
due to a pregnancy-associated decrease in aorta sensitivity to vasoconstrictors
on one side, and increased response to vasodilators on the other. Recent studies
have shown that alteration of blood flow or pressure could remodel some arteries
over a short time frame. However, the possibility of remodelling of aorta during
pregnancy has not yet been examined. Therefore, the aim of the present study was
to assess the morphometric and stereological characteristics of guinea-pig aorta
during different stages of pregnancy (non-pregnant, early-pregnant, mid-pregnant,
late-pregnant, n = 8-10 for each group). The cross-sectional areas of different
aortic layers and of endothelial cells were measured using both light and
electron microscopy. The values of external and internal diameters, wall
thickness, total cross-sectional area and cross-sectional area of media and
adventitia were not significantly different, regardless of the stage of
pregnancy. In contrast, the cross-sectional area of intima significantly and
progressively decreased during pregnancy (non-pregnant: 61 +/- 5 x 10(4) microm2,
late-pregnant: 38 +/- 3 microm2, P < 0.01). The volume:surface density ratio of
intima also significantly and progressively decreased during pregnancy (non
pregnant: 5.31 +/- 0.51, late-pregnant: 4.38 +/- 0.42, P < 0.01). Electron
microscopy revealed that the cross-sectional area of endothelial cells was
significantly decreased during different stages of pregnancy (non-pregnant: 56.8
+/- 6.2 microm2, late-pregnant: 28.9 +/- 3.8 microm2, P < 0.01). It is concluded
that during pregnancy there is selective thinning of intimal layer of guinea-pig
aorta, which probably reflects hypotrophy of aortic endothelial cells.
PMID- 9402300
TI - The obstetric implications of teenage pregnancy.
AB - A retrospective review was performed on the obstetric outcome of teenage
pregnancies delivered in 1 year in a tertiary centre. The results were compared
with the rest of the obstetric population in the same hospital in the same year.
The teenage mothers (n = 194) had increased incidence of sexually transmitted
diseases (5.2 versus 1.0%, P < 0.05), and preterm labour (13.0 versus 7.0%, P <
0.01), but decreased incidence of gestational glucose intolerance (3.1 versus
11.4%, P < 0.001), when compared with the non-teenage mothers (n = 4914). There
was no difference in the types of labour, while the incidence of Caesarean
section was lower (4.1 versus 12.6%, P < 0.001) in the teenage mothers. Although
the incidence of low birthweight was higher in the teenage mothers (13.5 versus
6.5%, P < 0.001), there was no significant difference in the mean birthweight,
gestation at delivery, incidence of total preterm delivery, or perinatal
mortality or morbidity. The results indicate that the major risk associated with
teenage pregnancies is preterm labour, but the perinatal outcome is favourable.
The good results accomplished in our centre could be attributed to the free and
readily available prenatal care and the quality of support from the family or
welfare agencies that are involved with the care of teenage mothers.
PMID- 9402301
TI - Expression of superoxide dismutase and xanthine oxidase in myometrium, fetal
membranes and placenta during normal human pregnancy and parturition.
AB - Superoxide, an agent which attenuates the half-life of nitric oxide, is
metabolized and synthesized by superoxide dismutase (SOD) and xanthine oxidase,
respectively. Over the last few years much work has focused on the role of nitric
oxide in human parturition. The aim of this study was to determine whether the
onset of human parturition is associated with a change in the expression of
copper/zinc superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (Mn
SOD) or xanthine oxidase within the uterus. Samples of myometrium, placenta,
decidua and fetal membranes were obtained from women before and after the onset
of labour at term. Immunocytochemistry was used to localize Cu/Zn SOD, Mn SOD and
xanthine oxidase and measure SOD enzyme activity. Cu/Zn and Mn SOD-like
immunoreactivity was detected in syncytiotrophoblast cells, villous stromal cells
and endothelial cells of blood vessels in the placenta. In the myometrium Cu/Zn
and Mn SOD were localized to myocytes and endothelial cells and to some vascular
smooth muscle cells. In the fetal membranes we observed staining for Cu/Zn SOD
and Mn SOD in the amnion, chorion, extravillous trophoblast and decidua. There
was no difference in SOD enzyme activity or staining intensity for SOD between
different cell types before and during labour. Xanthine oxidase immunoreactivity
was identified in each of the tissues examined and again there was no difference
in immunostaining in tissues obtained from women delivered before or after the
onset of labour. These results show that the pregnant uterus is capable of both
synthesizing and degrading superoxide and suggest that superoxide dismutase and
xanthine oxidase may play a role in the maintenance of uterine quiescence during
pregnancy, but not in the initiation of parturition.
PMID- 9402303
TI - A shift from a male to a female majority in newborns with the increasing age of
grand grand multiparous women.
AB - In this longitudinal study, we investigated the relationship of birth order and
the age of mother and father to the gender of 1795 newborns (mean +/- SD 12.5 +/-
1.6 per mother) of 143 grand grand multiparous (i.e women who have had >10
deliveries). The frequency of boys was 52.2% in the group of 1st to 9th paras and
46.2% in the group of 10th to 20th paras (P = 0.022). Mothers aged > or =35 years
had 7.0% more female than male newborns (P = 0.024). The respective figure for
fathers was 5.6% (P = 0.023). The interpregnancy interval evaluated for 96
mothers with 1091 deliveries had no correlation with the gender of the infants.
In the stepwise logistic regression analysis, the age of the mothers remained the
only significant independent factor for the shift from a male to a female
majority in the newborns (P = 0.0389). The present data thus indicate that the
age of the mother is the factor which explains why grand grand multiparous women
deliver more girls than boys.
PMID- 9402302
TI - Cyclooxygenase-1 and -2 in human placenta and placental bed after normal and pre
eclamptic pregnancies.
AB - In pre-eclampsia, the ratio of prostacyclin:thromboxane production rate is
decreased favouring the vasoconstrictive thromboxane. One of the rate-limiting
steps in prostaglandin synthesis is cyclooxygenase (COX) activity. Therefore, we
investigated the expression of COX-1 and COX-2 in human placenta and placental
bed. Tissue specimens from the 29th to 40th week of pregnancy were obtained from
Caesarean sections after uncomplicated and pre-eclamptic pregnancies before the
onset of labour. COX-1 and COX-2 were localized immunohistochemically with the
identification of positive cells by double immunofluorescence staining. The
protein and mRNA levels were analysed by immunoblotting and quantitative reverse
transcriptase-polymerase chain reaction. Expression of both COX-1 and COX-2 could
be observed in placenta and placental bed. COX-1-like immunoreactivity was
observed in most cell types with strongest staining in macrophages. Only
macrophages, endothelium, vascular leiomyocytes and fibroblasts stained
positively for COX-2. In placenta, COX-1 and -2 expression was unchanged after
pre-eclampsia. In placental bed, protein and mRNA levels of COX-1 were increased
in the pre-eclamptic group (P < 0.05), whereas COX-2 expression did not differ
significantly from normal pregnancies. An increased expression of COX-1 could be
involved in the pathophysiology of pre-eclamptic changes within the placental
bed. A therapy with drugs inhibiting COX-1 might be beneficial in this condition.
PMID- 9402304
TI - A prospective study of psychosocial stress and fertility in women.
AB - The objective of this study was to compare average stress levels during the month
of conception to those of previous infertile months. We postulated that stress
level during the actual month of conception would be lower than that during
previous non-conception cycles. Thirteen normal women from the general community,
who were attempting pregnancy, kept daily records of coital activity and basal
body temperature, and twice a month completed self-administered questionnaires
and provided a 12 h overnight urine sample. On average, women reported
significantly more favourable mood states on standard psychometric tests, during
the month of conception than during the previous non-conception cycles. In
addition, they felt significantly less 'hassled' during the month of conception.
However, mean urinary hormone excretion of adrenaline, noradrenaline and cortisol
did not significantly differ between conception and non-conception cycles and
there was little relationship between the psychological measures of mood state
and excretion of adrenaline and cortisol. There was no evidence of increased
coital frequency during the month of conception when mood states were improved,
suggesting that stress effects on libido were unlikely to account for the
findings. The results support the conclusion that psychosocial stress influences
fertility in females but as yet mechanisms remain unclear.
PMID- 9402305
TI - Semen donor recruitment strategies--a non-payment based approach.
AB - Actual and projected prohibition of payment for semen donation in the UK and
Canada has increased the need to examine alternative methods of donor
recruitment. Evidence from a number of sources suggests that there is a large
group of current and potential donors who are motivated more by meeting esteem
needs than by payment. We develop an argument for using social marketing tools to
create systematically an esteem-based approach to donor recruitment as an
alternative to the payment approach. We conclude that esteem is a useful method
of reciprocating the gift that donors make.
PMID- 9402306
TI - Mitotic chromosomal anomalies among infertile men.
PMID- 9402307
TI - DNA topoisomerase targeting drugs: mechanisms of action and perspectives.
AB - The nuclear enzymes DNA topoisomerases I and II appeared as cellular targets for
several antitumor drugs: campthotecin derivatives interacting with topoisomerase
I, and actinomycin D, anthracycline derivatives, elliptinium acetate,
mitoxantrone, epipodophyllotoxine derivatives, amsacrine and a new olivacine
derivative, NSC-6596871 (S 16020-2), which interact with topoisomerase II. The
functions of these enzymes are numerous and important since they are critical for
DNA functions and cell survival. Despite the fact that they share the same
target, topoisomerase II inhibitors have different mechanisms of action. Two
principle types of induced alterations are involved in cellular resistance to
topoisomerase II drugs: qualitative or quantitative alteration of the enzyme
and/or increased drug efflux due to overexpression of P-glycoprotein. S 16020-2,
a new olivacine derivative with a high antitumor activity against solid tumors,
shows a potent cytotoxic effect against tumor cells expressing P-glycoprotein.
This observation suggests that the comprehension of the respective effects of
topoisomerase inhibitors and the precise knowledge of their mechanisms of
resistance would improve the use of this therapeutic class in the clinic within
rational chemotherapeutic combinations.
PMID- 9402308
TI - A phase I study of ambulatory continuous infusion paclitaxel.
AB - Chemotherapy given by continuous infusion may have different toxicity profiles
and efficacy than when given by bolus administration. Thirty-one patients with
refractory tumors entered a phase I trial in which paclitaxel was administered
for 7 days by continuous infusion every 28 days. Only one patient required
hospitalization for treatment, because of an initial poor performance status, and
most carried out normal activities on an ambulatory basis. After the first three
patients, patients were entered in cohorts of five with the starting dose of 120
mg/m2. Each subsequent cohort was begun at a dose 10% higher than the previous
cohort. Later courses within each cohort were increased 10% in an individual
patient, if toxicity allowed. Nausea was rare. Of 15 patients with a soft tissue
sarcoma refractory to doxorubicin, dacarbazine, ifosfamide, and etoposide, there
were: one partial response (PR), five stable diseases and eight progressive; one
patient was not evaluable for response. The PR occurred in a patient with a very
aggressive sarcoma and very bulky disease, and was maintained for more than 1
year. We conclude that paclitaxel given by ambulatory continuous i.v. infusion is
well tolerated with a maximally tolerated starting dose of 160 mg/m2.
PMID- 9402309
TI - Phase I study of VRCTC-310, a purified phospholipase A2 purified from snake
venom, in patients with refractory cancer: safety and pharmacokinetic data.
AB - A phase I study was performed to evaluate the maximum tolerated dose (MTD),
safety profile and pharmacokinetic data with VRCTC-310, a natural product derived
from purified snake venom fractions, with phospholipase A2 activity and
inhibitory effects against human and murine tumor cell lines. Fifteen patients
with refractory malignancies were entered after providing written informed
consent. VRCTC-310 was administered as an intramuscular injection daily for 30
consecutive days. Doses were escalated from 0.0025 to 0.023 mg/kg. Toxicities
included local pain at the injection site, eosinophilia, reversible diplopia and
palpebral ptosis. Dose escalation was stopped at 0.023 mg/kg, when two patients
had developed anaphylactoid reactions. Both cases had high VRCTC-310-specific IgG
by EIA. MTD was 0.017 mg/kg and the recommended dose for phase II studies is
0.017 mg/kg. Stabilization was found in six patients.
PMID- 9402310
TI - Pharmacokinetics of methotrexate-albumin conjugates in tumor-bearing rats.
AB - Linking chemotherapeutic drugs to a macromolecular carrier system may enhance
tumor targeting, reduce toxicity and overcome drug resistance mechanisms. As an
elementary model to evaluate the pharmacological properties of macromolecular
drug carrier systems we chose rat serum albumin (RSA) for carrier and
methotrexate (MTX) as antineoplastic drug. The conjugation procedure yielded
conjugates with an approximate 1:1 molar loading rate (MTX(1)-RSA). In the first
part of the study a residualizing [111In]DTPA protein label was used for mapping
in vivo the catabolic sites of the native carrier protein and of the MTX(1)-RSA
drug conjugate in Walker 256 carcinosarcoma bearing rats. The tumor accumulation
was about 14% of the injected dose for the RSA and MTX(1)-RSA tracers after 24 h.
Tracer entrapment by organs with an active mononuclear phagocyte system was low
(liver below 7% and spleen below 1.5% of the injected dose after 24 h). The 1:1
conjugation of MTX to RSA did not decisively alter the pharmacokinetic properties
nor the tumor or tissue distribution of the native carrier protein RSA. In the
second part of the study the different properties of the MTX(1)-RSA conjugate
were compared with MTX in vivo. About 2 mg MTX/kg body weight either of the drug
conjugate or of the original drug were injected after being additionally spiked
with radiolabeled tracers. Plasma concentrations were simultaneously determined
by immunological and radioactive means. After 24 h about 12% MTX(1)-RSA was found
in circulation compared to 0.03% MTX. Favorable tumor accumulation rates of about
14% were achieved for MTX(1)-RSA versus 0.04% for MTX. About 45-fold more of the
injected dose of [3H]MTX accumulated in the liver as compared to the tumor (1.5
versus 0.03%) after 24 h. Conjugation of MTX to RSA reversed this ratio in favor
of the tumor to 1:1.4 (13.6 versus 9.6%). In conclusion, the potential
therapeutic benefit of the MTX(1)-RSA conjugate lies in its very long tumor
exposure time and its improved tumor accumulation rate compared to conventional
MTX. In addition the conjugation to albumin might enhance the therapeutic effects
over those achieved by long-term continuous infusion of MTX, as MTX(1)-RSA enters
the cells by a different uptake mechanism. This might also help to circumvent MTX
resistance mechanisms, such as a reduction in folate receptor numbers or impaired
MTX polyglutamylation.
PMID- 9402311
TI - Cytotoxic and antitumor activity of MEN 10710, a novel alkylating derivative of
distamycin.
AB - MEN 10710 is a new synthetic distamycin derivative possessing four pyrrole rings
and a bis-(2-chloroethyl)aminophenyl moiety linked to the oligopyrrole backbone
by a flexible butanamido chain. Its biological properties have been investigated
in comparison with the structurally related compound, tallimustine (FCE24517),
and the classical alkylating agent, melphalan (L-PAM). Cytotoxic potency of MEN
10710 was increased from 10- to 100-fold, as compared to tallimustine or L-PAM in
murine L1210, human LoVo and MCF7 tumor cell lines. MEN 10710 was still active
against L1210/L-PAM leukemic cells, while a partial cross-resistance was observed
in LoVo/DX and in MCF7/DX cells selected for resistance to doxorubicin and
expressing a MDR phenotype. Treatment with verapamil (VRP) reduced the resistance
to tallimustine, but not to MEN 10710, in MCF7/DX cells. The cytotoxic effects
reflect in vivo antitumor potency and toxicity in the treatment of human tumor
xenografts. MEN 10710 was more effective in A2780/DDP, an ovarian carcinoma
selected for resistance to cisplatin. On the other hand, the IC30 for inhibiting
murine granulocyte/macrophage colony formation was 50 times higher for MEN 10710
than for tallimustine, suggesting a lower myelotoxic potential. In conclusion,
the particular biological profile of MEN 10710 characterized by a marked
cytotoxic potency, an interesting antitumor efficacy and a reduced in vitro
myelosuppressive action may represent a further improvement in the rational
design of a novel distamycin-related alkylating compound.
PMID- 9402312
TI - Effects of cisplatin and taxol on inducible nitric oxide synthase, gastrin and
somatostatin in gastrointestinal toxicity.
AB - Cisplatin (9 mg/kg) or taxol (20 mg/kg) treatment of Wistar rats produced a sharp
decrease in inducible nitric oxide synthase (iNOS) and gastrin in the pyloric
region of the stomach, and an increase in iNOS and somatostatin in the pancreatic
islets. Nitric oxide (NO) functions as a relaxation factor in the smooth muscle
of the muscularis mucosa while gastrin plays an important role in the
gastroprotection of the mucosa through NO. It is proposed that a decline of the
iNOS and gastrin after cisplatin or taxol treatments is related to distention of
the stomach, and possibly nausea and vomiting. Hyperglycemia and glucose
intolerance after cisplatin treatment may be caused by increases of somatostatin
and iNOS in the pancreatic islets. Combination therapy with cisplatin and taxol
seems to ameliorate various toxicities due to these two individual drugs.
PMID- 9402313
TI - In vitro toxicity studies with mitomycins and bleomycin on endothelial cells.
AB - Pulmonary side effects are increasingly observed as dose-limiting toxicity (DLT)
of cancer treatment. The available preclinical models have a limited predictive
value for lung toxicity in humans. We have attempted to elucidate potential
mechanisms involved in these reactions, by studying the effects on cells,
possibly involved in these reactions after in vitro exposure to drugs with known
lung toxic effects. We have investigated the effects of bleomycin (BLM),
mitomycin C (MMC), KW-2149 and its two known metabolites, M16 and M18, on oxygen
radical production by granulocytes, on cytokine production: interleukin (IL)-6,
transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha by a
human macrophage cell line (THP-1), by human endothelial cells (HVEC and HMEC)
and a human colorectal cancer cell line (DLD-1), and on the cytotoxicity on
endothelial cells in both confluent and non-confluent culture. The generation of
oxygen radicals by normal and pre-stimulated granulocytes was not increased after
preincubation with any of the drugs, at the concentrations tested. None of the
cytokines (IL-6, TNF-alpha or TGF-beta) was found significantly increased in
culture medium after exposure to any of the mitomycins. This was in contrast with
the effect of BLM incubation, causing a rise in TGF-beta concentration. Both
types of endothelial cells showed a dose-dependent, exposure duration-dependent,
proliferation inhibition for all agents tested. This inhibitory effect was
clearly proliferation dependent as shown by the increased inhibition in semi
confluent as opposed to confluent endothelial cell cultures. Both mitomycins
tested were more cytotoxic than BLM to both confluent and proliferating
endothelial cells.
PMID- 9402314
TI - Comparative effect of verapamil, cyclosporin A and SDZ PSC 833 on rhodamine 123
transport and cell cycle in vinblastine-resistant Chinese hamster ovary cells
overexpressing P-glycoprotein.
AB - The product of the mdr1 gene, P-glycoprotein (P-gp), represents a common
mechanism of cellular resistance to a wide variety of structurally and
functionally unrelated drugs. A range of structurally different P-gp inhibitors,
such as verapamil, cyclosporin A and SDZ PSC 833, have been shown to modify
multidrug resistance (MDR). We used flow cytometry to investigate in vitro
modulation of P-gp-dependent efflux of rhodamine 123 (Rh123). The capacity to
modulate the MDR phenotype of vinblastine-resistant Chinese hamster ovary (CHO)
cells was assessed by analyzing the concentration of modulator needed to decrease
the Rh123 mean fluorescence intensity by 50%. We found that the cyclosporin
derivative SDZ PSC 833 was significantly more effective than cyclosporin A and
verapamil, either in the presence or absence of fetal calf serum-supplemented
media. This study indicates that analysis of Rh123 efflux modulation can be used
to determine the optimal doses of MDR inhibitors in vitro and suggests that more
than one modulator is needed to measure P-gp function, since verapamil had no
effect on Rh123 modulation when MDR cells were used.
PMID- 9402315
TI - Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the
thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers.
AB - Oxaliplatin, classical [5-fluorouracil (5-FU)] and non-classical (AG337)
thymidylate synthase inhibitors have shown promising activity in the treatment of
cancer. This study investigates the cytotoxic effects of oxaliplatin in
combination with 5-FU and AG337 in cultured human colon (HT29, CaCo2), breast
(MCF-7, MDA-MB-231) and ovarian (2008) cancer cell lines, and their derived
counterparts selected for their resistance to 5-FU (HT29-5-FU), doxorubicin (MCF
7mdr) or cisplatin (2008C13). Therapeutic experiments were conducted in mice
bearing colon-HT29 xenografts and in the GR hormone-independent mammary carcinoma
model. In vitro, oxaliplatin shows potent cytotoxic activity in colon (IC50 from
2.1 +/- 1.1 to 5.9 +/- 1.7 microM), ovarian (IC50 = 10 +/- 1.6 microM) and breast
cancer cells (IC50 from 7.4 +/- 2.7 to 17.9 +/- 7.1 microM). Oxaliplatin was a
potent inhibitor of DNA synthesis and bound to cellular DNA. Surprisingly, the
overall amount of oxaliplatin DNA binding was significantly inferior to that
induced by isocytotoxic concentrations of cisplatin in HT29 (p=0.026). In vitro,
synergistic antiproliferative effects were observed when oxaliplatin was added to
5-FU and AG337. Those synergistic effects of combinations were maintained in
colon HT29-5-FU cancer cells. In vivo, 5-FU increased significantly the antitumor
activity of oxaliplatin in HT29 xenografts (p=0.0036), and similarly 5-FU and
AG337 increased the activity of oxaliplatin in the GR tumor model (p=0.0012).
These data may encourage further clinical investigation of oxaliplatin in
combination with classical and non-classical thymidylate synthase inhibitors in
the treatment of human cancers.
PMID- 9402316
TI - The mechanism of locally enhanced production of tumor necrosis factor-alpha in
tumor tissues by the administration of a new synthetic lipid A analog, ONO-4007,
in hepatoma-bearing rats.
AB - ONO-4007 is a new synthetic lipid A analog with low endotoxic activities. We
previously found that ONO-4007 induced the production of tumor necrosis factor
(TNF)-alpha in rat hepatoma KDH-8 tumor tissues and brought about the regression
of transplanted KDH-8 cells. By contrast, ONO-4007 did not induce TNF-alpha
production in spleens and sera 90 min after treatment. In the present study we
attempted to elucidate how ONO-4007 induces TNF-alpha production in tumor tissues
locally. We found that extracellular matrix including gelatin, fibronectin and
Matrigel did not induce TNF-alpha production in splenocytes treated with ONO-4007
in vitro. However, splenocytes co-cultured with cKDH-8/11 tumor cells in the
presence of ONO-4007 produced more TNF-alpha than splenocytes cultured by
themselves in the presence of ONO-4007. The stimulation of cKDH-8/11 cells in the
presence of ONO-4007 for splenocytes to produce TNF-alpha depended on the type of
contact between the cells. The cKDH-8/11 cells fixed in formalin were not able to
induce TNF-alpha production of splenocytes even in the presence of ONO-4007.
However, syngeneic fibrosarcoma cell line KMT-17/A3, allogeneic hepatocellular
carcinoma cell line LDH and rat lung endotherial cell line RLE induced TNF-alpha
production in splenocytes, but their stimulation was weaker than that of cKDH
8/11. The soluble form of the cKDH-8/11 cell membrane did not stimulate
splenocytes to produce TNF-alpha in the presence of ONO-4007. cKDH-8/11 cells did
not stimulate the splenocytes devoid of macrophages to produce TNF-alpha in the
presence of ONO-4007.
PMID- 9402317
TI - Prevention of peritoneal metastasis of cancer with dextran sulfate--an
experimental study in mice.
AB - Peritoneal metastases occur most often in the greater omentum, where tumor
implantation sites are densely distributed. We used dextran sulfate (S-Dex) as an
anti-cell-adherence agent to prevent i.p. seeded malignant cells from causing
peritoneal metastases. S-Dex was tested for its anti-adherent activity against B
16 melanoma cells on plastic, and was examined for its ability to prevent
implantation in the omentum and to improve survival in mice after B-16 melanoma
was inoculated i.p. S-Dex prevented B-16 melanoma cells from adhering to the
plastic wall. S-Dex reduced the number of B-16 melanoma cells implanted into the
greater omentum and improved the survival of mice inoculated with B-16 melanoma
cells. We conclude that S-Dex attenuated peritoneal metastases when B-16 melanoma
cells were seeded i.p.
PMID- 9402318
TI - Therapeutic effects of a new synthetic lipid A analog, ONO-4007, on rat hepatoma
KDH-8 depend on tumor necrosis factor-sensitivity of the tumor cells.
AB - ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. ONO
4007 was effective against KDH-8, a tumor necrosis factor (TNF)-sensitive rat
hepatoma cell line, but neither effective against KMT-17, a TNF-resistant rat
fibrosarcoma cell line, nor SST-2, a TNF-resistant rat mammary adenocarcinoma
cell line. We have established two sublines from KDH-8 to further examine the
therapeutic mechanisms of ONO-4007 in vivo: TNF-sensitive KDH-8/YK and TNF
resistant cKDH-8/11. The two sublines equally proliferated in vitro. Multiple
systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after
tumor implantation. Although treatment with ONO-4007 had no effect on the growth
of cKDH-8/11 in WKAH rats in vivo, 60% of KDH-8/YK-bearing rats treated with ONO
4007 survived. The administration of ONO-4007 brought about significant
therapeutic effects on KDH-8/YK-bearing rats but not on cKDH-8/11-bearing rats.
These results suggest that ONO-4007 is therapeutically useful for the treatment
of TNF-alpha-sensitive tumors.
PMID- 9402319
TI - Reed-Sternberg cells and the TNF family of receptors/ligands.
AB - Treatment of cancer with means other than chemo- and radiation therapy becomes
more and more important. Through the better understanding of tumor biology
approaches towards the cure of cancer interfering with the pathophysiological
mechanisms of malignancy can be considered. Hodgkin's disease is a good example
for the role of the immune system in cancer. The Reed-Sternberg (RS) cells,
malignant cells of Hodgkin's disease (HD), are surrounded by tumor infiltrating
lymphocytes (TILs) and still evade immunesurveillance. In this respect the
importance of the superfamily of tumor necrosis factor (TNF) receptors and
ligands is becoming more and more clear. Ligand-receptor interaction either leads
to death or survival signals. Many of these receptors and ligands are expressed
by the RS cells and the surrounding lymphocytes. Their expression and function in
HD are discussed and future directions for possible therapeutical investigations
are proposed.
PMID- 9402320
TI - The Wilms tumour gene WT1 in leukaemia.
AB - The WT1 gene is essential for kidney development and is mutated in some Wilms
tumours. It is also expressed at a high level in many acute leukaemias and in
some haematopoietic progenitor cells, and mutations have been found in
leukaemias. The function of WT1, which is a zinc finger protein and has domains
characteristic of transcription factors, is not well understood. The level of
expression is highest in leukaemias with immature phenotypes. Expression of WT1
is downregulated during differentiation of leukaemic cell lines and high levels
of WT1 expression can cause cell cycle arrest and/or apoptosis. This may reflect
a role in the control of normal haematopoiesis, which can be abrogated by
mutations in the gene and form part of the pathway towards leukaemogenesis.
PMID- 9402321
TI - Fibroblast growth factors and early hemopoietic cell development.
AB - The role of fibroblast growth factors (FGFs) in the regulation of the human
hematopoiesis is controversial. Older publications suggest that FGFs play an
important role in regulating the proliferation of human hematopoietic progenitor
and stem cells. Such studies should be interpreted with caution because they were
typically carried out in the presence of serum which not only contains
significant amounts of FGFs, but other cytokines as well. The development of
greatly improved techniques for isolating purified populations of primitive
hematopoietic cells, for culturing such cells in serum free conditions, and for
analyzing the molecular consequences of exposing these cells to FGF cytokines
allow the conclusions of these earlier studies to be tested more rigorously. Our
investigations, and those of others, suggest that FGFs may not play an important
direct role in regulating the development of human hematopoietic stem cells.
These data, and our view of their implications, are discussed in this review.
PMID- 9402322
TI - Clonal populations of T-cells in patients with B-cell malignancies.
AB - Patients with B-cell malignancies are often immunosuppressed and have defective T
cell function in vitro. In addition they frequently have unusual T-cell
populations in the peripheral blood including an increase in the number of
activated T-cells and an inverted CD4:CD8 ratio. More recently several reports
have documented the presence of large, monoclonal populations of T-cells in
patients with paraproteinaemia, B-CLL and hairy cell leukemia. Such cells can
reach very high levels in the peripheral blood, occasionally representing over
50% of all CD8+ T-cells. These clonally expanded cells have a characteristic
morphology and phenotype in that they are often large, granular cells with
natural killer cells markers. Their properties have not been studied in detail
but they appear to suppress immunoglobulin production and kill cell targets in an
MHC-unrestricted manner. The relationship of clonal T-cells to the B-cell tumour
is unclear. They may be directly interacting with the malignant clone or
alternatively be nonspecifically activated secondary to a disruption of the
immune homeostasis by tumour cells. If they indeed represent an attempt by the
immune response to control the malignant cells it is possible that they may be
utilised in future attempts at immunotherapy.
PMID- 9402323
TI - The granulocyte colony-stimulating factor (G-CSF)/G-CSF receptor (G-CSFR) system
in B-cell chronic lymphocytic leukemia.
PMID- 9402324
TI - Characterization of the novel focal adhesion kinase RAFTK in hematopoietic cells.
AB - Protein tyrosine kinases (PTKs) mediate signals that respond to many pivotal
cellular functions. Tyrosine phosphorylation, controlled by the coordinated
actions of protein tyrosine phosphatases (PTPs) and PTKs, is a critical control
mechanism for various physiological processes, including cell growth,
differentiation, metabolism, cell cycle regulation and cytoskeleton function. The
focal adhesion kinase (FAK) is a widely expressed non-receptor tyrosine kinase
that is implicated in integrin-mediated signaling and plays a role in signal
transduction pathways mediating cell adhesion, motility and anchorage-independent
growth. Recently, we and others have identified a novel protein tyrosine kinase
termed RAFTK, (also known as Pyk2 or Cak-beta), which is related to FAK. This
review describes the role of RAFTK in various signaling cascades mainly in
reference to hematopoietic cell lineages.
PMID- 9402325
TI - P-glycoprotein expression in de novo acute myeloid leukemia.
AB - Detection of the multidrug resistance P-glycoprotein (PGP) phenotype was
performed at the time of diagnosis in 223 patients with acute myeloid leukemia
(AML) by flow cytometry using C219 Monoclonal Antibody (MoAb). On the other hand,
JSB1 MoAb was tested in 173 of these samples. At onset, PGP was detected in 57.4%
of cases with C219 and 75.9% of cases with JSB1. There was no correlation between
PGP expression and sex, age, marrow blast percentage or extramedullary disease.
On the contrary, strict correlations were noted either between C219 negativity
and FAB M3 subtype or between C219 positivity and FAB M5 group (P = 0.003).
Significant correlation was found between PGP phenotype and CD7, as 143 of 223
samples had similar patterns of staining with C219 (P < 0.0001). Finally, there
was a close relationship between C219 and JSB1 positivity: all the C219+ cases
were positive for JSB1 (P < 0.0001). Concerning the karyotype, most patients with
monosomy or del (7) were MDR positive; on the other hand, most patients with
t(8;21) or t(15;17) were MDR negative. Rh123 accumulation studies showed a
significant decrease of mean fluorescence intensities both in C219 and in JSB1
positive cases in comparison with PGP negative ones (P < 0.001). A significant
decrease of remission induction rates (CR) was highlighted both between C219+ and
C219- and between JSB1+ and JSB1- cases (32.1% v 62.1% and 32.6% v 73.8%,
respectively, with P < 0.0001). The overall survival and the remission duration
(CCR) were significantly shorter both in C219+ and in JSB1+ patients with no
relationship to age. Furthermore, a higher rate of early relapses was noted among
MDR+ when compared with MDR- patients both for C219+ and JSB1+ cases. The
combination (C219- JSB1+) identified a subset of patients with an intermediate
prognosis. On multivariate analysis, C219 and JSB1 were confirmed to be
independent prognostic factors for achievement of CR, overall survival and CCR.
In conclusion, the assessment of MDR phenotype by flow cytometry is a crucial
prognostic factor of treatment outcome in AML.
PMID- 9402326
TI - Large scale manufacturing of TXU(anti-CD7)-pokeweed antiviral protein (PAP)
immunoconjugate for clinical trials.
AB - We have conjugated the murine monoclonal anti-CD7 antibody TXU to the plant
hemitoxin pokeweed antiviral protein (PAP) to construct an effective immunotoxin
against CD7 antigen positive hematologic malignancies. The scaled-up production
and purification of TXU antibody, PAP toxin, and TXU-PAP immunotoxin permitted
the manufacturing of a highly purified clinical-grade TXU-PAP preparation. In
clonogenic assays, TXU-PAP elicited selective and potent cytotoxicity against CD7
antigen positive human leukemia cells and killed primary clonogenic leukemic
cells from T-lineage acute lymphoblastic leukemia (ALL) patients. To our
knowledge, this pre-IND work represents the first effort of producing a clinical
grade PAP immunotoxin for treatment of T-lineage ALL. Since the CD7 antigen is
also expressed on AML cells, TXU-PAP could also be useful for the treatment of
CD7 positive acute myeloid leukemia (AML) patients.
PMID- 9402327
TI - Benign and malignant smooth muscle tumors containing Epstein-Barr virus in
children with AIDS.
AB - Smooth muscle tumors (leiomyosarcomas) are the second most prevalent malignancy
of children with the acquired immunodeficiency syndrome (AIDS). We have
investigated the tumors, plasma, and peripheral white blood cells of eight
children with AIDS with smooth muscle tumors for evidence of tumor association
with human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV). Very low
levels of HIV were found in the tumors of the AIDS patients, probably resulting
from blood-borne carriage of virus. These smooth muscle tumors had very high
quantities of EBV in all the tumor cells by in situ hybridization, with an
average of 4.5 EBV genomes per cell by quantitative polymerase chain reaction
amplification. Increased amounts of EBV were found in the peripheral blood cells
of two AIDS patients before the time of tumor diagnosis. EBV clonality studies
demonstrated different monoclonal EBV infection of two separate colonic tumors
from one patient, and dual or mixed monoclonal EBV infection in another patient.
The muscle cells of leiomyomas and leiomyosarcomas of patients with AIDS
demonstrated prominent staining with antibodies to the EBV receptor. The uniform
distribution and striking amount of EBV in the tumor cells demonstrates that EBV
is capable of infecting smooth muscle cells and that these cells support EBV
replication. Clonal EBV proliferation suggests that EBV infection occurs at an
early stage of tumor development. These findings indicate that EBV has a causal
role in the oncogenesis of leiomyosarcomas of patients with AIDS.
PMID- 9402328
TI - Incidence and impact of light chain associated (AL) amyloidosis on the prognosis
of patients with multiple myeloma treated with autologous transplantation.
AB - Little is known about the incidence of clinically occult AL amyloid in patients
with multiple myeloma and its impact on prognosis of these patients. To address
these issues, subcutaneous fat pad aspirates (SAFA) and bone marrow biopsies were
evaluated for the presence of amyloid in a cohort of newly diagnosed patients
with multiple myeloma prior to enrollment on a phase II study including tandem
transplants. Organ directed biopsies were performed when clinically indicated.
Presence of amyloid at > or = 1 site was noted in 32 patients (38%). SAFA was
positive in 25 (31%), bone marrow in 8 patients (10%) and other organ sites in 7
patients. Patients with and without amyloid did not differ in disease
characteristics, in particular no lambda predominance was observed in patients
with amyloid. Event free survival (59+ vs 52 months; p = .9) and overall survival
(59+ vs 66+ months; p = .9) were similar in both groups. Even the seven patients
with symptomatic organ involvement with AL amyloid had a median overall survival
of 38+ months. In conclusion, AL amyloidosis occurs more often than previously
reported, but its presence does not influence the outcome of these patients after
transplantation.
PMID- 9402329
TI - Pharmacokinetics of high-dose cytarabine and its deamination product--a
reappraisal.
AB - Cytarabine is intracellularly activated and correlations have been established
between the pharmacokinetic behaviour of active metabolites and their
antileukemic effect. Recently, a good response to high-dose treatment of
leukemias has additionally been attributed to a so-called low deamination
phenotype of cytarabine inactivation. Consequently, these findings would support
plasma level monitoring of cytarabine and its metabolite uracil arabinoside in
high-dose cytarabine regimens. This pharmacokinetic study presents data
attempting to reevaluate these observations. Thirty-seven patients were treated
by 3-h high-dose cytarabine infusions (9 patients 1000 mg/m2, 28 patients 3000
mg/m2) as part of their treatment for acute leukemia. Serial blood samples during
and post infusion were analysed for cytarabine (araC) and its deamination product
uracil arabinoside (araU) using HPLC with UV-detection. Considerable
interindividual variation was observed in end-infusion plasma concentrations of
araC (1000 mg/m2: 2.1-fold, 3000 mg/m2: 5.5-fold) and araU (1000 mg/m2: 2.7-fold,
3000 mg/m2: 2.9-fold). The median ratio of end infusion concentrations araU/araC
(on a molar basis) was 5.6 (S.D. 3.0), extreme ratio values were 2 and 14. No
differences of the araU/araC ratio were found between the two dosages used.
Minimum plasma araC concentrations at the end of infusion were 10.5 micromol/l
and 22.0 micromol/l at a dose of 1000 and 3000 mg/m2, respectively. In our
European study population a "fast" deamination phenotype of cytarabine (araU/araC
ratio > 14) was not be observed.
PMID- 9402330
TI - Rearrangements of the BCL6 gene and chromosome aberrations affecting 3q27 in 54
patients with non-Hodgkin's lymphoma.
AB - Chromosome aberrations affecting 3q27 are among the most frequent non-random
abnormalities in non-Hodgkin's lymphomas (NHL), especially the diffuse, large
cell type. Recently, an association between BCL6 rearrangement and frequent
extranodal lesions, rare bone marrow infiltration and a favorable clinical
outcome was reported. We performed molecular studies of the BCL6 gene in 54
patients with NHL. Twelve patients (22%) with rearranged BCL6 genes were selected
for histological, clinical, molecular, and cytogenetic studies. Ten of these
cases were diffuse, large cell type lymphoma, one a follicular lymphoma, and one
a mantle cell lymphoma (MCL). All cases were of the B-cell type and this is the
first time a rearranged BCL6 gene has been found in an MCL. Cytogenetic data for
10 cases were available and the partner sites of the 3q27 translocation were
determined in 7 of 10 patients. These locations were variable, including 6p21.3,
9p22, and 14q11 in addition to the immunoglobulin loci 14q32 (IGH), 2p12 (IGK),
and 22q11 (IGL). The heterogeneity in partner sites is distinct from other
lymphoma subgroups and may suggest that the genetic events are not uniform among
patients with BCL6 rearrangements.
PMID- 9402331
TI - Eosinophilia associated with clonal T-cell proliferation.
AB - Eosinophilia associated with the expansion of cloned T-cells is reviewed in
relation to cytokine production. It has been proved that eosinophilopoiesis is
caused by eosinophil-stimulating cytokines, including interleukin-5 (IL-5),
granulocyte-macrophage colony-stimulating factor and interleukin-3, which are
secreted from T-cells. Recently, we and other groups have reported several cases
of eosinophilia including hypereosinophilic syndrome (HES) accompanied with
proliferation of abnormal T-cells with an unusual phenotype CD3- CD4+ or CD3+ CD4
CD8- in the peripheral blood. The T-cells clonally proliferate, as confirmed by
clonal rearrangements of the T-cell receptor (TCR) gene, and produce eosinophil
stimulating cytokines, especially IL-5, with or without stimulation in vitro.
Although HES is defined by the combination of unexplained prolonged eosinophilia
and evidence of organ involvement, these observations suggest that increased
production of eosinophil-stimulating cytokines from the abnormal T-cells with
phenotype CD3- CD4+ or CD3+ CD4- CD8- may cause eosinophilia, some of which have
been diagnosed as HES.
PMID- 9402332
TI - Viability and quantification of progenitor cells in venesected blood from
patients receiving escalated-dose epirubicin and cyclophosphamide with G-CSF for
lymphoma: potential role in further increasing dose-intensity.
AB - We assessed the concentration of haemopoietic progenitors in peripheral blood in
six patients with de novo intermediate grade non-Hodgkin's lymphoma receiving
multiple cycles of escalated dose epirubicin and cyclophosphamide on day 1
followed by 5 microg/kg of G-CSF (filgrastim) on days 2-14. Specimens were taken
at days 12, 15 and 18 in cycles 1 and 2 and on day 15 for cycles 3-6. Progenitor
numbers were maximal on day 15 in cycles 1 and 2. The median number of
granulocyte-macrophage colony forming cells (GM-CFC) and CD34+ cells on day 15 of
cycles 1 and 2 was 3.8 x 10(4)/ml and 11 x 10(4)/ml, respectively. A 600 ml
venesection at this time would contain a median of 36 x 10(4) GM-CFC/kg (range 25
47) and 1.04 x 10(6) CD34+ cells/kg (range 0.73-1.4), based on individual patient
weights. Day 15 progenitor numbers were maintained for the first 3 cycles but
tended to fall thereafter. The viability of the progenitors collected in whole
blood and stored at 4 degrees C for various time intervals was also assessed. The
median percent of GM-CFC and erythroid blast forming units (BFU-e) surviving
after storage for 48 hrs was 79% and 69% respectively and after 72 hrs was 48%
and 63% respectively. Serum collected 2 hrs after the completion of chemotherapy
had minimal inhibitory effect on progenitors collected prior to treatment. Our
data demonstrate that two weeks after anthracycline-based chemotherapy and G-CSF
in previously untreated patients the peripheral blood contains large numbers of
progenitors. A 600 ml venesection at this time stored at 4 degrees C, and then
reinfused after the next cycle of chemotherapy would contain sufficient viable
progenitors to potentially hasten haematological recovery.
PMID- 9402333
TI - Treatment of AL-amyloidosis with dexamethasone plus alpha interferon.
AB - Current therapy for primary systemic (AL) amyloidosis has only modest efficacy
(response rate 25%) and because it includes alkylating agents, it has a
significant leukemogenic potential (actuarial risk 21% at 3.5 years). We treated
9 consecutive patients with biopsy proven AL amyloidosis seen at our institution
with pulse dexamethasone induction (40 mg on days 1-4, 9-12, 17-20 repeated q 35
days) for 3-6 cycles followed by maintenance alpha interferon 3-6 million units
thrice weekly. Three patients also received maintenance dexamethasone (40 mg/day
x 4 days q 4-8 weeks) for the first year. Improvement in > or = 1 AL organ
involvement was seen in 8 of 9 patients. Of 7 patients with nephrotic range
proteinuria, 6 had > or = 50% reduction in nonspecific proteinuria with a median
time to response of 4 months (range 3-9 months). Marked improvement in organ
function was also seen in 4 patients with gastrointestinal, hepatic and
neuropathic involvement. However, none of the 2 patients with congestive heart
failure improved. This dexamethasone plus alpha interferon regimen, devoid of
leukemogenic potential, may lead to rapid and durable improvement in organ
function in a significant proportion of patients with AL amyloidosis and deserves
further evaluation as front line therapy.
PMID- 9402334
TI - A translocation t(8;14) and c-myc gene rearrangement associated with the
histological transformation of B-cell acute lymphocytic leukemia (FAB-L2) into
Burkitt's type (FAB-L3) leukemia.
AB - We report a case of B-cell acute lymphocytic leukemia which showed histological
transformation from an FAB-L2 into a Burkitt's type (FAB-L3). Both leukemias had
identical immunoglobulin heavy-chain joining gene and kappa light-chain joining
gene rearrangements, indicating the clonal identity of the two leukemias. A
chromosomal analysis of leukemia cells on the onset indicated normal karyotype,
whereas that of the transformed FAB-L3 showed t(8;14)(q24;q32). Furthermore, the
proto-oncogene c-myc was in the germline configuration in the initial leukemia
but in the rearranged configuration after transformation. Presence of
t(8;14)(q24;q32) and the c-myc gene rearrangement after transformation suggested
that the chromosomal translocation followed by the activation of the c-myc proto
oncogene might be involved in the Burkitt's type transformation of the FAB-L2
leukemic clone, but not in the leukemogenesis of the initial FAB-L2 leukemia.
PMID- 9402335
TI - Chronic myeloid leukemia in a woman with papillary carcinoma of the thyroid
treated with radioactive iodine.
AB - A 48-year-old woman presented with chronic myeloid leukemia six years after
beginning repeated radioiodine treatments for papillary carcinoma of the thyroid
gland. The literature on the association of radioiodine and chronic myeloid
leukemia is reviewed.
PMID- 9402337
TI - Maintained all-trans retinoic acid therapy in a patient with pseudotumour cerebri
despite aggravated symptoms.
PMID- 9402338
TI - The role of platelets in antimicrobial host defense.
PMID- 9402336
TI - Bilateral eyelid localisation of a lymphoplasmacytoid lymphoma.
AB - Eyelid localisation of non-Hodgkin's lymphoma is rare, and even more so when it
is bilateral. We report a 58 year-old man who presented with an eyelid
localisation of lymphoplasmacytoid lymphoma. The initial treatment was
chemotherapy with good improvement but the relapse lead us to give radiotherapy
with no further relapse 20 months later. Radiotherapy is the current treatment of
localised eyelid lymphomas with excellent results. The prognosis is related to
the initial staging and the 10-year survival rate is close to 80%.
PMID- 9402339
TI - Proceedings of the 2nd International Workshop on Helicobacter pylori Infections
in the Developing World. Lima, Peru, 28-31 January 1996.
PMID- 9402340
TI - Epidemiological features of Helicobacter pylori infection in developing
countries.
AB - Helicobacter pylori infection has a worldwide distribution, and it has distinct
epidemiological features in developing countries. In contrast to that in
developed countries, H. pylori infection in developing countries seems to be
nearly universal, beginning in early childhood. Children become infected in the
first few months of life; in some communities as many as 50% of the children are
infected by the age of 5 years, and up to 90% are infected by the time they reach
adulthood. In some developing countries with improvements in industrialization,
socioeconomic conditions, and hygiene, infection rates are lower. The incidence
of H. pylori infection, determined indirectly, also suggests a rate several times
higher than that in developed countries. Marked differences in H. pylori
seroprevalence have been observed between various ethnic and racial groups.
Although the mode of transmission of H. pylori remains uncertain, evidence
suggests person-to-person transmission occurs.
PMID- 9402341
TI - Helicobacter pylori infection in Desert Storm troops.
AB - To determine whether military personnel deployed outside the United States are at
increased risk of Helicobacter pylori infection, we evaluated U.S. Army personnel
who served in the Persian Gulf from August 1990 to April 1991. Of 204 subjects
from whom paired predeployment and postdeployment serum specimens were obtained,
76 (37%) were seropositive for IgG antibody to H. pylori before deployment by an
enzyme-linked immunosorbent assay. Of the 111 initially seronegative subjects
evaluated before and after a 7.5-month deployment, five (4.5%) seroconverted. The
calculated annual seroconversion rate was 7.3%. In a postdeployment
questionnaire, 62% of soldiers reported an episode of diarrhea while deployed,
but there was not an increased rate of diarrhea or upper gastrointestinal
symptoms in soldiers who were infected before deployment or in those who
seroconverted. These data suggest that the risk of H. pylori infection increases
during long-term deployment and that acute infection is not distinguishable from
other gastrointestinal illnesses encountered during deployment.
PMID- 9402342
TI - Helicobacter pylori infection in Chile.
AB - This article summarizes studies designed to evaluate the role of Helicobacter
pylori infection in Chile, described in 21 reports from nine centers in various
Chilean regions published between 1985 and 1995. According to their data, H.
pylori infection is quite frequent among patients with a variety of gastric
conditions, including adults (43%-92%) and children (6%-100%). Levels of specific
IgG antibodies to H. pylori are also elevated among patients with duodenal ulcers
(100%) and gastritis (86%) as well as asymptomatic adults (75%). Combination
therapy with three (but not two) drugs has been proved effective, with clinical
improvement, ulcer cure, and H. pylori eradication occurring in well-controlled
studies. Available evidence suggests that antibiotic resistance is not a major
problem in treatment. The H. pylori reinfection rate is low (4.2% per year),
suggesting that combination therapy with three drugs constitutes a cost-effective
alternative for treating colonized symptomatic patients. Concurrent preliminary
studies revealed that antibodies to VacA but not CagA proteins correlate with
disease severity in Chilean patients. It can be concluded that local research
assists local administrators of health resources to implement adequate policies
to prevent, control, and treat H. pylori-related pathologies.
PMID- 9402343
TI - Helicobacter pylori: prevalence, transmission, and serum pepsinogen II
concentrations in children of a poor periurban community in Bangladesh.
AB - The aim of this study was to determine the age-specific prevalence of
Helicobacter pylori infection in infants and children aged 1-99 months from a
poor periurban community in Bangladesh. We also examined the frequency of
infection among infants and their 53 immediate family members and evaluated the
relationship between infection and fasting serum group II pepsinogen (pepsinogen
II) concentration in 76 children. Sixty-one percent of 1-3 month-old infants
tested positive for H. pylori; this rate declined steadily to 33% in children
aged 10-15 months and then increased to 84% in children aged 5-8 years. The H.
pylori infection rate was 2.5 times higher in children with illiterate mothers.
No difference in infection rate was detected among the family contacts of
infected vs. noninfected infants. H. pylori-infected children had significantly
higher serum pepsinogen II concentrations than did noninfected children (P <
.001). We conclude that infection with H. pylori is highly prevalent and occurs
at an early age. An environmental factor or factors, rather than or in addition
to intrafamilial spread of this infection, are important in poor communities of
Bangladesh. The higher levels of serum pepsinogen II in H. pylori-positive
children might indicate the presence of gastritis in such asymptomatic children.
PMID- 9402345
TI - Nondispersive infrared spectrometry: a new method for the detection of
Helicobacter pylori infection with the 13C-urea breath test.
AB - Nondispersive infrared spectrometry (NDIRS) was used to detect Helicobacter
pylori infection with the 13C-urea breath test. The results were compared with
those of standard isotope ratio mass spectrometry (IRMS). Both methods accurately
distinguished between H. pylori-positive and H. pylori-negative individuals. The
results demonstrate that NDIRS technology is accurate and therefore of equal
value to standard IRMS for detection of H. pylori infection. It can be
recommended for routine clinical application. As NDIRS technology is much cheaper
than current IRMS machines, we consider the new method extremely useful for
clinical applications.
PMID- 9402344
TI - Helicobacter pylori populations in Peruvian patients.
AB - Helicobacter pylori is an extremely diverse species. The characterization of
strains isolated from individual patients should give insights into colonization
and disease mechanisms and bacterial evolution. We studied H. pylori isolates
from patients in the Japanese-Peruvian Polyclinic in Lima, Peru, by determining
metronidazole susceptibility or resistance and by random amplified polymorphic
DNA (RAPD) fingerprinting (a measure of overall genotype). Strains isolated from
several biopsy specimens from each of 24 patients were studied. Both
metronidazole-susceptible and -resistant strains were isolated from 13 patients,
whereas strains of more than one RAPD type were isolated from only seven
patients. We propose that the homogeneity in RAPD fingerprints for strains
isolated from most persons reflects selection for particular H. pylori genotypes
during chronic infection in individual hosts and the human diversity in traits
that are important to this pathogen. Carriage of related metronidazole-resistant
and -susceptible strains could reflect frequent metronidazole use in Peru and
alternating selection for resistant and susceptible phenotypes during and after
metronidazole therapy.
PMID- 9402346
TI - Chronic atrophic gastritis: early diagnosis in a population where Helicobacter
pylori infection is frequent.
AB - Chronic atrophic gastritis (CAG) is a premalignant condition characterized by
loss of gastric antral deep glands. The histologic changes in antral gastric
biopsy specimens from 54 Peruvian patients with dyspepsia were studied to detail
the development and characteristics of CAG. Ninety-six percent of the biopsies
revealed severe superficial mucosal inflammation and 89% showed deep
inflammation. Moderate or severe CAG was present in 36 (67%) of the 54 patients.
In the early stages of CAG, a glandular lymphoid adherence lesion was noted in 17
(31%) of the 54 biopsy specimens. This lesion consisted of lymphocytes adherent
to the antral deep gland cells and was associated with glandular epithelium
alterations. The late stage was characterized by small glands, remnants of
glands, and gland replacement with a fibrocellular infiltrate or intestinal
metaplasia. We propose that the development of CAG probably proceeds via a
stereotyped sequence, with an early deep inflammatory component that may trigger
local gland destruction and eventual permanent loss.
PMID- 9402347
TI - Geographic factors probably modulating alternative pathways in Helicobacter
pylori-associated gastroduodenal pathology: a hypothesis.
AB - It is hypothesized that probable geographic factors of nutritional type,
nonrelated to development or socioeconomic level, may modulate the conversion of
Helicobacter pylori-associated active chronic gastritis from its early stages to
chronic atrophic gastritis (CAG). The factors could be diets low in antioxidant
vitamins and other micronutrients such as selenium. In regions of the world where
these modulating factors are not present, active chronic gastritis tends to stay
in its early stages and to predispose individuals to duodenal ulcer. On the
contrary, in regions where the modulating factors are present, the frequency of
CAG increases markedly. When CAG becomes severe and extensive, hypochlorhydria
ensues. Hypochlorhydria decreases the predisposition to duodenal ulcer, while
CAG, a precancerous lesion, predisposes individuals to gastric cancer of the
intestinal type. The hypothesis could be tested in a multicenter, multiregional
study to (1) determine endoscopically and histologically the prevalence rates of
duodenal ulcer, gastric ulcer, gastric cancer, and H. pylori-associated CAG in
large series of dyspeptic patients and (2) correlate these prevalence rates with
blood levels of micronutrients in these patients.
PMID- 9402348
TI - Helicobacter pylori gastritis, peptic ulcer, and gastric cancer: clinical and
molecular aspects.
AB - Helicobacter pylori causes specific ultrastructural changes to the gastric
mucosa. In developing countries a high percentage of infants acquire this
infection, which initially causes a transient drop in stomach acid and thus
allows transit of lower bowel pathogens, with consequent diarrhea and
malnutrition. When infection occurs at an early age, the acid-producing cells of
the stomach are involved in the inflammation, and the lifelong reduced acid
output means a duodenal ulcer rarely develops. However, lifelong gastric
inflammation leads in due course to atrophy, and in the presence of other factors
gastric cancer may develop. People infected with H. pylori on average are of
shorter stature than uninfected people. Adherence of H. pylori to the gastric
mucosa is a prerequisite for infection, and a new binary model of adherence has
been shown recently. Chaperonins of H. pylori induce macrophages to secrete
cytokines, which leads to an immunologic cascade and inflammation.
PMID- 9402349
TI - Role of Helicobacter pylori infection in the development of pernicious anemia.
AB - It is now accepted that most patients with atrophic gastritis of the stomach have
been infected with Helicobacter pylori. Several investigators have also suggested
the possibility that H. pylori is involved in the early stages of pernicious
anemia, which leads to severe atrophic gastritis of the fundus. In this article,
studies investigating the association of this specific form of atrophic gastritis
and H. pylori infection are reviewed. Most of the published studies indicate that
patients with pernicious anemia are infected with H. pylori less often than are
age-matched controls. However, because H. pylori infection may be present before
the development of pernicious anemia, prospective studies during the pre
pernicious anemia stage of gastritis are needed.
PMID- 9402350
TI - Antimicrobial treatment of Helicobacter pylori infection.
AB - Helicobacter pylori is susceptible to many antimicrobials, but clinically only a
few are effective. Two antimicrobials with bismuth or ranitidine or a proton pump
inhibitor such as omeprazole are required to achieve a cure rate of >90% and to
avoid resistance, which occurs when clarithromycin or metronidazole is the single
antimicrobial used. Bismuth plus metronidazole and tetracycline is effective but
causes more side effects than does treatment with omeprazole, amoxicillin, and
clarithromycin; metronidazole can replace clarithromycin. To ensure a high cure
rate, treatment is required for 10 days, but 7-day regimens have sometimes been
as successful. A course of ranitidine bismuth citrate for 28 days, given with
clarithromycin for the first 14 days, cures 80%-85% of patients, but given with
amoxicillin it cures only 74%. In developing countries resistance to
metronidazole can reach 95%. An inexpensive regimen is bismuth subsalicylate (two
tablets) plus furazolidone (100 mg), four times daily for 4 weeks; however, as
this yields a cure rate of only 72%, this regimen is not truly cost-effective.
PMID- 9402351
TI - Rapid recurrence of Helicobacter pylori infection in Peruvian patients after
successful eradication. Gastrointestinal Physiology Working Group of the
Universidad Peruana Cayetano Heredia and The Johns Hopkins University.
AB - Helicobacter pylori is associated with gastritis, peptic ulcer disease, and
gastric cancer. Since gastric cancer is common in Peru, eradication of H. pylori
may help to reduce the occurrence of gastric cancer. This study involved three
randomized trials to determine the efficacy of four different triple-drug therapy
regimens. The most successful regimen was furazolidone combined with bismuth
subsalicylate and amoxicillin, which eradicated infection in 82% of patients.
Patients successfully treated were followed every 2-3 months to determine the
recurrence rate of H. pylori infection. Of 105 patients with H. pylori
eradication documented by pathology and culture, 52% (55) returned for follow-up
endoscopy, and in 73% (40) of these 55 the infection recurred during the 8-month
follow-up period. Thirty-five patients from whom H. pylori was eradicated and who
were tested for antibodies to H. pylori remained consistently seropositive. Rapid
recurrence of H. pylori infection after successful eradication suggests that
measures other than antimicrobial therapy are needed to fight H. pylori in
developing countries.
PMID- 9402353
TI - Value of serology as a noninvasive method for evaluating the efficacy of
treatment of Helicobacter pylori infection.
AB - The systemic humoral response to Helicobacter pylori was studied in 86 infected
adult patients before antimicrobial therapy and at intervals following therapy.
Endoscopy with collection of biopsy specimens was performed immediately before
treatment; a 13C-labeled urea breath test was performed, and blood specimens were
collected before treatment and at 1, 3, 6, 9, and 12 months after treatment.
Serum samples from three patient groups (eradication success [n = 50],
eradication failure [n = 16], and no treatment [n = 20]) were assayed for IgA and
IgG antibodies to H. pylori by enzyme-linked immunosorbent assay. Levels of
antibody to H. pylori before treatment were similar in all three groups. As
expected, the no treatment and eradication failure groups had no significant
changes in antibody levels during the study period. In contrast, for the
eradication success group, the specific IgA and IgG antibody levels decreased
progressively and significantly. We conclude that serology is a potentially
useful way to monitor the success of treatment of H. pylori infection without
using invasive or more expensive methods.
PMID- 9402352
TI - Ranitidine versus colloidal bismuth subcitrate in combination with amoxicillin
and metronidazole for eradicating Helicobacter pylori in patients with duodenal
ulcer.
AB - One hundred twenty-two patients were randomly assigned to three groups of
treatment (A, B, and C), with (1) ranitidine (300 mg q.d. for 6 weeks), (2)
ranitidine (300 mg q.d. for 6 weeks) with amoxicillin (500 mg t.i.d.) and
metronidazole (500 mg b.i.d.) for the first 12 days, or (3) colloidal bismuth
subcitrate (120 mg q.i.d. for 6 weeks) with amoxicillin and metronidazole (at
same dosages as in the latter group). Six weeks after the beginning of treatment,
an endoscopy showed that ulcers had healed in 49 of 52 patients (94.2%) from whom
Helicobacter pylori had been eradicated and in 59 of 70 patients (84.3%) from
whom it had not (NS). The rates of H. pylori eradication in groups A, B, and C
were zero, 47.5%, and 86.8%, respectively. At 6, 12, and 18 months, an endoscopy
was repeated for monitoring ulcer recurrence and H. pylori status. Reinfection
rates at 6 months were 42.1% and 15.1% in groups B and C, respectively (P < .05).
At 18 months, ulcers recurred in 82.9% (63) of 76 patients with noneradicated H.
pylori infection, vs. 5.7% (2) of 35 patients without H. pylori infection (P <
.001). We conclude that colloidal bismuth subcitrate is more effective for
eradication of H. pylori than ranitidine when given with amoxicillin plus
metronidazole for the treatment of duodenal ulcer, as both early reinfection and
ulcer recurrence are diminished.
PMID- 9402355
TI - Lactobacillus bacteremia and endocarditis: review of 45 cases.
AB - Lactobacilli are part of normal gastrointestinal and genitourinary flora but are
an uncommon cause of bacteremia. We reviewed the cases of 45 patients with
clinically significant lactobacillus bacteremia occurring over 15 years.
Underlying conditions were common, including cancer (40%), recent surgery (38%),
and diabetes mellitus (27%). Twenty-two patients were in the intensive care unit
at the time of onset of lactobacillus bacteremia. Eleven of the 45 patients were
receiving immunosuppressive therapy, 11 were receiving total parenteral
nutrition, and 23 had received antibiotics without activity against Lactobacillus
prior to the occurrence of bacteremia. Bacteremia was polymicrobial in 27
patients and developed during hospitalization in 39. Thirty-one patients died,
but only one death was attributable to lactobacillus bacteremia. Lactobacilli are
relatively avirulent pathogens that produce bacteremia in patients with serious
underlying illnesses, many of whom have received prior antibiotic therapy that
may select out for the organism. While rarely fatal in itself, lactobacillus
bacteremia identifies patients with serious and rapidly fatal illness.
PMID- 9402354
TI - Acquired drug resistance in Mycobacterium tuberculosis isolates recovered from
compliant patients with human immunodeficiency virus-associated tuberculosis.
AB - We describe five compliant patients with human immunodeficiency virus (HIV)
associated tuberculosis (TB) that relapsed, with acquisition of resistance by the
original Mycobacterium tuberculosis strains. Both the first and second isolates
from each patient had the same IS (insertion sequence) 6110-based DNA fingerprint
patterns. Three of the five patients developed TB that was resistant to rifampin
alone; no mutation in the region of the rpoB gene was detected by a line probe
assay in two of the isolates from these patients. We discuss several factors
presumably associated with acquired drug resistance in HIV-infected patients,
including exogenous reinfection, drug interactions, malabsorption of drugs, and
the presence of a large organism burden.
PMID- 9402356
TI - Clostridium difficile infection is a risk factor for bacteremia due to vancomycin
resistant enterococci (VRE) in VRE-colonized patients with acute leukemia.
AB - A cohort study was conducted in a cancer center to identify risk factors for
bacteremia with vancomycin-resistant enterococci (VRE) in neutropenic cancer
patients colonized with VRE. There were 10 patients with VRE bacteremia among 56
colonized with VRE, of whose charts 51 were available for review. One hundred
percent of patients with VRE bacteremia (10 of 10) vs. 56% of patients without
VRE bacteremia (23 of 41) had acute leukemia (P = .01, Fisher's exact test). Four
of the 10 patients with VRE bacteremia had a positive Clostridium difficile toxin
assay within 6 days of their first positive VRE blood culture. Both C. difficile
infection and antimicrobial (vancomycin and ciprofloxacin) use during VRE
colonization were significant risk factors for VRE bacteremia in univariate
analysis. When a Cox proportional hazards model was used to account for
differences in follow-up time, C. difficile infection was the only statistically
significant risk factor (risk ratio, 8.2; P = .007) for VRE bacteremia in VRE
colonized patients with acute leukemia.
PMID- 9402357
TI - Postsurgical mediastinitis: a case-control study.
AB - We report the results of a case-control study of postsurgical mediastinitis (PSM)
that we conducted from 1985 to 1993. The incidence of PSM was 2.2% (81 of 3,711
cases who underwent sternotomy); we analyzed the findings for 73 cases and 73
controls. Univariate analysis revealed that the risk factors for PSM were
emergency surgery (27% of cases vs. 13% of controls), New York Heart Association
functional class IV (46.5% vs. 21.9%), heart transplantation (12% vs. 0), and
coronary artery bypass graft (CABG) surgery (60% vs. 41%). The incidences of
fever, reoperation for bleeding, pacemaker placement, use of vasoactive drugs,
prolonged mechanical ventilation, use of central lines, and treatment in the
intensive care unit were also higher for cases. Multivariate analysis identified
the following independent risk factors for PSM: reoperation (risk ratio [RR],
9.2), need for vasoactive drugs (RR, 3.5), CABG surgery (RR, 3.2), and fever that
persisted after the third postsurgical day (RR, 406). The related mortality was
13.7%, and death was significantly more frequent among cases (17.7%) than among
controls (2.7%). Multivariate analysis identified the following independent risk
factors for mortality: bacteremia (RR, 21.5), the use of an intraaortic balloon
(RR, 14.9), advanced age (RR, 1.14 per year), and prolonged mechanical
ventilation (RR, 1.1 per day).
PMID- 9402358
TI - Subcutaneous phaeohyphomycosis.
PMID- 9402359
TI - Differential quantitative blood cultures in the diagnosis of catheter-related
sepsis in intensive care units.
AB - The aim of this prospective study was to compare differential blood cultures and
quantitative catheter tip cultures for the diagnosis of catheter-related sepsis.
Over a period of 2 years, 283 central venous catheters were inserted in 190 adult
patients. Catheters were removed when they were no longer needed or when
infection was suspected. Immediately before removal of the central venous
catheters, blood cultures were performed, with blood drawn simultaneously from
the catheter and the peripheral vein. After removal, quantitative catheter
culture was performed according to the Brun-Buisson modified Cleri technique.
Fifty-five quantitative catheter cultures were positive. They were classified as
contaminated (n = 18), colonized (n = 23), or infected (n = 14). Differential
blood cultures correctly identified 13 infections. With a catheter/peripheral cfu
ratio of 8, differential blood cultures had a sensitivity of 92.8% and a
specificity of 98.8%. When the catheters were removed because of suspected
infection, differential blood cultures had a sensitivity of 92.8% and a
specificity of 100%. Differential blood culture, a technique that does not
necessitate catheter removal, seems effective in the diagnosis of catheter
related sepsis in patients in the intensive care unit.
PMID- 9402360
TI - A molecular epidemiological approach to studying the transmission of tuberculosis
in Amsterdam.
AB - We conducted a retrospective, population-based study with use of restriction
fragment length polymorphism (RFLP) analysis to determine the incidence of and
risk factors for clustering of Mycobacterium tuberculosis isolates, indicative of
recently transmitted infection, among patients with culture-proven tuberculosis
diagnosed between 1 July 1992 and 1 January 1995 in Amsterdam. We found that 214
(47%) of 459 patients were in 53 clusters, probably because of recent
transmission of M. tuberculosis among 161 (35%) of these patients. Conventional
contact tracing resulted in identification of 5.6% of the 161 patients.
Clustering was more frequent among Dutch patients (59.3%) than among foreign
ethnic patients (42.1%) (P = .002). The independent risk factor for clustering
among Dutch patients was younger age; the independent risk factors among foreign
ethnic patients were hard-drug use; alcohol abuse; and country of origin (Surinam
or the Netherlands Antilles). These findings suggest the shortcomings of the
usual tuberculosis control policies in Amsterdam. We identified several risk
factors for clustering, which may guide adjustment of tuberculosis control and
contact tracing strategies.
PMID- 9402362
TI - Impaired pulmonary function in patients with hemorrhagic fever with renal
syndrome.
AB - Pulmonary and cardiac functions were investigated in 13 patients hospitalized
with nephropathia epidemica, a European form of hemorrhagic fever with renal
syndrome. As compared with reference values, the patients' diffusion capacity for
carbon monoxide was decreased (P = .002) and pulmonary clearance of inhaled
technetium-99m-labeled diethylenetriamine pentaacetic acid was increased (P =
.002). In four of 11 patients, arterial blood gas analysis disclosed a reduction
in partial pressure of O2 (< 10 kPa) and oxygen saturation (< 94%). In three of
13 patients, chest radiography revealed interstitial infiltrates or pleural
effusions. Lung volumes and expiratory flow rates of the patients were not
significantly changed. By electrocardiography and echocardiography, no
significant cardiac dysfunction was demonstrable. The pulmonary dysfunction was
best explained by an alveolocapillary lesion. The two hantavirus-caused clinical
syndromes, hemorrhagic fever with renal syndrome and hantavirus pulmonary
syndrome, may be pathophysiologically more similar than appears from the clinical
presentations.
PMID- 9402361
TI - Cytomegalovirus infection after intestinal transplantation in children.
AB - Sixteen episodes of cytomegalovirus (CMV) disease occurred in 10 of 41 children
undergoing intestinal transplantation from 1990 to 1995. Stratification of CMV
disease by donor (D)/recipient (R) serological status was as follows: 3 of 8,
D+/R-; 3 of 9, D+/R+; 4 of 9, D-/R+; and 0 of 15, D-/R-. Treatment resulted in
resolution of CMV disease in 93.3% of episodes. No deaths attributable to CMV
disease occurred in this series. CMV in D+/R- children resulted in more extensive
and persistent disease. However, patient and graft survival rates were similar in
the different D/R subgroups and between children with and without CMV disease.
Cumulative dose of steroid boluses (relative risk [RR], 1.59; 95% confidence
interval [CI], 1.14-2.21) and history of steroid recycles (RR, 2.72; 95% CI, 1.21
6.13) were associated with CMV disease. These results suggest that although CMV
associated morbidity in pediatric intestinal transplant recipients was
substantial, it was not associated with an increased rate of mortality or graft
loss, even among high-risk D+/R- patients.
PMID- 9402363
TI - Chlamydia pneumoniae in children with otitis media.
AB - In this study the polymerase chain reaction was used to test for the presence of
Chlamydia pneumoniae DNA in 118 middle-ear aspirates from 20 children with acute
otitis media (AOM) and 53 children with otitis media with effusion (OME). C.
pneumoniae was detected in 8 samples obtained from 5 children with OME and,
together with Streptococcus pneumoniae, in a sample from 1 child with AOM. The
mean age of these five children (6.6 +/- 1.4 years) was significantly higher than
that of the 48 children with OME in whom C. pneumoniae could not be detected (4.3
+/- 1.9 years). The presence of C. pneumoniae in 9.4% of the examined children
with OME suggests that C. pneumoniae might be a significant supplementary factor
in the etiology of this common children's disease.
PMID- 9402364
TI - Imipenem-resistant Pseudomonas aeruginosa: risk factors and antibiotic
susceptibility patterns.
AB - Potential risk factors for the detection of imipenem-resistant Pseudomonas
aeruginosa in hospitalized patients were assessed by a case-control study. Forty
patients whose first P. aeruginosa isolate was resistant or intermediate to
imipenem were more likely than 387 controls to have received imipenem (odds ratio
[OR] = 16.9; P < .0001) and to have undergone organ transplantation (OR = 3.9; P
= .008). No significant difference was found for treatments with other
antibiotics, other underlying diseases, demographic characteristics, different
exposures to the hospital environment, or the culture site. Imipenem-resistant P.
aeruginosa isolates were more likely to be resistant to other common
antipseudomonal agents than were imipenem-susceptible isolates. It is concluded
that treatment with imipenem, but not with other beta-lactam drugs, is a major
risk factor for the detection of imipenem-resistant P. aeruginosa in hospitalized
patients, that these organisms may relatively often be resistant to other
antipseudomonal agents, and that the hospital environment per se might not play a
major role in their epidemiology.
PMID- 9402365
TI - Evaluation of pertussis in U.S. Marine Corps trainees.
AB - One hundred twenty male U.S. Marine Corps trainees with histories of at least 7
days of cough underwent evaluation for Bordetella pertussis infection by culture,
B. pertussis-specific polymerase chain reaction (PCR) analysis, and serology.
Antibody levels in preexposure, acute-phase, and convalescent-phase serum samples
were measured in a microagglutination assay and in enzyme linked immunosorbent
assays (ELISAs) for IgG and IgA antibodies to pertussis toxin, filamentous
hemagglutinin, pertactin, and fimbriae types 2 and 3. Culture and PCR analysis
revealed that none of the patients were positive for B. pertussis; however, 20 of
120 trainees had serological evidence of B. pertussis infection. Of these cases,
one was confirmed by a rise in the level of antibody to pertussis toxin, and six
were classified as probable by increases in levels of antibodies measured by two
or more assays. Of the 20 individuals with serological evidence of infection, 16
had rises in levels of antibodies to fimbriae or agglutinating antibodies. The
utility of ELISA for detecting antibodies to fimbriae and the microagglutination
assay for diagnosing pertussis in adults should be evaluated by application to
larger and more diverse study populations. These results indicate that pertussis
should be considered in the diagnosis of coughing illness in military
populations.
PMID- 9402366
TI - Pyogenic brain abscess caused by Streptococcus pneumoniae: case report and
review.
AB - While Streptococcus pneumoniae is the most common cause of bacterial meningitis
in adults, cases of pneumococcal brain abscess have rarely been reported. We
describe a case of otogenic brain abscess caused by S. pneumoniae that developed
in a patient who was receiving ciprofloxacin for the empirical treatment of
otitis media. We also review 23 additional cases of pyogenic brain abscess caused
by S. pneumoniae that have previously been reported. The development of a
pneumococcal brain abscess was associated with a contiguous intracranial focus of
infection in 50% of cases. The majority of patients presented with headache (81%)
and focal neurological deficits (86%). However, the classic triad of headache,
fever, and focal neurological deficits was present in only 24% of patients. The
mortality rate for patients with brain abscess caused by S. pneumoniae was 35%;
persistent neurological deficits were documented in 40% of patients who survived.
PMID- 9402367
TI - Duration of nasopharyngeal carriage of penicillin-resistant Streptococcus
pneumoniae: experiences from the South Swedish Pneumococcal Intervention Project.
AB - As a part of an intervention project, all detected carriers of penicillin
resistant pneumococci (PRP) (MIC, > or = 0.5 mg/L) in Malmohus County, southern
Sweden, were followed by means of weekly nasopharyngeal cultures. The median
duration of carriage in 678 individuals was 19 days (range, 3-267 days). The
duration of carriage was longest in children < 1 year old (median, 30 days) and
shortest in adults > 18 years old (median, 14 days). Index cases, whose cultures
were performed during an acute infection, were carriers for a mean of 10 days
longer than asymptomatic contact cases (P < .05). The PRP spontaneously
disappeared from the nasopharynx within 4 weeks in 68%, within 8 weeks in 87%,
and within 12 weeks in 94% of the individuals. Other significant risk factors for
prolonged carriage were the occurrence of > 6 episodes of acute otitis media
(AOM) or first episode of AOM before the age of 1 year (P < .01), the carriage of
PRP by other family members (P < .05), and the obtainment of a first positive
culture during the winter months (P < .05).
PMID- 9402368
TI - Nontyphoidal salmonella intracranial infections in HIV-infected patients.
AB - Salmonella focal intracranial infections are unusual in human immunodeficiency
virus (HIV)-infected patients. Six such infections have been reported in the
world literature. We report a case of salmonella subdural and epidural cerebral
empyema with concomitant osteomyelitis of the frontal bone. Such a complication
in the course of salmonellosis is reported for the first time. In previously
published case reports, four patients had brain abscess and two had subdural
empyema. Salmonella typhimurium was isolated from two patients, and different
serotypes were recovered from the others. All patients had advanced HIV disease,
and all but two had had opportunistic infections before the diagnosis of
salmonella intracranial infection. Surgical drainage combined with systemic
antibiotic therapy resulted in the recovery of four of five patients. No
regression of the lesions occurred in one patient treated only with antibiotics
for multiple cerebral abscesses.
PMID- 9402369
TI - Increased risk of maternal-infant hepatitis C virus transmission for women
coinfected with human immunodeficiency virus type 1. Italian Study Group for HCV
Infection in Children.
AB - To estimate the risk of mother-to-child transmission of hepatitis C virus (HCV)
and identify correlates of transmission, 245 perinatally exposed singleton
children followed prospectively beyond 18 months of age were studied. Overall, 28
(11.4%) of the 245 children acquired HCV infection. Transmission occurred in 3 of
80 children (3.7%) whose mothers had HCV infection alone and in 25 of 165 (15.1%;
P < .01) whose mothers had concurrent infection with human immunodeficiency virus
type 1 (HIV-1). The percentage of HIV-1-infected children was similar (22 of 165,
13.3%), but each virus was transmitted independently; only six infants (3.6%)
were coinfected with HCV and HIV-1. The risk of HCV transmission was not
associated with maternal HIV-1-related symptoms, intravenous drug use,
prematurity, low birth weight, or breast-feeding, whereas it was lower with
cesarean section than with vaginal delivery (5.6% vs. 13.9%, P = .06). This
suggests that transmission occurs mainly around the time of delivery.
PMID- 9402370
TI - Effect of treatment with zidovudine on subsequent incidence of Kaposi's sarcoma.
AB - Despite much investigation of zidovudine, little has been reported regarding its
effect on the development of most individual AIDS-defining illnesses, including
Kaposi's sarcoma (KS). We used observational data from the Multicenter AIDS
Cohort Study (MACS) to estimate the effect of zidovudine use on the subsequent
incidence of KS. To do this, we examined and adjusted for predictors of
zidovudine use. CD4 lymphocyte counts, the development of HIV-related symptoms
and AIDS, and changes in these factors were important predictors of zidovudine
use. We used these associations to control for confounding by these and other
factors with the G-estimation approach. We found no evidence that zidovudine use
affected the time to KS in the MACS; the point estimate (95% confidence interval
[CI]) for increase in time to KS was zero (-28%-68%). The relative risk was 1.0
(95% CI, 0.54-1.84). Randomized trials suggest that zidovudine may prevent KS. We
discuss possible explanations for differences between results.
PMID- 9402371
TI - Elevated concentrations of human neutrophil peptides in plasma, blood, and body
fluids from patients with infections.
AB - Neutrophil peptides, also called defensins, are antimicrobial molecules localized
in the azurophil granules of neutrophils. We used a sensitive radioimmunoassay to
measure the concentrations of human neutrophil peptides (HNPs) 1-3 in the plasma
and blood of 86 healthy volunteers who served as controls and 54 patients with
various infections. The respective mean plasma concentrations of HNPs 1-3 in the
patients at the onset of bacterial infection, nonbacterial infection, and
pulmonary tuberculosis were 4.2, 3.2, and 1.8 times the mean value (+/- SE) for
the controls (254.8 +/- 7.1 pg/microL). Plasma concentrations of HNPs 1-3 for the
patients were correlated with the peripheral blood neutrophil counts (correlation
coefficient = 0.629; P = .0001). The mean concentration (+/- SE) of blood HNPs 1
3 in patients with bacterial infections was higher than the mean value (+/- SE)
for controls (10.4 +/- 0.6 ng/microL), whereas the mean concentration (+/- SE) in
patients with nonbacterial infections or tuberculosis did not differ from that
for controls. Reverse-phase high performance liquid chromatography of plasma
samples from patients with bacterial infections showed high concentrations of two
precursors of HNPs 1-3, indicating that the biosynthesis of HNPs in neutrophil
precursor cells is stimulated in response to infection and/or that the release of
pro-HNPs is enhanced. HNPs 1-3 concentrations in the pleural fluid,
bronchoalveolar lavage fluid, urine, and cerebrospinal fluid were also elevated
in patients with infections. Our results suggest that HNPs have physiological
significance in infection and that this family of peptides may be useful in
assessing neutrophil function during infection.
PMID- 9402372
TI - Questions and answers about defensins.
PMID- 9402373
TI - Imported yellow fever in a United States citizen.
AB - The last imported case of yellow fever seen in this country was in 1924. We
report a case of yellow fever acquired by an American tourist who visited the
jungles of Brazil along the Rio Negro and Amazon Rivers. The patient died 6 days
after hospital admission and 10 days after his first symptoms appeared. Yellow
fever virus was recovered from clinical specimens, and the isolate was
genetically similar to the E genotype IIB of South American yellow fever viruses.
This patient's illness represents a case of vaccine-preventable death since he
failed to be immunized with a recommended preexposure yellow fever vaccine.
PMID- 9402374
TI - Two strategies for managing invasive aspergillosis: a decision analysis.
AB - We devised a diagnostic approach based on screening plasma for an Aspergillus
antigen with use of a sandwich enzyme-linked immunosorbent assay (ELISA),
thoracic computed tomographic scanning, and radionuclide imaging for managing
patients at risk for invasive aspergillosis. We used a decision analytic model to
compare this alternative strategy with the conventional strategy, which relies
only on the presence of clinical symptoms, persistent fever, and chest
roentgenographic findings. Use of the alternative strategy reduced the number of
patients who would receive antifungal treatment empirically, but this strategy
was more expensive. The specificity of the sandwich ELISA had a significant
impact on cost, but the sensitivity did not. A 13% prevalence of infection
resulted in equal costs for both strategies. As much as 43.3% of the patients
treated empirically could be given liposomal amphotericin B (L-AmB) before the
conventional strategy became the most expensive. The costs of the alternative
strategy were less than those of the conventional strategy when >5.3% of all
patients, irrespective of strategy, were treated with L-AmB.
PMID- 9402375
TI - Spinal epidural abscess associated with the use of temporary epidural catheters:
report of two cases and review.
AB - Spinal epidural abscess has rarely been associated with the use of epidural
catheters. We describe two patients with epidural abscesses that occurred in
relation to the use of temporary epidural catheters; a literature review yielded
20 additional well-described cases. The mean age of these 22 patients was 49.9
years, the median duration of epidural catheter use was 3 days, and the median
time to onset of clinical symptoms after catheter placement was 5 days. The
majority of patients (63.6%) had major neurological deficits, and 22.7% also had
concomitant meningitis. Staphylococcus aureus was the predominant pathogen.
Despite antibiotic therapy and drainage procedures, 38% of the patients continued
to have neurological deficits. These unusual but serious complications of
temporary epidural catheter use require efficient and accurate diagnostic
evaluation, as they can be substantial.
PMID- 9402376
TI - Role of hemophagocytic histiocytosis in the etiology of thrombocytopenia in
patients with sepsis syndrome or septic shock.
AB - We conducted a study to assess the incidence and outcome of hemophagocytic
histiocytosis (HH) in thrombocytopenic patients with sepsis syndrome or septic
shock and to define the possible associations between HH, disseminated
intravascular coagulation (DIC), and platelet-associated IgG (PAIgG) in promoting
thrombocytopenia. Twenty immunocompetent thrombocytopenic patients were included.
Bone marrow aspirates were obtained from each patient to identify hemophagocytic
histiocytes. Coagulation parameters, PAIgG levels, and bacterial and viral
infections were studied. Twelve patients with HH were identified. The presence of
DIC and of PAIgG were often associated with this disease. No herpesvirus
infection was demonstrated. Eight of the 12 patients with HH and four of the
eight patients without HH died (P = NS). The results of this study suggest that
HH could be involved in the development of thrombocytopenia in immunocompetent
patients with sepsis syndrome or septic shock. HH does not seem to be associated
with increased mortality.
PMID- 9402377
TI - Streptococcus pneumoniae blood culture isolates from patients with and without
human immunodeficiency virus infection: alterations in penicillin
susceptibilities and in serogroups or serotypes.
AB - We performed a 3-year retrospective study of Streptococcus pneumoniae blood
culture isolates recovered at Baragwanath Hospital, Soweto, South Africa, from
1993 to 1995. The study group comprised 457 patients, including 98 children, of
known human immunodeficiency virus (HIV) serostatus. Of these patients, 70 (30
[8.4%] of 359 adults and 40 [40.8%] of the 98 children) were infected with
penicillin-resistant S. pneumoniae strains (minimal inhibitory concentration, >
or = 0.12 microg/mL); 56 of these strains were intermediately resistant to
penicillin. HIV-positive patients had significantly more penicillin-resistant
isolates than did HIV-negative patients (43 [29.7%] of 145 HIV-positive patients
vs. 27 [8.6%] of 312 HIV-negative patients; P < .001); this difference was found
for both adults (19% vs. 4.3%; P < .001) and children (53.3% vs. 30.2%; P <
.0343). Multiple resistance occurred more frequently in HIV-positive children (P
= .02). HIV-positive adults had a statistically significant increase in the
percentage of serogroups and serotype usually found in children and commonly
associated with antimicrobial resistance, i.e., serotype 14 and serogroups 6, 19,
and 23 (48% vs. 28.6%; P < .001). The increased prevalence of serogroups or
serotypes usually found in children was also found among penicillin-susceptible
strains. These data suggest that HIV-infected adults may again become susceptible
to the serogroups or serotypes found in children.
PMID- 9402379
TI - Group B streptococcal meningitis in adults: report of twelve cases and review.
AB - Group B streptococcus (GBS) is the leading etiologic agent of bacterial
meningitis and sepsis during the neonatal period, but it is an infrequent cause
of meningitis in adults. We report 12 episodes of group B streptococcal
meningitis in adults and review 52 cases reported in the literature. A total of
24 men and 40 women were included in the study; the mean age (+/- SD) was 49.2 +/
20.5 years (range, 17-89 years). All the patients had cerebrospinal fluid
cultures positive for GBS. Eighty-six percent of the patients had comorbid
conditions, 50% had a distant focus of infection, and blood cultures yielded GBS
for 78.7%. The overall case-fatality rate was 34.4% (22 patients). Factors
associated with a poor outcome were advanced mean age (+/- SD) (61.5 +/- 17.4
years vs. 42.8 +/- 19.2 years; P = .0003) and the presence of complications on
admission (P = .0001). Seven percent of survivors had neurological sequelae.
Group B streptococcal meningitis in adults has become increasingly frequent in
recent years; it tends to occur in patients with severe underlying conditions and
is associated with a high case-fatality rate. Factors associated with a poor
prognosis are advanced age and the occurrence of neurological and
extraneurological complications.
PMID- 9402378
TI - Randomized comparison of ganciclovir plus intravenous immune globulin (IVIG) with
IVIG alone for prevention of primary cytomegalovirus disease in children
receiving liver transplants.
AB - A randomized placebo-controlled trial was conducted to determine the benefit of
ganciclovir (5 mg/[kg x d]) for 30 days in addition to intravenous immune
globulin (IVIG) for 16 weeks for prevention of primary cytomegalovirus (CMV)
disease in children receiving liver transplants. Patients were monitored for 6
months after transplantation. The two groups of patients (recipients of 29
ganciclovir plus IVIG and 27 recipients of IVIG alone) were similar in terms of
age, sex, and underlying disease. The incidence of CMV disease among the
ganciclovir plus IVIG recipients and the IVIG alone recipients was 17% and 26%,
respectively, and the time to disease in these recipients was 46 days and 32
days, respectively. There was no difference between groups in terms of survival;
episodes of rejection, bacteremia, or fungemia; use of immunosuppressive agents;
and incidence of leukopenia or thrombocytopenia. These results suggest that a 4
week course of ganciclovir with IVIG is not more effective than IVIG alone for
prevention of primary CMV disease. Since short-term prophylaxis with ganciclovir
may delay the onset of CMV disease, further studies with a longer course of
ganciclovir prophylaxis are warranted.
PMID- 9402380
TI - Efficacy of brompheniramine maleate for the treatment of rhinovirus colds.
AB - We tested the efficacy of brompheniramine maleate in a large randomized,
controlled trial of volunteers with experimental rhinovirus colds.
Brompheniramine (12 mg) or placebo was administered at 8:00 A.M. and 8:00 P.M.
for < or = 4 days after the onset of symptoms (24, 36, or 48 hours after virus
challenge). During the first 3 days of treatment (the first 4 days after virus
challenge), nasal secretion weights were lower for infected evaluable subjects
receiving brompheniramine (n = 113) than for controls (day 1: 4.3 g vs. 6.8 g;
day 2: 4.8 g vs. 7.7 g; and day 3: 3.3 g vs. 5.3 g) (P < or = .03), as were
rhinorrhea scores (day 1: 0.6 vs. 0.8; day 2: 0.5 vs. 0.8; and day 3: 0.3 vs.
0.5) (P < .03), sneeze counts (day 1: 1.8 vs. 3.6; day 2: 2.1 vs. 5.1; and day 3:
1.3 vs. 3.3) (P < or = .001), and sneeze severity scores (day 1: 0.3 vs. 0.6; day
2: 0.25 vs. 0.7; and day 3: 0.2 vs. 0.4) (P < .001) (n = 112). Cough counts were
lower after day 1 of treatment for the brompheniramine group than for controls
(4.7 vs. 7.9) (P = .05) (day 2 after virus challenge), and other symptoms were
modestly reduced or were unaffected in the brompheniramine group. Total symptom
scores were also lower for the brompheniramine group than for controls on
treatment days 1 (4.8 vs. 6.0) (P = .03) and 2 (4.1 vs. 5.6) (days 2 and 3 after
virus challenge) (P = .003). Treatment with brompheniramine was associated with
the adverse effects of somnolence (n = 3) and confusion (n = 1). Brompheniramine
was efficacious treatment for the sneezing, rhinorrhea, and cough associated with
rhinovirus colds.
PMID- 9402381
TI - Quinolone arthropathy in animals versus children.
AB - The use of quinolones in children and accumulation of data on the
pharmacodynamics of these drugs have been limited and delayed by concern
regarding their chondrotoxicity. A comprehensive review of the findings in
animals compared with the cumulative published findings in children and
adolescents (>7,000 to date) allows the conclusion that such concern is not
justified. Prospective controlled studies in children are justifiable in view of
a continuing lack of correlation between findings in juvenile animals and those
in children and because of the selected therapeutic advantages of the current and
newer quinolones.
PMID- 9402382
TI - Prediction of relapse after treatment of coccidioidomycosis.
AB - Relapse after apparently successful treatment of coccidioidomycosis has been a
problem with both amphotericin B and the azoles. We conducted a retrospective
cohort study of 34 patients who required therapy for coccidioidomycosis between
1973 and 1993; 10 relapsed and 25 (one patient received two courses of therapy)
did not relapse during follow-up. The mean time to relapse after completion of
therapy was 7.3 months (range, 1-21 months). All 34 patients responded clinically
to therapy. A fourfold or greater decrease in titers of antibody, as determined
by complement fixation (CF), during therapy was seen in seven (78%) of nine
patients who relapsed and 17 (85%) of 20 patients who did not relapse (P = .956).
There was no significant difference between relapsers and nonrelapsers in terms
of the lowest CF titer during therapy, the CF titer at the end of therapy, or the
peak CF titer. The risk of relapse was increased among those with a peak CF titer
of > or = 1:256 (relative risk [RR] = 4.7; 95% confidence interval [CI] = 1.4
16.1), as compared with patients who did not mount such a high antibody response.
Similarly, the risk of relapse was higher among those with serially negative
coccidioidin skin tests (CSTs) than those with serially positive CSTs (RR = 4.8;
95% CI = 1.2-19.5). We conclude that clinical response, lowest CF titer, end-of
therapy CF titer, and decrease in the CF titer of at least fourfold are not
predictive of relapse in patients with coccidioidomycosis. Negative serial
coccidioidin skin tests and a peak CF antibody titer of > or = 1:256 are
independently associated with increased risk of relapse.
PMID- 9402383
TI - Adequacy of therapy for coccidioidomycosis.
PMID- 9402384
TI - The clinical use of fluoroquinolones for the treatment of mycobacterial diseases.
AB - Mycobacterial diseases often require prolonged therapy with multidrug regimens.
Fluoroquinolones have excellent bactericidal activity against many mycobacteria;
achieve effective serum, tissue, and intracellular levels following oral
administration; and produce few adverse effects. These properties have led to the
increasing use of fluoroquinolones for the treatment of mycobacterial infections.
We reviewed clinical studies and reports involving the use of fluoroquinolones
for mycobacterial diseases. Ofloxacin, ciprofloxacin, sparfloxacin, and
pefloxacin exhibit clinical efficacy against mycobacterial diseases, especially
tuberculosis and leprosy. Fluoroquinolones have generally been administered in
regimens that include other agents. However, when a fluoroquinolone has been
found to be the sole active agent in a multidrug regimen, the ready emergence of
resistance to fluoroquinolones has been recognized, just as when they have been
used as monotherapy. Therefore, to forestall the emergence of resistance to
fluoroquinolones during the treatment of mycobacterial diseases, these drugs
should always be used in combination with at least one other active agent, and
they should be used only when effective alternative drugs are not available.
PMID- 9402385
TI - Acremonium species: new emerging fungal opportunists--in vitro antifungal
susceptibilities and review.
AB - We provide an overview of opportunistic fungal infections caused by Acremonium
(Cephalosporium) species and discuss the classification of these species as well
as the diagnosis and treatment of acremonium infections. We used a microdilution
broth method to compare in vitro susceptibilities and minimum inhibitory
concentrations and minimum fungicidal concentrations of amphotericin B,
miconazole, itraconazole, 5-fluorocytosine, fluconazole, and ketoconazole for 33
clinical and environmental isolates of Acremonium. In general, the isolates
tested displayed little susceptibility to the antifungals tested. Fluconazole and
5-fluorocytosine were ineffective in all cases. The efficacy of the remaining
drugs was dependent on the strain. Amphotericin B showed the best results.
PMID- 9402386
TI - Nosocomial infections in human immunodeficiency virus-infected patients in a long
term-care setting.
AB - To our knowledge, the epidemiology of hospital-acquired infections in human
immunodeficiency virus (HIV)-infected patients during long-term care has not been
reported. For 13 months, we observed HIV-infected patients (50 men and 15 women)
in a dedicated 21-bed unit in a long-term-care facility to determine the rate of
nosocomial infections. The mean age of the patients was 39 years (range, 22-78
years); 74% of the patients had CD4 cell counts of < 200/mm3. There was a total
of 152 infections (24 infections per 1,000 long-term-care days). The factors
associated with the occurrence of a nosocomial infection were low CD4 cell
counts, poor functional status, and longer duration of stays at the facility. The
three most common infections were Clostridium difficile-associated diarrhea,
primary bacteremia, and urinary tract infection. Eighteen hospital-manifested
opportunistic infections occurred. More than 50% of the cases of bacteremia were
due to multidrug-resistant organisms. Nosocomial infections occur commonly in HIV
infected patients in long-term care and thus are important considerations in
patient management.
PMID- 9402387
TI - Endogenous interleukin-2 serum levels in children infected with human
immunodeficiency virus.
AB - Levels of interleukin-2 (IL-2) in serum obtained from human immunodeficiency
virus (HIV)-infected children at health maintenance visits were measured to
characterize endogenous IL-2 responses and to examine the association between
these responses and progression of immunosuppression. IL-2 was detectable (level
>8.7 pg/mL) in the serum of 28 of 45 HIV-infected children; 42% (19 of 45) had
serum IL-2 levels of >39 pg/mL. Children without evidence of immunosuppression
(Centers for Disease Control and Prevention Pediatric HIV Classification
Immunologic Category 1, n = 15) and children with severe immunosuppression
(immunologic category 3, n = 20) had statistically significant lower serum IL-2
levels (mean +/- [SD], 134.4 +/- 227.3 pg/mL and 18.2 +/- 30.3 pg/mL,
respectively) than those with moderate immunosuppression (mean +/- [SD], 450.5 +/
311.8 pg/ml; immunologic category 2, n = 10) (P < .05, Wilcoxon rank sum test).
In those children in whom immunosuppression was evident, decreasing serum IL-2
levels correlated with depletion of CD4+ lymphocytes (r = 0.74), whereas there
was an inverse correlation between serum IL-2 levels and CD4+ lymphocyte counts
(r = -0.47) in children with no or moderate immunosuppression.
PMID- 9402388
TI - Acute Epstein-Barr virus infection complicated by severe thrombocytopenia.
AB - We describe one patient with acute Epstein-Barr virus (EBV) infection associated
with severe thrombocytopenia and review 36 additional cases reported in the
literature. Complications of EBV infection due to severe thrombocytopenia
occurred in 10 (27.0%) of 37 patients, and 2 (5.4%) of 37 patients died. Although
acute EBV infections are generally benign and self-limiting, thrombocytopenia, a
potentially serious complication, should not be overlooked.
PMID- 9402390
TI - Rhabdomyolysis associated with acute Q fever.
PMID- 9402389
TI - Effect of eliminating seropositive canines on the transmission of visceral
leishmaniasis in Brazil.
AB - In Brazil, where Leishmania chagasi causes endemic American visceral
leishmaniasis (AVL), the spread and maintenance of human disease are attributed
to canine reservoirs. However, despite measures directed toward the elimination
of infected canines, the incidence of human disease continues to increase. To
evaluate the role of infected canines in the acquisition of AVL by humans, we
undertook a controlled intervention study in three similar, but isolated, valleys
of Pancas, Espirito Santo, Brazil. In the two experimental (intervention)
valleys, infected dogs were eliminated whereas in the control valley,
seropositive canines remained untouched. During the 12-month study period, human
seropositivity rates, as measured by dot enzyme-linked immunosorbent assay,
increased from 15% to 54% in the intervention valleys and from 14% to 54% in the
control valley. The elimination of infected canines in the intervention valleys
did not result in a statistically significant difference between the incidences
of human serological conversion in the intervention and control valleys at either
6 (20% and 22%, respectively; P = .5961) or 12 months (26% and 27%, respectively;
P = .9442). The role of humans as a significant reservoir for AVL is proposed as
an explanation for the study results.
PMID- 9402391
TI - Hepatic abscess: rare complication of ventriculoperitoneal shunts.
PMID- 9402392
TI - Mycobacterium lentiflavum: an etiologic agent of cervical lymphadenitis.
PMID- 9402393
TI - Adoptive immunotherapy for interstitial pneumonia associated with cytomegalovirus
infection.
PMID- 9402394
TI - Isolation of toxigenic Clostridium difficile from dialysate fluid in a fatal case
of chronic ambulatory peritoneal dialysis-related peritonitis.
PMID- 9402395
TI - Postpartum epidural abscess due to group B Streptococcus.
PMID- 9402396
TI - Recovery of small colony variants of Staphylococcus aureus following gentamicin
bead placement for osteomyelitis.
PMID- 9402397
TI - Phaeoacremonium parasiticum infective endocarditis following liver
transplantation.
PMID- 9402398
TI - Invasive cryptococcosis in a family with epidermodysplasia verruciformis and
idiopathic CD4 cell depletion.
PMID- 9402399
TI - IgG response to pneumococcal polysaccharide-protein conjugate appears similar to
IgG response to polysaccharide in bone marrow transplant recipients and healthy
adults.
PMID- 9402400
TI - Ocular toxoplasmosis after autologous peripheral-blood stem-cell transplantation.
PMID- 9402401
TI - Salmonella neck abscesses.
PMID- 9402402
TI - Treatment of acyclovir-resistant herpes simplex virus keratitis in a patient with
Wiskott-Aldrich syndrome.
PMID- 9402403
TI - Coinfection with human immunodeficiency virus and human T-cell lymphotropic virus
type I: reciprocal activation with clinical and immunologic consequences.
PMID- 9402404
TI - Pulmonary coccidioidomycosis in Japan: case report and review.
PMID- 9402405
TI - Hemorrhagic dengue with spontaneous splenic rupture: case report and review.
PMID- 9402406
TI - High serum ferritin concentration in an AIDS patient with miliary tuberculosis.
PMID- 9402407
TI - Bacteremia due to Burkholderia gladioli: case report.
PMID- 9402408
TI - Cutaneous protothecosis in a patient with AIDS and a severe functional neutrophil
defect: successful therapy with amphotericin B.
PMID- 9402409
TI - Fatal acute hepatic necrosis due to dose-dependent fluconazole hepatotoxicity.
PMID- 9402410
TI - Fever, erythroderma, abdominal pain, and renal failure following initiation of
indinavir therapy.
PMID- 9402411
TI - High-dose ampicillin plus streptomycin for treatment of a patient with severe
infection due to multiresistant enterococci.
PMID- 9402412
TI - Renal dysfunction in a human immunodeficiency virus-infected patient who was
treated with indinavir.
PMID- 9402413
TI - Nonsteroidal antiinflammatory drugs: concurrent or causative drugs in serious
infection?
PMID- 9402415
TI - The role of glucose-6-phosphate dehydrogenase deficiency in blackwater fever.
PMID- 9402414
TI - Transmission of tuberculosis during medical procedures.
PMID- 9402416
TI - High levels of adenosine deaminase in patients with aseptic meningitis.
PMID- 9402417
TI - [Chronic depression in the year 2000: therapeutic hopes. 10th World Congress for
Psychiatry. Madrid, 24 August 1996].
PMID- 9402418
TI - [Herpes genitalis, an underrated disease?].
PMID- 9402419
TI - [Amiodaron improves prognosis in high risk patients].
PMID- 9402420
TI - [Mibefradil: a new class calcium inhibitor].
PMID- 9402421
TI - [ACE-inhibitors indicated even in non-diabetic nephropathy].
PMID- 9402422
TI - [Uniform guidelines for manuscripts for publication in biomedical periodicals
1997. Abbreviations for titles in periodicals. International Committee of Medical
Journal Editors].
PMID- 9402423
TI - [The Giessen glaucoma symposium. Glaucoma: new aspects of research and therapy].
PMID- 9402424
TI - [New therapeutic methods in the treatment of multiple sclerosis].
PMID- 9402425
TI - [New methods in the pharmacotherapy of Parkinson disease].
PMID- 9402426
TI - [Effective anxiolytic therapy with Buspirone. Focusing on modulation of the
serotonin-neurotransmitter system].
PMID- 9402427
TI - The relationship between electromyography and work intensity revisited: a brief
review with references to lacticacidosis and hyperammonia.
AB - The aim of this investigation was to re-evaluate the relationship between
electromyography and work intensity during incremental work in light of highly
discrepant literature. Trained male subjects participated in the study (n = 14).
Each subject completed a VO2max test on a cycle ergometer. Tests started at a
power output of 60 Watts with a 30 Watt.4 min-1 work increment. Each test was
terminated at exhaustion. Blood was collected at the end of each work intensity
for lactate and ammonia analysis. EMG were recorded from the vastus lateralis,
rectus femoris and vastus medialis using pre-amplified surface electrodes. EMG
were collected at each intensity over a period of 60 cycle revolutions. EMG
signals were analyzed using integration and EMG spectral analysis. Gas exchange
variables were recorded on-line for each test (15 second interval). Ammonia and
lactate threshold points were surpassed at the same absolute work intensity (200
Watts) which was equivalent to 64-69% VO2max. When a linear model was applied to
the iEMG data, coefficients of determination achieved were greater than those
obtained when an exponential model was used for the vastus lateralis and
medialis. Gradients of regression lines fitted to iEMG data at pre- and post
lactate/ammonia threshold work intensities were not different. Alternatively, the
iEMG-work intensity relationship for the rectus femoris muscle tended to be
curvilinear. Significant increases in iEMG were observed at post-lactate/ammonia
threshold work intensities for the rectus femoris reflecting increases in fatigue
and type II motor unit recruitment at these intensities. In general, median
frequency of the EMG power spectrum function were unchanged during incremental
work, although highly individualistic results were observed between some subjects
and muscles. Grouped median frequency values were insensitive to changes in
recruitment, metabolite accumulation and fatigue associated with the increases in
work intensity. Consequently, the usefulness of EMG spectral analysis during
incremental work was questioned.
PMID- 9402428
TI - Early detection of diabetic neuropathy: a neurophysiological study on 100
patients.
AB - As a long-term complication of diabetes mellitus, autonomic neuropathy has
received considerable attention in the last few years since a tripled 5-year
mortality of patients with diabetic neuropathy including autonomic disturbances
has been observed. In a total of 100 diabetics with clinical manifest neuropathy
of different stages (N0 = 8, N1 = 15, N2a = 24, N2b = 28, N3 = 25), 26 of whom
were insulin-dependent and 74 non-insulin-dependent, the validity of different
neurophysiologic and autonomic function test procedures proposed in literature
was assessed. Apart from clinical examination, nerve conduction velocity
measurement of five nerves as well as amplitude measurement of evoked sensory and
motor actin potentials, electromyography of at least four muscles of the lower
limbs, and measurement of sympathetic skin response on hands and feet were
performed. Furthermore, heart rate variation at deep periodical breathing (E/I
ratio), during Valsalva's manoeuver and after standing up (30/15-ratio) was
determined. In addition, the drop in systolic blood pressure to standing up was
measured. The further developed the clinical picture of neuropathy, the more
pathological were the results obtained in different tests. The results suggest
that most changes leading to pathological values of nerve conduction velocity and
heart rate variation measurement take place in a clinical stage, in which no or
only very slight clinical signs give evidence of diabetic neuropathy (N0-N1).
Therefore, especially these examinations should be performed on diabetics with no
or only slight clinical signs of neuropathy in order to reveal those with
beginning neuropathic disturbances. EMG examination is preferable in later stages
of the disease.
PMID- 9402429
TI - Auditory event-related potentials in Parkinson's disease.
AB - We studied 49 patients with Parkinson's disease (PD) by a neuropsychological
battery examining the temporo-spatial orientation, short-term memory,
comprehension, non-verbal intelligence, long-term memory and anomia and the
Auditory Event-Related Potentials. In the patients the latencies of the N100 and
N200 waves were prolonged and the amplitude of the P300 wave was reduced compared
with controls. No difference was found in the ERP of patients with and without
cognitive deficits. Equally, no correlation was found between the ERP, the
cognitive impairment, the length or the severity of the disease evaluated by
Hoehn-Yahr's and Webster's scales.
PMID- 9402430
TI - Short and long latency cortical potentials evoked by electrical stimulation of
the oesophageal mucosa in normal alert humans.
AB - Cerebral responses from the oesophagus were investigated in 16 normal male and
female volunteers ranging in age from 20 to 54 years. The stimulus was applied by
a naso-oesophageal probe equipped with bipolar ring electrodes. Short and long
latency EP (SLEP and LLEP) were observed in all the subjects examined. SLEP
consisted in a low threshold potential of 30 to 70 microV amplitude, biphasic or
triphasic in shape and of approximately 5 to 10 ms duration; mean latency at the
largest peak was 4.5 +/- 1.7 at 25 cm from the nostrils. Early components at
about 2.5-3.5 ms and of small amplitude are also present. Recording from the neck
at C7 with a common non-cephalic reference, SLEP components occurred from 2 to 6
ms earlier than that from the scalp, suggesting an oligo-synaptic transmission of
the excitement via ganglion and lemniscal pathways to the cortex. SLEP was always
followed by a complex potential formed of a succession of negative and positive
waves with latencies ranging from 20 to 300 ms: the LLEP. This LLEP was usually
not very stable and reproducible during the course of successive recordings and
in the same subject because it tended to adjust. Preliminary observations
concerning the topographical cortical distribution of oesophageal evoked
potentials show a circumscribed localization of the SLEP in the parieto-temporal
region of the hemisphere whereas LLEP was more widespread. It is the authors'
opinion that oesophageal evoked potentials are generated both by the excitation
of myelinic fibres with a wide range of conduction speed and of amyelinic fibres
from the oesophageal mucosa and the paraoesophageal peripheral nerves of vagal
origin.
PMID- 9402431
TI - Brainstem auditory evoked potentials (BAEPs) and somatosensory evoked potentials
(SEPs) in enteric encephalopathy (EE).
AB - BAEPs and SEPs were studied in 25 patients of enteric encephalopathy in acute
phase and the results were compared with 25 healthy control persons. In the study
the important observations of BAEPs were delayed peak latency of wave III, wave V
and delayed ILP I-V, and of SEPs was prolonged peak latency of N20. The
electrophysiological evidence suggests metabolic cause for the coma and the SEP
changes were similar to those observed in cerebral malaria reported earlier in
this laboratory.
PMID- 9402432
TI - Three-Hertz postural oscillation in patients with brain stem or cerebellar
lesions.
AB - Postural instability was quantitatively studied in patients with lesions in the
1) pontine tegmentum, 2) deep cerebellar nuclei, or 3) cerebellar hemisphere. As
compared to controls, patients with each lesion demonstrated a characteristic 3
Hertz (Hz) body oscillation. Cross-correlation functions revealed a strong
correlation between the body sway and activities in the lower leg muscles. Based
on these findings, we conclude that the 3 Hz body oscillation may be the result
of any disturbance in the loop of long-latency reflexes mediated by the
cerebellum.
PMID- 9402433
TI - H-reflex latency: a maturity criterion for newborn babies.
AB - One hundred newborn babies were investigated for H-reflex latency (H-RL) in
between 33 to 40 weeks (wk) of post-conceptional age (PCA). Weekly data of both
preterms (33 to 36 wk PCA) and fullterms (37 to 40 wk PCA) were compared. A
significant reduction in H-RL was noticed at 37 wk PCA when newborns attain their
term. The babies could be classified into preterms and fullterms by using their H
RL values.
PMID- 9402434
TI - Comparison of surface EMG signals between electrode types, interelectrode
distances and electrode orientations in isometric exercise of the erector spinae
muscle.
AB - The influence of electrode type, interelectrode distance (IED) and electrode
orientation on EMG signals from the paraspinal muscles was investigated. Bipolar
electrodes were placed at distances 2, 3, 4, 6 and 8 cm over the erector spinae
in the cranio-caudal direction ("in series") as well as in the direction
perpendicular to it ("in parallel"). Ten subjects performed 5 s isometric
contractions of the erector spinae at 20, 40, 60, 80 and 100% MVC by pulling
upward on a handlebar attached to the floor. RMS EMG signals were analyzed for
mean average amplitude (AA). Mean total power (TP) and mean median frequency (MF)
of the raw EMG signal were determined using fast Fourier transform. In addition
to graded loading, sustained fatiguing contractions were performed from which TP
and MF were obtained. With increasing IED the AA and TP increased while MF
decreased. Although a trend towards higher AA, TP and MF was found for electrodes
"in series", as compared to those "in parallel", the difference never reached
significance. It is concluded that consistent information about muscle activity
was obtained with Miniature Biopotential Skin Electrodes and 14445C Hewlett
Packard electrodes independently from IED or orientation. Orientation "in
parallel" prevented the electrodes from sliding during muscle contraction. The
third tested type, electrodes developed in the Neuromuscular Research Center,
Boston, proved extremely sensitive to movement.
PMID- 9402435
TI - Optimizing cholesterol lowering therapy: contribution of the Post Coronary Artery
Bypass Graft Trial.
PMID- 9402436
TI - Digoxin in heart failure: results of the recent Digoxin Investigation Group trial
in the context of other treatments for heart failure.
PMID- 9402437
TI - Percutaneous mitral commissurotomy: an effective treatment in 'ideal' candidates
whatever the approach.
PMID- 9402438
TI - The absence of ventricular premature beats on a Holter is like a normal
sedimentation rate.
PMID- 9402439
TI - Determinants of peak aerobic capacity after heart transplantation.
PMID- 9402440
TI - Low energy intracardiac cardioversion of atrial fibrillation.
PMID- 9402441
TI - Cholesterol lowering in coronary disease: a step in the right direction.
PMID- 9402442
TI - Gap junctions and clinical cardiology: from molecular biology to molecular
medicine.
PMID- 9402444
TI - Endothelial dysfunction and accelerated coronary artery disease in cardiac
transplant recipients. Microcirculation Working Group, European Society of
Cardiology.
PMID- 9402443
TI - Reperfusion strategies in acute myocardial infarction.
PMID- 9402445
TI - Compliance and adverse event withdrawal: their impact on the West of Scotland
Coronary Prevention Study.
AB - AIMS: To assess the additional benefit gained from high compliance in the West of
Scotland Coronary Prevention Study and to examine cases where withdrawal from
trial medication was due to an adverse event. METHODS: The incidence of definite
coronary heart disease or non-fatal myocardial infarction, cardiovascular
mortality, definite or suspect coronary heart disease death or non-fatal
myocardial infarction, the need for coronary revascularization procedures, all
cause mortality and incident cancers were measured in the entire cohort and
compared with the high compliance group. The adverse events associated with
withdrawal were coded by body system. RESULTS: In subjects with compliance > or =
75%, treatment with pravastatin resulted in a 38% risk reduction for definite
coronary heart disease death or non-fatal myocardial infarction and for
cardiovascular mortality, a 46% reduction in risk or coronary revascularization
and a 32% risk reduction (P = 0.015) for all-cause mortality. CONCLUSIONS: The
analysis of the effect of pravastatin in the subgroup of high compliers to
randomized medication demonstrated a substantial increase in the estimated risk
reductions in comparison with that achieved in the intention-to-treat analysis.
This result has significant implications for the motivation of high compliance
among patients and for the assessment of the cost-effectiveness of treatment.
PMID- 9402446
TI - Cholesterol lowering after participation in the Scandinavian Simvastatin Survival
Study (4S) in Finland.
AB - BACKGROUND: Patient compliance is crucial for the effectiveness of preventive
medication. The aim of the study was to investigate changes in serum cholesterol
levels and the use of cholesterol lowering drugs one year after the end of the
Scandinavian Simvastatin Survival Study (4S), a randomized secondary prevention
study of coronary heart disease with simvastatin and placebo. METHODS AND
RESULTS: A questionnaire asking the current use of cholesterol lowering drugs,
most recent serum cholesterol value and attitudes towards cholesterol lowering
was sent to 785 surviving 4S participants in four 4S centres in Finland. The
response rate was 94%. The current use of cholesterol lowering drugs and the
reported mean serum cholesterol values were similar to the original simvastatin
and placebo groups. In all, 74% (n = 546) reported that they had used cholesterol
lowering drugs after the study, and 63% (n = 467) were currently using them,
mostly simvastatin (96%) with an average dose of 14 (SD 5) mg.day-1. Cholesterol
lowering was considered to be 'very important' by 53% and 'important' by 37% of
the respondents. The most frequent reasons for discontinuation were 'drug costs'
(38%) and 'normal cholesterol values' (30%). The reported mean serum cholesterol
levels were 5.1 (SD 1.0) and 5.7 (SD 1.1) mmol-1 in the current cholesterol
lowering drug users and non-users, respectively (P < 0.0001). The in-trial
treatment goal of serum cholesterol (< or = 5.2 mmol-1) was not met in 38% of the
users and in 68% of the non-users of cholesterol lowering drugs. CONCLUSION: One
year post-trial the original simvastatin and placebo groups of the 4S had become
similar with regard to the use of cholesterol lowering drugs and serum
cholesterol levels. The adherence to medication, however, still remained
relatively high, but there was a shift toward lower doses, and consequently
toward higher post-trial serum cholesterol levels.
PMID- 9402447
TI - Prevalence of coronary artery disease and coronary risk factors in rural and
urban populations of north India.
AB - OBJECTIVE: This study was conducted to determine and compare the prevalence of
coronary artery disease and coronary risk factors in both a rural and an urban
population of Moradabad in north India. DESIGN AND SETTING: A cross-sectional
survey of two randomly selected villages from the Moradabad district and 20
randomly selected streets in the city of Moradabad. SUBJECTS AND METHODS: The
3575 subjects were between 25 and 64 years old; 1769 (894 men and 875 women)
lived in the countryside and 1806 (904 men and 902 women) lived in the city. The
survey methods were questionnaires, physical examination and electrocardiography.
RESULTS: The overall prevalence of coronary artery disease, based on a clinical
diagnosis and an electrocardiogram, was 9.0% in the urban and 3.3% in the rural
population. The prevalences were significantly (P < 0.001) higher in the men
compared with the women in both urban (11.0 vs 6.9%) and rural (3.9 vs 2.6%)
populations, respectively. The prevalence of symptomatic coronary artery disease
(known coronary disease and Rose questionnaire-positive angina) was 2.3% in the
men (n = 19) and 1.5% in the women (n = 13) in the rural subjects, and 8.5% in
the men (n = 77) and 3.4% in the women (n = 31) in the urban population. When
diagnosed on the basis of electrocardiographic changes alone, the prevalences
were 1.5% (n = 26) in the rural population and 3.0% (n = 55) in the urban.
Coronary risk factors were two- or three-fold more common among urban subjects
compared to the rural population in both sexes. Central obesity was four times
more common in the urban population compared to the rural in both sexes.
Sedentary lifestyle and alcohol intake were significantly (P < 0.01) higher in
the urban population compared to the rural subjects. There was a significant
association between coronary disease and age, hypercholesterolaemia, hypertension
and central obesity in both sexes. Smoking was a significant risk factor of
coronary disease in men. CONCLUSIONS: Coronary artery disease and coronary risk
factors were two or three times higher among the urban compared with the rural
subjects, which may be due to greater sedentary behaviour and alcohol intake
among urbans. It is possible that some Indian populations can benefit by reducing
serum cholesterol, blood pressure and central obesity and increasing physical
activity.
PMID- 9402448
TI - 'Expected infarct size without thrombolysis', a concept that predicts immediate
and long-term benefit from thrombolysis for evolving myocardial infarction.
AB - BACKGROUND: Thrombolytic therapy should only be used when expected benefits
outweigh the risks. In order to obtain a precise estimation of prognosis, with
and without thrombolytic therapy, we postulated that mortality reduction by
thrombolytic therapy is a function of the area of myocardium at risk for
necrosis. We developed a model to estimate the myocardial area at risk for
necrosis from clinical parameters readily available upon hospital admission. This
model was validated in relation to long-term prognosis and benefits of
thrombolytic therapy. METHODS: Enzymatic infarct size with and without
thrombolysis was predicted from the haemodynamic state and the electrocardiogram
on hospital admission by multivariate regression analysis in 885 patients in the
rt-PA placebo and rt-PA/PTCA trial of the European Cooperative Study Group. This
multivariate function was used to validate the 'expected infarct size without
thrombolytic treatment' in a test population of 533 patients from the
Intracoronary Streptokinase trial of the Interuniversity Cardiology Institute of
The Netherlands (ICIN) and 1741 patients from the Intravenous Streptokinase in
Acute Myocardial Infarction (ISAM) study, both trials with a non-thrombolysed
control group. RESULTS: Expected infarct size correlated well with the actual
enzymatic infarct size in the non-thrombolysed patients of the latter two series.
Limitation of infarct size by thrombolytic therapy was greatest in patients with
a large 'expected infarct size' and absent in patients with a small area at risk.
Similarly, one year mortality reduction was greatest in patients with a large
'expected infarct size without thrombolysis'; four deaths were prevented per
hundred (95% confidence interval 0 to 9) if the area at risk was large, vs one
death (95% confidence interval -2 to 3) in patients with a small area at risk.
Benefit was most pronounced in patients with a large area at risk who were
treated early within 3 h of symptom onset. A score for the determination of 1
year mortality with and without thrombolytic therapy is presented to help the
clinician determine who to treat with thrombolytic therapy. CONCLUSION: 'Expected
infarct size without thrombolysis' is a useful tool for clinicians to estimate
the amount of myocardium at risk of necrosis in individual patients and to decide
whether thrombolytic therapy is warranted. It is the only validated parameter of
myocardium at risk for necrosis that is readily available for all patients with
myocardial infarction and does not need high-tech equipment.
PMID- 9402449
TI - Right coronary artery stenosis is associated with impaired cardiac endocrine
function during exercise.
AB - AIMS: Resting plasma levels of atrial natriuretic peptide and B-type natriuretic
peptide rise with left ventricular dysfunction, but little is known about effects
of cardiac ischaemia on atrial natriuretic peptide and B-type natriuretic peptide
levels during exercise. We investigated exercise levels of atrial natriuretic
peptide and B-type natriuretic peptide in patients with suspected angina to
determine whether these measurements could improve non-invasive assessment of
coronary disease severity. METHODS AND RESULTS: One hundred patients performed an
exercise test (Bruce protocol) within 2 weeks of coronary angiography. Plasma
levels of atrial natriuretic peptide and B-type natriuretic peptide were measured
at rest and at peak exercise. Multivariate regression analysis was used to assess
effects of age, sex, coronary anatomy, exercise time and ventricular function on
atrial natriuretic peptide and B-type natriuretic peptide levels. Increasing age
and female sex were significantly associated with higher resting atrial
natriuretic peptide levels; age alone was associated with higher exercise atrial
natriuretic peptide levels. As expected, left ventricular end-diastolic pressure
and disease of left anterior descending and circumflex coronary arteries were
associated with increased resting B-type natriuretic peptide levels. However, the
usual rise in B-type natriuretic peptide levels during exercise was independently
reduced by disease of the right coronary artery. CONCLUSION: This paradoxical
effect of right coronary artery disease limits the value of natriuretic peptide
measurements as predictors of coronary disease severity. Impaired release of B
type natriuretic peptide may reduce exercise tolerance in patients with right
coronary artery disease.
PMID- 9402450
TI - Addition of felodipine to metoprolol vs replacement of metoprolol by felodipine
in patients with angina pectoris despite adequate beta-blockade. Results of the
Felodipine ER and Metoprolol CR in Angina (FEMINA) Study. Working Group on
Cardiovascular Research, The Netherlands (WCN).
AB - AIMS: The study aimed to compare the addition of felodipine to metoprolol, and of
the replacement of metoprolol by felodipine, with continuation of metoprolol, in
patients with angina pectoris despite optimal beta-blockade. METHODS AND RESULTS:
The study was double-blind, parallel, randomized and controlled, and comprised
363 patients from 27 outpatient cardiology clinics in the Netherlands. The
patients had angina and positive bicycle exercise tests despite optimal beta
blockade (resting heart rate < 65 beats.min-1). Randomization was to three
treatment groups: continuation of metoprolol (control), addition of felodipine to
metoprolol, and replacement of metoprolol by felodipine. Exercise tests were
repeated after 2 and 5 weeks. The main outcome measure was: exercise result after
5 weeks, compared with baseline, between-group comparison of changes vs control.
There were no significant differences in exercise duration and onset of chest
pain vs control. The addition of felodipine increased time until 1 mm ST
depression (43 s, 95% confidence interval 20-65 s), and decreased both ST
depression at highest comparable work load (0.46 mm, 95% confidence interval 0.19
0.72), and maximal ST depression (0.49 mm, 95% confidence interval 0.23-0.74).
Exercise results after replacement of metoprolol by felodipine were not different
from control, apart from a significant increase in rate pressure product.
Significantly more patients experienced adverse events in the felodipine
monotherapy group. CONCLUSION: Combination of metoprolol and felodipine is to be
preferred to felodipine monotherapy in patients who have signs and symptoms of
myocardial ischaemia despite optimal beta-blockade.
PMID- 9402452
TI - Trends in hospitalization and mortality for heart failure in Spain, 1980-1993.
AB - AIMS: To describe, for the first time, trends in hospitalization and mortality
rates for congestive heart failure in Spain during the period 1980-1993. METHODS
AND RESULTS: Data on primary diagnosis of congestive heart failure were taken
from the National Hospital Morbidity Survey and the National Vital Statistics.
The number of hospital admissions for congestive heart failure rose by 71% (from
42,965 in 1980 to 73,448 in 1993) and hospitalization rates for congestive heart
failure increased by 47% (from 348 per 100,000 in 1980 to 511 per 100,000 in
1993). The rise in hospitalizations was limited to persons aged > or = 65 years,
and proved greater among women. Congestive heart failure was the leading cause of
hospitalization in persons aged > or = 65 years, accounting for 5% of all
hospital admissions in this age group. Age-adjusted congestive heart failure
mortality declined by 23%. The decline affected all age groups, with the sole
exception of the > or = 80-year group in which mortality rose. Nevertheless,
congestive heart failure remained the third leading cause of cardiovascular
death. CONCLUSION: Congestive heart failure represents a significant hospital and
demographic burden for the Spanish population. The hospital burden increased
substantially in the period 1980-1993, and will continue to do so in future with
the growth of the elderly population.
PMID- 9402451
TI - Balloon mitral valvotomy: comparison between antegrade Inoue and retrograde non
transseptal techniques.
AB - AIMS: The results of percutaneous mitral valvotomy performed by the antegrade
transseptal method using the Inoue balloon (n = 1000; group 1) and by the
retrograde non-transseptal technique using a polyethylene balloon (n = 100; group
2) were compared in a retrospective, non-randomized study. METHODS AND RESULTS:
Both the groups were similar with respect to baseline characteristics. The
success rate was 95% in group 1 and 93% in group 2. There was a significant
increase in mitral valve area estimated by Gorlin's equation (Group 1: from 0.8
+/- 0.5 to 2.1 +/- 0.8 cm2; Group 2: from 0.8 +/- 0.3 to 1.9 +/- 0.8 cm2, both P
< 0.001) and by Doppler echocardiography using the pressure half-time method
(Group 1: from 0.9 +/- 0.4 to 2.2 +/- 0.6 cm2; Group 2: from 0.9 +/- 0.3 to 2.0
+/- 0.7 cm2, both P < 0.001). However, the calculated immediate post-valvotomy
mitral valve area was larger with the Inoue technique (2.1 +/- 0.8 vs 1.9 +/- 0.8
cm2; (P < 0.02). Results were considered optimal when the mitral valve area
increased to > or = 1.5 cm2, the percentage increase was > or = 50, and mitral
regurgitation was < or = 2/4. Out of the total successful procedures, optimal
results were obtained in 95% patients in Group 1 and 94% in Group 2. Incidence of
significant mitral regurgitation (> or = grade 3/4) was similar in two groups
(Group 1: 4% vs Group 2: 5%, P = ns). A significant left to right atrial shunt
(Qp/Qs > or = 1.5:1) in 2.5% and tamponade in 2% of cases occurred exclusively
with the Inoue technique, while conduction disturbances, such as transient (< 24
h) left bundle branch block (28%) and complete heart block (2%) were noted with
the retrograde technique (Group 2). Local complications were significantly higher
in Group 2 (3% vs 0.5%, P < 0.01). The procedure time with the Inoue technique
was shorter than with the retrograde (Group 1: 15 +/- 8, range 10 to 35 min;
Group 2: 22 +/- 14, range 15 to 45 min, P = 0.05). Echocardiographic follow-up at
1 year showed no significant difference in mitral valve area between the two
groups (Group 1 (n = 300): 1.8 +/- 0.8 vs Group 2 (n = 60): 1.9 +/- 0.9 cm2; P =
0.3). CONCLUSIONS: Balloon mitral valvotomy using the Inoue balloon and the
retrograde non-transseptal technique results in significant immediate
haemodynamic and symptomatic improvement. The Inoue technique achieved a larger
immediate post-valvotomy mitral valve area, but the difference was not apparent
at 1 year follow-up. Incidence of significant mitral regurgitation was similar
with both the techniques; however, local complications occurred more frequently
with the retrograde technique. Both techniques may complement each other in
technically difficult cases.
PMID- 9402453
TI - A prospective, randomized comparison of temperature-controlled vs manually
delivered radiofrequency catheter ablation in patients undergoing
atrioventricular nodal modification or accessory pathway ablation.
AB - AIMS: In a prospective, randomized study, the effect of temperature control on
radiofrequency catheter ablation was compared in 69 patients undergoing
atrioventricular nodal modification (n = 32) or ablation of an accessory pathway
(n = 37). METHODS AND RESULTS: Thirty-five patients were randomized to
temperature control, 34 to manually delivered radiofrequency ablation. The
success rate was 92.5% for accessory pathway ablation and 100% for
atrioventricular nodal modification. Mapping duration was significantly reduced
only in patients undergoing atrioventricular nodal modification. The number of
applications was higher for manually delivered ablation in patients undergoing
atrioventricular nodal modification (5.6 +/- 1.1 vs 1.9 +/- 0.4, P = 0.004) as
was the cumulative energy delivered (5034 +/- 1008 vs 2054 +/- 517 W, P = 0.013)
whereas the mean power per application was higher with temperature control (41.4
+/- 1.8 vs 34.1 +/- 1.1 W, P = 0.002). No significant differences in these
parameters were found in patients undergoing accessory pathway ablation. Coagulum
formation on the catheter tip was observed more often with manually delivered
ablation 5.3% vs 0.9%, P = 0.026). The success rate with the initially randomized
application mode was higher for temperature control (94.3 vs 61.8%, P = 0.003).
CONCLUSIONS: Temperature control during radiofrequency current ablation
significantly reduces mapping duration, necessary applications and cumulative
energy in atrioventricular nodal modification, but not accessory pathway
ablation. Coagulum formation on the catheter tip still occurs but is
significantly reduced compared to manually delivered radiofrequency current.
PMID- 9402454
TI - Survival and incidence of myocardial infarction in men with ambulatory ECG
detected frequent and complex ventricular arrhythmias. 10 year follow-up of the
'Men born 1914' study in Malmo, Sweden.
AB - AIM: To assess to what extent do frequent or complex ventricular arrhythmias,
detected during 24 h ambulatory electrocardiographic recording (ECG), influence
prognosis with regard to survival and incidence of ischaemic heart disease.
METHODS AND RESULTS: The study subjects were the 456 randomly selected men born
in 1914, the population-based cohort study of 1982-83, in Malmo, Sweden. The main
outcome measures were total mortality and incidence of cardiac event (myocardial
infarction and death from ischaemic heart disease). Frequent or complex
ventricular arrhythmias (Lown classes 2-5) were detected in 49% of the men with
(n = 77), and in 35% of those without, a history of myocardial infarction or
angina pectoris at baseline, P = 0.019. Independent of clinically evident
coronary artery disease at baseline, and after adjustment for traditional
atherosclerotic risk factors and use of digitalis or beta-blocker therapy,
frequent or complex ventricular arrhythmias were associated with an increased
mortality from ischaemic heart disease (relative risk (RR), 2.1; 95% confidence
interval (CI), 1.2-3.9) and an increased cardiac event rate (RR, 1.6; 95% CI, 1.0
2.5)). Men free from both ischaemic-type ST depression and frequent or complex
ventricular arrhythmias (used as the control group) had the lowest ischaemic
heart disease death rate, 5.9 per 1000 person-years. The combination of ST
depression and frequent or complex ventricular arrhythmias was associated with an
ischaemic heart disease death rate of 20.9 per 1000 person-years. The cardiac
event rate in these two groups was 15.6 and 76.1 per 1000 person-years,
respectively (adjusted RR, 2.3; CI, 1.1-4.6). CONCLUSIONS: In elderly men without
a history of myocardial infarction and angina pectoris, frequent or complex
ventricular arrhythmias during ambulatory ECG recording is associated with an
increased incidence of myocardial infarction and mortality. Men who, during
ambulatory ECG recording, also demonstrate ST-segment depression have an even
less favourable prognosis.
PMID- 9402455
TI - A comparison of treatment of atrial fibrillation with low-energy intracardiac
cardioversion and conventional external cardioversion.
AB - AIM: Low-energy (1 to 15 J), catheter-based intracardiac cardioversion was
compared with transthoracic external cardioversion (360 J) in a prospective,
cross-over clinical trial. METHODS AND RESULTS: In 187 consecutive patients with
chronic atrial fibrillation, over a period of a mean of 10.0 +/- 7.3 (SD) months,
217 cardioversion attempts were made. Intracardiac shocks were randomly applied
between two 6-F catheters located in either the right atrium and coronary sinus
or between the right atrium and left pulmonary artery. When a cardioversion
attempt with one method failed, the other method was implemented. After
cardioversion, all patients were treated orally with sotalol with a mean daily
dose of 174 +/- 54 mg. Internal cardioversion was more effective than external
cardioversion (65/70 = 93% vs 92/117 = 79%, P < 0.01). The mean energy for
successful cardioversion was 5.8 +/- 3.2 J for the internal and 313 +/- 71 J for
the external cardioversion group. At a mean follow-up of 12.5 +/- 6.4 months, 48%
(38%) of the patients treated with internal (external) cardioversion were in
sinus rhythm (P < 0.05). In 22 of 25 patients in whom external cardioversion
failed, sinus rhythm was restored with internal cardioversion at a mean energy of
6.5 +/- 3.0 J. Overweight patients had twice the risk of unsuccessful external
cardioversion. CONCLUSIONS: Internal cardioversion is effective in restoring
sinus rhythm. It might be indicated in patients in whom external cardioversion
had failed or in whom external cardioversion is assumed to be difficult or even
contraindicated.
PMID- 9402456
TI - Electrophysiological properties in patients undergoing atrial compartment
operation for chronic atrial fibrillation with mitral valve disease.
AB - AIMS: Surgical treatment for atrial fibrillation is now feasible in selective
cases. The aim of this study was to assess the electrophysiological properties of
patients undergoing atrial compartment operation for chronic atrial fibrillation.
METHODS AND RESULTS: Electrophysiological studies were performed in 20 mitral
valve patients with atrial fibrillation who had been maintained in sinus rhythm
for more than 1 year after atrial compartment operation. Intra-cardiac recording
and programmed electrical stimulation were performed in various atrial
compartments. The parameters studied included sinus node function, atrial
conduction and refractoriness, atrioventricular conduction function and inducible
arrhythmias if any. Intra-cardiac recordings showed that the rhythm was of sinus
origin in all cases, with the earliest atrial activity located in the high right
atrium. The mean sinus cycle length was 750 +/- 110 ms, AH time 106 +/- 29 ms,
and HV time 53 +/- 7 ms. The sinus node function was normal in 18 patients (90%),
and only two patients had prolonged sinus node recovery and sino-atrial
conduction. The right atrial appendage compartment was driven by the sinus node
in all patients. However, the conduction time from the high right atrium to the
right atrial appendage compartment was markedly prolonged in 12 of 15 patients
(80%) undergoing the three-compartment operation in which an incision was placed
between the high right atrium and right atrial appendage compartments. On the
other hand, the electrical activities in the left atrial compartment were much
more varied. In 13 of 20 patients (65%), the left atrial compartment was driven
by the sinus node; 11 of the 13 patients had a normal or mildly prolonged
conduction time (ranged 75 to 146 ms), whereas two patients had a marked delay in
conduction (200 ms and 266 ms, respectively). In the remaining seven patients,
the left atrial compartments were dissociated from the rest of the heart; five of
them had a quiescent left atrium, one a fluttering left atrial rhythm, and one a
slow left atrial rhythm. The effective refractory period was longer in the left
atrial compartment (242 +/- 47 ms) as compared to that of the high right atrium
(224 +/- 26 ms, P < 0.01) and right atrial appendage compartments (219 +/- 25 ms,
P < 0.01). Programmed electrical stimulation could not induce atrial fibrillation
in any patient, whereas two patients had inducible atrial flutter and three
repetitive atrial responses. CONCLUSIONS: (1) Atrial compartment operation does
not impair sinus node function in most cases. (2) Elimination of atrial
fibrillation while maintaining the electrical connection between different atrial
compartments is feasible.
PMID- 9402457
TI - Cardiopulmonary physiology after surgical closure of asymptomatic secundum atrial
septal defects in childhood. Exercise performance is unaffected by age at repair.
AB - AIMS: Most secundum atrial septal defects, once diagnosed, are corrected at a
young age. The evidence to justify early vs delayed or even non-closure is
equivocal and little is known regarding long-term effects of later closure. This
is particularly pertinent to those patients awaiting transcatheter closure of
their defect for whom a device is only just becoming available. We examined the
exercise cardiorespiratory physiology of children surgically treated for an
isolated secundum defect. METHODS AND RESULTS: One hundred and six healthy
control children and 22 children more than 6 months after surgical repair for an
isolated secundum atrial septal defect were studied. All were asymptomatic.
Measurements of effective pulmonary blood flow, stroke volume, arteriovenous
oxygen difference, minute ventilation, heart rate, oxygen consumption and carbon
dioxide production were made using a quadrupole mass spectrometer during rest and
graded exercise. Data from the normal children allowed calculation of z scores
for the atrial septal defect group matched for age, sex, pubertal stage and
surface area. Maximal exercise performance was equal between control and atrial
septal defect groups, however, the atrial septal defect group had a significantly
greater effective pulmonary blood flow and stroke volume but a lower heart rate
than controls at a given exercise stage. Stroke volume abnormalities were most
closely related to duration of follow-up (29% of the variance explained, P <
0.01) rather than age at surgery. CONCLUSIONS: We were unable to show a medium
term benefit from early surgery for an asymptomatic secundum atrial septal defect
during exercise. The clinical relevance of the haemodynamic differences that do
exist remains unclear.
PMID- 9402458
TI - Predictive factors of maximal aerobic capacity after cardiac transplantation.
AB - Exercise capacity in cardiac transplanted patients has been reported to remain
decreased in some studies; however, functional results after transplantation may
vary, ranging from modest to spectacular improvement. The aim of the study was to
quantify exercise capacity in a large series of transplanted patients and to
search for factor predictive of a good functional result. Eighty-five patients
(mean 52.1 +/- 11.8 years) underwent exercise testing with respiratory gas
exchange measurements 1 to 100 months after transplantation. Mean performance was
112.4 +/- 33 W with a peak VO2 of 21.1 +/- 6 ml.min-1.kg-1. Heart rate was 103 +/
14 at rest, reaching 142 +/- 22 beats.min-1 at the end of exercising. In
univariate analysis, maximal or submaximal aerobic capacity parameters were
strongly correlated with chronotropic reserve (r = 0.63; P < 0.001) without
correlation with cold ischaemic time, number of rejection episodes or right
bundle branch block. In multiple regression analysis, chronotropic reserve, time
from transplantation, age of donor and age of patient were proved to be the
variables best correlated with peak VO2. Our study confirms the persistence of a
large decrease in aerobic functional capacity despite cardiac transplantation;
limited exercise capacity does not improve over time, and is limited not only by
the patient's age but by that of the donor, and especially by chronotropic
reserve.
PMID- 9402460
TI - C-reactive protein and complement in myocardial infarction and postinfarction
heart failure.
PMID- 9402459
TI - Catecholamines contribute to exertional dyspnoea and to the ventilatory response
to exercise in normal humans.
AB - BACKGROUND: Exogenous catecholamine administration in humans stimulates
ventilation. The present study was designed to investigate whether increased
endogenous catecholamine release influences objective measures of ventilation and
subjective measures of breathlessness in normal subjects. METHODS: Yohimbine, a
pre-synaptic alpha 2 adrenoceptor antagonist, or placebo was administered to 10
normal male subjects in a double-blind cross-over fashion. Ventilation and
metabolic gas exchange were measured during steady state exercise at 60% of
previously determined maximal oxygen consumption. Venous lactate and
noradrenaline were measured during exercise. Subjects' sensation of
breathlessness and fatigue were recorded using visual analogue scales. RESULTS:
Plasma noradrenaline was higher following yohimbine administration (at 6 min
exercise; 4.58 +/- 0.56 nmol.l-1 vs 8.74 +/- 1.53; P < 0.05). Oxygen consumption
was unchanged, but ventilation was greater throughout exercise following
yohimbine. The sensation of exertion was greater following yohimbine, and at any
given level of ventilation, the sensation of exertion was greater. CONCLUSIONS:
Yohimbine administration causes increased noradrenaline release. This is
associated with an increased ventilatory response and an increase in the
sensation of exertion during steady state exercise. An increase in circulating
noradrenaline might be a mechanism for both increased ventilation and
pathological conditions of breathlessness such as chronic heart failure.
PMID- 9402461
TI - Aspirin therapy in diabetic subjects post-myocardial infarction.
PMID- 9402462
TI - Valvular heart disease in systemic lupus erythematosus: another symptom of the
disease or a hallmark of secondary antiphospholipid syndrome?
PMID- 9402463
TI - Is thrombolytic therapy beneficial to acute stroke patients?
PMID- 9402464
TI - Arterial structural modifications in hypertension. Effects of treatment.
AB - Hypertensive changes in the vasculature occur at all levels of the circulation-
from the large arteries through to the microcirculation. Detection of these
changes may offer useful predictive information in assessing cardiovascular risk
and the need for treatment. Recent evidence shows that at least some of these
changes are reversible with anti-hypertensive treatment.
PMID- 9402465
TI - Rationalizing the heart failure trials: from theory to practice.
AB - It is 10 years since the CONSENSUS I study showed that ACE inhibitors improved
mortality in heart failure. This finding has been confirmed in numerous trials,
for example SOLVD, SAVE. Indeed, in the intervening 10 years, many other
potential therapies have been examined in mortality trials, but so far no other
therapy has had as good effect on mortality as ACE inhibitors. The other
therapies which have been examined are digoxin, amlodipine, beta-blockers,
amiodarone, etc. Despite ACE inhibitors being a very effective therapy for heart
failure, there is still remarkable under-use of them in clinical practice. The
reason for this needs to be explained further, but fear of hypothermia and renal
dysfunction appear to be major factors.
PMID- 9402466
TI - Adequate blood pressure control: perception and reality.
AB - Blood pressure should be controlled over 24 h to reduce or prevent cardiac
hypertrophy and reduce the prevalence of sudden death, myocardial infarction and
myocardial ischaemia at the time of the morning rise in blood pressure. Anti
hypertensive medication is usually given once-daily in the morning and the dose
is titrated on the basis of post-dose (peak) blood pressure. This frequently
leads to inadequate control prior to the next drug dose unless drugs with
appropriate pharmacokinetics or pharmacodynamics are used. ACE inhibitors exhibit
an E(max) plasma concentration: blood pressure response relationship, and thus
short-acting ACE inhibitors can exert an effect over 24 h if titrated based on
pre-dose (trough) blood pressure. However, when titrated in clinical practice on
post-dose (peak) blood pressure response, doses are used that are inadequate to
control blood pressure for 24 h. ACE inhibitors with appropriate pharmacokinetics
such as perindopril can control blood pressure when titrated at peak provided a
dose is used (4 or 8 mg) that is known to have a T:P close to 1.0. Shorter-acting
ACE inhibitors frequently give inadequate control when titrated at peak. An
understanding of the pharmacokinetics and pharmacodynamics of a drug, coupled
with knowledge of the time the drug was taken, together with the time of blood
pressure measurements, enables control to be achieved with once-daily therapy
even if the drug is titrated at peak response.
PMID- 9402467
TI - From kinetics to dynamics: are there differences between ACE inhibitors?
AB - Angiotensin converting enzyme inhibitors are established treatment for
hypertension and heart failure. There are well documented differences between ACE
inhibitors both in physicochemical properties and pharmacokinetics.
Pharmacodynamic actions are similar for most members of the ACE inhibitor class
but there are compounds with additional effects which may reflect protease
inhibition or non-enzyme-directed pharmacological properties. Clinically relevant
differences are few and far between, particularly in the treatment of
hypertension when the optimal dose and dose intervals are used. In heart failure
there may be a role for drugs with additional properties such as neutral
endopeptidase inhibition. In addition, ACE inhibitors differ in the profile of
blood pressure changes after the first dose. Early haemodynamic changes with a
fall in blood pressure in heart failure patients may be disadvantageous in terms
of subsequent outcome. Thus the haemodynamic effects of the first dose may be
relevant to the choice of ACE inhibitors in heart failure.
PMID- 9402468
TI - Endothelial dysfunction and atherosclerosis.
AB - The endothelium mediates a number of responses (relaxation or contraction) of
arteries and veins from animals and humans. The endothelium-dependent relaxations
are due to the release, by endothelial cells, of potent non-prostanoid
vasodilator substances. Among these, the best characterized is endothelium
derived relaxing factor (EDRF), which is believed to be nitric oxide (NO). Nitric
oxide is formed by the metabolism of L-arginine by the constitutive NO synthase
of endothelial cells. In arterial smooth muscle, the relaxation evoked by EDRF is
explained by the stimulation by NO of soluble guanylate cyclase that leads to the
accumulation of cGMP. In a number of animal blood vessels and in human coronary
arteries, the endothelial cells release a substance that causes hyperpolarization
of the cell membrane (endothelium-derived hyperpolarizing factor, EDHF). The
release of EDRF from the endothelium can be mediated by both pertussis toxin
sensitive (alpha 2-adrenoceptor activation, serotonin, aggregating platelets,
leukotrienes) and insensitive (adenosine diphosphate (ADP), bradykinin) G
proteins. In blood vessels from animals with regenerated and reperfused
endothelium, and/or atherosclerosis, there is a selective loss of the pertussin
toxin-sensitive mechanism of EDRF release, which favours the occurrence of
vasospasm, thrombosis and cellular growth. The available information from
isolated human blood vessels or obtained in situ concurs with the conclusions
reached from studies with isolated animal tissues. In addition to relaxing
factors, the endothelial cells can produce contracting factors (endothelium
derived contracting factors; EDCFs) which include superoxide anions,
endoperoxides, thromboxane A2 and endothelin. From animal studies it can be
concluded that the propensity to release EDCFs is maintained, or even augmented,
in diseased blood vessels. The switch from a normally predominant release of
EDRFs to that of EDCFs may play a crucial role in atherosclerosis.
PMID- 9402469
TI - The stimulatory effect of rabphilin 3a on regulated exocytosis from insulin
secreting cells does not require an association-dissociation cycle with membranes
mediated by Rab 3.
AB - Rabphilin 3a is a Rab 3-GTP binding protein concentrated on secretory vesicles of
neurons and endocrine cells. There is evidence that rabphilin 3a undergoes cycles
of association-dissociation with membranes and that recruitment of rabphilin 3a
to secretory vesicles is mediated by Rab 3a, suggesting that rabphilin 3a is a
downstream effector of this Rab. In this study we have investigated whether a
membrane-anchored form of rabphilin 3a mimics the action of rabphilin 3a on
secretion and bypasses the need for Rab 3 function. Overexpression of both wild
type rabphilin 3a and of a transmembrane anchored form of rabphilin 3a stimulated
(about 2-fold) evoked secretion of coexpressed human proinsulin from clonal HIT
T15 cells. A similar transmembrane-anchored protein which lacked the Rab 3
binding region stimulated secretion even more effectively. Unexpectedly, a
rabphilin 3a deletion mutant missing the Rab 3 binding domain was also
stimulatory on secretion, although a further deletion of rabphilin to exclude the
first of the two proline-rich regions abolished its stimulatory effect. The first
of these two mutants was primarily particulate, while the second mutant was
primarily soluble, suggesting that the first proline-rich region of rabphilin 3a
plays a role in targeting rabphilin to its site of action. We conclude that the
action of rabphilin 3a can be independent of Rab 3 if other mechanisms produce a
sufficient concentration of the protein in proximity of exocytotic sites. These
results provide new evidence for a fundamental similarity in the mechanisms by
which Ras and Rab GTPase produce their distinct physiological effects.
PMID- 9402470
TI - Rab3 dissociation and clathrin-mediated endocytosis, two key steps in the exo
endocytotic pathway of large dense-cored vesicles in primary cultures of superior
cervical ganglia.
AB - In this study we have used primary cultures of porcine superior cervical ganglia
as a model system to study exo-endocytosis in sympathetic neurons. Pure neuronal
cultures with a defined noradrenergic phenotype can be obtained when antimitotics
are included in the culture medium, and the high yield from prenatal piglets
allows a biochemical approach in addition to morphological studies. Release of
large dense-cored vesicles (LDCVs) was visualized by exposing stimulated neurons
to anti-dopamine-beta-hydroxylase (D beta H) prior to fixation. Double
immunofluorescent staining revealed that synaptotagmin was colocalized with anti
D beta H labeled exocytotic spots, but not the small GTP-binding protein rab3.
Density gradient centrifugation of a postmitochondrial supernatant of cultured
cells confirmed the dissociation of rab3 from a population of mature LDCVs. As
expected, rab3 did not reassociate with the lighter D beta H-positive membrane
fraction in the gradient representing internalized LDCV membranes. The fluid
phase marker horseradish peroxidase colocalized with retrieved LDCV membranes.
Indirect immunofluorescence demonstrated the colocalization of clathrin with D
beta H-positive exocytotic spots on the plasma membrane. At the ultrastructural
level, depolarization of neurons resulted in the abrupt loss of LDCVs and
concomitant appearance of clathrin-coated vesicles and coated omega profiles. The
size distribution of coated structures overlapped strongly with that of LDCVs.
Taken together, these data clearly suggest that two key regulatory events in the
process of exo-endocytosis, i.e. rab3 dissociation and clathrin-mediated
internalization, are not only reminiscent of small synaptic vesicles, but also
are a feature of the LDCV pathway at the presynaptic plasma membrane of
sympathetic neurons.
PMID- 9402471
TI - De novo acquisition of neuronal polarity in retinoic acid-induced embryonal
carcinoma cells.
AB - The mouse embryonal carcinoma cell line PCC7-Mz1 represents an advantageous model
to study acquisition of polarity by neurons. During the first two days after
differentiation is induced by the addition of retinoic acid, the neuronal
derivatives develop extensions which for at least four more days do not differ
from each other in growth characteristics, morphology, and marker expression.
Beginning around differentiation day 6 and following the relocation of the
nucleus from a central to a polar position in the cell soma, the morphology and
marker expression changes dramatically: expression of MAP2 diminishes and
eventually disappears in the thinner neurite (future axon), which originates at
the nucleated pole, but remains strong in the branched, broad based neurite(s).
The opposite changes in expression are observed for synaptophysin, together with
a clustering of the vesicle protein in varicosity-like areas. Complete
segregation of expression of the two markers is achieved around day 12, shortly
followed by dendrite-specific location of MAP2 mRNA and the ability to generate
and conduct action potentials. Our studies add several aspects to the process of
neuronal polarity acquisition, as it was previously studied in primary cultures
of embryonic neurons: (i) we monitored neuronal differentiation from the birth of
neurons, rather than from later and less defined maturation stages, (ii) cell
nucleus relocation may be associated with the induction of neuronal polarity, and
(iii) functional competence of neurons is closely associated with previous
acquisition of polarity. Acquisition of polarity by PCC7-Mz1 neuronal derivatives
probably refers to de novo acquisition rather than to reestablishment of
polarity.
PMID- 9402472
TI - Triglyceride synthesis and secretion and lipogenesis implicated gene expression
in the chicken hepatocarcinoma cell line LMH.
AB - Avian lipogenesis was studied in the chicken hepatocarcinoma LMH cell line. The
differentiated and lipogenic status of these cells was evidenced by the presence
of the albumin mRNA as well as of some mRNA coding for enzymes involved in
lipogenesis (acetyl-CoA carboxylase, fatty acid synthase, delta 9 desaturase) and
for apoproteins (apoprotein B and A1). These results were further confirmed by
the analysis of triglyceride synthesis and secretion rates in growing cells. A
time course analysis showed that triglyceride metabolism was affected by cell
density. Hormone responsiveness of triglyceride production was also analyzed.
Insulin, triiodothyronine and glucagon to a lesser extent were shown to regulate
lipogenesis of LMH cells. The results were compared with those obtained in
primary cultures of chicken hepatocytes.
PMID- 9402473
TI - Modulation of osteogenesis and adipogenesis by human serum in human bone marrow
cultures.
AB - Knowledge of the controlling mechanisms of human osteoprogenitor cell
differentiation has important implications for understanding bone turnover. The
in vitro differentiation of human bone marrow fibroblasts into adipogenic and
osteogenic cells and the interaction of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3)
and dexamethasone in this process has been investigated together with the effects
of human serum. Marrow fibroblasts cultured in human serum and dexamethasone for
28 days, generated lipid containing cells as confirmed by morphology, Oil red O
staining and immunocytochemistry using antiserum to the adipocyte-specific
protein, adipocyte P2 (aP2). In cultures containing 1,25(OH)2D3 and
dexamethasone, adipogenesis was stimulated within 21 days. Osteocalcin
expression, as assessed by in situ hybridization, was dependent on the presence
of 1,25(OH)2D3 and was decreased in cultures treated with dexamethasone. Northern
analysis confirmed the decrease in osteocalcin expression and increase in
lipoprotein lipase expression with the appearance of the adipogenic phenotype in
these cultures. Marrow cultures maintained for 14 days in human serum and
osteotropic agents before switching to fetal calf serum indicated the continuous
requirement of human serum in these cultures for adipogenesis. These results
demonstrate that human serum contains factors that exert dramatic effects on
human bone marrow cell differentiation to augment the osteogenic and adipogenic
activity of 1,25(OH)2D3 and dexamethasone.
PMID- 9402474
TI - Effect of PMA on the integrity of the membrane skeleton and morphology of
epithelial MDCK cells is dependent on the activity of amiloride-sensitive ion
transporters and membrane potential.
AB - The signaling pathways from an activation of protein kinase C (PKC) by phorbol
myristate acetate (PMA) to the rearrangement of actin-based cytoskeleton and
membrane skeleton of epithelial MDCK cells were studied by visualizing the
cytoskeletal organization with immunofluorescence microscopy and by measuring
intracellular pH, sodium ion concentration and membrane potential with the aid of
fluorescent intracellular indicators. Upon PMA treatment the MDCK cells lost
their cubic shape and acquired a spindle-like morphology. The stress fibers were
depolymerized, and fodrin, the main component of the membrane skeleton, was
released from the lateral walls to the cytosol. These changes were accompanied by
depolarization of the cells, decrease in the intracellular pH and sodium ion
concentration. In order to test the mutual correlation between the PMA-induced
alterations we treated the cells with PMA in the presence of channel inhibitors
or ionophores and in defined media. The effects of PMA on the membrane skeleton
and morphology could be reversed in media lacking Na+ or K+ ions or by
hyperpolarizing agents, dimethylamiloride and valinomycin, suggesting that the
effects of PMA on the cytoskeleton were dependent on the ion gradients and
membrane potential across the cell membrane. Moreover, the morphological changes
and instabilization of the membrane skeleton of MDCK cells took place
spontaneously without PMA in depolarizing conditions, in potassium gluconate
buffer. We suggest that the membrane potential across the cell membrane of MDCK
cells together with the activity of amiloride-sensitive cation transporters
transmits signals in the protein kinase C (PKC) pathway leading from activation
of PKC to fibroblast-like morphology and cytoplasmic localization of membrane
skeleton components, features characteristic for cancer cells.
PMID- 9402475
TI - Deuterium oxide (heavy water) accelerates actin assembly in vitro and changes
microfilament distribution in cultured cells.
AB - While deuterium oxide (D2O) is known to produce various biological effects in
living animals and cultured cells, the detailed mechanisms by which it does so
remain unclear. The present study was designed to assess the effects of D2O on
microfilaments (MFs) via fluorescence staining of BALB 3T3 cells and in vitro
actin polymerization studies. After BALB 3T3 cells had been exposed to a
concentration of more than 30% D2O for several hours, stress fibers in the
peripheral region became thick and distinct, while the quantity of perinuclear
MFs was drastically reduced. This effect was transient and returned to the
original distribution within 12 h. Cytoplasmic F-actin (FA) also increased
transiently coincident with the enhancement of stress fibers. The pattern of cell
locomotion became simpler, and total locomotor activity was suppressed in a D2O
concentration-dependent manner. Analysis of in vitro studies demonstrated that,
when purified G-actin was polymerized in D2O at a concentration greater than 10%,
the rate of actin polymerization was accelerated, whereas the total amount of
polymerized actin at the steady state in D2O was the same as that in H2O
controls. A gelation assay and transmission electron microscopy (TEM) showed that
the network of crosslinked FA with alpha-actinin became denser in 30% D2O than in
H2O. These findings concerning actin polymerization and FA gelation suggest that
the alteration of stress fibers in cultured cells is caused by a direct effect of
D2O on cellular MF dynamics.
PMID- 9402476
TI - Copy number, epigenetic state and expression of the rRNA genes in young and
senescent rat embryo fibroblasts.
AB - The recent cloning of the gene that causes the premature aging in Werner syndrome
patients has evoked speculations that deficits in expression of the ribosomal RNA
genes could be related to cellular aging in general. Here we compare the state of
the rRNA genes and the rRNA metabolism in young and senescent (aged) rat embryo
fibroblasts (REF). Southern blot analysis revealed that the copy number and the
methylation state of the genes did not change significantly with increasing
cumulative population doublings (CPD) of the culture. Hence, young (low numbers
of CPD) and senescent REF (high numbers of CPD), respectively, have the same
repertoire of rDNA units that can be transcribed. The rRNA synthesis in these
cells was analyzed by incorporation of labeled uridine at conditions allowing the
measurement of absolute rather than relative rRNA synthesis rates. We revealed
that the cell density dependence of the rRNA synthesis diminishes in senescent
cells. Exponentially growing young REF exhibited an rRNA synthesis of 16 amol
uridine incorporation per minute and cell. The rRNA synthesis decreased 10-fold
in quiescent cells at saturating cell densities. Exponentially growing REF near
the end of their replicative lifespan exhibited a 2-fold lower rRNA synthesis
rate compared to young cells. However, in senescent REF the rRNA synthesis rate
decreased only 2-fold with increasing cell densities resulting in a 3-fold higher
rRNA synthesis rate compared to young cells at saturating cell densities. These
data could be confirmed by calculating the rRNA synthesis rates from the rRNA
content, the rRNA half-life, and the proliferation rate of the cells. Hence,
senescent REF exhibited a higher rRNA synthesis rate when compared to young cells
at similar growth rates resulting in the generally observed higher rRNA content
(and cell size) of senescent cells. We conclude that cellular senescence of REF
is not accompanied by rRNA expression deficiencies.
PMID- 9402477
TI - Frailty of two cell cycle checkpoints which prevent entry into mitosis and
progression through early mitotic stages in higher plant cells.
AB - Allium cepa L. root meristems were given two short caffeine treatments spaced by
15 hours, the time which roughly corresponds to the duration of one cell cycle.
In this way two subsequent cytokineses were prevented, and multinucleate cells
with their in complement distributed into two, three or four nuclei were formed.
Though all nuclei started to replicate synchronously in these cells, some of them
(fast nuclei) completed their replication earlier than others (slow nuclei). The
present report shows that two successive checkpoints operate before prometaphase
in these cells. The first one prevents the entry of the fast nuclei into prophase
until the slow ones have completed their replication. The second checkpoint
ensures the synchronous entry into prometaphase after all nuclei have reached and
finished prophase. By treating the multinucleate cells with an inhibitor of DNA
synthesis at that time when fast but not slow nuclei had finished their
replication, it was observed that both checkpoint mechanisms became leaky with
time. Under these conditions the fast nuclei entered prophase in the presence of
nuclei which were prevented from finishing the replication of their DNA.
Subsequently, even prometaphase was triggered after a prolonged prophase.
Finally, as expected from the presence of mitotic stages in these cells, nuclei
with incompletely replicated DNA endured premature chromosome condensation. The
prematurely condensed chromosomes either remained in a prometaphase-like stage
until reconstitution nuclei formed or they followed the progression of the fast
nuclei into metaphase and anaphase leading to the appearance of acentric
chromosomal segments which after reconstitution gave rise to aneuploid nuclei
containing unstable and broken DNA.
PMID- 9402478
TI - Influence of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) on the localization
of cathepsin B and cathepsin L in human lung tumor cells.
AB - Cathepsins B and L are catabolic lysosomal enzymes but are likely candidates for
extracellular proteolysis in normal and malignant processes. The signal mediator
12(S)-HETE selectively triggers a shot-gun release of cathepsin B. We have
therefore investigated the intracellular distribution of cathepsins in
unstimulated and 12(S)-HETE-stimulated tumor cells. Cathepsins B and L have only
limited colocalization, which is found in the regions of synthesis and sorting
(endoplasmic reticulum, Golgi, trans Golgi network). Treatment by 12(S)-HETE
scatters cathepsin B but not cathepsin L and proform of cathepsin B.
Colocalization with both mannose 6-phosphate receptors is very limited for both
cathepsins. But extensive colocalization of cathepsin B and the
endosomal/lysosomal marker CD63 (LIMP-I) documents the main fraction of the
enzyme in these compartments. The supposed non-lysosomal fraction of cathepsin B
is very likely the secretable material which follows a regulated secretory
pathway. Storage and regulated secretion in tumor cells support extracellular
proteolysis as a means in invasion which may lead to metastasis. But the
mechanisms by which cells might acquire and eventually apply this means is still
unknown.
PMID- 9402479
TI - Phenoloxidase-dependent cytotoxic mechanism in ascidian (Styela plicata)
hemocytes active against erythrocytes and K562 tumor cells.
AB - The cytotoxic activity against rabbit erythrocytes (RE) and human K562 tumor
cells by Styela plicata hemocytes was significantly related to the phenoloxidase
(PO) which converts phenols to quinone and initiates the melanogenic pathway. The
effector hemocyte population, separated in a Percoll density gradient band,
enriched in a granulocyte type named "morula cells", was examined with RE in a
hemocyte cytotoxic assay and plaque forming cell assay. Inhibition experiments
with the copper chelating agents 1-phenyl-2-thiourea and tropolone, the substrate
analogue sodium benzoate and sodium ascorbate support the notion that hemocyte
cytotoxic activity is a PO-dependent mechanism. Treatments of hemocytes with the
antioxidant enzymes, superoxide dismutase and catalase rule out oxy radicals
produced by the melanogenic process as responsible of erythrolysis. Such a result
suggests that quinone compounds derived from the melanogenic pathway might be the
cytotoxic molecules. The PO-dependent anti-RE activity was also shown in a plaque
forming assay in which "morula cells", containing polyphenols and PO, were
identified as cytotoxic.
PMID- 9402480
TI - Muscle biopsy for malignant hyperthermia screening in children.
AB - Malignant Hyperthermia (MH) remains a life-threatening event in anaesthetic
practice. In paediatric patients, triggering agents such as volatile anaesthetics
and other succinylcholine are widely used. For children with a positive family
history or previous clinical signs of MH, muscle biopsy for the halothane and
caffeine in vitro muscle contracture tests is the only reliable procedure for
diagnosis of MH susceptibility. Here we investigated outcome and compliance of
patients and parents involved in the test. Twenty-four children between 6 and 14
yrs of age were admitted to hospital for biopsy. Muscle withdrawal was performed
at the upper leg from lateral vastus muscle using regional or trigger-free
general anaesthesia. Outcome and compliance were controlled by a telephone
interview or direct physical re-evaluation. Seventeen patients out of 24 were
diagnosed as clinically MH-susceptible according to the protocol of the European
MH Group. Seven children were excluded as MH-negative by the test. Twenty-one
children were evaluated postoperatively. Minor side effects of wound healing
occurred, but none of the patients showed any abnormalities of muscle contracture
or movement performance. Considering the high risk of fatal complications in the
presence of MH-susceptibility, muscle biopsy of the upper leg for in-vitro
diagnosis is a justified procedure that is acceptable to children and their
parents.
PMID- 9402481
TI - Characteristics of multisystem organ failure in neonates.
AB - The records of 45 neonatal deaths in a four year period were reviewed
retrospectively. Sixteen patients (35.5%) developed multisystem organ failure
(MSOF). The criteria for pulmonary, hepatic, renal, hematologic, cardiac and
microvascular failures were established. The onset of the first organ involvement
was calculated in days prior to death. The earliest organ involved was kidney
(14.2 +/- 15.1) followed by microvascular (9.4 +/- 7.6), hematologic (84. +/-
10.1), liver (6.8 +/- 6.7), lung (6.3 +/- 6.6) and cardiac (6.0 +/- 8.7) failure.
Blood culture analyses revealed 5 patients with culture-positive sepsis. Yeast
was the leading septic agent (n = 3) followed by Klebsiella pneumoniae (n = 2),
Pseudomonas sp. (n = 1) and E. coli (n = 1). The first organ involvement was
noted at 17.6 +/- 23.2 days. We concluded that the sequence of neonatal MSOF is
different from that of adults, yet the inciting events are not clear-cut. Lung,
which is the first organ involved in adults, seems to be a lately involved organ
in neonates.
PMID- 9402482
TI - Alpha-fetoprotein (AFP) levels in normal children.
AB - Alpha-fetoprotein (AFP) is an important tumor marker for yolk sac tumor and
hepatoblastoma in childhood. We have been using the graph of the normal range of
serum AFP made by Tsuchida et al, when we evaluate the serum AFP levels in early
infancy. We measured the serum AFP levels by an immunoradiometric assay in 163
normal infants under 2 years of age, in order to make a more precise graph. Our
normal range was a little wider than that of Tsuchida et al. According to our
graph, false-positive cases would be fewer. Referring to the half-lives of serum
AFP levels in normal infancy is also useful, when it is difficult to evaluate the
AFP level.
PMID- 9402483
TI - The effect of hepatic vascular exclusion on hepatic blood flow and oxygen supply-
uptake ratio in the pig.
AB - The hemodynamic disturbances produced by total hepatic vascular exclusion (THVE)
for 40 minutes were studied in 7 pigs (19-22 kg). THVE was produced by clamping
the hepatic pedicle and inferior vena cava, above and below the liver, for a 40
minutes period, followed by unclamping. Compared to baseline values, 30 minutes
after onset of THVE, there was a decrease in cardiac output (3.86 +/- 0.55 vs
1.23 +/- 0.23 L x min-1), systemic arterial pressure (97.54 +/- 13.58 vs 43.43 +/
11.38 mm Hg), and pulmonary artery pressure (16.57 +/- 6.38 vs 12.57 +/- 3.58)
and an increase in systemic and pulmonary vascular resistance (1772 +/- 198 vs
2351 +/- 462, and 182 +/- 66 vs 361 +/- 124 dyn x s x cm-5 respectively). As a
result of diminished cardiac output, the systemic oxygen supply decreased (461 +/
131 vs 101 +/- 46 ml x min-1), but the systemic oxygen extraction rate rose from
17.3% t0 31.2%. Thirty minutes after unclamping, the changes had reversed and all
the parameters tended to normalize. Total hepatic blood flow 30 minutes after
unclamping was higher than at baseline (5.08 +/- 1.2 vs 6.66 +/- 0.67 ml x min-1
x 100 g-1), because of the increase in portal blood flow (4.52 +/- 1.21 vs 6.07
+/- 0.70 ml x min-1 x 100 g-1). There were no significant differences in hepatic
oxygen supply and uptake at baseline and after unclamping (152.6 +/- 23.0 vs
187.0 +/- 34.7 and 22.7 +/- 4.9 vs 28.7 +/- 8.4 ml O2 respectively). AST rose (29
+/- 7 vs 136 +/- 91 U/l), but there was no change in the remaining liver enzymes,
glucose, creatinine and serum electrolytes, so we conclude that the hemodynamic
disturbances produced by 40 minutes of THVE are manageable and spontaneously
reversible. Liver metabolism was not greatly disturbed, so THVE was judged to be
a viable technique to be added to the surgeon's range of options.
PMID- 9402484
TI - Meconium ileus: a ten-year review of thirty-six patients.
AB - Of 36 neonates with meconium ileus secondary to cystic fibrosis treated over a 10
year period, twenty-one (58%) had simple uncomplicated disease while fifteen
(42%) had complications which included perforation (5), volvulus (6) and atresia
(5). Gastrografin enema was employed in 20 infants with relief of obstruction in
8 (40%). Operative procedures consisted of resection and primary anastomosis in
seventeen patients, stomas were fashioned in six, three had an enterotomy with
irrigation only and two had Bishop-Koop enterostomy. Post-operative complications
developed in 5 (18%) of these 28 patients. The overall survival rate was 97%. The
one death occurred in an infant with short bowel syndrome, patent ductus
arteriosus, hydrocephalus and pulmonary damage. There were eight additional
patients who had meconium obstruction in the absence of cystic fibrosis.
PMID- 9402485
TI - Effects of H2 receptor blocking agents on bacterial translocation in burn injury.
AB - We experimentally studied the effects of H2 receptor blockers (ranitidine) on
bacterial translocation (BT) in 42 male albino rats. Sham group (Group I, n = 12
rats) were exposed to 21 degrees C water while Burn group (Group II, n = 15 rats)
and Ranitidine group (Group III, n = 15 rats) were exposed to 95 degrees C hot
water for 10 seconds to produce a full thickness burn in 30% of total body
surface area. 300 mg/kg ranitidine was administered to Group III starting
immediately after the burn injury. Rats were sacrificed on the fifth postburn
day. Sham group gained weight while groups II and III had significant weight
loss. Gastric pH increased with the administration of ranitidine. Both gram
negative and total number of bacteria were found to be reduced in cecal stool
cultures in ranitidine group. Significant increase in BT was observed in Group
III, and translocating bacteria were found to be different in burn and ranitidine
groups with a final conclusion that administration of ranitidine changes
intestinal ecological equilibrium and promotes BT.
PMID- 9402486
TI - Compensatory renal growth post fetal nephrectomy in the rabbit.
AB - Compensatory renal growth post-nephrectomy is well documented both clinically and
experimentally. However, little is known about the capacity for compensatory
growth in utero. We performed unilateral nephrectomy in fetal rabbits and studied
the growth of the contralateral kidney. Thirty fetal rabbits underwent in utero
uninephrectomies at day 25 of gestation. On gestational day 28, all the fetuses
were delivered by cesarean section and the ratios kidney weight/body weight of
the operated fetuses were compared to those of control littermates. The kidneys
were then analysed by histology. A significant increase in renal weight was
observed. The histological study of the remaining kidneys indicated a
statistically significant increase of the glomerular area which confirmed the
renal hypertrophy. This experiment demonstrates the capacity for the rabbit to
develop in utero compensatory renal growth.
PMID- 9402487
TI - Chromosomal aberrations in Wilms' tumour.
AB - In 26 consecutive patients operated for Wilms' tumour samples from the tumour
were genetically analyzed. Clonal acquired chromosome aberrations were found in
13 patients and a constitutional trisomy 18 as the sole change in 1. The
chromosome number was altered in 13 patients. Numerical changes occurred in 16
patients and breakpoint of chromosome 1 in 6 patients. There was no structural
alteration of chromosome 11. The observed cytogenetic heterogeneity illustrates
the complexity of genetic changes involved in the genesis and progression of
Wilms' tumour. To further elucidate the phenotypic impact of chromosomal
aberrations the correlation to histology and the clinical course will be
important.
PMID- 9402488
TI - Microvascular autotransplantation of the testis: the "refluo" technique.
AB - We think that the microvascular orchidopexy is the best technique for the
treatment of the high intraabdominal testis. To prevent the problems related to
the performing of the anastomosis between the spermatic and the inferior
epigastric arteries we changed the traditional way for microvascular orchidopexy
performing the venous anastomosis only, relying on the collateral deferential
circle for the arterial supply; we called this technique the "refluo testicular
autotransplantation". We supported our idea with an experimental investigation in
rats and rabbits, with which we confirmed the efficacy of our proposal. This
original technique, performed in 41 cases, allowed us to gain three important
ends: a) reduction of the age at operation (under two years); b) reduction of the
operating time (2 hours); c) improved success rate compared with the Fowler
Stephens technique or staged orchidopexy.
PMID- 9402489
TI - Surgical treatment of buried penis.
AB - The buried penis is a rare congenital entity, whose treatment is surgical. There
are few publications concerning this matter. The authors report on their
experience in 10 cases (1990-1995). In this abnormality, the tip of the glans
does not project from the pubic or scrotal skin. It is due to: 1) an excessive
development of the penile fascia which retracts the penis; 2) insufficient
attachment of the penile skin at the base of the penis; 3) often excessive
prepubic fat worsens the appearance of the abnormality but does not by itself
totally explain it; 4) a tight phimosis is often present. Surgical treatment is
necessary because this aspect tends to persist even after puberty. One cannot
indeed count on the development at the age of puberty, neither on the diminution
of the fat, nor on the simple cure of the phimosis. One must above all ban
circumcision which causes the risk of eliminating the skin necessary for
reconstruction. The surgical procedure will comprise: 1) a longitudinal dorsal
incision extended circumferentially; 2) resection of the thickened fascia penis;
3) anchoring of the deep face of the dermis to the proximal part of the fascia
penis at the base of the penis. This surgical procedure has always brought a
significant improvement to the appearance of the penis.
PMID- 9402490
TI - Treatment of Madelung's deformity by lengthening and reaxation of the distal
extremity of the radius by Ilizarov's technique.
AB - Madelung's deformity was first described in 1878. It is characterised by a
typical deformity of the carpus and not only causes pain but also impedes
mobility and aesthetic appearance. Surgical correction can be effected during
adolescence, the most frequently employed technique being conical osteotomy. We
present a novel technique of lengthening and aligning the distal radial extremity
using Ilizarov's technique. Five carpal joints were operated on in three 13-year
old girls. An aesthetic effect was obvious in all the cases. Mobility improved by
30 degrees in the direction of the extension and pain always subsided directly
after surgery.
PMID- 9402491
TI - Ventriculoscopic implantation of ventricular shunts in children with
hydrocephalus.
AB - A modified technique of ventriculoscopy-aided implantation of ventricular shunts
in children with hydrocephalus or intracranial cysts is presented. A 1 mm 0
degrees optic is introduced into the ventricle catheter and the shunt is
positioned under video control. Finally, the optic is removed and the catheter
left in place. Four endoscopy-aided implantations were performed with excellent
visualization and without technical failure, the smallest patient weighted 680
grams.
PMID- 9402492
TI - A case of non-functioning antiperistaltic retrosternal colic conduit replaced in
situ and substituted with an isoperistaltic segment of ileum-caecum.
AB - The authors report the case of a female patient, affected by long-gap oesophageal
atresia, who, at 5 months old, was operated on for retrosternal substitution with
a right-transverse antiperistaltic colic segment, in her local district hospital.
Due to the anomalous position the neooesophagus never worked, and the baby was
seriously dysphagic and failed to thrive. For this reason, when she was 11 months
old, she was reoperated in our department. Through a medium sternolaparotomy the
antiperistaltic colon was removed and replaced between the left and right colon;
reconstruction was carried out with a retrosternal and isoperistaltic segment of
ileo-caecum. The reoperation resolved her problems. This case is reported to
confirm the author's opinion that all intestinal conduits must be positioned in
the isoperistaltic direction.
PMID- 9402493
TI - Bilateral adrenal neuroblastoma.
AB - Neuroblastoma has been recognized as the most common solid tumor of infancy and
childhood. The occurrence of bilateral adrenal neuroblastoma, however, is
extremely rare and only a small number of cases have been previously reported.
The authors herein report the clinical, histopathological and molecular
biological features of two bilateral adrenal cases out of 125 neuroblastoma
patients treated at Kyushu University Hospital over a 35-year period. The
clinical and histopathological data of the two cases of bilateral adrenal
neuroblastoma were reviewed. In Case 1, which had multiple liver metastases, a
post-mortem examination revealed bilateral adrenal involvement. In Case 2, which
had been detected by mass screening, CT showed masses in both adrenal glands. No
big differences in size were recognized between the tumors in either of the
cases. A histopathological examination revealed rosette fibrillary type
neuroblastomas in both cases. The DNA of these tumor samples stored at -80
degrees C was extracted and the number of copies of the N-myc gene was determined
by a Southern blot analysis. Fourteen copies of the gene were detected in Case 1,
whereas neither of the tumors in Case 2 showed any amplification. The clinical
outcome, histopathological findings and N-myc gene analysis of two cases might
support the variety of biological features of this rare group of neuroblastoma.
PMID- 9402494
TI - Synchronous occurrence of Wilms tumor and ganglioneuroblastoma in a child with
neurofibromatosis.
AB - A 2-year-old male with neurofibromatosis who had a Wilms tumor of the right
kidney and an ipsilateral adrenal ganglioneuroblastoma is reported. Both tumors
were completely removed and no recurrence occurred for 4 years after completion
of the therapy. In a review of the literature, the prognosis of neurofibromatosis
with these embryonal tumors is not satisfactory due to development of secondary
tumors and disseminated metastases of the tumors. The synchronous occurrence of
Wilms tumor and neuroblastoma in neurofibromatosis is extremely rare and this may
be the first report in the world.
PMID- 9402495
TI - Yolk sac tumor of the ovary in a conjoined twin.
AB - A 5-year-old conjoined twin girl had a yolk sac tumor of the right ovary. She was
admitted to our hospital because of abdominal distension. Comprehensive clinical
and radiological investigations revealed a tumor of the right ovary. She
underwent right salpingo-oophorectomy. The diagnosis was yolk sac tumor (stage I
A), and postoperative chemotherapy (vincristine, actinomycine-D,
cyclophosphamide) according to the UK-CCSG was provided. The postoperative course
was uneventful with no evidence of recurrence 3 years after surgery. Her twin
sister had no tumor. This is the first reported of yolk sac tumor of the ovary in
a conjoined twin.
PMID- 9402496
TI - Duplication of urethra--case report and review of literature.
AB - Duplication of urethra is very rare. The duplicated urethra is always dorsal to
the normal urethra which contains the sphincteric mechanism. A case is reported
of urethral duplication where the duplicated urethra presented as a sinus on the
dorsum of the penis.
PMID- 9402497
TI - Carcinoma of the colon in childhood; report of 2 cases expressing p53 without K
ras mutation.
AB - We report on 2 children with colonic carcinoma and also review 62 cases of
Japanese children with colonic carcinoma including ours. Although the dismal
prognosis in colonic cancer in children is possibly due to the predominance of
poorly differentiated carcinoma, there is no significant difference in the 5-year
survival rates among well, moderately and poorly differentiated carcinomas in
children. Positive staining with p53 in tumor cells was observed in each, but K
ras mutations were not detected in any. Therefore, these carcinomas possibly
developed from de-novo carcinoma. The development pathway of colonic carcinoma
may relate to the prognosis in children, and be different from that in adults.
PMID- 9402498
TI - Tooth mobility and periodontal disease.
AB - Tooth mobility (TM) is an important feature of periodontal disease. This is
evidenced by the large number of devices and methods of TM assessment that have
been developed and tested. TM had been considered and investigated as an indirect
measure of the functional condition of the periodontium as well as possible
aggravating co-factor for periodontal disease.
PMID- 9402499
TI - A study to investigate the effect of a propolis-containing mouthrinse on the
inhibition of de novo plaque formation.
AB - The results of a study to investigate the effectiveness of a propolis-containing
mouthrinse in the inhibition of de novo plaque formation are presented. Subjects
used a propolis-containing rinse, a negative control and a positive control in a
double-blind, parallel, de novo plaque formation study design. The chlorhexidine
mouthrinse was significantly better than the others in plaque inhibition. The
propolis-containing rinse was marginally better than the negative control, but
this difference was not significant.
PMID- 9402500
TI - Substance P and neurokinin A in gingival crevicular fluid in periodontal health
and disease.
AB - The aims of the present study were to investigate whether the tachykinins
substance P and neurokinin A were present in gingival crevicular fluid in both
periodontal health and disease and to study the relationship with periodontal
inflammation. Gingival crevicular fluid (GCF) was collected from a healthy, a
gingivitis and a periodontitis site in 20 subjects with periodontitis and from a
healthy site in 20 subjects without periodontitis. The volume of GCF was measured
and each sample subsequently analysed for substance P and neurokinin A by
radioimmunoassay. There were significantly increased levels of substance P-like
immunoreactivity (SP-LI) and neurokinin A-like immunoreactivity (NKA-LI) in
gingivitis and periodontitis sites compared with healthy sites. Both tachykinins
were significantly elevated in periodontitis affected subjects, with
significantly more tachykinin-like immunoreactivity at healthy sites in
periodontitis affected compared with periodontally-healthy subjects. Despite the
considerable individual variation in the levels of SP-LI and NKA-LI, both
tachykinins were present at levels at which they could have biological activity.
It is concluded that substance P and neurokinin A may have a role in the
pathogenesis of periodontal disease and that further investigations could prove
useful in clarifying the mechanisms through which neuropeptides could modulate
periodontal health and disease.
PMID- 9402501
TI - Amoxicillin and clavulanic acid concentrations in gingival crevicular fluid.
AB - The beta-lactams are bactericidal antibiotics, but some of them may be
inactivated by bacterial beta-lactamases which destroy the beta-lactam ring. The
inactivation of amoxicillin by beta-lactamases of gram negative anaerobic
bacteria can be circumvented by the addition of clavulanic acid, a beta
lactamases inhibitor. Thus, most of these bacteria are susceptible to this
combination. The aim of this study was to investigate the concentrations of
amoxicillin and clavulanic acid in gingival crevicular fluid (GCF). These
concentrations were measured in 20 patients with rapidly progressive
periodontitis 1 h after a dose of 500 mg (1 tablet Augmentin) on day 0 and 1 h
after the 10th intake on day 3. For the sampling of GCF, Periopapers were
introduced in 16 gingival sites per subject and time. The GCF volumes collected
were estimated using the Periotron 6000. A high performance liquid chromatography
method has been developed for the determination of amoxicillin and clavulanic
acid in microsamples (1 to 10 microliters) of GCF. The concentrations of
amoxicillin and clavulanic acid were respectively, 14.05 micrograms ml-1 and 0.40
microgram ml-1 at day 0, 13.93 micrograms ml-1 and 0.37 microgram ml-1 at day 3.
Effective levels of amoxicillin and clavulanic acid, well above the minimal
inhibitory concentrations of some susceptible periodontal anaerobes (P.
intermedia) involved in destructive periodontal diseases, are achieved following
the multiple administration of amoxicillin combined with clavulanic acid.
PMID- 9402502
TI - Guidelines for the design and conduct of clinical trials on dentine
hypersensitivity.
AB - Clinical trials on dentine hypersensitivity have been numerous and protocols
varied. To date there is little consensus as to the conduct of studies on this
poorly-understood yet common and painful dental condition. A committee of
interested persons from academia and industry was convened to discuss the subject
of clinical trials on dentine hypersensitivity and a consensus report is
presented. A double-blind randomized parallel groups design is recommended,
although cross-over designs may be used for the preliminary screening of agents.
Subjects may have multiple sites scored. Sample size will be determined by
estimating the variability in the study population, the effect to be detected and
the power of the statistical test to be used. Subject selection is based on a
clinical diagnosis of dentine hypersensitivity, excluding those with conflicting
characteristics such as currently-active medical or dental therapy. The
vestibular surfaces of incisors, cuspids and bicuspids are preferred as sites to
be tested. A range of sensitivity levels should be included. Tactile, cold and
evaporative air stimuli should be applied. Negative and benchmark controls should
be incorporated. Most trials should last 8 weeks. Sensitivity may be assessed
either in terms of the stimulus intensity required to evoke pain or the
subjective evaluation of pain produced by a stimulus using a visual analog or
other appropriate scale. The subject's overall assessment may be determined by
questionnaire. Outcomes should be expressed in terms of clinically significant
changes in symptoms. Follow-up evaluation is required to determine the
persistence of changes. At least 2 independent trials should be conducted before
a product receives approval.
PMID- 9402503
TI - CD11b mRNA expression in neutrophils isolated from peripheral blood and gingival
crevicular fluid.
AB - Adhesion molecule CD11b/CD18 expressed by neutrophils (PMNs) participates in cell
migration and phagocytosis of C3bi derivatized bacteria. It is this phagocytic
function that eliminates some of the known periodontal pathogens in periodontal
pockets. In patients with advanced periodontitis, homotypic aggregation of
crevicular fluid PMNs (CF-PMNs) may occur due to overexpression of CD11b/CD18 and
this may lead to ineffective elimination of periodontal pathogens. We have
previously shown that CF-PMNs isolated from the periodontal pockets overexpress
CD11b compared to PB-PMNs. This study tested the hypotheses that (1)
overexpression of surface CD11b correlates with expression of CD11b mRNA in CF
PMNs isolated from advanced periodontitis subjects, and (2) the intrinsic
capacity of CD11b mRNA upregulation by PB-PMNs from periodontitis patients
differs from that of control subjects. CF-PMNs and peripheral blood PMNs (PB
PMNs) were isolated from 13 subjects with healthy gingiva (control group) and 13
subjects with advanced periodontitis (patient group). The surface expression of
CD11b was determined by flow cytometry and CD11b mRNA was determined by
extraction of mRNA and reverse transcription to cDNA followed by DNA
amplification using primers to detect a segment of the cDNA which encodes CD11b.
The results of this study confirm that the surface expression of CD11b on CF-PMNs
is significantly higher in periodontitis subjects vs control subjects (p = 0.03),
whereas surface CD11b expression on PB-PMNs does not differ significantly between
groups (p = 0.06). The level of surface CD11b expression on CF-PMNs did not
correlate with the amount of mRNA present in CF-PMNs in either group (p = 0.056,
0.07 for control and periodontitis patients, respectively). Most (9 of 13)
individuals in the patient group expressed CD11b mRNA whereas very few control
subjects (2 of 11) had CD11b mRNA in their CF-PMNs. This difference between
groups was statistically significant (p = 0.004). The capacity to upregulate
CD11b mRNA upon stimulation with fMLP and/or GM-CSF was highly variable and there
was no statistical difference between the 2 groups.
PMID- 9402504
TI - Reduced serum IgG reactivities with bacteria from dental plaque in HIV-infected
persons with periodontitis.
AB - Serum samples were obtained from 44 HIV-seropositive (HIV+) and 37 HIV
seronegative (HIV-) persons that were grouped according to periodontal status.
Serum IgG and IgA reactivities towards Streptococcus mutans, Actinobacillus
actinomycetemcomitans, Porphyromonas gingivalis. Prevotella intermedia,
Prevotella nigrescens and Fusobacterium nucleatum were measured by means of
ELISA. HIV+ persons with chronic marginal periodontitis showed significantly
lower IgG reactivities to the periodontal pathogens A. actinomycetemcomitans, P.
gingivalis, P. intermedia and F. nucleatum as compared with their HIV-
counterparts (p < 0.05). Specific serum IgA reactivities were similar in the two
periodontitis groups, except for P. nigrescens where the HIV+ group with chronic
marginal periodontitis had lower values than their systemically healthy
counterparts (p < 0.05). The results indicate that HIV infection affects the
humoral serum immune responses against bacteria in dental plaque; the depressed
antibody responses may contribute to the increased susceptibility for periodontal
infections in HIV-infected patients.
PMID- 9402505
TI - Comparison of the subgingival microbiota of periodontally healthy and diseased
adults in northern Cameroon.
AB - Our study is the 1st report on subgingival microbiota in adult Cameronians. The
aim was to investigate, using the checkerboard DNA-DNA hybridization technique,
the prevalence of 18 oral species in subgingival plaque samples obtained from sex
and age-matched Cameronian adults with and without periodontal destruction. We
also compared cultivation and the Affirm DP test with the checkerboard technique
in their capability to detect some selected species among the 18. 21 adult
periodontitis patients and 21 periodontally healthy subjects were examined and
the results were compared statistically. Each periodontitis patient had at least
4 pockets of > or = 6 mm depth, while the healthy subjects had no sites more than
3 mm deep. Results of the checkerboard analysis showed that significantly (p <
0.05) more periodontitis patients tested positive for most of the 18 bacterial
species. The Gram-positive species Actinomyces naeslundii, Streptococcus mitis
and Streptococcus sanguis, known as microbiota of healthy sites, were detected
significantly more frequently in the healthy group. Cultivation demonstrated P.
gingivalis, B. forsythus, A. actinomycetemcomitans, P. intermedia and F.
nucleatum in significantly lower %s of patients as compared to the checkerboard
technique. Furthermore, the Affirm DP test detected P. gingivalis and B.
forsythus in significantly fewer patients than did the checkerboard technique. A.
actinomycetemcomitans was detected in 52.3% of the patients by the latter
technique while the Affirm DP test failed to detect the bacterium in any of the
samples. Overall, the results of the present study confirm the importance of the
screening method and indicate that the prevalences of the investigated putative
periodontal pathogens and beneficial species in the healthy and diseased adult
Cameronians were similar to those reported for adults in the West and in some
developing countries.
PMID- 9402506
TI - Loss of deciduous teeth and germs of permanent incisors in a 4-year-old child. An
atypic prepubertal periodontitis? A clinical, microbiological, immunological and
ultrastructural study.
AB - A 4-year-old child was referred, in April 1988, to Rennes Dental School (France)
for deciduous tooth mobility with premature loss of 4 deciduous teeth and germs
of 2 permanent incisors. Microbiological examinations by culture revealed the
presence of the periodontal pathogen Actinobacillus actinomycetemcomitans.
Immunofluorescence of plaque samples revealed the presence of Porphyromonas
gingivalis that had not been isolated by culture. Neutrophil functions were
within normal ranges. Transmission electron microscopy of gingiva showed a
disorganised epithelium. The connective tissue was infiltrated by inflammatory
cells. The basement membranes were normal, but the connective tissue-epithelium
interface was mainly composed of short rete pegs. Scanning electron microscopy of
extracted deciduous teeth revealed lack of cementum, lacunae in the cementum and
lack of fibrillar insertion on the middle part of the root. Skin lesions, mainly
situated on face, were observed. Treatment was by extraction of mobile deciduous
teeth combined with 3-week courses of metronidazole. Clinical and microbiological
follow-up was continued over a 7-year period. No periodontal lesions have been
detected since eruption of the permanent teeth. The present subgingival and
lingual microflora (December 1995) is composed of bacteria associated with
periodontal health. However, the future appearance of a hitherto undetected
systemic disease is still possible.
PMID- 9402507
TI - A semiquantitative approach to the evaluation of acute cardiac allograft
rejection at endomyocardial biopsy.
AB - BACKGROUND: Histopathologic criteria for grading of acute cardiac allograft
rejection are focused on the most severe lesion that is recognized among the
myocardial fragments provided by each endomyocardial biopsy specimen. Considering
the distribution of rejection lesions among all the fragments improved the
accuracy in characterizing the severity of rejection in pathologic studies. This
study was undertaken to verify the usefulness of a semiquantitative evaluation of
endomyocardial biopsy specimens, consisting of the calculation of the proportion
of fragments showing rejection in the clinical setting. METHODS: Of the 2386
biopsy specimens obtained during the first posttransplantation year in 168
consecutive cardiac allograft recipients, 290 biopsy specimens constituted by >
or = 3 adequate fragments and showing rejection not followed by treatment (n =
159) or being the first biopsy specimen prompting treatment with augmented
immunosuppression for that rejection episode (n = 131) were selected. These
biopsy specimens (index biopsy specimens) were grouped according to whether
rejection was present in < or = 33%, > 33% to < or = 67%, and > 67% of the
fragments. The rejection grade (according to the standardized grading system) and
the proportion of fragments positive for rejection were correlated with the
occurrence of clinical symptoms and signs of rejection at index biopsy and with
the results of the next biopsy. RESULTS: Rejections graded > or = 3A were more
frequently symptomatic (36% vs 9% for those graded < 3, p < 0.0001), as were
those involving increasing proportions of fragments (< or = 33%: 5 of 124, 4%; >
33 to < or = 67%: 13 of 99, 13%; > 67%: 19 of 67, 28% [p < 0.0001]). Spontaneous
resolution after untreated biopsies was more frequent in focal (grade 1A and 2)
than in diffuse mild (1B) rejections (68% vs 38% [p < 0.04]), whereas progression
to grade 3A or greater was less frequent (4% vs 27% [p < 0.01]). Increasing
proportions of positive fragments were associated with lower frequencies of
spontaneous resolution (p < 0.05) and higher frequencies of worsening (9%, 22%,
43% [p < 0.009]) or progression to grade 3A or greater (2%, 6%, 28% [p < 0.005]).
Complete resolution after treatment was less frequent for increasing proportions
of positive fragments at index biopsy (80%, 66%, 49% [p < 0.05]). CONCLUSIONS:
Diffuse versus focal rejection pattern and the proportion of positive fragments
seem to be clinically relevant in terms of occurrence of symptoms, spontaneous
evolution, and response to treatment.
PMID- 9402508
TI - Efficacy of combining donor-specific presensitization with a simultaneous single
injection of tacrolimus on pulmonary allografts.
AB - BACKGROUND: We investigated the effects of combining donor-specific
presensitization with a simultaneous injection of tacrolimus by use of a fully
allogeneic rat lung allograft model. METHODS: Lungs from Brown Norway donor rats
were orthotopically transplanted into Lewis recipient rats. Seven days before
transplantation, allograft recipients received a transfusion of donor splenocytes
(1 x 10(8) cells, intravenously), tacrolimus (3 or 1.5 mg/kg, intramuscularly),
or a combination. No posttransplantation immunosuppression was given. In the
transplantation study, graft survival was evaluated, and histologic
characteristics of acute rejection were graded. In the in vitro studies, mixed
lymphocyte reaction assays were used to investigate the effects of pretreatment
on immune response. RESULTS: The graft survival evaluation disclosed that
untreated rats rejected the allografts at 4.6 +/- 0.2 days. Donor splenocyte
transfusion alone accelerated the graft rejection (3.3 +/- 0.2 days). Tacrolimus
(3 mg/kg) alone moderately improved the graft survival (8.7 +/- 0.6 days). When
donor splenocyte transfusion was combined with tacrolimus, graft survival was
significantly increased to 29.6 +/- 12.0 days. In a mixed lymphocyte reaction
assay, peripheral blood lymphocytes obtained from animals pretreated with donor
splenocyte transfusion alone seemed to be hyperresponsive against the donor
lymphocytes. In contrast, donor splenocyte transfusion with tacrolimus
significantly suppressed the proliferative response against the donor lymphocytes
but not against third-party lymphocytes obtained from naive Wistar King A rats.
CONCLUSION: These data demonstrate that donor-specific presensitization with a
simultaneous single injection of tacrolimus prevented both sensitization and
graft rejection and induced donor-specific unresponsiveness.
PMID- 9402509
TI - Long-term renal function in heart transplant recipients receiving cyclosporine
therapy.
AB - BACKGROUND: Immunosuppression with cyclosporine has improved allograft function
and reduced both morbidity and mortality in organ transplantation. However,
cyclosporine-induced nephrotoxicity still is a concern. The purpose of our study
was to evaluate the effects of cyclosporine on renal function in orthotopic heart
transplant recipients. METHODS: Thirty-nine patients who received transplants
from 1985 to 1991 and had at least three yearly glomerular filtration rate
measurements posttransplantation by 125I-iothalamate clearance method were
included in the study. In addition, serum creatinine (before and after
transplantation) and cyclosporine doses were analyzed. RESULTS: Maintenance
immunosuppression at 1 year consisted of prednisone (0.1 mg/kg/day), azathioprine
(2 mg/kg/day), and cyclosporine (12-hour trough level 100 to 150 ng/ml by
fluorescence polarization immunoassay). The mean serum creatinine at 1 year was
significantly higher than the mean pretransplantation serum creatinine (1.51 +/-
0.32 versus 1.28 +/- 0.38, p < 0.05) and stabilized after the first year. The
mean glomerular filtration rate by 125I-iothalamate clearance method was 70.6 +/-
20.3 ml/min/1.73 m2 (range 32 to 105) at 1 year and remained relatively stable
during the follow-up period of up to 7 years. Creatinine clearance calculated by
the Cockcroft and Gault formula overestimated the true glomerular filtration rate
after the third year. The mean cyclosporine dosage was significantly lower after
the first-year dose of 3.9 +/- 1.8 mg/kg/day (p < 0.05). Three patients in 39
started hemodialysis at 5, 7, and 10 years after transplantation. CONCLUSION: Our
data indicate that the adequacy of renal function is preserved with long-term
cyclosporine therapy in heart transplant recipients.
PMID- 9402510
TI - Causes of late failure after heart transplantation: a ten-year survey.
AB - BACKGROUND: Little is known about the causes of death of heart transplant
recipients who survive long-term. METHODS: The pathologic and clinical records of
97 patients who underwent heart transplantation in Italy from 1985 to 1995 and
died (85 of 97) or underwent retransplantation (12 of 97) at least 2 years after
transplantation were surveyed. Graft failures were classified as late (occurring
between 2 and 5 years after transplantation) and belated (more than 5 years).
RESULTS: Graft vasculopathy was the single most common cause of death (40.0%) and
the only cause of late retransplantation. Tumors ranked second (23.5% of deaths),
but the expected non-Hodgkin's lymphomas and Kaposi's sarcoma were accompanied by
a high number of lung cancers (especially metastasizing adenocarcinomas). They
were followed by the emergence or recurrence of pretransplantation diseases
(9.4%), fatal infections (exclusively bacterial) (4.7%), the development of
transmissible diseases (viral hepatitis and acquired immunodeficiency syndrome,
4.7%), and late acute rejection (2.3%). The distribution of failures differed in
the late and belated periods: death and organ loss proportions for graft
vasculopathy, respectively, fell and rose from the late to the belated period;
some types of malignancy and fatal acute rejection were never observed in the
belated period, whereas the emergence of pretransplantation diseases prevailed in
the belated period. Graft vasculopathy was more frequent and tumors were less
frequent among patients undergoing transplantation for ischemic heart disease.
CONCLUSIONS: The reasons why heart transplant recipients die or undergo
retransplantation, respectively, in the late and belated periods slightly differ
from one another and are widely different than in short-term survivors.
PMID- 9402511
TI - Overcoming right ventricular failure with left ventricular assist devices.
AB - BACKGROUND: Right ventricular failure can lead to circulatory collapse while on
left ventricular assist device support. By shunting blood from the femoral vein
to the left ventricular assist device, cardiac output can be increased, but
arterial oxygen saturation will decrease. METHODS: To determine the effects on O2
delivery, a model was developed on the basis of O2 uptake in the lungs and whole
body O2 consumption. An equation was derived that related cardiac output,
pulmonary venous O2 saturation, O2 consumption, and the ratio of shunt-to
systemic blood flow to systemic O2 delivery. RESULTS: When total cardiac output
increases, the shunt will increase systemic O2 delivery while decreasing arterial
O2 saturation and leaving systemic venous O2 saturation unaltered. When total
output does not increase, the shunt will decrease systemic O2 delivery, arterial
O2 saturation, and systemic venous O2 saturation. CONCLUSIONS: The analysis
suggests that measuring systemic venous oxygen saturation may be a useful way to
monitor patient safety. A decrease in systemic venous O2 saturation when creating
the shunt implies an inadequate increase in cardiac output.
PMID- 9402512
TI - Cost-utility of lung transplantation: a pilot study.
AB - BACKGROUND: The purpose of this study was to conduct a pilot investigation of the
cost-utility of lung transplantation. With this study we provide a threshold
analysis to estimate the survival gains that must be achieved for lung
transplantation to be considered a beneficial use of society's resources.
METHODS: A cross-sectional cohort design was used. All patients having undergone
lung transplantation at the University of Pittsburgh Medical Center between March
1 and August 31, 1994, were identified via roster of transplant recipients (n =
20). Surviving patients were interviewed, by telephone, at their 1-year
anniversary date. Utility was assessed by use of the quality of well-being scale.
Direct cost of care was estimated from adjusted charges for the surgical
admission, plus physician fees per the Medicare Physician Fee Schedule. RESULTS:
The mean quality of well-being score for this group was 0.54 +/- 0.198 SD (median
= 0.599, range 0 to 0.728). Summing the physician cost and the adjusted charges
for the inpatient operative admission, the average cost of lung transplantation
was $153,921 +/- $133,981 SD (median $94,324, range $63,405 to $598,482). At a
cost of $94,324 and a utility of 0.599, the survival gain from surgery must be
2.7 years for the cost of the procedure to be justified from a societal
perspective. CONCLUSIONS: Because of the many limitations in this pilot study, no
firm policy implication may be drawn from these data. Directions for future
research are discussed.
PMID- 9402513
TI - Increased concentration of soluble human leukocyte antigen class I levels in the
bronchoalveolar lavage of human pulmonary allografts.
AB - BACKGROUND: Human leukocyte antigen (HLA) class I antigens, are glycoproteins
expressed on the cell surface and are also secreted (sHLA) into the surrounding
fluids. This study investigates whether pulmonary allograft rejection is
associated with an increased amount of sHLA class I in the bronchoalveolar lavage
(BAL) fluid. METHODS: Enzyme-linked immunosorbant assays were used to measure
sHLA class I levels in BAL samples from 66 lung transplant recipients. RESULTS:
Analysis of pulmonary allograft recipients revealed that the mean concentration
of sHLA class I was significantly higher in samples from recipients with acute
rejection than in recipients with no evidence of rejection. Seventy-two percent
of the patients with rejection had sHLA levels above the normal range for
patients with infection or rejection. Conversely, sHLA levels were within normal
limits in 94% of the control population. Time kinetic analysis revealed that in
subjects with rejection, sHLA class I levels peaked in the first 2 weeks after
transplantation and decreased thereafter. Increased levels of sHLA were found in
patients with acute rejection but not in those with chronic rejection. Fifty-nine
percent (n = 10) of the patients with infection had sHLA levels within the normal
(no infection or rejection) range. The remaining 41% (n = 7) with infection had
sHLA above the normal range. Fifty-seven percent (n = 4) of the latter group had
cytomegalovirus infection. These results were confirmed in a prospective study
carried out by analyzing paired samples obtained during and after rejection.
Eight of the nine patients had high BAL sHLA class I during acute rejection, and
low BAL sHLA class I levels after resolution of the acute rejection. CONCLUSION:
Our data demonstrate that measurement of sHLA class I levels in BAL samples is a
sensitive indicator of acute rejection.
PMID- 9402514
TI - Inhibition of accelerated coronary atherosclerosis with short-term blockade of
intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 in
a heterotopic murine model of heart transplantation.
AB - BACKGROUND: Graft arteriopathy limits the long-term survival of allograft
recipients. Cardiac allografts in mice develop graft coronary arteriopathy
similar to that observed in clinical chronic rejection in human beings. We found
that antiintercellular adhesion molecule-1 (ICAM-1) and antilymphocyte function
associated antigen-1 (LFA-1) monoclonal antibodies (mAbs) induce immunologic
tolerance to mice with cardiac allografts. METHODS: To evaluate the effects of
short-term administration of anti-ICAM-1 plus anti-LFA-1 mAbs in preventing graft
arteriopathy, we treated C3H/He mice that received cardiac allografts from BALB/c
mice with anti-ICAM-1 plus anti-LFA-1 mAbs for the first 5 days after
transplantation. For control studies, FK506 was administered daily to other
allograft recipients. Allografts were harvested on day 60. Immunohistochemical
analysis was used to detect the expression of ICAM-1 and vascular cell adhesion
molecule (VCAM)-1, and in situ reverse transcriptase polymerase chain reaction
was performed to detect platelet-derived growth factor (PDGF)-B mRNA expression
in the graft arteries. RESULTS: Allografts from mice that received FK506
treatment daily showed significant neointimal thickening with increased
expression of ICAM-1, VCAM-1, and PDGF-B mRNA, whereas there was almost no
intimal thickening and ICAM-1, VCAM-1, and PDGF-B mRNA expression in the mice
that received anti-ICAM-1 plus anti-LFA-1 mAbs. CONCLUSION: Short-term blockade
of ICAM-1 and LFA-1 adhesion not only induces immunologic tolerance to cardiac
allografts but also prevents graft arteriopathy.
PMID- 9402515
TI - Assessment of tolerance induction to cardiac allograft by anti-ICAM-1 and anti
LFA-1 monoclonal antibodies.
AB - BACKGROUND: Transplantation tolerance is induced by selective manipulation of
intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated
antigen-1 (LFA-1) molecules in the adult mouse. However, the mechanism of this
tolerance induction has not been elucidated. METHODS AND RESULTS: C3H/He mice
were heterotopically transplanted with BALB/c hearts; recipients were injected
with anti-ICAM-1 and anti-LFA-1 monoclonal antibodies (mAbs). Of 3-day
administration of both mAbs at 50 micrograms/day, all recipients accepted cardiac
allografts indefinitely (n = 20); this also occurred in 5 of 10 mice that were
not treated until day +4 or day +5. Long-term cardiac allograft acceptance was
also achieved in thymectomized recipients. This tolerance could not be abrogated
by the injection of either naive recipient lymphocytes or sensitized lymphocytes
taken from the recipient strain mice that rejected the same donor strain hearts.
Mixed lymphocyte culture showed that splenocytes from allograft recipient mice
treated with the mAbs showed normal allogeneic response without donor alloantigen
specificity. CONCLUSIONS: These results demonstrate the unique character of the
peripheral tolerance induced by anti-ICAM-1 and anti-LFA-1 mAbs. Further studies
are required to elucidate detailed mechanisms of transplantation tolerance
development.
PMID- 9402517
TI - Differential pulmonary flow after heart transplantation in patients with
malposition of the great arteries.
AB - In transposition of the great arteries the right lung is preferentially perfused,
and this may be due to the orientation of the right pulmonary artery when the
main pulmonary artery comes off in a posterior position. In this study the mean
perfusion of the right lung was 61% in six patients who had "correction" of the
great artery malposition at the time of heart transplantation. This suggests that
anatomic correction of pulmonary artery orientation does not correct the
preferential perfusion to the right lung.
PMID- 9402516
TI - Clinical correlates of the myocardial force-frequency relationship in patients
with end-stage heart failure.
AB - BACKGROUND: This study tested the hypothesis that in patients with suspected
heart failure, peak oxygen consumption was the best predictor of heart muscle
failure. Failing human myocardium is characterized by an abnormal force-frequency
relationship, which has been previously shown to be altered in parallel with the
severity of heart failure. METHODS: We examined whether seven different
functional parameters of isolated electrically driven ventricular trabeculae
carneae obtained from 34 explanted hearts of patients undergoing heart
transplantation for end-stage heart failure correlated with any of 47 separate
pretransplantation clinical parameters. The functional muscle parameters were
active force at 0.33 Hz, time to 80% relaxation (RT 80%) of twitch force at 0.33
Hz, optimal frequency (OF), active force at 1.0 Hz (AF1), diastolic force at 1.0
Hz (DF1), active force at 2.0 Hz (AF2), and diastolic force at 2.0 Hz (DF2).
RESULTS: Before transplantation the mean left ventricular ejection fraction was
21% +/- 10%, and all patients were in New York Heart Association class III or IV.
Mean peak whole body VO2 was 10.9 +/- 3.3 ml/min/kg and percent body mass/age/sex
adjusted maximum VO2 oxygen consumption was 34.7% +/- 10.4%. Univariate analysis
of VO2 yielded the following significant correlations: active force at 33 Hz,
RT80%, OF, AF1, DF1, AF2, DF2; whereas univariate analysis of percent body
mass/age/sex-adjusted VO2 yielded the following significant correlations: RT80%,
OF, DF1, AF2, DF2. Multivariate analysis showed that OF and DF1 were independent
predictors of peak VO2. CONCLUSION: In this study we show that peak oxygen uptake
measured during cardiopulmonary exercise testing obtained before transplantation
is correlated with the force-frequency behavior of isolated muscles at the time
of transplantation. Peak VO2 seems to be a strong indicator of the severity of
cardiac contractile dysfunction in patients with heart failure.
PMID- 9402518
TI - Cytomegalovirus infection presenting as an apple-core lesion of the colon.
AB - Cytomegalovirus infection is highly prevalent among heart transplant recipients.
Symptomatic cytomegalovirus infection can occur in all parts of the
gastrointestinal tract. Colonic lesions are usually manifest as hemorrhagic
colitis. This is a case of cytomegalovirus colitis presenting as a colonic
stricture mimicking a colonic carcinoma. The initial presentation was that of
both cellular and humoral rejection with fever, abdominal pain, and microcytic
anemia with heme-positive stools. An abdominal computed tomogram was pertinent
for a suspicion of carcinoma in the midtransverse colon. After resolution of the
rejection episode, colonoscopy was performed, the result of which was abnormal
for a short, high-grade stricture in the midtransverse colon. The patient
underwent a right hemicolectomy for the suspected tumor. The pathologic specimen
showed cytomegalovirus inclusion bodies with acute suppurative ulceration. The
early diagnosis and treatment of cytomegalovirus colitis may lead to avoidance of
more serious complications such as stricture formation.
PMID- 9402519
TI - Successful mechanical circulatory support for more than two years with a left
ventricular assist device in a patient with dilated cardiomyopathy.
AB - A 36-year-old man with dilated cardiomyopathy was supported with a left
ventricular assist device for 795 days. During this support time gradual
functional recovery was noted. The patient tolerated the device well, enjoyed a
good quality of life, and experienced no technical device-related problems. When
a suitable donor heart became available, the device was switched off, and native
ventricular function was assessed. This was judged to be acceptable, and the left
ventricular assist device was successfully explanted. Postexplantation function
remained acceptable and improved over the following days. The patient was
discharged on the twentieth postoperative day and remains well.
PMID- 9402520
TI - Left ventricular assist devices: permanent implant versus bridge to
transplantation--is either cost-effective?
PMID- 9402521
TI - SIADH and acute lung rejection.
PMID- 9402522
TI - Characterization of the phosphoribosylpyrophosphate synthetase gene from Candida
albicans.
AB - Phosphoribosylpyrophosphate (PRPP) synthetase catalyzes the transfer of phosphate
from ATP to D-ribose-5-phosphate during the synthesis of purine and pyrimidine
nucleotides and tryptophan and histidine biosynthesis in a variety of organisms.
We cloned and sequenced the PRPP synthetase gene (PRS1) of Candida albicans
because, in Saccharomyces cerevisiae, a deficiency in PRPP synthetase activity
interacts with a mutation in ELM4-1 (elongated morphology) to cause constitutive
pseudohyphal growth in nitrogen-rich media. In order to study the role of the C.
albicans PRS1 in growth and morphogenesis, we used gene disruption to isolate
PRS1 mutants; however, while heterozygous PRS1 clones were readily obtained,
homozygous, null strains were not recovered indicating that PRS1 is probably
essential for growth of the organism. Heterozygotes in PRS1 produced
approximately 35% less PRPP synthetase (P = 0.0004) and exhibited a similar
reduction in transcript levels. Confirmation of a heterozygous, single disruption
in PRS1 was obtained by I-SceI digestion of chromosomal-sized DNA and Southern
blot hybridizations. While no role in morphogenesis is elucidated by this work,
the data strongly suggests that PRS1 is an essential gene in C. albicans and
supports earlier results that indicated the presence of a single PRS gene in C.
albicans.
PMID- 9402523
TI - Study of Cryptococcus neoformans actin gene regulation with a beta-galactosidase
actin fusion.
AB - An expression plasmid carrying a heterologous gene fusion between the
Cryptococcus neoformans actin promoter and the Escherichia coli reporter gene,
LACZ, was constructed to study actin regulation in C. neoformans. Two randomly
stable transformants, designated 20.6 and 20.9, were selected for further
examination. Both ectopic and homologous recombination with vector insertion in
tandem repeats occurred in these transformants. Transformant 20.9 carried more
copies of ACTp::LACZ in its genome than 20.6 and this was reflected in expressing
higher levels of beta-galactosidase activity. In vitro, these transformants
showed higher levels of beta-galactosidase activity expressed when the
transformants were propagated at higher temperatures (37 degrees C vs 30 degrees
C). However, beta-galactosidase expression in the transformants was variable
during logarithmic and stationary growth phases and this differential expression
was temperature dependent. This report shows that the constitutive actin gene in
C. neoformans is regulated by temperature and growth and this fact should be
taken into consideration when actin expression is used as a standard to compare
the expression of other regulated genes. Also, a more sensitive reporter
construct will be needed for in vivo gene analysis of regulation.
PMID- 9402524
TI - Coccidioidomycosis in Tulare County, California, 1991: reemergence of an endemic
disease.
AB - In 1991, 1208 cases of coccidioidomycosis were reported to the California
Department of Health Services, compared with an annual average of 450 during 1986
90. We conducted a study in Tulare County to define the epidemiology of the
disease and identify risk factors for severe disease, focusing on the epidemic
period September 1991-December 1991. To identify cases, we used data from the
Coccidioidomycosis Serology Laboratory at the University of California, Davis,
other laboratories, and the Tulare County Health Department's coccidioidomycosis
reporting system. We compared patients who were hospitalized with those who were
not to determine risk factors for severe disease. We identified 128 cases of
acute coccidioidomycosis diagnosed between 1 September and 31 December 1991
(attack rate 41/100,000); south central Tulare County had the highest attack
rate. Thirty-five (27%) case-patients were hospitalized. Male sex (relative risk
(RR) 2.5, 95% confidence interval (CI) 1.2-5.0), black people and Asian races (RR
4.8, 95% CI 2.4-9.6), and age > or = 20 years (RR 8.3, 95% CI 1.2-57.4) were
univariately significant and remained independently associated with
hospitalization in multivariate analysis. The 1991 Tulare County outbreak of
coccidioidomycosis was part of a much larger outbreak that began in California
during 1991 and continued through 1993. The outbreak was preceded by an unusually
rainy spring. Although dust reduction measures during times of increased
coccidioidomycosis incidence can help reduce exposure, definitive control awaits
the development of a safe, effective vaccine.
PMID- 9402526
TI - Ascosubramania gen. nov., and its Fonsecaea-like anamorph causing
chromoblastomycosis in India.
AB - This paper deals with the discovery of the teleomorph of a Fonsecaea-like
pathogen causing chromoblastomycosis in India. A new genus, Ascosubramania, is
proposed to accommodate it.
PMID- 9402525
TI - Induction of interleukin-6 mRNA in rat alveolar macrophages by in vitro exposure
to both Cryptococcus neoformans and anti-C. neoformans antiserum.
AB - Lewis rat alveolar macrophages (AM) were harvested and exposed in vitro to
Cryptococcus neoformans to investigate the induction of inflammatory cytokines.
AM in tissue culture wells were incubated with viable yeast cells of C.
neoformans or the capsular polysaccharide, glucuronoxylomannan (GXM), with or
without rabbit anti-C. neoformans antiserum. At 3, 6, 12 and 24 h, AM were
washed, lyzed and total RNA was isolated. Using reverse transcription-PCR, the
transcripts of cytokine genes were semi-quantified by comparison with
constitutive transcripts. Incubation of AM with lipopolysaccharide, as positive
control, induced elevated levels of the three transcripts measured: interleukin
(IL)-1 alpha, IL-6 and tumour necrosis factor (TNF)-alpha. Under the same
conditions, no obvious changes were observed in the levels of transcription of
these cytokines by AM after exposure to several strains of C. neoformans.
However, AM that were incubated with both the yeast cells and rabbit polyclonal
antisera to C. neoformans manifested significantly increased levels of mRNA for
IL-6, but not IL-1 alpha or TNF-alpha. This increased level of IL-6 mRNA was
detectable after incubation for 6 or 12 h. Levels of transcription in AM were
unaffected by exposure to normal rabbit serum, specific antiserum alone. GXM at
concentrations of 10, 100 or 500 micrograms ml-1, or GXM and antiserum.
Adsorption of the antiserum with heat-killed yeast cells of C. neoformans
diminished its ability to induce IL-6 mRNA in combination with fresh, viable
yeast cells. The induction of IL-6 mRNA by yeast cells and antiserum does not
require intact complement. In the absence of complement, the rabbit antiserum
served as a potent opsonin and markedly increased phagocytosis of C. neoformans
by AM. These results indicate that antibody-opsonized C. neoformans are readily
phagocytosed by rat AM, and that antibody-mediated phagocytosis may differ from
complement-mediated phagocytosis in the subsequent stimulation of IL-6.
PMID- 9402527
TI - Expression of glycoprotein gp43 in stage-specific forms and during dimorphic
differentiation of Paracoccidioides brasiliensis.
AB - Expression of the 43 kDa glycoprotein (gp43) was analysed in several
Paracoccidioides brasiliensis isolates. Using one- and two-dimensional analysis
of crude cellular extracts, it was shown that protein expression in yeast and
mycelium was dependent on the isolate analysed. In two strains, in both yeast and
mycelium cells. gp43 was present, whereas expression was restricted to the yeast
phase of two other strains. The clinical implications of this phase-specific gp43
expression are uncertain.
PMID- 9402528
TI - Histopathological and electron microscopical studies on experimental Penicillium
marneffei infection in mice.
AB - Experimental Penicillium marneffei infection in mice was investigated
histopathologically and by electron microscopy. Viable conidia (5 x 10(6) cells)
of P. marneffei were inoculated into each mouse of group A (BALB/c mice) and
group B (BALB/c-nu/nu-SIc mice) through the tail vein. All the mice were
sacrificed at intervals and the livers were examined. In group A, the conidia
were phagocytosed by Kupffer cells soon after inoculation, and proliferated by
fission in the cytoplasm. Marked proliferation of yeast cells was observed 7 and
14 days after inoculation. With proliferation of the fungus, the number of
lysosomes in Kupffer cells increased, and numerous granulomas were formed in the
liver. These granulomas consisted mainly of macrophages with yeast cells,
together with a few polymorphonuclear leukocytes, lymphocytes and giant cells.
From 28 days on yeast cells were gradually cleared from the granulomas, and 56
days after inoculation almost all the granulomas disappeared. In group B, at an
early stage of infection, similar pathological changes to those seen in mice of
group A were observed. However, as the infection progressed, the number of
granulomas continued to increase and yeast cells continued to proliferate
although lymphocytes did not infiltrate these granulomas. With proliferation of
yeast cells the liver tissue was replaced with both yeast cells engulfed by
macrophages and extracellular yeasts, and dissemination occurred.
PMID- 9402529
TI - Identification by polymerase chain reaction fingerprinting of Cryptococcus
neoformans serotype AD.
AB - Seventy-three Cryptococcus neoformans isolates and eight other yeast strains were
studied. Fingerprints produced by priming with (GACA)4 differentiated C.
neoformans from all other yeasts tested and identified the five C. neoformans
serotypes. Four major bands of molecular size 800, 540, 475 and 410 bp were
recognized for serotypes A, AD and D. Two of them were specific for serotype A
and the other two for serotype D isolates. Serotype AD strains were identified by
five different genotypic patterns in which at least one of the two bands specific
for serotype A and D were present in different combinations. On repeated and
simultaneously performed genotype and serotype testing of nine strains, the
genotypic pattern did not change, whereas serotyping was unstable in three cases.
PCR-fingerprinting using (GACA)4 as a primer proved more stable than serology in
discriminating among C. neoformans serotypes A, D and AD and was able to
distinguish among serotype AD strains.
PMID- 9402530
TI - Fungal keratitis caused by Metarhizium anisopliae var. anisopliae.
AB - Metarhizium anisopliae var. anisopliae (Metschnikov) Sorokin 1883 to our
knowledge has never been reported as an agent of human or animal mycosis. This
fungus has great importance as an agent of biological control of different pests
and mosquito larvae in Colombia. It has been isolated as the aetiological agent
of keratomycosis for the first time from the eye of a Colombian male.
PMID- 9402531
TI - Maxillary sinusitis caused by Schizophyllum commune and experience with
treatment.
AB - A case of sinusitis caused by the basidiomycete Schizophyllum commune is reported
in a 36-year-old female with a history of allergic rhinitis and dermatitis. The
patient presented with sudden nasal obstruction, purulent nasal discharge,
headache and general discomfort. Computer tomography revealed extensive opacity
of the left maxillary sinus as well as erosion of the nasal wall and maxillary
bone. Mycological examinations of nasal discharges and material aspirated during
anthrostomy showed hyaline, septate hyphae with rare spicules. Primary isolation
yielded a white, woolly mould which demonstrated clamp connections and
basidiocarp primordia but these characteristics were lost in subculture.
Identification was confirmed by vegetative compatibility studies. The patient was
treated with itraconazole to avoid possible postsurgical dissemination. Three
months after cessation of therapy, no recurrence of infection had occurred.
PMID- 9402533
TI - In vitro susceptibility of Malassezia furfur to the essential oil of Melaleuca
alternifolia.
AB - The susceptibility of 64 Malassezia furfur isolates to Melaleuca alternifolia oil
was determined. The minimum inhibitory concentration for 90% of isolates was
0.25% by agar dilution and 0.12% by broth dilution. These data indicate that tea
tree oil may be useful in the treatment of skin conditions involving M. furfur.
PMID- 9402532
TI - Detection of plasma (1 --> 3)-beta-D-glucan in patients with Fusarium,
Trichosporon, Saccharomyces and Acremonium fungaemias.
AB - (1 --> 3)-beta-D-glucan, a characteristic fungal molecule, is known to increase
in blood in invasive candidiasis, aspergillosis and cryptococcosis. This report
shows that the plasma glucan concentration was also elevated in four patients
infected with Fusarium, Trichosporon beigelii, Saccharomyces cerevisiae and
Acremonium. In three of the patients, the elevation preceded positive blood
cultures by 5-17 days, and in one of them it even preceded the onset of fever by
6 days. In a fourth patient, the glucan level decreased with clinical
improvement. Plasma (1 --> 3)-beta-D-glucan determination appears to be useful
also for diagnosis and follow-up of these unusual deep mycoses.
PMID- 9402534
TI - Asymptomatic sequelae to acute sarin poisoning in the central and autonomic
nervous system 6 months after the Tokyo subway attack.
AB - Six to eight months after the Tokyo subway attack in March 1995, the
neurophysiological effects of acute sarin poisoning were investigated in 18
passengers exposed to sarin (sarin cases) in the subways to ascertain the focal
or functional brain deficits induced by sarin. The event-related and visual
evoked potentials (P300 and VEP), brainstem auditory evoked potential, and
electrocardiographic R-R interval variability (CVRR), together with the score on
the posttraumatic stress disorder (PTSD) checklist, were measured in the sarin
cases and the same number of control subjects matched for sex and age. None of
the sarin cases had any obvious clinical abnormalities at the time of testing.
The P300 and VEP (P100) latencies in the sarin cases were significantly prolonged
compared with the matched controls. In the sarin cases, the CVRR was
significantly related to serum cholinesterase (ChE) levels determined immediately
after exposure; the PTSD score was not significantly associated with any
neurophysiological data despite the high PTSD score in the sarin cases. These
findings suggest that asymptomatic sequelae to sarin exposure, rather than PTSD,
persist in the higher and visual nervous systems beyond the turnover period of
ChE; sarin may have neurotoxic actions in addition to the inhibitory action on
brain ChE.
PMID- 9402535
TI - Dissociated neglect for objective and subjective sizes.
AB - We examined the effect of line length and viewing distance on the line bisection
performance in near space in five patients with left unilateral spatial neglect
following right parietal lesions. A line bisection task by fixation was devised
to avoid the influence of manual responses. The rightward deviation measured in
visual angle increased linearly as a function of the visual angle of lines 150 mm
or more long. This linearity, however, did not hold for lines of 100 mm or less.
The deviation measured in length was nearly constant for each of these short
lengths, even when the visual angle was varied at different viewing distances.
The patients therefore discriminated the objective lengths of the short lines.
For small objects, neglect patients may distribute attention mainly on the
coordinates scaled for objective size.
PMID- 9402536
TI - Abnormal calcium metabolism in myotonic dystrophy as shown by the Ellsworth
Howard test and its relation to CTG triplet repeat length.
AB - Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by
peculiar clinical features. Its molecular basis is the unstable expansion of a
CTG triplet repeat in the gene encoding myotonin protein kinase (Mt-PK), the
nucleotide sequence of which has extensive homology to the cyclic AMP (cAMP)
dependent protein kinase gene. Extensive efforts have been made to clarify the
signal transduction pathway in which the responsible gene operates, but
confirming evidence has yet to be obtained. Because some symptoms in DM are
similar to those in hypoparathyroidism, we divided 24 DM patients into two groups
on the basis of their serum calcium levels; Group 1, those with normocalcemia (11
patients), and group 2, those with hypocalcemia (13 patients). The highly
sensitive parathyroid hormone (HS-PTH) plasma levels in group 1 were within
normal limits, whereas those in group 2 were abnormally high. Laboratory findings
for the group 2 patients resembled those for pseudohypoparathyroidism (PHP),
whereas those for group 1 patients were normal. The Ellsworth-Howard (EH) test
was used to determine which type of PHP the group 2 patients belonged to. Both
the phosphaturic (delta P) and urinary cAMP (UcAMP) responses were estimated. The
delta P responses in group 2 were significantly lower than those in group 1, but
their UcAMP responses did not differ. This is evidence that group 2 patients had
PHP type II, whereas group 1 patients were normal. We also investigated whether
the disease severity differed between the groups. Cataracts, ectopic
calcifications, and ossifications, which are associated with PHP, were more
frequent in group 2. In addition, the mean IQ in that group was significantly
lower. Clinically, the group 2 signs agreed well with those of PHP, whereas for
group 1 there was only a slight similarity. These results are additional evidence
that the patients in group 2 have abnormal calcium metabolism, the abnormality
being in the postadenylate cyclase-cAMP pathway in the renal tubular cells. The
degree of (CTG)n expansion, the so-called expanded DNA fragment (EF) size, was
determined by standard Southern blot analysis. The allelic EF sizes in both
groups were greater than in the healthy controls. Moreover, those in group 2 were
significantly longer than those in group 1. We therefore investigated whether EF
size is correlated with the serum calcium and plasma PTH levels, the delta P
responses in the EH test, and IQ. All these items were significantly correlated
with EF size. Our findings show that the expanded DNA fragment size in DM is
correlated with the degree of abnormal calcium metabolism.
PMID- 9402537
TI - Psychogenic pseudoptosis.
AB - Three patients with psychogenic pseudoptosis of one eyelid are reported. All
showed depression of the eyebrow on the affected side. The clinical course
varied: in two patients the symptom resolved spontaneously after positive
reassurance; in the third patient it remained unchanged for 2 years.
PMID- 9402539
TI - Facial palsy in multiple sclerosis.
AB - Facial palsy occurred in 21 (19.6%) of 107 Japanese patients with multiple
sclerosis (MS) during a mean follow-up period of 4.3 years. We observed residual
signs of facial palsy in five other patients in whom acute onset was confirmed
from medical records. Facial palsy began on average 7.6 years after the onset of
MS but in five patients (4.7%) was the first symptom of MS, preceding the next MS
symptom by 0.5-3 years. Facial palsy was usually associated with other brainstem
signs, while two patients showed only facial palsy 1 and 3 years after the onset
of MS. Twenty-one (84.0%) of the 25 patients who underwent brain magnetic
resonance imaging (MRI) showed brainstem lesions in the pontine tegmentum
ipsilateral to the facial palsy. However, the two patients without other symptoms
or signs had no apparent causal lesion on MRI, which suggests difficulty in
differentiating idiopathic Bell's palsy from MS- associated facial palsy by MRI,
although it has an excellent capacity to detect causal lesions of facial palsy
associated with MS.
PMID- 9402538
TI - Criteria for early detection of conduction block in multifocal motor neuropathy
(MMN): a study based on control populations and follow-up of MMN patients.
AB - Motor conduction block (MCB) has been used as the main diagnostic criterion in
multifocal motor neuropathy (MMN). Nonetheless, no agreed definition of block
currently exists; the proposed required percent decrement of proximal compound
muscle action potential (CMAP) amplitude varies from > 20% to > 50%. The aim of
this work was to evaluate, through a follow-up study of patients with MMN, the
behaviour of MCB over time. The percent decrement and temporal dispersion of
proximal CMAP have also been calculated in normal controls and in patients
affected by amyotrophic lateral sclerosis (ALS). The results show that MCB in
patients with MMN is a dynamic entity which greatly varies over time and that a >
50% CMAP amplitued reduction may well be preceded by a smaller decrement that is
nonetheless indicative of focal myelin damage in the appropriate clinical
context. This datum and the results obtained in the control group and in patients
with ALS suggest that a reappraisal of the diagnostic criteria for MCB, in cases
with clinical and electrophysiological data strongly indicative of MMN, should be
considered. Since MMN is a treatable disorder, the use of the proposed less
restrictive criteria for the identification of MCB could allow for a promp and
more effective treatment.
PMID- 9402540
TI - Level of transforming growth factor beta 1 is elevated in cerebrospinal fluid of
children with acute bacterial meningitis.
AB - We investigated the levels of transforming growth factor beta 1 (TGF-beta 1) in
cerebrospinal fluid (CSF) in children with meningitis, with a view to prognostic
relevance. CSF TGF-beta 1 levels on admission were measured by a sandwich enzyme
immunoassay in children with bacterial meningitis (n = 16), aseptic meningitis (n
= 12), and control subjects without evidence of central nervous system (CNS)
infection (n = 16). Patients were followed up for a mean duration of 13 months,
and neurodevelopmental sequelae was determined for those with bacterial
meningitis. On admission, CSF TGF-beta 1 levels were significantly higher in
children with bacterial meningitis (mean, standard error, 32.92, 2.36 pg/ml) as
opposed to those with aseptic meningitis (25.26, 1.72 pg/ml) (P = 0.0155), or
control subjects (20.53, 1.05 pg/ml) (P < 0.0001). The CSF TGF-beta 1 levels in
children with aseptic meningitis were higher than those in the control group, but
without significance (P = 0.02). No apparent correlation existed between CSF TGF
beta 1 levels and CSF protein or cell counts in patients with bacterial
meningitis. No significant difference in CSF TGF-beta 1 levels was found between
patients with or without major sequelae following bacterial meningitis.
PMID- 9402541
TI - Ocular palsies in the absence of other neurological or ocular symptoms: analysis
of 105 cases.
AB - We studied prospectively 105 unselected patients complaining of ptosis and/or
diplopia due to extrinsic ophthalmic muscle palsies without other neurological
signs. All patients underwent the same diagnostic protocol. The presenting
symptoms were: ptosis, 35 patients (33%); diplopia, 27 patients (26%); ptosis and
diplopia, 43 patients (41%). The oculomotor nerve was most frequently involved,
followed by the abducens nerve. The final diagnoses were: ocular myasthenia,
intracranial and/or orbital pathology, thyroid ophthalmopathy, diabetic
ophthalmoplegia, mitochondrial myopathy, oculopharyngeal muscular dystrophy. In
26 patients (25%) the cause remained undetermined. Our study confirms the
difficulty of establishing an aetiological diagnosis in patients with isolated
ocular palsies.
PMID- 9402542
TI - Difference in P300 latency in two types of leukoaraiosis.
AB - P300 examination was performed in patients with periventricular leukoaraiosis and
in patients with leukoaraiosis in the centrum semiovale. Ten patients with
periventricular leukoaraiosis, ten patients with leukoaraiosis in centrum
semiovale and ten age-matched controls without leukoaraiosis were studied. The
P300 was measured with an evoked potential recorder using an oddball paradigm.
The mini-mental state examination score was significantly lower and the P300
latency was significantly longer in the leukoaraiosis in the centrum semiovale
group than in the periventricular leukoaraiosis group and the control group.
Leukoaraiosis in centrum semiovale may be related to dementia and the
prolongation of P300 latency.
PMID- 9402544
TI - Evolution of cardiac abnormalities in Becker muscular dystrophy over a 13-year
period.
AB - We evaluated the course of cardiac involvement in 27 previously reported patients
with Becker muscular dystrophy (BMD) originating from nine kindreds. Since almost
all affected individuals of each kindred were included, intrafamilial variability
could be studied. We also attempted to identify associations between cardiac
involvement, functional ability and mutations at DNA level. The mean follow-up
period was 12.5 years. The number of patients with electrocardiographic
abnormalities progressed from 44% to 71%. Dilated cardiomyopathy (DCM) with or
without congestive heart failure was now present in 33% as compared with 15% in
the previous study. In addition, 22% developed borderline echocardiographic
abnormalities. Six patients (22%) became symptomatic and four patients died of
congestive heart failure. In all families cardiac abnormalities were found. There
was no association between DCM and mutation type. Despite equal functional motor
ability, there was a considerable intrafamilial variation in cardiac involvement,
even in brother pairs. We conclude that cardiac abnormalities are the rule and
not the exception in BMD and are progressive over time. Left ventricular
dilatation may begin at any moment in the course of BMD and the rate of
progression is unpredictable. A substantial proportion of patients will develop
an incapacitating and life-threatening DCM.
PMID- 9402543
TI - Slower recovery of muscle phosphocreatine in malignant hyperthermia-susceptible
individuals assessed by 31P-MR spectroscopy.
AB - Our aim was to develop an exercise protocol using 31P-magnetic resonance
spectroscopy (31P-MRS), which can discriminate between malignant hyperthermia
susceptible (MHS) individuals and controls. MRS spectra of the forearm muscles
were recorded at rest, during and after a standardized exercise protocol in 10
MHS patients and compared with spectra obtained in 10 controls. There was no
difference in resting intracellular pH (pHi) or PCr/(Pi+PCr) ratio between the
groups (PCr = phosphocreatine, Pi = inorganic phosphorus). At the end of the
exercise and during the initial recovery phase, the pHi and PCr/(Pi+PCr) ratio
were significantly lower in the MHS group ([pHi: 6.37 (0.07) for MHS vs 6.70
(0.05) for controls, P < 0.005; PCr/(Pi+PCr): 0.784 (0.017) for MHS vs 0.954
(0.020) for controls, P < 0.0005]). For PCr/(Pi+PCr), complete separation between
the two groups was observed during the initial recovery phase. The mean recovery
time of PCr/(Pi+PCr) was 0.57 min for the control group and 1.28 min for the MHS
group. The slower recovery of PCr/(Pi+PCr) is likely to be caused by a
combination of several factors, including the lower pHi in MHS subjects at the
start of recovery (inhibiting ATP production) and excessive sarcoplasmic calcium
overload (causing continued enzyme activation and ATP consumption). Our exercise
protocol can be a valuable adjunct to discriminate between MHS and non
susceptible subjects.
PMID- 9402545
TI - Slowly progressive isolated dysarthria: longitudinal course, speech features, and
neuropsychological deficits.
PMID- 9402546
TI - Vigabatrin-induced optic neuropathy.
PMID- 9402547
TI - Palliative therapy in the terminal stage of neurological disease.
AB - As recently pointed out by the American Academy of Neurology, providing adequate
palliative care to dying patients is the duty of every neurologist. Because of a
lack of relevant articles in the neurological literature, we have compiled
current treatment recommendations for the most important symptoms arising in the
endstage of neurological diseases. These recommendations include treatment of
dyspnea, death rattle, restlessness, pain, thirst, depression, and others. A
discussion of difficult decisions is included, e.g., the appropriate extent of
fluid substitution or the ethical implications of sedation in the terminal phase.
It is hoped that this compilation may provide a basis for future research in
palliative therapy in neurology.
PMID- 9402548
TI - Palliative care in amyotrophic lateral sclerosis.
AB - The poor prognosis of amyotrophic lateral sclerosis (ALS) makes palliative care a
challenge for the neurologist. Most disabilities associated with progressive
disease can be ameliorated by symptomatic treatment. Prognosis and treatment
options should be openly discussed with the patient and his/her relatives.
Nutritional deficiency due to pronounced dysphagia can be efficiently relieved by
a percutaneous enterogastrostomy. Respiratory insufficiency can be treated by non
invasive ventilation at home, provided the familial environment is supportive.
Adequate assistance and palliative treatment in the terminal phase is of
paramount importance.
PMID- 9402549
TI - Quality of life issues in palliative medicine.
AB - The assessment of patient's quality of life is assuming increasing importance in
medicine and health care. Illnesses, diseases and their treatments can have
significant impacts on such areas of functioning as mobility, mood, life
satisfaction, sexuality, cognition, and ability to fulfil occupational, social
and family roles. The emerging quality of life construct may be viewed as a
paradigm shift in outcome measurement since it shifts the focus of attention from
symptoms to functioning. This holistic approach more clearly establishes the
patient as the centre of attention and subsumes many of the traditional measures
of outcome. Quality of life assessment is particularly relevant to patients with
progressive conditions, particularly in the later phases of the disease. Despite
the fact that current definitions of palliative medicine include quality of life
as a central concern, relatively little research has been conducted on the impact
of palliative care on patient quality of life. This paper introduces the concept
of quality of life and describes the significant difficulties in definition,
measurement and interpretation that must be addressed before such measures can be
used as reliable and valid indicators of disease impact and treatment outcomes.
It is argued that the unique individual perspective of the patient on his or her
own quality of life must be incorporated into outcome assessments aimed at
improving the quality of health care delivery in progressive diseases.
PMID- 9402550
TI - Palliative medicine training for physicians.
AB - In recent years, it has been widely recognised that modern doctors are not
receiving the training they need to provide appropriate and effective palliative
care. Deficiencies in care have been reported in several formal studies and,
anecdotally, in many professional and popular lay publications. Doctors
themselves have attested to their lack of confidence and competence in many
aspects of palliative care. These problems cross national, cultural and religious
boundaries, as evidenced by initiatives in many countries to correct the
situation, which will be reviewed in this paper.
PMID- 9402551
TI - The zeta pulse: a new stimulus waveform for use in electrical stimulation of the
nervous system.
AB - A new waveform which can be used instead of pulses for general electrical
stimulation of the nervous system is described. This new waveform has been called
the 'Zeta' pulse. The potential advantages of the use of this waveform are
discussed together with a brief review and discussion of the mechanisms of
extracellular stimulation in nervous tissue. A circuit diagram for the generation
of the Zeta waveform is given.
PMID- 9402552
TI - Visualization of significant differences in somatotopic maps: a distributed t
test.
AB - In order to test for differences in the properties of two populations of cells
within a somatotopic map we need to be able to compare data sets in which sampled
cells are randomly scattered throughout the map, and the variable being compared
varies with location in the map. We can describe cell properties as exponentially
smoothed surfaces fitted to data in the plane of the map, where all data
contribute to the computation of the value of each grid point on the surface,
with weights which decline exponentially with distance from the grid point.
Means, variances and Student's t values can be computed at all grid points,
keeping in mind the fact that grid points' t values are not independent of each
other. We used Monte Carlo methods to demonstrate that two random samples of 500
values from two populations of 100,000 values at 4000 grid can provide a very
useful picture of regions with significant differences. We recommended this
procedure, or analogous approaches using other statistical tests, for any
analysis where it is necessary to compare values of dependent variables when
matched locations on the independent axis or plane cannot be sampled in the two
populations.
PMID- 9402553
TI - A new method for evaluation of motor deficits in 3-acetylpyridine-treated rats.
AB - We established a novel method for quantitative evaluation of the motor deficits
induced by 3-acetylpyridine (3-AP) in rats. 3-AP (75 mg/kg, i.p.) was injected in
a time-controlled manner by a following injection of niacinamide (NIA; 300 mg/kg,
i.p.). Changes in the motor function were evaluated by measuring the maximal
height of vertical jump (MHVJ) to escape from an electrical shock on the foot, as
well as ataxic gait. The MHVJ decreased and reached a minimum value 5-7 days
after the 3-AP treatment. The close correlation of the MHVJ and the incidence of
ataxic gait indicates that the decrease of MHVJ is a useful quantitative index of
motor deficits.
PMID- 9402554
TI - Development of a narrow water-immersion objective for laserinterferometric and
electrophysiological applications in cell biology.
AB - Laserinterferometric studies of the micromechanical properties of the organ of
Corti using isolated temporal bone preparations are well established. However,
there are relatively few measurements under in vivo conditions in the apical
region of the cochlea because of its inaccessibility with commonly used
techniques. Recently, optical-design programs have become affordable and
powerful, so that the development of an optimized optical system is within the
budget of physiologists and biophysicists. We describe here the development of a
long-range water-immersion objective. To circumvent anatomical constraints, it
has a narrow conical tip of taper 22 degrees and diameter 2.4 mm. It is a bright
field reflected-light illumination, achromatic objective with magnification of
25x/infinity, a working distance of 2.180 mm and a numerical aperture of 0.45.
Chromatic errors are corrected at 546.1 and 632.8 nm, with emphasis on the latter
wavelength which is used by the laser interferometer. The field curvature is
relatively flat and a diffraction limitation (Strehl ratio better than 0.8) can
be obtained in a field of 0.4 mm diameter. Using this objective, sound-induced
vibrations of hair cells and Hensen cells could be recorded without placing a
reflector on the target area. In addition, this objective was found to be
diffraction-limited in the near infra-red (750-830 nm), with a slightly different
working distance (2.186 mm), making it suitable for patch-clamp experiments using
infra-red, differential interference contrast.
PMID- 9402555
TI - Isolation of single immunohistochemically identified whole neuronal cell bodies
from post-mortem human brain for simultaneous analysis of multiple gene
expression.
AB - In Alzheimer's disease (AD), one cell in the brain may clearly be affected, while
an adjacent cell appears healthy or unaffected. Previous technology has allowed
us to examine one message at a time, at the level of a single cell (in situ
hybridization, ISH), or multiple messages in a heterogeneous population of cells
(Northern analysis). We have developed a methodology to build up a profile of
multiple mRNA expression in single, whole, post-mortem cells that have been
immunohistochemically (IHC) characterized. Fresh post-mortem tissue is spread
into a layer one cell thick and fixed. Neurons are identified using an antibody
to neurofilament and isolated using a micropipette. The mRNA is reverse
transcribed and PCR carried out to confirm that material is present. A
radioactively labeled antisense aRNA probe, which is representative of the
messages contained in the cell is then amplified. This aRNA is used as a probe
for a reverse Northern blot, allowing us to profile many genes from one cell at
the same time. This technology has the potential to be applied to a wide variety
of diseases encompassing many different cell types.
PMID- 9402556
TI - A simple method, using 2-hydroxypropyl-beta-cyclodextrin, of administering alpha
chloralose at room temperature.
AB - Effective long term stable anaesthesia is a goal of many drug regimens employed
in neuroscience in which procedures carried out are not practical in awake
animals. A particular problem is the study of nociceptive mechanisms where good
anaesthesia is essential. Similarly studies of cardiovascular or cerebrovascular
mechanisms require that normal physiological reflexes be preserved as much as is
practical. For non-recovery anaesthesia alpha-chloralose is a good choice since
it provides good anaesthesia without excess depression of physiological reflexes.
However, alpha-chloralose is sparingly soluble so that its use is not
straightforward. We describe the characterisation of a simple procedure to
solubilise alpha-chloralose in a solution of 2-hydroxypropyl-beta-cyclodextrin.
The resulting solution is stable at room temperature and gives a high
concentration of alpha-chloralose making it easier to administer regularly during
longer time course experiments.
PMID- 9402557
TI - A new protocol for the transmission of physiological signals by digital
telemetry.
AB - A method has been devised to transmit physiological signals from the brains of
rats using a new digital telemetry transmission protocol. The chief advantage of
the present system over existing systems is that the circuit only consumes power
during the transmission of a brief pulse of information. This results in a very
much extended battery life allowing the device to be implanted and recordings to
be carried out over a longer period of time.
PMID- 9402558
TI - Microelectrode arrays for stimulation of neural slice preparations.
AB - A planar 6 x 6 array of iridium electrodes with four reference electrodes has
been developed for use with neural tissue preparations. Precise knowledge of the
relative locations of the array elements allows for spatial neurophysiological
analyses. The 10 microns diameter platinized iridium electrodes on a 100 microns
pitch have been used to stimulate acutely prepared slices of spinal cord from
free-ranging rodents. An intracellular recording from a single neuron in the
substantia gelatinosa (SG) using the whole-cell, tight-seal technique allowed low
noise, high resolution studies of excitatory or inhibitory electrical responses
of a given neuron to inputs from the primary afferent fibers or from stimulation
by individual electrodes of the array. The resulting maps of responses provide an
indication of the interconnectivity of neural processes. The pattern emerging is
that of limited interconnectivity in the SG from areas surrounding a recorded
neuron but with strong excitatory or inhibitory effects from those oriented in a
longitudinal (rostral-caudal) direction relative to the neuron. The observations
to date suggest the neurons of the SG are arranged in sets of independent
networks, possibly related to sensory modality and input from particular body
regions.
PMID- 9402559
TI - Elvax as a slow-release delivery agent for a platelet-activating factor receptor
agonist and antagonist.
AB - The ability of the slow-release polymer, Elvax, to deliver a large number of
different molecules to distinct brain regions has been well-documented. However,
there are currently no reports of Elvax-mediated delivery of ether phospholipids,
whose lipid structure renders them difficult to solubilize and detect under
experimental conditions. In order to potentially examine the role of platelet
activating factor (PAF) receptors in the brain in vivo, we tested the ability of
Elvax to release the ether phospholipid. PAF receptor agonist, methyl-carbamyl
platelet-activating factor (mc-PAF), and the ginkolide, PAF receptor antagonist,
BN 52021. Mc-PAF and BN 52021 containing Elvax sections (200 microns) prepared in
methylene chloride were assayed for release characteristics with a rabbit
platelet aggregation bioassay. We measured a slow, sustained release of mc-PAF
and BN 52021 from Elvax in vitro over a 5 day period. Similar in vivo mc-PAF and
BN 52021 release kinetics were determined. Therefore, we believe that this novel
method of slow-release delivery of PAF receptor agonists and antagonists as
measured with platelet aggregation is viable and offers a simple, sensitive and
inexpensive method for potential in vivo studies of the roles of PAF and its
receptors in neural systems.
PMID- 9402560
TI - Pseudo-immunolabelling with the avidin-biotin-peroxidase complex (ABC) due to the
presence of endogenous biotin in retinal Muller cells of goldfish and salamander.
AB - Immunodetection techniques are dependent on enzyme-protein conjugates for the
visualisation of antigen-antibody complexes. One of the most widely used is the
avidin-biotin-peroxidase complex (ABC) method. The present study demonstrates
that direct treatment of goldfish and salamander retinal sections with ABC,
followed by an incubation with the chromogenic substrate 3,3-diaminobenzidine
tetrahydrochloride (DAB) and H2O2, manifested a punctate staining pattern across
the neural retinae, presumably through binding of avidin to endogenous biotin.
Incubation with a primary antiserum against biotin followed by immunoprocessing
with the peroxidase--anti-peroxidase (PAP) method showed a pattern similar to the
punctuate framework as detected with solo ABC-treated sections. Moreover, the ABC
DAB/H2O2 mediated pattern corresponded to the spatial orientation of Muller cells
as identified by GFAP immunostaining. These findings indicate the presence of
endogenous biotin in Muller cells and calls for caution in the application of the
ABC method in immunotechniques in retinal research.
PMID- 9402561
TI - Multivariate analysis of RNA levels from postmortem human brains as measured by
three different methods of RT-PCR. Stanley Neuropathology Consortium.
AB - The analysis of RNA from postmortem human brain tissue by reverse transcription
polymerase chain reaction (RT-PCR) provides a practical method to measure both
normal and abnormal brain gene expression. A major limitation in using human
material is that yields can vary dramatically from individual to individual,
making comparisons between samples difficult. In this report, we study the
association of pH and several pre- and postmortem factors on the RNA yields from
89 postmortem human occipital cortices. Glyceraldehyde phosphate dehydrogenase
(GAPdH) mRNA levels were measured by RT-PCR. A major variant in this method is
the priming used in the reverse transcription reaction. Three different methods
of reverse transcription were performed and the resultant levels of products
compared against the pre- and postmortem factors and pH. The levels of GAPdH
correlated significantly to pH and pH itself to the rapidity of death (RoD)
(agonal state) indicating that premortem factors may play the greatest role in
determining postmortem RNA levels. The three methods of priming showed different
sensitivities, most notably that oligo dT priming alone is vulnerable to long
freezer intervals (FI). We conclude that premortem factors are the major
affectors of RNA levels variations and that the polyA tail region of the molecule
appears to be adversely affected by extended freezer storage.
PMID- 9402562
TI - Identification of synaptic connections in neural ensembles by graphical models.
AB - A method for the identification of direct synaptic connections in a larger neural
net is presented. It is based on a conditional correlation graph for multivariate
point processes. The connections are identified via the partial spectral
coherence of two neurons, given all others. It is shown how these coherences can
be calculated by inversion of the spectral density matrix. In simulations with
GENESIS, we discuss the relevance of the method for identifying different neural
ensembles including an excitatory feedback loop and networks with lateral
inhibitions.
PMID- 9402563
TI - Generation of anti-peptide antibodies against serotonin 5-HT2A and 5-HT2C
receptors.
AB - Anti-peptide antibodies were generated against several 13-17 amino acid regions
of rat serotonin 5-HT2A and 5-HT2C receptors. Peptides containing terminal
cysteine residues were conjugated to bovine serum albumin (BSA) and ovalbumin
(OVA) with the cross-linking reagent sulfo-SMCC (sulfosuccinimidyl 4-(N
maleimidomethyl) cyclohexane-1-carboxylate). Both the carrier protein and the
number of peptide molecules per carrier molecule were changed during the
immunization schedule. For the early immunizations, immunogens were BSA-peptides
at ratios of 8-27 mol peptide per mol BSA. For the later boosts, immunogens were
OVA-peptides at ratios of 1-2 mol peptide per mol OVA. The peptide constructs
were used to immunize rabbits and chickens. Anti-peptide antibodies were purified
from sera (rabbits) or egg yolks (hens) using peptide matrices. Cell lines
expressing similar densities of rat 5-HT2A or 5-HT2C receptors were used to
monitor the specificity of purified antibodies on immunoblots and in
immunocytochemistry. A total of five out of the six rabbit antibodies were
positive on immunoblots (three anti-5-HT2A and two anti-5-HT2C) and four were
also positive in immunocytochemistry (three anti-5-HT2A and one anti-5-HT2C).
None of the anti-peptide chicken antibodies were useful on immunoblots or in
immunocytochemistry. Since there is a paucity of high affinity reagents selective
for 5-HT2A or 5-HT2C receptors, these rabbit antibodies will be useful tools. The
methods used to generate site-directed antibodies specific for 5-HT2A or 5-HT2C
receptors should be applicable to other proteins.
PMID- 9402564
TI - The effects of patellar taping on stride characteristics and joint motion in
subjects with patellofemoral pain.
AB - Although patellar taping has been reported to be effective in reducing pain, the
effects of this procedure on functional outcomes, such as ambulation, have not
been documented. The purpose of this study was to compare stride characteristics
and joint motion in subjects with patellofemoral pain, with and without the
application of patellar taping using the McConnell technique. Fifteen female
subjects between the ages of 14 and 41 years with diagnosis of patellofemoral
pain participated in this study. Stride characteristics (Stride Analyzer) and
sagittal plane joint motion (VICON) were recorded simultaneously during taped and
untaped trials of free walking, fast walking, and ascending and descending a ramp
and stairs. A repeated measures analysis of variance was used to determine
differences between taped and untaped trials. Although subjects reported an
average pain reduction of 78% using a visual analogue scale, the only significant
change in stride characteristics was an increase in stride length during ramp
ascent. Patellar taping did, however, result in a small but significant increase
in loading response knee flexion across all conditions tested. We believe this
finding demonstrates more willingness by the patellofemoral pain subjects to load
the knee joint, thus permitting increased shock absorption, increased quadriceps
activity, and tolerance of increased patellofemoral joint reaction force.
PMID- 9402565
TI - Electromyographic analysis of selected lower extremity musculature in normal
subjects during ambulation with and without a Protonics knee brace.
AB - Often, braces are an integral part of treatment programs for patients with
pathology of the knee joint. Little evidence exists, however, as to the effect of
braces on muscle function. The purpose of this investigation was to compare
electromyography (EMG) from six lower extremity muscles during level walking
without the Protonics knee brace and with the brace at eight resistance settings.
Surface electrodes were placed on one lower extremity of 19 subjects (ages = 21
57) to evaluate EMG activity during ambulation with and without the knee brace.
Data were normalized to maximum voluntary contractions and averaged across
cycles. There was a significant increase in muscle activity of the rectus
femoris, vastus medialis, and vastus lateralis muscles when the brace resisted
knee extension and was set at the level of 9. Significantly higher EMG levels
also occurred in the vastus lateralis and vastus medialis with the extension
module set at level 6 when compared with the no brace trial and resistance levels
set at 6 and 2 with the flexion module. In this normal population, there was an
increase in activity of selected muscles when the brace was set at the highest
resistance settings. These data serve as a guide for clinicians when considering
incorporation of a brace of this type into patient management.
PMID- 9402566
TI - The three-dimensional passive support characteristics of ankle braces.
AB - Studies of the passive support provided by ankle braces have focused primarily on
inversion support. The goal of this study was to develop a technique to measure
the support provided by ankle braces in all rotational directions and to use this
technique to compare four common braces (Ascend, Swede-O, Aircast, and Active
Ankle). For this purpose, a 6 degrees-of-freedom linkage was used to measure the
flexibility of the ankle complex in 10 healthy subjects. Each subject was tested
without brace support and with each of the four braces. Testing was repeated on
each subject on two different occasions. The angular displacement at specified
moment values and the four segmental flexibility values obtained from the loading
portion of the moment-angular displacement data were used in the data analysis.
Repeated measure analysis of variance followed by a Student Neuman-Keuls test at
p < 0.05 was performed. This statistical analysis was used to identify
significant differences among the braces and differences between each brace and
the no brace condition. Each of the four braces provided significant support in
inversion, eversion, and internal rotation, but the amount of support varied
significantly among the braces. In external rotation, only the stirrup braces
provided significant support. The braces also varied significantly in the amount
of interference with dorsiflexion and plantar flexion. Clinicians may be assisted
by objective data on the amount and nature of passive support when prescribing
braces to their patients.
PMID- 9402567
TI - The slump test: the effects of head and lower extremity position on knee
extension.
AB - Maitland's slump test is a widely used neural tissue tension test. During slump
testing, terminal knee extension is assessed for signs of restricted range of
motion (ROM), which may indicate impaired neural tissue mobility. A number of
refinements that modify hip and ankle position has been added to the basic slump
test procedure, but no research to date has measured the effects of ankle and hip
position on knee extension ROM during testing. The purpose of this study was to
examine the effect of neural tension-producing movements of the cervical spine
and lower extremity on knee extension ROM during the slump test. Thirty-four
males with no significant history of low back pain were tested in the slump
position with the cervical spine flexed and extended in each of three lower
extremity test positions: neutral hip rotation with the ankle in a position of
subject comfort (neutral), neutral hip rotation with ankle dorsiflexion (ankle
dorsiflexion), and medial hip rotation with ankle dorsiflexion. Results showed
significant decreases in active knee extension ROM (F1,198 = 29.53, p < 0.0001)
in the cervical flexion compared with the cervical extension conditions. Subjects
also exhibited significant decreases in active knee extension ROM (F2,198 =
56.76, p < 0.0001) as they were progressed from neutral to the ankle dorsiflexion
to the medial hip rotation with ankle dorsiflexion positions of the lower
extremity. The results of our study indicate that limitations in terminal knee
extension ROM may be considered a normal response to the inclusion of cervical
flexion, ankle dorsiflexion, or medial hip rotation in the slump test in young,
healthy, adult males. In addition, the presence of a cumulative effect on knee
extension ROM with the simultaneous application of these motions is noted. These
findings may assist clinicians when assessing knee extension ROM during slump
testing.
PMID- 9402568
TI - Effectiveness of visual feedback during isokinetic exercise.
AB - Although previous investigators have observed that knowledge of performance via
visual feedback tends to enhance performance during an isokinetic test, the time
frame over which visual feedback remains advantageous is unclear. The purpose of
this study was to compare knee extensor torques produced by visual feedback and
no visual feedback groups on three occasions, completed over a 2-week period, and
at 4 weeks after the third test. Healthy, sedentary subjects were each randomly
assigned to either a visual feedback or a no visual feedback group (N = 10 males
and 10 females per group). Visual feedback consisted of viewing a computer
monitor which displayed the current and a target knee extension force. Torques
produced by the visual feedback group were consistently greater (p < 0.05) and
more reliable than those produced by the no visual feedback group. The
effectiveness of visual feedback tended to decrease over the first three
occasions, suggesting that visual feedback may not be as advantageous once a
skill is well learned. Further research needs to examine the contribution of
visual feedback to motor learning as well as retention and transfer of motor
skills during more complex functional tasks.
PMID- 9402569
TI - Assessing anterior cruciate ligament injuries: the association and differential
value of questionnaires, clinical tests, and functional tests.
AB - It is important to examine the package of questionnaires and clinical and
functional tests as used in anterior cruciate ligament (ACL)-injured patients in
order to gain insight on the patient's present status. Nine measuring systems in
three categories were examined: four questionnaires, three clinical tests, and
two functional tests. Differences between sports activity rating system, factor
occupational rating system scale, and Tegner scores pre- and post-injury and the
differences between the affected and unaffected knee in the clinical and
functional tests were calculated using the Wilcoxon test for paired observations.
These differences proved to be significant (p < 0.05). The association between
the various tests was also examined. None of the associations satisfied the
preset standards. Based on these low levels of association, it does not seem
possible to reduce the package of tests to one questionnaire, one clinical test,
and one functional test as all questionnaires and tests seem to be related to
different aspects of the injured ACL. Based upon these results, the total package
should be used to gain insight in both impairment and disability level in
patients with an injured ACL.
PMID- 9402570
TI - The effects of the number and frequency of physical therapy treatments on
selected outcomes of treatment in patients with anterior cruciate ligament
reconstruction.
AB - Health care reform will quite possibly change the delivery of physical therapy by
demanding physical therapists to be more accountable for providing appropriate,
yet cost-effective treatment. The purpose of this study was to retrospectively
compare the results after anterior cruciate ligament (ACL) reconstruction between
two groups of patients with different numbers and frequencies of physical therapy
visits postoperatively. Two random samples of 100 patients from a total of 1,345
patients identified as undergoing ACL reconstruction from 1990 through 1993 were
included. Group A patients attended physical therapy regularly and participated
in a home exercise program, while patients in Group B attended limited physical
therapy visits and also performed a prescribed home exercise program. Both groups
followed the same postoperative rehabilitation program for early range of motion,
early weight bearing, and muscle control. The outcome variables measured 1, 6,
and 12 months postoperatively included the number of structured visits to
physical therapy, range of motion, isokinetic strength testing, and subjective
rating. Group A averaged 20 visits in the first 6 months while Group B averaged
seven visits. The results revealed no significant difference for flexion,
isokinetic strength, or subjective rating. There was a significant difference for
hyperextension (Group A, 2 degrees; Group B, 6 degrees). The results of this
investigation indicated that by following a structured physical therapy program
postoperatively, it is possible for patients to achieve a successful outcome with
a limited number of routine physical therapy visits.
PMID- 9402571
TI - Effects of detraining on knee extensor strength and functional mobility in a
group of elderly women.
AB - Long-term detraining results for individuals 75 years and older are needed. The
purpose of this study was to assess long-term detraining effects on quadriceps
strength and functional mobility in nursing home residents. Ten women (X = 82.8
years) who completed a strength training program were reassessed 1 year later.
Clinical methods were used to remeasure dynamic and isometric quadriceps strength
and functional mobility. One repetition maximum quadriceps strength declined
68.3% (p < 0.05) from trained values. Isometric strength losses were 29.8% at 90
degrees (p < 0.05), 28.7% at 60 degrees (p < 0.05), and 24.4% at 20 degrees (p <
0.05) of knee flexion 1 year postexercise. Fast-paced walking, self-selected
paced walking, and timed up and go speed decreased 28.6% (p < 0.05), 19.5% (p <
0.05), and 54.1% (not significant), respectively, from posttraining. One year vs.
baseline, isometric strength decreased 0-14.3%, dynamic strength decreased 48.9%,
and functional mobility declined 16.5-20.7% despite an intervening training
program. An increased strength loss rate beyond the age of 80 years may be a
major factor influencing functional independence.
PMID- 9402572
TI - Management of shoulder dysfunction with an alternative model of orthopaedic
physical therapy intervention: a case report.
AB - One common approach to patient care in dealing with many musculoskeletal
dysfunctions involves two to three patient visits to physical therapy per week
over a period of weeks. Some patients may benefit from an alternative, graduated
treatment model emphasizing a minimal number of office visits and focusing on
intensive patient education, home program therapeutic exercise, and specific
manual interventions. Patient education focuses on home program compliance and
empowerment of the patient by adjusting office visits as needed based on patient
progress rather than multiple patient contacts in the first weeks. This emphasis
may improve long-term patient compliance by preventing the development of an
external locus of control in which the patient is dependent upon the therapist
for management of his/her condition. This case study is an example of the use of
this alternative treatment model for the resolution of impingement syndrome and
adhesive capsulitis in a 53-year-old female. A comprehensive program of patient
education and home exercise was initiated during the first visit. Joint
mobilization and active exercise were performed at each subsequent visit. The
patient was seen a total of six visits over a period of approximately 10 1/2
weeks, followed up via telephone at 1 month after the last treatment and
reexamined after 1 year. The objective exam revealed no abnormalities after the
last visit or after 1 year. The patient subjectively reported compliance with the
home program for 6 months after the last visit. This model of patient care was
successful for the patient described in this case study. The treatment approach
may have contributed to the development of an internal locus of control by
allowing the patient to be as actively involved as possible in the treatment of
her condition. In addition, this approach is timely when one considers current
reimbursement systems. Though successful with this patient, this graduated
treatment model is not intended to be applicable to every patient with this
diagnosis.
PMID- 9402573
TI - Treatment of inoperable carotid aneurysms with endovascular carotid occlusion
after extracranial-intracranial bypass surgery.
AB - OBJECTIVE: Hunterian ligation of the internal carotid artery (ICA) is an accepted
treatment for inoperable carotid aneurysms. Preliminary extracranial-intracranial
(EC-IC) bypass surgery is required in some patients. The reported incidence of
thromboembolic and ischemic complications remains significant for these patients,
despite a variety of advocated management strategies. We present our treatment
paradigm. METHODS: Between April 1992 and March 1997, nine patients with
inoperable ICA aneurysms were treated using EC-IC bypass surgery and then
permanent endovascular ICA occlusion. All of the patients except one had been
selected for bypass surgery on the basis of failing results of the ICA test
occlusion with hypotensive challenge. ICA occlusion was performed by endovascular
means and was delayed after bypass surgery was performed by a mean of 6 days
(range, 2-20 d). All patients were managed in the intensive care unit after ICA
occlusion. RESULTS: Clinical improvement was noted in all patients (mean follow
up, 21 mo; range, 3-42 mo). There were no major complications. Aneurysmal
thrombosis was confirmed in all patients. Although ICA occlusion was delayed
after bypass surgery, only one bypass was noted to be occluded. The occluded
bypass occurred in a patient who subsequently underwent successful ICA occlusion.
This patient was thought to have been improperly selected for bypass surgery.
CONCLUSION: Certain carotid aneurysms can be effectively managed with hunterian
ICA ligation. After preliminary identification of patients with borderline
cerebrovascular reserve as candidates for EC-IC bypass surgery, close attention
to the following points may help enhance clinical outcome: 1) excellence in
surgical technique for EC-IC bypass surgery, 2) occlusion of the parent vessel as
close to the aneurysm neck as possible by endovascular means, and 3) judicious
postoperative combination of anticoagulation, fluid, and pressure management.
PMID- 9402574
TI - Safety and efficacy of endovascular treatment of acutely ruptured aneurysms.
AB - OBJECTIVE: To study the safety and efficacy of endovascular treatment of acutely
ruptured aneurysms with Guglielmi detachable coils. METHODS: From August 1992
until December 1995, 75 patients were referred for endovascular treatment of
acutely ruptured aneurysms. There were 49 women and 26 men, with a mean age of 55
years. Patients were classified according to the Hunt and Hess grading system.
There were 18 Grade I patients (24%), 13 Grade II patients (17%), 30 Grade III
patients (40%), 11 Grade IV patients (15%), and 3 Grade V patients (4%). Fifty
patients (66%) were treated within 48 hours, and 64 (85%) were treated within 1
week of hemorrhage. The most frequently treated aneurysms were located at the
basilar bifurcation (32%), anterior communicating artery (16%), posterior
communicating artery (15%), and ophthalmic segment of the carotid artery (11%).
Most of the aneurysms were smaller than 15 mm (77%). Fifty-six percent of the
aneurysms had small (4 mm) necks, and 44% had wide (> 4 mm) necks. Clinical
follow-up was performed at 6 months, and results were classified according to the
Glasgow Outcome Scale (GOS). Control angiograms were performed immediately, at 6
months, and yearly thereafter. RESULTS: Immediate angiographic results were
considered to be satisfactory in 58 patients (77%) (complete obliteration, 40%;
residual neck and dog ear, 37%). Technical failures occurred in 5 patients (7%),
and 12 patients experienced some residual opacification of their aneurysms (16%).
The procedure-related mortality and morbidity rate was 8%. At 6 months, the
outcomes were as follows: GOS score of 1, 50 patients (66.7%); GOS score of 2, 4
patients (5.3%); GOS score of 3, 4 patients (5.3%); and GOS score of 5, 17
patients (22.7%). The main causes of death and disability at 6 months were the
direct effect of the initial hemorrhage (9%), delayed ischemia (6.7%), subsequent
bleeding (4%), intraprocedural rupture (4%), open surgical complications (3%),
and unrelated deaths (4%). Six-month angiographic follow-up data were available
for 50 patients (67%). The morphological results were considered to be
satisfactory in 44 of these 50 patients (88%) (complete occlusion, 46%; residual
neck or dog ear, 42%). CONCLUSION: Endovascular treatment of acutely ruptured
aneurysms was attempted without clinically significant complication in 92% of the
patients. The morphological results were unsatisfactory in 23% of the patients.
Complete obliteration of the sac, with or without residual neck, is essential to
prevent subsequent bleeding, which occurred in 5% of the patients. The overall
outcome at 6 months was similar to that of surgical series, despite a selected
group of patients with negative prognostic factors.
PMID- 9402575
TI - Familial intracranial aneurysms: an autopsy study.
AB - OBJECTIVE: Familial intracranial aneurysms are more common than has been
appreciated, but systematic autopsy studies of affected individuals have not been
reported. We reviewed the autopsy findings of a group of patients with familial
aneurysms to elucidate the nature of the putative underlying arteriopathy.
METHODS: Using a computerized diagnostic index, we identified all patients with
intracranial aneurysms in whom postmortem examination had been performed at the
Mayo Clinic between January 1, 1992, and December 31, 1994. The medical records,
radiographic studies, and autopsy findings of these patients were reviewed.
RESULTS: Among the 28 patients with intracranial aneurysms, 3 (11%) had one or
more first-degree relatives with documented intracranial aneurysms. The mean age
of the three patients (two women and one man) was 54 years. Microscopic
examination of the vascular system revealed medial changes, consisting of
degeneration of elastic fibers and increased ground substance, in the systemic
arteries of 2 of the 3 patients with familial aneurysms but in none of the 25
patients with sporadic aneurysms. These nonspecific medial changes involved both
common and extracranial internal carotid arteries in one patient and the entire
aorta as well as intracranial and common carotid arteries in the other patient.
CONCLUSION: These observations suggest that an underlying arteriopathy in
patients with familial intracranial aneurysms involves the tunica media and
commonly may affect systemic (extracranial) arteries.
PMID- 9402576
TI - Preoperative activation and intraoperative stimulation of language-related areas
in patients with glioma.
AB - OBJECTIVE: Evaluation of the accuracy of preoperative localization of language
related cortex by magnetic resonance imaging-guided positron emission tomography.
METHODS: Patients with gliomas in the left dominant hemisphere were examined
preoperatively with magnetic resonance imaging-guided positron emission
tomography and intraoperatively by electrical stimulation of cortex. RESULTS: A
verb generation task yielded more intense and better lateralized local increases
of cerebral blood flow in the positron emission tomographic examination than did
a naming task. Significant correspondence of preoperative and intraoperative
findings was observed for the verb generation task. Cortical sites with aphasic
disturbance during electrical stimulation had a significantly higher cerebral
blood flow increase during preoperative activation than did sites without
intraoperative language impairment. Areas with cerebral blood flow increases
above an optimum threshold had 73% sensitivity and 81% specificity to predict
aphasic disturbance during intraoperative stimulation. CONCLUSION: The data
suggest that with further technical improvements, imaging of language function
may become a preoperative diagnostic tool for patients with tumors close to
language-related brain structures.
PMID- 9402577
TI - Infratentorial empyema: analysis of 22 cases.
AB - OBJECTIVE: Infratentorial empyema is an uncommon form of intracranial suppuration
that is usually secondary to neglected otogenic infection. The diagnosis is
frequently delayed and often confused with that of meningitis. The associated
mortality is distressingly high, yet it has, as a clinical entity, received scant
attention in the literature. We present a 13-year experience of this condition.
PATIENTS AND METHODS: From a retrospective analysis of 3865 patients with
intracranial suppuration during a 13-year period, 22 patients with infratentorial
empyema were identified. The inpatient notes for these patients were analyzed
with reference to clinical, radiological, bacteriological, operative, and outcome
data. RESULTS: Twenty-two patients with infratentorial empyema accounted for 0.6%
of admissions caused by intracranial suppuration during the study period. Of
these 22 empyemas, 13 were subdural and 9 epidural. Hydrocephalus was present in
17 (77.3%). Except for two epidural empyemas that did not warrant neurosurgical
intervention, all patients underwent standard surgical management (wide posterior
fossa craniectomy). Nineteen underwent mastoidectomy because the source of
infection was otogenic. Concomitant and persistent hydrocephalus was treated
aggressively. Five patients died (mortality rate of 22.7%). All fatalities had
subdural empyemas, and all three patients with cerebellopontine angle extension
of subdural purulent collections died. CONCLUSION: Although rare, infratentorial
empyema, especially when subdural, is a lethal disease. Cerebellopontine angle
extension of pus was a particularly ominous sign in our experience. Early
surgical drainage via wide posterior fossa craniectomy, aggressive treatment of
associated hydrocephalus, eradication of the primary source of sepsis, and,
finally, intravenous high dosage of appropriate antibiotics form the mainstay of
treatment.
PMID- 9402578
TI - Current treatment of brain abscess in patients with congenital cyanotic heart
disease.
AB - OBJECTIVE: The goal of this study was to define clearly the role of management in
patients with cyanotic heart disease and brain abscesses by evaluating
retrospectively the factors influencing poor outcome in these patients. METHODS:
This study included 62 patients with cyanotic heart disease and brain abscesses
diagnosed in the computed tomography era. Basic characteristic parameters
(number, size, location, computed tomographic classification and organism type of
abscess, convulsion, type of cyanotic heart disease, age distribution,
immunocompromised status, pretreatment neurological state, and intraventricular
rupture of brain abscess [IVROBA]) and therapeutic parameters (type of
antibiotics and duration of administration, steroid medication and therapeutic
modalities, aspiration with or without cerebrospinal fluid drainage, total
extirpation after aspiration, or primary extirpation and medical treatment) were
evaluated as independent predictors of poor outcome (totally disabled state or
death) by using univariate and multivariate logistic regression analysis. We also
statistically estimated the possible causes of IVROBA and the multiplicity of
brain abscess. RESULTS: Although there were no statistically significant
correlations between patients with good and poor outcomes in regard to other
basic characteristic and therapeutic parameters, patients with poor outcomes were
older (P < 0.02), more frequently had IVROBA (P < 0.005), and had a higher
frequency of neurological deterioration (P < 0.01) than those with good outcomes.
Multiple logistic regression analysis predicted that poor outcome increased the
relative risk of IVROBA by a factor of 18.9 (odds rate, 18.9; 95% confidence
interval, 1.7-211.6; P < 0.02). More patients with multiple abscesses had
positive immunocompromised states than those with single abscesses (P < 0.01).
Deep-located abscesses also more frequently had IVROBA (P < 0.005) and abscesses
located in the parieto-occipital region ruptured into the occipital horn of the
lateral ventricle in a short period (P < 0.02). CONCLUSIONS: Our findings suggest
that IVROBA strongly influences poor outcome in patients with cyanotic heart
disease. The key to decreasing poor outcomes may be the prevention and management
of IVROBA. To reduce operative and anesthetic risk in these patients, abscesses
should be managed by less invasive aspiration methods guided by computed
tomography. Abscesses larger than 2 cm in diameter, in deep-located or parieto
occipital regions, should be aspirated immediately and repeatedly, mainly using
computed tomography-guided methods to decrease intracranial pressure and avoid
IVROBA. IVROBA should be aggressively treated by aspiration methods for the
abscess coupled with the appropriate intravenous and intrathecal administration
of antibiotics while evaluating intracranial pressure pathophysiology.
PMID- 9402579
TI - Use of cerebrospinal fluid shunts in patients having acquired immunodeficiency
syndrome with cryptococcal meningitis and uncontrollable intracranial
hypertension.
AB - OBJECTIVE: To evaluate the treatment of serious and uncontrollable intracranial
hypertension in patients with acquired immunodeficiency syndrome who developed
cryptococcal meningitis. METHODS: All cases of cryptococcal meningitis with
elevated pressure and acquired immunodeficiency syndrome were reviewed in detail
and described. RESULTS: Cerebrospinal fluid shunting dramatically improved these
critically ill patients and was much more successful than serial lumbar punctures
or the use of high-dose dexamethasone. CONCLUSION: Patients with acquired
immunodeficiency syndrome who develop cryptococcal meningitis and who suffer
serious visual loss or ocular palsies with elevated pressures should be
considered for cerebrospinal fluid shunting at an early stage.
PMID- 9402581
TI - Recent advances in epilepsy surgery: temporal lobectomy and multiple subpial
transections.
AB - THIS ARTICLE REVIEWS four major advances in epilepsy surgery, especially the most
frequently performed surgery, temporal lobectomy, as follows: 1) the ability to
preoperatively identify (using magnetic resonance imaging) the pathological
condition of hippocampal sclerosis (a key component to the syndrome of mesial
temporal lobe epilepsy, 2) the ability to identify preoperatively which temporal
lobe candidates are at risk for postoperative memory problems, 3) the
standardization of temporal lobectomy with respect to how much hippocampus should
be resected, 4) a validation of the novel surgical technique of multiple subpial
transections. This technique allows surgeons to attack foci within nondispensible
cortex and therefore enlarges the applicability of surgical treatment to
otherwise inoperable patients and potentially improves outcome.
PMID- 9402580
TI - Cerebrospinal fluid adenosine concentration and uncoupling of cerebral blood flow
and oxidative metabolism after severe head injury in humans.
AB - OBJECTIVE: Uncoupling of cerebral blood flow (CBF) and oxidative metabolism is
observed after severe head injury in comatose patients; however, the mechanism(s)
involved remain undefined. Adenosine can produce cerebral vasodilation and reduce
neuronal activity and is a possible mediator of uncoupling. We hypothesized that
cerebrospinal fluid (CSF) adenosine concentrations would be increased during
uncoupling of CBF and oxidative metabolism, defined as a narrow arterio-jugular
venous oxygen difference [D(a-v)O2 4 vol%] after head injury. METHODS: Adenosine
concentrations were measured using fluorescent-based high-pressure liquid
chromatography in 67 CSF samples obtained from 13 comatose (Glasgow Coma Scale
score 7) adult patients who sustained a severe closed head injury. At the time
each sample was obtained, CBF was measured by the xenon-133 method, and blood
samples were obtained for determination of D(a-v)O2. RESULTS: CSF adenosine
concentration was negatively associated with D(a-v)O2 (P < 0.05, generalized
multivariate linear regression model). In addition, CSF adenosine concentration
was increased when D(a-v)O2 was 4 versus > 4 vol% (38.5 [3.2-306.3] versus 14.0
[2.7-795.5] nmol/L, respectively, median [range]; P < 0.025) and in patients who
died versus survivors (40.1 [6.9-306.3] versus 12.9 [2.7-795.5] nmol/L,
respectively, median [range]; P < 0.001). CONCLUSION: The association between
increased CSF adenosine concentration and a reduction in global cross-brain
extraction of oxygen supports a regulatory role for adenosine in the complex
balance between CBF and oxidative and nonoxidative metabolism severe head injury
in humans.
PMID- 9402582
TI - Analysis of pallidotomy lesion positions using three-dimensional reconstruction
of pallidal lesions, the basal ganglia, and the optic tract.
AB - OBJECTIVE: To assess the position of radiofrequency pallidotomy lesions placed
using microelectrode stimulation and cellular recordings in relation to a
stereotactically defined starting point. Radiofrequency lesion locations were
also evaluated in relation to the putamen, posterior limb of the internal
capsule, and optic tract. METHODS: Magnetic resonance images obtained from 23
patients with Parkinson's disease who underwent pallidotomy at the University of
Kansas Medical Center were analyzed. Using computerized techniques, lesion
positions in relation to the midcommissural point and a hypothetical starting
point were determined. Data segmentation and three-dimensional reconstruction of
pallidal lesions, the internal capsule, and the optic tract allowed assessment of
lesion position in relation to internal anatomy. Clinical outcome of pallidotomy
was assessed using both the Unified Parkinson's Disease Rating Scale and the
Dementia Rating Scale. RESULTS: Pallidal lesions were usually placed anterior and
dorsal to the stereotactically defined starting point. The position of pallidal
lesions in the men were observed, in four trials, to be significantly more dorsal
than the lesions in the women. The outer zone of the lesion was usually adjacent
to the internal capsule and the putamen and relatively close to the optic tract.
The inner zone of the lesion was usually several millimeters removed from
anatomic boundaries of the putamen, internal capsule, and optic tract. Patients
achieved favorable outcomes, with reduced dyskinesias and "off" time and
improvement of their Parkinsonian symptoms, as evidenced by clinical assessment,
the Unified Parkinson's Disease Rating Scale, and the Dementia Rating Scale.
CONCLUSION: Microelectrode stimulation and cellular recordings usually led to a
final pallidotomy lesion position that deviated from the stereotactically defined
starting point. The pallidotomy lesions in the men were observed to be more
dorsal than the lesions in the women. Clinical outcomes were not correlated with
either lesion location relative to the starting point or distances between the
pallidal lesion and the putamen, internal capsule, or optic tract.
Kinesthetically responsive cells may be localized generally more anterior and
dorsal to the starting point (within the globus pallidus) and may be grouped
variably from patient to patient in relation to other basal ganglia structures.
Although the primary lesion site is most likely within the sensorimotor region of
the globus pallidus internus, the more dorsal locations of responsive cell groups
may indicate that some lesion sites may be localized within the globus pallidus
externus.
PMID- 9402583
TI - Stereotactic transcranial magnetic stimulation: correlation with direct
electrical cortical stimulation.
AB - OBJECTIVE: To evaluate stereotactic transcranial magnetic stimulation (TMS) as a
tool for presurgical functional mapping of human motor cortex. METHODS:
Transcranial magnetic stimulation using a frameless stereotactic system was
performed in two patients with tumors near the central sulcus. TMS motor function
maps were plotted on the patients' three-dimensional volumetric magnetic
resonance imaging data and compared with direct electrical cortical stimulation
at surgery with the patient under local anesthesia. RESULTS: Stereotactic TMS was
well tolerated by both patients and was consistent with known somatotopic
representation of human motor cortex. The results demonstrated a good correlation
between the TMS and electrical cortical stimulation maps, with all TMS responses
eliciting more than 75% of the maximum motor evoked potential falling within 1 cm
of the electrical cortical stimulation site. CONCLUSIONS: Our findings indicate
that stereotactic TMS is feasible and can provide accurate noninvasive
localization of cortical motor function. It may prove to be a useful method for
presurgical planning.
PMID- 9402584
TI - The role of motor evoked potentials during surgery for intramedullary spinal cord
tumors.
AB - OBJECTIVE: This is a prospective study of the methodology and clinical
applications of motor evoked potentials (MEPs) during surgery for intramedullary
spinal cord tumors. METHODS: Transcranial electrical stimulation was used to
activate corticospinal motoneurons, and the traveling waves of the spinal cord
were recorded through catheter-electrodes placed epi- or subdurally.
Intraoperative MEP monitoring was performed in 32 consecutive patients (age
range, 1-50 yr) undergoing resection of intramedullary spinal cord tumors. In 19
patients, MEPs were present before myelotomy (monitorable group), and in 10
patients, MEPs were absent before myelotomy (unmonitorable group). Placement of
an epidural electrode was not possible in two patients, and technical problems
prevented recording in one. RESULTS: MEP amplitudes decreased intraoperatively by
more than 50% of baseline in three patients, all of whom had postoperative
paraplegia. Two of these patients recovered within 1 week after surgery, and one
remained paraplegic. None of the patients with preserved MEP amplitude (> 50%)
sustained immediate significant postoperative deterioration. Motor function was
significantly deteriorated 1 week after surgery in one patient in the monitorable
group and in five patients in the unmonitorable group. MEP monitorability was
significantly associated with good surgical outcome for adult patients (P <
0.05), although not for pediatric patients (P > 0.6). Preoperative motor status
and surgical outcome were not significantly associated for the adult (P = 0.13)
or pediatric groups (P > 0.4). CONCLUSION: MEP monitorability was a better
predictor of functional outcome than the patient's preoperative motor status for
the adult group. Significant predictors of MEP monitorability in the adult group
were preoperative motor function (P < 0.01), history of no previous treatment
(surgery or irradiation) (P < 0.01), and small tumor size (P < 0.05). Weak
associations with monitorable MEPs existed for low-grade tumors (P = 0.09), the
presence of baseline somatosensory evoked potentials (P = 0.10), and tumor
pathological abnormalities (ependymoma) (P = 0.13). No associations were
determined for sex (P > 0.4), associated syrinx (P > 0.3), or tumor location (P >
0.5). In the pediatric group, none of the examined factors were associated with
MEP monitorability (P > 0.3). A decline of more than 50% in MEP amplitude during
tumor removal should serve as a serious warning sign to the surgeon.
PMID- 9402585
TI - Value of nerve action potentials in the surgical management of traumatic nerve
lesions.
AB - OBJECTIVE: The goals of the study were to investigate the value of intraoperative
electrically evoked nerve action potentials (NAPs) in the surgical treatment of
traumatic peripheral nerve injuries (nerve lesions in continuity). METHODS: Sixty
four patients with 76 traumatic nerve lesions in continuity were investigated
intraoperatively by stimulating and recording NAP from the whole nerve across the
suspected lesion site. Among the 76 nerves (nerve lesions) were 43 with
incomplete and 33 with complete loss of function. In cases (nerves) with complete
loss of function (n = 33), the surgical procedure (external neurolysis, internal
neurolysis, or nerve repair) was performed according to the microscopic aspect of
the nerve and the result of the intraoperative electrophysiological testing. In
cases (nerves) with incomplete loss of function (n = 43), the surgical procedure
was performed solely according to the microscopic aspect of the nerve and
independently from the result of the intraoperative electrophysiological testing.
RESULTS: Of 43 nerves with incomplete loss of function, we were able to record
reproducible NAPs in 41 (95%) across the lesion site, thus demonstrating a high
reliability of the method. Of 33 nerves with complete loss of function, a
reproducible NAP could be recorded only in 3. Assuming an axonotmetic lesion in
regeneration, we did nothing else on the nerve with excellent clinical results
(full recovery). Of the remaining nerves with no NAP, 24 showed a caliber shift
of the nerve (in 20 cases a thickening of the nerve, suggesting a neuroma in
continuity). A grafting procedure was performed, and the histological evaluation
revealed a neurotmetic lesion. However, in six patients with no NAP, there was no
clear caliber shift of the nerve. The epineurium was opened and an internal
neurolysis performed showing fascicles in continuity. Three patients had good and
three had partial (but useful) recovery. CONCLUSIONS: In nerve lesions in
continuity with complete loss of nerve function, intraoperative NAPs are able to
detect axonotmetic lesions in regeneration. Thus, unnecessary further surgical
procedures can be avoided. On the other end of the spectrum, no recordable NAP
together with a caliber shift of the nerve (suggesting a neuroma in continuity)
may facilitate the surgeon's decision for a grafting procedure without a time
consuming internal neurolysis. But there is also evidence from our data that not
every nerve lesion in continuity without a NAP needs to be grafted.
PMID- 9402586
TI - Cerebral arteriovenous malformation feeding artery aneurysms: a theoretical model
of intravascular pressure changes after treatment.
AB - OBJECTIVE: A quantitative model may be used to estimate the magnitude of expected
pressure changes along the vascular tree with shunt ablation and may provide
information to assess the hemodynamic risk of arteriovenous malformation (AVM)
treatment. METHODS: A computer model of the cerebral circulation was applied to
estimate the changes in intravascular pressure, velocity, biomechanical stress,
and shear stress that might be expected from either endovascular or surgical
ablation of AVMs. Two AVM sizes and two feeding artery constellations were
simulated. The effect of different shunt flows on vascular pressure was modeled.
In each simulation, AVMs were occluded in a stepwise fashion. The effects of
systemic hypertension and hypotension in various vascular zones were also
simulated. RESULTS: As large (1000 ml/min) AVMs were occluded, the mean feeding
arterial pressure increased from 18 to 68 mm Hg; the percent-occlusion at half
maximal pressure increase was 92%. For medium (500 ml/min) AVMs, feeding arterial
pressure increased from 37 to 66 mm Hg; the percent-occlusion at half-maximal
pressure increase was 71%. During manipulation of systemic pressure, hemodynamic
changes in the circulation close to the nidus were proportionally less than
changes in systemic pressure; the degree of proportionality depended on the
magnitude of AVM shunt flow. CONCLUSION: In this simulation, shunt obliteration
increased pressure in the nidus and feeding arteries with little effect on the
proximal circulation. The shunt provided a "buffering" effect, i.e., higher flow
fistulas were exposed to smaller variations in intravascular pressure in feeding
artery and nidal pressures during manipulation of systemic pressure.
PMID- 9402587
TI - Progesterone receptor gene expression in craniopharyngiomas and evidence for
biological activity.
AB - OBJECTIVE: Previous studies have demonstrated the presence of estrogen receptors
in human craniopharyngiomas, raising the possibility that these lesions can be
influenced by steroids. To complement these earlier findings, we examined for the
presence of progesterone receptor (PR) messenger RNA in surgically removed
craniopharyngiomas and performed some studies to determine whether progestogens
can exert biological effects on these tumors in vitro. METHODS: Total RNA was
extracted from fresh surgically removed craniopharyngiomas and reverse
transcribed into cDNA. The polymerase chain reaction was applied to this
craniopharyngioma-derived cDNA using amplimers complementary to exons 4 and 7 of
the PR gene. Additionally, craniopharyngioma cell cultures were established, and
the in vitro effects of progesterone and 6 alpha-methyl-17 alpha
hydroxyprogesterone acetate on [3H]thymidine uptake and 17 beta-estradiol
oxidoreductase activity were determined. RESULTS: Reversed-transcribed polymerase
chain reaction of craniopharyngioma-derived RNA yielded bands of predicted size
(389 base pairs) in six of seven tumors studied. Hinfl digestion and direct
sequencing of the bands confirmed that the polymerase chain reaction DNA was
representative of PR messenger RNA. Treatment of craniopharyngioma cell cultures
with progesterone resulted in reduced [3H]thymidine uptake. Both progesterone and
6 alpha-methyl-17 alpha-hydroxyprogesterone acetate powerfully increased
oxidative 17 beta-estradiol oxidoreductase activity. CONCLUSION: These results
provide evidence that PR messenger RNA can be produced by at least some human
craniopharyngiomas and indirectly show that this is translated into biologically
active receptor protein.
PMID- 9402588
TI - Characterization of a spontaneous murine astrocytoma and abrogation of its
tumorigenicity by cytokine secretion.
AB - OBJECTIVE: The promise of immunotherapies developed against brain tumors in
animal models has not been realized in human clinical trials. This may be because
of the routine use of rodent tumors artificially induced by chemicals or viruses
that do not accurately portray the intrinsic qualities of spontaneously arising
human tumors and that often fail to incorporate the role of immunosuppressants,
such as transforming growth factor-beta, that are secreted by human gliomas. From
an astrocytoma that arose spontaneously in inbred VM/Dk mice, we have
characterized a highly tumorigenic spontaneous murine astrocytoma cell line (SMA
560) that retains features of glial differentiation and naturally produces high
levels of biologically active transforming growth factor-beta. We have used this
model to determine whether cytokine production by tumor cells will inhibit
intracerebral astrocytoma growth. METHODS: Packaging cell lines producing
replication-incompetent retroviral vectors were used to transfect the SMA-560
cell line in vitro with the genes encoding the murine cytokines interleukin (IL)
2, IL-3, IL-4, IL-6, tumor necrosis factor-alpha, gamma-interferon, or
granulocyte-macrophage colony-stimulating factor or the costimulatory molecule
B7.1 (CD80). RESULTS: Mice challenged intracerebrally with 5000 untransfected SMA
560 cells all succumbed to tumor within 30 days, with a median survival of 25
days. In contrast, mice challenged with SMA-560 cells producing IL-2, IL-4, or
tumor necrosis factor-alpha each had a more than 400% increase in median survival
(P < 0.0001). In these groups, 78.3% (18 of 23 mice), 66.7% (10 of 15 mice), and
60% (6 of 10 mice) of the mice, respectively, remained alive without evidence of
tumor for longer than 100 days after the initial tumor challenge. All other
cytokines tested and the expression of B7.1 failed to result in an increase in
median survival. CONCLUSION: Using a spontaneous astrocytoma model in an inbred
mouse strain, we have shown that cytokine production by glial tumors can abrogate
their tumorigenicity in vivo despite production of transforming growth factor
beta. These results predict that approaches directed at cytokine production
within intracerebral astrocytomas may be efficacious in human trials and that the
"immunological privilege" of the brain may not be absolute under such conditions.
PMID- 9402589
TI - Effect of implant dose/volume and surgical resection on survival in a rat glioma
brachytherapy model: implications for brain tumor therapy.
AB - OBJECTIVE: This study sought to investigate the effects of implant dose/volume
and surgical resection on survival in a rat glioma brachytherapy model. Two doses
were investigated to determine a suitable therapeutic range. METHODS: We
performed two experiments. Three treatment groups and one control group of male F
344 rats bearing 9L brain tumors 12 days after tumor inoculation were used in the
first experiment. Day 12 tumors were an average of 4 to 6 mm in diameter. Animals
treated with brachytherapy received a tumor dose of 80 Gy delivered to a 5.5-mm
radius volume. Total macroscopic tumor removal was achieved by microsurgical
techniques. A subsequent experiment compared the survival of tumor-burdened rats
treated with an implant dose of 60 Gy delivered to a 5.5-mm-radius volume with a
control group. RESULTS: Surgery alone produced an increased life span of 28.6%
over control animals treated with sham surgery and dummy seed implants, a
statistically significant increase in survival (P = 0.0023, log-rank test).
Brachytherapy alone produced the most significant increase in survival over
control animals (P = 0.0001, log-rank test; median survival not attained with an
implant dose of 80 Gy delivered to a 5.5-mm-radius volume; and P = 0.0001,
increased life span 121% with an implant dose of 60 Gy delivered to a 5.5-mm
radius volume). This was not improved by the addition of surgical tumor removal.
CONCLUSION: We have demonstrated a relationship between implant dose/volume and
survival of tumor-burdened rats in this model that is not improved by the
addition of tumor removal. Implications for brain tumor brachytherapy are
discussed.
PMID- 9402590
TI - Systemic administration of the iron chelator deferiprone attenuates subarachnoid
hemorrhage-induced cerebral vasospasm in the rabbit.
AB - OBJECTIVE: Iron catalyzed generation of injurious free radicals has been
implicated in the pathogenesis of cerebral vasospasm after subarachnoid
hemorrhage (SAH). The present study assessed the effects of the iron chelator
deferiprone on cerebral vasospasm in an in vivo rabbit model of SAH. METHODS:
Twenty-four rabbits were assigned to three groups as follows: SAH plus placebo (n
= 8), SAH plus deferiprone (n = 8), or control plus placebo (n = 8). Deferiprone
was administered to an additional group of three rabbits that were not subjected
to SAH. Drug administration was initiated 8 hours after SAH was induced and was
repeated at 8-hour intervals. The animals were killed using perfusion-fixation 48
hours after SAH. Cross-sectional areas of basilar artery histological sections
were measured by an investigator blinded to the treatment groups. RESULTS: In
placebo-treated animals, the average luminal cross-sectional area of the basilar
artery was reduced by 54% after SAH compared to controls (i.e., from 0.272 to
0.125 mm2). The vasospastic response after SAH was attenuated significantly in
animals treated with deferiprone (0.208 mm2, representing a 24% reduction).
CONCLUSION: Previous experimental studies suggested that iron chelation can be
effective in attenuating cerebral vasospasm after SAH. Deferiprone is a recently
developed iron chelator that has been extensively evaluated for the treatment of
patients requiring chronic blood transfusions. The present study demonstrates
that deferiprone is effective in attenuating experimental cerebral vasospasm.
Because of its stability, lipophilicity, and ability to penetrate the blood-brain
barrier, deferiprone represents an attractive candidate for the treatment of
cerebral vasospasm.
PMID- 9402591
TI - Bow Hunter's stroke caused by a nondominant vertebral artery occlusion: case
report.
AB - OBJECTIVE AND IMPORTANCE: Bow hunter's stroke is a consequence of vertebrobasilar
insufficiency as a result of mechanical occlusion or stenosis of the vertebral
artery at the C1-C2 level by head rotation. In most cases, a dominant vertebral
artery is involved. No case of bow hunter's stroke as a result of mechanical
occlusion of a nondominant vertebral artery has ever been reported. CLINICAL
PRESENTATION: We describe a rare case of Wallenberg's syndrome caused by
occlusion of a nondominant vertebral artery induced by head rotation. The patient
complained of vertigo and paresthesia of the left face and the right extremities
when he rotated his head 45 degrees or more to the right. INTERVENTION: Dynamic
angiography revealed that the left vertebral artery was smaller than the right,
terminated in a branch of the posteroinferior cerebellar artery, and was
stretched and completely occluded at the C1-C2 level with the head rotated 45
degrees to the right. The right vertebral artery was normal when the head was
rotated to either the right or the left. Three-dimensional enhanced computed
tomography with the head rotated 45 degrees to the right revealed that the left
vertebral artery was stretched and occluded by dislodgment between C1 and C2.
Cerebral blood flow scintigraphy with head rotation demonstrated that blood flow
was decreased in the lower portion of the left cerebellar hemisphere. C1-C2
posterior fixation was performed to prevent life-threatening neurological
accidents. CONCLUSION: We emphasize that the diagnosis of bow hunter's stroke
should be based not only on angiographic findings but also on hemodynamic studies
with head rotation.
PMID- 9402592
TI - Stroke related to a dermoid cyst: case report.
AB - OBJECTIVE AND IMPORTANCE: We report the case of a woman presenting with sudden
neurological deficit, revealing a parasellar dermoid cyst. To our knowledge, this
clinicopathological finding is the first reported in the literature. CLINICAL
PRESENTATION: A neurological examination of the patient revealed a left
hemiparesis, including central facial palsy, which hampered her speech. The well
documented neuroradiological work-up (including computed tomography, magnetic
resonance imaging, and magnetic resonance angiography) demonstrated right
frontorolandic ischemia caused by a right supra- and parasellar dermoid cyst
leading to middle and anterior cerebral arterial stenoses. INTERVENTION: Surgical
intervention, using a right subfrontopterional approach, was successful. Complete
dermoid cyst removal was achieved. The mechanism of the arterial stenoses is
extensively discussed and is thought to result from an inflammatory reaction of
the basal vessels. CONCLUSION: The patient recovered fully. Nevertheless,
postoperative magnetic resonance imaging confirmed cerebral infarction.
PMID- 9402593
TI - Traumatic basilar aneurysm after endoscopic third ventriculostomy: case report.
AB - OBJECTIVE AND IMPORTANCE: This case illustrates that although endoscopic third
ventriculostomy for patients with aqueductal stenosis is successful and minimally
invasive, it can have severe, life-threatening complications. CLINICAL
PRESENTATION: A 3-year-old girl presented with hydrocephalus and aqueductal
stenosis. She underwent endoscopic third ventriculostomy with laser fenestration
of the third ventricular floor. During the procedure, she developed a severe
intraventricular hemorrhage that required prolonged external ventricular drainage
and ultimately ventriculoperitoneal shunting. Despite having a negative angiogram
after the procedure, she presented 1 month later with a subarachnoid hemorrhage
and a traumatic basilar tip aneurysm. INTERVENTION: The patient underwent a right
subtemporal approach with clip ligation of the aneurysm and subsequently had a
good recovery. CONCLUSION: Hemorrhagic complications after endoscopic third
ventriculostomy are rare. The formation of a traumatic basilar tip aneurysm after
this procedure has not been reported in the literature. Laser fenestration of the
third ventricular floor may increase the risk of this event.
PMID- 9402594
TI - A diffuse white matter ischemic lesion appearing 7 years after stereotactic
radiosurgery for cerebral arteriovenous malformations: case report.
AB - OBJECTIVE AND IMPORTANCE: Little information is available about radiation-induced
complications occurring more than 5 years after radiosurgical treatment for
arteriovenous malformations. CLINICAL PRESENTATION: We present a patient with
arteriovenous malformations who experienced hemimotor weakness caused by a
diffuse white matter necrotic lesion developing 7 years after gamma knife
radiosurgery. The original nidus had been too large (24.1 cm3) to be totally
covered and irradiated with a peripheral dose of 20 to 25 Gy. Therefore, the
lower half of the nidus, which was adjacent to the major feeding artery, had been
partially covered with a 30% isodose volume using two target points with an 18-mm
collimator. A central dose of 70 Gy was used to obtain 21 Gy at the periphery.
Complete nidus obliteration was angiographically confirmed 38 months after
radiosurgery. After a 6-year uncomplicated period, this patient experienced a
convulsive seizure and then mild right hemiparesis. INTERVENTION: Computed
tomography demonstrated a diffuse hypodense area in the left white matter, which
had not been revealed by the previous examination. With steroid treatment, this
patient achieved clinical improvement, although there was no significant
improvement in the computed tomography-demonstrated white matter lesion.
CONCLUSION: Although the evaluation of this patient may not be sufficient and
further examinations may be necessary, we tentatively conclude that the computed
tomography-demonstrated hypodense lesion in this patient is a radiation-related
necrotic lesion. Long-term follow-up is crucial, even after the "treatment goal"
has been achieved.
PMID- 9402595
TI - Ganglioglioma of the spinal cord: report of two rare cases and review of the
literature.
AB - OBJECTIVE AND IMPORTANCE: The goal of this article is to present the clinical and
histopathological features of two rare cases of ganglioglioma occurring in the
cervicothoracic and thoracolumbar spinal cord. CLINICAL PRESENTATION: A 4-year
old female patient presented with tetraparesis, whereas a 54-year-old woman
showed paraparesis of both feet. INTERVENTION: Both tumors could be removed
totally by microsurgical techniques. Light microscopically, the tumors in both
cases showed basically identical histological features and were diagnosed as
benign gangliogliomas. Postoperatively, the two patients did not show
improvement. Tumor recurrence was not noted at follow-up examinations within 11
and 24 months after surgery, respectively. CONCLUSION: Ganglioglioma must be
considered in the differential diagnosis of tumors affecting the spinal cord. In
cases of suspected spinal ganglioglioma showing no sharp delineation from the
surrounding tissue, a subtotal tumor removal should be considered to prevent
severe neurological deficits.
PMID- 9402596
TI - Primary intramedullary primitive neuroectodermal tumor of the spinal cord: case
report and review of the literature.
AB - OBJECTIVE AND IMPORTANCE: Primary intraspinal primitive neuroectodermal tumors
(PNETs) are rare. We report a case and review the literature. CLINICAL
PRESENTATION: A 22-year-old woman presented with rapidly progressive paraparesis
and neurogenic bladder. INTERVENTION: Preoperative computed tomography myelograms
revealed a complete block at T12-L1, consistent with an intramedullary lesion. An
urgent operation was performed with gross total tumor removal. The pathological
findings were consistent with a PNET. Recurrence was noted within 10 weeks of
surgery and has been somewhat responsive to chemotherapy and radiotherapy thus
far. A review of the English literature shows that only 13 cases of primary
intraspinal PNETs have been reported to date, and the present case is the second
one in which the tumor was purely intramedullary. Most of the reported patients
survived less than 2 years. CONCLUSION: Primary intraspinal PNETs are rare tumors
and carry a poor prognosis.
PMID- 9402597
TI - Anterolateral lumbar lipomyelomeningocele: case report and review of the
literature.
AB - OBJECTIVE AND IMPORTANCE: Meningoceles associated with defects of the abdominal
wall are exceedingly rare. One such complex case is presented along with a review
of the relevant literature. The current pathophysiological theories and surgical
management are discussed. CLINICAL PRESENTATION: A case of a patient with an
anterolateral lumbar lipomyelomeningocele associated with multiple congenital
anomalies, including defects in the abdominal wall and urogenital system, is
presented. The lipomyelomeningocele presented as an expanding abdominal mass.
INTERVENTION: Ventriculoatrial shunting and two operations to repair the
myelomeningocele were performed to control the expanding abdominal mass.
CONCLUSION: This report illustrates that the surgical management of complex
lipomyelomeningoceles is similar to the more common types. It also demonstrates
that in the infant in whom the intra-abdominal cerebrospinal fluid collection is
the primary cause of the symptoms, cerebrospinal fluid shunting may be used to
delay the definitive repair until the dura strengthens, thus avoiding the
complications of complex repairs of dura with low tensile strength.
PMID- 9402598
TI - Telemetric intraventricular pressure measurements after third
ventriculocisternostomy in a patient with noncommunicating hydrocephalus.
AB - OBJECTIVE: To examine and document intraventricular pressure (IVP) dynamics in an
adult after endoscopic third ventriculocisternostomy performed as treatment for
hydrocephalus associated with aqueductal stenosis. METHODS: A 30-year-old man who
had undergone ventriculoperitoneal shunting at age 21 years for aqueductal
stenosis caused by a tectal mass presented with symptoms and imaging studies
consistent with shunt malfunction. He underwent urgent ventriculoscopic third
ventricular ventriculocisternostomy, which resolved his symptomatology. The
existing shunt was not revised. At the time of surgery, a catheter connected to
an intracranial pressure TeleSensor device (Radionics, Burlington, MA) was
inserted into the ventricular system. Postoperatively, the patient's recovery was
assessed by IVP recordings. This system allowed us to record IVP in an awake
patient with a functioning third ventriculocisternostomy. RESULTS: We observed an
initial postoperative IVP of 17 cm H2O in the supine position, which decreased to
0 cm H2O at 90 degrees of head elevation. The IVP decreased during the first 48
hours postoperatively to 0 to 2 cm H2O when supine. By 1 week postoperatively,
the patient's IVP had returned to a baseline of 15 to 17 cm H2O when supine, with
a gradual decrease to 0 cm H2O at 30 degrees of head elevation. Three months
postoperatively, the patient's IVP in the supine position was 8 cm H2O, with IVP
decreasing to 0 cm H2O at 45 degrees of head elevation. Magnetic resonance (MR)
imaging performed at that time revealed evidence of flow through the third
ventriculocisternostomy. CONCLUSION: We conclude that after an initial period of
adjustment, the IVP in this patient returned to an unremarkable baseline despite
the novel fluid pathway into the prepontine cistern. This may represent
maturation of the breach through the third ventricular floor or brain recovery
from a period of high pressure. Also, the shape of the postural IVP curve closely
resembled that observed in patients who are not hydrocephalic. These data
represent the first documentation of the intraventricular pressure response to
ventriculocisternostomy and suggest possible intracerebral responses to this
alteration in cerebrospinal fluid flow.
PMID- 9402599
TI - Technical accuracy of a neuronavigation system measured with a high-precision
mechanical micromanipulator.
AB - OBJECTIVE: This study was designed to determine and evaluate the different system
inherent sources of erroneous target localization of a light-emitting diode (LED)
based neuronavigation system (StealthStation, Stealth Technologies, Boulder, CO).
METHODS: The localization accuracy was estimated by applying a high-precision
mechanical micromanipulator to move and exactly locate (+/- 0.1 micron) the
pointer at multiple positions in the physical three-dimensional space. The
localization error was evaluated by calculating the spatial distance between the
(known) LED positions and the LED coordinates measured by the neuronavigator. The
results are based on a study of approximately 280,000 independent coordinate
measurements. RESULTS: The maximum localization error detected was 0.55 +/- 0.29
mm, with the z direction (distance to the camera array) being the most erroneous
coordinate. Minimum localization error was found at a distance of 1400 mm from
the central camera (optimal measurement position). Additional error due to 1)
mechanical vibrations of the camera tripod (+/- 0.15 mm) and the reference frame
(+/- 0.08 mm) and 2) extrapolation of the pointer tip position from the LED
coordinates of at least +/- 0.12 mm were detected, leading to a total technical
error of 0.55 +/- 0.64 mm. CONCLUSIONS: Based on this technical accuracy
analysis, a set of handling recommendations is proposed, leading to an improved
localization accuracy. The localization error could be reduced by 0.3 +/- 0.15 mm
by correct camera positioning (1400 mm distance) plus 0.15 mm by vibration
eliminating fixation of the camera. Correct handling of the probe during the
operation may improve the accuracy by up to 0.1 mm.
PMID- 9402600
TI - Exploration of the solar system and the introduction of advanced technology to
neurosurgery: pegasus or pandemonium.
PMID- 9402601
TI - Solar system exploration, technology development, and neurosurgery.
PMID- 9402602
TI - Charles S. Sherrington (1857-1952)
PMID- 9402603
TI - Bovine pericardium for dural grafts: clinical results in 35 patients.
PMID- 9402604
TI - Predictability of extracranial/intracranial bypass function: a retrospective
study of patients with occlusive cerebrovascular disease.
PMID- 9402605
TI - Frameless stereotactic guidance for surgery of the upper cervical spine.
PMID- 9402606
TI - Hemianopic visual field defects in children with intracranial shunts: report of
two cases.
PMID- 9402607
TI - Circadian variation in skin blood flow responses to passive heat stress.
AB - To examine whether there is a circadian variation in skin blood flow response to
passive heat stress and maximal skin blood flow, which was measured by local
warming to 42 degrees C for 45 min, we studied six men at an ambient temperature
of 28 degrees C at four different times of day [0400-0700 (morning), 1000-1300
(daytime), 1600-1900 (evening), and 2200-0100 hours (night)], each time of day
being examined on separate days. Heat stress at rest was performed by immersing
the legs below the knee in hot water (42 degrees C) for 60 min. The esophageal
temperature (Tes) at rest was significantly higher in the evening than in the
morning. The maximal skin blood flow (SkBFmax) on both sites, back and forearm,
did not show a significant difference among the four times of day. The variation
in Tes thresholds for cutaneous vasodilation to heat stress was similar to the
circadian rhythm in resting Tes. The relationship of the percentage of SkBFmax
(%SkBF) with Tes was significantly lower in the morning than in the evening. The
results suggest that the maximal skin blood flow during local warming does not
show variation over the day, but the sensitivity of vasodilation to passive heat
stress shows a circadian variation.
PMID- 9402608
TI - Flavor preferences conditioned by intragastric polycose in rats: more
concentrated polycose is not always more reinforcing.
AB - Prior studies have obtained conditioned preferences for flavors paired with
intragastric (IG) infusions of Polycose (hydrolyzed starch) at concentrations of
1-32% over a different flavor paired with IG water. The present study determined
if rats would also learn to prefer a flavor paired with concentrated Polycose
infusion over a flavor paired with a more dilute Polycose infusion. In Experiment
1, adult female rats were food-deprived and trained during alternating one-bottle
sessions (30 min/day) to associate one flavored solution (the CS + 8) with IG
infusions of 8% Polycose, a second flavored solution (the CS + 16) with IG
infusions of 16% Polycose, and a third flavored solution (the CS-) with IG water
infusions. In subsequent choice tests, the rats displayed similar preferences for
the CS + 8 and CS + 16 over the CS-, but preferred the CS + 16 to CS + 8 in a
direct choice test. A similar preference pattern was obtained in 22 h/day tests
with the rats nondeprived. In Experiment 2, new rats were similarly trained and
tested but with CS + 16 and CS + 32 solutions paired with 16% and 32% Polycose
infusions, respectively. The rats preferred both CS+ solutions over the CS-
solution in the short- and long-term tests. However, the CS + 16 was preferred
over the CS + 32 by the food-deprived rats in the short-term tests. The two CS+
solutions were equally preferred in the long-term tests with food ad lib. These
and other findings indicate that the postingestive reinforcing action of Polycose
increases as concentration increases from 1% to 16% but does not increase
further, and may actually decrease, at a 32% concentration. The rapid satiating
effect of concentrated carbohydrate solutions may limit their reinforcing
consequences.
PMID- 9402609
TI - Bombesin affects the central nervous system to produce sodium intake inhibition
in rats.
AB - Bombesin (BN) elicits in the rat important behavioural modifications, including
inhibition of food and of water intake. Recently, it has been observed that the
peptide also inhibits the intake of sodium chloride. To state whether BN
possesses a selective antinatriorexic effect or it elicits only an aspecific
depression of ingestive behaviour, we studied the effects of this peptide on the
intake of sodium, water or sucrose of Wistar rats after injections into the
fourth brain ventricle or into selected brain areas involved in the control of
sodium intake, containing BN-like peptides and/or their precursors or specific
receptors. We observed that: a) BN (100-200 ng/rat) injected into the fourth
brain ventricle inhibits not only the intake of 2% NaCl of sodium depleted rats
but also that of water and of 5% sucrose; b) BN (5-50 ng/rat) administered into
the nucleus of the solitary tract and the medial amygdala does not influence the
intake of these fluids and c) BN (5-50 ng/rat) injected into the paraventricular
nucleus does not influence the intake of water and 5% sucrose but potently
inhibits that of 2% NaCl. We concluded that the inhibitory effect elicited on
salt intake by intracranial administration of BN is selective for this behaviour
and is not the expression of an aspecific depression of ingestive behaviour.
PMID- 9402610
TI - Effects of interleukin-1 on sexual attractivity in a model of sickness behavior.
AB - Interleukin-1 (IL-1), a cytokine secreted by activated macrophages, inhibits
sexual behavior in female but not male rats. The present study examined the
effects of IL-1 on sexual attractiveness of the injected animal and on the sexual
responses exhibited by its mating partner. In Experiment 1, a male rat was placed
with an estrous female, injected with either IL-1 beta (2 or 10 micrograms/kg) or
saline. Males exhibited more mounts and intromissions per ejaculation and longer
ejaculation latencies with IL-1- than with saline-injected females. In a second
experiment, a male was placed with two estrous females, one injected with IL-1
beta (5 micrograms/kg) and the other with saline. Males performed less sexual
behavior and spent less time with the IL-1-injected female. In a third
experiment, an estrous female was placed with two males, one injected with IL-1
beta (5 or 20 micrograms/kg) and the other with saline. IL-1 had no effect on the
time spent by the female with each male, and only the high dose reduced
proceptive (courtship) behavior. In conclusion, IL-1 administration to females
reduces the quality of the sexual act, thus reducing the chances for conception
during infection, which is associated with spontaneous abortion and abnormal
development of the fetus. In males, the chances for reproduction are less
affected by IL-1, possibly because reproduction during infection is not as risky
in males as in females.
PMID- 9402611
TI - Decreased glucose utilisation does not increase food intake in the marsupial
Sminthopsis crassicaudata.
AB - The marsupial Sminthopsis crassicaudata increases food intake following a fast.
However, the role of metabolic fuel availability, in particular glucose, in the
regulation of food intake in this animal is unknown. In this study, we have
demonstrated that neither insulin-induced hypoglycaemia nor metabolic blockade of
glucose utilisation with 2-deoxy-D-glucose effects food intake compared to saline
treated controls, suggesting that mechanisms other than glucose availability are
important in the regulation of food intake in this marsupial. These data are
discussed in the context of the role of glucoprivation in feeding in other
mammals.
PMID- 9402612
TI - Caffeine withdrawal symptoms following brief caffeine deprivation.
AB - The effects of short-term caffeine deprivation on mood, withdrawal symptoms and
psychomotor performance were studied in habitual coffee drinkers. Thirty-one male
and female coffee drinkers were tested twice at midday (1130 to 1330 h) 4 h after
double-blind administration of 250 mg of caffeine or placebo. Mood and withdrawal
symptoms reports were collected by questionnaires. Psychomotor performance was
tested with a brief computerized test battery, and causal blood pressure was
measured. Caffeine deprivation was associated with decreased vigor and increased
fatigue and with symptoms including sleepiness and yawning. Blood pressure was
lower by 5-6 mm Hg. No changes in psychomotor performance were observed. Even
short periods of caffeine deprivation, equivalent in length to missing regular
morning coffee, can produce noticeable unpleasant caffeine withdrawal symptoms in
habitual coffee drinkers. Such symptoms may be common side effects of habitual
caffeine consumption that contribute to the maintenance of this behavior.
PMID- 9402613
TI - Paternal care reduces maternal hyperthermia in Djungarian hamsters (Phodopus
campbelli).
AB - Throughout lactation, maternal body temperature, nest attendance, activity level
and reproductive success of solitary female Djungarian hamsters housed at the
recommended ambient temperature of 23 degrees C (Canadian Council on Animal Care
guidelines) were compared with those of paired females housed at the same
temperature and with solitary females housed at the natural burrow temperature of
18 degrees C. As expected, cooler ambient temperature improved pup survival and
weaning weight. Likewise, paternal presence largely compensated for the poor pup
growth typical at 23 degrees C. However, the mechanisms were not the same.
Females at reduced ambient temperatures were as hyperthermic as females at the
higher temperature and spent the same proportion of their day at very high body
temperatures. However, the steeper temperature gradient available for passive
cooling allowed those females to enhance maternal care by shortening their nest
bout absences. In contrast, body temperatures of paired females were tightly
regulated compared to the hyperthermia of solitary females and rarely included
the highest body temperatures. This alleviation of maternal hyperthermia was not
achieved through a reduction in nest attendance. Therefore, maternal hyperthermia
in Djungarian hamsters is not essential and may be considered a substantial cost
to females when males are not present.
PMID- 9402614
TI - Effects of paraventricular lesions on sex behavior and seminal emission in male
rats.
AB - Oxytocinergic neurons of the paraventricular nucleus (PVN) of the hypothalamus
have been implicated in modulating male sexual responses in rats. Previous
investigators have shown that cerebrospinal fluid concentrations of oxytocin (OT)
increased after ejaculation and that intraventricular administration of OT and
electrolytic lesions of the PVN increased temporal measures of male sexual
behavior. Recently, we have demonstrated that OT-immunoreactive neurons in the
parvocellular subnuclei of the PVN project to lower levels of spinal cord. In the
present study, N-methyl-D-aspartic acid lesions, which have been shown to destroy
parvocellular PVN neurons while leaving magnocellular neurons intact, were used
to evaluate the role of parvocellular neurons on male copulatory behavior and
seminal emissions. OT-immunoreactive fibers were reduced in the lower lumbar
spinal cord (L5-L6) following N-methyl-D-aspartic acid lesions in the PVN. This
reduction was associated with a significant decrease in seminal emission at the
time of ejaculation, but mount, intromission and ejaculatory latencies were
unaffected.
PMID- 9402615
TI - A regional variation of acetylcholine-induced relaxation in different segments of
rat aorta.
AB - The tension of the isolated thoracic aorta of the rat was measured isometrically
to determine if there is a regional variation of the relaxation to acetylcholine
(ACh). Endothelium-derived nitric oxide (NO)-dependent relaxation to ACh in the
thoracic aorta precontracted with norepinephrine was significantly greater in the
middle and distal segments than in the proximal segments. The relaxation to ACh
was inhibited by NG-nitro-L-arginine methyl ester, an inhibitor of NO synthase.
The relaxation to the NO donor sodium nitroprusside did not differ between the
same three segments of the thoracic aorta. These results suggest that there are
regional variations in the ACh-induced release of endothelium-derived NO in the
rat thoracic aorta.
PMID- 9402616
TI - Metabolic fuel privation in hibernating and awake ground squirrels.
AB - The nature of metabolic fuel utilization during hibernation and periodic arousal
is not completely understood. 2-Deoxy-D-glucose (2DG) and mercaptoacetate (MA)
were administered to hibernating ground squirrels. These drugs disrupt glucose
and fatty acid oxidation, respectively. Telemetrically recorded body temperature
(Tb) was analyzed to determine rate of rewarming from hibernation, duration of
euthermia during periodic arousal, and proportion of animals arousing after
treatments. 2DG given during hibernation significantly increased latency to
regain euthermia, especially during the initial phase of rewarming (from first Tb
> 10 degrees C to first Tb > 15 degrees C), without affecting the duration or
other features of the ensuing euthermic period; MA did not affect rate of
rewarming. MA treatment during hibernation affected thermoregulation after the
animals aroused, including an increased duration of euthermia and maintenance of
erratic patterns of Tb. The percentage of animals that aroused from hibernation
was increased in a dose-dependent fashion by each drug. 2DG and MA treatments had
little or no impact on nonhibernating ground squirrels in the cold. We suggest
that glucose oxidation is important for rewarming from deep torpor; limited
glucose availability cannot, however, support normal levels of euthermia when
fatty acid oxidation is compromised. On the other hand, fatty acid oxidation may
be less necessary for normal arousal from torpor, but critical for the
maintenance of euthermia during the arousal phase.
PMID- 9402617
TI - Rat strain differences suggest a role for corticotropin-releasing hormone in
modulating sleep.
AB - Corticotropin-releasing hormone (CRH) mediates many of the hormonal, behavioral,
and autonomic responses to a variety of stressors. There is also evidence
suggesting that CRH may be involved in the modulation of physiologic waking.
Lewis (LEW) rats possess a hypothalamic gene defect that results in reduced
synthesis and secretion of CRH relative to genetically related Fischer 344 (F344)
and Sprague-Dawley (Sp-D) rat strains. We therefore hypothesized that LEW rats
would spend less time awake, and more time asleep, than either F344 or Sp-D rats.
Adult male LEW, F344, and Sp-D rats were surgically provided with
electroencephalograph (EEG) recording electrodes, and a thermistor to measure
cortical brain temperature [T(cort)]. Additional rats were also provided with a
chronic guide cannula directed into a lateral cerebral ventricle. Spontaneous
sleep-wake behavior was determined from 48-h recordings of the EEG, T(cort), and
body movements from freely behaving, undisturbed rats. Analyses of 48-h
recordings from undisturbed animals indicate that LEW rats spend less time awake
and more time in slow-wave sleep, relative to the other strains tested. Rapid eye
movement sleep did not differ consistently between rat strains. LEW and Sp-D rats
exhibit the same degree of waking in response to intracerebroventricular
administration of CRH, indicating central mechanisms mediating behavioral
responses to exogenously administered CRH are intact in LEW rats. These data
provide support for the hypothesis that CRH may be a modulator of waking and
sleep.
PMID- 9402618
TI - Alarm pheromone induces stress analgesia via an opioid system in the honeybee.
AB - Changes of the stinging response threshold of Apis mellifera scutellata were
measured on foragers fixed on a holder and stimulated with an electric shock as a
noxious stimulus. The threshold of responsiveness to the noxious stimulus
increased when bees were previously stimulated with isopentyl acetate, which is a
main component of the alarm pheromone of the sting chamber. This effect is
antagonised by previous injection of naloxone-hydrochloride (Endo Laboratories
Inc.). Results suggest that in the honeybee an endogenous opioid system activated
by isopentyl acetate is responsible for modulation of perception for nociceptive
stimuli. The resulting stress-induced analgesia in the defender bee would reduce
its probability of withdrawal thus increasing its efficiency against enemies.
PMID- 9402619
TI - Timing of mating, developmental asynchrony and the sex ratio in mice.
AB - According to the developmental asynchrony hypothesis, changing the time of mating
within the estrous cycle could alter the interval between completion of
blastocyst development and uterine responsiveness for implantation. This may then
lead to sex ratio skews in animals that exhibit sex-differential blastocyst
development, because uterine stage may now benefit either slow (female) or fast
(male) developing blastocysts. To test this hypothesis, the responses of two
strains of mice to altered mating dynamics were compared. In a strain that
exhibits higher male than female blastocyst developmental rates, sex ratios
became significantly female-biased when mated late during the estrous cycle as
opposed to early mating. However, timing of mating did not affect sex ratios in a
strain with synchronous development of male and female preimplantation embryos.
Hence, it is concluded that developmental asynchrony between male and female
blastocysts on the one hand, and blastocysts and uterus on the other, are indeed
responsible for the effect of timing of mating on litter sex ratios in mice.
PMID- 9402620
TI - Recovery from activity-stress ulcer by ad lib feeding in rats.
AB - In order to investigate the recovery from activity-stress ulcers by ad lib
feeding and/or cessation of running, male Wistar rats were exposed to the
activity-stress paradigm, and the rats that revealed hypothermia (their rectal
temperature fell below 36 degrees C) were sacrificed either immediately or after
several 24 h periods of healing. Rats that were sacrificed immediately after the
appearance of hypothermia and those that were exposed to restricted feeding plus
cessation of running revealed severe activity-stress ulcers, whereas few ulcers
were observed in rats given ad lib-feeding and those that were given ad lib
feeding plus cessation of running. Although no significant differences in
relative weights of spleen and thymus were obtained among the different recovery
conditions, the relative weights of the adrenal glands were highest in the
restricted feeding plus cessation of running group, whereas, the other animals
exposed to the activity-stress paradigm showed no differences. These results
indicate that activity-stress ulcers recover under conditions of ad lib-feeding
within 24 h, but they are not influenced by cessation of running. These data also
suggest that organ weights are not affected by any manipulations employed in the
present study.
PMID- 9402621
TI - Failure to change exploration or saccharin preference in rats exposed to chronic
mild stress.
AB - Chronic mild stress (CMS) exposes animals to unpredictable stressors. Reduced
consumption of sucrose or saccharin solutions by CMS rats has been used as a
putative measure of anhedonia, typical of depression. Our objective was to
determine whether saccharin consumption and preference and suppression of
exploratory and rearing behaviors in the open field were reliable indicators of
CMS-induced behavioral depression. In Experiment 1, male Wistar rats subjected to
6 weeks of CMS consumed significantly less food and gained less weight than
controls. CMS did not effect saccharin intake, or preference, measured in a two
bottle test with water. CMS rats exposed to a novel open field showed increased
exploration and rearing. In a second test, performed immediately after a novel
stress of restraint, there were no differences in exploratory or rearing behavior
of CMS and control rats. In Experiment 2, CMS was reduced to 3 weeks and rats
were single or group housed in their home cages. Open field activity of CMS rats
was similar to that in Experiment 1. Saccharin preference of CMS rats was
significantly suppressed when tested after 24 hours of water deprivation, but was
not different from controls after 5 hours of water deprivation. In the final
experiment Sprague Dawley rats behaved the same as Wistar rats in the CMS
paradigm. Therefore, the CMS protocol used in these experiments did not induce
behaviors indicative of depression but did cause a mild anorexia and weight loss.
Saccharin intake of CMS rats was dependent upon their dehydration state and could
not be attributed to stress-induced anhedonia.
PMID- 9402622
TI - Behavioral specificity of the bitter taste gene Soa.
AB - In mice, aversion to the bitter acetylated sugar sucrose octaacetate (SOA) is
determined by a single genetic locus with three alleles. SWR/J (SW) inbred mice
are SOA tasters: They avoid many compounds characterized as bitter-tasting by
humans, at concentrations to which C3HeB/FeJ (C3:SOA demitasters) mice are less
sensitive. C3.SW-Soa(a) congenic taster mice contain the taster allele transposed
to a 99% C3 bitter-insensitive genetic background. SW, C3, C3.SW-Soa(a) congenic
taster, and C3.SW demitaster mice were behaviorally tested with a series of 48-h
two-bottle preference tests to determine the influence of the Soa(a) taster
allele on sensitivity to a variety of bitter-tasting compounds. Soa allelic
variation had a major effect on sensitivity to 0.003-1.0 mM SOA and several
concentrations of the bitter-tasting alkaloids brucine, strychnine, and quinine.
Effects were also found for 0.1 mM denatonium and 1 mM propylthiouracil. For
caffeine, cycloheximide, thiamine, and two nonbitter compounds (NaCl and calcium
hydroxide), the SW mice avoided lower concentrations than the other strains, but
this avoidance was not due to the Soa(a) allele because both the C3 inbred and
C3.SW-Soa(a) congenics were less sensitive. These results suggest the Soa gene
product influences sensitivity to a subset of bitter-tasting compounds.
PMID- 9402623
TI - Relation between parotid saliva flow and composition and the perception of
gustatory and trigeminal stimuli in foods.
AB - The objective of this study was to investigate whether and how parotid saliva
flow and composition correlated with the perception of gustatory and/or
trigeminal stimuli in foods. Thirty (15 male and 15 female) subjects tasted seven
foods or beverages (lemonade, beer, wine, soup, methyl cellulose, peanut butter,
and crackers) with three levels each of a gustatory or trigeminal stimulus and
rated the perceived intensity of the corresponding sensation over time using the
time-intensity (TI) method while their parotid saliva was being collected.
Salivary flow rates of males were significantly higher than those of females for
all stimuli (p < 0.001). That did not translate, however, into consistent
differences in perception of sensory attributes between males and females.
Significant positive correlations were found between saliva flow and (1) TI
parameters for adhesiveness of peanut butter and cohesiveness of mass of crackers
(p < 0.05 or lower) and (2) time from intake to swallowing of crackers and peanut
butter (p < 0.05). No correlations were found between saliva composition (e.g.,
sodium and total protein) and TI parameters. These results indicate that parotid
saliva flow may correlate with the perception of some texture and mouthfeel
attributes (presumably through oral work and bolus formation) but not with that
of the taste attributes examined in this study (at the concentrations studied).
PMID- 9402624
TI - Modifications of operant thermoregulatory behavior of the young pig by
environmental temperature and food availability.
AB - Piglets (Sus scrofa domesticus) were weaned at 14 days and acclimated to 10
("cold animals") or 35 degrees C ("warm animals"). Cold animals were either fed
ad lib. (10HH) or maintained on a high (10H) or low (10L) nutrition plane. Warm
animals were maintained on a high (35H), low (35L), or a very low (35LL)
nutrition plane. After 3 weeks of acclimation, operant thermoregulatory behavior
(animals pressed a lever to turn on a heater) at 15 degrees C was assessed
immediately following or 22 h after a meal. It was found that cold piglets or
those on low nutrition planes produced more heat reinforcements than warm piglets
and those on high nutrition planes. All animals tested 22 h after a meal produced
more reinforcements than when tested immediately after a meal. Rectal temperature
before the sessions of operant heating was lower in cold animals and those on low
nutrition planes than in warm animals and those on high nutrition planes, but the
difference dissipated after 90 min of access to heat. Piglets were then
"deacclimated" for 24 h at 25 degrees C and their behavior observed once again.
Deacclimation eliminated the effect of acclimation temperature on body
temperature and behavior but it did not eliminate the effect due to nutrition.
There was no interaction between temperature of acclimation and nutrition. The
experiments demonstrate that the body temperature of the pig is independently
affected by environmental temperature, the quantity of food eaten by the animal,
and a possibility to use behavior. The behavioral drive is to reach body
temperature which can be defined as a thermal set-point (temperature at which
there is no need for a thermoregulatory response to occur) for behavioral
thermoregulatory responses. Adaptation to different environmental conditions does
not affect this behavioral set-point, but it can involve a temporary shift in the
set points for specific autonomic thermoregulatory responses.
PMID- 9402625
TI - Behavioural lateralisation of the tetrapod type in the zebrafish (Brachydanio
rerio).
AB - Visual lateralisation resembling that found in a bird (domestic chick) is here
demonstrated in a teleost (zebrafish, Brachydanio rerio). Zebrafish predominantly
view objects with the body axis close to facing the object (0-20 degrees on
either side of facing). Strange objects were viewed at first exposure chiefly
with the right frontal field; so was a complex and unfamiliar scene made up of
familiar components. In a second trial, using the same stimulus or scene, left
frontal viewing tended to be used instead. A familiar partner (a fish of another
species) was viewed left frontally. The domestic chick also uses the left eye to
view familiar stimuli, shifting to the right when it has to decide what response
is appropriate to the object at which it is looking. An empty scene in which
nothing could be concealed (and so no response was called for) was viewed by
zebrafish with the left eye from the start. In zebrafish and the chick, the right
eye is used when it is necessary to inhibit premature response, in order to
sustain viewing until a decision is reached, and the left is used when it is
necessary to keep an eye on a familiar or clearly empty scene. The findings
suggest homology of cerebral lateralisation in teleost fish and tetrapods.
PMID- 9402626
TI - D3 dopamine receptor-deficient mouse: evidence for reduced anxiety.
AB - Mice without functional D3 dopamine receptors were examined in two animal models
for anxiety: the open-field test and the elevated plus-maze test. In the open
field, D3 receptor-deficient mice (D3-/-) entered the center significantly more
often than normal (D3+/+) littermates, suggesting an anxiolytic-like effect of
the D3 receptor mutation. Consistent with this finding, D3-/- mice entered open
arms of the plus maze significantly more often and longer than D3+/+ littermates,
but did not differ in closed-arm entries, an index of general activity.
Heterozygous (D3 +/-) animals showed intermediate behavioral changes. We
interpret these results as indicative of reduced anxiety in mice without D3
receptors. Our findings thus suggest that D3 dopamine receptors are involved in
the regulation of anxiety.
PMID- 9402627
TI - Greater behavioral effects of stress in immature as compared to mature male mice.
AB - The effect of sexual maturity on behavioral effects of stress was examined in
male mice. Immature (4-week-old) or mature (8-week-old) animals were subjected to
either social stress (exposure to an isolated adult male) or restraint stress for
5 days and examined for body weight, food intake, or plus-maze behavior. Social
stress reduced food intake, body weight, and open-arm entries in 4-week-old but
not 8-week-old mice. Restraint reduced body weight in 4-week-old but not 8-week
old mice. It is concluded that immature male mice show greater behavioral
disturbances after stress than their mature counterparts. The findings are in
agreement with much anecdotal evidence that children are more vulnerable to
stress than adults.
PMID- 9402628
TI - Evidence that adaptation to cold water swim-induced analgesia is a learned
response.
AB - Controlling for novelty of the test context, the present experiment determined if
adaptation to forced cold water swim stress-induced analgesia is learned through
Pavlovian conditioning. Following baseline measurement of pain sensitivity, Group
A swam in Context A for 3 min and, 8 h later, sat in Context B for 3 min. The
conditions were reversed for Group B. All rats were given a tail-withdrawal test
immediately after swimming or sitting in each context. On the first test day,
conducted 24 h after the completion of the adaptation phase, all rats swam in
Context A for 3 min, and tail-withdrawal latencies were immediately obtained
after the swim. On the second test day, 24 h later, all rats swam in Context B,
with tail-withdrawal latencies measured immediately thereafter. Both groups
showed significantly less analgesia when tested in the adaptation context in
which they previously swam than in the other context. These data provide strong
evidence that adaptation to stress-induced analgesia is a learned response.
PMID- 9402629
TI - The postpubertal change in the playful defense of male rats depends upon neonatal
exposure to gonadal hormones.
AB - The pattern of playful defense used during play fighting by male rats (Rattus
norvegicus) castrated at birth was compared to that of sham-operated and
untreated controls during the juvenile phase and after puberty. The neonatal
castrates failed to exhibit the age-related changes in playful defense present in
intact male rats of the same age. Following puberty, control rats, but not
neonatal castrates, switched from juvenile to more adult-typical defensive
tactics. That the neonatal castrations were effective was independently shown by
the animals' failure to exhibit the asymmetries in weight and play behavior
indicative of dominance-subordinance relationships present in normal adult males.
A previous study found that castration following weaning did not prevent the
pubertal change in playful defense, but did block the formation of dominance
subordinance relationships. Therefore, it appears that the age-related shift in
playful defense is a feature of the development of play fighting in males that is
likely preprogrammed by gonadal hormone exposure in the perinatal period.
PMID- 9402630
TI - Measurement of resuspended aerosol in the Chernobyl area. I. Discussion of
instrumentation and estimation of measurement uncertainty.
AB - Results of measurements of the resuspended radioactive aerosols in the Chernobyl
area are presented which were obtained soon after the Chernobyl reactor accident
and in a European project in 1992-1993. The measurements were carried out with
the intention of obtaining a data base for dose assessment of resuspended
radioactive particles. Potential significant dose contributions may result from
inhalation and secondary contamination due to resuspended radionuclides. In this
first article of a series of three papers, the instrumentation and the
measurement uncertainties are discussed. An effort was made to sample
quantitatively giant aerosol particles (particles larger than 10 microns
aerodynamic diameter) as well. The comparison of the samplers shows, in general,
an agreement of concentration measurements of 137Cs and 7Be within a factor of
two. One sampler was identified with larger discrepancies and needs additional
investigation of its sampling characteristics; for another device, the
recalibration of the analysing system is recommended. Ordinary integrating
samplers have a loss of about 30% in 137Cs activity compared to an isokinetic
sampler collecting giant particles as well. The mean ratio of 137Cs activity
concentration between an instrument sampling only particles larger than 10
microns and an ordinary integrating sampler is 0.39 +/- 0.15 during anthropogenic
enhanced resuspension. These findings demonstrate the significant contribution of
giant particles to resuspended airborne radioactivity. The results of this study
concerning integral measurements during wind-driven resuspension proved to be in
good agreement with previously published data on resuspension.
PMID- 9402631
TI - Exposure levels for persons involved in recovery operations after the Chernobyl
accident. Statistical analysis based on the data of the Russian National Medical
and Dosimetric Registry (RNMDR).
AB - We present a detailed description of dosimetric data entered in the Russian
National Medical and Dosimetric Registry (RNMDR) for emergency workers
(liquidators) involved in recovery operations (RO) after the Chernobyl accident.
The data on the absorbed doses from external exposure are based on the documents
given to liquidators by organizations that performed dosimetric monitoring in the
zones of operation. Using the data on external doses currently available in the
RNMDR for 119,416 liquidators (78.4% of the total number of 152,325 persons),
different statistical characteristics were derived to assess the reliability of
the information. The paper also discusses dose distributions according to the
date of beginning work in the RO zone [up to 250 km from the Chernobyl nuclear
power plant (NPP)], on the distance of the settlement where the liquidators were
accommodated or worked from the NPP, and on the duration of their stay in the RO
zone. To analyse the reliability of the dosimetric data, the notion of an
effective exposure dose rate (EEDR), i.e. the ratio of the dose registered in
RNMDR and the duration of stay in the RO zone, was introduced for each
liquidator, and corresponding statistical characteristics for the distribution of
EEDR depending on the date of entry into the RO zone and distance from the place
of residence or work to the NPP were obtained. The analysis for different groups
of liquidators shows that the dosimetric information of the RNMDR is, as a
statistical aggregate, generally consistent with the data on the radiation
situation in the RO zones.
PMID- 9402632
TI - Cancer risks in the Kaluga oblast of the Russian Federation 10 years after the
Chernobyl accident.
AB - Cancer morbidity and mortality were studied in areas of the Kaluga oblast
contaminated with radionuclides. The main objective of the study was to assess
the influence of radiation exposure on existing levels of cancer morbidity and
mortality. Time trends and relative population risks were analysed. Based on this
analysis, it was concluded that the current levels of morbidity from cancers
among the populations residing in the studied areas were primarily a result of a
complex of factors which predated the exposure from the Chernobyl accident.
However, there seems to be an unfavourable trend concerning malignant neoplasms
of the respiratory organs for women residing in the contaminated areas. To date,
no statistically significant effect of radiation on cancer morbidity (except for
thyroid cancer in women) has been noted. The levels of cancer morbidity and
mortality in the contaminated areas generally reflect the changes in cancer
incidence in the oblast as a whole. The findings are consistent with
international data on latent periods for the induction of radiogenic cancers and
the biological effects for similar levels of exposure to populations residing in
contaminated territories. Further studies are necessary in order to monitor
possible effects that are related to the accident.
PMID- 9402633
TI - Dynamics and distribution of radiocaesium in broiler chicken.
AB - The distribution and biological half-life of radiocaesium (137Cs) in broiler
chickens after three oral applications (in course of 1 day at the age of 14 days)
of artificially contaminated feed mixture were studied. There was a rapid uptake
of the orally administered 137Cs (within a few hours) and also a rapid loss of
137Cs which varied in the different organs (the initial biological half-life was:
liver 0.6 day, intestine 0.6 day, breast meat 2 days, leg meat 1.2 days). More
than one-half of the total administered 137Cs activity (55%) was excreted from
the body within the 1st day after dosage, and after 14 days more than 90% had
been excreted. The highest accumulation of 137Cs occurred in meat (50%-90%), and
the proportion of total activity in breast and leg meat varied during
decontamination. The transfer of radiocaesium from feed into the chicken body
(measured as ratios of the 137Cs activity concentrations in the organ to the
137Cs activity concentration in the applied dose) 1 day after application was:
0.0220, 0.0294, 0.0216 and 0.0195 for breast meat, leg meat, intestine and liver,
respectively. Significant differences between the values were demonstrated (P <
0.05) except between those of breast meat and intestine. For the first 3 days
there was a higher proportion of 137Cs activity in leg meat, whereas from the 4th
day a greater part of total activity was found in breast meat. The latter results
were confirmed in a subsequent study. Data from this study suggest that if
broiler chickens are contaminated by radiocaesium to a level of 5 kBq/chicken in
the course of 1 day at the age of 14 days, then immediate feeding with
uncontaminated feed mixture for 18 days should be effective in decontaminating
the chicken's meat below the intervention levels for radiocaesium in animal
products, i.e. below 1000 Bq. kg-1.
PMID- 9402634
TI - Biological dosimetry: the potential use of radiation-induced apoptosis in human T
lymphocytes.
AB - An assay for biological dosimetry based on the induction of apoptosis in human T
lymphocytes is described. Radiation-induced apoptosis was assessed by flow
cytometric identification of cells displaying apoptosis-associated DNA
condensation. CD4 and CD8 T-lymphocytes were analysed. They were recognized on
the basis of their cell-surface antigens. Four parameters were measured for both
cell types: cell size, granularity, antigen immunofluorescence and DNA content.
Apoptosis was quantified as the fraction of CD4-, or CD8-positive cells with a
characteristic reduction of cell size and DNA content. At doses below 1 Gy,
levels of radiation-induced apoptosis increased for up to 5 days after
irradiation. Optimal dose discrimination was observed 4 days after irradiation,
at which time the dose-response curves were linear, with a slope of 8% +/- 0.5%
per 0.1 Gy. In controlled, dose-response experiments the lowest dose level at
which the radiation-induced apoptosis frequency was still significantly above
control was 0.05 Gy. After 5 days post-irradiation incubation, intra- and
interdonor variations were measured and found to be similar; thus, apoptotic
levels depend more on the dose than on the donor. The results demonstrate the
potential of this assay as a biological dosimeter.
PMID- 9402635
TI - PARATI--A dynamic model for radiological assessments in urban areas. Part II.
Specifications of individuals and populations, their radiation exposures and
variabilities.
AB - After a large-scale contamination of an urban area with gamma-ray emitting
radionuclides (e.g. caesium isotopes) decision makers will need guidance as to
its potential radiological consequences and to optimum means of mitigation. To
provide such information, a dynamic radioecological model PARATI has been
developed and used to simulate the contamination of realistic urban environments
in a computer model and to estimate the various radiation fields in such
environments. In this study, the computer-simulated realistic behaviour and
movements of individuals and populations in such radiation fields are described,
and the resulting radiation exposures and their variabilities are estimated. For
the scenarios considered, the doses of individuals in the same contaminated
environment may vary by more than one order of magnitude. Studies on population
habits and on the behaviour of radionuclides on important urban surfaces even a
long time after the contamination might reduce the uncertainty considerably.
PMID- 9402636
TI - Thyroid cancer incidence in the Ukraine after the Chernobyl accident: comparison
with spontaneous incidences.
AB - The thyroid cancer incidence in the Ukraine among those born in the period 1968
1986 was analyzed with the aim to identify the enhancement due to the Chernobyl
accident. Since any Ukrainian data referring to the time period before the
accident are scarce and the variation of spontaneous incidences in other
countries is immense, the Ukrainian incidences in the period 1986-1989 were used
to estimate the baseline risk. Following 1990, the incidence in the southern part
of the Ukraine increased by about 30%, independent of age. In the other parts the
increase of the incidence depended on age at exposure. In the age group of 9-year
old children, the incidences in three regions defined as the 'high-dose area',
the northern, and the middle oblasts, increased by factors of 50, 20, and 6,
respectively. These rates (1991-1995) are well above spontaneous rates in other
countries. In the age group of 17-year-old juveniles, the incidence increased by
a factor of 6 for the 'high dose area' and in the three northern oblasts, whereas
in the nine 'middle' oblasts it was similar to the incidence of the 'southern'
Ukraine. These rates are within the range found in other countries.
PMID- 9402637
TI - The Semipalatinsk nuclear test site: a first assessment of the radiological
situation and the test-related radiation doses in the surrounding territories.
AB - As a result of atmospheric nuclear tests at the Semipalatinsk test site
'Polygon', adjacent territories were contaminated by radionuclide fallout. The
population of some districts in the Semipalatinsk oblast were exposed to elevated
levels of radiation. Contamination and exposure mostly resulted from early
atmospheric tests. The radiological situation of the Semipalatinsk oblast is
described. Effective dose estimates due to external and internal exposure
attributable to the 1949 and 1953 tests in villages near the Polygon range from
70 mSv to 4470 mSv.
PMID- 9402638
TI - No evidence for increased tumor rates below 200 mSv in the atomic bomb survivors
data.
AB - We investigated for which doses a significantly increased tumor rate can be seen
in the RERF Life Span Study data sets on mortality or incidence of solid tumors.
No significant increase was found below about 200 mSv.
PMID- 9402639
TI - on: 'No evidence for increased tumor rates below 200 mSv in the atomic bomb
survivors' data'.
PMID- 9402640
TI - Radiation risk estimates for leukemia and thyroid cancer among Russian emergency
workers at Chernobyl.
PMID- 9402641
TI - Role of neurotrophins in synapse development and plasticity.
AB - Neurotrophic factors are traditionally viewed as secretory proteins that regulate
long-term survival and differentiation of neurons. The role of neurotrophic
factors in the structural integrity of the nervous system makes them attractive
candidates as therapeutic agents for neurodegenerative diseases. However, the
fact that expression of many neurotrophic factors in the central nervous system
is rapidly enhanced by neuronal activity suggests a new role for these factors in
activity-dependent processes, such as synaptic development and plasticity. A
series of recent studies has provided strong evidence for this novel function of
neurotrophic factors. The neurotrophin family of proteins has been shown to
acutely potentiate synaptic transmission at the neuromuscular junction and in the
brain. These factors are also involved in the maturation of the neuromuscular
synapses and in the development of synapses in the visual system. Gene targeting
and physiological experiments demonstrate that brain-derived neurotrophic factor
(BDNF) plays an important role in long-term potentiation (LTP), a cellular model
for learning and memory. These findings have brought together two hotly pursued
areas of neuroscience, namely, the function of neurotrophic factors and the
mechanisms for synaptic plasticity. Continuous studies in this new field will
help understand how synapses develop and function in the brain, and may have
significant implications in treating learning disorders in both children and
adults.
PMID- 9402642
TI - Neurotrophin regulation of the developing nervous system: analyses of knockout
mice.
AB - The neurotrophins, NGF, BDNF, NT3 and NT4, are one family in a growing repertoire
of neurotrophic factors. The neurotrophins have long been implicated in neuronal
survival and recent studies from mice with targeted disruptions of the
neurotrophin genes confirm this role, but also reveal that the action of the
neurotrophins is more complex, and in some instances more interactive, than
originally envisaged. Lack of functional NGF, BDNF and NT3 genes results in
severe neuronal deficits and an early postnatal death. However, NT4 is unique
among the neurotrophins and while the absence of NT4 does result in limited
sensory neuron loss these mice do not die early, suggesting that NT4-dependent
neurons are not critical for survival. Phenotypic analyses of mice lacking
neurotrophin receptors, TrkA, B and C, confirm that TrkA is the functional
receptor for NGF, TrkB acts as the primary receptor for BDNF and NT4, and NT3
signals primarily through TrkC. However, the finding that TrkC mutant mice have a
less dramatic phenotype than their NT3 counterparts implicates NT3 in signaling
via receptors other than TrkC. Further studies, using combinatorial Trk and
neurotrophin deletions, reveal that while BDNF and NT4 subserve distinct neuron
populations in most cases, other neuron sub-populations can be supported by
either BDNF or NT4, providing evidence for compensatory actions between
neurotrophins. As a mechanism to explain programmed cell death that occurs in the
developing nervous system, recent studies examining neurotrophin gene-dosage
effects suggest that the availability of neurotrophins, NGF, BDNF and NT3, may be
limiting for some neuron populations. In addition, the proposed switch in
neurotrophin dependency for some neuron populations is now being determined using
neurotrophin mutant mice. We discuss these and other recent findings on
neurotrophin requirements for the developing nervous system.
PMID- 9402643
TI - The neuroimmune hypothesis in Parkinson's disease.
AB - The role of immune mechanisms in the pathogenesis of Parkinson's disease is still
a matter of controversy. Immunological abnormalities have been reported in
various brain areas and in peripheral immune parameters. Beside antigen specific
findings which might indicate an autoimmune process directed against dopaminergic
neurons, non-antigen specific abnormalities have been found, which could be
caused either by a disease specific process and/or by immunological properties of
various anti-parkinsonian drugs, e.g. bromocriptine. Immune reactions may imitate
or maintain the degenerative process. In this case possible neuroprotective
strategies interfering with immune functions could be developed. Further
investigations are necessary to elucidate the impact of immune mechanisms on the
degenerative process in Parkinson's disease.
PMID- 9402644
TI - The neurobiological basis of movement initiation.
AB - Simple reaction time (RT) is defined as the elapsed time between presentation of
a single stimulus and onset of movement. In choice RT, there are at least two
stimuli, requiring two distinct responses. The neurobiological basis of RT in
humans has mostly been evaluated in patients with Parkinson's disease or
cerebellar disease. Lesion studies in animals have assessed the different
contributions of various subregions of the basal ganglia and the cerebellum.
There is a prolongation of simple RT and in some cases of choice RT in
Parkinson's disease. Both simple and choice RT are susceptible to modulation by
brain dopamine levels. However, such is not invariably the case, attesting to the
contribution of non-dopaminergic neurons in the sensori-motor slowing found in
Parkinson's disease. An increase in simple RT and in choice RT are found in
patients with cerebellar atrophy. The initiation of fast ballistic movements is
associated with the dentate efferent system. This system is modulated by
dopaminergic and glutamatergic pathways to the striatum.
PMID- 9402645
TI - The regulation of motor control: an evaluation of the role of dopamine receptors
in the substantia nigra.
AB - The importance of the nigrostriatal dopaminergic pathway in motor control is
widely accepted and it is generally believed that the motor symptoms of
Parkinson's disease result solely from reduced release of dopamine from terminals
in the striatum. Over recent years there has been a growing body of evidence
which suggests that dendritic dopamine release in the substantia nigra is of
importance in the regulation of neuronal activity and behaviour. This evidence is
reviewed together with a description of our recent findings that show nigral
dopamine receptors are essential for the maintenance of normal muscle tone. It is
concluded that current views of the basal ganglia circuitry involved in motor
control need to be re-evaluated to take into account these recent reports. A
scheme is suggested to explain how dopamine mechanisms in the substantia nigra
regulate motor activity.
PMID- 9402646
TI - Primary motor cortex reorganization in a long-term monkey amputee.
AB - The primary motor cortex (M1) was mapped with intracortical microstimulation
(ICMS) in a 15 year-old macaque whose right upper extremity was amputated at the
shoulder joint prior to 2 years of age. Movements of the right shoulder girdle
and stump were evoked by ICMS throughout the left M1 upper extremity region. The
size of the left M1 upper extremity region contralateral to the amputated arm was
not appreciably different from the size of the right upper extremity region
contralateral to the intact arm. Long stimulus trains and/or higher stimulus
currents were needed to evoke detectable movements at significantly more loci in
the left than in the right M1 upper extremity region. These observations would be
consistent with unmasking of a high threshold representation of shoulder
musculature that normally exists throughout the central core of the upper
extremity region, where it underlies a lower threshold representation of the
distal forelimb. Alternatively, invasion of the de-efferented distal forelimb
core by surrounding shoulder representation may have occurred. Differences
between the limited M1 reorganization observed in the present study and the more
extensive reorganization of S1 observed in other studies may reflect fundamental
differences between M1 and S1, and/or differences in the extent of de
efferentation versus deafferentation.
PMID- 9402647
TI - Organization, development, and effects of infraorbital nerve transection on
galanin binding sites in the trigeminal brainstem complex.
AB - Previous experiments from this laboratory have indicated that transection of the
infraorbital nerve (ION, the trigeminal [V] branch that supplies the mystacial
vibrissae follicles) at birth and in adulthood has markedly different effects on
galanin immunoreactivity in the V brainstem complex. Adult nerve transection
increases galanin immunoreactivity in the superficial layers of V subnucleus
caudalis (SpC) only, while neonatal nerve transection results in increased
galanin expression in vibrissae-related primary afferents throughout the V
brainstem complex. The present study describes the distribution of binding sites
for this peptide in the mature and developing V ganglion and brainstem complex
and determines the effects of neonatal and adult ION damage and the associated
changes in galanin levels upon their distribution and density. Galanin binding
sites are densely distributed in all V brainstem subnuclei and are particularly
dense in V subnucleus interpolaris and the superficial layers of SpC. They are
present at birth (P-0) and their distribution is similar to that in adult
animals. Transection of the ION in adulthood and examination of brainstem 7 days
later indicated marked reductions in the density of galanin binding sites in the
V brainstem complex. With the exception of the superficial laminae of SpC, the
same reduction in density remained apparent in rats that survived > 45 days after
nerve cuts. Transection of the ION on P-0 resulted in no change in the density of
galanin binding sites in the brainstem after either 7 or > 60 days survival.
These results indicate that densely distributed galanin binding sites are present
in the V brainstem complex of both neonatal and adult rats, that they are located
in regions not innervated by galanin-positive axons, and that their density is
not significantly influenced by large lesion-induced changes in the primary
afferent content of their natural ligand.
PMID- 9402648
TI - The effects of skin temperature on the detection and discrimination of tactile
stimulation.
AB - Detection thresholds and intensity-difference thresholds were measured on four
subjects ranging in age from 19 to 22 years. The stimuli were 250-Hz bursts of
vibration applied through a 3.0 cm2 contactor to the thenar eminence of the right
hand. Detection thresholds were substantially higher at 20 degrees C than at 30
degrees or 40 degrees C and were only slightly higher at 40 degrees C than 30
degrees C. When the intensity-difference threshold was expressed in relative
terms, as the proportion by which two stimuli must differ in amplitude to be
discriminated (delta phi/phi), discrimination capacities were unaffected by
surface-skin temperature. The results are consistent with the hypothesis that
surface-skin temperature alters the sensitivity of tactile receptors, and that,
because of the 'near miss' to Weber's law, the relative difference threshold is
unaffected substantially by skin temperature. It was concluded that, at least a
partial explanation of the 'near miss' lies in the fact that, at low to moderate
sensation levels, the P channel is exclusively activated whereas, at moderate to
high sensation levels, because of recruitment of activity in Non-Pacinian
channels, neural information for intensity discrimination is additionally
provided by channels with superior discriminative capacities.
PMID- 9402649
TI - Perceptions of effort and heaviness during fatigue and during the size-weight
illusion.
AB - Previous work has shown that force perception and the sense of motor effort are
different attributes of sensorimotor function. This study explores the hypothesis
that one reason force and effort perceptions are distinct is to inform an
individual of impaired motor function when muscular force lags effort. This
hypothesis predicts that effort and force perceptions will dissociate when motor
function is impaired by fatigue but not during the size-weight illusion. All
subjects reported a distinct increase in effort when lifting a standard test
weight as fatigue developed. When fatigue was sufficiently marked so that they
could barely lift the test weight, they rated their effort as similar to that
required to lift a maximal weight in the unfatigued state. The perceived
heaviness of the test weight also increased as fatigue developed, but this
fatigue-weight illusion was smaller than the increase in effort for all subjects
and displayed greater variability. In contrast, both the perceived weight of a
small object and the effort required to lift it increased in parallel when small
and large objects were lifted sequentially. The size-weight and size-effort
illusions appear to be examples of a common phenomenon in which perceptual
experience is rescaled to maintain acuity under different working conditions. The
fatigue-weight illusion also has the effect of increasing perceptual acuity as
the subject's weight lifting range decreases due to fatigue.
PMID- 9402650
TI - Matching object size by controlling finger span and hand shape.
AB - The ability of human subjects to accurately control finger span (distance between
thumb and one finger) was studied. The experiments were performed without visual
feedback of the hand and were designed to study the dependence of accuracy on
object size, shape, distance, orientation and finger configuration. The effects
of finger combination and sensory modality used to perceive object size (vision
and haptics) were also studied. Subjects were quite proficient at this task; the
small errors tended to be predominantly negative, i.e., finger span < object
size. The thumb-little finger combination was less accurate than the other finger
combinations, irrespective of the sensory modality used. Subjects made larger
under-estimating errors when matching the size of cylinders than when matching
cubes and parallelepipeds. No effect of viewing distance, object orientation and
finger configuration was found. Accuracy in matching object size was not
dependent on the sensory modality used. The question of how the individual
degrees of freedom of the fingers and thumb contributed to the control of finger
span was also addressed. Principal components analysis showed that two components
could characterize the hand postures used, irrespective of object size. The
amplitude of the first principal component was constant, and the amplitude of the
second scaled linearly with object size. This finding suggests that all of the
degrees of freedom of the hand are controlled as a unit. This result is discussed
in relation to the 'virtual finger' hypothesis for grasping.
PMID- 9402651
TI - The neocortical local circuit--a research workshop held in Sde-Boker, Israel, May
4-8, 1997.
AB - This report does not capture the raw vitality of the Sde-Boker workshop. We did
not anticipate that so many presentations would focus on the importance of spike
timing in the operations of cortical microcircuits and the profound effect of
this on other cortical and subcortical networks. The roles of individual spikes,
temporal firing patterns, neuronal synchronization, intrinsic neuronal and
network oscillation, coincidence detection, integration by individual cells or
even individual dendritic spines were also strong themes of nearly all
presentations. The cortex could be viewed as a network, which, is similar to an
orchestra, where each neuron (musician) generates particular timed spike patterns
(notes) for which 'every spike counts' (the symphony). This assertion would have
been the butt of considerable skepticism less than a decade ago. The conference
led to a view that the cerebral cortex is a spatially distributed timing network.
As such, the consensus reached provides a conceptual framework for exciting new
discoveries in the next decade. One of the truly exciting outcomes of the
workshop was the seamless integration of concepts derived from studies employing
direct approaches such as brain slices to cell cultures and computer simulations
to whole animal physiology. The availability of an ever expanding armamentarium
of increasingly sophisticated techniques and cross-fertilization promises develop
the field in a direction that is as flexible and as subtle as the cortical tissue
it seeks to explain. It was perhaps symbolic that this meeting was held at a
place in the desert where David Ben-Gurion, the first Prime Minister of the
modern state of Israel, had a vision of pioneers settling the untamed Negev that
had intrigued and intimidated mankind for so long. The hauntingly beautiful
Negev, like the cerebral cortex, was an unyielding frontier. Now thanks to modern
ingenuity and technology the Negev can, like the cerebral cortex, finally be
conquered.
PMID- 9402652
TI - Structure, function and expression on blood and bone marrow cells of the
urokinase-type plasminogen activator receptor, uPAR.
AB - Several important functions have been assigned to the receptor for urokinase-type
plasminogen activator, uPAR. As implied by the name, uPAR was first identified as
a high affinity cellular receptor for urokinase plasminogen activator (uPA). It
mediates the binding of the zymogen, pro-uPA, to the plasma membrane where trace
amounts of plasmin will initiate a series of events referred to as "reciprocal
zymogen activation" where plasmin converts pro-uPA to the active enzyme, uPA,
which in turn converts plasma membrane-associated plasminogen to plasmin. This is
an efficient machinery to generate broad-spectrum proteolytic activity which is
spatially restricted to the plasma membrane, since plasmin that diffuses away
from the plasma membrane is rapidly inactivated by circulating inhibitors (i.e.,
alpha 2-antiplasmin). The system is controlled by a series of plasminogen
activator inhibitors (PAIs), most importantly PAI-1 and PAI-2, providing means of
temporally restricting the process of plasminogen activation. In addition to its
role in plasminogen activation, compelling evidence has demonstrated a role for
uPAR in cell-cell and cell-extracellular matrix adhesion, both directly and
indirectly. uPAR is directly involved in binding to the extracellular matrix
molecule, vitronectin, and the affinity of this binding is increased when uPAR is
occupied by (pro-)uPA. A more indirect but presumably very important role of uPAR
in cell adhesion seems to be mediated through interactions between uPAR and beta
1- or beta 2-integrins. It has been demonstrated that uPAR may bind physically to
integrins in a reversible manner. The interaction seems to be of functional
importance since the affinity of the integrin for its corresponding ligand is
modulated by the association of integrin with uPAR. In some experimental setups
uPAR has been shown to reduce the affinity of the associated integrin for certain
ligands, while other experimental systems have demonstrated an increased affinity
of the interaction between integrin and ligand after binding of uPAR to the
integrin. Finally, uPAR has also been shown to participate in signal transduction
events. Since uPAR is not a transmembrane molecule but belongs to the group of
proteins that are tethered to the plasma membrane via a glycosyl
phosphatidylinositol anchor, association with a transmembrane adaptor is required
for transmission of signals via uPAR. Integrins may serve as such signal
transducers, and indeed uPAR has been shown to be associated in the plasma
membrane with complexes of integrins and (phosphorylated) tyrosin kinases
suggesting a role for these complexes in transmembrane transmission of signals
via uPAR. In the hematopoietic system it has been shown that urokinase-type
plasminogen activator (uPAR) is expressed as a differentiation antigen on cells
of the myelomonocytic lineage and as an activation antigen on monocytes and T
lymphocytes. Neutrophils contain intracellular reservoirs of uPAR that are
translocated to the plasma membrane upon activation, and neutrophils from
patients with the rare blood disease paroxysmal nocturnal hemoglobinuria (PNH)
that fail to express glycosyl-phosphatidylinositol-anchored proteins including
uPAR, show a very significantly reduced transmigration over an endothelial
barrier. Cell-associated plasminogen activation by PNH-affected neutrophils is
severely impaired, and it has been proposed that this may be causally related to
the propensity for thrombosis in PNH. The pattern of expression of uPAR in
hematological malignancies mirrors the expression by normal blood and bone marrow
counterparts with some exceptions (differentiated myeloid leukemias are positive,
undifferentiated myeloid may be negative and the majority of lymphoid leukemias
and lymphomas are negative). The potential clinical relevance of uPAR expression
in leukemias and lymphomas has not been determined.
PMID- 9402653
TI - Dendritic cell development: multiple pathways to nature's adjuvants.
AB - Dendritic cells are a system of bone marrow-derived antigen-presenting cells
specialized for interaction with T lymphocytes and essential for initiating
primary T cell immune responses. Recent investigation indicates that dendritic
cells are of diverse origin, with at least two types of myeloid precursors and a
lymphoid precursor implicated in their generation. Mature dendritic cell
subtypes, while sharing the capacity to activate T cells, show additional
functional specialization. Some dendritic cells are equipped with additional
mechanisms to regulate the response of the T cells they activate, while others
are able to interact with B cells and modify B cell responses.
PMID- 9402654
TI - Induction of c-kit molecules on human CD34+/c-kit < low cells: evidence for
CD34+/c-kit < low cells as primitive hematopoietic stem cells.
AB - c-kit, a receptor for stem cell factor, has been widely accepted as a distinctive
marker for hematopoietic stem cells. However, the level of c-kit expression on
pluripotent hematopoietic stem cells is still controversial in mice and humans.
We purified CD34+/c-kit < low cells (phenotypically c-kit-negative but only
detectable at the message level) from human cord blood and examined their
maturational steps in relation to the expression of c-kit molecules. When the
CD34+/c-kit < low cells were cultured with cytokines (flt 3 ligand, interleukin 6
and interleukin 7) plus immobilized anti-CD34 monoclonal antibody (to crosslink
CD34 molecules), c-kit molecules were clearly induced within 24 h. The c-kit
expression gradually increased until day 8. When CD34+/c-kit(low) or CD34+/c-kit+
cells that had been induced from CD34+/c-kit < low cells were resorted and
recultured using a methylcellulose culture system, they showed the same colony
forming ability as the freshly isolated CD34+/c-kit(low) or CD34+/c-kit+ cells,
respectively. Furthermore, CD34+/c-kit < low cells have a similar hematopoietic
potential to CD34+/c-kit(low) cells in assays for long-term culture initiating
cell and colony-forming unit culture generated from long-term cultures. These
findings suggest that CD34+/c-kit < low cells mature into CD34+/c-kit(low) and
CD34+/c-kit+ cells, and acquire the reactivity to various humoral hematopoietic
stimuli. Moreover, CD34+/c-kit < low cells showed a low level of rhodamine 123
retention, suggesting that CD34+/c-kit < low cells have multidrug resistance.
Therefore, the CD34+/c-kit < low cells without colony-forming unit-granulocyte
erythroid-macrophage-megakaryocyte activity are also a pluripotent hematopoietic
stem cell population, and the expression of c-kit on c-kit < low cells is the
first maturational step of hematopoiesis.
PMID- 9402655
TI - Intrathymically injected hemopoietic stem cells can differentiate into all
lineage cells in the thymus: differences between c-kit+ cells and c-kit < low
cells.
AB - To investigate whether hemopoietic stem cells (HSCs) can differentiate into all
lineage cells even in the thymus, we injected two types of HSCs (c-kit+ and c-kit
< low cells) obtained from C57BL/6 Ly5.1 mice directly into the thymus of 7.5 Gy
irradiated C57BL/6 Ly5.2 mice. When c-kit < low cells (low density/lineage-/CD71
/major histocompatibility complex class I high/Sca-1+/Thy-1low/ c-kit < low) were
injected, donor-derived (Ly5.1) cells were detected on day 8 after intrathymic
(i.t.) injection, and the number reached a maximum on day 24 after injection.
Granulocytes and macrophages were also detected on day 8 after injection.
However, B220+ B cells were observed on day 13. Eighteen days after i.t.
injection, the injected lobes showed red color due to the synchronous development
of erythroid cells. Histological studies revealed the development not only of
erythroid lineage cells but also of megakaryocytes in the thymus. In contrast,
when c-kit+ cells were injected, a significant number of donor-derived cells were
detected on day 5 after i.t. injection (three days earlier than in the case of c
kit < low cell injection). The differentiation into erythroid lineage cells was
also observed six days earlier than when c-kit < low HSCs were injected. These
findings suggest that c-kit < low HSCs are more primitive than c-kit+ HSCs,
although both can differentiate into all lineage cells after i.t. injection.
PMID- 9402656
TI - IL-6 interferes with stimulation of HPP-CFC and large CFU-Mk in conjunction with
cytokine combinations from primitive murine marrow cells.
AB - The growth-promoting activities of interleukin 6 (IL-6) in combination with early
acting hematopoietic factors, i.e., stem cell factor (SCF) and interleukin-1
alpha (IL-1 alpha), on primitive hematopoietic and megakaryocyte progenitors
(high proliferative potential colony-forming cells [HPP-CFC] and colony-forming
units-megakaryocyte [CFU-Mk], respectively) from 5-fluorouracil (5-FU)-treated
murine bone marrow cells (BMC) were evaluated in serum-free fibrin clot cultures.
IL-6 in combination with SCF and IL-1 induced an irregular and abortive
hematopoiesis characterized by a reduction in colony size of at least 50% over
those stimulated by SCF + IL-1 + IL-3 and an inability to continue growth to day
12. Moreover, IL-6 in combination with the early-acting factors, SCF and IL-1,
had no effect on the formation of HPP-CFC. IL-6 is synergistic with SCF + IL-1 on
day 7 CFU-Mk but did not stimulate large day 12 CFU-Mk. Our results suggest that,
in the absence of serum, IL-6 prevents the continued proliferation of early
hematopoietic and megakaryocytic progenitors initiated by SCF + IL-1 + IL-3.
Optimization of cytokine combinations for use in ex vivo expansion of marrow
progenitors, either for stem cell transplants or gene therapy, must consider not
only the number of colonies but their size, as well as the contributions of serum
components.
PMID- 9402657
TI - Long-term cytokine production from engineered primary human stromal cells
influences human hematopoiesis in an in vivo xenograft model.
AB - Human hematopoiesis can be supported in beige/nude/ XID (bnx) mice by coinjection
of human bone marrow stromal cells engineered to secrete human interleukin 3
(HuIL-3). The major limitation is a total absence of human B cell development in
the mice, which could be due to supraphysiological levels of HuIL-3 in the
circulation. In an effort to obtain human B lymphoid, as well as T lymphoid and
myeloid cell development in the mice, CD34+ cells were coinjected with human
marrow stromal cells engineered to secrete human IL-2, IL-7, stem cell factor or
FLT3 ligand, +/- IL-3. No single factor other than IL-3 supported sustained human
hematopoiesis in the mice, although cytokines were expressed for four to six
months post-transplantation. Production of both HuIL-3 and IL-7 in the mice
supported extrathymic development of human T lymphocytes, but no B cells, myeloid
cells, or clonogenic progenitors were detected. Human B cells were not produced
from CD34+ cells in the bnx mice under any condition tested. Another limitation
to the bnx/Hu system is a lack of maturation of human red blood cells, although
BFU-E are maintained. Stromal cells secreting human erythropoietin and IL-3 were
cotransplanted into mice with HuCD34+ cells and an increase in hematocrit from
40%-45% to 80%-85% resulted, with production of human and murine red blood cells.
Unfortunately, all mice (n = 9) suffered strokes, displayed paralysis and died
within three weeks. The bnx/Hu cotransplantation model provides an interesting
system in which to study human hematopoietic cell differentiation under the
influence of various cytokines.
PMID- 9402658
TI - Inhibitory action of the peptide AcSDKP on the proliferative state of
hematopoietic stem cells in the presence of captopril but not lisinopril.
AB - The effect of Angiotensin I-converting enzyme (ACE) inhibitors on their own and
in combination with the peptide AcSDKP on the proliferation of hematopoietic stem
cells has been investigated. Hematopoietic stem cells from murine bone marrow
induced into cell cycle following exposure to 2 Gy gamma-irradiation were
incubated in vitro for up to 24 h in the presence of medium,
captopril/lisinopril, AcSDKP, and AcSDKP with either ACE inhibitor. Hematopoietic
stem cells were monitored using the high proliferative potential-colony forming
cell-1 (HPP-CFC-1) population cloned in the presence of human IL-1 beta, murine
IL-3, and murine M-CSF. No significant inhibitory effect was observed in the
presence of AcSDKP on its own and AcSDKP in combination with lisinopril. However,
there was a significant inhibition of stem cell cycling when AcSDKP and captopril
were combined. This suggests that captopril inhibits AcSDKP breakdown better than
lisinopril. The combination of AcSDKP and captopril also had an inhibitory effect
on cell recruitment into S phase. The fact that a combination of AcSDKP and
captopril switches cycling hematopoietic stem cells out of cycle indicates the
importance of the N-active catalytic site of ACE in AcSDKP hydrolysis in vitro.
Thus, AcSDKP in combination with appropriate ACE inhibitors may be of use in
regulating the proliferation of hematopoietic stem cells in vitro.
PMID- 9402659
TI - Requirement of major histocompatibility complex-compatible microenvironment for
spleen colony formation (CFU-S on day 12 but not on day 8).
AB - To clarify major histocompatibility complex (MHC) restriction between
hematopoietic stem cells (HSCs) and microenvironments, T cell-depleted bone
marrow cells (BMCs) were transplanted into MHC-compatible and MHC-incompatible
recipients. A significantly larger number of spleen colony-forming units (CFU-S)
on day 12 were noted in MHC-compatible recipients, while only a small number were
observed in MHC-incompatible recipients. There was, however, no significant
difference in CFU-S counts on day 8 between the two groups. A large number of CFU
S counts on day 12 were also observed in F1 hybrid recipients, as seen in
syngeneic recipients. The decrease in CFU-S counts on day 12 in MHC-incompatible
recipients was also observed even after in vivo abrogation of T and NK cells. The
difference in CFU-S counts on day 12 became more prominent when HSC-enriched
cells were transferred. These results suggest that an MHC restriction exists
between pluripotent HSCs (P-HSCs) and spleen microenvironments. Furthermore,
experiments using B10. A recombinant strains revealed that H-2D and S loci play a
crucial role in the MHC restriction. The experiments of serial transplantation
suggest that the differentiation and proliferation of P-HSCs are inhibited in MHC
incompatible microenvironments. It is therefore likely that the MHC-compatible
microenvironment is essential to the differentiation and proliferation of P-HSCs.
PMID- 9402660
TI - Response of the cellular immune system to cardiopulmonary bypass in vivo.
AB - Cardiopulmonary bypass (CPB) is known to induce an inflammatory response.
Previous studies reported an impairment of the cellular immune response with
activation of neutrophils and changes in lymphocyte subpopulations. The objective
of the present study was to investigate the effect of CPB on leukocyte activation
in vivo. In 27 patients undergoing coronary artery bypass grafting, the
quantitative and the qualitative response of leukocyte populations to CPB was
analysed pre-, intra-, and postoperatively using flow cytometry. A significant
increase in leukocyte counts was detected during CPB, resulting in a marked
leukocytosis postoperatively. The total number of lymphocytes peaked in the early
phase of CPB, followed by a significant decrease, mainly due to a loss in B and
cytotoxic T lymphocytes. In contrast, the lymphocytopenia observed 8 h after
protamin administration was mainly caused by a drop in the population of helper T
lymphocytes. Activation of distinct cell populations could be detected during and
following CPB. The results indicate an influence of CPB on the cellular immune
system, however an immuno-suppression was detectable only transiently.
PMID- 9402662
TI - Tachyarrhythmias following coronary artery bypass graft surgery: epidemiology,
mechanisms, and current therapeutic strategies.
AB - The distribution pattern of perioperative complications of coronary artery bypass
graft surgery (CABG) is currently changing, due to the fact that it has become a
routine operation with an increasing proportion of patients older than 70 years.
Supraventricular and ventricular tachyarrhythmias are among the most commonly
observed postoperative adverse events following CABG. The aim of this review is
to give an update on epidemiology and mechanisms of postoperative arrhythmias and
to present current diagnostic tools and therapeutic strategies.
PMID- 9402661
TI - Improved myocardial protection using continuous coronary perfusion with
normothermic blood and beta-blockade with esmolol.
AB - Continuous coronary perfusion with warm beta-blocker-enriched blood has been
suggested as an alternative to cardioplegic arrest for myocardial protection
during coronary artery surgery. The purpose of the present work was 1.) to
experimentally investigate this technique using an animal model, and 2.) to
clinically apply this alternative myocardial protection technique and compare it
to standard crystalloid cardioplegia in a controlled study. We placed 6 dogs on
CPB and 6 dogs on a biventricular assist device and created "beta-blocker-induced
cardiac surgical conditions" by suppressing myocardial chronotropy and inotropy
with systemic infusion of the ultra-short acting beta-blocker esmolol. For the
clinical study we randomized 60 coronary artery surgery patients to receive
either crystalloid cardioplegia (Bretschneider HTK) or selective continuous
coronary perfusion via the aortic root with warm esmolol-enriched CPB blood. In
the experimental study we found that continuous coronary perfusion with warm
esmolol-enriched blood avoided myocardial ischemia and minimized myocardial
edema, thus completely preserving cardiac performance. Our clinical data showed
the alternative technique to be superior to standard crystalloid cardioplegia in
terms of both functional and structural myocardial protection. The concept of
beta-blocker-induced cardiac surgical conditions is a useful alternative for
myocardial protection during coronary artery surgery and may be particularly
beneficial for severely compromised hearts.
PMID- 9402663
TI - Open heart interventions in premature low- and very-low-birth-weight neonates:
risk profile and ethical considerations.
AB - In premature, very-low-birth-weight (VLBW) neonates, complex cardiac
malformations can be successfully repaired under conditions of cardiopulmonary
bypass. However, due to the immaturity of organ systems, these patients are
exposed to a specific risk resulting from noxious effects of extracorporeal
circulation, especially on the central nervous system. Two premature neonates
with low and very low birth weight of 1160 g and 1650 g, were operated on using
cardiopulmonary bypass for severe pulmonary artery stenosis and truncus
arteriosus communis type II, respectively. The neonate with pulmonary valve
stenosis survived, but at 2-year-follow-up examination motoricity retardation as
a result of cerebral immaturity-related changes was evident. The other neonate
died suddenly on the fifth postoperative day of a massive intracranial
haemorrhage. Due to the fact that the natural history of VLBW children is a
priori characterized by a high incidence of major neurological handicaps, open
heart surgery may by improving survival chances contribute to an increased
incidence of mentally handicapped children.
PMID- 9402664
TI - Long-term follow-up of patients with operative stabilisation of a flail chest.
AB - The outcome is reported of patients after external chest wall stabilisation for
respiratory insufficiency due to a traumatic flail chest. Since 1990, all
patients with a flail chest causing respiratory insufficiency despite peridural
analgesia and without further reason for prolonged mechanical ventilation
underwent osteosynthesis of the chest wall using the AO-technique with 3.5 mm
thick reconstruction plates, and were prospectively followed-up by use of
clinical and radiological evaluation. 23 patients underwent external chest wall
fixation between 1990 and 1996 and were followed for a mean time of 28 months. 2
patients died after the operation, giving a 30-day-survival rate of 91.3% 21
patients survived and were extubated and transferred to the ward after a mean
time interval of 3.9 and 7.8 days, respectively. 95% of the survivors revealed a
100% working capacity at assessment and 86% returned to preoperative sports
activities without complaining of chest wall or shoulder girdle pain or
dysfunction. External chest wall fixation appears to be an attractive alternative
to prolonged intubation and mechanical ventilation for selected patients with
flail-chest respiratory insufficiency despite peridural analgesia, providing they
do not require prolonged intubation for other reasons.
PMID- 9402665
TI - Myxoma complex associated with transient hyperthyroidism: are diseases of the
thyroid part of the complex?
AB - The myxoma complex is a very rare disease. We report on a 31-year-old woman who
suffered a hyperthyreosis, which resolved spontaneously. A few months later she
developed a Cushing's syndrome, caused by a primary adrenocortical nodular
dysplasia. A bilateral adrenalectomy had to be performed. 15 months after this
operation she developed a cerebral infarction caused by an embolus from a left
atrial myxoma. Our patient is a further case of Carney's syndrome. The aspect of
the hyperthyreosis is interesting: Perhaps disease of the thyroid represents a
new element of Carney's syndrome.
PMID- 9402666
TI - Sweet's syndrome and associated sarcoidosis--a rare clinical case.
AB - Sweet's syndrome is frequently idiopathic; however, it has been associated with
malignancy in up to 20% of reported cases. We report a case of concurrent
presentation of Sweet's syndrome with sarcoidosis. Although this association has
been infrequently described we feel that this could be an alternative diagnosis
in patients with Sweet's syndrome who present with mediastinal lymphadenopathy
with or without erythema nodosum. The relevant literature on this subject is
reviewed.
PMID- 9402667
TI - Cardiac hydatid cyst causing massive pulmonary embolism.
AB - Cardiac hydatid cyst is a rare parasitic disease. Since it may be associated with
fatal complications, early diagnosis and treatment of a cardiac hydatid cyst is
very important. We present a case with hydatid cyst localized in the right atrium
and bilaterally in the lungs, and embolized pulmonary arteries bilaterally. The
right atrial cyst localized on the interatrial septum was removed using
cardiopulmonary bypass and the cyst in the right pulmonary artery was extracted
by an embolectomy catheter. The patient died of pulmonary hypertension and
pulmonary insufficiency three months postoperatively.
PMID- 9402668
TI - Constrictive pericarditis caused by an old hematoma.
AB - A 46-year-old woman was admitted for surgery after diagnosis of a constrictive
pericarditis. She had suffered from acute pericarditis and undergone
pericardiocentesis to relieve pericardial effusion several times 10 years
previously. Cardiac catheterization showed elevated mean right-atrial and
pulmonary wedge pressures. Chest CT revealed only a calcified mass in the
retrosternal space. At surgery, there was no severe adhesion between the
pericardium and the epicardium, and the pericardium was thin and almost normal
except over the right artio-ventricular groove, where a hard mass with an
atheromatous content adhered to the epicardium. After resection of the mass,
central venous pressure and pulmonary wedge pressure decreased. The mass was
found to be an old hematoma by pathological examination. The patient was
subsequently discharged from hospital in good condition.
PMID- 9402669
TI - Primary tracheal fibrosarcoma in a child: a case of tracheal resection under ECMO
support.
AB - We report a case of severe airway obstruction due to endotracheal fibrosarcoma in
a 3-year-old boy. Successful tracheal resection and reconstruction was performed
under extracorporeal membrane oxygenation support. A solid, elastic hard tumor
with a smooth surface was attached by a tiny stalk structure to the membranous
part of the lower trachea. Histological findings of the tumor were consistent
with infantile fibrosarcoma, showing proliferation of spindle cells forming
interlacing patterns.
PMID- 9402670
TI - Epithelioid hemangioendothelioma presenting as a chest wall tumor.
AB - We report a case of epithelioid hemangioendothelioma presenting as a chest wall
tumor. The patient had invasive bladder carcinoma and a soft-density mass
protruding into the left thoracic cavity from the lateral chest wall on a
computed tomographic scan. Percutaneous needle biopsy was performed to obtain a
definite diagnosis of the chest wall tumor. Because of an intrathoracic
hemorrhage after the procedure, the patient underwent an emergency thoracotomy
and excision of the mass with adjacent structures. Pathologic examination
demonstrated the mass to be a subpleural epithelioid hemangioendothelioma. This
rare tumor has never been reported previously as arising from the chest wall.
PMID- 9402671
TI - "Reversed" latissimus dorsi musculocutaneous flap for closure of large
bronchopleural fistula.
AB - The patient was a 54-year-old male with diabetes mellitus and liver abscess
perforating into the right lung through the diaphragm. After right lower
lobectomy of the lung, S3-segmentectomy of the liver, and debridement of the
subdiaphragmatic abscess a bronchopleural fistula appeared. After open-drainage
thoractomy, secondary operation for closure of a large bronchopleural fistula and
obliteration of the empyema cavities was performed with a "reversed" latissimus
dorsi musculocutaneous flap.
PMID- 9402672
TI - Pulmonary metastasis from a basal-cell carcinoma of the retroauricular region.
AB - Basal-cell carcinoma of the skin is a common facial neoplasm, usually regarded as
benign. It is also called basalioma. Distant metastasis is very rare and may
involve the brain, lung, and bones. We report a 74-year-old white male who was
admitted to our hospital with cough and fever. Chest radiograph revealed an
opacity of 2 x 1 cm in diameter in the upper lobe of the right lung. Bronchoscopy
and thoracic fine-needle aspiration could not establish a diagnosis. Therefore
the patient underwent right thoracotomy and wedge excision of the lesion.
Histologic evaluation was consistent with pulmonary metastasis of a facial basal
cell carcinoma. The patient recovered uneventfully from surgery and is well 5
years after the operation. According to the English literature the median
survival of patients with metastatic basal-cell carcinoma is 10 months. The
clinical features, pathology, and treatment of this rare entity are discussed.
PMID- 9402673
TI - Bronchogenic carcinoma following pulmonary aspergilloma.
AB - We have observed two cases of bronchogenic carcinoma following pulmonary
aspergilloma among 25 cases of pulmonary aspergilloma. Patients with a pulmonary
aspergilloma may be susceptible to bronchogenic carcinoma.
PMID- 9402674
TI - Doubly angled pleural drain circumventing the transcostal route relieves pain
after cardiac surgery.
AB - Standard pleural drainage after cardiac surgery is accomplished through the
intercostal space and the divided parietal pleural, often causing severe
additional chest pain. To circumvent this route of insertion a doubly angled
polyvinyl chloride drain was developed which can be placed via the median
approach through the rectus abdominis muscle just beside the anterior mediastinal
drains without irritation of the heart and parietal pleura into the phrenico
costal sinus.
PMID- 9402675
TI - Surgical treatment of aortic root abscess with damage of the mitral valve
apparatus.
AB - A 35-year-old man with an aortic root abscess successfully underwent aortic valve
replacement and mitral valve repair using a prosthetic valve with a skirt which
was secured to the sewing cuff. This is a useful technique for reinforcement of a
fragile annulus and prevention of annular detachment. A further useful technique
is to infuse normal saline from a Foley catheter inserted into the aortic root to
estimate mitral valve coaptation.
PMID- 9402676
TI - Three-dimensional contrast-enhanced MR angiography.
AB - Three-dimensional contrast-enhanced magnetic resonance (MR) angiography is a
relatively new technique that uses the transient shortening in blood T1 following
the intravenous injection of gadolinium chelates to image blood vessels
irrespective of flow. For many applications, 3D contrast-enhanced MR angiography
is developing into a safe, fast, and cost-effective alternative to conventional
diagnostic angiography. One of its biggest advantages over other MR angiography
techniques (and CT angiography) is the ability to image in a plane parallel to
the vessel of interest. This feature, combined with the inherent properties of a
3D gradient refocused sequence, make 3D contrast-enhanced MR angiography
intrinsically fast, high resolution and free from saturation and turbulence
related artifacts. This article is designed to familiarize the reader with the
theory of 3D contrast-enhanced MR angiography and the application of the
technique to different vascular territories. Contrast agents, relaxation effects,
contrast bolus effects, pulse sequences, artifacts, and post-processing, as well
as the present state of thinking with regard to optimal contrast injection
timing/detection and Fourier space mapping are discussed. Patient preparation and
techniques and imaging parameters for body applications of gadolinium-enhanced MR
angiography, including aorta, renal arteries, mesenteric arteries, portal venous
system, pelvis and legs, pulmonary arteries, and carotid arteries are included.
PMID- 9402677
TI - MR angiography of the head and neck.
AB - A review of the basic physics and techniques for acquiring and evaluating
magnetic resonance angiograms is provided, including time-of-flight and phase
contrast techniques. Magnetic resonance (MR) angiography is becoming a routine
method of evaluating carotid bifurcation atherosclerotic disease in both a
screening and diagnostic capacity. The expanding clinical utility of MR
angiography in the detection of intracranial aneurysms, characterization of
arteriovenous malformations, and evaluation of intracranial atherosclerotic
disease are also reviewed. Furthermore, MR angiography allows for the noninvasive
diagnosis of arterial dissection. Magnetic resonance venography also allows the
confirmation of the previously elusive and likely underdiagnosed entity of
cerebral venous thrombosis.
PMID- 9402678
TI - MR angiography with three-dimensional MR digital subtraction angiography.
AB - We have developed a time-resolved, contrast-enhanced, volume-imaging technique
for magnetic resonance (MR) angiography, known as three-dimensional (3D) MR
digital subtraction angiography (DSA). This technique greatly improves MR
angiogram quality because it combines the injection of a contrast agent with the
ability to image the temporal passage of this agent and, thereby, obviates the
need for timing scans or other complicated synchronization schemes. Three
dimensional MR DSA also represents a potential improvement in the sense that,
relative to DSA and computed tomography (CT) angiography, the contrast agent is
less toxic. Additionally, unlike CT angiography, images may be acquired during
the passage of the contrast agent. Therefore, 3D MR DSA shows the sequential
passage of contrast through the arterial and venous system, followed by uptake in
various organs. Unlike conventional DSA, 3D MR DSA imaging acquires full volume
datasets, which allows subsequent reprojection and reformatting. Because images
are obtained at approximately 2-6 s time intervals using a temporal aperture on
the order of several seconds, motion (such as respiration) causes only a
temporary disruption of image quality, similar to that observed in MR
fluoroscopy. These temporal characteristics also make the proposed sequence
insensitive to variations in the shape and timing of the contrast-pass curve.
Although the individual time-resolved images will have somewhat decreased signal
to-noise ratio (SNR) relative to nontime-resolved scans collected in the same
acquisition time, the SNR improvement due to the gadolinium appears to
accommodate this trade-off. Additionally, if motion between successive images is
small, then the full suite of temporal processing schemes, previously
investigated in connection with DSA and time-resolved two-dimensional (2D) MR,
such as mask mode subtraction, simple matched filtering and Eigen filtering, can
be used to obtain composite images. These derived images generally have an
increased SNR or negligible venous signal if an arterial-phase image is not
obtained in the early time-resolved images. In summary, 3D MR DSA will
significantly advance MR angiography because of the following intrinsic
advantages: (1) improved signal-to-noise, (2) scan orientation may be chosen
independently of the direction of blood flow, (3) uniform vascular signal, even
from regions of complex flow, (4) minimization of motion artifacts, (5) greatly
reduced sensitivity to variation in the shape and timing of the contrast bolus,
(6) ability to be reformatted or reprojected, and (7) ability to apply a variety
of temporal postprocessing techniques.
PMID- 9402679
TI - Fluid-attenuated inversion recovery (FLAIR): clinical prospectus of current and
future applications.
AB - A relative weakness of the traditional spin-echo technique, and particularly of
the newer "FAST" or "TURBO" spin-echo sequences, has been diminished
conspicuousness of lesions affecting the peripheral cortical mantle or those
located in the periventricular region. This is a consequence of partial volume
effects and high cerebrospinal fluid (CSF) signal adjacent to pathologic regions.
Fluid-attenuated inversion recovery (FLAIR) is a magnetic resonance imaging (MRI)
sequence that produces strong T2 weighting, suppresses the CSF signal, and
minimizes contrast between gray matter and white matter. This effect produces
images with significantly increased lesion-to-background CSF contrast and
enhances the visibility of lesions as well as their detectability, particularly
in the peripheral subcortical and periventricular regions. Applications are
evolving, though preliminary reports highlight the superiority of FLAIR in the
evaluation of infarction, multiple sclerosis, metastatic disease, tuberous
sclerosis, and, possibly, subarachnoid hemorrhage. Early reports also address the
application of FLAIR to imaging of the spinal cord. Modified versions of FLAIR
are currently being developed; these modifications will further shorten
acquisition times and eliminate pulsation artifacts. FLAIR may ultimately
supplant conventional spin-echo imaging in routine MR screening of the brain.
PMID- 9402680
TI - Concerns regarding the current paradigm for chronic allograft rejection.
PMID- 9402681
TI - Role of macrophages in vascular tissue remodelling.
PMID- 9402682
TI - Cell-cell interactions in vessel assembly: a model for the fundamentals of
vascular remodelling.
PMID- 9402683
TI - Extracellular matrix modulation of vascular cell behaviour.
PMID- 9402684
TI - Apoptosis in vascular disease.
PMID- 9402685
TI - Cytokine mRNA expression in tolerant heart allografts after immunosuppression
with cyclosporine, sirolimus or brequinar.
AB - We sought to examine the impact of the preferential activation of Th2 cells on
the induction and maintenance of a tolerant state in heart allograft rat
recipients treated with a short course of cyclosporine (CsA), sirolimus (SRL) or
brequinar (BQR). A quantitative polymerase chain reaction (PCR) method was used
to measure the levels of cytokine mRNAs, namely interferon (IFN)-gamma and
interleukin (IL)-2 in T helper 1 (Th1) cells and IL-4, IL-5 and IL-10 in Th2
cells. Our main findings were that on day 5 postgrafting allografts from
untreated recipients had increased levels of IFN-gamma (216 +/- 119 fg), IL-2
(449 +/- 75 fg), IL-4 (6.2 +/- 1.3 fg), IL-5 (34.8 +/- 9.3 fg) and IL-10 (1554 +/
184 fg) mRNAs compared with normal hearts. CsA reduced the levels of IFN-gamma,
IL-2, IL-5 and IL-10, but not IL-4, mRNAs. SRL did not affect the expression of
cytokine mRNAs. BQR decreased the levels of IFN-gamma, IL-2 and IL-10, but not IL
5 or IL-4 mRNAs. Compared with grafts from untreated recipients, those from CsA-
or BQR-treated tolerant hosts (day 100) displayed undetectable IL-2 mRNA levels,
and reduced levels of IFN-gamma, IL-4 and IL-10 mRNAs. In fact, the patterns of
cytokine mRNA expression in grafts from CsA- and BQR-treated tolerant hosts were
similar to those of normal hearts. Grafts from SRL-treated tolerant hosts merely
showed slightly increased Th2 cell activity. In conclusion the selective
activation of Th2 cells is not absolutely required for induction or maintenance
of tolerance.
PMID- 9402686
TI - Interleukin-12 p40 m-RNA expression in human kidney allograft biopsies.
AB - Interleukin-12 (IL-12) is a heterodimeric cytokine implicated in the early
differentiation of naive T-lymphocytes into the Th1 subset. IL-12 is important
for induction of the cellular immune response against viruses, intracellular
parasites and neoplasms. Its role in alloresponsiveness has not been fully
elucidated. Preliminary data in the literature point toward the prevalence of Th1
lymphocytes in processes of allograft rejection. In attempt to further
investigate the expression of this cytokine during episodes of cellular rejection
of renal allografts, we searched for IL-12 message in human kidney allograft
biopsies using the reverse transcriptase-polymerase chain reaction technique.
Twenty-three allograft core biopsies from 19 patients were obtained
percutaneously for clinical indications in 18 cases, and as part of an
investigational protocol in five cases. A portion of the tissue was used for RNA
extraction using the guanidium-thiocyanide phenol-chloroform method. Histology
was performed on the remaining core material. Ten mg of total RNA were used for
reverse transcription. PCR of the c-DNAs was done for 40 cycles using primers for
the p40 subunit of IL-12 and GAPDH which was used as a control. PCR products were
photographed after electrophoresis, transferred to a nylon membrane and
hybridized with a radiolabelled cloned human IL-12 p40 1 kb c-DNA fragment.
Autoradiographies were developed after 20-min exposure. All samples were run in
triplicate. IL-12 p40 m-RNA was expressed in all 17 biopsies showing acute
cellular rejection as well as in all three biopsies showing focal interstitial
fibrosis. No message was found in the presence of normal allograft histology.
This is the first in vivo report of IL-12 p40 subunit m-RNA expression during
renal allograft rejection in humans. The role of this Th1 cytokine in the
alloresponse deserves further investigation.
PMID- 9402687
TI - Single dose anti-CD4 monoclonal antibody for induction of tolerance to cardiac
allograft in high- and low-responder rat strain combinations.
AB - Repeated administration of monoclonal antibodies (mAb) directed against the CD4
lymphocyte receptor may induce specific, long-lasting unresponsiveness to fully
MHC-mismatched cardiac allografts in rats without additional immunosuppression.
We assessed the effect of a single dose of murine anti-rat depleting anti-CD4 mAb
(OX-38) on allograft survival in high- and low-responder rat strain combinations.
Isogenic strains of DA (RT1av1), PVG (RT1c), AUG (RT1c), and WF (RT1u) rats were
used. Recipients in antibody treated groups were given one dose of 5 mg/kg OX-38
mAb on the day of transplant, a dose which was shown to effectively deplete (or
block) circulating CD4+ T cells. Other groups were treated for 10 days with
cyclosporin A (CsA) and/or Linomide, a novel immunomodulator, which is the first
compound able to fully eliminate the effect of CsA in the rat cardiac allograft
model. The DA strain was identified as a low-responder to the allogeneic
haplotype RT1c (PVG or AUG), but not to RT1u (WF), and developed true tolerance
following RT1c grafting and OX-38 or low-dose CsA (5 mg/kg) induction, as
verified by the response to retransplantation of a graft from the same donor
strain or a third-party challenge. PVG recipients of DA grafts were characterized
by high response and only modest (OX-38; median 9.5 days) or moderate (CsA; 23.5
days) prolongation of graft survival. Contrasting graft survival results were
obtained in the low-responder combination, either very early rejection (at 10
days) or permanent graft survival (> 100 days). Linomide challenge affected CsA
treatment in the high-responder combination but not tolerance induction in the
low-responder combination, or the effect of OX-38. It was concluded that in rat
heart transplantation a single-dose anti-CD4 mAb therapy may induce permanent
donor-specific unresponsiveness in a low-responder strain combination, and that
anti-CD4 mAb seems to be unique among immunosuppressive agents while being
resistent to challenge by Linomide.
PMID- 9402689
TI - Serum soluble human leucocyte antigen class I in paediatric liver transplantation
with live, related donors.
AB - Serum soluble human leucocyte antigen (HLA) class-I is a useful marker for
predicting immunological events in organ transplantation. In cadaver liver
transplant cases it is especially the case that high amounts of soluble HLA-I are
excreted from the grafts. In Japan, almost all liver transplants have been
performed from living parent donors to their children. Therefore, it is
interesting to know how soluble HLA-I changes in relation to clinical course. As
part of this study we first examined serum concentrations of soluble HLA-I in 33
paediatric patients using enzyme-linked immunosorbent assay. Soluble HLA-I is
composed of three different sized molecules (45, 39 and 34-36 kDa); then the
change of distribution of these three molecules was demonstrated by Western blot
analysis. When donor and recipient have different soluble HLA-I band patterns,
the origin of the antigen can be assumed by this method. We found that in a
comparison between pre- and post-transplants, the six out of eight (75%) patients
that suffered episodes of acute rejection showed a significant elevation of
soluble HLA-I, and all patients with infectious episodes had an elevated soluble
HLA-I. Meanwhile, 10 out of 22 (45%) patients without any clinical complications
still showed increased soluble HLA-I. The Western blot analysis showed that the
soluble HLA-I molecules were considerably derived from the grafted liver, from
one week to 24 months after grafting. In acute rejection, the band signals of
donor origin were significantly increased. These signals were attenuated after
immunosuppressive therapy. The grafted liver appears to contribute to the
increase of soluble HLA-I following liver transplantation, and this increase is
greater with the effects of the host immune system.
PMID- 9402690
TI - Unexpected augmentation of mycophenolic acid pharmacokinetics in renal transplant
patients receiving tacrolimus and mycophenolate mofetil in combination therapy,
and analogous in vitro findings.
AB - Mycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been
approved for clinical use (CellCept) in renal transplant patients in combination
with cyclosporine (CsA). With the expanded use of tacrolimus (Prograf) as well in
renal transplant patients, there is a lack of pharmacokinetic studies clarifying
drug interactions between the three agents. A pharmacokinetic study was performed
on 18 stable renal transplant patients receiving MMF and tacrolimus together, and
four control groups, one receiving tacrolimus alone, two receiving CsA, in
combination with MMF (1.0 or 1.5 g bid), and one receiving CsA microemulsion
(Neoral). Area-under-the-curve values were calculated for each drug to assess if
there was a reciprocal effect on the respective bioavailability of each. In
vitro, the immunosuppressive effect of trough level plasma from each patient
group was studied using mixed lymphocyte culture (MLC), as well as MLC reactions
spiked with various combinations of each drug. There was a minimal effect of MMF
on tacrolimus pharmacokinetics. However, patients receiving tacrolimus and MMF
displayed significantly higher levels (Cmin and area under the curve) of
mycophenolic acid (MPA) than those receiving CsA (Sandimmune or Neoral) and the
same dose of MMF (50.2 +/- 16.5 vs 32.1 +/- 16.7 micrograms h/ml AUC, p < 0.02).
Equivalent MPA levels could be attained in patients receiving CsA if the MMF dose
was increased by 50% (1.5 g bid). There were also significantly lower levels of
the glucuronide metabolite of MPA (MPAG) (755 +/- 280 vs 1230 +/- 250 micrograms
h/ml AUC, p = 0.02), suggesting a specific inhibition (either direct or indirect)
of the conversion of MPA to MPAG in tacrolimus patients, as opposed to those
receiving CsA. For each drug combination, there was a positive correlation
between the plasma immunosuppressive effect seen in MLC assays and the MMF dose.
In addition, trough plasma from patients receiving tacrolimus and MMF was
significantly more MLC inhibitory than from those receiving CsA or CsA
microemulsion and equivalent-dose MMF. Culture media containing MPA and
tacrolimus equal to clinical therapeutic trough concentrations (10 ng/ml) were
significantly more MLC inhibitory than CsA at equivalent clinical therapeutic
trough concentrations (200 ng/ml) with equivalent MPA levels. These studies in
renal transplant patients suggest that tacrolimus in combination with MMF may
result in a greater degree of immunosuppression than may be anticipated.
PMID- 9402691
TI - Antigen presentation by endothelium: heparin reduces the immunogenicity of
interferon-gamma-treated endothelial cells.
PMID- 9402688
TI - The role of natural anti-Gal alpha 1-3Gal antibodies in hyperacute rejection of
pig-to-baboon cardiac xenotransplants.
AB - Xenoreactive natural antibodies in humans and higher primates are directed
predominantly at Gal alpha 1-3Gal. These antibodies are thought to initiate
hyperacute rejection of porcine organ xenografts. The contribution of anti-Gal
alpha 1-3Gal antibodies to the xenoractive natural antibody repertoire and to the
initiation of hyperacute rejection was tested in a pig-to-baboon cardiac
xenograft model. Anti-Gal alpha 1-3Gal antibodies were depleted from baboons by
extracorporeal absorption of anti-Gal alpha 1-3Gal antibodies from plasma using
columns with a matrix bearing Gal alpha 1-3Galb1-4GlcNAc. Specific removal of
anti-Gal alpha 1-3Gal antibodies was achieved prior to transplantation as
demonstrated by immunoassay. Porcine hearts were then transplanted into these
baboons and the outcome of the transplants was analysed. Immunofluorescence
revealed little deposition of baboon antibodies in the grafts. The porcine hearts
did not undergo hyperacute rejection even though complement activity was
approximately 90% of baseline at the time of transplantation. These findings
demonstrate that anti-Gal alpha 1-3Gal antibodies constitute a major fraction of
xenoreactive natural antibodies in primate blood and that these antibodies
contribute significantly to the pathogenesis of hyperacute xenograft rejection.
PMID- 9402692
TI - Production of IL-2 by hepatocytes in allografted liver of rats.
PMID- 9402693
TI - Understanding the epidemiology of BSE.
PMID- 9402694
TI - Multiple myeloma and Kaposi's sarcoma-associated herpesvirus--a paracrine model
of tumorigenesis?
PMID- 9402695
TI - To be a mutator, or how pathogenic and commensal bacteria can evolve rapidly.
PMID- 9402696
TI - Mycobacterium tuberculosis: beyond genome sequencing.
PMID- 9402697
TI - Pathogenicity islands: important but not unique factors contributing to
Salmonella virulence.
PMID- 9402698
TI - Toxins or signals in Dutch elm disease pathogenesis.
PMID- 9402699
TI - Developmental biology of biofilms: implications for treatment and control.
AB - Although of heterogeneous spatiotemporal and species compositions, all biofilms
undergo certain common developmental events: organic molecules on the substratum
can play a role in initial attachment, attached cells grow and additional cells
attach from the bulk liquid. Biofilm growth is a four-dimensional (X, Y, Z and T)
process similar to organ development.
PMID- 9402700
TI - How rolling circle plasmids control their copy number.
AB - Rolling circle DNA replication is inherently continuous and unregulated. This 'go
for-broke' strategy works well for lytic phages but is suicidal for plasmids that
must coexist with their host. Plasmids have consequently evolved elaborate copy
number control systems that operate at the transcriptional, translational and
post-translational levels.
PMID- 9402701
TI - Why are hepadnaviruses DNA and not RNA viruses?
AB - Virion assembly in hepadnaviruses is a two-step process leading to (1) the
packaging of viral pregenomic RNA and reverse transcriptase into nucleocapsids
and (2) the assembly of nucleocapsids with envelope components, which results in
the formation of mature virus particles. Characteristically, both steps are
intimately coupled to viral DNA synthesis. While assembly of nucleocapsids is
coupled to the protein priming of reverse transcription, virion formation is
linked to genome maturation.
PMID- 9402702
TI - Filamentous growth in budding yeast.
AB - The recent discovery that some laboratory strains of Saccharomyces cerevisiae are
capable of limited filamentous growth has stimulated genetic analysis of
dimorphism in this microorganism. The puzzle of why most strains are
nonfilamentous is now resolved. Remarkably, a single point mutation with broad
consequences separates these domesticated yeast from their wild ancestors.
PMID- 9402703
TI - Are bacterial exotoxins cytokine network regulators?
AB - Bacterial exotoxins are generally thought to act by damaging cells or altering
cell metabolism. However, recent work has established that many exotoxins
modulate eukaryotic cell cytokine synthesis. Cytokine induction may play a
significant role in exotoxin action, and therapeutic targeting of cytokines could
be beneficial in infectious diseases involving bacterial exotoxins.
PMID- 9402704
TI - White collar proteins: PASsing the light signal in Neurospora crassa.
AB - The filamentous fungus Neurospora crassa is an excellent paradigm for the study
of blue light signal transduction. The isolation and characterization of the
genes for two central regulators of the blue light response, white collar-1 and
white collar-2, have begun to shed light on the mechanism of blue light signal
transduction in fungi. These proteins are not only proposed to encode blue-light
activated transcription factors but also to be elements of the blue light signal
transduction pathway.
PMID- 9402705
TI - Correlation between thoracic radiographic changes and remission/survival duration
in 270 dogs with lymphosarcoma.
AB - A retrospective study was undertaken wherein the medical records and thoracic
radiographs of 270 dogs with lymphosarcoma were reviewed to determine the type
and frequency of thoracic radiographic changes. Statistical evaluation of the
relationship between radiographic, clinical and immunologic factors and the
primary remission duration and survival times was performed using univariate and
multivariate analysis. One hundred ninety-two dogs (71%) had some type of
thoracic radiographic abnormality, including 80 dogs (29.6%) with pulmonary
infiltrates and 164 dogs (64.4%) with thoracic lymphadenomegaly. Only T-cell
phenotype (p = 0.0056 for survival, p = 0.0045 for remission) and the presence of
cranial mediastinal lymphadenomegaly (p = 0.0005 for survival, p = 0.0129 for
remission) were identified as having a significant negative correlation to both
primary remission and survival duration by multivariate analysis.
PMID- 9402706
TI - Radiographic imaging of otitis media and interna in pigs.
AB - Middle and inner ear infections have been reported as a clinical entity in swine,
other animal species and humans. In pigs, the anatomical-pathological and
microbiological findings have been described. In this report, we describe
radiographic findings in affected pigs. A total of 25 pigs with a head tilt and
circling, as clinical signs of otitis media and interna, were examined. The
majority were weaner-pigs with dyspnea or rhinitis. In radiographs, there was an
increased opacity of the bulla tympanica, often accompanied by marginal
destruction or thickening of the bulla wall. The radiographic findings confirmed
the clinical diagnosis in each affected pig, but there were 5 false positive
interpretations.
PMID- 9402707
TI - Computed tomographic evaluation of comminuted middle phalangeal fractures in the
horse.
AB - Comminuted fractures of the middle phalanx have been well described in the horse.
Choice of treatment, surgical planning and prognosis have traditionally been
based upon evaluation of radiographs. However, the complex nature of comminuted
fractures makes radiographic interpretation difficult. Computed tomography (CT)
allows the production of cross-sectional images with spatial separation of
structures which are superimposed on survey radiographs. This allows accurate
assessment of the number and direction of fracture lines within the bone. In this
paper we report the use of CT in the evaluation of 6 comminuted middle phalangeal
fractures. Computed tomography is potentially useful in deciding the type of
treatment, surgical planning and determining the prognosis.
PMID- 9402708
TI - Magnetic resonance imaging of the lateral ventricles in beagle-type dogs.
AB - Magnetic resonance (MR) imaging was performed on 21 presumed normal Beagle-type
dogs. The size and symmetry of their lateral ventricles were evaluated and dogs
were categorized on the basis of the percentage of their ventricular height (Vh)
to brain height (Bh) and the ratio of the largest to the smallest ventricular
area (rVA). Eleven dogs had lateral ventricles classified as normal sized (0-14%
Vh/Bh) while 10 of 21 dogs had moderate enlargement (15-25% Vh/Bh) of one or both
lateral ventricles. None of the dogs had severe lateral ventricular enlargement.
Degree of asymmetry was also arbitrarily categorized on basis of rVA as normal to
minimal (rVA < 1.5), mild (1.5 < rVA < 2.0), or severe (2.0 < rVA). Of the dogs
having normal-sized lateral ventricles, six of eleven had symmetric, three of
eleven had mildly asymmetric and two of eleven had severely asymmetric lateral
ventricles. Of the dogs having at least one moderately enlarged lateral
ventricles, five of ten had symmetric lateral ventricles, and two of ten had mild
asymmetry and three of ten had severe asymmetry. Gender and body weight had no
statistical relationship to lateral ventricle symmetry. Clinically insignificant
ventricular enlargement and asymmetry was common in this group of Beagle dogs.
PMID- 9402709
TI - Radiographic diagnosis: arachnoid cyst in a dog.
PMID- 9402710
TI - Quantification of cerebral ventricular volume in English bulldogs.
AB - Quantitative measurement of cerebral ventricle volume of eight English bulldogs
was performed using magnetic resonance (MR) imaging. The mean ventricular volume
was 14.8 ml. with a range of 8.6 ml.-38.1 ml. The mean ventricular volume of two
beagles was 2.2 ml with a range of 0.7 ml.-3.7 ml. The percent of intracranial
volume occupied by ventricle was found to be significantly larger in bulldogs
(14.0%; S.D. = 7.9%) than in beagles (Range = 1.0-4.8%). The relationship between
the percent of intracranial volume occupied by ventricle and measurements of body
weight, age, sex, and various measures of skull anatomy of the bulldog was also
determined. The relationship between ventricular volume and neurologic
dysfunction was examined. There was a possible trend between high percent of
intracranial volume occupied by ventricle and low body weight. This study will
serve as a pilot study for examining the relationship between ventricular volume
and neurologic disease in bulldogs.
PMID- 9402711
TI - Appearance of canine abdominal tumors with magnetic resonance imaging using a low
field permanent magnet.
AB - The study was carried out to evaluate the applicability of magnetic resonance
imaging (MRI) in detecting tumors in the abdomen of the dog. Abdominal ultrasound
and MRI were performed on 8 dogs having a mass lesion on abdominal radiography.
MR images were obtained in the transverse, sagittal and dorsal planes using T1-
and T2-weighted spin echo pulse sequences. There was good visual correlation of
the lesion site by MRI and ultrasonography (US).
PMID- 9402712
TI - Retrospective ultrasonographic evaluation of adrenal lesions in 26 dogs.
AB - A review was performed of ultrasonographic findings in 26 dogs with confirmed
adrenal lesions. Adrenal shape, size, echogenicity, laterality, and the presence
of vascular invasion were evaluated. Histopathologic diagnoses were obtained in
all dogs. Adrenal lesions were confirmed as pheochromocytomas (9),
adenocarcinomas (6), a poorly differentiated blastoma (1), bilateral adrenal
metastases of a carcinoma (1), adenomas--one of which was bilateral--(4) and
hyperplasia (6). Size and shape were extremely variable and not specific to
lesion type. There was a tendency for pheochromocytomas (7), adenocarcinomas (5)
and poorly differentiated blastoma (1) to be rounded masses. Adenomas (4),
hyperplasia (7) and adrenal metastases (2) presented predominantly as nodules. No
specificity in echogenicity was noted. Mineralization and bilaterality were
present in both benign and malignant lesions. Vascular extension or the presence
of a thrombus were suggestive but not specific signs of malignancy. Based on our
preliminary study, ultrasonography is an effective method for localizing adrenal
lesions and is helpful in assessing their extension. However, no definitive
differentiation between benign and malignant lesions was possible using
ultrasonographic criteria alone.
PMID- 9402713
TI - Peripheral neuroblastoma in a dog.
AB - Primitive neuroectodermal tumors are composed of primitive neuroepithelial cells
and include tumors of the central and peripheral nervous system. Neuroblastoma,
medulloblastoma and retinoblastoma are examples of these rare malignant tumors
that usually occur in young patients. This report describes a peripheral
neuroblastoma in a 2 year old Boxer that presented with signs of renal disease
and a palpable abdominal mass. The purpose of this paper is to describe the
clinical presentation, imaging and immunohistological studies of this abdominal
tumor in a young dog and to review the literature.
PMID- 9402714
TI - High-resolution parathyroid sonography.
AB - The purpose of this study was to assess the diagnostic utility of parathyroid
ultrasonography to differentiate causes of hypercalcemia in dogs. We analyzed
qualitative and quantitative ultrasound imaging findings and clinical pathology
data from 33 dogs that underwent parathyroid ultrasound examination as part of
the diagnostic evaluation for hypercalcemia. Diagnoses of the diseases causing
hypercalcemia included parathyroid carcinoma (n = 5), parathyroid adenoma (n =
15), parathyroid adenomatous hyperplasia (n = 6), chronic renal insufficiency (n
= 3), and hypercalcemia of malignancy (n = 4). All parathyroid lesions were round
or oval and hypoechoic compared with surrounding thyroid parenchyma. Adenomatous
and adenocarcinomatous glands were 4 mm or larger in longest linear measurement
on US examination and were statistically significantly larger than hyperplastic
glands. (p < 0.001) Linear measurements of parathyroid glands acquired at the
time of ultrasound examination correlated well with direct size determination
after surgical excision. (r2 = 0.9, p < 0.0001) Parathyroid lesions > or = 4 mm
are highly suspicious for parathyroid adenoma or carcinoma, while US lesions < 4
mm most likely represent primary adenomatous hyperplasia or secondary parathyroid
hyperplasia. Parathyroid size estimation from ultrasound examination is an
accurate predictor of true size.
PMID- 9402715
TI - Ultrasound diagnosis: left ventricular thrombus in a cat with hypertrophic
cardiomyopathy.
PMID- 9402716
TI - The effect of intravenous diazepam on solid phase gastric emptying in normal
cats.
AB - Intravenous diazepam has been advocated as an appetite stimulant in anorexic
cats. Diazepam has also been used to stimulate the intake of radiographic
contrast medium-food mixture to determine the gastric emptying time of a solid
meal. Diazepam has been suspected to delay gastric emptying in cats. One study
found diazepam combined with valium to have little effect on gastric transit
times in cats while diazepam alone accelerates gastric emptying in humans. The
purpose of this study was to determine if diazepam influences gastric emptying
times in normal cats. The gastric emptying half-time of solid food in normal, non
diazepam treated cats has been previously determined using a scintigraphic
technique using 99mTc-sulfur colloid to radiolabel solid dry food. The median
gastric emptying half-time was 2.3 hours and the mean meal size was 16.1 grams.
Gastric emptying half-times were determined in this study using diazepam as an
appetite stimulant. The median gastric emptying half-times of diazepam treatment
groups given both a 16.1 gram meal and a large meal were both significantly
longer than the normal non-treated group (P < 0.05). Solid phase gastric emptying
is therefore significantly delayed when diazepam is used as an appetite
stimulant, irrespective of the volume of the meal.
PMID- 9402718
TI - Subdural collection of contrast medium during cervical myelography.
PMID- 9402717
TI - Slow release cisplatin combined with radiation for the treatment of canine nasal
tumors.
AB - Thirteen dogs with malignant tumors of the nasal cavity were treated with a
combination of slow release cisplatin and megavoltage radiation. Radiation was
delivered on a Monday through Friday schedule using a 6 MV linear accelerator.
The median total dose was 49.5 Gy (range 49.5-56 Gy). Cisplatin was given using
an open-cell polylactic acid polymer, impregnated with the drug and implanted
intramuscularly at a distant site, as a slow release delivery system (OPLA-Pt
[THM Biomedical, Inc]). The median dose used was 60 mg/m2 (range 60-100 mg/m2).
When combined with radiation, this delivery system caused no systemic drug
toxicity, and a local tissue reaction was seen in only two dogs. Acute side
effects to normal tissue from radiation were not enhanced, as measured by
subjective assessment. When compared to a group of historical controls that
received radiation without OPLA-Pt, the dogs that received combined radiation and
cisplatin had longer overall survival times, with a median of 580 days. The
control group had a median survival of 325 days. Previously reported median
survival times for comparable megavoltage radiation treatment range from 6 to 13
months. Some dogs in both groups also received adjubant chemotherapy but this did
not influence survival time. By multivariate analysis, only the use of OPLA-Pt
was found to significantly influence survival, with a p value of p = 0.023. Mega
voltage radiation and slow release cisplatin appears to be a well tolerated
combination that may favorably affect survival of dogs with nasal tumors.
PMID- 9402719
TI - Comparison of histology with maternal and fetal serology for the diagnosis of
abortion due to bovine neosporosis.
AB - An indirect fluorescent antibody test was applied to sera from normally calving
and aborting cows and to samples of pleural fluid from their aborted calves, and
the antibody titres were compared with histology and immunocytochemistry for the
diagnosis of Neospora-associated abortion. Two groups of aborting cows and a
third group of cows which had calved normally were used; group A consisted of 36
cows which aborted calves showing characteristic non-suppurative inflammatory
lesions in which Neospora was demonstrated by immunocytochemistry, group B
consisted of 100 cows which aborted calves without histological evidence of
neosporosis, and group C consisted of 128 normally calved cows which were sampled
within one month of calving. Serology on the maternal sera and fetal fluids was
highly specific and sensitive for Neospora infection although 5 per cent of the
cows which aborted Neospora-negative calves and 4.7 per cent of the normally
calved cows were also seropositive. Anti-Neospora antibodies were also detected
in 7 per cent of the samples of fetal fluid from Neospora-negative abortions.
PMID- 9402720
TI - Gross and ultrasonographic anatomy of the carpal flexor tendon sheath in horses.
AB - This study was undertaken to establish the gross anatomy and the ultrasonographic
appearance of the carpal digital flexor tendon sheath (carpal sheath) and the
palmar carpal region in normal horses. The isolated forelimbs from 15 horses were
used to study the morphology of the sheath and associated structures, including a
detailed study of the location of the main blood vessels and nerves in that
region. These limbs and the forelimbs of five live, sound horses were also
examined ultrasonographically. The examination yielded good soft tissue detail of
the tendons and ligaments, synovial and perisynovial tissues and larger blood
vessels. There was a good correlation between the ultrasonographic and gross
anatomical appearance of the limbs. The sheath cavity was only identified after
it had been distended with water, and the various synovial recesses at the level
of the carpal canal were poorly imaged.
PMID- 9402721
TI - Canine dysautonomia resembling the Key-Gaskell syndrome in Germany.
PMID- 9402722
TI - Appearance of acute PRRS-like symptoms in sow herds after vaccination with a
modified live PRRS vaccine.
PMID- 9402723
TI - Morantel resistance by Haemonchus placei in cattle.
PMID- 9402724
TI - Beef exports: looking for an opening.
AB - BSE, food safety and the veterinarian's role in certification were among matters
discussed by the BVA's President, Mr Ted Chandler, at a speech in Ballymena on
October 29. Speaking at the BVA's Northern Ireland dinner, at which
representatives of Government, local veterinary associations, the farming
community and other organisations were present, Mr Chandler emphasised the need
for the Government to recognise the veterinary profession's vital contribution to
food hygiene and its pivotal role in ensuring that standards are maintained. The
main text of his speech is given here.
PMID- 9402725
TI - Availability of medicines.
PMID- 9402726
TI - Foxes and neosporosis.
PMID- 9402727
TI - Salmonella typhimurium DT104 in the northeast USA.
PMID- 9402728
TI - Equine foot care in an arid environment.
PMID- 9402729
TI - Equine headshaking survey.
PMID- 9402730
TI - Evolutionary dynamics of tandem repeats in the mitochondrial DNA control region
of the minnow Cyprinella spiloptera.
AB - Length variation due to tandem repeats is now recognized as a common feature of
animal mitochondrial DNA; however, the evolutionary dynamics of repeated
sequences are not well understood. Using phylogenetic analysis, predictions of
three models of repeat evolution were tested for arrays of 260-bp repeats in the
cyprinid fish Cyprinella spiloptera. Variation at different nucleotide positions
in individual repeats supported different models of repeat evolution. One set of
characters included several nucleotide variants found in all copies from a
limited number of individuals, while the other set included an 8-bp deletion
found in a limited number of copies in all individuals. The deletion and an
associated nucleotide change appear to be the result of a deterministic, rather
than stochastic, mutation process. Parallel origins of repeat arrays in different
mitochondrial lineages, possibly coupled with a homogenization mechanism, best
explain the distribution of nucleotide variation.
PMID- 9402731
TI - The Bag320 satellite DNA family in Bacillus stick insects (Phasmatodea):
different rates of molecular evolution of highly repetitive DNA in bisexual and
parthenogenic taxa.
AB - The Bag320 satellite DNA (satDNA) family was studied in seven populations of the
stick insects Bacillus atticus (parthenogenetic, unisexual) and Bacillus grandii
(bisexual). It was characterized as widespread in all zymoraces of B. atticus and
in all subspecies of B. grandii. The copy number of this satellite is higher in
the bisexual B. grandii (15%-20% of the genome) than in the parthenogenetic B.
atticus (2%-5% of the genome). The nucleotide sequences of 12 Bag320 clones from
B. atticus and 17 from B. grandii differed at 13 characteristic positions by
fixed nucleotide substitutions. Thus, nucleotide sequences from both species
cluster conspecifically in phylogenetic dendrograms. The nucleotide sequences
derived from B. grandii grandii could be clearly discriminated from those of B.
grandii benazzii and B. grandii maretimi on the basis of 25 variable sites,
although all taxa come from Sicily. In contrast, the Bag320 sequences from B.
atticus could not be discriminated accordingly, although they derive from
geographically quite distant populations of its three zymoraces (the Italian and
Greek B. atticus atticus, the Greek and Turkish B. atticus carius, and the
Cyprian B. atticus cyprius). The different rate of evolutionary turnover of the
Bag320 satDNA in both species can be related to their different modes of
reproduction. This indicates that meiosis and chromosome segregation affect
processes in satDNA diversification.
PMID- 9402732
TI - Determination of the entire sequence of turtle CR1: the first open reading frame
of the turtle CR1 element encodes a protein with a novel zinc finger motif.
AB - CR1 elements are a family of retroposons. They are classified as long
interspersed elements (LINEs) or non-long-terminal-repeat (non-LTR)
retrotransposons, and they have been found in the genomes of many vertebrates.
However, they have been only partially characterized, and only a 2-kb region of
the 3' end of chicken CR1 has been sequenced. In the present study, we determined
the entire consensus sequence of CR1 elements in the turtle genome, designated
PsCR1. The first open reading frame (ORF1) of PsCR1 has two unusual arrangements
of Cys residues. One of them includes a zinc finger motif, CX2CX14CX2C. The
putative zinc finger has cysteine residues with identical spacing and a similar
amino acid composition to those found in the species-specific transcription
initiation factors SL1 and TIF-IB. The 5' untranslated region (5' UTR) of PsCR1
contains a sequence similar to part of the human L1 promoter, L1 site A, and
several cis elements of the type found in eukaryotic genes. Within a region of
about 500 bp, there are nine "E boxes," cis elements that are recognized by the
basic helix-loop-helix (bHLH) family of proteins. This observation raises the
possibility that cellular transcription factors that bind to these sequences
might act in concert to regulate the expression of PsCR1. The extent of the
sequence divergence of the 3' UTR of CR1 between species was found to be lower
than the rate of nonsynonymous substitutions per site in ORF2, suggesting that a
strict functional constraint must exist for this region. This result strongly
suggests that the conserved 3'-end sequence of CR1 is the recognition site for
the reverse transcriptase of CR1. A discussion is presented of a possible
mechanism for the integration of CR1 elements and also of the intriguing possible
recruitment of the reverse transcriptase for the retroposition of SINEs.
PMID- 9402733
TI - A single lineage of r2 retrotransposable elements is an active, evolutionarily
stable component of the Drosophila rDNA locus.
AB - R2 elements are non-long-terminal-repeat (non-LTR) retrotransposons that insert
specifically in the 28S rRNA genes of many insects. Previous reports concerning
this element in the genus Drosophila have suggested that R2 elements are absent
from many species of this genus, particularly those species from the subgenus
Drosophila. In this report, we present an extensive study of the distribution and
evolution of R2 elements in Drosophila. A PCR survey of 59 species from 23
species groups of the two major Drosophila subgenera found that R2 elements are
present in all but two species of the melanogaster species subgroup. Phylogenetic
analysis based on partial nucleotide sequences of R2 elements from 23 species
demonstrates that the relationships of R2 elements are congruent with those of
the Drosophila species phylogeny, suggesting that these elements have been
vertically inherited since the divergence of this genus some 60 MYA. Sequence
variation between different copies of R2 elements within each species was less
than 0.16%, indicating that these elements are undergoing concerted evolution
similar to that of the 28S genes. Several properties of the R2 sequences suggest
that these elements depend on retrotransposition in addition to simple
recombination to remain within the rDNA locus: the rates of synonymous
substitutions averaged 4.8 times the rate of replacement substitutions, 82 of 83
R2 copies partially sequenced contained intact open reading frames, and, finally,
length variation associated with the poly(A) 3' tails indicated that many R2
copies are the direct result of retrotransposition.
PMID- 9402735
TI - Rates of DNA sequence evolution are not sex-biased in Drosophila melanogaster and
D. simulans.
AB - To determine whether male- or female-biased mutation rates have affected the
molecular evolution of Drosophila melanogaster and D. simulans, we calculated the
male-to-female ratio of germline cell divisions ([symbol: see text]) from
germline generation data and the male-to-female ratio of mutation rate ([symbol:
see text]) by comparing chromosomal levels of nucleotide divergence. We found
that the ratio of germline cell divisions changes from indicating a weak female
bias to indicating a weak male bias as the age of reproduction increases. The
range of [symbol: see text] values that we observed, however, does not lead us to
expect much, if any, difference in mutation rate between the sexes. Silent and
intron nucleotide divergence were compared between nine loci on the X chromosome
and nine loci on the second and third chromosomes. The average levels of
nucleotide divergence were not significantly different across the chromosomes,
although both silent and intron sites show a trend toward slightly more
divergence on the X. These results indicate a lack of sex- or chromosome-biased
molecular evolution in D. melanogaster and D. simulans.
PMID- 9402734
TI - Phylogenetic analyses of the rbcL sequences from haptophytes and heterokont algae
suggest their chloroplasts are unrelated.
AB - Using the large subunit of RuBisCo (rbcL) sequences from cyanobacteria,
proteobacteria, and diverse groups of algae and green plants, we evaluated the
plastid relationship between haptophytes and heterokont algae. The rbcL sequences
were determined from three taxa of heterokont algae (Bumilleriopsis filiformis,
Pelagomonas calceolata, and Pseudopedinella elastica) and added to 25 published
sequences to obtain a data set comprising 1,434 unambiguously aligned sites
(approximately 98% of the total rbcL gene). Higher levels of mutational
saturation in third codon positions were observed by plotting the pairwise
substitutions with and without corrections for multiple substitutions at the same
site for first and second codon positions only and for third positions only. In
accordance with this finding phylogeny reconstructions were completed by omitting
third codon positions, thus using 956 bp in weighted-parsimony and maximum
likelihood analyses. The midpoint-rooted phylogenies showed two major clusters,
one containing cyanobacteria, glaucocystophytes, a phototrophic euglenoid,
chlorophytes, and embryophytes (the green lineage), the other containing
proteobacteria, haptophytes, red algae, a cryptophyte, and heterokont algae (the
non-green lineage). In the nongreen lineage, the haptophytes formed a sister
group to the clade containing heterokont algae, red algae, and the cryptophyte
Guillardia theta. This branching pattern was well supported in terms of bootstrap
values in weighted-parsimony and maximum-likelihood analyses (100% and 92%,
respectively). However, the phylogenetic relationship among red algae,
heterokonts, and a cryptophyte taxon was not especially well resolved. A four
cluster analysis was performed to further explore the statistical significance of
the relationship between proteobacteria, red algae (including and excluding
Guillardia theta), haptophytes, and heterokont algae. This test strongly favored
the hypothesis that the heterokonts and red algae are more closely related to
each other than either is to proteobacteria or haptophytes. Hence, this molecular
study based on a plastid-encoded gene provides additional evidence for a distant
relationship between haptophytes and the heterokont algae. It suggests an
evolutionary scenario in which the ancestor of the haptophyte lineage engulfed a
phototrophic eukaryote and, more recently, the heterokont lineage became
phototrophic by engulfing a red alga.
PMID- 9402736
TI - Multiregional introgressions inferred from the mitochondrial DNA phylogeny of a
hybridizing species complex of gobiid fishes, genus Tridentiger.
AB - Partial sequences of the cytochrome b gene (402 bp) in mtDNA were determined for
brackishwater gobiid fishes, genus Tridentiger, collected from geographically
distant locations in the Japanese Archipelago, and their interspecific and
geographic variations were analyzed and compared. Contrary to the results of a
previous allozyme analysis which revealed the existence of considerable genetic
divergence (Nei's genetic distance > 0.5) between T. obscurus and T. brevispinis,
the mtDNA haplotypes (mitotypes) of these two species were very similar and could
not be distinguished by any of the neighbor-joining, maximum-likelihood or
parsimony analyses. Hybrid individuals between the two species were also found,
with several mitotypes being shared by both species and their hybrids. The
phylogenetic relationships of mitotypes were divided into three subgroups, the
geographical distributions of the latter being allied to geographical features of
the Archipelago. These results suggested the occurrence of multiregional
introgression between the two species, with mitotypes transferring from one
species to the other.
PMID- 9402737
TI - The complete mitochondrial genome of Alligator mississippiensis and the
separation between recent archosauria (birds and crocodiles).
AB - The complete mitochondrial genome of the alligator, Alligator mississippiensis,
was sequenced. The size of the molecule is 16,642 nucleotides. Previously
reported rearrangements of tRNAs in crocodile mitochondrial genomes were
confirmed and, relative to mammals, no other deviations of gene order were
observed. The analysis of protein-coding genes of the alligator showed an
evolutionary rate that is roughly the same as in mammals. Thus, the evolutionary
rate in the alligator is faster than that in birds as well as that in cold
blooded vertebrates. This contradicts hypotheses of constant body temperatures or
high metabolic rate being correlated with elevated molecular evolutionary rates.
It is commonly acknowledged that birds are the closest living relatives to
crocodiles. Birds and crocodiles represent the only archosaurian survivors of the
mass extinction at the Cretaceous/Tertiary boundary. On the basis of
mitochondrial protein-coding genes, the Haemothermia hypothesis, which defines
birds and mammals as sister groups and thus challenges the traditional view,
could be rejected. Maximum-likelihood branch length data of amino acid sequences
suggest that the divergence between the avian and crocodilian lineages took place
at approximately equal to 254 MYA.
PMID- 9402738
TI - Lactate dehydrogenase (LDH) gene duplication during chordate evolution: the cDNA
sequence of the LDH of the tunicate Styela plicata.
AB - L-Lactate dehydrogenase (L-LDH, E.C. 1.1.1.27) is encoded by two or three loci in
all vertebrates examined, with the exception of lampreys, which have a single LDH
locus. Biochemical characterizations of LDH proteins have suggested that a gene
duplication early in vertebrate evolution gave rise to Ldh-A and Ldh-B and that
an additional locus, Ldh-C arose in a number of lineages more recently. Although
some phylogenetic studies of LDH protein sequences have supported this pattern of
gene duplication, others have contradicted it. In particular, a number of studies
have suggested that Ldh-C represents the earliest divergence among vertebrate
LDHs and that it may have diverged from the other loci well before the origin of
vertebrates. Such hypotheses make explicit statements about the relationship of
vertebrate and invertebrate LDHs, but to date, no closely related invertebrate
LDH sequences have been available for comparison. We have attempted to provide
further data on the timing of gene duplications leading to multiple vertebrate
LDHs by determining the cDNA sequence of the LDH of the tunicate Styela plicata.
Phylogenetic analyses of this and other LDH sequences provide strong support for
the duplications giving rise to multiple vertebrate LDHs having occurred after
vertebrates diverged from tunicates. The timing of these LDH duplications is
consistent with data from a number of other gene families suggesting widespread
gene duplication near the origin of vertebrates. With respect to the
relationships among vertebrate LDHs, our data are not consistent with previous
claims that Ldh-C represented the earliest divergence. However, the precise
relationships among some of the main lineages of vertebrate LDHs were not
resolved in our analyses.
PMID- 9402739
TI - Intragenic duplication and divergence in the spectrin superfamily of proteins.
AB - Many structural, signaling, and adhesion molecules contain tandemly repeated
amino acid motifs. The alpha-actinin/spectrin/dystrophin superfamily of F-actin
crosslinking proteins contains an array of triple alpha-helical motifs (spectrin
repeats). We present here the complete sequence of the novel beta-spectrin
isoform beta(Heavy)-spectrin (beta H). The sequence of beta H supports the origin
of alpha- and beta-spectrins from a common ancestor, and we present a novel model
for the origin of the spectrins from a homodimeric actin-crosslinking precursor.
The pattern of similarity between the spectrin repeat units indicates that they
have evolved by a series of nested, nonuniform duplications. Furthermore, the
spectrins and dystrophins clearly have common ancestry, yet the repeat unit is of
a different length in each family. Together, these observations suggest a dynamic
period of increase in repeat number accompanied by homogenization within each
array by concerted evolution. However, today, there is greater similarity of
homologous repeats between species than there is across repeats within species,
suggesting that concerted evolution ceased some time before the
arthropod/vertebrate split. We propose a two-phase model for the evolution of the
spectrin repeat arrays in which an initial phase of concerted evolution is
subsequently retarded as each new protein becomes constrained to a specific
length and the repeats diverge at the DNA level. This evolutionary model has
general applicability to the origins of the many other proteins that have
tandemly repeated motifs.
PMID- 9402740
TI - Nucleotide polymorphism in the acidic chitinase locus (ChiA) region of the wild
plant Arabidopsis thaliana.
AB - To investigate DNA variation in natural plant populations, a 1.8-kb region of the
acidic chitinase locus (ChiA)was analyzed for 17 ecotypes of Arabidopsis thaliana
sampled worldwide and 3 Arabis species in Japan. As in the Adh region, dimorphism
was detected throughout the investigated ChiA region, suggesting the possibility
that dimorphic DNA variation exists in the entire nuclear genome of A. thaliana.
The ChiA region was divided into two blocks by an intragenic recombination
between two parental sequence types, which diverged 7.4 MYA under the assumption
that nucleotide mutation rate per site per year is mu = 10(-9). Nucleotide
diversity in the entire ChiA region was 0.0104. Tajima's test was significantly
negative for both nucleotide and indel variations, which was manifested as an
excess of unique polymorphisms. However, the level and pattern of polymorphism in
the ChiA region were inconsistent with simple theoretical explanations. The HKA
test detected no difference in the levels of intra- and interspecific variations
between the ChiA and Adh regions. In the ChiA coding region, no difference in the
patterns of synonymous and replacement variation was found in intra- and
interspecific comparisons by the MK test. Although it was difficult to determine
the exact genetic mechanism acting on the ChA locus, these results suggested that
the ChA locus region was under the same genetic mechanism before and after the
establishment of A. thaliana as a species.
PMID- 9402741
TI - Characterization and molecular analysis of Adh retrosequences in species of the
Drosophila obscura group.
AB - Retrosequences, genes, and pseudogenes originated by retrotranscription are
frequent components of vertebrate genomes, but they have only occasionally been
described in invertebrates. In Drosophila, very few retrosequences have been
reported, among them those of alcohol dehydrogenase (Adh) and
phosphoglyceromutase (Pglym). Although 52 Adh gene sequences are available for
comparison, Adh retrosequences have been described only in the sibling species D.
teissieri and D. yakuba (melanogaster subgroup) and in D. subobscura (obscura
subgroup). Here, we report the presence of Adh retrosequences in two closely
related species of D. subobscura: D. madeirensis and D. guanche. Extensive
sequence comparisons with their functional paralogs suggest separate
retrotranscriptional events: one in the melanogaster subgroup in the ancestor of
D. teissieri and D. yakuba, and the other in the obscura subgroup before the
radiation of the lineages leading to D. subobscura, D. madeirensis, and D.
guanche. In the former, the Adh retrotranscript originated a new expressed gene,
named jingwei. However, in the obscura Adh retrosequences, retention of codon
bias and higher Ks than Ka values, both distinctive evolutionary features
supporting functionality, have to be considered together with a frameshift,
premature stop codons, and other nucleotide substitutions, which, added to the
lack of the original promoter elements, suggest that they are pseudogenes. At
least two different Adh retrosequences have been characterized in each of the
obscura species, and their phylogenetic analysis indicates that paralogs and
their flanking genomic regions share a higher degree of similarity than
orthologous sequences. Two alternative hypotheses could explain this current
organization and structure: either a multiplication event occurred independently
in each species, or gene conversion events should be invoked after a single
duplication in the species ancestor. The significance of retrotranscriptional
events in the evolution of invertebrate genomes is discussed.
PMID- 9402743
TI - Small-sample tests of episodic adaptive evolution: a case study of primate
lysozymes.
PMID- 9402742
TI - Early evolution of metazoan serine/threonine and tyrosine kinases: identification
of selected kinases in marine sponges.
AB - The phylum Porifera (sponges) was the first to diverge from the common ancestor
of the Metazoa. In this study, six cDNAs coding for protein-serine/threonine
kinases (PS/TKs) are presented; they have been isolated from libraries obtained
from the demosponges Geodia cydonium and Suberites domuncula and from the
calcareous sponge Sycon raphanus. Sequence alignments of the catalytic domains
revealed that two major families of PS/TK, the "conventional" (Ca(2+)-dependent)
protein kinase C (PKC), the cPKC subfamily, as well as the "novel" (Ca(2+)
independent) PKC (nPKC), form two separate clusters. In each cluster, the
sequence from S. raphanus diverges first. To approach the question about the
origin of protein-tyrosine kinases (PTK), which are found only in Metazoa, we
analyzed two additional PS/TKs which have been cloned from S. domuncula: the
stress-responsive protein kinase (KRSvSD) and the protein-kinase-C-related kinase
(PRKvSD). The construction of the phylogenetic tree, comprising the eight PS/TKs
and the PTK cloned previously from G. cydonium, revealed that the PTK derived
from the branch including the KRSvSD kinase. These data facilitate the first
molecular approach to elucidate the origin of metazoan PTK within the PS/TK
superfamily.
PMID- 9402744
TI - Molecular evolution of the amy multigenes in the subgenus Sophophora of
Drosophila.
PMID- 9402745
TI - Pharmacology of chronic oral daily administration of idarubicin.
AB - Idarubicin (4-demethoxydaunorubicin) (IDA) is a daunorubicin analogue with
substantial activity in hematologic malignancies and solid tumors. Among several
reasons, IDA is of interest because of its main metabolite derivative, the C-13
alcohol analogue, idarubicinol (IDOL). Previous studies have suggested that IDOL,
unlike other anthracycline metabolic derivatives, possesses a striking growth
inhibitory activity in tumor cell lines. This suggests that IDOL, like IDA could
be useful in circumventing MDR. IDA is bioavailable in an oral dosage form. After
oral administration of IDA to the patients, the concentration of IDOL quickly
exceeds that of IDA and is retained in the plasma for a longer period. Hence,
administration of IDA to cancer patients results ina much greater overall
exposure of the tumor to IDOL than to the parent compound. At the Oncology Center
(CRO) in Aviano we performed a dose-finding and pharmacokinetic (PK) study of
chronic daily oral IDA with intrapatient escalation in patients with metastatic
breast cancer (MBC). All the patients were pretreated with anthracyclines (the
cumulative dose was 530 mg and 264 mg, respectively, for epirubicin and (DOX) and
had at admittance a PS < or = 2 and a left ventricular ejection fraction > 50%.
IDA (1 mg capsules) was administered orally twice a day for 21 days every two
weeks. Treatment was continued at escalating doses until progression or
intolerance. Twenty-five patients were enrolled. MTD has not yet been reached and
clinical results are reported in Table 1. Treatment was well-tolerated in all but
one patient (300 ANC at day 28). Three patients had tox G3 ANC for more than
three weeks after 3, 6, and 7 mg doses, respectively. Two of them stopped
chemotherapy after 1 cycle and 1 patient stopped after 2 cycles (6 mg doses).
Despite previous treatments with anthracyclines (the mean cumulative dose before
entering the study was 530 and 264 mg, respectively, for epirubicin and DOX) no
cardiotoxicity due to IDA treatment was observed. This trial demonstrates the
feasibility of chronic daily IDA administration. At the dosage reported,
treatment was generally well tolerated. The PK findings (high IDOL
concentrations) and the unexpected G4 myelotoxicity in patients with the highest
IDOL plasma concentrations suggest that IDOL is clinically relevant.
PMID- 9402746
TI - Low-dose long-term oral idarubicin in maintenance treatment of elderly acute
myeloid leukemia.
AB - BACKGROUND AND OBJECTIVE: Low-dose long-term oral IDA may play a role in
maintainance treatment of elderly patients with AML; in fact, continuous exposure
to IDA and IDAol could be efficacious in the disease control possibly inducing
cell-differentiation and/or apoptosis. METHODS: We enrolled 25 previous responder
patients in standard induction therapy to receive maintenance oral IDA 5 mg daily
on days 1-14 at 2-week intervals for at least 6 months. We also evaluated the
cell-cycle and apoptosis in leukemic cells from patients after IDA administration
and, as a control, from HL60 lines exposed to IDA and IDAol in vitro. RESULTS:
Long-term long-dose IDA was well-tolerated. Neutrophil and platelet count never
below under 1 x 10(9)/L and 50 x 10(9)/L respectively in CR patients, and no
infectious complications were encountered. Non-hematological toxicity was also
acceptable: easily controlled nausea and vomiting, non-recorded diarrhea or
mucositis were reported. The convenience of oral administration contributed to
excellent compliance. DNA analysis performed in vivo after IDA and IDAol exposure
showed an increase of G2/M cell frequencies and evidence of sub-G1 peak.
INTERPRETATION AND CONCLUSIONS: In conclusion, long-term low doses of oral IDA
would appear valuable as a maintenance regimen for elderly patients. Our results
seem to confirm the preliminary hypothesis that IDA + IDAol induce an increase of
apoptosis in leukemic cells.
PMID- 9402747
TI - Idarubicin and cytosine arabinoside in the induction and maintenance therapy of
high-risk myelodysplastic syndromes.
AB - BACKGROUND AND OBJECTIVE: Recently, the results of a few pilot studies have shown
the efficacy of the association of idarubicin (IDA) and cytosine arabinoside (Ara
C), already successfully employed in acute myeloid leukemia (AML), for remission
induction in patients with myelodysplastic syndrome (MDS). We set out to evaluate
in a multicenter study the efficacy and tolerability of an intensive therapy with
IDA and Ara-C in patients with RAEB and RAEB-t, the rate and duration of CR and
the overall survival in adults treated with full doses and in the elderly treated
with lower doses; furthermore, we investigated the efficacy of low-dose
maintenance chemotherapy. METHODS: Pretreated adult patients with de novo RAEB
and RAEB-t, meeting at least one of the following criteria, were included:
neutrophils < 0.5 x 10(9)/L or moderate neutropenia with infectious episodes,
platelets < 30 x 10(9)/L or moderate thrombocytopenia but with bleeding symptoms,
transfusion > 4 red cell units/months, rapid increase of bone marrow blasts.
Induction treatment consisted of a cycle with IDA and Ara-C. Adult patients less
than 65 years old were treated with the following doses: Ara-C 1 g/m2/day i.v. 6
hour infusion, on days 1-4, IDA 10 mg/m2/day i.v., on days 1-3. Elderly patients
(> or = 65 yrs) were treated with lower doses: Ara-C 1 g/m2/day 6 hours infusion,
on days 1 and 2, IDA 10 mg/m2/day i.v., on days 1 and 2. Responders followed a
consolidation course identical to induction. RESULTS: From February 1994 to
February 1997, 25 patients were enrolled, 20 males and 5 females aged between 22
and 76, 10 were > or = 65 years old, 7 had RAEB and 18 had RAEB-t. Twelve cases
(48%) achieved complete remission (CR), 7 cases (28%) achieved partial remission,
4 patients were resistant and two patients (8%) died during the aplastic phase. A
significantly higher CR rate was found in younger patients (p = 0.036), while
gender, FAB subtype, presence of Auer rods, cytogenetic findings, and the
interval from diagnosis to treatment did not significantly influence CR
achievement. INTERPRETATION AND CONCLUSIONS: Our results show that in de novo
RAEB and RAEB-t, the employed treatment with IDA and Ara-C is associated with
satisfactory frequency of response with acceptable toxicity.
PMID- 9402748
TI - Idarubicin in induction treatment of acute myeloid leukemia in the elderly.
AB - BACKGROUND AND OBJECTIVE: The best approach to treatment of acute myeloid
leukemia (AML) in elderly patients remains controversial. Intensive chemotherapy
is the treatment of choice in selected patients, but age related changes might
affect the pharmacokinetics of antineoplastic agents resulting in enhanced
toxicity. We report our experience in elderly patients treated with idarubicin at
attenuated doses plus cytarabine and etoposide. METHODS: Sixty-six AML patients,
median age 66, with progressive disease and high tumor burden received idarubicin
8 mg/sqm i.v. d 1,3,5; cytarabine 200 mg/sqm by continuous i.v. infusion d 1-7;
etoposide 60 mg/sqm i.v. d 1-5. A second course with the same drugs was planned
irrespective of complete remission (CR) achievement. No consolidation was given;
44% had a documented preexisting myelodysplasia, 45% had a documented preexisting
myelodysplasia, 45% presented with fever. Promyelocytic leukemias were excluded.
RESULTS: Thirty-five patients (53%) achieved CR and 9 PR for an overall response
rate of 67%. Nine of them (13%) died early or during the aplastic phase.
Preexisting myelodysplasia had no significant impact on CR achievement. Resistant
disease was associated with CD7 phenotype and unfavorable karyotype. Overall
survival and disease free survival were 14 and 13 months, respectively. The major
toxicity consisted of infectious complications (WHO > 2 in 24% of patients). Six
patients died for infection, 2 for heart failure, 1 for pulmonary embolism.
INTERPRETATION AND CONCLUSIONS: This induction regimen with attenuated doses of
idarubicin is feasible and effective, but long-term survival remains an
unresolved problem. Alternative post remission approaches are advisable in the
aim of improving the remission duration.
PMID- 9402749
TI - A single high dose of idarubicin combined with high-dose ABA-C (MSKCC ALL-3
protocol) in adult and pediatric patients with acute lymphoblastic leukemia.
Experience at the University La Sapienza of Rome.
AB - BACKGROUND AND OBJECTIVE: The anthracycline analogue idarubicin, either alone or
in combination with other antineoplastic drugs, has shown antileukemic activity
in relapsed and refractory acute lymphoblastic leukemia (ALL). In an attempt to
minimize the non-hematologic toxicity and obtain a potent antileukemic effect,
MSKCC activated a pilot study in previously treated adult ALL, using HD-ARA-C
combined with idarubicin administered as a single high-dose infusion. We herein
report our experience with a series of pediatric and adult high risk ALL and NHL
patients treated with the protocol above, which confirms its feasibility,
response rate and individual compliance. METHODS: In a clinical phase II study
the combination of a single high dose (HD) idarubicin and HD cytosine-arabinoside
(ARA-C), as designed at the Memorial Sloan Kettering Cancer Center, was applied
to 70 adults and children with refractory or early relapse acute lymphoblastic
leukemia (ALL) and T-cell lymphoblastic non-Hodgkin's lymphoma (NHL). Therapy
consisted of HD-ARA-C 3 g/m2/d on days 1-5, idarubicin 40 mg/m2 on day 3,
prophylactic intrathecal methotrexate on days 1 and 4, and G-CSF 5 mg/kg/d s.c.
from day 7 to hematopoietic reconstitution (PMN > 0.5 x 10(9)/L). RESULTS: Fifty
five of the 70 patients (78%) achieved complete remission (CR), four died in
aplasia due to infection and 11 were non-responders. Recovery of blood counts
occurred at a median of 21 days from the start of treatment. Non-hematologic side
effects were extremely limited and consisted predominantly of infections.
INTERPRETATION AND CONCLUSIONS: In view of the highly unfavorable series of
patients selected, this study confirms the feasibility and antileukemic activity
of the HD-idarubicin + HD- ARA-C combination in patients with refractory and
early relapse ALL and NHL. The excellent tolerance to this regimen does not
preclude bone marrow transplantation as post-remission treatment.
PMID- 9402750
TI - Idarubicin in low-grade non-Hodgkin's lymphomas.
AB - The majority of responses produced in patients with low-grade lymphomas are
unique among non-Hodgkin's lymphomas (NHL), and even with a more intensive
chemotherapy regimen, they are only partial; the very few complete responses
which are induced are usually of short duration and do not influence overall
survival. There is, therefore, a need for new approaches to the management of low
grade NHLs. Studies are currently in progress to assess the potential benefits in
the treatment of NHL offered by new drugs, including fludarabine, idarubicin and
2-chlorodeoxyadenosine. In order to evaluate idarubicin in combination with
purine analogs, we used a combination of fludarabine and idarubicin, called the
FLU-ID regimen, to treat 10 patients with recurrent low-grade NHL. Of the 10
patients, 2 (20%) achieved complete response, 5 (50%) partial response, and the
remaining 3 showed no benefit from the treatment. The 2 CR patients are still in
remission after 12 and 14 months, respectively. The median duration of overall
survival of all patients was 18 months. These results indicate the efficacy of
the FLU-ID regimen in inducing a good remission rate with moderate side effects
in recurrent low-grade NHL. On the basis of this pilot study, we planned a
cooperative randomized trial for untreated patients.
PMID- 9402751
TI - [Paclitaxel (Taxol) opens new perspectives on bronchial carcinoma. 8th World
Conference on Lung Cancer. Dublin, 10-15 August 1997].
PMID- 9402752
TI - Identification and characterization of a catalytic base in bacterial luciferase
by chemical rescue of a dark mutant.
AB - Mutation of the His44 residue of the alpha subunit of Vibrio harveyi luciferase
to an alanine was known to reduce the enzyme bioluminescence activity by five
orders of magnitude [Xin, X., Xi, L., and Tu, S.-C. (1991) Biochemistry 30, 11255
11262]. We found that the residual activity of the alpha H44A luciferase was
markedly enhanced by exogenously added imidazole and other simple amines. The
peak luminescence intensity in nonturnover assays was linearly proportional to
levels of alpha H44A and the rescue agent, indicating a lack of significant
binding under our experimental conditions. The rescue effect of imidazole was pH
dependent and quantitatively correlated well with the amount of imidazole base.
The rescue efficiencies of imidazole and amines were found to be regulated by
both their molecular volume and pKa. A Bronsted analysis revealed a beta value of
0.8 +/- 0.1. The enhancement of alpha H44A activity by imidazole took place after
the formation of the flavin 4a-hydroperoxide intermediate. The predominant form
of the flavin 4a-hydroperoxide intermediate generated by alpha H44A was inactive
in bioluminescence, but was reactive with the aldehyde substrate for
bioluminescence in the presence of imidazole. These findings, taken together,
provide evidence for assigning a role for the alpha His44 imidazole as a
catalytic base in the luciferase reaction. This study provides the first
characterization of a catalytic residue for bacterial luciferase and the first
demonstration of the rescue of a histidine-mutated enzyme by exogenous imidazole
and amines.
PMID- 9402753
TI - Decreased stability of transforming growth factor beta type II receptor mRNA in
RER+ human colon carcinoma cells.
AB - Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell growth
and tumor progression. Previous work has shown that loss of functional TGF-beta
type II receptor (RII) due to a frameshift mutation in the 5' half of the RII
gene leads to TGF-beta resistance in a highly progressed, RER+ human colon
carcinoma cell line designated HCT116. Expression of this mutated RII gene was
highly repressed in RER+ cell lines such as HCT116 and RKO, as analyzed by RNase
protection assays. Nuclear run-on and RII promoter-reporter (CAT) assays showed
that the transcriptional levels of the RII gene in these RER+ cells were not
reduced, compared to RII-expressing cells. However, the half-lives of the RII
mRNA, as analyzed by RNase protection assays following actinomycin D treatment,
were significantly decreased. This suggested that the decreased expression of the
RII gene mutant was due to decreased mRNA stability. Furthermore, RII mRNA from
HCT116 transfected with wild-type RII had a longer half-life than the endogenous
mutated RII mRNA. A dominant negative RII mutant, which encodes a similarly
truncated RII protein as HCT116 but lacks the extensive 3' untranslated region of
RII mRNA, gave the same half-life as endogenous wild-type RII mRNA. We conclude
that the frameshift mutation which results in a premature stop codon in the 5'
half of the mRNA transcript accounts for the reduced RII mRNA levels in RER+
cells.
PMID- 9402754
TI - Expression, purification, and inhibitory properties of human proteinase
inhibitor.
AB - In a previous report, the cDNA for human proteinase inhibitor 8 (PI8) was first
identified, isolated, and subcloned into a mammalian expression vector and
expressed in baby hamster kidney cells. Initial studies indicated that PI8 was
able to inhibit the amidolytic activity of trypsin and form an SDS-stable
approximately 67-kDa complex with human thrombin [Sprecher, C. A., et al. (1995)
J. Biol Chem. 270, 29854-29861]. In the present study, we have expressed
recombinant PI8 in the methylotropic yeast Pichia pastoris, purified the
inhibitor to homogeneity, and investigated its ability to inhibit a variety of
proteinases. PI8 inhibited the amidolytic activities of porcine trypsin, human
thrombin, human coagulation factor Xa, and the Bacillus subtilis dibasic
endoproteinase subtilisin A through different mechanisms but failed to inhibit
the Staphylococcus aureus endoproteinase Glu-C. PI8 inhibited trypsin in a purely
competitive manner, with an equilibrium inhibition constant (Ki) of less than 3.8
nM. The interaction between PI8 and thrombin occurred with a second-order
association rate constant (kassoc) of 1.0 x 10(5) M-1 s-1 and a Ki of 350 pM. A
slow-binding kinetics approach was used to determine the kinetic constants for
the interactions of PI8 with factor Xa and subtilisin A. PI8 inhibited factor Xa
via a two-step mechanism with a kassoc of 7.5 x 10(4) M-1 s-1 and an overall Ki
of 272 pM. PI8 was a potent inhibitor of subtilisin A via a single-step mechanism
with a kassoc of 1.16 x 10(6) M-1 s-1 and an overall Ki of 8.4 pM. The
interaction between PI8 and subtilisin A may be of physiological significance,
since subtilisin A is an evolutionary precursor to the intracellular mammalian
dibasic processing endoproteinases.
PMID- 9402755
TI - Mechanism of formation of novel covalent drug.DNA interstrand cross-links and
monoadducts by enediyne antitumor antibiotics.
AB - The potent enediyne antitumor antibiotic C1027 has been previously reported to
induce novel DNA interstrand cross-links and drug monoadducts under anaerobic
conditions [Xu et al. (1997) J. Am. Chem. Soc. 119, 1133-1134]. In the present
study, we explored the mechanism of formation of these anaerobic DNA lesions. We
found that, similar to the aerobic reaction, the diradical species of the
activated drug initiates anaerobic DNA damage by abstracting hydrogen atoms from
the C4', C1', and C5' positions of the A1, A2, and A3 nucleotides, respectively,
in the most preferred 5'GTTA1T/5'ATA2A3C binding sequence. It is proposed that
the newly generated deoxyribosyl radicals, which cannot undergo oxidation, likely
add back onto the nearby unsaturated ring system of the postactivated enediyne
core, inducing the formation of interstrand cross-links, connecting either A1 to
A2 or A1 to A3, or drug monoadducts mainly on A2 or A3. Comparative studies with
other enediynes, such as neocarzinostatin and calicheamicin gamma 1I under
similar reaction conditions indicate that the anaerobic reaction process is a
kinetically competitive one, depending on the proximity of the drug unsaturated
ring system or dioxygen to the sugar radicals and their quenching by other
hydrogen sources such as solvent or thiols. It was found that C1027 mainly
generates interstrand cross-links, whereas most of the anaerobic lesions produced
by neocarzinostatin are drug monoadducts. Calicheamicin gamma 1 (1) was found to
be less efficient in producing both lesions. The anaerobic DNA lesions induced by
enediyne antitumor antibiotics may have important implications for their potent
cytotoxicity in the central regions of large tumors, where relative anaerobic
conditions prevail.
PMID- 9402756
TI - Regional trauma systems.
PMID- 9402757
TI - Emergency medical admissions: taking stock and planning for winter.
PMID- 9402758
TI - Commissioning specialist services in the NHS.
PMID- 9402759
TI - Lumbar puncture needn't be a headache.
PMID- 9402760
TI - UK government fails its first test on public health.
PMID- 9402762
TI - Clearing house needed for specialist treatments.
PMID- 9402761
TI - Climate change: decision time in Kyoto.
PMID- 9402763
TI - Medical decisions must be logically defensible.
PMID- 9402765
TI - BMA wants licensing of cannabis to be changed.
PMID- 9402766
TI - US journal finds lower risk from diet pills.
PMID- 9402767
TI - Scottish trusts miss cataract surgery targets.
PMID- 9402768
TI - US hospital mergers threaten reproductive services.
PMID- 9402769
TI - UK needs more cancer specialists.
PMID- 9402770
TI - UK government consults on clinical disputes.
PMID- 9402771
TI - GPs will be at heart of overhaul of NHS.
PMID- 9402772
TI - Neonatal screening recommended for hearing impairment.
PMID- 9402773
TI - Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory
drugs with continued exposure: cohort study.
AB - OBJECTIVES: To determine the profile of risk of upper gastrointestinal toxicity
during continuous treatment with, and after cessation of, non-steroidal anti
inflammatory drugs. DESIGN: Cohort study with a prospectively constructed,
population based, record linkage database containing details of exposure to all
community dispensed non-steroidal anti-inflammatory drugs and also all admissions
to hospital for upper gastrointestinal diagnoses. SETTING: The population of
Tayside, Scotland. SUBJECTS: 52,293 subjects aged 50 and over who received one or
more non-steroidal anti-inflammatory between 1 January 1989 and 31 December 1991
and 73,792 subjects who did not receive one during the same period (controls).
MAIN OUTCOME MEASURES: Admission to hospital for upper gastrointestinal bleeding
and perforation, and admission for other upper gastrointestinal diagnoses.
RESULTS: About 2% of the non-steroidal anti-inflammatory cohort were admitted
with an upper gastrointestinal event during the study period compared with 1.4%
of controls. The risk of admission for upper gastrointestinal haemorrhage and
perforation was constant during continuous non-steroidal anti-inflammatory
exposure and carried over after the end of exposure. The results were similar for
admissions for all upper gastrointestinal events. CONCLUSION: This study provides
evidence that non-steroidal anti-inflammatory toxicity persists with continuous
exposure. There seems to be carryover toxicity after the end of prescribing.
These findings have implications for the management of patients requiring non
steroidal anti-inflammatory drugs.
PMID- 9402774
TI - Randomised trial of octreotide for long term management of cirrhosis after
variceal haemorrhage.
AB - OBJECTIVE: To assess the efficacy of long term octreotide as adjuvant treatment
to programmed endoscopic sclerotherapy after acute variceal haemorrhage in
cirrhotic portal hypertension. DESIGN: Randomised clinical trial. SETTING:
University hospital. SUBJECTS: 32 patients with cirrhotic portal hypertension.
INTERVENTIONS: Programmed injection sclerotherapy with subcutaneous octreotide 50
micrograms twice daily for 6 months, or programmed injection sclerotherapy alone.
MAIN OUTCOME MEASURES: Episodes of recurrent variceal bleeding and survival.
RESULTS: Significantly fewer patients receiving combined octreotide and
sclerotherapy had episodes of recurrent variceal bleeding compared with patients
given sclerotherapy alone (1/16 v 7/16; P = 0.037, Fisher's exact test), and
their survival was significantly improved (P < 0.02, log rank test); this
improvement was maintained for 12 months after the end of the study. Combined
treatment also resulted in a sustained decrease in portal pressure (median
decrease -6.0 mm Hg, interquartile range -10 to -4.75 mm Hg, P = 0.0002) compared
with sclerotherapy alone (median increase 1.5 mm Hg, interquartile range 0.25 to
3.25 mm Hg), as well as a significant improvement in liver function as assessed
by plasma concentrations of bilirubin, albumin, and alanine aminotransferase and
by hepatocyte metabolism of aminopyrine labelled with carbon-14. CONCLUSION: Long
term octreotide may be a valuable adjuvant to endoscopic sclerotherapy for acute
variceal haemorrhage in cirrhotic portal hypertension.
PMID- 9402775
TI - Does malnutrition in utero determine diabetes and coronary heart disease in
adulthood? Results from the Leningrad siege study, a cross sectional study.
AB - OBJECTIVE: To investigate the relation between decreased maternal food intake and
risk factors for coronary heart disease in adult life. DESIGN: Cross sectional
study. SUBJECTS: 169 subjects exposed to malnutrition in utero (intrauterine
group) during the siege of Leningrad (now St Petersburg) in 1941-4; 192 subjects
born in Leningrad just before rationing began, before the siege (infant group);
and 188 subjects born concurrently with the first two groups but outside the area
of the siege (unexposed group). SETTING: Ott Institute of Obstetrics and
Gynaecology, St Petersburg. MAIN OUTCOME MEASURES: Development of risk factors
for coronary heart disease and diabetes mellitus-obesity, blood pressure, glucose
tolerance, insulin concentrations, lipids, albumin excretion rate, and clotting
factors. RESULTS: There was no difference between the subjects exposed to
starvation in utero and those starved during infant life in: (a) glucose
tolerance (mean fasting glucose: intrauterine group 5.2 (95% confidence interval
5.1 to 5.3), infant group 5.3 (5.1 to 5.5), P = 0.94; mean 2 hour glucose:
intrauterine group 6.1 (5.8 to 6.4), infant group 6.0 (5.7 to 6.3), P = 0.99);
(b) insulin concentration; (c) blood pressure; (d) lipid concentration; or (e)
coagulation factors. Concentrations of von Willebrand factor were raised in the
intrauterine group (156.5 (79.1 to 309.5)) compared with the infant group (127.6
(63.9 to 254.8); P < 0.001), and female subjects in the intrauterine group had a
stronger interaction between obesity and both systolic (P = 0.01) and diastolic
(P = 0.04) blood pressure than in the infant group. Short adult stature was
associated with raised concentrations of glucose and insulin 2 hours after a
glucose load-independently of siege exposure. Subjects in the unexposed group had
non-systematic differences in subscapular to triceps skinfold ratio, diastolic
blood pressure, and clotting factors compared with the exposed groups.
CONCLUSIONS: Intrauterine malnutrition was not associated with glucose
intolerance, dyslipidaemia, hypertension, or cardiovascular disease in adulthood.
Subjects exposed to malnutrition showed evidence of endothelial dysfunction and a
stronger influence of obesity on blood pressure.
PMID- 9402776
TI - Commentary: a hypothesis challenged.
PMID- 9402777
TI - Effectiveness of a regional trauma system in reducing mortality from major
trauma: before and after study.
AB - OBJECTIVE: To assess the effect of the development of an experimental trauma
centre and regional trauma system on the survival of patients with major trauma.
DESIGN: Controlled before and after study examining outcomes between 1990 and
1993, spanning the introduction of the system in 1991-2. SETTING: Trauma centre
in North Staffordshire Royal Infirmary and five associated district general
hospitals in the North West Midlands regional trauma system, and two control
regions in Lancashire and Humberside. SUBJECTS: All trauma patients taken by the
ambulance services serving the regions or arriving other than by ambulance with
injury severity scores > 15, whether or not they had vital signs on arrival at
hospital. MAIN OUTCOME MEASURES: Survival rates standardised for age, severity of
injury, and revised trauma score. RESULTS: In 1990, 33% of major trauma patients
in the experimental region were taken to the trauma centre, and by 1993 this had
risen to only 39%. Crude death rates changed by the same amount in the control
regions (46.5% in 1990-1 to 44.4% in 1992-3) as in the experimental region (44.8%
to 41.3%). After standardisation, the estimated change in the probability of
dying in the experimental region compared with the control regions was -0.8% per
year (95% confidence interval -3.6% to 2.2%); for out of hours care, the change
was 1.6% per year (-2.3% to 5.6%), and, for multiply injured patients, the change
was -1.6% (-6.1% to 2.6%). CONCLUSION: Any reductions in mortality from
regionalising major trauma care in shire areas of England would probably be
modest compared with reports from the United States.
PMID- 9402778
TI - Effect of a strict HLA matching policy on distribution of cadaveric kidney
transplants to Indo-Asian and white European recipients: regional study.
PMID- 9402779
TI - Improving uptake of breast screening in multiethnic populations: a randomised
controlled trial using practice reception staff to contact non-attenders.
AB - OBJECTIVES: To determine whether a two hour training programme for general
practice reception staff could improve uptake in patients who had failed to
attend for breast screening, and whether women from different ethnic groups
benefited equally. DESIGN: Controlled trial, randomised by general practice.
SETTING: Inner London borough of Newham. SUBJECTS: 2064 women aged 50-64 years
who had failed to attend for breast screening. Women came from 26 of 37 eligible
practices, 31% were white, 17% were Indian, 10% Pakistani, 14% black, 6%
Bangladeshi, 1% Chinese, 4% were from other ethnic groups, and in 16% the ethnic
group was not reported. MAIN OUTCOME MEASURES: Attendance for breast screening in
relation to ethnic group in women who had not taken up their original invitation.
RESULTS: Attendance in the intervention group was significantly better than in
the control group (9% v 4%). The response was best in Indian women--it was 19% in
the intervention group and 5% in the control group. CONCLUSIONS: This simple, low
cost intervention improved breast screening rates modestly. Improvement was
greatest in Indian women--probably because many practice staff shared their
cultural and linguistic background. This intervention could be effective as part
of a multifaceted strategy to improve uptake in areas with low rates.
PMID- 9402780
TI - Work factors and upper limb disorders.
PMID- 9402781
TI - Oxybutynin and cognitive dysfunction.
PMID- 9402782
TI - ABC of palliative care. Depression, anxiety, and confusion.
PMID- 9402783
TI - Disclosure of clinical audit records in law: risks and possible defences.
PMID- 9402784
TI - New method for expressing survival in cancer. Use of percentage of "normal
remaining life" may be confusing.
PMID- 9402785
TI - New method for expressing survival in cancer. New method would be more meaningful
to patients than 10 year survival rates.
PMID- 9402786
TI - New method for expressing survival in cancer. Relation between survival times and
patients' age at diagnosis must be taken into account.
PMID- 9402787
TI - New method for expressing survival in cancer. Use of age specific relative
survival is sufficient.
PMID- 9402788
TI - Cognitive behaviour therapy. Review was unsystematic.
PMID- 9402789
TI - Cognitive behaviour therapy. Patients are more likely to be treated with drugs.
PMID- 9402790
TI - Patients with implants should be given implant cards for reference.
PMID- 9402791
TI - General practice should be central to community mental health services.
PMID- 9402792
TI - Treating diarrhoea. Proposals are irresponsible and impractical.
PMID- 9402793
TI - Treating diarrhoea. Patients must be educated about which symptoms require
treatment.
PMID- 9402794
TI - Treating diarrhoea. Rehydration should have been emphasised.
PMID- 9402795
TI - Treating diarrhoea. Diarrhoea is problem for animals too.
PMID- 9402796
TI - Treating diarrhoea. Children deserve special attention.
PMID- 9402797
TI - Treating diarrhoea. Advocating widespread use of antimicrobial agents has
economic implications.
PMID- 9402798
TI - Treating diarrhoea. More evidence is needed that widespread use of quinolones
will benefit patients.
PMID- 9402799
TI - Study linking enteroviral infection with motor neurone disease is not confirmed.
PMID- 9402801
TI - Family secrets. Patients have right to privacy and confidentiality.
PMID- 9402800
TI - Charity helps doctors with addictive diseases to obtain treatment.
PMID- 9402802
TI - Family secrets. Most patients speak more freely when on their own.
PMID- 9402803
TI - Nicotine replacement therapy on the NHS. Nicotine treatment cannot be regarded as
replacement therapy.
PMID- 9402804
TI - Nicotine replacement therapy on the NHS. Success rates of different smoking
cessation treatments need to be compared.
PMID- 9402805
TI - Old fashioned methods of diagnosis have their place.
PMID- 9402806
TI - Reflex sympathetic dystrophy: fact and fiction.
PMID- 9402807
TI - HIV management update.
PMID- 9402808
TI - Mirtazapine revisited.
PMID- 9402809
TI - Project Read--the importance of early learning. Rx: Read to your child.
PMID- 9402810
TI - Preventing stroke in atrial fibrillation.
AB - Atrial fibrillation, a common cardiac arrhythmia, is now recognized as a powerful
risk factor for stroke. Previously, atrial fibrillation was thought to predispose
persons to stroke only in the presence of rheumatic heart disease with mitral
stenosis. The significant impact of nonvalvular atrial fibrillation on stroke
incidence, recurrence and mortality was not fully appreciated. A series of
clinical trials have confirmed that a five-fold increase in stroke incidence
occurs in patients with atrial fibrillation, and that warfarin anticoagulation is
efficacious in stroke prevention. This anticoagulation benefit was achieved with
an acceptably low risk of serious hemorrhage.
PMID- 9402811
TI - Paresthesias: a practical diagnostic approach.
AB - Paresthesias may be caused by central or peripheral nervous system abnormalities.
Central nervous system-induced paresthesias are most commonly caused by ischemia,
structural or compressive phenomena, infection, inflammation or degenerative
conditions. Peripherally induced paresthesias can be caused by entrapment
syndromes, metabolic disturbances, trauma, inflammation, connective tissue
diseases, toxins, hereditary conditions, malignancies, nutritional deficiencies
and miscellaneous conditions. Confirming the diagnosis and establishing an
etiology may require appropriate laboratory and radiologic studies, or other
studies. In most cases, the specific clinical syndromes associated with the
paresthesias, coupled with the presenting neurologic findings, provide the
physician with a framework for the diagnosis.
PMID- 9402812
TI - Complex regional pain syndrome.
AB - The term "complex regional pain syndrome" encompasses causalgia and reflex
sympathetic dystrophy. Symptoms of burning pain with autonomic and tissue changes
begin shortly after an injury, usually to a distal extremity. The diagnosis is
based on the history and the clinical findings. No confirmatory tests are
available, although plain radiographs or a three-phase bone scan may be helpful
in diagnosing some cases. Aggressive treatment, which may include sympathetic
blockade, medications, physical therapy and psychotherapy, is essential for a
favorable outcome. Despite treatment, many patients are left with varying degrees
of chronic pain and disability.
PMID- 9402813
TI - Drug treatment of migraine: Part II. Preventive therapy.
AB - In most cases, successful preventive therapy for migraines requires daily
medication for months or years. Perimenstrual use of a preventive agent is a
common exception. Preventive therapy is usually undertaken in patients who have
more than two headache episodes per month or those very much disabled by
headaches. Beta blockers are usually the first choice for preventive therapy, and
amitriptyline is also commonly used. Despite widespread use of calcium channel
blockers for prevention of migraine, their benefits are controversial. Although
effective for prevention of migraine, methysergide and phenelzine are usually
relegated to last-resort use because of potentially serious side effects. The
migraine patient who is refractory to standard preventive therapy may have
rebound headache related to overuse of abortive migraine medications, or
concomitant psychopathology.
PMID- 9402814
TI - Occupational infections in health care workers: prevention and intervention.
AB - Health care workers may be exposed to a variety of infections as they carry out
their job responsibilities. Guidelines have been issued for prophylaxis following
exposure to blood or body fluids known to be infected with the human
immunodeficiency virus. Hepatitis B vaccine must be offered to all workers who
may be exposed to blood and body fluids. Chemoprophylaxis is not available for
workers exposed to hepatitis C. Health care facilities must conduct a
tuberculosis risk assessment, provide skin testing at least yearly and develop
isolation procedures for potentially infectious patients. The Occupational Safety
and Health Administration currently mandates two-stage skin testing for all new
employees at risk for tuberculosis exposure who have not had a skin test in the
past year. Recent skin-test converters should be evaluated for isoniazid
prophylaxis after a chest radiograph rules out active tuberculosis. Workers
should be removed from the workplace from days 10 to 21 following exposure to
varicella infection; vaccination of nonimmune workers should be considered.
Because of possible side effects, the standard pertussis vaccine is not used in
adults, but a new acellular pertussis vaccine has been effective in this group.
PMID- 9402815
TI - AAP develops recommendations for the evaluation and treatment of HIV-exposed
infants.
PMID- 9402816
TI - First combination drug for patients with HIV.
PMID- 9402817
TI - Prevalence of dry eye among the elderly.
AB - PURPOSE: To study the demographics and estimate the prevalence of dry eye among
elderly Americans. METHODS: A population-based prevalence study was performed in
2,520 residents of Salisbury, Maryland, aged 65 years and older as of September
1993. The population was derived from the Health Care Financing Administration
Medicare database. After completing a standardized questionnaire pertaining to
dry eye symptoms, 2,420 subjects underwent Schirmer and rose bengal tests and
anatomic assessment of the meibomian glands. RESULTS: In this population, 14.6%
(363/2,482) were symptomatic, defined as reporting one or more dry eye symptoms
often or all the time; 2.2% (53/2,448) were symptomatic and had a low Schirmer
test result (< or = 5 mm), and 2% (48/2,432) were symptomatic and had a high rose
bengal test score (> or = 5). Furthermore, 3.5% (84/2,425) were symptomatic and
had either a low Schirmer score or a high rose bengal score, and 0.7% (17/2,420)
were symptomatic and had both a low Schirmer score and a high rose bengal score.
No association of symptoms or signs was seen with age, sex, or race. Although
anatomic features of meibomianitis were associated with the presence of symptoms
(P = .01), 76% (67/88) of the individuals with these anatomic features were
asymptomatic; 10.5% (260/2,480) reported that they currently use artificial tears
or lubricants. CONCLUSIONS: Symptoms and signs of dry eye are common among the
elderly but were not associated with age, race, or sex in this population-based
sample of elderly Americans. Extrapolating to the United States population aged
65 to 84 years, the study yields an estimate of 4.3 million who experience
symptoms of ocular irritation often or all the time.
PMID- 9402818
TI - Use of high-speed, high-resolution thermography to evaluate the tear film layer.
AB - PURPOSE: To evaluate the tear film layer in patients with dry eye and in normal
subjects by measuring the corneal temperature with infrared radiation
thermography. METHODS: One eye of each of 13 patients with dry eye and one eye of
each of seven normal subjects were evaluated randomly. The corneal temperature
was measured continuously with a recently improved infrared radiation
thermography technique. We calculated the k value, which reflected the steepness
of the corneal temperature change. The bigger the k value was, the more rapid was
the decrease in corneal temperature, and this was directly related to increased
evaporation. RESULTS: With normal blinking, the mean k value for patients with
dry eye (5.6 +/- 2.9 per second) was significantly less than that in the control
subjects (9.3 +/- 5.0 per second; P < .05). Keeping the eyes open after closing
the eyes significantly decreased the k values compared with normal blinking in
both groups (P < .05). CONCLUSIONS: Our findings demonstrate the usefulness of
this method of measuring corneal temperature to evaluate the tear film layer.
High-speed, high-resolution thermography detected subtle changes in corneal
temperature with enhanced sensitivity and spatial and temporal resolution. We
found that the mean k value, and therefore the rate of decline in corneal
temperature in patients with dry eye, was significantly less than that in normal
subjects. The k value may therefore reflect tear film layer stability. The
measurement of the changes in the corneal temperature can thus give us valuable
information on the tear film layer.
PMID- 9402819
TI - Rose bengal staining and cytologic characteristics associated with lipid tear
deficiency.
AB - PURPOSE: To characterize ocular surface features of patients with an unstable
tear film caused primarily by a lipid tear abnormality resulting from noninflamed
meibomian gland dysfunction. METHODS: Retrospective clinical data and results
from rose bengal staining, modified meibography, and impression cytology were
reviewed in 78 patients (142 eyes), all of whom had normal tear secretion and
clearance verified by the fluorescein clearance test but an unstable tear film
evidenced by tear breakup time +/- SD of 3.4 +/- 2.1 seconds (normal, > 8
seconds). RESULTS: Of 201 symptoms, 147 (73%) were presumably caused by an
unstable tear film, 46 (23%) resulted from inflammation, and none were diurnally
worsened. All patients had meibomian gland dysfunction characterized by poor or
no meibum expression, orifice squamous metaplasia, or acinar atrophy. Rose bengal
staining was negative in 95 eyes (67%), positive on nonexposure zones in 30 eyes
(21%), and positive on exposure zones in 17 eyes (12%). Among 90 eyes receiving
impression cytology, six (7%) were normal, 49 (54%) had pure "lytic" changes
characterized by disrupted cell-cell junctions of normal small cells in the
nonexposure zone, three (3%) had pure squamous metaplasia without mucous
aggregates, two (2%) had squamous metaplasia with mucous aggregates (the latter
being a frequent finding of aqueous tear deficiency), and 31 (34%) were mixed
with lytic changes and squamous metaplasia. CONCLUSION: Preferential distribution
of rose bengal staining in the nonexposure zone and lytic cytologic changes
without squamous metaplasia characterize lipid tear deficiency and help to
differentiate it from aqueous tear deficiency in patients with an unstable tear
film.
PMID- 9402820
TI - Expression of a mucin-like glycoprotein produced by ocular surface epithelium in
normal and keratinized cells.
AB - PURPOSE: We previously characterized a monoclonal antibody (H185) to a mucin-like
glycoprotein produced by human ocular surface epithelium. In the current study,
we used H185 to investigate the pattern of the mucin-like glycoprotein in normal
and keratinized apical cells of the ocular surface epithelium. METHODS: We
compared the cell characteristics and the pattern of H185 binding in
cytologically and immunohistochemically stained samples of apical cells of
conjunctival surface epithelium from 20 normal subjects and six patients before
and after treatment for superior limbic keratoconjunctivitis. RESULTS: In the
superior bulbar conjunctiva of normal subjects, the intensity with which H185
antibody bound to apical surface epithelial cells varied, with areas of high-,
medium-, and low-intensity binding occurring in a mosaic pattern. This mosaic
pattern, and presumably expression of the mucin-like glycoprotein, was absent or
remarkably reduced in keratinized cells obtained from patients with superior
limbic keratoconjunctivitis before treatment. However, the pattern of H185
binding was normal in samples obtained 2 months after the start of treatment for
superior limbic keratoconjunctivitis, and cells had recovered their normal small,
round appearance. CONCLUSION: When they are keratinized, apical cells of the
ocular surface epithelium are altered in appearance and lack the normal mosaic
pattern of expression of a mucin-like glycoprotein.
PMID- 9402821
TI - Gravity, blink rate, and lacrimal drainage capacity.
AB - PURPOSE: To investigate the influence of gravity and blink rate on lacrimal
drainage capacity and to learn whether lacrimal pump function can be measured
with the drop test. METHODS: The drop test for lacrimal drainage capacity was
performed in 20 test subjects, aged 12 to 30 years. Drops of a known volume of
lukewarm saline solution were repeatedly instilled in the tear film for 3
minutes. Excessive saline solution was then removed, and the volume drained by
the lacrimal passages was calculated. The drop test was performed both with the
nasolacrimal duct in a 45-degree position and with the nasolacrimal duct in a
horizontal position. The drop test was performed two times in each position, with
the individual reading and not reading. A lower blink rate was induced by
reading. RESULTS: There was a high correlation between blink rate and lacrimal
drainage when the nasolacrimal duct was in a horizontal position. The volume
drained with each blink was approximately 2 microliters. However, when gravity
acted upon the fluid in the lacrimal sac-nasolacrimal duct in the direction of
the tear flow, the lacrimal drainage capacity showed a significant but variable
increase, and there was no significant correlation between blink rate and
lacrimal drainage capacity. CONCLUSIONS: Lacrimal drainage capacity in young
individuals was significantly affected by both blink rate and gravity. Lacrimal
pump function can be measured quantitatively with the drop test.
PMID- 9402823
TI - Changes in the anterior chamber configuration after small-incision cataract
surgery with posterior chamber intraocular lens implantation.
AB - PURPOSE: To report quantitative changes in the anterior chamber configuration
after small-incision cataract surgery with implantation of a posterior chamber
intraocular lens by means of ultrasound biomicroscopy. METHODS: We examined the
anterior chamber configuration of 20 eyes of 20 patients before and 3 months
after small-incision cataract surgery (phacoemulsification and aspiration plus
foldable intraocular lens implantation through a 3.0- to 4.0-mm self-sealing
wound) by means of ultrasound biomicroscopy. The following variables were
measured: the anterior chamber depth at the center of the cornea, the angle
opening distance 250 microns from the scleral spur (AOD250), the angle-opening
distance 500 microns from the scleral spur (AOD500), and the trabecular-iris
angle. RESULTS: The anterior chamber depth at the center of the cornea, AOD250,
AOD500, and trabecular-iris angle increased significantly after surgery. The
preoperative anterior chamber depth at the center of the cornea and trabecular
iris angle were negatively correlated with the differences between the
postoperative and preoperative values (P < .01). The preoperative values of all
variables examined were negatively correlated with the ratios of the
postoperative value to the preoperative value (P < .002). CONCLUSIONS: The
present results showed that small-incision cataract surgery significantly
deepened the anterior chamber and widened its angle. The more shallow the
preoperative anterior chamber was, the greater the postoperative change of the
chamber was; and the more narrow the preoperative angle was, the greater the
postoperative change of the angle was.
PMID- 9402822
TI - Amniotic membrane transplantation for conjunctival surface reconstruction.
AB - PURPOSE: To determine whether preserved human amniotic membrane can be used to
reconstruct the conjunctival defect created during surgical removal of a large
lesion or during symblepharon lysis. METHODS: Amniotic membrane transplantation
was performed in six consecutive patients (seven eyes) during removal of large
conjunctival lesions and in nine patients (nine eyes) during removal of
conjunctival scars or symblepharon. RESULTS: During a mean follow-up period +/-
SD of 10.9 +/- 9.1 months (range, 2.2 to 34.0 months), 10 patients (11 eyes)
showed successful surface reconstruction without recurrence, five patients (five
eyes) showed improved visual acuity, and one patient (one eye) showed
epithelialization within 3 weeks and resolution of motility restriction. Two
patients (two eyes) showed partial success, with surrounding conjunctival
inflammation. Three cases (three eyes) failed and exhibited recurrent scarring:
one patient had received mitomycin treatment and beta radiation, whereas the
transplanted amniotic membrane of the second patient was partially, and of the
third patient was completely, dissolved or replaced by the inflamed
pseudopterygial tissue. Two patients (two eyes) had epithelial cyst formation.
CONCLUSION: Amniotic membrane transplantation can be considered an alternative
substrate for conjunctival surface reconstruction during removal for large
tumors, disfiguring scars, or symblepharon, especially for those whose
surrounding conjunctival tissue remains relatively normal.
PMID- 9402824
TI - Evaluation of Nd:YAG laser membranectomy in blocked tubes after glaucoma tube
shunt surgery.
AB - PURPOSE: To determine the effectiveness of Nd:YAG laser membranectomy for
reopening blocked glaucoma tube shunts and maintaining the patency over time.
METHODS: We reviewed retrospectively the records of 13 patients (13 eyes) who,
during the period January 1990 through June 1996, underwent Nd:YAG laser
membranectomy in an attempt to reopen a blocked glaucoma tube shunt. Intraocular
pressure and tube patency were evaluated at each follow-up visit. RESULTS: Nd:YAG
laser membranectomy effectively opened the blocked glaucoma tube shunts in 11
(84.6%) of 13 eyes. Two tubes could not be reopened. Reblockage occurred in seven
eyes (53.8%) within the first 11 weeks; four tubes (30.8%) remained patent
through follow-up periods of 39, 82, 106, and 169 weeks. Postlaser complications
were moderate anterior chamber reaction in four eyes (30.8%), hyphema in two eyes
(15.4%), corneal edema in two eyes (15.4%), pressure spike in one eye (7.7%), and
shallow anterior chamber in one eye (7.7%). CONCLUSIONS: Nd:YAG laser
membranectomy is effective in reopening blocked glaucoma tube shunts but is
associated with a relatively high rate of subsequent reblockage in the initially
successful cases.
PMID- 9402825
TI - Endoscopic photocoagulation of the ciliary body for treatment of refractory
glaucomas.
AB - PURPOSE: To evaluate the safety and efficacy of endoscopic cyclophotocoagulation
in the treatment of refractory glaucomas. METHODS: The preoperative and
postoperative courses of 68 eyes of 68 patients who underwent endoscopic
cyclophotocoagulation at our institution were retrospectively reviewed. Study
patients had diverse forms of glaucoma, and most had failed maximal medical
therapy as well as failed filtration or transscleral cyclodestructive procedures,
or both. Endoscopic cyclophotocoagulation treatment encompassed 180 to 360
degrees of the ciliary body circumference and was performed through a limbal
incision (56 eyes, 12 of which underwent concurrent cataract extraction) or pars
plana incision (12 eyes). A second laser treatment was required in five eyes
(7%). RESULTS: During the mean follow-up period of 12.9 months, mean +/- SD
intraocular pressure decreased from 27.7 +/- 10.3 mm Hg preoperatively to 17.0 +/
6.7 mm Hg at the final postoperative visit (P < .0001), for a mean reduction of
10.7 mm Hg and a mean percent decrease of 34%. Sixty-one eyes (90%) achieved an
intraocular pressure < or = 21 mm Hg. Using this definition of success, Kaplan
Meier analysis predicted a successful outcome in 94% of patients after 1 year and
82% after 2 years. The mean number of glaucoma medications used by each patient
was reduced from 3.0 +/- 1.3 preoperatively to 2.0 +/- 1.3 postoperatively (P <
.0001). Best-corrected visual acuity was stable or improved in 64 eyes (94%),
with four (6%) losing 2 or more lines of Snellen acuity. No case of hypotony
(intraocular pressure < 5 mm Hg) or phthisis was observed. CONCLUSION: These
early results suggest that endoscopic cyclophotocoagulation is a safe and
effective therapeutic modality for refractory glaucomas.
PMID- 9402826
TI - Diode laser contact transscleral cyclophotocoagulation for refractory glaucoma in
Asian patients.
AB - PURPOSE: To evaluate the effectiveness and safety of diode laser contact
transscleral cyclophotocoagulation in Asian patients with refractory glaucoma by
lower energy settings with an innovative probe featuring a glass ball tip that
focused the laser beam onto the ciliary body. METHODS: This prospective clinical
study included consecutive Asian patients with dark irides and confirmed for
glaucoma. Only one eye of each patient was treated. Diode laser contact
transscleral cyclophotocoagulation treatment was performed with the center of the
probe placed 1.5 mm behind the limbus. About 30 pulses of 810-mm laser radiation
(power, 1.8 to 2.0 W; duration, 0.3 to 0.5 second) were applied around the eye.
Patients were examined at fixed postoperative intervals. Intraocular pressure
levels and postoperative complications were recorded. The relation between
patient and disease characteristics, total laser energy delivered, and
intraocular pressure effects were analyzed. RESULTS: Thirty-three patients were
studied, with a mean follow-up period of 9.4 months. An average 56% of patients
showed a 30% or greater drop in intraocular pressure. About 38% of patients
achieved sustained intraocular pressure lowering to below 22 mm Hg at 18 months.
Complications were few and included transient hypotony and iritis. CONCLUSIONS:
In Asian patients with refractory glaucoma or painful glaucomatous eyes with poor
visual acuity (defined for this study as worse than 20/200), low-energy-setting
diode laser contact transscleral cyclophotocoagulation by means of the glass ball
probe is relatively effective and safe.
PMID- 9402827
TI - Quantitative differences between the optic nerve head and peripapillary retina in
low-tension and high-tension primary open-angle glaucoma.
AB - PURPOSE: To determine whether quantitative differences in optic nerve topography
could be identified between patients having primary open-angle glaucoma with
normal intraocular pressure (low-tension primary open-angle glaucoma [LT-POAG])
vs those with elevated intraocular pressure (high-tension primary open-angle
glaucoma [HT-POAG]). METHODS: We attempted to match 31 eyes of 31 patients in the
LT-POAG group on a case-by-case basis with comparable eyes of 31 patients with HT
POAG. We used the Heidelberg Retina Tomograph to evaluate the optic nerve head
and retinal nerve fiber layer. RESULTS: Cup areas and cup:disk area ratios were
significantly larger (P < .05), whereas rim areas, rim volumes, retinal nerve
fiber layer heights, and retinal nerve fiber layer cross-sectional areas were
consistently smaller, but not significantly so (P > .05), in the LT-POAG group.
The inferior neuroretinal rim area was significantly smaller (P < .05) and the
mean deviation of superior arcuate area was significantly greater than the
opposite sector in patients with LT-POAG but not in those with HT-POAG. A
relationship between localized measurements of the optic nerve head and mean
deviation was more apparent in the LT-POAG group than in the HT-POAG group.
CONCLUSIONS: The optic cups were larger in patients with LT-POAG than in those
with HT-POAG. Measurements of sectors of the optic disk correlated better with
visual field changes in LT-POAG than did global measurements of the whole nerve
head, indicating more vulnerability of the optic nerve to focal damage with low
intraocular pressure.
PMID- 9402828
TI - Langerhans cell histiocytosis with orbital involvement.
AB - PURPOSE: To review three cases of Langerhans cell histiocytosis with orbital
involvement that represent a significantly excessive incidence of this rare
disease in one community. Current diagnostic criteria and therapeutic modalities
related to Langerhans cell histiocytosis are reviewed. METHODS: Case reports. We
present clinical, radiologic, histopathologic, and epidemiologic information on
three patients with Langerhans cell histiocytosis. RESULTS: All three children,
born within 18 months of one another, manifested rapidly progressive unilateral
proptosis at age 2 years. By computed tomography, all had moderately enhancing
lesions with involvement of the sphenoid bone and lateral orbit as well as the
temporal lobe of the brain. All patients were treated with a combination of
vincristine and prednisone, with variable resolution of their lesions. The
occurrence of three cases in children born in Nogales, Arizona/ Mexico, suggests
an incidence rate of 40 per million, which is approximately 26 times the expected
rate (P = .0001). CONCLUSIONS: The extraordinarily high incidence and the
concentration of cases in both time and space of this cluster implies that
Langerhans cell histiocytosis may be a sentinel disease for unusual environmental
exposures.
PMID- 9402829
TI - Important concepts for treating ocular surface and tear disorders.
AB - PURPOSE: To outline important concepts for treating ocular surface and tear
disorders. METHOD: A review was conducted of recently published findings.
RESULTS: Five concepts were delineated: ocular surface health is ensured by a
close relationship between ocular surface epithelia and the preocular tear film;
a stable tear film is inherently maintained by external adnexae; the intact
protective mechanism is controlled by effective neuroanatomic integration;
corneal epithelial stem cells are located at the corneoscleral limbus; and ocular
surface epithelial cell function is supported by stromal fibroblasts and matrix.
CONCLUSIONS: These concepts stress that ocular surface epithelia and the
preocular tear film function as a unit and, furthermore, that several corneal and
external diseases can be categorized as ocular surface and tear disorders. These
concepts also help one formulate unified diagnostic and therapeutic strategies
for management of these diseases.
PMID- 9402830
TI - Treatment of fungal corneal ulcers with amphotericin B ointment.
AB - PURPOSE: To report two patients with severe fungal corneal ulcers who were
treated successfully with topical amphotericin B ointment. METHODS: Two eyes of
two patients developed corneal ulcers and hypopyon after corneal foreign body
removal. Aspergillus fumigatus and Fusarium solani were isolated in Patients 1
and 2, respectively. By antifungal susceptibility testing, amphotericin B was
shown to have the lowest minimal inhibitory concentration. RESULT: Topical
administration of amphotericin B ointment resulted in dramatic improvement in
fungal corneal ulcers. CONCLUSIONS: Antifungal susceptibility tests may aid with
selection of antifungal agents. Amphotericin B ointment is one of the promising
therapies for keratomycosis caused by antimycotic-resistant fungi.
PMID- 9402831
TI - Serum beta carotene, alpha tocopherol, and age-related maculopathy: the Blue
Mountains Eye Study.
AB - PURPOSE: To assess associations between serum beta carotene, alpha tocopherol,
and age-related maculopathy. METHODS: We studied 156 subjects with age-related
maculopathy matched for age, sex, and month of blood collection to 156 control
subjects without age-related maculopathy. Subjects were identified from the Blue
Mountains Eye Study: those with late age-related macular degeneration and early
age-related maculopathy using examination and grading of retinal photographs, and
control subjects without age-related maculopathy randomly sampled from the study
population. RESULT: Neither serum alpha tocopherol nor beta carotene was
significantly associated with age-related maculopathy. CONCLUSION: These findings
provide no evidence of a protective association between serum alpha tocopherol or
beta carotene and age-related maculopathy.
PMID- 9402832
TI - Bilateral retinal vein occlusion associated with 5,10-methylenetetrahydrofolate
reductase mutation.
AB - PURPOSE: To report on the occurrence of 5,10-methylenetetrahydrofolate reductase
(MTHFR) deficiency, known to cause mild to moderate hyperhomocystinemia and
increased risk of vascular occlusive disease, in a young patient with bilateral
central retinal vein occlusion. METHODS: A 25-year-old man was initially examined
with central retinal vein occlusion in the right eye, followed 4 months later by
a central retinal vein occlusion in the left eye. Studies for risk factors
predisposing to thrombosis were performed. RESULTS: Hematologic studies failed to
detect any pathology. However, the patient was found to be homozygous for 677C-T
mutation in MTHFR enzyme. CONCLUSION: Central retinal vein occlusion may be
associated with a mutation in MTHFR.
PMID- 9402833
TI - Talc embolism: a static retinopathy.
AB - PURPOSE: To document the static nature of crystalline deposits in talc
retinopathy. METHOD: Case report. RESULTS: A 38-year-old woman with a remote
history of intravenous drug abuse showed the incidental finding of fine,
irregularly shaped refractile deposits in the retinal microvasculature. At 2-year
follow-up, fundus findings were identical to the initial manifestation with
respect to the distribution and position of crystalline deposits in each fundus.
CONCLUSION: This case documents the static nature of crystalline deposits in talc
retinopathy.
PMID- 9402834
TI - Retinal toxicity associated with occupational exposure to the fish anesthetic MS
222.
AB - PURPOSE: To report a case of retinopathy associated with chronic occupational
exposure to ethyl-m-aminobenzoic acid methanesulfonate (MS-222), a retinotoxic
fish anesthetic. METHOD: Case report with electroretinograms to document changes
in visual electrophysiology. RESULTS: An ichthyologist with a long history of
skin exposure to MS-222 was initially examined for decreased vision, photophobia,
and photopsia. His electroretinogram abnormalities were similar to those seen in
animal models of acute MS-222 toxicity. After terminating MS-222 contact for 7
months, his vision returned to normal, and his electroretinogram improved.
CONCLUSION: Individuals with occupational exposure to MS-222 should exercise
caution to avoid systemic absorption of this retinotoxic compound.
PMID- 9402835
TI - Bilateral congenital optic nerve head pits in monozygotic siblings.
AB - PURPOSE: To report bilateral congenital optic nerve head pits in monozygotic
siblings. METHOD: Case reports. RESULTS: Pits were found in abnormally large
optic disks in both eyes of two otherwise healthy female monozygotic siblings
aged 15 years. Pit size increased and visual acuity decreased with increased
optic disk area. In one eye, nonrhegmatogenous retinal detachment developed that
eventually necessitated pars plana vitrectomy. The siblings' parents were
unremarkable. CONCLUSIONS: Congenital optic nerve head pits can occur bilaterally
in otherwise healthy monozygotic siblings with ophthalmologically unremarkable
parents. Associated nonrhegmatogenous retinal detachment may be treated by pars
plana vitrectomy. Pit size is positively correlated with disk area.
PMID- 9402836
TI - Coats-type retinitis pigmentosa in a 4-year-old child.
AB - PURPOSE: To describe the occurrence of Coats-like exudative retinopathy secondary
to underlying retinitis pigmentosa in a 4-year-old child. METHOD: Case report.
RESULTS: A 4-year-old girl had bilateral exudative retinal telangiectasia
requiring photocoagulation. She subsequently developed progressive nyctalopia,
photophobia, and reduced peripheral vision. Electroretinography and dark
adaptometry at age 8 years confirmed the diagnosis of retinitis pigmentosa.
CONCLUSIONS: Coats-like exudative retinopathy secondary to retinitis pigmentosa
can manifest as early as age 4 years and can precede the diagnosis of the
underlying retinal dystrophy.
PMID- 9402837
TI - Trifocal uveal melanoma.
AB - PURPOSE: To report the singular case of a patient who developed three
noncontiguous uveal melanomas over a 30-year period. METHOD: Case report. RESULT:
Systemic evaluation of a 50-year-old man with an iris melanoma and bilateral
choroidal melanomas disclosed no evidence of metastases or other primary
neoplastic disease. CONCLUSION: Although rare, the possibility of bilateral and
multifocal uveal melanoma should be recognized.
PMID- 9402838
TI - Bilateral subinternal limiting membrane hemorrhage with Terson syndrome.
AB - PURPOSE: To report the anatomic location of bilateral dome-shaped posterior pole
hemorrhages in a patient with Terson syndrome. METHODS: Case report. We performed
bilateral vitrectomy for vitreous hemorrhage in a patient with Terson syndrome.
After removal of vitreous hemorrhage, the tissue overlying a large discrete
hemorrhage in the posterior pole was removed, and the tissue from one eye was
examined histologically. RESULT: The discrete dome-shaped hemorrhage in the
posterior pole was confined to the retina anteriorly by the internal limiting
membrane. CONCLUSION: Large dome-shaped retinal hemorrhages with Terson syndrome
can be located beneath the internal limiting membrane of the retina.
PMID- 9402839
TI - Cavernous-dural fistula with secondary angle-closure glaucoma.
AB - PURPOSE: To report a rare case of angle-closure glaucoma, secondary to the rapid
development of a choroidal effusion, in a patient with a long-standing cavernous
dural shunt. METHODS: Case report. Investigations included computed tomographic
scan, magnetic resonance imaging, and carotid angiography. RESULTS: The
development of the choroidal effusion occurred because of partial thrombosis of
the ipsilateral superior ophthalmic vein and cavernous sinus. Drainage of the
choroidal effusion resolved the angle-closure glaucoma. CONCLUSIONS: The
combination of worsening signs and evidence of thrombosis indicates impending
resolution of a cavernous-dural shunt. However, if a choroidal effusion causes
angle-closure glaucoma, prompt surgical drainage should be considered to prevent
permanent peripheral anterior synechiae formation, with the expectation that the
effusion will not recur.
PMID- 9402840
TI - Severe vision loss and neovascular glaucoma complicating superior ophthalmic vein
approach to carotid-cavernous sinus fistula.
AB - PURPOSE: To report a patient with unilateral vision loss and neovascular glaucoma
after attempted superior ophthalmic vein embolization in the treatment of a
carotid-cavernous sinus fistula. METHODS: A 69-year-old man with a history of a
left dural carotid-cavernous sinus fistula underwent attempted treatment with
superior ophthalmic vein embolization. The procedure was unsuccessful, and the
left superior ophthalmic vein was ligated. RESULTS: Uncontrolled left proptosis
and intraocular pressure necessitated urgent orbital decompression with severe
vision loss and neovascular glaucoma. CONCLUSION: Superior ophthalmic vein
embolization in the management of carotid-cavernous fistula may be associated
with vision-threatening complications.
PMID- 9402842
TI - Warthin tumor of the lacrimal gland.
AB - PURPOSE: To describe a case of Warthin tumor involving the lacrimal gland.
METHODS: Case report. The patient underwent a lateral orbitotomy to remove a
nodular lesion involving the lacrimal gland. The specimen was submitted for
histopathologic examination. RESULTS: The lesion was characterized by epithelial
columnar cells arranged in solid nests or lining cystic spaces containing an
exudative fluid and by pronounced lymphoid infiltrate with focal follicular
formation. CONCLUSIONS: To our knowledge, this is the first case of Warthin tumor
involving the lacrimal gland. Management requires complete excision of the
lesion.
PMID- 9402841
TI - Endometrial carcinoma in a patient with blepharophimosis syndrome and menstrual
abnormality.
AB - PURPOSE: To describe a woman with blepharophimosis syndrome and menstrual
abnormality who developed endometrial carcinoma. METHODS: A 26-year-old woman
with blepharophimosis syndrome and menstrual abnormality had increased serum
luteinizing hormone and serum follicle-stimulating hormone levels. She was
followed up for 5 years. RESULT: She developed endometrial carcinoma.
CONCLUSIONS: Patients with blepharophimosis syndrome and menstrual abnormality
should be examined gynecologically. Hormone-dependent endometrial carcinoma may
develop.
PMID- 9402843
TI - Non-African Burkitt lymphoma presenting with oral thrush and an orbital mass in a
child.
AB - PURPOSE: To report an unusual case of orbital involvement with non-African
Burkitt lymphoma in a child. METHODS: A 26-month-old boy developed oral thrush
and painless right proptosis with eyelid swelling. Magnetic resonance imaging
disclosed a diffuse mass involving the inferior, lateral, and superior right
orbit and both maxillary sinuses. Incisional biopsy of the orbital mass was
performed. RESULTS: Histopathology disclosed diffuse infiltration of the orbital
tissues by a high-grade lymphoid neoplasm that showed positive immunoreactivity
for B-cell markers. Immunoglobulin gene rearrangement studies disclosed a
characteristic t(8;14) translocation consistent with a small, noncleaved
malignant lymphoma of the Burkitt type. CONCLUSION: Non-African Burkitt lymphoma
may manifest with orbital involvement.
PMID- 9402844
TI - Familial aggregation of age-related maculopathy.
PMID- 9402846
TI - MTS1 expression and prognosis in acute myeloid leukemia.
AB - MTS1, a tumor suppressor gene located on chromosome 9p21, has been shown to be
altered in a number of human tumor cell lines, primary solid tumors, and
leukemias. In this study we found low expression of MTS1 in lymphocytes from
seven of nine healthy donors, but in none of eight granulocyte samples from the
same controls, suggesting a physiological role of MTS1 in peripheral blood cells
capable of proliferation, but not in end-stage differentiated cells. We detected
MTS1 mRNA expression in 38 of 57 patients (66%) with acute myelogenous leukemia
(AML) treated in a standardized clinical protocol. No deletion of the MTS1 gene
was found in any of the AML samples tested. There was no significant association
between expression of MTS1 and response to therapy, progression-free, or overall
survival. Except for a negative correlation between MTS1 level and leukocyte
count at diagnosis (p = 0.03), there was also no association with any of the
known prognostic parameters in AML. We conclude that MTS1 shows a significantly
higher expression in leukemic than in normal peripheral blood cells, that
deletion of MTS1 is not a frequent event in AML, and that its expression is not
significantly correlated with outcome of the disease.
PMID- 9402845
TI - Randomized open label phase III trial of CEOP/IMVP-Dexa alternating chemotherapy
and filgrastim versus CEOP/IMVP-Dexa alternating chemotherapy for aggressive non
Hodgkin's lymphoma (NHL). A multicenter trial by the Austrian Working Group for
Medical Tumor Therapy.
AB - Primary end point of this trial was to reduce neutropenic infections during the
treatment of aggressive NHL with CEOP/IMVP-Dexa (cyclophosphamide, epirubicin,
vincristine, prednisolone ifosfamide, methotrexate, VP-16, and dexamethasone).
Further, we studied the influence of filgrastim on dose intensity of CEOP/IMVP
Dexa, on the rate of complete remissions, on the time to relapse, and on
survival. Eighty-five patients with untreated large-cell NHL were randomized to
one of two treatment arms; 74 patients were eligible. Thirty-eight patients in
arm 1 were treated with CEOP/IMVP-Dexa chemotherapy and filgrastim, 36 in arm 2
with CEOP/IMVP-Dexa chemotherapy alone. In arm 1 filgrastim was self-injected by
the patients at 5 micrograms/kg body wt. s.c. daily, except on the days when
cytotoxic drugs were given. During treatment we did weekly complete blood counts.
Median leukocyte counts were 10.91 x 10(9)/l and 5.46 x 10(9)/l in arm 1 and 2,
respectively (p = 10(-6)). Median neutrophil counts were 7.7 x 10(9)/l in arm 1
and 2.72 x 10(9)/l in arm 2 (p < 10(-6)). Median neutrophil nadirs were 0.199 x
10(9)/l and 0.213 x 10(9)/l in arm 1 and 2, respectively (p = 0.09). Mean
platelet nadirs were 95 and 152 x 10(9)/l (p = 0.000004) and mean hemoglobin
nadirs 83.95 g/l and 92.78 g/l (p = 0.00558) in arm 1 and 2, respectively. Dose
intensity of CEOP/IMVP-Dexa was 82.3% and 76.2% in arm 1 and 2, respectively (p =
0.041). Forty-two percent and 58% of patients experienced a febrile neutropenia
in arm 1 and 2, respectively (not significant, NS). Median time to first
neutropenic infection was in treatment week 11 and 6 in arm 1 and 2, respectively
(NS). There was no significant difference in rate, duration, and kind of
infection, duration of hospitalization, or antibiotic treatment. Seven toxic
deaths occurred, all due to neutropenic infection, 6 and 1 in arm 1 and 2,
respectively (p = 0.0732). Four of the six patients, who died of infection in arm
1 were older than 60 years. Complete remission rate was 83% and 66.7% in arm 1
and 2, respectively (NS). After a median observation time of 3 years there was no
difference in time to relapse or survival. Filgrastim increases leukocyte and
neutrophil counts and dose intensity, if used with CEOP/IMVP-Dexa chemotherapy in
high-grade lymphomas. There was no significant effect on febrile neutropenia or
infections. The more frequent fatal neutropenic infection rate in the filgrastim
arm was not statistically significant. It is most appropriate to explain it by
the patient's age in combination with the high dose intensity. The small increase
in dose intensity had no effect on survival but probably decreased hemoglobin
levels and platelet counts in arm 1. We were unable to show a benefit for
filgrastim in combination with CEOP/IMVP-Dexa.
PMID- 9402847
TI - In vitro down-regulation of bcl-2 expression by all-trans retinoic acid in AML
blasts.
AB - Using flow cytometry, we have investigated the effects of 0.5 microM all-trans
retinoic acid (ATRA) on bcl-2 expression in the blast cells of 25 acute
myeloblastic leukemia (AML) patients and the HL-60 cell line after incubation for
6 days. We observed a significant decrease of bcl-2 expression after treatment
with ATRA in 12 of 25 AML samples and the HL-60 cells. The mean fluorescence
intensity (MFI) ratio for the bcl-2 levels of the ATRA responders (n = 12) was
reduced to 7.9 +/- 4.8 following incubation with ATRA compared with 10.9 +/- 6.5
(mean +/- SD) for control samples incubated without ATRA (p = 0.011). There was
no significant difference between the baseline bcl-2 MFI ratio in the ATRA
responders (11.14 +/- 7, n = 12) and the non responders (14.18 +/- 11.3, n = 13;
p = 0.432). The down-regulation of bcl-2 expression by ATRA was not significantly
associated with CD34-negative or -positive AML. There was no correlation between
AML subtypes and regulation of bcl-2 expression by ATRA. Complete remission and
overall survival were not significantly improved in bcl-2 down-regulated cases.
Our data confirm that ATRA can down-regulate the bcl-2 expression in AML blasts.
Because many chemotherapeutic agents also operate through the activation of
programmed cell death and bcl-2 levels are positively associated with resistance
to apoptosis, ATRA can be used in combination chemotherapy to increase the
chemosensitivity of some patients with AML.
PMID- 9402848
TI - Proliferative effect of postapheresis platelet donor plasma on a megakaryoblastic
leukemia cell line.
AB - Platelet donors sometimes show an increased platelet count following apheresis.
We analyzed the effect of plasma obtained from such donors, along with
thrombopoietin (Tpo), for growth and differentiation-inducing activity on a
megakaryoblastic leukemia cell line, Meg-J. Colony formation was stimulated by
donor plasma for Meg-J cells in a dose-dependent manner, and the time course of
the sampling peaked 1 day after apheresis. Neither the donor plasma nor Tpo
induced morphological differentiation. Donor plasma from any sampling time
decreased CD41 and CD42b expression by more than 10%, and more than a 10%
decrease of CD41 was induced by Tpo. The measurement of plasma Tpo showed no
statistically significant increase after platelet donation. Our data suggest
that, following apheresis, donor plasma contains factor(s) that: (a) stimulate
growth rather than induce differentiation of a megakaryoblastic cell line; (b)
are present in increased levels after apheresis; and (c) are different from Tpo.
PMID- 9402850
TI - Prolonged fever as an unusual manifestation of the hyaline vascular type of
Castleman's disease in the chest: report and review of the literature.
PMID- 9402849
TI - Serum levels of interleukin-1 beta, luteinizing hormone, and prolactin correlate
with the expression of CD45 isoforms on CD4+ peripheral blood T lymphocytes in
healthy women.
AB - The expected association between age and the CD45 isoforms expression on CD4+ T
PBL is much more obvious in men than in women. We investigated whether or not
circulating factors influence the differentiation of CD4+ T-PBL. Peripheral blood
samples were obtained from 56 healthy age-matched subjects (28 men and 28 women,
21-55 years old). Mononuclear leukocytes were analyzed by three-color flow
cytometry. The serum concentrations of interleukin-1 beta (IL-1 beta),
interleukin-6, tumor necrosis factor-alpha (TNF-alpha), GM colony-stimulating
factor, prolactin (Prl), and luteinizing hormone (LH) were determined by ELISA.
The expected age-related decrease of naive (CD45RA+,RO-) cells and increase of
memory (CD45RA-,RO+) cells among CD4+ T-PBL were observed in men only (p < 0.001
and 0.005). In women, these correlations were not significant. On the other hand,
in women only, elevated IL-1 beta was associated with fewer naive and more memory
cells among CD4+ T-PBL (p < 0.001). In both sexes, IL-1 beta correlated with the
expression of CD25 on CD4+ T-PBL (on either naive or memory cells, p < 0.001).
Other cytokines or the CD8+ T-PBL showed no significant correlation. In women,
the elevation of LH at mid-cycle inversely correlated with the proportion of
naive CD4+ T-PBL (p < 0.01). Elevated LH was associated with more CD25 on memory
CD4+ T-PBL (p < 0.01). A significant correlation exists between IL-1 beta and LH
(p < 0.001). Furthermore, in both sexes, Prl correlated with the proportion of
CD4+ cells among T-PBL. In men, elevated Prl was associated with more naive CD4+
T-PBL (p < 0.005), while in women, Prl correlated with more transient CD45RA+,
RO+ cells among CD4+ T-PBL and increased TNF-alpha (p < 0.05 for both). Thus,
circulating IL-1 beta could be involved in the expression of CD25 on CD4+ T-PBL
and favors the generation of memory CD4+ T-PBL. In women, the IL-1 beta- and/or
mid-cycle-dependent processes seem to overwhelm the age-related changes. Elevated
Prl might exert a dual influence: it favors the development of naive CD4+ T
lymphocytes and possibly acts in, synergy with other cytokines during immune
stimulation.
PMID- 9402851
TI - Subcutaneous low-molecular-weight heparin for treatment of Trousseau's syndrome.
AB - We report the case of a 76-year-old man with recurrent thromboses despite oral
anticoagulation with phenprocoumon and low-grade chronic disseminated
intravascular coagulation. Workup revealed a bronchial carcinoma (NSCCL) with
hilar and mediastinal lymph node metastases. The clinical condition was
consistent with Trousseau's syndrome. Based on reports in the literature, the
therapy was changed to intravenous unfractionated heparin (UFH), which was
effective in controlling the thrombotic coagulopathy. For practical reasons,
despite a lack of evidence of its effectiveness in Trousseau's syndrome, therapy
with UFH was changed to subcutaneous low-molecular-weight heparin (LMWH,
nadroparine) in therapeutic doses of 100 IU/ kg body wt. 12 hourly. On an
outpatient basis, five chemotherapy cycles were administered, and after
metastases of the brain had been detected radiotherapy was initiated. Following
7.5 months of progressive neoplastic disease the patient died. He had remained
free of thromboembolic complications under continued LMWH therapy during the last
6.5 months of his life. LMWH might be a convenient alternative to the established
therapy with UFH in Trousseau's syndrome.
PMID- 9402852
TI - Pancytopenia and fever of unknown origin in a 72-year-old woman.
PMID- 9402853
TI - A 75-year-old woman with fatigue, monocytosis, and hypothyroidism.
PMID- 9402854
TI - Mucosal tolerance and rheumatoid arthritis.
PMID- 9402856
TI - Rheumatology--the whole is more than the sum of the parts...
PMID- 9402855
TI - Musculoskeletal ultrasound imaging: a new diagnostic tool for the rheumatologist?
PMID- 9402857
TI - Cryptic T-cell epitopes and their role in the pathogenesis of autoimmune
diseases.
AB - Immune recognition of self-proteins features prominently in the early
pathogenesis of autoimmune rheumatic diseases such as rheumatoid arthritis (RA),
Sjogren's syndrome (SS), systemic lupus erythematosus (SLE) and systemic
sclerosis. The mechanisms which provide lymphocytes with access to such
autoantigens are therefore fundamental in creating the opportunity for autoimmune
responses to develop. It has long been thought that the tissue or cellular
location of some self-proteins may determine that they are normally 'hidden' from
immune recognition, thereby reducing their potential for autoantigenicity.
Recently, this concept has been extended to apply even to different epitopes
within the same protein. Many studies, encompassing a wide variety of antigens,
have shown that some epitopes are not presented for recognition by T lymphocytes
unless they are produced in unusually large concentrations or unless they are
freed from the configuration of their native antigen. Epitopes for which this
phenomenon occurs are described as cryptic. There is increasing interest in the
possibility that crypticity may be an important characteristic of epitopes which
are recognized by T lymphocytes in autoimmune pathogenesis. The evidence which
has led to this theory and its significance are reviewed.
PMID- 9402858
TI - Small fragments of cartilage oligomeric matrix protein in synovial fluid and
serum as markers for cartilage degradation.
AB - We determined the tissue distribution of cartilage oligomeric matrix protein
(COMP) in man and evaluated COMP in synovial fluid (SF) and serum. COMP was
purified from human articular cartilage. Polyclonal antibodies were used to
detect COMP in tissue cryosections and protein extracts. COMP was determined
quantitatively and qualitatively in SF and serum by competitive enzyme-linked
immunosorbent assay and immunoblotting. Knee joint SF was taken from nine
cadaveric and six living controls, 52 patients with osteoarthritis (OA), 85
patients with rheumatoid arthritis (RA) and 60 patients with other forms of
inflammatory arthritis. The degradative potential of SF on native COMP was tested
in vitro. The highest concentrations of COMP were measured in articular cartilage
and meniscus, the lowest in rib and trachea. Compared with controls, the
concentrations of COMP in SF and serum were elevated in 36 and 50% of the
patients. A total of 84% of patients with RA and 60% of patients with other forms
of inflammatory arthritis showed significant amounts of low-molecular-weight COMP
fragments (50-70 kDa) in SF. In contrast, SF fragments were present in only 21%
of the OA patients. Furthermore, 13% of SF taken from patients with RA or other
forms of inflammatory arthritis were able to degrade COMP in vitro. Using
inhibitors, the involvement of serine proteinases could be demonstrated in only
8% of the cases. Based on these results, the absolute levels of COMP in SF and
serum, and its fragmentation pattern in SF, seem to be promising as markers of
joint tissue metabolism.
PMID- 9402859
TI - Tissue-derived macromolecules and markers of inflammation in serum in early
rheumatoid arthritis: relationship to development of joint destruction in hands
and feet.
AB - We have previously shown that serum concentrations of cartilage oligomeric matrix
protein (COMP) are increased early in rheumatoid arthritis (RA) patients who
subsequently develop advanced large-joint destruction. A prognostic value for
joint damage of serum concentrations of hyaluronan (HA) is also suggested by
previous studies. In contrast, serum concentrations of bone sialoprotein (BSP)
have not been useful for identifying patients with progressive large-joint
destruction. In the present study, we have examined the hypothesis that serum
concentrations of these tissue-derived markers are of prognostic value in RA for
the development of radiographically detectable joint damage in hands and feet.
Serum concentrations of COMP, HA and BSP were quantified in samples obtained from
62 patients within the first year after onset of RA and were related to the
development of radiographically detectable damage in these joints after 5 yr.
Neither the serum concentrations of COMP nor of BSP at inclusion predicted joint
damage in hands and feet after 5 yr, and the concentration of these proteins did
not change over the 5 yr period. However, the serum concentration of HA at
inclusion correlated with the radiographic score at the 5 yr follow-up (r =
0.425, P < 0.01), but was not a better predictor in this respect than the
erythrocyte sedimentation rate or C-reactive protein levels at inclusion. Thus,
serum concentrations of the three studied tissue-derived macromolecules were in
this study not useful for identifying patients prone to small-joint destruction.
PMID- 9402860
TI - Different approaches to synovial membrane volume determination by magnetic
resonance imaging: manual versus automated segmentation.
AB - Automated fast (5-20 min) synovial membrane volume determination by MRI, based on
pre-set post-gadolinium-DTPA enhancement thresholds, was evaluated as a
substitute for a time-consuming (45-120 min), previously validated, manual
segmentation method. Twenty-nine knees [rheumatoid arthritis (RA) 13,
osteoarthritis (OA) 16] and 17 RA wrists were examined. At enhancement thresholds
between 30 and 60%, the automated volumes (Syn(x%)) were highly significantly
correlated to manual volumes (SynMan) (knees: rho = 0.78-0.91, P < 10(-5) to <
10(-9); wrists: rho = 0.87-0.95, P < 10(-4) to < 10(-6)). The absolute values of
the automated estimates were extremely dependent on the threshold chosen. At the
optimal threshold of 45%, the median numerical difference from SynMan was 7 ml
(17%) in knees and 2 ml (25%) in wrists. At this threshold, the difference was
not related to diagnosis, clinical inflammation or synovial membrane volume, e.g.
no systematic errors were found. The inter-MRI variation, evaluated in three
knees and three wrists, was higher than by manual segmentation, particularly due
to sensitivity to malalignment artefacts. Examination of test objects proved the
high accuracy of the general methodology for volume determinations (maximal error
6.3%). Preceded by the determination of reproducibility and the optimal threshold
at the available MR unit, automated 'threshold' segmentation appears to be
acceptable when changes rather than absolute values of synovial membrane volumes
are most important, e.g. in clinical trials.
PMID- 9402861
TI - Circulating soluble adhesion molecules in patients with classical polyarteritis
nodosa.
AB - The objective was to evaluate whether changes in circulating soluble adhesion
molecule levels reflect disease activity in patients with systemic polyarteritis
nodosa (PAN). A sandwich ELISA was used to measure soluble (s) intercellular
adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), E
selectin, L-selectin and P-selectin in sera and plasma from 22 patients with
active PAN, in sera from 13 of these patients taken serially during follow-up,
and in sera from 13 healthy controls. At the time of diagnosis, sICAM-1, sVCAM-1
and sE-selectin levels (488.5 +/- 201.3, 1176.5 +/- 514.1 and 60.6 +/- 27 ng/ml,
respectively) were significantly higher in patients than in controls (P < 0.0001,
P = 0.001 and P = 0.003, respectively). In contrast, sL-selectin levels tended to
be lower in patients than in controls. Within the first 7 days after starting
treatment, there was a significant increase in sICAM-1 concentrations, which fell
thereafter, but did not completely reach normal levels when patients achieved
clinical remission. sE-selectin also remained elevated during follow-up. Only
sVCAM-1 decreased, tending to reach normal values in inactive disease. Increased
levels of sICAM-1, sVCAM-1 and sE-selectin, and decreased levels of sL-selectin,
in active PAN suggest immune and endothelial stimulation during disease activity.
Abnormal levels of soluble adhesion molecules in clinically inactive patients
might reflect persistence of immune activation and/or endothelial cell exposure
to a remaining inflammatory microenvironment.
PMID- 9402862
TI - The association of HLA-DRB genes and the shared epitope with rheumatoid arthritis
in Pakistan.
AB - The association of particular HLA-DR alleles and the shared epitope with
rheumatoid arthritis (RA) is now well established. The strength of these links
varies between races. Furthermore, the proposition that the presence of the
shared epitope is indicative of severe disease has been more difficult to sustain
in non-Europeans. This study examines the frequency of HLA-DR and HLA-DRB1
amongst Pakistanis for the first time. Using the polymerase chain reaction (PCR)
and sequence-specific oligonucleotide probes (PCR-SSOP) and primers (PCR-SSP),
HLA-DR phenotype and genotype frequencies were ascertained in 86 RA hospital out
patients and 79 healthy controls matched for age, gender and ethnicity. HLA-DR1
and HLA-DR4 frequency was similar in patients and controls. HLA-DR10 occurred in
26 instances (15%) in RA and in eight (5%) controls (Pcorr = 0.048). HLA-DR2 was
also increased in patients (P = 0.053) and its major subtype DR15 was
significantly increased (Pcorr = 0.03). HLA-DR5 frequency was 5% in patients and
19% in controls (Pcorr = 0.002). The HLA-DR4 alleles possessing the shared
epitope were more common in RA (Pcorr = 0.03) and this difference was enhanced by
inclusion of other alleles possessing the shared epitope (Pcorr = 0.002). Shared
epitope alleles were observed in 43 (50%) patients and 17 (22%) controls (Pcorr =
0.003). The shared epitope did not distinguish patients with more severe disease,
as reflected by pain, joint deformities, disability, rheumatoid factor or X-ray
damage. The distribution of HLA-DR alleles in Pakistanis with RA supports the
shared epitope hypothesis. In common with other non-European racial groups, HLA
DR4 was not associated with RA. Unlike other groups, there was a weak link of RA
with HLA-DR2. A protective effect of HLA-DR5 was apparent. In accord with some
other studies, the shared epitope in this hospital out-patient population was not
a marker for more severe disease.
PMID- 9402863
TI - Mesangial glomerulonephritis as an extra-articular manifestation of rheumatoid
arthritis.
AB - Mesangial glomerulonephritis (MesGN) is a frequent renal biopsy finding in
patients with rheumatoid arthritis (RA) presenting with haematuria and/or
proteinuria. The purpose of this study was to describe the mesangial
immunofluorescence (IF) findings in 37 such RA patients, and to correlate the
nature of the glomerular immunodeposits with clinical data, levels of serum
immunoglobulins and the concentrations of serum rheumatoid factors (RFs). The
serological findings in RA patients with MesGN were correlated with those of RA
patients matched for age, sex and duration of RA, but without clinically evident
renal disease. The most characteristic mesangial IF finding in 37 RA patients
with MesGN was IgM observed in 29 specimens (78%). IgA (n = 16) and C3 (n = 15)
deposits were also frequently found, whereas C1q (n = 3) and IgG (n = 2) deposits
were only occasionally seen. Two main patterns of IF findings could be
classified. (1) Granular IgM deposits as a sole or main finding (IgM GN; 25
specimens). The intensity of the mesangial IgM deposits did not correlate with
the duration or severity of RA nor with the levels of serum immunoglobulins.
However, a significant correlation with the intensity of mesangial IgM deposits
and the levels of serum IgM class RF was observed. (2) Granular IgA deposits
usually together with the complement component C3, i.e. IgA glomerulonephritis
(IgA GN; nine specimens). The intensity of mesangial IgA deposits correlated
significantly with the duration and severity of RA, and especially with serum IgA
levels. Both RA patients with IgA GN or IgM GN were associated with a more
frequent occurrence and higher titres of serum RFs when compared with the RA
patients without nephropathy. The clinicopathological correlations and the
association with RF support the concept that MesGN is related to the basic
rheumatoid disease, and it should be regarded as an extra-articular manifestation
of RA.
PMID- 9402864
TI - The rational use of methotrexate in rheumatoid arthritis and other rheumatic
diseases.
AB - Methotrexate's mechanism of action affects both the inflammatory and
immunosuppressive aspects of response. Its kinetics are defined and include
variable absorption, intracellular metabolism, and both renal and biliary
excretion. Methotrexate is clearly effective in the treatment of rheumatoid
arthritis and may be able to decrease the rate of formation of new bony erosions.
It is also effective in psoriatic arthritis and is being used in a multiplicity
of other rheumatic diseases. The most common toxicities ascribed to methotrexate
are gastrointestinal (e.g. stomatitis) and central nervous system (e.g. headache,
fatigue, malaise). Methotrexate-induced hepatic cirrhosis is less common in
rheumatoid arthritis than previously thought, although its occurrence in
psoriasis is probably higher than in rheumatoid arthritis. Haematological, renal
and pulmonary toxicity occur, but are rare, while teratogenicity is well
documented. A new and disturbing adverse event, pseudolymphomas are being
reported at present.
PMID- 9402865
TI - Rheumatology in Switzerland.
PMID- 9402866
TI - Mycobacterium marinum infection causing septic arthritis and osteomyelitis.
AB - A 48-yr-old female on immunosuppressive therapy for fibrosing alveolitis and
polymyositis developed a septic arthritis of the left middle finger proximal
interphalangeal joint, tenosynovitis of the left palm and osteomyelitis of the
right hindfoot due to infection with Mycobacterium marinum. Such widespread and
severe bone and joint involvement has not been described previously with this
organism.
PMID- 9402867
TI - Polyarteritis nodosa and the antiphospholipid syndrome.
AB - We describe a case of classical polyarteritis nodosa (PAN) with visceral
aneurysms presenting with renal infarction and hypertension. The female patient
also had all the laboratory features of the antiphospholipid syndrome (APS) and 2
months into her illness developed a large iliofemoral thrombosis. She responded
well to immunosuppressive therapy and anti-coagulation. Repeat arteriogram showed
regression of the visceral aneurysms. The link between PAN and APS, and the
therapeutic dilemma posed by this association, are discussed.
PMID- 9402869
TI - School attendance and juvenile chronic arthritis.
AB - We studied the school attendance of 113 children and adolescents (mean age 11 yr,
S.D. 3.8, range 3-18 yr) with juvenile chronic arthritis (73 with pauci- and 40
with polyarthritis). The mean attendance rate for the group was 92% (equivalent
to 15 absent days a year) with a median of 97%. Attendance was significantly
lower in the more severely affected poly group (90% vs 98% in the pauci group; P
= 0.03). We found associations of school absence (i) with decreased compliance
with physical treatments (r = -0.35, P < 0.05 for compliance with physiotherapy)
in the poly group and (ii) with child psychological deviance (r = 0.36 for
parentally rated and r = 0.42 for teacher-rated psychological deviance; both P <
0.05) in the pauci group. We conclude that school attendance can be good in
severely affected children. Severity of illness, treatment compliance and
psychological problems in the child may affect school attendance.
PMID- 9402868
TI - Juvenile chronic arthritis: diagnosis and management of tibio-talar and sub-talar
disease.
AB - The aim of this study was to compare clinical evaluation of the site of hindfoot
synovitis with contrast-enhanced magnetic resonance imaging (MRI) findings in
children with juvenile chronic arthritis (JCA), and to evaluate the efficacy of
selective guided intra-articular steroid injections. Thirteen symptomatic ankles
of 11 consecutive JCA patients were examined clinically and with contrast
enhanced MRI. Pannus was demonstrated on MRI in both tibio-talar and sub-talar
joints in 10 ankles, in the tibio-talar joint only in one ankle and in neither
joint in two ankles. Correlation of clinical and MRI findings was good for the
tibio-talar joint with concordance in 11/13 cases. Correlation was poor for the
sub-talar joints. Of the 10 sub-talar joints shown to have pannus on MRI, only
two were thought to have had definite clinical evidence of synovitis. Guided
intra-articular steroid injection resulted in at least 6 months remission in 6/9
ankles compared with 1/10 ankles which had had previous unguided injections. We
therefore recommend the use of image guidance for intra-articular triamcinolone
hexacetonide injection in children with hindfoot synovitis.
PMID- 9402870
TI - Pachydermoperiostosis in childhood.
AB - We report a family with pachydermoperiostosis (idiopathic hypertrophic
osteoarthropathy) spanning four generations with 10 affected individuals, four of
whom are children although pachydermoperiostosis is rare in childhood. In this
family, with intermarriage, the inheritance is autosomal recessive and it is
possible that there are individuals who are homozygous for the
pachydermoperiostosis gene. These individuals do not appear to be more severely
affected, although one of them had a cleft palate and congenital heart defect
which may be a manifestation of being homozygous.
PMID- 9402871
TI - Protracted arthritis of familial Mediterranean fever (an unusual complication).
AB - An unusual case of familial Mediterranean fever and vasculitis in which the
patient developed amyloidosis and had protracted arthritis persisting for years
is presented. The long-standing arthritis did not respond to corticosteroid and
colchicine therapy, but an excellent response to synovectomy was achieved.
PMID- 9402872
TI - Clinical improvement and radiological deterioration in rheumatoid arthritis.
PMID- 9402873
TI - The use of granulocyte colony-stimulating factor in joint replacement surgery in
a patient with Felty's syndrome.
PMID- 9402874
TI - Gastrointestinal complications and meloxicam.
PMID- 9402875
TI - Pre-treatment X-rays for rheumatoid arthritis treated with methotrexate.
PMID- 9402876
TI - Anti-beta 2-glycoprotein I antibody testing in patients with antiphospholipid
syndrome.
PMID- 9402877
TI - Tibiofemoral joint space narrowing and meniscal lesions.
PMID- 9402878
TI - Kikuchi's lymphadenitis developing in a patient with mixed connective tissue
disease and Hashimoto's thyroiditis.
PMID- 9402879
TI - Iliopsoas bursa enlargement.
PMID- 9402880
TI - Mannose-binding lectin gene polymorphism in Greek systemic lupus erythematosus
patients.
PMID- 9402881
TI - EEG coherency. I: Statistics, reference electrode, volume conduction, Laplacians,
cortical imaging, and interpretation at multiple scales.
AB - Several methodological issues which impact experimental design and physiological
interpretations in EEG coherence studies are considered, including reference
electrode and volume conduction contributions to erroneous coherence estimates. A
new measure, 'reduced coherency', is introduced as the difference between
measured coherency and the coherency expected from uncorrelated neocortical
sources, based on simulations and analytic-statistical studies with a volume
conductor model. The concept of reduced coherency is shown to be in semi
quantitative agreement with experimental EEG data. The impact of volume
conduction on statistical confidence intervals for coherence estimates is
discussed. Conventional reference, average reference, bipolar, Laplacian, and
cortical image coherencies are shown to be partly independent measures of
neocortical dynamic function at different spatial scales, due to each method's
unique spatial filtering of intracranial source activity.
PMID- 9402882
TI - Correlation of developmental neurological findings with spectral analytical EEG
evaluations in pre-school age children.
AB - For the differentiation of developmental neurological disorders in pre-school age
children, the relationship between automatically derived EEG parameters and
developmental neurological findings was investigated. Within the scope of the
Munich Pediatric Longitudinal Study, the sample sets of 4- and 5-year-old
children (according to the frontal and parieto-occipital EEG derivations) with
selected abnormal findings categorized by special items were compared with the
corresponding control groups. This was carried out by means of one-sided t tests
and relative frequency band-related as well as single-step spectral power
parameters in the alpha range of the EEG. Automatic analysis using single-step
power values was superior to that using band-related parameters. This led to the
conclusion that use of age-specific single-step parameters for a quantitative EEG
analysis and ignoring the classical frequency bands will yield statistically
greatly improved results. For 4- and 5-year-old children, the best separation of
the neurologically abnormal groups from the normal control groups was obtained
using relative spectral values in the frequency range of 9.0-9.8 Hz with a
maximum at 9.4 Hz. At the same time, the topographical conditions of brain
immaturation should be taken into account. The results for the children examined
in this study differ in a stronger distinction over the frontocentral brain
region of 4- and 5-year-olds (P < 0.01) and through an additional distinction
over the parietooccipital region of the 5-year-olds (P < 0.001). It still must be
tested whether the spectral parameter at 9.4 Hz is age-specific for 4- and 5-year
old children or whether in other age groups different spectral parameters are of
use. As an examiner-independent method, the automatic EEG analysis should become
an integral component of developmental neurological diagnostics.
PMID- 9402883
TI - Quantitative analysis of discontinuous EEG in premature and full-term newborns
during quiet sleep.
AB - To assess the spatio-temporal structure of discontinuous EEG tracing in mature
and immature newborns, we analysed mean spectral power in frequency bands between
0.8 and 16.8 Hz in 6 full-term newborns and 7 premature newborns < 32 weeks of
conceptional age. The most striking results showed a significantly higher mean
spectral power for the first half of bursts than for the second half recorded in
> 2.8-14.8 Hz frequency bands. This pattern was more pronounced in premature than
in full-term newborns. No clear differences were observed in comparisons between
the first and the second half of the interburst periods. In addition, as far as
mid and high frequency band spectra were considered, the mean spectral power of
burst was, in both groups, higher in the right as compared to the left occipital
regions.
PMID- 9402885
TI - FFT analysis of EEG during stage 2-to-REM transitions in narcoleptic patients and
normal sleepers.
AB - The EEG in REM sleep is markedly different from the EEG in non-REM sleep;
however, very little research has been conducted analyzing the transition from
NREM to REM sleep. The purpose of this study was to describe the changes in EEG
power spectra that coincide with significant physiological events throughout the
transition from stage 2 to REM sleep. Furthermore, a comparison of the stage 2 to
REM transition between narcoleptic patients and normal sleepers was conducted.
Five female and five male patients diagnosed with narcolepsy-cataplexy and 10
normal sleepers matched for age and gender participated. Analyses were based on
the consecutive appearance of 3 common physiological indicators of REM sleep:
First, a decrease in tonic submental EMG activity; second, the appearance of saw
tooth waves; and third, the appearance of rapid eye movements. Systematic changes
in EEG power density were evident for delta, theta, alpha and sigma frequencies,
across the stage 2-REM transition. These changes appeared to be relatively
continuous throughout this transition rather than changing dramatically following
the onset of any one of the 3 primary physiological indicators of REM sleep.
Furthermore, the transition from stage 2 to stage REM appeared to be similar for
narcoleptic patients and normal sleepers.
PMID- 9402884
TI - Spindle frequency activity in the sleep EEG: individual differences and
topographic distribution.
AB - The brain topography of EEG power spectra in the frequency range of sleep
spindles was investigated in 34 sleep recordings from 20 healthy young men.
Referential (F3-A2, C3-A2, P3-A2 and O1-A2) and bipolar derivations (F3-C3, C3-P3
and P3-O1) along the anteroposterior axis were used. Sleep spindles gave rise to
a distinct peak in the EEG power spectrum. The distribution of the peak
frequencies pooled over subjects and derivations showed a bimodal pattern with
modes at 11.5 and 13.0 Hz, and a trough at 12.25 Hz. The large inter-subject
variation in peak frequency (range: 1.25 Hz) contrasted with the small intra
subject variation between derivations, non-REM sleep episodes and different
nights. In some individuals and/or some derivations, only a single spindle peak
was present. The topographic distributions from referential and bipolar
recordings showed differences. The power showed a declining trend over
consecutive non-REM sleep episodes in the low range of spindle frequency activity
and a rising trend in the high range. The functional and topographic
heterogeneity of sleep spindles in conjunction with the intra-subject stability
of their frequency are important characteristics for the analysis of sleep
regulation on the basis of the EEG.
PMID- 9402886
TI - A normative study of the maintenance of wakefulness test (MWT).
AB - The maintenance of wakefulness test (MWT) is a daytime polysomnographic procedure
which quantifies wake tendency by measuring the ability to remain awake during
soporific circumstances. We present normative data based on 64 healthy subjects
(27 males and 37 females) who adhered to uniform MWT procedural conditions
including polysomnographic montage, illuminance level, seating position, room
temperature, meal timing, and subject instructions. When allowed a maximum trial
duration of 40 min, subjects' mean sleep latency to the first epoch of sustained
sleep was 35.2 +/- 7.9 min. The lower normal limit, defined as two standard
deviations below the mean, was 19.4 min. Calculation of data on the basis of a
maximum trial duration of 20 min and sleep latency to the first appearance of
brief sleep (a microsleep episode or one epoch of any stage of sleep) yielded a
mean sleep latency of 18.1 +/- 3.6 min and a lower normal limit of 10.9 min.
Sleep latency scores were significantly higher than those previously reported in
patients with disorders of excessive somnolence. Therefore, the MWT appears to be
a useful procedure in differentiating groups with normal daytime wake tendency
from those with impaired wake tendency and in identifying individuals with
pathologic inability to remain awake under soporific circumstances.
PMID- 9402887
TI - G-force induced alterations in rat EEG activity: a quantitative analysis.
AB - A major physical limitation affecting pilots is G-force (+Gz, head-to-foot
inertial load) induced loss of consciousness. Previous studies have shown that
+Gz produces qualitatively similar effects on human and rat EEG activity. The
present study sought to quantitatively correlate changes in rat EEG activity with
increasing +Gz levels. A frontal-parietal differential electrode recorded rat EEG
data during +Gz exposures (30 s) ranging from +0.5 to +25.0 Gz. Acceleration
levels < or = +10 Gz had little effect on EEG activity. Acceleration levels of
+15 to +20 Gz were associated with increased EEG slowing, depression and sharp
waves. Acceleration levels > or = +17.5 Gz evoked burst suppression followed by
isoelectric activity. Times to first onset of delta, depressed, and isoelectric
EEG activity were approximately 12, 14 and 18 s, respectively. Acceleration
effects on delta (1-4 Hz), theta (5-8 Hz), alpha (9-12 Hz), beta (13-30 Hz) and
total (1-30 Hz) EEG powers were examined using Fourier transform analysis. EEG
measures with the most predictive value at the following post-acceleration onset
times (PAOT) were as follows (in s); increasing theta power: PAOT 0-2, decreasing
delta power: PAOT 3-9, and decreasing beta power: PAOT > or = 12. This study
provides a quantitative description of +Gz-induced alterations in EEG magnitude,
time course and spectral content. Additionally, several EEG measures were
identified which correlated with acceleration level at specific post-acceleration
onset times.
PMID- 9402888
TI - Somatosensory evoked potential monitoring in carotid surgery. I. Relationships
between qualitative SEP alterations and intraoperative events.
AB - This paper presents the results of intraoperative median nerve SEP monitoring in
205 successive patients undergoing isolated carotid endarterectomy (CE) (N = 172)
or CE followed by coronary bypass (CBP) and/or vascular replacement (VR) (N =
33). The left and right median nerves were alternately stimulated and recordings
performed on 4 channels: cervical, ipsi- and contralateral parietal, and frontal.
SEPs were qualitatively rated in terms of mild, moderate, or severe ipsilateral,
contralateral, or bilateral abnormalities. The SEP abnormalities were subdivided
into 5 categories as a function of their relationships with intraoperative
events: no alterations (67.3%), early or late SEP alterations after carotid cross
clamping (15.6%), SEP alterations after a drop in blood pressure (occurring
outside of or within the cross-clamping period) (15.1%), SEP alterations of a
most likely embolic origin (2.4%), SEP changes after head positioning (1%), and
SEP changes after a modification of the anesthetic regimen (1.5%). Only moderate
to severe SEP alterations occurring soon after carotid cross-clamping justified
shunt installation in 16% of the cases. SEP alterations after a drop in blood
pressure were reversed merely by restoring blood pressure. The neurological
outcome was uneventful in 94.2% of cases. Of the 12 patients who developed
neurological sequellae, only one case presented transient sequellae after
isolated CE without SEP changes while most cases either had undergone combined CE
and CBP and/or VR (6 cases) or had presented SEP alterations of embolic origin (3
cases). We conclude that our system of qualitative rating of SEPs proved very
sensitive to intraoperative hemodynamic disturbances or macroembolisms.
PMID- 9402889
TI - Long sensory tracts (cuneate fascicle) in cervical somatosensory evoked potential
after median nerve stimulation.
AB - Low amplitude high frequency waves (LHW) were investigated in normal and patient
cervical somatosensory evoked potentials after median nerve stimulation (CSEP) in
parallel to normal and patient conducted somatosensory evoked potentials (SEP)
after tibial nerve stimulation. Normal recordings were obtained in five subjects
undergoing dorsal root entry zone (DREZ) coagulation for pain relief. Patient
recordings were obtained in 11 subjects suffering from either syringomyelia,
spinal cord tumour, or both. All recordings were made intraoperatively from the
dorsal spinal cord surface using the subpial recording technique. Normal CSEP
showed typical triphasic potential starting with an initial P9, followed by N13
and a final positivity, P1. Numerous LHW were superimposed on slow triphasic
potential. To improve the visibility of LHW, slow triphasic potential was removed
from the original CSEP. Potentials thus obtained contained only high frequency
components of CSEP, i.e. LHW. They were compared with conducted SEP after tibial
nerve stimulation. Comparison revealed similarities in high frequency, low
amplitude and general wave form, LHW thus showing characteristics of conducted
potential. Duration was found to be significantly shorter than normal duration in
both patient LHW (Student's t-test, P < 0.0005) and patient conducted SEP
(Student's t-test, P = 0.064). A shorter duration was associated with worsening
of configuration in patient LHW and patient conducted SEP. These changes of LHW
could not be connected with distortion of N13 seen in patient CSEP. A shorter
duration and worsening of configuration in patient LHW were most prominent in
cases with a loss of vibration and posture senses, but were also observed in
cases where only pain and temperature senses were affected. We therefore
concluded that cuneate fascicle is the most likely generator of LHW, although the
participation of other cervical long sensory tracts, e.g. spinothalamic tract,
cannot be ruled out.
PMID- 9402890
TI - Somatosensory evoked magnetic fields to median nerve stimulation:
interhemispheric differences in a normal population.
AB - The objective of the present study was to evaluate the normal interhemispheric
variability of the locations and activation strengths of the somatosensory
cortices. Somatosensory evoked magnetic fields (SEFs) were recorded with a 122
channel magnetometer in 23 healthy subjects (mean age 57 years) to stimulation of
left and right median nerves. Equivalent current dipole (ECD) strengths and
locations were determined for the main SEF deflections at the contralateral
primary sensorimotor (SMI) and secondary somatosensory (SIIc) cortices. In a
Cartesian co-ordinate system, defined by the preauricular points and the nasion,
the SMI sources were slightly but significantly more laterally and anteriorly
located in the right than in the left hemisphere. No systematic co-ordinate
asymmetries were found for the SIIc sources. In individual subjects, the
interhemispheric differences in the ECD co-ordinates averaged less than 6 mm at
both SMI and SIIc. The group means of the source strengths did not differ between
the hemispheres, but individual differences were on average 20% for the SMI and
65% for the SIIc sources. We conclude that at the individual level, the median
nerve SEFs from SMI can be used to detect abnormally large interhemispheric
asymmetries of source locations in the centimetre scale.
PMID- 9402891
TI - P300 from a single-stimulus paradigm: passive versus active tasks and stimulus
modality.
AB - The P300 component of the event-related brain potential (ERP) was elicited with
auditory and visual stimuli in separate experiments. Each study compared an
oddball paradigm that presented both target and standard stimuli with a single
stimulus paradigm that presented a target but no standard stimuli. Subjects were
instructed in different conditions either to ignore the stimuli, press a response
key to the target, or maintain a mental count of the targets. For the passive
ignore conditions, P300 amplitude from the single-stimulus paradigm was larger
than that from the oddball paradigm. For the active tasks, P300 amplitude from
the oddball paradigm was larger than that from the single-stimulus paradigm. For
the press and count conditions, P300 amplitude and latency were highly similar
for the oddball and single-stimulus procedures. The findings suggest that the
single-stimulus paradigm can provide reliable cognitive measures in
clinical/applied testing for both passive and active response conditions.
PMID- 9402892
TI - An overview of age-related changes in the scalp distribution of P3b.
AB - In this overview of 7 studies, the scalp distribution of the P3b component (i.e.
the P3 or P300) of the event-related potential elicited by target events in young
and older adults was assessed. The target P3b data were recorded in either
auditory oddball paradigms or in visual study tasks in which orienting activity
was manipulated (as a within-subjects variable) in investigations of indirect
memory. Some of the studies required choice reaction time responses, whereas
others required responses only to the target stimuli. Motor response requirements
had a profound effect on the P3b scalp distribution of older but not of younger
subjects. The presence of a frontally oriented scalp focus in the topographies of
the older adults in most of the tasks described here is consistent with older
adults continuing to use prefrontal processes for stimuli that should have
already been well encoded and/or categorized. However, although older subjects
generally had different P3b scalp distributions than younger subjects, their
scalp distributions were modulated similarly by task requirements. These data
suggest that similar mechanisms modulate the scalp distribution of P3b in older
compared to younger adults. However, in the older adult, these scalp distribution
changes in response to task demands are superimposed on a frontally oriented
scalp focus due to a putative frontal lobe contribution to target P3b topography.
PMID- 9402893
TI - Differential changes of laser evoked potentials, late auditory evoked potentials
and P300 under morphine in chronic pain patients.
AB - The present study investigates the differential behavior of laser evoked brain
potentials (LEPs), late auditory evoked potentials (AEP) and the endogenous P300
in response to morphine treatment, examined in 6 chronic pain patients. The main
result was that in parallel with marked clinical pain relief, amplitudes of the
long latency LEP positivity (P400) were significantly reduced under morphine. One
patient suffering from extremely painful osteoporosis for 20 years exhibited a
large middle latency component (N170) which was prominently attenuated by
morphine. In contrast to LEP amplitude reductions, auditory N1 and P2 potentials
appeared either unchanged or even enlarged during morphine treatment. Also P300
amplitude was slightly increased under morphine. Reaction time and mood scales
also failed to indicate any sedation. Obviously, LEPs reflected specifically the
analgesic morphine effect in this study, while stability or enhancement of AEPs
and P300 during morphine treatment indicated lack of sedation or even improved
perception and concentration due to the removal of persistent pain as a
disruptive perceptual-cognitive stressor.
PMID- 9402894
TI - Short latency vestibular evoked potentials (VsEPs) to linear acceleration
impulses in rats.
AB - In this study, short latency (t < 12.7 ms) vestibular evoked potentials (VsEPs)
in response to linear acceleration impulses were recorded in 37 rats. A new
technique (based on a solenoid) was used for generating linear force impulses
that were delivered to the animal's head. The impulse had a maximal peak
acceleration of 12 g. During the impulse, the displacement was 50 microns (at 4
g) and the rise time was 1.0 ms. A stimulation rate of 2/s was usually used. The
VsEPs (averaged responses to 128 stimulations, digital filter: 300-1500 Hz) were
recorded with electrodes on pinna and vertex, and were composed of 4-6 clear
waves with mean amplitudes (for a 4 g stimulus) of 1-5 microV. The VsEPs were
resistant to white noise masking, and were significantly suppressed (P < 0.05)
following bilateral application of a saturated KCl solution to the inner ear,
showing that contributions of the auditory and somatosensory systems are
negligible. The latency of the response decreased as a power law function of
stimulus magnitude, and the amplitude of the first wave increased as a sigmoid
function of stimulus magnitude. VsEP responses were still present at the lowest
intensities attainable (0.06-0.4 g) and reached saturation at 9 g. The amplitude
of the later components was reduced when stimulus rate was elevated to 20/s.
These results suggest that VsEPs in response to linear accelerations are similar
in their nature to VsEPs in response to angular acceleration impulses that were
previously recorded. These VsEPs to linear accelerations are most likely
initiated in the otolith organs.
PMID- 9402895
TI - Activation of duration-sensitive auditory cortical fields in humans.
AB - The influence of stimulus duration on auditory evoked potentials (AEPs) was
examined for tones varying randomly in duration, location, and frequency in an
auditory selective attention task. Stimulus duration effects were isolated as
duration difference waves by subtracting AEPs to short duration tones from AEPs
to longer duration tones of identical location, frequency and rise time. This
analysis revealed that AEP components generally increased in amplitude and
decreased in latency with increments in signal duration, with evidence of longer
temporal integration times for lower frequency tones. Different temporal
integration functions were seen for different N1 subcomponents. The results
suggest that different auditory cortical areas have different temporal
integration times, and that these functions vary as a function of tone frequency.
PMID- 9402896
TI - Developmental changes in P1 and N1 central auditory responses elicited by
consonant-vowel syllables.
AB - Normal maturation and functioning of the central auditory system affects the
development of speech perception and oral language capabilities. This study
examined maturation of central auditory pathways as reflected by age-related
changes in the P1/N1 components of the auditory evoked potential (AEP). A
synthesized consonant-vowel syllable (ba) was used to elicit cortical AEPs in 86
normal children ranging in age from 6 to 15 years and ten normal adults. Distinct
age-related changes were observed in the morphology of the AEP waveform. The
adult response consists of a prominent negativity (N1) at about 100 ms, preceded
by a smaller P1 component at about 50 ms. In contrast, the child response is
characterized by a large P1 response at about 100 ms. This wave decreases
significantly in latency and amplitude up to about 20 years of age. In children,
P1 is followed by a broad negativity at about 200 ms which we term N1b. Many
subjects (especially older children) also show an earlier negativity (N1a). Both
N1a and N1b latencies decrease significantly with age. Amplitudes of N1a and N1b
do not show significant age-related changes. All children have the N1b; however,
the frequency of occurrence of N1a increases with age. Data indicate that the
child P1 develops systematically into the adult response; however, the
relationship of N1a and N1b to the adult N1 is unclear. These results indicate
that maturational changes in the central auditory system are complex and extend
well into the second decade of life.
PMID- 9402897
TI - Reflection of working memory: ERP mnemonic effects.
AB - The study of working memory often utilizes a delayed matching to sample paradigm
(DMS). Typically in the matching condition, the test and sample stimuli are
identical, raising the possible confound of retinotopic projections for the
matching stimuli in contrast to the non-matching stimuli. In the present study,
65 healthy subjects performed a modified delayed matching to sample task while
monitoring their ERP waveforms. The stimuli consisted of 60 different sample
stimuli (S1) and 60 different test stimuli (S2). Half of the S2s were
complementary to the sample stimuli (Fit), the other half of the S2s were not
complementary (Nonfit). After S2, the subjects pressed one of the buttons to
indicate whether the test stimulus fits the sample stimulus. Our statistical
results indicated that the ERPs to sample stimuli differed from the ERPs to test
stimuli from 200 ms poststimulus to the end of the recording epoch. The ERPs to
fitting stimuli were significantly different from those to non-fitting stimuli
from 200 to 400 ms poststimulus. The ERP patterns in the present study may
reflect ERP mnemonic effect for working memory. Our results ruled out the
retinotopic confound as a potential mediator variable, and are in agreement with
other animal or human neurophysiological studies on memory.
PMID- 9402898
TI - Use of nitrous oxide to dissociate the non-specific and specific components of
the human auditory N1.
AB - The components of the N1 are thought to be related to sensory functioning
(Components 1 and 2) and arousal (Component 3). To provide direct evidence for
the involvement of Component 3 in arousal, we hypothesized that it should be more
sensitive to the anesthetic gas nitrous oxide (N2O) than Component 1. Using the
technique of selective adaptation, 30 blocks of 5 tones were presented at 1 min
intervals to 9 subjects who breathed air, 25% and 35% N2O. As hypothesized, the
amplitude of Component 3 was significantly reduced in a dose-dependent manner by
N2O, but the amplitude of Component 1 was not, although the latter showed some
evidence of a decrease at 25% N2O.
PMID- 9402899
TI - The new environment for health services research: private and public sector
opportunities.
PMID- 9402900
TI - Managed care: achieving the benefits, negating the harm.
PMID- 9402901
TI - The determinants of dumping: a national study of economically motivated transfers
involving mental health care.
AB - OBJECTIVE: To examine the prevalence and determinants of economically motivated
transfers (aka "dumping") from hospitals treating mental illness. DATA SOURCES: A
composite data set constructed from three national random-sampled surveys
conducted in 1988 and 1989: (1) of hospitals providing mental health care, (2) of
community mental health centers, and (3) of psychiatrists. STUDY DESIGN: The
study uses reports from administrators of community mental health centers (CMHCs)
to assess the extent of patient dumping by hospitals. To assess the determinants
of dumping, reported perceptions of dumping are regressed on variables describing
the catchment area in terms of the proportion of for-profit hospitals, intensity
of competition among hospitals, extent of utilization review, and capacity of the
local treatment system, as well as competition among community mental health
centers. To assess if dumping is motivated by factors distinct from those
affecting other aspects of access, comparable regressions are estimated with ease
of hospital admission as the dependent variables. PRINCIPAL FINDINGS:
Economically motivated transfers of psychiatric patients were widespread in 1988:
according to the reports of CMHC administrators, 64.7 percent of all hospitals
providing inpatient mental health care engaged in transfers of this sort. The
extent of dumping was higher in catchment areas with more competition among
hospitals, more proprietary hospitals, and less inpatient capacity in the public
sector. Dumping appeared to be more sensitive to capacity in the public sector
but less sensitive to involvement by for-profit hospitals than were other
measures of access to care. CONCLUSIONS: Economically motivated transfers of
patients with mental illness were widespread in 1988 and likely have increased
since that time, affecting the viability of the community mental health care
system.
PMID- 9402902
TI - Commentary: economic transfers, the changing face of a familiar problem.
PMID- 9402903
TI - The cost and outcomes of community-based care for the seriously mentally ill.
AB - OBJECTIVE: To examine the cost-effectiveness of community-based mental health
care. DATA SOURCES/STUDY SETTING: Administrative data from Medicaid and the
Massachusetts Department of Mental Health; primary data from 144 psychiatrically
disabled adult Medicaid beneficiaries who lived in Boston, central Massachusetts,
and western Massachusetts. STUDY DESIGN: A cross-sectional observational study
compared the costs and outcomes of treatment in three different types of public
mental health service systems. DATA COLLECTION/EXTRACTION METHODS: Beneficiaries,
randomly sampled from outpatient mental health programs, were interviewed about
their mental health status. All their acute treatment and long-term continuing
care for the preceding year were abstracted from Medicaid and Department of
Mental Health files. Costs were extracted from Medicaid paid claims and from
Department of Mental Health contracts and other financial documents. PRINCIPAL
FINDINGS: Clients in the region allocating a greater proportion of its Department
of Mental Health budget to community support services used far fewer hospital
days, resulting in lower per person treatment expenditures. Outcomes, however,
were not significantly different from outcomes of clients in the other regions.
For all regions, substance abuse comorbidity increased hospitalization and total
treatment costs. An individual-level cost-effectiveness analysis identified
western Massachusetts (community-based care) as significantly more cost effective
than the other two regions. CONCLUSIONS: Systems with stronger community-based
orientation are more cost effective.
PMID- 9402904
TI - Cost-effectiveness of inpatient substance abuse treatment.
AB - OBJECTIVE: To identify the characteristics of cost-effective inpatient substance
abuse treatment programs. DATA SOURCES/STUDY SETTING: A survey of program
directors and cost and discharge data for study of 38,863 patients treated in 98
Veterans Affairs treatment programs. STUDY DESIGN: We used random-effects
regression to find the effect of program and patient characteristics on cost and
readmission rates. A treatment was defined as successful if the patient was not
readmitted for psychiatric or substance abuse care within six months. PRINCIPAL
FINDINGS: Treatment was more expensive when the program was smaller, or had a
longer intended length of stay (LOS) or a higher ratio of staff to patients.
Readmission was less likely when the program was smaller or had longer intended
LOS; the staff to patient ratio had no significant effect. The average treatment
cost $3,754 with a 75.0% chance of being effective, a cost-effectiveness ratio of
$5,007 per treatment success. A 28-day treatment program was $860 more costly and
3.3% more effective than a 21-day program, an incremental cost-effectiveness of
$26,450 per treatment success. Patient characteristics did not affect readmission
rates in the same way they affected costs. Patients with a history of prior
treatment were more likely to be readmitted but their subsequent stays were less
costly. CONCLUSIONS: A 21-day limit on intended LOS would increase the cost
effectiveness of treatment programs. Consolidation of small programs would reduce
cost, but would also reduce access to treatment. Reduction of the staff to
patient ratio would increase the cost-effectiveness of the most intensively
staffed programs.
PMID- 9402905
TI - Performance contracting for substance abuse treatment.
AB - OBJECTIVE: To describe an innovation in performance contracting for substance
abuse services in the State of Maine and examine data on measured performance by
providers before and after the innovation. DATA SOURCES AND COLLECTION: From the
Maine Addiction Treatment System (MATS), an admission and discharge data set
collected by the Maine Office of Substance Abuse (OSA). The MATS data for this
study include information on clients of programs receiving public funding from
October 1, 1989 through June 30, 1994. Additional data are drawn from the
contracts between the state and providers, and from service delivery reports
submitted to OSA. STUDY DESIGN: Client-level performance measures were calculated
directly from MATS using OSA's formulas and standards, and then aggregated to the
treatment program level. Multivariate regression analysis was done for each
performance indicator as a dependent variable with performance contracting, time,
extent of state funding, and provider characteristics as independent variables.
PRINCIPAL FINDINGS: Performance contracting is positively related to better
performance for effectiveness indicators overall. Individual effectiveness
indicators that showed improvement include drug use indicators (abstinence and
reduction in use) and social functioning indicators. In addition, performance
contracting is associated with an increase in efficiency performance, defined as
delivery of the contracted amount of service, for agencies that depend heavily on
OSA for funding. Finally, performance contracting appears unrelated to the
special populations indicators that measure services to target populations that
OSA considers harder to treat. CONCLUSIONS: There is tentative evidence of a
relationship between provider performance and the introduction of performance
contracting. More definite conclusions await more detailed analyses of client
level data.
PMID- 9402906
TI - Rehabilitation costs: implications for prospective payment.
AB - OBJECTIVE: To obtain information relevant to development of prospective payment
for Medicare rehabilitation facilities (RFs) and skilled nursing facilities
(SNFs): compares service utilization, length of stay (LOS), case mix, and
resource consumption for Medicare patients receiving postacute institutional
rehabilitation care. DATA SOURCES/STUDY SETTING: Longitudinal patient-level and
related facility-level data on Medicare hip fracture (n = 513) and stroke (n =
483) patients admitted in 1991-1994 to a sample of 27 RFs and 65 SNFs in urban
areas in 17 states. STUDY DESIGN: For each condition, two-group RF-SNF
comparisons were made. Regression analysis was used to adjust RF-SNF differences
in resource consumption per stay for patient condition (case mix) and other
factors, since random assignment was not possible. DATA COLLECTION/EXTRACTION
METHODS: Providers at each facility were trained to collect patient case-mix and
service utilization information. Secondary data also were obtained. PRINCIPAL
FINDINGS: RF patients had shorter LOS, fewer total nursing hours (but more
skilled nursing hours), and more ancillary hours than SNF patients. After
adjustment, ancillary resource consumption per stay remained substantially higher
for RF than SNF patients, particularly for stroke. The adjusted nursing resource
consumption differences were smaller than the ancillary differences and not
statistically significant for hip fracture. Supplemental outcome findings
suggested minimal differences for hip fracture patients but better outcomes for
RF than SNF stroke patients. CONCLUSIONS: Much can be gained from an integrated
approach to developing prospective payment for RFs and SNFs. In that context,
consideration of condition-specific per-stay payment methods applicable to both
settings appears warranted.
PMID- 9402907
TI - Introduction: research on health care organizations and markets--the best and
worst of times.
PMID- 9402908
TI - Managed care research: moving beyond incremental thinking.
PMID- 9402909
TI - Studying access to care in managed care environments.
PMID- 9402910
TI - Managed care and chronic illness: health services research needs.
PMID- 9402911
TI - Five priority areas for research on long-term care.
PMID- 9402912
TI - Advances in the management of chronic depressive and anxiety disorders.
Introduction.
PMID- 9402913
TI - Panic disorder as a chronic illness.
AB - Panic disorder is a chronic illness that waxes and wanes, and the prognosis is
worse with comorbid agoraphobia, depression, or personality disorder. Both
medication and cognitive-behavioral therapy have been found helpful in acute
treatment trials of panic disorder. However, recent studies suggest that
therapeutic gains are lost in many instances when treatment is stopped after
short-term medication or cognitive-behavioral therapy. Thus, maintenance
treatment appears necessary for many panic patients. Patients appear relatively
stable during medication maintenance, but studies of maintenance psychosocial
treatment for panic disorder have not yet been reported. Whether combined
medication and psychosocial treatment lead to more durable effects after
treatment discontinuation than are seen with individual treatments also remains
to be determined.
PMID- 9402914
TI - Treatment strategies for chronic and refractory obsessive-compulsive disorder.
AB - Obsessive-compulsive disorder (OCD), despite our increasing understanding of its
causes and its effective treatment, remains a chronic and underdiagnosed
disorder. Both treatment with SSRIs and the behavioral treatment strategy of
exposure with response prevention have been proved by clinical trials to be
effective and safe in treating OCD; however, even these treatments sometimes
elicit only moderate patient response, and some OCD patients do not respond to
them at all. Preliminary data suggest that OCD has lifelong persistence and that
discontinuation of pharmacotherapy often leads to relapse. Nonetheless, further
prospective, controlled, maintenance studies of OCD are needed to determine
factors in and predictors of recovery, remission, and relapse. Finally, new
procedures for treatment-refractory patients are needed; neurosurgical and new
pharmacologic approaches have shown promise in treating these patients and should
be studied in controlled trials.
PMID- 9402915
TI - Strategies and tactics in the treatment of chronic depression.
AB - Chronic depressions include major depressive disorder, recurrent, without full
interepisode recovery; major depressive disorder, currently in a chronic (i.e., >
or = 2 years) episode; double depression; dysthymic disorder; and those
depressive disorders--not otherwise specified (NOS)--that are persistent or
predictably recurrent with substantial disability. Strategic treatment decisions
include (1) whether to treat with medication, psychotherapy, ECT, or other
methods; (2) selection among specific agents with long-term efficacy and
tolerability (preferably established by randomized controlled trials); (3)
selection of the next treatment should the initial treatment fail or be found
intolerable; and (4) deciding whether to provide maintenance treatment. Tactical
decisions are those needed to optimally implement the strategies selected; for
example, (1) how to optimally dose, (2) how long to continue an acute phase
treatment trial, (3) how to measure outcome, and (4) how to identify and manage
subsequent symptomatic breakthroughs or side effects (which may also require
revisions in the initial strategies). Some antidepressant medications evidence
efficacy and safety in acute phase treatment of the chronically depressed, but
continuation and maintenance phase treatments for these patients are less well
investigated and deserve further study. The clinical implications of what is
known to date for managing these patients are discussed.
PMID- 9402916
TI - When at first you don't succeed: sequential strategies for antidepressant
nonresponders.
AB - Now, more than ever before, a wealth of options exists for depressed patients who
do not benefit from treatment with standard, first-line antidepressant agents. In
this paper, alternate antidepressant strategies are reviewed within the context
of a five-stage strategy, ranging from lesser to greater degrees of treatment
resistance. The overall strategy recommended progresses from simpler (i.e., an
alternate monotherapy) to more complex strategies (i.e., combination or
augmentation regimens), with the nonselective monoamine oxidase inhibitors (+/-
lithium salts) and electroconvulsive therapy typically reserved for treatment of
Stages III and IV of resistance, respectively. Psychotherapeutic management also
is an important ingredient in the ongoing treatment of these patients,
particularly to counteract the demoralization and frustration that understandably
accompany the failure to respond to so many treatments.
PMID- 9402917
TI - Psychotherapeutic approaches to the treatment of anxiety and depressive
disorders.
AB - Psychotherapy, both alone and in combination with pharmacotherapy, is one of the
most prevalent treatments for depression and anxiety. Research data are sparse,
but there is ample evidence that several psychotherapies are effective for acute
affective and panic disorders. The best data are for interpersonal and cognitive
behavioral therapies, with only early reports on the more common psychodynamic
psychotherapies. There has been less study of more chronic disorders, but once
again the suggestion is that appropriate psychotherapy is effective. Treatment
should be active and focused on the patient's symptoms and current problems, not
on character pathology or developmental psychodynamics.
PMID- 9402918
TI - Controlled release vaccines.
PMID- 9402919
TI - Resistance to beta-lactam antibiotics in Bacteroides spp.
AB - Bacteroides spp., particularly B. fragilis, are well-recognised bacterial
pathogens. Production of the typical beta-lactamases of Bacteroides restricts the
therapeutic use of beta-lactam agents mainly to the beta-lactamase inhibitor
combinations and carbapenems. These compounds have the advantage of broad
spectrum activity and the ability to combat polymicrobial infections. Resistance
of Bacteroides spp. to beta-lactam antibiotics appears to be increasing, largely
because of an overall increase in beta-lactamase activity. There has been a rise
in the prevalence of isolates showing high-level production of typical
Bacteroides beta-lactamases and an increase in reports other potent beta
lactamase types. In the case of B. fragilis, metallo-enzymes are a particular
threat to current therapeutic practice, as they are not inhibited by common beta
lactamase inhibitors and are able to hydrolyse carbapenems. The presence of
permeability barriers may confer low-level beta-lactam resistance and supplement
the effect of beta-lactamase activity. There are also sporadic reports of loss of
beta-lactam activity because of reduced affinity of the penicillin-binding
proteins.
PMID- 9402920
TI - The isolation and cloning of chromosomal DNA specific for a clonal population of
Staphylococcus aureus by subtractive hybridisation.
AB - Subtractive hybridisation was used to screen for and identify conserved DNA
sequences associated with clinical, clonal populations of Staphylococcus aureus.
DNA from S. aureus strain ISP8 (a clinical isolate) was digested with TaqI and
hybridised with randomly fragmented pooled DNA from 10 non-clinical (community)
isolates of S. aureus. The mixture of DNA fragments was then ligated to AccI
digested and dephosphorylated pTZ19U. One recombinant plasmid (pWASA) was
identified as containing specific DNA from strain ISP8; DNA sequencing revealed a
40-bp TaqI DNA fragment (WASA). PCR amplification and hybridisation analysis,
with pWASA as a probe, showed that 84% of clinical isolates from a clonal line
present in hospitals in major eastern Australian cities carried sequences
homologous to WASA, compared with only 10% of community isolates. The isolates
that hybridised were closely related by RFLP analysis to strain ISP8. The plasmid
pWASA was used to identify, isolate and clone a 3.5-kb DraI fragment (DSA) from
strain ISP8 total DNA. Sequence analysis of the DSA fragment identified two open
reading frames (ORFs) of 2475 and 576 bp, respectively; the larger ORF1 contained
a series of six tandem repeats, each consisting of 384 nucleotides. The
nucleotide sequence of the repeats was 96% identical, and no significant sequence
homologies to previously described protein sequences were identified. However,
tandem repeats of amino acids are structural motifs characteristic of a number of
gram-positive surface proteins, and are thought to play a role in generating
genetic and phenotypic diversity in these and other bacteria.
PMID- 9402921
TI - Streptococcus agalactiae beta gene and gene product variations.
AB - Streptococcus agalactiae (group B streptococci; GBS) are serotyped on the basis
of the capsular polysaccharide antigens and subtyped on the basis of the strain
variable and surface-localised c proteins c alpha, c beta, and R proteins. This
study compared c beta protein detection and the polymerase chain reaction (PCR)
for beta gene detection, by examining 50 clinical GBS strains. The c beta protein
was detected by antibody-based immunofluorescence in a GBS whole-cell assay and
Western blotting by probing with the anti-c beta antibody or human IgA.
Absorption experiments were performed to test for surface-anchoring of c beta;
and bacterial supernates were examined to test for c beta production. Primers for
the PCR target regions resulted in a 620-bp product that included beta gene
encoding IgA-binding domains. The results demonstrated four categories of GBS
with respect to the beta gene and the c beta protein: (1) strains (16 of 50) that
harboured the beta gene and regularly expressed normal surface-localised c beta
with a M(r) of 120 kDa; (2) strains (5 of 50) that harboured the gene but did not
express the protein; (3) strains (2 of 50) that harboured the gene but expressed
a c beta that was not surface-localised and had reduced M(r); (4) strains (27 of
50) without beta gene and c beta expression. One strain amongst the third group
generated a PCR product of 1330 bp. These results demonstrate considerable strain
variability of the beta gene of GBS and of its product the c beta protein.
PMID- 9402922
TI - Screening of TnphoA mutants of Vibrio cholerae O139 for identification of
antigens involved in colonisation.
AB - A new serogroup of Vibrio cholerae non-O1, designated as O139, has emerged
causing cholera-like disease among adults. Laboratory and field studies clearly
show that there is no cross-protection between O1 and O139 pathogenic strains.
Since colonisation of the intestine is a most important step in the pathogenesis
of cholera caused by O1 strains and colonising antigens are known to be
protective, investigation of the colonising antigens of O139 strain was
initiated. By TnphoA mutagenesis, mutants were generated with insertions in the
genome encoding membrane spanning or secretory proteins. Screening of the mutants
for adherence to rabbit intestinal surface and colonisation in 5-day-old mice
resulted in the identification of mutant clones, which were less adhesive than
was the wild-type parent strain and which could not efficiently colonise the gut.
Such non-colonising strains were attenuated in virulence. Analysis of the
proteins by SDS-PAGE revealed that the non-colonising mutants did not express a
40-kDa outer-membrane protein.
PMID- 9402923
TI - Structural studies of the surface projections of Chlamydia trachomatis by
electron microscopy.
AB - Rod-like projections on the surface of Chlamydia trachomatis have been studied by
a combination of computer image analysis and electron microscopy. The rods, c. 60
80 A in diameter and c. 500 A in length, were found on the surface of
prokaryocells of C. trachomatis inserted in the cytoplasmic membrane through a
ring-like structure in the outer membrane. The rod-like structures were found at
all stages of the life cycle, even in very small elementary bodies (EBs) of C.
trachomatis and in vesicles < 0.2 micron. Computer image analysis of isolated
rods indicated that they comprise helically arranged subunits with a periodicity
of c. 50 A. From their localisation and distribution, these structures may be
related to the proliferation, or to the infectivity, of chlamydiae.
PMID- 9402924
TI - An epidemiological study of Serratia marcescens isolates from nosocomial
infections by enzyme electrophoresis.
AB - Serratia marcescens isolates from 164 patients with suspected nosocomial
infection in several hospitals in the greater Paris region were investigated by
analysis of the electrophoretically demonstrable allelic variations of gene loci
coding for five esterases and five other enzymes. All the loci were polymorphic
and the mean number of alleles per locus was 6.1. A total of 72 distinctive
electrophoretic types (ETs) representing multilocus genotypes was distinguished.
The isolates were divided into two groups according to their resistance to
antibiotics: 82 multiresistant isolates (MRI) and 82 relatively susceptible
isolates (RSI). Seventy-two MRI (88%) were in four genetically related ETs: ET1,
ET2, ET8 and ET9; ET1 was found in 48 isolates, whereas the remaining MRI were in
10 ETs, and all RSI in 61 ETs. Three ETs contained both MRI and RSI. The mean
coefficients of genetic diversity for the 10 enzyme loci among ETs and isolates
were smaller for MRI than for RSI, while the modal ET of MRI resembled that of
RSI. The epidemiological significance of isolates varied according to their ET.
Thus, isolates belonging to ET1, ET2 and ET8 were responsible for outbreaks or
for sporadic infections, whereas isolates of other ETs were responsible for only
sporadic infections. The temporal distribution of ET1 isolates among hospitals
identified seven outbreaks in seven clinical departments.
PMID- 9402925
TI - Enhancement of the specific mucosal IgA response in vivo by interleukin-5
expressed by an attenuated strain of Salmonella serotype Dublin.
AB - It has been shown that cytokines have potential as therapeutic adjuvants in
vaccination. Interleukin-5 (IL-5) is a cytokine that regulates antibody
production, in particular enhancing IgA production by activated mucosal B cells.
This study examined the expression of a cloned cytokine gene encoding murine IL-5
(mIL-5) by an attenuated aroA strain (SL5631) of Salmonella serotype Dublin. The
resulting strain, SL5631(pTRXFUS-mIL-5), expressed mIL-5 as a fusion with
thioredoxin as demonstrated by immunological and biological assays. When strain
SL5631(pTRXFUS-mIL-5) was used as a live vaccine in BALB/c mice, it colonised and
multiplied at higher levels in spleens and livers than the strain carrying the
empty plasmid. A reduction in invasiveness of SL5631(pTRXFUS-mIL-5) was observed
in in-vitro invasion assays. Enhanced IgA response against salmonella LPS in
mucosal secretions and enhanced IgA and IgG responses were detected by ELISA and
ELISPOT methods in sera of mice immunised with the strain expressing mIL-5.
Results with IL-5-deficient mice showed that the enhanced IgA response was due to
Salmonella-expressed mIL-5 rather than endogenous mIL-5.
PMID- 9402926
TI - Low sensitivity of counter-current immuno-electrophoresis for serodiagnosis of
typhoid fever.
AB - Counter-current immuno-electrophoresis was evaluated as a diagnostic test for the
serodiagnosis of typhoid fever with somatic (O), flagellar (H) and capsular
polysaccharide (Vi) antigens of Salmonella typhi on the sera of patients who were
blood culture positive (confirmed typhoid cases) or had high Widal agglutination
titres, > or = 320, (presumptive typhoid cases). Of the 37 sera from confirmed
cases, 30% showed positivity with O antigen, 24% with H antigens and 51% with Vi
antigen. In patients with a presumptive diagnosis, 45% were positive for O
antibody, 27% for flagellar antibody and 52% for Vi antibody. When all three
antigens were combined the reactivity to any of the antigens was found to be 59%
in confirmed typhoid cases, 79% in presumptive typhoid cases and 93% in patients
who were simultaneously positive by blood culture and Widal agglutination.
However, none of the sera from 45 controls gave a positive precipitation reaction
with any of the antigens. It is concluded that counter-current immuno
electrophoresis is a rapid test with low sensitivity and high specificity with Vi
antigen, a panel of antigens being most effective, and is, therefore, recommended
for rapid diagnosis of typhoid fever.
PMID- 9402927
TI - PCR identification of Trichophyton mentagrophytes var. interdigitale and T.
mentagrophytes var. mentagrophytes dermatophytes with a random primer.
AB - Dermatophytes are a group of keratinophilic fungi falling within the genera of
Epidermophyton, Microsporum and Trichophyton. The genus Trichophyton is
particularly important and complex; it comprises at least 15 recognised species.
In addition, there are several different variants in the species T.
mentagrophytes, which occur both in man and animals. The current methods of
determining T. mentagrophytes varieties may require several different culture
media and time-consuming procedures, as well as specialist skills. This study
used a random primer, 5'-GAGCCCGACT-3', in the arbitrarily primed polymerase
chain reaction (AP-PCR) and showed that the two common T. mentagrophytes
varieties (var. interdigitale and var. mentagrophytes) can be clearly identified
on the basis of their characteristic DNA band patterns. The relative
reproducibility, ease of use and precision of this method make the AP-PCR a
valuable tool in the laboratory diagnosis of human dermatophytosis.
PMID- 9402928
TI - Drugs for HIV infection.
PMID- 9402929
TI - The age-associated alterations in late diastolic function in mice are improved by
caloric restriction.
AB - Caloric restriction reduces the magnitude of many age-related changes in rodents.
Cardiac function is altered with senescence in mice, rats, and healthy humans. We
examined the effects of life-long caloric restriction on diastolic and systolic
cardiac function in situ using Doppler techniques in ad libitum-fed 30- to 32
month-old (AL) and calorically restricted (CR) 32- to 35-month-old female B6D2-F1
hybrid mice. The heart weight to body weight ratio was similar in AL (5.74 +/-
.24 mg/g) and CR (5.68 +/- .20 mg/g) mice. Two systolic functional parameters
known to decrease with age in both humans and mice, peak aortic velocity and
aortic acceleration, were unchanged by CR compared to AL. In contrast, diastolic
function was altered by caloric restriction. Although left ventricular peak early
filling velocity (E) was not different between CR and AL, peak atrial filling
velocity (A) was 50% lower in CR compared to AL (p < .001). The ratio of early
diastolic filling to atrial filling (E/A ratio) was 64% higher in the CR (2.74 +/
.31) than the AL (1.55 +/- .07; p = .004). The fraction of ventricular filling
due to atrial systole, the atrial filling fraction, was also reduced in CR (.21
+/- .04) compared to AL (.36 +/- .02; p = .007). These changes occurred in CR
without alteration in E deceleration time, which is consistent with improved
diastolic function in CR. Through mechanisms that remain unknown, lifelong
caloric restriction may prevent the age-related impairments in late diastolic
function but does not alter the impairments in systolic or early diastolic
cardiac function.
PMID- 9402930
TI - The effects of age and dietary restriction on metabotropic glutamate receptors in
C57B1 mice.
AB - This study examined the effects of aging and dietary restriction on metabotropic
type 1 (met1; high quisqualate affinity) and type 2 (met2; low quisqualate
affinity) binding sites for glutamate and the relationship between these binding
sites and spatial memory. Quantitative autoradiography was performed on 3-, 10-,
and 26-month-old mice. Ten- and 26-month-old mice were fed ad libitum or fed
restricted diets. Met1 binding sites were not notably affected by age or diet.
Binding to met2 sites was maintained during aging in the ad libitum-fed mice, but
there were decreases in binding in the diet-restricted mice as compared to 3
month-old mice. Binding to met1 and met2 sites did not correlate significantly
with performance in the Morris water maze. These results suggest that dietary
restriction induces a decrease in one or more of the functions associated with
met2 binding sites during the aging process.
PMID- 9402931
TI - Effects of changes in calorie intake on intestinal nutrient uptake and
transporter mRNA levels in aged mice.
AB - In aged, chronically calorie-restricted (CR) mice, intestinal nutrient uptake is
significantly higher than in same-age ad libitum controls. Can this chronic
restriction-induced enhancement of uptake be reversed by ad libitum feeding? We
addressed this question by switching 32-mo-old chronically CR mice to ad libitum
feeding for 4 wk (CRAL). Intestinal transport rate and total intestinal
absorptive capacity for D-sugars and several nonessential L-amino acids decreased
significantly in CRAL mice. In contrast, switching CR mice to an ad libitum
regimen for only 3 d had no effect on intestinal nutrient transport, indicating
that the negative effects of ad libitum feeding require a duration longer than
the 3-d lifetime of most enterocytes. Permeability of the intestinal mucosa to L
glucose was independent of the switches in diet. Levels of the brushborder
glucose transporter SGLT1, brushborder fructose transporter GLUT5, and
basolateral sugar transporter GLUT2 mRNA as determined by reverse transcriptase
polymerase chain reaction in 6-, 24-, and 32-mo-old mice were each apparently
independent of caloric restriction and age. We conclude that the high rates of
intestinal nutrient uptake exhibited by chronically CR mice can be reversed by ad
libitum feeding of only 1 mo duration. These decreases in uptake were due mainly
to specific decreases in transport per unit weight of intestine and not to
nonspecific decreases in intestinal mass. Changes in rates of sugar uptake
induced by chronic CR and age are apparently not accompanied by changes in steady
state levels of mRNA coding for those transporters.
PMID- 9402932
TI - Ethanol activates the interleukin-6 promoter in a human bone marrow stromal cell
line.
AB - Chronic ethanol consumption is associated with the development of osteoporosis.
The pro-inflammatory cytokine interleukin-6 (IL-6) plays a role in the
development of osteoporosis through stimulation of osteoclastic activity. We
hypothesized that ethanol promotes osteoporosis, in part, by increasing IL-6
production in the bone microenvironment. Accordingly, we evaluated ethanol's
effect on IL-6 production in the Saka human bone marrow stromal cell line and in
the HOBIT human osteoblast-like cell line. We found that ethanol increased IL-6
protein levels in the culture supernatants from Saka, but not HOBIT, cells. In
addition, we observed that ethanol increased steady-state IL-6 mRNA levels and
activated an IL-6 promoter-driven reporter vector in Saka cells. We conclude that
ethanol stimulates IL-6 expression in the Saka bone marrow stromal cell line by
enhancing transcriptional activity of the IL-6 gene. Our findings support the
contention that ethanol may contribute to the pathogenesis of osteoporosis, in
part, by increasing IL-6 expression in the bone microenvironment.
PMID- 9402933
TI - Aging stimulates fatty acid oxidation in rat colonocytes but does not influence
the response to dietary fiber.
AB - Metabolism was studied in colonocytes isolated from young (4 mo) and aged (24 mo)
Fischer 344 rats. Animals were fed fiber-free, low-fiber (5% cellulose), or high
fiber (oat bran or NIH 31 stock) diets. Colonocytes isolated from aged animals
oxidized both short- and long-chain fatty acids at significantly higher rates
than did colonocytes isolated from young animals. No differences between the
young and aged were noted for the oxidation to CO2 of glucose and glutamine or
for flux of glucose through glycolysis. Net adenosine triphosphate (ATP)
production by colonocytes was calculated to be 20% higher for the aged than for
the young, although the relative contribution of substrates to net ATP production
from exogenous substrates was similar for the young and aged (45-50% from
butyrate, 20-25% from glucose, and 30% from other substrates including acetate,
propionate, palmitate, and glutamine). Substrate oxidation was generally higher
in colonocytes from the oat bran (17% total dietary fiber, highly soluble fiber)
versus fiber-free diet.
PMID- 9402934
TI - Cellular and molecular biomarkers indicate precocious in vitro senescence in
fibroblasts from SAMP6 mice. Evidence supporting a murine model of premature
senescence and osteopenia.
AB - A variety of short-lived mouse strains (SAMP strains) and control strains of less
abbreviated life span (SAMR strains) have been proposed as murine models of
accelerated senescence. Each SAMP strain, in addition to displaying "progeroid"
traits of accelerated aging, exhibits a singular age-related pathology. The
application of this animal model to the study of normal aging processes has been
and remains controversial. Therefore, we have undertaken a study of dermal
fibroblasts derived from the short-lived SAMP6 strain, which shows early-onset
and progressive osteopenia. We have investigated cellular and molecular
characteristics that are associated with in vitro aging of normal human
fibroblasts, and which are exacerbated in fibroblasts from patients with Werner
syndrome, a human model of premature senescence. We found that SAMP6 dermal
fibroblasts, relative to SAMR1 and C57BL/6 controls, exhibit characteristics of
premature or accelerated cellular senescence with regard to in vitro life span,
initial growth rate, and patterns of gene expression.
PMID- 9402936
TI - Geriatrics and medical oncology: finding the common ground.
PMID- 9402935
TI - An evaluation of the length-tension relationship in elderly human plantarflexor
muscles.
AB - The purpose of this study was to determine the effect of aging on the muscle
length-tension relationship in the plantarflexor muscles of 10 subjects aged 20
30 yr (Mean = 23; 5 males, 5 females), 10 subjects aged 60-80 yr (Mean = 72.3; 5
males, 5 females), and 10 subjects over 80 yr (Mean = 84.1, 5 males, 5 females).
Isometric twitch properties, maximum voluntary strength, passive tension, and
range of motion were measured at five different joint angles [20 degrees
dorsiflexion (DF), 10 degrees DF, 0 degree, 10 degrees plantarflexion (PF), and
20 degrees PF]. Active (evoked and voluntary) and passive torque production were
maximal when the ankle was rotated into the DF positions for all three age
groups, whereas the lowest values were recorded when the ankle was rotated into
20 degrees PF. Males were stronger than females at all joint angles (p < .01).
Also, young adults were stronger than both elderly adult groups (p < .01). These
results illustrate that despite the considerable age-associated loss in both
voluntary and evoked strength in the plantarflexors, the optimal angle for torque
production remains the same for younger and older adults.
PMID- 9402937
TI - Integration of aging and cancer research in geriatric medicine.
PMID- 9402938
TI - Failure to thrive in old age: follow-up on a workshop.
PMID- 9402939
TI - Determinants of bone mineral density in postmenopausal white Iowans.
AB - BACKGROUND: Osteoporosis is a major health problem for older individuals. For
women, development of osteoporosis is a function of the accretion of "peak" bone
mass in the third decade, age at menopause, and rate of bone loss with aging. Low
bone mineral density (BMD) is a major risk factor for osteoporosis and fracture.
The purpose of this study was to identify life style, nutritional, medical, and
genetic predictors of low BMD in postmenopausal Iowa women. METHODS: One hundred
thirty-four postmenopausal White women ranging in age from 57 to 81 years were
included in this case-control study. Bone mineral density was measured at the
femoral neck, using dual photon X-ray absorptiometry (Hologic 2000 QDR). Sixty
six women with BMD measurements below 0.68 g/cm2 (the bottom quartile of the BMD
distribution in the population from which participants were recruited), and 68
women with values at or above 0.83 g/cm2 (the top quartile of the BMD
distribution in the same population) were included. Information about
environmental, nutritional, medical, and life style modifiers of BMD was obtained
by written questionnaire and telephone interview. To assess familial factors that
might influence BMD, we obtained a detailed family history for each participant.
In addition, we tested the hypothesis that allelic variation at the Vitamin D
receptor (VDR), and the type I collagen gene (COL1A1 and COL1A2) loci influence
BMD. RESULTS: Weight, loss of height, age, and age at menopause were strong
predictors of BMD in our population. After adjustment for these differences, we
found no effect of genotype at the COL1A1, COL1A2, and VDR loci on BMD.
CONCLUSIONS: Bone mineral density is a complex trait that is influenced by
several different modifiers; in the present study, weight was the best predictor
of postmenopausal BMD. While several studies suggest that VDR genotype is an
important determinant of BMD, we did not find this association in our population,
nor did we identify an association between allelic variation at the type I
collagen gene loci and BMD. Identification of genes that determine body mass
index may provide additional insight into risk factors for low BMD, and
osteoporotic fractures.
PMID- 9402940
TI - Comparison of alveolar bone loss, alveolar bone density and second metacarpal
bone density, salivary and gingival crevicular fluid interleukin-6 concentrations
in healthy premenopausal and postmenopausal women on estrogen therapy.
AB - BACKGROUND: Osteoporosis is an age-related metabolic bone disease characterized
by decreased mass and increased susceptibility to fracture. The literature
suggests a relationship between oral bone loss and skeletal osteoporosis;
however, most studies have produced conflicting results. The purpose of this
study was to determine if a relationship exists among alveolar bone loss,
alveolar bone density, second metacarpal density, salivary and gingival
crevicular fluid interleukin 6 (IL-6), and IL-8 concentrations in premenopausal
and postmenopausal healthy women receiving estrogen therapy. METHODS: Twenty
eight healthy women (aged 23-78) were evaluated for this study. A vertical
bitewing and hand radiographs were taken, and the subjects were evaluated for the
presence of active periodontitis. The bitewing and hand radiographs were
digitized, and measurements were made from the cemento-enamel junction to the
alveolar crest from both arches. Bone density was evaluated in the maxillary and
mandibular alveolar process and at the mid-shaft of the second metacarpal.
Percent cortical area and the moment of inertia measurements were also
determined. Stimulated whole saliva was collected for a 5-min period using a cube
of paraffin as a stimulant and was analyzed for total protein by a colorimetric
reaction and IL-6 and IL-8 by ELISA. RESULTS: The results of the study showed
that postmenopausal women on estrogen therapy had more alveolar bone loss, more
missing teeth, and reduced alveolar and second metacarpal bone density than
premenopausal women. In addition, postmenopausal women on estrogen therapy had
higher salivary IL-6 concentrations than premenopausal women. Alveolar bone
densities were also strongly correlated to second metacarpal densities.
CONCLUSIONS: The results of the study suggest that changes in alveolar bone
density and levels of bone resorptive cytokines in saliva may be secondary to
changes in menopausal status. These changes may predispose loss of alveolar bone
with resultant loss of teeth.
PMID- 9402941
TI - A single bout of concentric resistance exercise increases basal metabolic rate 48
hours after exercise in healthy 59-77-year-old men.
AB - BACKGROUND: It has been shown that basal metabolic rate (BMR) decreases with age.
The extent to which some of the decrease can be reversed by exercise in older men
and women is unclear. Resistance exercise has been shown to significantly
increase muscle mass in older individuals, and because muscle is a highly active
metabolic tissue there is potential to increase BMR as a secondary outcome to the
training adaptation. METHODS: Twelve healthy men aged 59-77 years performed
single-leg knee extension exercise (right and left leg) and bench press lifts (16
sets, 10 reps/set with timed recovery between sets) at 75% of the individual's
3RM. Subjects only performed the concentric phase of the lift. BMR was measured
on two separate occasions, once after a nonexercise control period and again 48
hrs after a bout of resistance exercise. RESULTS: BMR was significantly increased
(p < .006) 48 hrs after exercise (EX) compared to control (CON) (284.0 +/- 34.0
vs 274.9 +/- 34.0 kJ/hr, respectively). Calculated over a 24-hour period, the
energy expenditure corresponded to 1570 +/- 193 and 1627 +/- 193 kcal/24 hr (p <
.0002) for the CON and EX measures, respectively. VO2 (L/min) was higher (p <
.0002) 48 hrs after the EX bout compared to 48 hrs post-CON (0.232 +/- 0.03 vs
0.225 +/- 0.03 L/min, respectively). CONCLUSION: We conclude that in healthy 59
77-year-old men, an acute bout of resistance exercise causes a sustained increase
in BMR that persists for up to 48 hours after exercise.
PMID- 9402942
TI - Predictors of mobility decline: the Hong Kong old-old study.
AB - BACKGROUND: Old age is often accompanied by functional decline and loss of
autonomy. This longitudinal study examines the factors associated with mobility
decline among a Chinese elderly cohort aged 70 years and above. METHODS: Analyses
were carried out on data collected from 1,483 elderly subjects who were
functionally mobile at baseline and survived the 18-month follow-up period. The
outcome variable "mobility decline" was measured using the Barthel Activities of
Daily Living Scale, which accesses subjects' ability to be independent in walking
a distance of 50 meters and/or moving up and downstairs during the 18-month
follow-up interview. RESULTS: Multivariate backward stepwise logistic regression
analysis revealed that the following baseline characteristics were independently
associated with mobility decline during the follow-up period: increasing age (OR
1.4, 95% CI 1.2-1.6 for every 5-year increase in age), no formal level of
education (OR 1.9, 95% CI 1.0-3.9), no current practice of exercise (OR 2.1, 95%
CI 1.4-3.1), symptoms of palpitation (OR 1.7, 95% CI 1.1-2.8), body mass index
[weight (kg)/height (m)2] below 20 (OR 1.7, 95% CI 1.1-2.6), and slow gait
velocity (OR 1.12, 95% CI 1.09-1.16 per second increase in gait time). There was
also significant association between the experience of falls during follow-up and
mobility decline (OR = 2.9, 95% CI = 1.9-4.5). CONCLUSION: Low body weight, lack
of exercise, and falls during the follow-up period might serve as markers as to
which subjects are at risk for mobility decline.
PMID- 9402943
TI - Reproducibility of performance-based and self-reported measures of functional
status.
AB - BACKGROUND: The reproducibility of a performance-based and a self-reported
measure of functional status was investigated, as well as the impact of age and
cognitive function on the reproducibility. METHODS: Of a random sample of 114 men
of the 1995 survey of the Zutphen Elderly Study, 105 men (aged 79.9 +/- 4.5
years) participated in a test-retest study. They filled out a questionnaire on
disabilities and carried out performance tests twice, in a 2-week interval. Four
performance tests were administered (standing balance, walking speed, chair
stand, and external shoulder rotation), and a summary performance score was
constructed. The number of self-reported disabilities in basic activities of
daily living, mobility, and instrumental activities of daily living were
assessed. Kappa statistics and Pearson correlation coefficients between test and
retest measurements were computed for the total group and stratified by age and
cognitive function. RESULTS: Three performance tests and the summary performance
score had fair to good reproducibility (walking speed: Pearsons r = .90, chair
stand: r = .82, shoulder rotation: kappa = .49, summary score: kappa = .52). Only
the test for standing balance was poorly reproducible (kappa = .29). The self
reported functional status was fairly to good reproducible (kappa = .63, r =
.87). Self-reported functional status was significantly less reproducible in very
old and cognitively impaired than in younger and nonimpaired individuals.
CONCLUSIONS: In the elderly male subjects, performance tests and self-reported
disabilities had moderate to good reproducibility, with the exception of the test
for standing balance. In very old or cognitively impaired populations, self
reported functional status may have a lower reproducibility.
PMID- 9402944
TI - Management of verbally disruptive behaviors in nursing home residents.
AB - BACKGROUND: Verbally disruptive behaviors (VDB) are verbal or vocal behaviors
that are inappropriate to the circumstances in which they are manifested. These
behaviors are a source of concern because they disturb persons around the older
person and may be an indicator of distress. METHODS: Three interventions were
tried and compared to a control no-intervention phase. The interventions were:
(1) Presentation of a videotape of a family member talking to the older person,
(2) in vivo social interaction, and (3) use of music. RESULTS: Thirty-two nursing
home residents suffering from dementia and manifesting VDB were observed before,
during, and after the interventions, and the duration of VDB was recorded. The
behaviors decreased by 56% during the social interaction, 46% during the
videotape, 31% during the music, and 16% during the no-intervention. CONCLUSIONS:
The effects of the interventions were clinically and statistically significant,
indicating the importance of providing stimulating activities and a richer
environment to cognitively impaired nursing home residents.
PMID- 9402945
TI - Primary hepatocyte culture as an experimental model for the evaluation of
interactions between xenobiotics and drug-metabolizing enzymes.
PMID- 9402946
TI - Preclinical evaluation of drug-drug interaction potential: present status of the
application of primary human hepatocytes in the evaluation of cytochrome P450
induction.
AB - Cytochrome P450 (CYP) inhibition and induction are the key mechanisms in drug
drug interactions. Aside from clinical studies, primary human hepatocytes may
represent the most appropriate experimental system for the evaluation of CYP
induction in humans. A consensus of an international panel on the present status
and future research directions in the application of primary human hepatocytes in
the evaluation of CYP-induction is presented here. The following observations are
concluded to be generally true: (1) Human hepatocytes isolated from both biopsy
samples and transplantable livers are suitable for induction studies. (2)
Hormonally-defined media can be used for the evaluation of CYP induction. (3)
Isozyme-selective induction of CYP1A and 3A by known inducers are observed. (4)
Reproducibility of induction could be improved by using hepatocytes plated as
confluent cultures. (5) Induction could be observed for hepatocytes treated at 1
3 days after culturing. (6) Treatment duration of 2 days in general leads to near
maximal induction. (7) In general, there is a good qualitative correlation
between human hepatocyte results in vitro and clinical observations in vivo. (8)
When the same inducers were evaluated in independent laboratories, similar data
were generally observed. We conclude that primary human hepatocytes represent an
appropriate model for mechanistic evaluation of CYP induction and as a screening
tool for CYP induction potential of xenobiotics. A set of data acceptance
criteria are proposed: (1) Positive response should be observed with concurrent
positive control chemicals; (2) reproducible observation should be observed with
multiple human donors; (3) for negative response, the doses used should not be
cytotoxic; and (4) replicate treatment and/or multiple dose treatment should be
performed to allow statistical analysis. Future studies should include the
further development of on: (1) The inducibility of CYP isozymes other than CYP1A
and 3A, and phase II enzymes; (2) further development of culturing condition to
allow optimal gene expression; (3) evaluation of the involvement of
nonparenchymal cells on CYP induction of parenchymal cells; (4) the and
validation of quantitative approaches to extrapolate in vitro data to in vivo
data; (5) evaluation of possible individual variations and potential genetic
polymorphism in inducibility; (6) further definition of species differences in
CYP induction; (7) development of a 'normal' human hepatocyte cell line for CYP
induction studies; (8) improvement of cryopreservation procedure of human
hepatocytes; (9) definition of the molecular mechanisms of CYP induction; and
(10) evaluation of the induction of phase II metabolic pathways.
PMID- 9402948
TI - Long-term primary cultures of adult human hepatocytes.
AB - In this work we have investigated a system of long-term primary cultures of adult
human hepatocytes which, in contrast to those previously described, has the
advantage of requiring neither the use of additive cells as in co-cultures, nor
of matrix component preparations like Matrigel or collagen sandwich. This system
has been used previously for long-term cultures of hepatocytes from young baboon,
and some modifications have been introduced here to take into account the
specificity of adult human hepatocytes. In this system, hepatocytes are plated at
confluence on collagen-coated dishes and cultured in a serum-free medium
consisting of Williams'E supplemented with hormones and growth factors. Proteins
secreted specifically by the liver, including albumin, alpha-1 antitrypsin,
plasminogen, fibrinogen, lipoproteins ApoA1 and ApoB100, have been quantified in
the extracellular medium as a function of time, either by immunoblot or ELISA. In
addition, the expression and inducibility of CYP proteins of the CYP1, CYP2 and
CYP3 families in response to their prototypical inducers including 2,3,7,8
tetrachlorodibenzo(p)dioxin and rifampicin, have been evaluated by immunoblot
analysis of microsomes or cell lysates. Moreover, the oxidative metabolism of
cyclosporin A, a monoxygenase activity depending on CYP3A4, has been monitored
directly on the cultured cells by HPLC analysis of extracellular medium. Our
results show that, under these culture conditions, adult human hepatocytes retain
these phenotypical characteristics for at least 35 days. This system meets the
requirements for use as a model for screening CYP protein inducers.
PMID- 9402947
TI - Primary human hepatocytes as a tool for the evaluation of structure-activity
relationship in cytochrome P450 induction potential of xenobiotics: evaluation of
rifampin, rifapentine and rifabutin.
AB - In our laboratory, primary human hepatocytes are being investigated as an in
vitro experimental system for the evaluation of pharmacokinetic drug-drug
interactions. Our study here represents the first reported study that directly
compares the cytochrome P450 isozyme 3A (CYP3A) induction potential of three
antimicrobials derived from rifamycin B, namely, rifampin, rifapentine and
rifabutin. Two endpoints of CYP3A activity, testosterone 6 beta-hydroxylation and
midazolam 1-hydroxylation have been used. Results obtained with hepatocytes from
four different human donors show consistently that rifampin and rifapentine are
potent inducers of CYP3A, while a significantly lower induction potential is
observed for rifabutin. The relative induction potency of the three
antimicrobials (rifampin > rifapentine >> rifabutin) is consistent with the
available human in vivo data. For CYP1A measured as ethoxyresorufin O-deethylase
activity, CYP2C8/9 measured as tolbutamide 4-hydroxylation activity, CYP2D6
measured as dextromethorphan O-demethylation, and AZT glucuronidation, there is
either no effect or, where induction is found to be statistically significant in
these other endpoints, the maximum induction values are consistently < 100% of
the control. Our results suggest that CYP3A is the major CYP induced by these
rifamycin B derivatives. These studies illustrate the application of human
hepatocytes in the evaluation of the structure-activity relationships in CYP
induction for this class of chemicals and as an in vitro screen for drug-drug
interaction potential via CYP induction.
PMID- 9402949
TI - Quantitative reverse transcriptase/PCR assay for the measurement of induction in
cultured hepatocytes.
AB - Hepatic enzyme induction is often evoked as the cause for a variety of effects in
animal studies, e.g. hepatic hypertrophy and secondary thyroid neoplasms in
rodents. In clinical practice, enzyme induction often enhances drug clearance and
may result in reduced efficacy. For example, carbamazepine or rifampin treatment
induces P450 3A in humans, and as a result, dramatically reduces the efficacy of
midazolam or cyclosporine. Due to species differences in substrate specificity
and the regulation of various drug-metabolizing enzymes, assessing enzyme
induction in human tissues is a desirable goal. Since induction often occurs as a
result of increased synthesis of mRNA coding for a particular enzyme, induction
may be quantified by measuring specific mRNA levels. We describe an approach to
quantifying mRNA levels using reverse transcriptase-polymerase chain reaction (RT
PCR). This approach makes use of either radiolabeled PCR primers or fluorimetric
quantification of product and does not require the synthesis of a competitor RNA
or DNA molecule. Thus, Cyp2B1/2 mRNA can be shown to be induced 17-fold in the
H4IIE rat hepatoma cell line. Likewise, Cyp3A and Cyp2A6 mRNAs can be shown to be
induced in primary human hepatocytes cultured on collagen-coated plates and
treated with rifampin for 72 h. By contrast, mRNA levels for Cyp1A1 and Cyp2E1
were not increased by rifampin treatment. This report demonstrates the potential
of this approach for examining a number of mRNAs from drug-treated cultured
cells, as a means of assessing metabolic enzyme induction.
PMID- 9402950
TI - An evaluation of the CYP1A induction potential of pantoprazole in primary rat
hepatocytes: a comparison with other proton pump inhibitors.
AB - The ability of pantoprazole to affect the induction of cytochrome P450 (CYP) 1A
subfamily was evaluated and compared with two other proton pump inhibitors,
omeprazole and lansoprazole, in primary cultured hepatocytes from female Sprague
Dawley rats. The hepatocytes were cultured for 2 days, followed by treatment for
2 days with the proton pump inhibitors at 2, 5 and 10 microM, concentrations that
are similar to plasma concentrations found in rats in vivo. The CYP1A inducer 3
methylcholanthrene (at 1 microM) was also evaluated as a positive control.
Induction potentials of these chemicals for CYP1A were determined by 7
ethoxyresorufin O-deethylase activity and isozyme contents. The results showed
that for CYP1A induction, the rank ordering in induction potential was
consistently lansoprazole > omeprazole > pantoprazole. The results are consistent
with the existing rat in vivo data, i.e. pantoprazole has lower CYP1A induction
potential than omeprazole and lansoprazole.
PMID- 9402951
TI - Insulin effects on CYP2E1, 2B, 3A, and 4A expression in primary cultured rat
hepatocytes.
AB - Although hyperketonemia and/or altered growth hormone secretion caused by
diabetes have been implicated in enhanced CYP2E1, 2B, 3A and 4A expression, the
effect of insulin on hepatic P450 expression, in the absence of associated
metabolic/hormonal alterations, remains unknown. Primary cultured rat hepatocytes
have been shown (Zangar et al., Drug Metab. Dispos., 23:681, 1995) to express
stable and inducible CYP2E1 mRNA and protein levels, and provide an excellent
system for mechanistic examination of the effect of insulin on CYP2E1, 2B, 3A and
4A expression. Maintaining primary rat hepatocytes in culture in the absence of
insulin for 48, 72, or 96 h increased CYP2E1 mRNA levels 5-, 11-, and 4-fold,
respectively, relative to cells maintained in the presence of the standard
concentration of 1 microM insulin. In contrast, CYP2B mRNA levels increased only
approximately 2-fold in the absence of insulin, when compared with the presence
of 1 microM insulin. CYP2E1 and 2B protein levels were increased 6.7- and 3.8
fold, respectively, in cells cultured for 96 h in the absence of insulin as
compared with those cultured in medium containing 1 microM insulin. Concentration
response studies revealed that decreasing the concentration of insulin below 10
nM (i.e. 1 nM, 0.1 nM, no insulin) increased CYP2E1 mRNA levels 4-, 7-, and 11
fold, respectively. In contrast, no such concentration-dependence was observed
for CYP2B mRNA expression. As CYP3A and 4A expression is also elevated in
diabetic rats, the effects of insulin on these P450s was also examined. CYP3A
mRNA levels were unaltered and CYP4A mRNA levels were decreased marginally
(approximately 50%) by the absence of insulin relative to levels in cells
cultured in the presence of 1 microM insulin over 96 h in culture. The results of
this study provide evidence that insulin itself, in the absence of other diabetes
induced metabolic or hormonal alterations, affects CYP2E1 and 2B, but not CYP3A
or 4A, expression in primary cultured rat hepatocytes. Furthermore, CYP2E1
expression is differentially regulated by insulin relative to CYP2B, 3A or 4A.
This study also demonstrates that decreasing the concentration of insulin in the
culture medium provides a method by which CYP2E1 levels can be increased in
primary cultured hepatocytes to facilitate mechanistic studies on the regulation
of CYP2E1 expression.
PMID- 9402952
TI - Pig hepatocytes as an in vitro model to study the regulation of human CYP3A4:
prediction of drug-drug interactions with 17 alpha-ethynylestradiol.
AB - The objective of this study was to provide evidence of the validity of pig
hepatocytes as a model to study the regulation of human CYP3A4 with special
emphasis on drug-drug interactions. Thirteen different drugs were incubated with
primary monolayer cultures of pig hepatocytes (n = 4). The study included both
drugs reported to cause drug interactions in the clinic with 17 alpha
ethynylestradiol (EE2), other drugs metabolized by CYP3A4, and drugs not reported
to cause any problems. Effect of the drug exposure to pig hepatocytes was
determined by immunodetection using a monoclonal human CYP3A4 antibody and
measurement of 6 beta-hydroxylation of testosterone and 2-hydroxylation of 17
alpha-ethynylestradiol (EE2), both reactions known to be catalyzed by CYP3A4 in
humans. Data were compared to data from human hepatocytes and to reported
observations of drug-drug interactions in the clinic. The drugs known to be
inducers of CYP3A4 in humans significantly increased a CYP isoform in pigs
catalyzing 6 beta-hydroxylation of testosterone and 2-hydroxylation of EE2,
whereas drugs not reported to have clinical interactions with EE2 had no or only
marginal effect. Induction by the drugs known to be inducers of CYP3A4 increased
with drug exposure time and the CYP3A4 activity, represented by testosterone 6
beta-hydroxylation, was highest at 72 h for the investigated induction periods
(24, 48 and 72 h), except for dexamethasone where the effect peaked after 24 h.
Induction of the 2-hydroxylation of EE2 correlated well with the increase in 6
beta-hydroxylation of testosterone (except for sulphinpyranzone) and the increase
in the protein level of CYP3A detected by a monoclonal human CYP3A4 antibody,
thus confirming the 2-hydroxylation of EE2 in pigs as being biotransformed by a
CYP isoform presumably belonging to the CYP3A subfamily as in humans. In
conclusion, these results indicate that pig hepatocytes may be a valuable model
to mimic the regulation of human CYP3A4.
PMID- 9402953
TI - Extrapolation of in vitro enzyme induction data to humans in vivo.
AB - Enzyme induction generally increases the rate and extent of xenobiotic metabolism
in vitro, but physiological constraints can dampen these effects in vivo.
Biotransformation kinetics determined in hepatocytes in vitro can be extrapolated
to whole animals based on the hepatocellularity of the liver, since the initial
velocity of an enzyme-catalyzed reaction is directly proportional to the total
enzyme present in the cell. The biotransformation kinetics of various xenobiotics
determined with isolated hepatocytes in vitro have been shown to accurately
predict pharmacokinetics in whole animals. Analysis of the kinetic data, using
physiologically based pharmacokinetics, allows extrapolation of xenobiotic
biotransformation across dose routes and species in a biologically realistic
context. Several fold variations were observed in the bioactivation of the
hepatotoxicant furan by isolated human hepatocytes, due to induction of
cytochrome P450 2E1. Extrapolation of these data to humans in vivo showed that
furan bioactivation was limited by hepatic blood flow delivery of the substrate.
One important consequence of hepatic blood flow limitation is that the amount of
metabolite formed in the liver is unaffected by increases in Vmax due to enzyme
induction. Therefore, interindividual variations in cytochrome P450 2E1 among
human populations would not affect the bioactivation of many rapidly metabolized
hazardous chemical air pollutants. The hepatic blood flow limitation of
biotransformation is also observed after oral bolus dosing of rapidly metabolized
compounds. More slowly metabolized xenobiotics, such as therapeutic agents, are
only partially limited by hepatic blood flow and other processes.
PMID- 9402954
TI - An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner
helicase mutations from wild-type and homozygous mutants.
AB - Immortalized B lymphocytes from Werner syndrome subjects are shown to be
hypersensitive to 4-nitroquinoline-1-oxide (4NQO), supporting earlier work on T
lymphocytes. We also show that B cell lines from clinically normal heterozygous
carriers exhibit sensitivities to this genotoxic agent, which are intermediate to
those of wild-type and homozygous mutants. 4NQO is shown to induce an apoptotic
response. These data encourage research on DNA repair with such cell lines and
raise the question of an enhanced sensitivity of the relatively prevalent
heterozygous carriers to certain environmental genotoxic agents.
PMID- 9402955
TI - Association of transferrin C2 allele with late-onset Alzheimer's disease.
AB - Transferrin (Tf), an iron-transporting protein, has many variants, but C1 and C2
variants account for the majority of the population in all races. Since Tf is
reported to be immunocytochemically detectable in senile plaques in Alzheimer's
disease (AD), we have examined the Tf allele frequency among AD patients. The C2
allele frequency in late-onset AD patients is significantly higher than that in
age-matched controls. Unexpectedly, the C2 allele frequency in AD patients
homozygous for the ApoE epsilon 4 allele is markedly increased, i.e., it is twice
as high as that in the remaining AD patients carrying zero or one copy of the
epsilon 4 allele.
PMID- 9402956
TI - Fine mapping of the gene for autosomal dominant juvenile-onset glaucoma with
iridogoniodysgenesis in 6p25-tel.
AB - Glaucoma is a group of ocular disorders leading to reduced visual capabilities
and sometimes blindness. The biochemical defect is unknown but it is shown that
reduced drainage of the aqueous humour from the anterior chamber may lead to
increased intraocular pressure and gradual atrophy of the optic neurons. Families
with various forms of autosomal dominant (AD) glaucoma have been linked to 1q21
31, 2cen-q13, 4q25-27, and 13q14 and autosomal recessive congenital glaucoma have
been localized to chromosome 1p36 and 2p21. Recently, a locus for AD
iridogoniodysgenesis anomaly (IGDA) was mapped to chromosome 6p25. This study
refines the localization of IGDA to an approximately 6-cM interval between
D6S1600 and D6S1617/D6S1713 at 6p25-tel, based on recombinations in affected
individuals with AD juvenile-onset glaucoma and concomitant iridogoniodysgenesis.
PMID- 9402957
TI - Evolutionary origins of two tightly linked mutations in arylsulfatase-A
pseudodeficiency.
AB - Deficient arylsulfatase A activity causes the neurodegenerative disease
metachromatic leukodystrophy. However, some individuals with deficient enzyme
activity appear clinically normal. This "pseudodeficiency" allele commonly found
among many reported populations (frequency approximately 0.10) is associated with
two A-->G transitions in cis in the arylsulfatase A gene causing the simultaneous
loss of an N-glycosylation and a polyadenylation signal. To understand the
evolutionary relationship between such common and tightly linked mutations, we
studied 400 individuals in the African, European, Indian and East Asian
populations and found none carrying the polyadenylation mutation alone. However,
the N-glycosylation mutation could occur independently. Its frequency varied from
0.01 in Indians, 0.06 in Europeans, 0.21 in East Asians to 0.32 in Africans. The
frequencies of both mutations occurring together ranged from almost non-existent
in the Africans and East Asians, to 0.075 in the Europeans and 0.125 in the
Indians. These frequencies were significantly different among populations.
Haplotype analysis among homozygous pseudodeficiency individuals and eight multi
generation families with six polymorphic enzymes showed that, of the five
haplotypes found in the general population, only one was linked to the double
mutations. Alleles among the four populations with only the N-glycosylation
mutation also supported linkage to the same haplotype except in some Europeans
whose alleles were discordant. These results are consistent with the hypothesis
that the N-glycosylation mutation may be a recurrent event among the Europeans
but first occurred in an ancestral allele before the emergence of modern Homo
sapiens from Africa at approximately 100,000-200,000 years ago. Subsequently, the
polyadenylation mutation occurred in this ancient allele with the N-glycosylation
mutation, an event that likely took place after the divergence between the
European and East Asian lineages.
PMID- 9402958
TI - Evidence for convergent evolution of A and B blood group antigens in primates.
AB - To determine whether convergent or trans-specific evolution is responsible for
the persistence of the ABO polymorphism in apes, we have sequenced segments of
introns 5 and 6 of the ABO gene. Four substitutions and one insertion or deletion
group human A, B, and O alleles together, separate from their chimpanzee A and
gorilla B counterparts. No shared substitutions support a trans-species mode of
evolution for any of the alleles examined. We conclude that the A and B antigens
of the chimpanzee and gorilla, respectively, have arisen by convergent evolution.
Phylogenetic analysis suggests that the human A and B alleles are ancient, having
diverged at least 3 million years ago. These alleles must have therefore been
trans-specifically inherited within the genus Homo.
PMID- 9402959
TI - A novel source of highly specific chromosome painting probes for human karyotype
analysis derived from primate homologues.
AB - We have established a series of highly specific painting probes for human
acrocentric chromosomes. These chromosomes are involved in the formation of the
nucleolar organizer region (NOR) and show DNA sequence homologies within their
pericentric heterochromatin. To date, these chromosomes have shown considerable
cross hybridization in chromosome painting experiments. Our probe set has been
established from primate homologues that are not involved in the NOR in that
particular species or from species in which highly repetitive sequences have
undergone rapid sequence divergence. The new painting probes should be of
particular value for automated microscopy, for which highly specific signals are
required as they are recorded at low magnification, e.g. when scoring chromosome
21 domains in interphase nuclei.
PMID- 9402960
TI - Gene structure and allelic expression assay of the human GLI3 gene.
AB - The GLI3 gene encodes a putative zinc finger transcription factor that is
important in early vertebrate development. Haploinsufficiency of this gene has
been associated with the Greig cephalopolysyndactyly syndrome and truncation
mutations cause Pallister-Hall syndrome. In the course of studies to determine
the etiology of Pallister-Hall syndrome, we required knowledge of the fine
structure of GLI3 to perform detailed genetic and physical mapping and mutation
screening of this gene. The coding region of GLI3 is composed of 14 exons,
including a large exon of more than 2500 bp. In addition, the gene contains two
intragenic dinucleotide repeats, and four single-base pair polymorphisms in the
coding region. We have used these coding region polymorphisms to design an allele
specific expression study that will be useful for studying patients with Greig
cephalopolysyndactyly syndrome. In addition, GLI3 should be considered a
candidate gene for related developmental anomalies of humans. Such hypotheses
will be more readily addressed with the availability of the fine structure of the
gene and the allele-expression assay.
PMID- 9402961
TI - ACP1 and human adaptability. 2. Association with season of conception.
AB - We have studied the pattern of association between the season of conception and
cytosolic low molecular weight phosphotyrosine phosphatase (ACP1) genetic
polymorphism in 329 consecutively newborn infants from the population of Penne
and 361 consecutively newborn infants from the population of Rome. In addition,
329 mothers were studied in the population of Penne. A concordant, highly
significant association was observed in the two populations between ACP1
parameters and the season of conception of newborn infants. The total activity of
ACP1 shows a minimum in infants conceived in January-February and a maximum in
those conceived at the end of the solar year. Analysis of the joint mother
newborn ACP1 distribution in relation to the season of fertilisation has shown
that among mothers carrying ACP1*A (the allele showing the lowest activity), the
proportion of newborns carrying this allele is higher in those conceived in the
first months of the year than in those conceived subsequently. Since ACP1
probably functions as a phosphotyrosine phosphatase and as a flavin
mononucleotide phosphatase, low activity could enhance the metabolic rate and
would be advantageous in a cold environment. The cycle of variation of ACP1 in
infants follows the cycle of solar illumination. It is possible that individuals
who have a genetic background allowing them to adapt easily and readily to
seasonal demand are more successful in reproducing themselves. The population of
zygotes conceived in a given season would therefore reproduce the pattern of gene
combination more fit for that season.
PMID- 9402962
TI - A new mutation in the type II hair cortex keratin hHb1 involved in the inherited
hair disorder monilethrix.
AB - Monilethrix is a rare dominant hair disease characterized by beaded or moniliform
hair which results from the periodic thinning of the hair shaft and shows a high
propensity to excess weathering and fracturing. Several cases of monilethrix have
been linked to the type II keratin gene cluster on chromosome 12q13 and causative
heterozygous mutations of a highly conserved glutamic acid residue (Glu 410 Lys
and Glu 410 Asp) in the helix termination motif of the type II hair keratin hHb6
have recently been identified in monilethrix patients of two unrelated families.
In the present study, we have investigated two further unrelated monilethrix
families as well as a single case. Affected members of one family and the single
patient exhibited the prevalent hHb6 Glu 410 Lys mutation. In the second family,
we identified in affected individuals a lysine substitution of the corresponding
glutamic acid residue, Glu 403, in the type II hair keratin hHb1, suggesting that
this site represents a mutational hotspot in these highly related type II hair
keratins. Both hHb1 and hHb6 are largely coexpressed in cortical trichocytes of
the hair shaft. This indicates that monilethrix is a disease of the hair cortex.
PMID- 9402963
TI - Phosphorylase-kinase-deficient liver glycogenosis with an unusual biochemical
phenotype in blood cells associated with a missense mutation in the beta subunit
gene (PHKB).
AB - We have identified mutations in the phosphorylase kinase (Phk) beta subunit gene
in a male patient with liver glycogenosis caused by Phk deficiency. The patient's
DNA has been analyzed for mutations in the genes encoding the alpha L, beta, and
gamma TL subunits of Phk, all of which can be responsible for liver glycogenosis,
by a strategy primarily based on reverse transcription/polymerase chain reaction
of blood RNA and complemented by analysis of genomic DNA. His alpha L and gamma
TL coding sequences are normal, whereas he is compound-heterozygous for two
mutations in the beta subunit gene, PHKB. The first is a splice-site mutation
(IVS4 [-2A-->G]) causing the reading-frame-disrupting deletion of exon 5 in the
mRNA from this allele. The second is an Ala117Pro missense mutation, also in exon
5. This is the first missense mutation identified in PHKB, as opposed to nine
translation-terminating mutations described to date. It offers an explanation for
the unique biochemical phenotype of this patient. In his leukocytes, low Phk
activity is measured when tested with the endogenous liver isoform of
phosphorylase as the protein substrate, but normal activity is observed when
tested with muscle phosphorylase added in vitro. In contrast, Phk activity in his
erythrocytes is low with both substrates. The missense mutation may selectively
impair the interaction of Phk with one isoform of its substrate protein and may
destabilize the enzyme in a cell-type-specific way. This phenotype shares some
aspects with X-linked liver glycogenosis subtype 2 (XLG2), a variant of liver Phk
deficiency arising from missense mutations in the alpha L subunit gene (PHKA2),
but differs from XLG2 in other respects. The present case demonstrates that
mutations in Phk genes other than PHKA2 can also be associated with untypically
high activity in certain blood cell types. Moreover, it emphasizes that missense
mutations in Phk may cause unusual patterns of tissue involvement that would not
be predicted a priori from the tissue specificity of expression of the mutated
gene sequences.
PMID- 9402964
TI - Inv(10)(p11.2q21.2), a variant chromosome.
AB - We present 33 families in which a pericentric inversion of chromosome 10 is
segregating. In addition, we summarise the data on 32 families in which an
apparently identical inv(10) has been reported in the literature. Ascertainment
was through prenatal diagnosis or with a normal phenotype in 21/33 families. In
the other 12 families, probands were ascertained through a wide variety of
referral reasons but in all but one case (a stillbirth), studies of the family
showed that the reason for referral was unrelated to the chromosome abnormality.
There has been, to our knowledge, no recorded instance of a recombinant
chromosome 10 arising from this inversion and no excess of infertility or
spontaneous abortion among carriers of either sex. We propose that
inv(10)(p11.2q21.2) can be regarded as a variant analogous to the pericentric
inversion of chromosome 2(p11q13). We conclude that prenatal chromosome analysis
is not justified for inv(10) carriers. In addition, family investigation of
carrier status is not warranted in view of the unnecessary concern this may cause
parents and other family members.
PMID- 9402965
TI - RB1 deletion in gonadoblastoma in an XY female.
AB - Cytogenetic studies of normal and tumor cells in a patient with gonadal
dysgenesis and bilateral gonadoblastoma were performed. The karyotype was 46,XY
in peripheral blood lymphocytes and skin fibroblasts. The conserved region of the
SRY gene was detected by polymerase chain reaction amplification. Sequencing of
this region did not reveal any alterations. A 46,XY chromosome constitution was
observed in the right gonadoblastoma, but a partial deletion of chromosome 13 was
present in the left tumor. This deletion included band 13q14, where the
retinoblastoma gene is mapped. The study of the polymorphism of the variable
number of tandem repeats region in intron 17 of the RB1 locus disclosed loss of
heterozygosity in both the left tumor, which showed the deletion of chromosome
13, and in the right tumor, where no chromosome alterations of chromosome 13 were
detected. In situ hybridization covering 130 kb of RB1 showed that a partial
deletion of one of the RB1 alleles had occurred in the right tumor. Since the
deletions affected different alleles in each tumor, independent events must have
been involved in the development of the tumors. These findings point toward a
significant role of RB1 in the development of gonadoblastoma.
PMID- 9402966
TI - No founder effect detected in Jewish Ashkenazi patients with fragile-X syndrome.
AB - Several studies on small homogenous populations suggested that fragile-X syndrome
originated from a limited number of founder chromosomes. The Israeli Jewish
population could serve as an adequate model for tracing a founder effect due to
the unique ethnic makeup and traditional lifestyle. Furthermore, a common
haplotype for Jewish Tunisian fragile X patients was recently reported. To test
for a similar occurrence in the Jewish Ashkenazi population, we performed
haplotype analysis of 23 fragile-X patients and 28 normal chromosomes, all Jewish
Ashkenazi, using microsatellite markers within and flanking the FMR-1 gene:
FRAXAC1, FRAXAC2, and DXS548. The combined triple-marker analysis identified a
wide range of diverse haplotypes in patients and controls, with no distinct
haplotype prevalent in the patient group. Our data suggest that no common
ancestral X chromosome is associated with the fragile-X syndrome in the Israeli
Jewish Ashkenazi patient population studied. These findings are in contrast to
other reports on founder effect associated with fragile-X syndrome in distinct
European as well as Jewish Tunisian populations. On this basis, a more complex
mechanism for the development of fragile-X syndrome in the Jewish Ashkenazi
population should be considered.
PMID- 9402967
TI - Identification of an amplified gene cluster in glioma including two novel
amplified genes isolated by exon trapping.
AB - Gene amplification, which occurs in more than 50% of malignant gliomas, is
considered to play a pivotal role in tumorigenesis. There are, however, few
studies aimed toward the isolation of novel genes from amplified sequences.
Previously, we reported amplification of the protooncogene MET (hepatocyte growth
factor receptor; 7q31) in more than 20% of glioblastomas. For an approximate size
estimation of the amplification unit we analyzed three glioblastomas all of which
carried an amplified MET gene, by Southern blot analysis and/or competitive
polymerase chain reaction using eight DNA markers. Although the extent of the
amplified domain varied, the close vicinity of the MET gene was the only region
consistently amplified in these glioblastomas. A yeast artificial chromosome
(YAC) contig of 900 kb was refined spanning the amplified region flanking the MET
gene. The YAC inserts were subcloned into 59 cosmids, which were used for exon
trapping. Eight sequences were identical to parts of the genes MET and CAPZA2
(human actin capping protein alpha-subunit). Two newly identified exons and the
CAPZA2 exons were amplified in tumor TX3095, which retains an amplified MET gene.
The new exons were localized close to MET and CAPZA2. Characterization of the
clones, which were termed glioma-amplified sequence (GAS)7-1 and GAS7-2, showed
an open reading frame and a different expression pattern in multiple human
tissues. This study reports the identification of a cluster of amplified genes
including two novel genes in a region amplified in more than 20% of
glioblastomas.
PMID- 9402968
TI - The human lysyl oxidase-like gene maps between STS markers D15S215 and
GHLC.GCT7C09 on chromosome 15.
AB - The lysyl oxidase-like (LOXL) gene is a new member of the lysyl oxidase family, a
copper-dependent enzyme that is implicated in the crosslinking of collagen and
elastin fibers. We have mapped the LOXL gene to chromosome 15q23, between STS
markers D15S215 and GHLC.GCT7C09. This position corresponds to the q23 locus, not
to the q24-25 locus suggested in a preliminary report.
PMID- 9402969
TI - Pepsinogen polymorphism in the Indian population and its association with
duodenal ulcer.
AB - To date, there have been few studies on pepsinogen polymorphism. The present
study examines the polymorphism of pepsinogen by PAGE in 155 duodenal ulcer cases
and 92 control subjects. The Indian population presents a higher frequency of the
B phenotype (associated with absence of the pg 5 fraction) and the C haplotype
compared to other populations. Heterozygotes, in particular AC phenotypic
individuals, are found to be associated significantly with the disease compared
to control subjects. All the genes of the multigene complex controlling
pepsinogen polymorphism seem to be interacting, thereby leading to such an
association. Thus, studies at the gene level may be helpful in explaining the
genetic etiology and heterogeneity of duodenal ulcer disease.
PMID- 9402970
TI - Assignment of human plasma methylumbelliferyl-tetra-N-acetylchitotetraoside
hydrolase or chitinase to chromosome 1q by a linkage study.
AB - Plasma methylumbelliferyl tetra-N-acetylchitotetraoside hydrolase or chitinase
(CHIT) might play a role in degrading the chitin wall of some microorganisms. In
about 6% of Caucasian people the enzyme shows pseudodeficiency (defined as very
low activity without apparent symptoms). We have mapped this locus by linkage
analysis to the marker D1S306 (z = 4.00 at theta M = F = 0.0) on chromosome 1q
between the flanking markers D1S191 and D1S245 in the area of 1q31-1qter.
PMID- 9402971
TI - Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous
for the A455E mutation.
AB - Cystic fibrosis (CF) has a high incidence in the French-Canadian population of
Saguenay Lac-Saint-Jean (Quebec). The A455E mutation accounts for 8.3% of the CF
chromosomes. This mutation was shown to be associated with a milder lung disease
in the Dutch population. Twenty two CF patients distributed in 17 families and
compound heterozygotes for the A455E mutation have been followed at the Clinique
de Fibrose Kystique de Chicoutimi. Fourteen patients also carried the delta F508
mutation while the remaining eight patients had the 621 + 1G-->T mutation. Each
patient was matched by sex and age to a patient homozygous for the delta F508
mutation. The pairs were analyzed for several clinical and laboratory variables.
The A455E compound heterozygotes were diagnosed at a later age (P = 0.003) and
had chloride concentrations at the sweat test lower than those homozygous for the
delta F508 mutation (P = 0.007). More patients were pancreatic sufficient (P =
0.004). They had a higher Shwachman score (P = 0.001) and better pulmonary
function tests (P < 0.02). CF patients compound heterozygous for the A455E
mutation have a milder pancreatic and lung disease than the delta F508
homozygotes. Therefore, the A455E should be associated with a better prognosis.
PMID- 9402972
TI - Genetic linkage study of a major susceptibility locus (D2S125) in a British
population of non-insulin dependent diabetic sib-pairs using a simple non
isotopic screening method.
AB - A polymorphic microsatellite marker (D2S125) was recently reported to show
significant linkage to non-insulin dependent diabetes mellitus (NIDDM) in a
population of Mexican-American affected sib-pairs. We have used a simple non
isotopic screening technique employing the polymerase chain reaction (PCR) with a
biotinylated primer to study the genetic linkage and allele frequency
distribution of the D2S125 marker in a population of 109 British NIDDMs (62
possible affected sib-pairs). The analysis provided no evidence for linkage of
the D2S125 marker in the British subjects (MLS = 0.029, P > 0.05). The PCR
screening method used proved to be a convenient and reliable alternative to the
radiolabelling of PCR products.
PMID- 9402973
TI - Sequence analysis of long FMR1 arrays in the Japanese population: insights into
the generation of long (CGG)n tracts.
AB - The human fragile-X syndrome is associated with expansions of a (CGG)n triplet
repeat within the FMR1 gene. Whilst normal FMR1 arrays consist of variable
numbers of (CGG)7-13 blocks punctuated with single AGG triplets, unstable arrays
contain longer blocks of uninterrupted (CGG)n. The degree of instability, and
subsequent risk of expansion to the fragile-X mutation, is dependent upon the
length of this uninterrupted repeat. Detailed analyses of normal FMR1 array
structures suggest that longer uninterrupted blocks of repeat could arise either
through a process of gradual slippage or a more dramatic loss of an intervening
AGG triplet. Up to 15% of Japanese and Chinese individuals have FMR1 triplet
arrays centred on 36 repeats in length, a modal group not found in Caucasians. As
longer FMR1 arrays have been associated with high-risk fragile-X haplotypes in
some populations, we investigated the nature of these larger arrays. Sequence
analysis revealed that the unusual length is due to the presence of a novel
(CGG)6 block within the array. Several haplotypically related arrays contain
blocks of (CGG)16 or (CGG)15, consistent with the fusion of adjacent (CGG)9 and
(CGG)6 blocks after loss of the intervening AGG triplet. This is compatible with
inferences from the Caucasian population that AGG loss is a mechanism by which
long blocks of identical repeats are generated.
PMID- 9402974
TI - Asynchronous replication of p53 and 21q22 loci in chronic lymphocytic leukemia.
AB - In this study, in order to evaluate the replication pattern and the cell cycle
dynamics of normal and malignant cells from patients with chronic lymphocytic
leukemia, we applied the FISH technique with the p53 gene. Asynchrony was
determined by the presence of one single and one set of double dots in the same
cell. The rate of asynchronous replication was significantly higher in malignant
cells than in normal cells (a mean of 28 vs 13, respectively, P = 0.023). There
were proportionately more cells with two single dots among the normal cells (P =
0.0047). These results probably reflect the changes in gene replication and cell
cycle progression that occur in malignant cells.
PMID- 9402975
TI - Dual blastomere analysis improves reliability of preimplantation trembler mouse
diagnosis.
AB - Dual blastomere biopsy and independent blastomere analysis dramatically improved
preimplantation diagnostic reliability as confirmed by testing the remaining
biopsied eight-cell mouse embryo. The autosomal dominant trembler mouse point
mutation was selected as a model for human preimplantation diagnosis because: (1)
single cell assay failure is predicted to be the highest when testing autosomal
dominant mutations; (2) point mutations represent the most common of all mutation
categories and the most demanding mutation to assay reliably; and (3) the
trembler mouse point mutation in peripheral myelin protein 22 (Pmp22) is a model
of human Charcot-Marie-Tooth type 1A disease. Mathematical models predict our
experimental results assuming amplification of 80% of each target allele as well
as trembler sperm DNA contamination in 1 of 44 normal biopsied single
blastomeres. Single blastomere analysis correctly predicted the genotype in only
84% of embryos that would have been implanted as normal. In contrast, when
independent tests of both biopsied blastomeres agreed, test results were
confirmed in 20 of 21 (95.2%) of the remaining six-cell biopsied embryos
designated as normal. Thus, biopsied six-cell embryo confirmation demonstrated
that dual biopsied blastomere analysis improved test reliability remarkably.
PMID- 9402976
TI - Novel stop and frameshifting mutations in the autosomal dominant polycystic
kidney disease 2 (PKD2) gene.
AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent
inherited disorders. The majority of cases are due to mutation of the PKD1 gene,
on 16p13.3, while in most of the remainder the disease maps to the PKD2 locus, at
chromosome 4q21-q23. Recently, the PKD2 gene has been positionally cloned and
three nonsense mutations within the coding sequence of the gene identified. Here
we report a systematic mutation screening of all 15 exons of the PKD2 gene in
chromosome 4-linked ADPKD families, using heteroduplex and SSCP analyses. We have
identified and characterized seven novel mutations, with a detection rate of
approximately 90% in the population studied. All of the mutations result in the
premature stop of translation: four nonsense changes and three deletions. The
deletions are all frameshifting, of four T nucleotides in one case and one G
nucleotide in the other two. All mutations are unique and are distributed
throughout the gene without evidence of clustering. Comparison of specific
mutations with the clinical profile in ADPKD2 families shows no clear
correlation.
PMID- 9402977
TI - Exclusion of PPEF as the gene causing X-linked juvenile retinoschisis.
AB - X-linked juvenile retinoschisis (RS) is a progressive vitreoretinal degeneration
localised in Xp22.1-p22.2. A human homologue of the retinal degeneration gene C
(rdgC), a gene that in Drosophila melanogaster prevents light-induced retinal
degeneration, was localised in the RS obligate gene region. We have tested the
gene, designated PPEF in humans, as a candidate gene in RS patients using RT-PCR
and the protein truncation test on RNA and SSCP on DNA. No mutations were
identified, making it highly unlikely that PPEF is the gene implicated in RS. The
data presented facilitate mutation analysis of the PPEF gene in other diseases
which have been or will be localised to this region.
PMID- 9402978
TI - Familial Mediterranean fever: clastogenic plasma factors correlated with
increased O2(-)--production by neutrophils.
AB - Familial Mediterranean fever (FMF) is an autosomal recessive disease
predominantly affecting Armenians and non-Ashkenazi Jews. The disease begins in
childhood with paroxysmal attacks of pain and fever accompanied by peritonitis,
pleuritis, and synovitis. During the acute phase, there is a massive influx of
polymorphonuclear leukocytes into the serosal membranes, connected with
degranulation of the neutrophils and with secretion of lysosomal enzymes and
pyrogenic substances. An increase in the lipoxygenase product, leukotriene B4, a
chemotactic agent, and a decrease in the activity of the inhibitor of chemotaxis,
C5a, in serosal fluids have been considered responsible. Previous work from our
laboratories had shown that the chromosomal instability observed in blood
cultures of patients with FMF is secondary to circulating clastogenic factors
(CFs), and that the antioxidant enzyme superoxide dismutase, as well as
lipoxygenase inhibitors, reduce the chromosome damaging effects. CFs are observed
in chronic inflammatory diseases and in various other pathological conditions
accompanied by oxidative stress. Similar clastogenic materials were found in
supernatants of neutrophils and monocytes after a respiratory burst and were
shown to contain lipid peroxidation products and cytokines. In the present study
we compared the clastogenic effects exerted by plasma ultrafiltrates from 20
adult patients with FMF to the unstimulated O2- production of their neutrophils.
In comparison to 20 age- and sex-matched controls, which were studied
simultaneously, the O2- production by patient's neutrophils was routinely higher
than that of controls. The clastogenic effects of patient's plasma, expressed as
the number of chromosomal aberrations induced in test cultures of healthy donors,
were correlated with the importance of O2- production by their neutrophils (r =
0.5235). Even if the relative contribution of disturbance in arachidonic acid
metabolism, neutrophil activation, and CF formation in the disease process
remains unclear, the demonstration of oxidative stress in this genetic disorder
suggests the use of antioxidants and free radical scavengers, in particular
during acute attacks, when the classical colchicine treatment is without effect.
PMID- 9402979
TI - Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and
linkage disequilibria in African- and European-American and Japanese populations
and in alcohol-dependent subjects.
AB - The SLC6A4 locus encodes the serotonin transporter, which in turn mediates the
synaptic inactivation of the neurotransmitter serotonin. Two PCR-formatted
polymorphisms at this locus have been described, the first of which is a variable
number tandem repeat located in exon 2, and the second a repeat sequence
polymorphism located in the promoter region. The latter polymorphism alters
transcriptional activity of SLC6A4, and has been reported to be associated with
anxiety and depression-related traits. We studied allele frequencies, and
computed haplotype frequencies and linkage disequilibrium measures, for these two
polymorphisms in European-American, African-American, and Japanese populations,
and in a set of alcohol-dependent European-American subjects. Allele frequencies
for both systems showed variation, with significant differences overall for each
system, and significant differences between each pair of populations for both
systems. Linkage disequilibrium also varied among the populations. There were no
significant differences in allele or haplotype frequencies between the European
American population samples and alcohol-dependent subjects. The population
differences demonstrate a potential for population stratification in association
studies of either of these SLC6A4 polymorphisms. If genetic variation at this
locus really is associated with behavioral variation, these results could reflect
either different behavioral adaptations in different populations, or random
genetic drift of a behaviorally important but selectively neutral polymorphism.
PMID- 9402980
TI - No mitochondrial cytochrome oxidase (COX) gene mutations in 18 cases of COX
deficiency.
AB - Cytochrome c oxidase (COX) deficiency causes a variety of neuromuscular and non
neuromuscular disorders in childhood and adulthood and can theoretically undergo
either a nuclear or a mitochondrial (mt) mode of inheritance, making genetic
counseling in COX deficiency particularly hazardous. In an attempt to determine
the respective roles of mtDNA and nuclear DNA mutations in COX deficiency, we
sequenced the three mitochondrially encoded COX subunits (COXI-III) in a series
of 18 patients with isolated COX deficiency, especially as COXI-III code for the
catalytic site of the enzyme. We failed to detect any deleterious mutations in
this series. Moreover, no mtDNA deletion was observed and sequencing of the
flanking tRNA genes involved in the maturation of the COX transcripts failed to
detect deleterious mutations as well. The present study supports the view that
the disease-causing mutations do not lie in the mt genome but, rather, in the
nuclear genes encoding either the COX subunits or the proteins involved in
assembly of the complex and suggests a recurrent risk of 25% rather than other
modes of inheritance in COX deficiencies.
PMID- 9402981
TI - Fragile site or dissociation of a t(Y;13)?
PMID- 9402983
TI - A pharmacophore model of tautomycin, an inhibitor of protein phosphatases 1 and
2A.
PMID- 9402984
TI - Amphistin, a new melanogenesis inhibitor, produced by an actinomycete.
AB - A new melanogenesis inhibitor, named amphistin, was isolated from the
fermentation broth of an actinomycete strain KP-3052. Amphistin was purified from
the culture filtrate by the combination of cation exchange, gel filtration, and
aminosilyl silica gel chromatographic methods. The structure of amphistin was
elucidated as gamma-(beta-histidinoalanino)homoalanine by NMR experiments
including 1H-15N HMBC experiment and other spectroscopic analyses. Amphistin
inhibited the melanogenesis of B16 melanoma cells at concentration of 6.8 microM.
PMID- 9402985
TI - BE-32030 A, B, C, D and E, new antitumor substances produced by Nocardia sp.
A32030.
AB - New antitumor substances, designated BE-32030A, B, C, D and E, were isolated from
the culture broth of Nocardia sp. A32030. The active principles were extracted
from the mycelium by methanol and purified by Sephadex LH-20 and reversed-phase
column chromatographies and finally by reversed-phase HPLC. BE-32030A, B, C, D
and E inhibited the growth of P388 murine leukemia, DLD-1 human colon cancer, PC
13 human lung cancer and MKN-45 human stomach cancer cell lines.
PMID- 9402986
TI - Nocardicyclins A and B: new anthracycline antibiotics produced by Nocardia
pseudobrasiliensis.
AB - Nocardicyclins A (1) and B (2), new anthracycline antibiotics have been isolated
from the mycelial cake of Nocardia pseudobrasiliensis IFM 0624 (JCM 9894). The
molecular formulae of 1 and 2 have been determined as C30H35NO11 and C32H37NO12,
respectively, and the structures were characterized by 1- and 8-methoxyl groups,
a 10-carbonyl group and a novel carbon-methylated aminosugar constituent.
Nocardicyclin A (1) exerts cytotoxic activity against L1210 and P388 leukemia.
Nocardicyclins A (1) and B (2) are active against Gram-positive bacteria
including Mycobacterium spp. and Nocardia spp., but inactive against Gram
negative bacteria.
PMID- 9402987
TI - A new antiherpetic agent, AH-1763 IIa, produced by Streptomyces cyaneus strain
no. 1763.
AB - A new antiherpetic agent, AH-1763 IIa, was isolated from the culture broth of
strain No. 1763 identified as Streptomyces cyaneus. It was purified through
column chromatographies of Diaion HP-10 and silica gel. The structure was
determined to be 11-hydroxy-5-methyl-2-(2-hydroxy-1-methylpropyl)-4H-anthraceno
[1,2-b]pyran-4,7,12-trione by several spectroscopic experiments, that is a new
antibiotic belonging to pluramycin-group.
PMID- 9402988
TI - CJ-12,954 and its congeners, new anti-Helicobacter pylori compounds produced by
Phanerochaete velutina: fermentation, isolation, structural elucidation and
biological activities.
AB - Seven new phthalide compounds with anti-Helicobacter pylori activities were
isolated from the basidiomycete Phanerochaete velutina CL6387. The two most
potent phthalide compounds, CJ-12,954 and CJ-13,014, have MICs of 5 ng/ml. The
structure-activity relationship shows that the presence of a spiroketal part in
addition to the phthalide part, greatly enhances the activity. The phthalide
compounds appear to be specific for H. pylori, since they did not show
antibacterial activities when tested against a panel of other microorganisms.
PMID- 9402989
TI - Novel anthelmintic metabolites from an Aspergillus species; the aspergillimides.
AB - Two members of a novel class of anthelmintics, the aspergillimides, have been
isolated from the Aspergillus strain IMI 337664. This novel fungus also produced
two known and one structurally novel paraherquamide. This paper describes the
fermentation, isolation, structure elucidation and anthelmintic activity of
aspergillimide (VM55598, 1), 16-keto aspergillimide (SB202327, 2), and the
paraherquamides VM54159 (3), SB203105 (4) and SB200437 (5). The aspergillimides
are equivalent to paraherquamides which have lost both the dioxygenated 7
membered ring and the phenyl ring to which this is fused; gaining in their place
a C8-keto group. SB203105 is the first example of a 4-substituted paraherquamide.
PMID- 9402990
TI - Involvement of afsA in A-factor biosynthesis as a key enzyme.
AB - The afsA gene of Streptomyces griseus has been postulated to encode a key enzyme
for A-factor biosynthesis from primary metabolites commonly present in
Streptomyces strains. Escherichia coli cells harboring afsA under the control of
the T7 promoter specified distinct A-factor activity in the culture broth, as
determined by induction of streptomycin production and aerial mycelium and spore
formation in an A-factor-deficient S. griseus mutant strain. Production of the
substance(s) having A-factor activity was inhibited by cerulenin, an inhibitor of
fatty acid biosynthesis. These observations suggest that afsA encodes a key
enzyme in the A-factor biosynthetic pathway in which a beta-keto acid derived
from fatty acid biosynthesis and a glycerol derivative serve as precursors.
PMID- 9402992
TI - New dihydro and tetrahydro derivatives of desmycosin. III. The opening of oxirane
ring of 12,13-epoxydesmycosin.
AB - Opening the oxirane ring of 12,13-epoxydesmycosin dimethylacetal (1) by catalytic
hydrogenation gave the 10,11-dihydro-12,13-epoxy derivative (3) as the main
product. Reductive oxirane cleavage was accomplished with dissolved metal (Zn)
giving the 10,13-dihydro-13-hydroxy compound (6). Mild acid hydrolysis of 6 gave
expected 10,13-dihydro-13-hydroxydesmycosin (8), but hydrolysis of 3, under the
same conditions, gave three tautomeric desepoxy products.
PMID- 9402991
TI - Inhibition of anchorage-independent growth of tumor cells by IT-62-B, a new
anthracycline.
AB - IT-62-B, a new anthracycline isolated from fermentation broths of Streptomyces
sp. IT-62, reversed certain tumor cell phenotypes in vitro including some of
human origin. The observed normal phenotypes were anchorage dependence of cell
growth, flattened cell morphology and restoration of actin stress fibers. The
extent of the anchorage dependence of cell growth induced by IT-62-B was
generally greater than that by doxorubicin or pirarubicin. The cell-flattening
effect of IT-62-B on cells of T24 (human bladder), but not on C-33A (human
cervix), accompanied inhibition of fos gene expression. T24 cells, once flattened
by IT-62-B, retained their flat morphology even in drug-free, fresh medium and
eventually died in several days. IT-62-B, unlike doxorubicin, only slightly
inhibited the topoisomerase II reaction in vitro and DNA synthesis in isolated
cell nuclei.
PMID- 9402993
TI - Chemical synthesis and structural study of lincomycin sulfoxides and a sulfone.
AB - Oxidation of lincomycin with dimethyldioxirane resulted in the sulfoxide
glycosides 3a and 3b, whose treatment with osmium tetraoxide and N
methylmorpholine-N-oxide afforded the same sulfone; 4. According to FAB-MS and CD
investigations, the absolute configuration of the sulfur atom in 3a and 3b is R
and S, respectively. The new, unsaturated antibiotic analog (6) derived from
clindamycin exists in the 4C1 conformation. The antibiotic activities of the
synthesized compounds were also studied.
PMID- 9402994
TI - delta-Indomycinone: a new member of pluramycin class of antibiotics isolated from
marine Streptomyces sp.
PMID- 9402995
TI - Macrosphelides C and D, novel inhibitors of cell adhesion.
PMID- 9402996
TI - Discovery of methyl-2-(2'-hydroxyphenyl)-2-oxazoline-4-carboxylate as a secondary
metabolite from Actinomadura sp.
PMID- 9402997
TI - Corynecandin: a novel antifungal glycolipid from Coryneum modonium.
PMID- 9402998
TI - The identification of 1,6'- and 1,3"-di-N-(L-4-amino-2-hydroxybutyryl)
derivatives of kanamycin as synthetic byproducts of amikacin.
PMID- 9402999
TI - Phomopsidin, a new inhibitor of microtubule assembly produced by Phomopsis sp.
isolated from coral reef in Pohnpei.
PMID- 9403000
TI - Induction of mixed allogeneic chimerism for leukemia.
AB - Hybrid (C56BL/6 x DBA) (BDF1; H-2b/H-2d) mice bearing the P815 leukemia (H-2d)
were grafted with a (CBA x C57BL/6)F1 (CBF1; H-2k/H-2b) cell suspension,
comprising bone marrow cells (BMC; 25 x 10(6)/mouse) and spleen cells (SC; 55 x
10(6)/mouse) on day-4, then treated with cyclophosphamide (200 mg/kg) on day-2
and finally grafted once more with CBF1 cells (25 x 10(6) BMC + 7 x 10(6) SC) on
day 0. Allogeneic cell graftings performed in this way induced durable mixed
hematopoietic chimerism and significantly prolonged the survival of recipients,
compared with that of leukemia-bearers grafted with syngeneic cells. The results
obtained raise the possibility of using allogeneic hematopoietic tissue
transplantation in combination with non-lethal cytoreductive therapy to induce a
long-lasting graft-vs-leukemia effect.
PMID- 9403002
TI - Allelic loss of the FMS gene in acute myeloid leukaemia.
AB - The FMS proto-oncogene encodes for the colony stimulating factor-1 receptor
expressed on monocytes and B lymphocytes within the peripheral blood system.
Allelic loss of the FMS gene occurs in patients with refractory anaemia and the
5q- syndrome associated with the myelodysplastic syndromes. To determine the
frequency of FMS gene loss in patients with myeloid malignancy, 50 DNA samples
from patients with acute myeloid leukaemia (AML) and 30 samples from
haematologically normal samples were analysed using a quantitative Southern
blotting technique. Allelic loss of one allele (hemizygous) was detected in five
of 18 samples of AM-M4 and eight of 27 samples of AML M1, M2 and M3. In addition,
loss of both FMS alleles (homozygous) was demonstrated in three of 18 samples of
AML M4 and 0127 samples of AML M1, M2 and M3. One patient with AML M5 and one
with AML M6 were assessed although no allelic loss of FMS was detected. Three
samples from patients with secondary AML were also analysed and hemizygous loss
was detected in one case. Homozygous or hemizygous loss of FMS was not detected
in any of 30 DNA samples isolated from haematologically normal individuals. These
data indicate that loss of the FMS gene is common in AML, with an increased
frequency in those patients with AML subtype M4.
PMID- 9403001
TI - The FEL (AF-4) protein donates transcriptional activation sequences to Hrx-Fel
fusion proteins in leukemias containing T(4;11)(Q21;Q23) chromosomal
translocations.
AB - The t(4;11) chromosomal translocation marks a subset of acute lymphoblastic and
secondary myeloid leukemias. It results in the fusion of the FEL (AF-4) gene on
chromosome band 4q21 with the HRX (MLL) gene on chromosome band 11q23. This
translocation results in the expression of fusion transcripts from both
translocated chromosomes, with the derivative 11 product (fusing the amino
terminal third of the Hrx protein to the C-terminal two-thirds of the Fel
protein) thought to be involved in leukemic transformation. The mechanism of
transformation by Hrx-Fel in leukemic cells, however, is unknown and the specific
leukemogenic contributions of Fel have not been defined. In this study, we
demonstrate that Fel is capable of activating transcription from a minimal
adenoviral E1b promoter as a Gal4-Fel fusion protein in transient transcriptional
assays. The Fel transactivating sequences were localized to amino acids 365-572
which are consistently retained by Hrx-Fel fusion proteins created by t(4;11)
translocations in leukemias. Furthermore, we demonstrate that the transactivation
properties of Fel vary in different cell types. While Gal4-Fel constructs
strongly activated transcription in Cos-7 cells and the MCF-7 breast tumor cell
line, they displayed low to no activity in the precursor B-cell line REH, breast
tumor cell line Gl-101A and epithelial-derived A431 cells. These data are
consistent with a potential role of Hrx-Fel as a chimeric transcription factor in
which Fel contributes transcriptional effector properties and suggest the
requirement for cell-specific accessory factors.
PMID- 9403003
TI - Growth inhibition of B-cell precursor acute lymphoblastic leukemia cell lines by
monocytes: a role for prostaglandin E2.
AB - Leukemic cell lines have proven invaluable in the molecular analysis of recurring
chromosomal translocations but the optimal methods for leukemia cell line
establishment are unknown. During in vitro culture, most B-cell precursor acute
lymphoblastic leukemia (BCP-ALL) cells die within 1 week at least partially
mediated by inhibitors elaborated by peripheral blood mononuclear cells (PB MNCs)
present within the leukemia sample. In experiments reported here, cyclooxygenase
inhibitors (indomethacin and meclofenamic acid) blocked the PB MNC-mediated
inhibition of BCP-ALL proliferation. Also, prostaglandin E2 (PGE2) was detected
in supernatants from PB MNC cultures. When PGE2 was mixed directly with BCP-ALL
cells, proliferation decreased significantly. Under the culture conditions used,
PB MNCs secreted PGE2 which appears to be one of the major inhibitors of BCP-ALL
growth in vitro.
PMID- 9403004
TI - A novel method for direct and fluorescence independent determination of drug
efflux out of leukemic blast cells.
AB - Multi drug resistance (MDR) is often due to an increased efflux of anti cancer
drugs out of leukemic blast cells. Efflux assays are used to get an impression of
functional resistance in those cells. Dyes like rhodamine 123 or 3'3'
diethyloxocarbocyanine iodide are commonly used for this purpose. A major known
disadvantage is that dyes do not behave like cytotoxic drugs in efflux
experiments. Assays using the self fluorescence of drugs like anthracyclines can
not reveal a real impression of intracellular or effluxed drug due to quenching
of the drug fluorescence in the nuclei of the cells. We have developed a
reproducible and sensitive assay for direct and quantitative determination of
drug efflux out of blast cells. This was done by a novel double radioactive
labelling using a 3H-labelled drug and 14C-labelled sucrose as extracellular
marker. So this assay can be applied to every drug of interest. Quenching of
fluorescence is also by-passed with this technique as well as protracting washing
or silicon oil procedures. As a model system we used the T-lymphoblastoid cell
line CCRF CEM and its resistant sublines vincristine 100 and adriamycin 5000. The
results were also transferable to clinical specimens of leukemic patients. In
conclusion our assay may be used for precise and direct efflux measurement of a
broad range of anti-cancer drugs in clinical MDR evaluation.
PMID- 9403005
TI - Characterization and sensitivity to interleukin 2 and interferon alpha of
leukemic cells from a patient with large granular lymphocytic leukemia associated
with chronic active Epstein-Barr virus infection.
AB - A patient presented with chronic large granular lymphocyte leukemia associated
with chronic active Epstein-Barr virus infection (CAEBV). Cell cycle analysis
revealed a minimal growth compatible with chronic lymphocytic leukemia After 5
months of treatment, the patient died from acute transformation of the leukemia.
Cell harvested during chronic phase were analyzed for sensitivity to interleukin
2 (IL-2) and interferon alpha (IFN alpha) in vitro by means of surface
phenotyping and cell cycle assay. IL-2 induced remarkable growth of the cells,
whereas IFN alpha did not confer a growth advantage. Since IFN alpha was expected
to have no growth induction effect on the leukemia cells, it was administered to
the patient to treat the CAEBV.
PMID- 9403006
TI - Retroviral transfer of herpes simplex virus-thymidine kinase and beta
galactosidase genes into U937 cells with bicistronic vector.
AB - In this study we describe a new retroviral vector utilizing an internal ribosome
entry site (IRES) from encephalomyocarditis virus to co-express two genes. One is
the herpes simplex virus type 1 thymidine kinase gene (HSV-TK) which induces
sensitivity to ganciclovir, and the second is the bacterial beta-galactosidase
gene (LacZ) which was revealed by an histochemical staining with 5-bromo-4-chloro
3-indolyl-beta-D-galactopyranoside (X-Gal). We engineered the U937 human cell
line to co-express both genes and monitored transduced cells using X-Gal
staining. Several transduced clones were selected. The clones exhibiting X-Gal
positive cells were sensitive to ganciclovir treatment (1 microgram/ml) while X
Gal negative clones were not. Monoclonal cell lines showed a single copy of the
provirus integrated in their genome with the TK-IRES-LacZ sequence stably
inserted in all clones. The band distribution pattern of the proviral DNA
differed only at the long terminal repeat (LTR) level. Northern blot analysis of
an X-Gal positive/ganciclovir sensitive clone showed an mRNA band of 6 kb with
both LacZ and TK probes. An X-Gal negative/ganciclovir resistant clone was
negative with both probes. This report shows: (1) a therapeutic gene can be
linked to a marker gene by an IRES element achieving equivalent expression of
both proteins; (2) the co-expression of a marker gene makes fluorescein-di-beta-D
galactopyranoside staining possible, and consequently separation of cells
expressing the LacZ gene by fluorescence activated cell sorting. Thus the cells
expressing the HSV-Tk gene are enriched; (3) the use of a marker gene such as
LacZ could open up interesting perspectives in gene therapy protocols because of
the opportunity to monitor the transduced cells using a simple cytochemical
stain.
PMID- 9403007
TI - Camptothecin causes cell cycle perturbations within T-lymphoblastoid cells
followed by dose dependent induction of apoptosis.
AB - We have investigated the effect of the anticancer compound, camptothecin on
Jurkat T-cells, a lymphoblastoid leukemic cell-line. Exposure to low
concentrations led to rapid cessation of DNA (more than 95%) and RNA (more than
75%) synthesis. Perturbations to the cell cycle were observed following exposure
which caused a significant accumulation of cells within G1 (P = 0.03) with a
concomitant decrease in G2/M (P = 0.025). Concentrations below 0.1 microM could
inhibit DNA synthesis but not induce apoptosis. Induction of apoptosis was dose
dependent and could be detected as early as 3 h post exposure. The apoptotic
population appeared to be derived from G1 and S-phase cells but not G2/M,
coinciding with the cell cycle compartments in which DNA and RNA polymerases
function. However, direct inhibition of DNA polymerase alone was not shown to be
associated the induction of apoptosis or with a decrease in susceptibility to
camptothecin-induced cell death. The effects of camptothecin on Jurkat T-cells
and the potential mechanisms involved are discussed in the context of
observations made in other transformed cell lines.
PMID- 9403008
TI - Mitochondrial ultracondensation, but not swelling, is involved in TNF alpha
induced apoptosis in human T-lymphoblastic leukaemic cells.
AB - Mitochondrial permeability transition (PT) pore opening and mitochondrial
swelling have been reported in association with apoptosis. Conformational
alterations of mitochondria induced by tumour necrosis factor-alpha (TNF alpha),
and the association with TNF alpha-induced apoptosis, were, therefore, studied in
the human acute T-lymphoblastic leukaemia (T-ALL) cell line, CCRF-CEM and its
vinblastine-resistant CEM/VLB100 cell line by transmission electron microscopy
(TEM). The CEM/VLB100 cell line possessed more condensed (C phase) mitochondria
in the resting state compared with its parental cell line, consistent with
increased activity of the mitochondrial electron transport chain (ETC). Following
exposure to TNF alpha, conformational alterations of mitochondria occurred in
both apoptotic and non-apoptotic cells. Orthodox (O phase) mitochondria in non
apoptotic cells underwent C-phase, transitional O-phase and slightly swollen (S
phase) conformational changes. TNF alpha-induced mitochondrial swelling was a
late event and was found to a far lesser extent than mitochondrial condensation.
No swollen mitochondria were observed in apoptotic cells. Ultracondensed (UC
phase) mitochondria were observed in cells undergoing both TNF alpha-induced and
spontaneous apoptosis and were seen when TNF alpha-induced apoptosis was
inhibited by 3-methyladenine (3MA). The structural integrity of UC phase
mitochondria persisted through the apoptotic process. We conclude that TNF alpha
induced mitochondrial swelling and apoptosis are separate events. Mitochondrial
ultracondensation is associated with the processes signalling apoptosis and is
not a result of TNF alpha-induced apoptotic shrinkage.
PMID- 9403010
TI - Getting plant toxins to fuse.
PMID- 9403011
TI - HL-60 growth suppression by citrate-seric growth factor interaction.
PMID- 9403009
TI - The prognostic significance of chromosomal analysis and immunophenotyping in 117
patients with de novo acute myeloid leukemia.
AB - Chromosomal abnormalities is one of the most important prognostic factors in
acute myeloid leukemia (AML). Other parameters which may influence the prognosis
include age, French-American-British-type, clinical variables and possibly the
expression of certain immunophenotypic surface makers. However, only rarely has
the expression of these markers been analyzed in multivariate models including
the information from cytogenetics and clinical variables. We conducted a
retrospective study of 117 consecutive adult patients with de novo AML diagnosed
and treated in our institution during a 6-year period. Following standard
induction chemotherapy with daunomycin and cytosine arabinoside 75 patients (64%)
achieved complete remission (CR). The overall 5 year survival rate was 23% and,
for patients achieving CR, 30%. When all patients were analyzed age, chromosomal
aberration and lack of CD33 expression were of independent prognostic value. The
overall 5 year survival rate was 28% for patients aged 55 years or younger, 25%
for patients aged 56-65 years and 4% for those > 65 years, P = 0.041. Patients
with good-risk chromosomal abnormalities presented an overall 5 year survival of
36%, compared to 25% in patients with normal karyotype, 22% in patients with
intermediate risk abnormalities and 5% in patients with poor-risk abnormalities,
P = 0.004. Patients with CD33+ myeloblasts had an overall survival of 25% at 5
years compared to 0% in the CD33- patients, P = 0.021. Analysis of the expression
of CD7, CD34 and terminal deoxynucleotidyl transferase on myeloblasts had no
impact on overall survival in a multivariate analysis. Thus, this study confirmed
the prognostic value of age and cytogenetic risk group and defined CD33 as a
novel factor of independent prognostic importance in adult de novo AML.
PMID- 9403012
TI - An atypical case of plasma cell leukemia.
PMID- 9403013
TI - Activity of high-dose cyclophosphamide in the treatment of childhood malignant
gliomas.
AB - Seventeen patients less than or equal to 20 years of age with newly diagnosed (n
= 10) or recurrent (n = 7) malignant gliomas (anaplastic astrocytoma and
glioblastoma multiforme) were treated with cyclophosphamide in association with
hematopoietic cytokines (GM-CSF or G-CSF). Cyclophosphamide was given at a dose
of 2 g/m2 daily for 2 days at 4-week intervals. Toxicity consisted of grade IV
neutropenia and thrombocytopenia in 95% and 48% of cycles, respectively. There
were no cyclophosphamide-related cardiac, pulmonary, or urothelial toxicities
observed. Four of 10 patients with newly diagnosed disease demonstrated responses
(three complete and one partial responses; one CR was only of 2 months duration).
None of the seven patients with recurrent tumors demonstrated a response. We
conclude that high-dose cyclophosphamide warrants further evaluation in children
with newly diagnosed malignant glioma.
PMID- 9403014
TI - Subcutaneous sacrococcygeal myxopapillary ependymoma.
AB - We report an 8-year-old boy with a primary subcutaneous sacrococcygeal
ependymoma, a rare tumor that is thought to arise in embryologic rests. The
lesion was completely removed in our patient, who has been followed without
recurrence for 20 months. Our experience, together with that of the other 15
cases in the world literature, supports surgical excision as the mainstay of
treatment.
PMID- 9403015
TI - Electronic measurement of compliance with mercaptopurine in pediatric patients
with acute lymphoblastic leukemia.
AB - Twenty-four pediatric patients with acute lymphoblastic leukemia (ALL) on
maintenance therapy were evaluated for their compliance with taking their
prescribed doses of oral mercaptopurine (6-MP). PROCEDURE AND RESULTS: We
utilized the Medication Event Monitoring System (MEMS; Aprex Corporation,
Fremont, CA) for the study. Compliance was defined as the number of days doses
were taken as a percentage of the total number of days doses were prescribed
during the study period. The mean age of the patients was 7.3 years (range 2.6
17.2 (years). Patients were evaluated for a mean of 44 days (range 15-94 days).
Thirty-three percent of patients (8) took less than 90% and 17% (4) took less
than 80% of their prescribed pills. Eight patients were also evaluated for a
difference in compliance between morning and evening administration. For the
comparison of compliance between a morning vs. an evening schedule a tren toward
improved compliance in the evening was found. Five patients had an increase and
one patient a decrease in compliance with an evening schedule (differences ranged
from 0.2% to 51.3%), with two patients having 100% compliance on both schedules.
CONCLUSIONS: Our data raise concern that a significant proportion of pediatric
patients are non-compliant with pill taking and demonstrate that the timing of
administration of 6-MP in children with ALL may be crucial in some patients and
supports the hypothesis that evening administration of 6-MP is associated with a
lower risk of relapse.
PMID- 9403016
TI - Cytogenetic evidence for a less malignant leukemic cell population in the central
nervous system in a critical case of acute myeloblastic leukemia.
AB - BACKGROUND: With the exception of a single study the cytogenetic aspects of
leukemic cells in the central nervous system (CNS) have not been investigated.
PATIENTS AND RESULTS: During the course of a work-in-progress on the chromosomal
constitution both of the spinal fluid and of bone marrow (BM) in children with
acute myeloblastic leukemia (AML), we have observed a unique case of AML and CNS
leukemia (CNSL) at diagnosis. The patient showed the simultaneous presence at
diagnosis of a 46 cytogenetic line in the spinal fluid and a 47 (+8) cell line in
the BM, present in the great majority of the metaphases examined. DISCUSSION:
This observation allows hypotheses on the relationship between BM and CNS disease
in AML. Regardless of the pathogenetic mechanism, the cytogenetic findings of the
present case clearly suggest that the leukemic population in the CNS compartment
represents a less malignant cell process compared to the BM leukemic population.
This easily fits in with the usually less malignant course of CNSL in AML.
CONCLUSION: The foregoing findings may have critical pathogenetic and therapeutic
implications.
PMID- 9403017
TI - Home intravenous antibiotic treatment for febrile episodes in immune-compromised
pediatric patients.
AB - The purpose of this work was to assess the feasibility of home intravenous
antibiotic treatment (HIAT) for febrile episodes in immune-compromised
(neutropenic, splenectomized), low-risk pediatric patients. Thirty hematology
oncology patients who presented to our emergency room from January 1993 to
January 1995 and who suffered from a febrile episode and were considered at low
risk for septic complications were immediately discharged on HIAT. Patients were
followed for at least 3 weeks after recovery. Patients and parents were
retrospectively questioned about adverse effects and about their degree of
satisfaction with home treatment. Patients who required hospitalization during
this period were considered unresponsive to HIAT and were analyzed for causes and
adverse effects. Thirteen out of 60 (22%) febrile episodes, or eight out of 42
(19%) episodes of fever and neutropenia eventually led to hospitalization.
Pseudomonas species infections were associated with the highest rate of
unresponsiveness (88%). A central venous catheter infection developed in two
cases following HIAT (two cases out of 640 days of therapy). No other
complications were identified. No infection-related morbidity was observed.
Patients and parents were highly satisfied with HIAT and wanted to use it again,
if necessary. Immediate discharge on HIAT for low-risk pediatric immune
compromised patients suffering from a febrile episode is feasible, safe, and well
accepted by patients and families. Patients who are found to have Pseudomonas
infections should probably be hospitalized. Our results are preliminary and must
be confirmed by a prospective, randomized trial before definite recommendations
can be made.
PMID- 9403018
TI - Emergent/urgent therapeutic irradiation in pediatric oncology: patterns of
presentation, treatment, and outcome.
AB - PURPOSE: We reviewed all pediatric cases referred for emergent/urgent therapy
(requiring treatment within 48 hours) to identify frequency, patterns of
presentation, and efficacy of therapy. We defined five categories of
emergent/urgent therapy based on irradiated site and/or signs: Group I, spinal
cord compression; Group II, respiratory compromise; Group III, infradiaphagmatic
distress; Group IV, intracranial signs; Group V, pain. MATERIALS AND METHODS:
From 2/1/88-3/1/ 94, 104 children with 115 problems were referred by specialists
at the Children's Hospital of Philadelphia. Diagnosis, nature of the emergency,
and response were examined. Responses were categorized as complete resolution,
improvement or stabilization, and progression. RESULTS: The 104 children
represented 12% of referrals during the study period. The most common tumors were
CNS PNET and gliomas (20%); and neuroblastoma (20%). Forty-five problems occurred
with newly diagnosed tumors and 70 after progression. Ninety-one episodes were
managed with radiation therapy and 24 with other modalities. Patients with spinal
cord/cauda equina (n = 33) compression improved (55%) or stabilized (30%).
Patients with respiratory compromise from thoracic (n = 14) or abdominal (n = 5)
disease had a response rate of 72%. Eight patients in group III had a 66%
response. In Group IV (n = 16), 63% had complete responses and 19% had
stabilization. Group V (n = 15) patients had a complete or partial response of
93%. CONCLUSION: Approximately 10% of children referred for radiation therapy
required emergent/urgent treatment. Eighty percent of patients achieved
stabilization or showed improvement in signs and symptoms, indicating that
radiotherapy is a valuable and reliable component of multimodal care in such
situations.
PMID- 9403019
TI - Successful management with octreotide of a child with L-asparaginase induced
hemorrhagic pancreatitis.
AB - BACKGROUND: Octreotide is a synthetic somatostatin analogue which has been
suggested for use in the management of acute pancreatitis. While studies have
looked at octreotide use in the setting of pancreatitis due to chronic alcohol
use or trauma, little is known of its role in management of drug induced acute
pancreatitis; particularly in the pediatric setting. PATIENTS AND METHODS: We
present a case of a 5 1/2-year-old white female who developed severe,
necrotizing, hemorrhagic pancreatitis with pseudocyst formation secondary to L
asparaginase use as a part of her therapy for acute lymphoblastic leukemia (ALL).
She was managed initially with intravenous fluids, bowel rest, nasogastric
suctioning, parenteral narcotices, and broad spectrum antibiotics. In addition,
within 12 hours of admission to The Children's Hospital (TCH) in Denver,
Colorado, she began therapy with octreotide (5 micrograms/kg/day IV divided
b.i.d.). With this management, her pseudocyst decompressed without need for
surgical intervention, her pancreatitis fully resolved, and she recovered full
pancreatic function without any long-term sequelae. CONCLUSION: Use of octreotide
may have served a role in limiting the severity of the disease process in this
case. Further studies need to be done to verify its usefulness in this setting.
PMID- 9403020
TI - Recombinant human erythropoietin for the treatment of anemia in children with
solid malignant tumors.
AB - BACKGROUND: Cancer is often associated with chronic anemia which frequently
requires blood transfusions. This study was performed to assess the efficacy and
safety of r-HuEPO therapy in children with cancer. PATIENTS AND METHODS: Twenty
five patients under 18 years of age with solid malignant tumors were treated with
150 U/kg/day of r-HuEPO 5 times weekly for 12 weeks. Response was defined as an
increase of the baseline hemoglobin level by at least 2 g/dl. r-HuEPO patients
were compared to 25 matched historical controls. RESULTS: Response was achieved
in 72% of r-HuEPO patients. Hemoglobin level increased from 9.8 +/- 0.6 g/dl at
baseline to 12.4 +/- 1.7 g/dl at the end of treatment in the r-HuEPO group and
increased from 9.5 +/- 0.7 g/dl to 9.6 +/- 1.4 g/dl in the control group (P <
.001, Student's t-test). Only 16% of patients receiving r-HuEPO required blood
transfusions vs 96% of control patients (P < .001, Student's t-test), with mean
units of blood transfused per patient being 0.35 in the r-HuEPO group and 3.56 in
controls (P < .001, Student's t-test). There was a statistically significance
improvement in Karnofsky's index in r-HuEPO patients. No adverse reaction related
to r-HuEPO therapy was observed. CONCLUSIONS: r-HuEPO is a safe and effective
means of increasing hemoglobin level and reducing blood requirements in children
with solid malignant tumors receiving chemotherapy.
PMID- 9403021
TI - Use of pamidronate in the management of acute cancer-related hypercalcemia in
children.
AB - PURPOSE: To determine whether pamidronate is a safe and effective agent for the
treatment of severe hypercalcemia of malignancy in children. MATERIALS AND
METHODS: A retrospective review of the charts of five children treated with
pamidronate 1-2 mg/kg for severe, refractory hypercalcemia of malignancy. All
children failed conventional therapy. Statistical analysis was done utilizing the
two-tailed Student's t-test. RESULTS: All five children had complete resolution
of their hypercalcemia in a predictable pattern within 24-48 hours. The average
decrease in serum calcium was 1.63 mmol/L (6.54 mg/dl). (P < .01) The adverse
effects were mild and transient, and consisted of hypocalcemia, hypophosphatemia,
and hypomagnesemia. CONCLUSIONS: Pamidronate at a dose of 1 mg/kg is a safe and
effective treatment for severe, refractory hypercalcemia of malignancy in
children.
PMID- 9403022
TI - Misleading leads: focal xanthogranulomatous pyelonephritis in childhood.
AB - Xanthogranulomatous pyelonephritis is a morphologic variant of pyelonephritis.
Focal disease is very rare and can be misdiagnosed.
PMID- 9403023
TI - "Arteriovenous fistula: a complication following renal biopsy of suspected
bilateral Wilms tumor".
PMID- 9403024
TI - "Pancreatoblastoma in childhood: the role of alpha-fetoprotein".
PMID- 9403025
TI - Interindividual variation in cytogenetic response to X-ray and colchicine
measured with the cytokinesis-block micronucleus assay.
AB - Interindividual variation in cytogenetic response to two different types of
micronucleus (MN) inducer, X-rays (a clastogen) and colchicine (a spindle
poison), was investigated in the peripheral blood lymphocytes of normal healthy
donors by the cytokinesis-block MN method. The data for 124 donors between the
ages of 19 and 80 years showed that the histogram of individual frequency of X
ray (2 Gy)-induced micronucleated cells followed the normal distribution (Shapiro
Wilks W-test) with a significant interindividual variance (ANOVA, p < 0.001).
This was, however, not the case for colchicine (0.03 microgram/ml)-induced
micronucleated cells. Instead, a skewed distribution illustrating interindividual
variation was evident (ANOVA, p < 0.001). Statistical analysis of the effect of
age and sex on MN incidence by using the Kruskal-Wallis test indicated that age
affected the baseline and colchicine-induced MN incidences strongly but not the X
ray-induced MN incidence. There was no effect of sex on the incidence of
micronuclei induced by either agent. In order to avoid any possible effect of age
on the MN index, data for young subjects aged less than 30 years old were
analyzed separately. The results of this analysis again showed significant
interindividual variations in baseline, X-ray-induced, and colchicine-induced
micronucleated cell rates. Results of the correlation-coefficient analysis showed
that neither X-ray-induced MN incidence nor colchicine-induced MN incidence was
related to baseline MN incidence. No correlation between X-ray-induced and
colchicine-induced MN incidences was also found by this analysis. These results
suggest that interindividual variance in chromosomal response to mutagens in
normal populations may be a real phenomenon, as is interindividual variance in
baseline MN frequency, and that individual susceptibilities to the two different
types of micronucleus inducers (X-ray and colchicine) are unrelated, and the
baseline MN level is not of predictive value for the susceptibilities.
PMID- 9403026
TI - New tester strains of Salmonella typhimurium lacking O6-methylguanine DNA
methyltransferases and highly sensitive to mutagenic alkylating agents.
AB - Salmonella typhimurium YG7104 and YG7108 are derivatives of the Ames tester
strain TA1535, and have chromosomal deletions of the ogtST gene or both the ogtST
and adaST genes, respectively. The ogtST and adaST genes encode O6-methylguanine
DNA methyltransferases that are involved in the repair of DNA damage caused by
alkylating agents. The sensitivities of these strains to 15 mutagens with
different structures were tested and compared with those of the parent strain
TA1535. Deletion of ogtST or ogtST plus adaST substantially increased the
sensitivity of strain TA1535 to the mutagenicity of alkylating agents, such as N
ethyl-N'-nitro-N-nitrosoguanidine, ethyl methanesulfonate or dimethylnitrosamine
(DMN). Preincubation of the chemical with S9 mix and bacteria for 20 min at 37
degrees C before pouring them together on agar plates was not necessary to detect
the mutagenicity of DMN when strain YG7104 or YG7108 was used as a tester strain.
Introduction of plasmid pKM101 did not enhance but rather decreased the
sensitivity of YG7104 and YG7108 to alkylating agents. Since the new strains are
highly sensitive only to alkylating agents, they will be useful to detect the
mutagenicity with high efficiency and to study the mechanism of mutagenesis
induced by environmental alkylating agents.
PMID- 9403027
TI - Mutations at codon 249 of p53 gene in human hepatocellular carcinomas from
Tongan, China.
AB - Codon 249 (exon 7) of the putative tumor suppressor gene p53 is a mutational hot
spot for hepatocellular carcinoma (HCC) but not other tumors. DNA samples from
primary HCC patients from Tongan, an area of high HCC incidence in China (> 40
per 100,000 population), were analyzed for specific mutations in codon 249 of the
p53 gene using polymerase chain reaction (PCR)/restriction-digest methods and
direct DNA sequencing. Seven of the 21 samples screened were found to have a
point mutation at the third base position of codon 249 (AGG to AGT). The result
is consistent with previous reports that the G-->T transversion is positively
associated with the level of dietary aflatoxin B1 (AFB1) contamination, which has
been implicated as one of the risk factors in Tongan area. Of the 7 HCC patients
that contained the codon 249 point mutation, one was hepatitis B virus (HBV)
negative. This is only the second documentation of an HCC patient harboring the
p53 codon 249 mutation, who was HBV-negative.
PMID- 9403028
TI - Comparison of alkaline single cell gel (Comet) and peripheral blood micronucleus
assays in detecting DNA damage caused by direct and indirect acting mutagens.
AB - The alkaline single cell gel (SCG) or 'comet' and peripheral blood micronucleus
(pbMN) assay have been used to compare the effects of the direct acting mutagens,
methyl methanesulfonate (MMS) and N-nitroso-N-methylurea (NMU), and the indirect
acting mutagens, benzo[a]pyrene (BAP), cyclophosphamide (CP) 9, 10-dimethyl-1,2
benzanthracene (DMBA), and mitomycin C (MMC) in an inbred house mouse (Mus
domesticus) strain. The alkaline SCG assay was able to detect DNA damage from
direct acting mutagens. However, it appears that, even at the highest
concentrations tested, the SCG assay was not able to detect DNA damage caused by
3 of 4 indirect acting mutagens tested. The exception was BAP. The pbMN assay was
sensitive to DNA damage caused by both groups of mutagens. Multiple injections
did not increase the sensitivity of the SCG assay to the indirect acting mutagen
CP. Further, simultaneous injections of CP and MMS, in one experiment, resulted
in significantly lower (p < 0.05) average DNA ratios and micronucleated
polychromatic erythrocyte counts than those obtained after treatment with MMS
alone. Although the SCG assay has been shown to be sufficiently sensitive to
detect DNA damage caused by both direct and indirect acting mutagens in deermice
(Peromyscus maniculatus) and bullheads (Ameiurus nebulosus), similar results are
not seen in the inbred house mouse strain tested.
PMID- 9403029
TI - Nitroreductase independent mutagenicity of 1-halogenated-2,4-dinitrobenzenes.
AB - The 1-halogen substituted 2,4-dinitrobenzenes have been found to be mutagenic in
Salmonella TA98 with an activity order of 1-fluoro > 1-chloro > 1-bromo > 1-iodo.
This specific activity was not lowered in the nitroreductase deficient strain
TA98NR and O-acetyltransferase deficient strain TA98/1,8-DNP6, indicating that
the mutagenicity of these compounds is not dependent upon -NO2 reduction to -NHOH
and its subsequent esterification. The activity was, rather, higher in the former
and remained almost equal in the latter strain compared to TA98, suggesting these
compounds to react directly with bacterial DNA. Further, the reaction of these
halodinitrobenzenes with methionine, at physiological pH, resulting in the
formation of 1-S-methyldinitrobenzene showed that these compounds have the
ability to attack DNA directly through nucleophilic substitution of the halogen
atom and the role of the bacterial nitroreductases for production of mutagenic
lesions was not considered. It was, further, proposed that these compounds
interact with DNA through SNAr mechanism instead of SN2 cited in literature.
PMID- 9403030
TI - Mutations induced by monofunctional and bifunctional phosphoramide mustards in
supF tRNA gene.
AB - The relative mutagenicity, nature of the mutations and the sequence specificity
of mutations induced by the bifunctional alkylating agent, phosphoramide mustard
(PM) and a monofunctional derivative, dechloroethyl phosphoramide mustard (dePM),
were analyzed by the Ames test and by an in vitro shuttle vector mutagenesis
assay. Both PM and dePM increased the mutation frequency above background in
either assay. However, on an equimolar basis, dePM was less mutagenic than PM. In
the in vitro shuttle vector mutagenesis assay, sequencing demonstrated that about
40% of the mutant plasmids contained more than one mutation in the supF tRNA gene
segment of the plasmid. About 70% of the mutations observed in dePM-treated
plasmids were single base substitutions with A:T and G:C base pairs being mutated
at equivalent rates. In contrast, only about 50% of the mutations observed in PM
treated plasmids were single base substitutions, 80% of which involved G:C base
pairs. Single base deletions and insertions were found in approximately equal
proportions with both compounds; however, these lesions were in greater abundance
in PM-treated plasmids. Putative hot-spots for mutation in the supF tRNA gene
included base pairs at position 102 and 110 for PM and positions 170 and 171 for
dePM.
PMID- 9403031
TI - In vitro fertilization rate of mouse oocytes with spermatozoa from the F1
offspring of males irradiated with 1.0 Gy 137Cs gamma-rays.
AB - Previous studies suggest that the spermatozoa from acutely irradiated male mice
exhibit a reduced fertilization rate in vitro with the maximum decrease occurring
for spermatozoa produced 6 weeks after irradiation (Y. Matsuda et al., Mutation
Res. 142 (1985) 59-63). We have found that spermatozoa from unirradiated F1 males
conceived 6 weeks after paternal F0 irradiation also exhibit a significantly
reduced fertilization rate in vitro. After acute 137Cs gamma-irradiation yielding
an absorbed dose of 1.0 Gy, adult CD1 F0 male mice were mated at weekly intervals
with unirradiated female CD1 mice. Unirradiated adult males from F1 litters
conceived 5 and 6 weeks after paternal F0 irradiation were allowed to mature.
Their epididymal spermatozoa were evaluated for in vitro fertilization rates
using oocytes from unirradiated 8-12-week-old CD1 females. The mean fertilization
rate for spermatozoa from F1 males conceived 5 weeks after paternal F0
irradiation (80.74 +/- 15.74 SD %, n = 5) did not differ significantly from the
control fertilization rate (89.40 +/- 10.94 SD %, n = 8). However, the
fertilization rate for spermatozoa from F1 males conceived 6 weeks after paternal
F0 irradiation (56.14 +/- 21.93 SD %, n = 5) was significantly less than the
fertilization rate for control spermatozoa (p < 0.006) or for that of the F1
males conceived 5 weeks after paternal F0 irradiation (p < 0.04). These data
suggest that spermatozoa obtained 6 weeks after paternal F0 irradiation can
transmit a decrease in fertilization rate to the F1 generation males as well as
exhibit decreased fertilization rate themselves when tested directly in vitro.
PMID- 9403032
TI - Modulation of NF-kappa B, and Bcl-2 in apoptosis induced by cisplatin in HeLa
cells.
AB - Cisplatin exposure induces apoptosis in HeLa cells. Since the interaction of this
drug with DNA produces reactive oxygen species, we performed an analysis of the
oxidative stress-responsive factors AP-1 and NF-kappa B. Although AP-1 levels
were not modified during cisplatin exposure, electrophoretic mobility shift
assays demonstrated an increase in NF-kappa B DNA binding activity that
correlated with a decrease of the inhibitory protein I kappa B alpha and a
specific relocalization of c-Rel, as assessed by immunoblotting and
immunofluorescence. No changes in the levels or localization of p65 were found.
Interestingly, I kappa B alpha relocalized to the nucleus, probably in order to
regulate the binding of specific complexes. This process was accompanied by a
decrease of the antiapoptotic protein Bcl-2, and a relocalization of p53 protein
to the nucleus. Since HeLa cells lost most of their p53 protein due to a specific
E6-dependent degradation, cisplatin could be inhibiting this degradation, since
the p53 total levels were not increased during the exposure to the drug.
PMID- 9403033
TI - Does the increase of 8-hydroxydeoxyguanosine lead to poor sperm quality?
AB - Several studies have suggested a population-wide decline in the quality of human
semen during the past three decades, but the mechanism remains unclear. It was
proved that damage to the DNA of germ cells would lead to mutation, and 8
hydroxydeoxyguanosine (8-OHdG), one of the major products of oxidative damage to
DNA, may serve as one of the important factors to affect the sperm quality. In
the present paper, 67 semen samples were collected to analyze the sperm quality
(density, sperm number, motility, normal head, etc.), and 8-OHdG was measured in
DNA isolated from the same sperm samples. The results showed that a significant
inverse correlation exists between 8-OHdG/dG(deoxyguanosine) and sperm density (r
= -0.358, p = 0.004), and between 8-OHdG/dG and sperm number (r = -0.389, p =
0.01). The results indicate that endogenous oxidative DNA damage could affect
sperm quality and subsequently increase the risk of genetic defects.
PMID- 9403034
TI - Pilot study of free and conjugated urinary mutagenicity during consumption of pan
fried meats: possible modulation by cruciferous vegetables, glutathione S
transferase-M1, and N-acetyltransferase-2.
AB - Epidemiological and experimental evidence indicates that consumption of fried
meats in conjunction with certain genotypes of phase I and II metabolism genes
poses an elevated risk for colorectal cancer. Parallel to this, the consumption
of cruciferous vegetables is associated with a reduced risk of colon cancer.
Therefore, we designed a 6-week pilot feeding study to evaluate the effect of
these variables on urinary mutagenicity, which is a biomarker associated with
fried-meat consumption. Eight subjects were fed fried meats daily for six weeks;
four ate cruciferous vegetables, and four ate non-cruciferous vegetables. Urinary
mutagenicity was evaluated in the presence of S9 in strain YG1024 of Salmonella,
which is a frameshift strain that overproduces acetyltransferase. C18/methanol
extracts of 24-h urines collected once each week were tested unhydrolyzed (free
mutagenicity) and hydrolyzed (total mutagenicity); the difference between the two
was the conjugated mutagenicity. Although not significant, the levels of
conjugated urinary mutagenicity doubled among crucifera consumers and decreased
to 30% of the initial levels among non-crucifera consumers, suggesting the
possibility that crucifera may enhance the level of conjugated urinary
mutagenicity resulting from consumption of fried meats. Such an effect would be
consistent with the documented ability of cruciferous vegetables to induce phase
II enzymes. The NAT2 rapid phenotype was significantly associated with
approximately 2-fold increases in conjugated (p = 0.05) and total (p = 0.004)
urinary mutagenicity relative to NAT2 slow subjects, consistent with the elevated
risk confirmed by the NAT2 rapid phenotype for colorectal cancer among meat
consumers. An approximately 2-fold increase in urinary mutagenicity among the
GSTM1- subjects relative to the GSTM1+ subjects approached significance for free
(p = 0.18) and total (p = 0.13) urinary mutagenicity. This is the first report on
(a) the mutagenicity of hydrolyzed urine, which was consistently more mutagenic
than unhydrolyzed urine; (b) the potential enhancement of conjugated urinary
mutagenicity by crucifera; and (c) the association of the rapid NAT2 and possibly
the GSTM1- phenotype with elevated levels of fried meat-associated urinary
mutagenicity.
PMID- 9403035
TI - Genetic disorders in house mouse germ cells after the Chernobyl catastrophe.
AB - Genetic effects were studied in house mice caught from 1986 to 1994 in regions
polluted by radionuclides as a result of the Chernobyl disaster. The dose rates
of gamma-radiation on the soil surface ranged from 0.0002 to 2 mGy/h. The
frequency of reciprocal translocations in mouse spermatocytes was relatively low,
but increased with the dose rate. Embryo mortality was increased only in the
progeny of male mice in males caught in 1987 in the area with maximal
contamination. The frequency of mice heterozygous for recessive lethal mutations
decreased with time after the accident.
PMID- 9403036
TI - Frequency of spontaneous and induced micronuclei in the peripheral blood of aging
mice.
AB - The mouse peripheral blood micronucleus assay, a measure of DNA damage in
erythroblastic cells, was used to determine: (1) the incidence of spontaneously
occurring micronucleated reticulocytes (MNRETs) as a function of age, and (2) the
induction of micronuclei following treatment of young and old animals with
mitomycin C. Male C57BL/6 mice, 92 weeks of age, exhibited a significantly higher
frequency of spontaneously occurring peripheral blood MNRETs than mice that were
6 or 10 weeks of age. Mice that were 5-6 weeks or 91-92 weeks old were treated
with one dose, or two consecutive doses of mitomycin C; this resulted in dose
related increases in the frequency of MNRETs. Mitomycin C, at a single dose of 1
or 2 mg/kg, induced one-third as many MNRETs in the older animals as compared to
the younger animals. When treated with a split dose of mitomycin C (total dose
0.5 to 2 mg/kg), older animals displayed on average two-thirds the mutagenic
response of the younger animals. However, analysis of variance performed on these
data indicated that the age of the animals did not have a significant effect on
their mutagenic response to mitomycin C at any dose level. It appears that aging
mice may not be more sensitive to the mutagenic effects of chemically-induced DNA
damage than younger mice, suggesting that the higher spontaneous mutation
frequency in older mice could be the result of an increased load of accumulated
DNA damage.
PMID- 9403037
TI - Involvement of recA and recF in the induced precise excision of Tn10 in
Escherichia coli.
AB - It has been shown that the increased frequency of precise excision of Tn10
observed after UV or mitomycin C (MMC) treatment or with uvrD- mutants is recA
dependent. Previous work has also shown that expression of SOS genes is required
for UV- or MMC-induced Tn10 precise excision. In order to determine if the
increased excision of Tn10 in uvrD- mutants requires only expression of recA, or
expression of other SOS genes, or both, we studied the precise excision of Tn10
in lexA3 (Ind-, SOS non-inducible) and lexA3 recAo98 (operator constitutive recA)
mutants. The results of these experiments indicate that the induced excision of
Tn10 in the uvrD- null mutant depends on the expression of recA rather than on
any of the other genes repressed by LexA. The effect of a null recF mutation on
the excision of Tn10 in a uvrD- mutant was also investigated and found to abolish
the increased frequencies of this process. Similarly, the recF mutation was found
to decrease markedly the increased precise excision of Tn10 induced by MMC in a
uvrD+ isogenic strain. These observations indicate that recA and recF are
involved in the increased frequencies of Tn10 excision exhibited by uvrD- mutants
or after MMC treatment. It remains to be determined whether these two genes
participate in these two induction processes in the same biochemical pathways.
PMID- 9403038
TI - Proposed mechanism for the photodynamic generation of 8-oxo-7,8-dihydro-2'
deoxyguanosine produced in cultured cells by exposure to lomefloxacin.
AB - In this study, lomefloxacin (LMX), a widely used quinolone antibiotic with a high
frequency of clinical phototoxicity, was investigated by measuring the effects of
several antioxidants on its ability to form of 8-oxo-7,8-dihydro-2'
deoxyguanosine (8-oxo-dG) in cultured adult rat liver cells after exposure to
UVA. In the current study the observed DNA damage, reflected by the formation of
8-oxo-dG, was almost completely inhibited by co-incubation of LMX and cultured
cells with sodium azide (NaN3) that specifically quenches singlet oxygen. Vitamin
E (alpha-tocopherol), known to quench both superoxide and singlet oxygen,
inhibited 8-oxo-dG formation by approximately 54%. Mannitol, a hydroxyl radical
scavenger, inhibited 8-oxo-dG formation by 64%. Butylated hydroxyanisole (BHA), a
scavenger of hydroxyl, peroxy and alkoxy radicals, showed no inhibition of 8-oxo
dG formation but in fact enhanced levels of 8-oxo-dG by 169%. The results of this
study suggest that the mechanism for the photodynamic generation of 8-oxo-dG by
LMX is mediated, at least in part, by both singlet oxygen and hydroxyl radical
and involves both type I and type II photosensitization.
PMID- 9403039
TI - Bioactivation of mushroom hydrazines to mutagenic products by mammalian and
fungal enzymes.
AB - Agaritine (N2-[L-(+)-glutamyl]-4-(hydroxymethylphenyl)hydrazine), the principal
hydrazine found in the edible mushroom Agaricus bisporus, as well as the N'
acetyl derivative of 4-(hydroxymethyl)phenylhydrazine and 4
(hydroxymethyl)benzene diazonium ion, as the tetraborate salt, considered as the
putative proximate and ultimate carcinogens of agaritine, were all synthesised
chemically. The mutagenicity of these compounds and of 4-hydrazinobenzoic acid, a
precursor of agaritine biosynthesis in mushroom, was investigated in the Ames
test, using Salmonella typhimurium strain TA104, in the absence and in the
presence of either mushroom tyrosinase or rat hepatic cytosol as activation
systems. In the absence of an activation system the diazonium ion was clearly the
most mutagenic of the four compounds studied. When tyrosinase was used as
activation system, the mutagenicity of N'-acetyl-4-(hydroxymethyl)phenylhydrazine
was enhanced; glutathione and superoxide dismutase markedly suppressed the
mutagenic response. When the mutagenicity of the four compounds was evaluated in
the presence of rat hepatic cytosol, an increase was seen only in the case of N'
acetyl-4-(hydroxymethyl)phenylhydrazine; this was shown to be due to
deacetylation releasing the more mutagenic free hydrazine. Collectively, the
above data are compatible with an activation of agaritine that involves an
initial loss of the gamma-glutamyl group followed by microsomal oxidation of the
free hydrazine to generate the diazonium ion. Also of interest is the observation
that mushroom tyrosinase can convert N'-acetyl-4-(hydroxymethyl)phenylhydrazine
to mutagenic product(s); whether these products contribute to the mutagenicity of
mushroom extracts remains to be established.
PMID- 9403040
TI - Increased sister chromatid exchanges in peripheral lymphocytes of patients with
Crohn's disease.
AB - A cytogenetic study was performed using Crohn's disease patients to determine
whether the presence of chromosome instability is related to Crohn's disease, a
chronic inflammatory bowel disease. Sister chromatid exchange (SCE) frequencies
in peripheral blood lymphocyte cultures from 22 Crohn's disease patients and an
equal number of healthy controls matched for sex and age were analyzed. The mean
of SCE frequency in Crohn's disease patients was 11.64 +/- 0.42 (SEM) per cell,
which was significantly higher than the value of 8.38 +/- 0.22 per cell in the
matched controls (p < 0.0001). The Crohn's disease patients showed significantly
increased high frequency cells (HFC) as compared to those among the matched
controls. There was a significant correlation between HFC frequencies of the
Crohn's disease patients and the severity of their disease as determined by the
number of relapses per year and the degree of chronic activity after adjusting
for the smoking status (r = 0.54, p = 0.011). In both smokers and non-smokers,
the mean SCE and HFC frequencies of the patients were significantly higher than
those of the controls. These results suggest that Crohn's disease is a condition
with increased chromosome instability characterized by a high level of SCE
frequencies which are associated with the inflammatory condition itself.
PMID- 9403041
TI - The Janeway Lecture. Iatrogenic carcinogenesis: clinical implications.
PMID- 9403042
TI - Intraoperative lymphatic mapping and sentinel lymphadenectomy: community standard
care or clinical investigation?
PMID- 9403043
TI - Exploring new technologies and treatment strategies for locally advanced prostate
cancer.
PMID- 9403044
TI - Positron emission tomography (PET)--measured biochemical response to radiotherapy
of laryngeal tumors.
PMID- 9403045
TI - Sentinel lymphadenectomy for breast cancer in a community managed care setting.
AB - PURPOSE: To evaluate the feasibility, accuracy, and reproducibility of
intraoperative lymphatic mapping and sentinel lymphadenectomy (IOLM/SL) in the
staging of breast cancer patients in a community managed care setting. PATIENTS
AND METHODS: One hundred forty-five patients with primary breast cancer were
prospectively studied over a 26-month period. They underwent vital dye injection
at their primary breast cancer site. Lymphatic channels were traced to the
sentinel lymph node, which was excised, serially sectioned, and examined. A level
I and II axillary lymph node dissection and definitive breast surgery were then
performed. RESULTS: Sentinel nodes were identified in 103 of 145 procedures
(71.0%). Sentinel and nonsentinel lymph nodes were concordant in 100 of 103 cases
(97.1%). Three patients (9.7%) had falsely negative sentinel nodes; there were
none in the last 80 patients. Of 28 positive sentinel nodes, 12 (42.9%)
represented the only tumor-containing node within the axilla. Sentinel nodes were
significantly more likely to contain tumor than nonsentinel nodes (33/50, 66.0%
vs 54/467, 11.6%, P < 0.0001). IOLM/SL identified more micrometastases (< 2 mm)
than standard axillary lymph node dissection (13/33, 39.6% vs 4/177, 2.2%, P <
0.001). Nine of 42 patients (21.4%) whose sentinel node could not be identified
had five or more nodal metastases. Two of six patients with presumed Tis
primaries had nodal metastases. DISCUSSION: IOLM/SL accurately identifies the
sentinel lymph node(s) most likely to contain metastatic disease. A procedural
learning curve was present. An unsuccessful IOLM/SL was a risk factor for
considerable nodal metastases. IOLM/SL with a tumor-free sentinel node may
obviate a formal axillary lymph node dissection. The technique was feasible,
economical, and reproducible within the context of a community managed care
facility, while not placing exacting demands on operating room, pathology, or
nuclear medicine personnel.
PMID- 9403046
TI - Radioguided surgery for the ultrastaging of the patient with melanoma.
AB - PURPOSE: Lymphatic mapping techniques have changed the standard of surgical care
for the malignant melanoma population and are being investigated to improve the
staging and decrease the morbidity of patients with all types of cancer. This
study aimed to describe a combination of techniques and the use of multiple
disciplines for accurately staging and treating patients with melanoma. MATERIALS
AND METHODS: Over a 4-year period, 595 patients were studied using a protocol
consisting of preoperative lymphoscintigraphy using filtered technetium sulfur
colloid to define all regional basins at risk for metastatic disease, and
intraoperative lymphatic mapping with a vital blue dye and radiocolloid to
identify the node in the basin most at risk for metastases (the sentinel lymph
node). Detailed pathological exam (serial sectioning, immunohistochemical
staining, reverse transcriptase polymerase chain reaction [RT-PCR] analysis) of
the sentinel lymph node was used to stage the melanoma patient. RESULTS: A
combination of blue dye and radiocolloid intraoperative mapping resulted in a 98%
success rate for the identification of the sentinel lymph node. Routine
pathological examination identified 73.8% of the metastases. The remainder were
detected with serial sectioning (7.8%) and immunohistochemical staining (18.4%).
RT-PCR analysis based on a tyrosinase probe has upstaged 47% of the histologic
sentinel lymph node-negative population. CONCLUSION: Lymphatic mapping technology
provides accurate staging of the melanoma patient, at lower costs for the health
care system and a lower morbidity for the patient.
PMID- 9403047
TI - Conformal high dose rate iridium-192 boost brachytherapy in locally advanced
prostate cancer: superior prostate-specific antigen response compared with
external beam treatment.
AB - PURPOSE: Prostate-specific antigen levels are used to judge disease control of
prostate cancer. No published data attest to the greater ability of conformal
brachytherapy to control disease compared with conventional radiation at a single
institution. This report compares the biochemical response rates in patients with
stages T2b to T3c prostate cancer treated with conformal brachytherapy boost and
external beam radiation with the rates in patients treated with conventional
external radiation alone. MATERIALS AND METHODS: From November 1991 through
November 1995, 58 patients received 45.6 Gy pelvic external irradiation and three
high dose rate iridium-192 conformal boost implants of 5.5 to 6.5 Gy each. They
were compared with 278 similarly staged patients treated from January 1987
through December 1991 with external beam radiation to prostate-only fields
(median dose 66.6 Gy). No patient received androgen deprivation. Patient outcome
was analyzed for biochemical control. Biochemical failure was defined as a
prostate-specific antigen level > 1.5 ng/mL and rising on two consecutive values.
If serial posttreatment prostate-specific antigen levels were showing a
continuous downward trend, failure was not scored. RESULTS: Median follow-up was
43 months for the conventionally treated group and 26 months for the
brachytherapy boost group. The median pretreatment prostate-specific antigen
level was 14.3 ng/mL for the external-beam-radiation-alone group and 14.0 ng/mL
for the brachytherapy boost group. The median Gleason scores were 6 and 7,
respectively, for the two groups. The biochemical control rate was significantly
higher in the brachytherapy boost treatment group. Three-year actuarial
biochemical control rates were 85% versus 52% for the conformally and
conventionally treated patients, respectively. In a multivariate analysis, the
use of conformal brachytherapy boost and pretreatment prostate-specific antigen
level were significant prognostic determinants of biochemical control. The 3-year
actuarial rates of biochemical control for conformally versus conventionally
treated patients, respectively, were 83% versus 72% for a pretreatment prostate
specific antigen level of 4.1 to 10.0 ng/mL, 85% versus 47% for a prostate
specific antigen level of 10.1 to 20.0 ng/mL, and 89% versus 29% for prostate
specific antigen > 20 ng/mL. When the analysis was limited to patients in both
groups with a minimum 12-month follow-up, the brachytherapy boost group continued
to show a higher biochemical control rate compared with the conventional
radiation group (3-year actuarial rates of 86% vs 53%). DISCUSSION: These
preliminary results show a significant improvement in the biochemical response
rate with conformal boost brachytherapy and pelvic external radiation compared
with conventional radiation alone. These results, coupled with our previously
reported acceptable toxicity rates, support the use of this technique.
PMID- 9403048
TI - Can positron emission tomography distinguish tumor recurrence from irradiation
sequelae in patients treated for larynx cancer?
AB - PURPOSE: Distinguishing persistent or recurrent tumor from post-radiation edema
or soft-tissue/cartilage necrosis in patients treated for carcinoma of the larynx
can be difficult. Because recurrent tumor is often submucosal, multiple deep
biopsies may be necessary before a diagnosis can be established. Positron
emission tomography with F-18 fluorodeoxyglucose was studied for its ability to
aid in this problem. PATIENTS AND METHODS: FDG PET scans were performed on 31
patients who were suspected of having persistent or recurrent tumor after
radiation treatment for carcinoma of the larynx. Patients underwent thorough
history and physical examinations, scans with computed tomography (23 patients),
and pathological evaluation when indicated. PET scans were interpreted by each of
the two radiologists, who were blinded to patient outcome and the other's report.
RESULTS: The time between completion of radiation treatment and positron emission
tomography examination ranged from 2 to 61 months with a median of 6 months.
Fifteen patients had pathological evidence of tumor in the larynx, while 16 have
remained without evidence of disease. The overall sensitivity and specificity of
the positron emission tomography interpretations were 80% and 81%, respectively.
The sensitivity and specificity of the computed tomography scan interpretations
were 58% and 100%, respectively. Of the 23 patients with computed tomography
scans, eight patients acquired useful information from the positron emission
tomography, three patients had incorrect positron emission tomography
interpretations and correct computed tomography interpretations, and one patient
had positive tumor despite a negative positron emission tomography and computed
tomography. DISCUSSION: Positron emission tomography is useful in distinguishing
benign from malignant changes in the larynx after radiation treatment. This
noninvasive technique can supplement information provided by computed tomography
scans. It is reasonable to delay biopsy, which could traumatize radiation-damaged
tissues and precipitate necrosis, for those patients with negative positron
emission tomography scans who have clinical signs and symptoms associated with
recurrence.
PMID- 9403049
TI - Whole-abdomen radiation therapy as salvage treatment for epithelial ovarian
carcinoma.
AB - PURPOSE: This study aimed to evaluate the efficacy and safety of whole-abdomen
radiation therapy as salvage treatment in patients with ovarian cancer. PATIENTS
AND METHODS: Twenty-seven patients who failed aggressive cytoreductive surgery
followed by multiple-drug platinum-based chemotherapy were found to have
recurrent epithelial carcinoma of the ovary and were treated with whole-abdomen
radiation as salvage therapy. Dosage fractions were planned at 100 to 150 cGy
daily to 3000 to 3500 cGy, followed by a pelvic boost at 150 to 180 cGy daily.
All patients completed the planned treatment. The average treatment program
required 53.5 days (range, 42-71 days). RESULTS: Survival rates at years 1
through 5 were 66%, 48%, 26%, 15%, and 15%, respectively. Residual disease at
initiation of radiation correlated strongly with length of survival. The patients
with microscopic disease survived an average of 63 months (range, 30-111 months).
Patients with disease larger than 2 cm survived an average of 9 months (range, 5
17 months). Toxicity was seen in all patients. Eight patients experienced grade 3
or 4 toxicity, primarily white blood cell count and gastrointestinal toxicity.
There were no deaths related to toxicity. DISCUSSION: This experience strongly
suggests that whole-abdomen radiation is a viable salvage option, especially for
patients with microscopic retroperitoneal disease or small-volume macroscopic
disease.
PMID- 9403051
TI - Telomerase. The end-replication problem.
PMID- 9403050
TI - TA90 immune complex predicts survival following surgery and adjuvant vaccine
immunotherapy for stage IV melanoma.
AB - PURPOSE: Although prognosis remains poor for patients with distant metastatic
melanoma, we have observed significantly prolonged survival in patients receiving
our polyvalent melanoma cell vaccine (PMCV) following complete metastasectomy for
American Joint Committee on Cancer (AJCC) stage IV melanoma. Clinical prognostic
factors specific to this stage IV subgroup have not been well characterized. We
previously reported that the serum immune complex (IC) level of a 90-kD
glycoprotein antigen (TA90) was an objective predictor of survival and recurrence
in patients with early-stage melanoma. In the present study we correlated the
postoperative TA90-IC level of AJCC stage IV patients prior to adjuvant PMCV
therapy with their duration of subsequent survival. PATIENTS AND METHODS: From
October 1, 1984, to December 31, 1995, 125 stage IV patients began PMCV after
complete resection of distant melanoma metastases. One blood sample was obtained
immediately prior to vaccine therapy, and the serum TA90-IC level was assessed as
positive or negative using our double-determinant ELISA. Disease-free and overall
survival were recorded prospectively from the start of vaccine therapy. The
correlation between prevaccine TA90-IC level and survival was assessed by the log
rank test and Cox proportional hazards model. RESULTS: Median follow-up after
PMCV therapy was 36.5 months, with a minimum of 12 months. Univariate analysis
demonstrated that TA90-IC level is significant for both overall survival and
disease-free survival. Median overall survival, median disease-free survival, and
rate of 5-year survival were higher for patients with negative TA90-IC levels
than for those with positive TA90-IC level (58 vs 19 months, 7 vs 4 months, and
49% vs 27%, respectively). Multivariate analysis established TA90-IC as an
independent prognostic indicator for both overall and disease-free survival
following adjuvant PMCV therapy for AJCC stage IV melanoma. CONCLUSION:
Prevaccine TA90-IC level correlated strongly with overall and disease-free
survival in our stage IV melanoma patients receiving postoperative PMCV
immunotherapy. This is the first serum marker shown to have importance in
predicting the survival of melanoma patients receiving adjuvant immunotherapy
after complete resection of distant metastases.
PMID- 9403052
TI - Mapping quantitative trait loci for fear-like behaviors in mice.
AB - Two mouse models developed for screening anxiolytic drugs were selected for
genetic analysis, namely "wall-seeking" tendency in an open field ("thigmotaxis")
and the light-to-dark transition (LD) paradigm, a conflict test. These tests
measure differences in naturalistic tendencies of mice to explore a novel
environment and to avoid a bright light or the center of an open field. In an F2
intercross of two strains of mice (A/J and C57BL/6J) that differ markedly in
these behaviors, we estimated a broad sense heritability ranging from 0.3 to
0.59. With this intercross (n = 518), we have mapped several quantitative trait
loci (QTL) for these behaviors by performing a genome-wide search. A significant
QTL on chromosome 10 (near D10Mit237; LOD of 9.3) that affects LD behavior was
identified, and suggestive QTL (LOD > 2.8) were mapped to chromosomes 6, 15, 19,
and X. For center time behaviors, QTL were identified on chromosome 1 (LOD of 7.7
and 4.0 for the initial 5-min epoch and the first trial average of the next two 5
min epochs, respectively), and suggestive QTL (LOD > 2.8) were mapped to
chromosomes 6 and 14. These QTL individually explain from 2.3 to 8.4% of the
phenotypic variance. Collectively, the multiple independent QTL explain from 3.5
to 26.5% of the F2 population's phenotypic variance, depending on the trait. The
complexity and heterogeneity of the genetic factors underlying these fear-like
behaviors are illustrated by the lack of shared QTL between paradigms and by
mapping different QTL for repeated trials of behavior. The identification of QTL
affecting individual differences in fear-like behavior may lead to the
identification of new gene products and pathways that modulate behavior,
providing targets for rational drug design.
PMID- 9403053
TI - A 2.5-Mb transcript map of a tumor-suppressing subchromosomal transferable
fragment from 11p15.5, and isolation and sequence analysis of three novel genes.
AB - 11p15.5 is an important tumor-suppressor gene region, showing loss of
heterozygosity in Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and
lung, ovarian, and breast cancer. We previously mapped directly by genetic
complementation a subtransferable fragment (STF) harboring an embryonal tumor
suppressor gene and spanning about 2.5 Mb. We have now mapped the centromeric end
of this STF between D11S988 and D11S12 and its telomeric end between D11S1318 and
TH. We have isolated a complete contig of PAC, P1, BAC, and cosmid genomic clones
spanning the entire 2.5-Mb region defined by this STF, as well as more than 200
exons from these genomic clones using exon trapping. We have isolated genes in
this region by directly screening DNA libraries as well as by database searching
for ESTs. Nine of these genes have been reported previously by us and by others.
However, the initial mapping of most of those genes was based on FISH or somatic
cell hybrid analysis, and here we precisely define their physical location. These
genes include RRM1, GOK (D11S4896E), Nup98, CARS, hNAP2 (NAP1L4), p57KIP2
(CDKN1C), KVLQT1 (KCNA9), TAPA-1, and ASCL2. In addition, we have identified
several novel genes in this region, three of which, termed TSSC1, TSSC2, and
TSSC3, are reported here. TSSC1 shows homology to Rb-associated protein p48 and
chromatin assembly factor CAF1, and it is located between GOK and Nup98. TSSC2 is
homologous to Caenorhabditis elegans beta-mannosyl transferase, and it lies
between Nup98 and CARS. TSSC3 shows homology to mouse TDAG51, which is implicated
in FasL-mediated apoptosis, and it is located between hNAP2 and p57KIP2. Thus,
these genes may play a role in malignancies that involve this region.
PMID- 9403054
TI - Improved analysis of microsatellites using mass spectrometry.
AB - The primer oligo base extension reaction combined with matrix-assisted laser
desorption/ionization time-of-flight mass spectrometry, recently introduced by
our group for detection of single-point mutations and small insertions/deletions,
has been applied to the reliable quantification of nucleotide repeat units in
microsatellites. The AluVpA DNA marker within intron 5 of the interferon-alpha
receptor gene was chosen as the model system. By varying the dNTP/ddNTP mixtures
used, the assay could also be directed to detect the location of second-site
mutations within the repeats, resulting in identification of alleles not
detectable by electrophoretic sizing methods and thus an increase of the
polymorphism information content for a sampling of 28 unrelated individuals. The
method results in highly informative mass signals and has the potential to
increase the polymorphism information content for systems containing second-site
mutations; thus it is a very attractive alternative technique in statistics-based
gene mapping, cancer diagnostics, and forensic applications.
PMID- 9403055
TI - Comparison of DNA sequences with protein sequences.
AB - The FASTA package of sequence comparison programs has been expanded to include
FASTX and FASTY, which compare a DNA sequence to a protein sequence database,
translating the DNA sequence in three frames and aligning the translated DNA
sequence to each sequence in the protein database, allowing gaps and frameshifts.
Also new are TFASTX and TFASTY, which compare a protein sequence to a DNA
sequence database, translating each sequence in the DNA database in six frames
and scoring alignments with gaps and frameshifts. FASTX and TFASTX allow only
frameshifts between codons, while FASTY and TFASTY allow substitutions or
frameshifts within a codon. We examined the performance of FASTX and FASTY using
different gap-opening, gap-extension, frameshift, and nucleotide substitution
penalties. In general, FASTX and FASTY perform equivalently when query sequences
contain 0-10% errors. We also evaluated the statistical estimates reported by
FASTX and FASTY. These estimates are quite accurate, except when an out-of-frame
translation produces a low-complexity protein sequence. We used FASTX to scan the
Mycoplasma genitalium, Haemophilus influenzae, and Methanococcus jannaschii
genomes for unidentified or misidentified protein-coding genes. We found at least
9 new protein-coding genes in the three genomes and at least 35 genes with
potentially incorrect boundaries.
PMID- 9403056
TI - A tool for analyzing and annotating genomic sequences.
AB - We describe a tool for analyzing and annotating large genomic sequences
containing introns. The analysis and annotation tool (AAT) includes two sets of
programs, one for comparing the query sequence with a protein database and the
other for comparing the query with a cDNA database. Each set contains a fast
database search program and a rigorous alignment program. The database search
program quickly identifies regions of the query sequence that are similar to a
database sequence. Then the alignment program constructs an optimal alignment for
each region and the database sequence. The alignment program also reports the
coordinates of exons in the query sequence. Pairwise alignments of the query
sequence with protein and cDNA database sequences are combined into multiple
sequence alignments, which provide a view of all protein and cDNA sequences
matching a query region. On a data set of 570 DNA sequences, AAT identified 94%
of coding nucleotides correctly and 74% of exons exactly. Results of analyzing a
human BAC sequence with the AAT tool are also presented. The AAT tool reduces the
labor-intensive work of locating the exons of the query sequence and improves the
process of defining intron-exon boundaries by using the wealth of available
protein and cDNA data.
PMID- 9403057
TI - Comparative gene mapping of the human and mouse TEP1 genes, which encode one
protein component of telomerases.
AB - The chromosomal locations of the human TEP1 (telomerase protein component 1) and
mouse Tep1 genes, which were originally named TLP1 (telomerase protein 1) or TP1
(telomerase-associated protein 1), were determined by direct R-banding FISH and a
molecular linkage analysis with interspecific backcross mice. The human TEP1 and
mouse Tep1 genes were mapped by FISH to human chromosome 14q11.2 and to the C2D1
band of mouse chromosome 14, respectively. By means of genetic linkage mapping,
the mouse gene was further localized as being 2.7 cM distal to D14Mit18 and
D14Mit134 and 2.0 cM proximal to D14Mit5 on mouse chromosome 14, where conserved
linkage homology with human chromosome 14q11-q12 has been identified.
PMID- 9403058
TI - The telomere-associated DNA from human chromosome 20p contains a pseudotelomere
structure and shares sequences with the subtelomeric regions of 4q and 18p.
AB - The human chromosome 20p telomere has been cloned on a yeast artificial
chromosome (YAC). The telomere-associated DNA contains an interstitial tract of
(TTAGGG)n telomeric repeats 60 kb in from the chromosome end. Frequent truncation
of the YAC clone was observed due to resolution of the internal telomeric array
into a telomere. The 20p internal telomeric repeat tract is flanked on its
centromeric side by telomere-associated repeated sequences that have previously
been found adjacent to terminal telomeric repeat arrays. The pseudotelomere
structure of the 20p subtelomeric region is similar to the structure of some
yeast subtelomeric regions where these sequences act as substrates for
recombinational repair of chromosome ends that have lost their terminal telomeric
repeat arrays. Sequences flanking the telomeric end of the internal (TTAGGG)n
repeat array on 20p are found adjacent to three other subtelomeric (TTAGGG)n
tracts on 4q, 18p, and an unknown chromosome end, respectively. These shared
sequences provide evidence of exchange between nonhomologous chromosomes in
humans.
PMID- 9403059
TI - The Charcot-Marie-Tooth binary repeat contains a gene transcribed from the
opposite strand of a partially duplicated region of the COX10 gene.
AB - Misalignment between the two elements of the CMT1A-REP binary repeat on
chromosome 17p11.2-p12 causes two inherited peripheral neuropathies, Charcot
Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure
palsies. This binary repeat contains repetitive DNA elements that include LINES,
SINES, medium reiteration frequency repeats, and a transposon-like element. The
COX10 gene has been mapped 10 kb centromeric to the distal CMT1A-REP element, and
a portion of this gene is present in both the proximal and the distal CMT1A-REP
elements. We report the isolation and characterization of a novel cDNA (C170RF1),
which maps centromeric to and partially within the proximal CMT1A-REP element.
Part of C170RF1 is transcribed from the opposite strand of the COX10 partial gene
duplication present in the proximal CMT1A-REP element. This finding shows that
C170RF1 and COX10 are being transcribed from opposite strands of identical DNA
sequences that are separated by 1.5 Mb in the genome. RT-PCR analysis showed the
proximal transcript was expressed in skeletal muscle. Sequence analysis
identified an open reading frame encoding a 199-amino-acid protein. Zoo blot
analysis showed that the transcript is conserved in nonhuman primates. The
presence of a binary repeat contributes to the instability of this region of
chromosome 17, yet two CMT1A-REP elements are present in the chimpanzee and all
human populations. The presence of expressed sequences in both elements of the
CMT1A-REP binary repeat could explain the maintenance of this repeat in humans.
PMID- 9403060
TI - Identification of new translocation breakpoints at 12q13 in lipomas.
AB - Cytogenetic studies of banded chromosomes and fluorescence in situ hybridization
(FISH) of several yeast artificial chromosomes (YACs) that are part of a 128-kb
resolution physical map of a portion of 12q13 revealed that 4/14 (28%) lipomas
have breakpoints in 12q13. These breakpoints are more than 10 Mb away from the
HMGIC gene at 12q14-q15, which is known to be modified in some lipomas. FISH with
individual YACs at 12q13 enabled us to identify four YACs that span three
breakpoints. Our results suggest that genes other than HMGIC on human chromosome
12 may be involved in the etiology of lipoma development.
PMID- 9403061
TI - Cloning and characterization of freac-9 (FKHL17), a novel kidney-expressed human
forkhead gene that maps to chromosome 1p32-p34.
AB - We describe the cloning of a near full-length cDNA of 4258 nucleotides encoding
freac-9 (HGMW-approved symbol FKHL17), a novel human forkhead gene. The 5'
untranslated region is unusual since it is very long, 2127 nucleotides, and
contains 15 upstream AUG codons. Hybridization to a panel consisting of RNA
derived from 50 different tissues showed that freac-9 is transcribed exclusively
in the kidney. The kidney-derived cell lines COS-7 and 293 are shown to express
freac-9. A combination of fluorescence in situ hybridization and somatic cell
hybrids localizes freac-9 to the chromosomal region of 1p32-p34. The conceptual
translation product predicts a protein of 372 amino acids with an N-terminal
domain rich in acidic amino acids and with a high likelihood of forming an
amphipatic helix, a DNA binding forkhead domain, and a C-terminal region that has
a high probability of forming an amphipatic beta-sheet. The amino acid sequence
of the DNA binding forkhead motif of FREAC-9 is identical to that of another
forkhead protein, FREAC-4, whereas 12 substitutions are present at the nucleotide
level. There are no similarities in regions outside of the DNA binding domains of
FREAC-9 and FREAC-4 and since freac-4 maps to a different chromosome (5q12-q13)
it is likely that an evolutionary selection has acted to maintain identical DNA
binding domains between these two kidney expressed transcription factors.
PMID- 9403062
TI - Aberrant mRNA splicing causes sorbitol dehydrogenase deficiency in C57BL/LiA
mice.
AB - Sorbitol dehydrogenase (Sord) catalyzes the interconversion of sorbitol and
fructose and is functionally important both in the metabolism of dietary sorbitol
and as a source of fructose in semen. Together with aldose reductase, Sord forms
the polyol pathway, which plays an important role in the etiology of diabetic
complications. The Sord-deficient mouse (C57BL/ LiA) is very useful in animal
model studies of the involvement of the polyol pathway in both diabetic and
congenital cataracts. To understand more about this strain, we characterized the
molecular basis underlying this Sord deficiency and found that this was due to a
point mutation in the exon 8/intron 8 junction. Substitution of an A for G at the
first position of the strictly conserved GT donor completely abolished normal
splicing of exon 8. Aberrant splicing of this junction generates at least three
types of transcripts: one lacking exon 8, another that has a truncated exon 8,
and a third that contains intron sequences. We have devised two convenient PCR
based methods to identify this mutation in C57BL/LiA mice. These methods are
useful in animal experiments that involve cross-breeding with these mice because
they allow early determination of genotype without the need to sacrifice the
animals for enzyme assay.
PMID- 9403063
TI - Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR
gamma (RORC) gene.
AB - The nuclear orphan receptor subfamily ROR/RZR is part of the steroid and thyroid
hormone/retinoid receptor superfamily and consists of three different genes,
alpha, beta, and gamma. In this study, we determined the genomic structure of
mouse ROR gamma and the chromosomal localization of both mouse ROR gamma and
human ROR gamma (HGMW-approved symbol RORC). The genomic structure of the mouse
ROR gamma gene was derived from the analysis of P1 vector clones containing large
genomic fragments encoding ROR gamma. These results revealed that the mROR gamma
gene has a complex structure consisting of 11 exons separated by 10 introns
spanning more than 21 kb of genomic DNA. The DNA-binding domain is contained in
two exons, 3 and 4, each encoding one zinc-finger. The splice site between exon 3
and exon 4 is identical to that found in RAR and TR3 receptors. ROR gamma is
expressed as two mRNAs, 2.3 and 3.0 kb in size, that are derived by the use of
alternative polyadenylation signals. We show by fluorescence in situ
hybridization that the mouse ROR gamma gene is located on chromosome 3, in a
region that corresponds to band 3F2.1-2.2. The human ROR gamma was mapped to
chromosome region 1q21. The results demonstrate that the ROR gamma genes are
located in chromosomal regions that are syntenic between mouse and human.
PMID- 9403064
TI - Characterization of human homologs of the Drosophila seven in absentia (sina)
gene.
AB - Studies of Drosophila photoreceptor development have illustrated the means by
which signal transduction events regulate cell fate decisions in a multicellular
organization. Development of the R7 photoreceptor is best understood, and its
formation is dependent on the seven in absentia (sina) gene. We have
characterized two highly conserved human homologs of sina, termed SIAH1 and
SIAH2. SIAH1 maps to chromosome 16q12 and encodes a 282-amino-acid protein with
76% amino acid identity to the Drosophila SINA protein. SIAH2 maps to chromosome
3q25 and encodes a 324-amino-acid protein that shares 68% identity with
Drosophila SINA and 77% identity with human SIAH1. SIAH1 and SIAH2 were expressed
in many normal and neoplastic tissues, and only subtle differences in their
expression were noted. However, one of three murine homologs, Siah1B, was
strongly induced in fibroblasts undergoing apoptotic cell death. While a previous
study suggested that SINA was a nuclear protein, epitope-tagged SINA and SIAH1
proteins were found in the cytoplasm of Drosophila and mammalian cells. Their
substantial evolutionary conservation, role in specifying cell fate, and
activation in apoptotic cells suggest the SIAH proteins have important roles in
vertebrate development. Furthermore, given the role of sina in Drosophila
photoreceptor development, SIAH2 is a candidate for the Usher syndrome type 3
gene at chromosome 3q21-q25.
PMID- 9403065
TI - Molecular cloning and characterization of the human mitochondrial 2,4-dienoyl-CoA
reductase gene (DECR).
AB - 2,4-Dienoyl-CoA reductase (EC 1.3.1.34) is an auxiliary enzyme of beta-oxidation,
and it participates in the metabolism of unsaturated fatty enoyl-CoA esters
having double bonds in both even- and odd-numbered positions. In this article we
describe the molecular cloning of the human gene for the 120-kDa isoform of
mitochondrial 2,4-dienoyl-CoA reductase (DECR). The gene is approximately 30 kb
and comprises 10 exons varying in size from 79 to 203 bp and 9 introns whose
sizes vary from 95 bp to about 10 kb. The 5' UTR and 3' UTR are included in exons
1 and 10, respectively. The promoter region contains putative binding sites for
several transcription factors, e.g., Sp1, AP-2, AP-4, and C/EBP, but no TATA box
was found. Primer extension analysis and 5' RACE-PCR revealed variability in the
length of the 5'-UTR, the longest being 72 bp. Through the use of FISH analysis
on metaphase chromosomes with a genomic fragment of 2,4-dienoyl-CoA reductase,
the gene was assigned to the chromosomal band 8q21.3.
PMID- 9403066
TI - Mouse connexin40: gene structure and promoter analysis.
AB - A family of related connexin genes encodes the subunit gap junction proteins that
form intercellular channels in different tissues. Connexin40 (Cx40) is one of
these proteins, and it exhibits limited expression only in a few cells of the
cardiovascular system. To begin to analyze Cx40 expression, we isolated a 3.3-kb
rat Cx40 cDNA by hybridization screening of a bacteriophage library prepared from
BWEM cells and isolated corresponding mouse genomic clones from a bacterial
artificial chromosome library. Restriction mapping, sequencing, and comparison to
the rat cDNA showed that the mouse Cx40 gene contained a short first exon, an
11.4-kb intron, and a second exon containing the complete coding region and 3'
UTR. Exon I contained only 1 base that differed between rat and mouse. Primer
extension experiments yielded a single band and confirmed the position of the
transcriptional start site. We obtained 1.2 kb of sequence 5' of the
transcriptional start site and 400 bp 3' of exon I. Exon I was closely preceded
by a consensus TATA box. The flanking sequences contained a number of potential
transcription factor binding sites (including AP-1, AP-2, SP1, TRE, and p53). To
identify transcriptional regulatory elements in the Cx40 promoter region, a
series of DNA deletion fragments flanking exon I was prepared, subcloned adjacent
to a luciferase reporter gene, and used for transient transfections of BWEM, SHM,
and N2A cells. The resulting luciferase activity determinations suggested that an
area of 300 bp 5' of the transcription start site acted as a basal promoter for
Cx40 and that there was a strong negative regulatory element in the region from
+100 to +297.
PMID- 9403067
TI - Site-specific retrotransposition of L1 elements within human alphoid satellite
sequences.
AB - In the course of a search for microsatellites as centromeric polymorphic markers
at the 3' ends of Alu or L1 elements, we observed a much higher frequency of L1
than Alu elements embedded within alpha satellite DNA. By sequence analysis of
the L1 elements at their alphoid locus of insertion, we found that the insertion
site was specific, with the consensus being (Py)2-10/ (Pu)3-7. All potential
sites within the consensus alphoid 171-bp repeat are occupied by such elements.
This confirms the finding by Feng et al. (1996; Human retrotransposon encodes a
conserved endonuclease required for retrotransposition, Cell 87:905-916) that the
progenitor L1 elements encode a site-specific endonuclease and that they generate
copies that are inserted at these specific sites. The analysis of retrotransposed
L1 elements within the alphoid domains of the acrocentric chromosomes showed that
a number of loci are shared among all five acrocentrics. This sheds light on the
manner in which centromeric regions of these chromosomes are exchanging
information during evolution.
PMID- 9403068
TI - Cloning and chromosomal mapping of human casein kinase I gamma 2 (CSNK1G2).
AB - A clone of immature cDNA for human casein kinase I gamma 2 (CSNK1G2) was isolated
by screening the human testis cDNA library with a PCR-amplified probe (about 400
bp) representing the kinase domain of rat casein kinase I gamma 2 (CKI gamma 2).
Comparison of the entire sequence with that of rat CKI gamma 2 showed that the
cDNA contained the complete coding sequence of CKI gamma 2 as well as an intron
like sequence of 1006 bp, part of which was homologous to the Alu sequence. To
obtain an insertion-free CSNK1G2 cDNA, PCR cloning was performed based on the
above sequence. The amplified 1687-bp fragment was subcloned and sequenced. The
predicted amino acid sequence consisted of 416 residues, 94% of which were
identical to that of the rat homologue. Although there are two Src homology 3
(SH3) domain-binding motifs (Pro-X-X-Pro consensus), Pro-Lys-Val-Pro and Pro-Ser
Glu-Pro in the C-terminal region of rat CKI gamma 2, only the latter was
conserved in the human counterpart. This finding suggests that the latter motif
is important for binding to the signal transduction adaptor protein Nck (NCK).
The human CSNK1G2 gene was mapped to chromosome 19p13.3 by fluorescence in situ
hybridization and PCR analysis of the human/rodent hybrid cell panel.
PMID- 9403069
TI - Mapping of eight testis-specific genes to mouse chromosomes.
AB - We previously identified eight testis-specific genes using antibodies raised
against testicular germ cells. They are expressed during spermatogenesis and are
presumed to be involved in testicular germ cell differentiation and sperm
formation. We have mapped the genomic loci for these testis-specific genes using
restriction fragment length variants in interspecific backcross mice. The
calmegin gene (Clgn) was mapped to Chr 8. The synaptonemal complex protein gene 1
(Sycp1) probe hybridized with two sequences on different chromosomes; Sycp1-rs2
was mapped to Chr 3, whereas Sycp1-rs3 was mapped to Chr 7. The relaxin-like
factor gene (Rlnl) was mapped to Chr 8, and collapsin response mediator protein 1
(Crmp1) was mapped to Chr 5. Three novel genes encoding testis-specific proteins
A2 (Tsga2), A8 (Tsga8), and A12 (Tsga12) were mapped to chromosomes 3, X, and 10,
respectively.
PMID- 9403070
TI - Use of the Indian muntjac idiogram to align conserved chromosomal segments in
sheep and human genomes by chromosome painting.
AB - We have hybridized all 28 chromosome-specific painting probes from the domestic
sheep (Ovis aries, 2n = 54) onto metaphase chromosomes of the Indian muntjac deer
(Muntiacus muntjak vaginalis, 2n = 6,7) and identified 35 conserved chromosomal
segments. Results from this study show that most of the sheep acrocentric
chromosomes hybridized to single regions in the Indian muntjac genome. This
conserved hybridization pattern supports the concept that the large Indian
muntjac chromosomes were derived from multiple tandem fusions from an ancestral
deer species. Using previously reported fluorescence in situ hybridization data
in which human chromosomes were hybridized onto the Indian muntjac genome, we
were able to align chromosomal segments of the sheep and human genomes. Using
this three-species genome alignment approach, we have identified a minimum of 42
conserved chromosomal segments between sheep and human genomes including 7 new
regions not previously reported.
PMID- 9403071
TI - Mapping of the human ribosomal large subunit protein gene RPL29 to human
chromosome 3q29-qter.
AB - The human ribosomal protein L29, which we reported previously, was subsequently
shown to have the same nucleotide sequence as that of cell surface
heparin/heparan sulfate-binding protein, designated HP/HS interacting protein. A
polymerase chain reaction-based strategy was used to distinguish the functional
intron-containing gene RPL29 (HGMW-approved symbol) from multiple pseudogenes. By
somatic cell hybrid analysis, radiation hybrid mapping, and fluorescence in situ
hybridization, we have located RPL29 on the telomeric region of the q arm of
chromosome 3. RPL29 is the most distal marker of the long armof chromosome 3. Of
the human ribosomal protein genes mapped, RPL29 is the shortest distance from
another ribosomal protein gene marker, RPL35 a which has also been mapped to the
3q29-qter region.
PMID- 9403072
TI - Linkage mapping of Thiel-Behnke corneal dystrophy (CDB2) to chromosome 10q23-q24.
AB - Corneal dystrophy of the anterior basement membrane is a heterogeneous set of
diseases characterized by painful, recurrent, bilateral erosions of the cornea,
which often result in significant visual impairment. There are several similar
but clinically distinct forms of anterior basement membrane/Bowman's membrane
disease, including two autosomal dominant forms, Reis-Bucklers and Thiel-Behnke
corneal dystrophy. Genes causing autosomal, nonsyndromic corneal dystrophy have
been mapped to human chromosomes 1p, 5q, 12q, 16q, 17p, and 20p. Using
microsatellite markers closely linked to the known corneal dystrophy loci, we
excluded linkage between the known sites and the disease locus in a large, four
generation family with Thiel-Behnke corneal dystrophy. A genome-wide search using
a panel of microsatellite markers demonstrated a maximum two-point lod score of
4.0 at 0% recombination between the disease locus in this family and the marker
D10S1239, which maps to 10q23-q24. Testing with additional microsatellite markers
from 10q places the disease locus between D10S677 and D10S1671, a distance of
approximately 12.0 cM, with a maximum multipoint lod score of 5.5. Based on this
evidence, we have identified another locus (CDB2) for corneal dystrophy of the
anterior basement membrane/Bowman's membrane, Thiel-Behnke type, further
demonstrating the exceptional genetic and phenotypic heterogeneity of these
diseases.
PMID- 9403073
TI - The chromosome location of the human homolog of the mouse mammary tumor
associated gene INT6 and its status in human breast carcinomas.
AB - The INT6 gene is a common integration site for the mouse mammary tumor virus in
mouse mammary tumors. We have determined that the human homolog of INT6 is
located on chromosome region 8q22-q23. A processed INT6 pseudogene is located on
chromosome 6q. INT6 is composed of 13 exons that span 45 kb of genomic DNA. The
deduced amino acid sequence of the gene product is identical to the mouse protein
and contains three potential translation start signals. We have examined 100
primary breast carcinoma DNAs for evidence of genetic alteration affecting INT6.
Loss of heterozyosity (LOH) was detected in 11 of 39 (28%) of the tumor samples
informative for a polymorphic sequence in intron 7 of INT6. Since single-strand
conformation and hybrid mismatch analysis of the remaining allele in these tumor
DNAs failed to detect any mutations, we conclude that the target gene for LOH
must be closely linked to INT6.
PMID- 9403074
TI - Evidence for linkage of chromosome 12q15-q24.1 markers to high total serum IgE
concentrations in children of the German Multicenter Allergy Study.
AB - Linkage of asthma and high total serum IgE levels to chromosome 12q15-q24.1 has
been recently described. To evaluate this region further in regard to total IgE
responsiveness, we genotyped 52 unrelated German children with persistently
"high" total serum IgE (selected from a noninterventional prospective multicenter
cohort study) and their parents. We carefully defined a most extreme IgE
phenotype and analyzed it as a dichotomous trait. We tested for linkage between
high total IgE concentrations and nine polymorphic microsatellite markers on
chromosome 12q15-q24.1 using the transmission/disequilibrium test. Evidence for
linkage and allelic association for high total IgE was observed for four markers
in this region. This study demonstrates the value of using extreme phenotypes in
genetic analysis of a complex quantitative trait.
PMID- 9403075
TI - Automated capillary electrophoresis in the genotyping of apolipoprotein E.
PMID- 9403076
TI - Radiation hybrid mapping of the genes for tenascin-R (TNR), phosducin (PDC),
laminin C1 (LAMC1), and TAX in 1q25-q32.
PMID- 9403077
TI - A low-copy repeat in Xq26 represents a novel putatively prenylated protein gene
(CXX1) and its pseudogenes (DXS9914, DXS9915, and DXS9916).
PMID- 9403078
TI - Scapula form and biomechanics in gorillas.
AB - Gorillas are generating renewed interest as mounting evidence from field and
molecular studies strongly suggests the western lowland (Gorilla gorilla gorilla)
and eastern mountain (Gorilla gorilla beringei) gorillas are considerably more
distinct than has previously been accepted. Schultz (1927, 1930, 1934) was one of
the earliest investigators to document morphological differences between the two
groups, noting differences in pedal, limb and scapular morphology. These
differences led Schultz to conclude that while lowland gorillas retained some
features suited to an arboreal habitat, the mountain gorilla had evolved into a
specialized terrestrial quadruped. In particular, he noted that mountain gorillas
exhibited lower values for the scapular index, higher values for ratios of
infraspinous fossa vs. scapula length and spine length vs. scapula length and
variability in the extent of curvature of the vertebral border. However, Schultz'
observations were based upon small sample sizes of mostly adult specimens. This
study extends Schultz' preliminary work by assessing, with appreciably larger
sample sizes, patterns of relative growth of the scapula in these two subspecies
of Gorilla. Scapula measurements were obtained for ontogenetic series of G.g.
gorilla (n = 366) and G. g. beringei (n = 43). Statistical analyses reveal
mountain gorillas exhibit significantly (P < 0.05) greater spine lengths and
scapula breadths and smaller scapula lengths than lowland gorillas of comparable
superior border lengths. However, at comparable body weights, mountain gorillas
exhibit significantly shorter spines and superior borders than lowland gorillas.
These differences in scapula proportions are evaluated in the context of
biomechanical predictions regarding scapula form and locomotion.
PMID- 9403079
TI - Experimental determinations of carcass processing by Plio-Pleistocene hominids
and carnivores at FLK 22 (Zinjanthropus). Olduvai Gorge, Tanzania.
AB - Published and unpublished skeletal and surface mark data from the large, well
preserved, bovid dominated FLK 22 (Zinjanthropus) archaeofauna are analyzed using
data derived from four different experimental control samples. The control
samples are realistic because they are based on natural history and
paleoecological data collected from FLK 22, and other Olduvai Gorge assemblages;
they are precise because independent experimental studies following the same
methods have generated the same results; and they restore generality to the study
of site formation because each one models a different hominid and/or carnivore
scenario of site formation. Comparability between FLK 22 and the control samples
is established by excluding specimens from the former which do not meet
identification and reporting standards derived from the latter. As in two
previous studies, a comprehensive analysis of tooth marks and tool marks on long
bone specimens from FLK 22 indicates that they were processed in three stages. In
stage one, carnivores defleshed long bones, as inferred from the high percentage
of tooth marks on midshaft fragments. In stage two, hominids processed intact
long bones for marrow, as inferred from percussion mark percentages. Cut marks
suggest that long bones retained flesh, but the amount, as yet, cannot be
determined using cut mark percentages. In stage three, carnivores processed long
bone epiphyses for grease, as inferred from the under-representation of long bone
epiphyses and the high percentage of tooth marks on near-epiphyses and surviving
epiphyses. The lack of comprehensive skeletal and surface mark data on cranial,
axial, compact, and other specimens currently limits the application of
experimental results. However, the available data suggest that the condition and
representation of these items in the FLK 22 assemblage are also consistent with a
carnivore to hominid to carnivore sequence of site formation. The variety of
elements present, and their extensive processing by hominids, indicates that FLK
22 functioned as a central place/refuge where hominids could transport a variety
of carcass parts and process them in an unhurried fashion. The presence of
numerous small and medium sized individuals also indicates that hominids could
have passively scavenged carcasses from a number of different sources including
lions, leopards, sabertooth cats, and mass drownings.
PMID- 9403080
TI - The occipital torus and developmental age of Sangiran-3.
AB - Since its discovery in 1938 Sangiran-3 has been considered a juvenile
Pithecanthropus (Homo) erectus, and therefore, excluded from studies of adult H.
erectus. Although morphological features align Sangiran-3 with H. erectus, its
age designation rests on an unconvincing reconstruction of the occipital torus
and lack of sutural fusion. Evaluation of the occipital shows the original
reconstruction is faulty and that the current midline occipital torus is actually
the right lateral torus. The new reconstruction of Sangiran-3 results in midline
toral morphology and development that is comparable with that in Sangiran-2.
Compared with juvenile and adult H. erectus and Homo sapiens Sangiran-3 has three
fully developed layers of vault bone with localized hypertrophy of the outer
table into a sagittal keel, bregmatic eminence, and occipital torus. Sangiran-3's
absolute vault thickness is also within the range of adult H. erectus. In
addition, the coronal suture is fully interdigitated and sagittal sutural
complexity is consistent with adult H. erectus. Sangiran-3's parietal sagittal
contours are indistinguishable from adult H. erectus, whereas sagittal vault
contours of juvenile H. erectus are usually more rounded than adults. These
features indicate that Sangiran-3 is best considered a young adult H. erectus and
should be included in metric and non-metric analyses of this taxon.
PMID- 9403081
TI - Fuente Nueva-3 (Orce, Granada, Spain) and the first human occupation of Europe.
PMID- 9403082
TI - Academy helps budding colleagues through ethics program.
PMID- 9403083
TI - Delayed allergy-like reactions to X-ray contrast media. Exploration of the
problem.
PMID- 9403084
TI - [What is new? Therapy with lipid lowering agents].
PMID- 9403086
TI - [Bronchial asthma. Fluticasone propionate--new perspectives in the management of
a frequently occurring disease entity].
PMID- 9403085
TI - [Sleep apnea and nightly hypertension. Interaction of sleep and respiration].
PMID- 9403087
TI - [Management of atherosclerosis--new findings for the practice].
PMID- 9403088
TI - [The effectiveness of the neurotropic agents: benfotiamin combinations].
PMID- 9403089
TI - [The metabolic syndrome].
PMID- 9403090
TI - [45th session of the Association of Ophthalmologists of Northwestern Germany.
Lubeck, 1-2 June 1996. 46th Session of the Association of Ophthalmologists of
Northwestern Germany, Bremen, 21-22 June 1997].
PMID- 9403091
TI - [Multiple sclerosis: from immunopathogenesis to disease management].
PMID- 9403092
TI - [3 years of clinical experience with risperidone: new therapeutic standards in
the management of schizophrenia].
PMID- 9403093
TI - [Thrombolysis: Reteplase as an innovative alternative].
PMID- 9403094
TI - Behavioral responses of Barbary macaques (Macaca sylvanus) to variations in
environmental conditions in Algeria.
AB - In this study, the behavioral responses of Barbary macaques to seasonal and
interhabitat variations in resource availability were analyzed over an entire
annual cycle. Two groups, one in an evergreen cedar-oak forest (Djurdjura) and
the other in a deciduous oak forest (Akfadou), were observed. In this paper,
references to data on resource availability published elsewhere are made. Time
budget has been studied. Variations in foraging and moving time, in day-range
lengths, and in time moving in trees have been considered to estimate the
variations in foraging effort and thus energy expenditure. Great monthly
variations in foraging effort and other activities were observed in both
habitats. In early spring, when resource availabilities were maximal, foraging
effort was low while monkeys maximized their feeding time (about 5 h/day). In
June, during the peak of the birth season and the rearing period, monkeys
minimized their feeding time to the benefit of social interactions (to 1.6-2.7
h/day), whatever the food availability, which was low in Akfadou and high in
Djurdjura. In addition, foraging effort remained low in Djurdjura, while it
increased in Akfadou. Thus, at the beginning of the dry summer period, monkeys in
Akfadou were in a less favorable position than those in Djurdjura. At both sites,
in periods of food shortage in summer or in winter, monkeys displayed two
different strategies. In the former case, their foraging effort increased, while
in the second one it remained relatively low. Whatever the foraging effort,
monkeys did not reach the same amount of feeding time as in early spring. In the
poorest site of Akfadou, foraging effort was globally greater than in the richest
site of Djurdjura, especially for adults. At both sites, adult males spent more
time feeding than juveniles and less time in social interactions. Results are
discussed according to rearing period, temperatures, and day length constraints.
The limits of adaptability to different habitats are considered in light of the
demographic parameters.
PMID- 9403095
TI - Seasonal variation in the feeding behavior and diet of Japanese macaques (Macaca
fuscata yakui) in lowland forest of Yakushima.
AB - The feeding behavior of the southern subspecies of Japanese macaque (Macaca
fuscata yakui) was studied over a period of 18 months in warm temperate broad
leaved forest on the island of Yakushima, Japan. Focal animal data were collected
for the eight adults in the troop. Over a full annual cycle, 35.0% of foraging on
identified foods was on leaves and shoots, 30.2% on fleshy fruit, 13.2% on seeds,
and 5.5% on flowers. Invertebrates and other animal matter accounted for 10.3% of
foraging and fungi for 4.6%. There was marked seasonal variation in the use of
different food categories, and seeds, leaves, fleshy fruit, and animal matter
were each predominant at different times of year. There was also evidence of
annual cyclicity in patterns of foraging on all major food types. The monkeys
spent less time moving and ate a greater variety of foods when feeding on leaves
than when feeding on fruit and seeds, or on insects. Time spent foraging was
positively correlated with diversity of the diet, but there was no simple
relationship between time spent foraging and the predominant food type. This
suggests that a wide variety of foods takes longer to harvest and process,
irrespective of the food type. The diet of the study troop was flexible and could
not be assigned to a simple dietary category, such as frugivorous or folivorous.
If these data are representative of the subspecies, the Yakushima macaque is much
more of a dietary generalist than most primates for which there are adequate
data.
PMID- 9403096
TI - Transvaginal ultrasonographic (TVS) evaluation of baboon gestation from 37-62
days postconception.
AB - Our objective was to determine the growth of the embryo and surrounding
structures during baboon (Papio anubis) gestation using transvaginal sonography
(TVS). To this end, we evaluated 19 timed-mated baboons using TVS between 37 and
62 days of gestation. After visualization of the gestational sac, amniotic sac,
and yolk sac, the three largest diameters of each of these extra embryonic
structures were measured using longitudinal and transverse views. Embryonic crown
rump length (CRL) was also recorded. Embryonic heart rates were determined using
the M-mode function of the ultrasound equipment. All 19 gestations developed
without complications. No significant trend could be demonstrated for heart rate
or yolk sac diameters over the 37-62 day gestational age period. Mean (SD)
gestational age in days, heart rate, and yolk sac diameter, respectively, for the
group were 48 (7.8) days (range: 37-61), 180 (15) beats per minute (range: 156
221) and 5 (0.1) mm (range: 3-8). Significant correlations (P < 0.0001) were
determined between gestational age and CRL and gestational and amniotic sacs. We
conclude that TVS allows a clear visualization of the embryo proper and all the
cavities within the gestational sac of the baboon gestation. This study has
determined the normal pattern of changes of these cavities from 37-62 days of
gestation. Future applications of these findings may include sampling fluid from
these cavities for biochemical, cytological, and metabolic studies.
PMID- 9403098
TI - Propagation of handclasp grooming among captive chimpanzees.
AB - A grooming posture previously reported for two wild chimpanzee (Pan troglodytes)
communities developed spontaneously in a captive group of the same species. This
offered a unique opportunity to follow the propagation of a new social custom.
The posture consists of two partners grasping hands--either both right hands or
both left hands--and raising the arms in an A-frame above their heads while
mutually grooming with their free hands. The propagation of this pattern was
followed over a 5 year period. In the beginning, handclasps were always initiated
by the same adult female. This female initiated the posture mainly with her adult
female kin. In subsequent years, these relatives became frequent participants in
the posture with each other as well as with nonrelatives. Over the years the
posture increased in frequency and duration and spread to the majority of adults
and also to a few adolescents and older juveniles. The pattern persisted after
removal of the apparent originator.
PMID- 9403097
TI - Reproductive events of wild cotton-top tamarins (Saguinus oedipus) in Colombia.
AB - Reproductive patterns of wild cotton-top tamarin (Saguinus oedipus) females
located in La Reserva Forestal Protectora Serrania de Coraza-Montes de Maria in
Coloso, Colombia, were examined using long-term behavioral observations and fecal
steroid analysis. Using an enzyme immunoassay, we analyzed fecal samples for E1C
and PdG. Comparisons of reproductive cycles of a reproductively active female and
her daughters were made. An inhibition of ovarian cycles has been observed in
daughters living in their families. However, daughters also exhibited normal
ovarian cycling that subsequently resulted in pregnancy. Factors influencing the
fertility are discussed as they relate to the reproductive strategies of wild
cotton-top tamarin females.
PMID- 9403099
TI - Ovarian function of pygmy marmoset daughters (Cebuella pygmaea) in intact and
motherless families.
AB - Reproductive inhibition of subordinate Callitrichid group members has been shown
to vary with genus; whereas female Leontopithecus subordinates have normal
ovarian cycles and occasionally breed within groups, subordinate Saguinus females
almost never do so, with Callithrix species showing intermediate levels of
reproductive inhibition. No information has been available on patterns of
reproduction or inhibition in subordinate females in the genus Cebuella. We
assessed fertility in Cebuella pygmaea daughters to allow comparison with the
remaining Callitrichid genera. Specifically, the project had two goals: 1) to
determine if there was evidence of reproductive inhibition of daughters living in
family groups, and 2) to compare the ovarian function of daughters living in
intact family groups with that of daughters residing in motherless families
(i.e., without the breeding female). We collected daily urine samples for 6-8
weeks from eight pygmy marmoset daughters living in intact family groups or
motherless families. Determination of ovulatory cycling or reproductive
quiescence depended on the hormonal profiles generated from urinary luteinizing
hormone and pregnanediol-3-glucuronide concentrations. All females in the
motherless condition (aged 13-30 months) (n = 4) ovulated during the study. In
contrast, only one of four daughters (aged 13-20 months) residing in intact
families was found to be cycling. Data from motherless groups indicate ovarian
cycling may begin between 15 and 17 months of age. Reproductive inhibition occurs
in pygmy marmosets, although in a pattern more similar to Callithrix than to
other Callitrichid genera.
PMID- 9403100
TI - Hypervariable microsatellite loci in the Japanese macaque (Macaca fuscata)
conserved in related species.
AB - We describe seven polymorphic microsatellites isolated from a Japanese macaque
(Macaca fuscata) genomic library selected for (GT)n content. The primer sets
amplified from four to 11 different alleles in a sample of 14 Japanese macaques
from nine different sites along the central and southern distribution of the
species. These heterologous primers also detected variability in four other
cercopithecine species.
PMID- 9403101
TI - DNA amplification polymorphisms of Mucor piriformis.
AB - Mucor piriformis can cause postharvest decay in various fruits and vegetables
stored at low temperatures. Thirty isolates of this fungus, collected from
infected fruit, were subjected to random amplified polymorphic DNA (RAPD)
analysis. Seven different 10-bp primers were used to determine the type and
extent of intraspecific genetic polymorphisms. Nineteen composite amplification
types were identified, indicating a higher degree of variability than found in
previous isoenzyme studies. Numerical analysis with the UPGMA technique revealed
three clusters, which correlated with the mating competency of the isolates or
their place of origin. These results demonstrate that RAPD analysis can identify
isolates and subspecific populations of M. piriformis.
PMID- 9403102
TI - Pyrimidine biosynthesis in Pseudomonas stutzeri ATCC 17588.
AB - The de novo pyrimidine biosynthetic enzymes in the denitrifying bacterium
Pseudomonas stutzeri ATCC 17588 were assayed and their activities were lower in
glucose-grown cells than in succinate-grown cells. When P. stutzeri was grown in
the presence of uracil, the de novo enzyme activities in succinate-grown cells
were lowered while they remained largely unchanged in glucose-grown cells. A
uracil auxotroph of P. stutzeri, deficient for aspartate transcarbamoylase
activity, was isolated and its auxotrophic requirement was met by only uracil and
cytosine. The inability of pyrimidine ribonucleosides to meet the auxotrophic
requirement was related to the limited ability of P. stutzeri to transport
uridine and cytidine. Pyrimidine limitation of the auxotroph elevated the de novo
enzyme activities indicating that this pathway may be repressible by a uracil
related compound in succinate-grown P. stutzeri cells. Regulation of pyrimidine
synthesis in P. stutzeri was similar to that observed for other pseudomonads
classified within rRNA homology group I.
PMID- 9403103
TI - Inhibition of denitrification activity but not of mRNA induction in Paracoccus
denitrificans by nitrite at a suboptimal pH.
AB - The influence of pH on the denitrification activity of a continuous culture of
Paracoccus denitrificans was studied in relation to the presence of nitrite.
After a transition from aerobic to anaerobic conditions at the suboptimal pH of
6.8, P. denitrificans was not able to build up a functional denitrification
pathway. Nitrite accumulated in the medium as the predominant denitrification
product. Although the nitrite reductase gene was induced properly, the enzyme
could not be detected at sufficient amounts in the culture. These observations
was somehow inhibited, or once synthesized nitrite reductase was inactivated,
possibly by the high concentrations of nitrous acid (HNO2). Interestingly, when a
P. denitrificans culture which was grown to steady-state under anaerobic
conditions was then exposed to suboptimal pHs, cells exhibited a reduced overall
denitrification activity, but neither nitrite nor any other denitrification
intermediate accumulated.
PMID- 9403104
TI - The production of gamma-linolenic acid by selected members of the Dikaryomycota
grown on different carbon sources.
AB - In this study, seven fungal strains, representing different phylogenetic groups
within the Dikaryomycota, were tested for the presence of gamma-linolenic acid
[18:3(omega 6)], when grown in synthetic liquid media devoid of fatty acids, on a
series of 40 different carbon sources. The fungal strains represented the species
Dipodascopsis uninucleata, Eurotium rubrum, Galactomyces geotrichum, Neurospora
crassa, Saccharomyces cerevisiae, Spongipellis unicolor and Talaromyces flavus.
Cultures were periodically harvested during growth and the fatty acids in the
total lipids analysed as methyl esters, using gas chromatography and mass
spectrometry. It was found that 18:3(omega 6) is present in E. rubrum CBS 350.65,
S. unicolor CBS 117.16 and in T. flavus CBS 310.38NT, when these strains were
grown on certain carbon sources. No correlation between the growth phase of the
organism and the presence of 18:3(omega 6) could be detected. In order to confirm
the production of 18:3(omega 6), the lipid metabolism of two unrelated
dikaryomycotan fungi (S. unicolor CBS 117.16 and E. rubrum CBS 350.65) grown on
two different carbon sources each, was examined. Cultures of E. rubrum CBS 350.65
were grown on glucose and sorbose and cultures of S. unicolor CBS 117.16 on
glucose and sucrose in synthetic liquid media with a C:N ratio of 50:1 (w/w). The
total lipids of these cultures were fractionated and the fatty acids in the
fractions analysed as methyl esters, using gas chromatography and mass
spectrometry. The lipid metabolism of both E. rubrum CBS 350.65 and S. unicolor
CBS 117.16 differed on the two carbon sources used. The ab initio production of
18:3(omega 6) by E. rubrum CBS 350.65 in synthetic liquid media was confirmed. In
contrast, the ab initio production of 18:3(omega 6) by S. unicolor CBS 117.16 in
synthetic liquid media could not be confirmed.
PMID- 9403105
TI - Assimilation of volatiles from ripe apples by Sporidiobolus salmonicolor and
Tilletiopsis washingtonensis.
AB - Sporidiobolus salmonicolor ATCC 623 and Tilletiopsis washingtonensis NRRL Y-2555
grew on carbon resources provided as volatiles by ripe 'Golden Delicious' apples.
This ability was not correlated with the reported natural habitats of the 21
species (26 strains) tested. Ethylene, the major volatile produced, was not
utilized but butyl acetate, hexyl acetate and hexyl-2-methyl-butanoate
(identified by GC-MS) were. These yeasts also assimilated ethanol, butanol,
hexanol (Tilletiopsis excepted), acetate, propionate, butyrate and ethyl acetate
at appropriately low concentrations. Ethanol and acetate aside, this is the first
report of such assimilations by any yeast.
PMID- 9403106
TI - Evolutionary advances in the higher fungi.
AB - In this report the phrase 'evolutionary advances' is used in three ways: 1. to
describe monophyletic changes perceived within a lineage; 2. to describe
evolutionary sequences that appear to have become parallel/convergent; 3. to
describe major transitions inferred between primary taxa. In monophyletic
evolution the changes occur within a specific lineage that arises from a common
ancestor, e.g., modern Man, horses, rusts. In parallel/convergent evolution
different lineages respond similarly over time to environmental challenges and
opportunities and come to acquire a great deal of comparability (e.g., Webster,
1987). Such lineages may be designated as separate taxa, e.g., similarities in
marsupial and placental carnivores, or, if the polyphyleticism is cryptic, as a
collective taxon, e.g., Aves, the class of birds, the obsolete Amentiferae for
catkin bearing plants, the Gasteromycetes, and lichens. In major transitions
there are significant paradigm shifts in which evolutionary changes from one
predominant life style pattern to another are accompanied by increases in
complexity (see Smith & Szathary, 1995), e.g., symbiosis, the water to land
transition, the changes between the phyla of land fungi. Three particular terms
are used in evaluating evolutionary relationships (Moore, 1996a): homology,
paramology, and analogy. Homology, from Darwin's theory of common descent, is the
phenomenon of having a common historical origin but not necessarily the same
final structure or function (e.g., vertebrate forelimbs). Paramology (Moore,
1971) applies to inferred relationships in evolutionary schemes based on
contemporary forms that lack fossil antecedents, e.g., the various phylogenetic
interpretations of prokaryotes, algae, and fungi; Boekhout et al. (1993) have
evaluated the taxonomic resolution of a variety of morphologic, biochemical,
physiological, and molecular characters (Table 1). Analogy is generally applied
to similar forms that are unrelated, e.g., insect/vertebrate wings;
prokaryote/eukaryote flagella. It should also be borne in mind that, in a given
taxon, biotrophism (Coffey, 1975) is an advanced character (Health, 1987) over,
respectively, weaker parasitism, symbiotism, commensalism, and freeliving and
that seemingly simple or less differentiated forms can be, and more than likely
than not are, reduced, polyphyletic, and specialized rather than ancient and
rudimentary, e.g., yeasts (Hoog et al., 1988; Kurtzman & Fell, 1996; Moore,
1988b; 1996a).
PMID- 9403107
TI - MauE and MauD proteins are essential in methylamine metabolism of Paracoccus
denitrificans.
AB - Synthesis of enzymes involved in methylamine oxidation via methylamine
dehydrogenase (MADH) is encoded by genes present in the mau cluster. Here we
describe the sequence of the mauE and mauD genes from Paracoccus denitrificans as
well as some properties of mauE and mauD mutants of this organism. The amino acid
sequences derived from the mauE and mauD genes showed high similarity with their
counterparts in related methylotrophs. Secondary structure analyses of the amino
acid sequences predicted that MauE is a membrane protein with five transmembrane
spanning helices and that MauD is a soluble protein with an N-terminal
hydrophobic tail. Sequence comparison of MauD proteins from different organisms
showed that these proteins have a conserved motif, Cys-Pro-Xaa-Cys, which is
similar to a conserved motif found in periplasmic proteins that are involved in
the biosynthesis of bacterial periplasmic enzymes containing haem c and/or
disulphide bonds. The mauE and mauD mutant strains were unable to grow on
methylamine but they grew well on other C1-compounds. These mutants grown under
MADH-inducing conditions contained normal levels of the natural electron acceptor
amicyanin, but undetectable levels of the beta-subunit and low levels of the
alpha-subunit of MADH. It is proposed, therefore, that MauE and MauD are
specifically involved in the processing, transport, and/or maturation of the beta
subunit and that the absence of each of these proteins leads to production of a
non-functional beta-subunit which becomes rapidly degraded.
PMID- 9403109
TI - Growth, maintenance and fermentation pattern of the salt-tolerant lactic acid
bacterium Tetragenococcus halophila in anaerobic glucose limited retention
cultures.
AB - The homofermentative lactic acid bacterium Tetragenococcus halophila showed mixed
acid fermentation at low growth-rates under glucose limiting conditions and in
the presence of 10% NaCl. Maximum growth yields in fermentors with cell retention
were not affected by pH, but maintenance requirement was at pH 5.2 four times
higher than at pH 7.0. Despite the high salt-concentration of the medium,
maintenance requirements were low compared to other lactic acid bacteria. The
possible causes of the observed differences in maintenance requirements are
discussed.
PMID- 9403108
TI - The incorporation of mannoproteins in the cell wall of S. cerevisiae and
filamentous Ascomycetes.
AB - In yeast, glucanase extractable cell wall proteins are anchored to the plasma
membrane at an intermediate stage in their biogenesis via a
glycosylphosphatidylinositol (GPI) moiety before they become anchored to the wall
glucan via a beta 1,6-glucan linkage. The mechanism of the membrane processing
step of cell wall proteins is not known. Here, we report that Ascomycete
filamentous fungi involved in food spoilage such as Aspergillus, Paecilomyces and
Penicillium, also contain GPI membrane-anchored proteins some of which are
processed by an endogenous phospholipase C activity. Furthermore, similar to the
situation in yeast, their cell walls contain mannoproteins which are linked to
the glucan backbone through a beta 1,6-glucan linkage. Interestingly, one mould
which contains a significant amount of non covalently linked beta 1,6
glucosylated cell wall proteins, is much more sensitive towards beta 1,3
glucanases and membrane perturbing peptides than the others.
PMID- 9403110
TI - Staphylococcal serine proteinase increases intracellular free calcium
concentration in human polymorphonuclear leukocytes.
AB - Staphylococcal serine proteinase (SSP) can influence various functions of human
polymorphonuclear leukocytes (PMNL) including chemotaxis and phagocytosis. Since
the rise in intracellular free calcium concentration is an important step in
signal transduction leading to phagocyte activation, we tested the ability of SSP
to increase the intracellular free calcium concentration in human PMNL using the
fluorescent calcium indicator Fura-2AM. PMNL isolated from healthy donors
responded to SSP in the concentration range of 10 to 100 micrograms/ml. The
highest Ca2+ rise (104 +/- 47 nM) was observed for 10 micrograms/ml SSP. It was
mainly dependent (81 +/- 11%) on extracellular calcium influx, however, SSP
mobilized 68 +/- 7% of Ca2+ from intracellular calcium stores. Boiling of SSP or
preincubation with phenylmethylsulphonylfluoride (an serine proteinase inhibitor)
did not change its ability to increase intracellular free calcium concentration
in PMNL. It suggests that active center of SSP is not responsible for Ca2+
mobilization. Finally, PMNL responded to each of three consecutive stimulations
with SSP independently of the presence of high or low extracellular Ca2+
concentration. This may be an additional mechanism responsible for activation of
human PMNL and degradation of alveolar walls during the staphylococcal infection
in the lower airways.
PMID- 9403111
TI - Molecular evolution and optimization.
AB - Microbial populations (and life) not only evolve, they optimize. The transition
from a random, unorganized, lifeless Earth to the present situation, where the
Earth is virtually covered with nucleic acids and diverse and complex species,
required numerous molecular changes and the integration of metabolic pathways
over billions of years. Primitive prokaryotic life was dependent on and
constrained by the physical-chemical conditions on the Earth, while slowly
reshaping conditions present. In this review, molecular evolution and molecular
optimization are examined with an emphasis on the order in which evolutionary
events occurred.
PMID- 9403112
TI - Soil mycoflora from the Dead Sea Oases of Ein Gedi and Einot Zuqim (Israel).
AB - Samples were taken from the top 10 cm of soils from 24 points in the Ein Gedi
area. Among 329 isolates, 142 species were identified: 11 genera of ascomycetes,
one genus of coelomycetes, 28 genera of hyphomycetes, 7 genera of zygomycetes and
one yeast, in addition to some unidentified basidiomycetes. The hyphomycetes were
represented by 17 dematiaceous, 9 mucedinaceous and two tuberculariaceous.
Melanconiaceous and stilbellaceous genera were not found. Two new varieties of
Microascus recently described were reisolated. No strict thermophiles or
halophiles were obtained. There is apparently no very characteristic or specific
fungal flora of the Dead Sea Oases although it was different from that found in
the desert soil surrounding this area.
PMID- 9403113
TI - Investigation of calcium-binding sites on the surfaces of selected gram-positive
oral organisms.
AB - Dental plaque is rich in anionic groups with a high calcium-binding capacity
which may affect mineral dynamics at the tooth surface. The two major calcium
binding sites on Gram-positive cell surfaces are carboxylate groups (in proteins
and peptidoglycan cross-links) and phosphate groups (in lipoteichoic and teichoic
acid). Equilibrium dialysis was used to measure calcium-binding capacities of
whole cells and purified cell-wall material (CWM) from Streptococcus mutans R9,
Strep. oralis EF186, Strep. gordonii NCTC 7865, Strep. downei NCTC 11391,
Actinomyces naeslundii WVU627 and Lactobacillus casei AC413. This material was
stripped of phosphate (PS-CWM) and treated to mask carboxylate groups (CM-CWM).
Whole-cell calcium-binding capacities ranged from 240 (Strep. downei) to 50 (L.
casei) mu mol/g (dry wt). Differences in CWM, PS-CWM and CM-CWM calcium-binding
capacities demonstrated the greater importance of phosphate in comparison with
carboxylate groups in cell calcium binding. These data indicate that, in
streptococci, calcium binding is predominantly phosphate group-based, especially
in the teichoic acid-containing Strep. oralis. In the other species tested,
calcium binding is predominantly carboxylate group-based.
PMID- 9403114
TI - Caries prevalence in the permanent dentition of a mediaeval population from the
south-west of Scotland.
AB - The prevalence, distribution and location of dental caries were studied in the
permanent dentition of skeletons from a large mediaeval cemetery, where
successive phases of use could be distinguished. The main phases dated from 1240
AD to 1440 AD. During this 200-year period, caries prevalence showed a
statistically significant linear trend to increase. There was an increase in
caries prevalence with increasing age from age band 20-25 through 26-35 to 36-45,
and this trend was statistically significant in all phase groups but one. The
teeth attacked by caries were chiefly molars, followed by premolars, with a low
rate of attack in incisors and canines. The differences in caries prevalence
between these major tooth classes were significant. Juveniles and adults
presented different patterns of carious attack on tooth surfaces, occlusal
surfaces being most frequently affected in juveniles, and approximal surfaces in
adults. The overall caries prevalence in the mediaeval population of Whithorn was
6.4% of the teeth present, a figure similar to those published for other Scottish
mediaeval groups, but lower than the caries prevalence in an English mediaeval
group.
PMID- 9403115
TI - Nitric oxide synthase activities in mammalian parotid and submandibular salivary
glands.
AB - Nitric oxide is important as a physiological messenger molecule in various organs
and cells. It is synthesized from the amino acid L-arginine by nitric oxide
synthase. Here, the specific activities of nitric oxide synthase in the cytosolic
fractions of rabbit, bovine, mice, rat, and guinea-pig parotid and submandibular
glands were compared. Marked specific activities were detected in the rabbit and
bovine parotid and submandibular glands and in the parotid of mice. The activity
in rabbit parotid was highest and was similar to that in rabbit brain. The
significant activities in the salivary glands were completely blocked in the
absence of Ca2+ or the presence of a calmodulin inhibitor. These findings suggest
that the rabbit parotid glands are useful for studying the regulation of nitric
oxide generation by Ca2+/calmodulin-dependent nitric oxide synthase in salivary
glands.
PMID- 9403116
TI - Spatiotemporal expression of the homeobox gene S8 during mouse tooth development.
AB - The murine S8 gene encodes a nuclear homeodomain containing transcription factor
that is expressed at sites of epithelial-mesenchymal interactions, including
those in cranofacial tissues. The spatiotemporal expression of S8 mRNA was
examined in tooth primordia by in situ hybridization. S8 transcripts were found
in all stages of tooth development in 13- to 16.5-day-old mouse embryos (E13
E16.5), covering the early bud stage up to the late bell stage. S8 mRNA was found
exclusively in the ectomesenchyme and its derivatives that originate from the
neural crest: future pulp cells, odontoblast precursors and dental follicle
cells. Expression was highest at the late cap and early bud stages and declined
at the mid-bell stage, in both first molar and incisor primordia. In E13 jaw
explants grown in organ culture for 48 h, S8 mRNA was still present in first and
second molar primordia after culture. At E15.5, S8 mRNA was also transiently
present in the surrounding osteogenic tissue. It is concluded that the
distribution pattern of S8 mRNA during tooth development indicates a role for the
gene in defining the identity of dental papilla and follicle cells. It is
speculated that the time-restricted expression of S8 in tooth primordia involves
establishing the definitive form of the tooth organ.
PMID- 9403117
TI - Comparison of calcium mobilization in response to noradrenaline and acetylcholine
in submandibular cells of newborn and adult rats.
AB - The response of mature and immature rat submandibular cells to alpha-receptor
stimulation was compared in terms of the generation of inositol triphosphate
(IP3) and Ca2+ mobilization, and of how the calcium mobilization response affects
acetycholine (ACh)-induced Ca2+ mobilization. In mature cells, noradrenaline (NA)
caused much smaller IP3 and Ca2+ responses than ACh. However, the Ca2+ release
induced by NA was enough to partially discharge an agonist-sensitive store and to
reduce Ca2+ release by a subsequent ACh stimulus. Exposure to NA also caused an
influx of Ca2+ in the mature cells, which was largely associated with Ca2+ entry
induced by store depletion (i.e. capacitative entry). In the immature
submandibular cells of newborn rats, NA caused essentially no IP3 response and a
small Ca2+ release, which only partially affected the Ca2+ released by a
subsequent exposure to ACh. In contrast to adult cells, immature cells did not
show an increased Ca2+ influx after exposure to NA. However, prestimulation with
this agonist potentiated the Ca2+ influx activated by ACh in the cells of newborn
rats, but not in cells of adult rats. As both mature and immature submandibular
cells have a well-developed phosphoinositide turnover response to ACh, the
findings in mature cells suggest a less efficient coupling between alpha
receptors and phospholipase C, while those in immature cells suggest that this
coupling is even less functional in the early stages of postnatal development. In
permeabilized and 45Ca(2+)-loaded mature cells, cyclic ADP-ribose (cADPR)
released 13.4% of loaded 45Ca2+ and this release was significantly reduced by pre
exposure to IP3. Similarly, pre-exposure to cADPR also reduced the IP3-induced
45Ca2+ release. It is concluded that: (1) stimulation with NA induces a smaller
Ca2+ release in mature and immature submandibular cells than ACh; (2) the
mediator for this small Ca2+ mobilization may be cADPR; and (3) NA stimulates
capacitative Ca2+ entry in mature cells, but not in immature cells, and it also
activates a Ca2+ entry pathway distinct from the one induced by store depletion,
particularly in immature cells.
PMID- 9403118
TI - The influence of dental metal alloys on cell proliferation and fibronectin
arrangement in human fibroblast cultures.
AB - The biocompatibility of six single-phase dental metal alloys was studied by
determining cell proliferation rates correlated to the arrangement of fibronectin
(FN) in fibroblast cultures. Immunocytochemical methods were used to detect cell
proliferation by 5-bromodeoxyuridine (BrdU) incorporation, and FN organization
[i.e. diffuse in the extracellular matrix and organized in fibrils or in focal
adhesions (FA)] in human fibroblast cultures. Cell proliferation rates were
related to FN arrangement and in particular a higher percentage of cells in the S
phase was related to a predominance of FA. The greatest difference in behaviour
compared to that of the controls was detected after 120 and 168 hr: at these
times, as well as at previous ones, the alloy with the highest Au content seemed
the most biocompatible among those tested, as it behaved in a very similar way to
the controls. In contrast, fibroblasts exposed to the other five alloys showed
different behaviours from the controls. It is assumed that a correlation exists
between FN organization and the percentage of BrdU-positive cells, and that these
features vary in the presence of different alloys. The observation of FN
arrangement together with cell proliferation rates could be another useful tool
in determining the biocompatibility of dental metal alloys.
PMID- 9403119
TI - Phenotypic characterization of mononuclear inflammatory cells in salivary glands
of bio-breeding rats.
AB - The purpose of this study was to assess whether mononuclear cell abnormalities
exist in salivary glands from autoimmune Bio-Breeding (BB) rats. Frozen sections
of gland tissues were prepared from five diabetes-resistant BB rats (BB-DR), from
five BB rats with diabetes (BB-DP) and from five Wistar rats. A panel of six
monoclonal antibodies was used to identify membrane antigens associated primarily
with monocytes (ED1), mature tissue macrophages (ED2), lymphoid macrophages
(ED3), MHC class II (Ia) antigen (OX6), CD5+ T lymphocytes (OX19), and rat B
lymphocytes (OX33). Normal submandibular, sublingual and parotid glands contained
few ED1-positive cells, usually two or fewer per field. Tissue macrophages
identified by clone ED2 comprised a major mononuclear cell subset in both Wistar
and BB rats. However, the number of ED2-positive mononuclear cells was
significantly depressed in the submandibular and parotid glands from BB-DR and BB
DP animals, being present in quantities 25-50% of those observed in glands from
normal Wistar rats (p < 0.001). In contrast, 25- to 30-fold greater numbers of
ED3-positive macrophages were observed in submandibular glands from BB rats (p <
0.001). MHC class II (Ia) antigen expression also was 4- to 6-fold greater in BB
rat submandibular glands, compared to Wistar rats (p < 0.001). CD5+ T-lymphocytes
were rare or entirely absent in BB sublingual glands (0 to 1 cell per 0.87 mm2
field), compared to 47 cells per field from Wistar sublingual glands. No B
lymphocytes were identified with antibody OX33 in any of the rat strains. These
findings indicate that BB rat salivary glands differ significantly from Wistar
salivary glands. In BB rats there is a rich population of ED3-positive
macrophages and T lymphocytes in submandibular gland, low quantities of T
lymphocytes in sublingual gland, and fewer ED2-positive macrophages in all three
major salivary glands. These differences in mononuclear cell subpopulations may
also influence salivary gland function in mucosal immunity.
PMID- 9403120
TI - Dissolution of powdered human enamel suspended in acid solutions at a high
solid/solution ratio under a 5% CO2 atmosphere at 20 degrees C.
AB - The aim was to examine the nature of enamel dissolution in aqueous suspensions
with a high solid/solution ratio and in a CO2-rich atmosphere. Before
experimentation, a water-saturated mixture of 95% N2-5% CO2 was passed through
the acid solutions for 24 hr. Samples of 2 g of powdered enamel were suspended in
7 ml of either 5 or 10 mmol/l HClO4, with or without 2 parts/10(6) fluoride and
kept gently agitated for 24 hr in the above atmosphere. The same enamel samples
were repeatedly exposed to fresh acid for 26 runs. All experiments were
duplicated. The aqueous phase was analysed after 20 min and 24 hr for calcium,
phosphate, fluoride, chloride, sodium and magnesium. It was found that after 20
min the fluoride was invariably taken up in the enamel and the solution was
supersaturated with respect to hydroxyapatite with pH ranging 6.7-5.6. During the
following 24 hr pH increased further, the supersaturation remained unchanged and
the concentrations of calcium and phosphate in solution decreased. In contrast,
sodium, magnesium and chloride were released from enamel during the entire
period. In the later runs, the supersaturation with respect to hydroxyapatite was
only modest and the decrease of calcium and phosphate concentrations limited, as
were the release of sodium, magnesium and chloride. It is concluded that despite
a CO2-rich atmosphere, calcium, phosphate and carbonate were released from enamel
and quickly established a supersaturation with respect to hydroxyapatite with a
secondary reprecipitation of mineral. It indicates that within the dental caries
lesion in vivo, lesion fluid cannot exist undersaturated with respect to enamel
apatite.
PMID- 9403121
TI - Growth hormone secretion in the elderly: ageing and the somatopause.
AB - The syndrome associated with lack of growth hormone (GH) in adults can be
reversed by treatment with recombinant human GH (rhGH) with apparently beneficial
clinical effects. This syndrome is strikingly similar to the characteristics of
normal older adults which are known as the somatopause. GH secretion and insulin
like growth factor I levels are reduced in healthy older people and it has been
suggested that the somatopause is an age-related GH deficiency state. This review
describes the physiological control of GH secretion in adults and seeks an
explanation for the age-related decline, considering the impact of other factors
such as nutrition and mobility, and particularly whether exercise offers a
physiological approach to changing both the GH decline and the somatopause. The
benefits and side-effects of treatment with rhGH for normal older people or older
patients facing catabolic stresses are reviewed together with alternative
approaches to stimulate GH such as GH-releasing hormone and the new
pharmaceutical GH secretagogues.
PMID- 9403122
TI - Thyroid diseases in the elderly.
AB - The ageing thyroid is associated with a number of morphological and functional
changes, such as decreased serum T3 and mean thyroid-stimulating hormone
concentrations, that are to some extent independent of intercurrent non-thyroidal
illnesses. All thyroid diseases, including clinical and subclinical hypo- and
hyperthyroidism, non-toxic nodular goitre and thyroid cancer, are encountered in
the elderly, but their prevalence and clinical expression differ from those
observed in younger patients. In the elderly, autoimmune hypothyroidism is
particularly prevalent, hyperthyroidism is mainly characterized by cardiovascular
symptoms and is frequently due to toxic nodular goitres, and differentiated
thyroid carcinoma is more aggressive. The interpretation of thyroid function
tests is difficult in old individuals, because of age-associated changes in
thyroid function and frequent alterations secondary to non-thyroidal illnesses
and/or drugs. Treatment of thyroid disease deserves special attention in old
patients because of the increased risk of complications.
PMID- 9403123
TI - Ageing and adrenal cortical function.
AB - Ageing is associated with changes in the secretion of adrenal cortical steroids.
In the elderly, cortisol secretion increases after stimulation, while the
secretion of dehydroepiandrosterone (DHEA) decreases. Each of these hormones
influences the age-related processes of energy metabolism, fat depot
distribution, immune function and neurodegeneration. In animals the effects of
adrenal steroids are dramatic and easily measured. In humans the effects are more
subtle. This review summarizes these actions and emphasizes the differences of
dosages used in various experimental designs. It is concluded that adrenal
hormones may play a significant role in human ageing, but research is hindered
because the molecular pathways of DHEA action are not known.
PMID- 9403124
TI - Declining gonadal function in elderly men.
AB - Ageing in men is accompanied by a progressive decline of gonadal function with,
in particular, a decline of total and free testosterone (T) plasma levels
resulting in a significant proportion of elderly men over age 60 years presenting
with subnormal T levels compared with the levels in young adults. A great
interindividual variation in T levels is observed in elderly men, a variability
explained in part by physiological variables and differences in life style, while
associated acute or chronic diseases may accentuate the age-related decline of T
levels. The progressive decrease of plasma T levels has been shown to result from
both primary testicular changes and altered neuroendocrine regulation of Leydig
cell function. At present, little is known about the clinical relevance of the
relative hypoandrogenism of elderly men and there is an urgent need for more
longitudinal studies, which may clarify a possible role of decreased T levels in
the modulation of the clinical consequences of ageing in men. In view of the lack
of relevant controlled clinical trials having careful assessment of the risks and
benefits of androgen replacement therapy in elderly men, this treatment should be
reserved for selected patients with clinically and biochemically manifest
hypogonadism, after careful screening for contraindications.
PMID- 9403125
TI - Menopause and post-menopause.
AB - From the endocrine point of view, menopause is considered a deficiency state and
oestrogen therapy regarded as restoring the pre-menopausal endocrine milieu.
Oestrogen therapy alleviates acute climacteric symptoms and also reduces the risk
of cardiovascular disease, osteoporosis and Alzheimer's disease. Cardiovascular
protection seems to be the major benefit of oestrogen replacement: it reduces
morbidity and mortality from coronary heart disease by approximately 50%. The
mechanisms are complex and not fully under-stood. In this review we discuss
currently available data on the effects of hormone replacement therapy on serum
lipids and lipoproteins, the vessel wall (endothelium dependent and endothelium
independent), blood flow, cardiac function, blood pressure, haemostasis, insulin
sensitivity and direct anti-atherosclerotic effect as possible mechanisms of
cardioprotection. Oestrogen therapy reduces the rate of post-menopausal bone
loss, increases bone mineral density (BMD) and decreases fracture rate. Recent
evidence suggests that initiation of oestrogen therapy in older women produces
larger increases in BMD which might provide a significant protective effect at
the time when fracture is common. The incidence of Alzheimer's disease is reduced
by 50% in post-menopausal women taking oestrogen replacement. Limited clinical
trials of oestrogen treatment in women with this disease have documented
beneficial effects on cognitive function. The results of epidemiological studies
of the effects of oestrogens on breast cancer risk are conflicting but recent
evidence suggests that the risk is increased in current users after 5 years of
use and among older women. In contrast, increase in the risk of venous
thromboembolism is most significant within the first 12 months of therapy,
strongly suggesting the importance of individual susceptibility.
PMID- 9403126
TI - Ageing and calcium metabolism.
AB - Ageing alters the metabolism of calcium and vitamin D in a number of ways. Intake
of calcium and vitamin D, exposure to sunlight, cutaneous production of vitamin
D3, renal production of 1,25-dihydroxyvitamin D (1,25(OH)2D3), intestinal
absorption of calcium and the ability to adapt to a low calcium diet may all be
reduced in elderly subjects. As a consequence, secondary hyperparathyroidism
often occurs with ageing and can contribute to accelerated bone loss. In fact,
alterations in calcium and vitamin D metabolism may be widespread in the ageing
population and play a central role in the pathogenesis of senile (age-related)
osteoporosis. From a preventive point of view, recent intervention studies have
indicated the need to optimize calcium intake and to maintain serum 25(OH)D3
levels within the normal range in elderly people.
PMID- 9403127
TI - Fluid and electrolyte homeostasis in the elderly: physiological changes of ageing
and clinical consequences.
AB - Characteristic of the normal ageing process are changes in the renal, hormonal
and thirst regulatory systems involved in the control of sodium and water
balance. In the presence of disease or drug use, the ageing changes put the
elderly person at increased risk of either sodium retention or loss and of water
retention or loss. Clinically, these alterations in water and sodium balance are
commonly expressed as either hyponatraemia or hypernatraemia with central nervous
system dysfunction as the symptomatic expression. Thus, the impaired homeostasis
of the many systems affecting fluid balance in the elderly is readily influenced
by many of the disease states and medications which are often present in the
elderly with resultant adverse clinical consequences. Awareness of these age
associated circumstances can allow the physician to anticipate the impact of
illnesses and drugs and to implement a rational approach to therapeutic
intervention and management.
PMID- 9403128
TI - Non-insulin-dependent diabetes mellitus in the elderly.
AB - The prevalence of non-insulin-dependent diabetes mellitus dramatically increases
with age. Older diabetic subjects have an increased frequency of complications
from diabetes compared with their younger counterparts and higher morbidity and
mortality rates compared with age-matched non-diabetic controls. Elderly patients
with diabetes are generally treated following the same approach as in younger
patients: dietary therapy first, followed by oral hypoglycaemic agents and
ultimately insulin. However, several specificities should be pointed out. Changes
associated with ageing may affect the pharmacokinetics and pharmacodynamics of
both sulphonylureas (increasing the risk of severe hypoglycaemia) and biguanides
(increasing the risk of lactic acidosis). The best insulin regimen in old age is
not known, but a twice-daily injection of a pre-mixed insulin preparation is
usually recommended. Goals of therapy must be realistic and not cause disabling
side-effects. The general practitioner plays a crucial role in the care of
elderly diabetic patients, but access to a multidisciplinary specialized team may
be necessary.
PMID- 9403129
TI - Pituitary tumours in the elderly.
AB - Pituitary tumours in the elderly are a neglected topic in the literature of
endocrinology and gerontology. Data from autopsy studies in the elderly show that
the commonest tumours are microadenomas, which are either immunocytochemically
negative or stain for prolactin. Prolactin-secreting pituitary tumours, however,
appear rarely in clinical series of patients in this age group and non
functioning adenomas are the commonest tumour seen, although pituitary metastasis
and craniopharyngiomas also occur. Diagnosis can be difficult, but the commonest
presentation is visual field loss. Hypopituitarism may be diagnosed late and
incidental radiological diagnosis is not uncommon. There are few data which
specifically answer the question, but there is a suggestion that the syndromes
associated with hormonal hypersecretion may be milder in this age group.
Conventional treatment with drugs, surgery and radiotherapy should be decided on
an individual basis as these therapies appear to be well tolerated and beneficial
in selected patients.
PMID- 9403130
TI - Effect of dietary selenium on the response of stressed and unstressed chickens to
Escherichia coli challenge and antigen.
AB - Selenium was added to the feed of White Leghorn type chickens 1 day prior to
challenge with either Escherichia coli or sheep erythrocyte antigen. The
incidence of death or lesions was reduced from 86% to 21% at the optimal dose of
selenium (0.4 mg/kg resulting in feed concentration of 0.45 mg/kg). After the
chickens were stressed by chilling, selenium was ineffective against E. coli.
Dietary additions of selenium between 0.1 and 0.8 mg/kg resulted in an antibody
titer increase from 2.2 to 3.9 to the log2 against sheep erythrocytes (SRBC).
Following chilling, antibody titer response was reduced from 4.9 to 2.4 to the
log2. This titer reduction could be prevented with dietary additions of selenium
between 0.1 and 1.2 mg/kg. The effects of a nitrofuran and selenium were additive
against E. coli challenge infection.
PMID- 9403131
TI - Intranigral iron infusion in the rat. Acute elevations in nigral lipid
peroxidation and striatal dopaminergic markers with ensuing nigral degeneration.
AB - Iron is known to induce lipid peroxidation and recent evidence indicates that
both iron and lipid peroxidation are elevated in the substantia nigra in
Parkinson's disease (PD). To test whether excess intranigral iron induces lipid
peroxidation, we infused an iron citrate solution (0.63 nmol in 0.25 microL) into
the rat substantia nigra and measured nigral thiobarbituric acid reactive
products at 1-h, 1-d, 1-wk, and 1-mo postinfusion. In a separate group of iron
infused animals, histologic analysis within the substantia nigra through 1-mo
postinfusion was accomplished by thionine- and iron-staining, with concurrent
assessment of striatal neurochemical markers. Concentrations of nigral
thiobarbituric acid reactive products were significantly elevated at 1 h and 1 d
in iron-infused animals compared to vehicle-infused and unoperated animals, with
a return to control values by 1 wk. Similarly, striatal dopamine turnover was
acutely elevated, suggesting damage to dopaminergic neurons, which was confirmed
histologically. Although iron-staining within the iron diffusionary area was
increased through the postinfusion month, there was an apparent progression of
the cellular character of staining from predominantly neuronal to reactive glial
and finally to oligodendroglial by 1 mo postinfusion. This progression of
cellular iron-staining may indicate a shifting of infused iron to a more bound
unreactive form, thus explaining only an acute elevation in lipid peroxidation
through 1 d following intranigral iron infusion. The data indicate that damage to
nigral neurons induced by iron infusion is transciently associated with a marker
of oxidative damage and supports the possibility that iron-induced oxidative
stress contributes to the pathogenesis of PD.
PMID- 9403132
TI - Changes in certain hematological and physiological variables following single
gallium arsenide exposure in rats.
AB - Gallium arsenide (GaAs), a group III-VA intermetallic semiconductor, possesses
superior electronic and optical properties and has a wide application in
electronic industry. Exposure to GaAs in the semiconductor industries could be a
possible occupational risk. The aim of the present study was to determine the
dose-dependent effect of single oral exposure to GaAs (500, 1000, or 2000 mg/kg)
on some biochemical variables in heme synthesis pathway and few selected
physiological variables at d 1, 7, and 15 following administration. The results
indicate that GaAs produced a significant effect on the activity of delta
aminolevulinic acid dehydratase (ALAD) in blood and heart (particularly at d 7)
following exposure to 2000 mg/kg, whereas urinary delta-aminolevulinic acid (ALA)
excretion was elevated only at d 7. No marked influence of GaAs on blood
hemoglobin, zinc protoporphyrin, and packed cell volume was noticed. Blood
glutathione (GSH) was significantly reduced at d 7, but remained unchanged at two
other time intervals. On the other hand, heart GSH contents remained uninfluenced
on GaAs exposure. Most of the physiological variables, viz. blood pressure, heart
and respiration rate, and twitch response, remained unchanged, except for some
minor alterations observed at d 7 and 15 following exposure to GaAs at a dose of
2000 mg/kg. Blood gallium concentration was not detectable in normal animals and
rats exposed to 500 mg/kg GaAs. Blood arsenic concentration was, however,
detectable even at the a lower dose level and increased in a dose-dependent
manner. All these changes showed a recovery pattern at d 21, indicating that the
alterations are reversible.
PMID- 9403133
TI - Trace element status of hemodialyzed patients.
AB - The trace elements Ba, Bi, Cd, Co, Cs, Cu, Hg, La, Mn, Mo, Pb, Rb, Sb, Sn, Sr,
Tl, and Zn were determined by inductively coupled plasma mass spectrometry in
plasma samples of 68 hemodialysis patients. The same elements (with exception of
La and Mn) were also determined in whole blood after mineralization with high
purity nitric acid/hydrogen peroxide in a closed-pressurized microwave system.
The accuracy and precision was checked by analyzing two Seronorm "whole blood"
reference materials. All samples were contaminated with barium (heparinized
tubes) and the plasma samples with tin (collection tubes). The concentrations for
Bi, Hg, Pb, Rb, Sb, and Sr in whole blood were within the literature ranges for
healthy adults. All of the concentrations for Co, and some of the concentrations
for Cd, Cs, Tl, and Zn were higher than the high limits of the normal ranges.
Approximately 14% of the Cu concentrations were lower than the low limit of the
normal range. The Mo and Sn concentrations are difficult to evaluate, because the
normal ranges appears to be unreliable. All concentrations for Cd, Co, Mo, Pb,
Sn, and Sr and some of the concentrations for Cu (15%) and Mn (75%) in the plasma
samples were higher than the high limits of the normal ranges. The concentrations
for Rb tended to be lower than the normal range. To establish unequivocally the
causes for elevated and reduced concentrations of trace elements in whole blood
and plasma of dialysis patients, all fluids in the dialysis process must be
investigated.
PMID- 9403134
TI - PIGE-PIXE analysis of medicinal plants and vegetables of pharmacological
importance.
AB - PIGE and PIXE techniques were employed to the study of elemental constituents of
some traditional medicinal plants generally used in curing many diseases and
ailments in southwestern Nigeria. Analyses were also carried out on commonly
edible vegetables of medicinal and pharmacological importance. PIGE measurements
were carried out using 3.5-MeV collimated protons from the 7 mV CN Van-de-Graaff
accelerator of INFN, LNL, Legnaro (Padova), Italy, whereas the PIXE measurements
were carried out using 1.8 MeV from the 2.5 MV AN 2000 Van-de-Graaff accelerator
of the same laboratory. The results show that many of the medicinal plants
contain elements of cardinal importance in human metabolism. The results from the
vegetables also show the presence of vital elements that are needed for growth
and development. In addition, some of the toxic elements, which include As, Cd,
Hg, and so forth, were not detected. However, some of the recipes contain trace
amounts of Pb at very low concentrations. This calls for proper control of dose
rates in some samples to prevent the attendant negative cumulative effects.
PMID- 9403135
TI - Dietary selenium- and vitamin E-induced alterations in some rabbit tissues.
AB - The present study was designed to investigate and compare the effects of dietary
selenium (Se) and vitamin E on some physiological parameters and histological
changes in liver, heart, and skin tissues, as well as the blood parameters and
the related enzymes. Both sex young rabbits were fed with deficient (9.8
micrograms/kg diet), adequate (225 micrograms/kg diet), and rich (4.2 mg/kg diet)
Se and vitamin E diets for 12-15 wk for this purpose. As the plasma Se levels and
the erythrocyte glutathione (GSH) peroxidase activity decreased (79.8 +/- 9.4
ng/mL and 2.0 +/- 0.3 U/g Hb, respectively) in the deficient group, these values
increased (100.4 +/- 2.7 ng/mL and 14.5 +/- 4.3 U/g Hb) in the rich group
significantly with respect to the control group. The other antioxidant enzyme
activities and the related element levels did not change significantly in either
one of the experimental groups. Although the platelet counts of the two
experimental groups were not different from the control values, the collagen and
the adenosine diphosphate (ADP) stimulated platelet aggregation rate and
intensity increased in the deficient group (p < 0.05) and decreased very
significantly (p < 0.001) in the rich group. In both of the experimental groups,
as the percentage values of the neutrophils decreased, the lymphocytes and the
eosinophils increased significantly. According to the light microscopic
investigations, the observed lesions of considerable intensity within the tissues
that elicit cell degenerations were more pronounced in the animals fed with the
rich diet than in those fed with the deficient diet. The deficiency as well as
toxicity of Se and the deficiency of vitamin E caused several alterations in the
physiological functions of the tissues, and these alterations were supported by
the histological lesions within these tissues.
PMID- 9403136
TI - Bioavailability of rumen bacterial selenium in mice using tissue uptake
technique.
AB - A tissue uptake experiment was conducted to determine the bioavailability of
rumen bacterial Selenium (Se) in mice. The donor animal was wether fed a diet
containing 0.2 mg Se/kg dietary dry matter (DM). Ruminal fluid was collected 2 h
postprandially. Bacterial-rich precipitate was obtained by differential
centrifugation of the ruminal fluids. This was later freeze-dried and mixed in
the diet to be used in feeding the mice experiment. Thirty growing female mice
with a body wt (mean +/- SD) of 21.4 +/- 0.74 g were housed in plastic cages (5
mice/cage) and allotted equally to three dietary treatments. Diet 1 and Diet 2
were formulated based on AIN-76, except that no Se supplementation in the form of
selenite was made in the former. In Diet 3, rumen bacterial matter was 20% of the
diet, which gave an equivalent of 0.1 mg Se/kg dietary DM. The other two diets,
Diet 1 and Diet 2, had an Se content of 0.025 and 0.1 mg/kg dietary DM,
respectively. A 7-d feeding commenced after 7 d of acclimatization of the
semipurified diet. Results showed that those mice fed an Se- (selenite)
supplemented diet (Diet 2) had higher (P < 0.05) tissue Se concentrations than
those mice fed the other two diets. No statistical differences were observed on
various tissue Se concentrations between Diet 1 and Diet 3, although the latter
diet had higher values. Kidney and liver had the highest Se concentrations
compared to the other tissues. This study concludes that bacterial Se collected
from the rumen of wether is not fully available for absorption in the intestine
of the mice.
PMID- 9403137
TI - Topology of ligand binding sites on the nicotinic acetylcholine receptor.
AB - The nicotinic acetylcholine receptor (AChR) presents two very well differentiated
domains for ligand binding that account for different cholinergic properties. In
the hydrophilic extracellular region of both alpha subunits there exist the
binding sites for agonists such as the neurotransmitter acetylcholine (ACh) and
for competitive antagonists such as d-tubocurarine. Agonists trigger the channel
opening upon binding while competitive antagonists compete for the former ones
and inhibit its pharmacological action. Identification of all residues involved
in recognition and binding of agonist and competitive antagonists is a primary
objective in order to understand which structural components are related to the
physiological function of the AChR. The picture for the localisation of the
agonist/competitive antagonist binding sites is now clearer in the light of newer
and better experimental evidence. These sites are mainly located on both alpha
subunits in a pocket approximately 30-35 A above the surface membrane. Since both
alpha subunits are sequentially identical, the observed high and low affinity for
agonists on the receptor is conditioned by the interaction of the alpha subunit
with the delta or the gamma chain, respectively. This relationship is opposite
for curare-related drugs. This molecular interaction takes place probably at the
interface formed by the different subunits. The principal component for the
agonist/competitive antagonist binding sites involves several aromatic residues,
in addition to the cysteine pair at 192-193, in three loops-forming binding
domains (loops A-C). Other residues such as the negatively changed aspartates and
glutamates (loop D), Thr or Tyr (loop E), and Trp (loop F) from non-alpha
subunits were also found to form the complementary component of the
agonist/competitive antagonist binding sites. Neurotoxins such as alpha-, kappa
bungarotoxin and several alpha-conotoxins seem to partially overlap with the
agonist/competitive antagonist binding sites at multiple point of contacts. The
alpha subunits also carry the binding site for certain acetylcholinesterase
inhibitors such as eserine and for the neurotransmitter 5-hydroxytryptamine which
activate the receptor without interacting with the classical agonist binding
sites. The link between specific subunits by means of the binding of ACh
molecules might play a pivotal role in the relative shift among receptor
subunits. This conformational change would allow for the opening of the intrinsic
receptor cation channel transducting the external chemical signal elicited by the
agonist into membrane depolarisation. The ion flux activity can be inhibited by
non-competitive inhibitors (NCIs). For this kind of drugs, a population of low
affinity binding sites has been found at the lipid-protein interface of the AChR.
In addition, several high-affinity binding sites have been found to be located at
different rings on the M2 transmembrane domain, namely luminal binding sites. In
this regard, the serine ring is the locus for exogenous NCIs such as
chlorpromazine, triphenylmethylphosphonium, the local anaesthetic QX-222,
phencyclidine, and trifluoromethyliodophenyldiazirine.
Trifluoromethyliodophenyldiazirine also binds to the valine ring, which is the
postulated site for cembranoids. Additionally, the local anaesthetic meproadifen
binding site seems to be located at the outer or extracellular ring.
Interestingly, the M2 domain is also the locus for endogenous NCIs such as the
neuropeptide substance P and the neurotransmitter 5-hydroxytryptamine. In
contrast with this fact, experimental evidence supports the hypothesis for the
existence of other NCI high-affinity binding sites located not at the channel
lumen but at non-luminal binding domains. (ABSTRACT TRUNCATED)
PMID- 9403138
TI - A circuitry model of the expression of behavioral sensitization to amphetamine
like psychostimulants.
AB - Repeated exposure to psychostimulants such as cocaine and amphetamine produces
behavioral sensitization, which is characterized by an augmented locomotor
response to a subsequent psychostimulant challenge injection. Experimentation
focused on the neural underpinnings of behavioral sensitization has progressed
from a singular focus on dopamine transmission in the nucleus accumbens and
striatum to the study of cellular and molecular mechanisms that occur throughout
the neural circuitry in which the mesocorticolimbic dopamine projections are
embedded. This research effort has yielded a conglomerate of data that has
resisted simple interpretations, primarily because no single neuronal effect is
likely to be responsible for the expression of behavioral sensitization. The
present review examines the literature and critically evaluates the extent to
which the neural consequences of repeated psychostimulant administration are
associated with the expression of behavioral sensitization. The neural
alterations found to contribute to the long-term expression of behavioral
sensitization are centered in a collection of interconnected limbic nuclei, which
are termed the 'motive' circuit. This neural circuit is used as a template to
organize the relevant biochemical and molecular findings into a model of the
expression of behavioral sensitization.
PMID- 9403139
TI - Cerebral cortex pathology in aging and Alzheimer's disease: a quantitative survey
of large hospital-based geriatric and psychiatric cohorts.
AB - In order to explore the relationships between the involvement of specific
neuronal populations and cognitive deterioration, and to compare the hierarchical
patterns of cortical involvement in normal brain aging and Alzheimer's disease,
over 1200 brains from elderly subjects without cognitive deficits, as well as
from patients with age-associated memory impairment and Alzheimer's disease, were
examined. Our results suggest that the neuropathological changes associated with
normal brain aging and Alzheimer's disease affect select cortical circuits at
different points in time. Extensive hippocampal alterations are correlated with
age-associated memory impairment, whereas substantial neurofibrillary tangle
formation in neocortical association areas of the temporal lobe is a prerequisite
for the development of Alzheimer's disease. Despite several lines of evidence
involving amyloid deposit in the pathogenesis of Alzheimer's disease and Down's
syndrome, our observations indicate that there is no correlation between senile
plaque densities and degree of dementia in both disorders. In contrast to younger
elderly cases, in the ninth and tenth decades of life, there is a differential
cortical involvement in that parietal and cingulate areas are early affected in
the course of Alzheimer's disease, and neocortical senile plaques densities are
strongly correlated with the severity of dementia. Moreover, Alzheimer's disease
symptomatology is characterized in these very old patients by high
neurofibrillary tangle densities in the anterior CA1 field, but not in the
entorhinal cortex and inferior temporal cortex. These observations are discussed
in the light of the hypothesis of global corticocortical disconnection and with
respect to the notion of selective neuronal vulnerability in Alzheimer's disease.
PMID- 9403140
TI - Low-threshold Na+ currents: a new family of receptor-operated inward currents in
mammalian nerve cells.
AB - In the mammalian nervous system, various neurotransmitters can modulate cell
excitability by inducing slow membrane potential changes. In the last decade,
inhibition of potassium currents has been characterized as the primary mechanism
by which neurones can undergo sustained depolarization. More recently (1990s), a
new class of inward currents, which are voltage-dependent and mainly carried by
sodium ions, has been found to be activated by various neurotransmitter receptors
in mammalian central and peripheral neurones. Because the channels involved pass
depolarizing current, are open at more negative membrane potentials than the
resting potential, and are voltage-gated and persistent, these currents are
capable of producing regenerative and maintained depolarizations and play an
important role in neuronal signalling.
PMID- 9403141
TI - Submissive behaviour and psychopathology.
AB - OBJECTIVES: A variety of behaviours have been identified as submissive (Buss &
Craik, 1986). These are believed to be associated with vulnerability to
psychopathology. This paper explores the construct and measurement of submissive
behaviours and their association with psychopathology. DESIGN: Two self-report
scales were designed to measure the frequencies of (a) typical submissive
behaviours (SBS) and (b) passive/withdrawal and affiliative strategies focused on
conflict de-escalation (CDS). The association of these scales with
psychopathology was explored in a series of questionnaire studies. METHODS: Study
1 assessed the SBS using a student sample (N = 332) and a mixed clinical group (N
= 136). Of these, 177 students and 66 patients also completed the SCL-90-R. In
Studies 2 and 3, the CDS and its association with depressive symptoms were
assessed using a student sample (N = 154) and a depressed patient group (N = 60).
RESULTS: The SBS and CDS appeared reliable. There was a positive relationship
between the SBS and the SCL-90-R, including interpersonal sensitivity and
unexpressed hostility. The passive/withdrawal subscale of the CDS was associated
with depressive symptoms. Evidence was obtained for sex differences with the
affiliative subscale. CONCLUSIONS: Some forms of submissive behaviour, especially
those associated with passive/withdrawal and inhibition, are associated with a
wide range of psychological problems.
PMID- 9403142
TI - Selective processing of concern-related information in depression.
AB - OBJECTIVES: The major question examined in this paper is whether selective
attentional and interpretative processing of emotional information occurs in
depression, and if so, whether it depends on a close match between the material
used and current concerns. DESIGN: Twenty-four depressed patients and the same
number of matched controls were tested using two selective processing tasks
(described below), and their performance related to self-reported sociotropic and
autonomy-related concerns. METHODS: Colour-naming interference and interpretation
of ambiguous situations were assessed using material judged relevant to each of
the Sociotropy-autonomy Scales. RESULTS: Depression was associated with a general
interference effect for all negative concern words, and more negative
interpretations of ambiguous situations, while controls showed a converse bias in
favour of all positive interpretations. There was no convincing evidence that
this negative processing bias was proportional to the match between material and
self-reported sociotropic or autonomous concerns. CONCLUSIONS: Depressed patients
showed evidence of cognitive biases favouring all negative self-related
information, on both attentional and interpretative tasks. We suggest that such
effects in depression may occur only under conditions allowing the elaborative
processing of negative material related to oneself.
PMID- 9403143
TI - Attributions and accessibility of explanations for future events in anxiety and
depression.
AB - OBJECTIVES: The research examined qualitative and quantitative aspects of future
thinking in mood-disturbed participants. DESIGN: A cross-sectional, mixed design
compared three groups of participants on measures of future thinking using an
adapted fluency paradigm. METHODS: Participants who were either anxious (N = 25),
anxious and depressed (mixed; N = 25), or neither anxious nor depressed (control;
N = 25) were presented with a range of future positive and negative events and
asked to provide explanations as to why those events would (pro reasons) or would
not (con reasons) happen to them. Number of reasons given of each type was
measured. The reasons were further analysed in terms of a number of attributional
dimensions. RESULTS: Mood-disturbed participants (anxious and mixed) provided
more pro relative to con reasons for negative events and more con relative to pro
reasons for positive events. Compared to the control group, mood-disturbed
participants also provided more internal and more global reasons for why negative
events would happen and for why positive events would not happen. CONCLUSION:
Mood-disturbed participants differ from controls on qualitative as well as
quantitative aspects of future thinking.
PMID- 9403144
TI - Interpersonal responses to threats to status and interpersonal relatedness:
effects of dependency and self-criticism.
AB - OBJECTIVES: Previous research investigating the interpersonal environments of
dependent and self-critical individuals has focused primarily on attachment
issues, such as relationship satisfaction. DESIGN: In the present study, we
examined how dependent and self-critical individuals respond to experimentally
manipulated events that threaten or bolster self-worth and status. METHOD: Forty
pairs of female college students were allowed to believe, first, that they
outperformed a close friend or were outperformed by a close friend on 14 trials
of a behaviour detection task and, second, that friends generally agreed or
disagreed with them on a second 14 trials, in which participants informed friends
who had the better response. RESULTS: Dependent women were more concerned with
maintaining interpersonal relatedness, whereas self-critical women were more
concerned with preserving self-worth and status. Dependent women adopted the
responses of friends they outperformed, praised friends even when friends
disagreed, and minimized disagreement with disagreeing friends. In contrast, self
critical individuals contested threats to status and self-worth, withheld praise
from friends who challenged them, and did not minimize disagreement with
disagreeing friends. CONCLUSIONS: Results support the utility of an interactional
framework in which depressive personality styles, such as dependency and self
criticism, and situational events interact to regulate interpersonal behaviour.
PMID- 9403145
TI - Automaticity of cognitive biases in addictive behaviours: further evidence with
gamblers.
AB - OBJECTIVES: The hypotheses that automatic, non-volitional, attentional and memory
biases for addiction-related constructs exist is tested with compulsive gamblers.
DESIGN: An independent groups design was employed. Processing of gambling,
compared to neutral and drug-related information was examined in 15 gamblers
recruited from new members of Gamblers Anonymous. Comparisons were made with the
performance of their spouses (N = 15) to help distinguish addiction mechanisms
from more non-specific emotional experiences with gambling, and an independent
control group (N = 15), recruited from the staff and students of a university
department. METHODS: A modified Stroop procedure was first employed. Automative
cognitive interference was assessed relatively, by comparing colour-naming times
on the gambling, drug and neutral Stroops. A subsequent word-stem completion task
of implicit memory was then used to assess selective and automatic priming of the
gambling constructs in memory. RESULTS: Only the gamblers showed selective and
automatic interference for gambling-related constructs on the Stroop task.
Spouses behaved like the control group on this task. An implicit memory bias for
gambling-related words was statistically detected only in the gamblers compared
to the control group, although the trend was similar in the comparison with
spouses. Further evidence for the specificity of these effects was obtained in
subgroup comparisons involving fruit-machine with racing gamblers. CONCLUSIONS:
Results are generally consistent with an automaticity in the cognitive biases
gamblers show for gambling-related information. Implications for cognitive
understanding and treatments are highlighted.
PMID- 9403147
TI - Social reasoning in individuals with persecutory delusions: the effects of
additional information on attributions for the observed behaviour of others.
AB - The extent to which individuals suffering from persecutory delusions, as compared
to matched controls, were prepared to change their attributional judgments
following additional information, was investigated. Participants were required to
decide whether the actor or target individual had caused an action before and
after information, which was either high or low in terms of distinctiveness,
consistency and consensus. There were no differences between the three
participant groups which all made decisions, and changed their decisions, in the
directions predicted by attribution theory.
PMID- 9403146
TI - Relatives' locus of control and expressed emotion in schizophrenia and related
psychoses.
AB - OBJECTIVES: Knowledge of what predicts relatives' expressed emotion (EE) may
contribute to improved family work in schizophrenia. In the present study we
examined locus of control (LOC) beliefs as determinants of EE components. DESIGN:
This study is observational, prospective and partly cross-sectional, partly
longitudinal (stability of LOC). METHODS: In a Norwegian sample of 47 recently
hospitalized patients (schizophrenia or schizophreniform disorder) and 70
relatives, the relatives' EE was assessed by the Camberwell Family Interview and
LOC by Levenson's Internality, Powerful Others and Chance scales. RESULTS:
Confirmatory multiple regression analyses showed that Chance LOC was positively
related to emotional overinvolvement (p < .005). Powerful Others LOC, especially
'wish to ingratiate' items, were positively linked to criticism and, among
workers/lower grade employees only, to emotional overinvolvement. Internal LOC
was not linked to any EE scale. CONCLUSIONS: This study indicates that LOC
beliefs may be determinants of emotional overinvolvement and criticism, and
should be taken into account in family work that aims at modifying relatives' EE.
PMID- 9403148
TI - The effect of self-referent material on the reasoning of people with delusions.
AB - People with delusions have been shown to have both generalized (Huq, Garety &
Hemsley, 1988) and content-specific biases in reasoning (Bentall, 1994). Our
concern here was whether the hastiness that has been found when people with
delusions reason on relatively abstract tasks would be present on a more
realistic task. A second concern was whether reasoning with salient or emotional
material would increase the hastiness bias in people with delusions. Two versions
of a probabilistic reasoning task were used to study the data gathering of people
with delusions. The first version employed realistic but emotionally neutral
material. People with delusions requested less evidence before making a decision
than psychiatric and normal comparison groups. Therefore, the hastiness found
previously with abstract materials was seen to generalize to a more realistic
task. In the second version participants were required to reason with material
that had an emotional content and may have been regarded as being personally
meaningful. In this condition all groups reduced the amount of evidence requested
before making a decision.
PMID- 9403149
TI - A three- to six-year follow-up of former long-stay residents of mental handicap
hospitals in Northern Ireland.
AB - OBJECTIVES: Little is known about the first cohorts of long-stay hospital
residents with learning disabilities who moved to the community. This study
describes the pattern of residential reprovision for all former long-stay
residents discharged from the three mental handicap hospitals in Northern Ireland
between 1987 and 1990 (N = 283) as well as describing aspects of quality of life
for a smaller sample of people. METHOD: The study employs a retrospective survey
design and the method and findings are discussed within a quality of life
framework. Information about destinational outcomes between 1987 and 1993 was
collected for each former resident. Several instruments were also used to assess
material, emotional and social well-being and development and activity for a 40
per cent sample of people (114/283) discharged from hospital during 1987-1990 and
followed up in 1993. RESULTS: Approximately 70 per cent of residents were
discharged to, and subsequently remained in, highly supported settings such as
residential and nursing homes. Only 3 per cent were discharged to 'independent
living' with their own families or foster families. Few of the sample had 'major'
problems with daily living skills and serious behavioural problems were uncommon.
Former patients were also more satisfied with their new homes and reported
feeling happier, healthier and more independent since discharge. However, social
networks were poor and there was no evidence to suggest that people were
undertaking new or 'ordinary' daytime activities. CONCLUSION: Although the
material needs of former hospital residents (many of whom may have been 'cream
skimmed' from the long-stay population) appeared to be met and they were content
with their new homes in the community, they had a limited choice of mainly
private sector accommodation and few opportunities for personal and social
development.
PMID- 9403150
TI - WAIS-R short forms: assessing the statistical significance of subtest
differences.
AB - OBJECTIVES: To assist with analysis, in the individual case, of subtest profiles
obtained from WAIS-R short-form administrations. Secondly, to offer a method of
profile analysis for a full-length WAIS-R which is appropriate for use with age
graded scaled scores. DESIGN: The study used a psychometric method for profile
analysis (Silverstein, 1982a) which deals more effectively than alternative
approaches with the problems raised by conducting multiple comparisons. METHODS:
A formula to compute the standard error of the difference between a subtest and
mean subtest scores was applied to nine short forms and the full-length WAIS-R.
The data used were derived from the WAIS-R standardization sample. RESULTS:
Tables for examining whether there are significant subtest differences in a
clients WAIS-R profile are presented. CONCLUSIONS: An elegant method of analysing
subtest profiles has been extended to permit its use with WAIS-R short forms.
Guidance on the use of the tables is offered; the distinction between reliable
and abnormal differences is highlighted.
PMID- 9403151
TI - Assessing the reliability and abnormality of subtest differences on the Test of
Everyday Attention.
AB - OBJECTIVES: To assist clinicians with the analysis of an individual's profile of
subtest strength and weaknesses on the Test of Everyday Attention (TEA). DESIGN:
The study applied psychometric methods for the quantitive analysis of subtest
profiles (Silverstein, 1982, 1984a, b). METHODS: Formulae to compute the standard
error of the difference and standard deviation of the difference between a
subtest and a client's mean subtest scores were applied to determine critical
values for reliable and abnormal differences. The data used were derived from the
TEA standardization sample (N = 154). RESULTS: Tables for examining whether an
individual's TEA subtest profile contains reliable and abnormal subtest
discrepancies are presented. CONCLUSIONS: Elegant methods of analysing a subtest
profile were extended for use with the Test of Everyday Attention. In keeping
with the rationale underlying the measurement of neuropsychological deficit
(Lezak, 1995), these methods complement the existing TEA normative comparison
standards by providing individual comparison standards for a client's
performance. Guidance on the use of the tables is offered; the distinction
between reliable and abnormal differences is highlighted.
PMID- 9403152
TI - Short NART, CCRT and Spot-the-Word: comparisons in older and demented persons.
AB - This study compares the efficacy of three measures of premorbid intelligence: the
National Adult Reading Test (NART), the Cambridge Contextual Reading Test (CCRT),
and the Spot-the-Word Test. The results in a population sample of elderly and
demented participants show that test efficacy varies between groups. In a
demented group and a normal group of average readers, the CCRT leads to a higher
estimate of premorbid word reading ability than the NART. Spot-the-Word results
in good performance by normal groups and participants with minimal dementia, but
performance is grossly impaired in subjects with mild/moderate dementia. We
conclude that each test may be appropriate for specific groups.
PMID- 9403153
TI - An evaluation of the Cambridge Contextual Reading Test (CCRT) in Alzheimer's
disease.
AB - Thirty patients with a diagnosis of probable Alzheimer's disease were assessed
using the traditional National Adult Reading Test (NART) and also by placing the
NART stimulus words in context (meaningful sentences)--the Cambridge Contextual
Reading Test (CCRT) condition. Placing the stimulus words in sentences acted to
significantly reduce overall pronunciation error rates. This beneficial effect
was most marked for more severely cognitively impaired patients. NART performance
was significantly correlated with Mini-Mental State total score; however, CCRT
performance was not. Placing the stimulus words in context acted to improve the
performance of more cognitively impaired Alzheimer patients and thus provides a
more valid estimate of premorbid ability compared with the standard presentation
of NART stimulus words in isolation.
PMID- 9403154
TI - The discriminant validity of the Eating Disorder Inventory--2.
AB - The scores of 78 bulimia nervosa (BN) patients and 67 general psychiatric
outpatients on the Revised Eating Disorder Inventory (EDI-2) were compared in a
multivariate discriminant analysis. The bulimia scale was found to correctly
classify 97 per cent of all cases. Of the EDI-2 scales thought to be not directly
related to food and weight, only interoceptive awareness (IA) and asceticism (AS)
showed discriminative validity. Three eating-related items were found to account
for the discriminative value of the IA scale, and the new AS scale was found to
be a discriminative extension of the EDI.
PMID- 9403156
TI - Schizotypal traits and dimensions of religiosity.
AB - In the present study the association between religiosity and schizotypal traits
was investigated. Two hundred and one respondents completed self-report measures
of schizotypal traits as well as measures of religiosity developed, on the basis
of theoretical work on the nature of delusional thinking, to tap the dimensions
of preoccupation, guidance, conviction, and emotional involvement. For women, no
associations were found between scores on the religiosity and schizotypy scales.
For men, however, higher scores on religious preoccupation were associated with
higher scores on magical ideation. It would seem that religiosity is not clearly
associated with schizotypal traits.
PMID- 9403155
TI - Processing of facial expressions of emotion and alexithymia.
AB - OBJECTIVE: The primary objective was to examine emotional responsiveness in
alexithymia. DESIGN: A quasi-experimental design was followed with the
alexithymia variable being manipulated by subject stratification based on Toronto
Alexithymia Scale-20-H. METHOD: Alexithymics (N = 12) and non-alexithymics (N =
12) were asked to match, label and verbally describe photographs displaying
facial emotions along with TAT card II. RESULTS: Alexithymics did not differ from
non-alexithymics in emotional matching and labelling tasks but had significant
difficulty in verbally describing emotional expressions as evident by less
duration of utterance, greater response latency and increased linguistic-type
speech disruptions. Speech disruptions did not produce a group difference for TAT
card II. CONCLUSION: Such difficulty in alexithymics may be associated with their
inability to use emotional words in the appropriate context.
PMID- 9403157
TI - Video games and clinical practice: issues, uses and treatments.
PMID- 9403158
TI - Psychology and risk assessment.
PMID- 9403159
TI - Cellular electrophysiologic mechanisms of cardiac arrhythmias.
AB - Cardiac arrhythmias are caused by alterations in the electrophysiologic
properties of the cardiac cells, which affect the characteristics of the
transmembrane potentials. The electrophysiologic properties that cause
arrhythmias are automaticity, triggered activity, and reentrant excitation. Each
of these mechanisms is described in terms of the characteristics of the
transmembrane potentials and how these influence the appearance of the arrhythmia
on the electrocardiogram.
PMID- 9403161
TI - Electrophysiologic evaluation of supraventricular tachycardia.
PMID- 9403160
TI - Role of the surface electrocardiogram in the diagnosis of patients with
supraventricular tachycardia.
AB - In this era of interventional electrophysiology, the accuracy of the
electrocardiogram in diagnosis of supraventricular tachycardia could be improved
by detailed endocardial mapping and confirmed by results of radiofrequency
catheter ablation. This article describes the electrocardiographic
characteristics for different types of supraventricular tachycardia: atrial
fibrillation, atrial flutter, atrial tachycardia, atrioventricular reciprocating
tachycardia using an accessory pathway, and atrioventricular node reentrant
tachycardia. Several limitations, including the identification of P wave
morphologies and polarities and separation between the terminal part of T wave
and P wave during tachycardia, should be resolved before an accurate algorithm of
the 12-lead surface electrocardiogram is developed for the diagnosis of
supraventricular tachycardia.
PMID- 9403162
TI - Current role of pharmacologic therapy for patients with paroxysmal
supraventricular tachycardia.
AB - Intravenous antiarrhythmic drugs will continue to have an important role in the
acute management of SVT. Long-term antiarrhythmic drug therapy is often effective
in preventing or reducing frequency and severity of arrhythmic episodes. The
cost, adverse effects, and inconvenience of long-term drug therapy will result in
the increasing use of curative ablation for most individuals with problematic
SVT.
PMID- 9403163
TI - Inappropriate sinus tachycardia. Diagnosis and treatment.
AB - Inappropriate sinus tachycardia is characterized by consistently elevated heart
rates and exaggerated responses to minimal physiologic activity. The syndrome of
inappropriate sinus tachycardia is defined by the clinical presentation of
palpitations and presyncope that commonly appear to be out of proportion to the
severity of the tachycardia. The development of a potentially curative procedure
for patients suffering from inappropriate sinus tachycardia has renewed interest
in the treatment of such patients. Continued research directed at the
pathophysiology of inappropriate sinus tachycardia and what the optimal end point
for achieving adequate rate control by radiofrequency catheter ablation without
the need for the implantation of a permanent pacemaker is required. The optimal
treatment may be the use of drugs that specifically inhibit sinus node pacemaker
current.
PMID- 9403164
TI - Catheter ablation for patients with atrial tachycardia.
AB - Although atrial tachycardias are relatively rare, their poor response to standard
therapies, the suboptimal hemodynamic results of complete atrioventricular node
ablation and pacer implantation, and their potential for serious hemodynamic
effects make management difficult. Although their mechanisms are complex and
divergent, catheter ablation has proven to be highly effective in management of
atrial tachycardias. This article discusses arrhythmia mechanisms and therapeutic
approaches by catheter ablation.
PMID- 9403165
TI - Catheter ablation for atrioventricular nodal reentrant tachycardia.
AB - The current status of catheter ablation techniques for the management of
atrioventricular nodal reentry tachycardia is outlined in this article. Some
pertinent aspects of the atrioventricular nodal anatomy and physiology are
discussed, to the extent that they are essential for understanding of the
mechanism of this arrhythmia and the technique of catheter ablation.
PMID- 9403166
TI - Catheter ablation of accessory pathways.
AB - Radiofrequency catheter ablation is a highly effective, curative treatment for
arrhythmias related to accessory atrioventricular connections. Compared with
medical therapy, ablation is more definitive, is more cost-effective, and is
associated with a lower risk of proarrhythmia. This article updates the reader on
the current indications, techniques, and innovations related to ablation of
accessory pathways using radiofrequency energy.
PMID- 9403167
TI - Mechanisms and medical management of patients with atrial flutter.
AB - Type I atrial flutter is due to reentrant excitation, principally in the right
atrium. The standard ECG remains the cornerstone for its clinical diagnosis.
Acute treatment should be directed at control of the ventricular response rate
and, if possible, restoration of sinus rhythm. Radiofrequency catheter ablation
therapy provides the best hope of cure, although atrial fibrillation may
subsequently occur after an ostensibly successful ablative procedure.
Alternatively, antiarrhythmic drug therapy to suppress recurrent atrial flutter
episodes may be useful, recognizing that occasional recurrences are common
despite therapy. Radiofrequency ablation of the His bundle ablation with
placement of an appropriate pacemaker system may be useful in selected patients.
PMID- 9403168
TI - The laboratory evaluation and role of catheter ablation for patients with atrial
flutter.
AB - The anatomic substrate for atrial flutter has now been recognized, and improved
methods for catheter ablation have been developed. Using mapping techniques such
as entrainment mapping, recognizing the different types of flutter that can
occur, and testing for conduction block with pacing after ablation, long-term
cure of atrial flutter can be achieved in most patients with catheter ablation.
Not only is catheter ablative cure of atrial flutter the treatment of choice for
drug-refractory patients, but also may now be offered as an alternative to drug
therapy.
PMID- 9403169
TI - The medical management of atrial fibrillation.
AB - Atrial fibrillation is an extremely common arrhythmia that is associated with
significant sequelae. Certain aspects of therapy, such as anticoagulation, are
studied in well-constructed randomized trials. Other therapy, such as the
maintenance of sinus rhythm with antiarrhythmic agents, is supported by limited
evidence. This article reviews the epidemiology and medical treatment of this
arrhythmia, addressing anticoagulation, ventricular rate control, and restoration
and maintenance of sinus rhythm. Randomized trials in progress that attempt to
answer important questions in the management of atrial fibrillation are also
discussed.
PMID- 9403170
TI - Radiofrequency catheter ablation for atrial fibrillation.
AB - Until recently, catheter-based radiofrequency ablation for atrial fibrillation
was limited to palliative approaches of either atrioventricular node ablation or
modification. It is now recognized that at least a proportion of patients with
paroxysmal atrial fibrillation may be suitable for curative ablation of an
underlying single arrhythmogenic focus. With the intense interest in this area, a
catheter-based cure involving endocardial linear lesion creation for patients
with chronic or paroxysmal atrial fibrillation may not be far in the future.
PMID- 9403171
TI - The maze procedure for cure of atrial fibrillation.
AB - Atrial fibrillation is the most common dysrhythmia encountered in clinical
practice. A significant number of patients fail medical therapy because of
inability to convert or control the rhythm pharmacologically, intolerance of the
requisite medication, or persistent symptoms despite apparently satisfactory rate
control. Based on experimental studies establishing the electrophysiologic basis
of atrial fibrillation, a surgical procedure has been developed that is highly
effective in restoring sinus rhythm without further requirement for medications.
The evolution of this procedure, its current indications, and results are
outlined.
PMID- 9403172
TI - Thermodynamics of peroxynitrite and its CO2 adduct.
AB - The equilibrium constant, K3, of aqueous homolysis of peroxynitrous acid into
hydroxyl and nitrogen dioxide free radicals was estimated to be 5 x 10(-10) M.
This value was derived from a thermodynamic cycle by use of the experimentally
known delta fH degree(ONOO-,aq) = -10.8 kcal/mol and the enthalpy of ionic
dissociation of ONOOH(aq), delta H degree 1 = 0 kcal/mol, as well as of the
entropy of gaseous ONOOH, S degree(ONOOH,g) = 72 eu. Furthermore we assumed the
entropy of hydration of ONOOH, delta S degree 2, to be -25 eu, a value closely
bracketed by the hydration entropies of analogous substances. The rate constant
of radical recombination of OH. with NO2. to yield ONOOH, k-3, was resimulated
from experimental data and found to be ca. 5 x 10(9) M-1 s-1. Together with the
estimated K3, this yields the homolysis rate constant k3 = 2.5 s-1. This value is
close to 0.5 s-1, the rate constant of formation of a reactive intermediate
during the isomerization of peroxynitrous acid to nitrate. Our thermodynamic
estimate is therefore consistent with substantial amounts of OH. and NO2. free
radicals being formed in this process. The thermodynamic implications for the
carbon dioxide/peroxynitrite system are also discussed.
PMID- 9403173
TI - Glutathione conjugation of bay- and fjord-region diol epoxides of polycyclic
aromatic hydrocarbons by glutathione transferases M1-1 and P1-1.
AB - Metabolism of polycyclic aromatic hydrocarbons in mammalian cells results in the
formation of vicinal diol epoxides considered as ultimate carcinogens if the
oxirane ring is located in a bay- or fjord-region of the parent compound. In the
present study, individual stereoisomers of the bay-region diol epoxides of
chrysene, dibenz[a,h]anthracene, and benzo[a]pyrene as well as of the fjord
region diol epoxides of benzo[c]phenanthrene, benzo[c]chrysene, and benzo[g]
chrysene have been incubated with GSH in the presence of human glutathione
transferases GSTM1-1 (a mu-class enzyme) and GSTP1-1 (a pi-class enzyme). As
previously shown with GSTA1-1 (an alpha-class enzyme) both M1-1 and P1-1
demonstrate considerable activity toward a number of the diol epoxides studied,
although a great variation in catalytic efficiency and enantioselectivity was
observed. With GSTM1-1, the bay-region diol epoxides, in particular the syn
diastereomers were in most cases more efficiently conjugated with GSH than the
fjord-region analogues. GSTM1-1 demonstrated an enantioselectivity ranging from
no preference (50%) to high preference (> or = 90%) for conjugation of the
enantiomers with R-configuration at the benzylic position of the oxirane ring.
With GSTP1-1, the enzyme demonstrated appreciable activity toward both bay- and
fjord-region diol epoxides and, in most cases, a preference for the anti
diastereomers. In contrast to GSTM1-1 and as previously shown for GSTA1-1, GSTP1
1 showed an exclusive preference for conjugation of the enantiomers with R
configuration at the benzylic oxirane carbon. With both GSTM1-1 and GSTP1-1, the
chemically most reactive diol epoxide, the (+)-syn-enantiomer of trans-7,8
dihydroxy-9,10-epoxy-7,8,9,-10-tetrahydrobenzo[a]pyrene (BPDE), was the best
substrate. As for GSTA1-1, no obvious correlation between chemical reactivity or
lipophilicity of the compounds and catalytic efficiencies was observed. Molecular
modeling of diol epoxides in the active sites of GSTP1-1 and -A1-1 is in
agreement with the assumption, based on functional studies, that the H-site of
GSTA1-1 [Jernstrom et al. (1996) Carcinogenesis 17, 1491-1498] can accommodate
stereoisomers of different sizes. Further, modeling of the enantiomers of anti-
and syn-BPDE in the active site of GSTP1-1 provides an explanation for the
exclusive preference for the enantiomers with R-configuration at the benzylic
oxirane carbon. These isomers could be snuggly fitted in the H-site close to the
GSH sulfur, whereas those with opposite stereochemistry could not.
PMID- 9403174
TI - Biotransformation of the naturally occurring isothiocyanate sulforaphane in the
rat: identification of phase I metabolites and glutathione conjugates.
AB - Sulforaphane (SFN) is a naturally occurring isothiocyanate present in cruciferous
vegetables, such as broccoli, that has been identified as a potent inducer of
glutathione S-transferase activities in laboratory animals. The present studies
were carried out to elucidate the metabolic fate of SFN in the rat. Particular
emphasis was placed on glutathione (GSH)-dependent pathways because conjugation
with GSH is a major route by which many isothiocyanates are eliminated in
mammals. Male Sprague-Dawley rats were administered a single dose of SFN (50 mg
kg-1 ip), and bile and urine were collected over ascorbic acid. Analysis of
biological fluids was carried out by ionspray LC-MS/MS using the neutral loss
(129 Da) and precursor ion (m/z 164) scan modes to detect GSH and N
acetylcysteine (NAC) conjugates, respectively. In bile, five thiol conjugates
(designated M1-M5) were detected. Metabolites M2 and M4 were identified as the
GSH conjugates of SFN and erucin (ERN, the sulfide analog of SFN), respectively,
by comparing their LC-MS/MS properties with those of standards obtained by
synthesis. M1 was characterized as the GSH conjugate of a desaturated metabolite
of SFN (tentatively assigned the structure of delta 1-SFN), suggesting that the
parent compound also undergoes oxidative metabolism. Metabolites M3 and M5 were
identified as the NAC conjugates of SFN and ERN, respectively, and together with
the NAC conjugate of delta 1-SFN, these species also were detected in urine.
Quantitative determination of the former two mercapturates in urine indicated
that approximately 60% and approximately 12% of a single dose of SFN is
eliminated in 24 h as the NAC conjugates of SFN and ERN, respectively. The
corresponding figures in rats dosed with ERN were approximately 67% and
approximately 29%. When the GSH conjugate of SFN was incubated with phosphate
buffer (pH 7.4, 37 degrees C), < 1% of the conjugate dissociated to liberate free
SFN. On the other hand, the conjugate underwent a facile thiol exchange reaction
(> 70% conversion) when incubated in the presence of excess cysteine, thereby
acting as an effective carbamoylating agent. It is concluded that SFN undergoes
metabolism by S-oxide reduction and dehydrogenation and that GSH conjugation is
the major pathway by which the parent compound and its phase I metabolites are
eliminated in the rat.
PMID- 9403175
TI - Substrate specificity of human O6-methylguanine-DNA methyltransferase for O6
benzylguanine derivatives in oligodeoxynucleotides.
AB - To investigate the substrate specificity of human O6-methylguanine-DNA
methyltransferase (MGMT) for O6-benzylguanine (6BG) derivatives incorporated in
oligodeoxynucleotides, we prepared 25-mer lengths of sequences containing various
6BG derivatives and their related compounds and then measured the ability of
these derivatives to inactivate MGMT in vitro. Oligodeoxynucleotides containing a
6BG, O6-(2-fluorobenzyl)guanine (2F-6BG), O6-(3-fluorobenzyl)guanine (3F-6BG), O6
(4-fluorobenzyl)guanine (4F-6BG), O6-benzylhypoxanthine (6BH), or O6
methylguanine (6MG) were all good substrates for MGMT, and no obvious differences
were observed among them. Oligodeoxynucleotides containing N2-isobutyrylated 6BG
and 6MG showed only a slightly reduced capacity for inactivating MGMT compared to
N2-nonmodified forms of these derivatives. No obvious differences were observed
in the corresponding double-stranded and single-stranded oligodeoxynucleotides.
MGMT substrate specificity for the 6BG derivatives in the oligodeoxynucleotide
was found to be quite different from that seen in our previous study [Mineura,
K., et al. (1994) Int. J. Cancer 58, 706-712; (1995) Int. J. Cancer 63, 148-151.
Kohda, K., et al. (1995) Biol. Pharm. Bull. 18, 424-430] and others [Moschel, R.
C., et al. (1992) J. Med. Chem. 35, 4486-4491. Chae, M.Y., et al. (1994) J. Med.
Chem. 37, 342-347] using the corresponding free bases. In brief, (i) 6BG, 3F-6BG,
and 4F-6BG greatly inhibited human MGMT, whereas 2F-6BG, 6BH, and 6MG displayed
much weaker activity; (ii) any modifications at the 2-amino group of the 6BG
resulted in severe reductions in the ability to inactivate MGMT. These results
obtained by the experiments using oligodeoxynucleotides and free bases suggest
that human MGMT has low substrate specificity for 6BGs in oligodeoxynucleotides.
Conformational changes in human MGMT which favor binding to oligodeoxynucleotides
containing 6BG derivatives and the subsequent transfer of their benzyl groups may
account for the difference in substrate specificity between the incorporated 6BG
derivatives and their free base form.
PMID- 9403176
TI - Hypochlorous acid-induced base modifications in isolated calf thymus DNA.
AB - Exposure of calf thymus DNA to hypochlorous acid/hypochlorite leads to extensive
DNA base modification. Large concentration-dependent increases in pyrimidine
oxidation products [thymine glycol (cis/trans), 5-hydroxycytosine, 5
hydroxyuracil, 5-hydroxyhydantoin] but not purine oxidation products (8
hydroxyguanine, 2- and 8-hydroxyadenine, FAPy guanine, FAPy adenine) were
observed at pH 7.4. In addition, large increases in 5-chlorouracil (probably
formed from 5-chlorocytosine during sample preparation), a novel chlorinated
base, were observed. Addition of HOCl to DNA already damaged by .OH generated by
a mixture of ascorbate, copper(II) chloride, and hydrogen peroxide showed that
hypochlorous acid led to a loss of 8-hydroxyguanine, 2- and 8-hydroxyadenine,
FAPy guanine, FAPy adenine, and 5-hydroxycytosine in a concentration- and pH
dependent manner. Nevertheless, time course studies suggested that the formation
of purine oxidation products in isolated DNA by hypochlorous acid was not a major
oxidation pathway. If this pattern of damage, especially the production of 5
chlorocytosine, is unique to hypochlorous acid, it might act as a "fingerprint"
of damage to DNA by HOCl.
PMID- 9403177
TI - Investigation of hydrolytic deamination of 1-(2-hydroxy-1-phenylethyl)adenosine.
AB - The ring nitrogen of adenosine reacts at both the alpha- (benzylic) and beta
carbons of styrene oxide to form 1-substituted products. The 1-(2-hydroxy-1
phenylethyl)adenosines formed by oxirane ring opening at the alpha-position are
prone to an unusually facile hydrolytic deamination. By conducting hydrolysis
reactions in [18O]water and analyzing the reaction products by electrospray mass
spectrometry, we find that deamination occurs by direct attack of water at the 6
position of the adenine ring system with displacement of the exocyclic amino
group.
PMID- 9403178
TI - Effect of glutathione depletion on exocyclic adduct levels in the liver DNA of
F344 rats.
AB - The effects of glutathione (GSH) depletion on the in vivo formation of cyclic
1,N2- propanodexoxyguanosine adducts (AdG and CdG) as background lesions in the
liver DNA of F344 rats were investigated. A group of 5 male F344 rats were given
drinking water containing 30 mM L-buthionine (S,R)-sulfoximine (BSO) for 21 days,
and another group of 8 rats were given only drinking water as controls. The BSO
treated rats had significantly lower weight gain than control rats. The hepatic
GSH levels in the BSO-treated group were reduced by 84% as compared with the
control group, from 4.43 to 0.72 mumol/g of tissue. The isomeric AdG3, CdG1, and
CdG2 were detected by the 32P-postlabeling/HPLC method in the liver DNA of rats
without carcinogen treatment, as we reported previously [Nath, R. G., and Chung,
F.-L. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 7491-7495. Nath, R. G., et al.
(1996) Cancer Res. 56, 452-456]. The mean levels (mumol/mol of guanine) for AdG3,
CdG1, and CdG2 were 0.57 +/- 0.25, 0.15 +/- 0.18, and 0.16 +/- 0.22 for the
control group and 1.18 +/- 1.03, 3.16 +/- 3.26, and 2.50 +/- 2.59 for the BSO
group, respectively. These increases correspond to approximately 2-fold for AdG
and 15-21-fold for CdG adducts. The dramatic increase in the cyclic adduct levels
in rat liver DNA could have resulted mainly from GSH depletion as a result of the
BSO treatment, even though other unknown effects due to the toxicity of BSO
cannot be ruled out. These results suggest that GSH plays an important role in
protecting the liver against cyclic propano DNA adduction and provide further
support for the endogenous origin of these adducts.
PMID- 9403179
TI - Synthesis and cleavage of oligodeoxynucleotides containing a 5-hydroxyuracil
residue at a defined site.
AB - Oxidation and hydrolysis of a cytosine residue can lead to the formation of 5
hydroxyuracil in DNA. The biological consequences of this modification are not
fully understood. To facilitate biochemical and biophysical studies aimed at
elucidating the effects of this modification in DNA, we have developed a solid
phase synthetic method for the placement of 5-hydroxyuracil residues at defined
sites in oligodeoxynucleotides. This method is based upon the enhanced acidity of
the 5-hydroxyl proton which allows selective aqueous acetylation. Under standard
aqueous ammonia deprotection conditions, however, we observed that 5
hydroxyuracil residues are lost substantially from synthetic oligonucleotides.
Substitution of aqueous ammonia with methanolic potassium carbonate and the use
of phosphoramidite derivatives with alternatively protected amino groups allow
synthesis of oligonucleotides containing 5-hydroxyuracil and all normal bases in
high yield. The composition of the oligodeoxynucleotides prepared by this method
has been verified by enzymatic digestion followed by high-performance liquid
chromatography (HPLC) analysis as well as acid hydrolysis followed by GC/MS
analysis. The location of the 5-hydroxyuracil residue is demonstrated by
selective permanganate oxidation of the 5-hydroxyuracil residue followed by beta
elimination. We have also probed a synthetic oligonucleotide containing a unique
5-hydroxyuracil residue with uracil DNA N-glycosylase, previously reported to
remove this lesion from DNA.
PMID- 9403180
TI - Synthesis and 32P-postlabeling/high-performance liquid chromatography separation
of diastereomeric 1,N2-(1,3-propano)-2'-deoxyguanosine 3'-phosphate adducts
formed from 4-hydroxy-2-nonenal.
AB - 4-Hydroxy-2-nonenal (HNE), a major electrophilic byproduct of lipid peroxidation,
is mutagenic and cytotoxic. The two pairs of HNE-derived diastereomeric 1,N2
propanodeoxyguanosine 3'-monophosphate adducts were synthesized from reaction of
HNE with 2'-deoxyguanosine 3'-monophosphate. After HPLC separation, these adducts
were characterized by UV-visible absorption and negative ion electrospray
ionization MS/MS analysis. To further characterize the structures, these adducts
were dephosphorylated to the corresponding HNE-modified deoxyguanosine adducts
and their HPLC retention times and UV spectra were compared with those of the
synthetic standards prepared from reaction of HNE with 2'-deoxyguanosine.
Separation of these adducts by 32P-postlabeling/HPLC was developed. Reaction of
HNE with calf thymus DNA resulted in only one pair of diastereomeric adducts,
with one adduct predominantly formed with a modification level of 1.2 +/- 0.5
adducts/10(7) nucleotides.
PMID- 9403181
TI - Effect of substitution site upon the oxidation potentials of alkylanilines, the
mutagenicities of N-hydroxyalkylanilines, and the conformations of alkylaniline
DNA adducts.
AB - Carcinogenic arylamines typically undergo metabolic activation via N
hydroxylation followed in most instances by O-esterification. In this study, the
ability of methyl-, dimethyl-, and ethylaniline constituents of tobacco smoke to
undergo oxidation at the nitrogen atom was analyzed. In addition, the
mutagenicity of the corresponding N-hydroxyalkylanilines and the conformational
properties of the DNA adducts generated from their N-acyloxy derivatives were
investigated. All the arylamines underwent irreversible electrochemical N
oxidation at potentials higher than those observed for the oxidation of
carcinogenic polynuclear aromatic amines. There were minor differences in the
oxidation potentials, which were consistent with the position and electron
donating abilities of the alkyl substituents; however, the differences appeared
to be too small to account for the range of genotoxic effects among the
alkylanilines. N-Hydroxyarylamines containing p-alkyl substituents had increased
mutagenicities in Salmonella typhimurium TA100, which was attributed to their
higher efficiencies of adduct formation. Increased mutagenicities were also
observed upon o-alkyl substitution; however, this property was not related to a
greater ability of the ortho-substituted species to form DNA adducts, which
suggested that adducts from ortho-substituted alkylanilines may be intrinsically
more mutagenic than their meta- and para-substituted analogues. In all instances,
N-(acyloxy)-arylamines generated from the N-hydroxyarylamines reacted with dG, dG
nucleotides, and DNA to yield C8-substituted dG derivatives as the major adducts.
The alkylaniline-dG adducts displayed distinct conformational trends that were
determined by the location of the alkyl substituents. Spectroscopic data
indicated higher percentages of low-energy syn conformers in the adducts that
contained alkyl groups ortho to the arylamine nitrogen as opposed to adducts not
bearing ortho substituents. The data strongly suggest that the conformational
properties of the DNA adducts, in particular their ability to adopt syn
conformations, may be determinant factors for the genotoxic responses elicited by
certain alkylanilines (e.g., 2-methylaniline and 2,6-dimethylaniline).
PMID- 9403182
TI - Covalent DNA adducts formed by benzo[c]chrysene in mouse epidermis and by
benzo[c]chrysene fjord-region diol epoxides reacted with DNA and polynucleotides.
AB - The metabolic activation in mouse skin of benzo[c]chrysene (B[c]C), a weakly
carcinogenic polycyclic aromatic hydrocarbon (PAH) present in coal tar and crude
oil, was investigated. Male Parkes mice were treated topically with 0.5 mumol of
B[c]C, and DNA was isolated from the treated areas of skin at various times after
treatment and analyzed by 32P-postlabeling. Seven adduct spots were detected, at
a maximum level of 0.89 fmol of adducts/microgram of DNA. Four B[c]C-DNA adducts
persisted in skin for at least 3 weeks. Treatment of mice with 0.5 mumol of the
optically pure putative proximate carcinogens (+)- and (-)-trans-benzo[c]chrysene
9,10-dihydrodiols [(+)- and (-)-B[c]C-diols] led to the formation of adducts
which comigrated on TLC and HPLC with some of those formed in B[c]C-treated mice.
The major adduct formed in mouse skin treated with B[c]C coeluted on TLC and HPLC
with an adduct formed in mouse skin treated with (-)-B[c]C-diol. These results
suggested that the detected adducts were formed by the fjord-region B[c]C-9,10
dihydrodiol 11,12-epoxides (B[c]CDEs). To test this, the four optically pure
synthetic B[c]CDEs were reacted in vitro with DNA and with synthetic
polynucleotides and these samples were 32P-postlabeled. Cochromatography, both on
TLC and HPLC, of in vitro and in vivo adducts indicated that B[c]C is activated
in mouse skin through formation of the (-)-anti- and (+)-syn-B[c]CDE with
9R,10S,11S,12R- and 9S,10R,11S,12R- absolute configuration, respectively, both of
which formed two DNA adducts in vivo. However, the major adduct present in the
B[c]C-treated skin DNA was not a fjord-region B[c]CDE adduct but was possibly
derived from a bay region B[c]CDE at the 1,2,3,4-position. The extent of DNA
adduct formation by B[c]C in mouse skin DNA was lower than that of moderately
carcinogenic PAHs previously studied by this method, suggesting a correlation
between extent of DNA adduct formation and carcinogenic potential.
PMID- 9403183
TI - Formation and properties of peroxynitrite as studied by laser flash photolysis,
high-pressure stopped-flow technique, and pulse radiolysis.
AB - Flash photolysis of alkaline peroxynitrite solutions results in the formation of
nitrogen monoxide and superoxide. From the rate of recombination it is concluded
that the rate constant of the reaction of nitrogen monoxide with superoxide is
(1.9 +/- 0.2) x 10(10) M-1 s-1. The pKa of hydrogen oxoperoxonitrate is dependent
on the medium. With the stopped-flow technique a value of 6.5 is found at
millimolar phosphate concentrations, while at 0.5 M phosphate the value is 7.5.
The kinetics of decay do not follow first-order kinetics when the pH is larger
than the pKa, combined with a total peroxynitrite and peroxynitrous acid
concentration that exceeds 0.1 mM. An adduct between ONOO- and ONOOH is formed
with a stability constant of (1.0 +/- 0.1) x 10(4) M. The kinetics of the decay
of hydrogen oxoperoxonitrate are not very pressure-dependent: from stopped-flow
experiments up to 152 MPa, an activation volume of 1.7 +/- 1.0 cm3 mol-1 was
calculated. This small value is not compatible with homolysis of the O-O bond to
yield free nitrogen dioxide and the hydroxyl radical. Pulse radiolysis of
alkaline peroxynitrite solutions indicates that the hydroxyl radical reacts with
ONOO- to form [(HO)ONOO].- with a rate constant of 5.8 x 10(9) M-1 s-1. This
radical absorbs with a maximum at 420 nm (epsilon = 1.8 x 10(3) M-1 cm-1) and
decays by second-order kinetics, k = 3.4 x 10(6) M-1 s-1. Improvements to the
biomimetic synthesis of peroxynitrite with solid potassium superoxide and gaseous
nitrogen monoxide result in higher peroxynitrite to nitrite yields than in most
other syntheses.
PMID- 9403184
TI - Preoperative pulmonary evaluation of the thoracic surgical patient.
AB - A test designed to separate those undergoing thoracic surgery without
complications and those with complications must be both highly specific and
sensitive. Clearly, the difference between patients at opposite ends of the
population curves is easy to identify. Spirometry can be helpful for screening,
although it is not a very discriminating test. If patients fall in the overlap
region between the populations, however, it is impossible to discern the risks
with any certainty using low-yield tests. A test with higher sensitivity,
specificity, and predictive values is necessary to ascertain such marginal
differences. With this kind of analysis at hand, preoperative testing can be
divided into three predictive value groups. Calculating the predictive value of
each preoperative test can provide a comparative measure of usefulness of
discriminative power (Table 1). In this way, spirometry, blood gas analysis, and
stair climbing tolerance are shown to be poor predictors of outcome. An
intermediate predictive value can be achieved using diffusion capacity, exercise
induced decreases in O2 saturation, and exercise PVR. High predictive value can
be accomplished with combination indexes (PPP, possibly PRQ), measurement of VO2
at 40 watts of exercise, or VO2max. Logic dictates a step-wise preoperative
evaluation using prediction value analysis (Fig.4). A flow decision chart for the
preoperative evaluation of patients for pulmonary resection begins with exercise
oximetry, spirometry, and blood gas analysis as general screening tests to
separate those patients at minimal or no risks for complications from those
patients that require further evaluation. Functional indexes (PPP, PRQ) or
exercise testing can aid further in the selection of those patients in whom a
nonsurgical option should be considered. Flow decision chart for the preoperative
evaluation of patients for pulmonary resection should continue to evolve as new
information about outcome studies is gathered. Examination of outcome data will
provide us with reduction of the size of the nonoperable population, so that we
can deny only those patients who truly pose a prohibitive risk.
PMID- 9403185
TI - Preoperative cardiac assessment of the thoracic surgical patient.
AB - The preoperative cardiac assessment of the thoracic patient differs very little
from the assessment of any patient for noncardiac surgery, aside from a few
special issues. Therefore, rather than reviewing the general issue of evaluation
for noncardiac surgery, which is a topic that has been reviewed many times in the
recent past, this article focuses on the purposes, methods, and limitations of
risk assessment in the noncardiac surgical patient with suspected coronary artery
disease (CAD), including thoracic surgical patients. Because risk assessment is
imprecise and the main indications for invasive coronary procedures prior to
noncardiac surgery are the same for any person for whom life-expectancy is
expected to be prolonged, meticulous preoperative evaluation for CAD is not
usually warranted, even for patients undergoing high-risk surgery or with
multiple risk factors for CAD. To help understand this point of view and to
utilize cardiology consultants appropriately, implications of basic
pathophysiology as well as statistical principles are also discussed.
PMID- 9403186
TI - Pulmonary rehabilitation exercise program for high-risk thoracic surgical
patients.
AB - Preoperative assessment of the patient with moderate to severe COPD continues to
be a difficult task. Pulmonary function tests cannot be the only deciding factor.
Exercise testing is supported in the literature to improve the sensitivity and
specificity in predicting perioperative morbidity and mortality rates. The
presence of comorbid disease, especially COPD, increases the chances of
postoperative pulmonary complications. Pulmonary rehabilitation in the
nonsurgical COPD patient has been proven to be beneficial in improved exercise
capacity and quality of life. The question which remains to be answered is
whether a short-term, intense, and focused preoperative program in surgical
candidates with resectable NSCLC and preexisting pulmonary dysfunction can
influence outcome.
PMID- 9403187
TI - Selection of anesthetic agents for thoracotomy.
AB - The selection of anesthetic agents for thoracotomy requires consideration of
multiple factors. The goals of anesthetic management are to choose an anesthetic
plan that will allow not only for appropriate intraoperative conditions but also
for rapid extubation and adequate pain control so that the perioperative course
will have the least possible associated risk of morbidity and mortality. A
patient's pre-existing medical condition must be optimized. Length and type of
surgical procedure, as well as the patient's medical status, determine anesthetic
technique and agents.
PMID- 9403189
TI - Lung isolation. Tube design and technical approaches.
AB - Airway management for thoracic surgery frequently requires isolation of a portion
of the respiratory system. In some circumstances lung isolation is mandatory and
in others elective. Several techniques utilizing specialized endotracheal tubes
and blockers are currently available. There are specific advantages and
complications associated with each that, in part, determine optimal outcome in
this specialized group of surgical patients.
PMID- 9403188
TI - Intraoperative monitoring.
AB - This article discusses some of the routine as well as more specialized monitoring
devices available. In thoracic surgery monitoring may be even more challenging
because the surgery itself may involve manipulation of the airways, the pulmonary
as well as cardiovascular systems. The anesthesiologist must have a full
understanding of the required monitoring devices and decide which if any special
techniques are needed depending on the surgical procedure and the patient's
preoperative condition.
PMID- 9403190
TI - Physiology of the lateral position and one-lung ventilation.
AB - The first part of this article reviews the distribution of ventilation (V) and
perfusion (Q) during the supine and the lateral decubitus position. The changes
in the V/Q during the lateral position with and without paralysis are discussed.
The second part evaluates the degree of transpulmonary shunt during one lung
ventilation (OLV) and the role of hypoxic pulmonary vasoconstriction in
maintaining arterial oxygenation. Finally, the influence and the use of nitric
oxide during OLV is reviewed.
PMID- 9403191
TI - Postoperative pain management.
AB - Postoperative pain management is essential and must be approached as an integral
part of the perioperative care. It should be systematic and based on sound
physiologic and pharmacologic principles. The intra-operative management of pain
is crucial, as there is perhaps an important role for preemptive analgesia.
Because of its unique nature, pain is difficult to assess, but for good results
adequate and repeated assessment are vital. The literature also points to the
detrimental effects of inadequate pain control. There are a variety of methods
available for pain management. In choosing a method, various factors need to be
considered including physician skill, knowledge of analgesics and routes of
administration, patient-related and clinical circumstances, the availability of
an environment supportive of effective pain management, and the knowledge and
skill of staff to assess and monitor patients. These need to be considered along
with the risks and benefits and cost-benefit of the various drugs and techniques.
The cornerstone of therapy is opioids, which can be administered by a variety of
routes. The use of TEA with opioids and local anesthetics is highly beneficial,
especially in high-risk patients. The aim should be to provide all patients a
balanced analgesic regimen based on the identification of multiple mechanisms
involved in postoperative pain.
PMID- 9403192
TI - Mechanical ventilation of the postoperative patient.
AB - This article explains the operating characteristics of the most commonly used
modes of mechanical ventilation and provides descriptions of how mechanical
breaths are delivered. Also included are simple guidelines for choosing tidal
volume, respiratory and flow rate, and alarm settings. The article concludes with
a brief overview of weaning techniques and commonly used criteria to determine
when patients are ready to be weaned from ventilating support.
PMID- 9403193
TI - Prevention and management of dysrhythmias following thoracic surgery.
AB - Supraventricular dysrhythmias (SVDs) occur frequently after thoracic surgery and
have been associated with prolonged hospital stays. The reported incidence of
supraventricular dysrhythmias in the thoracic surgery patient population ranges
from 10% to 40%, with factors such as age and extent of surgery markedly
influencing the incidence. This article focuses on new issues leading to improved
understanding of the pathophysiology and mechanisms of SVDs after surgery. New
approaches directed at prophylaxis and acute therapy of SVDs are also discussed.
PMID- 9403194
TI - Anesthesia for the pediatric patient.
AB - Infants and children have unique anatomic, physiologic, pharmacologic, and
psychological issues relating to perioperative management. Combining this
knowledge with the technical skills required for instrumentation of children is
essential when contemplating anesthesia for thoracic surgery. Experience and
versatility with anesthetic induction technique, airway instrumentation, vascular
access and monitoring, single-lung ventilation, regional anesthesia, and
postoperative pain management allow for the comprehensive management of thoracic
surgical patients at any age.
PMID- 9403195
TI - Aqueduct stenosis in animal models of hydrocephalus.
PMID- 9403196
TI - MRI in Smith-Lemli-Opitz syndrome type 1.
PMID- 9403197
TI - Primary intracranial neoplasms of infancy and early childhood.
AB - We investigated the age-related location, gender distribution, and histology of
107 brain tumors in children under 4 years of age seen in our department between
1984 and 1997. The male-to-female ratio was 1.4 (62/45 cases) with a prevalence
of supratentorial tumors (60/47 = 1.3); the main histological entity was
astrocytoma (33.6%), followed by ependymoma (14.0%). In the 1st year of life 22
cerebral neoplasms became clinically apparent. A higher ratio for supratentorial
tumors was revealed (17/5 = 3.4), but without gender preference, and primitive
neuroectodermal tumors (PNET) were the most frequent (5/22). In the 2nd year 25
tumors were found. The male-to-female ratio was 1.5 (15/10) and the
supratentorial-to-infratentorial ratio, 1.1 (13/12). The two most common entities
were astrocytoma and ependymoma (6 cases each). In addition, a survey of
previously published investigations into this subject was performed and a
compilation of data on 1960, 545 and 1084 tumors in children below the age of 1,
2 and 4 years, respectively, was prepared, which makes it the most extensive
review of brain tumors of infancy and early childhood yet undertaken.
PMID- 9403198
TI - Thalamic tumors in children.
AB - Thalamic tumors (TT) merit individual analysis and must not be confused with
tumors that, while involving the entire thalamus have a different origin. We
analyzed 26 patients who fulfilled our criteria of having "strictly" TT. We
examined incidence, clinical features, histology, response to treatment (mainly
surgery), recurrence rate, mortality and prognosis. We considered that histology
and surgical treatment were the most important items related to prognosis. Low
grade tumors (LGT) had a good prognosis, while anaplastic tumors (AT) had a
discouraging one; nevertheless both must be operated on. We believe that total
removal of LGT is curative and total removal of AT, even if it is not curative,
can extend survival by some months. Radiotherapy and chemotherapy seemed to be of
little value in our series of TT.
PMID- 9403199
TI - Cerebral cavernous hemangiomas in childhood. Clinical presentation and
therapeutic considerations.
AB - Cerebral cavernous hemangiomas (CCH) are relatively rare vascular hamartomas.
Since the introduction of MRI there has been an increase in the number of case
reports of CCH in the medical literature. CCH are often asymptomatic; they may,
however, cause epilepsy or neurological deficits due to their space-occupying
effects or hemorrhagic sequelae. The tendency of CCH to bleed has been well
recognized, though gross hemorrhage is infrequent owing to the relatively low
blood pressure and small blood flow in CCH. MRI findings of a CCH are
characteristic and can differentiate the lesions from other vascular
abnormalities. To date, there has been no consensus on indications for surgical
intervention. Three cases are presented, which together demonstrate by their
different presentation, clinical course and MRI findings that each patient with a
CCH requires an individually tailored management. Presentation, clinical course
and accessibility for operation are the factors that determine whether a surgical
or a conservative approach should be adopted.
PMID- 9403200
TI - Continuous external subdural drainage in the management of infantile subdural
collections: a prospective study.
AB - Continuous external subdural drainage (CESD) was suggested as a treatment step to
be inserted prior to SP shunting, primarily because it makes it possible to avoid
shunt placement in a significant number of patients. Thirty-three patients with
symptomatic chronic subdural collection confirmed by computed tomography were
included in this study. Unilateral CESD was performed in all cases, using a
lumbar drainage set. The drains were left in place for no more than 10 days. A
subduroperitoneal (SP) shunt was inserted in those patients in whom re
accumulation of the subdural collection had occurred. Of 33 patients, 17 were
definitively treated by CESD and 16 subsequently needed an SP shunt. The cost of
treatment with CESD was just less than half the cost of treatment with SP
shunting. CESD can be used as a step before SP shunting in the management of
chronic infantile subdural collections, since it is effective without further
treatment in half the patients and safer than subdural tapping.
PMID- 9403201
TI - Outcome and life prospects after surgical management of medically intractable
epilepsy in patients under 18 years of age.
AB - A retrospective analysis of seizure outcome and quality of life assessment was
done in 64 patients under 18 years of age with medically refractory epilepsy who
underwent 64 primary and 16 repeat operative procedures in an attempt to control
their epilepsy. At least 2 years' follow-up data were available for each patient.
Operative procedures were 44 temporal lobe resections; 16 extratemporal
resections; and 4 hemispherectomies. Effective control of previously intractable
seizures was obtained in most patients: 55%, 11%, and 17% achieved Engel class I,
II, and III status, respectively. Successful seizure control was thus obtained in
83%, while 17% (Engel class IV) failed to improve significantly after operation.
Quality-of-life measures parallelled the improvements in seizures control, being
highest in Engel I, outcome group and lowest in Engel IV outcome group. In
appropriately selected pediatric and adolescent patients with medical refractory
epilepsy, surgical management can offer a safe and effective adjunct to
medication.
PMID- 9403202
TI - Tumors of the orbit. Pitfalls of the surgical approach in 37 children with
orbital tumor.
AB - The authors review their experience with 37 children with orbital tumors,
summarizing their surgical techniques, the indications applied, and the pitfalls
of each surgical approach. Tumors located in the retro-ocular or intraorbital
space were surgically excised through a transcranial approach (28 cases), while
for tumors in other sites lateral orbitotomy (5 cases), medial orbitotomy (1
case) and biopsy (3 cases) were performed. A transcranial approach was used for
tumors with intracranial extension and for those located in the orbital apex and
deep medial orbital compartment. Lateral orbitotomy was used for tumors located
in the superior, temporal or inferior compartment of the orbit and those in the
lateral apex. A medial orbitotomy was used for tumors located medial to the optic
nerve. Outcomes of the surgical intervention varied, depending on the pathology,
location and extent of the individual tumors. To obtain optimal exposure and
minimize functional deficits, the pitfalls of surgical approaches to orbital
tumors are discussed.
PMID- 9403203
TI - Acute cerebellar ataxia in children.
AB - Acute cerebellar ataxia is a benign syndrome usually occurring after an acute
febrile disease. In a few cases neuroradiological investigations reveal
cerebellar alterations. Clinical and neuroradiological involvement of the brain
stem has rarely been reported in the literature. We present five cases of acute
cerebellar ataxia. In two cases the cerebellar symptomatology was associated with
neurological signs of brain stem involvement. CT scans did not show any
pathologic findings in three patients. MRI disclosed cerebellar or brain stem
alterations in all the patients. Clinical and neuroradiological findings allow
differentiation of this pathologic entity from other demyelinating or
dysmyelinating diseases. The value of MRI in detection and localization of the
lesions and in following their evolution is emphasized.
PMID- 9403204
TI - Immunoglobulin prophylaxis in shunt infections: a prospective randomized study.
AB - Cerebrospinal fluid shunt infection is serious and one of the most frequent
complications of shunt implantation. Age has been one of the most significant
host factors for the development of shunt infections. A relative deficiency of
the immune response against bacteria in infants could partly explain the higher
infection rate in the very young patients. This prospective-randomized study was
conducted in two groups: group A (immunoglobulin group) and group B (control
group). There were 30 patients in each group. The patients in group A received
intravenous immunoglobulin (Sandoglobulin) at a dose of 1 g/kg in the night
before surgery. Each patient was followed up to 6 months. No infection was seen
in group A. In group B, infection rate per procedure were 5.1% (P = 0.494) and
6.6% (P = 0.492), respectively. Intravenous immunoglobulin prophylaxis in infants
seems to reduce the shunt infections.
PMID- 9403205
TI - Intracranial and spinal metastases from a ganglioglioma with unusual cytogenetic
abnormalities in a patient with complex partial seizures.
AB - We describe an unusual clinical presentation of a ganglioglioma in a patient with
complex partial seizures. The patient underwent a right temporal lobectomy with
subtotal tumor resection at age 15 years, followed by a complete resection 1 year
later. Follow-up MRI scan a year later documented recurrence and leptomeningeal
dissemination. Another biopsy was performed. Pathological examination revealed
similar histology in all three resections, with a ganglioglioma showing no
evidence of anaplasia. The tumor exhibited a number of karyotypic abnormalities,
notably, a paracentric inversion of chromosome 7. In summary, despite lacking
anaplastic features by conventional histological criteria, this ganglioglioma
showed an unsusual karyotype and demonstrated radiological evidence of widespread
dissemination.
PMID- 9403206
TI - Congenital immature teratoma of the fetal brain.
AB - Congenital intracranial tumors are very rare and only account for 0.5-1.5% of all
childhood brain tumors. Even rarer are those with prenatal manifestation. The
most common of these present at birth are teratomas, which show divergent
differentiation with 90% of them containing tissues from all three germ layers.
We report a rare case of an intrauterine congenital immature teratoma in a female
fetus at 23 weeks of gestation, which was sonographically diagnosed in vivo by
detection of the tumor and associated craniomegaly. Because of the poor
prognosis, termination of the pregnancy was induced by Rivanol instillation. The
cerebral tumor was confirmed at autopsy and was not associated with any other
malformations. Histological and immunohistochemical features of this tumor are
presented.
PMID- 9403207
TI - Assessment of brain perfusion by 99mTc-HMPAO SPECT in akinetic mutism due to high
dose intravenous methotrexate therapy.
AB - Chemotherapy of the central nervous system may cause neurotoxicity in children
with acute lymphocytic leukemia. We evaluated regional blood flow in a 6-year-old
child presenting with akinetic mutism, using 99mTc-HMPAO single photon emission
tomography (SPECT) following high-dose intravenous methotrexate therapy. While
findings in X-ray computerized tomography were decreased density in bilateral
basal ganglia and thalamic nuclei with diffusely decreased attenuation of the
periventricular white matter, a global, frontal dominant profoundly abnormal
perfusion pattern involving both gray and white matter was observed in the SPECT
study. Treatment of the central nervous system with high dose intravenous
chemotherapy may cause profound abnormalities in white and gray matter blood flow
and early assessment of the neurotoxicity may be identified by 99mTc-HMPAO SPECT
in the pediatric age group.
PMID- 9403208
TI - Germinoma in cerebral hemisphere associated with Down syndrome.
AB - A Down syndrome patient with germinoma developing in the cerebral hemisphere is
reported. A review of the literature yielded only 14 cases of Down syndrome with
brain tumors, including our case. This finding of brain tumors in patients with
Down syndrome may reflect chance occurrence. However, it is of interest in this
regard that in 6 of the 14 (43%) reported cases the lesions were intracranial
germ cell tumors.
PMID- 9403209
TI - Rapidly progressive IgA nephropathy with anti-myeloperoxidase antibodies benefits
from immunosuppression.
AB - CLINICAL OBSERVATIONS: Three patients with previous pulmonary infections were
recently admitted with rapidly progressive renal failure. Renal biopsy showed
crescentic glomerulonephritis with deposits of IgA, C3c and C3d. Serology
disclosed P-ANCA with high-titer anti-myeloperoxidase antibodies. Two out of
three patients became dialysis dependent despite immunosuppression with
methylprednisolone and cyclophosphamide. Renal function improved in both patients
after 2 weeks and 9 months, respectively, permitting termination of hemodialysis.
All patients benefited from immunosuppressive treatment which is currently still
being continued. CONCLUSION: The data suggest that early immunosuppression is
beneficial in patients presenting with crescentic rapidly progressive IgA GN and
anti-myeloperoxidase antibodies, which may represent a novel subset of crescentic
IgA GN associated with high-titer anti-myeloperoxidase antibodies constituting an
overlap group between microscopic polyangiitis and IgA GN.
PMID- 9403210
TI - Membranoproliferative glomerulonephritis induced by portosystemic shunt surgery
for non-cirrhotic portal hypertension.
AB - The liver and spleen both have important phagocytic functions and contain
monocytes/macrophages which clear immune complexes. We describe here three
patients who presented proteinuria and hematuria 7 to 13 years after
portosystemic shunt surgery, which diverted portal venous blood to the systemic
circulation. They had hematemesis and/or melena and underwent mesocaval shunt
surgery and splenectomy in childhood because of non-cirrhotic portal hypertension
with esophageal varices. Renal biopsy specimens revealed findings characteristic
of membranoproliferative glomerulonephritis (MPGN) type I. Immunohistologically,
these three cases were accompanied by a distinct IgA deposition along with a
marked C3 deposition. The IgA observed in these three cases contained not only
IgA1 but also IgA2, which is the predominant form of mucosal IgA. On the other
hand, of 20 patients with idiopathic MPGN type I with IgA deposition (n = 20),
only two were positive for IgA2, and the distribution was focal and segmental.
Our study shows that MPGN type I may have developed secondary to portosystemic
shunt. This secondary form of MPGN type I may be caused by a reduced clearance of
immune complexes in the liver and their deposition in the glomerulus, since a
portosystemic shunt routes portal venous blood from the intestinal tract directly
to the systemic circulation.
PMID- 9403211
TI - Plasmapheresis in the treatment of steroid-resistant focal segmental
glomerulosclerosis.
AB - A patient presented with a severe nephrotic syndrome and a renal biopsy
consistent with early focal segmental glomerulosclerosis (FSGS). After a year of
intensive immunosuppressive therapy proteinuria was unabated and renal function
began to deteriorate. Treatment with weekly plasmapheresis combined with moderate
doses of prednisone and azathioprine produced a dramatic decrease in proteinuria
and serum creatinine. A marked fall in the B-cell population occurred during
treatment, as well as an increase both in T-lymphocytes of the mature CD4+
helper/suppressor phenotype and in the immature/cytotoxic CD8+ phenotype.
Activation of the immune system during treatment was demonstrated by an increase
in the rate of spontaneous proliferation of peripheral blood mononuclear cells
and an increase in T-cell expression of the interleukin-2 receptor.
PMID- 9403212
TI - Hematuria due to hyperuricosuria in children: 36-month follow-up.
AB - Hyperuricosuria (HU), defined as a urinary acid excretion higher than 95 percent
of normal values, is an important lithogenic factor, accounting for about 5-20%
of recurrent hematuria in childhood. We prospectively studied 30 children (15
male, 15 female; aged 3 to 13 years old) with previously undiagnosed isolated
hematuria and HU for 6 to 36 months. The family history of nephrolithiasis was
positive in 40%. Idiopathic hypercalciuria (IH), UCa > 4 mg/kg/day, was not found
initially, but was diagnosed after 6 to 24 months in 20% of the patients. The
following treatments were utilized: restricted purine diet (13%), allopurinol
(4%) and potassium citrate (1%). No specific treatment was given to 82% of the
patients. Therapy normalized uricosuria with resolution of hematuria over 6-12
months. Thirteen percent and 6% of untreated patients developed urolithiasis
after 6 and 12 months respectively. The data suggest that HU, like IH, is
associated with hematuria. Furthermore, recognition of this association may
prevent unnecessary, and in some cases, invasive diagnostic manoeuvres.
PMID- 9403213
TI - Validation by image analysis of a turbidimetric method to study calcium oxalate
crystallization.
AB - Numerous studies of calcium oxalate crystal formation have been carried out in
the past two decades. In the present study, experiments were carried out to
validate a turbidimetric method allowing to assess the calcium oxalate
crystallization process. This method is quick and reproducible and can be used to
quantify the inhibition of calcium oxalate crystal growth by various compounds.
An experimental method of validation has been developed, which consisted in
filtering solutions pure or containing modifiers at given crystallization times,
photographing the filters used on scanning electron microscopy and analyzing the
images using mathematical methodology. The results obtained through image
analysis, namely crystal density (mean particle number per unit volume) and mean
area, were correlated with the turbidimetric parameters. This finding was
consistent with the qualitative examination of the photographs. Moreover, the
morphological differences in crystals observed on the photographs were confirmed
by the calculated length/width ratio. One can therefore assume that inhibition of
calcium oxalate crystal growth is at least, partly explained by surface
adsorption phenomena, which may add to complex formation.
PMID- 9403214
TI - Fate of recurrent acute interstitial cellular rejection in an HLA identical
kidney transplant recipient: impact of donor microchimerism.
AB - We and others have shown that the incidence of acute interstitial rejection in
HLA identical and non-identical kidney transplantation is similar. Chronic
vascular rejection is, however, rare in full matched recipients. In light of the
known correlation between previous acute cellular and chronic vascular
rejections, lack of chronic rejection in full matched kidney allografts suggest
that the immunological basis of acute and chronic rejections are different and/or
only high-grade acute cellular rejection leads to chronic vascular rejection.
Herein, we present the case of an HLA identical kidney transplant from a male
donor to a female recipient who, because of poor compliance, had frequent acute
interstitial cellular rejection culminating into chronic interstitial fibrosis
with no evidence of vasculopathy or glomerulopathy characteristic of chronic
vascular rejection. Donor cells, as examined by the presence of the Y chromosome
DNA, were present in the peripheral blood during the most recent acute rejection
but not thereafter. These findings support the notion that acute interstitial
cellular rejection can lead to interstitial fibrosis but not chronic
vasculopathy/glomerulopathy, and that microchimerism did not confer protection
against acute cellular rejection.
PMID- 9403215
TI - Effects of isradipine on renal hemodynamics in renal transplant patients treated
with cyclosporine.
AB - Cyclosporine A is the mainstay of modern immunosuppressant therapy in human organ
transplants. However, its use has been associated with nephrotoxicity and
hypertension that may be hemodynamically mediated. This study was undertaken to
see if the calcium channel blocker, isradipine, could improve renal hemodynamics
by decreasing renal vascular resistance and to determine its effects on
cyclosporine pharmacokinetics. Eighteen hypertensive renal transplant recipients
(3 to 60 months post transplant) were enrolled. Antihypertensive medications were
stopped. Patients were placed on isradipine and followed for 8 weeks. Blood
pressure, creatinine clearance, cyclosporine trough levels, and renal plasma flow
using p-aminohippurate clearance, were measured pre- and at 8 weeks of therapy.
Only one patient did not complete renal plasma flow measurement. Systolic and
diastolic blood pressures dropped significantly (p < 0.001) from baseline to 8
weeks with isradipine. Sbp decreased from 166 +/- 18 to 142 +/- 14 mmHg and Dbp
decreased from 97 +/- 8 to 82 +/- 10 mmHg (mean +/- 1 SD). Renal vascular
resistance, calculated from mean arterial pressure and renal blood flow,
decreased significantly (p < 0.002) from 0.57 +/- 0.21 to 0.41 +/- 0.12
mmHg/ml/min (mean +/- 1 SD). Isradipine appeared to have no significant effect on
cyclosporine trough levels, creatinine clearance, or renal plasma flow. This
study shows a role for isradipine use in renal transplant recipients on
cyclosporine. Renal vasoconstriction caused by cyclosporine may be partially
prevented with isradipine therapy. Furthermore, isradipine is effective in the
treatment of hypertension in renal transplant recipients without affecting
cyclosporine levels.
PMID- 9403216
TI - A case of superantigen-related glomerulonephritis after methicillin-resistant
Staphylococcus aureus (MRSA) infection.
AB - A case in which the enterotoxins of Staphylococcus aureus may have served as
bacterial superantigens is presented. This 71-year-old man developed proteinuria
and renal dysfunction after contacting pneumonia caused by methicillin-resistant
Staphylococcus aureus (MRSA), coagulase type II. The infection occurred after
surgery for recurrent lung cancer. Staphylococcus enterotoxins B, C, and TSST-1
were detected from the bacillus. Ten days after the onset of pneumonia,
proteinuria was noted; urinary protein was as high as 1.8 g/day. The serum
creatinine was elevated from 1.0 mg/dl to 3.7 mg/dl. Several immunological
reactions were detected; the serum levels of IgG and IgA were increased, and the
selective usage of T-cell receptor V beta (TCRV beta) was observed. Serum levels
of IL-1 beta, IL-2, IL-6, IL-8, IL-12, and tumor necrosis factor alpha (TNF
alpha) were also elevated. Examination of the renal biopsy specimen by light
microscopy showed minor to mild mesangial proliferative glomerulonephritis.
Immunofluorescence microscopy demonstrated the deposition of IgG, IgA, and C3,
mainly along the capillary walls. Electron microscopy revealed electron dense
deposits, mainly in the subepithelial areas, and injury to the glomerular
basement membrane. When the pneumonia improved following antibiotic therapy, the
renal function also improved, and proteinuria decreased. The levels of
immunoglobulins and the usage of TCRV beta also decreased. Because staphylococcus
enterotoxins act as superantigens, we believe this to be a typical case of
superantigen-related glomerulonephritis.
PMID- 9403217
TI - Cerebral venous thrombosis in nephrotic syndrome.
AB - This report describes cerebral venous sinus thrombosis, a rare and perhaps under
diagnosed complication of nephrotic syndrome. We review the pathophysiology of
the coagulopathy associated with nephrotic syndrome including abrupt renal loss
of antithrombin III. We propose a rationale approach to treating this condition
with low-molecular-weight heparin and antithrombin III replacement.
PMID- 9403218
TI - Lobular form idiopathic glomerulonephritis with massive subendothelial and
paramesangial immune deposits, a three-year follow-up case.
AB - We report a patient with unusual glomerulonephritis. A 24-year-old Japanese
female was hospitalized in October 1995 because of nephrotic syndrome. Lobular
form glomerulonephritis with mesangial proliferation associated with massive wide
spread accumulation of slightly eosinophilic, periodic acid Schiff-positive
amorphous materials in the luminal side of the capillary walls and paramesangial
area was observed in the renal biopsy specimen. Immunofluorescent study revealed
massive strong staining for IgM and C4 along the capillary walls and in the
mesangium. Deposits of IgA, IgG, C3 and fibrinogen were also observed. Electron
microscopy showed normal thickness of the capillary basement membrane and a large
amount of subendothelial and paramesangial electron dense, finely granular
deposits without fibrils or tubular structures. There were no clinical or
laboratory findings of systemic diseases, such as systemic lupus erythematosus
and cryoglobulinemia. Therefore, we believed that this case involved an unusual
idiopathic glomerular disease with massive subendothelial and paramesangial
immune deposits. Glomerulonephritis in this patient appeared to be resistant to
treatment with corticosteroids and that this glomerulopathy may be a progressive
disease as shown during the 3-year observation. Furthermore, our patient had
idiopathic hyperprolactinemia and subclinical hypothyroidism. However, the
relationship between glomerulonephritis and endocrinopathy in our patient is
unknown.
PMID- 9403219
TI - Systemic lupus erythematosus in a patient with remitting minimal change nephrotic
syndrome.
AB - Minimal change nephrotic syndrome (MCNS) developed in a 17-year-old female and
spontaneously remitted. One month later the nephrotic syndrome relapsed.
Prednisolone therapy, 60 mg/day, was started and resulted in a full remission
within a week and the prednisolone dose was subsequently tapered. Seven months
later, when 10 mg/day of prednisolone was being administered, she developed
erythematous rash with photosensitivity and polyarthralgia without exacerbation
of the nephrotic syndrome, and fulfilled four of the American College of
Rheumatology criteria for classification of systemic lupus erythematosus (SLE).
Avoidance of direct sunlight ameliorated the erythematous rash and the
polyarthralgia disappeared even though the prednisolone dose was decreased
further. This is the first reported case of SLE developed in a patient with
remitting MCNS.
PMID- 9403220
TI - Acute renal failure with severe tubulointerstitial changes in a patient with
minimal change nephrotic syndrome treated with enalapril.
AB - A 35-year-old nephrotic man developed acute renal failure with serum creatinine
to 1543 micromol/l after a month of therapy with enalapril. Renal biopsy
demonstrated minimal glomerular changes with fusion of podocytes, tubular
necrosis with regeneration of tubular epithelial cells, interstitial edema with
focal interstitial fibrosis, and interstitial infiltration with neutrophils,
eosinophils, plasma cells and mononuclear cells. Three hemodialyses were
performed in the patient during the oliguric phase of the disease. Renal function
was restored after withdrawal of enalapril and initiation of steroid therapy.
Steroids also contributed to the improvement of the nephrotic syndrome and
proteinuria decreased from maximal ranges of 27 g/l to 2.2 g/l after six months
of the follow-up. Similar cases were previously described associated with
captopril treatment, but not with enalapril.
PMID- 9403221
TI - Losartan for therapy of posttransplant erythrocytosis.
PMID- 9403222
TI - Amlodipine has a minor effect on cyclosporine metabolism.
PMID- 9403223
TI - Role of peripheral-type benzodiazepine receptors in steroidogenesis.
AB - Peripheral-type benzodiazepine (BZ) receptors (PBRs) have been identified in
various peripheral tissues as well as in glial cells in in the brain. PBRs are
located mainly on the outer mitochondrial membrane and bind with high affinity
the BZ Ro 5-4864 (4'-cholorodiazepam) and the non-BZ PK 11195 (an isoquinoline
carboxamide derivative), but bind with very low affinity the BZ clonazepam. PBRs
have been cloned from various species. PBRs are multimeric receptors composed of
the 18-kDa binding site for isoquinolines, the 32-kDa voltage-dependent anion
channel, and the 30-kDa adenine nucleotide carrier (which binds BZs). The
expression of PBRs is especially high in steroidogenic organs. Steroid
administration affects PBR density, whereas depletion of hormones by
hypophysectomy in female rats, or castration (surgical or chemical) in male rats,
decreases PBR density in endocrine organs, which can be elevated to normal values
after administration of the appropriate hormone. PBRs are probably involved in
several functions, including cell proliferation, respiration, and
steroidogenesis. It has been suggested that PBRs are involved in the
translocation of cholesterol from the outer to the inner membrane of the
mitochondria and have an effect on the biosynthesis of steroids.
PMID- 9403224
TI - Melatonin, its receptors, and relationships with biological rhythm disorders.
AB - Melatonin is a neurohormone produced during the night by the pineal gland. Its
secretion is regulated by circadian and seasonal variations in daylength,
transmitted via visual projections to the suprachiasmatic nucleus which functions
as a circadian clock in mammals. Melatonin has been proposed to act as an
internal synchronizer of circadian rhythms generated at different levels of the
organism. The chronobiotic effects of melatonin in humans have been mainly
studied in circadian rhythm sleep disorders related to jet lag, shift work,
blindness or aging. Alterations of the melatonin profiles have also been reported
in other biological rhythm disorders.
PMID- 9403225
TI - Effect of citalopram on brain serotonin release in experimental hepatic
encephalopathy: implications for thymoleptic drug safety in liver insufficiency.
AB - In the present study, effects of citalopram (CIT) on brain 5-hydroxytryptamine (5
HT) release in experimental chronic hepatic encephalopathy (HE) were
investigated. Neocortical administration of CIT (1.0 microM) increased the brain
5-HT output to a similar extent in portacaval shunted (PCS) rats and sham
operated controls, indicating that a previous described mismatch between
increased 5-HT turnover and unchanged release in PCS rats is not explained by an
accelerated brain 5-HT reuptake. Subsequent systemic administration of CIT (5
mg/kg subcutaneously) resulted in a more pronounced attenuation of the brain 5-HT
release in PCS rats than in sham-operated controls, possibly indicating a higher
susceptibility to indirect mid-brain 5-HT1A autoreceptor activation in
experimental portal-systemic encephalopathy (PSE). A KCl (60 mM) challenge in the
presence of locally administered CIT (1 microM) induced a more marked neocortical
5-HT response in PCS rats than in sham-operated controls, confirming previous
results of a higher than normal amount of 5-HT available for depolarization
induced release in PCS rats. Although the pharmacodynamic parameters in this
study was investigated for CIT, the likelihood of a parallel pharmacokinetic
alteration existing for this drug in the PCS condition also was indicated. It is
thus suggested that otherwise generally safe central nervous system 5-HT-active
drugs may represent a potential hazard in patients with liver failure with or
without PSE.
PMID- 9403226
TI - Motor complications of chronic levodopa therapy in Parkinson's disease.
AB - We report on motor complications of chronic levodopa therapy among 811 levodopa
responsive patients with idiopathic Parkinson's disease (PD), stratified by
duration after diagnosis. Predictable "offs" were noted in 20.2% of patients in
the first 5 years, in 58.3% after 15 years. Unpredictable or sudden offs and
early morning dystonia were less common. Longer duration was associated with
greater percentages of patients with off periods or dyskinesias (up to 70% after
15 years), although patients with 6-15 years' duration saw relatively little
increase in frequency of those complications, and a minority of patients
(approximately 30%) with duration into the second decade did not experience off
periods or dyskinesia. Across groups, mean Hoehn and Yahr stage and daily
levodopa dosage progressively increase (and mean Schwab and England disability
ratings decrease), but more conservatively than in prior reports in the
postlevodopa era. We note that with advancing PD duration, levodopa complications
are more common, but in many cases there appear to be relatively stable periods
in terms of levodopa dosage and disease severity, and a minority of patients will
be relatively free of motor complications into the second decade of their
disease.
PMID- 9403227
TI - Effect of tolcapone on plasma levodopa concentrations after coadministration with
levodopa/carbidopa to healthy volunteers.
AB - Tolcapone (Ro 40-7592) is a novel inhibitor of catechol-O-methyltransferase that
is being developed for clinical use in the treatment of Parkinson's disease as
add-on therapy to a combination of levodopa and a peripheral amino acid
decarboxylase inhibitor (benserazide or carbidopa). The current single-blind,
randomized study was designed to evaluate the effect of tolcapone compared with
placebo on plasma levodopa concentrations in healthy volunteers concomitantly
receiving 25 mg of carbidopa and 100 mg of levodopa (Sinemet 25-100) and to
assess the tolerability and safety of this combination. Placebo or tolcapone at
doses of 5, 10, 25, 50, 100, 200, 400, and 800 mg was coadministered orally with
Sinemet 25-100. Each dose was tested in a crossover fashion in a new group of six
participants who each received active drug on one occasion and placebo on the
other. Tolcapone increased the area under the plasma concentration-time curve and
half-life of levodopa approximately twofold, without appreciably increasing the
peak concentration. The maximum effect on levodopa half-life was observed with
the 200-mg dose. Adverse effects were minor at all doses.
PMID- 9403228
TI - Selegiline and excess mortality.
PMID- 9403229
TI - Coronary intervention in myocardial infarction.
AB - The ability to achieve rapid and sustained reperfusion in cases of acute MI with
an interventional approach constitutes a true revolution in the practice of
cardiology. This article discusses those interventions.
PMID- 9403230
TI - Colon rectal cancer: a common disease.
AB - Early diagnosis is a key in properly screening and surveillance. The author
discusses preventive medicine, risk ratings, and fecal occult blood testing.
PMID- 9403231
TI - Lung transplantation: an overview.
PMID- 9403233
TI - Should circulating anticoagulant [AKA anti-phospholipid] assays be a routine
component of well-patient assessment?
AB - Circulating anticoagulants are a major risk factor for thrombotic problems (eg,
myocardial infarction, stroke) and pregnancy complications. The authors present a
retrospective survey of anticardiolipin antibody and lupus anticoagulant in 200
consecutive patients presenting to their office.
PMID- 9403232
TI - New developments in osteoporosis.
AB - Osteoporosis is no longer a disorder about which nothing can be done. Many of the
new developments in this field have already assumed important places in clinical
management. The author reviews many of the new developments in treating
osteoporosis and attempts to place them in a practical, clinical context.
PMID- 9403234
TI - Self-directed work teams: an 18-month review.
AB - Visionaries are individuals who imagine how the ideal practice should be setup.
Realists view practices the way they are actually setup. To bring these
individuals together toward a common goal is what self-directed work teams can
provide your practice. Components that make up a self-directed work team are
reviewed.
PMID- 9403235
TI - Benefit plans in a changing practice environment.
AB - Managed care is affecting the business of medical practices. Many physicians are
joining with larger organizations and employee benefits are even more significant
in each physician's financial security. Background on benefit issues and common
areas of caution when contemplating joining a large entity are addressed.
PMID- 9403236
TI - Cerebral evoked responses to gastrointestinal stimulation in humans.
AB - Recent advances have permitted recording of evoked potentials (EPs) in response
to electrical and mechanical stimulation of the gastrointestinal (GI) organs via
methods used primarily in clinical neurophysiology. Current research involving
stimulation of the esophagus, rectum, and colon, and recording the corresponding
responses on the scalp, is being practiced in only a few laboratories. This
review examines the engineering aspects of recording EPs, such as characteristics
of the stimuli, placement of stimulus electrodes in the GI tract, and enhancement
of evoked potential signals. We also discuss the physiological concepts involved
in the generation of EPs, and how these compare with somatosensory evoked
responses. Current experimental techniques employed by various investigators and
results reported from their laboratories are compared. We believe that cerebral
EPs to GI stimulation could be useful in studying a number of pathophysiological
conditions such as gastroesophageal reflux disease, diffuse esophageal spasm,
chronic inflammatory bowel disorders, chronic abdominal pain, and irritable bowel
syndrome, among others. We hope that the present review will generate interest in
the use of EPs arising out of GI stimulation, aiding in understanding their
physiological implications in healthy subjects and in GI disorders.
PMID- 9403237
TI - Biomechanics of atherosclerotic plaque.
AB - Atherosclerosis is the leading cause of death in the U.S. In balloon angioplasty,
pressure is applied directly to atherosclerotic plaque to reopen the occluded
blood vessel. The mechanical behavior of the plaque often determines the outcome
of the angioplasty. Little information on the material properties of
atherosclerotic plaque is available, yet the properties govern the plaque's
behavior. Our discussion of the experimental testing and numerical analysis of
plaque is directed toward summarizing the current knowledge of plaque material
properties. Atherosclerotic plaque exhibits a wide range of behaviors consistent
with the variability in the underlying composition. Overall, plaques exhibit
nonlinear and inelastic mechanical behavior, although geometry and material
properties are not well known. The histomorphological composition is critical in
determining the plaque's mechanical response. Finite element approximations have
been used to study the stresses developed in the diseased vessel; however,
material properties are a critical component of a finite element analysis: the
predictive capabilities depend on how accurately the material is modeled. When
more information on plaque behavior is generated through careful and extensive
experimental investigations, better models will be constructed to more accurately
predict plaque responses. As the biomechanics community learns about plaque
mechanics, we can use the knowledge to enhance the reliability of interventional
procedures.
PMID- 9403238
TI - Dental mercury amalgam: Part II. Safety of mercury amalgam.
PMID- 9403239
TI - Aural vignettes of dermatologic history. Interview by Victor H Witten.
PMID- 9403240
TI - Verrucous plaque on the back of a hand.
AB - We report the case of a 44-year-old slaughter-house operator with a skin lesion
that had been present for two years on the back of his left hand. The lesion had
increased progressively in size despite numerous topical treatments. Physical
examination revealed an infiltrated erythematous-violet plaque with a verrucous
surface featuring numerous orifices draining purulent material. Histologic study
of the lesion disclosed tuberculoid granulomatous infiltrates at the
dermoepidermal limit. Presence of Mycobacterium tuberculosis, together with other
epidemiologic, clinical, histologic, and immunologic data, permitted a diagnosis
of tuberculosis verrucosa cutis to be made. The excellent response of the patient
to treatment confirmed this hypothesis. However, polychemotherapy withdrawal was
temporarily needed due to analytical abnormalities.
PMID- 9403241
TI - Recurrent condyloma acuminatum due to piercing of the penis.
AB - An unusual case of recurrent condyloma acuminatum in a tubular penile piercing
scar is presented. This case documents a previously unreported dermatologic
infectious sequela of this practice. We comment on complications of bodily and
genital piercing.
PMID- 9403242
TI - Vitiligo.
AB - Vitiligo is a common disorder afflicting people of all ages around the world. It
produces milky white patches of depigmentation that cause significant morbidity
due to cosmetic disfigurement. One should distinguish segmental from nonsegmental
vitiligo, and be aware the latter is associated with an extremely small risk of
associated autoimmune disorders. New therapeutic options offer some additional
hope to patients with vitiligo, but more progress in the understanding of its
pathogenesis and therapy is still needed.
PMID- 9403243
TI - Linear focal elastosis associated with striae distensae in an elderly woman.
AB - We report the case of a 73-year-old woman with linear focal elastosis (LFE)
associated with striae distensae. Yellow palpable striae were found extending
horizontally in the lumbar region. The yellow striae appeared to be joined to
striae distensae in the lateral sides of the yellow striae. Striae distensae were
also present in regions other than the back but were not associated with yellow
striae. Histologic examination of a yellow stria revealed a focal increase in
elastic fibers in the dermis. Although there have been some unusual cases of LFE
arising in women or in young persons, this disorder still predominantly affects
aged men. A fairly uniform feature of LFE is its occurrence on the dorsal skin,
suggesting involvement of this specific anatomical site in its pathogenesis. We
suspect that LFE usually arises de novo in the skin, although striae distensae
may also be a cause of it.
PMID- 9403244
TI - Hair casts: a case of pseudonits.
AB - Hair casts are often misdiagnosed because of their close resemblance to nits from
an infestation with pediculosis capitis. In their clinical presentation both of
these disorders may appear to have white keratinous material adherent to hair
shafts and can look very similar. Microscopic examination provides the definitive
and correct diagnosis. We report a case of hair casts, also referred to as
pseudonits.
PMID- 9403245
TI - Trichophyton rubrum onychomycosis in a 17-year-old girl.
AB - Onychomycosis is one of the most common nail disorders seen by dermatologists. An
increasing number of immunocompromised patients, in combination with an aging
worldwide population, has resulted in a significant increase in the incidence of
this disorder. While nearly one fifth of all occurrences are found in patients
aged 40 to 60, the incidence dramatically increases in patients over 60. However,
onychomycosis is very uncommon in children.
PMID- 9403246
TI - Massive dystrophic calcinosis cutis secondary to chronic needle trauma.
AB - Extensive dystrophic calcinosis cutis of the hips and anterolateral thighs in a
woman with insulin-dependent diabetes mellitus is described. Clinical,
histologic, and radiographic data are provided to familiarize the reader with
this unique and newly described condition. We speculate that repetitive, chronic,
needle trauma in susceptible persons can induce massive dystrophic calcinosis
cutis.
PMID- 9403247
TI - Leukemia cutis as the initial manifestation of acute nonlymphocytic leukemia in a
young child.
AB - A 15-month-old boy was well except for asymptomatic, erythematous, wheal-like
papuloplaques, macules, and nodules on his face and four extremities. It was
misdiagnosed by a pediatrician and treated as urticaria for six months. Later, he
was sent to our hospital for evaluation of prolonged fever. Acute nonlymphocytic
leukemia (M5) with leukemia cutis was diagnosed by results of hematologic
examination and examination of a skin biopsy specimen. After one course of
chemotherapy, all of the skin lesions completely resolved and had not recurred.
Five months after acute nonlymphocytic leukemia was diagnosed, bone marrow
relapse and central nervous system involvement were noted.
PMID- 9403248
TI - Povidone-iodine in antisepsis--state of the art.
AB - The natural element iodine has been used for more than 150 years to prevent
infection and treat wounds. Yet only due to the development of iodophors has it
become possible to use this highly efficient microbicide in a wide range of
medical applications. The antimicrobial spectrum is universal. Its efficiency
against clinically and epidemiologically significant new pathogens, such as
methicillin-resistant Staphylococcus aureus and Enterococcus sp. has also been
validated. No development of resistance has been determined. New data are also
available on the excellent local tolerability of Betaisodona (povidone-iodine)
preparations. On these grounds, a number of clinical fields exist in prophylaxis
and therapy, for either once only or repeated applications: the disinfection of
hands and skin, mucosa antisepsis, intra- and postoperative wound treatment,
therapy of skin infections, burns and chronic wounds.
PMID- 9403249
TI - Nondevelopment of resistance by bacteria during hospital use of povidone-iodine.
AB - Since the bacterial ability to develop resistance against various factors of
their surroundings is a well-known phenomenon, resistance against iodine and
specifically against povidone-iodine (PVP-I) has been widely investigated. Yet
there is little known about bacterial resistance in long-term daily use of
disinfectants in continuous ambulatory peritoneal dialysis (CAPD) patients. The
aim of our study was to investigate whether on daily use of PVP-I over a period
of at least 6 months coagulase-negative staphylococci (CNS)--the predominant
infective organisms of peritonitis--developed resistance against PVP-I. At the
catheter exit site of 40 CAPD patients we isolated 36 CNS. 23 CNS (CNS + PVP)
orginate from patients using PVP-I, 13 CNS (CNS + CI) from patients using sodium
hypochlorite (NaOCl) as disinfectant. The strains were biotyped, antibiotic
resistance patterns were determined and resistance against PVP-I or NaOCl was
calculated as reduction factor using the quantitative suspension test combined
with a turbidimetric standardization. Resistance against PVP-I 0.01% and against
NaOCl 0.005% was determined at two contact times (30 and 300 s) for each patient
group. In addition, we investigated the effects of plasmid loss on sensitivity to
PVP-I. Out of 5 multiple-antibiotic-resistant CNS, 3 strains showed no difference
in reduction factor against PVP-I before and after curing. There was no
significant difference in reduction factor against NaOCl. CNS + PVP were even
significantly more sensitive to PVP-I than CNS + Cl. Taken together, our results
demonstrate that long-term use of PVP-I does not cause any bacterial resistance
in CNS of CAPD patients.
PMID- 9403250
TI - Investigation on the efficacy of povidone-iodine against antiseptic-resistant
species.
AB - The bactericidal activity of commonly used antiseptics against clinical isolates
was determined. It is noteworthy that povidone-iodine (PVP-I) solution showed
high bactericidal activity against all of the test strains after 30 s of
exposure. However, in the case of chlorhexidine gluconate (CHG), residual
bacteria were observed in most species. Next, acquisition of resistance to
antiseptics was examined, and it was found that remarkable increases in MICs were
seen for CHG and alkyldiaminoethylglycine hydrochloride. The strains which
acquired resistance against one antiseptic showed cross-resistance to all
antiseptics except for PVP-I. As for bactericidal activity against biofilm, no
viable cells were seen after a 10-min exposure to PVP-I solution. No decrease in
viable cell count was seen even after a 60-min exposure to any of the other
antiseptics. PVP-I showed high activities in all the tests conducted in this
study. Thus, PVP-I was confirmed to be a clinically useful antiseptic.
PMID- 9403251
TI - Comparison of bactericidal effects of commonly used antiseptics against pathogens
causing nosocomial infections. Part 2.
AB - Opportunistic infections caused by gram-negative rods (GNR), conventionally
regarded as organisms with low or no pathogenicity, and intractable infections
caused by various resistant organisms pose a great problem now. In view of this,
we determined the bactericidal effects of 5 commonly used disinfectants using as
the test strains Xanthomonas maltophilia and Serratia marcescens, chosen among
other GNR since they often cause nosocomial infections. Regarding the
bactericidal activities against X. maltophilia and S. marcescens, both sensitive
strains and resistant strains were killed within 20 s of exposure to povidone
iodine and sodium hypochlorite. With chlorhexidine, 1 strain each of both species
was not killed within 10 min of exposure at a concentration of 0.2%. Both
sensitive strains and resistant strains of X. maltophilia were killed within 20 s
of exposure to benzalkonium at 0.02%, while a concentration of 0.1% was required
for benzalkonium to kill S. marcescens within 20 s. With Tego-51, both sensitive
strains and resistant strains of X. maltophilia were killed within 20 s at 0.02%,
while 1 strain of S. marcescens was not killed within 20 s at a concentration of
0.1%. In the use of disinfectants, comparative bactericidal effects of various
disinfectants against clinical isolates should be taken into consideration.
PMID- 9403252
TI - Inactivation of human viruses by povidone-iodine in comparison with other
antiseptics.
AB - Inactivation of a range of viruses, such as adeno-, mumps, rota-, polio- (types 1
and 3), coxsackie-, rhino-, herpes simplex, rubella, measles, influenza and human
immunodeficiency viruses, by povidone-iodine (PVP-I) and other commercially
available antiseptics in Japan was studied in accordance with the standardized
protocol in vitro. In these experiments, antiseptics such as PVP-I solution, PVP
I gargle, PVP-I cream, chlorhexidine gluconate, alkyldiaminoethyl-glycine
hydrochloride, benzalkonium chloride (BAC) and benzethonium chloride (BEC) were
used. PVP-I was effective against all the virus species tested. PVP-I drug
products, which were examined in these experiments, inactivated all the viruses
within a short period of time. Rubella, measles, mumps viruses and HIV were
sensitive to all of the antiseptics, and rotavirus was inactivated by BAC and
BEC, while adeno-, polio- and rhinoviruses did not respond to the other
antiseptics. PVP-I had a wider virucidal spectrum, covering both enveloped and
nonenveloped viruses, than the other commercially available antiseptics.
PMID- 9403253
TI - Antiseptic efficacy of disinfecting solutions in suspension test in vitro against
methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and
Escherichia coli in pressure sore wounds after spinal cord injury.
AB - In pressure sore wounds after spinal cord injury, methicillin-resistant
Staphylococcus aureus can be detected in 2% of the cases. The elimination of the
germ is the aim of the treatment. Pressure sore wounds are an often found
complication after spinal cord injury. For local treatment five commercially
available antiseptics for the skin and mucous membrane were tested in vitro. The
method used is a modified qualitative and quantitative suspension test. The
antiseptics were tested without and with addition of 5% albumin in order to
simulate the conditions of the wound in vivo. The results show a superior
efficacy of the povidone-iodine preparations. Betadine, probably due to the
higher concentration, is more efficacious than Braunol; chlorhexidine is
sufficiently efficacious without the addition of albumin. These results still
have to be confirmed by in vivo studies.
PMID- 9403255
TI - Profile of patients treated with Betadine cream and ointment in a major burn
centre over a period of ten years (1986-1995).
AB - The management of burns has shown substantial progress over the years. The
application of an effective topical agent improves the healing rate of burns.
Betadine cream and ointment have been used in all the burn admissions since 1986.
The data collected over 10 years are analysed in this report. All the burn
patients admitted were evaluated and the factors investigated included patient
age, sex, cause of injury, extent of burn wound, length of hospital stay,
bacteriology, multi-organ failure and mortality. A total of 6,056 patients were
admitted to a 40-bed unit during the 10-year period. Sixty-two percent were
adults and 37% children. There were 67.5% males and 32.5% females. Eighty-one
percent were admitted directly to the unit. Intensive/high care admissions
accounted for 19.2% patients. The major cause of injury was accidental scalding
in 34.2% patients, and the majority (65.4%) stayed between 1 and 4 weeks in
hospital. There were 452 deaths. This audit reviewing 6,056 sequential burn cases
represents a 10-year experience of burn management, using Betadine cream and
ointment as topical agent.
PMID- 9403254
TI - Effects of Betaisodona on parameters of host defense.
AB - The numbers of patients in intensive care units, with immunosuppression, and of
elderly people increase in parallel with antibiotic-resistant microorganisms.
Therefore the demand for an effective antisepsis increases. Moreover, it became
evident that the pathophysiology and the outcome of infection are dependent on
the properties of the microorganisms, e.g. synthesis of endo- and exotoxins, and
on the host defense, the immune system. In addition to the microbicidal action,
we studied the effects of povidone-iodine (PVP-I, Betaisodona) on the generation,
release and activity of exotoxins (alpha-hemolysin, phospholipase C, lipase), as
well as on granulocyte-derived tissue-destructive enzymes (elastase, beta
glucuronidase) and microbial-induced cytokine generation from human neutrophils.
Our results clearly show that PVP-I does not only kill a wide range of bacteria
but also inhibits the generation and release of bacterial exotoxins; furthermore,
it also inactivates bacterial exotoxins as well as granulocyte-derived tissue
destructive enzymes and cytokines. These data support the usefulness and efficacy
of PVP-I as an effective therapeutic agent to combat infection.
PMID- 9403256
TI - Vaginal antisepsis for hysterectomy: a review of the literature.
AB - Infectious complications of hysterectomy remain common despite the use of
prophylactic antibiotics. Most are caused by contamination of the surgical site
by vaginal bacteria which are not controlled by current methods of pre-operative
antisepsis. The medical literature concerning antiseptic preparation of the
vagina for surgery was reviewed to discover the evidence on which practice may be
based. A search using Medline, Current Contents, the Cochrane Library and the
reference lists of articles on the subject and of major gynaecology textbooks
produced 13 comparative studies. No conclusive randomized controlled trials were
found and most of the studies had severe methodological problems limiting
interpretation of their results. The scant available data suggest that use of
vaginal antiseptics before the patient arrives in the operating room is probably
not useful, and that application of povidone-iodine vaginal gel at the beginning
of abdominal hysterectomy is sufficiently promising to justify further
investigation.
PMID- 9403257
TI - Povidone-iodine to prevent mucositis in patients during antineoplastic
radiochemotherapy.
AB - In an open study, the efficacy of povidone-iodine in the prophylaxis of mucositis
during antineoplastic radiochemotherapy was determined. 40 patients were randomly
assigned to a treatment or control group (each 20 patients). All patients
received standard prophylaxis of mucositis with nystatin, dexpanthenol, rutoside
and immunoglobulin. In addition, the patients of the treatment group performed 4
times daily rinsing with povidone-iodine, the control patients with sterile
water. Clinical examination of the oral mucosa was performed weekly during the
radiation period and up to 6 weeks after the end of therapy. Oral mucositis was
observed in 14 patients of the treatment group (mean grading: 1.0) and in all 20
patients of the control group (mean grading: 3.0). The mean onset of mucositis
was after 2.25 weeks in treatment patients and 1.5 weeks in control patients. The
mean total duration of mucositis was 2.75 weeks in treatment patients and 9.25
weeks in control patients. The mean AUC values were 2.5 in treatment patients and
15.75 in control patients. All findings were statistically significantly
different between the two groups. It is concluded that rinsing with povidone
iodine reduces the incidence, severity and duration of oral mucositis during
antineoplastic radiochemotherapy.
PMID- 9403258
TI - New successful treatment with disinfectant for atopic dermatitis.
AB - For the treatment of atopic dermatitis, a variety of therapies are used including
folk medicine. At present, there is no single treatment which is effective to
cure the symptoms of atopic dermatitis completely in all patients. We are drawing
attention to the high isolation rate of Staphylococcus aureus when starting
disinfectant treatment combined with topical steroid therapies for the purpose of
killing S. aureus. As a result, we examined many patients in whom almost a
complete remission was obtained even after short periods of therapy, though it
had been difficult to obtain improvement by conventional treatments. In many
patients, IgE values and reagin antibody titer decrease dramatically soon after
starting treatment. As a disinfectant, 10% povidone-iodine solution was used. We
investigated also the effect of iodine contained in the povidone-iodine solution
on the thyroid gland.
PMID- 9403260
TI - Prevention of catheter-associated urinary tract infection by meatal disinfection.
AB - The incidence of catheter-associated urinary tract infections (UTIs) becomes
higher with prolongation of the indwelling period of a catheter. As to the entry
of bacteria, ascending UTIs have now attracted attention. In the present study.
the metal area was examined bacteriologically and the possibility to use
antiseptics for blocking the route of developing infections was investigated. The
subjects included 72 patients with an indwelling, urethral catheter inserted post
operatively. These patients were divided into three groups treated with once or
twice daily application of povidone-iodine or once daily application of povidone
iodine cream. In these groups, the relation between changes in isolation of
bacteria from the meatal area and the incidence of UTI was evaluated. It was
found that reduction in bacterial count by antisepsis is effective to prevent
ascending UTIs. Moreover, once daily application of povidone-iodine was proven to
be effective in male patients. The effective antisepsis in females was twice
daily application of povidone-iodine.
PMID- 9403259
TI - The influence of long-term treatment with povidone-iodine on thyroid function.
AB - Povidone-iodine (PVP-I) is generally very safe, but cases of thyroid dysfunction
induced by PVP-I have been reported. The effect of long-term treatment with PVP-I
on thyroid function was to be assessed. In 40 inpatients of the department of
neurology, the status of the use of PVP-I preparations and their effects on serum
inorganic iodine levels and thyroid functions were investigated. In 27 patients
treated with PVP-I for a long term, inorganic iodine levels were significantly
increased as compared to those in 13 patients without PVP-I treatment. Out of 27
patients treated with PVP-I in the long term, subclinical hypothroidism was seen
in 3 patients, mild hyperthroidism was seen in 1 patient, and subclinical
hyperthyroidism was suspected in 7 patients. Patients treated with PVP-I for a
long time should be observed carefully for any manifestation of thyroid
dysfunction.
PMID- 9403262
TI - An open-label study conducted to evaluate the efficacy of Betadine cold sore
paint.
AB - An open-label, randomised, parallel-group efficacy study was designed to compare
Betadine cold sore paint and Stoxil topical ointment for the prevention of
shedding of herpes simplex virus (HSV) from cold sores. Seventy-two patients aged
18-61 years (mean 32.2 years), with symptoms indicating recent onset of herpes
labialis, were entered into the study. Patients were randomised to receive
Betadine cold sore paint, Stoxil topical ointment or no treatment. To detect
infectious virus, swabs were taken for virus culture before and 2 h after
treatment. The no-treatment control group was included to monitor the efficiency
of the swabbing technique. The primary measure of efficacy was the proportion of
patients in each group returning a swab positive for HSV prior to treatment
application and negative for HSV 2 h after treatment application. All 72 patients
completed the study. HSV clearance rates were 0.636 for the Betadine treatment
group and 0.092 for the Stoxil treatment group (p = 0.00056). It was concluded
that recovery of infectious HSV from the lips of patients who applied Betadine
cold sore paint to their lesions was significantly lower than from patients who
applied Stoxil topical ointment.
PMID- 9403261
TI - Antiseptic effect of povidone-iodine solution on abdominal skin during surgery
and on thyroid-gland-related substances.
AB - No definite guidelines have been published concerning the suitable exposure time
and frequency of skin antisepsis of the operative field. In the present study,
the antiseptic effect of a single use (single-application group) of 10%
povidoneiodine solution for skin antisepsis was compared with its triple use
(triple-application group). The exposure time was 2 min for both groups.
Moreover, the effects on blood levels of total iodine and thyroid-gland-related
substances were evaluated. High antiseptic efficacy was obtained in both groups,
indicating that our antiseptic method to disinfect the operative field is
effective. Slightly better results were obtained from the triple-application
group, although the difference was not statistically significant. Blood levels of
total iodine and thyroid-gland-related substances remained within the normal
range in all cases. However, in cases receiving a large amount of 10% povidone
iodine solution a transient elevation in blood total iodine was observed. Thus,
the 10% povidone-iodine solution is considered to be safe and effective for skin
antisepsis of the operative field when applied repeatedly in a small amount per
dose with an exposure time of about 2 min.
PMID- 9403263
TI - Cytotoxicity and sensitization of povidone-iodine and other frequently used anti
infective agents.
AB - Povidone-iodine is an antiseptic widely used in dermatology. In vitro experiments
showed a certain cytotoxicity, yet it is not easy to transfer these toxicological
data to in vivo circumstances. In vivo investigations in animals and in humans
could exclude cytotoxic effects of povidone-iodine, measured by the wound healing
process. Only when administered in combination with detergents was an obvious
cytotoxicity seen in wounds but not on the intact skin. In comparison to the
frequently used antibiotic neomycin, the sensitization rate of povidone-iodine is
very low.
PMID- 9403265
TI - Pharmaceutical and bacteriological study on povidone-iodine sugar ointment.
AB - Povidone-iodine sugar ointment is an excellent preparation for the treatment of
decubitus. It has been used as an intrahospital preparation made according to the
formula each hospital decided on from experience. Although commercial products
have also been developed and used, they are too expensive. The efficacy of a
povidone-iodine sugar ointment formulation which can be prepared by a single
method and which has the stability and antibacterial activity equal to
commercially available products was evaluated. As the test drugs, one
commercially available product (UP), and three preparations with different
formulas (P-1, P-2 and P-3) were used. All of these test drugs were stored at 20
and 40 degrees C. Specimens were sampled immediately after storage and after 20,
60, 90, 120 and 150 days and examined pharmaceutically (measurement of pH value
and determinations of available iodine and sucrose levels). For the determination
of bacteriological effects, 5 standard strains of 5 genera and 5 strains of
methicillin-resistant Staphylococcus aureus (MRSA) were used and the time
required to kill the bacteria was determined. For UP and P-3, no changes were
seen pharmaceutically after 150 days of storage at 20 and 40 degrees C. However,
MRSA could not be killed within 30 min. P-1 and P-2 showed remarkable changes
pharmaceutically after 60 days of storage at 40 degrees C and could not be used
any more. It became possible to make a preparation of povidone-iodine sugar
ointment which has a stability almost similar to that of UP. Moreover, such a
preparation can be made at low cost. However, since the bactericidal activity
against MRSA was not higher than those of other drugs, the future task is to
improve the bactericidal activity.
PMID- 9403264
TI - Povidone-iodine liposomes--an overview.
AB - In recent years, liposomes have been increasingly explored as novel drug delivery
systems, and several liposome-based drug products have been approved in Europe,
the USA and Japan. Depending on size, composition and surface characteristics,
liposomes interact specifically with biological structures. Liposomal drug
products provide a topical activity at the desired locus of action and are deemed
more effective and less toxic than conventional drug formulations. The
combination of povidone-iodine (PVP-I) and liposomes unites the exceptional
microbicidal activity of the antiseptic substance with the excellent tolerability
and lack of immunogenicity of liposomes; in addition, liposomes provide a moist
molecular film for the wound environment. The multilamellar vesicles act as
microreservoirs hence prolonging the release of the active ingredient. Although
no commercial product for repeated application on the eye is currently available,
PVP-I has been used in ophthalmology not only for pre- and postoperative
antisepsis, but also for the treatment of bacterial and viral conjunctivitis and
for prophylaxis against ophthalmia neonatorum. For these indications, liposomal
formulations with 2.5 and 5.0% PVP-I were developed. These eye drops are isotonic
with tear fluid at pH 6. First in vitro tests demonstrated an excellent
antimicrobial efficacy, and a placebo-controlled clinical study on volunteers
showed a very good local tolerability. A study on rabbits demonstrated positive
results of the PVP-I liposome eye drops compared to placebo and the broadspectrum
antibiotic Polyspectran in a standardized model of Staphylococcus aureus deep eye
infection. The other aim is a well-tolerated liposomal PVP-I hydrogel for
improved antiseptic wound treatment with moisturizer. It has been reported that
liposomes are enriched at the wound bottom for direct action against infection
and support of wound healing. An animal study on the efficacy and tolerability of
different formulations of a hydrogel with PVP-I liposomes in deep dermal burn
wounds has indicated an outstanding quality of wound healing with smooth
granulation tissue, less inflammation, less wound contraction and no
hyperkeratotic reactivity, especially with the 3% PVP-I liposome formulation.
PMID- 9403266
TI - Bactericidal activities of povidone-iodine against Mycobacterium.
AB - Three standard strains of Mycobacterium (M. tuberculosis H37Rv, M. avium
ATCC15769 and M. kansasii ATCC12478) and 15 clinical isolates of Mycobacterium (7
M. tuberculosis, 2 M. avium, 3 M. kansasii, 1 M. intracellulare, 1 M. chelonae
subsp. abscessus and 1 M. gordonae) were selected in order to study the
bactericidal activities of povidone-iodine (PVP-I) drug substance and a
commercially available PVP-I solution (Isodine solution) against Mycobacterium.
After the bacilli had been exposed to the disinfectant solution at concentrations
of 0.1 or 0.02% with 2% human serum for various incubation periods from 30 to 120
s, the PVP-I drug substance was inactivated by addition of 0.5% sodium
thiosulfate. In the case of the commercially available PVP-I solution, a mixture
of 10% Tween 80, 3% soybean lecithin and 0.5% sodium thiosulfate was used as
inactivator. It was demonstrated that the 3 standard strains were completely
inactivated within 30 s by 0.1% PVP-I drug substance and that the 15 clinical
isolates were almost killed by 0.1% commercially available PVP-I solution within
60 s. As a result, the commercially available PVP-I product appeared to be a
useful agent as disinfectant against all the tested species of Mycobacterium.
PMID- 9403267
TI - Antiseptic effects at injection sites.
AB - To our knowledge, there are no published papers detailing antisepsis for
injection sites. In view of this, the efficacies of povidone-iodine (PVP-I)
ethanol solution and chlorhexidine (CH) ethanol, the agents most commonly used
for antisepsis of the operative field, were compared. Before and after the
injection site was disinfected with either of these antiseptics, specimens of
indigenous bacteria on the skin were collected by the cylinder scrub method, and
the bacteria reduction rate and the reduction factor (RF) were determined to
evaluate the efficacy of antisepsis. The bacteria reduction rate and RF value
obtained for PVP-I ethanol were 95.1 +/- 11.2 and 2.1 +/- 0.9% and those for CH
ethanol were 93.5 +/- 9.3 and 1.8 +/- 0.9%. Since there were individual
differences in cell count before antisepsis, no significant difference was seen
in bactericidal activity. However, slightly more favorable results were obtained
with PVP-I ethanol. Although it is impossible to eradicate completely the
indigenous microbes with currently available methods, it is considered important
for the prevention of infection of the injection site to decrease bacterial
counts as much as possible.
PMID- 9403268
TI - Molecular effects of povidone-iodine on relevant microorganisms: an electron
microscopic and biochemical study.
AB - The aim of this study was to elucidate the effects of povidone-iodine (PVP-I) on
cell ultrastructure by electron microscopy and to monitor changes in enzyme
activity and nucleotide efflux. Staphylococcus aureus, Escherichia coli and
Candida albicans, medically relevant gram-positive, gram-negative and yeast
microorganisms, served as models. In the presence of PVP-I, rapid partitioning of
the cytoplasm and pronounced coagulation of nuclear material was noted. E. coli
and S. aureus showed no major structural wall damage. C. albicans exhibited a
rapid, dose-dependent 'loosening' of the cell wall; cells remained intact without
lysis, rupture or wall breakage. Changes in beta-galactosidase and nucleotide
concentrations were measured in E. coli. A rapid and dose-dependent loss of
cellular beta-galactosidase activity was found, with no increase in the
supernatant; loss of cellular nucleotides corresponded with an increase in the
supernatant. Electron-microscopic and biochemical observations support the
conclusion that PVP-I interacts with cell walls of microorganisms causing pore
formation or generating solid-liquid interfaces at the lipid membrane level which
lead to loss of cytosol material, in addition to enzyme denaturation.
PMID- 9403269
TI - Antiproliferation effects of hexadecylphosphocholine on solid tumour and
leukaemia selectively in vitro.
AB - Hexadecylphosphocholine (HePC), an alkylphospholipid analogue representing a new
class of antitumor agents, exerts sufficient oncolytic potencies that it might be
developed as a selective antitumour drug. This paper reports that 12 cell lines
of leukaemia and solid tumour employed in this study were inhibited by HePC in
vitro. This result indicated that HePC possessed general antitumour properties,
but did not interfere significantly with cell proliferation of normal BMC in
tests of colony formation in granulocytic-macrophage colonies (CFU-GM). Because
of these advantages, we suggest that HePC would be an excellent antitumour agent
for selectively killing tumour cells and is of low toxicity as compared to
conventional cytotoxic agents.
PMID- 9403270
TI - Effect of heparin on cell proliferation: lack of correlation with heparin binding
sites on cell membrane.
AB - In this study an attempt was made to correlate the in-vitro anti-proliferative
effect of heparin with the heparin binding on the cell surface. Cells with
different sensitivities to the anti-proliferative effect of heparin (BHK-21, FAO,
SMC, BAEC, A-431, V-79, and skin fibroblasts) were incubated with [3H]heparin
either in the presence or in the absence of unlabelled heparin. A saturable
binding was found only in BHK-21, FAO, SMC, BAEC and V-79. Scatchard analysis
revealed the presence of a single class of binding sites. The binding of [3H]
heparin was efficiently displaced by unlabelled heparin, pentosan polysulfate and
low-molecular-weight heparin, but not by dermatan sulfate. Although the
sensitivity to the anti-proliferative effect of heparin varied considerably among
the cell types (BHK-21 > SMC, FAO > BAEC > V-79), there was no correlation
between the reduction of proliferation of these cells and either their heparin
binding capacity or the number of binding sites per cell.
PMID- 9403271
TI - Effect of peroxovanadate compound on phosphoenolpyruvate carboxykinase gene
expression and lipid metabolism in diabetic rats.
AB - Although it was proved that peroxovanadate-nicotinic acid (POV) can decrease
hyperglycaemia and hyperlipaemia, its molecular biochemical mechanism of action
is unclear. The present investigation aimed at studying the effect of POV on gene
expression and enzymatic activity of hepatic phosphoenolpyruvate carboxykinase
(PEPCK) and blood lipid metabolism in streptozotocin-diabetic rats in order to
suggest the molecular biochemical mechanism of POV action in lowering
hyperglycaemia and hyperlipaemia. The results showed that the gene expression and
enzymatic activity of hepatic cytosolic PEPCK, which were increased in diabetic
rats, were significantly reduced following POV treatment. Similarly, POV was
shown to oppose significantly the hyperglycaemia and hyperlipaemia in these
diabetic rats. These results suggested that a possible mechanism of POV action
was to inhibit PEPCK gene expression as well as PEPCK activity which could
explain the reduced gluconeogenesis and hyperglycaemia.
PMID- 9403272
TI - Effect of acute and chronic inflammation on plasma growth hormone levels in rats.
AB - We investigated the effect of acute and chronic stress on growth hormone (GH)
plasma levels in rats. Acute stress was provoked by intravenous administrations
of IL-1 beta and TNF-alpha. Determinations were made at 10, 30, 60, 120 and 180
min following i.v. injection of these cytokines into the caudal vein. We also
investigated the chronic stress induced by hind paw injections of Freund's
adjuvant. Arthritis was developed by 21 days following such injection. GH levels
were studied at 7, 14 and 21 days after induction of arthritis on several blood
samples which were withdrawn from tail veins, and long-term hormonal profiles (3
hours' sampling) were determined at 12.00 am, 1.30 pm and 3.00 pm. Local
administration of dexamethasone and the monoclonal antibody anti-ICAM-1 were also
used in arthritic rats. Following acute stress, a significant reduction of plasma
GH levels has been evidenced, possibly related to the stimulation of
corticotropin-releasing hormone. Following chronic stress, we demonstrated a
significant increase of GH levels, which were significantly reduced by
dexamethasone treatment and to a lesser extent by anti-ICAM-1 administration.
PMID- 9403273
TI - Paradoxical effects of intra-arterial administration of basic fibroblast growth
factor on inflammatory angiogenesis in rats.
AB - The authors studied the effects of basic fibroblast growth factor (b-FGF) on
inflammatory angiogenesis in rats. In the corneal cauterization model b-FGF was
given intra-arterially (i.a.) (carotid) and in the mesenteric window angiogenesis
model, topically (i.e., intraperitoneally (i.p.)). The corneal cauterization was
done under anaesthesia by topical application of silver nitrate. Mesenteric
window angiogenesis was induced by injection of saline or b-FGF for four days.
There were the same two groups of treatment in both models b-FGF 2.5
micrograms/kg/day or saline 1.2-5 ml/kg/day. The area of neovessels and the
number of polymorphonuclear cells/field were considered for the corneal
angiogenesis, the total length of neovessels was measured for the mesenteric
window angiogenesis. The results were expressed as mean values (s.d.). When given
i.a., b-FGF significantly reduced the number of polymorphonuclear cells three
days after corneal cauterization (from 107 +/- 27 to 41.8 +/- 26, p < 0.01) and
inhibited the area covered by neovessels (30 +/- 7.7% vs 51 +/- 20%, p < 0.01)
after five days. In contrast, given through the extracellular space, it
significantly stimulated the length of mesenteric window microvessels (169 +/- 60
mm vs 90 +/- 31 mm, p < 0.05). These results suggest that b-FGF stimulates
inflammatory angiogenesis through interaction with extracellular matrix
components, but inhibits it directly when given intra-arterially.
PMID- 9403274
TI - Phase I clinical trial of cefditoren pivoxil (ME1207). Tolerance in healthy
volunteers.
AB - A tolerance study to ME1207 was conducted in healthy volunteers using five single
doses administered before a meal (50, 100, 200, 300 and 500 mg), a single 200 mg
dose administered after a meal, and 200 mg administered every 12 h for 7 days. No
subjective symptoms or changes in haematological and biochemical examinations and
urinalysis were observed after single administration of 50 to 500 mg Four
subjects complained of minimal upper abdominal discomfort when 200 mg was
administered every 12 h for 7 days, but this symptom disappeared without remedial
action in all cases. Therefore ME1207 was thought to be safe when orally
administered at the above-mentioned doses by the above-mentioned administration
methods.
PMID- 9403275
TI - Possible involvement of nitric oxide in the quinolone-induced tendon lesions in
rats.
AB - Quinolone antibacterial agents have been reported to induce adverse effects on
the tendon and the musculoskeletal system in humans. We have previously
demonstrated that Achilles tendon lesions could be induced in juvenile rats by a
single oral administration of quinolones at high doses with simultaneous
induction of lesions in the muscle, synovial membrane and articular cartilage. In
the present investigation, we examined the involvement of nitric oxide (NO) in
pefloxacin (PFLX)-induced lesions of the Achilles tendon in juvenile rats. The
incidence of lesions was diminished markedly by co-administration of a potent NO
synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). Further, the
urinary nitrate/nitrite excretion was decreased significantly by 4 h after
administration, unchanged between 4 and 8 h, and significantly increased in the 8
to 24-h samples in the PFLX group, as compared to the control group. In
contrast, the serum concentration of nitrate/nitrite was significantly higher in
the PFLX group 4 h after administration, but there was no difference from
controls was observed at 8 and 24 h. These results suggest that NO is involved in
the induction of Achilles tendon lesions in juvenile rats by pefloxacin (PFLX)
and may be similar to the tendon disorder of humans receiving quinolones.
PMID- 9403276
TI - Who cares about pharmacovigilance?
PMID- 9403277
TI - University hospital-based drug information service in a developing country.
AB - In 1994, a clinically oriented drug information unit was established at the
Tribhuvan University Teaching hospital in Nepal, with a view to providing
objective and independent information through a question-answer service and
bulletin production. During the first 2 years of its service, the unit received a
total of 674 encounters, with an average of 28 inquiries a month (range 13-42):
about three-quarters (74.5%) of all the inquiries were from prescribing doctors,
including 38.0% from specialist clinicians: about a quarter (24.6%) were related
to patient problems. Most (86.8%) of the responses were provided within 24 h of
the inquiry. Frequently encountered queries related to: pharmacotherapy of a
disease or drug indication(s), adverse drug reactions, drug doses, availability,
drug use in pregnancy, ingredient(s) of a proprietary product, precautions for
use and drug interactions. Details of the inquiries received and the responses
provided by the unit are documented in a standard question-answer form. The unit
also carries out proactive dissemination of information through the publication
and free distribution of a bimonthly bulletin which includes brief referenced
reviews on drug- and therapeutics-related topics. Nepal- or the local situation
related write-ups are now being increasingly included in the bulletin. A users'
survey carried out at the end of 1-year service indicated that the question
answer and bulletin production activities of the unit were well-perceived by its
target audiences, i.e. the prescribing doctors and postgraduate medical students.
Although Medline on CD-ROM and original journal articles available in the
hospital library were consulted for answering a few of the questions, the vast
majority of them could be adequately handled by consulting a limited number of
well-known drug information books. Our experience indicates that in developing
countries such as Nepal, where funds are often severely limited, a small-scale
drug information centre, serving a local area, can be usefully initiated by a few
motivated staff with a modest collection of about a dozen key reference books.
PMID- 9403278
TI - Twenty-four-hour blood pressure monitoring during treatment with extended-release
felodipine versus slow-release nifedipine in elderly patients with mild to
moderate hypertension: a randomized, double-blind, cross-over study.
AB - OBJECTIVE: This double-blind, placebo-controlled randomized study was designed to
compare the antihypertensive effect and tolerability of extended-release
felodipine and slow-release nifedipine retard in elderly hypertensive patients.
METHODS: Thirty patients of both sexes (mean age 71 years) with mild to moderate
essential hypertension were recruited from our hypertension outpatient clinic.
After a 2-week placebo period, felodipine extended-release (felodipine ER), 10 mg
once daily, nifedipine slow-release retard (nifedipine SR), 20 mg twice daily or
placebo were administered to each patient for 2 weeks according to a 3 x 3 latin
square design. At the end of each treatment period, the patients underwent 24-h
noninvasive blood pressure monitoring. RESULTS: All of the patients completed the
trial and no serious adverse experience was reported. In comparison with placebo,
felodipine and nifedipine decreased mean 24-h diastolic blood pressure by 6.7 and
4.3 mmHg, respectively, with no significant difference between the two drugs.
Mean 24-h systolic blood pressure also decreased after felodipine and nifedipine,
with no difference between the two drugs. Both drugs reduced blood pressure
variability, lowering the 24-h mean standard deviation of mean hourly blood
pressure values. The trough:peak ratio for felodipine was 80% for systolic and
75% for diastolic blood pressure. CONCLUSION: Felodipine ER once daily lowers
blood pressure in elderly hypertensives and is as effective as nifedipine SR
twice daily. The high trough:peak ratio suggests that the dose and the between
dose interval of felodipine provides adequate therapeutic coverage.
PMID- 9403279
TI - Povidone-iodine wash solutions in the prevention of superficial fungal
infections; predictive evaluation using the corneofungimetry bioassay.
AB - OBJECTIVE: Prevention of superficial mycoses remains a stubborn problem. The
effect of antiseptics for that purpose is largely unknown. We studied the
potential fungitoxic activity of povidone iodine (PVP-I) contained in wash
solutions. METHODS: The corneofungimetry bioassay was conducted using PVP-I at
1.33%, 2.5%, 4% and 7.5% as test products and four target fungi, namely Candida
albicans, Trichophyton rubrum, T. mentagrophytes, var. interdigitale (20 strains)
and Microsporum canis. RESULTS: Data show that PVP-I limits fungal growth on
stratum corneum. Different species and strains of fungi are not similarly
affected. There also exists a diversity of individual susceptibility of the
stratum corneum to promote germination of yeasts and arthroconidia.
PMID- 9403280
TI - Drug-induced chest pain and myocardial infarction. Reports to a national centre
and review of the literature.
AB - OBJECTIVES: To analyse reports of drug-induced myocardial infarction and chest
pain sent to a national reporting centre. To review which drugs were suspected of
exhibiting these adverse events and what mechanisms were involved. METHODS:
During the 20-year period 1975 through 1994, a total of 19,141 reports on adverse
reactions to drugs were received by the Netherlands Centre for Monitoring of
Adverse Reactions to Drugs. Of these 19,141 reports, 220 (1.1%) were concerned
with drug-induced chest pain or myocardial infarction. After excluding reports in
which the causal relationship was unlikely, poorly documented reports and reports
on cases of overdosage, 183 reports (84%) were analysed. RESULTS: There were 130
reports (71%) of drug-induced chest pain and 53 reports (29%) of drug-induced
myocardial infarction. A total of 104 reports concerned females (57%). The most
frequently reported suspected drugs were the antimigraine drug sumatriptan (33
reports, 4 concerning myocardial infarction), the calcium antagonist nifedipin (9
reports, 2 of myocardial infarction) and nicotine [9 reports (8 patches, 1
chewing gum), 5 concerning myocardial infarction]. There were 18 reports of a
fatal outcome. CONCLUSIONS: Several drugs can produce chest pain or myocardial
ischaemia. It is important to recognise drugs as a potential cause, especially in
patients with normal coronary arteries.
PMID- 9403281
TI - Pharmacokinetics of mezlocillin and sulbactam under continuous veno-venous
hemodialysis (CVVHD) in intensive care patients with acute renal failure.
AB - OBJECTIVE: In intensive care medicine, continuous detoxication methods, such as
continuous veno-venous hemodialysis (CVVHD), are used for treating acute renal
failure. However, in contrast to conventional hemodialysis, little is known about
the pharmacokinetics of many drugs administered in this setting and guidelines
for dosages of drugs often do not exist. This holds particularly true for broad
spectrum antibiotics, which are often required during intensive care. METHODS: In
this study, we investigated the pharmacokinetics of the acylureidopenicillin
mezlocillin and the beta-lactamase inhibitor sulbactam during CVVHD and deduced
dosage recommendations from the kinetic parameters with the goal of maintaining
trough levels of above 10 mg.l-1 for mezlocillin and 5 mg.l-1 for sulbactam. Six
intensive care patients with acute renal failure, receiving mezlocillin (n = 5)
and/or sulbactam (n = 4), were examined during CVVHD and during intervals between
CVVHD. The serum concentrations and the amounts of the drugs excreted into the
dialyzate and into the urine within one dosage interval were measured using high
performance liquid chromatography (HPLC). Three of the patients were jaundiced,
indicating functional impairment of the liver. RESULTS: The clearances by CVVHD
(CLCVVHD) for mezlocillin ranged between 11.0 and 44.9 ml.min-1 and the half
lives ranged between 1.12 and 8.84 h. Low CL and long half lives were observed in
the patients with jaundice. For sulbactam, CLCVVHD ranged between 10.1 and 22.8
ml.min-1 and serum half lives were 4.25-6.11 h, independent of liver function.
CONCLUSION: Due to high hepatobiliary clearance of mezlocillin, dosage
adjustments in patients with acute renal failure, treated by CVVHD, are needed
only with concurrent impaired liver function. For sulbactam, the optimal dose was
found to be 0.5 g, administered every 12 h, regardless of liver function.
PMID- 9403282
TI - The pharmacokinetics of pravastatin in patients on chronic hemodialysis.
AB - OBJECTIVE: The single-dose and steady-state pharmacokinetics of the HMG CoA
reductase inhibitor pravastatin and its two metabolites, SQ 31,906 and SQ 31,945,
were evaluated in 12 hemodialysis patients. A single 20-mg i.v. dose was
employed, followed by daily oral dosing of 20 mg over four hemodialysis
intervals. RESULTS: No statistical differences in the pharmacokinetics of
pravastatin or SQ 31,906 were evident when comparing the first and last days of
oral dosing with pravastatin. The pharmacokinetic parameters of pravastatin and
SQ 31,906 were similar to those of healthy volunteers. SQ 31,945, the inactive
polar metabolite, did accumulate in dialysis patients, as evidenced by an
accumulation index of 1.7 +/- 1.0. Although metabolic clearance is the
predominant mode of elimination of pravastatin, hemodialysis clearances of
pravastatin, SQ 31,906 and SQ 31,945 will contribute to total body clearance
since dialytic clearance ranged from 40 to 80 ml.min-1. CONCLUSION: Pravastatin
can be safely administered in the usual dosages to subjects with renal failure on
hemodialysis and no change in dosing is necessary.
PMID- 9403283
TI - Clearance of ceftriaxone during haemodialysis using cuprophane, haemophane and
polysulfone dialysers.
AB - OBJECTIVE: The purpose of the present study was to investigate whether the
clearance of ceftriaxone during haemodialysis is influenced by the type of
membrane used (cuprophane, haemophane or polysulphone). METHODS: After
administration of a single 2-g dose of ceftriaxone, the half-life of the drug
during haemodialysis and the clearance of the dialyser were measured. RESULTS:
The mean dialysis clearance normalised for square metre of membrane surface was
significantly different for the three dialysers (haemophane 24 ml.min-1.m-2;
cuprophane 32 ml.min-1.m-2; polysulphone 42 ml.min-1.m-2). CONCLUSIONS:
Polysulphone membranes are more permeable and increase the extraction of
ceftriaxone more than the other dialysers studied (haemophane and cuprophane
membranes). These results, taken together with previous data, show that an
increase of the dose in dialysis patients treated with large surface (> 0.8 m2)
and high permeability membranes might be necessary.
PMID- 9403284
TI - Comparative pharmacokinetics of dirithromycin and erythromycin in normal
volunteers with special regard to accumulation in polymorphonuclear leukocytes
and in saliva.
AB - OBJECTIVE: In a randomized cross-over study, we assessed pharmacokinetics and
intracellular concentrations in polymorphonuclear leukocytes (PMN) and saliva of
erythromycin and erythromycylamine, the active metabolite of dirithromycin.
METHODS: Ten healthy volunteers received 1 g erythromycin b.i.d. or 500 mg
dirithromycin qd for 5 days (wash out period, 35 days). Concentrations of
erythromycin and erythromycylamine were measured in serum, urine, saliva, and
granulocytes by bioassay and high-performance liquid chromatography (HPLC) on
days 1, 3, and 5 of each study period, respectively. RESULTS: While maximal serum
concentrations (Cmax) and the area under the data (AUDtot) of erythromycin were
significantly higher (Cmax 1.44 mg.l-1, AUDtot 5.66 mg.h.l-1) than those of
erythromycylamine (Cmax 0.29 mg.l-1, AUDtot 1.96 mg.h.l-1), erythromycylamine had
a significantly higher mean residence time (21 h) than erythromycin (5.5 h).
Erythromycylamine accumulated significantly more in PMN than erythromycin; the
accumulation factor of erythromycylamine was 100 with a maximal intracellular
concentration of 13.4 mg.l-1, whereas the maximal accumulation factor of
erythromycin was 4 with a maximal intracellular concentration of 6.1 mg.l-1.
There were no significant differences in maximal saliva concentrations
(erythromycin 0.35 mg.l-1, erythromycylamine 0.31 mg.l-1).
PMID- 9403285
TI - Food increases the bioavailability of mefloquine.
AB - OBJECTIVES: To assess the effect of food on the pharmacokinetics of the
antimalarial mefloquine and its major plasma metabolite in healthy volunteers.
METHODS: In an open, two-way cross-over study, 20 healthy male volunteers who had
fasted overnight were randomised to receive a single oral dose of 750 mg
mefloquine in the absence or presence of a standardised, high-fat breakfast,
administered 30 min before drug administration. Blood samples were taken at
specific times over an 8-week period. Plasma concentrations of mefloquine and its
carboxylic acid metabolite were determined by high-performance liquid
chromatography for pharmacokinetic evaluation. RESULTS: The parameters Cmax and
AUC of both mefloquine and its metabolite were significantly (P < 0.05) higher
under post-prandial conditions than under fasting conditions (mefloquine: mean
Cmax 1500 vs 868 micrograms.l-1, mean AUC 645 vs 461 mg l-1.h; metabolite: Cmax
1662 vs 1231 micrograms.l-1, AUC 1740 vs 1310 mg l-1.h). The intersubject
variability in Cmax and AUC of mefloquine was less than 30% (coefficient of
variation). The time to peak plasma concentration of mefloquine was significantly
shorter after food intake (17 vs 36 h). Compared with absorption in volunteers
who had fasted, food did not alter t1/2 (mefloquine and its metabolite) and tmax
(metabolite). CONCLUSION: Under the conditions of this study, food increases the
rate and the extent of mefloquine absorption. It is reasonable to recommend that
mefloquine be administered with food in travellers receiving chemoprophylaxis and
in patients on recovery receiving curative treatment. In acutely ill patients,
mefloquine should be taken as soon as possible and administration with or shortly
after meals should be attempted as soon as feasible.
PMID- 9403286
TI - The influence of two types of meal on the pharmacokinetics of a modified-release
formulation of nifedipine (Adalat Retard).
AB - OBJECTIVE: The effect of two different types of meal on the absorption of a
modified-release formulation of nifedipine (Adalat Retard) was studied. RESULTS:
A light breakfast produced a delay in gastric emptying (indicated by the rate of
paracetamol absorption) compared with the fasting state but did not alter the
tmax or Cmax for nifedipine significantly. After a cooked breakfast, there was
less delay in gastric emptying and again no delay in tmax for nifedipine.
However, the Cmax for nifedipine was significantly higher than in the fasting
state. Neither meal influenced the bioavailability of nifedipine. CONCLUSION: The
results suggest that the nature of the meal has an important influence on the
absorption profile of this formulation of nifedipine, probably by an effect on
its dissolution. This study illustrates the importance of considering the effects
of different types of meal before concluding that food does not affect the
pattern of drug absorption.
PMID- 9403287
TI - The effect of codeine on gastrointestinal transit in extensive and poor
metabolisers of debrisoquine.
AB - METHODS: Codeine (50 mg) was administered to 12 extensive metabolisers (EM) and
12 poor metabolisers (PM) of debrisoquine. The oro-caecal transit time was
estimated by the hydrogen breath test. The urinary excretion of codeine and
metabolites during a 6-h interval was estimated after simultaneous analysis of
codeine, morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), morphine
(M), normorphine (NM), norcodeine, norcodeine glucuronide and codeine-6
glucuronide using HPLC. RESULTS: The mean transit times after placebo were 1.3 h
in the EM and 1.4 h in the PM. The corresponding figures after ingestion of
codeine were 2.2 h and 2.1 h. The differences between the groups were
statistically and clinically insignificant. The effect of codeine compared with
placebo was significantly different in both groups. As expected, the metabolites
of the O-demethylation pathway, M, M6G, M3G and NM were significantly lower in
the PM. Interestingly, the recovery of the dose in the form of codeine (> 1.7
times) and norcodeine (> 2.5 times) was significantly higher in the PM,
indicating compensatory metabolism via N-demethylation. CONCLUSION: In contrast
to the analgesic effect, the prolongation of gastrointestinal transit caused by
the drug does not depend on the formation of O-demethylated active metabolites M,
M6G or NM.
PMID- 9403288
TI - Concomitant administration of the alpha-glucosidase inhibitor voglibose (AO-128)
does not alter the pharmacokinetics of glibenclamide.
AB - OBJECTIVE: Voglibose is a new and potent inhibitor of alpha-glucosidases used for
treatment of diabetes mellitus. It increases gastro-intestinal motility and could
thus affect absorption of other concurrently administered antidiabetic drugs. The
aim of this study was to investigate whether or not voglibose modifies the
pharmacokinetics of glibenclamide, a widely used oral antidiabetic, and the
glibenclamide-induced decrease in fasting serum glucose. METHODS: Twelve healthy
male subjects were included in this double-blind cross-over study and received a
single 1.75-mg dose of glibenclamide on the 8th day of continuous administration
of either placebo (reference) or voglibose 5 mg t.i.d. (test). Blood samples were
taken to determine the pharmacokinetic characteristics of glibenclamide and the
test/reference ratios were evaluated according to bioequivalence criteria.
Additional blood samples were taken to measure serum glucose on the same day.
RESULTS: The concentration-time course of glibenclamide under concomitant
voglibose administration was similar to that under placebo. The equivalence ratio
(test/reference) for the pharmacokinetic characteristics AUCnorm was 1.03
(geometric mean; 0.95-1.11, 90% confidence interval) and Cmax.norm 1.01 (0.94
1.08). The parameters were within the accepted range of 0.8-1.25 (AUC) or 0.7
1.43 (Cmax), thus fulfilling equivalence criteria and indicating no effect of
voglibose on glibenclamide kinetics. The glibenclamide-induced decrease in
fasting serum glucose concentration was similarly independent of placebo or
voglibose co-administration. CONCLUSIONS: Voglibose did not interact with
glibenclamide on a pharmacokinetic level. Concomitant treatment was well
tolerated and has been proven to be safe for further clinical use.
PMID- 9403289
TI - The alpha-glucosidase inhibitor voglibose (AO-128) does not change
pharmacodynamics or pharmacokinetics of warfarin.
AB - OBJECTIVE: Voglibose is a new and potent inhibitor of alpha-glucosidases and is
used for the treatment of diabetes mellitus. Since voglibose increases
gastrointestinal motility and could thus affect absorption of concomitantly
administered drugs, it was investigated whether or not voglibose modifies the
pharmacodynamics and pharmacokinetics of warfarin, an oral anticoagulant
frequently used in cardiovascular disorders likely to arise in diabetic patients.
METHODS: Twelve healthy male subjects were given individually adjusted doses of
warfarin to reduce prothrombin time (Quick's method) to a value of about 30-40%
of the normal range within the first 8 days. Then, the individuals maintenance
dose, given in the morning, was maintained until day 15. On study days 11-15,
voglibose was co-administered per os in a dose of 5 mg t.i.d. The prothrombin
time was determined on days 10 and 11 (reference) and on days 15 and 16 (test),
and the steady-state pharmacokinetic characteristics of the warfarin enantiomers
were determined on days 10 (reference) and 15 (test). The ratios test/reference
were evaluated according to bioequivalence criteria. RESULTS: The equivalence
ratio (test reference) for the pharmacodynamic parameter prothrombin time was
0.97 and for the pharmacokinetic characteristics AUC0-24 h.t.ss: S-(-)-warfarin,
1.05; R-(+)-warfarin, 1.01; and Cmax.ss: S-(-)-warfarin, 1.08; R-(+)-warfarin,
1.04. All parameters were within the predetermined accepted range of 0.7-1.43
(pharmacodynamics) or 0.8-1.25 (pharmacokinetics), thus fulfilling equivalence
criteria. CONCLUSIONS: Voglibose modified neither the pharmacodynamics nor the
pharmacokinetics of warfarin under steady-state conditions. Concomitant treatment
was well tolerated and has been proven to be safe for further clinical use.
PMID- 9403290
TI - Tramadol withdrawal in a neonate.
PMID- 9403291
TI - Internal fixation sets for use in the hand. A comparison of available
instrumentation.
AB - Optimal clinical results of internal fixation in the hand depend on appropriate
patient selection criteria, good surgical techniques, and appropriate implant
selection. A variety of implant sets with plates and screws from different
manufacturers are available for hand bone fixation. Traditionally, such sets have
been made of stainless steel, but more recently, implants have been manufactured
from titanium. Sizes and configurations vary significantly between manufacturers.
In this article, commonly available internal fixation sets are compared. Plate,
screw, and instrument design are considered. These comparisons should help the
surgeon make an enlightened choice of implant sets.
PMID- 9403292
TI - Fixation of phalangeal fractures.
AB - The indications and methods for operative treatment of phalangeal fractures are
reviewed. Included are descriptions with examples of closed reduction and
percutaneous pin fixation, percutaneous reduction and percutaneous fixation, open
reduction and internal fixation, and static and dynamic external fixation. Also
included are tips for facilitating phalangeal fixation and a description of
potential complications.
PMID- 9403293
TI - Metacarpal fixation.
AB - This article discusses and categorizes common metacarpal fractures and their
treatments, including various techniques of obtaining skeletal fixation. It
reviews metacarpal shaft fracture; intra-articular metacarpal head fractures; and
metacarpal neck and base fractures including carpal-metacarpal dislocations, and
Rolando's and Bennett's fractures of the base of thumb metacarpal. Also discussed
are the effects of shortening of lengthening the digital skeleton and
bioabsorbable implants, a potential treatment modality currently under
development.
PMID- 9403294
TI - Internal fixation of scaphoid fractures.
AB - Scaphoid fracture fixation is indicated in certain acute situations and for
scaphoid nonunion. Internal fixation requires an understanding of the distinctive
scaphoid anatomy with relation to its shape, blood supply, fracture healing, and
radiographic evaluation. The choice of surgical approach varies with the fracture
configuration and procedure planned. A variety of innovative implants are
available to accomplish internal fixation of the scaphoid. The ultimate goal is
to achieve union and restore stability to the carpus.
PMID- 9403295
TI - Fractures of the carpal bones.
AB - Fractures of the carpal bones, excluding the scaphoid, are less common and are
often missed on standard, plain radiographs. The diagnosis requires knowledge of
the anatomy and common fracture patterns of the bones and the specialized
radiographic views necessary to image them. Although the hamate hook, trapezial
ridge, and pisiform often fracture from direct trauma, other fractures of the
carpus may indicate more widespread injury and require a detailed evaluation to
rule out associated perilunate or carpometacarpal fracture-subluxations.
Fortunately, if treated appropriately, the vast majority of these fractures heal
uneventfully and allow recovery of motion and function of the wrist and hand.
PMID- 9403296
TI - Internal fixation for small joint arthrodeses in the hand. The interphalangeal
joints.
AB - Interphalangeal arthrodeses are performed frequently for disabling pain and
deformity in the proximal and distal interphalangeal joints. Such arthrodeses are
the gold standard for eliminating pain in arthritic joints of the fingers.
Kirschner wire fixation is simple to perform but often leads to nonunion or
delayed union. Fixation with tension band wires and Herbert and Accutrak screws
is discussed in this article. The techniques are simple and straightforward, and
they afford considerably more stability and a higher union rate than Kirschner
wires alone.
PMID- 9403298
TI - Static external fixation in the hand and carpus.
AB - Static external fixation in the hand and carpus remains a valuable part of the
hand surgeon's armamentarium for the treatment of complex injuries. This article
describes a brief history, indications, case examples, and complications using
these constructs. Pertinent pitfalls are emphasized to avoid suboptimal outcomes.
PMID- 9403297
TI - Limited wrist fusion.
AB - Limited wrist fusion can provide patients a measure of pain relief with retention
of a functional range of motion. Recent biomechanic investigations have shed
light on the potential benefits of such procedures. Clinical studies have
demonstrated the usefulness of limited wrist fusion for the treatment of numerous
conditions involving the wrist. Significant complications are associated with
many of these fusions and should be considered before performing these
procedures.
PMID- 9403299
TI - Dynamic skeletal fixation in the upper extremity.
AB - Recent advances in the understanding of the biomechanics of the elbow and
improvement in material designs have revolutionized the ability to treat
difficult problems of the proximal interphalangeal and elbow joints. Dynamic
skeletal fixation addresses the desire to allow an injured joint to heal, move,
and remain stable simultaneously. In the past, such goals were achieved
sequentially or in series. It is now possible to perform such tasks in parallel.
PMID- 9403300
TI - Fixation for distal radius fractures.
AB - Distal radius fractures are common fractures that can cause significant
disability. As techniques and implants have improved, better results can be
expected from internal and external fixation of complex wrist fractures. With
meticulous technique, articular alignment can be secured and small articular
fragments can be replaced in anatomic locations through limited open or
arthroscopic techniques. Bone graft should be used liberally in comminuted
articular fractures. Such procedures are demanding, however. Familiarity with the
techniques described in this article will enhance the surgeon's ability to
restore function in this group of patients.
PMID- 9403301
TI - Wrist fusion.
AB - Wrist arthrodesis is a reliable procedure for the treatment of a variety of
disorders of the wrist. It provides predictable pain relief, enhanced hand
function, and a high degree of patient satisfaction. The AO/ASIF wrist fusion
plate allows rigid internal fixation and optimizes wrist position for maximum
hand function. In comparison to other wrist arthrodesis techniques, the wrist
fusion plate produces a high rate of fusion utilizing local bone graft from the
distal radius.
PMID- 9403302
TI - Forearm fixation.
AB - The great majority of forearm fractures in adults are best treated by open
reduction and internal fixation. Although alternative methods exist, plate
fixation is favored by most surgeons. With strict attention to surgical detail,
complication rates are low and early active function is possible. The treatment
of high-energy, open fractures can include various techniques such as internal or
external fixation. Refracture remains the greatest risk following hardware
removal, which is not necessary for all patients.
PMID- 9403303
TI - Fixation of complex elbow fractures, Part I. General overview and distal humerus
fractures.
AB - Complex elbow fractures are those intra-articular injuries which result in
displacement or incongruity of one or more of the articulations between the
distal humerus, proximal radius, or proximal ulna. The article discusses a system
for clinical and radiographic evaluation, operative management, and
rehabilitation of distal humerus fractures. This review presents detailed
descriptions of skeletal reconstructive techniques for these injuries based on a
review of the literature, biomechanic principles, and clinical experience. The
importance of rigid internal fixation and early postoperative mobilization is
emphasized.
PMID- 9403304
TI - Fixation of complex elbow fractures, Part II. Proximal ulna and radius fractures.
AB - Complex fractures of the elbow often include significant injury to the proximal
ulna and/or proximal radius. Such injuries are often combined with injury to the
periarticular soft tissues. Appropriate treatment is dependent on accurate
diagnosis, definitive treatment of both the skeletal and ligamentous components
of injury, and initiation of rehabilitation programs the stress early motion.
PMID- 9403305
TI - Fixation methods in contaminated wounds and massive crush injuries of the
forearm.
AB - This article presents a critical review of the current literature on the
stabilization methods of severe open fractures or crush injuries of the forearm.
Due to the complexity of the problem, the advantages and disadvantages of the
different fixation methods are presented in order to provide the reader with a
combination of possibilities for timing and decision-making when confronted with
such fractures in clinical practice.
PMID- 9403306
TI - Infection in the presence of skeletal fixation in the upper extremity.
AB - Infection is infrequent after open fractures of the upper extremity. Treatment
begins with prevention through the appropriate use of prophylactic antibiotics,
adequate wound debridement, and timely soft-tissue coverage. If infection
supervenes, the surgeon must identify the responsible bacteria and administer
antibiotics accordingly. Stable fixation is retained. Unstable fixation is
removed and skeletal stability restored. Using these principles, infection in the
presence of skeletal fixation can be controlled and fracture union achieved.
PMID- 9403307
TI - Therapy after skeletal fixation in the hand and wrist.
AB - Skeletal fixation can be very beneficial to the recovery of wrist and hand
function after a displaced fracture because it allows mobilization of soft
tissues before the completion of fracture healing. The benefits of skeletal
fixation can be greatly diminished, however, if excessive force causes the
fixation to fail before fracture healing has occurred, infection occurs around
the implant, or the patient develops reflex sympathetic dystrophy. Those
complications, as well as others, are often caused by inappropriate or inadequate
hand therapy. This article discusses the techniques needed to avoid many such
complications while providing the best possible functional result for every
patient.
PMID- 9403308
TI - Wave-intensity analysis: a new approach to left ventricular filling dynamics.
AB - In order to explore a new approach to the analysis of diastolic dysfunction, we
adapted wave-intensity analysis (WIA), a time-domain analysis that provides
information regarding both upstream and downstream events, to left ventricular
(LV) filling. WIA considers the pressure and flow waves as summations of
successive wavelets, characterised by the direction they travel and by the sign
of the pressure gradient associated with them. Wave intensity is the product,
dPdU, calculated from the incremental differences in LV pressure (dP) and mitral
velocity (dU) and, during the diastolic filling interval, yields up to five dPdU
peaks. Peak 1 is caused by backward-travelling expansion waves that accelerate
the blood while LV pressure falls, and may be related to "diastolic suction".
Peak 2 is caused by forward-travelling compression waves which occur if
acceleration continues after LV pressure begins to increase. Peak 3 is caused by
backward compression waves and is associated with rising LV pressure and
deceleration. Peak 4 is caused by forward compression waves and is associated
with the increasing LV pressure and acceleration caused by atrial contraction.
Peak 5 is caused by backward compression waves and is associated with increasing
pressure and deceleration. These preliminary observations suggest that WIA can be
useful in describing the mechanics of LV filling and, after much further work has
been accomplished, it might prove useful in the detection and characterization of
diastolic dysfunction.
PMID- 9403309
TI - Anti-atherogenicity in women does not prevent restenosis after balloon
angioplasty.
AB - To test the hypothesis that anti-atherogenicity in women exerts beneficial
effects to prevent restenosis formation after coronary angioplasty, we studied
493 men (988 lesions) and 81 women (159 lesions), aged 40-60 years, who had
undergone successful balloon angioplasty and had follow-up angiography, 4.9 +/-
4.1 months later. We compared the extent of restenosis between men and women, and
between pre- and post-menopausal women, which was assessed by a categorical
definition of restenosis (more than 50% diameter stenosis at follow-up) and by
percent diameter measured immediately after angioplasty and at follow-up.
Hypertension was more frequent in women and a significantly lower percentage of
women smoked. In women, the levels of total cholesterol and low-density
lipoprotein cholesterol were higher. The location of dilated lesions, frequency
of angioplasty for lesions with chronic total occlusion, and frequency of
emergency angioplasty in patients with unstable angina or acute myocardial
infarction were similar in men and women. Restenosis formation, estimated by the
categorical definition or percent diameter, did not differ between men and women,
or between pre- and post-menopausal women. Menopausal status or sex was not an
independent predictor of restenosis by multivariate analysis. Thus, the benefit
of anti-atherogenicity in women does not play an important role in preventing
restenosis after coronary angioplasty.
PMID- 9403310
TI - Effects of levamisole, an immunomodulator, upon murine encephalomyocarditis virus
myocarditis.
AB - To test the therapeutic efficacy of levamisole, 5-week-old DBA/2 mice were
inoculated intraperitoneally with 10 plaque-forming units of encephalo
myocarditis virus. Levamisole (2.5 mg/kg/per day) was administered
intraperitoneally daily, starting simultaneously with the virus inoculation, in
experiment I for 14 days, and daily on days 14 to 28 in experiment II in mice
that survived to 14 days after virus inoculation. In experiment I, survival was
higher, the severity of myocarditis was less, and myocardial virus titers were
lower in treated than in untreated animals. In experiment II, levamisole was not
effective. No significant changes in serum neutralizing antibody titers occurred
in either experiment. Furthermore, levamisole prevented associated lymphoid organ
atrophy induced by the virus infection. An additional in vitro study revealed the
absence of anti-viral activity of the drug. Thus, levamisole may have favorable
effects upon encephalomyocarditis virus myocarditis by preventing the virus
induced lymphoid organ atrophy and reducing myocardial virus replication in the
acute stage.
PMID- 9403311
TI - Activation of cardiac muscarinic receptor and ischemic preconditioning effects in
in situ rat heart.
AB - Activation of cardiac muscarinic receptors by vagal stimulation decreases cardiac
work, which may have a protective effect against ischemic injury. To determine
whether cardiac muscarinic receptors contribute to the mechanisms of
preconditioning effects, we examined the effect of carbachol on
ischemia/reperfusion damage and the effect of vagotomy on cardioprotection
induced by ischemic preconditioning. Rats were subjected to 30 min of left
coronary artery occlusion followed by 30-min reperfusion in situ. Pre
conditioning was induced by three cycles of 2-min coronary artery occlusion and,
subsequently by 5 min of reperfusion. The incidence of ischemic arrhythmias, such
as ventricular tachycardia (VT) and ventricular fibrillation (VF), and the
development of myocardial infarction were markedly reduced by the
preconditioning. Carbachol infusion (4 micrograms/kg per min) delayed the
occurrence of VT and VF during ischemia and reduced the infarct size. Compared
with non-ischemic left ventricle, the cyclic guanosine monophosphate (GMP)
content in the ischemic region of the left ventricle was decreased by
ischemia/reperfusion, whereas the cyclic adenosine monophosphate (AMP) content of
this region was increased. These changes were reversed by preconditioning.
Similar changes in cyclic GMP and AMP content in the ischemic region were seen in
rats undergoing carbachol treatment. These results suggest the possible
contribution of muscarinic receptor stimulation to preconditioning. Vagotomy
prior to preconditioning diminished the antiarrhythmic effects, whereas it did
not block the anti-infarct effect afforded by pre-conditioning. Vagotomy
abolished the preconditioning effect on the tissue cyclic GMP, but it did not
attenuate the decrease in tissue cyclic AMP. The results suggest that muscarinic
stimulation exerts preconditioning-mimetic protective effects in
ischemic/reperfused hearts, but that a contribution of reflective vagal activity
to the mechanism for preconditioning is unlikely.
PMID- 9403313
TI - Flow characteristics and required control algorithm of an implantable centrifugal
left ventricular assist device.
AB - As the clinical application of LVADs has increased, attempts have been made to
develop smaller, less expensive, more durable and efficient implantable devices
using rotary blood pumps. Since chronic circulatory support with implantable
continuous-flow LVADs will be established in the near future, we need to
determine the flow characteristics through an implantable continuous-flow LVAD.
This study describes the flow characteristics through an implantable centrifugal
blood pump as a left ventricular assist device (LVAD) to obtain a simple non
invasive algorithm to control its assist flow rate adequately. A prototype of the
completely seal-less and pivot bearing-supported centrifugal blood pump was
implanted into two calves, bypassing from the left ventricle to the descending
aorta. Device motor speed, voltage, current, flow rate, and aortic blood pressure
were monitored continuously. The flow patterns revealed forward flow in
ventricular systole and backward flow in diastole. As the pump speed increased,
an end-diastolic notch became evident in the flow profile. Although the flow rate
(Q [l/min]) and rotational speed (R [rpm]) had a linear correlation (Q = 0.0042R
5.159; r = 0.96), this linearity was altered after the end-diastolic notch was
evident. The end-diastolic notch is considered to be a sign of the sucking
phenomenon of the centrifugal pump. Also, although the consumed current (I [A])
and flow rate had a linear correlation (I = 0.212Q + 0.29; r = 0.97), this
linearity also changed after the end-diastolic notch was evident. Based upon the
above findings, we propose a simple algorithm to maintain submaximal flow without
inducing sucking. To maintain the submaximal flow rate without measuring flow
rate, the sucking point is determined by monitoring consumed current according to
gradual increases in voltage.
PMID- 9403312
TI - Effects of methylprednisolone on hemodynamics and beta-adrenergic receptor
signaling in rabbits with acute left ventricular failure.
AB - Studies suggest that corticosteroids may restore the responsiveness to
catecholamines in hypotensive patients. Since the significance of this promising
intervention in congestive heart failure remains to be explored, we determined
the effects of methylprednisolone, a potent activator of beta-adrenergic receptor
signaling, on hemodynamics and beta-adrenergic receptor regulation in an animal
model of heart failure. Acute left ventricular overloading was produced by aortic
regurgitation (AR) in 22 Japanese white rabbits. Eleven animals received an
intravenous administration of methylprednisolone (AR + PSL), while 11 received
saline (AR + C) for 1 week. A sham operation was performed on 10 other rabbits
(S). There was no difference between the AR + C and AR + PSL groups in the
decrease in aortic diastolic pressure immediately after the production of AR. The
aortic diastolic pressure and regurgitant fractions were also similar in the two
groups. The left ventricular end-diastolic and end-systolic dimensions were both
larger, and the left ventricular end-diastolic pressure was higher in AR + C or
AR + PSL than in S rabbits. Between the AR + C and AR + PSL, there were no
differences in any of these variables. Cardiac output was lower in AR + C, but
not in AR + PSL, than in S. Cardiac output in AR + PSL was significantly higher
than in AR + C. The myocardial concentration of norepinephrine and the number of
beta-adrenergic receptors were both lower in the AR + C and AR + PSL than in the
S groups. The number of receptors in AR + PSL was higher than in AR + C. Maximal
isoproterenol-stimulated adenylyl cyclase activity was similar in the AR + C and
AR + PSL groups. Results suggest methylprednisolone yielded some benefits,
including an increase in cardiac output and in total beta-adrenergic receptor
number, in this animal model of heart failure.
PMID- 9403314
TI - Myocardial histological changes in dilated cardiomyopathy during a long-term left
ventricular assist device support.
AB - As the myocardium in patients with dilated cardiomyopathy (DCM) is deteriorating
progressively, resulting in a decrease in left ventricular function, patients
with end-stage DCM may require implantation of a left ventricular assist device
(LVAD) unless they undergo heart transplantation. Although LVAD has been reported
to provide excellent hemodynamic support, no data are currently available about
the effects of long-term LVAD support on the myocardium in patients with DCM. We
describe two patients with end-stage DCM who underwent LVAD implantation and were
supported with LVAD for 524 and 245 days, respectively. Serial myocardial
biopsies showed increases in myocardial cell diameter and intercellular fibrosis,
despite excellent hemodynamic support by LVAD. These data suggest that the
myocardium in patients with end-stage DCM deteriorates progressively, even if the
pre-load of the left ventricle is reduced by LVAD.
PMID- 9403315
TI - Weight, nutrition and hormonal events in women. Introduction.
PMID- 9403316
TI - Genetic determinants of regional fat distribution.
AB - Upper body fat and abdominal visceral fat are two obesity-related phenotypes of
interest because of their relationships with a variety of metabolic
complications. The heritability of the amount of upper body fat or the level of
upper body fat relative to lower body fat ranges from approximately 30-50% of the
phenotype's age, sex and total body fat adjusted variance. On the other hand,
familial studies of abdominal visceral fat reveal that the familial transmission
reaches > 50% of the age, sex and total body fat adjusted variance. Complex
segregation analysis undertaken with a panel of nuclear families indicates that
major genes may account for a significant fraction of the variance in upper body
fat and abdominal visceral fat. Two intervention studies conducted with pairs of
male identical twins have shown that changes in upper body fat and visceral fat
are more similar within pairs than between pairs, either in phenotype increments
when challenged by chronic overfeeding, or in adipose tissue losses after
exposure to long-term negative energy balance conditions. The evidence
accumulated to date is sufficient to justify undertaking a search for the
specific genes and molecular markers involved in the heterogeneity commonly
observed in human fat topography.
PMID- 9403317
TI - Adrenergic regulation of adipocyte metabolism.
AB - Five adrenoceptor (AR) subtypes (beta 1, beta 2, beta 3, alpha 2 and alpha 1),
are involved in the control of white and brown fat cell function. A number of
metabolic events are controlled by the adrenergic system in fat cells. The
stimulatory effect of catecholamines on lipolysis and metabolism is mainly
connected to increments in cAMP levels, cAMP protein kinase activation and
phosphorylation of various target proteins. Norepinephrine and epinephrine
operate through differential recruitment of alpha 2- and beta-AR subtypes on the
basis of their relative affinity for the different subtypes (the relative order
of affinity is alpha 2 > beta 1 > or = beta 2 > beta 3 for norepinephrine).
Antagonistic actions at the level of cAMP production exist between alpha 2- and
beta 1-, beta 2- and beta 3-AR-mediated lipolytic effects in human white fat
cells. The role of fat cell alpha 2-ARs, which largely outnumber beta-ARs in fat
cells of certain fat deposits, in human and primate has never been clearly
understood. The other AR type which is not linked to lipolysis regulation, the
alpha 1-AR, is involved in the control of glycogenolysis and lactate production.
Pharmacological approaches using in-situ microdialysis and selective alpha 2- and
beta-AR agonists and antagonists have revealed sex- and tissue-specific
differences in the adrenergic control of fat cell function and nutritive blood
flow in the tissue surrounding the microdialysis probe.
PMID- 9403319
TI - Obesity and reproduction.
AB - Obesity produces a variety of alterations in the reproductive system and,
similarly, manipulations of the hypothalamic-pituitary-gonadal axis produce
changes in food intake, body weight and fat distribution. In men, the primary
effects of obesity are a weight related reduction in testosterone and, with
massive overweight, a reduction in free testosterone. In females, the weight
related development of menarche leads to earlier menarche in obese girls than in
normal weight girls. One explanation for the relationship of fatness to menarche
may be the ob protein (leptin) which is defective in the obese (ob/ob) mouse.
Leptin is secreted by adipose tissue in proportion to the quantity of fat and may
serve as a signal to the hypothalamus that fat stores are adequate to nourish a
conceptus to term. In women, parity affects obesity and obesity in turn affects
the regularity of the menstrual cycle. In many experimental animals with obesity,
particularly the genetic forms of obesity, there is complete infertility in the
females and marked impairment of reproductive function in the males. In animals
with hypothalamic lesions, there is a gender effect on the magnitude of weight
gain associated with the sexually dimorphic regions in the medial preoptic area.
Castration with removal of oestrogen is followed by obesity in female animals and
this can be prevented, as can most forms of obesity, by adrenalectomy. The
inhibitory effects of oestrogen on food intake may result from suppression of
neuropeptide-Y or galanin peptidergic systems in the arcuate nucleus or medial
preoptic area.
PMID- 9403318
TI - Hormonal control of regional fat distribution.
AB - Hormones exert powerful influences on body fat distribution in humans. Studies
under fully controlled conditions in vitro have indicated that cortisol and
insulin facilitate lipid accumulation by expressing lipoprotein lipase (LPL).
Growth hormone (GH) abolishes this and turns metabolism towards lipid
mobilization. Testosterone and GH inhibit LPL and stimulate lipolysis markedly.
Cortisol effects are mediated via a glucocorticoid receptor, and testosterone
effects via an androgen receptor, the density of which appears to be higher in
visceral than subcutaneous adipose tissue. The receptor-mediated effects are
probably expressed via transcription of appropriate genes. The female sex
steroids also regulate adipose tissue metabolism, but apparently not directly in
the absence of specific cellular receptors. Oestrogens seem to exert net effects
similar to those of testosterone. These results of cellular studies agree well
with in-vivo studies of triglyceride uptake and turnover in different adipose
tissue regions. Furthermore, clinical entities with characteristic disturbances
in hormone levels show the expected redistribution patterns.
PMID- 9403320
TI - Involvement of insulin-like growth factors in the interactions between nutrition
and reproduction in female mammals.
AB - The effects of nutrition on the reproductive system of female mammals are
discussed in an attempt to determine the importance of the role of the insulin
like growth factor (IGF) system of proteins in the physiological mechanisms. The
IGF system comprises IGF-I, IGF-II, their receptors and binding proteins. For
this review, insulin and its receptors have been included in this system. The
reproductive responses have been separated into two classes, based on fundamental
differences in the reproductive biology and physiological mechanisms underlying
them. The first involves the effects of nutrition on the induction of ovulation,
at puberty or postpartum. In this case, the question is whether or not the animal
will reproduce. The second class of response, changes in ovulation rate, involves
consideration of reproductive efficiency in animals in which ovulation is
inevitable.
PMID- 9403321
TI - Insulin regulation of human ovarian androgens.
AB - Hyperinsulinaemic insulin resistance is characteristic of many, if not all, women
with polycystic ovary syndrome (PCOS). We will review evidence suggesting that
hyperinsulinaemia promotes hyperandrogenism in PCOS by two distinct and
independent mechanisms: (i) by increasing circulating ovarian androgens; and (ii)
by directly reducing serum sex hormone-binding globulin concentrations. The net
result of these actions is to increase circulating free testosterone
concentrations. It appears likely that an inherent (probably genetically
determined) ovarian defect need be present in women with PCOS, which makes the
ovary susceptible to insulin stimulation of androgen production. Limited evidence
suggests that hyperinsulinaemia might also promote ovarian androgen production by
influencing pituitary release of gonadotrophins. This latter possibility,
however, has not been critically evaluated. The clinical implication of these
findings is that amelioration of hyperandrogenism in women with PCOS may be
achieved by interventions which improve insulin sensitivity and reduce
circulating insulin. Such measures might include, but are not limited to, weight
loss, dietary modification, and insulin-sensitizing medications.
PMID- 9403322
TI - Perspective in the treatment of insulin resistance.
AB - Improving the action of insulin is a relatively new concept in therapy. It
should, however, become more and more important because of the rapid expansion of
the insulin resistance syndrome (including upper body adiposity, glucose
intolerance, hypertension, dyslipidaemia, etc.) in industrialized countries and
its dramatic consequences for public health. Insulin sensitivity can be improved
by non-pharmacological means, essentially reduction of excessive body weight,
promotion of regular physical activity and modification of dietary habits, as
well as, possibly, cessation of smoking and correction of subclinical magnesium
deficiency. Currently available pharmacological means mainly include the
biguanide compound metformin and possibly anti-obesity agents, such as (d-)
fenfluramine, fluoxetine and benfluorex. New compounds aiming at improving the
action of insulin are in development, especially the thiazolidinedione
derivatives (e.g. troglitazone), known as 'insulin sensitizers'. Treatment of
insulin resistance may have important gynaecological applications, essentially in
polycystic ovary syndrome and, possibly, after menopause. Hopefully, improving
insulin sensitivity could ameliorate the cardiovascular prognosis of numerous
individuals having some or all components of insulin resistance syndrome.
PMID- 9403323
TI - Influences of weight, body fat patterning and nutrition on the management of
PCOS.
AB - Polycystic ovary syndrome (PCOS) is a heterogeneous clinical entity that is
defined as the association of hyperandrogenism with chronic anovulation in women
without specific underlying diseases of the adrenal or pituitary glands. PCOS is
also associated with a metabolic disturbance (insulin resistance). The nature of
the complex interrelation of obesity, insulin resistance and endocrine
abnormalities in PCOS remains unresolved. However, several studies link obesity,
body fat distribution and nutritional habitus with the hormonal and metabolic
profiles of PCOS. Moreover, intervention studies have suggested that reducing
weight and/or hyperinsulinaemia either by diet alone or by a combination of diet
and drugs improves hirsutism, fertility and the hormonal and metabolic profiles
of PCOS. In fact, the evaluation of nutritional factors in PCOS is helpful for
the screening of metabolic abnormalities and the management of women with PCOS. A
point of particular interest in the management of PCOS is that the choice of
contraception remains difficult in these high cardiovascular risk women. The
impact of pills with ethinyl oestradiol on weight, body fat distribution and
carbohydrate metabolism in women with PCOS has not been thoroughly evaluated. The
lack of prospective studies to evaluate long-term metabolic and cardiovascular
tolerance necessitates care and the assessment of other hormonal possibilities.
PMID- 9403324
TI - Weight control and its beneficial effect on fertility in women with obesity and
polycystic ovary syndrome.
AB - Obesity may be an important pathogenetic factor involved in the development of
hyper-androgenism in women with polycystic ovary syndrome (PCOS). Among several
other mechanisms, hyperinsulinaemia plays a fundamental role, due to its
gonadotrophic function, which has been demonstrated both in vitro and in vivo.
Therefore, not surprisingly, weight loss may be expected to have several
beneficial effects upon clinical, endocrinological and metabolic features of
obese women presenting both PCOS. In particular, weight loss appears to be
associated with a significant improvement in menses abnormalities, ovulation and
fertility rates, and with a reduction of hyperandrogenism, hyperinsulinaemia, and
altered gonadotrophin pulsatile secretion. The central role of improved insulin
concentrations and insulin-resistant state is emphasized by the fact that similar
effects can be achieved by both short- and long-term administration of metformin,
an insulin-lowering drug which ameliorates peripheral insulin action in non
diabetic insulin resistant states. We therefore recommend weight loss as a first
line therapeutic option in all women with obesity and PCOS.
PMID- 9403325
TI - Choice of stimulation in polycystic ovarian syndrome: the influence of obesity.
AB - Obesity modifies insulin sensitivity and gonadotrophins dynamics, and is
associated with disorders of spontaneous ovulation. High concentrations of leptin
are possibly a link between weight and spontaneous ovulation. Weight excess in
polycystic ovary syndrome (PCOS) patients increases hyperinsulinaemia, which may
result in altered follicular maturation. Obese PCOS women are characterized by a
decreased efficiency of the different stimulation treatments. Although clomiphene
resistance is not associated with obesity, the dose of clomiphene required to
achieve ovulation is positively correlated with body weight. Obese PCOS women
also require higher doses of gonadotrophins than their lean counterparts, with
ultimately poorer results in pulsatile gonadotrophin releasing hormone-stimulated
cycles. The first stage in the optimal management of obese PCOS anovulatory women
is a weight loss programme, which helps to correct the clinical and endocrine
abnormalities.
PMID- 9403326
TI - Deficiency of energy balance and ovulatory disorders.
PMID- 9403327
TI - Weight gain in pregnancy.
AB - Pregnancy and body weight development are intertwined in complicated patterns. Of
the obese patients at our Obesity Unit, 73% had retained > 10 kg in connection
with a pregnancy. For the general population the effect of a pregnancy on future
weight development is surprisingly difficult to predict. In the Stockholm
pregnancy and weight development study the estimated mean weight retention
associated with a pregnancy and estimated 1 year after delivery was 0.5 kg but
ranged from -12 to +26 kg. Weight increase during pregnancy was the strongest
predictor for sustained weight retention 1 year later. Pre-pregnancy weight did
not predict the weight development outcome. The lactation pattern had only a
minor influence on weight development. Smoke cessation was an important predictor
for sustained weight increase. More weight retention was observed in those women
who reported an unfavorable change in lifestyle as regarded eating habits, meal
patterns and physical activity. The eventual body weight after pregnancy seems to
be more determined by the changes associated with that particular pregnancy than
with the lifestyle before.
PMID- 9403328
TI - Obesity and breast cancer risk.
AB - Being overweight appears to be associated with a higher risk of post-menopausal
breast cancer in most studies. Although the relative risk of breast cancer
related to Quetelet's index is generally weak (range 1.1-1.9 in the major cohort
studies), some studies have found that timing of weight gain and body fat
distribution could be more significant factors of an increased risk. Conversely,
obesity appears to be slightly correlated with a decreased risk of breast cancer
in pre-menopausal women. These contrasting effects of excess weight on breast
cancer incidence according to menopausal status, and the lack of a strong
association between obesity and breast cancer in some studies, could be due to a
number of confounding factors. Among these factors, age, country of origin,
family history, alcohol consumption, nutrition, and hormonal treatment could
account for the differences observed, and are reviewed in the present study.
Obesity and central fat distribution are believed to act through endocrine
intermediates such as hyperinsulinaemia and steroid hormones. Since obesity is
one of the few breast cancer risk factors that can be modified, the influence of
weight loss, particularly in women at high risk, deserves to be further
investigated.
PMID- 9403329
TI - Weight gain at the time of menopause.
AB - The menopause is associated with changes in body composition: a decline in bone
mineral content, a decrease in collagen synthesis, a loss of lean body mass and
an increase in total and abdominal fat mass. Oestrogen deficiency seems to play a
role in the menopause-related changes in body composition, but life styles (diet,
exercise, smoking habits, alcohol consumption) are also involved. The time course
of the decrease in lean mass deserves attention since it could justify specific
actions, i.e. exercising or hormonal treatment, early during the perimenopausal
period. A decrease in fat-free mass may be responsible for a decrease in energy
expenditure favouring weight gain if the calorie intake is not reduced.
PMID- 9403330
TI - Weight gain and cardiovascular risk factors in the post-menopausal women.
AB - Cardiovascular disease is the leading cause of mortality and morbidity in the
post-menopausal woman. The natural menopause does not appear to be an independent
risk factor (or a minor one) for coronary heart disease. Obesity, more precisely
excessive intra-abdominal fat, is a cardiovascular risk factor especially with
regard to the metabolic risk factors associated with this type of obesity. There
is a progressive increase in weight gain at the age of menopause but this weight
gain is related to ageing independent of whether women are post-menopausal or
not, or treated with oestrogens or not. At the same time, there is a central
redistribution of fat with a decrease in gluteo--femoral fat and an increase in
intra-abdominal fat with an associated muscle mass loss. This trend to central
obesity obviously favours an increased cardiovascular risk. With regard to weight
gain, these changes in body composition are related to ageing. Different factors
(e.g., diet, physical activity, GH secretion, etc.) may be involved. Are these
changes related to menopause? Can hormonal replacement therapy prevent them? The
results of the studies in this field are not consistent and these questions
remain under debate.
PMID- 9403332
TI - Sensory neuropeptides: their role in inflammation and wound healing.
AB - Vasoactive neuropeptides including substance P and calcitonin gene-related
peptide (CGRP) are localised in sensory nerves which innervate blood vessels.
These are the major vasoactive neuropeptides released from sensory nerve endings
and both have been suggested to have roles in inflammatory and cardiovascular
disease. The neuropeptides have potent effects on microvascular tone and
permeability, which are seen soon after release from perivascular nerves. There
is also evidence that neuropeptides can affect various activities of inflammatory
cells and that sensory nerves play a role in the recovery of the healthy
microcirculation during wound healing phases. This review concentrates on
evidence that the neuropeptides substance P, acting via tachykinin NK1 and NK2
receptors, and CGRP, acting via CGRP1 receptors, play a pro-inflammatory role in
disease and a beneficial role in wound healing. In addition, results from
clinical trials of recently developed neuropeptide antagonists are discussed.
PMID- 9403331
TI - Vascular leak syndrome: a side effect of immunotherapy.
AB - The major dose-limiting toxicity of interleukin-2 (IL-2) and of immunotoxin (IT)
therapies is vascular leak syndrome (VLS). VLS is characterized by an increase in
vascular permeability accompanied by extravasation of fluids and proteins
resulting in interstitial edema and organ failure. Manifestations of VLS include
fluid retention, increase in body weight, peripheral edema, pleural and
pericardial effusions, ascites, anasarca and, in severe form, signs of pulmonary
and cardiovascular failure. Symptoms are highly variable among patients and the
causes are poorly understood. The pathogenesis of endothelial cell (EC) damage is
complex and can involve activation or damage to ECs and leukocytes, release of
cytokines and of inflammatory mediators, alteration in cell-cell and cell-matrix
adhesion and in cytoskeleton function. VLS restricts the doses of IL-2 and of ITs
which can be administered to humans and, in some cases, necessitates the
cessation of therapy. This review discusses the diversity of clinical
manifestation, possible mechanisms and therapeutic modalities for VLS induced by
IL-2 and ITs.
PMID- 9403333
TI - Prevention of ultraviolet radiation-induced suppression of accessory cell
function of Langerhans cells by Aloe vera gel components.
AB - The active components of Aloe vera gel that can prevent ultraviolet B (UVB)
induced suppression of accessory cell function of Langerhans cells (LC) were
purified by activity-guided sequential fractionation followed by in vitro
functional assay. The functional assay was based on the fact that exposure of
freshly isolated murine epidermal cells (EC) to UVB radiation resulted in
impairment of accessory cell function of LC, as measured by their ability to
support anti-CD3 monoclonal antibody (mAb)-primed T-cell mitogenesis. This UVB
suppressed LC accessory cell function was prevented by addition of partially
purified Aloe gel components to cultures of UVB-irradiated EC. The Aloe gel
components appeared to prevent events occurring within the first 24 h after UVB
irradiation that lead to the impairment of accessory cell function. The Aloe gel
components did not cause proliferation of anti-CD3 mAb-primed T-cells, nor did
induce proliferation of normal EC. The activity-guided final purification of Aloe
gel components resulted in the isolation of two components. Both of the
components were small molecular weight (MW) substances with an apparent MW of
less than 1,000 Da but different from each other in net charge characteristics at
pH 7.4. These results suggest that Aloe vera gel contains at least two small
molecular weight immunomodulators that may prevent UVB-induced immune suppression
in the skin.
PMID- 9403334
TI - Inhaled corticosteroids and beta-agonists inhibit oxidant production by
bronchoalveolar lavage cells from normal volunteers in vivo.
AB - To study the anti-inflammatory mechanisms of inhaled corticosteroids and beta
agonist therapies, we evaluated basal and stimulus-induced superoxide production
by human airway inflammatory cells obtained by bronchoalveolar lavage from normal
volunteers before and after 3 weeks of an inhaled corticosteroid (flunisolide)
and beta-agonist (metaproterenol). Assay of superoxide production by the
bronchoalveolar lavage cells was performed in the presence of media alone or
media containing phorbol ester by optical density determination of reduced
ferricytochrome c at 550 nm. Interleukin-1 beta released from unstimulated cells
and cells stimulated with lipopolysaccharide was quantitated by enzyme
immunoassay. Interestingly, phorbol ester-stimulated superoxide production was
strikingly inhibited (P < 0.05) by inhaled therapies, while stimulus induced
Interleukin-1 beta production was not significantly affected (P = 0.12).
Suppression of oxidant production by airway inflammatory cells may be a major
mechanism for the beneficial anti-inflammatory effects of inhaled corticosteroids
and beta-agonists.
PMID- 9403335
TI - Reduction of disease causative T-cells in experimental autoimmune disease models
by a new antirheumatic drug, TAK-603.
AB - We investigated the mode of action of a new quinoline derivative, TAK-603 (ethyl
4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmeth yl) quinoline-3
carboxylate), in adjuvant arthritis (AA), a model of rheumatoid arthritis. AA rat
splenocytes transferred the arthritis to normal syngeneic rats upon inoculation,
but the cells from AA rats treated with TAK-603 (6.25 mg/kg/day) caused only mild
arthritis with significantly less foot pad swelling and a lower arthritis score.
An effect of TAK-603 in the induction phase of AA was suggested. TAK-603 had
little effect on CD4+ and CD8+ T-cell populations in the AA rat splenocytes. We
therefore estimated the frequency of T-cells which are reactive to the so-called
disease causative antigen using a limiting dilution assay (LDA). The ratio of T
cells responsive to PPD, which increased in AA rat splenocytes with the severity
of the arthritis, was reduced in AA rats treated with TAK-603. Furthermore, the
ratio of MBP (myelin basic protein)-reactive T-cells, which were generated in
experimental allergic encephalomyelitis (EAE) rats, were also reduced by TAK-603
administration. These data suggest that TAK-603 acts on the immune system and
reduces the number of cells reactive to the relevant antigen.
PMID- 9403336
TI - Monophosphoryl lipid A stimulated up-regulation of nitric oxide synthase and
nitric oxide release by human monocytes in vitro.
AB - Monophosphoryl lipid A (MPL) is a derivative of lipopolysaccharide (LPS) with
reduced toxicity which has been shown to modulate various immune functions in
monocytes. We examined whether human monocytes can be stimulated to produce
nitric oxide (NO) and its catalytic enzyme nitric oxide synthase (NOS). Monocytes
were stimulated with LPS or MPL and both NOS and NO (as nitrite) production were
measured. MPL at high doses (> 100 micrograms/ml) stimulated monocytes to release
NO that was significantly greater than both the control and LPS-treated monocytes
(p < 0.05). NO release by control cells and the LPS treated cells was not
significantly different. Both arginase and N-monomethyl arginine (NMLA) inhibited
the MPL stimulated release of NO (p < 0.01). MPL significantly increased
inducible NOS (iNOS) expression as measured by both fluorescent microscopy and
flow cytometry (p < 0.05). Similarly, both soluble NOS (sNOS) and particulate NOS
(pNOS) activity were significantly up-regulated by MPL (p < 0.05). Significant
correlations were found between pNOS expression and sNOS release (r = 0.72, p <
0.0001) and between 12 h NO release and sNOS production (r = 0.44, p < 0.005).
These experiments confirm that human monocytes can be stimulated with MPL to
produce NO in vitro and suggest that up-regulation of pNOS does not preclude NO
release.
PMID- 9403337
TI - Superoxide generation by monocytes following infection with human
cytomegalovirus.
AB - A significant level of superoxide (O2-) generation was observed in a U937-derived
subclone following infection with human cytomegalovirus (HCMV). Although there
were no detectable levels of viral mRNA and/or protein expression, HCMV DNA
content transiently increased immediately before O2- generation. Similarly, O2-
generation was also observed in peripheral blood monocytes derived from healthy
donors.
PMID- 9403338
TI - Immunosuppressive activity of 13-cis-retinoic acid in rats: aspects of
pharmacokinetics and pharmacodynamics.
AB - Pharmacokinetics and pharmacodynamics of 13-cis-retinoic acid (13-cRA)
administered at doses that suppress experimental autoimmune encephalomyelitis
(EAE) have been investigated in rats. Serum concentration of the drug measured
following oral administration of 37 mg/kg/12 h reached a peak of 1.8 x 10(-5) M
in 2 h and linearly declined to 7.8 x 10(-7) M at hour 12. When spleen cells (SC)
collected from 13-cRA-administered animals were cultured in vitro, their
proliferative response to the T-cell mitogen concanavalin A (ConA) was suppressed
and this effect was dependent on in vivo serum concentrations of the drug. In
addition, in vitro exposure of antigen-specific T-cell lines to 13-cRA
concentrations equivalent to those observed in vivo caused a dose-dependent
suppression of the proliferation induced by the antigen as well as by T-cell
mitogens. On a molar basis, 13-cRA showed a stronger in vitro immunosuppressive
activity than two immunosuppressive agents used in human therapy, cyclosporin A
and 6-mercaptopurin.
PMID- 9403339
TI - Thymotrophic effect of ether lipid 1-O-octadecyl-2-O-methoxy-rac-glicero-3
phosphocholine in the mouse.
AB - 1-O-octadecyl-2-O-methoxy-rac-glicero-3-phosphocholine (ET-18-OCH3) is a
synthetic derivate of 2-lysophosphatidyl-choline, endowed with some
immunomodulatory and anticancer effects. In the present work we report that a
chronic (1 microgram/g b.w. for 2 weeks) or acute single dose injection of ET-18
OCH3 produced a recovery of thymus weight and thymocytes cellularity in two
different strains of mice, C57BL6 and Swiss mice, undergoing thymus age-dependent
involution. This effect was significant when the thymus weight was reduced at 50%
and it was without effect on thymus lacking age dependent involution, such as
young mice. The ability of ET-18-OCH3 to produce thymus weight and thymocyte
cellularity recovery was also demonstrated in adult mice showing hypotrophy of
thymus induced by chronic corticosterone treatment, suggesting that this compound
could be effective against thymus hypotrophy induced by external stimuli. This
thymotrophic effect of ET-18-OCH3 was not dependent on direct action on thymocyte
proliferation, but probably it was dependent on its action on thymic epithelial
cells to produce hormone thymulin, which level was found significantly increased
in the plasma. These results provide further immunomodulatory propriety of ET-18
OCH3 and open the possibility to use this compound to counteract thymus
hypotrophy.
PMID- 9403340
TI - A dimeric form of soluble recombinant sheep LFA-3(CD58) inhibits human T-cell
proliferation by generating regulatory T cells.
AB - We recently observed that the soluble recombinant from of sheep LFA-3, termed
sLFA-3 is biologically active as determined by E-rosette inhibition and
inhibition of human T-cell proliferation in response to the recall antigen. In
the present study, we examined the immunosuppressive properties of a derivative
of sLFA-3, a dimeric form of the first domain (D1) of sLFA-3, named sD1Hcys dimer
which was made by oxidative binding of the two D1 molecules through disulfide
bonds formed between the SH side chains of a cysteine which was added to the C
terminal of the D1 domain. By investigating the suppressive properties of the
sD1Hcys dimer, we obtained evidence that antigen-stimulated T-cell proliferation
was inhibited by the suppressor T cell, mainly CD4 + CD45RA - CD45RO + and CD8 +
CD45RA - CD45RO + T cells, generated by incubating PBLs with a low dose (0.5
microgram/ml) of sD1Hcys dimer in the presence of a low dose of IL-2 and GM-CSF.
Flow cytometric analysis showed that the expression of some surface molecules on
T cells were modulated by a high dose (5 micrograms/ml) of sD1Hcys dimer such as
downregulation of CD3 and upregulation of IL-2R, but were not modulated by a low
dose (0.5 microgram/ml) of the sD1Hcys dimer. These findings suggest that the
sD1Hcys dimer exerts its suppressive effects on the antigen-induced proliferation
assay by generating suppressor T cells. The sD1Hcys dimer might therefore have
potential as an immunotherapeutic agent to inhibit and/or anergize antigen
specific T-cell responses.
PMID- 9403341
TI - Inhibition of contact hypersensitivity with different analogs of benzoporphyrin
derivative.
AB - Four structural analogs of benzoporphyrin derivative (BPD), a potent anti-tumor
photosensitizer, were evaluated for their capacity to influence the
immunologically-mediated contact hypersensitivity (CHS) response against the
hapten 2,4-dinitrofluorobenzene (DNFB). Immunocompetent hairless strain mice
received BPD monoacid ring A (BPD-MA, verteporfin) and returned to normal housing
conditions or treated with 690 nm red light (transcutaneous photodynamic therapy,
PDT). Unexpectedly, we found that mice given BPD-MA exhibited significantly
reduced CHS ear swelling responses to DNFB upon antigenic challenge, whether or
not they had been treated with PDT. A significant reduction in the CHS response
to DNFB was observed when BPD-MA or PDT was given 48 or 24 h prior to, on the
same day, or 24 or 72 h after DNFB sensitization. However, the magnitude of the
CHS response was unaffected if these treatments were given 96 h after DNFB
sensitization, 24 h before challenge with DNFB. Significantly reduced CHS
responses also occurred in Balb/c mice given BPD-MA with or without PDT. Mice
given BPD-MA but retained in total darkness throughout the experimental period
generated full-fledged ear swelling responses to DNFB indicating that CHS
suppression with BPD-MA was light dependent. BPD monoacid ring B (BPD-MB)
strongly reduced the CHS response of Balb/c mice kept under ambient light while
BPD diacid ring A (BPD-DA) and BPD diacid ring B (BPD-DB) also lowered the CHS
response but were less effective than the monoacid forms. Other photosensitizers
including Photofrin, tin etiopurpurin, and zinc phthalocyanine did not alter the
CHS response of Balb/c mice maintained under ambient light. The ability of
different BPD analogs to inhibit the CHS response in mice held under ambient
light conditions appears related to the potent photosensitizing activity of these
compounds.
PMID- 9403343
TI - Augmented antibody-mediated footpad responses in mice treated with an anti-IL-4
monoclonal antibody.
AB - The effect of the anti-IL-4 monoclonal antibody 11B11 mAb on antigen-induced
footpad responses in mice in which Arthus reaction is involved was investigated.
Antigen-induced footpad responses were induced by immunization with hen egg
lysozyme (HEL) and by challenge injection of HEL into the footpads on day 20
after the immunization. Five hours after the challenge injection, footpad
swelling was measured. 11B11 mAb was daily administered i.p. over a period of 10
days, commencing on the day of immunization with HEL. The results showed that the
treatment with 11B11 mAb significantly augmented the footpad swelling. There was
an increase in the production of anti-HEL IgG2a antibodies in 11B11 mAb-treated
mice, while a decrease in anti-HEL IgG1 and IgG antibody production was observed
in the animals. The secretion of IL-4 from lymphoid cells of 11B11 mAb-treated
mice was markedly reduced. In contrast, increased IFN-gamma production was
observed in these animals. Thus, treatment with anti-IL-4 antibodies appears to
be effective in augmenting antibody-mediated in vivo responses in which antigen
specific IgG2a antibodies and IFN-gamma produced following the antibody treatment
play a role.
PMID- 9403342
TI - A purine nucleoside phosphorylase (PNP) inhibitor induces apoptosis via caspase-3
like protease activity in MOLT-4 T cells.
AB - Children with congenital homozygous deficiency of purine nucleoside phosphorylase
(PNP) have abnormalities in purine metabolism that result in T-cell selective
immune deficiency. The mechanism of action for cell death has been attributed to
intracellular accumulation of dGTP, a potent inhibitor of ribonucleotide
reductase and subsequently DNA synthesis, in thymocytes and T-cells but not B
cells. However, the mode of cell death has not been determined to be either
necrosis or apoptosis. To examine the involvement of apoptosis in T-cells
following PNP inhibition, MOLT-4 cells, a human T cell leukemia cell line, were
co-treated with the PNP inhibitor, CI-1000 (2-amino 3,5-dihydro-7-(3
thienylmethyl)-4H-pyrrolo[3,2-d]-pyrimidin-4-one HCl), and 2'-deoxyguanosine
(dGuo) which resulted in a concentration-dependent loss of cell viability (trypan
blue) and inhibition of tritiated thymidine ([3H]-TdR) uptake. Staining of cells
with the DNA dye Hoechst 33,258 showed nuclear morphology characteristic of
apoptosis. Western blots (24 h lysates) were probed with antibodies against
several proteins implicated in apoptosis. Anti-PARP revealed the presence of an
85 kD PARP breakdown product while, anti-alpha-spectrin revealed the accumulation
a 120 kD breakdown product, both suggestive of CPP32 cleavage (caspase-3; an ICE
like cysteine protease). Western blots also detected the loss of the intact 32 kD
caspase-3 isoform, a biochemical event associated with caspase-3 activation.
Corresponding fluorometric activity assays detected a marked increase in caspase
3-like activity using the substrate Ac-DEVD-MCA. Lastly, a pan caspase inhibitor
(Z-D-DCB) and 2'-deoxycytidine (dCyd), which is known to prevent dGTP
accumulation following PNP inhibition, were able to prevent cell death and all
indicators of caspase-3-like activity in MOLT-4 cells co-treated with dGuo and CI
1000. In summary, we provided several lines of evidence for the role of apoptosis
and the contribution of caspase-3-like proteases in T-cell death following PNP
inhibition.
PMID- 9403344
TI - Effects of aprotinin on the kallikrein-kinin system in type I diabetes
(insulitis).
AB - Sub-diabetogenic doses of streptozotocin (STZ) produce insulitis, beta cell
destruction and diabetes in mice. Since kinin have been proposed as an
inflammatory mediator in several diseases, we decided to evaluate the role of the
kallikrein-kinin system in the evolution of insulitis. Male C 57 BL/KsJ mdb mice
were injected with STZ (40 mg/kg) for 5 consecutive d. Aprotinin (4000 KIU/d) was
injected simultaneously with STZ during 10 d. Plasma and urine samples collected
on day 15 were assayed for glucose concentration and proteins, nitrites and
kallikrein. Diabetic mice showed hyperglycemia and increased diuresis, marked
proteinuria, nitrites and kallikrein. Administration of aprotinin, a potent
tissue kallikrein inhibitor, to STZ mice, reduced the hyperglycemia and the
altered renal function of the diabetic mice to level no different from normal
mice. The present studies are consistent with the hypothesis that the over
production of tissue kallikrein in insulitis could be controlled by the effect of
aprotinin.
PMID- 9403345
TI - Potentiation and inhibition of fMLP-activated exocytosis in neutrophils by
exogenous nitric oxide.
AB - Exogenous nitric oxide (NO), not derived from NO-donors, but applied directly,
could enhance exocytosis of rabbit peritoneal neutrophils induced by suboptimal
concentrations of the chemotactic peptide fMLP. The enhancement was maximal at 30
microM NO. Higher concentrations of NO strongly inhibited fMLP-induced
exocytosis. The potentiation of fMLP-induced exocytosis by NO could not be
reversed by the inhibitors of guanosine-3',5'-cyclic monophosphate (cGMP)
accumulation, LY-83583 and methylene blue, or the antagonists of cGMP-dependent
protein kinase, Rp-8-pCPT-cGMPS and Rp-8-Br-cGMPS. The concentration of NO needed
to enhance fMLP-induced exocytosis was much higher than the concentration leading
to an increase in intracellular cGMP levels. These observations suggest that the
enhancement of exocytosis by NO is not likely to be mediated by cGMP. At the
concentration which inhibited fMLP-induced exocytosis, NO reduced the
intracellular level of glutathione. Since it is known that inactivation of
intracellular sulfhydryl groups causes complete inhibition of the exocytotic
response, it seems evident that the very strong inhibition of exocytosis by high
NO concentrations is due to the reaction of NO with glutathione or with other
sulfhydryl group-containing targets.
PMID- 9403347
TI - Predictions of serum vancomycin concentrations by means of six different
equations for calculation of creatinine clearance.
AB - Serum vancomycin concentrations were predicted in 59 patients by means of the PKS
programme using six different equations to calculate creatinine clearance. These
equations are (i) Chiou & Hsu equation, (ii) Cockroft-Gault lean body-weight
equation, (iii) Cockroft-Gault total body-weight equation, (iv) Jelliffe
equation, (v) Jelliffe & Jelliffe equation, and (vi) Siersback-Neilsen equation.
The predictions were made by using (i) the implemented population pharmacokinetic
parameters (IPPP), and (ii) the Bayesian method (BM). The results show that (i)
if IPPP can lead to under-predictions, and Chiou & Hsu equation is most suited
for predictions, and (ii) if IPPP can lead to over-predictions, the Cockroft
Gault total body-weight equation is the most suited for predictions.
PMID- 9403346
TI - In vivo cimetidine immunomodulatory effects on the cutaneous reaction to
oxazolone in the chicken.
AB - The effect of the histamine H2-receptor antagonist, cimetidine, on the cutaneous
Arthus-like hypersensitivity to oxazolone elicited injecting subcutaneously
oxazolone conjugated to egg-albumin (EA-OX) has been examined in the chicken.
Cimetidine had opposite effects on the cutaneous reaction to oxazolone in
relation to a different immunization schedule. Cimetidine enhanced the cutaneous
reaction to oxazolone obtained immunizing chickens with oxazolone dissolved in
ethanol (Eth-OX); instead cimetidine inhibited the cutaneous reaction obtained in
chickens immunized with oxazolone dissolved in complete Freund adjuvant (CFA-OX).
Optimum enhancement of the cutaneous arthus-like reaction to oxazolone occurred
when cimetidine was given for three consecutive days starting at the
immunization. The enhancing effect was absent in neonatally bursectomized
chickens. Moreover, cimetidine stimulated bursal cell proliferation at day 1
after sensitization. The study of the immunoglobulin class of oxazolone
antibodies produced in the immunized chickens demonstrated that cimetidine
stimulated the IgM oxazolone antibody synthesis in Eth-OX immunized chickens and
inhibited the IgY oxazolone antibody production in Eth-OX and total oxazolone
antibody production in CFA-OX immunized chickens. The relationship between
increased IgM oxazolone antibody synthesis and enhancement of the cutaneous
Arthus reaction is discussed. The role of IgM antibodies in the pathogenesis of
Arthus reaction in the chicken is hypothesized.
PMID- 9403348
TI - Efficacy of alpha,beta-arteether in acute uncomplicated P. falciparum malaria.
AB - A phase-III clinical trial was conducted in 50 patients (42M + 8F) with acute
uncomplicated falciparum malaria from Delhi during the period of September to
November 1995. Their mean age was 27.2 years, and the mean parasitaemia on day 0
was 0.65%. Patients were hospitalized and treated with a new ethyl derivative of
artemisinin developed at CDRI called alpha, beta-arteether, at the dosage of 150
mg l/M for three consecutive days. Peripheral smears were examined every day for
4 days and then weekly up to 28 days. The results of the study showed that the
mean parasite and fever clearance times were respectively 19.94 +/- 6.87 and
37.81 +/- 21.67 hours. Within 48 h, 70% of the cases became afebrile and the
peripheral smear was negative in 100% of the cases. The drug was well tolerated.
Three cases (6%) had recrudescence within 28 days. It is concluded that alpha,
beta-arteether is a safe, effective and rapidly acting antimalarial.
PMID- 9403349
TI - Evaluation of clinical patterns in ulcerative colitis: a long-term follow-up.
AB - The aim of this prospective research was to compare, in a seven-year follow-up,
the clinical outcome of ulcerative pancolitis with that of non-progressive
ulcerative colitis. The activity of the disease was evaluated by a Clinical
Activity Index and an Endoscopic Index. Of 112 cases of ulcerative colitis
observed, 95 showed no change in extent and were studied as examples of non
progressive UC, and in this group the extension of the disease was: pancolitis in
19%, left-sided colitis in 39%, proctosigmoiditis in 17% and proctitis in 25%. A
colectomy had to be performed in 5%. None of the enrolled cases developed a
cancer during the follow-up. The patients with ulcerative pancolitis or left
sided colitis were treated with 5-ASA 1.6 g/day in a delayed-release formulation,
while the cases with proctosigmoiditis or proctitis were treated with 5-ASA
enemas 4 g/day. The cases with more than one relapse/year were 39%. The
proportion of patients with only one relapse/year was 53%. The patients with
steady remission for all the seven years of the trial were only 8%, but with a
statistically significant difference between the groups with initial diagnosis of
proctosigmoiditis or proctitis and the group with initial diagnosis of pancolitis
or left-sided colitis (12% versus 5%). Among the cases with continuous remission,
37% showed colonic alterations, with an endoscopic score higher than 4 but a
clinical score less than 6. Side-effects were observed in 6% patients but without
treatment withdrawal. Non-progressive ulcerative colitis throughout the colon has
a relatively good prognosis which seems to be independent of the location of the
disease, even if we have found a statistically significant higher percentage of
cases with steady remission among the patients with more distal disease.
PMID- 9403350
TI - Synthesis and disposition of 14C-labelled 81/470, a new anthelminthic agent in
rats.
AB - CDRI compound 81/470 (AH) is a new broad-spectrum anthelminthic agent under
development for clinical and veterinary application. We herewith report the
synthesis of 14C-labelled AH, and a study of the tissue distribution and
excretion of radioactivity after administering a single 1 mg/kg p.o. or i.v. dose
in young male rats. After oral administration of the dose, percent radioactivity
recovered in 24-h urine, faeces and tissues were 17.9, 59.7 and 22.9
respectively. The levels were below detection limit in brain and gonads up to 24
h. In bile-duct-cannulated rats, the majority (37.8 +/- 2.8 and 43.8 +/- 6.4) of
the radioactivity was excreted in the bile within 24 h of p.o. and i.v.
administration, respectively. After an oral dose (1 mg/kg), the urinary excretion
of radioactivity in rats was found to be approximately one-half (21 +/- 5.7, 18.3
+/- 2.1) of that obtained by i.v. administration of an equal dose (40.2 +/- 3.1
and 35 +/- 1.3), in bile-duct-intact and cannulated rats respectively.
PMID- 9403351
TI - Natural killer (NK) cell assay within bladder mucosa of patients bearing
transitional cell carcinoma (TCC) after interferon (IFN) therapy: an
immunohistochemical and ultrastructural study.
AB - The authors studied the number and the ultrastructural evidence of NK cell
activation in the non-involved urothelium in patients with transitional cell
carcinoma (TCC) of the urinary bladder, before and after transurethral resection
(TUR) and interferon (IFN) therapy. Eight male patients, free of recurrence 1
year after TUR and IFN-a2b therapy, were studied. Each patient received 22
instillations of 50MU of IFN-a2b over a period of 1 year. Two specimens from the
non-involved urothelium, one adjacent to and another away from the tumour, were
obtained before and after therapy, for immunohistochemical and ultrastructural
studies. The number of NK cells was evaluated immunohistochemically in paraffin
sections with the CD57 monoclonal antibody, and their activation was detected by
routine electron microscopy processing. Before treatment, few NK cells were
randomly found in the lamina propria. At the end of therapy, however, their
number increased and NK cells were found to infiltrate the urothelium, a finding
that was not observed before treatment. The number of NK cells did not correlate
with the degree of the inflammatory infiltrate of the mucosa. Moreover, the
ultrastructural study revealed activation of NK cells with enhanced cytolytic
activity. IFN therapy increases the number and promotes the activation of NK
cells within the bladder mucosa. This finding could be of clinical significance
in the prevention of tumour recurrence, given that NK cells enhance the
immunological defense mechanisms of the bladder.
PMID- 9403352
TI - Intracerebroventricular self-injection of beta-endorphin by rats in response to
intermittent electrical shocks.
AB - Rats were taught to self-administer beta-endorphin (0.1 microgram or 0.5
microgram/microliter) or NaCl 9% by pressing a lever that activated a pump
connected with a cannula implanted in the lateral cerebral ventricle (icv). The
pump delivered 1 microliter at each lever pressing. After a training period of 2
weeks, the self-injection behaviour was studied before, during and after
nociceptive stimulation. In response to a nociceptive stimulation, 4 rats
increased their self-injection of beta-endorphin at 0.5 microgram/microliter per
injection. This effect is specific for beta-endorphin since under identical
conditions 6 rats did not increase the injection of isotonic NaCl saline
solution. Another 6 rats did not increase their self-injection during nociceptive
electrical stimulation and the post-nociceptive period when the dose of beta
endorphin was 0.1 microgram/microliter per injection. However these animals self
administered significantly higher levels of beta-endorphin during the pre-control
period. Also studied were the acute effects of 10 micrograms of icv beta
endorphin on tail-flick latency in sec. The acute administration of 10 micrograms
of beta-endorphin induced a long-lasting analgesia. The results show that the
rats increased beta-endorphin self-administration during the pre-control period
when the dose was 0.1 microgram/microliter and during the nociceptive stimulation
period when the dose was 0.5 microgram/microliter. In the former case the self
administration had the profile of a voluntary doping drug intake, in the latter
case the profile was that of an antalgic self-medication.
PMID- 9403353
TI - Effect of flurenizide on adaptive reactions in patients with chronic obstructive
pulmonary disease.
AB - A total of 75 patients with chronic obstructive pulmonary disease (COPD) was
investigated, 50 of which received Flurenizide in addition to traditional
therapy. The remaining 25 received traditional therapy only and constituted the
control group. Clinical improvement was observed in both groups, but this was
attained in different ways. This depended on the type of the adaptive reactions
at the beginning of exacerbation and the transition from one reaction to the
other. In the basic group that received Flurenizide, clinical improvement was
attained by a transition from physical conditions of defective adaptation (DA) or
reaction of orientation (RO) into positive reactions of slight (RSA) or elevated
(REA) activation in 72% of patients. Negative transition was not observed, and
14% of the patients remained in the DA condition. In the control group, a
transition from DA into RO was observed in 27% of the patients, while 73%
remained in DA without any positive adaptive reactions being definable. A
significant improvement in the parameters of immunological and lung function
tests was observed only in the group of patients who received Flurenizide. The
highest levels of the above-mentioned parameters were observed in patients whose
adaptive reactions had transited into the RSA or REA condition. We suggest that
the reason for this positive dynamics was induced by the immunostimulating effect
of Flurenizide.
PMID- 9403354
TI - Evolution of the dopaminergic system and its relationships with the
psychopathology of pleasure.
AB - This paper summarizes the fundamental steps in the evolution of the dopaminergic
system. A rudimentary dopaminergic system is present in primitive creatures,
already able to select information processing, modulate "emotional" behaviours
and react to perturbations in environmental conditions. Pharmacological
manipulations of the dopaminergic transmission are able to modify basic
behaviours present in all animals from fishes to lizards to mammals. The ability
to put the organism in motion and the hedonic capacity of giving pleasure, would
justify the conservation through evolution of such a neuronal system. The fact
however that the dopaminergic system has remained identical for the last several
centuries, while many external conditions which interfere with its physiology
have dramatically changed, may contribute to explain the transition from the
original vital advantages of the dopaminergic system to its crucial role in the
psychopathology of pleasure.
PMID- 9403355
TI - Immediate-early genes expression in spinal cord as related to acute noxious
stimulus.
AB - During the "central sensitization" phenomenon, noxious stimuli lead to expression
of IEGs (c-fos, c-jun, krox-24); their proteic products have been postulated to
convert short-term stimulations into long-lasting responses in dorsal-horn
neurons. The aim of this study was to verify if analgesic drugs, such as morphine
and ketorolac, may affect the c-fos protooncogene expression by using a method
highly sensitive and specific, based on transformation of activated c-fos
specific mRNA in cDNA (reverse transcription), its amplification (PCR) and final
visualization by electrophoresis on agarose gel. Male Wistar rats were submitted
to various stimuli in order to assess which procedure resulted in genic
derepression; monolateral sciatic nerve ligature appeared to be the most
effective. When the animals were pretreated with morphine or ketorolac and
subsequently exposed to the monolateral sciatic nerve ligature, or treated with
ketorolac immediately after the same painful stimulus, we found that only
pretreatment with morphine completely blocked c-fos depression. Our results
confirm that pretreatment with opioids is able to prevent IEGs derepression and
the central sensitization phenomenon.
PMID- 9403356
TI - Central neuronal changes in recurrent visceral pain.
AB - Repeated colics from urinary calculosis produce referred muscle hyperalgesia
whose extent is proportional to the number of colics. The pathophysiology of this
hyperalgesia was investigated in electrophysiological studies (spinal cord
recordings) on an animal model of artificial ureteral calculosis. Stone-implanted
rats show both visceral pain episodes and muscle hyperalgesia of the ipsilateral
lumbar musculature; the extent of hyperalgesia is a function of the number of
episodes. In the dorsal horn of stone-rats compared to controls the following
were found: a) significantly higher percentages of neurons driven by stimulation
of the hyperalgesic muscle, of spontaneously active cells with muscle input and
of neurons with muscle input with a low mechanical threshold of activation, and
b) a significantly higher frequency of background activity of spontaneously
active cells with muscle input. These findings were proportional in extent to the
number of visceral episodes presented by the rats before recordings; in cases of
an extremely high number (> 50), several neurons also displayed abnormal
activity, i.e. permanent short rhythmic bursts. These changes reflect a state of
central sensitization and are probably due to the abnormal inflow from the
affected ureter which facilitates the central effect of muscular input, thus
accounting for the referred hyperalgesia. The degree of sensitization appears to
be a function of the repetition of the visceral afferent barrage.
PMID- 9403357
TI - Decentralization monoamine super-sensitivity of migraine and opiate abstinence:
common features and different target mechanisms?
AB - The similarity between opiate withdrawal and migraine (M) has been confirmed
regarding increased monoamine sensitivity at the neuromuscular junction of the
hand's dorsal vein as well as at the neuraxis where dopamine (DA)
supersensitivity was observed. Similarities also included an increase in cAMP
levels as a precocious sign in both M and opiate withdrawal. Particular attention
has been devoted to the time-course of monoamine supersensitivity in M and in
abstinence. It has been found that the maximum level of super-sensitivity occurs
in M at the end of the M attack, whereas the maximum super-sensitivity is present
at the very beginning of opiate abstinence. The inverse time-course of this
phenomenon suggests that it could play some pathophysiological role in inducing
the end of the M attack. Conversely, it can represent the expected transient
result of a pharmacological denervation which ought to result in a
supersensitivity of opioid-dependent neuron during withdrawal. In M, the super
sensitivity is wider, indeed, it involves more receptor types. This could be an
indirect proof of the involvement of inhibitory pathways other than the
opioidergic one.
PMID- 9403358
TI - Hypersensitivity to meta-chlorophenylpiperazine (mCPP) in migraine and drug
withdrawal.
AB - Administration of a bolus dose of mCPP, a 5-HT2C receptor agonist, to rats
provokes endocrine and behavioural effects that are reminiscent of some of the
symptoms of human depression. Rats exposed to chronic mild stress (which is also
a key factor in the precipitation of human depression) were hypersensitive to
mCPP, whilst chronic treatment with antidepressant serotonin re-uptake inhibitors
suppressed the responsiveness to mCPP. Similarities also exist with respect to
withdrawal reactions following chronic alcohol or benzodiazepine abuse. In
humans, a bolus dose of mCPP can cause alcohol craving (in abstinent alcoholics)
and migraine (in susceptible persons), suggesting that there is a 5-HT2C receptor
hyperresponsiveness in these conditions also. It is hypothesized that chronic
treatment with SSRI's can prevent migraine attacks and drug craving.
PMID- 9403359
TI - The way to serotonergic use and abuse in migraine.
AB - 5-HT is currently indicated to play a role in migraine (M). Previously evidenced
5-HT supersensitivity which characterizes M is insufficient to compensate for a
possible deficit in 5-HT bioavailability. Inducing a further up-regulation of 5
HT receptor can yield improvement of M syndrome. Chronic treatments of
methysergide and propranolol, drugs exerting antagonist action at 5-HT receptors,
induced a significant amelioration in 256M sufferers. On the contrary, chronic
treatments of ergotamine and sumatriptan, both provided with a 5-HT1 agonist
activity, induced a worsening of M in 134 M sufferers. The M worsening was
paralleled by an increase in consumption of analgesic drugs. Discussion concerns
the effects of the chronically given 5-HT agonists and antagonists as well as the
possible receptor mechanism underlying "craving for serotonin" in severe M. The
increase of 5-HT supersensitivity evidenced at the end of M attacks is also
discussed and its role in determining the interruption of the attack is here
suggested.
PMID- 9403360
TI - Inheritable and acquired hyperalgesia associated to abnormal opioid receptor set
up seem to act as opiate addiction preventors.
AB - Hyperalgesia is known to depend on neuroplastic changes chiefly represented by
long-term potentiation. These phenomena are proved to depend on excitatory amino
acids (EAAs) action at the level of NMDA receptors. This action is known to be
related to nitric oxide (NO) release. We found a visceral/vascular hyperalgesia
state in migraine (M) sufferers as well as an inheritable systemic hyperalgesia
in healthy subjects who are first-degree consanguineous with M sufferers; this
type was labelled 'third hyperalgesia'. We discovered that a hyper-increase of
plasma L-citrulline, equimolar co-product in the synthesis of NO, characterizes
both M sufferers and their first-degree relatives who are exempt from primary
headache. A similar pattern never occurred in healthy subjects having both a
personal and family history negative for primary headache. We conclude that both
'third hyperalgesia' and a pattern of NO synthase (NOS) hyperactivity seems to be
inheritable and can constitute, at least in part, a ground for developing
headache. Morphine, proved to be unable to relieve M attack, was given in low
doses that caused pain and side-effects in M sufferers only. This outcome
seemingly indicates that M sufferers are characterized by a set-up of opioid
receptor subtypes different from that of healthy headache-exempts. Following a
period of morphine addiction and a withdrawal period, 65.07% of a group of 63
opiate addicts developed M syndrome. All these subjects were first-degree
consanguineous relatives of primary headache sufferers. Discussion topics concern
the activity of morphine in NO release and the role of NO in sensory transmission
of both controls and hyperalgesia sufferers. It is suggested that the inheritable
couple consisting of hyperalgesia and NOS hyperactivity can play some role in
setting off the pain occurring following morphine in M sufferers.
PMID- 9403361
TI - Bradykinin and cerebral circulation: selective non-receptor interaction with
histamine and serotonin through the system of nitric oxide.
AB - Bradykinin, histamine and serotonin were the most active physiological agonists
in increasing jugular levels of nitric oxide when administered into the left
common carotid artery of anaesthetized rabbits. Bradykinin potentiated
selectively the effects of histamine and serotonin (but not vice versa) on both
nitric oxide and carotid blood flow, without involving activation of specific
receptors. Since these effects were demonstrated using doses of the three
agonists in the order of their physiological plasma concentrations, it was
concluded that cerebral circulation in regulated, also within its autoregulatory
limits, by bradykinin through selective autocoidal interactions converging on
nitric oxide.
PMID- 9403362
TI - Bioeffects of a nitric oxide donor in a human preosteoclastic cell line.
AB - Nitric oxide is a short-lived free radical produced by different isoforms of the
enzyme nitric oxide synthase. It regulates a whole range of functions in the
body, but little is known about its effects on bone. Rat osteoclasts and a human
preosteoclast cell line (FLG 29.1) have been shown to produce nitric oxide and to
express nitric oxide synthases. In the present study we investigated the role of
a nitric oxide donor, 3-morpholinosydnonimine hydrochloride, on the FLG 29.1
cells. 3-Morpholinosydnonimine hydrochloride has been shown to significantly
increase IL6 production and tartrate resistant acid phosphatase activity in FLG
29.1 cells, indicating a positive modulation of osteoclast differentiation.
However FLG 29.1 cell adhesion on osteoblast-like cells was significantly
inhibited, suggesting an inhibition of osteoclast motility. All these results
confirm the bidirectional effect of nitric oxide whose basal production is
necessary in promoting osteoclast differentiation, while at high levels it is
effective in inhibiting osteoclast activity.
PMID- 9403363
TI - Modulation of excitatory amino acids pathway: a possible therapeutic approach to
chronic daily headache associated with analgesic drugs abuse.
AB - The use of antagonists of N-methyl-D-aspartate (NMDA) receptors, or the
administration of inhibitors of the synthesis or of the release of excitatory
amino acids, enables the analgesic drug-dependence associated with chronic daily
migraine to be overcome without any physical abstinence sign. Follow-up period
indicates that negative modulators of excitatory amino-acid function can induce a
stable benefit. The persistent benefit is seemingly due to an inhibitory effect
on the process underlying the hyperalgesia state which is a crucial feature of
migraine. It can also be suggested that the antagonist activity at NMDA receptor
might play a role in very severe non-opioid analgesic drug dependence.
PMID- 9403364
TI - Therapy of migraine by modulating dopamine hypersensitivity: its effect on mood
and pain.
AB - Clinical and pharmacological evidences support the hypothesis of a
hypersensitivity of dopamine (DA) receptors in migraine patients. The aim of our
single-blind and placebo-controlled study is to evaluate the presence of this
hypersensitivity and to desensitize the DA system with apomorphine, a classical
DA receptor agonist. We studied six patients suffering from migraine without aura
resistant to the prophylactic treatment and with high frequency of attacks. In
these patients, we first tested individual sensitivity by a single i.m. low dose
of apomorphine to assess the lowest effective dose to be administered s.c. in
continuous infusion without side-effects. We used the response of growth hormone
(GH) to apomorphine as a marker of DA2-receptor function. Clinical evaluation,
blood pressure and heart rate were recorded before placebo or apomorphine
administration and monitored every 15 min for 1 h after each injection. The
treatment consisted of the continuous subcutaneous infusion of apomorphine for
three weeks at the dosage previously assessed by the test. No difference in blood
pressure and heart rate was found during test and treatment. The treatment was
effective in reducing the frequency and the severity of migraine attacks.
PMID- 9403365
TI - Involvement of central cholinergic system in antinociception induced by
sumatriptan in mouse.
AB - The antinociceptive effect of the antimigraine drug sumatriptan was assessed in
mice (hot-plate and abdominal constriction tests). Antinociception induced by
sumatriptan (10-30 mg kg-1 i.p.) was prevented by the muscarinic antagonist
atropine (5 mg kg-1 i.p.), the ACh-depletor hemicolinium-3 (1 microgram per mouse
i.c.v.) and the 5-HT1A antagonist NAN-190 (0.5 mg kg-1 i.p.). Naloxone, CGP-35348
and reserpine administered in doses suitable for blocking analgesia respectively
induced by morphine, baclofen and clomipramine did not modify sumatriptan
antinociception. On the basis of the above findings, we can deduce that
sumatriptan was able to induce antinociception by increasing cholinergic
neurotransmission through the stimulation of 5-HT1A receptors.
PMID- 9403366
TI - Stress, mood disorders and memory in headache.
AB - Comorbidity between headache and other disorders such as psychological or memory
problems is a topic of increasing scientific interest both for us diagnostic and
therapeutic implications but also for pathogenetic advances. A central neurogenic
mechanism such as a dysregulation of some neurotransmitter system might underlie
not only headache but also other coexistent disorders; findings highlight the
role of serotonin pathways.
PMID- 9403367
TI - Intermittent but not continuous inescapable footshock stress and
intracerebroventricular interleukin-1 similarly affect immune responses and
immunocyte beta-endorphin concentrations in the rat.
AB - Both CNS- and immunocyte(lymphocytes, splenocytes)-derived beta-endorphin is
involved in immune responses to stress. We show in the rat that stress-induced
immunodepression (decrease of mitogen-induced lymphocyte proliferation and NK
activity) is present only after the administration of a stress paradigm that
increases immunocyte-derived beta-endorphin, while this is absent when the
concentrations of the opioid are not modified. Interestingly, plasma
corticosterone levels were similarly elevated after stresses whether or not they
suppress immune responses, thus suggesting a pivotal role of the opioid. The
increase of immunocyte beta-endorphin and immunosuppression are similarly present
also after the intracerebroventricular administration of interleukin 1, thus
suggesting a role for this cytokine in stress responses. The modifications of
immunocyte beta-endorphin concentrations and immune responses induced by stress
and interleukin 1 are not affected by indomethacin, adrenalectomy or
hypophysectomy, whereas they are completely blocked by a CRH antagonist and
depletion of the serotoninergic or catecholaminergic systems. In conclusion, our
results suggest that immune responses to stress are not uniquely linked to an
activation of the HPA axis.
PMID- 9403368
TI - Psychological characteristics of juvenile headache: differences between tension
headache and migraine.
AB - In 235 juveniles equalized for sex and averaging 10 years of age, comparisons
were made between 76 with migraine without aura, 79 with episodic tension type H,
and 80 normal controls, on the basis of five psychological characteristics and
six formal tests. The results allowed the description of definitely different
profiles for the two groups of headache sufferers.
PMID- 9403369
TI - Diagnosing autism: analyses of data from the Autism Diagnostic Interview.
AB - Results from ROC curves of items from two scales, the Autism Diagnostic Interview
(ADI) and Autism Diagnostic Interview-Revised (ADI-R), operationalizing DSM-IV
criteria for autism are presented for 319 autistic and 113 other subjects from 8
international autism centers. Analyses indicate that multiple items were
necessary to attain adequate sensitivity and specificity if samples with varying
levels of language were considered separately. Although considering only current
behavior was generally sufficient when a combination cutoff and additive model
was employed, predictive power was highest when history was taken into account. A
single set of criteria, as operationalized by individually structured questions
in the ADI/ADI-R, was effective in differentiating autism from mental handicap
and language impairment in subjects with a range of chronological ages and
developmental levels.
PMID- 9403370
TI - Does teaching theory of mind have an effect on the ability to develop
conversation in children with autism?
AB - The present research examined whether teaching children with autism to pass tasks
that assess mental state understanding had any positive effects on communication.
Two aspects of communication previously shown to be deficient in children with
autism were considered. These are conversational ability, in particular the
ability to expand on conversation, and the use of mental state terms in speech.
Results showed that no discernible improvement was seen on either measure of
communication following mental state teaching. Discussion centers on real versus
superficial changes in understanding mental states as a result of teaching.
PMID- 9403371
TI - Are deficits in the decoding of affective cues and in mentalizing abilities
independent?
AB - It has been hypothesized that deficits in theory of mind (ToM) and emotion
recognition abilities in subjects with autisticlike disorders are independent. We
examined the relationships between deficits in the various social cognitive
domains in children with an autistic disorder (N = 20), in children with a
pervasive developmental disorder not otherwise specified (PDDNOS) (N = 20), and
in psychiatric control (N = 20) and normal children (N = 20). The clinical groups
were matched person-to-person on age and verbal IQ. The clinical children were 8
18 years old, the normal children 8-13 years old. The test battery included tasks
for the matching and the context recognition of emotional expressions, and a set
of first- and second-order ToM tasks. ToM and emotion recognition functioning
proved to be better integrated in the non-PDD children than in the PDD children,
but also in the PDD children significant correlations were found between ToM and
emotion recognition measures.
PMID- 9403372
TI - Delay versus deviance in autistic social behavior.
AB - The pattern of acquisition of social, communication, and daily living skills was
examined for autistic children, compared to retarded and normal controls, by
quantifying intradomain scatter on the Vineland Adaptive Behavior Scales.
Autistic children were matched to normal children and mentally retarded children
on Vineland raw scores; group differences in scatter were examined for each
domain of adaptive behavior. Autistic children had significantly more scatter on
Communication and Socialization than both control groups. Item analyses showed
that the autistic children had particular weaknesses on items reflecting
attention to and pragmatic use of language, as well as play and reciprocal social
interaction; the autistic children had particular strengths on items reflecting
written language and rote language skills, and rule-governed social behavior. The
number of items showing consistent group differences, however, was small,
suggesting that although autistic development appears sequentially deviant and
not merely delayed, individual autistic children derive their scatter from
different items, and are a developmentally heterogeneous group.
PMID- 9403373
TI - The role of touch in facilitated communication.
AB - Imagine that one day a nonverbal autistic child suddenly starts to type messages,
such as "I am not retarded," using a computer keyboard while being touched by an
assistant. Facilitated communication (FC) appears to create this miracle around
the world. To understand how this works, experiments were conducted involving a
"telepathy game" using a rod with an attached strain gauge. A force from the
assistant, which controlled what was spelled through physical support, was
measured. It was thus completely possible for any message to appear to be typed
with FC regardless of the autistic child's actual knowledge or language ability.
PMID- 9403374
TI - Brief report: motor incoordination in children with Asperger syndrome and
learning disabilities.
PMID- 9403376
TI - Brief report: interrater reliability of the psychoeducational profile (PEP).
PMID- 9403375
TI - Brief report: electroencephalographic paroxysmal activities in the frontal area
emerged in middle childhood and during adolescence in a follow-up study of
autism.
PMID- 9403377
TI - Piracetam: a novel therapy for autism?
PMID- 9403378
TI - Sensation Seeking Scales and consumer satisfaction with a substance abuse
treatment program.
AB - Satisfaction of 119 addicts with an addiction treatment program was measured by
an 11 item satisfaction scale. The scale's internal consistency was acceptable
(Cronbach's alpha = .75). The total satisfaction score was weakly but
significantly correlated with Zuckerman's Sensation Seeking scales: Those with
higher scores on the Boredom Susceptibility scale (i.e., those easily bored)
reported less satisfaction, whereas those with higher scores on Thrill and
Adventure Seeking scale (i.e., risk, adventure, and thrill seekers) reported
higher levels of treatment satisfaction. Older patients were more satisfied with
the feedback they received from their psychological tests and also with staff's
respect for their rights.
PMID- 9403379
TI - Readability of self-report clinical outcome measures.
AB - Because the validity of data obtained from self-report clinical outcome measures
depends upon the ability of the client to comprehend the inventories, readability
was assessed for five frequently employed measures: Beck Depression Inventory,
Integra Outpatient Tracking Assessment, MOS 36-Item Short-Form Health Survey,
Social Adjustment Scale-Self Report, and Symptoms Checklist-90-Revised. The
Flesch Reading Ease (RE) formula and a Flesch abstraction formula were applied.
The measures are generally shown to be useful for patients with an eighth or
ninth grade education, suggesting that outcome researchers must choose only those
measures appropriate to the educational background of their clients.
PMID- 9403380
TI - MMPI-2 profiles of women differing in sexual abuse history and sexual
orientation.
AB - Four groups of women (N = 115) self-identified as having histories of childhood
sexual abuse or no such histories and self-identified as either heterosexual or
lesbian were compared using a questionnaire and the MMPI-2. Subjects ranged in
age from 21-60 years with 60% between ages 30-50 years. Results of a Three-Way
MANOVA for abuse history and sexual orientation repeated across MMPI-2 clinical
scales showed a between-subjects effect for abuse, and within-subjects effects
for orientation and abuse. T scores of women with abuse histories were
significantly higher than those of women without abuse histories on Hs, D, Pd,
Pa, Pt, Sc, and Ma scales of the MMPI-2. Profiles indicated an 8-4 codetype and a
Scarlett O'Hara V configuration for the group with abuse history. Heterosexual
women obtained significantly higher t scores than did lesbians on the Depression
scale. Results show that the MMPI-2 can be used to help detect lesbian as well as
heterosexual adults who were sexually molested as children.
PMID- 9403381
TI - Combat guilt and its relationship to PTSD symptoms.
AB - Guilt regarding combat experiences is often considered an associated symptom of
PTSD in military veterans. Little is known, however, about the role combat guilt
plays in the development and maintenance of PTSD. Inadequate measurement of
combat-related guilt may be one reason for this deficiency in the literature. In
the present study, 40 veterans with PTSD completed a novel measure of combat
guilt. Items on the scale assessed various types of guilt and shame concerning
combat experiences (i.e., survival guilt, guilt over acts of omission and acts of
commission, guilt about thoughts/feelings). Guilt was quite prevalent within this
sample, and severity of guilt regarding combat was positively correlated with the
reexperiencing and avoidance symptoms of PTSD and a general measure of PTSD
severity. Implications of these findings and recommendations for the development
of measures for combat-related guilt are discussed.
PMID- 9403382
TI - Assessment of PTSD symptoms in a community exposed to serial murder.
AB - This study examined the presence of PTSD symptoms across time in a community
exposed to serial murder. One hundred eighty four subjects (48% response rate)
responded to the initial survey while 64 and 30 subjects, respectively,
participated in the 9- and 18-month follow-up studies. Results indicated
widespread endorsement of PTSD symptoms following the murders. The most severe
reactions were found among residents demographically similar to the victims. PTSD
symptoms, while not transient, appeared to decrease over time with few subjects
still reporting symptoms at 18 months. These data suggest that violent acts such
as serial murder can have far reaching psychological consequences for the
community and result in vicarious victimization.
PMID- 9403383
TI - The brief admission unit in emergency psychiatry.
AB - The study evaluates a Brief Admission Unit for clients of an emergency service
located within a comprehensive community psychiatric program. Eighty-five clients
completed the Brief Symptom inventory and a structured interview. Substance abuse
disorder (n = 29) and major depression (n = 24) were the most common Axis I
diagnoses, of which 30 subjects had two or more. Sixty subjects had an Axis II
diagnosis. Mean duration of admission was 3.9 days, compared with the average in
other acute units of 11.5 days. At discharge, half the subjects were rated as
moderately to greatly improved and client satisfaction was high. The unit was
crucial to the psychiatric emergency service and had a key role in relieving
pressure on beds elsewhere within the system.
PMID- 9403384
TI - MCMI-III as a treatment outcome measure for psychiatric inpatients.
AB - The Million Clinical Multiaxial Inventory-III (MCMI-III) recently was introduced
to replace and update the MCMI-II. A sample of 97 psychiatric inpatients were
administered the MCMI-III shortly following admission, and again 7-10 days later.
Changes in the personality and symptom scales generally paralleled those found in
previous work with the MCMI-II, although the mean retest interval was
considerably shorter than in the earlier study. However, some differences between
the two instruments were observed, confirming the need for ongoing cross
validation work on the MCMI-III as an instrument that is distinct from the MCMI
II.
PMID- 9403385
TI - Stability of psychiatric patients' perceptions of their admission experience.
AB - The primary aim of this study was to evaluate the stability (i.e., consistency of
patients' responses over time) of newly developed scales to measure the admission
experience of psychiatric hospitalization. Eighty-four psychiatric patients
involuntarily committed to a crisis stabilization unit participated. All
participants were admitted under an emergency petition or ex parte order for a
psychiatric evaluation. Patients were interviewed soon after admission (M = 3.33
days, SD = 1.86 days). The test-retest interval was 24-48 hours with most (83.3%)
re-evaluated at 24 hours. Overall, the measures showed acceptable levels of
stability (r's range from .62 to .72). Factors associated with reliable responses
were lower overall psychiatric symptom severity, less severe psychotic symptoms,
and mentioning the same person as an influence of perceptions about the admission
experience at each assessment point.
PMID- 9403386
TI - Utilizing the PK scale of the MMPI-2 to detect posttraumatic stress disorder in
college students.
AB - This study investigated the utility of the PK scale of the MMPI-2 with college
students. Results indicated that the PK scale, when combined with DSM IV
criteria, does discriminate between college students who obtain a score of 65 or
higher and those who score below 65.
PMID- 9403387
TI - Minnesota Multiphasic Personality Inventory profiles of Vietnam combat veterans
with posttraumatic stress disorder and their children.
AB - Forty children of 28 fathers who are Vietnam veterans with posttraumatic stress
disorder (PTSD) completed the Minnesota Multiphasic Personality Inventory. Each
of the fathers had at least one elevated clinical scale. Fathers averaged eight
elevated clinical scales, and compared to more recent norms, fathers averaged
seven elevated clinical scales. Seventy-eight percent of the children had at
least one clinically elevated scale (averaging three elevated clinical scales).
Compared to contemporary normal adolescents and adults, 65% of children had at
least one clinically elevated scale (still averaging three elevated clinical
scales). No consistent MMPI profile patterns emerged within or across the two
groups. No gender differences were detected among child MMPI profiles. Forty
percent of the children reported illegal drug use, and 35% reported behavior
problems. Fifteen percent of children reported previous violent behavior. Eighty
three percent of the children reported elevated Cook-Medley hostility scores as
compared to an age-matched national normative sample. Children with higher PK
scores were also significantly more likely to report higher Cook-Medley hostility
scores. Forty-five percent of children reported significant elevations on the
PTSD/PK subscales.
PMID- 9403388
TI - A preliminary evaluation of treatment outcomes at a veterans' hospital's
inpatient psychiatry unit.
AB - This article describes a preliminary effort to evaluate inpatient psychiatric
services at the Carl Vinson DVA Medical Center in Dublin, Georgia. The facility
annually treats a large number of veterans for a variety of psychiatric
disorders. To determine whether these veterans improved following care, a simple
pretest-posttest group design was employed, using the SCL-90-R, to assess
psychiatric symptomatology before and after inpatient treatment. Both
statistically significant and practically meaningful improvements in
symptomatology were evident at discharge. While the research design does not
permit causal inferences, low-cost evaluations such as this one simply
demonstrating that patients get better are important first steps in empirically
determining the efficacy of inpatient psychiatric services, and represent one
means of demonstrating accountable practice.
PMID- 9403389
TI - Interpersonal violence and its correlates in Vietnam veterans with chronic
posttraumatic stress disorder.
AB - Two studies were conducted to investigate interpersonal violence in Vietnam
veterans with posttraumatic stress disorder (PTSD). In study one, combat veterans
with PTSD reported significantly greater occurrence of violent behaviors over the
past year (22 acts) versus combat veterans without PTSD (.2 acts). Combat
exposure had an independent positive association with interpersonal violence. In
study two, variables related to current interpersonal violent behavior in 118
PTSD combat veterans were evaluated. In rank order of importance, lower
socioeconomic status, increased aggressive responding and increased PTSD severity
were related to interpersonal violence. These results suggest that combat
veterans with PTSD exhibit greater interpersonal violence than combat veterans
without PTSD, and that there are multiple factors in this population which
determine violent behavior.
PMID- 9403390
TI - Relationship between scores on anger measures and PTSD symptomatology,
employment, and compensation-seeking status in combat veterans.
AB - The interrelationship between the theoretically related constructs of anger and
posttraumatic stress disorder (PTSD) symptoms was examined in a group of 42
combat veterans with PTSD using a multimeasure assessment strategy. Scores on
several anger measures were found to be quite high in this sample and were
significantly correlated with PTSD symptomatology. Furthermore, anger measures
were found to be related to employment status independent of PTSD severity, but
were not related to disability compensation-seeking status. Clinicians are
advised to be aware of the potential implications for physical health and
interpersonal functioning, and to incorporate anger management strategies into
treatment plans for this population.
PMID- 9403391
TI - The MMPI-2 GM and GF Scales as measures of psychological well-being.
AB - The MMPI-2, Symptom Checklist (SCL-90-R), and Tennessee Self-Concept Scales
(TSCS) scores were analyzed for 117 male and 139 female college students. A
median split on the MMPI-2 GM and GF scores by gender divided subjects into high
and low groupings on the MMPI-2 gender variables. Multivariate analyses revealed
that scores on the MMPI-2, TSCS, and SCL-90-R consistently differed by GM and GF
status with differences most pronounced for the GM scale. Higher scores on the GM
variable were associated with scores on the MMPI-2, TSCS, and SCL-90-R that
reflected less psychopathology. Similar trends were noted for higher scorers on
the GF variable, but fewer significant differences across the scales were found.
The results are consistent with an interpretation of GM and GF as correlates of
psychological wellbeing.
PMID- 9403392
TI - Secondary trauma: assessing inter-generational transmission of war experiences
with a modified Stroop procedure.
AB - Intergenerational transmission of war experiences was assessed using a modified
Stroop task. Adult children of war veterans and those of nonveterans named the
colors in which war related words were printed. They also named the colors of
neutral, positive, and OCD related words in addition to color naming a series of
zeros contained on a control card. All participants completed the MMPI-II PTSD
Scale, the Impact of Event Scale, and a demographic questionnaire. A
statistically significant difference between the children of veterans and
nonveterans was found only on the Stroop card containing war related words.
Results suggest that the modified Stroop task is a sensitive measure that may
have value in assessing transmission of war experiences from parents to children.
PMID- 9403393
TI - A moratorium on research using the Jenkins Activity Survey for Type A behavior?
AB - This article presents a brief review of literature which indicates that it may be
premature to abandon the use of the Jenkins Activity Survey (JAS) for assessing
Type A behavior. In particular, the literature suggests that the time
urgency/irritability subcomponent of the JAS may represent a nonspecific
susceptibility factor for general ill health. Moreover, studies demonstrate that
the time urgency/irritability facet of the JAS is associated with a negative
health-risk profile which consists of the presence of vulnerability factors and
the absence of protective factors. Finally, results of this brief review are
consistent with previous research with paper and pencil measures of Type A
behavior showing that subcomponent measures are superior to global measures.
PMID- 9403394
TI - Perceptions of the media in a community exposed to serial murder.
AB - This study examined resident perceptions of the media in a community exposed to
serial murder. Residents were surveyed regarding the popularity, accuracy and
trust of various information sources. One hundred eighty-four residents (48%
response rate) responded to mailed questionnaires. Results indicated that
traditional sources of news (television, radio, and newspapers) were the most
popular sources of information. However, police press conferences were judged to
be the most accurate and trustworthy. Residents viewed media reports on methods
of reducing personal risk as beneficial and enhancing feelings of safety.
However, details of mutilations and sensational reporting were judged to increase
personal fears and led to widespread dissatisfaction with the media.
PMID- 9403395
TI - The efficacies of three relaxation regimens in the treatment of PTSD in Vietnam
War veterans.
AB - Ninety male Vietnam veterans with posttraumatic stress disorder (PTSD) were
administered relaxation instructions, relaxation instruction with deep breathing
exercises, or relaxation instructions with deep breathing training and thermal
biofeedback. Improvement appeared on only 4 of the 21 PTSD and physiological
dependent variables studied. All 21 Treatment x Time interactions were
nonsignificant. This suggests that the treatments were mildly therapeutic, but
that the additions of training in deep breathing and thermal biofeedback did not
produce improvement beyond that associated with simple instructions to relax in a
comfortable chair.
PMID- 9403396
TI - Psychotherapeutic change is predictable, spontaneous change is not.
AB - As a test of the possibility clinically to predict psychotherapy outcome for
individual patients, eight psychotherapist judges rated 30 patients for
suitability for psychotherapy and predicted individual outcomes of psychotherapy.
Unknown to the judges, 15 of the patients had been in psychotherapy (T group),
whereas the remaining 15 had not (NT group), but all patients had been rated with
respect to change. The hypothesis was confirmed that judges would be able to
predict change in the T group better than in the NT group, but that their
suitability ratings would be equally predictive of change in the two groups. It
was concluded that psychotherapeutic change was a systematic effect over and
above initial status, large with some patients, small with others, but reliably
so.
PMID- 9403397
TI - The relationship of male self-report of rape supportive attitudes, sexual
fantasy, social desirability and physiological arousal to sexually coercive
stimuli.
AB - Studies have supported the finding that sexually coercive behavior exists between
males and females on college campuses and that when women say "no" to sexual
behavior, men do not believe them. This study utilized penile plethysmography to
investigate male sexual arousal to rape myth scenarios in a college population.
The scenarios portrayed a woman who said "no" to sexually coercive intercourse
behavior by a male. Results indicated that a low level of social desirability,
sexual fantasies involving group sexual activity, as well as hurting and being
hurt by a partner were associated with greater levels of physiological responding
to coercive stimuli. Supportive attitudes about rape showed no relationship with
physiological responding, yet did correlate with the sexual fantasy of being hurt
by a partner, which was itself related to increased sexual arousal to sexually
coercive audio stimuli.
PMID- 9403398
TI - Assessing PTSD with the Millon Clinical Multiaxial Inventory-III.
AB - We studied the utility of the Millon Clinical Multiaxial Inventory-III (MCMI-III)
in assessing substance-abusing (n = 228), combat-related PTSD patients (n = 32).
The MCMI-III produced a code type (16A) that was quite different from MCMI-I and
MCMI-II code types (8A2) among similar populations. The PTSD Scale (R)
successfully differentiated between a PTSD and non-PTSD substance-abusing group
using mean Base Rate scores, was the best predictor of PTSD in a multiple
regression equation, and the scale's sensitivity and specificity in detecting
and/or ruling out the disorder was above that provided by chance alone and higher
than the values reported in the test manual for that scale. The MCMI-III may be
used as a broad band screening instrument for PTSD, at least among patients with
combat-related stress.
PMID- 9403399
TI - Do physicians discuss HIV and AIDS with patients? A survey of physician
practices.
AB - HIV and AIDS continue to be major concerns to the health care community and the
world around them. Preventive efforts and education have been the focus of the
fight against AIDS thus far. By the year 2000, 75% of physicians are expected to
conduct risk-reduction counseling for patients regularly. Previous studies show
that a smaller percentage "routinely" follow this recommendation. The purpose of
our study was to assess with what percentage of patients physicians discuss
several HIV/ AIDS-related topics, what percentage of their patients are
considered at risk for infection, and how comfortable the physicians are with
their knowledge level and discussing the subject matter. We sent surveys to the
last five graduating classes from St. Louis University School of Medicine and to
169 physician preceptors in the community. The survey asked about patients
considered at risk, physician comfort level with HIV/ AIDS, the percentage of
patients they discuss various HIV/AIDS topics with, and his or her preparedness
for these discussions. Total responses were 464 (53.7%) representing all areas of
medicine. Most of the physicians (72.9%) consider 0-25% of their patients at risk
for HIV/AIDS. Eighty-one percent claim they are moderately or very comfortable
discussing the material with patients and more than 90% feel they have at least
adequate knowledge. Most of the respondents discuss the HIV/ AIDS topics with 0
25% of patients. Recent medical school graduates and primary care physicians are
more comfortable with HIV/AIDS and discuss the surveyed topics with a higher
percentage of patients.
PMID- 9403400
TI - Preventive services in a Medicare managed care environment.
AB - The results of a four year demonstration project of preventive services for
Medicare managed care enrollees suggest that health promotion programs can impact
health behaviors and outcomes. The study provided selected preventive services to
1,800 Medicare enrollees in a managed care environment. Participants were
randomly assigned to control and experimental groups with the experimental group
receiving an intervention service package and the control group usual care. The
results included enhanced health behavior practices, lower depression, and higher
immunization rates among those individuals in the experimental group. This study
suggests that selected preventive services can be provided in a managed care
environment to Medicare enrollees with likely positive health status and
utilization outcomes.
PMID- 9403401
TI - Heart disease education and prevention program targeting immigrant Latinos: using
focus group responses to develop effective interventions.
AB - Although research has provided considerable knowledge concerning the positive
effects of behavioral change on morbidity and mortality from heart disease and
related risk factors, some segments of the population have not benefited
equitably from this information. In April 1995, the National Heart, Lung, and
Blood Institute (NHLBI) conducted seven focus groups to determine knowledge and
attitudes about heart disease and associated risk factors, identify media usage
and preferences, and assess publications usage and preferences among Spanish
speaking Latino immigrants residing in the Washington, D.C., metropolitan area.
This information was gathered to assist in the development of key messages and
strategies for the NHLBI Latino Community Cardiovascular Disease Prevention and
Outreach Initiative, Salud para su Corazon--a heart disease prevention and
education campaign. Findings from these focus groups indicate that Latinos may
not benefit from heart disease prevention messages developed for the general
population because of language and cultural differences. The researchers
concluded that health education and disease prevention programs targeting the
Latino community should develop educational materials and interventions that
address language preferences and cultural values. Furthermore, to be effective,
these programs should show people how to make positive behavioral changes based
on their current circumstances, while remaining sensitive to the fact that Latino
immigrants face major life adjustments and many are still greatly influenced by
their country of origin.
PMID- 9403402
TI - The "Yes, I Quit" smoking cessation course: does it help women in a low income
community quit?
AB - The objectives were to evaluate the impact of "Yes, I Quit" (a smoking cessation
course tailored for women in a low income, low education community), and to
identify baseline predictors of short and longer-term self-reported cessation.
The impact was evaluated in a before-after study design with no comparison group.
Baseline data were collected in self-administered questionnaires at the beginning
of the first session of the course. Follow-up data were collected in telephone
interviews at one, three and six months after the designated Quit Day. Self
reported quit rates among 122 participants were 31.1%, 24.7% and 22.3% at one,
three and six months. Non-quitters reduced their consumption by 10.3, 8.3, and
7.1 cigarettes per day at one, three and six months. Multivariate logistic
regression analyses showed that being in excellent/good health was significantly
associated with cessation at one month (odds ratio (OR) = 2.4). Being married (OR
= 13.0) and no other smokers in the household (OR = 3.6) were associated with
three-month cessation. Only being married was associated with six-month cessation
(OR = 6.8). "Yes, I Quit" produced quit rates among low income, low education
participants comparable to those reported for cessation programs directed at the
general population of smokers. Good health is associated with early cessation,
while support from a spouse is important to maintaining a non-smoking status
among quitters.
PMID- 9403403
TI - Pharmacists' opinions and practices related to the sale of cigarettes and alcohol
-a follow-up study.
AB - Opinions that pharmacists hold and their practices concerning sale of cigarettes
and alcohol are of interest to health experts. As a follow-up to a 1990 statewide
survey of pharmacists opinions and practices related to the sale of cigarettes
and alcohol, this study was designed (1) to determine current opinions and
practices of pharmacists' related to the sale of cigarettes and alcohol; (2)
compare these findings with results from the 1990 study; and (3) to gather new
information on pharmacists' practice of health promotion activities. A structured
survey questionnaire was designed and reviewed by a jury of experts and
subsequently administered to half of the 1340 pharmacies in Indiana. Collected
data were analyzed by using descriptive and inferential statistical methods.
Findings reveal that 64 percent of responding pharmacists sell cigarettes in
their stores even though 82 percent think that their stores should not sell
cigarettes. Approximately 42 percent of the pharmacies sell alcoholic beverages
while more than two-thirds of the pharmacists (68%) think pharmacies should not
sell alcoholic beverages. These findings represent a decline of 7.2 percent in
pharmacies that sell cigarettes and a 6.8 percent increase in pharmacies selling
alcoholic beverages compared to the 1990 study. Study results also revealed that
most pharmacists agree the use of cigarettes and alcohol were important causes of
morbidity and mortality and that pharmacists should play a role in health
promotion and disease prevention to the public. However, the majority do not ask
their patients about their smoking and alcohol habits and do not participate in
health education/promotion programs for the general community.
PMID- 9403404
TI - A clinimetric approach to the components of the patient-physician relationship.
AB - Although patient-physician relationships have been expressed with diverse
concepts and models, we have formulated a clinimetric classification derived from
several years of observation and discussions at weekly house-staff conferences
devoted to "difficult" patients. The observed phenomena are classified into the
following components: (1) background factors intrinsic to patient and physician
before they meet, (2) individual anticipations and hopes for what may happen, (3)
extrinsic features of the setting, (4) individual reactions during the encounter,
and (5) the consequences thereafter. These interacting components are usually too
complex for characterizations based on single models for the relationship or
single titles (such as "hateful" or "noncompliant") for the patient. The
components can serve as a "review of systems" for identifying manifestations,
sources, and solutions to such common problems as discordant hopes, the
physician's unawareness of the patient's pertinent extramedical status,
psychiatric and mental-status challenges, and cogent factors in chronic illness.
PMID- 9403405
TI - Worry grows as antibiotic-resistant bacteria continue to gain ground.
PMID- 9403406
TI - Studies suggest a darker side of 'benign' microbes.
PMID- 9403407
TI - From the Centers for Disease Control and Prevention. Impact of promotion of the
Great American Smokeout and availability of over-the-counter nicotine
medications, 1996.
PMID- 9403408
TI - From the Centers for Disease Control and Prevention. State-specific prevalence of
cigarette smoking among adults, and children's and adolescents' exposure to
environmental tobacco smoke--United States, 1996.
PMID- 9403410
TI - A piece of my mind. Whispering through the keyhole.
PMID- 9403409
TI - From the Centers for Disease Control and Prevention. Medical-care expenditures
attributable to cigarette smoking during pregnancy--United States, 1995.
PMID- 9403411
TI - Mortality and length of stay in teaching vs nonteaching hospitals.
PMID- 9403412
TI - Mortality and length of stay in teaching vs nonteaching hospitals.
PMID- 9403413
TI - Mortality and length of stay in teaching vs nonteaching hospitals.
PMID- 9403414
TI - Prepublication of NIH Consensus Conferences on the Internet.
PMID- 9403415
TI - Correction and clarification: factors contributing to the death of General
Stonewall Jackson.
PMID- 9403416
TI - Early discharge of newborns.
PMID- 9403417
TI - Early discharge of newborns.
PMID- 9403418
TI - Early discharge of newborns.
PMID- 9403419
TI - Early discharge of newborns.
PMID- 9403420
TI - Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study
of men screened for MRFIT. Multiple Risk Factor Intervention Trial.
AB - CONTEXT: Diabetes is a frequent cause of end-stage renal disease (ESRD). However,
the degree of risk is uncertain. OBJECTIVE: To determine the relative risk (RR)
of ESRD related to diabetes in the United States. DESIGN: Nonconcurrent
prospective cohort study. PARTICIPANTS: A total of 332544 men aged 35 to 57 years
from 18 US cities screened in 1973 to 1975 for participation in the Multiple Risk
Factor Intervention Trial (MRFIT). MAIN EXPOSURE: Diabetes mellitus defined by
self-reported use of medication for diabetes at baseline. MAIN OUTCOME: Incident
ESRD through 1990 assessed from a national ESRD registry and by surveillance for
death from renal disease. RESULTS: Over an average follow-up of 16 years, there
were 136 cases of ESRD in 5147 diabetic men and 678 cases in 327397 nondiabetic
men. Age-adjusted incidence of all-cause ESRD in the diabetic men was 199.8 per
100000 person-years compared with 13.7 per 100000 person years in their
nondiabetic counterparts (RR, 12.7; 95% confidence interval [CI], 10.5-15.4).
Diabetic men were also at higher risk for ESRD ascribed to causes other than
diabetes (RR=4.3; 95% CI, 3.2-5.9). With simultaneous adjustment for age,
ethnicity, income, blood pressure, serum cholesterol level, and history of
myocardial infarction, diabetic men remained at higher risk for all-cause ESRD
(RR, 9.0; 95% CI, 7.4-11.0), ESRD ascribed to diabetes (RR, 92.3; 95% CI, 64.6
131.9), and ESRD ascribed to nondiabetic causes (RR, 3.0; 95% CI, 2.2-4.1).
CONCLUSIONS: Diabetes mellitus is a strong independent risk factor for ESRD, even
for ESRD ascribed to causes other than diabetes. Improvements in the prevention
and control of diabetes should produce substantial reductions in ESRD incidence.
PMID- 9403421
TI - Implementation of the Ottawa Knee Rule for the use of radiography in acute knee
injuries.
AB - CONTEXT: The Ottawa Knee Rule is a previously validated clinical decision rule
that was developed to allow physicians to be more selective and efficient in
their use of plain radiography for patients with acute knee injuries. OBJECTIVE:
To assess the impact on clinical practice of implementing the Ottawa Knee Rule.
DESIGN: Controlled clinical trial with before-after and concurrent controls.
SETTING: Emergency departments of 2 teaching and 2 community hospitals. PATIENTS:
All 3907 consecutive eligible adults seen with acute knee injuries during two 12
month periods before and after the intervention. INTERVENTION: During the after
period in the 2 intervention hospitals, the Ottawa Knee Rule was taught to all
house staff and attending physicians who were encouraged to order knee
radiography according to the rule. MAIN OUTCOME MEASURES: Referral for knee
radiography, accuracy and reliability of the rule, mean time in emergency
department, and mean charges. RESULTS: There was a relative reduction of 26.4% in
the proportion of patients referred for knee radiography in the intervention
group (77.6% vs 57.1 %; P<.001), but a relative reduction of only 1.3% in the
control group (76.9% vs 75.9%; P=.60). These changes over time were significant
when the intervention and control groups were compared (P<.001). The rule was
found to have a sensitivity of 1.0 (95% confidence interval [CI], 0.94-1.0) for
detecting 58 knee fractures. The K coefficient for interpretation of the rule was
0.91 (95% CI, 0.82-1.0). Compared with nonfracture patients who underwent
radiography during the after-intervention period, those discharged without
radiography spent less time in the emergency department (85.7 minutes vs 118.8
minutes) and incurred lower estimated total medical charges for physician visits
and radiography (US $80 vs US $183). CONCLUSIONS: Implementation of the Ottawa
Knee Rule led to a decrease in use of knee radiography without patient
dissatisfaction or missed fractures and was associated with reduced waiting times
and costs. Widespread use of the rule could lead to important health care savings
without jeopardizing patient care.
PMID- 9403422
TI - Quality of care, process, and outcomes in elderly patients with pneumonia.
AB - CONTEXT: Pneumonia is a frequent cause of hospitalization and death among elderly
patients, but the relationships between processes of care for pneumonia and
outcomes are uncertain, making quality improvement a challenge. OBJECTIVES: To
assess quality of care for Medicare patients hospitalized with pneumonia and to
determine whether process of care performance is associated with lower 30-day
mortality. DESIGN: Multicenter retrospective cohort study with medical record
review. SETTING: A total of 3555 acute care hospitals throughout the United
States. PATIENTS: A total of 14069 patients at least 65 years old hospitalized
with pneumonia. MAIN OUTCOME MEASURES: Four processes of care: time from hospital
arrival to initial antibiotic administration; blood culture collection before
initial hospital antibiotics; blood culture collection within 24 hours of
hospital arrival; and oxygenation assessment within 24 hours of hospital arrival.
Associations between processes of care and 30-day mortality were determined with
logistic regression analysis. RESULTS: National estimates of process-of-care
performance were antibiotic administration within 8 hours of hospital arrival,
75.5% (95% confidence interval [CI], 73.1-77.9); blood cultures before
antibiotics, 57.3% (95% CI, 54.5-60.1); initial blood culture collection, 68.7%
(95% CI, 66.2-71.2); and initial oxygenation assessment, 89.3% (95% CI, 87.5
90.9). Lower 30-day mortality was associated with antibiotic administration
within 8 hours of hospital arrival (odds ratio [OR], 0.85; 95% CI, 0.75-0.96) and
blood culture collection within 24 hours of arrival (OR, 0.90; 95% CI, 0.81
1.00). State and territory performance estimates varied from 49.0% to 89.7% for
antibiotics given within 8 hours and from 45.6% to 82.6% for blood cultures drawn
within 24 hours. CONCLUSIONS: Administering antibiotics within 8 hours of
hospital arrival and collecting blood cultures within 24 hours were associated
with improved survival. The fact that states varied widely in the performance of
these measures suggests that opportunities exist to improve hospital care of
elderly patients with pneumonia.
PMID- 9403423
TI - Risk factors and clinical presentation of acute primary HIV infection in India.
AB - CONTEXT: Most previous studies of clinical presentation and risk factors in early
human immunodeficiency virus (HIV) infection have relied on retrospective
analyses and referred seroconverters, and thus were subject to possible bias.
OBJECTIVES: To apply a method based on measurement of prevalent HIV-1 p24
antigenemia for identification of risk factors for newly acquired HIV infection
and to describe the signs and symptoms of acute HIV infection. DESIGN AND
SETTING: Nested case-control study in Pune, India. PARTICIPANTS: HIV antibody
negative persons attending 2 sexually transmitted disease (STD) clinics between
May 1993 and June 1996. OUTCOME MEASURES: Prevalent p24 antigenemia, risk factors
for HIV infection, and clinical symptoms of acute primary HIV infection. RESULTS:
Of 3874 HIV antibody-negative persons tested, 58 (1.5%) were p24 antigen positive
at initial presentation to the clinics. Unprotected sexual contact with a
commercial sex worker (CSW) was reported by 39 (77%) of the 51 p24 antigenemic
men, compared with 131 (51 %) of 255 control men (adjusted odds ratio [AOR], 3.4;
95% confidence interval [CI], 1.2-9.6; P=.02). The presence of an active genital
ulcer at the time of screening was found in 46 (79%) of the 58 p24 antigenemic
men and women, compared with 137 (47%) of the 290 control subjects (AOR, 4.2; 95%
CI, 2.0-9.0; P<.001). Signs and symptoms independently associated with p24
antigenemia in HIV antibody-seronegative persons included fever, which was
reported by 28 (48%) of the 58 p24 antigenemic subjects, but only 52 (18%) of the
290 control subjects (AOR, 4.7; 95% CI, 2.4-9.0; P<.001). Joint pain was reported
by 10% of subjects recently HIV infected, compared with 2% of the control
subjects (AOR, 6.5; 95% CI, 1.7-24.8; P=.006). Night sweats were reported by 9%
of the p24 antigenemic, but only 1% of the control subjects (AOR, 9.1; 95% CI,
1.7-47.6; P=.009). Overall, fever, joint pain, and/or night sweats were reported
in 27 (47%) of the 58 subjects with recent HIV infection. CONCLUSIONS: This
systematic case-control study of p24 antigen screening in HIV-seronegative
patients attending STD clinics in India identified unprotected sex with a CSW and
a genital ulcer as independent risk factors associated with newly acquired HIV
infection. In addition, p24 antigen positivity identified recent fever, night
sweats, and arthralgias as symptoms that may be predictive of recent HIV
infection. In a study of patients attending STD clinics in India, screening for
p24 antigen in HIV antibody-negative persons was found to be a reliable and
effective research method for determining recent risk behavior and identifying
clinical signs of acute primary HIV infection.
PMID- 9403424
TI - Spread of HIV infection in married monogamous women in India.
AB - CONTEXT: A high prevalence of human immunodeficiency virus (HIV) infection in
female sex workers (FSWs) and men who attend sexually transmitted disease (STD)
clinics poses a risk for spread of infection to other populations. OBJECTIVE: To
examine spread of HIV to a low-risk population by comparing prevalence of, and
risk factors for, HIV and STDs in FSWs and non-FSWs. METHODS: Women attending STD
clinics in Pune, India, were assessed for STDs and HIV from May 13, 1993, to July
11, 1996. Demographic and behavioral information was collected, and clinical and
laboratory assessment was performed. MAIN OUTCOME MEASURE: Prevalence and risk
determinants of HIV infection. RESULTS: Of 916 women enrolled, 525 were FSWs and
391 were non-FSWs. Prevalence of HIV in FSWs and non-FSWs was 49.9% and 13.6%,
respectively (P<.001). In multivariate analysis, inconsistent condom use and
genital ulcer disease or genital warts were associated with prevalent HIV in
FSWs. History of sexual contact with a partner with an STD was associated with
HIV in non-FSWs. CONCLUSIONS: Infection with HIV is increasing in non-FSWs,
previously thought to be at low risk in India. Since history of sexual contact
with their only sex partner was the only risk factor significantly associated
with HIV infection, it is likely that these women are being infected by their
spouses. This underscores the need for strengthening partner-notification
strategies and counseling facilities in India.
PMID- 9403425
TI - Comparison of primary coronary angioplasty and intravenous thrombolytic therapy
for acute myocardial infarction: a quantitative review.
AB - OBJECTIVE: To provide a quantitative review of the treatment effects of primary
coronary angioplasty vs intravenous thrombolysis for acute myocardial infarction.
DATA SOURCES: Ten randomized trials were identified through computerized
bibliographic search of MEDLINE from January 1985 through March 1996 and by
queries of principal investigators. STUDY SELECTION: Single-center and
multicenter randomized trials comparing primary angioplasty with intravenous
thrombolytic therapy among 2606 patients were included. Four trials compared
angioplasty with streptokinase, 3 compared angioplasty with a 3- to 4-hour
infusion of tissue-type plasminogen activator, and 3 compared angioplasty with
"accelerated" administration of tissue-type plasminogen activator over 90
minutes. DATA EXTRACTION: Each investigator provided definitions and exact data
for outcome events. Odds ratios (ORs), 95% confidence intervals (CIs), and P
values were calculated using exact tests for categorical data. DATA SYNTHESIS:
Mortality at 30 days or less was 4.4% for the 1290 patients treated with primary
angioplasty compared with 6.5% for the 1316 patients treated with thrombolysis
(34% reduction; OR, 0.66; 95% CI, 0.46-0.94; P=.02). The effect was similar among
thrombolytic regimens, and no subgroup demonstrated a significant reduction in
death. The rates of death or nonfatal reinfarction were 7.2% for angioplasty and
11.9% for thrombolytic therapy (OR, 0.58; 95% CI, 0.44-0.76; P<.001). Angioplasty
was associated with a significant reduction in total stroke (0.7% vs 2.0%;
P=.007) and hemorrhagic stroke (0.1% vs 1.1%; P<.001). CONCLUSIONS: Based on
outcomes at hospital discharge or 30 days, primary angioplasty appears to be
superior to thrombolytic therapy for treatment of patients with acute myocardial
infarction, with the proviso that success rates for angioplasty are as good as
those achieved in these trials. Data evaluating longer-term outcomes, operator
experience, and time delay before treatment are needed before primary angioplasty
can be universally recommended as the preferred treatment.
PMID- 9403426
TI - Palliative options of last resort: a comparison of voluntarily stopping eating
and drinking, terminal sedation, physician-assisted suicide, and voluntary active
euthanasia.
AB - Palliative care is generally agreed to be the standard of care for the dying, but
there remain some patients for whom intolerable suffering persists. In the face
of ethical and legal controversy about the acceptability of physician-assisted
suicide and voluntary active euthanasia, voluntarily stopping eating and drinking
and terminal sedation have been proposed as ethically superior responses of last
resort that do not require changes in professional standards or the law. The
clinical and ethical differences and similarities between these 4 practices are
critically compared in light of the doctrine of double effect, the active/passive
distinction, patient voluntariness, proportionality between risks and benefits,
and the physician's potential conflict of duties. Terminal sedation and
voluntarily stopping eating and drinking would allow clinicians to remain
responsive to a wide range of patient suffering, but they are ethically and
clinically more complex and closer to physician-assisted suicide and voluntary
active euthanasia than is ordinarily acknowledged. Safeguards are presented for
any medical action that may hasten death, including determining that palliative
care is ineffective, obtaining informed consent, ensuring diagnostic and
prognostic clarity, obtaining an independent second opinion, and implementing
reporting and monitoring processes. Explicit public policy about which of these
practices are permissible would reassure the many patients who fear a bad death
in their future and allow for a predictable response for the few whose suffering
becomes intolerable in spite of optimal palliative care.
PMID- 9403427
TI - Preserving scientific debate and patient choice: lessons from the Consensus Panel
on Mammography Screening. National Institutes of Health.
PMID- 9403428
TI - Translating good advice into better practice.
PMID- 9403429
TI - Primary angioplasty compared with thrombolytic therapy for acute myocardial
infarction.
PMID- 9403430
TI - Effect of CCR2 and CCR5 variants on HIV disease: abstract and commentary.
PMID- 9403431
TI - Derek F. C. Harwood Nash, MB, ChB, DSc, FRCPC, FACR, FC RAD (SA).
PMID- 9403432
TI - Can academic neuroradiology survive in this era of managed care?
PMID- 9403433
TI - The encephalopathic neonate: choosing the proper imaging technique.
PMID- 9403434
TI - The roles of MR angiography, CT angiography, and sonography in vascular imaging
of the head and neck.
PMID- 9403435
TI - The treatment of acutely ruptured cerebral aneurysms: endovascular therapy versus
surgery.
PMID- 9403436
TI - Prethrombolysis brain imaging: trends and controversies.
PMID- 9403437
TI - Rule out eighth nerve tumor: contrast-enhanced T1-weighted or high-resolution T2
weighted MR?
PMID- 9403438
TI - Cryptic vascular malformations: controversies in terminology, diagnosis,
pathophysiology, and treatment.
PMID- 9403439
TI - Imaging the brain in dementia: expensive and futile?
PMID- 9403440
TI - Screening sinus CT: a good idea gone bad?
PMID- 9403441
TI - Do the benefits of image guidance in neurosurgery justify the costs? From
stereotaxy to intraoperative MR.
PMID- 9403442
TI - The proper terminology for reporting lumbar intervertebral disk disorders.
PMID- 9403443
TI - Controversies in imaging acute cervical spine trauma.
PMID- 9403444
TI - The present controversy over the imaging method of choice for evaluating the soft
tissues of the neck.
PMID- 9403445
TI - The value of proton MR spectroscopy in pediatric metabolic brain disease.
PMID- 9403446
TI - Cardiac rupture complicating cerebral intraarterial thrombolytic therapy.
AB - We report a case of fatal cardiac rupture occurring during intraarterial
thrombolytic therapy for acute embolic stroke in a patient with recent myocardial
infarction.
PMID- 9403447
TI - Failure as teacher.
PMID- 9403448
TI - Foreign bodies in small arteries after use of an infusion microcatheter.
AB - Over a 31-month period, we performed four neurointerventional procedures after
which unexpected foreign bodies were noted in multiple arteries. All four
procedures had in common the use of Fastracker-18 infusion microcatheters.
Histologically, the intravascular debris looked strikingly similar to the
hydrophilic coating on the catheter. An in vitro test mimicking clinical use of
the microcatheter revealed that the hydrophilic coating can separate from the
catheter. Until the coating is refined to make it more resistant to stripping, it
may be advisable to reduce the amount of back-and-forth movement of these
microcatheters if they have been positioned through guide catheters with small
inner diameters and angled tips.
PMID- 9403449
TI - The use of hydrophilic catheters in small arteries.
PMID- 9403450
TI - An arteriovenous malformation model for testing liquid embolic materials.
AB - An arteriovenous malformation model with a transparent nidus was constructed to
investigate the embolization behavior of polyvinyl acetate (PVAc) solution
relative to flow velocity in the feeding artery and injection speed. It was found
that the liquid embolic material flowed distally when injected too fast or when
the flow velocity was too low. In addition, we found that solution consisting of
PVAc plus metrizamide was a better embolic material than solution containing only
PVAc.
PMID- 9403451
TI - Percutaneous polymethylmethacrylate vertebroplasty in the treatment of
osteoporotic vertebral body compression fractures: technical aspects.
AB - PURPOSE: To describe a technique for percutaneous vertebroplasty of osteoporotic
vertebral body compression fractures and to report early results of its use.
METHODS: The technique was used over a 3-year period in 29 patients with 47
painful vertebral fractures. The technique involves percutaneous puncture of the
involved vertebra(e) via a transpedicular approach followed by injection of
polymethylmethacrylate (PMMA) into the vertebral body. RESULTS: The procedure was
technically successful in all patients, with an average injection amount of 7.1
mL PMMA per vertebral body. Two patients sustained single, nondisplaced rib
fractures during the procedure; otherwise, no clinically significant
complications were noted. Twenty-six patients (90%) reported significant pain
relief immediately after treatment. CONCLUSION: Vertebroplasty is a valuable tool
in the treatment of painful osteoporotic vertebral fractures, providing acute
pain relief and early mobilization in appropriate patients.
PMID- 9403452
TI - Paradoxical hyperfixation of hexamethylpropyleneamine oxime in cerebral
infarction.
AB - We describe four patients with cerebral infarction and 99mTc
hexamethylpropyleneamine oxime (HMPAO) hyperfixation in distributions
corresponding to the infarctions seen at CT and/or MR imaging. Increased HMPAO
extraction due to hyperpermeability across the blood-brain barrier and increased
retention due to reduced back diffusion of the tracer probably accounted for the
increased fractional fixation in infarcts seen in our patients.
PMID- 9403453
TI - Proton MR spectroscopy and neuropsychological testing in adrenoleukodystrophy.
AB - PURPOSE: To determine early signs of disease in patients with childhood-onset
cerebral adrenoleukodystrophy (COCALD) with the use of proton MR spectroscopy.
METHODS: Eleven children with posterior COCALD involvement and three children
with anterior COCALD involvement were studied with single-voxel proton MR
spectroscopy and neuropsychological testing. Findings were compared with those in
five healthy control subjects. RESULTS: Areas of abnormal T2 signal intensity in
children with COCALD showed abnormal metabolite ratios relative to those of
control subjects as follows: decreased N-acetylaspartate (NAA)/Creatine (Cr) and
NAA/Choline (Ch) and increased Ch/Cr. Metabolite ratios from normal-appearing
brain regions in the same patients also were abnormal, with reduced NAA/Cr and
NAA/Ch and increased Ch/Cr values. The mean metabolite ratios in normal-appearing
regions were between those in the abnormal regions and those found in the control
subjects. Statistical comparison of these ratios with neuropsychological test
scores, which are specific for anterior and posterior brain functions, showed a
significant correlation with the abnormal metabolite ratios. Our results indicate
that the normal-appearing brain regions in these patients are metabolically
abnormal. CONCLUSION: Proton MR spectroscopy could be a useful noninvasive tool
to evaluate extent of disease in patients with COCALD.
PMID- 9403454
TI - Congenital ocular motor apraxia: imaging findings.
AB - PURPOSE: To determine the frequency of cerebellar and cerebral abnormalities on
brain imaging studies in children with congenital ocular motor apraxia. METHODS:
Brain imaging studies were performed in 19 children with typical congenital
ocular motor apraxia who were in the care of a visual impairment program at a
children's hospital. Independent clinical review categorized the subjects as
having partial (n = 10) or expanded (n = 9) congenital ocular motor apraxia on
the basis of extent of associated speech or neurodevelopmental problems. Fifteen
CT studies and 13 MR examinations of the brain performed in these children were
reviewed independently by two pediatric neuroradiologists. Radiologic findings
were agreed on by consensus. RESULTS: Cerebellar abnormalities were found in 12
of 19 cases. The cerebellar vermis was small in 10 children. A small cerebellar
vermis was the only abnormality in five of 10 children with partial congenital
ocular motor apraxia and in two of nine children with expanded congenital ocular
motor apraxia. Among seven children with a small vermis examined with high
resolution MR imaging, the inferior portion of the vermis was preferentially
involved in each case. Of these seven subjects, none of four with partial
congenital ocular motor apraxia but two of three with expanded congenital ocular
motor apraxia had an abnormality of the superior portion of the vermis.
Miscellaneous supratentorial lesions affecting both gray and white matter were
found in six subjects. Five of the 19 children had normal imaging findings.
CONCLUSION: Inferior vermian hypoplasia is the most common abnormality in
children with congenital ocular motor apraxia.
PMID- 9403455
TI - GRASE (gradient- and spin-echo) MR of the brain.
AB - PURPOSE: To assess the clinical utility of GRASE (gradient- and spin-echo) MR
imaging of the brain by comparing it with the T2-weighted turbo spin-echo
technique. METHODS: Fifty-three consecutive patients referred for MR imaging of
the brain were studied with T2-weighted turbo spin-echo and GRASE techniques,
matched for effective echo time (110 milliseconds), echo train length (eight),
and spatial resolution. The examinations were evaluated independently by two
neuroradiologists for lesion detection (high- and low-signal-intensity lesions)
and lesion conspicuity, and for susceptibility, motion, and chemical-shift
artifacts. RESULTS: The GRASE technique provided greater detection of both high-
and low-signal-intensity lesions and of low-signal-intensity lesions with
paramagnetic susceptibility characteristics (ie, calcium and hemorrhage).
Chemical-shift artifacts in the frequency-encoding direction were more prominent
with the turbo spin-echo technique, whereas chemical-shift artifacts in the phase
encoding direction were more prominent with the GRASE technique. There was no
significant difference in the degree of diamagnetic susceptibility artifacts at
the base of the skull, or in motion artifacts. CONCLUSION: T2-weighted GRASE is a
fast imaging technique with a potential for replacing turbo spin-echo in routine
MR imaging of the brain. GRASE maintains the contrast resolution of turbo spin
echo imaging and is better at depicting lesions with paramagnetic susceptibility
characteristics.
PMID- 9403456
TI - Changes in blood flow velocity and diameter of the middle cerebral artery during
hyperventilation: assessment with MR and transcranial Doppler sonography.
AB - PURPOSE: To compare blood flow velocity changes within the middle cerebral artery
(MCA) during hyperventilation, as measured with by both transcranial Doppler
sonography and MR imaging, with the diameter of the MCA as measured with MR
imaging alone. METHODS: The studies were performed in six healthy volunteers
ranging in age from 22 to 31 years (mean, 27 years). Transcranial Doppler
sonography was carried out with a range-gated 2-MHz transducer. MR examinations
were done on a 1.5-T imaging unit. MR angiography was performed using the time-of
flight technique. MR flow measurements were carried out by using the phase
mapping technique with an ECG-triggered phase-contrast sequence. RESULTS: During
hyperventilation, the mean blood flow velocity of the proximal MCA declined by
49.6% +/- 5.7 (mean +/- standard deviation) as measured with Doppler sonography,
and by 47% +/- 4.6 as measured with MR flow calculation. The diameter of the MCA
(3.4 +/- 0.3 mm) remained unchanged on MR imaging studies (3.3 +/- 0.3 mm).
CONCLUSION: We found a good correlation between relative flow velocity changes
measured by transcranial Doppler sonography and MR techniques. MR imaging
revealed no significant changes in the diameter of the proximal MCA during normal
versus hyperventilation. Relative changes in flow velocity in the MCA would
thereby reflect relative changes in cerebral blood flow, at least during
hyperventilation.
PMID- 9403457
TI - Cerebral complications of murine monoclonal CD3 antibody (OKT3): CT and MR
findings.
AB - Treatment of acute renal allograft rejection with mouse monoclonal antibody
(OKT3) is associated with systemic and neurologic side effects. We describe
cerebral abnormalities in a 13-year-old boy with steroid-resistant renal
allograft rejection. After treatment with OKT3, an acute neurologic syndrome
developed, including seizures, lethargy, and decreased mental function. CT and MR
imaging revealed confluent cerebral lesions at the corticomedullary junction.
Contrast-enhanced MR images showed patchy enhancement, indicating blood-brain
barrier dysfunction. The diagnosis of OKT3-induced encephalopathy with cerebral
edema and capillary leak syndrome was made. Although CT and MR findings are
nonspecific, neuroradiologists should be aware of this condition in transplant
patients treated with OKT3.
PMID- 9403458
TI - T2-weighted three-dimensional turbo spin-echo MR of intracranial aneurysms.
AB - A T2-weighted three-dimensional turbo spin-echo sequence is described that
accurately depicted the anatomy of 18 intracranial aneurysms in 10 patients.
PMID- 9403459
TI - True malignant mixed tumor (carcinosarcoma) of tonsillar minor salivary gland
origin: diagnostic imaging and endovascular therapeutic embolization.
AB - We report a case of carcinosarcoma of the minor salivary glands of the left
palatine tonsil, an especially rare location. Imaging characteristics assessed at
CT, MR imaging, and angiography are presented. In addition, we describe our
experience with preoperative therapeutic endovascular embolization of this
hypervascular tumor.
PMID- 9403460
TI - Self-induced ethmoidectomy from rhinotillexomania.
AB - A 53-year-old woman with a long history of compulsive nose picking
(rhinotillexomania) presented with a large, self-inflicted nasal septal
perforation and right-sided penetration of the ethmoidal sinus, or
"ethmoidectomy."
PMID- 9403461
TI - New vistas in occupational health.
PMID- 9403462
TI - Occupational health and safety in national development--the case of Australia.
AB - Over the last 15 years occupational health and safety has undergone a rapid
transformation in Australia. This review discusses the changes, emphasizing, the
sociopolitical and economic context, national developments in policy and
practice, and the dialogue between the public and occupational health and safety
agencies and professionals about occupational health and safety matters. First
came the classical phase when activities followed the accepted hygienic, medical,
and inspection traditions laid down early in the century. A phase followed in
which modern legislation was introduced, new institutions were created, and
research and data gathering on important issues was intensified. Finally came the
current phase characterized by a performance paradigm. Emphasis was given to
regulatory reform and the use of nonregulatory initiatives to facilitate better
occupational health and safety.
PMID- 9403463
TI - Mortality from cardiovascular diseases and sudden death in ferroalloy plants.
AB - OBJECTIVES: The aim of this study was to examine mortality from circulatory
diseases and sudden death among workers in 12 Norwegian ferroalloy plants.
METHODS: The cohort comprised 14730 men employed for the first time during 1933
1990 and for at least 6 months. Deaths observed during 1962-1990 were compared
with expected figures calculated from national mortality rates. Internal
comparisons of rates were performed by Poisson regression analysis. RESULTS: The
overall mortality from cardiovascular diseases was not increased [standardized
mortality ratio (SMR) 1.01], but a significantly increased mortality from sudden
death (SMR 1.55) and hypertensive disease (SMR 1.37) was observed. Among the
ferromanganese/silicomanganese (FeMn/SiMn) furnace workers the sudden death
mortality was significantly increased during the employment period (SMR 2.47). In
an internal comparison of the sudden death rates, a significant increase of 0.05
in the rate ratio per workyear was observed in this group. The mortality from 3
hypertension-related diseases combined (cerebrovascular, hypertensive, and renal
diseases) showed identical positive mortality trends among the
ferrosilicon/silicon-metal (FeSi/Si-met) and the FeMn/SiMn furnace workers by
increasing duration of work. CONCLUSIONS: Increased mortality from sudden death
among the FeMn/SiMn furnace workers is not likely to be explained by smoking or
alcohol consumption. Associations with work exposures (manganese and possibly
carbon monoxide and heat) are suspected. The increasing mortality from
hypertension-related diseases with increasing duration of work in both groups of
furnace workers may be associated with common furnace work conditions (eg, heat,
psychosocial stress, shift work, noise, carbon monoxide).
PMID- 9403464
TI - Mortality from nonmalignant respiratory diseases among male workers in Norwegian
ferroalloy plants.
AB - OBJECTIVES: This study examined mortality from nonmalignant respiratory diseases
among ferroalloy workers. METHODS: The cohort comprised 14730 men employed for
the first time in 1933-1990 and for at least 6 months in 1 of 12 plants. The
duration of work in specific departments and exposure to amorphous silica in the
ferrosilicon/silicon-metal (FeSi/Si-met) plants, estimated from a job-exposure
matrix, were the main exposure variables. Deaths were observed during 1962-1990.
The mortality was analyzed with the use of standardized mortality ratios (SMR)
and internal comparisons of rates. RESULTS: Overall mortality from nonmalignant
respiratory diseases was not increased, but mortality from bronchitis, emphysema,
and asthma combined was significantly increased among the men with at least 3
years of FeSi/Si-met furnace work (SMR 1.82, 16 deaths). A Poisson regression
analysis of the mortality from these causes among 6359 employees in the FeSi/Si
met plants showed a significant increase of 0.06 per unit of amorphous silica
exposure observed 10-20 years after the exposure. Six men died of pneumonia while
still employed in a ferromanganese/silicomanganese (FeMn/SiMn) plant. No
corresponding deaths occurred among employees in FeSi/Si-met plants. Only 2
deaths from pneumoconiosis were observed in the total cohort. CONCLUSIONS: Among
employees in FeSi/Si-met plants increased mortality from bronchitis, emphysema,
and asthma may be associated with previous exposure to amorphous silica. Deaths
from pneumonia among FeMn/SiMn workers may be associated with manganese exposure.
PMID- 9403465
TI - Respiratory symptoms, across-shift lung function changes and lifetime exposures
of welders in New Zealand.
AB - OBJECTIVES: The possibility was investigated that exposure to welding fumes
causes an acute decrease in pulmonary function. METHODS: Changes in the pulmonary
function of 62 current welders and 75 nonwelders at the same sites and the
relationship with work-related symptoms were recorded. RESULTS: Work-related
cough was reported by 22.6% of the current welders and 6.7% of the nonwelders
[odds ratio (OR) 4.1, 95% confidence interval (95% CI) 1.5-11.5], and the
respective figures for at least 1 work-related symptom were 30.7% and 16.0% (OR
2.3, 95% CI 1.0-5.2). The groups' preshift lung function did not differ. The mean
percentage change from the base-line value of the forced expiratory volume in 1 s
(FEV1.0) after 15 minutes of work was -2.8% (range -29.3% to +20.9%) for the
current welders and +1.0% (range -20.7% to +22.6%) for the nonwelders (P = 0.01).
A multivariate analysis identified current welding as the most significant risk
factor for a decrease of at least 5% in FEV1.0 after 15 minutes, the risk being
greater for those with no local exhaust ventilation (OR 22.4, 95% CI 4.5-113.4)
than for those with personal protection only (OR 16.0, 95% CI 2.1-122.9) and
those with local exhaust ventilation (OR 2.8, 95% CI 0.2-41.2) or passive
exposure only (OR 2.0, 95% CI 0.5-8.8). CONCLUSIONS: An acute decrease in FEV1.0
in relation to work is more prevalent among welders than among nonwelders, and is
more common among welders without local exhaust ventilation than among those with
it.
PMID- 9403466
TI - Lead concentrations in human plasma, urine and whole blood.
AB - OBJECTIVES: Blood-lead levels (B-Pb), and to some extent urinary lead (U-Pb), are
the most employed measures of lead exposure and risk. However, the small fraction
of lead present in plasma (usually below 1% of that in blood) is probably more
relevant to lead exposure and toxicity. Nevertheless, the lead content of plasma
lead (P-Pb) has only seldom been used, mainly due to analytical limitations,
which have now been overcome. We examined P-Pb in occupationally exposed
subjects, as well as its relationship with B-Pb and U-Pb. METHODS: Blood samples
were obtained from 145 male workers, 110 of whom were employed in lead work.
After a simple dilution of plasma, P-Pb was determined by inductively coupled
plasma mass spectrometry. The detection limit was 0.04 microg/l, and the
imprecision was 5%. RESULTS: The lead concentration ranges were 0.20-37 microg/l
for P-Pb, 0.9-176 microg/l (density adjusted) for U-Pb, and 9-930 microg/l for B
Pb. A close exponential relation was obtained between B-Pb and P-Pb. When B-Pb
was plotted versus log P-Pb, a straight line (log P-Pb = 0.00225 x B-Pb - 0.58; r
= 0.97) was obtained. Both the relation between U-Pb and P-Pb and that between U
Pb and B-Pb showed a large scattering (r = 0.78 in both cases). The relation to B
Pb appeared to be exponential, while that to P-Pb appeared to be linear.
CONCLUSIONS: The low detection limit and good precision of P-Pb determinations
make it possible to use P-Pb in assessments of lead exposure and risk.
Furthermore, in relative terms, P-Pb is a more sensitive measure than B-Pb,
especially at high lead levels. This development is of importance for studies of
exposure, possibly also for studies of risks.
PMID- 9403467
TI - Occupational and personal risk factors for carpal tunnel syndrome in industrial
workers.
AB - OBJECTIVES: The purpose of the study was to evaluate both nonoccupational and
occupational factors associated with carpal tunnel syndrome (CTS) in industrial
workers. METHODS: Sixty-five workers with CTS were compared with 65 referents
matched for gender, age, and plant. The medical history and household activities
of the workers and the ergonomic and organizational characteristics of the job
were analyzed. RESULTS: Exertion of force over 1 kg was associated with CTS [odds
ratio (OR) 9.0]. Two risk factors were related to motion repetitiveness: length
of the shortest elementary operation of < or = 10 s (OR 8.8) and lack of change
in tasks or lack of breaks for at least 15% of the daily worktime (OR 6.0). No
posture of the upper limb was associated with CTS. Workstation design involving
the manual supply of the workers (OR 5.0) and the lack of job rotation (OR 6.3)
were associated with CTS. The only personal factor associated with CTS was a
parity of at least 3 (OR 3.2). There was a continuous increase in the odds ratio
against the number of risk factors accumulated by the workers; the odds ratio
thus ranged from 5.6 when 3 of the 6 risk factors were present to > or = 90 when
4, 5, or 6 risk factors were accumulated. CONCLUSIONS: The results were in
agreement with a model for CTS which included 1 personal and 5 occupational risk
factors. The number of risk factors cumulated by the workers seems to be a major
determinant of CTS.
PMID- 9403468
TI - Possible bias from rating behavior when subjects rate both exposure and outcome.
AB - OBJECTIVES: In many epidemiologic studies the subjects rate both the exposure and
the outcome, assigning numerical values to the variables according to their
perceptions and judgments. Hypothetically, subjects who tend to overestimate,
exaggerate, or use high numerical values in rating tasks would rate both exposure
and outcome higher than subjects who tend to underestimate, dissimulate, or use
low numerical values. A range of such rating behaviors among the subjects would
introduce uncontrollable bias to relative risk estimates, in most cases an
overestimation. The aim of this study was to assess the possible presence of and
effects on relative risk estimates of such high and low rating behavior among
subjects in an epidemiologic study of musculoskeletal disorders. METHODS: Rating
behavior was analyzed by intercorrelating the ratings of 19 different stimuli.
High positive correlations would indicate the presence of high and low rating
behavior. RESULTS: The correlations were, however, both positive and negative and
close to zero. Adjusting for rating behavior did not affect relative risk
estimates, based on subjective ratings of both exposure and outcome. CONCLUSION:
There is no support in this study for the existence of a range of high and low
rating behavior among subjects who rate neutral and nonaffective stimuli, such as
time, weight, number and physical exposure, as well as pain and other symptoms.
There is therefore no support for the idea of a bias to relative risk estimates
from such rating behavior in studies where subjects rate both exposure and
outcome variables of this kind.
PMID- 9403469
TI - Job adjustment as a means to reduce sickness absence during pregnancy.
AB - OBJECTIVES: This study examined the effect of job adjustment on sickness absence
during pregnancy and also determined the conditions under which such adjustments
are obtained. METHODS: Data were derived from a nationally representative survey
on work conditions during pregnancy in Norway in 1989. For employees (N = 2713)
remaining in the same job throughout pregnancy, the percentage of women on sick
leave immediately before delivery was determined according to the need for job
adjustment and the obtainment of job adjustment. Those obtaining job adjustment
were grouped according to workplace size, labor-market sector, co-worker gender,
educational level, work schedules, weekly workhours, children under 16 years of
age in the household, and age. RESULTS: All told, 1691 women (62.3%) needed job
adjustment, among whom 936 (55.4%) obtained such adjustment. The proportions of
those on sick leave before delivery were 45.2% for "no need", 67.9% for "need -
adjustment obtained", and 79.2% for "need - adjustment not obtained". In the last
category, the difference (versus "adjustment obtained") constituted 44.5% of the
weeks lost because of sickness absence in the last half of pregnancy. The odds
ratio (OR) for obtaining job adjustment was larger for workplaces with more than
50 employees (OR 1.4) and smaller for jobs with work schedules other than daytime
or shift work (OR 0.5) and also for women living with children under 16 years of
age (OR 0.8). CONCLUSIONS: Job adjustment is associated with reduced sickness
absence during pregnancy. Further studies should explore workplace
characteristics that make it difficult to obtain such adjustments, as required by
law.
PMID- 9403470
TI - Sensitization to industrial enzymes in enzyme research and production.
AB - OBJECTIVES: This study investigated sensitization to industrial enzymes in
Finnish enzyme production and in Finnish laboratories. METHODS: A cross-sectional
study was conducted in 2 plants producing industrial enzymes and in their product
development and research laboratories. Sensitization to enzymes and environmental
allergens was examined by skin prick tests and specific immunoglobulin E
determinations (radioallergosorbent test). The employees were interviewed for
work-related respiratory symptoms. Altogether 173 employees were examined.
RESULTS: The skin prick test showed 21 employees (12%) to be sensitized to one or
more enzymes. Sixteen positive persons also had specific immunoglobulin E. Atopy
was distinctly associated with enzyme sensitization. An exposure-response
relationship was found for enzyme sensitization and for respiratory symptoms
during work. For sensitization, the exposure-response linear trend was
statistically significant. It weakened but remained statistically significant
after stratification for atopy. For symptoms, likewise, the exposure-response
linear trend was statistically significant, and the statistical significance
remained after stratification for atopy. CONCLUSION: The study confirmed that
industrial enzymes are potent sensitizers. The handling of dry enzymes in
laboratory work may cause sensitization. Sensitization may even follow minute
degrees of exposure, such as among office personnel. Atopics are more susceptible
to sensitization than nonatopics. Nonatopics are also clearly at risk; the
demonstrated exposure-response relationship emphasizes the need for and
advantages of proper exposure control.
PMID- 9403471
TI - Developing national indicators for occupational health.
PMID- 9403472
TI - Occupational diseases in Finland in 1996.
PMID- 9403473
TI - Aging and the brain: a new frontier.
AB - With aging, both "normal" senescent age-related changes (ARCs) and late-onset
diseases affect the brain, producing declines in performance. The brain as a
postmitotic structure is particularly vulnerable to ARCs, and senescence is by
far the most powerful risk factor for neurological diseases of the elderly such
as sporadic Alzheimer's disease. The concept of senescence as an immutable result
of the passage of time is yielding to understanding of the biology of ARCs. Both
individual and species differences in longevity illustrate the variable effects
of time. Whereas human life expectancy has been extended by prevention and
treatment of specific diseases, life span can be altered by modifying the
processes producing ARCs. Models of prolonged life span (eg, modifications of
Caenorhabditis elegans longevity genes, restricted caloric intake) demonstrate
the feasibility of extending longevity throughout the phylogenetic spectrum. Both
programmed and variable factors produce ARCs. Cell survival depends on a balance
of opposing factors--oncogene and anti-oncogene products, cyclins, growth
factors, and so on; apoptotic death results when the balance shifts. Variable
factors, including accumulation of oxygen free radicals, protein conformational
changes, decline in chaperone functions, and secondary loss of mitochondrial
energy production, can also result in neuronal degeneration. To prevent the
increased neuronal vulnerability of senescence, ARCs must be modified. The "new
frontier" in neurology is the challenge of understanding the changes of aging,
both to determine their impact on disease and to prevent their consequences.
PMID- 9403475
TI - Inhibition of axonal growth from sensory neurons by excess nerve growth factor.
AB - Fifteen-day embryonic rat dorsal root ganglion (DRG) neurons were exposed to 1 to
200 ng/ml nerve growth factor (NGF). Maximal neurite outgrowth was obtained with
10 to 20 ng/ml. Neurite outgrowth was reduced to 89% of maximal by increasing NGF
to 50 ng/ml, to 66% by 100 ng/ml, and to 18% by 200 ng/ml NGF. Identical effects
were seen with mouse 2.5S NGF and recombinant human NGF. Neuron cell counts
demonstrated that significant cell death did not occur. In time course
experiments, significant inhibition, compared with control, began within 1 hour
of adding 200 ng/ml and 3 hours of adding 50 ng/ml NGF. The inhibitory effect of
NGF on neurite outgrowth was reversed within 3 hours when DRG were incubated with
5 ng/ml NGF after treatment with 50 or 200 ng/ml NGF medium for 12 hours. The
inhibition demonstrated for neurons did not occur in PC12 cells; axonal growth
was not inhibited by up to 1,000 ng/ml NGF. Excess brain-derived neurotrophic
factor or neurotrophin-3 did not inhibit neurite outgrowth. We conclude that high
concentrations of NGF produces specific and reversible arrest of neurite
outgrowth from sensory neurons. This observation has important clinical
implications, because these inhibitory concentrations have been exceeded when NGF
has been administered into the central nervous system of humans and animals.
PMID- 9403474
TI - Presurgical multimodality neuroimaging in electroencephalographic lateralized
temporal lobe epilepsy.
AB - The purpose of this study was to compare 2-[18F]fluoro-2-deoxy-D-glucose positron
emission tomography (FDG-PET), hippocampal volumetry (HV), T2 relaxometry, and
proton magnetic resonance spectroscopic imaging (1H-MRSI) in the presurgical
neuroimaging lateralization of patients with nonlesional, electroencephalogram
(EEG)-defined unilateral temporal lobe epilepsy (TLE). Twenty-five patients were
prospectively studied, along with age-matched controls. T2 relaxometry
examinations were performed in 13 patients. Comparison of FDG-PET, HV, and 1H
MRSI was possible in 23 patients. FDG-PET lateralized 87% of patients, HV 65%, N
acetyl aspartate (NAA)/(choline [Cho] + creatine [Cr]) 61%, and [NAA] 57%.
Combined HV and NAA/(Cho + Cr) results lateralized 83% of the patients, a value
similar to PET. Of 10 patients with normal magnetic resonance imaging (MRI)
scans, 2 were lateralized with HV, 6 with FDG-PET, 4 with NAA/(Cho + Cr), and 3
with [NAA]. T2 relaxometry lateralized no patients without hippocampal atrophy.
Bilateral abnormality was present in 29 to 33% of patients with 1H-MRSI measures
and 17% with HV. Only hippocampal atrophy correlated with postoperative seizure
free outcome. FDG-PET remains the most sensitive imaging method to correlate with
EEG-lateralized TLE. Both FDG-PET and 1H-MRSI can lateralize patients with normal
MRI, but only the presence of relative unilateral hippocampal atrophy is
predictive of seizure-free outcome. Bilaterally abnormal MRI and 1H-MRSI measures
do not preclude good surgical outcome.
PMID- 9403476
TI - Human immunodeficiency virus type 1 and its coat protein gp120 induce apoptosis
and activate JNK and ERK mitogen-activated protein kinases in human neurons.
AB - Detection of apoptotic neurons and microglial cells in the brains of human
immunodeficiency virus type 1 (HIV-1)-infected patients has suggested that
programmed cell death may be implicated in the physiopathology of HIV-1
encephalopathy. To analyze in vitro the intracellular signals induced by HIV-1 in
human neurons and the associated neuronal death, we tested cultured human central
nervous system (CNS) cells for apoptosis induced by HIV-1 and gp120 and for
signaling pathways activated by gp120. HIV-1 and gp120 induced apoptosis of
neurons and microglial cells but not of astrocytes or transformed microglial
cells. Gp120 activated c-Jun N-terminal kinase (JNK) and p42 extracellular
regulated kinase (ERK) in primary CNS cells, with an early peak of activation at
2 to 5 minutes that was not present when pure microglial or astrocyte cultures
were tested, followed by a late and sustained activation (10 and 60 minutes) in
primary and enriched glial cell cultures as well as in transformed microglial
cells. This demonstrates that gp120 could be an effector of HIV-1-induced
apoptosis in the CNS and act directly on neuronal and glial cells.
PMID- 9403477
TI - A randomized trial of anticoagulants versus aspirin after cerebral ischemia of
presumed arterial origin. The Stroke Prevention in Reversible Ischemia Trial
(SPIRIT) Study Group.
AB - Aspirin is only modestly effective in the secondary prevention after cerebral
ischemia. Studies in other vascular disorders suggest that anticoagulant drugs in
patients with cerebral ischemia of presumed arterial (noncardiac) origin might be
more effective. The aim of the Stroke Prevention in Reversible Ischemia Trial
(SPIRIT) therefore was to compare the efficacy and safety of 30 mg aspirin daily
and oral anticoagulation (international normalized ratio [INR] 3.0-4.5). Patients
referred to a neurologist in one of 58 collaborating centers because of a
transient ischemic attack or minor ischemic stroke (Rankin grade < or =3) were
eligible. Randomization was concealed, treatment assignment was open, and
assessment of outcome events was masked. The primary measure of outcome was the
composite event "death from all vascular causes, nonfatal stroke, nonfatal
myocardial infarction, or nonfatal major bleeding complication." The trial was
stopped at the first interim analysis. A total of 1,316 patients participated;
their mean follow-up was 14 months. There was an excess of the primary outcome
event in the anticoagulated group (81 of 651) versus 36 of 665 in the aspirin
group (hazard ratio, 2.3; 95% confidence interval [CI], 1.6-3.5). This excess
could be attributed to 53 major bleeding complications (27 intracranial; 17
fatal) during anticoagulant therapy versus 6 on aspirin (3 intracranial; 1
fatal). The bleeding incidence increased by a factor of 1.43 (95% CI, 0.96-2.13)
for each 0.5 unit increase of the achieved INR. Anticoagulant therapy with an INR
range of 3.0 to 4.5 in patients after cerebral ischemia of presumed arterial
origin is not safe. The efficacy of a lower intensity anticoagulation regimen
remains to be determined.
PMID- 9403478
TI - Correlation between PMP-22 messenger RNA expression and phenotype in hereditary
neuropathy with liability to pressure palsies.
AB - Hereditary neuropathy with liability to pressure palsies (HNPP) is associated
with a deletion in chromosome 17p11.2, which includes the gene for the peripheral
myelin protein 22 (PMP-22). A "gene dosage" effect is probably the mechanism
underlying HNPP, but the amount of PMP-22 mRNA in sural nerves of HNPP patients
is highly variable and the role of PMP-22 underexpression in impairing
myelination has yet to be clarified. We have studied 6 genetically proven HNPP
patients, to evaluate the relationship between PMP-22 mRNA levels, and clinical,
neurophysiological, and neuropathological findings. Underexpression of PMP-22
mRNA correlates with disease severity and with mean axon diameter and g ratio,
but not with myelin thickness, number of "tomacula," or nerve conduction
parameters. Our findings further confirm that underexpression of PMP-22 is the
main pathogenetic mechanism underlying the severity of clinical symptoms and
signs in HNPP. Smaller axons in sural nerves of HNPP patients with lower PMP-22
levels suggests that underexpression of PMP-22 may also affect axon development.
PMID- 9403479
TI - Outcome after temporal lobectomy in bilateral temporal lobe epilepsy.
AB - We determined how noninvasive presurgical data relate to prognosis after temporal
lobectomy in patients with independent bilateral temporal lobe (IBTL) complex
partial seizures on the intracranial electroencephalogram (EEG). Between 1986 and
1994, 28 patients had IBTL seizures on intracranial EEG. Fifteen of these 28
patients underwent temporal lobectomy and 13 were not offered surgery. Of the 15
patients who had surgery, 10 patients became seizure-free. Magnetic resonance
imaging (MRI) and the Wada test were the only variables associated with a seizure
free outcome. Seven of 10 seizure-free patients had a lateralized Wada result or
the presence of unilateral hippocampal sclerosis, whereas none of the patients
with persistent seizures had either of these findings. Variables not found to be
predictive of a seizure-free outcome included location of scalp interictal
spikes, degree of seizure-onset laterality, presence of early epilepsy risk
factor, duration of epilepsy, and full-scale intelligence quotient. We conclude
that MRI and the Wada test provide information of prognostic value in patients
with bilateral temporal seizures independent of intracranial EEG data.
PMID- 9403480
TI - Spinocerebellar ataxia type 6: CAG repeat expansion in alpha1A voltage-dependent
calcium channel gene and clinical variations in Japanese population.
AB - Autosomal dominant spinocerebellar ataxias (SCAs) are clinically and genetically
a heterogeneous group of neurodegenerative disorders. Recently, mild CAG repeat
expansion in the alpha1A voltage-dependent calcium channel gene has been found to
be associated with a type of autosomal dominant SCA (SCA6). We analyzed 98
Japanese families with autosomal dominant SCAs, for whom CAG repeat expansions of
the SCA1, SCA2, Machado-Joseph disease/SCA3, and dentatorubral-pallidoluysian
atrophy genes were excluded, and 5 apparently sporadic cases of cortical
cerebellar atrophy. The diagnosis of SCA6 was confirmed in 30 families (31%)
comprising 47 affected individuals and 1 sporadic case. The size of expanded CAG
repeats ranged from 21 to 26 repeat units and was found to be correlated
inversely with age at onset. We identified 2 SCA6 patients homozygous for
expanded CAG repeats, whose ages at onset were earlier than the 95% lower
confidence level, suggesting the presence of a gene dosage effect of expanded CAG
repeat. Ataxia is the most common initial symptom found in 45 of the 48 patients.
Patients with a prolonged disease course showed other accompanying clinical
features including dystonic postures, involuntary movements, and abnormalities in
tendon reflexes.
PMID- 9403481
TI - Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and
evidence of further heterogeneity.
AB - Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine
with aura. We previously mapped an FHM gene on the short arm of chromosome 19.
Mutations in this gene, recently shown to be the alpha1 subunit of a P/Q-type
voltage-dependent calcium channel, CACNL1A4, are involved in approximately 50% of
unselected FHM families and in all families where migraine attacks are associated
with permanent cerebellar ataxia. As a first step toward the identification of
other FHM genes, we conducted a genetic linkage analysis in one large French
pedigree and showed significant linkage to two microsatellite markers D1S2635
(Zmax: 3.33 at theta = 0.05) and D1S2705 (Zmax: 3.64 at theta = 0.05),
establishing the existence of a second locus for FHM (FHM2) on chromosome 1q21
q23. Analysis of six additional FHM families favored linkage to this locus in two
of them; linkage was excluded in the last four families, indicating further
heterogeneity. Chromosome 1-linked families differ from the ones linked to
chromosome 19, because penetrance in those families is much lower, and in some of
their members, epileptic seizures occur during severe migraine attacks.
PMID- 9403482
TI - Unilateral cerebellar lesions affect initiation of ipsilateral smooth pursuit eye
movements in humans.
AB - To clarify the role of the cerebellum in pursuit initiation (first 100 msec), we
used infrared oculography to examine the effect of unilateral cerebellar lesions
on the initial (0-20 msec) and later (80-100 msec) periods as well as the steady
state response (200-300 msec) of horizontal smooth pursuit in 10 patients with
unilateral cerebellar lesions. These results were compared with those of 17 age
matched healthy subjects. Smooth pursuit was elicited with a step-ramp target
movement with randomized horizontal directions and velocities of 10 degrees/sec
and 30 degrees/sec. In the first 20-msec pursuit, velocity was 22% lower toward
the side of the cerebellar lesion than away from it and 16% lower in the period
80 to 100 msec (normal differences, 2% and 3%). Later (200-300 msec), the
ipsiversive/contraversive difference was smaller, but pursuit velocity in both
directions was significantly lower in patients than in normals. No lesion
affected the floccular region and/or the nodulus/uvula. Five lesions extended so
far medially that they could have affected the medial deep cerebellar nucleus
(fastigial nucleus). The remaining five were in the lateral hemisphere in areas
previously considered uninvolved in pursuit generation. Our findings prove that
the cerebellum participates in human pursuit initiation and that lesions in the
lateral cerebellum possibly affect smooth pursuit.
PMID- 9403483
TI - Amyloid beta-protein deposition in the leptomeninges and cerebral cortex.
AB - To further investigate the process of amyloid beta-protein (Abeta) deposition, we
determined, using sensitive enzyme immunoassays, the levels of Abeta40 and
Abeta42 (Abetas) in the soluble and insoluble fractions of the leptomeninges
(containing arachnoid mater and leptomeningeal vessels) and cerebral cortices
from elderly control subjects showing various stages of Abeta deposition and from
patients affected by Alzheimer's disease (AD). In both locations, insoluble Abeta
levels were higher by orders of magnitude than soluble Abeta levels. Soluble
Abeta levels in cortices were much lower than those in leptomeninges. In
insoluble Abeta in the cortex, Abeta42 was by far the predominant species, and
Abeta42 in AD cortices was characterized by the highest degree of modifications
in the amino terminus. In contrast, this Abeta42 predominance was not observed in
insoluble Abeta in the leptomeninges, which were found to be able to accumulate
Abetas to an extent similar to that in the cortex, on a weight basis. The levels
of insoluble Abeta in the leptomeninges or cortex generally correlated with the
degree of cerebral amyloid angiopathy or the abundance of senile plaque,
respectively. However, the presence of plaque-free cortical samples showing
significant levels of insoluble Abeta42 suggests that biochemically detectable
Abeta accumulation precedes immunocytochemically detectable Abeta deposition in
the cortex.
PMID- 9403484
TI - Butyrylcholinesterase in the life cycle of amyloid plaques.
AB - Deposits of diffuse beta-amyloid (Abeta) may exist in the brain for many years
before leading to neuritic degeneration and dementia. The factors that contribute
to the putative transformation of the Abeta amyloid from a relatively inert to a
pathogenic state remain unknown and may involve interactions with additional
plaque constituents. Matching brain sections from 2 demented and 4 nondemented
subjects were processed for the demonstration of Abeta immunoreactivity,
butyrylcholinesterase (BChE) enzyme activity, and thioflavine S binding.
Additional sections were processed for the concurrent demonstration of two or
three of these markers. A comparative analysis of multiple cytoarchitectonic
areas processed with each of these markers indicated that Abeta plaque deposits
are likely to undergo three stages of maturation, ie, a "diffuse" thioflavine S
negative stage, a thioflavine S-positive (ie, compact) but nonneuritic stage, and
a compact neuritic stage. A multiregional analysis showed that BChE-positive
plaques were not found in cytoarchitectonic areas or cortical layers that
contained only the thioflavine S-negative, diffuse type of Abeta plaques. The
BChE-positive plaques were found only in areas containing thioflavine S-positive
compact plaques, both neuritic and nonneuritic. Within such areas, almost all
(>98%) BChE-containing plaques bound thioflavine S, and almost all (93%)
thioflavine S plaques contained BChE. These results suggest that BChE becomes
associated with amyloid plaques at approximately the same time that the Abeta
deposit assumes a compact beta-pleated conformation. BChE may therefore
participate in the transformation of Abeta from an initially benign form to an
eventually malignant form associated with neuritic tissue degeneration and
clinical dementia.
PMID- 9403485
TI - A triethnic comparison of intracerebral hemorrhage mortality in Texas.
AB - Intracerebral hemorrhage (ICH) is a significant cause of stroke death. Little is
known about the relative risk of Hispanic Americans (HAs), African Americans
(AAs), and non-Hispanic whites (NHWs) for ICH mortality. Based on the high
prevalence of hypertension in AAs and the low prevalence of hypertension in HAs,
we expected AAs to have the highest ICH mortality rates and HAs the lowest.
Race/ethnic age-specific ICH mortality rates were calculated from Texas vital
statistics for the years 1980 through 1995. Rate ratios (RRs) are reported with
NHWs as the referent group. There were 15,042 deaths due to ICH in Texas during
this time. In the 45- to 59-year age group, AAs had an RR of 4. The RR for HAs
was 1.9. In the 60- to 74-year age range, AAs had an RR of 1.7 and HAs had an RR
of 1.3. In the 75+ age group, the rates were similar among all three race/ethnic
groups. We conclude that there is a significant interaction of age and
race/ethnicity for ICH. At younger ages, AAs and HAs have the highest ICH
mortality rates. Access to care and socioeconomic status may play a role in the
unexpectedly high ICH mortality rates in HAs.
PMID- 9403486
TI - Autosomal dominant cerebellar ataxia: phenotypic differences in genetically
defined subtypes?
AB - Seventy-seven families with autosomal dominant cerebellar ataxia were analyzed
for the CAG repeat expansions causing spinocerebellar ataxia (SCA) types 1, 2, 3,
and 6. The SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6
for 22% of German ataxia families. Seven of 27 SCA6 patients had no family
history of ataxia. Age at onset correlated inversely with repeat length in all
subtypes. Yet the average effect of one CAG unit on onset age was different for
each SCA subtype. We compared clinical, electrophysiological, and magnetic
resonance imaging (MRI) findings to identify phenotypic characteristics of
genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and
action tremor proposed SCA2. SCA3 patients frequently developed diplopia, severe
spasticity or pronounced peripheral neuropathy, and impaired temperature
discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar
syndrome and patients often had onset after 55 years of age. SCA1 was
characterized by markedly prolonged peripheral and central motor conduction times
in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in
SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel
of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. However, overlap
between the four SCA subtypes was broad.
PMID- 9403487
TI - Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell
degeneration, and variable age of onset.
AB - Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of
autosomal dominant cerebellar ataxia associated with small expansions of the
trinucleotide repeat (CAG)n in the gene CACNL1A4 on chromosome 19p13, which
encodes the alpha1 subunit of a P/Q-type voltage-gated calcium channel. We
describe clinical, genetic, neuroimaging, neuropathological, and quantitative
oculomotor studies in four kindreds with SCA6. We found strong genetic linkage of
the disease to the CACNL1A4 locus and strong association with the expanded (CAG)n
alleles in two large ataxia kindreds. The expanded alleles were all of a single
size (repeat number) within the two large kindreds, numbering 22 and 23 repeat
units. It is noteworthy that the age of onset of ataxia ranged from 24 to 63
years among all affected individuals, despite the uniform repeat number.
Radiographically and pathologically, there was selective atrophy of the
cerebellum and extensive loss of Purkinje cells in the cerebellar cortex. In
addition, clinical and quantitative measurement of extraocular movements
demonstrated a characteristic pattern of ocular motor and vestibular
abnormalities, including horizontal and vertical nystagmus and an abnormal
vestibulo-ocular reflex. These studies identify a distinct phenotype associated
with this newly recognized form of dominant SCA.
PMID- 9403488
TI - Morphometry of in vivo human white matter association pathways with diffusion
weighted magnetic resonance imaging.
AB - The precise characterization of cortical connectivity is important for the
understanding of brain morphological and functional organization. Such
connectivity is conveyed by specific pathways or tracts in the white matter.
Diffusion-weighted magnetic resonance imaging detects the diffusivity of water
molecules in three dimensions. Diffusivity is anisotropic in oriented tissues
such as fiber tracts. In the present study, we used this method to map (in terms
of orientation, location, and size) the "stem" (compact portion) of the principal
association, projection, and commissural white matter pathways of the human brain
in vivo, in 3 normal subjects. In addition, its use in clinical neurology is
illustrated in a patient with left inferior parietal lobule embolic infarction in
whom a significant reduction in relative size of the stem of the left superior
longitudinal fasciculus was observed. This represents an important method for the
characterization of major association pathways in the living human that are not
discernible by conventional magnetic resonance imaging. In the clinical domain,
this method will have a potential impact on the understanding of the diseases
that involve white matter such as stroke, multiple sclerosis, amyotrophic lateral
sclerosis, head injury, and spinal cord injury.
PMID- 9403489
TI - Dendritic injury is a pathological substrate for human immunodeficiency virus
related cognitive disorders. HNRC Group. The HIV Neurobehavioral Research Center.
AB - To determine the neuropathological substrate of human immunodeficiency virus
(HIV)-associated neurocognitive disorders, we examined persons with acquired
immunodeficiency syndrome before their death and related their antemortem
neuropsychological performance to postmortem indicators of HIV encephalitis,
viral burden, and presynaptic and postsynaptic neuronal injury. Of 20
prospectively examined cases, 9 were neurocognitively normal, 5 showed
neuropsychological impairment, 5 had minor cognitive/motor disorder, and 1 was
demented. Degree of neurocognitive impairment was strongly related to the amount
of dendritic simplification based on microtubule-associated protein 2
immunohistochemical staining, somewhat less so to a semiquantitative viral burden
score based on numbers of HIV gp41-immunoreactive cells, and much less so to the
presence of multinucleated giant cells or microglial nodules. It appears that
even milder neurocognitive impairment reflects microneuroanatomical injury to
synaptic structures.
PMID- 9403490
TI - Treatment of gustatory sweating with botulinum toxin.
AB - Gustatory sweating is an autonomic disorder that frequently occurs after parotid
gland surgery. We investigated the action of intracutaneous injections of
botulinum toxin (BTX) (1.0-2.0 mouse units/2.25-cm2 skin area) in 45 patients
(mean age, 52 years) with gustatory sweating. The area of hyperhidrosis was
determined by Minor's iodine test before and up to 24 weeks after the injection.
The effect of BTX was assessed by measuring the hyperhidrotic area. The maximum
BTX-induced reduction of gustatory sweating was seen at 7.4 +/- 4.5 days after
injection. The area of sweating decreased from 17.6 +/- 8.6 cm2 before BTX to 1.3
+/- 1.6 cm2 after BTX (p < 0.0001). Half the patients rated gustatory sweating
subjectively as completely abolished, and the remainder felt pronounced
improvement. No toxic effects were observed. In none of the patients did
hyperhidrosis recur over a 6-month follow-up. We conclude that BTX is a safe and
effective treatment that can be recommended as the therapy of choice in gustatory
sweating.
PMID- 9403491
TI - Are portable folding chairs useful to combat orthostatic hypotension?
AB - The effect of sitting on a derby chair (height, 48 cm), fishing chair (38 cm),
and footstool (20 cm) on the improvement of postural hypotension was studied
serially in 8 patients with autonomic failure. The increment in blood pressure
during sitting was higher by using a lower portable chair. This was related to an
increasing cardiac output at lower sitting heights. The fishing chair was,
according to our patients' experience, most useful.
PMID- 9403492
TI - Decreased cerebrospinal fluid levels of substance P in patients with Rett
syndrome.
AB - To clarify the mechanism of brain and spinal cord impairment in Rett syndrome
(RS), we measured the cerebrospinal fluid (CSF) levels of substance P in 20
patients with RS including 16 childhood patients and 4 adult patients. Findings
were compared with those obtained in age-matched controls and diseased controls.
The CSF level of substance P was significantly lower in patients with RS compared
with controls. The alteration in the CSF level of substance P may be related to
the neurological impairment, especially autonomic dysfunction, and
neuropathological involvement of dorsal root ganglia and peripheral nerve
observed in RS.
PMID- 9403494
TI - Application of the Poser criteria in primary progressive multiple sclerosis.
PMID- 9403493
TI - Ibuprofen does not suppress active multiple sclerosis lesions on gadolinium
enhanced MR images.
PMID- 9403495
TI - Cortical matching of visual and vestibular 3D coordinate maps.
PMID- 9403496
TI - Multiple sclerosis and retroviruses.
PMID- 9403497
TI - Xenotransplantation with special reference to genetic engineering.
PMID- 9403499
TI - Participation of CD14 in the phagocytosis of smooth-type Salmonella typhimurium
by the macrophage-like cell line, J774.1.
AB - The role of CD14 in the phagocytosis and killing of microorganisms was
investigated using macrophage-like cell lines, CD14-positive J774.1 cells and
CD14-negative mutant J7.DEF.3 cells derived from J744.1 cells. The cells were
infected with Salmonella typhimurium organisms of the smooth (S)-form LT2, mutant
rough (R)-form TV148 or Staphylococcus aureus 248betaH. At 30 or 180 min
incubation, the cells were washed and disrupted. Colony-forming units (CFUs)
liberated from the disrupted cells were determined by quantitative cultivation,
and the phagocytic index and killing rate were calculated. Both the phagocytic
index and killing rate of J774.1 cells against LT2 organisms were greater than
those of J7.DEF.3 cells. However, the index and rate of J774.1 cells against
TV148 and 248betaH organisms were similar to those of the J7.DEF.3 cells. The
phagocytosis of LT2 organisms by J774.1 cells was partially inhibited by S-form
LPS (S-LPS) and anti-CD14 antibody, but not by R-chemotype LPS (R-LPS). These
results suggest that CD14 participates in the phagocytosis of S-form Salmonella.
PMID- 9403498
TI - Morphological features of a filamentous phage of Vibrio cholerae O139 Bengal.
AB - A filamentous phage was isolated from carrier strain AI-1841 of Vibrio cholerae
0139 Bengal and thus was termed fs phage. The phage was measured to be
approximately 1 microm in length and 6 nm in width. One end of the phage was
slightly tapered and had a fibrous appendage. The plaques developed on strain AI
4450 of V. cholerae 0139 were small and turbid. The phage grew in strain AI-4450
and reached a size of 10(8) to 10(9) pfu/ml at 5 hr after infection without
inducing any lysis of the host bacteria. The group of phages attached on rod
shaped materials like fimbriae of this bacteria, with their fibrous appendages at
the pointed end, were often found in the phage-infected culture. The anti
fimbrial serum effectively inhibited the infection of fs phage to the host strain
AI-4450. We thus concluded that the phage can be adsorbed on fimbriae with a
fibrous appendage on the pointed end of the phage filament.
PMID- 9403500
TI - Epidemiological study on infectious diarrheal diseases in children in a coastal
rural area of Kenya.
AB - Diarrheal diseases are major causes of morbidity and mortality among children in
developing countries. We have analyzed the causative agents of diarrhea in
children under five years of age who resided in rural environments but attended a
hospital in Malindi, a coastal town in Kenya. Bacterial diarrhea was found in 239
(27.7%) of 862 patients with diarrhea. Diarrheagenic Escherichia coli, including
enteropathogenic, enterotoxigenic, and enterohaemorrhagic strains, was isolated
from 119 (13.8%) patients, followed by Salmonella spp. (63 cases, 7.3%) and
Shigella spp. (56 cases, 6.5%). Intestinal parasites were found in 109 (12.6%) of
the patients. Entamoeba histolytica and Giardia lamblia were found in 67 (7.8%)
and 42 (4.9%) of the cases, respectively. Rotavirus was found in 69 (16.1%) of
428 cases, a part of the 862 cases. Significant differences in age distribution
were seen in diarrheal cases due to Campylobacter spp., G. lamblia, and
rotavirus. No significant seasonal incidence of specific pathogens was found, but
the number of diarrheal patients was significantly correlated to rainfall.
Drinking water was contaminated with bacteria at concentrations ranging from
10(3) to 10(6) CFU/ml in 98% of the households and by coliform bacteria at
concentrations of 10(2) to 10(5) CFU/ml in 72% of the households. These results
suggest that the main routes of infection may be contaminated drinking water and
fecal-oral transmission of enteric pathogens. Consequently, we propose that the
enhancement of hygienic practice through health education is a feasible control
measure of diarrhea in the study area.
PMID- 9403501
TI - Modification of delivery system enhances MHC nonrestricted immunogenicity of V3
loop region of HIV-1 gp120.
AB - A successful peptide vaccine for AIDS is desired to elicit T-helper and cytotoxic
T lymphocyte responses besides neutralizing antibodies. The V3 loop peptide of
HIV-1 has been shown to contain the principal neutralizing domain, one of the
most immunodominant regions, having both B-cell and T-cell determinants. In this
study, the tip of the V3 loop region was mutated from GPGR to GPGQ based on the
sequence of Indian isolates (CKRKIHIGPGQAFYT). To further enhance the
immunogenicity of this epitope, two delivery systems of immune stimulating
complexes (ISCOMs) and liposomes were used to incorporate the peptide. Mice of
differing haplotypes, H-2b, H-2d, H-2k and H-2s, showed no MHC restriction when
immunized with these formulations. The IgG levels as assessed by ELISA were found
to be significantly higher (P < 0.05 to P < 0.001) for even five-fold lower doses
of the peptide in ISCOMs and liposomes as compared to the conventional alum-based
preparation. The major subtype elicited was IgG2a/IgG2b, suggestive of a Th1-like
response for all the formulations. Thus, it would appear that the same peptide
incorporated in ISCOMs and liposomes selects a Th1 response and may therefore be
important not only for neutralization but also for virus clearance.
PMID- 9403502
TI - Characteristics of IgA anti-HIV antibodies in plasma from patients with HIV
infection.
AB - The concentration of total IgA and the specificity and molecular size of IgA anti
human immunodeficiency virus (HIV) type-1 antibodies in plasma obtained from
individuals at different stages of HIV infection were analyzed. The concentration
of total IgA in the plasma was not decreased even in the late stage of HIV
infection, in contrast with those of total IgG and IgM. The IgA anti-HIV
antibodies differed to the IgG anti-HIV antibodies in their specificity as
determined by Western blotting. The IgA antibodies mainly bind to Env
glycoproteins. The IgA anti-HIV antibodies in plasma were detected between IgG
and IgM by gel filtration, suggesting the presence of polymeric IgA anti-HIV
antibodies. These results indicate that the production of non-specific IgA in
plasma is enhanced by unknown mechanisms in every stages of HIV infection, and
suggest that IgA anti-HIV antibodies in plasma which are possibly polymeric and
have unique specificity may play an important role in HIV infection.
PMID- 9403503
TI - Amplification of rfbE and fliC genes by polymerase chain reaction for
identification and detection of Salmonella serovar Enteritidis, Dublin and
Gallinarum-Pullorum.
AB - Polymerase chain reaction (PCR) primers for O9 antigen (rfbE) and phase 1
flagellin antigen (fliC) were designed for the rapid identification and detection
of Salmonella serovar Enteritidis and Dublin. The rfbE primer pairs selectively
amplified the rfbE region of group O9 Salmonella serovars. The fliC primer pairs
amplified the DNAs of g,m and g,p-type flagellar antigen; Salmonella serovar
Enteritidis, Dublin, and Essen. However, DNA from flagellar-negative Salmonella
serovar Gallinarum-Pullorum was also amplified. The sensitivity of PCR primer
pairs was 10(4) CFU/assay by boiled DNA preparation and 10(2) CFU/assay by
proteinase K-treated DNA preparation.
PMID- 9403504
TI - Hyaluronidase activity in human pus from which Streptococcus intermedius was
isolated.
AB - Hyaluronidase (HAase) activity was detected in both a human pus sample and the
culture supernatant of the only bacterial isolate from the pus, Streptococcus
intermedius, using a zymographic technique. The optimum pH range for HAase
activity was similar for both samples. Although the bands showing the strongest
HAase activity of these samples differed from each other with respect to
molecular size, both samples were equally inhibited by an antiserum raised
against HAase of S. intermedius. These results suggest that S. intermedius may
produce HAase in vivo as well as in vitro, and that this enzyme and/or its
fragments may play an important role in host tissue degradation.
PMID- 9403505
TI - Protease-induced multicell formation in Staphylococcus haemolyticus.
AB - Multicellular cells were efficiently induced in Staphylococcus haemolyticus by
the addition of protease to exponentially growing cultures at 30 C. Electron
microscopy revealed the formation of tetrad-shaped multicells that were septated
but not separated from each other. Incubation of the multicells with extract from
the cells grown without protease resulted in a fourfold increase in the number of
colony-forming units as compared with the untreated control. An electrophoretic
analysis showed that protease caused a loss of cell wall-lytic activity of the
cell, which possibly led to the formation of multicells through cessation of
cross wall separation.
PMID- 9403506
TI - Cloning and sequence analysis of another Shiga-like toxin IIe variant gene (slt
IIera) from an Escherichia coli R107 strain isolated from rabbit.
AB - An Escherichia coli R107 strain (O26 serotype) producing a Shiga-like toxin IIe
variant (SLT-IIera) was isolated from the mesenteric lymph node of a freshly dead
rabbit carcass. The entire structural gene for this SLT-IIera was cloned from
chromosomal DNA by PCR using primers based on previously published slt-IIe
sequences. Nucleotide sequence analysis indicated that the slt-IIera gene was
very similar to slt-IIe (formerly called slt-IIv) from E. coli strains S1191 and
412; five and one nucleotide changes were detected in A and B subunits,
respectively, which resulted in changes in amino acid sequences of the
corresponding subunits by three and one residues. Recombinant SLT-IIera and SLT
IIe produced using an E. coli host-vector system showed similar cytotoxicity,
suggesting that the variations in the structural gene of SLT-IIera have no
significant effect on cytotoxic level.
PMID- 9403507
TI - Cloning and characterisation of the aroA and aroD genes of Shigella dysenteriae
type 1.
AB - The aroA and aroD genes from Shigella dysenteriae type 1, encoding 5
enolpyruvylshikimate 3-phosphate synthase and 3-dehydroquinase, respectively,
were cloned by polymerase chain reaction (PCR). Their nucleotide sequences were
determined and predicted to code for 46 kDa and 27.5 kDa proteins, respectively.
Protein expressed from these genes using the minicell system, corresponded to the
size of the predicted protein products. The cloned genes were shown to be
functional by complementation of Escherichia coli aroA- and aroD- mutants. The
predicted amino acid sequences of the cloned aroA (427 amino acids) and aroD (252
amino acids) genes of S. dysenteriae type 1 were found to be highly homologous to
the corresponding genes in other bacterial species, indicating the high
conservation of these housekeeping genes. The use of the cloned aroA and aroD
genes in the development of a vaccine strain against S. dysenteriae is discussed.
PMID- 9403508
TI - Intracytoplasmic localization of antigenic heat-stable 120- to 130-kilodalton
proteins (PS120) common to spotted fever group rickettsiae demonstrated by
immunoelectron microscopy.
AB - Immunoelectron microscopy demonstrated antigenic heat-stable 120- to 130
kilodalton proteins (PS120) of spotted fever group (SFG) rickettsiae with
antiserum against recombinant PS120 of Rickettsia japonica. In the case of R.
japonica, a major part of the protein was shown to be localized outside the
electron-lucent nucleoid-like region in the cytoplasm of the organisms. The other
SFG rickettsiae represented a similar localization of the PS120 antigens cross
reactive to that of R. japonica. On the other hand, a typhus group rickettsia
demonstrated no antigens cross-reactive to the PS120 of SFG rickettsiae.
PMID- 9403510
TI - Prevalence of herpes simplex virus type 1- and 2- specific antibodies among the
acute, recurrent, and provoked types of female genital herpes.
AB - Sixty-eight sera from the acute, recurrent, and provoked types of female genital
herpes were compared for the seroprevalence of herpes simplex virus (HSV) types 1
and 2 by immunodot assay using HSV glycoprotein G. In the HSV-1-isolated
patients, no HSV-2 antibodies were detected, whereas in the HSV-2-isolated
patients, HSV-1 seroprevalence was 9% for the acute type, 89% for the provoked
type (P < 0.005), and 55% for the recurrent type (P < 0.05). The natural history
of female genital herpes and the possible protective role of pre-existing
antibodies in preventing the acquisition or clinical manifestation of a
subsequent HSV infection are discussed.
PMID- 9403511
TI - Genotypic analysis of the 5'-untranslated region of a pestivirus strain isolated
from human leucocytes.
AB - The 5'-untranslated genomic region of the pestivirus strain Europa, originated in
human leucocytes and previously identified as bovine diarrhea virus (BVDV), was
amplified by reverse transcription-PCR and sequenced. Analyses based on primary
nucleotide sequence homology and on secondary palindromic sequence structures
characteristic to genotypes revealed that this human isolate should be assigned
to a novel genotype of pestivirus, type Ic. This newly emerged genotype was
related to, but distinguishable from the three known BVDV genotypes, Ia, Ib and
II. Three other bovine field isolates of BVDV originated from Germany were also
found to belong to this new genotype Ic. Within pestivirus genotype Ic strains,
the overall nucleotide sequence homology was 95-96%, and 88-92%, 88-90% and 77
79% with the other BVDV genotypes Ia, Ib and II, respectively. With the strains
from border disease virus (genotype III) and hog cholera virus (genotype IV),
homologies were less than 75%.
PMID- 9403509
TI - Direct detection by PCR of Escherichia coli O157 and enteropathogens in patients
with bloody diarrhea.
AB - Direct detection of Escherichia coli O157 and foodborne pathogens associated with
bloody diarrhea were achieved using polymerase chain reaction (PCR) after the
preparation of DNA from stool specimens using the microspin technique. PCR was
compared with cultivation and toxin production tests with respect to the
efficiency of detection of each pathogen; E. coli O157, Vibrio parahaemolyticus,
Salmonella serovar Enteritidis and Campylobacter jejuni. Detection of some or all
of the above pathogens in clinical stool specimens was achieved using PCR. The
minimum number of cells required for the detection of the above pathogens by PCR
was 10(1) CFUs/0.5 g of stool sample. PCR was completed within 6 hr. The above
pathogens were also detected in cultivation and toxin production tests. Partial
purification of the template DNA using the microspin technique was essential for
the elimination of PCR inhibitors from the DNA samples. This PCR method is an
accurate, easy-to-read screening method for the detection of Shiga-like toxin
producing E. coli O157 and enteropathogens associated with bloody diarrhea in
stool specimens.
PMID- 9403512
TI - Sho-saiko-to, a traditional Kampo medicine, enhances the anti-HIV-1 activity of
lamivudine (3TC) in vitro.
AB - Sho-saiko-to (SST), a traditional Kampo medicine, has been examined for its
inhibitory effect on human immunodeficiency virus type 1 (HIV-1) replication in
peripheral blood mononuclear cells (PBMCs). SST alone moderately inhibited HIV-1
replication at a concentration of 25 microg/ml. When SST was combined with
zidovudine (AZT), lamivudine (3TC) or AZT plus 3TC, SST enhanced the anti-HIV-1
activity of 3TC. In contrast, SST slightly enhanced the anti-HIV-1 activity of
AZT plus 3TC but did not enhance the activity of AZT alone. These results suggest
that the combination of SST and 3TC has potential as a chemotherapeutic modality
of HIV-1 infection.
PMID- 9403513
TI - Immune response to neutralizing epitope on human cytomegalovirus gylcoprotein B
in Japanese: correlation of serologic response with HLA-type.
AB - Antigenic domain 1 (AD-1), located between amino acids 608 and 625 of human
cytomegalovirus (CMV) gB protein, is the major domain recognized by neutralizing
antibodies. Amino acids 552 to 630 are essential for the binding of neutralizing
antibodies. We developed an enzyme-linked immunosorbent assay (ELISA) to detect
antibodies against a fusion protein containing amino acid residues 549 to 644 of
the gB polypeptide and maltose binding protein (MBP). Of 180 seropositive
samples, 106 (58.9%) showed positive immuno-reactivity against the fusion
protein. None of the seronegative samples reacted with the fusion protein. Among
57 seropositive individuals typed for HLA, subjects with HLA-DR9 had a higher
positive rate against the fusion protein (13/14=92.9%) than those without HLA-DR9
(25/43=58.1%). In addition, subjects with HLA-DR15 had a lower positive rate
against the fusion protein (7/16=43.3%) than those without HLA-DR15
(31/41=75.6%). Mean OD values of HLA-DR15-positive individuals were significantly
lower than those of HLA-DR15-negative individuals. Thus, among CMV-infected
individuals, HLA-DR9 may be associated with responders for neutralizing
antibodies and HLA-DR15 may be associated with non/low-responders.
PMID- 9403514
TI - Language, aging, and inhibitory deficits: evaluation of a theory.
AB - This article evaluates the success of Inhibitory Deficit theory in addressing two
basic functions of a theory: explaining available results and predicting new
findings. The review focuses on language comprehension and production, domains of
cognition vulnerable to age-linked inhibitory deficits under the theory.
Considerable research, however, reports remarkable age constancy in many aspects
of language performance, contrary to the predictions of Inhibitory Deficit
theory. For conditions that do produce age differences in language comprehension
and production, evidence for inhibitory deficits is controversial at best. In
predicting new findings, Inhibitory Deficit theory is constrained by lack of a
well specified model, producing confusion between inhibition that occurs at a
behavioral level versus a theoretical level. Modification of the theory is
required to bring it in line with empirical findings on language and aging, and
greater specification of underlying processes is required to reduce
contradictions in predictions.
PMID- 9403515
TI - Inhibition in attention and aging.
AB - The literature on inhibition and aging has grown steadily in the wake of Hasher &
Zacks' (1988) inhibitory deficit theory of cognitive aging. Not all of the
findings support the notion of an age-related inhibitory decline, and some
refinement of the theory is now required. This article has three goals: (a) to
evaluate the role of inhibitory mechanisms in selective attention and aging; (b)
to provide an evaluation of inhibition as a theoretical concept in theories of
cognitive aging, with a specific focus on attention and aging; and (c) to
consider the more general problem of evaluating progress in theory development.
PMID- 9403516
TI - Cognitive gerontology and attentional inhibition: a reply to Burke and McDowd.
AB - Our response to the Burke and McDowd critiques (in this issue) begins with a
history of the origins of the inhibitory deficit view and of its development
since 1988 as well as with an account of some particularly useful findings and of
our preferred mode of theory building, which is nonformal and empirically driven.
Against this background, we find many points of agreement with Burke and McDowd
but also many points of disagreement. For example, we agree with Burke that many
aspects of language comprehension and production are age invariant, but we
disagree that all such findings count against our viewpoint. Likewise, we readily
acknowledge the problems in measuring inhibition that McDowd so clearly
documents, but do not feel that this is a fatal problem as long as the inhibitory
deficit view continues to be viable within the basic attentional literature,
continues to permit the integration of a large body of existing data, and
continues to generate new predictions.
PMID- 9403517
TI - Anticipated support, received support, and economic stress among older adults.
AB - This study examined the interface between anticipated support, received support,
recent economic stressors, and depressive symptoms in later life. A theoretical
perspective was developed suggesting that received support exacerbates the
effects of financial stress on depressive symptoms. However, this conceptual
framework further specified that the noxious effects of economic stress are
buffered or offset by anticipated support. Data from a nationwide survey of
elderly people provided empirical support for both hypotheses.
PMID- 9403518
TI - Predicting change in activities of daily living: a longitudinal study of the
oldest old in Sweden.
AB - We examined predictors of stability and decline in activities of daily living
(ADLs) and mobility in a population-based sample of the oldest old. Respondents
were people aged 84 to 90 living in South Central Sweden. Predictors were drawn
from three domains: sociodemographic variables, vitality, and physical and
psychological health. Using a logistic regression model, we sought to identify
variables that were associated with changes in functioning. Over the 2-year
interval, we found significant main effects for stability in ADL functioning for
three variables: residential status (e.g., living in the community), subjective
health, and mastery (n = 142). For mobility, we identified three variables
associated with stability: lung function, subjective health, and mastery (n =
137). Over the 4-year period we found that residential status was significantly
associated with stability in ADL performance (n = 89), while age, marital status,
grip strength, and mastery were significant predictors for stability in mobility
(n = 90). The findings can direct researchers toward interventions within
particular residential environments that maintain a sense of mastery and an
individual's aggressive attitude toward challenging situations.
PMID- 9403519
TI - Forgetful but forgiven: how age and life style affect perceptions of memory
failure.
AB - Young and older perceivers read a narrative in which a forgetful young or old
target was described as having either a young or old life style. Perceivers
attributed memory failures more to mental difficulty for old targets but to lack
of effort for young targets, regardless of life style. Life style did make a
difference in perceivers' memory opinion and sympathy for the old but not for the
young targets. Perceivers had a less negative memory opinion when the old target
had an old rather than a young life style. Also, the old target with the old life
style elicited a greater degree of sympathy in young perceivers, but a lesser
degree of sympathy in older perceivers.
PMID- 9403520
TI - Processing speed and memory in aging and dementia.
AB - We examined the role of processing speed (PS) as a mediator of age-related and
dementia-related differences in cued recall and text memory. Consistent with
previous research, statistical control of PS significantly attenuated or
eliminated age differences on each of the memory measures. However, age-related
decline in the ability to benefit from conditions of increased encoding
specificity was not mediated by PS. In contrast to the results for age effects,
statistical control of PS did not significantly attenuate dementia-related memory
differences, suggesting that processing speed is not an important dementia
related memory impairment. The implications of these findings for interpreting
residual age effects and the possible influence of preclinical dementia on
studies of normal aging are discussed.
PMID- 9403521
TI - Frequency discrimination vs frequency estimation: adult age differences and the
effect of divided attention.
AB - In this experiment we explored age differences in frequency judgment. Young and
older adults studied words occurring from one to six times under divided or
focused attention and then completed either a frequency discrimination or a
frequency estimation test for these items. Divided attention led to poorer
performance on both frequency judgment tests, suggesting that distraction during
the encoding of target events results in less optimal encoding of the information
that is necessary for any type of frequency judgment. Contrary to the notion that
older adults encode this information more superficially than young adults, older
adults were as sensitive as young adults to relative differences in the frequency
of target words, and distraction did not magnify age differences for either type
of frequency judgment task. On the other hand, older adults were less accurate in
assigning an absolute numerical value to the frequency of the target words.
Altogether, the results are consistent with the idea that the encoding and/or
retrieval processes required for accurate numerical estimation of frequency
suffer a larger age-related decline than do those required for accurate
discrimination of relative frequency.
PMID- 9403522
TI - Religion, aging, and health: current status and future prospects.
PMID- 9403523
TI - Religion among disabled and nondisabled persons I: cross-sectional patterns in
health practices, social activities, and well-being.
AB - What is the relationship between religious involvement and functional disability
among elderly people? Is being disabled different for those who frequently attend
religious services? Does religious involvement have an effect on subsequent
change in disability? Deriving our hypotheses from traditional theories in the
sociology of religion, these questions are explored in these two related
articles. Both employ data from the New Haven site of the Established Populations
for the Epidemiologic Study of the Elderly (N = 2812). In the first, cross
sectional correlates of religious involvement and disability are examined at the
baseline of the study, including multiple indicators of health practices, social
activities, and subjective well-being. We test for interactions between religious
attendance and disability. Findings are (a) that religious involvement in 1982 is
tied to a broad array of behavioral and psychosocial resources, (b) that these
resources are associated primarily with attendance at services, and not with
subjective feelings of religiousness, and (c) that some of these associations are
especially pronounced among disabled respondents.
PMID- 9403524
TI - Religion among disabled and nondisabled persons II: attendance at religious
services as a predictor of the course of disability.
AB - Does religious involvement influence changes in physical health? We perform a
longitudinal analysis of the effect of religious participation on functioning
over a 12-year follow-up period, in a large, prospective, representative sample
of elderly persons from New Haven, Connecticut, a religiously diverse community.
To examine the possibility that disability or changes in disability may be
affecting religious involvement, we perform a second longitudinal analysis of
changes in religious practices. Finally, we ask whether psychosocial correlates
explain the effect of religious involvement on disability. Findings are (a) that
attendance at services is a strong predictor of better functioning, even when
intermediate changes in functioning are included, (b) that health practices,
social ties, and indicators of well-being reduce, but do not eliminate these
effects, and (c) that disability has minimal effects on subsequent attendance.
The findings illustrate the short- and long-term importance of religious
participation to the health and well-being of elderly people, and suggest a
particular significance for religious participation in the lives of disabled
elders.
PMID- 9403525
TI - Determining the amount of help used by disabled elderly persons at home: the role
of coping resources.
AB - The purpose of this study is to quantify the effects of coping resources on the
amount (hours) of help used by disabled elderly persons in their home. The
findings are based on the 1989 National Long-Term Care Survey. The distribution
of help-hours is very skewed, mirroring the skewness of limitations in physical
and cognitive functioning. Controlling for these limitations, the most important
coping resources are the combinations of helpers who join forces, and coresidence
with a helper. The effect of helpers' networks is large and consistent across
marital status and living arrangements. The networks are more extensive for
married than for unmarried persons. In reference to persons who rely only on
nonrelatives: (a) a network of a spouse and children enables a married person to
have 40 additional weekly hours of help, (b) a network of children and others
enables an unmarried person to have 29 additional help-hours per week if he/she
coresides with other adults and 10 additional weekly help-hours if he/she does
not. The issue of concern for public policy is whether such family networks will
be preserved and, if not, how to obtain the funds for the alternative of
sufficient paid help in the community.
PMID- 9403526
TI - Use of medical care by African American and White older persons: comparative
analysis of three national data sets.
AB - Historically, there has been a large gap between African Americans and Whites in
access to health care, but this gap was ostensibly lessened by the advent of
Medicare and Medicaid for older adults in the mid 1960s. The extent to which
older African Americans continue to receive less access to medical care as a
result of economic inequalities, institutionalized forms of discrimination, and
life-style factors remains a subject of policy debate. Empirical enquiry has
produced inconsistent results. The purpose of this study is to test the same set
of models of medical use using identically measured predictor variables in three
nationally representative data sets of older Americans: 1984 Study of Aging
(SOA); 1984 National Long-Term Care Survey (NLTC); and the 1987 National Medical
Care Expenditure Survey (NMES). Multivariate logistic regression of use of
physician and hospital services and Poisson regression of amount of service use
identified inconsistent results in race differences across data sets, but
consistent results in terms of the importance of health status and insurance as
predictors of use and amount of use. The findings suggest that health status and
financial resources may be more relevant areas for policy interventions than
considerations related to race and ethnicity.
PMID- 9403527
TI - Differences by race in the decline of health over time.
AB - Previous research on race differences in health, we believe, has failed to take
into account the initial state of health of the respondents. Other research has
demonstrated that elders in poor health are more likely to experience a change in
their health over time. It is unclear if the greater probability of decline in
health observed among African Americans is a result of being more likely to begin
such observations in health states that are worse than those for Whites. This
investigation examines declines in health over a 30-month period in a sample of
African American and White elders who began the study in similar "good health."
Findings support the supposition that African Americans are more likely to report
a decline in their health, regardless of the health measure used. Differences by
race in the decline of health appear to be a consequence of economic and
educational discrepancies between the two groups.
PMID- 9403528
TI - Dysregulated expression of neutrophil apoptosis in the systemic inflammatory
response syndrome.
AB - OBJECTIVE: To study the effect of the systemic inflammatory response syndrome
(SIRS) or major elective surgery on the apoptosis of circulating
polymorphonuclear neutrophils because an activated inflammatory response is
terminated, in part, through the programmed cell death, or apoptosis, of its
effector cells. DESIGN: A prospective inception cohort study. SETTING: A mixed
surgical and medical intensive care unit of an adult tertiary care hospital.
PATIENTS: Sixteen patients with SIRS, 7 uninfected patients who had undergone
elective aortic aneurysmectomy, and 8 healthy laboratory control subjects.
INTERVENTIONS: Serial blood samples were drawn for evaluation of neutrophil
apoptosis, activational state, and surface receptor expression by flow cytometry.
MAIN OUTCOME MEASURES: Spontaneous apoptosis was significantly delayed in
neutrophils from patients with SIRS (8.6%+/-6.8%) and patients who had undergone
elective aortic aneurysmectomy (11.0%+/-5.0%) when compared with controls
(34.9%+/-6.8%). These neutrophils were activated as evidenced by enhanced
respiratory burst activity and augmented surface expression of CD11b. Apoptosis
in response to engagement of cell surface Fas (also known as CD95 or APO-1) with
an agonistic antibody was blunted. Plasma from patients with SIRS or patients who
had undergone elective aortic aneurysmectomy suppressed the apoptotic responses
of control neutrophils (plasma from patients with SIRS, 18.8%+/-10.3%; plasma
from patients who had undergone elective aortic aneurysmectomy, 20.0%+/-6.1%;
P<.01). Western blot analysis showed normal expression of the key proapoptotic
proteases, interleukin 1beta converting enzyme and CPP32 (also known as YAMA,
apopain, and caspase 3), indicating that delayed apoptosis was not a consequence
of decreased levels of proapoptotic enzymes. CONCLUSIONS: Circulating neutrophils
from patients with SIRS or from patients who have undergone major elective
surgery show delayed expression of constitutive programmed cell death, and
antiapoptotic factors are present in the general circulation. While prolonged
neutrophil survival may represent an appropriate adaptive response to injury, the
presence of activated and apoptosis-resistant cells in an antiapoptotic
environment may contribute to the systemic inflammatory injury characteristic of
SIRS and predispose to the development of the multiple organ dysfunction
syndrome.
PMID- 9403529
TI - Intestinal epithelial cell regulation of macrophage and lymphocyte interleukin 10
expression.
AB - BACKGROUND: The intestinal mucosa is subject to daily antigenic challenge and to
injury by proinflammatory cytokines. Interleukin 10 (IL-10) is an important anti
inflammatory cytokine produced by macrophages and lymphocytes that modulates this
response. OBJECTIVE: To investigate the hypothesis that intestinal epithelial
cells are a significant local source of IL-10 in the gut milieu and also
participate in the regulation of macrophage and lymphocyte IL-10 expression in
the intestinal microenvironment. METHODS: C-205 cells, a human intestinal
epithelial cell line, were cultured for 2 days; lipopolysaccharide or tumor
necrosis factor was then added. Media and cells were harvested at specific time
points to determine the kinetics of IL-10 expression. C-205 cells were then
cocultured with macrophages or lymphocytes isolated from human peripheral blood
mononuclear cells, and IL-10 expression was assessed in unstimulated and
stimulated conditions. Interleukin 10 protein was measured by enzyme-linked
immunosorbent assay; IL-10 gene expression was measured by reverse transcriptase
polymerase chain reaction. RESULTS: Constitutive production of IL-10 protein by C
205 cells was maximal at 3 days, paralleled by a peak in IL-10 messenger RNA
(mRNA) expression at 24 hours. Lipopolysaccharide or tumor necrosis factor
strikingly up-regulated IL-10 mRNA and protein expression by C-205 cells.
Coculture of C-205 cells with macrophages or lymphocytes significantly increased
lipopolysaccharide-stimulated IL-10 protein and mRNA release compared with C-205
cells, macrophages, or lymphocytes cultured alone. CONCLUSIONS: Enterocytes are a
responsive source of IL-10 and may play a role in modulating production of this
important cytokine by the local inflammatory cells of the gut. These redundant
mechanisms to augment IL-10 production suggest a central role for this cytokine
in regulation of the local intestinal inflammatory response.
PMID- 9403530
TI - Induction of heat shock protein 70 protects thymocytes against radiation-induced
apoptosis.
AB - OBJECTIVES: To determine if induction of heat shock protein 70 (HSP 70), a stress
protein that plays a cytoprotective role and inhibits cell death in response to
various stimuli, will protect thymocytes and T-cell clones from radiation-induced
apoptosis, and to define the mechanism of such protection. DESIGN: Thymocytes
from BALB/c mice or T-lymphocyte clones were incubated at 43 degrees C for 1 hour
to induce HSP 70, then irradiated. Control cells were irradiated but not heated.
Fragmentation of DNA was quantitated, and p53, bax, and bcl-2 expression was
analyzed at various times by the Western blot method. RESULTS: Only heated cells
expressed HSP 70. The induction of HSP 70 increased basal apoptosis but
significantly decreased radiation-induced apoptosis. Furthermore, introduction of
an HSP 70 antisense oligomer prior to heating reversed the protective effect of
HSP 70. Induction of HSP 70 in T-cell clones with sodium arsenite had a similar
protective effect against radiation-induced apoptosis. Irradiation induced p53
and markedly up-regulated bax. The expression of p53 peaked at 4 hours and
preceded maximal bax induction. Induction of HSP 70 prior to irradiation
suppressed p53 and significantly decreased bax levels. Levels of bcl-2 were
unaffected. CONCLUSIONS: Our data show that HSP 70 induction protects thymocytes
from radiation-induced apoptosis by down-regulating p53 and bax expression. The
induction of HSP 70 may represent a novel mechanism by which the
immunosuppressive effects and the associated infectious complications of
radiation therapy can be minimized.
PMID- 9403531
TI - Heat shock induces IkappaB-alpha and prevents stress-induced endothelial cell
apoptosis.
AB - OBJECTIVE: To determine whether prior heat shock would attenuate endothelial cell
apoptosis and whether any effect of preemptive heat shock is mediated through a
nuclear factor kappa B and inhibitor kappa B alpha mechanism. DESIGN: A
randomized, controlled in vitro study. SETTING: A laboratory in a large, academic
medical center. INTERVENTIONS: Cultured primary porcine endothelial cells were
treated with increasing doses of sodium arsenite (40-160 micromol/L), after which
the interval until subsequent apoptotic (lipopolysaccharide-arsenite) challenge
was varied (4-16 hours). The degree of cell death and apoptosis were determined
using neutral red uptake and staining with annexin V and propidium iodide,
respectively. Inducible heat shock protein 70 and inhibitor kappa B alpha levels
in treated cells were determined by Western blot analysis. Lipopolysaccharide
induced nuclear factor kappa B activity was assessed using an electrophoretic
mobility shift assay. RESULTS: Prior arsenite treatment decreased cell death by
apoptosis in a time- and dose-dependent manner. Specifically, a higher sodium
arsenite concentration and shorter intervals afforded better protection (P=.01,
160 micromol/L at 4 hours). Protection against apoptosis correlated with
increased heat shock protein 70 and inhibitor kappa B alpha levels and decreased
nuclear factor kappa B binding activity. CONCLUSIONS: Arsenite, an inducer of the
heat shock response, decreased stress-induced endothelial cell apoptosis. The
mechanism of this protection may include decreased nuclear factor kappa B
activity or increased inducible heat shock protein 70 levels. Heat shock protein
70 may serve as a molecular marker to determine not only the phenotypic state of
the cell but also the durability of protection afforded by heat shock. These data
support the hypothesis that stress-induced changes in transcription factor
activity and protein expression can regulate the induction of apoptosis.
PMID- 9403532
TI - Complement C3 production in human intestinal epithelial cells is regulated by
interleukin 1beta and tumor necrosis factor alpha.
AB - BACKGROUND: Sepsis and endotoxemia are associated with increased mucosal
production of complement component C3; the enterocyte may be a source of C3 in
these conditions. OBJECTIVE: To test the hypothesis that interleukin 1beta (IL
1beta) and tumor necrosis factor alpha (TNF-alpha) regulate the production of C3
in the enterocyte at the transcriptional level and that this regulation is
potentiated by interferon gamma (IFN-gamma). METHODS: Cultured Caco-2 cells, a
human intestinal epithelial cell line, were treated with various concentrations
of human recombinant IL-1beta (0.005-1.25 ng/mL) or TNF-alpha (1-1000 U/mL) with
or without the addition of IFN-gamma (250 U/mL). C3 levels in the culture medium
were measured by enzyme-linked immunosorbent assay and cellular messenger RNA
levels by Northern blot analysis. RESULTS: Treatment of the Caco-2 cells with IL
1beta or TNF-alpha resulted in a time- and dose-dependent increase in C3
production. The use of IFN-gamma alone did not affect C3 production but
potentiated the effect of IL-1beta and TNF-alpha in a synergistic manner. C3
messenger RNA levels were increased following stimulation with either cytokine.
CONCLUSIONS: C3 production in the enterocyte is regulated by IL-1beta and TNF
alpha at the transcriptional level, and this response is potentiated by IFN
gamma. The results suggest that C3 production in the intestinal mucosa may be
regulated locally by cytokines in a paracrine or autocrine manner.
PMID- 9403533
TI - A randomized, double-blind clinical trial comparing cefepime plus metronidazole
with imipenem-cilastatin in the treatment of complicated intra-abdominal
infections. Cefepime Intra-abdominal Infection Study Group.
AB - OBJECTIVE: To evaluate the safety and efficacy of cefepime hydrochloride plus
metronidazole vs the combination of imipenem and cilastatin sodium in the
treatment of complicated intra-abdominal infections in adult patients. DESIGN:
Prospective, randomized, double-blind multicenter study. SETTING: University
affiliated hospitals in the United States and Canada. PATIENTS: Three hundred
twenty-three patients with complicated intra-abdominal infections in whom an
operative procedure or percutaneous drainage was required for diagnosis and
management. INTERVENTION: Cefepime, 2 g, was administered intravenously every 12
hours (n= 164) in addition to metronidazole, 500 mg (or 7.5 mg/kg) intravenously
every 6 hours. Imipenen-cilastatin sodium, 500 mg, was administered intravenously
every 6 hours (n= 159). Surgical infection management was determined by the
patients' surgeons. MAIN OUTCOME ASSESSMENTS: Clinical cure, defined as
elimination of all signs and symptoms relevant to the original infection; and
treatment failure, defined as persistence, increase or worsening of signs and
symptoms resulting in an antibiotic change, requirement of an additional surgical
procedure to cure the infection, or a wound infection with fever. RESULTS: Of the
initial isolates, 84% were susceptible to cefepime and 92% were susceptible to
imipenem-cilastatin. Among the 217 protocol-valid patients, those treated with
cefepime+metronidizole were deemed clinical cures (88%) more frequently than were
imipenem-cilastatin-treated patients (76%) (P=.02). Using multivariate analysis
to adjust for identified clinical risk factors for an adverse outcome (severity
of presenting illness, isolation of enterococcus, type of infection, and duration
of prestudy hospitalization), there was a trend (P=.06) toward a higher cure rate
favoring cefepime+metronidazole. Pathogens were eradicated in significantly
(P=.01) more patients treated with combined cefepime and metronidazole (89%) than
with imipenem-cilastatin (76%). CONCLUSION: The combination of cefepime plus
metronidazole is safe and effective therapy for patients with severe intra
abdominal infections.
PMID- 9403535
TI - Enteral feeding intolerance: an indicator of sepsis-associated mortality in
burned children.
AB - OBJECTIVE: To determine if enteral feeding intolerance (EFI) is associated with
sepsis and increased mortality in children with severe burns. DESIGN: A survey.
SETTING: A pediatric burn unit. PATIENTS: Ninety-one children surviving longer
than 5 days with greater than 80% total body surface area burns. INTERVENTIONS:
None. MAIN OUTCOME MEASURES: Enteral feeding intolerance indicated by high
gastric residuals (> 150 mL/h) or uncontrollable diarrhea (> 2500 mL/d);
thrombocytopenia (platelet count < 100 x 10(9)/L); hyperglycemia (glucose level >
11.1 mmol/L [> 200 mg/dL]); sepsis (pathogenic bacteremia or fungemia noted on
blood culture results); and mortality. RESULTS: Neither EFI nor sepsis developed
in 71 patients, EFI alone developed in 2 patients, sepsis alone developed in 5
patients, and EFI and sepsis developed in 13 patients. Enteral feeding
intolerance and sepsis were associated by contingency table analysis (P<.001).
Mortality was 8% (6 patients) in those with neither EFI nor sepsis, 50% (1
patient) in those with EFI alone, 60% (3 patients) in those with sepsis alone,
and 77% (10 patients) in those with EFI-associated sepsis. The 2 latter groups
were different from the group with neither EFI nor sepsis (P<.05). Enteral
feeding intolerance was identified in 70% of patients before sepsis;
thrombocytopenia, 64%; and hyperglycemia, 66%. When compared with
thrombocytopenia and hyperthermia, no variables were found to be superior to
others for predicting sepsis. CONCLUSIONS: Enteral feeding intolerance was
associated with the development of sepsis and increased mortality in children
with greater than 80% total body surface area burns. This sign was identified in
70% of the cases before pathogens were found in the blood; no difference could be
shown between the identification of EFI, thrombocytopenia, and hyperglycemia
before sepsis. These data indicate that the development of EFI should be used as
an indicator of infection and should prompt a search for an inciting focus.
PMID- 9403534
TI - A temporal study of TPN-induced changes in gut-associated lymphoid tissue and
mucosal immunity.
AB - BACKGROUND: Total parenteral nutrition (TPN) is associated with decreases in
small-intestinal gut-associated lymphoid tissue (GALT) T cells, B cells, and IgA
levels and impairs IgA-mediated defenses in the respiratory tract. The impaired
respiratory tract defenses are speculated to be due to reduced respiratory tract
IgA levels. OBJECTIVES: To determine the time course of GALT cell reductions and
document any changes in respiratory tract IgA levels in mice receiving TPN.
DESIGN: Prospective randomized trial. SETTING: Animal research laboratory.
MATERIALS: Thirty-five male ICR mice weighing 25 to 35 g. INTERVENTIONS: Mice
underwent cannulation with intravenous catheters and received chow for 2 days
followed by TPN for 0 (n=6), 1 (n=6), 2 (n=6), 3 (n=6), 4 (n=6), or 5 (n=5) days.
Mice were killed after receiving TPN their respective number of days. The small
intestine was harvested, and washings were obtained from the small intestine and
the respiratory tract. Lymphocytes and IgA levels were analyzed by flow cytometry
and enzyme-linked immunosorbent assay, respectively. MAIN OUTCOME MEASURES:
Lymphocyte yields from Peyer patches, intraepithelial spaces, and the lamina
propria; IgA levels from the small intestine and the respiratory tract. RESULTS:
T- and B-cell yields in the Peyer patches and lamina propria were significantly
reduced by day 2 (P<.05) and thereafter compared with day 0. The lamina propria
CD4+/CD8+ ratio declined significantly by day 4 (P<.05) compared with day 0.
Small-intestinal and respiratory tract IgA levels were significantly diminished
by day 3 (P<.05) and thereafter compared with day 0. CONCLUSION: Total parenteral
nutrition produces rapid changes in GALT cell profiles and reduces respiratory
tract IgA levels consistent with the impairment of respiratory IgA-mediated
defenses.
PMID- 9403536
TI - Surgical wound infection in renal transplantation: outcome data in 102
consecutive patients without perioperative systemic antibiotic coverage.
AB - BACKGROUND: The incidence of surgical wound infection in the presence of
immunosuppression has been reported in the literature to approach 7%.
Perioperative systemic antibiotic therapy is routinely used to reduce the
occurrence of wound infections. This therapy is not without complications,
including adverse effects and development of resistant strains. DESIGN: Surgical
wound infection rates during the first 100 days after renal transplantation were
studied in 102 consecutive patients. Eighty-one patients underwent cadaveric
transplantation and 21 patients underwent living-related donor transplantation
from February 1, 1991, to January 1, 1992. No systemic perioperative antibiotic
coverage was used, but local antibiotic irrigation was part of the perioperative
protocol. SETTING: Hahnemann University Hospital, Philadelphia, Pa, is a large,
tertiary care center. Patients were initially hospitalized and were discharged
during the 100-day follow-up period based on clinical status and improvement in
renal function. PATIENTS: Twenty-seven (25%) of 102 patients had diabetes
mellitus. INTERVENTIONS: Induction immunosuppression consisted of azathioprine,
prednisone, and anitlymphocyte globulin, while maintenance immunosuppression
consisted of azathioprine, prednisone, and cyclosporine. Acute allograft
rejection episodes were treated with steroids and/or OKT3 (Ortho Pharmaceutical
Group, Raritan, NJ). RESULTS: Two surgical wound infections (2%) occurred. In
both, infection was superficial, resolving with wound drainage and intravenous
antibiotics. The surgical wound infection rate was not significantly affected by
age, sex, allograft source, or presence of diabetes mellitus. CONCLUSIONS:
Despite immunosuppression, the incidence of surgical wound infection was minimal,
comparing favorably to rates reported for renal transplantation with the use of
systemic antibiotics. Possible explanations for the low incidence of surgical
wound infections include local wound irrigation, meticulous hemostasis, improved
organ procurement techniques, and continuity in perioperative care.
PMID- 9403537
TI - Influences of type and duration of antimicrobial prophylaxis on an outbreak of
methicillin-resistant Staphylococcus aureus and on the incidence of wound
infection.
AB - OBJECTIVE: To clarify how antibiotic prophylaxis influenced an outbreak of
methicillin-resistant Staphylococcus aureus (MRSA) and postoperative infection.
DESIGN: Retrospective review. SETTING: University-affiliated teaching hospital.
PATIENTS: All patients (n=1824) undergoing subtotal esophagectomy, gastrectomy,
or colorectal surgery during the period 1982 through 1995. MAIN OUTCOME MEASURES:
Type, timing, and duration of prophylactic antibiotics. Postoperative infection
by the Centers for Disease Control and Prevention definition and the organisms
isolated. RESULTS: Third-generation cephalosporins were frequently administered
for prophylaxis during the period 1982 through 1990. The rate of isolates of MRSA
from the infected site increased, peaking in 1988 to 1990. Since 1991 to 1992,
along with a marked decrease in third-generation cephalosporin use, the rates of
MRSA isolated have declined dramatically. The timing of administration changed
from postoperative to intraoperative. Although the duration was gradually
decreased, coverage was still provided until about the fifth postoperative day,
even during 1993 to 1995. Prolonged coverage did not reduce the rate of
superficial incisional or organ/space surgical site infection or that of
pneumonia. CONCLUSIONS: Overuse of third-generation cephalosporins for long
periods caused an MRSA outbreak. Long-term prophylaxis did not lower infection
rates. The briefest possible prophylaxis with first- or second-generation
cephalosporins should be used in general surgery.
PMID- 9403538
TI - Suppression of natural killer cell activity in patients with fracture/soft tissue
injury.
AB - BACKGROUND: Natural killer cells (NKCs) participate in "innate" cell-mediated
immunity. Fracture/soft tissue injuries are cytokine rich and may influence cell
mediated immunity. OBJECTIVE: To study the effects of fracture cytokines on NKC
function. DESIGN: A case-control study. SETTING: A level I trauma center and
laboratory in a university medical center. PARTICIPANTS: Patients requiring open
fracture fixation and healthy volunteers. INTERVENTIONS: Fracture supernatants
and peripheral plasma were collected during open fracture fixation. Volunteer
mononuclear cells were used as effector (NKC) sources. Mononuclear cells were
preincubated with fracture supernatants, paired peripheral plasma, or normal
plasma under various conditions. MAIN OUTCOME MEASURES: Natural killer cell lysis
of K562 target cells was assessed by chromium 51 release. RESULTS: Fracture
supernatants suppressed NKC function more rapidly than peripheral plasma.
Fracture supernatants from 1 to 4 days after injury were most suppressive.
Inactivation of complement and reactive oxygen species failed to restore lysis.
Neutralizing antibodies to interleukin 4 and interleukin 10 further suppressed
lysis. Antibodies to transforming growth factor beta1 failed to restore lysis.
The addition of interferon gamma did not restore lysis but the addition of
interleukin 12 did. CONCLUSIONS: Fracture supernatants and peripheral plasma from
patients with fractures suppress NKCs. The responsible mediators may be
concentrated in fracture/soft tissue injuries. Responses to manipulation of the
cytokine environment suggest that fracture cytokines may impair cooperation
between NKCs and accessory cells.
PMID- 9403539
TI - Splenic abscess: another look at an old disease.
AB - OBJECTIVE: To study the changes in the incidence, causes, bacteriologic profile,
and management of a splenic abscess. DESIGN: Retrospective case study. SETTING:
Tertiary, university referral center. PATIENTS: Thirty-nine patients with a
splenic abscess. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Demographics, signs
and symptoms, causes, risk factors, diagnostic methods, bacteriologic profile,
treatment, and outcome. RESULTS: Patients presented at a mean age of 43 years
(range, 2-83 years), after a mean symptomatic period of 16 days, with fever
(69%), abdominal pain (56%), nausea and vomiting (38%), and splenomegaly (31%).
The majority of abscesses represented metastatic infection (n=19), and 11 were
secondary to immunosuppression. Twelve patients had human immunodeficiency virus
disease and 9 used intravenous drugs. In patients who underwent computed
tomography, all had abnormal scans (n=33), with a well-defined abscess(es) in 28.
Nine abscesses were polymicrobial; monomicrobial isolates included gram-positive
organisms (23%), gram-negative organisms (31%), fungi (23%), and mycobacteria
(23%). Patients presenting before 1989 (1981-1988) (n=15) and those presenting
after 1989 (1989-1996) (n=24) differed in risk factors (intravenous drug abuse,
0% vs 47% [P=.02]; hematologic malignancy, 43% vs 9% [P=.04]) and gram-positive
isolates (18% vs 64%; P=.06). Patients underwent splenectomy (n=18), open
drainage (n=4), medical therapy (n=10), or percutaneous drainage (n=5) with
respective survival rates of 94%, 50%, 70%, and 100%. CONCLUSIONS: In 1996,
splenic abscesses are increasingly common. Intravenous drug abuse and human
immunodeficiency virus disease are significant risk factors, and the diagnosis
should be considered in a patient with fever and abdominal pain who uses
intravenous drugs. Antimicrobial agents should be broad since 36% of abscesses
were polymicrobial, and should include coverage of gram-positive organisms.
PMID- 9403540
TI - Enteral vitamin E supplementation inhibits the cytokine response to endotoxin.
AB - OBJECTIVE: To evaluate the effect of short-term, high-dose enteral
supplementation of 3 different vitamin E derivatives: free alpha-tocopherol (VE),
alpha-tocopherol succinate (VES), and alpha-tocopherol acetate (VEA) on
macrophage and monocyte activation. DESIGN: Sprague-Dawley rats (weight, 150-200
g) were assigned to 1 of 5 experimental groups: saline (control), ethanol
(control), VES (100 mg/kg), VEA (100 mg/kg), or VE (100 mg/kg). Rats underwent
oral gavage once per day for 5 days with 0.5 mL of their assigned solution. All
vitamin E derivatives were diluted in 75% ethanol. Rats were then killed and
whole-blood and peritoneal macrophages were harvested and stimulated with
lipopolysaccharide (10 microg/mL) in vitro. Tumor necrosis factor (TNF)
production was measured by enzyme-linked immunosorbent assay. Additional serum
samples were analyzed for alpha-tocopherol concentration by high-performance
lipid chromatography. RESULTS: Whole-blood TNF production was maximal in the
control groups after 3 hours of incubation and began to decline by 6 hours.
Supplementation with all 3 vitamin E derivatives resulted in suppression of
lipopolysaccharide-induced TNF production at both time points when compared with
both ethanol and saline controls (P<.05, analysis of variance [ANOVA]). All 3
vitamin E derivatives also resulted in significant inhibition of
lipopolysaccharide-induced TNF production by peritoneal macrophages when compared
with their ethanol-carrier control but not with the saline control (P<.05,
ANOVA). The degree of TNF suppression correlated directly with serum alpha
tocopherol levels. CONCLUSIONS: Our data demonstrate that a short-term, high-dose
enteral supplementation of vitamin E can modulate the monocyte and macrophage
response to endotoxin. These data, along with other animal studies showing a
protective effect of vitamin E treatment in sepsis and ischemia-reperfusion
injury, suggest a potential role for vitamin E supplementation in patients at
risk of the systemic inflammatory response syndrome.
PMID- 9403541
TI - Endotoxin-induced macrophage gene expression depends on platelet-activating
factor.
AB - BACKGROUND: The development of multiple organ failure in septic patients is due
to a systemic inflammation orchestrated by macrophages (Mphi). Elucidation and
control of the mechanism involved in Mphi activation in sepsis is crucial to
improving survival. An early event of Mphi activation involves the hydrolysis of
membrane phospholipid by phospholipase A2 (PLA2) and subsequent generation of
platelet-activating factor (PAF). OBJECTIVE: We designed this study to test the
hypothesis that Mphi gene expression depends on PAF. DESIGN: Rabbit alveolar Mphi
were obtained by bronchoalveolar lavage and were stimulated with 10 ng/mL of
Escherichia coli endotoxin lipopolysaccharide (LPS), PAF (1 micromol/L), LPS+/
CV3988 (10 micromol/L), a PAF receptor antagonist, or LPS+/-PLA2 inhibitors:
AACOCF3 (50 micromol/L) or manoalide (10 micromol/L). After 4 hours of
incubation, Mphi tumor necrosis factor (TNF) messenger RNA (mRNA) expression was
assessed by Northern blot analyses. The TNF production in the Mphi supernatant
was measured by L929 bioassays. RESULTS: The LPS-stimulated Mphi expressed
increased levels of TNF mRNA and produced an enormous amount of TNF. CV3988, a
PAF antagonist, inhibited LPS-induced TNF mRNA. Furthermore, inhibiting PAF
production with AACOCF3, or manoalide, also inhibited LPS-induced Mphi TNF mRNA
expression. The effect of PAF depends on changes in intracellular calcium
concentration. Inhibitors of calcium flux attenuated the PAF effects on LPS
stimulated Mphi. CONCLUSIONS: Our data suggest that LPS-induced Mphi gene
expression is mediated by PAF. It is likely that modulation of PAF production or
activity may be beneficial in down-regulating the overactivity of Mphi in sepsis.
PMID- 9403542
TI - A prospective randomized trial of an antibiotic- and antiseptic-coated central
venous catheter in the prevention of catheter-related infections.
AB - OBJECTIVE: To test the efficacy of the ARROWgard (Arrow International Inc,
Reading, Pa) central venous catheter (CVC) coated with silver sulfadiazine and
chlorhexidine (A-CVC) in the prevention of CVC-related infections. DESIGN:
Prospective, randomized trial. SETTING: A tertiary care medical center. PATIENTS
AND INTERVENTION: Two hundred eighty-two patients who required CVC placement were
evaluated in this study. Patients were prospectively randomized to receive either
a standard CVC (S-CVC) or the A-CVC. Only fresh-stick double- and triple-lumen
catheters were studied. MAIN OUTCOME MEASURES: Patients were evaluated for
catheter site inflammation, catheter site colonization, local catheter-related
infection, and catheter-related septicemia. RESULTS: The 2 groups were matched
for age, percentage in the intensive care unit, percentage receiving total
parenteral nutrition, percentage with triple-lumen catheters, and duration of
catheterization. Rates of catheter site inflammation in the 2 groups were similar
(12% vs 10%, S-CVC group and A-CVC group, respectively). The A-CVC was associated
with a significantly decreased catheter site colonization rate (49% vs 28%; 43%
reduction; P<.001) and local catheter-related infection rate (22.4% vs 5.8%; 74%
reduction; P<.001). Rates of catheter-related septicemia were reduced by 41% in
the A-CVC group (6.4% vs 3.8%, S-CVC group and A-CVC group, respectively), but
this was not statistically significant. CONCLUSIONS: Despite a marked decrease in
catheter site colonization and catheter-related infection rates, the A-CVC did
not significantly reduce the incidence of catheter-related septicemia. This may
be due to a greater pathogenic dependence on catheter hub contamination rather
than catheter site colonization or local catheter-related infection, or the
relatively short (5.2 days) duration of catheterization in this study.
PMID- 9403544
TI - Willy Meyer's radical mastectomy.
PMID- 9403543
TI - Carbon monoxide contributes to the cytokine-induced inhibition of surfactant
synthesis by human type II pneumocytes.
AB - BACKGROUND: An increase in cyclic guanosine 3',5'-monophosphate (cGMP) due to
nitric oxide generation is known to participate in the mediation of the tumor
necrosis factor alpha (TNF-alpha) effect in type II cells. Because guanylyl
cyclase can be activated also by carbon monoxide (CO), in this study we examined
the ability of human type II pneumocytes to produce CO in the presence of
cytokines and the relative contribution of this molecule to the TNF-alpha and
interleukin 1 effects. DESIGN: Type II pneumocytes were isolated from cadaveric
multiple-organ donors by enzymatic digestion, adherence separation of
macrophages, and gradient purification. After preculture for 24 hours, cells were
cultured for 24 hours in the presence or absence of TNF-alpha, interleukin 1,
sodium nitroprusside, N(omega)-nitro-1-arginine, CO, hemin, zinc-protoporphyrin
type IX, deferoxamine mesylate, S-adenosyl-L-methionine, alpha-tocopherol,
methylene blue (a guanylyl cyclase inhibitor), 8-bromine-cGMP, and combinations
of these reagents. Both CO (picomole per microgram of protein) and nitric oxide
release to the medium and the cGMP (picomole per microgram of protein) content of
the cells were measured. In a different set of experiments, D-glucose labeled
with radioactive carbon (14C) was added to the medium, and the labeling of
several lipid fractions was determined (picomole per microgram of protein).
RESULTS: D-[14C]glucose incorporation into phosphatidylcholine, the main
surfactant component, was selectively inhibited in the presence of cytokines, CO,
sodium nitroprusside, or 8-bromine-cGMP. The inhibitory effect of TNF-alpha was
partially reversed by N(omega)-nitro-L-arginine, deferoxamine, or alpha
tocopherol and totally reversed by methylene blue. Tumor necrosis factor alpha
induced an increase in cGMP cell content and in the CO and nitric oxide release
to the medium. Hemin increased CO and cGMP production and decreased
phosphatidylcholine synthesis. Zinc-protoporphyrin type IX, an inhibitor of heme
oxygenase, and all 3 antioxidants, which inhibited CO production, also
antagonized the TNF-alpha effect on cGMP and phosphatidylcholine synthesis.
CONCLUSIONS: Intracellular cGMP increase due to an endogenous generation of both
CO and nitric oxide mediates the cytokine-induced inhibition of surfactant
synthesis by type II pneumocytes. Both lipid peroxidation and heme oxygenase
activity are sources for the observed CO production.
PMID- 9403545
TI - The sixth report of the Joint National Committee: an appropriate celebration of
the 25th anniversary of the National High Blood Pressure Education Program.
PMID- 9403546
TI - A history of the Council for High Blood Pressure Research: the first 50 years.
PMID- 9403547
TI - Theodore Cooper Memorial Lecture. A mouse view of hypertension.
AB - Essential hypertension probably results from combinations of genetic variations,
not necessarily the same in all afflicted persons, which individually may not
cause sufficient deviation from normality to be significantly harmful. Genes
contributing to hypertension are being sought by analytic experiments aimed at
identifying candidate genes associated or segregating with the phenotype in
humans and animals and by synthetic experiments in which changes are made in
candidate genes in animals and their effects on blood pressure are determined. We
have used gene targeting to vary the amounts of angiotensinogen and angiotensin
converting enzyme (ACE) synthesized from their genes (Agt and Ace). These "gene
titration" experiments establish that changes in Agt gene expression cause
changes in the blood pressures of mice. Surprisingly, quantitative changes in Ace
gene expression over a threefold range do not affect blood pressures. Computer
simulations with a simple version of the renin-angiotensin system predict that
changes in Agt function alter the steady state levels of both angiotensin I (Ang
I) and angiotensin II (Ang II). In contrast, modest changes in Ace function alter
Ang I levels considerably but scarcely affect Ang II levels. Simulations over the
ranges of ACE levels that can be achieved with ACE inhibitors predict that Ang II
levels will decrease only when Ang I levels have plateaued. Comparisons of the
computer simulations with our genetic experiments and with prior work of others
using wide dose ranges of ACE inhibitor show a satisfactory agreement and help
reconcile the apparent contradictions between the genetic and pharmacological
experiments.
PMID- 9403549
TI - Association between the angiotensinogen 235T-variant and essential hypertension
in whites: a systematic review and methodological appraisal.
AB - Recently, an allelic variant of the angiotensinogen gene (AGT 235T) has been
associated with increased risk of hypertension. However, this finding has not
been confirmed by all investigators. A meta-analysis was performed to examine the
association between the AGT 235T-allele and hypertension in whites and to
identify potential reasons for the controversial results. All relevant articles
published between 1992 and 1996 were identified through multiple sources. The
studies were methodologically appraised, and the frequency of the AGT 235T-allele
was extracted. The 235T-allele frequency was pooled using the common odds ratio
(OR) estimator by Mantel-Haenszel. Homogeneity was assessed using the Breslow-Day
test. Together these studies present data on 5493 patients. The AGT 235T-allele
was significantly associated with hypertension (OR: 1.20; 95% [CI]: 1.11 to 1.29;
P<.0001). This association increased in studies with positive family history (OR:
1.42; 95% CI: 1.25 to 1.61, P<.0001), recruitment of cases from referral centers
(OR: 1.39; 95% CI: 1.20 to 1.62, P<.0001), and more severe hypertension (OR:
1.34; 95% CI: 1.22 to 1.47, P<.0001). However, the presence of methodological
problems in all studies gives rise to serious concerns regarding bias and
confounding. Despite a statistically significant, albeit weak, association
between the AGT 235T variant and hypertension that has been confirmed through
sensitivity analysis, this finding has to be interpreted with caution, as the
methodological weaknesses of the individual studies are likely to have biased the
outcome of the meta-analysis. Clearly, more rigorous methods need to be applied
in association studies on the genetics of human hypertension.
PMID- 9403548
TI - Essential hypertension and 5' upstream core promoter region of human
angiotensinogen gene.
AB - The angiotensinogen (AGT) gene M235T variant is associated with essential
hypertension and elevated plasma AGT concentrations, although the underlying
mechanisms are unknown. Recent studies have suggested that AGCE 1 (human AGT gene
core promoter element 1) located in the 5' upstream core promoter region
(position -25 to -1) of the human AGT gene has an important part in the
expression of AGT mRNA by binding with transcription factor AGCF 1 (human AGT
gene core promoter element binding factor 1), and a mutation at -20 from adenine
to cytosine (A-20C) increases the level of expression of this transcript. We
therefore examined subjects with this mutation to study the association with
increased plasma AGT concentrations and with essential hypertension. One hundred
eighty-eight subjects receiving no antihypertensive medication were examined with
regard to the correlation between A-20C and plasma AGT concentrations, and 234
subjects were studied with respect to the association between A-20C and essential
hypertension. A-20C was determined by polymerase chain reaction-restriction
fragment length polymorphism analysis with EcoOR 109I. Multiple regression
analysis showed a weak but significant correlation between A-20C and plasma AGT
concentrations (P=.047) and essential hypertension (P=.049). The results suggest
that A-20C may underlie the increase in plasma AGT concentrations and be involved
in the development of essential hypertension.
PMID- 9403550
TI - Membrane ion transport in Bartter's syndrome: evidence for a new syndrome
subtype.
AB - Fifteen patients with Bartter's syndrome (hyponatremic hypochloremic hypokalemic
metabolic alkalosis) were compared with 15 healthy volunteers. Red blood cell
Na+/H+ and Cl-/HCO3- exchanges were enhanced in all patients with Bartter's
syndrome. In calciuric normomagnesemic patients, sensitive to nonsteroidal anti
inflammatory drugs (classic Bartter's syndrome), red blood cell Na+,K+,2Cl-
cotransport was markedly reduced, calcium-dependent K+ permeability was
moderately increased, and up to 60% of sodium permeability was represented by
cAMP-activated fraction (presumably human analog of beta-isoform of Na+/H+
exchange). In noncalciuric hypomagnesemic patients insensitive to indomethacin
(Gitelman's syndrome), Na+,K+,2Cl- cotransport was enhanced, Na+ permeability was
increased due to calmodulin-dependent fraction, and calcium-dependent K+
permeability was markedly enhanced. A new subtype of Bartter-like syndrome
("variant Bartter's syndrome") has been described in which calciuria,
hypomagnesemia, and insensitivity to nonsteroidal anti-inflammatory drugs were
associated with decreased Na+,K+,2Cl- cotransport, enhanced calmodulin-activated
fraction of Na+ influx, and reduced calcium-dependent K+ permeability.
PMID- 9403552
TI - Regulation of the rat atrial natriuretic peptide gene after acute imposition of
left ventricular pressure overload.
AB - The upregulation of left ventricular (LV) atrial natriuretic peptide (ANP) mRNA
is a highly conserved marker of cardiac hypertrophy. The aim of this study was to
further examine the pathway leading to ANP induction during pressure overload of
the heart. Systolic wall stress was imposed acutely on isovolumetrically beating
rat hearts in a Langendorff apparatus (sigma-=300 x 10[3] dyne/cm2). Northern and
Western blots revealed that elevated wall stress induced LV c-fos and c-jun mRNAs
(3.5- and 3-fold, P<.05 after 60 minutes), c-Fos and c-Jun proteins (3.9- and 4.3
fold, P<.05 after 120 minutes), as well as ANP mRNA (2.2-fold, P<.05 after 120
minutes). ANP upregulation was prevented by inhibition of protein synthesis
(cycloheximide). Electrophoresis mobility shift assays were performed to link c
Fos and c-Jun (ie, components of the heterodimeric transcription factor AP-1) and
ANP induction. A putative AP-1 binding site within the rat ANP promoter
(nucleotides -512 to -473) bound specifically to nuclear proteins of wall stress
stimulated hearts. Antibodies directed against c-Fos protein resulted in a shift
of this DNA/protein complex, suggesting physical interaction between AP-1 and the
ANP promoter. Myocardial transfection of promoter constructs revealed that after
acute imposition of wall stress, this AP-1 site enhanced a reporter gene (8- to
10-fold compared with a minimal promoter, P<.05). Interestingly, nuclear extracts
of stimulated hearts as well as pure AP-1 protein bound to a putative CRE site
(nucleotides -613 to -584) as well. Like the AP-1 site, this cAMP-responsible
element (CRE) site was found to enhance the transfected ANP promoter/reporter
gene significantly (17.5-fold, P<.05). Mutation of either AP-1 or CRE sites did
not decrease reporter gene activity, whereas mutation of both resulted in loss of
inducibility. These experiments suggest that LV ANP regulation after acute wall
stress includes the activation of AP-1 and/or CRE cis acting elements. However,
the transient nature of c-fos and c-jun upregulation also suggests that AP-1 is
not the only mediator of ANP induction in LV hypertrophy.
PMID- 9403551
TI - Tissue-specific regulation of renal and cardiac atrial natriuretic factor gene
expression in deoxycorticosterone acetate-salt rats.
AB - Atrial natriuretic factor (ANF) is expressed in several noncardiac tissues where
it may have an autocrine or paracrine function. Such function may be expected of
locally synthesized ANF in the renal parenchyma. Previous investigations of the
existence of ANF mRNA in the renal parenchyma have yielded conflicting results.
The investigations reported here were designed to detect and measure ANF mRNA in
normal rats and in rats subjected to a deoxycorticosterone acetate (DOCA)-salt
treatment schedule known to strongly activate cardiac ANF gene expression. The
expression of the renal ANF gene was measured using a newly developed
quantitative competitive reverse transcription-polymerase chain reaction (QC-RT
PCR). This method uses an internal competitor that serves as an internal standard
and makes the procedure independent of measurement relative to housekeeping
genes. It was found that renal ANF mRNA levels were 10(7) times lower than those
found in left or right atria, but immunoreactive (ir) renal ANF concentration by
specific radioimmunoassay was 10(4) times lower than that of atrial irANF levels.
Reverse-phase high-performance liquid chromatography analysis revealed that more
than 99% of renal irANF is processed ANF(99-126). This finding suggests that most
of the irANF measured in kidney extracts likely originates from atrial sources.
Left atrial ANF mRNA levels after 1 week of DOCA-salt treatment was significantly
higher than that of control rats ([21.06+/-2.99] x 10(-l5) mol/microg total
RNAversus [8.59 +/-1.26] x 10(-5) mol/microg total RNA, P<.05). However, renal
ANF mRNA levels in DOCA-salt rats were significantly decreased compared with
those of control rats ([1.64+/-0.34] x 10(-22) mol/microg total RNA versus
[3.96+/-0.61]x 10(-22) mol/microg total RNA, P<.05). These results indicate that
(1) renal ANF mRNA can be consistently and specifically demonstrated after
reverse transcription and PCR amplification; (2) renal and cardiac ANF synthesis
are regulated in a tissue-specific, opposite manner during DOCA-salt treatment;
and (3) the finding that renal ANF mRNA is downregulated by DOCA-salt treatment
together with previous findings suggest the need for further investigation into
the role of renal ANF mRNA downregulation in the pathogenetic mechanism that
leads to volume expansion and hypertension after chronic DOCA-salt treatment.
PMID- 9403553
TI - Alpha-adrenergic signal transduction in renin transgenic rats.
AB - The alpha1-adrenoceptor-G protein-phosphoinositide-specific phospholipase C (PLC)
signal transduction pathway is assumed to play an important role in the
regulation of contractile force and in the pathophysiology of myocardial
hypertrophy. In the present study, the components of this pathway were
investigated in left ventricles of hearts from hypertensive transgenic rats
overexpressing the mouse renin gene [TG(mREN2)27] in comparison to age- and
weight-matched Sprague-Dawley control rats. Contractile force was assessed in
isolated electrically driven left ventricular papillary muscle strips. Alpha1
adrenoceptor density was measured by radioligand binding using [3H]prazosin,
steady state levels of alpha q/11, and G protein beta-subunits by Western
blotting. PLC activity was determined by a cell-free assay using exogenous
phospholipid vesicles containing [3H]phosphatidylinositol (4,5)-bisphosphate as a
substrate. Alpha1-adrenoceptor density was significantly increased (by 80%) in
transgenic rats compared with control rats, while the positive inotropic response
to the alpha1-adrenoceptor agonist phenylephrine was significantly reduced,
suggesting a postreceptor defect in TG(mREN2)27. The expression of alpha q and
alpha11 was verified by reverse transcription-polymerase chain reaction, and
alpha q/11 steady state protein levels were shown to be similar in transgenic and
control rats. Western blotting using a beta-common antibody revealed two bands at
approximately 35 and 36 kD. The quantities of both were similar in TG(mREN2)27
compared with those in control rats. In contrast, PLC activity was significantly
reduced (by 32%) in transgenic rats. In conclusion, our findings are consistent
with a desensitization of the alpha1-adrenergic signal transduction pathway at
the level of the effector.
PMID- 9403554
TI - Captopril modifies gene expression in hypertrophied and failing hearts of aged
spontaneously hypertensive rats.
AB - The spontaneously hypertensive rat (SHR) exhibits a transition from stable
compensated left ventricular (LV) hypertrophy to heart failure (HF) at a mean age
of 21 months that is characterized by a decrease in alpha-myosin heavy chain
(alpha-MHC) gene expression and increases in the expression of the atrial
natriuretic factor (ANF), pro-alpha1(III) collagen, and transforming growth
factor beta1 (TGF-beta1) genes. We tested the hypotheses that angiotensin
converting enzyme inhibition (ACEI) in SHR would prevent and reverse HF
associated changes in gene expression when administered prior to and after the
onset of HF, respectively. We also investigated the effect of ACEI on circulating
and cardiac components of the renin-angiotensin system. ACEI (captopril 2 g/L in
the drinking water) was initiated at 12, 18, and 21 months of age in SHR without
HF and in SHR with HF. Results were compared with those of age-matched
normotensive Wistar-Kyoto (WKY) rats, and to untreated SHR with and without
evidence of HF. ACEI initiated prior to failure prevented the changes in alpha
MHC, ANF, pro-alpha1(III) collagen, and TGF-beta1 gene expression that are
associated with the transition to HF. ACEI initiated after the onset of HF
lowered levels of TGF-beta1 mRNA by 50% (P<.05) and elevated levels of alpha-MHC
mRNA two- to threefold (P<.05). Circulating levels of renin and angiotensin I
were elevated four- to sixfold by ACEI, but surprisingly, plasma levels of
angiotensin II were not reduced. ACEI increased LV renin mRNA levels in WKY and
SHR by two- to threefold but did not influence LV levels of angiotensinogen mRNA.
The results suggest that the anti-HF benefits of ACEI in SHR may be mediated, at
least in part, by effects on the expression of specific genes, including those
encoding alpha-MHC, ANF, TGF-beta1, pro-alpha1(III) collagen, and renin
angiotensin system components.
PMID- 9403555
TI - Cardiac production and secretion of adrenomedullin are increased in heart
failure.
AB - Plasma adrenomedullin (AM) levels are reportedly increased in heart failure, but
whether the cardiac production and secretion of AM is increased in heart failure
remains unknown. To investigate the sites of production and secretion of AM in
heart failure, we measured plasma AM levels and peptide and mRNA levels of AM in
various tissues in rats with heart failure. We also examined whether the heart
actually secretes AM into the circulation in patients with heart failure. We
measured plasma and tissue AM levels by specific radioimmunoassay and AM mRNA by
Northern blot analysis in rats with heart failure produced by aortocaval fistula.
We also measured plasma AM levels in the coronary sinus and aorta in patients
with left ventricular dysfunction before and after rapid right ventricular
pacing. The increase in plasma AM levels in heart failure rats correlated with
ventricular weight. Tissue AM levels were increased in the heart and lungs but
not in the kidneys or adrenals of rats with heart failure. Similarly, tissue AM
mRNA levels were also increased in the heart and lungs of heart failure rats.
Plasma AM levels were higher in the coronary sinus than in the aorta in patients
with left ventricular dysfunction. Rapid right ventricular pacing increased
plasma atrial natriuretic peptide but not AM. These results suggest that plasma
AM levels are increased in heart failure in proportion to the severity of heart
failure and that cardiac production and secretion of AM is increased in heart
failure rats. The lung may be another site for increased production of AM in
heart failure rats. Human failing heart actually secretes AM into the
circulation, and the regulation of AM secretion appears to differ from that of
atrial natriuretic peptide.
PMID- 9403556
TI - Reduced cardiac contractile responsiveness to isoproterenol in obese rabbits.
AB - Although obesity is characterized by increased sympathetic nervous system
activity, there is often a paradoxical reduction in cardiovascular end-organ
response to sympathetic stimulation. Mechanisms involved in reduced sympathetic
responsiveness in obesity have not been well characterized. Therefore, we
determined cardiac contractile responsiveness to beta-stimulation in the obese
rabbit model using both isolated heart (IH) and isolated papillary muscle (IPM)
preparations. Female New Zealand White rabbits were fed control (IH: n=9; IPM:
n=6) or 10% fat diets (IH: n=9; IPM: n=7) for 12 weeks. Contractile
responsiveness in the IH was determined using a modified Langendorff preparation
to evaluate the dose-response relationship between isoproterenol and 1) peak
developed pressure/g of left ventricular wet weight and 2) maximal rate of
pressure development (+dP/dt/P). Contractile responsiveness in the IPM was
determined using right ventricular papillary muscles to evaluate the dose
response relationship between isoproterenol and (1) peak developed tension
(T)/mm2 cross-sectional area (CSA) and (2) maximal rate of tension development
(dT/dt/CSA). In the IH, baseline and maximum developed pressure/g were reduced in
obese rabbits by 37% and 31%, respectively (P< or =.05). In the IPM, baseline and
maximum T/CSA responses were reduced in obese rabbits by 59% and 33%,
respectively (P< or =.05). Potency of isoproterenol as reflected by the EC50 did
not differ between lean and obese animals in either preparation. These results
demonstrate that left ventricular contractility in obesity is reduced at baseline
and in response to stimulation with isoproterenol and suggest that decreased
responsiveness to beta-stimulation may be a factor in the obesity-related
systolic dysfunction.
PMID- 9403557
TI - Relation of exercise-induced myocardial ischemia to cardiac and carotid
structure.
AB - There is a strong relation of carotid atherosclerosis to coronary artery disease
and left ventricular hypertrophy. In addition, abnormalities of carotid structure
are strongly associated with abnormal left ventricular geometry and structure.
However, little is known regarding the relation of exercise-induced ST depression
to carotid atherosclerosis, carotid, or left ventricular structure in the absence
of apparent coronary disease. The relationship of exercise ECG myocardial
ischemia to the presence of carotid atherosclerosis and to carotid and left
ventricular structure was assessed in 204 asymptomatic subjects free of clinical
evidence of cardiovascular disease. Myocardial ischemia on the exercise ECG,
defined by a chronotropically adjusted ST/HR slope of >3.47 microV/bpm, was
associated with a nearly threefold greater likelihood of discrete carotid
atherosclerosis (50% [6 of 12] versus 17% [29 of 192], P=.007) and with older
age, male sex, higher systolic and diastolic blood pressures, greater left
ventricular mass and mass index, and greater common carotid artery intimal-medial
thickness and cross-sectional area index. Stepwise logistic regression analyses,
including standard risk factors, revealed that only carotid artery cross
sectional area index (P=.0007) and systolic blood pressure (P=.005) independently
predicted an abnormal chronotropically adjusted ST/heart rate slope. Moreover,
among 132 subjects with > or = 10 microV of ST-segment depression, only left
ventricular mass index and carotid artery cross-sectional area index were
significant predictors of the chronotropically adjusted ST/heart rate slope
response. Subendocardial ischemia on the exercise ECG is strongly associated with
the presence of carotid atherosclerosis and is related to systolic blood
pressure, carotid artery cross-sectional area index, and left ventricular mass
index, independent of age, sex, and other cardiac risk factors. These findings
provide additional insights into the relation between coronary and carotid
atherosclerosis and suggest that an association among ischemia and left
ventricular and carotid structural abnormalities may contribute to the
pathogenesis of coronary events.
PMID- 9403558
TI - Mannose 6-phosphate receptor-mediated internalization and activation of prorenin
by cardiac cells.
AB - The binding and internalization of recombinant human renin and prorenin (2500
microU/mL) and the activation of prorenin were studied in neonatal rat cardiac
myocytes and fibroblasts cultured in a chemically defined medium. Surface-bound
and internalized enzymes were distinguished by the addition of mannose 6
phosphate to the medium, by incubating the cells both at 37 degrees C and 4
degrees C, and by the acid-wash method. Mannose 6-phosphate inhibited the binding
of renin and prorenin to the myocyte cell surface in a dose-dependent manner. At
37 degrees C, after incubation at 4 degrees C for 2 hours, 60% to 70% of cell
surface-bound renin or prorenin was internalized within 5 minutes. Intracellular
prorenin was activated, but extracellular prorenin was not. The half-time of
activation at 37 degrees C was 25 minutes. Ammonium chloride and monensin, which
interfere with the normal trafficking and recycling of internalized receptors and
ligands, inhibited the activation of prorenin. Results obtained with cardiac
fibroblasts were comparable to those in the myocytes. This study is the first to
show experimental evidence for the internalization and activation of prorenin in
extrarenal cells by a mannose 6-phosphate receptor-dependent process. Our
findings may have physiological significance in light of recent experimental data
indicating that angiotensin I and II are produced at cardiac and other extrarenal
tissue sites by the action of renal renin and that intracellular angiotensin II
can elicit important physiological responses.
PMID- 9403559
TI - Monocyte chemoattractant protein-1 expression in aortic tissues of hypertensive
rats.
AB - Monocyte chemoattractant protein-1 (MCP-1), a potent monocyte chemoattractant
synthesized by vascular cells and monocytes, has been proposed to be an important
mediator of inflammatory responses in the arterial vasculature. It was recently
demonstrated that hypertension is associated with an inflammatory response in the
arterial wall. To determine the effect of hypertension on arterial MCP-1
expression, we induced hypertension in Sprague-Dawley rats by infusing
angiotensin II (0.75 mg x kg[-1] x d[-1] SC) for 7 days. Using Northern blot
analysis, we detected a 3.6-fold increase in MCP-1 mRNA in the aortas of
hypertensive rats. When we normalized blood pressure in angiotensin II-treated
rats through oral administration of the nonspecific vasodilator hydralazine (15
mg x kg[-1] x d[-1]), aortic MCP-1 mRNA expression was significantly reduced.
Similar results were obtained with a norepinephrine model of hypertension. Taken
together, these data suggest that mechanical factors may be responsible in part
for the upregulation of expression. Consistent with this interpretation, we found
that cultured rat aortic vascular smooth muscle cells exposed to mechanical
strain (20% peak deformation at 1 Hz) exhibited a marked increase in MCP-1
expression, suggesting the hemodynamic strain imparted onto arterial cells in
hypertension is an important stimulus underlying this phenomenon. These results
provide important insights into the in vivo regulation of MCP-1 and have
potential implications for understanding the influence of hypertension on
atherosclerosis.
PMID- 9403560
TI - Increased expression of Ca2+-sensitive K+ channels in aorta of hypertensive rats.
AB - Potassium efflux through Ca2+-sensitive K+ channels (K[Ca] channels) is increased
in arterial smooth muscle cells from hypertensive rats, but the molecular
mechanism is unknown. The goal of this study was to compare the levels of K(Ca)
channel current between aortic smooth muscle cells from adult Wistar-Kyoto rats
(WKY) and spontaneously hypertensive rats (SHR) and then use Western blot methods
and ribonuclease protection assays to examine the expression and mRNA levels for
the K(Ca) channel in these same vascular tissues. Whole-cell patch-clamp methods
indicated a larger component of K(Ca) channel current, sensitive to block by
iberiotoxin (100 nmol/L), in single aortic smooth muscle cells from SHR compared
with WKY. Subsequent Western blot analysis using a site-specific antibody (anti
alpha[913-926]) directed against the S9/S10 linker of the alpha-subunit of the
K(Ca), channel revealed a 125-kD immunoreactive band in lanes loaded with either
WKY or SHR aortic muscle membranes. The immunoreactive density of this band,
which corresponded to the known molecular size of the alpha-subunit, was 2.2-fold
greater in lanes loaded with aortic smooth muscle membranes from the hypertensive
animals. However, despite this evidence for an increased expression and
functional enhancement of K(Ca) channels in aortic smooth muscle membranes of
SHR, ribonuclease protection assays with a 32P-labeled riboprobe targeted against
the S9/S10 linker of the K(Ca) channel alpha-subunit revealed no difference in
mRNA levels for the alpha-subunit between WKY and SHR aortic tissue. These
findings provide initial evidence that (1) an increased expression of K(Ca)
channels may be a mechanism for the enhanced K(Ca) current in aortic smooth
muscle membranes of SHR, and (2) the upregulation of K(Ca) channels in arterial
muscle membranes during hypertension, which is regarded as a homeostatic
mechanism for buffering vascular excitability, may rely on posttranscriptional
events.
PMID- 9403561
TI - Pulse pressure: a predictor of long-term cardiovascular mortality in a French
male population.
AB - Studies on the usefulness of blood pressure as a prognostic factor in
cardiovascular disease have more often involved investigations of the levels of
diastolic or systolic blood pressure. However, blood pressure may be divided into
two other components: steady (mean pressure) and pulsatile (pulse pressure). In
this study, the relationship of pulse pressure to cardiovascular mortality was
investigated in 19 083 men 40 to 69 years old who were undergoing a routine
systematic health examination and were being followed up after a mean period of
19.5 years. Subjects were divided into four groups according to age (40 to 54 and
55 to 69 years) and mean arterial pressure (<107 and > or =107 mm Hg). Each group
was further divided into four subgroups according to the pulse pressure level. A
wide pulse pressure (evaluated according to the quartile group or as a continuous
quantitative variable) was an independent and significant predictor of all-cause,
total cardiovascular, and, especially, coronary mortality in all age and mean
pressure groups. No significant association between pulse pressure and
cerebrovascular mortality was observed. In conclusion, in a large population of
men with a relatively low cardiovascular risk, a wide pulse pressure is a
significant independent predictor of all-cause, cardiovascular, and, especially,
coronary mortality.
PMID- 9403562
TI - On-line synthesis of the human ascending aortic pressure pulse from the finger
pulse.
AB - Although systolic pressure in the ascending aorta (AA) can be determined
accurately from the radial arterial waveform using a single generalized transfer
function (TF) of the upper limb, a better on-line methods is needed for accurate
noninvasive synthesis of the AA pressure contour to characterize left ventricular
contractile function and ventricular-vascular coupling. AA, tonometric carotid
(CA), and photoplethysmographic finger (FA) arterial pressure waveforms were
recorded in 12 subjects (10 male, aged 59.1+/-10.3 years, mean+/-SD) during
cardiac catheterization. The AA-FA TF was estimated using (1) a single
generalized TF (GAA), (2) individualized TFs directly determined from CA-FA
recordings in each patient (DAA), and (3) individualized TFs computed from CA-FA
recordings in each patient with a mathematical model of the human upper limb
(MAA). AA pressure waveforms were synthesized from FA recordings in real time
using convolution windows derived from these TFs. Under steady state conditions,
the root mean square error (RMSE) between measured and synthesized AA was lower
by DAA (3.3+/-1.3 mm Hg) and MAA (3.9+/-1.2 mmHg) than by GAA (4.8+/-2.0 mm Hg,
P<.05). During dynamic load alteration induced by the Valsalva maneuver, however,
the MAA method performed better (5.4+/-2.8 mm Hg) than both the GAA (5.8+/-3.3 mm
Hg, P<.05) and DAA (6.5+/-2.7 mm Hg, P<.01) methods. The beat-to-beat AA contour
can be accurately and noninvasively synthesized on-line using individualized TFs.
During dynamic load alteration, individualized TFs derived with an upper limb
arterial model provide greater accuracy.
PMID- 9403563
TI - Increased stiffness of radial artery wall material in end-stage renal disease.
AB - The incremental elastic modulus (Einc), which is the slope of the relationship
between stress and strain of arteries, is a marker of vascular wall material
stiffness. Isobaric Einc is reduced at the site of the radial artery in patients
with essential hypertension and increased at the site of the common carotid
artery in subjects with end-stage renal disease (ESRD). Whether the changes in
Einc are influenced by the topography of the vessels, the composition of the
arterial wall, and/or by the presence of ESRD is largely ignored. Radial artery
Einc was measured in 19 patients with ESRD and compared with the Einc of 89
subjects with essential hypertension and 20 normotensive control subjects.
Transcutaneous measurements of radial artery internal diameter and wall thickness
(echo-tracking device) and digital pulse pressure (Finapres) were allowed to
calculate Einc under operational (ie, at the mean arterial pressure of each
group) and isobaric (100 mm Hg) conditions, as well as for a given wall stress.
Internal diameter and pulsatile changes in diameter were identical in the three
groups. Wall thickness and mean blood pressure were significantly elevated in
subjects with hypertension but not in ESRD patients. Circumferential wall stress
was identical in the three groups. For the same operational wall stress, and
therefore at the operational mean arterial pressure of each group, Einc (kPa x
10[3]) was increased in patients with ESRD (5.53+/-4.0 versus 3.3+/-2.4 in
control subjects; P<.05) and normal in subjects with essential hypertension
(3.87+/-4.0). Under isobaric conditions, Einc was also significantly lower in
subjects with hypertension and elevated in patients with ESRD. Thus, at the site
of a medium-sized muscular artery constantly devoid of atherosclerosis, the
stiffness of wall material is increased in patients with ESRD. The demonstrated
alterations of the arterial wall are independent of the level of blood pressure
and tensile stress and should be related to the status ESRD.
PMID- 9403564
TI - Perivascular sensory nerve Ca2+ receptor and Ca2+-induced relaxation of isolated
arteries.
AB - The present study tested two hypotheses: (1) that a receptor for extracellular
Ca2+ (Ca2+ receptor [CaR]) is located in the perivascular sensory nerve system
and (2) that activation of this receptor by physiological concentrations of
extracellular Ca2+ results in the release of vasodilator substance that mediates
Ca2+-induced relaxation. Reverse transcription-polymerase chain reaction using
primers derived from rat kidney CaR cDNA sequence showed that mRNA encoding a CaR
is present in dorsal root ganglia but not the mesenteric resistance artery.
Western blot analysis using monoclonal anti-CaR showed that a 140-kD protein that
comigrates with the parathyroid CaR is present in both the dorsal root ganglia
and intact mesenteric resistance artery. Immunocytochemical analysis of whole
mount preparations of mesenteric resistance arteries showed that the anti-CaR
stained perivascular nerves restricted to the adventitial layer. Biophysical
analysis of mesenteric resistance arteries showed that cumulatively raising Ca2+
from 1 to 1.25 mol/L and above relaxes precontracted arteries with an ED50 value
of 2.47+/-0.17 mmol/L (n=12). The relaxation is endothelium independent and is
unaffected by blockade of nitric oxide synthase but is completely antagonized by
acute and subacute phenolic destruction of perivascular nerves. A bioassay showed
further that superfusion of Ca2+ across the adventitial surface of resistance
arteries releases a diffusible vasodilator substance. Pharmacological analysis
indicates that the relaxing substance is not a common sensory nerve peptide
transmitter but is a phospholipase A2/cytochrome P450-derived hyperpolarizing
factor that we have classified as nerve-derived hyperpolarizing factor. These
data demonstrate that a CaR is expressed in the perivascular nerve network, show
that raising Ca2+ from 1 to 1.25 mol/L and above causes nerve-dependent
relaxation of resistance arteries, and suggest that activation of the CaR induces
the release of a diffusible hyperpolarizing vasodilator. We propose that this
system could serve as a molecular link between whole-animal Ca2+ balance and
arterial tone.
PMID- 9403565
TI - Growth factors mediate intracellular signaling in vascular smooth muscle cells
through protein kinase C-linked pathways.
AB - Intracellular Ca2+ and pH are potent modulators of growth factor-induced
mitogenesis and contraction. This study examined platelet-derived growth factor
(PDGF-BB) and insulin-like growth factor (IGF-1)-mediated signal transduction in
primary cultured unpassaged vascular smooth muscle cells (VSMC) from mesenteric
arteries of Sprague-Dawley rats. Intracellular free Ca2+ concentration ([Ca2+]i)
and intracellular pH (pHi) were measured by fluorescence digital imaging using
fura-2 AM and 2'7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, respectively.
Characteristics of [Ca2+]i transients were determined by pre-exposing cells to
Ca2+-free buffer, and involvement of the Na+/Ca2+ exchanger was assessed by
withdrawal of extracellular Na+ and by exposure to dimethylbenzamil (Na+/Ca2+
exchange blocker). To determine whether pHi responses were mediated via the
Na+/H+ exchanger, cells were preincubated with 10(-5) mol/L 5-(N-ethyl-N
isopropyl)amiloride (a selective Na+/H+ exchange blocker). The role of protein
kinase C (PKC) and tyrosine kinases in growth factor signaling was assessed by
pre-exposing cells to calphostin C and chelerythrine chloride (selective PKC
inhibitors; 10(-5) mol/L) and tyrphostin A23 (a selective tyrosine kinase
inhibitor; 10(-5) mol/L). PDGF-BB and IGF-1 (1 to 10 ng/mL) increased [Ca2+]i and
pHi in a dose-dependent manner. At concentrations greater than 1 ng/mL both
growth factors induced a biphasic [Ca2+]i response with an initial transient peak
followed by a sustained elevation. At 5 ng/mL PDGF-BB and IGF-1 significantly
increased [Ca2+]i from 95+/-3 nmol/L to 328+/-28 and 251+/-18 nmol/L,
respectively. Ca2+ withdrawal abolished the second phase of [Ca2+]i elevation.
Agonist-induced [Ca2+]i responses were similarly altered by Na+ withdrawal, by
Na+/ Ca2+ exchange blockade, and by PKC inhibition; latency, the period from
stimulus application to the first [Ca2+]i peak, was increased, the initial
[Ca2+]i peak was attenuated, and the sustained phase was prolonged. PDGF-BB and
IGF-1 (10 ng/mL) significantly increased pHi from 6.89+/-0.04 nmol/L to 7.11+/
0.01 and 7.09+/-0.02 nmol/L, respectively. EIPA and calphostin C completely
inhibited agonist-elicited alkalinization. Tyrphostin A-23 abolished second
messenger responses to PDGF-BB and IGF-1, whose receptors have tyrosine kinase
activity. In conclusion, PDGF-BB and IGF-1 elicit significant [Ca2+]i and pHi
responses in VSMC. The underlying pathways that mediate these responses are
partially dependent on Na+/ Ca2+ transporters and the Na+/H+ exchanger, both of
which are linked to PKC activation.
PMID- 9403566
TI - Role of angiotensin II in the regulation of a novel vascular modulator,
hepatocyte growth factor (HGF), in experimental hypertensive rats.
AB - Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor that
regulates cell growth, cell motility, and morphogenesis of various types of
cells, and is thus considered a humoral mediator of epithelial-mesenchymal
interactions responsible for morphogenic tissue interactions. We have previously
reported that HGF is a novel member of endothelium-specific growth factors whose
serum concentration is positively associated with blood pressure in humans.
Therefore, we speculated that serum HGF secretion might be elevated in response
to high blood pressure as a counter-system against endothelial dysfunction.
However, it is difficult to elucidate the role of circulating and tissue HGFs in
human hypertension. To address this issue, we measured circulating and tissue HGF
concentrations in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats
(WKY) at different ages. Serum HGF concentration in SHR was significantly higher
than that in WKY at 6, 15, and 25 weeks of age (P<.01). Serum HGF concentration
was also significantly positively correlated with blood pressure in SHR (P<.02,
r=.455). In contrast, tissue HGF concentrations in heart, aorta, and kidney were
significantly decreased in SHR as compared with WKY at 25 weeks of age, when
these organs showed hypertrophic changes induced by hypertension (P<.01). Cardiac
HGF mRNA was also decreased in SHR as compared with WKY at 25 weeks of age.
Moreover, cardiac HGF concentration showed a significant negative correlation
with left ventricular (LV) weight (P<.01), whereas serum HGF concentration showed
a significant positive correlation with LV weight (P<.05). Interestingly,
concentrations of cardiac and vascular angiotensin II, a suppressor of HGF, were
increased in SHR as compared with WKY at 25 weeks of age (P<.01). Therefore, we
examined the effects of angiotensin blockade on circulating and tissue HGF
concentrations, to study the role of angiotensin II in HGF regulation.
Administration of an angiotensin-converting enzyme inhibitor (enalapril) and
angiotensin II type 1 receptor antagonists (losartan and HR 720) for 6 weeks
resulted in a significant increase in cardiac HGF concentration, accompanied by
increased cardiac HGF mRNA, and a significant decrease in serum HGF
concentration, accompanied by lowered blood pressure and reduced LV weight
(P<.01). Here, we demonstrated increased circulating HGF and decreased vascular,
cardiac, and renal HGF in SHR as compared with WKY at the maintenance stage of
hypertension. Decreased tissue HGF in target organs of hypertension may be due to
increased tissue angiotensin II. These results suggest that decreased local HGF
production may have an important role in the cardiovascular remodeling of target
organs in hypertension, since HGF prevented endothelial injury and promoted
angiogenesis. Blockade of angiotensin augmented local decreased cardiovascular
HGF in hypertension, potentially resulting in the improvement of endothelial
dysfunction.
PMID- 9403567
TI - Cellular aspects of vascular remodeling in hypertension revealed by confocal
microscopy.
AB - Cellular aspects of remodeling in intact arteries have not been fully
investigated, mainly due to the lack of an appropriate methodology that allows
for simple measurements. The aim of this study was to develop a method based on
laser scanning confocal microscopy (LSCM), compare it with previous methodology,
and apply it to the study of remodeling in hypertension. The morphology of
mesenteric resistance arteries from stroke-prone spontaneously hypertensive rats
(SHRSP) and Wistar-Kyoto rats (WKY) was determined with wire myography on one
segment with a standardized diameter setting (0.9[d100]) and with perfusion
myography on a second segment from the same artery at the calculated equivalent
pressure. The second segments were stained with the nuclear dye Hoechst 33342
(live tissue) or propidium iodide (fixed tissue) and measured with LSCM and
MetaMorph software. Compared with wire myography, perfusion myography showed
similar differences from those previously reported. Compared with LSCM, perfusion
myography showed a similar lumen but significantly smaller wall thickness in both
live and fixed tissue, probably due to measurement underestimation. In the study
with LSCM, arteries from SHRSP compared with those from WKY showed (1) reduced
lumen, (2) altered cell density that was significantly increased in the
adventitia, decreased in the media, and unchanged in the intima, (3)
significantly increased medial volume, (4) significantly smaller endothelial cell
nuclei, and (5) adventitial-like cells in the media. We conclude that (1) LSCM is
a reliable and straightforward method to study morphology in intact vessels, (2)
it provides new information on the cellular changes in remodeling, (3) adventitia
might play an active role in the process of remodeling in hypertension, and (4)
endothelium "remodels" in hypertension.
PMID- 9403569
TI - AT1 receptor antagonist treatment caused persistent arterial functional changes
in young spontaneously hypertensive rats.
AB - The effects of chronic treatment with an AT1 receptor antagonist (L-158,809) on
hypertension development and cardiovascular changes were studied in spontaneously
hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). L-158,809 treatment (0.6
mg/kg PO) was initiated at 3 weeks of age and lasted 12 weeks, to 15 weeks of
age. The treatment prevented hypertension development in the SHR (systolic blood
pressure, BP, of 136+/-1 mm Hg compared with 198+/-3 mm Hg in control SHR), and
lowered the BP of WKY (99+/-2 vs 128+/-1 mm Hg in control WKY). Treatment
significantly reduced the heart weight in SHR and WKY. Ten weeks after treatment
withdrawal (25 weeks of age), BP had increased in SHR and WKY to 172+/-8 and
117+/-3 mm Hg, respectively. Body weight and kidney weight were not affected by
the treatment. Mesenteric arteries from treated SHR were less responsive than
control SHR arteries to periarterial nerve stimulations at transmural pressures
higher than 80 mm Hg (15 and 25 weeks). Control WKY arteries were less responsive
than control SHR arteries at almost all transmural pressures tested (15 weeks)
and to pressures greater than 80 mm Hg (25 weeks). Pretreatment of arteries with
10(-8) mol/L angiotensin II enhanced their response to nerve stimulation in
vessels from control SHR and WKY (25 weeks) but not from treatment-withdrawn SHR
and WKY. Treatment did not alter arterial reactivity in response to
norepinephrine. Alteration in arterial structure due to L-158,809 treatment was
found only when measured at a transmural pressure of 100 mm Hg. In conclusion, L
158,809 was effective in preventing hypertension during the treatment period, in
reducing hypertension severity during the withdrawal period, and in persistently
decreasing the reactivity of the arteries.
PMID- 9403568
TI - Role of nitric oxide in the regulation of the mechanical properties of peripheral
conduit arteries in humans.
AB - Whether nitric oxide (NO) contributes to the regulation of the mechanical
properties of large arteries in humans is not known. We measured the effect of
local administration of the inhibitor of NO synthesis N(G)-monomethyl-L-arginine
(L-NMMA; 1 and 4 micromol x L[-1] x min[-1] for 5 minutes) and acetylcholine (3
and 30 nmol x L[-1] x min[-1] for 3 minutes) on radial artery diameter and wall
thickness in 11 healthy volunteers using an echo-tracking system coupled to a
measurement of radial blood flow (Doppler) and arterial pressure. At the highest
dose, L-NMMA reduced radial blood flow but surprisingly decreased incremental
elastic modulus (from 1.36+/-0.22 to 1.00+/-0.22 kPa x 10[3]; P<.05) and
increased arterial compliance (from 3.20+/-0.46 to 4.07+/-0.45 m2 x kPa x 10(-8),
P<.05), without affecting radial artery internal diameter, wall thickness or
midwall stress, thus reflecting a decrease in vascular tone. Acetylcholine
decreased incremental elastic modulus (from 1.27+/-0.08 to 0.88+/-0.07 kPa x
10[3]; P<.05) and increased arterial diameter, radial blood flow, and compliance
(from 2.82+/-0.16 to 5.30+/-0.62m2 x kPa x 10[-8]; P<.05). These results
demonstrate in vivo that NO is involved in the regulation of the mechanical
properties of large arteries in humans. However, the effects of L-NMMA, ie, a
decrease in arterial wall rigidity and an increase in arterial compliance, which
occur in the absence of any changes in blood pressure or arterial geometry,
suggest that inhibition of NO synthesis is associated in humans with a
paradoxical isometric smooth muscle relaxation. This effect could be due to the
development of compensatory vasodilating mechanisms after NO synthesis
inhibition.
PMID- 9403570
TI - Regional renal nitric oxide release in stroke-prone spontaneously hypertensive
rats.
AB - Diminished nitric oxide (NO) production has been implicated in the pathogenesis
of salt-sensitive hypertension. We questioned whether such a defect is
responsible for the malignant hypertension and nephrosclerosis in stroke-prone
spontaneously hypertensive rats (SHRSP) fed a high-salt/stroke-prone diet (S)
versus a regular diet (R). NO release from 30-minute incubates of cortex and
outer and inner medulla were studied in SHRSP at 10, 12, and 16 weeks of age on
the S diet versus R diet. SHRSP-S (n=16) exhibited a marked age-dependent
increase in NO release, especially in the cortex. Increases were only modest in
SHRSP-R (n=21). At 16 weeks, cortical NO was 93+/-25 versus 6+/-1 pmol/mg tissue
in SHRSP-S versus SHRSP-R (P<.001). Immunohistochemical staining increased mostly
for neuronal, slightly for endothelial, and negligibly for inducible isoforms of
NO synthase and was predominantly in the cortex of SHRSP-S versus SHRSP-R.
Despite similar hypertension in SHRSP-S versus SHRSP-R (mean arterial pressure,
174+/-7 versus 177+/-2 mm Hg), malignant nephrosclerosis was seen only in SHRSP
S, affecting 22+/-6% of glomeruli and 23+/-4 vessels per 100 glomeruli by 16
weeks. N omega-nitro-L-arginine (15 mg/kg per day) in SHRSP-S (n=6) abrogated the
increase in cortical NO but further augmented the hypertension and accelerated
lesion development. Wistar-Kyoto rats at 16 weeks on the R diet (n=8) had NO
levels similar to those of SHRSP-R, showed increased cortical NO to only 28+/-10
pmol/mg on the S diet (n=9) (P<.05 versus SHRSP-S), but remained normotensive and
lesion-free. We conclude that hypertension and lesion development in SHRSP are
not due to deficient renal NO. Accelerated onset of malignant nephrosclerosis by
NO synthase inhibition suggests that NO is protective in these animals,
mitigating the effects of hypertension and S diet on renal pathology.
PMID- 9403571
TI - Lead-induced hypertension: interplay of nitric oxide and reactive oxygen species.
AB - An elevation of mean blood pressure was found in rats treated with low lead
(0.01% lead acetate) for 3 months, as contrasted to paired Sprague-Dawley control
rats. In these rats, measurement of plasma and urine endothelins-1 and -3
revealed that plasma concentration and urinary excretion of endothelin-3
increased significantly after 3 months (plasma: lead group, 31.8+/-2.2, versus
controls, 23.0+1.7 pg/mL, P<.001; urinary excretion: lead group, 46.6+11.7,
versus controls, 35.6+6.7 pg/24 h, P<.05), whereas endothelin-1 was unaffected.
Plasma and urinary nitric oxide (NO) and cyclic GMP concentrations were not
significantly changed. However, assay of plasma and kidney cortex malondialdehyde
by high-pressure liquid chromatography, as a measure of reactive oxygen species,
was elevated in lead-treated rats compared with that in control rats (plasma:
lead group, 4.74+1.27, versus controls, 2.14+.49 micromol/L, P<.001; kidney
cortex: lead group, 28.75+3.46, versus controls, 16.38+2.37 nmol/g wet weight,
P<.001). There was increased NO synthase activity in lead-treated rat brain
cortex and cerebellum. In lead-treated rat kidney cortex, the endothelial
constitutive NO synthase protein mass was unaffected, whereas the inducible NO
synthase protein mass was increased. These data suggest a balance between
increased NO synthesis and degradation (by reactive oxygen species) in lead
treated rats, which results in normal levels of NO. Thus, the hypertension may be
related to an increase in the pressure substances, endothelin-3 and reactive
oxygen species, rather than to an absolute decrease in nitric NO.
PMID- 9403572
TI - Hypothalamic hypertensive factor: an inhibitor of nitric oxide synthase activity.
AB - Human and rat plasma and rat hypothalamus contain a cytochemically detectable
substance, the concentration of which rises with an increase in salt intake. The
plasma concentration of this material is also raised in essential hypertension
and in the spontaneously hypertensive rat (SHR), the Milan hypertensive rat, and
the reduced renal mass (RRM) hypertensive rat. In the normal rat, the greatest
concentration is found in the hypothalamus of the SHR and the RRM hypertensive
rat. The physicochemical characteristics of this cytochemically detectable
hypothalamic hypertensive factor (HHF), including chromatographic behavior and
molecular weight range, suggest that it may share features common to a
substituted guanidine that is present in established nitric oxide synthase (NOS)
inhibitors. It was therefore decided to determine the effect on NOS activity of
the HHF obtained from mature SHR. The ability of HHF to inhibit NOS activity was
studied on (1) NOS extracted from bovine aorta, rat brain, and human platelets by
measuring the conversion of radiolabeled L-arginine to L-citrulline and (2) rat
liver NOS measured indirectly with a cytochemical technique based on the
stimulation of soluble guanylate cyclase activity in hepatocytes by NO. HHF
showed a biphasic inhibitory action on platelet NOS activity that was greater
with HHF obtained from SHR than from Wistar-Kyoto rats. HHF also had a biphasic
inhibitory effect on hepatocyte NOS activity that was more potent when obtained
from SHR. It is proposed that the increase in HHF, a novel form of NOS inhibitor
that is elevated in SHR, may be involved in the rise in arterial pressure.
PMID- 9403573
TI - Cardiovascular effects of nitric oxide and N-methyl-D-aspartate receptors in the
nucleus tractus solitarii of rats.
AB - Nitric oxide (NO) is an endogenously synthesized effector molecule that acts as a
neurotransmitter with novel properties in both the central and peripheral nervous
systems. We previously reported that NO was involved in central cardiovascular
regulation and modulated the baroreflex in the nucleus tractus solitarii (NTS) of
rats. The aim of the present study was to determine whether NO and excitatory
amino acids reciprocally release each other in the NTS. In normotensive Sprague
Dawley rats, intra-NTS microinjection of L-arginine (1 to 100 nmol/60 nL)
produced a dose-dependent decrease in blood pressure and heart rate.
Microinjection of excitatory amino acids L-glutamate and NMDA also produced
depressor and bradycardic effects. These effects of L-glutamate or NMDA were
blocked by prior administration of NO synthase inhibitor N(G)-methyl-L-arginine
or N(G)-nitro-L-arginine methyl ester. Similarly, prior administration of N
methyl-D-aspartate (NMDA) receptor antagonist MK-801 and non-NMDA receptor
antagonist 6,7-dinitroquinoxaline-2,3-dione significantly attenuated the
depressor and bradycardic effect of L-arginine. These results demonstrated a
reciprocal attenuation of NO synthase inhibitor and NMDA receptor antagonist on
NMDA and L-arginine responses, respectively, in the NTS and suggest that NO and
NMDA receptors may interact in central cardiovascular regulation.
PMID- 9403574
TI - Autonomic nervous system dysfunction in elderly hypertensive patients with
abnormal diurnal blood pressure variation: relation to silent cerebrovascular
disease.
AB - To investigate the relationships among diurnal blood pressure (BP) variations and
autonomic nervous system dysfunction, we assessed heart rate variability (HRV)
using power spectral analysis of the 24-hour RR interval in 51 asymptomatic
elderly hypertensive patients with various patterns of nocturnal BP fall. The
extreme-dippers with marked nocturnal BP fall (n=16) had lower asleep low
frequency power (LF)/high-frequency power (HF) ratios (a relative index of
sympathetic nervous system activity), while the nondippers without nocturnal BP
fall (n=18) had lower awake LF/HF ratios and asleep/awake ratio for HF (an index
of parasympathetic nervous activity), when compared with dippers with appropriate
nocturnal BP fall (n=17). The incidence of multiple lacunar infarction detected
by brain magnetic resonance imaging was 56% in the extreme-dippers and 38% in the
nondippers, and both were markedly higher than that (6.3%) in the dippers (both
P<.01). There was no significant relationship between the BP level and any HRV
parameter for either the daytime or nighttime period. The asleep/awake ratio for
systolic BP was significantly correlated with the asleep/awake ratio for HF (r=
.363, P<.01) and with the asleep/awake ratio for the LF/HF ratio (r=.540,
P<.001), regardless of whether multiple lacunar infarction was present. In
conclusion, the autonomic nervous system activity is not related to high BP level
per se, rather its diurnal variation is more important as a determinant of the
diurnal BP patterns, regardless of the presence or absence of cerebrovascular
disease.
PMID- 9403575
TI - Relationship between blood pressure and body mass index in lean populations.
AB - Associations between body mass index (BMI) and blood pressure (BP) have been
consistently observed, but remain poorly understood. One unresolved question is
whether there is a linear relationship across the entire BMI range. We
investigated this question among 11,235 adult men and women from seven low-BMI
populations in Africa and the Caribbean. We used kernel smoothing and
multivariate linear and spline regression modeling to examine gender differences
in the relationship and to test for a threshold. Age-adjusted slopes of BP on BMI
were uniformly higher in men than women, with pooled slope ratios of 2.00 and
2.20 for systolic and diastolic BPs, respectively. Men displayed no evidence of
age modification or nonlinearity in the relationship, and the age-adjusted slope
of systolic BP on BMI was 0.90 (95% confidence interval [CI], 0.76 to 1.04).
Women demonstrated both age modification and nonlinearity. For both younger (<45
years) and older (45+ years) women, the optimal change point for a single
threshold model was found to be 21 kg/m2. Slopes of systolic BP on BMI above this
threshold were positive and significant: 0.68 (95% CI, 0.54 to 0.81) and 0.53
(95% CI, 0.29 to 0.76) for younger and older women, respectively. Slopes below
the threshold were essentially zero for both groups of women, and the difference
between the slopes above and below the threshold was significant for younger
women (P=.019). In summary, we observed a threshold at 21 kg/m2 in the
relationship between BMI and BP for women but not for men. This contributes to
the effort to identify the mechanisms that underlie this relationship and how
they differ by gender.
PMID- 9403576
TI - Sex differences in the abundance of endothelial nitric oxide in a model of
genetic hypertension.
AB - A deficiency of nitric oxide may be responsible for the increased vascular
resistance associated with human essential hypertension and that seen in animal
models of hypertension. Premenopausal females are relatively protected from
hypertension and cardiovascular complications. Levels of superoxide can influence
the availability of nitric oxide. We hypothesize that there are differences in
nitric oxide availability between stroke-prone spontaneously hypertensive rats
(SHRSP) and Wistar-Kyoto rats (WKY) and that superoxide may be responsible for at
least some of these differences. We studied vascular reactivity in endothelium
intact aortic rings from WKY and SHRSP. We measured nitric oxide synthase
activity in endothelial cells removed from aortas and also measured circulating
nitrite/nitrate levels. We found the response to N(G)-nitro-L-arginine methyl
ester to be significantly greater in WKY compared with SHRSP (95% CI: 20 to 174;
P=.015) and in females compared with males in WKY (95% CI: 143 to 333; P=.00004)
and SHRSP (95% CI: 70 to 224; P=.0006). Endothelial nitric oxide synthase
activity was significantly greater in SHRSP compared with WKY (95% CI: 2.3 to
17.6; P=.016). The EC50 for relaxation to carbachol was significantly greater in
male rats compared with female rats (95% CI: -1.1 to -0.2; P=.003) within the
SHRSP strain. The maximum relaxation to carbachol was significantly attenuated in
stroke prone spontaneously hypertensive compared with Wistar-Kyoto rats (95% CI:
1.7 to 14.4; P=.015). Diethyldithiocarbamate had a significantly greater effect
on the stroke prone spontaneously hypertensive rats' carbachol response than that
of Wistar-Kyoto rats (95% CI: 14.3 to 47.0; P=.0008). We conclude that superoxide
may be responsible for strain differences in vascular reactivity, whereas nitric
oxide availability may be responsible for sex differences independently of
endothelial nitric oxide synthase activity and superoxide.
PMID- 9403577
TI - Maintenance of maternal diet-induced hypertension in the rat is dependent on
glucocorticoids.
AB - Recent epidemiological evidence suggests that adult cardiovascular risk is
determined by birth weight and factors that influence birth weight, such as
maternal nutrition. Data from animal models suggest that an interaction between
nutrition and glucocorticoid hormones "programs" increased risk of adult
hypertension. Increased fetal exposure to maternal glucocorticoids that is
proposed to occur from a reduction in the placental barrier to maternal
glucocorticoid, 11beta-hydroxysteroid dehydrogenase, is suggested to program
hypertension in the resultant offspring from both glucocorticoid-treated and
maternally protein-restricted rats. The extent to which postnatal glucocorticoid
stimulation may influence the progression of hypertension in the offspring from
protein-restricted rat dams was assessed in 6-week-old male Wistar rats,
prenatally exposed to either an 18% casein (control) or 9% casein (low protein)
diet. Rats from each dietary group were sham operated, adrenalectomized or
adrenalectomized, and treated with 20 mg corticosterone/kg body weight per day.
Before surgery, systolic blood pressure was significantly higher in the low
protein-exposed rats compared with controls (165+/-3.8 versus 142+/-3.3 mm Hg,
P<.0001). Adrenalectomy of the low protein-exposed animals significantly reduced
the blood pressure to control levels, while corticosterone replacement restored
the hypertensive state. No effect of adrenalectomy on blood pressure was observed
in 18% casein controls. In both dietary groups adrenalectomy decreased brain, but
not hepatic, glucocorticoid-sensitive enzyme activities and corticosterone
treatment elevated activities of all enzymes. The data suggest that maternal diet
induced hypertension is dependent on an intact adrenal gland postnatally and that
glucocorticoids are key trophic agents in maintaining the high blood pressure.
PMID- 9403578
TI - Diagnosing gestational hypertension and preeclampsia with the 24-hour mean of
blood pressure.
AB - The use of ambulatory blood pressure monitoring has provided a method of blood
pressure assessment that may compensate for some of the limitations of isolated
measurements. Here we aim to examine prospectively the effectiveness of the
commonly used 24-hour mean as a potential screening test for the identification
of gestational hypertension and preeclampsia. We analyzed 503 blood pressure
series from 71 healthy pregnant women and 256 series from 42 women who developed
gestational hypertension or preeclampsia. Forty-eight-hour blood pressure
monitoring was done once every 4 weeks after the first obstetric consultation.
Sensitivity and specificity of the 24-hour mean of blood pressure were computed
for each trimester of pregnancy by comparing distributions of values obtained for
healthy and complicated pregnancies, without assuming an a priori threshold for
diagnosing gestational hypertension on the basis of mean blood pressure.
Sensitivity ranges from 31.8% for diastolic blood pressure in the second
trimester to 84.1% for systolic blood pressure in the third trimester. However,
specificity is as low as 6.9% for diastolic blood pressure in the first
trimester. The positive predictive value does not reach 55% for any variable in
any trimester. The higher relative risk was consistently obtained for systolic
blood pressure (4.9 in the third trimester). Despite the highly statistically
significant differences in blood pressure found between healthy and complicated
pregnancies in all trimesters, the daily mean of blood pressure does not provide
a proper and stable individualized test for diagnosing hypertensive complications
in pregnancy. Other indexes obtained from the blood pressure series have been
shown, however, to identify early in pregnancy those women who subsequently will
develop gestational hypertension or preeclampsia, rendering ambulatory blood
pressure monitoring a useful, but still costly, technique in pregnancy.
PMID- 9403579
TI - Estrogen supplementation decreases norepinephrine-induced vasoconstriction and
total body norepinephrine spillover in perimenopausal women.
AB - Estrogens are reported to provide protection against the development of
cardiovascular disease in women, but the mechanisms underlying these effects are
not well defined. We hypothesized that estrogen might reduce neural
cardiovascular tone. We therefore studied responses to exogenous norepinephrine
and norepinephrine spillover in 12 perimenopausal women randomized to 8 weeks of
estrogen supplementation (estradiol valerate, 2 mg daily, n=7) or placebo (n=5).
Forearm blood flow was measured by venous occlusion plethysmography, and
vasoactive agents were infused through a brachial artery cannula in doses that
did not influence blood pressure or heart rate. Total body and forearm
norepinephrine spillover were measured by radiotracer methodology. Forearm
vasoconstrictor responses to norepinephrine (25, 50, and 100 ng/min) were
attenuated after estrogen supplementation (P=.002). Vasoconstrictor responses to
angiotensin II (8, 16, and 32 ng/min) were unchanged postestrogen. There was a
significant reduction in total body spillover of norepinephrine after estrogen
supplementation (pre-estrogen, 700+/-152; postestrogen, 439+/-150 ng/min; P<.05),
but there was no change after placebo. Total body clearance and forearm spillover
of norepinephrine were unchanged by either estrogen or placebo. Estrogen
supplementation also significantly decreased both systolic and diastolic blood
pressures. Therefore, estrogen supplementation in perimenopausal women
selectively attenuates vasoconstrictor responses to norepinephrine and reduces
total body norepinephrine spillover, which is an index of sympathetic neural
activity.
PMID- 9403580
TI - Effect of carbidopa on the excretion of sodium, dopamine, and ouabain-like
substance in the rat.
AB - The effect of carbidopa, a competitive inhibitor of dopamine synthesis on the
excretion of sodium, dopamine (DA), and endogenous sodium transport inhibitor
(ESTI), was examined in rats on normal and high salt diets for 7 days. ESTI
activity was measured (1) as ouabain-like substance (OLS) by radioimmunoassay
using an antibody raised against ouabain, (2) by inhibition of purified Na+,K+
ATPase activity (ATPI), and (3) as digoxin-like substance (DLS) using a
commercial digoxin assay. The OLS immunoassay was validated against rubidium
transport studies. High salt diet caused an increase in OLS and ATPI but not DLS.
Sodium excretion in rats on normal sodium intake was not affected by carbidopa
treatment but was significantly lower in the high sodium diet group during the
first 5 days of the study. In the low salt group, carbidopa treatment caused
significant increases in OLS. We conclude that ESTI (measured as OLS) and DA are
important in the natriuresis of salt loading.
PMID- 9403581
TI - Improvement of insulin sensitivity by short-term exercise training in
hypertensive African American women.
AB - African American women have a high prevalence of insulin resistance, non-insulin
dependent diabetes mellitus, obesity, and hypertension that may be linked to low
levels of physical activity. We sought to determine whether 7 days of aerobic
exercise improved glucose and insulin metabolism in 12 obese (body fat >35%),
hypertensive (systolic blood pressure > or =140 and/or diastolic blood pressure >
or =90 mmHg) African American women (mean age 51+/-8 years). Insulin-assisted
frequently-sampled intravenous glucose tolerance tests were performed at baseline
and 14 to 18 hours after the 7th exercise session. There was no significant
change in maximal oxygen consumption, body composition, or body weight after the
7 days of aerobic exercise. The insulin sensitivity index increased (2.68+/-0.45
x 10[-5] to 4.23+/-0.10 x 10[-5] [min(-1)/pmol/L], P=.02). Fasting (73+/-9 to
50+/-9 pmol/L, P=.02) and glucose-stimulated (332+/-58 to 261+/-45 pmol/L, P=.05)
plasma insulin levels decreased. Additional measures related to the insulin
resistance syndrome also changed with the 7 days of exercise: basal plasma
norepinephrine concentrations were reduced (2.46+/-0.27 to 1.81+/-0.27 nmol/L,
P=.02) and sodium excretion rate increased from 100+/-13 to 137+/-7 mmol/d
(P=.03); however, there was no change in potassium excretion or 24-hour
ambulatory blood pressure. We conclude that a short-term aerobic exercise program
improves insulin sensitivity in African American hypertensive women independent
of changes in fitness levels, body composition, or body weight. The present study
indicates that short-term exercise can improve insulin resistance in
hypertensive, obese, sedentary African American women and confirms previous
reports that a portion of the exercise-induced improvements in glucose and
insulin metabolism may be the result of recent exercise.
PMID- 9403582
TI - Relation of fasting insulin to blood pressure and lipids in adolescents and
parents.
AB - This study was intended to clarify the relation between fasting insulin, lipids,
and blood pressure in adolescents before the onset of hypertension and to examine
the association of these data with similar data obtained in their parents. The
participants in this study were 183 adolescents 14 to 18 years old (96 girls)
completing a 4-year intervention trial and their parents (164 mothers, 122
fathers). Blood pressure was measured twice on the right arm in a seated position
using a random-zero sphygmomanometer. Fasting blood samples were obtained for
lipid and insulin analyses. Fasting insulin was significantly correlated with
systolic blood pressure in the adolescents and also in the parents before and
after adjustment for body mass index. Fasting insulin was correlated
significantly with levels of cholesterol, triglycerides, and HDL and LDL
cholesterol in the adolescents. It was correlated only with triglycerides and HDL
cholesterol in mothers and fathers. After adjustment for body mass index, the
correlations between fasting insulin and lipids in the children were not
significant. A significant relation was shown between children's systolic blood
pressure and mothers' fasting insulin and systolic blood pressure. Significant
correlations were found between the children's and fathers' triglycerides and HDL
cholesterol, whereas significant correlations were found for fasting insulin and
all lipids between mothers and children, and these remained significant after
adjustment for body mass index. These results show (1) a significant relation
between fasting insulin and both lipids and systolic blood pressure in
adolescents and (2) a significant relation for these factors between adolescents
and their parents. Although weight appears to play an important role in this
relation during adolescence, genetic and environmental factors other than those
mediated via weight may control insulin metabolism within families. The data
support a role for studies during early biological development to address these
issues.
PMID- 9403583
TI - Antihypertensive agent moxonidine enhances muscle glucose transport in insulin
resistant rats.
AB - The sympatholytic antihypertensive agent moxonidine, a centrally acting selective
I1-imidazoline receptor modulator (putative agonist), may be beneficial in
hypertensive patients with insulin resistance. In the present study, the effects
of chronic in vivo moxonidine treatment of obese Zucker rats--a model of severe
glucose intolerance, hyperinsulinemia and insulin resistance, and dyslipidemia-
on whole-body glucose tolerance, plasma lipids, and insulin-stimulated skeletal
muscle glucose transport activity (2-deoxyglucose uptake) were investigated.
Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10
mg/kg body weight. Body weights in control and moxonidine-treated groups were
matched, except at the highest dose, at which final body weight was 17% lower in
the moxonidine-treated animals compared with controls. The moxonidine-treated (6
and 10 mg/kg) obese animals had significantly lower fasting plasma levels of
insulin (17% and 19%, respectively) and free fatty acids (36% and 28%,
respectively), whereas plasma glucose was not altered. During an oral glucose
tolerance test, the glucose response (area under the curve) was 47% and 67%
lower, respectively, in the two highest moxonidine-treated obese groups.
Moreover, glucose transport activity in the isolated epitrochlearis muscle
stimulated by a maximally effective insulin dose (13.3 nmol/L) was 39% and 70%
greater in the 6 and 10 mg/kg moxonidine-treated groups, respectively (P<.05 for
all effects). No significant alterations in muscle glucose transport were
elicited by 2 mg/kg moxonidine. These findings indicate that in the severely
insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment
with moxonidine can significantly improve, in a dose-dependent manner, whole-body
glucose tolerance, possibly as a result of enhanced insulin-stimulated skeletal
muscle glucose transport activity and reduced circulating free fatty acids.
PMID- 9403584
TI - Dopamine D3 receptor in peripheral mononuclear cells of essential hypertensives.
AB - Dopamine D3 receptor was studied in peripheral mononuclear cells of high-normal,
stage 1, stage 2, and stage 3 essential hypertensives using a radioligand binding
assay technique with [3H]-7-hydroxy-N,N-di-n-propyl-2-aminotetraline (7-OH-DPAT)
as a radioligand. A group of de novo Parkinsonian patients was also examined as a
reference group of impaired dopaminergic function. [3H]-7-OH-DPAT was bound
specifically to human peripheral mononuclear cells in a manner consistent with
the labeling of a dopamine D3 receptor. No changes in free dopamine,
norepinephrine, epinephrine and aldosterone levels, renin activity, dissociation
constant of [3H]-7-OH-DPAT binding, or the pharmacological profile of [3H]-7-OH
DPAT binding were found between normotensive control subjects and essential
hypertensives or Parkinsonians. The density of peripheral mononuclear cell [3H]-7
OH-DPAT binding sites increased in essential hypertensives parallel to blood
pressure value augmentation. A higher density of [3H]-7-OH-DPAT binding sites was
found in Parkinsonians. In these patients, the density of [3H]-7-OH-DPAT binding
sites was similar to that observed in high-normal subjects and in stage 1
essential hypertensives. The increased density of peripheral mononuclear cell
dopamine D3 receptor in hypertension as well as in Parkinson's disease may
represent an upregulation mechanism consequent to impaired dopaminergic function.
In view of the difficulty in identifying markers of peripheral dopamine function,
analysis of dopamine D3 receptor in peripheral mononuclear cells may help
evaluate whether the dopaminergic system is involved in hypertension.
PMID- 9403585
TI - Patterns of neuronal activation during development of sodium sensitive
hypertension in SHR.
AB - The effects of regular (RNa) or high (HNa) sodium diet for 3, 7, and 14 days on
Fra-like immunoreactivity (Fra-LI) in the brains of Wistar-Kyoto rats (WKY) and
spontaneously hypertensive rats (SHR) were examined using an antibody that
recognizes all known members of the Fos family (Fos, Fos-B, Fra-1, and Fra-2).
Two weeks of HNa significantly exacerbated hypertension in SHR but had no effects
in WKY. On RNa, compared with WKY, SHR showed higher Fra-LI in the median
preoptic nucleus, supraoptic nucleus, both parts of the paraventricular nucleus,
nucleus of the solitary tract, and central gray. Fra-LI in the subfornical organ
did not differ between the two strains. On RNa, Fra-LI in the anterior
hypothalamic area could be detected only in WKY. In osmoregulatory areas, HNa
diet increased Fra-LI in both SHR and WKY to comparable extents, but in the
median preoptic nucleus, Fra-LI was increased to a greater extent in SHR. HNa
produced smaller increases in the subfornical organ of SHR compared with WKY. In
both the parvocellular and magnocellular paraventricular nuclei, increases in Fra
LI by HNa were more pronounced in SHR than in WKY. In the anterior hypothalamic
area, Fra-LI could no longer be detected in WKY on HNa, whereas it appeared in
SHR. HNa increased Fra-LI in the NTS and central gray to similar levels in WKY
and SHR. These results indicate that WKY and SHR differ in the pattern of
neuronal activation accompanying maturation on RNa. HNa activates neurons in a
number of brain areas, and the pattern of these changes also differs between WKY
and SHR.
PMID- 9403586
TI - Role of endothelin in hypertension of experimental chronic renal failure.
AB - Surgical ablation of renal mass leads to a reduction in kidney function and
commonly to the development of hypertension and chronic renal failure (CRF) in
rats. The objective of this study was to determine whether endothelin (ET)-1 is
involved in the maintenance of the hypertension that accompanies loss of renal
mass. First, we demonstrated the antihypertensive efficacy of PD 155080, a
selective, orally active ET(A) receptor antagonist, in a group of rats made
hypertensive by continuous intravenous infusion of ET-1 (2.5 pmol x kg(-1) x min[
1]) for 7 days. ET-1 produced a sustained hypertension and PD 155080 (56.4
micromol/kg [25mg/kg] BID PO) normalized blood pressure (BP) during the 5 days of
drug administration. In a second experiment, Sprague-Dawley rats underwent a 5/6
reduction in renal mass (RRM); 4 weeks later, PD 155080 administered for 7 days
resulted in a sustained reduction in BP. Sham-operated rats also showed a slight
hypotensive response to PD 155080 administration. Plasma urea nitrogen, plasma
creatinine, urinary protein excretion, and creatinine clearance were not altered
by PD 155080 administration in RRM or sham rats. In a third experiment, we
investigated the contribution of the renin-angiotensin system to BP control in
RRM rats given PD 155080. In these rats, PD 155080 reduced BP during 5 treatment
days, and this antihypertensive effect was not altered by coadministration of the
angiotensin-converting enzyme inhibitor enalapril in the drinking water (508
micromol/L [250 mg/L]). These results demonstrate that (1) ET-1 plays a role in
established RRM hypertension through activation of the ET(A) receptor subtype,
(2) lowering blood pressure with PD 155080 in RRM rats does not adversely affect
renal function, and 3) the antihypertensive effect of ET(A) receptor antagonism
is not opposed by the renin-angiotensin system.
PMID- 9403587
TI - Effects of continuous infusion of endothelin-1 in pregnant sheep.
AB - Plasma concentration of endothelin-1, a potent vasoconstrictor produced by the
vascular endothelium, has been observed to be significantly increased in a number
of pathophysiological states, including preeclampsia. In the present study we
have evaluated the effects of elevated plasma endothelin-1 in pregnant sheep by
continuous exogenous endothelin-1 administration. Nine pregnant ewes (110+/-5
days' gestation) were instrumented for measurements of maternal mean arterial
pressure, renal blood flow, and uterine blood flow. After recovery, endothelin-1
was infused intravenously for 4 hours at a dose that was adjusted to raise mean
arterial pressure by approximately 20 mm Hg by the end of the first hour (range 5
to 20 ng/kg per minute). Mean arterial pressure, renal blood flow, uterine blood
flow, urinary protein excretion, hematocrit, and plasma endothelin-1
concentration were measured hourly, and renal and uterine vascular resistances
were calculated. Endothelin-1 produced significant increases (% change from
baseline at t=4 hours) in mean arterial pressure (45+/-8%), renal vascular
resistance (353+/-66 %), and uterine vascular resistance (59+/-21%). Endothelin-1
also increased microvascular permeability both systemically and within the
kidney, as suggested by marked increases in hematocrit (0.27+/-0.01 to 0.32+/
0.01) and urinary protein concentration (0.95+/-0.1 to 7.9+/-3.2 mg/mL per mg
creatinine). There was a highly significant correlation (P<.0001) between plasma
endothelin-1 and mean arterial pressure, renal vascular resistance, uterine
vascular resistance, hematocrit, and urinary protein content in all sheep
studied. In addition, plasma endothelin-1 corresponded well with the time course
of the changes in cardiovascular parameters and urinary protein excretion
observed. These results provide evidence to suggest that elevation of circulating
endothelin-1 in pregnant sheep can produce cardiovascular and hemodynamic changes
that in many ways resemble the human disease preeclampsia. This supports the
hypothesis that endothelial cell damage and/or dysfunction that is associated
with increased production of endothelin-1 could directly contribute to the
progression of preeclampsia.
PMID- 9403588
TI - Endothelin converting enzyme-1 gene expression in the kidney of spontaneously
hypertensive rats.
AB - Abnormal renal handling of water and sodium is implicated in the pathogenesis of
hypertension in spontaneously hypertensive rats (SHR). Alteration of renal
endothelin-1 synthesis is also reported in SHR. Endothelin-1, a potent
vasoconstrictor and regulator of sodium reabsorption in the nephron, has a
pathophysiological potential in the development of hypertension. Because
synthesis of bioactive endothelin-1 requires endothelin converting enzyme-1 (ECE
1), we investigated whether renal ECE-1 gene expression is altered in the kidney
of SHR. Kidneys from both 4- and 12-week-old SHR and age-matched Wistar-Kyoto
rats (WKY) were studied. ECE-1 mRNA in microdissected nephron segments was
assessed by reverse transcription-competitive polymerase chain reaction, and ECE
1 protein level by Western blot. In 4-week-old SHR, ECE-1 mRNA was significantly
increased in the proximal straight tubule, medullary thick ascending limb,
cortical thick ascending limb, and inner medullary collecting duct. ECE-1 protein
level was increased in both the outer and inner medulla. In 12-week-old SHR, ECE
1 gene expression was significantly increased in the proximal straight tubule,
medullary thick ascending limb, and also in the glomeruli. Glomerular
preproendothelin-1 mRNA expression was not different between the two strains at
both 4 and 12 weeks. We conclude that high ECE-1 gene expression in the nephron,
via increase of endothelin-1 synthesis, may promote sodium retention that
contributes to the development and/or maintenance of hypertension in SHR.
PMID- 9403589
TI - Endothelium-derived hyperpolarizing factor, but not nitric oxide, is reversibly
inhibited by brefeldin A.
AB - The subcellular localization of the enzymes synthesizing endothelium-derived
vasodilator autacoids has been proposed to play a role in determining the ability
of endothelial cells to enhance autacoid production in response to stimulation.
We therefore investigated the effects of brefeldin A-induced disruption of the
Golgi apparatus and Golgi-plasma membrane trafficking on the production of nitric
oxide (NO), prostacyclin, and the endothelium-derived hyperpolarizing factor
(EDHF) by native and cultured endothelial cells. In porcine coronary artery
segments, brefeldin A (35 micromol/L, 90 minutes) did not affect relaxations to
sodium nitroprusside or the K+ channel opener cromakalim but elicited a rightward
shift in the concentration-response curve to bradykinin without altering the
maximum vasodilator response (Rmax). Brefeldin A failed to attenuate the
bradykinin-induced, NO-mediated relaxation under depolarizing conditions but
inhibited the bradykinin response under conditions of combined cyclooxygenase/NO
synthase blockade, suggesting that this agent selectively interferes with the
production of EDHF. Indeed, incubation of porcine coronary arteries with
brefeldin A, which did not affect the bradykinin-induced accumulation of either
cyclic GMP or 6-keto-prostaglandin F1alpha, markedly and reversibly attenuated
the EDHF-mediated hyperpolarization of detector smooth muscle cells in a patch
clamp bioassay system. The microtubule destabilizer nocodazole also affected both
the EC50 and Rmax to bradykinin in porcine coronary arteries. Since EDHF is
thought to be a cytochrome P450-derived metabolite of arachidonic acid and both
brefeldin A and nocodazole are known to interfere with the targeting of
cytochrome P450 from the Golgi apparatus to the plasma membrane, it is
conceivable that brefeldin A inhibits EDHF formation by preventing the targeting
of the EDHF-synthesizing enzymes to the plasma membrane.
PMID- 9403590
TI - Lacidipine restores endothelium-dependent vasodilation in essential hypertensive
patients.
AB - Essential hypertension is characterized by impaired endothel